WO2022239068A1 - Cytokine storm inhibitor - Google Patents
Cytokine storm inhibitor Download PDFInfo
- Publication number
- WO2022239068A1 WO2022239068A1 PCT/JP2021/017721 JP2021017721W WO2022239068A1 WO 2022239068 A1 WO2022239068 A1 WO 2022239068A1 JP 2021017721 W JP2021017721 W JP 2021017721W WO 2022239068 A1 WO2022239068 A1 WO 2022239068A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- fluorophenyl
- pyrazin
- ylamino
- ethylamino
- ethyl
- Prior art date
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- 206010052015 cytokine release syndrome Diseases 0.000 title claims abstract description 35
- 206010050685 Cytokine storm Diseases 0.000 title claims abstract description 13
- 239000003112 inhibitor Substances 0.000 title claims abstract description 11
- 150000001875 compounds Chemical class 0.000 claims abstract description 132
- 150000003839 salts Chemical class 0.000 claims abstract description 32
- 239000004480 active ingredient Substances 0.000 claims abstract description 16
- 125000000217 alkyl group Chemical group 0.000 claims description 78
- -1 hydroxy, amino Chemical group 0.000 claims description 52
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 46
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 38
- 125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 claims description 34
- 125000003545 alkoxy group Chemical group 0.000 claims description 33
- 125000004122 cyclic group Chemical group 0.000 claims description 29
- 150000002367 halogens Chemical class 0.000 claims description 26
- 229910052736 halogen Inorganic materials 0.000 claims description 25
- 125000003277 amino group Chemical group 0.000 claims description 24
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 24
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 21
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 17
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 17
- 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 claims description 17
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 16
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 16
- QLUWOZLFVNOUFN-ZDUSSCGKSA-N 4-[2-[[(1s)-1-(4-fluorophenyl)ethyl]amino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl]piperazin-2-one Chemical compound N([C@@H](C)C=1C=CC(F)=CC=1)C(N=C(C=1)N2CC(=O)NCC2)=NC=1NC1=CN=CC=N1 QLUWOZLFVNOUFN-ZDUSSCGKSA-N 0.000 claims description 14
- 108010017324 STAT3 Transcription Factor Proteins 0.000 claims description 14
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Natural products OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 14
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 14
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 13
- LWPASYMORFEOKT-ZDUSSCGKSA-N 2-[2-[[(1s)-1-(4-fluorophenyl)ethyl]amino]-6-(pyrazin-2-ylamino)pyridin-4-yl]oxyethanol Chemical compound N([C@@H](C)C=1C=CC(F)=CC=1)C(N=1)=CC(OCCO)=CC=1NC1=CN=CC=N1 LWPASYMORFEOKT-ZDUSSCGKSA-N 0.000 claims description 12
- 125000001072 heteroaryl group Chemical group 0.000 claims description 12
- 230000024949 interleukin-17 production Effects 0.000 claims description 11
- 125000004663 dialkyl amino group Chemical group 0.000 claims description 10
- 150000004985 diamines Chemical class 0.000 claims description 10
- 239000003814 drug Substances 0.000 claims description 10
- ORTFAQDWJHRMNX-UHFFFAOYSA-N hydroxidooxidocarbon(.) Chemical group O[C]=O ORTFAQDWJHRMNX-UHFFFAOYSA-N 0.000 claims description 10
- RSNWFMVKIGCTMU-LBPRGKRZSA-N 2-n-[(1s)-1-(4-fluorophenyl)ethyl]-4-n-pyrazin-2-yl-6-(1h-pyrazol-4-yl)pyrimidine-2,4-diamine Chemical compound N([C@@H](C)C=1C=CC(F)=CC=1)C(N=C(C=1)C2=CNN=C2)=NC=1NC1=CN=CC=N1 RSNWFMVKIGCTMU-LBPRGKRZSA-N 0.000 claims description 9
- 125000001188 haloalkyl group Chemical group 0.000 claims description 9
- JLAKCHGEEBPDQI-UHFFFAOYSA-N 4-(4-fluorobenzyl)piperidine Chemical compound C1=CC(F)=CC=C1CC1CCNCC1 JLAKCHGEEBPDQI-UHFFFAOYSA-N 0.000 claims description 8
- 125000003806 alkyl carbonyl amino group Chemical group 0.000 claims description 8
- 125000000623 heterocyclic group Chemical group 0.000 claims description 8
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 8
- VGKLFRFXSJOZJG-ZDUSSCGKSA-N 1-[2-[[(1s)-1-(4-fluorophenyl)ethyl]amino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl]-1,3-diazinan-2-one Chemical compound N([C@@H](C)C=1C=CC(F)=CC=1)C(N=C(C=1)N2C(NCCC2)=O)=NC=1NC1=CN=CC=N1 VGKLFRFXSJOZJG-ZDUSSCGKSA-N 0.000 claims description 7
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 7
- 125000003282 alkyl amino group Chemical group 0.000 claims description 7
- 125000004656 alkyl sulfonylamino group Chemical group 0.000 claims description 6
- 150000003857 carboxamides Chemical class 0.000 claims description 6
- 230000000069 prophylactic effect Effects 0.000 claims description 6
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 6
- 229940124597 therapeutic agent Drugs 0.000 claims description 6
- XZNVDGQNALXJKC-ZDUSSCGKSA-N 4-[2-[[(1s)-1-(4-fluorophenyl)ethyl]amino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl]-1h-pyridin-2-one Chemical compound N([C@@H](C)C=1C=CC(F)=CC=1)C(N=C(C=1)C=2C=C(O)N=CC=2)=NC=1NC1=CN=CC=N1 XZNVDGQNALXJKC-ZDUSSCGKSA-N 0.000 claims description 5
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- 125000004985 dialkyl amino alkyl group Chemical group 0.000 claims description 5
- SCVPFKWGRMPVIL-KNVGNIICSA-N 1-[2-[[(1s)-1-(4-fluorophenyl)ethyl]amino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl]pyrrolidin-3-ol Chemical compound N([C@@H](C)C=1C=CC(F)=CC=1)C(N=C(C=1)N2CC(O)CC2)=NC=1NC1=CN=CC=N1 SCVPFKWGRMPVIL-KNVGNIICSA-N 0.000 claims description 4
- LWBGGUWQTRBGOH-NSHDSACASA-N 2-[[(1s)-1-(4-fluorophenyl)ethyl]amino]-6-(pyrazin-2-ylamino)pyrimidine-4-carbonitrile Chemical compound N([C@@H](C)C=1C=CC(F)=CC=1)C(N=C(C=1)C#N)=NC=1NC1=CN=CC=N1 LWBGGUWQTRBGOH-NSHDSACASA-N 0.000 claims description 4
- WKHWJRUZCMHAKP-HNNXBMFYSA-N 4-(1-ethylpyrazol-4-yl)-6-n-[(1s)-1-(4-fluorophenyl)ethyl]-2-n-pyrazin-2-ylpyridine-2,6-diamine Chemical compound C1=NN(CC)C=C1C1=CC(N[C@@H](C)C=2C=CC(F)=CC=2)=NC(NC=2N=CC=NC=2)=C1 WKHWJRUZCMHAKP-HNNXBMFYSA-N 0.000 claims description 4
- WFHBXDDTNRJWAY-LBPRGKRZSA-N 4-[2-[[(1s)-1-(4-fluorophenyl)ethyl]amino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl]piperazine-2,6-dione Chemical compound N([C@@H](C)C=1C=CC(F)=CC=1)C(N=C(C=1)N2CC(=O)NC(=O)C2)=NC=1NC1=CN=CC=N1 WFHBXDDTNRJWAY-LBPRGKRZSA-N 0.000 claims description 4
- KGEOSMUHWRXPDI-UAXOWTEWSA-N FC1=CC=C(C=C1)[C@H](C)C1(NC(=CC(=N1)NC1=NC=CN=C1)NCC1OCCC1)N Chemical compound FC1=CC=C(C=C1)[C@H](C)C1(NC(=CC(=N1)NC1=NC=CN=C1)NCC1OCCC1)N KGEOSMUHWRXPDI-UAXOWTEWSA-N 0.000 claims description 4
- 206010037575 Pustular psoriasis Diseases 0.000 claims description 4
- 125000003118 aryl group Chemical group 0.000 claims description 4
- 201000001981 dermatomyositis Diseases 0.000 claims description 4
- 208000002557 hidradenitis Diseases 0.000 claims description 4
- 201000007162 hidradenitis suppurativa Diseases 0.000 claims description 4
- VFQXVTODMYMSMJ-UHFFFAOYSA-N isonicotinamide Chemical compound NC(=O)C1=CC=NC=C1 VFQXVTODMYMSMJ-UHFFFAOYSA-N 0.000 claims description 4
- YNBADRVTZLEFNH-UHFFFAOYSA-N methyl nicotinate Chemical compound COC(=O)C1=CC=CN=C1 YNBADRVTZLEFNH-UHFFFAOYSA-N 0.000 claims description 4
- 208000005987 polymyositis Diseases 0.000 claims description 4
- 201000010914 pustulosis of palm and sole Diseases 0.000 claims description 4
- 208000011797 pustulosis palmaris et plantaris Diseases 0.000 claims description 4
- 201000000596 systemic lupus erythematosus Diseases 0.000 claims description 4
- NAWXUBYGYWOOIX-SFHVURJKSA-N (2s)-2-[[4-[2-(2,4-diaminoquinazolin-6-yl)ethyl]benzoyl]amino]-4-methylidenepentanedioic acid Chemical compound C1=CC2=NC(N)=NC(N)=C2C=C1CCC1=CC=C(C(=O)N[C@@H](CC(=C)C(O)=O)C(O)=O)C=C1 NAWXUBYGYWOOIX-SFHVURJKSA-N 0.000 claims description 3
- OVAGJAAQMBYZDS-FXSDFHGDSA-N (z)-but-2-enedioic acid;6-n-[(1s)-1-(4-fluorophenyl)ethyl]-4-(1-methylpyrazol-4-yl)-2-n-pyrazin-2-ylpyridine-2,6-diamine Chemical compound OC(=O)\C=C/C(O)=O.N([C@@H](C)C=1C=CC(F)=CC=1)C(N=1)=CC(C2=CN(C)N=C2)=CC=1NC1=CN=CC=N1 OVAGJAAQMBYZDS-FXSDFHGDSA-N 0.000 claims description 3
- XIKUBFZCKKMLMC-LBPRGKRZSA-N 1-[2-[[(1s)-1-(4-fluorophenyl)ethyl]amino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl]imidazolidin-2-one Chemical compound N([C@@H](C)C=1C=CC(F)=CC=1)C(N=C(C=1)N2C(NCC2)=O)=NC=1NC1=CN=CC=N1 XIKUBFZCKKMLMC-LBPRGKRZSA-N 0.000 claims description 3
- JXQLLFDFRXUSCN-LBPRGKRZSA-N 2-n-[(1s)-1-(4-fluorophenyl)ethyl]-4-n-pyrazin-2-yl-6-(1h-pyrazol-5-yl)pyrimidine-2,4-diamine Chemical compound N([C@@H](C)C=1C=CC(F)=CC=1)C(N=C(C=1)C2=NNC=C2)=NC=1NC1=CN=CC=N1 JXQLLFDFRXUSCN-LBPRGKRZSA-N 0.000 claims description 3
- IAXYONBBKSZJPZ-AWEZNQCLSA-N 2-n-[(1s)-1-(4-fluorophenyl)ethyl]-4-n-pyrazin-2-yl-6-pyridin-2-ylpyrimidine-2,4-diamine Chemical compound N([C@@H](C)C=1C=CC(F)=CC=1)C(N=C(C=1)C=2N=CC=CC=2)=NC=1NC1=CN=CC=N1 IAXYONBBKSZJPZ-AWEZNQCLSA-N 0.000 claims description 3
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- QOXIAXNUEKOVBH-AWEZNQCLSA-N 2-n-[(1s)-1-(4-fluorophenyl)ethyl]-4-n-pyrazin-2-yl-6-pyridin-4-ylpyrimidine-2,4-diamine Chemical compound N([C@@H](C)C=1C=CC(F)=CC=1)C(N=C(C=1)C=2C=CN=CC=2)=NC=1NC1=CN=CC=N1 QOXIAXNUEKOVBH-AWEZNQCLSA-N 0.000 claims description 3
- HFONCUIJJLPYDA-LBPRGKRZSA-N 2-n-[(1s)-1-(4-fluorophenyl)ethyl]-6-(1,3-oxazol-5-yl)-4-n-pyrazin-2-ylpyrimidine-2,4-diamine Chemical compound N([C@@H](C)C=1C=CC(F)=CC=1)C(N=C(C=1)C=2OC=NC=2)=NC=1NC1=CN=CC=N1 HFONCUIJJLPYDA-LBPRGKRZSA-N 0.000 claims description 3
- LEOMMWPYUGSOMZ-HNNXBMFYSA-N 2-n-[(1s)-1-(4-fluorophenyl)ethyl]-6-(3-methylsulfonylphenyl)-4-n-pyrazin-2-ylpyrimidine-2,4-diamine Chemical compound N([C@@H](C)C=1C=CC(F)=CC=1)C(N=C(C=1)C=2C=C(C=CC=2)S(C)(=O)=O)=NC=1NC1=CN=CC=N1 LEOMMWPYUGSOMZ-HNNXBMFYSA-N 0.000 claims description 3
- XPHCBKDYRMGOAR-AWEZNQCLSA-N 2-n-[(1s)-1-(4-fluorophenyl)ethyl]-6-morpholin-4-yl-4-n-pyrazin-2-ylpyrimidine-2,4-diamine Chemical compound N([C@@H](C)C=1C=CC(F)=CC=1)C(N=C(C=1)N2CCOCC2)=NC=1NC1=CN=CC=N1 XPHCBKDYRMGOAR-AWEZNQCLSA-N 0.000 claims description 3
- HEWQQGVIJBRBEN-AWEZNQCLSA-N 3-[2-[[(1s)-1-(4-fluorophenyl)ethyl]amino]-6-(pyrazin-2-ylamino)pyridin-4-yl]propan-1-ol Chemical compound N([C@@H](C)C=1C=CC(F)=CC=1)C(N=1)=CC(CCCO)=CC=1NC1=CN=CC=N1 HEWQQGVIJBRBEN-AWEZNQCLSA-N 0.000 claims description 3
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- 125000004466 alkoxycarbonylamino group Chemical group 0.000 claims description 3
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- BUCZCHGSUGHQBB-KSSFIOAISA-N n-[(3s)-1-[2-[[(1s)-1-(4-fluorophenyl)ethyl]amino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl]pyrrolidin-3-yl]acetamide Chemical compound N([C@@H](C)C=1C=CC(F)=CC=1)C(N=C(C=1)N2C[C@H](CC2)NC(C)=O)=NC=1NC1=CN=CC=N1 BUCZCHGSUGHQBB-KSSFIOAISA-N 0.000 claims description 3
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- KDPIQLKDURLHRR-HNNXBMFYSA-N 8-[2-[[(1s)-1-(4-fluorophenyl)ethyl]amino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl]-8-azaspiro[4.5]decane-2,3,4-trione Chemical compound N([C@@H](C)C=1C=CC(F)=CC=1)C(N=C(C=1)N2CCC3(C(C(=O)C(=O)C3)=O)CC2)=NC=1NC1=CN=CC=N1 KDPIQLKDURLHRR-HNNXBMFYSA-N 0.000 claims description 2
- WHUZMQWCBAINFE-GZWBLTSWSA-N FC1=CC=C(C=C1)[C@H](C)C1(NC(=CC(=N1)NC1=NC=CN=C1)N1CCC2(OCCO2)CC1)N Chemical compound FC1=CC=C(C=C1)[C@H](C)C1(NC(=CC(=N1)NC1=NC=CN=C1)N1CCC2(OCCO2)CC1)N WHUZMQWCBAINFE-GZWBLTSWSA-N 0.000 claims description 2
- QHYLJILWSSVSLB-INIZCTEOSA-N [1-[2-[[(1s)-1-(4-fluorophenyl)ethyl]amino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl]azetidin-3-yl]-morpholin-4-ylmethanone Chemical compound N([C@@H](C)C=1C=CC(F)=CC=1)C(N=C(C=1)N2CC(C2)C(=O)N2CCOCC2)=NC=1NC1=CN=CC=N1 QHYLJILWSSVSLB-INIZCTEOSA-N 0.000 claims description 2
- YDXOXXMDJLZCQL-KRWDZBQOSA-N [1-[2-[[(1s)-1-(4-fluorophenyl)ethyl]amino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl]azetidin-3-yl]-piperidin-1-ylmethanone Chemical compound N([C@@H](C)C=1C=CC(F)=CC=1)C(N=C(C=1)N2CC(C2)C(=O)N2CCCCC2)=NC=1NC1=CN=CC=N1 YDXOXXMDJLZCQL-KRWDZBQOSA-N 0.000 claims description 2
- IXTZNQOFEHNJEY-INIZCTEOSA-N [1-[2-[[(1s)-1-(4-fluorophenyl)ethyl]amino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl]azetidin-3-yl]-pyrrolidin-1-ylmethanone Chemical compound N([C@@H](C)C=1C=CC(F)=CC=1)C(N=C(C=1)N2CC(C2)C(=O)N2CCCC2)=NC=1NC1=CN=CC=N1 IXTZNQOFEHNJEY-INIZCTEOSA-N 0.000 claims description 2
- VTVFELPAJPZRJX-ZDUSSCGKSA-N [1-[2-[[(1s)-1-(4-fluorophenyl)ethyl]amino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl]azetidin-3-yl]methanol Chemical compound N([C@@H](C)C=1C=CC(F)=CC=1)C(N=C(C=1)N2CC(CO)C2)=NC=1NC1=CN=CC=N1 VTVFELPAJPZRJX-ZDUSSCGKSA-N 0.000 claims description 2
- SQFHLJBBDSLIRF-LBPRGKRZSA-N [1-[2-[[(1s)-1-(4-fluorophenyl)ethyl]amino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl]azetidin-3-yl]urea Chemical compound N([C@@H](C)C=1C=CC(F)=CC=1)C(N=C(C=1)N2CC(C2)NC(N)=O)=NC=1NC1=CN=CC=N1 SQFHLJBBDSLIRF-LBPRGKRZSA-N 0.000 claims description 2
- ACHIEUOEMXAISJ-HNNXBMFYSA-N [2-[[(1s)-1-(4-fluorophenyl)ethyl]amino]-6-(pyrazin-2-ylamino)pyridin-3-yl]-morpholin-4-ylmethanone Chemical compound N([C@@H](C)C=1C=CC(F)=CC=1)C(C(=CC=1)C(=O)N2CCOCC2)=NC=1NC1=CN=CC=N1 ACHIEUOEMXAISJ-HNNXBMFYSA-N 0.000 claims description 2
- NVSFBNGYKHTPPY-INIZCTEOSA-N [2-[[(1s)-1-(4-fluorophenyl)ethyl]amino]-6-(pyrazin-2-ylamino)pyridin-4-yl]-(4-methylsulfonylpiperazin-1-yl)methanone Chemical compound N([C@@H](C)C=1C=CC(F)=CC=1)C(N=1)=CC(C(=O)N2CCN(CC2)S(C)(=O)=O)=CC=1NC1=CN=CC=N1 NVSFBNGYKHTPPY-INIZCTEOSA-N 0.000 claims description 2
- GPTOOPNAMNMIHS-HNNXBMFYSA-N [2-[[(1s)-1-(4-fluorophenyl)ethyl]amino]-6-(pyrazin-2-ylamino)pyridin-4-yl]-morpholin-4-ylmethanone Chemical compound N([C@@H](C)C=1C=CC(F)=CC=1)C(N=1)=CC(C(=O)N2CCOCC2)=CC=1NC1=CN=CC=N1 GPTOOPNAMNMIHS-HNNXBMFYSA-N 0.000 claims description 2
- BCWJLKGUULEOKY-HNNXBMFYSA-N [2-[[(1s)-1-(4-fluorophenyl)ethyl]amino]-6-(pyrazin-2-ylamino)pyridin-4-yl]-pyrrolidin-1-ylmethanone Chemical compound N([C@@H](C)C=1C=CC(F)=CC=1)C(N=1)=CC(C(=O)N2CCCC2)=CC=1NC1=CN=CC=N1 BCWJLKGUULEOKY-HNNXBMFYSA-N 0.000 claims description 2
- BFFVUOOCOOTDMA-LBPRGKRZSA-N [2-[[(1s)-1-(4-fluorophenyl)ethyl]amino]-6-(pyrazin-2-ylamino)pyridin-4-yl]methanol Chemical compound N([C@@H](C)C=1C=CC(F)=CC=1)C(N=1)=CC(CO)=CC=1NC1=CN=CC=N1 BFFVUOOCOOTDMA-LBPRGKRZSA-N 0.000 claims description 2
- QCXQIEBFUBUQPC-NSHDSACASA-N [2-[[(1s)-1-(4-fluorophenyl)ethyl]amino]-6-(pyrazin-2-ylamino)pyridin-4-yl]urea Chemical compound N([C@@H](C)C=1C=CC(F)=CC=1)C(N=1)=CC(NC(N)=O)=CC=1NC1=CN=CC=N1 QCXQIEBFUBUQPC-NSHDSACASA-N 0.000 claims description 2
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 2
- SLXAKRCXCJOGKK-INIZCTEOSA-N ethyl 1-[2-[[(1s)-1-(4-fluorophenyl)ethyl]amino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl]piperidine-4-carboxylate Chemical compound C1CC(C(=O)OCC)CCN1C1=CC(NC=2N=CC=NC=2)=NC(N[C@@H](C)C=2C=CC(F)=CC=2)=N1 SLXAKRCXCJOGKK-INIZCTEOSA-N 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- NWYHINIPXDUMBD-LBPRGKRZSA-N methyl 2-[[(1s)-1-(4-fluorophenyl)ethyl]amino]-6-(pyrazin-2-ylamino)pyridine-4-carboxylate Chemical compound C1([C@H](C)NC=2C=C(C=C(NC=3N=CC=NC=3)N=2)C(=O)OC)=CC=C(F)C=C1 NWYHINIPXDUMBD-LBPRGKRZSA-N 0.000 claims description 2
- 229960001238 methylnicotinate Drugs 0.000 claims description 2
- DIVKAHBZOLDDFI-INIZCTEOSA-N n,n-diethyl-1-[2-[[(1s)-1-(4-fluorophenyl)ethyl]amino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl]azetidine-3-carboxamide Chemical compound C1C(C(=O)N(CC)CC)CN1C1=CC(NC=2N=CC=NC=2)=NC(N[C@@H](C)C=2C=CC(F)=CC=2)=N1 DIVKAHBZOLDDFI-INIZCTEOSA-N 0.000 claims description 2
- UUOOGMYMGDYUBZ-HNNXBMFYSA-N n-(2-ethoxyethyl)-2-[[(1s)-1-(4-fluorophenyl)ethyl]amino]-6-(pyrazin-2-ylamino)pyridine-4-carboxamide Chemical compound C1([C@H](C)NC=2C=C(C=C(NC=3N=CC=NC=3)N=2)C(=O)NCCOCC)=CC=C(F)C=C1 UUOOGMYMGDYUBZ-HNNXBMFYSA-N 0.000 claims description 2
- GYELJUSFRTXOMH-HNNXBMFYSA-N n-(cyclopropylmethyl)-1-[2-[[(1s)-1-(4-fluorophenyl)ethyl]amino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl]azetidine-3-carboxamide Chemical compound N([C@@H](C)C=1C=CC(F)=CC=1)C(N=C(C=1)N2CC(C2)C(=O)NCC2CC2)=NC=1NC1=CN=CC=N1 GYELJUSFRTXOMH-HNNXBMFYSA-N 0.000 claims description 2
- OXLUYFKXOYVPGP-AWEZNQCLSA-N n-(cyclopropylmethyl)-2-[[(1s)-1-(4-fluorophenyl)ethyl]amino]-6-(pyrazin-2-ylamino)pyridine-3-carboxamide Chemical compound N([C@@H](C)C=1C=CC(F)=CC=1)C(C(=CC=1)C(=O)NCC2CC2)=NC=1NC1=CN=CC=N1 OXLUYFKXOYVPGP-AWEZNQCLSA-N 0.000 claims description 2
- MFTBCZLQMZZGCS-AWEZNQCLSA-N n-(cyclopropylmethyl)-2-[[(1s)-1-(4-fluorophenyl)ethyl]amino]-6-(pyrazin-2-ylamino)pyridine-4-carboxamide Chemical compound N([C@@H](C)C=1C=CC(F)=CC=1)C(N=1)=CC(C(=O)NCC2CC2)=CC=1NC1=CN=CC=N1 MFTBCZLQMZZGCS-AWEZNQCLSA-N 0.000 claims description 2
- BUCZCHGSUGHQBB-KBXCAEBGSA-N n-[(3r)-1-[2-[[(1s)-1-(4-fluorophenyl)ethyl]amino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl]pyrrolidin-3-yl]acetamide Chemical compound N([C@@H](C)C=1C=CC(F)=CC=1)C(N=C(C=1)N2C[C@@H](CC2)NC(C)=O)=NC=1NC1=CN=CC=N1 BUCZCHGSUGHQBB-KBXCAEBGSA-N 0.000 claims description 2
- HJGHIUQFFXFJNQ-ZDUSSCGKSA-N n-[1-[2-[[(1s)-1-(4-fluorophenyl)ethyl]amino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl]azetidin-3-yl]acetamide Chemical compound N([C@@H](C)C=1C=CC(F)=CC=1)C(N=C(C=1)N2CC(C2)NC(C)=O)=NC=1NC1=CN=CC=N1 HJGHIUQFFXFJNQ-ZDUSSCGKSA-N 0.000 claims description 2
- MJPOYJSTACHJRV-AWEZNQCLSA-N n-[1-[2-[[(1s)-1-(4-fluorophenyl)ethyl]amino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl]azetidin-3-yl]ethanesulfonamide Chemical compound C1C(NS(=O)(=O)CC)CN1C1=CC(NC=2N=CC=NC=2)=NC(N[C@@H](C)C=2C=CC(F)=CC=2)=N1 MJPOYJSTACHJRV-AWEZNQCLSA-N 0.000 claims description 2
- QTJDIIOCEFSAAS-ZDUSSCGKSA-N n-[1-[2-[[(1s)-1-(4-fluorophenyl)ethyl]amino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl]azetidin-3-yl]methanesulfonamide Chemical compound N([C@@H](C)C=1C=CC(F)=CC=1)C(N=C(C=1)N2CC(C2)NS(C)(=O)=O)=NC=1NC1=CN=CC=N1 QTJDIIOCEFSAAS-ZDUSSCGKSA-N 0.000 claims description 2
- QKYKPHRBCZQSLC-MBIQTGHCSA-N n-[1-[2-[[(1s)-1-(4-fluorophenyl)ethyl]amino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl]pyrrolidin-3-yl]methanesulfonamide Chemical compound N([C@@H](C)C=1C=CC(F)=CC=1)C(N=C(C=1)N2CC(CC2)NS(C)(=O)=O)=NC=1NC1=CN=CC=N1 QKYKPHRBCZQSLC-MBIQTGHCSA-N 0.000 claims description 2
- PRDDRCVMOGOQKD-HNNXBMFYSA-N n-[2-(dimethylamino)ethyl]-2-[[(1s)-1-(4-fluorophenyl)ethyl]amino]-6-(pyrazin-2-ylamino)pyridine-4-carboxamide Chemical compound N([C@@H](C)C=1C=CC(F)=CC=1)C(N=1)=CC(C(=O)NCCN(C)C)=CC=1NC1=CN=CC=N1 PRDDRCVMOGOQKD-HNNXBMFYSA-N 0.000 claims description 2
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- LKTUVGZTJQKSFU-LBPRGKRZSA-N n-[2-[[(1s)-1-(4-fluorophenyl)ethyl]amino]-6-(pyrazin-2-ylamino)pyridin-4-yl]methanesulfonamide Chemical compound N([C@@H](C)C=1C=CC(F)=CC=1)C(N=1)=CC(NS(C)(=O)=O)=CC=1NC1=CN=CC=N1 LKTUVGZTJQKSFU-LBPRGKRZSA-N 0.000 claims description 2
- LLXXMLJECIXVAY-ZDUSSCGKSA-N n-[2-[[(1s)-1-(4-fluorophenyl)ethyl]amino]-6-(pyrazin-2-ylamino)pyridin-4-yl]propanamide Chemical compound C1([C@H](C)NC=2C=C(C=C(NC=3N=CC=NC=3)N=2)NC(=O)CC)=CC=C(F)C=C1 LLXXMLJECIXVAY-ZDUSSCGKSA-N 0.000 claims description 2
- KPDANEDSHMNEMT-ZDUSSCGKSA-N n-[2-[[2-[[(1s)-1-(4-fluorophenyl)ethyl]amino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl]amino]ethyl]acetamide Chemical compound N([C@@H](C)C=1C=CC(F)=CC=1)C(N=1)=NC(NCCNC(C)=O)=CC=1NC1=CN=CC=N1 KPDANEDSHMNEMT-ZDUSSCGKSA-N 0.000 claims description 2
- JXNUUEYPNMOAGE-ZDUSSCGKSA-N n-[2-[[2-[[(1s)-1-(4-fluorophenyl)ethyl]amino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl]amino]ethyl]methanesulfonamide Chemical compound N([C@@H](C)C=1C=CC(F)=CC=1)C(N=1)=NC(NCCNS(C)(=O)=O)=CC=1NC1=CN=CC=N1 JXNUUEYPNMOAGE-ZDUSSCGKSA-N 0.000 claims description 2
- NLOYPWJDDFXNDV-AWEZNQCLSA-N n-[[1-[2-[[(1s)-1-(4-fluorophenyl)ethyl]amino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl]azetidin-3-yl]methyl]acetamide Chemical compound N([C@@H](C)C=1C=CC(F)=CC=1)C(N=C(C=1)N2CC(CNC(C)=O)C2)=NC=1NC1=CN=CC=N1 NLOYPWJDDFXNDV-AWEZNQCLSA-N 0.000 claims description 2
- OHDNTNCQYISUIL-HNNXBMFYSA-N n-[[1-[2-[[(1s)-1-(4-fluorophenyl)ethyl]amino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl]azetidin-3-yl]methyl]ethanesulfonamide Chemical compound C1C(CNS(=O)(=O)CC)CN1C1=CC(NC=2N=CC=NC=2)=NC(N[C@@H](C)C=2C=CC(F)=CC=2)=N1 OHDNTNCQYISUIL-HNNXBMFYSA-N 0.000 claims description 2
- WRJCQTGURCRZIA-KRWDZBQOSA-N n-benzyl-2-[[(1s)-1-(4-fluorophenyl)ethyl]amino]-6-(pyrazin-2-ylamino)pyridine-4-carboxamide Chemical compound N([C@@H](C)C=1C=CC(F)=CC=1)C(N=1)=CC(C(=O)NCC=2C=CC=CC=2)=CC=1NC1=CN=CC=N1 WRJCQTGURCRZIA-KRWDZBQOSA-N 0.000 claims description 2
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- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 208000026425 severe pneumonia Diseases 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 229910001923 silver oxide Inorganic materials 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 108091006106 transcriptional activators Proteins 0.000 description 1
- 230000026683 transduction Effects 0.000 description 1
- 238000010361 transduction Methods 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- GTLDTDOJJJZVBW-UHFFFAOYSA-N zinc cyanide Chemical compound [Zn+2].N#[C-].N#[C-] GTLDTDOJJJZVBW-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- 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
- A61K31/4965—Non-condensed pyrazines
- A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- 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
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Definitions
- Cycloalkyl includes, for example, those having 3 to 8 carbon atoms, specifically cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.
- alkoxyalkyl examples include the same as the above-mentioned "alkoxy”.
- saturated cyclic amino group includes, for example, a 4- to 7-membered saturated cyclic amino group having one or two N, optionally having one O or S as a ring-constituting atom, specifically include 1-azetidinyl, 1-pyrrolidinyl, 1-imidazolidinyl, piperidino, 1-piperazinyl, 1-tetrahydropyrimidinyl, morpholino, thiomorpholino, 1-homopiperazinyl.
- thiazolyl e.g. 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), thiadiazolyl, isothiazolyl ( 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl), pyridyl (e.g. 2-pyridyl, 3-pyridyl, 4-pyridyl), pyridazinyl (e.g. 3-pyridazinyl, 4-pyridazinyl), pyrimidinyl (e.g. 2 -pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), pyrazinyl (eg 2-pyrazinyl).
- pyridyl e.g. 2-pyridyl, 3-pyridyl, 4-pyridyl
- pyridazinyl e.g. 3-pyridazinyl, 4-pyridazinyl
- pyrimidinyl e
- Palladium catalyst ligands that can be used include, for example, 1,1′-bis(diphenylphosphino)ferrocene, 4,5-bis(diphenylphosphino)-9,9′-dimethylxanthene, 2-dicyclohexylphosphino- 2',4',6'-triisopropylbiphenyl, ( ⁇ )-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl, 2-(di-t-butylphosphino)biphenyl, bis Mention may be made of [2-(diphenylphosphino)phenyl]ether, tri-t-butylphosphine.
- Palladium catalysts include, for example, tris(dibenzylideneacetone)(chloroform)dipalladium(0), tris(dibenzylideneacetone)dipalladium(0), and palladium(II) acetate.
- the amount of palladium catalyst that can be used is suitably in the range of 0.001 to 0.1 mol per 1 mol of the aryl halide.
- Process 1 Compound [18] can be produced by reacting compound [16] and alcohol compound [17] in a suitable solvent in the presence of a base at -20°C to 100°C.
- Usable bases include, for example, sodium hydride and sodium hydroxide.
- Solvents that can be used are not particularly limited as long as they do not participate in the reaction. Examples include hydrocarbons such as toluene and xylene, ethers such as 1,4-dioxane and tetrahydrofuran, N,N-dimethylformamide, N, Amides such as N-dimethylacetamide and N-methyl-2-pyrrolidone, water, and mixed solvents thereof can be used.
- the reaction time varies depending on the type of raw materials used and the reaction temperature, but is generally 30 minutes to 24 hours.
- Palladium catalysts that can be used include, for example, tris(dibenzylideneacetone)(chloroform)dipalladium(0), tris(dibenzylideneacetone)dipalladium(0), and palladium(II) acetate.
- the amount of palladium catalyst that can be used is suitably in the range of 0.001 to 0.1 mol per 1 mol of the aryl halide.
- Palladium catalyst ligands that can be used include, for example, 4,5-bis(diphenylphosphino)-9,9′-dimethylxanthene, ( ⁇ )-2,2′-bis(diphenylphosphino)-1,1 '-Binaphthyl, 2-(di-t-butylphosphino)biphenyl, bis[2-(diphenylphosphino)phenyl]ether, tri-t-butylphosphine can be mentioned.
- Usable bases include, for example, sodium t-butoxide, tripotassium phosphate, and cesium carbonate.
- the reaction time varies depending on the type of raw material used, the reaction temperature, etc., but is usually within the range of 10 minutes to 24 hours.
- R 8 is a group represented by the following general formula [9], (Wherein, R M , R N , R O , * are as defined above.), or even substituted with 1 or 2 groups selected from the group consisting of cyano, halogen, hydroxy, alkoxy, alkylcarbonyl, carbamoyl, alkyl, cycloalkyl, (cycloalkyl)alkyl, aralkyl, hydroxycarbonyl and alkoxyalkyl It represents good heteroaryl (limited to those in which the bond is from C). )
- This reaction is a cross-coupling reaction using compound [1a] and organoboron compound [20], and can be carried out by a method known per se.
- This reaction can be carried out, for example, in the presence of a palladium catalyst and a base in a suitable solvent at 20-200°C.
- Palladium catalysts that may be used include, for example, tetrakis(triphenylphosphine)palladium, dichlorobis(triphenylphosphine)palladium, 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride-dichloromethane complexes. can be done.
- This reaction is a condensation reaction of compound [21] and compound [13] using a palladium catalyst, and is carried out by a method known per se.
- Solvents that can be used are not particularly limited as long as they do not participate in the reaction. Examples include hydrocarbons such as toluene and xylene, ethers such as 1,4-dioxane and tetrahydrofuran, N,N-dimethylformamide, N,N -dimethylacetamide, amides such as N-methyl-2-pyrrolidone, or mixed solvents thereof.
- This reaction can be carried out in the presence of a base within the range of 20°C to 200°C.
- Palladium catalysts that may be used include, for example, tris(dibenzylideneacetone)(chloroform)dipalladium(0), tris(dibenzylideneacetone)dipalladium(0), palladium(II) acetate.
- the amount of palladium catalyst that can be used is suitably in the range of 0.001 to 0.1 mol per 1 mol of the aryl halide.
- Palladium catalyst ligands that can be used include, for example, 1,1′-bis(diphenylphosphino)ferrocene, 4,5-bis(diphenylphosphino)-9,9′-dimethylxanthene, 2-dicyclohexylphosphino- 2',4',6'-triisopropylbiphenyl, ( ⁇ )-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl, 2-(di-t-butylphosphino)biphenyl, bis Mention may be made of [2-(diphenylphosphino)phenyl]ether, tri-t-butylphosphine.
- Usable bases include, for example, sodium t-butoxide, tripotassium phosphate, and cesium carbonate.
- the reaction time varies depending on the type of raw material used, the reaction temperature, etc., but is usually within the range of 10 minutes to 24 hours.
- Compound [21] which is a raw material compound, can be produced, for example, according to the following three methods.
- This reaction is a cross-coupling reaction using compound [22] and organoboron compound [20], and can be carried out by a method known per se.
- This reaction can be carried out, for example, in the presence of a palladium catalyst and a base in a suitable solvent at 20 to 200°C.
- Palladium catalysts that may be used include, for example, tetrakis(triphenylphosphine)palladium, dichlorobis(triphenylphosphine)palladium, 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride-dichloromethane complexes. can be done.
- Palladium catalysts that can be used include, for example, tris(dibenzylideneacetone)(chloroform)dipalladium(0), tris(dibenzylideneacetone)dipalladium(0), and palladium(II) acetate.
- the amount of palladium catalyst that can be used is suitably in the range of 0.001 to 0.1 mol per 1 mol of the aryl halide.
- This reaction is a condensation reaction of compound [26] and compound [13] using a palladium catalyst, and can be carried out by a method known per se.
- Solvents that can be used are not particularly limited as long as they do not participate in the reaction. Examples include hydrocarbons such as toluene and xylene, ethers such as 1,4-dioxane and tetrahydrofuran, N,N-dimethylformamide, N, Amides such as N-dimethylacetamide and N-methyl-2-pyrrolidone, or mixed solvents thereof can be used.
- This reaction can be carried out in the presence of a base within the range of 20°C to 200°C.
- Palladium catalyst ligands that can be used include, for example, 1,1′-bis(diphenylphosphino)ferrocene, 4,5-bis(diphenylphosphino)-9,9′-dimethylxanthene, 2-dicyclohexylphosphino- 2',4',6'-triisopropylbiphenyl, ( ⁇ )-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl, 2-(di-t-butylphosphino)biphenyl, bis Mention may be made of [2-(diphenylphosphino)phenyl]ether, tri-t-butylphosphine.
- Usable bases include, for example, sodium t-butoxide, tripotassium phosphate, and cesium carbonate.
- the reaction time varies depending on the type of raw material used, the reaction temperature, etc., but is usually within the range of 10 minutes to 24 hours.
- Compound [26] which is a starting compound, can be produced, for example, according to the following two methods. (X 1 , R 1 , R 12 , Hal 1 and Hal 2 are as defined above.)
- a Compound [26] can be produced by reacting compound [12] and compound [25] in a suitable solvent in the presence of a base at 20°C to 200°C.
- bases include, for example, pyridine, triethylamine, N,N-diisopropylethylamine, potassium carbonate and sodium hydrogen carbonate.
- Palladium catalyst ligands that can be used include, for example, 1,1′-bis(diphenylphosphino)ferrocene, 4,5-bis(diphenylphosphino)-9,9′-dimethylxanthene, 2-dicyclohexylphosphino- 2',4',6'-triisopropylbiphenyl, ( ⁇ )-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl, 2-(di-t-butylphosphino)biphenyl, bis Mention may be made of [2-(diphenylphosphino)phenyl]ether, tri-t-butylphosphine.
- Usable bases include, for example, sodium t-butoxide, tripotassium phosphate, and cesium carbonate.
- the reaction time varies depending on the type of raw material used, the reaction temperature, etc., but is usually within the range of 10 minutes to 24 hours.
- R 2 is 1 or 2 groups selected from the group consisting of cyano, halogen, hydroxy, alkoxy, alkylcarbonyl, carbamoyl, alkyl, cycloalkyl, (cycloalkyl)alkyl, aralkyl, hydroxycarbonyl and alkoxyalkyl
- X 1 , R 1 , R 5 and Hal 1 are as defined above.
- R 13 is cyano, halogen, hydroxy, alkoxy, alkylcarbonyl, carbamoyl, alkyl, cycloalkyl, (cycloalkyl)alkyl, aralkyl, heteroaryl optionally substituted with 1 or 2 groups selected from the group consisting of hydroxycarbonyl and alkoxyalkyl (limited to those with a bond extending from N);
- the starting compound, compound [27] can be produced according to the following method.
- This reaction is a cross-coupling reaction using compound [12] and compound [28], and can be carried out by a method known per se.
- This reaction can be carried out, for example, in the presence or absence of a copper catalyst in a suitable solvent at 20 to 200°C.
- a copper catalyst examples include copper iodide and copper acetate.
- the amount of copper catalyst that can be used is suitably within the range of 0.01 to 0.2 mol per 1 mol of the aryl halide.
- examples of copper ligands include trans-N,N'-dimethylcyclohexane-1,2-diamine, trans-1,2-cyclohexanediamine, 1,10-phenanthroline, and the like.
- Usable reaction solvents are not particularly limited as long as they do not participate in the reaction. Examples include ethers such as tetrahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane; Examples include amides such as N-dimethylformamide and N,N-dimethylacetamide, hydrocarbons such as benzene and toluene, and mixed solvents thereof. Usable bases include, for example, tripotassium phosphate, potassium carbonate, sodium carbonate, cesium carbonate and the like.
- the reaction time varies depending on the type of raw material used and the reaction temperature, but is usually within the range of 30 minutes to 24 hours.
- R 2 is alkoxycarbonyl (X 1 , R 1 , R 5 and Hal 1 are as defined above.
- R 14 represents alkyl.
- This reaction is a condensation reaction of compound [30] and compound [19] using a palladium catalyst, and can be carried out in the same manner as in step 2 of the method for producing compound [15], which is the raw material compound.
- This reaction is a hydrolysis reaction of compound [1f] and can be carried out by a method known per se.
- compound [1g] can be produced by hydrolyzing compound [1f] in the presence of an acid or base.
- the acid used in this reaction include inorganic acids such as hydrochloric acid and sulfuric acid
- examples of the base include inorganic bases such as sodium hydroxide and potassium hydroxide.
- the reaction solvent that can be used in this reaction include alcohols such as methanol and ethanol, ethers such as tetrahydrofuran and 1,4-dioxane, water, and mixed solvents thereof.
- the reaction temperature is 0° C. to 100° C., and the reaction time is usually 30 minutes to 24 hours.
- R 2 is (a) a saturated cyclic amino group optionally substituted with alkyl or alkylsulfonyl, or (b) alkyl, cycloalkyl, (cycloalkyl)alkyl, aralkyl, haloalkyl, dialkylaminoalkyl, alkoxyalkyl , and aminocarbonyl optionally substituted with 1 or 2 groups selected from the group consisting of hydroxyalkyl (X 1 , R 1 and R 5 are as defined above.
- R 15 and R 16 are the same or different and are H, alkyl, cycloalkyl, (cycloalkyl)alkyl, aralkyl, haloalkyl, dialkylaminoalkyl, represents alkoxyalkyl or hydroxyalkyl, or together with adjacent N represents a saturated cyclic amino group. Such saturated cyclic amino group may be substituted with alkyl or alkylsulfonyl.
- This reaction is a condensation reaction between compound [1g] and compound [31], and can be carried out by a method known per se as a condensation reaction.
- Compound [1h] can be synthesized by reacting a carboxylic acid represented by compound [1g] or a reactive derivative thereof with compound [31].
- Examples of reactive derivatives of compound [1g] include those commonly used in amide condensation formation reactions, such as acid halides (e.g., acid chlorides, acid bromides), mixed acid anhydrides, imidazolides, and active amides. .
- the reaction can be carried out at -20 to 100°C using a condensing agent in the presence or absence of a base.
- Condensing agents that can be used in this reaction include, for example, 1,1′-oxalyldiimidazole, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, dicyclohexylcarbodiimide, diethyl cyanophosphonate, O-(benzotriazole -1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate, 1H-benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate.
- Additives that can be used include, for example, 1-hydroxybenzotriazole and 1-hydroxy-7-azabenzotriazole.
- the reaction time varies depending on the type of raw material used, the reaction temperature, etc., but is usually within the range of 10 minutes to 24 hours.
- the amount of the compound [31] and the condensing agent to be used is, for example, in the range of 1 to 3 mol per 1 mol of the compound [1g].
- R 2 is H, alkylcarbonyl, saturated heterocyclic group containing 1 N optionally substituted with alkylsulfonyl, or alkyl optionally substituted with hydroxy or alkoxy
- X 1 , R 1 , R 5 and Hal 1 are as defined above.
- R 17 is a saturated heterocyclic group containing one N optionally substituted with H, alkylcarbonyl, alkylsulfonyl, or represents alkyl optionally substituted with hydroxy or alkoxy
- This reaction is a condensation reaction of compound [32] and compound [13] using a palladium catalyst, and can be carried out in the same manner as in production method 1 above.
- the amount of palladium catalyst that can be used is suitably in the range of 0.001 to 0.1 mol per 1 mol of the aryl halide.
- 4,5-bis(diphenylphosphino)-9,9'-dimethylxanthene, 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, 2-dicyclohexyl as ligands for palladium if necessary Phosphino-2',6'-dimethoxybiphenyl and the like can be used.
- Usable cyano compounds include copper (I) cyanide, zinc (II) cyanide, potassium cyanide, and sodium cyanide.
- Usable reaction solvents are not particularly limited as long as they do not participate in the reaction. Examples include ethers such as tetrahydrofuran and 1,4-dioxane, alcohols such as methanol and ethanol, N,N-dimethylformamide, N, Examples include amides such as N-dimethylacetamide and N-methyl-2-pyrrolidone, hydrocarbons such as benzene and toluene, dimethylsulfoxide, water, and mixed solvents thereof.
- the reaction time varies depending on the type of raw material used and the reaction temperature, but is usually within the range of 30 minutes to 24 hours.
- This reaction is a condensation reaction of compound [33] and compound [13] using a palladium catalyst, and can be carried out in the same manner as in Production Method 4-2 above.
- Compound [33] which is a starting compound, can be produced according to the following method. (R 1 , R 18 , Hal 1 and Hal 3 are as defined above.)
- This reaction is a condensation reaction of compound [34] and compound [19] using a palladium catalyst, and can be carried out in the same manner as in step 2 of method A in production method 3-2 above.
- This reaction is a hydrolysis reaction of compound [1k] and can be carried out in the same manner as in Production Method 7 above.
- R A is a group represented by the following general formula [35] (Wherein, * is as defined above.
- R 19 and R 20 are the same or different and represent H, alkyl, cycloalkyl, (cycloalkyl)alkyl or alkoxyalkyl, or adjacent N together with represents a saturated cyclic amino group.)
- This reaction is a condensation reaction between compound [1j] and compound [36], and can be carried out in the same manner as in production method 8 above.
- R 4 is alkyl (X, R 1 , R 2 , R 3 , R 5 and Hal 1 are as defined above.
- R 21 represents alkyl.
- This reaction is a condensation reaction of compound [37] and compound [13] using a palladium catalyst, and can be carried out in the same manner as in Production Method 4-2 above.
- Compound [37] which is a starting compound, can be produced according to the following method. (X 1 , R 1 , R 2 , R 21 and Hal 1 are as defined above. Hal 4 represents halogen.)
- This step can be produced by reacting compound [38] and compound [39] in an appropriate solvent in the presence of a base at 20°C to 200°C using a microwave if necessary.
- Usable bases include, for example, sodium hydride, lithium diisopropylamide, n-butyllithium and the like.
- Solvents that can be used are not particularly limited as long as they do not participate in the reaction. Hydrocarbons such as benzene and toluene, acetonitrile, or mixed solvents thereof can be mentioned.
- the reaction time varies depending on the type of raw materials used and the reaction temperature, but is usually within the range of 10 minutes to 24 hours.
- This reaction is a condensation reaction of compound [40] and compound [13] using a palladium catalyst, and can be carried out in the same manner as in production method 1 above.
- Sodium t-butoxide is suitable as a base that can be used in this reaction.
- Compound [40] which is a starting compound, can be produced according to the following method. (X 1 , R 1 , R 2 , Hal 1 and Hal 3 are as defined above.)
- Process 1 Compound [42] can be produced according to known methods (J.Org.Chem., 65, 2000, 9059-9068, etc.).
- This step is a condensation reaction of compound [42] and compound [43] using a palladium catalyst, and can be carried out, for example, by the same method as in Production Method 1 above.
- the compound of the present invention can be used as a medicine as it is, it can also be used in the form of a pharmaceutically acceptable salt by a known method.
- Such salts include salts of mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, citric acid, tartaric acid, maleic acid, succinic acid, fumaric acid, p-toluenesulfonic acid, benzenesulfonic acid, Examples include salts of organic acids such as methanesulfonic acid.
- the hydrochloride of the compound of the present invention can be obtained by dissolving the compound of the present invention in an alcohol solution, ethyl acetate solution or diethyl ether solution of hydrogen chloride.
- optical isomers are known, for example, from the racemate obtained as described above using an optically active acid (tartaric acid, dibenzoyltartaric acid, mandelic acid, 10-camphorsulfonic acid, etc.) by utilizing its basicity. or optically active compounds prepared in advance can be used as starting materials. In addition, it can also be produced by optical resolution using a chiral column or by asymmetric synthesis.
- an optically active acid tartaric acid, dibenzoyltartaric acid, mandelic acid, 10-camphorsulfonic acid, etc.
- the compound of the present invention has geometric isomers or tautomers, not only any one of the isomers but also a mixture thereof is included in the compound of the present invention.
- the compound of the present invention or a pharmaceutically acceptable salt thereof has STAT3 inhibitory activity and/or IL-17 production inhibitory activity, as shown in the test examples below, and is useful as a pharmaceutical.
- compositions containing the compound of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient include, for example, cytokine storm/cytokine release syndrome (CRS), respiratory disorders, psoriasis, Crohn's disease, It can be used as a prophylactic or therapeutic agent for ulcerative colitis, ankylosing myelitis, axial spinal arthritis, palmoplantar pustulosis, hidradenitis suppurativa, lupus nephritis, systemic lupus erythematosus, polymyositis/dermatomyositis. .
- CRS cytokine storm/cytokine release syndrome
- respiratory disorders psoriasis
- Crohn's disease It can be used as a prophylactic or therapeutic agent for ulcerative colitis, ankylosing myelitis, axial spinal arthritis, palmoplantar pustulosis, hidradenitis suppurativa, lupus neph
- a pharmaceutical composition containing the compound of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient is, for example, a prophylactic or therapeutic agent for cytokine storm/cytokine release syndrome (CRS) or respiratory disorders.
- CRS cytokine storm/cytokine release syndrome
- respiratory disorders can be used as a prophylactic or therapeutic agent for cytokine storm/cytokine release syndrome (CRS) or respiratory disorders.
- cytokine storm/cytokine release syndrome is, for example, cytokine storm/cytokine release syndrome (CRS) associated with viral infections, preferably influenza virus, novel influenza virus, coronavirus (e.g., SARS-CoV, MERS-CoV, etc.), or cytokine storm/cytokine release syndrome (CRS) due to novel coronavirus, more preferably cytokine storm/cytokine release due to SARS-CoV-2 (or COVID-19) syndrome (CRS).
- CRS cytokine storm/cytokine release syndrome
- the respiratory disorder is, for example, pneumonia or acute respiratory distress syndrome associated with a viral infection, preferably influenza virus, pandemic influenza virus, coronavirus (e.g., SARS-CoV, MERS- CoV, etc.), or pneumonia or acute respiratory distress syndrome associated with viral infections caused by the novel coronavirus, more preferably pneumonia (especially severe pneumonia) caused by SARS-CoV-2 (or COVID-19).
- a viral infection preferably influenza virus, pandemic influenza virus, coronavirus (e.g., SARS-CoV, MERS- CoV, etc.), or pneumonia or acute respiratory distress syndrome associated with viral infections caused by the novel coronavirus, more preferably pneumonia (especially severe pneumonia) caused by SARS-CoV-2 (or COVID-19).
- compositions containing the compound of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient are, for example, COVID-19 patients, preferably COVID-19 patients, and L- This is a pharmaceutical composition for administration to a patient with enhanced 17 production.
- a pharmaceutical composition containing the compound of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient can be It can be used as a prophylactic or therapeutic agent for arthritis, palmoplantar pustulosis, hidradenitis suppurativa, lupus nephritis, systemic lupus erythematosus, polymyositis/dermatomyositis.
- a pharmaceutical composition containing the compound of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient is a pharmaceutical composition for administration to patients with enhanced L-17 production.
- the compound of the present invention or a pharmaceutically acceptable salt thereof has STAT3 inhibitory activity and/or IL-17 production inhibitory activity, and is useful as a cytokine storm inhibitor.
- the compound of the present invention or a pharmaceutically acceptable salt thereof has IL-17 production inhibitory activity and is useful as an IL-17 production inhibitor.
- the compound of the present invention or a pharmaceutically acceptable salt thereof has STAT3 inhibitory activity and is useful as a STAT3 inhibitory agent.
- the compound of the present invention or a pharmaceutically acceptable salt thereof when administering the compound of the present invention or a pharmaceutically acceptable salt thereof as a medicament, the compound of the present invention or a pharmaceutically acceptable salt thereof as such or in a pharmaceutically acceptable non-toxic and inert carrier, for example, It is administered to mammals, including humans, as a pharmaceutical composition containing 0.001% to 99.5%, preferably 0.1% to 90%.
- compositions of the present invention are preferably administered in dosage unit form.
- the pharmaceutical composition can be administered intratissueally, orally, intravenously, locally (percutaneously, eye drops, etc.), or rectally. Of course, it is administered in dosage forms suitable for these administration methods.
- the compounds of Examples 1 to 234 were synthesized with reference to the descriptions in WO2010/090290 and WO2012/005299. Structural formulas of the compounds of Examples 1 to 234 are shown in Tables 1 to 12.
- Test Example 1 STAT3 phosphorylation inhibitory action on mouse blood cells 1.
- Administration of test substance to mice and blood collection Compound A was orally administered to mice (BALB/cA Jcl, 7 weeks old, male) at 10, 25 and 50 mg/kg. 0.5% methylcellulose was orally administered to the vehicle group. Blood was collected from the posterior vena cava under isoflurane inhalation anesthesia before administration and 1 and 3 hours after administration. Three mice were used in each group.
- pSTAT3 production 150 ⁇ L of blood was taken and washed twice with phosphate buffer. Thereafter, pSTAT3 was measured according to the procedure of the ELISA kit (phosphoELISA kit STAT3 [pY705], Invitrogen cat#KHO0481).
- Test Example 2 IL-17 production inhibitory action 1.
- DMSO Dimethylsulfoxide
- RPMI Roswell Park Memorial Institute
- FBS fetal bovine serum
- Peripheral blood mononuclear cells were suspended at 0.56 ⁇ 10 6 cells/mL in RPMI-1640 medium containing 10% FBS, and each 90 ⁇ L (0.5 ⁇ 10 5 cells) was placed in a 96-well plate (Corning, 353075). sown in Immediately after seeding, 10 ⁇ L of the test substance solution was added and cultured in a 5% carbon dioxide (CO2), 37°C incubator. During culture, Dynabeads (registered trademark) Human T-Activator CD3/CD28 for T Cell Expansion and Activation (Thermo Fisher Scientific, 11161D) was added at a ratio of 0.88 ⁇ L per 10 ⁇ L of RPMI-1640 medium containing 10% FBS. mixed with.
- CO2 carbon dioxide
- Formulation example 1 Tablet (oral tablet) 5.0 mg of the compound of the present invention of Example 1 in 80 mg of one prescription tablet Corn starch 46.6 mg Crystalline cellulose 24.0 mg Methyl cellulose 4.0 mg Magnesium stearate 0.4 mg The mixed powder of this ratio is tableted by a conventional method to give tablets for oral use.
- Formulation example 2 Tablet (oral tablet) 5.0 mg of the compound of the present invention of Example 2 in 80 mg of one prescription tablet Corn starch 46.6 mg Crystalline cellulose 24.0mg Methyl cellulose 4.0 mg Magnesium stearate 0.4 mg The mixed powder of this ratio is tableted by a usual method to give an oral tablet.
- compositions that treat, for example, cytokine storm/cytokine release syndrome (CRS), psoriasis, Crohn's disease, ulcerative colitis, ankylosing myelitis, axial spinal arthritis, palmoplantar pustulosis, hidradenitis suppurativa, lupus It can be used as a prophylactic or therapeutic agent for nephritis, systemic lupus erythematosus, or polymyositis/dermatomyositis.
- CRS cytokine storm/cytokine release syndrome
- psoriasis Crohn's disease
- ulcerative colitis ankylosing myelitis
- axial spinal arthritis palmoplantar pustulosis
- hidradenitis suppurativa lupus It can be used as a prophylactic or therapeutic agent for nephritis, systemic lupus erythematosus, or polymyositis/derma
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Abstract
The present invention relates to a novel cytokine storm inhibitor containing, as an active ingredient, a compound represented by general formula [1]: [in the formula, R1 R2, R3, R4, R5, and X are as defined in the description], or a pharmacologically acceptable salt thereof.
Description
本発明は、一般式[1]:
[式中、R1、R2、R3、R4、R5、Xは、本明細書に記載の通りである]
で表される化合物又はその医薬上許容される塩を有効成分として含有する新規なサイトカインストーム抑制剤に関するものである。 The present invention provides the general formula [1]:
[wherein R 1 , R 2 , R 3 , R 4 , R 5 , X are as described herein]
It relates to a novel cytokine storm inhibitor containing a compound represented by or a pharmaceutically acceptable salt thereof as an active ingredient.
で表される化合物又はその医薬上許容される塩を有効成分として含有する新規なサイトカインストーム抑制剤に関するものである。 The present invention provides the general formula [1]:
It relates to a novel cytokine storm inhibitor containing a compound represented by or a pharmaceutically acceptable salt thereof as an active ingredient.
新型コロナウイルス感染症(COVID-19)は、SARS-CoV-2ウイルスにより引き起こされる感染症である。SARS-CoV-2はACE2を受容体として感染し、自然免疫系とAngII-AT1Rを介して、NF-kBとSTAT3転写因子の活性化を誘導する。STAT3はNF-kBの活性化を増強することにより、IL-6などの炎症性サイトカイン産生を増強する。サイトカインストーム(cytokine storm)は、血液中のサイトカイン濃度が異常上昇した状態であり、例えば感染症や薬剤投与などの原因により、血中サイトカイン(IL-1,IL-6,TNF-αなど)の異常上昇が起こる(非特許文献1)。
The novel coronavirus infection (COVID-19) is an infectious disease caused by the SARS-CoV-2 virus. SARS-CoV-2 infects using ACE2 as a receptor and induces activation of NF-kB and STAT3 transcription factors via the innate immune system and AngII-AT1R. STAT3 enhances inflammatory cytokine production such as IL-6 by enhancing activation of NF-kB. Cytokine storm is a state in which the concentration of cytokines in the blood is abnormally elevated. Abnormal elevation occurs (Non-Patent Document 1).
JAK(ヤヌスキナーゼ)及びSTAT(シグナル伝達兼転写活性化因子)はサイトカイン調節の情報伝達において重要な役割を果たしており、細胞の成長や分化,細胞死を調節している。JAKは、細胞内非受容体型チロシンキナーゼのファミリーであり、このファミリーにはJAK1、JAK2、JAK3、およびTyk2の4つのプロテインキナーゼが含まれる。また、STATタンパクは、STAT1、STAT2、STAT3、STAT4、STAT5A、STAT5B、STAT6の7つあることが知られている。
JAK (Janus kinase) and STAT (signal transduction and transcriptional activator) play an important role in information transduction of cytokine regulation, regulating cell growth, differentiation, and cell death. JAKs are a family of intracellular, non-receptor tyrosine kinases that include four protein kinases, JAK1, JAK2, JAK3, and Tyk2. It is also known that there are seven STAT proteins: STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, and STAT6.
バリシチニブは、JAK1/2阻害薬であり、新型コロナウイルス感染症による肺炎に対し、抗ウイルス薬レムデシビルと併用して用いられる(非特許文献2)。
Baricitinib is a JAK1/2 inhibitor and is used in combination with the antiviral drug remdesivir for pneumonia caused by new coronavirus infection (Non-Patent Document 2).
ルキソリチニブは、JAK1/2阻害薬であるが、新型コロナウイルス感染症によるサイトカインストームに対して有効性が確認できなかったことが報告されている(非特許文献3)。
Although ruxolitinib is a JAK1/2 inhibitor, it has been reported that its efficacy against cytokine storm caused by novel coronavirus infection could not be confirmed (Non-Patent Document 3).
フェドラチニブは、JAK2選択的阻害薬であるが、ウェルニッケ脳症の副作用が報告されており(非特許文献4)、COVID-19などに起因するサイトカインストームの治療薬としても承認されていない。
Fedratinib is a JAK2 selective inhibitor, but side effects of Wernicke encephalopathy have been reported (Non-Patent Document 4), and it has not been approved as a therapeutic drug for cytokine storm caused by COVID-19.
前記一般式[1]で示される化合物は、JAK2選択的阻害薬であることが報告されている(特許文献1~3)。しかしながら、一般式[1]で示される化合物が、STAT3阻害活性やIL-17産生阻害活性を示すこと、更にサイトカインストームを抑制することはこれまでに報告されていない。
It has been reported that the compound represented by the general formula [1] is a JAK2 selective inhibitor (Patent Documents 1 to 3). However, it has not been reported that the compound represented by the general formula [1] exhibits STAT3 inhibitory activity or IL-17 production inhibitory activity and further suppresses cytokine storm.
本発明の主目的は、新規なサイトカインストーム抑制剤を提供することにある。
The main purpose of the present invention is to provide a novel cytokine storm inhibitor.
本発明として、次の(I)又は(II)のいずれかの場合である、次の一般式[1]で表される化合物(以下、「本発明化合物」という。)又はその医薬上許容される塩を有効成分として含有するサイトカインストーム抑制剤を挙げることができる。
(I)
Xは、CH又はNを表す。
R1は、ハロゲンを表す。
R2は、
(1)H、
(2)ハロゲン、
(3)シアノ、
(4)次の一般式[2]で表される基、 As the present invention, a compound represented by the following general formula [1] (hereinafter referred to as "the compound of the present invention") or a pharmaceutically acceptable Cytokine storm inhibitors containing a salt as an active ingredient can be mentioned.
(I)
X represents CH or N;
R 1 represents halogen.
R2 is
(1) H,
(2) halogen,
(3) cyano,
(4) a group represented by the following general formula [2],
Xは、CH又はNを表す。
R1は、ハロゲンを表す。
R2は、
(1)H、
(2)ハロゲン、
(3)シアノ、
(4)次の一般式[2]で表される基、 As the present invention, a compound represented by the following general formula [1] (hereinafter referred to as "the compound of the present invention") or a pharmaceutically acceptable Cytokine storm inhibitors containing a salt as an active ingredient can be mentioned.
X represents CH or N;
R 1 represents halogen.
R2 is
(1) H,
(2) halogen,
(3) cyano,
(4) a group represented by the following general formula [2],
(5)次の一般式[3]で表される基、
(5) a group represented by the following general formula [3],
(6)次の一般式[8]で表される基、
(6) a group represented by the following general formula [8],
(7)次の一般式[9]で表される基、
(7) a group represented by the following general formula [9],
(8)-ORP(RPは、ヒドロキシ、ジアルキルアミノ、アルコキシ、テトラヒドロフラニル、及びシクロアルキルからなる群から選択される基で置換されていてもよいアルキル、又は、ヒドロキシで置換されていてもよく、1個のOを含んでいてもよい飽和環式基を表す。)、又は
(9)シアノ、ハロゲン、ヒドロキシ、アルコキシ、アルキルカルボニル、カルバモイル、アルキル、シクロアルキル、(シクロアルキル)アルキル、アラルキル、ヒドロキシカルボニル及びアルコキシアルキルからなる群から選択される1若しくは2個の基で置換されていてもよいヘテロアリールを表す。
R3は、H又はヒドロキシを表す。
R4は、H又はアルキルを表す。
R5は、H又はアルキルを表す。
(8) —OR P (R P is alkyl optionally substituted by a group selected from the group consisting of hydroxy, dialkylamino, alkoxy, tetrahydrofuranyl, and cycloalkyl, or optionally substituted by hydroxy represents a saturated cyclic group optionally containing one O.), or (9) cyano, halogen, hydroxy, alkoxy, alkylcarbonyl, carbamoyl, alkyl, cycloalkyl, (cycloalkyl)alkyl, aralkyl , represents heteroaryl optionally substituted with one or two groups selected from the group consisting of hydroxycarbonyl and alkoxyalkyl.
R3 represents H or hydroxy.
R 4 represents H or alkyl.
R5 represents H or alkyl.
(II)
Xは、-CRAを表す。
RAは、次の一般式[10]で表される基を表す。
(式中、*は、前記と同義である。RBは、(a)アルキル、シクロアルキル、(シクロアルキル)アルキル、及びアルコキシアルキルからなる群から選択される1若しくは2個の基で置換されていてもよいアミノ、(b)アルコキシ、(c)ヒドロキシ、又は(d)飽和環状アミノ基を表す。)
R1は、ハロゲンを表す。
R2は、Hを表す。
R3は、H又はヒドロキシを表す。
R4は、H又はアルキルを表す。
R5は、H又はアルキルを表す。 (II)
X represents -CR A.
RA represents a group represented by the following general formula [10].
(wherein * is as defined above. RB is (a) substituted with one or two groups selected from the group consisting of alkyl, cycloalkyl, (cycloalkyl)alkyl, and alkoxyalkyl; optionally amino, (b) alkoxy, (c) hydroxy, or (d) saturated cyclic amino group.)
R 1 represents halogen.
R2 represents H;
R3 represents H or hydroxy.
R 4 represents H or alkyl.
R5 represents H or alkyl.
Xは、-CRAを表す。
RAは、次の一般式[10]で表される基を表す。
R1は、ハロゲンを表す。
R2は、Hを表す。
R3は、H又はヒドロキシを表す。
R4は、H又はアルキルを表す。
R5は、H又はアルキルを表す。 (II)
X represents -CR A.
RA represents a group represented by the following general formula [10].
R 1 represents halogen.
R2 represents H;
R3 represents H or hydroxy.
R 4 represents H or alkyl.
R5 represents H or alkyl.
本発明化合物の中で、一般式[1]で表される化合物であって、次の[i]又は[ii]のいずれかの場合である化合物、又はその医薬上許容される塩が好ましい。
[i]
XがCH又はN、
R2が、
(1)次の一般式[11]で表される基、
(式中、*は、前記と同義である。RF1、RG1は、同一又は異なって、(a)H、(b)ヒドロキシ、アミノ、ジアルキルアミノ、飽和環状アミノ基、アルキルカルボニルアミノ、アルキルスルホニルアミノ、アリール、アルキルで置換されていてもよいヘテロアリール、テトラヒドロフラニル、及びカルバモイルからなる群から選択される1若しくは2個の基で置換されていてもよいアルキル、(c)アルキルカルボニル、(d)アルキルスルホニル、(e)カルバモイル、若しくは(f)アルキルで置換されていてもよいヘテロアリールを表すか、又は、RF1とRG1が隣接するNと一緒になって、飽和環状アミノ基を表す。かかる飽和環状アミノ基は、(a)ハロゲン、(b)シアノ、(c)ヒドロキシ、(d)ヒドロキシ、アルコキシ、アミノ、アルコキシカルボニルアミノ、アルキルスルホニルアミノ、及びアルキルカルボニルアミノからなる群から選択される1若しくは2個の基で置換されていてもよいアルキル、(e)シクロアルキル、(f)ハロアルキル、(g)アルコキシ、(h)オキソ、(i)次の一般式[4]で表される基、
(式中、*、RHは、前記と同義である。)、(j)次の一般式[5]で表される基、
(式中、*、RI、RJは、前記と同義である。)、(k)次の一般式[6]で表される基、
(式中、*、RKは、前記と同義である。)、及び(l)ヒドロキシで置換されていてもよい飽和環状アミノ基からなる群から選択される1又は2個の基で置換されていてもよい。)、
(2)次の一般式[8]で表される基、
(式中、*、RLは、前記と同義である。)、
(3)次の一般式[9]で表される基、
(式中、*、RM、RN、ROは、前記と同義である。)、
(4)-ORP1(式中、RP1は、ヒドロキシ、ジアルキルアミノ、アルコキシ、テトラヒドロフラニル、及びシクロアルキルからなる群から選択される基で置換されていてもよいアルキルを表す。)、又は
(5)シアノ、ハロゲン、ヒドロキシ、アルコキシ、アルキルカルボニル、カルバモイル、アルキル、シクロアルキル、(シクロアルキル)アルキル、アラルキル、ヒドロキシカルボニル及びアルコキシアルキルからなる群から選択される1若しくは2個の基で置換されていてもよいヘテロアリール。 Among the compounds of the present invention, preferred are compounds represented by the general formula [1] and satisfying either [i] or [ii] below, or pharmaceutically acceptable salts thereof.
[i]
X is CH or N,
R2 is
(1) a group represented by the following general formula [11],
(In the formula, * has the same definition as above. R F1 and R G1 are the same or different and are (a) H, (b) hydroxy, amino, dialkylamino, saturated cyclic amino group, alkylcarbonylamino, alkyl (c) alkylcarbonyl, ( d) alkylsulfonyl, (e) carbamoyl, or (f) heteroaryl optionally substituted with alkyl, or R F1 and R G1 together with adjacent N represent a saturated cyclic amino group; Such saturated cyclic amino groups are selected from the group consisting of (a) halogen, (b) cyano, (c) hydroxy, (d) hydroxy, alkoxy, amino, alkoxycarbonylamino, alkylsulfonylamino, and alkylcarbonylamino (e) cycloalkyl, (f) haloalkyl, (g) alkoxy, (h) oxo, (i) represented by the following general formula [4] group to be
(Wherein, * and RH are as defined above.), (j) a group represented by the following general formula [5],
(Wherein, *, R I and R J are as defined above.), (k) a group represented by the following general formula [6],
(Wherein, * and RK are as defined above.), and (l) substituted with one or two groups selected from the group consisting of a saturated cyclic amino group optionally substituted with hydroxy may be ),
(2) a group represented by the following general formula [8],
(Wherein, *, RL are as defined above.),
(3) a group represented by the following general formula [9],
(Wherein, *, R M , R N , and R O are as defined above.),
(4) —OR P1 (wherein R P1 represents alkyl optionally substituted with a group selected from the group consisting of hydroxy, dialkylamino, alkoxy, tetrahydrofuranyl, and cycloalkyl), or ( 5) substituted with 1 or 2 groups selected from the group consisting of cyano, halogen, hydroxy, alkoxy, alkylcarbonyl, carbamoyl, alkyl, cycloalkyl, (cycloalkyl)alkyl, aralkyl, hydroxycarbonyl and alkoxyalkyl; heteroaryl.
[i]
XがCH又はN、
R2が、
(1)次の一般式[11]で表される基、
(2)次の一般式[8]で表される基、
(3)次の一般式[9]で表される基、
(4)-ORP1(式中、RP1は、ヒドロキシ、ジアルキルアミノ、アルコキシ、テトラヒドロフラニル、及びシクロアルキルからなる群から選択される基で置換されていてもよいアルキルを表す。)、又は
(5)シアノ、ハロゲン、ヒドロキシ、アルコキシ、アルキルカルボニル、カルバモイル、アルキル、シクロアルキル、(シクロアルキル)アルキル、アラルキル、ヒドロキシカルボニル及びアルコキシアルキルからなる群から選択される1若しくは2個の基で置換されていてもよいヘテロアリール。 Among the compounds of the present invention, preferred are compounds represented by the general formula [1] and satisfying either [i] or [ii] below, or pharmaceutically acceptable salts thereof.
[i]
X is CH or N,
R2 is
(1) a group represented by the following general formula [11],
(2) a group represented by the following general formula [8],
(3) a group represented by the following general formula [9],
(4) —OR P1 (wherein R P1 represents alkyl optionally substituted with a group selected from the group consisting of hydroxy, dialkylamino, alkoxy, tetrahydrofuranyl, and cycloalkyl), or ( 5) substituted with 1 or 2 groups selected from the group consisting of cyano, halogen, hydroxy, alkoxy, alkylcarbonyl, carbamoyl, alkyl, cycloalkyl, (cycloalkyl)alkyl, aralkyl, hydroxycarbonyl and alkoxyalkyl; heteroaryl.
[ii]
Xが、-CRA、
RAが、次の一般式[10]で表される基、
(式中、*、RBは、前記と同義である。)
R2がH。 [ii]
X is -CR A ,
R A is a group represented by the following general formula [10],
( Wherein , * and RB are as defined above.)
R2 is H;
Xが、-CRA、
RAが、次の一般式[10]で表される基、
R2がH。 [ii]
X is -CR A ,
R A is a group represented by the following general formula [10],
R2 is H;
本発明化合物の中で、
XがCHであり、
R2が、
(1)次の一般式[11]で表される基、
(式中、*、RF1、RG1は、前記と同義である。)、
(2)次の一般式[8]で表される基、
(式中、*、RLは、前記と同義である。)、
(3)次の一般式[9]で表される基、
(式中、*、RM、RN、ROは、前記と同義である。)、
(4)-ORP1(式中、RP1は、前記と同義である。)、又は
(5)シアノ、ハロゲン、ヒドロキシ、アルコキシ、アルキルカルボニル、カルバモイル、アルキル、シクロアルキル、(シクロアルキル)アルキル、アラルキル、ヒドロキシカルボニル及びアルコキシアルキルからなる群から選択される1若しくは2個の基で置換されていてもよいヘテロアリールである、本発明化合物又はその医薬上許容される塩がさらに好ましい。 Among the compounds of the present invention,
X is CH,
R2 is
(1) a group represented by the following general formula [11],
(Wherein, *, R F1 and R G1 are as defined above.),
(2) a group represented by the following general formula [8],
(Wherein, *, RL are as defined above.),
(3) a group represented by the following general formula [9],
(Wherein, *, R M , R N , and R O are as defined above.),
(4) —OR P1 (wherein R P1 is as defined above), or (5) cyano, halogen, hydroxy, alkoxy, alkylcarbonyl, carbamoyl, alkyl, cycloalkyl, (cycloalkyl)alkyl, Further preferred are compounds of the present invention or pharmaceutically acceptable salts thereof which are heteroaryl optionally substituted with one or two groups selected from the group consisting of aralkyl, hydroxycarbonyl and alkoxyalkyl.
XがCHであり、
R2が、
(1)次の一般式[11]で表される基、
(2)次の一般式[8]で表される基、
(3)次の一般式[9]で表される基、
(4)-ORP1(式中、RP1は、前記と同義である。)、又は
(5)シアノ、ハロゲン、ヒドロキシ、アルコキシ、アルキルカルボニル、カルバモイル、アルキル、シクロアルキル、(シクロアルキル)アルキル、アラルキル、ヒドロキシカルボニル及びアルコキシアルキルからなる群から選択される1若しくは2個の基で置換されていてもよいヘテロアリールである、本発明化合物又はその医薬上許容される塩がさらに好ましい。 Among the compounds of the present invention,
X is CH,
R2 is
(1) a group represented by the following general formula [11],
(2) a group represented by the following general formula [8],
(3) a group represented by the following general formula [9],
(4) —OR P1 (wherein R P1 is as defined above), or (5) cyano, halogen, hydroxy, alkoxy, alkylcarbonyl, carbamoyl, alkyl, cycloalkyl, (cycloalkyl)alkyl, Further preferred are compounds of the present invention or pharmaceutically acceptable salts thereof which are heteroaryl optionally substituted with one or two groups selected from the group consisting of aralkyl, hydroxycarbonyl and alkoxyalkyl.
本発明化合物の中で、具体的に次の化合物又はその医薬上許容される塩が好ましい。
(1)(S)-4-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}ピペラジン-2-オン、
(2)N-{(S)-1-[2-{[(S)-1-(4-フルオロフェニル)エチル]アミノ}-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル]ピロリジン-3-イル}アセトアミド、
(3)(S)-6-(3,3-ジフルオロアゼチジン-1-イル)-N2-[1-(4-フルオロフェニル)エチル]-N4-(ピラジン-2-イル)ピリミジン-2,4-ジアミン、
(4)(S)-N2-[1-(4-フルオロフェニル)エチル]-4-(1-メチル-1H-ピラゾール-4-イル)-N6-(ピラジン-2-イル)ピリジン-2,6-ジアミン、
(5)(S)-N2’-[1-(4-フルオロフェニル)エチル]-N6’-(ピラジン-2-イル)-3,4’-ビピリジン-2’,6’-ジアミン、
(6)(S)-N2’-[1-(4-フルオロフェニル)エチル]-6-メトキシ-N6’-(ピラジン-2-イル)-3,4’-ビピリジン-2’,6’-ジアミン、
(7)(S)-2’-[1-(4-フルオロフェニル)エチルアミノ]-6’-(ピラジン-2-イルアミノ)-3,4’-ビピリジン-6-オール、
(8)(S)-N2-[1-(4-フルオロフェニル)エチル]-4-(オキサゾール-5-イル)-N6-(ピラジン-2-イル)ピリジン-2,6-ジアミン、
(9)(S)-6-クロロ-N2-[1-(4-フルオロフェニル)エチル]-N4-(ピラジン-2-イル)ピリミジン-2,4-ジアミン、
(10)(S)-N2-[1-(4-フルオロフェニル)エチル]-6-[4-(メチルスルホニル)フェニル]-N4-(ピラジン-2-イル)ピリミジン-2,4-ジアミン、
(11)(S)-N2-[1-(4-フルオロフェニル)エチル]-N4-(ピラジン-2-イル)-6-(1H-ピラゾール-4-イル)ピリミジン-2,4-ジアミン、
(12)(S)-2-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリジン-4-イルオキシ}エタノール、
(13)(S)-N2-[1-(4-フルオロフェニル)エチル]-N4-(ピラジン-2-イル)-6-(ピリジン-3-イル)ピリミジン-2,4-ジアミン、
(14)(S)-N2-[1-(4-フルオロフェニル)エチル]-N4-(ピラジン-2-イル)-6-(ピリジン-2-イル)ピリミジン-2,4-ジアミン、
(15)(S)-N2-[1-(4-フルオロフェニル)エチル]-N4-(ピラジン-2-イル)-6-(ピリジン-4-イル)ピリミジン-2,4-ジアミン、
(16)(S)-1-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}ピロリジン-2-オン、
(17)(S)-4-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}ピペラジン-2,6-ジオン、
(18)(S)-1-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}テトラヒドロピリミジン-2(1H)-オン、
(19)(S)-N2-[1-(4-フルオロフェニル)エチル]-N4-(ピラジン-2-イル)-6-(ピロリジン-1-イル)ピリミジン-2,4-ジアミン、
(20)(S)-N2-[1-(4-フルオロフェニル)エチル]-6-モルホリノ-N4-(ピラジン-2-イル)ピリミジン-2,4-ジアミン、
(21)(S)-1-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}イミダゾリジン-2-オン、
(22)(S)-N2-[1-(4-フルオロフェニル)エチル]-6-(オキサゾール-5-イル)-N4-(ピラジン-2-イル)ピリミジン-2,4-ジアミン、
(23)(S)-N2-[1-(4-フルオロフェニル)エチル]-6-(6-メトキシピリジン-3-イル)-N4-(ピラジン-2-イル)ピリミジン-2,4-ジアミン、
(24)(S)-N2-[1-(4-フルオロフェニル)エチル]-N4-(ピラジン-2-イル)-6-(1H-ピラゾール-3-イル)ピリミジン-2,4-ジアミン、
(25)(S)-4-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}ピリジン-2-オール、
(26)(S)-5-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}ピリジン-2-オール、
(27)N-((R)-1-{2-[(S)-1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}ピロリジン-3-イル)アセトアミド、
(28)(S)-N2-[1-(4-フルオロフェニル)エチル]-N6-(ピラジン-2-イル)-4-(1H-ピラゾール-4-イル)ピリジン-2,6-ジアミン、
(29)(S)-N2-[1-(4-フルオロフェニル)エチル]-N6-(ピラジン-2-イル)-4-(1H-ピラゾール-3-イル)ピリジン-2,6-ジアミン、
(30)(S)-N2-[1-(4-フルオロフェニル)エチル]-6-[3-(メチルスルホニル)フェニル]-N4-(ピラジン-2-イル)ピリミジン-2,4-ジアミン、
(31)(S)-N2-[1-(4-フルオロフェニル)エチル]-4-[4-(メチルスルホニル)フェニル]-N6-(ピラジン-2-イル)ピリジン-2,6-ジアミン、
(32)(S)-N2-[1-(4-フルオロフェニル)エチル]-4-(1-イソプロピル-1H-ピラゾール-4-イル)-N6-(ピラジン-2-イル)ピリジン-2,6-ジアミン、
(33)N-{(S)-1-[2-{[(S)-1-(4-フルオロフェニル)エチル]アミノ}-6-(ピラジン-2-イルアミノ)ピリジン-4-イル]ピロリジン-3-イル}アセトアミド、
(34)(S)-N2-[1-(4-フルオロフェニル)エチル]-4-モルホリノ-N6-(ピラジン-2-イル)ピリジン-2,6-ジアミン、
(35)(S)-N2-[1-(4-フルオロフェニル)エチル]-N6-(ピラジン-2-イル)-4-チオモルホリノピリジン-2,6-ジアミン、
(36)(S)-3-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリジン-4-イル}プロパン-1-オール、
(37)(S)-N-(1-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}アゼチジン-3-イル)アセトアミド、
(38)(S)-6-(アゼチジン-1-イル)-N2-[1-(4-フルオロフェニル)エチル]-N4-(ピラジン-2-イル)ピリミジン-2,4-ジアミン、
(39)(S)-6-(3-フルオロアゼチジン-1-イル)-N2-[1-(4-フルオロフェニル)エチル]-N4-(ピラジン-2-イル)ピリミジン-2,4-ジアミン、
(40)(S)-1-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}アゼチジン-2-オン、
(41)(S)-4-(1-エチル-1H-ピラゾール-4-イル)-N2-[1-(4-フルオロフェニル)エチル]-N6-(ピラジン-2-イル)ピリジン-2,6-ジアミン、
(42)(S)-N2-[1-(4-フルオロフェニル)エチル]-4-(1-メチル-1H-ピラゾール-5-イル)-N6-(ピラジン-2-イル)ピリジン-2,6-ジアミン、
(43)(S)-4-(1-(シクロプロピルメチル)-1H-ピラゾール-4-イル)-N2-[1-(4-フルオロフェニル)エチル]-N6-(ピラジン-2-イル)ピリジン-2,6-ジアミン、
(44)(S)-N2-[1-(4-フルオロフェニル)エチル]-N4-(ピラジン-2-イル)-6-(チアゾール-5-イル)ピリミジン-2,4-ジアミン、
(45)1-{2-[(S)-1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}ピロリジン-3-オール
(46)(S)-N2-[1-(4-フルオロフェニル)エチル]-N4-(5-メチルチアゾール-2-イル)-N6-(ピラジン-2-イル)ピリミジン-2,4,6-トリアミン、
(47)(S)-N2-[1-(4-フルオロフェニル)エチル]-N6-(ピラジン-2-イル)-4,5’-ビピリミジン-2,6-ジアミン、
(48)(S)-N2-[1-(4-フルオロフェニル)エチル]-6-(2-メトキシチアゾール-5-イル)-N4-(ピラジン-2-イル)ピリミジン-2,4-ジアミン、
(49)(S)-N2-[1-(4-フルオロフェニル)エチル]-N4-(ピラジン-2-イル)-6-(チアゾール-2-イル)ピリミジン-2,4-ジアミン、
(50)(S)-5-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}ピコリノニトリル、
(51)(S)-1-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}ピペリジン-4-カルボキサミド、(52) (S)-5-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}ピコリンアミド、
(53)4-{2-[(S)-1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}ピペラジン-2-カルボキサミド、
(54)6-(3-アミノピロリジン-1-イル)-N2-[(S)-1-(4-フルオロフェニル)エチル]-N4-(ピラジン-2-イル)ピリミジン-2,4-ジアミン、
(55)N-(1-{2-[(S)-1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}ピロリジン-3-イル)メタンスルホンアミド、
(56)(S)-2-({2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}(2-ヒドロキシエチル)アミノ)エタン-1-オール、
(57)(S)-N4-[2-(ジメチルアミノ)エチル]-N2-[1-(4-フルオロフェニル)エチル]-N6-(ピラジン-2-イル)ピリミジン-2,4,6-トリアミン、
(58)1-{2-[(S)-1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}ピペリジン-3-カルボキサミド、
(59)(S)-1-{2-[(S)-1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}ピロリジン-2-カルボキサミド、
(60)(S)-N2-[1-(4-フルオロフェニル)エチル]-6-[4-(メチルスルホニル)ピペラジン-1-イル]-N4-(ピラジン-2-イル)ピリミジン-2,4-ジアミン、
(61)(S)-N2-[1-(4-フルオロフェニル)エチル]-N4-(ピラジン-2-イル)-6-(1H-ピロール-3-イル)ピリミジン-2,4-ジアミン、
(62)(R)-1-{2-[(S)-1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}-4-ヒドロキシピロリジン-2-オン、
(63)N2-[(S)-1-(4-フルオロフェニル)エチル]-N4-(ピラジン-2-イル)-N6-[(テトラヒドロフラン-2-イル)メチル]ピリミジン-2,4,6-トリアミン
(64)((S)-1-{2-[(S)-1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}ピロリジン-2-イル)メタノール、
(65)((R)-1-{2-[(S)-1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}ピロリジン-2-イル)メタノール、
(66)(S)-1-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}ピペリジン-4-オール、
(67)(S)-1-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}アゼチジン-3-オール、
(68)1-{2-[(S)-1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}ピペリジン-3-オール、
(69)(S)-5-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}ニコチノニトリル、
(70)(S)-N2-[1-(4-フルオロフェニル)エチル]-N4-(ピラジン-2-イル)-6-(2H-テトラゾール-5-イル)ピリミジン-2,4-ジアミン、
(71)(S)-N4-(2-アミノエチル)-N2-[1-(4-フルオロフェニル)エチル]-N6-(ピラジン-2-イル)ピリミジン-2,4,6-トリアミン、
(72)(S)-N-(2-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イルアミノ}エチル)メタンスルホンアミド、
(73)(S)-N-(2-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イルアミノ}エチル)アセトアミド、
(74)(S)-2-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イルアミノ}アセトアミド、
(75)(S)-4-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}ベンズアミド、
(76)(S)-3-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}ベンゾニトリル、
(77)(S)-N2-[1-(4-フルオロフェニル)エチル]-6-(フラン-3-イル)-N4-(ピラジン-2-イル)ピリミジン-2,4-ジアミン、
(78)(S)-1-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}ピペリジン-4-カルボン酸エチル、
(79)(S)-5-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}ニコチンアミド、
(80)(S)-1-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}ピペリジン-4-カルボン酸、
(81)(S)-2-{2-[(S)-1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イルアミノ}-2-フェニルエタノール、
(82)(S)-2-{2-[(S)-1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イルアミノ}-3-フェニルプロパン-1-オール、
(83)(R)-2-{2-[(S)-1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イルアミノ}-4-メチルペンタン-1-オール、
(84)(S)-6-[2-(ジメチルアミノ)エトキシ]-N2-[1-(4-フルオロフェニル)エチル]-N4-(ピラジン-2-イル)ピリミジン-2,4-ジアミン、
(85)(S)-1-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}-1H-ピラゾール-4-カルボン酸、
(86)(S)-3-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}ベンズアミド、
(87)(S)-6-(ベンゾ[d]1,3-ジオキソール-5-イル)-N2-[1-(4-フルオロフェニル)エチル]-N4-(ピラジン-2-イル)ピリミジン-2,4-ジアミン、
(88)(S)-N2-[1-(4-フルオロフェニル)エチル]-6-(2-フルオロピリジン-4-イル)-N4-(ピラジン-2-イル)ピリミジン-2,4-ジアミン、
(89)N2-[(S)-1-(4-フルオロフェニル)エチル]-N4-(ピラジン-2-イル)-6-[(テトラヒドロフラン-2-イル)メトキシ]ピリミジン-2,4-ジアミン、
(90)(S)-2-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イルオキシ}エタノール、
(91)(S)-N2-[1-(4-フルオロフェニル)エチル]-N4-(ピラジン-2-イル)-N6-[2-(ピロリジン-1-イル)エチル]ピリミジン-2,4,6-トリアミン、
(92)(S)-3-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}イソニコチンアミド、
(93)(S)-3-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}イソニコチノニトリル、
(94)(S)-2-{2-[(S)-1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イルアミノ}-3-メチルブタン-1-オール、
(95)(S)-N2-[1-(4-クロロフェニル)エチル]-6-[4-(メチルスルホニル)ピペラジン-1-イル]-N4-(ピラジン-2-イル)ピリミジン-2,4-ジアミン、
(96)(1S,2S)-2-{2-[(S)-1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イルオキシ}シクロヘキサノール、
(97)(S)-N2-[1-(4-フルオロフェニル)エチル]-N4-[(5-メチルピラジン-2-イル)メチル]-N6-(ピラジン-2-イル)ピリミジン-2,4,6-トリアミン、
(98)(S)-N2-[1-(4-フルオロフェニル)エチル]-N4-(フラン-2-イルメチル)-N6-(ピラジン-2-イル)ピリミジン-2,4,6-トリアミン、
(99)(S)-N2-[1-(4-フルオロフェニル)エチル]-N4-(ピラジン-2-イル)-N6-[1-(ピリジン-3-イル)エチル]ピリミジン-2,4,6-トリアミン、
(100)(S)-1-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}-4-(ヒドロキシメチル)ピペリジン-4-オール、
(101)(S)-N2-[1-(4-フルオロフェニル)エチル]-N4-(ピラジン-2-イル)-N6-(ピリジン-2-イルメチル)ピリミジン-2,4,6-トリアミン、
(102)(S)-N2-[1-(4-フルオロフェニル)エチル]-N4-(ピラジン-2-イル)-N6-(ピリジン-3-イルメチル)ピリミジン-2,4,6-トリアミン、
(103)(S)-N2-[1-(4-フルオロフェニル)エチル]-N4-(ピラジン-2-イル)-N6-(ピリジン-4-イルメチル)ピリミジン-2,4,6-トリアミン、
(104)(S)-2-{2-[(S)-1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イルアミノ}-3-ヒドロキシプロパンアミド、
(105)(3S,4S)-1-{2-[(S)-1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}ピロリジン-3,4-ジオール、
(106)N2-[(S)-1-(4-フルオロフェニル)エチル]-N4-(ピラジン-2-イル)-6-(1,4-ジオキサ-8-アザスピロ[4.5]デカン-8-イル)ピリミジン-2,4-ジアミン、
(107)(S)-8-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}-1,3-ジオキソ-8-アザスピロ[4.5]デカン-2-オン、
(108)(S)-4-(1-ベンジル-1H-ピラゾール-4-イル)-N2-[1-(4-フルオロフェニル)エチル]-N6-(ピラジン-2-イル)ピリジン-2,6-ジアミン、
(109)(S)-N2-[1-(4-フルオロフェニル)エチル]-6-[4-(フェニルスルホニル)ピペラジン-1-イル]-N4-(ピラジン-2-イル)ピリミジン-2,4-ジアミン、
(110)(S)-4-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリジン-4-イル}ベンズアミド、
(111)(S)-N2-[1-(4-フルオロフェニル)エチル]-N6-(ピラジン-2-イル)-4-(1H-ピロール-3-イル)ピリジン-2,6-ジアミン、
(112)(S)-N2-[1-(4-フルオロフェニル)エチル]-N6-(ピラジン-2-イル)ピリジン-2,6-ジアミン、
(113)(S)-N2-[1-(4-フルオロフェニル)エチル]-6-(4-メチル-1H-イミダゾール-1-イル)-N4-(ピラジン-2-イル)ピリミジン-2,4-ジアミン、
(114)(S)-N2-[1-(4-フルオロフェニル)エチル]-4-(4-メトキシフェニル)-N6-(ピラジン-2-イル)ピリジン-2,6-ジアミン、
(115)(S)-4-(4-フルオロフェニル)-N2-[1-(4-フルオロフェニル)エチル]-N6-(ピラジン-2-イル)ピリジン-2,6-ジアミン、
(116)(S)-N2-[1-(4-フルオロフェニル)エチル]-4-メチル-N6-(ピラジン-2-イル)ピリジン-2,6-ジアミン、
(117)(S)-1-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}-N-(メチルスルホニル)ピペリジン-4-カルボキサミド、
(118)(S)-N2-[1-(4-フルオロフェニル)エチル]-4-(フラン-3-イル)-N6-(ピラジン-2-イル)ピリジン-2,6-ジアミン、
(119)(S)-N2-[1-(4-フルオロフェニル)エチル]-4-[4-(メチルスルホニル)ピペラジン-1-イル]-N6-(ピラジン-2-イル)ピリジン-2,6-ジアミン、
(120)(S)-1-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリジン-4-イル}-4-(ヒドロキシメチル)ピペリジン-4-オール、
(121)(S)-4-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリジン-4-イル}ベンゼンスルホンアミド、
(122)(S)-N2-[1-(4-フルオロフェニル)エチル]-4-メトキシ-N6-(ピラジン-2-イル)ピリジン-2,6-ジアミン、
(123)4-{2-[(1S)-1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリジン-4-イル}-1λ6,4-チオモルホリン-1,1-ジオン、
(124)(S)-1-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリジン-4-イル}ピペリジン-4-オール、
(125)(S)-1-(4-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリジン-4-イル}-1,4-ジアゼパン-1-イル)エタノン、
(126)(S)-N2-[1-(4-フルオロフェニル)エチル]-N6-(ピラジン-2-イル)-N4-(ピリミジン-2-イル)ピリジン-2,4,6-トリアミン、
(127)(S)-N2-[1-(4-フルオロフェニル)エチル]-N6-(ピラジン-2-イル)-N4-(ピリジン-2-イル)ピリジン-2,4,6-トリアミン、
(128)N2-[(S)-1-(4-フルオロフェニル)エチル]-N6-(ピラジン-2-イル)-4-(1,4-ジオキサ-8-アザスピロ[4.5]デカン-8-イル)ピリジン-2,6-ジアミン、
(129)(S)-2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)イソニコチン酸メチルエステル、
(130)(S)-4-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}-N-メチルベンゼンスルホンアミド、
(131)(S)-N2-[1-(4-フルオロフェニル)エチル]-4-(4-メチル-1H-イミダゾール-1-イル)-N6-(ピラジン-2-イル)ピリジン-2,6-ジアミン、
(132)(S)-N2-[1-(4-フルオロフェニル)エチル]-N4,N6-ジ(ピラジン-2-イル)ピリジン-2,4,6-トリアミン、
(133)(S)-4-(シクロプロピルメトキシ)-N2-[1-(4-フルオロフェニル)エチル]-N6-(ピラジン-2-イル)ピリジン-2,6-ジアミン、
(134)(S)-N2-[1-(4-フルオロフェニル)エチル]-N2-メチル-4-(1-メチル-1H-ピラゾール-4-イル)-N6-(ピラジン-2-イル)ピリジン-2,6-ジアミン、
(135)(S)-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリジン-4-イル}メタノール、
(136)(S)-2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)イソニコチン酸、
(137)(S)-N2-[1-(4-フルオロフェニル)エチル]-4-(2-メトキシエトキシ)-N6-(ピラジン-2-イル)ピリジン-2,6-ジアミン、
(138)(S)-2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-カルボニトリル
(139)(S)-2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)イソニコチノニトリル、
(140)(S)-2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)イソニコチンアミド、
(141)(S)-N2-[1-(4-フルオロフェニル)エチル]-6-(1,2,4-オキサジアゾール-3-イル)-N4-(ピラジン-2-イル)ピリミジン-2,4-ジアミン、
(142)(S)-N2-[1-(4-フルオロフェニル)エチル]-4-(1,2,4-オキサジアゾール-3-イル)-N6-(ピラジン-2-イル)ピリジン-2,6-ジアミン、
(143)(S)-2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ニコチン酸メチル、
(144)(S)-2-[1-(4-フルオロフェニル)エチルアミノ]-N,N-ジメチル-6-(ピラジン-2-イルアミノ)イソニコチンアミド、
(145)(S)-N-[2-(ジメチルアミノ)エチル]-2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)イソニコチンアミド、
(146)(S)-N-t-ブチル-2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)イソニコチンアミド、
(147)(S)-N-エチル-2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)イソニコチンアミド、
(148)(S)-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリジン-4-イル}[4-(メタンスルホニル)ピペラジン-1-イル]メタノン、
(149)(S)-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリジン-4-イル}(ピロリジン-1-イル)メタノン、
(150)(S)-2-[1-(4-フルオロフェニル)エチルアミノ]-N-イソプロピル-6-(ピラジン-2-イルアミノ)イソニコチンアミド、
(151)(S)-1-{2-[(S)-1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}アゼチジン-2-カルボキサミド、
(152)(S)-N2-[1-(4-フルオロフェニル)エチル]-N6-(ピラジン-2-イル)-4-(テトラヒドロ-2H-ピラン-4-イルオキシ)ピリジン-2,6-ジアミン、
(153)(S)-1-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}アゼチジン-3-カルボキサミド、
(154)(S)-2-[1-(4-フルオロフェニル)エチルアミノ]-N-(2-ヒドロキシエチル)-6-(ピラジン-2-イルアミノ)イソニコチンアミド、
(155)(S)-2-[1-(4-フルオロフェニル)エチルアミノ]-N-メチル-6-(ピラジン-2-イルアミノ)イソニコチンアミド、
(156)(S)-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリジン-4-イル}(モルホリノ)メタノン、
(157)(S)-N-ベンジル-2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)イソニコチンアミド、
(158)(S)-N-シクロプロピル-2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)イソニコチンアミド、
(159)(S)-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリジン-4-イル})(4-メチルピペラジン-1-イル)メタノン、
(160)(S)-2-[1-(4-フルオロフェニル)エチルアミノ]-N-(2-メトキシエチル)-6-(ピラジン-2-イルアミノ)イソニコチンアミド、
(161)(S)-2-[1-(4-フルオロフェニル)エチルアミノ]-N-プロピル-6-(ピラジン-2-イルアミノ)イソニコチンアミド、
(162)(S)-N-シクロプロピルメチル-2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)イソニコチンアミド、
(163)(S)-N-シクロブチル-2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)イソニコチンアミド、
(164)(S)-N-ブチル-2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)イソニコチンアミド、
(165)(S)-2-[1-(4-フルオロフェニル)エチルアミノ]-N-イソブチル-6-(ピラジン-2-イルアミノ)イソニコチンアミド、
(166)(S)-2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)-N-(2,2,2,-トリフルオロエチル)イソニコチンアミド、
(167)(S)-2-[1-(4-フルオロフェニル)エチルアミノ]-N-(3-ヒドロキシプロピル)-6-(ピラジン-2-イルアミノ)イソニコチンアミド、
(168)(S)-N-(2-エトキシエチル)-2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)イソニコチンアミド、
(169)(S)-1-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}-N-メチルアゼチジン-3-カルボキサミド、
(170)(S)-N2-[1-(4-フルオロフェニル)エチル]-4-(メトキシメチル)-N6-(ピラジン-2-イル)ピリジン-2,6-ジアミン、
(171)(S)-1-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}-N,N-ジメチルアゼチジン-3-カルボキサミド、
(172)(S)-N-(1-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}アゼチジン-3-イル)メタンスルホンアミド、
(173)(S)-1-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}アゼチジン-3-カルボニトリル、
(174)2-(4-フルオロフェニル)-2-[4-(1-メチル-1H-ピラゾール-4-イル)-6-(ピラジン-2-イルアミノ)ピリジン-2-イルアミノ]エタノール、
(175)(S)-N-エチル-1-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}アゼチジン-3-カルボキサミド、
(176)(S)-N,N-ジエチル-1-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}アゼチジン-3-カルボキサミド、
(177)(S)-1-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリジン-4-イル}エタノン、
(178)(S)-N2-[1-(4-フルオロフェニル)エチル]-6-(3-メトキシアゼチジン-1-イル)-N4-(ピラジン-2-イル)ピリミジン-2,4-ジアミン、
(179)(S)-1-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}-3-メチルアゼチジン-3-オール、
(180)(S)-2-[1-(4-フルオロフェニル)エチルアミノ]-N-メチル-6-(ピラジン-2-イルアミノ)ニコチンアミド、
(181)(S)-2-[1-(4-フルオロフェニル)エチルアミノ]-N,N-ジメチル-6-(ピラジン-2-イルアミノ)ニコチンアミド、
(182)(S)-2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ニコチンアミド、
(183)(S)-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリジン-3-イル}(モルホリノ)メタノン、
(184)(S)-N-(シクロプロピルメチル)-2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ニコチンアミド、
(185)(S)-N-(1-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}アゼチジン-3-イル)エタンスルホンアミド、
(186)(S)-1-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}-N-イソプロピルアゼチジン-3-カルボキサミド、
(187)(S)-1-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}-3-(トリフルオロメチル)アゼチジン-3-オール、
(188)(S)-(1-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}アゼチジン-3-イル)(ピロリジン-1-イル)メタノン、
(189)(S)-1-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}-N-(2-メトキシエチル)アゼチジン-3-カルボキサミド、
(190)(S)-(1-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}アゼチジン-3-イル)(ピペリジン-1-イル)メタノン、
(191)(S)-(1-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}アゼチジン-3-イル)(モルホリノ)メタノン、
(192)(S)-N-(シクロプロピル)-1-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}アゼチジン-3-カルボキサミド、
(193)(S)-N-(シクロプロピルメチル)-1-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}アゼチジン-3-カルボキサミド、
(194)(S)-1-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}-N-(2-ヒドロキシエチル)アゼチジン-3-カルボキサミド、
(195)(S)-3-シクロプロピル-1-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}アゼチジン-3-オール、
(196)(S)-1-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}-3-イソプロピルアゼチジン-3-オール、
(197)(S)-1-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリジン-4-イル}アゼチジン-3-オール、
(198)(S)-3-シクロプロピル-1-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリジン-4-イル}アゼチジン-3-オール、
(199)(S)-1-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリジン-4-イル}-3-イソプロピルアゼチジン-3-オール、
(200)(S)-1-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリジン-4-イル}-3-メチルアゼチジン-3-オール、
(201)(S)-1-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリジン-4-イル}-3-(トリフルオロメチル)アゼチジン-3-オール、
(202)(S)-4-(3,3-ジフルオロアゼチジン-1-イル)-N2-[1-(4-フルオロフェニル)エチル]-N6-(ピラジン-2-イル)ピリジン-2,6-ジアミン、
(203)(S)-N-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリジン-4-イル}アセトアミド、
(204)(S)-N-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリジン-4-イル}メタンスルホンアミド、
(205)(S)-1-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリジン-4-イル}ウレア、
(206)(S)-4-(3-シクロプロピル-3-メトキシアゼチジン-1-イル)-N2-[1-(4-フルオロフェニル)エチル]-N6-(ピラジン-2-イル)ピリジン-2,6-ジアミン、
(207)(S)-N2-[1-(4-フルオロフェニル)エチル]-4-(3-イソプロピル-3-メトキシアゼチジン-1-イル)-N6-(ピラジン-2-イル)ピリジン-2,6-ジアミン、
(208)(S)-N2-[1-(4-フルオロフェニル)エチル]-4-(3-メトキシ-3-メチルアゼチジン-1-イル)-N6-(ピラジン-2-イル)ピリジン-2,6-ジアミン、
(209)(S)-N2-[1-(4-フルオロフェニル)エチル]-4-(1-メチル-1H-ピラゾール-4-イル)-N6-(5-メチルピラジン-2-イル)ピリジン-2,6-ジアミン、
(210)(S)-N2-[1-(4-フルオロフェニル)エチル]-4-[1-(メタンスルホニル)ピペリジン-4-イル]-N6-(ピラジン-2-イル)ピリジン-2,6-ジアミン、
(211)(S)-N-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリジン-4-イル}プロピオンアミド、
(212)(S)-N2-[1-(4-フルオロフェニル)エチル]-4-[1-(2-メトキシエチル)-1H-ピラゾール-4-イル]-N6-(ピラジン-2-イル)ピリジン-2,6-ジアミン、
(213)(S)-4-(1-シクロプロピル-1H-ピラゾール-4-イル)-N2-[1-(4-フルオロフェニル)エチル]-N6-(ピラジン-2-イル)ピリジン-2,6-ジアミン、
(214)(S)-N2-[1-(4-フルオロフェニル)エチル]-4-[1-(メトキシメチル)-1H-ピラゾール-4-イル]-N6-(ピラジン-2-イル)ピリジン-2,6-ジアミン、
(215)(S)-6-[3-(ジメチルアミノ)アゼチジン-1-イル]-N2-[1-(4-フルオロフェニル)エチル]-N4-(ピラジン-2-イル)ピリミジン-2,4-ジアミン、
(216)(S)-N2-[1-(4-フルオロフェニル)エチル]-6-[3-(メチルアミノ)アゼチジン-1-イル]-N4-(ピラジン-2-イル)ピリミジン-2,4-ジアミン、
(217)(S)-N2-[1-(4-フルオロフェニル)エチル]-N4-(ピラジン-2-イル)-6-[3-(ピロリジン-1-イル)アゼチジン-1-イル]ピリミジン-2,4-ジアミン、
(218)(S)-N2-[1-(4-フルオロフェニル)エチル]-6-(3-モルホリノアゼチジン-1-イル)-N4-(ピラジン-2-イル)ピリミジン-2,4-ジアミン、
(219)(S)-N2-[1-(4-フルオロフェニル)エチル]-6-[3-(4-メチルピペラジン-1-イル)アゼチジン-1-イル]-N4-(ピラジン-2-イル)ピリミジン-2,4-ジアミン、
(220)(S)-(1-{1-[2-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}アゼチジン-3-イル)ピペリジン-4-オール、
(221)4-{2-[(1S)-1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}-1λ6,4-チオモルホリン-1,1-ジオン、
(222)(S)-1-(1-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}アゼチジン-3-イル)ウレア、
(223)(S)-(1-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}アゼチジン-3-イル)メタノール、
(224)(S)-(1-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}アゼチジン-3-イル)メチルカルバミン酸t-ブチル、
(225)(S)-6-[3-(アミノメチル)アゼチジン-1-イル]-N2-[1-(4-フルオロフェニル)エチル]-N4-(ピラジン-2-イル)ピリミジン-2,4-ジアミン、
(226)(S)-N-[(1-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}アゼチジン-3-イル)メチル]エタンスルホンアミド、
(227)(S)-N-[(1-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}アゼチジン-3-イル)メチル]アセトアミド、
(228)(S)-N2-[1-(4-フルオロフェニル)エチル]-4-[3-モルホリノアゼチジン-1-イル]-N6-(ピラジン-2-イル)ピリジン-2,6-ジアミン、
(229)(S)-1-(1-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリジン-4-イル}アゼチジン-3-イル)ピペリジン-4-オール。
(230)(S)-N2-[1-(4-フルオロフェニル)エチル]-4-(1-メチル-1H-ピラゾール-4-イル)-N6-(ピラジン-2-イル)ピリジン-2,6-ジアミン マレイン酸塩(以下、「化合物A」)。 Among the compounds of the present invention, specifically the following compounds or pharmaceutically acceptable salts thereof are preferred.
(1) (S)-4-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}piperazin-2-one,
(2) N-{(S)-1-[2-{[(S)-1-(4-fluorophenyl)ethyl]amino}-6-(pyrazin-2-ylamino)pyrimidin-4-yl]pyrrolidine -3-yl}acetamide,
(3) (S)-6-(3,3-difluoroazetidin-1-yl)-N 2 -[1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)pyrimidine- 2,4-diamine,
(4) (S)—N 2 -[1-(4-fluorophenyl)ethyl]-4-(1-methyl-1H-pyrazol-4-yl)-N 6 -(pyrazin-2-yl)pyridine- 2,6-diamine,
(5) (S)—N 2′ -[1-(4-fluorophenyl)ethyl]-N 6′ -(pyrazin-2-yl)-3,4′-bipyridine-2′,6′-diamine,
(6) (S)—N 2′ -[1-(4-fluorophenyl)ethyl]-6-methoxy-N 6′ -(pyrazin-2-yl)-3,4′-bipyridine-2′,6 '-diamine,
(7) (S)-2′-[1-(4-fluorophenyl)ethylamino]-6′-(pyrazin-2-ylamino)-3,4′-bipyridin-6-ol,
(8) (S)—N 2 -[1-(4-fluorophenyl)ethyl]-4-(oxazol-5-yl)-N 6 -(pyrazin-2-yl)pyridine-2,6-diamine,
(9) (S)-6-chloro-N 2 -[1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)pyrimidine-2,4-diamine,
(10) (S)—N 2 -[1-(4-fluorophenyl)ethyl]-6-[4-(methylsulfonyl)phenyl]-N 4 -(pyrazin-2-yl)pyrimidine-2,4- Diamine,
(11) (S)-N 2 -[1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)-6-(1H-pyrazol-4-yl)pyrimidine-2,4- Diamine,
(12) (S)-2-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyridin-4-yloxy}ethanol,
(13) (S)—N 2 -[1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)-6-(pyridin-3-yl)pyrimidine-2,4-diamine,
(14) (S)—N 2 -[1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)-6-(pyridin-2-yl)pyrimidine-2,4-diamine,
(15) (S)-N 2 -[1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)-6-(pyridin-4-yl)pyrimidine-2,4-diamine,
(16) (S)-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}pyrrolidin-2-one,
(17) (S)-4-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}piperazine-2,6-dione,
(18) (S)-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}tetrahydropyrimidin-2(1H)-one,
(19) (S)-N 2 -[1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)-6-(pyrrolidin-1-yl)pyrimidine-2,4-diamine,
(20) (S)—N 2 -[1-(4-fluorophenyl)ethyl]-6-morpholino-N 4 -(pyrazin-2-yl)pyrimidine-2,4-diamine,
(21) (S)-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}imidazolidin-2-one,
(22) (S)—N 2 -[1-(4-fluorophenyl)ethyl]-6-(oxazol-5-yl)-N 4 -(pyrazin-2-yl)pyrimidine-2,4-diamine,
(23) (S)—N 2 -[1-(4-fluorophenyl)ethyl]-6-(6-methoxypyridin-3-yl)-N 4 -(pyrazin-2-yl)pyrimidine-2,4 - a diamine,
(24) (S)-N 2 -[1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)-6-(1H-pyrazol-3-yl)pyrimidine-2,4- Diamine,
(25) (S)-4-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}pyridin-2-ol,
(26) (S)-5-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}pyridin-2-ol,
(27) N-((R)-1-{2-[(S)-1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}pyrrolidine-3 -yl) acetamide,
(28) (S)—N 2 -[1-(4-fluorophenyl)ethyl]-N 6 -(pyrazin-2-yl)-4-(1H-pyrazol-4-yl)pyridine-2,6- Diamine,
(29) (S)—N 2 -[1-(4-fluorophenyl)ethyl]-N 6 -(pyrazin-2-yl)-4-(1H-pyrazol-3-yl)pyridine-2,6- Diamine,
(30) (S)—N 2 -[1-(4-fluorophenyl)ethyl]-6-[3-(methylsulfonyl)phenyl]-N 4 -(pyrazin-2-yl)pyrimidine-2,4- Diamine,
(31) (S)—N 2 -[1-(4-fluorophenyl)ethyl]-4-[4-(methylsulfonyl)phenyl]-N 6 -(pyrazin-2-yl)pyridine-2,6- Diamine,
(32) (S)—N 2 -[1-(4-fluorophenyl)ethyl]-4-(1-isopropyl-1H-pyrazol-4-yl)-N 6 -(pyrazin-2-yl)pyridine- 2,6-diamine,
(33) N-{(S)-1-[2-{[(S)-1-(4-fluorophenyl)ethyl]amino}-6-(pyrazin-2-ylamino)pyridin-4-yl]pyrrolidine -3-yl}acetamide,
(34) (S)—N 2 -[1-(4-fluorophenyl)ethyl]-4-morpholino-N 6 -(pyrazin-2-yl)pyridine-2,6-diamine,
(35) (S)—N 2 -[1-(4-fluorophenyl)ethyl]-N 6 -(pyrazin-2-yl)-4-thiomorpholinopyridine-2,6-diamine,
(36) (S)-3-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyridin-4-yl}propan-1-ol,
(37) (S)-N-(1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}azetidin-3-yl)acetamide ,
(38) (S)-6-(azetidin-1-yl)-N 2 -[1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)pyrimidine-2,4-diamine,
(39) (S)-6-(3-fluoroazetidin-1-yl)-N 2 -[1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)pyrimidine-2, 4-diamine,
(40) (S)-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}azetidin-2-one,
(41) (S)-4-(1-ethyl-1H-pyrazol-4-yl)-N 2 -[1-(4-fluorophenyl)ethyl]-N 6 -(pyrazin-2-yl)pyridine- 2,6-diamine,
(42) (S)—N 2 -[1-(4-fluorophenyl)ethyl]-4-(1-methyl-1H-pyrazol-5-yl)-N 6 -(pyrazin-2-yl)pyridine- 2,6-diamine,
(43) (S)-4-(1-(cyclopropylmethyl)-1H-pyrazol-4-yl)-N 2 -[1-(4-fluorophenyl)ethyl]-N 6 -(pyrazine-2- yl) pyridine-2,6-diamine,
(44) (S)-N 2 -[1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)-6-(thiazol-5-yl)pyrimidine-2,4-diamine,
(45) 1-{2-[(S)-1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}pyrrolidin-3-ol (46) (S )-N 2 -[1-(4-fluorophenyl)ethyl]-N 4 -(5-methylthiazol-2-yl)-N 6 -(pyrazin-2-yl)pyrimidine-2,4,6-triamine ,
(47) (S)—N 2 -[1-(4-fluorophenyl)ethyl]-N 6 -(pyrazin-2-yl)-4,5′-bipyrimidine-2,6-diamine,
(48) (S)-N 2 -[1-(4-fluorophenyl)ethyl]-6-(2-methoxythiazol-5-yl)-N 4 -(pyrazin-2-yl)pyrimidine-2,4 - a diamine,
(49) (S)-N 2 -[1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)-6-(thiazol-2-yl)pyrimidine-2,4-diamine,
(50) (S)-5-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}picolinonitrile,
(51) (S)-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}piperidine-4-carboxamide, (52) ( S)-5-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}picolinamide,
(53) 4-{2-[(S)-1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}piperazine-2-carboxamide,
(54) 6-(3-aminopyrrolidin-1-yl)-N 2 -[(S)-1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)pyrimidine-2,4 - a diamine,
(55) N-(1-{2-[(S)-1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}pyrrolidin-3-yl)methane sulfonamide,
(56) (S)-2-({2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}(2-hydroxyethyl)amino)ethane -1-ol,
(57) (S)—N 4 -[2-(dimethylamino)ethyl]-N 2 -[1-(4-fluorophenyl)ethyl]-N 6 -(pyrazin-2-yl)pyrimidine-2,4 , 6-triamine,
(58) 1-{2-[(S)-1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}piperidine-3-carboxamide,
(59) (S)-1-{2-[(S)-1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}pyrrolidine-2-carboxamide,
(60) (S)—N 2 -[1-(4-fluorophenyl)ethyl]-6-[4-(methylsulfonyl)piperazin-1-yl]-N 4 -(pyrazin-2-yl)pyrimidine- 2,4-diamine,
(61) (S)—N 2 -[1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)-6-(1H-pyrrol-3-yl)pyrimidine-2,4- Diamine,
(62) (R)-1-{2-[(S)-1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}-4-hydroxypyrrolidine- 2-on,
(63) N 2 -[(S)-1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)-N 6 -[(tetrahydrofuran-2-yl)methyl]pyrimidine-2, 4,6-triamine (64) ((S)-1-{2-[(S)-1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl} pyrrolidin-2-yl)methanol,
(65) ((R)-1-{2-[(S)-1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}pyrrolidin-2-yl )methanol,
(66) (S)-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}piperidin-4-ol,
(67) (S)-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}azetidin-3-ol,
(68) 1-{2-[(S)-1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}piperidin-3-ol,
(69) (S)-5-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}nicotinonitrile,
(70) (S)-N 2 -[1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)-6-(2H-tetrazol-5-yl)pyrimidine-2,4- Diamine,
(71) (S)—N 4 -(2-aminoethyl)-N 2 -[1-(4-fluorophenyl)ethyl]-N 6 -(pyrazin-2-yl)pyrimidine-2,4,6- triamine,
(72) (S)-N-(2-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-ylamino}ethyl)methanesulfonamide,
(73) (S)-N-(2-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-ylamino}ethyl)acetamide,
(74) (S)-2-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-ylamino}acetamide,
(75) (S)-4-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}benzamide,
(76) (S)-3-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}benzonitrile,
(77) (S)-N 2 -[1-(4-fluorophenyl)ethyl]-6-(furan-3-yl)-N 4 -(pyrazin-2-yl)pyrimidine-2,4-diamine,
(78) ethyl (S)-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}piperidine-4-carboxylate,
(79) (S)-5-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}nicotinamide,
(80) (S)-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}piperidine-4-carboxylic acid,
(81) (S)-2-{2-[(S)-1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-ylamino}-2-phenylethanol,
(82) (S)-2-{2-[(S)-1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-ylamino}-3-phenylpropane- 1-all,
(83) (R)-2-{2-[(S)-1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-ylamino}-4-methylpentane- 1-all,
(84) (S)-6-[2-(dimethylamino)ethoxy]-N 2 -[1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)pyrimidine-2,4- Diamine,
(85) (S)-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}-1H-pyrazole-4-carboxylic acid,
(86) (S)-3-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}benzamide,
(87) (S)-6-(benzo[d]1,3-dioxol-5-yl)-N 2 -[1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl) pyrimidine-2,4-diamine,
(88) (S)—N 2 -[1-(4-fluorophenyl)ethyl]-6-(2-fluoropyridin-4-yl)-N 4 -(pyrazin-2-yl)pyrimidine-2,4 - a diamine,
(89) N 2 -[(S)-1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)-6-[(tetrahydrofuran-2-yl)methoxy]pyrimidine-2,4 - a diamine,
(90) (S)-2-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yloxy}ethanol,
(91) (S)—N 2 -[1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)-N 6 -[2-(pyrrolidin-1-yl)ethyl]pyrimidine- 2,4,6-triamine,
(92) (S)-3-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}isonicotinamide,
(93) (S)-3-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}isonicotinonitrile,
(94) (S)-2-{2-[(S)-1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-ylamino}-3-methylbutane-1 - all,
(95) (S)—N 2 -[1-(4-chlorophenyl)ethyl]-6-[4-(methylsulfonyl)piperazin-1-yl]-N 4 -(pyrazin-2-yl)pyrimidine-2 , 4-diamine,
(96) (1S,2S)-2-{2-[(S)-1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yloxy}cyclohexanol,
(97) (S)-N 2 -[1-(4-fluorophenyl)ethyl]-N 4 -[(5-methylpyrazin-2-yl)methyl]-N 6 -(pyrazin-2-yl)pyrimidine -2,4,6-triamine,
(98) (S)-N 2 -[1-(4-fluorophenyl)ethyl]-N 4 -(furan-2-ylmethyl)-N 6 -(pyrazin-2-yl)pyrimidine-2,4,6 - a triamine,
(99) (S)—N 2 -[1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)-N 6 -[1-(pyridin-3-yl)ethyl]pyrimidine- 2,4,6-triamine,
(100) (S)-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}-4-(hydroxymethyl)piperidine-4 - all,
(101) (S)-N 2 -[1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)-N 6 -(pyridin-2-ylmethyl)pyrimidine-2,4,6 - a triamine,
(102) (S)—N 2 -[1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)-N 6 -(pyridin-3-ylmethyl)pyrimidine-2,4,6 - a triamine,
(103) (S)-N 2 -[1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)-N 6 -(pyridin-4-ylmethyl)pyrimidine-2,4,6 - a triamine,
(104) (S)-2-{2-[(S)-1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-ylamino}-3-hydroxypropanamide ,
(105) (3S,4S)-1-{2-[(S)-1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}pyrrolidine-3, 4-diol,
(106) N 2 -[(S)-1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)-6-(1,4-dioxa-8-azaspiro[4.5] decan-8-yl)pyrimidine-2,4-diamine,
(107) (S)-8-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}-1,3-dioxo-8-azaspiro [4.5] decan-2-one,
(108) (S)-4-(1-benzyl-1H-pyrazol-4-yl)-N 2 -[1-(4-fluorophenyl)ethyl]-N 6 -(pyrazin-2-yl)pyridine- 2,6-diamine,
(109) (S)—N 2 -[1-(4-fluorophenyl)ethyl]-6-[4-(phenylsulfonyl)piperazin-1-yl]-N 4 -(pyrazin-2-yl)pyrimidine- 2,4-diamine,
(110) (S)-4-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyridin-4-yl}benzamide,
(111) (S)—N 2 -[1-(4-fluorophenyl)ethyl]-N 6 -(pyrazin-2-yl)-4-(1H-pyrrol-3-yl)pyridine-2,6- Diamine,
(112) (S)—N 2 -[1-(4-fluorophenyl)ethyl]-N 6 -(pyrazin-2-yl)pyridine-2,6-diamine,
(113) (S)—N 2 -[1-(4-fluorophenyl)ethyl]-6-(4-methyl-1H-imidazol-1-yl)-N 4 -(pyrazin-2-yl)pyrimidine- 2,4-diamine,
(114) (S)—N 2 -[1-(4-fluorophenyl)ethyl]-4-(4-methoxyphenyl)-N 6 -(pyrazin-2-yl)pyridine-2,6-diamine,
(115) (S)-4-(4-fluorophenyl)-N 2 -[1-(4-fluorophenyl)ethyl]-N 6 -(pyrazin-2-yl)pyridine-2,6-diamine,
(116) (S)—N 2 -[1-(4-fluorophenyl)ethyl]-4-methyl-N 6 -(pyrazin-2-yl)pyridine-2,6-diamine,
(117) (S)-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}-N-(methylsulfonyl)piperidine-4 - a carboxamide,
(118) (S)—N 2 -[1-(4-fluorophenyl)ethyl]-4-(furan-3-yl)-N 6 -(pyrazin-2-yl)pyridine-2,6-diamine,
(119) (S)—N 2 -[1-(4-fluorophenyl)ethyl]-4-[4-(methylsulfonyl)piperazin-1-yl]-N 6 -(pyrazin-2-yl)pyridine- 2,6-diamine,
(120) (S)-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyridin-4-yl}-4-(hydroxymethyl)piperidine-4 - all,
(121) (S)-4-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyridin-4-yl}benzenesulfonamide,
(122) (S)—N 2 -[1-(4-fluorophenyl)ethyl]-4-methoxy-N 6 -(pyrazin-2-yl)pyridine-2,6-diamine,
(123) 4-{2-[(1S)-1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyridin-4-yl}-1λ 6 ,4-thiomorpholine-1 , 1-dione,
(124) (S)-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyridin-4-yl}piperidin-4-ol,
(125) (S)-1-(4-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyridin-4-yl}-1,4-diazepane- 1-yl)ethanone,
(126) (S)—N 2 -[1-(4-fluorophenyl)ethyl]-N 6 -(pyrazin-2-yl)-N 4 -(pyrimidin-2-yl)pyridine-2,4,6 - a triamine,
(127) (S)—N 2 -[1-(4-fluorophenyl)ethyl]-N 6 -(pyrazin-2-yl)-N 4 -(pyridin-2-yl)pyridine-2,4,6 - a triamine,
(128) N 2 -[(S)-1-(4-fluorophenyl)ethyl]-N 6 -(pyrazin-2-yl)-4-(1,4-dioxa-8-azaspiro[4.5] decan-8-yl)pyridine-2,6-diamine,
(129) (S)-2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)isonicotinic acid methyl ester,
(130) (S)-4-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}-N-methylbenzenesulfonamide,
(131) (S)—N 2 -[1-(4-fluorophenyl)ethyl]-4-(4-methyl-1H-imidazol-1-yl)-N 6 -(pyrazin-2-yl)pyridine- 2,6-diamine,
(132) (S)-N 2 -[1-(4-fluorophenyl)ethyl]-N 4 ,N 6 -di(pyrazin-2-yl)pyridine-2,4,6-triamine,
(133) (S)-4-(cyclopropylmethoxy)-N 2 -[1-(4-fluorophenyl)ethyl]-N 6 -(pyrazin-2-yl)pyridine-2,6-diamine,
(134) (S)-N 2 -[1-(4-fluorophenyl)ethyl]-N 2 -methyl-4-(1-methyl-1H-pyrazol-4-yl)-N 6 -(pyrazine-2 -yl)pyridine-2,6-diamine,
(135) (S)-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyridin-4-yl}methanol,
(136) (S)-2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)isonicotinic acid,
(137) (S)—N 2 -[1-(4-fluorophenyl)ethyl]-4-(2-methoxyethoxy)-N 6 -(pyrazin-2-yl)pyridine-2,6-diamine,
(138) (S)-2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-carbonitrile (139) (S)-2-[1-( 4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)isonicotinonitrile,
(140) (S)-2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)isonicotinamide,
(141) (S)—N 2 -[1-(4-fluorophenyl)ethyl]-6-(1,2,4-oxadiazol-3-yl)-N 4 -(pyrazin-2-yl) pyrimidine-2,4-diamine,
(142) (S)—N 2 -[1-(4-fluorophenyl)ethyl]-4-(1,2,4-oxadiazol-3-yl)-N 6 -(pyrazin-2-yl) pyridine-2,6-diamine,
(143) (S)-2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)methyl nicotinate,
(144) (S)-2-[1-(4-fluorophenyl)ethylamino]-N,N-dimethyl-6-(pyrazin-2-ylamino)isonicotinamide,
(145) (S)-N-[2-(dimethylamino)ethyl]-2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)isonicotinamide,
(146) (S)-Nt-butyl-2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)isonicotinamide,
(147) (S)-N-ethyl-2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)isonicotinamide,
(148) (S)-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyridin-4-yl}[4-(methanesulfonyl)piperazin-1-yl ] methanone,
(149) (S)-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyridin-4-yl}(pyrrolidin-1-yl)methanone,
(150) (S)-2-[1-(4-fluorophenyl)ethylamino]-N-isopropyl-6-(pyrazin-2-ylamino)isonicotinamide,
(151) (S)-1-{2-[(S)-1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}azetidine-2-carboxamide,
(152) (S)—N 2 -[1-(4-fluorophenyl)ethyl]-N 6 -(pyrazin-2-yl)-4-(tetrahydro-2H-pyran-4-yloxy)pyridine-2, 6-diamine,
(153) (S)-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}azetidine-3-carboxamide,
(154) (S)-2-[1-(4-fluorophenyl)ethylamino]-N-(2-hydroxyethyl)-6-(pyrazin-2-ylamino)isonicotinamide,
(155) (S)-2-[1-(4-fluorophenyl)ethylamino]-N-methyl-6-(pyrazin-2-ylamino)isonicotinamide,
(156) (S)-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyridin-4-yl}(morpholino)methanone,
(157) (S)-N-benzyl-2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)isonicotinamide,
(158) (S)-N-cyclopropyl-2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)isonicotinamide,
(159) (S)-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyridin-4-yl})(4-methylpiperazin-1-yl)methanone ,
(160) (S)-2-[1-(4-fluorophenyl)ethylamino]-N-(2-methoxyethyl)-6-(pyrazin-2-ylamino)isonicotinamide,
(161) (S)-2-[1-(4-fluorophenyl)ethylamino]-N-propyl-6-(pyrazin-2-ylamino)isonicotinamide,
(162) (S)-N-cyclopropylmethyl-2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)isonicotinamide,
(163) (S)-N-cyclobutyl-2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)isonicotinamide,
(164) (S)-N-butyl-2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)isonicotinamide,
(165) (S)-2-[1-(4-fluorophenyl)ethylamino]-N-isobutyl-6-(pyrazin-2-ylamino)isonicotinamide,
(166) (S)-2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)-N-(2,2,2,-trifluoroethyl)isonicotinamide,
(167) (S)-2-[1-(4-fluorophenyl)ethylamino]-N-(3-hydroxypropyl)-6-(pyrazin-2-ylamino)isonicotinamide,
(168) (S)-N-(2-ethoxyethyl)-2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)isonicotinamide,
(169) (S)-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}-N-methylazetidine-3-carboxamide ,
(170) (S)-N 2 -[1-(4-fluorophenyl)ethyl]-4-(methoxymethyl)-N 6 -(pyrazin-2-yl)pyridine-2,6-diamine,
(171) (S)-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}-N,N-dimethylazetidine-3 - a carboxamide,
(172) (S)-N-(1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}azetidin-3-yl)methane sulfonamide,
(173) (S)-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}azetidine-3-carbonitrile,
(174) 2-(4-fluorophenyl)-2-[4-(1-methyl-1H-pyrazol-4-yl)-6-(pyrazin-2-ylamino)pyridin-2-ylamino]ethanol,
(175) (S)-N-ethyl-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}azetidine-3-carboxamide,
(176) (S)-N,N-diethyl-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}azetidin-3- carboxamide,
(177) (S)-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyridin-4-yl}ethanone,
(178) (S)-N 2 -[1-(4-fluorophenyl)ethyl]-6-(3-methoxyazetidin-1-yl)-N 4 -(pyrazin-2-yl)pyrimidine-2, 4-diamine,
(179) (S)-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}-3-methylazetidin-3-ol ,
(180) (S)-2-[1-(4-fluorophenyl)ethylamino]-N-methyl-6-(pyrazin-2-ylamino)nicotinamide,
(181) (S)-2-[1-(4-fluorophenyl)ethylamino]-N,N-dimethyl-6-(pyrazin-2-ylamino)nicotinamide,
(182) (S)-2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)nicotinamide,
(183) (S)-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyridin-3-yl}(morpholino)methanone,
(184) (S)-N-(cyclopropylmethyl)-2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)nicotinamide,
(185) (S)-N-(1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}azetidin-3-yl)ethane sulfonamide,
(186) (S)-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}-N-isopropylazetidine-3-carboxamide ,
(187) (S)-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}-3-(trifluoromethyl)azetidine- 3-all,
(188) (S)-(1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}azetidin-3-yl) (pyrrolidine- 1-yl)methanone,
(189) (S)-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}-N-(2-methoxyethyl)azetidine -3-carboxamide,
(190) (S)-(1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}azetidin-3-yl) (piperidin- 1-yl)methanone,
(191) (S)-(1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}azetidin-3-yl) (morpholino) methanone,
(192) (S)-N-(cyclopropyl)-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}azetidin-3 - a carboxamide,
(193) (S)-N-(cyclopropylmethyl)-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}azetidin- 3-carboxamide,
(194) (S)-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}-N-(2-hydroxyethyl)azetidine -3-carboxamide,
(195) (S)-3-cyclopropyl-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}azetidin-3-ol ,
(196) (S)-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}-3-isopropylazetidin-3-ol ,
(197) (S)-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyridin-4-yl}azetidin-3-ol,
(198) (S)-3-cyclopropyl-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyridin-4-yl}azetidin-3-ol ,
(199) (S)-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyridin-4-yl}-3-isopropylazetidin-3-ol ,
(200) (S)-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyridin-4-yl}-3-methylazetidin-3-ol ,
(201) (S)-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyridin-4-yl}-3-(trifluoromethyl)azetidine- 3-all,
(202) (S)-4-(3,3-difluoroazetidin-1-yl)-N 2 -[1-(4-fluorophenyl)ethyl]-N 6 -(pyrazin-2-yl)pyridine- 2,6-diamine,
(203) (S)-N-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyridin-4-yl}acetamide,
(204) (S)-N-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyridin-4-yl}methanesulfonamide,
(205) (S)-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyridin-4-yl}urea,
(206) (S)-4-(3-cyclopropyl-3-methoxyazetidin-1-yl)-N 2 -[1-(4-fluorophenyl)ethyl]-N 6 -(pyrazin-2-yl ) pyridine-2,6-diamine,
(207) (S)-N 2 -[1-(4-fluorophenyl)ethyl]-4-(3-isopropyl-3-methoxyazetidin-1-yl)-N 6 -(pyrazin-2-yl) pyridine-2,6-diamine,
(208) (S)—N 2 -[1-(4-fluorophenyl)ethyl]-4-(3-methoxy-3-methylazetidin-1-yl)-N 6 -(pyrazin-2-yl) pyridine-2,6-diamine,
(209) (S)-N 2 -[1-(4-fluorophenyl)ethyl]-4-(1-methyl-1H-pyrazol-4-yl)-N 6 -(5-methylpyrazin-2-yl ) pyridine-2,6-diamine,
(210) (S)—N 2 -[1-(4-fluorophenyl)ethyl]-4-[1-(methanesulfonyl)piperidin-4-yl]-N 6 -(pyrazin-2-yl)pyridine- 2,6-diamine,
(211) (S)-N-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyridin-4-yl}propionamide,
(212) (S)-N 2 -[1-(4-fluorophenyl)ethyl]-4-[1-(2-methoxyethyl)-1H-pyrazol-4-yl]-N 6 -(pyrazine-2 -yl)pyridine-2,6-diamine,
(213) (S)-4-(1-cyclopropyl-1H-pyrazol-4-yl)-N 2 -[1-(4-fluorophenyl)ethyl]-N 6 -(pyrazin-2-yl)pyridine -2,6-diamine,
(214) (S)—N 2 -[1-(4-fluorophenyl)ethyl]-4-[1-(methoxymethyl)-1H-pyrazol-4-yl]-N 6 -(pyrazin-2-yl ) pyridine-2,6-diamine,
(215) (S)-6-[3-(dimethylamino)azetidin-1-yl]-N 2 -[1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)pyrimidine- 2,4-diamine,
(216) (S)—N 2 -[1-(4-fluorophenyl)ethyl]-6-[3-(methylamino)azetidin-1-yl]-N 4 -(pyrazin-2-yl)pyrimidine- 2,4-diamine,
(217) (S)-N 2 -[1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)-6-[3-(pyrrolidin-1-yl)azetidin-1-yl ] pyrimidine-2,4-diamine,
(218) (S)—N 2 -[1-(4-fluorophenyl)ethyl]-6-(3-morpholinoazetidin-1-yl)-N 4 -(pyrazin-2-yl)pyrimidine-2, 4-diamine,
(219) (S)—N 2 -[1-(4-fluorophenyl)ethyl]-6-[3-(4-methylpiperazin-1-yl)azetidin-1-yl]-N 4 -(pyrazine- 2-yl)pyrimidine-2,4-diamine,
(220) (S)-(1-{1-[2-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}azetidin-3-yl)piperidine-4 - all,
(221) 4-{2-[(1S)-1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}-1λ 6 ,4-thiomorpholine-1 , 1-dione,
(222) (S)-1-(1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}azetidin-3-yl)urea ,
(223) (S)-(1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}azetidin-3-yl)methanol,
(224) (S)-(1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}azetidin-3-yl)methylcarbamate t - butyl,
(225) (S)-6-[3-(aminomethyl)azetidin-1-yl]-N 2 -[1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)pyrimidine- 2,4-diamine,
(226) (S)-N-[(1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}azetidin-3-yl) methyl]ethanesulfonamide,
(227) (S)-N-[(1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}azetidin-3-yl) methyl]acetamide,
(228) (S)—N 2 -[1-(4-fluorophenyl)ethyl]-4-[3-morpholinoazetidin-1-yl]-N 6 -(pyrazin-2-yl)pyridine-2, 6-diamine,
(229) (S)-1-(1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyridin-4-yl}azetidin-3-yl)piperidine -4-ol.
(230) (S)—N 2 -[1-(4-fluorophenyl)ethyl]-4-(1-methyl-1H-pyrazol-4-yl)-N 6 -(pyrazin-2-yl)pyridine- 2,6-diamine maleate (hereinafter "compound A").
(1)(S)-4-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}ピペラジン-2-オン、
(2)N-{(S)-1-[2-{[(S)-1-(4-フルオロフェニル)エチル]アミノ}-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル]ピロリジン-3-イル}アセトアミド、
(3)(S)-6-(3,3-ジフルオロアゼチジン-1-イル)-N2-[1-(4-フルオロフェニル)エチル]-N4-(ピラジン-2-イル)ピリミジン-2,4-ジアミン、
(4)(S)-N2-[1-(4-フルオロフェニル)エチル]-4-(1-メチル-1H-ピラゾール-4-イル)-N6-(ピラジン-2-イル)ピリジン-2,6-ジアミン、
(5)(S)-N2’-[1-(4-フルオロフェニル)エチル]-N6’-(ピラジン-2-イル)-3,4’-ビピリジン-2’,6’-ジアミン、
(6)(S)-N2’-[1-(4-フルオロフェニル)エチル]-6-メトキシ-N6’-(ピラジン-2-イル)-3,4’-ビピリジン-2’,6’-ジアミン、
(7)(S)-2’-[1-(4-フルオロフェニル)エチルアミノ]-6’-(ピラジン-2-イルアミノ)-3,4’-ビピリジン-6-オール、
(8)(S)-N2-[1-(4-フルオロフェニル)エチル]-4-(オキサゾール-5-イル)-N6-(ピラジン-2-イル)ピリジン-2,6-ジアミン、
(9)(S)-6-クロロ-N2-[1-(4-フルオロフェニル)エチル]-N4-(ピラジン-2-イル)ピリミジン-2,4-ジアミン、
(10)(S)-N2-[1-(4-フルオロフェニル)エチル]-6-[4-(メチルスルホニル)フェニル]-N4-(ピラジン-2-イル)ピリミジン-2,4-ジアミン、
(11)(S)-N2-[1-(4-フルオロフェニル)エチル]-N4-(ピラジン-2-イル)-6-(1H-ピラゾール-4-イル)ピリミジン-2,4-ジアミン、
(12)(S)-2-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリジン-4-イルオキシ}エタノール、
(13)(S)-N2-[1-(4-フルオロフェニル)エチル]-N4-(ピラジン-2-イル)-6-(ピリジン-3-イル)ピリミジン-2,4-ジアミン、
(14)(S)-N2-[1-(4-フルオロフェニル)エチル]-N4-(ピラジン-2-イル)-6-(ピリジン-2-イル)ピリミジン-2,4-ジアミン、
(15)(S)-N2-[1-(4-フルオロフェニル)エチル]-N4-(ピラジン-2-イル)-6-(ピリジン-4-イル)ピリミジン-2,4-ジアミン、
(16)(S)-1-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}ピロリジン-2-オン、
(17)(S)-4-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}ピペラジン-2,6-ジオン、
(18)(S)-1-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}テトラヒドロピリミジン-2(1H)-オン、
(19)(S)-N2-[1-(4-フルオロフェニル)エチル]-N4-(ピラジン-2-イル)-6-(ピロリジン-1-イル)ピリミジン-2,4-ジアミン、
(20)(S)-N2-[1-(4-フルオロフェニル)エチル]-6-モルホリノ-N4-(ピラジン-2-イル)ピリミジン-2,4-ジアミン、
(21)(S)-1-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}イミダゾリジン-2-オン、
(22)(S)-N2-[1-(4-フルオロフェニル)エチル]-6-(オキサゾール-5-イル)-N4-(ピラジン-2-イル)ピリミジン-2,4-ジアミン、
(23)(S)-N2-[1-(4-フルオロフェニル)エチル]-6-(6-メトキシピリジン-3-イル)-N4-(ピラジン-2-イル)ピリミジン-2,4-ジアミン、
(24)(S)-N2-[1-(4-フルオロフェニル)エチル]-N4-(ピラジン-2-イル)-6-(1H-ピラゾール-3-イル)ピリミジン-2,4-ジアミン、
(25)(S)-4-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}ピリジン-2-オール、
(26)(S)-5-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}ピリジン-2-オール、
(27)N-((R)-1-{2-[(S)-1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}ピロリジン-3-イル)アセトアミド、
(28)(S)-N2-[1-(4-フルオロフェニル)エチル]-N6-(ピラジン-2-イル)-4-(1H-ピラゾール-4-イル)ピリジン-2,6-ジアミン、
(29)(S)-N2-[1-(4-フルオロフェニル)エチル]-N6-(ピラジン-2-イル)-4-(1H-ピラゾール-3-イル)ピリジン-2,6-ジアミン、
(30)(S)-N2-[1-(4-フルオロフェニル)エチル]-6-[3-(メチルスルホニル)フェニル]-N4-(ピラジン-2-イル)ピリミジン-2,4-ジアミン、
(31)(S)-N2-[1-(4-フルオロフェニル)エチル]-4-[4-(メチルスルホニル)フェニル]-N6-(ピラジン-2-イル)ピリジン-2,6-ジアミン、
(32)(S)-N2-[1-(4-フルオロフェニル)エチル]-4-(1-イソプロピル-1H-ピラゾール-4-イル)-N6-(ピラジン-2-イル)ピリジン-2,6-ジアミン、
(33)N-{(S)-1-[2-{[(S)-1-(4-フルオロフェニル)エチル]アミノ}-6-(ピラジン-2-イルアミノ)ピリジン-4-イル]ピロリジン-3-イル}アセトアミド、
(34)(S)-N2-[1-(4-フルオロフェニル)エチル]-4-モルホリノ-N6-(ピラジン-2-イル)ピリジン-2,6-ジアミン、
(35)(S)-N2-[1-(4-フルオロフェニル)エチル]-N6-(ピラジン-2-イル)-4-チオモルホリノピリジン-2,6-ジアミン、
(36)(S)-3-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリジン-4-イル}プロパン-1-オール、
(37)(S)-N-(1-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}アゼチジン-3-イル)アセトアミド、
(38)(S)-6-(アゼチジン-1-イル)-N2-[1-(4-フルオロフェニル)エチル]-N4-(ピラジン-2-イル)ピリミジン-2,4-ジアミン、
(39)(S)-6-(3-フルオロアゼチジン-1-イル)-N2-[1-(4-フルオロフェニル)エチル]-N4-(ピラジン-2-イル)ピリミジン-2,4-ジアミン、
(40)(S)-1-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}アゼチジン-2-オン、
(41)(S)-4-(1-エチル-1H-ピラゾール-4-イル)-N2-[1-(4-フルオロフェニル)エチル]-N6-(ピラジン-2-イル)ピリジン-2,6-ジアミン、
(42)(S)-N2-[1-(4-フルオロフェニル)エチル]-4-(1-メチル-1H-ピラゾール-5-イル)-N6-(ピラジン-2-イル)ピリジン-2,6-ジアミン、
(43)(S)-4-(1-(シクロプロピルメチル)-1H-ピラゾール-4-イル)-N2-[1-(4-フルオロフェニル)エチル]-N6-(ピラジン-2-イル)ピリジン-2,6-ジアミン、
(44)(S)-N2-[1-(4-フルオロフェニル)エチル]-N4-(ピラジン-2-イル)-6-(チアゾール-5-イル)ピリミジン-2,4-ジアミン、
(45)1-{2-[(S)-1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}ピロリジン-3-オール
(46)(S)-N2-[1-(4-フルオロフェニル)エチル]-N4-(5-メチルチアゾール-2-イル)-N6-(ピラジン-2-イル)ピリミジン-2,4,6-トリアミン、
(47)(S)-N2-[1-(4-フルオロフェニル)エチル]-N6-(ピラジン-2-イル)-4,5’-ビピリミジン-2,6-ジアミン、
(48)(S)-N2-[1-(4-フルオロフェニル)エチル]-6-(2-メトキシチアゾール-5-イル)-N4-(ピラジン-2-イル)ピリミジン-2,4-ジアミン、
(49)(S)-N2-[1-(4-フルオロフェニル)エチル]-N4-(ピラジン-2-イル)-6-(チアゾール-2-イル)ピリミジン-2,4-ジアミン、
(50)(S)-5-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}ピコリノニトリル、
(51)(S)-1-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}ピペリジン-4-カルボキサミド、(52) (S)-5-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}ピコリンアミド、
(53)4-{2-[(S)-1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}ピペラジン-2-カルボキサミド、
(54)6-(3-アミノピロリジン-1-イル)-N2-[(S)-1-(4-フルオロフェニル)エチル]-N4-(ピラジン-2-イル)ピリミジン-2,4-ジアミン、
(55)N-(1-{2-[(S)-1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}ピロリジン-3-イル)メタンスルホンアミド、
(56)(S)-2-({2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}(2-ヒドロキシエチル)アミノ)エタン-1-オール、
(57)(S)-N4-[2-(ジメチルアミノ)エチル]-N2-[1-(4-フルオロフェニル)エチル]-N6-(ピラジン-2-イル)ピリミジン-2,4,6-トリアミン、
(58)1-{2-[(S)-1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}ピペリジン-3-カルボキサミド、
(59)(S)-1-{2-[(S)-1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}ピロリジン-2-カルボキサミド、
(60)(S)-N2-[1-(4-フルオロフェニル)エチル]-6-[4-(メチルスルホニル)ピペラジン-1-イル]-N4-(ピラジン-2-イル)ピリミジン-2,4-ジアミン、
(61)(S)-N2-[1-(4-フルオロフェニル)エチル]-N4-(ピラジン-2-イル)-6-(1H-ピロール-3-イル)ピリミジン-2,4-ジアミン、
(62)(R)-1-{2-[(S)-1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}-4-ヒドロキシピロリジン-2-オン、
(63)N2-[(S)-1-(4-フルオロフェニル)エチル]-N4-(ピラジン-2-イル)-N6-[(テトラヒドロフラン-2-イル)メチル]ピリミジン-2,4,6-トリアミン
(64)((S)-1-{2-[(S)-1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}ピロリジン-2-イル)メタノール、
(65)((R)-1-{2-[(S)-1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}ピロリジン-2-イル)メタノール、
(66)(S)-1-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}ピペリジン-4-オール、
(67)(S)-1-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}アゼチジン-3-オール、
(68)1-{2-[(S)-1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}ピペリジン-3-オール、
(69)(S)-5-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}ニコチノニトリル、
(70)(S)-N2-[1-(4-フルオロフェニル)エチル]-N4-(ピラジン-2-イル)-6-(2H-テトラゾール-5-イル)ピリミジン-2,4-ジアミン、
(71)(S)-N4-(2-アミノエチル)-N2-[1-(4-フルオロフェニル)エチル]-N6-(ピラジン-2-イル)ピリミジン-2,4,6-トリアミン、
(72)(S)-N-(2-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イルアミノ}エチル)メタンスルホンアミド、
(73)(S)-N-(2-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イルアミノ}エチル)アセトアミド、
(74)(S)-2-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イルアミノ}アセトアミド、
(75)(S)-4-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}ベンズアミド、
(76)(S)-3-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}ベンゾニトリル、
(77)(S)-N2-[1-(4-フルオロフェニル)エチル]-6-(フラン-3-イル)-N4-(ピラジン-2-イル)ピリミジン-2,4-ジアミン、
(78)(S)-1-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}ピペリジン-4-カルボン酸エチル、
(79)(S)-5-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}ニコチンアミド、
(80)(S)-1-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}ピペリジン-4-カルボン酸、
(81)(S)-2-{2-[(S)-1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イルアミノ}-2-フェニルエタノール、
(82)(S)-2-{2-[(S)-1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イルアミノ}-3-フェニルプロパン-1-オール、
(83)(R)-2-{2-[(S)-1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イルアミノ}-4-メチルペンタン-1-オール、
(84)(S)-6-[2-(ジメチルアミノ)エトキシ]-N2-[1-(4-フルオロフェニル)エチル]-N4-(ピラジン-2-イル)ピリミジン-2,4-ジアミン、
(85)(S)-1-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}-1H-ピラゾール-4-カルボン酸、
(86)(S)-3-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}ベンズアミド、
(87)(S)-6-(ベンゾ[d]1,3-ジオキソール-5-イル)-N2-[1-(4-フルオロフェニル)エチル]-N4-(ピラジン-2-イル)ピリミジン-2,4-ジアミン、
(88)(S)-N2-[1-(4-フルオロフェニル)エチル]-6-(2-フルオロピリジン-4-イル)-N4-(ピラジン-2-イル)ピリミジン-2,4-ジアミン、
(89)N2-[(S)-1-(4-フルオロフェニル)エチル]-N4-(ピラジン-2-イル)-6-[(テトラヒドロフラン-2-イル)メトキシ]ピリミジン-2,4-ジアミン、
(90)(S)-2-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イルオキシ}エタノール、
(91)(S)-N2-[1-(4-フルオロフェニル)エチル]-N4-(ピラジン-2-イル)-N6-[2-(ピロリジン-1-イル)エチル]ピリミジン-2,4,6-トリアミン、
(92)(S)-3-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}イソニコチンアミド、
(93)(S)-3-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}イソニコチノニトリル、
(94)(S)-2-{2-[(S)-1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イルアミノ}-3-メチルブタン-1-オール、
(95)(S)-N2-[1-(4-クロロフェニル)エチル]-6-[4-(メチルスルホニル)ピペラジン-1-イル]-N4-(ピラジン-2-イル)ピリミジン-2,4-ジアミン、
(96)(1S,2S)-2-{2-[(S)-1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イルオキシ}シクロヘキサノール、
(97)(S)-N2-[1-(4-フルオロフェニル)エチル]-N4-[(5-メチルピラジン-2-イル)メチル]-N6-(ピラジン-2-イル)ピリミジン-2,4,6-トリアミン、
(98)(S)-N2-[1-(4-フルオロフェニル)エチル]-N4-(フラン-2-イルメチル)-N6-(ピラジン-2-イル)ピリミジン-2,4,6-トリアミン、
(99)(S)-N2-[1-(4-フルオロフェニル)エチル]-N4-(ピラジン-2-イル)-N6-[1-(ピリジン-3-イル)エチル]ピリミジン-2,4,6-トリアミン、
(100)(S)-1-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}-4-(ヒドロキシメチル)ピペリジン-4-オール、
(101)(S)-N2-[1-(4-フルオロフェニル)エチル]-N4-(ピラジン-2-イル)-N6-(ピリジン-2-イルメチル)ピリミジン-2,4,6-トリアミン、
(102)(S)-N2-[1-(4-フルオロフェニル)エチル]-N4-(ピラジン-2-イル)-N6-(ピリジン-3-イルメチル)ピリミジン-2,4,6-トリアミン、
(103)(S)-N2-[1-(4-フルオロフェニル)エチル]-N4-(ピラジン-2-イル)-N6-(ピリジン-4-イルメチル)ピリミジン-2,4,6-トリアミン、
(104)(S)-2-{2-[(S)-1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イルアミノ}-3-ヒドロキシプロパンアミド、
(105)(3S,4S)-1-{2-[(S)-1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}ピロリジン-3,4-ジオール、
(106)N2-[(S)-1-(4-フルオロフェニル)エチル]-N4-(ピラジン-2-イル)-6-(1,4-ジオキサ-8-アザスピロ[4.5]デカン-8-イル)ピリミジン-2,4-ジアミン、
(107)(S)-8-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}-1,3-ジオキソ-8-アザスピロ[4.5]デカン-2-オン、
(108)(S)-4-(1-ベンジル-1H-ピラゾール-4-イル)-N2-[1-(4-フルオロフェニル)エチル]-N6-(ピラジン-2-イル)ピリジン-2,6-ジアミン、
(109)(S)-N2-[1-(4-フルオロフェニル)エチル]-6-[4-(フェニルスルホニル)ピペラジン-1-イル]-N4-(ピラジン-2-イル)ピリミジン-2,4-ジアミン、
(110)(S)-4-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリジン-4-イル}ベンズアミド、
(111)(S)-N2-[1-(4-フルオロフェニル)エチル]-N6-(ピラジン-2-イル)-4-(1H-ピロール-3-イル)ピリジン-2,6-ジアミン、
(112)(S)-N2-[1-(4-フルオロフェニル)エチル]-N6-(ピラジン-2-イル)ピリジン-2,6-ジアミン、
(113)(S)-N2-[1-(4-フルオロフェニル)エチル]-6-(4-メチル-1H-イミダゾール-1-イル)-N4-(ピラジン-2-イル)ピリミジン-2,4-ジアミン、
(114)(S)-N2-[1-(4-フルオロフェニル)エチル]-4-(4-メトキシフェニル)-N6-(ピラジン-2-イル)ピリジン-2,6-ジアミン、
(115)(S)-4-(4-フルオロフェニル)-N2-[1-(4-フルオロフェニル)エチル]-N6-(ピラジン-2-イル)ピリジン-2,6-ジアミン、
(116)(S)-N2-[1-(4-フルオロフェニル)エチル]-4-メチル-N6-(ピラジン-2-イル)ピリジン-2,6-ジアミン、
(117)(S)-1-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}-N-(メチルスルホニル)ピペリジン-4-カルボキサミド、
(118)(S)-N2-[1-(4-フルオロフェニル)エチル]-4-(フラン-3-イル)-N6-(ピラジン-2-イル)ピリジン-2,6-ジアミン、
(119)(S)-N2-[1-(4-フルオロフェニル)エチル]-4-[4-(メチルスルホニル)ピペラジン-1-イル]-N6-(ピラジン-2-イル)ピリジン-2,6-ジアミン、
(120)(S)-1-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリジン-4-イル}-4-(ヒドロキシメチル)ピペリジン-4-オール、
(121)(S)-4-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリジン-4-イル}ベンゼンスルホンアミド、
(122)(S)-N2-[1-(4-フルオロフェニル)エチル]-4-メトキシ-N6-(ピラジン-2-イル)ピリジン-2,6-ジアミン、
(123)4-{2-[(1S)-1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリジン-4-イル}-1λ6,4-チオモルホリン-1,1-ジオン、
(124)(S)-1-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリジン-4-イル}ピペリジン-4-オール、
(125)(S)-1-(4-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリジン-4-イル}-1,4-ジアゼパン-1-イル)エタノン、
(126)(S)-N2-[1-(4-フルオロフェニル)エチル]-N6-(ピラジン-2-イル)-N4-(ピリミジン-2-イル)ピリジン-2,4,6-トリアミン、
(127)(S)-N2-[1-(4-フルオロフェニル)エチル]-N6-(ピラジン-2-イル)-N4-(ピリジン-2-イル)ピリジン-2,4,6-トリアミン、
(128)N2-[(S)-1-(4-フルオロフェニル)エチル]-N6-(ピラジン-2-イル)-4-(1,4-ジオキサ-8-アザスピロ[4.5]デカン-8-イル)ピリジン-2,6-ジアミン、
(129)(S)-2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)イソニコチン酸メチルエステル、
(130)(S)-4-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}-N-メチルベンゼンスルホンアミド、
(131)(S)-N2-[1-(4-フルオロフェニル)エチル]-4-(4-メチル-1H-イミダゾール-1-イル)-N6-(ピラジン-2-イル)ピリジン-2,6-ジアミン、
(132)(S)-N2-[1-(4-フルオロフェニル)エチル]-N4,N6-ジ(ピラジン-2-イル)ピリジン-2,4,6-トリアミン、
(133)(S)-4-(シクロプロピルメトキシ)-N2-[1-(4-フルオロフェニル)エチル]-N6-(ピラジン-2-イル)ピリジン-2,6-ジアミン、
(134)(S)-N2-[1-(4-フルオロフェニル)エチル]-N2-メチル-4-(1-メチル-1H-ピラゾール-4-イル)-N6-(ピラジン-2-イル)ピリジン-2,6-ジアミン、
(135)(S)-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリジン-4-イル}メタノール、
(136)(S)-2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)イソニコチン酸、
(137)(S)-N2-[1-(4-フルオロフェニル)エチル]-4-(2-メトキシエトキシ)-N6-(ピラジン-2-イル)ピリジン-2,6-ジアミン、
(138)(S)-2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-カルボニトリル
(139)(S)-2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)イソニコチノニトリル、
(140)(S)-2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)イソニコチンアミド、
(141)(S)-N2-[1-(4-フルオロフェニル)エチル]-6-(1,2,4-オキサジアゾール-3-イル)-N4-(ピラジン-2-イル)ピリミジン-2,4-ジアミン、
(142)(S)-N2-[1-(4-フルオロフェニル)エチル]-4-(1,2,4-オキサジアゾール-3-イル)-N6-(ピラジン-2-イル)ピリジン-2,6-ジアミン、
(143)(S)-2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ニコチン酸メチル、
(144)(S)-2-[1-(4-フルオロフェニル)エチルアミノ]-N,N-ジメチル-6-(ピラジン-2-イルアミノ)イソニコチンアミド、
(145)(S)-N-[2-(ジメチルアミノ)エチル]-2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)イソニコチンアミド、
(146)(S)-N-t-ブチル-2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)イソニコチンアミド、
(147)(S)-N-エチル-2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)イソニコチンアミド、
(148)(S)-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリジン-4-イル}[4-(メタンスルホニル)ピペラジン-1-イル]メタノン、
(149)(S)-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリジン-4-イル}(ピロリジン-1-イル)メタノン、
(150)(S)-2-[1-(4-フルオロフェニル)エチルアミノ]-N-イソプロピル-6-(ピラジン-2-イルアミノ)イソニコチンアミド、
(151)(S)-1-{2-[(S)-1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}アゼチジン-2-カルボキサミド、
(152)(S)-N2-[1-(4-フルオロフェニル)エチル]-N6-(ピラジン-2-イル)-4-(テトラヒドロ-2H-ピラン-4-イルオキシ)ピリジン-2,6-ジアミン、
(153)(S)-1-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}アゼチジン-3-カルボキサミド、
(154)(S)-2-[1-(4-フルオロフェニル)エチルアミノ]-N-(2-ヒドロキシエチル)-6-(ピラジン-2-イルアミノ)イソニコチンアミド、
(155)(S)-2-[1-(4-フルオロフェニル)エチルアミノ]-N-メチル-6-(ピラジン-2-イルアミノ)イソニコチンアミド、
(156)(S)-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリジン-4-イル}(モルホリノ)メタノン、
(157)(S)-N-ベンジル-2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)イソニコチンアミド、
(158)(S)-N-シクロプロピル-2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)イソニコチンアミド、
(159)(S)-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリジン-4-イル})(4-メチルピペラジン-1-イル)メタノン、
(160)(S)-2-[1-(4-フルオロフェニル)エチルアミノ]-N-(2-メトキシエチル)-6-(ピラジン-2-イルアミノ)イソニコチンアミド、
(161)(S)-2-[1-(4-フルオロフェニル)エチルアミノ]-N-プロピル-6-(ピラジン-2-イルアミノ)イソニコチンアミド、
(162)(S)-N-シクロプロピルメチル-2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)イソニコチンアミド、
(163)(S)-N-シクロブチル-2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)イソニコチンアミド、
(164)(S)-N-ブチル-2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)イソニコチンアミド、
(165)(S)-2-[1-(4-フルオロフェニル)エチルアミノ]-N-イソブチル-6-(ピラジン-2-イルアミノ)イソニコチンアミド、
(166)(S)-2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)-N-(2,2,2,-トリフルオロエチル)イソニコチンアミド、
(167)(S)-2-[1-(4-フルオロフェニル)エチルアミノ]-N-(3-ヒドロキシプロピル)-6-(ピラジン-2-イルアミノ)イソニコチンアミド、
(168)(S)-N-(2-エトキシエチル)-2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)イソニコチンアミド、
(169)(S)-1-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}-N-メチルアゼチジン-3-カルボキサミド、
(170)(S)-N2-[1-(4-フルオロフェニル)エチル]-4-(メトキシメチル)-N6-(ピラジン-2-イル)ピリジン-2,6-ジアミン、
(171)(S)-1-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}-N,N-ジメチルアゼチジン-3-カルボキサミド、
(172)(S)-N-(1-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}アゼチジン-3-イル)メタンスルホンアミド、
(173)(S)-1-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}アゼチジン-3-カルボニトリル、
(174)2-(4-フルオロフェニル)-2-[4-(1-メチル-1H-ピラゾール-4-イル)-6-(ピラジン-2-イルアミノ)ピリジン-2-イルアミノ]エタノール、
(175)(S)-N-エチル-1-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}アゼチジン-3-カルボキサミド、
(176)(S)-N,N-ジエチル-1-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}アゼチジン-3-カルボキサミド、
(177)(S)-1-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリジン-4-イル}エタノン、
(178)(S)-N2-[1-(4-フルオロフェニル)エチル]-6-(3-メトキシアゼチジン-1-イル)-N4-(ピラジン-2-イル)ピリミジン-2,4-ジアミン、
(179)(S)-1-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}-3-メチルアゼチジン-3-オール、
(180)(S)-2-[1-(4-フルオロフェニル)エチルアミノ]-N-メチル-6-(ピラジン-2-イルアミノ)ニコチンアミド、
(181)(S)-2-[1-(4-フルオロフェニル)エチルアミノ]-N,N-ジメチル-6-(ピラジン-2-イルアミノ)ニコチンアミド、
(182)(S)-2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ニコチンアミド、
(183)(S)-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリジン-3-イル}(モルホリノ)メタノン、
(184)(S)-N-(シクロプロピルメチル)-2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ニコチンアミド、
(185)(S)-N-(1-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}アゼチジン-3-イル)エタンスルホンアミド、
(186)(S)-1-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}-N-イソプロピルアゼチジン-3-カルボキサミド、
(187)(S)-1-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}-3-(トリフルオロメチル)アゼチジン-3-オール、
(188)(S)-(1-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}アゼチジン-3-イル)(ピロリジン-1-イル)メタノン、
(189)(S)-1-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}-N-(2-メトキシエチル)アゼチジン-3-カルボキサミド、
(190)(S)-(1-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}アゼチジン-3-イル)(ピペリジン-1-イル)メタノン、
(191)(S)-(1-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}アゼチジン-3-イル)(モルホリノ)メタノン、
(192)(S)-N-(シクロプロピル)-1-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}アゼチジン-3-カルボキサミド、
(193)(S)-N-(シクロプロピルメチル)-1-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}アゼチジン-3-カルボキサミド、
(194)(S)-1-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}-N-(2-ヒドロキシエチル)アゼチジン-3-カルボキサミド、
(195)(S)-3-シクロプロピル-1-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}アゼチジン-3-オール、
(196)(S)-1-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}-3-イソプロピルアゼチジン-3-オール、
(197)(S)-1-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリジン-4-イル}アゼチジン-3-オール、
(198)(S)-3-シクロプロピル-1-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリジン-4-イル}アゼチジン-3-オール、
(199)(S)-1-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリジン-4-イル}-3-イソプロピルアゼチジン-3-オール、
(200)(S)-1-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリジン-4-イル}-3-メチルアゼチジン-3-オール、
(201)(S)-1-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリジン-4-イル}-3-(トリフルオロメチル)アゼチジン-3-オール、
(202)(S)-4-(3,3-ジフルオロアゼチジン-1-イル)-N2-[1-(4-フルオロフェニル)エチル]-N6-(ピラジン-2-イル)ピリジン-2,6-ジアミン、
(203)(S)-N-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリジン-4-イル}アセトアミド、
(204)(S)-N-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリジン-4-イル}メタンスルホンアミド、
(205)(S)-1-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリジン-4-イル}ウレア、
(206)(S)-4-(3-シクロプロピル-3-メトキシアゼチジン-1-イル)-N2-[1-(4-フルオロフェニル)エチル]-N6-(ピラジン-2-イル)ピリジン-2,6-ジアミン、
(207)(S)-N2-[1-(4-フルオロフェニル)エチル]-4-(3-イソプロピル-3-メトキシアゼチジン-1-イル)-N6-(ピラジン-2-イル)ピリジン-2,6-ジアミン、
(208)(S)-N2-[1-(4-フルオロフェニル)エチル]-4-(3-メトキシ-3-メチルアゼチジン-1-イル)-N6-(ピラジン-2-イル)ピリジン-2,6-ジアミン、
(209)(S)-N2-[1-(4-フルオロフェニル)エチル]-4-(1-メチル-1H-ピラゾール-4-イル)-N6-(5-メチルピラジン-2-イル)ピリジン-2,6-ジアミン、
(210)(S)-N2-[1-(4-フルオロフェニル)エチル]-4-[1-(メタンスルホニル)ピペリジン-4-イル]-N6-(ピラジン-2-イル)ピリジン-2,6-ジアミン、
(211)(S)-N-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリジン-4-イル}プロピオンアミド、
(212)(S)-N2-[1-(4-フルオロフェニル)エチル]-4-[1-(2-メトキシエチル)-1H-ピラゾール-4-イル]-N6-(ピラジン-2-イル)ピリジン-2,6-ジアミン、
(213)(S)-4-(1-シクロプロピル-1H-ピラゾール-4-イル)-N2-[1-(4-フルオロフェニル)エチル]-N6-(ピラジン-2-イル)ピリジン-2,6-ジアミン、
(214)(S)-N2-[1-(4-フルオロフェニル)エチル]-4-[1-(メトキシメチル)-1H-ピラゾール-4-イル]-N6-(ピラジン-2-イル)ピリジン-2,6-ジアミン、
(215)(S)-6-[3-(ジメチルアミノ)アゼチジン-1-イル]-N2-[1-(4-フルオロフェニル)エチル]-N4-(ピラジン-2-イル)ピリミジン-2,4-ジアミン、
(216)(S)-N2-[1-(4-フルオロフェニル)エチル]-6-[3-(メチルアミノ)アゼチジン-1-イル]-N4-(ピラジン-2-イル)ピリミジン-2,4-ジアミン、
(217)(S)-N2-[1-(4-フルオロフェニル)エチル]-N4-(ピラジン-2-イル)-6-[3-(ピロリジン-1-イル)アゼチジン-1-イル]ピリミジン-2,4-ジアミン、
(218)(S)-N2-[1-(4-フルオロフェニル)エチル]-6-(3-モルホリノアゼチジン-1-イル)-N4-(ピラジン-2-イル)ピリミジン-2,4-ジアミン、
(219)(S)-N2-[1-(4-フルオロフェニル)エチル]-6-[3-(4-メチルピペラジン-1-イル)アゼチジン-1-イル]-N4-(ピラジン-2-イル)ピリミジン-2,4-ジアミン、
(220)(S)-(1-{1-[2-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}アゼチジン-3-イル)ピペリジン-4-オール、
(221)4-{2-[(1S)-1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}-1λ6,4-チオモルホリン-1,1-ジオン、
(222)(S)-1-(1-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}アゼチジン-3-イル)ウレア、
(223)(S)-(1-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}アゼチジン-3-イル)メタノール、
(224)(S)-(1-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}アゼチジン-3-イル)メチルカルバミン酸t-ブチル、
(225)(S)-6-[3-(アミノメチル)アゼチジン-1-イル]-N2-[1-(4-フルオロフェニル)エチル]-N4-(ピラジン-2-イル)ピリミジン-2,4-ジアミン、
(226)(S)-N-[(1-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}アゼチジン-3-イル)メチル]エタンスルホンアミド、
(227)(S)-N-[(1-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}アゼチジン-3-イル)メチル]アセトアミド、
(228)(S)-N2-[1-(4-フルオロフェニル)エチル]-4-[3-モルホリノアゼチジン-1-イル]-N6-(ピラジン-2-イル)ピリジン-2,6-ジアミン、
(229)(S)-1-(1-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリジン-4-イル}アゼチジン-3-イル)ピペリジン-4-オール。
(230)(S)-N2-[1-(4-フルオロフェニル)エチル]-4-(1-メチル-1H-ピラゾール-4-イル)-N6-(ピラジン-2-イル)ピリジン-2,6-ジアミン マレイン酸塩(以下、「化合物A」)。 Among the compounds of the present invention, specifically the following compounds or pharmaceutically acceptable salts thereof are preferred.
(1) (S)-4-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}piperazin-2-one,
(2) N-{(S)-1-[2-{[(S)-1-(4-fluorophenyl)ethyl]amino}-6-(pyrazin-2-ylamino)pyrimidin-4-yl]pyrrolidine -3-yl}acetamide,
(3) (S)-6-(3,3-difluoroazetidin-1-yl)-N 2 -[1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)pyrimidine- 2,4-diamine,
(4) (S)—N 2 -[1-(4-fluorophenyl)ethyl]-4-(1-methyl-1H-pyrazol-4-yl)-N 6 -(pyrazin-2-yl)pyridine- 2,6-diamine,
(5) (S)—N 2′ -[1-(4-fluorophenyl)ethyl]-N 6′ -(pyrazin-2-yl)-3,4′-bipyridine-2′,6′-diamine,
(6) (S)—N 2′ -[1-(4-fluorophenyl)ethyl]-6-methoxy-N 6′ -(pyrazin-2-yl)-3,4′-bipyridine-2′,6 '-diamine,
(7) (S)-2′-[1-(4-fluorophenyl)ethylamino]-6′-(pyrazin-2-ylamino)-3,4′-bipyridin-6-ol,
(8) (S)—N 2 -[1-(4-fluorophenyl)ethyl]-4-(oxazol-5-yl)-N 6 -(pyrazin-2-yl)pyridine-2,6-diamine,
(9) (S)-6-chloro-N 2 -[1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)pyrimidine-2,4-diamine,
(10) (S)—N 2 -[1-(4-fluorophenyl)ethyl]-6-[4-(methylsulfonyl)phenyl]-N 4 -(pyrazin-2-yl)pyrimidine-2,4- Diamine,
(11) (S)-N 2 -[1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)-6-(1H-pyrazol-4-yl)pyrimidine-2,4- Diamine,
(12) (S)-2-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyridin-4-yloxy}ethanol,
(13) (S)—N 2 -[1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)-6-(pyridin-3-yl)pyrimidine-2,4-diamine,
(14) (S)—N 2 -[1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)-6-(pyridin-2-yl)pyrimidine-2,4-diamine,
(15) (S)-N 2 -[1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)-6-(pyridin-4-yl)pyrimidine-2,4-diamine,
(16) (S)-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}pyrrolidin-2-one,
(17) (S)-4-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}piperazine-2,6-dione,
(18) (S)-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}tetrahydropyrimidin-2(1H)-one,
(19) (S)-N 2 -[1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)-6-(pyrrolidin-1-yl)pyrimidine-2,4-diamine,
(20) (S)—N 2 -[1-(4-fluorophenyl)ethyl]-6-morpholino-N 4 -(pyrazin-2-yl)pyrimidine-2,4-diamine,
(21) (S)-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}imidazolidin-2-one,
(22) (S)—N 2 -[1-(4-fluorophenyl)ethyl]-6-(oxazol-5-yl)-N 4 -(pyrazin-2-yl)pyrimidine-2,4-diamine,
(23) (S)—N 2 -[1-(4-fluorophenyl)ethyl]-6-(6-methoxypyridin-3-yl)-N 4 -(pyrazin-2-yl)pyrimidine-2,4 - a diamine,
(24) (S)-N 2 -[1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)-6-(1H-pyrazol-3-yl)pyrimidine-2,4- Diamine,
(25) (S)-4-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}pyridin-2-ol,
(26) (S)-5-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}pyridin-2-ol,
(27) N-((R)-1-{2-[(S)-1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}pyrrolidine-3 -yl) acetamide,
(28) (S)—N 2 -[1-(4-fluorophenyl)ethyl]-N 6 -(pyrazin-2-yl)-4-(1H-pyrazol-4-yl)pyridine-2,6- Diamine,
(29) (S)—N 2 -[1-(4-fluorophenyl)ethyl]-N 6 -(pyrazin-2-yl)-4-(1H-pyrazol-3-yl)pyridine-2,6- Diamine,
(30) (S)—N 2 -[1-(4-fluorophenyl)ethyl]-6-[3-(methylsulfonyl)phenyl]-N 4 -(pyrazin-2-yl)pyrimidine-2,4- Diamine,
(31) (S)—N 2 -[1-(4-fluorophenyl)ethyl]-4-[4-(methylsulfonyl)phenyl]-N 6 -(pyrazin-2-yl)pyridine-2,6- Diamine,
(32) (S)—N 2 -[1-(4-fluorophenyl)ethyl]-4-(1-isopropyl-1H-pyrazol-4-yl)-N 6 -(pyrazin-2-yl)pyridine- 2,6-diamine,
(33) N-{(S)-1-[2-{[(S)-1-(4-fluorophenyl)ethyl]amino}-6-(pyrazin-2-ylamino)pyridin-4-yl]pyrrolidine -3-yl}acetamide,
(34) (S)—N 2 -[1-(4-fluorophenyl)ethyl]-4-morpholino-N 6 -(pyrazin-2-yl)pyridine-2,6-diamine,
(35) (S)—N 2 -[1-(4-fluorophenyl)ethyl]-N 6 -(pyrazin-2-yl)-4-thiomorpholinopyridine-2,6-diamine,
(36) (S)-3-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyridin-4-yl}propan-1-ol,
(37) (S)-N-(1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}azetidin-3-yl)acetamide ,
(38) (S)-6-(azetidin-1-yl)-N 2 -[1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)pyrimidine-2,4-diamine,
(39) (S)-6-(3-fluoroazetidin-1-yl)-N 2 -[1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)pyrimidine-2, 4-diamine,
(40) (S)-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}azetidin-2-one,
(41) (S)-4-(1-ethyl-1H-pyrazol-4-yl)-N 2 -[1-(4-fluorophenyl)ethyl]-N 6 -(pyrazin-2-yl)pyridine- 2,6-diamine,
(42) (S)—N 2 -[1-(4-fluorophenyl)ethyl]-4-(1-methyl-1H-pyrazol-5-yl)-N 6 -(pyrazin-2-yl)pyridine- 2,6-diamine,
(43) (S)-4-(1-(cyclopropylmethyl)-1H-pyrazol-4-yl)-N 2 -[1-(4-fluorophenyl)ethyl]-N 6 -(pyrazine-2- yl) pyridine-2,6-diamine,
(44) (S)-N 2 -[1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)-6-(thiazol-5-yl)pyrimidine-2,4-diamine,
(45) 1-{2-[(S)-1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}pyrrolidin-3-ol (46) (S )-N 2 -[1-(4-fluorophenyl)ethyl]-N 4 -(5-methylthiazol-2-yl)-N 6 -(pyrazin-2-yl)pyrimidine-2,4,6-triamine ,
(47) (S)—N 2 -[1-(4-fluorophenyl)ethyl]-N 6 -(pyrazin-2-yl)-4,5′-bipyrimidine-2,6-diamine,
(48) (S)-N 2 -[1-(4-fluorophenyl)ethyl]-6-(2-methoxythiazol-5-yl)-N 4 -(pyrazin-2-yl)pyrimidine-2,4 - a diamine,
(49) (S)-N 2 -[1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)-6-(thiazol-2-yl)pyrimidine-2,4-diamine,
(50) (S)-5-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}picolinonitrile,
(51) (S)-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}piperidine-4-carboxamide, (52) ( S)-5-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}picolinamide,
(53) 4-{2-[(S)-1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}piperazine-2-carboxamide,
(54) 6-(3-aminopyrrolidin-1-yl)-N 2 -[(S)-1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)pyrimidine-2,4 - a diamine,
(55) N-(1-{2-[(S)-1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}pyrrolidin-3-yl)methane sulfonamide,
(56) (S)-2-({2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}(2-hydroxyethyl)amino)ethane -1-ol,
(57) (S)—N 4 -[2-(dimethylamino)ethyl]-N 2 -[1-(4-fluorophenyl)ethyl]-N 6 -(pyrazin-2-yl)pyrimidine-2,4 , 6-triamine,
(58) 1-{2-[(S)-1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}piperidine-3-carboxamide,
(59) (S)-1-{2-[(S)-1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}pyrrolidine-2-carboxamide,
(60) (S)—N 2 -[1-(4-fluorophenyl)ethyl]-6-[4-(methylsulfonyl)piperazin-1-yl]-N 4 -(pyrazin-2-yl)pyrimidine- 2,4-diamine,
(61) (S)—N 2 -[1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)-6-(1H-pyrrol-3-yl)pyrimidine-2,4- Diamine,
(62) (R)-1-{2-[(S)-1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}-4-hydroxypyrrolidine- 2-on,
(63) N 2 -[(S)-1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)-N 6 -[(tetrahydrofuran-2-yl)methyl]pyrimidine-2, 4,6-triamine (64) ((S)-1-{2-[(S)-1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl} pyrrolidin-2-yl)methanol,
(65) ((R)-1-{2-[(S)-1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}pyrrolidin-2-yl )methanol,
(66) (S)-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}piperidin-4-ol,
(67) (S)-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}azetidin-3-ol,
(68) 1-{2-[(S)-1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}piperidin-3-ol,
(69) (S)-5-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}nicotinonitrile,
(70) (S)-N 2 -[1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)-6-(2H-tetrazol-5-yl)pyrimidine-2,4- Diamine,
(71) (S)—N 4 -(2-aminoethyl)-N 2 -[1-(4-fluorophenyl)ethyl]-N 6 -(pyrazin-2-yl)pyrimidine-2,4,6- triamine,
(72) (S)-N-(2-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-ylamino}ethyl)methanesulfonamide,
(73) (S)-N-(2-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-ylamino}ethyl)acetamide,
(74) (S)-2-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-ylamino}acetamide,
(75) (S)-4-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}benzamide,
(76) (S)-3-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}benzonitrile,
(77) (S)-N 2 -[1-(4-fluorophenyl)ethyl]-6-(furan-3-yl)-N 4 -(pyrazin-2-yl)pyrimidine-2,4-diamine,
(78) ethyl (S)-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}piperidine-4-carboxylate,
(79) (S)-5-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}nicotinamide,
(80) (S)-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}piperidine-4-carboxylic acid,
(81) (S)-2-{2-[(S)-1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-ylamino}-2-phenylethanol,
(82) (S)-2-{2-[(S)-1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-ylamino}-3-phenylpropane- 1-all,
(83) (R)-2-{2-[(S)-1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-ylamino}-4-methylpentane- 1-all,
(84) (S)-6-[2-(dimethylamino)ethoxy]-N 2 -[1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)pyrimidine-2,4- Diamine,
(85) (S)-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}-1H-pyrazole-4-carboxylic acid,
(86) (S)-3-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}benzamide,
(87) (S)-6-(benzo[d]1,3-dioxol-5-yl)-N 2 -[1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl) pyrimidine-2,4-diamine,
(88) (S)—N 2 -[1-(4-fluorophenyl)ethyl]-6-(2-fluoropyridin-4-yl)-N 4 -(pyrazin-2-yl)pyrimidine-2,4 - a diamine,
(89) N 2 -[(S)-1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)-6-[(tetrahydrofuran-2-yl)methoxy]pyrimidine-2,4 - a diamine,
(90) (S)-2-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yloxy}ethanol,
(91) (S)—N 2 -[1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)-N 6 -[2-(pyrrolidin-1-yl)ethyl]pyrimidine- 2,4,6-triamine,
(92) (S)-3-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}isonicotinamide,
(93) (S)-3-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}isonicotinonitrile,
(94) (S)-2-{2-[(S)-1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-ylamino}-3-methylbutane-1 - all,
(95) (S)—N 2 -[1-(4-chlorophenyl)ethyl]-6-[4-(methylsulfonyl)piperazin-1-yl]-N 4 -(pyrazin-2-yl)pyrimidine-2 , 4-diamine,
(96) (1S,2S)-2-{2-[(S)-1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yloxy}cyclohexanol,
(97) (S)-N 2 -[1-(4-fluorophenyl)ethyl]-N 4 -[(5-methylpyrazin-2-yl)methyl]-N 6 -(pyrazin-2-yl)pyrimidine -2,4,6-triamine,
(98) (S)-N 2 -[1-(4-fluorophenyl)ethyl]-N 4 -(furan-2-ylmethyl)-N 6 -(pyrazin-2-yl)pyrimidine-2,4,6 - a triamine,
(99) (S)—N 2 -[1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)-N 6 -[1-(pyridin-3-yl)ethyl]pyrimidine- 2,4,6-triamine,
(100) (S)-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}-4-(hydroxymethyl)piperidine-4 - all,
(101) (S)-N 2 -[1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)-N 6 -(pyridin-2-ylmethyl)pyrimidine-2,4,6 - a triamine,
(102) (S)—N 2 -[1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)-N 6 -(pyridin-3-ylmethyl)pyrimidine-2,4,6 - a triamine,
(103) (S)-N 2 -[1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)-N 6 -(pyridin-4-ylmethyl)pyrimidine-2,4,6 - a triamine,
(104) (S)-2-{2-[(S)-1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-ylamino}-3-hydroxypropanamide ,
(105) (3S,4S)-1-{2-[(S)-1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}pyrrolidine-3, 4-diol,
(106) N 2 -[(S)-1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)-6-(1,4-dioxa-8-azaspiro[4.5] decan-8-yl)pyrimidine-2,4-diamine,
(107) (S)-8-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}-1,3-dioxo-8-azaspiro [4.5] decan-2-one,
(108) (S)-4-(1-benzyl-1H-pyrazol-4-yl)-N 2 -[1-(4-fluorophenyl)ethyl]-N 6 -(pyrazin-2-yl)pyridine- 2,6-diamine,
(109) (S)—N 2 -[1-(4-fluorophenyl)ethyl]-6-[4-(phenylsulfonyl)piperazin-1-yl]-N 4 -(pyrazin-2-yl)pyrimidine- 2,4-diamine,
(110) (S)-4-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyridin-4-yl}benzamide,
(111) (S)—N 2 -[1-(4-fluorophenyl)ethyl]-N 6 -(pyrazin-2-yl)-4-(1H-pyrrol-3-yl)pyridine-2,6- Diamine,
(112) (S)—N 2 -[1-(4-fluorophenyl)ethyl]-N 6 -(pyrazin-2-yl)pyridine-2,6-diamine,
(113) (S)—N 2 -[1-(4-fluorophenyl)ethyl]-6-(4-methyl-1H-imidazol-1-yl)-N 4 -(pyrazin-2-yl)pyrimidine- 2,4-diamine,
(114) (S)—N 2 -[1-(4-fluorophenyl)ethyl]-4-(4-methoxyphenyl)-N 6 -(pyrazin-2-yl)pyridine-2,6-diamine,
(115) (S)-4-(4-fluorophenyl)-N 2 -[1-(4-fluorophenyl)ethyl]-N 6 -(pyrazin-2-yl)pyridine-2,6-diamine,
(116) (S)—N 2 -[1-(4-fluorophenyl)ethyl]-4-methyl-N 6 -(pyrazin-2-yl)pyridine-2,6-diamine,
(117) (S)-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}-N-(methylsulfonyl)piperidine-4 - a carboxamide,
(118) (S)—N 2 -[1-(4-fluorophenyl)ethyl]-4-(furan-3-yl)-N 6 -(pyrazin-2-yl)pyridine-2,6-diamine,
(119) (S)—N 2 -[1-(4-fluorophenyl)ethyl]-4-[4-(methylsulfonyl)piperazin-1-yl]-N 6 -(pyrazin-2-yl)pyridine- 2,6-diamine,
(120) (S)-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyridin-4-yl}-4-(hydroxymethyl)piperidine-4 - all,
(121) (S)-4-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyridin-4-yl}benzenesulfonamide,
(122) (S)—N 2 -[1-(4-fluorophenyl)ethyl]-4-methoxy-N 6 -(pyrazin-2-yl)pyridine-2,6-diamine,
(123) 4-{2-[(1S)-1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyridin-4-yl}-1λ 6 ,4-thiomorpholine-1 , 1-dione,
(124) (S)-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyridin-4-yl}piperidin-4-ol,
(125) (S)-1-(4-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyridin-4-yl}-1,4-diazepane- 1-yl)ethanone,
(126) (S)—N 2 -[1-(4-fluorophenyl)ethyl]-N 6 -(pyrazin-2-yl)-N 4 -(pyrimidin-2-yl)pyridine-2,4,6 - a triamine,
(127) (S)—N 2 -[1-(4-fluorophenyl)ethyl]-N 6 -(pyrazin-2-yl)-N 4 -(pyridin-2-yl)pyridine-2,4,6 - a triamine,
(128) N 2 -[(S)-1-(4-fluorophenyl)ethyl]-N 6 -(pyrazin-2-yl)-4-(1,4-dioxa-8-azaspiro[4.5] decan-8-yl)pyridine-2,6-diamine,
(129) (S)-2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)isonicotinic acid methyl ester,
(130) (S)-4-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}-N-methylbenzenesulfonamide,
(131) (S)—N 2 -[1-(4-fluorophenyl)ethyl]-4-(4-methyl-1H-imidazol-1-yl)-N 6 -(pyrazin-2-yl)pyridine- 2,6-diamine,
(132) (S)-N 2 -[1-(4-fluorophenyl)ethyl]-N 4 ,N 6 -di(pyrazin-2-yl)pyridine-2,4,6-triamine,
(133) (S)-4-(cyclopropylmethoxy)-N 2 -[1-(4-fluorophenyl)ethyl]-N 6 -(pyrazin-2-yl)pyridine-2,6-diamine,
(134) (S)-N 2 -[1-(4-fluorophenyl)ethyl]-N 2 -methyl-4-(1-methyl-1H-pyrazol-4-yl)-N 6 -(pyrazine-2 -yl)pyridine-2,6-diamine,
(135) (S)-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyridin-4-yl}methanol,
(136) (S)-2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)isonicotinic acid,
(137) (S)—N 2 -[1-(4-fluorophenyl)ethyl]-4-(2-methoxyethoxy)-N 6 -(pyrazin-2-yl)pyridine-2,6-diamine,
(138) (S)-2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-carbonitrile (139) (S)-2-[1-( 4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)isonicotinonitrile,
(140) (S)-2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)isonicotinamide,
(141) (S)—N 2 -[1-(4-fluorophenyl)ethyl]-6-(1,2,4-oxadiazol-3-yl)-N 4 -(pyrazin-2-yl) pyrimidine-2,4-diamine,
(142) (S)—N 2 -[1-(4-fluorophenyl)ethyl]-4-(1,2,4-oxadiazol-3-yl)-N 6 -(pyrazin-2-yl) pyridine-2,6-diamine,
(143) (S)-2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)methyl nicotinate,
(144) (S)-2-[1-(4-fluorophenyl)ethylamino]-N,N-dimethyl-6-(pyrazin-2-ylamino)isonicotinamide,
(145) (S)-N-[2-(dimethylamino)ethyl]-2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)isonicotinamide,
(146) (S)-Nt-butyl-2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)isonicotinamide,
(147) (S)-N-ethyl-2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)isonicotinamide,
(148) (S)-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyridin-4-yl}[4-(methanesulfonyl)piperazin-1-yl ] methanone,
(149) (S)-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyridin-4-yl}(pyrrolidin-1-yl)methanone,
(150) (S)-2-[1-(4-fluorophenyl)ethylamino]-N-isopropyl-6-(pyrazin-2-ylamino)isonicotinamide,
(151) (S)-1-{2-[(S)-1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}azetidine-2-carboxamide,
(152) (S)—N 2 -[1-(4-fluorophenyl)ethyl]-N 6 -(pyrazin-2-yl)-4-(tetrahydro-2H-pyran-4-yloxy)pyridine-2, 6-diamine,
(153) (S)-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}azetidine-3-carboxamide,
(154) (S)-2-[1-(4-fluorophenyl)ethylamino]-N-(2-hydroxyethyl)-6-(pyrazin-2-ylamino)isonicotinamide,
(155) (S)-2-[1-(4-fluorophenyl)ethylamino]-N-methyl-6-(pyrazin-2-ylamino)isonicotinamide,
(156) (S)-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyridin-4-yl}(morpholino)methanone,
(157) (S)-N-benzyl-2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)isonicotinamide,
(158) (S)-N-cyclopropyl-2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)isonicotinamide,
(159) (S)-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyridin-4-yl})(4-methylpiperazin-1-yl)methanone ,
(160) (S)-2-[1-(4-fluorophenyl)ethylamino]-N-(2-methoxyethyl)-6-(pyrazin-2-ylamino)isonicotinamide,
(161) (S)-2-[1-(4-fluorophenyl)ethylamino]-N-propyl-6-(pyrazin-2-ylamino)isonicotinamide,
(162) (S)-N-cyclopropylmethyl-2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)isonicotinamide,
(163) (S)-N-cyclobutyl-2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)isonicotinamide,
(164) (S)-N-butyl-2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)isonicotinamide,
(165) (S)-2-[1-(4-fluorophenyl)ethylamino]-N-isobutyl-6-(pyrazin-2-ylamino)isonicotinamide,
(166) (S)-2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)-N-(2,2,2,-trifluoroethyl)isonicotinamide,
(167) (S)-2-[1-(4-fluorophenyl)ethylamino]-N-(3-hydroxypropyl)-6-(pyrazin-2-ylamino)isonicotinamide,
(168) (S)-N-(2-ethoxyethyl)-2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)isonicotinamide,
(169) (S)-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}-N-methylazetidine-3-carboxamide ,
(170) (S)-N 2 -[1-(4-fluorophenyl)ethyl]-4-(methoxymethyl)-N 6 -(pyrazin-2-yl)pyridine-2,6-diamine,
(171) (S)-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}-N,N-dimethylazetidine-3 - a carboxamide,
(172) (S)-N-(1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}azetidin-3-yl)methane sulfonamide,
(173) (S)-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}azetidine-3-carbonitrile,
(174) 2-(4-fluorophenyl)-2-[4-(1-methyl-1H-pyrazol-4-yl)-6-(pyrazin-2-ylamino)pyridin-2-ylamino]ethanol,
(175) (S)-N-ethyl-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}azetidine-3-carboxamide,
(176) (S)-N,N-diethyl-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}azetidin-3- carboxamide,
(177) (S)-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyridin-4-yl}ethanone,
(178) (S)-N 2 -[1-(4-fluorophenyl)ethyl]-6-(3-methoxyazetidin-1-yl)-N 4 -(pyrazin-2-yl)pyrimidine-2, 4-diamine,
(179) (S)-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}-3-methylazetidin-3-ol ,
(180) (S)-2-[1-(4-fluorophenyl)ethylamino]-N-methyl-6-(pyrazin-2-ylamino)nicotinamide,
(181) (S)-2-[1-(4-fluorophenyl)ethylamino]-N,N-dimethyl-6-(pyrazin-2-ylamino)nicotinamide,
(182) (S)-2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)nicotinamide,
(183) (S)-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyridin-3-yl}(morpholino)methanone,
(184) (S)-N-(cyclopropylmethyl)-2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)nicotinamide,
(185) (S)-N-(1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}azetidin-3-yl)ethane sulfonamide,
(186) (S)-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}-N-isopropylazetidine-3-carboxamide ,
(187) (S)-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}-3-(trifluoromethyl)azetidine- 3-all,
(188) (S)-(1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}azetidin-3-yl) (pyrrolidine- 1-yl)methanone,
(189) (S)-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}-N-(2-methoxyethyl)azetidine -3-carboxamide,
(190) (S)-(1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}azetidin-3-yl) (piperidin- 1-yl)methanone,
(191) (S)-(1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}azetidin-3-yl) (morpholino) methanone,
(192) (S)-N-(cyclopropyl)-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}azetidin-3 - a carboxamide,
(193) (S)-N-(cyclopropylmethyl)-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}azetidin- 3-carboxamide,
(194) (S)-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}-N-(2-hydroxyethyl)azetidine -3-carboxamide,
(195) (S)-3-cyclopropyl-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}azetidin-3-ol ,
(196) (S)-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}-3-isopropylazetidin-3-ol ,
(197) (S)-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyridin-4-yl}azetidin-3-ol,
(198) (S)-3-cyclopropyl-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyridin-4-yl}azetidin-3-ol ,
(199) (S)-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyridin-4-yl}-3-isopropylazetidin-3-ol ,
(200) (S)-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyridin-4-yl}-3-methylazetidin-3-ol ,
(201) (S)-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyridin-4-yl}-3-(trifluoromethyl)azetidine- 3-all,
(202) (S)-4-(3,3-difluoroazetidin-1-yl)-N 2 -[1-(4-fluorophenyl)ethyl]-N 6 -(pyrazin-2-yl)pyridine- 2,6-diamine,
(203) (S)-N-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyridin-4-yl}acetamide,
(204) (S)-N-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyridin-4-yl}methanesulfonamide,
(205) (S)-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyridin-4-yl}urea,
(206) (S)-4-(3-cyclopropyl-3-methoxyazetidin-1-yl)-N 2 -[1-(4-fluorophenyl)ethyl]-N 6 -(pyrazin-2-yl ) pyridine-2,6-diamine,
(207) (S)-N 2 -[1-(4-fluorophenyl)ethyl]-4-(3-isopropyl-3-methoxyazetidin-1-yl)-N 6 -(pyrazin-2-yl) pyridine-2,6-diamine,
(208) (S)—N 2 -[1-(4-fluorophenyl)ethyl]-4-(3-methoxy-3-methylazetidin-1-yl)-N 6 -(pyrazin-2-yl) pyridine-2,6-diamine,
(209) (S)-N 2 -[1-(4-fluorophenyl)ethyl]-4-(1-methyl-1H-pyrazol-4-yl)-N 6 -(5-methylpyrazin-2-yl ) pyridine-2,6-diamine,
(210) (S)—N 2 -[1-(4-fluorophenyl)ethyl]-4-[1-(methanesulfonyl)piperidin-4-yl]-N 6 -(pyrazin-2-yl)pyridine- 2,6-diamine,
(211) (S)-N-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyridin-4-yl}propionamide,
(212) (S)-N 2 -[1-(4-fluorophenyl)ethyl]-4-[1-(2-methoxyethyl)-1H-pyrazol-4-yl]-N 6 -(pyrazine-2 -yl)pyridine-2,6-diamine,
(213) (S)-4-(1-cyclopropyl-1H-pyrazol-4-yl)-N 2 -[1-(4-fluorophenyl)ethyl]-N 6 -(pyrazin-2-yl)pyridine -2,6-diamine,
(214) (S)—N 2 -[1-(4-fluorophenyl)ethyl]-4-[1-(methoxymethyl)-1H-pyrazol-4-yl]-N 6 -(pyrazin-2-yl ) pyridine-2,6-diamine,
(215) (S)-6-[3-(dimethylamino)azetidin-1-yl]-N 2 -[1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)pyrimidine- 2,4-diamine,
(216) (S)—N 2 -[1-(4-fluorophenyl)ethyl]-6-[3-(methylamino)azetidin-1-yl]-N 4 -(pyrazin-2-yl)pyrimidine- 2,4-diamine,
(217) (S)-N 2 -[1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)-6-[3-(pyrrolidin-1-yl)azetidin-1-yl ] pyrimidine-2,4-diamine,
(218) (S)—N 2 -[1-(4-fluorophenyl)ethyl]-6-(3-morpholinoazetidin-1-yl)-N 4 -(pyrazin-2-yl)pyrimidine-2, 4-diamine,
(219) (S)—N 2 -[1-(4-fluorophenyl)ethyl]-6-[3-(4-methylpiperazin-1-yl)azetidin-1-yl]-N 4 -(pyrazine- 2-yl)pyrimidine-2,4-diamine,
(220) (S)-(1-{1-[2-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}azetidin-3-yl)piperidine-4 - all,
(221) 4-{2-[(1S)-1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}-1λ 6 ,4-thiomorpholine-1 , 1-dione,
(222) (S)-1-(1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}azetidin-3-yl)urea ,
(223) (S)-(1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}azetidin-3-yl)methanol,
(224) (S)-(1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}azetidin-3-yl)methylcarbamate t - butyl,
(225) (S)-6-[3-(aminomethyl)azetidin-1-yl]-N 2 -[1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)pyrimidine- 2,4-diamine,
(226) (S)-N-[(1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}azetidin-3-yl) methyl]ethanesulfonamide,
(227) (S)-N-[(1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}azetidin-3-yl) methyl]acetamide,
(228) (S)—N 2 -[1-(4-fluorophenyl)ethyl]-4-[3-morpholinoazetidin-1-yl]-N 6 -(pyrazin-2-yl)pyridine-2, 6-diamine,
(229) (S)-1-(1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyridin-4-yl}azetidin-3-yl)piperidine -4-ol.
(230) (S)—N 2 -[1-(4-fluorophenyl)ethyl]-4-(1-methyl-1H-pyrazol-4-yl)-N 6 -(pyrazin-2-yl)pyridine- 2,6-diamine maleate (hereinafter "compound A").
本発明化合物の中で、具体的に次の化合物又はその医薬上許容される塩が更に好ましい。
(S)-N2-[1-(4-フルオロフェニル)エチル]-4-(1-メチル-1H-ピラゾール-4-イル)-N6-(ピラジン-2-イル)ピリジン-2,6-ジアミン、
(S)-N2-[1-(4-フルオロフェニル)エチル]-4-(1-メチル-1H-ピラゾール-4-イル)-N6-(ピラジン-2-イル)ピリジン-2,6-ジアミン 塩酸塩、
(S)-N2-[1-(4-フルオロフェニル)エチル]-4-(1-メチル-1H-ピラゾール-4-イル)-N6-(ピラジン-2-イル)ピリジン-2,6-ジアミン マレイン酸塩(以下、「化合物A」)。 Among the compounds of the present invention, specifically the following compounds or pharmaceutically acceptable salts thereof are more preferred.
(S)-N2-[1-(4-fluorophenyl)ethyl]-4-(1-methyl-1H-pyrazol-4-yl)-N6-(pyrazin-2-yl)pyridine-2,6-diamine ,
(S)-N2-[1-(4-fluorophenyl)ethyl]-4-(1-methyl-1H-pyrazol-4-yl)-N6-(pyrazin-2-yl)pyridine-2,6-diamine hydrochloride,
(S)—N 2 -[1-(4-fluorophenyl)ethyl]-4-(1-methyl-1H-pyrazol-4-yl)-N 6 -(pyrazin-2-yl)pyridine-2,6 - diamine maleate (hereinafter "Compound A").
(S)-N2-[1-(4-フルオロフェニル)エチル]-4-(1-メチル-1H-ピラゾール-4-イル)-N6-(ピラジン-2-イル)ピリジン-2,6-ジアミン、
(S)-N2-[1-(4-フルオロフェニル)エチル]-4-(1-メチル-1H-ピラゾール-4-イル)-N6-(ピラジン-2-イル)ピリジン-2,6-ジアミン 塩酸塩、
(S)-N2-[1-(4-フルオロフェニル)エチル]-4-(1-メチル-1H-ピラゾール-4-イル)-N6-(ピラジン-2-イル)ピリジン-2,6-ジアミン マレイン酸塩(以下、「化合物A」)。 Among the compounds of the present invention, specifically the following compounds or pharmaceutically acceptable salts thereof are more preferred.
(S)-N2-[1-(4-fluorophenyl)ethyl]-4-(1-methyl-1H-pyrazol-4-yl)-N6-(pyrazin-2-yl)pyridine-2,6-diamine ,
(S)-N2-[1-(4-fluorophenyl)ethyl]-4-(1-methyl-1H-pyrazol-4-yl)-N6-(pyrazin-2-yl)pyridine-2,6-diamine hydrochloride,
(S)—N 2 -[1-(4-fluorophenyl)ethyl]-4-(1-methyl-1H-pyrazol-4-yl)-N 6 -(pyrazin-2-yl)pyridine-2,6 - diamine maleate (hereinafter "Compound A").
本発明化合物又はその医薬上許容される塩は、医薬として有用である。
The compound of the present invention or a pharmaceutically acceptable salt thereof is useful as a medicament.
以下に本発明に係る各用語を詳述する。
Each term related to the present invention will be described in detail below.
「ハロゲン」としては、例えば、フッ素、塩素、臭素、ヨウ素を挙げることができる。
"Halogen" includes, for example, fluorine, chlorine, bromine, and iodine.
「アルキル」としては、例えば、直鎖状又は分枝鎖状の炭素数1~8のもの、具体的には、メチル、エチル、n-プロピル、イソプロピル、n-ブチル、イソブチル、sec-ブチル、tert-ブチル、n-ペンチル、イソペンチル、n-ヘキシル、イソヘキシル、n-ヘプチル、イソヘプチル、n-オクチルを挙げることができる。なかでも、炭素数1~6のものが好ましく、炭素数1~3のものがより好ましい。
"Alkyl" includes, for example, linear or branched ones having 1 to 8 carbon atoms, specifically methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, Mention may be made of tert-butyl, n-pentyl, isopentyl, n-hexyl, isohexyl, n-heptyl, isoheptyl, n-octyl. Among them, those having 1 to 6 carbon atoms are preferable, and those having 1 to 3 carbon atoms are more preferable.
「アルキルスルホニル」、「アルキルカルボニルアミノ」、「ヒドロキシアルキル」、「(シクロアルキル)アルキル」、「アルコキシアルキル」、「アルキルアミノ」、「(ヒドロキシアルキル)アミノ」、「(アルコキシアルキル)アミノ」、「ジアルキルアミノ」、「ジアルキルアミノアルキル」「(シクロアルキル)アルキルアミノ」、「アルキルカルボニル」、「アルキルカルボニルアミノ」、「アルキルスルホニル」、「アルキルスルホニルアミノ」、「モノアルキルアミノスルホニル」のアルキル部分としては、上記の「アルキル」と同様のものを挙げることができる。
"alkylsulfonyl", "alkylcarbonylamino", "hydroxyalkyl", "(cycloalkyl)alkyl", "alkoxyalkyl", "alkylamino", "(hydroxyalkyl)amino", "(alkoxyalkyl)amino", Alkyl moieties of "dialkylamino", "dialkylaminoalkyl", "(cycloalkyl)alkylamino", "alkylcarbonyl", "alkylcarbonylamino", "alkylsulfonyl", "alkylsulfonylamino" and "monoalkylaminosulfonyl" Examples of the group include those similar to the above-mentioned "alkyl".
「ハロアルキル」としては、例えば、1個又はそれ以上のハロゲン原子が置換可能な任意の位置で置換された直鎖状又は分枝鎖状の炭素数1~8のアルキルを挙げることができる。「ハロアルキル」のアルキル部分、ハロゲン部分としては、それぞれ上記の「アルキル」、「ハロゲン」と同様のものを挙げることができる。
"Haloalkyl" includes, for example, linear or branched alkyl having 1 to 8 carbon atoms substituted at any position where one or more halogen atoms can be substituted. Examples of the alkyl moiety and halogen moiety of "haloalkyl" include those similar to the above-mentioned "alkyl" and "halogen", respectively.
「シクロアルキル」としては、例えば、炭素数3~8のもの、具体的には、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル、シクロヘプチル、シクロオクチル等が挙げられる。
"Cycloalkyl" includes, for example, those having 3 to 8 carbon atoms, specifically cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.
「(シクロアルキル)アルキル」、「シクロアルキルアミノ」、「(シクロアルキル)アルキルアミノ」のシクロアルキル部分としては、上記の「シクロアルキル」と同様のものを挙げることができる。
As the cycloalkyl portion of "(cycloalkyl)alkyl", "cycloalkylamino", and "(cycloalkyl)alkylamino", the same ones as the above-mentioned "cycloalkyl" can be mentioned.
「アルコキシ」としては、例えば、直鎖状又は分枝鎖状の炭素数1~8のもの、具体的には、メトキシ、エトキシ、n-プロポキシ、イソプロポキシ、n-ブトキシ、イソブトキシ、sec-ブトキシ、t-ブトキシ、n-ペンチルオキシ、n-ヘキシルオキシ、n-ヘプチルオキシ、n-オクチルオキシを挙げることができる。
"Alkoxy" includes, for example, linear or branched chain having 1 to 8 carbon atoms, specifically methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy , t-butoxy, n-pentyloxy, n-hexyloxy, n-heptyloxy, n-octyloxy.
「アルコキシアルキル」、「(アルコキシアルキル)アミノ」のアルコキシ部分としては、上記の「アルコキシ」と同様のものを挙げることができる。
Examples of the alkoxy moiety of "alkoxyalkyl" and "(alkoxyalkyl)amino" include the same as the above-mentioned "alkoxy".
「アリール」としては、炭素数6~10のもの、例えば、フェニル、1-ナフチル、2-ナフチルを挙げることができる。なかでもフェニルが好ましい。
"Aryl" includes those having 6 to 10 carbon atoms, such as phenyl, 1-naphthyl, and 2-naphthyl. Among them, phenyl is preferred.
「アラルキル」としては、例えば、炭素数6~10のアリールが置換可能な任意の位置で置換された直鎖状又は分枝鎖状の炭素数1~8のアルキル、例えば、ベンジル、フェニルエチル(例えば、1-フェニルエチル,2-フェニルエチル)、フェニルプロピル(1-フェニルプロピル、2-フェニルプロピル、3-フェニルプロピル等)、ナフチルメチル(例えば、1-ナフチルメチル、2-ナフチルメチル等)が挙げることができる。
"Aralkyl" includes, for example, straight- or branched-chain alkyl having 1 to 8 carbon atoms substituted at any position where aryl having 6 to 10 carbon atoms can be substituted, such as benzyl, phenylethyl ( For example, 1-phenylethyl, 2-phenylethyl), phenylpropyl (1-phenylpropyl, 2-phenylpropyl, 3-phenylpropyl, etc.), naphthylmethyl (eg, 1-naphthylmethyl, 2-naphthylmethyl, etc.) can be mentioned.
「飽和環状アミノ基」としては、例えば、環構成原子として、O又はSを1個有していてもよい、Nを1個又は2個有する4員~7員の飽和環状アミノ基、具体的には、1-アゼチジニル、1-ピロリジニル、1-イミダゾリジニル、ピペリジノ、1-ピペラジニル、1-テトラヒドロピリミジニル、モルホリノ、チオモルホリノ、1-ホモピペラジニルを挙げることができる。
The "saturated cyclic amino group" includes, for example, a 4- to 7-membered saturated cyclic amino group having one or two N, optionally having one O or S as a ring-constituting atom, specifically include 1-azetidinyl, 1-pyrrolidinyl, 1-imidazolidinyl, piperidino, 1-piperazinyl, 1-tetrahydropyrimidinyl, morpholino, thiomorpholino, 1-homopiperazinyl.
「1個のNを含む飽和複素環式基」としては、例えば、環構成原子として、Nを1個有する5員又は6員の飽和複素環式基、具体的には、例えば、2-ピロリジニル、3-ピロリジニル、2-ピペリジニル、3-ピペリジニル、4-ピペリジニルを挙げることができる。
Examples of the "saturated heterocyclic group containing one N" include, for example, a 5- or 6-membered saturated heterocyclic group having one N as a ring-constituting atom, specifically, for example, 2-pyrrolidinyl , 3-pyrrolidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl.
「1個のOを含んでいてもよい飽和環式基」としては、例えば、環構成原子として、Oを1個有していてもよい5員又は6員の飽和環式基、具体的には、例えば、シクロペンチル、シクロヘキシル、テトラヒドロフラニル、テトラヒドロピラニルを挙げることができる。
The "saturated cyclic group optionally containing 1 O" includes, for example, a 5- or 6-membered saturated cyclic group optionally having 1 O as a ring-constituting atom, specifically is, for example, cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl.
「ヘテロアリール」としては、例えば、環構成原子として、N、O、Sを1個ないし4個有する5員若しくは6員のもの、具体的には、例えば、フリル(例えば、2-フリル、3-フリル)、チエニル(例えば、2-チエニル、3-チエニル)、ピロリル(例えば、1-ピロリル、2-ピロリル、3-ピロリル)、イミダゾリル(例えば、1-イミダゾリル、2-イミダゾリル、4-イミダゾリル)、ピラゾリル(例えば、1-ピラゾリル、3-ピラゾリル、4-ピラゾリル)、トリアゾリル(例えば、1,2,4-トリアゾール-1-イル、1,2,4-トリアゾール-3-イル、1,2,4-トリアゾール-4-イル)、テトラゾリル(例えば、1-テトラゾリル、2-テトラゾリル、5-テトラゾリル)、オキサゾリル(例えば、2-オキサゾリル、4-オキサゾリル、5-オキサゾリル)、イソキサゾリル(例えば、3-イソキサゾリル、4-イソキサゾリル、5-イソキサゾリル)、オキサジアゾリル(例えば、1,3,4-オキサジアゾール-2-イル)、チアゾリル(例えば、2-チアゾリル、4-チアゾリル、5-チアゾリル)、チアジアゾリル、イソチアゾリル(例えば、3-イソチアゾリル、4-イソチアゾリル、5-イソチアゾリル)、ピリジル(例えば、2-ピリジル、3-ピリジル、4-ピリジル)、ピリダジニル(例えば、3-ピリダジニル、4-ピリダジニル)、ピリミジニル(例えば、2-ピリミジニル、4-ピリミジニル、5-ピリミジニル)、ピラジニル(例えば、2-ピラジニル)を挙げることができる。
"Heteroaryl" includes, for example, 5- or 6-membered ones having 1 to 4 N, O, and S as ring-constituting atoms, specifically, for example, furyl (e.g., 2-furyl, 3 -furyl), thienyl (e.g. 2-thienyl, 3-thienyl), pyrrolyl (e.g. 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), imidazolyl (e.g. 1-imidazolyl, 2-imidazolyl, 4-imidazolyl) , pyrazolyl (eg 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl), triazolyl (eg 1,2,4-triazol-1-yl, 1,2,4-triazol-3-yl, 1,2, 4-triazol-4-yl), tetrazolyl (eg 1-tetrazolyl, 2-tetrazolyl, 5-tetrazolyl), oxazolyl (eg 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), isoxazolyl (eg 3-isoxazolyl) , 4-isoxazolyl, 5-isothiazolyl), oxadiazolyl (e.g. 1,3,4-oxadiazol-2-yl), thiazolyl (e.g. 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), thiadiazolyl, isothiazolyl ( 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl), pyridyl (e.g. 2-pyridyl, 3-pyridyl, 4-pyridyl), pyridazinyl (e.g. 3-pyridazinyl, 4-pyridazinyl), pyrimidinyl (e.g. 2 -pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), pyrazinyl (eg 2-pyrazinyl).
「テトラヒドロフラニル」としては、例えば、2-テトラヒドフラニル、3-ヒドロフラニルを挙げることができる。
"Tetrahydrofuranyl" includes, for example, 2-tetrahydrofuranyl and 3-hydrofuranyl.
「テトラヒドロピラニル」としては、例えば、2-テトラヒドロピラニル、3-テトラヒドロピラニル、4-テトラヒドロピラニルを挙げることができる。
"Tetrahydropyranyl" includes, for example, 2-tetrahydropyranyl, 3-tetrahydropyranyl, and 4-tetrahydropyranyl.
本発明化合物は、公知化合物又は容易に合成可能な中間体から、例えば下記の方法に従って製造することができる。本発明化合物の製造において、原料が反応に影響を及ぼす置換基を有する場合には、原料をあらかじめ公知の方法により適当な保護基で保護した後に反応を行うのが一般的である。保護基は、反応後に、公知の方法により脱離することができる。
The compounds of the present invention can be produced from known compounds or easily synthesizable intermediates according to, for example, the following methods. In the production of the compound of the present invention, when the raw material has a substituent group that affects the reaction, the raw material is generally protected in advance with a suitable protecting group by a known method before the reaction is carried out. The protecting group can be removed by a known method after the reaction.
製法1 R
2
がハロゲンの場合
(R1、R5は、前記と同義である。X1は、CH又はNを表す。Hal1、Hal2は、同一又は異なって、ハロゲンを表す。)
Production method 1 When R 2 is halogen
(R 1 and R 5 are as defined above. X 1 represents CH or N. Hal 1 and Hal 2 are the same or different and represent halogen.)
本反応は、化合物[12]と化合物[13]とのパラジウム触媒を用いた縮合反応であって、それ故、縮合反応としてそれ自体公知の方法によって行うことができる。使用しうる溶媒としては、反応に関与しなければ特に限定されないが、例えば、トルエン、キシレンなどの炭化水素類、1,4-ジオキサン、テトラヒドロフランなどのエーテル類、N,N-ジメチルホルムアミド、N,N-ジメチルアセトアミド、N-メチル-2-ピロリドンなどのアミド類、又はこれらの混合溶媒を挙げることができる。反応は塩基の存在下、20℃~200℃の範囲内で行う。使用しうるパラジウム触媒としては、例えば、トリス(ジベンジリデンアセトン)(クロロホルム)ジパラジウム(0)、トリス(ジベンジリデンアセトン)ジパラジウム(0)、酢酸パラジウム(II)が挙げられる。使用しうるパラジウム触媒の量は、ハロゲン化アリール1モルに対して、0.001~0.1モルの範囲内が適当である。使用しうるパラジウム触媒のリガンドとしては、例えば、1,1’-ビス(ジフェニルホスフィノ)フェロセン、4,5-ビス(ジフェニルホスフィノ)-9,9’-ジメチルキサンテン、2-ジシクロヘキシルホスフィノ-2’,4’,6’-トリイソプロピルビフェニル、(±)-2,2’-ビス(ジフェニルホスフィノ)-1,1’-ビナフチル、2-(ジ-t-ブチルホスフィノ)ビフェニル、ビス[2-(ジフェニルホスフィノ)フェニル]エーテル、トリt-ブチルホスフィンを挙げることができる。使用しうる塩基としては、例えば、ナトリウムt-ブトキシド、リン酸三カリウム、炭酸セシウムを挙げることができる。反応時間は、使用する原料の種類、反応温度等によって異なるが、通常、10分~24時間の範囲内が適当である。
This reaction is a condensation reaction of compound [12] and compound [13] using a palladium catalyst, and therefore can be carried out by a method known per se as a condensation reaction. Solvents that can be used are not particularly limited as long as they do not participate in the reaction. Examples include hydrocarbons such as toluene and xylene, ethers such as 1,4-dioxane and tetrahydrofuran, N,N-dimethylformamide, N, Amides such as N-dimethylacetamide and N-methyl-2-pyrrolidone, or mixed solvents thereof can be used. The reaction is carried out in the presence of a base within the range of 20°C to 200°C. Palladium catalysts that may be used include, for example, tris(dibenzylideneacetone)(chloroform)dipalladium(0), tris(dibenzylideneacetone)dipalladium(0), palladium(II) acetate. The amount of palladium catalyst that can be used is suitably in the range of 0.001 to 0.1 mol per 1 mol of the aryl halide. Palladium catalyst ligands that can be used include, for example, 1,1′-bis(diphenylphosphino)ferrocene, 4,5-bis(diphenylphosphino)-9,9′-dimethylxanthene, 2-dicyclohexylphosphino- 2',4',6'-triisopropylbiphenyl, (±)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl, 2-(di-t-butylphosphino)biphenyl, bis Mention may be made of [2-(diphenylphosphino)phenyl]ether, tri-t-butylphosphine. Usable bases include, for example, sodium t-butoxide, tripotassium phosphate, and cesium carbonate. The reaction time varies depending on the type of raw material used, the reaction temperature, etc., but is usually within the range of 10 minutes to 24 hours.
原料化合物である化合物[12]は、公知の方法(Bioorg.Med.Chem.Lett.,14,2004,4249-4252、Org.Lett.,6,2004,3671-3674など)に準じて製造することができる。
Compound [12] as a starting compound is produced according to known methods (Bioorg. Med. Chem. Lett., 14, 2004, 4249-4252, Org. Lett., 6, 2004, 3671-3674, etc.). be able to.
製法2 R
2
が-OR
P
の場合(式中、RPは、前記と同義である。)
製法2-1
(X1、R1、R5、Hal2は、前記と同義である。RPは、ヒドロキシ、ジアルキルアミノ、アルコキシ、テトラヒドロフラニル、及びシクロアルキルからなる群から選択される基で置換されていてもよいアルキル、又は、ヒドロキシで置換されていてもよく、1個のOを含んでいてもよい飽和環式基を表す。)
Production Method 2 When R 2 is —OR P (Wherein, R P has the same definition as above.)
Manufacturing method 2-1
(X 1 , R 1 , R 5 and Hal 2 are as defined above; R P is substituted with a group selected from the group consisting of hydroxy, dialkylamino, alkoxy, tetrahydrofuranyl and cycloalkyl; may be alkyl, or a saturated cyclic group optionally substituted by hydroxy and optionally containing one O).
製法2-1
Manufacturing method 2-1
本反応は、化合物[1a]とアルコール化合物[14]とのパラジウム触媒を用いた縮合反応により行われる。使用しうる溶媒としては、反応に関与しなければ特に限定されないが、例えば、トルエン、キシレンなどの炭化水素類、1,4-ジオキサン、テトラヒドロフランなどのエーテル類、N,N-ジメチルホルムアミド、N,N-ジメチルアセトアミド、N-メチル-2-ピロリドンなどのアミド類、又はこれらの混合溶媒を挙げることができる。本反応は塩基の存在下、20℃~200℃の範囲内で行うことができる。パラジウム触媒としては、例えば、トリス(ジベンジリデンアセトン)(クロロホルム)ジパラジウム(0)、トリス(ジベンジリデンアセトン)ジパラジウム(0)、酢酸パラジウム(II)が挙げられる。使用しうるパラジウム触媒の量は、ハロゲン化アリール1モルに対して、0.001~0.1モルの範囲内が適当である。使用しうるパラジウム触媒のリガンドとしては、例えば、4,5-ビス(ジフェニルホスフィノ)-9,9’-ジメチルキサンテン、2-ジシクロヘキシルホスフィノ-2’,4’,6’-トリイソプロピルビフェニル、(±)-2,2’-ビス(ジフェニルホスフィノ)-1,1’-ビナフチル、2-(ジ-t-ブチルホスフィノ)ビフェニル、ビス[2-(ジフェニルホスフィノ)フェニル]エーテルを挙げることができる。使用しうる塩基としては、例えば、ナトリウムt-ブトキシド、リン酸三カリウムを挙げることができる。反応時間は、使用する原料の種類、反応温度等によって異なるが、通常、10分~24時間の範囲内が適当である。
This reaction is carried out by condensation reaction of compound [1a] and alcohol compound [14] using a palladium catalyst. Solvents that can be used are not particularly limited as long as they do not participate in the reaction. Examples include hydrocarbons such as toluene and xylene, ethers such as 1,4-dioxane and tetrahydrofuran, N,N-dimethylformamide, N, Amides such as N-dimethylacetamide and N-methyl-2-pyrrolidone, or mixed solvents thereof can be used. This reaction can be carried out in the presence of a base at a temperature within the range of 20°C to 200°C. Palladium catalysts include, for example, tris(dibenzylideneacetone)(chloroform)dipalladium(0), tris(dibenzylideneacetone)dipalladium(0), and palladium(II) acetate. The amount of palladium catalyst that can be used is suitably in the range of 0.001 to 0.1 mol per 1 mol of the aryl halide. Palladium catalyst ligands that can be used include, for example, 4,5-bis(diphenylphosphino)-9,9′-dimethylxanthene, 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, (±)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, 2-(di-t-butylphosphino)biphenyl, bis[2-(diphenylphosphino)phenyl]ether be able to. Usable bases include, for example, sodium t-butoxide and tripotassium phosphate. The reaction time varies depending on the type of raw material used, the reaction temperature, etc., but is usually within the range of 10 minutes to 24 hours.
製法2-2
(X1、R1、R5、RP、Hal1は、前記と同義である。)
本反応は、化合物[15]と化合物[13]とのパラジウム触媒を用いた縮合反応であって、前記製法1と同様の方法によって行うことができる。 Manufacturing method 2-2
(X 1 , R 1 , R 5 , R P , and Hal 1 are as defined above.)
This reaction is a condensation reaction of compound [15] and compound [13] using a palladium catalyst, and can be carried out in the same manner as in production method 1 above.
本反応は、化合物[15]と化合物[13]とのパラジウム触媒を用いた縮合反応であって、前記製法1と同様の方法によって行うことができる。 Manufacturing method 2-2
This reaction is a condensation reaction of compound [15] and compound [13] using a palladium catalyst, and can be carried out in the same manner as in production method 1 above.
原料化合物である化合物[15]は、例えば、次の方法に従って製造することができる。
Compound [15], which is a raw material compound, can be produced, for example, according to the following method.
工程1
化合物[18]は、化合物[16]とアルコール化合物[17]とを適当な溶媒中、塩基の存在下、-20℃~100℃の範囲内で反応させることにより製造することができる。使用しうる塩基としては、例えば、水素化ナトリウム、水酸化ナトリウム等を挙げることができる。使用しうる溶媒としては、反応に関与しなければ特に限定されないが、例えば、トルエン、キシレンなどの炭化水素類、1,4-ジオキサン、テトラヒドロフランなどのエーテル類、N,N-ジメチルホルムアミド、N,N-ジメチルアセトアミド、N-メチル-2-ピロリドンなどのアミド類、水、又はこれらの混合溶媒を挙げることができる。反応時間は、使用する原料の種類、反応温度によって異なるが、通常30分から24時間が適当である。 Process 1
Compound [18] can be produced by reacting compound [16] and alcohol compound [17] in a suitable solvent in the presence of a base at -20°C to 100°C. Usable bases include, for example, sodium hydride and sodium hydroxide. Solvents that can be used are not particularly limited as long as they do not participate in the reaction. Examples include hydrocarbons such as toluene and xylene, ethers such as 1,4-dioxane and tetrahydrofuran, N,N-dimethylformamide, N, Amides such as N-dimethylacetamide and N-methyl-2-pyrrolidone, water, and mixed solvents thereof can be used. The reaction time varies depending on the type of raw materials used and the reaction temperature, but is generally 30 minutes to 24 hours.
化合物[18]は、化合物[16]とアルコール化合物[17]とを適当な溶媒中、塩基の存在下、-20℃~100℃の範囲内で反応させることにより製造することができる。使用しうる塩基としては、例えば、水素化ナトリウム、水酸化ナトリウム等を挙げることができる。使用しうる溶媒としては、反応に関与しなければ特に限定されないが、例えば、トルエン、キシレンなどの炭化水素類、1,4-ジオキサン、テトラヒドロフランなどのエーテル類、N,N-ジメチルホルムアミド、N,N-ジメチルアセトアミド、N-メチル-2-ピロリドンなどのアミド類、水、又はこれらの混合溶媒を挙げることができる。反応時間は、使用する原料の種類、反応温度によって異なるが、通常30分から24時間が適当である。 Process 1
Compound [18] can be produced by reacting compound [16] and alcohol compound [17] in a suitable solvent in the presence of a base at -20°C to 100°C. Usable bases include, for example, sodium hydride and sodium hydroxide. Solvents that can be used are not particularly limited as long as they do not participate in the reaction. Examples include hydrocarbons such as toluene and xylene, ethers such as 1,4-dioxane and tetrahydrofuran, N,N-dimethylformamide, N, Amides such as N-dimethylacetamide and N-methyl-2-pyrrolidone, water, and mixed solvents thereof can be used. The reaction time varies depending on the type of raw materials used and the reaction temperature, but is generally 30 minutes to 24 hours.
工程2
本反応は、化合物[18]と化合物[19]とのパラジウム触媒を用いた縮合反応であって、それ故、縮合反応としてそれ自体公知の方法によって行うことができる。使用しうる溶媒としては、反応に関与しなければ特に限定されないが、例えば、トルエン、キシレンなどの炭化水素類、1,4-ジオキサン、テトラヒドロフランなどのエーテル類、N,N-ジメチルホルムアミド、N,N-ジメチルアセトアミド、N-メチル-2-ピロリドンなどのアミド類、又はこれらの混合溶媒を挙げることができる。本反応は、塩基の存在下、20℃~200℃の範囲内で反応を行うことができる。使用しうるパラジウム触媒としては、例えば、トリス(ジベンジリデンアセトン)(クロロホルム)ジパラジウム(0)、トリス(ジベンジリデンアセトン)ジパラジウム(0)、酢酸パラジウム(II)を挙げることができる。使用しうるパラジウム触媒の量は、ハロゲン化アリール1モルに対して、0.001~0.1モルの範囲内が適当である。使用しうるパラジウム触媒のリガンドとしては、例えば、4,5-ビス(ジフェニルホスフィノ)-9,9’-ジメチルキサンテン、(±)-2,2’-ビス(ジフェニルホスフィノ)-1,1’-ビナフチル、2-(ジ-t-ブチルホスフィノ)ビフェニル、ビス[2-(ジフェニルホスフィノ)フェニル]エーテル、トリt-ブチルホスフィンを挙げることができる。使用しうる塩基としては、例えば、ナトリウムt-ブトキシド、リン酸三カリウム、炭酸セシウムを挙げることができる。反応時間は、使用する原料の種類、反応温度等によって異なるが、通常、10分~24時間の範囲内が適当である。 Process 2
This reaction is a condensation reaction of compound [18] and compound [19] using a palladium catalyst, and therefore can be carried out by a method known per se as a condensation reaction. Solvents that can be used are not particularly limited as long as they do not participate in the reaction. Examples include hydrocarbons such as toluene and xylene, ethers such as 1,4-dioxane and tetrahydrofuran, N,N-dimethylformamide, N, Amides such as N-dimethylacetamide and N-methyl-2-pyrrolidone, or mixed solvents thereof can be used. This reaction can be carried out in the presence of a base within the range of 20°C to 200°C. Palladium catalysts that can be used include, for example, tris(dibenzylideneacetone)(chloroform)dipalladium(0), tris(dibenzylideneacetone)dipalladium(0), and palladium(II) acetate. The amount of palladium catalyst that can be used is suitably in the range of 0.001 to 0.1 mol per 1 mol of the aryl halide. Palladium catalyst ligands that can be used include, for example, 4,5-bis(diphenylphosphino)-9,9′-dimethylxanthene, (±)-2,2′-bis(diphenylphosphino)-1,1 '-Binaphthyl, 2-(di-t-butylphosphino)biphenyl, bis[2-(diphenylphosphino)phenyl]ether, tri-t-butylphosphine can be mentioned. Usable bases include, for example, sodium t-butoxide, tripotassium phosphate, and cesium carbonate. The reaction time varies depending on the type of raw material used, the reaction temperature, etc., but is usually within the range of 10 minutes to 24 hours.
本反応は、化合物[18]と化合物[19]とのパラジウム触媒を用いた縮合反応であって、それ故、縮合反応としてそれ自体公知の方法によって行うことができる。使用しうる溶媒としては、反応に関与しなければ特に限定されないが、例えば、トルエン、キシレンなどの炭化水素類、1,4-ジオキサン、テトラヒドロフランなどのエーテル類、N,N-ジメチルホルムアミド、N,N-ジメチルアセトアミド、N-メチル-2-ピロリドンなどのアミド類、又はこれらの混合溶媒を挙げることができる。本反応は、塩基の存在下、20℃~200℃の範囲内で反応を行うことができる。使用しうるパラジウム触媒としては、例えば、トリス(ジベンジリデンアセトン)(クロロホルム)ジパラジウム(0)、トリス(ジベンジリデンアセトン)ジパラジウム(0)、酢酸パラジウム(II)を挙げることができる。使用しうるパラジウム触媒の量は、ハロゲン化アリール1モルに対して、0.001~0.1モルの範囲内が適当である。使用しうるパラジウム触媒のリガンドとしては、例えば、4,5-ビス(ジフェニルホスフィノ)-9,9’-ジメチルキサンテン、(±)-2,2’-ビス(ジフェニルホスフィノ)-1,1’-ビナフチル、2-(ジ-t-ブチルホスフィノ)ビフェニル、ビス[2-(ジフェニルホスフィノ)フェニル]エーテル、トリt-ブチルホスフィンを挙げることができる。使用しうる塩基としては、例えば、ナトリウムt-ブトキシド、リン酸三カリウム、炭酸セシウムを挙げることができる。反応時間は、使用する原料の種類、反応温度等によって異なるが、通常、10分~24時間の範囲内が適当である。 Process 2
This reaction is a condensation reaction of compound [18] and compound [19] using a palladium catalyst, and therefore can be carried out by a method known per se as a condensation reaction. Solvents that can be used are not particularly limited as long as they do not participate in the reaction. Examples include hydrocarbons such as toluene and xylene, ethers such as 1,4-dioxane and tetrahydrofuran, N,N-dimethylformamide, N, Amides such as N-dimethylacetamide and N-methyl-2-pyrrolidone, or mixed solvents thereof can be used. This reaction can be carried out in the presence of a base within the range of 20°C to 200°C. Palladium catalysts that can be used include, for example, tris(dibenzylideneacetone)(chloroform)dipalladium(0), tris(dibenzylideneacetone)dipalladium(0), and palladium(II) acetate. The amount of palladium catalyst that can be used is suitably in the range of 0.001 to 0.1 mol per 1 mol of the aryl halide. Palladium catalyst ligands that can be used include, for example, 4,5-bis(diphenylphosphino)-9,9′-dimethylxanthene, (±)-2,2′-bis(diphenylphosphino)-1,1 '-Binaphthyl, 2-(di-t-butylphosphino)biphenyl, bis[2-(diphenylphosphino)phenyl]ether, tri-t-butylphosphine can be mentioned. Usable bases include, for example, sodium t-butoxide, tripotassium phosphate, and cesium carbonate. The reaction time varies depending on the type of raw material used, the reaction temperature, etc., but is usually within the range of 10 minutes to 24 hours.
製法3 R
2
が次の一般式[9]で表される基、
(式中、R
M
、R
N
、R
O
、*は、前記と同義である。)、又は、
シアノ、ハロゲン、ヒドロキシ、アルコキシ、アルキルカルボニル、カルバモイル、アルキル、シクロアルキル、(シクロアルキル)アルキル、アラルキル、ヒドロキシカルボニル及びアルコキシアルキルからなる群から選択される1若しくは2個の基で置換されていてもよいヘテロアリール(但し、結合手がCから出ているものに限る。)の場合 Production method 3 R 2 is a group represented by the following general formula [9],
(Wherein, R M , R N , R O , * are as defined above.), or
even substituted with 1 or 2 groups selected from the group consisting of cyano, halogen, hydroxy, alkoxy, alkylcarbonyl, carbamoyl, alkyl, cycloalkyl, (cycloalkyl)alkyl, aralkyl, hydroxycarbonyl and alkoxyalkyl In the case of good heteroaryl (limited to those where the bond is from C)
シアノ、ハロゲン、ヒドロキシ、アルコキシ、アルキルカルボニル、カルバモイル、アルキル、シクロアルキル、(シクロアルキル)アルキル、アラルキル、ヒドロキシカルボニル及びアルコキシアルキルからなる群から選択される1若しくは2個の基で置換されていてもよいヘテロアリール(但し、結合手がCから出ているものに限る。)の場合 Production method 3 R 2 is a group represented by the following general formula [9],
even substituted with 1 or 2 groups selected from the group consisting of cyano, halogen, hydroxy, alkoxy, alkylcarbonyl, carbamoyl, alkyl, cycloalkyl, (cycloalkyl)alkyl, aralkyl, hydroxycarbonyl and alkoxyalkyl In the case of good heteroaryl (limited to those where the bond is from C)
製法3-1
(X1、R1、R5、Hal2は、前記と同義である。R6、R7は、いずれもヒドロキシを表すか、R6とR7が一緒になって、-O-C(CH3)2-C(CH3)2-O-、-O-(CH2)3-O-、又は、-O-CH2-C(CH3)2-CH2-O-を表す。
Manufacturing method 3-1
(X 1 , R 1 , R 5 and Hal 2 are as defined above. R 6 and R 7 both represent hydroxy, or R 6 and R 7 together represent —O—C ( represents CH 3 ) 2 -C(CH 3 ) 2 -O-, -O-(CH 2 ) 3 -O-, or -O-CH 2 -C(CH 3 ) 2 -CH 2 -O-.
R8は、次の一般式[9]で表される基、
(式中、RM、RN、RO、*は、前記と同義である。)、又は、
シアノ、ハロゲン、ヒドロキシ、アルコキシ、アルキルカルボニル、カルバモイル、アルキル、シクロアルキル、(シクロアルキル)アルキル、アラルキル、ヒドロキシカルボニル及びアルコキシアルキルからなる群から選択される1若しくは2個の基で置換されていてもよいヘテロアリール(但し、結合手がCから出ているものに限る。)を表す。) R 8 is a group represented by the following general formula [9],
(Wherein, R M , R N , R O , * are as defined above.), or
even substituted with 1 or 2 groups selected from the group consisting of cyano, halogen, hydroxy, alkoxy, alkylcarbonyl, carbamoyl, alkyl, cycloalkyl, (cycloalkyl)alkyl, aralkyl, hydroxycarbonyl and alkoxyalkyl It represents good heteroaryl (limited to those in which the bond is from C). )
シアノ、ハロゲン、ヒドロキシ、アルコキシ、アルキルカルボニル、カルバモイル、アルキル、シクロアルキル、(シクロアルキル)アルキル、アラルキル、ヒドロキシカルボニル及びアルコキシアルキルからなる群から選択される1若しくは2個の基で置換されていてもよいヘテロアリール(但し、結合手がCから出ているものに限る。)を表す。) R 8 is a group represented by the following general formula [9],
even substituted with 1 or 2 groups selected from the group consisting of cyano, halogen, hydroxy, alkoxy, alkylcarbonyl, carbamoyl, alkyl, cycloalkyl, (cycloalkyl)alkyl, aralkyl, hydroxycarbonyl and alkoxyalkyl It represents good heteroaryl (limited to those in which the bond is from C). )
本反応は、化合物[1a]と有機ホウ素化合物[20]とを用いたクロスカップリング反応であり、それ自体公知の方法によって行うことができる。本反応は、例えばパラジウム触媒と塩基の存在下、適当な溶媒中、20~200℃で行うことができる。使用しうるパラジウム触媒としては、例えば、テトラキス(トリフェニルホスフィン)パラジウム、ジクロロビス(トリフェニルホスフィン)パラジウム、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を挙げることができる。使用しうるパラジウム触媒の量は、ハロゲン化アリール1モルに対して、0.001~0.1モルの範囲内が適当である。使用しうる反応溶媒としては、反応に関与しなければ特に限定されないが、例えば、テトラヒドロフラン、1,4-ジオキサン、1,2-ジメトキシエタンなどのエーテル類、メタノール、エタノールなどのアルコール類、N,N-ジメチルホルムアミド、N,N-ジメチルアセトアミドなどのアミド類、ベンゼン、トルエンなどの炭化水素類、水、又はこれらの混合溶媒を挙げることができる。また、使用しうる塩基としては、例えば、水酸化ナトリウム、炭酸カリウム、炭酸ナトリウムを挙げることができる。反応時間は、使用する原料の種類、反応温度によって異なるが、通常、30分~24時間の範囲内が適当である。
This reaction is a cross-coupling reaction using compound [1a] and organoboron compound [20], and can be carried out by a method known per se. This reaction can be carried out, for example, in the presence of a palladium catalyst and a base in a suitable solvent at 20-200°C. Palladium catalysts that may be used include, for example, tetrakis(triphenylphosphine)palladium, dichlorobis(triphenylphosphine)palladium, 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride-dichloromethane complexes. can be done. The amount of palladium catalyst that can be used is suitably in the range of 0.001 to 0.1 mol per 1 mol of the aryl halide. Usable reaction solvents are not particularly limited as long as they do not participate in the reaction. Examples include ethers such as tetrahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane; Examples include amides such as N-dimethylformamide and N,N-dimethylacetamide, hydrocarbons such as benzene and toluene, water, and mixed solvents thereof. Examples of usable bases include sodium hydroxide, potassium carbonate, and sodium carbonate. The reaction time varies depending on the type of raw material used and the reaction temperature, but is usually within the range of 30 minutes to 24 hours.
製法3-2
(X1、R1、R5、R8、Hal1は、前記と同義である。)
Manufacturing method 3-2
(X 1 , R 1 , R 5 , R 8 and Hal 1 are as defined above.)
本反応は、化合物[21]と化合物[13]とのパラジウム触媒を用いた縮合反応であって、それ自体公知の方法によって行われる。使用しうる溶媒は、反応に関与しなければ特に限定されないが、例えば、トルエン、キシレンなどの炭化水素類、1,4-ジオキサン、テトラヒドロフランなどのエーテル類、N,N-ジメチルホルムアミド、N,N-ジメチルアセトアミド、N-メチル-2-ピロリドンなどのアミド類、又はこれらの混合溶媒を挙げることができる。本反応は塩基の存在下、20℃~200℃の範囲内で反応を行うことができる。使用しうるパラジウム触媒としては、例えば、トリス(ジベンジリデンアセトン)(クロロホルム)ジパラジウム(0)、トリス(ジベンジリデンアセトン)ジパラジウム(0)、酢酸パラジウム(II)が挙げられる。使用しうるパラジウム触媒の量は、ハロゲン化アリール1モルに対して、0.001~0.1モルの範囲内が適当である。使用しうるパラジウム触媒のリガンドとしては、例えば、1,1’-ビス(ジフェニルホスフィノ)フェロセン、4,5-ビス(ジフェニルホスフィノ)-9,9’-ジメチルキサンテン、2-ジシクロヘキシルホスフィノ-2’,4’,6’-トリイソプロピルビフェニル、(±)-2,2’-ビス(ジフェニルホスフィノ)-1,1’-ビナフチル、2-(ジ-t-ブチルホスフィノ)ビフェニル、ビス[2-(ジフェニルホスフィノ)フェニル]エーテル、トリt-ブチルホスフィンを挙げることができる。使用しうる塩基としては、例えば、ナトリウムt-ブトキシド、リン酸三カリウム、炭酸セシウムを挙げることができる。反応時間は、使用する原料の種類、反応温度等によって異なるが、通常、10分~24時間の範囲内が適当である。
This reaction is a condensation reaction of compound [21] and compound [13] using a palladium catalyst, and is carried out by a method known per se. Solvents that can be used are not particularly limited as long as they do not participate in the reaction. Examples include hydrocarbons such as toluene and xylene, ethers such as 1,4-dioxane and tetrahydrofuran, N,N-dimethylformamide, N,N -dimethylacetamide, amides such as N-methyl-2-pyrrolidone, or mixed solvents thereof. This reaction can be carried out in the presence of a base within the range of 20°C to 200°C. Palladium catalysts that may be used include, for example, tris(dibenzylideneacetone)(chloroform)dipalladium(0), tris(dibenzylideneacetone)dipalladium(0), palladium(II) acetate. The amount of palladium catalyst that can be used is suitably in the range of 0.001 to 0.1 mol per 1 mol of the aryl halide. Palladium catalyst ligands that can be used include, for example, 1,1′-bis(diphenylphosphino)ferrocene, 4,5-bis(diphenylphosphino)-9,9′-dimethylxanthene, 2-dicyclohexylphosphino- 2',4',6'-triisopropylbiphenyl, (±)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl, 2-(di-t-butylphosphino)biphenyl, bis Mention may be made of [2-(diphenylphosphino)phenyl]ether, tri-t-butylphosphine. Usable bases include, for example, sodium t-butoxide, tripotassium phosphate, and cesium carbonate. The reaction time varies depending on the type of raw material used, the reaction temperature, etc., but is usually within the range of 10 minutes to 24 hours.
原料化合物である化合物[21]は、例えば次の3つの方法に従って製造することができる。
Compound [21], which is a raw material compound, can be produced, for example, according to the following three methods.
方法A
(X1、R1、R6、R7、R8、Hal1、Hal2は、前記と同義である。Hal3は、ハロゲンを表す。)
Method A
(X 1 , R 1 , R 6 , R 7 , R 8 , Hal 1 and Hal 2 are as defined above. Hal 3 represents halogen.)
工程1
本反応は、化合物[22]と有機ホウ素化合物[20]とを用いたクロスカップリング反応であり、それ自体公知の方法によって行うことができる。本反応は、例えばパラジウム触媒と塩基の存在下、適当な溶媒中、20~200℃の範囲内で行うことができる。使用しうるパラジウム触媒としては、例えば、テトラキス(トリフェニルホスフィン)パラジウム、ジクロロビス(トリフェニルホスフィン)パラジウム、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を挙げることができる。使用しうるパラジウム触媒の量は、ハロゲン化アリール1モルに対して、0.001~0.1モルの範囲内が適当である。使用しうる反応溶媒としては、反応に関与しなければ特に限定されないが、例えば、テトラヒドロフラン、1,4-ジオキサン、1,2-ジメトキシエタンなどのエーテル類、メタノール、エタノールなどのアルコール類、N,N-ジメチルホルムアミド、N,N-ジメチルアセトアミドなどのアミド類、ベンゼン、トルエンなどの炭化水素類、水、又はこれらの混合溶媒を挙げることができる。使用しうる塩基としては、例えば、水酸化ナトリウム、炭酸カリウム、炭酸ナトリウムを挙げることができる。反応時間は、使用する原料の種類、反応温度によって異なるが、通常、30分~24時間の範囲内が適当である。 Process 1
This reaction is a cross-coupling reaction using compound [22] and organoboron compound [20], and can be carried out by a method known per se. This reaction can be carried out, for example, in the presence of a palladium catalyst and a base in a suitable solvent at 20 to 200°C. Palladium catalysts that may be used include, for example, tetrakis(triphenylphosphine)palladium, dichlorobis(triphenylphosphine)palladium, 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride-dichloromethane complexes. can be done. The amount of palladium catalyst that can be used is suitably in the range of 0.001 to 0.1 mol per 1 mol of the aryl halide. Usable reaction solvents are not particularly limited as long as they do not participate in the reaction. Examples include ethers such as tetrahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane; Examples include amides such as N-dimethylformamide and N,N-dimethylacetamide, hydrocarbons such as benzene and toluene, water, and mixed solvents thereof. Usable bases include, for example, sodium hydroxide, potassium carbonate, and sodium carbonate. The reaction time varies depending on the type of raw material used and the reaction temperature, but is usually within the range of 30 minutes to 24 hours.
本反応は、化合物[22]と有機ホウ素化合物[20]とを用いたクロスカップリング反応であり、それ自体公知の方法によって行うことができる。本反応は、例えばパラジウム触媒と塩基の存在下、適当な溶媒中、20~200℃の範囲内で行うことができる。使用しうるパラジウム触媒としては、例えば、テトラキス(トリフェニルホスフィン)パラジウム、ジクロロビス(トリフェニルホスフィン)パラジウム、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を挙げることができる。使用しうるパラジウム触媒の量は、ハロゲン化アリール1モルに対して、0.001~0.1モルの範囲内が適当である。使用しうる反応溶媒としては、反応に関与しなければ特に限定されないが、例えば、テトラヒドロフラン、1,4-ジオキサン、1,2-ジメトキシエタンなどのエーテル類、メタノール、エタノールなどのアルコール類、N,N-ジメチルホルムアミド、N,N-ジメチルアセトアミドなどのアミド類、ベンゼン、トルエンなどの炭化水素類、水、又はこれらの混合溶媒を挙げることができる。使用しうる塩基としては、例えば、水酸化ナトリウム、炭酸カリウム、炭酸ナトリウムを挙げることができる。反応時間は、使用する原料の種類、反応温度によって異なるが、通常、30分~24時間の範囲内が適当である。 Process 1
This reaction is a cross-coupling reaction using compound [22] and organoboron compound [20], and can be carried out by a method known per se. This reaction can be carried out, for example, in the presence of a palladium catalyst and a base in a suitable solvent at 20 to 200°C. Palladium catalysts that may be used include, for example, tetrakis(triphenylphosphine)palladium, dichlorobis(triphenylphosphine)palladium, 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride-dichloromethane complexes. can be done. The amount of palladium catalyst that can be used is suitably in the range of 0.001 to 0.1 mol per 1 mol of the aryl halide. Usable reaction solvents are not particularly limited as long as they do not participate in the reaction. Examples include ethers such as tetrahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane; Examples include amides such as N-dimethylformamide and N,N-dimethylacetamide, hydrocarbons such as benzene and toluene, water, and mixed solvents thereof. Usable bases include, for example, sodium hydroxide, potassium carbonate, and sodium carbonate. The reaction time varies depending on the type of raw material used and the reaction temperature, but is usually within the range of 30 minutes to 24 hours.
工程2
本反応は、化合物[23]と化合物[19]とのパラジウム触媒を用いた縮合反応であって、それ故、縮合反応としてそれ自体公知の方法によって行うことができる。使用しうる溶媒としては、反応に関与しなければ特に限定されないが、例えば、トルエン、キシレンなどの炭化水素類、1,4-ジオキサン、テトラヒドロフランなどのエーテル類、N,N-ジメチルホルムアミド、N,N-ジメチルアセトアミド、N-メチル-2-ピロリドンなどのアミド類、又はこれらの混合溶媒を挙げることができる。本反応は、塩基の存在下、20℃~200℃の範囲内で反応を行うことができる。使用しうるパラジウム触媒としては、例えば、トリス(ジベンジリデンアセトン)(クロロホルム)ジパラジウム(0)、トリス(ジベンジリデンアセトン)ジパラジウム(0)、酢酸パラジウム(II)を挙げることができる。使用しうるパラジウム触媒の量は、ハロゲン化アリール1モルに対して、0.001~0.1モルの範囲内が適当である。使用しうるパラジウム触媒のリガンドとしては、例えば、4,5-ビス(ジフェニルホスフィノ)-9,9’-ジメチルキサンテン、(±)-2,2’-ビス(ジフェニルホスフィノ)-1,1’-ビナフチル、2-(ジ-t-ブチルホスフィノ)ビフェニル、ビス[2-(ジフェニルホスフィノ)フェニル]エーテル、トリt-ブチルホスフィンを挙げることができる。使用しうる塩基としては、例えば、ナトリウムt-ブトキシド、リン酸三カリウム、炭酸セシウムを挙げることができる。反応時間は、使用する原料の種類、反応温度等によって異なるが、通常、10分~24時間の範囲内が適当である。 Process 2
This reaction is a condensation reaction of compound [23] and compound [19] using a palladium catalyst, and therefore can be carried out by a method known per se as a condensation reaction. Solvents that can be used are not particularly limited as long as they do not participate in the reaction. Examples include hydrocarbons such as toluene and xylene, ethers such as 1,4-dioxane and tetrahydrofuran, N,N-dimethylformamide, N, Amides such as N-dimethylacetamide and N-methyl-2-pyrrolidone, or mixed solvents thereof can be used. This reaction can be carried out in the presence of a base within the range of 20°C to 200°C. Palladium catalysts that can be used include, for example, tris(dibenzylideneacetone)(chloroform)dipalladium(0), tris(dibenzylideneacetone)dipalladium(0), and palladium(II) acetate. The amount of palladium catalyst that can be used is suitably in the range of 0.001 to 0.1 mol per 1 mol of the aryl halide. Palladium catalyst ligands that can be used include, for example, 4,5-bis(diphenylphosphino)-9,9′-dimethylxanthene, (±)-2,2′-bis(diphenylphosphino)-1,1 '-Binaphthyl, 2-(di-t-butylphosphino)biphenyl, bis[2-(diphenylphosphino)phenyl]ether, tri-t-butylphosphine can be mentioned. Usable bases include, for example, sodium t-butoxide, tripotassium phosphate, and cesium carbonate. The reaction time varies depending on the type of raw material used, the reaction temperature, etc., but is usually within the range of 10 minutes to 24 hours.
本反応は、化合物[23]と化合物[19]とのパラジウム触媒を用いた縮合反応であって、それ故、縮合反応としてそれ自体公知の方法によって行うことができる。使用しうる溶媒としては、反応に関与しなければ特に限定されないが、例えば、トルエン、キシレンなどの炭化水素類、1,4-ジオキサン、テトラヒドロフランなどのエーテル類、N,N-ジメチルホルムアミド、N,N-ジメチルアセトアミド、N-メチル-2-ピロリドンなどのアミド類、又はこれらの混合溶媒を挙げることができる。本反応は、塩基の存在下、20℃~200℃の範囲内で反応を行うことができる。使用しうるパラジウム触媒としては、例えば、トリス(ジベンジリデンアセトン)(クロロホルム)ジパラジウム(0)、トリス(ジベンジリデンアセトン)ジパラジウム(0)、酢酸パラジウム(II)を挙げることができる。使用しうるパラジウム触媒の量は、ハロゲン化アリール1モルに対して、0.001~0.1モルの範囲内が適当である。使用しうるパラジウム触媒のリガンドとしては、例えば、4,5-ビス(ジフェニルホスフィノ)-9,9’-ジメチルキサンテン、(±)-2,2’-ビス(ジフェニルホスフィノ)-1,1’-ビナフチル、2-(ジ-t-ブチルホスフィノ)ビフェニル、ビス[2-(ジフェニルホスフィノ)フェニル]エーテル、トリt-ブチルホスフィンを挙げることができる。使用しうる塩基としては、例えば、ナトリウムt-ブトキシド、リン酸三カリウム、炭酸セシウムを挙げることができる。反応時間は、使用する原料の種類、反応温度等によって異なるが、通常、10分~24時間の範囲内が適当である。 Process 2
This reaction is a condensation reaction of compound [23] and compound [19] using a palladium catalyst, and therefore can be carried out by a method known per se as a condensation reaction. Solvents that can be used are not particularly limited as long as they do not participate in the reaction. Examples include hydrocarbons such as toluene and xylene, ethers such as 1,4-dioxane and tetrahydrofuran, N,N-dimethylformamide, N, Amides such as N-dimethylacetamide and N-methyl-2-pyrrolidone, or mixed solvents thereof can be used. This reaction can be carried out in the presence of a base within the range of 20°C to 200°C. Palladium catalysts that can be used include, for example, tris(dibenzylideneacetone)(chloroform)dipalladium(0), tris(dibenzylideneacetone)dipalladium(0), and palladium(II) acetate. The amount of palladium catalyst that can be used is suitably in the range of 0.001 to 0.1 mol per 1 mol of the aryl halide. Palladium catalyst ligands that can be used include, for example, 4,5-bis(diphenylphosphino)-9,9′-dimethylxanthene, (±)-2,2′-bis(diphenylphosphino)-1,1 '-Binaphthyl, 2-(di-t-butylphosphino)biphenyl, bis[2-(diphenylphosphino)phenyl]ether, tri-t-butylphosphine can be mentioned. Usable bases include, for example, sodium t-butoxide, tripotassium phosphate, and cesium carbonate. The reaction time varies depending on the type of raw material used, the reaction temperature, etc., but is usually within the range of 10 minutes to 24 hours.
方法B
(X1、R1、R8、Hal1、Hal2は、前記と同義である。R9、R10、R11は、同一又は異なって、アルキルを表す。)
Method B.
(X 1 , R 1 , R 8 , Hal 1 and Hal 2 are as defined above. R 9 , R 10 and R 11 are the same or different and represent alkyl.)
本反応は、化合物[12]と有機スズ化合物[24]とを用いたクロスカップリング反応で、それ自体公知の方法によって行うことができる。本反応は、例えばパラジウム触媒存在下、適当な溶媒中、20~200℃で行うことができる。使用しうるパラジウム触媒としては、例えば、テトラキス(トリフェニルホスフィン)パラジウム、ジクロロビス(トリフェニルホスフィン)パラジウム、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、酢酸パラジウムを挙げることができる。使用しうるパラジウム触媒の量は、ハロゲン化アリール1モルに対して、0.001~0.1モルの範囲内が適当である。使用しうる反応溶媒としては、反応に関与しなければ特に限定されないが、例えば、テトラヒドロフラン、1,4-ジオキサン、1,2-ジメトキシエタンなどのエーテル類、N,N-ジメチルホルムアミド、N,N-ジメチルアセトアミドなどのアミド類、ベンゼン、トルエンなどの炭化水素類、又はこれらの混合溶媒を挙げることができる。また酸化銅や酸化銀のような添加剤を加えることも出来る。反応時間は、使用する原料の種類、反応温度によって異なるが、通常、1~24時間の範囲内が適当である。
This reaction is a cross-coupling reaction using compound [12] and organotin compound [24], and can be carried out by a method known per se. This reaction can be carried out, for example, in the presence of a palladium catalyst in a suitable solvent at 20 to 200°C. Palladium catalysts that can be used include, for example, tetrakis(triphenylphosphine)palladium, dichlorobis(triphenylphosphine)palladium, 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride-dichloromethane complex, palladium acetate can be mentioned. The amount of palladium catalyst that can be used is suitably in the range of 0.001 to 0.1 mol per 1 mol of the aryl halide. The reaction solvent that can be used is not particularly limited as long as it does not participate in the reaction. - amides such as dimethylacetamide, hydrocarbons such as benzene and toluene, or mixed solvents thereof. Additives such as copper oxide and silver oxide can also be added. The reaction time varies depending on the type of raw materials used and the reaction temperature, but is usually within the range of 1 to 24 hours.
方法C
(X1、R1、R6、R7、R8、Hal1、Hal2は、前記と同義である。)
Method C.
(X 1 , R 1 , R 6 , R 7 , R 8 , Hal 1 and Hal 2 are as defined above.)
本反応は、化合物[12]と有機ホウ素化合物[20]とを用いたクロスカップリング反応であり、それ自体公知の方法によって行うことができる。本反応は、例えばパラジウム触媒と塩基の存在下、適当な溶媒中、20~200℃の範囲内で行うことができる。使用しうるパラジウム触媒としては、例えば、テトラキス(トリフェニルホスフィン)パラジウム、ジクロロビス(トリフェニルホスフィン)パラジウム、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を挙げることができる。使用しうるパラジウム触媒の量は、ハロゲン化アリール1モルに対して、0.001~0.1モルの範囲内が適当である。使用しうる反応溶媒としては、反応に関与しなければ特に限定されないが、例えば、テトラヒドロフラン、1,4-ジオキサン、1,2-ジメトキシエタンなどのエーテル類、メタノール、エタノールなどのアルコール類、N,N-ジメチルホルムアミド、N,N-ジメチルアセトアミドなどのアミド類、ベンゼン、トルエンなどの炭化水素類、水、又はこれらの混合溶媒を挙げることができる。使用しうる塩基としては、例えば、水酸化ナトリウム、炭酸カリウム、炭酸ナトリウムを挙げることができる。反応時間は、使用する原料の種類、反応温度によって異なるが、通常、30分~24時間の範囲内が適当である。
This reaction is a cross-coupling reaction using compound [12] and organoboron compound [20], and can be carried out by a method known per se. This reaction can be carried out, for example, in the presence of a palladium catalyst and a base in a suitable solvent at 20 to 200°C. Palladium catalysts that may be used include, for example, tetrakis(triphenylphosphine)palladium, dichlorobis(triphenylphosphine)palladium, 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride-dichloromethane complexes. can be done. The amount of palladium catalyst that can be used is suitably in the range of 0.001 to 0.1 mol per 1 mol of the aryl halide. Usable reaction solvents are not particularly limited as long as they do not participate in the reaction. Examples include ethers such as tetrahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane; Examples include amides such as N-dimethylformamide and N,N-dimethylacetamide, hydrocarbons such as benzene and toluene, water, and mixed solvents thereof. Usable bases include, for example, sodium hydroxide, potassium carbonate, and sodium carbonate. The reaction time varies depending on the type of raw material used and the reaction temperature, but is usually within the range of 30 minutes to 24 hours.
製法4 R
2
が次の一般式[3]で表される基
(式中、R
F
、R
G
は、前記と同義である。)の場合
Production method 4 R 2 is a group represented by the following general formula [3]
(Wherein, R F and R G are as defined above.)
製法4-1
(X1、R1、R5、Hal2は、前記と同義である。R12は、次の一般式[3]で表される基を表す。
Manufacturing method 4-1
(X 1 , R 1 , R 5 and Hal 2 are as defined above. R 12 represents a group represented by the following general formula [3].
本反応は、化合物[1a]と化合物[25]とを用いたクロスカップリング反応であり、それ自体公知の方法によって行うことができる。使用しうる溶媒としては、反応に関与しなければ特に限定されないが、例えば、トルエン、キシレンなどの炭化水素類、1,4-ジオキサン、テトラヒドロフランなどのエーテル類、N,N-ジメチルホルムアミド、N,N-ジメチルアセトアミド、N-メチル-2-ピロリドンなどのアミド類、又はこれらの混合溶媒を挙げることができる。本反応は、例えばパラジウム触媒と塩基の存在下、適当な溶媒中、20~200℃の範囲内で行うことができる。使用しうるパラジウム触媒としては、例えば、トリス(ジベンジリデンアセトン)(クロロホルム)ジパラジウム(0)、トリス(ジベンジリデンアセトン)ジパラジウム(0)、酢酸パラジウム(II)を挙げることができる。使用しうるパラジウム触媒の量は、ハロゲン化アリール1モルに対して、0.001~0.1モルの範囲内が適当である。使用しうるパラジウム触媒のリガンドとしては、例えば、1,1’-ビス(ジフェニルホスフィノ)フェロセン、4,5-ビス(ジフェニルホスフィノ)-9,9’-ジメチルキサンテン、2-ジシクロヘキシルホスフィノ-2’,4’,6’-トリイソプロピルビフェニル、(±)-2,2’-ビス(ジフェニルホスフィノ)-1,1’-ビナフチル、2-(ジ-t-ブチルホスフィノ)ビフェニル、ビス[2-(ジフェニルホスフィノ)フェニル]エーテル、トリt-ブチルホスフィンを挙げることができる。使用しうる塩基としては、例えば、ナトリウムt-ブトキシド、リン酸三カリウム、炭酸セシウムを挙げることができる。反応時間は、使用する原料の種類、反応温度によって異なるが、通常、30分~24時間の範囲内が適当である。
This reaction is a cross-coupling reaction using compound [1a] and compound [25], and can be carried out by a method known per se. Solvents that can be used are not particularly limited as long as they do not participate in the reaction. Examples include hydrocarbons such as toluene and xylene, ethers such as 1,4-dioxane and tetrahydrofuran, N,N-dimethylformamide, N, Amides such as N-dimethylacetamide and N-methyl-2-pyrrolidone, or mixed solvents thereof can be used. This reaction can be carried out, for example, in the presence of a palladium catalyst and a base in a suitable solvent at 20 to 200°C. Palladium catalysts that can be used include, for example, tris(dibenzylideneacetone)(chloroform)dipalladium(0), tris(dibenzylideneacetone)dipalladium(0), and palladium(II) acetate. The amount of palladium catalyst that can be used is suitably in the range of 0.001 to 0.1 mol per 1 mol of the aryl halide. Palladium catalyst ligands that can be used include, for example, 1,1′-bis(diphenylphosphino)ferrocene, 4,5-bis(diphenylphosphino)-9,9′-dimethylxanthene, 2-dicyclohexylphosphino- 2',4',6'-triisopropylbiphenyl, (±)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl, 2-(di-t-butylphosphino)biphenyl, bis Mention may be made of [2-(diphenylphosphino)phenyl]ether, tri-t-butylphosphine. Usable bases include, for example, sodium t-butoxide, tripotassium phosphate, and cesium carbonate. The reaction time varies depending on the type of raw material used and the reaction temperature, but is usually within the range of 30 minutes to 24 hours.
製法4-2
(X1、R1、R5、R12、Hal1は、前記と同義である。)
Manufacturing method 4-2
(X 1 , R 1 , R 5 , R 12 and Hal 1 are as defined above.)
本反応は、化合物[26]と化合物[13]とのパラジウム触媒を用いた縮合反応であって、それ自体公知の方法によって行うことができる。使用しうる溶媒としては、反応に関与しなければ特に限定されないが、例えば、トルエン、キシレンなどの炭化水素類、1,4-ジオキサン、テトラヒドロフランなどのエーテル類、N,N-ジメチルホルムアミド、N,N-ジメチルアセトアミド、N-メチル-2-ピロリドンなどのアミド類、又はこれらの混合溶媒を挙げることができる。本反応は塩基の存在下、20℃~200℃の範囲内で反応を行うことができる。使用しうるパラジウム触媒としては、例えば、トリス(ジベンジリデンアセトン)(クロロホルム)ジパラジウム(0)、トリス(ジベンジリデンアセトン)ジパラジウム(0)、酢酸パラジウム(II)を挙げることができる。使用しうるパラジウム触媒の量は、ハロゲン化アリール1モルに対して、0.001~0.1モルの範囲内が適当である。使用しうるパラジウム触媒のリガンドとしては、例えば、1,1’-ビス(ジフェニルホスフィノ)フェロセン、4,5-ビス(ジフェニルホスフィノ)-9,9’-ジメチルキサンテン、2-ジシクロヘキシルホスフィノ-2’,4’,6’-トリイソプロピルビフェニル、(±)-2,2’-ビス(ジフェニルホスフィノ)-1,1’-ビナフチル、2-(ジ-t-ブチルホスフィノ)ビフェニル、ビス[2-(ジフェニルホスフィノ)フェニル]エーテル、トリt-ブチルホスフィンを挙げることができる。使用しうる塩基としては、例えば、ナトリウムt-ブトキシド、リン酸三カリウム、炭酸セシウムを挙げることができる。反応時間は、使用する原料の種類、反応温度等によって異なるが、通常、10分~24時間の範囲内が適当である。
This reaction is a condensation reaction of compound [26] and compound [13] using a palladium catalyst, and can be carried out by a method known per se. Solvents that can be used are not particularly limited as long as they do not participate in the reaction. Examples include hydrocarbons such as toluene and xylene, ethers such as 1,4-dioxane and tetrahydrofuran, N,N-dimethylformamide, N, Amides such as N-dimethylacetamide and N-methyl-2-pyrrolidone, or mixed solvents thereof can be used. This reaction can be carried out in the presence of a base within the range of 20°C to 200°C. Palladium catalysts that can be used include, for example, tris(dibenzylideneacetone)(chloroform)dipalladium(0), tris(dibenzylideneacetone)dipalladium(0), and palladium(II) acetate. The amount of palladium catalyst that can be used is suitably in the range of 0.001 to 0.1 mol per 1 mol of the aryl halide. Palladium catalyst ligands that can be used include, for example, 1,1′-bis(diphenylphosphino)ferrocene, 4,5-bis(diphenylphosphino)-9,9′-dimethylxanthene, 2-dicyclohexylphosphino- 2',4',6'-triisopropylbiphenyl, (±)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl, 2-(di-t-butylphosphino)biphenyl, bis Mention may be made of [2-(diphenylphosphino)phenyl]ether, tri-t-butylphosphine. Usable bases include, for example, sodium t-butoxide, tripotassium phosphate, and cesium carbonate. The reaction time varies depending on the type of raw material used, the reaction temperature, etc., but is usually within the range of 10 minutes to 24 hours.
原料化合物である化合物[26]は、例えば、次の2つの方法に従って製造することができる。
(X1、R1、R12、Hal1、Hal2は、前記と同義である。)
Compound [26], which is a starting compound, can be produced, for example, according to the following two methods.
(X 1 , R 1 , R 12 , Hal 1 and Hal 2 are as defined above.)
方法a
化合物[26]は、化合物[12]と化合物[25]とを適当な溶媒中、塩基の存在下、20℃~200℃の範囲内で反応させることにより製造することができる。使用しうる塩基は、例えば、ピリジン、トリエチルアミン、N,N-ジイソプロピルエチルアミン、炭酸カリウム、炭酸水素ナトリウムを挙げることができる。使用しうる溶媒としては、反応に関与しなければ特に限定されないが、1-ブタノール、2-メトキシエタノールなどのアルコール類、テトラヒドロフラン、1,4-ジオキサンなどのエーテル類、N,N-ジメチルホルムアミド、N,N-ジメチルアセトアミドなどのアミド類、ベンゼン、トルエンなどの炭化水素類、アセトニトリル、又はこれらの混合溶媒を挙げることができる。反応時間は、使用する原料の種類、反応温度によって異なるが、通常、1~24時間の範囲内が適当である。 method a
Compound [26] can be produced by reacting compound [12] and compound [25] in a suitable solvent in the presence of a base at 20°C to 200°C. Usable bases include, for example, pyridine, triethylamine, N,N-diisopropylethylamine, potassium carbonate and sodium hydrogen carbonate. Solvents that can be used are not particularly limited as long as they do not participate in the reaction, but alcohols such as 1-butanol and 2-methoxyethanol, ethers such as tetrahydrofuran and 1,4-dioxane, N,N-dimethylformamide, Examples include amides such as N,N-dimethylacetamide, hydrocarbons such as benzene and toluene, acetonitrile, and mixed solvents thereof. The reaction time varies depending on the type of raw materials used and the reaction temperature, but is usually within the range of 1 to 24 hours.
化合物[26]は、化合物[12]と化合物[25]とを適当な溶媒中、塩基の存在下、20℃~200℃の範囲内で反応させることにより製造することができる。使用しうる塩基は、例えば、ピリジン、トリエチルアミン、N,N-ジイソプロピルエチルアミン、炭酸カリウム、炭酸水素ナトリウムを挙げることができる。使用しうる溶媒としては、反応に関与しなければ特に限定されないが、1-ブタノール、2-メトキシエタノールなどのアルコール類、テトラヒドロフラン、1,4-ジオキサンなどのエーテル類、N,N-ジメチルホルムアミド、N,N-ジメチルアセトアミドなどのアミド類、ベンゼン、トルエンなどの炭化水素類、アセトニトリル、又はこれらの混合溶媒を挙げることができる。反応時間は、使用する原料の種類、反応温度によって異なるが、通常、1~24時間の範囲内が適当である。 method a
Compound [26] can be produced by reacting compound [12] and compound [25] in a suitable solvent in the presence of a base at 20°C to 200°C. Usable bases include, for example, pyridine, triethylamine, N,N-diisopropylethylamine, potassium carbonate and sodium hydrogen carbonate. Solvents that can be used are not particularly limited as long as they do not participate in the reaction, but alcohols such as 1-butanol and 2-methoxyethanol, ethers such as tetrahydrofuran and 1,4-dioxane, N,N-dimethylformamide, Examples include amides such as N,N-dimethylacetamide, hydrocarbons such as benzene and toluene, acetonitrile, and mixed solvents thereof. The reaction time varies depending on the type of raw materials used and the reaction temperature, but is usually within the range of 1 to 24 hours.
方法b
化合物[26]は、化合物[12]と化合物[25]とのパラジウム触媒を用いた縮合反応であって、それ自体公知の方法によって行うことができる。使用しうる溶媒としては、反応に関与しなければ特に限定されないが、例えば、トルエン、キシレンなどの炭化水素類、1,4-ジオキサン、テトラヒドロフランなどのエーテル類、又はこれらの混合溶媒を挙げることができる。本反応は塩基の存在下、20℃~200℃の範囲内で反応を行うことができる。使用しうるパラジウム触媒としては、例えば、トリス(ジベンジリデンアセトン)(クロロホルム)ジパラジウム(0)、トリス(ジベンジリデンアセトン)ジパラジウム(0)、酢酸パラジウム(II)を挙げることができる。使用しうるパラジウム触媒の量は、ハロゲン化アリール1モルに対して、0.001~0.1モルの範囲内が適当である。使用しうるパラジウム触媒のリガンドとしては、例えば、1,1’-ビス(ジフェニルホスフィノ)フェロセン、4,5-ビス(ジフェニルホスフィノ)-9,9’-ジメチルキサンテン、2-ジシクロヘキシルホスフィノ-2’,4’,6’-トリイソプロピルビフェニル、(±)-2,2’-ビス(ジフェニルホスフィノ)-1,1’-ビナフチル、2-(ジ-t-ブチルホスフィノ)ビフェニル、ビス[2-(ジフェニルホスフィノ)フェニル]エーテル、トリt-ブチルホスフィンを挙げることができる。使用しうる塩基としては、例えば、ナトリウムt-ブトキシド、リン酸三カリウム、炭酸セシウムを挙げることができる。反応時間は、使用する原料の種類、反応温度等によって異なるが、通常、10分~24時間の範囲内が適当である。 Method b.
Compound [26] is a condensation reaction of compound [12] and compound [25] using a palladium catalyst, which can be carried out by a method known per se. Solvents that can be used are not particularly limited as long as they do not participate in the reaction. Examples include hydrocarbons such as toluene and xylene, ethers such as 1,4-dioxane and tetrahydrofuran, and mixed solvents thereof. can. This reaction can be carried out in the presence of a base within the range of 20°C to 200°C. Palladium catalysts that can be used include, for example, tris(dibenzylideneacetone)(chloroform)dipalladium(0), tris(dibenzylideneacetone)dipalladium(0), and palladium(II) acetate. The amount of palladium catalyst that can be used is suitably in the range of 0.001 to 0.1 mol per 1 mol of the aryl halide. Palladium catalyst ligands that can be used include, for example, 1,1′-bis(diphenylphosphino)ferrocene, 4,5-bis(diphenylphosphino)-9,9′-dimethylxanthene, 2-dicyclohexylphosphino- 2',4',6'-triisopropylbiphenyl, (±)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl, 2-(di-t-butylphosphino)biphenyl, bis Mention may be made of [2-(diphenylphosphino)phenyl]ether, tri-t-butylphosphine. Usable bases include, for example, sodium t-butoxide, tripotassium phosphate, and cesium carbonate. The reaction time varies depending on the type of raw material used, the reaction temperature, etc., but is usually within the range of 10 minutes to 24 hours.
化合物[26]は、化合物[12]と化合物[25]とのパラジウム触媒を用いた縮合反応であって、それ自体公知の方法によって行うことができる。使用しうる溶媒としては、反応に関与しなければ特に限定されないが、例えば、トルエン、キシレンなどの炭化水素類、1,4-ジオキサン、テトラヒドロフランなどのエーテル類、又はこれらの混合溶媒を挙げることができる。本反応は塩基の存在下、20℃~200℃の範囲内で反応を行うことができる。使用しうるパラジウム触媒としては、例えば、トリス(ジベンジリデンアセトン)(クロロホルム)ジパラジウム(0)、トリス(ジベンジリデンアセトン)ジパラジウム(0)、酢酸パラジウム(II)を挙げることができる。使用しうるパラジウム触媒の量は、ハロゲン化アリール1モルに対して、0.001~0.1モルの範囲内が適当である。使用しうるパラジウム触媒のリガンドとしては、例えば、1,1’-ビス(ジフェニルホスフィノ)フェロセン、4,5-ビス(ジフェニルホスフィノ)-9,9’-ジメチルキサンテン、2-ジシクロヘキシルホスフィノ-2’,4’,6’-トリイソプロピルビフェニル、(±)-2,2’-ビス(ジフェニルホスフィノ)-1,1’-ビナフチル、2-(ジ-t-ブチルホスフィノ)ビフェニル、ビス[2-(ジフェニルホスフィノ)フェニル]エーテル、トリt-ブチルホスフィンを挙げることができる。使用しうる塩基としては、例えば、ナトリウムt-ブトキシド、リン酸三カリウム、炭酸セシウムを挙げることができる。反応時間は、使用する原料の種類、反応温度等によって異なるが、通常、10分~24時間の範囲内が適当である。 Method b.
Compound [26] is a condensation reaction of compound [12] and compound [25] using a palladium catalyst, which can be carried out by a method known per se. Solvents that can be used are not particularly limited as long as they do not participate in the reaction. Examples include hydrocarbons such as toluene and xylene, ethers such as 1,4-dioxane and tetrahydrofuran, and mixed solvents thereof. can. This reaction can be carried out in the presence of a base within the range of 20°C to 200°C. Palladium catalysts that can be used include, for example, tris(dibenzylideneacetone)(chloroform)dipalladium(0), tris(dibenzylideneacetone)dipalladium(0), and palladium(II) acetate. The amount of palladium catalyst that can be used is suitably in the range of 0.001 to 0.1 mol per 1 mol of the aryl halide. Palladium catalyst ligands that can be used include, for example, 1,1′-bis(diphenylphosphino)ferrocene, 4,5-bis(diphenylphosphino)-9,9′-dimethylxanthene, 2-dicyclohexylphosphino- 2',4',6'-triisopropylbiphenyl, (±)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl, 2-(di-t-butylphosphino)biphenyl, bis Mention may be made of [2-(diphenylphosphino)phenyl]ether, tri-t-butylphosphine. Usable bases include, for example, sodium t-butoxide, tripotassium phosphate, and cesium carbonate. The reaction time varies depending on the type of raw material used, the reaction temperature, etc., but is usually within the range of 10 minutes to 24 hours.
製法5 R
2
がシアノ、ハロゲン、ヒドロキシ、アルコキシ、アルキルカルボニル、カルバモイル、アルキル、シクロアルキル、(シクロアルキル)アルキル、アラルキル、ヒドロキシカルボニル及びアルコキシアルキルからなる群から選択される1若しくは2個の基で置換されていてもよいヘテロアリール(但し、結合手がNから出ているものに限る。)の場合
(X1、R1、R5、Hal1は、前記と同義である。R13は、シアノ、ハロゲン、ヒドロキシ、アルコキシ、アルキルカルボニル、カルバモイル、アルキル、シクロアルキル、(シクロアルキル)アルキル、アラルキル、ヒドロキシカルボニル及びアルコキシアルキルからなる群から選択される1若しくは2個の基で置換されていてもよいヘテロアリール(但し、結合手がNから出ているものに限る。)を表す。)
Production Method 5 R 2 is 1 or 2 groups selected from the group consisting of cyano, halogen, hydroxy, alkoxy, alkylcarbonyl, carbamoyl, alkyl, cycloalkyl, (cycloalkyl)alkyl, aralkyl, hydroxycarbonyl and alkoxyalkyl In the case of optionally substituted heteroaryl (provided that the bond is limited to those originating from N)
(X 1 , R 1 , R 5 and Hal 1 are as defined above. R 13 is cyano, halogen, hydroxy, alkoxy, alkylcarbonyl, carbamoyl, alkyl, cycloalkyl, (cycloalkyl)alkyl, aralkyl, heteroaryl optionally substituted with 1 or 2 groups selected from the group consisting of hydroxycarbonyl and alkoxyalkyl (limited to those with a bond extending from N);
本反応は、化合物[27]と化合物[13]とのパラジウム触媒を用いた縮合反応であって、前記製法4-2と同様の方法により行うことができる。
This reaction is a condensation reaction of compound [27] and compound [13] using a palladium catalyst, and can be carried out in the same manner as in Production Method 4-2 above.
原料化合物である化合物[27]は、次の方法に従って製造することができる。
The starting compound, compound [27], can be produced according to the following method.
本反応は、化合物[12]と化合物[28]とを用いたクロスカップリング反応であり、それ自体公知の方法によって行うことができる。本反応は、例えば、銅触媒の存在又は非存在下に、適当な溶媒中、20~200℃の範囲内で行うことができる。使用しうる銅触媒としては、例えば、ヨウ化銅、酢酸銅などを挙げることができる。使用しうる銅触媒の量は、ハロゲン化アリール1モルに対して、0.01~0.2モルの範囲内が適当である。また、銅の配位子として、トランス-N,N’-ジメチルシクロヘキサン-1,2-ジアミン、トランス-1,2-シクロヘキサンジアミン、1,10-フェナントロリンなどを挙げることができる。使用しうる反応溶媒としては、反応に関与しなければ特に限定されないが、例えば、テトラヒドロフラン、1,4-ジオキサン、1,2-ジメトキシエタンなどのエーテル類、メタノール、エタノールなどのアルコール類、N,N-ジメチルホルムアミド、N,N-ジメチルアセトアミドなどのアミド類、ベンゼン、トルエンなどの炭化水素類、又はこれらの混合溶媒を挙げることができる。使用しうる塩基としては、例えば、リン酸三カリウム、炭酸カリウム、炭酸ナトリウム、炭酸セシウムなどを挙げることができる。反応時間は、使用する原料の種類、反応温度によって異なるが、通常、30分~24時間の範囲内が適当である。
This reaction is a cross-coupling reaction using compound [12] and compound [28], and can be carried out by a method known per se. This reaction can be carried out, for example, in the presence or absence of a copper catalyst in a suitable solvent at 20 to 200°C. Examples of usable copper catalysts include copper iodide and copper acetate. The amount of copper catalyst that can be used is suitably within the range of 0.01 to 0.2 mol per 1 mol of the aryl halide. Further, examples of copper ligands include trans-N,N'-dimethylcyclohexane-1,2-diamine, trans-1,2-cyclohexanediamine, 1,10-phenanthroline, and the like. Usable reaction solvents are not particularly limited as long as they do not participate in the reaction. Examples include ethers such as tetrahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane; Examples include amides such as N-dimethylformamide and N,N-dimethylacetamide, hydrocarbons such as benzene and toluene, and mixed solvents thereof. Usable bases include, for example, tripotassium phosphate, potassium carbonate, sodium carbonate, cesium carbonate and the like. The reaction time varies depending on the type of raw material used and the reaction temperature, but is usually within the range of 30 minutes to 24 hours.
製法6 R
2
がアルコキシカルボニルの場合
(X1、R1、R5、Hal1は、前記と同義である。R14は、アルキルを表す。)
Production method 6 When R 2 is alkoxycarbonyl
(X 1 , R 1 , R 5 and Hal 1 are as defined above. R 14 represents alkyl.)
本反応は、化合物[29]と化合物[13]とのパラジウム触媒を用いた縮合反応であって、前記製法4-2と同様の方法により行うことができる。
This reaction is a condensation reaction of compound [29] and compound [13] using a palladium catalyst, and can be carried out in the same manner as in Production Method 4-2 above.
原料化合物である化合物[29]は、次の方法に従って製造することができる。
(X1、R1、R14、Hal1、Hal3は、前記と同義である。)
Compound [29], which is a starting compound, can be produced according to the following method.
(X 1 , R 1 , R 14 , Hal 1 and Hal 3 are as defined above.)
本反応は、化合物[30]と化合物[19]とのパラジウム触媒を用いた縮合反応であって、前記原料化合物である化合物[15]の製法の工程2と同様の方法により行うことができる。
This reaction is a condensation reaction of compound [30] and compound [19] using a palladium catalyst, and can be carried out in the same manner as in step 2 of the method for producing compound [15], which is the raw material compound.
製法7 R
2
がヒドロキシカルボニルの場合
(X1、R1、R5、R14は、前記と同義である。)
Production method 7 When R 2 is hydroxycarbonyl
(X 1 , R 1 , R 5 and R 14 are as defined above.)
本反応は、化合物[1f]の加水分解反応であって、それ自体公知の方法によって行うことができる。通常、酸又は塩基存在下において、化合物[1f]を加水分解することにより化合物[1g]を製造することができる。本反応に使用される酸としては、例えば、塩酸、硫酸のような無機酸、塩基としては、例えば、水酸化ナトリウム、水酸化カリウムなどの無機塩基を挙げることができる。本反応に使用しうる反応溶媒としては、例えば、メタノール、エタノールなどのアルコール類、テトラヒドロフラン、1,4-ジオキサンなどのエーテル類、水、又はこれらの混合溶媒を挙げることができる。反応温度は、0℃~100℃で行われ、反応時間は通常30分~24時間である。
This reaction is a hydrolysis reaction of compound [1f] and can be carried out by a method known per se. Generally, compound [1g] can be produced by hydrolyzing compound [1f] in the presence of an acid or base. Examples of the acid used in this reaction include inorganic acids such as hydrochloric acid and sulfuric acid, and examples of the base include inorganic bases such as sodium hydroxide and potassium hydroxide. Examples of the reaction solvent that can be used in this reaction include alcohols such as methanol and ethanol, ethers such as tetrahydrofuran and 1,4-dioxane, water, and mixed solvents thereof. The reaction temperature is 0° C. to 100° C., and the reaction time is usually 30 minutes to 24 hours.
製法8 R
2
が(a)アルキル若しくはアルキルスルホニルで置換されていてもよい飽和環状アミノ基、又は、(b)アルキル、シクロアルキル、(シクロアルキル)アルキル、アラルキル、ハロアルキル、ジアルキルアミノアルキル、アルコキシアルキル、及びヒドロキシアルキルからなる群から選択される1若しくは2個の基を置換されていてもよいアミノカルボニルの場合
(X1、R1、R5は、前記と同義である。R15、R16は、同一又は異なって、H、アルキル、シクロアルキル、(シクロアルキル)アルキル、アラルキル、ハロアルキル、ジアルキルアミノアルキル、アルコキシアルキル、若しくは、ヒドロキシアルキルを表すか、又は隣接するNと一緒になって、飽和環状アミノ基を表す。かかる飽和環状アミノ基は、アルキル又はアルキルスルホニルで置換されていてもよい。)
Production Method 8 R 2 is (a) a saturated cyclic amino group optionally substituted with alkyl or alkylsulfonyl, or (b) alkyl, cycloalkyl, (cycloalkyl)alkyl, aralkyl, haloalkyl, dialkylaminoalkyl, alkoxyalkyl , and aminocarbonyl optionally substituted with 1 or 2 groups selected from the group consisting of hydroxyalkyl
(X 1 , R 1 and R 5 are as defined above. R 15 and R 16 are the same or different and are H, alkyl, cycloalkyl, (cycloalkyl)alkyl, aralkyl, haloalkyl, dialkylaminoalkyl, represents alkoxyalkyl or hydroxyalkyl, or together with adjacent N represents a saturated cyclic amino group. Such saturated cyclic amino group may be substituted with alkyl or alkylsulfonyl.)
本反応は、化合物[1g]と化合物[31]との縮合反応であって、縮合反応としてそれ自体公知の方法によって行うことができる。化合物[1g]で表されるカルボン酸又はその反応性誘導体と、化合物[31]を反応させることにより、化合物[1h]を合成することができる。化合物[1g]の反応性誘導体としては、例えば、酸ハライド(例えば、酸クロリド、酸ブロミド)、混合酸無水物、イミダゾリド、活性アミド等、アミド縮合形成反応に通常用いられるものを挙げることができる。化合物[1g]を用いる場合には、塩基の存在又は非存在下において、縮合剤を使用して、-20~100℃で反応を行うことができる。本反応に使用しうる縮合剤としては、例えば、1,1’-オキサリルジイミダゾール、1-エチル-3-(3-ジメチルアミノプロピル)カルボジイミド、ジシクロヘキシルカルボジイミド、シアノホスホン酸ジエチル、O-(ベンゾトリアゾール-1-イル)-N,N,N’,N’-テトラメチルウロニウムヘキサフルオロリン酸塩、1H-ベンゾトリアゾール-1-イルオキシトリピロリジノホスホニウムヘキサフルオロホスファートを挙げることができる。本反応に使用しうる塩基としては、例えば、トリエチルアミン、N,N-ジイソプロピルエチルアミン、N,N-ジメチルアニリン、ピリジン、1,8-ジアザビシクロ[5,4,0]-7-ウンデセンの有機塩基を挙げることができる。使用しうる溶媒としては、反応に関与しなければ特に限定されないが、例えば、テトラヒドロフラン、1,4-ジオキサン、ジエチルエーテルなどのエーテル類、N,N-ジメチルホルムアミド、N,N-ジメチルアセトアミドなどのアミド類、アセトニトリル、プロピオンニトリルなどのニトリル類、ベンゼン、トルエンなどの炭化水素類、クロロホルム、塩化メチレンなどのハロゲン化炭化水素類、又はこれらの混合溶媒を挙げることができる。また、必要に応じて、添加剤を使用することができる。使用しうる添加剤としては、例えば、1-ヒドロキシベンゾトリアゾール、1-ヒドロキシ-7-アザベンゾトリアゾールを挙げることができる。反応時間は、使用する原料の種類、反応温度等によって異なるが、通常、10分~24時間の範囲内が適当である。化合物[31]及び縮合剤の使用量としては、例えば、化合物[1g]1モルに対して1倍モル~3倍モルの範囲内が適当である。
This reaction is a condensation reaction between compound [1g] and compound [31], and can be carried out by a method known per se as a condensation reaction. Compound [1h] can be synthesized by reacting a carboxylic acid represented by compound [1g] or a reactive derivative thereof with compound [31]. Examples of reactive derivatives of compound [1g] include those commonly used in amide condensation formation reactions, such as acid halides (e.g., acid chlorides, acid bromides), mixed acid anhydrides, imidazolides, and active amides. . When compound [1g] is used, the reaction can be carried out at -20 to 100°C using a condensing agent in the presence or absence of a base. Condensing agents that can be used in this reaction include, for example, 1,1′-oxalyldiimidazole, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, dicyclohexylcarbodiimide, diethyl cyanophosphonate, O-(benzotriazole -1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate, 1H-benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate. Examples of bases that can be used in this reaction include organic bases such as triethylamine, N,N-diisopropylethylamine, N,N-dimethylaniline, pyridine, and 1,8-diazabicyclo[5,4,0]-7-undecene. can be mentioned. Solvents that can be used are not particularly limited as long as they do not participate in the reaction. Examples include amides, nitriles such as acetonitrile and propiononitrile, hydrocarbons such as benzene and toluene, halogenated hydrocarbons such as chloroform and methylene chloride, and mixed solvents thereof. Moreover, an additive can be used as needed. Additives that can be used include, for example, 1-hydroxybenzotriazole and 1-hydroxy-7-azabenzotriazole. The reaction time varies depending on the type of raw material used, the reaction temperature, etc., but is usually within the range of 10 minutes to 24 hours. The amount of the compound [31] and the condensing agent to be used is, for example, in the range of 1 to 3 mol per 1 mol of the compound [1g].
製法9 R
2
がH、アルキルカルボニル、アルキルスルホニルで置換されていてもよい1個のNを含む飽和複素環式基、又は、ヒドロキシ若しくはアルコキシで置換されていてもよいアルキルである場合
(X1、R1、R5、Hal1は、前記と同義である。R17は、H、アルキルカルボニル、アルキルスルホニルで置換されていてもよい1個のNを含む飽和複素環式基、又は、ヒドロキシ若しくはアルコキシで置換されていてもよいアルキルを表す)
Process 9 When R 2 is H, alkylcarbonyl, saturated heterocyclic group containing 1 N optionally substituted with alkylsulfonyl, or alkyl optionally substituted with hydroxy or alkoxy
(X 1 , R 1 , R 5 and Hal 1 are as defined above. R 17 is a saturated heterocyclic group containing one N optionally substituted with H, alkylcarbonyl, alkylsulfonyl, or represents alkyl optionally substituted with hydroxy or alkoxy)
本反応は、化合物[32]と化合物[13]とのパラジウム触媒を用いた縮合反応であって、前記製法1と同様の方法によって行うことができる。
This reaction is a condensation reaction of compound [32] and compound [13] using a palladium catalyst, and can be carried out in the same manner as in production method 1 above.
製法10 R
2
がシアノである場合
(X1、R1、R5、Hal2は、前記と同義である。)
Production method 10 When R 2 is cyano
(X 1 , R 1 , R 5 and Hal 2 are as defined above.)
本反応は、化合物[1a]のシアノ化反応であって、それ自体公知の方法によって行うことができる。本反応は、例えばパラジウム触媒の存在又は非存在下に、適当な溶媒中、シアノ化合物と20~200℃の範囲内で、必要であればマイクロウエーブを用いて行うことができる。使用しうるパラジウム触媒としては、例えば、テトラキス(トリフェニルホスフィン)パラジウム、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、トリス(ジベンジリデンアセトン)ジパラジウム(0)を挙げることができる。使用しうるパラジウム触媒の量は、ハロゲン化アリール1モルに対して、0.001~0.1モルの範囲内が適当である。必要であればパラジウムのリガンドとして、4,5-ビス(ジフェニルホスフィノ)-9,9’-ジメチルキサンテン、2-ジシクロヘキシルホスフィノ-2’,4’,6’-トリイソプロピルビフェニル、2-ジシクロヘキシルホスフィノ-2’,6’-ジメトキシビフェニルなどを用いることができる。使用しうるシアノ化合物としては、シアン化銅(I)、シアン化亜鉛(II)、シアン化カリウム、シアン化ナトリウムを挙げることができる。使用しうる反応溶媒としては、反応に関与しなければ特に限定されないが、例えば、テトラヒドロフラン、1,4-ジオキサンなどのエーテル類、メタノール、エタノールなどのアルコール類、N,N-ジメチルホルムアミド、N,N-ジメチルアセトアミド、N-メチル-2-ピロリドンなどのアミド類、ベンゼン、トルエンなどの炭化水素類、ジメチルスルホキシド、水、又はこれらの混合溶媒を挙げることができる。反応時間は、使用する原料の種類、反応温度によって異なるが、通常、30分~24時間の範囲内が適当である。
This reaction is a cyanation reaction of compound [1a] and can be carried out by a method known per se. This reaction can be carried out with a cyano compound in the presence or absence of a palladium catalyst in a suitable solvent at a temperature of 20 to 200° C. using a microwave if necessary. Palladium catalysts that can be used include, for example, tetrakis(triphenylphosphine)palladium, 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride-dichloromethane complex, tris(dibenzylideneacetone)dipalladium(0 ) can be mentioned. The amount of palladium catalyst that can be used is suitably in the range of 0.001 to 0.1 mol per 1 mol of the aryl halide. 4,5-bis(diphenylphosphino)-9,9'-dimethylxanthene, 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, 2-dicyclohexyl as ligands for palladium if necessary Phosphino-2',6'-dimethoxybiphenyl and the like can be used. Usable cyano compounds include copper (I) cyanide, zinc (II) cyanide, potassium cyanide, and sodium cyanide. Usable reaction solvents are not particularly limited as long as they do not participate in the reaction. Examples include ethers such as tetrahydrofuran and 1,4-dioxane, alcohols such as methanol and ethanol, N,N-dimethylformamide, N, Examples include amides such as N-dimethylacetamide and N-methyl-2-pyrrolidone, hydrocarbons such as benzene and toluene, dimethylsulfoxide, water, and mixed solvents thereof. The reaction time varies depending on the type of raw material used and the reaction temperature, but is usually within the range of 30 minutes to 24 hours.
製法11 Xが-CR
A
であって、R
A
がアルコキシカルボニルの場合
(R1、R5、Hal1は、前記と同義である。R18は、アルキルを表す。)
Production Method 11 When X is —CR A and R A is alkoxycarbonyl
(R 1 , R 5 and Hal 1 are as defined above. R 18 represents alkyl.)
本反応は、化合物[33]と化合物[13]とのパラジウム触媒を用いた縮合反応であって、前記製法4-2と同様の方法により行うことができる。
This reaction is a condensation reaction of compound [33] and compound [13] using a palladium catalyst, and can be carried out in the same manner as in Production Method 4-2 above.
原料化合物である化合物[33]は、次の方法に従って製造することができる。
(R1、R18、Hal1、Hal3は、前記と同義である。)
Compound [33], which is a starting compound, can be produced according to the following method.
(R 1 , R 18 , Hal 1 and Hal 3 are as defined above.)
本反応は、化合物[34]と化合物[19]とのパラジウム触媒を用いた縮合反応であって、前記製法3-2、方法Aの工程2と同様の方法により行うことができる。
This reaction is a condensation reaction of compound [34] and compound [19] using a palladium catalyst, and can be carried out in the same manner as in step 2 of method A in production method 3-2 above.
製法12 Xが-CR
A
であって、R
A
がヒドロキシカルボニルの場合
(R1、R5、R18は、前記と同義である。)
Production method 12 When X is -CR A and R A is hydroxycarbonyl
(R 1 , R 5 and R 18 are as defined above.)
本反応は、化合物[1k]の加水分解反応であり、前記製法7と同様の方法によって行うことができる。
This reaction is a hydrolysis reaction of compound [1k] and can be carried out in the same manner as in Production Method 7 above.
製法13 Xが-CR
A
であって、R
A
が次の一般式[35]で表される基の場合
(式中、*は前記と同義である。R
19
、R
20
は、同一又は異なって、H、アルキル、シクロアルキル、(シクロアルキル)アルキル、若しくは、アルコキシアルキルを表すか、又は、隣接するNと一緒になって、飽和環状アミノ基を表す。)
Production Method 13 When X is —CR A and R A is a group represented by the following general formula [35]
(Wherein, * is as defined above. R 19 and R 20 are the same or different and represent H, alkyl, cycloalkyl, (cycloalkyl)alkyl or alkoxyalkyl, or adjacent N together with represents a saturated cyclic amino group.)
本反応は、化合物[1j]と化合物[36]との縮合反応であって、前記製法8と同様の方法によって行うことができる。
This reaction is a condensation reaction between compound [1j] and compound [36], and can be carried out in the same manner as in production method 8 above.
製法14 R
4
がアルキルの場合
(X、R1、R2、R3、R5、Hal1は、前記と同義である。R21は、アルキルを表す。)
Production method 14 When R 4 is alkyl
(X, R 1 , R 2 , R 3 , R 5 and Hal 1 are as defined above. R 21 represents alkyl.)
本反応は、化合物[37]と化合物[13]とのパラジウム触媒を用いた縮合反応であって、前記製法4-2と同様の方法により行うことができる。
This reaction is a condensation reaction of compound [37] and compound [13] using a palladium catalyst, and can be carried out in the same manner as in Production Method 4-2 above.
原料化合物である化合物[37]は、次の方法に従って製造することができる。
(X1、R1、R2、R21、Hal1は、前記と同義である。Hal4はハロゲンを表す。)
Compound [37], which is a starting compound, can be produced according to the following method.
(X 1 , R 1 , R 2 , R 21 and Hal 1 are as defined above. Hal 4 represents halogen.)
本工程は、化合物[38]と化合物[39]を適当な溶媒中、塩基の存在下、20℃~200℃で、必要であればマイクロウエーブを用いて、反応させることにより製造することができる。使用しうる塩基は、例えば、水素化ナトリウム、リチウムジイソプロピルアミド、n-ブチルリチウムなどを挙げることができる。使用しうる溶媒としては、反応に関与しなければ特に限定されないが、例えば、テトラヒドロフラン、1,4-ジオキサンなどのエーテル類、N,N-ジメチルホルムアミド、N,N-ジメチルアセトアミドなどのアミド類、ベンゼン、トルエンなどの炭化水素類、アセトニトリル、又はこれらの混合溶媒を挙げることができる。反応時間は、使用する原料の種類、反応温度によって異なるが、通常、10分~24時間の範囲内が適当である。
This step can be produced by reacting compound [38] and compound [39] in an appropriate solvent in the presence of a base at 20°C to 200°C using a microwave if necessary. . Usable bases include, for example, sodium hydride, lithium diisopropylamide, n-butyllithium and the like. Solvents that can be used are not particularly limited as long as they do not participate in the reaction. Hydrocarbons such as benzene and toluene, acetonitrile, or mixed solvents thereof can be mentioned. The reaction time varies depending on the type of raw materials used and the reaction temperature, but is usually within the range of 10 minutes to 24 hours.
製法15 R
3
がヒドロキシである場合
(X1、R1、R2、R5、Hal1は、前記と同義である。)
Process 15 When R 3 is Hydroxy
(X 1 , R 1 , R 2 , R 5 and Hal 1 are as defined above.)
本反応は、化合物[40]と化合物[13]とのパラジウム触媒を用いた縮合反応であって、前記製法1と同様の方法によって行うことができる。本反応に使用しうる塩基としては、ナトリウムt-ブトキシドが適当である。
This reaction is a condensation reaction of compound [40] and compound [13] using a palladium catalyst, and can be carried out in the same manner as in production method 1 above. Sodium t-butoxide is suitable as a base that can be used in this reaction.
原料化合物である化合物[40]は、次の方法に従って製造することができる。
(X1、R1、R2、Hal1、Hal3は、前記と同義である。)
Compound [40], which is a starting compound, can be produced according to the following method.
(X 1 , R 1 , R 2 , Hal 1 and Hal 3 are as defined above.)
工程1
化合物[42]は、公知の方法(J.Org.Chem.,65,2000,9059-9068など)に準じて製造することができる。 Process 1
Compound [42] can be produced according to known methods (J.Org.Chem., 65, 2000, 9059-9068, etc.).
化合物[42]は、公知の方法(J.Org.Chem.,65,2000,9059-9068など)に準じて製造することができる。 Process 1
Compound [42] can be produced according to known methods (J.Org.Chem., 65, 2000, 9059-9068, etc.).
工程2
本工程は、化合物[42]と化合物[43]とのパラジウム触媒を用いた縮合反応であって、例えば、前記製法1と同様の方法によって行うことができる。 Process 2
This step is a condensation reaction of compound [42] and compound [43] using a palladium catalyst, and can be carried out, for example, by the same method as in Production Method 1 above.
本工程は、化合物[42]と化合物[43]とのパラジウム触媒を用いた縮合反応であって、例えば、前記製法1と同様の方法によって行うことができる。 Process 2
This step is a condensation reaction of compound [42] and compound [43] using a palladium catalyst, and can be carried out, for example, by the same method as in Production Method 1 above.
本発明化合物は、そのまま医薬として用いることができるが、公知の方法により医薬上許容される塩の形にして用いることもできる。このような塩としては、塩酸、臭化水素酸、硫酸、燐酸などの鉱酸の塩、酢酸、クエン酸、酒石酸、マレイン酸、コハク酸、フマル酸、p-トルエンスルホン酸、ベンゼンスルホン酸、メタンスルホン酸などの有機酸の塩などを挙げることができる。
Although the compound of the present invention can be used as a medicine as it is, it can also be used in the form of a pharmaceutically acceptable salt by a known method. Such salts include salts of mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, citric acid, tartaric acid, maleic acid, succinic acid, fumaric acid, p-toluenesulfonic acid, benzenesulfonic acid, Examples include salts of organic acids such as methanesulfonic acid.
例えば、本発明化合物の塩酸塩は、本発明化合物を塩化水素のアルコール溶液、酢酸エチル溶液又はジエチルエーテル溶液に溶解することにより得ることができる。
For example, the hydrochloride of the compound of the present invention can be obtained by dissolving the compound of the present invention in an alcohol solution, ethyl acetate solution or diethyl ether solution of hydrogen chloride.
本発明化合物の中には、不斉炭素を有するものも存在するが、各光学異性体及びそれらの混合物のいずれも本発明に含まれる。光学異性体は、例えば、上記のようにして得られたラセミ体から、その塩基性を利用して光学活性な酸(酒石酸、ジベンゾイル酒石酸、マンデル酸、10-カンファースルホン酸等)を用いて公知の方法により光学分割するか、予め調製した光学活性な化合物を原料に用いて製造することができる。その他、キラルカラムを用いた光学分割や不斉合成により製造することもできる。
Among the compounds of the present invention, some have an asymmetric carbon, but both optical isomers and mixtures thereof are included in the present invention. Optical isomers are known, for example, from the racemate obtained as described above using an optically active acid (tartaric acid, dibenzoyltartaric acid, mandelic acid, 10-camphorsulfonic acid, etc.) by utilizing its basicity. or optically active compounds prepared in advance can be used as starting materials. In addition, it can also be produced by optical resolution using a chiral column or by asymmetric synthesis.
また、本発明化合物に幾何異性体や互変異性体が存在する場合は、いずれか一方の異性体のみならず、それらの混合物も本発明化合物に含まれる。
In addition, when the compound of the present invention has geometric isomers or tautomers, not only any one of the isomers but also a mixture thereof is included in the compound of the present invention.
本発明化合物又はその医薬上許容される塩は、後記の試験例に示すように、STAT3阻害活性及び/又はIL-17産生阻害活性を有しており、医薬として有用である。
The compound of the present invention or a pharmaceutically acceptable salt thereof has STAT3 inhibitory activity and/or IL-17 production inhibitory activity, as shown in the test examples below, and is useful as a pharmaceutical.
本発明の一態様として、本発明化合物又はその医薬上許容される塩を有効成分として含有する医薬組成物は、STAT3及び/又はIL-17が関与する疾患の予防剤又は治療剤として用いることができる。
In one aspect of the present invention, a pharmaceutical composition containing the compound of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient can be used as a prophylactic or therapeutic agent for diseases associated with STAT3 and/or IL-17. can.
本発明の一態様として、本発明化合物又はその医薬上許容される塩を有効成分として含有する医薬組成物は、例えば、サイトカインストーム/サイトカイン放出症候群(CRS)、呼吸器障害、乾癬、クローン病、潰瘍性大腸炎、強直性脊髄炎、体軸性脊髄関節炎、掌蹠膿疱症、化膿性汗腺炎、ループス腎炎、全身性エリテマトーデス、多発性筋炎/皮膚筋炎の予防剤又は治療剤として用いることができる。
As one aspect of the present invention, pharmaceutical compositions containing the compound of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient include, for example, cytokine storm/cytokine release syndrome (CRS), respiratory disorders, psoriasis, Crohn's disease, It can be used as a prophylactic or therapeutic agent for ulcerative colitis, ankylosing myelitis, axial spinal arthritis, palmoplantar pustulosis, hidradenitis suppurativa, lupus nephritis, systemic lupus erythematosus, polymyositis/dermatomyositis. .
本発明の一態様として、本発明化合物又はその医薬上許容される塩を有効成分として含有する医薬組成物は、例えば、サイトカインストーム/サイトカイン放出症候群(CRS)又は呼吸器障害の予防剤又は治療剤として用いることができる。
As one aspect of the present invention, a pharmaceutical composition containing the compound of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient is, for example, a prophylactic or therapeutic agent for cytokine storm/cytokine release syndrome (CRS) or respiratory disorders. can be used as
本発明の一態様として、サイトカインストーム/サイトカイン放出症候群(CRS)は、例えば、ウイルス感染症に関連するサイトカインストーム/サイトカイン放出症候群(CRS)であり、好ましくは、インフルエンザウイルス、新型インフルエンザウイルス、コロナウイルス(例えば、SARS-CoV、MERS-CoVなど)、又は新型コロナウイルスによるサイトカインストーム/サイトカイン放出症候群(CRS)であり、更に好ましくはSARS-CoV-2(又はCOVID-19)によるサイトカインストーム/サイトカイン放出症候群(CRS)である。
As one aspect of the present invention, cytokine storm/cytokine release syndrome (CRS) is, for example, cytokine storm/cytokine release syndrome (CRS) associated with viral infections, preferably influenza virus, novel influenza virus, coronavirus (e.g., SARS-CoV, MERS-CoV, etc.), or cytokine storm/cytokine release syndrome (CRS) due to novel coronavirus, more preferably cytokine storm/cytokine release due to SARS-CoV-2 (or COVID-19) syndrome (CRS).
本発明の一態様として、呼吸器障害は、例えば、ウイルス感染症に関連する肺炎又は急性呼吸窮迫症候群であり、好ましくは、インフルエンザウイルス、新型インフルエンザウイルス、コロナウイルス(例えば、SARS-CoV、MERS-CoVなど)、又は新型コロナウイルスによるウイルス感染症に関連する肺炎又は急性呼吸窮迫症候群であり、更に好ましくはSARS-CoV-2(又はCOVID-19)による肺炎(特に、重症肺炎)である。
In one aspect of the invention, the respiratory disorder is, for example, pneumonia or acute respiratory distress syndrome associated with a viral infection, preferably influenza virus, pandemic influenza virus, coronavirus (e.g., SARS-CoV, MERS- CoV, etc.), or pneumonia or acute respiratory distress syndrome associated with viral infections caused by the novel coronavirus, more preferably pneumonia (especially severe pneumonia) caused by SARS-CoV-2 (or COVID-19).
本発明の一態様として、本発明化合物又はその医薬上許容される塩を有効成分として含有する医薬組成物は、例えば、COVID-19の患者、好ましくはCOVID-19の患者であり、そしてL-17産生が亢進している患者に投与するための医薬組成物である。
As one aspect of the present invention, pharmaceutical compositions containing the compound of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient are, for example, COVID-19 patients, preferably COVID-19 patients, and L- This is a pharmaceutical composition for administration to a patient with enhanced 17 production.
本発明の一態様として、本発明化合物又はその医薬上許容される塩を有効成分として含有する医薬組成物は、例えば、乾癬、クローン病、潰瘍性大腸炎、強直性脊髄炎、体軸性脊髄関節炎、掌蹠膿疱症、化膿性汗腺炎、ループス腎炎、全身性エリテマトーデス、多発性筋炎/皮膚筋炎の予防剤又は治療剤として用いることができる。
As one aspect of the present invention, a pharmaceutical composition containing the compound of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient can be It can be used as a prophylactic or therapeutic agent for arthritis, palmoplantar pustulosis, hidradenitis suppurativa, lupus nephritis, systemic lupus erythematosus, polymyositis/dermatomyositis.
本発明の一態様として、本発明化合物又はその医薬上許容される塩を有効成分として含有する医薬組成物は、L-17産生が亢進している患者に投与するための医薬組成物である。
As one aspect of the present invention, a pharmaceutical composition containing the compound of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient is a pharmaceutical composition for administration to patients with enhanced L-17 production.
本発明化合物又はその医薬上許容される塩は、STAT3阻害活性及び/又はIL-17産生阻害活性を有しており、サイトカインストーム抑制剤として有用である。
The compound of the present invention or a pharmaceutically acceptable salt thereof has STAT3 inhibitory activity and/or IL-17 production inhibitory activity, and is useful as a cytokine storm inhibitor.
本発明化合物又はその医薬上許容される塩は、IL-17産生阻害活性を有しており、IL-17産生阻害剤として有用である。
The compound of the present invention or a pharmaceutically acceptable salt thereof has IL-17 production inhibitory activity and is useful as an IL-17 production inhibitor.
本発明化合物又はその医薬上許容される塩は、STAT3阻害活性を有しており、STAT3阻害活性剤として有用である。
The compound of the present invention or a pharmaceutically acceptable salt thereof has STAT3 inhibitory activity and is useful as a STAT3 inhibitory agent.
本発明化合物又はその医薬上許容される塩を医薬として投与する場合、本発明化合物又はその医薬上許容される塩をそのまま又は医薬的に許容される無毒性かつ不活性の担体中に、例えば、0.001%~99.5%、好ましくは0.1%~90%含有する医薬組成物として、人を含む哺乳動物に投与される。
When administering the compound of the present invention or a pharmaceutically acceptable salt thereof as a medicament, the compound of the present invention or a pharmaceutically acceptable salt thereof as such or in a pharmaceutically acceptable non-toxic and inert carrier, for example, It is administered to mammals, including humans, as a pharmaceutical composition containing 0.001% to 99.5%, preferably 0.1% to 90%.
担体としては、固形、半固形、又は液状の希釈剤、充填剤、及びその他の処方用の助剤一種以上が用いられる。本発明に係る医薬組成物は、投与単位形態で投与することが望ましい。医薬組成物は、組織内投与、経口投与、静脈内投与、局所投与(経皮投与、点眼等)又は経直腸的に投与することができる。これらの投与方法に適した剤型で投与されるのはもちろんである。
As the carrier, one or more solid, semi-solid, or liquid diluents, fillers, and other formulation aids are used. The pharmaceutical compositions of the present invention are preferably administered in dosage unit form. The pharmaceutical composition can be administered intratissueally, orally, intravenously, locally (percutaneously, eye drops, etc.), or rectally. Of course, it is administered in dosage forms suitable for these administration methods.
医薬としての用量は、年齢、体重、疾病の種類、程度等の患者の状態、投与経路を考慮した上で調製することが望ましいが、通常は、成人に対して本発明化合物又はその医薬上許容される塩の有効成分量として、経口投与の場合、1日あたり、0.1mg~5g/成人の範囲、好ましくは、1mg~500mg/成人の範囲が適当である。場合によっては、これ以下でも足りるし、また逆にこれ以上の用量を必要とすることもある。通常、1日1回又は数回に分けて投与するか又は1~24時間かけて静脈内に連続投与することができる。
The dosage as a pharmaceutical should preferably be prepared in consideration of the patient's condition such as age, body weight, type and degree of disease, and route of administration. In the case of oral administration, the amount of the active ingredient of the salt used is preferably in the range of 0.1 mg to 5 g/adult per day, preferably 1 mg to 500 mg/adult. Depending on the case, less than this dose may be sufficient, and conversely, more than this dose may be required. Usually, it can be administered once or several times a day, or can be administered intravenously continuously over 1 to 24 hours.
以下に参考例、実施例、試験例及び製剤例を掲げて本発明を更に詳しく説明するが、本発明はこれらのみに限定されるものではない。
The present invention will be described in more detail below with reference examples, examples, test examples, and formulation examples, but the present invention is not limited to these.
実施例1~実施例234の化合物は、国際公開第2010/090290号及び国際公開第2012/005299号の記載を参照して合成した。実施例1~実施例234の化合物の構造式を表1~表12に示す。
The compounds of Examples 1 to 234 were synthesized with reference to the descriptions in WO2010/090290 and WO2012/005299. Structural formulas of the compounds of Examples 1 to 234 are shown in Tables 1 to 12.
(S)-N2-[1-(4-フルオロフェニル)エチル]-4-(1-メチル-1H-ピラゾール-4-イル)-N6-(ピラジン-2-イル)ピリジン-2,6-ジアミン マレイン酸塩(以下、「化合物A」)の合成
(S)—N 2 -[1-(4-fluorophenyl)ethyl]-4-(1-methyl-1H-pyrazol-4-yl)-N 6 -(pyrazin-2-yl)pyridine-2,6 - Synthesis of diamine maleate (hereinafter "compound A")
化合物Aは、国際公開第2019/065793号の記載を参照して合成した。化合物Aの構造式を下記に示す。
Compound A was synthesized with reference to the description in International Publication No. 2019/065793. The structural formula of compound A is shown below.
試験例1:マウス血球におけるSTAT3リン酸化抑制作用
1.マウスへの被験物質の投与及び採血
マウス(BALB/cA Jcl、7週齢、雄)に化合物Aを10、25、50mg/kgで経口投与を行った。Vehicle群には0.5%メチルセルロースを経口投与した。投与前および投与後1、3時間後にイソフルラン吸入麻酔下で、後大静脈より採血を行った。各群に3匹のマウスを用いた。 Test Example 1: STAT3 phosphorylation inhibitory action on mouse blood cells 1. Administration of test substance to mice and blood collection Compound A was orally administered to mice (BALB/cA Jcl, 7 weeks old, male) at 10, 25 and 50 mg/kg. 0.5% methylcellulose was orally administered to the vehicle group. Blood was collected from the posterior vena cava under isoflurane inhalation anesthesia before administration and 1 and 3 hours after administration. Three mice were used in each group.
1.マウスへの被験物質の投与及び採血
マウス(BALB/cA Jcl、7週齢、雄)に化合物Aを10、25、50mg/kgで経口投与を行った。Vehicle群には0.5%メチルセルロースを経口投与した。投与前および投与後1、3時間後にイソフルラン吸入麻酔下で、後大静脈より採血を行った。各群に3匹のマウスを用いた。 Test Example 1: STAT3 phosphorylation inhibitory action on mouse blood cells 1. Administration of test substance to mice and blood collection Compound A was orally administered to mice (BALB/cA Jcl, 7 weeks old, male) at 10, 25 and 50 mg/kg. 0.5% methylcellulose was orally administered to the vehicle group. Blood was collected from the posterior vena cava under isoflurane inhalation anesthesia before administration and 1 and 3 hours after administration. Three mice were used in each group.
2.pSTAT3産生の測定
血液150μLを分取し、リン酸緩衝液で2回洗浄した。以降、ELISAキット(phosphoELISA kit STAT3[pY705]、Invitrogen cat#KHO0481)の手順書に従って行い、pSTAT3を測定した。 2. Measurement of pSTAT3 production 150 μL of blood was taken and washed twice with phosphate buffer. Thereafter, pSTAT3 was measured according to the procedure of the ELISA kit (phosphoELISA kit STAT3 [pY705], Invitrogen cat#KHO0481).
血液150μLを分取し、リン酸緩衝液で2回洗浄した。以降、ELISAキット(phosphoELISA kit STAT3[pY705]、Invitrogen cat#KHO0481)の手順書に従って行い、pSTAT3を測定した。 2. Measurement of pSTAT3 production 150 μL of blood was taken and washed twice with phosphate buffer. Thereafter, pSTAT3 was measured according to the procedure of the ELISA kit (phosphoELISA kit STAT3 [pY705], Invitrogen cat#KHO0481).
3.結果
化合物A投与後1時間において、25mg/kg以上の用量でpSTAT3の抑制がみられ、3時間において回復する傾向が見られた。この化合物A投与後1時間における強いpSTAT3抑制は、化合物Aのマウスにおける最高血中濃度到達時間(Tmax)が0.5時間であり、その後3時間後には血漿中濃度が低下することと相関した結果であり、化合物Aがその血漿中濃度に応じて血球細胞のSTAT3のリン酸化を抑制することが示された(表13)。 3. Results At 1 hour after administration of compound A, suppression of pSTAT3 was observed at doses of 25 mg/kg or higher, and a tendency toward recovery was observed at 3 hours. This strong pSTAT3 suppression 1 hour after administration of compound A correlated with the time to reach maximum blood concentration (Tmax) of compound A in mice of 0.5 hours, followed by a decrease in plasma concentration after 3 hours. The results showed that compound A inhibited STAT3 phosphorylation of blood cells depending on its plasma concentration (Table 13).
化合物A投与後1時間において、25mg/kg以上の用量でpSTAT3の抑制がみられ、3時間において回復する傾向が見られた。この化合物A投与後1時間における強いpSTAT3抑制は、化合物Aのマウスにおける最高血中濃度到達時間(Tmax)が0.5時間であり、その後3時間後には血漿中濃度が低下することと相関した結果であり、化合物Aがその血漿中濃度に応じて血球細胞のSTAT3のリン酸化を抑制することが示された(表13)。 3. Results At 1 hour after administration of compound A, suppression of pSTAT3 was observed at doses of 25 mg/kg or higher, and a tendency toward recovery was observed at 3 hours. This strong pSTAT3 suppression 1 hour after administration of compound A correlated with the time to reach maximum blood concentration (Tmax) of compound A in mice of 0.5 hours, followed by a decrease in plasma concentration after 3 hours. The results showed that compound A inhibited STAT3 phosphorylation of blood cells depending on its plasma concentration (Table 13).
試験例2:IL-17産生阻害作用
1.被験物質の調製
化合物A、バリシチニブ、ルキソリチニブは、Dimethylsulfoxide(DMSO、ナカライテスク社)で、3、1、0.3、0.1、0.03mMになるように希釈した。さらに、この溶液を10%ウシ胎児血清(FBS、Sigma社、173012)含有Roswell Park Memorial Institute(RPMI)1640培地(ナカライテスク社、30264-56)で、30、10、3、1、0.3μMになるように希釈し、被験物質溶液とした。陰性コントロール、無刺激群には、DMSOを10%FBS含有RPMI-1640で、100倍希釈した溶液を添加した。 Test Example 2: IL-17 production inhibitory action 1. Preparation of Test Substances Compound A, baricitinib, and ruxolitinib were diluted with Dimethylsulfoxide (DMSO, Nacalai Tesque) to 3, 1, 0.3, 0.1, and 0.03 mM. Furthermore, this solution was added to Roswell Park Memorial Institute (RPMI) 1640 medium (Nacalai Tesque, 30264-56) containing 10% fetal bovine serum (FBS, Sigma, 173012) at 30, 10, 3, 1, 0.3 μM. and used as the test substance solution. A 100-fold diluted solution of DMSO in RPMI-1640 containing 10% FBS was added to the negative control and non-stimulated group.
1.被験物質の調製
化合物A、バリシチニブ、ルキソリチニブは、Dimethylsulfoxide(DMSO、ナカライテスク社)で、3、1、0.3、0.1、0.03mMになるように希釈した。さらに、この溶液を10%ウシ胎児血清(FBS、Sigma社、173012)含有Roswell Park Memorial Institute(RPMI)1640培地(ナカライテスク社、30264-56)で、30、10、3、1、0.3μMになるように希釈し、被験物質溶液とした。陰性コントロール、無刺激群には、DMSOを10%FBS含有RPMI-1640で、100倍希釈した溶液を添加した。 Test Example 2: IL-17 production inhibitory action 1. Preparation of Test Substances Compound A, baricitinib, and ruxolitinib were diluted with Dimethylsulfoxide (DMSO, Nacalai Tesque) to 3, 1, 0.3, 0.1, and 0.03 mM. Furthermore, this solution was added to Roswell Park Memorial Institute (RPMI) 1640 medium (Nacalai Tesque, 30264-56) containing 10% fetal bovine serum (FBS, Sigma, 173012) at 30, 10, 3, 1, 0.3 μM. and used as the test substance solution. A 100-fold diluted solution of DMSO in RPMI-1640 containing 10% FBS was added to the negative control and non-stimulated group.
2.IL-17産生の測定
凍結ヒト末梢血単核細胞(Cellular Technology社、CTL-UP1)を37℃の恒温槽で8分間温め、解凍した。溶解した細胞懸濁液を50mL遠心チューブ(Thermo Fisher Scientific社、339652)に移した後、10%FBS含有RPMI-1640培地を8.5mL加えた。細胞懸濁液を室温、330g、10分間遠心遠心分離し、上澄みを捨てた。10%FBS含有RPMI-1640培地で、末梢血単核細胞を0.56×106cells/mLに懸濁し、90μLずつ(0.5×105細胞)を96ウェルプレート(Corning社、353075)に播種した。播種直後に、被験物質溶液を10μLずつ添加し、5%二酸化炭素(CO2)、37℃のインキュベーターで培養した。培養の間、10μLの10%FBS含有RPMI-1640培地に対して、Dynabeads(登録商標) Human T-Activator CD3/CD28 for T Cell Expansion and Activation(Thermo Fisher Scientific社、11161D)を0.88μLの割合で混合した。培養開始から30分後、この混合培地を10μLずつ末梢血単核細胞に添加した。5%CO2、37℃のインキュベーターで72時間培養後、3000rpmで96ウェルプレートを遠心し、上清を回収した。回収した上清中のIL-17の測定には、Human IL-17 Quantikine ELISA Kit(R&D社、D1700)を使用し、Envision(Perkinelmer社)にて450nmの吸光度を測定した。試験は、Duplicateで行った。 2. Measurement of IL-17 Production Frozen human peripheral blood mononuclear cells (Cellular Technology, CTL-UP1) were warmed in a 37° C. thermostat for 8 minutes and thawed. After transferring the lysed cell suspension to a 50 mL centrifuge tube (Thermo Fisher Scientific, 339652), 8.5 mL of RPMI-1640 medium containing 10% FBS was added. The cell suspension was centrifuged at 330 g for 10 minutes at room temperature, and the supernatant was discarded. Peripheral blood mononuclear cells were suspended at 0.56×10 6 cells/mL in RPMI-1640 medium containing 10% FBS, and each 90 μL (0.5×10 5 cells) was placed in a 96-well plate (Corning, 353075). sown in Immediately after seeding, 10 µL of the test substance solution was added and cultured in a 5% carbon dioxide (CO2), 37°C incubator. During culture, Dynabeads (registered trademark) Human T-Activator CD3/CD28 for T Cell Expansion and Activation (Thermo Fisher Scientific, 11161D) was added at a ratio of 0.88 μL per 10 μL of RPMI-1640 medium containing 10% FBS. mixed with. Thirty minutes after the start of culture, 10 μL of this mixed medium was added to the peripheral blood mononuclear cells. After culturing for 72 hours in a 5% CO2, 37°C incubator, the 96-well plate was centrifuged at 3000 rpm to collect the supernatant. Human IL-17 Quantikine ELISA Kit (R&D, D1700) was used to measure IL-17 in the recovered supernatant, and absorbance at 450 nm was measured with Envision (Perkinelmer). Testing was done in Duplicate.
凍結ヒト末梢血単核細胞(Cellular Technology社、CTL-UP1)を37℃の恒温槽で8分間温め、解凍した。溶解した細胞懸濁液を50mL遠心チューブ(Thermo Fisher Scientific社、339652)に移した後、10%FBS含有RPMI-1640培地を8.5mL加えた。細胞懸濁液を室温、330g、10分間遠心遠心分離し、上澄みを捨てた。10%FBS含有RPMI-1640培地で、末梢血単核細胞を0.56×106cells/mLに懸濁し、90μLずつ(0.5×105細胞)を96ウェルプレート(Corning社、353075)に播種した。播種直後に、被験物質溶液を10μLずつ添加し、5%二酸化炭素(CO2)、37℃のインキュベーターで培養した。培養の間、10μLの10%FBS含有RPMI-1640培地に対して、Dynabeads(登録商標) Human T-Activator CD3/CD28 for T Cell Expansion and Activation(Thermo Fisher Scientific社、11161D)を0.88μLの割合で混合した。培養開始から30分後、この混合培地を10μLずつ末梢血単核細胞に添加した。5%CO2、37℃のインキュベーターで72時間培養後、3000rpmで96ウェルプレートを遠心し、上清を回収した。回収した上清中のIL-17の測定には、Human IL-17 Quantikine ELISA Kit(R&D社、D1700)を使用し、Envision(Perkinelmer社)にて450nmの吸光度を測定した。試験は、Duplicateで行った。 2. Measurement of IL-17 Production Frozen human peripheral blood mononuclear cells (Cellular Technology, CTL-UP1) were warmed in a 37° C. thermostat for 8 minutes and thawed. After transferring the lysed cell suspension to a 50 mL centrifuge tube (Thermo Fisher Scientific, 339652), 8.5 mL of RPMI-1640 medium containing 10% FBS was added. The cell suspension was centrifuged at 330 g for 10 minutes at room temperature, and the supernatant was discarded. Peripheral blood mononuclear cells were suspended at 0.56×10 6 cells/mL in RPMI-1640 medium containing 10% FBS, and each 90 μL (0.5×10 5 cells) was placed in a 96-well plate (Corning, 353075). sown in Immediately after seeding, 10 µL of the test substance solution was added and cultured in a 5% carbon dioxide (CO2), 37°C incubator. During culture, Dynabeads (registered trademark) Human T-Activator CD3/CD28 for T Cell Expansion and Activation (Thermo Fisher Scientific, 11161D) was added at a ratio of 0.88 μL per 10 μL of RPMI-1640 medium containing 10% FBS. mixed with. Thirty minutes after the start of culture, 10 μL of this mixed medium was added to the peripheral blood mononuclear cells. After culturing for 72 hours in a 5% CO2, 37°C incubator, the 96-well plate was centrifuged at 3000 rpm to collect the supernatant. Human IL-17 Quantikine ELISA Kit (R&D, D1700) was used to measure IL-17 in the recovered supernatant, and absorbance at 450 nm was measured with Envision (Perkinelmer). Testing was done in Duplicate.
3.試験結果の解析
解析には、Envisionのソフトウェア(Perkinelmer EnvisionManager)を用いた。標準物質の平均吸光度を縦軸に、濃度を横軸にプロットし、4パラメータロジスティック回帰(4PL)により、標準曲線を作成した。この標準曲線と、被験物質添加群の吸光度から、上清のIL-17濃度を算出した。 3. Analysis of test results Envision's software (Perkinelmer EnvisionManager) was used for the analysis. A standard curve was constructed by 4-parameter logistic regression (4PL) by plotting the average absorbance of the standards on the vertical axis and the concentration on the horizontal axis. The IL-17 concentration of the supernatant was calculated from this standard curve and the absorbance of the test substance-added group.
解析には、Envisionのソフトウェア(Perkinelmer EnvisionManager)を用いた。標準物質の平均吸光度を縦軸に、濃度を横軸にプロットし、4パラメータロジスティック回帰(4PL)により、標準曲線を作成した。この標準曲線と、被験物質添加群の吸光度から、上清のIL-17濃度を算出した。 3. Analysis of test results Envision's software (Perkinelmer EnvisionManager) was used for the analysis. A standard curve was constructed by 4-parameter logistic regression (4PL) by plotting the average absorbance of the standards on the vertical axis and the concentration on the horizontal axis. The IL-17 concentration of the supernatant was calculated from this standard curve and the absorbance of the test substance-added group.
4.結果
ヒト末梢血単核細胞は、Dynabeads(登録商標) Human T-Activator CD3/CD28 for T Cell Expansion and Activationで刺激後、IL-17を産生することが示された。また、化合物Aの添加により、濃度依存的にIL-17産生が阻害されることを示された。化合物AのIL-17産生抑制作用は他のJAK阻害剤と同程度であったが、化合物Aは3000nMにおいて強い産生阻害を示した(表14)。 4. Results Human peripheral blood mononuclear cells were shown to produce IL-17 after stimulation with Dynabeads® Human T-Activator CD3/CD28 for T Cell Expansion and Activation. It was also shown that addition of compound A inhibits IL-17 production in a concentration-dependent manner. The inhibitory effect of compound A on IL-17 production was comparable to that of other JAK inhibitors, but compound A showed strong production inhibition at 3000 nM (Table 14).
ヒト末梢血単核細胞は、Dynabeads(登録商標) Human T-Activator CD3/CD28 for T Cell Expansion and Activationで刺激後、IL-17を産生することが示された。また、化合物Aの添加により、濃度依存的にIL-17産生が阻害されることを示された。化合物AのIL-17産生抑制作用は他のJAK阻害剤と同程度であったが、化合物Aは3000nMにおいて強い産生阻害を示した(表14)。 4. Results Human peripheral blood mononuclear cells were shown to produce IL-17 after stimulation with Dynabeads® Human T-Activator CD3/CD28 for T Cell Expansion and Activation. It was also shown that addition of compound A inhibits IL-17 production in a concentration-dependent manner. The inhibitory effect of compound A on IL-17 production was comparable to that of other JAK inhibitors, but compound A showed strong production inhibition at 3000 nM (Table 14).
製剤例1
錠剤(内服錠)
処方1錠80mg中
実施例1の本発明化合物 5.0mg
トウモロコシ澱粉 46.6mg
結晶セルロース 24.0mg
メチルセルロース 4.0mg
ステアリン酸マグネシウム 0.4mg
この割合の混合末を通常の方法により打錠成形し内服錠とする。 Formulation example 1
Tablet (oral tablet)
5.0 mg of the compound of the present invention of Example 1 in 80 mg of one prescription tablet
Corn starch 46.6 mg
Crystalline cellulose 24.0 mg
Methyl cellulose 4.0 mg
Magnesium stearate 0.4 mg
The mixed powder of this ratio is tableted by a conventional method to give tablets for oral use.
錠剤(内服錠)
処方1錠80mg中
実施例1の本発明化合物 5.0mg
トウモロコシ澱粉 46.6mg
結晶セルロース 24.0mg
メチルセルロース 4.0mg
ステアリン酸マグネシウム 0.4mg
この割合の混合末を通常の方法により打錠成形し内服錠とする。 Formulation example 1
Tablet (oral tablet)
5.0 mg of the compound of the present invention of Example 1 in 80 mg of one prescription tablet
Corn starch 46.6 mg
Crystalline cellulose 24.0 mg
Methyl cellulose 4.0 mg
Magnesium stearate 0.4 mg
The mixed powder of this ratio is tableted by a conventional method to give tablets for oral use.
製剤例2
錠剤(内服錠)
処方1錠80mg中
実施例2の本発明化合物 5.0mg
トウモロコシ澱粉 46.6mg
結晶セルロース 24.0mg
メチルセルロース 4.0mg
ステアリン酸マグネシウム 0.4mg
この割合の混合末を通常の方法により打錠成形し内服錠とする。 Formulation example 2
Tablet (oral tablet)
5.0 mg of the compound of the present invention of Example 2 in 80 mg of one prescription tablet
Corn starch 46.6 mg
Crystalline cellulose 24.0mg
Methyl cellulose 4.0 mg
Magnesium stearate 0.4 mg
The mixed powder of this ratio is tableted by a usual method to give an oral tablet.
錠剤(内服錠)
処方1錠80mg中
実施例2の本発明化合物 5.0mg
トウモロコシ澱粉 46.6mg
結晶セルロース 24.0mg
メチルセルロース 4.0mg
ステアリン酸マグネシウム 0.4mg
この割合の混合末を通常の方法により打錠成形し内服錠とする。 Formulation example 2
Tablet (oral tablet)
5.0 mg of the compound of the present invention of Example 2 in 80 mg of one prescription tablet
Corn starch 46.6 mg
Crystalline cellulose 24.0mg
Methyl cellulose 4.0 mg
Magnesium stearate 0.4 mg
The mixed powder of this ratio is tableted by a usual method to give an oral tablet.
上記の通り、本発明化合物又はその医薬上許容される塩は、STAT3阻害活性及び/又はIL-17産生阻害活性を有することから、本発明化合物又はその医薬上許容される塩を有効成分として含有する医薬組成物は、例えば、サイトカインストーム/サイトカイン放出症候群(CRS)、乾癬、クローン病、潰瘍性大腸炎、強直性脊髄炎、体軸性脊髄関節炎、掌蹠膿疱症、化膿性汗腺炎、ループス腎炎、全身性エリテマトーデス、又は多発性筋炎/皮膚筋炎の予防剤又は治療剤として用いることができる。
As described above, since the compound of the present invention or a pharmaceutically acceptable salt thereof has STAT3 inhibitory activity and/or IL-17 production inhibitory activity, the compound of the present invention or a pharmaceutically acceptable salt thereof is contained as an active ingredient. Pharmaceutical compositions that treat, for example, cytokine storm/cytokine release syndrome (CRS), psoriasis, Crohn's disease, ulcerative colitis, ankylosing myelitis, axial spinal arthritis, palmoplantar pustulosis, hidradenitis suppurativa, lupus It can be used as a prophylactic or therapeutic agent for nephritis, systemic lupus erythematosus, or polymyositis/dermatomyositis.
Claims (5)
- 次の(I)又は(II)のいずれかの場合である、次の一般式[1]で表される化合物又はその医薬上許容される塩を有効成分として含有するサイトカインストーム抑制剤。
Xは、CH又はNを表す。
R1は、ハロゲンを表す。
R2は、
(1)H、
(2)ハロゲン、
(3)シアノ、
(4)次の一般式[2]で表される基、
(5)次の一般式[3]で表される基、
(6)次の一般式[8]で表される基、
(7)次の一般式[9]で表される基、
(8)-ORP(RPは、ヒドロキシ、ジアルキルアミノ、アルコキシ、テトラヒドロフラニル、及びシクロアルキルからなる群から選択される基で置換されていてもよいアルキル、又は、ヒドロキシで置換されていてもよく、1個のOを含んでいてもよい飽和環式基を表す。)、又は
(9)シアノ、ハロゲン、ヒドロキシ、アルコキシ、アルキルカルボニル、カルバモイル、アルキル、シクロアルキル、(シクロアルキル)アルキル、アラルキル、ヒドロキシカルボニル及びアルコキシアルキルからなる群から選択される1若しくは2個の基で置換されていてもよいヘテロアリールを表す。
R3は、H又はヒドロキシを表す。
R4は、H又はアルキルを表す。
R5は、H又はアルキルを表す。
(II)
Xは、-CRAを表す。
RAは、次の一般式[10]で表される基を表す。
R1は、ハロゲンを表す。
R2は、Hを表す。
R3は、H又はヒドロキシを表す。
R4は、H又はアルキルを表す。
R5は、H又はアルキルを表す。 A cytokine storm suppressing agent comprising, as an active ingredient, a compound represented by the following general formula [1] or a pharmaceutically acceptable salt thereof, which is either the case of (I) or (II) below.
X represents CH or N;
R 1 represents halogen.
R2 is
(1) H,
(2) halogen,
(3) cyano,
(4) a group represented by the following general formula [2],
(5) a group represented by the following general formula [3],
(6) a group represented by the following general formula [8],
(7) a group represented by the following general formula [9],
(8) —OR P (R P is alkyl optionally substituted by a group selected from the group consisting of hydroxy, dialkylamino, alkoxy, tetrahydrofuranyl, and cycloalkyl, or optionally substituted by hydroxy represents a saturated cyclic group optionally containing one O.), or (9) cyano, halogen, hydroxy, alkoxy, alkylcarbonyl, carbamoyl, alkyl, cycloalkyl, (cycloalkyl)alkyl, aralkyl , represents heteroaryl optionally substituted with one or two groups selected from the group consisting of hydroxycarbonyl and alkoxyalkyl.
R3 represents H or hydroxy.
R 4 represents H or alkyl.
R5 represents H or alkyl.
(II)
X represents -CR A.
RA represents a group represented by the following general formula [10].
R 1 represents halogen.
R2 represents H;
R3 represents H or hydroxy.
R 4 represents H or alkyl.
R5 represents H or alkyl. - 次の化合物(1)~(230)からなる群から選択される化合物又はその医薬上許容される塩を有効成分として含有する、請求項1に記載のサイトカインストーム抑制剤。
(1)(S)-4-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}ピペラジン-2-オン、
(2)N-{(S)-1-[2-{[(S)-1-(4-フルオロフェニル)エチル]アミノ}-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル]ピロリジン-3-イル}アセトアミド、
(3)(S)-6-(3,3-ジフルオロアゼチジン-1-イル)-N2-[1-(4-フルオロフェニル)エチル]-N4-(ピラジン-2-イル)ピリミジン-2,4-ジアミン、
(4)(S)-N2-[1-(4-フルオロフェニル)エチル]-4-(1-メチル-1H-ピラゾール-4-イル)-N6-(ピラジン-2-イル)ピリジン-2,6-ジアミン、
(5)(S)-N2’-[1-(4-フルオロフェニル)エチル]-N6’-(ピラジン-2-イル)-3,4’-ビピリジン-2’,6’-ジアミン、
(6)(S)-N2’-[1-(4-フルオロフェニル)エチル]-6-メトキシ-N6’-(ピラジン-2-イル)-3,4’-ビピリジン-2’,6’-ジアミン、
(7)(S)-2’-[1-(4-フルオロフェニル)エチルアミノ]-6’-(ピラジン-2-イルアミノ)-3,4’-ビピリジン-6-オール、
(8)(S)-N2-[1-(4-フルオロフェニル)エチル]-4-(オキサゾール-5-イル)-N6-(ピラジン-2-イル)ピリジン-2,6-ジアミン、
(9)(S)-6-クロロ-N2-[1-(4-フルオロフェニル)エチル]-N4-(ピラジン-2-イル)ピリミジン-2,4-ジアミン、
(10)(S)-N2-[1-(4-フルオロフェニル)エチル]-6-[4-(メチルスルホニル)フェニル]-N4-(ピラジン-2-イル)ピリミジン-2,4-ジアミン、
(11)(S)-N2-[1-(4-フルオロフェニル)エチル]-N4-(ピラジン-2-イル)-6-(1H-ピラゾール-4-イル)ピリミジン-2,4-ジアミン、
(12)(S)-2-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリジン-4-イルオキシ}エタノール、
(13)(S)-N2-[1-(4-フルオロフェニル)エチル]-N4-(ピラジン-2-イル)-6-(ピリジン-3-イル)ピリミジン-2,4-ジアミン、
(14)(S)-N2-[1-(4-フルオロフェニル)エチル]-N4-(ピラジン-2-イル)-6-(ピリジン-2-イル)ピリミジン-2,4-ジアミン、
(15)(S)-N2-[1-(4-フルオロフェニル)エチル]-N4-(ピラジン-2-イル)-6-(ピリジン-4-イル)ピリミジン-2,4-ジアミン、
(16)(S)-1-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}ピロリジン-2-オン、
(17)(S)-4-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}ピペラジン-2,6-ジオン、
(18)(S)-1-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}テトラヒドロピリミジン-2(1H)-オン、
(19)(S)-N2-[1-(4-フルオロフェニル)エチル]-N4-(ピラジン-2-イル)-6-(ピロリジン-1-イル)ピリミジン-2,4-ジアミン、
(20)(S)-N2-[1-(4-フルオロフェニル)エチル]-6-モルホリノ-N4-(ピラジン-2-イル)ピリミジン-2,4-ジアミン、
(21)(S)-1-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}イミダゾリジン-2-オン、
(22)(S)-N2-[1-(4-フルオロフェニル)エチル]-6-(オキサゾール-5-イル)-N4-(ピラジン-2-イル)ピリミジン-2,4-ジアミン、
(23)(S)-N2-[1-(4-フルオロフェニル)エチル]-6-(6-メトキシピリジン-3-イル)-N4-(ピラジン-2-イル)ピリミジン-2,4-ジアミン、
(24)(S)-N2-[1-(4-フルオロフェニル)エチル]-N4-(ピラジン-2-イル)-6-(1H-ピラゾール-3-イル)ピリミジン-2,4-ジアミン、
(25)(S)-4-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}ピリジン-2-オール、
(26)(S)-5-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}ピリジン-2-オール、
(27)N-((R)-1-{2-[(S)-1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}ピロリジン-3-イル)アセトアミド、
(28)(S)-N2-[1-(4-フルオロフェニル)エチル]-N6-(ピラジン-2-イル)-4-(1H-ピラゾール-4-イル)ピリジン-2,6-ジアミン、
(29)(S)-N2-[1-(4-フルオロフェニル)エチル]-N6-(ピラジン-2-イル)-4-(1H-ピラゾール-3-イル)ピリジン-2,6-ジアミン、
(30)(S)-N2-[1-(4-フルオロフェニル)エチル]-6-[3-(メチルスルホニル)フェニル]-N4-(ピラジン-2-イル)ピリミジン-2,4-ジアミン、
(31)(S)-N2-[1-(4-フルオロフェニル)エチル]-4-[4-(メチルスルホニル)フェニル]-N6-(ピラジン-2-イル)ピリジン-2,6-ジアミン、
(32)(S)-N2-[1-(4-フルオロフェニル)エチル]-4-(1-イソプロピル-1H-ピラゾール-4-イル)-N6-(ピラジン-2-イル)ピリジン-2,6-ジアミン、
(33)N-{(S)-1-[2-{[(S)-1-(4-フルオロフェニル)エチル]アミノ}-6-(ピラジン-2-イルアミノ)ピリジン-4-イル]ピロリジン-3-イル}アセトアミド、
(34)(S)-N2-[1-(4-フルオロフェニル)エチル]-4-モルホリノ-N6-(ピラジン-2-イル)ピリジン-2,6-ジアミン、
(35)(S)-N2-[1-(4-フルオロフェニル)エチル]-N6-(ピラジン-2-イル)-4-チオモルホリノピリジン-2,6-ジアミン、
(36)(S)-3-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリジン-4-イル}プロパン-1-オール、
(37)(S)-N-(1-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}アゼチジン-3-イル)アセトアミド、
(38)(S)-6-(アゼチジン-1-イル)-N2-[1-(4-フルオロフェニル)エチル]-N4-(ピラジン-2-イル)ピリミジン-2,4-ジアミン、
(39)(S)-6-(3-フルオロアゼチジン-1-イル)-N2-[1-(4-フルオロフェニル)エチル]-N4-(ピラジン-2-イル)ピリミジン-2,4-ジアミン、
(40)(S)-1-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}アゼチジン-2-オン、
(41)(S)-4-(1-エチル-1H-ピラゾール-4-イル)-N2-[1-(4-フルオロフェニル)エチル]-N6-(ピラジン-2-イル)ピリジン-2,6-ジアミン、
(42)(S)-N2-[1-(4-フルオロフェニル)エチル]-4-(1-メチル-1H-ピラゾール-5-イル)-N6-(ピラジン-2-イル)ピリジン-2,6-ジアミン、
(43)(S)-4-(1-(シクロプロピルメチル)-1H-ピラゾール-4-イル)-N2-[1-(4-フルオロフェニル)エチル]-N6-(ピラジン-2-イル)ピリジン-2,6-ジアミン、
(44)(S)-N2-[1-(4-フルオロフェニル)エチル]-N4-(ピラジン-2-イル)-6-(チアゾール-5-イル)ピリミジン-2,4-ジアミン、
(45)1-{2-[(S)-1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}ピロリジン-3-オール
(46)(S)-N2-[1-(4-フルオロフェニル)エチル]-N4-(5-メチルチアゾール-2-イル)-N6-(ピラジン-2-イル)ピリミジン-2,4,6-トリアミン、
(47)(S)-N2-[1-(4-フルオロフェニル)エチル]-N6-(ピラジン-2-イル)-4,5’-ビピリミジン-2,6-ジアミン、
(48)(S)-N2-[1-(4-フルオロフェニル)エチル]-6-(2-メトキシチアゾール-5-イル)-N4-(ピラジン-2-イル)ピリミジン-2,4-ジアミン、
(49)(S)-N2-[1-(4-フルオロフェニル)エチル]-N4-(ピラジン-2-イル)-6-(チアゾール-2-イル)ピリミジン-2,4-ジアミン、
(50)(S)-5-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}ピコリノニトリル、
(51)(S)-1-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}ピペリジン-4-カルボキサミド、
(52)(S)-5-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}ピコリンアミド、
(53)4-{2-[(S)-1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}ピペラジン-2-カルボキサミド、
(54)6-(3-アミノピロリジン-1-イル)-N2-[(S)-1-(4-フルオロフェニル)エチル]-N4-(ピラジン-2-イル)ピリミジン-2,4-ジアミン、
(55)N-(1-{2-[(S)-1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}ピロリジン-3-イル)メタンスルホンアミド、
(56)(S)-2-({2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}(2-ヒドロキシエチル)アミノ)エタン-1-オール、
(57)(S)-N4-[2-(ジメチルアミノ)エチル]-N2-[1-(4-フルオロフェニル)エチル]-N6-(ピラジン-2-イル)ピリミジン-2,4,6-トリアミン、
(58)1-{2-[(S)-1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}ピペリジン-3-カルボキサミド、
(59)(S)-1-{2-[(S)-1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}ピロリジン-2-カルボキサミド、
(60)(S)-N2-[1-(4-フルオロフェニル)エチル]-6-[4-(メチルスルホニル)ピペラジン-1-イル]-N4-(ピラジン-2-イル)ピリミジン-2,4-ジアミン、
(61)(S)-N2-[1-(4-フルオロフェニル)エチル]-N4-(ピラジン-2-イル)-6-(1H-ピロール-3-イル)ピリミジン-2,4-ジアミン、
(62)(R)-1-{2-[(S)-1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}-4-ヒドロキシピロリジン-2-オン、
(63)N2-[(S)-1-(4-フルオロフェニル)エチル]-N4-(ピラジン-2-イル)-N6-[(テトラヒドロフラン-2-イル)メチル]ピリミジン-2,4,6-トリアミン
(64)((S)-1-{2-[(S)-1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}ピロリジン-2-イル)メタノール、
(65)((R)-1-{2-[(S)-1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}ピロリジン-2-イル)メタノール、
(66)(S)-1-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}ピペリジン-4-オール、
(67)(S)-1-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}アゼチジン-3-オール、
(68)1-{2-[(S)-1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}ピペリジン-3-オール、
(69)(S)-5-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}ニコチノニトリル、
(70)(S)-N2-[1-(4-フルオロフェニル)エチル]-N4-(ピラジン-2-イル)-6-(2H-テトラゾール-5-イル)ピリミジン-2,4-ジアミン、
(71)(S)-N4-(2-アミノエチル)-N2-[1-(4-フルオロフェニル)エチル]-N6-(ピラジン-2-イル)ピリミジン-2,4,6-トリアミン、
(72)(S)-N-(2-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イルアミノ}エチル)メタンスルホンアミド、
(73)(S)-N-(2-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イルアミノ}エチル)アセトアミド、
(74)(S)-2-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イルアミノ}アセトアミド、
(75)(S)-4-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}ベンズアミド、
(76)(S)-3-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}ベンゾニトリル、
(77)(S)-N2-[1-(4-フルオロフェニル)エチル]-6-(フラン-3-イル)-N4-(ピラジン-2-イル)ピリミジン-2,4-ジアミン、
(78)(S)-1-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}ピペリジン-4-カルボン酸エチル、
(79)(S)-5-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}ニコチンアミド、
(80)(S)-1-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}ピペリジン-4-カルボン酸、
(81)(S)-2-{2-[(S)-1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イルアミノ}-2-フェニルエタノール、
(82)(S)-2-{2-[(S)-1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イルアミノ}-3-フェニルプロパン-1-オール、
(83)(R)-2-{2-[(S)-1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イルアミノ}-4-メチルペンタン-1-オール、
(84)(S)-6-[2-(ジメチルアミノ)エトキシ]-N2-[1-(4-フルオロフェニル)エチル]-N4-(ピラジン-2-イル)ピリミジン-2,4-ジアミン、
(85)(S)-1-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}-1H-ピラゾール-4-カルボン酸、
(86)(S)-3-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}ベンズアミド、
(87)(S)-6-(ベンゾ[d]1,3-ジオキソール-5-イル)-N2-[1-(4-フルオロフェニル)エチル]-N4-(ピラジン-2-イル)ピリミジン-2,4-ジアミン、
(88)(S)-N2-[1-(4-フルオロフェニル)エチル]-6-(2-フルオロピリジン-4-イル)-N4-(ピラジン-2-イル)ピリミジン-2,4-ジアミン、
(89)N2-[(S)-1-(4-フルオロフェニル)エチル]-N4-(ピラジン-2-イル)-6-[(テトラヒドロフラン-2-イル)メトキシ]ピリミジン-2,4-ジアミン、
(90)(S)-2-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イルオキシ}エタノール、
(91)(S)-N2-[1-(4-フルオロフェニル)エチル]-N4-(ピラジン-2-イル)-N6-[2-(ピロリジン-1-イル)エチル]ピリミジン-2,4,6-トリアミン、
(92)(S)-3-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}イソニコチンアミド、
(93)(S)-3-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}イソニコチノニトリル、
(94)(S)-2-{2-[(S)-1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イルアミノ}-3-メチルブタン-1-オール、
(95)(S)-N2-[1-(4-クロロフェニル)エチル]-6-[4-(メチルスルホニル)ピペラジン-1-イル]-N4-(ピラジン-2-イル)ピリミジン-2,4-ジアミン、
(96)(1S,2S)-2-{2-[(S)-1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イルオキシ}シクロヘキサノール、
(97)(S)-N2-[1-(4-フルオロフェニル)エチル]-N4-[(5-メチルピラジン-2-イル)メチル]-N6-(ピラジン-2-イル)ピリミジン-2,4,6-トリアミン、
(98)(S)-N2-[1-(4-フルオロフェニル)エチル]-N4-(フラン-2-イルメチル)-N6-(ピラジン-2-イル)ピリミジン-2,4,6-トリアミン、
(99)(S)-N2-[1-(4-フルオロフェニル)エチル]-N4-(ピラジン-2-イル)-N6-[1-(ピリジン-3-イル)エチル]ピリミジン-2,4,6-トリアミン、
(100)(S)-1-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}-4-(ヒドロキシメチル)ピペリジン-4-オール、
(101)(S)-N2-[1-(4-フルオロフェニル)エチル]-N4-(ピラジン-2-イル)-N6-(ピリジン-2-イルメチル)ピリミジン-2,4,6-トリアミン、
(102)(S)-N2-[1-(4-フルオロフェニル)エチル]-N4-(ピラジン-2-イル)-N6-(ピリジン-3-イルメチル)ピリミジン-2,4,6-トリアミン、
(103)(S)-N2-[1-(4-フルオロフェニル)エチル]-N4-(ピラジン-2-イル)-N6-(ピリジン-4-イルメチル)ピリミジン-2,4,6-トリアミン、
(104)(S)-2-{2-[(S)-1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イルアミノ}-3-ヒドロキシプロパンアミド、
(105)(3S,4S)-1-{2-[(S)-1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}ピロリジン-3,4-ジオール、
(106)N2-[(S)-1-(4-フルオロフェニル)エチル]-N4-(ピラジン-2-イル)-6-(1,4-ジオキサ-8-アザスピロ[4.5]デカン-8-イル)ピリミジン-2,4-ジアミン、
(107)(S)-8-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}-1,3-ジオキソ-8-アザスピロ[4.5]デカン-2-オン、
(108)(S)-4-(1-ベンジル-1H-ピラゾール-4-イル)-N2-[1-(4-フルオロフェニル)エチル]-N6-(ピラジン-2-イル)ピリジン-2,6-ジアミン、
(109)(S)-N2-[1-(4-フルオロフェニル)エチル]-6-[4-(フェニルスルホニル)ピペラジン-1-イル]-N4-(ピラジン-2-イル)ピリミジン-2,4-ジアミン、
(110)(S)-4-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリジン-4-イル}ベンズアミド、
(111)(S)-N2-[1-(4-フルオロフェニル)エチル]-N6-(ピラジン-2-イル)-4-(1H-ピロール-3-イル)ピリジン-2,6-ジアミン、
(112)(S)-N2-[1-(4-フルオロフェニル)エチル]-N6-(ピラジン-2-イル)ピリジン-2,6-ジアミン、
(113)(S)-N2-[1-(4-フルオロフェニル)エチル]-6-(4-メチル-1H-イミダゾール-1-イル)-N4-(ピラジン-2-イル)ピリミジン-2,4-ジアミン、
(114)(S)-N2-[1-(4-フルオロフェニル)エチル]-4-(4-メトキシフェニル)-N6-(ピラジン-2-イル)ピリジン-2,6-ジアミン、
(115)(S)-4-(4-フルオロフェニル)-N2-[1-(4-フルオロフェニル)エチル]-N6-(ピラジン-2-イル)ピリジン-2,6-ジアミン、
(116)(S)-N2-[1-(4-フルオロフェニル)エチル]-4-メチル-N6-(ピラジン-2-イル)ピリジン-2,6-ジアミン、
(117)(S)-1-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}-N-(メチルスルホニル)ピペリジン-4-カルボキサミド、
(118)(S)-N2-[1-(4-フルオロフェニル)エチル]-4-(フラン-3-イル)-N6-(ピラジン-2-イル)ピリジン-2,6-ジアミン、
(119)(S)-N2-[1-(4-フルオロフェニル)エチル]-4-[4-(メチルスルホニル)ピペラジン-1-イル]-N6-(ピラジン-2-イル)ピリジン-2,6-ジアミン、
(120)(S)-1-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリジン-4-イル}-4-(ヒドロキシメチル)ピペリジン-4-オール、
(121)(S)-4-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリジン-4-イル}ベンゼンスルホンアミド、
(122)(S)-N2-[1-(4-フルオロフェニル)エチル]-4-メトキシ-N6-(ピラジン-2-イル)ピリジン-2,6-ジアミン、
(123)4-{2-[(1S)-1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリジン-4-イル}-1λ6,4-チオモルホリン-1,1-ジオン、
(124)(S)-1-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリジン-4-イル}ピペリジン-4-オール、
(125)(S)-1-(4-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリジン-4-イル}-1,4-ジアゼパン-1-イル)エタノン、
(126)(S)-N2-[1-(4-フルオロフェニル)エチル]-N6-(ピラジン-2-イル)-N4-(ピリミジン-2-イル)ピリジン-2,4,6-トリアミン、
(127)(S)-N2-[1-(4-フルオロフェニル)エチル]-N6-(ピラジン-2-イル)-N4-(ピリジン-2-イル)ピリジン-2,4,6-トリアミン、
(128)N2-[(S)-1-(4-フルオロフェニル)エチル]-N6-(ピラジン-2-イル)-4-(1,4-ジオキサ-8-アザスピロ[4.5]デカン-8-イル)ピリジン-2,6-ジアミン、
(129)(S)-2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)イソニコチン酸メチルエステル、
(130)(S)-4-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}-N-メチルベンゼンスルホンアミド、
(131)(S)-N2-[1-(4-フルオロフェニル)エチル]-4-(4-メチル-1H-イミダゾール-1-イル)-N6-(ピラジン-2-イル)ピリジン-2,6-ジアミン、
(132)(S)-N2-[1-(4-フルオロフェニル)エチル]-N4,N6-ジ(ピラジン-2-イル)ピリジン-2,4,6-トリアミン、
(133)(S)-4-(シクロプロピルメトキシ)-N2-[1-(4-フルオロフェニル)エチル]-N6-(ピラジン-2-イル)ピリジン-2,6-ジアミン、
(134)(S)-N2-[1-(4-フルオロフェニル)エチル]-N2-メチル-4-(1-メチル-1H-ピラゾール-4-イル)-N6-(ピラジン-2-イル)ピリジン-2,6-ジアミン、
(135)(S)-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリジン-4-イル}メタノール、
(136)(S)-2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)イソニコチン酸、
(137)(S)-N2-[1-(4-フルオロフェニル)エチル]-4-(2-メトキシエトキシ)-N6-(ピラジン-2-イル)ピリジン-2,6-ジアミン、
(138)(S)-2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-カルボニトリル
(139)(S)-2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)イソニコチノニトリル、
(140)(S)-2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)イソニコチンアミド、
(141)(S)-N2-[1-(4-フルオロフェニル)エチル]-6-(1,2,4-オキサジアゾール-3-イル)-N4-(ピラジン-2-イル)ピリミジン-2,4-ジアミン、
(142)(S)-N2-[1-(4-フルオロフェニル)エチル]-4-(1,2,4-オキサジアゾール-3-イル)-N6-(ピラジン-2-イル)ピリジン-2,6-ジアミン、
(143)(S)-2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ニコチン酸メチル、
(144)(S)-2-[1-(4-フルオロフェニル)エチルアミノ]-N,N-ジメチル-6-(ピラジン-2-イルアミノ)イソニコチンアミド、
(145)(S)-N-[2-(ジメチルアミノ)エチル]-2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)イソニコチンアミド、(146) (S)-N-t-ブチル-2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)イソニコチンアミド、
(147)(S)-N-エチル-2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)イソニコチンアミド、
(148)(S)-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリジン-4-イル}[4-(メタンスルホニル)ピペラジン-1-イル]メタノン、
(149)(S)-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリジン-4-イル}(ピロリジン-1-イル)メタノン、
(150)(S)-2-[1-(4-フルオロフェニル)エチルアミノ]-N-イソプロピル-6-(ピラジン-2-イルアミノ)イソニコチンアミド、
(151)(S)-1-{2-[(S)-1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}アゼチジン-2-カルボキサミド、
(152)(S)-N2-[1-(4-フルオロフェニル)エチル]-N6-(ピラジン-2-イル)-4-(テトラヒドロ-2H-ピラン-4-イルオキシ)ピリジン-2,6-ジアミン、
(153)(S)-1-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}アゼチジン-3-カルボキサミド、
(154)(S)-2-[1-(4-フルオロフェニル)エチルアミノ]-N-(2-ヒドロキシエチル)-6-(ピラジン-2-イルアミノ)イソニコチンアミド、
(155)(S)-2-[1-(4-フルオロフェニル)エチルアミノ]-N-メチル-6-(ピラジン-2-イルアミノ)イソニコチンアミド、
(156)(S)-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリジン-4-イル}(モルホリノ)メタノン、
(157)(S)-N-ベンジル-2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)イソニコチンアミド、
(158)(S)-N-シクロプロピル-2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)イソニコチンアミド、
(159)(S)-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリジン-4-イル})(4-メチルピペラジン-1-イル)メタノン、
(160)(S)-2-[1-(4-フルオロフェニル)エチルアミノ]-N-(2-メトキシエチル)-6-(ピラジン-2-イルアミノ)イソニコチンアミド、
(161)(S)-2-[1-(4-フルオロフェニル)エチルアミノ]-N-プロピル-6-(ピラジン-2-イルアミノ)イソニコチンアミド、
(162)(S)-N-シクロプロピルメチル-2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)イソニコチンアミド、
(163)(S)-N-シクロブチル-2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)イソニコチンアミド、
(164)(S)-N-ブチル-2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)イソニコチンアミド、
(165)(S)-2-[1-(4-フルオロフェニル)エチルアミノ]-N-イソブチル-6-(ピラジン-2-イルアミノ)イソニコチンアミド、
(166)(S)-2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)-N-(2,2,2,-トリフルオロエチル)イソニコチンアミド、
(167)(S)-2-[1-(4-フルオロフェニル)エチルアミノ]-N-(3-ヒドロキシプロピル)-6-(ピラジン-2-イルアミノ)イソニコチンアミド、
(168)(S)-N-(2-エトキシエチル)-2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)イソニコチンアミド、
(169)(S)-1-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}-N-メチルアゼチジン-3-カルボキサミド、
(170)(S)-N2-[1-(4-フルオロフェニル)エチル]-4-(メトキシメチル)-N6-(ピラジン-2-イル)ピリジン-2,6-ジアミン、
(171)(S)-1-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}-N,N-ジメチルアゼチジン-3-カルボキサミド、
(172)(S)-N-(1-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}アゼチジン-3-イル)メタンスルホンアミド、
(173)(S)-1-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}アゼチジン-3-カルボニトリル、
(174)2-(4-フルオロフェニル)-2-[4-(1-メチル-1H-ピラゾール-4-イル)-6-(ピラジン-2-イルアミノ)ピリジン-2-イルアミノ]エタノール、
(175)(S)-N-エチル-1-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}アゼチジン-3-カルボキサミド、
(176)(S)-N,N-ジエチル-1-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}アゼチジン-3-カルボキサミド、
(177)(S)-1-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリジン-4-イル}エタノン、
(178)(S)-N2-[1-(4-フルオロフェニル)エチル]-6-(3-メトキシアゼチジン-1-イル)-N4-(ピラジン-2-イル)ピリミジン-2,4-ジアミン、
(179)(S)-1-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}-3-メチルアゼチジン-3-オール、
(180)(S)-2-[1-(4-フルオロフェニル)エチルアミノ]-N-メチル-6-(ピラジン-2-イルアミノ)ニコチンアミド、
(181)(S)-2-[1-(4-フルオロフェニル)エチルアミノ]-N,N-ジメチル-6-(ピラジン-2-イルアミノ)ニコチンアミド、
(182)(S)-2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ニコチンアミド、
(183)(S)-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリジン-3-イル}(モルホリノ)メタノン、
(184)(S)-N-(シクロプロピルメチル)-2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ニコチンアミド、
(185)(S)-N-(1-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}アゼチジン-3-イル)エタンスルホンアミド、
(186)(S)-1-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}-N-イソプロピルアゼチジン-3-カルボキサミド、
(187)(S)-1-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}-3-(トリフルオロメチル)アゼチジン-3-オール、
(188)(S)-(1-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}アゼチジン-3-イル)(ピロリジン-1-イル)メタノン、
(189)(S)-1-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}-N-(2-メトキシエチル)アゼチジン-3-カルボキサミド、
(190)(S)-(1-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}アゼチジン-3-イル)(ピペリジン-1-イル)メタノン、
(191)(S)-(1-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}アゼチジン-3-イル)(モルホリノ)メタノン、
(192)(S)-N-(シクロプロピル)-1-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}アゼチジン-3-カルボキサミド、
(193)(S)-N-(シクロプロピルメチル)-1-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}アゼチジン-3-カルボキサミド、
(194)(S)-1-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}-N-(2-ヒドロキシエチル)アゼチジン-3-カルボキサミド、
(195)(S)-3-シクロプロピル-1-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}アゼチジン-3-オール、
(196)(S)-1-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}-3-イソプロピルアゼチジン-3-オール、
(197)(S)-1-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリジン-4-イル}アゼチジン-3-オール、
(198)(S)-3-シクロプロピル-1-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリジン-4-イル}アゼチジン-3-オール、
(199)(S)-1-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリジン-4-イル}-3-イソプロピルアゼチジン-3-オール、
(200)(S)-1-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリジン-4-イル}-3-メチルアゼチジン-3-オール、
(201)(S)-1-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリジン-4-イル}-3-(トリフルオロメチル)アゼチジン-3-オール、
(202)(S)-4-(3,3-ジフルオロアゼチジン-1-イル)-N2-[1-(4-フルオロフェニル)エチル]-N6-(ピラジン-2-イル)ピリジン-2,6-ジアミン、
(203)(S)-N-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリジン-4-イル}アセトアミド、
(204)(S)-N-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリジン-4-イル}メタンスルホンアミド、
(205)(S)-1-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリジン-4-イル}ウレア、
(206)(S)-4-(3-シクロプロピル-3-メトキシアゼチジン-1-イル)-N2-[1-(4-フルオロフェニル)エチル]-N6-(ピラジン-2-イル)ピリジン-2,6-ジアミン、
(207)(S)-N2-[1-(4-フルオロフェニル)エチル]-4-(3-イソプロピル-3-メトキシアゼチジン-1-イル)-N6-(ピラジン-2-イル)ピリジン-2,6-ジアミン、
(208)(S)-N2-[1-(4-フルオロフェニル)エチル]-4-(3-メトキシ-3-メチルアゼチジン-1-イル)-N6-(ピラジン-2-イル)ピリジン-2,6-ジアミン、
(209)(S)-N2-[1-(4-フルオロフェニル)エチル]-4-(1-メチル-1H-ピラゾール-4-イル)-N6-(5-メチルピラジン-2-イル)ピリジン-2,6-ジアミン、
(210)(S)-N2-[1-(4-フルオロフェニル)エチル]-4-[1-(メタンスルホニル)ピペリジン-4-イル]-N6-(ピラジン-2-イル)ピリジン-2,6-ジアミン、
(211)(S)-N-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリジン-4-イル}プロピオンアミド、
(212)(S)-N2-[1-(4-フルオロフェニル)エチル]-4-[1-(2-メトキシエチル)-1H-ピラゾール-4-イル]-N6-(ピラジン-2-イル)ピリジン-2,6-ジアミン、
(213)(S)-4-(1-シクロプロピル-1H-ピラゾール-4-イル)-N2-[1-(4-フルオロフェニル)エチル]-N6-(ピラジン-2-イル)ピリジン-2,6-ジアミン、
(214)(S)-N2-[1-(4-フルオロフェニル)エチル]-4-[1-(メトキシメチル)-1H-ピラゾール-4-イル]-N6-(ピラジン-2-イル)ピリジン-2,6-ジアミン、
(215)(S)-6-[3-(ジメチルアミノ)アゼチジン-1-イル]-N2-[1-(4-フルオロフェニル)エチル]-N4-(ピラジン-2-イル)ピリミジン-2,4-ジアミン、
(216)(S)-N2-[1-(4-フルオロフェニル)エチル]-6-[3-(メチルアミノ)アゼチジン-1-イル]-N4-(ピラジン-2-イル)ピリミジン-2,4-ジアミン、
(217)(S)-N2-[1-(4-フルオロフェニル)エチル]-N4-(ピラジン-2-イル)-6-[3-(ピロリジン-1-イル)アゼチジン-1-イル]ピリミジン-2,4-ジアミン、
(218)(S)-N2-[1-(4-フルオロフェニル)エチル]-6-(3-モルホリノアゼチジン-1-イル)-N4-(ピラジン-2-イル)ピリミジン-2,4-ジアミン、
(219)(S)-N2-[1-(4-フルオロフェニル)エチル]-6-[3-(4-メチルピペラジン-1-イル)アゼチジン-1-イル]-N4-(ピラジン-2-イル)ピリミジン-2,4-ジアミン、
(220)(S)-(1-{1-[2-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}アゼチジン-3-イル)ピペリジン-4-オール、
(221)4-{2-[(1S)-1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}-1λ6,4-チオモルホリン-1,1-ジオン、
(222)(S)-1-(1-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}アゼチジン-3-イル)ウレア、
(223)(S)-(1-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}アゼチジン-3-イル)メタノール、
(224)(S)-(1-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}アゼチジン-3-イル)メチルカルバミン酸t-ブチル、
(225)(S)-6-[3-(アミノメチル)アゼチジン-1-イル]-N2-[1-(4-フルオロフェニル)エチル]-N4-(ピラジン-2-イル)ピリミジン-2,4-ジアミン、
(226)(S)-N-[(1-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}アゼチジン-3-イル)メチル]エタンスルホンアミド、
(227)(S)-N-[(1-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリミジン-4-イル}アゼチジン-3-イル)メチル]アセトアミド、
(228)(S)-N2-[1-(4-フルオロフェニル)エチル]-4-[3-モルホリノアゼチジン-1-イル]-N6-(ピラジン-2-イル)ピリジン-2,6-ジアミン、
(229)(S)-1-(1-{2-[1-(4-フルオロフェニル)エチルアミノ]-6-(ピラジン-2-イルアミノ)ピリジン-4-イル}アゼチジン-3-イル)ピペリジン-4-オール。
(230)(S)-N2-[1-(4-フルオロフェニル)エチル]-4-(1-メチル-1H-ピラゾール-4-イル)-N6-(ピラジン-2-イル)ピリジン-2,6-ジアミン マレイン酸塩 The cytokine storm suppressant according to claim 1, which contains as an active ingredient a compound selected from the group consisting of the following compounds (1) to (230) or a pharmaceutically acceptable salt thereof.
(1) (S)-4-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}piperazin-2-one,
(2) N-{(S)-1-[2-{[(S)-1-(4-fluorophenyl)ethyl]amino}-6-(pyrazin-2-ylamino)pyrimidin-4-yl]pyrrolidine -3-yl}acetamide,
(3) (S)-6-(3,3-difluoroazetidin-1-yl)-N 2 -[1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)pyrimidine- 2,4-diamine,
(4) (S)—N 2 -[1-(4-fluorophenyl)ethyl]-4-(1-methyl-1H-pyrazol-4-yl)-N 6 -(pyrazin-2-yl)pyridine- 2,6-diamine,
(5) (S)—N 2′ -[1-(4-fluorophenyl)ethyl]-N 6′ -(pyrazin-2-yl)-3,4′-bipyridine-2′,6′-diamine,
(6) (S)—N 2′ -[1-(4-fluorophenyl)ethyl]-6-methoxy-N 6′ -(pyrazin-2-yl)-3,4′-bipyridine-2′,6 '-diamine,
(7) (S)-2′-[1-(4-fluorophenyl)ethylamino]-6′-(pyrazin-2-ylamino)-3,4′-bipyridin-6-ol,
(8) (S)—N 2 -[1-(4-fluorophenyl)ethyl]-4-(oxazol-5-yl)-N 6 -(pyrazin-2-yl)pyridine-2,6-diamine,
(9) (S)-6-chloro-N 2 -[1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)pyrimidine-2,4-diamine,
(10) (S)—N 2 -[1-(4-fluorophenyl)ethyl]-6-[4-(methylsulfonyl)phenyl]-N 4 -(pyrazin-2-yl)pyrimidine-2,4- Diamine,
(11) (S)-N 2 -[1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)-6-(1H-pyrazol-4-yl)pyrimidine-2,4- Diamine,
(12) (S)-2-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyridin-4-yloxy}ethanol,
(13) (S)—N 2 -[1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)-6-(pyridin-3-yl)pyrimidine-2,4-diamine,
(14) (S)—N 2 -[1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)-6-(pyridin-2-yl)pyrimidine-2,4-diamine,
(15) (S)-N 2 -[1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)-6-(pyridin-4-yl)pyrimidine-2,4-diamine,
(16) (S)-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}pyrrolidin-2-one,
(17) (S)-4-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}piperazine-2,6-dione,
(18) (S)-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}tetrahydropyrimidin-2(1H)-one,
(19) (S)-N 2 -[1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)-6-(pyrrolidin-1-yl)pyrimidine-2,4-diamine,
(20) (S)—N 2 -[1-(4-fluorophenyl)ethyl]-6-morpholino-N 4 -(pyrazin-2-yl)pyrimidine-2,4-diamine,
(21) (S)-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}imidazolidin-2-one,
(22) (S)—N 2 -[1-(4-fluorophenyl)ethyl]-6-(oxazol-5-yl)-N 4 -(pyrazin-2-yl)pyrimidine-2,4-diamine,
(23) (S)—N 2 -[1-(4-fluorophenyl)ethyl]-6-(6-methoxypyridin-3-yl)-N 4 -(pyrazin-2-yl)pyrimidine-2,4 - a diamine,
(24) (S)-N 2 -[1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)-6-(1H-pyrazol-3-yl)pyrimidine-2,4- Diamine,
(25) (S)-4-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}pyridin-2-ol,
(26) (S)-5-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}pyridin-2-ol,
(27) N-((R)-1-{2-[(S)-1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}pyrrolidine-3 -yl) acetamide,
(28) (S)—N 2 -[1-(4-fluorophenyl)ethyl]-N 6 -(pyrazin-2-yl)-4-(1H-pyrazol-4-yl)pyridine-2,6- Diamine,
(29) (S)—N 2 -[1-(4-fluorophenyl)ethyl]-N 6 -(pyrazin-2-yl)-4-(1H-pyrazol-3-yl)pyridine-2,6- Diamine,
(30) (S)—N 2 -[1-(4-fluorophenyl)ethyl]-6-[3-(methylsulfonyl)phenyl]-N 4 -(pyrazin-2-yl)pyrimidine-2,4- Diamine,
(31) (S)—N 2 -[1-(4-fluorophenyl)ethyl]-4-[4-(methylsulfonyl)phenyl]-N 6 -(pyrazin-2-yl)pyridine-2,6- Diamine,
(32) (S)—N 2 -[1-(4-fluorophenyl)ethyl]-4-(1-isopropyl-1H-pyrazol-4-yl)-N 6 -(pyrazin-2-yl)pyridine- 2,6-diamine,
(33) N-{(S)-1-[2-{[(S)-1-(4-fluorophenyl)ethyl]amino}-6-(pyrazin-2-ylamino)pyridin-4-yl]pyrrolidine -3-yl}acetamide,
(34) (S)—N 2 -[1-(4-fluorophenyl)ethyl]-4-morpholino-N 6 -(pyrazin-2-yl)pyridine-2,6-diamine,
(35) (S)—N 2 -[1-(4-fluorophenyl)ethyl]-N 6 -(pyrazin-2-yl)-4-thiomorpholinopyridine-2,6-diamine,
(36) (S)-3-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyridin-4-yl}propan-1-ol,
(37) (S)-N-(1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}azetidin-3-yl)acetamide ,
(38) (S)-6-(azetidin-1-yl)-N 2 -[1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)pyrimidine-2,4-diamine,
(39) (S)-6-(3-fluoroazetidin-1-yl)-N 2 -[1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)pyrimidine-2, 4-diamine,
(40) (S)-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}azetidin-2-one,
(41) (S)-4-(1-ethyl-1H-pyrazol-4-yl)-N 2 -[1-(4-fluorophenyl)ethyl]-N 6 -(pyrazin-2-yl)pyridine- 2,6-diamine,
(42) (S)—N 2 -[1-(4-fluorophenyl)ethyl]-4-(1-methyl-1H-pyrazol-5-yl)-N 6 -(pyrazin-2-yl)pyridine- 2,6-diamine,
(43) (S)-4-(1-(cyclopropylmethyl)-1H-pyrazol-4-yl)-N 2 -[1-(4-fluorophenyl)ethyl]-N 6 -(pyrazine-2- yl) pyridine-2,6-diamine,
(44) (S)-N 2 -[1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)-6-(thiazol-5-yl)pyrimidine-2,4-diamine,
(45) 1-{2-[(S)-1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}pyrrolidin-3-ol (46) (S )-N 2 -[1-(4-fluorophenyl)ethyl]-N 4 -(5-methylthiazol-2-yl)-N 6 -(pyrazin-2-yl)pyrimidine-2,4,6-triamine ,
(47) (S)—N 2 -[1-(4-fluorophenyl)ethyl]-N 6 -(pyrazin-2-yl)-4,5′-bipyrimidine-2,6-diamine,
(48) (S)-N 2 -[1-(4-fluorophenyl)ethyl]-6-(2-methoxythiazol-5-yl)-N 4 -(pyrazin-2-yl)pyrimidine-2,4 - a diamine,
(49) (S)-N 2 -[1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)-6-(thiazol-2-yl)pyrimidine-2,4-diamine,
(50) (S)-5-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}picolinonitrile,
(51) (S)-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}piperidine-4-carboxamide,
(52) (S)-5-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}picolinamide,
(53) 4-{2-[(S)-1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}piperazine-2-carboxamide,
(54) 6-(3-aminopyrrolidin-1-yl)-N 2 -[(S)-1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)pyrimidine-2,4 - a diamine,
(55) N-(1-{2-[(S)-1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}pyrrolidin-3-yl)methane sulfonamide,
(56) (S)-2-({2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}(2-hydroxyethyl)amino)ethane -1-ol,
(57) (S)—N 4 -[2-(dimethylamino)ethyl]-N 2 -[1-(4-fluorophenyl)ethyl]-N 6 -(pyrazin-2-yl)pyrimidine-2,4 , 6-triamine,
(58) 1-{2-[(S)-1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}piperidine-3-carboxamide,
(59) (S)-1-{2-[(S)-1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}pyrrolidine-2-carboxamide,
(60) (S)—N 2 -[1-(4-fluorophenyl)ethyl]-6-[4-(methylsulfonyl)piperazin-1-yl]-N 4 -(pyrazin-2-yl)pyrimidine- 2,4-diamine,
(61) (S)—N 2 -[1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)-6-(1H-pyrrol-3-yl)pyrimidine-2,4- Diamine,
(62) (R)-1-{2-[(S)-1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}-4-hydroxypyrrolidine- 2-on,
(63) N 2 -[(S)-1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)-N 6 -[(tetrahydrofuran-2-yl)methyl]pyrimidine-2, 4,6-triamine (64) ((S)-1-{2-[(S)-1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl} pyrrolidin-2-yl)methanol,
(65) ((R)-1-{2-[(S)-1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}pyrrolidin-2-yl )methanol,
(66) (S)-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}piperidin-4-ol,
(67) (S)-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}azetidin-3-ol,
(68) 1-{2-[(S)-1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}piperidin-3-ol,
(69) (S)-5-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}nicotinonitrile,
(70) (S)-N 2 -[1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)-6-(2H-tetrazol-5-yl)pyrimidine-2,4- Diamine,
(71) (S)—N 4 -(2-aminoethyl)-N 2 -[1-(4-fluorophenyl)ethyl]-N 6 -(pyrazin-2-yl)pyrimidine-2,4,6- triamine,
(72) (S)-N-(2-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-ylamino}ethyl)methanesulfonamide,
(73) (S)-N-(2-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-ylamino}ethyl)acetamide,
(74) (S)-2-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-ylamino}acetamide,
(75) (S)-4-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}benzamide,
(76) (S)-3-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}benzonitrile,
(77) (S)-N 2 -[1-(4-fluorophenyl)ethyl]-6-(furan-3-yl)-N 4 -(pyrazin-2-yl)pyrimidine-2,4-diamine,
(78) ethyl (S)-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}piperidine-4-carboxylate,
(79) (S)-5-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}nicotinamide,
(80) (S)-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}piperidine-4-carboxylic acid,
(81) (S)-2-{2-[(S)-1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-ylamino}-2-phenylethanol,
(82) (S)-2-{2-[(S)-1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-ylamino}-3-phenylpropane- 1-all,
(83) (R)-2-{2-[(S)-1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-ylamino}-4-methylpentane- 1-all,
(84) (S)-6-[2-(dimethylamino)ethoxy]-N 2 -[1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)pyrimidine-2,4- Diamine,
(85) (S)-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}-1H-pyrazole-4-carboxylic acid,
(86) (S)-3-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}benzamide,
(87) (S)-6-(benzo[d]1,3-dioxol-5-yl)-N 2 -[1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl) pyrimidine-2,4-diamine,
(88) (S)—N 2 -[1-(4-fluorophenyl)ethyl]-6-(2-fluoropyridin-4-yl)-N 4 -(pyrazin-2-yl)pyrimidine-2,4 - a diamine,
(89) N 2 -[(S)-1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)-6-[(tetrahydrofuran-2-yl)methoxy]pyrimidine-2,4 - a diamine,
(90) (S)-2-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yloxy}ethanol,
(91) (S)—N 2 -[1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)-N 6 -[2-(pyrrolidin-1-yl)ethyl]pyrimidine- 2,4,6-triamine,
(92) (S)-3-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}isonicotinamide,
(93) (S)-3-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}isonicotinonitrile,
(94) (S)-2-{2-[(S)-1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-ylamino}-3-methylbutane-1 - all,
(95) (S)—N 2 -[1-(4-chlorophenyl)ethyl]-6-[4-(methylsulfonyl)piperazin-1-yl]-N 4 -(pyrazin-2-yl)pyrimidine-2 , 4-diamine,
(96) (1S,2S)-2-{2-[(S)-1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yloxy}cyclohexanol,
(97) (S)-N 2 -[1-(4-fluorophenyl)ethyl]-N 4 -[(5-methylpyrazin-2-yl)methyl]-N 6 -(pyrazin-2-yl)pyrimidine -2,4,6-triamine,
(98) (S)-N 2 -[1-(4-fluorophenyl)ethyl]-N 4 -(furan-2-ylmethyl)-N 6 -(pyrazin-2-yl)pyrimidine-2,4,6 - a triamine,
(99) (S)—N 2 -[1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)-N 6 -[1-(pyridin-3-yl)ethyl]pyrimidine- 2,4,6-triamine,
(100) (S)-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}-4-(hydroxymethyl)piperidine-4 - all,
(101) (S)-N 2 -[1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)-N 6 -(pyridin-2-ylmethyl)pyrimidine-2,4,6 - a triamine,
(102) (S)—N 2 -[1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)-N 6 -(pyridin-3-ylmethyl)pyrimidine-2,4,6 - a triamine,
(103) (S)-N 2 -[1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)-N 6 -(pyridin-4-ylmethyl)pyrimidine-2,4,6 - a triamine,
(104) (S)-2-{2-[(S)-1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-ylamino}-3-hydroxypropanamide ,
(105) (3S,4S)-1-{2-[(S)-1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}pyrrolidine-3, 4-diol,
(106) N 2 -[(S)-1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)-6-(1,4-dioxa-8-azaspiro[4.5] decan-8-yl)pyrimidine-2,4-diamine,
(107) (S)-8-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}-1,3-dioxo-8-azaspiro [4.5] decan-2-one,
(108) (S)-4-(1-benzyl-1H-pyrazol-4-yl)-N 2 -[1-(4-fluorophenyl)ethyl]-N 6 -(pyrazin-2-yl)pyridine- 2,6-diamine,
(109) (S)—N 2 -[1-(4-fluorophenyl)ethyl]-6-[4-(phenylsulfonyl)piperazin-1-yl]-N 4 -(pyrazin-2-yl)pyrimidine- 2,4-diamine,
(110) (S)-4-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyridin-4-yl}benzamide,
(111) (S)—N 2 -[1-(4-fluorophenyl)ethyl]-N 6 -(pyrazin-2-yl)-4-(1H-pyrrol-3-yl)pyridine-2,6- Diamine,
(112) (S)—N 2 -[1-(4-fluorophenyl)ethyl]-N 6 -(pyrazin-2-yl)pyridine-2,6-diamine,
(113) (S)—N 2 -[1-(4-fluorophenyl)ethyl]-6-(4-methyl-1H-imidazol-1-yl)-N 4 -(pyrazin-2-yl)pyrimidine- 2,4-diamine,
(114) (S)—N 2 -[1-(4-fluorophenyl)ethyl]-4-(4-methoxyphenyl)-N 6 -(pyrazin-2-yl)pyridine-2,6-diamine,
(115) (S)-4-(4-fluorophenyl)-N 2 -[1-(4-fluorophenyl)ethyl]-N 6 -(pyrazin-2-yl)pyridine-2,6-diamine,
(116) (S)—N 2 -[1-(4-fluorophenyl)ethyl]-4-methyl-N 6 -(pyrazin-2-yl)pyridine-2,6-diamine,
(117) (S)-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}-N-(methylsulfonyl)piperidine-4 - a carboxamide,
(118) (S)—N 2 -[1-(4-fluorophenyl)ethyl]-4-(furan-3-yl)-N 6 -(pyrazin-2-yl)pyridine-2,6-diamine,
(119) (S)—N 2 -[1-(4-fluorophenyl)ethyl]-4-[4-(methylsulfonyl)piperazin-1-yl]-N 6 -(pyrazin-2-yl)pyridine- 2,6-diamine,
(120) (S)-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyridin-4-yl}-4-(hydroxymethyl)piperidine-4 - all,
(121) (S)-4-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyridin-4-yl}benzenesulfonamide,
(122) (S)—N 2 -[1-(4-fluorophenyl)ethyl]-4-methoxy-N 6 -(pyrazin-2-yl)pyridine-2,6-diamine,
(123) 4-{2-[(1S)-1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyridin-4-yl}-1λ 6 ,4-thiomorpholine-1 , 1-dione,
(124) (S)-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyridin-4-yl}piperidin-4-ol,
(125) (S)-1-(4-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyridin-4-yl}-1,4-diazepane- 1-yl)ethanone,
(126) (S)—N 2 -[1-(4-fluorophenyl)ethyl]-N 6 -(pyrazin-2-yl)-N 4 -(pyrimidin-2-yl)pyridine-2,4,6 - a triamine,
(127) (S)—N 2 -[1-(4-fluorophenyl)ethyl]-N 6 -(pyrazin-2-yl)-N 4 -(pyridin-2-yl)pyridine-2,4,6 - a triamine,
(128) N 2 -[(S)-1-(4-fluorophenyl)ethyl]-N 6 -(pyrazin-2-yl)-4-(1,4-dioxa-8-azaspiro[4.5] decan-8-yl)pyridine-2,6-diamine,
(129) (S)-2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)isonicotinic acid methyl ester,
(130) (S)-4-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}-N-methylbenzenesulfonamide,
(131) (S)—N 2 -[1-(4-fluorophenyl)ethyl]-4-(4-methyl-1H-imidazol-1-yl)-N 6 -(pyrazin-2-yl)pyridine- 2,6-diamine,
(132) (S)-N 2 -[1-(4-fluorophenyl)ethyl]-N 4 ,N 6 -di(pyrazin-2-yl)pyridine-2,4,6-triamine,
(133) (S)-4-(cyclopropylmethoxy)-N 2 -[1-(4-fluorophenyl)ethyl]-N 6 -(pyrazin-2-yl)pyridine-2,6-diamine,
(134) (S)-N 2 -[1-(4-fluorophenyl)ethyl]-N 2 -methyl-4-(1-methyl-1H-pyrazol-4-yl)-N 6 -(pyrazine-2 -yl)pyridine-2,6-diamine,
(135) (S)-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyridin-4-yl}methanol,
(136) (S)-2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)isonicotinic acid,
(137) (S)—N 2 -[1-(4-fluorophenyl)ethyl]-4-(2-methoxyethoxy)-N 6 -(pyrazin-2-yl)pyridine-2,6-diamine,
(138) (S)-2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidine-4-carbonitrile (139) (S)-2-[1-( 4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)isonicotinonitrile,
(140) (S)-2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)isonicotinamide,
(141) (S)—N 2 -[1-(4-fluorophenyl)ethyl]-6-(1,2,4-oxadiazol-3-yl)-N 4 -(pyrazin-2-yl) pyrimidine-2,4-diamine,
(142) (S)—N 2 -[1-(4-fluorophenyl)ethyl]-4-(1,2,4-oxadiazol-3-yl)-N 6 -(pyrazin-2-yl) pyridine-2,6-diamine,
(143) (S)-2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)methyl nicotinate,
(144) (S)-2-[1-(4-fluorophenyl)ethylamino]-N,N-dimethyl-6-(pyrazin-2-ylamino)isonicotinamide,
(145) (S)-N-[2-(dimethylamino)ethyl]-2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)isonicotinamide, (146) (S)-Nt-butyl-2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)isonicotinamide,
(147) (S)-N-ethyl-2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)isonicotinamide,
(148) (S)-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyridin-4-yl}[4-(methanesulfonyl)piperazin-1-yl ] methanone,
(149) (S)-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyridin-4-yl}(pyrrolidin-1-yl)methanone,
(150) (S)-2-[1-(4-fluorophenyl)ethylamino]-N-isopropyl-6-(pyrazin-2-ylamino)isonicotinamide,
(151) (S)-1-{2-[(S)-1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}azetidine-2-carboxamide,
(152) (S)—N 2 -[1-(4-fluorophenyl)ethyl]-N 6 -(pyrazin-2-yl)-4-(tetrahydro-2H-pyran-4-yloxy)pyridine-2, 6-diamine,
(153) (S)-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}azetidine-3-carboxamide,
(154) (S)-2-[1-(4-fluorophenyl)ethylamino]-N-(2-hydroxyethyl)-6-(pyrazin-2-ylamino)isonicotinamide,
(155) (S)-2-[1-(4-fluorophenyl)ethylamino]-N-methyl-6-(pyrazin-2-ylamino)isonicotinamide,
(156) (S)-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyridin-4-yl}(morpholino)methanone,
(157) (S)-N-benzyl-2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)isonicotinamide,
(158) (S)-N-cyclopropyl-2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)isonicotinamide,
(159) (S)-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyridin-4-yl})(4-methylpiperazin-1-yl)methanone ,
(160) (S)-2-[1-(4-fluorophenyl)ethylamino]-N-(2-methoxyethyl)-6-(pyrazin-2-ylamino)isonicotinamide,
(161) (S)-2-[1-(4-fluorophenyl)ethylamino]-N-propyl-6-(pyrazin-2-ylamino)isonicotinamide,
(162) (S)-N-cyclopropylmethyl-2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)isonicotinamide,
(163) (S)-N-cyclobutyl-2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)isonicotinamide,
(164) (S)-N-butyl-2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)isonicotinamide,
(165) (S)-2-[1-(4-fluorophenyl)ethylamino]-N-isobutyl-6-(pyrazin-2-ylamino)isonicotinamide,
(166) (S)-2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)-N-(2,2,2,-trifluoroethyl)isonicotinamide,
(167) (S)-2-[1-(4-fluorophenyl)ethylamino]-N-(3-hydroxypropyl)-6-(pyrazin-2-ylamino)isonicotinamide,
(168) (S)-N-(2-ethoxyethyl)-2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)isonicotinamide,
(169) (S)-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}-N-methylazetidine-3-carboxamide ,
(170) (S)-N 2 -[1-(4-fluorophenyl)ethyl]-4-(methoxymethyl)-N 6 -(pyrazin-2-yl)pyridine-2,6-diamine,
(171) (S)-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}-N,N-dimethylazetidine-3 - a carboxamide,
(172) (S)-N-(1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}azetidin-3-yl)methane sulfonamide,
(173) (S)-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}azetidine-3-carbonitrile,
(174) 2-(4-fluorophenyl)-2-[4-(1-methyl-1H-pyrazol-4-yl)-6-(pyrazin-2-ylamino)pyridin-2-ylamino]ethanol,
(175) (S)-N-ethyl-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}azetidine-3-carboxamide,
(176) (S)-N,N-diethyl-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}azetidin-3- carboxamide,
(177) (S)-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyridin-4-yl}ethanone,
(178) (S)-N 2 -[1-(4-fluorophenyl)ethyl]-6-(3-methoxyazetidin-1-yl)-N 4 -(pyrazin-2-yl)pyrimidine-2, 4-diamine,
(179) (S)-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}-3-methylazetidin-3-ol ,
(180) (S)-2-[1-(4-fluorophenyl)ethylamino]-N-methyl-6-(pyrazin-2-ylamino)nicotinamide,
(181) (S)-2-[1-(4-fluorophenyl)ethylamino]-N,N-dimethyl-6-(pyrazin-2-ylamino)nicotinamide,
(182) (S)-2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)nicotinamide,
(183) (S)-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyridin-3-yl}(morpholino)methanone,
(184) (S)-N-(cyclopropylmethyl)-2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)nicotinamide,
(185) (S)-N-(1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}azetidin-3-yl)ethane sulfonamide,
(186) (S)-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}-N-isopropylazetidine-3-carboxamide ,
(187) (S)-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}-3-(trifluoromethyl)azetidine- 3-all,
(188) (S)-(1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}azetidin-3-yl) (pyrrolidine- 1-yl)methanone,
(189) (S)-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}-N-(2-methoxyethyl)azetidine -3-carboxamide,
(190) (S)-(1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}azetidin-3-yl) (piperidin- 1-yl)methanone,
(191) (S)-(1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}azetidin-3-yl) (morpholino) methanone,
(192) (S)-N-(cyclopropyl)-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}azetidin-3 - a carboxamide,
(193) (S)-N-(cyclopropylmethyl)-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}azetidin- 3-carboxamide,
(194) (S)-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}-N-(2-hydroxyethyl)azetidine -3-carboxamide,
(195) (S)-3-cyclopropyl-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}azetidin-3-ol ,
(196) (S)-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}-3-isopropylazetidin-3-ol ,
(197) (S)-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyridin-4-yl}azetidin-3-ol,
(198) (S)-3-cyclopropyl-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyridin-4-yl}azetidin-3-ol ,
(199) (S)-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyridin-4-yl}-3-isopropylazetidin-3-ol ,
(200) (S)-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyridin-4-yl}-3-methylazetidin-3-ol ,
(201) (S)-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyridin-4-yl}-3-(trifluoromethyl)azetidine- 3-all,
(202) (S)-4-(3,3-difluoroazetidin-1-yl)-N 2 -[1-(4-fluorophenyl)ethyl]-N 6 -(pyrazin-2-yl)pyridine- 2,6-diamine,
(203) (S)-N-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyridin-4-yl}acetamide,
(204) (S)-N-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyridin-4-yl}methanesulfonamide,
(205) (S)-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyridin-4-yl}urea,
(206) (S)-4-(3-cyclopropyl-3-methoxyazetidin-1-yl)-N 2 -[1-(4-fluorophenyl)ethyl]-N 6 -(pyrazin-2-yl ) pyridine-2,6-diamine,
(207) (S)-N 2 -[1-(4-fluorophenyl)ethyl]-4-(3-isopropyl-3-methoxyazetidin-1-yl)-N 6 -(pyrazin-2-yl) pyridine-2,6-diamine,
(208) (S)—N 2 -[1-(4-fluorophenyl)ethyl]-4-(3-methoxy-3-methylazetidin-1-yl)-N 6 -(pyrazin-2-yl) pyridine-2,6-diamine,
(209) (S)-N 2 -[1-(4-fluorophenyl)ethyl]-4-(1-methyl-1H-pyrazol-4-yl)-N 6 -(5-methylpyrazin-2-yl ) pyridine-2,6-diamine,
(210) (S)—N 2 -[1-(4-fluorophenyl)ethyl]-4-[1-(methanesulfonyl)piperidin-4-yl]-N 6 -(pyrazin-2-yl)pyridine- 2,6-diamine,
(211) (S)-N-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyridin-4-yl}propionamide,
(212) (S)-N 2 -[1-(4-fluorophenyl)ethyl]-4-[1-(2-methoxyethyl)-1H-pyrazol-4-yl]-N 6 -(pyrazine-2 -yl)pyridine-2,6-diamine,
(213) (S)-4-(1-cyclopropyl-1H-pyrazol-4-yl)-N 2 -[1-(4-fluorophenyl)ethyl]-N 6 -(pyrazin-2-yl)pyridine -2,6-diamine,
(214) (S)—N 2 -[1-(4-fluorophenyl)ethyl]-4-[1-(methoxymethyl)-1H-pyrazol-4-yl]-N 6 -(pyrazin-2-yl ) pyridine-2,6-diamine,
(215) (S)-6-[3-(dimethylamino)azetidin-1-yl]-N 2 -[1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)pyrimidine- 2,4-diamine,
(216) (S)—N 2 -[1-(4-fluorophenyl)ethyl]-6-[3-(methylamino)azetidin-1-yl]-N 4 -(pyrazin-2-yl)pyrimidine- 2,4-diamine,
(217) (S)-N 2 -[1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)-6-[3-(pyrrolidin-1-yl)azetidin-1-yl ] pyrimidine-2,4-diamine,
(218) (S)—N 2 -[1-(4-fluorophenyl)ethyl]-6-(3-morpholinoazetidin-1-yl)-N 4 -(pyrazin-2-yl)pyrimidine-2, 4-diamine,
(219) (S)—N 2 -[1-(4-fluorophenyl)ethyl]-6-[3-(4-methylpiperazin-1-yl)azetidin-1-yl]-N 4 -(pyrazine- 2-yl)pyrimidine-2,4-diamine,
(220) (S)-(1-{1-[2-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}azetidin-3-yl)piperidine-4 - all,
(221) 4-{2-[(1S)-1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}-1λ 6 ,4-thiomorpholine-1 , 1-dione,
(222) (S)-1-(1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}azetidin-3-yl)urea ,
(223) (S)-(1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}azetidin-3-yl)methanol,
(224) (S)-(1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}azetidin-3-yl)methylcarbamate t - butyl,
(225) (S)-6-[3-(aminomethyl)azetidin-1-yl]-N 2 -[1-(4-fluorophenyl)ethyl]-N 4 -(pyrazin-2-yl)pyrimidine- 2,4-diamine,
(226) (S)-N-[(1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}azetidin-3-yl) methyl]ethanesulfonamide,
(227) (S)-N-[(1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}azetidin-3-yl) methyl]acetamide,
(228) (S)—N 2 -[1-(4-fluorophenyl)ethyl]-4-[3-morpholinoazetidin-1-yl]-N 6 -(pyrazin-2-yl)pyridine-2, 6-diamine,
(229) (S)-1-(1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyridin-4-yl}azetidin-3-yl)piperidine -4-ol.
(230) (S)-N2-[1-(4-fluorophenyl)ethyl]-4-(1-methyl-1H-pyrazol-4-yl)-N6-(pyrazin-2-yl)pyridine-2, 6-diamine maleate - 請求項1又は2に記載の化合物又はその医薬上許容される塩を有効成分として含有する、STAT3阻害剤。 A STAT3 inhibitor containing the compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof as an active ingredient.
- 請求項1又は2に記載の化合物又はその医薬上許容される塩を有効成分として含有する、IL-17産生阻害剤。 An IL-17 production inhibitor containing the compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof as an active ingredient.
- 請求項1又は2に記載の化合物又はその医薬上許容される塩を有効成分として含有する、サイトカインストーム/サイトカイン放出症候群(CRS)、乾癬、クローン病、潰瘍性大腸炎、強直性脊髄炎、体軸性脊髄関節炎、掌蹠膿疱症、化膿性汗腺炎、ループス腎炎、全身性エリテマトーデス、又は多発性筋炎/皮膚筋炎の予防剤又は治療剤。 Cytokine storm/cytokine release syndrome (CRS), psoriasis, Crohn's disease, ulcerative colitis, ankylosing myelitis, body containing the compound or pharmaceutically acceptable salt thereof according to claim 1 or 2 as an active ingredient A prophylactic or therapeutic agent for axial spinal arthritis, palmoplantar pustulosis, hidradenitis suppurativa, lupus nephritis, systemic lupus erythematosus, or polymyositis/dermatomyositis.
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HONDA AYUMI, KURAMOTO KAZUYA, NIWA TOMOKO, NAITO HARUNA: "NS-018 reduces myeloma cell proliferation and suppresses osteolysis through inhibition of the JAK2 and Src signaling pathways", BLOOD CANCER JOURNAL, vol. 8, no. 7, 1 July 2018 (2018-07-01), pages 62, XP093007556, DOI: 10.1038/s41408-018-0098-z * |
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KURAMOTO KAZUYA; KODAMA AYUMI; HOMAN JUNKO; NAKAYA YOHEI; KITAMURA TOSHIO; NAITO HARUNA: "Dual Inhibition of the STAT3 and Src Pathways by NS-018, a JAK2 and Src-Family Kinase Inhibitor, Reduces Myeloma Cell Proliferation and Adhesion and Suppresses Osteoclast Formation", BLOOD, AMERICAN SOCIETY OF HEMATOLOGY, US, vol. 118, no. 21, 18 November 2011 (2011-11-18), US , pages 2900, XP086625506, ISSN: 0006-4971, DOI: 10.1182/blood.V118.21.2900.2900 * |
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