JP2018076234A - Pyrazolo[1,5-a]pyrimidine compound - Google Patents
Pyrazolo[1,5-a]pyrimidine compound Download PDFInfo
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- JP2018076234A JP2018076234A JP2015052424A JP2015052424A JP2018076234A JP 2018076234 A JP2018076234 A JP 2018076234A JP 2015052424 A JP2015052424 A JP 2015052424A JP 2015052424 A JP2015052424 A JP 2015052424A JP 2018076234 A JP2018076234 A JP 2018076234A
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- -1 Pyrazolo[1,5-a]pyrimidine compound Chemical class 0.000 title claims description 273
- 150000001875 compounds Chemical class 0.000 claims abstract description 693
- 150000003839 salts Chemical class 0.000 claims abstract description 43
- 241000725643 Respiratory syncytial virus Species 0.000 claims abstract description 23
- 208000015181 infectious disease Diseases 0.000 claims abstract description 8
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 96
- 125000004739 (C1-C6) alkylsulfonyl group Chemical group 0.000 claims description 73
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 69
- 125000003277 amino group Chemical group 0.000 claims description 68
- 125000005236 alkanoylamino group Chemical group 0.000 claims description 64
- 125000000623 heterocyclic group Chemical group 0.000 claims description 51
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 50
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 48
- 125000004845 (C1-C6) alkylsulfonylamino group Chemical group 0.000 claims description 45
- 125000005843 halogen group Chemical group 0.000 claims description 45
- 125000003118 aryl group Chemical group 0.000 claims description 43
- 150000001924 cycloalkanes Chemical class 0.000 claims description 41
- 125000001072 heteroaryl group Chemical group 0.000 claims description 40
- 125000001424 substituent group Chemical group 0.000 claims description 40
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 37
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 28
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 24
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 24
- 125000002252 acyl group Chemical group 0.000 claims description 23
- 125000004432 carbon atom Chemical group C* 0.000 claims description 20
- 125000006310 cycloalkyl amino group Chemical group 0.000 claims description 15
- 125000004043 oxo group Chemical group O=* 0.000 claims description 14
- 125000006624 (C1-C6) alkoxycarbonylamino group Chemical group 0.000 claims description 13
- 125000000217 alkyl group Chemical group 0.000 claims description 12
- 241000700605 Viruses Species 0.000 claims description 11
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 11
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 11
- 125000004750 (C1-C6) alkylaminosulfonyl group Chemical group 0.000 claims description 10
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 10
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 10
- 125000004391 aryl sulfonyl group Chemical group 0.000 claims description 9
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 9
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 9
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 claims description 8
- 125000004657 aryl sulfonyl amino group Chemical group 0.000 claims description 8
- 241000711902 Pneumovirus Species 0.000 claims description 7
- 125000004104 aryloxy group Chemical group 0.000 claims description 7
- 125000004076 pyridyl group Chemical group 0.000 claims description 7
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 6
- 125000004656 alkyl sulfonylamino group Chemical group 0.000 claims description 6
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 5
- 125000006254 cycloalkyl carbonyl group Chemical group 0.000 claims description 5
- 239000004480 active ingredient Substances 0.000 claims description 4
- 125000003282 alkyl amino group Chemical group 0.000 claims description 4
- 125000003739 carbamimidoyl group Chemical group C(N)(=N)* 0.000 claims description 4
- 230000003449 preventive effect Effects 0.000 claims description 4
- 238000006467 substitution reaction Methods 0.000 claims description 4
- 125000006296 sulfonyl amino group Chemical group [H]N(*)S(*)(=O)=O 0.000 claims description 4
- 208000035473 Communicable disease Diseases 0.000 claims description 3
- 229910052799 carbon Inorganic materials 0.000 claims description 3
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 3
- 125000005844 heterocyclyloxy group Chemical group 0.000 claims description 3
- 125000004466 alkoxycarbonylamino group Chemical group 0.000 claims description 2
- 150000005840 aryl radicals Chemical class 0.000 claims description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 2
- 229940126585 therapeutic drug Drugs 0.000 claims description 2
- 125000002029 aromatic hydrocarbon group Chemical group 0.000 claims 4
- 230000000694 effects Effects 0.000 abstract description 7
- 241000711904 Pneumoviridae Species 0.000 abstract description 5
- 230000002265 prevention Effects 0.000 abstract description 4
- 238000000132 electrospray ionisation Methods 0.000 description 329
- 238000002514 liquid chromatography mass spectrum Methods 0.000 description 327
- 238000000034 method Methods 0.000 description 278
- 239000000243 solution Substances 0.000 description 221
- 239000007787 solid Substances 0.000 description 199
- 238000003786 synthesis reaction Methods 0.000 description 166
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 154
- 230000015572 biosynthetic process Effects 0.000 description 152
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical group CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 142
- 238000005481 NMR spectroscopy Methods 0.000 description 139
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 138
- 230000002829 reductive effect Effects 0.000 description 98
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 description 85
- 238000006243 chemical reaction Methods 0.000 description 83
- 235000019439 ethyl acetate Nutrition 0.000 description 76
- 239000000203 mixture Substances 0.000 description 73
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 71
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 67
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 60
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 60
- 239000012044 organic layer Substances 0.000 description 57
- 239000007788 liquid Substances 0.000 description 53
- 238000010898 silica gel chromatography Methods 0.000 description 53
- 239000000706 filtrate Substances 0.000 description 50
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 43
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 36
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 35
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 33
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 33
- 239000011541 reaction mixture Substances 0.000 description 33
- 235000002639 sodium chloride Nutrition 0.000 description 33
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 30
- 229920006395 saturated elastomer Polymers 0.000 description 29
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 27
- 239000012267 brine Substances 0.000 description 25
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 24
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 22
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 22
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 21
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 21
- 239000012442 inert solvent Substances 0.000 description 20
- 239000010410 layer Substances 0.000 description 19
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 18
- 125000004528 pyrimidin-5-yl group Chemical group N1=CN=CC(=C1)* 0.000 description 18
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 18
- 239000007821 HATU Substances 0.000 description 17
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 17
- 238000001816 cooling Methods 0.000 description 17
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 16
- HNYOPLTXPVRDBG-UHFFFAOYSA-N barbituric acid Chemical compound O=C1CC(=O)NC(=O)N1 HNYOPLTXPVRDBG-UHFFFAOYSA-N 0.000 description 16
- 239000002585 base Substances 0.000 description 16
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 15
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 12
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 12
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- 239000003795 chemical substances by application Substances 0.000 description 12
- 239000003921 oil Substances 0.000 description 12
- 235000019198 oils Nutrition 0.000 description 12
- 230000002441 reversible effect Effects 0.000 description 12
- 239000002904 solvent Substances 0.000 description 12
- 238000002953 preparative HPLC Methods 0.000 description 11
- 238000000746 purification Methods 0.000 description 11
- 238000003756 stirring Methods 0.000 description 11
- SRDRJPICFUKSBH-UHFFFAOYSA-N 1-(2-ethylsulfonylethyl)-2-[(2-methylpropan-2-yl)oxycarbonyl]-3H-isoindole-1-carboxylic acid Chemical compound CCS(=O)(=O)CCC1(N(Cc2ccccc12)C(=O)OC(C)(C)C)C(O)=O SRDRJPICFUKSBH-UHFFFAOYSA-N 0.000 description 10
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 10
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 10
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 10
- 239000007864 aqueous solution Substances 0.000 description 10
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 10
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 10
- RKOTXQYWCBGZLP-UHFFFAOYSA-N N-[(2,4-difluorophenyl)methyl]-2-ethyl-9-hydroxy-3-methoxy-1,8-dioxospiro[3H-pyrido[1,2-a]pyrazine-4,3'-oxolane]-7-carboxamide Chemical compound CCN1C(OC)C2(CCOC2)N2C=C(C(=O)NCC3=C(F)C=C(F)C=C3)C(=O)C(O)=C2C1=O RKOTXQYWCBGZLP-UHFFFAOYSA-N 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 239000002253 acid Substances 0.000 description 9
- 238000004458 analytical method Methods 0.000 description 9
- 239000003814 drug Substances 0.000 description 9
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 9
- HVTICUPFWKNHNG-UHFFFAOYSA-N iodoethane Chemical compound CCI HVTICUPFWKNHNG-UHFFFAOYSA-N 0.000 description 9
- 238000012360 testing method Methods 0.000 description 9
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 8
- 125000004575 3-pyrrolidinyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 8
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 8
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 8
- LQZMLBORDGWNPD-UHFFFAOYSA-N N-iodosuccinimide Chemical compound IN1C(=O)CCC1=O LQZMLBORDGWNPD-UHFFFAOYSA-N 0.000 description 8
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 8
- 238000007112 amidation reaction Methods 0.000 description 8
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 8
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 8
- 239000012230 colorless oil Substances 0.000 description 8
- 238000001514 detection method Methods 0.000 description 8
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 8
- 238000002360 preparation method Methods 0.000 description 8
- 239000000376 reactant Substances 0.000 description 8
- 239000000126 substance Substances 0.000 description 8
- 238000004808 supercritical fluid chromatography Methods 0.000 description 8
- NYEHUAQIJXERLP-UHFFFAOYSA-N 2-methylsulfonylacetic acid Chemical compound CS(=O)(=O)CC(O)=O NYEHUAQIJXERLP-UHFFFAOYSA-N 0.000 description 7
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 7
- 239000000460 chlorine Substances 0.000 description 7
- 238000005859 coupling reaction Methods 0.000 description 7
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 7
- 238000000926 separation method Methods 0.000 description 7
- 239000011734 sodium Substances 0.000 description 7
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 7
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 6
- IFXKXCLVKQVVDI-UHFFFAOYSA-N 2-amino-5-chlorobenzoic acid Chemical compound NC1=CC=C(Cl)C=C1C(O)=O IFXKXCLVKQVVDI-UHFFFAOYSA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- 229910052783 alkali metal Inorganic materials 0.000 description 6
- 239000012298 atmosphere Substances 0.000 description 6
- 230000000120 cytopathologic effect Effects 0.000 description 6
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 6
- 239000011259 mixed solution Substances 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 6
- 238000010992 reflux Methods 0.000 description 6
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 description 6
- 230000009466 transformation Effects 0.000 description 6
- 238000000844 transformation Methods 0.000 description 6
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 6
- VESLFCBOKMWCRG-UHFFFAOYSA-N 2-(methanesulfonamido)benzoic acid Chemical compound CS(=O)(=O)NC1=CC=CC=C1C(O)=O VESLFCBOKMWCRG-UHFFFAOYSA-N 0.000 description 5
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 5
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 5
- 241000711920 Human orthopneumovirus Species 0.000 description 5
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 5
- 125000003545 alkoxy group Chemical group 0.000 description 5
- 150000004945 aromatic hydrocarbons Chemical group 0.000 description 5
- 235000019253 formic acid Nutrition 0.000 description 5
- 238000010438 heat treatment Methods 0.000 description 5
- 239000001257 hydrogen Substances 0.000 description 5
- 229910052739 hydrogen Inorganic materials 0.000 description 5
- 230000014759 maintenance of location Effects 0.000 description 5
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 5
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 5
- 125000006239 protecting group Chemical group 0.000 description 5
- 239000000741 silica gel Substances 0.000 description 5
- 229910002027 silica gel Inorganic materials 0.000 description 5
- 239000003643 water by type Substances 0.000 description 5
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 4
- IAVAVGYTZPNJLD-UHFFFAOYSA-N 2-(methanesulfonamido)-5-methylbenzoic acid Chemical compound CC1=CC=C(NS(C)(=O)=O)C(C(O)=O)=C1 IAVAVGYTZPNJLD-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 4
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 4
- 101150003085 Pdcl gene Proteins 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 229920002472 Starch Polymers 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 4
- 150000001340 alkali metals Chemical class 0.000 description 4
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 4
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 4
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 4
- 229910000024 caesium carbonate Inorganic materials 0.000 description 4
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N dichloromethane Natural products ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 4
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 4
- FFUAGWLWBBFQJT-UHFFFAOYSA-N hexamethyldisilazane Chemical compound C[Si](C)(C)N[Si](C)(C)C FFUAGWLWBBFQJT-UHFFFAOYSA-N 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 4
- 239000003446 ligand Substances 0.000 description 4
- 235000010355 mannitol Nutrition 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 4
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 4
- 150000002902 organometallic compounds Chemical class 0.000 description 4
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 description 4
- MUJIDPITZJWBSW-UHFFFAOYSA-N palladium(2+) Chemical compound [Pd+2] MUJIDPITZJWBSW-UHFFFAOYSA-N 0.000 description 4
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 4
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical group CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 description 4
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- 150000003852 triazoles Chemical class 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
- AEXDMFVPDVVSQJ-UHFFFAOYSA-N trifluoro(trifluoromethylsulfonyl)methane Chemical compound FC(F)(F)S(=O)(=O)C(F)(F)F AEXDMFVPDVVSQJ-UHFFFAOYSA-N 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 229960005486 vaccine Drugs 0.000 description 1
- 239000006216 vaginal suppository Substances 0.000 description 1
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
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- 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
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- 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
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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- 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
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
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- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
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- Nitrogen Condensed Heterocyclic Rings (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Abstract
Description
本発明は、ニューモウイルス亜科のウイルスが関与する感染症の予防又は治療に有用な化合物及びその医薬上許容される塩に関する。 The present invention relates to compounds useful for the prevention or treatment of infections involving viruses of the Pneumovirus subfamily and pharmaceutically acceptable salts thereof.
ニューモウイルス亜科のウイルスは、パラミクソウイルス科に含まれるネガティブセンス一本鎖RNAウイルスである。呼吸器合胞体ウイルス(RSV)をはじめとするニューモウイルス亜科のウイルスは、多くの流行性のヒト及び動物疾患に関与する。
ヒト呼吸器合胞体ウイルス(HRSV)は、乳幼児において最も頻度の高い呼吸器感染症の原因のひとつであり、細気管支炎や肺炎などの下気道感染の重症化は、入院や死亡をももたらす。特に低出生体重児や先天性の心臓あるいは肺疾患を有する乳幼児などのハイリスク群においては、重症化及び合併症のリスクが高い。
ニューモウイルス亜科のウイルス感染症には、現在有効な治療薬及びワクチンが存在しない。ハイリスク乳幼児におけるHRSVによる重篤な下気道感染症の発症抑制のために、高い中和能を有するヒト化モノクローナル抗体パリビズマブが予防薬として用いられているが、その薬価は非常に高額である。そのため有効な治療薬あるいはワクチンが必要とされている。
Pneumovirus subfamily viruses are negative sense single-stranded RNA viruses included in the Paramyxoviridae family. Pneumoviridae viruses, including respiratory syncytial virus (RSV), are involved in many epidemic human and animal diseases.
Human respiratory syncytial virus (HRSV) is one of the most common causes of respiratory infections in infants, and the severity of lower respiratory tract infections such as bronchiolitis and pneumonia also results in hospitalization and death. Particularly in high-risk groups such as low birth weight infants and infants with congenital heart or lung disease, the risk of seriousness and complications is high.
There are currently no effective therapeutics and vaccines for viral infections of the Pneumovirus subfamily. The humanized monoclonal antibody palivizumab having a high neutralizing ability is used as a preventive drug for suppressing the onset of serious lower respiratory tract infections caused by HRSV in high-risk infants, but the drug price is very high. Therefore, there is a need for effective therapeutic drugs or vaccines.
最近、抗RSV活性を示しピラゾロ[1,5−a]ピリミジン骨格を有する化合物は特許文献1、2、及び3、並びに非特許文献1に開示されている。しかしながら、これら文献には、本願発明の化合物の構造は、開示されていない。 Recently, compounds exhibiting anti-RSV activity and having a pyrazolo [1,5-a] pyrimidine skeleton have been disclosed in Patent Documents 1, 2, and 3, and Non-Patent Document 1. However, these documents do not disclose the structure of the compound of the present invention.
本発明は、呼吸器合胞体ウイルス(RSV)を含むニューモウイルス亜科のウイルスが関与する感染症の予防又は治療に有用な、新規化合物又はその医薬上許容される塩を提供することを目的とする。 An object of the present invention is to provide a novel compound or a pharmaceutically acceptable salt thereof useful for the prevention or treatment of infections involving viruses of the Pneumovirinae family including respiratory syncytial virus (RSV). To do.
本発明者らは鋭意検討を重ねた結果、下記、式(I)で表されるピラゾロ[1,5−a]ピリミジン化合物が優れた抗RSV活性を有することを見出し、この知見に基づいて本発明を完成するに到った。 As a result of intensive studies, the present inventors have found that a pyrazolo [1,5-a] pyrimidine compound represented by the following formula (I) has an excellent anti-RSV activity. The invention has been completed.
即ち、本発明は、
(1)式(I)、
That is, the present invention
(1) Formula (I),
A1は、水素原子又はC1-6アルキル基を示し、
A2は、水素原子、C1-6アルキル基、C3-6シクロアルキル基、カルボキシ基、又はC1-6アルコキシカルボニル基を示し、
A3は、ハロゲン原子、C1-6アルコキシ基(ここで、該C1-6アルコキシ基は、1個のアミノ基で置換されてもよい。)、ヘテロシクリルオキシ基、C1-6アルキルアミノ基{ここで、該C1-6アルキルアミノ基は、アミノ基及びC3-6シクロアルキル基(ここで、該C3-6シクロアルキル基は、1個のアミノ基で置換されてもよい)からなる群から選ばれる同一又は異なる1〜2個の置換基で置換されてもよい。}、C3-6シクロアルキルアミノ基(ここで、 該C3-6シクロアルキルアミノ基は、1個のアミノ基で置換されてもよい。)、又はヘテロシクリル基(ここで、該ヘテロシクリル基は、ハロゲン原子、水酸基、アミノ基、及び1個のアミノ基で置換されたC1-6アルキル基からなる群から選ばれる同一又は異なる1〜3個の置換基で置換されてもよい。)を示し、
A4は、水素原子、ハロゲン原子、C1-6アルキル基、C2-6アルキニル基(ここで、該C2-6アルキニル基は、1個の水酸基で置換されてもよい。)、又はアリール基を示し、
R1及びR2は、同一又は異なって、それぞれ水素原子、C1-6アルキル基(ここで、該C1-6アルキル基は、1個の水酸基で置換されてもよい。)、又はC3-6シクロアルキル基を示すか、
又は、R1及びR2は、隣接する炭素原子と一緒になって、C3-6シクロアルカンを形成してもよく、
R3は、C1-6アルキル基{ここで、該C1-6アルキル基は、ハロゲン原子、水酸基、アミノ基、C1-6アルコキシ基(ここで、該C1-6アルコキシ基は、1〜3個のハロゲン原子で置換されてもよい。)、アリールオキシ基、C1-6アルキルスルホニルアミノ基、C1-6アルキルスルホニル基、ヘテロシクリル基(ここで、該ヘテロシクリル基は、1〜2個のオキソで置換されてもよい。)、アリール基、及びヘテロアリール基からなる群から選ばれる同一又は異なる1〜3個の置換基で置換されてもよい。}を示し、
Yは、アリール基、ヘテロアリール基{ここで、該アリール基及びヘテロアリール基は、ハロゲン原子、アミノ基、C1-6アルキル基、C1-6アルコキシ基、C2-6アルカノイルアミノ基(ここで、該C2-6アルカノイルアミノ基は、1個のC1-6アルキルスルホニル基で置換されてもよい。)、C1-6アルキルスルホニルアミノ基(ここで、該C1-6アルキルスルホニルアミノ基は、1〜3個のハロゲン原子で置換されてもよい。)、アリールスルホニルアミノ基、C1-6アルキルスルホニル基、ヘテロシクリル基、アリール基、及びヘテロアリール基からなる群から選ばれる同一又は異なる1〜3個の置換基で置換されてもよい。}、又はヘテロシクリル基(ここで、該ヘテロシクリル基は、1個のオキソで置換されてもよい。)を示し、
又は、Yは、下記式群(II)のいずれかの構造を示し、
A 1 represents a hydrogen atom or a C 1-6 alkyl group,
A 2 represents a hydrogen atom, a C 1-6 alkyl group, a C 3-6 cycloalkyl group, a carboxy group, or a C 1-6 alkoxycarbonyl group,
A 3 represents a halogen atom, a C 1-6 alkoxy group (wherein the C 1-6 alkoxy group may be substituted with one amino group), a heterocyclyloxy group, a C 1-6 alkylamino group. A group {wherein the C 1-6 alkylamino group is an amino group and a C 3-6 cycloalkyl group (wherein the C 3-6 cycloalkyl group may be substituted with one amino group); ) May be substituted with the same or different 1 to 2 substituents selected from the group consisting of: }, A C 3-6 cycloalkylamino group (wherein the C 3-6 cycloalkylamino group may be substituted with one amino group), or a heterocyclyl group (wherein the heterocyclyl group is , A halogen atom, a hydroxyl group, an amino group, and a C 1-6 alkyl group substituted with one amino group may be substituted with 1 to 3 identical or different substituents. Show
A 4 represents a hydrogen atom, a halogen atom, a C 1-6 alkyl group, a C 2-6 alkynyl group (wherein the C 2-6 alkynyl group may be substituted with one hydroxyl group), or Represents an aryl group,
R 1 and R 2 are the same or different and are each a hydrogen atom, a C 1-6 alkyl group (wherein the C 1-6 alkyl group may be substituted with one hydroxyl group), or C Represents a 3-6 cycloalkyl group,
Or R 1 and R 2 may be taken together with adjacent carbon atoms to form a C 3-6 cycloalkane;
R 3 is a C 1-6 alkyl group (wherein the C 1-6 alkyl group is a halogen atom, a hydroxyl group, an amino group, a C 1-6 alkoxy group (wherein the C 1-6 alkoxy group is 1 to 3 halogen atoms may be substituted), an aryloxy group, a C 1-6 alkylsulfonylamino group, a C 1-6 alkylsulfonyl group, a heterocyclyl group (wherein the heterocyclyl group is 1 to And may be substituted with 1 to 3 identical or different substituents selected from the group consisting of an aryl group and a heteroaryl group. },
Y is an aryl group, a heteroaryl group {wherein the aryl group and heteroaryl group are a halogen atom, an amino group, a C 1-6 alkyl group, a C 1-6 alkoxy group, a C 2-6 alkanoylamino group ( Here, the C 2-6 alkanoylamino group may be substituted with one C 1-6 alkylsulfonyl group), a C 1-6 alkylsulfonylamino group (wherein the C 1-6 alkylsulfonyl group) The sulfonylamino group may be substituted with 1 to 3 halogen atoms.), An arylsulfonylamino group, a C 1-6 alkylsulfonyl group, a heterocyclyl group, an aryl group, and a heteroaryl group. It may be substituted with 1 to 3 identical or different substituents. }, Or a heterocyclyl group, wherein the heterocyclyl group may be substituted with one oxo,
Or, Y represents any structure of the following formula group (II),
Wが単結合のとき、Zは、式(CH2)n又は式CH2NR7を示し、
nは、2〜4の整数を示し、
Wが式CH2のとき、Zは、式CH2CH2を示し、
B1、B2、B3、B4、及びB5は、同一又は異なって、それぞれ水素原子、ハロゲン原子、又はC1-6アルキル基を示し、
R4及びR5は、同一又は異なって、それぞれ水素原子、C1-6アルキル基を示すか、
又は、R4及びR5は、隣接する炭素原子と一緒になってC3-6シクロアルカン{ここで、該C3-6シクロアルカンは、オキソ、水酸基、C2-6アルカノイルアミノ基(ここで、該C2-6アルカノイルアミノ基は、1個のC1-6アルキルスルホニル基で置換されてもよい。)、及びC1-6アルキルスルホニルアミノ基からなる群から選ばれる1個の置換基で置換されてもよい。}を形成してもよく、さらに該C3-6シクロアルカンは、環中の1個の式CH2が式NR8で置換されてもよく、
R6は、水素原子、アミノ基、C1-6アルキル基(ここで、該C1-6アルキル基は、C3-6シクロアルキルカルボニル基、C1-6アルキルスルホニル基、及びC1-6アルキルスルホニルアミノ基からなる群から選ばれる1個の置換基で置換されてもよい。)、C1-6アルキルアミノ基(ここで、該C1-6アルキルアミノ基は、1個のC1-6アルキルスルホニル基で置換されてもよい。)、C2-6アルカノイルアミノ基(ここで、該C2-6アルカノイルアミノ基は、アミノ基、 スルファモイル基、C3-6シクロアルキル基、C1-6アルコキシ基、C1-6アルキルアミノ基、C2-6アルカノイルアミノ基、C1-6アルキルスルホニルアミノ基、C1-6アルキルスルホニル基、C1-6アルキルアミノスルホニル基、アリールスルホニル基、アリール基、及びヘテロアリール基からなる群から選ばれる1個の置換基で置換されてもよい。)、C1-6アルコキシカルボニルアミノ基(ここで、該C1-6アルコキシカルボニルアミノ基は、1個のアリール基で置換されてもよい。)、又はC1-6アルキルスルホニルアミノ基を示し、
R7は、水素原子又はC1-6アルキル基を示し、
R8は、カルバモイル基、アミジノ基、C2-6アルカノイル基(ここで、該C2-6アルカノイル基は、1個のC1-6アルキルスルホニル基で置換されてもよい。)、C1-6アルコキシカルボニル基(ここで、該C1-6アルコキシカルボニル基は、1個のアリール基で置換されてもよい。)、又はC1-6アルキルスルホニル基である。]
で表される化合物、又はその医薬上許容される塩、
(2)上記式(I)中、
R1が、水素原子であり、
R2が、C1-6アルキル基(ここで、該C1-6アルキル基は、1個の水酸基で置換されてもよい。)、又はC3-6シクロアルキル基であるか、
又は、R1及びR2が、隣接する炭素原子と一緒になって、C3-6シクロアルカンを形成してもよい、(1)に記載の化合物、又はその医薬上許容される塩、
(3)上記式(I)中、
Yが、アリール基、ヘテロアリール基{ここで、該アリール基及びヘテロアリール基は、ハロゲン原子、アミノ基、C1-6アルキル基、C1-6アルコキシ基、C2-6アルカノイルアミノ基(ここで、該C2-6アルカノイルアミノ基は、1個のC1-6アルキルスルホニル基で置換されてもよい。)、C1-6アルキルスルホニルアミノ基(ここで、該C1-6アルキルスルホニルアミノ基は、1〜3個のハロゲン原子で置換されてもよい。)、アリールスルホニルアミノ基、C1-6アルキルスルホニル基、ヘテロシクリル基、アリール基、及びヘテロアリール基からなる群から選ばれる同一又は異なる1〜3個の置換基で置換されてもよい。}、又はヘテロシクリル基(ここで、該ヘテロシクリル基は、1個のオキソで置換されてもよい。)である、(1)又は(2)に記載の化合物、又はその医薬上許容される塩、
(4)上記式(I)中、
A1が、水素原子又はC1-6アルキル基であり、
A2が、水素原子、C1-6アルキル基、又はC3-6シクロアルキル基であり、
A3が、C1-6アルコキシ基(ここで、該C1-6アルコキシ基は、1個のアミノ基で置換されてもよい。)、C1-6アルキルアミノ基(ここで、該C1-6アルキルアミノ基は、1個のアミノ基で置換されてもよい。)、C3-6シクロアルキルアミノ基(ここで、 該C3-6シクロアルキルアミノ基は、1個のアミノ基で置換されてもよい。)、又はヘテロシクリル基(ここで、該ヘテロシクリル基は、1個のアミノ基で置換されてもよい。)であり、
A4が、水素原子であり、
R1が、水素原子であり、
R2が、C1-6アルキル基又はC3-6シクロアルキル基であり、
R3が、C1-6アルキル基{ここで、該C1-6アルキル基は、ハロゲン原子、水酸基、C1-6アルコキシ基(ここで、該C1-6アルコキシ基は、1〜3個のハロゲン原子で置換されてもよい。)、アリールオキシ基、C1-6アルキルスルホニルアミノ基、C1-6アルキルスルホニル基、ヘテロシクリル基(ここで、該ヘテロシクリル基は、1〜2個のオキソで置換されてもよい。)、及びアリール基からなる群から選ばれる同一又は異なる1〜3個の置換基で置換されてもよい。}であり、
Yが、アリール基、ヘテロアリール基{ここで、該アリール基及びヘテロアリール基は、ハロゲン原子、アミノ基、C1-6アルキル基、C1-6アルコキシ基、C2-6アルカノイルアミノ基(ここで、該C2-6アルカノイルアミノ基は、1個のC1-6アルキルスルホニル基で置換されてもよい。)、C1-6アルキルスルホニルアミノ基、アリールスルホニルアミノ基、及びヘテロアリール基からなる群から選ばれる同一又は異なる1〜3個の置換基で置換されてもよい。}、又はヘテロシクリル基(ここで、該ヘテロシクリル基は、1個のオキソで置換されてもよい。)である(1)〜(3)いずれか1つに記載の化合物、又はその医薬上許容される塩、
(5)上記式(I)中、
A1が、水素原子であり、
A2が、メチル基、エチル基、又はシクロプロピル基であり、
A3が、下記式群(III)のいずれかの構造であり、
When W is a single bond, Z represents the formula (CH 2 ) n or the formula CH 2 NR 7 ,
n represents an integer of 2 to 4,
When W is of the formula CH 2 , Z represents the formula CH 2 CH 2 ;
B 1 , B 2 , B 3 , B 4 , and B 5 are the same or different and each represents a hydrogen atom, a halogen atom, or a C 1-6 alkyl group,
R 4 and R 5 are the same or different and each represents a hydrogen atom or a C 1-6 alkyl group,
Or R 4 and R 5 together with adjacent carbon atoms are C 3-6 cycloalkane {where C 3-6 cycloalkane is oxo, hydroxyl, C 2-6 alkanoylamino group (here And the C 2-6 alkanoylamino group may be substituted with one C 1-6 alkylsulfonyl group.), And one substitution selected from the group consisting of C 1-6 alkylsulfonylamino groups It may be substituted with a group. Furthermore, the C 3-6 cycloalkane may have one formula CH 2 in the ring substituted with the formula NR 8 ,
R 6 represents a hydrogen atom, an amino group, a C 1-6 alkyl group (wherein the C 1-6 alkyl group is a C 3-6 cycloalkylcarbonyl group, a C 1-6 alkylsulfonyl group, and a C 1- alkyl group). Which may be substituted with one substituent selected from the group consisting of 6 alkylsulfonylamino groups), a C 1-6 alkylamino group (wherein the C 1-6 alkylamino group is one C 1-6 alkylsulfonyl group may be substituted), C 2-6 alkanoylamino group (wherein the C 2-6 alkanoylamino group is an amino group, a sulfamoyl group, a C 3-6 cycloalkyl group, C 1-6 alkoxy group, C 1-6 alkylamino group, C 2-6 alkanoylamino group, C 1-6 alkylsulfonylamino group, C 1-6 alkylsulfonyl group, C 1-6 alkylaminosulfonyl group, aryl Sulfonyl group, aryl group, and heteroaryl May be substituted with one substituent selected from the group consisting of.), By C 1-6 alkoxycarbonylamino group (wherein the C 1-6 alkoxycarbonylamino group, substituted with one aryl group Or a C 1-6 alkylsulfonylamino group,
R 7 represents a hydrogen atom or a C 1-6 alkyl group,
R 8 is carbamoyl group, amidino group, C (wherein said C 2-6 alkanoyl group may be substituted with one C 1-6 alkylsulfonyl group.) 2-6 alkanoyl group, C 1 A -6 alkoxycarbonyl group (wherein the C 1-6 alkoxycarbonyl group may be substituted with one aryl group), or a C 1-6 alkylsulfonyl group. ]
Or a pharmaceutically acceptable salt thereof,
(2) In the above formula (I),
R 1 is a hydrogen atom,
R 2 is a C 1-6 alkyl group (wherein the C 1-6 alkyl group may be substituted with one hydroxyl group), or a C 3-6 cycloalkyl group,
Or the compound according to (1), or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 may be combined with adjacent carbon atoms to form a C 3-6 cycloalkane;
(3) In the above formula (I),
Y is an aryl group, heteroaryl group {wherein the aryl group and heteroaryl group are a halogen atom, an amino group, a C 1-6 alkyl group, a C 1-6 alkoxy group, a C 2-6 alkanoylamino group ( Here, the C 2-6 alkanoylamino group may be substituted with one C 1-6 alkylsulfonyl group), a C 1-6 alkylsulfonylamino group (wherein the C 1-6 alkylsulfonyl group) The sulfonylamino group may be substituted with 1 to 3 halogen atoms.), An arylsulfonylamino group, a C 1-6 alkylsulfonyl group, a heterocyclyl group, an aryl group, and a heteroaryl group. It may be substituted with 1 to 3 identical or different substituents. Or a heterocyclyl group (wherein the heterocyclyl group may be substituted with one oxo), or a pharmaceutically acceptable salt thereof,
(4) In the above formula (I),
A 1 is a hydrogen atom or a C 1-6 alkyl group,
A 2 is a hydrogen atom, a C 1-6 alkyl group, or a C 3-6 cycloalkyl group,
A 3 is a C 1-6 alkoxy group (wherein the C 1-6 alkoxy group may be substituted with one amino group), a C 1-6 alkylamino group (wherein the C 1-6 1-6 alkylamino group may be substituted with one amino group.), C 3-6 cycloalkylamino group (wherein the C 3-6 cycloalkylamino group is one amino group) Or a heterocyclyl group (wherein the heterocyclyl group may be substituted with one amino group),
A 4 is a hydrogen atom,
R 1 is a hydrogen atom,
R 2 is a C 1-6 alkyl group or a C 3-6 cycloalkyl group,
R 3 is a C 1-6 alkyl group {wherein the C 1-6 alkyl group is a halogen atom, a hydroxyl group, a C 1-6 alkoxy group (wherein the C 1-6 alkoxy group is 1 to 3 May be substituted with 1 halogen atom), an aryloxy group, a C 1-6 alkylsulfonylamino group, a C 1-6 alkylsulfonyl group, a heterocyclyl group (wherein the heterocyclyl group has 1 to 2 And may be substituted with 1 to 3 identical or different substituents selected from the group consisting of aryl groups. },
Y is an aryl group, heteroaryl group {wherein the aryl group and heteroaryl group are a halogen atom, an amino group, a C 1-6 alkyl group, a C 1-6 alkoxy group, a C 2-6 alkanoylamino group ( Here, the C 2-6 alkanoylamino group may be substituted with one C 1-6 alkylsulfonyl group.), C 1-6 alkylsulfonylamino group, arylsulfonylamino group, and heteroaryl group May be substituted with the same or different 1 to 3 substituents selected from the group consisting of }, Or a heterocyclyl group (wherein the heterocyclyl group may be substituted with one oxo), or a pharmaceutically acceptable compound thereof, or any one thereof Salt,
(5) In the above formula (I),
A 1 is a hydrogen atom,
A 2 is a methyl group, an ethyl group, or a cyclopropyl group;
A 3 is any structure of the following formula group (III),
R1が、水素原子であり、
R2が、メチル基、エチル基、プロピル基、又はシクロプロピル基であり、
R3が、C1-6アルキル基{ここで、該C1-6アルキル基は、ハロゲン原子、水酸基、C1-6アルコキシ基(ここで、該C1-6アルコキシ基は、1〜3個のハロゲン原子で置換されてもよい。)、C1-6アルキルスルホニルアミノ基、及びヘテロシクリル基(ここで、該ヘテロシクリル基は、1〜2個のオキソで置換されてもよい。)からなる群から選ばれる同一又は異なる1〜3個の置換基で置換されてもよい。}であり、
Yが、フェニル基又はピリジル基{ここで、該フェニル基及びピリジル基は、ハロゲン原子、アミノ基、C1-6アルキル基、C1-6アルコキシ基、C2-6アルカノイルアミノ基(ここで、該C2-6アルカノイルアミノ基は、1個のC1-6アルキルスルホニル基で置換されてもよい。)、C1-6アルキルスルホニルアミノ基、フェニルスルホニルアミノ基、及びC1-6アルキルスルホニル基からなる群から選ばれる同一又は異なる1〜3個の置換基で置換されてもよい。}である(1)〜(4)いずれか1つに記載の化合物、又はその医薬上許容される塩、
(6)上記式(I)中、
Yが、上記式群(II)のいずれかの構造であり、
環Qは、芳香族炭化水素環又はヘテロ芳香環(ここで、該芳香族炭化水素環及びヘテロ芳香環は、1個のC1-6アルキル基で置換されてもよい。)であり、
Wが単結合のとき、Zが、式(CH2)n又は式CH2NR7であり、
nが、2〜4の整数であり、
Wが式CH2のとき、Zが、式CH2CH2であり、
B1、B2、B3、B4、及びB5が、同一又は異なって、それぞれ水素原子、ハロゲン原子、又はC1-6アルキル基であり、
R4及びR5が、同一又は異なって、それぞれ水素原子、C1-6アルキル基であるか、
又は、R4及びR5が、隣接する炭素原子と一緒になってC3-6シクロアルカン{ここで、該C3-6シクロアルカンは、オキソ、水酸基、C2-6アルカノイルアミノ基(ここで、該C2-6アルカノイルアミノ基は、1個のC1-6アルキルスルホニル基で置換されてもよい。)、及びC1-6アルキルスルホニルアミノ基からなる群から選ばれる1個の置換基で置換されてもよい。}を形成してもよく、さらに該C3-6シクロアルカンは、環中の1個の式CH2が式NR8で置換されてもよく、
R6が、水素原子、アミノ基、C1-6アルキル基(ここで、該C1-6アルキル基は、C3-6シクロアルキルカルボニル基、C1-6アルキルスルホニル基、及びC1-6アルキルスルホニルアミノ基からなる群から選ばれる1個の置換基で置換されてもよい。)、C1-6アルキルアミノ基(ここで、該C1-6アルキルアミノ基は、1個のC1-6アルキルスルホニル基で置換されてもよい。)、C2-6アルカノイルアミノ基(ここで、該C2-6アルカノイルアミノ基は、アミノ基、 スルファモイル基、C3-6シクロアルキル基、C1-6アルコキシ基、C1-6アルキルアミノ基、C2-6アルカノイルアミノ基、C1-6アルキルスルホニルアミノ基、C1-6アルキルスルホニル基、C1-6アルキルアミノスルホニル基、アリールスルホニル基、アリール基、及びヘテロアリール基からなる群から選ばれる1個の置換基で置換されてもよい。)、C1-6アルコキシカルボニルアミノ基(ここで、該C1-6アルコキシカルボニルアミノ基は、1個のアリール基で置換されてもよい。)、又はC1-6アルキルスルホニルアミノ基であり、
R7が、水素原子又はC1-6アルキル基であり、
R8が、カルバモイル基、アミジノ基、C2-6アルカノイル基(ここで、該C2-6アルカノイル基は、1個のC1-6アルキルスルホニル基で置換されてもよい。)、C1-6アルコキシカルボニル基(ここで、該C1-6アルコキシカルボニル基は、1個のアリール基で置換されてもよい。)、又はC1-6アルキルスルホニル基である(1)又は(2)に記載の化合物、又はその医薬上許容される塩、
(7)上記式(I)中、
A1が、水素原子又はC1-6アルキル基であり、
A2が、水素原子、C1-6アルキル基、又はC3-6シクロアルキル基であり、
A3が、C1-6アルコキシ基(ここで、該C1-6アルコキシ基は、1個のアミノ基で置換されてもよい。)、C1-6アルキルアミノ基(ここで、該C1-6アルキルアミノ基は、1個のアミノ基で置換されてもよい。)、C3-6シクロアルキルアミノ基(ここで、 該C3-6シクロアルキルアミノ基は、1個のアミノ基で置換されてもよい。)、又はヘテロシクリル基(ここで、該ヘテロシクリル基は、1個のアミノ基で置換されてもよい。)であり、
A4が、水素原子であり、
R1が、水素原子であり、
R2が、C1-6アルキル基又はC3-6シクロアルキル基であり、
R3が、C1-6アルキル基{ここで、該C1-6アルキル基は、ハロゲン原子、水酸基、C1-6アルコキシ基(ここで、該C1-6アルコキシ基は、1〜3個のハロゲン原子で置換されてもよい。)、アリールオキシ基、C1-6アルキルスルホニルアミノ基、C1-6アルキルスルホニル基、ヘテロシクリル基(ここで、該ヘテロシクリル基は、1〜2個のオキソで置換されてもよい。)、及びアリール基からなる群から選ばれる同一又は異なる1〜3個の置換基で置換されてもよい。}であり、
Yが、下記式群(IV)のいずれかの構造であり、
R 1 is a hydrogen atom,
R 2 is a methyl group, an ethyl group, a propyl group, or a cyclopropyl group;
R 3 is a C 1-6 alkyl group {wherein the C 1-6 alkyl group is a halogen atom, a hydroxyl group, a C 1-6 alkoxy group (wherein the C 1-6 alkoxy group is 1 to 3 A C 1-6 alkylsulfonylamino group, and a heterocyclyl group (wherein the heterocyclyl group may be substituted with 1 to 2 oxo groups). It may be substituted with 1 to 3 identical or different substituents selected from the group. },
Y is a phenyl group or a pyridyl group {wherein the phenyl group and the pyridyl group are a halogen atom, an amino group, a C 1-6 alkyl group, a C 1-6 alkoxy group, a C 2-6 alkanoylamino group (where The C 2-6 alkanoylamino group may be substituted with one C 1-6 alkylsulfonyl group.), C 1-6 alkylsulfonylamino group, phenylsulfonylamino group, and C 1-6 alkyl It may be substituted with 1 to 3 identical or different substituents selected from the group consisting of sulfonyl groups. } The compound according to any one of (1) to (4), or a pharmaceutically acceptable salt thereof,
(6) In the above formula (I),
Y is any structure of the above formula group (II),
Ring Q is an aromatic hydrocarbon ring or a heteroaromatic ring (wherein the aromatic hydrocarbon ring and the heteroaromatic ring may be substituted with one C 1-6 alkyl group),
When W is a single bond, Z is the formula (CH 2 ) n or the formula CH 2 NR 7 ;
n is an integer of 2 to 4,
When W is of formula CH 2 , Z is of formula CH 2 CH 2 ;
B 1 , B 2 , B 3 , B 4 , and B 5 are the same or different and each is a hydrogen atom, a halogen atom, or a C 1-6 alkyl group,
R 4 and R 5 are the same or different and each represents a hydrogen atom or a C 1-6 alkyl group,
Or R 4 and R 5 together with an adjacent carbon atom are C 3-6 cycloalkane {where C 3-6 cycloalkane is an oxo, hydroxyl group, C 2-6 alkanoylamino group (here And the C 2-6 alkanoylamino group may be substituted with one C 1-6 alkylsulfonyl group.), And one substitution selected from the group consisting of C 1-6 alkylsulfonylamino groups It may be substituted with a group. Furthermore, the C 3-6 cycloalkane may have one formula CH 2 in the ring substituted with the formula NR 8 ,
R 6 is a hydrogen atom, an amino group, a C 1-6 alkyl group (wherein the C 1-6 alkyl group is a C 3-6 cycloalkylcarbonyl group, a C 1-6 alkylsulfonyl group, and a C 1- Which may be substituted with one substituent selected from the group consisting of 6 alkylsulfonylamino groups), a C 1-6 alkylamino group (wherein the C 1-6 alkylamino group is one C 1-6 alkylsulfonyl group may be substituted), C 2-6 alkanoylamino group (wherein the C 2-6 alkanoylamino group is an amino group, a sulfamoyl group, a C 3-6 cycloalkyl group, C 1-6 alkoxy group, C 1-6 alkylamino group, C 2-6 alkanoylamino group, C 1-6 alkylsulfonylamino group, C 1-6 alkylsulfonyl group, C 1-6 alkylaminosulfonyl group, aryl Sulfonyl group, aryl group, and heteroaryl May be substituted with one substituent selected from the group consisting of.), By C 1-6 alkoxycarbonylamino group (wherein the C 1-6 alkoxycarbonylamino group, substituted with one aryl group Or a C 1-6 alkylsulfonylamino group,
R 7 is a hydrogen atom or a C 1-6 alkyl group,
R 8 is a carbamoyl group, an amidino group, a C 2-6 alkanoyl group (wherein the C 2-6 alkanoyl group may be substituted with one C 1-6 alkylsulfonyl group), C 1 ( 6) an alkoxycarbonyl group (wherein the C 1-6 alkoxycarbonyl group may be substituted with one aryl group), or a C 1-6 alkylsulfonyl group (1) or (2) Or a pharmaceutically acceptable salt thereof,
(7) In the above formula (I),
A 1 is a hydrogen atom or a C 1-6 alkyl group,
A 2 is a hydrogen atom, a C 1-6 alkyl group, or a C 3-6 cycloalkyl group,
A 3 is a C 1-6 alkoxy group (wherein the C 1-6 alkoxy group may be substituted with one amino group), a C 1-6 alkylamino group (wherein the C 1-6 1-6 alkylamino group may be substituted with one amino group.), C 3-6 cycloalkylamino group (wherein the C 3-6 cycloalkylamino group is one amino group) Or a heterocyclyl group (wherein the heterocyclyl group may be substituted with one amino group),
A 4 is a hydrogen atom,
R 1 is a hydrogen atom,
R 2 is a C 1-6 alkyl group or a C 3-6 cycloalkyl group,
R 3 is a C 1-6 alkyl group {wherein the C 1-6 alkyl group is a halogen atom, a hydroxyl group, a C 1-6 alkoxy group (wherein the C 1-6 alkoxy group is 1 to 3 May be substituted with 1 halogen atom), an aryloxy group, a C 1-6 alkylsulfonylamino group, a C 1-6 alkylsulfonyl group, a heterocyclyl group (wherein the heterocyclyl group has 1 to 2 And may be substituted with 1 to 3 identical or different substituents selected from the group consisting of aryl groups. },
Y is any structure of the following formula group (IV),
nが、2〜4の整数であり、
B1、B2、B3、B4、及びB5が、それぞれ水素原子であり、
B6、B7、B8、及びB9が、同一又は異なって、それぞれ水素原子、又はC1-6アルキル基であり、
R4及びR5が、隣接する炭素原子と一緒になってC3-6シクロアルカン{ここで、該C3-6シクロアルカンは、C2-6アルカノイルアミノ基(ここで、該C2-6アルカノイルアミノ基は、1個のC1-6アルキルスルホニル基で置換されてもよい。)、及びC1-6アルキルスルホニルアミノ基からなる群から選ばれる1個の置換基で置換されてもよい。}を形成してもよく、さらに該C3-6シクロアルカンは、環中の1個の式CH2が式NR8で置換されていてもよく、
R6が、アミノ基、C1-6アルキル基(ここで、該C1-6アルキル基はC1-6アルキルスルホニル基及びC1-6アルキルスルホニルアミノ基からなる群から選ばれる1個の置換基で置換されてもよい。)、C2-6アルカノイルアミノ基(ここで、該C2-6アルカノイルアミノ基は、スルファモイル基、C3-6シクロアルキル基、C1-6アルキルスルホニルアミノ基、C1-6アルキルスルホニル基、C1-6アルキルアミノスルホニル基、アリールスルホニル基、及びアリール基からなる群から選ばれる1個の置換基で置換されてもよい。)、C1-6アルコキシカルボニルアミノ基、又はC1-6アルキルスルホニルアミノ基であり、
R8が、C2-6アルカノイル基(ここで、該C2-6アルカノイル基は、1個のC1-6アルキルスルホニル基で置換されてもよい。)、又はC1-6アルキルスルホニル基である、(1)、(2)、又は(6)いずれか1つに記載の化合物、又はその医薬上許容される塩、
(8)上記式(I)中、
A1が、水素原子であり、
A2が、メチル基であり、
A3が、下記式(V)の構造であり、
n is an integer of 2 to 4,
B 1 , B 2 , B 3 , B 4 , and B 5 are each a hydrogen atom,
B 6 , B 7 , B 8 and B 9 are the same or different and each is a hydrogen atom or a C 1-6 alkyl group,
R 4 and R 5, with C 3-6 cycloalkane {here together with the adjacent carbon atoms, the C 3-6 cycloalkane, C 2-6 at alkanoylamino group (wherein said C 2- The 6 alkanoylamino group may be substituted with one C 1-6 alkylsulfonyl group.), And may be substituted with one substituent selected from the group consisting of C 1-6 alkylsulfonylamino groups. Good. Furthermore, the C 3-6 cycloalkane may have one formula CH 2 in the ring substituted with the formula NR 8 ,
R 6 is an amino group, with a C 1-6 alkyl group (wherein, the C 1-6 alkyl groups one selected from the group consisting of C 1-6 alkylsulfonyl group and a C 1-6 alkylsulfonylamino group A C 2-6 alkanoylamino group (wherein the C 2-6 alkanoylamino group is a sulfamoyl group, a C 3-6 cycloalkyl group, a C 1-6 alkylsulfonylamino group). group, C 1-6 alkylsulfonyl group, C 1-6 alkylaminosulfonyl group, may be substituted with an arylsulfonyl group 1 substituents selected from the group consisting of and aryl radicals,.), C 1-6 An alkoxycarbonylamino group, or a C 1-6 alkylsulfonylamino group,
R 8 represents a C 2-6 alkanoyl group (wherein the C 2-6 alkanoyl group may be substituted with one C 1-6 alkylsulfonyl group), or a C 1-6 alkylsulfonyl group The compound according to any one of (1), (2), or (6), or a pharmaceutically acceptable salt thereof,
(8) In the above formula (I),
A 1 is a hydrogen atom,
A 2 is a methyl group,
A 3 is a structure of the following formula (V),
R1が、水素原子であり、
R2が、メチル基又はエチル基であり、
R3が、メチル基であり、
Yが、上記式群(IV)のいずれかの構造であり、
Wが単結合のとき、Zが、式(CH2)nであり、
nが、2〜4の整数であり、
B1、B2、B3、B4、B5、B6、B7、B8、及びB9が、水素原子であり、
R4及びR5が、隣接する炭素原子と一緒になってC3-6シクロアルカン{ここで、該C3-6シクロアルカンは、C2-6アルカノイルアミノ基(ここで、該C2-6アルカノイルアミノ基は、1個のC1-6アルキルスルホニル基で置換されてもよい。)で置換されてもよい。}を形成してもよく、さらに該C3-6シクロアルカンは、環中の1個の式CH2が式NR8で置換されてもよく、
R6が、C2-6アルカノイルアミノ基(ここで、該C2-6アルカノイルアミノ基は、スルファモイル基、C1-6アルキルスルホニル基、及びC1-6アルキルアミノスルホニル基からなる群から選ばれる1個の置換基で置換されてもよい。)、C1-6アルコキシカルボニルアミノ基、又はC1-6アルキルスルホニルアミノ基であり、
R8が、C2-6アルカノイル基(ここで、該C2-6アルカノイル基は、1個のC1-6アルキルスルホニル基で置換されてもよい。)である、(1)、(2)、(6)、又は(7)いずれか1つに記載の化合物又はその医薬上許容される塩、
(9)上記(1)〜(8)のいずれか1つ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医薬、
(10)上記(1)〜(8)のいずれか1つ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、呼吸器合胞体ウイルス(RSV)を含むニューモウイルス亜科のウイルスが関与する感染症の予防又は治療薬、
である。
R 1 is a hydrogen atom,
R 2 is a methyl group or an ethyl group,
R 3 is a methyl group,
Y is any structure of the above formula group (IV),
When W is a single bond, Z is the formula (CH 2 ) n;
n is an integer of 2 to 4,
B 1 , B 2 , B 3 , B 4 , B 5 , B 6 , B 7 , B 8 , and B 9 are hydrogen atoms;
R 4 and R 5, with C 3-6 cycloalkane {here together with the adjacent carbon atoms, the C 3-6 cycloalkane, C 2-6 at alkanoylamino group (wherein said C 2- The 6 alkanoylamino group may be substituted with one C 1-6 alkylsulfonyl group. Furthermore, the C 3-6 cycloalkane may have one formula CH 2 in the ring substituted with the formula NR 8 ,
R 6 is a C 2-6 alkanoylamino group (wherein the C 2-6 alkanoylamino group is selected from the group consisting of a sulfamoyl group, a C 1-6 alkylsulfonyl group, and a C 1-6 alkylaminosulfonyl group) And a C 1-6 alkoxycarbonylamino group, or a C 1-6 alkylsulfonylamino group,
R 8 is a C 2-6 alkanoyl group (wherein the C 2-6 alkanoyl group may be substituted with one C 1-6 alkylsulfonyl group), (1), (2 ), (6), or (7) any one of the compounds or pharmaceutically acceptable salts thereof,
(9) A medicament comprising the compound according to any one of (1) to (8) above or a pharmaceutically acceptable salt thereof as an active ingredient,
(10) Pneumovirus subfamily including respiratory syncytial virus (RSV), comprising as an active ingredient the compound according to any one of (1) to (8) above or a pharmaceutically acceptable salt thereof. Preventive or therapeutic agents for infections involving viruses,
It is.
本発明化合物は抗RSV活性を有することが示された。本発明化合物を含む医薬は、呼吸器合胞体ウイルス(RSV)を含むニューモウイルス亜科のウイルスが関与する感染症の予防又は治療薬として有用である。 The compounds of the present invention have been shown to have anti-RSV activity. The medicament containing the compound of the present invention is useful as a preventive or therapeutic agent for infectious diseases involving viruses of the Pneumovirus subfamily including respiratory syncytial virus (RSV).
本明細書中で用いられる用語は以下に定義される通りである。 The terms used in this specification are as defined below.
「ハロゲン原子」とは、フッ素原子、塩素原子、臭素原子、ヨウ素原子である。
「C1-6アルキル基」とは、炭素原子を1〜6個有する直鎖状アルキル基又は分岐鎖状アルキル基を示す。直鎖状アルキル基とは、メチル、エチル、プロピル、ブチル、ペンチル、ヘキシルのアルキル基が挙げられる。分岐鎖状アルキル基とは、例えば、イソプロピル、イソブチル、tert−ブチル、イソペンチル、1−エチルプロピル、イソヘキシル等のアルキル基が挙げられる。
「C3-6シクロアルキル基」とは、炭素原子を3〜6個有する環状のアルキル基を示し、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル基が挙げられる。
「C2-6アルキニル基」とは、炭素原子を2〜6個有するアルキニル基を示し、例えば、エチニル、プロピニル、ブチニル、ペンチニル、ヘキシニル基等が挙げられる。
「アリール基」とは、例えばフェニル、1−ナフチル、2−ナフチル基等が挙げられる。
「ヘテロアリール基」とは、酸素原子、窒素原子及び硫黄原子からなる群より、同一又は異なる1〜4個の複素原子を含有する単環ヘテロアリール基又は縮環ヘテロアリール基を意味し、例えばピロリル、フリル、チエニル、イミダゾリル、ピラゾリル、チアゾリル、イソチアゾリル、オキサゾリル、イソオキサゾリル、トリアゾリル、テトラゾリル、オキサジアゾリル、ピリジル、ピラジニル、ピリミジニル、ピリダジニル、トリアジニル、インドリル、ベンゾフラニル、ベンゾチエニル、ベンゾイミダゾリル、ベンゾオキサゾリル、ベンゾイソオキサゾリル、ベンゾチアゾリル、ベンゾイソチアゾリル、インダゾリル、キノリル、イソキノリル基等が挙げられる。
「C3-6シクロアルカン」とは、炭素原子を3〜6個有する環状のアルカンを示し、シクロプロパン、シクロブタン、シクロペンタン、シクロヘキサンが挙げられる。
「C1-6アルコキシ基」とは、炭素原子を1〜6個有する直鎖状アルコキシ基又は分岐鎖状アルコキシ基を示す。直鎖状アルコキシ基とは、メトキシ、エトキシ、プロポキシ、ブトキシ、ペンチルオキシ、ヘキシルオキシのアルコキシ基が挙げられる。分岐鎖状アルコキシ基とは、例えば、イソプロポキシ、イソブトキシ、tert−ブトキシ、イソペンチルオキシ、1−エチルプロポキシ、イソヘキシルオキシ等のアルコキシ基が挙げられる。
「C2-6アルカノイル基」とは、炭素原子を2〜6個有するアルカノイル基を示し、例えば、アセチル、プロピオニル、ブチリル、イソブチリル、バレリル、イソバレリル、ピバロイル等が挙げられる。
「C2-6アルカノイルアミノ基」とは、前記「C2-6アルカノイル基」とアミノ基が結合した基を意味し、例えば、アセチルアミノ、プロピオニルアミノ、ブチリルアミノ、イソブチリルアミノ、バレリルアミノ、イソバレリルアミノ、ピバロイルアミノ等が挙げられる。
「C1-6アルコキシカルボニル基」とは、前記「C1-6アルコキシ基」とカルボニル基が結合した基を意味し、例えば、メトキシカルボニル、エトキシカルボニル、プロポキシカルボニル、イソプロポキシカルボニル、ブトキシカルボニル、イソブトキシカルボニル、tert−ブトキシカルボニル、ペンチルオキシカルボニル基等が挙げられる。
「C1-6アルコキシカルボニルアミノ基」とは、前記「C1-6アルコキシカルボニル基」とアミノ基が結合した基を意味し、例えば、メトキシカルボニルアミノ、エトキシカルボニルアミノ、プロポキシカルボニルアミノ、イソプロポキシカルボニルアミノ、ブトキシカルボニルアミノ、イソブトキシカルボニルアミノ、tert−ブトキシカルボニルアミノ、ペンチルオキシカルボニルアミノ基等が挙げられる。
「C1-6アルキルアミノ基」とは、1個あるいは同一又は異なった2個の前記「C1-6アルキル基」とアミノ基が結合した基を意味し、例えば、メチルアミノ、エチルアミノ、プロピルアミノ、ブチルアミノ、ペンチルアミノ、ヘキシルアミノ、イソプロピルアミノ、イソブチルアミノ、tert−ブチルアミノ、イソペンチルアミノ、1−エチルプロピルアミノ、イソヘキシルアミノ、ジメチルアミノ、ジエチルアミノ、ジプロピルアミノ、エチルメチルアミノ、メチルプロピルアミノ、エチルプロピルアミノ基等が挙げられる。
「C1-6アルキルアミノスルホニル基」とは、前記「C1-6アルキルアミノ基」とスルホニル基が結合した基を意味し、例えば、メチルアミノスルホニル、エチルアミノスルホニル、プロピルアミノスルホニル、ブチルアミノスルホニル、ペンチルアミノスルホニル、ヘキシルアミノスルホニル、イソプロピルアミノスルホニル、イソブチルアミノスルホニル、tert−ブチルアミノスルホニル、イソペンチルアミノスルホニル、1−エチルプロピルアミノスルホニル、イソヘキシルアミノスルホニル、ジメチルアミノスルホニル、ジエチルアミノスルホニル、ジプロピルアミノスルホニル、エチルメチルアミノスルホニル、メチルプロピルアミノスルホニル、エチルプロピルアミノスルホニル基等が挙げられる。
「C3-6シクロアルキルカルボニル基」とは、前記「C3-6シクロアルキル基」とカルボニル基が結合した基を意味し、シクロプロピルカルボニル、シクロブチルカルボニル、シクロペンチルカルボニル、シクロヘキシルカルボニル基が挙げられる。
「C1-6アルキルスルホニル基」とは、前記「C1-6アルキル基」とスルホニル基が結合した基を意味し、例えば、メチルスルホニル、エチルスルホニル、プロピルスルホニル、ブチルスルホニル、ペンチルスルホニル、ヘキシルスルホニル、イソプロピルスルホニル、イソブチルスルホニル、tert−ブチルスルホニル、イソペンチルスルホニル、1−エチルプロピルスルホニル、イソヘキシルスルホニル基等が挙げられる。
「C1-6アルキルスルホニルアミノ基」とは、前記「C1-6アルキルスルホニル基」とアミノ基が結合した基を意味し、例えば、メチルスルホニルアミノ、エチルスルホニルアミノ、プロピルスルホニルアミノ、ブチルスルホニルアミノ、ペンチルスルホニルアミノ、ヘキシルスルホニルアミノ、イソプロピルスルホニルアミノ、イソブチルスルホニルアミノ、tert−ブチルスルホニルアミノ、イソペンチルスルホニルアミノ、1−エチルプロピルスルホニルアミノ、イソヘキシルスルホニルアミノ基等が挙げられる。
「C3-6シクロアルキルアミノ基」とは、前記「C3-6シクロアルキル基」とアミノ基が結合した基を意味し、シクロプロピルアミノ、シクロブチルアミノ、シクロペンチルアミノ、シクロヘキシルアミノ基が挙げられる。
「アリールオキシ基」とは、前記「アリール基」とオキシ基が結合した基を意味し、例えばフェノキシ基、1−ナフトキシ基、2−ナフトキシ基等が挙げられる。
「アリールスルホニル基」とは、前記「アリール基」とスルホニル基が結合した基を意味し、例えばフェニルスルホニル、1−ナフチルスルホニル、2−ナフチルスルホニル基等が挙げられる。
「アリールスルホニルアミノ基」とは、前記「アリールスルホニル基」とアミノ基が結合した基を意味し、例えばフェニルスルホニルアミノ、1−ナフチルスルホニルアミノ、2−ナフチルスルホニルアミノ基等が挙げられる。
「芳香族炭化水素環」とは、例えばベンゼン環、ナフタレン環等が挙げられる。
「ヘテロ芳香環」とは、酸素原子、窒素原子、及び硫黄原子からなる群より、同一又は異なる1〜4個の複素原子を含有する単環式ヘテロ芳香環又は縮環式ヘテロ芳香環を意味し、例えばピロール、フラン、チオフェン、イミダゾール、ピラゾール、チアゾール、イソチアゾール、オキサゾール、イソオキサゾール、トリアゾール、テトラゾール、オキサジアゾール、ピリジン、ピラジン、ピリミジン、ピリダジン、トリアジン、インドール、ベンゾフラン、ベンゾチオフェン、ベンゾイミダゾール、ベンゾオキサゾール、ベンゾイソオキサゾール、ベンゾチアゾール、ベンゾイソチアゾール、インダゾール、キノリン、イソキノリン等が挙げられる。
「ヘテロシクリル基」とは、酸素原子、窒素原子及び硫黄原子からなる群より、同一又は異なる1〜3個の複素原子を含有するヘテロシクリル基を意味し、例えばアゼチジニル、ピロリジニル、ピペリジニル、オキセタニル、テトラヒドロフラニル、テトラヒドロピラニル、ピペラジニル、モルホリニル、チオモルホリニル、1,1−ジオキシドチオモルホリニル、インドリニル、イソインドリニル、3,4−ジヒドロ−2H−ベンゾオキサジニル基等が挙げられる。
「ヘテロシクリルオキシ基」とは、前記の「ヘテロシクリル基」とオキシ基が結合した基を意味し、例えばアゼチジニルオキシ、ピロリジニルオキシ、ピペリジニルオキシ、オキセタニルオキシ、テトラヒドロフラニルオキシ、テトラヒドロピラニルオキシ、ピペラジニルオキシ、モルホリニルオキシ、チオモルホリニルオキシ、1,1−ジオキシドチオモルホリニルオキシ、インドリニルオキシ、イソインドリニルオキシ、3,4−ジヒドロ−2H−ベンゾオキサジニルオキシ基等が挙げられる。
The “halogen atom” is a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.
The “C 1-6 alkyl group” refers to a linear alkyl group or branched alkyl group having 1 to 6 carbon atoms. Examples of the linear alkyl group include methyl, ethyl, propyl, butyl, pentyl, and hexyl alkyl groups. Examples of the branched alkyl group include alkyl groups such as isopropyl, isobutyl, tert-butyl, isopentyl, 1-ethylpropyl, and isohexyl.
The “C 3-6 cycloalkyl group” refers to a cyclic alkyl group having 3 to 6 carbon atoms, and examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups.
The “C 2-6 alkynyl group” refers to an alkynyl group having 2 to 6 carbon atoms, and examples thereof include ethynyl, propynyl, butynyl, pentynyl, hexynyl group and the like.
Examples of the “aryl group” include phenyl, 1-naphthyl, 2-naphthyl group and the like.
The “heteroaryl group” means a monocyclic heteroaryl group or a condensed heteroaryl group containing 1 to 4 heteroatoms which are the same or different from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom. Pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, oxadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, indolyl, benzofuranyl, benzothienyl, benzoimidazolyl, benzooxazolyl Examples thereof include oxazolyl, benzothiazolyl, benzoisothiazolyl, indazolyl, quinolyl, and isoquinolyl groups.
“C 3-6 cycloalkane” refers to a cyclic alkane having 3 to 6 carbon atoms, and examples thereof include cyclopropane, cyclobutane, cyclopentane, and cyclohexane.
“C 1-6 alkoxy group” refers to a linear or branched alkoxy group having 1 to 6 carbon atoms. Examples of the linear alkoxy group include methoxy, ethoxy, propoxy, butoxy, pentyloxy, and hexyloxy alkoxy groups. Examples of the branched alkoxy group include alkoxy groups such as isopropoxy, isobutoxy, tert-butoxy, isopentyloxy, 1-ethylpropoxy, isohexyloxy and the like.
The “C 2-6 alkanoyl group” refers to an alkanoyl group having 2 to 6 carbon atoms, and examples thereof include acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl and the like.
The “C 2-6 alkanoylamino group” means a group in which the above “C 2-6 alkanoyl group” and an amino group are bonded. For example, acetylamino, propionylamino, butyrylamino, isobutyrylamino, valerylamino, iso Examples include valerylamino and pivaloylamino.
The “C 1-6 alkoxycarbonyl group” means a group in which the “C 1-6 alkoxy group” is bonded to a carbonyl group. For example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, Examples include isobutoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl group and the like.
The “C 1-6 alkoxycarbonylamino group” means a group in which the “C 1-6 alkoxycarbonyl group” is bonded to an amino group, and examples thereof include methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, isopropoxy Examples include carbonylamino, butoxycarbonylamino, isobutoxycarbonylamino, tert-butoxycarbonylamino, pentyloxycarbonylamino group and the like.
The “C 1-6 alkylamino group” means a group in which one or two identical or different “C 1-6 alkyl groups” and an amino group are bonded to each other, and examples thereof include methylamino, ethylamino, Propylamino, butylamino, pentylamino, hexylamino, isopropylamino, isobutylamino, tert-butylamino, isopentylamino, 1-ethylpropylamino, isohexylamino, dimethylamino, diethylamino, dipropylamino, ethylmethylamino, Examples include methylpropylamino and ethylpropylamino groups.
The “C 1-6 alkylaminosulfonyl group” means a group in which the “C 1-6 alkylamino group” is bonded to a sulfonyl group, and examples thereof include methylaminosulfonyl, ethylaminosulfonyl, propylaminosulfonyl, butylamino. Sulfonyl, pentylaminosulfonyl, hexylaminosulfonyl, isopropylaminosulfonyl, isobutylaminosulfonyl, tert-butylaminosulfonyl, isopentylaminosulfonyl, 1-ethylpropylaminosulfonyl, isohexylaminosulfonyl, dimethylaminosulfonyl, diethylaminosulfonyl, dipropyl Examples include aminosulfonyl, ethylmethylaminosulfonyl, methylpropylaminosulfonyl, and ethylpropylaminosulfonyl groups.
The “C 3-6 cycloalkylcarbonyl group” means a group in which the “C 3-6 cycloalkyl group” is bonded to a carbonyl group, and examples thereof include cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, and cyclohexylcarbonyl groups. It is done.
The “C 1-6 alkylsulfonyl group” means a group in which the “C 1-6 alkyl group” is bonded to a sulfonyl group, such as methylsulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl, pentylsulfonyl, hexyl. Examples include sulfonyl, isopropylsulfonyl, isobutylsulfonyl, tert-butylsulfonyl, isopentylsulfonyl, 1-ethylpropylsulfonyl, and isohexylsulfonyl groups.
The “C 1-6 alkylsulfonylamino group” means a group in which the “C 1-6 alkylsulfonyl group” is bonded to an amino group, such as methylsulfonylamino, ethylsulfonylamino, propylsulfonylamino, butylsulfonyl. Examples include amino, pentylsulfonylamino, hexylsulfonylamino, isopropylsulfonylamino, isobutylsulfonylamino, tert-butylsulfonylamino, isopentylsulfonylamino, 1-ethylpropylsulfonylamino, isohexylsulfonylamino group and the like.
The “C 3-6 cycloalkylamino group” means a group in which the “C 3-6 cycloalkyl group” is bonded to an amino group, and examples thereof include cyclopropylamino, cyclobutylamino, cyclopentylamino, and cyclohexylamino groups. It is done.
The “aryloxy group” means a group in which the “aryl group” and the oxy group are bonded, and examples thereof include a phenoxy group, a 1-naphthoxy group, and a 2-naphthoxy group.
The “arylsulfonyl group” means a group in which the “aryl group” and the sulfonyl group are bonded, and examples thereof include phenylsulfonyl, 1-naphthylsulfonyl, 2-naphthylsulfonyl group and the like.
The “arylsulfonylamino group” means a group in which the above “arylsulfonyl group” is bonded to an amino group, and examples thereof include phenylsulfonylamino, 1-naphthylsulfonylamino, 2-naphthylsulfonylamino groups and the like.
Examples of the “aromatic hydrocarbon ring” include a benzene ring and a naphthalene ring.
“Heteroaromatic ring” means a monocyclic heteroaromatic ring or a condensed heteroaromatic ring containing 1 to 4 heteroatoms which are the same or different from the group consisting of oxygen atom, nitrogen atom and sulfur atom. For example, pyrrole, furan, thiophene, imidazole, pyrazole, thiazole, isothiazole, oxazole, isoxazole, triazole, tetrazole, oxadiazole, pyridine, pyrazine, pyrimidine, pyridazine, triazine, indole, benzofuran, benzothiophene, benzimidazole Benzoxazole, benzisoxazole, benzothiazole, benzisothiazole, indazole, quinoline, isoquinoline and the like.
"Heterocyclyl group" means a heterocyclyl group containing 1 to 3 heteroatoms which are the same or different from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, such as azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, tetrahydrofuranyl , Tetrahydropyranyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,1-dioxidethiomorpholinyl, indolinyl, isoindolinyl, 3,4-dihydro-2H-benzoxazinyl group and the like.
“Heterocyclyloxy group” means a group in which the above “heterocyclyl group” is bonded to an oxy group. For example, azetidinyloxy, pyrrolidinyloxy, piperidinyloxy, oxetanyloxy, tetrahydrofuranyloxy, tetrahydropyranyl Ruoxy, piperazinyloxy, morpholinyloxy, thiomorpholinyloxy, 1,1-dioxidethiomorpholinyloxy, indolinyloxy, isoindolinyloxy, 3,4-dihydro-2H-benzoxa A dinyloxy group etc. are mentioned.
呼吸器合胞体ウイルス(RSV)を含むニューモウイルス亜科のウイルスとは、パラミクソウイルス科に含まれるネガティブセンス一本鎖RNAウイルスであり、ヒト呼吸器合胞体ウイルス(HRSV)及びヒトメタニューモウイルス(HMPV)などが挙げられる。 Pneumovirinae virus including respiratory syncytial virus (RSV) is a negative sense single-stranded RNA virus included in Paramyxoviridae, human respiratory syncytial virus (HRSV) and human metapneumovirus (HMPV).
呼吸器合胞体ウイルス(RSV)を含むニューモウイルス亜科のウイルスが関与する感染症とは、流行性のヒト及び動物における感染症であり、RSV感染症及びHMPV感染症などが挙げられる。 Infectious diseases involving viruses of the Pneumovirinae family including respiratory syncytial virus (RSV) are epidemic in humans and animals, and include RSV infections and HMPV infections.
本発明化合物(I)が塩を形成し、それが医薬品として用いられる場合、それは医薬上許容される塩が好ましい。「医薬上許容される塩」としては、例えば、塩酸塩、硫酸塩、臭化水素酸塩、硝酸塩及びリン酸塩の様な無機酸との塩又は酢酸塩、シュウ酸塩、乳酸塩、クエン酸塩、リンゴ酸塩、酒石酸塩、マレイン酸塩、フマル酸塩、コハク酸塩、メタンスルホン酸塩、エタンスルホン酸塩、ベンゼンスルホン酸塩及びp−トルエンスルホン酸塩の様な有機酸との塩が用いられるが、これらの塩に限定されるものではない。遊離体から当該塩への変換は従来の方法で行うことができる。 When the compound (I) of the present invention forms a salt and it is used as a pharmaceutical, it is preferably a pharmaceutically acceptable salt. “Pharmaceutically acceptable salts” include, for example, salts with inorganic acids such as hydrochloride, sulfate, hydrobromide, nitrate and phosphate, or acetate, oxalate, lactate, citric acid. With organic acids such as acid, malate, tartrate, maleate, fumarate, succinate, methanesulfonate, ethanesulfonate, benzenesulfonate and p-toluenesulfonate Although a salt is used, it is not limited to these salts. Conversion from the educt to the salt can be performed by conventional methods.
また、「医薬的に許容される塩」としては、無機塩基との塩及び有機塩基との塩等が挙げられる。無機塩基との塩の好適な例としては、例えば、アルカリ金属塩(例えば、ナトリウム塩、カリウム塩等)、アルカリ土類金属塩(例えば、カルシウム塩、マグネシウム塩、バリウム塩等)、アルミニウム塩及びアンモニウム塩等が挙げられる。有機塩基との塩の好適な例としては、例えば、トリメチルアミン、トリエチルアミン、ピリジン、ピコリン、エタノールアミン、ジエタノールアミン、トリエタノールアミン、ジシクロヘキシルアミン及びN,N−ジベンジルエチレンジアミン等が挙げられる。 In addition, examples of the “pharmaceutically acceptable salt” include salts with inorganic bases and salts with organic bases. Suitable examples of the salt with an inorganic base include, for example, alkali metal salts (for example, sodium salts, potassium salts, etc.), alkaline earth metal salts (for example, calcium salts, magnesium salts, barium salts, etc.), aluminum salts and An ammonium salt etc. are mentioned. Preferable examples of the salt with an organic base include trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine and N, N-dibenzylethylenediamine.
本発明化合物において、好ましい態様を以下に挙げる。
A1は、水素原子又はC1-6アルキル基である化合物が好ましく、水素原子である化合物がより好ましい。
A2は、水素原子、C1-6アルキル基、又はC3-6シクロアルキル基である化合物が好ましく、メチル基、エチル基、プロピル基、又はシクロプロピル基である化合物がより好ましい。
A3は、1個のアミノ基で置換されてもよいC1-6アルコキシ基、1個のアミノ基で置換されてもよいC1-6アルキルアミノ基、1個のアミノ基で置換されてもよいC3-6シクロアルキルアミノ基、又は1個のアミノ基で置換されてもよいヘテロシクリル基である化合物が好ましく、1個のアミノ基で置換されたC1-6アルコキシ基、1個のアミノ基で置換されたC1-6アルキルアミノ基、1個のアミノ基で置換されたC3-6シクロアルキルアミノ基、又は1個のアミノ基で置換されたヘテロシクリル基である化合物がより好ましく、下記式群(III)のいずれかの構造である化合物がさらに好ましい。
Preferred embodiments of the compound of the present invention are listed below.
A 1 is preferably a compound that is a hydrogen atom or a C 1-6 alkyl group, and more preferably a compound that is a hydrogen atom.
A 2 is preferably a compound that is a hydrogen atom, a C 1-6 alkyl group, or a C 3-6 cycloalkyl group, and more preferably a compound that is a methyl group, an ethyl group, a propyl group, or a cyclopropyl group.
A 3 is a C 1-6 alkoxy group which may be substituted with one amino group, a C 1-6 alkylamino group which may be substituted with one amino group, or a single amino group. Preferred is a compound which is a C 3-6 cycloalkylamino group or a heterocyclyl group which may be substituted with one amino group, preferably a C 1-6 alkoxy group substituted with one amino group, one More preferably, the compound is a C 1-6 alkylamino group substituted with an amino group, a C 3-6 cycloalkylamino group substituted with one amino group, or a heterocyclyl group substituted with one amino group. Further, a compound having a structure of any one of the following formula group (III) is more preferable.
R1は、水素原子である化合物が好ましい。
R2は、C1-6アルキル基(該C1-6アルキル基は、1個の水酸基で置換されてもよい。)、又はC3-6シクロアルキル基である化合物が好ましく、C1-6アルキル基、又はC3-6シクロアルキル基である化合物がより好ましく、メチル基、エチル基、又はシクロプロピル基である化合物がさらに好ましい。
又は他の好ましい態様として、R1及びR2が、隣接する炭素原子と一緒になって、C3-6シクロアルカンを形成した化合物が好ましい。
Yは、アリール基、ヘテロアリール基{該アリール基及びヘテロアリール基は、ハロゲン原子、アミノ基、C1-6アルキル基、C1-6アルコキシ基、C2-6アルカノイルアミノ基(該C2-6アルカノイルアミノ基は、1個のC1-6アルキルスルホニル基で置換されてもよい。)、C1-6アルキルスルホニルアミノ基(該C1-6アルキルスルホニルアミノ基は、1〜3個のハロゲン原子で置換されてもよい。)、アリールスルホニルアミノ基、C1-6アルキルスルホニル基、ヘテロシクリル基、アリール基、及びヘテロアリール基からなる群から選ばれる同一又は異なる1〜3個の置換基で置換されてもよい。}、又はヘテロシクリル基(ここで、該シクロシクリル基は、1個のオキソで置換されてもよい。)である化合物が好ましく、フェニル基、ピリジル基{該フェニル基及びピリジル基は、ハロゲン原子、アミノ基、C1-6アルキル基、C1-6アルコキシ基、C2-6アルカノイルアミノ基(該C2-6アルカノイルアミノ基は、1個のC1-6アルキルスルホニル基で置換されてもよい。)、C1-6アルキルスルホニルアミノ基、フェニルスルホニルアミノ基、及びC1-6アルキルスルホニル基からなる群から選ばれる同一又は異なる1〜3個の置換基で置換されてもよい。}である化合物がより好ましい。
又は他の好ましい態様として、Yが、式群(IV)のいずれかの構造である化合物が好ましい。
R 1 is preferably a compound that is a hydrogen atom.
R 2 is C 1-6 alkyl group (the C 1-6 alkyl group may be substituted with one hydroxy group.), Or C 3-6 is preferable compound is a cycloalkyl group, C 1- A compound that is a 6 alkyl group or a C 3-6 cycloalkyl group is more preferable, and a compound that is a methyl group, an ethyl group, or a cyclopropyl group is more preferable.
Alternatively, as another preferred embodiment, a compound in which R 1 and R 2 are combined with adjacent carbon atoms to form a C 3-6 cycloalkane is preferred.
Y represents an aryl group, a heteroaryl group (the aryl group and heteroaryl group are a halogen atom, an amino group, a C 1-6 alkyl group, a C 1-6 alkoxy group, a C 2-6 alkanoylamino group (the C 2 -6 alkanoylamino group may be substituted with one C 1-6 alkylsulfonyl group), C 1-6 alkylsulfonylamino group (the C 1-6 alkylsulfonylamino group is 1 to 3 The same or different 1 to 3 substituents selected from the group consisting of an arylsulfonylamino group, a C 1-6 alkylsulfonyl group, a heterocyclyl group, an aryl group, and a heteroaryl group It may be substituted with a group. Or a heterocyclyl group (wherein the cyclocyclyl group may be substituted with one oxo group), a phenyl group, a pyridyl group {the phenyl group and the pyridyl group are a halogen atom, an amino group, Group, C 1-6 alkyl group, C 1-6 alkoxy group, C 2-6 alkanoylamino group (the C 2-6 alkanoylamino group may be substituted with one C 1-6 alkylsulfonyl group) ), A C 1-6 alkylsulfonylamino group, a phenylsulfonylamino group, and a C 1-6 alkylsulfonyl group, the same or different 1 to 3 substituents may be substituted. } Is more preferable.
Or as another preferable aspect, the compound whose Y is a structure in any one of Formula group (IV) is preferable.
nは、2〜4の整数である化合物か、
又はWは式CH2であり、Zは式CH2CH2である化合物が好ましく、Wは単結合であり、Zは、式(CH2)nであり、nは、2〜4の整数である化合物がより好ましい。
B1、B2、B3、B4、及びB5は、同一又は異なって、それぞれ水素原子、ハロゲン原子、又はC1-6アルキル基である化合物が好ましく、水素原子である化合物がより好ましい。
B6、B7、B8、及びB9は、同一又は異なって、それぞれ水素原子又はC1-6アルキル基である化合物が好ましく、水素原子である化合物がより好ましい。
R4及びR5は、隣接する炭素原子と一緒になってC3-6シクロアルカン{該C3-6シクロアルカンは、オキソ、水酸基、C2-6アルカノイルアミノ基(該C2-6アルカノイルアミノ基は、1個のC1-6アルキルスルホニル基で置換されてもよい。)、及びC1-6アルキルスルホニルアミノ基からなる群から選ばれる1個の置換基で置換されてもよい。}を形成する化合物か、又は該C3-6シクロアルカンが、環中の1個の式CH2が式NR8で置換された化合物が好ましく、C3-6シクロアルカン{該C3-6シクロアルカンは、C2-6アルカノイルアミノ基(該C2-6アルカノイルアミノ基は、1個のC1-6アルキルスルホニル基で置換されてもよい。)で置換されてもよい。}を形成する化合物か、又は該C3-6シクロアルカンが、環中の1個の式CH2が式NR8で置換された化合物がより好ましい。
R6は、アミノ基、C1-6アルキル基(該C1-6アルキル基はC1-6アルキルスルホニル基及びC1-6アルキルスルホニルアミノ基からなる群から選ばれる1個の置換基で置換されてもよい。)、C2-6アルカノイルアミノ基(該C2-6アルカノイルアミノ基は、スルファモイル基、C3-6シクロアルキル基、C1-6アルキルスルホニルアミノ基、C1-6アルキルスルホニル基、C1-6アルキルアミノスルホニル基、アリールスルホニル基、及びアリール基からなる群から選ばれる1個の置換基で置換されてもよい。)、C1-6アルコキシカルボニルアミノ基、又はC1-6アルキルスルホニルアミノ基である化合物が好ましく、C2-6アルカノイルアミノ基(該C2-6アルカノイルアミノ基は、スルファモイル基、C1-6アルキルスルホニル基、及びC1-6アルキルアミノスルホニル基からなる群から選ばれる1個の置換基で置換されてもよい。)、C1-6アルコキシカルボニルアミノ基、又はC1-6アルキルスルホニルアミノ基である化合物がより好ましい。
R8は、1個のC1-6アルキルスルホニル基で置換されたC2-6アルカノイル基である化合物又はC1-6アルキルスルホニル基である化合物が好ましく、1個のC1-6アルキルスルホニル基で置換されたC2-6アルカノイル基である化合物がより好ましい。
n is a compound that is an integer of 2 to 4,
Or W is a formula CH 2, Z is preferably compounds of the formula CH 2 CH 2, W is a single bond, Z is a formula (CH 2) n, n is 2 to 4 integer Certain compounds are more preferred.
B 1 , B 2 , B 3 , B 4 , and B 5 are the same or different and are each preferably a hydrogen atom, a halogen atom, or a C 1-6 alkyl group, more preferably a compound that is a hydrogen atom. .
B 6 , B 7 , B 8 and B 9 are the same or different and are each preferably a hydrogen atom or a C 1-6 alkyl group, more preferably a hydrogen atom.
R 4 and R 5 together with the adjacent carbon atom are C 3-6 cycloalkane {the C 3-6 cycloalkane is an oxo, hydroxyl group, C 2-6 alkanoylamino group (the C 2-6 alkanoyl The amino group may be substituted with one C 1-6 alkylsulfonyl group.), And may be substituted with one substituent selected from the group consisting of C 1-6 alkylsulfonylamino groups. Or the C 3-6 cycloalkane is a compound in which one formula CH 2 in the ring is substituted by the formula NR 8 , and the C 3-6 cycloalkane {the C 3-6 The cycloalkane may be substituted with a C 2-6 alkanoylamino group (the C 2-6 alkanoylamino group may be substituted with one C 1-6 alkylsulfonyl group). Or a compound in which the C 3-6 cycloalkane is substituted with one formula CH 2 in the ring with the formula NR 8 .
R 6 is an amino group, a C 1-6 alkyl group (the C 1-6 alkyl group with one substituent selected from the group consisting of C 1-6 alkylsulfonyl group and a C 1-6 alkylsulfonylamino group May be substituted), a C 2-6 alkanoylamino group (the C 2-6 alkanoylamino group is a sulfamoyl group, a C 3-6 cycloalkyl group, a C 1-6 alkylsulfonylamino group, a C 1-6). And may be substituted with one substituent selected from the group consisting of an alkylsulfonyl group, a C 1-6 alkylaminosulfonyl group, an arylsulfonyl group, and an aryl group), a C 1-6 alkoxycarbonylamino group, or C 1-6 compound is alkylsulfonylamino group are preferred, C 2-6 alkanoylamino group (said C 2-6 alkanoylamino group, a sulfamoyl group, C 1-6 alkylsulfonyl group, and C 1-6 alkyl With 1 substituent selected from the group consisting of Minosuruhoniru group may be substituted.), C 1-6 alkoxycarbonylamino group, or a C 1-6 compound is alkylsulfonylamino group is more preferred.
R 8 is one of C 1-6 compound alkylsulfonyl C 2-6 alkanoyl group substituted by a group or a C 1-6 compound alkylsulfonyl group is preferable, one C 1-6 alkylsulfonyl More preferred are compounds that are C 2-6 alkanoyl groups substituted with groups.
本発明化合物(I)が光学異性体、立体異性体、位置異性体、回転異性体を含む場合は、単一の化合物及びその混合物が本発明の化合物として含まれる。また、本発明化合物(I)が水和物又は溶媒和物を形成する場合、これらも本発明の範囲内に含まれる。同様に、本発明化合物の水和物又は溶媒和物の医薬上許容される塩も本発明の範囲内に含まれる。さらに、本発明化合物(I)は同位元素(例えば、D、3H、13C、14C、15N、35S、125I等)で標識されていてもよい。 When this invention compound (I) contains an optical isomer, a stereoisomer, a positional isomer, and a rotational isomer, a single compound and its mixture are included as a compound of this invention. Moreover, when this invention compound (I) forms a hydrate or a solvate, these are also contained in the scope of the present invention. Similarly, pharmaceutically acceptable salts of hydrates or solvates of the compounds of the invention are also included within the scope of the invention. Further, the compound (I) of the present invention may be labeled with an isotope (for example, D, 3 H, 13 C, 14 C, 15 N, 35 S, 125 I, etc.).
本発明化合物(I)又は医薬上許容される塩を、そのまま或いは薬理学的に許容される担体とともに、自体公知の手段に従って製剤化することによって製造される。薬理学的に許容される担体としては、製剤素材として慣用の各種有機或いは無機担体物質、例えば、固形製剤における賦形剤(例えば、乳糖、白糖、D−マンニトール、デンプン、コーンスターチ、結晶セルロース、軽質無水ケイ酸等)、滑沢剤(例えば、ステアリング酸マグネシウム、ステアリング酸カルシウム、タルク、コロイドシリカ等)、結合剤(例えば、結晶セルロース、白糖、D−マンニトール、デキストリン、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、ポリビニルピロリドン、デンプン、ショ糖、ゼラチン、メチルセルロース、カルボキシメチルセルロースナトリウム等)、崩壊剤(例えば、デンプン、カルボキシメチルセルロース、カルボキシメチルセルロースカルシウム、クロスカルメロースナトリウム、カルボキシメチルスターチナトリウム、低置換度ヒドロキシプロピルセルロース等)、又は液状製剤における溶剤(例えば、注射用水、アルコール、プロピレングリコール、マクロゴール、ゴマ油、トウモロコシ油等)、溶解補助剤(例えば、ポリエチレングリコール、プロピレングリコール、D−マンニトール、安息香酸ベンジル、エタノール、トリスアミノメタン、コレステロール、トリエタノールアミン、炭酸ナトリウム、クエン酸ナトリウム等)、懸濁化剤(例えば、ステアリルトリエタノールアミン、ラウリル硫酸ナトリウム、ラウリルアミノプロピオン酸、レシチン、塩化ベンザルコニウム、塩化ベンゼトニウム、モノステアリン酸グリセリン等の界面活性剤、若しくは例えば、ポリビニルアルコール、ポリビニルピロリドン、カルボキシメチルセルロースナトリウム、メチルセルロース、ヒドロキシメチルセルロース、ヒドロキシプロピルセルロース等の親水性高分子等)、等張化剤(例えば、ブドウ糖、D−ソルビトール、塩化ナトリウム、グリセリン、D−マンニトール等)、緩衝剤(例えば、リン酸塩、酢酸塩、炭酸塩、クエン酸塩等)、無痛化剤(例えば、ベンジルアルコール等)等が挙げられる。また、製剤化の際に、必要に応じて、防腐剤(例えば、パラオキシ安息香酸エステル類、クロロブタノール、ベンジルアルコール、フェネチルアルコール、デヒドロ酢酸、ソルビン酸等)、抗酸化剤(例えば、亜硫酸塩、アスコルビン酸等)、着色剤、甘味剤、吸着剤、湿潤剤等を用いることもできる。 The compound (I) of the present invention or a pharmaceutically acceptable salt is produced by formulating it as it is or with a pharmacologically acceptable carrier according to a method known per se. Examples of pharmacologically acceptable carriers include various organic or inorganic carrier substances commonly used as pharmaceutical materials, such as excipients in solid formulations (eg, lactose, sucrose, D-mannitol, starch, corn starch, crystalline cellulose, light Silicic anhydride, etc.), lubricants (eg, magnesium stearate, calcium stearate, talc, colloidal silica), binders (eg, crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose) , Polyvinylpyrrolidone, starch, sucrose, gelatin, methylcellulose, sodium carboxymethylcellulose, etc.), disintegrant (eg starch, carboxymethylcellulose, carboxymethylcellulose calcium, croscarmello) Sodium, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, etc.) or solvents in liquid formulations (eg water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil, etc.), solubilizers (eg polyethylene glycol) , Propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, etc.), suspending agents (eg, stearyltriethanolamine, sodium lauryl sulfate, lauryl) Surfactants such as aminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glyceryl monostearate, or, for example, polyvinyl alcohol, polyvinylidene Pyrrolidone, sodium carboxymethylcellulose, hydrophilic polymers such as methylcellulose, hydroxymethylcellulose, and hydroxypropylcellulose), isotonic agents (eg, glucose, D-sorbitol, sodium chloride, glycerin, D-mannitol, etc.), buffers ( For example, phosphates, acetates, carbonates, citrates, etc.), soothing agents (eg, benzyl alcohol, etc.) and the like. In addition, preservatives (for example, paraoxybenzoates, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid, etc.), antioxidants (for example, sulfites, Ascorbic acid and the like), colorants, sweeteners, adsorbents, wetting agents and the like can also be used.
本発明化合物(I)又は医薬上許容される塩は、経口的又は非経口的(例えば、静脈、局所、直腸投与等)に投与することができる。その投与剤型は、例えば、錠剤(糖衣錠、フィルムコーティング錠を含む)、散剤、顆粒剤、粉剤、トローチ剤、カプセル剤(ソフトカプセルを含む)、液剤、注射剤(例えば、皮下注射剤、静脈内注射剤、筋肉内注射剤、腹腔内注射剤等)、外用剤(例えば、経鼻投与製剤、経皮製剤、軟膏剤、クリーム剤等)、坐剤(例えば、直腸坐剤、膣坐剤等)、徐放剤(例えば、徐放性マイクロカプセル等)、ペレット、点滴剤等であり、いずれも慣用の製剤技術(例えば、第16改正日本薬局方に記載する方法等)によって製造することができる。 The compound (I) or pharmaceutically acceptable salt of the present invention can be administered orally or parenterally (for example, intravenous, topical, rectal administration, etc.). The dosage form includes, for example, tablets (including sugar-coated tablets and film-coated tablets), powders, granules, powders, troches, capsules (including soft capsules), liquids, injections (for example, subcutaneous injections, intravenous injections) Injections, intramuscular injections, intraperitoneal injections, etc.), external preparations (eg, nasal preparations, transdermal preparations, ointments, creams, etc.), suppositories (eg, rectal suppositories, vaginal suppositories, etc.) ), Sustained-release agents (eg, sustained-release microcapsules), pellets, infusions, etc., all of which can be produced by conventional formulation techniques (eg, the method described in the 16th revised Japanese Pharmacopoeia, etc.). it can.
本発明化合物(I)又は医薬上許容される塩の投与量は、投与対象、投与経路、疾患、患者の年齢、体重及び症状によって適宜選択される。例えば、成人患者を治療する場合、その投与量は1日1〜5000 mgであり、この量を1日1回又は数回に分けて投与する。 The dose of the compound (I) of the present invention or a pharmaceutically acceptable salt is appropriately selected depending on the administration subject, administration route, disease, patient age, weight and symptoms. For example, when treating an adult patient, the dosage is 1 to 5000 mg per day, and this amount is administered once or divided into several times a day.
本発明化合物(I)及びその医薬上許容される塩は、当業者に公知である種々の有機合成手法を用いて合成することができる。例えば、以下に製造法を示すが、本合成法に限られたものではない。また、以下の反応式中R1、R2、R3、A1、A2、A3、A4及びYは、前記と同意義である。 The compound (I) of the present invention and pharmaceutically acceptable salts thereof can be synthesized using various organic synthesis methods known to those skilled in the art. For example, the production method is shown below, but is not limited to this synthesis method. In the following reaction formulas, R 1 , R 2 , R 3 , A 1 , A 2 , A 3 , A 4 and Y are as defined above.
本発明の化合物は、いずれも刊行物に未記載の新規化合物であるが、刊行物に記載の公知の方法又はそれと類似した方法で製造することができる。刊行物としては、例えばオーガニック・ファンクショナル・グループ・プレパレーションズ(Organic Functional Group Preparations, 1968年, S.R.サンドラーら著, Academic Press INC.)、シンセティック・オーガニック・ケミストリー(Synthetic Organic Chemistry, 1961年, S.R.ワーグナーら著, John Wiley INC.)、コンプリヘンシブ・オーガニック・トランスフォーメーションズ(Comprehensive Organic Transformations, 1989年, R.C.ラロック著, VCH Publishers, INC.)、エンサイクロペディア・オブ・レージェンツ・フォー・オーガニック・シンセシス(Encyclopedia of Reagents for Organic Synthesis, 1995年, L.A.パケットら著, Wiley INC.)、コンペンジアム・オブ・オーガニック・シンセティック・メソッド(Compendium of Organic Synthetic Methods, 第12版, 2009年, マイケル B. スミス著, Wiley INC.)等があげられる。 The compounds of the present invention are all novel compounds not described in publications, but can be produced by known methods described in publications or similar methods. Publications include, for example, Organic Functional Group Preparations (1968, SR Sandler et al., Academic Press Inc.), Synthetic Organic 61 (Synthetic Organic Chemistry 19). , SR Wagner et al., John Wiley Inc.), Comprehensive Organic Transformations (1989, RC Larlock, VCH Publishers, INC.). Of Regents for Organic Synth (Encyclopedia of Reagents for Organic Synthesis, 1995, LA Packet et al., Wiley INC.), Compendium of Organic Synthetic Method 9th Edition, Michael 9th Edition. B. Smith, Wiley Inc.).
「不活性溶媒」とは例えば、ベンゼン、トルエン、キシレン、ピリジン等の芳香族系溶媒;ヘキサン、ペンタン、シクロヘキサン等の炭化水素系溶媒;ジクロロメタン、クロロホルム、1,2−ジクロロエタン、四塩化炭素等のハロゲン化炭化水素系溶媒;テトラヒドロフラン、ジエチルエーテル、1,2−ジメトキシエタン、1,4−ジオキサン等のエーテル系溶媒;酢酸エチル、ギ酸エチル等のエステル系溶媒;メタノール、エタノール、イソプロピルアルコール、tert−ブチルアルコール、エチレングリコール等のアルコール系溶媒;アセトン、メチルエチルケトン等のケトン系溶媒;N、N−ジメチルホルムアミド、N−メチルピロリドン、N、N−ジメチルアセトアミド等のアミド系溶媒;ジメチルスルホキシド等のスルホキシド系溶媒;アセトニトリル、プロピオニトリル等のニトリル系溶媒及び水であり、並びにこれらの均一系及び不均一系混合溶媒等であるがこれらに限定されることはない。これらの不活性溶媒は当業者に公知である種々の反応条件に応じて適宜選択される Examples of the “inert solvent” include aromatic solvents such as benzene, toluene, xylene and pyridine; hydrocarbon solvents such as hexane, pentane and cyclohexane; dichloromethane, chloroform, 1,2-dichloroethane, carbon tetrachloride and the like. Halogenated hydrocarbon solvents; ether solvents such as tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, 1,4-dioxane; ester solvents such as ethyl acetate and ethyl formate; methanol, ethanol, isopropyl alcohol, tert- Alcohol solvents such as butyl alcohol and ethylene glycol; ketone solvents such as acetone and methyl ethyl ketone; amide solvents such as N, N-dimethylformamide, N-methylpyrrolidone and N, N-dimethylacetamide; sulfoxides such as dimethyl sulfoxide De solvents; acetonitrile, nitriles and water, such as propionitrile, and never is a these homogeneous and heterogeneous mixed solvents is not limited thereto. These inert solvents are appropriately selected according to various reaction conditions known to those skilled in the art.
「塩基」とは例えば、水素化リチウム、水素化ナトリウム、水素化カリウム、水素化カルシウム等のアルカリ金属又はアルカリ土類金属の水素化物;リチウムアミド、ナトリウムアミド、リチウムジイソプロピルアミド、リチウムジシクロヘキシルアミド、リチウムヘキサメチルジシラジド、ナトリウムヘキサメチルジシラジド、カリウムヘキサメチルジシラジド等のアルカリ金属又はアルカリ土類金属のアミド;ナトリウムメトキシド、ナトリウムエトキシド、カリウム tert−ブトキシド等のアルカリ金属又はアルカリ土類金属の低級アルコキシド;ブチルリチウム、sec−ブチルリチウム、tert−ブチルリチウム、メチルリチウム等のアルキルリチウム;水酸化ナトリウム、水酸化カリウム、水酸化リチウム、水酸化バリウム等のアルカリ金属又はアルカリ土類金属の水酸化物;炭酸ナトリウム、炭酸カリウム、炭酸セシウム等のアルカリ金属又はアルカリ土類金属の炭酸塩;炭酸水素ナトリウム、炭酸水素カリウム等のアルカリ金属又はアルカリ土類金属の炭酸水素塩;トリエチルアミン、N−メチルモルホリン、N,N−ジイソプロピルエチルアミン、1,8−ジアザビシクロ[5.4.0]ウンデカ−7−エン(DBU)、1,5−ジアザビシクロ[4.3.0]ノン−5−エン(DBN)、N,N−ジメチルアニリン等のアミン;ピリジン、イミダゾール、2,6−ルチジン等の塩基性複素環化合物等であるがこれらに限定されることはない。これらの塩基は当業者に公知である種々の反応条件に応じて適宜選択される。 Examples of the “base” include hydrides of alkali metals or alkaline earth metals such as lithium hydride, sodium hydride, potassium hydride, calcium hydride; lithium amide, sodium amide, lithium diisopropylamide, lithium dicyclohexylamide, lithium Alkali metal or alkaline earth metal amides such as hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide; alkali metals such as sodium methoxide, sodium ethoxide, potassium tert-butoxide or alkaline earth Lower metal alkoxides; alkyl lithiums such as butyl lithium, sec-butyl lithium, tert-butyl lithium, methyl lithium; sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide Alkali metal or alkaline earth metal hydroxide such as sodium carbonate, potassium carbonate, cesium carbonate or other alkali metal or alkaline earth metal carbonate; Sodium hydrogen carbonate, potassium hydrogen carbonate or other alkali metal or alkaline earth Metal bicarbonate; triethylamine, N-methylmorpholine, N, N-diisopropylethylamine, 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), 1,5-diazabicyclo [4.3 0.0] amines such as non-5-ene (DBN) and N, N-dimethylaniline; basic heterocyclic compounds such as pyridine, imidazole and 2,6-lutidine, but not limited thereto. . These bases are appropriately selected according to various reaction conditions known to those skilled in the art.
「酸」とは例えば、塩酸、臭化水素酸、硫酸、硝酸、リン酸等の無機酸及びp−トルエンスルホン酸、メタンスルホン酸、トリフルオロ酢酸、ギ酸、酢酸等の有機酸であるがこれらに限定されることはない。これらの酸は当業者に公知である種々の反応条件に応じて適宜選択される。 Examples of the “acid” include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid, and organic acids such as p-toluenesulfonic acid, methanesulfonic acid, trifluoroacetic acid, formic acid, and acetic acid. It is not limited to. These acids are appropriately selected according to various reaction conditions known to those skilled in the art.
〔製造法1〕
本発明化合物(I)は、スキーム1に示す方法によって製造することができる。
(スキーム1)
[Production method 1]
The compound (I) of the present invention can be produced by the method shown in Scheme 1.
(Scheme 1)
式中、Lvは、メトキシ基, エトキシ基, メトキシメチルアミノ基等の脱離基を示す。
P1は、メトキシカルボニル基、エトキシカルボニル基、tert−ブトキシカルボニル基、ベンジルオキシカルボニル基、アセチル基又はベンジル基等のアミノ基の保護基を示す[プロテクティブ グループズ イン オーガニック シンセシス(Protective Groups in Organic Synthesis, 第4版、2006年, T. W. グリーンら著, Wiley INC.)参照]。
X1は、ハロゲン原子、トリフルオロメタンスルホニルオキシ基等の脱離基を示す。
In the formula, Lv represents a leaving group such as a methoxy group, an ethoxy group, or a methoxymethylamino group.
P 1 represents an amino-protecting group such as a methoxycarbonyl group, an ethoxycarbonyl group, a tert-butoxycarbonyl group, a benzyloxycarbonyl group, an acetyl group or a benzyl group [Protective Groups in Organic Synthesis] , 4th Edition, 2006, TW Green et al., Wiley Inc.)].
X 1 represents a leaving group such as a halogen atom or a trifluoromethanesulfonyloxy group.
工程1−1:不活性溶媒中、化合物(1−1)を炭酸セシウム等の塩基存在下、ヨウ化メチル、ヨウ化エチル等のハロゲン化アルキルを用いて、アルキル化することにより、化合物(1−2)を得ることができる。また、不活性溶媒中、トリメチルシリルジアゾメタン等のアルキル剤と作用させることにより、化合物(1−2)を得ることができる。さらに、アルコール溶媒中、硫酸等の酸を作用することにより、化合物(1−2)を得ることができる。もしくは、不活性溶媒中、塩基存在下又は非存在下、メタノール、エタノール等のアルコール類又はメトキシメチルアミン等のアルコキシアミン化合物との脱水縮合反応に供することにより、化合物(1−2)を得ることができる。ここで脱水縮合反応とは、不活性溶媒中、塩基存在下又は非存在下、N,N’−ジシクロヘキシルカルボジイミド、1−エチル−3−(3−ジメチルアミノプロピル)カルボジイミド塩酸塩、ジフェニルホスホリルアジド又はカルボニルジイミダゾール等の縮合剤を用いたエステル化反応又はアミド化反応、或いはクロロ炭酸エチル、クロロ炭酸イソブチル又はピバロイルクロリド等を用いた混合酸無水物経由のエステル化反応又はアミド化反応等を意味する[ペプチド合成の基礎と実験 (1995年, 脇 道典ら著, 丸善株式会社)参照]。ここで縮合剤を用いたエステル化反応又はアミド化反応の際、必要に応じて1−ヒドロキシベンゾトリアゾール等の添加剤を使用することができる。カルボン酸(1−1)は、市販化合物、公知化合物として入手可能である。また、カルボン酸(1−1)は、当業者に公知である種々の有機合成手法を用いて市販化合物又は公知化合物より合成することが可能である。
工程1−2:不活性溶媒中、化合物(1−2)に対し、ナトリウムヘキサメチルジシラジド、リチウムヘキサメチルジシラジド等の塩基存在下、アセトニトリル、プロピオニトリル等のニトリル化合物を作用させることにより、化合物(1−3)を得ることができる。
工程1−3:不活性溶媒中、化合物(1−3)を酢酸等の酸存在下又は非存在下、ヒドラジン水和物と作用させることにより、化合物(1−4)を得ることができる。
工程1−4:不活性溶媒中、化合物(1−4)を炭酸セシウム等の塩基存在下又は非存在下、エチル (2E)-3-エトキシ-2-メチルプロパ-2-エノアート等のアクリル酸エステルと作用させることにより、化合物(1−5)を得ることができる。種々のアクリル酸エステルは市販化合物、公知化合物として入手可能である。また、種々のアクリル酸エステルは、当業者に公知である種々の有機合成手法を用いて市販化合物又は公知化合物より合成することが可能である。
工程1−5:化合物(1−6)のX1がハロゲン原子を示す場合、化合物(1−5)を不活性溶媒中又は無溶媒にて、塩基存在下又は非存在下、塩化チオニル、三塩化リン、五塩化リン、三臭化リン、五臭化リン、オキシ塩化リン等のハロゲン化剤を用いてハロゲン化反応を行うことにより化合物(1−6)を得ることができる。或いは化合物(1−6)のX1がトリフルオロメタンスルホニルオキシ基を示す場合、不活性溶媒中、塩基存在下又は非存在下、化合物(1−5)をトリフルオロメタンスルホニル化剤と反応することにより、化合物(1−6)を得ることができる。ここでトリフルオロメタンスルホニル化剤とは例えば、トリフルオロメタンスルホン酸無水物、N−フェニル−ビス(トリフルオロメタンスルホンイミド)等である[コンプリヘンシブ・オーガニック・トランスフォーメーションズ(Comprehensive Organic Transformations, 1989年, R.C.ラロック著, VCH Publishers, INC.)参照]。
工程1−6:不活性溶媒中、化合物(1−6)のアミノ基の保護基P1を当業者に公知である種々の有機合成手法[プロテクティブ グループズ イン オーガニック シンセシス(Protective Groups in Organic Synthesis, 第4版、2006年, T. W. グリーンら著, Wiley INC.)参照]を用いて除去することにより、アミン化合物(1−7)を得ることができる。
工程1−7:不活性溶媒中、化合物(1−7)に塩基存在下又は非存在下、ピロリジン等のアミン化合物又はメタノール、エタノール等のアルコール化合物を作用させることにより、化合物(1−8)を得ることができる。もしくは不活性溶媒中、塩基存在下又は非存在下、遷移金属触媒存在下、必要に応じて配位子を用いて、化合物(1−7)をアミン化合物、アルコール化合物、有機金属化合物、オレフィン化合物又は末端アルキン化合物とのカップリング反応に供することにより、化合物(1−8)を得ることができる。ここでカップリング反応としては、当業者に公知なカップリング反応の条件が挙げられ、例えば、コンプリヘンシブ・オーガニック・トランスフォーメーションズ(Comprehensive Organic Transformations, 1989年, R.C.ラロック著, VCH Publishers, INC.)等に記載の方法、それに準じた方法又はこれらの方法を組み合わせることにより実施することができる。ここで有機金属化合物として、例えばマグネシウム反応剤、亜鉛反応剤、ホウ素反応剤又はスズ反応剤等が挙げられ、市販化合物、公知化合物又は当業者に公知である種々の有機合成手法を用いて市販化合物又は公知化合物より合成した化合物を用いることができる。ここで、オレフィン化合物及び末端アルキン化合物として、市販化合物、公知化合物又は当業者に公知である種々の有機合成手法を用いて市販化合物又は公知化合物より合成した化合物を用いることができる。ここで遷移金属触媒とは、例えば酢酸パラジウム(II)、塩化パラジウム(II)、ビス(トリフェニルホスフィン)酢酸パラジウム(II)、ビス(トリフェニルホスフィン)塩化パラジウム(II)、トリス(ジベンジリデンアセトン)ジパラジウム(0)、ビス(ジベンジリデンアセトン)パラジウム(0)、テトラキストリフェニルホスフィンパラジウム(0)、塩化[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)、塩化アリルパラジウム(II)、ビス(アセトニトリル)塩化パラジウム(II)、[1,3−ビス(2,6−ジイソプロピルフェニル)イミダゾル−2−イリデン](3−クロロピリジル)パラジウム(II)ジクロリド又は[1,3−ビス(2,6−ジイソプロピルフェニル)イミダゾリデン](3−クロロピリジル)パラジウム(II)ジクロリド、[1,1´−ビス(ジフェニルホスフィノ)フェロセン]パラジウム(II)ジクロリド ジクロロメタン錯体(1:1)、銅粉、塩化銅(I)、臭化銅(I)、ヨウ化銅(I)、酢酸銅(I)等が挙げられる。配位子とは例えばトリフェニルホスフィン、トリブチルホスフィン、トリ(2−フリル)ホスフィン、2,2−ビス(ジフェニルホスフィノ)−1,1−ビナフチル(BINAP)、2−(ジ−tert−ブチルホスフィノ)ビフェニル、1,1−ビス(ジフェニルホスフィノ)フェロセン、1,10−フェナントロリン、N,N’−ジメチルエチレンジアミン又はテトラメチルエチレンジアミン等が挙げられる。
工程1−8:不活性溶媒中、塩基存在下又は非存在下、アミン化合物(1−8)と酸ハライド化合物又はカルボン酸化合物をアミド化反応に供することにより、本発明化合物(I)を得ることができる。酸ハライド化合物又はカルボン酸化合物は、市販の化合物又は公知化合物として入手可能である。また、酸ハライド化合物又はカルボン酸化合物は、当業者に公知である種々の有機合成手法を用いて市販化合物又は公知化合物より合成することが可能である。ここでアミド化反応とは、不活性溶媒中、塩基存在下又は非存在下、N,N’−ジシクロヘキシルカルボジイミド、1−エチル−3−(3−ジメチルアミノプロピル)カルボジイミド塩酸塩、ジフェニルホスホリルアジド又はカルボニルジイミダゾール等の縮合剤を用いたアミド化反応、或いはクロロ炭酸エチル、クロロ炭酸イソブチル又はピバロイルクロリド等を用いた混合酸無水物経由のアミド化反応等を意味する[ペプチド合成の基礎と実験, (1995年, 脇 道典ら著, 丸善株式会社)参照]。ここで縮合剤を用いたアミド化反応の際、必要に応じて1−ヒドロキシベンゾトリアゾール等の添加剤を使用することができる。
工程1−9:前記の工程1−8と同様の手法により、化合物(1−7)を化合物(1−9)に変換することができる。
工程1−10:前記の工程1−7と同様の手法により、化合物(1−9)を本発明化合物(I)に変換することができる。
工程1−11:前記の工程1−7と同様の手法により、化合物(1−6)を化合物(1−10)に変換することができる。
工程1−12:前記の工程1−6と同様の手法により、化合物(1−10)を化合物(1−8)に変換することができる。
Step 1-1: Compound (1) is alkylated with an alkyl halide such as methyl iodide and ethyl iodide in the presence of a base such as cesium carbonate in an inert solvent. -2) can be obtained. Alternatively, compound (1-2) can be obtained by reacting with an alkyl agent such as trimethylsilyldiazomethane in an inert solvent. Furthermore, a compound (1-2) can be obtained by acting an acid such as sulfuric acid in an alcohol solvent. Alternatively, the compound (1-2) is obtained by subjecting it to a dehydration condensation reaction with an alcohol such as methanol or ethanol or an alkoxyamine compound such as methoxymethylamine in the presence or absence of a base in an inert solvent. Can do. Here, the dehydration condensation reaction means N, N′-dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, diphenylphosphoryl azide, or in the presence or absence of a base in an inert solvent. Esterification reaction or amidation reaction using a condensing agent such as carbonyldiimidazole, esterification reaction or amidation reaction via mixed acid anhydride using ethyl chlorocarbonate, isobutyl chlorocarbonate or pivaloyl chloride, etc. Meaning [Refer to Peptide Synthesis Fundamentals and Experiments (1995, written by Michinori Waki et al., Maruzen Corporation)] Here, in the esterification reaction or amidation reaction using a condensing agent, additives such as 1-hydroxybenzotriazole can be used as necessary. Carboxylic acid (1-1) is available as a commercially available compound or a known compound. The carboxylic acid (1-1) can be synthesized from a commercially available compound or a known compound using various organic synthesis methods known to those skilled in the art.
Step 1-2: In an inert solvent, nitrile compounds such as acetonitrile and propionitrile are allowed to act on compound (1-2) in the presence of a base such as sodium hexamethyldisilazide and lithium hexamethyldisilazide. Thus, the compound (1-3) can be obtained.
Step 1-3: Compound (1-4) can be obtained by reacting compound (1-3) with hydrazine hydrate in an inert solvent in the presence or absence of an acid such as acetic acid.
Step 1-4: A compound (1-4) in an inert solvent in the presence or absence of a base such as cesium carbonate and an acrylic ester such as ethyl (2E) -3-ethoxy-2-methylprop-2-enoate To give compound (1-5). Various acrylic esters are available as commercially available compounds and known compounds. Various acrylic esters can be synthesized from commercially available compounds or known compounds using various organic synthesis methods known to those skilled in the art.
Step 1-5: When X 1 of the compound (1-6) represents a halogen atom, the compound (1-5) is thionyl chloride, 3 in the presence or absence of a base in an inert solvent or without solvent. Compound (1-6) can be obtained by conducting a halogenation reaction using a halogenating agent such as phosphorus chloride, phosphorus pentachloride, phosphorus tribromide, phosphorus pentabromide, phosphorus oxychloride and the like. Alternatively, when X 1 of compound (1-6) represents a trifluoromethanesulfonyloxy group, by reacting compound (1-5) with a trifluoromethanesulfonylating agent in an inert solvent in the presence or absence of a base. Compound (1-6) can be obtained. Here, the trifluoromethanesulfonylating agent is, for example, trifluoromethanesulfonic anhydride, N-phenyl-bis (trifluoromethanesulfonimide) or the like [Comprehensive Organic Transformations, 1989, RC RC Laroc, VCH Publishers, INC.)].
Step 1-6: Various protective methods known in the art for protecting the amino group P 1 of the compound (1-6) in an inert solvent [Protective Groups in Organic Synthesis, Protective Groups in Organic Synthesis, 4th edition, 2006, TW Green et al., Wiley INC.)] To obtain the amine compound (1-7).
Step 1-7: Compound (1-8) by reacting compound (1-7) with an amine compound such as pyrrolidine or an alcohol compound such as methanol or ethanol in an inert solvent in the presence or absence of a base. Can be obtained. Alternatively, in an inert solvent, in the presence or absence of a base, in the presence of a transition metal catalyst, and optionally using a ligand, the compound (1-7) is converted into an amine compound, alcohol compound, organometallic compound, olefin compound. Alternatively, the compound (1-8) can be obtained by subjecting it to a coupling reaction with a terminal alkyne compound. Here, examples of the coupling reaction include coupling reaction conditions known to those skilled in the art. For example, Comprehensive Organic Transformations (1989) by RC Larlock, VCH Publishers. , INC.) And the like, a method according to the method, or a combination of these methods. Here, examples of the organometallic compound include a magnesium reactant, a zinc reactant, a boron reactant, a tin reactant, and the like, and are commercially available compounds, known compounds, or commercially available compounds using various organic synthesis techniques known to those skilled in the art. Alternatively, a compound synthesized from a known compound can be used. Here, as the olefin compound and the terminal alkyne compound, a commercially available compound, a known compound or a compound synthesized from a known compound using various organic synthesis methods known to those skilled in the art can be used. Examples of the transition metal catalyst include palladium (II) acetate, palladium (II) chloride, palladium (II) bis (triphenylphosphine) acetate, palladium (II) bis (triphenylphosphine) chloride, tris (dibenzylideneacetone). ) Dipalladium (0), bis (dibenzylideneacetone) palladium (0), tetrakistriphenylphosphine palladium (0), [1,1′-bis (diphenylphosphino) ferrocene] palladium (II), allyl palladium chloride (II), bis (acetonitrile) palladium chloride (II), [1,3-bis (2,6-diisopropylphenyl) imidazol-2-ylidene] (3-chloropyridyl) palladium (II) dichloride or [1,3 -Bis (2,6-diisopropylphenyl) imidazo Den] (3-chloropyridyl) palladium (II) dichloride, [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane complex (1: 1), copper powder, copper (I) chloride, Examples thereof include copper (I) bromide, copper (I) iodide, and copper (I) acetate. Examples of the ligand include triphenylphosphine, tributylphosphine, tri (2-furyl) phosphine, 2,2-bis (diphenylphosphino) -1,1-binaphthyl (BINAP), 2- (di-tert-butylphosphine). Phino) biphenyl, 1,1-bis (diphenylphosphino) ferrocene, 1,10-phenanthroline, N, N′-dimethylethylenediamine or tetramethylethylenediamine.
Step 1-8: The present compound (I) is obtained by subjecting the amine compound (1-8) and an acid halide compound or carboxylic acid compound to an amidation reaction in an inert solvent in the presence or absence of a base. be able to. The acid halide compound or carboxylic acid compound is available as a commercially available compound or a known compound. Moreover, an acid halide compound or a carboxylic acid compound can be synthesized from a commercially available compound or a known compound using various organic synthesis methods known to those skilled in the art. Here, the amidation reaction means N, N′-dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, diphenylphosphoryl azide, or in the presence or absence of a base in an inert solvent. It means an amidation reaction using a condensing agent such as carbonyldiimidazole or an amidation reaction via a mixed acid anhydride using ethyl chlorocarbonate, isobutyl chlorocarbonate or pivaloyl chloride, etc. Experiment, (1995, written by Michinori Waki, Maruzen)]. Here, in the amidation reaction using a condensing agent, an additive such as 1-hydroxybenzotriazole can be used as necessary.
Step 1-9: The compound (1-7) can be converted to a compound (1-9) by the same method as in the above step 1-8.
Step 1-10: The compound (1-9) can be converted to the compound (I) of the present invention by the same method as in the above step 1-7.
Step 1-11: The compound (1-6) can be converted to a compound (1-10) by the same method as in the above step 1-7.
Step 1-12: The compound (1-10) can be converted to a compound (1-8) by the same method as in the above step 1-6.
本発明化合物(I)は、スキーム2に示す方法によって製造することもできる。
(スキーム2)
The compound (I) of the present invention can also be produced by the method shown in Scheme 2.
(Scheme 2)
工程2−1:前記の工程1−1〜工程1-7と同様の手法又は工程1−1〜工程1−5、工程1−11及び工程1−12と同様の手法により、化合物(2−1)を化合物(2−2)に変換することができる。
工程2−2:不活性溶媒中、化合物(2−2)に炭酸カリウムのような塩基存在下又は非存在下、ヨウ化メチル、ヨウ化エチル等のアルキルハライドを作用させることにより、化合物(1−8)を得ることができる。また、化合物(2−2)を種々の還元的アミノ化反応[コンプリヘンシブ・オーガニック・トランスフォーメーションズ(Comprehensive Organic Transformations, 1989年, R.C.ラロック著, VCH Publishers, INC.)参照]により、化合物(1−8)に変換できる。
工程2−3:不活性溶媒中、化合物(2−2)にトリエチルアミンのような塩基存在下又は非存在下、トリフルオロ酢酸エステル、トリフルオロ酢酸無水物等のトリフルオロアセチル化剤を作用させることにより、化合物(2−3)を得ることができる。
工程2−4:
化合物(2−3)を当業者に公知である種々のアルキル化反応[コンプリヘンシブ・オーガニック・トランスフォーメーションズ(Comprehensive Organic Transformations, 1989年, R.C.ラロック著, VCH Publishers, INC.)参照]により、化合物(2−4)に変換することができる。
工程2−5:化合物(2−4)を当業者に公知である種々の加水分解反応[プロテクティブ グループズ イン オーガニック シンセシス(Protective Groups in Organic Synthesis, 第4版、2006年, T. W. グリーンら著, Wiley INC.)参照]により、化合物(1−8)に変換することができる。
工程2−6:前記の工程1−8と同様の手法により、化合物(1−8)を本発明化合物(I)に変換することができる。
Step 2-1: Compound (2) by the same method as in Step 1-1 to Step 1-7 or the same method as in Step 1-1 to Step 1-5, Step 1-11, and Step 1-12 1) can be converted to compound (2-2).
Step 2-2: Compound (1) is reacted with an alkyl halide such as methyl iodide or ethyl iodide in an inert solvent in the presence or absence of a base such as potassium carbonate. -8) can be obtained. In addition, compound (2-2) is subjected to various reductive amination reactions [see Comprehensive Organic Transformations, 1989, RC Larlock, VCH Publishers, Inc.]. Can be converted to compound (1-8).
Step 2-3: Allowing a compound (2-2) to react with a trifluoroacetylating agent such as trifluoroacetic acid ester or trifluoroacetic anhydride in the presence of a base such as triethylamine in an inert solvent. Thus, the compound (2-3) can be obtained.
Step 2-4:
Various alkylation reactions known to those skilled in the art (see Comprehensive Organic Transformations, 1989, RC Larlock, VCH Publishers, Inc.) ] To convert to compound (2-4).
Step 2-5: Various hydrolysis reactions known to those skilled in the art [Protective Groups in Organic Synthesis, 4th edition, 2006, TW Green et al., Wiley INC.)] To convert the compound (1-8).
Step 2-6: The compound (1-8) can be converted to the compound (I) of the present invention by the same method as in the above step 1-8.
本発明化合物(I)は、スキーム3に示す方法によって製造することもできる。
(スキーム3)
The compound (I) of the present invention can also be produced by the method shown in Scheme 3.
(Scheme 3)
式中、X2は、ハロゲン原子を示す。
化合物(1−5)及び化合物(1−8)が、それぞれ、化合物(3−1)及び(3−4)で示される場合、以下の方法にて本発明化合物(I)に変換できる。
工程3−1:不活性溶媒中、化合物(3−1)にN−クロロスクシンイミド、N−ブロモスクシンイミド、N−ヨードスクシンイミド、Selectfluoro(AIR Pruducts and Chemicals商標)等のハロゲン化剤を作用させることにより、化合物(3−2)を得ることができる。
工程3−2:前記の工程1−5〜工程1−12と同様の手法により、化合物(3−2)を化合物(3−3)に変換することができる。
工程3−3:不活性溶媒中、塩基存在下又は非存在下、遷移金属触媒存在下、必要に応じて配位子を用いて、化合物(3-3)を有機金属化合物、オレフィン化合物又は末端アルキン化合物とのカップリング反応に供することにより本発明化合物(I)を製造することができる。ここでカップリング反応としては、当業者に公知なカップリング反応の条件が挙げられ、例えば、コンプリヘンシブ・オーガニック・トランスフォーメーションズ(Comprehensive Organic Transformations, 1989年, R.C.ラロック著, VCH Publishers, INC.)等に記載の方法、それに準じた方法又はこれらの方法を組み合わせることにより実施することができる。ここで有機金属化合物として、例えばマグネシウム反応剤、亜鉛反応剤、ホウ素反応剤又はスズ反応剤等が挙げられ、市販化合物、公知化合物又は当業者に公知である種々の有機合成手法を用いて市販化合物又は公知化合物より合成した化合物を用いることができる。ここで、オレフィン化合物及び末端アルキン化合物として、市販化合物、公知化合物又は当業者に公知である種々の有機合成手法を用いて市販化合物又は公知化合物より合成した化合物を用いることができる。ここで遷移金属触媒とは、例えば酢酸パラジウム(II)、塩化パラジウム(II)、ビス(トリフェニルホスフィン)酢酸パラジウム(II)、ビス(トリフェニルホスフィン)塩化パラジウム(II)、トリス(ジベンジリデンアセトン)ジパラジウム(0)、ビス(ジベンジリデンアセトン)パラジウム(0)、テトラキストリフェニルホスフィンパラジウム(0)、塩化[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)、塩化アリルパラジウム(II)、ビス(アセトニトリル)塩化パラジウム(II)、[1,3−ビス(2,6−ジイソプロピルフェニル)イミダゾル−2−イリデン](3−クロロピリジル)パラジウム(II)ジクロリド又は[1,3−ビス(2,6−ジイソプロピルフェニル)イミダゾリデン](3−クロロピリジル)パラジウム(II)ジクロリド、銅粉、塩化銅(I)、臭化銅(I)、ヨウ化銅(I)、酢酸銅(I)等が挙げられる。配位子とは例えばトリフェニルホスフィン、トリフリルホスフィン、トリブチルホスフィン、2,2−ビス(ジフェニルホスフィノ)−1,1−ビナフチル(BINAP)、2−(ジ−tert−ブチルホスフィノ)ビフェニル、1,1−ビス(ジフェニルホスフィノ)フェロセン、1,10−フェナントロリン、N,N’−ジメチルエチレンジアミン又はテトラメチルエチレンジアミン等が挙げられる。
工程3−4:前記の工程3−1と同様の手法により、化合物(3−4)を化合物(3−5)に変換することができる。
工程3−5:前記の工程1−8と同様の手法により、化合物(3−5)を化合物(3−3)に変換することができる。
In the formula, X 2 represents a halogen atom.
When compound (1-5) and compound (1-8) are represented by compounds (3-1) and (3-4), respectively, they can be converted to the present compound (I) by the following method.
Step 3-1: By reacting a compound (3-1) with a halogenating agent such as N-chlorosuccinimide, N-bromosuccinimide, N-iodosuccinimide, Selectfluor (AIR Products and Chemicals) in an inert solvent. Compound (3-2) can be obtained.
Step 3-2: The compound (3-2) can be converted to a compound (3-3) by the same method as in the above step 1-5 to step 1-12.
Step 3-3: In an inert solvent, in the presence or absence of a base, in the presence of a transition metal catalyst, and optionally using a ligand, the compound (3-3) is converted into an organometallic compound, an olefin compound, or a terminal. The compound (I) of the present invention can be produced by subjecting it to a coupling reaction with an alkyne compound. Here, examples of the coupling reaction include coupling reaction conditions known to those skilled in the art. For example, Comprehensive Organic Transformations (1989) by RC Larlock, VCH Publishers. , INC.) And the like, a method according to the method, or a combination of these methods. Here, examples of the organometallic compound include a magnesium reactant, a zinc reactant, a boron reactant, a tin reactant, and the like, and are commercially available compounds, known compounds, or commercially available compounds using various organic synthesis techniques known to those skilled in the art. Alternatively, a compound synthesized from a known compound can be used. Here, as the olefin compound and the terminal alkyne compound, a commercially available compound, a known compound or a compound synthesized from a known compound using various organic synthesis methods known to those skilled in the art can be used. Examples of the transition metal catalyst include palladium (II) acetate, palladium (II) chloride, palladium (II) bis (triphenylphosphine) acetate, palladium (II) bis (triphenylphosphine) chloride, tris (dibenzylideneacetone). ) Dipalladium (0), bis (dibenzylideneacetone) palladium (0), tetrakistriphenylphosphine palladium (0), [1,1′-bis (diphenylphosphino) ferrocene] palladium (II), allyl palladium chloride (II), bis (acetonitrile) palladium chloride (II), [1,3-bis (2,6-diisopropylphenyl) imidazol-2-ylidene] (3-chloropyridyl) palladium (II) dichloride or [1,3 -Bis (2,6-diisopropylphenyl) imidazo Den] (3-chloropyridyl) palladium (II) dichloride, copper powder, copper chloride (I), copper bromide (I), copper iodide (I), copper (I) acetate, and the like. Examples of the ligand include triphenylphosphine, trifurylphosphine, tributylphosphine, 2,2-bis (diphenylphosphino) -1,1-binaphthyl (BINAP), 2- (di-tert-butylphosphino) biphenyl, Examples include 1,1-bis (diphenylphosphino) ferrocene, 1,10-phenanthroline, N, N′-dimethylethylenediamine, tetramethylethylenediamine, and the like.
Step 3-4: The compound (3-4) can be converted to a compound (3-5) by the same method as in the above step 3-1.
Step 3-5: The compound (3-5) can be converted to a compound (3-3) by the same method as in the above step 1-8.
さらに、工程を実施する順番を変更する、ヒドロキシ基やアミノ基に保護基を施して反応を実施し後の工程で脱保護を実施する、それぞれの工程途中において新たな工程を追加することにより、R1、R2、R3、A1、A2、A3、A4及びYを本発明から逸脱しない範囲内で、当業者に公知である種々の有機合成手法を用いて官能基変換することでも本発明化合物(I)は製造できる。 Furthermore, by changing the order of carrying out the steps, adding a protective step to the hydroxy group or amino group, carrying out the reaction and carrying out the deprotection in a later step, adding a new step in the middle of each step, R 1 , R 2 , R 3 , A 1 , A 2 , A 3 , A 4 and Y are functionally converted using various organic synthesis methods known to those skilled in the art without departing from the present invention. The compound (I) of the present invention can also be produced.
アミノ基の保護基としては、例えば、ペプチド合成時に一般的に用いられるC1-6アシル基(ホルミル、アセチル、プロピオニル等)、C2-12アルコキシカルボニル基(メトキシカルボニル、エトキシカルボニル、tert−ブトキシカルボニル、ベンジルオキシカルボニル、9−フルオレニルメチレノキシカルボニル等)、アリールカルボニル基(ベンゾイル等)、トリチル基、フタロイル基、N,N−ジメチルアミノメチレン基、置換シリル基(トリメチルシリル、トリエチルシリル、ジメチルフェニルシリル、tert−ブチルジメチルシリル、tert−ブチルジエチルシリル等)、C2-6アルケニル基(1−アリル等)が挙げられる。これらの基は、ハロゲン原子、C1-6アルコキシ基(メトキシ、エトキシ、プロポキシ等)、及びニトロ基から選ばれる1つ以上の置換基で置換されていてもよい。
ヒドロキシ基の保護基としては、例えば、C1-6アルキル基(メチル、エチル、tert−ブチル等)、C7-20アラルキル基(ベンジル、トリチル等)、フェニル基、置換シリル基(トリメチルシリル、トリエチルシリル、ジメチルフェニルシリル、tert−ブチルジメチルシリル、tert−ブチルジエチルシリル等)、C2-6アルケニル基(1−アリル等)、C1-6アシル基(ホルミル、アセチル、プロピオニル等)、C2-12アルコキシカルボニル基(メトキシカルボニル、エトキシカルボニル、tert−ブトキシカルボニル、ベンジルオキシカルボニル、9−フルオレニルメチレノキシカルボニル等)、アリールカルボニル基(ベンゾイル等)、2−テトラヒドロピラニル基、2−テトラヒドロフラニル基が挙げられる。これらの基は、ハロゲン原子、C1-6アルコキシ基(メトキシ、エトキシ、プロポキシ等)、ニトロ基から選ばれる1つ以上の置換基で置換されていてもよい。
Examples of amino-protecting groups include C 1-6 acyl groups (formyl, acetyl, propionyl, etc.) and C 2-12 alkoxycarbonyl groups (methoxycarbonyl, ethoxycarbonyl, tert-butoxy) generally used during peptide synthesis. Carbonyl, benzyloxycarbonyl, 9-fluorenylmethylenoxycarbonyl, etc.), arylcarbonyl group (benzoyl, etc.), trityl group, phthaloyl group, N, N-dimethylaminomethylene group, substituted silyl group (trimethylsilyl, triethylsilyl, Dimethylphenylsilyl, tert-butyldimethylsilyl, tert-butyldiethylsilyl, etc.) and C 2-6 alkenyl groups (1-allyl etc.). These groups may be substituted with one or more substituents selected from a halogen atom, a C 1-6 alkoxy group (methoxy, ethoxy, propoxy, etc.), and a nitro group.
Examples of the protecting group for the hydroxy group include C 1-6 alkyl groups (methyl, ethyl, tert-butyl, etc.), C 7-20 aralkyl groups (benzyl, trityl, etc.), phenyl groups, substituted silyl groups (trimethylsilyl, triethyl). Silyl, dimethylphenylsilyl, tert-butyldimethylsilyl, tert-butyldiethylsilyl, etc.), C 2-6 alkenyl group (1-allyl etc.), C 1-6 acyl group (formyl, acetyl, propionyl etc.), C 2 -12 alkoxycarbonyl group (methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethylenoxycarbonyl etc.), arylcarbonyl group (benzoyl etc.), 2-tetrahydropyranyl group, 2- A tetrahydrofuranyl group is mentioned. These groups may be substituted with one or more substituents selected from a halogen atom, a C 1-6 alkoxy group (methoxy, ethoxy, propoxy, etc.), and a nitro group.
本発明化合物の一般的製造法の反応温度とは、−78℃乃至250℃、好ましくは−78℃乃至120℃である。反応時間は5分乃至3日間であり、好ましくは30分間乃至18時間である。本製造方法は常圧下、加圧下、マイクロウエーブ照射下等で実施することができる。 The reaction temperature of the general production method of the compound of the present invention is −78 ° C. to 250 ° C., preferably −78 ° C. to 120 ° C. The reaction time is 5 minutes to 3 days, preferably 30 minutes to 18 hours. This production method can be carried out under normal pressure, under pressure, under microwave irradiation, or the like.
以下、参考例、実施例及び試験例を挙げて本発明を更に詳細に説明するが、これらは本発明を限定するものではなく、また本発明の範囲を逸脱しない範囲で変化させてもよい。
参考例、実施例において、後処理の際の「Phase Separator」とはBiotage社のISOLUTE(商標登録)Phase Separatorである。シリカゲルカラムクロマトグラフィーを使用して精製した際には、メルク「シリカゲル60」、富士シリシア化学「シリカゲルPSQ60」、関東化学「シリカゲル60」、「シリカゲル60N」、富士シリシア化学「クロマトレックスNH」、もしくはパックドカラムBiotage社SNAP Cartridge KP-NH、Biotage社SNAP Cartridge KP-Sil、Biotage社SNAP Cartridge HP-Sil、GRACE社REVELERISTM(Amino, 40 μM)及びGRACE社REVELERISTM(Silica, 40 μM)等を使用した。特に断りがない限り、富士シリシア化学「シリカゲルPSQ60」、関東化学「シリカゲル60N」もしくはパックドカラムを使用した。分取薄層クロマトグラフィー(PTLC)を使用して精製した際にはメルク社シリカゲル60F254、20 cm×20 cmを使用した。超臨界流体クロマトグラフィー(SFC)法による分取精製はWaters社のSFC30を用いた。精製の際の「逆相カラムクロマトグラフィー」(以下、逆相分取HPLCと記載する場合もある)には,Waters Sunfire prep C18 OBD, 5.0 μm, φ30×50 mmまたはYMC-Actus Triart C18, 5.0 μm, φ30×50 mm, Xbridge Prep C18 5.0 μm OBD, φ30×50 mm, Water XSlect CSH C18, 5.0 μm, φ30×50 mmを用いた(以下、逆相分取HPLCと記載する場合もある)。分取条件は下記3条件より適宜選択し、精製を行った。
Hereinafter, the present invention will be described in more detail with reference examples, examples, and test examples. However, the present invention is not limited to these examples, and may be changed without departing from the scope of the present invention.
In the reference examples and examples, “Phase Separator” at the time of post-processing is ISOLUTE (registered trademark) Phase Separator manufactured by Biotage. When purified using silica gel column chromatography, Merck "Silica gel 60", Fuji Silysia Chemical "silica gel PSQ60", Kanto Chemical "silica gel 60", "Silica gel 60N", Fuji Silysia Chemical "Chromatolex NH", or Packed columns Biotage SNAP Cartridge KP-NH, Biotage SNAP Cartridge KP-Sil, Biotage SNAP Cartridge HP-Sil, GRACE REVELERISTM (Amino, 40 μM), GRACE REVELERISTM (Silica, 40 μM) and the like were used. Unless otherwise noted, Fuji Silysia Chemical "silica gel PSQ60", Kanto Chemical "silica gel 60N" or packed column was used. When purified using preparative thin layer chromatography (PTLC) was used Merck silica gel 60F 254, 20 cm × 20 cm . Water purification SFC30 was used for preparative purification by the supercritical fluid chromatography (SFC) method. For “reverse phase column chromatography” (hereinafter sometimes referred to as reverse phase preparative HPLC) during purification, Waters Sunfire prep C18 OBD, 5.0 μm, φ30 × 50 mm or YMC-Actus Triart C18, 5.0 μm, φ30 × 50 mm, Xbridge Prep C18 5.0 μm OBD, φ30 × 50 mm, Water XSlect CSH C18, 5.0 μm, φ30 × 50 mm (hereinafter sometimes referred to as reverse phase preparative HPLC). The preparative conditions were appropriately selected from the following three conditions for purification.
分取装置:Agilent 1260 及び Agilent 6130
移動相A:0.1%ギ酸含有水,B:0.1%ギ酸含有アセトニトリル,
流速:50 mL/min
分取条件1:
0.0-0.5 min(A液/B液 = 90/10)
0.5-7.5 min(A液/B液 = 90/10〜20/80)
7.5-7.9 5min(A液/B液 = 20/80)
7.95-8.0 min(A液/B液 = 20/80〜5/95)
8.0-9.0 min(A液/B液 = 5/95)
分取条件2:
0.0-0.5 min(A液/B液 = 95/5)
0.5-7.5 min(A液/B液 = 95/5〜50/50)
7.5-7.95 min(A液/B液 = 50/50)
7.95-8.0 min(A液/B液 = 50/50〜5/95)
8.0-9.0 min(A液/B液 = 5/95)
分取条件3:
0.0-0.5 min(A液/B液 = 80/20)
0.5-7.0 min(A液/B液 = 80/20〜5/95)
7.0-7.45 min(A液/B液 = 5/95)
7.45-7.5 min(A液/B液 = 5/95〜1/99)
7.5-9.0 min(A液/B液 = 1/99)
Preparative equipment: Agilent 1260 and Agilent 6130
Mobile phase A: water containing 0.1% formic acid, B: acetonitrile containing 0.1% formic acid,
Flow rate: 50 mL / min
Preparative condition 1:
0.0-0.5 min (A liquid / B liquid = 90/10)
0.5-7.5 min (A liquid / B liquid = 90/10 ~ 20/80)
7.5-7.9 5min (A liquid / B liquid = 20/80)
7.95-8.0 min (A liquid / B liquid = 20/80 to 5/95)
8.0-9.0 min (A liquid / B liquid = 5/95)
Preparative condition 2:
0.0-0.5 min (A liquid / B liquid = 95/5)
0.5-7.5 min (A liquid / B liquid = 95/5 ~ 50/50)
7.5-7.95 min (A liquid / B liquid = 50/50)
7.95-8.0 min (A liquid / B liquid = 50/50-5/95)
8.0-9.0 min (A liquid / B liquid = 5/95)
Preparative condition 3:
0.0-0.5 min (A liquid / B liquid = 80/20)
0.5-7.0 min (A liquid / B liquid = 80/20-5/95)
7.0-7.45 min (A / B = 5/95)
7.45-7.5 min (A liquid / B liquid = 5/95-1/99)
7.5-9.0 min (A liquid / B liquid = 1/99)
以下の参考例、実施例中記載の各機器データは以下の測定機器で測定した。
NMRスペクトル:日本電子社JNM-ECA600(600 MHz)、日本電子社JNM-ECA500(500 MHz)、Varian社UNITYNOVA300(300 MHz)、Varian社GEMINI2000/200(200 MHz)
MSスペクトル:島津社LCMS-2010EVあるいはmicromass社 Platform LC
以下の参考例、実施例において、高速液体クロマトグラフィーマススペクトル(LCMS)は以下の条件により測定した。
分析条件1
測定機器:micromass社 Platform LC及びAgilent社 Agilent1100
カラム:Waters社 SunFire C18, 2.5 μm, φ4.6×50 mm
イオン化法:電子衝撃イオン化法Electron Spray Ionization:ESI
溶媒:A液;0.1%トリフルオロ酢酸含有水、B液;0.1%トリフルオロ酢酸含有アセトニトリル
検出法:254 nm,流速:1 mL/min
グラジエント:0 min(A液/B液 = 90/10)、0.5 min(A液/B液 = 90/10)、5.5 min(A液/B液 = 20/80)、6.0 min(A液/B液 = 1/99)、6.3 min(A液/B液 = 1/99)
分析条件2(以下、mode H と記載する)
測定機械:Agilent 1290及びAgilent 6130
カラム:Waters Acquity CSH C18, 1.7 μm, φ2.1×50 mm
イオン化法:電子衝撃イオン化法Electron Spray Ionization:ESI
溶媒:A液;0.1%ギ酸含有水、B液;0.1%ギ酸含有アセトニトリル
検出法:254 nm
流速及びグラジエント:0.8 mL/min,0min(A液/B液 = 80/20)→1.2 min(A液/B液 = 50/50),1.0 mL/min →1.38 min(A液/B液 = 3/97).
分析条件3(以下、mode N と記載する)
測定機器、カラム、溶媒、イオン化法、検出法は分析条件2と同じ。
流速及びグラジエント:0.8 mL/min,0 min(A液/B液 = 80/20)→1.2-1.4 min(A液/B液 =1/99).
分析条件4(以下、mode L と記載する)
流速及びグラジエント:0 min(A液/B液 = 70/30)→0.8 min(A液/B液 = 5/95)、1.5 mL/min →1.0-1.4 min(A液/B液 = 1/99)
以下の参考例、実施例において、超臨界流体クロマトグラフィー(SFC)法による分析はWaters社のUPC2を用いた。
以下の参考例、実施例において、化合物名はACD/Name(ACD/Labs 12.01, Advanced Chemistry Development Inc.)により命名した。
Each instrument data described in the following reference examples and examples was measured with the following measuring instruments.
NMR spectrum: JEOL JNM-ECA600 (600 MHz), JEOL JNM-ECA500 (500 MHz), Varian UNITYNOVA300 (300 MHz), Varian GEMINI2000 / 200 (200 MHz)
MS spectrum: Shimadzu LCMS-2010EV or micromass Platform LC
In the following Reference Examples and Examples, high performance liquid chromatography mass spectrum (LCMS) was measured under the following conditions.
Analysis condition 1
Measuring instrument: micromass Platform LC and Agilent Agilent 1100
Column: Waters SunFire C18, 2.5 μm, φ4.6 × 50 mm
Ionization method: Electron Spray Ionization: ESI
Solvent: Solution A; 0.1% trifluoroacetic acid-containing water, Solution B; 0.1% trifluoroacetic acid-containing acetonitrile Detection method: 254 nm, flow rate: 1 mL / min
Gradient: 0 min (A liquid / B liquid = 90/10), 0.5 min (A liquid / B liquid = 90/10), 5.5 min (A liquid / B liquid = 20/80), 6.0 min (A liquid / B solution = 1/99), 6.3 min (A solution / B solution = 1/99)
Analysis condition 2 (hereinafter referred to as mode H)
Measuring machine: Agilent 1290 and Agilent 6130
Column: Waters Acquity CSH C18, 1.7 μm, φ2.1 × 50 mm
Ionization method: Electron Spray Ionization: ESI
Solvent: Solution A; 0.1% formic acid-containing water, Solution B; 0.1% formic acid-containing acetonitrile Detection method: 254 nm
Flow rate and gradient: 0.8 mL / min, 0 min (A liquid / B liquid = 80/20) → 1.2 min (A liquid / B liquid = 50/50), 1.0 mL / min → 1.38 min (A liquid / B liquid = 3/97).
Analysis condition 3 (hereinafter referred to as mode N)
The measurement equipment, column, solvent, ionization method, and detection method are the same as in Analysis Condition 2.
Flow rate and gradient: 0.8 mL / min, 0 min (A liquid / B liquid = 80/20) → 1.2-1.4 min (A liquid / B liquid = 1/99).
Analysis condition 4 (hereinafter referred to as mode L)
Flow rate and gradient: 0 min (A / B solution = 70/30) → 0.8 min (A / B solution = 5/95), 1.5 mL / min → 1.0-1.4 min (A / B solution = 1 / 99)
In the following Reference Examples and Examples, Waters UPC2 was used for analysis by the supercritical fluid chromatography (SFC) method.
In the following Reference Examples and Examples, the compound names were named by ACD / Name (ACD / Labs 12.01, Advanced Chemistry Development Inc.).
本参考例、実施例中、以下の用語及び試薬は下記のように表記した。
AcCl(塩化アセチル)、AcOH(酢酸)、Boc(tert-ブトキシカルボニル)、Brine(飽和食塩水)、br s(広幅1重線)、Bu(ブチル)、CDCl3(重水素化クロロホルム)、CD3OD(重水素化メタノール)、CHCl3(クロロホルム)、CMBP(シアノメチレントリブチルホスホラン)、CO2(二酸化炭素)、cPr(シクロプロピル)、Cs2CO3(炭酸セシウム)、CuI(ヨウ化銅(I))、d(2重線)、dd(2重2重線)、DIPEA(N,N-ジイソプロピルエチルアミン)、DMAP(N,N-ジメチル-4-アミノピリジン)、DMF(N,N-ジメチルホルムアミド)、DMSO(ジメチル スルホキシド)、DMSO-d6(重水素化ジメチルスルホキシド)、dt(2重3重線)、ee(エナンチオマー過剰率)、ESI(エレクトロスプレーイオン化)、Et(エチル)、EtI(ヨウ化エチル)、Et3N(トリエチルアミン)、Et2O(ジエチルエーテル)、EtOAc(酢酸エチル)、EtOH(エタノール)、H(プロトン)、HATU[O-(7-アザ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 ヘキサフルオロホスファート]、HCl(塩化水素)、HMDS(1,1,1,3,3,3-ヘキサメチルジシラザン)、HPLC(高速液体クロマトグラフィー)、Hz(ヘルツ)、IPA(イソプロピルアルコール)、IPE(イソプロピルエーテル)、iPr(イソプロピル)、J(カップリング定数)、K2CO3(炭酸カリウム)、KOH(水酸化カリウム)、LCMS(高速液体クロマトグラフィーマススペクトル)、m(多重線)、M(mol/L)、Me(メチル)、MeCN(アセトニトリル)、MeI(ヨウ化メチル)、MeOH(メタノール)、MHz(メガヘルツ)、MgSO4(無水硫酸マグネシウム)、min(分)、MS(質量分析)、MsCl(塩化メタンスルホニル)、m/z(質量電荷比)、NaHCO3(炭酸水素ナトリウム)、NaHMDS(ヘキサメチルジシラザンナトリウム)、NaOH(水酸化ナトリウム)、NaOMe(ナトリウムメトキシド)、NaOEt(ナトリウムエトキシド)、Na2SO4(無水硫酸ナトリウム)、NCS(N-クロロスクシンイミド)、NH4Cl(塩化アンモニウム)、NH4OH(25〜28%アンモニア水)、NIS(N-ヨードスクシンイミド)、NMR(核磁気共鳴分光法)、PdCl2(PPh3)2[ビス(トリフェニルホスフィン)パラジウム(II) 二塩化物]、PdCl2(dppf)・CH2Cl2{[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(1:1)}、Pd2(dba)3[トリス(ジベンジリデンアセトン)ジパラジウム(0)]、Ph(フェニル)、POCl3(オキシ塩化リン)、PPh3(トリフェニルホスフィン)、Pr(プロピル)、q(4重線)、s(1重線)、SFC(超臨界流体クロマトグラフィー)、t(3重線)、TBAF(テトラブチルアンモニウムフルオリド)、TBDPSCl(tert-ブチルジフェニルクロロシラン)、td(3重2重線)、TFA(トリフルオロ酢酸)、TFP[トリ(2-フリル)ホスフィン]、THF(テトラヒドロフラン)、tR(保持時間)、v/v(容量/容量)、δ[テトラメチルシランからの低磁場の度合い(百万分率)]。
In the present Reference Examples and Examples, the following terms and reagents are expressed as follows.
AcCl (acetyl chloride), AcOH (acetic acid), Boc (tert-butoxycarbonyl), Brine (saturated saline), br s (wide singlet), Bu (butyl), CDCl 3 (deuterated chloroform), CD 3 OD (deuterated methanol), CHCl 3 (chloroform), CMBP (cyanomethylenetributylphosphorane), CO 2 (carbon dioxide), cPr (cyclopropyl), Cs 2 CO 3 (cesium carbonate), CuI (iodide) Copper (I)), d (double wire), dd (double double wire), DIPEA (N, N-diisopropylethylamine), DMAP (N, N-dimethyl-4-aminopyridine), DMF (N, N-dimethylformamide), DMSO (dimethyl sulfoxide), DMSO-d 6 (deuterated dimethyl sulfoxide), dt (double triplet), ee (enantiomeric excess), ESI (electrospray ionization), Et (ethyl) ), EtI (ethyl iodide), Et 3 N (triethylamine), Et 2 O ( Ethyl ether), EtOAc (ethyl acetate), EtOH (ethanol), H (proton), HATU [O- (7-azabenzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium Hexafluorophosphate], HCl (hydrogen chloride), HMDS (1,1,1,3,3,3-hexamethyldisilazane), HPLC (high performance liquid chromatography), Hz (hertz), IPA (isopropyl alcohol) , IPE (isopropyl ether), iPr (isopropyl), J (coupling constant), K 2 CO 3 (potassium carbonate), KOH (potassium hydroxide), LCMS (high performance liquid chromatography mass spectrum), m (multiple line) , M (mol / L), Me (methyl), MeCN (acetonitrile), MeI (methyl iodide), MeOH (methanol), MHz (megahertz), MgSO 4 (anhydrous magnesium sulfate), min (min), MS ( Mass spectrometry), MsCl (meta chloride) Sulfonyl), m / z (mass-to-charge ratio), NaHCO 3 (sodium bicarbonate), NaHMDS (sodium hexamethyldisilazane), NaOH (sodium hydroxide), NaOMe (sodium methoxide), NaOEt (sodium ethoxide) , Na 2 SO 4 (anhydrous sodium sulfate), NCS (N-chlorosuccinimide), NH 4 Cl (ammonium chloride), NH 4 OH (25-28% aqueous ammonia), NIS (N-iodosuccinimide), NMR (nuclear Magnetic resonance spectroscopy), PdCl 2 (PPh 3 ) 2 [bis (triphenylphosphine) palladium (II) dichloride], PdCl 2 (dppf) · CH 2 Cl 2 {[1,1'-bis (diphenylphos Fino) ferrocene] palladium (II) dichloride dichloromethane complex (1: 1)}, Pd 2 (dba) 3 [tris (dibenzylideneacetone) dipalladium (0)], Ph (phenyl), POCl 3 (phosphorus oxychloride) , PPh 3 (triphenylphosphine), Pr (flop Pill), q (quadruplex), s (singlestrand), SFC (supercritical fluid chromatography), t (triple), TBAF (tetrabutylammonium fluoride), TBDPSCl (tert-butyldiphenylchlorosilane) , Td (triple duplex), TFA (trifluoroacetic acid), TFP [tri (2-furyl) phosphine], THF (tetrahydrofuran), t R (retention time), v / v (volume / volume), δ [Degree of low magnetic field from tetramethylsilane (parts per million)].
参考例1:1-メチル-4-[(メチルスルホニル)アミノ]-1H-ピラゾール-5-カルボン酸の合成
(1)メチル 4-アミノ-1-メチル-1H-ピラゾール-5-カルボキシラート(100 mg)のCHCl3(2.0 mL)溶液に、氷冷下、Et3N(0.90 mL)及びMsCl(0.15 mL)を加え、0 ℃で10分間攪拌した。反応溶液を減圧下濃縮し、これにEtOH(2.0 mL)及び20% NaOEt/EtOH溶液(2.2 mL)を加え、室温で15分間攪拌した。反応溶液に1 M HCl水溶液、CHCl3を加え、分液操作を行った。有機層をPhase Separatorにてろ過後、ろ液を減圧下濃縮した。得られた残渣を逆相分取HPLCで精製することにより、エチル 1-メチル-4-[(メチルスルホニル)アミノ]-1H-ピラゾール-5-カルボキシレート(120 mg, 無色油状物)を得た。
(2)参考例(1)で得られた化合物(110 mg)のEtOH(2.0 mL)溶液に1 M 水酸化ナトリウム水溶液(0.9 mL)を加え、室温で18時間撹拌した。反応液に1 M 水酸化ナトリウム水溶液(0.9 mL)を加え、室温で4時間撹拌した。反応溶液に1 M HCl水溶液、CHCl3を加え分液操作を行った。有機層をPhase Separatorにてろ過後、ろ液を減圧下濃縮することにより、表題化合物(86 mg, 白色結晶)を得た。
1H NMR (600 MHz, DMSO-d6, δ): 2.99 (s, 3H), 4.01 (s, 3H), 7.48 (s, 1H), 8.69 (br s, 1H), 13.90 (br s, 1H).
LCMS (ESI) m/z 220 [M+H]+, tR = 0.73 min, mode H.
Reference Example 1: Synthesis of 1-methyl-4-[(methylsulfonyl) amino] -1H-pyrazole-5-carboxylic acid (1) Methyl 4-amino-1-methyl-1H-pyrazole-5-carboxylate (100 mg) in CHCl 3 (2.0 mL) was added with Et 3 N (0.90 mL) and MsCl (0.15 mL) under ice-cooling, and the mixture was stirred at 0 ° C. for 10 minutes. The reaction solution was concentrated under reduced pressure, EtOH (2.0 mL) and 20% NaOEt / EtOH solution (2.2 mL) were added thereto, and the mixture was stirred at room temperature for 15 minutes. 1 M HCl aqueous solution and CHCl 3 were added to the reaction solution, and liquid separation operation was performed. The organic layer was filtered through a phase separator, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by reverse phase preparative HPLC to give ethyl 1-methyl-4-[(methylsulfonyl) amino] -1H-pyrazole-5-carboxylate (120 mg, colorless oil) .
(2) To a solution of the compound (110 mg) obtained in Reference Example (1) in EtOH (2.0 mL) was added 1 M aqueous sodium hydroxide solution (0.9 mL), and the mixture was stirred at room temperature for 18 hours. To the reaction solution was added 1 M aqueous sodium hydroxide solution (0.9 mL), and the mixture was stirred at room temperature for 4 hours. A 1 M HCl aqueous solution and CHCl 3 were added to the reaction solution to carry out a liquid separation operation. The organic layer was filtered through a phase separator, and the filtrate was concentrated under reduced pressure to give the title compound (86 mg, white crystals).
1 H NMR (600 MHz, DMSO-d 6 , δ): 2.99 (s, 3H), 4.01 (s, 3H), 7.48 (s, 1H), 8.69 (br s, 1H), 13.90 (br s, 1H ).
LCMS (ESI) m / z 220 [M + H] + , t R = 0.73 min, mode H.
参考例2:1-メチル-4-[(メチルスルホニル)アミノ]-1H-ピラゾール-3-カルボン酸
参考例1と同様の手法を用いて、メチル 4-アミノ-1-メチル-1H-ピラゾール-3-カルボキシラート(100 mg)より表題化合物(45 mg, 白色結晶)を得た。
1H NMR (600 MHz, DMSO-d6, δ): 2.98 (s, 3H), 3.87 (s, 3H), 7.78 (s, 1H), 8.61 (br s, 1H), 13.02 (br s, 1H).
LCMS (ESI) m/z 218 [M-H]-, tR = 0.55 min, mode H.
Reference Example 2: 1-methyl-4-[(methylsulfonyl) amino] -1H-pyrazole-3-carboxylic acid Using the same procedure as in Reference Example 1, methyl 4-amino-1-methyl-1H-pyrazole- The title compound (45 mg, white crystals) was obtained from 3-carboxylate (100 mg).
1 H NMR (600 MHz, DMSO-d 6 , δ): 2.98 (s, 3H), 3.87 (s, 3H), 7.78 (s, 1H), 8.61 (br s, 1H), 13.02 (br s, 1H ).
LCMS (ESI) m / z 218 [MH] - , t R = 0.55 min, mode H.
参考例3:3-クロロ-5-メチル-2-[(メチルスルホニル)アミノ]安息香酸の合成
5-メチル-2-[(メチルスルホニル)アミノ]安息香酸(100 mg)のDMF(1.0 mL)溶液に、NCS(76 mg)を加え、室温で17時間攪拌した。反応液を逆相分取HPLCで精製し、表題化合物(34 mg, 白色結晶)を得た。
1H NMR (600 MHz, DMSO-d6, δ): 2.33 (s, 3H), 3.02 (s, 3H), 7.53 (d, J = 1.7 Hz, 1H), 7.57 (d, J = 1.2 Hz, 1H), 9.43 (br s, 1H), 13.28 (br s, 1H).
LCMS (ESI) m/z 262 [M-H]- , tR = 0.70 min, mode N.
Reference Example 3: Synthesis of 3-chloro-5-methyl-2-[(methylsulfonyl) amino] benzoic acid
NCS (76 mg) was added to a DMF (1.0 mL) solution of 5-methyl-2-[(methylsulfonyl) amino] benzoic acid (100 mg), and the mixture was stirred at room temperature for 17 hours. The reaction solution was purified by reverse phase preparative HPLC to give the title compound (34 mg, white crystals).
1 H NMR (600 MHz, DMSO-d 6 , δ): 2.33 (s, 3H), 3.02 (s, 3H), 7.53 (d, J = 1.7 Hz, 1H), 7.57 (d, J = 1.2 Hz, 1H), 9.43 (br s, 1H), 13.28 (br s, 1H).
LCMS (ESI) m / z 262 [MH] - , t R = 0.70 min, mode N.
参考例4:1-{[(ベンジルオキシ)カルボニル]アミノ}-2,3-ジヒドロ-1H-インデン-1-カルボン酸の合成
(1)シアン化カリウム(4.93 g)、炭酸アンモニウム(36.3 g)の水(50 mL)溶液に1-インダノン(5.00 g)のMeOH(50 mL)溶液を滴下し、60 ℃にて24時間攪拌した。反応液を室温まで冷却後、反応液に水を加え、攪拌した。生じた固体をろ取して、減圧下乾燥し、2',3'-ジヒドロ-2H,5H-スピロ[イミダゾリジン-4,1'-インデン]-2,5-ジオン(6.47 g, 無色固体)を得た。
1H NMR (600 MHz, DMSO-d6, δ): 2.12-2.18 (m, 1H), 2.50-2.56 (m, 1H), 2.95-3.05 (m, 2H), 7.15 (d, J = 7.4 Hz, 1H), 7.23-7.27 (m, 1H), 7.29-7.33 (m, 2H), 8.41 (s, 1H), 10.74 (br s, 1H).
LCMS (ESI) m/z 201 [M-H]- , tR = 0.50 min, mode N.
(2)参考例4(1)で得られた化合物(6.47 g)を5 M NaOH水溶液(40 mL)に溶解し、加熱還流下、2日間攪拌した。反応液を室温に冷却後、NaOH(3.20 g)の水(20 mL)溶液を加え、加熱還流下、8時間攪拌した。反応液を室温に冷却後、水(60 mL)、THF(120 mL)を加え、氷冷下、クロロギ酸 ベンジルエステル(9.00 mL)を滴下した。反応液を室温にて16時間攪拌後、氷冷下、クロロギ酸 ベンジルエステル(3.00 mL)を滴下し、室温にて4時間攪拌した。反応液を減圧下濃縮して得た溶液をEtOAcにて3回抽出した。水層に氷冷下、濃塩酸を加えて酸性にした後、水層をCHCl3にて3回抽出した。有機層をPhase Separatorにてろ過した。ろ液を減圧下濃縮し、表題化合物(6.20 g, 無色固体)を得た。
1H NMR (600 MHz, DMSO-d6, δ): 2.14-2.22 (m, 1H), 2.78-2.86 (m, 1H), 2.92-2.97 (m, 2H), 5.03 (s, 2H), 7.16-7.21 (m, 1H), 7.24-7.27 (m, 2H), 7.29-7.39 (m, 5H), 7.45 (d, J = 7.8 Hz, 1H), 8.01 (s, 1H), 12.54 (br s, 1H).
LCMS (ESI) m/z 310 [M-H]- , tR = 0.95 min, mode N.
Reference Example 4: Synthesis of 1-{[(benzyloxy) carbonyl] amino} -2,3-dihydro-1H-indene-1-carboxylic acid (1) Potassium cyanide (4.93 g), ammonium carbonate (36.3 g) in water A solution of 1-indanone (5.00 g) in MeOH (50 mL) was added dropwise to the (50 mL) solution, and the mixture was stirred at 60 ° C. for 24 hours. After cooling the reaction solution to room temperature, water was added to the reaction solution and stirred. The resulting solid was collected by filtration, dried under reduced pressure, and 2 ', 3'-dihydro-2H, 5H-spiro [imidazolidine-4,1'-indene] -2,5-dione (6.47 g, colorless solid) )
1 H NMR (600 MHz, DMSO-d 6 , δ): 2.12-2.18 (m, 1H), 2.50-2.56 (m, 1H), 2.95-3.05 (m, 2H), 7.15 (d, J = 7.4 Hz , 1H), 7.23-7.27 (m, 1H), 7.29-7.33 (m, 2H), 8.41 (s, 1H), 10.74 (br s, 1H).
LCMS (ESI) m / z 201 [MH] - , t R = 0.50 min, mode N.
(2) The compound (6.47 g) obtained in Reference Example 4 (1) was dissolved in 5 M NaOH aqueous solution (40 mL), and stirred for 2 days while heating under reflux. After cooling the reaction solution to room temperature, a solution of NaOH (3.20 g) in water (20 mL) was added, and the mixture was stirred for 8 hours under reflux with heating. After cooling the reaction solution to room temperature, water (60 mL) and THF (120 mL) were added, and chloroformic acid benzyl ester (9.00 mL) was added dropwise under ice cooling. After stirring the reaction solution at room temperature for 16 hours, benzyl chloroformate (3.00 mL) was added dropwise under ice cooling, and the mixture was stirred at room temperature for 4 hours. The solution obtained by concentrating the reaction solution under reduced pressure was extracted three times with EtOAc. The aqueous layer was acidified with concentrated hydrochloric acid under ice-cooling, and the aqueous layer was extracted 3 times with CHCl 3 . The organic layer was filtered with a Phase Separator. The filtrate was concentrated under reduced pressure to obtain the title compound (6.20 g, colorless solid).
1 H NMR (600 MHz, DMSO-d 6 , δ): 2.14-2.22 (m, 1H), 2.78-2.86 (m, 1H), 2.92-2.97 (m, 2H), 5.03 (s, 2H), 7.16 -7.21 (m, 1H), 7.24-7.27 (m, 2H), 7.29-7.39 (m, 5H), 7.45 (d, J = 7.8 Hz, 1H), 8.01 (s, 1H), 12.54 (br s, 1H).
LCMS (ESI) m / z 310 [MH] - , t R = 0.95 min, mode N.
参考例5:1-{[(ベンジルオキシ)カルボニル]アミノ}-6-メチル-2,3-ジヒドロ-1H-インデン-1-カルボン酸の合成
参考例4と同様の手法を用いて、6-メチル-1-インダノン(200 mg)より表題化合物(165 mg, 淡黄色固体)を得た。
1H NMR (600 MHz, DMSO-d6,δ): 2.16 (dt, J = 12.7, 7.3 Hz, 1H), 2.27 (s, 3H), 2.80-2.86 (m, 1H), 2.87-2.91 (m, 2H), 5.00-5.07 (m, 2H), 7.07 (d, J = 7.4 Hz, 1H), 7.13 (d, J = 7.4 Hz, 1H), 7.25 (br s, 1H), 7.28-7.33 (m, 2H), 7.36 (d, J = 4.5 Hz, 4H), 7.96 (br s, 1H).
LCMS (ESI) m/z 324 [M-H]- , tR = 1.02 min, mode N.
Reference Example 5: Synthesis of 1-{[(benzyloxy) carbonyl] amino} -6-methyl-2,3-dihydro-1H-indene-1-carboxylic acid In the same manner as in Reference Example 4, 6- The title compound (165 mg, pale yellow solid) was obtained from methyl-1-indanone (200 mg).
1 H NMR (600 MHz, DMSO-d 6 , δ): 2.16 (dt, J = 12.7, 7.3 Hz, 1H), 2.27 (s, 3H), 2.80-2.86 (m, 1H), 2.87-2.91 (m , 2H), 5.00-5.07 (m, 2H), 7.07 (d, J = 7.4 Hz, 1H), 7.13 (d, J = 7.4 Hz, 1H), 7.25 (br s, 1H), 7.28-7.33 (m , 2H), 7.36 (d, J = 4.5 Hz, 4H), 7.96 (br s, 1H).
LCMS (ESI) m / z 324 [MH] - , t R = 1.02 min, mode N.
参考例6:2-(tert-ブトキシカルボニル)-1-[2-(エチルスルホニル)エチル]-2,3-ジヒドロ-1H-イソインドール-1-カルボン酸の合成
(1)2-tert-ブチル 1-メチル イソインドリン-1,2-ジカルボキシラート(100 mg)のTHF(1.5 mL)溶液に-78 ℃にて1.9 M NaHMDS/THF溶液(0.25 mL)を滴下し、同温にて10分間攪拌した。反応液に1-クロロ-2-(エチルスルホニル)エタン(92 μL)を滴下し、同温にて30分間攪拌後、室温に昇温して2時間攪拌した。反応液に水を加え、CHCl3を加えて分液した。有機層を減圧下濃縮し、得られた残渣をOH型シリカゲルカラムクロマトグラフィー (移動相:ヘキサン/EtOAc = 90/10〜0/100; v/v)にて精製し、2-tert-ブチル 1-メチル 1-[2-(エチルスルホニル)エチル]-1,3-ジヒドロ-2H-イソインドール-1,2-ジカルボキシラート(131 mg, 無色油状物)を得た。
LCMS (ESI) m/z 420 [M+Na]+, tR = 0.95 min, mode N.
(2)参考例6(1)で得られた化合物(115 mg)の1,4-ジオキサン/水混合溶液(4.0 mL, 3/1; v/v)に水酸化リチウム1水和物(48 mg)を加え、加熱還流下、3時間攪拌した。反応液を室温まで冷却後、1 M HCl水溶液を滴下し、pHを3-4にした後、反応液をEtOAcにて抽出した。有機層を無水硫酸ナトリウムで乾燥してろ過した後、ろ液を減圧下濃縮し、表題化合物(54 mg, 淡黄色固体)を得た。
1H NMR (600 MHz, DMSO-d6, δ): 1.09 (q, J = 7.8 Hz, 3H), 1.42 (s, 6H), 1.46 (s, 3H), 2.20-2.30 (m, 1H), 2.56-2.63 (m, 1H), 2.70-2.79 (m, 1H), 2.88 (td, J = 13.5, 3.9 Hz, 0.6H), 2.96 (td, J = 13.5, 3.9 Hz, 0.4H), 3.01-3.07 (m, 2H), 4.61-4.71 (m, 2H), 5.11 (br s, 1H), 7.26 (d, J = 7.4 Hz, 1H), 7.34-7.43 (m, 3H).
LCMS (ESI) m/z 406 [M+Na]+, tR = 0.80 min, mode N.
Reference Example 6: Synthesis of 2- (tert-butoxycarbonyl) -1- [2- (ethylsulfonyl) ethyl] -2,3-dihydro-1H-isoindole-1-carboxylic acid (1) 2-tert-butyl To a solution of 1-methylisoindoline-1,2-dicarboxylate (100 mg) in THF (1.5 mL), add a 1.9 M NaHMDS / THF solution (0.25 mL) dropwise at -78 ° C and continue at the same temperature for 10 minutes. Stir. 1-Chloro-2- (ethylsulfonyl) ethane (92 μL) was added dropwise to the reaction solution, stirred at the same temperature for 30 minutes, then warmed to room temperature and stirred for 2 hours. Water was added to the reaction solution, and CHCl 3 was added to separate the layers. The organic layer was concentrated under reduced pressure, and the obtained residue was purified by OH-type silica gel column chromatography (mobile phase: hexane / EtOAc = 90 / 10-0 / 100; v / v) to give 2-tert-butyl 1 -Methyl 1- [2- (ethylsulfonyl) ethyl] -1,3-dihydro-2H-isoindole-1,2-dicarboxylate (131 mg, colorless oil) was obtained.
LCMS (ESI) m / z 420 [M + Na] + , t R = 0.95 min, mode N.
(2) Lithium hydroxide monohydrate (48) was added to a 1,4-dioxane / water mixed solution (4.0 mL, 3/1; v / v) of the compound (115 mg) obtained in Reference Example 6 (1). mg) was added, and the mixture was stirred for 3 hours under reflux. The reaction mixture was cooled to room temperature, 1 M aqueous HCl was added dropwise to adjust the pH to 3-4, and the reaction mixture was extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate and filtered, and then the filtrate was concentrated under reduced pressure to obtain the title compound (54 mg, pale yellow solid).
1 H NMR (600 MHz, DMSO-d 6 , δ): 1.09 (q, J = 7.8 Hz, 3H), 1.42 (s, 6H), 1.46 (s, 3H), 2.20-2.30 (m, 1H), 2.56-2.63 (m, 1H), 2.70-2.79 (m, 1H), 2.88 (td, J = 13.5, 3.9 Hz, 0.6H), 2.96 (td, J = 13.5, 3.9 Hz, 0.4H), 3.01- 3.07 (m, 2H), 4.61-4.71 (m, 2H), 5.11 (br s, 1H), 7.26 (d, J = 7.4 Hz, 1H), 7.34-7.43 (m, 3H).
LCMS (ESI) m / z 406 [M + Na] + , t R = 0.80 min, mode N.
参考例7:1-(2-シクロプロピル-2-オキソエチル)-2,3-ジヒドロ-1H-インデン-1-カルボン酸の合成
参考例6と同様の手法を用いて、2,3-ジヒドロ-1H-インデン-1-カルボン酸 メチルエステル(50 mg)及び2-ブロモ-1-シクロプロピルエタン-1-オン(93 μL)より表題化合物(102 mg, 無色固体)を得た。
LCMS (ESI) m/z 245 [M+H]+, tR = 0.88 min, mode N.
Reference Example 7: Synthesis of 1- (2-cyclopropyl-2-oxoethyl) -2,3-dihydro-1H-indene-1-carboxylic acid In the same manner as in Reference Example 6, 2,3-dihydro- The title compound (102 mg, colorless solid) was obtained from 1H-indene-1-carboxylic acid methyl ester (50 mg) and 2-bromo-1-cyclopropylethane-1-one (93 μL).
LCMS (ESI) m / z 245 [M + H] + , t R = 0.88 min, mode N.
参考例8:2-メチル-1-[2-(メチルスルホニル)エチル]-2,3-ジヒドロ-1H-イソインドール-1-カルボン酸の合成
(1)参考例6(1)と同様の手法を用いて、1-メチル 2-tert-ブチル イソインドリン-1,2-ジカルボキシラート(100 mg)、2-ブロモエチル-1-メチルスルホン(100 μL)より2-tert-ブチル 1-メチル 1-(2-(メチルスルホニル)エチル)イソインドリン-1,2-ジカルボキシラート(39.3 mg, 無色油状物)を得た。
LCMS (ESI) m/z 406 [M+Na]+, tR = 0.90 min, mode N.
(2)参考例8(1)で得られた化合物(36 mg)の 1,4-ジオキサン(1 mL)溶液に4 M HCl/1,4-ジオキサン溶液(1 mL) を滴下し、室温にて2時間攪拌した。反応液を減圧下濃縮し、メチル 1-[2-(メチルスルホニル)エチル]-2,3-ジヒドロ-1H-イソインドール-1-カルボキシラート 塩酸塩(39 mg, 淡黄色アモルファス)を得た。
(3)参考例8(2)で得られた化合物(30 mg)のDMF(1 mL)溶液にK2CO3(52 mg)、MeI(12 μL)を加え、室温にて3時間攪拌した。反応液にMeI(12 μL)を加え、室温にて16時間攪拌した。反応液に水を加え、攪拌した後、EtOAcで抽出した。有機層を減圧下濃縮して得られた残渣をOH型シリカゲルカラムクロマトグラフィー (移動相:ヘキサン/EtOAc = 90/10〜0/100; v/v)にて精製し、メチル 1-[2-(メチルスルホニル)エチル]-2-メチル-2,3-ジヒドロ-1H-イソインドール-1-カルボキシラート(6.0 mg, 黄色油状物)を得た。
(4)参考例6(2)と同様の手法を用いて、参考例8(3)で得られた化合物(6.0 mg)より表題化合物(2.5 mg, 淡黄色固体)を得た。
LCMS (ESI) m/z 284 [M+H]+, tR = 0.26 min, mode N.
Reference Example 8: Synthesis of 2-methyl-1- [2- (methylsulfonyl) ethyl] -2,3-dihydro-1H-isoindole-1-carboxylic acid (1) The same procedure as in Reference Example 6 (1) 1-methyl 2-tert-butyl isoindoline-1,2-dicarboxylate (100 mg), 2-bromoethyl-1-methylsulfone (100 μL) to 2-tert-butyl 1-methyl 1-methyl (2- (Methylsulfonyl) ethyl) isoindoline-1,2-dicarboxylate (39.3 mg, colorless oil) was obtained.
LCMS (ESI) m / z 406 [M + Na] + , t R = 0.90 min, mode N.
(2) 4 M HCl / 1,4-dioxane solution (1 mL) was added dropwise to a solution of the compound (36 mg) obtained in Reference Example 8 (1) in 1,4-dioxane (1 mL), and the mixture was brought to room temperature. And stirred for 2 hours. The reaction solution was concentrated under reduced pressure to obtain methyl 1- [2- (methylsulfonyl) ethyl] -2,3-dihydro-1H-isoindole-1-carboxylate hydrochloride (39 mg, pale yellow amorphous).
(3) K 2 CO 3 (52 mg) and MeI (12 μL) were added to a DMF (1 mL) solution of the compound (30 mg) obtained in Reference Example 8 (2) and stirred at room temperature for 3 hours. . MeI (12 μL) was added to the reaction solution, and the mixture was stirred at room temperature for 16 hours. Water was added to the reaction mixture, and the mixture was stirred and extracted with EtOAc. The residue obtained by concentrating the organic layer under reduced pressure was purified by OH-type silica gel column chromatography (mobile phase: hexane / EtOAc = 90 / 10-0 / 100; v / v), and methyl 1- [2- (Methylsulfonyl) ethyl] -2-methyl-2,3-dihydro-1H-isoindole-1-carboxylate (6.0 mg, yellow oil) was obtained.
(4) The title compound (2.5 mg, pale yellow solid) was obtained from the compound (6.0 mg) obtained in Reference Example 8 (3) using the same method as in Reference Example 6 (2).
LCMS (ESI) m / z 284 [M + H] + , t R = 0.26 min, mode N.
参考例9:1-[(1,3-ジオキソ-1,3-ジヒドロ-2H-イソインドル-2-イル)メチル]-2,3-ジヒドロ-1H-インデン-1-カルボン酸の合成
参考例6と同様の手法を用いて、2,3-ジヒドロ-1H-インデン-1-カルボン酸 メチルエステル(100 mg)及びN-(ブロモメチル)フタルイミド(204 mg)より表題化合物(110 mg, 無色固体)を得た。
1H NMR (600 MHz, DMSO-d6, δ): 2.29 (m, 1H), 2.51-2.58 (m, 1H), 2.88-2.99 (m, 2H), 3.67 (dd, J = 13.4, 6.8 Hz, 1H), 3.77 (dd, J = 13.4, 6.8 Hz, 1H), 7.16-7.20 (m, 2H), 7.22 (td, J = 7.2, 1.2 Hz, 1H), 7.26 (d, J = 7.4 Hz, 1H), 7.34 (d, J = 7.4 Hz, 1H), 7.47 (td, J = 7.2, 1.2 Hz, 1H), 7.52 (td, J = 7.2, 1.2 Hz, 1H), 7.73 (dd, J = 7.4, 1.2 Hz, 1H), 8.29 (t, J = 6.2 Hz, 1H).
Reference Example 9: Synthesis of 1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl) methyl] -2,3-dihydro-1H-indene-1-carboxylic acid Reference Example 6 Using the same procedure, the title compound (110 mg, colorless solid) was obtained from 2,3-dihydro-1H-indene-1-carboxylic acid methyl ester (100 mg) and N- (bromomethyl) phthalimide (204 mg). Obtained.
1 H NMR (600 MHz, DMSO-d 6 , δ): 2.29 (m, 1H), 2.51-2.58 (m, 1H), 2.88-2.99 (m, 2H), 3.67 (dd, J = 13.4, 6.8 Hz , 1H), 3.77 (dd, J = 13.4, 6.8 Hz, 1H), 7.16-7.20 (m, 2H), 7.22 (td, J = 7.2, 1.2 Hz, 1H), 7.26 (d, J = 7.4 Hz, 1H), 7.34 (d, J = 7.4 Hz, 1H), 7.47 (td, J = 7.2, 1.2 Hz, 1H), 7.52 (td, J = 7.2, 1.2 Hz, 1H), 7.73 (dd, J = 7.4 , 1.2 Hz, 1H), 8.29 (t, J = 6.2 Hz, 1H).
参考例10:1-{[(ベンジルオキシ)カルボニル]アミノ}-1,2,3,4-テトラヒドロナフタレン-1-カルボン酸の合成
1-アミノ-1,2,3,4-テトラヒドロ-1-ナフタレンカルボン酸 塩酸塩(397 mg)の1 M 水酸化ナトリウム水溶液/THF混合溶液(20 mL, 1/1; v/v)にクロロギ酸 ベンジルエステル(0.37 mL)を加え、室温にて16時間攪拌した。反応液にCHCl3を加えて分液し、水層に1M HCl水溶液を滴下し、酸性にした後、EtOAcにて抽出した。有機層を無水硫酸ナトリウムで乾燥してろ過した後、ろ液を減圧下濃縮し、表題化合物(157 mg, 淡黄色アモルファス)を得た。
1H NMR (600 MHz, DMSO-d6,δ): 1.70-1.78 (m, 1H), 1.81-1.90 (m, 1H), 2.23-2.29 (m, 1H), 2.32-2.40 (m, 1H), 2.60-2.62 (m, 0.2H), 2.71-2.76 (m, 1.8H), 4.49 (d, J = 5.8 Hz, 0.5H), 4.96-5.04 (m, 2H), 5.16 (t, J = 5.8 Hz, 0.5H), 7.07-7.20 (m, 3H), 7.21-7.32 (m, 2H), 7.33-7.37 (m, 3H), 7.48 (d, J = 7.4 Hz, 1H), 7.63 (br s, 1H).
LCMS (ESI) m/z 348 [M+Na]+, tR = 1.04 min, mode N.
Reference Example 10: Synthesis of 1-{[(benzyloxy) carbonyl] amino} -1,2,3,4-tetrahydronaphthalene-1-carboxylic acid
1-Amino-1,2,3,4-tetrahydro-1-naphthalenecarboxylic acid hydrochloride (397 mg) in 1 M aqueous sodium hydroxide / THF (20 mL, 1/1; v / v) Acid benzyl ester (0.37 mL) was added, and the mixture was stirred at room temperature for 16 hours. CHCl 3 was added to the reaction solution for liquid separation, and 1M HCl aqueous solution was added dropwise to the aqueous layer to make it acidic, followed by extraction with EtOAc. The organic layer was dried over anhydrous sodium sulfate and filtered, and then the filtrate was concentrated under reduced pressure to obtain the title compound (157 mg, pale yellow amorphous).
1 H NMR (600 MHz, DMSO-d 6 , δ): 1.70-1.78 (m, 1H), 1.81-1.90 (m, 1H), 2.23-2.29 (m, 1H), 2.32-2.40 (m, 1H) , 2.60-2.62 (m, 0.2H), 2.71-2.76 (m, 1.8H), 4.49 (d, J = 5.8 Hz, 0.5H), 4.96-5.04 (m, 2H), 5.16 (t, J = 5.8 Hz, 0.5H), 7.07-7.20 (m, 3H), 7.21-7.32 (m, 2H), 7.33-7.37 (m, 3H), 7.48 (d, J = 7.4 Hz, 1H), 7.63 (br s, 1H).
LCMS (ESI) m / z 348 [M + Na] + , t R = 1.04 min, mode N.
参考例11:1-{[(ベンジルオキシ)カルボニル]アミノ}-2,3-ジヒドロ-1H-インデン-1-カルボン酸(単一エナンチオマー)の合成
参考例4で得られた化合物(859 mg)をキラルカラムにて分取精製を行い(分取条件:SFC法; カラム:CHIRALPAK AD-H/SFC(ダイセル社商標)、カラムサイズ:5 μm 20 mm×250 mm、移動相:MeOH/CO2 = 30/70 (v/v)、流速:30 mL/min、カラム温度:40 ℃、検出波長:210 nM)、表題化合物(318 mg, 無色アモルファス)を得た。
1H NMR (600 MHz, DMSO-d6, δ): 2.15-2.22 (m, 1H), 2.77-2.85 (m, 1H), 2.90-2.99 (m, 2H), 5.03 (s, 2H), 7.15-7.21 (m, 1H), 7.23-7.27 (m, 2H), 7.28-7.38 (m, 5H), 7.44 (d, J = 7.0 Hz, 1H), 8.00 (br s, 1H), 12.55 (br s, 1H).
LCMS (ESI) m/z 310 [M-H]- , tR = 0.95 min, mode N.
tR = 2.13 min, 分析条件:SFC法; 分析装置:waters社 UPC2; カラム:CHIRALPAK AD-H/SFC(ダイセル社商標)、カラムサイズ:5 μm 4.6 mm×250 mm、移動相:MeOH/CO2 = 40/60 (v/v)、流速:3 mL/min、カラム温度:40 ℃、検出波長:254 nm.
参考例1〜11で得られた化合物の構造式を表1に記載する。
Reference Example 11: Synthesis of 1-{[(benzyloxy) carbonyl] amino} -2,3-dihydro-1H-indene-1-carboxylic acid (single enantiomer) Compound obtained in Reference Example 4 (859 mg) (Preparation conditions: SFC method; column: CHIRALPAK AD-H / SFC (trademark of Daicel), column size: 5 μm 20 mm × 250 mm, mobile phase: MeOH / CO 2 = 30/70 (v / v), flow rate: 30 mL / min, column temperature: 40 ° C., detection wavelength: 210 nM), the title compound (318 mg, colorless amorphous) was obtained.
1 H NMR (600 MHz, DMSO-d 6 , δ): 2.15-2.22 (m, 1H), 2.77-2.85 (m, 1H), 2.90-2.99 (m, 2H), 5.03 (s, 2H), 7.15 -7.21 (m, 1H), 7.23-7.27 (m, 2H), 7.28-7.38 (m, 5H), 7.44 (d, J = 7.0 Hz, 1H), 8.00 (br s, 1H), 12.55 (br s , 1H).
LCMS (ESI) m / z 310 [MH] - , t R = 0.95 min, mode N.
t R = 2.13 min, Analysis conditions: SFC method; Analyzer: waters UPC2; Column: CHIRALPAK AD-H / SFC (trademark of Daicel), column size: 5 μm 4.6 mm × 250 mm, mobile phase: MeOH / CO 2 = 40/60 (v / v), flow rate: 3 mL / min, column temperature: 40 ° C, detection wavelength: 254 nm.
The structural formulas of the compounds obtained in Reference Examples 1 to 11 are shown in Table 1.
実施例1−1:N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}エチル]-5-クロロ-N-メチル-2-[(メチルスルホニル)アミノ]ベンズアミドの合成
工程1−1−1:N-(tert-ブトキシカルボニル)-N-メチル-L-アラニン (25 g) の トルエン/MeOH 混合溶液(125 mL, 3/2; v/v)に、氷冷下、2 M トリメチルシリルジアゾメタン/Et2O溶液 (92 mL) を加え、室温にて1時間攪拌した。反応溶液が透明になるまで反応液に 酢酸を加えた。反応溶液を CHCl3にて希釈し、飽和NaHCO3水溶液にて洗浄した。有機層をMgSO4で乾燥ろ過後、ろ液を減圧下濃縮し、メチル N-(tert-ブトキシカルボニル)-N-メチル-L-アラニナート(27.5 g, 無色油状物)を得た。
工程1−1−2:アセトニトリル(20 mL)のTHF(250 mL)溶液に、-78 ℃にて、1.9 M NaHMDS/THF溶液(200 mL)を加え、-50〜-45 ℃にて20分間攪拌した。再び、-78 ℃に冷却し、工程1−1−1で得られた化合物(27.5 g)の THF(150 mL)溶液を加え、-50〜-45 ℃にて1時間攪拌した。再び、-78 ℃に冷却し、酢酸(22.5 mL)を加え、室温に昇温した。反応液を 飽和NH4Cl水溶液 にあけ、EtOAcにて抽出を行った。その有機層をBrineで洗浄、MgSO4 で乾燥ろ過後、溶媒を濃縮し、tert-ブチル [(2S)-4-シアノ-3-オキソブタン-2-イル](メチル)カルバマート(26.5 g, 褐色油状物)を得た。
工程1−1−3:ヒドラジン1水和物(18.4 mL)及び酢酸(21.6 mL)のEtOH(160 mL)溶液に、氷冷下、工程1−1−2で得られた化合物(26.5 g)のEtOH(100 mL)溶液を加え、室温で2日間攪拌した。反応液を減圧下濃縮後、残渣をCHCl3で希釈し、飽和NaHCO3水溶液、Brineにて洗浄、MgSO4で乾燥ろ過後、ろ液を減圧下濃縮した。得られた残渣をNH型シリカゲルカラムクロマトグラフィー(移動相:CHCl3/MeOH = 100/0〜90/10; v/v)で精製した。得られた化合物をキラルカラムにて分取精製を行い(分取条件:カラム:CHIRALPAK OZ-3(ダイセル商標)、カラムサイズ:20 mm×250 mm、移動相:ヘキサン/IPA = 80/20 (v/v)、流速:14 mL/min)、tert-ブチル [(1S)-1-(5-アミノ-1H-ピラゾール-3-イル)エチル](メチル)カルバマート(18.5 g, 褐色油状物)及び tert-ブチル [(1R)-1-(5-アミノ-1H-ピラゾール-3-イル)エチル](メチル)カルバマート(910 mg)を得た。
tert-ブチル [(1S)-1-(5-アミノ-1H-ピラゾール-3-イル)エチル](メチル)カルバマート:1H NMR (600 MHz, CDCl3, δ): 1.44 (d, J = 7.0 Hz, 3H), 1.48 (s, 9H), 2.65 (s, 3H), 5.36 (br s, 1H), 5.55 (br s, 1H).
LCMS (ESI) m/z 241 [M+H]+, tR = 0.46 min, mode N.
工程1−1−4:工程1−1−3で得られた化合物(1.65 g)のDMF (10 mL)溶液に、エチル エチル (2E)-3-エトキシ-2-メチルプロパ-2-エノアート(1.63 g)、Cs2CO3(6.71 g)を加え、120 ℃にて8時間攪拌した。反応液を水にあけ、CHCl3 にて抽出を行った。その有機層をBrineで洗浄、MgSO4 で乾燥ろ過後、ろ液を減圧下濃縮した。得られた残渣をOH型シリカゲルカラムクロマトグラフィー (移動相:CHCl3/MeOH = 100/0〜90/10; v/v) で精製し、tert-ブチル メチル[(1S)-1-(6-メチル-5-オキソ-4,5-ジヒドロピラゾロ[1,5-a]ピリミジン-2-イル)エチル]カルバマート(1.35 g, 褐色アモルファス)を得た。
1H NMR (600 MHz, CDCl3, δ): 1.49 (s, 9H), 1.51 (d, J = 7.0 Hz, 3H), 2.10 (s, 3H), 2.67 (br s, 3H), 5.28-5.62 (m, 1H), 5.78 (s, 1H), 8.01 (s, 1H), 10.85 (br s, 1H).
LCMS (ESI) m/z 307 [M+H]+, tR = 0.79 min, mode N.
工程1−1−5:工程1−1−4で得られた化合物(600 mg)のCHCl3 (8 mL)溶液に、ピリジン(790 μL)を加えた後、氷冷下、トリフルオロメチルスルホン酸無水物(659 μL)を滴下し、そのまま10分間攪拌した後、室温まで昇温して2時間攪拌した。反応液に 飽和NH4Cl水溶液を加え、CHCl3 にて抽出した。有機層を Phase Separator にてろ過後、ろ液を減圧下濃縮した。得られた残渣をOH型シリカゲルカラムクロマトグラフィー(移動相:ヘキサン/EtOAc = 95/5〜0/100; v/v)にて精製し、2-{(1S)-1-[(tert-ブトキシカルボニル)(メチル)アミノ]エチル}-6-メチルピラゾロ[1,5-a]ピリミジン-5-イル トリフルオロメタンスルホナート(835 mg, 黄色固体)を得た。
1H NMR (600 MHz, CDCl3, δ): 1.46-1.61 (m, 12H), 2.33 (s, 3H), 2.69 (br s, 3H), 5.44-5.79 (m, 1H), 6.50 (s, 1H), 8.54 (s, 1H).
工程1−1−6:工程1−1−5で得られた化合物(707 mg)、(3S)-(-)-3-(ベンジルオキシカルボニルアミノ)-ピロリジン(709 mg)のTHF(8.0 mL)溶液に、Et3N(907 μL)を加え、80 ℃で30分攪拌した。反応液を室温まで冷却後、水を加えて分液、水層をCHCl3にて抽出した。有機層をPhase Separatorにてろ過後、ろ液を減圧下濃縮した。得られた残渣をOH型シリカゲルカラムクロマトグラフィー(移動相:ヘキサン:EtOAc = 95:5〜0:100; v/v)にて精製し、ベンジル [(3S)-1-(2-{(1S)-1-[(tert-ブトキシカルボニル)(メチル)アミノ]エチル}-6-メチルピラゾロ[1,5-a]ピリミジン-5-イル)ピロリジン-3-イル]カルバマート(693 mg, 無色アモルファス)を得た。
1H NMR (600 MHz, CDCl3, δ): 1.49 (s, 9H), 1.53 (d, J = 7.0 Hz, 3H), 1.91-2.00 (m, 1H), 2.18-2.27 (m, 1H), 2.32 (s, 3H), 2.66 (br s, 3H), 3.58 (m, 1H), 3.67-3.75 (m, 1H), 3.76-3.83 (m, 1H), 3.88-3.97 (m, 1H), 4.32-4.40 (m, 1H), 4.92 (br s, 1H), 5.10 (br s, 2H), 5.38-5.71 (m, 1H), 5.98 (s, 1H), 7.29-7.41 (m, 5H), 8.07 (s, 1H).
LCMS (ESI) m/z 509 [M+H]+, tR = 1.13 min, mode N.
工程1−1−7:工程1−1−6で得られた化合物(690 mg)の1,4-ジオキサン(5.0 mL) 溶液に、4 M HCl/1,4-ジオキサン溶液(5.0 mL)を滴下して、室温にて2時間攪拌した。反応液を減圧下濃縮後、減圧下乾燥し、ベンジル [(3S)-1-{6-メチル-2-[(1S)-1-(メチルアミノ)エチル]ピラゾロ[1,5-a]ピリミジン-5-イル}ピロリジン-3-イル]カルバマート(858 mg, 無色アモルファス)を得た。
LCMS (ESI) m/z 409 [M+H]+, tR = 0.52 min, mode N.
工程1−1−8:工程1−1−7で得られた化合物(186 mg)、5-クロロ-2-メタンスルホンアミドベンゼンカルボン酸(116 mg)のDMF (2.0 mL) 溶液に HATU(220 mg)、Et3N (0.325 mL) を加え、室温で30分間撹拌した。反応液を減圧下濃縮、トルエン共沸した。得られた残渣をOH型シリカゲルカラムクロマトグラフィー (移動相:ヘキサン/EtOAc = 90/10〜0:100; v/v)にて精製し、ベンジル [(3S)-1-(2-{(1S)-1-[{5-クロロ-2-[(メチルスルホニル)アミノ]ベンゾイル}(メチル)アミノ]エチル}-6-メチルピラゾロ[1,5-a]ピリミジン-5-イル)ピロリジン-3-イル]カルバマート (186 mg, 無色アモルファス)を得た。
1H NMR (600 MHz, CDCl3, δ): 1.60 (d, J = 7.0 Hz, 1.8H), 1.64 (d, J = 7.0 Hz, 1.2H), 1.92-2.00 (m, 1H), 2.20-2.29 (m, 1H), 2.35 (br s, 1.2H), 2.36 (br s, 1.8H), 2.62 (s, 1.2H), 2.80 (s, 1.8H), 2.95 (s, 1.2H), 3.04 (s, 1.8H), 3.55-3.62 (m, 1H), 3.70-3.77 (m, 1H), 3.77-3.85 (m, 1H), 3.92-3.99 (m, 1H), 4.32-4.40 (m, 1H), 4.88 (q, J = 7.0 Hz, 0.5H), 4.91-4.99 (m, 1H), 5.11 (br s, 2H), 6.00 (s, 0.6H), 6.01 (s, 0.4H), 6.22 (q, J = 7.0 Hz, 0.5H), 7.28-7.40 (m, 5.5H), 7.60 (d, J = 8.7 Hz, 0.6H), 7.68 (d, J = 8.7 Hz, 0.4H), 8.36 (s, 0.5H), 8.39 (dd, J = 8.7, 1.2 Hz, 0.5H), 8.62-8.66 (m, 1H), 9.39 (br s, 0.5H).
LCMS (ESI) m/z 640 [M+H]+, tR = 1.15 min, mode N.
工程1−1−9:工程1−1−8で得られた化合物(21 mg)のMeOH(1.0 mL)溶液に 10% パラジウム-炭素(2 mg)を加え、水素ガス雰囲気下で6時間撹拌した。反応溶液をセライト(登録商標)でろ過、MeOHで洗浄して得られたろ液を減圧下濃縮した。得られた残渣をOH型カラムクロマトグラフィー(移動相:EtOAc〜ヘキサン/MeOH = 9:1; v/v) にて精製し、表題化合物(7.0 mg, 無色固体)を得た。
1H NMR (600 MHz, CDCl3, δ): 1.59 (d, J = 7.0 Hz, 1.8H), 1.64 (d, J = 7.0 Hz, 1.2H), 1.76-1.86 (m, 1H), 2.11-2.22 (m, 1H), 2.37 (s, 1.2H), 2.38 (s, 1.8H), 2.62 (s, 1.2H), 2.81 (s, 1.8H), 2.95 (s, 1.2H), 3.03 (s, 1.8H), 3.46 (dd, J = 10.9, 4.3 Hz, 1H), 3.66-3.78 (m, 2H), 3.88 (dd, J = 10.3, 4.5 Hz, 2H), 4.88 (q, J = 6.6 Hz, 0.6H), 5.98 (s, 0.6H), 5.99 (s, 0.4H), 6.22 (d, J = 7.0 Hz, 0.4H), 7.22-7.32 (m, 1H), 7.32-7.40 (m, 1H), 7.61 (d, J = 8.7 Hz, 0.6H), 7.68 (d, J = 8.7 Hz, 0.4H), 8.34 (s, 0.6H), 8.61 (s, 0.4H).
LCMS (ESI) m/z 506.2 [M+H]+, tR = 0.58 min, mode N.
Example 1-1: N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidin-2-yl} ethyl Synthesis of] -5-chloro-N-methyl-2-[(methylsulfonyl) amino] benzamide
Step 1-1-1: To a toluene / MeOH mixed solution (125 mL, 3/2; v / v) of N- (tert-butoxycarbonyl) -N-methyl-L-alanine (25 g) under ice-cooling , 2 M trimethylsilyldiazomethane / Et 2 O solution (92 mL) was added, and the mixture was stirred at room temperature for 1 hr. Acetic acid was added to the reaction solution until the reaction solution became clear. The reaction solution was diluted with CHCl 3 and washed with saturated aqueous NaHCO 3 solution. The organic layer was dried and filtered with MgSO 4 , and the filtrate was concentrated under reduced pressure to obtain methyl N- (tert-butoxycarbonyl) -N-methyl-L-alaninate (27.5 g, colorless oil).
Step 1-1-2: To a THF (250 mL) solution of acetonitrile (20 mL), a 1.9 M NaHMDS / THF solution (200 mL) is added at -78 ° C, and then at -50 to -45 ° C for 20 minutes. Stir. Again, it cooled to -78 degreeC, the THF (150 mL) solution of the compound (27.5 g) obtained by process 1-1-1 was added, and it stirred at -50--45 degreeC for 1 hour. Again, it cooled to -78 degreeC, the acetic acid (22.5 mL) was added, and it heated up to room temperature. The reaction solution was poured into a saturated aqueous NH 4 Cl solution and extracted with EtOAc. The organic layer was washed with Brine, dried and filtered with MgSO 4 , the solvent was concentrated, and tert-butyl [(2S) -4-cyano-3-oxobutan-2-yl] (methyl) carbamate (26.5 g, brown oil) Product).
Step 1-1-3: Compound (26.5 g) obtained in Step 1-1-2 under ice-cooling in a solution of hydrazine monohydrate (18.4 mL) and acetic acid (21.6 mL) in EtOH (160 mL) Of EtOH (100 mL) was added and stirred at room temperature for 2 days. After the reaction solution was concentrated under reduced pressure, the residue was diluted with CHCl 3 , washed with a saturated aqueous NaHCO 3 solution and Brine, dried and filtered with MgSO 4 , and the filtrate was concentrated under reduced pressure. The obtained residue was purified by NH-type silica gel column chromatography (mobile phase: CHCl 3 / MeOH = 100/0 to 90/10; v / v). The obtained compound was subjected to preparative purification on a chiral column (preparation conditions: column: CHIRALPAK OZ-3 (Daicel Trademark), column size: 20 mm × 250 mm, mobile phase: hexane / IPA = 80/20 (v / v), flow rate: 14 mL / min), tert-butyl [(1S) -1- (5-amino-1H-pyrazol-3-yl) ethyl] (methyl) carbamate (18.5 g, brown oil) and tert-Butyl [(1R) -1- (5-amino-1H-pyrazol-3-yl) ethyl] (methyl) carbamate (910 mg) was obtained.
tert-butyl [(1S) -1- (5-amino-1H-pyrazol-3-yl) ethyl] (methyl) carbamate: 1 H NMR (600 MHz, CDCl 3 , δ): 1.44 (d, J = 7.0 Hz, 3H), 1.48 (s, 9H), 2.65 (s, 3H), 5.36 (br s, 1H), 5.55 (br s, 1H).
LCMS (ESI) m / z 241 [M + H] + , t R = 0.46 min, mode N.
Step 1-1-4: To a solution of the compound obtained in Step 1-1-3 (1.65 g) in DMF (10 mL) was added ethyl ethyl (2E) -3-ethoxy-2-methylprop-2-enoate (1.63). g) and Cs 2 CO 3 (6.71 g) were added, and the mixture was stirred at 120 ° C. for 8 hours. The reaction solution was poured into water and extracted with CHCl 3 . The organic layer was washed with Brine, dried and filtered with MgSO 4 , and the filtrate was concentrated under reduced pressure. The obtained residue was purified by OH-type silica gel column chromatography (mobile phase: CHCl 3 / MeOH = 100/0 to 90/10; v / v), and tert-butyl methyl [(1S) -1- (6- Methyl-5-oxo-4,5-dihydropyrazolo [1,5-a] pyrimidin-2-yl) ethyl] carbamate (1.35 g, brown amorphous) was obtained.
1 H NMR (600 MHz, CDCl 3 , δ): 1.49 (s, 9H), 1.51 (d, J = 7.0 Hz, 3H), 2.10 (s, 3H), 2.67 (br s, 3H), 5.28-5.62 (m, 1H), 5.78 (s, 1H), 8.01 (s, 1H), 10.85 (br s, 1H).
LCMS (ESI) m / z 307 [M + H] + , t R = 0.79 min, mode N.
Step 1-1-5: To a solution of the compound obtained in Step 1-1-4 (600 mg) in CHCl 3 (8 mL), pyridine (790 μL) was added, and then ice-cooled trifluoromethylsulfone. Acid anhydride (659 μL) was added dropwise, and the mixture was stirred as it was for 10 minutes, then warmed to room temperature and stirred for 2 hours. A saturated aqueous NH 4 Cl solution was added to the reaction solution, and the mixture was extracted with CHCl 3 . The organic layer was filtered through a phase separator, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by OH-type silica gel column chromatography (mobile phase: hexane / EtOAc = 95 / 5-0 / 100; v / v) to give 2-{(1S) -1-[(tert-butoxy Carbonyl) (methyl) amino] ethyl} -6-methylpyrazolo [1,5-a] pyrimidin-5-yl trifluoromethanesulfonate (835 mg, yellow solid) was obtained.
1 H NMR (600 MHz, CDCl 3 , δ): 1.46-1.61 (m, 12H), 2.33 (s, 3H), 2.69 (br s, 3H), 5.44-5.79 (m, 1H), 6.50 (s, 1H), 8.54 (s, 1H).
Step 1-1-6: Compound (707 mg) obtained in Step 1-1-5, (3S)-(−)-3- (benzyloxycarbonylamino) -pyrrolidine (709 mg) in THF (8.0 mL) ) Et 3 N (907 μL) was added to the solution and stirred at 80 ° C. for 30 minutes. After cooling the reaction solution to room temperature, water was added to separate the solution, and the aqueous layer was extracted with CHCl 3 . The organic layer was filtered through a phase separator, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by OH-type silica gel column chromatography (mobile phase: hexane: EtOAc = 95: 5 to 0: 100; v / v), and benzyl [(3S) -1- (2-{(1S ) -1-[(tert-Butoxycarbonyl) (methyl) amino] ethyl} -6-methylpyrazolo [1,5-a] pyrimidin-5-yl) pyrrolidin-3-yl] carbamate (693 mg, colorless amorphous) Obtained.
1 H NMR (600 MHz, CDCl 3 , δ): 1.49 (s, 9H), 1.53 (d, J = 7.0 Hz, 3H), 1.91-2.00 (m, 1H), 2.18-2.27 (m, 1H), 2.32 (s, 3H), 2.66 (br s, 3H), 3.58 (m, 1H), 3.67-3.75 (m, 1H), 3.76-3.83 (m, 1H), 3.88-3.97 (m, 1H), 4.32 -4.40 (m, 1H), 4.92 (br s, 1H), 5.10 (br s, 2H), 5.38-5.71 (m, 1H), 5.98 (s, 1H), 7.29-7.41 (m, 5H), 8.07 (s, 1H).
LCMS (ESI) m / z 509 [M + H] + , t R = 1.13 min, mode N.
Step 1-1-7: To a solution of the compound (690 mg) obtained in Step 1-1-6 in 1,4-dioxane (5.0 mL), 4 M HCl / 1,4-dioxane solution (5.0 mL) was added. The solution was added dropwise and stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, dried under reduced pressure, and benzyl [(3S) -1- {6-methyl-2-[(1S) -1- (methylamino) ethyl] pyrazolo [1,5-a] pyrimidine -5-yl} pyrrolidin-3-yl] carbamate (858 mg, colorless amorphous) was obtained.
LCMS (ESI) m / z 409 [M + H] + , t R = 0.52 min, mode N.
Step 1-1-8: To a solution of the compound obtained in Step 1-1-7 (186 mg) and 5-chloro-2-methanesulfonamidobenzenecarboxylic acid (116 mg) in DMF (2.0 mL), HATU (220 mg) and Et 3 N (0.325 mL) were added, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure and azeotroped with toluene. The obtained residue was purified by OH-type silica gel column chromatography (mobile phase: hexane / EtOAc = 90 / 10-0: 100; v / v), and benzyl [(3S) -1- (2-{(1S ) -1-[{5-Chloro-2-[(methylsulfonyl) amino] benzoyl} (methyl) amino] ethyl} -6-methylpyrazolo [1,5-a] pyrimidin-5-yl) pyrrolidin-3-yl ] Carbamate (186 mg, colorless amorphous) was obtained.
1 H NMR (600 MHz, CDCl 3 , δ): 1.60 (d, J = 7.0 Hz, 1.8H), 1.64 (d, J = 7.0 Hz, 1.2H), 1.92-2.00 (m, 1H), 2.20- 2.29 (m, 1H), 2.35 (br s, 1.2H), 2.36 (br s, 1.8H), 2.62 (s, 1.2H), 2.80 (s, 1.8H), 2.95 (s, 1.2H), 3.04 (s, 1.8H), 3.55-3.62 (m, 1H), 3.70-3.77 (m, 1H), 3.77-3.85 (m, 1H), 3.92-3.99 (m, 1H), 4.32-4.40 (m, 1H ), 4.88 (q, J = 7.0 Hz, 0.5H), 4.91-4.99 (m, 1H), 5.11 (br s, 2H), 6.00 (s, 0.6H), 6.01 (s, 0.4H), 6.22 ( q, J = 7.0 Hz, 0.5H), 7.28-7.40 (m, 5.5H), 7.60 (d, J = 8.7 Hz, 0.6H), 7.68 (d, J = 8.7 Hz, 0.4H), 8.36 (s , 0.5H), 8.39 (dd, J = 8.7, 1.2 Hz, 0.5H), 8.62-8.66 (m, 1H), 9.39 (br s, 0.5H).
LCMS (ESI) m / z 640 [M + H] + , t R = 1.15 min, mode N.
Step 1-1-9: To a solution of the compound obtained in Step 1-1-8 (21 mg) in MeOH (1.0 mL) was added 10% palladium-carbon (2 mg), and the mixture was stirred under a hydrogen gas atmosphere for 6 hours. did. The reaction solution was filtered through Celite (registered trademark) and washed with MeOH, and the filtrate obtained was concentrated under reduced pressure. The obtained residue was purified by OH column chromatography (mobile phase: EtOAc to hexane / MeOH = 9: 1; v / v) to obtain the title compound (7.0 mg, colorless solid).
1 H NMR (600 MHz, CDCl 3 , δ): 1.59 (d, J = 7.0 Hz, 1.8H), 1.64 (d, J = 7.0 Hz, 1.2H), 1.76-1.86 (m, 1H), 2.11- 2.22 (m, 1H), 2.37 (s, 1.2H), 2.38 (s, 1.8H), 2.62 (s, 1.2H), 2.81 (s, 1.8H), 2.95 (s, 1.2H), 3.03 (s , 1.8H), 3.46 (dd, J = 10.9, 4.3 Hz, 1H), 3.66-3.78 (m, 2H), 3.88 (dd, J = 10.3, 4.5 Hz, 2H), 4.88 (q, J = 6.6 Hz , 0.6H), 5.98 (s, 0.6H), 5.99 (s, 0.4H), 6.22 (d, J = 7.0 Hz, 0.4H), 7.22-7.32 (m, 1H), 7.32-7.40 (m, 1H ), 7.61 (d, J = 8.7 Hz, 0.6H), 7.68 (d, J = 8.7 Hz, 0.4H), 8.34 (s, 0.6H), 8.61 (s, 0.4H).
LCMS (ESI) m / z 506.2 [M + H] + , t R = 0.58 min, mode N.
実施例1−2:N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}エチル]-5-クロロ-2-[(メチルスルホニル)アミノ]-N-プロピルベンズアミド 塩酸塩の合成
工程1−2−1:工程1−1−2及び工程1−1−3と同様の手法を用いて、メチル N-(tert-ブトキシカルボニル)-L-アラニナート(25.0 g)より、tert-ブチル [(1S)-1-(5-アミノ-1H-ピラゾール-3-イル)エチル]カルバマート (21.9 g, 淡黄色アモルファス)を得た。
1H NMR (600 MHz, CDCl3, δ): 1.43-1.49 (m, 12H), 4.71-4.81 (m, 1H), 4.85 (br s, 1H), 5.49 (s, 1H), 5.64 (br s, 1H).
LCMS (ESI) m/z 227 [M+H]+, tR = 0.28 min, mode N.
工程1−2−2:工程1−2−1で得られた化合物(21.9 g)のEtOH(320 mL)にエチル (2E)-3-エトキシ-2-メチルプロパ-2-エノアート(23 mL), 2.94 M NaOEt/EtOH溶液(115 mL) を加え、加熱還流下、30時間攪拌した。反応溶液にEtOAcを加え、飽和NaHCO3水溶液で分液操作を行った。水層をBrine及びMgSO4を用いて分離した後、有機層を減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー(移動相:CHCl3:MeOH = 100:0〜95:5; v/v)で精製し、tert-ブチル [(1S)-1-(6-メチル-5-オキソ-4,5-ジヒドロピラゾロ[1,5-a]ピリミジン-2-イル)エチル]カルバマート(6.2 g, 淡黄色固体)を得た。
1H NMR (600 MHz, CDCl3, δ): 1.45 (s, 9H), 1.50 (d, J = 6.6 Hz, 3H), 2.09 (s, 3H), 4.88 (br s, 1H), 5.06 (br s, 1H), 5.81 (s, 1H), 7.96 (s, 1H), 10.23 (br s, 1H).
LCMS (ESI) m/z 293 [M+H]+, tR = 0.68 min, mode N.
工程1−2−3:工程1−2−2で得られた化合物(6.2 g)の1,4-ジオキサン(26 mL)溶液 に、4 M HCl/1,4-ジオキサン溶液(26 mL)を滴下して、室温にて2時間攪拌した。反応液を減圧下濃縮、減圧乾燥し、2-[(1S)-1-アミノエチル]-6-メチルピラゾロ[1,5-a]ピリミジン-5(4H)-オン 塩酸塩を粗精製物(褐色固体)として得た。
LCMS (ESI) m/z 193 [M+H]+, tR = 0.18 min, mode N.
工程1−2−4:工程1−2−3で得られた化合物にPOCl3(40 mL)を加え、100 ℃で1.5時間攪拌した。反応溶液を減圧下濃縮し、(1S)-1-(5-クロロ-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル)エタンアミン 塩酸塩を粗精製物(褐色アモルファス)として得た。
LCMS (ESI) m/z 211 [M+H]+, tR = 0.56 min, mode N.
工程1−2−5:工程1−2−4で得られた化合物の MeOH(90 mL)溶液に、(3S)-(-)-3-(tert-ブトキシカルボニルアミノ)ピロリジン(19.6 g)、Et3N(23.6 mL)を加え、80 ℃にて1時間攪拌した、反応液を水にあけ、CHCl3にて抽出を行った。その有機層をPhase Separator にてろ過後、ろ液を減圧下濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー (CHCl3/MeOH = 95/5〜85/15; v/v) 及びシリカゲルカラムクロマトグラフィー (移動相:ヘキサン/EtOAc = 5/95〜0/100〜CHCl3/MeOH = 95/5)で精製し、tert-ブチル [(3S)-1-{2-[(1S)-1-アミノエチル]-6-メチルピラゾロ[1,5-a]ピリミジン-5-イル}ピロリジン-3-イル]カルバマート(3.7 g, 淡黄色固体)を得た。
1H NMR (600 MHz, CDCl3, δ): 1.41-1.50 (m, 12H), 1.89-1.95 (m, 1H), 2.18-2.24 (m, 1H), 2.33 (m, 3H), 3.53 (dd, J = 11.4, 3.9 Hz, 1H), 3.68-3.74 (m, 1H), 3.77-3.83 (m, 1H), 3.88-3.95 (m, 1H), 4.20 (q, J = 6.9 Hz, 1H), 4.30 (br s, 1H), 4.69 (br s, 1H), 6.02 (s, 1H), 8.02 (s, 1H).
LCMS (ESI) m/z 361 [M+H]+, tR = 0.85 min, mode H.
工程1−2−6:工程1−2−5で得られた化合物(30 mg)のDMF (1 mL) 溶液に、1-ヨードプロパン (16 μL) 及び K2CO3 (29 mg) を加え、80 ℃で1時間攪拌した。反応液を逆相分取HPLCにて精製し、tert-ブチル [(3S)-1-{6-メチル-2-[(1S)-1-(プロピルアミノ)エチル]ピラゾロ[1,5-a]ピリミジン-5-イル}ピロリジン-3-イル]カルバマート(13 mg, 無色固体)を得た。
工程1−2−7:プロピル体 (13 mg)のDMF(1.0 mL)溶液に、5-クロロ-2-メタンスルホンアミドベンゼンカルボン酸(9.5 mg)、HATU(16 mg)とEt3N(22 μL)を加え、室温で3日間撹拌した。反応液を逆相分取HPLCにて精製し、tert-ブチル [(3S)-1-(2-{(1S)-1-[{5-クロロ-2-[(メチルスルホニル)アミノ]ベンゾイル}(プロピル)アミノ]エチル}-6-メチルピラゾロ[1,5-a]ピリミジン-5-イル)ピロリジン-3-イル]カルバマート(13 mg, 無色固体)を得た。
LCMS (ESI) m/z 634 [M+H]+, tR = 1.26 min, mode N.
工程1−2−8:工程1−2−7で得られた化合物(21 mg)の1,4-ジオキサン(1.0 mL) 溶液に4 M HCl/1,4-ジオキサン溶液(1 mL)を加え、室温で一晩撹拌した。反応液を減圧下濃縮し、表題化合物 (15 mg, 無色固体)を得た。
1H NMR (600 MHz, DMSO-d6, δ): 0.53 (t, J = 7.2 Hz, 1H), 0.77 (t, J = 7.4 Hz, 2H), 1.21-1.54 (m, 4H), 1.57 (d, J = 7.0 Hz, 2H), 1.66 (d, J = 7.0 Hz, 1H), 2.00-2.10 (m, 1H), 2.20-2.30 (m, 1H), 2.34-2.38 (m, 3H), 2.85-2.98 (m, 2H), 3.04 (s, 3H), 3.81-3.96 (m, 5H), 4.74-4.82 (m, 0.7H), 5.73 (br s, 0.3H), 6.13 (s, 1H), 7.43-7.58 (m, 3H), 8.18 (br s, 3H), 8.52 (s, 0.5H), 9.34 (s, 0.5H).
LCMS (ESI) m/z 534 [M+H]+, tR = 0.62 min, mode N.
Example 1-2: N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidin-2-yl} ethyl ] -5-Chloro-2-[(methylsulfonyl) amino] -N-propylbenzamide Hydrochloride Synthesis Step 1-2-1: Using the same method as in Step 1-1-2 and Step 1-1-3 From methyl N- (tert-butoxycarbonyl) -L-alaninate (25.0 g), tert-butyl [(1S) -1- (5-amino-1H-pyrazol-3-yl) ethyl] carbamate (21.9 g , Pale yellow amorphous).
1 H NMR (600 MHz, CDCl 3 , δ): 1.43-1.49 (m, 12H), 4.71-4.81 (m, 1H), 4.85 (br s, 1H), 5.49 (s, 1H), 5.64 (br s , 1H).
LCMS (ESI) m / z 227 [M + H] + , t R = 0.28 min, mode N.
Step 1-2-2: Ethyl (2E) -3-ethoxy-2-methylprop-2-enoate (23 mL) was added to EtOH (320 mL) of the compound (21.9 g) obtained in Step 1-2-1. 2.94 M NaOEt / EtOH solution (115 mL) was added, and the mixture was stirred for 30 hours with heating under reflux. EtOAc was added to the reaction solution, and a liquid separation operation was performed with a saturated aqueous NaHCO 3 solution. The aqueous layer was separated using Brine and MgSO 4 , and then the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase: CHCl 3 : MeOH = 100: 0 to 95: 5; v / v), and tert-butyl [(1S) -1- (6-methyl-5-oxo- 4,5-Dihydropyrazolo [1,5-a] pyrimidin-2-yl) ethyl] carbamate (6.2 g, pale yellow solid) was obtained.
1 H NMR (600 MHz, CDCl 3 , δ): 1.45 (s, 9H), 1.50 (d, J = 6.6 Hz, 3H), 2.09 (s, 3H), 4.88 (br s, 1H), 5.06 (br s, 1H), 5.81 (s, 1H), 7.96 (s, 1H), 10.23 (br s, 1H).
LCMS (ESI) m / z 293 [M + H] + , t R = 0.68 min, mode N.
Step 1-2-3: To a solution of the compound (6.2 g) obtained in Step 1-2-2 in 1,4-dioxane (26 mL), add 4 M HCl / 1,4-dioxane solution (26 mL). The solution was added dropwise and stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure and dried under reduced pressure to give 2-[(1S) -1-aminoethyl] -6-methylpyrazolo [1,5-a] pyrimidin-5 (4H) -one hydrochloride as a crude product (brown As a solid).
LCMS (ESI) m / z 193 [M + H] + , t R = 0.18 min, mode N.
Step 1-2-4: POCl 3 (40 mL) was added to the compound obtained in Step 1-2-3, and the mixture was stirred at 100 ° C. for 1.5 hr. The reaction solution was concentrated under reduced pressure to obtain (1S) -1- (5-chloro-6-methylpyrazolo [1,5-a] pyrimidin-2-yl) ethanamine hydrochloride as a crude product (brown amorphous).
LCMS (ESI) m / z 211 [M + H] + , t R = 0.56 min, mode N.
Step 1-2-5: To a solution of the compound obtained in Step 1-2-4 in MeOH (90 mL), (3S)-(−)-3- (tert-butoxycarbonylamino) pyrrolidine (19.6 g), Et 3 N (23.6 mL) was added, and the mixture was stirred at 80 ° C. for 1 hr. The reaction mixture was poured into water and extracted with CHCl 3 . The organic layer was filtered through a phase separator, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (CHCl 3 / MeOH = 95/5 to 85/15; v / v) and silica gel column chromatography (mobile phase: hexane / EtOAc = 5/95 to 0/100 to CHCl 3 / MeOH = 95/5) and tert-butyl [(3S) -1- {2-[(1S) -1-aminoethyl] -6-methylpyrazolo [1,5-a] pyrimidin-5-yl } Pyrrolidin-3-yl] carbamate (3.7 g, pale yellow solid) was obtained.
1 H NMR (600 MHz, CDCl 3 , δ): 1.41-1.50 (m, 12H), 1.89-1.95 (m, 1H), 2.18-2.24 (m, 1H), 2.33 (m, 3H), 3.53 (dd , J = 11.4, 3.9 Hz, 1H), 3.68-3.74 (m, 1H), 3.77-3.83 (m, 1H), 3.88-3.95 (m, 1H), 4.20 (q, J = 6.9 Hz, 1H), 4.30 (br s, 1H), 4.69 (br s, 1H), 6.02 (s, 1H), 8.02 (s, 1H).
LCMS (ESI) m / z 361 [M + H] + , t R = 0.85 min, mode H.
Step 1-2-6: 1-iodopropane (16 μL) and K 2 CO 3 (29 mg) were added to a DMF (1 mL) solution of the compound (30 mg) obtained in Step 1-2-5. , And stirred at 80 ° C. for 1 hour. The reaction solution was purified by reverse phase preparative HPLC, and tert-butyl [(3S) -1- {6-methyl-2-[(1S) -1- (propylamino) ethyl] pyrazolo [1,5-a ] Pyrimidin-5-yl} pyrrolidin-3-yl] carbamate (13 mg, colorless solid) was obtained.
Step 1-2-7: To a solution of propyl (13 mg) in DMF (1.0 mL), 5-chloro-2-methanesulfonamidobenzenecarboxylic acid (9.5 mg), HATU (16 mg) and Et 3 N (22 μL) was added and stirred at room temperature for 3 days. The reaction solution was purified by reverse phase preparative HPLC, and tert-butyl [(3S) -1- (2-{(1S) -1-[{5-chloro-2-[(methylsulfonyl) amino] benzoyl} (Propyl) amino] ethyl} -6-methylpyrazolo [1,5-a] pyrimidin-5-yl) pyrrolidin-3-yl] carbamate (13 mg, colorless solid) was obtained.
LCMS (ESI) m / z 634 [M + H] + , t R = 1.26 min, mode N.
Step 1-2-8: To a solution of the compound obtained in Step 1-2-7 (21 mg) in 1,4-dioxane (1.0 mL) was added 4 M HCl / 1,4-dioxane solution (1 mL). Stir at room temperature overnight. The reaction mixture was concentrated under reduced pressure to obtain the title compound (15 mg, colorless solid).
1 H NMR (600 MHz, DMSO-d 6 , δ): 0.53 (t, J = 7.2 Hz, 1H), 0.77 (t, J = 7.4 Hz, 2H), 1.21-1.54 (m, 4H), 1.57 ( d, J = 7.0 Hz, 2H), 1.66 (d, J = 7.0 Hz, 1H), 2.00-2.10 (m, 1H), 2.20-2.30 (m, 1H), 2.34-2.38 (m, 3H), 2.85 -2.98 (m, 2H), 3.04 (s, 3H), 3.81-3.96 (m, 5H), 4.74-4.82 (m, 0.7H), 5.73 (br s, 0.3H), 6.13 (s, 1H), 7.43-7.58 (m, 3H), 8.18 (br s, 3H), 8.52 (s, 0.5H), 9.34 (s, 0.5H).
LCMS (ESI) m / z 534 [M + H] + , t R = 0.62 min, mode N.
実施例1−3:N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}プロピル]-5-クロロ-N-メチル-2-[(メチルスルホニル)アミノ]ベンズアミド 塩酸塩の合成
工程1−3−1:工程1−1−1〜工程1−1−3と同様の手法を用いて、(2S)-2-[(tert-ブトキシカルボニル)アミノ]ブタン酸(25.0 g)より、tert-ブチル [(1S)-1-(5-アミノ-1H-ピラゾール-3-イル)プロピル]カルバマート (17.5 g, 黄色アモルファス)を得た。
1H NMR (600 MHz, CDCl3, δ): 0.95-1.06 (m, 3H), 1.43-1.46 (m, 9H), 1.63-1.77 (m, 1H), 1.83-1.98 (m, 1H), 4.35-4.58 (m, 1H), 4.61-4.90 (m, 1H), 5.49 (s, 1H).
LCMS (ESI) m/z 241 [M+H]+, tR = 0.33 min, mode N.
同様の手法により合成したtert-ブチル [(1S)-1-(5-アミノ-1H-ピラゾール-3-イル)プロピル]カルバマートの別ロットの分析データを以下に示す。
tR = 6.62 min (98.8%ee), 分析条件:カラム:CHIRALPAK IC3(ダイセル社商標)、カラムサイズ:5 μm 4.6 mm×250 mm、移動相:ヘキサン/EtOH = 80/20 (v/v)、流速:1 mL/min、カラム温度:40 ℃、検出波長:210 nm.
同様の手法により合成したtert-ブチル [(1R)-1-(5-アミノ-1H-ピラゾール-3-イル)プロピル]カルバマートの分析データを以下に示す。
tR = 5.13 min, 分析条件:カラム:CHIRALPAK IC3(ダイセル社商標)、カラムサイズ:5 μm 4.6 mm×250 mm、移動相:ヘキサン/EtOH = 80/20 (v/v)、流速:1 mL/min、カラム温度:40 ℃、検出波長:210 nm.
工程1−3−2:工程1−2−2と同様の手法を用いて、工程1−3−1で得られた化合物(16.5 g)より、tert-ブチル [(1S)-1-(6-メチル-5-オキソ-4,5-ジヒドロピラゾロ[1,5-a]ピリミジン-2-イル)プロピル]カルバマート(5.80 g, 黄色アモルファス)を得た。
1H NMR (600 MHz, CDCl3, δ): 0.88-0.97 (m, 3H), 1.39-1.51 (m, 9H), 1.78 (dt, J = 13.8, 7.1 Hz, 1H), 1.90 (dd, J = 13.6, 7.0 Hz, 1H), 2.07-2.14 (m, 3H), 4.72 (d, J = 6.2 Hz, 1H), 5.06 (d, J = 7.0 Hz, 1H), 5.82 (s, 1H), 7.98 (d, J = 0.8 Hz, 1H), 10.81 (br s, 1H).
LCMS (ESI) m/z 307 [M+H]+, tR = 0.74 min, mode N.
工程1−3−3:工程1−2−3と同様の手法を用いて、工程1−3−2で得られた化合物 (5.4 g)より、2-[(1S)-1-アミノプロピル]-6-メチルピラゾロ[1,5-a]ピリミジン-5(4H)-オン 塩酸塩 (4.7 g, 黄色固体)を得た。
1H NMR (600 MHz, DMSO-d6, δ): 0.78-0.89 (m, 3H), 1.77-2.01 (m, 5H), 4.07-4.25 (m, 1H), 5.97-6.10 (m, 1H), 8.38-8.48 (m, 1H), 8.57 (br s, 3H), 12.29 (br s, 1H).
工程1−3−4:工程1−2−4と同様の手法を用いて、工程1−3−3で得られた化合物 (4.7 g)より、(1S)-1-(5-クロロ-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル)プロパン-1-アミン 塩酸塩(5.0 g, 褐色アモルファス)を得た。
工程1−3−5:工程1−2−5と同様の手法を用いて、工程1−3−4で得られた化合物 (16.5 g)より、tert-ブチル [(3S)-1-{2-[(1S)-1-アミノプロピル]-6-メチルピラゾロ[1,5-a]ピリミジン-5-イル}ピロリジン-3-イル]カルバマート(4.5 g, 黄色アモルファス)を得た。
1H NMR (600 MHz, CDCl3, δ): 0.88-0.99 (m, 3H), 1.45 (s, 9H), 1.72-1.97 (m, 3H), 2.16-2.25 (m, 1H), 2.33 (s, 3H), 3.53 (dd, J = 10.7, 3.7 Hz, 1H), 3.71 (ddd, J = 10.7, 7.8, 5.8 Hz, 1H), 3.80 (dt, J = 10.7, 7.4 Hz, 1H), 3.88-3.97 (m, 2H), 4.30 (br s, 1H), 4.71 (br s, 1H), 5.91-6.09 (m, 1H), 8.02 (s, 1H).
LCMS (ESI) m/z 375 [M+H]+, tR = 0.48 min, mode N.
工程1−3−6:工程1−2−6及び工程1−2−7と同様の手法を用いて、工程1−3−5で得られた化合物(3.60 g)及びMeI(300 μL)より、tert-ブチル [(3S)-1-(2-{(1S)-1-[{5-クロロ-2-[(メチルスルホニル)アミノ]ベンゾイル}(メチル)アミノ]プロピル}-6-メチルピラゾロ[1,5-a]ピリミジン-5-イル)ピロリジン-3-イル]カルバマート (758 mg, 淡黄色固体)を得た。
1H NMR (600 MHz, CDCl3, δ): 1.06 (t, J = 7.4 Hz, 2H), 1.13 (t, J = 7.2 Hz, 1H), 1.45 (s, 9H), 1.86-1.95(m, 1H), 2.01-2.06 (m, 1H), 2.15-2.27 (m, 1H), 2.36 (s, 1H), 2.37 (s, 2H), 2.58 (s, 1H), 2.77 (s, 2H), 2.95 (s, 1H), 3.03 (s, 2H), 3.54 (dd, J = 11.4, 4.3 Hz, 1H), 3.69-3.76 (m, 1H), 3.77-3.83 (m, 1H), 3.94 (br s, 1H), 4.30 (br s, 1H), 4.57-4.64 (m, 1H), 4.67 (br s, 1H), 5.99 (s, 0.7H), 6.02 (s, 0.3H), 7.24-7.28 (m, 0.7H), 7.29 (d, J = 2.5 Hz, 0.3H), 7.35 (dd, J = 8.7, 2.5 Hz, 0.7H), 7.38 (dd, J = 8.9, 2.3 Hz, 0.3H), 7.60 (d, J = 8.7 Hz, 0.7H), 7.68 (d, J = 8.7 Hz, 0.3H), 8.38 (s, 0.7H), 8.63 (s, 0.3H), 9.37-9.48 (m, 0.3H), 11.26 (br s, 0.7H).
LCMS (ESI) m/z 620[M+H]+, tR = 1.21 min, mode N.
工程1−3−7:工程1−2−8と同様の手法を用いて、工程1−3−6で得られた化合物 (637 mg)より、表題化合物 (623 mg, 無色固体)を得た。
1H NMR (600 MHz, DMSO-d6, δ): 0.91 (br s, 1.5H), 1.03 (t, J = 7.4 Hz, 1.5H), 1.82-2.11 (m, 3H), 2.12-2.30 (m, 2H), 2.35 (s, 1.5H), 2.37 (s, 1.5H), 2.58 (s, 1.5H), 2.72 (br s, 1.5H), 2.97-3.06 (m, 3H), 3.71-3.82 (m, 2H), 3.82-3.90 (m, 2H), 3.90-3.98 (m, 1H), 4.54 (dd, J = 9.9, 5.0 Hz, 0.5H), 5.73 (dd, J = 10.3, 5.4 Hz, 0.5H), 6.13 (s, 1H), 7.36-7.57 (m, 3H), 8.34 (br s, 3H), 8.51 (s, 0.5H), 9.21 (s, 0.5H).
LCMS (ESI) m/z 520 [M+H]+, tR = 1.07 min, mode H.
Example 1-3: N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidin-2-yl} propyl ] -5-Chloro-N-methyl-2-[(methylsulfonyl) amino] benzamide Hydrochloride Synthesis Step 1-3-1: Using the same method as in Step 1-1-1 to Step 1-1-3 From (2S) -2-[(tert-butoxycarbonyl) amino] butanoic acid (25.0 g), tert-butyl [(1S) -1- (5-amino-1H-pyrazol-3-yl) propyl] Carbamate (17.5 g, yellow amorphous) was obtained.
1 H NMR (600 MHz, CDCl 3 , δ): 0.95-1.06 (m, 3H), 1.43-1.46 (m, 9H), 1.63-1.77 (m, 1H), 1.83-1.98 (m, 1H), 4.35 -4.58 (m, 1H), 4.61-4.90 (m, 1H), 5.49 (s, 1H).
LCMS (ESI) m / z 241 [M + H] + , t R = 0.33 min, mode N.
Analytical data of another lot of tert-butyl [(1S) -1- (5-amino-1H-pyrazol-3-yl) propyl] carbamate synthesized by the same method is shown below.
t R = 6.62 min (98.8% ee), Analysis conditions: Column: CHIRALPAK IC3 (trademark of Daicel), Column size: 5 μm 4.6 mm × 250 mm, Mobile phase: Hexane / EtOH = 80/20 (v / v) , Flow rate: 1 mL / min, Column temperature: 40 ° C, Detection wavelength: 210 nm.
Analytical data of tert-butyl [(1R) -1- (5-amino-1H-pyrazol-3-yl) propyl] carbamate synthesized by the same method is shown below.
t R = 5.13 min, Analysis conditions: Column: CHIRALPAK IC3 (trademark of Daicel), Column size: 5 μm 4.6 mm × 250 mm, Mobile phase: Hexane / EtOH = 80/20 (v / v), Flow rate: 1 mL / min, column temperature: 40 ° C, detection wavelength: 210 nm.
Step 1-3-2: Using a method similar to that in Step 1-2-2, tert-butyl [(1S) -1- (6) from the compound (16.5 g) obtained in Step 1-3-1. -Methyl-5-oxo-4,5-dihydropyrazolo [1,5-a] pyrimidin-2-yl) propyl] carbamate (5.80 g, yellow amorphous) was obtained.
1 H NMR (600 MHz, CDCl 3 , δ): 0.88-0.97 (m, 3H), 1.39-1.51 (m, 9H), 1.78 (dt, J = 13.8, 7.1 Hz, 1H), 1.90 (dd, J = 13.6, 7.0 Hz, 1H), 2.07-2.14 (m, 3H), 4.72 (d, J = 6.2 Hz, 1H), 5.06 (d, J = 7.0 Hz, 1H), 5.82 (s, 1H), 7.98 (d, J = 0.8 Hz, 1H), 10.81 (br s, 1H).
LCMS (ESI) m / z 307 [M + H] + , t R = 0.74 min, mode N.
Step 1-3-3: Using the same method as in Step 1-2-3, from the compound (5.4 g) obtained in Step 1-3-2, 2-[(1S) -1-aminopropyl] -6-methylpyrazolo [1,5-a] pyrimidin-5 (4H) -one hydrochloride (4.7 g, yellow solid) was obtained.
1 H NMR (600 MHz, DMSO-d 6 , δ): 0.78-0.89 (m, 3H), 1.77-2.01 (m, 5H), 4.07-4.25 (m, 1H), 5.97-6.10 (m, 1H) , 8.38-8.48 (m, 1H), 8.57 (br s, 3H), 12.29 (br s, 1H).
Step 1-3-4: Using a method similar to that in Step 1-2-4, from the compound (4.7 g) obtained in Step 1-3-3, (1S) -1- (5-chloro-6 -Methylpyrazolo [1,5-a] pyrimidin-2-yl) propan-1-amine hydrochloride (5.0 g, brown amorphous) was obtained.
Step 1-3-5: Using a method similar to that in Step 1-2-5, from the compound (16.5 g) obtained in Step 1-3-4, tert-butyl [(3S) -1- {2 -[(1S) -1-Aminopropyl] -6-methylpyrazolo [1,5-a] pyrimidin-5-yl} pyrrolidin-3-yl] carbamate (4.5 g, yellow amorphous) was obtained.
1 H NMR (600 MHz, CDCl 3 , δ): 0.88-0.99 (m, 3H), 1.45 (s, 9H), 1.72-1.97 (m, 3H), 2.16-2.25 (m, 1H), 2.33 (s , 3H), 3.53 (dd, J = 10.7, 3.7 Hz, 1H), 3.71 (ddd, J = 10.7, 7.8, 5.8 Hz, 1H), 3.80 (dt, J = 10.7, 7.4 Hz, 1H), 3.88- 3.97 (m, 2H), 4.30 (br s, 1H), 4.71 (br s, 1H), 5.91-6.09 (m, 1H), 8.02 (s, 1H).
LCMS (ESI) m / z 375 [M + H] + , t R = 0.48 min, mode N.
Step 1-3-6: From the compound (3.60 g) obtained in Step 1-3-5 and MeI (300 μL) using the same method as in Step 1-2-6 and Step 1-2-7 Tert-butyl [(3S) -1- (2-{(1S) -1-[{5-chloro-2-[(methylsulfonyl) amino] benzoyl} (methyl) amino] propyl} -6-methylpyrazolo [ 1,5-a] pyrimidin-5-yl) pyrrolidin-3-yl] carbamate (758 mg, pale yellow solid) was obtained.
1 H NMR (600 MHz, CDCl 3 , δ): 1.06 (t, J = 7.4 Hz, 2H), 1.13 (t, J = 7.2 Hz, 1H), 1.45 (s, 9H), 1.86-1.95 (m, 1H), 2.01-2.06 (m, 1H), 2.15-2.27 (m, 1H), 2.36 (s, 1H), 2.37 (s, 2H), 2.58 (s, 1H), 2.77 (s, 2H), 2.95 (s, 1H), 3.03 (s, 2H), 3.54 (dd, J = 11.4, 4.3 Hz, 1H), 3.69-3.76 (m, 1H), 3.77-3.83 (m, 1H), 3.94 (br s, 1H), 4.30 (br s, 1H), 4.57-4.64 (m, 1H), 4.67 (br s, 1H), 5.99 (s, 0.7H), 6.02 (s, 0.3H), 7.24-7.28 (m, 0.7H), 7.29 (d, J = 2.5 Hz, 0.3H), 7.35 (dd, J = 8.7, 2.5 Hz, 0.7H), 7.38 (dd, J = 8.9, 2.3 Hz, 0.3H), 7.60 (d , J = 8.7 Hz, 0.7H), 7.68 (d, J = 8.7 Hz, 0.3H), 8.38 (s, 0.7H), 8.63 (s, 0.3H), 9.37-9.48 (m, 0.3H), 11.26 (br s, 0.7H).
LCMS (ESI) m / z 620 [M + H] + , t R = 1.21 min, mode N.
Step 1-3-7: The title compound (623 mg, colorless solid) was obtained from the compound (637 mg) obtained in Step 1-3-6 using the same method as in Step 1-2-8. .
1 H NMR (600 MHz, DMSO-d 6 , δ): 0.91 (br s, 1.5H), 1.03 (t, J = 7.4 Hz, 1.5H), 1.82-2.11 (m, 3H), 2.12-2.30 ( m, 2H), 2.35 (s, 1.5H), 2.37 (s, 1.5H), 2.58 (s, 1.5H), 2.72 (br s, 1.5H), 2.97-3.06 (m, 3H), 3.71-3.82 (m, 2H), 3.82-3.90 (m, 2H), 3.90-3.98 (m, 1H), 4.54 (dd, J = 9.9, 5.0 Hz, 0.5H), 5.73 (dd, J = 10.3, 5.4 Hz, 0.5H), 6.13 (s, 1H), 7.36-7.57 (m, 3H), 8.34 (br s, 3H), 8.51 (s, 0.5H), 9.21 (s, 0.5H).
LCMS (ESI) m / z 520 [M + H] + , t R = 1.07 min, mode H.
実施例1−4:N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}プロピル]-N,5-ジメチル-2-[(メチルスルホニル)アミノ]ベンズアミド 塩酸塩の合成
工程1−4−1:工程1−3−5で得られた化合物(4.3 g)のMeOH(48 mL)溶液に、エチル トリフルオロアセテート (2.1 g) 及びEt3N(2.5 mL) を加え、室温で一晩攪拌した。反応液を減圧下濃縮し、tert-ブチル [(3S)-1-(6-メチル-2-{(1S)-1-[(トリフルオロアセチル)アミノ]プロピル}ピラゾロ[1,5-a]ピリミジン-5-イル)ピロリジン-3-イル]カルバマート(6.5 g, 淡黄色固体) を得た。
LCMS (ESI) m/z 471 [M+H]+, tR = 0.98 min, mode N.
工程1−4−2:工程1−4−1で得られた化合物(5.4 g)のDMF(50 mL)溶液に、MeI(2.2 mL)、 Cs2CO3(15 g)を加え、65 ℃で2時間攪拌した。反応液を水にあけ、EtOAcにて抽出を行った。有機層をBrineで洗浄、MgSO4で乾燥ろ過後、ろ液を減圧下濃縮し、tert-ブチル [(3S)-1-(6-メチル-2-{(1S)-1-[メチル(トリフルオロアセチル)アミノ]プロピル}ピラゾロ[1,5-a]ピリミジン-5-イル)ピロリジン-3-イル]カルバマート(5.6 g, 淡黄色油状物)を得た。
LCMS (ESI) m/z 485 [M+H]+, tR = 1.10 min, mode N.
工程1−4−3:工程1−4−2で得られた化合物(5.5 g)のTHF/MeOH混合溶液(80 mL, 1/1; v/v)に、1 M NaOH水溶液(40 mL)を加え、室温にて1時間攪拌した。反応液を水にあけ、CHCl3 にて抽出を行った。有機層をBrineで洗浄、MgSO4で乾燥ろ過後、ろ液を減圧下濃縮し、tert-ブチル [(3S)-1-{6-メチル-2-[(1S)-1-(メチルアミノ)プロピル]ピラゾロ[1,5-a]ピリミジン-5-イル}ピロリジン-3-イル]カルバマート(4.3 g, 褐色アモルファス)を得た。
1H NMR (600 MHz, CDCl3, δ): 0.88 (t, J = 7.4 Hz, 3H), 1.45 (s, 9H), 1.68-1.98 (m, 3H), 2.14-2.25 (m, 1H), 2.28-2.42 (m, 6H), 3.48-3.63 (m, 2H), 3.66-3.85 (m, 2H), 3.87-3.98 (m, 1H), 4.30 (br s, 1H), 4.59-4.78 (m, 1H), 5.91-6.07 (m, 1H), 7.96-8.10 (m, 1H).
LCMS (ESI) m/z 389 [M+H]+, tR = 0.50 min, mode N.
工程1−4−4:工程1−2−7及び工程1−2−8と同様の手法を用いて、工程1−4−3で得られた化合物(30 mg)及び5-メチル-2-[(メチルスルホニル)アミノ]安息香酸(26 mg)より、表題化合物(30 mg, 無色固体)を得た。
1H NMR (600 MHz, DMSO-d6, δ): 0.91 (br s, 1.5H), 1.02 (t, J = 7.2 Hz, 1.5H), 1.84-2.29 (m, 4H), 2.30-2.38 (m, 6H), 2.55-2.58 (m, 1.5H), 2.72 (br s, 1.5H), 2.97 (s, 3H), 3.70-3.98 (m, 5H), 4.49-4.59 (m, 0.5H), 5.74-5.80(m, 0.5H), 6.11 (s, 1H), 7.14 (s, 1H), 7.22-7.30 (m, 1H), 7.30-7.38 (m, 1H), 8.30-8.39 (m, 3H), 8.51 (s, 0.5H), 8.97 (s, 0.5H).
LCMS (ESI) m/z 500 [M+H]+, tR = 0.54 min, mode N.
Example 1-4: N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidin-2-yl} propyl ] -N, 5-Dimethyl-2-[(methylsulfonyl) amino] benzamide Hydrochloride Synthesis Step 1-4-1: Compound (4.3 g) MeOH (48 mL) obtained in Step 1-3-5 Ethyl trifluoroacetate (2.1 g) and Et 3 N (2.5 mL) were added to the solution, and the mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, and tert-butyl [(3S) -1- (6-methyl-2-{(1S) -1-[(trifluoroacetyl) amino] propyl} pyrazolo [1,5-a] Pyrimidin-5-yl) pyrrolidin-3-yl] carbamate (6.5 g, pale yellow solid) was obtained.
LCMS (ESI) m / z 471 [M + H] + , t R = 0.98 min, mode N.
Step 1-4-2: MeI (2.2 mL) and Cs 2 CO 3 (15 g) were added to a DMF (50 mL) solution of the compound (5.4 g) obtained in Step 1-4-1 at 65 ° C. For 2 hours. The reaction solution was poured into water and extracted with EtOAc. The organic layer was washed with Brine, dried and filtered with MgSO 4 , the filtrate was concentrated under reduced pressure, and tert-butyl [(3S) -1- (6-methyl-2-{(1S) -1- [methyl (tri Fluoroacetyl) amino] propyl} pyrazolo [1,5-a] pyrimidin-5-yl) pyrrolidin-3-yl] carbamate (5.6 g, pale yellow oil) was obtained.
LCMS (ESI) m / z 485 [M + H] + , t R = 1.10 min, mode N.
Step 1-4-3: 1M NaOH aqueous solution (40 mL) was added to a THF / MeOH mixed solution (80 mL, 1/1; v / v) of the compound (5.5 g) obtained in Step 1-4-2. And stirred at room temperature for 1 hour. The reaction solution was poured into water and extracted with CHCl 3 . The organic layer was washed with Brine, dried and filtered with MgSO 4 , and the filtrate was concentrated under reduced pressure to give tert-butyl [(3S) -1- {6-methyl-2-[(1S) -1- (methylamino)]. Propyl] pyrazolo [1,5-a] pyrimidin-5-yl} pyrrolidin-3-yl] carbamate (4.3 g, brown amorphous) was obtained.
1 H NMR (600 MHz, CDCl 3 , δ): 0.88 (t, J = 7.4 Hz, 3H), 1.45 (s, 9H), 1.68-1.98 (m, 3H), 2.14-2.25 (m, 1H), 2.28-2.42 (m, 6H), 3.48-3.63 (m, 2H), 3.66-3.85 (m, 2H), 3.87-3.98 (m, 1H), 4.30 (br s, 1H), 4.59-4.78 (m, 1H), 5.91-6.07 (m, 1H), 7.96-8.10 (m, 1H).
LCMS (ESI) m / z 389 [M + H] + , t R = 0.50 min, mode N.
Step 1-4-4: Using a method similar to that of Step 1-2-7 and Step 1-2-8, the compound (30 mg) obtained in Step 1-4-3 and 5-methyl-2- The title compound (30 mg, colorless solid) was obtained from [(methylsulfonyl) amino] benzoic acid (26 mg).
1 H NMR (600 MHz, DMSO-d 6 , δ): 0.91 (br s, 1.5H), 1.02 (t, J = 7.2 Hz, 1.5H), 1.84-2.29 (m, 4H), 2.30-2.38 ( m, 6H), 2.55-2.58 (m, 1.5H), 2.72 (br s, 1.5H), 2.97 (s, 3H), 3.70-3.98 (m, 5H), 4.49-4.59 (m, 0.5H), 5.74-5.80 (m, 0.5H), 6.11 (s, 1H), 7.14 (s, 1H), 7.22-7.30 (m, 1H), 7.30-7.38 (m, 1H), 8.30-8.39 (m, 3H) , 8.51 (s, 0.5H), 8.97 (s, 0.5H).
LCMS (ESI) m / z 500 [M + H] + , t R = 0.54 min, mode N.
実施例1−5:N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}プロピル]-N-エチル-5-メチル-2-[(メチルスルホニル)アミノ]ベンズアミド 塩酸塩の合成
工程1−2−6〜工程1−2−8と同様の手法を用いて、工程1−3−5で得られた化合物(1.50 g)、5-メチル-2-[(メチルスルホニル)アミノ]安息香酸(1.10 g)及び EtI(320 μL)より、表題化合物(907 mg, 無色固体)を得た。
1H NMR (600 MHz, DMSO-d6, δ): 0.80 (t, J = 6.8 Hz, 1H), 0.86-1.00 (m, 4H), 1.07 (t, J = 7.2 Hz, 1H), 1.93-2.10 (m, 3H), 2.21-2.29 (m, 2H), 2.32-2.38 (m, 6H), 2.91-3.05 (m, 4H), 3.25-3.33 (m, 1H), 3.72-3.82 (m, 2H), 3.82-3.90 (m, 2H), 3.90-3.97 (m, 1H), 4.51 (br s, 0.5H), 5.56 (br s, 0.5H), 6.12-6.23 (m, 1H), 7.09-7.40 (m, 3H), 8.30 (br s, 3H), 8.52 (s, 0.5H), 8.97 (s, 0.5H).
LCMS (ESI) m/z 514 [M+H]+, tR = 1.08 min, mode H.
Example 1-5: N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidin-2-yl} propyl ] -N-ethyl-5-methyl-2-[(methylsulfonyl) amino] benzamide hydrochloride Synthesis of step 1-3-6 to step 1-2-8 using the same method as in step 1-3-3- The title compound (907 mg, colorless solid) was obtained from the compound obtained in 5 (1.50 g), 5-methyl-2-[(methylsulfonyl) amino] benzoic acid (1.10 g) and EtI (320 μL). .
1 H NMR (600 MHz, DMSO-d 6 , δ): 0.80 (t, J = 6.8 Hz, 1H), 0.86-1.00 (m, 4H), 1.07 (t, J = 7.2 Hz, 1H), 1.93- 2.10 (m, 3H), 2.21-2.29 (m, 2H), 2.32-2.38 (m, 6H), 2.91-3.05 (m, 4H), 3.25-3.33 (m, 1H), 3.72-3.82 (m, 2H ), 3.82-3.90 (m, 2H), 3.90-3.97 (m, 1H), 4.51 (br s, 0.5H), 5.56 (br s, 0.5H), 6.12-6.23 (m, 1H), 7.09-7.40 (m, 3H), 8.30 (br s, 3H), 8.52 (s, 0.5H), 8.97 (s, 0.5H).
LCMS (ESI) m / z 514 [M + H] + , t R = 1.08 min, mode H.
実施例1−6:N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}ブチル]-N,5-ジメチル-2-[(メチルスルホニル)アミノ]ベンズアミド 塩酸塩の合成
工程1−6−1:工程1−1−2及び工程1−1−3と同様の手法を用いて、メチル N-(tert-ブトキシカルボニル)-L-ノルバリナート(5800 mg)より、tert-ブチル [(1S)-1-(5-アミノ-1H-ピラゾール-3-イル)ブチル]カルバマート(4600 mg) を得た。
1H NMR (600 MHz, CDCl3, δ): 0.89-0.98 (m, 3H), 1.31-1.48 (m, 1H), 1.63-1.85 (m, 2H), 4.55-4.67 (m, 1H), 4.85 (br s, 1H), 5.49 (s, 1H).
LCMS (ESI) m/z 255 [M+H]+, tR = 0.51 min, mode N.
工程1−6−2:工程1−2−2と同様の手法を用いて、工程1−6−1で得られた化合物(4600 mg)より、tert-ブチル [(1S)-1-(6-メチル-5-オキソ-4,5-ジヒドロピラゾロ[1,5-a]ピリミジン-2-イル)ブチル]カルバマート(2000 mg) を得た。
1H NMR (600 MHz, CDCl3, δ): 0.90-0.96 (m, 3H), 1.30-1.47 (m, 11H), 1.68-1.89 (m, 2H), 2.10 (s, 3H), 4.73-4.83 (m, 1H), 4.97- 5.09 (m, 1H), 5.83 (s, 1H), 7.98 (s, 1H), 11.04 (br s, 1H).
LCMS (ESI) m/z 321 [M+H]+, tR = 0.86 min, mode N.
工程1−6−3:工程1−2−3と同様の手法を用いて、工程1−6−2で得られた化合物(500 mg)より、2-[(1S)-1-アミノブチル]-6-メチルピラゾロ[1,5-a]ピリミジン-5(4H)-オン 塩酸塩(460 mg) を得た。
1H NMR (600 MHz, DMSO-d6, δ): 0.87 (t, J = 7.4 Hz, 3H), 1.19-1.30 (m, 2H), 1.79-1.90 (m, 2H), 1.93- 1.96 (m, 3H), 4.23-4.29 (m, 1H), 6.01 (s, 1H), 8.43 (s, 1H), 8.50 (br s, 3 ), 12.27 (br s, 1H).
LCMS (ESI) m/z 221 [M+H]+, tR = 0.54 min, mode H.
工程1−6−4:工程1−2−4と同様の手法を用いて、工程1−6−3で得られた化合物(400 mg)より、(1S)-1-(5-クロロ-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル)ブタン-1-アミン 塩酸塩を粗精製物として得た。
LCMS (ESI) m/z 239 [M+H]+, tR = 0.78 min, mode H.
工程1−6−5:工程1−2−5と同様の手法を用いて、工程1−6−4で得られた化合物(430 mg)より、tert-ブチル [(3S)-1-{2-[(1S)-1-アミノブチル]-6-メチルピラゾロ[1,5-a]ピリミジン-5-イル}ピロリジン-3-イル]カルバマート(400 mg) を得た。
1H NMR (600 MHz, CDCl3, δ): 0.90-0.95 (m, 3H), 1.30-1.51 (m, 11H), 1.68-1.82 (m, 2H), 1.88-1.97 (m, 1H), 2.16-2.25 (m, 1H), 2.33 (s, 3H), 3.49-3.56 (m, 1H), 3.67-3.74 (m, 1H), 3.76-3.83 (m, 1H), 3.88-3.95 (m, 1H), 4.02 (t, J = 7.0 Hz, 1H), 4.30 (br s, 1H), 4.70 (br s, 1H), 6.02 (s, 1H), 8.02 (s, 1H).
LCMS (ESI) m/z 389 [M+H]+, tR = 1.01 min, mode H.
工程1−6−6:工程1−2−6及び工程1−2−7と同様の手法を用いて、工程1−6−5で得られた化合物(0.27 g)、5-メチル-2-[(メチルスルホニル)アミノ]安息香酸(96 mg)及び MeI (0.11 mL)より、tert-ブチル [(3S)-1-{6-メチル-2-[(1S)-1-(メチル{5-メチル-2-[(メチルスルホニル)アミノ]ベンゾイル}アミノ)ブチル]ピラゾロ[1,5-a]ピリミジン-5-イル}ピロリジン-3-イル]カルバマート(49 mg) を得た。
LCMS (ESI) m/z 614 [M+H]+, tR =1.26 min, mode N.
工程1−6−7:工程1−2−8と同様の手法を用いて、工程1−6−6で得られた化合物 (45 mg)より、表題化合物 (42 mg, 無色固体)を得た。
1H NMR (600 MHz, DMSO-d6, δ): 0.86 (br s, 1.5H), 1.00 (t, J = 7.4 Hz, 1.5H), 1.20-1.57 (m, 2H), 1.83-1.98 (m, 1H), 2.01-2.14 (m, 1H), 2.21-2.37 (m, 8H), 2.56 (s, 1.5H), 2.72 (br s, 1.5H), 2.96 (s, 3H), 3.64-3.95 (m, 5H), 4.57-4.69 (m, 0.5H), 5.84-5.92 (m, 0.5H), 6.07-6.14 (m, 1H), 7.09-7.39 (m, 3H), 8.13-8.37 (m, 3H), 8.51 (s, 0.5H), 8.96 (s, 0.5H).
LCMS (ESI) m/z 514 [M+H]+, tR = 0.63 min, mode N.
Example 1-6: N-[(1S) -1- {5-[(3S) -3-Aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidin-2-yl} butyl ] -N, 5-dimethyl-2-[(methylsulfonyl) amino] benzamide Hydrochloride Synthesis Step 1-6-1: Using the same method as in Step 1-1-2 and Step 1-1-3, From methyl N- (tert-butoxycarbonyl) -L-norvalinate (5800 mg), tert-butyl [(1S) -1- (5-amino-1H-pyrazol-3-yl) butyl] carbamate (4600 mg) Obtained.
1 H NMR (600 MHz, CDCl 3 , δ): 0.89-0.98 (m, 3H), 1.31-1.48 (m, 1H), 1.63-1.85 (m, 2H), 4.55-4.67 (m, 1H), 4.85 (br s, 1H), 5.49 (s, 1H).
LCMS (ESI) m / z 255 [M + H] + , t R = 0.51 min, mode N.
Step 1-6-2: Using a method similar to that of Step 1-2-2, tert-butyl [(1S) -1- (6) from the compound (4600 mg) obtained in Step 1-6-1 -Methyl-5-oxo-4,5-dihydropyrazolo [1,5-a] pyrimidin-2-yl) butyl] carbamate (2000 mg) was obtained.
1 H NMR (600 MHz, CDCl 3 , δ): 0.90-0.96 (m, 3H), 1.30-1.47 (m, 11H), 1.68-1.89 (m, 2H), 2.10 (s, 3H), 4.73-4.83 (m, 1H), 4.97- 5.09 (m, 1H), 5.83 (s, 1H), 7.98 (s, 1H), 11.04 (br s, 1H).
LCMS (ESI) m / z 321 [M + H] + , t R = 0.86 min, mode N.
Step 1-6-3: Using a method similar to that of Step 1-2-3, 2-[(1S) -1-aminobutyl] from the compound (500 mg) obtained in Step 1-6-2 -6-methylpyrazolo [1,5-a] pyrimidin-5 (4H) -one hydrochloride (460 mg) was obtained.
1 H NMR (600 MHz, DMSO-d 6 , δ): 0.87 (t, J = 7.4 Hz, 3H), 1.19-1.30 (m, 2H), 1.79-1.90 (m, 2H), 1.93- 1.96 (m , 3H), 4.23-4.29 (m, 1H), 6.01 (s, 1H), 8.43 (s, 1H), 8.50 (br s, 3), 12.27 (br s, 1H).
LCMS (ESI) m / z 221 [M + H] + , t R = 0.54 min, mode H.
Step 1-6-4: Using a method similar to that of Step 1-2-4, from the compound (400 mg) obtained in Step 1-6-3, (1S) -1- (5-chloro-6 -Methylpyrazolo [1,5-a] pyrimidin-2-yl) butan-1-amine hydrochloride was obtained as a crude product.
LCMS (ESI) m / z 239 [M + H] + , t R = 0.78 min, mode H.
Step 1-6-5: Using a method similar to that of Step 1-2-5, tert-butyl [(3S) -1- {2] from the compound (430 mg) obtained in Step 1-6-4 -[(1S) -1-Aminobutyl] -6-methylpyrazolo [1,5-a] pyrimidin-5-yl} pyrrolidin-3-yl] carbamate (400 mg) was obtained.
1 H NMR (600 MHz, CDCl 3 , δ): 0.90-0.95 (m, 3H), 1.30-1.51 (m, 11H), 1.68-1.82 (m, 2H), 1.88-1.97 (m, 1H), 2.16 -2.25 (m, 1H), 2.33 (s, 3H), 3.49-3.56 (m, 1H), 3.67-3.74 (m, 1H), 3.76-3.83 (m, 1H), 3.88-3.95 (m, 1H) , 4.02 (t, J = 7.0 Hz, 1H), 4.30 (br s, 1H), 4.70 (br s, 1H), 6.02 (s, 1H), 8.02 (s, 1H).
LCMS (ESI) m / z 389 [M + H] + , t R = 1.01 min, mode H.
Step 1-6-6: Using the same method as in Step 1-2-6 and Step 1-2-7, the compound (0.27 g) obtained in Step 1-6-5, 5-methyl-2- From [(methylsulfonyl) amino] benzoic acid (96 mg) and MeI (0.11 mL), tert-butyl [(3S) -1- {6-methyl-2-[(1S) -1- (methyl {5- Methyl-2-[(methylsulfonyl) amino] benzoyl} amino) butyl] pyrazolo [1,5-a] pyrimidin-5-yl} pyrrolidin-3-yl] carbamate (49 mg) was obtained.
LCMS (ESI) m / z 614 [M + H] + , t R = 1.26 min, mode N.
Step 1-6-7: Using the same method as in Step 1-2-8, the title compound (42 mg, colorless solid) was obtained from the compound (45 mg) obtained in Step 1-6-6. .
1 H NMR (600 MHz, DMSO-d 6 , δ): 0.86 (br s, 1.5H), 1.00 (t, J = 7.4 Hz, 1.5H), 1.20-1.57 (m, 2H), 1.83-1.98 ( m, 1H), 2.01-2.14 (m, 1H), 2.21-2.37 (m, 8H), 2.56 (s, 1.5H), 2.72 (br s, 1.5H), 2.96 (s, 3H), 3.64-3.95 (m, 5H), 4.57-4.69 (m, 0.5H), 5.84-5.92 (m, 0.5H), 6.07-6.14 (m, 1H), 7.09-7.39 (m, 3H), 8.13-8.37 (m, 3H), 8.51 (s, 0.5H), 8.96 (s, 0.5H).
LCMS (ESI) m / z 514 [M + H] + , t R = 0.63 min, mode N.
実施例1−7:N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}ブチル]-N-エチル-5-メチル-2-[(メチルスルホニル)アミノ]ベンズアミド 塩酸塩の合成
工程1−2−6〜工程1−2−8と同様の手法を用いて、工程1−6−5で得られた化合物(0.13 g)、5-メチル-2-[(メチルスルホニル)アミノ]安息香酸(46 mg)及び EtI (54 μL)より、表題化合物(2.5 mg, 無色アモルファス)を得た。
LCMS (ESI) m/z 528 [M+H]+, tR = 0.67 min, mode N.
Example 1-7: N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidin-2-yl} butyl ] -N-ethyl-5-methyl-2-[(methylsulfonyl) amino] benzamide Step 1-6 using the same method as in Step 1-2-6 to Step 1-2-8 The title compound (2.5 mg, colorless amorphous) was obtained from the compound obtained in 5 (0.13 g), 5-methyl-2-[(methylsulfonyl) amino] benzoic acid (46 mg) and EtI (54 μL). .
LCMS (ESI) m / z 528 [M + H] + , t R = 0.67 min, mode N.
実施例1−8:N-({5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}メチル)-5-クロロ-N-メチル-2-[(メチルスルホニル)アミノ]ベンズアミド 塩酸塩の合成
工程1−8−1:工程1−1−1〜工程1−1−3と同様の手法を用いて、N-(tert-ブトキシカルボニル)-N-メチルグリシン(4.00 g)より、tert-ブチル [(5-アミノ-1H-ピラゾール-3-イル)メチル](メチル)カルバマート (1.35 g, 黄色アモルファス)を得た。
1H NMR (600 MHz, CDCl3, δ): 1.41-1.57 (m, 9H), 2.75-3.01 (m, 3H), 4.26 (br s, 2H), 5.59 (s, 1H).
LCMS (ESI) m/z 227 [M+H]+, tR = 0.37 min, mode N.
工程1−8−2:工程1−1−4と同様の手法を用いて、工程1−8−1で得られた化合物(1.35 g)より、tert-ブチル メチル[(6-メチル-5-オキソ-4,5-ジヒドロピラゾロ[1,5-a]ピリミジン-2-イル)メチル]カルバマート(0.41 g, 黄色アモルファス)を得た。
1H NMR (600 MHz, CDCl3, δ): 1.39-1.54 (m, 9H), 2.09 (s, 3H), 2.78-2.95 (m, 3H), 4.31-4.51 (m, 2H), 5.72-5.90 (m, 1H), 7.96 (s, 1H), 10.77 (br s, 1H).
LCMS (ESI) m/z 291 [M-H] -, tR = 0.74 min, mode N.
工程1−8−3:工程1−1−5と同様の手法を用いて、工程1−8−2で得られた化合物 (410 mg)より、2-{[(tert-ブトキシカルボニル)(メチル)アミノ]メチル}-6-メチルピラゾロ[1,5-a]ピリミジン-5-イル トリフルオロメタンスルホナート (590 mg, 黄色アモルファス)を得た。
1H NMR (600 MHz, CDCl3, δ): 1.49 (s, 9H), 2.34 (s, 3H), 2.90 (d, J = 15.7 Hz, 3H), 4.53-4.69 (m, 2H), 6.54 (d, J = 15.3 Hz, 1H), 8.47-8.58 (m, 1H).
工程1−8−4:工程1−2−3と同様の手法を用いて、工程1−8−3で得られた化合物 (590 mg)より、6-メチル-2-[(メチルアミノ)メチル]ピラゾロ[1,5-a]ピリミジン-5-イル トリフルオロメタンスルホナート (500 mg, 黄色油状物)を得た。
工程1−8−5:工程1−1−8と同様の手法を用いて、工程1−8−4で得られた化合物 (500 mg)より、2-{[{5-クロロ-2-[(メチルスルホニル)アミノ]ベンゾイル}(メチル)アミノ]メチル}-6-メチルピラゾロ[1,5-a]ピリミジン-5-イル トリフルオロメタンスルホナート (590 mg, 黄色アモルファス)を得た。
1H NMR (600 MHz, CDCl3, δ): 2.36-2.42 (m, 3H), 2.83-3.14 (m, 6H), 4.58 (br s, 0.6H), 5.02 (br s, 1.4H), 6.37-6.51 (m, 1H), 7.15-7.78 (m, 3H), 8.72-8.87 (m, 1H), 9.08 (s, 0.7H), 10.09 (s, 0.3H).
工程1−8−6:工程1−2−5と同様の手法を用いて、工程1−8−5で得られた化合物(60 mg)より、tert-ブチル [(3S)-1-(2-{[{5-クロロ-2-[(メチルスルホニル)アミノ]ベンゾイル}(メチル)アミノ]メチル}-6-メチルピラゾロ[1,5-a]ピリミジン-5-イル)ピロリジン-3-イル]カルバマート (55 mg, 黄色アモルファス)を得た。
1H NMR (600 MHz, CDCl3, δ): 1.39-1.48 (m, 9H), 1.92 (dd, J = 12.6, 6.4 Hz, 1H), 2.17-2.26 (m, 1H), 2.36 (d, J = 9.5 Hz, 3H), 2.82-3.11 (m, 6H), 3.55 (d, J = 12.0 Hz, 1H), 3.68-3.86 (m, 2H), 3.93 (br s, 1H), 4.29 (br s, 1H), 4.44 (br s, 1H), 4.66 (br s, 1H), 4.92 (br s, 1H), 5.88-6.05 (m, 1H), 7.27-7.45 (m, 2H), 7.56-7.63 (m, 0.5H), 7.66-7.77 (m, 0.5H), 8.35 (s, 0.5H), 8.62 (s, 0.5H), 9.26 (s, 0.5H), 10.89 (s, 0.5H).
LCMS (ESI) m/z 592[M+H]+, tR = 1.30 min, mode N.
工程1−8−7:工程1−2−8と同様の手法を用いて、工程1−8−6で得られた化合物(55 mg)より、表題化合物(45 mg, 無色固体)を得た。
LCMS (ESI) m/z 492 [M+H]+, tR = 0.46 min, mode N.
Example 1-8: N-({5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidin-2-yl} methyl) -5-chloro- N-methyl-2-[(methylsulfonyl) amino] benzamide hydrochloride synthesis step 1-8-1: Using the same method as in step 1-1-1 to step 1-1-3, N- (tert -Butoxycarbonyl) -N-methylglycine (4.00 g) gave tert-butyl [(5-amino-1H-pyrazol-3-yl) methyl] (methyl) carbamate (1.35 g, yellow amorphous).
1 H NMR (600 MHz, CDCl 3 , δ): 1.41-1.57 (m, 9H), 2.75-3.01 (m, 3H), 4.26 (br s, 2H), 5.59 (s, 1H).
LCMS (ESI) m / z 227 [M + H] + , t R = 0.37 min, mode N.
Step 1-8-2: Using a method similar to that in Step 1-1-4, tert-butyl methyl [(6-methyl-5- Oxo-4,5-dihydropyrazolo [1,5-a] pyrimidin-2-yl) methyl] carbamate (0.41 g, yellow amorphous) was obtained.
1 H NMR (600 MHz, CDCl 3 , δ): 1.39-1.54 (m, 9H), 2.09 (s, 3H), 2.78-2.95 (m, 3H), 4.31-4.51 (m, 2H), 5.72-5.90 (m, 1H), 7.96 (s, 1H), 10.77 (br s, 1H).
LCMS (ESI) m / z 291 [MH] - , t R = 0.74 min, mode N.
Step 1-8-3: Using a method similar to that of Step 1-1-5, from the compound obtained in Step 1-8-2 (410 mg), 2-{[(tert-butoxycarbonyl) (methyl ) Amino] methyl} -6-methylpyrazolo [1,5-a] pyrimidin-5-yl trifluoromethanesulfonate (590 mg, yellow amorphous) was obtained.
1 H NMR (600 MHz, CDCl 3 , δ): 1.49 (s, 9H), 2.34 (s, 3H), 2.90 (d, J = 15.7 Hz, 3H), 4.53-4.69 (m, 2H), 6.54 ( d, J = 15.3 Hz, 1H), 8.47-8.58 (m, 1H).
Step 1-8-4: Using a method similar to that of Step 1-2-3, from the compound (590 mg) obtained in Step 1-8-3, 6-methyl-2-[(methylamino) methyl Pyrazolo [1,5-a] pyrimidin-5-yl trifluoromethanesulfonate (500 mg, yellow oil) was obtained.
Step 1-8-5: Using a method similar to that of Step 1-1-8, the compound (500 mg) obtained in Step 1-8-4 was used to give 2-{[{5-chloro-2- [ (Methylsulfonyl) amino] benzoyl} (methyl) amino] methyl} -6-methylpyrazolo [1,5-a] pyrimidin-5-yl trifluoromethanesulfonate (590 mg, yellow amorphous) was obtained.
1 H NMR (600 MHz, CDCl 3 , δ): 2.36-2.42 (m, 3H), 2.83-3.14 (m, 6H), 4.58 (br s, 0.6H), 5.02 (br s, 1.4H), 6.37 -6.51 (m, 1H), 7.15-7.78 (m, 3H), 8.72-8.87 (m, 1H), 9.08 (s, 0.7H), 10.09 (s, 0.3H).
Step 1-8-6: Using a method similar to that in Step 1-2-5, from the compound obtained in Step 1-8-5 (60 mg), tert-butyl [(3S) -1- (2 -{[{5-Chloro-2-[(methylsulfonyl) amino] benzoyl} (methyl) amino] methyl} -6-methylpyrazolo [1,5-a] pyrimidin-5-yl) pyrrolidin-3-yl] carbamate (55 mg, yellow amorphous) was obtained.
1 H NMR (600 MHz, CDCl 3 , δ): 1.39-1.48 (m, 9H), 1.92 (dd, J = 12.6, 6.4 Hz, 1H), 2.17-2.26 (m, 1H), 2.36 (d, J = 9.5 Hz, 3H), 2.82-3.11 (m, 6H), 3.55 (d, J = 12.0 Hz, 1H), 3.68-3.86 (m, 2H), 3.93 (br s, 1H), 4.29 (br s, 1H), 4.44 (br s, 1H), 4.66 (br s, 1H), 4.92 (br s, 1H), 5.88-6.05 (m, 1H), 7.27-7.45 (m, 2H), 7.56-7.63 (m , 0.5H), 7.66-7.77 (m, 0.5H), 8.35 (s, 0.5H), 8.62 (s, 0.5H), 9.26 (s, 0.5H), 10.89 (s, 0.5H).
LCMS (ESI) m / z 592 [M + H] + , t R = 1.30 min, mode N.
Step 1-8-7: Using the same method as in Step 1-2-8, the title compound (45 mg, colorless solid) was obtained from the compound (55 mg) obtained in Step 1-8-6. .
LCMS (ESI) m / z 492 [M + H] + , t R = 0.46 min, mode N.
実施例1−9:N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}-2-メチルプロピル]-5-クロロ-N-メチル-2-[(メチルスルホニル)アミノ]ベンズアミドの合成
工程1−1−1〜工程1−1−9と同様の手法にて、N-(tert-ブトキシカルボニル)-N-メチル-L-バリン(5.0 g)より、表題化合物(15 mg, 無色固体)を得た。
LCMS (ESI) m/z 534 [M+H]+, tR = 0.66 min, mode N.
Example 1-9: N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidin-2-yl}- Synthesis of 2-methylpropyl] -5-chloro-N-methyl-2-[(methylsulfonyl) amino] benzamide N- (tert The title compound (15 mg, colorless solid) was obtained from -butoxycarbonyl) -N-methyl-L-valine (5.0 g).
LCMS (ESI) m / z 534 [M + H] + , t R = 0.66 min, mode N.
実施例1−10:N-(1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}シクロプロピル)-5-クロロ-N-メチル-2-[(メチルスルホニル)アミノ]ベンズアミドの合成
工程1−10−1:工程1−1−1〜工程1−1−3と同様の手法を用いて、1-[(tert-ブトキシカルボニル)アミノ]シクロプロパンカルボン酸(4.0 g)より、tert-ブチル [1-(5-アミノ-1H-ピラゾール-3-イル)シクロプロピル]カルバマート (4.7 g、黄色アモルファス)を得た。
1H NMR (600 MHz, CDCl3, δ): 1.14 (s, 4H), 1.44 (s, 9H), 5.26 (br s, 1H), 5.35 (br s, 1H).
工程1−10−2:工程1−10−1で得られた化合物(2.5 g)のEtOH(110 mL)にエチル (2E)-3-エトキシ-2-メチルプロパ-2-エノアート(3.7 mL)及び28% NaOEt/EtOH溶液(7.3 mL)を加え、90 ℃で30時間撹拌した。反応溶液にEtOAcを加え、飽和NaHCO3水溶液で分液操作を行った。水層をBrineにて洗浄後、有機層をMgSO4にて乾燥し、ろ過後、ろ液を減圧下濃縮した。残渣をOH型シリカゲルカラムクロマトグラフィー(移動相:CHCl3/MeOH = 100:0〜95/5; v/v)で精製し、tert-ブチル [1-(6-メチル-5-オキソ-4,5-ジヒドロピラゾロ[1,5-a]ピリミジン-2-イル)シクロプロピル]カルバマート (2.0 g, 褐色固体)を得た。
1H NMR (600 MHz, CDCl3, δ): 1.09-1.54 (m, 13H), 2.06 (s, 3H), 4.06-4.29 (m, 1H), 5.36 (s, 1H), 5.76 (br s, 1H), 7.89 (s, 1H), 10.71 (br s, 1H).
LCMS (ESI) m/z 305 [M+H]+, tR = 0.66 min, mode N.
工程1−10−3:工程1−1−5と同様の手法を用いて、工程1−10−2で得た化合物 (1.9 g)より、2-{1-[(tert-ブトキシカルボニル)アミノ]シクロプロピル}-6-メチルピラゾロ[1,5-a]ピリミジン-5-イル トリフルオロメタンスルホナート(0.69 g, 黄色固体)を得た。
1H NMR (600 MHz, CDCl3, δ): 1.28-1.54 (m, 13H), 2.30 (s, 3H), 5.39 (br s, 1H), 6.49 (s, 1H), 8.43 (s, 1H).
工程1−10−4:工程1−1−6と同様の手法を用いて、工程1−10−3で得た化合物(100 mg)より、ベンジル [(3S)-1-(2-{1-[(tert-ブトキシカルボニル)アミノ]シクロプロピル}-6-メチルピラゾロ[1,5-a]ピリミジン-5-イル)ピロリジン-3-イル]カルバマート(120 mg, 淡黄色固体)を得た。
1H NMR (600 MHz, CDCl3, δ): 1.17-1.51 (m, 13H), 1.89-2.00 (m, 1H), 2.17-2.35 (m, 4H), 3.51-3.60 (m, 1H), 3.65-3.73 (m, 1H), 3.74-3.82 (m, 1H), 3.86-3.96 (m, 1H), 4.30-4.40 (m, 1H), 4.88-4.98 (m, 1H), 5.11 (br s, 2H), 5.36 (br s, 1H), 5.99 (s, 1H), 7.29-7.41 (m, 5H), 7.96 (s, 1H).
工程1−10−5:工程1−1−7と同様の手法を用いて、工程1−10−4で得た化合物 (120 mg)より、ベンジル {(3S)-1-[2-(1-アミノシクロプロピル)-6-メチルピラゾロ[1,5-a]ピリミジン-5-イル]ピロリジン-3-イル}カルバマート 塩酸塩(110 mg, 淡黄色固体)を得た。
1H NMR (600 MHz, DMSO-d6, δ): 1.22-1.28 (m, 2H), 1.41-1.46 (m, 2H), 1.83-1.90 (m, 1H), 2.04-2.13 (m, 1H), 2.34 (s, 3H), 3.47-3.89 (m, 4H), 4.06-4.17 (m, 1H), 5.03 (s, 2H), 5.96 (s, 1H), 7.30-7.40 (m, 4H), 7.60-7.67 (m, 1H), 8.43 (s, 1H), 8.87 (br s, 3H).
LCMS (ESI) m/z 407 [M+H]+, tR = 0.52 min, mode N.
工程1−10−6:工程1−2−6及び工程1−2−7と同様の手法を用いて、工程1−10−5で得た化合物(88 mg)、5-クロロ-2-[(メチルスルホニル)アミノ]安息香酸(28 mg)及び MeI (12 μL)より、ベンジル [(3S)-1-(2-{1-[{5-クロロ-2-[(メチルスルホニル)アミノ]ベンゾイル}(メチル)アミノ]シクロプロピル}-6-メチルピラゾロ[1,5-a]ピリミジン-5-イル)ピロリジン-3-イル]カルバマート(27 mg, 淡黄色固体)を得た。
LCMS (ESI) m/z 652[M+H]+, tR = 1.15 min, mode N.
工程1−10−7:工程1−1−9と同様の手法を用いて、工程1−10−6で得られた化合物 (27 mg) より、表題化合物 (8.0 mg, 白色固体) を得た。
LCMS (ESI) m/z 518 [M+H]+, tR = 0.55 min, mode N.
Example 1-10: N- (1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidin-2-yl} cyclopropyl) -5 Step 1-10-1 for Synthesis of 1-Chloro-N-methyl-2-[(methylsulfonyl) amino] benzamide: Using the same method as in Step 1-1-1 to Step 1-1-3, (tert-Butoxycarbonyl) amino] cyclopropanecarboxylic acid (4.0 g) gave tert-butyl [1- (5-amino-1H-pyrazol-3-yl) cyclopropyl] carbamate (4.7 g, yellow amorphous) It was.
1 H NMR (600 MHz, CDCl 3 , δ): 1.14 (s, 4H), 1.44 (s, 9H), 5.26 (br s, 1H), 5.35 (br s, 1H).
Step 1-10-2: Ethyl (2E) -3-ethoxy-2-methylprop-2-enoate (3.7 mL) and EtOH (110 mL) of the compound (2.5 g) obtained in Step 1-10-1 and 28% NaOEt / EtOH solution (7.3 mL) was added, and the mixture was stirred at 90 ° C. for 30 hr. EtOAc was added to the reaction solution, and a liquid separation operation was performed with a saturated aqueous NaHCO 3 solution. The aqueous layer was washed with Brine, the organic layer was dried with MgSO 4 , filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by OH-type silica gel column chromatography (mobile phase: CHCl 3 / MeOH = 100: 0 to 95/5; v / v), and tert-butyl [1- (6-methyl-5-oxo-4, 5-Dihydropyrazolo [1,5-a] pyrimidin-2-yl) cyclopropyl] carbamate (2.0 g, brown solid) was obtained.
1 H NMR (600 MHz, CDCl 3 , δ): 1.09-1.54 (m, 13H), 2.06 (s, 3H), 4.06-4.29 (m, 1H), 5.36 (s, 1H), 5.76 (br s, 1H), 7.89 (s, 1H), 10.71 (br s, 1H).
LCMS (ESI) m / z 305 [M + H] + , t R = 0.66 min, mode N.
Step 1-10-3: Using a method similar to that of Step 1-1-5, 2- {1-[(tert-butoxycarbonyl) amino from the compound (1.9 g) obtained in Step 1-10-2 ] Cyclopropyl} -6-methylpyrazolo [1,5-a] pyrimidin-5-yl trifluoromethanesulfonate (0.69 g, yellow solid) was obtained.
1 H NMR (600 MHz, CDCl 3 , δ): 1.28-1.54 (m, 13H), 2.30 (s, 3H), 5.39 (br s, 1H), 6.49 (s, 1H), 8.43 (s, 1H) .
Step 1-10-4: Using a method similar to that of Step 1-1-6, benzyl [(3S) -1- (2- {1] from the compound (100 mg) obtained in Step 1-10-3 -[(tert-Butoxycarbonyl) amino] cyclopropyl} -6-methylpyrazolo [1,5-a] pyrimidin-5-yl) pyrrolidin-3-yl] carbamate (120 mg, pale yellow solid) was obtained.
1 H NMR (600 MHz, CDCl 3 , δ): 1.17-1.51 (m, 13H), 1.89-2.00 (m, 1H), 2.17-2.35 (m, 4H), 3.51-3.60 (m, 1H), 3.65 -3.73 (m, 1H), 3.74-3.82 (m, 1H), 3.86-3.96 (m, 1H), 4.30-4.40 (m, 1H), 4.88-4.98 (m, 1H), 5.11 (br s, 2H ), 5.36 (br s, 1H), 5.99 (s, 1H), 7.29-7.41 (m, 5H), 7.96 (s, 1H).
Step 1-10-5: Using a method similar to that of Step 1-1-7, benzyl {(3S) -1- [2- (1) from the compound (120 mg) obtained in Step 1-10-4 -Aminocyclopropyl) -6-methylpyrazolo [1,5-a] pyrimidin-5-yl] pyrrolidin-3-yl} carbamate hydrochloride (110 mg, pale yellow solid) was obtained.
1 H NMR (600 MHz, DMSO-d 6 , δ): 1.22-1.28 (m, 2H), 1.41-1.46 (m, 2H), 1.83-1.90 (m, 1H), 2.04-2.13 (m, 1H) , 2.34 (s, 3H), 3.47-3.89 (m, 4H), 4.06-4.17 (m, 1H), 5.03 (s, 2H), 5.96 (s, 1H), 7.30-7.40 (m, 4H), 7.60 -7.67 (m, 1H), 8.43 (s, 1H), 8.87 (br s, 3H).
LCMS (ESI) m / z 407 [M + H] + , t R = 0.52 min, mode N.
Step 1-10-6: Using a method similar to that of Step 1-2-6 and Step 1-2-7, the compound (88 mg) obtained in Step 1-10-5, 5-chloro-2- [ From (methylsulfonyl) amino] benzoic acid (28 mg) and MeI (12 μL), benzyl [(3S) -1- (2- {1-[{5-chloro-2-[(methylsulfonyl) amino] benzoyl } (Methyl) amino] cyclopropyl} -6-methylpyrazolo [1,5-a] pyrimidin-5-yl) pyrrolidin-3-yl] carbamate (27 mg, pale yellow solid) was obtained.
LCMS (ESI) m / z 652 [M + H] + , t R = 1.15 min, mode N.
Step 1-10-7: Using the same method as in Step 1-1-9, the title compound (8.0 mg, white solid) was obtained from the compound (27 mg) obtained in Step 1-10-6. .
LCMS (ESI) m / z 518 [M + H] + , t R = 0.55 min, mode N.
実施例1−11:N-[(S)-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}(シクロプロピル)メチル]-5-クロロ-N-エチル-2-[(メチルスルホニル)アミノ]ベンズアミド 塩酸塩の合成
工程1−11−1:工程1−1−1〜工程1−1−3と同様の手法を用いて、(2S)-[(tert-ブトキシカルボニル)アミノ](シクロプロピル)酢酸(2.0 g)より、tert-ブチル [(S)-(5-アミノ-1H-ピラゾール-3-イル)(シクロプロピル)メチル]カルバマート (1.65 g, 黄色アモルファス)を得た。
1H NMR (600 MHz, CDCl3, δ): 0.30-0.76 (m, 4H), 1.16 (dt, J = 8.4, 4.3 Hz, 1H), 1.37-1.52 (m, 9H), 3.94 (dd, J = 9.1, 7.4 Hz, 1H), 5.00 (br s, 1H), 5.63 (s, 1H).
LCMS (ESI) m/z 253 [M+H]+, tR = 0.369 min, mode N.
工程1−11−2:工程1−2−2と同様の手法を用いて、工程1−11−1で得られた化合物(1.65 g)より、tert-ブチル [(S)-シクロプロピル(6-メチル-5-オキソ-4,5-ジヒドロピラゾロ[1,5-a]ピリミジン-2-イル)メチル]カルバマート(0.31 g, 黄色アモルファス)を得た。
1H NMR (600 MHz, CDCl3, δ): 0.36-0.59 (m, 4H), 1.13-1.21 (m, 1H), 1.43-1.46 (m, 9H), 2.10 (d, J = 1.2 Hz, 3H), 4.27 (br s, 1H), 5.22 (d, J = 7.8 Hz, 1H), 5.87 (s, 1H), 7.99 (s, 1H), 10.57-11.23 (m, 1H).
LCMS (ESI) m/z 319 [M+H]+, tR = 0.75 min, mode N.
工程1−11−3:工程1−2−3と同様の手法を用いて、工程1−11−2で得られた化合物(310 mg)より、2-[(S)-アミノ(シクロプロピル)メチル]-6-メチルピラゾロ[1,5-a]ピリミジン-5(4H)-オン 塩酸塩(250 mg, 黄色固体)を得た。
1H NMR (600 MHz, DMSO-d6, δ): 0.38-0.72 (m, 4H), 1.22-1.36 (m, 1H), 1.86-1.97 (m, 3H), 3.63-3.75 (m, 1H), 6.02 (s, 1H), 8.38-8.48 (m, 1H), 8.57 (br s, 3H), 12.28 (br s, 1H).
LCMS (ESI) m/z 202 [M-NH2]+, tR = 0.34 min, mode N.
工程1−11−4:工程1−2−4と同様の手法を用いて、工程1−11−3で得られた化合物(250 mg)より、(S)-1-(5-クロロ-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル)-1-シクロプロピルメタンアミン 塩酸塩(260 mg, 褐色アモルファス)を得た。
LCMS (ESI) m/z 221 [M-NH2]+, tR = 0.659 min, mode H.
工程1−11−5:工程1−2−5と同様の手法を用いて、工程1−11−4で得られた化合物(260 mg)より、tert-ブチル [(3S)-1-{2-[(S)-アミノ(シクロプロピル)メチル]-6-メチルピラゾロ[1,5-a]ピリミジン-5-イル}ピロリジン-3-イル]カルバマート(235 mg, 無色アモルファス)を得た。
1H NMR (600 MHz, CDCl3, δ): 0.30-0.41 (m, 2H), 0.48-0.63 (m, 2H), 1.15-1.22 (m, 1H), 1.45 (s, 9H), 1.89-1.96 (m, 1H), 2.17-2.25 (m, 1H), 2.33 (d, J = 0.8 Hz, 3H), 3.38 (d, J = 8.7 Hz, 1H), 3.53 (dd, J = 11.1, 3.7 Hz, 1H), 3.66-3.74 (m, 1H), 3.80 (dt, J = 10.7, 7.4 Hz, 1H), 3.92 (dd, J = 10.3, 5.8 Hz, 1H), 4.30 (br s, 1H), 4.71 (br s, 1H), 6.12 (s, 1H), 8.04 (s, 1H).
LCMS (ESI) m/z 370 [M-NH2]+, tR = 0.49 min, mode N.
工程1−11−6:工程1−2−6及び工程1−2−7と同様の手法を用いて、工程1−11−5で得られた化合物(235 mg)、5-クロロ-2-[(メチルスルホニル)アミノ]安息香酸(99 mg)及び EtI (48 μL)より、tert-ブチル [(3S)-1-{2-[(S)-[{5-クロロ-2-[(メチルスルホニル)アミノ]ベンゾイル}(エチル)アミノ](シクロプロピル)メチル]-6-メチルピラゾロ[1,5-a]ピリミジン-5-イル}ピロリジン-3-イル]カルバマート(100 mg, 淡黄色固体)を得た。
1H NMR (600 MHz, CDCl3, δ): 0.21-1.36 (m, 8H), 1.45 (s, 9H), 1.92 (dd, J = 12.2, 6.0 Hz, 1H), 2.15-2.27 (m, 1H), 2.37 (d, J = 8.3 Hz, 3H), 2.87-3.13 (m, 5H), 3.49-3.59 (m, 1H), 3.65-3.84 (m, 3H), 3.94 (br s, 1H), 4.30 (br s, 1H), 4.67 (br s, 1H), 6.15-6.37 (m, 1H), 6.98-7.74 (m, 3H), 8.37 (s, 0.5H), 8.66 (s, 0.5H), 9.61 (br s, 0.5H), 11.20 (br s, 0.5H).
工程1−11−7:工程1−2−8と同様の手法を用いて、工程1−11−6で得られた化合物(100 mg)より、表題化合物(70 mg, 無色固体)を得た。
1H NMR (600 MHz, DMSO-d6, δ): 0.26 (br s, 1H), 0.48-0.83 (m, 3H), 0.91-1.17 (m, 3H), 1.44-1.62 (m, 1H), 2.03-2.12 (m, 1H), 2.20-2.31 (m, 1H), 2.32-2.40 (m, 3H), 3.00 (s, 3H), 3.05-3.19 (m, 2H), 3.69-4.01 (m, 5H), 4.87 (br s, 1H), 6.21-6.32 (m, 1H), 7.33-7.58 (m, 3H), 8.36-8.45 (m, 3H), 8.53 (s, 0.5H), 9.24 (s, 0.5H).
LCMS (ESI) m/z 546 [M+H]+, tR = 0.64 min, mode N.
Example 1-11: N-[(S)-{5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidin-2-yl} (cyclopropyl ) Methyl] -5-chloro-N-ethyl-2-[(methylsulfonyl) amino] benzamide Hydrochloride Synthesis Step 1-11-1: Procedure similar to Step 1-1-1 to Step 1-1-3 From (2S)-[(tert-butoxycarbonyl) amino] (cyclopropyl) acetic acid (2.0 g) to tert-butyl [(S)-(5-amino-1H-pyrazol-3-yl) ( Cyclopropyl) methyl] carbamate (1.65 g, yellow amorphous) was obtained.
1 H NMR (600 MHz, CDCl 3 , δ): 0.30-0.76 (m, 4H), 1.16 (dt, J = 8.4, 4.3 Hz, 1H), 1.37-1.52 (m, 9H), 3.94 (dd, J = 9.1, 7.4 Hz, 1H), 5.00 (br s, 1H), 5.63 (s, 1H).
LCMS (ESI) m / z 253 [M + H] + , t R = 0.369 min, mode N.
Step 1-11-2: Using a method similar to that of Step 1-2-2, tert-butyl [(S) -cyclopropyl (6) from the compound (1.65 g) obtained in Step 1-11-1 -Methyl-5-oxo-4,5-dihydropyrazolo [1,5-a] pyrimidin-2-yl) methyl] carbamate (0.31 g, yellow amorphous) was obtained.
1 H NMR (600 MHz, CDCl 3 , δ): 0.36-0.59 (m, 4H), 1.13-1.21 (m, 1H), 1.43-1.46 (m, 9H), 2.10 (d, J = 1.2 Hz, 3H ), 4.27 (br s, 1H), 5.22 (d, J = 7.8 Hz, 1H), 5.87 (s, 1H), 7.99 (s, 1H), 10.57-11.23 (m, 1H).
LCMS (ESI) m / z 319 [M + H] + , t R = 0.75 min, mode N.
Step 1-11-3: Using the same method as in Step 1-2-3, from the compound (310 mg) obtained in Step 1-11-2, 2-[(S) -amino (cyclopropyl) Methyl] -6-methylpyrazolo [1,5-a] pyrimidin-5 (4H) -one hydrochloride (250 mg, yellow solid) was obtained.
1 H NMR (600 MHz, DMSO-d 6 , δ): 0.38-0.72 (m, 4H), 1.22-1.36 (m, 1H), 1.86-1.97 (m, 3H), 3.63-3.75 (m, 1H) , 6.02 (s, 1H), 8.38-8.48 (m, 1H), 8.57 (br s, 3H), 12.28 (br s, 1H).
LCMS (ESI) m / z 202 [M-NH 2 ] + , t R = 0.34 min, mode N.
Step 1-11-4: Using the same method as in Step 1-2-4, from the compound (250 mg) obtained in Step 1-11-3, (S) -1- (5-chloro-6 -Methylpyrazolo [1,5-a] pyrimidin-2-yl) -1-cyclopropylmethanamine hydrochloride (260 mg, brown amorphous) was obtained.
LCMS (ESI) m / z 221 [M-NH 2 ] + , t R = 0.659 min, mode H.
Step 1-11-5: Using the same method as in Step 1-2-5, from the compound (260 mg) obtained in Step 1-11-4, tert-butyl [(3S) -1- {2 -[(S) -Amino (cyclopropyl) methyl] -6-methylpyrazolo [1,5-a] pyrimidin-5-yl} pyrrolidin-3-yl] carbamate (235 mg, colorless amorphous) was obtained.
1 H NMR (600 MHz, CDCl 3 , δ): 0.30-0.41 (m, 2H), 0.48-0.63 (m, 2H), 1.15-1.22 (m, 1H), 1.45 (s, 9H), 1.89-1.96 (m, 1H), 2.17-2.25 (m, 1H), 2.33 (d, J = 0.8 Hz, 3H), 3.38 (d, J = 8.7 Hz, 1H), 3.53 (dd, J = 11.1, 3.7 Hz, 1H), 3.66-3.74 (m, 1H), 3.80 (dt, J = 10.7, 7.4 Hz, 1H), 3.92 (dd, J = 10.3, 5.8 Hz, 1H), 4.30 (br s, 1H), 4.71 ( br s, 1H), 6.12 (s, 1H), 8.04 (s, 1H).
LCMS (ESI) m / z 370 [M-NH 2 ] + , t R = 0.49 min, mode N.
Step 1-11-6: Using the same method as in Step 1-2-6 and Step 1-2-7, the compound (235 mg) obtained in Step 1-11-1-5, 5-chloro-2- From [(methylsulfonyl) amino] benzoic acid (99 mg) and EtI (48 μL), tert-butyl [(3S) -1- {2-[(S)-[{5-chloro-2-[(methyl Sulfonyl) amino] benzoyl} (ethyl) amino] (cyclopropyl) methyl] -6-methylpyrazolo [1,5-a] pyrimidin-5-yl} pyrrolidin-3-yl] carbamate (100 mg, pale yellow solid) Obtained.
1 H NMR (600 MHz, CDCl 3 , δ): 0.21-1.36 (m, 8H), 1.45 (s, 9H), 1.92 (dd, J = 12.2, 6.0 Hz, 1H), 2.15-2.27 (m, 1H ), 2.37 (d, J = 8.3 Hz, 3H), 2.87-3.13 (m, 5H), 3.49-3.59 (m, 1H), 3.65-3.84 (m, 3H), 3.94 (br s, 1H), 4.30 (br s, 1H), 4.67 (br s, 1H), 6.15-6.37 (m, 1H), 6.98-7.74 (m, 3H), 8.37 (s, 0.5H), 8.66 (s, 0.5H), 9.61 (br s, 0.5H), 11.20 (br s, 0.5H).
Step 1-11-7: Using the same method as in Step 1-2-8, the title compound (70 mg, colorless solid) was obtained from the compound (100 mg) obtained in Step 1-11-6. .
1 H NMR (600 MHz, DMSO-d 6 , δ): 0.26 (br s, 1H), 0.48-0.83 (m, 3H), 0.91-1.17 (m, 3H), 1.44-1.62 (m, 1H), 2.03-2.12 (m, 1H), 2.20-2.31 (m, 1H), 2.32-2.40 (m, 3H), 3.00 (s, 3H), 3.05-3.19 (m, 2H), 3.69-4.01 (m, 5H ), 4.87 (br s, 1H), 6.21-6.32 (m, 1H), 7.33-7.58 (m, 3H), 8.36-8.45 (m, 3H), 8.53 (s, 0.5H), 9.24 (s, 0.5 H).
LCMS (ESI) m / z 546 [M + H] + , t R = 0.64 min, mode N.
実施例1−12:N-[(1R)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}-2-ヒドロキシエチル]-5-クロロ-N-メチル-2-[(メチルスルホニル)アミノ]ベンズアミド 塩酸塩の合成
工程1−12−1:工程1−1−1と同様の手法を用いて、N-(tert-ブトキシカルボニル)-N-メチル-L-セリン(5.0 g)より、メチル N-(tert-ブトキシカルボニル)-N-メチル-L-セリナート (5.6 g, 無色油状物)を得た。
工程1−12−2:工程1−12−1で得られた化合物(5.50 g)のDMF(50 mL)溶液に、TBDPSCl(7.58 g), イミダゾール(3.42 g)を加え、室温にて一晩攪拌した。反応液を水にあけ、EtOAc にて抽出を行った。有機層をBrineで洗浄、MgSO4で乾燥ろ過後、ろ液を減圧下濃縮した。得られた残渣をOH型シリカゲルカラムクロマトグラフィー (移動相: ヘキサン/EtOAc = 80/20〜0/100; v/v) で精製し、メチル N-(tert-ブトキシカルボニル)-O-[tert-ブチル(ジフェニル)シリル]-N-メチル-L-セリナート(12.2 g, 無色油状物)を得た。
工程1−12−3:工程1−1−2及び工程1−1−3と同様の手法を用いて、工程1−12−2で得られた化合物(12 g)より、tert-ブチル [(1R)-1-(5-アミノ-1H-ピラゾール-3-イル)-2-{[tert-ブチル(ジフェニル)シリル]オキシ}エチル](メチル)カルバマート(8.5 g, 淡黄色アモルファス)を得た。
1H NMR (600 MHz, CDCl3, δ): 1.06 (br s, 9H), 1.42-1.53 (m, 9H), 2.73 (s, 3H), 3.88-4.06 (m, 2H), 5.17-5.32 (m, 1H), 5.44 (s, 1H), 7.34-7.46 (m, 6H), 7.60-7.68 (m, 4H).
LCMS (ESI) m/z 495 [M+H]+, tR = 1.22 min, mode N.
工程1−12−4:工程1−1−4と同様の手法を用いて、工程1−12−3で得られた化合物(3.85 g)より、tert-ブチル [(1R)-2-{[tert-ブチル(ジフェニル)シリル]オキシ}-1-(6-メチル-5-オキソ-4,5-ジヒドロピラゾロ[1,5-a]ピリミジン-2-イル)エチル](メチル)カルバマート(150 mg, 黄色アモルファス)を得た。
1H NMR (600 MHz, CDCl3, δ): 1.01-1.09 (m, 9H), 1.45-1.54 (m, 9H), 2.01-2.12 (m, 3H), 2.75 (d, J = 14.0 Hz, 3H), 3.96-4.24 (m, 2H), 5.36-5.83 (m, 2H), 7.33-7.48 (m, 6H), 7.68 (d, J = 6.2 Hz, 4H), 7.90 (s, 1H), 10.28 (br s, 1H).
工程1−12−5:工程1−1−5と同様の手法を用いて、工程1−12−4で得られた化合物(145 mg)より、6-メチル-2-[(6R)-2,2,7,10,10-ペンタメチル-8-オキソ-3,3-ジフェニル-4,9-ジオキサ-7-アザ-3-シラウンデカン-6-イル]ピラゾロ[1,5-a]ピリミジン-5-イル トリフルオロメタンスルホナート(150 mg, 黄色アモルファス)を得た。
1H NMR (600 MHz, CDCl3, δ): 1.06 (br s, 9H), 1.46-1.53 (m, 9H), 2.30 (br s, 3H), 2.77 (d, J = 16.9 Hz, 3H), 4.06-4.26 (m, 2H), 5.48-5.86 (m, 1H), 6.42-6.51 (m, 1H), 7.35-7.45 (m, 6H), 7.68 (d, J = 6.6 Hz, 4H), 8.44 (br s, 1H).
工程1−12−6:工程1−2−3と同様の手法を用いて、工程1−12−5で得られた化合物(150 mg)より、2-[(1R)-2-{[tert-ブチル(ジフェニル)シリル]オキシ}-1-(メチルアミノ)エチル]-6-メチルピラゾロ[1,5-a]ピリミジン-5-イル トリフルオロメタンスルホナート 塩酸塩(150 mg, 黄色油状物)を得た。
工程1−12−7:工程1−1−8と同様の手法を用いて、工程1−12−6で得られた化合物(150 mg)より、2-{(1R)-2-{[tert-ブチル(ジフェニル)シリル]オキシ}-1-[{5-クロロ-2-[(メチルスルホニル)アミノ]ベンゾイル}(メチル)アミノ]エチル}-6-メチルピラゾロ[1,5-a]ピリミジン-5-イル トリフルオロメタンスルホナート(100 mg, 黄色アモルファス)を得た。
1H NMR (600 MHz, CDCl3, δ): 1.05-1.18 (m, 9H), 2.25-2.49 (m, 3H), 2.67-2.85 (m, 3H), 2.88-3.14 (m, 3H), 3.98-4.41 (m, 2H), 5.07 (dd, J = 8.9, 5.6 Hz, 0.5H), 6.21-6.38 (m, 1.5H), 7.32-7.78 (m, 13H), 8.71-8.86 (m, 1H), 9.03 (s, 0.5H), 10.21 (br s, 0.5H).
工程1−12−8:工程1−2−5と同様の手法を用いて、工程1−12−7で得られた化合物(100 mg)より、tert-ブチル [(3S)-1-(2-{(1R)-2-{[tert-ブチル(ジフェニル)シリル]オキシ}-1-[{5-クロロ-2-[(メチルスルホニル)アミノ]ベンゾイル}(メチル)アミノ]エチル}-6-メチルピラゾロ[1,5-a]ピリミジン-5-イル)ピロリジン-3-イル]カルバマート (100 mg, 黄色アモルファス)を得た。
工程1−12−9:工程1−12−8で得られた化合物(100 mg)のTHF(3 mL)溶液に、1M TBAF/THF溶液(0.24 mL) を加え、65 ℃にて4時間攪拌した。反応液を減圧下濃縮後、得られた残渣をシリカゲルカラムクロマトグラフィー(移動相:ヘキサン/EtOAc = 50/50〜0/100; v/v)で精製し、tert-ブチル [(3S)-1-(2-{(1R)-1-[{5-クロロ-2-[(メチルスルホニル)アミノ]ベンゾイル}(メチル)アミノ]-2-ヒドロキシエチル}-6-メチルピラゾロ[1,5-a]ピリミジン-5-イル)ピロリジン-3-イル]カルバマート(75 mg, 無色アモルファス)を得た。
1H NMR (600 MHz, CDCl3, δ): 1.46 (s, 9H), 1.92 (d, J = 5.8 Hz, 1H), 2.22 (br s, 1H), 2.37 (d, J = 5.8 Hz, 3H), 2.78-3.04 (m, 6H), 3.50-3.59 (m, 1H), 3.55 (d, J = 10.7 Hz, 1H), 3.68-3.85 (m, 2H), 3.94 (br s, 1H), 4.07-4.21 (m, 2H), 4.25-4.35 (m, 1H), 4.68 (br s, 1H), 4.94 (t, J = 7.2 Hz, 0.5H), 5.88-6.04 (m, 1H), 6.08 (br s, 0.5H), 7.30-7.72 (m, 3H), 8.32 (br s, 0.5H), 8.50 (s, 0.5H).
LCMS (ESI) m/z 622 [M+H]+, tR = 0.96 min, mode N.
工程1−12−10:工程1−2−8と同様の手法を用いて、工程1−12−9で得られた化合物(73 mg) より、表題化合物 (50 mg, 白色固体) を得た。
LCMS (ESI) m/z 522 [M+H]+, tR = 0.42 min, mode N.
Example 1-12: N-[(1R) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidin-2-yl}- 2-Hydroxyethyl] -5-chloro-N-methyl-2-[(methylsulfonyl) amino] benzamide Hydrochloride Synthesis Step 1-12-1: Using the same method as in Step 1-1-1, Methyl N- (tert-butoxycarbonyl) -N-methyl-L-selinate (5.6 g, colorless oil) was obtained from-(tert-butoxycarbonyl) -N-methyl-L-serine (5.0 g).
Step 1-12-2: To a DMF (50 mL) solution of the compound obtained in Step 1-12-1 (5.50 g), TBDPSCl (7.58 g) and imidazole (3.42 g) were added, and overnight at room temperature. Stir. The reaction solution was poured into water and extracted with EtOAc. The organic layer was washed with Brine, dried and filtered with MgSO 4 , and the filtrate was concentrated under reduced pressure. The obtained residue was purified by OH-type silica gel column chromatography (mobile phase: hexane / EtOAc = 80 / 20-0 / 100; v / v), and methyl N- (tert-butoxycarbonyl) -O- [tert- Butyl (diphenyl) silyl] -N-methyl-L-selinate (12.2 g, colorless oil) was obtained.
Step 1-12-3: Using a method similar to that in Step 1-1-2 and Step 1-1-3, from the compound (12 g) obtained in Step 1-12-2, tert-butyl [( 1R) -1- (5-Amino-1H-pyrazol-3-yl) -2-{[tert-butyl (diphenyl) silyl] oxy} ethyl] (methyl) carbamate (8.5 g, pale yellow amorphous) was obtained. .
1 H NMR (600 MHz, CDCl 3 , δ): 1.06 (br s, 9H), 1.42-1.53 (m, 9H), 2.73 (s, 3H), 3.88-4.06 (m, 2H), 5.17-5.32 ( m, 1H), 5.44 (s, 1H), 7.34-7.46 (m, 6H), 7.60-7.68 (m, 4H).
LCMS (ESI) m / z 495 [M + H] + , t R = 1.22 min, mode N.
Step 1-12-4: Using a method similar to that in Step 1-1-4, the compound (3.85 g) obtained in Step 1-12-3 was used to obtain tert-butyl [(1R) -2-{[[ tert-butyl (diphenyl) silyl] oxy} -1- (6-methyl-5-oxo-4,5-dihydropyrazolo [1,5-a] pyrimidin-2-yl) ethyl] (methyl) carbamate (150 mg, yellow amorphous).
1 H NMR (600 MHz, CDCl 3 , δ): 1.01-1.09 (m, 9H), 1.45-1.54 (m, 9H), 2.01-2.12 (m, 3H), 2.75 (d, J = 14.0 Hz, 3H ), 3.96-4.24 (m, 2H), 5.36-5.83 (m, 2H), 7.33-7.48 (m, 6H), 7.68 (d, J = 6.2 Hz, 4H), 7.90 (s, 1H), 10.28 ( br s, 1H).
Step 1-12-5: Using a method similar to that of Step 1-1-5, from the compound (145 mg) obtained in Step 1-12-4, 6-methyl-2-[(6R) -2 , 2,7,10,10-Pentamethyl-8-oxo-3,3-diphenyl-4,9-dioxa-7-aza-3-silaundecan-6-yl] pyrazolo [1,5-a] pyrimidine- 5-yl trifluoromethanesulfonate (150 mg, yellow amorphous) was obtained.
1 H NMR (600 MHz, CDCl 3 , δ): 1.06 (br s, 9H), 1.46-1.53 (m, 9H), 2.30 (br s, 3H), 2.77 (d, J = 16.9 Hz, 3H), 4.06-4.26 (m, 2H), 5.48-5.86 (m, 1H), 6.42-6.51 (m, 1H), 7.35-7.45 (m, 6H), 7.68 (d, J = 6.6 Hz, 4H), 8.44 ( br s, 1H).
Step 1-12-6: Using a method similar to that of Step 1-2-3, from the compound (150 mg) obtained in Step 1-12-5, 2-[(1R) -2-{[tert -Butyl (diphenyl) silyl] oxy} -1- (methylamino) ethyl] -6-methylpyrazolo [1,5-a] pyrimidin-5-yl trifluoromethanesulfonate hydrochloride (150 mg, yellow oil) It was.
Step 1-12-7: Using a method similar to that of Step 1-1-8, the compound (150 mg) obtained in Step 1-12-6 was used to give 2-{(1R) -2-{[tert -Butyl (diphenyl) silyl] oxy} -1-[{5-chloro-2-[(methylsulfonyl) amino] benzoyl} (methyl) amino] ethyl} -6-methylpyrazolo [1,5-a] pyrimidine-5 -Il trifluoromethanesulfonate (100 mg, yellow amorphous) was obtained.
1 H NMR (600 MHz, CDCl 3 , δ): 1.05-1.18 (m, 9H), 2.25-2.49 (m, 3H), 2.67-2.85 (m, 3H), 2.88-3.14 (m, 3H), 3.98 -4.41 (m, 2H), 5.07 (dd, J = 8.9, 5.6 Hz, 0.5H), 6.21-6.38 (m, 1.5H), 7.32-7.78 (m, 13H), 8.71-8.86 (m, 1H) , 9.03 (s, 0.5H), 10.21 (br s, 0.5H).
Step 1-12-8: Using a method similar to that of Step 1-2-5, from the compound (100 mg) obtained in Step 1-12-7, tert-butyl [(3S) -1- (2 -{(1R) -2-{[tert-butyl (diphenyl) silyl] oxy} -1-[{5-chloro-2-[(methylsulfonyl) amino] benzoyl} (methyl) amino] ethyl} -6- Methylpyrazolo [1,5-a] pyrimidin-5-yl) pyrrolidin-3-yl] carbamate (100 mg, yellow amorphous) was obtained.
Step 1-12-9: 1M TBAF / THF solution (0.24 mL) was added to a THF (3 mL) solution of the compound (100 mg) obtained in Step 1-12-8, and the mixture was stirred at 65 ° C. for 4 hours. did. After the reaction solution was concentrated under reduced pressure, the obtained residue was purified by silica gel column chromatography (mobile phase: hexane / EtOAc = 50 / 50-0 / 100; v / v), and tert-butyl [(3S) -1 -(2-{(1R) -1-[{5-Chloro-2-[(methylsulfonyl) amino] benzoyl} (methyl) amino] -2-hydroxyethyl} -6-methylpyrazolo [1,5-a] Pyrimidin-5-yl) pyrrolidin-3-yl] carbamate (75 mg, colorless amorphous) was obtained.
1 H NMR (600 MHz, CDCl 3 , δ): 1.46 (s, 9H), 1.92 (d, J = 5.8 Hz, 1H), 2.22 (br s, 1H), 2.37 (d, J = 5.8 Hz, 3H ), 2.78-3.04 (m, 6H), 3.50-3.59 (m, 1H), 3.55 (d, J = 10.7 Hz, 1H), 3.68-3.85 (m, 2H), 3.94 (br s, 1H), 4.07 -4.21 (m, 2H), 4.25-4.35 (m, 1H), 4.68 (br s, 1H), 4.94 (t, J = 7.2 Hz, 0.5H), 5.88-6.04 (m, 1H), 6.08 (br s, 0.5H), 7.30-7.72 (m, 3H), 8.32 (br s, 0.5H), 8.50 (s, 0.5H).
LCMS (ESI) m / z 622 [M + H] + , t R = 0.96 min, mode N.
Step 1-12-10: Using the same method as in Step 1-2-8, the title compound (50 mg, white solid) was obtained from the compound (73 mg) obtained in Step 1-12-9. .
LCMS (ESI) m / z 522 [M + H] + , t R = 0.42 min, mode N.
実施例2−1:N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}エチル]-N-メチル-2-[(メチルスルホニル)アミノ]ベンズアミドの合成
工程1−1−8及び工程1−1−9と同様の手法を用いて、工程1−1−7で得た化合物 (30 mg)及び2-[(メチルスルホニル)アミノ]安息香酸(16 mg)より、表題化合物(6.9 mg, 無色アモルファス)を得た。
1H NMR (600 MHz, CDCl3, δ): 1.65-1.75 (m, 3H), 2.36-2.44 (m, 3H), 2.66 (s, 2H), 2.81 (s, 1H), 2.96 (s, 2H), 3.05 (s, 1H), 4.97-5.03 (m, 0.5H), 6.31 (q, J = 7.2 Hz, 1H), 6.43-6.47 (m, 1H), 7.28-7.48 (m, 3H), 7.59-7.75 (m, 1H), 8.76-9.13 (m, 1H).
LCMS (ESI) m/z 472 [M+H]+, tR = 0.40 min, mode N.
Example 2-1 N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidin-2-yl} ethyl Synthesis of —N-methyl-2-[(methylsulfonyl) amino] benzamide The compound obtained in Step 1-1-7 using the same method as in Step 1-1-8 and Step 1-1-9 ( The title compound (6.9 mg, colorless amorphous) was obtained from 30 mg) and 2-[(methylsulfonyl) amino] benzoic acid (16 mg).
1 H NMR (600 MHz, CDCl 3 , δ): 1.65-1.75 (m, 3H), 2.36-2.44 (m, 3H), 2.66 (s, 2H), 2.81 (s, 1H), 2.96 (s, 2H ), 3.05 (s, 1H), 4.97-5.03 (m, 0.5H), 6.31 (q, J = 7.2 Hz, 1H), 6.43-6.47 (m, 1H), 7.28-7.48 (m, 3H), 7.59 -7.75 (m, 1H), 8.76-9.13 (m, 1H).
LCMS (ESI) m / z 472 [M + H] + , t R = 0.40 min, mode N.
実施例2−2:N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}エチル]-3-クロロ-N-メチルベンズアミド の合成
工程1−1−8及び工程1−1−9と同様の手法を用いて、工程1−1−7で得た化合物 (30mg) 及び3-クロロ安息香酸(12 mg)より、表題化合物(0.9 mg, 無色アモルファス)を得た。
LCMS (ESI) m/z 413 [M+H]+, tR = 0.48 min, mode N.
Example 2-2: N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidin-2-yl} ethyl Synthesis of] -3-Chloro-N-methylbenzamide
In the same manner as in Step 1-1-8 and Step 1-1-9, the title compound (0.9 mg) was obtained from the compound (30 mg) obtained in Step 1-1-7 and 3-chlorobenzoic acid (12 mg). mg, colorless amorphous).
LCMS (ESI) m / z 413 [M + H] + , t R = 0.48 min, mode N.
実施例2−3:2-アミノ-N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}エチル]-5-クロロ-N-メチルベンズアミドの合成
工程1−1−8及び工程1−1−9と同様の手法を用いて、工程1−1−7で得た化合物 (60 mg) 及び2-アミノ-5-クロロ安息香酸(26 mg)より、表題化合物(3.9 mg, 無色アモルファス)を得た。
LCMS (ESI) m/z 428 [M+H]+, tR = 0.46 min, mode N.
Example 2-3: 2-amino-N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidine-2 -Il} ethyl] -5-chloro-N-methylbenzamide synthesis The compound obtained in Step 1-1-7 using the same method as in Step 1-1-8 and Step 1-1-9 (60 mg ) And 2-amino-5-chlorobenzoic acid (26 mg) to give the title compound (3.9 mg, colorless amorphous).
LCMS (ESI) m / z 428 [M + H] + , t R = 0.46 min, mode N.
実施例2−4:N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}エチル]-N-メチルベンズアミドの合成
工程1−1−8及び工程1−1−9と同様の手法を用いて、工程1−1−7で得た化合物 (40 mg) 及び安息香酸(12 mg)より、表題化合物 (8.0 mg) を得た。
LCMS (ESI) m/z 379 [M+H]+, tR = 0.34 min, mode N.
Example 2-4: N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidin-2-yl} ethyl ] -N-methylbenzamide synthesis step 1-1-8 and step 1-1-9 were used in the same manner as in step 1-1-7 to obtain the compound (40 mg) and benzoic acid (12 mg). This gave the title compound (8.0 mg).
LCMS (ESI) m / z 379 [M + H] + , t R = 0.34 min, mode N.
実施例2−5:2-アミノ-N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}エチル]-5-メトキシ-N-メチルベンズアミドの合成
工程1−1−8及び工程1−1−9と同様の手法を用いて、工程1−1−7で得た化合物 (40 mg) 及び2-アミノ-5-メトキシ安息香酸(17 mg)より、表題化合物(6.6 mg)を得た。
LCMS (ESI) m/z 424 [M+H]+, tR = 0.25 min, mode N.
実施例2−6:N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}エチル]-N,5-ジメチル-2-[(メチルスルホニル)アミノ]ベンズアミドの合成
工程1−1−8及び工程1−1−9と同様の手法を用いて、工程1−1−7で得た化合物 (40 mg) 及び5-メチル-2-[(メチルスルホニル)アミノ]安息香酸(22 mg)より、表題化合物(3.1 mg) を得た。
1H NMR (600 MHz, CDCl3, δ): 1.73-1.80 (m, 1H), 2.11-2.19 (m, 1H), 2.33-2.37 (m, 6H), 2.37-2.41 (m, 1.8H), 2.59-2.66 (m, 1.2H), 2.78-3.03 (m, 6H), 3.30-4.05 (m, 5H), 4.88-4.96 (m, 0.6H), 5.96-6.05 (m, 1H), 6.16-6.25 (m, 0.4H), 7.07-7.29 (m, 2H), 7.48-7.63 (m, 1H), 8.36 (br s, 0.6H), 8.64 (br s, 0.4H).
LCMS (ESI) m/z 486 [M+H]+, tR = 0.49 min, mode N.
Example 2-5: 2-amino-N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidine-2 -Il} ethyl] -5-methoxy-N-methylbenzamide synthesis step 1-1-8 and the compound obtained in step 1-1-7 using the same method as in step 1-1-9 (40 mg ) And 2-amino-5-methoxybenzoic acid (17 mg) to give the title compound (6.6 mg).
LCMS (ESI) m / z 424 [M + H] + , t R = 0.25 min, mode N.
Example 2-6: N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidin-2-yl} ethyl ] -N, 5-dimethyl-2-[(methylsulfonyl) amino] benzamide was obtained in Step 1-1-7 using the same method as in Step 1-1-8 and Step 1-1-9. The title compound (3.1 mg) was obtained from the compound (40 mg) and 5-methyl-2-[(methylsulfonyl) amino] benzoic acid (22 mg).
1 H NMR (600 MHz, CDCl 3 , δ): 1.73-1.80 (m, 1H), 2.11-2.19 (m, 1H), 2.33-2.37 (m, 6H), 2.37-2.41 (m, 1.8H), 2.59-2.66 (m, 1.2H), 2.78-3.03 (m, 6H), 3.30-4.05 (m, 5H), 4.88-4.96 (m, 0.6H), 5.96-6.05 (m, 1H), 6.16-6.25 (m, 0.4H), 7.07-7.29 (m, 2H), 7.48-7.63 (m, 1H), 8.36 (br s, 0.6H), 8.64 (br s, 0.4H).
LCMS (ESI) m / z 486 [M + H] + , t R = 0.49 min, mode N.
実施例2−7:N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}エチル]-2-(1,1-ジオキシドチオモルホリン-4-イル)-N-メチルベンズアミド の合成
工程1−1−8及び工程1−1−9と同様の手法を用いて、工程1−1−7で得た化合物 (40 mg) 及び2-(1,1-ジオキシドチオモルホリン-4-イル)安息香酸(25 mg)より、表題化合物(13 mg)を得た。
LCMS (ESI) m/z 512 [M+H]+, tR = 0.36 min, mode N.
Example 2-7: N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidin-2-yl} ethyl ] -2- (1,1-dioxidethiomorpholin-4-yl) -N-methylbenzamide is synthesized in the same manner as in Step 1-1-1 using the same procedure as in Step 1-1-8 and Step 1-1-9. The title compound (13 mg) was obtained from the compound obtained in -7 (40 mg) and 2- (1,1-dioxidethiomorpholin-4-yl) benzoic acid (25 mg).
LCMS (ESI) m / z 512 [M + H] + , t R = 0.36 min, mode N.
実施例2−8:N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}エチル]-2-クロロ-N-メチルベンズアミド の合成
工程1−1−8及び工程1−1−9と同様の手法を用いて、工程1−1−7で得た化合物 (40 mg) 及び2-クロロ安息香酸(15 mg)より、表題化合物(4.6 mg)を得た。
LCMS (ESI) m/z 413 [M+H]+, tR = 0.45 min, mode N.
Example 2-8: N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidin-2-yl} ethyl ] -2-Chloro-N-methylbenzamide Synthesis Using the same method as in Step 1-1-8 and Step 1-1-9, the compound (40 mg) obtained in Step 1-1-7 and 2- The title compound (4.6 mg) was obtained from chlorobenzoic acid (15 mg).
LCMS (ESI) m / z 413 [M + H] + , t R = 0.45 min, mode N.
実施例2−9:N-[(1R)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}エチル]-5-クロロ-N-メチル-2-[(メチルスルホニル)アミノ]ベンズアミド 塩酸塩の合成
工程2−9−1:工程1−1−7と同様の手法を用いて、工程1−1−5で得られた化合物(861 mg)より、6-メチル-2-[(1S)-1-(メチルアミノ)エチル]ピラゾロ[1,5-a]ピリミジン-5-イル トリフルオロメタンスルホナート 塩酸塩(1.07 g)を得た。
LCMS (ESI) m/z 339 [M+H]+, tR = 0.52 min, mode N.
工程2−9−2:工程1−2−7と同様の手法を用いて、工程2−9−1で得られた化合物 (1.07 g)より、2-{(1S)-1-[{5-クロロ-2-[(メチルスルホニル)アミノ]ベンゾイル}(メチル)アミノ]エチル}-6-メチルピラゾロ[1,5-a]ピリミジン-5-イル トリフルオロメタンスルホナート(709 mg)を得た。
1H NMR (600 MHz, CDCl3, δ): 1.68 (d, J = 7.4 Hz, 1.4H), 1.72 (d, J = 7.4 Hz, 1.6H), 2.39 (s, 1.8H), 2.40 (s, 1.2H), 2.66 (s, 1.6H), 2.80 (s, 1.4H), 2.96 (s, 1.8H), 3.05 (s, 1.2H), 5.00 (q, J = 7.4 Hz, 0.5H), 6.31 (q, J = 7.4 Hz, 0.5H), 6.45 (s, 0.5H), 6.46 (s, 0.5H), 7.28-7.34 (m, 1H), 7.35-7.42 (m, 1H), 7.62 (d, J = 8.7 Hz, 0.5H), 7.71 (d, J = 8.7 Hz, 0.5H), 8.79 (s, 1H), 8.93 (s, 0.5H), 9.10 (s, 0.5H).
工程2−9−3:工程1−1−6と同様の手法を用いて、工程2−9−2で得られた化合物(702 mg)及び(3S)-(-)-3-(tert-ブトキシカルボニルアミノ)ピロリジン(459 mg)より、tert-ブチル [(3S)-1-(2-{(1S)-1-[{5-クロロ-2-[(メチルスルホニル)アミノ]ベンゾイル}(メチル)アミノ]エチル}-6-メチルピラゾロ[1,5-a]ピリミジン-5-イル)ピロリジン-3-イル]カルバマート(732 mg)を得た。
1H NMR (600 MHz, CDCl3, δ): 1.45 (s, 9H), 1.60 (d, J = 7.0 Hz, 2H), 1.64 (d, J = 7.0 Hz, 1H), 1.86-1.97 (m, 1H), 2.16-2.27 (m, 1H), 2.35-2.39 (m, 3H), 2.63 (s, 1H), 2.81 (s, 2H), 2.95 (s, 1H), 3.03 (s, 2H), 3.50-3.58 (m, 1H), 3.69-3.76 (m, 1H), 3.77-3.85 (m, 1H), 3.90-3.97 (m, 1H), 4.24-4.34 (m, 1H), 4.67 (br s, 1H), 4.88 (q, J = 7.0 Hz, 0.5H), 5.97-6.04 (m, 1H), 6.23 (q, J = 7.0 Hz, 0.5H), 7.27-7.31 (m, 1H), 7.33-7.40 (m, 1H), 7.61 (d, J = 8.7 Hz, 0.6H), 7.69 (d, J = 8.7 Hz, 0.4H), 8.36 (s, 1H), 8.64 (s, 0.5H), 9.40 (s, 0.5H).
LCMS (ESI) m/z 606 [M+H]+, tR = 1.15 min, mode N.
工程2−9−4:工程2−9−3で得られた化合物(730 mg)をキラルカラムにて分取精製を行い(分取条件:カラム:CHIRALPAK AD-H(ダイセル商標)、カラムサイズ:20 mm×250 mm、移動相:ヘキサン/EtOH = 20/80 (v/v)、流速:10 mL/min)、保持時間20.0分〜27.0分で溶出した画分を減圧下濃縮することで、tert-ブチル [(3S)-1-(2-{(1R)-1-[{5-クロロ-2-[(メチルスルホニル)アミノ]ベンゾイル}(メチル)アミノ]エチル}-6-メチルピラゾロ[1,5-a]ピリミジン-5-イル)ピロリジン-3-イル]カルバマート(70.4 mg)及び保持時間10.5分〜16.0分で溶出した画分を減圧下濃縮することで、tert-ブチル [(3S)-1-(2-{(1S)-1-[{5-クロロ-2-[(メチルスルホニル)アミノ]ベンゾイル}(メチル)アミノ]エチル}-6-メチルピラゾロ[1,5-a]ピリミジン-5-イル)ピロリジン-3-イル]カルバマート(685 mg)を得た。
tert-ブチル [(3S)-1-(2-{(1R)-1-[{5-クロロ-2-[(メチルスルホニル)アミノ]ベンゾイル}(メチル)アミノ]エチル}-6-メチルピラゾロ[1,5-a]ピリミジン-5-イル)ピロリジン-3-イル]カルバマート:LCMS (ESI) m/z 606 [M+H]+, tR = 1.147 min, mode N.
工程2−9−5:工程1−1−7と同様の手法を用いて、工程2−9−4で得たtert-ブチル [(3S)-1-(2-{(1R)-1-[{5-クロロ-2-[(メチルスルホニル)アミノ]ベンゾイル}(メチル)アミノ]エチル}-6-メチルピラゾロ[1,5-a]ピリミジン-5-イル)ピロリジン-3-イル]カルバマート(63.0 mg)より、表題化合物(69.5 mg, 無色アモルファス)を得た。
LCMS (ESI) m/z 506 [M+H]+, tR = 0.54 min, mode N.
Example 2-9: N-[(1R) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidin-2-yl} ethyl ] -5-Chloro-N-methyl-2-[(methylsulfonyl) amino] benzamide Synthesis of hydrochloride
Step 2-9-1: Using a method similar to that of Step 1-1-7, from the compound (861 mg) obtained in Step 1-1-5, 6-methyl-2-[(1S) -1 -(Methylamino) ethyl] pyrazolo [1,5-a] pyrimidin-5-yl trifluoromethanesulfonate hydrochloride (1.07 g) was obtained.
LCMS (ESI) m / z 339 [M + H] + , t R = 0.52 min, mode N.
Step 2-9-2: Using a method similar to that of Step 1-2-7, from the compound (1.07 g) obtained in Step 2-9-1, 2-{(1S) -1-[{5 -Chloro-2-[(methylsulfonyl) amino] benzoyl} (methyl) amino] ethyl} -6-methylpyrazolo [1,5-a] pyrimidin-5-yl trifluoromethanesulfonate (709 mg) was obtained.
1 H NMR (600 MHz, CDCl 3 , δ): 1.68 (d, J = 7.4 Hz, 1.4H), 1.72 (d, J = 7.4 Hz, 1.6H), 2.39 (s, 1.8H), 2.40 (s , 1.2H), 2.66 (s, 1.6H), 2.80 (s, 1.4H), 2.96 (s, 1.8H), 3.05 (s, 1.2H), 5.00 (q, J = 7.4 Hz, 0.5H), 6.31 (q, J = 7.4 Hz, 0.5H), 6.45 (s, 0.5H), 6.46 (s, 0.5H), 7.28-7.34 (m, 1H), 7.35-7.42 (m, 1H), 7.62 (d , J = 8.7 Hz, 0.5H), 7.71 (d, J = 8.7 Hz, 0.5H), 8.79 (s, 1H), 8.93 (s, 0.5H), 9.10 (s, 0.5H).
Step 2-9-3: Using a method similar to that of Step 1-1-6, the compound (702 mg) obtained in Step 2-9-2 and (3S)-(-)-3- (tert- From butoxycarbonylamino) pyrrolidine (459 mg), tert-butyl [(3S) -1- (2-{(1S) -1-[{5-chloro-2-[(methylsulfonyl) amino] benzoyl} (methyl ) Amino] ethyl} -6-methylpyrazolo [1,5-a] pyrimidin-5-yl) pyrrolidin-3-yl] carbamate (732 mg) was obtained.
1 H NMR (600 MHz, CDCl 3 , δ): 1.45 (s, 9H), 1.60 (d, J = 7.0 Hz, 2H), 1.64 (d, J = 7.0 Hz, 1H), 1.86-1.97 (m, 1H), 2.16-2.27 (m, 1H), 2.35-2.39 (m, 3H), 2.63 (s, 1H), 2.81 (s, 2H), 2.95 (s, 1H), 3.03 (s, 2H), 3.50 -3.58 (m, 1H), 3.69-3.76 (m, 1H), 3.77-3.85 (m, 1H), 3.90-3.97 (m, 1H), 4.24-4.34 (m, 1H), 4.67 (br s, 1H ), 4.88 (q, J = 7.0 Hz, 0.5H), 5.97-6.04 (m, 1H), 6.23 (q, J = 7.0 Hz, 0.5H), 7.27-7.31 (m, 1H), 7.33-7.40 ( m, 1H), 7.61 (d, J = 8.7 Hz, 0.6H), 7.69 (d, J = 8.7 Hz, 0.4H), 8.36 (s, 1H), 8.64 (s, 0.5H), 9.40 (s, 0.5H).
LCMS (ESI) m / z 606 [M + H] + , t R = 1.15 min, mode N.
Step 2-9-4: The compound (730 mg) obtained in Step 2-9-3 was subjected to preparative purification using a chiral column (preparation conditions: column: CHIRALPAK AD-H (Daicel), column size: By concentrating the fraction eluted at 20 mm x 250 mm, mobile phase: hexane / EtOH = 20/80 (v / v), flow rate: 10 mL / min), retention time 20.0 min-27.0 min under reduced pressure, tert-butyl [(3S) -1- (2-{(1R) -1-[{5-chloro-2-[(methylsulfonyl) amino] benzoyl} (methyl) amino] ethyl} -6-methylpyrazolo [1 , 5-a] pyrimidin-5-yl) pyrrolidin-3-yl] carbamate (70.4 mg) and the fraction eluted with a retention time of 10.5 to 16.0 minutes were concentrated under reduced pressure to give tert-butyl [(3S) -1- (2-{(1S) -1-[{5-chloro-2-[(methylsulfonyl) amino] benzoyl} (methyl) amino] ethyl} -6-methylpyrazolo [1,5-a] pyrimidine- 5-yl) pyrrolidin-3-yl] carbamate (685 mg) was obtained.
tert-butyl [(3S) -1- (2-{(1R) -1-[{5-chloro-2-[(methylsulfonyl) amino] benzoyl} (methyl) amino] ethyl} -6-methylpyrazolo [1 , 5-a] pyrimidin-5-yl) pyrrolidin-3-yl] carbamate: LCMS (ESI) m / z 606 [M + H] + , t R = 1.147 min, mode N.
Step 2-9-5: Using a method similar to that of Step 1-1-7, tert-butyl [(3S) -1- (2-{(1R) -1- [{5-Chloro-2-[(methylsulfonyl) amino] benzoyl} (methyl) amino] ethyl} -6-methylpyrazolo [1,5-a] pyrimidin-5-yl) pyrrolidin-3-yl] carbamate (63.0 mg) gave the title compound (69.5 mg, colorless amorphous).
LCMS (ESI) m / z 506 [M + H] + , t R = 0.54 min, mode N.
実施例2−10:4-アミノ-N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}プロピル]-N-メチルピリジン-3-カルボキサミド 塩酸塩の合成
工程1−2−7及び工程1−2−8と同様の手法を用いて、工程1−4−3で得た化合物 (50 mg) 及び4-アミノピリジン-3-カルボン酸(21 mg)より、表題化合物(16 mg, 無色固体)を得た。
LCMS (ESI) m/z 409 [M+H]+, tR = 0.35 min, mode N.
Example 2-10: 4-amino-N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidine-2 -Il} propyl] -N-methylpyridine-3-carboxamide hydrochloride The compound obtained in Step 1-4-3 using the same method as in Step 1-2-7 and Step 1-2-8 ( The title compound (16 mg, colorless solid) was obtained from 50 mg) and 4-aminopyridine-3-carboxylic acid (21 mg).
LCMS (ESI) m / z 409 [M + H] + , t R = 0.35 min, mode N.
実施例2−11:3-アミノ-N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}プロピル]-N-メチルピリジン-2-カルボキサミド 塩酸塩の合成
工程1−2−7及び工程1−2−8と同様の手法を用いて、工程1−4−3で得た化合物 (50 mg) 及び3-アミノピリジン-2-カルボン酸(21 mg)より、表題化合物(12 mg, 無色固体)を得た。
LCMS (ESI) m/z 409 [M+H]+, tR = 0.65 min, mode H.
Example 2-11: 3-amino-N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidine-2 -Il} propyl] -N-methylpyridine-2-carboxamide hydrochloride The compound obtained in Step 1-4-3 using the same method as in Step 1-2-7 and Step 1-2-8 ( The title compound (12 mg, colorless solid) was obtained from 50 mg) and 3-aminopyridine-2-carboxylic acid (21 mg).
LCMS (ESI) m / z 409 [M + H] + , t R = 0.65 min, mode H.
実施例2−12:5-アミノ-N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}プロピル]-2-クロロ-N-メチルピリジン-4-カルボキサミド 塩酸塩の合成
工程1−2−7及び工程1−2−8と同様の手法を用いて、工程1−4−3で得た化合物 (50 mg) 及び5-アミノ-2-クロロピリジン-4-カルボン酸(26 mg)より、表題化合物(14 mg, 無色固体)を得た。
LCMS (ESI) m/z 443 [M+H]+, tR = 0.79 min, mode H.
実施例2−13:N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}プロピル]-N-メチル-3-[(メチルスルホニル)アミノ]チオフェン-2-カルボキサミド 塩酸塩の合成
工程1−2−7及び工程1−2−8と同様の手法を用いて、工程1−4−3で得た化合物 (30 mg) 及び3-[(メチルスルホニル)アミノ]チオフェン-2-カルボン酸(20 mg)より、表題化合物(17 mg, 無色固体)を得た。
LCMS (ESI) m/z 492 [M+H]+, tR = 0.87 min, mode H.
Example 2-12: 5-amino-N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidine-2 -Il} propyl] -2-chloro-N-methylpyridine-4-carboxamide hydrochloride In step 1-4-3 using the same procedure as in step 1-2-7 and step 1-2-8 The title compound (14 mg, colorless solid) was obtained from the obtained compound (50 mg) and 5-amino-2-chloropyridine-4-carboxylic acid (26 mg).
LCMS (ESI) m / z 443 [M + H] + , t R = 0.79 min, mode H.
Example 2-13: N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidin-2-yl} propyl ] -N-methyl-3-[(methylsulfonyl) amino] thiophene-2-carboxamide hydrochloride Synthesis of Step 1-4-4 using the same method as in Step 1-2-7 and Step 1-2-8 The title compound (17 mg, colorless solid) was obtained from the compound obtained in 3 (30 mg) and 3-[(methylsulfonyl) amino] thiophene-2-carboxylic acid (20 mg).
LCMS (ESI) m / z 492 [M + H] + , t R = 0.87 min, mode H.
実施例2−14:N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}プロピル]-N-メチル-2-[(メチルスルホニル)アミノ]チオフェン-3-カルボキサミド 塩酸塩の合成
工程1−2−7及び工程1−2−8と同様の手法を用いて、工程1−4−3で得た化合物 (30 mg) 及び2-[(メチルスルホニル)アミノ]チオフェン-3-カルボン酸(20 mg)より、表題化合物(20 mg, 無色固体)を得た。
LCMS (ESI) m/z 492 [M+H]+, tR = 0.86 min, mode H.
Example 2-14: N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidin-2-yl} propyl ] -N-methyl-2-[(methylsulfonyl) amino] thiophene-3-carboxamide hydrochloride Synthesis of step 1-4-4 using the same procedure as in step 1-2-7 and step 1-2-8 The title compound (20 mg, colorless solid) was obtained from the compound obtained in 3 (30 mg) and 2-[(methylsulfonyl) amino] thiophene-3-carboxylic acid (20 mg).
LCMS (ESI) m / z 492 [M + H] + , t R = 0.86 min, mode H.
実施例2−15:2-アミノ-N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}プロピル]-5-クロロ-N-メチルベンズアミド 塩酸塩の合成
工程1−2−7及び工程1−2−8と同様の手法を用いて、工程1−4−3で得た化合物 (50 mg) 及び2-アミノ-5-クロロ安息香酸(26 mg)より、表題化合物(9.5 mg, 無色固体)を得た。
1H NMR (600 MHz, DMSO-d6, δ): 0.76-1.03 (m, 3H), 1.83-1.93 (m, 1H), 2.00-2.29 (m, 3H), 2.35 (s, 3H), 2.58-2.79 (m, 3H), 3.69-3.95 (m, 5H), 5.74 (br s, 1H), 6.07 (s, 1H), 6.77 (d, J = 8.7 Hz, 1H), 6.98-7.25 (m, 2H), 8.28 (br s, 3H), 8.44-8.59 (m, 1H).
LCMS (ESI) m/z 442 [M+H]+, tR = 0.93 min, mode H.
Example 2-15: 2-amino-N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidine-2 -Yl} propyl] -5-chloro-N-methylbenzamide hydrochloride synthesis
Using the same method as in Step 1-2-7 and Step 1-2-8, from the compound obtained in Step 1-4-3 (50 mg) and 2-amino-5-chlorobenzoic acid (26 mg) To give the title compound (9.5 mg, colorless solid).
1 H NMR (600 MHz, DMSO-d 6 , δ): 0.76-1.03 (m, 3H), 1.83-1.93 (m, 1H), 2.00-2.29 (m, 3H), 2.35 (s, 3H), 2.58 -2.79 (m, 3H), 3.69-3.95 (m, 5H), 5.74 (br s, 1H), 6.07 (s, 1H), 6.77 (d, J = 8.7 Hz, 1H), 6.98-7.25 (m, 2H), 8.28 (br s, 3H), 8.44-8.59 (m, 1H).
LCMS (ESI) m / z 442 [M + H] + , t R = 0.93 min, mode H.
実施例2−16: N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}プロピル]-N-メチル-2-[(メチルスルホニル)アミノ]ベンズアミド 塩酸塩 の合成
工程1−2−7及び工程1−2−8と同様の手法を用いて、工程1−4−3で得た化合物 (30 mg) 及び2-[(メチルスルホニル)アミノ]安息香酸(24 mg)より、表題化合物(21 mg, 無色固体)を得た。
1H NMR (600 MHz, DMSO-d6, δ): 0.85-1.06 (m, 3H), 1.86-2.30 (m, 4H), 2.33-2.40 (m, 3H), 2.57 (s, 1.5H), 2.73 (br s, 1.5H), 3.02 (s, 3H), 3.76 (br s, 2H), 3.82-3.89 (m, 2H), 3.90-3.99 (m, 1H), 4.55 (br s, 0.5H), 5.77 (dd, J = 9.7, 5.6 Hz, 0.5H), 6.12 (s, 1H), 7.26-7.39 (m, 2H), 7.41-7.52 (m, 2H), 8.39 (br s, 3H), 8.51 (s, 0.5H), 9.08 (s, 0.5H).
LCMS (ESI) m/z 486 [M+H]+, tR = 0.49 min, mode N.
Example 2-16: N-[(1S) -1- {5-[(3S) -3-Aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidin-2-yl} propyl ] -N-methyl-2-[(methylsulfonyl) amino] benzamide hydrochloride obtained in Step 1-4-3 using the same method as in Step 1-2-7 and Step 1-2-8. The title compound (21 mg, colorless solid) was obtained from the compound (30 mg) and 2-[(methylsulfonyl) amino] benzoic acid (24 mg).
1 H NMR (600 MHz, DMSO-d 6 , δ): 0.85-1.06 (m, 3H), 1.86-2.30 (m, 4H), 2.33-2.40 (m, 3H), 2.57 (s, 1.5H), 2.73 (br s, 1.5H), 3.02 (s, 3H), 3.76 (br s, 2H), 3.82-3.89 (m, 2H), 3.90-3.99 (m, 1H), 4.55 (br s, 0.5H) , 5.77 (dd, J = 9.7, 5.6 Hz, 0.5H), 6.12 (s, 1H), 7.26-7.39 (m, 2H), 7.41-7.52 (m, 2H), 8.39 (br s, 3H), 8.51 (s, 0.5H), 9.08 (s, 0.5H).
LCMS (ESI) m / z 486 [M + H] + , t R = 0.49 min, mode N.
実施例2−17: N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}プロピル]-N-メチルベンズアミド 塩酸塩の合成
工程1−2−7及び工程1−2−8と同様の手法を用いて、工程1−4−3で得た化合物 (30 mg) 及び安息香酸(14 mg)より、表題化合物(18 mg, 無色固体)を得た。
LCMS (ESI) m/z 393 [M+H]+, tR = 0.43 min, mode N.
Example 2-17: N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidin-2-yl} propyl ] -N-methylbenzamide Hydrochloride Synthesis of the compound obtained in Step 1-4-3 (30 mg) and benzoic acid (14) using the same method as in Step 1-2-7 and Step 1-2-8 mg) gave the title compound (18 mg, colorless solid).
LCMS (ESI) m / z 393 [M + H] + , t R = 0.43 min, mode N.
実施例2−18:N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}プロピル]-N-メチル-2-オキソ-2,3-ジヒドロ-1H-インドール-7-カルボキサミド 塩酸塩の合成
工程1−2−7及び工程1−2−8と同様の手法を用いて、工程1−4−3で得た化合物 (30 mg)及び2-オキソ-2,3-ジヒドロ-1H-インドール-7-カルボン酸(20 mg)より、表題化合物(26 mg, 無色固体)を得た。
LCMS (ESI) m/z 448 [M+H]+, tR = 0.38 min, mode N.
Example 2-18: N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidin-2-yl} propyl ] -N-methyl-2-oxo-2,3-dihydro-1H-indole-7-carboxamide Hydrochloride Synthesis Step 1-2-7 and Step 1-2-8 The title compound (26 mg, colorless solid) was obtained from the compound (30 mg) obtained in -4--3 and 2-oxo-2,3-dihydro-1H-indole-7-carboxylic acid (20 mg).
LCMS (ESI) m / z 448 [M + H] + , t R = 0.38 min, mode N.
実施例2−19:N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}プロピル]-N-メチル-1H-インダゾール-7-カルボキサミド 塩酸塩の合成
工程1−2−7及び工程1−2−8と同様の手法を用いて、工程1−4−3で得た化合物 (30 mg) 及び1H-インダゾール-7-カルボン酸(18 mg)より、表題化合物(31 mg, 無色固体)を得た。
LCMS (ESI) m/z 433 [M+H]+, tR = 0.43 in, mode N.
Example 2-19: N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidin-2-yl} propyl ] -N-methyl-1H-indazole-7-carboxamide hydrochloride The compound obtained in Step 1-4-3 using the same method as in Step 1-2-7 and Step 1-2-8 (30 mg) and 1H-indazole-7-carboxylic acid (18 mg) gave the title compound (31 mg, colorless solid).
LCMS (ESI) m / z 433 [M + H] + , t R = 0.43 in, mode N.
実施例2−20: N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}プロピル]-N-メチル-2-(1H-ピラゾール-1-イル)ベンズアミド塩酸塩の合成
工程1−2−7及び工程1−2−8と同様の手法を用いて、工程1−4−3で得た化合物 (30 mg) 及び2-(1H-ピラゾール-1-イル)安息香酸(21 mg)より、表題化合物(26 mg, 無色固体)を得た。
LCMS (ESI) m/z 459 [M+H]+, tR = 0.85 in, mode H.
Example 2-20: N-[(1S) -1- {5-[(3S) -3-Aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidin-2-yl} propyl ] -N-methyl-2- (1H-pyrazol-1-yl) benzamide hydrochloride in step 1-4-3 using the same method as in step 1-2-7 and step 1-2-8 The title compound (26 mg, colorless solid) was obtained from the obtained compound (30 mg) and 2- (1H-pyrazol-1-yl) benzoic acid (21 mg).
LCMS (ESI) m / z 459 [M + H] + , t R = 0.85 in, mode H.
実施例2−21:N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}プロピル]-N-メチルビフェニル-2-カルボキサミド 塩酸塩の合成
工程1−2−7及び工程1−2−8と同様の手法を用いて、工程1−4−3で得た化合物 (30 mg) 及びビフェニル-2-カルボン酸(22 mg)より、表題化合物(25 mg, 無色固体)を得た。
LCMS (ESI) m/z 469 [M+H]+, tR = 0.60 min, mode N.
Example 2-21: N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidin-2-yl} propyl ] -N-Methylbiphenyl-2-carboxamide Hydrochloride Synthesis Using the same method as in Step 1-2-7 and Step 1-2-8, the compound obtained in Step 1-4-3 (30 mg) and The title compound (25 mg, colorless solid) was obtained from biphenyl-2-carboxylic acid (22 mg).
LCMS (ESI) m / z 469 [M + H] + , t R = 0.60 min, mode N.
実施例2−22: N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}プロピル]-N-メチル-2-(1H-テトラゾール-1-イル)ベンズアミド 塩酸塩の合成
工程1−2−7及び工程1−2−8と同様の手法を用いて、工程1−4−3で得た化合物 (30 mg) 及び2-(1H-テトラゾール-1-イル)安息香酸(22 mg)より、表題化合物(25 mg, 無色固体)を得た。
LCMS (ESI) m/z 461 [M+H]+, tR = 0.340 min, mode N.
Example 2-22: N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidin-2-yl} propyl ] -N-methyl-2- (1H-tetrazol-1-yl) benzamide Hydrochloride Synthesis Step 1-2-3 using the same method as in Step 1-2-7 and Step 1-2-8 The title compound (25 mg, colorless solid) was obtained from the obtained compound (30 mg) and 2- (1H-tetrazol-1-yl) benzoic acid (22 mg).
LCMS (ESI) m / z 461 [M + H] + , t R = 0.340 min, mode N.
実施例2−23: N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}プロピル]-3-クロロ-N-メチル-2-[(メチルスルホニル)アミノ]ベンズアミド 塩酸塩の合成
工程1−2−7及び工程1−2−8と同様の手法を用いて、工程1−4−3で得た化合物 (10 mg) 及び3-クロロ-2-[(メチルスルホニル)アミノ]安息香酸(6.4 mg)より、表題化合物(10 mg, 無色固体)を得た。
1H NMR (600 MHz, DMSO-d6, δ): 0.79-1.05 (m, 3H), 1.84-2.30 (m, 4H), 2.33-2.42 (m, 3H), 2.43-2.59 (m, 3H), 2.98-3.17 (m, 3H), 3.68-4.01 (m, 5H), 4.37 (br s, 0.5H), 5.75 (br s, 0.5H), 6.06-6.25 (m, 1H), 7.23-7.67 (m, 3H), 8.17-8.27 (m, 3H), 8.51 (s, 0.5H), 9.43 (br s, 0.5H).
LCMS (ESI) m/z 520 [M+H]+, tR = 0.46 min, mode N.
Example 2-23: N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidin-2-yl} propyl ] -3-Chloro-N-methyl-2-[(methylsulfonyl) amino] benzamide Hydrochloride Synthesis Step 1-2-4 Using the same procedure as in Step 1-2-7 and Step 1-2-8 The title compound (10 mg, colorless solid) was obtained from the compound (10 mg) obtained in 3 and 3-chloro-2-[(methylsulfonyl) amino] benzoic acid (6.4 mg).
1 H NMR (600 MHz, DMSO-d 6 , δ): 0.79-1.05 (m, 3H), 1.84-2.30 (m, 4H), 2.33-2.42 (m, 3H), 2.43-2.59 (m, 3H) , 2.98-3.17 (m, 3H), 3.68-4.01 (m, 5H), 4.37 (br s, 0.5H), 5.75 (br s, 0.5H), 6.06-6.25 (m, 1H), 7.23-7.67 ( m, 3H), 8.17-8.27 (m, 3H), 8.51 (s, 0.5H), 9.43 (br s, 0.5H).
LCMS (ESI) m / z 520 [M + H] + , t R = 0.46 min, mode N.
実施例2−24: N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}プロピル]-3,5-ジクロロ-N-メチル-2-[(メチルスルホニル)アミノ]ベンズアミド 塩酸塩の合成
工程1−2−7及び工程1−2−8と同様の手法を用いて、工程1−4−3で得た化合物 (30 mg) 及び3,5-ジクロロ-2-[(メチルスルホニル)アミノ]安息香酸(24 mg)より、表題化合物(34 mg, 無色固体)を得た。
1H NMR (600 MHz, DMSO-d6, δ): 0.80-1.06 (m, 3H), 1.83-2.30 (m, 4H), 2.31-2.41 (m, 3H), 2.46-2.61 (m, 3H), 2.89-3.16 (m, 3H), 3.70-3.81 (m, 2H), 3.81-3.90 (m, 2H), 3.90-3.98 (m, 1H), 5.72 (br s, 1H), 6.15 (br s, 1H), 7.31-7.47 (m, 1H), 7.78-7.86 (m, 1H), 8.30-8.57 (m, 3H), 9.48 (br s, 1H).
LCMS (ESI) m/z 554 [M+H]+, tR = 0.58 min, mode N.
Example 2-24: N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidin-2-yl} propyl ] -3,5-Dichloro-N-methyl-2-[(methylsulfonyl) amino] benzamide hydrochloride Using the same procedure as in Step 1-2-7 and Step 1-2-8, Step 1- The title compound (34 mg, colorless solid) was obtained from the compound (30 mg) obtained in 4-3 and 3,5-dichloro-2-[(methylsulfonyl) amino] benzoic acid (24 mg).
1 H NMR (600 MHz, DMSO-d 6 , δ): 0.80-1.06 (m, 3H), 1.83-2.30 (m, 4H), 2.31-2.41 (m, 3H), 2.46-2.61 (m, 3H) , 2.89-3.16 (m, 3H), 3.70-3.81 (m, 2H), 3.81-3.90 (m, 2H), 3.90-3.98 (m, 1H), 5.72 (br s, 1H), 6.15 (br s, 1H), 7.31-7.47 (m, 1H), 7.78-7.86 (m, 1H), 8.30-8.57 (m, 3H), 9.48 (br s, 1H).
LCMS (ESI) m / z 554 [M + H] + , t R = 0.58 min, mode N.
実施例2−25: N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}プロピル]-N-メチル-2-{[(トリフルオロメチル)スルホニル]アミノ}ベンズアミド 塩酸塩の合成
工程1−2−7及び工程1−2−8と同様の手法を用いて、工程1−4−3で得た化合物 (30 mg) 及び2-{[(トリフルオロメチル)スルホニル]アミノ}安息香酸(25 mg)より、表題化合物(7.2 mg, 無色固体)を得た。
LCMS (ESI) m/z 540 [M+H]+, tR = 0.61 min, mode N.
Example 2-25: N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidin-2-yl} propyl ] -N-Methyl-2-{[(trifluoromethyl) sulfonyl] amino} benzamide Hydrochloride Synthesis Step 1-2-4 Using the same method as in Step 1-2-7 and Step 1-2-8 The title compound (7.2 mg, colorless solid) was obtained from the compound (30 mg) obtained in 3 and 2-{[(trifluoromethyl) sulfonyl] amino} benzoic acid (25 mg).
LCMS (ESI) m / z 540 [M + H] + , t R = 0.61 min, mode N.
実施例2−26: N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}プロピル]-5-クロロ-N-メチル-2-[(フェニルスルホニル)アミノ]ベンズアミド 塩酸塩の合成
工程1−2−7及び工程1−2−8と同様の手法を用いて、工程1−4−3で得た化合物 (30 mg) 及び5-クロロ-2-[(フェニルスルホニル)アミノ]安息香酸(29 mg)より、表題化合物(29 mg, 無色固体)を得た。
1H NMR (600 MHz, DMSO-d6, δ): 0.83 (br s, 1H), 1.01 (t, J = 7.2 Hz, 2H), 1.84-2.30 (m, 4H), 2.34-2.38 (m, 3H), 2.54-2.74 (m, 3H), 3.69-3.99 (m, 5H), 4.51 (dd, J = 9.5, 5.8 Hz, 0.5H), 5.69 (dd, J = 9.5, 5.8 Hz, 0.5H), 6.13 (s, 1H), 7.04-7.82 (m, 8H), 8.22 (br s, 3H), 8.58 (s, 0.5H), 9.61 (s, 0.5H).
LCMS (ESI) m/z 582 [M+H]+, tR = 0.67 min, mode N.
Example 2-26: N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidin-2-yl} propyl ] -5-Chloro-N-methyl-2-[(phenylsulfonyl) amino] benzamide Hydrochloride Synthesis Using the same method as in Step 1-2-7 and Step 1-2-8, Step 1-4-4- The title compound (29 mg, colorless solid) was obtained from the compound (30 mg) obtained in 3 and 5-chloro-2-[(phenylsulfonyl) amino] benzoic acid (29 mg).
1 H NMR (600 MHz, DMSO-d 6 , δ): 0.83 (br s, 1H), 1.01 (t, J = 7.2 Hz, 2H), 1.84-2.30 (m, 4H), 2.34-2.38 (m, 3H), 2.54-2.74 (m, 3H), 3.69-3.99 (m, 5H), 4.51 (dd, J = 9.5, 5.8 Hz, 0.5H), 5.69 (dd, J = 9.5, 5.8 Hz, 0.5H) , 6.13 (s, 1H), 7.04-7.82 (m, 8H), 8.22 (br s, 3H), 8.58 (s, 0.5H), 9.61 (s, 0.5H).
LCMS (ESI) m / z 582 [M + H] + , t R = 0.67 min, mode N.
実施例2−27:N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}プロピル]-N-メチル-3-オキソ-3,4-ジヒドロ-2H-1,4-ベンゾオキサジン-8-カルボキサミド 塩酸塩の合成
工程1−2−7及び工程1−2−8と同様の手法を用いて、工程1−4−3で得た化合物 (35 mg) 及び3-オキソ-3,4-ジヒドロ-2H-1,4-ベンゾオキサジン-8-カルボン酸(16 mg)より、表題化合物(30 mg, 無色固体)を得た。
LCMS (ESI) m/z 464 [M+H]+, tR = 0.73 min, mode N.
Example 2-27: N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidin-2-yl} propyl ] -N-Methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-8-carboxamide Similar procedure to steps 1-2-7 and 1-2-8 From the compound obtained in Step 1-4-3 (35 mg) and 3-oxo-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid (16 mg) to give the title compound ( 30 mg, a colorless solid) was obtained.
LCMS (ESI) m / z 464 [M + H] + , t R = 0.73 min, mode N.
実施例2−28:N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}プロピル]-N,1-ジメチル-4-[(メチルスルホニル)アミノ]-1H-ピラゾール-5-カルボキサミド 塩酸塩の合成
工程1−2−7及び工程1−2−8と同様の手法を用いて、工程1−4−3で得た化合物 (30 mg) 及び1-メチル-4-[(メチルスルホニル)アミノ]-1H-ピラゾール-5-カルボン酸(19 mg)より、表題化合物(23 mg, 無色固体)を得た。
LCMS (ESI) m/z 490 [M+H]+, tR = 0.71 min, mode H.
Example 2-28: N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidin-2-yl} propyl ] -N, 1-Dimethyl-4-[(methylsulfonyl) amino] -1H-pyrazole-5-carboxamide Hydrochloride Synthesis using the same method as in Step 1-2-7 and Step 1-2-8, From the compound obtained in Step 1-4-3 (30 mg) and 1-methyl-4-[(methylsulfonyl) amino] -1H-pyrazole-5-carboxylic acid (19 mg), the title compound (23 mg, colorless Solid) was obtained.
LCMS (ESI) m / z 490 [M + H] + , t R = 0.71 min, mode H.
実施例2−29: N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}プロピル]-3-クロロ-N,5-ジメチル-2-[(メチルスルホニル)アミノ]ベンズアミド 塩酸塩の合成
工程1−2−7及び工程1−2−8と同様の手法を用いて、工程1−4−3で得た化合物 (30 mg) 及び3-クロロ-5-メチル-2-[(メチルスルホニル)アミノ]安息香酸(22 mg)より、表題化合物(37 mg, 無色固体)を得た。
1H NMR (600 MHz, DMSO-d6, δ): 0.75-1.04 (m, 3H), 1.84-2.29 (m, 4H), 2.31-2.41 (m, 6H), 2.53-2.72 (m, 3H), 2.88-3.13 (m, 3H), 3.69-3.98 (m, 5H), 5.74 (br s, 1H), 6.11 (br s, 1H), 7.00-7.15 (m, 1H), 7.42-7.50 (m, 1H), 8.24-8.33 (m, 3H), 8.46-8.55 (m, 0.5H), 9.29 (br s, 0.5H).
LCMS (ESI) m/z 534 [M+H]+, tR = 0.97 min, mode H.
Example 2-29: N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidin-2-yl} propyl ] -3-Chloro-N, 5-dimethyl-2-[(methylsulfonyl) amino] benzamide Hydrochloride Synthesis Step 1-2-7 and Step 1-2-8 The title compound (37 mg, colorless solid) was obtained from the compound obtained in 4-3 (30 mg) and 3-chloro-5-methyl-2-[(methylsulfonyl) amino] benzoic acid (22 mg).
1 H NMR (600 MHz, DMSO-d 6 , δ): 0.75-1.04 (m, 3H), 1.84-2.29 (m, 4H), 2.31-2.41 (m, 6H), 2.53-2.72 (m, 3H) , 2.88-3.13 (m, 3H), 3.69-3.98 (m, 5H), 5.74 (br s, 1H), 6.11 (br s, 1H), 7.00-7.15 (m, 1H), 7.42-7.50 (m, 1H), 8.24-8.33 (m, 3H), 8.46-8.55 (m, 0.5H), 9.29 (br s, 0.5H).
LCMS (ESI) m / z 534 [M + H] + , t R = 0.97 min, mode H.
実施例2−30: N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}プロピル]-N,1-ジメチル-4-[(メチルスルホニル)アミノ]-1H-ピラゾール-3-カルボキサミド 塩酸塩の合成
工程1−2−7及び工程1−2−8と同様の手法を用いて、工程1−4−3で得た化合物 (30 mg) 及び1-メチル-4-[(メチルスルホニル)アミノ]-1H-ピラゾール-3-カルボン酸(18 mg)より、表題化合物(29 mg, 無色固体)を得た。
LCMS (ESI) m/z 490 [M+H]+, tR = 0.73 min, mode H.
Example 2-30: N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidin-2-yl} propyl ] -N, 1-Dimethyl-4-[(methylsulfonyl) amino] -1H-pyrazole-3-carboxamide Hydrochloride Synthesis using the same method as in Step 1-2-7 and Step 1-2-8, From the compound obtained in Step 1-4-3 (30 mg) and 1-methyl-4-[(methylsulfonyl) amino] -1H-pyrazole-3-carboxylic acid (18 mg), the title compound (29 mg, colorless Solid) was obtained.
LCMS (ESI) m / z 490 [M + H] + , t R = 0.73 min, mode H.
実施例2−31: N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}エチル]-5-クロロ-2-[(エチルスルホニル)アミノ]-N-メチルベンズアミド の合成
工程2−31−1:工程1−1−8と同様の手法を用いて、工程1−1−7で得られた化合物 (100 mg) 及び2-アミノ-5-クロロ安息香酸(43 mg)より、ベンジル [(3S)-1-(2-{(1S)-1-[(2-アミノ-5-クロロベンゾイル)(メチル)アミノ]エチル}-6-メチルピラゾロ[1,5-a]ピリミジン-5-イル)ピロリジン-3-イル]カルバマート(63 mg)を得た。
LCMS (ESI) m/z 562 [M+H]+, tR = 1.06 min, mode N.
工程2−31−2:工程2−31−1で得られた化合物(28 mg)をTHF(1.0 mL)に溶解し、Et3N(42μL) とエタンスルホニルクロリド (28 μL) を加え、室温で4時間攪拌した。反応液を水にあけ、CHCl3にて抽出した。有機層をPhase Separatorにてろ過後、ろ液を減圧下濃縮した。得られた残渣をOH型シリカゲルカラムクロマトグラフィー(移動相:ヘキサン/EtOAc = 95/5〜0/100; v/v)NH型シリカゲルカラムクロマトグラフィー(移動相:CHCl3/MeOH = 95/5; v/v)にて精製し、ベンジル [(3S)-1-(2-{(1S)-1-[{5-クロロ-2-[(エチルスルホニル)アミノ]ベンゾイル}(メチル)アミノ]エチル}-6-メチルピラゾロ[1,5-a]ピリミジン-5-イル)ピロリジン-3-イル]カルバマート(12 mg, 無色アモルファス)を得た。
LCMS (ESI) m/z 654 [M+H]+, tR = 1.19 min, mode N.
工程2−31−3:工程1−1−9と同様の手法を用いて、工程2−31−2で得られた化合物(11.8 mg)より、表題化合物(1.62 mg, 無色アモルファス)を得た。
LCMS (ESI) m/z 520 [M+H]+, tR = 0.55 min, mode N.
Example 2-31: N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidin-2-yl} ethyl ] Synthesis step 2-31-1 of 5-chloro-2-[(ethylsulfonyl) amino] -N-methylbenzamide: In step 1-1-7, using the same method as in step 1-1-8 From the obtained compound (100 mg) and 2-amino-5-chlorobenzoic acid (43 mg), benzyl [(3S) -1- (2-{(1S) -1-[(2-amino-5- Chlorobenzoyl) (methyl) amino] ethyl} -6-methylpyrazolo [1,5-a] pyrimidin-5-yl) pyrrolidin-3-yl] carbamate (63 mg) was obtained.
LCMS (ESI) m / z 562 [M + H] + , t R = 1.06 min, mode N.
Step 2-31-2: The compound (28 mg) obtained in Step 2-3-1 was dissolved in THF (1.0 mL), Et 3 N (42 μL) and ethanesulfonyl chloride (28 μL) were added, and room temperature was added. For 4 hours. The reaction solution was poured into water and extracted with CHCl 3 . The organic layer was filtered through a phase separator, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to OH type silica gel column chromatography (mobile phase: hexane / EtOAc = 95/5 to 0/100; v / v) NH type silica gel column chromatography (mobile phase: CHCl 3 / MeOH = 95/5; v / v) and purified by benzyl [(3S) -1- (2-{(1S) -1-[{5-chloro-2-[(ethylsulfonyl) amino] benzoyl} (methyl) amino] ethyl } -6-methylpyrazolo [1,5-a] pyrimidin-5-yl) pyrrolidin-3-yl] carbamate (12 mg, colorless amorphous) was obtained.
LCMS (ESI) m / z 654 [M + H] + , t R = 1.19 min, mode N.
Step 2-31-3: Using the same method as in Step 1-1-9, the title compound (1.62 mg, colorless amorphous) was obtained from the compound (11.8 mg) obtained in Step 2-31-2. .
LCMS (ESI) m / z 520 [M + H] + , t R = 0.55 min, mode N.
実施例2−32: 2-(アセチルアミノ)-N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}エチル]-5-クロロ-N-メチルベンズアミド の合成
工程2−32−1:工程1−1−8と同様の手法を用いて、工程1−1−7で得られた化合物(60 mg) 及び2-アミノ-5-クロロ安息香酸(26 mg)より、ベンジル [(3S)-1-(2-{(1S)-1-[(2-アミノ-5-クロロベンゾイル)(メチル)アミノ]エチル}-6-メチルピラゾロ[1,5-a]ピリミジン-5-イル)ピロリジン-3-イル]カルバマート(46 mg)を得た。
LCMS (ESI) m/z 562 [M+H]+, tR = 1.05 min, mode N.
工程2−32−2:工程2−32−1で得られた化合物(28 mg)のCHCl3(1.0 mL)溶液に、氷冷下 、Et3N (42 μL)、AcCl(10 μL)を加えて、室温で2時間攪拌した。反応液を水にあけ、CHCl3にて抽出した。有機層をPhase Separatorにてろ過後、ろ液を減圧下濃縮した。得られた残渣をOH型シリカゲルカラムクロマトグラフィー(移動相:ヘキサン/EtOAc = 95/5〜0/100; v/v)にて精製し、ベンジル [(3S)-1-{2-[(1S)-1-{[2-(アセチルアミノ)-5-クロロベンゾイル](メチル)アミノ}エチル]-6-メチルピラゾロ[1,5-a]ピリミジン-5-イル}ピロリジン-3-イル]カルバマート(24 mg, 無色アモルファス)を得た。
LCMS (ESI) m/z 604 [M+H]+, tR = 1.00 min, mode N.
Example 2-32: 2- (acetylamino) -N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] Pyrimidin-2-yl} ethyl] -5-chloro-N-methylbenzamide Step 2-32-1: Obtained in Step 1-1-7 using a method similar to Step 1-1-8. From the compound (60 mg) and 2-amino-5-chlorobenzoic acid (26 mg), benzyl [(3S) -1- (2-{(1S) -1-[(2-amino-5-chlorobenzoyl) (Methyl) amino] ethyl} -6-methylpyrazolo [1,5-a] pyrimidin-5-yl) pyrrolidin-3-yl] carbamate (46 mg) was obtained.
LCMS (ESI) m / z 562 [M + H] + , t R = 1.05 min, mode N.
Step 2-32-2: in CHCl 3 (1.0 mL) solution of the compound obtained in step 2-32-1 (28 mg), under ice-cooling, Et 3 N (42 μL) , AcCl a (10 [mu] L) In addition, the mixture was stirred at room temperature for 2 hours. The reaction solution was poured into water and extracted with CHCl 3 . The organic layer was filtered through a phase separator, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by OH-type silica gel column chromatography (mobile phase: hexane / EtOAc = 95 / 5-0 / 100; v / v), and benzyl [(3S) -1- {2-[(1S ) -1-{[2- (acetylamino) -5-chlorobenzoyl] (methyl) amino} ethyl] -6-methylpyrazolo [1,5-a] pyrimidin-5-yl} pyrrolidin-3-yl] carbamate ( 24 mg, colorless amorphous) was obtained.
LCMS (ESI) m / z 604 [M + H] + , t R = 1.00 min, mode N.
工程2−32−3:工程1−1−9と同様の手法を用いて、工程2−32−2で得られた化合物(24mg)より、表題化合物(4.6 mg, 無色固体)を得た。
LCMS (ESI) m/z 470 [M+H]+, tR = 0.39 min, mode N.
Step 2-332: Using the same method as in Step 1-1-9, the title compound (4.6 mg, colorless solid) was obtained from the compound (24 mg) obtained in Step 2-3-2.
LCMS (ESI) m / z 470 [M + H] + , t R = 0.39 min, mode N.
実施例2−33: N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}プロピル]-5-エチル-N-メチル-2-[(メチルスルホニル)アミノ]ベンズアミド 塩酸塩の合成
工程1−1−8、工程2−31−2及び工程1−2−8と同様の手法を用いて、工程1−4−3で得られた化合物(64 mg) 、2-アミノ-5-エチル安息香酸(38 mg)及びMsCl(36 μL)より、表題化合物(30 mg, 無色固体)を得た。
1H NMR (600 MHz, DMSO-d6, δ): 0.85-0.96 (m, 1.5H), 1.03 (t, J = 7.2 Hz, 1.5H), 1.14-1.22 (m, 3H), 1.82-2.32 (m, 4H), 2.33-2.38 (m, 3H), 2.57 (s, 1.5H), 2.59-2.68 (m, 2H), 2.72 (br s, 1.5H), 2.97 (s, 3H), 3.69-4.05 (m, 5H), 4.50-4.57 (m, 0.5H), 5.75-5.80 (m, 0.5H), 6.12 (s, 1H), 7.15 (s, 1H), 7.26-7.33 (m, 1H), 7.33-7.40 (m, 1H), 8.30-8.39 (m, 3H), 8.51 (s, 0.5H), 8.98 (s, 0.5H).
LCMS (ESI) m/z 514 [M+H]+, tR = 0.59 min, mode N.
Example 2-33: N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidin-2-yl} propyl ] -5-Ethyl-N-methyl-2-[(methylsulfonyl) amino] benzamide Hydrochloride Synthesis Method 1-1-8, Step 2-3-2 and Step 1-2-8 The title compound (30 mg, colorless solid) was obtained from the compound (64 mg) obtained in Step 1-4-3, 2-amino-5-ethylbenzoic acid (38 mg) and MsCl (36 μL). It was.
1 H NMR (600 MHz, DMSO-d 6 , δ): 0.85-0.96 (m, 1.5H), 1.03 (t, J = 7.2 Hz, 1.5H), 1.14-1.22 (m, 3H), 1.82-2.32 (m, 4H), 2.33-2.38 (m, 3H), 2.57 (s, 1.5H), 2.59-2.68 (m, 2H), 2.72 (br s, 1.5H), 2.97 (s, 3H), 3.69- 4.05 (m, 5H), 4.50-4.57 (m, 0.5H), 5.75-5.80 (m, 0.5H), 6.12 (s, 1H), 7.15 (s, 1H), 7.26-7.33 (m, 1H), 7.33-7.40 (m, 1H), 8.30-8.39 (m, 3H), 8.51 (s, 0.5H), 8.98 (s, 0.5H).
LCMS (ESI) m / z 514 [M + H] + , t R = 0.59 min, mode N.
実施例2−34:N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}プロピル]-N,4-ジメチル-2-[(メチルスルホニル)アミノ]ベンズアミド 塩酸塩の合成
工程1−1−8、工程2−31−2及び工程1−2−8と同様の手法を用いて、工程1−4−3で得られた化合物(45 mg) 、2-アミノ-4-メチル安息香酸(21 mg)及びMsCl(36 μL)より、表題化合物(25 mg, 無色固体)を得た。
LCMS (ESI) m/z 500 [M+H]+, tR = 0.54 min, mode N.
Example 2-34: N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidin-2-yl} propyl ] -N, 4-Dimethyl-2-[(methylsulfonyl) amino] benzamide hydrochloride Synthesis step 1-1-8, step 2-31-2 and step 1-2-8 The title compound (25 mg, colorless solid) was obtained from the compound (45 mg) obtained in Step 1-4-3, 2-amino-4-methylbenzoic acid (21 mg) and MsCl (36 μL).
LCMS (ESI) m / z 500 [M + H] + , t R = 0.54 min, mode N.
実施例2−35: N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}プロピル]-5-メトキシ-N-メチル-2-[(メチルスルホニル)アミノ]ベンズアミド 塩酸塩の合成
工程1−1−8、工程2−31−2及び工程1−2−8と同様の手法を持ち知恵、工程1−4−3で得られた化合物(45 mg)、2-アミノ-5-メトキシ安息香酸(23 mg)及びMsCl(36 μL)より、表題化合物(19 mg, 無色固体)を得た。
LCMS (ESI) m/z 516 [M+H]+, tR = 0.50 min, mode N.
Example 2-35: N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidin-2-yl} propyl ] -5-Methoxy-N-methyl-2-[(methylsulfonyl) amino] benzamide Hydrochloride has the same method as in Step 1-1-8, Step 2-31-2 and Step 1-2-8 From the wisdom, the compound obtained in Step 1-4-3 (45 mg), 2-amino-5-methoxybenzoic acid (23 mg) and MsCl (36 μL), the title compound (19 mg, colorless solid) was obtained. It was.
LCMS (ESI) m / z 516 [M + H] + , t R = 0.50 min, mode N.
実施例2−36: N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}プロピル]-N-メチル-3-[(メチルスルホニル)アミノ]ピリジン-2-カルボキサミド 塩酸塩の合成
工程2−36−1:工程1−1−8と同様の手法を用いて、工程1−4−3で得られた化合物(50 mg) 及び3-アミノピリジン-2-カルボン酸(21 mg)より、tert-ブチル [(3S)-1-{2-[(1S)-1-{[(3-アミノピリジン-2-イル)カルボニル](メチル)アミノ}プロピル]-6-メチルピラゾロ[1,5-a]ピリミジン-5-イル}ピロリジン-3-イル]カルバマート(33 mg)を得た。
工程2−36−2:工程2−36−1で得られた化合物(20 mg)のCHCl3 (1.0 mL)溶液に、Et3N (57 μL)、MsCl (9.5 μL)を加えて、室温で2時間攪拌した。反応液を減圧下濃縮し、得られた残渣を EtOH (1 mL) に溶解し、2.94 M NaOEt/EtOH溶液(50 μL)を加え、室温で30分間攪拌した。反応液を水にあけ、CHCl3にて抽出した。有機層をPhase Separatorにてろ過後、ろ液を減圧下濃縮した。得られた残渣を逆相分取HPLCにて精製し、tert-ブチル [(3S)-1-(6-メチル-2-{(1S)-1-[メチル({3-[(メチルスルホニル)アミノ]ピリジン-2-イル}カルボニル)アミノ]プロピル}ピラゾロ[1,5-a]ピリミジン-5-イル)ピロリジン-3-イル]カルバマート(16 mg, 無色アモルファス)を得た。
工程2−36−3:工程1−2−8と同様の手法を用いて、工程2−36−2で得られた化合物(16 mg)より、表題化合物(15 mg, 無色固体)を得た。
LCMS (ESI) m/z 487 [M+H]+, tR = 0.77 min, mode H.
Example 2-36: N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidin-2-yl} propyl ] -N-methyl-3-[(methylsulfonyl) amino] pyridine-2-carboxamide hydrochloride synthesis step 2-36-1: using a method similar to that of step 1-1-8, step 1-4-4 From the compound (50 mg) obtained in 3 and 3-aminopyridine-2-carboxylic acid (21 mg), tert-butyl [(3S) -1- {2-[(1S) -1-{[(3 -Aminopyridin-2-yl) carbonyl] (methyl) amino} propyl] -6-methylpyrazolo [1,5-a] pyrimidin-5-yl} pyrrolidin-3-yl] carbamate (33 mg) was obtained.
Step 2-36-2: Et 3 N (57 μL) and MsCl (9.5 μL) were added to a solution of the compound obtained in Step 2-36-1 (20 mg) in CHCl 3 (1.0 mL) at room temperature. For 2 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was dissolved in EtOH (1 mL), 2.94 M NaOEt / EtOH solution (50 μL) was added, and the mixture was stirred at room temperature for 30 min. The reaction solution was poured into water and extracted with CHCl 3 . The organic layer was filtered through a phase separator, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by reverse phase preparative HPLC, and tert-butyl [(3S) -1- (6-methyl-2-{(1S) -1- [methyl ({3-[(methylsulfonyl)) Amino] pyridin-2-yl} carbonyl) amino] propyl} pyrazolo [1,5-a] pyrimidin-5-yl) pyrrolidin-3-yl] carbamate (16 mg, colorless amorphous) was obtained.
Step 2-36-3: Using the same method as in Step 1-2-8, the title compound (15 mg, colorless solid) was obtained from the compound (16 mg) obtained in Step 2-3-6. .
LCMS (ESI) m / z 487 [M + H] + , t R = 0.77 min, mode H.
実施例2−37: N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}プロピル]-N-メチル-3-[(メチルスルホニル)アミノ]ピリジン-4-カルボキサミド 塩酸塩の合成
工程1−1−8、工程2−36−2及び工程1−2−8と同様の手法を用いて、工程1−4−3で得られた化合物(50 mg) 及び3-アミノピリジン-4-カルボン酸(21 mg)より、表題化合物(19 mg, 無色固体)を得た。
LCMS (ESI) m/z 487 [M+H]+, tR = 0.72 min, mode H.
Example 2-37: N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidin-2-yl} propyl ] -N-Methyl-3-[(methylsulfonyl) amino] pyridine-4-carboxamide Hydrochloride Synthesis Using the same method as in Step 1-1-8, Step 2-3-2 and Step 1-2-8 Then, the title compound (19 mg, colorless solid) was obtained from the compound obtained in Step 1-4-3 (50 mg) and 3-aminopyridine-4-carboxylic acid (21 mg).
LCMS (ESI) m / z 487 [M + H] + , t R = 0.72 min, mode H.
実施例2−38: N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}プロピル]-2-クロロ-N-メチル-5-[(メチルスルホニル)アミノ]ピリジン-4-カルボキサミド 塩酸塩の合成
工程1−1−8、工程2−36−2及び工程1−2−8と同様の手法を用いて、工程1−4−3で得られた化合物(50 mg) 及び5-アミノ-2-クロロピリジン-4-カルボン酸(21 mg)より、表題化合物(19 mg, 無色固体)を得た。
LCMS (ESI) m/z 521 [M+H]+, tR = 0.92 min, mode H.
Example 2-38: N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidin-2-yl} propyl ] -2-Chloro-N-methyl-5-[(methylsulfonyl) amino] pyridine-4-carboxamide Similar to Step 1-1-8, Step 2-36-2 and Step 1-2-8 of hydrochloride The title compound (19 mg, colorless solid) was obtained from the compound (50 mg) obtained in Step 1-4-3 and 5-amino-2-chloropyridine-4-carboxylic acid (21 mg) using the procedure of Got.
LCMS (ESI) m / z 521 [M + H] + , t R = 0.92 min, mode H.
実施例2−39: N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}プロピル]-N-メチル-4-[(メチルスルホニル)アミノ]-1,2-チアゾール-3-カルボキサミド 塩酸塩の合成
工程1−1−8、工程2−36−2及び工程1−2−8と同様の手法を利用し、工程1−4−3で得られた化合物 (50 mg) 及び4-アミノ-1,2-チアゾール-3-カルボン酸(28 mg)より、表題化合物(16 mg, 無色固体)を得た。
LCMS (ESI) m/z 493 [M+H]+, tR = 0.82 min, mode H.
Example 2-39: N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidin-2-yl} propyl ] -N-methyl-4-[(methylsulfonyl) amino] -1,2-thiazole-3-carboxamide Hydrochloride Synthesis Step 1-1-8, Step 2-3-6 and Step 1-2-8 Using a similar method, the title compound (16 mg, colorless) was obtained from the compound obtained in Step 1-4-3 (50 mg) and 4-amino-1,2-thiazole-3-carboxylic acid (28 mg). Solid) was obtained.
LCMS (ESI) m / z 493 [M + H] + , t R = 0.82 min, mode H.
実施例2−40: N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}プロピル]-6-クロロ-N-メチル-3-[(メチルスルホニル)アミノ]ピリジン-2-カルボキサミド 塩酸塩の合成
工程1−1−8、工程2−36−2及び工程1−2−8と同様の手法を利用し、工程1−4−3で得られた化合物(50 mg) 及び3-アミノ-6-クロロピリジン-2-カルボン酸(27 mg)より、表題化合物(27 mg, 無色固体)を得た。
1H NMR (600 MHz, DMSO-d6, δ): 0.89-1.03 (m, 3H), 1.88-2.30 (m, 4H), 2.33-2.38 (m, 3H), 2.62 (s, 1.5H), 2.74 (s, 1.5H), 3.07-3.14 (m, 3H), 3.69-4.08 (m, 5H), 4.60 (dd, J = 9.7, 5.6 Hz, 0.5H), 5.72 (dd, J = 9.3, 6.0 Hz, 0.5H), 6.10-6.17 (m, 1H), 7.63 (t, J = 9.1 Hz, 1H), 7.95 (d, J = 8.7 Hz, 1H), 8.28 (br s, 3H), 8.52 (s, 0.5H), 9.56 (s, 0.5H).
LCMS (ESI) m/z 521 [M+H]+, tR = 0.95 min, mode H.
Example 2-40: N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidin-2-yl} propyl ] -6-Chloro-N-methyl-3-[(methylsulfonyl) amino] pyridine-2-carboxamide Hydrochloride Synthesis Step 1-1-8, Step 2-3-2 and Step 1-2-8 From the compound obtained in Step 1-4-3 and 3-amino-6-chloropyridine-2-carboxylic acid (27 mg), the title compound (27 mg, colorless solid) Got.
1 H NMR (600 MHz, DMSO-d 6 , δ): 0.89-1.03 (m, 3H), 1.88-2.30 (m, 4H), 2.33-2.38 (m, 3H), 2.62 (s, 1.5H), 2.74 (s, 1.5H), 3.07-3.14 (m, 3H), 3.69-4.08 (m, 5H), 4.60 (dd, J = 9.7, 5.6 Hz, 0.5H), 5.72 (dd, J = 9.3, 6.0 Hz, 0.5H), 6.10-6.17 (m, 1H), 7.63 (t, J = 9.1 Hz, 1H), 7.95 (d, J = 8.7 Hz, 1H), 8.28 (br s, 3H), 8.52 (s , 0.5H), 9.56 (s, 0.5H).
LCMS (ESI) m / z 521 [M + H] + , t R = 0.95 min, mode H.
実施例2−41: N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}プロピル]-4-クロロ-N-メチル-2-[(メチルスルホニル)アミノ]ベンズアミド 塩酸塩の合成
工程1−1−8、工程2−36−2及び工程1−2−8と同様の手法を利用し、工程1−4−3で得られた化合物(50 mg)及び2-アミノ-4-クロロ安息香酸(26 mg)より、表題化合物(35 mg, 無色固体)を得た。
1H NMR (600 MHz, DMSO-d6, δ): 0.86-0.92 (m, 1.5H), 1.02 (t, J = 7.2 Hz, 1.5H), 1.86-2.30 (m, 4H), 2.33-2.38 (m, 3H), 2.58 (s, 1.5H), 2.73 (br s, 1.5H), 3.01-3.12 (m, 3H), 3.68-4.15 (m, 5H), 4.56 (dd, J = 9.9, 4.5 Hz, 0.5H), 5.73 (dd, J = 10.1, 5.6 Hz, 0.5H), 6.11 (s, 1H), 7.39 (s, 2H), 7.49 (d, J = 11.6 Hz, 1H), 8.23 (br s, 3H), 8.51 (s, 0.5H), 9.28 (s, 0.5H).
LCMS (ESI) m/z 520 [M+H]+, tR = 1.04 min, mode H.
Example 2-41: N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidin-2-yl} propyl ] -4-Chloro-N-methyl-2-[(methylsulfonyl) amino] benzamide Using the same method as in Step 1-1-8, Step 2-36-2 and Step 1-2-8 of hydrochloride The title compound (35 mg, colorless solid) was obtained from the compound (50 mg) obtained in Step 1-4-3 and 2-amino-4-chlorobenzoic acid (26 mg).
1 H NMR (600 MHz, DMSO-d 6 , δ): 0.86-0.92 (m, 1.5H), 1.02 (t, J = 7.2 Hz, 1.5H), 1.86-2.30 (m, 4H), 2.33-2.38 (m, 3H), 2.58 (s, 1.5H), 2.73 (br s, 1.5H), 3.01-3.12 (m, 3H), 3.68-4.15 (m, 5H), 4.56 (dd, J = 9.9, 4.5 Hz, 0.5H), 5.73 (dd, J = 10.1, 5.6 Hz, 0.5H), 6.11 (s, 1H), 7.39 (s, 2H), 7.49 (d, J = 11.6 Hz, 1H), 8.23 (br s, 3H), 8.51 (s, 0.5H), 9.28 (s, 0.5H).
LCMS (ESI) m / z 520 [M + H] + , t R = 1.04 min, mode H.
実施例2−42: N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}プロピル]-2-フルオロ-N-メチル-6-[(メチルスルホニル)アミノ]ベンズアミド 塩酸塩の合成
工程1−1−8、工程2−36−2及び工程1−2−8と同様の手法を利用し、工程1−4−3で得られた化合物(45 mg) 及び2-アミノ-6-フルオロ安息香酸(21 mg)より、表題化合物(25 mg, 無色固体)を得た。
LCMS (ESI) m/z 504 [M+H]+, tR = 0.52 min, mode N.
Example 2-42: N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidin-2-yl} propyl ] -2-Fluoro-N-methyl-6-[(methylsulfonyl) amino] benzamide Hydrochloride Synthesis Method 1-1-8, Step 2-3-2 and Step 1-2-8 The title compound (25 mg, colorless solid) was obtained from the compound obtained in Step 1-4-3 (45 mg) and 2-amino-6-fluorobenzoic acid (21 mg).
LCMS (ESI) m / z 504 [M + H] + , t R = 0.52 min, mode N.
実施例2−43: N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}プロピル]-5-クロロ-N-メチル-2-{[(メチルスルホニル)アセチル]アミノ}ベンズアミド 塩酸塩の合成
工程2−43−1:工程1−4−3で得られた化合物(50 mg)と5-クロロ-アントラニル酸 (26 mg)のDMF(1 mL) 溶液にHATU(63 mg)、Et3N(89 μL)を 加え、室温で30分間撹拌した。反応液を逆相分取HPLCにて精製し、tert-ブチル [(3S)-1-(2-{(1S)-1-[(2-アミノ-5-クロロベンゾイル)(メチル)アミノ]プロピル}-6-メチルピラゾロ[1,5-a]ピリミジン-5-イル)ピロリジン-3-イル]カルバマート(37 mg, 無色固体)を得た。
工程2−43−2:工程2−43−1で得られた化合物 (25 mg)とメタンスルホニル酢酸(7 mg)のDMF(1 mL)溶液にHATU(22 mg)、Et3N(31 μL)を加え、室温で30分間撹拌した。反応液を逆相分取HPLCにて精製し、tert-ブチル [(3S)-1-(2-{(1S)-1-[(5-クロロ-2-{[(メチルスルホニル)アセチル]アミノ}ベンゾイル)(メチル)アミノ]プロピル}-6-メチルピラゾロ[1,5-a]ピリミジン-5-イル)ピロリジン-3-イル]カルバマート(16 mg, 無色固体)を得た。
工程2−43−3:工程1−2−8と同様の手法を用いて、工程2−43−2で得られた化合物(17 mg)より、表題化合物(15 mg, 無色固体)を得た。
1H NMR (600 MHz, DMSO-d6, δ): 0.71-0.89 (m, 1.5H), 0.98 (t, J = 7.2 Hz, 1.5H), 1.82-2.30 (m, 4H), 2.31 -2.37 (m, 3H), 2.53-2.54 (m, 1.5H), 2.82 (br s, 1.5H), 3.15 (s, 3H), 3.81-3.95 (m, 5H), 4.23-4.35 (m, 1.5H), 4.47 (br s, 1H), 5.65-5.73 (m, 0.5H), 6.02-6.17 (m, 1H), 7.34-7.57 (m, 3H), 8.22 (br s, 3H), 8.52 (s, 0.5H), 10.21 (s, 0.5H).
LCMS (ESI) m/z 562 [M+H]+, tR = 0.91 min, mode H.
Example 2-43: N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidin-2-yl} propyl ] -5-Chloro-N-methyl-2-{[(methylsulfonyl) acetyl] amino} benzamide Hydrochloride Synthesis Step 2-43-1: Compound (50 mg) obtained in Step 1-4-3 and HATU (63 mg) and Et 3 N (89 μL) were added to a solution of 5-chloro-anthranilic acid (26 mg) in DMF (1 mL), and the mixture was stirred at room temperature for 30 minutes. The reaction solution was purified by reverse phase preparative HPLC and tert-butyl [(3S) -1- (2-{(1S) -1-[(2-amino-5-chlorobenzoyl) (methyl) amino] propyl. } -6-methylpyrazolo [1,5-a] pyrimidin-5-yl) pyrrolidin-3-yl] carbamate (37 mg, colorless solid) was obtained.
Step 2-43-2: A solution of the compound obtained in Step 2-43-1 (25 mg) and methanesulfonylacetic acid (7 mg) in DMF (1 mL) was added to HATU (22 mg), Et 3 N (31 μL). ) Was added and stirred at room temperature for 30 minutes. The reaction solution was purified by reverse phase preparative HPLC, and tert-butyl [(3S) -1- (2-{(1S) -1-[(5-chloro-2-{[(methylsulfonyl) acetyl] amino } Benzoyl) (methyl) amino] propyl} -6-methylpyrazolo [1,5-a] pyrimidin-5-yl) pyrrolidin-3-yl] carbamate (16 mg, colorless solid) was obtained.
Step 2-43-3: The title compound (15 mg, colorless solid) was obtained from the compound (17 mg) obtained in Step 2-43-2 using the same method as in Step 1-2-8. .
1 H NMR (600 MHz, DMSO-d 6 , δ): 0.71-0.89 (m, 1.5H), 0.98 (t, J = 7.2 Hz, 1.5H), 1.82-2.30 (m, 4H), 2.31 -2.37 (m, 3H), 2.53-2.54 (m, 1.5H), 2.82 (br s, 1.5H), 3.15 (s, 3H), 3.81-3.95 (m, 5H), 4.23-4.35 (m, 1.5H) , 4.47 (br s, 1H), 5.65-5.73 (m, 0.5H), 6.02-6.17 (m, 1H), 7.34-7.57 (m, 3H), 8.22 (br s, 3H), 8.52 (s, 0.5 H), 10.21 (s, 0.5H).
LCMS (ESI) m / z 562 [M + H] + , t R = 0.91 min, mode H.
実施例2−44: N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}エチル]-5-クロロ-N-エチル-2-[(メチルスルホニル)アミノ]ベンズアミドの合成
工程2−44−1:工程1−1−5〜工程1−1−7と同様の手法を用いて、工程1−2−2で得られた化合物(540 mg)より、ベンジル ((3S)-1-(2-((1S)-1-アミノエチル)-6-メチルピラゾロ[1,5-a]ピリミジン-5-イル)ピロリジン-3-イル)カルバマート(296 mg)を得た。
工程2−44−2:工程1−2−6、工程1−2−7及び工程1−1−9と同様の手法を用いて、工程2−44−1で得られた化合物(0.10 g)及びEtI(46 μL)より、表題化合物(25 mg, 無色アモルファス)を得た。
1H NMR (600 MHz, DMSO-d6, δ): 0.83 (t, J = 6.6 Hz, 1H), 1.00 (t, J = 7.0 Hz, 2H), 1.52-1.68 (m, 3H), 1.77 (br s, 1H), 2.01-2.10 (m, 1H), 2.33 (s, 3H), 2.79-2.94 (m, 3H), 2.94-3.17 (m, 2H), 3.45 (dd, J = 11.1, 4.1 Hz, 1H), 3.57-3.73 (m, 2H), 3.74-3.85 (m, 2H), 4.73-4.83 (m, 0.7H), 5.78 (br s, 0.3H), 6.16 (s, 1H), 7.21-7.49 (m, 3H), 8.31 (s, 0.5H), 8.46 (s, 0.5H).
LCMS (ESI) m/z 520 [M+H]+, tR = 0.57 min, mode N.
Example 2-44: N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidin-2-yl} ethyl Synthesis of] -5-chloro-N-ethyl-2-[(methylsulfonyl) amino] benzamide
Step 2-44-1: Using a method similar to that of Step 1-1-5 to Step 1-1-7, from the compound (540 mg) obtained in Step 1-2-2, benzyl ((3S) -1- (2-((1S) -1-aminoethyl) -6-methylpyrazolo [1,5-a] pyrimidin-5-yl) pyrrolidin-3-yl) carbamate (296 mg) was obtained.
Step 2-44-2: Compound (0.10 g) obtained in Step 2-44-1 using the same method as in Step 1-2-6, Step 1-2-7 and Step 1-1-9 And EtI (46 μL) gave the title compound (25 mg, colorless amorphous).
1 H NMR (600 MHz, DMSO-d 6 , δ): 0.83 (t, J = 6.6 Hz, 1H), 1.00 (t, J = 7.0 Hz, 2H), 1.52-1.68 (m, 3H), 1.77 ( br s, 1H), 2.01-2.10 (m, 1H), 2.33 (s, 3H), 2.79-2.94 (m, 3H), 2.94-3.17 (m, 2H), 3.45 (dd, J = 11.1, 4.1 Hz , 1H), 3.57-3.73 (m, 2H), 3.74-3.85 (m, 2H), 4.73-4.83 (m, 0.7H), 5.78 (br s, 0.3H), 6.16 (s, 1H), 7.21- 7.49 (m, 3H), 8.31 (s, 0.5H), 8.46 (s, 0.5H).
LCMS (ESI) m / z 520 [M + H] + , t R = 0.57 min, mode N.
実施例2−45: N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}エチル]-3-クロロ-N-(プロパン-2-イル)ベンズアミドの合成
工程2−45−1:工程2−44−1で得られた化合物(100 mg)のTHF(2 mL)溶液に、アセトン(20 μL)、AcOH(39 μL)、Et3N(64 μL)及びトリアセトキシ水素化ホウ素ナトリウム(123 mg)を加え、室温で5時間攪拌した。反応液を飽和NaHCO3水溶液にあけ、CHCl3にて抽出した。有機層をPhase Separatorにてろ過後、ろ液を減圧下濃縮した。得られた残渣をOH型シリカゲルカラムクロマトグラフィー(移動相:CHCl3/MeOH = 95/5〜80/20; v/v)にて精製し、ベンジル [(3S)-1-{6-メチル-2-[(1S)-1-(プロパン-2-イルアミノ)エチル]ピラゾロ[1,5-a]ピリミジン-5-イル}ピロリジン-3-イル]カルバマート(73 mg, 淡黄色固体)を得た。
工程2−45−2:工程2−45−1で得られた化合物(62 mg)のCHCl3(2 mL)溶液に、 3-クロロベンゾイルクロリド(22 μL)及びEt3N(99 μL)を加え、室温で18時間攪拌した。反応溶液にEtOAcを加え、飽和NaHCO3水溶液で分液操作を行った。水層をBrineにて洗浄後、有機層をMgSO4にて乾燥し、ろ過後、ろ液を減圧下濃縮した。残渣をOH型シリカゲルカラムクロマトグラフィー(移動相:ヘキサン/EtOAc = 70/30〜30/70; v/v)で精製し、ベンジル [(3S)-1-(2-{(1S)-1-[(3-クロロベンゾイル)(プロパン-2-イル)アミノ]エチル}-6-メチルピラゾロ[1,5-a]ピリミジン-5-イル)ピロリジン-3-イル]カルバマート(35 mg, 無色固体)を得た。
工程2−45−3:工程1−1−9と同様の手法を用いて、工程2−45−2で得た化合物 (34 mg)より、表題化合物(10 mg, 無色アモルファス)を得た。
LCMS (ESI) m/z 441 [M+H]+, tR = 0.56 min, mode N.
Example 2-45: N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidin-2-yl} ethyl ] -3-Chloro-N- (propan-2-yl) benzamide synthesis step 2-451: A solution of the compound obtained in step 24-1 (100 mg) in THF (2 mL) was added to acetone. (20 μL), AcOH (39 μL), Et 3 N (64 μL) and sodium triacetoxyborohydride (123 mg) were added, and the mixture was stirred at room temperature for 5 hours. The reaction solution was poured into a saturated aqueous NaHCO 3 solution and extracted with CHCl 3 . The organic layer was filtered through a phase separator, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by OH-type silica gel column chromatography (mobile phase: CHCl 3 / MeOH = 95/5 to 80/20; v / v) to obtain benzyl [(3S) -1- {6-methyl- 2-[(1S) -1- (propan-2-ylamino) ethyl] pyrazolo [1,5-a] pyrimidin-5-yl} pyrrolidin-3-yl] carbamate (73 mg, pale yellow solid) was obtained. .
Step 2-45-2: To a solution of the compound obtained in Step 2-45-1 (62 mg) in CHCl 3 (2 mL), add 3-chlorobenzoyl chloride (22 μL) and Et 3 N (99 μL). The mixture was further stirred at room temperature for 18 hours. EtOAc was added to the reaction solution, and a liquid separation operation was performed with a saturated aqueous NaHCO 3 solution. The aqueous layer was washed with Brine, the organic layer was dried with MgSO 4 , filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by OH-type silica gel column chromatography (mobile phase: hexane / EtOAc = 70 / 30-30 / 70; v / v), and benzyl [(3S) -1- (2-{(1S) -1- [(3-Chlorobenzoyl) (propan-2-yl) amino] ethyl} -6-methylpyrazolo [1,5-a] pyrimidin-5-yl) pyrrolidin-3-yl] carbamate (35 mg, colorless solid) Obtained.
Step 2-45-3: Using the same method as in Step 1-1-9, the title compound (10 mg, colorless amorphous) was obtained from the compound (34 mg) obtained in Step 2-45-2.
LCMS (ESI) m / z 441 [M + H] + , t R = 0.56 min, mode N.
実施例2−46: N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}エチル]-N-ブチル-5-クロロ-2-[(メチルスルホニル)アミノ]ベンズアミド 塩酸塩の合成
工程1−2−6〜工程1−2−8と同様の手法を用いて、工程1−2−5で得た化合物 (30 mg)及び1-ヨードブタン(19 μL)より、表題化合物(15 mg, 無色固体)を得た。
1H NMR (600 MHz, DMSO-d6, δ): 0.55 (t, J = 7.2 Hz, 1H), 0.81 (t, J = 7.4 Hz, 2H), 0.84-1.52 (m, 6H), 1.57 (d, J = 7.0 Hz, 2H), 1.66 (d, J = 7.0 Hz, 1H), 2.00-2.10 (m, 1H), 2.22-2.29 (m, 1H), 2.33-2.38 (m, 3H), 2.85-3.08 (m, 5H), 3.69-3.95 (m, 5H), 4.74-4.82 (m, 0.7H), 5.74 (br s, 0.3H), 6.13 (s, 1H), 7.42-7.57 (m, 3H), 8.17 (br s, 3H), 8.52 (s, 0.5H), 9.34 (s, 0.5H).
LCMS (ESI) m/z 548 [M+H]+, tR = 0.67 min, mode N.
Example 2-46: N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidin-2-yl} ethyl ] -N-butyl-5-chloro-2-[(methylsulfonyl) amino] benzamide Hydrochloride Synthesis Step 1-2-6 to Step 1-2-8 The title compound (15 mg, colorless solid) was obtained from the compound obtained in 5 (30 mg) and 1-iodobutane (19 μL).
1 H NMR (600 MHz, DMSO-d 6 , δ): 0.55 (t, J = 7.2 Hz, 1H), 0.81 (t, J = 7.4 Hz, 2H), 0.84-1.52 (m, 6H), 1.57 ( d, J = 7.0 Hz, 2H), 1.66 (d, J = 7.0 Hz, 1H), 2.00-2.10 (m, 1H), 2.22-2.29 (m, 1H), 2.33-2.38 (m, 3H), 2.85 -3.08 (m, 5H), 3.69-3.95 (m, 5H), 4.74-4.82 (m, 0.7H), 5.74 (br s, 0.3H), 6.13 (s, 1H), 7.42-7.57 (m, 3H ), 8.17 (br s, 3H), 8.52 (s, 0.5H), 9.34 (s, 0.5H).
LCMS (ESI) m / z 548 [M + H] + , t R = 0.67 min, mode N.
実施例2−47: N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}エチル]-5-クロロ-N-(2-メチルブチル)-2-[(メチルスルホニル)アミノ]ベンズアミド 塩酸塩の合成
工程1−2−6〜工程1−2−8と同様の手法を用いて、工程1−2−5で得た化合物 (30 mg) 及び1-ヨード-2-メチルブタン(21 μL)より、表題化合物(12 mg, 無色固体)を得た。
1H NMR (600 MHz, DMSO-d6, δ): 0.55-1.07 (m, 8H), 1.08-1.77 (m, 6H), 2.01-2.11 (m, 1H), 2.21-2.31 (m, 1H), 2.33-2.38 (m, 3H), 2.76-3.36 (m, 5H), 3.69-3.95 (m, 5H), 4.80-4.89 (m, 1H), 6.04-6.16 (m, 1H), 7.31-7.58 (m, 3H), 8.16 (br s, 3H), 8.30 (br s, 0.5H), 8.51 (s, 0.5H).
LCMS (ESI) m/z 562 [M+H]+, tR = 0.72 min, mode N.
Example 2-47: N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidin-2-yl} ethyl ] -5-Chloro-N- (2-methylbutyl) -2-[(methylsulfonyl) amino] benzamide hydrochloride Synthesis step 1-2-6 to step 1-2-8 The title compound (12 mg, colorless solid) was obtained from the compound obtained in 1-2-5 (30 mg) and 1-iodo-2-methylbutane (21 μL).
1 H NMR (600 MHz, DMSO-d 6 , δ): 0.55-1.07 (m, 8H), 1.08-1.77 (m, 6H), 2.01-2.11 (m, 1H), 2.21-2.31 (m, 1H) , 2.33-2.38 (m, 3H), 2.76-3.36 (m, 5H), 3.69-3.95 (m, 5H), 4.80-4.89 (m, 1H), 6.04-6.16 (m, 1H), 7.31-7.58 ( m, 3H), 8.16 (br s, 3H), 8.30 (br s, 0.5H), 8.51 (s, 0.5H).
LCMS (ESI) m / z 562 [M + H] + , t R = 0.72 min, mode N.
実施例2−48: N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}エチル]-5-クロロ-2-[(メチルスルホニル)アミノ]-N-ペンチルベンズアミド 塩酸塩の合成
工程1−2−6〜工程1−2−8と同様の手法を用いて、工程1−2−5で得た化合物 (30 mg) 及び1-ヨードペンタン(22 μL)より、表題化合物(12 mg, 無色固体)を得た。
1H NMR (600 MHz, DMSO-d6, δ): 0.62 (t, J = 7.0 Hz, 1H), 0.77 (t, J = 7.0 Hz, 2H), 0.80-1.48 (m, 6H), 1.53 (d, J = 7.0 Hz, 2H), 1.62 (d, J = 6.6 Hz, 1H), 1.97-2.05 (m, 1H), 2.17-2.25 (m, 1H), 2.27-2.34 (m, 3H), 2.82-3.05 (m, 3H), 3.24-3.60 (m, 4H), 3.78-3.92 (m, 3H), 4.68-4.78 (m, 0.7H), 5.70 (s, 0.3H), 6.09 (s, 1H), 7.36-7.55 (m, 3H), 8.13 (br s, 3H), 8.48 (s, 0.5H), 9.30 (s, 0.5H).
LCMS (ESI) m/z 562 [M+H]+, tR = 1.27 min, mode H.
Example 2-48: N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidin-2-yl} ethyl ] -5-Chloro-2-[(methylsulfonyl) amino] -N-pentylbenzamide Step 1-2-6 using the same method as in Step 1-2-6 to Step 1-2-8 The title compound (12 mg, colorless solid) was obtained from the compound obtained in 5 (30 mg) and 1-iodopentane (22 μL).
1 H NMR (600 MHz, DMSO-d 6 , δ): 0.62 (t, J = 7.0 Hz, 1H), 0.77 (t, J = 7.0 Hz, 2H), 0.80-1.48 (m, 6H), 1.53 ( d, J = 7.0 Hz, 2H), 1.62 (d, J = 6.6 Hz, 1H), 1.97-2.05 (m, 1H), 2.17-2.25 (m, 1H), 2.27-2.34 (m, 3H), 2.82 -3.05 (m, 3H), 3.24-3.60 (m, 4H), 3.78-3.92 (m, 3H), 4.68-4.78 (m, 0.7H), 5.70 (s, 0.3H), 6.09 (s, 1H) , 7.36-7.55 (m, 3H), 8.13 (br s, 3H), 8.48 (s, 0.5H), 9.30 (s, 0.5H).
LCMS (ESI) m / z 562 [M + H] + , t R = 1.27 min, mode H.
実施例2−49: N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}エチル]-5-クロロ-N-(2-フルオロエチル)-2-[(メチルスルホニル)アミノ]ベンズアミド 塩酸塩の合成
工程1−2−6〜工程1−2−8と同様の手法を用いて、工程1−2−5で得た化合物 (30 mg) 及び1-ヨード-2-フルオロエタン(13 μL)より、表題化合物(14 mg, 無色固体)を得た。
1H NMR (600 MHz, DMSO-d6, δ): 1.50-1.73 (m, 3H), 2.00-2.10 (m, 1H), 2.20-2.30 (m, 1H), 2.32-2.40 (m, 3H), 2.99-3.13 (m, 3H), 3.43-3.96 (m, 8H), 4.19-4.87 (m, 2H), 6.07-6.17 (m, 1H), 7.38-7.61 (m, 3H), 8.19 (br s, 3H), 8.52 (s, 0.5H), 9.37 (s, 0.5H).
LCMS (ESI) m/z 538 [M+H]+, tR = 0.57 min, mode N.
Example 2-49: N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidin-2-yl} ethyl ] -5-Chloro-N- (2-fluoroethyl) -2-[(methylsulfonyl) amino] benzamide Using a method similar to the synthesis steps 1-2-6 to 1-2-8 of hydrochloride, The title compound (14 mg, colorless solid) was obtained from the compound obtained in Step 1-2-5 (30 mg) and 1-iodo-2-fluoroethane (13 μL).
1 H NMR (600 MHz, DMSO-d 6 , δ): 1.50-1.73 (m, 3H), 2.00-2.10 (m, 1H), 2.20-2.30 (m, 1H), 2.32-2.40 (m, 3H) , 2.99-3.13 (m, 3H), 3.43-3.96 (m, 8H), 4.19-4.87 (m, 2H), 6.07-6.17 (m, 1H), 7.38-7.61 (m, 3H), 8.19 (br s , 3H), 8.52 (s, 0.5H), 9.37 (s, 0.5H).
LCMS (ESI) m / z 538 [M + H] + , t R = 0.57 min, mode N.
実施例2−50: N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}エチル]-5-クロロ-N-(3-フルオロプロピル)-2-[(メチルスルホニル)アミノ]ベンズアミド 塩酸塩の合成
工程1−2−6〜工程1−2−8と同様の手法を用いて、工程1−2−5で得た化合物(30 mg) 及び1-ヨード-3-フルオロプロパン(17 μL)より、表題化合物(11 mg, 無色固体)を得た。
1H NMR (600 MHz, DMSO-d6, δ): 1.52-1.97 (m, 5H), 2.00-2.10 (m, 1H), 2.20-2.30 (m, 1H), 2.32-2.40 (m, 3H), 2.97-3.17 (m, 5H), 3.42-3.96 (m, 5H), 4.10-4.56 (m, 2.5H), 4.77-4.83 (m, 1H), 6.05-6.18 (m, 1H), 7.44-7.75 (m, 3H), 8.15 (br s, 3H), 8.52 (s, 0.5H), 9.34 (s, 1H).
LCMS (ESI) m/z 552 [M+H]+, tR = 0.59 min, mode N.
Example 2-50: N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidin-2-yl} ethyl ] -5-Chloro-N- (3-fluoropropyl) -2-[(methylsulfonyl) amino] benzamide Using a method similar to the synthesis steps 1-2-6 to 1-2-8 of hydrochloride, The title compound (11 mg, colorless solid) was obtained from the compound obtained in Step 1-2-5 (30 mg) and 1-iodo-3-fluoropropane (17 μL).
1 H NMR (600 MHz, DMSO-d 6 , δ): 1.52-1.97 (m, 5H), 2.00-2.10 (m, 1H), 2.20-2.30 (m, 1H), 2.32-2.40 (m, 3H) , 2.97-3.17 (m, 5H), 3.42-3.96 (m, 5H), 4.10-4.56 (m, 2.5H), 4.77-4.83 (m, 1H), 6.05-6.18 (m, 1H), 7.44-7.75 (m, 3H), 8.15 (br s, 3H), 8.52 (s, 0.5H), 9.34 (s, 1H).
LCMS (ESI) m / z 552 [M + H] + , t R = 0.59 min, mode N.
実施例2−51: N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}エチル]-5-クロロ-2-[(メチルスルホニル)アミノ]-N-(2-フェニルエチル)ベンズアミド 塩酸塩の合成
工程1−2−6〜工程1−2−8と同様の手法を用いて、工程1−2−5で得た化合物(30 mg) 及び(2-ブロモエチル)ベンゼン(22 μL)より、表題化合物(12 mg, 無色固体)を得た。
LCMS (ESI) m/z 596 [M+H]+, tR = 1.26 min, mode H.
Example 2-51: N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidin-2-yl} ethyl ] -5-Chloro-2-[(methylsulfonyl) amino] -N- (2-phenylethyl) benzamide hydrochloride In the same manner as in Step 1-2-6 to Step 1-2-8, The title compound (12 mg, colorless solid) was obtained from the compound obtained in Step 1-2-5 (30 mg) and (2-bromoethyl) benzene (22 μL).
LCMS (ESI) m / z 596 [M + H] + , t R = 1.26 min, mode H.
実施例2−52: N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}エチル]-5-クロロ-2-[(メチルスルホニル)アミノ]-N-(3-フェニルプロピル)ベンズアミド 塩酸塩の合成
工程1−2−6〜工程1−2−8と同様の手法を用いて、工程1−2−5で得た化合物(30 mg) 及び(3-ブロモプロピル)ベンゼン(25 μL)より、表題化合物(18 mg, 無色固体)を得た。
LCMS (ESI) m/z 610 [M+H]+, tR = 1.29 min, mode H.
Example 2-52: N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidin-2-yl} ethyl ] -5-Chloro-2-[(methylsulfonyl) amino] -N- (3-phenylpropyl) benzamide Using the same method as in Step 1-2-6 to Step 1-2-8 of hydrochloride, The title compound (18 mg, colorless solid) was obtained from the compound obtained in Step 1-2-5 (30 mg) and (3-bromopropyl) benzene (25 μL).
LCMS (ESI) m / z 610 [M + H] + , t R = 1.29 min, mode H.
実施例2−53: N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}エチル]-5-クロロ-N-(2-メトキシエチル)-2-[(メチルスルホニル)アミノ]ベンズアミド 塩酸塩の合成
工程1−2−6〜工程1−2−8と同様の手法を用いて、工程1−2−5で得た化合物(30 mg) 及び2-ブロモエチル メチル エーテル(16 μL)より、表題化合物(10 mg, 無色固体)を得た。
1H NMR (600 MHz, DMSO-d6, δ): 1.52-1.72 (m, 3H), 2.00-2.07 (m, 1H), 2.20-2.32 (m, 1H), 2.32-2.38 (m, 3H), 2.97-3.10 (m, 5H), 3.12-3.35 (m, 5H), 3.65-3.95 (m, 7H), 4.74-4.82 (m, 0.5H), 5.61 (br s, 0.5H), 6.12 (br s, 1H), 7.41-7.58 (m, 3H), 8.06-8.22 (m, 3H), 8.52 (s, 0.5H), 9.22 (s, 0.5H).
LCMS (ESI) m/z 550 [M+H]+, tR = 0.56 min, mode N.
Example 2-53: N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidin-2-yl} ethyl ] -5-Chloro-N- (2-methoxyethyl) -2-[(methylsulfonyl) amino] benzamide Using a method similar to the synthesis steps 1-2-6 to 1-2-8 of hydrochloride, The title compound (10 mg, colorless solid) was obtained from the compound obtained in Step 1-2-5 (30 mg) and 2-bromoethyl methyl ether (16 μL).
1 H NMR (600 MHz, DMSO-d 6 , δ): 1.52-1.72 (m, 3H), 2.00-2.07 (m, 1H), 2.20-2.32 (m, 1H), 2.32-2.38 (m, 3H) , 2.97-3.10 (m, 5H), 3.12-3.35 (m, 5H), 3.65-3.95 (m, 7H), 4.74-4.82 (m, 0.5H), 5.61 (br s, 0.5H), 6.12 (br s, 1H), 7.41-7.58 (m, 3H), 8.06-8.22 (m, 3H), 8.52 (s, 0.5H), 9.22 (s, 0.5H).
LCMS (ESI) m / z 550 [M + H] + , t R = 0.56 min, mode N.
実施例2−54: N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}エチル]-5-クロロ-N-(3-メトキシプロピル)-2-[(メチルスルホニル)アミノ]ベンズアミド 塩酸塩の合成
工程1−2−6〜工程1−2−8と同様の手法を用いて、工程1−2−5で得た化合物(30 mg) 及び1-ブロモ-3-メトキシプロパン(18 μL)より、表題化合物(13 mg, 無色固体)を得た。
1H NMR (600 MHz, DMSO-d6, δ): 1.45-1.78 (m, 5H), 2.00-2.09 (m, 1H), 2.20-2.32 (m, 1H), 2.32-2.40 (m, 3H), 2.95-3.18 (m, 6H), 3.21-3.52 (m, 4H), 3.65-3.95 (m, 5H), 4.78 (q, J = 6.9 Hz, 0.5H), 5.74 (br s, 0.5H), 6.06-6.16 (s, 1H), 7.43-7.60 (m, 3H), 8.14 (br s, 3H), 8.52 (s, 0.5H), 9.33 (s, 0.5H).
LCMS (ESI) m/z 564 [M+H]+, tR = 0.58 min, mode N.
Example 2-54: N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidin-2-yl} ethyl ] -5-Chloro-N- (3-methoxypropyl) -2-[(methylsulfonyl) amino] benzamide Using a method similar to the synthesis steps 1-2-6 to 1-2-8 of hydrochloride, The title compound (13 mg, colorless solid) was obtained from the compound obtained in Step 1-2-5 (30 mg) and 1-bromo-3-methoxypropane (18 μL).
1 H NMR (600 MHz, DMSO-d 6 , δ): 1.45-1.78 (m, 5H), 2.00-2.09 (m, 1H), 2.20-2.32 (m, 1H), 2.32-2.40 (m, 3H) , 2.95-3.18 (m, 6H), 3.21-3.52 (m, 4H), 3.65-3.95 (m, 5H), 4.78 (q, J = 6.9 Hz, 0.5H), 5.74 (br s, 0.5H), 6.06-6.16 (s, 1H), 7.43-7.60 (m, 3H), 8.14 (br s, 3H), 8.52 (s, 0.5H), 9.33 (s, 0.5H).
LCMS (ESI) m / z 564 [M + H] + , t R = 0.58 min, mode N.
実施例2−55: N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}エチル]-5-クロロ-2-[(メチルスルホニル)アミノ]-N-[2-(2,2,2-トリフルオロエトキシ)エチル]ベンズアミド 塩酸塩の合成
工程1−2−6〜工程1−2−8と同様の手法を用いて、工程1−2−5で得た化合物(30 mg) 及び2-(2-ブロモエトキシ)-1,1,1-トリフルオロエタン(35 mg)より、表題化合物(11 mg, 無色固体)を得た。
1H NMR (600 MHz, DMSO-d6, δ): 1.52-1.73 (m, 3H), 1.99-2.09 (m, 1H), 2.20-2.32 (m, 1H), 2.33-2.38 (m, 3H), 2.98-3.13 (m, 5H), 3.41-4.10 (m, 9H), 4.76-4.84 (m, 1H), 6.05-6.18(m, 1H), 7.39-7.59 (m, 3H), 8.14 (br s, 3H), 8.51 (s, 0.5H), 9.36 (s, 0.5H).
LCMS (ESI) m/z 618 [M+H]+, tR = 0.67 min, mode N.
Example 2-55: N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidin-2-yl} ethyl ] -5-Chloro-2-[(methylsulfonyl) amino] -N- [2- (2,2,2-trifluoroethoxy) ethyl] benzamide Synthesis of Hydrochloride Step 1-2-6 to Step 1-2 Using the same method as for -8, from the compound obtained in Step 1-2-5 (30 mg) and 2- (2-bromoethoxy) -1,1,1-trifluoroethane (35 mg), the title Compound (11 mg, colorless solid) was obtained.
1 H NMR (600 MHz, DMSO-d 6 , δ): 1.52-1.73 (m, 3H), 1.99-2.09 (m, 1H), 2.20-2.32 (m, 1H), 2.33-2.38 (m, 3H) , 2.98-3.13 (m, 5H), 3.41-4.10 (m, 9H), 4.76-4.84 (m, 1H), 6.05-6.18 (m, 1H), 7.39-7.59 (m, 3H), 8.14 (br s , 3H), 8.51 (s, 0.5H), 9.36 (s, 0.5H).
LCMS (ESI) m / z 618 [M + H] + , t R = 0.67 min, mode N.
実施例2−56: N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}エチル]-5-クロロ-2-[(メチルスルホニル)アミノ]-N-(2-フェノキシエチル)ベンズアミド 塩酸塩の合成
工程1−2−6〜工程1−2−8と同様の手法を用いて、工程1−2−5で得た化合物(30 mg) 及び(2-ブロモエトキシ)ベンゼン(33 mg)より、表題化合物(15 mg, 無色固体)を得た。
LCMS (ESI) m/z 612 [M+H]+, tR = 0.70 min, mode N.
Example 2-56: N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidin-2-yl} ethyl ] -5-Chloro-2-[(methylsulfonyl) amino] -N- (2-phenoxyethyl) benzamide Hydrochloride Synthesis Using the same method as in Step 1-2-6 to Step 1-2-8, The title compound (15 mg, colorless solid) was obtained from the compound obtained in Step 1-2-5 (30 mg) and (2-bromoethoxy) benzene (33 mg).
LCMS (ESI) m / z 612 [M + H] + , t R = 0.70 min, mode N.
実施例2−57: N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}エチル]-5-クロロ-2-[(メチルスルホニル)アミノ]-N-[2-(1H-ピラゾール-1-イル)エチル]ベンズアミド 塩酸塩の合成
工程1−2−6〜工程1−2−8と同様の手法を用いて、工程1−2−5で得た化合物(30 mg) 及び1-(2-ブロモエチル)-1H-ピラゾール(18 μL)より、表題化合物(4.1 mg, 無色固体)を得た。
LCMS (ESI) m/z 586 [M+H]+, tR = 0.57 min, mode N.
Example 2-57: N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidin-2-yl} ethyl ] -5-Chloro-2-[(methylsulfonyl) amino] -N- [2- (1H-pyrazol-1-yl) ethyl] benzamide Synthesis Step 1-2-6 to Step 1-2-8 of Hydrochloride Using the same procedure as above, the title compound (4.1 mg, colorless solid) was obtained from the compound obtained in Step 1-2-5 (30 mg) and 1- (2-bromoethyl) -1H-pyrazole (18 μL). Obtained.
LCMS (ESI) m / z 586 [M + H] + , t R = 0.57 min, mode N.
実施例2−58: N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}エチル]-5-クロロ-2-[(メチルスルホニル)アミノ]-N-[3-(メチルスルホニル)プロピル]ベンズアミド 塩酸塩の合成
工程1−2−6〜工程1−2−8と同様の手法を用いて、工程1−2−5で得た化合物(30 mg) 及び1-ブロモ-3-(メチルスルホニル)プロパン(35 mg)より、表題化合物(17 mg, 無色固体)を得た。
LCMS (ESI) m/z 612 [M+H]+, tR = 0.95 min, mode H.
Example 2-58: N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidin-2-yl} ethyl ] -5-Chloro-2-[(methylsulfonyl) amino] -N- [3- (methylsulfonyl) propyl] benzamide The same procedure as in Synthesis step 1-2-6 to Step 1-2-8 of hydrochloride The title compound (17 mg, colorless solid) was obtained from the compound (30 mg) obtained in Step 1-2-5 and 1-bromo-3- (methylsulfonyl) propane (35 mg).
LCMS (ESI) m / z 612 [M + H] + , t R = 0.95 min, mode H.
実施例2−59: N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}エチル]-5-クロロ-N-(2-ヒドロキシエチル)-2-[(メチルスルホニル)アミノ]ベンズアミドの合成
工程1−2−6〜工程1−2−8と同様の手法を用いて、工程1−2−5で得た化合物(30 mg) 及び2-ブロモエタノール(12 μL)より、表題化合物(13 mg, 無色アモルファス)を得た。
LCMS (ESI) m/z 536 [M+H]+, tR = 0.90 min, mode H.
Example 2-59: N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidin-2-yl} ethyl Synthesis of Step-5-6-chloro-N- (2-hydroxyethyl) -2-[(methylsulfonyl) amino] benzamide Step 1-2-6 to Step 1-2-8 The title compound (13 mg, colorless amorphous) was obtained from the compound obtained in 2-5 (30 mg) and 2-bromoethanol (12 μL).
LCMS (ESI) m / z 536 [M + H] + , t R = 0.90 min, mode H.
実施例2−60: N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}エチル]-5-クロロ-N-[(2S)-3-ヒドロキシ-2-メチルプロピル]-2-[(メチルスルホニル)アミノ]ベンズアミド 塩酸塩の合成
工程1−2−6〜工程1−2−8と同様の手法を用いて、工程1−2−5で得た化合物(30 mg) 及び(2R)-3-ブロモ-2-メチルプロパン-1-オール(17 μL)より、表題化合物(2.7 mg, 無色固体)を得た。
LCMS (ESI) m/z 564 [M+H]+, tR = 0.52 min, mode N.
Example 2-60: N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidin-2-yl} ethyl ] -5-Chloro-N-[(2S) -3-hydroxy-2-methylpropyl] -2-[(methylsulfonyl) amino] benzamide Hydrochloride Synthesis Step 1-2-6 to Step 1-2-8 In the same manner as above, from the compound (30 mg) obtained in Step 1-2-5 and (2R) -3-bromo-2-methylpropan-1-ol (17 μL), the title compound (2.7 mg , Colorless solid).
LCMS (ESI) m / z 564 [M + H] + , t R = 0.52 min, mode N.
実施例2−61: N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}エチル]-5-クロロ-N-[(2R)-3-ヒドロキシ-2-メチルプロピル]-2-[(メチルスルホニル)アミノ]ベンズアミド 塩酸塩の合成
工程1−2−6〜工程1−2−8と同様の手法を用いて、工程1−2−5で得た化合物(30 mg) 及び(2S)-3-ブロモ-2-メチルプロパン-1-オール(17 μL)より、表題化合物(2.2 mg, 無色固体)を得た。
LCMS (ESI) m/z 564 [M+H]+, tR = 0.53 min, mode N.
Example 2-61: N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidin-2-yl} ethyl ] -5-Chloro-N-[(2R) -3-hydroxy-2-methylpropyl] -2-[(methylsulfonyl) amino] benzamide Hydrochloride Synthesis Step 1-2-6 to Step 1-2-8 The title compound (2.2 mg) was prepared from the compound (30 mg) obtained in Step 1-2-5 and (2S) -3-bromo-2-methylpropan-1-ol (17 μL) using the same procedure as described above. , Colorless solid).
LCMS (ESI) m / z 564 [M + H] + , t R = 0.53 min, mode N.
実施例2−62: N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}エチル]-5-クロロ-N-(3-ヒドロキシプロピル)-2-[(メチルスルホニル)アミノ]ベンズアミド 塩酸塩の合成
工程1−2−6〜工程1−2−8と同様の手法を用いて、工程1−2−5で得た化合物(30 mg) 及び2-(3-ブロモプロポキシ)テトラヒドロ-2H-ピラン(28 μL)より、表題化合物(18 mg, 無色固体)を得た。
1H NMR (600 MHz, DMSO-d6, δ): 1.53-1.71 (m, 5H), 2.00-2.10 (m, 1H), 2.20-2.29 (m, 1H), 2.32-2.38 (m, 3H), 2.92-3.18 (m, 5H), 3.28-3.52 (m, 2H), 3.64-3.96 (m, 5H), 4.75-4.82 (m, 0.5H), 5.76 (br s, 0.5H), 6.06-6.17 (m, 1H), 7.42-7.58 (m, 3H), 8.23 (br s, 3H), 8.52 (s, 0.5H), 9.32 (s, 0.5H).
LCMS (ESI) m/z 550 [M+H]+, tR = 0.93 min, mode H.
Example 2-62: N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidin-2-yl} ethyl ] -5-Chloro-N- (3-hydroxypropyl) -2-[(methylsulfonyl) amino] benzamide Using a method similar to the synthesis steps 1-2-6 to 1-2-8 of hydrochloride, The title compound (18 mg, colorless solid) was obtained from the compound obtained in Step 1-2-5 (30 mg) and 2- (3-bromopropoxy) tetrahydro-2H-pyran (28 μL).
1 H NMR (600 MHz, DMSO-d 6 , δ): 1.53-1.71 (m, 5H), 2.00-2.10 (m, 1H), 2.20-2.29 (m, 1H), 2.32-2.38 (m, 3H) , 2.92-3.18 (m, 5H), 3.28-3.52 (m, 2H), 3.64-3.96 (m, 5H), 4.75-4.82 (m, 0.5H), 5.76 (br s, 0.5H), 6.06-6.17 (m, 1H), 7.42-7.58 (m, 3H), 8.23 (br s, 3H), 8.52 (s, 0.5H), 9.32 (s, 0.5H).
LCMS (ESI) m / z 550 [M + H] + , t R = 0.93 min, mode H.
実施例2−63: N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}エチル]-5-クロロ-N-(4-ヒドロキシブチル)-2-[(メチルスルホニル)アミノ]ベンズアミド 塩酸塩の合成
工程2−63−1:工程1−2−6及び工程1−2−7と同様の手法を用いて、工程1−2−5で得られた化合物(30 mg)及び4-ブロモブチル アセタート(24 μL)より、4-([(1S)-1-(5-{(3S)-3-[(tert-ブトキシカルボニル)アミノ]ピロリジン-1-イル}-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル)エチル]{5-クロロ-2-[(メチルスルホニル)アミノ]ベンゾイル}アミノ)ブチル アセタート(18 mg, 無色固体)を得た。
LCMS (ESI) m/z 706 [M+H]+, tR = 1.19 min, mode N.
工程2−63−2:工程2−63−1で得られた化合物(17 mg)のMeOH(2.0 mL)溶液にK2CO3(8.0 mg)を加え、室温で4時間撹拌した。反応溶液にCHCl3、水を加え抽出を行った。水層をPhase Separatorを用いて分離した後、有機層を減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー(移動相:ヘキサン/EtOAc = 30/70〜1/99; v/v)で精製し、tert-ブチル [(3S)-1-(2-{(1S)-1-[{5-クロロ-2-[(メチルスルホニル)アミノ]ベンゾイル}(4-ヒドロキシブチル)アミノ]エチル}-6-メチルピラゾロ[1,5-a]ピリミジン-5-イル)ピロリジン-3-イル]カルバマート(16 mg, 無色固体)を得た。
LCMS (ESI) m/z 664 [M+H]+, tR = 1.07 min, mode N.
工程2−63−3:工程1−2−8と同様の手法を用いて、工程2−63−2で得た化合物(15 mg)より、表題化合物(16 mg, 無色固体)を得た。
1H NMR (600 MHz, DMSO-d6, δ): 1.00-1.55 (m, 4H), 1.55-1.71 (m, 3H), 2.01-2.10 (m, 1H), 2.20-2.30 (m, 1H), 2.34-2.38 (m, 3H), 2.92-3.13 (m, 5H), 3.29-3.96 (m, 7H), 4.74-4.82 (m, 0.5H), 5.71 (br s, 0.5H), 6.07-6.16 (m, 1H), 7.43-7.58 (m, 3H), 8.24 (br s, 3H), 8.52 (s, 0.5H), 9.34 (s, 0.5H).
LCMS (ESI) m/z 564 [M+H]+, tR = 0.54 min, mode N.
Example 2-63: N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidin-2-yl} ethyl ] -5-Chloro-N- (4-hydroxybutyl) -2-[(methylsulfonyl) amino] benzamide Hydrochloride Synthesis Step 2-63-1: Step 1-2-6 and Step 1-2-7 Using a similar method, 4-([((1S) -1- (5-{(3S)) was obtained from the compound obtained in Step 1-2-5 (30 mg) and 4-bromobutyl acetate (24 μL). -3-[(tert-Butoxycarbonyl) amino] pyrrolidin-1-yl} -6-methylpyrazolo [1,5-a] pyrimidin-2-yl) ethyl] {5-chloro-2-[(methylsulfonyl) amino ] Benzoyl} amino) butyl acetate (18 mg, colorless solid) was obtained.
LCMS (ESI) m / z 706 [M + H] + , t R = 1.19 min, mode N.
Step 2-63-2: K 2 CO 3 (8.0 mg) was added to a solution of the compound obtained in Step 2-63-1 (17 mg) in MeOH (2.0 mL), and the mixture was stirred at room temperature for 4 hours. The reaction solution was extracted by adding CHCl 3 and water. The aqueous layer was separated using a Phase Separator, and then the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase: hexane / EtOAc = 30/70 to 1/99; v / v) and tert-butyl [(3S) -1- (2-{(1S) -1- [{5-Chloro-2-[(methylsulfonyl) amino] benzoyl} (4-hydroxybutyl) amino] ethyl} -6-methylpyrazolo [1,5-a] pyrimidin-5-yl) pyrrolidin-3-yl] Carbamate (16 mg, colorless solid) was obtained.
LCMS (ESI) m / z 664 [M + H] + , t R = 1.07 min, mode N.
Step 2-63-3: The title compound (16 mg, colorless solid) was obtained from the compound (15 mg) obtained in Step 2-63-2 using the same method as in Step 1-2-8.
1 H NMR (600 MHz, DMSO-d 6 , δ): 1.00-1.55 (m, 4H), 1.55-1.71 (m, 3H), 2.01-2.10 (m, 1H), 2.20-2.30 (m, 1H) , 2.34-2.38 (m, 3H), 2.92-3.13 (m, 5H), 3.29-3.96 (m, 7H), 4.74-4.82 (m, 0.5H), 5.71 (br s, 0.5H), 6.07-6.16 (m, 1H), 7.43-7.58 (m, 3H), 8.24 (br s, 3H), 8.52 (s, 0.5H), 9.34 (s, 0.5H).
LCMS (ESI) m / z 564 [M + H] + , t R = 0.54 min, mode N.
実施例2−64: N-(3-アミノプロピル)-N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}エチル]-5-クロロ-2-[(メチルスルホニル)アミノ]ベンズアミド 塩酸塩の合成
工程1−2−6〜工程1−2−8と同様の手法を用いて、工程1−2−5で得た化合物(30 mg)及びtert-ブチル (3-ブロモプロピル)カルバマート(39 mg)より、表題化合物(23 mg, 無色固体)を得た。
LCMS (ESI) m/z 549 [M+H]+, tR = 0.69 min, mode H.
Example 2-64: N- (3-aminopropyl) -N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5- a] Pyrimidin-2-yl} ethyl] -5-chloro-2-[(methylsulfonyl) amino] benzamide Using the same procedure as in Step 1-2-6 to Step 1-2-8 of hydrochloride, The title compound (23 mg, colorless solid) was obtained from the compound obtained in Step 1-2-5 (30 mg) and tert-butyl (3-bromopropyl) carbamate (39 mg).
LCMS (ESI) m / z 549 [M + H] + , t R = 0.69 min, mode H.
実施例2−65: N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}エチル]-5-クロロ-2-[(メチルスルホニル)アミノ]-N-{3-[(メチルスルホニル)アミノ]プロピル}ベンズアミド 塩酸塩の合成
工程1−2−6〜工程1−2−8と同様の手法を用いて、工程1−2−5で得た化合物(30 mg) 及びN-(3-ブロモプロピル)メタンスルホンアミド(36 mg)より、表題化合物(12 mg, 無色固体)を得た。
1H NMR (600 MHz, DMSO-d6, δ): 1.52-1.74 (m, 5H), 2.00-2.10 (m, 1H), 2.20-2.29 (m, 1H), 2.33-2.38 (m, 3H), 2.71-2.96 (m, 5H), 3.00-3.07 (m, 3H), 3.35-3.97 (m, 7H), 4.11-4.15 (m, 0.5H), 4.75-4.82 (m, 0.5H), 6.06-6.17 (m, 1H), 6.92-6.98 (m, 1H), 7.43-7.62 (m, 3H), 8.16 (br s, 3H), 8.52 (s, 0.5H), 9.32 (s, 0.5H).
LCMS (ESI) m/z 627 [M+H]+, tR = 0.52 min, mode N.
Example 2-65: N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidin-2-yl} ethyl ] -5-Chloro-2-[(methylsulfonyl) amino] -N- {3-[(methylsulfonyl) amino] propyl} benzamide Similar to the synthesis steps 1-2-6 to 1-2-8 of hydrochloride Was used to obtain the title compound (12 mg, colorless solid) from the compound (30 mg) obtained in Step 1-2-5 and N- (3-bromopropyl) methanesulfonamide (36 mg). .
1 H NMR (600 MHz, DMSO-d 6 , δ): 1.52-1.74 (m, 5H), 2.00-2.10 (m, 1H), 2.20-2.29 (m, 1H), 2.33-2.38 (m, 3H) , 2.71-2.96 (m, 5H), 3.00-3.07 (m, 3H), 3.35-3.97 (m, 7H), 4.11-4.15 (m, 0.5H), 4.75-4.82 (m, 0.5H), 6.06- 6.17 (m, 1H), 6.92-6.98 (m, 1H), 7.43-7.62 (m, 3H), 8.16 (br s, 3H), 8.52 (s, 0.5H), 9.32 (s, 0.5H).
LCMS (ESI) m / z 627 [M + H] + , t R = 0.52 min, mode N.
実施例2−66: N-(3-アミノプロピル)-5-クロロ-N-{(1S)-1-[6-メチル-5-(ピロリジン-1-イル)ピラゾロ[1,5-a]ピリミジン-2-イル]プロピル}-2-[(メチルスルホニル)アミノ]ベンズアミド 塩酸塩の合成
工程2−66−1:工程1−2−5と同様の手法を用いて、工程1−3−4で得られた化合物(930 mg)及びピロリジン(2.50 mL)より、(1S)-1-[6-メチル-5-(ピロリジン-1-イル)ピラゾロ[1,5-a]ピリミジン-2-イル]プロパン-1-アミン(380 mg, 褐色油状物)を得た。
LCMS (ESI) m/z 260 [M+H]+, tR = 0.67 min, mode H.
工程2−66−2:工程1−2−6及び工程1−2−7と同様の手法を用いて、工程2−66−1で得られた化合物(30 mg)及びtert-ブチル (3-ブロモプロピル)カルバマート(55 mg)より、tert-ブチル [3-({5-クロロ-2-[(メチルスルホニル)アミノ]ベンゾイル}{(1S)-1-[6-メチル-5-(ピロリジン-1-イル)ピラゾロ[1,5-a]ピリミジン-2-イル]プロピル}アミノ)プロピル]カルバマート(10 mg, 白色固体)を得た。
LCMS (ESI) m/z 648 [M+H]+, tR = 1.32 min, mode N.
工程2−66−3:工程1−2−8と同様の手法を用いて、工程2−66−2で得た化合物(10 mg)より、表題化合物(11 mg, 無色固体)を得た。
LCMS (ESI) m/z 548 [M+H]+, tR = 0.71 min, mode N.
Example 2-66: N- (3-aminopropyl) -5-chloro-N-{(1S) -1- [6-methyl-5- (pyrrolidin-1-yl) pyrazolo [1,5-a] Pyrimidin-2-yl] propyl} -2-[(methylsulfonyl) amino] benzamide hydrochloride synthesis step 2-66-1: Step 1-3-4 using the same method as in Step 1-2-5 (1S) -1- [6-Methyl-5- (pyrrolidin-1-yl) pyrazolo [1,5-a] pyrimidin-2-yl was obtained from the compound (930 mg) and pyrrolidine (2.50 mL) obtained in 1 ] Propan-1-amine (380 mg, brown oil) was obtained.
LCMS (ESI) m / z 260 [M + H] + , t R = 0.67 min, mode H.
Step 2-66-2: Using a method similar to that in Step 1-2-6 and Step 1-2-7, the compound (30 mg) obtained in Step 2-66-1 and tert-butyl (3- From bromopropyl) carbamate (55 mg), tert-butyl [3-({5-chloro-2-[(methylsulfonyl) amino] benzoyl} {(1S) -1- [6-methyl-5- (pyrrolidine- 1-yl) pyrazolo [1,5-a] pyrimidin-2-yl] propyl} amino) propyl] carbamate (10 mg, white solid) was obtained.
LCMS (ESI) m / z 648 [M + H] + , t R = 1.32 min, mode N.
Step 2-66-3: Using the same method as in Step 1-2-8, the title compound (11 mg, colorless solid) was obtained from the compound (10 mg) obtained in Step 2-66-2.
LCMS (ESI) m / z 548 [M + H] + , t R = 0.71 min, mode N.
実施例2−67: N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}エチル]-5-クロロ-N-[4-(1,3-ジオキソ-1,3-ジヒドロ-2H-イソインドール-2-イル)ブチル]-2-[(メチルスルホニル)アミノ]ベンズアミド 塩酸塩の合成
工程2−67−1:工程1−2−6及び工程1−2−7と同様の手法を用いて、工程1−2−5で得られた化合物(150 mg)及び2-(4-ブロモブチル)-1H-イソインドール-1,3(2H)-ジオン(234 mg)より、tert-ブチル [(3S)-1-{2-[(1S)-1-({5-クロロ-2-[(メチルスルホニル)アミノ]ベンゾイル}[4-(1,3-ジオキソ-1,3-ジヒドロ-2H-イソインドール-2-イル)ブチル]アミノ)エチル]-6-メチルピラゾロ[1,5-a]ピリミジン-5-イル}ピロリジン-3-イル]カルバマート(138 mg, 無色固体)を得た。
LCMS (ESI) m/z 793 [M+H]+, tR = 1.25 min, mode N.
工程2−67−2:工程1−2−8と同様の手法を用いて、工程2−67−1で得た化合物(15 mg)より、表題化合物(15 mg, 無色固体)を得た。
1H NMR (600 MHz, DMSO-d6, δ): 1.20-1.68 (m, 7H), 2.01-2.10 (m, 1H), 2.21-2.30 (m, 1H), 2.35 (s, 3H), 2.91-3.06 (m, 5H), 3.28-3.75 (m, 7H), 4.72-4.80 (m, 1H), 6.02-6.10 (m, 1H), 7.40-7.58 (m, 3H), 7.80-7.86 (m, 4H), 8.23 (br s, 3H), 8.48 (s, 0.5H), 9.32 (s, 0.5H).
LCMS (ESI) m/z 693 [M+H]+, tR = 0.67 min, mode N.
Example 2-67: N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidin-2-yl} ethyl Synthesis of] -5-chloro-N- [4- (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl) butyl] -2-[(methylsulfonyl) amino] benzamide hydrochloride Step 2-67-1: Using a method similar to that of Step 1-2-6 and Step 1-2-7, the compound (150 mg) obtained in Step 1-2-5 and 2- (4-bromobutyl) ) -1H-isoindole-1,3 (2H) -dione (234 mg), tert-butyl [(3S) -1- {2-[(1S) -1-({5-chloro-2- [ (Methylsulfonyl) amino] benzoyl} [4- (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl) butyl] amino) ethyl] -6-methylpyrazolo [1,5-a] Pyrimidin-5-yl} pyrrolidin-3-yl] carbamate (138 mg, colorless solid) was obtained.
LCMS (ESI) m / z 793 [M + H] + , t R = 1.25 min, mode N.
Step 2-67-2: Using the same method as in Step 1-2-8, the title compound (15 mg, colorless solid) was obtained from the compound (15 mg) obtained in Step 2-67-1.
1 H NMR (600 MHz, DMSO-d 6 , δ): 1.20-1.68 (m, 7H), 2.01-2.10 (m, 1H), 2.21-2.30 (m, 1H), 2.35 (s, 3H), 2.91 -3.06 (m, 5H), 3.28-3.75 (m, 7H), 4.72-4.80 (m, 1H), 6.02-6.10 (m, 1H), 7.40-7.58 (m, 3H), 7.80-7.86 (m, 4H), 8.23 (br s, 3H), 8.48 (s, 0.5H), 9.32 (s, 0.5H).
LCMS (ESI) m / z 693 [M + H] + , t R = 0.67 min, mode N.
実施例2−68: N-(4-アミノブチル)-N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}エチル]-5-クロロ-2-[(メチルスルホニル)アミノ]ベンズアミド 塩酸塩の合成
工程2−68−1:工程2−67−1で得られた化合物(0.12 g)のEtOH(2.0 mL)溶液にヒドラジン1水和物(37 μL)を加え、60 ℃で4時間撹拌した。反応溶液に飽和NH4Cl水溶液を加え、CHCl3で抽出した。水層をPhase Separatorを用いて分離し、有機層を減圧下濃縮した。残渣をNH型シリカゲルカラムクロマトグラフィー(移動相:CHCl3/MeOH = 97/3〜90/10; v/v)で精製し、tert-ブチル [(3S)-1-(2-{(1S)-1-[(4-アミノブチル){5-クロロ-2-[(メチルスルホニル)アミノ]ベンゾイル}アミノ]エチル}-6-メチルピラゾロ[1,5-a]ピリミジン-5-イル)ピロリジン-3-イル]カルバマート (71 mg, 無色固体)を得た。
LCMS (ESI) m/z 663 [M+H]+, tR = 0.72 min, mode N.
工程2−68−2:工程1−2−8と同様の手法を用いて、工程2−68−1で得た化合物(15 mg)より、表題化合物(18 mg, 無色固体)を得た。
LCMS (ESI) m/z 563 [M+H]+, tR = 0.74 min, mode H.
Example 2-68: N- (4-aminobutyl) -N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5- a] pyrimidin-2-yl} ethyl] -5-chloro-2-[(methylsulfonyl) amino] benzamide hydrochloride synthesis step 2-68-1: compound obtained in step 2-67-1 (0.12 g ) In EtOH (2.0 mL) was added hydrazine monohydrate (37 μL) and stirred at 60 ° C. for 4 hours. A saturated aqueous NH 4 Cl solution was added to the reaction solution, and the mixture was extracted with CHCl 3 . The aqueous layer was separated using a Phase Separator, and the organic layer was concentrated under reduced pressure. The residue was purified by NH-type silica gel column chromatography (mobile phase: CHCl 3 / MeOH = 97/3 to 90/10; v / v), and tert-butyl [(3S) -1- (2-{(1S) -1-[(4-aminobutyl) {5-chloro-2-[(methylsulfonyl) amino] benzoyl} amino] ethyl} -6-methylpyrazolo [1,5-a] pyrimidin-5-yl) pyrrolidine-3 -Il] carbamate (71 mg, colorless solid) was obtained.
LCMS (ESI) m / z 663 [M + H] + , t R = 0.72 min, mode N.
Step 2-68-2: Using the same method as in Step 1-2-8, the title compound (18 mg, colorless solid) was obtained from the compound (15 mg) obtained in Step 2-68-1.
LCMS (ESI) m / z 563 [M + H] + , t R = 0.74 min, mode H.
実施例2−69: N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}エチル]-5-クロロ-2-[(メチルスルホニル)アミノ]-N-{4-[(メチルスルホニル)アミノ]ブチル}ベンズアミド 塩酸塩の合成
工程2−69−1:工程2−68−1で得られた化合物(53 mg)のCHCl3(2.0 mL)溶液に氷冷下、Et3N(33 μL)、MsCl(7.4 μL)を加え、室温で30分間撹拌した。反応溶液に飽和NaHCO3水溶液を加え、CHCl3で抽出した。水層をPhase Separatorを用いて分離し、有機層を減圧下濃縮した。OH型シリカゲルカラムクロマトグラフィー(移動相:CHCl3/MeOH = 100/0〜97/3; v/v)で精製し、tert-ブチル [(3S)-1-{2-[(1S)-1-({5-クロロ-2-[(メチルスルホニル)アミノ]ベンゾイル}{4-[(メチルスルホニル)アミノ]ブチル}アミノ)エチル]-6-メチルピラゾロ[1,5-a]ピリミジン-5-イル}ピロリジン-3-イル]カルバマート(56 mg, 無色固体)を得た。
LCMS (ESI) m/z 741 [M+H]+, tR = 1.09 min, mode N.
工程2−69−2:工程1−2−8と同様の手法を用いて、工程2−69−1で得た化合物(54 mg)より、表題化合物(54 mg, 無色固体)を得た。
1H NMR (600 MHz, DMSO-d6, δ): 1.06-1.56 (m, 4H), 1.56-1.71 (m, 3H), 2.02-2.12 (m, 1H), 2.20-2.30 (m, 1H), 2.32-2.38 (m, 3H), 2.60-2.67 (m, 1H), 2.75-2.89 (m, 4H), 2.92-3.09 (m, 4H), 3.33-3.52 (m, 1H), 3.70-3.98 (m, 5H), 4.78 (q, J = 6.6 Hz, 1H), 6.06-6.17 (m, 1H), 6.80-6.97 (m, 1H), 7.42-7.57 (m, 3H), 8.31 (br s, 3H), 8.51 (s, 0.5H), 9.36 (s, 0.5H).
LCMS (ESI) m/z 641 [M+H]+, tR = 0.99 min, mode H.
Example 2-69: N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidin-2-yl} ethyl ] -5-Chloro-2-[(methylsulfonyl) amino] -N- {4-[(methylsulfonyl) amino] butyl} benzamide Hydrochloride Synthesis Step 2-69-1: Obtained in Step 2-68-1 Et 3 N (33 μL) and MsCl (7.4 μL) were added to a CHCl 3 (2.0 mL) solution of the obtained compound (53 mg) under ice cooling, and the mixture was stirred at room temperature for 30 minutes. A saturated aqueous NaHCO 3 solution was added to the reaction solution, and the mixture was extracted with CHCl 3 . The aqueous layer was separated using a Phase Separator, and the organic layer was concentrated under reduced pressure. Purification by OH-type silica gel column chromatography (mobile phase: CHCl 3 / MeOH = 100/0 to 97/3; v / v) and tert-butyl [(3S) -1- {2-[(1S) -1 -({5-Chloro-2-[(methylsulfonyl) amino] benzoyl} {4-[(methylsulfonyl) amino] butyl} amino) ethyl] -6-methylpyrazolo [1,5-a] pyrimidin-5-yl } Pyrrolidin-3-yl] carbamate (56 mg, colorless solid) was obtained.
LCMS (ESI) m / z 741 [M + H] + , t R = 1.09 min, mode N.
Step 2-69-2: The title compound (54 mg, colorless solid) was obtained from the compound (54 mg) obtained in Step 2-69-1 using the same method as in Step 1-2-8.
1 H NMR (600 MHz, DMSO-d 6 , δ): 1.06-1.56 (m, 4H), 1.56-1.71 (m, 3H), 2.02-2.12 (m, 1H), 2.20-2.30 (m, 1H) , 2.32-2.38 (m, 3H), 2.60-2.67 (m, 1H), 2.75-2.89 (m, 4H), 2.92-3.09 (m, 4H), 3.33-3.52 (m, 1H), 3.70-3.98 ( m, 5H), 4.78 (q, J = 6.6 Hz, 1H), 6.06-6.17 (m, 1H), 6.80-6.97 (m, 1H), 7.42-7.57 (m, 3H), 8.31 (br s, 3H ), 8.51 (s, 0.5H), 9.36 (s, 0.5H).
LCMS (ESI) m / z 641 [M + H] + , t R = 0.99 min, mode H.
実施例2−70: 2-(アセチルアミノ)-N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}プロピル]-5-クロロ-N-メチルベンズアミド の合成
工程2−70−1:工程1−1−8と同様の手法を用いて、工程1−4−3で得られた化合物(50 mg) 及び2-アミノ-5-クロロ安息香酸(26 mg)より、tert-ブチル [(3S)-1-(2-{(1S)-1-[(2-アミノ-5-クロロベンゾイル)(メチル)アミノ]プロピル}-6-メチルピラゾロ[1,5-a]ピリミジン-5-イル)ピロリジン-3-イル]カルバマート(41 mg)を得た。
工程2−70−2:工程2−70−1で得られた化合物(41 mg)のCHCl3(1.0 mL)溶液に、氷冷下、 ピリジン (32 μL)、無水酢酸(21 μL)を加え、室温で2時間攪拌した。反応液を水にあけ、CHCl3にて抽出した。有機層をPhase Separatorにてろ過後、ろ液を減圧下濃縮した。得られた残渣を逆相分取HPLCにて精製し、tert-ブチル [(3S)-1-{2-[(1S)-1-{[2-(アセチルアミノ)-5-クロロベンゾイル](メチル)アミノ}プロピル]-6-メチルピラゾロ[1,5-a]ピリミジン-5-イル}ピロリジン-3-イル]カルバマート(34 mg, 無色固体)を得た。
工程2−70−3:工程2−70−2で得られた化合物(34 mg)のCHCl3(1 mL)溶液に、TFA (1 mL) を加え、室温にて2時間攪拌した。反応液を 飽和NaHCO3水溶液 にあけ、CHCl3にて抽出した。有機層をPhase Separatorにてろ過後、ろ液を減圧下濃縮し、表題化合物(34 mg, 無色アモルファス)を得た。
1H NMR (600 MHz, CDCl3, δ): 0.80-1.13 (m, 3H), 1.74-1.82 (m, 1H), 1.90-2.09 (m, 2H), 2.10-2.20 (m, 4H), 2.34-2.43 (m, 3H), 2.73 (br s, 1H), 2.86-2.96 (m, 2H), 3.43 (dd, J = 10.5, 4.3 Hz, 1H), 3.66-3.79 (m, 2H), 3.89 (br s, 2H), 4.83 (br s, 0.5H), 5.89-6.08 (m, 1.5H), 7.17-7.40 (m, 1H), 7.94-8.23 (m, 2H), 8.62-9.04 (m, 1H).
LCMS (ESI) m/z 484 [M+H]+, tR = 0.46 min, mode N.
Example 2-70: 2- (acetylamino) -N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] Pyrimidin-2-yl} propyl] -5-chloro-N-methylbenzamide Step 2-70-1: Obtained in Step 1-4-3 using a method similar to that of Step 1-1-8. From the compound (50 mg) and 2-amino-5-chlorobenzoic acid (26 mg), tert-butyl [(3S) -1- (2-{(1S) -1-[(2-amino-5-chloro Benzoyl) (methyl) amino] propyl} -6-methylpyrazolo [1,5-a] pyrimidin-5-yl) pyrrolidin-3-yl] carbamate (41 mg) was obtained.
Step 2-70-2: To a solution of the compound (41 mg) obtained in Step 2-70-1 in CHCl 3 (1.0 mL) was added pyridine (32 μL) and acetic anhydride (21 μL) under ice-cooling. And stirred at room temperature for 2 hours. The reaction solution was poured into water and extracted with CHCl 3 . The organic layer was filtered through a phase separator, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by reverse phase preparative HPLC and tert-butyl [(3S) -1- {2-[(1S) -1-{[2- (acetylamino) -5-chlorobenzoyl] ( Methyl) amino} propyl] -6-methylpyrazolo [1,5-a] pyrimidin-5-yl} pyrrolidin-3-yl] carbamate (34 mg, colorless solid) was obtained.
Step 2-70-3: TFA (1 mL) was added to a solution of the compound obtained in Step 2-70-2 (34 mg) in CHCl 3 (1 mL), and the mixture was stirred at room temperature for 2 hours. The reaction solution was poured into a saturated aqueous NaHCO 3 solution and extracted with CHCl 3 . The organic layer was filtered through a phase separator, and the filtrate was concentrated under reduced pressure to obtain the title compound (34 mg, colorless amorphous).
1 H NMR (600 MHz, CDCl 3 , δ): 0.80-1.13 (m, 3H), 1.74-1.82 (m, 1H), 1.90-2.09 (m, 2H), 2.10-2.20 (m, 4H), 2.34 -2.43 (m, 3H), 2.73 (br s, 1H), 2.86-2.96 (m, 2H), 3.43 (dd, J = 10.5, 4.3 Hz, 1H), 3.66-3.79 (m, 2H), 3.89 ( br s, 2H), 4.83 (br s, 0.5H), 5.89-6.08 (m, 1.5H), 7.17-7.40 (m, 1H), 7.94-8.23 (m, 2H), 8.62-9.04 (m, 1H ).
LCMS (ESI) m / z 484 [M + H] + , t R = 0.46 min, mode N.
実施例2−71: 2-(アセチルアミノ)-N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}プロピル]-N,5-ジメチルベンズアミドの合成
工程1−1−8、工程2−70−2及び工程2−70−3と同様の手法にて、工程1−4−3で得られた化合物(50 mg) 及び2-アミノ-5-メチル安息香酸(23 mg)より、表題化合物(21 mg, 無色アモルファス)を得た。
1H NMR (600 MHz, CDCl3, δ): 0.77-1.13 (m, 3H), 1.75-2.24 (m, 7H), 2.25-2.34 (m, 3H), 2.38 (br s, 3H), 2.67-2.97 (m, 3H), 3.44 (dd, J = 10.9, 4.3 Hz, 1H), 3.66-3.78 (m, 2H), 3.89 (br s, 2H), 4.90 (br s, 0.5H), 5.88-6.18 (m, 1.5H), 7.00-7.23 (m, 1.5H), 8.01 (br s, 1.5H), 8.55 (br s, 0.5H), 8.83 (br s, 0.5H).LCMS (ESI) m/z 464 [M+H]+, tR = 0.38 min, mode N.
Example 2-71: 2- (acetylamino) -N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] Pyrimidin-2-yl} propyl] -N, 5-dimethylbenzamide in the same manner as in Step 1-1-8, Step 2-70-2 and Step 2-70-3, Step 1-4-3 The title compound (21 mg, colorless amorphous) was obtained from the compound (50 mg) obtained in 1 and 2-amino-5-methylbenzoic acid (23 mg).
1 H NMR (600 MHz, CDCl 3 , δ): 0.77-1.13 (m, 3H), 1.75-2.24 (m, 7H), 2.25-2.34 (m, 3H), 2.38 (br s, 3H), 2.67- 2.97 (m, 3H), 3.44 (dd, J = 10.9, 4.3 Hz, 1H), 3.66-3.78 (m, 2H), 3.89 (br s, 2H), 4.90 (br s, 0.5H), 5.88-6.18 (m, 1.5H), 7.00-7.23 (m, 1.5H), 8.01 (br s, 1.5H), 8.55 (br s, 0.5H), 8.83 (br s, 0.5H) .LCMS (ESI) m / z 464 [M + H] + , t R = 0.38 min, mode N.
実施例2−72: N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}エチル]-5-クロロ-2-[(メチルスルホニル)アミノ]-N-(4,4,4-トリフルオロブチル)ベンズアミド 塩酸塩の合成
工程1−2−6〜工程1−2−8と同様の手法を用いて、工程1−2−5で得た化合物(80 mg) 及び4-ブロモ-1,1,1-トリフルオロブタン(42 mg)より、表題化合物(30 mg, 無色固体)を得た。
1H NMR (600 MHz, DMSO-d6, δ): 1.43-1.97 (m, 5H), 2.02-2.12 (m, 1H), 2.17-2.32 (m, 3H), 2.32-2.40 (m, 3H), 2.98-3.11 (m, 3H), 3.41-4.00 (m, 7H), 4.79 (q, J = 6.9 Hz, 1H), 6.04-6.18 (m, 1H), 7.43-7.65 (m, 3H), 8.35 (br s, 3H), 8.49-8.55 (m, 0.5H), 9.33 (s, 0.5H).LCMS (ESI) m/z 602 [M+H]+, tR = 0.67 min, mode N.
Example 2-72: N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidin-2-yl} ethyl ] -5-Chloro-2-[(methylsulfonyl) amino] -N- (4,4,4-trifluorobutyl) benzamide Similar to the synthesis steps 1-2-6 to 1-2-8 of hydrochloride Using the method, the title compound (30 mg, colorless solid) was obtained from the compound obtained in Step 1-2-5 (80 mg) and 4-bromo-1,1,1-trifluorobutane (42 mg). It was.
1 H NMR (600 MHz, DMSO-d 6 , δ): 1.43-1.97 (m, 5H), 2.02-2.12 (m, 1H), 2.17-2.32 (m, 3H), 2.32-2.40 (m, 3H) , 2.98-3.11 (m, 3H), 3.41-4.00 (m, 7H), 4.79 (q, J = 6.9 Hz, 1H), 6.04-6.18 (m, 1H), 7.43-7.65 (m, 3H), 8.35 (br s, 3H), 8.49-8.55 (m, 0.5H), 9.33 (s, 0.5H) .LCMS (ESI) m / z 602 [M + H] + , t R = 0.67 min, mode N.
実施例2−73: N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}プロピル]-N-メチル-2-(メチルスルホニル)ベンズアミド 塩酸塩の合成
工程1−2−7及び工程1−2−8と同様の手法を用いて、工程1−4−3で得た化合物(30 mg) 及び2-(メチルスルホニル)安息香酸(17 mg)より、表題化合物(28 mg)を得た。
LCMS (ESI) m/z 471 [M+H]+, tR = 0.80 min, mode H.
Example 2-73: N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidin-2-yl} propyl ] -N-methyl-2- (methylsulfonyl) benzamide Compound synthesized in Step 1-4-3 using the same method as in Step 1-2-7 and Step 1-2-8 of hydrochloride (30) mg) and 2- (methylsulfonyl) benzoic acid (17 mg) gave the title compound (28 mg).
LCMS (ESI) m / z 471 [M + H] + , t R = 0.80 min, mode H.
実施例2−74:N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}プロピル]-5-クロロ-3-フルオロ-N-メチル-2-[(メチルスルホニル)アミノ]ベンズアミド 塩酸塩の合成
工程1−2−7及び工程1−2−8と同様の手法を用いて、工程1−4−3で得た化合物(40 mg)及び5-クロロ-3-フルオロ-2-[(メチルスルホニル)アミノ]安息香酸(33 mg)より、表題化合物(40 mg, 無色固体)を得た。
1H NMR (600 MHz, DMSO-d6, δ): 0.87 (br s, 1H), 1.01 (t, J = 7.2 Hz, 2H), 1.83-2.30 (m, 4H), 2.33-2.40 (m, 3H), 2.56 (s, 1.5H), 2.66-2.74 (m, 0.5H), 2.98-3.07 (m, 3H), 3.67-3.99 (m, 5H), 4.46 (br s, 0.3H), 5.73 (dd, J = 9.5, 6.2 Hz, 0.7H), 6.14 (s, 0.7H), 6.21 (br s, 0.3H), 7.24-7.34 (m, 1H), 7.63-7.69 (m, 1H), 8.22-8.42 (m, 3H), 8.50 (s, 0.7H), 9.46 (br s, 0.3H)
LCMS (ESI) m/z 538 [M+H]+, tR = 0.54 min, mode N.
Example 2-74: N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidin-2-yl} propyl ] -5-Chloro-3-fluoro-N-methyl-2-[(methylsulfonyl) amino] benzamide Hydrochloride Synthesis Step 1-2-7 and Step 1-2-8 The title compound (40 mg, colorless solid) was obtained from the compound obtained in 1-4-3 (40 mg) and 5-chloro-3-fluoro-2-[(methylsulfonyl) amino] benzoic acid (33 mg). It was.
1 H NMR (600 MHz, DMSO-d 6 , δ): 0.87 (br s, 1H), 1.01 (t, J = 7.2 Hz, 2H), 1.83-2.30 (m, 4H), 2.33-2.40 (m, 3H), 2.56 (s, 1.5H), 2.66-2.74 (m, 0.5H), 2.98-3.07 (m, 3H), 3.67-3.99 (m, 5H), 4.46 (br s, 0.3H), 5.73 ( dd, J = 9.5, 6.2 Hz, 0.7H), 6.14 (s, 0.7H), 6.21 (br s, 0.3H), 7.24-7.34 (m, 1H), 7.63-7.69 (m, 1H), 8.22- 8.42 (m, 3H), 8.50 (s, 0.7H), 9.46 (br s, 0.3H)
LCMS (ESI) m / z 538 [M + H] + , t R = 0.54 min, mode N.
実施例2−75:N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}プロピル]-5-クロロ-N-エチル-2-[(メチルスルホニル)アミノ]ベンズアミド 塩酸塩の合成
工程1−2−6〜工程1−2−8と同様の手法を用いて、工程1−3−5で得た化合物(50 mg)及びEtI(10 μL)より、表題化合物(15 mg, 無色固体)を得た。
1H NMR (600 MHz, DMSO-d6, δ): 0.80-1.10 (m, 6H), 1.94-2.31 (m, 4H), 2.34-2.38 (m, 3H), 2.96-3.05 (m, 4H), 3.25-3.33 (m, 1H), 3.69-4.00 (m, 5H), 4.51 (br s, 0.7H), 5.51 (s, 0.3H), 6.15-6.22 (m, 1H), 7.45-7.55 (m, 3H), 8.21 (br s, 3H), 8.52 (s, 0.5H), 9.20 (s, 0.5H)
LCMS (ESI) m/z 534 [M+H]+, tR = 1.11 min, mode H.
Example 2-75: N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidin-2-yl} propyl ] -5-Chloro-N-ethyl-2-[(methylsulfonyl) amino] benzamide Hydrochloride Synthesis Step 1-2-6 to Step 1-2-8 The title compound (15 mg, colorless solid) was obtained from the compound (50 mg) obtained in 5 and EtI (10 μL).
1 H NMR (600 MHz, DMSO-d 6 , δ): 0.80-1.10 (m, 6H), 1.94-2.31 (m, 4H), 2.34-2.38 (m, 3H), 2.96-3.05 (m, 4H) , 3.25-3.33 (m, 1H), 3.69-4.00 (m, 5H), 4.51 (br s, 0.7H), 5.51 (s, 0.3H), 6.15-6.22 (m, 1H), 7.45-7.55 (m , 3H), 8.21 (br s, 3H), 8.52 (s, 0.5H), 9.20 (s, 0.5H)
LCMS (ESI) m / z 534 [M + H] + , t R = 1.11 min, mode H.
実施例2−76:N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}プロピル]-5-クロロ-N-(3-フルオロプロピル)-2-[(メチルスルホニル)アミノ]ベンズアミド 塩酸塩の合成
工程1−2−6〜工程1−2−8と同様の手法を用いて、工程1−3−5で得た化合物(50 mg)及び1-ヨード-3-フルオロプロパン(27 μL)より、表題化合物(11 mg, 無色固体)を得た。
1H NMR (600 MHz, DMSO-d6, δ): 0.87-1.10 (m, 3H), 1.64-2.30 (m, 6H), 2.34-2.38 (m, 3H), 2.97-3.12 (m, 4H), 3.30-3.37 (m, 1H), 4.29-4.49 (m, 2H), 4.51-4.57 (m, 1H), 6.17 (s, 1H), 7.44-7.57 (m, 3H), 8.19 (br s, 3H), 8.53 (s, 0.5H), 9.25 (s, 0.5H)
LCMS (ESI) m/z 566 [M+H]+, tR = 1.13 min, mode H.
Example 2-76: N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidin-2-yl} propyl ] -5-Chloro-N- (3-fluoropropyl) -2-[(methylsulfonyl) amino] benzamide Using a method similar to the synthesis steps 1-2-6 to 1-2-8 of hydrochloride, The title compound (11 mg, colorless solid) was obtained from the compound obtained in Step 1-3-5 (50 mg) and 1-iodo-3-fluoropropane (27 μL).
1 H NMR (600 MHz, DMSO-d 6 , δ): 0.87-1.10 (m, 3H), 1.64-2.30 (m, 6H), 2.34-2.38 (m, 3H), 2.97-3.12 (m, 4H) , 3.30-3.37 (m, 1H), 4.29-4.49 (m, 2H), 4.51-4.57 (m, 1H), 6.17 (s, 1H), 7.44-7.57 (m, 3H), 8.19 (br s, 3H ), 8.53 (s, 0.5H), 9.25 (s, 0.5H)
LCMS (ESI) m / z 566 [M + H] + , t R = 1.13 min, mode H.
実施例2−77:N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}プロピル]-5-クロロ-N-(4-ヒドロキシブチル)-2-[(メチルスルホニル)アミノ]ベンズアミド 塩酸塩の合成
工程1−2−6、工程1−2−7、工程2−63−2及び工程1−2−8と同様の手法を用いて、工程1−3−5で得た化合物(50 mg)及び4-ブロモブチル アセタート(38 μL)より、表題化合物(13 mg, 無色固体)を得た。
1H NMR (600 MHz, DMSO-d6, δ): 0.87-1.53 (m, 7H), 1.94-2.30 (m, 4H), 2.34-2.38 (m, 3H), 2.87-3.09 (m, 5H), 3.22-3.32 (m, 2H), 3.63-3.97 (m, 5H), 4.51 (br s, 1H), 6.15 (s, 1H), 7.45-7.56 (m, 3H), 8.20 (br s, 3H), 8.52 (s, 0.5H), 9.23 (s, 0.5H)
LCMS (ESI) m/z 578 [M+H]+, tR = 1.03 min, mode H.
Example 2-77: N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidin-2-yl} propyl ] -5-Chloro-N- (4-hydroxybutyl) -2-[(methylsulfonyl) amino] benzamide Hydrochloride Synthesis Step 1-2-6, Step 1-2-7, Step 2-63-2 and Using the same method as in Step 1-2-8, the title compound (13 mg, colorless solid) was obtained from the compound obtained in Step 1-3-5 (50 mg) and 4-bromobutyl acetate (38 μL). It was.
1 H NMR (600 MHz, DMSO-d 6 , δ): 0.87-1.53 (m, 7H), 1.94-2.30 (m, 4H), 2.34-2.38 (m, 3H), 2.87-3.09 (m, 5H) , 3.22-3.32 (m, 2H), 3.63-3.97 (m, 5H), 4.51 (br s, 1H), 6.15 (s, 1H), 7.45-7.56 (m, 3H), 8.20 (br s, 3H) , 8.52 (s, 0.5H), 9.23 (s, 0.5H)
LCMS (ESI) m / z 578 [M + H] + , t R = 1.03 min, mode H.
実施例2−78:N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}プロピル]-5-クロロ-N-(5-ヒドロキシペンチル)-2-[(メチルスルホニル)アミノ]ベンズアミド 塩酸塩の合成
工程1−2−6、工程1−2−7、工程2−63−2及び工程1−2−8と同様の手法を用いて、工程1−3−5で得た化合物(50 mg)及び5-ブロモペンチル アセタート(42 μL)より、表題化合物(13 mg, 無色固体)を得た。
1H NMR (600 MHz, DMSO-d6, δ): 0.78-1.49 (m, 9H), 1.93-2.30 (m, 4H), 2.33-2.38 (m, 3H), 2.84-3.33 (m, 7H), 3.61-3.96 (m, 5H), 4.52 (br s, 1H), 6.16 (s, 1H), 7.44-7.55 (m, 3H), 8.20 (br s, 3H), 8.52 (s, 0.5H), 9.24 (s, 0.5H)
LCMS (ESI) m/z 592 [M+H]+, tR = 1.07 min, mode H.
Example 2-78: N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidin-2-yl} propyl ] -5-chloro-N- (5-hydroxypentyl) -2-[(methylsulfonyl) amino] benzamide hydrochloride synthesis step 1-2-6, step 1-2-7, step 2-63-2 and Using the same method as in Step 1-2-8, the title compound (13 mg, colorless solid) was obtained from the compound obtained in Step 1-3-5 (50 mg) and 5-bromopentyl acetate (42 μL). Obtained.
1 H NMR (600 MHz, DMSO-d 6 , δ): 0.78-1.49 (m, 9H), 1.93-2.30 (m, 4H), 2.33-2.38 (m, 3H), 2.84-3.33 (m, 7H) , 3.61-3.96 (m, 5H), 4.52 (br s, 1H), 6.16 (s, 1H), 7.44-7.55 (m, 3H), 8.20 (br s, 3H), 8.52 (s, 0.5H), 9.24 (s, 0.5H)
LCMS (ESI) m / z 592 [M + H] + , t R = 1.07 min, mode H.
実施例3−1:N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}エチル]-N-メチル-1-[(メチルスルホニル)アミノ]-2,3-ジヒドロ-1H-インデン-1-カルボキサミド 塩酸塩の合成
工程3−1−1:工程1−1−4で得られた化合物(4.73 g)の1,4-ジオキサン(30 mL)溶液に4M HCl/1,4-ジオキサン溶液(30 mL)を滴下し、室温にて3日間攪拌した。反応液を減圧下濃縮し、6-メチル-2-[(1S)-1-(メチルアミノ)エチル]ピラゾロ[1,5-a]ピリミジン-5(4H)-オン 塩酸塩(3.81 g, 無色固体)を得た。
1H NMR (600 MHz, DMSO-d6, δ): 1.55 (d, J = 7.0 Hz, 3H), 1.95 (br s, 3H), 2.46 (t, J = 5.4 Hz, 3H), 4.34-4.42 (m, 1H), 6.04 (s, 1H), 8.43 (s, 1H), 9.11-9.38 (m, 1H), 12.28 (s, 1H).
LCMS (ESI) m/z 207 [M+H]+, tR = 0.22 min, mode H.
工程3−1−2:工程3−1−1で得られた化合物(3.81 g)をPOCl3(29 mL)に懸濁し、加熱還流下、2.5時間攪拌した。反応溶液を減圧下濃縮し、(1S)-1-(5-クロロ-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル)-N-メチルエタンアミン塩酸塩(4.62 g, 褐色固体)を得た。
1H NMR (600 MHz, DMSO-d6, δ): 1.64 (d, J = 6.2 Hz, 3H), 2.34 (s, 3H), 4.59 (br s, 1H), 6.88 (s, 1H), 6.95-7.62 (m, 3H), 9.19 (s, 1H), 9.26-9.53 (m, 1H).
LCMS (ESI) m/z 225 [M+H]+, tR = 0.56 min, mode H.
工程3−1−3:工程3−1−2で得られた化合物(4.50 g)のMeOH(60 mL)溶液に(3S)-(-)-3-(tert-ブトキシカルボニルアミノ)ピロリジン(14.4 g), Et3N (17.2 mL) を加え、加熱還流下、2時間攪拌後、室温にて14時間攪拌した。反応液を減圧下濃縮し、得られた残渣をEtOAc、飽和NaHCO3水溶液にて分液した。有機層を飽和NaHCO3水溶液にて洗浄後、MgSO4で乾燥してろ過した後、ろ液を減圧下濃縮した。得られた残渣をOH型シリカゲルカラムクロマトグラフィー (移動相:CHCl3/MeOH/NH4OH= 100/0/0〜80/20/2; v/v/v)にて精製し、tert-ブチル [(3S)-1-{6-メチル-2-[(1S)-1-(メチルアミノ)エチル]ピラゾロ[1,5-a]ピリミジン-5-イル}ピロリジン-3-イル]カルバマート (6.16 g, 淡黄色アモルファス)を得た。
1H NMR (600 MHz, CDCl3, δ): 1.42-1.48 (m, 12H), 1.88-1.95 (m, 1H), 2.17-2.24 (m, 1H), 2.33 (br s, 3H), 2.39 (s, 3H), 3.53 (dd, J = 10.9, 3.9 Hz, 1H), 3.68-3.74 (m, 1H), 3.76-3.82 (m, 1H), 3.80 (dt, J = 10.7, 7.4 Hz, 1H), 3.84 (q, J = 6.6 Hz, 1H), 3.88-3.95 (m, 1H), 4.30 (br s, 1H), 4.69 (br s, 1H), 6.04 (s, 1H), 8.02 (s, 1H).
LCMS (ESI) m/z 375 [M+H]+, tR = 0.46 min, mode N.
工程3−1−4:工程3−1−3で得られた化合物(606 mg)、参考例4で得られた化合物(705 mg)のDMF(20 mL)溶液にHATU(1.66 g)、Et3N(1.35 mL) を加え、室温にて4日間攪拌した。反応液をEtOAc、飽和NaHCO3水溶液にて分液した。有機層をBrineにて洗浄後、MgSO4で乾燥してろ過した後、ろ液を減圧下濃縮した。得られた残渣をOH型シリカゲルカラムクロマトグラフィー (移動相:ヘキサン/EtOAc = 95/5〜0/100; v/v)にて精製し、ベンジル (1-{[(1S)-1-(5-{(3S)-3-[(tert-ブトキシカルボニル)アミノ]ピロリジン-1-イル}-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル)エチル](メチル)カルバモイル}-2,3-ジヒドロ-1H-インデン-1-イル)カルバマート(1.10 g, 淡褐色アモルファス)を得た。
1H NMR (600 MHz, CDCl3, δ): 0.79-0.89 (m, 1H), 1.37-1.62 (m, 13H), 1.86-1.96 (m, 1H), 2.10-2.25 (m, 1H), 2.32 (br s, 3H), 2.57-3.11 (m, 5H), 3.49-3.55 (m, 1H), 3.66-3.73 (m, 1H), 3.74-3.83 (m, 1H), 3.87-3.96 (m, 1H), 4.23-4.34 (m, 1H), 4.61-4.71 (m, 1H), 4.85-4.96 (m, 1H), 4.97-5.05 (m, 1H), 5.90-5.97 (m, 0.5H), 6.11-6.18 (m, 0.5H), 7.12-8.01 (m, 10H).
LCMS (ESI) m/z 668 [M+H]+, tR = 1.17 min, mode N.
工程3−1−5:工程3−1−4で得られた化合物(856 mg)のMeOH(20 mL)溶液に10%パラジウム-炭素(428 mg)を加え、水素雰囲気下、室温にて1時間攪拌した。反応液をセライト(登録商標)ろ過後、ろ液を減圧下濃縮し、tert-ブチル [(3S)-1-{2-[(1S)-1-{[(1-アミノ-2,3-ジヒドロ-1H-インデン-1-イル)カルボニル](メチル)アミノ}エチル]-6-メチルピラゾロ[1,5-a]ピリミジン-5-イル}ピロリジン-3-イル]カルバマート (681 mg, 無色アモルファス)を得た。
1H NMR (600 MHz, CD3OD, δ): 0.96-1.04 (m, 1H), 1.40-1.58 (m, 10H), 1.87-1.98 (m, 1H), 2.12-2.21 (m, 1H), 2.22-2.33 (m, 2H), 2.38 (br s, 3H), 2.66-2.83 (m, 6H), 3.49-3.57 (m, 1H), 3.71-3.78 (m, 1H), 3.79-3.86 (m, 1H), 3.87-3.96 (m, 1H), 4.11-4.19 (m, 1H), 4.55-4.66 (m, 0.5H), 5.82-5.96 (m, 1H), 6.04-6.11 (m, 0.5H), 7.17-7.46 (m, 4H), 8.08-8.15 (m, 1H).
LCMS (ESI) m/z 534 [M+H]+, tR = 0.62 min, mode N.
工程3−1−6:工程3−1−5で得られた化合物(31 mg)のCHCl3(1 mL)溶液に氷冷下、Et3N(24 μL)、MsCl(6.0 μL)を加え、室温にて30分間攪拌した。反応液をCHCl3、飽和NaHCO3水溶液にて分液し、水層をCHCl3にて抽出した。有機層をPhase Separatorにてろ過した。ろ液を減圧下濃縮し、得られた残渣をOH型シリカゲルカラムクロマトグラフィー (移動相:ヘキサン/EtOAc = 95/5〜0/100; v/v)にて精製し、tert-ブチル [(3S)-1-(6-メチル-2-{(1S)-1-[メチル({1-[(メチルスルホニル)アミノ]-2,3-ジヒドロ-1H-インデン-1-イル}カルボニル)アミノ]エチル}ピラゾロ[1,5-a]ピリミジン-5-イル)ピロリジン-3-イル]カルバマート (27 mg, 無色油状物)を得た。
LCMS (ESI) m/z 612 [M+H]+, tR = 0.97, 0.99 min, mode N.
工程3−1−7:工程3−1−1と同様の手法を用いて、工程3−1−6で得られた化合物(26.0 mg)より表題化合物(22.4 mg, 無色固体)を得た。
LCMS (ESI) m/z 512 [M+H]+, tR = 0.84 min, mode H.
Example 3-1 N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidin-2-yl} ethyl ] -N-Methyl-1-[(methylsulfonyl) amino] -2,3-dihydro-1H-indene-1-carboxamide Hydrochloride Synthesis Step 3-1-1: Obtained in Step 1-1-4 A 4M HCl / 1,4-dioxane solution (30 mL) was added dropwise to a solution of the compound (4.73 g) in 1,4-dioxane (30 mL), and the mixture was stirred at room temperature for 3 days. The reaction mixture was concentrated under reduced pressure, and 6-methyl-2-[(1S) -1- (methylamino) ethyl] pyrazolo [1,5-a] pyrimidin-5 (4H) -one hydrochloride (3.81 g, colorless Solid) was obtained.
1 H NMR (600 MHz, DMSO-d 6 , δ): 1.55 (d, J = 7.0 Hz, 3H), 1.95 (br s, 3H), 2.46 (t, J = 5.4 Hz, 3H), 4.34-4.42 (m, 1H), 6.04 (s, 1H), 8.43 (s, 1H), 9.11-9.38 (m, 1H), 12.28 (s, 1H).
LCMS (ESI) m / z 207 [M + H] + , t R = 0.22 min, mode H.
Step 3-1-2: The compound (3.81 g) obtained in Step 3-1-1 was suspended in POCl 3 (29 mL), and stirred for 2.5 hours under heating to reflux. The reaction solution was concentrated under reduced pressure, and (1S) -1- (5-chloro-6-methylpyrazolo [1,5-a] pyrimidin-2-yl) -N-methylethanamine hydrochloride (4.62 g, brown solid) Got.
1 H NMR (600 MHz, DMSO-d 6 , δ): 1.64 (d, J = 6.2 Hz, 3H), 2.34 (s, 3H), 4.59 (br s, 1H), 6.88 (s, 1H), 6.95 -7.62 (m, 3H), 9.19 (s, 1H), 9.26-9.53 (m, 1H).
LCMS (ESI) m / z 225 [M + H] + , t R = 0.56 min, mode H.
Step 3-1-3: A solution of the compound (4.50 g) obtained in Step 3-1-2 in a solution of (3S)-(−)-3- (tert-butoxycarbonylamino) pyrrolidine (14.4) in MeOH (60 mL). g), Et 3 N (17.2 mL) was added, and the mixture was stirred for 2 hours under reflux with heating and then for 14 hours at room temperature. The reaction solution was concentrated under reduced pressure, and the resulting residue was partitioned between EtOAc and saturated aqueous NaHCO 3 solution. The organic layer was washed with a saturated aqueous NaHCO 3 solution, dried over MgSO 4 and filtered, and then the filtrate was concentrated under reduced pressure. The obtained residue was purified by OH-type silica gel column chromatography (mobile phase: CHCl 3 / MeOH / NH 4 OH = 100/0/0 to 80/20/2; v / v / v), and tert-butyl [(3S) -1- {6-Methyl-2-[(1S) -1- (methylamino) ethyl] pyrazolo [1,5-a] pyrimidin-5-yl} pyrrolidin-3-yl] carbamate (6.16 g, pale yellow amorphous).
1 H NMR (600 MHz, CDCl 3 , δ): 1.42-1.48 (m, 12H), 1.88-1.95 (m, 1H), 2.17-2.24 (m, 1H), 2.33 (br s, 3H), 2.39 ( s, 3H), 3.53 (dd, J = 10.9, 3.9 Hz, 1H), 3.68-3.74 (m, 1H), 3.76-3.82 (m, 1H), 3.80 (dt, J = 10.7, 7.4 Hz, 1H) , 3.84 (q, J = 6.6 Hz, 1H), 3.88-3.95 (m, 1H), 4.30 (br s, 1H), 4.69 (br s, 1H), 6.04 (s, 1H), 8.02 (s, 1H ).
LCMS (ESI) m / z 375 [M + H] + , t R = 0.46 min, mode N.
Step 3-1-4: HATU (1.66 g), Et in a DMF (20 mL) solution of the compound obtained in Step 3-1-3 (606 mg) and the compound obtained in Reference Example 4 (705 mg) 3 N (1.35 mL) was added, and the mixture was stirred at room temperature for 4 days. The reaction mixture was partitioned between EtOAc and saturated aqueous NaHCO 3 solution. The organic layer was washed with Brine, dried over MgSO 4 and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by OH-type silica gel column chromatography (mobile phase: hexane / EtOAc = 95/5 to 0/100; v / v) to obtain benzyl (1-{[(1S) -1- (5 -{(3S) -3-[(tert-butoxycarbonyl) amino] pyrrolidin-1-yl} -6-methylpyrazolo [1,5-a] pyrimidin-2-yl) ethyl] (methyl) carbamoyl} -2, 3-Dihydro-1H-inden-1-yl) carbamate (1.10 g, light brown amorphous) was obtained.
1 H NMR (600 MHz, CDCl 3 , δ): 0.79-0.89 (m, 1H), 1.37-1.62 (m, 13H), 1.86-1.96 (m, 1H), 2.10-2.25 (m, 1H), 2.32 (br s, 3H), 2.57-3.11 (m, 5H), 3.49-3.55 (m, 1H), 3.66-3.73 (m, 1H), 3.74-3.83 (m, 1H), 3.87-3.96 (m, 1H ), 4.23-4.34 (m, 1H), 4.61-4.71 (m, 1H), 4.85-4.96 (m, 1H), 4.97-5.05 (m, 1H), 5.90-5.97 (m, 0.5H), 6.11- 6.18 (m, 0.5H), 7.12-8.01 (m, 10H).
LCMS (ESI) m / z 668 [M + H] + , t R = 1.17 min, mode N.
Step 3-1-5: To a solution of the compound obtained in Step 3-1-4 (856 mg) in MeOH (20 mL) was added 10% palladium-carbon (428 mg), and the reaction was performed at room temperature under a hydrogen atmosphere. Stir for hours. After the reaction solution was filtered through Celite (registered trademark), the filtrate was concentrated under reduced pressure, and tert-butyl [(3S) -1- {2-[(1S) -1-{[(1-amino-2,3- Dihydro-1H-inden-1-yl) carbonyl] (methyl) amino} ethyl] -6-methylpyrazolo [1,5-a] pyrimidin-5-yl} pyrrolidin-3-yl] carbamate (681 mg, colorless amorphous) Got.
1 H NMR (600 MHz, CD 3 OD, δ): 0.96-1.04 (m, 1H), 1.40-1.58 (m, 10H), 1.87-1.98 (m, 1H), 2.12-2.21 (m, 1H), 2.22-2.33 (m, 2H), 2.38 (br s, 3H), 2.66-2.83 (m, 6H), 3.49-3.57 (m, 1H), 3.71-3.78 (m, 1H), 3.79-3.86 (m, 1H), 3.87-3.96 (m, 1H), 4.11-4.19 (m, 1H), 4.55-4.66 (m, 0.5H), 5.82-5.96 (m, 1H), 6.04-6.11 (m, 0.5H), 7.17-7.46 (m, 4H), 8.08-8.15 (m, 1H).
LCMS (ESI) m / z 534 [M + H] + , t R = 0.62 min, mode N.
Step 3-1-6: Et 3 N (24 μL) and MsCl (6.0 μL) were added to a CHCl 3 (1 mL) solution of the compound (31 mg) obtained in Step 3-1-5 under ice cooling. And stirred for 30 minutes at room temperature. The reaction solution was partitioned between CHCl 3 and saturated NaHCO 3 aqueous solution, and the aqueous layer was extracted with CHCl 3 . The organic layer was filtered with a Phase Separator. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by OH-type silica gel column chromatography (mobile phase: hexane / EtOAc = 95/5 to 0/100; v / v) to obtain tert-butyl [(3S ) -1- (6-Methyl-2-{(1S) -1- [methyl ({1-[(methylsulfonyl) amino] -2,3-dihydro-1H-inden-1-yl} carbonyl) amino] Ethyl} pyrazolo [1,5-a] pyrimidin-5-yl) pyrrolidin-3-yl] carbamate (27 mg, colorless oil) was obtained.
LCMS (ESI) m / z 612 [M + H] + , t R = 0.97, 0.99 min, mode N.
Step 3-1-7: The title compound (22.4 mg, colorless solid) was obtained from the compound (26.0 mg) obtained in Step 3-1-6 using the same method as in Step 3-1-1.
LCMS (ESI) m / z 512 [M + H] + , t R = 0.84 min, mode H.
実施例3−2:N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}エチル]-1-[(エチルスルホニル)アミノ]-N-メチル-2,3-ジヒドロ-1H-インデン-1-カルボキサミド 塩酸塩の合成
工程3−1−6及び工程3−1−1と同様の手法を用いて、工程3−1−5で得られた化合物(30 mg)、エタンスルホニルクロリド(16 μL)より表題化合物(6.8 mg, 無色固体)を得た。
LCMS (ESI) m/z 526 [M+H]+, tR = 0.50 min, mode N.
Example 3-2: N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidin-2-yl} ethyl ] -1-[(Ethylsulfonyl) amino] -N-methyl-2,3-dihydro-1H-indene-1-carboxamide Similar procedure as in step 3-1-6 and step 3-1-1 for the synthesis of hydrochloride Was used to give the title compound (6.8 mg, colorless solid) from the compound (30 mg) obtained in Step 3-1-5 and ethanesulfonyl chloride (16 μL).
LCMS (ESI) m / z 526 [M + H] + , t R = 0.50 min, mode N.
実施例3−3:ベンジル (1-{[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}エチル](メチル)カルバモイル}-2,3-ジヒドロ-1H-インデン-1-イル)カルバマート 塩酸塩の合成
工程3−1−1と同様の手法を用いて、工程3−1−4で得られた化合物(10 mg)より表題化合物(8.7 mg, 無色固体)を得た。
LCMS (ESI) m/z 568 [M+H]+, tR = 1.09 min, mode H.
Example 3-3: benzyl (1-{[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidine-2- Yl} ethyl] (methyl) carbamoyl} -2,3-dihydro-1H-inden-1-yl) carbamate In step 3-1-4 using the same procedure as in step 3-1-1 for the synthesis of hydrochloride The title compound (8.7 mg, colorless solid) was obtained from the obtained compound (10 mg).
LCMS (ESI) m / z 568 [M + H] + , t R = 1.09 min, mode H.
実施例3−4:tert-ブチル (1-{[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}エチル](メチル)カルバモイル}-2,3-ジヒドロ-1H-インデン-1-イル)カルバマートの合成
工程3−1−4及び工程3−1−5と同様の手法を用いて、工程1−1−7で得られた化合物(65 mg)、N-tert-ブトキシカルボニル-1-アミノインダン-1-カルボン酸(0.11 g)より表題化合物(2.9 mg, 無色アモルファス)を得た。
1H NMR (600 MHz, CDCl3, δ): 0.78-0.90 (m, 1H), 1.32 (br s, 3H), 1.49-1.67 (br s, 9H), 1.70-1.80 (m, 1H), 2.08-2.16 (m, 1H), 2.17-3.05 (m, 6H), 2.32 (br s, 3H), 3.40 (dd, J = 10.5, 4.3 Hz, 1H), 3.61-3.75 (m, 2H), 3.77-3.91 (m, 2H), 4.62-4.73 (m, 0.5H), 5.78-6.25 (m, 1.5H), 7.11-7.30 (m, 4H), 7.98 (s, 1H).
LCMS (ESI) m/z 534 [M+H]+, tR = 0.59 min, mode H.
Example 3-4: tert-butyl (1-{[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidine- 2-yl} ethyl] (methyl) carbamoyl} -2,3-dihydro-1H-inden-1-yl) carbamate using the same procedure as in Steps 3-1-4 and 3-1-5, The title compound (2.9 mg, colorless amorphous) was obtained from the compound obtained in Step 1-1-7 (65 mg) and N-tert-butoxycarbonyl-1-aminoindan-1-carboxylic acid (0.11 g).
1 H NMR (600 MHz, CDCl 3 , δ): 0.78-0.90 (m, 1H), 1.32 (br s, 3H), 1.49-1.67 (br s, 9H), 1.70-1.80 (m, 1H), 2.08 -2.16 (m, 1H), 2.17-3.05 (m, 6H), 2.32 (br s, 3H), 3.40 (dd, J = 10.5, 4.3 Hz, 1H), 3.61-3.75 (m, 2H), 3.77- 3.91 (m, 2H), 4.62-4.73 (m, 0.5H), 5.78-6.25 (m, 1.5H), 7.11-7.30 (m, 4H), 7.98 (s, 1H).
LCMS (ESI) m / z 534 [M + H] + , t R = 0.59 min, mode H.
実施例3−5:1-アミノ-N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}エチル]-N-メチル-2,3-ジヒドロ-1H-インデン-1-カルボキサミド 塩酸塩の合成
工程3−1−1と同様の手法を用いて、実施例3−4で得られた化合物(1.5 mg)より表題化合物(1.6 mg, 無色固体)を得た。
LCMS (ESI) m/z 434 [M+H]+, tR = 0.54 min, mode H.
Example 3-5: 1-amino-N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidine-2 -Il} ethyl] -N-methyl-2,3-dihydro-1H-indene-1-carboxamide obtained in Example 3-4 using the same procedure as in Synthesis step 3-1-1 of hydrochloride. The title compound (1.6 mg, colorless solid) was obtained from the compound (1.5 mg).
LCMS (ESI) m / z 434 [M + H] + , t R = 0.54 min, mode H.
実施例3−6:1-(アセチルアミノ)-N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}エチル]-N-メチル-2,3-ジヒドロ-1H-インデン-1-カルボキサミド塩酸塩の合成
工程3−6−1:工程3−1−5で得られた化合物(20 mg)のCHCl3(1 mL)溶液に氷冷下、Et3N(16 μL)、AcCl(3.5 μL)を加え、同温にて1時間攪拌した。反応液をCHCl3、飽和NaHCO3水溶液にて分液し、水層をCHCl3にて抽出した。有機層をPhase Separatorにてろ過した。ろ液を減圧下濃縮し、得られた残渣をOH型シリカゲルカラムクロマトグラフィー (移動相:ヘキサン/EtOAc = 95/5〜0/100; v/v)にて精製し、tert-ブチル [(3S)-1-(2-{(1S)-1-[{[1-(アセチルアミノ)-2,3-ジヒドロ-1H-インデン-1-イル]カルボニル}(メチル)アミノ]エチル}-6-メチルピラゾロ[1,5-a]ピリミジン-5-イル)ピロリジン-3-イル]カルバマート(14 mg, 無色アモルファス)を得た。
LCMS (ESI) m/z 576 [M+H]+, tR = 0.90 min, mode N.
工程3−6−2:工程3−1−1と同様の手法を用いて、工程3−6−1で得られた化合物(13.5 mg)より表題化合物(13.3 mg, 無色固体)を得た。
LCMS (ESI) m/z 476 [M+H]+, tR = 0.76 min, mode H.
Example 3-6: 1- (acetylamino) -N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] Pyrimidin-2-yl} ethyl] -N-methyl-2,3-dihydro-1H-indene-1-carboxamide hydrochloride synthesis step 3-6-1: compound obtained in step 3-1-5 (20 mg) in CHCl 3 (1 mL) was added with Et 3 N (16 μL) and AcCl (3.5 μL) under ice cooling, followed by stirring at the same temperature for 1 hour. The reaction solution was partitioned between CHCl 3 and saturated NaHCO 3 aqueous solution, and the aqueous layer was extracted with CHCl 3 . The organic layer was filtered with a Phase Separator. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by OH-type silica gel column chromatography (mobile phase: hexane / EtOAc = 95/5 to 0/100; v / v) to obtain tert-butyl [(3S ) -1- (2-{(1S) -1-[{[1- (acetylamino) -2,3-dihydro-1H-inden-1-yl] carbonyl} (methyl) amino] ethyl} -6- Methylpyrazolo [1,5-a] pyrimidin-5-yl) pyrrolidin-3-yl] carbamate (14 mg, colorless amorphous) was obtained.
LCMS (ESI) m / z 576 [M + H] + , t R = 0.90 min, mode N.
Step 3-6-2: The title compound (13.3 mg, colorless solid) was obtained from the compound (13.5 mg) obtained in Step 3-6-1 using the same method as in Step 3-1-1.
LCMS (ESI) m / z 476 [M + H] + , t R = 0.76 min, mode H.
実施例3−7:メチル (1-{[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}エチル](メチル)カルバモイル}-2,3-ジヒドロ-1H-インデン-1-イル)カルバマート 塩酸塩の合成
工程3−6−1及び工程3−1−1と同様の手法を用いて、工程3−1−5で得られた化合物(20 mg)及びクロロギ酸 メチルエステル(4.0 μL)より表題化合物(7.3 mg, 無色固体)を得た。
LCMS (ESI) m/z 492 [M+H]+, tR = 0.85 min, mode H.
Example 3-7: Methyl (1-{[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidine-2- Yl} ethyl] (methyl) carbamoyl} -2,3-dihydro-1H-inden-1-yl) carbamate hydrochloride using the same procedure as in Steps 3-6-1 and 3-1-1, The title compound (7.3 mg, colorless solid) was obtained from the compound obtained in Step 3-1-5 (20 mg) and chloroformic acid methyl ester (4.0 μL).
LCMS (ESI) m / z 492 [M + H] + , t R = 0.85 min, mode H.
実施例3−8:プロパン-2-イル (1-{[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}エチル](メチル)カルバモイル}-2,3-ジヒドロ-1H-インデン-1-イル)カルバマートの合成
工程3−8−1:工程3−6−1と同様の手法を用いて、工程3−1−5で得られた化合物(30 mg)及びクロロギ酸 イソプロピルエステル(19 μL)より、プロパン-2-イル (1-{[(1S)-1-(5-{(3S)-3-[(tert-ブトキシカルボニル)アミノ]ピロリジン-1-イル}-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル)エチル](メチル)カルバモイル}-2,3-ジヒドロ-1H-インデン-1-イル)カルバマート(6.9 mg, 淡黄色アモルファス)を得た。
LCMS (ESI) m/z 620 [M+H]+, tR = 1.11, 1.13 min, mode N.
工程3−8−2:工程3−8−1で得られた化合物(6.9 mg)の1,4-ジオキサン(1 mL)溶液に4 M HCl/1,4-ジオキサン溶液(1 mL)を滴下して、室温にて2時間攪拌した。反応液をCHCl3、飽和NaHCO3水溶液にて分液し、水層をCHCl3にて抽出した。有機層を減圧下濃縮し、表題化合物(6.3 mg, 無色アモルファス)を得た。
LCMS (ESI) m/z 520 [M+H]+, tR = 0.57 min, mode N.
Example 3-8: Propan-2-yl (1-{[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] Synthesis of Pyrimidin-2-yl} ethyl] (methyl) carbamoyl} -2,3-dihydro-1H-inden-1-yl) carbamate Step 3-8-1: Using the same method as in Step 3-6-1 From the compound (30 mg) obtained in Step 3-1-5 and chloroformic acid isopropyl ester (19 μL), propan-2-yl (1-{[(1S) -1- (5-{(3S ) -3-[(tert-Butoxycarbonyl) amino] pyrrolidin-1-yl} -6-methylpyrazolo [1,5-a] pyrimidin-2-yl) ethyl] (methyl) carbamoyl} -2,3-dihydro- 1H-Inden-1-yl) carbamate (6.9 mg, pale yellow amorphous) was obtained.
LCMS (ESI) m / z 620 [M + H] + , t R = 1.11, 1.13 min, mode N.
Step 3-8-2: A 4 M HCl / 1,4-dioxane solution (1 mL) was added dropwise to a solution of the compound obtained in Step 3-8-1 (6.9 mg) in 1,4-dioxane (1 mL). The mixture was stirred at room temperature for 2 hours. The reaction solution was partitioned between CHCl 3 and saturated NaHCO 3 aqueous solution, and the aqueous layer was extracted with CHCl 3 . The organic layer was concentrated under reduced pressure to obtain the title compound (6.3 mg, colorless amorphous).
LCMS (ESI) m / z 520 [M + H] + , t R = 0.57 min, mode N.
実施例3−9:N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}エチル]-N-メチル-1-[(2-メチルプロパノイル)アミノ]-2,3-ジヒドロ-1H-インデン-1-カルボキサミドの合成
工程3−6−1及び工程3−8−2と同様の手法を用いて、工程3−1−5で得られた化合物(30 mg)及びイソブチリルクロリド(18 μL)より表題化合物(2.6 mg, 無色アモルファス)を得た。
LCMS (ESI) m/z 504 [M+H]+, tR = 0.49 min, mode N.
Example 3-9: N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidin-2-yl} ethyl ] -N-methyl-1-[(2-methylpropanoyl) amino] -2,3-dihydro-1H-indene-1-carboxamide similar to steps 3-6-1 and 3-8-2 Using the method, the title compound (2.6 mg, colorless amorphous) was obtained from the compound obtained in Step 3-1-5 (30 mg) and isobutyryl chloride (18 μL).
LCMS (ESI) m / z 504 [M + H] + , t R = 0.49 min, mode N.
実施例3−10:N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}エチル]-N-メチル-1-[(フェニルアセチル)アミノ]-2,3-ジヒドロ-1H-インデン-1-カルボキサミドの合成
工程3−6−1及び工程3−8−2と同様の手法を用いて、工程3−1−5で得られた化合物(25 mg)及びフェニルアセチルクロリド(12 μL)より表題化合物(9.2 mg, 無色アモルファス)を得た。
LCMS (ESI) m/z 552 [M+H]+, tR = 1.00 min, mode H.
Example 3-10: N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidin-2-yl} ethyl ] -N-Methyl-1-[(phenylacetyl) amino] -2,3-dihydro-1H-indene-1-carboxamide was synthesized in the same manner as in Steps 3-6-1 and 3-8-2. Thus, the title compound (9.2 mg, colorless amorphous) was obtained from the compound (25 mg) obtained in Step 3-1-5 and phenylacetyl chloride (12 μL).
LCMS (ESI) m / z 552 [M + H] + , t R = 1.00 min, mode H.
実施例3−11:N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}エチル]-N-メチル-1-{[2-(メチルスルホニル)エチル]アミノ}-2,3-ジヒドロ-1H-インデン-1-カルボキサミド 塩酸塩の合成
工程3−11−1:工程3−1−5で得られた化合物(20 mg)のMeOH(1 mL)溶液にメチルビニルスルホン(7.0 μL)を加え、室温にて6時間攪拌した。反応液にメチルビニルスルホン(14 μL)を加え、室温にて3日間攪拌した。反応液にメチルビニルスルホン(14 μL)を加え、50 ℃で8時間、室温にて3日間攪拌した。反応液を減圧下濃縮し、得られた残渣をNH型シリカゲルカラムクロマトグラフィー(移動相:ヘキサン/EtOAc = 95/5〜0/100〜EtOAc/MeOH = 100/0〜90/10; v/v)にて精製し、tert-ブチル [(3S)-1-{6-メチル-2-[(1S)-1-{メチル[(1-{[2-(メチルスルホニル)エチル]アミノ}-2,3-ジヒドロ-1H-インデン-1-イル)カルボニル]アミノ}エチル]ピラゾロ[1,5-a]ピリミジン-5-イル}ピロリジン-3-イル]カルバマート (5.5 mg, 無色アモルファス)を得た。
LCMS (ESI) m/z 640 [M+H]+, tR = 0.65 min, mode N.
工程3−11−2:工程3−1−1と同様の手法を用いて、工程3−11−1で得られた化合物(5.3 mg)より表題化合物(8.0 mg, 無色固体)を得た。
LCMS (ESI) m/z 540 [M+H]+, tR = 0.58 min, mode H.
Example 3-11: N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidin-2-yl} ethyl ] -N-Methyl-1-{[2- (methylsulfonyl) ethyl] amino} -2,3-dihydro-1H-indene-1-carboxamide Hydrochloride Synthesis Step 3-11-1: Step 3-1 Methyl vinyl sulfone (7.0 μL) was added to a solution of the compound obtained in 5 (20 mg) in MeOH (1 mL) and stirred at room temperature for 6 hours. Methyl vinyl sulfone (14 μL) was added to the reaction solution, and the mixture was stirred at room temperature for 3 days. Methyl vinyl sulfone (14 μL) was added to the reaction solution, and the mixture was stirred at 50 ° C. for 8 hours and at room temperature for 3 days. The reaction mixture was concentrated under reduced pressure, and the resulting residue was subjected to NH-type silica gel column chromatography (mobile phase: hexane / EtOAc = 95/5 to 0/100 to EtOAc / MeOH = 100/0 to 90/10; v / v ) Tert-butyl [(3S) -1- {6-methyl-2-[(1S) -1- {methyl [(1-{[2- (methylsulfonyl) ethyl] amino} -2 , 3-Dihydro-1H-inden-1-yl) carbonyl] amino} ethyl] pyrazolo [1,5-a] pyrimidin-5-yl} pyrrolidin-3-yl] carbamate (5.5 mg, colorless amorphous) was obtained. .
LCMS (ESI) m / z 640 [M + H] + , t R = 0.65 min, mode N.
Step 3-11-2: Using the same method as in Step 3-1-1, the title compound (8.0 mg, colorless solid) was obtained from the compound (5.3 mg) obtained in Step 3-11-1.
LCMS (ESI) m / z 540 [M + H] + , t R = 0.58 min, mode H.
実施例3−12:N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}エチル]-N-メチル-1-{[(メチルスルホニル)アセチル]アミノ}-2,3-ジヒドロ-1H-インデン-1-カルボキサミド 塩酸塩の合成
工程3−12−1:工程3−1−5で得られた化合物(20 mg)、メタンスルホニル酢酸(10 mg)のDMF(1 mL)溶液にHATU(28 mg)、Et3N(31 μL) を加え、室温にて16時間攪拌した。反応液をEtOAc、飽和NaHCO3水溶液にて分液した。有機層をBrineにて洗浄後、MgSO4で乾燥してろ過した後、ろ液を減圧下濃縮した。得られた残渣をOH型シリカゲルカラムクロマトグラフィー (移動相:ヘキサン/EtOAc = 95/5〜0/100〜EtOAc/MeOH = 100/0〜95/5; v/v)にて精製し、tert-ブチル [(3S)-1-{6-メチル-2-[(1S)-1-{メチル[(1-{[(メチルスルホニル)アセチル]アミノ}-2,3-ジヒドロ-1H-インデン-1-イル)カルボニル]アミノ}エチル]ピラゾロ[1,5-a]ピリミジン-5-イル}ピロリジン-3-イル]カルバマート(9.1 mg, 無色アモルファス)を得た。
LCMS (ESI) m/z 654 [M+H]+, tR = 0.92, 0.93 min, mode N.
工程3−12−2:工程3−12−1で得られた化合物(8.8 mg)の1,4-ジオキサン(0.5 mL)溶液に4 M HCl/1,4-ジオキサン溶液(1.0 mL)を滴下し、室温にて2時間攪拌した。反応液を減圧下濃縮し、表題化合物(9.0 mg, 無色固体)を得た。
1H NMR (600 MHz, DMSO-d6, δ): 1.39 (br s, 3H), 1.98-2.09 (m, 1H), 2.19-2.29 (m, 1H), 2.34 (s, 3H), 2.40-3.19 (m, 10H), 3.44-3.52 (m, 1H), 3.58-3.93 (m, 4H), 4.00-4.24 (m, 2H), 5.79-5.96 (m, 2H), 7.14-7.21 (m, 1H), 7.25 (br s, 2H), 7.44-7.51 (m, 1H), 8.18 (br s, 3H), 8.50 (br s, 0.5H), 9.17 (br s, 0.5H).
LCMS (ESI) m/z 554 [M+H]+, tR = 0.78 min, mode H.
Example 3-12: N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidin-2-yl} ethyl ] -N-methyl-1-{[(methylsulfonyl) acetyl] amino} -2,3-dihydro-1H-indene-1-carboxamide hydrochloride synthesis step 3-12-1: in step 3-1-5 HATU (28 mg) and Et 3 N (31 μL) were added to a DMF (1 mL) solution of the obtained compound (20 mg) and methanesulfonylacetic acid (10 mg), and the mixture was stirred at room temperature for 16 hours. The reaction mixture was partitioned between EtOAc and saturated aqueous NaHCO 3 solution. The organic layer was washed with Brine, dried over MgSO 4 and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by OH-type silica gel column chromatography (mobile phase: hexane / EtOAc = 95/5 to 0/100 to EtOAc / MeOH = 100/0 to 95/5; v / v), and tert- Butyl [(3S) -1- {6-methyl-2-[(1S) -1- {methyl [(1-{[(methylsulfonyl) acetyl] amino} -2,3-dihydro-1H-indene-1 -Yl) carbonyl] amino} ethyl] pyrazolo [1,5-a] pyrimidin-5-yl} pyrrolidin-3-yl] carbamate (9.1 mg, colorless amorphous) was obtained.
LCMS (ESI) m / z 654 [M + H] + , t R = 0.92, 0.93 min, mode N.
Step 3-12-2: 4 M HCl / 1,4-dioxane solution (1.0 mL) was added dropwise to a solution of the compound obtained in Step 3-12-1 (8.8 mg) in 1,4-dioxane (0.5 mL). And stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain the title compound (9.0 mg, colorless solid).
1 H NMR (600 MHz, DMSO-d 6 , δ): 1.39 (br s, 3H), 1.98-2.09 (m, 1H), 2.19-2.29 (m, 1H), 2.34 (s, 3H), 2.40- 3.19 (m, 10H), 3.44-3.52 (m, 1H), 3.58-3.93 (m, 4H), 4.00-4.24 (m, 2H), 5.79-5.96 (m, 2H), 7.14-7.21 (m, 1H ), 7.25 (br s, 2H), 7.44-7.51 (m, 1H), 8.18 (br s, 3H), 8.50 (br s, 0.5H), 9.17 (br s, 0.5H).
LCMS (ESI) m / z 554 [M + H] + , t R = 0.78 min, mode H.
実施例3−13:N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}エチル]-1-{[N-(エチルスルホニル)グリシル]アミノ}-N-メチル-2,3-ジヒドロ-1H-インデン-1-カルボキサミド 塩酸塩の合成
実施例3−12と同様の手法を用いて、工程3−1−5で得られた化合物(20 mg)及び[(エチルスルホニル)アミノ]酢酸(13 mg)より表題化合物(13 mg, 無色固体)を得た。
LCMS (ESI) m/z 583 [M+H]+, tR = 0.82 min, mode H.
Example 3-13: N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidin-2-yl} ethyl ] -1-{[N- (Ethylsulfonyl) glycyl] amino} -N-methyl-2,3-dihydro-1H-indene-1-carboxamide Hydrochloride Synthesis Using the same procedure as Example 3-12 The title compound (13 mg, colorless solid) was obtained from the compound (20 mg) obtained in Step 3-1-5 and [(ethylsulfonyl) amino] acetic acid (13 mg).
LCMS (ESI) m / z 583 [M + H] + , t R = 0.82 min, mode H.
実施例3−14:N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}エチル]-1-{[(エチルスルホニル)アセチル]アミノ}-N-メチル-2,3-ジヒドロ-1H-インデン-1-カルボキサミド 塩酸塩の合成
実施例3−12と同様の手法を用いて、工程3−1−5で得られた化合物(25 mg)及び2-(エタンスルホニル)酢酸(9 mg)より表題化合物(13 mg, 無色固体)を得た。
1H NMR (600 MHz, DMSO-d6, δ): 1.19 (br s, 3H), 1.41 (br s, 3H), 2.01-2.10 (m, 1H), 2.18-2.28 (m, 1H), 2.34 (s, 3H), 2.41-3.30 (m, 9H), 3.69-3.95 (m, 5H), 3.96-4.33 (m, 2H), 5.81-5.94 (m, 2H), 7.12-7.20 (m, 1H), 7.24 (br s, 2H), 7.43-7.52 (m, 1H), 8.33 (br s, 3H), 8.51 (br s, 0.5H), 9.25 (m, 0.5H).
LCMS (ESI) m/z 568 [M+H]+, tR = 0.42 min, mode N.
Example 3-14: N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidin-2-yl} ethyl ] -1-{[(Ethylsulfonyl) acetyl] amino} -N-methyl-2,3-dihydro-1H-indene-1-carboxamide Hydrochloride Synthesis Using the same procedure as in Example 3-12, The title compound (13 mg, colorless solid) was obtained from the compound obtained in 3-1-5 (25 mg) and 2- (ethanesulfonyl) acetic acid (9 mg).
1 H NMR (600 MHz, DMSO-d 6 , δ): 1.19 (br s, 3H), 1.41 (br s, 3H), 2.01-2.10 (m, 1H), 2.18-2.28 (m, 1H), 2.34 (s, 3H), 2.41-3.30 (m, 9H), 3.69-3.95 (m, 5H), 3.96-4.33 (m, 2H), 5.81-5.94 (m, 2H), 7.12-7.20 (m, 1H) , 7.24 (br s, 2H), 7.43-7.52 (m, 1H), 8.33 (br s, 3H), 8.51 (br s, 0.5H), 9.25 (m, 0.5H).
LCMS (ESI) m / z 568 [M + H] + , t R = 0.42 min, mode N.
実施例3−15:N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}エチル]-N-メチル-1-({[(2-メチルプロピル)スルホニル]アセチル}アミノ)-2,3-ジヒドロ-1H-インデン-1-カルボキサミド 塩酸塩の合成
実施例3−12と同様の手法を用いて、工程3−1−5で得られた化合物(25 mg)及び2-( 2-メチルプロピルスルホニル)酢酸(10 mg)より表題化合物(15 mg, 無色固体)を得た。
1H NMR (600 MHz, DMSO-d6, δ): 0.93-1.06 (m, 6H), 1.41 (br s, 3H), 2.00-2.09 (m, 1H), 2.18-2.28 (m, 2H), 2.34 (s, 3H), 2.40-3.26 (m, 9H), 3.68-4.18 (m, 7H), 5.79-5.93 (m, 2H), 7.13-7.28 (m, 3H), 7.42-7.51 (m, 1H), 8.28 (br s, 3H), 8.50 (br s, 0.5H), 9.16-9.24 (m, 0.5H).
LCMS (ESI) m/z 596 [M+H]+, tR = 0.55 min, mode N.
Example 3-15: N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidin-2-yl} ethyl ] -N-Methyl-1-({[(2-methylpropyl) sulfonyl] acetyl} amino) -2,3-dihydro-1H-indene-1-carboxamide Hydrochloride Synthesis Method Similar to Example 3-12 Was used to give the title compound (15 mg, colorless solid) from the compound obtained in Step 3-1-5 (25 mg) and 2- (2-methylpropylsulfonyl) acetic acid (10 mg).
1 H NMR (600 MHz, DMSO-d 6 , δ): 0.93-1.06 (m, 6H), 1.41 (br s, 3H), 2.00-2.09 (m, 1H), 2.18-2.28 (m, 2H), 2.34 (s, 3H), 2.40-3.26 (m, 9H), 3.68-4.18 (m, 7H), 5.79-5.93 (m, 2H), 7.13-7.28 (m, 3H), 7.42-7.51 (m, 1H ), 8.28 (br s, 3H), 8.50 (br s, 0.5H), 9.16-9.24 (m, 0.5H).
LCMS (ESI) m / z 596 [M + H] + , t R = 0.55 min, mode N.
実施例3−16:N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}エチル]-1-[(3,3-ジメチルブタノイル)アミノ]-N-メチル-2,3-ジヒドロ-1H-インデン-1-カルボキサミド 塩酸塩の合成
実施例3−12と同様の手法を用いて、工程3−1−5で得られた化合物(25 mg)及びtert-ブチル酢酸(7 mg)より表題化合物(2 mg, 無色固体)を得た。
LCMS (ESI) m/z 532 [M+H]+, tR = 0.60 min, mode N.
Example 3-16: N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidin-2-yl} ethyl ] -1-[(3,3-Dimethylbutanoyl) amino] -N-methyl-2,3-dihydro-1H-indene-1-carboxamide Hydrochloride Synthesis Using the same procedure as Example 3-12 The title compound (2 mg, colorless solid) was obtained from the compound (25 mg) obtained in Step 3-1-5 and tert-butylacetic acid (7 mg).
LCMS (ESI) m / z 532 [M + H] + , t R = 0.60 min, mode N.
実施例3−17:1-[(N-アセチルグリシル)アミノ]-N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}エチル]-N-メチル-2,3-ジヒドロ-1H-インデン-1-カルボキサミド 塩酸塩の合成
実施例3−12と同様の手法を用いて、工程3−1−5で得られた化合物(25 mg)及びN-アセチルグリシン(11 mg)より表題化合物(13 mg, 無色固体)を得た。
LCMS (ESI) m/z 533 [M+H]+, tR = 0.72 min, mode H.
Example 3-17: 1-[(N-acetylglycyl) amino] -N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [ 1,5-a] pyrimidin-2-yl} ethyl] -N-methyl-2,3-dihydro-1H-indene-1-carboxamide Hydrochloride Synthesis Using the same procedure as in Example 3-12, The title compound (13 mg, colorless solid) was obtained from the compound (25 mg) obtained in 3-1-5 and N-acetylglycine (11 mg).
LCMS (ESI) m / z 533 [M + H] + , t R = 0.72 min, mode H.
実施例3−18:N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}エチル]-1-[(N,N-ジメチルグリシル)アミノ]-N-メチル-2,3-ジヒドロ-1H-インデン-1-カルボキサミド 塩酸塩の合成
実施例3−12と同様の手法を用いて、工程3−1−5で得られた化合物(25 mg)及びN,N-ジメチルグリシン 塩酸塩(13 mg)より表題化合物(12 mg, 無色固体)を得た。
LCMS (ESI) m/z 519 [M+H]+, tR = 0.58 min, mode H.
Example 3-18: N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidin-2-yl} ethyl ] -1-[(N, N-dimethylglycyl) amino] -N-methyl-2,3-dihydro-1H-indene-1-carboxamide Hydrochloride Synthesis Using the same procedure as Example 3-12 The title compound (12 mg, colorless solid) was obtained from the compound obtained in Step 3-1-5 (25 mg) and N, N-dimethylglycine hydrochloride (13 mg).
LCMS (ESI) m / z 519 [M + H] + , t R = 0.58 min, mode H.
実施例3−19:N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}エチル]-1-[(メトキシアセチル)アミノ]-N-メチル-2,3-ジヒドロ-1H-インデン-1-カルボキサミド 塩酸塩の合成
実施例3−12と同様の手法を用いて、工程3−1−5で得られた化合物(25 mg)及びメトキシ酢酸(8 mg)より表題化合物(14 mg, 淡褐色固体)を得た。
LCMS (ESI) m/z 506 [M+H]+, tR = 0.84 min, mode H.
Example 3-19: N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidin-2-yl} ethyl ] -1-[(Methoxyacetyl) amino] -N-methyl-2,3-dihydro-1H-indene-1-carboxamide Hydrochloride Synthesis Using the same procedure as in Example 3-12, step 3-1 The title compound (14 mg, light brown solid) was obtained from the compound obtained in -5 (25 mg) and methoxyacetic acid (8 mg).
LCMS (ESI) m / z 506 [M + H] + , t R = 0.84 min, mode H.
実施例3−20:N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}エチル]-N-メチル-1-[(スルファモイルアセチル)アミノ]-2,3-ジヒドロ-1H-インデン-1-カルボキサミド 塩酸塩の合成
実施例3−12と同様の手法を用いて、工程3−1−5で得られた化合物(22 mg)及び2-スルファモイル酢酸(11 mg)より表題化合物(19 mg, 無色固体)を得た。
1H NMR (600 MHz, DMSO-d6, δ): 1.32-1.52 (m, 3H), 2.00-2.08 (m, 1H), 2.24 (m, 1H), 2.30-2.36 (m, 3H), 2.37-3.16 (m, 7H), 3.40-3.99 (m, 7H), 5.76-5.96 (m, 2H), 6.79-7.54 (m, 4H), 8.21 (br s, 3H), 8.51 (br s, 0.5H), 8.87-9.09 (m, 0.5H).
LCMS (ESI) m/z 555 [M+H]+, tR = 0.79 min, mode H.
Example 3-20: N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidin-2-yl} ethyl Synthesis of] -N-methyl-1-[(sulfamoylacetyl) amino] -2,3-dihydro-1H-indene-1-carboxamide hydrochloride Step 3 was carried out using the same procedure as in Example 3-12. The title compound (19 mg, colorless solid) was obtained from the compound obtained in -1-5 (22 mg) and 2-sulfamoyl acetic acid (11 mg).
1 H NMR (600 MHz, DMSO-d 6 , δ): 1.32-1.52 (m, 3H), 2.00-2.08 (m, 1H), 2.24 (m, 1H), 2.30-2.36 (m, 3H), 2.37 -3.16 (m, 7H), 3.40-3.99 (m, 7H), 5.76-5.96 (m, 2H), 6.79-7.54 (m, 4H), 8.21 (br s, 3H), 8.51 (br s, 0.5H ), 8.87-9.09 (m, 0.5H).
LCMS (ESI) m / z 555 [M + H] + , t R = 0.79 min, mode H.
実施例3−21:N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}エチル]-N-メチル-1-{[(フェニルスルホニル)アセチル]アミノ}-2,3-ジヒドロ-1H-インデン-1-カルボキサミド 塩酸塩の合成
実施例3−12と同様の手法を用いて、工程3−1−5で得られた化合物(22 mg)及びフェニルスルホニル酢酸(17 mg)より表題化合物(23 mg, 無色固体)を得た。
LCMS (ESI) m/z 616 [M+H]+, tR = 0.99 min, mode H.
Example 3-21: N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidin-2-yl} ethyl ] -N-Methyl-1-{[(phenylsulfonyl) acetyl] amino} -2,3-dihydro-1H-indene-1-carboxamide Hydrochloride Synthesis Using the same procedure as in Example 3-12, The title compound (23 mg, colorless solid) was obtained from the compound obtained in 3-1-5 (22 mg) and phenylsulfonylacetic acid (17 mg).
LCMS (ESI) m / z 616 [M + H] + , t R = 0.99 min, mode H.
実施例3−22:N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}エチル]-N-メチル-1-[(1H-1,2,4-トリアゾール-1-イルアセチル)アミノ]-2,3-ジヒドロ-1H-インデン-1-カルボキサミド 塩酸塩の合成
実施例3−12と同様の手法を用いて、工程3−1−5で得られた化合物(22 mg)及び1,2,4-トリアゾール-1-酢酸(10 mg)より表題化合物(20 mg, 無色固体)を得た。
LCMS (ESI) m/z 543 [M+H]+, tR = 0.79 min, mode H.
Example 3-22: N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidin-2-yl} ethyl ] -N-Methyl-1-[(1H-1,2,4-triazol-1-ylacetyl) amino] -2,3-dihydro-1H-indene-1-carboxamide Synthesis Example 3-12 with hydrochloride Using the same method, the title compound (20 mg, colorless solid) was obtained from the compound obtained in Step 3-1-5 (22 mg) and 1,2,4-triazole-1-acetic acid (10 mg). It was.
LCMS (ESI) m / z 543 [M + H] + , t R = 0.79 min, mode H.
実施例3−23:N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}エチル]-N-メチル-1-{[3-(メチルスルホニル)プロパノイル]アミノ}-2,3-ジヒドロ-1H-インデン-1-カルボキサミド 塩酸塩の合成
実施例3−12と同様の手法を用いて、工程3−1−5で得られた化合物(21 mg)及び3-(メチルスルホニル)プロパン酸(10 mg)より表題化合物(24 mg, 無色固体)を得た。
LCMS (ESI) m/z 568 [M+H]+, tR = 0.77 min, mode H.
実施例3−24:N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}エチル]-N-メチル-1-{[2-メチル-2-(メチルスルホニル)プロパノイル]アミノ}-2,3-ジヒドロ-1H-インデン-1-カルボキサミド 塩酸塩の合成
実施例3−12と同様の手法を用いて、工程3−1−5で得られた化合物(20 mg)及び2-メタンスルホニル-2-メチルプロパン酸(7 mg)より表題化合物(5 mg, 淡黄色固体)を得た。
LCMS (ESI) m/z 582 [M+H]+, tR = 0.69 min, mode N.
Example 3-23: N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidin-2-yl} ethyl ] -N-Methyl-1-{[3- (methylsulfonyl) propanoyl] amino} -2,3-dihydro-1H-indene-1-carboxamide Hydrochloride Synthesis Using the same procedure as Example 3-12 The title compound (24 mg, colorless solid) was obtained from the compound (21 mg) obtained in Step 3-1-5 and 3- (methylsulfonyl) propanoic acid (10 mg).
LCMS (ESI) m / z 568 [M + H] + , t R = 0.77 min, mode H.
Example 3-24: N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidin-2-yl} ethyl ] -N-Methyl-1-{[2-methyl-2- (methylsulfonyl) propanoyl] amino} -2,3-dihydro-1H-indene-1-carboxamide Synthesis of hydrochloride Similar to Example 3-12 Using the method, the title compound (5 mg, pale yellow solid) was obtained from the compound (20 mg) obtained in Step 3-1-5 and 2-methanesulfonyl-2-methylpropanoic acid (7 mg).
LCMS (ESI) m / z 582 [M + H] + , t R = 0.69 min, mode N.
実施例3−25:N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}エチル]-1-{[(ジメチルスルファモイル)アセチル]アミノ}-N-メチル-2,3-ジヒドロ-1H-インデン-1-カルボキサミド 塩酸塩の合成
実施例3−12と同様の手法を用いて、工程3−1−5で得られた化合物(20 mg)及び2-(ジメチルスルファモイル)酢酸(8 mg)より表題化合物(21 mg, 無色固体)を得た。
LCMS (ESI) m/z 583 [M+H]+, tR = 0.66 min, mode N.
Example 3-25: N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidin-2-yl} ethyl ] -1-{[(Dimethylsulfamoyl) acetyl] amino} -N-methyl-2,3-dihydro-1H-indene-1-carboxamide Hydrochloride Synthesis Using the same procedure as Example 3-12 The title compound (21 mg, colorless solid) was obtained from the compound obtained in Step 3-1-5 (20 mg) and 2- (dimethylsulfamoyl) acetic acid (8 mg).
LCMS (ESI) m / z 583 [M + H] + , t R = 0.66 min, mode N.
実施例3−26:N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}エチル]-1-[(シクロプロピルアセチル)アミノ]-N-メチル-2,3-ジヒドロ-1H-インデン-1-カルボキサミドの合成
工程3−12−1及び工程3−8−2と同様の手法を用いて、工程3−1−5で得られた化合物(22 mg)、シクロプロピル酢酸(8 mg)より表題化合物(9 mg, 無色アモルファス)を得た。
LCMS (ESI) m/z 516 [M+H]+, tR = 0.91 min, mode H.
Example 3-26: N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidin-2-yl} ethyl ] -1-[(Cyclopropylacetyl) amino] -N-methyl-2,3-dihydro-1H-indene-1-carboxamide in the same manner as in Steps 3-12-1 and 3-8-2 The title compound (9 mg, colorless amorphous) was obtained from the compound (22 mg) obtained in Step 3-1-5 and cyclopropylacetic acid (8 mg).
LCMS (ESI) m / z 516 [M + H] + , t R = 0.91 min, mode H.
実施例3−27:N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}エチル]-1-(グリシルアミノ)-N-メチル-2,3-ジヒドロ-1H-インデン-1-カルボキサミド 塩酸塩の合成
工程3−27−1:工程3−12−1及び工程3−1−5と同様の手法を用いて、工程3−1−5で得られた化合物(75 mg)、ベンジルオキシカルボニルグリシン(44 mg)よりtert-ブチル [(3S)-1-(2-{(1S)-1-[{[1-(グリシルアミノ)-2,3-ジヒドロ-1H-インデン-1-イル]カルボニル}(メチル)アミノ]エチル}-6-メチルピラゾロ[1,5-a]ピリミジン-5-イル)ピロリジン-3-イル]カルバマート(34 mg, 無色アモルファス)を得た。
LCMS (ESI) m/z 591 [M+H]+, tR = 0.61 min, mode N.
工程3−27−2:工程3−1−1と同様の手法を用いて、工程3−27−1で得られた化合物(5.7 mg)より表題化合物(7.2 mg, 無色固体)を得た。
LCMS (ESI) m/z 491 [M+H]+, tR = 0.56 min, mode H.
Example 3-27: N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidin-2-yl} ethyl ] -1- (Glycylamino) -N-methyl-2,3-dihydro-1H-indene-1-carboxamide Hydrochloride Synthesis Step 3-27-1: Steps 3-12-1 and 3-1-5 Using a similar method, the compound (75 mg) obtained in Step 3-1-5, benzyloxycarbonylglycine (44 mg) and tert-butyl [(3S) -1- (2-{(1S)- 1-[{[1- (Glycylamino) -2,3-dihydro-1H-inden-1-yl] carbonyl} (methyl) amino] ethyl} -6-methylpyrazolo [1,5-a] pyrimidin-5-yl ) Pyrrolidin-3-yl] carbamate (34 mg, colorless amorphous) was obtained.
LCMS (ESI) m / z 591 [M + H] + , t R = 0.61 min, mode N.
Step 3-27-2: Using the same method as in Step 3-1-1, the title compound (7.2 mg, colorless solid) was obtained from the compound (5.7 mg) obtained in Step 3-27-1.
LCMS (ESI) m / z 491 [M + H] + , t R = 0.56 min, mode H.
実施例3−28:N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}エチル]-N-メチル-1-{[N-(メチルスルホニル)グリシル]アミノ}-2,3-ジヒドロ-1H-インデン-1-カルボキサミド 塩酸塩の合成
工程3−1−6及び工程3−1−1と同様の手法を用いて、工程3−27−1で得られた化合物(27 mg)より表題化合物(4.8 mg, 無色アモルファス)を得た。
LCMS (ESI) m/z 569 [M+H]+, tR = 0.78 min, mode H.
Example 3-28: N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidin-2-yl} ethyl ] -N-Methyl-1-{[N- (methylsulfonyl) glycyl] amino} -2,3-dihydro-1H-indene-1-carboxamide Hydrochloride Synthesis Steps 3-1-6 and 3-1 1 was used to give the title compound (4.8 mg, colorless amorphous) from the compound (27 mg) obtained in Step 3-27-1.
LCMS (ESI) m / z 569 [M + H] + , t R = 0.78 min, mode H.
実施例3−29:N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}エチル]-N,6-ジメチル-1-[(メチルスルホニル)アミノ]-2,3-ジヒドロ-1H-インデン-1-カルボキサミド 塩酸塩の合成
工程3−29−1:工程3−1−3で得られた化合物(69 mg)と参考例5で得られた化合物(50 mg)のDMF(1 mL)溶液にHATU(117 mg)、Et3N(130 μL) を加え、50 ℃で6時間攪拌した。反応液に水を加え攪拌した後、EtOAcで抽出した。有機層を減圧下濃縮し、得られた残渣をOH型シリカゲルカラムクロマトグラフィー(移動相:ヘキサン/EtOAc = 90/10〜0/100; v/v)にて精製し、ベンジル (1-{[(1S)-1-(5-{(3S)-3-[(tert-ブトキシカルボニル)アミノ]ピロリジン-1-イル}-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル)エチル](メチル)カルバモイル}-6-メチル-2,3-ジヒドロ-1H-インデン-1-イル)カルバマート(57 mg, 無色アモルファス)を得た。
LCMS (ESI) m/z 682 [M+H]+, tR = 1.22, 1.23 min, mode N.
工程3−29−2:工程3−1−5と同様の手法を用いて、工程3−29−1で得られた化合物(37 mg)よりtert-ブチル [(3S)-1-{2-[(1S)-1-{[(1-アミノ-6-メチル-2,3-ジヒドロ-1H-インデン-1-イル)カルボニル](メチル)アミノ}エチル]-6-メチルピラゾロ[1,5-a]ピリミジン-5-イル}ピロリジン-3-イル]カルバマート(30 mg, 無色アモルファス)を得た。
LCMS (ESI) m/z 548 [M+H]+, tR = 0.66, 0.68 min, mode N.
工程3−29−3:工程3−1−6及び工程3−1−1と同様の手法を用いて、工程3−29−2で得られた化合物(20 mg)より表題化合物(15 mg, 無色固体)を得た。
LCMS (ESI) m/z 526 [M+H]+, tR = 0.51 min, mode N.
Example 3-29: N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidin-2-yl} ethyl ] -N, 6-Dimethyl-1-[(methylsulfonyl) amino] -2,3-dihydro-1H-indene-1-carboxamide Hydrochloride Synthesis Step 3-29-1: Obtained in Step 3-1-3 HATU (117 mg) and Et 3 N (130 μL) were added to a DMF (1 mL) solution of the obtained compound (69 mg) and the compound (50 mg) obtained in Reference Example 5 and stirred at 50 ° C. for 6 hours. did. Water was added to the reaction mixture and stirred, followed by extraction with EtOAc. The organic layer was concentrated under reduced pressure, and the obtained residue was purified by OH-type silica gel column chromatography (mobile phase: hexane / EtOAc = 90/10 to 0/100; v / v) to obtain benzyl (1-{[ (1S) -1- (5-{(3S) -3-[(tert-butoxycarbonyl) amino] pyrrolidin-1-yl} -6-methylpyrazolo [1,5-a] pyrimidin-2-yl) ethyl] (Methyl) carbamoyl} -6-methyl-2,3-dihydro-1H-inden-1-yl) carbamate (57 mg, colorless amorphous) was obtained.
LCMS (ESI) m / z 682 [M + H] + , t R = 1.22, 1.23 min, mode N.
Step 3-29-2: Using a method similar to that of Step 3-1-5, tert-butyl [(3S) -1- {2-] from the compound (37 mg) obtained in Step 3-29-1 [(1S) -1-{[(1-Amino-6-methyl-2,3-dihydro-1H-inden-1-yl) carbonyl] (methyl) amino} ethyl] -6-methylpyrazolo [1,5- a] pyrimidin-5-yl} pyrrolidin-3-yl] carbamate (30 mg, colorless amorphous) was obtained.
LCMS (ESI) m / z 548 [M + H] + , t R = 0.66, 0.68 min, mode N.
Step 3-29-3: Using a method similar to that of Step 3-1-6 and Step 3-1-1, the title compound (15 mg, A colorless solid was obtained.
LCMS (ESI) m / z 526 [M + H] + , t R = 0.51 min, mode N.
実施例3−30:ベンジル (1-{[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}エチル](メチル)カルバモイル}-6-メチル-2,3-ジヒドロ-1H-インデン-1-イル)カルバマート 塩酸塩の合成
工程3−1−1と同様の手法を用いて、工程3−29−1で得られた化合物(14.7 mg)より表題化合物(15.9 mg, 無色固体)を得た。
LCMS (ESI) m/z 582 [M+H]+, tR = 0.68 min, mode N.
Example 3-30: benzyl (1-{[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidine-2- Yl} ethyl] (methyl) carbamoyl} -6-methyl-2,3-dihydro-1H-inden-1-yl) carbamate hydrochloride using the same procedure as in step 3-1-1, The title compound (15.9 mg, colorless solid) was obtained from the compound (14.7 mg) obtained in 29-1.
LCMS (ESI) m / z 582 [M + H] + , t R = 0.68 min, mode N.
実施例3−31:1-アミノ-N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}エチル]-N,6-ジメチル-2,3-ジヒドロ-1H-インデン-1-カルボキサミド 塩酸塩の合成
工程3−1−1と同様の手法を用いて、工程3−29−2で得られた化合物(8.2 mg)より表題化合物(8.8 mg, 無色固体)を得た。
LCMS (ESI) m/z 448 [M+H]+, tR = 0.18 min, mode N.
実施例3−32:N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}エチル]-1-[2-(エチルスルホニル)エチル]-N-メチル-2,3-ジヒドロ-1H-イソインドール-1-カルボキサミド 塩酸塩の合成
工程3−29−1及び工程3−1−1と同様の手法を用いて、工程3−1−3で得られた化合物(59 mg)及び参考例6で得られた化合物(50 mg)より表題化合物(27 mg, 無色固体)を得た。
LCMS (ESI) m/z 540 [M+H]+, tR = 0.20 min, mode N.
Example 3-31: 1-amino-N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidine-2 -Il} ethyl] -N, 6-dimethyl-2,3-dihydro-1H-indene-1-carboxamide hydrochloride in step 3-29-2 using the same procedure as in step 3-1-1 The title compound (8.8 mg, colorless solid) was obtained from the obtained compound (8.2 mg).
LCMS (ESI) m / z 448 [M + H] + , t R = 0.18 min, mode N.
Example 3-32: N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidin-2-yl} ethyl ] -1- [2- (Ethylsulfonyl) ethyl] -N-methyl-2,3-dihydro-1H-isoindole-1-carboxamide Hydrochloride Synthesis Steps 3-29-1 and 3-1-1 Using the same method, the title compound (27 mg, colorless solid) was obtained from the compound (59 mg) obtained in Step 3-1-3 and the compound (50 mg) obtained in Reference Example 6.
LCMS (ESI) m / z 540 [M + H] + , t R = 0.20 min, mode N.
実施例3−33:N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}エチル]-1-(2-シクロプロピル-2-オキソエチル)-N-メチル-2,3-ジヒドロ-1H-インデン-1-カルボキサミドの合成
工程3−33−1:工程3−29−1と同様の手法を用いて、工程3−1−3で得られた化合物(90 mg)及び参考例7で得られた化合物(69 mg)よりtert-ブチル [(3S)-1-(2-{(1S)-1-[{[1-(2-シクロプロピル-2-オキソエチル)-2,3-ジヒドロ-1H-インデン-1-イル]カルボニル}(メチル)アミノ]エチル}-6-メチルピラゾロ[1,5-a]ピリミジン-5-イル)ピロリジン-3-イル]カルバマート(40 mg, 無色固体)を得た。
LCMS (ESI) m/z 601 [M+H]+, tR = 1.16 min, mode N.
工程3−33−2:工程3−33−1で得られた化合物(18 mg)のCHCl3(0.5 mL)溶液にTFA(0.5 mL)を滴下して、室温にて2時間攪拌した。反応液をCHCl3、飽和NaHCO3水溶液にて分液した。有機層を減圧下濃縮し、表題化合物(15 mg, 無色固体)を得た。
LCMS (ESI) m/z 501 [M+H]+, tR = 0.61 min, mode N.
実施例3−34:N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}エチル]-N,2-ジメチル-1-[2-(メチルスルホニル)エチル]-2,3-ジヒドロ-1H-イソインドール-1-カルボキサミドの合成
工程3−29−1及び工程3−33−2と同様の手法を用いて、工程3−1−3で得られた化合物(4.0 mg)及び参考例8で得られた化合物(2.5 mg)より表題化合物(1.9 mg, 橙色アモルファス)を得た。
LCMS (ESI) m/z 540 [M+H]+, tR = 0.49 min, mode N.
Example 3-33: N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidin-2-yl} ethyl ] Synthetic step 3-33-1 of step -3-3-1: step 3-29-1 of 2- (2-cyclopropyl-2-oxoethyl) -N-methyl-2,3-dihydro-1H-indene-1-carboxamide From the compound obtained in Step 3-1-3 (90 mg) and the compound obtained in Reference Example 7 (69 mg), tert-butyl [(3S) -1- (2-{(1S ) -1-[{[1- (2-Cyclopropyl-2-oxoethyl) -2,3-dihydro-1H-inden-1-yl] carbonyl} (methyl) amino] ethyl} -6-methylpyrazolo [1, 5-a] pyrimidin-5-yl) pyrrolidin-3-yl] carbamate (40 mg, colorless solid) was obtained.
LCMS (ESI) m / z 601 [M + H] + , t R = 1.16 min, mode N.
Step 3-33-2: TFA (0.5 mL) was added dropwise to a solution of the compound obtained in Step 3-33-1 (18 mg) in CHCl 3 (0.5 mL), and the mixture was stirred at room temperature for 2 hours. The reaction solution was separated with CHCl 3 and saturated NaHCO 3 aqueous solution. The organic layer was concentrated under reduced pressure to obtain the title compound (15 mg, colorless solid).
LCMS (ESI) m / z 501 [M + H] + , t R = 0.61 min, mode N.
Example 3-34: N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidin-2-yl} ethyl Synthesis steps 3-29-1 and 3-33-2 of] -N, 2-dimethyl-1- [2- (methylsulfonyl) ethyl] -2,3-dihydro-1H-isoindole-1-carboxamide Using the same method, the title compound (1.9 mg, orange amorphous) was obtained from the compound (4.0 mg) obtained in Step 3-1-3 and the compound (2.5 mg) obtained in Reference Example 8.
LCMS (ESI) m / z 540 [M + H] + , t R = 0.49 min, mode N.
実施例3−35:N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}エチル]-N-メチル-1-{[(メチルスルホニル)アミノ]メチル}-2,3-ジヒドロ-1H-インデン-1-カルボキサミド 塩酸塩の合成
工程3−35−1:工程3−29−1と同様の手法を用いて、工程3−1−3で得られた化合物(137 mg)及び参考例9で得られた化合物(107 mg)よりtert-ブチル [(3S)-1-(2-{(1S)-1-[({1-[(1,3-ジオキソ-1,3-ジヒドロ-2H-イソインドル-2-イル)メチル]-2,3-ジヒドロ-1H-インデン-1-イル}カルボニル)(メチル)アミノ]エチル}-6-メチルピラゾロ[1,5-a]ピリミジン-5-イル)ピロリジン-3-イル]カルバマート(31 mg, 淡黄色アモルファス)を得た。
LCMS (ESI) m/z 678 [M+H]+, tR = 1.18 min, mode N.
工程3−35−2:工程3−35−1で得られた化合物(31 mg)のEtOH(1.0 mL)溶液にヒドラジン1水和物(15 mg)を加え、60 ℃で3時間攪拌した。反応液を減圧下濃縮し、得られた残渣にCHCl3を加え、固体を析出させた。固体をろ別し、CHCl3洗浄して得られたろ液を減圧下濃縮し、tert-ブチル [(3S)-1-(2-{(1S)-1-[{[1-(アミノメチル)-2,3-ジヒドロ-1H-インデン-1-イル]カルボニル}(メチル)アミノ]エチル}-6-メチルピラゾロ[1,5-a]ピリミジン-5-イル)ピロリジン-3-イル]カルバマート(26 mg, 無色アモルファス)を得た。
LCMS (ESI) m/z 548 [M+H]+, tR = 0.68 min, mode N.
工程3−35−3:工程3−1−6及び工程3−1−1と同様の手法を用いて、工程3−35−2で得られた化合物(26 mg)より表題化合物(3.2 mg, 無色固体)を得た。
LCMS (ESI) m/z 526 [M+H]+, tR = 0.51 min, mode N.
Example 3-35: N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidin-2-yl} ethyl ] -N-methyl-1-{[(methylsulfonyl) amino] methyl} -2,3-dihydro-1H-indene-1-carboxamide Hydrochloride Synthesis Step 3-35-1: Step 3-29-1 and Using a similar method, the compound obtained in Step 3-1-3 (137 mg) and the compound obtained in Reference Example 9 (107 mg) were tert-butyl [(3S) -1- (2- { (1S) -1-[({1-[(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl) methyl] -2,3-dihydro-1H-inden-1-yl} Carbonyl) (methyl) amino] ethyl} -6-methylpyrazolo [1,5-a] pyrimidin-5-yl) pyrrolidin-3-yl] carbamate (31 mg, pale yellow amorphous) was obtained.
LCMS (ESI) m / z 678 [M + H] + , t R = 1.18 min, mode N.
Step 3-35-2: Hydrazine monohydrate (15 mg) was added to a solution of the compound obtained in Step 3-35-1 (31 mg) in EtOH (1.0 mL), and the mixture was stirred at 60 ° C. for 3 hours. The reaction solution was concentrated under reduced pressure, and CHCl 3 was added to the resulting residue to precipitate a solid. The solid was filtered off and the filtrate obtained by washing with CHCl 3 was concentrated under reduced pressure, and tert-butyl [(3S) -1- (2-{(1S) -1-[{[1- (aminomethyl) -2,3-dihydro-1H-inden-1-yl] carbonyl} (methyl) amino] ethyl} -6-methylpyrazolo [1,5-a] pyrimidin-5-yl) pyrrolidin-3-yl] carbamate (26 mg, colorless amorphous).
LCMS (ESI) m / z 548 [M + H] + , t R = 0.68 min, mode N.
Step 3-35-3: Using a method similar to that of Step 3-1-6 and Step 3-1-1, the title compound (3.2 mg, A colorless solid was obtained.
LCMS (ESI) m / z 526 [M + H] + , t R = 0.51 min, mode N.
実施例3−36:N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}エチル]-N,1-ジメチル-2,3-ジヒドロ-1H-インデン-1-カルボキサミド 塩酸塩の合成
工程3−29−1及び工程3−1−1と同様の手法を用いて、工程3−1−3で得られた化合物(78 mg)及び1-メチル-2,3-ジヒドロ-1H-インデン-1-カルボン酸(31 mg)より表題化合物(83 mg, 淡緑色固体)を得た。
LCMS (ESI) m/z 433 [M+H]+, tR = 0.58 min, mode N.
Example 3-36: N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidin-2-yl} ethyl ] -N, 1-dimethyl-2,3-dihydro-1H-indene-1-carboxamide Hydrochloride Synthesis Step 3-3-1 using the same procedure as in Step 3-29-1 and Step 3-1-1 The title compound (83 mg, light green solid) was obtained from the compound obtained in -3 (78 mg) and 1-methyl-2,3-dihydro-1H-indene-1-carboxylic acid (31 mg).
LCMS (ESI) m / z 433 [M + H] + , t R = 0.58 min, mode N.
実施例3−37:N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}エチル]-1-[2-(エチルスルホニル)エチル]-N-メチル-2,3-ジヒドロ-1H-インデン-1-カルボキサミド 塩酸塩の合成
工程3−29−1及び工程3−1−1と同様の手法を用いて、工程3−1−3で得られた化合物(64 mg)及び1-[2-(エタンスルホニル)エチル]-2,3-ジヒドロ-1H-インデン-1-カルボン酸(40 mg)より表題化合物(83 mg, 淡緑色固体)を得た。
LCMS (ESI) m/z 539 [M+H]+, tR = 0.53 min, mode N.
Example 3-37: N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidin-2-yl} ethyl ] -1- [2- (Ethylsulfonyl) ethyl] -N-methyl-2,3-dihydro-1H-indene-1-carboxamide Similar to Synthesis Steps 3-29-1 and 3-1-1 of hydrochloride salt The compound obtained in Step 3-1-3 (64 mg) and 1- [2- (ethanesulfonyl) ethyl] -2,3-dihydro-1H-indene-1-carboxylic acid (40 mg) gave the title compound (83 mg, pale green solid).
LCMS (ESI) m / z 539 [M + H] + , t R = 0.53 min, mode N.
実施例3−38:N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}エチル]-N-メチル-1-[3-(メチルスルホニル)プロピル]-2,3-ジヒドロ-1H-インデン-1-カルボキサミド 塩酸塩の合成
工程3−29−1及び工程3−1−1と同様の手法を用いて、工程3−1−3で得られた化合物(28 mg)及び1-[3-(メタンスルホニル)プロピル]-2,3-ジヒドロ-1H-インデン-1-カルボン酸(20 mg)より表題化合物(5.3 mg, 緑色アモルファス)を得た。
LCMS (ESI) m/z 539 [M+H]+, tR = 0.52 min, mode N.
Example 3-38: N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidin-2-yl} ethyl ] -N-Methyl-1- [3- (methylsulfonyl) propyl] -2,3-dihydro-1H-indene-1-carboxamide Similar to Steps 3-29-1 and 3-1-1 of Synthesis of Hydrochloride The compound obtained in Step 3-1-3 (28 mg) and 1- [3- (methanesulfonyl) propyl] -2,3-dihydro-1H-indene-1-carboxylic acid (20 mg) gave the title compound (5.3 mg, green amorphous).
LCMS (ESI) m / z 539 [M + H] + , t R = 0.52 min, mode N.
実施例3−39:1-アミノ-N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}エチル]-N-メチル-2,3-ジヒドロ-1H-インデン-1-カルボキサミド塩酸塩(単一ジアステレオマー)の合成
工程3−39−1:工程3−1−4で得られた化合物(210 mg)をキラルカラムにて分取精製を行い(分取条件:カラム:CHIRALPAK IB(ダイセル商標)、カラムサイズ:20 mm×250 mm、移動相:ヘキサン/EtOH = 80/20 (v/v)、流速:10 mL/min、カラム温度:25℃、検出波長:254 nm)、ベンジル (1-{[(1S)-1-(5-{(3S)-3-[(tert-ブトキシカルボニル)アミノ]ピロリジン-1-イル}-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル)エチル](メチル)カルバモイル}-2,3-ジヒドロ-1H-インデン-1-イル)カルバマートのジアステレオマーA(87.5 mg)及びジアステレオマーB(76.7mg)を得た。
ジアステレオマーA:1H NMR (600 MHz, CD3OD, δ): 1.36-1.53 (m, 12H), 1.84-1.97 (m, 1H), 2.10-2.22 (m, 1H), 2.25-2.44 (m, 3H), 2.46-3.38 (m, 7H), 3.45-3.96 (m, 4H), 4.08-4.22 (m, 1H), 4.91-5.15 (m, 2H), 5.45-5.60 (m, 0.5H), 5.82-6.07 (m, 1.5H), 7.02-7.40 (m, 7H), 7.49-7.65 (m, 1H), 7.86-7.93 (m, 1H), 8.12 (br s, 1H).
LCMS (ESI) m/z 668 [M+H]+, tR = 1.18 min, mode N.
ジアステレオマーB:LCMS (ESI) m/z 668 [M+H]+, tR = 1.17 min, mode N.
Example 3-39: 1-amino-N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidine-2 -Il} ethyl] -N-methyl-2,3-dihydro-1H-indene-1-carboxamide hydrochloride (single diastereomer) synthesis step 3-39-1: obtained in step 3-1-4 The compound (210 mg) was subjected to preparative purification on a chiral column (preparation conditions: column: CHIRALPAK IB (Daicel Trademark), column size: 20 mm × 250 mm, mobile phase: hexane / EtOH = 80/20 (v / v), flow rate: 10 mL / min, column temperature: 25 ° C., detection wavelength: 254 nm), benzyl (1-{[(1S) -1- (5-{(3S) -3-[(tert- Butoxycarbonyl) amino] pyrrolidin-1-yl} -6-methylpyrazolo [1,5-a] pyrimidin-2-yl) ethyl] (methyl) carbamoyl} -2,3-dihydro-1H-inden-1-yl) The carbamate diastereomer A (87.5 mg) and diastereomer B (76.7 mg) were obtained.
Diastereomer A: 1 H NMR (600 MHz, CD 3 OD, δ): 1.36-1.53 (m, 12H), 1.84-1.97 (m, 1H), 2.10-2.22 (m, 1H), 2.25-2.44 ( m, 3H), 2.46-3.38 (m, 7H), 3.45-3.96 (m, 4H), 4.08-4.22 (m, 1H), 4.91-5.15 (m, 2H), 5.45-5.60 (m, 0.5H) , 5.82-6.07 (m, 1.5H), 7.02-7.40 (m, 7H), 7.49-7.65 (m, 1H), 7.86-7.93 (m, 1H), 8.12 (br s, 1H).
LCMS (ESI) m / z 668 [M + H] + , t R = 1.18 min, mode N.
Diastereomer B: LCMS (ESI) m / z 668 [M + H] + , t R = 1.17 min, mode N.
工程3−39−2:工程3−39−1で得られたベンジル (1-{[(1S)-1-(5-{(3S)-3-[(tert-ブトキシカルボニル)アミノ]ピロリジン-1-イル}-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル)エチル](メチル)カルバモイル}-2,3-ジヒドロ-1H-インデン-1-イル)カルバマートのジアステレオマーA(78 mg)のMeOH(2 mL)溶液に10%パラジウム-炭素(39 mg)を加え、水素雰囲気下、室温にて3時間攪拌した。反応液をセライト(登録商標)ろ過後、ろ液を減圧下濃縮し、得られた残渣をNH型シリカゲルカラムクロマトグラフィー (移動相:ヘキサン/EtOAc = 80/20〜0/100〜CHCl3/MeOH = 100/0〜70/30; v/v)にて精製し、tert-ブチル [(3S)-1-{2-[(1S)-1-{[(1-アミノ-2,3-ジヒドロ-1H-インデン-1-イル)カルボニル](メチル)アミノ}エチル]-6-メチルピラゾロ[1,5-a]ピリミジン-5-イル}ピロリジン-3-イル]カルバマート(単一ジアステレオマー) (48 mg, 無色アモルファス)を得た。
1H NMR (600 MHz, CD3OD, δ):(br s, 1.5H), 1.38-1.57 (m, 10.5H), 1.90-1.97 (m, 1H), 2.13-2.22 (m, 2H), 2.29 (br s, 1H), 2.39 (s, 3H), 2.56-3.16 (m, 4H), 3.24-3.39 (m, 3H), 3.55 (dd, J = 10.7, 4.5 Hz, 1H), 3.72-3.79 (m, 1H), 3.80-3.87 (m, 1H), 3.89-3.95 (m, 1H), 4.13-4.19 (m, 1H), 4.55-4.76 (m, 0.5H), 5.83-5.94 (m, 1H), 6.05-6.12 (m, 0.5H), 7.21-7.38 (m, 4H), 8.13 (s, 1H).
LCMS (ESI) m/z 534 [M+H]+, tR = 0.67 min, mode N.
Step 3-39-2: The benzyl (1-{[(1S) -1- (5-{(3S) -3-[(tert-butoxycarbonyl) amino] pyrrolidine-) obtained in Step 3-39-1 1-yl} -6-methylpyrazolo [1,5-a] pyrimidin-2-yl) ethyl] (methyl) carbamoyl} -2,3-dihydro-1H-inden-1-yl) carbamate diastereomer A ( To a solution of 78 mg) in MeOH (2 mL) was added 10% palladium-carbon (39 mg), and the mixture was stirred at room temperature for 3 hours in a hydrogen atmosphere. The reaction mixture was filtered through Celite (registered trademark), and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to NH silica gel column chromatography (mobile phase: hexane / EtOAc = 80 / 20-0 / 100-CHCl 3 / MeOH). = 100/0 to 70/30; v / v), and tert-butyl [(3S) -1- {2-[(1S) -1-{[(1-amino-2,3-dihydro -1H-Inden-1-yl) carbonyl] (methyl) amino} ethyl] -6-methylpyrazolo [1,5-a] pyrimidin-5-yl} pyrrolidin-3-yl] carbamate (single diastereomer) ( 48 mg, colorless amorphous) was obtained.
1 H NMR (600 MHz, CD 3 OD, δ): (br s, 1.5H), 1.38-1.57 (m, 10.5H), 1.90-1.97 (m, 1H), 2.13-2.22 (m, 2H), 2.29 (br s, 1H), 2.39 (s, 3H), 2.56-3.16 (m, 4H), 3.24-3.39 (m, 3H), 3.55 (dd, J = 10.7, 4.5 Hz, 1H), 3.72-3.79 (m, 1H), 3.80-3.87 (m, 1H), 3.89-3.95 (m, 1H), 4.13-4.19 (m, 1H), 4.55-4.76 (m, 0.5H), 5.83-5.94 (m, 1H ), 6.05-6.12 (m, 0.5H), 7.21-7.38 (m, 4H), 8.13 (s, 1H).
LCMS (ESI) m / z 534 [M + H] + , t R = 0.67 min, mode N.
工程3−39−3:工程3−1−1と同様の手法を用いて、工程3−39−2で得られた化合物(23.8 mg)より表題化合物(27.3 mg, 無色固体)を得た。
LCMS (ESI) m/z 434 [M+H]+, tR = 0.54 min, mode H.
Step 3-39-3: The title compound (27.3 mg, colorless solid) was obtained from the compound (23.8 mg) obtained in Step 3-39-2 using the same method as in Step 3-1-1.
LCMS (ESI) m / z 434 [M + H] + , t R = 0.54 min, mode H.
実施例3−40:N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}エチル]-N-メチル-1-[(メチルスルホニル)アミノ]-2,3-ジヒドロ-1H-インデン-1-カルボキサミド 塩酸塩(単一ジアステレオマー)の合成
工程3−1−6及び工程3−1−1と同様の手法を用いて、工程3−39−2で得られた化合物(23.6 mg)より表題化合物(23.1 mg, 無色固体)を得た。
1H NMR (600 MHz, DMSO-d6, δ): 1.20-1.48 (m, 3H), 2.00-2.08 (m, 1H), 2.19-2.26 (m, 1H), 2.28-3.23 (m, 10H), 2.34 (s, 3H), 3.44-4.04 (m, 5H), 5.81-6.16 (m, 2H), 7.19-7.56 (m, 4H), 7.93 (br s, 0.5H), 8.22 (br s, 3H), 8.51 (br s, 0.5H).
LCMS (ESI) m/z 512 [M+H]+, tR = 0.84 min, mode H.
Example 3-40: N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidin-2-yl} ethyl ] -N-Methyl-1-[(methylsulfonyl) amino] -2,3-dihydro-1H-indene-1-carboxamide Synthesis Steps 3-1-6 and Step 3- of Hydrochloride (Single Diastereomer) The title compound (23.1 mg, colorless solid) was obtained from the compound (23.6 mg) obtained in Step 3-39-2 using a method similar to 1-1.
1 H NMR (600 MHz, DMSO-d 6 , δ): 1.20-1.48 (m, 3H), 2.00-2.08 (m, 1H), 2.19-2.26 (m, 1H), 2.28-3.23 (m, 10H) , 2.34 (s, 3H), 3.44-4.04 (m, 5H), 5.81-6.16 (m, 2H), 7.19-7.56 (m, 4H), 7.93 (br s, 0.5H), 8.22 (br s, 3H ), 8.51 (br s, 0.5H).
LCMS (ESI) m / z 512 [M + H] + , t R = 0.84 min, mode H.
実施例3−41:N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}エチル]-N-メチル-1-[(メチルスルホニル)アミノ]-2,3-ジヒドロ-1H-インデン-1-カルボキサミド 塩酸塩(単一ジアステレオマー)の合成
工程3−41−1:工程3−39−2と同様の手法を用いて、工程3−39−1で得られたベンジル (1-{[(1S)-1-(5-{(3S)-3-[(tert-ブトキシカルボニル)アミノ]ピロリジン-1-イル}-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル)エチル](メチル)カルバモイル}-2,3-ジヒドロ-1H-インデン-1-イル)カルバマートのジアステレオマーB(68 mg)よりtert-ブチル [(3S)-1-{2-[(1S)-1-{[(1-アミノ-2,3-ジヒドロ-1H-インデン-1-イル)カルボニル](メチル)アミノ}エチル]-6-メチルピラゾロ[1,5-a]ピリミジン-5-イル}ピロリジン-3-イル]カルバマート(単一ジアステレオマー)(48 mg, 無色アモルファス)を得た。
LCMS (ESI) m/z 534 [M+H]+, tR = 0.61 min, mode N.
工程3−41−2:工程3−1−6及び工程3−1−1と同様の手法を用いて、工程3−41−1で得られた化合物(24.1 mg)より表題化合物(18.5 mg, 無色固体)を得た。
LCMS (ESI) m/z 512 [M+H]+, tR = 0.84 min, mode H.
Example 3-41: N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidin-2-yl} ethyl ] -N-methyl-1-[(methylsulfonyl) amino] -2,3-dihydro-1H-indene-1-carboxamide Hydrochloride (single diastereomer) synthesis step 3-41-1: step 3- Using the same method as for 39-2, the benzyl (1-{[(1S) -1- (5-{(3S) -3-[(tert-butoxycarbonyl)) obtained in Step 3-39-1 was used. Amino] pyrrolidin-1-yl} -6-methylpyrazolo [1,5-a] pyrimidin-2-yl) ethyl] (methyl) carbamoyl} -2,3-dihydro-1H-inden-1-yl) carbamate dia From stereomer B (68 mg) tert-butyl [(3S) -1- {2-[(1S) -1-{[(1-amino-2,3-dihydro-1H-inden-1-yl) carbonyl ] (Methyl) amino} ethyl] -6-methylpyrazolo [1,5-a] pyrimidin-5-yl} pyrrolidin-3-yl] carbamate (single diastere Omar) (48 mg, to obtain a colorless amorphous).
LCMS (ESI) m / z 534 [M + H] + , t R = 0.61 min, mode N.
Step 3-41-2: Using a method similar to that of Step 3-1-6 and Step 3-1-1, the title compound (18.5 mg, A colorless solid was obtained.
LCMS (ESI) m / z 512 [M + H] + , t R = 0.84 min, mode H.
実施例3−42:N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}エチル]-N-メチル-1-{[(メチルスルホニル)アセチル]アミノ}-2,3-ジヒドロ-1H-インデン-1-カルボキサミド 塩酸塩(単一ジアステレオマー)の合成
工程3−42−1:工程3−1−5で得られた化合物(70 mg)、メタンスルホニル酢酸(36 mg)のDMF(1 mL)溶液にHATU(100 mg)、Et3N(110 μL) を加え、室温にて16時間攪拌した。反応液をEtOAc、飽和NaHCO3水溶液にて分液した。有機層をBrineにて洗浄後、MgSO4で乾燥してろ過した後、ろ液を減圧下濃縮した。得られた残渣をOH型シリカゲルカラムクロマトグラフィー (移動相:ヘキサン/EtOAc = 95/5〜0/100〜EtOAc/MeOH = 100/0〜90/10; v/v)にて精製し、tert-ブチル [(3S)-1-{6-メチル-2-[(1S)-1-{メチル[(1-{[(メチルスルホニル)アセチル]アミノ}-2,3-ジヒドロ-1H-インデン-1-イル)カルボニル]アミノ}エチル]ピラゾロ[1,5-a]ピリミジン-5-イル}ピロリジン-3-イル]カルバマートのジアステレオマーA(24 mg, 無色アモルファス)及びジアステレオマーB(20 mg, 無色アモルファス)を得た。
ジアステレオマーA:1H NMR (600 MHz, CD3OD, δ): 1.38-1.61 (m, 12H), 1.88-1.96 (m, 1H), 2.11-2.23 (m, 1H), 2.38 (br s, 3H), 2.51-3.12 (m, 10H), 3.50-3.57 (m, 2H), 3.71-3.78 (m, 1H), 3.79-3.86 (m, 1H), 3.88-3.94 (m, 1H), 3.96-4.03 (m, 1H), 4.12-4.20 (m, 1H), 4.95-5.07 (m, 0.5H), 5.92 (br s, 1H), 5.99-6.10 (m, 0.5H), 7.14-7.57 (m, 4H), 8.10-8.19 (m, 1H).
LCMS (ESI) m/z 654 [M+H]+, tR = 0.93 min, mode N.
ジアステレオマーB:LCMS (ESI) m/z 654 [M+H]+, tR = 0.91 min, mode N.
工程3−42−2:工程3−42−1で得られたtert-ブチル [(3S)-1-{6-メチル-2-[(1S)-1-{メチル[(1-{[(メチルスルホニル)アセチル]アミノ}-2,3-ジヒドロ-1H-インデン-1-イル)カルボニル]アミノ}エチル]ピラゾロ[1,5-a]ピリミジン-5-イル}ピロリジン-3-イル]カルバマートのジアステレオマーA (23.2 mg)の1,4-ジオキサン(0.5 mL)溶液に4M HCl/1,4-ジオキサン溶液(1.0 mL)を滴下し、室温にて2時間攪拌した。反応液を減圧下濃縮し、表題化合物(23.6 mg, 無色固体)を得た。
1H NMR (600 MHz, DMSO-d6, δ): 0.97-1.51 (m, 3H), 1.98-2.10 (m, 1H), 2.17-2.28 (m, 1H), 2.33 (s, 3H), 2.37-3.17 (m, 10H), 3.40-3.94 (m, 5H), 3.99-4.23 (m, 2H), 5.78-5.95 (m, 2H), 7.10-7.53 (m, 4H), 8.16 (br s, 3H), 8.50 (br s, 0.5H), 9.01-9.23 (m, 0.5H).
LCMS (ESI) m/z 554 [M+H]+, tR = 0.78 min, mode H.
Example 3-42: N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidin-2-yl} ethyl ] -N-methyl-1-{[(methylsulfonyl) acetyl] amino} -2,3-dihydro-1H-indene-1-carboxamide Step 3-42-1 for Synthesis of Hydrochloride (Single Diastereomer): HATU (100 mg) and Et 3 N (110 μL) were added to a DMF (1 mL) solution of the compound obtained in Step 3-1-5 (70 mg) and methanesulfonylacetic acid (36 mg) at room temperature. Stir for 16 hours. The reaction mixture was partitioned between EtOAc and saturated aqueous NaHCO 3 solution. The organic layer was washed with Brine, dried over MgSO 4 and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by OH-type silica gel column chromatography (mobile phase: hexane / EtOAc = 95/5 to 0/100 to EtOAc / MeOH = 100/0 to 90/10; v / v), and tert- Butyl [(3S) -1- {6-methyl-2-[(1S) -1- {methyl [(1-{[(methylsulfonyl) acetyl] amino} -2,3-dihydro-1H-indene-1 -Il) carbonyl] amino} ethyl] pyrazolo [1,5-a] pyrimidin-5-yl} pyrrolidin-3-yl] carbamate diastereomer A (24 mg, colorless amorphous) and diastereomer B (20 mg , Colorless amorphous).
Diastereomer A: 1 H NMR (600 MHz, CD 3 OD, δ): 1.38-1.61 (m, 12H), 1.88-1.96 (m, 1H), 2.11-2.23 (m, 1H), 2.38 (br s , 3H), 2.51-3.12 (m, 10H), 3.50-3.57 (m, 2H), 3.71-3.78 (m, 1H), 3.79-3.86 (m, 1H), 3.88-3.94 (m, 1H), 3.96 -4.03 (m, 1H), 4.12-4.20 (m, 1H), 4.95-5.07 (m, 0.5H), 5.92 (br s, 1H), 5.99-6.10 (m, 0.5H), 7.14-7.57 (m , 4H), 8.10-8.19 (m, 1H).
LCMS (ESI) m / z 654 [M + H] + , t R = 0.93 min, mode N.
Diastereomer B: LCMS (ESI) m / z 654 [M + H] + , t R = 0.91 min, mode N.
Step 3-42-2: tert-butyl [(3S) -1- {6-methyl-2-[(1S) -1- {methyl [(1-{[( Methylsulfonyl) acetyl] amino} -2,3-dihydro-1H-inden-1-yl) carbonyl] amino} ethyl] pyrazolo [1,5-a] pyrimidin-5-yl} pyrrolidin-3-yl] carbamate To a 1,4-dioxane (0.5 mL) solution of diastereomer A (23.2 mg), 4M HCl / 1,4-dioxane solution (1.0 mL) was added dropwise, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain the title compound (23.6 mg, colorless solid).
1 H NMR (600 MHz, DMSO-d 6 , δ): 0.97-1.51 (m, 3H), 1.98-2.10 (m, 1H), 2.17-2.28 (m, 1H), 2.33 (s, 3H), 2.37 -3.17 (m, 10H), 3.40-3.94 (m, 5H), 3.99-4.23 (m, 2H), 5.78-5.95 (m, 2H), 7.10-7.53 (m, 4H), 8.16 (br s, 3H ), 8.50 (br s, 0.5H), 9.01-9.23 (m, 0.5H).
LCMS (ESI) m / z 554 [M + H] + , t R = 0.78 min, mode H.
実施例3−43:N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}エチル]-N-メチル-1-{[(メチルスルホニル)アセチル]アミノ}-2,3-ジヒドロ-1H-インデン-1-カルボキサミド 塩酸塩(単一ジアステレオマー)の合成
工程3−1−1と同様の手法を用いて、3−42−1で得られたtert-ブチル [(3S)-1-{6-メチル-2-[(1S)-1-{メチル[(1-{[(メチルスルホニル)アセチル]アミノ}-2,3-ジヒドロ-1H-インデン-1-イル)カルボニル]アミノ}エチル]ピラゾロ[1,5-a]ピリミジン-5-イル}ピロリジン-3-イル]カルバマートのジアステレオマーB(19 mg)より表題化合物(18 mg, 無色固体)を得た。
LCMS (ESI) m/z 554 [M+H]+, tR = 0.78 min, mode H.
実施例3−44:N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}エチル]-N-メチル-2,3-ジヒドロ-1H-インデン-1-カルボキサミド 塩酸塩の合成
工程3−1−4及び工程3−1−1と同様の手法を用いて、工程3−1−3で得られた化合物(20 mg)及び2,3-ジヒドロ-1H-インデン-1-カルボン酸(10 mg)より表題化合物(27 mg, 無色固体)を得た。
LCMS (ESI) m/z 419 [M+H]+, tR = 0.92 min, mode H.
Example 3-43: N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidin-2-yl} ethyl Synthesis step 3-1-1 of] -N-methyl-1-{[(methylsulfonyl) acetyl] amino} -2,3-dihydro-1H-indene-1-carboxamide hydrochloride (single diastereomer) Using a similar procedure, tert-butyl [(3S) -1- {6-methyl-2-[(1S) -1- {methyl [(1-{[(methyl Sulfonyl) acetyl] amino} -2,3-dihydro-1H-inden-1-yl) carbonyl] amino} ethyl] pyrazolo [1,5-a] pyrimidin-5-yl} pyrrolidin-3-yl] carbamate The title compound (18 mg, colorless solid) was obtained from stereomer B (19 mg).
LCMS (ESI) m / z 554 [M + H] + , t R = 0.78 min, mode H.
Example 3-44: N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidin-2-yl} ethyl ] -N-methyl-2,3-dihydro-1H-indene-1-carboxamide hydrochloride Synthesis step 3-1-4 and step 3-1-1 The title compound (27 mg, colorless solid) was obtained from the compound obtained in (20 mg) and 2,3-dihydro-1H-indene-1-carboxylic acid (10 mg).
LCMS (ESI) m / z 419 [M + H] + , t R = 0.92 min, mode H.
実施例3−45:N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}エチル]-N-メチル-1-フェニルシクロプロパンカルボキサミド 塩酸塩の合成
工程3−1−4及び工程3−1−1と同様の手法を用いて、工程3−1−3で得られた化合物(25 mg)及び1-フェニル-1-シクロプロパンカルボン酸(13 mg)より表題化合物(34 mg, 無色固体)を得た。
LCMS (ESI) m/z 419 [M+H]+, tR = 0.93 min, mode H.
Example 3-45: N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidin-2-yl} ethyl ] -N-methyl-1-phenylcyclopropanecarboxamide hydrochloride The compound (25) obtained in Step 3-1-3 using the same method as in Step 3-1-4 and Step 3-1-1 mg) and 1-phenyl-1-cyclopropanecarboxylic acid (13 mg) gave the title compound (34 mg, colorless solid).
LCMS (ESI) m / z 419 [M + H] + , t R = 0.93 min, mode H.
実施例3−46:N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}エチル]-N,2-ジメチル-2-フェニルプロパンアミド 塩酸塩の合成
工程3−1−4及び工程3−1−1と同様の手法を用いて、工程3−1−3で得られた化合物(20 mg)及び2-フェニルイソ酪酸(12 mg)より表題化合物(24 mg, 無色固体)を得た。
LCMS (ESI) m/z 421 [M+H]+, tR = 0.96 min, mode H.
Example 3-46: N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidin-2-yl} ethyl ] -N, 2-dimethyl-2-phenylpropanamide hydrochloride The compound obtained in Step 3-1-3 using the same method as in Step 3-1-4 and Step 3-1-1 ( The title compound (24 mg, colorless solid) was obtained from 20 mg) and 2-phenylisobutyric acid (12 mg).
LCMS (ESI) m / z 421 [M + H] + , t R = 0.96 min, mode H.
実施例3−47:N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}エチル]-N-メチル-1-(3-メチルフェニル)シクロプロパンカルボキサミド 塩酸塩の合成
工程3−1−4及び工程3−1−1と同様の手法を用いて、工程3−1−3で得られた化合物(25 mg)及び1-(3-メチルフェニル)シクロプロパン-1-カルボン酸(18 mg)より表題化合物(17 mg, 無色固体)を得た。
LCMS (ESI) m/z 433 [M+H]+, tR = 0.98 min, mode H.
Example 3-47: N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidin-2-yl} ethyl ] -N-methyl-1- (3-methylphenyl) cyclopropanecarboxamide obtained in Step 3-1-3 using the same procedure as in Step 3-1-4 and Step 3-1-1 of hydrochloride The title compound (17 mg, colorless solid) was obtained from the obtained compound (25 mg) and 1- (3-methylphenyl) cyclopropane-1-carboxylic acid (18 mg).
LCMS (ESI) m / z 433 [M + H] + , t R = 0.98 min, mode H.
実施例3−48:N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}エチル]-1-(3-フルオロフェニル)-N-メチルシクロプロパンカルボキサミド 塩酸塩の合成
工程3−1−4及び工程3−1−1と同様の手法を用いて、工程3−1−3で得られた化合物(25 mg)及び1-(3-フルオロフェニル)シクロプロパン-1-カルボン酸(18 mg)より表題化合物(11 mg, 無色固体)を得た。
LCMS (ESI) m/z 437 [M+H]+, tR = 0.93 min, mode H.
Example 3-48: N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidin-2-yl} ethyl ] -1- (3-Fluorophenyl) -N-methylcyclopropanecarboxamide Obtained in Step 3-1-3 using the same method as in Synthesis Step 3-1-4 and Step 3-1-1 of hydrochloride The title compound (11 mg, colorless solid) was obtained from the obtained compound (25 mg) and 1- (3-fluorophenyl) cyclopropane-1-carboxylic acid (18 mg).
LCMS (ESI) m / z 437 [M + H] + , t R = 0.93 min, mode H.
実施例3−49:N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}プロピル]-N-メチル-5,6,7,8-テトラヒドロイミダゾ[1,2-a]ピリジン-8-カルボキサミド 塩酸塩の合成
工程3−1−4及び工程3−1−1と同様の手法を用いて、工程1−4−3で得られた化合物(30 mg)及び5,6,7,8-テトラヒドロイミダゾ[1,2-a]ピリジン-8-カルボン酸(29 mg)より表題化合物(25 mg, 無色固体)を得た。
LCMS (ESI) m/z 437 [M+H]+, tR = 0.49 min, mode H.
Example 3-49: N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidin-2-yl} propyl ] -N-Methyl-5,6,7,8-tetrahydroimidazo [1,2-a] pyridine-8-carboxamide Hydrochloric acid salt The same procedure as in Step 3-1-4 and Step 3-1-1 The title compound (30 mg) obtained from Step 1-4-3 and 5,6,7,8-tetrahydroimidazo [1,2-a] pyridine-8-carboxylic acid (29 mg) were used. 25 mg, a colorless solid) was obtained.
LCMS (ESI) m / z 437 [M + H] + , t R = 0.49 min, mode H.
実施例3−50:N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}エチル]-1-(エチルスルホニル)-N-メチル-4-フェニルピペリジン-4-カルボキサミド 塩酸塩の合成
工程3−29−1及び工程3−1−1と同様の手法を用いて、工程3−1−3で得られた化合物(40 mg)及び1-(エタンスルホニル)-4-フェニルピペリジン-4-カルボン酸(64 mg)より表題化合物(48 mg, 無色固体)を得た。
LCMS (ESI) m/z 554 [M+H]+, tR = 1.00 min, mode H.
Example 3-50: N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidin-2-yl} ethyl ] -1- (Ethylsulfonyl) -N-methyl-4-phenylpiperidine-4-carboxamide Hydrochloride Synthesis using the same method as in Step 3-29-1 and Step 3-1-1, Step 3-1 The title compound (48 mg, colorless solid) was obtained from the compound obtained in -3 (40 mg) and 1- (ethanesulfonyl) -4-phenylpiperidine-4-carboxylic acid (64 mg).
LCMS (ESI) m / z 554 [M + H] + , t R = 1.00 min, mode H.
実施例3−51:1-アセチル-N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}エチル]-N-メチル-4-フェニルピペリジン-4-カルボキサミド 塩酸塩の合成
工程3−29−1及び工程3−1−1と同様の手法を用いて、工程3−1−3で得られた化合物(42 mg)及び1-アセチル-4-フェニルピペリジン-4-カルボン酸(55 mg)より表題化合物(66 mg, 褐色アモルファス)を得た。
LCMS (ESI) m/z 504 [M+H]+, tR = 0.47 min, mode N.
Example 3-51: 1-acetyl-N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidine-2 -Il} ethyl] -N-methyl-4-phenylpiperidine-4-carboxamide Hydrochloride Synthesis in Step 3-1-3 using the same method as in Step 3-29-1 and Step 3-1-1 The title compound (66 mg, brown amorphous) was obtained from the obtained compound (42 mg) and 1-acetyl-4-phenylpiperidine-4-carboxylic acid (55 mg).
LCMS (ESI) m / z 504 [M + H] + , t R = 0.47 min, mode N.
実施例3−52:N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}エチル]-1-(3-クロロフェニル)-N-メチルシクロプロパンカルボキサミド 塩酸塩の合成
工程3−29−1及び工程3−1−1と同様の手法を用いて、工程3−1−3で得られた化合物(30 mg)及び1-(3-クロロフェニル)シクロプロパン-1-カルボン酸(32 mg)より表題化合物(51 mg, 桃色アモルファス)を得た。
LCMS (ESI) m/z 453 [M+H]+, tR = 0.57 min, mode N.
Example 3-52: N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidin-2-yl} ethyl ] -1- (3-Chlorophenyl) -N-methylcyclopropanecarboxamide Obtained in Step 3-1-3 using the same method as in Step 3-29-1 and Step 3-1-1 of hydrochloride The title compound (51 mg, pink amorphous) was obtained from the compound (30 mg) and 1- (3-chlorophenyl) cyclopropane-1-carboxylic acid (32 mg).
LCMS (ESI) m / z 453 [M + H] + , t R = 0.57 min, mode N.
実施例3−53:tert-ブチル 4-{[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}エチル](メチル)カルバモイル}-4-フェニルピペリジン-1-カルボキシラートの合成
工程3−29−1及び工程3−1−5と同様の手法を用いて、工程1−1−7で得られた化合物(50 mg)及び1-(tert-ブトキシカルボニル)-4-フェニルピペリジン-4-カルボン酸(0.13 g)より表題化合物(9.8 mg, 無色油状物)を得た。
LCMS (ESI) m/z 562 [M+H]+, tR = 0.67 min, mode H.
Example 3-53: tert-butyl 4-{[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidine-2 -Il} ethyl] (methyl) carbamoyl} -4-phenylpiperidine-1-carboxylate in Step 1-1-7 using the same procedure as in Steps 3-29-1 and 3-1-5 The title compound (9.8 mg, colorless oil) was obtained from the obtained compound (50 mg) and 1- (tert-butoxycarbonyl) -4-phenylpiperidine-4-carboxylic acid (0.13 g).
LCMS (ESI) m / z 562 [M + H] + , t R = 0.67 min, mode H.
実施例3−54:N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}エチル]-N-メチル-1-(メチルスルホニル)-4-フェニルピペリジン-4-カルボキサミド 塩酸塩の合成
工程3−54−1:工程3−29−1及び工程3−1−5と同様の手法を用いて、工程3−1−3で得られた化合物(240 mg)及び1-[(ベンジルオキシ)カルボニル]-4-フェニルピペリジン-4-カルボン酸(435 mg)よりtert-ブチル [(3S)-1-{6-メチル-2-[(1S)-1-{メチル[(4-フェニルピペリジン-4-イル)カルボニル]アミノ}エチル]ピラゾロ[1,5-a]ピリミジン-5-イル}ピロリジン-3-イル]カルバマート(155 mg, 無色アモルファス)を得た。
LCMS (ESI) m/z 562 [M+H]+, tR = 0.63 min, mode N.
工程3−54−2:工程3−1−6及び工程3−1−1と同様の手法を用いて、工程3−54−1で得られた化合物(20 mg)より表題化合物(31 mg, 無色アモルファス)を得た。
LCMS (ESI) m/z 540 [M+H]+, tR = 0.54 min, mode N.
Example 3-54: N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidin-2-yl} ethyl ] -N-Methyl-1- (methylsulfonyl) -4-phenylpiperidine-4-carboxamide Hydrochloride Synthesis Step 3-54-1: The same procedure as in Steps 3-29-1 and 3-1-5 is used. Tert-butyl [(3S) from the compound (240 mg) obtained in Step 3-1-3 and 1-[(benzyloxy) carbonyl] -4-phenylpiperidine-4-carboxylic acid (435 mg). -1- {6-methyl-2-[(1S) -1- {methyl [(4-phenylpiperidin-4-yl) carbonyl] amino} ethyl] pyrazolo [1,5-a] pyrimidin-5-yl} Pyrrolidin-3-yl] carbamate (155 mg, colorless amorphous) was obtained.
LCMS (ESI) m / z 562 [M + H] + , t R = 0.63 min, mode N.
Step 3-54-2: Using a method similar to that of Step 3-1-6 and Step 3-1-1, the title compound (31 mg, Colorless amorphous) was obtained.
LCMS (ESI) m / z 540 [M + H] + , t R = 0.54 min, mode N.
実施例3−55:N4-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}エチル]-N4-メチル-4-フェニルピペリジン-1,4-ジカルボキサミドの合成
工程3−55−1:工程3−54−1で得られた化合物(20 mg)のCHCl3(1 mL)溶液にトリメチルシリルイソシアネート(9.0 μL)を加え、室温で2日間攪拌した。反応液をCHCl3、水にて分液した。有機層をPhase Separatorにてろ過した。ろ液を減圧下濃縮し、tert-ブチル [(3S)-1-{2-[(1S)-1-{[(1-カルバモイル-4-フェニルピペリジン-4-イル)カルボニル](メチル)アミノ}エチル]-6-メチルピラゾロ[1,5-a]ピリミジン-5-イル}ピロリジン-3-イル]カルバマート(22 mg, 無色アモルファス)を得た。
LCMS (ESI) m/z 605 [M+H]+, tR = 0.91 min, mode N.
工程3−55−2:工程3−55−1で得られた化合物(22 mg)の1,4-ジオキサン(1 mL)溶液に4 M HCl/1,4-ジオキサン溶液(1 mL)を滴下して、室温にて24時間攪拌した。反応液を減圧下濃縮して得られた残渣を、NH型カラムクロマトグラフィー(移動相:CHCl3/MeOH = 100/0〜80/20; v/v)にて精製し、表題化合物(8.8 mg, 無色アモルファス)を得た。
LCMS (ESI) m/z 505 [M+H]+, tR = 0.41 min, mode N.
Example 3-55: N4-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidin-2-yl} ethyl ] -N4-Methyl-4-phenylpiperidine-1,4-dicarboxamide Step 3-55-1: To a solution of the compound obtained in Step 3-54-1 (20 mg) in CHCl 3 (1 mL) Trimethylsilyl isocyanate (9.0 μL) was added, and the mixture was stirred at room temperature for 2 days. The reaction solution was separated with CHCl 3 and water. The organic layer was filtered with a Phase Separator. The filtrate was concentrated under reduced pressure and tert-butyl [(3S) -1- {2-[(1S) -1-{[(1-carbamoyl-4-phenylpiperidin-4-yl) carbonyl] (methyl) amino } Ethyl] -6-methylpyrazolo [1,5-a] pyrimidin-5-yl} pyrrolidin-3-yl] carbamate (22 mg, colorless amorphous) was obtained.
LCMS (ESI) m / z 605 [M + H] + , t R = 0.91 min, mode N.
Step 3-55-2: 4 M HCl / 1,4-dioxane solution (1 mL) was added dropwise to a solution of the compound obtained in Step 3-55-1 (22 mg) in 1,4-dioxane (1 mL). The mixture was stirred at room temperature for 24 hours. The residue obtained by concentrating the reaction solution under reduced pressure was purified by NH column chromatography (mobile phase: CHCl 3 / MeOH = 100/0 to 80/20; v / v) to give the title compound (8.8 mg , Colorless amorphous).
LCMS (ESI) m / z 505 [M + H] + , t R = 0.41 min, mode N.
実施例3−56:N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}エチル]-1-カルバムイミドイル-N-メチル-4-フェニルピペリジン-4-カルボキサミドの合成
工程3−56−1:工程3−54−1で得られた化合物(20 mg)のEtOH(1 mL)溶液にシアナミド(7 mg)を加え、80 ℃にて2時間攪拌した。反応液にシアナミド(20 mg)を加え、80 ℃にて16時間攪拌した。反応液をろ過し、ろ液を減圧下濃縮し、得られた残渣をNH型シリカゲルカラムクロマトグラフィー (移動相:CHCl3/MeOH = 95/5; v/v)にて精製し、tert-ブチル [(3S)-1-{2-[(1S)-1-{[(1-カルバムイミドイル-4-フェニルピペリジン-4-イル)カルボニル](メチル)アミノ}エチル]-6-メチルピラゾロ[1,5-a]ピリミジン-5-イル}ピロリジン-3-イル]カルバマート(7.4 mg, 無色アモルファス)を得た。
LCMS (ESI) m/z 604 [M+H]+, tR = 0.69 min, mode N.
工程3−56−2:工程3−55−2と同様の手法を用いて、工程3−56−1で得られた化合物(7.4 mg)より表題化合物(5.1 mg, 無色アモルファス)を得た。
LCMS (ESI) m/z 504 [M+H]+, tR = 0.17 min, mode N.
Example 3-56: N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidin-2-yl} ethyl ] -1-Carbamimidoyl-N-methyl-4-phenylpiperidine-4-carboxamide Step 3-56-1: EtOH (1 mL) of the compound (20 mg) obtained in Step 3-54-1 ) Cyanamide (7 mg) was added to the solution and stirred at 80 ° C. for 2 hours. Cyanamide (20 mg) was added to the reaction solution, and the mixture was stirred at 80 ° C. for 16 hours. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by NH-type silica gel column chromatography (mobile phase: CHCl 3 / MeOH = 95/5; v / v) and tert-butyl. [(3S) -1- {2-[(1S) -1-{[(1-carbamimidoyl-4-phenylpiperidin-4-yl) carbonyl] (methyl) amino} ethyl] -6-methylpyrazolo [ 1,5-a] pyrimidin-5-yl} pyrrolidin-3-yl] carbamate (7.4 mg, colorless amorphous) was obtained.
LCMS (ESI) m / z 604 [M + H] + , t R = 0.69 min, mode N.
Step 3-56-2: The title compound (5.1 mg, colorless amorphous) was obtained from the compound (7.4 mg) obtained in Step 3-56-1 using the same method as in Step 3-55-2.
LCMS (ESI) m / z 504 [M + H] + , t R = 0.17 min, mode N.
実施例3−57:N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}エチル]-N-メチル-1-[(メチルスルホニル)アセチル]-3-フェニルピロリジン-3-カルボキサミド 塩酸塩の合成
工程3−57−1:工程3−1−4と同様の手法を用いて、工程3−1−3で得られた化合物(100 mg)及び文献(Tetrahedron Letters, 2005年, 46巻, 8463ページ)に記載の方法にて得られた1-[(ベンジルオキシ)カルボニル]-3-フェニルピロリジン-3-カルボン酸(130 mg)よりベンジル 3-{[(1S)-1-(5-{(3S)-3-[(tert-ブトキシカルボニル)アミノ]ピロリジン-1-イル}-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル)エチル](メチル)カルバモイル}-3-フェニルピロリジン-1-カルボキシラート(160 mg, 淡褐色アモルファス)を得た。
LCMS (ESI) m/z 682 [M+H]+, tR = 1.20 min, mode N.
工程3−57−2:工程3−1−5と同様の手法を用いて、工程3−57−1で得られた化合物(150 mg)よりtert-ブチル [(3S)-1-{6-メチル-2-[(1S)-1-{メチル[(3-フェニルピロリジン-3-イル)カルボニル]アミノ}エチル]ピラゾロ[1,5-a]ピリミジン-5-イル}ピロリジン-3-イル]カルバマート(92.1 mg, 無色アモルファス)を得た。
LCMS (ESI) m/z 548 [M+H]+, tR = 0.63 min, mode N.
工程3−57−3:実施例3−12と同様の手法を用いて、工程3−57−2で得られた化合物(23 mg)より表題化合物(22 mg, 無色固体)を得た。
1H NMR (600 MHz, DMSO-d6, δ): 0.76-1.42 (m, 3H), 1.98-2.07 (m, 1H), 2.16-3.18 (m, 9H), 2.32 (s, 3H), 3.29-3.91 (m, 9H), 4.25-4.47 (m, 2H), 5.49-5.98 (m, 2H), 7.23-7.48 (m, 5H), 8.16 (br s, 2H), 8.48 (s, 1H).
LCMS (ESI) m/z 568 [M+H]+, tR = 0.83 min, mode H.
Example 3-57: N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidin-2-yl} ethyl ] -N-methyl-1-[(methylsulfonyl) acetyl] -3-phenylpyrrolidine-3-carboxamide hydrochloride synthesis step 3-57-1: using the same method as in step 3-1-4, The compound (100 mg) obtained in 3-1-3 and 1-[(benzyloxy) carbonyl] -3- obtained by the method described in the literature (Tetrahedron Letters, 2005, 46, 8463) Benzyl 3-{[(1S) -1- (5-{(3S) -3-[(tert-butoxycarbonyl) amino] pyrrolidin-1-yl} -6 from phenylpyrrolidine-3-carboxylic acid (130 mg) -Methylpyrazolo [1,5-a] pyrimidin-2-yl) ethyl] (methyl) carbamoyl} -3-phenylpyrrolidine-1-carboxylate (160 mg, light brown amorphous) was obtained.
LCMS (ESI) m / z 682 [M + H] + , t R = 1.20 min, mode N.
Step 3-57-2: Using a method similar to that of Step 3-1-5, tert-butyl [(3S) -1- {6- Methyl-2-[(1S) -1- {methyl [(3-phenylpyrrolidin-3-yl) carbonyl] amino} ethyl] pyrazolo [1,5-a] pyrimidin-5-yl} pyrrolidin-3-yl] Carbamate (92.1 mg, colorless amorphous) was obtained.
LCMS (ESI) m / z 548 [M + H] + , t R = 0.63 min, mode N.
Step 3-57-3: The title compound (22 mg, colorless solid) was obtained from the compound (23 mg) obtained in Step 3-57-2 using the same method as in Example 3-12.
1 H NMR (600 MHz, DMSO-d 6 , δ): 0.76-1.42 (m, 3H), 1.98-2.07 (m, 1H), 2.16-3.18 (m, 9H), 2.32 (s, 3H), 3.29 -3.91 (m, 9H), 4.25-4.47 (m, 2H), 5.49-5.98 (m, 2H), 7.23-7.48 (m, 5H), 8.16 (br s, 2H), 8.48 (s, 1H).
LCMS (ESI) m / z 568 [M + H] + , t R = 0.83 min, mode H.
実施例3−58:ベンジル 3-{[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}エチル](メチル)カルバモイル}-3-フェニルピロリジン-1-カルボキシラート 塩酸塩の合成
工程3−1−1と同様の手法を用いて、工程3−57−1で得られた化合物(13.7 mg)より表題化合物(13.0 mg, 無色固体)を得た。
LCMS (ESI) m/z 582 [M+H]+, tR = 1.16, 1.18 min, mode H.
Example 3-58: benzyl 3-{[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidin-2-yl } Ethyl] (methyl) carbamoyl} -3-phenylpyrrolidine-1-carboxylate The compound obtained in Step 3-57-1 (13.7 mg) using the same method as in Synthesis Step 3-1-1 of hydrochloride ) Afforded the title compound (13.0 mg, colorless solid).
LCMS (ESI) m / z 582 [M + H] + , t R = 1.16, 1.18 min, mode H.
実施例3−59:N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}エチル]-N-メチル-1-(メチルスルホニル)-3-フェニルピロリジン-3-カルボキサミド 塩酸塩の合成
工程3−59−1:工程3−57−2で得られた化合物(20 mg)のCHCl3(1 mL)溶液に氷冷下、Et3N(20 μL)、メタンスルホン酸無水物(8.0 mg)を加え、同温にて1時間攪拌した。反応液をCHCl3、飽和NaHCO3水溶液にて分液し、水層をCHCl3にて抽出した。有機層をPhase Separatorにてろ過した。ろ液を減圧下濃縮し、得られた残渣をOH型シリカゲルカラムクロマトグラフィー (移動相:ヘキサン/EtOAc = 95/5〜0/100〜EtOAc/MeOH = 100/0〜90/10; v/v)にて精製し、tert-ブチル [(3S)-1-{6-メチル-2-[(1S)-1-(メチル{[1-(メチルスルホニル)-3-フェニルピロリジン-3-イル]カルボニル}アミノ)エチル]ピラゾロ[1,5-a]ピリミジン-5-イル}ピロリジン-3-イル]カルバマート(23 mg, 無色アモルファス)を得た。
LCMS (ESI) m/z 626 [M+H]+, tR = 1.02 min, mode N.
工程3−59−2:工程3−1−1と同様の手法を用いて、工程3−59−1で得られた化合物(22.5 mg)より表題化合物(22.4 mg, 無色固体)を得た。
LCMS (ESI) m/z 526 [M+H]+, tR = 0.90 min, mode H.
Example 3-59: N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidin-2-yl} ethyl ] -N-Methyl-1- (methylsulfonyl) -3-phenylpyrrolidine-3-carboxamide Hydrochloride Synthesis Step 3-59-1: CHCl 3 of the compound (20 mg) obtained in Step 3-57-2 To the (1 mL) solution, Et 3 N (20 μL) and methanesulfonic anhydride (8.0 mg) were added under ice-cooling, and the mixture was stirred at the same temperature for 1 hour. The reaction solution was partitioned between CHCl 3 and saturated NaHCO 3 aqueous solution, and the aqueous layer was extracted with CHCl 3 . The organic layer was filtered with a Phase Separator. The filtrate was concentrated under reduced pressure, and the obtained residue was subjected to OH-type silica gel column chromatography (mobile phase: hexane / EtOAc = 95/5 to 0/100 to EtOAc / MeOH = 100/0 to 90/10; v / v ) Tert-butyl [(3S) -1- {6-methyl-2-[(1S) -1- (methyl {[1- (methylsulfonyl) -3-phenylpyrrolidin-3-yl] Carbonyl} amino) ethyl] pyrazolo [1,5-a] pyrimidin-5-yl} pyrrolidin-3-yl] carbamate (23 mg, colorless amorphous) was obtained.
LCMS (ESI) m / z 626 [M + H] + , t R = 1.02 min, mode N.
Step 3-59-2: The title compound (22.4 mg, colorless solid) was obtained from the compound (22.5 mg) obtained in Step 3-59-1 using the same method as in Step 3-1-1.
LCMS (ESI) m / z 526 [M + H] + , t R = 0.90 min, mode H.
実施例3−60:N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}エチル]-1-(エチルスルホニル)-N-メチル-3-フェニルピロリジン-3-カルボキサミド 塩酸塩の合成
工程3−1−6及び工程3−1−1と同様の手法を用いて、工程3−57−2で得られた化合物(20 mg)及びエタンスルホニルクロリド(4.5 μL)より表題化合物(20 mg, 無色固体)を得た。
LCMS (ESI) m/z 540 [M+H]+, tR = 0.94 min, mode H.
Example 3-60: N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidin-2-yl} ethyl ] -3- (Ethylsulfonyl) -N-methyl-3-phenylpyrrolidine-3-carboxamide Hydrochloride Synthesis Step 3-1-6 and Step 3-1-1 were performed in the same manner as in Step 3-57. The title compound (20 mg, colorless solid) was obtained from the compound obtained in -2 (20 mg) and ethanesulfonyl chloride (4.5 μL).
LCMS (ESI) m / z 540 [M + H] + , t R = 0.94 min, mode H.
実施例3−61:N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}エチル]-N-メチル-4-オキソ-1-フェニルシクロヘキサンカルボキサミドの合成
工程3−61−1:工程3−29−1と同様の手法を用いて、工程3−1−3で得られた化合物(100 mg)及び4-オキソ-1-フェニルシクロヘキサンカルボン酸(117 mg)よりtert-ブチル [(3S)-1-{6-メチル-2-[(1S)-1-{メチル[(4-オキソ-1-フェニルシクロヘキシル)カルボニル]アミノ}エチル]ピラゾロ[1,5-a]ピリミジン-5-イル}ピロリジン-3-イル]カルバマート(94.0 mg, 淡黄色アモルファス)を得た。
LCMS (ESI) m/z 575 [M+H]+, tR = 1.07 min, mode N.
工程3−61−2:工程3−33−2と同様の手法を用いて、工程3−61−1で得られた化合物(18 mg)より表題化合物(14 mg, 淡黄色アモルファス)を得た。
LCMS (ESI) m/z 475 [M+H]+, tR = 0.52 min, mode N.
Example 3-61: N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidin-2-yl} ethyl ] -N-methyl-4-oxo-1-phenylcyclohexanecarboxamide synthesis step 3-61-1: Using a method similar to that in step 3-29-1, the compound obtained in step 3-1-3 ( 100 mg) and 4-oxo-1-phenylcyclohexanecarboxylic acid (117 mg) from tert-butyl [(3S) -1- {6-methyl-2-[(1S) -1- {methyl [(4-oxo 1-Phenylcyclohexyl) carbonyl] amino} ethyl] pyrazolo [1,5-a] pyrimidin-5-yl} pyrrolidin-3-yl] carbamate (94.0 mg, pale yellow amorphous) was obtained.
LCMS (ESI) m / z 575 [M + H] + , t R = 1.07 min, mode N.
Step 3-61-2: Using the same method as in Step 3-33-2, the title compound (14 mg, pale yellow amorphous) was obtained from the compound (18 mg) obtained in Step 3-61-1. .
LCMS (ESI) m / z 475 [M + H] + , t R = 0.52 min, mode N.
実施例3−62:trans-N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}エチル]-4-ヒドロキシ-N-メチル-1-フェニルシクロヘキサンカルボキサミド 塩酸塩の合成
工程3−62−1:工程3−61−1で得られた化合物(300 mg)のMeOH(5 mL)溶液に、水素化ホウ素ナトリウム(30 mg)を加え、室温にて3時間攪拌した。反応液に氷冷下、水を加え、CHCl3を加えて分液した。有機層をPhase Separatorにてろ過した。ろ液を減圧下濃縮し、得られた残渣をNH型シリカゲルカラムクロマトグラフィー (移動相:ヘキサン/EtOAc = 50/50〜30/70; v/v)にて精製し、tert-ブチル [(3S)-1-{2-[(1S)-1-{[(trans-4-ヒドロキシ-1-フェニルシクロヘキシル)カルボニル](メチル)アミノ}エチル]-6-メチルピラゾロ[1,5-a]ピリミジン-5-イル}ピロリジン-3-イル]カルバマート(24.6 mg, 無色アモルファス)及びtert-ブチル [(3S)-1-{2-[(1S)-1-{[(cis-4-ヒドロキシ-1-フェニルシクロヘキシル)カルボニル](メチル)アミノ}エチル]-6-メチルピラゾロ[1,5-a]ピリミジン-5-イル}ピロリジン-3-イル]カルバマート(174 mg, 無色アモルファス)を得た。
tert-ブチル [(3S)-1-{2-[(1S)-1-{[(trans-4-ヒドロキシ-1-フェニルシクロヘキシル)カルボニル](メチル)アミノ}エチル]-6-メチルピラゾロ[1,5-a]ピリミジン-5-イル}ピロリジン-3-イル]カルバマート:LCMS (ESI) m/z 577 [M+H]+, tR = 0.94 min, mode N.
tert-ブチル [(3S)-1-{2-[(1S)-1-{[(cis-4-ヒドロキシ-1-フェニルシクロヘキシル)カルボニル](メチル)アミノ}エチル]-6-メチルピラゾロ[1,5-a]ピリミジン-5-イル}ピロリジン-3-イル]カルバマート:LCMS (ESI) m/z 577 [M+H]+, tR = 1.01 min, mode N.
工程3−62−2:工程3−1−1と同様の手法を用いて、工程3−62−1で得られたtert-ブチル [(3S)-1-{2-[(1S)-1-{[(trans-4-ヒドロキシ-1-フェニルシクロヘキシル)カルボニル](メチル)アミノ}エチル]-6-メチルピラゾロ[1,5-a]ピリミジン-5-イル}ピロリジン-3-イル]カルバマート(6.0 mg)より表題化合物(2.4 mg, 無色固体)を得た。
LCMS (ESI) m/z 477 [M+H]+, tR = 0.44 min, mode N.
Example 3-62: trans-N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidin-2-yl } Ethyl] -4-hydroxy-N-methyl-1-phenylcyclohexanecarboxamide Hydrochloride Synthesis Step 3-62-1: A solution of the compound obtained in Step 3-61-1 (300 mg) in MeOH (5 mL) Was added with sodium borohydride (30 mg), and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction solution under ice cooling, and CHCl 3 was added to separate the layers. The organic layer was filtered with a Phase Separator. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by NH-type silica gel column chromatography (mobile phase: hexane / EtOAc = 50 / 50-30 / 70; v / v), and tert-butyl [(3S ) -1- {2-[(1S) -1-{[(trans-4-hydroxy-1-phenylcyclohexyl) carbonyl] (methyl) amino} ethyl] -6-methylpyrazolo [1,5-a] pyrimidine- 5-yl} pyrrolidin-3-yl] carbamate (24.6 mg, colorless amorphous) and tert-butyl [(3S) -1- {2-[(1S) -1-{[(cis-4-hydroxy-1- Phenylcyclohexyl) carbonyl] (methyl) amino} ethyl] -6-methylpyrazolo [1,5-a] pyrimidin-5-yl} pyrrolidin-3-yl] carbamate (174 mg, colorless amorphous) was obtained.
tert-butyl [(3S) -1- {2-[(1S) -1-{[(trans-4-hydroxy-1-phenylcyclohexyl) carbonyl] (methyl) amino} ethyl] -6-methylpyrazolo [1, 5-a] pyrimidin-5-yl} pyrrolidin-3-yl] carbamate: LCMS (ESI) m / z 577 [M + H] + , t R = 0.94 min, mode N.
tert-butyl [(3S) -1- {2-[(1S) -1-{[(cis-4-hydroxy-1-phenylcyclohexyl) carbonyl] (methyl) amino} ethyl] -6-methylpyrazolo [1, 5-a] pyrimidin-5-yl} pyrrolidin-3-yl] carbamate: LCMS (ESI) m / z 577 [M + H] + , t R = 1.01 min, mode N.
Step 3-62-2: Using a method similar to that of Step 3-1-1, tert-butyl [(3S) -1- {2-[(1S) -1] obtained in Step 3-62-1 was used. -{[(trans-4-hydroxy-1-phenylcyclohexyl) carbonyl] (methyl) amino} ethyl] -6-methylpyrazolo [1,5-a] pyrimidin-5-yl} pyrrolidin-3-yl] carbamate (6.0 mg) gave the title compound (2.4 mg, colorless solid).
LCMS (ESI) m / z 477 [M + H] + , t R = 0.44 min, mode N.
実施例3−63:cis-N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}エチル]-4-ヒドロキシ-N-メチル-1-フェニルシクロヘキサンカルボキサミド 塩酸塩の合成
工程3−1−1と同様の手法を用いて、工程3−62−1で得られたtert-ブチル [(3S)-1-{2-[(1S)-1-{[(cis-4-ヒドロキシ-1-フェニルシクロヘキシル)カルボニル](メチル)アミノ}エチル]-6-メチルピラゾロ[1,5-a]ピリミジン-5-イル}ピロリジン-3-イル]カルバマート(15.0 mg)より表題化合物(10.9 mg, 無色固体)を得た。
LCMS (ESI) m/z 477 [M+H]+, tR = 0.51 min, mode N.
Example 3-63: cis-N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidin-2-yl } Ethyl] -4-hydroxy-N-methyl-1-phenylcyclohexanecarboxamide hydrochloride Using the same method as in Synthesis step 3-1-1, tert-butyl obtained in step 3-62-1 [( 3S) -1- {2-[(1S) -1-{[(cis-4-hydroxy-1-phenylcyclohexyl) carbonyl] (methyl) amino} ethyl] -6-methylpyrazolo [1,5-a] pyrimidine The title compound (10.9 mg, colorless solid) was obtained from -5-yl} pyrrolidin-3-yl] carbamate (15.0 mg).
LCMS (ESI) m / z 477 [M + H] + , t R = 0.51 min, mode N.
実施例3−64:N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}エチル]-N-メチル-4-[(メチルスルホニル)アミノ]-1-フェニルシクロヘキサンカルボキサミド 塩酸塩の合成
工程3−64−1:工程3−61−1で得られた化合物(100 mg)のMeOH/CHCl3混合溶液(2 mL, 1/1; v/v)に、酢酸アンモニウム(268 mg)を加え、室温にて30分間攪拌した。反応液にシアノ水素化ホウ素ナトリウム(17 mg)を加え、室温にて16時間攪拌した。反応液に、飽和NaHCO3水溶液を加え、CHCl3を加えて分液した。有機層を減圧下濃縮し、得られた残渣をNH型シリカゲルカラムクロマトグラフィー(移動相:ヘキサン/EtOAc = 80/20〜0/100; v/v)にて精製し、tert-ブチル [(3S)-1-{2-[(1S)-1-{[(4-アミノ-1-フェニルシクロヘキシル)カルボニル](メチル)アミノ}エチル]-6-メチルピラゾロ[1,5-a]ピリミジン-5-イル}ピロリジン-3-イル]カルバマート(71 mg, 無色アモルファス)を得た。
LCMS (ESI) m/z 576 [M+H]+, tR = 0.65, 0.69 min, mode N.
工程3−64−2:工程3−1−6及び工程3−1−1と同様の手法を用いて、工程3−64−1で得られた化合物(35 mg)より表題化合物(14 mg, 無色固体)を得た。
LCMS (ESI) m/z 554 [M+H]+, tR = 0.50, 0.56 min, mode N.
Example 3-64: N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidin-2-yl} ethyl ] -N-Methyl-4-[(methylsulfonyl) amino] -1-phenylcyclohexanecarboxamide Hydrochloride Synthesis Step 3-64-1: Compound (100 mg) obtained in Step 3-61-1 in MeOH / Ammonium acetate (268 mg) was added to a CHCl 3 mixed solution (2 mL, 1/1; v / v), and the mixture was stirred at room temperature for 30 minutes. Sodium cyanoborohydride (17 mg) was added to the reaction solution, and the mixture was stirred at room temperature for 16 hours. A saturated aqueous NaHCO 3 solution was added to the reaction solution, and CHCl 3 was added to separate the layers. The organic layer was concentrated under reduced pressure, and the obtained residue was purified by NH-type silica gel column chromatography (mobile phase: hexane / EtOAc = 80 / 20-0 / 100; v / v) to obtain tert-butyl [(3S ) -1- {2-[(1S) -1-{[(4-Amino-1-phenylcyclohexyl) carbonyl] (methyl) amino} ethyl] -6-methylpyrazolo [1,5-a] pyrimidine-5- Ir} pyrrolidin-3-yl] carbamate (71 mg, colorless amorphous) was obtained.
LCMS (ESI) m / z 576 [M + H] + , t R = 0.65, 0.69 min, mode N.
Step 3-64-2: Using a method similar to that of Step 3-1-6 and Step 3-1-1, the title compound (14 mg, A colorless solid was obtained.
LCMS (ESI) m / z 554 [M + H] + , t R = 0.50, 0.56 min, mode N.
実施例3−65:N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}エチル]-N-メチル-4-[(メチルスルホニル)アミノ]-1-フェニルシクロヘキサンカルボキサミド 塩酸塩(単一ジアステレオマー)の合成
工程3−65−1:工程3−64−1で得られた化合物(15 mg)とメタンスルホニル酢酸(5 mg)のDMF(1 mL)溶液にHATU(20 mg)、Et3N(22 μL) を加え、60 ℃にて2時間攪拌した。反応液に水を加え、攪拌後、EtOAcにて抽出した。有機層を減圧下濃縮して、得られた残渣をOH型シリカゲルカラムクロマトグラフィー (移動相:ヘキサン/EtOAc = 90/10〜0/100; v/v)にて精製し、tert-ブチル [(3S)-1-{6-メチル-2-[(1S)-1-{メチル[(4-{[(メチルスルホニル)アセチル]アミノ}-1-フェニルシクロヘキシル)カルボニル]アミノ}エチル]ピラゾロ[1,5-a]ピリミジン-5-イル}ピロリジン-3-イル]カルバマートのジアステレオマーA(15 mg, 無色アモルファス)及びジアステレオマーB(2.7 mg, 無色アモルファス)を得た。
ジアステレオマーA:LCMS (ESI) m/z 696 [M+H]+, tR = 1.18 min, mode N.
ジアステレオマーB:LCMS (ESI) m/z 696 [M+H]+, tR = 1.13 min, mode N.
工程3−65−2:工程3−1−1と同様の手法を用いて、工程3−65−1で得られたtert-ブチル [(3S)-1-{6-メチル-2-[(1S)-1-{メチル[(4-{[(メチルスルホニル)アセチル]アミノ}-1-フェニルシクロヘキシル)カルボニル]アミノ}エチル]ピラゾロ[1,5-a]ピリミジン-5-イル}ピロリジン-3-イル]カルバマートのジアステレオマーA(15 mg)より表題化合物(5.7 mg, 無色固体)を得た。
LCMS (ESI) m/z 596 [M+H]+, tR = 0.50 min, mode N.
Example 3-65: N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidin-2-yl} ethyl ] -N-methyl-4-[(methylsulfonyl) amino] -1-phenylcyclohexanecarboxamide hydrochloride (single diastereomer) synthesis step 3-65-1: compound obtained in step 3-64-1 HATU (20 mg) and Et 3 N (22 μL) were added to a DMF (1 mL) solution of (15 mg) and methanesulfonylacetic acid (5 mg), and the mixture was stirred at 60 ° C. for 2 hours. Water was added to the reaction mixture, and the mixture was stirred and extracted with EtOAc. The organic layer was concentrated under reduced pressure, and the obtained residue was purified by OH-type silica gel column chromatography (mobile phase: hexane / EtOAc = 90/10 to 0/100; v / v) to obtain tert-butyl [( 3S) -1- {6-methyl-2-[(1S) -1- {methyl [(4-{[(methylsulfonyl) acetyl] amino} -1-phenylcyclohexyl) carbonyl] amino} ethyl] pyrazolo [1 , 5-a] pyrimidin-5-yl} pyrrolidin-3-yl] carbamate diastereomer A (15 mg, colorless amorphous) and diastereomer B (2.7 mg, colorless amorphous) were obtained.
Diastereomer A: LCMS (ESI) m / z 696 [M + H] + , t R = 1.18 min, mode N.
Diastereomer B: LCMS (ESI) m / z 696 [M + H] + , t R = 1.13 min, mode N.
Step 3-65-2: Using a method similar to that of Step 3-1-1, tert-butyl [(3S) -1- {6-methyl-2-[( 1S) -1- {Methyl [(4-{[(methylsulfonyl) acetyl] amino} -1-phenylcyclohexyl) carbonyl] amino} ethyl] pyrazolo [1,5-a] pyrimidin-5-yl} pyrrolidine-3 The title compound (5.7 mg, colorless solid) was obtained from diastereomer A (15 mg) of -yl] carbamate.
LCMS (ESI) m / z 596 [M + H] + , t R = 0.50 min, mode N.
実施例3−66:N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}エチル]-N-メチル-4-{[(メチルスルホニル)アセチル]アミノ}-1-フェニルシクロヘキサンカルボキサミド 塩酸塩(単一ジアステレオマー)の合成
工程3−1−1と同様の手法を用いて、工程3−65−1で得られたtert-ブチル [(3S)-1-{6-メチル-2-[(1S)-1-{メチル[(4-{[(メチルスルホニル)アセチル]アミノ}-1-フェニルシクロヘキシル)カルボニル]アミノ}エチル]ピラゾロ[1,5-a]ピリミジン-5-イル}ピロリジン-3-イル]カルバマートのジアステレオマーB(3 mg)より表題化合物(0.6 mg, 無色固体)を得た。
LCMS (ESI) m/z 596 [M+H]+, tR = 0.45 min, mode N.
Example 3-66: N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidin-2-yl} ethyl ] -N-Methyl-4-{[(methylsulfonyl) acetyl] amino} -1-phenylcyclohexanecarboxamide hydrochloride (single diastereomer) synthesis step 3-1-1 using the same procedure Tert-butyl [(3S) -1- {6-methyl-2-[(1S) -1- {methyl [(4-{[(methylsulfonyl) acetyl] amino}-] obtained from 3-65-1 1-Phenylcyclohexyl) carbonyl] amino} ethyl] pyrazolo [1,5-a] pyrimidin-5-yl} pyrrolidin-3-yl] carbamate diastereomer B (3 mg), title compound (0.6 mg, colorless solid) )
LCMS (ESI) m / z 596 [M + H] + , t R = 0.45 min, mode N.
実施例3−67:ベンジル 3-{[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}エチル](メチル)カルバモイル}-3-フェニルアゼチジン-1-カルボキシラートの合成
工程3−1−4及び工程3−33−2と同様の手法を用いて、工程3−1−3(17 mg)で得られた化合物及び1-[(ベンジルオキシ)カルボニル]-3-フェニルアゼチジン-3-カルボン酸(14 mg)より表題化合物(4.4 mg, 無色固体)を得た。
LCMS (ESI) m/z 568 [M+H]+, tR = 1.18 min, mode N.
Example 3-67: benzyl 3-{[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidin-2-yl } Ethyl] (methyl) carbamoyl} -3-phenylazetidine-1-carboxylate Synthesis Step 3-1-3 (17 mg) and the 1-[(benzyloxy) carbonyl] -3-phenylazetidine-3-carboxylic acid (14 mg) to give the title compound (4.4 mg, colorless solid).
LCMS (ESI) m / z 568 [M + H] + , t R = 1.18 min, mode N.
実施例3−68:N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}エチル]-N-メチル-3-オキソ-1-フェニルシクロブタンカルボキサミドの合成
工程3−68−1:工程3−29−1と同様の手法を用いて、工程3−1−3で得られた化合物(0.10 g)及び3-オキソ-1-フェニルシクロブタン-1-カルボン酸(61 mg)よりtert-ブチル [(3S)-1-{6-メチル-2-[(1S)-1-{メチル[(3-オキソ-1-フェニルシクロブチル)カルボニル]アミノ}エチル]ピラゾロ[1,5-a]ピリミジン-5-イル}ピロリジン-3-イル]カルバマート(0.15 g, 淡黄色アモルファス)を得た。
LCMS (ESI) m/z 547 [M+H]+, tR = 1.04 min, mode N.
工程3−68−2:工程3−33−2と同様の手法を用いて、工程3−68−1で得られた化合物(20.6 mg)より表題化合物(14.9 mg, 無色固体)を得た。
LCMS (ESI) m/z 447 [M+H]+, tR = 0.48 min, mode N.
Example 3-68: N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidin-2-yl} ethyl ] -N-Methyl-3-oxo-1-phenylcyclobutanecarboxamide synthesis step 3-68-1: Using a method similar to that in step 3-29-1, the compound obtained in step 3-1-3 ( 0.10 g) and 3-oxo-1-phenylcyclobutane-1-carboxylic acid (61 mg), tert-butyl [(3S) -1- {6-methyl-2-[(1S) -1- {methyl [( 3-Oxo-1-phenylcyclobutyl) carbonyl] amino} ethyl] pyrazolo [1,5-a] pyrimidin-5-yl} pyrrolidin-3-yl] carbamate (0.15 g, pale yellow amorphous) was obtained.
LCMS (ESI) m / z 547 [M + H] + , t R = 1.04 min, mode N.
Step 3-68-2: The title compound (14.9 mg, colorless solid) was obtained from the compound (20.6 mg) obtained in Step 3-68-1 using the same method as in Step 3-33-2.
LCMS (ESI) m / z 447 [M + H] + , t R = 0.48 min, mode N.
実施例3−69:N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}エチル]-3-ヒドロキシ-N-メチル-1-フェニルシクロブタンカルボキサミド 塩酸塩の合成
工程3−64−1及び工程3−1−1と同様の手法を用いて、工程3−68−1で得られた化合物(130 mg)より表題化合物(12.5 mg, 無色固体)を得た。
LCMS (ESI) m/z 449 [M+H]+, tR = 0.39 min, mode N.
Example 3-69: N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidin-2-yl} ethyl ] -3-Hydroxy-N-methyl-1-phenylcyclobutanecarboxamide obtained in Step 3-68-1 using the same method as in Step 3-64-1 and Step 3-1-1 of hydrochloride The title compound (12.5 mg, colorless solid) was obtained from the compound (130 mg).
LCMS (ESI) m / z 449 [M + H] + , t R = 0.39 min, mode N.
実施例3−70:N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}エチル]-N-メチル-1-{[(メチルスルホニル)アセチル]アミノ}-1,2,3,4-テトラヒドロナフタレン-1-カルボキサミド 塩酸塩の合成
工程3−70−1:工程3−1−3で得られた化合物(81 mg)と参考例10で得られた化合物(59 mg)のDMF(1 mL)溶液にHATU(137 mg)、Et3N(0.15 mL) を加え、60 ℃にて6時間攪拌した。反応液に水を加え、攪拌後、EtOAcにて抽出した。有機層を減圧下濃縮して、得られた残渣をOH型シリカゲルカラムクロマトグラフィー (移動相:ヘキサン/EtOAc = 90/10〜0/100; v/v)にて精製し、ベンジル (1-{[(1S)-1-(5-{(3S)-3-[(tert-ブトキシカルボニル)アミノ]ピロリジン-1-イル}-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル)エチル](メチル)カルバモイル}-1,2,3,4-テトラヒドロナフタレン-1-イル)カルバマート(24 mg, 淡黄色アモルファス)を得た。
LCMS (ESI) m/z 682 [M+H]+, tR = 1.27 min, mode N.
工程3−70−2:工程3−70−1で得られた化合物(24 mg)のMeOH(1 mL)溶液に10%パラジウム-炭素(12 mg)を加え、水素雰囲気下、室温にて2時間攪拌した。反応液をセライト(登録商標)ろ過後、ろ液を減圧下濃縮し、得られた残渣をNH型シリカゲルカラムクロマトグラフィー (移動相:ヘキサン/EtOAc = 80/20〜0/100; v/v)にて精製し、tert-ブチル [(3S)-1-{2-[(1S)-1-{[(1-アミノ-1,2,3,4-テトラヒドロナフタレン-1-イル)カルボニル](メチル)アミノ}エチル]-6-メチルピラゾロ[1,5-a]ピリミジン-5-イル}ピロリジン-3-イル]カルバマート(8.8 mg, 無色アモルファス)を得た。
LCMS (ESI) m/z 548 [M+H]+, tR = 0.66 min, mode N.
工程3−70−3:工程3−70−2で得られた化合物(8.8 mg)とメタンスルホニル酢酸(4.0 mg)のDMF(1 mL)溶液にHATU(12 mg)、Et3N(14 μL) を加え、60 ℃にて1.5時間攪拌した。反応液に水を加え、攪拌後、EtOAcにて抽出した。有機層を減圧下濃縮して、得られた残渣をOH型シリカゲルカラムクロマトグラフィー (移動相:ヘキサン/EtOAc = 90/10〜0/100; v/v)にて精製し、tert-ブチル [(3S)-1-{6-メチル-2-[(1S)-1-{メチル[(1-{[(メチルスルホニル)アセチル]アミノ}-1,2,3,4-テトラヒドロナフタレン-1-イル)カルボニル]アミノ}エチル]ピラゾロ[1,5-a]ピリミジン-5-イル}ピロリジン-3-イル]カルバマート(9.7 mg, 無色アモルファス)を得た。
LCMS (ESI) m/z 668 [M+H]+, tR = 1.00 min, mode N.
工程3−70−4:工程3−70−3で得られた化合物(9.7 mg)の1,4-ジオキサン(1 mL)溶液に4 M HCl/1,4-ジオキサン溶液(1 mL)を滴下し、室温にて2時間攪拌した。反応液をろ過し、濾取した固体を減圧下乾燥し、表題化合物(6.6 mg, 無色固体)を得た。
1H NMR (600 MHz, DMSO-d6, δ): 1.33-1.49 (m, 3H), 1.71-1.82 (m, 1H), 1.89-2.01 (m, 1H), 2.02-2.09 (m, 1H), 2.19-2.29 (m, 1H), 2.31-3.13 (m, 13H), 3.65-3.94 (m, 5H), 4.18 (s, 2H), 4.62-4.76 (m, 0.5H), 5.78-5.99 (m, 1.5H), 7.06-7.33 (m, 4H), 8.22 (br s, 3H), 8.38-8.54 (m, 1H).
LCMS (ESI) m/z 568 [M+H]+, tR = 0.47 min, mode N.
Example 3-70: N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidin-2-yl} ethyl ] -N-Methyl-1-{[(methylsulfonyl) acetyl] amino} -1,2,3,4-tetrahydronaphthalene-1-carboxamide Hydrochloride Synthesis Step 3-70-1: Step 3-1-3 HATU (137 mg) and Et 3 N (0.15 mL) were added to a DMF (1 mL) solution of the compound (81 mg) obtained in Example 10 and the compound (59 mg) obtained in Reference Example 10 at 60 ° C. Stir for 6 hours. Water was added to the reaction mixture, and the mixture was stirred and extracted with EtOAc. The organic layer was concentrated under reduced pressure, and the resulting residue was purified by OH-type silica gel column chromatography (mobile phase: hexane / EtOAc = 90/10 to 0/100; v / v) to obtain benzyl (1- { [(1S) -1- (5-{(3S) -3-[(tert-butoxycarbonyl) amino] pyrrolidin-1-yl} -6-methylpyrazolo [1,5-a] pyrimidin-2-yl) ethyl ] (Methyl) carbamoyl} -1,2,3,4-tetrahydronaphthalen-1-yl) carbamate (24 mg, pale yellow amorphous) was obtained.
LCMS (ESI) m / z 682 [M + H] + , t R = 1.27 min, mode N.
Step 3-70-2: 10% palladium-carbon (12 mg) was added to a solution of the compound obtained in Step 3-70-1 (24 mg) in MeOH (1 mL) and added at room temperature under a hydrogen atmosphere at room temperature. Stir for hours. The reaction mixture was filtered through Celite (registered trademark), and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to NH silica gel column chromatography (mobile phase: hexane / EtOAc = 80 / 20-0 / 100; v / v) Tert-butyl [(3S) -1- {2-[(1S) -1-{[(1-amino-1,2,3,4-tetrahydronaphthalen-1-yl) carbonyl] ( Methyl) amino} ethyl] -6-methylpyrazolo [1,5-a] pyrimidin-5-yl} pyrrolidin-3-yl] carbamate (8.8 mg, colorless amorphous) was obtained.
LCMS (ESI) m / z 548 [M + H] + , t R = 0.66 min, mode N.
Step 3-70-3: To a solution of the compound obtained in Step 3-70-2 (8.8 mg) and methanesulfonylacetic acid (4.0 mg) in DMF (1 mL), HATU (12 mg), Et 3 N (14 μL ) Was added and stirred at 60 ° C. for 1.5 hours. Water was added to the reaction mixture, and the mixture was stirred and extracted with EtOAc. The organic layer was concentrated under reduced pressure, and the obtained residue was purified by OH-type silica gel column chromatography (mobile phase: hexane / EtOAc = 90/10 to 0/100; v / v) to obtain tert-butyl [( 3S) -1- {6-Methyl-2-[(1S) -1- {methyl [(1-{[(methylsulfonyl) acetyl] amino} -1,2,3,4-tetrahydronaphthalen-1-yl ) Carbonyl] amino} ethyl] pyrazolo [1,5-a] pyrimidin-5-yl} pyrrolidin-3-yl] carbamate (9.7 mg, colorless amorphous) was obtained.
LCMS (ESI) m / z 668 [M + H] + , t R = 1.00 min, mode N.
Step 3-70-4: 4 M HCl / 1,4-dioxane solution (1 mL) was added dropwise to a solution of the compound obtained in Step 3-70-3 (9.7 mg) in 1,4-dioxane (1 mL). And stirred at room temperature for 2 hours. The reaction mixture was filtered, and the collected solid was dried under reduced pressure to give the title compound (6.6 mg, colorless solid).
1 H NMR (600 MHz, DMSO-d 6 , δ): 1.33-1.49 (m, 3H), 1.71-1.82 (m, 1H), 1.89-2.01 (m, 1H), 2.02-2.09 (m, 1H) , 2.19-2.29 (m, 1H), 2.31-3.13 (m, 13H), 3.65-3.94 (m, 5H), 4.18 (s, 2H), 4.62-4.76 (m, 0.5H), 5.78-5.99 (m , 1.5H), 7.06-7.33 (m, 4H), 8.22 (br s, 3H), 8.38-8.54 (m, 1H).
LCMS (ESI) m / z 568 [M + H] + , t R = 0.47 min, mode N.
実施例3−71:1-アミノ-N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}エチル]-N-メチル-1,2,3,4-テトラヒドロナフタレン-1-カルボキサミド 塩酸塩の合成
工程3−70−4と同様の手法を用いて、工程3−70−2で得られた化合物(7.9 mg)より表題化合物(8.5 mg, 無色固体)を得た。
LCMS (ESI) m/z 448 [M+H]+, tR = 0.59 min, mode H.
Example 3-71: 1-amino-N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidine-2 -Il} ethyl] -N-methyl-1,2,3,4-tetrahydronaphthalene-1-carboxamide obtained in Step 3-70-2 using a method similar to that of Synthesis Step 3-70-4 of hydrochloride. The title compound (8.5 mg, colorless solid) was obtained from the obtained compound (7.9 mg).
LCMS (ESI) m / z 448 [M + H] + , t R = 0.59 min, mode H.
実施例3−72:N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}プロピル]-N-メチル-1-{[(メチルスルホニル)アセチル]アミノ}-2,3-ジヒドロ-1H-インデン-1-カルボキサミド 塩酸塩(単一ジアステレオマー)の合成
工程3−72−1:工程1−4−3で得られた化合物(60 mg)と参考例11で得られた化合物(63 mg)のDMF(2 mL)溶液にHATU(88 mg)、Et3N(0.13 mL) を加え、室温にて3日間攪拌した。反応液をEtOAc、飽和NaHCO3水溶液にて分液した。有機層をBrineにて洗浄後、MgSO4で乾燥してろ過した後、ろ液を減圧下濃縮した。得られた残渣をOH型シリカゲルカラムクロマトグラフィー (移動相:ヘキサン/EtOAc = 95/5〜0/100; v/v)にて精製し、ベンジル (1-{[(1S)-1-(5-{(3S)-3-[(tert-ブトキシカルボニル)アミノ]ピロリジン-1-イル}-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル)プロピル](メチル)カルバモイル}-2,3-ジヒドロ-1H-インデン-1-イル)カルバマート(単一ジアステレオマー)(89 mg, 無色アモルファス)を得た。
1H NMR (600 MHz, CD3OD, δ): 0.66-0.97 (m, 3H), 1.44 (br s, 9H), 1.75-1.96 (m, 2H), 2.01-2.20 (m, 2H), 2.31 (br s, 1H), 2.38 (br s, 2H), 2.42-3.21 (m, 7H), 3.45-3.57 (m, 1H), 3.71-3.78 (m, 1H), 3.78-3.86 (m, 1H), 3.87-3.94 (m, 1H), 4.07-4.19 (m, 1H), 4.98-5.10 (m, 2H), 5.10-5.14 (m, 0.5H), 5.76-5.83 (m, 0.5H), 5.86-6.02 (m, 1H), 7.02-7.38 (m, 8H), 7.51-7.60 (m, 1H), 8.05-8.15 (m, 1H).
LCMS (ESI) m/z 682 [M+H]+, tR = 1.23 min, mode N.
工程3−72−2:工程3−72−1で得られた化合物(85 mg)のMeOH(2 mL)溶液に10%パラジウム-炭素(43 mg)を加え、水素雰囲気下、室温にて1.5時間攪拌した。反応液をセライト(登録商標)ろ過後、ろ液を減圧下濃縮し、得られた残渣をNH型シリカゲルカラムクロマトグラフィー (移動相:CHCl3/MeOH = 100/0〜80/20; v/v)にて精製し、tert-ブチル [(3S)-1-{2-[(1S)-1-{[(1-アミノ-2,3-ジヒドロ-1H-インデン-1-イル)カルボニル](メチル)アミノ}プロピル]-6-メチルピラゾロ[1,5-a]ピリミジン-5-イル}ピロリジン-3-イル]カルバマート(単一ジアステレオマー)(52 mg, 無色アモルファス)を得た。
1H NMR (600 MHz, CD3OD, δ): 0.91-1.01 (m, 2H), 1.24-1.34 (m, 1H), 1.45 (br s, 9H), 1.84-1.97 (m, 2H), 2.05-2.23 (m, 2H), 2.28 (br s, 1H), 2.38 (br s, 2H), 2.62-2.73 (m, 1H), 2.88 (br s, 1H), 3.07-3.16 (m, 1H), 3.16-3.39 (m, 4H), 3.49-3.59 (m, 1H), 3.70-3.79 (m, 1H), 3.79-3.87 (m, 1H), 3.87-3.96 (m, 1H), 4.11-4.21 (m, 1H), 5.91 (br s, 2H), 7.15-7.42 (m, 4H), 8.09-8.19 (m, 1H).
LCMS (ESI) m/z 548 [M+H]+, tR = 0.65 min, mode N.
工程3−72−3:工程3−72−2で得られた化合物(19 mg)、メタンスルホニル酢酸(7.7 mg)のDMF(1 mL)溶液にHATU(21 mg)、Et3N(29 μL) を加え、室温にて1時間攪拌した。反応液をEtOAc、飽和NaHCO3水溶液にて分液した。有機層をBrineにて洗浄後、MgSO4で乾燥してろ過した後、ろ液を減圧下濃縮した。得られた残渣をOH型シリカゲルカラムクロマトグラフィー (移動相:ヘキサン/EtOAc = 95/5〜0/100; v/v)にて精製し、tert-ブチル [(3S)-1-{6-メチル-2-[(1S)-1-{メチル[(1-{[(メチルスルホニル)アセチル]アミノ}-2,3-ジヒドロ-1H-インデン-1-イル)カルボニル]アミノ}プロピル]ピラゾロ[1,5-a]ピリミジン-5-イル}ピロリジン-3-イル]カルバマート(単一ジアステレオマー)(20 mg, 無色アモルファス)を得た。
1H NMR (600 MHz, CD3OD, δ): 0.94-1.03 (m, 3H), 1.45 (br s, 9H), 1.88-1.97 (m, 2H), 2.09-2.22 (m, 2H), 2.39 (br s, 3H), 2.51-2.76 (m, 2H), 2.77-2.94 (m, 4H), 2.97-3.11 (m, 4H), 3.24-3.41 (m, 2H), 3.52-3.58 (m, 1H), 3.71-3.79 (m, 1H), 3.80-3.88 (m, 1H), 3.88-3.95 (m, 1H), 4.12-4.21 (m, 1H), 5.81-6.01 (m, 2H), 7.16-7.40 (m, 3H), 7.50-7.56 (m, 0.7H), 7.98 (br s, 0.3H), 8.13 (br s, 0.7H), 8.18-8.23 (m, 0.3H).
LCMS (ESI) m/z 668 [M+H]+, tR = 0.98 min, mode N.
工程3−72−4:工程3−72−3で得られた化合物(19.0 mg)の1,4-ジオキサン(0.5 mL)溶液に4M HCl/1,4-ジオキサン溶液(1 mL)を滴下し、室温にて2時間攪拌した。反応液を減圧下濃縮し、表題化合物(18.5 mg, 無色固体)を得た。
1H NMR (600 MHz, DMSO-d6, δ): 0.88 (t, J = 7.4 Hz, 3H), 1.70-1.80 (m, 1H), 1.98-2.10 (m, 2H), 2.18-2.28 (m, 1H), 2.33 (s, 3H), 2.36-3.13 (m, 10H), 3.43-4.02 (m, 5H), 4.03-4.22 (m, 2H), 5.65-6.06 (m, 2H), 7.12-7.55 (m, 4H), 8.23 (br s, 3H), 8.48 (s, 0.5H), 9.20 (s, 0.5H).
LCMS (ESI) m/z 568 [M+H]+, tR = 0.85 min, mode H.
Example 3-72: N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidin-2-yl} propyl Synthesis step 3-72-1 of] -N-methyl-1-{[(methylsulfonyl) acetyl] amino} -2,3-dihydro-1H-indene-1-carboxamide hydrochloride (single diastereomer): HATU (88 mg) and Et 3 N (0.13 mL) were added to a DMF (2 mL) solution of the compound obtained in Step 1-4-3 (60 mg) and the compound obtained in Reference Example 11 (63 mg). The mixture was further stirred at room temperature for 3 days. The reaction mixture was partitioned between EtOAc and saturated aqueous NaHCO 3 solution. The organic layer was washed with Brine, dried over MgSO 4 and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by OH-type silica gel column chromatography (mobile phase: hexane / EtOAc = 95/5 to 0/100; v / v) to obtain benzyl (1-{[(1S) -1- (5 -{(3S) -3-[(tert-butoxycarbonyl) amino] pyrrolidin-1-yl} -6-methylpyrazolo [1,5-a] pyrimidin-2-yl) propyl] (methyl) carbamoyl} -2, 3-Dihydro-1H-inden-1-yl) carbamate (single diastereomer) (89 mg, colorless amorphous) was obtained.
1 H NMR (600 MHz, CD 3 OD, δ): 0.66-0.97 (m, 3H), 1.44 (br s, 9H), 1.75-1.96 (m, 2H), 2.01-2.20 (m, 2H), 2.31 (br s, 1H), 2.38 (br s, 2H), 2.42-3.21 (m, 7H), 3.45-3.57 (m, 1H), 3.71-3.78 (m, 1H), 3.78-3.86 (m, 1H) , 3.87-3.94 (m, 1H), 4.07-4.19 (m, 1H), 4.98-5.10 (m, 2H), 5.10-5.14 (m, 0.5H), 5.76-5.83 (m, 0.5H), 5.86- 6.02 (m, 1H), 7.02-7.38 (m, 8H), 7.51-7.60 (m, 1H), 8.05-8.15 (m, 1H).
LCMS (ESI) m / z 682 [M + H] + , t R = 1.23 min, mode N.
Step 3-72-2: To a solution of the compound obtained in Step 3-72-1 (85 mg) in MeOH (2 mL) was added 10% palladium-carbon (43 mg), and 1.5% at room temperature under a hydrogen atmosphere. Stir for hours. The reaction solution was filtered through Celite (registered trademark), and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to NH silica gel column chromatography (mobile phase: CHCl 3 / MeOH = 100/0 to 80/20; v / v ) Tert-butyl [(3S) -1- {2-[(1S) -1-{[(1-amino-2,3-dihydro-1H-inden-1-yl) carbonyl] ( Methyl) amino} propyl] -6-methylpyrazolo [1,5-a] pyrimidin-5-yl} pyrrolidin-3-yl] carbamate (single diastereomer) (52 mg, colorless amorphous) was obtained.
1 H NMR (600 MHz, CD 3 OD, δ): 0.91-1.01 (m, 2H), 1.24-1.34 (m, 1H), 1.45 (br s, 9H), 1.84-1.97 (m, 2H), 2.05 -2.23 (m, 2H), 2.28 (br s, 1H), 2.38 (br s, 2H), 2.62-2.73 (m, 1H), 2.88 (br s, 1H), 3.07-3.16 (m, 1H), 3.16-3.39 (m, 4H), 3.49-3.59 (m, 1H), 3.70-3.79 (m, 1H), 3.79-3.87 (m, 1H), 3.87-3.96 (m, 1H), 4.11-4.21 (m , 1H), 5.91 (br s, 2H), 7.15-7.42 (m, 4H), 8.09-8.19 (m, 1H).
LCMS (ESI) m / z 548 [M + H] + , t R = 0.65 min, mode N.
Step 3-72-3: A solution of the compound obtained in Step 3-72-2 (19 mg) and methanesulfonylacetic acid (7.7 mg) in DMF (1 mL) was added to HATU (21 mg), Et 3 N (29 μL ) Was added and stirred at room temperature for 1 hour. The reaction mixture was partitioned between EtOAc and saturated aqueous NaHCO 3 solution. The organic layer was washed with Brine, dried over MgSO 4 and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by OH-type silica gel column chromatography (mobile phase: hexane / EtOAc = 95 / 5-0 / 100; v / v), and tert-butyl [(3S) -1- {6-methyl -2-[(1S) -1- {methyl [(1-{[(methylsulfonyl) acetyl] amino} -2,3-dihydro-1H-inden-1-yl) carbonyl] amino} propyl] pyrazolo [1 , 5-a] pyrimidin-5-yl} pyrrolidin-3-yl] carbamate (single diastereomer) (20 mg, colorless amorphous) was obtained.
1 H NMR (600 MHz, CD 3 OD, δ): 0.94-1.03 (m, 3H), 1.45 (br s, 9H), 1.88-1.97 (m, 2H), 2.09-2.22 (m, 2H), 2.39 (br s, 3H), 2.51-2.76 (m, 2H), 2.77-2.94 (m, 4H), 2.97-3.11 (m, 4H), 3.24-3.41 (m, 2H), 3.52-3.58 (m, 1H ), 3.71-3.79 (m, 1H), 3.80-3.88 (m, 1H), 3.88-3.95 (m, 1H), 4.12-4.21 (m, 1H), 5.81-6.01 (m, 2H), 7.16-7.40 (m, 3H), 7.50-7.56 (m, 0.7H), 7.98 (br s, 0.3H), 8.13 (br s, 0.7H), 8.18-8.23 (m, 0.3H).
LCMS (ESI) m / z 668 [M + H] + , t R = 0.98 min, mode N.
Step 3-72-4: To a solution of the compound (19.0 mg) obtained in Step 3-72-3 in 1,4-dioxane (0.5 mL), 4M HCl / 1,4-dioxane solution (1 mL) was added dropwise. The mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain the title compound (18.5 mg, colorless solid).
1 H NMR (600 MHz, DMSO-d 6 , δ): 0.88 (t, J = 7.4 Hz, 3H), 1.70-1.80 (m, 1H), 1.98-2.10 (m, 2H), 2.18-2.28 (m , 1H), 2.33 (s, 3H), 2.36-3.13 (m, 10H), 3.43-4.02 (m, 5H), 4.03-4.22 (m, 2H), 5.65-6.06 (m, 2H), 7.12-7.55 (m, 4H), 8.23 (br s, 3H), 8.48 (s, 0.5H), 9.20 (s, 0.5H).
LCMS (ESI) m / z 568 [M + H] + , t R = 0.85 min, mode H.
実施例3−73:N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}プロピル]-1-{[(エチルスルホニル)アセチル]アミノ}-N-メチル-2,3-ジヒドロ-1H-インデン-1-カルボキサミド 塩酸塩(単一ジアステレオマー)の合成
工程3−73−1:工程3−72−2で得られた化合物(16 mg)、2-(エタンスルホニル)酢酸(7.1 mg)のDMF(1 mL)溶液にHATU(18 mg)、Et3N(24 μL) を加え、室温にて2時間攪拌した。反応液をEtOAc、飽和NaHCO3水溶液にて分液した。有機層をBrineにて洗浄後、MgSO4で乾燥してろ過した後、ろ液を減圧下濃縮した。得られた残渣をOH型シリカゲルカラムクロマトグラフィー (移動相:ヘキサン/EtOAc = 95/5〜0/100; v/v)にて精製し、tert-ブチル [(3S)-1-{2-[(1S)-1-{[(1-{[(エチルスルホニル)アセチル]アミノ}-2,3-ジヒドロ-1H-インデン-1-イル)カルボニル](メチル)アミノ}プロピル]-6-メチルピラゾロ[1,5-a]ピリミジン-5-イル}ピロリジン-3-イル]カルバマート(単一ジアステレオマー)(16 mg, 無色アモルファス)を得た。
1H NMR (600 MHz, CD3OD, δ): 0.97 (t, J = 7.4 Hz, 2H), 1.24 (t, J = 7.4 Hz, 1H), 1.26-1.36 (m, 3H), 1.45 (s, 9H), 1.86-1.97 (m, 2H), 2.09-2.21 (m, 2H), 2.38 (s, 3H), 2.49-3.39 (m, 11H), 3.50-3.58 (m, 1H), 3.70-3.79 (m, 1H), 3.79-3.87 (m, 1H), 3.88-3.94 (m, 1H), 4.12-4.18 (m, 1H), 5.79-6.01 (m, 2H), 7.15-7.38 (m, 3H), 7.52 (d, J = 7.4 Hz, 1H), 7.98 (s, 0.5H), 8.13 (br s, 0.5H).
LCMS (ESI) m/z 682 [M+H]+, tR = 1.01 min, mode N.
工程3−73−2:工程3−73−1で得られた化合物(14.8 mg)の1,4-ジオキサン(0.5 mL)溶液に4 M HCl/1,4-ジオキサン溶液(1 mL)を滴下し、室温にて2時間攪拌した。反応液を減圧下濃縮し、表題化合物(14.8 mg, 無色固体)を得た。
1H NMR (600 MHz, DMSO-d6, δ): 0.86 (t, J = 7.2 Hz, 3H), 1.22 (t, J = 7.4 Hz, 3H), 1.71-1.80 (m, 1H), 1.99-2.10 (m, 2H), 2.19-2.28 (m, 1H), 2.33 (s, 3H), 2.36-3.27 (m, 9H), 3.44-3.95 (m, 5H), 4.01-4.18 (m, 2H), 5.65-5.83 (m, 2H), 7.13-7.52 (m, 4H), 8.19 (br s, 3H), 8.48 (s, 0.5H), 9.20 (s, 0.5H).
LCMS (ESI) m/z 582 [M+H]+, tR = 0.89 min, mode H.
Example 3-73: N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidin-2-yl} propyl ] -1-{[(Ethylsulfonyl) acetyl] amino} -N-methyl-2,3-dihydro-1H-indene-1-carboxamide Step 373-1 for Synthesis of Hydrochloride (Single Diastereomer): HATU (18 mg) and Et 3 N (24 μL) were added to a DMF (1 mL) solution of the compound obtained in step 3-72-2 (16 mg) and 2- (ethanesulfonyl) acetic acid (7.1 mg). The mixture was stirred at room temperature for 2 hours. The reaction mixture was partitioned between EtOAc and saturated aqueous NaHCO 3 solution. The organic layer was washed with Brine, dried over MgSO 4 and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by OH-type silica gel column chromatography (mobile phase: hexane / EtOAc = 95/5 to 0/100; v / v), and tert-butyl [(3S) -1- {2- [ (1S) -1-{[(1-{[(Ethylsulfonyl) acetyl] amino} -2,3-dihydro-1H-inden-1-yl) carbonyl] (methyl) amino} propyl] -6-methylpyrazolo [ 1,5-a] pyrimidin-5-yl} pyrrolidin-3-yl] carbamate (single diastereomer) (16 mg, colorless amorphous) was obtained.
1 H NMR (600 MHz, CD 3 OD, δ): 0.97 (t, J = 7.4 Hz, 2H), 1.24 (t, J = 7.4 Hz, 1H), 1.26-1.36 (m, 3H), 1.45 (s , 9H), 1.86-1.97 (m, 2H), 2.09-2.21 (m, 2H), 2.38 (s, 3H), 2.49-3.39 (m, 11H), 3.50-3.58 (m, 1H), 3.70-3.79 (m, 1H), 3.79-3.87 (m, 1H), 3.88-3.94 (m, 1H), 4.12-4.18 (m, 1H), 5.79-6.01 (m, 2H), 7.15-7.38 (m, 3H) , 7.52 (d, J = 7.4 Hz, 1H), 7.98 (s, 0.5H), 8.13 (br s, 0.5H).
LCMS (ESI) m / z 682 [M + H] + , t R = 1.01 min, mode N.
Step 3-73-2: 4 M HCl / 1,4-dioxane solution (1 mL) was added dropwise to a solution of the compound obtained in Step 3-73-1 (14.8 mg) in 1,4-dioxane (0.5 mL). And stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain the title compound (14.8 mg, colorless solid).
1 H NMR (600 MHz, DMSO-d 6 , δ): 0.86 (t, J = 7.2 Hz, 3H), 1.22 (t, J = 7.4 Hz, 3H), 1.71-1.80 (m, 1H), 1.99- 2.10 (m, 2H), 2.19-2.28 (m, 1H), 2.33 (s, 3H), 2.36-3.27 (m, 9H), 3.44-3.95 (m, 5H), 4.01-4.18 (m, 2H), 5.65-5.83 (m, 2H), 7.13-7.52 (m, 4H), 8.19 (br s, 3H), 8.48 (s, 0.5H), 9.20 (s, 0.5H).
LCMS (ESI) m / z 582 [M + H] + , t R = 0.89 min, mode H.
実施例3−74:1-アミノ-N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}プロピル]-N-メチル-1,2,3,4-テトラヒドロナフタレン-1-カルボキサミド 塩酸塩の合成
工程3−74−1:工程1−4−3で得られた化合物(100 mg)と参考例10で得られた化合物(167 mg)のDMF(2 mL)溶液にHATU(196 mg)、DMAP(63 mg)、DIPEA(269 μL) を加え、80 ℃にて20時間攪拌した。反応液をEtOAc、飽和NaHCO3水溶液にて分液した。有機層をBrineにて洗浄後、MgSO4で乾燥してろ過した後、ろ液を減圧下濃縮した。得られた残渣をOH型シリカゲルカラムクロマトグラフィー (移動相:ヘキサン/EtOAc = 95/5〜0/100; v/v)にて精製し、ベンジル (1-{[(1S)-1-(5-{(3S)-3-[(tert-ブトキシカルボニル)アミノ]ピロリジン-1-イル}-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル)プロピル](メチル)カルバモイル}-1,2,3,4-テトラヒドロナフタレン-1-イル)カルバマート(55 mg, 淡黄色アモルファス)を得た。
1H NMR (600 MHz, CDCl3, δ): 0.90-0.99 (m, 3H), 1.45 (br s, 9H), 1.72-3.06 (m, 13H), 2.29-2.34 (m, 3H), 3.47-4.34 (m, 5H), 4.56-4.70 (m, 1H), 4.90-5.01 (m, 2H), 5.89-6.02 (m, 1H), 7.05-7.36 (m, 9H), 7.98-8.04 (m, 1H).
LCMS (ESI) m/z 696 [M+H]+, tR = 1.42 min, mode N.
工程3−74−2:工程3−74−1で得られた化合物(50 mg)のMeOH(1 mL)溶液に10%パラジウム-炭素(20 mg)を加え、水素雰囲気下、室温にて2時間攪拌した。反応液をセライト(登録商標)ろ過後、ろ液を減圧下濃縮し、tert-ブチル [(3S)-1-{2-[(1S)-1-{[(1-アミノ-1,2,3,4-テトラヒドロナフタレン-1-イル)カルボニル](メチル)アミノ}プロピル]-6-メチルピラゾロ[1,5-a]ピリミジン-5-イル}ピロリジン-3-イル]カルバマート(39 mg, 無色アモルファス)を得た。
1H NMR (600 MHz, CDCl3, δ): 0.94-1.00 (m, 3H), 1.45 (br s, 9H), 1.72-2.26 (m, 9H), 2.30-2.34 (m, 3H), 2.48-3.02 (m, 4H), 3.48-3.55 (m, 1H), 3.67-3.73 (m, 1H), 3.75-3.83 (m, 1H), 3.87-3.97 (m, 1H), 4.23-4.36 (m, 1H), 4.64-4.74 (m, 1H), 5.90-6.08 (m, 1H), 7.05-7.20 (m, 4H), 7.97-8.05 (m, 1H).
LCMS (ESI) m/z 562 [M+H]+, tR = 0.90 min, mode N.
工程3−74−3:工程3−74−2で得られた化合物(18.6 mg)の1,4-ジオキサン(1 mL)溶液に4M HCl/1,4-ジオキサン溶液(1 mL)を滴下し、室温にて2時間攪拌した。反応液をろ取し、ろ物を減圧下乾燥し、表題化合物(19.9 mg, 無色固体)を得た。
1H NMR (600 MHz, CDCl3, δ): 0.94-1.00 (m, 3H), 1.45 (br s, 9H), 1.72-2.26 (m, 9H), 2.30-2.34 (m, 3H), 2.48-3.02 (m, 4H), 3.48-3.55 (m, 1H), 3.67-3.73 (m, 1H), 3.75-3.83 (m, 1H), 3.87-3.97 (m, 1H), 4.23-4.36 (m, 1H), 4.64-4.74 (m, 1H), 5.90-6.08 (m, 1H), 7.05-7.20 (m, 4H), 7.97-8.05 (m, 1H).
LCMS (ESI) m/z 462 [M+H]+, tR = 0.62 min, mode H.
Example 3-74: 1-amino-N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidine-2 -Il} propyl] -N-methyl-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride synthesis step 3-74-1: compound obtained in step 1-4-3 (100 mg) HATU (196 mg), DMAP (63 mg), and DIPEA (269 μL) were added to a DMF (2 mL) solution of the compound (167 mg) obtained in Reference Example 10 and stirred at 80 ° C. for 20 hours. The reaction mixture was partitioned between EtOAc and saturated aqueous NaHCO 3 solution. The organic layer was washed with Brine, dried over MgSO 4 and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by OH-type silica gel column chromatography (mobile phase: hexane / EtOAc = 95/5 to 0/100; v / v) to obtain benzyl (1-{[(1S) -1- (5 -{(3S) -3-[(tert-butoxycarbonyl) amino] pyrrolidin-1-yl} -6-methylpyrazolo [1,5-a] pyrimidin-2-yl) propyl] (methyl) carbamoyl} -1, 2,3,4-Tetrahydronaphthalen-1-yl) carbamate (55 mg, pale yellow amorphous) was obtained.
1 H NMR (600 MHz, CDCl 3 , δ): 0.90-0.99 (m, 3H), 1.45 (br s, 9H), 1.72-3.06 (m, 13H), 2.29-2.34 (m, 3H), 3.47- 4.34 (m, 5H), 4.56-4.70 (m, 1H), 4.90-5.01 (m, 2H), 5.89-6.02 (m, 1H), 7.05-7.36 (m, 9H), 7.98-8.04 (m, 1H ).
LCMS (ESI) m / z 696 [M + H] + , t R = 1.42 min, mode N.
Step 3-74-2: 10% palladium-carbon (20 mg) was added to a solution of the compound obtained in Step 3-74-1 (50 mg) in MeOH (1 mL) and added at room temperature under a hydrogen atmosphere at room temperature. Stir for hours. After the reaction solution was filtered through Celite (registered trademark), the filtrate was concentrated under reduced pressure, and tert-butyl [(3S) -1- {2-[(1S) -1-{[(1-amino-1,2, 3,4-Tetrahydronaphthalen-1-yl) carbonyl] (methyl) amino} propyl] -6-methylpyrazolo [1,5-a] pyrimidin-5-yl} pyrrolidin-3-yl] carbamate (39 mg, colorless amorphous )
1 H NMR (600 MHz, CDCl 3 , δ): 0.94-1.00 (m, 3H), 1.45 (br s, 9H), 1.72-2.26 (m, 9H), 2.30-2.34 (m, 3H), 2.48- 3.02 (m, 4H), 3.48-3.55 (m, 1H), 3.67-3.73 (m, 1H), 3.75-3.83 (m, 1H), 3.87-3.97 (m, 1H), 4.23-4.36 (m, 1H ), 4.64-4.74 (m, 1H), 5.90-6.08 (m, 1H), 7.05-7.20 (m, 4H), 7.97-8.05 (m, 1H).
LCMS (ESI) m / z 562 [M + H] + , t R = 0.90 min, mode N.
Step 3-74-3: 4M HCl / 1,4-dioxane solution (1 mL) was added dropwise to a solution of the compound obtained in Step 3-74-2 (18.6 mg) in 1,4-dioxane (1 mL). The mixture was stirred at room temperature for 2 hours. The reaction mixture was collected by filtration, and the filtrate was dried under reduced pressure to give the title compound (19.9 mg, colorless solid).
1 H NMR (600 MHz, CDCl 3 , δ): 0.94-1.00 (m, 3H), 1.45 (br s, 9H), 1.72-2.26 (m, 9H), 2.30-2.34 (m, 3H), 2.48- 3.02 (m, 4H), 3.48-3.55 (m, 1H), 3.67-3.73 (m, 1H), 3.75-3.83 (m, 1H), 3.87-3.97 (m, 1H), 4.23-4.36 (m, 1H ), 4.64-4.74 (m, 1H), 5.90-6.08 (m, 1H), 7.05-7.20 (m, 4H), 7.97-8.05 (m, 1H).
LCMS (ESI) m / z 462 [M + H] + , t R = 0.62 min, mode H.
実施例3−75:N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}プロピル]-N-メチル-1-{[(メチルスルホニル)アセチル]アミノ}-1,2,3,4-テトラヒドロナフタレン-1-カルボキサミド 塩酸塩の合成
工程3−75−1:工程3−74−2で得られた化合物(32.0 mg)とメタンスルホニル酢酸(15 mg)のDMF(1 mL)溶液にHATU(42 mg)、Et3N(46 μL) を加え、室温にて1時間攪拌した。反応液をEtOAc、飽和NaHCO3水溶液にて分液した。有機層をBrineにて洗浄後、MgSO4で乾燥してろ過した後、ろ液を減圧下濃縮した。得られた残渣をOH型シリカゲルカラムクロマトグラフィー (移動相:ヘキサン/EtOAc = 95/5〜0/100; v/v)にて精製し、tert-ブチル [(3S)-1-{6-メチル-2-[(1S)-1-{メチル[(1-{[(メチルスルホニル)アセチル]アミノ}-1,2,3,4-テトラヒドロナフタレン-1-イル)カルボニル]アミノ}プロピル]ピラゾロ[1,5-a]ピリミジン-5-イル}ピロリジン-3-イル]カルバマート(27 mg, 無色アモルファス)を得た。
1H NMR (600 MHz, CD3OD, δ): 0.90-1.04 (m, 3H), 1.45 (br s, 9H), 1.82-2.28 (m, 9H), 2.32-2.40 (m, 3H), 2.72-3.44 (m, 9H), 3.50-3.58 (m, 1H), 3.72-3.78 (m, 1H), 3.80-3.87 (m, 1H), 3.89-3.95 (m, 1H), 4.03-4.10 (m, 1H), 4.13-4.20 (m, 1H), 4.57-4.95 (m, 1H), 5.81-6.01 (m, 1H), 7.09-7.32 (m, 4H), 7.94-8.16 (m, 1H).
LCMS (ESI) m/z 682 [M+H]+, tR = 1.05 min, mode N.
工程3−75−2:工程3−75−1で得られた化合物(11.6 mg)の1,4-ジオキサン(0.5 mL)溶液に4 M HCl/1,4-ジオキサン溶液(1 mL)を滴下し、室温にて1.5時間攪拌した。反応液を減圧下濃縮し、表題化合物(10.5 mg, 無色固体)を得た。
1H NMR (600 MHz, DMSO-d6, δ): 0.79-0.95 (m, 3H), 1.68-2.29 (m, 6H), 2.31-2.35 (m, 3H), 2.36-3.11 (m, 10H), 3.42-3.94 (m, 5H), 4.13-4.21 (m, 2H), 5.69-6.04 (m, 2H), 7.08-7.30 (m, 2H), 8.11-8.26 (m, 2H), 8.35-8.50 (m, 1H).
LCMS (ESI) m/z 582 [M+H]+, tR = 0.93 min, mode H.
Example 3-75: N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidin-2-yl} propyl ] -N-Methyl-1-{[(methylsulfonyl) acetyl] amino} -1,2,3,4-tetrahydronaphthalene-1-carboxamide Hydrochloride Synthesis Step 3-75-1: Step 3-74-2 HATU (42 mg) and Et 3 N (46 μL) were added to a DMF (1 mL) solution of the compound obtained in (32.0 mg) and methanesulfonylacetic acid (15 mg), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was partitioned between EtOAc and saturated aqueous NaHCO 3 solution. The organic layer was washed with Brine, dried over MgSO 4 and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by OH-type silica gel column chromatography (mobile phase: hexane / EtOAc = 95 / 5-0 / 100; v / v), and tert-butyl [(3S) -1- {6-methyl -2-[(1S) -1- {methyl [(1-{[(methylsulfonyl) acetyl] amino} -1,2,3,4-tetrahydronaphthalen-1-yl) carbonyl] amino} propyl] pyrazolo [ 1,5-a] pyrimidin-5-yl} pyrrolidin-3-yl] carbamate (27 mg, colorless amorphous) was obtained.
1 H NMR (600 MHz, CD 3 OD, δ): 0.90-1.04 (m, 3H), 1.45 (br s, 9H), 1.82-2.28 (m, 9H), 2.32-2.40 (m, 3H), 2.72 -3.44 (m, 9H), 3.50-3.58 (m, 1H), 3.72-3.78 (m, 1H), 3.80-3.87 (m, 1H), 3.89-3.95 (m, 1H), 4.03-4.10 (m, 1H), 4.13-4.20 (m, 1H), 4.57-4.95 (m, 1H), 5.81-6.01 (m, 1H), 7.09-7.32 (m, 4H), 7.94-8.16 (m, 1H).
LCMS (ESI) m / z 682 [M + H] + , t R = 1.05 min, mode N.
Step 3-75-2: 4 M HCl / 1,4-dioxane solution (1 mL) was added dropwise to a solution of the compound (11.6 mg) obtained in Step 3-75-1 in 1,4-dioxane (0.5 mL). And stirred at room temperature for 1.5 hours. The reaction mixture was concentrated under reduced pressure to obtain the title compound (10.5 mg, colorless solid).
1 H NMR (600 MHz, DMSO-d 6 , δ): 0.79-0.95 (m, 3H), 1.68-2.29 (m, 6H), 2.31-2.35 (m, 3H), 2.36-3.11 (m, 10H) , 3.42-3.94 (m, 5H), 4.13-4.21 (m, 2H), 5.69-6.04 (m, 2H), 7.08-7.30 (m, 2H), 8.11-8.26 (m, 2H), 8.35-8.50 ( m, 1H).
LCMS (ESI) m / z 582 [M + H] + , t R = 0.93 min, mode H.
実施例3−76:N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}プロピル]-N-メチル-1-{[(メチルスルホニル)アセチル]アミノ}-1,2,3,4-テトラヒドロナフタレン-1-カルボキサミド 塩酸塩(単一ジアステレオマー)の合成
工程3−76−1:工程3−75−1で得られた化合物(12 mg)をキラルカラムを用いて分取精製を行い(分取条件:カラム:CHIRALPAK IC(ダイセル商標)、カラムサイズ:20 mm×250 mm、移動相:ヘキサン/EtOH = 10/90 (v/v)、流速:10 mL/mL)、保持時間16分〜18分で溶出した画分を減圧下濃縮することで、tert-ブチル [(3S)-1-{6-メチル-2-[(1S)-1-{メチル[(1-{[(メチルスルホニル)アセチル]アミノ}-1,2,3,4-テトラヒドロナフタレン-1-イル)カルボニル]アミノ}プロピル]ピラゾロ[1,5-a]ピリミジン-5-イル}ピロリジン-3-イル]カルバマートのジアステレオマーA(6.5 mg)、保持時間32分〜37分で溶出した画分を減圧下濃縮することで、tert-ブチル [(3S)-1-{6-メチル-2-[(1S)-1-{メチル[(1-{[(メチルスルホニル)アセチル]アミノ}-1,2,3,4-テトラヒドロナフタレン-1-イル)カルボニル]アミノ}プロピル]ピラゾロ[1,5-a]ピリミジン-5-イル}ピロリジン-3-イル]カルバマートのジアステレオマーB(3.1mg)を得た。
ジアステレオマーA: 1H NMR (600 MHz, CD3OD, δ): 0.92-1.03 (m, 3H), 1.45 (br s, 9H), 1.80-2.29 (m, 9H), 2.33-2.41 (m, 3H), 2.81-3.46 (m, 9H), 3.50-3.59 (m, 1H), 3.70-3.79 (m, 1H), 3.79-3.87 (m, 1H), 3.88-3.96 (m, 1H), 4.11-4.23 (m, 1H), 4.58-4.71 (m, 1H), 5.72-6.06 (m, 1H), 7.05-7.33 (m, 4H), 8.01-8.23 (m, 1H).
LCMS (ESI) m/z 682 [M+H]+, tR = 1.05 min, mode N.
ジアステレオマーB:LCMS (ESI) m/z 682 [M+H]+, tR = 1.05 min, mode N.
工程3−76−2:工程3−76−1で得られたtert-ブチル [(3S)-1-{6-メチル-2-[(1S)-1-{メチル[(1-{[(メチルスルホニル)アセチル]アミノ}-1,2,3,4-テトラヒドロナフタレン-1-イル)カルボニル]アミノ}プロピル]ピラゾロ[1,5-a]ピリミジン-5-イル}ピロリジン-3-イル]カルバマートのジアステレオマーA(5.8 mg)の1,4-ジオキサン(0.5 mL)溶液に4 M HCl/1,4-ジオキサン溶液(1 mL)を滴下し、室温にて1.5時間攪拌した。反応液を減圧下濃縮し、表題化合物(6.9 mg, 無色固体)を得た。
1H NMR (600 MHz, DMSO-d6, δ): 0.81-0.95 (m, 3H), 1.68-2.28 (m, 6H), 2.30-2.36 (m, 3H), 2.38-3.14 (m, 10H), 3.52-3.94 (m, 5H), 4.11-4.22 (m, 2H), 5.67-6.05 (m, 2H), 7.06-7.32 (m, 2H), 8.22-8.34 (m, 2H), 8.37-8.56 (m, 1H).
LCMS (ESI) m/z 582 [M+H]+, tR = 0.93 min, mode H.
Example 3-76: N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidin-2-yl} propyl ] -N-Methyl-1-{[(methylsulfonyl) acetyl] amino} -1,2,3,4-tetrahydronaphthalene-1-carboxamide Hydrochloride (Single Diastereomer) Synthesis Step 3-76-1 : Preparative purification of the compound (12 mg) obtained in Step 3-75-1 using a chiral column (Preparation conditions: Column: CHIRALPAK IC (Daicel)), column size: 20 mm × 250 mm, migration Phase: hexane / EtOH = 10/90 (v / v), flow rate: 10 mL / mL), fractions eluted with a retention time of 16-18 min were concentrated under reduced pressure to give tert-butyl [(3S) -1- {6-Methyl-2-[(1S) -1- {methyl [(1-{[(methylsulfonyl) acetyl] amino} -1,2,3,4-tetrahydronaphthalen-1-yl) carbonyl ] Amino} propyl] pyrazolo [1,5-a] pyrimidin-5-yl} pyrrolidin-3-y ] The fraction eluted with carbamate diastereomer A (6.5 mg), retention time 32 min to 37 min, was concentrated under reduced pressure to give tert-butyl [(3S) -1- {6-methyl-2- [ (1S) -1- {Methyl [(1-{[(methylsulfonyl) acetyl] amino} -1,2,3,4-tetrahydronaphthalen-1-yl) carbonyl] amino} propyl] pyrazolo [1,5- a] Pyrimidin-5-yl} pyrrolidin-3-yl] carbamate diastereomer B (3.1 mg) was obtained.
Diastereomer A: 1 H NMR (600 MHz, CD 3 OD, δ): 0.92-1.03 (m, 3H), 1.45 (br s, 9H), 1.80-2.29 (m, 9H), 2.33-2.41 (m , 3H), 2.81-3.46 (m, 9H), 3.50-3.59 (m, 1H), 3.70-3.79 (m, 1H), 3.79-3.87 (m, 1H), 3.88-3.96 (m, 1H), 4.11 -4.23 (m, 1H), 4.58-4.71 (m, 1H), 5.72-6.06 (m, 1H), 7.05-7.33 (m, 4H), 8.01-8.23 (m, 1H).
LCMS (ESI) m / z 682 [M + H] + , t R = 1.05 min, mode N.
Diastereomer B: LCMS (ESI) m / z 682 [M + H] + , t R = 1.05 min, mode N.
Step 3-76-2: tert-butyl [(3S) -1- {6-methyl-2-[(1S) -1- {methyl [(1-{[( Methylsulfonyl) acetyl] amino} -1,2,3,4-tetrahydronaphthalen-1-yl) carbonyl] amino} propyl] pyrazolo [1,5-a] pyrimidin-5-yl} pyrrolidin-3-yl] carbamate 4 M HCl / 1,4-dioxane solution (1 mL) was added dropwise to a solution of diastereomer A (5.8 mg) in 1,4-dioxane (0.5 mL), and the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was concentrated under reduced pressure to obtain the title compound (6.9 mg, colorless solid).
1 H NMR (600 MHz, DMSO-d 6 , δ): 0.81-0.95 (m, 3H), 1.68-2.28 (m, 6H), 2.30-2.36 (m, 3H), 2.38-3.14 (m, 10H) , 3.52-3.94 (m, 5H), 4.11-4.22 (m, 2H), 5.67-6.05 (m, 2H), 7.06-7.32 (m, 2H), 8.22-8.34 (m, 2H), 8.37-8.56 ( m, 1H).
LCMS (ESI) m / z 582 [M + H] + , t R = 0.93 min, mode H.
実施例3−77:N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}プロピル]-N-メチル-5-{[(メチルスルホニル)アセチル]アミノ}-6,7,8,9-テトラヒドロ-5H-ベンゾ[7]アンヌレン-5-カルボキサミド 塩酸塩の合成
工程3−1−4、工程3−12−1及び工程3−1−1と同様の手法を用いて、工程1−4−3で得られた化合物(30 mg)及び5-アミノ-6,7,8,9-テトラヒドロ-5H-ベンゾ[7]アンヌレン-5-カルボン酸 塩酸塩(21 mg)より表題化合物(5.5 mg, 無色固体)を得た。
LCMS (ESI) m/z 596 [M+H]+, tR = 0.88, 0.98 min, mode H.
Example 3-77: N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidin-2-yl} propyl ] -N-Methyl-5-{[(methylsulfonyl) acetyl] amino} -6,7,8,9-tetrahydro-5H-benzo [7] annulene-5-carboxamide Hydrochloride Synthesis Step 3-1-4 Using the same method as in Step 3-12-1 and Step 3-1-1, the compound (30 mg) obtained in Step 1-4-3 and 5-amino-6,7,8,9- The title compound (5.5 mg, colorless solid) was obtained from tetrahydro-5H-benzo [7] annulene-5-carboxylic acid hydrochloride (21 mg).
LCMS (ESI) m / z 596 [M + H] + , t R = 0.88, 0.98 min, mode H.
実施例3−78:2-アミノ-N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}プロピル]-N-メチル-1,2,3,4-テトラヒドロナフタレン-2-カルボキサミド 塩酸塩の合成
工程3−29−1及び工程3−1−1と同様の手法を用いて、工程1−4−3で得られた化合物(11 mg)及び2-[(tert-ブトキシカルボニル)アミノ]-1,2,3,4-テトラヒドロナフタレン-2-カルボン酸(7.9 mg)より表題化合物(2.1 mg, 淡黄色固体)を得た。
LCMS (ESI) m/z 462 [M+H]+, tR = 0.50 min, mode N.
Example 3-78: 2-amino-N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidine-2 -Il} propyl] -N-methyl-1,2,3,4-tetrahydronaphthalene-2-carboxamide hydrochloride using the same procedure as in Steps 3-29-1 and 3-1-1 From the compound (11 mg) obtained in 1-4-3 and 2-[(tert-butoxycarbonyl) amino] -1,2,3,4-tetrahydronaphthalene-2-carboxylic acid (7.9 mg), the title compound ( 2.1 mg, a pale yellow solid).
LCMS (ESI) m / z 462 [M + H] + , t R = 0.50 min, mode N.
実施例4−1:N-{(1S)-1-[5-(2-アミノエトキシ)-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル]エチル}-5-クロロ-N-メチル-2-[(メチルスルホニル)アミノ]ベンズアミドの合成
工程4−1−1:工程1−1−4で得られた化合物(70 mg)及びベンジル (2-ヒドロキシエチル)カルバマート(67 mg)のTHF懸濁液(1 mL)にCMBP(0.18 mL)を加え、80 ℃にて2.5時間攪拌した。反応液を減圧下濃縮し、得られた残渣をOH型シリカゲルカラムクロマトグラフィー(移動相:ヘキサン/EtOAc)にて精製し、ベンジル {2-[(2-{(1S)-1-[(tert-ブトキシカルボニル)(メチル)アミノ]エチル}-6-メチルピラゾロ[1,5-a]ピリミジン-5-イル)オキシ]エチル}カルバマート(39 mg, 淡褐色油状物)を得た。
LCMS (ESI) m/z 484 [M+H]+.
工程4−1−2:工程1−2−8、工程1−1−8及び工程1−1−9と同様の手法を用いて、工程4−1−1で得られた化合物(37 mg)より表題化合物(15 mg, 無色アモルファス)を得た。
LCMS (ESI) m/z 481 [M+H]+, tR = 0.55 min, mode N.
Example 4-1 N-{(1S) -1- [5- (2-aminoethoxy) -6-methylpyrazolo [1,5-a] pyrimidin-2-yl] ethyl} -5-chloro-N- Synthesis step 4-1-1 of methyl-2-[(methylsulfonyl) amino] benzamide: (70 mg) of the compound obtained in step 1-1-4 and benzyl (2-hydroxyethyl) carbamate (67 mg) CMBP (0.18 mL) was added to the THF suspension (1 mL), and the mixture was stirred at 80 ° C. for 2.5 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by OH-type silica gel column chromatography (mobile phase: hexane / EtOAc) to give benzyl {2-[(2-{(1S) -1-[(tert -Butoxycarbonyl) (methyl) amino] ethyl} -6-methylpyrazolo [1,5-a] pyrimidin-5-yl) oxy] ethyl} carbamate (39 mg, light brown oil) was obtained.
LCMS (ESI) m / z 484 [M + H] + .
Step 4-1-2: Compound obtained in Step 4-1-1 (37 mg) using the same method as in Step 1-2-8, Step 1-1-8 and Step 1-1-9 The title compound (15 mg, colorless amorphous) was obtained.
LCMS (ESI) m / z 481 [M + H] + , t R = 0.55 min, mode N.
実施例4−2:N-{(1S)-1-[5-(アゼチジン-3-イルオキシ)-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル]エチル}-5-クロロ-N-メチル-2-[(メチルスルホニル)アミノ]ベンズアミドの合成
工程4−1−1、工程2−70−3、工程1−1−8及び工程1−1−9と同様の手法を用いて、工程1−1−4で得られた化合物(70 mg)及びベンジル (3-ヒドロキシアゼチジン)-1-カルボキシラート(71 mg)より表題化合物(17 mg, 無色アモルファス)を得た。
LCMS (ESI) m/z 493 [M+H]+, tR = 0.56 min, mode N.
Example 4-2: N-{(1S) -1- [5- (azetidin-3-yloxy) -6-methylpyrazolo [1,5-a] pyrimidin-2-yl] ethyl} -5-chloro-N Synthesis of 4-methyl-2-[(methylsulfonyl) amino] benzamide using the same method as in Step 4-1-1, Step 2-70-3, Step 1-1-8 and Step 1-1-9, The title compound (17 mg, colorless amorphous) was obtained from the compound (70 mg) obtained in Step 1-1-4 and benzyl (3-hydroxyazetidine) -1-carboxylate (71 mg).
LCMS (ESI) m / z 493 [M + H] + , t R = 0.56 min, mode N.
実施例4−3:N-{(1S)-1-[5-(3-アミノアゼチジン-1-イル)-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル]エチル}-5-クロロ-N-メチル-2-[(メチルスルホニル)アミノ]ベンズアミドの合成
工程4−3−1:工程1−1−6と同様の手法を用いて、工程2−9−2で得られた化合物(20 mg)及びtert-ブチル アゼチジン-3-イルカルバマート メタンスルホン酸塩(47 mg)よりtert-ブチル [1-(2-{(1S)-1-[{5-クロロ-2-[(メチルスルホニル)アミノ]ベンゾイル}(メチル)アミノ]エチル}-6-メチルピラゾロ[1,5-a]ピリミジン-5-イル)アゼチジン-3-イル]カルバマート(17 mg)を得た。
LCMS (ESI) m/z 592 [M+H]+, tR = 1.10 min, mode N.
工程4−3−2:工程2−70−3と同様の手法を用いて、工程4−3−1で得られ化合物(17 mg)より表題化合物(14 mg, 無色アモルファス)を得た。
LCMS (ESI) m/z 492 [M+H]+, tR = 0.53 min, mode N.
Example 4-3: N-{(1S) -1- [5- (3-aminoazetidin-1-yl) -6-methylpyrazolo [1,5-a] pyrimidin-2-yl] ethyl} -5 Step 4-3-1: Synthesis of 4-chloro-N-methyl-2-[(methylsulfonyl) amino] benzamide obtained in Step 2-9-2 using the same method as in Step 1-1-6. Compound (20 mg) and tert-butyl azetidin-3-ylcarbamate methanesulfonate (47 mg) from tert-butyl [1- (2-{(1S) -1-[{5-chloro-2- [ (Methylsulfonyl) amino] benzoyl} (methyl) amino] ethyl} -6-methylpyrazolo [1,5-a] pyrimidin-5-yl) azetidin-3-yl] carbamate (17 mg) was obtained.
LCMS (ESI) m / z 592 [M + H] + , t R = 1.10 min, mode N.
Step 4-3-2: Using the same method as in Step 2-70-3, the title compound (14 mg, colorless amorphous) was obtained from the compound (17 mg) obtained in Step 4-3-1.
LCMS (ESI) m / z 492 [M + H] + , t R = 0.53 min, mode N.
実施例4−4:N-[(1S)-1-(5-{[(1-アミノシクロブチル)メチル]アミノ}-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル)エチル]-5-クロロ-N-メチル-2-[(メチルスルホニル)アミノ]ベンズアミドの合成
工程4−4−1:工程1−1−6と同様の手法を用いて、工程2−9−2で得られた化合物(20 mg)及びtert-ブチル (1-[(アミノメチル)シクロブチル]カルバマート(35 mg)よりtert-ブチル (1-{[(2-{(1S)-1-[{5-クロロ-2-[(メチルスルホニル)アミノ]ベンゾイル}(メチル)アミノ]エチル}-6-メチルピラゾロ[1,5-a]ピリミジン-5-イル)アミノ]メチル}シクロブチル)カルバマート(11 mg)を得た。
LCMS (ESI) m/z 620 [M+H]+, tR = 1.26 min, mode N.
工程4−4−2:工程2−70−3と同様の手法を用いて、工程4−4−1で得られ化合物(10 mg)より表題化合物(8.0 mg)を得た。
LCMS (ESI) m/z 520 [M+H]+, tR = 0.58 min, mode N.
Example 4-4: N-[(1S) -1- (5-{[(1-aminocyclobutyl) methyl] amino} -6-methylpyrazolo [1,5-a] pyrimidin-2-yl) ethyl] Synthesis of 4-5-chloro-N-methyl-2-[(methylsulfonyl) amino] benzamide Step 4-4-1: Obtained in Step 2-9-2 using the same method as in Step 1-1-6. From the obtained compound (20 mg) and tert-butyl (1-[(aminomethyl) cyclobutyl] carbamate (35 mg), tert-butyl (1-{[(2-{(1S) -1-[{5-chloro -2-[(Methylsulfonyl) amino] benzoyl} (methyl) amino] ethyl} -6-methylpyrazolo [1,5-a] pyrimidin-5-yl) amino] methyl} cyclobutyl) carbamate (11 mg) was obtained. .
LCMS (ESI) m / z 620 [M + H] + , t R = 1.26 min, mode N.
Step 4-4-2: The title compound (8.0 mg) was obtained from the compound (10 mg) obtained in Step 4-4-1 using the same method as in Step 2-70-3.
LCMS (ESI) m / z 520 [M + H] + , t R = 0.58 min, mode N.
実施例4−5:5-クロロ-N-メチル-N-{(1S)-1-[6-メチル-5-(ピペラジン-1-イル)ピラゾロ[1,5-a]ピリミジン-2-イル]エチル}-2-[(メチルスルホニル)アミノ]ベンズアミド 塩酸塩の合成
工程1−1−6及び工程1−1−7と同様の手法を用いて、工程2−9−2で得られた化合物(20 mg)及び1-tert-ブトキシカルボニルピペラジン(33 mg)より表題化合物(17 mg, 無色アモルファス)を得た。
LCMS (ESI) m/z 506 [M+H]+, tR = 0.55 min, mode N.
Example 4-5: 5-chloro-N-methyl-N-{(1S) -1- [6-methyl-5- (piperazin-1-yl) pyrazolo [1,5-a] pyrimidin-2-yl Ethyl} -2-[(methylsulfonyl) amino] benzamide Compound obtained in Step 2-9-2 using the same method as in Step 1-1-6 and Step 1-1-7 of hydrochloride The title compound (17 mg, colorless amorphous) was obtained from (20 mg) and 1-tert-butoxycarbonylpiperazine (33 mg).
LCMS (ESI) m / z 506 [M + H] + , t R = 0.55 min, mode N.
実施例4−6:N-[(1S)-1-{5-[(2-アミノエチル)アミノ]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}エチル]-5-クロロ-N-メチル-2-[(メチルスルホニル)アミノ]ベンズアミド 塩酸塩の合成
工程1−1−6及び工程1−1−7と同様の手法を用いて、工程2−9−2で得られた化合物(22 mg)及びtert-ブチル (2-アミノエチル)カルバマート(12 mg)より表題化合物(7 mg, 淡黄色固体)を得た。
1H NMR (600 MHz, DMSO-d6, δ): 1.51-1.63 (m, 3H), 2.11 (s, 1.5H), 2.11 (s, 1.5H), 2.60 (s, 1.5H), 2.92- 3.11 (m, 3H), 3.05 (s, 1.5H), 3.43-3.72 (m, 4H), 4.74-4.83 (m, 0.5H), 5.89-5.96 (m, 0.5H), 5.98-6.11 (m, 1H), 7.35-7.57 (m, 3H), 7.89 (br s, 1H), 7.98 (br s, 3H), 8.46 (s, 0.5H), 9.25 (s, 0.5H).
LCMS (ESI) m/z 480 [M+H]+, tR = 0.52 min, mode N.
Example 4-6: N-[(1S) -1- {5-[(2-aminoethyl) amino] -6-methylpyrazolo [1,5-a] pyrimidin-2-yl} ethyl] -5-chloro -N-methyl-2-[(methylsulfonyl) amino] benzamide obtained in Step 2-9-2 using the same procedure as in Step 1-1-6 and Step 1-1-7 of hydrochloride The title compound (7 mg, pale yellow solid) was obtained from the compound (22 mg) and tert-butyl (2-aminoethyl) carbamate (12 mg).
1 H NMR (600 MHz, DMSO-d 6 , δ): 1.51-1.63 (m, 3H), 2.11 (s, 1.5H), 2.11 (s, 1.5H), 2.60 (s, 1.5H), 2.92- 3.11 (m, 3H), 3.05 (s, 1.5H), 3.43-3.72 (m, 4H), 4.74-4.83 (m, 0.5H), 5.89-5.96 (m, 0.5H), 5.98-6.11 (m, 1H), 7.35-7.57 (m, 3H), 7.89 (br s, 1H), 7.98 (br s, 3H), 8.46 (s, 0.5H), 9.25 (s, 0.5H).
LCMS (ESI) m / z 480 [M + H] + , t R = 0.52 min, mode N.
実施例4−7:N-[(1S)-1-{5-[(trans-3-アミノシクロブチル)アミノ]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}エチル]-5-クロロ-N-メチル-2-[(メチルスルホニル)アミノ]ベンズアミド 塩酸塩の合成
工程1−1−6及び工程1−1−7と同様の手法を用いて、工程2−9−2で得られた化合物(20 mg)及びtrans-tert-ブチル(-3-アミノシクロブチル)カルバマート(33 mg)より表題化合物(19 mg, 無色アモルファス)を得た。
LCMS (ESI) m/z 506 [M+H]+, tR = 0.55 min, mode N.
Example 4-7: N-[(1S) -1- {5-[(trans-3-aminocyclobutyl) amino] -6-methylpyrazolo [1,5-a] pyrimidin-2-yl} ethyl]- 5-Chloro-N-methyl-2-[(methylsulfonyl) amino] benzamide In the step 2-9-2, using the same procedure as in Step 1-1-6 and Step 1-1-7 The title compound (19 mg, colorless amorphous) was obtained from the obtained compound (20 mg) and trans-tert-butyl (-3-aminocyclobutyl) carbamate (33 mg).
LCMS (ESI) m / z 506 [M + H] + , t R = 0.55 min, mode N.
実施例4−8:N-[(1S)-1-{5-[(3-アミノプロピル)アミノ]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}エチル]-5-クロロ-N-メチル-2-[(メチルスルホニル)アミノ]ベンズアミド 塩酸塩の合成
工程1−1−6及び工程1−1−7と同様の手法を用いて、工程2−9−2で得られた化合物(20 mg)及びtert-ブチル (3-アミノプロピル)カルバマート(31 mg)より表題化合物(21 mg, 無色アモルファス)を得た。
LCMS (ESI) m/z 494 [M+H]+, tR = 0.54 min, mode N.
Example 4-8: N-[(1S) -1- {5-[(3-aminopropyl) amino] -6-methylpyrazolo [1,5-a] pyrimidin-2-yl} ethyl] -5-chloro -N-methyl-2-[(methylsulfonyl) amino] benzamide obtained in Step 2-9-2 using the same procedure as in Step 1-1-6 and Step 1-1-7 of hydrochloride The title compound (21 mg, colorless amorphous) was obtained from the compound (20 mg) and tert-butyl (3-aminopropyl) carbamate (31 mg).
LCMS (ESI) m / z 494 [M + H] + , t R = 0.54 min, mode N.
実施例4−9:N-[(1S)-1-{5-[(3R)-3-(アミノメチル)ピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}エチル]-5-クロロ-N-メチル-2-[(メチルスルホニル)アミノ]ベンズアミド 塩酸塩の合成
工程1−1−6及び工程1−1−7と同様の手法を用いて、工程2−9−2で得られた化合物(20 mg)及び(S)-tert-ブチル (ピロリジン-3-イルメチル)カルバマート(35 mg)より表題化合物(19 mg, 無色アモルファス)を得た。
LCMS (ESI) m/z 520 [M+H]+, tR = 0.56 min, mode N.
Example 4-9: N-[(1S) -1- {5-[(3R) -3- (aminomethyl) pyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidine-2- Yl} ethyl] -5-chloro-N-methyl-2-[(methylsulfonyl) amino] benzamide Hydrochloride Synthesis Step 1-1-6 and Step 1-1-7 using the same procedure as in Step 2 The title compound (19 mg, colorless amorphous) was obtained from the compound (20 mg) obtained in -9-2 and (S) -tert-butyl (pyrrolidin-3-ylmethyl) carbamate (35 mg).
LCMS (ESI) m / z 520 [M + H] + , t R = 0.56 min, mode N.
実施例4−10:N-[(1S)-1-{5-[(3S)-3-(アミノメチル)ピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}エチル]-5-クロロ-N-メチル-2-[(メチルスルホニル)アミノ]ベンズアミド 塩酸塩の合成
工程1−1−6及び工程1−1−7と同様の手法を用いて、工程2−9−2で得られた化合物(20 mg)及び(R)-tert-ブチル (ピロリジン-3-イルメチル)カルバマート(35 mg)より表題化合物(20 mg, 無色アモルファス)を得た。
LCMS (ESI) m/z 520 [M+H]+, tR = 0.56 min, mode N.
Example 4-10: N-[(1S) -1- {5-[(3S) -3- (aminomethyl) pyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidine-2- Yl} ethyl] -5-chloro-N-methyl-2-[(methylsulfonyl) amino] benzamide Hydrochloride Synthesis Step 1-1-6 and Step 1-1-7 using the same procedure as in Step 2 The title compound (20 mg, colorless amorphous) was obtained from the compound obtained in -9-2 (20 mg) and (R) -tert-butyl (pyrrolidin-3-ylmethyl) carbamate (35 mg).
LCMS (ESI) m / z 520 [M + H] + , t R = 0.56 min, mode N.
実施例4−11:5-クロロ-N-[(1S)-1-{5-[(3S)-3-ヒドロキシピロリジン-1-イル]-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}エチル]-N-メチル-2-[(メチルスルホニル)アミノ]ベンズアミドの合成
工程1−1−6と同様の手法を用いて、工程2−9−2で得られた化合物(20 mg)及び(S)-3-ピロリジノール(15 mg)より表題化合物(22 mg)を得た。
LCMS (ESI) m/z 507 [M+H]+, tR = 0.85 min, mode N.
Example 4-11: 5-chloro-N-[(1S) -1- {5-[(3S) -3-hydroxypyrrolidin-1-yl] -6-methylpyrazolo [1,5-a] pyrimidine-2 -Il} ethyl] -N-methyl-2-[(methylsulfonyl) amino] benzamide, using the same method as in Step 1-1-6, the compound obtained in Step 2-9-2 (20 mg ) And (S) -3-pyrrolidinol (15 mg) to give the title compound (22 mg).
LCMS (ESI) m / z 507 [M + H] + , t R = 0.85 min, mode N.
実施例4−12:5-クロロ-N-{(1S)-1-[5-(3,3-ジフルオロピロリジン-1-イル)-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル]エチル}-N-メチル-2-[(メチルスルホニル)アミノ]ベンズアミドの合成
工程1−1−6と同様の手法を用いて、工程2−9−2で得られた化合物(20 mg)及び3,3-ジフルオロピロリジン(25 mg)より表題化合物(16 mg, 無色アモルファス)を得た。
LCMS (ESI) m/z 527 [M+H]+, tR = 1.17 min, mode N.
Example 4-12: 5-chloro-N-{(1S) -1- [5- (3,3-difluoropyrrolidin-1-yl) -6-methylpyrazolo [1,5-a] pyrimidin-2-yl Synthesis of ethyl] -N-methyl-2-[(methylsulfonyl) amino] benzamide Using the same method as in Step 1-1-6, the compound (20 mg) obtained in Step 2-9-2 and The title compound (16 mg, colorless amorphous) was obtained from 3,3-difluoropyrrolidine (25 mg).
LCMS (ESI) m / z 527 [M + H] + , t R = 1.17 min, mode N.
実施例4−13:5-クロロ-N-{(1S)-1-[5-(3,3-ジフルオロアゼチジン-1-イル)-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル]エチル}-N-メチル-2-[(メチルスルホニル)アミノ]ベンズアミドの合成
工程1−1−6と同様の手法を用いて、工程2−9−2で得られた化合物(20 mg)及び3,3-ジフルオロアゼチジン(23 mg)より表題化合物(18 mg, 無色アモルファス)を得た。
LCMS (ESI) m/z 513 [M+H]+, tR = 1.13 min, mode N.
Example 4-13: 5-chloro-N-{(1S) -1- [5- (3,3-difluoroazetidin-1-yl) -6-methylpyrazolo [1,5-a] pyrimidine-2- Yl] ethyl} -N-methyl-2-[(methylsulfonyl) amino] benzamide Compound (20 mg) obtained in Step 2-9-2 using the same method as in Step 1-1-6. The title compound (18 mg, colorless amorphous) was obtained from 3,3-difluoroazetidine (23 mg).
LCMS (ESI) m / z 513 [M + H] + , t R = 1.13 min, mode N.
実施例5−1:N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-3-クロロ-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}エチル]-5-クロロ-N-メチル-2-[(メチルスルホニル)アミノ]ベンズアミド 塩酸塩の合成
工程5−1−1:工程1−1−4で得られた化合物(170 mg)のDMF(5 mL)溶液に、NCS(78 mg) を加え、室温にて4時間攪拌した。反応液を水にあけ、EtOAcにて抽出を行った。その有機層をBrineで洗浄、MgSO4で乾燥ろ過後、ろ液を減圧下濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー(移動相:ヘキサン/EtOAc = 80/20〜0/100; v/v) で精製し、tert-ブチル [(1S)-1-(3-クロロ-6-メチル-5-オキソ-4,5-ジヒドロピラゾロ[1,5-a]ピリミジン-2-イル)エチル](メチル)カルバマート(90 mg, 無色アモルファス)を得た。
1H NMR (600 MHz, CDCl3, δ): 1.45-1.55 (m, 12H), 2.02-2.21 (m, 3H), 2.64 (br s, 3H), 7.93 (d, J = 1.2 Hz, 1H), 9.95 (br s, 1H).
LCMS (ESI) m/z 341 [M+H]+.
工程5−1−2:工程1−1−5と同様の手法を用いて、工程5−1−1で得られた化合物(90 mg)より、2-{(1S)-1-[(tert-ブトキシカルボニル)(メチル)アミノ]エチル}-3-クロロ-6-メチルピラゾロ[1,5-a]ピリミジン-5-イル トリフルオロメタンスルホナート(115 mg)を得た。
LCMS (ESI) m/z 373 [M+H-Boc]+, tR = 1.30 min, mode N.
工程5−1−3:工程1−1−6と同様の手法を用いて、工程5−1−2で得られた化合物(0.11 g)より、3-クロロ-6-メチル-2-[(1S)-1-(メチルアミノ)エチル]ピラゾロ[1,5-a]ピリミジン-5-イル トリフルオロメタンスルホナート(90 mg)を得た。
LCMS (ESI) m/z 373 [M+H]+, tR = 0.59 min, mode N.
工程5−1−4:工程1−1−7と同様の手法を用いて、工程5−1−3で得られた化合物(90 mg)より、3-クロロ-2-{(1S)-1-[{5-クロロ-2-[(メチルスルホニル)アミノ]ベンゾイル}(メチル)アミノ]エチル}-6-メチルピラゾロ[1,5-a]ピリミジン-5-イル トリフルオロメタンスルホナート(70 mg) を得た。
工程5−1−5:工程1−1−8と同様の手法を用いて、工程5−1−4で得られた化合物(70 mg)より、tert-ブチル [(3S)-1-(3-クロロ-2-{(1S)-1-[{5-クロロ-2-[(メチルスルホニル)アミノ]ベンゾイル}(メチル)アミノ]エチル}-6-メチルピラゾロ[1,5-a]ピリミジン-5-イル)ピロリジン-3-イル]カルバマート(61 mg)を得た。
1H NMR (600 MHz, CDCl3, δ): 1.46 (s, 9H), 1.78 (d, J = 7.4 Hz, 3H), 1.90-1.98 (m, 1H), 2.22 (d, J = 5.0 Hz, 1H), 2.37 (s, 3H), 2.78-3.06 (m, 6H), 3.62 (dd, J = 11.1, 4.1 Hz, 1H), 3.77-3.92 (m, 1H), 4.00 (dd, J = 10.7, 5.4 Hz, 1H), 4.31 (br s, 1H), 4.67 (br s, 1H), 5.03 (br s, 1H), 6.15 (d, J = 7.4 Hz, 1H), 7.28-7.76 (m, 3H), 8.36 (s, 1H), 8.77 (br s, 1H).
LCMS (ESI) m/z 640 [M+H]+, tR = 1.19 min, mode N.
工程5−1−6:工程1−2−8と同様の手法を用いて、工程5−1−5で得られた化合物(56 mg)より、表題化合物 (42 mg, 無色固体)を得た。
LCMS (ESI) m/z 541 [M+H]+, tR = 0.56 min, mode N.
Example 5-1: N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -3-chloro-6-methylpyrazolo [1,5-a] pyrimidine-2 -Yl} ethyl] -5-chloro-N-methyl-2-[(methylsulfonyl) amino] benzamide hydrochloride synthesis step 5-1-1: compound obtained in step 1-1-4 (170 mg) NCS (78 mg) was added to a DMF (5 mL) solution, and the mixture was stirred at room temperature for 4 hours. The reaction solution was poured into water and extracted with EtOAc. The organic layer was washed with Brine, dried and filtered with MgSO 4 , and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (mobile phase: hexane / EtOAc = 80 / 20-0 / 100; v / v), and tert-butyl [(1S) -1- (3-chloro-6- Methyl-5-oxo-4,5-dihydropyrazolo [1,5-a] pyrimidin-2-yl) ethyl] (methyl) carbamate (90 mg, colorless amorphous) was obtained.
1 H NMR (600 MHz, CDCl 3 , δ): 1.45-1.55 (m, 12H), 2.02-2.21 (m, 3H), 2.64 (br s, 3H), 7.93 (d, J = 1.2 Hz, 1H) , 9.95 (br s, 1H).
LCMS (ESI) m / z 341 [M + H] + .
Step 5-1-2: Using a method similar to that of Step 1-1-5, the compound (90 mg) obtained in Step 5-1-1 was used to give 2-{(1S) -1-[(tert -Butoxycarbonyl) (methyl) amino] ethyl} -3-chloro-6-methylpyrazolo [1,5-a] pyrimidin-5-yl trifluoromethanesulfonate (115 mg) was obtained.
LCMS (ESI) m / z 373 [M + H-Boc] +, t R = 1.30 min, mode N.
Step 5-1-3: Using the same method as in Step 1-1-6, 3-chloro-6-methyl-2-[((1)) was obtained from the compound (0.11 g) obtained in Step 5-1-2. 1S) -1- (Methylamino) ethyl] pyrazolo [1,5-a] pyrimidin-5-yl trifluoromethanesulfonate (90 mg) was obtained.
LCMS (ESI) m / z 373 [M + H] + , t R = 0.59 min, mode N.
Step 5-1-4: Using a method similar to that of Step 1-1-7, 3-chloro-2-{(1S) -1 from the compound (90 mg) obtained in Step 5-1-3 -[{5-Chloro-2-[(methylsulfonyl) amino] benzoyl} (methyl) amino] ethyl} -6-methylpyrazolo [1,5-a] pyrimidin-5-yl trifluoromethanesulfonate (70 mg) Obtained.
Step 5-1-5: Using a method similar to that of Step 1-1-8, from the compound obtained in Step 5-1-4 (70 mg), tert-butyl [(3S) -1- (3 -Chloro-2-{(1S) -1-[{5-chloro-2-[(methylsulfonyl) amino] benzoyl} (methyl) amino] ethyl} -6-methylpyrazolo [1,5-a] pyrimidine-5 -Yl) pyrrolidin-3-yl] carbamate (61 mg) was obtained.
1 H NMR (600 MHz, CDCl 3 , δ): 1.46 (s, 9H), 1.78 (d, J = 7.4 Hz, 3H), 1.90-1.98 (m, 1H), 2.22 (d, J = 5.0 Hz, 1H), 2.37 (s, 3H), 2.78-3.06 (m, 6H), 3.62 (dd, J = 11.1, 4.1 Hz, 1H), 3.77-3.92 (m, 1H), 4.00 (dd, J = 10.7, 5.4 Hz, 1H), 4.31 (br s, 1H), 4.67 (br s, 1H), 5.03 (br s, 1H), 6.15 (d, J = 7.4 Hz, 1H), 7.28-7.76 (m, 3H) , 8.36 (s, 1H), 8.77 (br s, 1H).
LCMS (ESI) m / z 640 [M + H] + , t R = 1.19 min, mode N.
Step 5-1-6: Using the same method as in Step 1-2-8, the title compound (42 mg, colorless solid) was obtained from the compound (56 mg) obtained in Step 5-1-5. .
LCMS (ESI) m / z 541 [M + H] +, t R = 0.56 min, mode N.
実施例5−2:N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-3,6-ジメチルピラゾロ[1,5-a]ピリミジン-2-イル}エチル]-5-クロロ-N-メチル-2-[(メチルスルホニル)アミノ]ベンズアミド 塩酸塩の合成
工程5−2−1:工程3−1−3で得られた化合物(400 mg)のDMF(8 mL)溶液に、NIS(256 mg)を加え、室温にて4時間攪拌した。反応液を水にあけ、EtOAcにて抽出を行った。有機層をBrineで洗浄、MgSO4で乾燥ろ過後、ろ液を減圧下濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー(移動相:ヘキサン/EtOAc = 80/20〜0/100; v/v) で精製し、tert-ブチル [(3S)-1-{3-ヨード-6-メチル-2-[(1S)-1-(メチルアミノ)エチル]ピラゾロ[1,5-a]ピリミジン-5-イル}ピロリジン-3-イル]カルバマート(510 mg, 無色アモルファス)を得た。
LCMS (ESI) m/z 501 [M+H]+, tR = 0.60 min, mode N.
工程5−2−2:工程1−1−7と同様の手法を用いて、工程5−2−1で得られた化合物(510 mg)より、tert-ブチル [(3S)-1-(2-{(1S)-1-[{5-クロロ-2-[(メチルスルホニル)アミノ]ベンゾイル}(メチル)アミノ]エチル}-3-ヨード-6-メチルピラゾロ[1,5-a]ピリミジン-5-イル)ピロリジン-3-イル]カルバマート(460 mg)を得た。
1H NMR (600 MHz, CDCl3, δ): 1.44 (s, 9H), 1.71-1.82 (m, 3H), 1.93 (dd, J = 12.0, 6.6 Hz, 1H), 2.17-2.27 (m, 1H), 2.37 (s, 3H), 2.77-3.04 (m, 6H), 3.62 (d, J = 7.0 Hz, 1H), 3.75-3.91 (m, 2H), 3.99 (dd, J = 10.9, 6.0 Hz, 1H), 4.31 (br s, 1H), 4.68 (br s, 1H), 4.99 (br s, 0.2H), 5.99 (d, J = 7.0 Hz, 0.8H), 7.27-7.70 (m, 3H), 8.03 (s, 1H), 8.19-8.32 (m, 0.2H), 8.57 (br s, 0.8H).
LCMS (ESI) m/z 732 [M+H]+, tR = 1.22 min, mode N.
工程5−2−3:工程5−2−2で得られた化合物(200 mg)のDMF(5 mL)溶液に、2,4,6-トリメチルボロキシン(102 mg), PdCl2(dppf)・CH2Cl2(33 mg)、K2CO3(188 mg)を加え、110 ℃で3時間攪拌した。反応液を水にあけ、EtOAcにて抽出を行った。有機層をBrineで洗浄、MgSO4で乾燥ろ過後、ろ液を減圧下濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー (移動相:ヘキサン/EtOAc = 80/20〜0/100; v/v) にて精製し、tert-ブチル [(3S)-1-(2-{(1S)-1-[{5-クロロ-2-[(メチルスルホニル)アミノ]ベンゾイル}(メチル)アミノ]エチル}-3,6-ジメチルピラゾロ[1,5-a]ピリミジン-5-イル)ピロリジン-3-イル]カルバマート(43 mg, 無色アモルファス)を得た。
1H NMR (600 MHz, CDCl3, δ): 1.44 (s, 9H), 1.63-1.74 (m, 3H), 1.86-1.95 (m, 1H), 2.20 (d, J = 13.2 Hz, 4H), 2.33 (d, J = 9.1 Hz, 3H), 2.72-3.05 (m, 6H), 3.55 (dd, J = 10.9, 3.9 Hz, 1H), 3.67-3.84 (m, 2H), 3.92 (br s, 1H), 4.30 (br s, 1H), 4.70 (br s, 1H), 4.99 (d, J = 7.0 Hz, 0.4H), 6.08-6.21 (m, 0.6H), 7.20-7.70 (m, 3H), 8.24-8.44 (m, 1H), 9.19 (s, 0.6H), 10.93 (br s, 0.4H).
LCMS (ESI) m/z 620 [M+H]+, tR = 1.21 min, mode N.
工程5−2−4:工程1−2−8と同様の手法を用いて、工程5−2−3で得られた化合物(43 mgより、表題化合物(32 mg, 無色固体)を得た。
LCMS (ESI) m/z 520 [M+H]+, tR = 0.56 min, mode N.
Example 5-2: N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -3,6-dimethylpyrazolo [1,5-a] pyrimidine-2 -Il} ethyl] -5-chloro-N-methyl-2-[(methylsulfonyl) amino] benzamide hydrochloride synthesis step 5-2-1: compound obtained in step 3-1-3 (400 mg) NIS (256 mg) was added to a DMF (8 mL) solution, and the mixture was stirred at room temperature for 4 hours. The reaction solution was poured into water and extracted with EtOAc. The organic layer was washed with Brine, dried and filtered with MgSO 4 , and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (mobile phase: hexane / EtOAc = 80 / 20-0 / 100; v / v), and tert-butyl [(3S) -1- {3-iodo-6- Methyl-2-[(1S) -1- (methylamino) ethyl] pyrazolo [1,5-a] pyrimidin-5-yl} pyrrolidin-3-yl] carbamate (510 mg, colorless amorphous) was obtained.
LCMS (ESI) m / z 501 [M + H] + , t R = 0.60 min, mode N.
Step 5-2-2: Using a method similar to that of Step 1-1-7, tert-butyl [(3S) -1- (2) from the compound (510 mg) obtained in Step 5-2-1. -{(1S) -1-[{5-Chloro-2-[(methylsulfonyl) amino] benzoyl} (methyl) amino] ethyl} -3-iodo-6-methylpyrazolo [1,5-a] pyrimidine-5 -Yl) pyrrolidin-3-yl] carbamate (460 mg) was obtained.
1 H NMR (600 MHz, CDCl 3 , δ): 1.44 (s, 9H), 1.71-1.82 (m, 3H), 1.93 (dd, J = 12.0, 6.6 Hz, 1H), 2.17-2.27 (m, 1H ), 2.37 (s, 3H), 2.77-3.04 (m, 6H), 3.62 (d, J = 7.0 Hz, 1H), 3.75-3.91 (m, 2H), 3.99 (dd, J = 10.9, 6.0 Hz, 1H), 4.31 (br s, 1H), 4.68 (br s, 1H), 4.99 (br s, 0.2H), 5.99 (d, J = 7.0 Hz, 0.8H), 7.27-7.70 (m, 3H), 8.03 (s, 1H), 8.19-8.32 (m, 0.2H), 8.57 (br s, 0.8H).
LCMS (ESI) m / z 732 [M + H] + , t R = 1.22 min, mode N.
Step 5-2-3: To a DMF (5 mL) solution of the compound (200 mg) obtained in Step 5-2-2, add 2,4,6-trimethylboroxine (102 mg), PdCl 2 (dppf) · CH 2 Cl 2 (33 mg ), K 2 CO 3 to (188 mg) was added and stirred for 3 hours at 110 ° C.. The reaction solution was poured into water and extracted with EtOAc. The organic layer was washed with Brine, dried and filtered with MgSO 4 , and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (mobile phase: hexane / EtOAc = 80 / 20-0 / 100; v / v), and tert-butyl [(3S) -1- (2-{(1S ) -1-[{5-Chloro-2-[(methylsulfonyl) amino] benzoyl} (methyl) amino] ethyl} -3,6-dimethylpyrazolo [1,5-a] pyrimidin-5-yl) pyrrolidine -3-yl] carbamate (43 mg, colorless amorphous) was obtained.
1 H NMR (600 MHz, CDCl 3 , δ): 1.44 (s, 9H), 1.63-1.74 (m, 3H), 1.86-1.95 (m, 1H), 2.20 (d, J = 13.2 Hz, 4H), 2.33 (d, J = 9.1 Hz, 3H), 2.72-3.05 (m, 6H), 3.55 (dd, J = 10.9, 3.9 Hz, 1H), 3.67-3.84 (m, 2H), 3.92 (br s, 1H ), 4.30 (br s, 1H), 4.70 (br s, 1H), 4.99 (d, J = 7.0 Hz, 0.4H), 6.08-6.21 (m, 0.6H), 7.20-7.70 (m, 3H), 8.24-8.44 (m, 1H), 9.19 (s, 0.6H), 10.93 (br s, 0.4H).
LCMS (ESI) m / z 620 [M + H] + , t R = 1.21 min, mode N.
Step 5-2-4: Using a method similar to that of Step 1-2-8, the title compound (32 mg, colorless solid) was obtained from 43 mg (43 mg).
LCMS (ESI) m / z 520 [M + H] + , t R = 0.56 min, mode N.
実施例5−3:N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-メチル-3-フェニルピラゾロ[1,5-a]ピリミジン-2-イル}エチル]-5-クロロ-N-メチル-2-[(メチルスルホニル)アミノ]ベンズアミド 塩酸塩の合成
工程5−3−1:工程5−2−2で得られた化合物(60 mg)の1,4-ジオキサン/水混合溶液 (3.3 mL, 10/1; v/v)に、フェニルボロン酸(30 mg),Pd2(dba)3(7.5 mg),TFP(11 mg), Cs2CO3(80 mg)を加え、90 ℃で2時間攪拌した。反応液を水にあけ、EtOAcにて抽出を行った。有機層をBrineで洗浄、MgSO4で乾燥ろ過後、ろ液を減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー(移動相:ヘキサン/EtOAc = 80/20〜0/100; v/v) にて精製し、tert-ブチル [(3S)-1-(2-{(1S)-1-[{5-クロロ-2-[(メチルスルホニル)アミノ]ベンゾイル}(メチル)アミノ]エチル}-6-メチル-3-フェニルピラゾロ[1,5-a]ピリミジン-5-イル)ピロリジン-3-イル]カルバマート(25 mg, 無色アモルファス)を得た。
LCMS (ESI) m/z 682 [M+H]+, tR = 0.82 min, mode N.
工程5−3−2:工程1−2−8と同様の手法を用いて、工程5−3−1で得られた化合物(34 mg)より、表題化合物 (28 mg, 無色固体)を得た。
LCMS (ESI) m/z 582 [M+H]+, tR = 0.62 min, mode N.
Example 5-3: N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-methyl-3-phenylpyrazolo [1,5-a] pyrimidine 2-yl} ethyl] -5-chloro-N-methyl-2-[(methylsulfonyl) amino] benzamide Hydrochloride Synthesis Step 5-3-1: Compound (60) obtained in Step 5-2-2 mg) in 1,4-dioxane / water mixed solution (3.3 mL, 10/1; v / v), phenylboronic acid (30 mg), Pd 2 (dba) 3 (7.5 mg), TFP (11 mg) , Cs 2 CO 3 (80 mg) was added, and the mixture was stirred at 90 ° C. for 2 hr. The reaction solution was poured into water and extracted with EtOAc. The organic layer was washed with Brine, dried and filtered with MgSO 4 , and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase: hexane / EtOAc = 80 / 20-0 / 100; v / v) and tert-butyl [(3S) -1- (2-{(1S) -1 -[{5-Chloro-2-[(methylsulfonyl) amino] benzoyl} (methyl) amino] ethyl} -6-methyl-3-phenylpyrazolo [1,5-a] pyrimidin-5-yl) pyrrolidine- 3-yl] carbamate (25 mg, colorless amorphous) was obtained.
LCMS (ESI) m / z 682 [M + H] + , t R = 0.82 min, mode N.
Step 5-3-2: The title compound (28 mg, colorless solid) was obtained from the compound (34 mg) obtained in Step 5-3-1 using the same method as in Step 1-2-8. .
LCMS (ESI) m / z 582 [M + H] + , t R = 0.62 min, mode N.
実施例5−4:N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-3-(4-ヒドロキシブタ-1-イン-1-イル)-6-メチルピラゾロ[1,5-a]ピリミジン-2-イル}エチル]-5-クロロ-N-メチル-2-[(メチルスルホニル)アミノ]ベンズアミドの合成
工程5−4−1:工程5−2−2で得られた化合物(50 mg)のDMF/Et3N混合溶液(4.5 mL, 2/1; v/v)に、4-ヒドロキシ-1-ブチン(14 mg)、PdCl2(Ph3P)2(4.8 mg)、CuI(1.3 mg)、Ph3P(3.6 mg)、HMDS(22 μL)を加え、110 ℃で2時間攪拌した。反応液を水にあけ、EtOAc にて抽出を行った。有機層をBrineで洗浄、MgSO4で乾燥ろ過後、ろ液を減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー(移動相:ヘキサン/EtOAc = 80/20〜0/100; v/v) にて精製し、tert-ブチル {(3S)-1-[2-{(1S)-1-[{5-クロロ-2-[(メチルスルホニル)アミノ]ベンゾイル}(メチル)アミノ]エチル}-3-(4-ヒドロキシブタ-1-イン-1-イル)-6-メチルピラゾロ[1,5-a]ピリミジン-5-イル]ピロリジン-3-イル}カルバマート(12 mg, 無色アモルファス)を得た。
工程5−4−2:工程1−2−8と同様の手法を用いて、工程5−4−1で得られた化合物(12 mg)より、表題化合物(3.0 mg, 無色固体)を得た。
LCMS (ESI) m/z 574 [M+H]+, tR = 0.53 min, mode N.
Example 5-4: N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -3- (4-hydroxybut-1-in-1-yl)- Synthesis Step 5-4-1: Step 5-2 of 6-methylpyrazolo [1,5-a] pyrimidin-2-yl} ethyl] -5-chloro-N-methyl-2-[(methylsulfonyl) amino] benzamide -2 compound (50 mg) in DMF / Et 3 N mixed solution (4.5 mL, 2/1; v / v) was added 4-hydroxy-1-butyne (14 mg), PdCl 2 (Ph 3 P) 2 (4.8 mg), CuI (1.3 mg), Ph 3 P (3.6 mg), and HMDS (22 μL) were added, and the mixture was stirred at 110 ° C. for 2 hours. The reaction solution was poured into water and extracted with EtOAc. The organic layer was washed with Brine, dried and filtered with MgSO 4 , and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase: hexane / EtOAc = 80 / 20-0 / 100; v / v) and tert-butyl {(3S) -1- [2-{(1S) -1 -[{5-Chloro-2-[(methylsulfonyl) amino] benzoyl} (methyl) amino] ethyl} -3- (4-hydroxybut-1-in-1-yl) -6-methylpyrazolo [1,5 -a] pyrimidin-5-yl] pyrrolidin-3-yl} carbamate (12 mg, colorless amorphous) was obtained.
Step 5-4-2: Using the same method as in Step 1-2-8, the title compound (3.0 mg, colorless solid) was obtained from the compound (12 mg) obtained in Step 5-4-1. .
LCMS (ESI) m / z 574 [M + H] + , t R = 0.53 min, mode N.
実施例5−5:N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]ピラゾロ[1,5-a]ピリミジン-2-イル}エチル]-5-クロロ-N-メチル-2-[(メチルスルホニル)アミノ]ベンズアミド 塩酸塩の合成
工程1−2−2、工程1−1−5、工程1−1−7、工程1−1−8、工程1−2−5及び工程1−2−8と同様の手法を用いて、工程1−1−3で得られた化合物(1.00 g)及びジメチルウラシル(700 mg)より、表題化合物(147 mg, 無色固体)を得た。
LCMS (ESI) m/z 492 [M+H]+, tR = 0.92 min, mode H.
Example 5-5: N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] pyrazolo [1,5-a] pyrimidin-2-yl} ethyl] -5 -Chloro-N-methyl-2-[(methylsulfonyl) amino] benzamide hydrochloride synthesis step 1-2-2, step 1-1-5, step 1-1-7, step 1-1-8, step Using the same method as in 1-2-5 and step 1-2-8, the title compound (147 mg, 147 mg,) was obtained from the compound (1.00 g) obtained in step 1-1-3 and dimethyluracil (700 mg). A colorless solid was obtained.
LCMS (ESI) m / z 492 [M + H] + , t R = 0.92 min, mode H.
実施例5−6:N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-7-メチルピラゾロ[1,5-a]ピリミジン-2-イル}エチル]-5-クロロ-N-メチル-2-[(メチルスルホニル)アミノ]ベンズアミド 塩酸塩の合成
工程1−1−4、工程1−1−5、工程1−1−7、工程1−1−8、工程1−2−5及び工程1−2−8と同様の手法を用いて、工程1−1−3で得られた化合物(1.31 g)及びエチル 3-エトキシ-2-ブテノエート(1.55 g)より、表題化合物(65.0 mg, 無色固体)を得た。
LCMS (ESI) m/z 506 [M+H]+, tR = 0.89 min, mode H.
Example 5-6: N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -7-methylpyrazolo [1,5-a] pyrimidin-2-yl} ethyl ] -5-Chloro-N-methyl-2-[(methylsulfonyl) amino] benzamide Hydrochloride Synthesis Step 1-1-4, Step 1-1-5, Step 1-1-7, Step 1-1 8. Using the same method as in Step 1-2-5 and Step 1-2-8, the compound obtained in Step 1-1-3 (1.31 g) and ethyl 3-ethoxy-2-butenoate (1.55 g ) Afforded the title compound (65.0 mg, colorless solid).
LCMS (ESI) m / z 506 [M + H] + , t R = 0.89 min, mode H.
実施例5−7:N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-エチルピラゾロ[1,5-a]ピリミジン-2-イル}エチル]-5-クロロ-N-メチル-2-[(メチルスルホニル)アミノ]ベンズアミド 塩酸塩の合成
工程5−7−1:工程1−1−3で得られた化合物(390 mg)のEtOH(8.0 mL)溶液にエチル (2E)-2-(メトキシメチリデン)ブタノエート(380 mg)及び28%NaOMe/MeOH溶液(1.1 mL)を加え、90 ℃で21時間撹拌した。反応溶液にEtOAcを加え、飽和NaHCO3水溶液で分液操作を行った。水層をBrine及びMgSO4を用いて分離した後、有機層を減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー(移動相:ヘキサン/EtOAc = 70/30〜35/65; v/v)にて精製し、tert-ブチル [(1S)-1-(6-エチル-5-オキソ-4,5-ジヒドロピラゾロ[1,5-a]ピリミジン-2-イル)エチル](メチル)カルバマート(96 mg, 褐色油状物)を得た。
1H NMR (600 MHz, CDCl3, δ): 1.23 (t, J = 7.4 Hz, 3H), 1.50 (s, 9H), 1.52 (d, J = 7.0 Hz, 3H), 2.50-2.55 (m, 2H), 2.67 (br s, 3H), 5.25-5.65 (m, 1H), 5.75 (s, 1H), 7.96 (s, 1H), 9.97 (br s, 1H).
LCMS (ESI) m/z 321 [M+H]+, tR = 0.86 min, mode N.
工程5−7−2:工程1−1−5と同様の手法を用いて、工程5−7−1で得られた化合物(92 mg)より、2-{(1S)-1-[(tert-ブトキシカルボニル)(メチル)アミノ]エチル}-6-エチルピラゾロ[1,5-a]ピリミジン-5-イル トリフルオロメタンスルホナート(100 mg, 褐色油状物)を得た。
工程5−7−3:工程1−2−3と同様の手法を用いて、工程5−7−2で得られた化合物(0.10 g)より、6-エチル-2-[(1S)-1-(メチルアミノ)エチル]ピラゾロ[1,5-a]ピリミジン-5-イル トリフルオロメタンスルホナート 塩酸塩 (90 mg, 淡黄色状物質)を得た。
工程5−7−4:工程1−1−8と同様の手法を用いて、工程5−7−3で得られた化合物(90 mg)より、2-{(1S)-1-[{5-クロロ-2-[(メチルスルホニル)アミノ]ベンゾイル}(メチル)アミノ]エチル}-6-エチルピラゾロ[1,5-a]ピリミジン-5-イル トリフルオロメタンスルホナート(65 mg, 白色固体)を得た。
1H NMR (600 MHz, CDCl3, δ): 1.32-1.40 (m, 3H), 1.65-1.75 (m, 3H), 2.67 (s, 2H), 2.73-2.86 (m, 4H), 2.96 (s, 2H), 3.06 (s, 1H), 4.97-5.04 (m, 0.4H), 6.31 (q, J = 7.2 Hz, 0.6H), 6.42-6.48 (m, 1H), 7.24-7.42 (m, 2H), 7.62 (d, J = 8.3 Hz, 0.4H), 7.72 (d, J = 8.7 Hz, 0.6H), 8.80 (s, 0.4H), 8.95 (s, 0.6H), 9.10 (s, 0.6H), 10.43 (br s, 0.4H).
工程5−7−5:工程1−2−5と同様の手法を用いて、工程5−7−4で得られた化合物(58 mg)より、tert-ブチル [(3S)-1-(2-{(1S)-1-[{5-クロロ-2-[(メチルスルホニル)アミノ]ベンゾイル}(メチル)アミノ]エチル}-6-エチルピラゾロ[1,5-a]ピリミジン-5-イル)ピロリジン-3-イル]カルバマート(71 mg, 無色固体)を得た。
1H NMR (600 MHz, CDCl3, δ): 1.26-1.30 (m, 3H), 1.45 (br s, 9H), 1.61 (d, J = 7.0 Hz, 2H), 1.65 (d, J = 7.4 Hz, 1H), 1.88-1.96 (m, 1H), 2.18-2.26 (m, 1H), 2.64 (s, 1H), 2.69-2.78 (m, 2H), 2.82 (s, 2H), 2.95 (s, 1H), 3.03 (s, 2H), 3.48 -3.55 (m, 1H), 3.65-3.82 (m, 2H), 3.87-3.94 (m, 1H), 4.30 (br s, 1H), 4.66 (br s, 1H), 4.87-4.93 (m, 0.6H), 5.97-6.04 (m, 1H), 6.19-6.27 (m, 0.4H), 7.24-7.40 (m, 2H), 7.62 (d, J = 8.7 Hz, 0.6H), 7.69 (d, J = 9.1 Hz, 0.4H), 8.44 (s, 0.6H), 8.70 (s, 0.4H), 9.41 (s, 0.4H), 11.13 (br s, 0.6H).
工程5−7−6:工程1−2−8と同様の手法を用いて、工程5−7−5:工程1−2−5と同様の手法を用いて、工程5−7−4で得られた化合物(58 mg)で得られた化合物(69 mg)より、表題化合物(60 mg, 白色固体)を得た。
1H NMR (600 MHz, DMSO-d6, δ): 1.21 (t, J = 7.2 Hz, 3H), 1.52-1.62 (m, 3H), 2.01-2.11 (m, 1H), 2.21-2.31 (m, 1H), 2.57-2.63 (m, 1.5H), 2.69-2.80 (m, 3.5H), 2.99-3.09 (m, 3H), 3.65-3.76 (m, 2H), 3.81-3.92 (m, 3H), 4.77-4.84 (m, 0.5H), 5.95 (q, J = 7.4 Hz, 0.5H), 6.08-6.18 (m, 1H), 7.44-7.57 (m, 3H), 8.25-8.44 (m, 3H), 8.53 (s, 0.5H), 9.26 (s, 0.5H).
LCMS (ESI) m/z 520 [M+H]+, tR = 0.57 min, mode N.
Example 5-7: N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-ethylpyrazolo [1,5-a] pyrimidin-2-yl} ethyl ] -5-Chloro-N-methyl-2-[(methylsulfonyl) amino] benzamide Hydrochloride Synthesis Step 5-7-1: EtOH (8.0 mg) of the compound obtained in Step 1-1-3 (390 mg) To the solution, ethyl (2E) -2- (methoxymethylidene) butanoate (380 mg) and 28% NaOMe / MeOH solution (1.1 mL) were added, and the mixture was stirred at 90 ° C. for 21 hours. EtOAc was added to the reaction solution, and a liquid separation operation was performed with a saturated aqueous NaHCO 3 solution. The aqueous layer was separated using Brine and MgSO 4 , and then the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase: hexane / EtOAc = 70/30 to 35/65; v / v), and tert-butyl [(1S) -1- (6-ethyl-5-oxo- 4,5-Dihydropyrazolo [1,5-a] pyrimidin-2-yl) ethyl] (methyl) carbamate (96 mg, brown oil) was obtained.
1 H NMR (600 MHz, CDCl 3 , δ): 1.23 (t, J = 7.4 Hz, 3H), 1.50 (s, 9H), 1.52 (d, J = 7.0 Hz, 3H), 2.50-2.55 (m, 2H), 2.67 (br s, 3H), 5.25-5.65 (m, 1H), 5.75 (s, 1H), 7.96 (s, 1H), 9.97 (br s, 1H).
LCMS (ESI) m / z 321 [M + H] + , t R = 0.86 min, mode N.
Step 5-7-2: Using a method similar to that of Step 1-1-5, from the compound (92 mg) obtained in Step 5-7-1, 2-{(1S) -1-[(tert -Butoxycarbonyl) (methyl) amino] ethyl} -6-ethylpyrazolo [1,5-a] pyrimidin-5-yl trifluoromethanesulfonate (100 mg, brown oil) was obtained.
Step 5-7-3: Using a method similar to that of Step 1-2-3, from the compound (0.10 g) obtained in Step 5-7-2, 6-ethyl-2-[(1S) -1 -(Methylamino) ethyl] pyrazolo [1,5-a] pyrimidin-5-yl trifluoromethanesulfonate hydrochloride (90 mg, pale yellow substance) was obtained.
Step 5-7-4: Using a method similar to that of Step 1-1-8, from the compound obtained in Step 5-7-3 (90 mg), 2-{(1S) -1-[{5 -Chloro-2-[(methylsulfonyl) amino] benzoyl} (methyl) amino] ethyl} -6-ethylpyrazolo [1,5-a] pyrimidin-5-yl trifluoromethanesulfonate (65 mg, white solid) was obtained. It was.
1 H NMR (600 MHz, CDCl 3 , δ): 1.32-1.40 (m, 3H), 1.65-1.75 (m, 3H), 2.67 (s, 2H), 2.73-2.86 (m, 4H), 2.96 (s , 2H), 3.06 (s, 1H), 4.97-5.04 (m, 0.4H), 6.31 (q, J = 7.2 Hz, 0.6H), 6.42-6.48 (m, 1H), 7.24-7.42 (m, 2H ), 7.62 (d, J = 8.3 Hz, 0.4H), 7.72 (d, J = 8.7 Hz, 0.6H), 8.80 (s, 0.4H), 8.95 (s, 0.6H), 9.10 (s, 0.6H ), 10.43 (br s, 0.4H).
Step 5-7-5: Using a method similar to that of Step 1-2-5, from the compound (58 mg) obtained in Step 5-7-4, tert-butyl [(3S) -1- (2 -{(1S) -1-[{5-Chloro-2-[(methylsulfonyl) amino] benzoyl} (methyl) amino] ethyl} -6-ethylpyrazolo [1,5-a] pyrimidin-5-yl) pyrrolidine -3-yl] carbamate (71 mg, colorless solid) was obtained.
1 H NMR (600 MHz, CDCl 3 , δ): 1.26-1.30 (m, 3H), 1.45 (br s, 9H), 1.61 (d, J = 7.0 Hz, 2H), 1.65 (d, J = 7.4 Hz , 1H), 1.88-1.96 (m, 1H), 2.18-2.26 (m, 1H), 2.64 (s, 1H), 2.69-2.78 (m, 2H), 2.82 (s, 2H), 2.95 (s, 1H ), 3.03 (s, 2H), 3.48 -3.55 (m, 1H), 3.65-3.82 (m, 2H), 3.87-3.94 (m, 1H), 4.30 (br s, 1H), 4.66 (br s, 1H ), 4.87-4.93 (m, 0.6H), 5.97-6.04 (m, 1H), 6.19-6.27 (m, 0.4H), 7.24-7.40 (m, 2H), 7.62 (d, J = 8.7 Hz, 0.6 H), 7.69 (d, J = 9.1 Hz, 0.4H), 8.44 (s, 0.6H), 8.70 (s, 0.4H), 9.41 (s, 0.4H), 11.13 (br s, 0.6H).
Step 5-7-6: Using the same method as in Step 1-2-8, Step 5-7-5: Obtaining in Step 5-7-4 using the same method as in Step 1-2-5 The title compound (60 mg, white solid) was obtained from the compound (69 mg) obtained in the obtained compound (58 mg).
1 H NMR (600 MHz, DMSO-d 6 , δ): 1.21 (t, J = 7.2 Hz, 3H), 1.52-1.62 (m, 3H), 2.01-2.11 (m, 1H), 2.21-2.31 (m , 1H), 2.57-2.63 (m, 1.5H), 2.69-2.80 (m, 3.5H), 2.99-3.09 (m, 3H), 3.65-3.76 (m, 2H), 3.81-3.92 (m, 3H) , 4.77-4.84 (m, 0.5H), 5.95 (q, J = 7.4 Hz, 0.5H), 6.08-6.18 (m, 1H), 7.44-7.57 (m, 3H), 8.25-8.44 (m, 3H) , 8.53 (s, 0.5H), 9.26 (s, 0.5H).
LCMS (ESI) m / z 520 [M + H] + , t R = 0.57 min, mode N.
実施例5−8:N-[(1S)-1-{5-[(3S)-3-アミノピロリジン-1-イル]-6-シクロプロピルピラゾロ[1,5-a]ピリミジン-2-イル}エチル]-5-クロロ-N-メチル-2-[(メチルスルホニル)アミノ]ベンズアミド 塩酸塩の合成
工程5−8−1:工程1−1−4と同様の手法を用いて、工程1−1−3で得られた化合物(350 mg)及び(E)-エチル 2-シクロプロピル-3-メトキシアクリレート(370 mg)より、tert-ブチル [(1S)-1-(6-シクロプロピル-5-オキソ-4,5-ジヒドロピラゾロ[1,5-a]ピリミジン-2-イル)エチル](メチル)カルバマート (250 mg, 淡黄色アモルファス)を得た。
1H NMR (600 MHz, CDCl3, δ): 0.59-0.64 (m, 2H), 0.94-1.01 (m, 2H), 1.46-1.54 (m, 12H), 1.88-1.98 (m, 1H), 2.66 (br s, 3H), 5.26-5.62 (m, 1H), 5.78 (br s, 1H), 7.81 (s, 1H), 10.61 (br s, 1H).
LCMS (ESI) m/z 333 [M+H]+, tR = 0.88 min, mode N.
工程5−8−2:工程1−2−3と同様の手法を用いて、工程5−8−1で得られた化合物(240 mg)より、6-シクロプロピル-2-[(1S)-1-(メチルアミノ)エチル]ピラゾロ[1,5-a]ピリミジン-5(4H)-オン 塩酸塩(190 mg、淡黄色固体)を得た。
1H NMR (600 MHz, DMSO-d6, δ): 0.70-0.76 (m, 2H), 0.79-0.85 (m, 2H), 1.54 (d, J = 7.0 Hz, 3H), 1.77-1.84 (m, 1H), 2.46 (t, J = 5.2 Hz, 3H), 4.32-4.41 (m, 1H), 6.03 (s, 1H), 8.15 (s, 1H), 9.13 (br s, 1H), 9.30 (br s, 1H), 12.29 (s, 1H).
LCMS (ESI) m/z 233 [M+H]+, tR = 0.39 min, mode H.
工程5−8−3:工程1−2−4と同様の手法を用いて、工程5−8−2で得られた化合物(190 mg)より、(1S)-1-(5-クロロ-6-シクロプロピルピラゾロ[1,5-a]ピリミジン-2-イル)-N-メチルエタンアミン 塩酸塩(200 mg、褐色油状物)を得た。
LCMS (ESI) m/z 251 [M+H]+, tR = 0.75 min, mode H.
工程5−8−4:工程1−2−5と同様の手法を用いて、工程5−8−3で得られた化合物(200 mg)より、tert-ブチル [(3S)-1-{6-シクロプロピル-2-[(1S)-1-(メチルアミノ)エチル]ピラゾロ[1,5-a]ピリミジン-5-イル}ピロリジン-3-イル]カルバマート(240 mg, 褐色固体)を得た。
1H NMR (600 MHz, CDCl3, δ): 0.67-0.75 (m, 2H), 0.93-1.01 (m, 2H), 1.42-1.50 (m, 12H), 1.88-1.98 (m, 2H), 2.18-2.27 (m, 1H), 2.40 (s, 3H), 3.71-3.80 (m, 1H), 3.81-3.97 (m, 3H), 4.03-4.11 (m, 1H), 4.31 (br s, 1H), 4.68 (br s, 1H), 6.03 (s, 1H), 8.07 (s, 1H).
LCMS (ESI) m/z 401 [M+H]+, tR = 0.55 min, mode N.
工程5−8−5:工程1−2−7と同様の手法を用いて、工程5−8−4で得られた化合物(20 mg)より、tert-ブチル [(3S)-1-(2-{(1S)-1-[{5-クロロ-2-[(メチルスルホニル)アミノ]ベンゾイル}(メチル)アミノ]エチル}-6-シクロプロピルピラゾロ[1,5-a]ピリミジン-5-イル)ピロリジン-3-イル]カルバマート(24 mg, 白色固体)を得た。
LCMS (ESI) m/z 632 [M+H]+, tR = 1.21 min, mode N.
工程5−8−6:工程1−2−8と同様の手法を用いて、工程5−8−5で得られた化合物(24 mg)より、表題化合物(24 mg, 白色固体)を得た。
1H NMR (600 MHz, DMSO-d6, δ): 0.72-1.00 (m, 4H), 1.53-1.60 (m, 3H), 2.00-2.11 (m, 1H), 2.21-2.34 (m, 1H), 2.59 (s, 1.5H), 2.74 (br s, 1.5H), 3.00-3.07 (m, 3H), 3.59-4.09 (m, 5H), 4.75-4.83 (m, 0.5H), 5.89-5.97 (m, 0.5H), 6.05-6.13 (m, 1H), 7.44-7.57 (m, 3H), 8.15-8.36 (m, 3H), 8.47 (s, 0.5H), 9.22 (s, 0.5H).
LCMS (ESI) m/z 532 [M+H]+, tR = 0.61 min, mode N.
Example 5-8: N-[(1S) -1- {5-[(3S) -3-aminopyrrolidin-1-yl] -6-cyclopropylpyrazolo [1,5-a] pyrimidine-2- Yl} ethyl] -5-chloro-N-methyl-2-[(methylsulfonyl) amino] benzamide Hydrochloride Synthesis Step 5-8-1: Using a method similar to Step 1-1-4, Step 1 From the compound (350 mg) obtained in 1-3, and (E) -ethyl 2-cyclopropyl-3-methoxyacrylate (370 mg), tert-butyl [(1S) -1- (6-cyclopropyl- 5-Oxo-4,5-dihydropyrazolo [1,5-a] pyrimidin-2-yl) ethyl] (methyl) carbamate (250 mg, pale yellow amorphous) was obtained.
1 H NMR (600 MHz, CDCl 3 , δ): 0.59-0.64 (m, 2H), 0.94-1.01 (m, 2H), 1.46-1.54 (m, 12H), 1.88-1.98 (m, 1H), 2.66 (br s, 3H), 5.26-5.62 (m, 1H), 5.78 (br s, 1H), 7.81 (s, 1H), 10.61 (br s, 1H).
LCMS (ESI) m / z 333 [M + H] + , t R = 0.88 min, mode N.
Step 5-8-2: Using a method similar to that of Step 1-2-3, from the compound (240 mg) obtained in Step 5-8-1, 6-cyclopropyl-2-[(1S)- 1- (Methylamino) ethyl] pyrazolo [1,5-a] pyrimidin-5 (4H) -one hydrochloride (190 mg, pale yellow solid) was obtained.
1 H NMR (600 MHz, DMSO-d 6 , δ): 0.70-0.76 (m, 2H), 0.79-0.85 (m, 2H), 1.54 (d, J = 7.0 Hz, 3H), 1.77-1.84 (m , 1H), 2.46 (t, J = 5.2 Hz, 3H), 4.32-4.41 (m, 1H), 6.03 (s, 1H), 8.15 (s, 1H), 9.13 (br s, 1H), 9.30 (br s, 1H), 12.29 (s, 1H).
LCMS (ESI) m / z 233 [M + H] + , t R = 0.39 min, mode H.
Step 5-8-3: Using a method similar to that of Step 1-2-4, from the compound (190 mg) obtained in Step 5-8-2, (1S) -1- (5-chloro-6 -Cyclopropylpyrazolo [1,5-a] pyrimidin-2-yl) -N-methylethanamine hydrochloride (200 mg, brown oil) was obtained.
LCMS (ESI) m / z 251 [M + H] + , t R = 0.75 min, mode H.
Step 5-8-4: Using a method similar to that in Step 1-2-5, from the compound (200 mg) obtained in Step 5-8-3, tert-butyl [(3S) -1- {6 -Cyclopropyl-2-[(1S) -1- (methylamino) ethyl] pyrazolo [1,5-a] pyrimidin-5-yl} pyrrolidin-3-yl] carbamate (240 mg, brown solid) was obtained. .
1 H NMR (600 MHz, CDCl 3 , δ): 0.67-0.75 (m, 2H), 0.93-1.01 (m, 2H), 1.42-1.50 (m, 12H), 1.88-1.98 (m, 2H), 2.18 -2.27 (m, 1H), 2.40 (s, 3H), 3.71-3.80 (m, 1H), 3.81-3.97 (m, 3H), 4.03-4.11 (m, 1H), 4.31 (br s, 1H), 4.68 (br s, 1H), 6.03 (s, 1H), 8.07 (s, 1H).
LCMS (ESI) m / z 401 [M + H] + , t R = 0.55 min, mode N.
Step 5-8-5: Using a method similar to that of Step 1-2-7, from the compound obtained in Step 5-8-4 (20 mg), tert-butyl [(3S) -1- (2 -{(1S) -1-[{5-Chloro-2-[(methylsulfonyl) amino] benzoyl} (methyl) amino] ethyl} -6-cyclopropylpyrazolo [1,5-a] pyrimidine-5- Yl) pyrrolidin-3-yl] carbamate (24 mg, white solid) was obtained.
LCMS (ESI) m / z 632 [M + H] + , t R = 1.21 min, mode N.
Step 5-8-6: Using a method similar to that of Step 1-2-8, the title compound (24 mg, white solid) was obtained from the compound (24 mg) obtained in Step 5-8-5. .
1 H NMR (600 MHz, DMSO-d 6 , δ): 0.72-1.00 (m, 4H), 1.53-1.60 (m, 3H), 2.00-2.11 (m, 1H), 2.21-2.34 (m, 1H) , 2.59 (s, 1.5H), 2.74 (br s, 1.5H), 3.00-3.07 (m, 3H), 3.59-4.09 (m, 5H), 4.75-4.83 (m, 0.5H), 5.89-5.97 ( m, 0.5H), 6.05-6.13 (m, 1H), 7.44-7.57 (m, 3H), 8.15-8.36 (m, 3H), 8.47 (s, 0.5H), 9.22 (s, 0.5H).
LCMS (ESI) m / z 532 [M + H] + , t R = 0.61 min, mode N.
実施例5−9:エチル 5-[(3S)-3-アミノピロリジン-1-イル]-2-{(1S)-1-[{5-クロロ-2-[(メチルスルホニル)アミノ]ベンゾイル}(メチル)アミノ]エチル}ピラゾロ[1,5-a]ピリミジン-6-カルボキシラート 塩酸塩の合成
工程5−9−1:工程5−7−1と同様の手法を用いて、工程1−1−3で得られた化合物(1.0 g)及びエトキシメチレンマロン酸ジエチル(1.6 mL)よりエチル 2-{(1S)-1-[(tert-ブトキシカルボニル)(メチル)アミノ]エチル}-5-オキソ-4,5-ジヒドロピラゾロ[1,5-a]ピリミジン-6-カルボキシラート(210 mg, 褐色固体)を得た。
1H NMR (600 MHz, CDCl3, δ): 1.39 (t, J = 7.2 Hz, 3H), 1.49 (s, 9H), 1.53 (d, J = 7.0 Hz, 3H), 2.68 (br s, 3H), 4.40 (q, J = 7.0 Hz, 2H), 5.28-5.68 (m, 1H), 5.92 (br s, 1H), 9.00 (s, 1H), 10.72 (br s, 1H).
LCMS (ESI) m/z 365 [M+H]+, tR = 0.84 min, mode N.
工程5−9−2:工程1−2−3と同様の手法を用いて、工程5−9−1で得られた化合物(200 mg)より、エチル 2-[(1S)-1-(メチルアミノ)エチル]-5-オキソ-4,5-ジヒドロピラゾロ[1,5-a]ピリミジン-6-カルボキシラート 塩酸塩(170 mg, 褐色固体)を得た。
LCMS (ESI) m/z 265 [M+H]+, tR = 0.35 min, mode H.
工程5−9−3:工程1−2−4と同様の手法を用いて、工程5−9−2で得られた化合物(170 mg)より、エチル 5-クロロ-2-[(1S)-1-(メチルアミノ)エチル]ピラゾロ[1,5-a]ピリミジン-6-カルボキシラート 塩酸塩(160 mg, 褐色油状物)を得た。
LCMS (ESI) m/z 283 [M+H]+, tR = 0.68 min, mode H.
工程5−9−4:工程1−2−5と同様の手法を用いて、工程5−9−3で得られた化合物(160 mg)より、エチル 5-{(3S)-3-[(tert-ブトキシカルボニル)アミノ]ピロリジン-1-イル}-2-[(1S)-1-(メチルアミノ)エチル]ピラゾロ[1,5-a]ピリミジン-6-カルボキシラート(230 mg, 褐色固体)を得た。
1H NMR (600 MHz, CDCl3, δ): 1.38 (t, J = 7.2 Hz, 3H), 1.41-1.46 (m, 12H), 1.92 (br s, 1H), 2.16-2.24 (m, 1H), 2.40 (s, 3H), 3.27-3.34 (m, 1H), 3.53- 3.61 (m, 1H), 3.65-3.79 (m, 2H), 4.29 (br s, 1H), 4.36 (q, J = 7.3 Hz, 2H), 4.67 (br s, 1H), 6.05 (s, 1H), 8.82 (s, 1H).
LCMS (ESI) m/z 433 [M+H]+, tR = 0.53 min, mode N.
工程5−9−5:工程1−2−7と同様の手法を用いて、工程5−9−4で得られた化合物(220 mg)より、エチル 5-{(3S)-3-[(tert-ブトキシカルボニル)アミノ]ピロリジン-1-イル}-2-{(1S)-1-[{5-クロロ-2-[(メチルスルホニル)アミノ]ベンゾイル}(メチル)アミノ]エチル}ピラゾロ[1,5-a]ピリミジン-6-カルボキシラート(200 mg, 白色固体)を得た。
1H NMR (600 MHz, CDCl3, δ): 1.42-1.46 (m, 15H), 1.63 (d, J = 7.0 Hz, 1H), 1.66 (d, J = 7.4 Hz, 2H), 1.92 (br s, 1H), 2.16-2.27 (m, 1H), 2.67 (s, 2H), 2.83 (s, 1H), 2.94 (s, 2H), 3.04 (s, 1H), 3.30-3.37 (m, 1H), 3.54-3.62 (m, 1H), 3.64-3.76 (m, 2H), 4.29 (br s, 1H), 4.34-4.43 (m, 2H), 4.65 (br s, 1H), 4.88-4.97 (m, 0.4H), 5.99-6.05 (m, 1H), 6.20-6.27 (m, 0.6H), 7.22-7.41 (m, 2H), 7.61 (d, J = 8.3 Hz, 0.4H), 7.70 (d, J = 9.1 Hz, 0.6H), 9.10-9.19 (m, 1H), 9.45 (s, 0.6H), 10.70 (br s, 0.4H).
LCMS (ESI) m/z 664 [M+H]+, tR = 1.17 min, mode N.
工程5−9−6:工程1−2−8と同様の手法を用いて、工程5−9−5得られた化合物(10 mg)より、表題化合物(10 mg, 白色固体)を得た。
LCMS (ESI) m/z 564 [M+H]+, tR = 0.59 min, mode N.
Example 5-9: ethyl 5-[(3S) -3-aminopyrrolidin-1-yl] -2-{(1S) -1-[{5-chloro-2-[(methylsulfonyl) amino] benzoyl} (Methyl) amino] ethyl} pyrazolo [1,5-a] pyrimidine-6-carboxylate hydrochloride synthesis step 5-9-1: using the same method as in step 5-7-1, step 1-1 2-((1S) -1-[(tert-butoxycarbonyl) (methyl) amino] ethyl} -5-oxo from the compound (1.0 g) obtained in -3 and diethyl ethoxymethylenemalonate (1.6 mL) -4,5-dihydropyrazolo [1,5-a] pyrimidine-6-carboxylate (210 mg, brown solid) was obtained.
1 H NMR (600 MHz, CDCl 3 , δ): 1.39 (t, J = 7.2 Hz, 3H), 1.49 (s, 9H), 1.53 (d, J = 7.0 Hz, 3H), 2.68 (br s, 3H ), 4.40 (q, J = 7.0 Hz, 2H), 5.28-5.68 (m, 1H), 5.92 (br s, 1H), 9.00 (s, 1H), 10.72 (br s, 1H).
LCMS (ESI) m / z 365 [M + H] + , t R = 0.84 min, mode N.
Step 5-9-2: Using a method similar to that of Step 1-2-3, from the compound (200 mg) obtained in Step 5-9-1, ethyl 2-[(1S) -1- (methyl Amino) ethyl] -5-oxo-4,5-dihydropyrazolo [1,5-a] pyrimidine-6-carboxylate hydrochloride (170 mg, brown solid) was obtained.
LCMS (ESI) m / z 265 [M + H] + , t R = 0.35 min, mode H.
Step 5-9-3: Using a method similar to that in Step 1-2-4, from the compound obtained in Step 5-9-2 (170 mg), ethyl 5-chloro-2-[(1S)- 1- (Methylamino) ethyl] pyrazolo [1,5-a] pyrimidine-6-carboxylate hydrochloride (160 mg, brown oil) was obtained.
LCMS (ESI) m / z 283 [M + H] + , t R = 0.68 min, mode H.
Step 5-9-4: Using a method similar to that of Step 1-2-5, from the compound (160 mg) obtained in Step 5-9-3, ethyl 5-{(3S) -3-[( tert-Butoxycarbonyl) amino] pyrrolidin-1-yl} -2-[(1S) -1- (methylamino) ethyl] pyrazolo [1,5-a] pyrimidine-6-carboxylate (230 mg, brown solid) Got.
1 H NMR (600 MHz, CDCl 3 , δ): 1.38 (t, J = 7.2 Hz, 3H), 1.41-1.46 (m, 12H), 1.92 (br s, 1H), 2.16-2.24 (m, 1H) , 2.40 (s, 3H), 3.27-3.34 (m, 1H), 3.53- 3.61 (m, 1H), 3.65-3.79 (m, 2H), 4.29 (br s, 1H), 4.36 (q, J = 7.3 Hz, 2H), 4.67 (br s, 1H), 6.05 (s, 1H), 8.82 (s, 1H).
LCMS (ESI) m / z 433 [M + H] + , t R = 0.53 min, mode N.
Step 5-9-5: Using a method similar to that of Step 1-2-7, from the compound (220 mg) obtained in Step 5-9-4, ethyl 5-{(3S) -3-[( tert-butoxycarbonyl) amino] pyrrolidin-1-yl} -2-{(1S) -1-[{5-chloro-2-[(methylsulfonyl) amino] benzoyl} (methyl) amino] ethyl} pyrazolo [1 , 5-a] pyrimidine-6-carboxylate (200 mg, white solid) was obtained.
1 H NMR (600 MHz, CDCl 3 , δ): 1.42-1.46 (m, 15H), 1.63 (d, J = 7.0 Hz, 1H), 1.66 (d, J = 7.4 Hz, 2H), 1.92 (br s , 1H), 2.16-2.27 (m, 1H), 2.67 (s, 2H), 2.83 (s, 1H), 2.94 (s, 2H), 3.04 (s, 1H), 3.30-3.37 (m, 1H), 3.54-3.62 (m, 1H), 3.64-3.76 (m, 2H), 4.29 (br s, 1H), 4.34-4.43 (m, 2H), 4.65 (br s, 1H), 4.88-4.97 (m, 0.4 H), 5.99-6.05 (m, 1H), 6.20-6.27 (m, 0.6H), 7.22-7.41 (m, 2H), 7.61 (d, J = 8.3 Hz, 0.4H), 7.70 (d, J = 9.1 Hz, 0.6H), 9.10-9.19 (m, 1H), 9.45 (s, 0.6H), 10.70 (br s, 0.4H).
LCMS (ESI) m / z 664 [M + H] + , t R = 1.17 min, mode N.
Step 5-9-6: Using a method similar to that of Step 1-2-8, the title compound (10 mg, white solid) was obtained from the compound (10 mg) obtained in Step 5-9-5.
LCMS (ESI) m / z 564 [M + H] + , t R = 0.59 min, mode N.
実施例5−10:5-[(3S)-3-アミノピロリジン-1-イル]-2-{(1S)-1-[{5-クロロ-2-[(メチルスルホニル)アミノ]ベンゾイル}(メチル)アミノ]エチル}ピラゾロ[1,5-a]ピリミジン-6-カルボン酸 塩酸塩の合成
工程5−10−1:工程5−9−5で得られた化合物(100 mg)のTHF(1.0 mL)溶液にMeOH(0.5 mL)及び2M KOH水溶液(150 μL)加え、室温で3時間撹拌した。反応溶液に飽和NH4Cl水溶液を加え、CHCl3で抽出操作を行った。有機層をBrineで洗浄後、 Phase Separatorを用いて水層を分離し、有機層を減圧下濃縮した。OH型シリカゲルカラムクロマトグラフィー(移動相:CHCl3/MeOH = 100/0〜80/20; v/v)で精製した後、逆相分取HPLCで精製し、5-[(3S)-3-アミノピロリジン-1-イル]-2-{(1S)-1-[{5-クロロ-2-[(メチルスルホニル)アミノ]ベンゾイル}(メチル)アミノ]エチル}ピラゾロ[1,5-a]ピリミジン-6-カルボン酸 塩酸塩(60 mg, 白色固体)を得た。
LCMS (ESI) m/z 636 [M+H]+, tR = 0.81 min, mode N.
工程5−10−2:工程1−2−8と同様の手法を用いて、工程5−10−1で得られた化合物(8.0 mg)より、表題化合物 (9.0 mg, 白色固体)を得た。
LCMS (ESI) m/z 536 [M+H]+, tR = 0.53 min, mode N.
実施例1−1〜1−12で得られた化合物の構造式を表2に、実施例2−1〜2−78で得られた化合物の構造式を表3−1〜3−8に、実施例3−1〜3−78で得られた化合物の構造式を表4−1〜4−8に、実施例4−1〜4−13で得られた化合物の構造式を表5に、実施例5−1〜5−10で得られた化合物の構造式を表6に、記載する。
Example 5-10: 5-[(3S) -3-aminopyrrolidin-1-yl] -2-{(1S) -1-[{5-chloro-2-[(methylsulfonyl) amino] benzoyl} ( Methyl) amino] ethyl} pyrazolo [1,5-a] pyrimidine-6-carboxylic acid hydrochloride synthesis step 5-10-1: THF (1.0 mg) of the compound (100 mg) obtained in step 5-9-5 MeOH (0.5 mL) and 2M aqueous KOH solution (150 μL) were added to the solution, and the mixture was stirred at room temperature for 3 hours. A saturated aqueous NH 4 Cl solution was added to the reaction solution, and extraction was performed with CHCl 3 . After washing the organic layer with Brine, the aqueous layer was separated using Phase Separator, and the organic layer was concentrated under reduced pressure. After purification by OH type silica gel column chromatography (mobile phase: CHCl 3 / MeOH = 100/0 to 80/20; v / v), purification by reverse phase preparative HPLC was performed, and 5-[(3S) -3- Aminopyrrolidin-1-yl] -2-{(1S) -1-[{5-chloro-2-[(methylsulfonyl) amino] benzoyl} (methyl) amino] ethyl} pyrazolo [1,5-a] pyrimidine -6-carboxylic acid hydrochloride (60 mg, white solid) was obtained.
LCMS (ESI) m / z 636 [M + H] + , t R = 0.81 min, mode N.
Step 5-10-2: Using the same method as in Step 1-2-8, the title compound (9.0 mg, white solid) was obtained from the compound (8.0 mg) obtained in Step 5-10-1. .
LCMS (ESI) m / z 536 [M + H] + , t R = 0.53 min, mode N.
The structural formulas of the compounds obtained in Examples 1-1 to 1-12 are shown in Table 2, the structural formulas of the compounds obtained in Examples 2-1 to 2-78 are shown in Tables 3-1 to 3-8, The structural formulas of the compounds obtained in Examples 3-1 to 3-78 are shown in Tables 4-1 to 4-8, and the structural formulas of the compounds obtained in Examples 4-1 to 4-13 are shown in Table 5. Table 6 shows the structural formulas of the compounds obtained in Examples 5-1 to 5-10.
試験例1(in vitro抗RSV活性評価試験)
本発明の化合物のRSVに対する抗ウイルス活性を、細胞変性効果(CPE)阻害試験により決定した。
Hep2細胞をDSファーマバイオメディカル株式会社から入手し、増殖培地(10%ウシ胎児血清及びゲンタマイシンを補充したMEM培地)で培養した。RSV A2株をATCCより入手し、Hep2細胞を宿主として増幅後、-80 ℃で保管した。試験前に、Hep2細胞において望ましい細胞変性効果を生じさせるRSV A2株ウイルス液の適当な希釈倍率を決定した。
CPE阻害試験のために、試験の1日前にHep2細胞を細胞数1.0×104個/ウェルの密度で96ウェルプレートに播種した。別の96ウェルプレートにアッセイ培地(2%ウシ胎児血清及びストレプトマイシン/ペニシリンを補充したMEM培地)を用いて化合物の希釈系列を作成し、増殖培地を除去した細胞に50 μL/ウェルで添加した。続いて、アッセイ培地を用いて適宜希釈したRSV A2株ウイルス液を、50 μL/ウェルで細胞及び化合物を含有する試験プレートに加えた。各プレートには、0%及び100%ウイルス阻害対照として、感染した未処理細胞及び未感染細胞のウェルを設けた。RSVによる感染の後、試験プレートを37 ℃ 5% CO2条件下で4日間培養した。培養後、RSVによる細胞変性効果を、XTT細胞増殖アッセイキット(Biological Industries,コスモバイオ)を使用して決定した。マイクロプレートリーダーを使用して2種の波長(450及び655 nm)での吸光度を測定し、655 nmでの吸光度を450 nmでの吸光度から差し引いて、非特異的吸収の影響を排除した。CPEを50 %阻害した化合物濃度(EC50)を非線形回帰によって決定した。
本発明化合物中のEC50値を以下に示すように分類し、表2〜表6に示す。
A: EC50 < 100 nM,B: 100 nM ≦ EC50 < 1000 nM,C: EC50 ≧ 1000 nM。さらに、本発明化合物の幾つかについて、EC50値を表7に示す。
Test Example 1 (In vitro anti-RSV activity evaluation test)
The antiviral activity against RSV of the compounds of the present invention was determined by cytopathic effect (CPE) inhibition test.
Hep2 cells were obtained from DS Pharma Biomedical Co., Ltd. and cultured in a growth medium (MEM medium supplemented with 10% fetal bovine serum and gentamicin). RSV A2 strain was obtained from ATCC, amplified with Hep2 cells as a host, and stored at −80 ° C. Prior to testing, the appropriate dilution factor of RSV A2 strain virus solution that produces the desired cytopathic effect in Hep2 cells was determined.
For the CPE inhibition test, Hep2 cells were seeded in a 96-well plate at a density of 1.0 × 10 4 cells / well one day before the test. A dilution series of the compound was prepared in a separate 96-well plate using assay medium (MEM medium supplemented with 2% fetal bovine serum and streptomycin / penicillin), and added to the cells from which the growth medium had been removed at 50 μL / well. Subsequently, RSV A2 strain virus solution appropriately diluted with assay medium was added to a test plate containing cells and compounds at 50 μL / well. Each plate was provided with wells of infected untreated cells and uninfected cells as 0% and 100% virus inhibition controls. After infection with RSV, test plates were cultured for 4 days at 37 ° C. and 5% CO 2 . After culture, cytopathic effect by RSV was determined using XTT cell proliferation assay kit (Biological Industries, Cosmo Bio). Absorbance at two wavelengths (450 and 655 nm) was measured using a microplate reader, and the absorbance at 655 nm was subtracted from the absorbance at 450 nm to eliminate the effect of non-specific absorption. The compound concentration that inhibited CPE by 50% (EC 50 ) was determined by non-linear regression.
EC 50 values in the compounds of the present invention are classified as shown below and shown in Tables 2 to 6.
A: EC 50 <100 nM, B: 100 nM ≤ EC 50 <1000 nM, C: EC 50 ≥ 1000 nM. Furthermore, EC 50 values are shown in Table 7 for some of the compounds of the present invention.
本発明化合物(I)又はその医薬上許容される塩は、抗RSV活性を有し、呼吸器合胞体ウイルス(RSV)を含むニューモウイルス亜科のウイルスが関与する感染症に対し、有用な予防薬又は治療薬として利用できる。 The compound (I) of the present invention or a pharmaceutically acceptable salt thereof has anti-RSV activity and is useful for prevention of infections involving viruses of the Pneumovirus subfamily including respiratory syncytial virus (RSV). It can be used as a medicine or therapeutic agent.
Claims (10)
A1は、水素原子又はC1-6アルキル基を示し、
A2は、水素原子、C1-6アルキル基、C3-6シクロアルキル基、カルボキシ基、又はC1-6アルコキシカルボニル基を示し、
A3は、ハロゲン原子、C1-6アルコキシ基(ここで、該C1-6アルコキシ基は、1個のアミノ基で置換されてもよい。)、ヘテロシクリルオキシ基、C1-6アルキルアミノ基{ここで、該C1-6アルキルアミノ基は、アミノ基及びC3-6シクロアルキル基(ここで、該C3-6シクロアルキル基は、1個のアミノ基で置換されてもよい)からなる群から選ばれる同一又は異なる1〜2個の置換基で置換されてもよい。}、C3-6シクロアルキルアミノ基(ここで、 該C3-6シクロアルキルアミノ基は、1個のアミノ基で置換されてもよい。)、又はヘテロシクリル基(ここで、該ヘテロシクリル基は、ハロゲン原子、水酸基、アミノ基、及び1個のアミノ基で置換されたC1-6アルキル基からなる群から選ばれる同一又は異なる1〜3個の置換基で置換されてもよい。)を示し、
A4は、水素原子、ハロゲン原子、C1-6アルキル基、C2-6アルキニル基(ここで、該C2-6アルキニル基は、1個の水酸基で置換されてもよい。)、又はアリール基を示し、
R1及びR2は、同一又は異なって、それぞれ水素原子、C1-6アルキル基(ここで、該C1-6アルキル基は、1個の水酸基で置換されてもよい。)、又はC3-6シクロアルキル基を示すか、
又は、R1及びR2は、隣接する炭素原子と一緒になって、C3-6シクロアルカンを形成してもよく、
R3は、C1-6アルキル基{ここで、該C1-6アルキル基は、ハロゲン原子、水酸基、アミノ基、C1-6アルコキシ基(ここで、該C1-6アルコキシ基は、1〜3個のハロゲン原子で置換されてもよい。)、アリールオキシ基、C1-6アルキルスルホニルアミノ基、C1-6アルキルスルホニル基、ヘテロシクリル基(ここで、該ヘテロシクリル基は、1〜2個のオキソで置換されてもよい。)、アリール基、及びヘテロアリール基からなる群から選ばれる同一又は異なる1〜3個の置換基で置換されてもよい。}を示し、
Yは、アリール基、ヘテロアリール基{ここで、該アリール基及びヘテロアリール基は、ハロゲン原子、アミノ基、C1-6アルキル基、C1-6アルコキシ基、C2-6アルカノイルアミノ基(ここで、該C2-6アルカノイルアミノ基は、1個のC1-6アルキルスルホニル基で置換されてもよい。)、C1-6アルキルスルホニルアミノ基(ここで、該C1-6アルキルスルホニルアミノ基は、1〜3個のハロゲン原子で置換されてもよい。)、アリールスルホニルアミノ基、C1-6アルキルスルホニル基、ヘテロシクリル基、アリール基、及びヘテロアリール基からなる群から選ばれる同一又は異なる1〜3個の置換基で置換されてもよい。}、又はヘテロシクリル基(ここで、該ヘテロシクリル基は、1個のオキソで置換されてもよい。)を示し、
又は、Yは、下記式群(II)のいずれかの構造を示し、
Wが単結合のとき、Zは、式(CH2)n又は式CH2NR7を示し、
nは、2〜4の整数を示し、
Wが式CH2のとき、Zは、式CH2CH2を示し、
B1、B2、B3、B4、及びB5は、同一又は異なって、それぞれ水素原子、ハロゲン原子、又はC1-6アルキル基を示し、
R4及びR5は、同一又は異なって、それぞれ水素原子、C1-6アルキル基を示すか、
又は、R4及びR5は、隣接する炭素原子と一緒になってC3-6シクロアルカン{ここで、該C3-6シクロアルカンは、オキソ、水酸基、C2-6アルカノイルアミノ基(ここで、該C2-6アルカノイルアミノ基は、1個のC1-6アルキルスルホニル基で置換されてもよい。)、及びC1-6アルキルスルホニルアミノ基からなる群から選ばれる1個の置換基で置換されてもよい。}を形成してもよく、さらに該C3-6シクロアルカンは、環中の1個の式CH2が式NR8で置換されてもよく、
R6は、水素原子、アミノ基、C1-6アルキル基(ここで、該C1-6アルキル基は、C3-6シクロアルキルカルボニル基、C1-6アルキルスルホニル基、及びC1-6アルキルスルホニルアミノ基からなる群から選ばれる1個の置換基で置換されてもよい。)、C1-6アルキルアミノ基(ここで、該C1-6アルキルアミノ基は、1個のC1-6アルキルスルホニル基で置換されてもよい。)、C2-6アルカノイルアミノ基(ここで、該C2-6アルカノイルアミノ基は、アミノ基、 スルファモイル基、C3-6シクロアルキル基、C1-6アルコキシ基、C1-6アルキルアミノ基、C2-6アルカノイルアミノ基、C1-6アルキルスルホニルアミノ基、C1-6アルキルスルホニル基、C1-6アルキルアミノスルホニル基、アリールスルホニル基、アリール基、及びヘテロアリール基からなる群から選ばれる1個の置換基で置換されてもよい。)、C1-6アルコキシカルボニルアミノ基(ここで、該C1-6アルコキシカルボニルアミノ基は、1個のアリール基で置換されてもよい。)、又はC1-6アルキルスルホニルアミノ基を示し、
R7は、水素原子又はC1-6アルキル基を示し、
R8は、カルバモイル基、アミジノ基、C2-6アルカノイル基(ここで、該C2-6アルカノイル基は、1個のC1-6アルキルスルホニル基で置換されてもよい。)、C1-6アルコキシカルボニル基(ここで、該C1-6アルコキシカルボニル基は、1個のアリール基で置換されてもよい。)、又はC1-6アルキルスルホニル基である。]
で表される化合物、又はその医薬上許容される塩。 Formula (I),
A 1 represents a hydrogen atom or a C 1-6 alkyl group,
A 2 represents a hydrogen atom, a C 1-6 alkyl group, a C 3-6 cycloalkyl group, a carboxy group, or a C 1-6 alkoxycarbonyl group,
A 3 represents a halogen atom, a C 1-6 alkoxy group (wherein the C 1-6 alkoxy group may be substituted with one amino group), a heterocyclyloxy group, a C 1-6 alkylamino group. A group {wherein the C 1-6 alkylamino group is an amino group and a C 3-6 cycloalkyl group (wherein the C 3-6 cycloalkyl group may be substituted with one amino group); ) May be substituted with the same or different 1 to 2 substituents selected from the group consisting of: }, A C 3-6 cycloalkylamino group (wherein the C 3-6 cycloalkylamino group may be substituted with one amino group), or a heterocyclyl group (wherein the heterocyclyl group is , A halogen atom, a hydroxyl group, an amino group, and a C 1-6 alkyl group substituted with one amino group may be substituted with 1 to 3 identical or different substituents. Show
A 4 represents a hydrogen atom, a halogen atom, a C 1-6 alkyl group, a C 2-6 alkynyl group (wherein the C 2-6 alkynyl group may be substituted with one hydroxyl group), or Represents an aryl group,
R 1 and R 2 are the same or different and are each a hydrogen atom, a C 1-6 alkyl group (wherein the C 1-6 alkyl group may be substituted with one hydroxyl group), or C Represents a 3-6 cycloalkyl group,
Or R 1 and R 2 may be taken together with adjacent carbon atoms to form a C 3-6 cycloalkane;
R 3 is a C 1-6 alkyl group (wherein the C 1-6 alkyl group is a halogen atom, a hydroxyl group, an amino group, a C 1-6 alkoxy group (wherein the C 1-6 alkoxy group is 1 to 3 halogen atoms may be substituted), an aryloxy group, a C 1-6 alkylsulfonylamino group, a C 1-6 alkylsulfonyl group, a heterocyclyl group (wherein the heterocyclyl group is 1 to And may be substituted with 1 to 3 identical or different substituents selected from the group consisting of an aryl group and a heteroaryl group. },
Y is an aryl group, a heteroaryl group {wherein the aryl group and heteroaryl group are a halogen atom, an amino group, a C 1-6 alkyl group, a C 1-6 alkoxy group, a C 2-6 alkanoylamino group ( Here, the C 2-6 alkanoylamino group may be substituted with one C 1-6 alkylsulfonyl group), a C 1-6 alkylsulfonylamino group (wherein the C 1-6 alkylsulfonyl group) The sulfonylamino group may be substituted with 1 to 3 halogen atoms.), An arylsulfonylamino group, a C 1-6 alkylsulfonyl group, a heterocyclyl group, an aryl group, and a heteroaryl group. It may be substituted with 1 to 3 identical or different substituents. }, Or a heterocyclyl group, wherein the heterocyclyl group may be substituted with one oxo,
Or, Y represents any structure of the following formula group (II),
When W is a single bond, Z represents the formula (CH 2 ) n or the formula CH 2 NR 7 ,
n represents an integer of 2 to 4,
When W is of the formula CH 2 , Z represents the formula CH 2 CH 2 ;
B 1 , B 2 , B 3 , B 4 , and B 5 are the same or different and each represents a hydrogen atom, a halogen atom, or a C 1-6 alkyl group,
R 4 and R 5 are the same or different and each represents a hydrogen atom or a C 1-6 alkyl group,
Or R 4 and R 5 together with adjacent carbon atoms are C 3-6 cycloalkane {where C 3-6 cycloalkane is oxo, hydroxyl, C 2-6 alkanoylamino group (here And the C 2-6 alkanoylamino group may be substituted with one C 1-6 alkylsulfonyl group.), And one substitution selected from the group consisting of C 1-6 alkylsulfonylamino groups It may be substituted with a group. Furthermore, the C 3-6 cycloalkane may have one formula CH 2 in the ring substituted with the formula NR 8 ,
R 6 represents a hydrogen atom, an amino group, a C 1-6 alkyl group (wherein the C 1-6 alkyl group is a C 3-6 cycloalkylcarbonyl group, a C 1-6 alkylsulfonyl group, and a C 1- alkyl group). Which may be substituted with one substituent selected from the group consisting of 6 alkylsulfonylamino groups), a C 1-6 alkylamino group (wherein the C 1-6 alkylamino group is one C 1-6 alkylsulfonyl group may be substituted), C 2-6 alkanoylamino group (wherein the C 2-6 alkanoylamino group is an amino group, a sulfamoyl group, a C 3-6 cycloalkyl group, C 1-6 alkoxy group, C 1-6 alkylamino group, C 2-6 alkanoylamino group, C 1-6 alkylsulfonylamino group, C 1-6 alkylsulfonyl group, C 1-6 alkylaminosulfonyl group, aryl Sulfonyl group, aryl group, and heteroaryl May be substituted with one substituent selected from the group consisting of.), By C 1-6 alkoxycarbonylamino group (wherein the C 1-6 alkoxycarbonylamino group, substituted with one aryl group Or a C 1-6 alkylsulfonylamino group,
R 7 represents a hydrogen atom or a C 1-6 alkyl group,
R 8 is carbamoyl group, amidino group, C (wherein said C 2-6 alkanoyl group may be substituted with one C 1-6 alkylsulfonyl group.) 2-6 alkanoyl group, C 1 A -6 alkoxycarbonyl group (wherein the C 1-6 alkoxycarbonyl group may be substituted with one aryl group), or a C 1-6 alkylsulfonyl group. ]
Or a pharmaceutically acceptable salt thereof.
R1が、水素原子であり、
R2が、C1-6アルキル基(ここで、該C1-6アルキル基は、1個の水酸基で置換されてもよい。)、又はC3-6シクロアルキル基であるか、
又は、R1及びR2が、隣接する炭素原子と一緒になって、C3-6シクロアルカンを形成してもよい、
請求項1に記載の化合物、又はその医薬上許容される塩。 In the above formula (I),
R 1 is a hydrogen atom,
R 2 is a C 1-6 alkyl group (wherein the C 1-6 alkyl group may be substituted with one hydroxyl group), or a C 3-6 cycloalkyl group,
Or R 1 and R 2 together with adjacent carbon atoms may form a C 3-6 cycloalkane,
The compound according to claim 1, or a pharmaceutically acceptable salt thereof.
Yが、アリール基、ヘテロアリール基{ここで、該アリール基及びヘテロアリール基は、ハロゲン原子、アミノ基、C1-6アルキル基、C1-6アルコキシ基、C2-6アルカノイルアミノ基(ここで、該C2-6アルカノイルアミノ基は、1個のC1-6アルキルスルホニル基で置換されてもよい。)、C1-6アルキルスルホニルアミノ基(ここで、該C1-6アルキルスルホニルアミノ基は、1〜3個のハロゲン原子で置換されてもよい。)、アリールスルホニルアミノ基、C1-6アルキルスルホニル基、ヘテロシクリル基、アリール基、及びヘテロアリール基からなる群から選ばれる同一又は異なる1〜3個の置換基で置換されてもよい。}、又はヘテロシクリル基(ここで、該ヘテロシクリル基は、1個のオキソで置換されてもよい。)である、
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。 In the above formula (I),
Y is an aryl group, heteroaryl group {wherein the aryl group and heteroaryl group are a halogen atom, an amino group, a C 1-6 alkyl group, a C 1-6 alkoxy group, a C 2-6 alkanoylamino group ( Here, the C 2-6 alkanoylamino group may be substituted with one C 1-6 alkylsulfonyl group), a C 1-6 alkylsulfonylamino group (wherein the C 1-6 alkylsulfonyl group) The sulfonylamino group may be substituted with 1 to 3 halogen atoms.), An arylsulfonylamino group, a C 1-6 alkylsulfonyl group, a heterocyclyl group, an aryl group, and a heteroaryl group. It may be substituted with 1 to 3 identical or different substituents. Or a heterocyclyl group (wherein the heterocyclyl group may be substituted with one oxo).
The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof.
A1が、水素原子又はC1-6アルキル基であり、
A2が、水素原子、C1-6アルキル基、又はC3-6シクロアルキル基であり、
A3が、C1-6アルコキシ基(ここで、該C1-6アルコキシ基は、1個のアミノ基で置換されてもよい。)、C1-6アルキルアミノ基(ここで、該C1-6アルキルアミノ基は、1個のアミノ基で置換されてもよい。)、C3-6シクロアルキルアミノ基(ここで、 該C3-6シクロアルキルアミノ基は、1個のアミノ基で置換されてもよい。)、又はヘテロシクリル基(ここで、該ヘテロシクリル基は、1個のアミノ基で置換されてもよい。)であり、
A4が、水素原子であり、
R1が、水素原子であり、
R2が、C1-6アルキル基又はC3-6シクロアルキル基であり、
R3が、C1-6アルキル基{ここで、該C1-6アルキル基は、ハロゲン原子、水酸基、C1-6アルコキシ基(ここで、該C1-6アルコキシ基は、1〜3個のハロゲン原子で置換されてもよい。)、アリールオキシ基、C1-6アルキルスルホニルアミノ基、C1-6アルキルスルホニル基、ヘテロシクリル基(ここで、該ヘテロシクリル基は、1〜2個のオキソで置換されてもよい。)、及びアリール基からなる群から選ばれる同一又は異なる1〜3個の置換基で置換されてもよい。}であり、
Yが、アリール基、ヘテロアリール基{ここで、該アリール基及びヘテロアリール基は、ハロゲン原子、アミノ基、C1-6アルキル基、C1-6アルコキシ基、C2-6アルカノイルアミノ基(ここで、該C2-6アルカノイルアミノ基は、1個のC1-6アルキルスルホニル基で置換されてもよい。)、C1-6アルキルスルホニルアミノ基、アリールスルホニルアミノ基、及びヘテロアリール基からなる群から選ばれる同一又は異なる1〜3個の置換基で置換されてもよい。}、又はヘテロシクリル基(ここで、該ヘテロシクリル基は、1個のオキソで置換されてもよい。)である請求項1〜3いずれか1項に記載の化合物、又はその医薬上許容される塩。 In the above formula (I),
A 1 is a hydrogen atom or a C 1-6 alkyl group,
A 2 is a hydrogen atom, a C 1-6 alkyl group, or a C 3-6 cycloalkyl group,
A 3 is a C 1-6 alkoxy group (wherein the C 1-6 alkoxy group may be substituted with one amino group), a C 1-6 alkylamino group (wherein the C 1-6 1-6 alkylamino group may be substituted with one amino group.), C 3-6 cycloalkylamino group (wherein the C 3-6 cycloalkylamino group is one amino group) Or a heterocyclyl group (wherein the heterocyclyl group may be substituted with one amino group),
A 4 is a hydrogen atom,
R 1 is a hydrogen atom,
R 2 is a C 1-6 alkyl group or a C 3-6 cycloalkyl group,
R 3 is a C 1-6 alkyl group {wherein the C 1-6 alkyl group is a halogen atom, a hydroxyl group, a C 1-6 alkoxy group (wherein the C 1-6 alkoxy group is 1 to 3 May be substituted with 1 halogen atom), an aryloxy group, a C 1-6 alkylsulfonylamino group, a C 1-6 alkylsulfonyl group, a heterocyclyl group (wherein the heterocyclyl group has 1 to 2 And may be substituted with 1 to 3 identical or different substituents selected from the group consisting of aryl groups. },
Y is an aryl group, heteroaryl group {wherein the aryl group and heteroaryl group are a halogen atom, an amino group, a C 1-6 alkyl group, a C 1-6 alkoxy group, a C 2-6 alkanoylamino group ( Here, the C 2-6 alkanoylamino group may be substituted with one C 1-6 alkylsulfonyl group.), C 1-6 alkylsulfonylamino group, arylsulfonylamino group, and heteroaryl group May be substituted with the same or different 1 to 3 substituents selected from the group consisting of Or a heterocyclyl group (wherein the heterocyclyl group may be substituted with one oxo), or a pharmaceutically acceptable salt thereof. .
A1が、水素原子であり、
A2が、メチル基、エチル基、又はシクロプロピル基であり、
A3が、下記式群(III)のいずれかの構造であり、
R1が、水素原子であり、
R2が、メチル基、エチル基、プロピル基、又はシクロプロピル基であり、
R3が、C1-6アルキル基{ここで、該C1-6アルキル基は、ハロゲン原子、水酸基、C1-6アルコキシ基(ここで、該C1-6アルコキシ基は、1〜3個のハロゲン原子で置換されてもよい。)、C1-6アルキルスルホニルアミノ基、及びヘテロシクリル基(ここで、該ヘテロシクリル基は、1〜2個のオキソで置換されてもよい。)からなる群から選ばれる同一又は異なる1〜3個の置換基で置換されてもよい。}であり、
Yが、フェニル基又はピリジル基{ここで、該フェニル基及びピリジル基は、ハロゲン原子、アミノ基、C1-6アルキル基、C1-6アルコキシ基、C2-6アルカノイルアミノ基(ここで、該C2-6アルカノイルアミノ基は、1個のC1-6アルキルスルホニル基で置換されてもよい。)、C1-6アルキルスルホニルアミノ基、フェニルスルホニルアミノ基、及びC1-6アルキルスルホニル基からなる群から選ばれる同一又は異なる1〜3個の置換基で置換されてもよい。}である請求項1〜4いずれか1項に記載の化合物、又はその医薬上許容される塩。 In the above formula (I),
A 1 is a hydrogen atom,
A 2 is a methyl group, an ethyl group, or a cyclopropyl group;
A 3 is any structure of the following formula group (III),
R 1 is a hydrogen atom,
R 2 is a methyl group, an ethyl group, a propyl group, or a cyclopropyl group;
R 3 is a C 1-6 alkyl group {wherein the C 1-6 alkyl group is a halogen atom, a hydroxyl group, a C 1-6 alkoxy group (wherein the C 1-6 alkoxy group is 1 to 3 A C 1-6 alkylsulfonylamino group, and a heterocyclyl group (wherein the heterocyclyl group may be substituted with 1 to 2 oxo groups). It may be substituted with 1 to 3 identical or different substituents selected from the group. },
Y is a phenyl group or a pyridyl group {wherein the phenyl group and the pyridyl group are a halogen atom, an amino group, a C 1-6 alkyl group, a C 1-6 alkoxy group, a C 2-6 alkanoylamino group (where The C 2-6 alkanoylamino group may be substituted with one C 1-6 alkylsulfonyl group.), C 1-6 alkylsulfonylamino group, phenylsulfonylamino group, and C 1-6 alkyl It may be substituted with 1 to 3 identical or different substituents selected from the group consisting of sulfonyl groups. } The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof.
Yが、上記式群(II)のいずれかの構造であり、
環Qは、芳香族炭化水素環又はヘテロ芳香環(ここで、該芳香族炭化水素環及びヘテロ芳香環は、1個のC1-6アルキル基で置換されてもよい。)であり、
Wが単結合のとき、Zが、式(CH2)n又は式CH2NR7であり、
nが、2〜4の整数であり、
Wが式CH2のとき、Zが、式CH2CH2であり、
B1、B2、B3、B4、及びB5が、同一又は異なって、それぞれ水素原子、ハロゲン原子、又はC1-6アルキル基であり、
R4及びR5が、同一又は異なって、それぞれ水素原子、C1-6アルキル基であるか、
又は、R4及びR5が、隣接する炭素原子と一緒になってC3-6シクロアルカン{ここで、該C3-6シクロアルカンは、オキソ、水酸基、C2-6アルカノイルアミノ基(ここで、該C2-6アルカノイルアミノ基は、1個のC1-6アルキルスルホニル基で置換されてもよい。)、及びC1-6アルキルスルホニルアミノ基からなる群から選ばれる1個の置換基で置換されてもよい。}を形成してもよく、さらに該C3-6シクロアルカンは、環中の1個の式CH2が式NR8で置換されてもよく、
R6が、水素原子、アミノ基、C1-6アルキル基(ここで、該C1-6アルキル基は、C3-6シクロアルキルカルボニル基、C1-6アルキルスルホニル基、及びC1-6アルキルスルホニルアミノ基からなる群から選ばれる1個の置換基で置換されてもよい。)、C1-6アルキルアミノ基(ここで、該C1-6アルキルアミノ基は、1個のC1-6アルキルスルホニル基で置換されてもよい。)、C2-6アルカノイルアミノ基(ここで、該C2-6アルカノイルアミノ基は、アミノ基、 スルファモイル基、C3-6シクロアルキル基、C1-6アルコキシ基、C1-6アルキルアミノ基、C2-6アルカノイルアミノ基、C1-6アルキルスルホニルアミノ基、C1-6アルキルスルホニル基、C1-6アルキルアミノスルホニル基、アリールスルホニル基、アリール基、及びヘテロアリール基からなる群から選ばれる1個の置換基で置換されてもよい。)、C1-6アルコキシカルボニルアミノ基(ここで、該C1-6アルコキシカルボニルアミノ基は、1個のアリール基で置換されてもよい。)、又はC1-6アルキルスルホニルアミノ基であり、
R7が、水素原子又はC1-6アルキル基であり、
R8が、カルバモイル基、アミジノ基、C2-6アルカノイル基(ここで、該C2-6アルカノイル基は、1個のC1-6アルキルスルホニル基で置換されてもよい。)、C1-6アルコキシカルボニル基(ここで、該C1-6アルコキシカルボニル基は、1個のアリール基で置換されてもよい。)、又はC1-6アルキルスルホニル基である請求項1又は2に記載の化合物、又はその医薬上許容される塩。 In the above formula (I),
Y is any structure of the above formula group (II),
Ring Q is an aromatic hydrocarbon ring or a heteroaromatic ring (wherein the aromatic hydrocarbon ring and the heteroaromatic ring may be substituted with one C 1-6 alkyl group),
When W is a single bond, Z is the formula (CH 2 ) n or the formula CH 2 NR 7 ;
n is an integer of 2 to 4,
When W is of formula CH 2 , Z is of formula CH 2 CH 2 ;
B 1 , B 2 , B 3 , B 4 , and B 5 are the same or different and each is a hydrogen atom, a halogen atom, or a C 1-6 alkyl group,
R 4 and R 5 are the same or different and each represents a hydrogen atom or a C 1-6 alkyl group,
Or R 4 and R 5 together with an adjacent carbon atom are C 3-6 cycloalkane {where C 3-6 cycloalkane is an oxo, hydroxyl group, C 2-6 alkanoylamino group (here And the C 2-6 alkanoylamino group may be substituted with one C 1-6 alkylsulfonyl group.), And one substitution selected from the group consisting of C 1-6 alkylsulfonylamino groups It may be substituted with a group. Furthermore, the C 3-6 cycloalkane may have one formula CH 2 in the ring substituted with the formula NR 8 ,
R 6 is a hydrogen atom, an amino group, a C 1-6 alkyl group (wherein the C 1-6 alkyl group is a C 3-6 cycloalkylcarbonyl group, a C 1-6 alkylsulfonyl group, and a C 1- Which may be substituted with one substituent selected from the group consisting of 6 alkylsulfonylamino groups), a C 1-6 alkylamino group (wherein the C 1-6 alkylamino group is one C 1-6 alkylsulfonyl group may be substituted), C 2-6 alkanoylamino group (wherein the C 2-6 alkanoylamino group is an amino group, a sulfamoyl group, a C 3-6 cycloalkyl group, C 1-6 alkoxy group, C 1-6 alkylamino group, C 2-6 alkanoylamino group, C 1-6 alkylsulfonylamino group, C 1-6 alkylsulfonyl group, C 1-6 alkylaminosulfonyl group, aryl Sulfonyl group, aryl group, and heteroaryl May be substituted with one substituent selected from the group consisting of.), By C 1-6 alkoxycarbonylamino group (wherein the C 1-6 alkoxycarbonylamino group, substituted with one aryl group Or a C 1-6 alkylsulfonylamino group,
R 7 is a hydrogen atom or a C 1-6 alkyl group,
R 8 is a carbamoyl group, an amidino group, a C 2-6 alkanoyl group (wherein the C 2-6 alkanoyl group may be substituted with one C 1-6 alkylsulfonyl group), C 1 The -6 alkoxycarbonyl group (wherein the C 1-6 alkoxycarbonyl group may be substituted with one aryl group) or a C 1-6 alkylsulfonyl group. Or a pharmaceutically acceptable salt thereof.
A1が、水素原子又はC1-6アルキル基であり、
A2が、水素原子、C1-6アルキル基、又はC3-6シクロアルキル基であり、
A3が、C1-6アルコキシ基(ここで、該C1-6アルコキシ基は、1個のアミノ基で置換されてもよい。)、C1-6アルキルアミノ基(ここで、該C1-6アルキルアミノ基は、1個のアミノ基で置換されてもよい。)、C3-6シクロアルキルアミノ基(ここで、 該C3-6シクロアルキルアミノ基は、1個のアミノ基で置換されてもよい。)、又はヘテロシクリル基(ここで、該ヘテロシクリル基は、1個のアミノ基で置換されてもよい。)であり、
A4が、水素原子であり、
R1が、水素原子であり、
R2が、C1-6アルキル基又はC3-6シクロアルキル基であり、
R3が、C1-6アルキル基{ここで、該C1-6アルキル基は、ハロゲン原子、水酸基、C1-6アルコキシ基(ここで、該C1-6アルコキシ基は、1〜3個のハロゲン原子で置換されてもよい。)、アリールオキシ基、C1-6アルキルスルホニルアミノ基、C1-6アルキルスルホニル基、ヘテロシクリル基(ここで、該ヘテロシクリル基は、1〜2個のオキソで置換されてもよい。)、及びアリール基からなる群から選ばれる同一又は異なる1〜3個の置換基で置換されてもよい。}であり、
Yが、下記式群(IV)のいずれかの構造であり、
nが、2〜4の整数であり、
B1、B2、B3、B4、及びB5が、それぞれ水素原子であり、
B6、B7、B8、及びB9が、同一又は異なって、それぞれ水素原子、又はC1-6アルキル基であり、
R4及びR5が、隣接する炭素原子と一緒になってC3-6シクロアルカン{ここで、該C3-6シクロアルカンは、C2-6アルカノイルアミノ基(ここで、該C2-6アルカノイルアミノ基は、1個のC1-6アルキルスルホニル基で置換されてもよい。)、及びC1-6アルキルスルホニルアミノ基からなる群から選ばれる1個の置換基で置換されてもよい。}を形成してもよく、さらに該C3-6シクロアルカンは、環中の1個の式CH2が式NR8で置換されていてもよく、
R6が、アミノ基、C1-6アルキル基(ここで、該C1-6アルキル基はC1-6アルキルスルホニル基及びC1-6アルキルスルホニルアミノ基からなる群から選ばれる1個の置換基で置換されてもよい。)、C2-6アルカノイルアミノ基(ここで、該C2-6アルカノイルアミノ基は、スルファモイル基、C3-6シクロアルキル基、C1-6アルキルスルホニルアミノ基、C1-6アルキルスルホニル基、C1-6アルキルアミノスルホニル基、アリールスルホニル基、及びアリール基からなる群から選ばれる1個の置換基で置換されてもよい。)、C1-6アルコキシカルボニルアミノ基、又はC1-6アルキルスルホニルアミノ基であり、
R8が、C2-6アルカノイル基(ここで、該C2-6アルカノイル基は、1個のC1-6アルキルスルホニル基で置換されてもよい。)、又はC1-6アルキルスルホニル基である請求項1、2又は6いずれか1項に記載の化合物、又はその医薬上許容される塩。 In the above formula (I),
A 1 is a hydrogen atom or a C 1-6 alkyl group,
A 2 is a hydrogen atom, a C 1-6 alkyl group, or a C 3-6 cycloalkyl group,
A 3 is a C 1-6 alkoxy group (wherein the C 1-6 alkoxy group may be substituted with one amino group), a C 1-6 alkylamino group (wherein the C 1-6 1-6 alkylamino group may be substituted with one amino group.), C 3-6 cycloalkylamino group (wherein the C 3-6 cycloalkylamino group is one amino group) Or a heterocyclyl group (wherein the heterocyclyl group may be substituted with one amino group),
A 4 is a hydrogen atom,
R 1 is a hydrogen atom,
R 2 is a C 1-6 alkyl group or a C 3-6 cycloalkyl group,
R 3 is a C 1-6 alkyl group {wherein the C 1-6 alkyl group is a halogen atom, a hydroxyl group, a C 1-6 alkoxy group (wherein the C 1-6 alkoxy group is 1 to 3 May be substituted with 1 halogen atom), an aryloxy group, a C 1-6 alkylsulfonylamino group, a C 1-6 alkylsulfonyl group, a heterocyclyl group (wherein the heterocyclyl group has 1 to 2 And may be substituted with 1 to 3 identical or different substituents selected from the group consisting of aryl groups. },
Y is any structure of the following formula group (IV),
n is an integer of 2 to 4,
B 1 , B 2 , B 3 , B 4 , and B 5 are each a hydrogen atom,
B 6 , B 7 , B 8 and B 9 are the same or different and each is a hydrogen atom or a C 1-6 alkyl group,
R 4 and R 5, with C 3-6 cycloalkane {here together with the adjacent carbon atoms, the C 3-6 cycloalkane, C 2-6 at alkanoylamino group (wherein said C 2- The 6 alkanoylamino group may be substituted with one C 1-6 alkylsulfonyl group.), And may be substituted with one substituent selected from the group consisting of C 1-6 alkylsulfonylamino groups. Good. Furthermore, the C 3-6 cycloalkane may have one formula CH 2 in the ring substituted with the formula NR 8 ,
R 6 is an amino group, with a C 1-6 alkyl group (wherein, the C 1-6 alkyl groups one selected from the group consisting of C 1-6 alkylsulfonyl group and a C 1-6 alkylsulfonylamino group A C 2-6 alkanoylamino group (wherein the C 2-6 alkanoylamino group is a sulfamoyl group, a C 3-6 cycloalkyl group, a C 1-6 alkylsulfonylamino group). group, C 1-6 alkylsulfonyl group, C 1-6 alkylaminosulfonyl group, may be substituted with an arylsulfonyl group 1 substituents selected from the group consisting of and aryl radicals,.), C 1-6 An alkoxycarbonylamino group, or a C 1-6 alkylsulfonylamino group,
R 8 represents a C 2-6 alkanoyl group (wherein the C 2-6 alkanoyl group may be substituted with one C 1-6 alkylsulfonyl group), or a C 1-6 alkylsulfonyl group The compound according to any one of claims 1, 2, and 6, or a pharmaceutically acceptable salt thereof.
A1が、水素原子であり、
A2が、メチル基であり、
A3が、下記式(V)の構造であり、
R1が、水素原子であり、
R2が、メチル基又はエチル基であり、
R3が、メチル基であり、
Yが、上記式群(IV)のいずれかの構造であり、
Wが単結合のとき、Zが、式(CH2)nであり、
nが、2〜4の整数であり、
B1、B2、B3、B4、B5、B6、B7、B8、及びB9が、水素原子であり、
R4及びR5が、隣接する炭素原子と一緒になってC3-6シクロアルカン{ここで、該C3-6シクロアルカンは、C2-6アルカノイルアミノ基(ここで、該C2-6アルカノイルアミノ基は、1個のC1-6アルキルスルホニル基で置換されてもよい。)で置換されてもよい。}を形成してもよく、さらに該C3-6シクロアルカンは、環中の1個の式CH2が式NR8で置換されてもよく、
R6が、C2-6アルカノイルアミノ基(ここで、該C2-6アルカノイルアミノ基は、スルファモイル基、C1-6アルキルスルホニル基、及びC1-6アルキルアミノスルホニル基からなる群から選ばれる1個の置換基で置換されてもよい。)、C1-6アルコキシカルボニルアミノ基、又はC1-6アルキルスルホニルアミノ基であり、
R8が、C2-6アルカノイル基(ここで、該C2-6アルカノイル基は、1個のC1-6アルキルスルホニル基で置換されてもよい。)である請求項1、2、6、又は7いずれか1項に記載の化合物又はその医薬上許容される塩。 In the above formula (I),
A 1 is a hydrogen atom,
A 2 is a methyl group,
A 3 is a structure of the following formula (V),
R 1 is a hydrogen atom,
R 2 is a methyl group or an ethyl group,
R 3 is a methyl group,
Y is any structure of the above formula group (IV),
When W is a single bond, Z is the formula (CH 2 ) n;
n is an integer of 2 to 4,
B 1 , B 2 , B 3 , B 4 , B 5 , B 6 , B 7 , B 8 , and B 9 are hydrogen atoms;
R 4 and R 5, with C 3-6 cycloalkane {here together with the adjacent carbon atoms, the C 3-6 cycloalkane, C 2-6 at alkanoylamino group (wherein said C 2- The 6 alkanoylamino group may be substituted with one C 1-6 alkylsulfonyl group. Furthermore, the C 3-6 cycloalkane may have one formula CH 2 in the ring substituted with the formula NR 8 ,
R 6 is a C 2-6 alkanoylamino group (wherein the C 2-6 alkanoylamino group is selected from the group consisting of a sulfamoyl group, a C 1-6 alkylsulfonyl group, and a C 1-6 alkylaminosulfonyl group) And a C 1-6 alkoxycarbonylamino group, or a C 1-6 alkylsulfonylamino group,
R 8 is a C 2-6 alkanoyl group (wherein the C 2-6 alkanoyl group may be substituted with one C 1-6 alkylsulfonyl group). Or the compound according to any one of 7 or a pharmaceutically acceptable salt thereof.
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MA46092A (en) | 2016-08-31 | 2021-04-21 | Agios Pharmaceuticals Inc | CELLULAR METABOLIC PROCESS INHIBITORS |
KR20200042906A (en) * | 2017-08-07 | 2020-04-24 | 고쿠리츠다이가쿠호진 히로시마다이가쿠 | New anthranilic acid compounds, and Pin1 inhibitors using the same, therapeutic agents for inflammatory diseases and therapeutic agents for cancer |
US20230069963A1 (en) | 2018-12-27 | 2023-03-09 | Taisho Pharmaceutical Co., Ltd. | Pyrazolo[1,5-a]pyrimidine macrocyclic compound |
EP4038052B1 (en) * | 2019-10-02 | 2024-02-07 | Domain Therapeutics | Prostaglandin e2 (pge2) ep4 receptor antagonists |
CN115427045A (en) * | 2020-04-21 | 2022-12-02 | 莱西肯医药有限公司 | 4- (3- (pyridin-3-yl) pyrazolo [1,5-a ] pyrimidin-5-yl) piperazine for the treatment of COV-229E or COV-OC43 coronavirus infection |
WO2022092141A1 (en) * | 2020-10-28 | 2022-05-05 | 塩野義製薬株式会社 | Amide derivative having antiviral activity |
JP7454729B2 (en) | 2022-04-27 | 2024-03-22 | 塩野義製薬株式会社 | Pharmaceutical composition containing an amide derivative with antiviral activity |
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EP1392692B1 (en) * | 2001-03-27 | 2006-11-15 | Neurogen Corporation | (oxo-pyrazolo¬1,5a|pyrimidin-2-yl)alkyl-carboxamides |
MX2010001650A (en) * | 2007-08-10 | 2010-08-02 | Glaxosmithkline Llc | Certain nitrogen containing bicyclic chemical entities for treating viral infections. |
PE20130395A1 (en) * | 2010-06-24 | 2013-04-10 | Gilead Sciences Inc | PYRAZOLO [1,5-A] PYRIMIDINES FOR ANTIVIRAL TREATMENT |
US8946238B2 (en) * | 2011-12-22 | 2015-02-03 | Gilead Sciences, Inc. | Pyrazolo[1,5-A]pyrimidines as antiviral agents |
KR102181318B1 (en) * | 2012-04-17 | 2020-11-20 | 길리애드 사이언시즈, 인코포레이티드 | Compounds and methods for antiviral treatment |
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US11827640B2 (en) | 2020-10-23 | 2023-11-28 | Ildong Pharmaceutical Co., Ltd. | Substituted pyrazolo[1,5-a]pyrimidines as CFTR modulators |
US11787812B2 (en) | 2020-12-11 | 2023-10-17 | Ildong Pharmaceutical Co., Ltd. | Substituted pyrazolo[4,3-d]pyrimidines and imidazo[5,1 -f][1,2,4]triazines as androgen receptor and phosphodiesterase dual inhibitors |
WO2023067388A1 (en) * | 2021-10-22 | 2023-04-27 | Ildong Pharmaceutical Co., Ltd. | Uses of cftr modulator and/or pde4 inhibitor compounds |
WO2023204630A1 (en) * | 2022-04-20 | 2023-10-26 | 일동제약(주) | Composition comprising cftr activator |
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