JPWO2021176366A5 - - Google Patents
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- JPWO2021176366A5 JPWO2021176366A5 JP2022553213A JP2022553213A JPWO2021176366A5 JP WO2021176366 A5 JPWO2021176366 A5 JP WO2021176366A5 JP 2022553213 A JP2022553213 A JP 2022553213A JP 2022553213 A JP2022553213 A JP 2022553213A JP WO2021176366 A5 JPWO2021176366 A5 JP WO2021176366A5
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- 150000001875 compounds Chemical class 0.000 claims description 51
- 150000003839 salts Chemical class 0.000 claims 33
- 125000001153 fluoro group Chemical group F* 0.000 claims 17
- 235000019000 fluorine Nutrition 0.000 claims 16
- 239000008194 pharmaceutical composition Substances 0.000 claims 12
- 125000000217 alkyl group Chemical group 0.000 claims 9
- 208000031886 HIV Infections Diseases 0.000 claims 6
- 208000037357 HIV infectious disease Diseases 0.000 claims 6
- 208000033519 human immunodeficiency virus infectious disease Diseases 0.000 claims 6
- 229910052739 hydrogen Inorganic materials 0.000 claims 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 5
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims 4
- 229910052801 chlorine Inorganic materials 0.000 claims 3
- 239000003814 drug Substances 0.000 claims 3
- 229910052731 fluorine Inorganic materials 0.000 claims 3
- 238000011282 treatment Methods 0.000 claims 3
- 125000006645 (C3-C4) cycloalkyl group Chemical group 0.000 claims 2
- 239000003795 chemical substances by application Substances 0.000 claims 2
- HGCIXCUEYOPUTN-UHFFFAOYSA-N cyclohexene Chemical compound C1CCC=CC1 HGCIXCUEYOPUTN-UHFFFAOYSA-N 0.000 claims 2
- LPIQUOYDBNQMRZ-UHFFFAOYSA-N cyclopentene Chemical compound C1CC=CC1 LPIQUOYDBNQMRZ-UHFFFAOYSA-N 0.000 claims 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims 2
- 239000001257 hydrogen Substances 0.000 claims 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 2
- 238000010255 intramuscular injection Methods 0.000 claims 2
- 239000007927 intramuscular injection Substances 0.000 claims 2
- 238000004519 manufacturing process Methods 0.000 claims 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 2
- 238000011321 prophylaxis Methods 0.000 claims 2
- 238000010254 subcutaneous injection Methods 0.000 claims 2
- 239000007929 subcutaneous injection Substances 0.000 claims 2
- 125000001424 substituent group Chemical group 0.000 claims 2
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims 1
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 claims 1
- 125000004778 2,2-difluoroethyl group Chemical group [H]C([H])(*)C([H])(F)F 0.000 claims 1
- 229940126250 GSK3640254 Drugs 0.000 claims 1
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims 1
- YFSNREBZTKMFEB-DHGHKPCRSA-N [H][C@]12[C@@H](CC[C@@]1(CC[C@]1(C)[C@]2([H])CC[C@]2([H])[C@@]3(C)CC=C(C4=CC[C@](CF)(CC4)C(O)=O)C(C)(C)[C@]3([H])CC[C@@]12C)NCCN1CCS(=O)(=O)CC1)C(C)=C Chemical compound [H][C@]12[C@@H](CC[C@@]1(CC[C@]1(C)[C@]2([H])CC[C@]2([H])[C@@]3(C)CC=C(C4=CC[C@](CF)(CC4)C(O)=O)C(C)(C)[C@]3([H])CC[C@@]12C)NCCN1CCS(=O)(=O)CC1)C(C)=C YFSNREBZTKMFEB-DHGHKPCRSA-N 0.000 claims 1
- 229950004159 bictegravir Drugs 0.000 claims 1
- SOLUWJRYJLAZCX-LYOVBCGYSA-N bictegravir Chemical compound C([C@H]1O[C@@H]2CC[C@@H](C2)N1C(=O)C1=C(C2=O)O)N1C=C2C(=O)NCC1=C(F)C=C(F)C=C1F SOLUWJRYJLAZCX-LYOVBCGYSA-N 0.000 claims 1
- 229950005928 cabotegravir Drugs 0.000 claims 1
- WCWSTNLSLKSJPK-LKFCYVNXSA-N cabotegravir Chemical compound C([C@H]1OC[C@@H](N1C(=O)C1=C(O)C2=O)C)N1C=C2C(=O)NCC1=CC=C(F)C=C1F WCWSTNLSLKSJPK-LKFCYVNXSA-N 0.000 claims 1
- 125000000753 cycloalkyl group Chemical group 0.000 claims 1
- 229960002542 dolutegravir Drugs 0.000 claims 1
- RHWKPHLQXYSBKR-BMIGLBTASA-N dolutegravir Chemical compound C([C@@H]1OCC[C@H](N1C(=O)C1=C(O)C2=O)C)N1C=C2C(=O)NCC1=CC=C(F)C=C1F RHWKPHLQXYSBKR-BMIGLBTASA-N 0.000 claims 1
- 229940079593 drug Drugs 0.000 claims 1
- SWMDAPWAQQTBOG-UHFFFAOYSA-N fostemsavir Chemical compound C1=2N(COP(O)(O)=O)C=C(C(=O)C(=O)N3CCN(CC3)C(=O)C=3C=CC=CC=3)C=2C(OC)=CN=C1N1C=NC(C)=N1 SWMDAPWAQQTBOG-UHFFFAOYSA-N 0.000 claims 1
- 229950010812 fostemsavir Drugs 0.000 claims 1
- 125000001072 heteroaryl group Chemical group 0.000 claims 1
- JTEGQNOMFQHVDC-NKWVEPMBSA-N lamivudine Chemical compound O=C1N=C(N)C=CN1[C@H]1O[C@@H](CO)SC1 JTEGQNOMFQHVDC-NKWVEPMBSA-N 0.000 claims 1
- 229960001627 lamivudine Drugs 0.000 claims 1
- RGSFGYAAUTVSQA-UHFFFAOYSA-N pentamethylene Natural products C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 claims 1
- 239000000546 pharmaceutical excipient Substances 0.000 claims 1
- 238000002560 therapeutic procedure Methods 0.000 claims 1
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 26
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 7
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 6
- 239000007819 coupling partner Substances 0.000 description 6
- 238000002474 experimental method Methods 0.000 description 6
- 150000002500 ions Chemical class 0.000 description 6
- 230000014759 maintenance of location Effects 0.000 description 6
- 238000000034 method Methods 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- PAQZWJGSJMLPMG-UHFFFAOYSA-N 2,4,6-tripropyl-1,3,5,2$l^{5},4$l^{5},6$l^{5}-trioxatriphosphinane 2,4,6-trioxide Chemical compound CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1 PAQZWJGSJMLPMG-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 235000019439 ethyl acetate Nutrition 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 125000004353 pyrazol-1-yl group Chemical group [H]C1=NN(*)C([H])=C1[H] 0.000 description 2
- HRBLSBRWIWIOGW-UHFFFAOYSA-N 2-(2,2,2-trifluoroethoxy)ethanol Chemical compound OCCOCC(F)(F)F HRBLSBRWIWIOGW-UHFFFAOYSA-N 0.000 description 1
- RYMMYJLSBIHSDT-UHFFFAOYSA-N 2-(2,2,2-trifluoroethylamino)ethanol Chemical compound OCCNCC(F)(F)F RYMMYJLSBIHSDT-UHFFFAOYSA-N 0.000 description 1
- GHICVYMOCZKQOD-UHFFFAOYSA-N 2-(2,2-difluorocyclopropyl)oxyethanol Chemical compound OCCOC1CC1(F)F GHICVYMOCZKQOD-UHFFFAOYSA-N 0.000 description 1
- JPMHUDBOKDBBLG-UHFFFAOYSA-N 3,3,4,4,4-pentafluorobutan-1-ol Chemical compound OCCC(F)(F)C(F)(F)F JPMHUDBOKDBBLG-UHFFFAOYSA-N 0.000 description 1
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- BBEOXYIIWAUVSW-UHFFFAOYSA-N [1-(2,2,2-trifluoroethyl)pyrazol-3-yl]methanol Chemical compound OCC=1C=CN(CC(F)(F)F)N=1 BBEOXYIIWAUVSW-UHFFFAOYSA-N 0.000 description 1
- VIGAFTQUOHZWIC-UHFFFAOYSA-N [4-(trifluoromethyl)-1,3-thiazol-2-yl]methanol Chemical compound OCC1=NC(C(F)(F)F)=CS1 VIGAFTQUOHZWIC-UHFFFAOYSA-N 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 239000010931 gold Substances 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
Description
実施例１９：Ｎ－（（Ｓ）－１－（（３Ｐ）－３－（４－クロロ－１－メチル－３－（メチルスルホンアミド）－１Ｈ－インダゾール－７－イル）－４－オキソ－７－（３，３，４，４，４－ペンタフルオロブトキシ）－３，４－ジヒドロピリド［２，３－ｄ］ピリミジン－２－イル）－２－（３，５－ジフルオロフェニル）エチル）－２－（（３ｂＳ，４ａＲ）－３－（ジフルオロメチル）－５，５－ジフルオロ－３ｂ，４，４ａ，５－テトラヒドロ－１Ｈ－シクロプロパ［３，４］シクロペンタ［１，２－ｃ］ピラゾール－１－イル）アセトアミドの調製Example 19: N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-4-oxo- 7-(3,3,4,4,4-pentafluorobutoxy)-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)- 2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole- Preparation of 1-yl)acetamide
３，３，４，４，４－ペンタフルオロブタン－１－オールをカップリングパートナーとして使用して、一般手順Ａに従って表題化合物を調製した。この実験により、表題化合物Ｎ－（（Ｓ）－１－（（３Ｐ）－３－（４－クロロ－１－メチル－３－（メチルスルホンアミド）－１Ｈ－インダゾール－７－イル）－４－オキソ－７－（３，３，４，４，４－ペンタフルオロブトキシ）－３，４－ジヒドロピリド［２，３－ｄ］ピリミジン－２－イル）－２－（３，５－ジフルオロフェニル）エチル）－２－（（３ｂＳ，４ａＲ）－３－（ジフルオロメチル）－５，５－ジフルオロ－３ｂ，４，４ａ，５－テトラヒドロ－１Ｈ－シクロプロパ［３，４］シクロペンタ［１，２－ｃ］ピラゾール－１－イル）アセトアミドを得た。ＬＣＭＳ Ａを使用してサンプルを分析した：保持時間＝１．５２分；観測されたイオン＝９６８．４（Ｍ＋Ｈ）。
1H NMR (500 MHz, METHANOL-d4) δ ppm 8.47 - 8.58 (m, 1 H) 7.16 - 7.32 (m, 2 H) 7.07 (d, J=8.64 Hz, 1 H) 6.52 - 6.83 (m, 4 H) 4.82 - 4.85 (m, 3 H) 4.51 - 4.64 (m, 2 H) 3.55 - 3.63 (m, 3 H) 3.41 - 3.49 (m, 1 H) 3.21 (s, 3 H) 3.11 (dd, J=14.16, 9.69 Hz, 1 H) 2.72 - 2.92 (m, 2 H) 2.35 - 2.46 (m, 2 H) 1.31 - 1.40 (m, 1 H) 0.93 - 1.02 (m, 1 H)
The title compound was prepared according to General Procedure A using 3,3,4,4,4-pentafluorobutan-1-ol as the coupling partner. This experiment yielded the title compound N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-4- Oxo- 7- (3,3,4,4,4-pentafluorobutoxy)-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl )-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c] Pyrazol-1-yl)acetamide was obtained. Samples were analyzed using LCMS A: Retention time = 1.52 minutes; Observed ions = 968.4 (M+H).
1H NMR (500 MHz, METHANOL-d4) δ ppm 8.47 - 8.58 (m, 1 H) 7.16 - 7.32 (m, 2 H) 7.07 (d, J=8.64 Hz, 1 H) 6.52 - 6.83 (m, 4 H ) 4.82 - 4.85 (m, 3 H) 4.51 - 4.64 (m, 2 H) 3.55 - 3.63 (m, 3 H) 3.41 - 3.49 (m, 1 H) 3.21 (s, 3 H) 3.11 (dd, J= 14.16, 9.69 Hz, 1 H) 2.72 - 2.92 (m, 2 H) 2.35 - 2.46 (m, 2 H) 1.31 - 1.40 (m, 1 H) 0.93 - 1.02 (m, 1 H)
（４－（トリフルオロメチル）チアゾール－２－イル）メタノールをカップリングパートナーとして使用して、一般手順Ａに従って表題化合物を調製した。この実験により、表題化合物Ｎ－（（Ｓ）－１－（（３Ｐ）－３－（４－クロロ－１－メチル－３－（メチルスルホンアミド）－１Ｈ－インダゾール－７－イル）－４－オキソ－７－（（４－（トリフルオロメチル）チアゾール－２－イル）メトキシ）－３，４－ジヒドロピリド［２，３－ｄ］ピリミジン－２－イル）－２－（３，５－ジフルオロフェニル）エチル）－２－（（３ｂＳ，４ａＲ）－３－（ジフルオロメチル）－５，５－ジフルオロ－３ｂ，４，４ａ，５－テトラヒドロ－１Ｈ－シクロプロパ［３，４］シクロペンタ［１，２－ｃ］ピラゾール－１－イル）アセトアミドを得た。ＬＣＭＳ Ａを使用してサンプルを分析した：保持時間＝１．４９分；観測されたイオン＝９８７．２（Ｍ＋Ｈ）。 The title compound was prepared according to General Procedure A using ( 4-(trifluoromethyl)thiazol-2-yl)methanol as the coupling partner. This experiment yielded the title compound N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-4- Oxo-7-((4-(trifluoromethyl)thiazol-2-yl)methoxy)-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl) )ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2- c] pyrazol-1-yl)acetamide was obtained. Samples were analyzed using LCMS A: Retention time = 1.49 minutes; Observed ions = 987.2 (M+H).
（１－（２，２，２－トリフルオロエチル）－１Ｈ－ピラゾール－３－イル）メタノールをカップリングパートナーとして使用して、一般手順Ａに従って表題化合物を調製した。この実験により、表題化合物Ｎ－（（Ｓ）－１－（（３Ｐ）－３－（４－クロロ－１－メチル－３－（メチルスルホンアミド）－１Ｈ－インダゾール－７－イル）－４－オキソ－７）－（（１－（２，２，２－トリフルオロエチル）－１Ｈ－ピラゾール－３－イル）メトキシ）－３，４－ジヒドロピリド［２，３－ｄ］ピリミジン－２－イル）－２－（３，５－ジフルオロフェニル）エチル）－２－（（３ｂＳ，４ａＲ）－３－（ジフルオロメチル）－５，５－ジフルオロ－３ｂ，４，４ａ，５－テトラヒドロ－１Ｈ－シクロプロパ［３，４］シクロペンタ［１，２－ｃ］ピラゾール－１－イル）アセトアミドを得た。ＬＣＭＳ Ａを使用してサンプルを分析した：保持時間＝１．３９分；観測されたイオン＝９８４．２（Ｍ＋Ｈ）。
1H NMR (500 MHz, METHANOL-d4) δ ppm 8.46 - 8.52 (m, 1 H) 7.80 - 7.84 (m, 1 H) 7.28 - 7.35 (m, 1 H) 7.18 - 7.24 (m, 1 H) 7.03 - 7.09 (m, 1 H) 6.54 - 6.87 (m, 5 H) 5.52 - 5.62 (m, 2 H) 4.93 - 5.01 (m, 2 H) 4.52 - 4.62 (m, 2 H) 3.61 - 3.67 (m, 3 H) 3.47 - 3.52 (m, 1 H) 3.25 (s, 3 H) 3.12 - 3.18 (m, 1 H) 2.41 - 2.50 (m, 2 H) 1.35 - 1.41 (m, 1 H) 0.99 - 1.05 (m, 1 H)
The title compound was prepared according to General Procedure A using ( 1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)methanol as the coupling partner. This experiment yielded the title compound N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-4- Oxo-7)-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)methoxy)-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl) -2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[ 3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide was obtained. Samples were analyzed using LCMS A: Retention time = 1.39 minutes; Observed ions = 984.2 (M+H).
1H NMR (500 MHz, METHANOL-d4) δ ppm 8.46 - 8.52 (m, 1 H) 7.80 - 7.84 (m, 1 H) 7.28 - 7.35 (m, 1 H) 7.18 - 7.24 (m, 1 H) 7.03 - 7.09 (m, 1 H) 6.54 - 6.87 (m, 5 H) 5.52 - 5.62 (m, 2 H) 4.93 - 5.01 (m, 2 H) 4.52 - 4.62 (m, 2 H) 3.61 - 3.67 (m, 3 H) 3.47 - 3.52 (m, 1 H) 3.25 (s, 3 H) 3.12 - 3.18 (m, 1 H) 2.41 - 2.50 (m, 2 H) 1.35 - 1.41 (m, 1 H) 0.99 - 1.05 (m , 1 H)
実施例２５：Ｎ－（（Ｓ）－１－（（３Ｐ）－３－（４－クロロ－１－メチル－３－（メチルスルホンアミド）－１Ｈ－インダゾール－７－イル）－４－オキソ－７－（２－（（２，２，２－トリフルオロエチル）アミノ）エトキシ）－３，４－ジヒドロピリド［２，３－ｄ］ピリミジン－２－イル）－２－（３，５－ジフルオロフェニル）エチル）－２－（（３ｂＳ，４ａＲ）－３－（ジフルオロメチル）－５，５－ジフルオロ－３ｂ，４，４ａ，５－テトラヒドロ－１Ｈ－シクロプロパ［３，４］シクロペンタ［１，２－ｃ］ピラゾール－１－イル）アセトアミドの調製Example 25: N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-4-oxo- 7-(2-((2,2,2-trifluoroethyl)amino)ethoxy)-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl )ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2- c] Preparation of pyrazol-1-yl)acetamide
２－（（２，２，２－トリフルオロエチル）アミノ）エタン－１－オールをカップリングパートナーとして使用して、一般手順Ａに従って表題化合物を調製した。この実験により、表題化合物Ｎ－（（Ｓ）－１－（（３Ｐ）－３－（４－クロロ－１－メチル－３－（メチルスルホンアミド）－１Ｈ－インダゾール－７－イル）－４－オキソ－７－（２－（（２，２，２－トリフルオロエチル）アミノ）エトキシ）－３，４－ジヒドロピリド［２，３－ｄ］ピリミジン－２－イル）－２－（３，５－ジフルオロフェニル）エチル）－２－（（３ｂＳ，４ａＲ）－３－（ジフルオロメチル）－５，５－ジフルオロ－３ｂ，４，４ａ，５－テトラヒドロ－１Ｈ－シクロプロパ［３，４］シクロペンタ［１，２－ｃ］ピラゾール－１－イル）アセトアミドを得た。ＬＣＭＳ Ａを使用してサンプルを分析した：保持時間＝１．３１分；観測されたイオン＝９４７．２
1H NMR (500 MHz, METHANOL-d4) δ ppm 8.09 - 8.17 (m, 1 H) 7.29 - 7.37 (m, 2 H) 6.55 - 6.87 (m, 6 H) 4.44 - 4.79 (m, 5 H) 3.64 (s, 3 H) 3.44 - 3.48 (m, 1 H) 3.36 - 3.38 (m, 2 H) 3.25 - 3.26 (m, 4 H) 3.13 - 3.18 (m, 3 H) 2.43 - 2.48 (m, 2 H) 1.36 - 1.41 (m, 1 H) 0.97 - 1.02 (m, 1 H)
The title compound was prepared according to General Procedure A using 2-((2,2,2-trifluoroethyl)amino)ethan-1-ol as the coupling partner. This experiment yielded the title compound N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-4- Oxo- 7- (2-((2,2,2-trifluoroethyl)amino)ethoxy)-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5- difluorophenyl)ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1, 2-c]pyrazol-1-yl)acetamide was obtained. Samples were analyzed using LCMS A: Retention time = 1.31 minutes; Observed ions = 947.2
1H NMR (500 MHz, METHANOL-d4) δ ppm 8.09 - 8.17 (m, 1 H) 7.29 - 7.37 (m, 2 H) 6.55 - 6.87 (m, 6 H) 4.44 - 4.79 (m, 5 H) 3.64 ( s, 3 H) 3.44 - 3.48 (m, 1 H) 3.36 - 3.38 (m, 2 H) 3.25 - 3.26 (m, 4 H) 3.13 - 3.18 (m, 3 H) 2.43 - 2.48 (m, 2 H) 1.36 - 1.41 (m, 1 H) 0.97 - 1.02 (m, 1 H)
実施例２６：Ｎ－（（Ｓ）－１－（（３Ｐ）－３－（４－クロロ－１－メチル－３－（メチルスルホンアミド）－１Ｈ－インダゾール－７－イル）－４－オキソ－７－（２－（２，２，２－トリフルオロエトキシ）エトキシ）－３，４－ジヒドロピリド［２，３－ｄ］ピリミジン－２－イル）－２－（３，５－ジフルオロフェニル）エチル）－２－（（３ｂＳ，４ａＲ）－３－（ジフルオロメチル）－５，５－ジフルオロ－３ｂ，４，４ａ，５－テトラヒドロ－１Ｈ－シクロプロパ［３，４］シクロペンタ［１，２－ｃ］ピラゾール－１－イル）アセトアミドの調製Example 26: N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-4-oxo- 7-(2-(2,2,2-trifluoroethoxy)ethoxy)-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl) -2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole Preparation of -1-yl)acetamide
２－（２，２，２－トリフルオロエトキシ）エタン－１－オールをカップリングパートナーとして使用して、一般手順Ａに従って表題化合物を調製した。この実験により、表題化合物Ｎ－（（Ｓ）－１－（（３Ｐ）－３－（４－クロロ－１－メチル－３－（メチルスルホンアミド）－１Ｈ－インダゾール－７－イル）－４－オキソ－７－（２－（２，２，２－トリフルオロエトキシ）エトキシ）－３，４－ジヒドロピリド［２，３－ｄ］ピリミジン－２－イル）－２－（３，５－ジフルオロフェニル）エチル）－２－（（３ｂＳ，４ａＲ）－３－（ジフルオロメチル）－５，５－ジフルオロ－３ｂ，４，４ａ，５－テトラヒドロ－１Ｈ－シクロプロパ［３，４］シクロペンタ［１，２－ｃ］ピラゾール－１－イル）アセトアミドを得た。ＬＣＭＳ Ａを使用してサンプルを分析した：保持時間＝１．４３分；観測されたイオン＝９４８．４（Ｍ＋Ｈ）。
1H NMR (500 MHz, METHANOL-d4) δ ppm 8.44 - 8.52 (m, 1 H) 7.27 (br d, J=8.05 Hz, 1 H) 7.18 (d, J=7.75 Hz, 1 H) 7.09 (d, J=8.64 Hz, 1 H) 6.53 - 6.82 (m, 4 H) 4.83 (t, J=4.77 Hz, 1 H) 4.70 - 4.75 (m, 2 H) 4.50 - 4.61 (m, 2 H) 4.02 - 4.13 (m, 4 H) 3.59 (s, 3 H) 3.41 - 3.49 (m, 1 H) 3.21 (s, 3 H) 3.10 (dd, J=14.16, 9.69 Hz, 1 H) 2.41 (ddd, J=11.55, 7.53, 4.17 Hz, 2 H) 1.33 - 1.38 (m, 1 H) 0.96 - 1.03 (m, 1 H)
The title compound was prepared according to General Procedure A using 2-(2,2,2-trifluoroethoxy)ethane-1-ol as the coupling partner. This experiment yielded the title compound N-((S)-1-((3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-4- Oxo- 7- (2-(2,2,2-trifluoroethoxy)ethoxy)-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl) ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c ] pyrazol-1-yl)acetamide was obtained. LCMS Samples were analyzed using A: Retention time = 1.43 minutes; Observed ions = 948.4 (M+H).
1H NMR (500 MHz, METHANOL-d4) δ ppm 8.44 - 8.52 (m, 1 H) 7.27 (br d, J=8.05 Hz, 1 H) 7.18 (d, J=7.75 Hz, 1 H) 7.09 (d, J=8.64 Hz, 1 H) 6.53 - 6.82 (m, 4 H) 4.83 (t, J=4.77 Hz, 1 H) 4.70 - 4.75 (m, 2 H) 4.50 - 4.61 (m, 2 H) 4.02 - 4.13 (m, 4 H) 3.59 (s, 3 H) 3.41 - 3.49 (m, 1 H) 3.21 (s, 3 H) 3.10 (dd, J=14.16, 9.69 Hz, 1 H) 2.41 (ddd, J=11.55 , 7.53, 4.17 Hz, 2 H) 1.33 - 1.38 (m, 1 H) 0.96 - 1.03 (m, 1 H)
実施例３４：Ｎ－（（１Ｓ）－１－（（３Ｐ，３Ｐ）－３－（４－クロロ－１－メチル－３－（メチルスルホンアミド）－１Ｈ－インダゾール－７－イル）－７－（２－（２，２－ジフルオロシクロプロポキシ）エトキシ）－４－オキソ－３，４－ジヒドロピリド［２，３－ｄ］ピリミジン－２－イル）－２－（３，５－ジフルオロフェニル）エチル）－２－（（３ｂＳ，４ａＲ）－３－（ジフルオロメチル）－５，５－ジフルオロ－３ｂ，４，４ａ，５－テトラヒドロ－１Ｈ－シクロプロパ［３，４］シクロペンタ［１，２－ｃ］ピラゾール－１－イル）アセトアミドの調製Example 34: N-((1S)-1-((3P,3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-7- (2-(2,2-difluorocyclopropoxy)ethoxy)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl) -2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole -1-yl)acetamide preparation
２－（２，２－ジフルオロシクロプロポキシ）エタン－１－オールをカップリングパートナーとして使用して、一般手順Ａに従って表題化合物を調製した。この実験により、表題化合物Ｎ－（（１Ｓ）－１－（（３Ｐ，３Ｐ）－３－（４－クロロ－１－メチル－３－（メチルスルホンアミド）－１Ｈ－インダゾール－７－イル）－７－（２－（２，２－ジフルオロシクロプロポキシ）エトキシ）－４－オキソ－３，４－ジヒドロピリド［２，３－ｄ］ピリミジン－２－イル）－２－（３，５－ジフルオロフェニル）エチル）－２－（（３ｂＳ，４ａＲ）－３－（ジフルオロメチル）－５，５－ジフルオロ－３ｂ，４，４ａ，５－テトラヒドロ－１Ｈ－シクロプロパ［３，４］シクロペンタ［１，２－ｃ］ピラゾール－１－イル）アセトアミドを得た。ＬＣＭＳ Ａを使用してサンプルを分析した：
保持時間＝１．４１分；観測されたイオン＝９４２．２（Ｍ＋Ｈ）。
1H NMR (500 MHz, METHANOL-d4) δ ppm 8.48 (d, J=8.64 Hz, 1 H) 7.25 - 7.33 (m, 1 H) 7.20 (dd, J=7.75, 1.79 Hz, 1 H) 7.08 (d, J=8.64 Hz, 1 H) 6.52 - 6.83 (m, 4 H) 4.69 - 4.75 (m, 2 H) 4.50 - 4.59 (m, 2 H) 4.05 (t, J=4.62 Hz, 2 H) 3.83 - 3.93 (m, 1 H) 3.60 (s, 3 H) 3.39 - 3.50 (m, 1 H) 3.23 (s, 3 H) 3.11 (dd, J=13.86, 9.39 Hz, 1 H) 2.38 - 2.45 (m, 2 H) 1.57 - 1.66 (m, 1 H) 1.43 - 1.52 (m, 1 H) 1.32 - 1.38 (m, 1 H) 0.97 - 1.02 (m, 1 H)
The title compound was prepared according to General Procedure A using 2-(2,2-difluorocyclopropoxy)ethane-1-ol as the coupling partner. This experiment yielded the title compound N-((1S)-1-((3P,3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)- 7-(2-(2,2-difluorocyclopropoxy)ethoxy)-4-oxo - 3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl) ethyl)-2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c ] pyrazol-1-yl)acetamide was obtained. Samples were analyzed using LCMS A:
Retention time = 1.41 minutes; observed ions = 942.2 (M+H).
1H NMR (500 MHz, METHANOL-d4) δ ppm 8.48 (d, J=8.64 Hz, 1 H) 7.25 - 7.33 (m, 1 H) 7.20 (dd, J=7.75, 1.79 Hz, 1 H) 7.08 (d , J=8.64 Hz, 1 H) 6.52 - 6.83 (m, 4 H) 4.69 - 4.75 (m, 2 H) 4.50 - 4.59 (m, 2 H) 4.05 (t, J=4.62 Hz, 2 H) 3.83 - 3.93 (m, 1 H) 3.60 (s, 3 H) 3.39 - 3.50 (m, 1 H) 3.23 (s, 3 H) 3.11 (dd, J=13.86, 9.39 Hz, 1 H) 2.38 - 2.45 (m, 2 H) 1.57 - 1.66 (m, 1 H) 1.43 - 1.52 (m, 1 H) 1.32 - 1.38 (m, 1 H) 0.97 - 1.02 (m, 1 H)
実施例４１：Ｎ－（（Ｓ）－１－（（３Ｐ，３Ｐ）－３－（４－クロロ－１－メチル－３－（メチルスルホンアミド）－１Ｈ－インダゾール－７－イル）－４－オキソ－７－（２，２，３，３，３－ペンタフルオロプロポキシ）－３，４－ジヒドロピリド［２，３－ｄ］ピリミジン－２－イル）－２－（３，５－ジフルオロフェニル）エチル）－２－（（３ｂＳ，４ａＲ）－３－シクロプロピル－５，５－ジフルオロ－３ｂ，４，４ａ，５－テトラヒドロ－１Ｈ－シクロプロパ［３，４］シクロペンタ［１，２－ｃ］ピラゾール－１－イル）アセトアミドの調製Example 41: N-((S)-1-((3P,3P)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-4- Oxo-7-(2,2,3,3,3-pentafluoropropoxy)-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl )-2-((3bS,4aR)-3-cyclopropyl-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole- Preparation of 1-yl)acetamide
（Ｓ）－Ｎ－（（６Ｐ）－７－（（３Ｐ）－２－（１－アミノ－２－（３，５－ジフルオロフェニル）エチル）－４－オキソ－７－（２，２，３，３，３－ペンタフルオロプロポキシ）ピリド［２，３－ｄ］ピリミジン－３（４Ｈ）－イル）－４－クロロ－１－メチル－１Ｈ－インダゾール－３－イル）－Ｎ－（メチルスルホニル）アセトアミド（０．１２ｇ、０．１６０ｍｍｏｌ）のテトラヒドロフラン（２．３８８ｍＬ）撹拌溶液に、２－（（３ｂＳ，４ａＲ）－３－シクロプロピル－５，５－ジフルオロ－３ｂ，４，４ａ，５－テトラヒドロ－１Ｈ－シクロプロパ［３，４］シクロペンタ［１，２－ｃ］ピラゾール－１－イル）酢酸（０．０４３ｇ、０．１６８ｍｍｏｌ）、Ｎ－エチル－Ｎ－イソプロピルプロパン－２－アミン（０．０８４ｍＬ、０．４８０ｍｍｏｌ）及び２，４，６－トリプロピル－１，３，５，２，４，６－トリオキサトリホスフィナン２，４，６－トリオキシド（「Ｔ３Ｐ」、５０重量％ ＥｔＯＡｃ溶液、０．０９５ｍＬ、０．３２０ｍｍｏｌ）を加えた。反応混合物を室温で１．５時間撹拌した。混合物に、アンモニアのメタノール溶液（２Ｍ、１ｍＬ）を加えた。混合物を１時間撹拌し、次いで、減圧下で濃縮した。得られた残留物をシリカゲルクロマトグラフィー（４０ｇ ＲｅｄｉＳｅｐ Ｇｏｌｄカラム）に供して、２０ＣＶの１０～７０％酢酸エチルのヘキサン溶液で溶出した。純粋な所望の生成物を含む画分をプールし、次いで、減圧下で濃縮して、Ｎ－（（Ｓ）－１－（（３Ｐ，３Ｐ）－３－（４－クロロ－１－メチル－３－（メチルスルホンアミド）－１Ｈ－インダゾール－７－イル）－４－オキソ－７－（２，２，３，３，３－ペンタフルオロプロポキシ）－３，４－ジヒドロピリド［２，３－ｄ］ピリミジン－２－イル）－２－（３，５－ジフルオロフェニル）エチル）－２－（（３ｂＳ，４ａＲ）－３－シクロプロピル－５，５－ジフルオロ－３ｂ，４，４ａ，５－テトラヒドロ－１Ｈ－シクロプロパ［３，４］シクロペンタ［１，２－ｃ］ピラゾール－１－イル）アセトアミド（０．１１ｇ、０．１１６ｍｍｏｌ、収率７２．２％）を白色の固体として得た。
1H NMR (500 MHz, METHANOL-d4) δ ppm 8.58 (d, J=8.64 Hz, 1 H) 7.31 (d, J=8.05 Hz, 1 H) 7.22 (d, J=7.75 Hz, 1 H) 7.18 (d, J=8.64 Hz, 1 H) 6.75 - 6.81 (m, 1 H) 6.54 - 6.61 (m, 2 H) 5.24 (t, J=13.26 Hz, 2 H) 4.38 - 4.46 (m, 2 H) 3.61 (s, 3 H) 3.40 - 3.46 (m, 1 H) 3.25 (s, 3 H) 3.05 - 3.11 (m, 1 H) 2.19 - 2.33 (m, 2 H) 1.78 - 1.85 (m, 1 H) 1.25 - 1.30 (m, 1 H) 0.86 - 0.93 (m, 3 H) 0.74 - 0.79 (m, 2 H). LC/MS: m/z = 944.0 [M+1]+.
(S)-N-((6P)-7-((3P)-2-(1-amino-2-(3,5-difluorophenyl)ethyl)-4-oxo-7-(2,2,3 ,3,3-pentafluoropropoxy)pyrido[2,3-d]pyrimidin-3(4H)-yl)-4-chloro-1-methyl-1H-indazol-3-yl)-N-(methylsulfonyl) To a stirred solution of acetamide (0.12 g, 0.160 mmol) in tetrahydrofuran (2.388 mL) was added 2-((3bS,4aR)-3-cyclopropyl-5,5-difluoro-3b,4,4a,5-tetrahydrofuran). -1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetic acid (0.043 g, 0.168 mmol), N-ethyl-N-isopropylpropan-2-amine (0.084 mL) , 0.480 mmol) and 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (“T3P”, 50 wt% EtOAc solution, 0.095 mL, 0.320 mmol) was added. The reaction mixture was stirred at room temperature for 1.5 hours. To the mixture was added ammonia in methanol (2M, 1 mL). The mixture was stirred for 1 hour, then concentrated under reduced pressure. The resulting residue was subjected to silica gel chromatography (40 g RediSep Gold column) and eluted with 20 CV of 10-70% ethyl acetate in hexane. Fractions containing pure desired product were pooled and then concentrated under reduced pressure to yield N-((S)-1-((3P,3P)-3-(4-chloro-1-methyl- 3-(Methylsulfonamido)-1H-indazol-7-yl)-4- oxo- 7-(2,2,3,3,3-pentafluoropropoxy)-3,4-dihydropyrido[2,3- d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-3-cyclopropyl-5,5-difluoro-3b,4,4a,5- Tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide (0.11 g, 0.116 mmol, 72.2% yield) was obtained as a white solid.
1 H NMR (500 MHz, METHANOL-d 4 ) δ ppm 8.58 (d, J=8.64 Hz, 1 H) 7.31 (d, J=8.05 Hz, 1 H) 7.22 (d, J=7.75 Hz, 1 H) 7.18 (d, J=8.64 Hz, 1 H) 6.75 - 6.81 (m, 1 H) 6.54 - 6.61 (m, 2 H) 5.24 (t, J=13.26 Hz, 2 H) 4.38 - 4.46 (m, 2 H) ) 3.61 (s, 3 H) 3.40 - 3.46 (m, 1 H) 3.25 (s, 3 H) 3.05 - 3.11 (m, 1 H) 2.19 - 2.33 (m, 2 H) 1.78 - 1.85 (m, 1 H) ) 1.25 - 1.30 (m, 1 H) 0.86 - 0.93 (m, 3 H) 0.74 - 0.79 (m, 2 H). LC/MS: m/z = 944.0 [M+1]+.
Claims (40)
［式中、
Ｘ１及びＸ２は、Ｈ、Ｆ、Ｃｌ及び－ＣＨ３から独立して選択され、Ｘ３は、Ｈ、Ｆ、Ｃｌ、－ＣＨ３、－ＯＣＨ３、－ＯＣＨＦ２又は－ＯＣＦ３であるが、ただし、Ｘ１、Ｘ２及びＸ３の群において、置換基Ｃｌは２回を超えて使用されておらず、且つ、置換基－ＣＨ３は２回を超えて使用されておらず、
Ｒ１は、水素、Ｃｌ、Ｆ又はＣＨ３であり、
Ｒ２は、水素、１～３個のフッ素で置換されていてもよいＣ１－Ｃ３アルキル又は１～２個のフッ素で置換されていてもよいＣ３－Ｃ６シクロアルキルであり、
Ｒ３は、Ｃ１－Ｃ３アルキル又はＣ３－Ｃ４シクロアルキルであり、
Ｇ１は、１～５個のフッ素で置換されたフェニルであるか、又はＧ１は、Ｇ２、Ｇ３若しくはＧ４のいずれかで１回置換されたＣ１－Ｃ３アルキルであるか、又はＧ１は、４～９個のフッ素で置換されたＣ２－Ｃ６アルキル、Ｇ５で１回置換されたＣ２－Ｃ３アルキル、Ｇ６で１回置換されたＣ４－Ｃ８アルキル、１～４個のフッ素で置換されたＣ３－Ｃ６シクロアルキル、シクロヘキセン又はシクロペンテンであり、
Ｇ２は、Ｃ１－Ｃ２アルキルで１回又は２回独立して置換された５～６員のヘテロアリールであり、ここで、Ｃ１－Ｃ２アルキルは、１～３個のフッ素で置換されていてもよく、
Ｇ３は、２－ピリジン、２－ピラジン及び２－ピリミジンを除く、６員のヘテロアリールであり、
Ｇ４は、１～４個のフッ素で置換されたＣ３－Ｃ６シクロアルキル、１～３個のフッ素で置換されていてもよいＣ１－Ｃ２アルキルで置換されたＣ３－Ｃ６シクロアルキル、又は１～３個のフッ素で置換されていてもよい－Ｏ－（Ｃ１－Ｃ２アルキル）で置換されたＣ３－Ｃ６シクロアルキルであり、
Ｇ５は、－Ｏ（１～５個のフッ素で置換されたＣ１－Ｃ４アルキル）、－Ｏ（１～４個のフッ素で置換されたＣ３－Ｃ４シクロアルキル）、－Ｎ（Ｈ）（１～５個のフッ素で置換されたＣ１－Ｃ２アルキル）、－Ｎ（１～５個のフッ素で置換されたＣ１－Ｃ２アルキル）（１～３個のフッ素で置換されていてもよいＣ１－Ｃ３アルキル）、－Ｎ（Ｈ）（ＳＯ２（Ｃ１－Ｃ３アルキル））、又は－Ｎ（Ｃ１－Ｃ３アルキル）（ＳＯ２（Ｃ１－Ｃ３アルキル））であり、
Ｇ６は、フェニル、又は１～３個のフッ素で置換されていてもよい－Ｏ－（Ｃ１－Ｃ２アルキル）であり、
Ｗは、
から選択され、
Ｒ４は、１～３個のフッ素で置換されていてもよいメチルであるか、又はＲ４は、シクロプロピルである。］
又はその薬学的に許容可能な塩。 Compounds of formula I:
[In the formula,
X 1 and X 2 are independently selected from H, F, Cl and -CH 3 and X 3 is H, F, Cl, -CH 3 , -OCH 3 , -OCHF 2 or -OCF 3 However, in the group of X 1 , X 2 and X 3 , the substituent Cl is not used more than twice, and the substituent -CH 3 is not used more than twice,
R1 is hydrogen, Cl, F or CH3 ,
R 2 is hydrogen, C 1 -C 3 alkyl optionally substituted with 1 to 3 fluorines, or C 3 -C 6 cycloalkyl optionally substituted with 1 to 2 fluorines,
R 3 is C 1 -C 3 alkyl or C 3 -C 4 cycloalkyl;
G 1 is phenyl substituted with 1 to 5 fluorines, or G 1 is C 1 -C 3 alkyl substituted once with any of G 2 , G 3 or G 4 , or G 1 is C 2 -C 6 alkyl substituted with 4 to 9 fluorines, C 2 -C 3 alkyl substituted once with G 5 , C 4 -C substituted once with G 6 8 alkyl, C 3 -C 6 cycloalkyl substituted with 1 to 4 fluorines, cyclohexene or cyclopentene;
G 2 is a 5- to 6-membered heteroaryl substituted once or twice independently with C 1 -C 2 alkyl, where C 1 -C 2 alkyl is substituted with 1 to 3 fluorine atoms. May be replaced,
G3 is a 6-membered heteroaryl excluding 2-pyridine, 2-pyrazine and 2-pyrimidine;
G 4 is C 3 -C 6 cycloalkyl substituted with 1 to 4 fluorines, C 3 -C 6 substituted with C 1 -C 2 alkyl optionally substituted with 1 to 3 fluorines; cycloalkyl, or C 3 -C 6 cycloalkyl substituted with -O-(C 1 -C 2 alkyl) optionally substituted with 1 to 3 fluorines,
G 5 is -O (C 1 -C 4 alkyl substituted with 1 to 5 fluorines), -O (C 3 -C 4 cycloalkyl substituted with 1 to 4 fluorines), -N( H) (C 1 -C 2 alkyl substituted with 1 to 5 fluorines), -N (C 1 -C 2 alkyl substituted with 1 to 5 fluorines) (substituted with 1 to 3 fluorines) C 1 -C 3 alkyl), -N(H)(SO 2 (C 1 -C 3 alkyl)), or -N(C 1 -C 3 alkyl)(SO 2 (C 1 -C 3 alkyl)) 3 alkyl)),
G 6 is phenyl or -O-(C 1 -C 2 alkyl) optionally substituted with 1 to 3 fluorines,
W is
selected from
R 4 is methyl optionally substituted with 1 to 3 fluorines, or R 4 is cyclopropyl. ]
or a pharmaceutically acceptable salt thereof.
である、請求項１に記載の化合物又は塩。 W is the following group:
The compound or salt according to claim 1, which is
である、請求項１に記載の化合物又は塩。 W is the following group:
The compound or salt according to claim 1, which is
である、請求項１に記載の化合物又は塩。 W is the following group:
The compound or salt according to claim 1, which is
である、請求項１に記載の化合物又は塩。 W is the following group:
The compound or salt according to claim 1, which is
のうちの１種であり、Ｒ４が、１～３個のフッ素で置換されていてもよいメチルである、請求項１に記載の化合物又は塩。 W is the following group:
The compound or salt according to claim 1, wherein R 4 is methyl optionally substituted with 1 to 3 fluorines.
のうちの１種である、請求項１～１０のいずれか一項に記載の化合物又は塩。 G1 is the following group:
A compound or salt according to any one of claims 1 to 10, which is one of the following.
に示すとおりである、請求項１～１３のいずれか一項に記載の化合物又は塩。 Stereochemistry is
The compound or salt according to any one of claims 1 to 13, which is as shown in .
に示すとおりである、請求項１～１３のいずれか一項に記載の化合物又は塩。 Stereochemistry is
The compound or salt according to any one of claims 1 to 13, which is as shown in .
及びそれらの薬学的に許容可能な塩からなる群から選択される、請求項１に記載の化合物又は塩。 The following compounds:
and a pharmaceutically acceptable salt thereof.
及びそれらの薬学的に許容可能な塩からなる群から選択される、請求項１に記載の化合物又は塩。 The following compounds:
and a pharmaceutically acceptable salt thereof.
及びそれらの薬学的に許容可能な塩からなる群から選択される、請求項１に記載の化合物又は塩。 The following compounds:
and a pharmaceutically acceptable salt thereof.
及びそれらの薬学的に許容可能な塩からなる群から選択される、請求項１に記載の化合物又は塩。 The following compounds:
and a pharmaceutically acceptable salt thereof.
及びそれらの薬学的に許容可能な塩からなる群から選択される、請求項１に記載の化合物又は塩。 The following compounds:
and a pharmaceutically acceptable salt thereof.
である、請求項１に記載の化合物又は塩。 The following compounds:
The compound or salt according to claim 1, which is
である、請求項１に記載の化合物又は塩。 The following compounds:
The compound or salt according to claim 1, which is
である、請求項１に記載の化合物又は塩。 The following compounds:
The compound or salt according to claim 1, which is
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