TW201542543A - 用於治療脊髓性肌肉萎縮症之化合物 - Google Patents

Info

Publication number

TW201542543A

TW201542543A TW103121679A TW103121679A TW201542543A TW 201542543 A TW201542543 A TW 201542543A TW 103121679 A TW103121679 A TW 103121679A TW 103121679 A TW103121679 A TW 103121679A TW 201542543 A TW201542543 A TW 201542543A

Authority

TW

Taiwan

Prior art keywords

fluoro

pyridin

methylimidazo

compound

benzamide

Prior art date

2013-06-25

Links

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• 150000001875 compounds Chemical class 0.000 title claims abstract description 232
• 208000002320 spinal muscular atrophy Diseases 0.000 title claims description 92
• 150000003839 salts Chemical class 0.000 claims abstract description 48
• 239000003814 drug Substances 0.000 claims abstract description 15
• 238000004519 manufacturing process Methods 0.000 claims abstract description 13
• 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 12
• -1 imidazo[1,2-a]pyrazin-2-yl Chemical group 0.000 claims description 145
• 150000001408 amides Chemical class 0.000 claims description 118
• 239000001257 hydrogen Substances 0.000 claims description 57
• 229910052739 hydrogen Inorganic materials 0.000 claims description 57
• 238000000034 method Methods 0.000 claims description 48
• 238000002360 preparation method Methods 0.000 claims description 45
• 125000005843 halogen group Chemical group 0.000 claims description 35
• 125000000217 alkyl group Chemical group 0.000 claims description 34
• 150000002431 hydrogen Chemical class 0.000 claims description 33
• 229910052757 nitrogen Inorganic materials 0.000 claims description 31
• 238000011282 treatment Methods 0.000 claims description 27
• UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 25
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 24
• 125000001188 haloalkyl group Chemical group 0.000 claims description 22
• 125000001153 fluoro group Chemical group F* 0.000 claims description 21
• 125000003545 alkoxy group Chemical group 0.000 claims description 20
• DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 claims description 18
• 238000006243 chemical reaction Methods 0.000 claims description 18
• 239000002585 base Substances 0.000 claims description 17
• 230000002265 prevention Effects 0.000 claims description 16
• 239000002904 solvent Substances 0.000 claims description 16
• 125000006701 (C1-C7) alkyl group Chemical group 0.000 claims description 13
• 125000004438 haloalkoxy group Chemical group 0.000 claims description 13
• 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 13
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 13
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 12
• 125000004429 atom Chemical group 0.000 claims description 11
• 125000001309 chloro group Chemical group Cl* 0.000 claims description 11
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 10
• 125000002619 bicyclic group Chemical group 0.000 claims description 10
• 229910052731 fluorine Inorganic materials 0.000 claims description 9
• 235000005152 nicotinamide Nutrition 0.000 claims description 9
• 239000011570 nicotinamide Substances 0.000 claims description 9
• 229960003966 nicotinamide Drugs 0.000 claims description 9
• 229960002715 nicotine Drugs 0.000 claims description 9
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 9
• 229920006395 saturated elastomer Polymers 0.000 claims description 9
• 125000004939 6-pyridyl group Chemical group N1=CC=CC=C1* 0.000 claims description 8
• 229910052799 carbon Inorganic materials 0.000 claims description 8
• 125000001072 heteroaryl group Chemical group 0.000 claims description 8
• 125000002950 monocyclic group Chemical group 0.000 claims description 8
• SNICXCGAKADSCV-UHFFFAOYSA-N nicotine Natural products CN1CCCC1C1=CC=CN=C1 SNICXCGAKADSCV-UHFFFAOYSA-N 0.000 claims description 8
• IHWDSEPNZDYMNF-UHFFFAOYSA-N 1H-indol-2-amine Chemical compound C1=CC=C2NC(N)=CC2=C1 IHWDSEPNZDYMNF-UHFFFAOYSA-N 0.000 claims description 7
• 125000006242 amine protecting group Chemical group 0.000 claims description 7
• 150000001412 amines Chemical class 0.000 claims description 7
• 239000000460 chlorine Substances 0.000 claims description 7
• 229910052801 chlorine Inorganic materials 0.000 claims description 7
• 239000011737 fluorine Substances 0.000 claims description 7
• 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims description 7
• 230000008569 process Effects 0.000 claims description 7
• VZXTWGWHSMCWGA-UHFFFAOYSA-N 1,3,5-triazine-2,4-diamine Chemical compound NC1=NC=NC(N)=N1 VZXTWGWHSMCWGA-UHFFFAOYSA-N 0.000 claims description 6
• 125000002947 alkylene group Chemical group 0.000 claims description 6
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 6
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 6
• 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 5
• YJLUPSHULWHEFR-UHFFFAOYSA-N 2,6-difluoro-n-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3-methylpiperazin-1-yl)benzamide Chemical compound C1CNC(C)CN1C(C=C1F)=CC(F)=C1C(=O)NC1=CN2C=C(C)N=C2C(F)=C1 YJLUPSHULWHEFR-UHFFFAOYSA-N 0.000 claims description 5
• WXDSFKVEUQARAL-UHFFFAOYSA-N 2-fluoro-n-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(1,2,3,6-tetrahydropyridin-4-yl)benzamide Chemical compound C1=C(F)C2=NC(C)=CN2C=C1NC(=O)C(C(=C1)F)=CC=C1C1=CCNCC1 WXDSFKVEUQARAL-UHFFFAOYSA-N 0.000 claims description 5
• BEEFXPXLOVUQJM-LBPRGKRZSA-N 2-fluoro-n-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-[(3s)-3-methylpiperazin-1-yl]benzamide Chemical compound C1CN[C@@H](C)CN1C(C=C1F)=CC=C1C(=O)NC1=CN2C=C(C)N=C2C(F)=C1 BEEFXPXLOVUQJM-LBPRGKRZSA-N 0.000 claims description 5
• KKIJUDRQFQKRMV-UHFFFAOYSA-N 6-(3,4-dimethylpiperazin-1-yl)-n-(2-methylimidazo[1,2-a]pyridin-6-yl)pyridine-3-carboxamide Chemical compound C1CN(C)C(C)CN1C1=CC=C(C(=O)NC2=CN3C=C(C)N=C3C=C2)C=N1 KKIJUDRQFQKRMV-UHFFFAOYSA-N 0.000 claims description 5
• 239000003054 catalyst Substances 0.000 claims description 5
• 239000003153 chemical reaction reagent Substances 0.000 claims description 5
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 5
• QUJOVOYZKLBJOP-UHFFFAOYSA-N n-(4-fluoro-2-methyl-1,3-benzoxazol-6-yl)-4-(3-methylpiperazin-1-yl)benzamide Chemical compound C1CNC(C)CN1C1=CC=C(C(=O)NC=2C=C3OC(C)=NC3=C(F)C=2)C=C1 QUJOVOYZKLBJOP-UHFFFAOYSA-N 0.000 claims description 5
• QNMLZXPESKFTCH-UHFFFAOYSA-N n-(4-fluoro-2-methyl-1,3-benzoxazol-6-yl)-4-piperazin-1-ylbenzamide Chemical compound C1=C2OC(C)=NC2=C(F)C=C1NC(=O)C(C=C1)=CC=C1N1CCNCC1 QNMLZXPESKFTCH-UHFFFAOYSA-N 0.000 claims description 5
• 125000004193 piperazinyl group Chemical group 0.000 claims description 5
• SNICXCGAKADSCV-JTQLQIEISA-N (-)-Nicotine Chemical compound CN1CCC[C@H]1C1=CC=CN=C1 SNICXCGAKADSCV-JTQLQIEISA-N 0.000 claims description 4
• ONYFYCFGMPJTJH-UHFFFAOYSA-N 2-ethoxy-n-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-piperazin-1-ylpyridine-3-carboxamide Chemical compound C=1C=C(C(=O)NC2=CN3C=C(C)N=C3C(F)=C2)C(OCC)=NC=1N1CCNCC1 ONYFYCFGMPJTJH-UHFFFAOYSA-N 0.000 claims description 4
• CDFYPSURDFQWHV-UHFFFAOYSA-N 2-fluoro-n-(2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3-methylpiperazin-1-yl)benzamide Chemical compound C1CNC(C)CN1C(C=C1F)=CC=C1C(=O)NC1=CN2C=C(C)N=C2C=C1 CDFYPSURDFQWHV-UHFFFAOYSA-N 0.000 claims description 4
• VGQGGSXEFWCYFA-UHFFFAOYSA-N 2-fluoro-n-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-piperazin-1-ylbenzamide Chemical compound C1=C(F)C2=NC(C)=CN2C=C1NC(=O)C(C(=C1)F)=CC=C1N1CCNCC1 VGQGGSXEFWCYFA-UHFFFAOYSA-N 0.000 claims description 4
• FYDXFOSDKWKKCU-UHFFFAOYSA-N 4-(3,5-dimethylpiperazin-1-yl)-n-(4-fluoro-2-methyl-1,3-benzoxazol-6-yl)benzamide Chemical compound C1C(C)NC(C)CN1C1=CC=C(C(=O)NC=2C=C3OC(C)=NC3=C(F)C=2)C=C1 FYDXFOSDKWKKCU-UHFFFAOYSA-N 0.000 claims description 4
• 239000013543 active substance Substances 0.000 claims description 4
• 239000003513 alkali Substances 0.000 claims description 4
• ZKLAQRFKZCJHJW-UHFFFAOYSA-N n-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-2-fluoro-4-(3-methylpiperazin-1-yl)benzamide Chemical compound C1CNC(C)CN1C(C=C1F)=CC=C1C(=O)NC1=CN(C=C(C)N=C2C)C2=N1 ZKLAQRFKZCJHJW-UHFFFAOYSA-N 0.000 claims description 4
• YTYYMBZTLZDAMO-UHFFFAOYSA-N n-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-4-(3-methylpiperazin-1-yl)benzamide Chemical compound C1CNC(C)CN1C1=CC=C(C(=O)NC=2N=C3C(C)=NC(C)=CN3C=2)C=C1 YTYYMBZTLZDAMO-UHFFFAOYSA-N 0.000 claims description 4
• RKDSASAFBWZLDW-UHFFFAOYSA-N n-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-5-methyl-6-piperazin-1-ylpyridine-3-carboxamide Chemical compound C1=C(F)C2=NC(C)=CN2C=C1NC(=O)C(C=C1C)=CN=C1N1CCNCC1 RKDSASAFBWZLDW-UHFFFAOYSA-N 0.000 claims description 4
• 125000003386 piperidinyl group Chemical group 0.000 claims description 4
• JUJWROOIHBZHMG-UHFFFAOYSA-O pyridinium Chemical compound C1=CC=[NH+]C=C1 JUJWROOIHBZHMG-UHFFFAOYSA-O 0.000 claims description 4
• 125000003652 trifluoroethoxy group Chemical group FC(CO*)(F)F 0.000 claims description 4
• HFOKVKNPEMHSJN-UHFFFAOYSA-N 2,5-difluoro-n-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3-methylpiperazin-1-yl)benzamide Chemical compound C1CNC(C)CN1C1=CC(F)=C(C(=O)NC2=CN3C=C(C)N=C3C(F)=C2)C=C1F HFOKVKNPEMHSJN-UHFFFAOYSA-N 0.000 claims description 3
• RPMHUCKFZNXWHV-UHFFFAOYSA-N 2-fluoro-n-(2-methyl-1,3-benzoxazol-6-yl)-4-(3-methylpiperazin-1-yl)benzamide Chemical compound C1CNC(C)CN1C(C=C1F)=CC=C1C(=O)NC1=CC=C(N=C(C)O2)C2=C1 RPMHUCKFZNXWHV-UHFFFAOYSA-N 0.000 claims description 3
• BEEFXPXLOVUQJM-UHFFFAOYSA-N 2-fluoro-n-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3-methylpiperazin-1-yl)benzamide Chemical compound C1CNC(C)CN1C(C=C1F)=CC=C1C(=O)NC1=CN2C=C(C)N=C2C(F)=C1 BEEFXPXLOVUQJM-UHFFFAOYSA-N 0.000 claims description 3
• STIYQLJDPISHDQ-UHFFFAOYSA-N 2-fluoro-n-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-piperidin-4-ylbenzamide Chemical compound C1=C(F)C2=NC(C)=CN2C=C1NC(=O)C(C(=C1)F)=CC=C1C1CCNCC1 STIYQLJDPISHDQ-UHFFFAOYSA-N 0.000 claims description 3
• OARKCOYNBVFPCR-UHFFFAOYSA-N 4-fluoro-n-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-piperazin-1-ylpyridine-3-carboxamide Chemical compound C1=C(F)C2=NC(C)=CN2C=C1NC(=O)C(C(=C1)F)=CN=C1N1CCNCC1 OARKCOYNBVFPCR-UHFFFAOYSA-N 0.000 claims description 3
• ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 3
• PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 claims description 3
• LMAVPIIJOYURAF-UHFFFAOYSA-N benzene guanidine Chemical compound NC(=N)N.C1=CC=CC=C1.C1=CC=CC=C1 LMAVPIIJOYURAF-UHFFFAOYSA-N 0.000 claims description 3
• 125000005605 benzo group Chemical group 0.000 claims description 3
• XRUFCZNZLGDUTC-UHFFFAOYSA-N n-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-2,6-difluoro-4-(3-methylpiperazin-1-yl)benzamide Chemical compound C1CNC(C)CN1C(C=C1F)=CC(F)=C1C(=O)NC1=CN2C=C(C)N=C2C(Cl)=C1 XRUFCZNZLGDUTC-UHFFFAOYSA-N 0.000 claims description 3
• BHDBXXZOKWKFSQ-UHFFFAOYSA-N n-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-methoxy-6-piperazin-1-ylpyridine-3-carboxamide Chemical compound N=1C=C(C(=O)NC2=CN3C=C(C)N=C3C(F)=C2)C(OC)=CC=1N1CCNCC1 BHDBXXZOKWKFSQ-UHFFFAOYSA-N 0.000 claims description 3
• GBESJSDFWIKMFD-UHFFFAOYSA-N n-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-piperazin-1-ylpyridine-3-carboxamide Chemical compound C1=C(F)C2=NC(C)=CN2C=C1NC(=O)C(C=N1)=CC=C1N1CCNCC1 GBESJSDFWIKMFD-UHFFFAOYSA-N 0.000 claims description 3
• 125000000168 pyrrolyl group Chemical group 0.000 claims description 3
• 125000005943 1,2,3,6-tetrahydropyridyl group Chemical group 0.000 claims description 2
• UVDCWTFXXKSREY-UHFFFAOYSA-N 2-fluoro-n-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-piperazin-1-ylpyridine-3-carboxamide Chemical compound C1=C(F)C2=NC(C)=CN2C=C1NC(=O)C(C(=N1)F)=CC=C1N1CCNCC1 UVDCWTFXXKSREY-UHFFFAOYSA-N 0.000 claims description 2
• LZPWAYBEOJRFAX-UHFFFAOYSA-N 4,4,5,5-tetramethyl-1,3,2$l^{2}-dioxaborolane Chemical group CC1(C)O[B]OC1(C)C LZPWAYBEOJRFAX-UHFFFAOYSA-N 0.000 claims description 2
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