RU2019131017A - Соединения гетероарила в качестве ингибиторов btk и их применение - Google Patents
Соединения гетероарила в качестве ингибиторов btk и их применение Download PDFInfo
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- RU2019131017A RU2019131017A RU2019131017A RU2019131017A RU2019131017A RU 2019131017 A RU2019131017 A RU 2019131017A RU 2019131017 A RU2019131017 A RU 2019131017A RU 2019131017 A RU2019131017 A RU 2019131017A RU 2019131017 A RU2019131017 A RU 2019131017A
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- Prior art keywords
- compound
- nitrogen
- nrc
- sulfur
- oxygen
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- 125000001072 heteroaryl group Chemical group 0.000 title claims 2
- 229940124291 BTK inhibitor Drugs 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims 23
- 229910052760 oxygen Inorganic materials 0.000 claims 14
- 229910052717 sulfur Chemical group 0.000 claims 14
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims 13
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims 12
- 125000005842 heteroatom Chemical group 0.000 claims 12
- 229910052757 nitrogen Inorganic materials 0.000 claims 12
- 239000011593 sulfur Chemical group 0.000 claims 12
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims 11
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims 11
- 239000001301 oxygen Chemical group 0.000 claims 11
- 229910005965 SO 2 Inorganic materials 0.000 claims 6
- 125000003118 aryl group Chemical group 0.000 claims 6
- 125000002837 carbocyclic group Chemical group 0.000 claims 6
- 150000003839 salts Chemical class 0.000 claims 6
- 229920006395 saturated elastomer Polymers 0.000 claims 6
- 125000001931 aliphatic group Chemical group 0.000 claims 5
- 229910052739 hydrogen Inorganic materials 0.000 claims 5
- 239000001257 hydrogen Substances 0.000 claims 5
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 5
- 229910052736 halogen Inorganic materials 0.000 claims 4
- 150000002367 halogens Chemical class 0.000 claims 4
- 238000000034 method Methods 0.000 claims 3
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 claims 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims 2
- 125000004429 atom Chemical group 0.000 claims 2
- 239000012472 biological sample Substances 0.000 claims 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims 2
- 208000035475 disorder Diseases 0.000 claims 2
- 238000004519 manufacturing process Methods 0.000 claims 2
- 230000001404 mediated effect Effects 0.000 claims 2
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 claims 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims 1
- 239000002671 adjuvant Substances 0.000 claims 1
- 229910052799 carbon Inorganic materials 0.000 claims 1
- 239000003814 drug Substances 0.000 claims 1
- 230000000694 effects Effects 0.000 claims 1
- 125000000623 heterocyclic group Chemical group 0.000 claims 1
- 230000002401 inhibitory effect Effects 0.000 claims 1
- 230000003993 interaction Effects 0.000 claims 1
- 206010025135 lupus erythematosus Diseases 0.000 claims 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 1
- DOTMOQHOJINYBL-UHFFFAOYSA-N molecular nitrogen;molecular oxygen Chemical group N#N.O=O DOTMOQHOJINYBL-UHFFFAOYSA-N 0.000 claims 1
- 239000008194 pharmaceutical composition Substances 0.000 claims 1
- 239000000546 pharmaceutical excipient Substances 0.000 claims 1
- 230000000069 prophylactic effect Effects 0.000 claims 1
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 claims 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims 1
- 230000001225 therapeutic effect Effects 0.000 claims 1
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- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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Claims (54)
1. Соединение формулы I,
или его фармацевтически приемлемая соль, где:
Кольцо A представляет собой 6-членное гетероарильное кольцо, содержащее 1 или 2 азота, выбранное из пиридина, пиразина, пиридазина и пиримидина;
R2 выбирают из -R, галогена, -галоалкила, -OR, -SR, -CN, -NO2, -SO2R, -SOR, -C(O)R, -CO2R, -C(O)N(R)2, -NRC(O)R, -NRC(O)N(R)2, -NRSO2R или -N(R)2;
R3 выбирают из -R, галогена, -галоалкила, -OR, -SR, -CN, -NO2, -SO2R, -SOR, -C(O)R, -CO2R, -C(O)N(R)2, -NRC(O)R, -NRC(O)N(R)2, -NRSO2R или -N(R)2;
где, по меньшей мере, один из R2 или R3 представляет собой -C(O)N(R)2 или CN;
каждый R независимо представляет собой водород, C1-6 алифатическую группу, C3-10 арил, 3-8-членное насыщенное или частично ненасыщенное карбоциклическое кольцо, 3-7-членное гетероциклическое кольцо, содержащее 1-4 гетероатома, независимо выбранных из азота, кислорода или серы, или 5-6-членное моноциклическое гетероарильное кольцо, содержащее 1-4 гетероатома, независимо выбранных из азота, кислорода или серы; каждое из которых необязательно замещено; или
две R группы на одном и том же атоме, взятые вместе с атомом, к которому они присоединены, образуют C3-10 арил, 3-8-членное насыщенное или частично ненасыщенное карбоциклическое кольцо, 3-7-членное гетероциклическое кольцо, содержащее 1-4 гетероатома, независимо выбранных из азота, кислорода или серы, или 5-6-членное моноциклическое гетероарильное кольцо, содержащее 1-4 гетероатома, независимо выбранных из азота, кислорода или серы; каждый из которых необязательно замещен;
L представляет собой двухвалентную группу, выбранную из C1-6 алифатической группы, C3-10 арила, 3-8-членного насыщенного или частично ненасыщенного карбоциклического кольца, 3-7-членного гетероциклического кольца, содержащего 1-4 гетероатома, независимо выбранных из азота, кислорода или серы, и 5-6-членного моноциклического гетероарильного кольца, содержащего 1-4 гетероатома, независимо выбранных из азота, кислорода или серы; каждый из которых необязательно замещен; или L представляет собой двухвалентную группу, выбранную из C1-6 алифатического-C3-10 арила, C1-6 алифатического-3-8-членного насыщенного или частично ненасыщенного карбоциклического кольца, C1-6 алифатического-3-7-членного гетероциклического кольца, содержащего 1-4 гетероатома, независимо выбранных из азота, кислорода или серы, и C1-6 алифатического-5-6-членного моноциклического гетероарильного кольца, содержащего 1-4 гетероатома, независимо выбранных из азота, кислорода или серы; каждый из которых необязательно замещен;
Y представляет собой O, S, SO2, SO, C(O), CO2, C(O)N(R), -NRC(O), -NRC(O)N(R), -NRSO2 или N(R); или Y отсутствует;
R1 представляет собой C1-6 алифатическую группу, C3-10 арил, 3-8-членное насыщенное или частично ненасыщенное карбоциклическое кольцо, 3-7-членное гетероциклическое кольцо, содержащее 1-4 гетероатома, независимо выбранных из азота, кислорода или серы, или 5-6-членное моноциклическое гетероарильное кольцо, содержащее 1-4 гетероатома, независимо выбранных из азота, кислорода или серы; каждый из которых необязательно замещен;
X представляет собой O, S, SO2, SO, C(O), CO2, C(O)N(R), -NRC(O), -NRC(O)N(R), -NRSO2 или N(R); или X отсутствует; и
R4 представляет собой водород, C1-6 алифатическую группу, C3-10 арил, 3-8-членное насыщенное или частично ненасыщенное карбоциклическое кольцо, 3-7-членное гетероциклическое кольцо, содержащее 1-4 гетероатома, независимо выбранных из азота, кислорода или серы, или 5-6-членное моноциклическое гетероарильное кольцо, содержащее 1-4 гетероатома, независимо выбранных из азота, кислорода или серы; каждое из которых необязательно замещено; или
X-R4 отсутствует.
2. Соединение по п. 1, где R2 представляет собой водород, галоген, -OR, -SR, -CN, -NO2, -SO2R, -SOR, -C(O)R, -CO2R, -C(O)N(R)2, -NRC(O)R, -NRC(O)N(R)2, -NRSO2R или -N(R)2 и R3 представляет собой водород, галоген, -OR, -SR, -CN, -NO2, -SO2R, -SOR, -C(O)R, -CO2R, -C(O)N(R)2, -NRC(O)R, -NRC(O)N(R)2, -NRSO2R или -N(R)2; где по меньшей мере, один из R2 или R3 представляет собой -C(O)N(R)2.
3. Соединение по п. 1, где L представляет собой
4. Соединение по п. 1, где Y представляет собой
и R1 представляет собой
5. Соединение по п. 1, где X представляет собой O, C(O)NH, -NHC(O), NH или N(Me); или X отсутствует.
6. Соединение по п. 1, где R4 представляет собой водород, метилом,
7. Соединение по п. 1, где X-R4 отсутствует.
8. Соединение по п. 1, формулы I-a1
I-a1;
или его фармацевтически приемлемая соль.
9. Соединение по п. 8, где R2 представляет собой -C(O)NH2, и R3 отсутствует.
11. Соединение по п. 1, формулы I-c1:
I-c1;
или его фармацевтически приемлемая соль.
12. Соединение по п. 11, где R2 представляет собой -C(O)NH2, и R3 отсутствует.
14. Соединение по п. 1, выбранное из таблицы 1.
15. Фармацевтическая композиция, содержащая соединение по пункту 1 и фармацевтически приемлемый адъювант, носитель или наполнитель.
16. Способ ингибирования активности BTK или ее мутанта у пациента или в биологическом образце, включающий стадию введения указанному пациенту или контакта указанного биологического образца с соединением по п. 1 или его физиологически приемлемой солью.
17. Способ лечения опосредованного BTK расстройства у пациента, нуждающегося в таковом, включающий стадию введения указанному пациенту соединения по п. 1.
18. Способ лечения волчанки у пациента, включающий стадию введения указанному пациенту соединения по п. 1 или его физиологически приемлемой соли.
19. Применение соединения по п. 1 или его физиологически приемлемых солей для производства лекарственного средства для профилактического или терапевтического лечения опосредованного BTK расстройства.
20. Способ производства соединения формулы I по п. 1, включающий стадии:
взаимодействия соединения формулы (II):
где X, X1 и X2, такие, как определены в п. 1;
с соединением с получением соединения формулы I:
где X, R1, R2, R3, R4, L и Y такие, как определены в п. 1.
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