RU2014144309A - Индазольные ингибиторы сигнального пути wnt и их терапевтические применения - Google Patents
Индазольные ингибиторы сигнального пути wnt и их терапевтические применения Download PDFInfo
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- RU2014144309A RU2014144309A RU2014144309A RU2014144309A RU2014144309A RU 2014144309 A RU2014144309 A RU 2014144309A RU 2014144309 A RU2014144309 A RU 2014144309A RU 2014144309 A RU2014144309 A RU 2014144309A RU 2014144309 A RU2014144309 A RU 2014144309A
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- 239000003112 inhibitor Substances 0.000 title 1
- 230000001225 therapeutic effect Effects 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract 42
- 125000001424 substituent group Chemical group 0.000 claims abstract 13
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract 12
- 150000004820 halides Chemical class 0.000 claims abstract 10
- 150000003839 salts Chemical class 0.000 claims abstract 10
- -1 —OR Chemical group 0.000 claims abstract 8
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims 33
- 201000010099 disease Diseases 0.000 claims 17
- 208000035475 disorder Diseases 0.000 claims 16
- 125000000217 alkyl group Chemical group 0.000 claims 14
- 125000006545 (C1-C9) alkyl group Chemical group 0.000 claims 8
- 102000013814 Wnt Human genes 0.000 claims 7
- 108050003627 Wnt Proteins 0.000 claims 7
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims 4
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims 4
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims 4
- 125000001153 fluoro group Chemical group F* 0.000 claims 4
- 208000011580 syndromic disease Diseases 0.000 claims 4
- 230000004663 cell proliferation Effects 0.000 claims 3
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- 125000004452 carbocyclyl group Chemical group 0.000 claims 2
- 229910052731 fluorine Inorganic materials 0.000 claims 2
- 208000016361 genetic disease Diseases 0.000 claims 2
- 230000001404 mediated effect Effects 0.000 claims 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 2
- 102000020233 phosphotransferase Human genes 0.000 claims 2
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- 101100317380 Danio rerio wnt4a gene Proteins 0.000 claims 1
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- 201000008251 Focal dermal hypoplasia Diseases 0.000 claims 1
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- 101000781981 Homo sapiens Protein Wnt-11 Proteins 0.000 claims 1
- 101000781950 Homo sapiens Protein Wnt-16 Proteins 0.000 claims 1
- 101000804728 Homo sapiens Protein Wnt-2b Proteins 0.000 claims 1
- 101000804792 Homo sapiens Protein Wnt-5a Proteins 0.000 claims 1
- 101000804804 Homo sapiens Protein Wnt-5b Proteins 0.000 claims 1
- 101000855002 Homo sapiens Protein Wnt-6 Proteins 0.000 claims 1
- 101000855004 Homo sapiens Protein Wnt-7a Proteins 0.000 claims 1
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- 101000814350 Homo sapiens Protein Wnt-8a Proteins 0.000 claims 1
- 101000650149 Homo sapiens Protein Wnt-8b Proteins 0.000 claims 1
- 101000781955 Homo sapiens Proto-oncogene Wnt-1 Proteins 0.000 claims 1
- 101000954762 Homo sapiens Proto-oncogene Wnt-3 Proteins 0.000 claims 1
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- 206010061902 Pancreatic neoplasm Diseases 0.000 claims 1
- 201000010769 Prader-Willi syndrome Diseases 0.000 claims 1
- 102000001253 Protein Kinase Human genes 0.000 claims 1
- 102100036567 Protein Wnt-11 Human genes 0.000 claims 1
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- 102100035289 Protein Wnt-2b Human genes 0.000 claims 1
- 102100035331 Protein Wnt-5b Human genes 0.000 claims 1
- 102100020732 Protein Wnt-6 Human genes 0.000 claims 1
- 102100020729 Protein Wnt-7a Human genes 0.000 claims 1
- 102100039470 Protein Wnt-7b Human genes 0.000 claims 1
- 102100039453 Protein Wnt-8a Human genes 0.000 claims 1
- 102100027542 Protein Wnt-8b Human genes 0.000 claims 1
- 208000006289 Rett Syndrome Diseases 0.000 claims 1
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- 101150010310 WNT-4 gene Proteins 0.000 claims 1
- 101150019524 WNT2 gene Proteins 0.000 claims 1
- 208000008383 Wilms tumor Diseases 0.000 claims 1
- 102000052547 Wnt-1 Human genes 0.000 claims 1
- 102000052556 Wnt-2 Human genes 0.000 claims 1
- 108700020986 Wnt-2 Proteins 0.000 claims 1
- 102000052549 Wnt-3 Human genes 0.000 claims 1
- 102000052548 Wnt-4 Human genes 0.000 claims 1
- 108700020984 Wnt-4 Proteins 0.000 claims 1
- 102000043366 Wnt-5a Human genes 0.000 claims 1
- 102000044880 Wnt3A Human genes 0.000 claims 1
- 108700013515 Wnt3A Proteins 0.000 claims 1
- 101100485099 Xenopus laevis wnt2b-b gene Proteins 0.000 claims 1
- 230000001594 aberrant effect Effects 0.000 claims 1
- 230000002159 abnormal effect Effects 0.000 claims 1
- 230000001154 acute effect Effects 0.000 claims 1
- 201000006288 alpha thalassemia Diseases 0.000 claims 1
- 210000000988 bone and bone Anatomy 0.000 claims 1
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- 201000006902 exudative vitreoretinopathy Diseases 0.000 claims 1
- 230000002538 fungal effect Effects 0.000 claims 1
- 125000005843 halogen group Chemical group 0.000 claims 1
- 206010073071 hepatocellular carcinoma Diseases 0.000 claims 1
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- 230000002401 inhibitory effect Effects 0.000 claims 1
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- 239000008194 pharmaceutical composition Substances 0.000 claims 1
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- 108060006633 protein kinase Proteins 0.000 claims 1
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- 101150068520 wnt3a gene Proteins 0.000 claims 1
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- Ophthalmology & Optometry (AREA)
Abstract
1. Соединение или его фармацевтически приемлемая соль, имеющее структуру, представленную формулой I,где Rпредставляет собой гетероарил-RR;Rвыбирают из группы, состоящей из Н, гетероарил-R, гетероциклил-Rи арил-R;Rвыбирают из группы, состоящей из Н, гетероциклил-R, -NHC(=O)R, -NHSOR, -NRRи (С-алкил)NRR;при условии, что Rи Rне являются оба Н;Rпредставляет собой 1-3 заместителя, выбранные, каждый, из группы, состоящей из Н, С-алкила, галогенида, -CF, -CN, -ORи амино;каждый Rпредставляет собой независимо 1-4 заместителя, выбранные, каждый, из группы, состоящей из Н, С-алкила, галогенида, -CF, -CN, -OR, -С(=O)R, амино и (С-алкил)NRR;каждый Rпредставляет собой независимо 1-5 заместителей, выбранных, каждый, из группы, состоящей из Н, С-алкила, галогенида, CF, CN, ORи амино;каждый Rпредставляет собой независимо 1-5 заместителей,выбранных, каждый, из группы, включающей Н, С-алкил, галогенид, -CF, -CN, -OR, амино, (С-алкил)NHSOR, -NR(С-алкил)NRRи (С-алкил)NRR;Rпредставляет собой 1-5 заместителей, выбранных, каждый, из группы, состоящей из Н, С-алкила, галогенида, -CF, -CN, -ORи амино;Rвыбирают из группы, состоящей из С-алкила, гетероарил-R, гетероциклил-R, арил-Rи СН-карбоциклила;Rвыбирают из группы, состоящей из С-алкила, гетероарил-R, гетероциклил-R, арил-Rи карбоциклил-R;каждый Rвыбирают независимо из С-алкила;каждый Rвыбирают независимо из группы, состоящей из Н и С-алкила;каждые Rи Rнеобязательно соединены с образованием пяти- или шестичленного гетероциклила;каждый Rвыбирают независимо из группы, состоящей из Н и С-алкила;Rпредставляет собой 1-5 заместителей, выбранных, каждый, из группы, состоящей из Н, С-алкила, галогенида, -CF, -CN, -ORи амино;при условии, что формула I не является структурой, выбранной из группы, состоящей из:2. Соединение по п. 1, где Rпредставляет собой пиридин-RR.3. Соединение по п. 2, где Rпредставляет собой пиридин-3-ил-RR.4. Соединени
Claims (53)
1. Соединение или его фармацевтически приемлемая соль, имеющее структуру, представленную формулой I
где R1 представляет собой гетероарил-R3R4;
R2 выбирают из группы, состоящей из Н, гетероарил-R5, гетероциклил-R6 и арил-R7;
R3 выбирают из группы, состоящей из Н, гетероциклил-R8, -NHC(=O)R9, -NHSO2R10, -NR11R12 и (С1-6-алкил)NR11R12;
при условии, что R2 и R3 не являются оба Н;
R4 представляет собой 1-3 заместителя, выбранные, каждый, из группы, состоящей из Н, С1-9-алкила, галогенида, -CF3, -CN, -OR13 и амино;
каждый R5 представляет собой независимо 1-4 заместителя, выбранные, каждый, из группы, состоящей из Н, С1-9-алкила, галогенида, -CF3, -CN, -OR13, -С(=O)R11, амино и (С1-6-алкил)NR11R12;
каждый R6 представляет собой независимо 1-5 заместителей, выбранных, каждый, из группы, состоящей из Н, С1-9-алкила, галогенида, CF3, CN, OR13 и амино;
каждый R7 представляет собой независимо 1-5 заместителей,
выбранных, каждый, из группы, включающей Н, С1-9-алкил, галогенид, -CF3, -CN, -OR13, амино, (С1-6-алкил)NHSO2R11, -NR12(С1-6-алкил)NR11R12 и (С1-6-алкил)NR11R12;
R8 представляет собой 1-5 заместителей, выбранных, каждый, из группы, состоящей из Н, С1-9-алкила, галогенида, -CF3, -CN, -OR13 и амино;
R9 выбирают из группы, состоящей из С1-9-алкила, гетероарил-R5, гетероциклил-R6, арил-R7 и СН2-карбоциклила;
R10 выбирают из группы, состоящей из С1-9-алкила, гетероарил-R5, гетероциклил-R6, арил-R7 и карбоциклил-R14;
каждый R11 выбирают независимо из С1-6-алкила;
каждый R12 выбирают независимо из группы, состоящей из Н и С1-6-алкила;
каждые R11 и R12 необязательно соединены с образованием пяти- или шестичленного гетероциклила;
каждый R13 выбирают независимо из группы, состоящей из Н и С1-6-алкила;
R14 представляет собой 1-5 заместителей, выбранных, каждый, из группы, состоящей из Н, С1-9-алкила, галогенида, -CF3, -CN, -OR13 и амино;
при условии, что формула I не является структурой, выбранной из группы, состоящей из:
2. Соединение по п. 1, где R1 представляет собой пиридин-R3R4.
3. Соединение по п. 2, где R1 представляет собой пиридин-3-ил-R3R4.
4. Соединение по п. 3, где R3 представляет собой (С1-6-алкил)NR11R12.
5. Соединение по п. 4, где R3 представляет собой (С1-2-алкил)NR11R12, R11 представляет собой (С1-2-алкил), R12 представляет собой (С1-2-алкил), и R4 представляет собой Н.
6. Соединение по п. 4, где R11 и R12 необязательно соединены с образованием пяти- или шестичленного гетероциклила, и R4 представляет собой Н.
7. Соединение по п. 6, где пяти- или шестичленный гетероциклил замещен 1-2 атомами фтора.
8. Соединение по п. 3, где R3 представляет собой NHC(=O)R9.
9. Соединение по п. 8, где R4 представляет собой Н, и R9 выбирают из группы, состоящей из (С2-5-алкила), фенила, карбоциклила и СН2-карбоциклила.
10. Соединение по п. 3, где R3 представляет собой -NHSO2R10.
11. Соединение по п. 10, где R4 представляет собой Н, и R10 выбирают из группы, состоящей из (С1-4-алкила) и фенила.
12. Соединение по п. 3, где R3 представляет собой гетероциклил-R8.
13. Соединение по п. 12, где R4 представляет собой Н, и гетероциклил выбирают из группы, состоящей из морфолина, пиперазина и пиперидина.
14. Соединение по п. 3, где R3 представляет собой Н, и R4 представляет собой амино.
15. Соединение по любому из пп. 3-14, в котором R2 представляет собой гетероарил-R5.
16. Соединение по любому из пп. 3-14, в котором R2 представляет собой пиридин-3-ил-R5.
17. Соединение по любому из пп. 3-14, в котором R2 представляет собой пиридин-3-ил-R5, и R5 представляет собой 1-2 атома фтора.
18. Соединение по любому из пп. 3-14, в котором R2 представляет собой тиофен-R5.
19. Соединение по любому из пп. 3-14, в котором R2 представляет собой гетероциклил-R6.
20. Соединение по любому из пп. 3-14, в котором R2 представляет собой гетероциклил-R6, при этом R6 выбирают из группы, состоящей из Н, F и (С1-4-алкила), и гетероциклил выбирают из группы, состоящей из морфолина, пиперазина и пиперидина.
21. Соединение по любому из пп. 3-14, в котором R2 представляет собой арил-R7.
22. Соединение по любому из пп. 3-14, в котором R2 представляет собой фенил-R7, и R7 представляет собой 1-2 атома фтора.
23. Соединение по любому из пп. 3-14, в котором R2 представляет собой фенил-R7, и R7 представляет собой 2 заместителя, состоящих из 1 атома фтора и или NR12(С1-6-алкил)NR11R12 или (С1-6-алкил)NHSO2R11.
27. Фармацевтическая композиция, включающая терапевтически эффективное количество соединения по п. 1 или его фармацевтически приемлемой соли и фармацевтически приемлемый эксципиент.
28. Способ лечения расстройства или заболевания у пациента, в которое вовлечена Wnt-сигнализация, включающий введение пациенту терапевтически эффективного количества соединения по п. 1 или его фармацевтически приемлемой соли.
29. Способ по п. 28, где расстройство или заболевание представляет собой рак.
30. Способ по п. 28, где расстройство или заболевание представляет собой диабетическую ретинопатию.
31. Способ по п. 28, где расстройство или заболевание представляет собой фиброз легких.
32. Способ по п. 28, где расстройство или заболевание представляет собой ревматоидный артрит.
33. Способ по п. 28, где расстройство или заболевание представляет собой склеродермию.
34. Способ по п. 28, где расстройство или заболевание представляет собой грибковую или вирусную инфекцию.
35. Способ по п. 28, где расстройство или заболевание представляет собой болезнь костей или хрящей.
36. Способ по п. 28, где расстройство или заболевание представляет собой болезнь Альцгеймера.
37. Способ по п. 28, где расстройство или заболевание представляет собой остеоартрит.
38. Способ по п. 28, где расстройство или заболевание представляет собой болезнь легких.
39. Способ по п. 28, где расстройство или заболевание представляет собой генетическое заболевание, вызванное мутациями в компонентах Wnt-сигнализации, при этом генетическое заболевание выбирают из коли-полипоза, синдрома остеопороза-псевдоглиомы, семейной экссудативной витреоретинопатии, ретинального ангиогенеза, начальной коронарной болезни, синдрома Тетра-Амелия, регрессии и вирилизации Мюллерова протока, синдрома SERKAL, сахарного диабета 2 типа, синдрома Фурмана, синдрома фокомелии Аль-Авади/Рааса-Ротшильда/Шинцеля, одонто-ониходермальной дисплазии, ожирения, мальформации расщепленной кисти/стопы, синдрома дупликации хвостовой части, агенезии зубов, опухоли Вильмса, дисплазии скелета, очаговой дермальной гипоплазии, аутосомно-рециссивной анонихии, дефектов нервной трубки, синдрома альфа-талассемии (ARTX), синдрома ломкой Х хромосомы, синдрома ICF, синдрома Ангельмана, синдрома Прадера-Вилли, синдрома Беквита-Видемана и синдрома Ретта.
40. Способ по п. 28, где пациентом является человек.
41. Способ по п. 29, где рак выбирают из гепатоцеллюлярной карциномы, рака толстой кишки, рака молочной железы, панкреатического рака, лейкоза, лимфомы, саркомы и рака яичников.
42. Способ по п. 28, где соединение ингибирует один или несколько белков на пути Wnt.
43. Способ по п. 28, где соединение ингибирует сигнализацию, индуцированную одним или несколькими белками Wnt.
44. Способ по любому из п. 42 или 43, где белки Wnt выбирают из WNT1, WNT2, WNT2B, WNT3, WNT3A, WNT4, WNT5A, WNT5B, WNT6, WNT7A, WNT7B, WNT8A, WNT8B, WNT9A, WNT9B, WNT10A, WNT10B, WNT11 и WNT16.
45. Способ по п. 28, где соединение ингибирует киназную активность.
46. Способ лечения у пациента заболевания или расстройства, опосредуемого путем Wnt, включающий введение пациенту терапевтически эффективного количества соединения по п. 1 или его фармацевтически приемлемой соли.
47. Способ по п. 44, где соединение ингибирует один или несколько белков Wnt.
48. Способ лечения у пациента заболевания или расстройства, опосредуемого киназной активностью, включающий введение пациенту терапевтически эффективного количества соединения по п. 1 или его фармацевтически приемлемой соли.
49. Способ по п. 46, где заболевание или расстройство включает рост опухоли, клеточную пролиферацию или ангиогенез.
50. Способ ингибирования активности протеинкиназного рецептора, включающий контактирование рецептора с эффективным количеством соединения по п. 1 или его фармацевтически приемлемой соли.
51. Способ лечения у пациента заболевания или расстройства, ассоциированного с аберрантной клеточной пролиферацией, включающий введение пациенту терапевтически эффективного количества соединения по п. 1 или его фармацевтически приемлемой соли.
52. Способ предупреждения или уменьшения ангиогенеза у пациента, включающий введение пациенту терапевтически эффективного количества соединения по п. 1 или его фармацевтически приемлемой соли.
53. Способ предупреждения или уменьшения анормальной клеточной пролиферации у пациента, включающий введение пациенту терапевтически эффективного количества соединения по п. 1 или его фармацевтически приемлемой соли.
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