RU2015137756A - Макроциклические производные пиридазинона - Google Patents
Макроциклические производные пиридазинона Download PDFInfo
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- RU2015137756A RU2015137756A RU2015137756A RU2015137756A RU2015137756A RU 2015137756 A RU2015137756 A RU 2015137756A RU 2015137756 A RU2015137756 A RU 2015137756A RU 2015137756 A RU2015137756 A RU 2015137756A RU 2015137756 A RU2015137756 A RU 2015137756A
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- AAILEWXSEQLMNI-UHFFFAOYSA-N 1h-pyridazin-6-one Chemical class OC1=CC=CN=N1 AAILEWXSEQLMNI-UHFFFAOYSA-N 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims 16
- -1 pyridine-diyl Chemical group 0.000 claims 7
- 239000012453 solvate Substances 0.000 claims 6
- 125000000217 alkyl group Chemical group 0.000 claims 5
- 239000000203 mixture Substances 0.000 claims 5
- 150000003839 salts Chemical class 0.000 claims 5
- 125000004432 carbon atom Chemical group C* 0.000 claims 4
- 201000010099 disease Diseases 0.000 claims 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims 4
- 201000006417 multiple sclerosis Diseases 0.000 claims 4
- 206010039073 rheumatoid arthritis Diseases 0.000 claims 4
- 208000023275 Autoimmune disease Diseases 0.000 claims 3
- 239000003814 drug Substances 0.000 claims 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 3
- 125000000896 monocarboxylic acid group Chemical group 0.000 claims 3
- 239000008194 pharmaceutical composition Substances 0.000 claims 3
- 208000011580 syndromic disease Diseases 0.000 claims 3
- 206010002556 Ankylosing Spondylitis Diseases 0.000 claims 2
- 208000015943 Coeliac disease Diseases 0.000 claims 2
- 206010009900 Colitis ulcerative Diseases 0.000 claims 2
- 208000011231 Crohn disease Diseases 0.000 claims 2
- 208000035895 Guillain-Barré syndrome Diseases 0.000 claims 2
- 208000005777 Lupus Nephritis Diseases 0.000 claims 2
- 206010049567 Miller Fisher syndrome Diseases 0.000 claims 2
- 206010028980 Neoplasm Diseases 0.000 claims 2
- 201000004681 Psoriasis Diseases 0.000 claims 2
- 201000001263 Psoriatic Arthritis Diseases 0.000 claims 2
- 208000036824 Psoriatic arthropathy Diseases 0.000 claims 2
- 206010039710 Scleroderma Diseases 0.000 claims 2
- 201000009594 Systemic Scleroderma Diseases 0.000 claims 2
- 206010042953 Systemic sclerosis Diseases 0.000 claims 2
- 201000006704 Ulcerative Colitis Diseases 0.000 claims 2
- 201000011510 cancer Diseases 0.000 claims 2
- 229940079593 drug Drugs 0.000 claims 2
- 208000027866 inflammatory disease Diseases 0.000 claims 2
- 125000002757 morpholinyl group Chemical group 0.000 claims 2
- 125000003386 piperidinyl group Chemical group 0.000 claims 2
- 230000002265 prevention Effects 0.000 claims 2
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims 2
- 201000000596 systemic lupus erythematosus Diseases 0.000 claims 2
- 125000001989 1,3-phenylene group Chemical group [H]C1=C([H])C([*:1])=C([H])C([*:2])=C1[H] 0.000 claims 1
- 125000001140 1,4-phenylene group Chemical group [H]C1=C([H])C([*:2])=C([H])C([H])=C1[*:1] 0.000 claims 1
- 102100027573 ATP synthase subunit alpha, mitochondrial Human genes 0.000 claims 1
- 208000026872 Addison Disease Diseases 0.000 claims 1
- 201000004384 Alopecia Diseases 0.000 claims 1
- 208000024827 Alzheimer disease Diseases 0.000 claims 1
- 206010001935 American trypanosomiasis Diseases 0.000 claims 1
- 208000003343 Antiphospholipid Syndrome Diseases 0.000 claims 1
- 201000001320 Atherosclerosis Diseases 0.000 claims 1
- 206010003827 Autoimmune hepatitis Diseases 0.000 claims 1
- 208000009137 Behcet syndrome Diseases 0.000 claims 1
- 208000005024 Castleman disease Diseases 0.000 claims 1
- 208000024699 Chagas disease Diseases 0.000 claims 1
- 206010008690 Chondrocalcinosis pyrophosphate Diseases 0.000 claims 1
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims 1
- 201000009273 Endometriosis Diseases 0.000 claims 1
- 206010016654 Fibrosis Diseases 0.000 claims 1
- 208000007465 Giant cell arteritis Diseases 0.000 claims 1
- 201000005569 Gout Diseases 0.000 claims 1
- 206010072579 Granulomatosis with polyangiitis Diseases 0.000 claims 1
- 208000003807 Graves Disease Diseases 0.000 claims 1
- 208000015023 Graves' disease Diseases 0.000 claims 1
- 208000001204 Hashimoto Disease Diseases 0.000 claims 1
- 208000030836 Hashimoto thyroiditis Diseases 0.000 claims 1
- 101000936262 Homo sapiens ATP synthase subunit alpha, mitochondrial Proteins 0.000 claims 1
- 101000936965 Homo sapiens ATP synthase-coupling factor 6, mitochondrial Proteins 0.000 claims 1
- 206010021245 Idiopathic thrombocytopenic purpura Diseases 0.000 claims 1
- 208000010159 IgA glomerulonephritis Diseases 0.000 claims 1
- 206010021263 IgA nephropathy Diseases 0.000 claims 1
- 208000022559 Inflammatory bowel disease Diseases 0.000 claims 1
- 102100026018 Interleukin-1 receptor antagonist protein Human genes 0.000 claims 1
- 101710144554 Interleukin-1 receptor antagonist protein Proteins 0.000 claims 1
- 102100036342 Interleukin-1 receptor-associated kinase 1 Human genes 0.000 claims 1
- 101710199015 Interleukin-1 receptor-associated kinase 1 Proteins 0.000 claims 1
- 208000005615 Interstitial Cystitis Diseases 0.000 claims 1
- 206010059176 Juvenile idiopathic arthritis Diseases 0.000 claims 1
- 208000001132 Osteoporosis Diseases 0.000 claims 1
- 208000018737 Parkinson disease Diseases 0.000 claims 1
- 206010034277 Pemphigoid Diseases 0.000 claims 1
- 201000011152 Pemphigus Diseases 0.000 claims 1
- 201000010848 Schnitzler Syndrome Diseases 0.000 claims 1
- 206010040047 Sepsis Diseases 0.000 claims 1
- 208000021386 Sjogren Syndrome Diseases 0.000 claims 1
- 206010072148 Stiff-Person syndrome Diseases 0.000 claims 1
- 208000006011 Stroke Diseases 0.000 claims 1
- 208000031981 Thrombocytopenic Idiopathic Purpura Diseases 0.000 claims 1
- 241000223109 Trypanosoma cruzi Species 0.000 claims 1
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 claims 1
- 206010047115 Vasculitis Diseases 0.000 claims 1
- 206010047642 Vitiligo Diseases 0.000 claims 1
- 239000013543 active substance Substances 0.000 claims 1
- 230000001154 acute effect Effects 0.000 claims 1
- 231100000360 alopecia Toxicity 0.000 claims 1
- 208000007502 anemia Diseases 0.000 claims 1
- 206010003246 arthritis Diseases 0.000 claims 1
- 125000003118 aryl group Chemical group 0.000 claims 1
- 208000006673 asthma Diseases 0.000 claims 1
- 201000003710 autoimmune thrombocytopenic purpura Diseases 0.000 claims 1
- 208000000594 bullous pemphigoid Diseases 0.000 claims 1
- 239000003795 chemical substances by application Substances 0.000 claims 1
- 208000002849 chondrocalcinosis Diseases 0.000 claims 1
- 208000025302 chronic primary adrenal insufficiency Diseases 0.000 claims 1
- 230000007882 cirrhosis Effects 0.000 claims 1
- 208000019425 cirrhosis of liver Diseases 0.000 claims 1
- 208000022993 cryopyrin-associated periodic syndrome Diseases 0.000 claims 1
- 201000003146 cystitis Diseases 0.000 claims 1
- 230000007812 deficiency Effects 0.000 claims 1
- 210000003027 ear inner Anatomy 0.000 claims 1
- 201000002491 encephalomyelitis Diseases 0.000 claims 1
- 125000000623 heterocyclic group Chemical group 0.000 claims 1
- 208000002557 hidradenitis Diseases 0.000 claims 1
- 150000004677 hydrates Chemical class 0.000 claims 1
- 230000002519 immonomodulatory effect Effects 0.000 claims 1
- 208000026278 immune system disease Diseases 0.000 claims 1
- 230000000366 juvenile effect Effects 0.000 claims 1
- 201000002215 juvenile rheumatoid arthritis Diseases 0.000 claims 1
- 210000004185 liver Anatomy 0.000 claims 1
- 238000005710 macrocyclization reaction Methods 0.000 claims 1
- 230000003211 malignant effect Effects 0.000 claims 1
- 238000000034 method Methods 0.000 claims 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 1
- 206010072221 mevalonate kinase deficiency Diseases 0.000 claims 1
- 206010028417 myasthenia gravis Diseases 0.000 claims 1
- 201000003631 narcolepsy Diseases 0.000 claims 1
- 125000004433 nitrogen atom Chemical group N* 0.000 claims 1
- 201000008482 osteoarthritis Diseases 0.000 claims 1
- 125000004430 oxygen atom Chemical group O* 0.000 claims 1
- 201000001976 pemphigus vulgaris Diseases 0.000 claims 1
- 208000005987 polymyositis Diseases 0.000 claims 1
- 229920006395 saturated elastomer Polymers 0.000 claims 1
- 201000000980 schizophrenia Diseases 0.000 claims 1
- 125000004434 sulfur atom Chemical group 0.000 claims 1
- 230000002194 synthesizing effect Effects 0.000 claims 1
- 230000009885 systemic effect Effects 0.000 claims 1
- 206010043207 temporal arteritis Diseases 0.000 claims 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 claims 1
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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
- A61K31/50—Pyridazines; Hydrogenated pyridazines
- A61K31/504—Pyridazines; Hydrogenated pyridazines forming part of bridged ring systems
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Claims (49)
1. Соединение формулы (I)
R1, R3 каждый независимо друг от друга означают Н, (CH2)pCON(R5)2, OA, Hal, СООН, COOA, (CH2)pNHCOA, (CH2)pHet1, (CH2)pNR2R5, или ОН;
R2 означает Н или линейный, или разветвленный алкил с 1, 2 или 3 атомами углерода, причем один или два Н атома алкильной группы могут быть заменены посредством OR6, NR5R6,NHCOR5, CONR5R6;
R4 означает Н или А;
R5 означает Н или линейный или разветвленный алкил с 1, 2 или 3 атомами углерода;
R6 означает Н или линейный или разветвленный алкил с 1, 2 или 3 атомами углерода;
Z отсутствует или означает Ar-диил или Het-диил;
L означает (СН2)n, причем одна или две группы СН2 могут быть заменены посредством О и/или группы СН=СН, и/или причем один или два Н атома могут быть замещены посредством OR2, NR2R5 или Het1;
Ar-диил означает 1,2-, 1,3- или 1,4-фенилен, по выбору замещенный посредством от 1 до 5 групп, независимо выбранных из Hal, CN, -CF3, -OCF3, ОН, О-А, SO2-A, СООН, СООА, -СО-А, О-фенил, SO2-фенил, SO2-CF3, Het2 и/или А;
Het-диил означает ненасыщенный, насыщенный или ароматический 5-или 6-членный гетероцикл, имеющий от 1 до 2 атомов N, О и/или S, который может быть незамещенным или моно-, ди- или тризамещенным посредством Hal, CN, -CF3, -OCF3, О-А, SO2-A, СООН, СООА, -СО-А, О-фенил, SO2-фенил, SO2-CF3, Het2 и/или А;
А означает неразветвленный или разветвленный алкил, имеющий от 1 до 10 атомов углерода, в котором от 1 до 5 атомов Н могут быть заменены посредством F и/или в котором одна или две несмежных СН2 группы могут быть заменены посредством О;
Het1 означает морфолинил, пиперидинил или пирролидинил;
Het2 означает морфолинил, пиперидинил или пирролидинил;
Hal означает F, Cl, Br, I;
n означает 1, 2, 3, 4, 5 или 6;
р означает 0, 1 или 2;
и его фармацевтически приемлемые таутомеры, сольваты, соли и стереоизомеры, включая их смеси во всех соотношениях.
2. Соединение формулы (I) по п. 1, причем R4 означает Н или метил.
3. Соединение формулы (I) по п. 1 или 2, причем Het-диил означает пиридин-диил, пиримидин-диил, пиридазин-диил, пиразол-диил, имидазол-диил, пиперидин-диил или пирролидин-диил, каждый из которых является незамещенным или дизамещенным посредством А.
4. Соединение формулы (I) по п. 1 или 2, причем Z означает 1,3-фенилен, являющийся незамещенным или монозамещенным посредством A, Hal, ОН, или OA.
5. Соединение формулы (I), выбранное из следующей группы:
и его фармацевтически приемлемые таутомеры, сольваты, соли и стереоизомеры, включая их смеси во всех соотношениях.
6. Соединение формулы (I) по пп. 1, 2 или 5 и его фармацевтически приемлемые таутомеры, сольваты, соли, сольваты и стереоизомеры, включая их смеси во всех соотношениях, для применения в качестве лекарственного средства.
7. Соединение по п. 6 для применения в лечении или предупреждения воспалительного заболевания, аутоиммунного заболевания, рака или множественного склероза и связанных заболеваний.
8. Соединение по п. 7, при этом аутоиммунное заболевание выбирают из группы, состоящей из астмы, ревматоидного артрита, острого множественного энцефаломиелита (ОМЭМ), болезни Аддисона, очаговой алопеции, анкилозирующего спондилита, синдрома антифосфолипидных антител (АФС), аутоиммунной гемолитической анемии, аутоиммунного гепатита, аутоиммунного заболевания внутреннего уха, буллезного пемфигоида, болезни Бехчета, целиакии, антитрансглутаминазы, болезни Чагаса, хронического обструктивного заболевания легких, болезни Крона, дерматомиозита, сахарного диабета 1 типа, эндометриоза, синдрома Гудпасчера, болезни Грейвса, синдрома Гийена-Барре (СГБ), тиреоидита Хашимото, гнойного гидраденита, синдрома Кавасаки, нефропатии IgA, идиопатической тромбоцитопенической пурпуры, интерстициального цистита, эритематозной волчанки, смешанной болезни соединительной ткани, кольцевидной склеродермии, множественного склероза (МС), тяжелой миастении, нарколепсии, нейромиотомии, обыкновенной пузырчатки, злокачественной анемии, псориаза, псориатического артрита, полимиозита, билиарного первичного цирроза печени, ревматоидного артрита, шизофрении, склеродермии, синдрома Шегрена, синдрома скованного человека, системного склероза, височного артериита, язвенного колита, васкулита, витилиго, гранулематоза Вегенера.
9. Соединение по п. 7, при этом заболевание выбирают из ревматоидного артрита, псориатического артрита, остеоартрита, системной красной волчанки, волчаночного нефрита, анкилозирующего спондилоартрита, остеопороза, системного склероза, множественного склероза, псориаза, сахарного диабета I типа, сахарного диабета II типа, воспалительного заболевания кишечника (болезнь Крона и язвенный колит), гипериммуноглобулинемии D и синдрома периодической лихорадки, криопирин-связанных периодических синдромов, синдрома Шницлера, системного ювенильного идиопатического артрита, приобретенной болезни Стилла, подагры, псевдоподагры, синдрома САПГО, болезни Кастлемана, сепсиса, инсульта, атеросклероза, целиакии, DIRA (дефицит антагониста рецептора IL-1), болезни Альцгеймера, болезни Паркинсона, рака.
10. Соединение по п. 7, при этом заболевание выбирают из ревматоидного артрита, волчаночного нефрита, системной красной волчанки.
11. Соединение формулы (I) по п. 1 для предотвращения и/или лечения заболеваний, связанных с повышенной экспрессией IRAK.
12. Набор, состоящий из
(а) эффективного количества соединения формулы (I) и/или его фармацевтически приемлемых производных, сольватов, солей, гидратов и стереоизомеров, включая их смеси во всех соотношениях, и
(б) эффективного количества дополнительного действующего вещества лекарственного средства.
13. Фармацевтическая композиция, содержащая по меньшей мере одно из соединений формулы (I) по любому из пп. 1 - 5 и/или его фармацевтически приемлемые таутомеры, сольваты, соли и стереоизомеры, включая их смеси во всех соотношениях.
14. Фармацевтическая композиция по п. 13, дополнительно содержащая по меньшей мере одно другое лекарственное средство, применяемое в лечении воспалительных заболеваний или иммунных заболеваний.
15. Фармацевтическая композиция по п. 14, дополнительно содержащая по меньшей мере одно другое иммуномодулирующее средство.
16. Способ синтеза соединения формулы (I) по п. 1, в котором соединение формулы (I) получают макроциклизацией соединения формулы (II), в которой R1, R2, R3, R4, Z и L являются такими, как определены в п. 1, и А1 означает Н, Li, Na или K
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AU2016215184B2 (en) * | 2015-02-06 | 2020-11-12 | Merck Patent Gmbh | Pyridazinone macrocycles as IRAK inhibitors and uses thereof |
LT3286181T (lt) | 2015-04-22 | 2021-04-26 | Rigel Pharmaceuticals, Inc. | Pirazolo junginiai ir junginių gamybos bei naudojimo būdas |
JOP20180011A1 (ar) | 2017-02-16 | 2019-01-30 | Gilead Sciences Inc | مشتقات بيرولو [1، 2-b]بيريدازين |
WO2019060742A1 (en) | 2017-09-22 | 2019-03-28 | Kymera Therapeutics, Inc | AGENTS FOR DEGRADING PROTEINS AND USES THEREOF |
WO2019060693A1 (en) | 2017-09-22 | 2019-03-28 | Kymera Therapeutics, Inc. | CRBN LIGANDS AND USES THEREOF |
WO2019111218A1 (en) | 2017-12-08 | 2019-06-13 | Cadila Healthcare Limited | Novel heterocyclic compounds as irak4 inhibitors |
IL315310A (en) | 2017-12-26 | 2024-10-01 | Kymera Therapeutics Inc | Irak degraders and uses thereof |
EP3737675A4 (en) | 2018-01-12 | 2022-01-05 | Kymera Therapeutics, Inc. | Crbn ligands and uses thereof |
EP3737666A4 (en) | 2018-01-12 | 2022-01-05 | Kymera Therapeutics, Inc. | PROTEIN DEGRADATION AGENTS AND ASSOCIATED USES |
AU2019282231B2 (en) | 2018-06-04 | 2025-04-17 | Ohio State Innovation Foundation | EAAT2 activators and methods of using thereof |
US11292792B2 (en) | 2018-07-06 | 2022-04-05 | Kymera Therapeutics, Inc. | Tricyclic CRBN ligands and uses thereof |
TWI721483B (zh) | 2018-07-13 | 2021-03-11 | 美商基利科學股份有限公司 | 吡咯并[1,2-b]嗒𠯤衍生物 |
CN113423427A (zh) | 2018-11-30 | 2021-09-21 | 凯麦拉医疗公司 | Irak降解剂和其用途 |
JP7590996B2 (ja) | 2019-06-24 | 2024-11-27 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | Egfr阻害剤としての新たな大環状化合物および誘導体 |
MX2022002292A (es) | 2019-08-30 | 2022-06-02 | Rigel Pharmaceuticals Inc | Compuestos de pirazol, formulaciones de los mismos y un metodo para usar los compuestos y/o formulaciones. |
WO2021127283A2 (en) | 2019-12-17 | 2021-06-24 | Kymera Therapeutics, Inc. | Irak degraders and uses thereof |
US11779578B2 (en) | 2019-12-17 | 2023-10-10 | Kymera Therapeutics, Inc. | IRAK degraders and uses thereof |
TW202210483A (zh) | 2020-06-03 | 2022-03-16 | 美商凱麥拉醫療公司 | Irak降解劑之結晶型 |
US11690915B2 (en) | 2020-09-15 | 2023-07-04 | Revolution Medicines, Inc. | Ras inhibitors |
CN114057771B (zh) * | 2020-12-03 | 2023-10-03 | 北京鞍石生物科技有限责任公司 | 大环化合物及其制备方法和应用 |
CA3202360A1 (en) | 2020-12-30 | 2022-07-07 | Nello Mainolfi | Irak degraders and uses thereof |
CA3207049A1 (en) | 2021-02-15 | 2022-08-18 | Jared Gollob | Irak4 degraders and uses thereof |
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CA3217920A1 (en) | 2021-05-05 | 2022-11-10 | Andreas BUCKL | Ras inhibitors for the treatment of cancer |
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