RU2016135922A - Терапевтические соединения и композиции - Google Patents

Терапевтические соединения и композиции Download PDF

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RU2016135922A
RU2016135922A RU2016135922A RU2016135922A RU2016135922A RU 2016135922 A RU2016135922 A RU 2016135922A RU 2016135922 A RU2016135922 A RU 2016135922A RU 2016135922 A RU2016135922 A RU 2016135922A RU 2016135922 A RU2016135922 A RU 2016135922A
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alkyl
heteroaryl
compound
substituted
aryl
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RU2016135922A
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RU2733405C2 (ru
RU2016135922A3 (ru
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Роберт А. ХРУСЬЦЕЛЬ
Роберт К. ГЭДВУД
Нил Дж. ХЭЙВОРД
Майкл Дж. МЕЛЬНИК
Мануэль НАВИА
Тони Дж. ПОЭЛЬ
Кэтрин А. СТЮАРТ
Франс Л. СТАССЕН
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Экзитера Фармасьютикалз Инк.
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Claims (78)

1. Соединение формулы (II):
Figure 00000001
(II),
или его фармацевтически приемлемая соль, где
R1 представляет собой H или -C1-6 алкил;
R2 представляет собой H, –C1-6 алкил, –CO2R5, –C(O)NR9R10, –CN, –CNH(OR5), –CHN(OR5) или гетероарил;
R3 представляет собой H или -C1-6 алкил;
A представляет собой связь, C1-6 алкилен, C2-6 алкинилен или C2-6 алкинилен;
R4 представляет собой циклоалкил, арил, гетероарил или гетероциклил, каждый из которых замещен 0-3 R6;
каждый R5 независимо представляет собой H, -C1-6 алкил, аралкил или арил, замещенный 0-3 -NH2 или R6;
X представляет собой –C(O)O–, –OC(O)–, –C(O)S(O)2–, –S(O)2C(O)–, –C(O)N(R5)– или –N(R5)C(O)–;
Y представляет собой циклоалкил, гетероарил или гетероциклил, каждый из которых замещен 0-3 –NH2 или R6; или замщенный -С1-6алкил или фенил, замещенный 1-2 R6;
R7 представляет собой H, –C1-6 алкил, циклоалкил, арил, гетероарил или гетероциклил, каждый из которых замещен 0-3 –NH2 или R6;
где, если R6 представляет собой заместитель для любого R4, R5 или R7, то каждый R6 независимо представляет собой галоген, гидрокси, циано, нитро, C1-6 алкил, C1-6 алкокси, -NR9R10, -NHR10, -C(O)R11, -C(O)OR11, –C(O)NR9R10, –C(NR8)(N(R8)2), –SOqR11, –SO2NR9R10, –NHC(O)OR11, –NHC(O)R11, арил, гетероарил, аралкил, циклоалкил, гетероаралкил, гетероциклил или гетероциклилалкил; или
две группы R6, взятые вместе с атомами, к которым они присоединены образуют 5-7-членное кольцо; и
если R6 является заместителем Y, то каждый R6 независимо представляет собой галоген, галогеналкокси; или
две группы R6, взятые вместе с атомами, к которым они присоединены образуют:
Figure 00000002
или
Figure 00000003
;
каждый R8 независимо представляет собой H, –C1-6 алкил, –C(O)R5, –C(O)OR5, арил, гетероарил, аралкил, гетероаралкил, гетероциклил или гетероциклилалкил;
каждый R9 и R10 независимо представляет собой –C1-6 алкил, циклоалкил, гетероциклил, арил или гетероарил, или
R9 и R10 вместе образуют необязательно замещенное 5-7-членное кольцо;
каждый R11 независимо представляет собой H, –C1-10 алкил, аралкил или арил;
q равно целому числу от 0 до 2; и
n равно целому числу от 0 до 2.
2. Соединение по п.1, где R1 представляет собой H.
3. Соединение по п.1, где R2 представляет собой –CO2R5, где R5 представляет собой H или –C1-6 алкил.
4. Соединение по п.1, где A представляет собой C1-6 алкилен.
5. Соединение по п.1, где R4 представляет собой арил или гетероарил.
6. Соединение по п.5, где R4 представляет собой 6-членный гетероарил, замещенный 0-3 -NH2 или R6.
7. Соединение по п.1, где X представляет собой –C(O)N(R5)– или –N(R5)C(O)–.
8. Соединение по п.1, где соединение формулы (II) является фармацевтически приемлемой солью.
9. Соединение по п.1, где соединение формулы (II) выбрано из соединения формулы (IIa):
Figure 00000004
(IIa),
где
R1, R2, R3, R4, R7 и Y такие, как описано для формулы (II), и
m равно целому числу от 1 до 6.
10. Соединение по п.9, где соединение формулы (II) выбрано из соединения формулы (IIb):
Figure 00000005
(Ib),
где
R1, R2, R3, R4, R7, Y и m такие, как описано для формулы (IIa).
11. Соединение по п.10, где соединение формулы (IIb) представляет собой:
Figure 00000006
Figure 00000007
Figure 00000008
Figure 00000009
Figure 00000010
Figure 00000011
Figure 00000012
Figure 00000013
Figure 00000014
Figure 00000015
Figure 00000016
Figure 00000017
Figure 00000018
Figure 00000019
Figure 00000020
Figure 00000021
Figure 00000021
Figure 00000022
Figure 00000023
Figure 00000024
Figure 00000025
Figure 00000026
Figure 00000027
Figure 00000028
или
Figure 00000029
.
12. Соединение по п.10, где соединение формулы (IIb) выбрано из соединения формулы (IIc):
Figure 00000030
.
13. Фармацевтическая композиция, содержащая соединение формулы (II):
Figure 00000031
(II),
или его фармацевтически приемлемая соль, где
R1 представляет собой H или -C1-6 алкил;
R2 представляет собой H, –C1-6 алкил, –CO2R5, –C(O)NR9R10, –CN, –CHN(OR5) или гетероарил;
R3 представляет собой H или -C1-6 алкил;
A представляет собой связь, C1-6 алкилен, C2-6 алкинилен или C2-6 алкинилен;
R4 представляет собой циклоалкил, арил, гетероарил или гетероциклил, каждый из которых замещен 0-3 –NH2 или R6;
каждый R5 независимо представляет собой H, -C1-6 алкил, аралкил или арил, замещенный 0-3 -NH2 или R6;
X представляет собой–C(O)O–, –OC(O)–, –C(O)S(O)2–, –S(O)2C(O)–, –C(O)N(R5)– или –N(R5)C(O)–;
Y представляет собой циклоалкил, гетероарил или гетероциклил, каждый из которых замещен 0-3 –NH2 или R6; или замещенный–C1-6 алкил или фенил, замещенный 1-2 R6;
R7 представляет собой H, –C1-6 алкил, циклоалкил, арил, гетероарил или гетероциклил, каждый из которых замещен 0-3 –NH2 или R6;
где если R6 представляет собой заместителя для любого R4, R5 или R7, то каждый R6 независимо представляет собой галоген, гидрокси, циано, нитро, C1-6 алкил, C1-6 алкокси, -NR9R10, -NHR10, -C(O)R11, -C(O)OR11, –C(O)NR9R10, –C(NR8)(N(R8)2), –SOqR11, –SO2NR9R10, –NHC(O)OR11, –NHC(O)R11, арил, гетероарил, аралкил, циклоалкил, гетероаралкил, гетероциклил или гетероциклилалкил; или
если R6 является заместителем для Y, то каждый R6 независимо представляет собой галоген, галогеналкокси; или
две R6 группы, взятые вместе с атомами, к которым они присоединены, образуют:
Figure 00000032
или
Figure 00000033
;
каждый R8 независимо представляет собой H, –C1-6 алкил, –C(O)R5, –C(O)OR5, арил, гетероарил, аралкил, гетероаралкил, гетероциклил или гетероциклилалкил;
каждый R9 и R10 независимо представляет собой –C1-6 алкил, циклоалкил, гетероциклил, арил или гетероарил, или
R9 и R10 вместе образуют необязательно замещенное 5-7-членное кольцо;
каждый R11 независимо представляет собой H, –C1-10 алкил, аралкил или арил;
q равно целому числу от 0 до 2;
n равно целому числу от 0 до 2;
и один или несколько фармацевтически приемлемых носителей.
14. Соединение по п.1, где Y представляет собой фенил, замещенный 1 раз R6.
15. Соединение по п.1, где Y представляет собой фенил, а R6 представляет собой галогеналкокси.
16. Соединение по п.1, где Y представляет собой фенил, и R6 представляет собой галоген.
17. Соединение по п.1, где Y представляет собой фенил, замещенный 2 R6.
18. Соединение по п.17, где две R6 группы, взятые вместе с атомами, к которым они присоединены, образуют:
Figure 00000032
или
Figure 00000033
.
19.Соединение по п.1, где Y представляет собой циклоалкил.
20. Соединение по п.19, где Y представляет собой циклогексил.
21. Соединение по п.1, где R7 представляет собой–C1-6 алкил, замещенный 0-3–NH2 или R6.
22. Соединение по п. 21, где R7 представляет собой метил или –CF3.
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Families Citing this family (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ES2712699T3 (es) 2013-03-25 2019-05-14 Bristol Myers Squibb Co Tetrahidroisoquinolinas que contienen azoles sustituidos como inhibidores del factor XIa
NO2760821T3 (ru) 2014-01-31 2018-03-10
EP3392249B1 (en) 2014-01-31 2021-08-25 Bristol-Myers Squibb Company Macrocycles with heterocyclic p2' groups as factor xia inhibitors
FI3102200T3 (fi) * 2014-02-07 2023-05-31 Exithera Pharmaceuticals Inc Terapeuttisia yhdisteitä ja koostumuksia
EP3189047B1 (en) 2014-09-04 2018-12-26 Bristol-Myers Squibb Company Diamide macrocycles that are fxia inhibitors
US9453018B2 (en) 2014-10-01 2016-09-27 Bristol-Myers Squibb Company Pyrimidinones as factor XIa inhibitors
WO2017074833A1 (en) 2015-10-29 2017-05-04 Merck Sharp & Dohme Corp. Macrocyclic spirocarbamate derivatives as factor xia inhibitors, pharmaceutically acceptable compositions and their use
EP3500556B1 (en) 2016-08-22 2023-08-02 Merck Sharp & Dohme LLC Pyridine-1-oxide derivatives and their use as factor xia inhibitors
IL266223B2 (en) 2016-10-31 2024-04-01 Biocryst Pharm Inc Drug inhibitors of kallikrein inhibitors
US20190315711A1 (en) * 2016-12-23 2019-10-17 Exithera Pharmaceuticals, Inc. Therapeutic compounds and compositions
CN111902404A (zh) * 2018-02-07 2020-11-06 艾克赛特赫拉制药有限责任公司 治疗化合物和组合物
US11345679B2 (en) 2018-03-30 2022-05-31 Shanghai Meiyue Biotech Development Co., Ltd. Quaternary lactam compound and pharmaceutical use thereof
EP3873444A4 (en) * 2018-10-30 2022-08-10 Exithera Pharmaceuticals Inc. THERAPEUTIC COMPOUNDS AND COMPOSITIONS
AU2019369518A1 (en) * 2018-10-30 2021-04-22 Exithera Pharmaceuticals, Inc. Therapeutic compounds and compositions
KR20210119432A (ko) * 2019-01-29 2021-10-05 엑시테라 파마슈티컬스 인코퍼레이티드 치료 화합물 및 조성물
EP4213857A1 (en) * 2020-09-17 2023-07-26 Exithera Pharmaceuticals Inc. Therapeutic compounds, compositions, and methods of use thereof

Family Cites Families (25)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4595532A (en) 1983-02-02 1986-06-17 University Of Notre Dame Du Lac N-(substituted-methyl)-azetidin-2-ones
US5739135A (en) 1993-09-03 1998-04-14 Bristol-Myers Squibb Company Inhibitors of microsomal triglyceride transfer protein and method
SE9602263D0 (sv) * 1996-06-07 1996-06-07 Astra Ab New amino acid derivatives
US5760246A (en) 1996-12-17 1998-06-02 Biller; Scott A. Conformationally restricted aromatic inhibitors of microsomal triglyceride transfer protein and method
WO1999037668A1 (de) 1998-01-26 1999-07-29 Basf Aktiengesellschaft Thrombininhibitoren
US6335324B1 (en) 1998-06-25 2002-01-01 Bristol-Myers Squibb Co. Beta lactam compounds and their use as inhibitors of tryptase
ES2249017T3 (es) * 1998-06-25 2006-03-16 Bristol-Myers Squibb Company Amino y guanidino azetidinonas como inhibidores de triptasa.
WO2000005204A1 (fr) * 1998-07-23 2000-02-03 Shionogi & Co., Ltd. COMPOSES DE β-LACTAME MONOCYCLIQUES ET INHIBITEURS DE LA CHYMASE LES RENFERMANT
GB0205527D0 (en) 2002-03-08 2002-04-24 Ferring Bv Inhibitors
JO2785B1 (en) * 2003-05-27 2014-03-15 شركة جانسين فارماسوتيكا ان. في Quinazoline derivatives
CN1871029A (zh) * 2003-08-22 2006-11-29 帝人制药株式会社 含有类糜蛋白酶抑制剂作为有效成分的药物
AU2004298448B2 (en) * 2003-12-18 2010-09-09 Janssen Pharmaceutica N.V. Pyrido- and pyrimidopyrimidine derivatives as anti- proliferative agents
JO3088B1 (ar) * 2004-12-08 2017-03-15 Janssen Pharmaceutica Nv مشتقات كوينازولين كبيرة الحلقات و استعمالها بصفتها موانع كينيز متعددة الاهداف
WO2006108039A2 (en) * 2005-04-04 2006-10-12 Daiamed, Inc. Substituted azetidinones
PE20070171A1 (es) * 2005-06-30 2007-03-08 Boehringer Ingelheim Int GLICINAMIDAS SUSTITUIDAS CON EFECTO ANTITROMBOTICO E INHIBIDOR DEL FACTOR Xa
TW200745084A (en) 2006-03-08 2007-12-16 Astrazeneca Ab Novel compounds
EP1873157A1 (en) * 2006-06-21 2008-01-02 Bayer Schering Pharma Aktiengesellschaft Pyrazolopyrimidines and salts thereof, pharmaceutical compositions comprising same, methods of preparing same and uses of same
AU2008265104B2 (en) * 2007-06-21 2013-09-12 Janssen Pharmaceutica Nv Indolin-2-ones and aza-indolin-2-ones
ES2380648T3 (es) * 2008-03-13 2012-05-17 Bristol-Myers Squibb Company Derivados de piridazina como inhibidores del factor XIA
UY32192A (es) * 2008-10-22 2011-05-31 Array Biopharma Inc COMPUESTOS PIRAZOLO[1,5-a]PIRIMIDINA SUSTITUIDA COMO INHIBIDORES DE TRK CINASA
EA020528B1 (ru) 2010-02-11 2014-11-28 Бристол-Майерс Сквибб Компани Макроциклы в качестве ингибиторов фактора xia
RS56168B1 (sr) 2011-10-14 2017-11-30 Bristol Myers Squibb Co Supstituisana jedinjenja tetrahidroizohinolina kao inhibitori xia faktora
BR112014024287A2 (pt) * 2012-03-27 2018-05-08 Duke University composições e métodos para a prevenção e tratamento do derrame vascular induzido por mastócitos
FI3102200T3 (fi) * 2014-02-07 2023-05-31 Exithera Pharmaceuticals Inc Terapeuttisia yhdisteitä ja koostumuksia
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