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RU2017145929A - МОДУЛЯТОРЫ ROR ГАММА(RORγ) - Google Patents

МОДУЛЯТОРЫ ROR ГАММА(RORγ) Download PDF

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Publication number
RU2017145929A
RU2017145929A RU2017145929A RU2017145929A RU2017145929A RU 2017145929 A RU2017145929 A RU 2017145929A RU 2017145929 A RU2017145929 A RU 2017145929A RU 2017145929 A RU2017145929 A RU 2017145929A RU 2017145929 A RU2017145929 A RU 2017145929A
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RU
Russia
Prior art keywords
phenyl
acetamide
cyclopropylmethanesulfonylphenyl
alkyl
methyl
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RU2017145929A
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English (en)
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RU2017145929A3 (ru
RU2727191C2 (ru
Inventor
Йосеф Мария Герардус Барбара Калс
КИМПЕ Вера ДЕ
Сандер Бернардус Набююрс
Козимо Дамиано КАДИКАМО
Яп Герардус Хенрикус ЛЕММЕРС
Original Assignee
Лид Фарма Холдинг Б.В.
Санофи
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Publication of RU2017145929A publication Critical patent/RU2017145929A/ru
Publication of RU2017145929A3 publication Critical patent/RU2017145929A3/ru
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Publication of RU2727191C2 publication Critical patent/RU2727191C2/ru

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/26—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C317/32—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/095—Sulfur, selenium, or tellurium compounds, e.g. thiols
    • A61K31/10—Sulfides; Sulfoxides; Sulfones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/18—Sulfonamides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A—HUMAN NECESSITIES
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
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    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/421—1,3-Oxazoles, e.g. pemoline, trimethadione
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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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
    • A61K31/4436—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom
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    • A61K31/33—Heterocyclic compounds
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • 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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    • C07D—HETEROCYCLIC COMPOUNDS
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Claims (106)

1. Соединение формулы I
Figure 00000001
(формула I)
или его фармацевтически приемлемая соль, где:
A1 является NR1 или CR1, где R1 является H или метилом, где метил, если присутствует, необязательно замещен одним или более F;
циклопропильная часть может быть необязательно замещена одним или более метилом и одним или более F;
A2-A5 являются N или CR2-CR5, соответственно, при условии, что не более двух из четырех положений А в A2-A5 одновременно могут быть N;
R2-R5 независимо являются H, галогеном, амино, C(1-3)алкокси, (ди)C(1-3)алкиламино или C(1-6)алкилом;
R6 и R7 независимо являются H, F, метилом, этилом, гидроксилом или метокси, или R2 и R3 вместе являются карбонилом, все алкильные группы, если присутствуют, необязательно замещены одним или более F;
R8 является Н или C(1-6)алкилом;
R 9 выбирают из группы, включающей формулу II, III, IV и V
Figure 00000002
(формула II)
где:
A10-A13 являются N или CR10-CR13, соответственно, при условии, что не более двух из четырех положений А в A10-A13 одновременно могут быть N;
R10-R13 независимо являются H, галогеном, амино, C(1-3)алкокси, (ди)C(1-3)алкиламино или C(1-6)алкилом;
X14 является либо C(6-10)арилом, либо C(1-9)гетероарилом, где все атомы углерода необязательно замещены галогеном, амино, циано, C(1-3)алкокси, (ди)C(1 3)алкиламино или C(1-3)алкилом;
Figure 00000003
(формула III)
где:
A20-A27 являются N или CR20-CR27, соответственно, при условии, что не более двух из трех положений А в A20-A22 одновременно могут быть N, и что не более трех из пяти положений А в A23-A27 одновременно могут быть N;
R20-R22 независимо являются H, галогеном, амино, C(1-3)алкокси, (ди)C(1-3)алкиламино или C(1-6)алкилом;
R23-R27 независимо являются H, галогеном, амино, циано, C(1-3)алкокси, (ди)C(1-3)алкиламино или C(1-3)алкилом;
X28 является либо C(6-10)арилом, либо C(1-9)гетероарилом, где все атомы углерода необязательно замещены галогеном, амино, циано, C(1-3)алкокси, (ди)C(1-3)алкиламино или C(1-3)алкилом;
Figure 00000004
Figure 00000005
 (формула IV) (формула V)
где:
A30 является N или C;
A31 является O, карбонилом, NR31 или CR32;
R31 является Н или C(1-6)алкилом;
R32 является либо H, OH, либо C(1-3)алкилом, где все алкильные группы необязательно замещены одним или более F или OH;
A33-A42 являются N или CR33-CR42, соответственно, при условии, что не более трех из пяти положений А в A33-A37 одновременно могут быть N, и что не более трех из пяти положений А в A38-A42 одновременно могут быть N;
R33-R42 независимо являются H, галогеном, амино, циано, C(1-3)алкокси, (ди)C(1-3)алкиламино или C(1-3)алкилом.
2. Соединение по п. 1, где A1 является CR1.
3. Соединение по п. 1, где A1 является NR1.
4. Соединение по пп. 1-3, где R1 является водородом.
5. Соединение по пп. 1-4, где R6 и R7 оба являются H.
6. Соединение по пп. 1-5, где R8 является H.
7. Соединение по пп. 1-6, где все положения А в A2-A5 являются CR2-R5 и все положения R в R2-R5 являются H.
8. Соединение по пп. 1-7, где R9 имеет формулу II, где:
A10-A13 являются N или CR10-CR13, соответственно, при условии, что не более двух из четырех положений А в A10-A13 одновременно могут быть N;
R10-R13 независимо являются H, амино, галогеном, C(1-3)алкокси, (ди)C(1-3)алкиламино или C(1-6)алкилом;
X14 является либо C(6)арилом, либо C(1-5)гетероарилом, где все атомы углерода необязательно замещены галогеном, циано, C(1-3)алкокси, (ди)C(1-3)алкиламино или C(1-3)алкилом.
9. Соединение по пп. 1-7, где R9 имеет формулу III, где:
A20-A27 являются N или CR20-CR27 соответственно, при условии, что не более двух из трех положений А в A20-A22 одновременно могут быть N, и что не более трех из пяти положений А в A23-A27 одновременно могут быть N;
R20-R22 независимо являются H, галогеном, амино, C(1-3)алкокси, (ди)C(1-3)алкиламино или C(1-6)алкилом;
R23-R27 независимо являются H, галогеном, циано, амино, C(1-3)алкокси, (ди)C(1-3)алкиламино или C(1-3)алкилом;
X28 является либо C(6)арилом или C(1-5)гетероарилом, где все атомы углерода необязательно замещены галогеном, циано, C(1-3)алкокси, (ди)C(1-3)алкиламино или C(1-3)алкилом.
10. Соединение по пп. 1-7, где R9 имеет формулу IV или V, где:
A30 является N или C;
A31 является O, карбонилом, NR31 или CR32;
R31 является Н или C(1-6)алкилом;
R32 является H, OH или C(1-6)алкилом, где все алкильные группы необязательно замещены одним или более F или OH;
A33-A42 являются N или CR33-CR42, соответственно, при условии, что не более трех из пяти положений A33-A37 одновременно могут быть N, и что не более трех из пяти положений A38-A42 одновременно могут быть N;
R33-R42 независимо являются H, галогеном, циано, C(1-3)алкокси, (ди)C(1-3)алкиламино или C(1-3)алкилом.
11. Соединение по п. 1, которое выбирают из группы:
2-(4-циклопропилметансульфонилфенил)-N-(3-фенокси-4-фенилфенил)ацетамид;
2-(4-циклопропилметансульфонилфенил)-N-[4-(3-фторфенил)-3-(3-метоксифенокси)фенил]ацетамид;
2-(4-циклопропилметансульфонилфенил)-N-[3-(3-метоксифенокси)-4-(4-метил-1H-имидазол-1-ил)фенил]ацетамид;
N-[3-(3-хлорфенокси)-4-(3-фторфенил)фенил]-2-(4-циклопропилметансульфонилфенил)ацетамид;
N-[3-(3-хлорфенокси)-4-(3,4-дифторфенил)фенил]-2-(4-циклопропилметансульфонилфенил)ацетамид;
N-[3-(3-цианофенокси)-4-(3,4-дифторфенил)фенил]-2-(4-циклопропилметансульфонилфенил)ацетамид;
2-(4-циклопропилметансульфонилфенил)-N-[3-(3-метоксифенокси)-4-(5-метил-1H-пиразол-1-ил)фенил]ацетамид;
N-[3-(3-хлорфенокси)-4-(3,5-дифторфенил)фенил]-2-(4-циклопропилметансульфонилфенил)ацетамид;
N-[4-(4-цианофенил)-3-(3-фторфенокси)фенил]-2-(4-циклопропилметансульфонилфенил)ацетамид;
N-[3-(3-хлорфенокси)-4-(3-цианофенил)фенил]-2-(4-циклопропилметансульфонилфенил)ацетамид;
2-(4-циклопропилметансульфонилфенил)-N-[4-(3-фторфенил)-3-[3-(трифторметил)фенокси]фенил]ацетамид;
2-(4-циклопропилметансульфонилфенил)-N-[3-(3-фторфенокси)-4-(4-фторфенил)фенил]ацетамид;
2-(4-циклопропилметансульфонилфенил)-N-[3-(3,5-дифторфенокси)-4-(3-фторфенил)фенил]ацетамид;
2-[4-(циклопропилсульфамоил)фенил]-N-[3-(3-метоксифенокси)-4-(4-метил-1H-имидазол-1-ил)фенил]ацетамид;
2-[4-(циклопропилсульфамоил)фенил]-N-[3-(3-метоксифенокси)-4-(5-метил-1H-пиразол-1-ил)фенил]ацетамид;
2-[4-(циклопропилсульфамоил)фенил]-N-[4-(3-фторфенил)-3-(3-метоксифенокси)фенил]ацетамид;
N-[3-(3-хлорфенокси)-4-(3-фторфенил)фенил]-2-[4-(циклопропилсульфамоил)фенил]ацетамид;
N-[3-(3-хлорфенокси)-4-(3,4-дифторфенил)фенил]-2-[4-(циклопропилсульфамоил)фенил]ацетамид;
2-[4-(циклопропилсульфамоил)фенил]-N-[4-(3-фторфенил)-3-[3-(трифторметил)фенокси]фенил]ацетамид;
2-(4-циклопропилметансульфонилфенил)-N-(5-фенокси-4-фенил-1,3-тиазол-2-ил)ацетамид;
2-(4-циклопропилметансульфонилфенил)-N-[4-фенил-5-(пиридин-3-илокси)-1,3-тиазол-2-ил]ацетамид;
N-(5-бензоил-4-фенил-1,3-тиазол-2-ил)-2-(4-циклопропилметансульфонилфенил)ацетамид;
N-[5-(4-хлорбензоил)-4-(3-хлорфенил)-1,3-тиазол-2-ил]-2-(4-циклопропилметансульфонилфенил)ацетамид;
2-(4-циклопропилметансульфонилфенил)-N-(4-фенилтиофен-2-ил)ацетамид;
2-(4-циклопропилметансульфонилфенил)-N-[4-(пиридин-3-ил)тиофен-2-ил]ацетамид;
N-(5-бензоил-4-фенил-1,3-тиазол-2-ил)-2-[4-(циклопропилсульфамоил)фенил]ацетамид;
N-(5-бензоил-4-фенилтиофен-2-ил)-2-(4-циклопропилметансульфонилфенил)ацетамид;
N-{3-хлор-4-[2-(трифторметокси)фенил]фенил}-2-(4-циклопропилметансульфонилфенил)ацетамид;
2-(4-циклопропилметансульфонилфенил)-N-{3-метил-4-[2-(трифторметокси)фенил]фенил}ацетамид;
2-(4-циклопропилметансульфонилфенил)-N-{3,5-дихлор-4-[2-(трифторметокси)фенил]фенил}ацетамид;
2-(4-циклопропилметансульфонилфенил)-N-{4-метил-5-[2-(трифторметокси)фенил]пиридин-2-ил}ацетамид;
2-(4-циклопропилметансульфонилфенил)-N-{6-метил-5-[2-(трифторметокси)фенил]пиридин-2-ил}ацетамид;
N-{3-хлор-4-[2-(трифторметокси)фенил]фенил}-2-[4-(циклопропилсульфамоил)фенил]ацетамид;
2-[4-(циклопропилсульфамоил)фенил]-N-{6-метил-5-[2-(трифторметокси)фенил]пиридин-2-ил}ацетамид;
2-[4-(циклопропилсульфамоил)фенил]-N-{4-метил-5-[2-(трифторметокси)фенил]пиридин-2-ил}ацетамид;
2-[4-(циклопропилсульфамоил)фенил]-N-{3-метил-4-[2-(трифторметокси)фенил]фенил}ацетамид;
2-(4-циклопропилметансульфонилфенил)-N-{4,6-диметил-5-[2-(трифторметокси)фенил]пиридин-2-ил}ацетамид;
2-(4-циклопропилметансульфонилфенил)-N-[4-(4-метил-1H-имидазол-1-ил)фенил]ацетамид;
2-(4-циклопропилметансульфонилфенил)-N-[4-(5-метил-1H-имидазол-1-ил)фенил]ацетамид;
2-(4-циклопропилметансульфонилфенил)-N-[4-(3-метил-1H-пиразол-1-ил)фенил]ацетамид;
2-(4-циклопропилметансульфонилфенил)-N-[4-(5-метил-1H-пиразол-1-ил)фенил]ацетамид;
2-(4-циклопропилметансульфонилфенил)-N-[4-(4-метил-1H-пиразол-1-ил)фенил]ацетамид;
2-(4-циклопропилметансульфонилфенил)-N-[4-(1,3-оксазол-5-ил)фенил]ацетамид;
2-(4-циклопропилметансульфонилфенил)-N-[4-(1H-пиразол-1-ил)фенил]ацетамид;
2-(4-циклопропилметансульфонилфенил)-N-[4-(1H-имидазол-1-ил)фенил]ацетамид;
2-(4-циклопропилметансульфонилфенил)-N-[4-(1H-1,2,4-триазол-1-ил)фенил]ацетамид и
2-(4-циклопропилметансульфонилфенил)-N-[4-(1,2,4-оксадиазол-3-ил)фенил]ацетамид.
12. Соединение по любому из пп. 1-11 или его фармацевтически приемлемая соль для применения в терапии.
13. Соединение по любому из пп. 1-11 или его фармацевтически приемлемая соль для лечения RORγ-медиированных заболеваний или состояний.
14. Фармацевтическая композиция, которая содержит соединение формулы I по любому из пп. 1-11 или его фармацевтически приемлемую соль и один или более фармацевтически приемлемых наполнителей.
15. Фармацевтическая композиция по п. 14, которая также содержит, по крайней мере, один терапевтически активный агент.
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