US2023287034A1PendingUtilityA1
Cyclic dinucleotides as sting agonists
Est. expiryJul 17, 2038(~12 yrs left)· nominal 20-yr term from priority
Inventors:Stuart EmanuelMark RichterPeter J. ConnollyJames P. EdwardsGuangyi WangSanthosh Kumar ThatikondaLeonid BeigelmanGilles BignanWim Bert Griet SchepensMarcel ViellevoyeJohannes Wilhelmus John F. Thuring
C07H 21/02C07H 21/00C07H 19/207C07H 21/04A61P 37/02A61P 35/00A61K 31/7084A61P 31/12C07H 19/23
73
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Claims
Abstract
Disclosed are compounds, compositions and methods for treating of diseases, syndromes, or disorders that are affected by the modulation of STING. Such compounds are represented by Formula (I) as follows: wherein R 1 , R 1 ′, X 1 , B 1 , R 2 , R 2 ′, B 2 , X 2 , R 3 , Z-M-Y, and Y 1 -M 1 -Z 1 are as defined herein.
Claims
exact text as granted — not AI-modified1 - 45 . (canceled)
46 . A pharmaceutical composition comprising a compound of formula (Ia)-(Ip) or (Ir) and at least one of a pharmaceutically acceptable carrier, a pharmaceutically acceptable excipient, or a pharmaceutically acceptable diluent, wherein the compound of formula (Ia)-(Ip) or (Ir) is:
wherein:
B 1 is b1, b2, b3, b4, b5, b6, b7, b8, b9, b10, b11, b12, b13, b14, b15, b16, b17, b18, b19, b20, b21, b22, b23, b24, b25, b26, b27, b28, b29, or b30:
R 1 is hydrogen; hydroxy; fluoro; optionally substituted C 1-3 alkoxy; C 3-6 alkenyloxy; C 2-6 alkynyloxy; hydroxy(C 1-3 alkoxy); or optionally substituted C 1-3 alkyl;
R 1′ is hydrogen, fluoro, or hydroxy; provided that when R 1 ′ is fluoro, R 1 is hydrogen or fluoro;
R 2 is hydrogen; hydroxy; fluoro; optionally substituted C 1-3 alkoxy; C 3-6 alkenyloxy; C 2-6 alkynyloxy; hydroxy(C 1-3 alkoxy); or optionally substituted C 1-3 alkyl; and R 3 is hydrogen;
or, R 3 is —CH 2 —, and R 2 is —O—; such that R 2 , R 3 and the atoms to which they are attached form a 5-membered ring;
R 2′ is hydrogen, fluoro, or hydroxy; provided that when R 2′ is fluoro, R 2 is hydrogen or fluoro;
R 3 hydrogen, fluoro, CH 3 , or CH 2 F;
X 1 and X 2 are, independently, O, S, or CH 2 ;
L and L 1 are, independently, —CH 2 — or —CH 2 CH 2 —;
Y and Y 1 are, independently, absent, O, or NH;
Z and Z 1 are, independently, O or NH;
one of M and M 1 is
and the other of M and M 1 is
wherein:
(i) when M is
one of Y and Z is NH, and the other of Y and Z is O; and
(ii) when M 1 is
one of Y 1 and Z 1 is NH, and the other of Y 1 and Z 1 is O;
(iii) when Y 1 is absent, L is —CH 2 CH 2 , and M is
and
(iv) when Y 1 is absent, L 1 is absent, and M 1 is
R 4 is hydroxy, methyl, BH 3 , or —SR 5 ; wherein:
R 5 is hydrogen, —CH 2 OC(O)R 6 , —CH 2 OC(O)OR 6 , —CH 2 CH 2 SC(O)R 6 , or —CH 2 CH 2 S—SCH 2 R 6 ; and
R 6 is C 6-10 aryl, heteroaryl, heterocycloalkyl, C 3-12 cycloalkyl, or optionally substituted C 1-20 alkyl;
or an enantiomer, diastereomer, or pharmaceutically acceptable salt form thereof.
47 . The pharmaceutical composition of claim 46 , wherein R 1 and R 2 are, independently, C 1-3 alkoxy or C 1-3 alkyl, wherein the C 1-3 alkoxy is further optionally substituted with one to seven halogen, methoxy, or optionally substituted C 6-10 aryl, and the C 1-3 alkyl is substituted with one to three substituents that are fluoro, chloro, bromo, iodo or hydroxy.
48 . The pharmaceutical composition of claim 47 , wherein the C 6-10 aryl is optionally substituted with one or two fluoro, chloro, bromo, iodo, C 1-3 alkoxy, C 1-3 alkyl, hydroxy, nitro or cyano.
49 . The pharmaceutical composition of claim 46 , wherein R 1 and R 2 are, independently, F, H, or OH.
50 . The pharmaceutical composition of claim 46 , wherein R 1 is H or F.
51 . The pharmaceutical composition of claim 46 , wherein R 2 is H.
52 . The pharmaceutical composition of claim 46 , wherein R 3 is H.
53 . The pharmaceutical composition of claim 46 , wherein L is CH 2 .
54 . The pharmaceutical composition of claim 46 , wherein M is P(O)(OH), P(O)(SH), or S(O) 2 .
55 . The pharmaceutical composition of claim 46 , wherein M 1 is S(O) 2 , P(O)(OH), or P(O)(SH).
56 . The pharmaceutical composition of claim 46 , wherein X 1 and X 2 are, independently, O or CH 2 .
57 . The pharmaceutical composition of claim 46 , wherein Y and Y 1 are, independently, O or NH.
58 . The pharmaceutical composition of claim 46 , wherein B 1 is
59 . The pharmaceutical composition of claim 46 , wherein the pharmaceutical composition is in a solid oral dosage form, syrup form, an elixir or a suspension.
60 . A method of treating a disease, syndrome, or condition modulated by STING in a subject in need thereof, comprising administering the pharmaceutical composition of claim 46 to the subject.
61 . A method of treating a disease, syndrome, or condition affected by the agonism of STING in a subject in need thereof, comprising administering the pharmaceutical composition of claim 46 to the subject.
62 . A method of treating a disease, syndrome, or condition that is viral infection, melanoma, colon cancer, breast cancer, prostate cancer, lung cancer, or fibrosarcoma, comprising administering the pharmaceutical composition of claim 46 to a subject in need thereof.
63 . The method of claim 62 , wherein said disease, syndrome, or condition is melanoma, colon cancer, breast cancer, prostate cancer, lung cancer, or fibrosarcoma.
64 . The method of claim 62 , wherein the viral infection is hepatitis B.Cited by (0)
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