US2022213114A1PendingUtilityA1
Pyranopyrazole and pyrazolopyridine immunomodulators for treatment of autoimmune diseases
Est. expiryNov 29, 2037(~11.4 yrs left)· nominal 20-yr term from priority
A61P 37/00C07D 471/04C07D 519/00C07D 491/052A61K 31/437A61K 31/4709
61
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Claims
Abstract
Pyranoyrazoles and pyrazolopyridines of formula I or formula II are disclosed:These compounds inhibit Coagulation Factor XIIa in the presence of thrombin and other coagulation factors. They are useful to treat autoimmune diseases.
Claims
exact text as granted — not AI-modified1 . A compound of formula I or formula II:
wherein
R 1 is an optionally substituted bicyclic ring system;
R 2 is chosen from hydrogen, halogen, hydroxy, amino, cyano, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )alkylamino, di(C 1 -C 4 )alkylamino, (C 1 -C 4 )acylamino, (C 1 -C 4 )fluoroalkyl, (C 1 -C 4 )fluoroalkoxy, and (C 1 -C 6 )oxaalkyl;
one of X 1 and X 2 is chosen from —O—, and —N(QR)—, and the other is —CR 3 R 4 —;
Q is chosen from a direct bond, —CH 2 —, —C(═O)—, —C(═O)O—, and —C(═O)NR 6 —;
R 3 , R 4 , R 6 and R 7 are independently chosen from hydrogen and (C 1 -C 6 )alkyl; and
R 5 is chosen from hydrogen, (C 1 -C 6 )alkyl, hydroxy(C 2 -C 6 )alkyl, a three- to seven-membered carbocycle, and a three- to seven-membered heterocycle.
2 . A compound according to claim 1 wherein R 1 is a 6:6 or 6:5 bicycle optionally substituted with one to three substituents chosen from halogen, hydroxy, amino, cyano, oxo, (C 1 -C 6 )aliphatic hydrocarbyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )alkylamino, di(C 1 -C 4 )alkylamino, (C 1 -C 4 )acylamino, (C 1 -C 4 )alkylsulfonyl, [(C 1 -C 4 )alkylsulfonyl]amino, (C 1 -C 4 )fluoroalkyl, (C 1 -C 4 )fluoroalkoxy, (C 1 -C 6 )oxaalkyl, aryl, and heteroaryl.
3 . A compound according to claim 2 , wherein the optionally substituted bicyclic ring system is chosen from an optionally substituted indole, isoindole, oxindole, tetrahydroindole, tetralin, indoline, isoindoline, tetrahydroquinoline, tetrahydroisoquinoline, 3,4-dihydro-1H-isochromene, 3,4-dihydro-2H-chromene, benzofuran, dihydrobenzofuran, tetrahydrobenzofuran, benzothiophene, tetrahydrobenzothiophene, indazole, tetrahydroindazole, 2,3-dihydro-1H-indene, naphthalene, tetrahydronaphthalene, naphthyridine, tetrahydronaphthyridine, and isochroman.
4 . A compound according to claim 2 wherein R 1 is a nitrogenous bicycle.
5 . A compound according to claim 4 wherein R 1 is optionally substituted tetrahydroquinoline, indole, or tetrahydroindole.
6 . A compound according to claim 3 wherein R 1 is optionally substituted with one or more of halogen, (C 1 -C 6 )aliphatic hydrocarbyl, (C 1 -C 4 )fluoroalkyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )acylamino, (C 1 -C 4 )alkylsulfonyl, phenyl, and pyridinyl.
7 . A compound according to claim 6 wherein R 1 is optionally substituted with one or two fluoro, chloro, bromo, methyl, ethyl, propyl, trifluoromethyl, methoxy, methanesulfonyl, acetamido, phenyl, and pyridinyl.
8 . A compound according to claim 2 , wherein R 1 is chosen from
wherein
R 10 is chosen from H, halogen, (C 1 -C 4 )alkyl, and (C 3 -C 6 )cycloalkyl;
R 11 is chosen from H and methoxy; and
R 12 is chosen from H and (C 1 -C 4 )alkyl.
9 . A compound according to claim 2 , wherein R 1 is
wherein
R 13 and R 14 are chosen independently from H, halogen, (C 1 -C 4 )alkyl, fluoro(C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )acylamino (C 1 -C 4 )alkylsulfonyl, phenyl, and pyridinyl; and
R 15a and R 15b are chosen independently from —H, and —(C 1 -C 4 )alkyl or, taken together, R 15a and R 15b are oxo.
10 . A compound according to claim 9 , wherein the carbon marked with an asterisk is >90% e.e. in the (R) absolute configuration.
11 . A compound according to claim 9 , wherein the carbon marked with an asterisk is >90% e.e. in the (S) absolute configuration.
12 . A compound according to claim 6 , wherein R 1 is an optionally substituted tetrahydro-1,8-naphthyridine.
13 . A compound according to claim 1 wherein X 1 is —CR 3 R 4 — and X 2 is —O—.
14 . A compound according to claim 1 wherein X 1 is —O— and X 2 is —CR 3 R 4 —.
15 . A compound according to claim 1 wherein X 1 is —CR 3 R 4 — and X 2 is —N(QR 5 )—.
16 . A compound according to claim 1 wherein X 1 is —N(QR 5 )— and X 2 is —CR 3 R 4 —.
17 . (canceled)
18 . (canceled)
19 . (canceled)
20 . A compound according to claim 1 wherein R 3 and R 4 are both hydrogen.
21 . A compound according to claim 1 wherein Q is chosen from a direct bond, —CH 2 —, —C(═O)—, —C(═O)O—, and —C(═O)NR 6 —, and R 6 is hydrogen or methyl.
22 . A compound according to claim 21 wherein R 5 is chosen from H, (C 1 -C 4 )alkyl, (C 3 -C 6 )cycloalkyl, hydroxy(C 2 -C 6 )alkyl, fluoromethyl, difluoromethyl, phenyl, pyridinyl, oxetanyl, tetrahydrofuranyl, and tetrahydropyranyl.
23 . (canceled)
24 . A compound according to claim 1 of formula I:
25 . A compound according to claim 24 wherein R 3 and R 4 are both hydrogen; Q is chosen from a direct bond, —CH 2 —, —C(═O)—, —C(═O)O—, and —C(═O)NR 6 —; R 6 is hydrogen or methyl; and R 5 is chosen from H, (C 1 -C 4 )alkyl, (C 3 -C 6 )cycloalkyl, fluoromethyl, difluoromethyl, phenyl, pyridinyl, oxetanyl, tetrahydrofuranyl, and tetrahydropyranyl.
26 . A method for inhibiting Factor XIIa in a subject comprising administering to said subject an inhibitory amount of a compound according to claim 1 .
27 . (canceled)
28 . A method for selectively inhibiting Factor XIIa in the presence of thrombin and kallikrein, said method comprising contacting an inhibitory amount of a compound according to claim 1 with Factor XIIa.
29 . (canceled)
30 . (canceled)
31 . A method for treating inflammation in a patient, said method comprising administering to said patient a therapeutically effective amount of a compound according to claim 1 .
32 .- 35 . (canceled)Join the waitlist — get patent alerts
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