US2021186969A1PendingUtilityA1
Aza-pyridone compounds and uses thereof
Est. expirySep 12, 2033(~7.1 yrs left)· nominal 20-yr term from priority
A61K 31/215A61K 31/196A61P 31/14A61P 43/00C07D 487/04A61P 31/16C07B 2200/05A61K 31/13A61K 31/351A61K 31/5025A61K 31/4965C07B 59/002A61K 31/495A61K 38/212A61K 31/5377A61K 31/7056A61K 45/06A61K 31/4985A61K 2300/00
73
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Claims
Abstract
Disclosed herein are aza-pyridone compounds, pharmaceutical compositions that include one or more aza-pyridone compounds, and methods of synthesizing the same. Also disclosed herein are methods of ameliorating and/or treating a disease and/or a condition, including an orthomyxovirus infection, with an aza-pyridone compounds. Examples of an orthomyxovirus viral infection include an influenza infection.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (I) has the structure:
wherein:
is a single bond or double bond;
R 1 is selected from the group consisting of hydrogen, an unsubstituted C 1-4 alkyl, —C(═O)Y 1 , —C(═O)—O—Y 1 , —(CH 2 )—O—(C═O)—Y 1 , —(CH 2 )—O—(C═O)—O—Y 1 , —(CHCH 3 )—O—(C═O)—Y 1 and —(CHCH 3 )—O—(C═O)—O—Y 1 ;
R 2 is selected from the group consisting of hydrogen, an optionally substituted C 1-6 alkyl, an optionally substituted heterocyclyl, an optionally substituted cycloalkyl(C 1-6 alkyl), an optionally substituted aryl(C 1-6 alkyl), an optionally substituted heteroaryl(C 1-6 alkyl) and an optionally substituted heterocyclyl(C 1-6 alkyl);
R 3a and R 3b are independently hydrogen or an optionally substituted C 1-4 alkyl;
R 4 and R 5 are independently selected from the group consisting of hydrogen, an optionally substituted aryl, an optionally substituted aryl(C 1-6 alkyl) an optionally substituted heteroaryl and an optionally substituted heteroaryl(C 1-6 alkyl), provided that at least one of R 4 and R 5 is not hydrogen; or
R 4 and R 5 are taken together to form an optionally substituted tricyclic cycloalkenyl or an optionally substituted tricyclic heterocyclyl;
R 6 is selected from the group consisting of hydrogen, halogen, —CN, an optionally substituted C 1-6 alkyl, an optionally substituted aryl, an optionally substituted heteroaryl, —CH 2 OH, —CH(Y 2 )(OH) and —C(O)Y 2 ;
Y 1 and Y 2 are independently selected from the group consisting of an optionally substituted C 1-6 alkyl, an optionally substituted C 3-6 cycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl, a mono-substituted amino group, a di-substituted amino and —C(R 7 )NHR 8 ; and
R 7 and R 8 are independently hydrogen or an optionally substituted C 1-4 alkyl.
2 . The compound of claim 1 , wherein R 4 is hydrogen.
3 . The compound of claim 1 , wherein R 4 is an optionally substituted aryl.
4 . The compound of claim 3 , wherein the optionally substituted aryl is an optionally substituted phenyl.
5 . The compound of claim 1 , wherein R 4 is an optionally substituted aryl(C 1-6 alkyl).
6 . The compound of claim 1 , wherein R 4 is an optionally substituted heteroaryl.
7 . The compound of claim 6 , wherein the optionally substituted heteroaryl is an optionally substituted imidazole or an optionally substituted pyrazole.
8 . The compound of claim 1 , wherein R 4 is an optionally substituted heteroaryl(C 1-6 alkyl).
9 . The compound of any one of claims 1 - 8 , wherein R 5 is an optionally substituted aryl.
10 . The compound of claim 9 , wherein the optionally substituted aryl is an optionally substituted phenyl.
11 . The compound of any one of claims 1 - 8 , wherein R 5 is an optionally substituted aryl(C 1-6 alkyl).
12 . The compound of any one of claims 1 - 8 , wherein R 5 is an optionally substituted heteroaryl.
13 . The compound of any one of claims 1 - 8 , wherein R 5 is an optionally substituted heteroaryl(C 1-6 alkyl).
14 . The compound of claim 1 , wherein R 4 and R 5 are each a substituted phenyl substituted with one or more group selected from fluoro, chloro, iodo, C 1-4 alkyl, C 2-4 alkynyl, hydroxy, C 1-4 alkoxy, an optionally substituted phenyl, cyano, NC—(CH 2 )—, H 2 N—C(═O)—(CH 2 )—, O-amido(CH 2 )—, optionally substituted
and optionally substituted
15 . The compound of claim 1 , wherein R 4 and R 5 are taken together to form an optionally substituted tricyclic heterocyclyl.
16 . The compound of claim 15 , wherein the optionally substituted tricyclic heterocyclyl is an optionally substituted moiety selected from the group consisting of:
17 . The compound of claim 15 or 16 , wherein the tricyclic heterocyclyl is substituted with one or more group selected from fluoro, chloro, iodo and C 1-4 alkyl.
18 . The compound of any one of claims 1 - 17 , wherein R 2 is hydrogen.
19 . The compound of any one of claims 1 - 17 , wherein R 2 is an optionally substituted C 1-6 alkyl.
20 . The compound of claim 19 , wherein the optionally substituted C 1-6 alkyl is substituted with substituent selected from the group consisting of halogen, haloalkyl, hydroxy and alkoxy.
21 . The compound of any one of claims 1 - 17 , wherein R 2 is an optionally substituted aryl(C 1-6 alkyl).
22 . The compound of any one of claims 1 - 21 , wherein R 1 is hydrogen.
23 . The compound of any one of claims 1 - 21 , wherein R 1 is an unsubstituted C 1-4 alkyl.
24 . The compound of any one of claims 1 - 21 , wherein R 1 is —C(═O)Y 1 , —C(═O)—O—Y 1 , —(CH 2 )—O—(C═O)—Y 1 , —(CH 2 )—O—(C═O)—O—Y 1 , —(CHCH 3 )—O—(C═O)—Y 1 or —(CHCH 3 )—O—(C═O)—O—Y 1 .
25 . The compound of claim 24 , R 1 is —C(═O)Y 1 .
26 . The compound of claim 24 , R 1 is —C(═O)—O—Y 1 .
27 . The compound of claim 24 , R 1 is —(CH 2 )—O—(C═O)—Y 1 .
28 . The compound of claim 24 , R 1 is —(CH 2 )—O—(C═O)—O—Y 1 .
29 . The compound of claim 24 , R 1 is —(CHCH 3 )—O—(C═O)—Y 1 .
30 . The compound of claim 24 , R 1 is —(CHCH 3 )—O—(C═O)—O—Y 1 .
31 . The compound of any one of claims 24 - 30 , Y 1 is an optionally substituted C 1-6 alkyl.
32 . The compound of any one of claims 24 - 30 , Y 1 is an optionally substituted C 3-6 cycloalkyl.
33 . The compound of any one of claims 24 - 30 , Y 1 is an optionally substituted aryl.
34 . The compound of any one of claims 24 - 30 , Y 1 is an optionally substituted heteroaryl.
35 . The compound of any one of claims 24 - 30 , Y 1 is an optionally substituted heterocyclyl.
36 . The compound of any one of claims 24 - 30 , Y 1 is a mono-substituted amino group.
37 . The compound of any one of claims 24 - 30 , Y 1 is a di-substituted amino
38 . The compound of any one of claims 24 - 30 , Y 1 is —C(R 7 )NHR 8 .
39 . The compound of claim 38 , wherein R 7 is hydrogen.
40 . The compound of claim 38 , wherein R 7 is an optionally substituted C 1-4 alkyl.
41 . The compound of any one of claims 38 - 40 , wherein R 8 is hydrogen.
42 . The compound of any one of claims 38 - 40 , wherein R 8 is an optionally substituted C 1-4 alkyl.
43 . The compound of claim 38 , wherein —C(R 7 )NHR 8 is selected from
wherein Het can be an optionally substituted heteroaryl or an optionally substituted heterocyclyl.
44 . The compound of any one of claims 1 - 43 , wherein R 6 is hydrogen.
45 . The compound of any one of claims 1 - 43 , wherein R 6 is halogen or —CN.
46 . The compound of any one of claims 1 - 43 , wherein R 6 is an optionally substituted C 1-6 alkyl, an optionally substituted aryl or an optionally substituted heteroaryl.
47 . The compound of any one of claims 1 - 43 , wherein R 6 is —CH 2 OH, —CH(Y 2 )(OH) or —C(O)Y 2 .
48 . The compound of any one of claims 1 - 47 , wherein R 3a is hydrogen.
49 . The compound of any one of claims 1 - 47 , wherein R 3a is an optionally substituted C 1-4 alkyl.
50 . The compound of any one of claims 1 - 49 , wherein R 3b is hydrogen.
51 . The compound of any one of claims 1 - 49 , wherein R 3b is an optionally substituted C 1-4 alkyl.
52 . The compound of any one of claims 1 - 51 , wherein is a single bond.
53 . The compound of any one of claims 1 - 51 , wherein is a double bond.
54 . The compound of claim 1 , wherein the compound is selected from the group consisting of:
or a pharmaceutically acceptable salt of the foregoing.
55 . The compound of claim 1 , wherein the compound is selected from the group consisting of:
or a pharmaceutically acceptable salt of the foregoing.
56 . The compound of claim 1 , wherein the compound is selected from the group consisting of:
or a pharmaceutically acceptable salt of the foregoing.
57 . The compound of claim 1 , wherein the compound is selected from the group consisting of:
or a pharmaceutically acceptable salt of the foregoing.
58 . A pharmaceutical composition comprising an effective amount of a compound of any one of claims 1 - 57 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, excipient, or combination thereof.
59 . A method for ameliorating or treating an orthomyxovirus infection comprising administering an effective amount of a compound of any one of claims 1 - 57 , or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 58 .
60 . A method for inhibiting replication of an orthomyxovirus virus comprising contacting a cell infected with the virus with an effective amount of a compound of any one of claims 1 - 57 , or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 58 .
61 . A method for contacting a cell infected with an orthomyxovirus virus comprising contacting a cell infected with the virus with an effective amount of a compound of any one of claims 1 - 57 , or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 58 .
62 . A method for ameliorating or treating an orthomyxovirus infection in combination with one or more agents comprising administering or contacting a cell with an effective amount of a compound of any one of claims 1 - 57 , or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 58 .
63 . A method for inhibiting endonuclease activity of an influenza endonuclease comprising contacting the active site of the endonuclease with an effective amount of a compound of any one of claims 1 - 57 , or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 58 .
64 . The method of any one of claims 59 - 61 , wherein the orthomyxovirus viral infection is influenza.
65 . The method of claim 62 , wherein the orthomyxovirus viral infection is an influenza virus infection; and wherein the one or more agents is selected from the group consisting of a neuraminidase inhibitor, a M2 protein inhibitor, a polymerase inhibitor, a PB2 inhibitor, amantadine, rimantadine, zanamivir, oseltamivir, peramivir, laninamivir, laninamivir octanoate, favipiravir, fludase, ADS-8902, an immuno-modulator, beraprost, Neugene®, ribavirin, CAS Reg. No. 1422050-75-6, CAS Reg. No. 1259366-34-1 (VX-787), FluMist Quadrivalent® (MedImmune), Fluarix® Quadrivalent (GlaxoSmithKline), Fluzone® Quadrivalent (Sanofi Pasteur), Flucelvax® (Novartis) and FluBlok® (Protein Sciences).
66 . The method of 65 , wherein the one or more agents is oseltamivir.
67 . The method of any one of claims 64 - 66 , wherein the influenza is influenza A.
68 . The method of any one of claims 64 - 66 , wherein the influenza is influenza B.
69 . The method of any one of claims 64 - 66 , wherein the influenza is influenza C.
70 . The method of any one of claims 64 - 66 , wherein the influenza is selected from the group consisting of H1N1, H3N2, H5N1 and H7N9.
71 . The method of any one of claims 59 - 70 , wherein the compound of any one of claims 1 - 57 , or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 58 is effective against more than 1 subtype of influenza.
72 . Use of an effective amount of a compound of any one of claims 1 - 57 , or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 58 in the preparation of a medicament for ameliorating or treating an orthomyxovirus viral infection.
73 . Use of an effective amount of a compound of any one of claims 1 - 57 , or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 58 in the preparation of a medicament for inhibiting replication of an orthomyxovirus virus.
74 . Use of an effective amount of a compound of any one of claims 1 - 57 , or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 58 in the preparation of a medicament for contacting a cell infected with an orthomyxovirus virus.
75 . Use of an effective amount of a compound of any one of claims 1 - 57 , or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 58 in the preparation of a medicament for ameliorating or treating an orthomyxovirus viral infection in combination with one or more agents comprising administering or contacting a cell with an effective amount of the compound, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition.
76 . Use of an effective amount of a compound of any one of claims 1 - 57 , or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 58 in the preparation of a medicament for inhibiting endonuclease activity of an influenza endonuclease.
77 . The use of any one of claims 72 - 74 , wherein the orthomyxovirus viral infection is influenza.
78 . The use of claim 75 , wherein the orthomyxovirus viral infection is an influenza virus infection; and wherein the one or more agents is selected from the group consisting of a neuraminidase inhibitor, a M2 protein inhibitor, a polymerase inhibitor, a PB2 inhibitor, amantadine, rimantadine, zanamivir, oseltamivir, peramivir, laninamivir, laninamivir octanoate, favipiravir, fludase, ADS-8902, an immuno-modulator, beraprost, Neugene®, ribavirin, CAS Reg. No. 1422050-75-6, CAS Reg. No. 1259366-34-1 (VX-787), FluMist Quadrivalent® (MedImmune), Fluarix® Quadrivalent (GlaxoSmithKline), Fluzone® Quadrivalent (Sanofi Pasteur), Flucelvax® (Novartis) and FluBlok® (Protein Sciences).
79 . The use of 78 , wherein the one or more agents is oseltamivir.
80 . The use of any one of claims 77 - 79 , wherein the influenza is influenza A,
81 . The use of any one of claims 77 - 79 , wherein the influenza is influenza B.
82 . The use of any one of claims 77 - 79 , wherein the influenza is influenza C.
83 . The use of any one of claims 77 - 79 , wherein the influenza is selected from the group consisting of H1N1, H3N2, H5N1 and H7N9.
84 . The use of any one of claims 72 - 83 , wherein the compound of any one of claims 1 - 57 , or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 58 is effective against more than 1 subtype of influenza.Join the waitlist — get patent alerts
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