US2022033383A1PendingUtilityA1
Functionalized peptides as antiviral agents
Est. expiryJul 20, 2040(~14 yrs left)· nominal 20-yr term from priority
Inventors:Joseph PanareseDexter DavisNathaniel Thomas KentonSamuel BartlettSean M. RaffertyYat Sun Or
C07D 405/14C07D 403/14C07D 403/12C07D 401/14A61K 31/454A61K 31/404A61K 31/403A61P 31/14A61K 31/4155C07K 5/06C07K 5/02A61K 38/00A61K 31/4045C07K 5/06165A61K 31/4025C07K 5/06139C07K 5/0202C07K 5/0823
67
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Claims
Abstract
The present invention discloses compounds of Formula (I), and pharmaceutically acceptable salts, thereof:which inhibit coronavirus replication activity. The invention further relates to pharmaceutical compositions comprising a compound of Formula (I) or a pharmaceutically acceptable slat thereof, and methods of treating or preventing a coronavirus infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
Claims
exact text as granted — not AI-modified1 . A compound represented by Formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
A is selected from:
1) Optionally substituted —C 1 -C 8 alkyl;
2) Optionally substituted —C 3 -C 12 cycloalkyl;
3) Optionally substituted 3- to 12-membered heterocycloalkyl;
4) Optionally substituted aryl; and
5) Optionally substituted heteroaryl;
L 1 is —C(R 11 R 12 )—;
L 2 is —C(R 11 R 12 )—;
n1 is 0, 1, 2, 3, or 4;
X is optionally substituted —C 1 -C 6 alkyl, —CN, —C(O)R 15 , —C(O)NR 13 R 14 , or —C(O)C(O)NR 13 R 14 ;
Q is —C(R 11 ′R 12 ′)—;
n2 is 0, 1, 2, 3, or 4;
Each R 11 , R 11 ′, R 12 , and R 12 ′ are each independently selected from:
1) Hydrogen;
2) Halogen;
3) —OR 16 ;
4) —SR 16 ;
5) —NR 13 R 14 ;
6) —OC(O)NR 13 R 14 ;
7) Optionally substituted —C 1 -C 6 alkyl;
8) Optionally substituted —C 3 -C 8 cycloalkyl;
9) Optionally substituted 3- to 8-membered heterocycloalkyl;
10) Optionally substituted aryl; and
11) Optionally substituted heteroaryl;
alternatively, R 11 and R 12 are taken together with the carbon atom to which they are attached to form an optionally substituted 3- to 8-membered carbocyclic or heterocyclic ring;
alternatively, when n1 is not 0, two adjacent Ru groups are taken together with the carbon atoms to which they are attached to form an optionally substituted 3- to 8-membered carbocyclic or heterocyclic ring;
alternatively, n1 is 2, 3 or 4, and the Ru groups on two non-adjacent carbon atoms are taken together with the carbon atoms to which they are attached to form an optionally substituted bridging moiety;
R 13 and R 14 are each independently selected from:
1) Hydrogen;
2) Optionally substituted —C 1 -C 6 alkyl;
3) Optionally substituted —C 3 -C 8 cycloalkyl;
4) Optionally substituted 3- to 8-membered heterocycloalkyl;
5) Optionally substituted aryl;
6) Optionally substituted arylalkyl;
7) Optionally substituted heteroaryl;
8) Optionally substituted heteroarylalkyl;
9) —C(O)R 15 ;
10) —S(O) 2 R 16 ; and
11) —NH 2 ;
alternatively, R 13 and R 14 are taken together with the nitrogen atom to which they are attached to form an optionally substituted 3- to 8-membered heterocyclic ring;
R 15 is selected from:
1) Hydrogen;
2) Halogen;
3) —OH;
4) Optionally substituted —C 1 -C 6 alkyl;
5) Optionally substituted —C 1 -C 6 alkoxy;
6) Optionally substituted —C 3 -C 8 cycloalkyl;
7) Optionally substituted 3- to 8-membered heterocycloalkyl;
8) Optionally substituted aryl;
9) Optionally substituted arylalkyl;
10) Optionally substituted heteroaryl; and
11) Optionally substituted heteroarylalkyl;
R 16 is selected from:
1) Hydrogen;
2) —OH;
3) Optionally substituted —C 1 -C 6 alkyl;
4) Optionally substituted —C 3 -C 8 cycloalkyl;
5) Optionally substituted 3- to 8-membered heterocycloalkyl;
6) Optionally substituted aryl;
7) Optionally substituted arylalkyl;
8) Optionally substituted heteroaryl, and
9) Optionally substituted heteroarylalkyl.
2 . The compound of claim 1 , wherein A is derived from one of the following, and optionally substituted:
3 . The compound of claim 1 , wherein A is —C(NR 13 R 14 )R 24 R 25 , wherein R 24 is hydrogen, halogen, optionally substituted —C 1 -C 6 alkyl, optionally substituted —C 1 -C 6 alkoxy, optionally substituted —C 3 -C 12 cycloalkyl, optionally substituted 3- to 12-membered heterocycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl; R 25 is hydrogen or halogen; and R 13 and R 14 are as defined in claim 1 .
4 . The compound of claim 1 , wherein X is —CN, —C(O)CH 2 OC(O)R 21 , —C(O)CH 2 C(O) 2 R 21 , —C(O)CH 2 OR 21 , —C(O)CH 2 R 22 , —C(O)C(O)NHR 21 , —C(O)R 21 , —CHR 21 OC(O)R 21 , —CHR 21 C(O) 2 R 21 , —CHR 21 (OR 21 ), or —CH(OR 21 ) 2 , R 21 is hydrogen, optionally substituted —C 1 -C 6 alkyl, optionally substituted —C 3 -C 8 cycloalkyl, optionally substituted 3- to 8-membered heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; and R 22 is halogen, or —NR 13 R 14 , and R 13 and R 14 are as defined in claim 1 .
5 . The compound of claim 1 , represented by one of Formulas (IV-1) to (IV-4), or a pharmaceutically acceptable salt thereof:
wherein R 17 is halogen, —OR 16 , —SR 16 ; —NR 13 R 14 ; —OC(O)NR 13 R 14 ; optionally substituted —C 1 -C 6 alkyl; optionally substituted —C 3 -C 8 cycloalkyl; optionally substituted 3- to 8-membered heterocycloalkyl; optionally substituted aryl; or optionally substituted heteroaryl; m1 is 0, 1, 2, or 3; m2 is 0, 1, 2, 3, or 4; A, R 11 , R 11 ′, and X are as defined in claim 1 .
6 . The compound of claim 1 , represented by one of Formula (V-1), Formula (V-2), Formula (V-3), or Formula (V-4), or a pharmaceutically acceptable salt thereof:
wherein each T is CR 11 ; each U is —C(R 11 R 12 )—; each V is —O—, —S—, —C(R 11 R 12 )—, or —N(R 13 R 14 )—; m is 0, 1 or 2; m′ is 0, 1, 2, or 3; and A, Q, n2, Ru, R 12 , R 13 , R 14 , and X are as defined in claim 1 .
7 . The compound of claim 1 , represented by one of Formulas (VI-1a) to (VI-8a), or a pharmaceutically acceptable salt thereof:
wherein X and A are as defined in claim 1 .
8 . The compound of claim 1 , represented by one of Formulas (IX-1) to (IX-8), or a pharmaceutically acceptable salt thereof:
wherein R 32 is hydrogen, —F, C 1 , —CH 3 , —CF 3 or —OR; R 33 is —Cl, —Br, —OR 21 , —NHR 21 , or —OC(O)R 21 ; R 34 is R 21 ; R 21 is hydrogen, optionally substituted —C 1 -C 6 alkyl, optionally substituted —C 3 -C 8 cycloalkyl, optionally substituted 3- to 8-membered heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; and A are as defined in claim 1 .
9 . The compound of claim 1 , represented by one of Formulas (IX-1) to (IX-8), or a pharmaceutically acceptable salt thereof:
wherein R 24 is hydrogen, halogen, optionally substituted —C 1 -C 6 alkyl, optionally substituted —C 1 -C 6 alkoxy, optionally substituted —C 3 -C 12 cycloalkyl, optionally substituted 3- to 12-membered heterocycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl; R 25 is hydrogen or halogen; and X, R 13 and R 14 are as defined in claim 1 .
10 . The compound of claim 1 , represented by one of Formulas (XIII-1) to (XIII-4), or a pharmaceutically acceptable salt thereof:
wherein R 24 is hydrogen, halogen, optionally substituted —C 1 -C 6 alkyl, optionally substituted —C 1 -C 6 alkoxy, optionally substituted —C 3 -C 12 cycloalkyl, optionally substituted 3- to 12-membered heterocycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl; and R 15 and X are as defined in claim 1 .
11 . The compound of claim 1 , selected from the compounds set forth below or a pharmaceutically acceptable salt thereof:
Compound
Structure
1
2
3
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5
6
7
8
9
10
11
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13
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22
23
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12 . A pharmaceutical composition comprising a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
13 . A method of treating or preventing a virus infection, including a virus infection from an RNA-based virus, a coronavirus, a rhinovirus and a norovirus, in a subject susceptible to or suffering from the virus infection, the method comprising administering to the subject an inhibitor of a 3C protease enzyme wherein the inhibitor is a compound according to claim 1 , or a pharmaceutically acceptable salt thereof.
14 . A method of treating or preventing a coronavirus infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound or a combination of compounds according to claim 1 , or a pharmaceutically acceptable salt thereof.
15 . A method according to claim 13 , wherein the virus is a coronavirus selected from a 229E, NL63, OC43, HKU1, SARS-CoV or a MERS coronavirus.
16 . A method of treating or preventing a virus infection in a subject in need thereof, comprising administering to the subject an inhibitor of a 3C protease enzyme wherein the inhibitor comprises a compound according to claim 1 , or a pharmaceutically acceptable salt thereof.
17 . A method of inhibiting viral 3C protease or viral 3CL protease in a mammal, comprising administering to said subject an effective amount of a compound according to claim 1 , or a pharmaceutically acceptable salt thereof.
18 . The method according to claim 17 , wherein the subject is a human.
19 . A method of treating a respiratory disorder, including acute asthma, lung disease secondary to environmental exposures, acute lung infection, chronic lung infection, in a subject in need thereof, comprising administering to the subject a compound of claim 1 .
20 . The method according to claim 19 wherein the compound or pharmaceutical composition is administered orally, subcutaneously, intravenously or by inhalation.Join the waitlist — get patent alerts
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