US2021040092A1PendingUtilityA1
Inhibitors of influenza viruses replication
Est. expiryAug 1, 2031(~5 yrs left)· nominal 20-yr term from priority
Inventors:Paul S. CharifsonMichael P. ClarkUpal K. BandarageRandy S. BethielMichael BoydIoana DaviesHongbo DengJohn P. DuffyLuc FarmerHuai GaoWenxin GuJoseph M. KennedyBrain LedfordMark LedeboerFrancois MaltaisEmanuele PerolaTiansheng Wang
A61P 31/16C07D 471/04A61K 31/506A61K 31/437A61K 31/444A61K 31/497C07F 9/6561A61K 45/06A61K 31/215A61K 31/351A61P 43/00A61P 31/00
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Claims
Abstract
or a pharmaceutically acceptable salt thereof, wherein the values of Structural Formula (I) are as described herein. A compound is represented by Structural Formula (I) or a pharmaceutically acceptable salt thereof, wherein the values of Structural Formula (I) are as described herein. A pharmaceutical composition comprises an effective amount of such a compound or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant or vehicle.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A compound represented by Structural Formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
X 1 is —F, —Cl, —CF 3 , —CN, or CH 3 ;
X 2 is —H, —F, or —Cl;
Z 1 is N or CH;
Z 2 is N or CR 0 ;
Z 3 is CH or N;
Y is —C(R 4 R 5 )—[C(R 6 R 7 )]n-Q or —C(R 4 )═C(R 6 )-Q
R 0 is —H, —F, or CN;
R 1 , R 2 , and R 3 are each and independently —CH 3 , —CH 2 F, —CF 3 , —C 2 H5, —CH 2 CH 2 F, —CH 2 CF 3 ; or optionally R 2 and R 3 , or R 1 , R 2 and R 3 , together with the carbon atom to which they are attached, form a 3-10 membered carbocyclic ring;
R 4 and R 5 are each and independently —H;
R 6 and R 7 are each and independently —H, —OH, —CH 3 , or —CF 3 ; or
optionally, R 5 and R 7 together with the carbon atoms to which they are attached form a cyclopropane ring; and
each Q is independently —C(O)OR, —OH, —CH 2 OH, —S(O)R′, —P(O)(OH) 2 , —S(O) 2 R′, —S(O) 2 —NR″R′″, or a 5-membered heterocycle selected from the group consisting of:
J Q is —H, —OH or —CH 2 OH;
R is —H or C 1-4 alkyl;
R′ is —OH, C 1-4 alkyl, or —CH 2 C(O)OH;
R″ is —H or —CH 3 ;
R′″ is —H, a 3-6 membered carbocyclic ring, or C 1-4 alkyl optionally substituted with one or more substituents selected from the group consisting of halogen, —OR a and —C(O)OR a ;
R a is —H or C 1-4 alkyl; and
n is 0 or 1.
2 . The compound of claim 1 , wherein X 1 is —F or —Cl.
3 . The compound of claim 1 or 2 , wherein X 2 is —F or —Cl.
4 . The compound of any one of claims 1 - 3 , wherein Z 1 is CH.
5 . The compound of any one of claims 1 - 3 , wherein Z 1 is N.
6 . The compound of any one of claims 1 - 5 , wherein Z 2 is N, C—F, or C—CN.
7 . The compound of any one of claims 1 - 6 , wherein R 1 , R 2 , and R 3 are each and independently —CH 3 or —C 2 H5; or optionally R 2 and R 3 , or R 1 , R 2 and R 3 , together with the carbon atom to which they are attached, form a 3-10 membered carbocyclic ring.
8 . The compound of any one of claims 1 - 6 , wherein R 1 , R 2 , and R 3 are each and independently —CH 3 , —CH 2 F, —CF 3 , or —C 2 H5; or R 1 is —CH 3 , and R 2 and R 3 together with the carbon atom to which they are attached form a 3-6 membered carbocyclic ring.
9 . The compound of claim 8 , wherein each of R 1 , R 2 , and R 3 is independently —CH 3 or —C 2 H 5 ; or R 1 is —CH 3 , and R 2 and R 3 together with the carbon atom to which they are attached form a 3-6 membered carbocyclic ring.
10 . The compound of any one of claims 1 - 9 , wherein:
R 6 and R 7 are each and independently —H, —OH, —CH 3 , or —CF 3 .
11 . The compound of any one of claims 1 - 10 , wherein each Q is independently —C(O)OR, —OH, —CH 2 OH, —S(O) 2 R′, —S(O) 2 —NR″R′″, or a 5-membered heterocycle selected from the group consisting of:
12 . The compound of claim 11 , wherein Q is —C(O)OR, —OH, —S(O) 2 R′, or —S(O) 2 —NR″R′″.
13 . The compound of any one of claims 1 - 12 , wherein:
R′ is —OH or —CH 2 C(O)OH; R″ is —H; and R′″ is —H, a 3-6 membered carbocyclic ring, or optionally substituted C 1-4 alkyl.
14 . The compound of any one of claims 1 - 13 , wherein R is —H.
15 . The compound of any one of claims 1 - 14 , wherein the compound is represented by Structural Formula II:
or a pharmaceutically acceptable salt thereof.
16 . The compound of claim 1 , wherein the compound is represented by Structural Formula III:
or a pharmaceutically acceptable salt thereof.
17 . The compound of claim 16 , wherein X 1 is —F or —Cl.
18 . The compound of claim 16 or 17 , wherein X 2 is —F or —Cl.
19 . The compound of any one of claims 16 - 18 , wherein Z 1 is CH.
20 . The compound of any one of claims 16 - 18 , wherein Z 1 is N.
21 . The compound of any one of claims 16 - 20 , wherein Z 2 is N, C—F, or C—CN.
22 . The compound of any one of claims 16 - 21 , wherein R 1 , R 2 , and R 3 are each and independently —CH 3 or —C 2 H 5 ; or optionally R 2 and R 3 , or R 1 , R 2 and R 3 , together with the carbon atom to which they are attached, form a 3-10 membered carbocyclic ring.
23 . The compound of any one of claims 16 - 21 , wherein R 1 , R 2 , and R 3 are each and independently —CH 3 , —CH 2 F, —CF 3 , or —C 2 H 5 ; or R 1 is —CH 3 , and R 2 and R 3 together with the carbon atom to which they are attached form a 3-6 membered carbocyclic ring.
24 . The compound of claim 23 , wherein each of R 1 , R 2 , and R 3 is independently —CH 3 or —C 2 H 5 ; or R 1 is —CH 3 , and R 2 and R 3 together with the carbon atom to which they are attached form a 3-6 membered carbocyclic ring.
25 . The compound of any one of claims 16 - 24 , wherein Q is —C(O)OR, —OH, —S(O) 2 R′, or —S(O) 2 —NR″R′″.
26 . The compound of any one of claims 16 - 25 , wherein:
R′ is —OH or —CH 2 C(O)OH; R″ is —H; and R′″ is —H, a 3-6 membered carbocyclic ring, or optionally substituted C 1-4 alkyl.
27 . The compound of any one of claims 16 - 26 , wherein R is —H.
28 . The compound of any one of claims 16 - 27 , wherein the compound is represented by Structural Formula (IV) or (V):
or a pharmaceutically acceptable salt thereof.
29 . The compound of claim 1 , wherein the compound is represented by any one of Structural Formulae (VI)-(X):
or a pharmaceutically acceptable salt thereof, wherein:
R 1 , R 2 , and R 3 are each and independently —CH 3 , —CH 2 F, —CF 3 , —C 2 H5, —CH 2 CH 2 F, —CH 2 CF 3 ; and
ring P is a 3-6 membered carbocyclic ring.
30 . The compound of claim 29 , wherein X 1 is —F or —Cl.
31 . The compound of claim 29 or 30 , wherein X 2 is —F or —Cl.
32 . The compound of any one of claims 29 - 31 , wherein Z 1 is CH.
33 . The compound of any one of claims 29 - 31 , wherein Z 1 is N.
34 . The compound of any one of claims 29 - 33 , wherein Z 2 is N, C—F, or C—CN.
35 . The compound of any one of claims 29 - 34 , wherein R 1 , R 2 , and R 3 are each and independently —CH 3 or —C 2 H5.
36 . The compound of any one of claims 29 - 35 , wherein:
R′ is —OH or —CH 2 C(O)OH; R″ is —H; and R′″ is —H, a 3-6 membered carbocyclic ring, or optionally substituted C 1-4 alkyl.
37 . The compound of any one of claims 29 - 36 , wherein R is —H.
38 . The compound of claim 1 , selected from any one of the compounds depicted in FIG. 1 or a pharmaceutically acceptable salt thereof.
39 . A pharmaceutical composition, comprising a compound according to any one of claims 1 - 38 , and a pharmaceutically acceptable carrier, adjuvant or vehicle.
40 . A method of inhibiting the replication of influenza viruses in a biological sample or patient, comprising the step of administering to said biological sample or patient an effective amount of a compound as described in any one of claims 1 - 38 .
41 . The method of claim 40 , further comprising co-administering an additional therapeutic agent.
42 . The method of claim 41 , wherein the additional therapeutic agent is selected from an antiviral agent or an Influenza vaccine.
43 . A method of reducing the amount of influenza viruses in a biological sample or in a patient, comprising administering to said biological sample or patient an effective amount of a compound as described in any one of claims 1 - 38 .
44 . A method of treating influenza in a patient, comprising administering to said patient an effective amount of a compound as described in any one of claims 1 - 38 .
45 . A method preparing a compound represented by Structural Formula (I):
or a pharmaceutically acceptable salt thereof, comprising the steps of:
i) reacting compound A:
with compound B:
to form a compound represented by Structural Formula (XX):
and
ii) deprotecting the G group of the compound of Structural Formula (XX) under suitable conditions to form the compound of Structural Formula (I), wherein:
the variables of Structural Formulae (I) and (XX), and compounds (A) and (B) are independently as defined in any one of claims 1 - 38 ; and
L 2 is a halogen; and
when Z 1 is N, G is trityl; when Z 1 is CH, G is tosyl or trityl.
46 . The method of claim 45 , wherein L 2 is Br or Cl.
47 . A method preparing a compound represented by Structural Formula (I):
or a pharmaceutically acceptable salt thereof, comprising the steps of:
i) reacting compound K or L:
with compound D: NH 2 —Z 3 ((CR 1 R 2 R 3 )—Y to form a compound represented by Structural Formula (XX):
and
ii) deprotecting the G group of the compound of Structural Formula (XX) under suitable conditions to form the compound of Structural Formula (I), wherein:
the variables of Structural Formulae (I) and (XX), and compounds (L), (K), and (D) are each and independently as defined in any one of claims 1 - 38 ; and
when Z 1 is N, G is trityl; when Z 1 is CH, G is tosyl or trityl.
48 . A method preparing a compound represented by Structural Formula (I):
or a pharmaceutically acceptable salt thereof, comprising the steps of:
i) reacting Compound (G) with Compound (D):
NH 2 —Z 3 ((CR 1 R 2 R 3 )—Y (D),
under suitable conditions to form a compound represented by Structural Formula (XX):
and
ii) deprotecting the G group of the compound of Structural Formula (XX) under suitable conditions to form the compound of Structural Formula (I), wherein:
the variables of Structural Formulae (I) and (XX), and Compounds (G) and (D) are each and independently as defined in any one of claims 1 - 38 ;
L 1 is a halogen; and
when Z 1 is N, G is trityl; when Z 1 is CH, G is tosyl or trityl.
49 . The method of claim 48 , wherein L 1 is Br or Cl.
50 . A compound represented by Structural Formula (XX) or a pharmaceutically acceptable salt thereof:
wherein the variables of Structural Formula (XX) are each and independently as defined in any one of claims 1 - 38 ; and
when Z 1 is N, G is trityl; when Z 1 is CH, G is tosyl or trityl.Cited by (0)
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