US2021251957A1PendingUtilityA1
Substituted pyrrolizine compounds and uses thereof
Est. expiryAug 26, 2036(~10.1 yrs left)· nominal 20-yr term from priority
Inventors:Jinfa DuJoshua A. KaplanThorsten A. KirschbergTetsuya KobayashiScott E. LazerwithRick LeeJonathan William MedleyMichael L. MitchellPhilip Anthony MorganelliHyung-Jung PyunSophia L. ShevickNeil H. SquiresWilliam J. Watkins
C07D 519/00C07D 487/04A61P 31/20A61K 45/06A61K 31/4439A61K 31/03A61K 31/403A61K 31/38A61K 31/433A61K 31/675C07D 409/12A61K 31/4192A61K 31/16C07D 495/10A61K 31/4196A61K 31/407A61P 1/16A61K 31/4245C07D 405/12
70
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Claims
Abstract
This application relates generally to certain substituted pyrrolizine compounds, and pharmaceutical compositions which inhibit HBV replication, and methods of making and using them.
Claims
exact text as granted — not AI-modified1 . A compound of Formula (I),
or a pharmaceutically acceptable salt thereof,
wherein:
R 1 is C 1-6 alkyl optionally substituted with 1 to 3 R 1A , C 3-8 cycloalkyl optionally substituted with 1 to 4 R 1B , or 3 to 8 membered monocyclic or bicyclic heterocyclyl having 1 to 3 heteroatoms selected from N, O, and S, optionally substituted with 1 to 3 R 1C ;
each R 1A is independently halogen, —OH, —CN, C 1-2 haloalkyl, —C(O)NR X R Y , C 6-10 aryl optionally substituted with 1 to 3 R 1D , or a 5 to 8 membered heteroaryl having 1 to 3 heteroatoms selected from N, O, and S, optionally substituted with 1 to 3 R 1D , provided no more than 1 R 1A is C 6-10 aryl optionally substituted with 1 to 3 R 1D or 5 to 8 membered heteroaryl having 1 to 3 heteroatoms selected from N, O, and S;
each R 1B is independently —CN, halogen, C 1-6 alkyl optionally substituted with 1 to 3 —OH or —NR a R b , C 2-4 alkynyl, C 1-4 alkoxy, C 1-2 haloalkyl, C 3-6 cycloalkyl, —C(O)NR X R Y , or a 5 to 8 membered heteroaryl having 1 to 3 heteroatoms selected from N, O, and S optionally substituted with 1 to 3 R 1D , provided no more than 1 R 1B is C 3-6 cycloalkyl or 5 to 8 membered heteroaryl having 1 to 3 heteroatoms selected from N, O, and S;
each R 1C is independently C 1-6 alkyl, oxo, C 1-4 haloalkyl, —C(O)H, —C(O)C 1-4 alkyl, —C(O)OC 1-4 alkyl, or a 5 to 12 membered heteroaryl having 1 to 3 heteroatoms selected from N, O, and S optionally substituted with 1 to 3 R 1D , provided no more than 1 R 1C is a 5 to 12 membered heteroaryl having 1 to 3 heteroatoms selected from N, O, and S;
each R X is independently —H, C 3-6 cycloalkyl, C 1-6 alkyl optionally substituted with 1 to 3 R Z , 3 to 8 membered monocyclic or bicyclic heterocyclyl having 1 to 3 heteroatoms selected from N, O, and S, optionally substituted with 1 to 3 R Z ;
each R Y is independently —H or C 1-6 alkyl optionally substituted with 1 to 3 R Z ;
or R X and R Y are taken together to form a 3 to 8 membered monocyclic or bicyclic heterocyclyl having 1 to 3 heteroatoms selected from N, O, and S, optionally substituted with 1 to 3 R Z ;
wherein each R Z is independently halogen, methyl, ethyl, oxo, —OH, —S(O) 2 C 1-3 alkyl, or 3 to 8 membered monocyclic or bicyclic heterocyclyl having 1 to 3 heteroatoms selected from N, O, and S;
each R a is —H, C 1-3 alkyl, or a 3 to 8 membered monocyclic or bicyclic heterocyclyl having 1 to 3 heteroatoms selected from N, O, and S, optionally substituted with 1 to 3 R Z ;
each R b is —H or C 1-3 alkyl; or
R a and R b taken together form a 3 to 8 membered monocyclic or bicyclic heterocycle optionally substituted with 1 to 3 R Z ;
the moiety
is a pyrrolidine or a 5-7 membered bicyclic heterocycle having one nitrogen, optionally substituted with 1 to 6 R 2 groups;
wherein each R 2 is independently halogen, C 1-3 alkyl, —OH, or —OC 1-3 alkyl; R 3 is —H, halogen, or C 1-4 alkyl; R 4 is phenyl optionally substituted with 1 to 5 R 4A , or pyridinyl optionally substituted with 1 to 4 R 4B ; and each R 1D , R 4A , and R 4B are independently —CN, halogen, C 1-4 alkyl, —OC 1-4 alkyl, —OC 1-4 haloalkyl, or C 1-4 haloalkyl.
2 . (canceled)
3 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is phenyl optionally substituted with 1 to 3 R 4A .
4 . (canceled)
5 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is —Cl or —CH 3 .
6 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is —CH 3 .
7 . (canceled)
8 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the moiety s
each of which is optionally substituted with 1 to 6 R 2 .
9 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula (II)
wherein:
R 1 is C 1-6 alkyl optionally substituted with 1 to 3 R 1A , C 3-8 cycloalkyl optionally substituted with 1 to 4 R 1B , or 3 to 8 membered monocyclic or bicyclic heterocyclyl having 1 to 3 heteroatoms selected from N, O, and S, optionally substituted with 1 to 3 R 1C ;
each R 1A is independently halogen, —OH, —CN, C 1-2 haloalkyl, —C(O)NR X R Y , C 6-10 aryl optionally substituted with 1 to 3 R 1D , or a 5 to 8 membered heteroaryl having 1 to 3 heteroatoms selected from N, O, and S, optionally substituted with 1 to 3 R 1D , provided no more than 1 R 1A is C 6-10 aryl optionally substituted with 1 to 3 R 1D or 5 to 8 membered heteroaryl having 1 to 3 heteroatoms selected from N, O, and S;
each R 1B is independently halogen, C 1-6 alkyl optionally substituted with 1 to 3 —OH or —NR a R b , C 1-4 alkoxy, C 1-2 haloalkyl, —C(O)NR X R Y , or 5 to 8 membered heteroaryl having 1 to 3 heteroatoms selected from N, O, and S optionally substituted with 1 to 3 R 1D , provided no more than 1 R 1B is 5 to 8 membered heteroaryl having 1 to 3 heteroatoms selected from N, O, and S;
each R 1C is independently C 1-6 alkyl, oxo, C 1-4 haloalkyl, —C(O)H, —C(O)C 1-4 alkyl or —C(O)OC 1-4 alkyl;
each R X is independently —H, C 3-6 cycloalkyl, C 1-6 alkyl optionally substituted with 1 to 3 R Z , 3 to 8 membered monocyclic or bicyclic heterocyclyl having 1 to 3 heteroatoms selected from N, O, and S, optionally substituted with 1 to 3 R Z ;
each R Y is independently —H or C 1-6 alkyl optionally substituted with 1 to 3 R Z ;
or R X and R Y are taken together to form a 3 to 8 membered monocyclic or bicyclic heterocyclyl having 1 to 3 heteroatoms selected from N, O, and S, optionally substituted with 1 to 3 R Z
wherein each R Z is independently halogen, methyl, ethyl, oxo, —OH, —S(O) 2 C 1-3 alkyl, or 3 to 8 membered monocyclic or bicyclic heterocyclyl having 1 to 3 heteroatoms selected from N, O, and S;
each R a is —H, C 1-3 alkyl, or a 3 to 8 membered monocyclic or bicyclic heterocyclyl having 1 to 3 heteroatoms selected from N, O, and S, optionally substituted with 1 to 3 R Z ;
each R b is —H or C 1-3 alkyl; or
R a and R b taken together form a 3 to 8 membered monocyclic or bicyclic heterocyclyl optionally substituted with 1 to 3 R Z ;
each of R 2A , R 2B , R 2C , R 2D , R 2E , and R 2F are independently —H, halogen, C 1-3 alkyl, —OH, or —OC 1-3 alkyl, or R 2C or R 2D may be taken together with R 2E or R 2F to form a cyclopropyl group;
R 3 is halogen or methyl;
R 4 is phenyl optionally substituted with 1 to 5 R 4A , or pyridinyl, optionally substituted with 1 to 4 R 4B ; and
each R 1D , R 4A , and R 4B are independently —CN, halogen, C 1-4 alkyl, —OC 1-4 alkyl, —OC 1-4 haloalkyl, or C 1-4 haloalkyl.
10 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula (III)
11 . (canceled)
12 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula (IV):
13 . (canceled)
14 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is C 1-6 alkyl optionally substituted with 1 to 3 R 1A .
15 .- 17 . (canceled)
18 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is ethyl, propyl, or butyl optionally substituted with 1 to 3 R 1A , wherein each R 1A is independently C 1-2 haloalkyl, —OH, —C(O)NH 2 , —C(O)NH(C 1-3 alkyl), or —C(O)N(C 1-3 alkyl) 2 .
19 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is
20 . (canceled)
21 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is cyclopropyl or cyclobutyl, optionally substituted with 1 to 3 R 1B .
22 . (canceled)
23 . The compound claim 1 , or a pharmaceutically acceptable salt thereof, wherein each R 1B is independently fluoro, —CH 2 NR a R b or —C(O)NR X R Y .
24 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
R a is methyl or a 4 to 7 membered monocyclic or bicyclic heterocyclyl having 1 to 3 heteroatoms selected from N, O, and S optionally substituted with 1 to 3 R 1Z ; R b is —H; or R a and R b are taken together to form a 4 to 7 membered monocyclic or bicyclic heterocyclyl having 1 to 3 heteroatoms selected from N, O, and S optionally substituted with 1 to 3 R 1Z ; R X is methyl or a 4 to 7 membered monocyclic or bicyclic heterocyclyl having 1 to 3 heteroatoms selected from N, O, and S optionally substituted with 1 to 3 R Z ; R Y is —H; or R X and R Y are taken together to form a 4 to 7 membered monocyclic or bicyclic heterocyclyl having 1 to 3 heteroatoms selected from N, O, and S optionally substituted with 1 to 3 R Z .
25 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein 1 or 2 R 1B is optionally fluoro and one R 1B is —CH 2 NR a R b , where R a is thietanyl substituted with 1 to 3 oxo or methyl groups or 2-oxa-6-azaspiro[3.3]heptanyl and R b is —H or R a and R b are taken together to form 2-oxa-6-azaspiro[3.3]heptanyl.
26 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein 1 or 2 R 1B is optionally fluoro and one R 1B is —C(O)NR X R Y , wherein R X is methyl or thietanyl optionally substituted with 1 to 3 methyl or oxo groups, R Y is —H, or R X and R Y are taken together to form 2-oxa-6-azaspiro[3.3]heptanyl, 2-thia-6-azaspiro[3.3]heptan-6-yl, azetidinyl, 2,6-diazaspiro[3.3]heptanyl, 6-oxa-1-azaspiro[3.3]heptan-1-yl, each of which is optionally substituted with 1 to 3 groups that are independently fluoro, oxo, methyl, or —S(O) 2 CH 3 .
27 . (canceled)
28 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is cyclobutyl substituted with 2 halogens and —C(O)NR X R Y , wherein R X is C 1-3 alkyl and R Y is —H.
29 . (canceled)
30 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is cyclopropyl or cyclobutyl, optionally substituted with 1 or 2 halogens and a 5 membered heteroaryl having 1 to 3 heteroatoms selected from N, O, and S optionally substituted with 1 to 3 R 1D .
31 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is cyclopropyl or cyclobutyl, optionally substituted with 1 or 2 fluoro and triazolyl or thiadiazolyl.
32 .- 34 . (canceled)
35 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is cyclopropyl, bicyclo[1.1.1]pentanyl, cyclobutyl optionally substituted with 1 to 3 R 1B wherein:
each R 1B is independently halogen, ethynyl, —CN, C 1-3 alkyl substituted with —OH or —NR a R b , —C(O)NR X R Y , or 5 membered heteroaryl having 1 to 3 heteroatoms selected from N, O, and S optionally substituted with 1 to 3 R 1D .
36 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is cyclopropyl or cyclobutyl, optionally substituted with 1 or 2 fluoro and one of oxadiazolyl optionally substituted with C 1-3 alkyl, triazolyl optionally substituted with C 1-3 alkyl, or thiadiazolyl.
37 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is
38 . (canceled)
39 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is a 3 to 5 membered heterocyclyl having 1 to 3 heteroatoms selected from N, O, and S, optionally substituted with 1 to 3 R 1C .
40 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is oxetanyl or thietanyl optionally substituted with 1 to 3 R 1C .
41 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each R 1C is independently C 1-3 alkyl, —CF 3 , or oxo.
42 . (canceled)
43 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is.
44 . The compound of claim 1 , wherein R 2C is taken together with R 2E to form a cyclopropyl group and R 2D and R 2F are each —H.
45 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2A and R 2B are —H.
46 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is pyridinyl, optionally substituted with 1 to 4 R 4B .
47 . The compound of claim 1 , wherein R 4 is pyridin-4-yl, optionally substituted with 1 to 3 groups selected from F, Cl, CF 3 , and CHF 2 .
48 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, which is
49 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, which is
50 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, which is
51 . The compound of claim 1 , which is
or a pharmaceutically acceptable salt thereof.
52 . The compound of claim 1 , which is
or a pharmaceutically acceptable salt thereof.
53 . (canceled)
54 . The compound of claim 1 , which is
or a pharmaceutically acceptable salt thereof.
55 . The compound of claim 1 , which is
or a pharmaceutically acceptable salt thereof.
56 . The compound of claim 1 , which is
or a pharmaceutically acceptable salt thereof.
57 . The compound of claim 1 , which is
or a pharmaceutically acceptable salt thereof.
58 . A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
59 .- 62 . (canceled)
63 . A method of treating or preventing a HBV infection, comprising administering to an individual in need thereof a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.
64 .- 75 . (canceled)Join the waitlist — get patent alerts
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