US2022348577A1PendingUtilityA1
CXCR4 Receptor Antagonists
Est. expiryOct 14, 2030(~4.3 yrs left)· nominal 20-yr term from priority
Inventors:Giles Albert BrownMichael HigginbottomAlison StewartLee PatientAllison CarleyIain SimpsonEdward SavoryKathryn OliverAndrew G. Cole
C07D 417/12C07D 401/14A61P 31/12C07D 405/14C07D 401/12A61P 35/00C07D 471/08C07D 413/12A61K 45/06C07D 471/04A61P 11/00C07B 2200/05A61P 43/00A61P 25/00C07D 401/04A61P 29/00A61P 25/04A61P 7/00A61P 35/04A61P 27/02C07B 59/002C07D 413/14A61P 31/18A61P 25/28A61P 9/00A61P 37/08C07D 417/14A61P 15/00
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Claims
Abstract
The compounds of formula (I) are antagonists of the CXCR4 receptor Wherein R1, X, Y and R2 are as defined in the claims.
Claims
exact text as granted — not AI-modified1 - 20 . (canceled)
21 . A method of treating a viral infection in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound having a structure represented by a formula:
wherein:
R 1 is selected from cyano, —COR 3 , —CONR 3 R 4 , and heteroaryl;
Y is selected from a radical of formula (H) and (J), which is optionally substituted with one or more substituents independently selected from fluorine, hydroxyl, C 1-4 -alkyl, C 1-4 -alkoxy, and fluoro-C 1-4 -alkoxy, wherein the bond marked * is attached to
and the bond marked ** is attached to R 2 :
n and m are each independently 1 or 2;
R 2 is selected from radicals of formulae (N)-(S) inclusive, any of which is optionally substituted with one or more substituents independently selected from fluorine, hydroxyl, C 1-4 -alkyl, C 1-4 -alkoxy, fluoro-C 1-4 -alkyl, and fluoro-C 1-4 -alkoxy, wherein the bond marked * is attached to Y
o and p are each independently 1 or 2;
W is O or NR 9 ;
R 3 is selected from hydrogen, C 1-6 -alkyl, C 3-5 -cycloalkyl, C 3-5 -cycloalkyl-C 1-4 -alkyl, heterocyclyl, heterocyclyl-C 1-4 -alkyl, C 6-10 -aryl, heteroaryl, C 6-10 -aryl-C 1-4 -alkyl, and heteroaryl-C 1-4 -alkyl, wherein:
(i) the C 1-6 -alkyl, the C 3-5 -cycloalkyl, the heterocyclyl, the heterocyclyl part of the heterocyclyl-C 1-4 -alkyl, the C 1-4 -alkyl part of the heterocyclyl-C 1-4 -alkyl, the C 6-10 -aryl-C 1-4 -alkyl, or the heteroaryl-C 1-4 -alkyl is optionally substituted with one or more substituents independently selected from fluorine, hydroxy, cyano, C 1-4 -alkoxy, and —NR 5A R 5B , and
(ii) the C 6-10 -aryl, the heteroaryl, the C 6-10 -aryl part of the C 6-10 -aryl-C 1-4 -alkyl or the heteroaryl part of the heteroaryl-C 1-4 -alkyl is optionally substituted with one or more substituents independently selected from halogen, hydroxy, cyano, nitro, C 1-4 -alkyl, C 1-4 -alkoxy, fluoro-C 1-4 -alkyl, fluoro-C 1-4 -alkoxy, C 1-4 -alkoxy-C 1-4 -alkyl, fluoro-C 1-4 -alkoxy-C 1-4 -alkyl, —NR 5A R 5B , —C 1-4 -alkyl-NR 5A R 5B , —NR 4 C(O)O—C 1-4 alkyl, —NR 4 C(O)—C 1-4 alkyl, —NR 4 C(O)O-fluoro-C 1-4 alkyl, —NR 4 C(O)-fluoro-C 1-4 alkyl, —NR 4 C(O)NR 5A R 5B , —C(O)NR 5A R 5B , —C(O)OR 4 , —C(O)OR 4 , —NR 4 S(O) 2 —C 1-4 alkyl, and —NR 4 S(O) 2 -fluoro-C 1-4 alkyl;
R 4 , R 5A , and R 5B are each independently selected from hydrogen, C 1-4 -alkyl, and fluoro-C 1-4 -alkyl,
or
R 5A and R 5B , together with the nitrogen atom to which they are bound, form a 4- to 7-membered saturated heterocyclic ring or a heteroaryl ring, the ring being optionally substituted with one or more substituents independently selected from fluorine, hydroxyl, C 1-4 -alkyl, fluoro-C 1-4 -alkyl, and C 1-4 -alkoxy,
or
R 3 and R 4 , together with the nitrogen atom to which they are bound, form a 4- to 7-membered saturated heterocyclic ring or a heteroaryl ring, the ring being optionally substituted with one or more substituents independently selected from fluorine, hydroxyl, C 1-4 -alkyl, fluoro-C 1-4 -alkyl, and C 1-4 -alkoxy;
R 6 is selected from C 1-6 -alkyl, C 3-5 -cycloalkyl, C 3-5 -cycloalkyl-C 1-4 -alkyl, heterocyclyl, heterocyclyl-C 1-4 -alkyl, and C 6-10 -aryl, wherein:
(i) the C 1-6 -alkyl, the C 3-5 -cycloalkyl, the heterocyclyl, or the C 1-4 -alkyl part of the heterocyclyl-C 1-4 -alkyl, or the heterocyclyl part of the heterocyclyl-C 1-4 -alkyl is optionally substituted with one or more substituents independently selected from fluorine, hydroxyl, and C 1-4 -alkoxy, and
(ii) the C 6-10 -aryl is optionally substituted with one or more substituents independently selected from halogen, hydroxyl, cyano, nitro, C 1-4 -alkyl, C 1-4 -alkoxy, fluoro-C 1-4 -alkyl, fluoro-C 1-4 -alkoxy, C 1-4 -alkoxy-C 1-4 -alkyl, and fluoro-C 1-4 -alkoxy-C 1-4 -alkyl;
R 7 is selected from C 1-6 -alkyl, C 3-5 -cycloalkyl, C 3-5 -cycloalkyl-C 1-4 -alkyl, heterocyclyl, heterocyclyl-C 1-4 -alkyl, C 6-10 -aryl-C 1-4 -alkyl, C 6-10 -aryl, and —NR 10A R 10B wherein:
(i) the C 1-6 -alkyl, the C 3-5 -cycloalkyl, the heterocyclyl, the C 1-4 -alkyl part of the heterocyclyl-C 1-4 -alkyl or the C 6-10 -aryl-C 1-4 -alkyl, or the heterocyclyl part of the heterocyclyl-C 1-4 -alkyl is optionally substituted with one or more substituents independently selected from fluorine, hydroxyl, and C 1-4 -alkoxy, and
(ii) the C 6-10 -aryl or the C 6-10 -aryl part of the C 6-10 -aryl-C 1-4 -alkyl is optionally substituted with one or more substituents independently selected from halogen, hydroxy, cyano, nitro, C 1-4 -alkyl, C 1-4 -alkoxy, fluoro-C 1-4 -alkyl, fluoro-C 1-4 -alkoxy, C 1-4 -alkoxy-C 1-4 -alkyl, and fluoro-C 1-4 -alkoxy-C 1-4 -alkyl;
R 8A , R 8B and R 9 are each independently selected from hydrogen, C 3-5 -cycloalkyl, C 1-6 -alkyl, and C 6-10 -aryl-C 1-4 -alkyl wherein any alkyl residue or cycloalkyl or C 6-10 -aryl ring system is optionally substituted with one or more substituents independently selected from halogen, hydroxyl, and C 1-4 -alkoxy,
or
R 8A and R 8B , together with the nitrogen atom to which they are bound, form a 4- to 7-membered saturated heterocyclic ring which is optionally fused to a C 6-10 -aryl or heteroaryl ring system, the 4- to 7-membered saturated heterocyclic ring or the C 6-10 -aryl or heteroaryl ring systems being optionally substituted with one or more substituents independently selected from halogen, hydroxyl, C 1-4 -alkyl, fluoro-C 1-4 -alkyl, and C 1-4 -alkoxy; and
R 10A and R 10B are each independently selected from hydrogen and C 1-6 -alkyl, wherein the C 1-6 -alkyl is optionally substituted with one or more substituents independently selected from fluorine, hydroxyl, and C 1-4 -alkoxy,
or
R 10A and R 10B , together with the nitrogen atom to which they are bound, form a 4- to 7-membered saturated heterocyclic ring or a heteroaryl ring, optionally substituted with one or more substituents independently selected from fluorine, hydroxyl, C 1-4 -alkyl, fluoro-C 1-4 -alkyl, and C 1-4 -alkoxy,
or a pharmaceutically acceptable salt thereof.
22 . The method according to claim 21 , wherein R 1 is —CONR 3 R 4 .
23 . The method according to claim 22 , wherein R 4 is hydrogen or methyl.
24 . The method according to claim 22 , wherein R 3 is tetrahydropyranyl, isopropylmethyl, tetrahydropyranylmethyl, imidazolylethyl, methoxyethyl, N-methylimidazolylmethyl, tetrahydrofuranylmethyl, 1-fluoroethyl, oxazolylmethyl, pyridylmethyl, 2,2-difluoromethyl, tetrahydrofuranyl, methyl, ethyl, n- or iso-propyl, n-sec- or n-sec- or tert-butyl, cyclopropyl, hydroxyethyl, cyanoethyl, phenyl, chlorophenyl, methoxyphenyl, methylphenyl, hydroxyphenyl, thiazoloylmethyl, indolyl, methoxypropyl, tetrahydroisoquinolinyl, furylmethyl, pyridylethyl, thiazolyl, or cyclopropylmethyl.
25 . The method according to claim 22 , wherein R 3 is pyridyl optionally substituted with one or more substituents selected from halogen, C 1-4 -alkyl, C 1-4 -alkoxy, and fluoro-C 1-4 -alkyl.
26 . The method according to claim 21 , wherein R 6 is C 1-6 -alkyl, C 1-6 fluoroalkyl, C 3-5 cycloalkyl, or C 3-5 fluorocycloalkyl.
27 . The method according to claim 21 , wherein R 3 is C 3-5 -cycloalkyl-C 1-4 -alkyl, heterocyclyl, or heterocyclyl-C 1-4 -alkyl, and wherein R 4 is hydrogen or methyl.
28 . The method according to claim 21 , wherein R 1 is selected from cyano, —COR 5 , —CONR 3 R 4 , and heteroaryl, wherein the heteroaryl has 5 to 10 ring atoms in which one or more of the ring atoms is N, S, or O, and is optionally substituted with one or more groups selected from fluoro, chloro, bromo hydroxy, cyano, nitro, C 1-6 -alkyl, C 3-5 -cycloalkyl, C 1-4 -alkoxy, fluoro-C 1-6 -alkyl, fluoro-C 1-4 -alkoxy, C 1-4 -alkoxy-C 1-4 -alkyl, fluoro-C 1-4 -alkoxy-C 1-4 -alkyl, C 6-10 -aryl, —NR 5A R 5B , —C 1-4 -alkyl-NR 5A R 5B , —NR 4 C(O)O—C 1-4 -alkyl, —NR 4 C(O)—C 1-4 -alkyl, —NR 4 C(O)O-fluoro-C 1-4 -alkyl, —NR 4 C(O)-fluoro-C 1-4 -alkyl, —NR 4 C(O)NR 5A R 5B , —C(O)NR 5A R 5B , —C(O)R 4 , —C(O)OR 4 , —NR 4 S(O) 2 —C 1-4 -alkyl, and —NR 4 S(O) 2 -fluoro-C 1-4 -alkyl.
29 . The method according to claim 21 , wherein Y is
30 . The method according to claim 21 , wherein R 2 is
31 . The method according to claim 21 , wherein R 6 is isopropyl.
32 . The method according to claim 21 , wherein R 1 is heteroaryl.
33 . The method according to claim 21 , wherein the compound has a structure represented by a formula:
34 . The method according to claim 33 , wherein R 1 is heteroaryl.
35 . The method according to claim 21 , wherein the compound has a structure represented by a formula:
36 . The method according to claim 21 , wherein the compound is selected from:
37 . The method according to claim 36 , wherein the compound is
38 . The method according to claim 21 , wherein the viral infection is HIV/AIDS.
39 . A method of treating a viral infection in a subject in need thereof, comprising administering to the subject an effective amount of a compound selected from:
or a pharmaceutically acceptable salt thereof.
40 . The method according to claim 39 , wherein the viral infection is HIV/AIDS.Cited by (0)
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