US2021171516A1PendingUtilityA1
Therapeutic compounds and methods of use thereof
Est. expirySep 28, 2035(~9.2 yrs left)· nominal 20-yr term from priority
Inventors:Philippe BergeronKristen Nicole BurfordSultan ChowdhuryChristoph Martin DehnhardtThilo FockenMichael Edward GrimwoodAbid HasanKwong Wah LaiZhiguo LiuSteven MckerrallTeresa NguyenBrian SafinaDaniel P. SutherlinTao Wang
C07D 491/107A61P 9/00C07D 405/14C07D 417/12C07D 401/12C07D 417/14A61P 17/04A61P 11/00A61P 25/00A61K 31/4523
60
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Claims
Abstract
The invention provides a compound of formula:or a salt thereof, wherein the variables RAA, n, ring A, ring B, R1a, R1b, R2, R3, R4, R5, R6, R7, R8, and R9 have the meaning as described herein, and compositions containing such compounds and methods for using such compounds and compositions.
Claims
exact text as granted — not AI-modified1 - 58 . (canceled)
59 . A method of treating pain, comprising administering to a mammal in need thereof, a therapeutically effective amount of a compound of formula (I):
or a pharmaceutically acceptable salt thereof, wherein
each R AA is independently selected from the group consisting of F, Cl, Br, I, —CN, —C(═O)OR A1 , —SO 2 R A1 , —OR A1 , —(X RA )-(3-15 membered carbocyclyl), —(X RA )-(6-12 membered aryl), —(X RA )-(5-12 membered heteroaryl), and —R A2 , wherein said 3-15 membered carbocyclyl, 6-12 membered aryl, and 5-12 membered heteroaryl of R AA is optionally substituted with from 1 to 5 substituents R b that are independently selected from the group consisting of F, Cl, Br, I, C 1-4 alkyl, C 1-4 haloalkyl, amino, C 1-4 alkylamino, di(C 1-4 alkyl)amino, and C 1-4 (halo)alkoxy; R A1 is selected from the group consisting of hydrogen, C 1-8 alkyl, C 2-8 alkenyl, C 1-8 haloalkyl, C 3-8 cycloalkyl, phenyl and benzyl; R A2 is selected from the group consisting of C 1-8 alkyl that is optionally substituted with one or more substituents selected from oxo, fluoro, hydroxy, amino, C 1-4 alkylamino and di(C 1-4 alkyl)amino; X RA is selected from the group consisting of absent, —C(═O)—, and C 1-4 alkylene; wherein any C 1-4 alkylene, of X RA is optionally substituted with 1 to 3 substituents selected from the group consisting of C 1-4 alkyl,
C 1-4 haloalkyl, and phenyl that is optionally substituted with 1 to 5 substituents selected from, F, Cl, Br, I, —NH 2 , —OH, —CN, —NO 2 , C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 (halo)alkoxy, C 1-4 alkylamino and C 1-4 dialkylamino;
ring “A” is a 5-6 membered heterocycle;
R 1a is H or C 1-4 alkyl;
R 1b is H or C 1-4 alkyl;
R 2 is selected from the group consisting of H, F, Cl, Br, I, —CN, C 1-8 alkyl, C 3-8 cycloalkyl, C 1-8 haloalkyl and C 1-8 alkoxy;
R 3 , R 4 , and R S are each independently selected from the group consisting of H, F, Cl, Br, I, —CN, C 1-8 alkyl, C 3-8 cycloalkyl, C 1-8 haloalkyl and C 1-8 alkoxy;
R 6 is selected from the group consisting of H, C 1-8 alkyl, C 3-8 cycloalkyl, aryl, and aryl(C 1-4 alkyl); and R 7 is selected from the group consisting of 3-15 membered heterocyclyl, 5-12 membered heteroaryl, —C(O)N(R c ) 2 and —C(═NCN)N(R c ) 2 ; or R 6 and R 7 , together with the nitrogen to which they are attached, form a 3-15 membered heterocyclyl or 5-12 membered heteroaryl; wherein any C 1-8 alkyl, C 3-8 cycloalkyl, aryl, aryl(C 1-4 alkyl), 3-15 membered heterocyclyl, and 5-12 membered heteroaryl is optionally substituted with one or more groups R d that are independently selected from the group consisting of F, Cl, Br, I, —NH 2 , —OH, —CN, —NO 2 , C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 (halo)alkoxy, C 1-4 alkylamino and C 1-4 dialkylamino; each R c is independently selected from the group consisting of hydrogen, C 1-8 alkyl, C 3-8 cycloalkyl, phenyl and benzyl; and
n is 0, 1, 2, 3, 4, 5, or 6;
provided at least one of R 2 , R 3 , R 4 , and R 5 is not H.
60 . A method of treating pain, comprising administering to the mammal in need thereof, a therapeutically effective amount of a compound of formula (Ix):
or a pharmaceutically acceptable salt thereof, wherein,
each R AA is independently selected from the group consisting of F, Cl, Br, I, —CN, —C(═O)OR A1 , —SO 2 R A1 , —OR A1 , —(X RA )-(3-15 membered carbocyclyl), —(X RA )-(6-12 membered aryl), —(X RA )-(5-12 membered heteroaryl), and —R A2 , wherein said 3-15 membered carbocyclyl, 6-12 membered aryl, and 5-12 membered heteroaryl of R AA is optionally substituted with from 1 to 5 substituents R b that are independently selected from the group consisting of F, Cl, Br, I, C 1-4 alkyl, C 1-4 haloalkyl, amino, C 1-4 alkylamino, di(C 1-4 alkyl)amino, C 1-4 (halo)alkoxy, and —C(O)N(R c ) 2 ; R A1 is selected from the group consisting of hydrogen, C 1-8 alkyl, C 2-8 alkenyl, C 1-8 haloalkyl, C 3-8 cycloalkyl, phenyl and benzyl; R A2 is selected from the group consisting of C 1-8 alkyl that is optionally substituted with one or more substituents selected from oxo, fluoro, hydroxy, amino, C 1-4 alkylamino and di(C 1-4 alkyl)amino; X RA is selected from the group consisting of absent, —C(═O)—, and C 1-4 alkylene; wherein any C 1-4 alkylene, of X RA is optionally substituted with 1 to 3 substituents selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, and phenyl that is optionally substituted with 1 to 5 substituents selected from, F, Cl, Br, I, —NH 2 , —OH, —CN, —NO 2 , C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 (halo)alkoxy, C 1-4 alkylamino and C 1-4 dialkylamino;
ring “A” is a 5-12 membered heteroaryl, or a 3-15 membered heterocyclyl;
Ring B is a 5, 6, or 7 membered carbocyclyl or a 5, 6, or 7 membered heterocyclyl, which 5, 6, or 7 membered carbocyclyl and 5, 6, or 7 membered heterocyclyl is optionally substituted with one or more groups independently selected from C 1-4 alkyl, halo, and haloC 1-4 alkyl;
R 1b is H or C 1-4 alkyl;
R 3 , R 4 , and R 5 are each independently selected from the group consisting of H, F, Cl, Br, I, —CN, C 1-8 alkyl, C 3-8 cycloalkyl, C 1-8 haloalkyl and C 1-8 alkoxy;
R 6 is selected from the group consisting of H, C 1-8 alkyl, C 3-8 cycloalkyl, aryl, and aryl(C 1-4 alkyl); and R 7 is selected from the group consisting of C 1-8 alkyl, 3-15 membered heterocyclyl, 5-12 membered heteroaryl, —C(O)N(R c ) 2 and —C(═NCN)N(R c ) 2 ; or R 6 and R 7 , together with the nitrogen to which they are attached, form a 3-15 membered heterocyclyl or 5-12 membered heteroaryl; wherein any C 1-8 alkyl, C 3-8 cycloalkyl, aryl, aralkyl, 3-15 membered heterocyclyl, and 5-12 membered heteroaryl is optionally substituted with one or more groups R d that are independently selected from the group consisting of F, Cl, Br, I, —NH 2 , —OH, —CN, —NO 2 , C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 (halo)alkoxy, C 1-4 alkylamino and C 1-4 dialkylamino; each R c is independently selected from the group consisting of hydrogen, C 1-8 alkyl, C 3-8 cycloalkyl, phenyl and benzyl; and
n is 0, 1, 2, 3, 4, 5, or 6.
61 . The method of claim 60 , wherein the compound is a compound of formula (Ix):
wherein,
each R AA is independently selected from the group consisting of F, Cl, Br, I, —CN, —OR A1 , —(X RA )-(3-15 membered carbocyclyl), —(X RA )-(6-12 membered aryl), —(X RA )-(5-12 membered heteroaryl), and —R A2 , wherein said (3-15 membered carbocyclyl), 6-12 membered aryl, and 5-12 membered heteroaryl of R AA is optionally substituted with from 1 to 5 substituents R b that are independently selected from the group consisting of F, Cl, Br, I, C 1-4 alkyl, C 1-4 haloalkyl, amino, C 1-4 alkylamino and di(C 1-4 alkyl)amino, and C 1-4 (halo)alkoxy; R A1 is selected from the group consisting of hydrogen, C 1-8 alkyl, C 2-8 alkenyl, C 1-8 haloalkyl, C 3-8 cycloalkyl, phenyl and benzyl; R A2 is selected from the group consisting of C 1-8 alkyl that is optionally substituted with one or more substituents selected from oxo, fluoro, hydroxy, amino, C 1-4 alkylamino and di(C 1-4 alkyl)amino; X RA is selected from the group consisting of absent, —C(═O)—, and C 1-4 alkylene; wherein any C 1-4 alkylene, of X RA is optionally substituted with 1 to 3 substituents selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, and phenyl that is optionally substituted with 1 to 5 substituents selected from, F, Cl, Br, I, —NH 2 , —OH, —CN, —NO 2 , C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 (halo)alkoxy, C 1-4 alkylamino and C 1-4 dialkylamino;
ring “A” is a 5-12 membered heteroaryl, or a 3-15 membered heterocyclyl;
Ring B is a 5, 6, or 7 membered carbocyclyl or a 5, 6, or 7 membered heterocyclyl, which 5, 6, or 7 membered carbocyclyl and 5, 6, or 7 membered heterocyclyl is optionally substituted with one or more groups independently selected from C 1-4 alkyl, halo, and haloC 1-4 alkyl;
R 1b is H or C 1-4 alkyl;
R 3 , R 4 , and R 5 are each independently selected from the group consisting of H, F, Cl, Br, I, —CN, C 1-8 alkyl, C 3-8 cycloalkyl, C 1-8 haloalkyl and C 1-8 alkoxy;
R 6 is selected from the group consisting of H, C 1-8 alkyl, C 3-8 cycloalkyl, aryl, and aryl(C 1-4 alkyl); and R 7 is selected from the group consisting of C 1-8 alkyl, 3-15 membered heterocyclyl, 5-12 membered heteroaryl, —C(O)N(R c ) 2 and —C(═NCN)N(R c ) 2 ; or R 6 and R 7 , together with the nitrogen to which they are attached, form a 3-15 membered heterocyclyl or 5-12 membered heteroaryl; wherein any C 1-8 alkyl, C 3-8 cycloalkyl, aryl, aralkyl, 3-15 membered heterocyclyl, and 5-12 membered heteroaryl is optionally substituted with one of more groups R d that are independently selected from the group consisting of F, Cl, Br, I, —NH 2 , —OH, —CN, —NO 2 , C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 (halo)alkoxy, C 1-4 alkylamino and C 1-4 dialkylamino; each R c is independently selected from the group consisting of hydrogen, C 1-8 alkyl, C 3-8 cycloalkyl, phenyl and benzyl; and
n is 0, 1, 2, 3, 4, 5, or 6.
62 . The method of claim 60 , wherein the compound is a compound of formula (Ic):
wherein, the ring B is a 5, 6, or 7 membered carbocyclyl or a 5, 6, or 7 membered heterocyclyl.
63 . The method of claim 60 , wherein the compound is a compound of formula (Id):
wherein, X is O, S, SO, or SO 2 ; m is 0, 1, 2, 3, 4 or 5; and p is 0, 1, 2, 3, 4, or 5.
64 . The method of claim 60 , wherein the compound is a compound of formula (Ih):
65 . The method of claim 60 , wherein the compound is a compound of formula (Ij):
wherein, m is 0, 1, 2, 3, 4 or 5; and p is 0, 1, 2, 3, 4, or 5; or a pharmaceutically acceptable salt thereof.
66 . The method of claim 59 , wherein the group
is selected from the group consisting of:
67 . The method of claim 59 , wherein the group
is selected from the group consisting of:
68 . The method of claim 60 , wherein the compound is a compound of formula (Ik):
wherein,
each R AA is independently selected from the group consisting of F, Cl, Br, I, —CN, —OR A1 , —(X RA )-(3-15 membered carbocyclyl), —(X RA )-(6-12 membered aryl), —(X RA )-(5-12 membered heteroaryl), and —R A2 , wherein said (3-15 membered carbocyclyl), 6-12 membered aryl, and 5-12 membered heteroaryl of R AA is optionally substituted with from 1 to 5 substituents R b that are independently selected from the group consisting of F, Cl, Br, I, C 1-4 alkyl, C 1-4 haloalkyl, amino, C 1-4 alkylamino and di(C 1-4 alkyl)amino, and C 1-4 (halo)alkoxy; R A1 is selected from the group consisting of hydrogen, C 1-8 alkyl, C 2-8 alkenyl, C 1-8 haloalkyl, C 3-8 cycloalkyl, phenyl and benzyl; R A2 is selected from the group consisting of C 1-8 alkyl that is optionally substituted with one or more substituents selected from oxo, fluoro, hydroxy, amino, C 1-4 alkylamino and di(C 1-4 alkyl)amino; X RA is selected from the group consisting of absent, —C(═O)—, and C 1-4 alkylene; wherein any C 1-4 alkylene, of X RA is optionally substituted with 1 to 3 substituents selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, and phenyl that is optionally substituted with 1 to 5 substituents selected from, F, Cl, Br, I, —NH 2 , —OH, —CN, —NO 2 , C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 (halo)alkoxy, C 1-4 alkylamino and C 1-4 dialkylamino;
ring “A” is a 5-12 membered heteroaryl, or a 3-15 membered heterocyclyl;
Ring B is a 5, 6, or 7 membered carbocyclyl or a 5, 6, or 7 membered heterocyclyl, which 5, 6, or 7 membered carbocyclyl and 5, 6, or 7 membered heterocyclyl is optionally substituted with one or more groups independently selected from C 1-4 alkyl, halo, and haloC 1-4 alkyl;
R 1b is H or C 1-4 alkyl;
R 3 , R 4 , and R 5 are each independently selected from the group consisting of H, F, Cl, Br, I, —CN, C 1-8 alkyl, C 3-8 cycloalkyl, C 1-8 haloalkyl and C 1-8 alkoxy;
R 6 is selected from the group consisting of H, C 1-8 alkyl, C 3-8 cycloalkyl, aryl, and aryl(C 1-4 alkyl); and R 7 is selected from the group consisting of C 1-8 alkyl, 3-15 membered heterocyclyl, 5-12 membered heteroaryl, —C(O)N(R c ) 2 and —C(═NCN)N(R c ) 2 ; or R 6 and R 7 , together with the nitrogen to which they are attached, form a 3-15 membered heterocyclyl or 5-12 membered heteroaryl; wherein any C 1-8 alkyl, C 3-8 cycloalkyl, aryl, aralkyl, 3-15 membered heterocyclyl, and 5-12 membered heteroaryl is optionally substituted with one of more groups R d that are independently selected from the group consisting of F, Cl, Br, I, —NH 2 , —OH, —CN, —NO 2 , C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 (halo)alkoxy, C 1-4 alkylamino and C 1-4 dialkylamino; each R c is independently selected from the group consisting of hydrogen, C 1-8 alkyl, C 3-8 cycloalkyl, phenyl and benzyl;
n is 0, 1, 2, 3, 4, 5, or 6; and
X is CH 2 , NR A2 , S, or O.
69 . The method of claim 60 , wherein the compound is a compound of formula (Im):
70 . The method of claim 60 , wherein the compound is a compound of formula (Io):
71 . The method of claim 60 , wherein the compound is a compound of formula (Is):
wherein, m is 0, 1, 2, 3, 4 or 5; and p is 0, 1, 2, 3, 4, or 5.
72 . The method of claim 59 , wherein the compound is selected from the group consisting of:
73 . The method of claim 60 , wherein the compound is selected from the group consisting of:
74 . The method of claim 59 , wherein the compound is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
75 . The method of claim 60 , wherein the compound is selected from the group consisting of:
76 . The method of claim 60 , wherein the compound is selected from the group consisting of:
77 . A method of claim 59 , wherein the mammal is a human.Join the waitlist — get patent alerts
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