Azaspiro[4.5] decane derivatives and use thereof
The invention provides azaspiro[4.5]decane derivatives of Formula (A): and pharmaceutically acceptable salts, solvates, hydrates, N-oxides, and diastereomers thereof, wherein A 1 , X, A 2 , Rr, R 2′ , W 1 , R 3′ , R 4′ , a, and b are defined in the disclosure. The invention also provides compounds of Formulae I, and B-G, and pharmaceutically acceptable salts, solvates, hydrates, N-oxides, and diastereomers thereof. Further, the invention provides use of the compounds of Formulae A-G and I, and the pharmaceutically acceptable salts, solvates, hydrates, N-oxides, and diastereomers thereof, to treat pain. In certain embodiments, Compounds of the Disclosure are useful for treating a disorder responsive to blockade of one or more sodium channels.
1. A compound having Formula I:
or a pharmaceutically acceptable salt or solvate thereof,
wherein:
R 1 is selected from the group consisting of:
R 2a and R 2b are each independently selected from the group consisting of:
a) hydrogen;
b) halo;
c) nitro;
d) cyano;
e) hydroxy;
f) amino;
g) alkylamino;
h) dialkylamino;
i) alkyl;
j) haloalkyl;
k) hydroxyalkyl;
l) alkoxy;
m) haloalkoxy; and
n) alkoxyalkyl;
is a single bond or a double bond;
X 1 is selected from the group consisting of O and NR 3 ;
R 3 is selected from the group consisting of hydrogen and alkyl;
R 5a is selected from the group consisting of:
a) hydrogen;
b) halo;
c) nitro;
d) cyano;
e) hydroxy;
f) amino;
g) alkylamino;
h) dialkylamino;
i) haloalkyl;
j) hydroxyalkyl;
k) alkoxy;
l) haloalkoxy;
m) alkoxyalkyl; and
n) —Z—R 9 ;
R 5b is selected from the group consisting of:
a) hydrogen;
b) halo;
c) nitro;
d) cyano;
e) hydroxy;
f) amino;
g) alkylamino;
h) dialkylamino;
i) haloalkyl;
j) hydroxyalkyl;
k) alkoxy;
l) haloalkoxy; and
m) alkoxyalkyl;
E is selected from the group consisting of:
a) hydroxy;
b) alkoxy; and
c) —NR 6 R 7 ;
R 6 is selected from the group consisting of:
a) hydrogen;
b) alkyl;
c) aralkyl;
d) (heterocyclo)alkyl;
e) (heteroaryl)alkyl;
f) (amino)alkyl;
g) (alkylamino)alkyl;
h) (dialkylamino)alkyl;
i) (carboxamido)alkyl;
j) (cyano)alkyl;
k) alkoxyalkyl;
l) hydroxyalkyl; and
m) heteroalkyl;
R 7 is selected from the group consisting of hydrogen and alkyl; or
R 6 and R 7 taken together with the nitrogen atom to which they are attached form a 3- to 8-membered optionally substituted heterocyclo;
Z is selected from the group consisting of —NR 8 — and —O—;
R 8 is selected from the group consisting of:
a) hydrogen
b) alkyl; and
c) hydroxyalkyl;
R 9 is selected from the group consisting of:
and
c) hydroxyalkyl; or
R 8 and R 9 taken together with the nitrogen atom to which they are attached form a 3- to 8-membered optionally substituted heterocyclo;
R 10 is selected from the group consisting of:
a) hydrogen;
b) optionally substituted alkyl;
c) aralkyl;
d) (heterocyclo)alkyl;
e) (heteroaryl)alkyl;
f) (amino)alkyl;
g) (alkylamino)alkyl;
h) (dialkylamino)alkyl;
i) (carboxamido)alkyl;
j) (cyano)alkyl;
k) alkoxyalkyl;
l) hydroxyalkyl;
m) heteroalkyl;
n) optionally substituted cycloalkyl;
o) optionally substituted aryl;
p) optionally substituted heterocyclo; and
q) optionally substituted heteroaryl;
R 11 is selected from the group consisting of:
a) hydroxy;
b) alkoxy; and
c) —NR 13a R 13b ;
R 13a is selected from the group consisting of:
a) hydrogen;
b) alkyl;
c) aralkyl;
d) (heterocyclo)alkyl;
e) (heteroaryl)alkyl;
f) (amino)alkyl;
g) (alkylamino)alkyl;
h) (dialkylamino)alkyl;
i) (carboxamido)alkyl;
j) (cyano)alkyl;
k) alkoxyalkyl;
l) hydroxyalkyl; and
m) heteroalkyl;
R 13b is selected from the group consisting of hydrogen and alkyl; or
R 13a and R 13b taken together with the nitrogen atom to which they are attached form a 3- to 8-membered optionally substituted heterocyclo;
R 12 is selected from the group consisting of hydrogen and alkyl; and
s is 1, 2, or 3.
2. The compound of claim 1 , wherein:
R 5a is —Z—R 9 ;
Z is —NH— or —O—;
R 9 is
and
R 11 is —NH 2 , or a pharmaceutically acceptable salt or solvate thereof.
3. The compound of claim 1 , wherein:
R 5a is —Z—R 9 ;
Z is —NH— or —O—; and
R 9 is
or a pharmaceutically acceptable salt or solvate thereof.
4. The compound of claim 3 , wherein R 9 is selected from the group consisting of:
wherein Z is —NH—,
or a pharmaceutically acceptable salt or solvate thereof.
5. The compound of claim 1 , wherein R 1 is R 1 —I, R 1 —II, R 1 —III, or R 1 —IV, or a pharmaceutically acceptable salt or solvate thereof.
6. The compound of claim 1 selected from the group consisting of:
(S)-6-((2-oxopyrrolidin-3-yl)amino)-2-(3H-spiro[isobenzofuran-1,4′-piperidin]-1′-yl)pyrimidine-4-carboxamide;
(S)-6-((2-oxopyrrolidin-3-yl)amino)-2-(spiro[indene-1,4′-piperidin]-1′-yl)pyrimidine-4-carboxamide; and
(S)-2-(3-oxo-3H-spiro[isobenzofuran-1,4′-piperidin]-1′-yl)-6-((2-oxopyrrolidin-3-yl)amino)pyrimidine-4-carboxamide;
or a pharmaceutically acceptable salt, or solvate thereof.
7. A pharmaceutical composition, comprising the compound of claim 1 , or a pharmaceutically acceptable salt, or solvate thereof, and a pharmaceutically acceptable carrier.
8. A method of modulating Nav1.7 sodium channels in a mammal, comprising administering to the mammal at least one compound as claimed in claim 1 , or a pharmaceutically acceptable salt, or solvate thereof.
9. The compound of claim 1 , wherein
R 5a is —Z—R 9 ; and
R 5b is hydrogen,
or a pharmaceutically acceptable salt or solvate thereof.
10. The compound of claim 1 , wherein
R 5a is hydroxyalkyl; and
R 5b is hydrogen,
or a pharmaceutically acceptable salt or solvate thereof.
11. The compound of claim 1 , wherein E is —NH 2 , or a pharmaceutically acceptable salt or solvate thereof.
12. The compound of claim 2 , wherein R 9 is selected from the group consisting of:
and
R 19 is a C 1 -C 4 alkyl, or a pharmaceutically acceptable salt or solvate thereof.
13. The compound of claim 12 , wherein Z is —NH—, or a pharmaceutically acceptable salt or solvate thereof.
14. The compound of claim 1 , wherein
Z is —NR 8 —, and R 9 is
or a pharmaceutically acceptable salt or solvate thereof.
15. The compound of claim 1 , wherein R 1 is R 1 —I, and is a double bond, or a pharmaceutically acceptable salt or solvate thereof.
16. The compound of claim 15 , wherein R 2a and R 2b are both hydrogen, or a pharmaceutically acceptable salt or solvate thereof.
17. The compound of claim 1 , wherein R 1 is R′—II, R 2a and R 2b are hydrogen, and X 1 is oxygen, or a pharmaceutically acceptable salt or solvate thereof.
18. The compound of claim 1 , wherein R 1 is R 1 —III, R 2a and R 2b are hydrogen, and X 1 is oxygen, or a pharmaceutically acceptable salt or solvate thereof.
19. The compound of claim 1 , wherein R 1 is R 1 —IV, R 2a and R 2b are hydrogen, and X 1 is oxygen, or a pharmaceutically acceptable salt or solvate thereof.