Inhibitors of histone deacetylase
First Claim
Patent Images
1. A compound of the formula (I):
- wherein;
Ring A is a heterocyclyl, wherein if said heterocyclyl contains an —
NH—
moiety that nitrogen may be optionally substituted by a group selected from G;
R1 is a substituent on carbon and is selected from halo, nitro, cyano, hydroxy, oxo, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkoxy, C1-6alkanoyl, C1-6alkanoyloxy, N-(C1-6alkyl)amino, N,N-(C1-6alkyl)2amino, C1-6alkanoylamino, N-(C1-6alkyl)carbamoyl, N,N-(C1-6alkyl)2carbamoyl, C1-6alkylS(O)a wherein a is 0 to 2, C1-6alkoxycarbonyl, N-(C1-6alkyl)sulphamoyl, N,N-(C1-6alkyl)2sulphamoyl, aryl, aryloxy, arylC1-6alkyl, heterocyclic group, (heterocyclic group)C1-6alkyl or a group (D-E-);
wherein R1, including group (D-E-), may be optionally substituted on carbon by one or more V; and
wherein, if said heterocyclic group contains an —
NH—
moiety that nitrogen may be optionally substituted by a group selected from J;
V is halo, nitro, cyano, hydroxy, oxo, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkoxy, C1-6alkanoyl, C1-6alkanoyloxy, N-(C1-6alkyl)amino, N,N-(C1-6alkyl)2amino, C1-6alkanoylamino, N-(C1-6alkyl)carbamoyl, N,N-(C1-6alkyl)2carbamoyl, C1-6alkylS(O)a wherein a is 0 to 2, C1-6alkoxycarbonyl, N-(C1-6alkyl)sulphamoyl, N,N-(C1-6alkyl)2sulphamoyl or a group (D′
-E′
-);
wherein V, including group (D′
-E′
-), may be optionally substituted on carbon by one or more W;
W and Z are independently selected from halo, nitro, cyano, hydroxy, oxo, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkoxy, C1-6alkanoyl, C1-6alkanoyloxy, N-(C1-6alkyl)amino, N,N-(C1-6alkyl)2amino, C1-6alkanoylamino, N-(C1-6alkyl)carbamoyl, N,N-(C1-6alkyl)2carbamoyl, C1-6alkylS(O)a wherein a is 0 to 2, C1-6alkoxycarbonyl, N-(C1-6alkyl)sulphamoyl or N,N-(C1-6alkyl)2sulphamoyl;
G, J and K are independently selected from C1-8alkyl, C2-8alkenyl, C2-8alkynyl, C1-8alkanoyl, C1-8alkylsulphonyl, C1-6alkoxycarbonyl, carbamoyl, N-(C1-8alkyl)carbamoyl, N,N-(C1-8alkyl)carbamoyl, benzyloxycarbonyl, benzoyl and phenylsulphonyl, aryl, arylC1-6alkyl or (heterocyclic group)C1-6alkyl;
wherein G, J and K may be optionally substituted on carbon by one or more Q; and
wherein if said heterocyclic group contains an —
NH—
moiety that nitrogen may be optionally substituted by a group selected from hydrogen or C1-6alkyl;
Q is halo, nitro, cyano, hydroxy, oxo, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkoxy, C1-6alkanoyl, C1-6alkanoyloxy, N-(C1-6alkyl)amino, N,N-(C1-6alkyl)2amino, C1-6alkanoylamino, N-(C1-6alkyl)carbamoyl, N,N-(C1-6alkyl)2carbamoyl, C1-6alkylS(O)a wherein a is 0 to 2, C1-6alkoxycarbonyl, C1-6alkoxycarbonylamino, N-(C1-6alkyl)sulphamoyl, N,N-(C1-6alkyl)2sulphamoyl, aryl, aryloxy, arylC1-6alkyl, arylC1-6alkoxy, heterocyclic group, (heterocyclic group)C1-6alkyl, (heterocyclic group)C1-6alkoxy, or a group (D″
-E″
-);
wherein Q, including group (D″
-E″
-), may be optionally substituted on carbon by one or more Z;
D, D′ and
D″
are independently selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, C3-8cycloalkylC1-6alkyl, aryl, arylC1-6alkyl, heterocyclic group, (heterocyclic group)C1-6alkyl;
wherein D, D′ and
D″
may be optionally substituted on carbon by one or more F′
; and
wherein if said heterocyclic group contains an —
NH—
moiety that nitrogen may be optionally substituted by a group selected from K;
E, E′ and
E″
are independently selected from —
N(Ra)—
, —
O—
, —
C(O)O—
, —
OC(O)—
, —
C(O)—
, —
N(Ra)C(O)—
, —
N(Ra)C(O)N(Rb)—
, —
N(Ra)C(O)O—
, —
OC(O)N(Ra)—
, —
C(O)N(Ra)—
, —
S(O)r—
, —
SO2N(Ra)_, —
N(Ra)SO2—
;
wherein Ra and Rb are independently selected from hydrogen or C1-6alkyl optionally substituted by one or more F and r is 0-2;
F and F′
are independently selected from halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkoxy, C1-6alkanoyl, C1-6alkanoyloxy, N-(C1-6alkyl)amino, N,N-(C1-6alkyl)2amino, C1-6alkanoylamino, N-(C1-6alkyl)carbamoyl, N,N-(C1-6alkyl)2carbamoyl, C1-6alkylS(O)a wherein a is 0 to 2, C1-6alkoxycarbonyl, N-(C1-6alkyl)sulphamoyl and N,N-(C1-6alkyl)2sulphamoyl;
m is 0, 1, 2, 3 or 4;
wherein the values of R1 may be the same or different;
Ring B is a ring selected from wherein, X1 and X2 are selected from CH or N, and Y1, Y2, Y3 and Y4 are selected from CH or N provided that at least one of Y1, Y2, Y3 and Y4 is N;
R2 is halo;
n is 0, 1 or 2;
wherein the values of R2 may be the same or different;
R3 is amino or hydroxy;
R4 is halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C1-3alkyl, C2-3alkenyl, C2-3alkynyl, C1-3alkoxy, C1-3alkanoyl, C1-3alkanoyloxy, N-(C1-3alkyl)amino, N,N-(C1-3alkyl)2amino, C1-3alkanoylamino, N-(C1-3alkyl)carbamoyl, N,N-(C1-3alkyl)2carbamoyl, C1-3alkylS(O)a wherein a is 0 to 2, C1-3alkoxycarbonyl, N-(C1-3alkyl)sulphamoyl, N,N-(C1-3alkyl)2sulphamoyl; and
p is 0, 1 or 2;
wherein the values of R4 may be the same or different;
or a pharmaceutically acceptable salt or in vivo hydrolysable ester or amide thereof.
1 Assignment
0 Petitions
Accused Products
Abstract
The invention concerns a compound of the formula (I); wherein Ring A is heterocyclyl; m is 0-4 and each R1 is a group such as hydroxy, halo, trifluoromethyl and cyano; Ring B is ring such as thienyl, thiadiazolyl, thiazolyl, pyrimidyl, pyrazinyl, pyridazinyl and pyridyl; R2 is halo and n is 0-2; and each R4 is a group such as hydroxy, halo, trifluoromethyl and cyano; p is 0-4; and R3 is amino or hydroxy; or pharmaceutically-acceptable salts or in-vivo-hydrolysable ester or amide thereof; processes for their preparation, pharmaceutical compositions containing them and their use in the treatment of diseases or medical conditions mediated by histone deacetylase.
-
Citations
20 Claims
-
1. A compound of the formula (I):
-
wherein;
Ring A is a heterocyclyl, wherein if said heterocyclyl contains an —
NH—
moiety that nitrogen may be optionally substituted by a group selected from G;
R1 is a substituent on carbon and is selected from halo, nitro, cyano, hydroxy, oxo, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkoxy, C1-6alkanoyl, C1-6alkanoyloxy, N-(C1-6alkyl)amino, N,N-(C1-6alkyl)2amino, C1-6alkanoylamino, N-(C1-6alkyl)carbamoyl, N,N-(C1-6alkyl)2carbamoyl, C1-6alkylS(O)a wherein a is 0 to 2, C1-6alkoxycarbonyl, N-(C1-6alkyl)sulphamoyl, N,N-(C1-6alkyl)2sulphamoyl, aryl, aryloxy, arylC1-6alkyl, heterocyclic group, (heterocyclic group)C1-6alkyl or a group (D-E-);
wherein R1, including group (D-E-), may be optionally substituted on carbon by one or more V; and
wherein, if said heterocyclic group contains an —
NH—
moiety that nitrogen may be optionally substituted by a group selected from J;
V is halo, nitro, cyano, hydroxy, oxo, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkoxy, C1-6alkanoyl, C1-6alkanoyloxy, N-(C1-6alkyl)amino, N,N-(C1-6alkyl)2amino, C1-6alkanoylamino, N-(C1-6alkyl)carbamoyl, N,N-(C1-6alkyl)2carbamoyl, C1-6alkylS(O)a wherein a is 0 to 2, C1-6alkoxycarbonyl, N-(C1-6alkyl)sulphamoyl, N,N-(C1-6alkyl)2sulphamoyl or a group (D′
-E′
-);
wherein V, including group (D′
-E′
-), may be optionally substituted on carbon by one or more W;
W and Z are independently selected from halo, nitro, cyano, hydroxy, oxo, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkoxy, C1-6alkanoyl, C1-6alkanoyloxy, N-(C1-6alkyl)amino, N,N-(C1-6alkyl)2amino, C1-6alkanoylamino, N-(C1-6alkyl)carbamoyl, N,N-(C1-6alkyl)2carbamoyl, C1-6alkylS(O)a wherein a is 0 to 2, C1-6alkoxycarbonyl, N-(C1-6alkyl)sulphamoyl or N,N-(C1-6alkyl)2sulphamoyl;
G, J and K are independently selected from C1-8alkyl, C2-8alkenyl, C2-8alkynyl, C1-8alkanoyl, C1-8alkylsulphonyl, C1-6alkoxycarbonyl, carbamoyl, N-(C1-8alkyl)carbamoyl, N,N-(C1-8alkyl)carbamoyl, benzyloxycarbonyl, benzoyl and phenylsulphonyl, aryl, arylC1-6alkyl or (heterocyclic group)C1-6alkyl;
wherein G, J and K may be optionally substituted on carbon by one or more Q; and
wherein if said heterocyclic group contains an —
NH—
moiety that nitrogen may be optionally substituted by a group selected from hydrogen or C1-6alkyl;
Q is halo, nitro, cyano, hydroxy, oxo, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkoxy, C1-6alkanoyl, C1-6alkanoyloxy, N-(C1-6alkyl)amino, N,N-(C1-6alkyl)2amino, C1-6alkanoylamino, N-(C1-6alkyl)carbamoyl, N,N-(C1-6alkyl)2carbamoyl, C1-6alkylS(O)a wherein a is 0 to 2, C1-6alkoxycarbonyl, C1-6alkoxycarbonylamino, N-(C1-6alkyl)sulphamoyl, N,N-(C1-6alkyl)2sulphamoyl, aryl, aryloxy, arylC1-6alkyl, arylC1-6alkoxy, heterocyclic group, (heterocyclic group)C1-6alkyl, (heterocyclic group)C1-6alkoxy, or a group (D″
-E″
-);
wherein Q, including group (D″
-E″
-), may be optionally substituted on carbon by one or more Z;
D, D′ and
D″
are independently selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, C3-8cycloalkylC1-6alkyl, aryl, arylC1-6alkyl, heterocyclic group, (heterocyclic group)C1-6alkyl;
wherein D, D′ and
D″
may be optionally substituted on carbon by one or more F′
; and
wherein if said heterocyclic group contains an —
NH—
moiety that nitrogen may be optionally substituted by a group selected from K;
E, E′ and
E″
are independently selected from —
N(Ra)—
, —
O—
, —
C(O)O—
, —
OC(O)—
, —
C(O)—
, —
N(Ra)C(O)—
, —
N(Ra)C(O)N(Rb)—
, —
N(Ra)C(O)O—
, —
OC(O)N(Ra)—
, —
C(O)N(Ra)—
, —
S(O)r—
, —
SO2N(Ra)_, —
N(Ra)SO2—
;
wherein Ra and Rb are independently selected from hydrogen or C1-6alkyl optionally substituted by one or more F and r is 0-2;
F and F′
are independently selected from halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkoxy, C1-6alkanoyl, C1-6alkanoyloxy, N-(C1-6alkyl)amino, N,N-(C1-6alkyl)2amino, C1-6alkanoylamino, N-(C1-6alkyl)carbamoyl, N,N-(C1-6alkyl)2carbamoyl, C1-6alkylS(O)a wherein a is 0 to 2, C1-6alkoxycarbonyl, N-(C1-6alkyl)sulphamoyl and N,N-(C1-6alkyl)2sulphamoyl;
m is 0, 1, 2, 3 or 4;
wherein the values of R1 may be the same or different;
Ring B is a ring selected from wherein, X1 and X2 are selected from CH or N, and Y1, Y2, Y3 and Y4 are selected from CH or N provided that at least one of Y1, Y2, Y3 and Y4 is N;
R2 is halo;
n is 0, 1 or 2;
wherein the values of R2 may be the same or different;
R3 is amino or hydroxy;
R4 is halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C1-3alkyl, C2-3alkenyl, C2-3alkynyl, C1-3alkoxy, C1-3alkanoyl, C1-3alkanoyloxy, N-(C1-3alkyl)amino, N,N-(C1-3alkyl)2amino, C1-3alkanoylamino, N-(C1-3alkyl)carbamoyl, N,N-(C1-3alkyl)2carbamoyl, C1-3alkylS(O)a wherein a is 0 to 2, C1-3alkoxycarbonyl, N-(C1-3alkyl)sulphamoyl, N,N-(C1-3alkyl)2sulphamoyl; and
p is 0, 1 or 2;
wherein the values of R4 may be the same or different;
or a pharmaceutically acceptable salt or in vivo hydrolysable ester or amide thereof. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 17, 19)
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-
15-16. -16. (canceled)
-
18. (canceled)
-
20. (canceled)
Specification