Phosphodiesterase 10 inhibitors
First Claim
Patent Images
1. A compound of Formula (I):
- wherein;
Y and Z are nitrogen and X is —
CR═
(where R is hydrogen, alkyl, halo, or cyano);
or X and Y are nitrogen and Z is —
CH═
;
or X and Z are nitrogen and Y is ═
CH—
;
one of R1, R2, and R3 is cycloalkyloxy, cycloalkylalkyloxy, hydroxyalkyl, hydroxyalkyloxy, alkoxyalkyl, alkoxyalkyloxy, -(alkylene)NR13R14 or —
O-(alkylene)NR15R16 [(where R13, R14, R15, and R16 are independently hydrogen or alkyl) and wherein one or two carbon atoms in the alkyl chain in hydroxyalkyl, hydroxyalkyloxy, alkoxyalkyl, alkoxyalkyloxy, -(alkylene)NR13R14 or —
O-(alkylene)NR15R16 are optionally replaced by one to two oxygen or nitrogen atom(s)] and the other two of R1, R2, and R3 are independently selected from hydrogen, alkyl, alkoxy, cycloalkyl, halo, haloalkyl, haloalkoxy, cyano, hydroxy, carboxy, alkoxycarbonyl, amino, alkylamino, dialkylamino, alkylcarbonyl, cycloalkyl, cycloalkyloxy, cycloalkylalkyloxy, hydroxyalkyl, hydroxyalkyloxy, alkoxyalkyl, alkoxyalkyloxy, -(alkylene)NR17R18 or —
O-(alkylene)NR19R20 [(where R17, R18, R19, and R20 are independently hydrogen or alkyl and wherein one or two carbon atoms in the alkyl chain in hydroxyalkyl, alkoxyalkyl, -(alkylene)NR17R18 or —
O-(alkylene)NR19R20 are optionally replaced by one to two oxygen or nitrogen atom(s)]; and
R3a is aryl, heteroaryl, or heterocyclyl ring substituted with;
R4 where R4 is hydrogen, alkyl, halo, haloalkyl, haloalkoxy, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, heterocyclylalkyl, or —
X1R7 (where X1 is —
O—
, —
CO—
, —
C(O)O—
, —
OC(O)—
, —
NR8CO—
, —
CONR9—
, —
NR10—
, —
S—
, —
SO—
, —
SO2—
, —
NR11SO2—
, or —
SO2NR1—
where R8-R12 are independently hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, acyl, or heterocyclylalkyl and R7 is cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, or heterocyclylalkyl); and
R5 and R6 where R5 and R6 are independently hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, alkoxyalkyl, hydroxyalkoxy, alkoxyalkyloxy, aminoalkyl, aminoalkoxy, cyano, nitro, carboxy, alkoxycarbonyl, alkylthio, sulfinyl, sulfonyl, acyl, aminocarbonyl, aminosulfinyl, aminosulfonyl, monosubstituted amino, disubstituted amino, aryl, heteroaryl or heterocyclyl;
and wherein the aromatic or alicyclic ring in R4, R5, R6, and R7 is optionally substituted with one to three substitutents independently selected from Ra, Rb, and Rc which are alkyl, cycloalkyl, cycloalkylalkyl, cycloalkoxy, cycloalkylalkyloxy, alkoxy, halo, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, alkoxyalkyl, hydroxyalkoxy, alkoxyalkyloxy, aminoalkyl, aminoalkoxy, cyano, nitro, carboxy, alkoxycarbonyl, alkylthio, sulfinyl, sulfonyl, aminocarbonyl, aminosulfinyl, aminosulfonyl, monosubstituted amino, disubstituted amino, optionally substituted phenyl, optionally substituted heteroaryl, or optionally substituted heterocyclyl; and
additionally substituted with one or two substitutents independently selected from Rd and Re where Rd and Re are hydrogen or fluoro;
or an individual stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, provided that;
(i) when X and Z are nitrogen, R1 is hydrogen, R2 is alkoxy, alkoxyalkyloxy (wherein one or two carbon atoms in alkoxyalkyloxy are optionally replaced by one to two oxygen atoms), hydroxyalkoxy, or —
O-(alkylene)-NR13R14 where R13 and R14 are independently hydrogen or alkyl, and R3 is hydrogen, alkoxy, alkoxyalkyloxy, or hydroxyalkyloxy, then R3a is not 2,3-dihydroindolyl, 2-oxoindolyl, indolyl, 7-aza-2-oxo-indol-3-yl, 4-aza-2-oxo-indol-3-yl, 5,7-diazaoxindol-3-yl, or piperidinyl, each of which is substituted with R4, R5 or R6 as defined above;
6-chloro-7-aza-2-oxo-indol-3-yl;
2-alkyl-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one-5-yl;
4-carboxypiperidin-1-yl;
or piperazin-1-yl substituted with R4, R5 or R6 at the 4-position of the piperazin-1-yl ring where R4, R5 or R6 are as defined above or where R4, R5 or R6 are hydrogen, alkoxycarbonyl, or —
CONHR where R is phenyl substituted with alkoxy, cyano, alkyl, 5-hydroxyindol-1-yl, or cyclopropyl;
(ii) when X and Z are nitrogen, R1 is hydrogen, R2 is cycloalkylpropoxy, R3 is alkoxy, then and R3a is not piperazin-1-yl substituted with R4, R5 or R6 where two of R4, R5 or R6 are hydrogen and the other of R4, R5 or R6 is at the 4-position of the piperazin-1-yl ring and is hydrogen or —
CONHR where R is phenyl substituted with alkoxy; and
(iii) when X and Z are nitrogen, R1 is hydrogen, R2 is 2-(dimethylamino)ethoxy, and R3 is methoxy, then R3a is not 1,6-dimethyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl-piperidin-1-yl;
or a salt of (i)-(iii).
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Abstract
The present invention if directed to certain cinnoline compounds that are PDE10 inhibitors, pharmaceutical compounds containing the same and processes for preparing the same. The invention is also directed to methods of treating diseases mediated by PDE10 enzyme such as obesity, non-insulin dependent diabetes, schizophrenia or bipolar disorder, obsessive-compulsive disorder, and the like.
-
Citations
20 Claims
-
1. A compound of Formula (I):
-
wherein;
Y and Z are nitrogen and X is —
CR═
(where R is hydrogen, alkyl, halo, or cyano);
or X and Y are nitrogen and Z is —
CH═
;
or X and Z are nitrogen and Y is ═
CH—
;
one of R1, R2, and R3 is cycloalkyloxy, cycloalkylalkyloxy, hydroxyalkyl, hydroxyalkyloxy, alkoxyalkyl, alkoxyalkyloxy, -(alkylene)NR13R14 or —
O-(alkylene)NR15R16 [(where R13, R14, R15, and R16 are independently hydrogen or alkyl) and wherein one or two carbon atoms in the alkyl chain in hydroxyalkyl, hydroxyalkyloxy, alkoxyalkyl, alkoxyalkyloxy, -(alkylene)NR13R14 or —
O-(alkylene)NR15R16 are optionally replaced by one to two oxygen or nitrogen atom(s)] and the other two of R1, R2, and R3 are independently selected from hydrogen, alkyl, alkoxy, cycloalkyl, halo, haloalkyl, haloalkoxy, cyano, hydroxy, carboxy, alkoxycarbonyl, amino, alkylamino, dialkylamino, alkylcarbonyl, cycloalkyl, cycloalkyloxy, cycloalkylalkyloxy, hydroxyalkyl, hydroxyalkyloxy, alkoxyalkyl, alkoxyalkyloxy, -(alkylene)NR17R18 or —
O-(alkylene)NR19R20 [(where R17, R18, R19, and R20 are independently hydrogen or alkyl and wherein one or two carbon atoms in the alkyl chain in hydroxyalkyl, alkoxyalkyl, -(alkylene)NR17R18 or —
O-(alkylene)NR19R20 are optionally replaced by one to two oxygen or nitrogen atom(s)]; and
R3a is aryl, heteroaryl, or heterocyclyl ring substituted with;
R4 where R4 is hydrogen, alkyl, halo, haloalkyl, haloalkoxy, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, heterocyclylalkyl, or —
X1R7 (where X1 is —
O—
, —
CO—
, —
C(O)O—
, —
OC(O)—
, —
NR8CO—
, —
CONR9—
, —
NR10—
, —
S—
, —
SO—
, —
SO2—
, —
NR11SO2—
, or —
SO2NR1—
where R8-R12 are independently hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, acyl, or heterocyclylalkyl and R7 is cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, or heterocyclylalkyl); and
R5 and R6 where R5 and R6 are independently hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, alkoxyalkyl, hydroxyalkoxy, alkoxyalkyloxy, aminoalkyl, aminoalkoxy, cyano, nitro, carboxy, alkoxycarbonyl, alkylthio, sulfinyl, sulfonyl, acyl, aminocarbonyl, aminosulfinyl, aminosulfonyl, monosubstituted amino, disubstituted amino, aryl, heteroaryl or heterocyclyl;
and wherein the aromatic or alicyclic ring in R4, R5, R6, and R7 is optionally substituted with one to three substitutents independently selected from Ra, Rb, and Rc which are alkyl, cycloalkyl, cycloalkylalkyl, cycloalkoxy, cycloalkylalkyloxy, alkoxy, halo, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, alkoxyalkyl, hydroxyalkoxy, alkoxyalkyloxy, aminoalkyl, aminoalkoxy, cyano, nitro, carboxy, alkoxycarbonyl, alkylthio, sulfinyl, sulfonyl, aminocarbonyl, aminosulfinyl, aminosulfonyl, monosubstituted amino, disubstituted amino, optionally substituted phenyl, optionally substituted heteroaryl, or optionally substituted heterocyclyl; and
additionally substituted with one or two substitutents independently selected from Rd and Re where Rd and Re are hydrogen or fluoro;
oran individual stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, provided that;
(i) when X and Z are nitrogen, R1 is hydrogen, R2 is alkoxy, alkoxyalkyloxy (wherein one or two carbon atoms in alkoxyalkyloxy are optionally replaced by one to two oxygen atoms), hydroxyalkoxy, or —
O-(alkylene)-NR13R14 where R13 and R14 are independently hydrogen or alkyl, and R3 is hydrogen, alkoxy, alkoxyalkyloxy, or hydroxyalkyloxy, then R3a is not2,3-dihydroindolyl, 2-oxoindolyl, indolyl, 7-aza-2-oxo-indol-3-yl, 4-aza-2-oxo-indol-3-yl, 5,7-diazaoxindol-3-yl, or piperidinyl, each of which is substituted with R4, R5 or R6 as defined above;
6-chloro-7-aza-2-oxo-indol-3-yl;
2-alkyl-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one-5-yl;
4-carboxypiperidin-1-yl;
orpiperazin-1-yl substituted with R4, R5 or R6 at the 4-position of the piperazin-1-yl ring where R4, R5 or R6 are as defined above or where R4, R5 or R6 are hydrogen, alkoxycarbonyl, or —
CONHR where R is phenyl substituted with alkoxy, cyano, alkyl, 5-hydroxyindol-1-yl, or cyclopropyl;
(ii) when X and Z are nitrogen, R1 is hydrogen, R2 is cycloalkylpropoxy, R3 is alkoxy, then and R3a is not piperazin-1-yl substituted with R4, R5 or R6 where two of R4, R5 or R6 are hydrogen and the other of R4, R5 or R6 is at the 4-position of the piperazin-1-yl ring and is hydrogen or —
CONHR where R is phenyl substituted with alkoxy; and
(iii) when X and Z are nitrogen, R1 is hydrogen, R2 is 2-(dimethylamino)ethoxy, and R3 is methoxy, then R3a is not 1,6-dimethyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl-piperidin-1-yl;
or a salt of (i)-(iii).- View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20)
where R4 phenyl, heteroaryl, or six membered saturated heterocyclyl optionally substituted with Ra, Rb and Rc and the rings are substituted, including the hydrogen atom on the —
NH—
group within the ring, with R5 and R6.
-
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9. The compound of claim 2 wherein R1 is hydrogen, one of R2 and R3 is alkyl and the other is hydroxyalkoxy or alkoxyalkoxy, and R3a is a ring of formula:
-
where R4 is phenyl, heteroaryl, or six membered saturated heterocyclyl optionally substituted with Ra, Rb and Rc and the rings are substituted, including the hydrogen atom on the —
NH—
group within the ring, with R5 and R6.
-
-
10. The compound of claim 2 wherein R1 is hydrogen, one of R2 and R3 is alkoxy and the other is —
- O-(alkylene)-NR15R16, and R3a is a ring of formula;
where R4 is phenyl, heteroaryl, or six membered saturated heterocyclyl optionally substituted with Ra, Rb and Rc and the rings are substituted, including the hydrogen atom on the —
NH—
group within the ring, with R5 and R6.
- O-(alkylene)-NR15R16, and R3a is a ring of formula;
-
11. The compound of claim 2 wherein R1 is hydrogen, one of R2 and R3 is alkoxy and the other is alkoxyalkoxy, and R3a is a ring of formula:
-
12. The compound of claim 2 wherein R1 is hydrogen, one of R2 and R3 is alkyl and the other is hydroxyalkoxy or alkoxyalkyloxy, and R3a is a ring of formula:
-
13. The compound of claim 2 wherein R1 is hydrogen, one of R2 and R3 is alkoxy and the other is alkoxyalkoxy, and R3a is a ring of formula:
-
14. The compound of claim 2 wherein R1 is hydrogen, one of R2 and R3 is alkyl and the other is hydroxyalkoxy or alkoxyalkyloxy, and R3a is a ring of formula:
-
15. The compound of claim 2 wherein R1 is hydrogen, one of R2 and R3 is alkyl and the other is hydroxyalkoxy or alkoxyalkyloxy, and R3a is a ring of formula:
-
where R5 is monosubstituted or disubstituted amino and R4 is hydrogen, alkyl, or halo.
-
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16. The compound of claim 2 wherein R1 is hydrogen, one of R2 and R3 is alkoxy and the other is hydroxyalkoxy or alkoxyalkyloxy, and R3a is a ring of formula:
where R5 is hydrogen or alkyl and R4 is aryl, heteroaryl, aralkyl, heteroaralkyl, or heterocyclyl optionally substituted with one to three substitutents independently selected from Ra, Rb, and Rc which are alkyl, cycloalkyl, cycloalkylalkyl, cycloalkoxy, cycloalkylalkyloxy, alkoxy, halo, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, alkoxyalkyl, hydroxyalkoxy, alkoxyalkyloxy, aminoalkyl, aminoalkoxy, acyl, cyano, carboxy, alkoxycarbonyl, alkylthio, sulfinyl, sulfonyl, aminocarbonyl, aminosulfonyl, monosubstituted amino, disubstituted amino, optionally substituted phenyl, optionally substituted heteroaryl, or optionally substituted heterocyclyl.
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17. The compound of claim 2 wherein R1 is hydrogen, one of R2 and R3 is alkyl and the other is hydroxyalkoxy or alkoxyalkyloxy, and R3a is a ring of formula:
where R5 is hydrogen or alkyl and R4 is aryl, heteroaryl, aralkyl, heteroaralkyl, or heterocyclyl optionally substituted with one to three substitutents independently selected from Ra, Rb, and Rc which are alkyl, cycloalkyl, cycloalkylalkyl, cycloalkoxy, cycloalkylalkyloxy, alkoxy, halo, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, alkoxyalkyl, hydroxyalkoxy, alkoxyalkyloxy, aminoalkyl, aminoalkoxy, acyl, cyano, carboxy, alkoxycarbonyl, alkylthio, sulfinyl, sulfonyl, aminocarbonyl, aminosulfonyl, monosubstituted amino, disubstituted amino, optionally substituted phenyl, optionally substituted heteroaryl, or optionally substituted heterocyclyl.
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18. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable expicient.
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19. A method of treating a disorder treatable by inhibition of PDE10 enzyme in a patient which method comprises administering to the patient a pharmaceutical composition comprising a a compound of claim 1 and a pharmaceutically acceptable expicient.
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20. The method of claim 18 wherein the disease is schizophrenia, bipolar disorder, or obsessive-compulsive disorder.
Specification