Aryl methyl benzoquinazolinine M1 receptor positive allosteric modulators
View Patent ↗The present invention is directed to benzoquinazilinone compounds of formula (I) which are M1 receptor positive allosteric modulators and that are useful in the treatment of diseases in which the M1 receptor is involved, such as Alzheimer's disease, schizophrenia, pain or sleep disorders. The invention is also directed to pharmaceutical compositions comprising the compounds, and to the use of the compounds and compositions in the treatment of diseases mediated by the M1 receptor.
1. A compound of formula (I):
or a pharmaceutically acceptable salt thereof, wherein
X, Y and Z are each CH and Q is C, or one of X, Y, Q and Z is N and the others are CH or C, or X and Y are CH and Q, R 1 and Z are linked together to form a naphthyl group;
R 1 is selected from the group consisting of
(1) hydrogen,
(2) aryl,
(3) a heteroaryl group which is a cyclic or polycyclic group, having from five to twelve ring atoms, said ring atoms selected from C, O, N or S, at least one of which is O, N or S,
(4) halogen,
(5) —CN,
(6) —O—C 1-6 alkyl,
(7) —C 1-6 alkyl,
(8) —C 2-6 alkenyl
(9) —S(═O) n —R 4 ,
(10) —NR 5A R 5B ,
wherein said aryl, heteroaryl, alkyl and alkenyl moiety is optionally substituted with one or more
(a) halogen,
(b) hydroxy,
(c) —O—C 1-6 alkyl,
(d) —C 1-6 alkyl,
(e) —C(═O)—(O) m —R 6 ,
(f) —N(R 5A R 5B ),
(g) —S(═O) n —R 8 , or
(h) oxo,
provided that when Q is N then R 1 is absent;
R 2 is selected from the group consisting of
(1) hydrogen,
(2) aryl,
(3) a heteroaryl group which is a cyclic or polycyclic group, having from five to twelve ring atoms, said ring atoms selected from C, O, N or S, at least one of which is O, N or S,
(4) a heterocyclic group, which is a non-aromatic cyclic or polycyclic group having from five to twelve ring atoms selected from C, O, N or S, at least one of which is O, N or S,
(5) —O—C 1-6 alkyl,
(6) —C 1-6 alkyl,
(7) —C 2-6 alkenyl,
(8) —S(═O) n —R 4 ,
(9) —C 3-8 cycloalkyl,
(10) —C 5-8 cycloalkenyl,
(11) —NR 5A R 5B ,
wherein said aryl, heteroaryl, heterocyclyl, alkyl, alkenyl, cycloalkyl and cycloalkenyl moiety is optionally substituted with one or more
(a) halogen,
(b) hydroxy,
(c) —O—C 1-6 alkyl,
(d) —C 1-6 alkyl,
(e) —S(═O) n —R 8 ,
(f) —C 2-6 alkenyl,
(g) —CN,
(h) —C(═O)—(O) m —R 6 ,
(i) —NR 5A R 5B ,
(j) oxo,
(k) aryl,
(l) a heteroaryl group which is a cyclic or polycyclic group, having from five to twelve ring atoms, said ring atoms selected from C, O, N or S, at least one of which is O, N or S,
(m) a heterocyclic group, which is a non-aromatic cyclic or polycyclic group having from five to twelve ring atoms selected from C, O, N or S, at least one of which is O, N or S
(n) —OC(═O)—R 6 ,
wherein the alkyl, alkenyl, aryl, heteroaryl or heterocyclic moiety is optionally substituted with one or more
(i) halogen,
(ii) —C 1-6 alkyl, or
(iii) —OC 1-6 alkyl;
R 3 is selected from the group consisting of
(1) hydrogen,
(2) —C 1-6 alkyl, and
(3) —S(O) n —R 4 ,
wherein said R 3 alkyl moiety is optionally substituted with one or more
(a) halogen,
(b) cyano, and
(c) —O—C 1-6 alkyl, wherein said alkyl is optionally substituted with one or more halo;
R 4 , R 6 and R 8 are independently selected from the group consisting of
(1) hydrogen,
(2) —C 1-6 alkyl, and
(3) —(CH 2 ) n -aryl,
wherein said R 4 , R 6 or R 8 alkyl or aryl moiety is optionally substituted with one or more
(a) halogen,
(b) cyano, and
(c) —O—C 1-6 alkyl, wherein said alkyl is optionally substituted with one or more halogen;
R 5A and R 5B are selected from the group consisting of
(1) hydrogen,
(2) —C 1-6 alkyl,
(3) —C 3-6 cycloalkyl,
(4) —C(═O)—O—R 6 ,
(5) —S(O) 2 —R 6 ,
or R 5A and R 5B are linked together with the nitrogen to which they are both attached to form a 2-6 membered carbocyclic ring, wherein one or two of the ring carbon atoms is optionally replaced by a nitrogen, oxygen or sulfur;
m is 0 or 1; and
n is 0, 1 or 2.
2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
Q is C, X and Y are each CH and Z is N;
X, Y and Z are each CH, and Q is C, or
X and Z are each CH, Q is C and Y is N.
3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from the group consisting of
(1) halogen,
(2) —CN,
(3) —O—C 1-6 alkyl, or
(4) —C 1-6 alkyl,
wherein said alkyl is optionally substituted with one or more
(a) halogen,
(b) hydroxy,
(c) —O—C 1-6 alkyl,
(d) —C 1-6 alkyl,
(e) —C(═O)—(O) m —R 6 ,
(f) —NR 5A R 5B , or
(g) oxo,
(5) aryl, or
(6) heteroaryl, wherein the R 1 aryl or heteroaryl moiety is optionally substituted with one or more
(a) halogen,
(b) hydroxy,
(c) —O—C 1-6 alkyl,
(d) —C 1-6 alkyl, or
(e) —S(O) n —R 8 .
4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is:
(1) —C 3-8 cycloalkyl, optionally substituted with one or more
(a) hydroxy,
(b) —O—C 1-6 alkyl, or
(c) oxo,
(2) aryl,
(3) heteroaryl, or
(4) —C 1-6 alkyl, wherein said aryl, heteroaryl or alkyl is optionally substituted with one or more
(a) halogen,
(b) hydroxy,
(c) —O—C 1-6 alkyl,
(d) —C 1-6 alkyl,
(e) —CN,
(f) —C(═O)—(O) m —R 6 ,
(g) —NR 5A R 5B ,
(h) oxo,
(i) aryl, and
(j) heteroaryl.
5. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 3 is hydrogen.
6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of
rac-3-[trans-2-hydroxycyclohexyl]-6-[(6-methylpyridin-3-yl)methyl]benzo[h]quinazolin-4(3H)-one;
3-[(1S,2S)-2-hydroxycyclohexyl]-6-[(6-methylpyridin-3-yl)methyl]benzo[h]quinazolin-4(3H)-one;
6-(4-methoxybenzyl)-3-(5-methyl)-1H-pyrazol-3-yl)benzo[h]quinazolin-4(3H)-one;
6-(4-methoxybenzyl)-3-pyridin-3-ylbenzo[h]quinazolin-4(3H)-one;
rac-3-[trans-2-hydroxycyclohexyl]-6-{[6-(1-methyl-1H-pyrazol-4-yl)pyridine-3-yl]methyl}benzo[h]quinazolin-4(3H)-one;
rac-3-[trans-2-hydroxycyclohexyl]-6-{[6-(1H-pyrazol-1-yl)pyridin-3-yl]methyl}benzo[h]quinazolin-4(3H)-one;
rac-5-({3-[trans-2-hydroxycyclohexyl]-4-oxo-3,4-dihydrobenzo[h]quinazolin-6-yl}methyl)pyridine-2-carbonitrile;
rac-3-[trans-2-hydroxycyclohexyl]-6-{[6-methylsulfonyl)pyridine-3-yl]methyl}benzo[h]quinazolin-4(3H)-one;
rac-3-[trans-2-hydroxycyclohexyl]-6-[(6-methoxypyridin-3-yl)methyl]benzo[h]quinazolin-4(3H)-one;
6-[(6-chloropyridin-3-yl)methyl]-3-(2-oxycyclohexyl)benzo[h]quinazolin-4(3H)-one;
trans-2-[6-[(6-chloropyridin-3-yl)methyl]-4-oxobenzo[h]quinazolin-3(4H)-yl]cyclohexyl rac-acetate;
N-{(1S,2S)-2-[6-[(6-chloropyridin-3-yl)methyl]-4-oxobenzo[h]quinazolin-3(4H)-yl]cyclohexyl}acetamide;
3-[(1S,2S)-2-hydroxycyclohexyl]-6-[(6-isopropylpyridin-3-yl)methylbenzo[h]quinazolin-4(3H)-one;
3-[(1S,2S)-2-hydroxycyclohexyl]-6-{[(6-(1-hydroxy-1-methylethyl)pyridin-3-yl]methyl}benzo[h]quinazolin-4(3H)-one;
rac-3-[trans-2-hydroxycyclohexyl]-6-{[6-(hydroxymethyl)pyridine-3-yl]methyl}benzo[h]quinazolin-4(3H)-one;
rac-3-[trans-2-hydroxycyclohexyl]-6-[(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]benzo[h]quinazolin-4(3H)-one;
3-[(1S,2S)-2-hydroxycyclohexyl]-6-[(6-methyl-1-oxidopyridin-3-yl)methyl]benzo[h]quinazolin-4(3H)-one;
3-[(1S,2S)-2-hydroxycyclohexyl]-6-(pyridin-2-ylmethyl)benzo[h]quinazolin-4(3H)-one;
6-[(6-chloropyridin-3-yl)methyl]-3-[(1S,2S)-2-hydroxycyclohexyl]-2-methylbenzo[h]quinazolin-4(3H)-one;
or a pharmaceutically acceptable salt thereof.
7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of
rac-3-[trans-2-hydroxycyclohexyl]-6-[(6-methylpyridin-3-yl)methyl]benzo[h]quinazolin-4(3H)-one;
3-[(1S,2S)-2-hydroxycyclohexyl]-6-[(6-methylpyridin-3-yl)methyl]benzo[h]quinazolin-4(3H)-one;
6-(4-methoxybenzyl)-3-(5-methyl)-1H-pyrazol-3-yl)benzo[h]quinazolin-4(3H)-one;
6-(4-methoxybenzyl)-3-pyridin-3-ylbenzo[h]quinazolin-4(3H)-one;
rac-3-[trans-2-hydroxycyclohexyl]-6-{[6-(1-methyl-1H-pyrazol-4-yl)pyridine-3-yl]methyl}benzo[h]quinazolin-4(3H)-one;
rac-3-[trans-2-hydroxycyclohexyl]-6-{[6-(1H-pyrazol-1-yl)pyridin-3-yl]methyl}benzo[h]quinazolin-4(3H)-one;
rac-5-({3-[trans-2-hydroxycyclohexyl]-4-oxo-3,4-dihydrobenzo[h]quinazolin-6-yl}methyl)pyridine-2-carbonitrile;
or a pharmaceutically acceptable salt thereof.
8. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein X and Y are CH, Q is C, and R 1 , R 2 , R 3 , and Z are depicted below:
R 2
R 1
R 3
Z
OCH 3
SCH 3
CH
Cl
CH 3
N.
9. The compound of claim 1 , wherein the compound of formula (I) is a compound of formula (II):
or a pharmaceutically acceptable salt thereof, wherein
R 7 is selected from the group consisting of
(1) hydrogen,
(2) aryl,
(3) heteroaryl,
(4) halogen,
(5) —CN,
(6) —O—C 1-6 alkyl,
(7) —C 1-6 alkyl,
(8) —C 2-6 alkenyl
(9) —S(═O) n —R 4 , and
(10) —NR 5A R 5B ,
wherein said aryl, heteroaryl, alkyl and alkenyl moiety is optionally substituted with one or more
(a) halogen,
(b) hydroxy,
(c) —O—C 1-6 alkyl,
(d) —C 1-6 alkyl,
(e) —C(═O)—(O) m —R 6 ,
(f) —N(R 5A R 5B ),
(g) —S(═O) n —R 8 , and
(h) oxo.
10. The compound of claim 9 , or a pharmaceutically acceptable salt thereof, wherein R 3 is hydrogen and R 2 and R 7 are paired as depicted below:
Stereo-
specificity
R 2
R 7
Racemic
(1S, 2S)
Racemic
Racemic
Cl
(1S, 2S)
Cl
Racemic
Cl
(1S, 2S)
Cl
racemic
(1S, 2S)
racemic
racemic
N(CH 3 ) 2
racemic
CH 3
(1S, 2S)
CH 3
(1S, 2S)
CH 3
racemic
CN
racemic
racemic
racemic
racemic
(1S, 2S)
racemic
racemic
(1S, 2S)
(1S, 2S)
(1S, 2S)
(1S, 2S)
(1S, 2S)
(1S, 2S)
(1S, 2S)
racemic
racemic
racemic
(1S, 2S)
racemic
racemic
racemic
SCH 3
(1S, 2S)
SCH 3
racemic
SO 2 CH 3
racemic
CH 2 ═CH—
racemic
CH 2 CH 3
(1S, 2S)
CH 2 CH 3
(1S, 2S)
CH 2 OH
(1S, 2S)
(1S, 2S)
(1S, 2S)
(1S, 2S)
racemic
CHO
racemic
OCH 3
(1S, 2S)
OCH 3
racemic
H
racemic
Cl
racemic
Cl
(1S, 2S)
CH 3
racemic
Cl
(1S, 2S)
Cl
(1S, 2S)
Cl
(1S, 2S)
Cl
(1S, 2S)
Cl
(1S, 2S)
Cl
(1S, 2S)
Cl
racemic
(1S, 2S)
11. The compound of claim 1 , wherein the compound of formula (I) is a compound of formula (III):
or a pharmaceutically acceptable salt thereof, wherein
R 2 and R 3 are as described above, and R 7 is selected from the group consisting of
(1) hydrogen,
(2) aryl,
(3) heteroaryl,
(4) halogen,
(5) —CN,
(6) —O—C 1-6 alkyl,
(7) —C 1-6 alkyl,
(8) —C 2-6 alkenyl
(9) —S(═O) n —R 4 , and
(10) —NR 5A R 5B ,
wherein said aryl, heteroaryl, alkyl and alkenyl moiety is optionally substituted with one or more
(a) halogen,
(b) hydroxy,
(c) —O—C 1-6 alkyl,
(d) —C 1-6 alkyl,
(e) —C(═O)—(O) m —R 6 ,
(f) —N(R 5A R 5B ),
(g) —S(═O) n —R 8 , and
(h) oxo.
12. The compound of claim 11 , wherein R 3 is hydrogen, and R 2 and R 7 are paired from the group consisting of
R 2
R 7
OCH 3
H
OCH 3
Allyl
OCH 3
Me
OCH 3
Ph
OCH 3
OCH 3
3-pyridyl
OCH 3
4-pyridyl
OCH 3
OCH 3
OCH 3
CH 2 CH 2 CN
OCH 3
OCH 3
CH 2 CH 2 OH
OCH 3
OCH 3
OCH 3
OCH 3
OCH 3
OCH 3
OCH 3
OCH 3
OCH 3
OCH 3
OCH 3
OCH 3
OCH 3
OCH 3
OCH 3
OCH 3
OCH 3
OCH 3
OCH 3
OCH 3
Cl
Cl
Cl
Cl
PMB
OCH 3
H
or a pharmaceutically acceptable salt thereof.
13. The compound of claim 1 , wherein the compound of formula (I) is a compound of formula (IV):
or a pharmaceutically acceptable salt thereof, wherein X, Y, Z, R 1 and R 3 are as defined in claim 1 .
14. The compound of claim 13 , wherein the compound of formula (IV) is a compound of (IVA)
or a pharmaceutically acceptable salt thereof, wherein the bonds between the benzoquinazoline nitrogen and the 1-carbon on the cyclohexyl ring, and the bond between the hydroxy and the 2-carbon on the cyclohexyl ring, are trans.
15. The compound of claim 13 , wherein X and Y are each CH and Z is N.
16. The compound of claim 14 , wherein X and Y are each CH and Z is N.
17. The compound of claim 13 , wherein X, Y and Z are each CH.
18. The compound of claim 14 , wherein X, Y and Z are each CH.
19. A compound of formula (V),
wherein R 2 and Q′ are paired as below:
R 2
Q′
H
or a pharmaceutically acceptable salt thereof.
20. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
21. A compound which is rac-3-[trans-2-hydroxycyclohexyl]-6-[(6-methylpyridin-3-yl)methyl]benzo[h]quinazolin-4(3H)-one, or a pharmaceutically acceptable salt thereof.
22. A compound which is 3-[(1S,2S)-2-hydroxycyclohexyl]-6-[(6-methylpyridin-3-yl)methyl]benzo[h]quinazolin-4(3H)-one, or a pharmaceutically acceptable salt thereof.
23. A compound which is rac-3-[trans-2-hydroxycyclohexyl]-6-[(6-methoxypyridin-3-yl)methyl]benzo[h]quinazolin-4(3H)-one, or a pharmaceutically acceptable salt thereof.
24. A compound which is 3-[(1S,2S)-2-hydroxycyclohexyl]-6-[(6-isopropylpyridin-3-yl)methylbenzo[h]quinazolin-4(3H)-one, or a pharmaceutically acceptable salt thereof.
25. A compound which is rac-3-[trans-2-hydroxycyclohexyl]-6-{[6-(hydroxymethyl)pyridine-3-yl]methyl}benzo[h]quinazolin-4(3H)-one, or a pharmaceutically acceptable salt thereof.