Compounds for treating neuropsychiatric conditions
Provided herein are pyrido[2,3-D]pyrimidin-7(8H)-one compounds and compositions useful as PAK inhibitors. Also provided herein are methods of utilizing these compounds for the treatment of neuropsychiatric conditions. The compounds modulate dendritic spine morphology and/or synaptic function.
1. A compound having the structure of Formula X or a pharmaceutically acceptable salt thereof:
wherein:
W is a bond;
R 6 is H, halogen, —CN, —OH, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, —N(R 10 ) 2 , substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;
R 7 is H, halogen, —CN, —OH, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, —C(═O)N(R 10 ) 2 , —CO 2 R 10 , —N(R 10 ) 2 , acyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;
Q is
wherein
R 1 and R 2 are each independently H or substituted or unsubstituted alkyl; or R 1 and R 2 together with the carbon to which they are attached form a C 3 -C 6 cycloalkyl ring;
p is 1, 2 or 3;
ring A is aryl substituted with R 3 and R 4 ;
R 3 is a substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocycloalkyl attached to ring A via a carbon atom;
each R 4 is independently halogen, —CN, —NO 2 , —OH, —OCF 3 , —OCF 2 H, —CF 3 , —SR 8 , —S(═O)R 9 , —S(═O) 2 R 9 , —NR 10 S(═O) 2 R 9 , —S(═O) 2 N(R 10 ) 2 , —C(═O)R 9 , —OC(═O)R 9 , —CO 2 R 10 , —N(R 10 ) 2 , —C(═O)N(R 10 ) 2 , —NR 1 OC(═O)R 10 , —N R 10 C(═O)OR 10 , —NR 10 C(═O)N(R 10 ) 2 , substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocycloalkyl;
R 8 is H or substituted or unsubstituted alkyl;
R 9 is substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl
each R 10 is independently H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, or two R 10 together with the atoms to which they are attached form a heterocycle;
s is 0-4;
ring B is aryl or heteroaryl substituted with R 5 ;
wherein each R 5 is independently halogen, —CN, —NO 2 , —OH, —SR 8 , —S(═O)R 9 , —S(═O) 2 R 9 , NR 10 S(═O) 2 R 9 , —S(═O) 2 N(R 10 ) 2 , —C(═O)R 9 , —OC(═O)R 9 , —CO 2 R 10 , —N(R 10 ) 2 , —C(═O)N(R 10 ) 2 , —NR 10 C(═O)R 10 , —NR 10 C(═O)OR 10 , —NR 10 C(═O)N(R 10 ) 2 , substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocycloalkyl; and
r is 0-8.
2. The compound of claim 1 wherein Q is:
3. The compound of claim 1 , wherein Q is
4. The compound of claim 1 , wherein R 3 is a C 3 -C 6 cycloalkyl ring, a 5-6-membered heteroaryl ring comprising 1-3 nitrogen atoms, an oxygen atom, a sulfur atom, or any combination thereof, or a 3-6-membered heterocycloalkyl ring comprising 1-3 nitrogen atoms, an oxygen atom, a sulfur atom, or any combination thereof, that is attached to ring via a carbon atom and wherein R 3 is further substituted by halogen, cyano, alkyl, alkoxy, —SR 8 , (R) or (S)—S(O)R 9 or —S(O) 2 R 9 .
5. The compound of claim 4 , wherein R 1 and R 2 are H.
6. The compound of claim 1 , wherein variables B, R 6 , R 7 , and R 5 , and substructure
are each defined as shown in the following table:
Entry
B
R 6
R 7
R 5
1
H
OH
2
H
Me
3
H
H
4
Cl
H
5
H
H
6
H
H
7
H
CONH 2
8
H
9
Cl
10
H
H
11
H
Cl
12
Me
H
13
H
OMe
14
H
H
15
H
CN
16
H
H
17
H
isopropyl
18
Cl
H
p-SO 2 Me
20
F
21
H
22
H
23
H
H
24
H
H
or a pharmaceutically acceptable salt thereof.
7. A compound selected from the group consisting of:
and pharmaceutically acceptable salts thereof.