8-ETHYL-6-(ARYL)PYRIDO[2,3-D]PYRIMIDIN-7(8H)-ONES FOR THE TREATMENT OF CNS DISORDERS

1 . A compound having the structure of Formula I or pharmaceutically acceptable salt or N-oxide thereof:

wherein:

wherein ring T is an aryl, or a heteroaryl ring;

R 3 is a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heteroaryl attached to ring T via a carbon atom of R 3 , or a substituted or unsubstituted heterocycloalkyl attached to ring T via a carbon atom of R 3 ;

Q is a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted cycloalkylalkyl, a substituted or unsubstituted heterocycloalkylalkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted arylalkyl, a substituted or unsubstituted heteroaryl, or a substituted or unsubstituted heteroarylalkyl;

each R 4 is independently halogen, —CN, —NO 2 , —OH, —OCF 3 , —OCH 2 F, —OCF 2 H, —CF 3 , —NR 10 S(═O) 2 R 9 , —S(═O) 2 N(R 10 ) 2 , —C(═O)R 8 , —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 , a substituted or unsubstituted alkyl, a substituted or unsubstituted alkoxy, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, or a substituted or unsubstituted heterocycloalkyl;

R 8 is H or R 9 ;

R 9 is a substituted or unsubstituted alkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl;

each R 10 is independently H, a substituted or unsubstituted alkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl; or two R 10 , together with the atoms to which they are attached form a heterocycle;

ring B is aryl or heteroaryl;

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 8 , —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 , —OR 10 , a substituted or unsubstituted alkyl, a substituted or unsubstituted alkoxy, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, or a substituted or unsubstituted heterocycloalkyl;

r is 0 to 8; and

s is 0 to 4.

2 . The compound of claim 1 , wherein ring T is an aryl ring.

3 . The compound of claim 1 , wherein ring T is a heteroaryl ring.

4 . The compound of claim 1 or 3 , wherein ring T is selected from pyrrole, furan, thiophene, pyrazole, imidazole, isoxazole, oxazole, isothiazole, thiazole, 1,2,3-triazole, 1,3,4-triazole, 1-oxa-2,3-diazole, 1-oxa-2,4-diazole, 1-oxa-2,5-diazole, 1-oxa-3,4-diazole, 1-thia-2,3-diazole, 1-thia-2,4-diazole, 1-thia-2,5-diazole, 1-thia-3,4-diazole, tetrazole, pyridine, pyridazine, pyrimidine, and pyrazine.

5 . The compound of claim 2 , wherein R 3 is a C-linked heterocycloalkyl.

6 . The compound of claim 3 or 4 , wherein R 3 is a C-linked heterocycloalkyl.

7 . The compound of claim 2 , wherein R 3 is a substituted or unsubstituted C-linked heteroaryl.

8 . The compound of claim 3 or 4 , wherein R 3 is a substituted or unsubstituted C-linked heteroaryl.

9 . The compound of claim 1 , wherein R 3 is a substituted or unsubstituted cycloalkyl.

10 . The compound of claim 9 wherein cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.

11 . The compound of any of claims 1 - 10 having the structure of Formula II:

12 . The compound of any of claims 1 - 10 having the structure of Formula III:

wherein s1 is 0 to 3.

13 . The compound of any of claims 1 - 10 having the structure of Formula IV:

wherein s1 is 0 to 4.

14 . The compound of any of claims 1 - 10 having the structure of Formula V:

wherein s1 is 0 to 4.

15 . The compound of any of claims 1 - 10 having the structure of Formula Va:

wherein s1 is 0 to 4.

16 . The compound of any of claims 1 - 10 having the structure of Formula Vb:

17 . The compound of any one of claim 1 - 4 or 7 - 16 wherein R 3 is selected from pyrrole, furan, thiophene, pyrazole, imidazole, isoxazole, oxazole, isothiazole, thiazole, 1,2,3-triazole, 1,3,4-triazole, 1-oxa-2,3-diazole, 1-oxa-2,4-diazole, 1-oxa-2,5-diazole, 1-oxa-3,4-diazole, 1-thia-2,3-diazole, 1-thia-2,4-diazole, 1-thia-2,5-diazole, 1-thia-3,4-diazole, tetrazole, pyridine, pyridazine, pyrimidine, and pyrazine.

18 . The compound of any one of claims 1 - 17 , wherein

19 . The compound of any one of claims 1 - 18 , where R 5 is halogen, —CN, —OH, a substituted or unsubstituted alkyl, —OR 10 , —NR 10 S(═O) 2 R 9 , —S(═O) 2 N(R 10 ) 2 , —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 , or a substituted or unsubstituted heterocycloalkyl.

20 . The compound of any one of claims 1 - 18 , wherein at least one R 5 is —NR 10 S(═O) 2 R 9 , —S(═O) 2 N(R 10 ) 2 , —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 , or a substituted or unsubstituted heterocycloalkyl.

21 . The compound of any one of claims 1 - 18 , wherein at least one R 5 is —N(R 10 ) 2 , or a substituted or unsubstituted heterocycloalkyl.

22 . The compound of any one of claims 1 - 18 wherein at least one of R 5 is a substituted or unsubstituted piperazine, a substituted or unsubstituted piperidine, a substituted or unsubstituted pyrrolidine, or a substituted or unsubstituted morpholine.

23 . The compound of any one of claims 1 - 18 , wherein at least one R 5 is —OR 10 .

24 . The compound of any one of claims 1 - 23 , wherein R 4 is independently halogen, —CN, —OH, —OCF 3 , —OCF 3 , —OCF 2 H, —CF 3 , —SR 8 , a substituted or unsubstituted alkyl, or a substituted or unsubstituted alkoxy.

25 . The compound of any one of claim 1 - 11 or 17 - 23 , wherein s is zero.

26 . The compound of any one of claims 1 - 25 , wherein Q is a substituted or unsubstituted alkyl, or a substituted or unsubstituted heteroalkyl.

27 . The compound of any one of claims 1 - 25 , wherein Q is a substituted or unsubstituted cycloalkyl, or a substituted or unsubstituted heterocycloalkyl.

28 . The compound of any one of claims 1 - 25 , wherein Q is a substituted or unsubstituted cycloalkylalkyl, or a substituted or unsubstituted heterocycloalkylalkyl.

29 . The compound of any one of claims 1 - 25 , wherein Q is a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl.

30 . The compound of any one of claims 1 - 25 , wherein Q is a substituted or unsubstituted arylalkyl, or a substituted or unsubstituted heteroarylalkyl.

31 . A compound selected from:

32 . A pharmaceutical composition comprising a compound of any of claims 1 - 31 and a pharmaceutically acceptable excipient, carrier, or binder thereof.

33 . A method of inhibiting or partially inhibiting the activity of a p21-activated kinase comprising contacting the kinase with a compound of any one of claims 1 - 31 , or a pharmaceutically acceptable salt, solvate, or N-oxide thereof, or a composition of claim 32 .

34 . The method of claim 33 wherein the p21-activated kinase is contacted with a compound of any one of claims 1 - 31 or the composition of claim 32 in vivo.

35 . The method of claim 33 , wherein the p21-activated kinase is contacted with a compound of any one of claims 1 - 31 or the composition of claim 32 in vitro.

36 . The method of claim 33 , wherein the p21-activated kinase is PAK1, PAK2, PAK3, PAK4, PAK5, or PAK6.

37 . The method of claim 33 , wherein the p21-activated kinase is a Group I p21-activated kinase.

38 . The method of claim 33 , wherein administration of a therapeutically effective amount of a compound of any one of claims 1 - 31 or the composition of claim 32 causes substantially complete inhibition of one of more Group I p21-activated kinases.

39 . The method of claim 33 , wherein administration of a therapeutically effective amount of a compound of any one of claims 1 - 31 or the composition of claim 32 causes partial inhibition of one of more Group I p21-activated kinases.

40 . The method of claim 33 , wherein administration of a therapeutically effective amount of a compound of any one of claims 1 - 31 or the composition of claim 32 modulates dendritic spine morphology or synaptic function.

41 . The method of claim 33 , wherein administration of a therapeutically effective amount of a compound of any one of claims 1 - 31 or the composition of claim 32 modulates dendritic spine density.

42 . The method of claim 33 , wherein administration of a therapeutically effective amount of a compound of any one of claims 1 - 31 or the composition of claim 32 modulates dendritic spine length.

43 . The method of claim 33 , wherein administration of a therapeutically effective amount of a compound of any one of claims 1 - 31 or the composition of claim 32 modulates dendritic spine neck diameter.

44 . The method of claim 33 , wherein administration of a therapeutically effective amount of a compound of any one of claims 1 - 31 or the composition of claim 32 modulates dendritic spine head diameter.

45 . A method of treating a CNS disorder in an individual comprising administering to an individual in need thereof a therapeutically effective amount of a compound of any one of claims 1 - 31 , or a pharmaceutically acceptable salt, solvate, or N-oxide thereof, or the composition of claim 32 .

46 . The method of claim 45 , wherein the CNS disorder is a neuropsychiatric, neurodegenerative or neurodevelopmental disorder.

47 . The method of claim 45 or 46 , wherein the CNS disorder is schizophrenia, Alzheimer's disease, Mild cognitive impairment, autism, an autism spectrum disorder, neurofibromatosis, bipolar disorder, and depression.

48 . The method of claim 45 wherein the autism spectrum disorder is selected from Fragile X, Retts Aspergers, and Angelman syndrome.

49 . The method of claim 45 , wherein administration of a therapeutically effective amount of a compound of any one of claims 1 - 31 or the composition of claim 32 normalizes or partially normalizes aberrant synaptic plasticity associated with a CNS disorder.

50 . The method of claim 45 , wherein administration of a therapeutically effective amount of a compound of any one of claims 1 - 31 or the composition of claim 32 normalizes or partially normalizes aberrant long term depression (LTD) associated with a CNS disorder.

51 . The method of claim 45 wherein administration of a therapeutically effective amount of a compound of any one of claims 1 - 31 or the composition of claim 32 normalizes or partially normalizes aberrant long term potentiation (LTP) associated with a CNS disorder.

52 . A method of treating a subject suffering from cancer comprising administering to the is subject a therapeutically effective amount of a compound of any one of claims 1 - 31 or the composition of claim 32 .

53 . The method of claim 52 wherein the cancer is selected from ovarian, breast, colon, brain, neurofibromatosis, chronic myelogenous leukemia, renal cell carcinoma, gastric, leukemia, NSCLC, CNS, melanoma, prostate, T-cell lymphoma, heptocellular, bladder and glioblastoma.