US2013035335A1PendingUtilityA1
8-ethyl-6-(aryl)pyrido[2,3-d]pyrimidin-7(8h)-ones for the treatment of cns disorders
Est. expiryOct 9, 2029(~3.2 yrs left)· nominal 20-yr term from priority
A61P 43/00A61P 35/02A61P 35/00A61P 25/28A61P 25/24A61P 25/18A61P 25/00C07D 471/04A61K 31/519C07D 403/12
47
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Claims
Abstract
Provided herein are PAK inhibitors and methods of utilizing PAK inhibitors for the treatment of CNS disorders such as neuropsychiatric disorders.
Claims
exact text as granted — not AI-modified1 . 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.Cited by (0)
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