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(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date _ . 14 April 2011 (14.04.2011) 2 11/044535 A2 (51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every C07D 471/04 (2006.01) A61P 25/18 (2006.01) kind of national protection available): AE, AG, AL, AM, C07D 413/14 (2006.01) A61P 25/28 (2006.01) AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, C07D 409/14 (2006.01) A61P 25/24 (2006.01) CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, A61K 31/519 (2006.01) DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, (21) International Application Number: KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, PCT/US20 10/052 106 ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, (22) International Filing Date: NO, NZ, OM, PE, PG, PH, PL, PT, RO, RS, RU, SC, SD, 8 October 2010 (08.10.2010) SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (25) Filing Language: English (84) Designated States (unless otherwise indicated, for every (26) Publication Language: English kind of regional protection available): ARIPO (BW, GH, (30) Priority Data: GM, KE, LR, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, 61/250,262 >October 2009 (09.10.2009) US ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, 61/353,054 9 June 2010 (09.06.2010) US TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, ΓΓ, LT, LU, (71) Applicant (for all designated States except US): LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, AFRAXIS, INC. [US/US]; 5626 Oberlin Drive, San SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, Diego, California 92121 (US). GW, ML, MR, NE, SN, TD, TG). (72) Inventors; and Declarations under Rule 4.17 : (75) Inventors/Applicants (for US only): VOLLRATH, — as to applicant's entitlement to apply for and be granted Benedikt [DE/US]; 4704 Niagara Avenue, San Diego, a patent (Rule 4.1 7(H)) California 92107 (US). CAMPBELL, David [US/US]; 1331 8 Seagrove Street, San Diego, California 92130 — as to the applicant's entitlement to claim the priority of (US). DURON, Sergio G. [US/US]; 1605 Neale Street, the earlier application (Rule 4.17(Hi)) San Diego, California 92103 (US). WADE, Warren [US/ Published: US]; 10940 Shy Bird Lane, San Diego, California 92128 (US). — without international search report and to be republished upon receipt of that report (Rule 48.2(g)) (74) Agents: WILSON SONSINI GOODRICH & ROSATI et al; 650 Page Mill Road, Palo Alto, California 94304 (US). < o (54) Title: 8-ETHYL-6-(ARYL)PYRIDO[2,3-D]PYRIMIDIN-7(8H)-ONES FOR THE TREATMENT OF CNS DISORDERS (57) Abstract: Provided herein are PAK inhibitors and methods of utilizing PAK inhibitors for the treatment of CNS disorders such as neuropsychiatric disorders. 8-ETHYL-6-(ARYL)PYRIDO[2,3-D]PYRIMIDIN-7(8H)-ONES FOR THE TREATMENT OF CNS DISORDERS CROSS-REFERENCE [0001] This application claims the benefit of U.S. Provisional Application No. 61/250,262, filed October 9, 2009, and U.S. Provisional Application No. 61/353,054, filed June 9, 2010, which are both incorporated herein by reference in their entirety. BACKGROUND OF THE INVENTION [0002] Central Nervous System (CNS) disorders are characterized by a variety of debilitating affective and cognitive impairments. For example, a clinical sign of individuals with Alzheimer's disease is progressive cognition deterioration. Worldwide, approximately 24 million people have dementia, 60% of these cases are due to Alzheimer's. [0003] Other CNS disorders include, e.g., mood disorders, age-related cognitive decline, and neurological disorders (e.g., epilepsy, schizophrenia, Fragile X mental retardation syndrome and Huntington's disease). The effects of CNS disorders are devastating to the quality of life of those afflicted as well as that of their families. Moreover, CNS disorders impose an enormous health care burden on society. A number of CNS disorders, as well as other conditions that affect cognitive function, have been associated with alterations in the morphology and/or density of dendritic spines, membranous protrusions from dendritic shafts of neurons that serve as highly specialized structures for the formation, maintenance, and function of synapses. SUMMARY OF THE INVENTION [0004] Described herein are compounds, compositions and methods for treating an individual suffering from a CNS disorder, such as by way of example only schizophrenia, Fragile X Syndrome (FXS), clinical depression, age-related cognitive decline, Mild Cognitive Impairment, Huntington's disease, Parkinson's disease, neurofibromatosis, Alzheimer's disease, epilepsy, autism spectrum disorders, mental retardation, Down's syndrome or the like, by administering to an individual a pharmaceutical composition comprising a therapeutically effective amount of an inhibitor of a p21 -activated kinase (PAK), e.g., an inhibitor of PAK1, PAK2, PAK3 or PAK4, as described herein. PAK activation is shown to play a key role in spine morphogenesis. In some instances, attenuation of PAK activity reduces, prevents or reverses defects in spine morphogenesis. In some embodiments, inhibitors of one or more of Group I PAKs (PAK1, PAK2 and/or PAK3) and/or Group II PAKs (PAK4, PAK5 and/or PAK6) are administered to rescue defects in spine morphogenesis in individuals suffering from a condition in which dendritic spine morphology, density, and/or function are aberrant, including but not limited to abnormal spine density, spine size, spine shape, spine plasticity, spine motility or spine plasticity leading to improvements in synaptic function, cognition and/or behavior. [0005] In one aspect is a compound having the structure of Formula I or pharmaceutically acceptable salt or N-oxide thereof: Formula I; wherein: wherein ring T is an aryl, or a heteroaryl ring; R3 is a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heteroaryl attached to ring T via a carbon atom of R , or a substituted or unsubstituted heterocycloalkyl attached to ring T via a carbon atom of R ; 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; 4 each R is independently halogen, -CN, -N0 2, -OH, -OCF3, -OCH2F, -OCF2H, -CF3, 8 10 9 10 8 9 10 -SR , -NR S(=O)2R , -S(=O)2N(R )2, -C(=0)R , -OC(=0)R , -C0 2R , 10 10 10 10 10 10 -N(R )2, -C(=O)N(R )2, -NR C(=O)R , -N R C(=O)OR , 10 10 -NR C(=O)N(R )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; R8 is H or R9; R9 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 R10 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 R10, together with the atoms to which they are attached form a heterocycle; ring B is aryl or heteroaryl; 5 8 9 9 each R is independently halogen, -CN, -N0 2, -OH, -SR , -S(=0)R , -S(=0) 2R , 10 9 10 8 9 10 10 NR S(=O)2R , -S(=O)2N(R )2, -C(=0)R , -OC(=0)R , -C0 2R , -N(R )2, - 10 10 10 10 10 10 10 10 C(=O)N(R )2, -NR C(=O)R , -NR C(=O)OR , -NR C(=O)N(R )2, -OR , 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. [0006] In one embodiment is a compound of Formula I wherein ring T is an aryl ring. In another embodiment is a compound of Formula I wherein ring T is a heteroaryl ring. In yet another embodiment is a compound of Formula I, wherein ring T is selected from pyrrole, furan, thiophene, pyrazole, imidazole, isoxazole, oxazole, isothiazole, thiazole, 1,2,3-triazole, 1,3,4-triazole, l-oxa-2,3-diazole, l-oxa-2,4-diazole, l-oxa-2,5-diazole, 1-oxa- 3,4-diazole, l-thia-2,3-diazole, 1-thia-2,4-diazole, l-thia-2,5-diazole, l-thia-3,4-diazole, tetrazole, pyridine, pyridazine, pyrimidine, and pyrazine. In yet a further embodiment is a compound of Formula I, wherein R is a C-linked heterocycloalkyl. In another embodiment is a compound of Formula I, wherein R is a substituted or unsubstituted C-linked heteroaryl. In another embodiment, R3 is a substituted or unsubstituted cycloalkyl. In a further embodiment, cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. [0007] In yet another embodiment is a compound having the structure of Formula II: Formula II. [0008] In a further embodiment is a compound having the structure of Formula III: Formula III; wherein si is 0 to 3.
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  • Convergent Pharmacological Mechanisms in Impulsivity And

    Convergent Pharmacological Mechanisms in Impulsivity And

    British Journal of DOI:10.1111/bph.12787 www.brjpharmacol.org BJP Pharmacology Themed Section: Animal Models in Psychiatry Research Correspondence Jeffrey W Dalley, Department of Psychology, University of REVIEW Cambridge, Downing St, Cambridge CB2 3EB, UK. E-mail: [email protected] Convergent ---------------------------------------------------------------- Received 20 February 2014 pharmacological Revised 2 May 2014 Accepted mechanisms in impulsivity 12 May 2014 and addiction: insights from rodent models B Jupp1,2 and J W Dalley1,3 1Behavioural and Clinical Neuroscience Institute and Department of Psychology, University of Cambridge, Cambridge, UK, 2Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, Australia, and 3Department of Psychiatry, University of Cambridge, Cambridge, UK Research over the last two decades has widely demonstrated that impulsivity, in its various forms, is antecedent to the development of drug addiction and an important behavioural trait underlying the inability of addicts to refrain from continued drug use. Impulsivity describes a variety of rapidly and prematurely expressed behaviours that span several domains from impaired response inhibition to an intolerance of delayed rewards, and is a core symptom of attention deficit hyperactivity disorder (ADHD) and other brain disorders. Various theories have been advanced to explain how impulsivity interacts with addiction both causally and as a consequence of chronic drug abuse; these acknowledge the strong overlaps in neural circuitry and mechanisms between impulsivity and addiction and the seemingly paradoxical treatment of ADHD with stimulant drugs with high abuse potential. Recent years have witnessed unprecedented progress in the elucidation of pharmacological mechanisms underpinning impulsivity. Collectively, this work has significantly improved the prospect for new therapies in ADHD as well as our understanding of the neural mechanisms underlying the shift from recreational drug use to addiction.