US 2007 O142328A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2007/0142328A1 Chapdelaine et al. (43) Pub. Date: Jun. 21, 2007 (54) COMPOUNDS AND USES THEREOF Publication Classification (51) Int. Cl. (75) Inventors: Marc J. Chapdelaine, Wilmington, DE A6II 3/695 (2006.01) (US); Cyrus J. Ohnmacht, A6II 3 L/502 (2006.01) Wilmington, DE (US); Christopher C07F 7/02 (2006.01) Becker, West Chester, PA (US); C07D 237/28 (2006.01) Hui-Fang Chang, Wilmington, DE (52) U.S. Cl. ............................ 514/63; 514/248; 544/235; (US); Bruce T. Dembofsky, 544,229 Wallingford, PA (US) (57) ABSTRACT This invention relates to novel compounds having the struc Correspondence Address: tural formula I below: ASTRAZENECA PHARMACEUTICALS LP GLOBAL INTELLECTUAL PROPERTY 18OO CONCORD PIKE R3 yH O WILMINGTON, DE 19850-5437 (US) R RI N N1 H (73) Assignee: AstraZeneca AB, Sodertalje (SE) 2 N R5 2 (21) Appl. No.: 11/611,936 (22) Filed: Dec. 18, 2006 Related U.S. Application Data and their pharmaceutically acceptable salts, tautomers or in vivo-hydrolysable precursors, compositions and methods of (60) Provisional application No. 60/752,137, filed on Dec. use thereof. These novel compounds provide a treatment or 20, 2005. Provisional application No. 60/823,693, prophylaxis of anxiety disorders, cognitive disorders, and/or filed on Aug. 28, 2006. mood disorders. US 2007/0142328A1 Jun. 21, 2007 COMPOUNDS AND USES THEREOF are pentameric, ligand-gated chloride ion (Cl) channels 0001. The present application claims the benefit of U.S. belonging to a Superfamily of ligand-gated ionotropic recep Provisional Applications 60/752,137, filed Dec. 20, 2005 tors that includes the nicotinic acetylcholine receptor. and 60/823,693, filed Aug. 28, 2006 under 35 U.S.C. S GABAA receptors are very heterogeneous, with at least 16 119(e), the entireties of which are incorporated herein by different subunits producing potentially thousands of differ reference. ent receptor types. 0007 GABAA receptor subunits aggregate into com FIELD OF THE INVENTION plexes that form chloride ion selective channels and contain 0002 The present invention relates to novel cinnoline sites that bind GABA along with a variety of pharmacologi compounds, their pharmaceutical compositions, methods of cally active substances. When GABA binds to this receptor, use and processes to make Such compounds. In addition, the the anion channel is activated, causing it to open and present invention relates to therapeutic methods for the allowing chloride ions (Cl) to enter the neuron. This influx treatment and/or prevention of anxiety disorders, cognitive of Clions hyperpolarizes the neuron, making it less excit disorders, and/or mood disorders. able. The resultant decrease in neuronal activity following activation of the GABAA receptor complex can rapidly alter BACKGROUND OF THE INVENTION brain function, to Such an extent that consciousness and 0003. The present invention comprises, inter alia, cinno motor control may be impaired. line compounds, their use as central nervous system (CNS) 0008. The numerous possible combinations of GABAA depressants (especially anxiolytics), and pharmacological receptor subunits and the widespread distribution of these tools, methods for their preparation, pharmaceutical com receptors in the nervous system likely contributes to the positions containing the same, and intermediates used in diverse and variable physiological functions of GABAA their preparation. receptors, which have been implicated in many neurological 0004 Some cinnoline compounds including selected and psychiatric disorders, and related conditions, including: 4-amino- and 4-oxo-cinnoline-3-carboxamides are disclosed stroke, head trauma, epilepsy, pain, migraine, mood disor in East German Patent 123525 (Verfahren Zur Herstellung ders, anxiety, post traumatic stress disorder, obsessive com von substituierten 4-Aminocinnolinen): U.S. Pat. No. 4,379, pulsive disorders, Schizophrenia, seizures, convulsions, tin 929 to Conrad etal; U.S. Pat. Nos. 4,886,800 and 4,925,844 nitus, neurodegenerative disorders including Alzheimer's to Resch; Daunis et al., “Preparation et proprietes de cin disease, amyotrophic lateral sclerosis, Huntington's Chorea, nolones-3 et cinnolones-4.” Bull. de la Societe Chimique de Parkinson's disease, depression, bipolar disorders, mania, France, 8:3198-3202 (1972); Lunt et al. “A New Cinnoline trigeminal and other neuralgia, neuropathic pain, hyperten Synthesis,” J. Chem. Soc. (C), 687-695 (1968); Gewald, et Sion, cerebral ischemia, cardiac arrhythmia, myotonia, Sub al., “Synthese von 4-Aminocinnolinen aus (Arylhydrazono) stance abuse, myoclonus, essential tremor, dyskinesia and (cyan)-essigsaurederivaten.” Liebigs Ann. Chem., 1390 other movement disorders, neonatal cerebral hemorrhage, 1394 (1984); and U.S. Pat. No. 3,657.241 to Kurihara. and spasticity. GABAA receptors are also believed to play a Additionally, selected cinnoline compounds, including role in cognition, consciousness, and sleep. 3-acyl-4-substituted cinnoline derivatives are disclosed in 0009 Currently available drugs for modulating GABAA Liebigs Ann. Chem. 1390-1394 (1984) supra and Sandison, receptor activity include barbiturates, such as pentobarbital et al., “A New Heterocyclisation Reaction Leading to Cin and secobarbital, and benzodiazepines such as diazepam, nolin-4(1H)-one Derivatives. J. Chem. Soc. Chem. Comm. chlordiazepoxide and midazolam. Barbiturates can directly 752-753 (1974). Additionally, cinnoline compounds are also activate GABAA receptors, significantly increasing Clcur disclosed in EP205272 and EP 328282. However, none of rents in the absence of further intervention by GABA itself the foregoing discloses or Suggests the novel compounds of and can also indirectly augment GABAergic neural trans the present invention or suggests their use as CNS depres mission. In contrast, benzodiazepines act as indirect allos SantS. teric modulators, and are largely incapable of increasing 0005 gamma-Aminobutyric acid (GABA) is a common Clcurrents in the absence of GABA, but enhance GABA inhibitory neurotransmitter in the mammalian brain and is activated increases in Clconductance. This latter property is estimated to be present at about one third of all synapses. thought to be responsible for the usefulness of benzodiaz When GABA binds to a GABA receptor, it affects the ability epines for treating a number of disorders, including gener of neurons expressing the receptors to conduct neural alized anxiety disorder, panic disorder, seizures, movement impulses. In the adult mammalian nervous system, GABA disorders, epilepsy, psychosis, mood disorders, and muscle typically inhibits neuron firing (depolarization). Neurons in spasms, as well as the relative safety of benzodiazepines the brain express three main types of GABA receptors: compared to barbiturates. GABA type A receptors (GABAA), GABA type B receptors 0010 Both barbiturates and benzodiazepines are addic (GABAB), and GABA type C receptors (GABAC). GABAA tive and can cause drowsiness, poor concentration, ataxia, receptors function as ligand-gated ion channels to mediate dysarthria, motor incoordination, diplopia, muscle weak fast inhibitory synaptic transmissions that regulate neuronal ness, vertigo and mental confusion. These side effects can excitability involved in such responses as seizure threshold, interfere with an individual’s ability to perform daily rou skeletal muscle tone, and emotional status. GABAA recep tines such as driving, operating heavy machinery or per tors are targets of many sedating drugs, such as benzodiaz forming other complex motor tasks while under therapy, epines, barbiturates and neurosteroids. making barbiturates and benzodiazepines less than optimal 0006 The intrinsic inhibitory signal of GABA is trans for treating chronic disorders involving GABA and GABAA duced principally by GABAA receptors. GABAA receptors receptors. US 2007/0142328A1 Jun. 21, 2007 0011 GABAA receptors and GABAergic neural trans missions are implicated as targets for therapeutic interven tion in a myriad of neurological and psychiatric disorders. Adverse side effects, including addictive properties exhib 0018) A is halo, CN, NO, OR', SR, C(=O)R, ited by currently available GABA and GABAA receptor C(=O)NR'R'', C(=O)CR, OC(=O)R, OC(=O)NR'R'', modulating drugs, make these drugs unsuitable in many NRR, NRC(=O)R, NRC(=O)CR', NRS(=O)R, therapeutic contexts. Accordingly, there remains an impor NRS(=O),R, S(=O)R, S(=O)NR'R'', S(=O).R., tant, unmet need in the art for alternative compositions, S(=O)NR'R'', C. alkoxy, C, a haloalkoxy, amino, Ca methods and tools that will be useful in broad clinical alkylamino, C2-s dialkylamino, C- alkyl, C2-alkenyl, C2 applications to modulate the function and activity of GABA alkynyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, hetero and GABA receptors in mammalian Subjects, including cycloalkylalkyl, aryl, cycloalkyl, heteroaryl or heterocy humans, and/or to target GABAergic neural transmission. cloalkyl, wherein each of the C- alkyl, Calkenyl, C The present invention is also, interalia, directed toward this alkynyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, hetero end. cycloalkylalkyl, aryl, cycloalkyl, heteroaryl or heterocy cloalkyl is optionally substituted by 1, 2, 3, 4 or 5 substitu DESCRIPTION OF EMBODIMENTS ents independently selected from halo, Ce alkyl, C 0012 Provided herein are novel compounds of structural alkenyl, C- alkynyl, Chaloalkyl, aryl, cycloalkyl, het formula I: eroaryl, heterocycloalkyl,