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, CN, NO, OR, SR, C(=O)R.

R2 R3 YNH O 0.019 R and Rare each, independently, H. C. alkyl, R RI N N1 Chaloalkyl, C, alkenyl, C. alkynyl, aryl, cycloalkyl, H heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, 2 N cycloalkylalkyl or heterocycloalkylalkyl, wherein the C R5 2 alkyl, Ce haloalkyl, C- alkenyl, C- alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, het eroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally Substituted with OH. amino, halo, Ce alkyl, C. or a pharmaceutically acceptable salt, tautomer, atropisomer, haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, or in vivo-hydrolysable precursor thereof, wherein: cycloalkyl or heterocycloalkyl; 0013) R' is C, alkyl, Ce haloalkyl, aryl, heteroaryl, 0020 R and Rare each, independently, H, C, alkyl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, Chaloalkyl, C. alkenyl, C. alkynyl, aryl, cycloalkyl, cycloalkylalkyl or heterocycloalkylalkyl, each optionally heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein the C substituted by 1, 2, 3, 4 or 5 R7: alkyl, C- haloalkyl, C2- alkenyl, C2- alkynyl, aryl, 0014) R is H, C(=O)Rb, C(=O)NR'R'', C(=O)CR', cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, het S(=O).R. C. alkyl, C- haloalkyl, aryl, heteroaryl, eroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, optionally Substituted with OH. amino, halo, Ce alkyl, C. cycloalkylalkyl or heterocycloalkylalkyl, wherein each of haloalkyl, C. haloalkyl, aryl, arylalkyl, heteroaryl, het the C- alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, eroarylalkyl, cycloalkyl or heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocy 0021) R' and Rare each, independently, H, C, to alkyl, cloalkylalkyl is optionally substituted by 1, 2, 3, 4 or 5 R: C. haloalkyl, C- alkenyl, Ce alkynyl, aryl, heteroaryl, 0015 R, R and R are each, independently, H, halo, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, Si(C., alkyl), CN, NO, OR', SR", OC(=O)R’, cycloalkylalkyl or heterocycloalkylalkyl, wherein the Co OC(CO)OR, OC(=O)NR'R'', C(=O)R., C(=O)CR, alkyl, Ce haloalkyl, C- alkenyl, C- alkynyl, aryl, het C(=O)NR'R'', NRR, NRC(=O)R, NRC(=O)CR, eroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroary NRS(=O),R, S(=O)R', S(=O)NR'R'', S(=O),R, lalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally S(=O)NR'R'', C. alkyl, Chaloalkyl, Coalkenyl, C Substituted with OH, amino, halo, Ce alkyl, Chaloalkyl, alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, ary C. haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, lalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalky cycloalkyl or heterocycloalkyl; lalkyl, wherein the C- alkyl, Ce haloalkyl, Calkenyl, C. alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, 0022 or R and R together with the N atom to which arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocy they are attached form a 4-, 5-, 6- or 7-membered hetero cloalkylalkyl is optionally substituted by 1, 2 or 3 R': cycloalkyl group; and 0016 R is aryl, cycloalkyl, heteroaryl or heterocy 0023 R and Rare each, independently, H, Co alkyl, Chaloalkyl, C. alkenyl, C. alkynyl, aryl, heteroaryl, cloalkyl, each optionally substituted by 1, 2, 3, 4 or 5 A'; cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, 0017 R, R and R are each, independently, halo, Ca cycloalkylalkyl or heterocycloalkylalkyl, wherein the Co alkyl, Chaloalkyl, aryl, cycloalkyl, heteroaryl, heterocy alkyl, Ce haloalkyl, C- alkenyl, C- alkynyl, aryl, het cloalkyl, CN, NO, OR, SR, C(=O)Rb, C(=O)NR'R'', eroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroary

US 2007/0142328A1 Jun. 21, 2007 described herein, or a pharmaceutically acceptable salt, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, tautomer, atropisomer, or in vivo-hydrolysable precursor cycloalkylalkyl or heterocycloalkylalkyl, wherein each of thereof. the C- alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, 0085. The present invention further provides methods of arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocy treating or preventing a cognitive disorder in a patient, cloalkylalkyl is optionally substituted by 1, 2, 3, 4 or 5 R: comprising administering to the patient a therapeutically 0094) R, R and R are each, independently, H, halo, effective amount of a compound of any of the formulas Si(C., alkyl), CN, NO, OR', SR", OC(=O)R’, described herein, or a pharmaceutically acceptable salt, OC(CO)OR, OC(=O)NR'R'', C(=O)R, C(=O)CR, tautomer, atropisomer, or in vivo-hydrolysable precursor C(=O)NR'R'', NRR, NRC(=O)R, NRC(=O)CR, thereof. NRS(=O),R, S(=O)R', S(=O)NR'R'', S(=O),R, 0.086 The present invention further provides methods of S(=O)NR'R'', C. alkyl, Chaloalkyl, Calkenyl, C. treating or preventing a mood disorder in a patient, com alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, ary prising administering to the patient a therapeutically effec lalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalky lalkyl, wherein the C- alkyl, Ce haloalkyl, Calkenyl, tive amount of a compound of any of the formulas described C. alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, herein, or a pharmaceutically acceptable salt, tautomer, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocy atropisomer, or in vivo-hydrolysable precursor thereof. cloalkylalkyl is optionally substituted by 1, 2 or 3 R': 0087. The present invention further provides a compound of any of the formulas described herein, or a pharmaceuti 0.095 R is aryl, cycloalkyl, heteroaryl or heterocy cally acceptable salt, tautomer, atropisomer, or in vivo cloalkyl, each optionally substituted by 1, 2, 3, 4 or 5 A'; hydrolysable precursor thereof, described herein for use as 0096) R, R and R are each, independently, halo, Ca a medicament. alkyl, Chaloalkyl, aryl, cycloalkyl, heteroaryl, heterocy 0088. The present invention further provides a compound cloalkyl, CN, NO, OR, SR, C(=O)Rb, C(=O)NR'R'', of any of the formulas described herein, or a pharmaceuti C(=O)CR, OC(=O)R, OC(=O)NR'R'', NR'R'', cally acceptable salt, tautomer, atropisomer, or in vivo NRC(=O)R, NRC(=O)CR, NRS(=O),R, hydrolysable precursor thereof, described herein for the S(=O)R', S(=O)NR'R'', S(=O).R, or S(=O)NR'R''. manufacture of a medicament. 0097 A' is halo, CN, NO, OR', SR, C(=O)R, 0089. The present invention further provides methods of C(=O)NR'R'', C(=O)CR, OC(=O)R, OC(=O)NR'R'', modulating activity of GABAA receptor comprising con NRR, NRC(=O)R, NRC(=O)CR, NRS(=O)R, tacting the GABAA receptor with a compound of any of the NRS(=O).Rb, S(=O)R, S(=O)NR'R'', S(=O).R, formulas described herein, or a pharmaceutically acceptable S(=O)NR'R'', C. alkoxy, C, a haloalkoxy, amino, Ca salt, tautomer, atropisomer, or in vivo-hydrolysable precur alkylamino, C2-s dialkylamino, C- alkyl, C2-alkenyl, C2 sor thereof. alkynyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, hetero cycloalkylalkyl, aryl, cycloalkyl, heteroaryl or heterocy 0090 The present invention further provides synthetic cloalkyl, wherein each of the C- alkyl, Calkenyl, C methods of making a compound of any of the formulas alkynyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, hetero described herein, or a pharmaceutically acceptable salt, cycloalkylalkyl, aryl, cycloalkyl, heteroaryl or heterocy tautomer, atropisomer, or in vivo-hydrolysable precursor cloalkyl is optionally substituted by 1, 2, 3, 4 or 5 substitu thereof. ents independently selected from halo, Ce alkyl, C 0.091 Provided herein are novel compounds of structural alkenyl, C- alkynyl, Chaloalkyl, aryl, cycloalkyl, het formula I: eroaryl, heterocycloalkyl, CN, NO, OR', SR", C(=O)R.

R2 R3 YNH O 0098) R' and Rare each, independently, H, C, alkyl, R RI N N1 Chaloalkyl, C. alkenyl, C. alkynyl, aryl, cycloalkyl, H heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein the C R5 22 N alkyl, C- haloalkyl, C2- alkenyl, C2- alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, het eroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally Substituted with OH. amino, halo, Ce alkyl, C. or a pharmaceutically acceptable salt, tautomer, atropisomer, haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, or in vivo-hydrolysable precursor thereof, wherein: cycloalkyl or heterocycloalkyl; 0099 R and Rare each, independently, H, C, alkyl, 0092) R' is C, alkyl, Ce haloalkyl, aryl, heteroaryl, Chaloalkyl, C, alkenyl, C. alkynyl, aryl, cycloalkyl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, each optionally cycloalkylalkyl or heterocycloalkylalkyl, wherein the C substituted by 1, 2, 3, 4 or 5 R7: alkyl, C- haloalkyl, C2- alkenyl, C2- alkynyl, aryl, 0093) R is H, C(=O)R, C(=O)NR'R'', C(=O)CR, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, het S(=O).R. C. alkyl, Ce haloalkyl, aryl, heteroaryl, eroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is

US 2007/0142328A1 Jun. 21, 2007

0251 4-amino-N-butyl-8-(2,5-dimethoxyphenyl)cinno 0276 4-amino-8-(3-chlorophenyl)-N-propyl-cinnoline line-3-carboxamide; 3-carboxamide: 0252) 4-amino-8-(2,5-dimethoxyphenyl)-N-ethylcinno 0277 4-amino-8-(4-chlorophenyl)-N-propyl-cinnoline line-3-carboxamide; 3-carboxamide: 0253) 4-amino-8-(2,5-dimethoxyphenyl)-N-methylcin 0278 4-amino-8-(o-tolyl)-N-propyl-cinnoline-3-car noline-3-carboxamide; boxamide; 0254 4-amino-N-butyl-8-(2,4-dimethoxypyrimidin-5- yl)cinnoline-3-carboxamide; 0279 4-amino-8-(m-tolyl)-N-propyl-cinnoline-3-car boxamide; 0255 4-amino-8-(2,4-dimethoxypyrimidin-5-yl)-N-eth ylcinnoline-3-carboxamide; 0280 4-amino-N-propyl-8-(3-thienyl)cinnoline-3-car boxamide; and 0256 4-amino-8-(2,4-dimethoxypyrimidin-5-yl)-N-me thylcinnoline-3-carboxamide: 0281 4-amino-8-(2,6-dimethylphenyl)-N-propyl-cinno 0257 4-amino-8-(4-methoxypyridin-3-yl)-N-(tetrahy line-3-carboxamide; drofuran-2-ylmethyl)cinnoline-3-carboxamide: or a pharmaceutically acceptable salt thereof, or any Sub 0258 4-amino-N-isobutyl-8-(4-methoxypyridin-3-yl group thereof. )cinnoline-3-carboxamide; 0282 Compounds of the present invention also include 0259 4-amino-N-(2-hydroxypropyl)-8-(4-methoxypyri pharmaceutically acceptable salts, tautomers and in vivo din-3-yl)cinnoline-3-carboxamide: hydrolysable precursors of the compounds of any of the formulas described herein. Compounds of the invention 0260 4-amino-8-(2-methoxy-5-methylphenyl)-N-(tet further include hydrates and solvates. rahydrofuran-2-ylmethyl)cinnoline-3-carboxamide: 0283 Compounds of the invention can be used as medi 0261 4-amino-N-isobutyl-8-(2-methoxy-5-methylphe caments. In some embodiments, the present invention pro nyl)cinnoline-3-carboxamide; vides compounds of any of the formulas described herein, or 0262 4-amino-N-(2-hydroxypropyl)-8-(2-methoxy-5- pharmaceutically acceptable salts, tautomers or in vivo methylphenyl)cinnoline-3-carboxamide: hydrolysable precursors thereof, for use as medicaments. In Some embodiments, the present invention provides com 0263 4-amino-8-(2,5-dimethoxyphenyl)-N-(tetrahydro pounds described herein for use as medicaments for treating furan-2-ylmethyl)cinnoline-3-carboxamide: or preventing an anxiety disorder, cognitive disorder, or 0264 4-amino-8-(2,5-dimethoxyphenyl)-N-isobutylcin mood disorder. noline-3-carboxamide; 0284. In some embodiments, the present invention pro 0265 4-amino-8-(2,5-dimethoxyphenyl)-N-(2-hydrox vides compounds of any of the formulas described herein, or ypropyl)cinnoline-3-carboxamide; pharmaceutically acceptable salts, tautomers or in vivo hydrolysable precursors thereof, in the manufacture of a 0266 4-amino-8-(2,4-dimethoxypyrimidin-5-yl)-N-(tet medicament for the treatment or prophylaxis of an anxiety rahydrofuran-2-ylmethyl)cinnoline-3-carboxamide: disorder, cognitive disorder, or mood disorder. 0267 4-amino-8-(2,4-dimethoxypyrimidin-5-yl)-N- 0285) In some embodiments, the present invention pro isobutylcinnoline-3-carboxamide; and vides a method for the treatment or prophylaxis of an anxiety 0268 4-amino-8-(2,4-dimethoxypyrimidin-5-yl)-N-(2- disorder comprising administering to a mammal (including hydroxypropyl)cinnoline-3-carboxamide; a human) a therapeutically effective amount of a compound of any of the formulas described herein, or a pharmaceuti or a pharmaceutically acceptable salt thereof, or any Sub cally acceptable salt, tautomer or in vivo-hydrolysable pre group thereof cursor thereof As used herein, the phrase "anxiety disorder 0269. In some embodiments, the present invention pro includes, but is not limited to, one or more of the following: vides the following compounds: panic disorder, panic disorder without agoraphobia, panic disorder with agoraphobia, agoraphobia without history of 0270 4-amino-8-(2,3-dimethylphenyl)-N-propyl-cinno panic disorder, specific phobia, Social phobia, Social anxiety line-3-carboxamide; disorder, obsessive-compulsive disorder, posttraumatic 0271 4-amino-8-(3,5-dimethylphenyl)-N-propyl-cinno stress disorder, acute stress disorder, generalized anxiety line-3-carboxamide; disorder, generalized anxiety disorder due to a general medical condition, and the like. 0272 4-amino-8-(2,4-dimethylphenyl)-N-propyl-cinno 0286. In some embodiments, the present invention pro line-3-carboxamide; vides a method for the treatment or prophylaxis of a cog 0273 4-amino-8-(3,4-dimethylphenyl)-N-propyl-cinno nitive disorder comprising administering to a mammal line-3-carboxamide; (including a human) a therapeutically effective amount of a compound of any of the formulas described herein, or a 0274 4-amino-N-(cyclopropylmethyl)-8-phenyl-cinno pharmaceutically acceptable salt, tautomer or in vivo-hy line-3-carboxamide; drolysable precursor thereof As used herein, the phrase 0275 4-amino-N-propyl-8-(p-tolyl)cinnoline-3-carboxa “cognitive disorder” includes, but is not limited to, one or mide; more of the following: Alzheimer's disease, dementia, US 2007/0142328A1 Jun. 21, 2007

dementia due to Alzheimer's disease, dementia due to Par 0294. When used for pharmaceutical compositions, kinson's disease, and the like. medicaments, manufacture of a medicament, or treating or 0287. In some embodiments, the present invention pro preventing an anxiety disorder, cognitive disorder, or mood vides a method for the treatment or prophylaxis of a mood disorder (Such as any of those described herein), compounds disorder comprising administering to a mammal (including of the present invention include the compounds of any of the a human) a therapeutically effective amount of a compound formulas described herein, and pharmaceutically acceptable of any of the formulas described herein, or a pharmaceuti salts, tautomers and in vivo-hydrolysable precursors thereof cally acceptable salt, tautomer or in vivo-hydrolysable pre Compounds of the present invention further include hydrates cursor thereof As used herein, the phrase “mood disorder is and Solvates. a depressive disorder including, but is not limited to, one or 0295) The definitions set forth in this application are more of the following: major depressive disorder, dysthymic intended to clarify terms used throughout this application. disorder, bipolar depression and/or bipolar mania, bipolar I The term “herein” means the entire application. with or without manic, depressive or mixed episodes, bipo lar II, cyclothymic disorder, mood disorder due to a general 0296. As used in this application, the term “optionally medical condition, manic episodes associated with bipolar Substituted,” as used herein, means that Substitution is disorder, mixed episodes associated with bipolar disorder, optional and therefore it is possible for the designated atom and the like. or moiety to be unsubstituted. In the event a substitution is desired then Such substitution means that any number of 0288 Anxiety disorders, cognitive disorders, and mood hydrogens on the designated atom or moiety is replaced with disorders are defined, for example, in the American Psychi a selection from the indicated group, provided that the atric Association: Diagnostic and Statistical Manual of Men normal valency of the designated atom or moiety is not tal Disorders, Fourth Edition, Text Revision, Washington, exceeded, and that the Substitution results in a stable com D.C., American Psychiatric Association, 2000. pound. For example, if a methyl group (i.e., CH) is option 0289. In some embodiments, the present invention pro ally Substituted, then 3 hydrogens on the carbon atom can be vides a method of treating or preventing an anxiety disorder, replaced. Examples of suitable substituents include, but are cognitive disorder, or mood disorder (such as any of those not limited to: halogen, CN, NH, OH, SO, SO, COOH, described herein), by administering to a mammal (including OC-alkyl, CH-OH, SOH, Calkyl, OC-alkyl, a human) a compound of any of the formulas described C(=O)Calkyl, C(=O)CC-alkyl, C(=O)NH, herein or a pharmaceutically acceptable salt, tautomer or in C(=O)NHCalkyl, C(=O)N(Calkyl), SOC-alkyl, vivo-hydrolysable precursors and a cognitive and/or SONHC alkyl, SON(Calkyl). NH(Calkyl), N(C. memory enhancing agent. 6alkyl), NHC(=O)Calkyl, NC(=O)(Calkyl). Csaryl, OCsaryl, C(=O)Csaryl, C(=O)CCsaryl, 0290. In some embodiments, the present invention pro C(=O)NHCsaryl, C(=O)N(Csaryl), SOCsaryl, vides a method of treating or preventing an anxiety disorder, SONHCsaryl, SON(Csaryl), NH(Csaryl), N(Cs. cognitive disorder, or mood disorder (such as any of those 6aryl), NC(=O)Csaryl, NC(=O)(Csaryl), Chetero described herein), by administering to a mammal (including cyclyl, OCs-heterocyclyl, C(=O)Cs-heterocyclyl, a human) a compound of any of the formulas described C(=O)CCsheterocyclyl, C(=O)NHCheterocyclyl, herein or a pharmaceutically acceptable salt, tautomer or in C(=O)N(Cs-heterocyclyl), SOCs-heterocyclyl, vivo-hydrolysable precursors thereof wherein constituent SONHCs heterocyclyl, SON(Cs-heterocyclyl), NH(Cs. members are provided herein, and a choline esterase inhibi 6heterocyclyl), N(Csheterocyclyl), NC(=O)Cshetero tor or anti-inflammatory agent. cyclyl, NC(=O)(Cs-heterocyclyl). 0291. In some embodiments, the present invention pro vides a method of treating or preventing an anxiety disorder, 0297. A variety of compounds in the present invention cognitive disorder, or mood disorder (such as any of those may exist in particular Stereoisomeric forms. The present described herein), by administering to a mammal (including invention takes into account all Such compounds, including human) a compound of the present invention, and an atypi cis- and trans isomers, R- and S-enantiomers, diastereomers, cal antipsychotic agent. Atypical antipsychotic agents (D)-isomers, (L)-isomers, the racemic mixtures thereof, and include, but not limited to, Olanzapine (marketed as other mixtures thereof, as being covered within the scope of Zyprexa), Aripiprazole (marketed as Abilify), Risperidone this invention. Additional asymmetric carbon atoms may be (marketed as Risperdal), Quetiapine (marketed as Seroquel), present in a Substituent such as an alkyl group. All Such Clozapine (marketed as CloZaril), Ziprasidone (marketed as isomers, as well as mixtures thereof, are intended to be Geodon) and Olanzapine/Fluoxetine (marketed as Symb included in this invention. The compounds herein described yax). may have asymmetric centers. Compounds of the present invention containing an asymmetrically Substituted atom 0292. In some embodiments, the mammal or human may be isolated in optically active or racemic forms. It is being treated with a compound of the present invention, has well known in the art how to prepare optically active forms, been diagnosed with a particular disease or disorder. Such as Such as by resolution of racemic forms or by synthesis from those described herein. In these cases, the mammal or optically active starting materials. When required, separa human being treated is in need of Such treatment. Diagnosis, tion of the racemic material can be achieved by methods however, need not be previously performed. known in the art. Many stereoisomers of olefins, C=N 0293. The present invention also includes pharmaceutical double bonds, and the like can also be present in the compositions which contain, as the active ingredient, one or compounds described herein, and all Such stable isomers are more of the compounds of the invention herein together with contemplated in the present invention. Cis and trans isomers at least one pharmaceutically acceptable carrier, diluent or of the compounds of the present invention are described and excipent. may be isolated as a mixture of isomers or as separated US 2007/0142328A1 Jun. 21, 2007

isomeric forms. All chiral, diastereomeric, racemic forms substituents as described above. The term “aryl also and all stereoisomeric forms of a structure are intended, includes polycyclic ring systems having two or more cyclic unless the specific stereochemistry or isomeric form is rings in which two or more carbons are common to two specifically indicated. adjoining rings (the rings are “fused rings’) wherein at least 0298 The compounds of the invention may form isolable one of the rings is aromatic, for example, the other cyclic atropisomers in certain solvents (e.g. Supercritical CO rings can be cycloalkyls, cycloalkenyls or cycloalkynyls. containing 25-35% methanol) at room temperature. The The terms ortho, meta and para apply to 1.2-, 1.3- and atropisomers of the compounds may be isolated using chiral 1,4-disubstituted benzenes, respectively. For example, the LC. All atropisomers of a structure are intended, unless the names 1,2-dimethylbenzene and ortho-dimethylbenzene are specific atropisomer is specifically indicated. synonymous. 0299 When a bond to a substituent is shown to cross a 0307 The term “cycloalkyl,” used alone or as suffix or bond connecting two atoms in a ring, then such substituent prefix, refers to a saturated monovalent ring-containing may be bonded to any atom on the ring. When a substituent hydrocarbon radical comprising at least 3 up to about 12 is listed without indicating the atom via which such sub carbon atoms. Examples of cycloalkyls include, but are not stituent is bonded to the rest of the compound of a given limited to, C-cycloalkyl groups, such as cyclopropyl. formula, then such substituent may be bonded via any atom cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl, and in such substituent. Combinations of substituents and/or saturated cyclic and bicyclic terpenes. A cycloalkyl can be variables are permissible only if such combinations result in unsubstituted or substituted by one or two suitable substitu stable compounds. ents. Preferably, the cycloalkyl is a monocyclic ring or bicyclic ring. 0300. The term “C.” or "C group' used alone or as a prefix, refers to any group having m to n carbon atoms. 0308) As used herein, “cycloalkenyl refers to ring-con taining hydrocarbyl groups having at least one carbon 0301 The term “alkyl used alone or as a suffix or prefix, carbon double bond in the ring, and having from 3 to 12 refers to a saturated monovalent straight or branched chain hydrocarbon radical comprising 1 to about 12 carbon atoms. carbons atoms. Illustrative examples of alkyls include, but are not limited to, 0309 As used herein, “halo” or “halogen” refers to Calkyl groups, such as methyl, ethyl, propyl, isopropyl. fluoro, chloro, bromo, and iodo. "Counterion' is used to 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, represent a small, negatively or positively charged species 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl. such as chloride (Cl), bromide (Br), hydroxide (OH), 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, acetate (CHCOO), sulfate (SO), tosylate (CH-phenyl 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, SO), benezensulfonate (phenyl-SO), sodium ion (Na"), 2,2-dimethyl-1-butyl, 3.3-dimethyl-1-butyl, 2-ethyl-1-butyl, potassium (K), ammonium (NH), and the like. butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, and hexyl, and longer alkyl groups, such as heptyl, and octyl. 0310. The term "heterocycle' used alone or as a suffix or prefix, refers to a ring-containing structure or molecule 0302) The term “alkylene' used alone or as suffix or having one or more multivalent heteroatoms, independently prefix, refers to divalent straight or branched chain hydro selected from N, O, P and S, as a part of the ring structure carbon radicals comprising 1 to about 12 carbon atoms, and including at least 3 and up to about 20 atoms in the which serves to links two structures together. ring(s). Heterocycle may be saturated or unsaturated, con 0303 As used herein, “alkenyl refers to an alkyl group taining one or more double bonds, and heterocycle may having one or more double carbon-carbon bonds. Example contain more than one ring. When a heterocycle contains alkenyl groups include ethenyl, propenyl, cyclohexenyl, and more than one ring, the rings may be fused or unfused. Fused the like. The term “alkenylenyl refers to a divalent linking rings generally refer to at least two rings share two atoms alkenyl group. therebetween. Heterocycle may have aromatic character or 0304 As used herein, “alkynyl refers to an alkyl group may not have aromatic character. having one or more triple carbon-carbon bonds. Example 0311. The term "heteroaromatic” used alone or as a suffix alkynyl groups include ethynyl, propynyl, and the like. The or prefix, refers to a ring-containing structure or molecule term “alkynylenyl refers to a divalent linking alkynyl having one or more multivalent heteroatoms, independently group. selected from N, O, P and S, as a part of the ring structure 0305 As used herein, “aromatic' refers to hydrocarbyl and including at least 3 and up to about 20 atoms in the groups having one or more polyunsaturated carbon rings ring(s), wherein the ring-containing structure or molecule having aromatic characters, (e.g., 4n+2 delocalized elec has an aromatic character (e.g., 4n+2 delocalized electrons). trons) and comprising up to about 14 carbon atoms. 0312 The term "heterocyclic group.”heterocyclic moi 0306 As used herein, the term “aryl” refers to an aro ety.”heterocyclic.' or "heterocyclo’ used alone or as a matic ring structure made up of from 5 to 14 carbon atoms. suffix or prefix, refers to a radical derived from a heterocycle Ring structures containing 5, 6, 7 and 8 carbon atoms would by removing one or more hydrogens therefrom. be single-ring aromatic groups, for example, phenyl. Ring 0313 The term "heterocyclyl used alone or as a suffix or structures containing 8, 9, 10, 11, 12, 13, or 14 would be a prefix, refers a monovalent radical derived from a hetero polycyclic moiety in which at least one carbon is common cycle by removing one hydrogen therefrom. to any two adjoining rings therein (for example, the rings are “fused rings'), for example naphthyl. The aromatic ring can 0314. The term "heterocyclylene' used alone or as a be substituted at one or more ring positions with Such suffix or prefix, refers to a divalent radical derived from a US 2007/0142328A1 Jun. 21, 2007 heterocycle by removing two hydrogens therefrom, which nyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, serves to links two structures together. 1.2.3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1.3, 4-oxadiazolyl, oxazolidinyl, oxazolyl, oxirane, oxazolidi 0315. The term "heteroaryl used alone or as a suffix or nylperimidinyl, phenanthridinyl, phenanthrolinyl, phenar prefix, refers to a heterocyclyl having aromatic character. Sazinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, 0316 The term "heterocylcoalkyl used alone or as a phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridi Suffix or prefix, refers to a monocyclic or polycyclic ring nyl, piperidonyl, 4-piperidonyl, purinyl, pyranyl, pyrrolidi comprising carbon and hydrogen atoms and at least one nyl, pyrroline, pyrrolidine, pyrazinyl, pyrazolidinyl, pyra heteroatom, preferably, 1 to 3 heteroatoms selected from Zolinyl, pyrazolyl, pyridazinyl, pyridooxazole, nitrogen, oxygen, and Sulfur, and having no unsaturation. pyridoimidazole, pyridothiazole, pyridinyl, N-oxide-pyridi Examples of heterocycloalkyl groups include pyrrolidinyl, nyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolidinyl dione, pyrrolidino, piperidinyl, piperidino, piperazinyl, piperazino, pyrrolinyl, pyrrolyl pyridine, quinazolinyl, quinolinyl, morpholinyl, morpholino, thiomorpholinyl, thiomorpholino, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, carbolinyl, tet and pyranyl. A heterocycloalkyl group can be unsubstituted rahydrofuranyl, tetramethylpiperidinyl, tetrahydroquinoline, or substituted with one or two suitable substituents. Prefer tetrahydroisoquinolinyl, thiophane, thiotetrahydroquinoli ably, the heterocycloalkyl group is a monocyclic or bicyclic nyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadia ring, more preferably, a monocyclic ring, wherein the ring Zolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, comprises from 3 to 6 carbon atoms and form 1 to 3 thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, heteroatoms, referred to herein as C. heterocycloalkyl. thienoimidazolyl, thiopheneyl, thirane, triazinyl, 1,2,3-tria 0317. The term "heteroarylene' used alone or as a suffix Zolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1.3,4-triazolyl, Xanthe or prefix, refers to a heterocyclylene having aromatic char nyl. acter. 0326. As used herein, “alkoxy” or “alkyloxy' represents 0318. The term "heterocycloalkylene' used alone or as a an alkyl group as defined above with the indicated number suffix or prefix, refers to a heterocyclylene that does not have of carbon atoms attached through an oxygen bridge. Examples of alkoxy include, but are not limited to, methoxy, aromatic character. ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, t-bu 0319. The term “six-membered” used as prefix refers to toxy, n-pentoxy, isopentoxy, cyclopropylmethoxy, allyloxy a group having a ring that contains six ring atoms. and propargyloxy. Similarly, “alkylthio’ or “thioalkoxy” 0320) The term “five-membered” used as prefix refers to represent an alkyl group as defined above with the indicated a group having a ring that contains five ring atoms. number of carbon atoms attached through a Sulphur bridge. 0321) A five-membered ring heteroaryl is a heteroaryl 0327 “Halogenated,” used as a prefix of a group, means with a ring having five ring atoms wherein 1, 2 or 3 ring one or more hydrogens on the group is replaced with one or atoms are independently selected from N, O and S. more halogens. 0322 Exemplary five-membered ring heteroaryls are 0328. As used herein, the term “carbonyl is art recog thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl pyra nized and includes the -CO=O) groups of Such moieties as Zolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazolyl, 1.2, can be represented by the general formula: 3-thiadiazolyl, 1.2.3-oxadiazolyl, 1,2,4-triazolyl, 1,2,4-thia diazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl, 1,3,4- thiadiazolyl, and 1,3,4-oxadiazolyl. O O

0323) A six-membered ring heteroaryl is a heteroaryl --x-Rs O -x-I-R with a ring having six ring atoms wherein 1, 2 or 3 ring atoms are independently selected from N, O and S. wherein X is a bond or represents an oxygen or Sulfur, and 0324 Exemplary six-membered ring heteroaryls are R represents a hydrogen, an alkyl, an alkenyl, -(CH) - pyridyl, pyrazinyl, pyrimidinyl, triazinyl and pyridazinyl. R" or a pharmaceutically acceptable salt, R' represents a 0325 Examples of heterocyclyls include, but are not hydrogen, an alkyl, an alkenyl or —(CH), R", where m limited to, 1H-indazole, 2-pyrrolidonyl, 2H, 6H-1.5.2-dithi is an integer less than or equal to ten, and R" is alkyl, azinyl, 2H-pyrrolyl, 3H-indolyl, 4-piperidonyl, 4aH-carba cycloalkyl, alkenyl, aryl, or heteroaryl. Where X is an Zole, 4H-quinolizinyl, 6H-1,2,5-thiadiazinyl, acridinyl, oxygen and RandR is not hydrogen, the formula represents aZabicyclo, aZetidine, azepane, aziridine, azocinyl, benzimi an “ester. Where X is an oxygen, and R is as defined above, dazolyl, benzodioxol, benzofuranyl, benzothiofuranyl, ben the moiety is referred to herein as a carboxyl group, and Zothiophenyl, benzoxazolyl, benzthiazolyl, benzotriazolyl, particularly when R is a hydrogen, the formula represents a benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimi “carboxylic acid.” Where X is oxygen, and R' is a hydrogen, dazalonyl, carbazolyl, 4aH-carbazolyl b-carbolinyl, chro the formula represents a “formate.” In general, where the manyl, chromenyl, cinnolinyl, diazepane, decahydroquino oxygen atom of the above formula is replaced by sulfur, the linyl, 2H,6H-1.5.2-dithiazinyl, dioxolane, furyl, 2.3- formula represents a “thiolcarbonyl group. Where X is a dihydrofuran, 2,5-dihydrofuran, dihydrofuro 2,3-b sulfur and R and R' is not hydrogen, the formula represents tetrahydrofuran, furanyl, furazanyl, homopiperidinyl, a “thiolester.” Where X is sulfur and R is hydrogen, the imidazolidine, imidazolidinyl, imidazolinyl, imidazolyl, formula represents a “thiolcarboxylic acid.” Where X is 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, sulfur and R' is hydrogen, the formula represents a “thiol isobenzofuranyl, isochromanyl, isolindazolyl, isoindolinyl, formate.” On the other hand, where X is a bond, and R is not isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, morpholi a hydrogen, the above formula represents a “ketone' group. US 2007/0142328A1 Jun. 21, 2007 20

Where X is a bond, and R is hydrogen, the above formula is acids. For example, such conventional non-toxic salts represents an 'aldehyde' group. include those derived from inorganic acids such as hydro 0329. As used herein, the term “sulfonyl refers to the chloric, phosphoric, and the like; and the salts prepared from —S(=O) of a moiety that can be represented by the organic acids such as lactic, maleic, citric, benzoic, meth general formula: anesulfonic, and the like. 0334 The pharmaceutically acceptable salts of the present invention can be synthesized from the parent com pound that contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by HS-R reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two: nonaqueous media like ether, ethyl acetate, ethanol, isopro wherein R is represented by but not limited to hydrogen, panol, or acetonitrile can be used. alkyl, cycloalkyl, alkenyl, aryl, heteroaryl, aralkyl, or het 0335). As used herein, “in vivo hydrolysable precursors” eroaralkyl. means an in vivo hydroysable (or cleavable) ester of a compound of any of the formulas described herein that 0330. As used herein, some substituents are described in contains a carboxy or a hydroxy group. For example amino a combination of two or more groups. For example, the acid esters, C. alkoxymethyl esters like methoxymethyl: expression of “C(=O)ClocycloalkylR" is meant to refer to C, alkanoyloxymethyl esters like pivaloyloxymethyl: a Structure: C-scycloalkoxycarbonyloxy Calkyl esters like 1-cyclo hexylcarbonyloxyethyl, acetoxymethoxy, or phosphora midic cyclic esters. 0336. As used herein, “tautomer means other structural isomers that exist in equilibrium resulting from the migra tion of a hydrogen atom. For example, keto-enol tautomer ism where the resulting compound has the properties of both a ketone and an unsaturated alcohol. wherein p is 1, 2, 3, 4, 5, 6 or 7 (i.e., Cocycloalkyl); the 0337 As used herein “stable compound” and “stable Cocycloalkyl is substituted by R'; and the point of attach structure' are meant to indicate a compound that is Sufi ment of the “C(=O)ClocycloalkylR" is through the car ciently robust to survive isolation to a useful degree of purity bon atom of the carbonyl group, which is on the left of the from a reaction mixture, and formulation into an efficacious expression. therapeutic agent. 0331. As used herein, the phrase “protecting group' 0338. The present invention further includes isotopically means temporary Substituents which protect a potentially labeled compounds of the invention. An "isotopically” or reactive functional group from undesired chemical transfor “radio-labeled compound is a compound of the invention mations. Examples of Such protecting groups include esters where one or more atoms are replaced or Substituted by an of carboxylic acids, silyl ethers of alcohols, and acetals and atom having an atomic mass or mass number different from ketals of aldehydes and ketones respectively. The field of the atomic mass or mass number typically found in nature protecting group chemistry has been reviewed (Greene, T. (i.e., naturally occurring). Suitable radionuclides that may be W.; Wuts, P. G. M. Protective Groups in Organic Synthesis, incorporated in compounds of the present invention include 3" ed.: Wiley: New York, 1999). but are not limited to H (also written as D for deuterium), *H (also written as T for tritium), ''C, C, C, N, 'N, 0332. As used herein, “pharmaceutically acceptable' is 15O, 17O, 18O, 18F 35S, 36C1, 82Br, 75 Br, 7°Br, 77Br, 123, 1241, employed herein to refer to those compounds, materials, 'I and ''I. The radionuclide that is incorporated in the compositions, and/or dosage forms which are, within the instant radio-labeled compounds will depend on the specific Scope of sound medical judgment, Suitable for use in contact application of that radio-labeled compound. For example, with the tissues of human beings and animals without for in vitro receptor labeling and competition assays, com excessive toxicity, irritation, allergic response, or other pounds that incorporate H, C, Br, I, I, S or will problem or complication, commensurate with a reasonable generally be most useful. For radio-imaging applications benefit/risk ratio. IC, 18F 125I, 123, 1241, 131I. 75 Br, 7Br or 77Br will 0333 As used herein, “pharmaceutically acceptable generally be most useful. salts' refer to derivatives of the disclosed compounds 0339. It is understood that a “radio-labeled compound is wherein the parent compound is modified by making acid or a compound that has incorporated at least one radionuclide. base salts thereof (i.e., also include counterions). Examples In some embodiments the radionuclide is selected from the of pharmaceutically acceptable salts include, but are not group consisting of H, C, 'I, S and Br. limited to, mineral or organic acid salts of basic residues Such as amines; alkali or organic salts of acidic residues such 0340. The antidementia treatment defined herein may be as carboxylic acids; and the like. The pharmaceutically applied as a sole therapy or may involve, in addition to the acceptable salts include the conventional non-toxic salts or compound of the invention, conventional chemotherapy. the quaternary ammonium salts of the parent compound 0341 Such conjoint treatment may be achieved by way formed, for example, from non-toxic inorganic or organic of the simultaneous, sequential or separate dosing of the US 2007/0142328A1 Jun. 21, 2007

individual components of the treatment. Such combination 0352. In addition to the compounds of the present inven products employ the compounds of this invention. tion, the pharmaceutical composition of this invention may also contain, or be co-administered (simultaneously or 0342 Compounds of the present invention may be sequentially) with, one or more pharmacological agents of administered orally, parenteral, buccal, vaginal, rectal, inha lation, insufflation, Sublingually, intramuscularly, Subcuta value in treating one or more disease conditions referred to neously, topically, intranasally, intraperitoneally, intrathora herein. cially, intravenously, epidurally, intrathecally, 0353. The term composition is intended to include the intracerebroventricularly and by injection into the joints. formulation of the active component or a pharmaceutically acceptable salt with a pharmaceutically acceptable carrier. 0343. The dosage will depend on the route of adminis For example this invention may be formulated by means tration, the severity of the disease, age and weight of the known in the art into the form of, for example, tablets, patient and other factors normally considered by the attend capsules, aqueous or oily solutions, Suspensions, emulsions, ing physician, when determining the individual regimen and creams, ointments, gels, nasal sprays, Suppositories, finely dosage level as the most appropriate for a particular patient. divided powders or aerosols or nebulisers for inhalation, and 0344) An effective amount of a compound of the present for parenteral use (including intravenous, intramuscular or invention for use in therapy of dementia is an amount infusion) sterile aqueous or oily Solutions or Suspensions or sufficient to symptomatically relieve in a warm-blooded sterile emulsions. animal, particularly a human the symptoms of dementia, to 0354) Liquid form compositions include solutions, sus slow the progression of dementia, or to reduce in patients pensions, and emulsions. Sterile water or water-propylene with symptoms of dementia the risk of getting worse. glycol Solutions of the active compounds may be mentioned as an example of liquid preparations Suitable for parenteral 0345 For preparing pharmaceutical compositions from administration. Liquid compositions can also be formulated the compounds of this invention, inert, pharmaceutically in solution in aqueous polyethylene glycol solution. Aque acceptable carriers can be either solid or liquid. Solid form ous solutions for oral administration can be prepared by preparations include powders, tablets, dispersible granules, dissolving the active component in water and adding Suit capsules, cachets, and Suppositories. able colorants, flavoring agents, stabilizers, and thickening 0346 A solid carrier can be one or more substances, agents as desired. Aqueous Suspensions for oral use can be which may also act as diluents, flavoring agents, solubiliz made by dispersing the finely divided active component in ers, lubricants, Suspending agents, binders, or tablet disin water together with a viscous material Such as natural tegrating agents; it can also be an encapsulating material. synthetic gums, resins, methyl cellulose, Sodium carboxym ethyl cellulose, and other Suspending agents known to the 0347 In powders, the carrier is a finely divided solid, pharmaceutical formulation art. which is in a mixture with the finely divided active com 0355 The pharmaceutical compositions can be in unit ponent. In tablets, the active component is mixed with the dosage form. In Such form, the composition is divided into carrier having the necessary binding properties in Suitable unit doses containing appropriate quantities of the active proportions and compacted in the shape and size desired. component. The unit dosage form can be a packaged prepa 0348 For preparing suppository compositions, a low ration, the package containing discrete quantities of the melting wax Such as a mixture of fatty acid glycerides and preparations, for example, packeted tablets, capsules, and cocoa butter is first melted and the active ingredient is powders in vials or ampoules. The unit dosage form can also dispersed therein by, for example, stirring. The molten be a capsule, cachet, or tablet itself, or it can be the homogeneous mixture is then poured into convenient sized appropriate number of any of these packaged forms. molds and allowed to cool and solidify. 0356 Compositions may be formulated for any suitable 0349 Suitable carriers include magnesium carbonate, route and means of administration. Pharmaceutically accept magnesium Stearate, talc, lactose, Sugar, pectin, dextrin, able carriers or diluents include those used in formulations starch, tragacanth, methyl cellulose, sodium carboxymethyl Suitable for oral, rectal, nasal, topical (including buccal and cellulose, a low-melting wax, cocoa butter, and the like. Sublingual), vaginal or parenteral (including Subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epi 0350 Some of the compounds of the present invention dural) administration. The formulations may conveniently are capable of forming salts with various inorganic and be presented in unit dosage form and may be prepared by organic acids and bases and Such salts are also within the any of the methods well known in the art of pharmacy. Scope of this invention. For example, such conventional non-toxic salts include those derived from inorganic acids 0357 For solid compositions, conventional non-toxic Such as hydrochloric, phosphoric, and the like; and the salts Solid carriers include, for example, pharmaceutical grades of prepared from organic acids such as lactic, maleic, citric, mannitol, lactose, cellulose, cellulose derivatives, starch, benzoic, methanesulfonic, trifluoroacetate and the like. magnesium Stearate, Sodium saccharin, talcum, glucose, Sucrose, magnesium carbonate, and the like may be used. 0351. In some embodiments, the present invention pro Liquid pharmaceutically administrable compositions can, vides a compound of any of the formulas described herein or for example, be prepared by dissolving, dispersing, etc., an a pharmaceutically acceptable salt thereof for the therapeutic active compound as defined above and optional pharmaceu treatment (including prophylactic treatment) of mammals tical adjuvants in a carrier, Such as, for example, water, including humans, it is normally formulated in accordance saline aqueous dextrose, glycerol, ethanol, and the like, to with standard pharmaceutical practice as a pharmaceutical thereby form a solution or suspension. If desired, the phar composition. maceutical composition to be administered may also contain US 2007/0142328A1 Jun. 21, 2007 22 minor amounts of non-toxic auxiliary Substances such as reaction with an alkylating agent according to methods well wetting or emulsifying agents, pH buffering agents and the known to the skilled person. Such quaternary ammonium like, for example, Sodium acetate, Sorbitan monolaurate, compounds are within the scope of the invention. triethanolamine sodium acetate, Sorbitan monolaurate, tri ethanolamine oleate, etc. Actual methods of preparing Such 0364 Compounds containing an amine function may also dosage forms are known, or will be apparent, to those skilled form N-oxides. A reference herein to a compound that in this art; for example, see Remington's Pharmaceutical contains an amine function also includes the N-oxide. Sciences, Mack Publishing Company, Easton, Pa., 15th 0365. Where a compound contains several amine func Edition, 1975. tions, one or more than one nitrogen atom may be oxidised 0358. The compounds of the invention may be deriva to form an N-oxide. Particular examples of N-oxides are the tised in various ways. As used herein “derivatives” of the N-oxides of a tertiary amine or a nitrogen atom of a compounds includes salts (e.g. pharmaceutically acceptable nitrogen-containing heterocycle. salts), any complexes (e.g. inclusion complexes or clathrates with compounds such as cyclodextrins, or coordination 0366 N-Oxides can be formed by treatment of the cor complexes with metal ions such as Mn"and Zn"), esters responding amine with an oxidizing agent such as hydrogen Such as in Vivo hydrolysable esters, free acids or bases, peroxide or a per-acid (e.g. a peroxycarboxylic acid), see for polymorphic forms of the compounds, Solvates (e.g. example Advanced Organic Chemistry, by Jerry March, 4" hydrates), prodrugs or lipids, coupling partners and protect Edition, Wiley Interscience, pages. More particularly, N-ox ing groups. By "prodrugs' is meant for example any com ides can be made by the procedure of L. W. Deady (Syn. pound that is converted in vivo into a biologically active Comm. 1977, 7, 509-514) in which the amine compound is compound. reacted with m-chloroperoxybenzoic acid (MCPBA), for example, in an inert Solvent such as dichloromethane. 0359 Salts of the compounds of the invention are pref erably physiologically well tolerated and non toxic. Many 0367 Esters can be formed between hydroxyl or car examples of salts are known to those skilled in the art. All boxylic acid groups present in the compound and an appro Such salts are within the scope of this invention, and priate carboxylic acid or alcohol reaction partner, using references to compounds include the salt forms of the techniques well known in the art. Examples of esters are compounds. compounds containing the group C(=O)CR, wherein R is an ester Substituent, for example, a C, alkyl group, a Co 0360 Compounds having acidic groups, such as carboxy heterocyclyl group, or a Cso aryl group, preferably a C, late, phosphates or Sulfates, can form salts with alkaline or alkyl group. Particular examples of ester groups include, but alkaline earth metals such as Na, K, Mg and Ca, and with are not limited to, C(=O)CCH, C(=O)CCHCH organic amines such as triethylamine and Tris (2-hydroxy C(=O)CC(CH), and C(=O)CPh. Examples of acyloxy ethyl)amine. Salts can be formed between compounds with (reverse ester) groups are represented by OC(=O)R. basic groups, e.g. amines, with inorganic acids such as wherein R is an acyloxy substituent, for example, a C, alkyl hydrochloric acid, phosphoric acid or Sulfuric acid, or group, a Co heterocyclyl group, or a Cs2c aryl group. organic acids such as acetic acid, citric acid, benzoic acid, preferably a C, alkyl group. Particular examples of acyloxy fumaric acid, or tartaric acid. Compounds having both acidic groups include, but are not limited to, OC(=O)CH and basic groups can form internal salts. (acetoxy), OC(=O)CHCH, OC(=O)C(CH), 0361 Acid addition salts may be formed with a wide variety of acids, both inorganic and organic. Examples of OC(=O)Ph, and OC(=O)CHPh. acid addition salts include salts formed with hydrochloric, 0368 Derivatives which are prodrugs of the compounds hydriodic, phosphoric, nitric, Sulphuric, citric, lactic, suc are convertible in vivo or in vitro into one of the parent cinic, maleic, malic, isethionic, fumaric, benzenesulphonic, compounds. Typically, at least one of the biological activi toluenesulphonic, methanesulphonic, ethaneSulphonic, ties of compound will be reduced in the prodrug form of the naphthalenesulphonic, Valeric, acetic, propanoic, butanoic, compound, and can be activated by conversion of the malonic, glucuronic and lactobionic acids. prodrug to release the compound or a metabolite of it. Some 0362) If the compound is anionic, or has a functional prodrugs are esters of the active compound (e.g., a physi group which may be anionic (e.g., COOH may be COO), ologically acceptable metabolically labile ester). During then a salt may be formed with a suitable cation. Examples metabolism, the ester group ( C(=O)CR) is cleaved to of Suitable inorganic cations include, but are not limited to, yield the active drug. Such esters may be formed by esteri alkali metal ions such as Na'and K", alkaline earth cations fication, for example, of any of the carboxylic acid groups such as Ca" and Mg", and other cations such as Al". (—C(=O)CH) in the parent compound, with, where appro Examples of Suitable organic cations include, but are not priate, prior protection of any other reactive groups present limited to, ammonium ion (i.e., NH) and substituted in the parent compound, followed by deprotection if ammonium ions (e.g., NHR'. NHR'. NHR'. NR). required. Examples of Some Suitable Substituted ammonium ions are 0369 Examples of such metabolically labile esters those derived from: ethylamine, diethylamine, dicyclohexy include those of the formula —C(=O)CR wherein R is: lamine, triethylamine, butylamine, ethylenediamine, etha Calkyl (e.g., Me, Et, -nPr, -iPr, -nBu, -sBu, -i Bu, thBu); nolamine, diethanolamine, piperazine, benzylamine, phe Czaminoalkyl (e.g., aminoethyl: 2-(N,N-diethylamino)et nylbenzylamine, choline, meglumine, and tromethamine, as hyl; 204morpholino)ethyl); and acyloxy-Calkyl (e.g., acy well as amino acids, such as lysine and arginine. An example loxymethyl; acyloxyethyl, pivaloyloxymethyl; acetoxym of a common quaternary ammonium ion is N(CH). ethyl: 1 acetoxyethyl: 1-(1-methoxy-1-methyl)ethyl 0363. Where the compounds contain an amine function, carbonyloxyethyl: 1-(benzoyloxy)ethyl, isopropoxy these may form quaternary ammonium salts, for example by carbonyloxymethyl; lisopropoxy-carbonyloxyethyl; US 2007/0142328A1 Jun. 21, 2007

cyclohexyl-carbonyloxymethyl, 1 cyclohexyl-carbonyloxy mg/kg dosage in an adult human. A minimum effective ethyl, cyclohexyloxy-carbonyloxymethyl, 1-cyclohexy dosage for a compound of formula (I) will be at least about loxy-carbonyloxyethyl; (4-tetrahydropyranyloxy) carbony 0.1 mg/kg of body weight per day for mammals with a loxymethyl, 1-(4-tetrahydropyranyloxy)carbonyloxyethyl; maximum dosage for a small mammal Such as a dog, of (4-tetrahydropyranyl)carbonyloxymethyl; and 1 (4tetrahy about 100 mg/kg per day. For humans, a dosage of about 0.1 dropyranyl)carbonyloxyethyl). to 12 mg/kg per day will be effective, for example, about 5 0370 Also, some prodrugs are activated enzymatically to to 600 mg/day for an average man. The dosage can be given yield the active compound, or a compound which, upon once daily or in divided doses, for example, 2 to 4 doses further chemical reaction, yields the active compound (for daily, and Such dosage will depend on the duration and example, as in ADEPT, GDEPT, LIDEPT, etc.). For maximum level of activity of a particular compound. The example, the prodrug may be a Sugar derivative or other dose may be conventionally formulated in an oral or glycoside conjugate, or may be an amino acid ester deriva parenteral dosage form by compounding about 5 to 250 mg tive. per unit of dosage of conventional vehicle, excipient, binder, preservative, stabilizer, flavor or the like as called for by 0371 Other derivatives include coupling partners of the accepted pharmaceutical practice, for example, as described compounds in which the compounds is linked to a coupling in U.S. Pat. No. 3,755,340. The compounds of this invention partner, e.g. by being chemically coupled to the compound may be used in pharmaceutical compositions comprising a or physically associated with it. Examples of coupling compound of any of the formulas described herein or can be partners include a label or reporter molecule, a Supporting contained in the same formulation with or co-administered Substrate, a carrier or transport molecule, an effector, a drug, with one or more known drugs. an antibody or an inhibitor. Coupling partners can be covalently linked to compounds of the invention via an 0376 Some example tests that can be conducted to appropriate functional group on the compound Such as a demonstrate the anxiolytic activity of the present com hydroxyl group, a carboxyl group or an amino group. Other pounds include binding tests of GABAA receptors. In some derivatives include formulating the compounds with lipo embodiments, the binding test was directed to a subtype of SOS. GABAA receptors, such as GABAA1 receptors (i.e., those containing the C. Subunit), GABAA2 receptors (i.e., those 0372. Where the compounds contain chiral centres, all containing the C. Subunit), GABAA3 receptors (i.e., those individual optical forms such as enantiomers, epimers, atro containing the C. Subunit) and GABAA5 receptors (i.e., pisomers and diastereoisomers, as well as racemic mixtures of the compounds are within the scope of the invention. those containing the Cs subunit). 0377 Presently available GABAA modulator anxiolytics 0373 Compounds may exist in a number of tautomeric work via interactions at the classical benzodiazepine binding forms and references to compounds include all Such forms. site. To a large degree these anxiolytics lack GABAA For the avoidance of doubt, where a compound can exist in receptor subtype-selectivity. The subtype-selective GABAA one of several tautomeric forms and only one is specifically receptor modulators may offer more advantages. For described or shown, all others are nevertheless embraced by example, a growing body of work Suggests that desirable the scope of this invention. anxiolytic activity is driven primarily by interactions with 0374. The quantity of the compound to be administered GABAA receptors containing the C subunit. Sedation, a will vary for the patient being treated and will vary from side-effect common to all marketed benzodiazepines, is about 100 ng/kg of body weight to 100 mg/kg of body believed to be mediated by interactions at GABAARs con weight per day and preferably will be from 10 pg/kg to 10 taining the C. Subunit. To develop anxiolytics with minimal mg/kg per day. For instance, dosages can be readily ascer liabilities due to interactions with other subunits, an elec tained by those skilled in the art from this disclosure and the trophysiological assay was developed to screen modulatory knowledge in the art. Thus, the skilled artisan can readily effects of various compounds on different GABA subunit determine the amount of compound and optional additives, combinations heterologously expressed in Xenopus oocytes. vehicles, and/or carrier in compositions and to be adminis 0378 GABAA receptors were heterologously expressed tered in methods of the invention. in Xenopus oocytes by injecting cRNA corresponding to 0375. In some embodiments, the compounds described human C. C. C., C.s, B2, B and Y. Subunits of the GABAA herein are central nervous system depressants and may be receptor genes. The specific subunit combinations (Sub used as tranquilizers or ataractic agents for the relief of types) were as follows: C. B.Y. C2fBY2. Cla?sy, and C.sfbaya. anxiety and tension states, for example, in mice, cats, rats, The EC10 of GABA was approximated for each cell. Sta dogs and other mammalian species such as humans, in the bility of GABA-mediated (EC10) current was established. same manner as chlordiazepoxide. For this purpose a com Modulatory effect of test compound was determined and pound or mixture of compounds of any of the formulas compared across Subtypes. The assay developed has repro described herein, or non-toxic physiologically acceptable ducibility which allows discrimination of modulatory activ salts, such as acid addition salts thereof, may be adminis ity down to minimal effect of about 25% potentiation (prior tered orally or parenterally in a conventional dosage form to normalization to standard) for all four subtypes. Thus, the Such as tablet, pill, capsule, injectable or the like. The dosage assay can characterize modulatory effects and determine in mg/kg of body weight of compounds of the present Subtype selectivity of test compounds on major subtypes of invention in mammals will vary according to the size of the GABAA receptors. In some embodiments, a compound can animal and particularly with respect to the brain/body selectively bind to one subtype of GABAA receptor (by weight ratio. In general, a higher mg/kg dosage for a small showing about 25% or more of binding comparing to animal Such as a dog will have the same effect as a lower another subtype of GABAA receptor). US 2007/0142328A1 Jun. 21, 2007 24

0379 Anxiolytic activity is indicated in the GABAA 0385) In a further embodiment, a compound of formula I binding test by a displacement of the flunitrazepam Such as or a pharmaceutically acceptable salt, Solvate or in vivo is exhibited by benzodiazepines or by enhancement of the hydrolysable ester thereof, or a pharmaceutical composition binding Such as is shown by cartazolate and tracazolate. or formulation comprising a compound of formula I may be 0380. In some embodiments, the compounds of the administered concurrently, simultaneously, sequentially or invention can bind to GABAA receptors. In some embodi separately with one or more pharmaceutically active com ments, the compounds of the invention can bind to GABAA pound(s) selected from the following: receptors by displacement of benzodiazepines. Accordingly, 0386 (i) antidepressants such as amitriptyline, amoxap the compounds of the invention can be used to modulate ine, bupropion, citalopram, clomipramine, desipramine, activities of GABAA receptors. In some embodiments, the doxepin dulloxetine, elzasonan, escitalopram, fluvoxamine, compounds of the invention can selectively bind to a Sub fluoxetine, gepirone, imipramine, ipsapirone, maprotiline, type of GABAA receptors, such as such as GABAA1 nortriptyline, nefazodone, paroxetine, phenelzine, protrip receptors (i.e., those containing the C. Subunit), GABAA2 tyline, reboxetine, robalZotan, Sertraline, Sibutramine, thion receptors (i.e., those containing the C. Subunit), GABAA3 isoxetine, tranylcypromaine, traZodone, trimipramine, Ven receptors (i.e., those containing the C. Subunit) or GABAA5 lafaxine and equivalents and pharmaceutically active receptors (i.e., those containing the Cs subunit). In some isomer(s) and metabolite(s) thereof, embodiments, the compounds of the invention can selec 0387 (ii) atypical antipsychotics including for example tively bind to a subtype of GABAA receptors by displace quetiapine and pharmaceutically active isomer(s) and ment of benzodiazepines. Accordingly, the compounds of metabolite(s) thereof, amisulpride, aripiprazole, asenapine, the invention can be used to selectively modulate activities benzisoxidil, bifeprunoX, carbamazepine, clozapine, chlor of a subtype of GABAA receptors, such as GABAA1 promazine, debenzapine, divalproex, duloxetine, esZopi receptors, GABAA2 receptors, GABAA3 receptors or clone, haloperidol, illoperidone, lamotrigine, lithium, loxap GABAA5 receptors. ine, mesoridazine, olanzapine, paliperidone, perlapine, 0381. In some embodiments, certain compounds of the perphenazine, phenothiazine, phenylbutlypiperidine, invention are GABAA1 receptor antagonists and GABAA2 pimozide, prochlorperazine, risperidone, quetiapine, Sertin receptor agonists. dole, Sulpiride, Suproclone, Suriclone, thioridazine, trifluop 0382 Because the compounds of the invention can be erazine, trimetozine, Valproate, valproic acid, Zopiclone, used to modulate activities of GABAA receptors, or to Zotepine, Ziprasidone and equivalents thereof; selectively modulate activities of a subtype of GABAA 0388 (iii) antipsychotics including for example amisul receptors, the compounds of the invention are envisioned to pride, aripiprazole, asenapine, benzisoxidil, bifeprunoX, car be useful for treating or preventing diseases mediated by bamazepine, clozapine, chlorpromazine, debenzapine, GABAA receptors or a subtype of GABAA receptors. Such divalproex, dulloxetine, esZopiclone, haloperidol, illoperi disease, include, but is not limited to, stroke, head trauma, done, lamotrigine, loxapine, mesoridazine, olanzapine, pali epilepsy, pain, migraine, mood disorders, anxiety, post trau peridone, perlapine, perphenazine, phenothiazine, phenyl matic stress disorder, obsessive compulsive disorders, butlypiperidine, pimozide, prochlorperazine, risperidone, Schizophrenia, seizures, convulsions, tinnitus, neurodegen sertindole, Sulpiride, Suproclone, Suriclone, thioridazine, tri erative disorders including Alzheimer's disease, amyo fluoperazine, trimetozine, Valproate, Valproic acid, Zopi trophic lateral sclerosis, Huntington's Chorea, Parkinson's clone, Zotepine, Ziprasidone and equivalents and pharma disease, depression, bipolar disorders, mania, trigeminal and ceutically active isomer(s) and metabolite(s) thereof, other neuralgia, neuropathic pain, hypertension, cerebral 0389 (iv) anxiolytics including for example alnespirone, ischemia, cardiac arrhythmia, myotonia, Substance abuse, aZapirones, benzodiazepines, barbiturates Such as adina myoclonus, essential tremor, dyskinesia and other move Zolam, alprazolam, balezepam, bentazepam, bromazepam, ment disorders, neonatal cerebral hemorrhage, spasticity, brotizolam, buspirone, clonazepam, cloraZepate, chlordiaz cognitive disorder, and sleeping disorder. epoxide, cyprazepam, diazepam, diphenhydramine, esta 0383. It is known that melatonin receptor agonists are Zolam, fenobam, flunitrazepam, flurazepam, fosazepam, effective in treating depression. We find that the compounds lorazepam, lormetazepam, meprobamate, midazolam, of the invention can selectively modulate activities of a nitrazepam, oxazepam, prazepam, quaZepam, reclazepam, subtype of melatonin receptors, melatonin receptor 1 (MT tracazolate, trepipam, temazepam, triazolam, uldazepam, 1). In certain embodiments, certain compounds of the inven Zolazepam and equivalents and pharmaceutically active iso tion are MT1 agonists. As a results, the compounds of the mer(s) and metabolite(s) thereof; invention may be effective in treating depression disorders 0390 (v) anticonvulsants including, for example, car Such as major depressive disorder, dysthymic disorder, bipo bamazepine, valproate, lamotrogine, gabapentin and equiva lar depression and/or bipolar mania, bipolar I with or with out manic, depressive or mixed episodes, bipolar II, lents and pharmaceutically active isomer(s) and metabo cyclothymic disorder, mood disorder due to a general medi lite(s) thereof; cal condition, manic episodes associated with bipolar dis 0391 (vi) Alzheimer's therapies including, for example, order, or mixed episodes associated with bipolar disorder. To donepezil, memantine, tacrine and equivalents and pharma treat depression disorders, an effective amount of one or ceutically active isomer(s) and metabolite(s) thereof; more compounds of the invention is administered to a 0392 (vii) Parkinson's therapies including, for example, patient with Such a need. deprenyl, L-dopa, Requip, Mirapex, MAOB inhibitors such 0384. In another embodiment, certain compounds of the as selegine and rasagiline, comP inhibitors such as Tasmar, present invention may be effective in treating insomnia. A-2 inhibitors, dopamine reuptake inhibitors, NMDA US 2007/0142328A1 Jun. 21, 2007 25 antagonists, Nicotine agonists, Dopamine agonists and ethchlorVynol, etomidate, glutethimide, halazepam, hydrox inhibitors of neuronal nitric oxide synthase and equivalents yZine, mecloqualone, melatonin, mephobarbital, methaqua and pharmaceutically active isomer(s) and metabolite(s) lone, midaflur, nisobamate, pentobarbital, phenobarbital, thereof propofol, roletamide, triclofos, secobarbital, Zaleplon, Zolpi 0393 (viii) migraine therapies including, for example, dem and equivalents and pharmaceutically active isomer(s) almotriptan, amantadine, bromocriptine, butalbital, caber and metabolite(s) thereof; and goline, dichloralphenaZone, eletriptan, froVatriptan, lisuride, 0399 (xiv) mood stabilizers including, for example, car naratriptan, pergolide, pramipexole, rizatriptan, ropinirole, bamazepine, divalproex, gabapentin, lamotrigine, lithium, Sumatriptan, Zolmitriptan, Zomitriptan, and equivalents and olanzapine, quetiapine, Valproate, valproic acid, Verapamil, pharmaceutically active isomer(s) and metabolite(s) thereof; and equivalents and pharmaceutically active isomer(s) and 0394 (ix) stroke therapies including, for example, abcix metabolite(s) thereof. imab, activase, NXY-059, citicoline, crobenetine, des 0400 Such combinations employ the compounds of this moteplase, repinotan, traxoprodil and equivalents and phar invention within the dosage range described herein and the maceutically active isomer(s) and metabolite(s) thereof, other pharmaceutically active compound or compounds 0395 (x) over active bladder urinary incontinence thera within approved dosage ranges and/or the dosage described pies including, for example, darafenacin, falvoxate, oxybu in the publication reference. tynin, propiverine, robalZotan, Solifenacin, tolterodine and General Procedures for Making the Compounds of the and equivalents and pharmaceutically active isomer(s) and Invention is as Follows: metabolite(s) thereof; 0396 (xi) neuropathic pain therapies including, for 04.01 The invention will now be illustrated by the fol example, gabapentin, lidoderm, pregablin and equivalents lowing non-limiting examples, in which, unless stated oth and pharmaceutically active isomer(s) and metabolite(s) erwise: thereof 0402. In order that the invention disclosed herein may be 0397 (xii) nociceptive pain therapies such as celecoxib, more efficiently understood, examples are provided below. It etoricoxib, lumiracoxib, rofecoxib, Valdecoxib, diclofenac, should be understood that these examples are for illustrative loxoprofen, naproxen, paracetamol and equivalents and purposes only and are not to be construed as limiting the pharmaceutically active isomer(s) and metabolite(s) thereof; invention in any manner. 0398 (xiii) insomnia therapies including, for example, 0403. Some example compounds of the invention in table allobarbital, alonimid, amobarbital, benzoctamine, butabar 1 were made according to the methods described herein bital, capuride, chloral, cloperidone, clorethate, dexclamol. below.

TABLE 1.

Example Synthesis Number Method Compound Name Structure

1 F 4-amino-7-fluoro-8-phenyl- NH2 O N-propyl-cinnoline-3- carboxamide N 1)N-1 H N F N?a

2 F 4-amino-7-chloro-8-phenyl- NH2 O N-propyl-cinnoline-3- carboxamide N 1n-1 H N C N22 Jun. 21, 2007

TABLE 1-continued

Example Synthesis Number Method Compound Name Structure

3 F 4-amino-7-methoxy-8- NH2 O phenyl-N-propyl-cinnoline-3- carboxamide N 1n-1 H No N? N

4 A. 4-amino-7-chloro-8-(2,5- NH2 O dimethylphenyl)-N-propyl cinnoline-3-carboxamide N NH

N C N22

5 A. 4-amino-8-(2,4-dimethoxy- NH2 O pyrimidin-5-yl)-N-propyl cinnoline-3-carboxamide N NH

N N2 O 21 N 1. O

6 A. 4-amino-8-(5-methoxy-3- NH2 O pyridyl)-N-propyl-cinnoline 3-carboxamide N NH

N N?2 21 N1S-N US 2007/0142328A1 Jun. 21, 2007 27

TABLE 1-continued

Example Synthesis Number Method Compound Name Structure

7 A. 4-amino-8-(2-methoxy- NH2 O pyrimidin-5-yl)-N-propyl cinnoline-3-carboxamide N

21 N 1. O

8 A. 4-amino-8-(3-fluoro-2- NH2 methoxy-phenyl)-N-propyl-N- cinnoline-3-carboxamide NH O NN N a12 O C F

9 A. 4-amino-8-4-methoxy-2- NH2 (trifluoromethyl)phenyl-N- propyl-cinnoline-3-carboxamide O N NH F N22 F F O

1. O

10 A. 4-amino-8-(2,5-difluoro-4- NH2 methoxy-phenyl)-N-propyl cinnoline-3-carboxamide NH

US 2007/0142328A1 Jun. 21, 2007

TABLE 1-continued

Example Synthesis Number Method Compound Name Structure

15 D 4-amino-8-(5-azetidin-1- NH2 O ylcarbonyl-3-pyridyl)-N-propyl cinnoline-3-carboxamide N 1N-1 H N N 2

21

O N-N K>

16 A. 4-amino-8-(2,3- NH2 O dimethoxyphenyl)-N-propyl cinnoline-3-carboxamide N 1n-1 H N N a2

O No C

17 A. 4-amino-8-(4-dimethyl- NH2 O aminophenyl)-N-propyl cinnoline-3-carboxamide N 1)N-1 H N N 2

1 N'N

18 A. 4-amino-8-(3-methoxy phenyl)-N-propyl cinnoline-3-carboxamide US 2007/0142328A1 Jun. 21, 2007 30

TABLE 1-continued

Example Synthesis Number Method Compound Name Structure

19 A. 4-amino-8-(3,4-dimethoxy phenyl)-N-propyl cinnoline-3-carboxamide

2O B 4-amino-8-(2,5- NH2 O dimethoxyphenyl)-N-propyl cinnoline-3-carboxamide N 1N1 H N N 22

1. O

O

21 A. 4-amino-8-(3,5-dimethoxy- NH2 O phenyl)-N-propyl cinnoline-3-carboxamide N 1N1 H N N 2

No O

22 A. 4-amino-8-(2,4- NH2 O dimethoxyphenyl)-N-propyl cinnoline-3-carboxamide N 1n-1 H N N 22

O

1. O US 2007/0142328A1 Jun. 21, 2007

TABLE 1-continued

Example Synthesis Number Method Compound Name Structure

23 E 4-amino-8-(2-fluoro-3- NH2 O pyridyl)-N-propyl-cinnoline-N- 3-carboxamide N 1)N-1 H N N2

21 F

N N

24 A. 4-amino-8-(2,3- NH2 O difluorophenyl)-N-propyl cinnoline-3-carboxamide N 1N1 H N N212 C F F

25 A. 4-amino-8-(2,3- dichlorophenyl)-N-propyl cinnoline-3-carboxamide

26 A. 4-amino-N-propyl-8-(6- quinolyl)cinnoline-3- carboxamide US 2007/0142328A1 Jun. 21, 2007 32

TABLE 1-continued

Example Synthesis Number Method Compound Name Structure

27 A. 4-amino-N-propyl-8-(3- quinolyl)cinnoline-3- carboxamide

21 NS

28 A. 4-amino-8-(2-naphthyl)-N- propyl-cinnoline-3- carboxamide

29 A. 4-amino-8-(1H-indol-5-yl)-N- propyl-cinnoline-3- carboxamide

30 B 4-amino-8-(4-methoxy-3- pyridyl)-N-propyl-cinnoline 3-carboxamide US 2007/0142328A1 Jun. 21, 2007 33

TABLE 1-continued

Example Synthesis Number Method Compound Name Structure

31 A. 4-amino-8-(3-dimethyl aminophenyl)-N-propyl cinnoline-3-carboxamide

32 A. 4-amino-N-propyl-8-(3,4,5- trimethoxyphenyl)-cinnoline 3-carboxamide

33 A. 4-amino-8-(2,4- difluorophenyl)-N-propyl cinnoline-3-carboxamide

34 A. 4-amino-8-(3,4- difluorophenyl)-N-propyl cinnoline-3-carboxamide US 2007/0142328A1 Jun. 21, 2007 34

TABLE 1-continued

Example Synthesis Number Method Compound Name Structure

35 A. 4-amino-N-propyl-8-(2,3,4- trimethoxyphenyl)-cinnoline 3-carboxamide

36 A. 4-amino-8-(2-methoxy-3- NH2 O pyridyl)-N-propyl-cinnoline-N- 3-carboxamide N 1N1 H N N 212

1. O 21

N N

37 A. 4-amino-8-(2,6-dimethoxy-3- NH2 O pyridyl)-N-propyl-cinnoline 3-carboxamide N 1n-1 H N N22

O 21 Nan

O N

38 B 4-amino-8-(2,5- NH2 O dimethylphenyl)-N-propyl cinnoline-3-carboxamide 21 1S-1 H S. N1 N US 2007/0142328A1 Jun. 21, 2007

TABLE 1-continued

Example Synthesis Number Method Compound Name Structure

39 B 3-4-amino-3- NH2 O (propylcarbamoyl)cinnolin-8- ylbenzoic acid N 1N-1 H N N 212

HO

O

40 4-amino-8-(3-azetidin-1- ylcarbonylphenyl)-N-propyl cinnoline-3-carboxamide

41 C 4-amino-N-propyl-8-pyrazin- NH2 O 2-yl-cinnoline-3-carboxamide N 1N1 H N N a12

21 NN su

42 A. 4-amino-N-propyl-8-(3- NH2 O pyridyl)cinnoline-3- carboxamide N 1n-1 US 2007/0142328A1 Jun. 21, 2007

TABLE 1-continued

Example Synthesis Number Method Compound Name Structure

43 A. 4-amino-8-(3-methylsulfonyl phenyl)-N-propyl-cinnoline-3- carboxamide

44 A. 4-amino-8-(3-cyanophenyl)- NH2 O N-propyl-cinnoline-3- carboxamide N 1N1 H N N 2

Š

45 C 4-amino-N-propyl-8-(2- NH2 O pyridyl)cinnoline-3- carboxamide

46 A. 4-amino-8-3,5-bis(trifluoro- NH2 O methyl)phenyl-N-propyl cinnoline-3-carboxamide N 1n-1 H

12 N N 2

F F F F

US 2007/0142328A1 Jun. 21, 2007

TABLE 1-continued

Example Synthesis Number Method Compound Name Structure

62 A. 4-amino-8-(4-fluoro-2- NH2 O methoxy-phenyl)-N-propyl cinnoline-3-carboxamide N 1N1 H N N 2

1. O

F

63 A. 4-amino-8-(3-fluoro-4- NH2 O methoxy-phenyl)-N-propyl cinnoline-3-carboxamide N 1N1 H N N 2

F

1 O

64 A. 4-amino-8-(2-fluoro-6- NH2 O methoxy-phenyl)-N-propyl cinnoline-3-carboxamide N 1n-1 H N N 22

O 1. O

65 A. 4-amino-8-(2-fluoro-5- methoxy-phenyl)-N-propyl cinnoline-3-carboxamide 1N1 N N H N N 2 F C O US 2007/0142328A1 Jun. 21, 2007

TABLE 1-continued

Example Synthesis Number Method Compound Name Structure

66 A. 4-amino-8-(5-fluoro-2- NH2 O methoxy-phenyl)-N-propyl cinnoline-3-carboxamide N 1n-1 H N N 2

1. O

F

67 F 4-amino-8-(4-methoxyphenyl)- NH2 O N-propyl-cinnoline-3- carboxamide N NH

N N22

1. O

68 F 4-amino-8-(4-fluorophenyl)- NH2 O N-propyl-cinnoline-3- carboxamide N NH

N N2

F

69 F 4-amino-N-propyl-8-4- NH O (trifluoromethoxy)phenyl cinnoline-3-carboxamide US 2007/0142328A1 Jun. 21, 2007

TABLE 1-continued

Example Synthesis Number Method Compound Name Structure

70 F 4-amino-N-propyl-8-3- NH2 O (trifluoromethoxy)phenyl cinnoline-3-carboxamide N NH

N N22

O

F F F

71 A. 4-amino-8-(6-methoxy-3- NH2 O pyridyl)-N-propyl-cinnoline 3-carboxamide N NH

N N22

N&

1 O

72 A. 4-amino-8-(4-methoxy-3,5- NH2 O dimethyl-phenyl)-N-propyl cinnoline-3-carboxamide N 1n-1 H N N 2

1. O

73 A. 4-amino-8-(4-methoxy-3- NH2 O methyl-phenyl)-N-propyl cinnoline-3-carboxamide N 1N1 H N N 2

O Jun. 21, 2007 43

TABLE 1-continued

Example Synthesis Number Method Compound Name Structure

74 A. 4-amino-8-(2-fluoro-4- methoxy-phenyl)-N-propyl cinnoline-3-carboxamide

75 C 4-amino-8-(6-methylpyridin 3-yl)-N-propylcinnoline-3- carboxamide

21 N

76 A. 4-amino-8-(4-methylpyridin 3-yl)-N-propylcinnoline-3- carboxamide

77 A. 4-amino-8-(5-methoxy-2- methylphenyl)-N-propyl cinnoline-3-carboxamide US 2007/0142328A1 Jun. 21, 2007

TABLE 1-continued

Example Synthesis Number Method Compound Name Structure

78 A. 4-Amino-8-(2,4-dimethoxy- NH2 O phenyl)-7-fluoro-N- propylcinnoline-3-carboxamide N 1)N-1 H N F N2

O N

O N

79 A. 4-amino-8-(2,5-methoxyphenyl)- 7-fluoro-N-propyl cinnoline-3-carboxamide

8O A. 4-amino-8-(2,4-dimethoxy- NH2 O pyrimidin-5-yl)-7-fluoro-N- propylcinnoline-3-carboxamide N 1n-1 H N F N22

1. O 21 s N O N

81 A. 4-amino-N-ethyl-8-(4- NH O methoxypyridin-3- yl)cinnoline-3-carboxamide US 2007/0142328A1 Jun. 21, 2007 45

TABLE 1-continued

Example Synthesis Number Method Compound Name Structure

82 A. 4-amino-N-butyl-8-(2,5- dimethoxyphenyl)cinnoline 3-carboxamide

83 A. 4-amino-8-(2,5- dimethoxyphenyl)-N- ethylcinnoline-3-carboxamide

84 B 4-amino-8-(2,5-dimethoxy phenyl)-N-methylcinnoline 3-carboxamide

85 B 4-amino-N-butyl-8-(2,4- NH2 O dimethoxypyrimidin-5- yl)cinnoline-3-carboxamide N 1N1\ H N N a12

1. O 21 s N O US 2007/0142328A1 Jun. 21, 2007

TABLE 1-continued

Example Synthesis Number Method Compound Name Structure

86 B 4-amino-8-(2,4- NH2 O dimethoxypyrimidin-5-yl)-N- ethylcinnoline-3-carboxamide N 1n H N N a2

O N O N

87 A. 4-Amino-8-(2,5-dimethoxy phenyl)-cinnoline-3- carboxylic acid allylamide

88 4-amino-N-(cyclopropyl- NH2 O methyl)-8-phenyl-cinnoline 3-carboxamide 21 N H

89 A. 4-amino-8-(m-tolyl)-N- NH2 O propyl-cinnoline-3- carboxamide

N N1 N US 2007/0142328A1 Jun. 21, 2007

TABLE 1-continued

Example Synthesis Number Method Compound Name Structure

90 A. 4-Amino-8-(2-fluoro-6- methylpyridin-3-yl)- cinnoline-3-carboxylic acid propylamide

91 A. 4-Amino-7-fluoro-8-(5- N O fluoro-2-methoxyphenyl)- cinnoline-3-carboxylic acid propylamide 21 1n-1 S.- F N

O N

F

92 A. 4-Amino-8-(2-chloro-5- N O methoxyphenyl)-7-fluoro cinnoline-3-carboxylic acid propylamide 21 1n-1 N-1 F N

C

O

93 A. 4-amino-N-cyclopropyl-8- NH2 O (2,6-dimethoxypyridin-3- yl)cinnoline-3-carboxamide N N H 2N N

N O N 2N

O US 2007/0142328A1 Jun. 21, 2007 48

TABLE 1-continued

Example Synthesis Number Method Compound Name Structure

94 A. 4-amino-N-cyclopropyl-8-(2- NH2 O methoxy-5-methyl-phenyl) cinnoline-3-carboxamide H Ors2 N O ON

95 A. 4-amino-N-cyclopropyl-8- NH2 O (2,4-dimethoxyphenyl) cinnoline-3-carboxamide N N1 H 2 N On

ON

96 A. 4-amino-N-cyclopropyl-8- NH2 O (2,4-dimethoxypyrimidin-5- yl)cinnoline-3-carboxamide N N1 H 2 N N's N. On

97 A. 4-amino-N-cyclopropyl-8- (2,5-dimethoxyphenyl) cinnoline-3-carboxamide US 2007/0142328A1 Jun. 21, 2007

TABLE 1-continued

Example Synthesis Number Method Compound Name Structure

98 A. 4-amino-N-ethyl-8-(2-fluoro 6-methoxy-phenyl)cinnoline 3-carboxamide NH2 HN

N O

N N 2

O F

99 G 4-amino-7-fluoro-8-(2-fluoro- NH2 O 6-methoxy-phenyl)-N-propyl cinnoline-3-carboxamide N 1S-1 H N F N21

1. O F

100 G 4-amino-7-cyano-8-(2,4- NH2 O dimethoxyphenyl)-N-propyl cinnoline-3-carboxamide N 1N1 H 2 N 2. N N O 1. C

1. O

101 H 4-amino-N-cyclobutyl-8-(2- NH2 O fluoro-6-methoxy-phenyl) cinnoline-3-carboxamide N N H N N 2

F O

US 2007/0142328A1 Jun. 21, 2007 51

TABLE 1-continued Example Synthesis Number Method Compound Name Structure

107 A. 4-amino-7-fluoro-8-(4-fluoro NH2 O 2-methoxy-phenyl)-N-propyl cinnoline-3-carboxamide N 1n-1 H 2 N F N2 -O

F

108 A. 4-amino-7-fluoro-8-(2-fluoro 4-methoxy-phenyl)-N-propyl cinnoline-3-carboxamide

109 A. 4-amino-8-(4-chlorophenyl)- 7-fluoro-N-propyl-cinnoline 3-carboxamide

C

110 A. 4-amino-7-fluoro-8-(5-fluoro 2-methyl-phenyl)-N-propyl cinnoline-3-carboxamide US 2007/0142328A1 Jun. 21, 2007

TABLE 1-continued Example Synthesis Number Method Compound Name Structure 111 A. 4-amino-8-(2,3-dimethyl- NH2 O phenyl)-7-fluoro-N-propyl cinnoline-3-carboxamide N 1)N-1 H N F N1

112 A. 4-amino-8-(2,5-dimethoxy- NH2 O F phenyl)-N-(3,3,3-trifluoro- F propyl)cinnoline-3-carboxamide N H F

O O O

113 A. 4-amino-8-(2,5-difluoro- NH2 O phenyl)-7-fluoro-N-propyl cinnoline-3-carboxamide N 1n-1 H N F N?2 F O F

04.04 The compounds in Table 2 can also made according to the methods described herein below.

TABLE 2

Synthesis Method Compound Name Structure

E 4-amino-8-(3,5-dimethyl-1H pyrazol-4-yl)-N-propyl cinnoline-3-carboxamide

US 2007/0142328A1 Jun. 21, 2007 54

TABLE 2-continued

Synthesis Method Compound Name Structure

A. 4-amino-N-propyl-8-(2,4,6- trifluoro-3-methoxyphenyl) cinnoline-3-carboxamide

E 4-amino-8-(2-fluoro-5- NH2 O methylpyridin-3-yl)-N- propylcinnoline-3-carboxamide N 1)N-1 H N N 2 F rn Na2

E 4-amino-8-(1,3-dimethyl-1H pyrazol-5-yl)-N-propylcinnoline 3-carboxamide

E 4-amino-8-(2-fluoro-4,6- dimethoxyphenyl)-N- propylcinnoline-3-carboxamide US 2007/0142328A1 Jun. 21, 2007

TABLE 2-continued

Synthesis Method Compound Name Structure

A. 4-amino-8-(3,5-difluoro-2- NH2 O methoxyphenyl)-N- propylcinnoline-3-carboxamide N 1N-1 H N N 212

O

F F

A. 4-amino-8-(2,3-dihydro-1,4- NH2 O benzodioxin-6-yl)-N- propylcinnoline-3-carboxamide N 1)N-1 H N N 2a

O

E 4-amino-8-(4,5-difluoro-2- NH2 O methoxyphenyl)-N- propylcinnoline-3-carboxamide N 1)N-1 H N N 212

O

F

E 4-amino-8-(1,3-benzodioxol-4- yl)-N-propylcinnoline-3- carboxamide

US 2007/0142328A1 Jun. 21, 2007 60

TABLE 2-continued

Synthesis Method Compound Name Structure

A. 4-amino-8-(2,5-dimethoxyphenyl)- N-(tetrahydrofuran-2- ylmethyl)cinnoline-3- carboxamide

A. 4-amino-8-(2,5- dimethoxyphenyl)-N- isobutylcinnoline-3-carboxamide

A. 4-amino-8-(2,5-dimethoxy phenyl)-N-(2-hydroxypropyl) cinnoline-3-carboxamide

A. 4-amino-8-(2,4-dimethoxy- NH2 O pyrimidin-5-yl)-N-(tetrahydro furan-2-ylmethyl) cinnoline-3-carboxamide N N O H US 2007/0142328A1 Jun. 21, 2007 61

TABLE 2-continued Synthesis Method Compound Name Structure A 4-amino-8-(2,4- NH2 O dimethoxypyrimidin-5-yl)-N- isobutylcinnoline-3-carboxamide N N H N N a2

O N O N A. 4-amino-8-(2,4-dimethoxy- NH2 O propyl)cinnoline-3-carboxamide N N H 2 N OH 1'Ne N ON

04.05 The compounds in Table 3 were also made accord ing to the methods described herein below.

TABLE 3 Example Number Compound Name Structure 114 4-amino-8-(2,3-dimethylphenyl)- NH2 O N-propyl-cinnoline-3- carboxamide

Sn N1 N

115 4-amino-8-(3,5-dimethylphenyl)- NH2 O N-propyl-cinnoline-3- carboxamide

CCN N1 N ^^- US 2007/0142328A1 Jun. 21, 2007

TABLE 3-continued

Example Number Compound Name Structure

116 4-amino-8-(2,4-dimethylphenyl)- NH2 O N-propyl-cinnoline-3- carboxamide 21 1N-1 H N N1 N

117 4-amino-8-(3,4-dimethylphenyl)- NH2 O N-propyl-cinnoline-3-

carboxamide 21 H 1N1 Sa N1 N

118 4-amino-N-propyl-8-(p- NH2 O tolyl)cinnoline-3-carboxamide 21 1N1 H N N1 N

119 4-amino-8-(3-chlorophenyl)-N- NH2 O propyl-cinnoline-3-carboxamide 21 1n-1 H S. N1 N

C US 2007/0142328A1 Jun. 21, 2007 63

TABLE 3-continued

Example Number Compound Name Structure

120 4-amino-8-(4-chlorophenyl)-N- propyl-cinnoline-3-carboxamide

C

121 4-amino-8-(o-tolyl)-N-propyl cinnoline-3-carboxamide

122 4-amino-N-propyl-8-(3- thienyl)cinnoline-3-carboxamide

123 4-amino-8-(2,6-dimethylphenyl)- NH2 O N-propyl-cinnoline-3- carboxamide CrN-N US 2007/0142328A1 Jun. 21, 2007 64

0406 Additional example compounds of the invention in table 4 were made according to the methods described herein below.

TABLE 4

Mass Synthesis Spectrum Example No. Structure Compound Name Method mz

124 NH2 O 4-amino-N-cyclobutyl A. 381 -O methyl-phenyl)cinnoline7-fluoro-8-(2-ethoxy-5- N N 3-carboxamide H N F N22

O O N

125 NH2 O 4-amino-N-cyclobutyl 385 -O methoxy-phenyl)cinnoline-3-7-fluoro-8-(5-fluoro-2- N N carboxamide H N F N1

O O N F

126 NH2 O 4-amino-N-cyclobutyl 385 JJ methoxy-phenyl)cinnoline-3-7-fluoro-8-(2-fluoro-6- N N carboxamide H N F N2

F O O N

127 NH2 O 4-amino-N-cyclobutyl 385 7-fluoro-8-(2-fluoro-3- methoxy-phenyl)cinnoline-3- N carboxamide H

US 2007/0142328A1 Jun. 21, 2007 69

TABLE 4-continued

Mass Synthesis Spectrum Example No. Structure Compound Name Method mz

145 NH2 O 4-amino-N-cyclobutyl A. 350 8-(2-methoxypyridin 3-yl)cinnoline-3-carboxamide N N H N N 2

N O N 2N

147 NH2 O 4-amino-N-cyclobutyl A. 347 8-(3,5-dimethylphenyl) cinnoline-3-carboxamide N N H N N 2

148 NH2 O 4-amino-N-cyclobutyl A. 355 8-(2,5-difluorophenyl) cinnoline-3-carboxamide N CCS.-

149 NH2 O 4-amino-N-cyclobutyl A. 333 methylphenyl)cinnoline 3-carboxamide N N H 22 N

150 NH2 O 4-amino-N-cyclobutyl A. 379 8-(2,3-dimethoxyphenyl) cinnoline-3-carboxamide

2 N N US 2007/0142328A1 Jun. 21, 2007

TABLE 4-continued

Mass Synthesis Spectrum Example No. Structure Compound Name Method mz

151 NH2 O 4-amino-N-cyclobutyl A. 349 8-(2-methoxyphenyl) cinnoline-3-carboxamide N N H N N 2

1. O

152 NH2 O 4-amino-N-cyclobutyl A. 334 8-(4-methylpyridin-3- yl)cinnoline-3-carboxamide N N H N N 2

21 N N

153 NH2 O 4-amino-N-cyclobutyl A. 409 8-(2,3,4-trimethoxyphenyl) cinnoline-3-carboxamide

154 NH2 O 4-amino-8-(4-chloro A. 353 phenyl)-N-cyclobutyl cinnoline-3-carboxamide 21 N H S. N1 N

US 2007/0142328A1 Jun. 21, 2007 74

TABLE 4-continued

Mass Synthesis Spectrum Example No. Structure Compound Name Method mz

168 4-amino-N-cyclopropyl-8- 383 (2,4-dimethoxyphenyl)-7- fluoro-cinnoline-3-carboxamide

169 4-amino-8-(2,4-dimethoxy 371 phenyl)-N-ethyl-7-fluoro cinnoline-3-carboxamide

170 4-amino-N-ethyl-8-(2- 341 fluoro-3-methoxy-phenyl) cinnoline-3-carboxamide

171 4-amino-N-ethyl-8-(2- 324 methoxypyridin-3-yl) cinnoline-3-carboxamide US 2007/0142328A1 Jun. 21, 2007 75

TABLE 4-continued

Mass Synthesis Spectrum Example No. Structure Compound Name Method mz

172 4-amino-N-ethyl-8-(6- A. methylpyridin-3-yl) cinnoline-3-carboxamide NH

N O 22 N 21

N S.

173 4-amino-N-ethyl-8-(5- 342 fluoro-6-methoxy-pyridin 3-yl)cinnoline-3-carboxamide NH HN

N O %2 N rs N a n

1. O

174 NH2 O 4-amino-N-cyclopropyl 353 -A phenyl)cinnoline-3-carboxamide8-(5-fluoro-2-methoxy N N H 22 N

O N

F

175 NH2 O 4-amino-N-cyclopropyl 336 8-(4-methoxypyridin-3- yl)cinnoline-3-carboxamide N N H 22 N 1. O 21 S. N US 2007/0142328A1 Jun. 21, 2007 76

TABLE 4-continued

Mass Synthesis Spectrum Example No. Structure Compound Name Method mz

176 NH2 O 4-amino-N-cyclopropyl A. 336 8-(2-methoxypyridin-3- yl)cinnoline-3-carboxamide N N H 2N N

N O N 2N

177 NH2 O 4-amino-N-cyclobutyl 363 -D phenyl)cinnoline-3-carboxamide8-(2-methoxy-5-methyl N N H 22 N

O O N

178 NH2 O 4-amino-N-cyclobutyl 379

JJ cinnoline-3-carboxamide8-(2,4-dimethoxyphenyl) N N H 22 N

O N

O N

179 4-amino-8-(2,6-dimethoxy pyridin-3-yl)-N-ethyl cinnoline-3-carboxamide NH HN

N O 22 N

N O N 2N

1. O

US 2007/0142328A1 Jun. 21, 2007 78

TABLE 4-continued

Mass Synthesis Spectrum Example No. Structure Compound Name Method mz

184 4-amino-8-(2,4-dimethoxy- A. 353 phenyl)-N-ethyl-cinnoline-3- carboxamide NH2 HN

N O

2 N N

O

1. O

185 4-amino-N-cyclopropyl-7- A. 371 -A methoxyphenyl)cinnolinefluoro-8-(2-fluoro-3- NH2 HN 3-carboxamide

O N2 N O F N

NoF O

186 NH2 O 4-amino-8-(2,4-dimethoxy- A. 373 pyrimidin-5-yl)-N-ethyl-7- fluoro-cinnoline-3-carboxamide N NH

2 N F N

21 O N s N 1. O

187 NH2 O 4-amino-N-ethyl-8-(4-methyl- A. 3O8 pyridin3-yl)cinnoline-3- carboxamide N NH

2 N N

21 US 2007/0142328A1 Jun. 21, 2007

TABLE 4-continued

Mass Synthesis Spectrum Example No. Structure Compound Name Method mz

188 NH2 O 4-amino-N-ethyl-7-fluoro-8- A. 359 (2-fluoro-6-methoxy phenyl)cinnoline-3-carboxamide O N NH F 2- N F O O N

189 NH O 4-amino-8-(2,6-dimethoxy- A. 372 pyridin-3-yl)-N-ethyl-7-fluoro cinnoline-3-carboxamide N NH

F 2- 21 O N

N N

1 O

190 NH2 O 4-amino-N-ethyl-7-fluoro-8- A. 359 (5-fluoro-2-methoxy-phenyl) cinnoline-3-carboxamide O N NH F 2- O O N F

191 NH2 O 4-amino-N-ethyl-7-fluoro-8- A. 360 (5-fluoro-6-methoxy-pyridin-3- yl)cinnoline-3-carboxamide N NH F 4N N 21

Nan F

O US 2007/0142328A1 Jun. 21, 2007

TABLE 4-continued

Mass Synthesis Spectrum Example No. Structure Compound Name Method mz 192 NH2 O 4-amino-N-ethyl-7-fluoro-8- A. 326 (6-methylpyridin-3- yl)cinnoline-3-carboxamide

21 N-N

193 NH2 O 4-amino-N-ethyl-7-fluoro-8- A. 342 (2-methoxypyridin-3- yl)cinnoline-3-carboxamide N NH F 4N N 4n-'N al 194 NH2 O 4-amino-N-ethyl-7-fluoro-8- A. 359 (2-fluoro-3-methoxy-phenyl) cinnoline-3-carboxamide F Crit4N N COF 195 NH2 O 4-amino-8-(2,5-dimethoxy- A. 371 phenyl)-N-methyl-7-fluoro cinnoline-3-carboxamide F Ort4N N

No Crs

Synthesis organic synthesis methods. It is understood by one skilled in the art of organic synthesis that the functionality present on 0407. The compounds of the present invention can be various portions of the molecule must be compatible with prepared in a number of ways well known to one skilled in the reagents and reactions proposed. Such restrictions to the the art of organic synthesis. The compounds of the present substituents which are compatible with the reaction condi invention can be synthesized using the methods described tions will be readily apparent to one skilled in the art and below, together with synthetic methods known in the art of alternate methods should then be used. synthetic organic chemistry, or variations thereon as appre ciated by those skilled in the art. The starting materials and 0408 Chemical abbreviations used in the Examples are precursors used in the processes described herein were either defined as follows: “DMSO denotes dimethylsulfoxide, commercially available or readily prepared by established “THF denotes tetrahydrofuran, “DMF denotes N,N-dim US 2007/0142328A1 Jun. 21, 2007 ethylformamide. Unless otherwise stated reaction progress dimethoxyethane and tetrahydrofuran. Suitable alcohols was monitored by HPLC, LC-MS or TLC. Oven-dried include ethanol, propanol and isopropanol. A suitable sol standard laboratory glassware was used and routine manipu vent also includes a mixture of two or more individual lations were done at ambient temperature under a blanket of solvents. Suitable solvents can further contain water. The nitrogen unless otherwise indicated. Commercially available coupling reaction can be carried out at a suitable temperature reagents and anhydrous solvents were typically used as to afford the compound 1-3. In some embodiments, the received. Evaporations were typically performed under reaction mixture is heated to an elevated temperature (i.e., reduced pressure using a rotary evaporator. Preparative above the room temperature). In some embodiments, the chromatography was performed using ICN silica gel 60, reaction mixture is heated to a temperature of about 40° C. 32-63L or a suitable equivalent. Products were dried under about 50° C., about 60° C., about 70° C., about 80°C., about reduced pressure at 40° C. or a suitable temperature. 90° C., about 100° C., about 110° C., about 120° C., about 04.09 HPLC-Mass Spectroscopy data were collected uti 130° C., about 140° C., about 150° C., about 160° C. The lizing an Agilent Zorbax 5L SB-C8 column 2.1 mmx5 cm. reaction progress can be monitored by conventional methods with a column temperature of 30° C. Solvents: A=98:2 Such as TLC or NMR. Water: Acetonitrile with 0.1% formic acid added, B=98:2 Acetonitrile:Water with 0.05% formic acid added. Flow rate 1.4 mL/min, injection volume 2.0 uL, initial conditions 5% Scheme 1 B, eluting with a linear gradient from 5 to 90% B from time R2 Zero to 3 minutes holding at 90% B until 4 minutes. R3 YNH O Photodiode array UV detection was used averaging signal R RI from 210 through 400 nm. Mass Spectral data were collected N N1 using Full Scan APCI (+), base peak index, 150.0 to 900.0 H -- amu.., 30 cone volts with a probe temperature of 450° C. 2N R5 2 0410 "H NMR data (8, ppm) were obtained on a Bruker 300 MHz instrument at 30° C. with tetramethylsilane as an XI internal standard set at 0.00 ppm. The multiplicities of the 1-1 NMR spectra absorptions may be abbreviated by: s, singlet: R2n br, broad peak; bs, broad singlet; d, doublet, t, triplet: q. R3 NH O OR 101 catalyst, quartet; dd, doublet of doublets; dt, doublet of triplets; m, base R RI multiplet. In many cases proton resonances associated with R-B6- -- N N1 the cinnoline 4-amino group protons were not readily OR 102 H observable in the proton NMR spectra recorded at 30°C. in 2 N chloroform-d due to severe broadening into the baseline. 1-2 R5 2 These protons can be clearly observed by recording the R6 spectrum at -20°C. 1-3 0411. As shown in Scheme 1, a compound 1-3 can be 1-2 made by coupling of a halogenated cinnoline derivative 1-1 OR 101 (wherein X is halo such as bromo or iodo) to a boron R6-B compound 1-2 wherein R can be an optionally substituted OR 102 aryl or heteroaryl (suitable substituents can be alkyl, CN 1-2A etc.), R'' and R'' are each, independently, hydrogen or OH C, alkyl; or R'' and R', together with the two oxygen R-B-Y atoms to which they are attached and the boron atom to V which the two oxygen atoms are attached, form a 4-7 OH, membered heterocyclic ring whose ring-forming atoms 1-2B comprises B, O and C atoms and which is optionally O R-B6. / Substituted by 1, 2, 3, or 4C alkyl (i.e., a moiety shown N as 1-2B-R whereintl is 0, 1, 2 or 3: t2 is 0, 1, 2, 3 or 4; and O R" is each, independently, Calkyl). Two examples of the boron compound 1-2 are 1-2A (a boronic acid derivative) 1-2B-R and 1-2B (a 4.4.5.5,-tetramethyl-1,3,2-dioxoborolane y9Ns) t derivative). The coupling reaction can be carried out in the presence of a Suitable catalyst, Such as a metal catalyst. \O Some exemplary metal catalysts include palladium catalyst, (R400) such as bis(triphenylphosphine)palladium(II) dichloride and tetrakis(triphenylphosphine)palladium(0). The coupling reaction can be carried out in the presence of a suitable base 0412. As shown in Scheme 2, a compound 2-3 can be Such as an inorganic base. Some exemplar Suitable inorganic made by coupling of a halogenated cinnoline derivative 2-1 base include cesium carbonate, sodium carbonate, and (wherein X is halo such as bromo or iodo) to a tin com potassium phosphate. The coupling reaction can be carried pound 2-2 wherein R can be an optionally substituted aryl out in a Suitable solvent Such as an organic solvent. Some or heteroaryl (suitable substituents can be alkyl, CN etc.), Suitable organic solvent include polar organic solvents, such R', R'' and R'' are each, independently, Calkyl. The as an ether and an alcohol. Suitable ethers include 12 coupling reaction can be carried out in the presence of a US 2007/0142328A1 Jun. 21, 2007

Suitable catalyst, such as a metal catalyst. Some exemplary mixture is heated to a temperature of about 40°C., about 50° metal catalysts include palladium catalysts, such as bis C., about 60° C., about 70° C., about 80° C., about 90° C., (triphenylphosphine)palladium(II) dichloride and tetraki about 100° C., about 110° C., about 120° C., about 130°C., s(triphenylphosphine)palladium(0). The coupling reaction about 140° C., about 150° C., about 160° C. The reaction can be carried out in a Suitable organic solvent. Some progress can be monitored by conventional methods such as Suitable organic solvent include polar organic solvent. Some TLC or NMR Suitable organic solvent include aprotic solvent. Some Suit 0414. Also as shown in Scheme 3, the trialkylstannyl able organic solvent include polar aprotic organic solvent cinnoline derivative 3-1 can be made by coupling of a Such as N,N-dimethylformamide. The coupling reaction can halogenated cinnoline derivative 3-0-1 (wherein X* is halo be carried out at a suitable temperature for a time sufficient such as bromo or iodo) to a di-tin compound 3-0-2 (wherein to afford the compound 2-3. In some embodiments, the R', R'' and Rare each, independently, C alkyl) in reaction mixture is heated to an elevated temperature (i.e., the presence of a Suitable catalyst, such as a palladium above the room temperature). In some embodiments, the catalyst. Some exemplar palladium catalysts include bis reaction mixture is heated to a temperature of about 40° C. (triphenylphosphine)palladium(II) dichloride and tetraki about 50° C., about 60° C., about 70° C., about 80°C., about s(triphenylphosphine)palladium(0). 90° C., about 100° C., about 110° C., about 120° C., about 130° C., about 140° C., about 150° C., about 160° C. The reaction progress can be monitored by conventional methods Scheme 3 Such as TLC or NMR. R2 R3 YNH O Scheme 2 R RI N N1 R2 H R6-X catalyst R3 YNH O R5 2 N 3-2 R R1 N N1 S H -- R301 "YR303 R302 R5 N2N 3-1 X2 R2 2-1 R3 YNH O R2 R RI R3 YNH O N N1 R201 H 6- / - D202 catalyst R. RI R s R2UZ --- N N1 R5 22. N R203 H 2-2 R5 22. N R6 3-3 R6 R2 2-3 R3 YNH O R RI N N1 R301 R301 0413. As shown in Scheme 3, a compound 3-3 can be H R302-Sn-Sn-R302 made by coupling of a trialkylstannyl-cinnoline derivative 2N A V 3-1 (wherein R', R'' and R' are each, independently, R5 N R303 R303 Calkyl) to a halogenated compound RX 3-2 wherein X X4 3-0-2 is halo such as bromo or iodo, and wherein R can be an 3-0-1 optionally substituted aryl or heteroaryl (suitable substitu R2 ents can be alkyl, CN etc.). The coupling reaction can be R3 YNH O carried out in the presence of a suitable catalyst, such as a R RI metal catalyst. Some exemplary metal catalysts include N N1 palladium catalysts, such as bis(triphenylphosphine)palla H dium(II) dichloride and tetrakis(triphenylphosphine 2 N )palladium(0). The coupling reaction can be carried out in a R5 % Suitable organic solvent. Some Suitable organic solvent Sn include polar organic solvent. Some Suitable organic Sol R3011 NR303 vents include aprotic organic solvent. Some Suitable organic R302 Solvents include polar aprotic organic Solvents such as 3-1 N,N-dimethylformamide. The coupling reaction can be car ried out at a suitable temperature for a time sufficient to afford the compound 2-3. In some embodiments, the reac 0415. It should noted that in all of the schemes described tion mixture is heated to an elevated temperature (i.e., above herein, if there are fuinctional (reactive) groups present on the room temperature). In some embodiments, the reaction a substituent group such as R', R. R. R. R. R. etc., US 2007/0142328A1 Jun. 21, 2007

further modification can be made if appropriate and/or des (3B Medical, 47.7 g, 179 mmol) and 500 mL absolute ired. For example, a CN group can be hydrolyzed to afford ethanol. To this stirred solution was added iron powder (325 an amide group; a carboxylic acid can be converted to an mesh, Aldrich, 30 g, 537 mmol) followed by dropwise amide; a carboxylic acid can be converted to a ester, which addition of concentrated HCl (30 mL, 360 mmol). The in turn can be reduced to an alcohol, which in turn can be internal temperature rose from 23 to ~60° C. over the fuirther modified. In another example, an OH group can be addition. The flask was fitted with a heating mantle and converted into a better leaving group Such as mesylate, heated with vigorous stirring for 90 minutes. After cooling which in turn is suitable for nucleophilic substitution, such to room temperature, 1 N sodium carbonate (300 mL) was as by CN. One skilled in the art will recognize further such added followed by ethyl acetate (200 mL). The mixture was modifications. Thus, a compound of formula I (such as stirred for 30 minutes and then filtered through a pad of compound 1-3 of Scheme 1, compound 2-3 in Scheme 2 and celite. The celite was washed with ethyl acetate (3x150 mL). compound 3-3 of Scheme 3) having a substituent which The filtrates were placed in a separatory funnel and the water contains a function group can be converted to another layer was removed. The organic layer was concentrated compound of formula I having a different Substituent group. under reduced pressure to a volume of ~200 mL, placed in 0416) As used herein, the term “reacting refers to the a separatory funnel, diluted with ethyl acetate (400 mL), bringing together of designated chemical reactants such that washed with brine, dried over sodium sulfate, filtered and a chemical transformation takes place generating a com concentrated to dryness. The crude product was taken up in pound different from any initially introduced into the sys ether (300 mL) and made acidic to pH 1 with 2M hydro tem. Reacting can take place in the presence or absence of chloric acid/ether (Aldrich). After 1 hour, the tan solid was solvent. isolated by filtration (39.2 g, 80%). The above aqueous layers were extracted with diethyl ether (300 mL), dried over 0417. Some more detailed methods, procedures and pre sodium sulfate, combined with the filtrate of the 1 crop, cursors as outlined in Schemes 1-3 and additional detailed made acidic to pH1, and isolated as above to give additional procedures and characterization data for certain above tan solid (9.0 g, 18%) for an overall yield of 98%. "H NMR exemplified compounds are further described herein below. (300 MHz, CDC1) & 7.06 (m. 1H), 6.58 (m. 1H), 6.39 (m, Precursor 1 1H), 5.73 (bm, 1H). MS APCI, m/z=238 (M+H). HPLC 2.19 4-Amino-7-fluoro-8-iodo-N-propyl-cinnoline-3- min. carboxamide (2E)-2-Cyano-2-(3-fluoro-2-iodophenyl)hydra 0418 To a 1 L, 3-necked flask equipped with a mechani Zono-N-propylacetamide cal stirrer charged with (2E)-2-cyano-2-(3-fluoro-2-io dophenyl)hydrazono-N-propylacetamide (43.9 g, 117 0421. Using the procedure outlined in the patent U.S. Pat. mmol) in anhydrous toluene (Aldrich, 600 mL) under N No. 4,886,800 example 89b substituting 3-fluoro-2-iodoa was added portion-wise aluminum chloride (Aldrich, 46.8 g. niline hydrochloride (8.8 g. 32.5 mmol) for 2-iodoaniline, 352 mmol) over 20 minutes. The mixture was heated to 60° the title compound (2E)-2-cyano-2-(3-fluoro-2-iodophe C. with vigorous stirring for 2 hours and then cooled to ~15° nyl)hydrazono-N-propylacetamide (8.5 g. 70% yield) was C. Ethyl acetate (30 mL) was carefully added while main obtained as a light brown Solid. An analytically pure sample taining the internal temperature between 20-25° C. Addi was obtained by recrystallization from ethyl acetate as a tional ethyl acetate (900 mL) was then added, followed by yellow crystalline solid. "H NMR (300 MHz, CDC1) & careful addition of Rochelle's salt (saturated aqueous potas 14.39 (s, 1H), 8.67 (bm, 1H), 7.45 (m. 1H), 7.32 (m. 1H), sium sodium tartrate, 500 mL). Upon addition of the first 50 7.03 (m. 1H), 3.1 (apparent q, J=6.6 Hz, 2H), 1.53 (apparent mL, the temperature rose from 20 to 36°C. The reaction was sextet, J=7.4 Hz, 2H), 0.88 (t, J=7.4 Hz, 3H). heated with stirring at 60° C. for 30 minutes. The aqueous layer contained a thick white precipitate and the organic Precursor 2 layer slowly solubilized the brownish yellow solid. Note: If 4-Amino-7-chloro-8-iodo-N-propyl-cinnoline-3- a non-white (brown/yellow) solid still existed at the aque carboxamide ous/organic interface, the hot extraction was repeated. The mixture was placed in a separatory funnel and the aqueous 0422. Using a procedure similar to that used in the layer was removed. The organic layer was washed with synthesis of 4-amino-7-fluoro-8-iodo-N-propyl-cinnoline-3- Rochelle’s salt (500 mL) and brine, dried over magnesium carboxamide, the title compound 4-amino-7-chloro-8-iodo sulfate, filtered and concentrated to give 38 g of product N-propyl-cinnoline-3-carboxamide (2.75 g. 67% yield) was (86.5%). Further purification by trituration with ethyl obtained from (2E)-2-cyano-2-(3-chloro-2-iodophenyl)hy acetate/hexanes was carried out when appropriate. An ana drazono-N-propylacetamide (4.1 g, 10.5 mmol) as a white lytically pure sample was obtained by recrystallization from solid. "H NMR (300 MHz, CDC1) & 8.54 (bs, 1H), 7.76 (d. ethyl acetate. "H NMR (300 MHz, CDC1) & 8.54 (br. 1H), J=9.0 Hz, 1H), 7.66 (d. J=9.0 Hz, 1H), 3.47 (apparent q, 7.84 (dd, J=5.3, 9.2 Hz, 1H), 7.39 (dd, J=7.0, 9.2 Hz, 1H), J=7.0 Hz, 2H), 1.68 (apparent sextet, J=7.0 Hz, 2H), 1.03 (t, 3.47 (apparent q, J=7.0 Hz, 2H), 1.68 (apparent sextet, J-7.0 7.4 Hz, 3H). MS APCI, m/z=391 (M+H) HPLC 2.38 min. Hz, 2H), 1.03 (t, J=7.4 Hz, 3H). MS APCI, m/z=375 (M+H). 0423. The intermediate compounds were prepared as HPLC 2.13 min. follows: 0419. The intermediate compounds were prepared as follows: (2E)-2-Cyano-2-(3-chloro-2-iodophenyl)hydra 3-Fluoro-2-iodoaniline hydrochloride Zono-N-propylacetamide 0420. To a 1 L, 3 necked round bottom flask fitted with 0424 Prepared according to the method described in a mechanical stirrer was added 3-fluoro-2-iodonitrobenzene patent U.S. Pat. No. 4,886,800 example 89b substituting US 2007/0142328A1 Jun. 21, 2007

3-chloro-2-iodoaniline (7.1 g, 28.1 mmol) for 2-iodoaniline, recrystallizations to afford a total of 164.6 g of the desired the title compound (2E)-2-cyano-2-(3-chloro-2-iodophe compound as a white crystalline solid (84%). "H NMR nyl)hydrazono-N-propylacetamide (4.2g, 38% yield) was (300. 132 MHz, CDC1) & 8.57 (bs, 1H), 8.12 (dd, J=7.6, 1.1 obtained as a yellow solid. "H NMR (300 MHz, CDC1) & HZ, 1H), 7.83 (dd, J=8.4, 1.0 Hz, 1H), 7.50 (dd, J=8.4, 7.5 14.30 (s, 1H), 7.48 (m. 1H), 7.24-7.33 (m, 3H), 6.28 (bm, HZ, 1H), 3.48 (q, J=6.7 Hz, 2H), 1.69 (sextet, J=7.3 Hz, 2H), 1H), 3.37 (apparent q, J=7.0 Hz, 2H), 1.64 (apparent sextet, 1.03 (t, J=7.4 Hz, 3H). MS APCI, m/z=309/311 (M+H). J=7.4 Hz, 2H), 1.00 (t, J=7.4 Hz, 3H) MS APCI, m/z=391 HPLC 1.66 min. (M+H) HPLC 3.00 min. Precursor 4 3-Chloro-2-iodoaniline 4-Amino-8-iodo-N-propyl-cinnoline-3-carboxamide 0425 Prepared according to the method described in patent U.S. Pat. No. 4,822,781, process 1, substituting 0427 Prepared according to the method described in the 2-chloro-6-nitrophenol for 2-fluoro-6-nitrophenol, the title patent U.S. Pat. No. 4,886,800 example 36a. compound, 3-chloro-2-iodoaniline (7.1 g, 3 step overall Precursor 5 yield 55% yield) was obtained from 2-chloro-6-nitrophenol as a yellow solid. "H NMR (300 MHz, CDC1) & 7.04 (t, 4-Amino-8-fluoro-N-propyl-cinnoline-3-carboxamide J=8.0 Hz, 1H), 6.84 (dd, J=8.0, 1.3 Hz, 1H), 6.60 (dd, J=8.0, 0428 To a suspension of N-propyl-2-cyano-2-(2-fluo 1.3 Hz, 1H), 4.31 (bs, 2H). MS APCI, m/z=254 (M+H) rophenyl)hydrazonoacetamide (11.1 g, 44.71 mmol) in HPLC 2.38 min toluene (275 mL) was added aluminum chloride (20.90 g, Precursor 3 156.74 mmol). The mixture was stirred at 90° C. for 2.5 hours. The reaction mixture was cooled to 0°C., and then 4-Amino-8-bromo-N-propyl-cinnoline-3-carboxamide diluted with chloroform (1 L). A small amount of water was added to quench the reaction at 0° C. Aqueous Sodium 0426 A.22 L, 3-necked flask equipped with a mechanical hydroxide (750 mL. 20% w/v solution) was poured into the stirrer, thermometer, nitrogen inlet, reflux condenser, and mixture slowly at 0°C., and the mixture stirred at ambient addition funnel was charged with N-propyl-2-cyano-2-(2- temperature for one hour. A precipitate was formed gradu bromophenyl)hydrazonoacetamide (195.4g, 0.632 mol) in ally. The mixture was diluted with chloroform (2 L) until all toluene (4 L). Aluminum chloride (295 g, 2.21 mol) was of the precipitate was dissolved, washed twice with water, added in three portions. The mixture was heated with a dried through magnesium sulfate, and concentrated to a mantle to 90° C. in approximately 30 minutes. After 2.5 volume of approximately 200 mL to leave a suspension of hours, the heat was removed and the reaction mixture was the product. The title compound as a light beige solid (11.06 allowed to cool to room temperature overnight. The reaction g) was collected by filtration and washed with methylene mixture was cooled in an ice bath to s 10° C. and celite was chloride (50 mLx2), methanol (50 mL) and hexane (100 added. Water (680 mL) was added dropwise over 1 hr at mLX2). The mother liquor was concentrated, and purified by s 10° C. After stirring for 30 minutes, methylene chloride flash chromatography using a gradient of ethyl acetate in was added (8 L). The reaction mixture was cooled to s 10° hexane to give an additional 400 mg of the title compound C. and 10% sodium hydroxide (5.8 L) was added dropwise as a beige solid. "H NMR (300 MHz, CDC1) & 8.55 (br. over 45 minutes at s 10° C. After stirring for 30 minutes, 1H), 7.55-7.70 (m, 2H), 3.49 (m, 2H), 1.71 (m, 2H), 1.03 (t, tetrahydrofuran (2 L) was added and the phases were J=7.4 Hz, 3H) MS APCI, m/z=249 (M+H) HPLC 1.30 min. allowed to separate. The aqueous layer was removed, fil tered through celite, and the filter cake washed with 2:1 0429 The intermediate compounds were prepared as methylene chloride:tetrahydrofuran (4 L). Note: Addition of follows: fresh portions of methylene chloride helped expediate the rather tedious filtration. The phases of the filtrate were N-propyl separated and the organic phase was transferred to a sepa 2-cyano-2-(2-fluorophenyl)hydrazonoacetamide ratory funnel. Separation of the organic phase from the 0430 Solution A: To a mechanically stirred solution of aqueous base as quickly as possible helped avoid undue 2-fluoroaniline (11.51 g, 100.34 mmol) in acetic acid (50 hydrolysis of the propyl amide in the product. The solids mL) was added water (30 mL) at ambient temperature. The remaining in the reaction flask were dissolved with 2:1 mixture was cooled to 0°C., and then concentrated aqueous tetrahydrofuran:methanol (4 L) and then 10% methanol in HCl (25 mL) added. A precipitate was formed as soon as the chloroform (4 L). The layers were separated and the organic concentrated HCl was added, and the Suspension was stirred layer was washed with brine (500 mL), dried over magne at 0° C. for 20 minutes. To this suspension was added sium Sulfate, filtered, and concentrated under reduced pres dropwise a solution of sodium nitrite (7.72 g, 111.88 mmol) sure to a dark brown solid. The solid was slurried in diethyl in water (30 mL), maintaining the internal temperature ether, collected by filtration and dried. The crude solid (188 below 5°C. The resulting clear orange solution was stirred g) was then dissolved in hot methanol (6 L), treated with at 0° C. for another 30 minutes. activated charcoal (19 g), stirred 15 minutes at reflux, filtered through celite while hot, concentrated to approxi 0431 Solution B: To a mechanically stirred solution of mately 3 L, and allowed to crystallize overnight. The solids N-propyl-2-cyanoacetamide (15.69 g, 124.37 mmol) in etha were collected, washed with diethyl ether (400 mL) and nol (220 mL) was added a solution of sodium acetate dried in a vacuum oven at 50° C. to give a white crystalline (136.00 g, 1.66 moles) in water (600 mL), and chilled to solid. The filtrate was concentrated to approximately 1 Land between 0° C. and -5° C. a second crop obtained. The mother liquors were stripped 0432 Solution A was poured into solution B, maintaining and a third and fourth crop were obtained from additional the internal temperature below 0°C. An orange precipitate US 2007/0142328A1 Jun. 21, 2007

was formed gradually after 10 minutes. The mixture was mL) was added 70% ethyl amine in water (16 mL. 20.2 stirred below 0° C. for another hour, and was then diluted mmol) followed by triethyl amine (468 uL, 3.6 mmol). The with water (500 mL). After 30 minutes, the orange precipi reaction was stirred at room temperature overnight, concen tate was collected by filtration, washed with water (100 trated and dried under high vacuum. The material was mLX3), and dried at 50° C. under high vacuum to remove routinely used crude. Purification on silica gel using a water. An orange solid (9.50 g) was obtained, which was the gradient of 10 to 50% ethyl acetate in hexanes afforded the “E” isomer, and used for the next step without further title compound as a yellow solid. "H NMR (300.132 MHz, purification. "H NMR (300 MHz, CDC1) & 14.18 (br. 1H), CDC1) & 14.33 (s, 1H), 7.67 (dd, J=8.3, 1.4 Hz, 1H), 7.53 7.68 (td, 1H, J=7.94 Hz, J'=1.47 Hz), 7.00-7.20 (m, 3H), (dd, J=8.1, 1.3 Hz, 1H), 7.34 (td, J=7.8, 0.6 Hz, 1H), 7.01 6.28 (s, 1H), 3.34 (m, 2H), 1.64 (m, 2H), 0.99 (t, 3H, J=7.40 (td, J=7.7, 1.6 Hz, 1H), 3.45 (dq, J=5.9, 7.2 Hz, 2H), 1.26 (t, Hz) J-7.3 Hz, 3H). HPLC 4.66 min. Precursor 6 Precursor 8 4-amino-8-trimethylstannyl-N-propyl-cinnoline-3- 2-(Biphenyl-2-yl-hydrazono)-2-cyano-N-cyclopro carboxamide pylmethyl-acetamide 0433) To a stirred solution of 4-amino-8-iodo-N-propyl 0437. To a stirred solution of 2-aminobiphenyl (2.95 g, cinnoline-3-carboxamide (3.4 g., 9.4 mmol) and tetraki 17.4 mmol) in glacial acetic acid (16 mL) and water (14 mL) s(triphenylphosphine)palladium(0) (800 mg. 0.69 mmol) in with cooling was added dropwise concentrated hydrochloric anhydrous N,N-dimethylformamide at ambient temperature acid (10 mL). Additional water (10 mL) was added to under nitrogen was added hexamethylditin (5.0 g, 15.2 maintain stirring. The mixture was cooled to 0° C. and a mmol). The reaction was heated to 150° C. for 1-1.5 hours. solution of sodium nitrite (1.44 g. 20.7 mmol) in water (10 The reaction mixture was filtered through Celite, and the mL) was added dropwise maintaining an internal tempera solution evaporated. The residue was dissolved in methylene ture of <5° C. Upon complete addition, the reaction was chloride, washed with water twice, dried through MgSO, stirred at 0°C. for 30 minutes, poured portionwise into a and then the solvent was evaporated. The residue was mechanically stirred 3-necked round bottomed flask charged purified by flash chromatography using an increasingly polar with a predissolved solution of 2-cyano-N-cyclopropylm gradient of ethyl acetate in hexane to give a yellow solid as ethylacetamide (2.8 g. 20.3 mmol), sodium acetate (12.0 g, the title compound (2.4 g. 68.4% yield). H NMR (300 146 mmol), and Sodium carbonate (12.8 g. 121 mmol) in 2:1 MHz, CDC1) & 8.56 (br. 1H), 7.99 (dd, J=6.6 Hz, J'=1.0 Hz, water:ethanol (180 mL). Vigorous CO(g) evolution was 1H), 7.83 (dd, J=8.4 Hz, J'=1.1 Hz, 1H), 7.61 (dd, J=8.3 Hz, observed. After 1 hour at 0°C., the reaction was diluted with J'=6.6 Hz, 1H), 3.47 (q, J=6.8 Hz, 2H), 1.70 (m, J=7.3 Hz, water (200 mL) and extracted with ethyl acetate (400 mL). 2H), 1.02 (t, 3H, J=7.40 Hz), 0.44 (s, 9H). MS APCI, The organic layer was washed with water (200 mL) and brine (200 mL) and dried over sodium sulfate. The mixture m/z=391/392/395 (M+H). HPLC 2.75 min. was filtered, concentrated, and purified by recrystallization Precursor 7 from ethyl acetate/hexanes to afford the title compound as a yellow solid (2.0 g, 36%). H NMR (500.133 MHz, CDC1) 4-Amino-8-bromo-N-ethyl-cinnoline-3-carboxamide & 9.23 (t, J=5.3 Hz, 1H), 9.13 (bs, 1H), 8.43 (d. J=8.3 Hz, 0434) To a stirred solution of 2-(2-bromophenyl)-hydra 1H), 8.17 (bs, 1H), 7.86 (d. J=7.2 Hz, 1H), 7.81 (t, J=7.6 Hz, Zono-N-ethyl-2-cyanoacetamide (260 mg, 0.88 mmol) in 1H), 7.71 (d. J=7.5 Hz, 2H), 7.49 (t, J=7.2 Hz, 2H), 7.43 (t, anhydrous toluene (10 mL) was added aluminum chloride J=7.2 Hz, 1H), 3.30 (s, OH), 3.23 (t, J=6.1 Hz, 2H), 1.12 (370 mg, 2.78 mmol). The reaction was heated with vigor (septet, J=6.4 Hz, 1H), 0.45 (d. J=8.0 Hz, 2H), 0.29 (d. J=4.1 ous stirring at 90° C. for 1.5 hours, cooled, diluted with ethyl Hz, 2H). MS APCI, m/z=319 (M+H). HPLC 1.84 min. acetate (40 mL), and treated with Rochelle's salt (saturated 0438. The intermediate compounds were prepared as aqueous solution). After stirring for 30 minutes, the organic follows: layer was decanted into a separatory funnel. (The white precipitate was rinsed with ethyl acetate three times.) The 2-Cyano-N-cyclopropylmethylacetamide organic layer was washed with 1:1 brine:Rochelle’s salt 0439. To an ice-cooled flask charged with cyclopropyl Solution, dried over sodium Sulfate, and concentrated to a methyl amine (4.25 g, 59.8 mmol) was added ethyl cyano light brown solid. The solid was slurried in ether and filtered acetate (3.17 mL, 29.7 mmol). The reaction was stirred at 0° to afford the title compound as a brown solid (180 mg, 69%). C. for 1.75 hour at which point a precipitate had formed and H NMR (300. 132 MHz, CDC1) & 8.52 (s, 1H), 8.13 (dd. 1:1 ether:hexanes (40 mL) was added. The mixture was J=7.4, 1.1 Hz, 1H), 7.82 (dd, J=8.4, 1.1 Hz, 1H), 7.51 (dd. stirred for 15 minutes, filtered, and the solids washed with J=8.4, 7.5 Hz, 1H), 3.56 (dq, J=5.8, 7.3 Hz, 2H), 1.31 (t, hexanes to give the title compound as a white Solid (3.44 g. J-7.3 Hz, 3H). MS APCI, m/z=395/397 (M+H). HPLC 1.90 84%). "H NMR (300. 132 MHz, CDC1) & 6.17 (s, 1H), 3.37 1. (s. 2H), 3.17 (dd, J=7.1, 5.4 Hz, 2H), 1.06-0.92 (m. 1H), 0435 The intermediate compounds were prepared as 0.62-0.51 (m, 2H), 0.24 (q, J=5.1 Hz, 2H). follows: Precursor 9 2-(2-Bromophenyl)-hydrazono-N-ethyl-2-cyanoac 4-Amino-8-bromo-N-butyl-cinnoline-3-carboxamide etamide 0440 To a solution of 2-(2-bromophenyl)-hydrazono 0436 To a solution of (2-bromophenyl)-hydrazono-cy N-butyl-2-cyanoacetamide (2.5 g, 7.7 mmol) in anhydrous anoacetic acid ethyl ester (1.0 g, 3.4 mmol) in methanol (14 toluene (Aldrich, 50 mL) under N2 was added portion-wise US 2007/0142328A1 Jun. 21, 2007

aluminum chloride (Aldrich, 3.1 g, 23.2 mmol) over 5 0444 The intermediate compounds were prepared as minutes. The mixture was heated to 90° C. with vigorous follows: stirring for 1.5 hours then cooled to ~0° C. Water (3 mL) was added dropwise followed by careful addition of Rochelle's 2-(2-Bromophenyl)-hydrazono-N-methyl-2-cy salt (saturated aqueous potassium sodium tartrate, 50 mL). anoacetamide The reaction was stirred for 25 minutes and then poured into 0445 (2-Bromophenyl)-hydrazono-cyanoacetic acid a separatory funnel. The aqueous layer contained a thick ethyl ester (15.28 g, 51.60 mmol) was dissolved in 40% white precipitate and was quickly removed. The organic methylamine in water (67.5 mL) and stirred at room tem perature overnight. The reaction mixture was concentrated layer was washed with Rochelle's salt and brine, dried over to dryness, slurried in diethyl ether, and filtered. After drying magnesium Sulfate, filtered and concentrated to give 2.6 g. under high vacuum at 40° C., the title compound was slightly crude product which was purified on silica gel using obtained as a yellow solid (11.16 g., 77%). "H NMR a gradient of 20 to 60% ethyl acetate in hexane. Recrystal (300. 132 MHz, CDC1) & 7.68 (dd, J=8.2, 1.4 Hz, 1H), 7.54 lization from ethyl acetate/hexanes (10 mL each, 0° C. (dd, J=8.1, 1.3 Hz, 1H), 7.35 (t, J=7.9 Hz, 1H), 7.01 (td, overnight) afforded the title compound as a white solid (650 J=7.7, 1.5 Hz, 1H), 6.29 (s, 1H), 2.98 (d. J=4.9 Hz, 3H). MS mg, 26%). "H NMR (300. 132 MHz, CDC1) & 8.55 (bs, 1H), APCI, m/z=281/283 (M+H). HPLC 4.08 min. 8.13 (dd, J=7.4, 1.0 Hz, 1H), 7.82 (dd, J=8.5, 1.0 Hz, 1H), Precursor 11 7.50 (dd, J=8.5, 7.6 Hz, 1H), 3.52 (q, J=6.6 Hz, 2H), 1.65 (quintet, J=7.2 Hz, 2H), 1.47 (sextet, J=7.3 Hz, 2H), 0.97 (t, 4-Amino-8-bromo-cinnoline-3-carboxylic acid J-7.3 Hz, 3H). MS APCI, m/z=323/325 (M+H). HPLC 1.93 allylamide 1. 0446. To an ice-cooled suspension of 4-amino-8-bromo cinnoline-3-carboxylic acid (360 mg, 1.34 mmol) in dim 0441 The intermediate compounds were prepared as ethylformamide (5 mL) was added CDI (370 mg, 2.3 mmol) follows: and the mixture was stirred at room temperature for 1 hour. Additional DMF (14 mL) was added to enable stirring. After 2-(2-Bromophenyl)-hydrazono-N-butyl-2-cyanoac an additional 1 hour at room temperature, the mixture was etamide treated with allyl amine (120 u, 91 mg, 1.60 mmol) in one 0442. To a microwave vial charged with (2-bromophe portion. The reaction was stirred at room temperature for 1 nyl)-hydrazono-cyanoacetic acid ethyl ester (387 mg, 1.31 hour and then concentrated. Purification on silica gel using a gradient of 20 to 80% ethyl acetate in hexanes afforded the mmol) was added methanol (3 mL) and n-butylamine (520 title compound (300 mg, 73%). H NMR (300. 132 MHz, uL. 5.24 mmol). The reaction temperature rose approxi CDC1) & 8.14 (dd, J=7.4, 1.0 Hz, 1H), 7.83 (dd, J=8.4, 1.0 mately 30° C. and everything went into solution. After 25 HZ, 1H), 7.51 (dd, J=8.4, 7.5 Hz, 1H), 6.04-5.91 (m, 1H), minutes, additional n-butylamine (260 u, mg, 2.6 mmol) 5.33 (dq, J=17.1, 1.6 Hz, 1H), 5.21 (dq, J=10.4, 1.4 Hz, 1H), and triethyl amine (182 ul, 1.3 mmol) were added. The 4.15 (ddt, J=6.2, 5.8, 1.6 Hz, 2H). MS APCI, m/z=307/309 reaction was stirred at room temperature overnight and then (M+H). HPLC 1.59 min. concentrated to afford the title compound which was used without further purification (420 mg. 99%). "H NMR Precursor 12 (300. 132 MHz, CDC1) & 14.33 (s, 1H), 7.67 (dd, J=8.3, 1.5 2,4-Dimethoxy-5-(4,4,5,5-tetramethyl-1,3,2diox HZ, 1H), 7.53 (dd, J=8.1, 1.3 Hz, 1H), 7.34 (td, J=7.8, 1.2 aborolan-2-yl)-pyrimidine HZ, 1H), 7.01 (dt?ddd, J=6.1 Hz, J=8.0 Hz, J=1.5 Hz, 1H), 0447 To a 100 mL round-bottomed flask charged with 4 6.22 (bs, 1H), 3.40 (dt, J=5.9, 7.2 Hz, 2H), 1.65-1.35 (m, A molecular sieves (approximately 1 g) was added the 4H), 0.96 (td, J=7.3, 1.9 Hz, 3H). MS APCI, m/z=323/325 2,4-dimethoxypyrimidine-5-boronic acid (5.34 g, 29.0 (M+H). HPLC 2.94 min mmol) and anhydrous tetrahydrofuran (25 mL). The pinocol Precursor 10 (2.98 g. 25.3 mmol) was added and the reaction stirred at room temperature for 1.5 hours. Additional 2,4-dimethoxy 4-Amino-8-bromo-N-methyl-cinnoline-3-carboxamide pyrimidine-5-boronic acid (662.2 mg, 3.6 mmol) was added hydrochloric acid salt and the reaction stirred overnight. Molecular sieves and 2,4-dimethoxypyrimidine-5-boronic acid (1.53 g, 8.3 mmol) 0443 A 250 mL round-bottomed flask was charged with were added and the reaction stirred for 0.5 hours. Pinacol 2-(2-bromophenyl)-hydrazono-N-methyl-2-cyanoaceta (0.613 g, 5.2 mmol) was then added. After 2 hours, the mide (2.00 g, 7.12 mmol), aluminum chloride (3.46g, 25.97 molecular sieves were removed by filtration and the filtrate mmol), and anhydrous toluene (68 mL). The reaction was was concentrated. After drying under high vacuum, the title gently refluxed for 45 minutes, cooled to room temperature, compound was obtained as a fine yellow solid (8.61 g, 79%). and slowly treated with 2N HCl (68 mL). A precipitate "H NMR (300. 132 MHz, CDC1) & 8.56 (s, 1H), 4.01 (d. formed. The mixture was heated to 90° C. for 10 minutes, J=1.5 Hz, 6H), 1.34 (s, 12H). cooled to room temperature, and filtered. The solids were Precursor 13 dried under high vacuum at 50° C. to afford the title compound (2.02 g, 90%). "H NMR (300. 132 MHz, DMSO) 4-Amino-8-bromo-N-cyclopropyl-cinnoline-3- 89.08 (d. J=4.7 Hz, 1H), 8.56 (dd, J=8.4, 0.8 Hz, 1H), 8.28 carboxamide (dd, J=7.6, 0.7 Hz, 1H), 7.65 (t, J=8.0 Hz, 1H), 2.89 (d. J=4.7 0448. A 500 mL, 3-necked flask equipped with a Hz, 3H). MS APCI, m/z=281/283 (M+H). HPLC 1.61 min. mechanical stirrer, thermometer, nitrogen inlet, reflux con US 2007/0142328A1 Jun. 21, 2007 denser, and addition funnel was charged with N-cyclopro lents), cesium carbonate (2 molar equivalents) and bis(triph pyl-2-cyano-2-(2-bromophenyl)hydrazonoacetamide (1.7 enylphosphine)palladium(II) dichloride (0.025 molar g, 5.6 mmol) in anhydrous toluene (0.2 L). The reaction equivalents) were placed in a microwave reaction vessel and mixture was cooled with stirring in an ice bath. Aluminum dissolved in 7:3:2 (v/v/v) 1,2-dimethoxyethane: water: etha chloride (1.6 g. 12.0 mmol) was added in three portions. nol (5 mL/mmol cinnoline-halide) at ambient temperature. Removed ice bath and heated at 70-75° C. for 60 hours. The The reaction vessel was capped, the head-space purged with reaction mixture was allowed to cool to room temperature, dry nitrogen and the stirred mixture was heated on a Biotage diluted with ethyl acetate (200 mL), added saturated Roch Optimizer (300 W) microwave system maintaining a reac elle's salt (100 mL), stirred vigorously for 1 hour (until tion temperature of 150° C. for 30-90 minutes, reaction purple color dissipated to orange/yellow). Decanted organic pressures of 7 bar were typically observed. The reaction was layer from thick white aqueous layer, washed with addi then cooled to ambient temperature and extracted with ethyl tional Rochelle’s salt, brine, dried and concentrated to an acetate. The residue from the organic extracts was purified orange residue. The residue was slurried in ether (20 mL) to by flash chromatography on silica gel eluting with increas give title compound (930 mg, 52% yield). MS APCI, m/z= ingly polar gradient of ethyl acetate in hexanes to afford the 307/309 (M+H). desired compound. (2E)-2-Cyano-2-(2-bromoophenyl)hydrazono-N- 0455 Method B: To a solution of the cinnoline-halide in cyclopropylacetamide 1,2-dimethoxyethane (10 mL/mmol cinnoline-halide) under nitrogen at ambient temperature was added tetrakis(triph 0449. Using the procedure outlined in the patent U.S. Pat. enylphosphine)palladium (O) (0.05-0.15 molar equivalents). No. 4,886,800 example 89b substituting 2-bromoaniline for After stirring 10-20 min an arylboronic acid, heteroaryl 2-iodoaniline and 2-cyano-N-cyclopropylacetamide for boronic acid, or a boron compound 1-2B of Scheme 2 (1-4 2-cyano-N-propylacetamide, to give 11.1 g (85% yield) of molar equivalents) was added followed by a solution of the title compound as a yellow solid. MS APCI, m/z=307/ Sodium carbonate (2.5 molar equivalents) in water (3 309 (M+H). H NMR (300 MHz, CDC1) & 14.39 (s, 1H), mL/mmol halide). The resulting mixture was heated at reflux 8.67 (bm, 1H), 7.45 (m, 1H), 7.32 (m, 1H), 7.03 (m. 1H), 3.1 for 2-24 h. The reaction was then cooled to ambient tem (apparent q, J=6.6 Hz, 2H), 1.53 (apparent sextet, J=7.4 Hz, perature and extracted with ethyl acetate. The residue from 2H), 0.88 (t, J=7.4 Hz, 3H). the organic extracts was purified by flash chromatography 0450. The intermediate compounds were prepared as on silica gel eluting with increasingly polar gradient of ethyl follows: acetate in hexanes to afford the desired compound. 2-Cyano-N-cyclopropylacetamide 0456 Method C: To a stirred solution of the cinnoline halide in anhydrous N,N-dimethylformamide (2 mL/mmol 0451. To a flask charged with cyclopropylamine (12.3 g, cinnoline-halide) at ambient temperature was added an 215.3 mmol) was added ethyl cyanoacetate (9.8 g. 86.1 optionally substituted aryl- or heteroaryl-tin reagent (1.2 mmol). The reaction was stirred at 45° C. for 1.5 hour, molar equivalents) and tetrakis(triphenylphosphine cooled and concentrated under reduced pressure to give 10.7 )palladium(0) (0.05 molar equivalents). The mixture was g title compound (~100%) as a light yellow solid. "H NMR heated at 100° C. for 8-48 h. The reaction was then cooled (300. 132 MHz, CDC1) & 6.20 (bs, 1H), 3.34 (s. 2H), 2.75 to ambient temperature and extracted with ethyl acetate. The (m. 2H), 0.83 (m, 2H), 0.59 (m, 2H). residue from the organic extracts was purified by flash Precursor 14 chromatography on silica gel eluting with an increasingly polar gradient of ethyl acetate in hexanes to afford the 4-Amino-7-fluoro-8-iodo-N-cyclopropyl-cinnoline-3- desired compound. carboxamide 0457 Method D: The cinnoline-halide, an optionally 0452. Using the procedure outline for 4-Amino-8-bromo substituted aryl- or heteroaryl-tin reagent (1.2-3 molar N-cyclopropyl-cinnoline-3-carboxamide (precursor 13) sub equivalents) and tetrakis(triphenylphosphine) palladium(0) stituting N-cyclopropyl-2-cyano-2-(3-fluoro-2-iodophenyl (0.05-0.10 molar equivalents) were placed in a microwave )hydrazonoacetamide (5.8 g. 15.6 mmol) for reaction vessel and dissolved in 2-4 mL of anhydrous N-cyclopropyl-2-cyano-2-(2-bromophenyl)hydrazonolac N,N-dimethylformamide at ambient temperature. The reac etamide to give title compound (3.3 g, 57% yield). MS tion vessel was purged with nitrogen, capped, and the stirred APCI, m/z=373 (M+H). mixture was heated on a Biotage Optimizer (300 W) micro (2E)-2-Cyano-2-(3-fluoro-2-iodophenyl)hydra wave system maintaining a reaction temperature of 150° C. Zono-N-cyclopropylacetamide for 30 minutes. The reaction was cooled to ambient tem perature, diluted with methylene chloride, washed with 0453 Using the procedure outlined in the patent U.S. Pat. water, dried over magnesium Sulfate and the solvent was No. 4,886,800 example 89b substituting 3-fluoro-2-iodoa evaporated. The residue was purified by flash chromatogra niline for 2-iodoaniline and 2-cyano-N-cyclopropylaceta phy on silica gel eluting with increasingly polar gradient of mide for 2-cyano-N-propylacetamide, to give 8.9 g (94% ethyl acetate in hexanes to afford the desired compound. yield) of the title compound as a yellow solid. MS APCI. m/z=373 (M+H) 0458 Method E: To a stirred solution of 8-trimethylstan nyl-cinnoline derivative and tetrakis(triphenylphosphine) Detailed Synthesis Methods/Procedures: palladium(0) (0.05-0.10 molar equivalents) in anhydrous 0454 Method A: The cinnoline-halide, an optionally sub N,N-dimethylformamide at ambient temperature under stituted arylboronic acid, heteroarylboronic acid, or a boron nitrogen was added an optionally Substituted aryl- or het compound 1-2B of Scheme 2 (typically 2-3 molar equiva eroaryl bromide (1.2-3 molar equivalents). The reaction was US 2007/0142328A1 Jun. 21, 2007

heated to 150° C. for 4-16 hours. The reaction mixture was EXAMPLE 1. evaporated under reduced pressure. The residue was dis solved in methylene chloride, washed with water twice, 4-amino-7-fluoro-8-phenyl-N-propyl-cinnoline-3- dried through MgSO4, and then the solvent was evaporated. carboxamide The residue was purified by flash chromatography on silica 0462. Using method F 4-amino-7-fluoro-8-iodo-N-pro gel eluting with an increasingly polar gradient of ethyl pyl-cinnoline-3-carboxamide (291 mg, 0.78 mmol) and phe acetate in hexane to afford the desired compound. nylboronic acid (379 mg, 3.11 mmol) were reacted (reflux 4 hours) to afford the title compound (65 mg, 26% yield) as a 0459 Method F. To a solution of the cinnoline-halide in white solid. "H NMR (300 MHz, CDC1) & 8.52 (bs, 1H), anhydrous tetrahydrofuran (10 mL/mmol cinnoline-halide) 7.89 (dd, J=9.2, 4.6 Hz, 1H), 7.42-7.60 (m, 6H), 3.45 under nitrogen at ambient temperature was added (triph (apparent q, J=6.6 Hz, 2H), 1.65 (apparent sextet, J=7.2 Hz, enylphosphine)palladium(II) dichloride (0.10 molar equiva 2H), 1.00 (t, J=7.4 Hz, 3H). MS APCI, m/z=325 (M+H) lents) followed by an optionally substituted arylboronic HPLC 1.92 min. acid, heteroarylboronic acid, or a boron compound 1-2B of EXAMPLE 2 Scheme 2 (2-4 molar equivalents) followed by freshly ground potassium phosphate (2.0 molar equivalents). The 4-amino-7-chloro-8-phenyl-N-propyl-cinnoline-3- resulting mixture was heated at reflux for 2-40 h. The carboxamide reaction was then cooled to ambient temperature and diluted 0463 Using Method F, 4-amino-7-chloro-8-iodo-N-pro with saturated sodium bicarbonate and extracted with ethyl pyl-cinnoline-3-carboxamide (184 mg., 0.47 mmol) and phe acetate. The residue from the organic extracts was purified nylboronic acid (229 mg, 1.89 mmol) were reacted (refluxed by flash chromatography on silica gel eluting with 5% ether 40 hours) to afford the title compound (90 mg, 56% yield) in chloroform to afford the desired compound. as a white solid. "H NMR (300 MHz, CDC1) & 8.49 (bs, 1H), 7.82 (d. J=9.0 Hz, 1H), 7.75 (d. J=9.0 Hz, 1H), 0460 Method G: The cinnoline-halide, an optionally 742-7.55 (m, 5H), 3.43 (apparent q, J=6.6 Hz, 2H), 1.63 substituted arylboronic acid, heteroaryl boronic acid, or a (apparent sextet, J=7.2 Hz, 2H), 0.98 (t, J=7.4 Hz, 3H). MS boron compound 1-2B of Scheme 2 (4-5 molar equivalents), APCI, m/z=341 (M+H) HPLC 2.04 min. cesium carbonate (4-5 molar equivalents), 2-dicyclohexy lphosphino-2',4',6'-trisopropylbiphenyl (0.24 molar equiva EXAMPLE 3 lents) and tris(dibenzylidene-acetone)dipalladium(0) (0.06 4-amino-7-methoxy-8-phenyl-N-propyl-cinnoline-3- molar equivalents) were placed in a 3-neck flask under N carboxamide and dissolved in 7:3:2 (v/v/v) THF: water:2-propanol (5 mL/mmol cinnoline-halide) at ambient temperature. The 0464 Using Method F, 4-amino-7-methoxy-8-iodo-N- reaction vessel was fitted with a reflux condenser, capped, propyl-cinnoline-3-carboxamide (311 mg, 0.81 mmol) and vacuum degassed (3x) backfilling with N and placed in a phenylboronic acid (394 mg. 3.24 mmol) were reacted preheated oil bath (70° C.) and heated for 20 hours. (* if (refluxed overnight) to afford the title compound (140 mg. reaction not complete more boronic acid and cesium car 52% yield) as a white solid. "H NMR (300 MHz, CDC1) & bonate in equal proportions were added with additional 8.51 (bm, 1H), 7.90 (d. J=9.2 Hz, 1H), 7.52 (d. J=9.2 Hz, heating time). The reaction was then cooled to ambient 1H), 7.36-7.50 (m, 5H), 3.92 (s.3H), 3.43 (apparent q, J=6.4 temperature, decanted organic layer and concentrated under Hz, 2H), 1.63 (apparent sextet, J=7.2 Hz, 2H), 0.98 (t, J=7.4 reduced pressure. Residue partitioned between ethyl acetate Hz, 3H). MS APCI, m/z=337 (M+H) HPLC 1.76 min. and 5% sodium bicarbonate (aq). The residue from the EXAMPLE 4 organic extracts was purified by flash chromatography on silica gel eluting with increasingly polar gradient of ethyl 4-amino-7-chloro-8-(2,5-dimethylphenyl)-N-propyl acetate in hexanes (alternately 1% methanol/dichlo cinnoline-3-carboxamide romethane) to afford the desired compound. 0465. Using method A, 4-amino-7-chloro-8-iodo-N-pro 0461) Method H: The cinnoline-halide, an optionally pyl-cinnoline-3-carboxamide (78 mg 0.20 mmol) and (2.5- substituted arylboronic acid, heteroaryl boronic acid, or a dimethylphenyl)boronic acid (63 mg, 0.417 mmol) were boron compound 1-2B of Scheme 2 (3-5 molar equivalents), reacted to afford the title compound (33 mg, 45% yield) as sodium carbonate (4-5 molar equivalents), 1,1'-bis(diphe a white solid. "H NMR (300 MHz, CDC1) & 8.48 (bm, 1H), nylphospino)-ferrocenedichloropalladium(II) complex with 7.85 (bm, 1H), 7.75 (m. 1H), 7.15-7.24 (m, 2H), 6.98 (s, dichloromethane (1:1) (0.075 molar equivalents) were 1H), 3.43 (apparent q, J=6.7 Hz, 2H), 2.36 (s, 3H), 1.95 (s, placed in a 3-neck flask under N, and dissolved in 7:3:2 3H), 1.63 (apparent sextet, J=7.2 Hz, 2H), 0.98 (t, J=7.4 Hz, (v/v/v) THF: water:2-propanol (5 mL/mmol cinnoline-ha 3H). MS APCI, m/z=369 (M+H) HPLC 2.15 min. lide) at ambient temperature. The reaction vessel was fitted EXAMPLE 5 with a reflux condenser, under N2 and placed in a preheated oil bath (85°C.) and refluxed 2-20 hours (* if reaction not 4-amino-8-(2,4-dimethoxypyrimidin-5-yl)-N-propyl complete added more boronic acid with additional heating cinnoline-3-carboxamide time). The reaction was then cooled to ambient temperature, 0466. Using method A, 4-amino-8-bromo-N-propyl-cin reduced Volume under reduced pressure, partitioned noline-3-carboxamide (100 mg, 0.324 mmol) and (2,4- between ethyl acetate and water. The residue from the dimethoxypyrimidin-5-yl)boronic acid (125 mg 0.68 mmol) organic extracts was purified by flash chromatography on were reacted to afford the title compound (33 mg, 28% silica gel eluting with increasingly polar gradient of ethyl yield) as a white solid. "H NMR (300 MHz, CDC1) & 8.52 acetate in hexanes to afford the desired compound. (bm, 1H), 8.33 (s, 1H), 7.91 (dd, J=7.7, 2.0 Hz, 1H),

US 2007/0142328A1 Jun. 21, 2007 90 rophenylboronic acid (300 mg, 1.90 mmol) and bis(triph dimethoxyphenyl boronic acid (148 mg, 0.97 mmol) were enylphosphine) palladium(II) dichloride (24 mg., 0.034 reacted to afford the title compound (106 mg. 89.5% yield) mmol) were reacted to afford the title compound (200 mg. as a pale-yellow solid. "H NMR (300 MHz, CDC1) & 8.55 89.7% yield) as an off-white solid. "H NMR (300 MHz, (br. 1H), 7.89 (d. J=8.1 Hz, 1H), 7.78 (dd, J=7.1 Hz, J'=1.5 CDC1) & 8.55 (br. 1H), 7.92 (dd, J=8.1 Hz, J'=1.4 Hz, 1H), HZ, 1H), 7.71 (t, J=7.6 Hz, 1H), 7.15 (t, J=7.9 Hz, 1H), 6.99 7.67-7.82 (m, 2H), 7.22 (m, 2H), 6.88 (m, 1H), 3.47 (q, (m. 2H), 3.92 (s, 3H), 3.53 (s, 3H), 3.45 (q, J=6.7 Hz, 2H), J=6.7 Hz, 2H), 1.68 (m, J=7.2 Hz, 2H), 1.01 (t, J=7.4 Hz, 1.65 (m, J=7.2 Hz, 2H), 0.99 (t, J=7.4 Hz, 3H) MS APCI, 3H). MS APCI, m/z=343 (M+H). HPLC 2.14 min. m/z=367 (M+H) HPLC 1.86 min. EXAMPLE 1.5 EXAMPLE 17 4-amino-8-(5-azetidin-1-ylcarbonyl-3-pyridyl)-N- propyl-cinnoline-3-carboxamide 4-amino-8-(4-dimethylaminophenyl)-N-propyl-cin 0476. Using method D, 4-amino-8-iodo-N-propyl-cinno noline-3-carboxamide line-3-carboxamide (100 mg, 0.28 mmol) and 3-trimethyl 0480. Using method A, 4-amino-8-bromo-N-propyl-cin Stannyl-5-(aZetidin-1-ylcarbonyl)-pyridine (182 mg. of noline-3-carboxamide (100 mg, 0.33 mmol) and 4-dimethy 80%, 0.45 mmol) were reacted to afford the title compound laminophenyl boronic acid (160 mg. 0.97 mmol) were (48 mg, 44.0% yield) as an off-white solid. "H NMR (300 reacted to afford the title compound (105 mg. 93.0% yield) MHz, CDC1) & 9.00 (s, 1H), 8.89 (s, 1H), 8.51 (br. 1H), 8.40 as a pale-yellow solid. "H NMR (300 MHz, CDC1) & 8.61 (s, 1H), 7.96 (d. J=7.0 Hz, 1H), 7.72-7.88 (m, 2H), 4.46 (br. (br. 1H), 7.58-7.85 (m, 5H), 6.88 (d. J=8.8 Hz, 2H), 3.47 (q, 2H), 4.28 (br, 2H), 3.48 (q, J=6.7 Hz, 2H), 2.40 (m, J=7.8 J=6.7 Hz, 2H), 3.02 (s, 6H), 1.67 (m, J=7.3 Hz, 2H), 1.01 (t, Hz, 2H), 1.69 (m, J=7.3 Hz, 2H), 1.02 (t, J=7.4 Hz, 3H). MS J=7.4 Hz, 3H) MS APCI, m/z=350 (M+H) HPLC 2.67 min. APCI, m/z=391 (M+H). HPLC 1.74 min. 0477 The reagent, 3-trimethylstannyl-5-(azetidin-1-yl EXAMPLE 1.8 carbonyl)-pyridine, was synthesized by the following 4-amino-8-(3-methoxyphenyl)-N-propyl-cinnoline method: 3-carboxamide 0478. To a stirred suspension of 5-bromonicotinic acid 0481. Using method A, 4-amino-8-bromo-N-propyl-cin (1.0 g, 4.95 mmol) in 15 mL of anhydrous methylene noline-3-carboxamide (100 mg, 0.33 mmol) and 3-methox chloride at 0°C. under nitrogen was added oxaylic chloride yphenylboronic acid (147 mg, 0.97 mmol) were reacted to (817 mg, 6.44 mmol). The reaction mixture was stirred at 0° afford the title compound (69 mg, 64.2% yield) as an C. for 30 minutes. Then triethylamine (1.25 g, 12.38 mmol) off-white crystal. "H NMR (300 MHz, CDC1) & 8.58 (br. was added slowly, and followed by the addition of azetidine 1H), 7.87 (dd, J=8.3 Hz, J'=1.4 Hz, 1H), 7.81 (dd, J=7.1 Hz, (565 mg, 9.90 mmol) at 0°C. The reaction was warmed to J'=1.4 Hz, 1H), 7.72 (t, J=8.1 Hz, 1H), 7.41 (t, J=8.0 Hz, ambient temperature, and stirred for another hour. The 1H), 7.15-7.35 (m, overlapped with CHCl), 6.98 (dd, J=8.1 reaction mixture was diluted with methylene chloride, quenched with water, washed with 10% potassium carbonate HZ, J'=1.8 Hz, 1H), 3.86 (s.3H), 3.46 (q, J=6.7 Hz, 2H), 1.67 aqueous Solution twice, dried through magnesium sulfate, (m, J-7.3 Hz, 2H), 1.01 (t, J=7.4 Hz, 3H) MS APCI, and the solvent was evaporated to dry. The residue was m/z=337 (M+H) HPLC 1.89 min. purified by flash chromatography using a gradient of metha EXAMPLE 19 nol in methylene chloride to give a yellow liquid as 3-bromo-5-(azetidin-1-ylcarbonyl)-pyridine (84.6 mg, 4-amino-8-(3,4-dimethoxyphenyl)-N-propyl-cinno 70.9% yield). Following, to a stirred solution of 3-bromo line-3-carboxamide 5-(azetidin-1-ylcarbonyl)-pyridine (600 mg, 2.50 mmol) and tetrakis(triphenylphosphine) palladium(0) (240 mg, 0.21 0482. Using method A, 4-amino-8-bromo-N-propyl-cin mmol) in 40 mL of xylene at ambient temperature under noline-3-carboxamide (100 mg. 0.33 mmol) and 3,4- nitrogen was added hexamethylditin (1.58 g. 4.50 mmol). dimethoxyphenyl boronic acid (148 mg, 0.97 mmol) were The reaction was heated to 150° C. overnight. The reaction reacted to afford the title compound (91 mg, 77.7% yield) as mixture was filtrated through Celite, and the filtrate was a pale-yellow solid. "H NMR (300 MHz, CDC1) & 8.58 (br. vacuumed to dry. The residual was dissolved in methylene 1H), 7.76-7.88 (m, 2H), 7.71 (t, J=7.7 Hz, 1H), 7.29 (m, chloride, washed with water twice, dried through MgSO, overlapped with CHCl), 7.23 (d. J=1.9 HZ, 1H), 7.02 (d. and then the solvent was evaporated. The precipitate was J=8.3 Hz, 1H), 3.95 (s.3H), 3.93 (s.3H), 3.47 (q, J=6.7 Hz, purified by flash chromatography using a gradient of ethyl 2H), 1.68 (m, J=7.2 Hz, 2H), 1.01 (t, J=7.4 Hz, 3H) MS acetate in hexane to give a yellow solid as 3-trimethylstan APCI, m/z=367 (M+H) HPLC 1.78 min. nyl-5-(azetidin-1-ylcarbonyl)-pyridine (84.6 mg, 83.0% yield). "H NMR (300 MHz, CDC1) & 8.65-8.70 (m, 2H), EXAMPLE 20 8.04 (t, J=1.9 HZ, 1H), 4.31 (t, J=7.63 Hz, 2H), 4.00-4.10 (m, overlapped with HO), 2.27 (m, J=6.2 Hz, 2H MS APCI, 4-amino-8-(2,5-dimethoxyphenyl)-N-propyl-cinno m/z=323/325/327 (M+H) HPLC 1.61 min. line-3-carboxamide EXAMPLE 16 0483 Using method B, 4-amino-8-bromo-N-propyl-cin noline-3-carboxamide (13.0 g, 42.1 mmol), 2,5-dimethox 4-amino-8-(2,3-dimethoxyphenyl)-N-propyl-cinno yphenyl boronic acid (15.4 g, 84.6 mmol) and bis(triph line-3-carboxamide enylphosphine) palladium(II) dichloride (88.6 mg, 1.3 0479. Using method A, 4-amino-8-bromo-N-propyl-cin mmol) were reacted to afford the title compound (13.51 g, noline-3-carboxamide (100 mg. 0.33 mmol) and 2,3- 87.7% yield) as an off-white needle. "H NMR (300 MHz,

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2H), 1.65 (apparent sextet, J=7.0 Hz, 2H), 0.99 (t, 3H, J=7.0 Hz). MS APCI, m/z=355 (M+H). HPLC 1.66 min. -continued NH2 O B(OH(OH)2 EXAMPLE 63 F O N 1n-1 N 4-amino-8-(3-fluoro-4-methoxy-phenyl)-N-propyl H cinnoline-3-carboxamide 2N N Pd(dppf)Cl2 Na2CO3 0527 Using method A, 4-amino-8-bromo-N-propyl-cin Br THFIPA water noline-3-carboxamide (150 mg, 0.485 mmol) and 3-fluoro 65° C., 90 min, 88% 4-methoxy-phenylboronic acid (170 mg, 1.000 mmol) were NH2 O reacted to afford the title compound (135 mg, 78% yield) as a white solid. "H NMR (300 MHz, CDC1) & 8.57 (br. 1H), N 1)N-1 7.88-7.66 (m, 3H), 7.52-7.41 (m, 2H), 7.10 (m, 1H), 3.96 (s, H 3H), 3.47 (apparent quartet, J-7.0 Hz, 2H), 1.67 (apparent 2 N sextet, J=7.0 Hz, 2H), 1.01 (t, J=7.0 Hz, 3H). MS APCI, m/z=355 (M+H). HPLC 1.76 min. F O N

EXAMPLE 64 4-amino-8-(2-fluoro-6-methoxy-phenyl)-N-propyl cinnoline-3-carboxamide 0530 A 2 L, 3-necked flask equipped with a reflux condenser, mechanical stirrer, and 250 mL addition funnel 0528. Using method A, 4-amino-8-bromo-N-propyl-cin was charged with 4-amino-8-bromo-N-propyl-cinnoline-3- noline-3-carboxamide (150 mg, 0.485 mmol) and 2-fluoro carboxamide (36.80 g, 119.09 mmol), 2-fluoro-6-methoxy 6-methoxy-phenylboronic acid (170 mg, 1.000 mmol) were phenylboronic acid (60.70 g., 357.06 mmol), and reacted to afford the title compound (73 mg, 42% yield) as Pd(dppf)Cl. CHCl (740 g, 9.06 mmol) under Argon at ambient temperature. A gentle vacuum was applied and the a white solid. 'H NMR (300 MHz, CDC1) & 8.54 (br. 1H), apparatus was back-filled with Argon two times. Tetrahy 7.93 (m, 1H), 7.78-7.69 (m, 2H), 742-7.31 (m, 1H), 6.89 drofuran (515 mL, anhydrous) and isopropanol (147 mL, 6.80 (m. 2H), 3.70 (s, 3H), 3.44 (apparent quartet, J=7.0 Hz, anhydrous) were added and the resulting red Suspension was 2H), 1.64 (apparent sextet, J=7.0 Hz, 2H), 0.99 (t, J=7.0 Hz, stirred at room temperature for 15 minutes. A solution of 3H). MS APCI, m/z=355 (M+H). HPLC 1.68 min. sodium carbonate (57.0 g, 537.7 mmol) in water (220 mL) was added rapidly through the addition funnel and the EXAMPLE 64A resulting mixture immediately placed into a pre-heated 80° C. oil bath. After 90 minutes at reflux (observed internal Large Scale Synthesis of 4-Amino-8-(2-fluoro-6- temperature 65° C.), the reaction mixture was cooled to methoxy-phenyl)-N-propylcinnoline-3-carboxamide room temperature and filtered though a bed of Celite Sup ported on a sintered glass funnel topped with Norite decol 0529) orizing carbon (30 g). The residual salts and filter-cake were washed with 4:1 (v/v) THF: isopropanol until no additional material could be detected in the eluent by TLC (silica gel, 1:1 (v/v) hexanes: ethyl acetate, UV detection, R=0.25). The dark red solution was concentrated to a small volume NC ~ n1N under reduced pressure and then diluted with ethyl acetate O (250 mL). The organic phase was separated and the aqueous NaNO phase extracted with ethyl acetate (2x250 mL). The com NH2 AcOH, H2O, HCI bined organic layers were washed with brine, dried over 98% sodium sulfate, filtered and then concentrated under reduced Br pressure. The residues were passed through a small pad of silica gel on a sintered glass funnel washing with ethyl acetate until no more material was detected in the eluent. NH The solution was evaporated to afford the crude product as --- a foamy red-brown solid. This material was purified by flash Br N ON AICl3, Tol chromatography on silica gel using a gradient of 40 to 50% C 50° C., 86% ethyl acetate in hexanes. Product containing fractions were combined and evaporated. The residue was precipitated HN O from dichloromethane by addition of hexanes at room temperature. Recrystallization of this material from hot 1:1 (v/v) ethanol: water afforded the title compound as off-white white crystals (32.78 g. 78% yield). Additional title com pound (4.30 g, 10% yield) was isolated by processing the residues form the crystallization liquors through an acid US 2007/0142328A1 Jun. 21, 2007 97 base extractive workup. "H NMR (500.3 MHz, CDC1) & EXAMPLE 68 8.54 (br. 1H), 7.90 (dd, J=8.1 Hz, 1H), 7.75-7.67 (m, 2H), 7.37-7.31 (m. 1H), 6.86-6.80 (m, 2H), 3.69 (s.3H), 3.44 (qd, 4-amino-8-(4-fluorophenyl)-N-propyl-cinnoline-3- J=7.1 Hz, 2H), 1.64 (apparent sextet, J=7 Hz, 2H), 0.99 (t, carboxamide J=7 Hz, 3H). The 4-Amino protons were not observable in 0537. Using method F, 4-amino-8-iodo-N-propyl-cinno the reported proton NMR spectra recorded at 30° C. due to line-3-carboxamide (178 mg, 0.50 mmol) and 4-fluorophe severe broadening into the baseline. These protons can be nylboronic acid (280 mg, 2.00 mmol) were reacted (reflux clearly observed by recording the spectrum at -20° C. 24 hours) to afford the title compound (76 mg, 47% yield) HRMS (C19H19FN4O2) Cald=355.1570, Observed= as a white solid. "H NMR (300 MHz, CDC1) & 8.56 (bm, 355.1531. HPLC 1.68 min. 1H), 7.86 (dd, J=7.7 Hz, 1H), 7.65-7.80 (m, 4H), 7.19 (t, 0531. It is found that the titled compound can be sepa J=8.6 Hz, 2H), 3.45 (apparent q, J=6.6 Hz, 2H), 1.67 rated into two atropisomers using Supercritical Fluid Chro (apparent sextet, J=7.4 Hz, 2H), 1.01 (t, J=7.4 Hz, 3H). matography. Generally, in Supercritical CO modified with 0538 MS APCI, m/z=325 (M+H) HPLC 1.74 min. methanol, these atropisomers are stable and hence are sepa rable on a chiral Support. However, in aqueous media and EXAMPLE 69 acidic aqueous media, in particular, the atropisomers inter conversion is greatly facilitated. 4-amino-N-propyl-8-4-(trifluoromethoxy)phenyl cinnoline-3-carboxamide 4-Amino-8-bromo-N-propyl-cinnoline-3-carboxamide 0539 Using method F, 4-amino-8-iodo-N-propyl-cinno 0532 Prepared according to the method described in the line-3-carboxamide (178 mg, 0.42 mmol) and 4-trifluorom patent U.S. Pat. No. 4,886,800 example 35a. ethylphenylboronic acid (347 mg, 1.68 mmol) were reacted (reflux 16 hours) to afford the title compound (119 mg, 73% EXAMPLE 65 yield) as a white solid. "H NMR (300 MHz, CDC1) & 8.56 (bs, 1H), 7.90 (dd, J=7.9, 1.5 Hz, 1H), 7.71-7.82 (m, 4H), 4-amino-8-(2-fluoro-5-methoxy-phenyl)-N-propyl 7.35 (d. J=8.3 Hz, 2H), 3.45 (apparent q, J=6.8 Hz, 2H), 1.67 cinnoline-3-carboxamide (apparent sextet, J=7.3 Hz, 2H), 1.01 (t, J=7.3 Hz, 3H). 0533. Using method A, 4-amino-8-bromo-N-propyl-cin 0540 MS APCI, m/z=391 (M+H) HPLC 2.21 min. noline-3-carboxamide (150 mg, 0.485 mmol) and 2-fluoro 5-methoxy-phenylboronic acid (170 mg, 1.000 mmol) were EXAMPLE 70 reacted to afford the title compound (142 mg, 83% yield) as a white solid. "H NMR (300 MHz, CDC1) & 8.56 (br. 1H), 4-amino-N-propyl-8-3-(trifluoromethoxy)phenyl 7.92 (m. 1H), 7.82-7.69 (m, 2H), 7.12 (m. 1H), 7.02-6.89 cinnoline-3-carboxamide (m. 2H), 3.81 (s.3H), 3.45 (apparent quartet, J-7.0 Hz, 2H), 0541. Using method F, 4-amino-8-iodo-N-propyl-cinno 1.66 (apparent sextet, J=7.0 Hz, 2H), 1.00 (t, J=7.0 Hz, 3H). line-3-carboxamide (178 mg, 0.42 mmol) and 3-trifluorom MS APCI, m/z=355 (M+H). HPLC 1.78 min. ethylphenylboronic acid (347 mg, 1.68 mmol) were reacted (reflux 16 hours) to afford the title compound (94 mg, 57% EXAMPLE 66 yield) as a white solid. "H NMR (300 MHz, CDC1) & 8.56 (bs, 1H), 7.90 (d. J=8.3, 1H), 7.71-7.81 (m, 2H), 7.67 (d. 4-amino-8-(5-fluoro-2-methoxy-phenyl)-N-propyl J=7.9, 1H), 7.49-7.57 (m, 2H), 7.28 (m, 1H), 3.47 (apparent cinnoline-3-carboxamide q, J=6.7 Hz, 2H), 1.67 (apparent sextet, J=7.3 Hz, 2H), 1.01 0534. Using method A, 4-amino-8-bromo-N-propyl-cin (t, J=74 Hz, 3H). MS APCI, m/z=391 (M+H) HPLC 2.20 noline-3-carboxamide (150 mg, 0.485 mmol) and 5-fluoro min. 2-methoxy-phenylboronic acid (170 mg, 1.000 mmol) were reacted to afford the title compound (140 mg, 81% yield) as EXAMPLE 71 a white solid. "H NMR (300 MHz, CDC1) & 8.54 (br. 1H), 4-amino-8-(6-methoxy-3-pyridyl)-N-propyl-cinno 7.89 (m, 1H), 7.75-7.67 (m, 2H), 7.14-7.04 (m, 2H), 6.99 line-3-carboxamide 6.92 (m. 1H), 3.67 (s, 3H), 3.45 (apparent quartet, J=7.0 Hz, 2H), 1.65 (apparent sextet, J=7.0 Hz, 2H), 1.00 (t, J=7.0 Hz, 0542. Using method A, 4-amino-8-bromo-N-propyl-cin 3H). MS APCI, m/z=355 (M+H). HPLC 1.67 min. noline-3-carboxamide (150 mg, 0.49 mmol) and (6-meth oxypyridin-3-yl)boronic acid (153 mg, 1.00 mmol) were EXAMPLE 67 reacted to afford the title compound (117 mg, 72% yield) as a white solid. "H NMR (300 MHz, CDC1,) & 8.55 (bs, 1H), 4-amino-8-(4-methoxyphenyl)-N-propyl-cinnoline 8.43 (d. J=1.65 Hz, 1H), 8.05 (dd, J=8.5, 1.9 Hz, 1H), 7.87 3-carboxamide (d. J=7.9 Hz, 1H), 7.71-7.81 (m, 2H), 6.89 (d. J=8.5 Hz, 1H), 0535. Using method F, 4-amino-8-iodo-N-propyl-cinno 4.01 (s.3H), 3.46 (apparent q, J=6.6 Hz, 2H), 1.67 (apparent line-3-carboxamide (178 mg 0.50 mmol) and 4-methox sextet, J=7.2 Hz, 2H), 1.01 (t, J=7.4 Hz, 3H). MS APCI, yphenylboronic acid (303 mg, 2.00 mmol) were reacted m/z=338 (M+H) HPLC 1.73 min. (reflux 14 hours) to afford the title compound (118 mg, 70% yield) as a white solid. "H NMR (300 MHz, CDC1) & 8.58 EXAMPLE 72 (bm, 1H), 7.69-7.83 (m, 3H), 7.62 (d. J=8.9 Hz, 2H), 7.05 (d. 4-amino-8-(4-methoxy-3,5-dimethyl-phenyl)-N- J=8.9 Hz, 2H), 3.87 (s.3H), 3.45 (apparent q, J=6.6 Hz, 2H), propyl-cinnoline-3-carboxamide 1.65 (apparent sextet, J=7.4 Hz, 2H), 1.00 (t, J=7.4 Hz, 3H). 0543. Using method A, 4-amino-8-bromo-N-propyl-cin 0536. MS APCI, m/z=337 (M+H) HPLC 1.71 min. noline-3-carboxamide (125 mg, 0.40 mmol) and (4-meth

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2H), 1.64 (sextet, J=7.3 Hz, 2H), 0.99 (t, J=7.4 Hz, 3H). MS -continued APCI, m/z=385 (M+H). HPLC: 2.61 min. B(OH)2 4-Amino-7-fluoro-8-iodo-N-propyl-cinnoline-3- O N carboxamide 0553 To a 1 L, 3-necked flask equipped with a mechani NH2 O cal stirrer charged with (2E)-2-cyano-2-(3-fluoro-2-io N 1N1 O dophenyl)hydrazono-N-propylacetamide (43.9 g, 117 H N mmol) in anhydrous toluene (Aldrich, 600 mL) under N a N HePdCl2(PPH3)2, CsCO3 was added portion-wise aluminum chloride (Aldrich, 46.8 g. F N DME:EtOH:HO 352 mmol) over 20 minutes. The mixture was heated to 60° I 80° C., 63% C. with vigorous stirring for 2 hours then cooled to 15° C. NH2 O Ethyl acetate (30 mL) was carefully added while maintain ing the internal temperature between 20-25° C. Additional N 1N-1 ethyl acetate (900 mL) was then added, followed by careful H addition of Rochelle’s salt (saturated aqueous potassium 2 N sodium tartrate, 500 mL). Upon addition of the first 50 mL. F 2 the temperature rose from 20 to 36° C. The reaction was heated with stirring at 60° C. for 30 minutes. The aqueous layer contained a thick white precipitate and the organic layer slowly solubilized the brownish yellow solid. (Note: If O On a non-white (brown/yellow) solid still existed at the aque ous/organic interface, the hot extraction was repeated). The mixture was placed in a separatory funnel and the aqueous On layer was removed. The organic layer was washed with Rochelle’s salt (500 mL), washed with brine, dried over magnesium Sulfate, filtered and concentrated to give 38 g 0552. A 2 L, 3-necked flask equipped with a mechanical slightly crude product (86.5%). Further purification by tritu stirrer was charged with 4-amino7-fluoro-8-iodo-N-propyl ration with ethyl acetate/hexanes was carried out when cinnoline-3-carboxamide (40.5 g. 108.2 mmol), DME (700 appropriate. An analytically pure sample was obtained by mL, anhydrous), and ethanol (200 mL, absolute). A nitrogen recrystallization from ethyl acetate. "H NMR (300 MHz, dispersion tube was fitted into the Suspension and the CDC1) & 8.54 (br. 1H), 7.84 (dd, J=5.3, 9.2 Hz, 1H), 7.39 mixture was stirred until a solution was obtained. Water (300 (dd, J=7.0, 9.2 Hz, 1H), 3.47 (apparent q, J=7.0 Hz, 2H), mL) and PdCl2(PPh) (7.6 g. 10 mol %) were added. After 1.68 (apparent sextet, J=7.0 Hz, 2H), 1.03 (t, J=7.4 Hz, 3H). 5 minutes, 2,4-dimethoxyphenylboronic acid (39.4g, 216.5 MS APCI, m/z=375 (M+H). HPLC 2.13 min. mmol) was added followed by cesium carbonate (70.3 g, (2E)-2-Cyano-2-(3-fluoro-2-iodophenyl)hydra 216.5 mmol). Nitrogen was bubbled through the suspension Zono-N-propylacetamide for 5 minutes. The mixture was heated to approximately 80° C. Additional 7:3:2 DME: HO:EtOH (340 mL) was added 0554 Using the procedure outlined in the patent U.S. Pat. as the reflux started. The reaction was refluxed 18 hours and No. 4,886,800 example 89b substituting 3-fluoro-2-iodoa then cooled to room temperature, diluted with ethyl acetate niline hydrochloride (8.8 g. 32.5 mmol) for 2-iodoaniline, (1.5 L), and washed with water (3x500 mL). The aqueous the title compound (2E)-2-cyano-2-(3-fluoro-2-iodophe layers were extracted with ethyl acetate (3x150 mL). The nyl)hydrazono-N-propylacetamide was obtained as a light combined organic layers were stirred for 1 hour with 40 g of brown solid (8.5g, 70% yield). An analytically pure sample DARCO, dried over sodium sulfate, and filtered through was obtained by recrystallization from ethyl acetate as a Celite. The solids were washed with 5% methanol in chlo yellow crystalline solid. "H NMR (300 MHz, CDC1) & roform (3x200 mL) and the filtrates concentrated to a dark 14.39, (s, 1H), 8.67 (bm, 1H), 7.45 (m, 1H), 7.32 (m. 1H), semisolid. This was taken up in 200 mL 1% methanol in 7.03 (m. 1H), 3.1 (apparent q, J=6.6 Hz, 2H), 1.53 (apparent chloroform and warmed to solubilize the material. The sextet, J=7.4 Hz, 2H), 0.88 (t, J=7.4 Hz, 3H). Solution was divided into two portions. Each portion was filtered through Whatman fluted filter paper onto a 330 g 3-Fluoro-2-iodoaniline hydrochloride silica gel column and eluted with 5% ethyl acetate in 0555) To a 1 L, 3 necked round bottom flask fitted with dichloromethane. (Note: Some solid catalyst appeared to be a mechanical stirrer was added 3-fluoro-2-iodonitrobenzene removed via the filter paper.) The purest fractions from each (3B Medical, 47.7 g, 179 mmol) and 500 mL absolute column were combined in 5-10% ethyl acetate in dichlo ethanol. To this stirred solution was added iron powder (325 romethane. The solution was concentrated to approximately mesh, Aldrich, 30 g, 537 mmol) followed by dropwise 200 mL, diluted with hexane (200 mL), and let stand at room addition of concentrated HCl (30 mL, 360 mmol). The temperature overnight. The resulting solids were isolated by internal temperature rose from 23 to ~60° C. over the filtration, washed with ether (3 times), and dried under addition. The flask was fitted with a heating mantle and vacuum at room temperature to afford the desired product heated with vigorous stirring for 90 minutes. After cooling (26.4g, 63%). "H NMR (500.333 MHz, CDC1) & 8.51 (bs, to room temperature, 1 N NaCO (300 mL) was added 1H), 7.86 (dd, J=9.4, 5.2 Hz, 1H), 7.50 (t, J=8.8 Hz, 1H), followed by EtOAc (200 mL). The mixture was stirred for 7.27 (d. J=9.2, 1H), 6.66 (dd, J=8.2, 2.3 Hz, 1H), 6.63 (d. 30 minutes and then filtered through a pad of Celite. The J=2.3 Hz, 1H), 3.87 (s.3H), 3.71 (s.3H), 3.44 (q, J=6.7 Hz, Celite was washed with EtOAc (3x150 mL). The filtrates