WO2009029617A1 - Diarylamine-substituted quinolones useful as inducible nitric oxide synthase inhibitors - Google Patents

Abstract

Novel diarylamine-substituted quinolone compounds and pharmaceutical compositions, certain of which have been found to inhibit inducible NOS synthase have been discovered, together with methods of synthesizing and using the compounds including methods for the treatment of iNOS-mediated diseases in a patient by administering the compounds.

Description

DIARYLAMINE-SUBSTITUTED QUINOLONES USEFUL AS INDUCIBLE NITRIC OXIDE SYNTHASE INHIBITORS

[001] This application claims the benefit of priority of United States provisional applications No. 60/968,167, filed August 27, 2007, the disclosure of which is hereby incorporated by reference as if written herein in its entirety.

[002] Disclosed herein are new diarylamine-substituted quinolone compounds and compositions and their application as pharmaceuticals for the treatment of disease. Methods of inhibition of nitric oxide synthase activity in a human or animal subject are also provided for the treatment disease.

[003] Nitric oxide (NO) is involved in the regulation of many physiological processes as well as the pathophysiology of a number of diseases. It is synthesized enzymatically from L-arginine in numerous tissues and cell types by three distinct isoforms of the enzyme NO synthase (NOS). Two of these isoforms, endothelial NOS (eNOS) and neuronal NOS (nNOS) are expressed in a constitutive manner and are calcium/calmodulin dependent. Endothelial NOS is expressed by endothelium and other cell types and is involved in cardiovascular homeostasis. Neuronal NOS is constitutively present in both the central and peripheral nervous system where NO acts a neurotransmitter. Under normal physiological conditions, these constitutive forms of NOS generate low, transient levels of NO in response to increases in intracellular calcium concentrations. These low levels of NO act to regulate blood pressure, platelet adhesion, gastrointestinal motility, bronchomotor tone and neurotransmission. [004] In contrast, the third isoform of NOS, inducible NOS (iNOS), a virtually calcium independent enzyme, is absent in resting cells, but is rapidly expressed in virtually all nucleated mammalian cells in response to stimuli such as endotoxins and/or cytokines. The inducible isoform is neither stimulated by calcium nor blocked by calmodulin antagonists. It contains several tightly bound co-factors, including FMN, FAD and tetrahydrobiopterin. The inducible isoform of nitric oxide synthase (NOS₂ or iNOS) is expressed in virtually all nucleated mammalian cells following exposure to inflammatory cytokines or lipopolysaccharide.

[005] The enzyme iNOS synthase is a homodimer composed of 130 kDa subunits. Each subunit comprises an oxygenase domain and a reductase domain. Importantly, dimerization of the iNOS synthase is required for enzyme activity. If the dimerization mechanism is disrupted, the production of nitric oxide via inducible NOS enzyme is inhibited.

[006] The presence of iNOS in macrophages and lung epithelial cells is significant. Once present, iNOS synthesizes 100-1000 times more NO than the constitutive enzymes synthesize and does so for prolonged periods. This excessive production of NO and resulting NO-derived metabolites (e.g., peroxynitrite) elicit cellular toxicity and tissue damage which contribute to the pathophysiology of a number of diseases, disorders and conditions.

[007] Nitric oxide generated by the inducible form of NOS has also been implicated in the pathogenesis of inflammatory diseases. In experimental animals, hypotension induced by lipopolysaccharide or tumor necrosis factor alpha can be reversed by NOS inhibitors. Conditions which lead to cytokine-induced hypotension include septic shock, hemodialysis and interleukin therapy in cancer patients. An iNOS inhibitor has been shown to be effective in treating cytokine-induced hypotension, inflammatory bowel disease, cerebral ischemia, osteoarthritis, asthma and neuropathies such as diabetic neuropathy and post-herpetic neuralgia. [008] In addition, nitric oxide localized in high amounts in inflamed tissues has been shown to induce pain locally and to enhance central as well as peripheral stimuli. Because nitric oxide produced by an inflammatory response is thought to be synthesized by iNOS, the inhibition of iNOS dimerization produces both prophylactic and remedial analgesia in patients. Nitric oxide and NOS activity and expression have been linked to neuropathic pain and postherpetic neuralgia, as well, conditions for which treatment options have been equivocal at best(Wu CL and Raja SN, J Pain. 2008 Jan;9(l Suppl l):S19-30). Inhibitors of iNOS show promise in the treatment of these debilitating diseases. By way of example, several recent studies in rats administered an iNOS inhibitor demonstrate a role for peripherally-expressed iNOS in pain conditions with an inflammatory component and the potential value of iNOS inhibitors in such conditions. In one, rats administered iNOS inhibitor GW274150 24 hours after Freund's Complete Adjuvant (FCA) injection in the hind paw demonstrated suppressed accumulation of nitrite in the inflamed paw indicating substantial iNOS inhibition and attenuated hypersensitivity to pain and edema in a dose-dependent manner (De Alba J et al, J Pain. 2006 Jan; 120(1 -2): 170-81). In another, evidence for local NOS expression and NO action in the chronic constriction injury (CCI) model of neuropathic pain was demonstrated (Levy D and Zochodne DW, Eur J Neurosci. 1998 May;10(5):1846-55), and administration of GW274150 following chronic constrictive injury surgery reversed significantly the CCI-associated hypersensitivity to pain (De Alba J et al., ] Pain. 2006 Jan; 120(1 -2): 170-81).

[009] INOS-selective and nonselective inhibitors have long been known in the art, and have been investigated for the treatment of iNOS-mediated diseases and conditions including pain, as described above. In situations where the overproduction of nitric oxide is deleterious, it makes logical sense to pursue an inhibitor of iNOS to reduce the production of NO, thereby relieving inflammation, pain, and other NO-mediated diseases. To date, however, no NOS inhibitor has made it to market, for reasons that will not be exhaustively addressed here. The earliest compounds tended to fall in to the category of active-site inhibitors, leading to unacceptable side effects. As the important physiological roles played by the constitutive NOS isoforms, particularly eNOS, became more clear, later compounds were designed to have isoform selectivity to ensure that the inhibition of iNOS has the least possible effect on the activity of eNOS. Other agents failed to have pharmacokinetic properties suitable for orally- administered agents that will have good patient compliance. What is clear is that a need still exists for a selective, effective, pharmacologically appropriate inhibitor of iNOS.

[010] Novel compounds and pharmaceutical compositions, certain of which have been found to inhibit inducible NOS synthase have been discovered, together with methods of synthesizing and using the compounds including methods for the treatment of iNOS-mediated diseases in a patient by administering the compounds. Certain of these compounds have additionally demonstrated efficacy in vivo as anti-inflammatory agents. Finally, certain compounds disclosed herein exhibit good metabolic stability. [Oi l] In certain embodiments of the present invention, compounds have structural Formula I:

wherein:

R¹ is selected from the group consisting of acyl, alkyl, alkylene, aminoalkyl, amidoalkyl, alkynyl, amido, amino, aminoalkyl, aryl, arylalkyl, arylalkoxy, arylamino, arylaminoalkyl, arylthio, carboxy, cycloalkyl, ester, ether, halo, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkyl, heteroarylamino, heteroarylaminoalkyl, heterocycloalkyl, heterocycloalkylalkyl, hydrazinyl, hydrogen, imino, thio, sulfonate, sulfonylamino and sulfonylaminoalkyl, any of which may be optionally substituted;

R² is selected from the group consisting of acyl, alkoxy, alkoxyalkyl, alkyl, alkylene, alkylamino, alkynyl, alkylimino, amido, amino, aryl, carboxy, cyano, cycloalkyl, ester, halo, haloalkyl, heteroaryl, heterocycloalkyl and hydrogen, any of which may be optionally substituted; or, alternatively, R² may combine with R¹ to form heterocycloalkyl, which may be optionally substituted;

R³ is selected from the group consisting of alkyl, amino, arylalkyl, aryl, cycloalkyl, haloalkyl, heteroarylalkyl, heterocycloalkyl and hydrogen, any of which may be optionally substituted; and

A, B, C and D are each independently selected from the group consisting of acyl, alkoxy, alkyl, alkylene, alkylamino, alkynyl, amido, amino, aminosulfonyl, aryl, arylalkoxy, arylamino, arylthio, carboxy, cycloalkyl, ester, ether, halo, haloalkoxy, haloalkyl, heteroaryl, heteroarylamino, heterocycloalkyl, hydrazinyl, hydrogen, imino, thio, sulfonate and sulfonylamino, any of which may be optionally substituted; or, alternatively, any two or more A, B, C and D may combine to form aryl, cycloalkyl, heteroaryl or heterocycloalkyl, any of which may be optionally substituted. [012] Certain compounds disclosed herein may possess useful iNOS inhibitory activity, and may be used in the treatment or prophylaxis of a disease or condition in which iNOS plays an active role. Thus, in broad aspect, the certain embodiments also provide pharmaceutical compositions comprising one or more compounds disclosed herein together with a pharmaceutically acceptable carrier, as well as methods of making and using the compounds and compositions. Certain embodiments provide methods for inhibiting iNOS. Other embodiments provide methods for treating an iNOS-mediated disorder in a patient in need of such treatment, comprising administering to said patient a therapeutically effective amount of a compound or composition according to the present invention. Also provided is the use of certain compounds disclosed herein for use in the manufacture of a medicament for the treatment of a disease or condition ameliorated by the inhibition of iNOS. [013] In further embodiments, compounds have structural Formula II

II or a salt, ester, or prodrug thereof, wherein:

R⁴ is selected from the group consisting of lower aryl and lower heteroaryl, either of which may be optionally substituted with one to three substituents selected from the group consisting of halogen, cyano, lower alkyl, lower haloalkyl, lower amino, lower aminoalkyl, lower alkoxy, and lower haloalkoxy;

R⁵ is selected from the group consisting of monocyclic lower heteroaryl, monocyclic lower aryl, monocyclic lower cycloalkyl, and lower alkyl, any of which may be optionally substituted with one to three substituents selected from the group consisting of halogen, cyano, lower alkyl, lower haloalkyl, lower amino, lower aminoalkyl, lower alkoxy, lower haloalkoxy, monocyclic lower aryl, monocyclic lower heteroaryl, and monocyclic lower heterocycloalkyl; R⁶, R⁷, R⁸ and R⁹ are independently selected from the group consisting of hydrogen, lower alkyl, and halogen; and n is 0, 1, or 2.

[014] In further embodiments, R⁸ and R⁹ are hydrogen. [015] In further embodiments, n is 0 or 1.

[016] In further embodiments, R⁶ is selected from the group consisting of methyl, methoxy, chlorine, fluorine, and hydrogen. [017] In further embodiments, R⁶ is hydrogen. [018] In further embodiments, R⁷ is fluorine. [019] In further embodiments, R⁷ is hydrogen.

[020] In further embodiments, R⁵ is selected from the group consisting of isopropyl, t-butyl, cyclopentyl, cyclopropyl, phenyl, and pyridine, any of which may be optionally substituted with one or two substituents selected from the group consisting of halogen, cyano, lower alkyl, lower haloalkyl, lower amino, lower aminoalkyl, monocyclic lower heterocycloalkyl, lower alkoxy, and lower haloalkoxy. [021] In yet further embodiments, R⁴ is selected from the group consisting of pyridine, pyridazine, pyrimidine, pyrazine, imidazole, thienopyrimidine, pyrazolopyrimidine, furopyridine, quinolone, isoquinoline, quinoxaline, quinazoline, benzimidazole, benzoxazole, and benzthiazole, any of which may be optionally substituted with one to three substituents selected from the group consisting of halogen, cyano, lower alkyl, lower haloalkyl, lower amino, lower aminoalkyl, monocyclic lower heterocycloalkyl, lower alkoxy, and lower haloalkoxy.

[022] In further embodiments, R⁵ is selected from the group consisting of isopropyl, t-butyl, cyclopentyl, cyclopropyl, cyclopropylmethyl, phenyl, and pyridine, any of which may be optionally substituted with one or two substituents selected from the group consisting of halogen, lower alkyl, trifluoromethoxy, and methoxy. [023] As used herein, the terms below have the meanings indicated. [024] When ranges of values are disclosed, and the notation "from ni ... to n₂" is used, where ni and n₂ are the numbers, then unless otherwise specified, this notation is intended to include the numbers themselves and the range between them. This range may be integral or continuous between and including the end values. By way of example, the range "from 2 to 6 carbons" is intended to include two, three, four, five, and six carbons, since carbons come in integer units. Compare, by way of example, the range "from 1 to 3 μM (micromolar)," which is intended to include 1 μM, 3 μM, and everything in between to any number of significant figures (e.g., 1.255 μM, 2.1 μM, 2.9999 μM, etc.).

[025] The term "about," as used herein, is intended to qualify the numerical values which it modifies, denoting such a value as variable within a margin of error. When no particular margin of error, such as a standard deviation to a mean value given in a chart or table of data, is recited, the term "about" should be understood to mean that range which would encompass the recited value and the range which would be included by rounding up or down to that figure as well, taking into account significant figures.

[026] The term "acyl," as used herein, alone or in combination, refers to a carbonyl attached to an alkenyl, alkyl, aryl, cycloalkyl, heteroaryl, heterocycle, or any other moiety were the atom attached to the carbonyl is carbon. An "acetyl" group refers to a -C(O)CH3 group. An "alkylcarbonyl" or "alkanoyl" group refers to an alkyl group attached to the parent molecular moiety through a carbonyl group. Examples of such groups include methylcarbonyl and ethylcarbonyl. Examples of acyl groups include formyl, alkanoyl and aroyl.

[027] The term "alkenyl," as used herein, alone or in combination, refers to a straight-chain or branched-chain hydrocarbon group having one or more double bonds and containing from 2 to 20 carbon atoms. In certain embodiments, said alkenyl will comprise from 2 to 6 carbon atoms. The term "alkenylene" refers to a carbon-carbon double bond system attached at two or more positions such as ethenylene [(-CH=CH- ),(-C::C-)]. Examples of suitable alkenyl groups include ethenyl, propenyl, 2- methylpropenyl, 1 ,4-butadienyl and the like. Unless otherwise specified, the term "alkenyl" may include "alkenylene" groups.

[028] The term "alkoxy," as used herein, alone or in combination, refers to an alkyl ether group, wherein the term alkyl is as defined below. Examples of suitable alkyl ether groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso- butoxy, sec-butoxy, tert-butoxy, and the like. [029] The term "alkyl," as used herein, alone or in combination, refers to a straight-chain or branched-chain alkyl group containing from 1 to 20 carbon atoms. In certain embodiments, said alkyl will comprise from 1 to 10 carbon atoms. In further embodiments, said alkyl will comprise from 1 to 6 carbon atoms. Alkyl groups may be optionally substituted as defined herein. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl, octyl, noyl and the like. The term "alkylene," as used herein, alone or in combination, refers to a saturated aliphatic group derived from a straight or branched chain saturated hydrocarbon attached at two or more positions, such as methylene (- CH₂-). Unless otherwise specified, the term "alkyl" may include "alkylene" groups. [030] The term "alkylamino," as used herein, alone or in combination, refers to an alkyl group attached to the parent molecular moiety through an amino group. Suitable alkylamino groups may be mono- or dialkylated, forming groups such as, for example, N-methylamino, N-ethylamino, N,N-dimethylamino, N,N-ethylmethylamino and the like.

[031] The term "alkylidene," as used herein, alone or in combination, refers to an alkenyl group in which one carbon atom of the carbon-carbon double bond belongs to the moiety to which the alkenyl group is attached.

[032] The term "alkylthio," as used herein, alone or in combination, refers to an alkyl thioether (R-S-) group wherein the term alkyl is as defined above and wherein the sulfur may be singly or doubly oxidized. Examples of suitable alkyl thioether groups include methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, iso- butylthio, sec-butylthio, tert-butylthio, methanesulfonyl, ethanesulfmyl, and the like. [033] The term "alkynyl," as used herein, alone or in combination, refers to a straight-chain or branched chain hydrocarbon group having one or more triple bonds and containing from 2 to 20 carbon atoms. In certain embodiments, said alkynyl comprises from 2 to 6 carbon atoms. In further embodiments, said alkynyl comprises from 2 to 4 carbon atoms. The term "alkynylene" refers to a carbon-carbon triple bond attached at two positions such as ethynylene (-C:::C-, -C≡C-). Examples of alkynyl groups include ethynyl, propynyl, hydroxypropynyl, butyn-1-yl, butyn-2-yl, pentyn-1- yl, 3-methylbutyn-l-yl, hexyn-2-yl, and the like. Unless otherwise specified, the term "alkynyl" may include "alkynylene" groups.

[034] The terms "amido" and "carbamoyl," as used herein, alone or in combination, refer to an amino group as described below attached to the parent molecular moiety through a carbonyl group, or vice versa. The term "C-amido" as used herein, alone or in combination, refers to a -C(=O)-NR₂ group with R as defined herein. The term "N-amido" as used herein, alone or in combination, refers to a RC(=O)NH- group, with R as defined herein. The term "acylamino" as used herein, alone or in combination, embraces an acyl group attached to the parent moiety through an amino group. An example of an "acylamino" group is acetylamino (CH₃C(O)NH-). [035] The term "amino," as used herein, alone or in combination, refers to — NRR , wherein R and R are independently selected from the group consisting of hydrogen, alkyl, acyl, heteroalkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl, any of which may themselves be optionally substituted. Additionally, R and R' may combine to form heterocycloalkyl, either of which may be optionally substituted. [036] The term "aryl," as used herein, alone or in combination, means a carbocyclic aromatic system containing one, two or three rings wherein such polycyclic ring systems are fused together. The term "aryl" embraces aromatic groups such as phenyl, naphthyl, anthracenyl, and phenanthryl.

[037] The term "arylalkenyl" or "aralkenyl," as used herein, alone or in combination, refers to an aryl group attached to the parent molecular moiety through an alkenyl group.

[038] The term "arylalkoxy" or "aralkoxy," as used herein, alone or in combination, refers to an aryl group attached to the parent molecular moiety through an alkoxy group.

[039] The term "arylalkyl" or "aralkyl," as used herein, alone or in combination, refers to an aryl group attached to the parent molecular moiety through an alkyl group. [040] The term "arylalkynyl" or "aralkynyl," as used herein, alone or in combination, refers to an aryl group attached to the parent molecular moiety through an alkynyl group. [041] The term "arylalkanoyl" or "aralkanoyl" or "aroyl," as used herein, alone or in combination, refers to an acyl group derived from an aryl-substituted alkanecarboxylic acid such as benzoyl, naphthyl, phenylacetyl, 3-phenylpropionyl

(hydrocinnamoyl), 4-phenylbutyryl, (2-naphthyl)acetyl, 4-chlorohydrocinnamoyl, and the like.

[042] The term aryloxy as used herein, alone or in combination, refers to an aryl group attached to the parent molecular moiety through an oxy.

[043] The terms "benzo" and "benz," as used herein, alone or in combination, refer to the divalent group C₆H₄= derived from benzene. Examples include benzo thiophene and benzimidazole.

[044] The term "carbamate," as used herein, alone or in combination, refers to an ester of carbamic acid (-NHCOO-) which may be attached to the parent molecular moiety from either the nitrogen or acid end, and which may be optionally substituted as defined herein.

[045] The term "O-carbamyl" as used herein, alone or in combination, refers to a

-OC(O)NRR', group with R and R' as defined herein.

[046] The term "N-carbamyl" as used herein, alone or in combination, refers to a

ROC(O)NR'- group, with R and R' as defined herein.

[047] The term "carbonyl," as used herein, when alone includes formyl [-C(O)H] and in combination is a -C(O)- group.

[048] The term "carboxyl" or "carboxy," as used herein, refers to -C(O)OH or the corresponding "carboxylate" anion, such as is in a carboxylic acid salt. An

"O-carboxy" group refers to a RC(O)O- group, where R is as defined herein. A

"C-carboxy" group refers to a -C(O)OR groups where R is as defined herein.

[049] The term "cyano," as used herein, alone or in combination, refers to -CN.

[050] The term "cycloalkyl," or, alternatively, "carbocycle," as used herein, alone or in combination, refers to a saturated or partially saturated monocyclic, bicyclic or tricyclic alkyl group wherein each cyclic moiety contains from 3 to 12 carbon atom ring members and which may optionally be a benzo fused ring system which is optionally substituted as defined herein. In certain embodiments, said cycloalkyl will comprise from 5 to 7 carbon atoms. Examples of such cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, tetrahydronaphthyl, indanyl, octahydronaphthyl, 2,3-dihydro-lH-indenyl, adamantyl and the like.

"Bicyclic" and "tricyclic" as used herein are intended to include both fused ring systems, such as decahydronaphthalene, octahydronaphthalene as well as the multicyclic (multicentered) saturated or partially unsaturated type. The latter type of isomer is exemplified in general by, bicyclo[l,l,l]pentane, camphor, adamantane, and bicyclo[3,2,l]octane.

[051] The term "ester," as used herein, alone or in combination, refers to a carboxy group bridging two moieties linked at carbon atoms.

[052] The term "ether," as used herein, alone or in combination, refers to an oxy group bridging two moieties linked at carbon atoms.

[053] The term "halo," or "halogen," as used herein, alone or in combination, refers to fluorine, chlorine, bromine, or iodine.

[054] The term "haloalkoxy," as used herein, alone or in combination, refers to a haloalkyl group attached to the parent molecular moiety through an oxygen atom.

[055] The term "haloalkyl," as used herein, alone or in combination, refers to an alkyl group having the meaning as defined above wherein one or more hydrogens are replaced with a halogen. Specifically embraced are monohaloalkyl, dihaloalkyl and polyhaloalkyl groups. A monohaloalkyl group, for one example, may have an iodo, bromo, chloro or fluoro atom within the group. Dihalo and polyhaloalkyl groups may have two or more of the same halo atoms or a combination of different halo groups.

Examples of haloalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl. "Haloalkylene" refers to a haloalkyl group attached at two or more positions. Examples include fluoromethylene

(-CFH-), difluoromethylene (-CF₂ -), chloromethylene (-CHC1-) and the like.

[056] The term "heteroalkyl," as used herein, alone or in combination, refers to a stable straight or branched chain, or cyclic hydrocarbon group, or combinations thereof, fully saturated or containing from 1 to 3 degrees of unsaturation, consisting of the stated number of carbon atoms and from one to three heteroatoms selected from the group consisting of O, N, and S, and wherein the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized. The heteroatom(s) O, N and S may be placed at any interior position of the heteroalkyl group. Up to two heteroatoms may be consecutive, such as, for example, -CH₂-NH- OCH₃.

[057] The term "heteroaryl," as used herein, alone or in combination, refers to a 3 to 7 membered unsaturated heteromonocyclic ring, or a fused monocyclic, bicyclic, or tricyclic ring system in which at least one of the fused rings is aromatic, which contains at least one atom selected from the group consisting of O, S, and N. In certain embodiments, said heteroaryl will comprise from 5 to 7 carbon atoms. The term also embraces fused polycyclic groups wherein heterocyclic rings are fused with aryl rings, wherein heteroaryl rings are fused with other heteroaryl rings, wherein heteroaryl rings are fused with heterocycloalkyl rings, or wherein heteroaryl rings are fused with cycloalkyl rings. Examples of heteroaryl groups include pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, pyranyl, furyl, thienyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, isothiazolyl, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, quinoxalinyl, quinazolinyl, indazolyl, benzotriazolyl, benzodioxolyl, benzopyranyl, benzoxazolyl, benzoxadiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuryl, benzothienyl, chromonyl, coumarinyl, benzopyranyl, tetrahydroquinolinyl, tetrazolopyridazinyl, tetrahydroisoquinolinyl, thienopyridinyl, furopyridinyl, pyrrolopyridinyl and the like. Exemplary tricyclic heterocyclic groups include carbazolyl, benzidolyl, phenanthrolinyl, dibenzofuranyl, acridinyl, phenanthridinyl, xanthenyl and the like. [058] The terms "heterocycloalkyl" and, interchangeably, "heterocycle," as used herein, alone or in combination, each refer to a saturated, partially unsaturated, or fully unsaturated monocyclic, bicyclic, or tricyclic heterocyclic group containing at least one heteroatom as a ring member, wherein each said heteroatom may be independently selected from the group consisting of nitrogen, oxygen, and sulfur In certain embodiments, said heterocycloalkyl will comprise from 1 to 4 heteroatoms as ring members. In further embodiments, said heterocycloalkyl will comprise from 1 to 2 heteroatoms as ring members. In certain embodiments, said heterocycloalkyl will comprise from 3 to 8 ring members in each ring. In further embodiments, said heterocycloalkyl will comprise from 3 to 7 ring members in each ring. In yet further embodiments, said heterocycloalkyl will comprise from 5 to 6 ring members in each ring. "Heterocycloalkyl" and "heterocycle" are intended to include sulfones, sulfoxides, N-oxides of tertiary nitrogen ring members, and carbocyclic fused and benzo fused ring systems; additionally, both terms also include systems where a heterocycle ring is fused to an aryl group, as defined herein, or an additional heterocycle group. Examples of heterocycle groups include aziridinyl, azetidinyl, 1,3- benzodioxolyl, dihydroisoindolyl, dihydroisoquinolinyl, dihydrocinnolinyl, dihydrobenzodioxinyl, dihydro[ 1 ,3]oxazolo[4,5-b]pyridinyl, benzothiazolyl, dihydroindolyl, dihy-dropyridinyl, 1,3-dioxanyl, 1 ,4-dioxanyl, 1,3-dioxolanyl, isoindolinyl, morpholinyl, piperazinyl, pyrrolidinyl, tetrahydropyridinyl, piperidinyl, thiomorpholinyl, and the like. The heterocycle groups may be optionally substituted unless specifically prohibited.

[059] The term "hydrazinyl" as used herein, alone or in combination, refers to two amino groups joined by a single bond, i.e., -N-N-.

[060] The term "hydroxy," as used herein, alone or in combination, refers to -OH.

[061] The term "hydroxyalkyl," as used herein, alone or in combination, refers to a hydroxy group attached to the parent molecular moiety through an alkyl group.

[062] The term "imino," as used herein, alone or in combination, refers to =N-.

[063] The term "iminohydroxy," as used herein, alone or in combination, refers to

=N(0H) and =N-O-.

[064] The phrase "in the main chain" refers to the longest contiguous or adjacent chain of carbon atoms starting at the point of attachment of a group to the compounds of any one of the formulas disclosed herein.

[065] The term "isocyanato" refers to a -NCO group.

[066] The term "isothiocyanato" refers to a -NCS group.

[067] The phrase "linear chain of atoms" refers to the longest straight chain of atoms independently selected from carbon, nitrogen, oxygen and sulfur. [068] The term "lower," as used herein, alone or in a combination, where not otherwise specifically defined, means containing from 1 to and including 6 carbon atoms.

[069] The term "lower aryl," as used herein, alone or in combination, means phenyl or naphthyl, which may be optionally substituted as provided.

[070] The term "lower heteroaryl," as used herein, alone or in combination, means either 1) monocyclic heteroaryl comprising five or six ring members, of which between one and four of said members may be heteroatoms selected from the group consisting of O, S, and N, or 2) bicyclic heteroaryl, wherein each of the fused rings comprises five or six ring members, comprising between them one to four heteroatoms selected from the group consisting of O, S, and N.

[071] The term "lower cycloalkyl," as used herein, alone or in combination, means a monocyclic cycloalkyl having between three and six ring members. Lower cycloalkyls may be unsaturated. Examples of lower cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[072] The term "lower heterocycloalkyl," as used herein, alone or in combination, means a monocyclic heterocycloalkyl having between three and six ring members, of which between one and four may be heteroatoms selected from the group consisting of

O, S, and N. Examples of lower heterocycloalkyls include pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, and morpholinyl. Lower heterocycloalkyls may be unsaturated.

[073] The term "lower amino," as used herein, alone or in combination, refers to

— NRR , wherein R and R are independently selected from the group consisting of hydrogen, lower alkyl, and lower heteroalkyl, any of which may be optionally substituted. Additionally, the R and R' of a lower amino group may combine to form a five- or six-membered heterocycloalkyl, either of which may be optionally substituted.

[074] The term "mercaptyl" as used herein, alone or in combination, refers to an

RS- group, where R is as defined herein.

[075] The term "nitro," as used herein, alone or in combination, refers to -NO₂.

[076] The terms "oxy" or "oxa," as used herein, alone or in combination, refer to

-O-. [077] The term "oxo," as used herein, alone or in combination, refers to =0.

[078] The term "perhaloalkoxy" refers to an alkoxy group where all of the hydrogen atoms are replaced by halogen atoms.

[079] The term "perhaloalkyl" as used herein, alone or in combination, refers to an alkyl group where all of the hydrogen atoms are replaced by halogen atoms.

[080] The terms "sulfonate," "sulfonic acid," and "sulfonic," as used herein, alone or in combination, refer to the -SO3H group and its anion as the sulfonic acid is used in salt formation.

[081] The term "sulfanyl," as used herein, alone or in combination, refers to -S-.

[082] The term "sulfmyl," as used herein, alone or in combination, refers to

-S(O)-.

[083] The term "sulfonyl," as used herein, alone or in combination, refers to -

S(O)₂-.

[084] The term "N-sulfonamido" refers to a RS(=O)₂NR'- group with R and R' as defined herein.

[085] The term "S-sulfonamido" refers to a -S(=O)₂NRR' , group, with R and R' as defined herein.

[086] The terms "thia" and "thio," as used herein, alone or in combination, refer to a -S- group or an ether wherein the oxygen is replaced with sulfur. The oxidized derivatives of the thio group, namely sulfmyl and sulfonyl, are included in the definition of thia and thio.

[087] The term "thiol," as used herein, alone or in combination, refers to an -SH group.

[088] The term "thiocarbonyl," as used herein, when alone includes thioformyl -

C(S)H and in combination is a -C(S)- group.

[089] The term "N-thiocarbamyl" refers to an ROC(S)NR'- group, with R and R' as defined herein.

[090] The term "O-thiocarbamyl" refers to a -OC(S)NRR', group with R and R' as defined herein.

[091] The term "thiocyanato" refers to a -CNS group.

[092] The term "trihalomethoxy" refers to a X₃CO- group where X is a halogen. [093] The term "trisubstituted silyl," as used herein, alone or in combination, refers to a silicone group substituted at its three free valences with groups as listed herein under the definition of substituted amino. Examples include trimethysilyl, tert- butyldimethylsilyl, triphenylsilyl and the like.

[094] Any definition herein may be used in combination with any other definition to describe a composite structural group. By convention, the trailing element of any such definition is that which attaches to the parent moiety. For example, the composite group alkylamido would represent an alkyl group attached to the parent molecule through an amido group, and the term alkoxyalkyl would represent an alkoxy group attached to the parent molecule through an alkyl group.

[095] When a group is defined to be "null," what is meant is that said group is absent.

[096] When n is set at 0, for example as in the context of "0 carbon atoms" or "n is 0," it is intended to indicate a bond or null.

[097] The term "optionally substituted" means the anteceding group may be substituted or unsubstituted. When substituted, the substituents of an "optionally substituted" group may include, without limitation, one or more substituents independently selected from the following groups or a particular designated set of groups, alone or in combination: lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower heteroalkyl, lower heterocycloalkyl, lower haloalkyl, lower haloalkenyl, lower haloalkynyl, lower perhaloalkyl, lower perhaloalkoxy, lower cycloalkyl, phenyl, aryl, aryloxy, lower alkoxy, lower haloalkoxy, oxo, lower acyloxy, carbonyl, carboxyl, lower alkylcarbonyl, lower carboxyester, lower carboxamido, cyano, hydrogen, halogen, hydroxy, amino, lower alkylamino, arylamino, amido, nitro, thiol, lower alkylthio, lower haloalkylthio, lower perhaloalkylthio, arylthio, sulfonate, sulfonic acid, trisubstituted silyl, N₃, SH, SCH₃, C(O)CH₃, CO₂CH₃, CO₂H, pyridinyl, thiophene, furanyl, lower carbamate, and lower urea. Two substituents may be joined together to form a fused five-, six-, or seven-membered carbocyclic or heterocyclic ring consisting of zero to three heteroatoms, for example forming methylenedioxy or ethylenedioxy. An optionally substituted group may be unsubstituted (e.g., -CH₂CH₃), fully substituted (e.g., -CF₂CF₃), monosubstituted (e.g., -CH₂CH₂F) or substituted at a level anywhere in-between fully substituted and monosubstituted (e.g., -CH2CF3). Where substituents are recited without qualification as to substitution, both substituted and unsubstituted forms are encompassed. Where a substituent is qualified as "substituted," the substituted form is specifically intended. Additionally, different sets of optional substituents to a particular moiety may be defined as needed; in these cases, the optional substitution will be as defined, often immediately following the phrase, "optionally substituted with."

[098] The term R or the term R' , appearing by itself and without a number designation, unless otherwise defined, refers to a moiety selected from the group consisting of hydrogen, alkyl, cycloalkyl, heteroalkyl, aryl, heteroaryl and heterocycloalkyl, any of which may be optionally substituted. Such R and R' groups should be understood to be optionally substituted as defined herein. Whether an R group has a number designation or not, every R group, including R, R' and Rⁿ where n=(l, 2, 3, ...n), every substituent, and every term should be understood to be independent of every other in terms of selection from a group. Should any variable, substituent, or term (e.g. aryl, heterocycle, R, etc.) occur more than one time in a formula or generic structure, its definition at each occurrence is independent of the definition at every other occurrence. Those of skill in the art will further recognize that certain groups may be attached to a parent molecule or may occupy a position in a chain of elements from either end as written. Thus, by way of example only, an unsymmetrical group such as -C(O)N(R)- may be attached to the parent moiety at either the carbon or the nitrogen.

[099] Asymmetric centers exist in the compounds disclosed herein. These centers are designated by the symbols "R" or "S," depending on the configuration of substituents around the chiral carbon atom. It should be understood that the invention encompasses all stereochemical isomeric forms, including diastereomeric, enantiomeric, and epimeric forms, as well as d-isomers and 1 -isomers, and mixtures thereof. Individual stereoisomers of compounds can be prepared synthetically from commercially available starting materials which contain chiral centers or by preparation of mixtures of enantiomeric products followed by separation such as conversion to a mixture of diastereomers followed by separation or recrystallization, chromatographic techniques, direct separation of enantiomers on chiral chromatographic columns, or any other appropriate method known in the art. Starting compounds of particular stereochemistry are either commercially available or can be made and resolved by techniques known in the art. Additionally, the compounds disclosed herein may exist as geometric isomers. The present invention includes all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well as the appropriate mixtures thereof. Additionally, compounds may exist as tautomers; all tautomeric isomers are provided by this invention. Additionally, the compounds disclosed herein can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. In general, the solvated forms are considered equivalent to the unsolvated forms.

[0100] The term "bond" refers to a covalent linkage between two atoms, or two moieties when the atoms joined by the bond are considered to be part of larger substructure. A bond may be single, double, or triple unless otherwise specified. A dashed line between two atoms in a drawing of a molecule indicates that an additional bond may be present or absent at that position.

[0101] The term "disease" as used herein is intended to be generally synonymous, and is used interchangeably with, the terms "disorder" and "condition" (as in medical condition), in that all reflect an abnormal condition of the human or animal body or of one of its parts that impairs normal functioning, is typically manifested by distinguishing signs and symptoms, and causes the human or animal to have a reduced duration or quality of life.

[0102] The term "combination therapy" means the administration of two or more therapeutic agents to treat a therapeutic condition or disorder described in the present disclosure. Such administration encompasses co-administration of these therapeutic agents in a substantially simultaneous manner, such as in a single capsule having a fixed ratio of active ingredients or in multiple, separate capsules for each active ingredient. In addition, such administration also encompasses use of each type of therapeutic agent in a sequential manner. In either case, the treatment regimen will provide beneficial effects of the drug combination in treating the conditions or disorders described herein. [0103] "iNOS inhibitor" is used herein to refer to a compound that exhibits an IC50 with respect to iNOS activity of no more than about 100 μM and more typically not more than about 50 μM, as measured in the iNOS assay described generally hereinbelow. "IC50" is that concentration of inhibitor which reduces the activity of an enzyme (e.g., iNOS) to half-maximal level. Certain compounds disclosed herein have been discovered to exhibit inhibition against iNOS. In certain embodiments, compounds will exhibit an EC50 with respect to iNOS of no more than about 10 μM; in further embodiments, compounds will exhibit an EC50 with respect to iNOS of no more than about 5 μM; in yet further embodiments, compounds will exhibit an EC50 with respect to iNOS of not more than about 1 μM; in yet further embodiments, compounds will exhibit an EC50 with respect to iNOS of not more than about 200 nM, as measured in the iNOS assay described herein.

[0104] The phrase "therapeutically effective" is intended to qualify the amount of active ingredients used in the treatment of a disease or disorder. This amount will achieve the goal of reducing or eliminating the said disease or disorder. [0105] The term "therapeutically acceptable" refers to those compounds (or salts, prodrugs, tautomers, zwitterionic forms, etc.) which are suitable for use in contact with the tissues of patients without undue toxicity, irritation, and allergic response, are commensurate with a reasonable benefit/risk ratio, and are effective for their intended use.

[0106] As used herein, reference to "treatment" of a patient is intended to include prophylaxis. The term "patient" means all mammals including humans. Examples of patients include humans, cows, dogs, cats, goats, sheep, pigs, and rabbits. Preferably, the patient is a human.

[0107] The term "prodrug" refers to a compound that is made more active in vivo. Certain compounds disclosed herein may also exist as prodrugs, as described in Hydrolysis in Drug and Prodrug Metabolism : Chemistry, Biochemistry, and Enzymology (Testa, Bernard and Mayer, Joachim M. Wiley- VHC A, Zurich, Switzerland 2003). Prodrugs of the compounds described herein are structurally modified forms of the compound that readily undergo chemical changes under physiological conditions to provide the compound. Additionally, prodrugs can be converted to the compound by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to a compound when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent. Prodrugs are often useful because, in some situations, they may be easier to administer than the compound, or parent drug. They may, for instance, be bioavailable by oral administration whereas the parent drug is not. The prodrug may also have improved solubility in pharmaceutical compositions over the parent drug. A wide variety of prodrug derivatives are known in the art, such as those that rely on hydrolytic cleavage or oxidative activation of the prodrug. An example, without limitation, of a prodrug would be a compound which is administered as an ester (the "prodrug"), but then is metabolically hydrolyzed to the carboxylic acid, the active entity. Additional examples include peptidyl derivatives of a compound.

[0108] The compounds disclosed herein can exist as therapeutically acceptable salts. The present invention includes compounds listed above in the form of salts, including acid addition salts. Suitable salts include those formed with both organic and inorganic acids. Such acid addition salts will normally be pharmaceutically acceptable. However, salts of non-pharmaceutically acceptable salts may be of utility in the preparation and purification of the compound in question. Basic addition salts may also be formed and be pharmaceutically acceptable. For a more complete discussion of the preparation and selection of salts, refer to Pharmaceutical Salts: Properties, Selection, and Use (Stahl, P. Heinrich. Wiley- VCHA, Zurich, Switzerland, 2002). [0109] The term "therapeutically acceptable salt," as used herein, represents salts or zwitterionic forms of the compounds disclosed herein which are water or oil-soluble or dispersible and therapeutically acceptable as defined herein. The salts can be prepared during the final isolation and purification of the compounds or separately by reacting the appropriate compound in the form of the free base with a suitable acid. Representative acid addition salts include acetate, adipate, alginate, L-ascorbate, aspartate, benzoate, benzenesulfonate (besylate), bisulfate, butyrate, camphorate, camphorsulfonate, citrate, digluconate, formate, fumarate, gentisate, glutarate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hippurate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethansulfonate (isethionate), lactate, maleate, malonate, DL-mandelate, mesitylenesulfonate, methanesulfonate, naphthylenesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylproprionate, phosphonate, picrate, pivalate, propionate, pyroglutamate, succinate, sulfonate, tartrate, L-tartrate, trichloroacetate, trifluoroacetate, phosphate, glutamate, bicarbonate, para-toluenesulfonate (p-tosylate), and undecanoate. Also, basic groups in the compounds disclosed herein can be quaternized with methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dimethyl, diethyl, dibutyl, and diamyl sulfates; decyl, lauryl, myristyl, and steryl chlorides, bromides, and iodides; and benzyl and phenethyl bromides. Examples of acids which can be employed to form therapeutically acceptable addition salts include inorganic acids such as hydrochloric, hydrobromic, sulfuric, and phosphoric, and organic acids such as oxalic, maleic, succinic, and citric. Salts can also be formed by coordination of the compounds with an alkali metal or alkaline earth ion. Hence, the present invention contemplates sodium, potassium, magnesium, and calcium salts of the compounds disclosed herein, and the like.

[0110] Basic addition salts can be prepared during the final isolation and purification of the compounds by reacting a carboxy group with a suitable base such as the hydroxide, carbonate, or bicarbonate of a metal cation or with ammonia or an organic primary, secondary, or tertiary amine. The cations of therapeutically acceptable salts include lithium, sodium, potassium, calcium, magnesium, and aluminum, as well as nontoxic quaternary amine cations such as ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributylamine, pyridine, N,N-dimethylaniline, N- methylpiperidine, N-methylmorpholine, dicyclohexylamine, procaine, dibenzylamine, NN-dibenzylphenethylamine, 1-ephenamine, and NN-dibenzylethylenediamine. Other representative organic amines useful for the formation of base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, and piperazine. [0111] While it may be possible for the compounds of the subject invention to be administered as the raw chemical, it is also possible to present them as a pharmaceutical formulation. Accordingly, provided herein are pharmaceutical formulations which comprise one or more of certain compounds disclosed herein, or one or more pharmaceutically acceptable salts, esters, prodrugs, amides, or solvates thereof, together with one or more pharmaceutically acceptable carriers thereof and optionally one or more other therapeutic ingredients. The carrier(s) must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. Proper formulation is dependent upon the route of administration chosen. Any of the well-known techniques, carriers, and excipients may be used as suitable and as understood in the art; e.g., in Remington's Pharmaceutical Sciences. The pharmaceutical compositions disclosed herein may be manufactured in any manner known in the art, e.g. , by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or compression processes. [0112] The formulations include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous, intraarticular, and intramedullary), intraperitoneal, transmucosal, transdermal, rectal and topical (including dermal, buccal, sublingual and intraocular) administration although the most suitable route may depend upon for example the condition and disorder of the recipient. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Typically, these methods include the step of bringing into association a compound of the subject invention or a pharmaceutically acceptable salt, ester, amide, prodrug or solvate thereof ("active ingredient") with the carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.

[0113] Formulations of the compounds disclosed herein suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in- water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be presented as a bolus, electuary or paste. [0114] Pharmaceutical preparations which can be used orally include tablets, push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. Tablets may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free- flowing form such as a powder or granules, optionally mixed with binders, inert diluents, or lubricating, surface active or dispersing agents. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein. All formulations for oral administration should be in dosages suitable for such administration. The push- fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added. Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses. [0115] The compounds may be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. The formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in powder form or in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, saline or sterile pyrogen- free water, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.

[0116] Formulations for parenteral administration include aqueous and nonaqueous (oily) sterile injection solutions of the active compounds which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions. [0117] In addition to the formulations described previously, the compounds may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.

[0118] For buccal or sublingual administration, the compositions may take the form of tablets, lozenges, pastilles, or gels formulated in conventional manner. Such compositions may comprise the active ingredient in a flavored basis such as sucrose and acacia or tragacanth.

[0119] The compounds may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter, polyethylene glycol, or other glycerides.

[0120] Certain compounds disclosed herein may be administered topically, that is by non-systemic administration. This includes the application of a compound disclosed herein externally to the epidermis or the buccal cavity and the instillation of such a compound into the ear, eye and nose, such that the compound does not significantly enter the blood stream. In contrast, systemic administration refers to oral, intravenous, intraperitoneal and intramuscular administration.

[0121] Formulations suitable for topical administration include liquid or semi- liquid preparations suitable for penetration through the skin to the site of inflammation such as gels, liniments, lotions, creams, ointments or pastes, and drops suitable for administration to the eye, ear or nose. The active ingredient for topical administration may comprise, for example, from 0.001% to 10% w/w (by weight) of the formulation. In certain embodiments, the active ingredient may comprise as much as 10% w/w. In other embodiments, it may comprise less than 5% w/w. In certain embodiments, the active ingredient may comprise from 2% w/w to 5% w/w. In other embodiments, it may comprise from 0.1% to 1% w/w of the formulation.

[0122] Gels for topical or transdermal administration may comprise, generally, a mixture of volatile solvents, nonvolatile solvents, and water. In certain embodiments, the volatile solvent component of the buffered solvent system may include lower (Cl- C6) alkyl alcohols, lower alkyl glycols and lower glycol polymers. In further embodiments, the volatile solvent is ethanol. The volatile solvent component is thought to act as a penetration enhancer, while also producing a cooling effect on the skin as it evaporates. The nonvolatile solvent portion of the buffered solvent system is selected from lower alkylene glycols and lower glycol polymers. In certain embodiments, propylene glycol is used. The nonvolatile solvent slows the evaporation of the volatile solvent and reduces the vapor pressure of the buffered solvent system. The amount of this nonvolatile solvent component, as with the volatile solvent, is determined by the pharmaceutical compound or drug being used. When too little of the nonvolatile solvent is in the system, the pharmaceutical compound may crystallize due to evaporation of volatile solvent, while an excess may result in a lack of bioavailability due to poor release of drug from solvent mixture. The buffer component of the buffered solvent system may be selected from any buffer commonly used in the art; in certain embodiments, water is used. A common ratio of ingredients is about 20% of the nonvolatile solvent, about 40% of the volatile solvent, and about 40% water. There are several optional ingredients which can be added to the topical composition. These include, but are not limited to, chelators and gelling agents. Appropriate gelling agents can include, but are not limited to, semisynthetic cellulose derivatives (such as hydroxypropylmethylcellulose) and synthetic polymers, and cosmetic agents.

[0123] Lotions include those suitable for application to the skin or eye. An eye lotion may comprise a sterile aqueous solution optionally containing a bactericide and may be prepared by methods similar to those for the preparation of drops. Lotions or liniments for application to the skin may also include an agent to hasten drying and to cool the skin, such as an alcohol or acetone, and/or a moisturizer such as glycerol or an oil such as castor oil or arachis oil.

[0124] Creams, ointments or pastes are semi-solid formulations of the active ingredient for external application. They may be made by mixing the active ingredient in finely-divided or powdered form, alone or in solution or suspension in an aqueous or non-aqueous fluid, with the aid of suitable machinery, with a greasy or non-greasy base. The base may comprise hydrocarbons such as hard, soft or liquid paraffin, glycerol, beeswax, a metallic soap; a mucilage; an oil of natural origin such as almond, corn, arachis, castor or olive oil; wool fat or its derivatives or a fatty acid such as stearic or oleic acid together with an alcohol such as propylene glycol or a macrogel. The formulation may incorporate any suitable surface active agent such as an anionic, cationic or non-ionic surfactant such as a sorbitan ester or a polyoxyethylene derivative thereof. Suspending agents such as natural gums, cellulose derivatives or inorganic materials such as silicaceous silicas, and other ingredients such as lanolin, may also be included.

[0125] Drops may comprise sterile aqueous or oily solutions or suspensions and may be prepared by dissolving the active ingredient in a suitable aqueous solution of a bactericidal and/or fungicidal agent and/or any other suitable preservative, and, in certain embodiments, including a surface active agent. The resulting solution may then be clarified by filtration, transferred to a suitable container which is then sealed and sterilized by autoclaving or maintaining at 98-100⁰C for half an hour. Alternatively, the solution may be sterilized by filtration and transferred to the container by an aseptic technique. Examples of bactericidal and fungicidal agents suitable for inclusion in the drops are phenylmercuric nitrate or acetate (0.002%), benzalkonium chloride (0.01%) and chlorhexidine acetate (0.01%). Suitable solvents for the preparation of an oily solution include glycerol, diluted alcohol and propylene glycol. [0126] Formulations for topical administration in the mouth, for example buccally or sublingually, include lozenges comprising the active ingredient in a flavored basis such as sucrose and acacia or tragacanth, and pastilles comprising the active ingredient in a basis such as gelatin and glycerin or sucrose and acacia.

[0127] For administration by inhalation, compounds may be conveniently delivered from an insufflator, nebulizer pressurized packs or other convenient means of delivering an aerosol spray. Pressurized packs may comprise a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. Alternatively, for administration by inhalation or insufflation, the compounds according to the invention may take the form of a dry powder composition, for example a powder mix of the compound and a suitable powder base such as lactose or starch. The powder composition may be presented in unit dosage form, in for example, capsules, cartridges, gelatin or blister packs from which the powder may be administered with the aid of an inhalator or insufflator.

[0128] Preferred unit dosage formulations are those containing an effective dose, as herein below recited, or an appropriate fraction thereof, of the active ingredient. [0129] It should be understood that in addition to the ingredients particularly mentioned above, the formulations described above may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents. [0130] Compounds may be administered orally or via injection at a dose of from 0.1 to 500 mg/kg per day. The dose range for adult humans is generally from 5 mg to 2 g/day. Tablets or other forms of presentation provided in discrete units may conveniently contain an amount of one or more compounds which is effective at such dosage or as a multiple of the same, for instance, units containing 5 mg to 500 mg, usually around 10 mg to 200 mg. [0131] The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.

[0132] The compounds can be administered in various modes, e.g. orally, topically, or by injection. The precise amount of compound administered to a patient will be the responsibility of the attendant physician. The specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diets, time of administration, route of administration, rate of excretion, drug combination, the precise disorder being treated, and the severity of the indication or condition being treated. Also, the route of administration may vary depending on the condition and its severity. [0133] In certain instances, it may be appropriate to administer at least one of the compounds described herein (or a pharmaceutically acceptable salt, ester, or prodrug thereof) in combination with another therapeutic agent. By way of example only, if one of the side effects experienced by a patient upon receiving one of the compounds herein is hypertension, then it may be appropriate to administer an anti-hypertensive agent in combination with the initial therapeutic agent. Or, by way of example only, the therapeutic effectiveness of one of the compounds described herein may be enhanced by administration of an adjuvant (i.e., by itself the adjuvant may only have minimal therapeutic benefit, but in combination with another therapeutic agent, the overall therapeutic benefit to the patient is enhanced). Or, by way of example only, the benefit of experienced by a patient may be increased by administering one of the compounds described herein with another therapeutic agent (which also includes a therapeutic regimen) that also has therapeutic benefit. By way of example only, in a treatment for diabetes involving administration of one of the compounds described herein, increased therapeutic benefit may result by also providing the patient with another therapeutic agent for diabetes. In any case, regardless of the disease, disorder or condition being treated, the overall benefit experienced by the patient may simply be additive of the two therapeutic agents or the patient may experience a synergistic benefit. [0134] Specific, non- limiting examples of possible combination therapies include use of the compounds of the invention with: a) corticosteroids including betamethasone dipropionate (augmented and nonaugemented), betamethasone valerate, clobetasol propionate, diflorasone diacetate, halobetasol propionate, amcinonide, dexosimethasone, fluocinolone acetononide, fluocinonide, halocinonide, clocortalone pivalate, and flurandrenalide; b) non-steroidal anti-inflammatory drugs including diclofenac, ketoprofen, and piroxicam; c) muscle relaxants and combinations thereof with other agents, including cyclobenzaprine, baclofen, cyclobenzaprine/lidocaine, baclofen/cyclobenzaprine, and cyclobenzaprine/lidocaine/ketoprofen; d) anaesthetics and combinations thereof with other agents, including lidocaine, lidocaine/deoxy-D- glucose (an antiviral), prilocaine, and EMLA Cream [Eutectic Mixture of Local Anesthetics (lidocaine 2.5% and prilocaine 2.5%; an emulsion in which the oil phase is a eutectic mixture of lidocaine and prilocaine in a ratio of 1 : 1 by weight. This eutectic mixture has a melting point below room temperature and therefore both local anesthetics exist as a liquid oil rather then as crystals)]; e) expectorants and combinations thereof with other agents, including guaifenesin and guaifenesin/ketoprofen/cyclobenzaprine; f) antidepressants including tricyclic antidepressants (e.g., amitryptiline, doxepin, desipramine, imipramine, amoxapine, clomipramine, nortriptyline, and protriptyline), selective serotonin/norepinephrine reuptake inhibitors including (e.g., duloxetine and mirtazepine), and selective norepinephrine reuptake inhibitors (e.g., nisoxetine, maprotiline, and reboxetine), selective serotonin reuptake inhibitors (e.g., fluoxetine and fluvoxamine); g) anticonvulsants and combinations thereof, including gabapentin, carbamazepine, felbamate, lamotrigine, topiramate, tiagabine, oxcarbazepine, carbamezipine, zonisamide, mexiletine, gabapentin/clonidine, gabapentin/carbamazepine, and carbamazepine/cyclobenzaprine; h) antihypertensives including clonidine; i) opioids including loperamide, tramadol, morphine, fentanyl, oxycodone, levorphanol, and butorphanol; j) topical counter-irritants including menthol, oil of wintergreen, camphor, eucalyptus oil and turpentine oil; k) topical cannabinoids including selective and non-selective CB1/CB2 ligands; 1) histamine receptor antagonists including selective and non-selective HiR and H₄R ligands; and other agents, such as TRVPl antagonists and capsaicin.

[0135] In any case, the multiple therapeutic agents (at least one of which is a compound disclosed herein) may be administered in any order or even simultaneously. If simultaneously, the multiple therapeutic agents may be provided in a single, unified form, or in multiple forms (by way of example only, either as a single pill or as two separate pills). One of the therapeutic agents may be given in multiple doses, or both may be given as multiple doses. If not simultaneous, the timing between the multiple doses may be any duration of time ranging from a few minutes to four weeks. [0136] Thus, in another aspect, certain embodiments provide methods for treating iNOS-mediated disorders in a human or animal subject in need of such treatment comprising administering to said subject an amount of a compound disclosed herein effective to reduce or prevent said disorder in the subject, in combination with at least one additional agent for the treatment of said disorder that is known in the art. In a related aspect, certain embodiments provide therapeutic compositions comprising at least one compound disclosed herein in combination with one or more additional agents for the treatment of iNOS-mediated disorders.

[0137] Compounds of the subject invention are useful in treating nitric oxide synthase-mediated disease, disorders and conditions, and are particularly suitable as inhibitors of nitric oxide synthase. A recent study in iNOS knockout mice found that during microvascular changes following injury, axon and myelin breakdown, and "clearance" prior to regeneration, nitric oxide contributes to the development of neuropathic pain (Levy D, Kubes P, and Zochodne DW, J Neuropathol Exp Neurol. 2001 May;60(5):411-21). The compounds of the present invention are useful to treat patients with neuropathy or inflammatory pain such as reflex sympathetic dystrophy/causalgia (nerve injury), peripheral neuropathy (including diabetic neuropathy; Kern TS, Exp Diabetes Res. 2007;2007:95-103), intractable cancer pain, complex regional pain syndrome, chemotherapy-induced neuropathy, HIV neuropathy, and entrapment neuropathy (carpel tunnel syndrome). The compounds are also useful in the treatment of pain associated with acute herpes zoster (shingles), postherpetic neuralgia (PHN), and associated pain syndromes such as ocular pain. The compounds are further useful as analgesics in the treatment of pain such as surgical analgesia, or as an antipyretic for the treatment of fever. Pain indications include, but are not limited to, treatment or prophylaxis of surgical or post-surgical pain for various surgical procedures including amputation, post-cardiac surgery, dental pain/dental extraction, pain resulting from cancer, muscular pain, mastalgia, pain resulting from dermal injuries, lower back pain, headaches of various etiologies, including migraine, and the like. The compounds are also useful for the treatment of pain-related disorders such as tactile allodynia and hyperalgesia. The pain may be somatogenic (either nociceptive or neuropathic), acute and/or chronic. The nitric oxide inhibitors of the subject invention are also useful in conditions where NSAIDs, morphine or fentanyl opiates and/or other opioid analgesics would traditionally be administered.

[0138] Furthermore, the compounds of the subject invention can be used in the treatment or prevention of opiate tolerance in patients needing protracted opiate analgesics, and benzodiazepine tolerance in patients taking benzodiazepines, and other addictive behavior, for example, nicotine addiction, alcoholism, and eating disorders. Moreover, the compounds and methods of the present invention are useful in the treatment or prevention of drug withdrawal symptoms, for example treatment or prevention of symptoms of withdrawal from opiate, alcohol, or tobacco addiction. [0139] In addition, the compounds of the subject invention can be used to treat insulin resistance and other metabolic disorders such as atherosclerosis that are typically associated with an exaggerated inflammatory signaling. [0140] The present invention encompasses therapeutic methods using novel selective iNOS inhibitors to treat or prevent respiratory disease or conditions, including therapeutic methods of use in medicine for preventing and treating a respiratory disease or condition including: asthmatic conditions including allergen-induced asthma, exercise-induced asthma, pollution-induced asthma, cold-induced asthma, and viral- induced-asthma; chronic obstructive pulmonary diseases including chronic bronchitis with normal airflow, chronic bronchitis with airway obstruction (chronic obstructive bronchitis), emphysema, asthmatic bronchitis, and bullous disease; and other pulmonary diseases involving inflammation including bronchioectasis cystic fibrosis, pigeon fancier's disease, farmer's lung, acute respiratory distress syndrome, pneumonia, aspiration or inhalation injury, fat embolism in the lung, acidosis inflammation of the lung, acute pulmonary edema, acute mountain sickness, acute pulmonary hypertension, persistent pulmonary hypertension of the newborn, perinatal aspiration syndrome, hyaline membrane disease, acute pulmonary thromboembolism, heparin-protamine reactions, sepsis, status asthamticus, hypoxia, hyperoxic lung injuries {Respiratory Research 2004, 5:1), and injury induced by inhalation of certain injurious agents including cigarette smoking, leading up to complications thereof such as lung carcinoma.

[0141] Other disorders or conditions which can be advantageously treated by the compounds of the present invention include inflammation. The compounds of the present invention are useful as anti-inflammatory agents with the additional benefit of having significantly less harmful side effects. The compounds are useful to treat arthritis (Cuzzocrea S., Curr Pharm Des. 2006;12(27):3551-70, including but not limited to rheumatoid arthritis (Maki-Petaja KM et al, MJ Cardiol. 2008 Jun 18. [Epub ahead of print]), spondyloarthropathies, gouty arthritis, osteoarthritis, systemic lupus erythematosus, juvenile arthritis, acute rheumatic arthritis, enteropathic arthritis, neuropathic arthritis, psoriatic arthritis, and pyogenic arthritis. The compounds are also useful in treating osteoporosis and other related bone disorders. These compounds can also be used to treat gastrointestinal conditions such as reflux esophagitis, diarrhea, inflammatory bowel disease, Crohn's disease, gastritis, irritable bowel syndrome, ulcerative colitis, and acute and chronic inflammation of the pancreas. The compounds may also be used in the treatment of pulmonary inflammation, such as that associated with viral infections and cystic fibrosis. In addition, compounds of invention are also useful in organ transplant patients either alone or in combination with conventional immunomodulators. Yet further, the compounds of the invention are useful in the treatment of pruritis and vitaligo.

[0142] The compounds of the present invention are also useful in treating organ and tissue injury injury associated with severe burns, sepsis, trauma, and hemorrhage- or resuscitation-induced hypotension, and also in such diseases as vascular diseases, migraine headaches, periarteritis nodosa, thyroiditis, aplastic anemia, Hodgkin's disease, sclerodoma, rheumatic fever, type I diabetes, neuromuscular junction disease including myasthenia gravis, white matter disease including multiple sclerosis, sarcoidosis, nephritis, nephrotic syndrome, Behcet's syndrome, polymyositis, gingivitis, periodontis, swelling occurring after injury, ischemias including myocardial ischemia, cardiovascular ischemia, and ischemia secondary to cardiac arrest, and the like.

[0143] The compounds of the subject invention are also be useful for the treatment of certain diseases and disorders of the nervous system. Central nervous system disorders in which nitric oxide inhibition is useful include cortical dementias including Alzheimer's disease, central nervous system damage resulting from stroke, ischemias including cerebral ischemia (both focal ischemia, thrombotic stroke and global ischemia (for example, secondary to cardiac arrest), and trauma. Neurodegenerative disorders in which nitric oxide inhibition is useful include nerve degeneration or nerve necrosis in disorders such as hypoxia, hypoglycemia, epilepsy, and in cases of central nervous system (CNS) trauma (such as spinal cord and head injury), hyperbaric oxygen-induced convulsions and toxicity, dementia e.g. pre-senile dementia, and AIDS-related dementia, cachexia, Sydenham's chorea, Huntington's disease, Parkinson's Disease, amyotrophic lateral sclerosis (ALS), Korsakoff s disease, cognitive disorders relating to a cerebral vessel disorder, hypersensitivity, sleeping disorders, schizophrenia, depression, depression or other symptoms associated with Premenstrual Syndrome (PMS), and anxiety.

[0144] Furthermore, the compounds of the present invention are also useful in inhibiting NO production from L-arginine including systemic hypotension associated with septic and/or toxic hemorrhagic shock induced by a wide variety of agents; therapy with cytokines such as TNF, IL-I and IL-2; and as an adjuvant to short term immunosuppression in transplant therapy. These compounds can also be used to treat allergic rhinitis, respiratory distress syndrome, endotoxic shock syndrome, and atherosclerosis.

[0145] Still other disorders or conditions advantageously treated by the compounds of the subject invention include the prevention or treatment of hyperproliferative diseases, especially cancers, either alone or incombination of standards of care especially those agents that target tumor growth by re-instating the aberrant apoptotic machinery in the malignant cells. Hematological and non-hematological malignancies which may be treated or prevented include but are not limited to multiple myeloma, acute and chronic leukemias including Acute Lymphocytic Leukemia (ALL), Chronic Lymphocytic Leukemia (CLL), and Chronic Myelogenous Leukemia(CLL), lymphomas, including Hodgkin's lymphoma and non-Hodgkin's lymphoma (low, intermediate, and high grade), as well as solid tumors and malignancies of the brain, head and neck, breast, lung, reproductive tract, upper digestive tract, pancreas, liver, renal, bladder, prostate and colorectal. The present compounds and methods can also be used to treat the fibrosis, such as that which occurs with radiation therapy. The present compounds and methods can be used to treat subjects having adenomatous polyps, including those with familial adenomatous polyposis (FAP). Additionally, the present compounds and methods can be used to prevent polyps from forming in patients at risk of FAP.

[0146] The compounds of the subject invention can be used in the treatment of ophthalmic diseases, such as glaucoma, retinal ganglion degeneration, ocular ischemia, corneal neovascularization, optic neuritis, retinitis, retinopathies such as glaucomatous retinopathy and/or diabetic retinopathy, uveitis, ocular photophobia, dry eye, Sjogren's syndrome, seasonal and chronic allergic conjunctivitis, and of inflammation and pain associated with chronic ocular disorders and acute injury to the eye tissue. The compounds can also be used to treat post-operative inflammation or pain as from ophthalmic surgery such as cataract surgery and refractive surgery. [0147] Moreover, compounds of the subject invention may be used in the treatment of menstrual cramps, dysmenorrhea, premature labor, tendonitis, bursitis, skin-related conditions such as psoriasis, eczema, burns, sunburn, dermatitis, pancreatitis, hepatitis, and the like. Other conditions in which the compounds of the subject invention provide an advantage in inhibiting nitric oxide inhibition include diabetes (type I or type II), congestive heart failure, myocarditis, atherosclerosis, and aortic aneurysm. [0148] The present compounds may also be used in co-therapies, partially or completely, in place of other conventional anti-inflammatory therapies, such as together with steroids, NSAIDs, COX-2 selective inhibitors, 5 -lipoxygenase inhibitors, LTB₄ antagonists and LTA₄ hydrolase inhibitors. The compounds of the subject invention may also be used to prevent tissue damage when therapeutically combined with antibacterial or antiviral agents.

[0149] Besides being useful for human treatment, certain compounds and formulations disclosed herein may also be useful for veterinary treatment of companion animals, exotic animals and farm animals, including mammals, rodents, and the like.

More preferred animals include horses, dogs, and cats.

[0150] All references, patents or applications, U.S. or foreign, cited in the application are hereby incorporated by reference as if written herein in their entireties.

Where any inconsistencies arise, material literally disclosed herein controls.

GENERAL SYNTHETIC METHODS FOR PREPARING COMPOUNDS

[0151] The following schemes can be used to practice the present invention.

Scheme 1

Reagents: (a) Xylene, pyridine reflux, 3-18 h. (b) (i) Br₂, AcOH, 25-50⁰C, 5-18 h. (ii) Acetone, 25°C, 2h. (c) Selectfluor^®, ACN, 60⁰C, 6 h. (d) H₂SO₄, 40⁰C, 2-18 h. (e) NaH, DMF, 25°C, 1-5 h. (f) Pd₂(dba)₃, rac-binap, NaOtBu, toluene, MW, 150⁰C, 15 min or NMP, MW, 200⁰C, 15 min.

Scheme 2

Reagents: (a) Xylene, pyridine reflux, 3-18 h. (b) H₂SO₄, 40⁰C, 2-18 h. (c) PCl₅, POCl₃, 100⁰C, 2h. (d) MeONa, MeOH, reflux, 6h. (e) NBS, benzoyl peroxide, CCl₄, refluxed, 24h. (f) DMSO, 50⁰C, 18 h. (g) R107-X, 2- dicyclohexylphosphino-2 ' ,4 ' ,6 '-triisopropylbiphenyl, Pd₂(dba)₃, NaOtBu, toluene, 15O⁰C (MW) 10 min. (h) cHCl, THF/H₂O, 60 ⁰C, 18 h.

INTERMEDIATE 1 4-(Bromomethyl)-7,8-difluoroquinolin-2(lH)-one

N-(2,3-Difluorophenyl)-3-oxobutanamide

A solution of methyl 3-oxobutanoate (300 g, 2.4 mol) in xylene/pyridine (900mL/20mL) was heated to gentle reflux for 0.5h. Then 2,3-difluoroaniline (145 g, 1.1 mol) was added dropwise into above reaction mixture. The mixture was stirred at reflux for 3Oh. No further progress was observed by HPLC at this point. The solution was allowed to cool and was extracted with 500 mL 20% aqueous NaOH. At this point precipitated salts were removed by filtration. The aqueous layer was separated and made weakly acidic with concentrated HCl. The resulting precipitate was collected by filtration and air dried to give 149 g (62%) of N-(2,3-difluorophenyl)-3-oxobutanamide as a brown solid, 90% pure by HPLC. ¹H NMR (400 MHz, DMSO-d₆) δ 9.48 (s, IH), 8.10 (m, IH), 7.04 (m, IH), 6.92 (m, IH), 3.64 (s, 2H), 2.34 (s, 3H).

4-Bromo-N-(2,3-difluorophenyl)-3-oxobutanamide

To a solution of N-(2,3-difluorophenyl)-3-oxobutanamide (111 g, .52 mol) in AcOH (500 mL) was added dropwise Br₂ (80 mL, 1.5 mol). The mixture was stirred for 22h at RT. To it was then added 50 mL acetone. Once the reaction was complete by HPLC, to the mixture was added dropwise 170 mL of water. The mixture was seeded and crystals rapidly formed. The mixture was cooled and the solid was collected by filtration and air dried to give 80 g (52%) of 4-bromo-N-(2,3-difluorophenyl)-3- oxobutanamide as a light tan solid, 99% pure by HPLC.

Step 3: 4-(Bromomethyl)-7,8-difluoroquinolin-2(lH)-one

4-Bromo-N-(2,3-difluorophenyl)-3-oxobutanamide (79g) was dissolved in concentrated H₂SO₄ (400 mL) heated to 40°C.The solution was stirred for 2Oh at 40⁰C. After cooling to RT, the solution was poured into 200Og of H₂OZiCe. The solid was filtered and washed with H₂O. It was then washed with 5% aqueous sodium bicarbonate, again with water, and dried under vacuum to give 59g of 4- (bromomethyl)-7,8-difluoroquinolin-2(lH)-one as an off-white solid (80 %). ¹H NMR (400 MHz, DMSO-de) δ 12.07 (s, IH), 7.72 (m, IH), 7.37 (m, IH), 6.78 (s, IH), 4.89 (s, 2H). LCMS: 274 (M+H)⁺.

INTERMEDIATE 2 4-(Bromomethyl)-7,8-difluoro-3-methylquinolin-2(lH)-one

4-(Bromomethyl)-7,8-difluoro-3-methylquinolin-2(lH)-one was synthesized as described for INTERMEDIATE 1 using ethyl 2-methyl-3-oxobutanoate and 2,3- difluoroaniline as starting materials. ¹H NMR (400 MHz, DMSO-d₆) δ 12.07 (s, IH), 7.68 (m, IH), 7.30 (m, IH), 4.90 (s, 2H), 2.14 (s, 3H). LCMS: 287 (M+H)⁺. INTERMEDIATE 3 4-(Bromomethyl)-3,7,8-trifluoroquinolin-2(lH)-one

4-Bromo-N-(2,3-difluorophenyl)-2-fluoro-3-oxobutanamide

A mixture of -bromo-N-(2,3-difluorophenyl)-3-oxobutanamide (3.17 g, 10.9 mmol) and Selectfluor ® (4.60 g, 13.00 mmol) in ACN (50 mL) was heated to 50⁰C for 18h. The reaction mixture was cooled to RT and the solvent was removed. The residue was partitioned between DCM and water. Purification by flash chromatography on silica gel afforded 1.2g of 4-bromo-2-fluoro-N-(2,3-fluorophenyl)-3-oxobutanamide as a yellow solid.

Step 2: 4-(Bromomethyl)-3,7,8-trifluoroquinolin-2(lH)-one

4-(Bromomethyl)-3,7,8-trifluoroquinolin-2(lH)-one was synthesized as described for INTERMEDIATE 1, Step 3 using 4-bromo-2-fluoro-N-(2,3-fluorophenyl)-3- oxobutanamide as a starting material. ¹H NMR (400 MHz, DMSO-d₆) δ 12.65 (s, IH), 7.73 (m, IH), 7.43 (m, IH), 4.89 (s, 2H). INTERMEDIATE 4 4-(Bromomethyl)-7,8-difluoro-2-methoxyquinoline

7,8-Difluoro-4-methylquinolin-2(lH)-one

7,8-Difluoro-4-methylquinolin-2(lH)-one was synthesized as described for INTERMEDIATE 1, Step 3 using N-(2,3-difluorophenyl)-3-oxobutanamide as a starting material.

2-Chloro-7,8-difluoro-4-methylquinoline

PCI5 (1 g) was added to a solution of 7,8-difluoro-4-methylquinolin-2(lH)-one (14 g) in POCI3 (302. Ig) and it was heated to 100⁰C for 2h. The mixture was concentrated and the residue was dissolved in EtOAc (100 mL) and it was washed with NaOH (40%, 2x30 mL), dried over Na₂SO₄, and concentrated to afford 14 g (crude) of 2- chloro-7,8-difluoro-4-methylquinoline as a white solid.

7,8-Difluoro-2-methoxy-4-methylquinoline

A mixture of 2-chloro-7,8-difluoro-4-methylquinoline (14g) and MeONa (7.1 g) in MeOH (250 mL) was refluxed for 6h. The residue was purified by flash chromatography on silica gel (eluting with 1 :100 EtOAc/PE) to afford 13 g (94%) of 7,8-difluoro-2-methoxy-4-methylquinoline as a white solid.

Step 4: 4-(Bromomethyl)-7,8-difluoro-2-methoxyquinoline

A mixture of 7,8-difluoro-2-methoxy-4-methylquinoline (4.39 g, 21.00 mmol), NBS (7.4 g, 41.57 mmol), and BPO (350 mg, 2.13 mmol) in CCl₄ (100 mL) was refluxed for 24h. The reaction progress was followed by TLC (EtOAc/PE = 1 :10). The residue was purified by flash chromatography on silica gel (eluting with 1 :250 EtOAc/PE) to afford 1.8 g (29%) of 4-(bromomethyl)-7,8-difluoro-2-methoxyquinoline as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 7.68 (m, IH), 7.28 (m, IH), 6.92 (s, IH), 4.66 (s, 2H), 4.06 (s, 3H).

INTERMEDIATE 5 4-(Bromomethyl)-8-fluoroquinolin-2(lH)-one

4-(Bromomethyl)-8-fluoroquinolin-2(lH)-one was synthesized as described for INTERMEDIATE 1 using 2-fluoroaniline in Step 1 as a starting material. LCMS: 255 (M+H)⁺. INTERMEDIATE 6 4-(Bromomethyl)-3-ethyl-7,8-difluoroquinolin-2(lH)-one

4-(Bromomethyl)-3-ethyl-7,8-difluoroquinolin-2(lH)-one was synthesized as described for INTERMEDIATE 1 using ethyl 2-ethyl-3-oxobutanoate and 2,3-difluoroaniline in Step 1 as starting materials. LCMS: 302 (M+H)⁺.

INTERMEDIATE 7 4-(l-Bromoethyl)-7,8-difluoroquinolin-2(lH)-one

4-(l-Bromoethyl)-7,8-difluoroquinolin-2(lH)-one was synthesized as described for

INTERMEDIATE 1 using ethyl 3-oxopentanoate and 2,3-difluoroaniline in Step 1 as starting materials. LCMS: 288 (M+H)⁺.

INTERMEDIATE 8 4-(Bromomethyl)quinolin-2(lH)-one

4-(Bromomethyl)quinolin-2(lH)-one was synthesized as described for INTERMEDIATE 1 using aniline in Step 1 as a starting material. LCMS: 237 (M+H)⁺. EXAMPLE 1 4-(((3-Chlorophenyl)(pyridin-3-yl)amino)methyl)-7,8-difluoroquinolin-2(lH)-one

N-(3-Chlorophenyl)pyridin-3-amine

A mixture of 3-bromopyridine (1.12 g, 7.08 mmol), 3-chloroaniline (0.6 g, 4.72 mmol), and NaOtBu (0.68 g, 7.08 mmol) in Toluene (15 mL) was degassed with Nitrogen for 5 min. Pd₂(dba)₃ (0.21 g, 0.24 mmol) and rac-Binap (0.147 g, 0.24 mmol) were then added and the resulting mixture was heated in the microwave (150⁰C, 15 min). The reaction mixture was partitioned between H₂O and EtOAc. The aqueous layer was extracted with EtOAc (2x) and the organics were combined, dried over Na₂SO₄, and evaporated to dryness. The residue was purified by flash chromatography on silica gel (eluting with 0 to 50% EtOAc/Hexanes) to afford 0.46 g of N-(3-chlorophenyl)pyridin- 3-amine as a yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 8.39 (s, IH), 8.22 (d, IH), 7.43 (d, IH), 7.26-7.18 (m, 2H), 7.05 (m, IH), 6.94-6.90 (m, 2H), 5.83 (bs, IH).

Step 2: 4-(((3-Chlorophenyl)(pyridin-3-yl)amino)methyl)-7,8-difluoroquinolin- 2(lH)-one

Sodium hydride (60%, 131 mg, 3.29 mmol) was added to a solution of N-(3- chlorophenyl)pyridin-3 -amine (291 mg, 1.43 mmol) in DMF (5 mL). After stirring for 10 min at RT, 4-(bromomethyl)-7,8-difluoroquinolin-2(lH)-one (INTERMEDIATE 1, 300 mg, 1.09 mmol) was added and the resulting mixture was stirred at RT for 2 h. Methanol was added and the solvents were removed to give a dark oily residue. The residue was purified by flash chromatography on silica gel (e luting with 0 to 100% EtOAc/Hexanes) to afford 4-(((3-chlorophenyl)(pyridin-3-yl)amino)methyl)-7,8- difluoroquinolin-2(lH)-one as a yellow solid. ¹U NMR (400 MHz, DMSO-d₆, HCl salt) δ 8.35 (s, IH), 8.3 (d, IH), 7.95-7.92 (d, IH), 7.81 (t, IH), 7.63-7.59 (m, 2H), 7.46 (m, 2H), 7.36-7.31 (m, 2H), 6.43 (s, IH), 5.44 (s, 2H). LCMS: 398 (M+H)⁺.

EXAMPLE 2

4-(((3-Chlorophenyl)(pyrimidin-2-yl)amino)methyl)-7,8-difluoroquinolin-2(lH)- one

Step 1 : N-(3-Chlorophenyl)pyrimidin-2-amine

A mixture of 2-chloropyrimidine (4 g, 35 mmol) and 3-chloroaniline (4.4 g, 35 mmol) in NMP (15 mL) was heated to 150⁰C for 15 min in a microwave. The cooled reaction mixture was poured into EtOAc and the organic layer was washed with NaOH (IM, 3x), brine (2x), dried, and evaporated to dryness. The residue was purified by flash chromatography on silica gel (eluting with 0 to 50% EtOAc/Hexanes) to afford 4 g of N-(3-chlorophenyl)pyrimidin-2-amine as a yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 8.45 (d, 2H), 7.86 (t, IH), 7.54 (s, IH), 7.39 (d, IH), 7.25 (d, IH), 7.01 (d, IH), 6.77 (t, IH).

Step 2: 4-(((3-Chlorophenyl)(pyrimidin-2-yl)amino)methyl)-7,8-difluoroquinolin- 2(lH)-one

4-(((3-Chlorophenyl)(pyrimidin-2-yl)amino)methyl)-7,8-difluoroquinolin-2(lH)-one was synthesized as described in EXAMPLE 1, Step 2 using N-(3- chlorophenyl)pyrimidin-2-amine and 4-(bromomethyl)-7,8-difluoroquinolin-2( 1 H)-one (INTERMEDIATE 1) as starting materials. ¹H NMR (400 MHz, DMSO-d₆) δ 11.95 (s, IH), 8.44 (d, 2H), 7.68 (m, IH), 7.53 (s, IH), 7.36-7.22 (m, 4H), 6.88 (t, IH), 6.22 (s, IH), 5.47 (s, 2H). LCMS: 399 (M+H)⁺.

EXAMPLE 3

4-(((3-Chlorophenyl)(5-ethylpyrimidin-2-yl)amino)methyl)-7,8-difluoroquinolin-

2(lH)-one

4-(((3-Chlorophenyl)(5-ethylpyrimidin-2-yl)amino)methyl)-7,8-difluoroquinolin- 2(lH)-one was synthesized as described in EXAMPLE 2 using 2-chloro-5- ethylpyrimidine in Step 1 and N-(3-chlorophenyl)-5-ethylpyrimidin-2-amine in Step 2. ¹H NMR (400 MHz, DMSO-d₆) δ 11.95 (s, IH), 8.33 (s, 2H), 7.69 (m, IH), 7.51 (s, IH), 7.38-7.27 (m, 3H), 7.22-7.19 (m, IH), 6.19 (s, IH), 5.46 (s, 2H), 2.48 (qt, 2H), 1.13 (t, 3H). LCMS: 427 (M+H)⁺.

EXAMPLE 4

4-(((3-Chlorophenyl)(4-(dimethylamino)pyridin-2-yl)amino)methyl)-7,8- difluoroquinolin-2(lH)-one

Step 1 : 2-Chloro-N,N-dimethylpyridin-4-amine

A mixture of 2,4-dichloropyridine (2 g, 13.5 mmol) and dimethylamine (40% in H₂O, 13.5 rnL) was heated to 50⁰C in a sealed tube for 18h. The reaction mixture was added Et₂O and the 2 layers were separated. The desired 2-chloro-N,N-dimethylpyridin-4- amine was separated from the undesired 4-chloro-N,N-dimethylpyridin-2-amine by flash chromatography on silica gel (eluting with 10 to 50% EtOAc/Hexanes). ¹H NMR (400 MHz, DMSO-de) δ 7.86 (d, IH), 6.57 (m, 2H), 2.94 (s, 6H).

Step 2: N2-(3-Chlorophenyl)-N4,N4-dimethylpyridine-2,4-diamine

N2-(3-chlorophenyl)-N4,N4-dimethylpyridine-2,4-diamine was synthesized as described in EXAMPLE 1 , Step 1 using 2-chloro-N,N-dimethylpyridin-4-amine as a starting material. ¹H NMR (400 MHz, CDCl₃) δ 7.91 (d, IH), 7.40 (s, IH), 7.26-7.15 (m, 2H), 6.92 (m, IH), 6.58 (s, IH), 6.17 (dd, IH), 6.06 (d, IH), 2.97 (s, 6H).

Step 3: 4-(((3-Chlorophenyl)(4-(dimethylamino)pyridin-2-yl)amino)methyl)-7,8- difluoroquinolin-2(lH)-one

4-(((3-Chlorophenyl)(4-(dimethylamino)pyridin-2-yl)amino)methyl)-7,8- difluoroquinolin-2(lH)-one was synthesized as described in EXAMPLE 1, Step 2 using N2-(3-chlorophenyl)-N4,N4-dimethylpyridine-2,4-diamine and 4- (bromomethyl)-7,8-difluoroquinolin-2(lH)-one (INTERMEDIATE 1) as starting materials. ¹H NMR (400 MHz, DMSO-d₆) δ 11.96 (s, IH), 7.80 (d, IH), 7.73 (m, IH), 7.34-7.21 (m, 4H), 7.11 (d, IH), 6.27 (m, 2H), 6.02 (s, IH), 5.43 (s, 2H), 2.83 (s, 6H). LCMS: 441 (M+H)⁺.

EXAMPLE 5

4-(((3-Chlorophenyl)(4-(dimethylamino)pyrimidin-2-yl)amino)methyl)-7,8- difluoroquinolin-2(lH)-one

Step 1 : 2-Chloro-N,N-dimethylpyrimidin-4-amine

2-Chloro-N,N-dimethylpyrimidin-4-amine was synthesized as described in EXAMPLE 4, Step 1 using 2,4-dichloropyrimidine. ¹H NMR (400 MHz, DMSO-d₆) δ 8.00 (d, IH), 6.31 (d, IH), 3.12 (s, 6H).

Step 2: 4-(((3-Chlorophenyl)(4-(dimethylamino)pyrimidin-2-yl)amino)methyl)- 7,8-difluoroquinolin-2(lH)-one

4-(((3-Chlorophenyl)(4-(dimethylamino)pyrimidin-2-yl)amino)methyl)-7,8- difluoroquinolin-2(lH)-one was synthesized as described in EXAMPLE 2 using 2- chloro-N,N-dimethylpyrimidin-4-amine in Step 1 and N2-(3-chlorophenyl)-N4,N4- dimethylpyrimidine-2,4-diamine in Step 2. ¹U NMR (400 MHz, DMSO-d₆) δ 11.92 (s, IH), 7.90 (d, IH), 7.75 (m, IH), 7.54 (s, IH), 7.33-7.29 (m, 3H), 7.18-7.16 (m, IH), 6.17 (m, 2H), 5.47 (s, 2H), 2.89 (s, 6H). LCMS: 442 (M+H)⁺.

EXAMPLE 6 4-(((3-Chlorophenyl)(pyridin-2-yl)amino)methyl)-7,8-difluoroquinolin-2(lH)-one

4-(((3-Chlorophenyl)(pyridin-2-yl)amino)methyl)-7,8-difluoroquinolin-2(lH)-one was synthesized as described in EXAMPLE 1 using 2-chloropyridine in Step 1 and N-(3- chlorophenyl)pyridin-2-amine in Step 2. ¹H NMR (400 MHz, DMSO-d₆) δ 11.95 (s, IH), 8.17 (d, IH), 7.72 (m, IH), 7.56 (td, IH), 7.43-7.37 (m, 2H), 7.31-7.22 (m, 3H), 6.83-6.78 (m, 2H), 6.26 (s, IH), 5.45 (s, 2H). LCMS: 398 (M+H)⁺.

EXAMPLE 7

4-(((3-Chlorophenyl)(4,6-dimethylpyrimidin-2-yl)amino)methyl)-7,8- difluoroquinolin-2(lH)-one

4-(((3-Chlorophenyl)(4,6-dimethylpyrimidin-2-yl)amino)methyl)-7,8-difluoroquinolin-

2(lH)-one was synthesized as described in EXAMPLE 2 using 2-chloro-4,6- dimethylpyrimidine in Step 1 and N-(3-chlorophenyl)-4,6-dimethylpyrimidin-2-amine in Step 2. ¹H NMR (400 MHz, DMSO-d₆) δ 11.95 (s, IH), 7.71 (m, IH), 7.47 (s, IH), 7.35-7.26 (m, 3H), 7.20-7.17 (m, IH), 6.65 (s, IH), 6.19 (s, IH), 5.49 (s, 2H), 2.20 (s, 6H). LCMS: 427 (M+H)⁺.

EXAMPLE 8 4-(((3-Chlorophenyl)(pyrazin-2-yl)amino)methyl)-7,8-difluoroquinolin-2(lH)-one

4-(((3-Chlorophenyl)(pyrazin-2-yl)amino)methyl)-7,8-difluoroquinolin-2(lH)-one was synthesized as described for EXAMPLE 1 using 2-iodopyrazine in Step 1 and N-(3- chlorophenyl)pyrazin-2-amine in Step 2. ¹H NMR (400 MHz, DMSO-d₆) δ 11.95 (s, IH), 8.16 (d, IH), 8.13 (s, IH), 8.00 (d, IH), 7.69-7.65 (m, IH), 7.59 (s, IH), 7.44-7.13 (m, 2H), 7.32-7.25 (m, 2H), 6.33 (s, IH), 5.42 (s, 2H). LCMS: 399 (M+H)⁺.

EXAMPLE 9

4-(((3-Chlorophenyl)(6-methylpyridin-2-yl)amino)methyl)-7,8-difluoroquinolin-

2(lH)-one

4-(((3-Chlorophenyl)(6-methylpyridin-2-yl)amino)methyl)-7,8-difluoroquinolin-2(lH)- one was synthesized as described for EXAMPLE 1 using 2-chloro-6-methylpyridine in Step 1 and N-(3-chlorophenyl)-6-methylpyridin-2-amine in Step 2. ¹H NMR (400 MHz, DMSO-de) δ 11.95 (s, IH), 7.75 (m, IH), 7.44 (t, IH), 7.38-7.34 (m, 2H), 7.30- 7.18 (m, 3H), 6.68 (d, IH), 6.56 (d, IH), 6.26 (s, IH), 5.46 (s, 2H), 2.28 (s, 3H).

EXAMPLE 10

4-(((3-Chlorophenyl)(3-(dimethylamino)pyrazin-2-yl)amino)methyl)-7,8- difluoroquinolin-2(lH)-one

4-(((3-Chlorophenyl)(3-(dimethylamino)pyrazin-2-yl)amino)methyl)-7,8- difluoroquinolin-2(lH)-one was synthesized as described in EXAMPLE 4 using 2,3- dichloropyrazine in Step 1, 3-chloro-N,N-dimethylpyrazin-2-amine in Step 2, and N2- (3-chlorophenyl)-N3,N3-dimethylpyrazine-2,3-diamine in Step 3. ¹H NMR (400 MHz, DMSO-de) δ 11.95 (s, IH), 8.05 (d, IH), 7.86 (d, IH), 7.73-7.69 (m, IH), 7.32-7.25 (m, IH), 7.19 (t, IH), 6.88 (dd, IH), 6.77 (tt, IH), 6.66 (dd, IH), 6.43 (s, IH), 5.28 (s, 2H), 2.81 (s, 6H). LCMS: 442 (M+H)⁺.

EXAMPLE 11

4-(((3-Chlorophenyl)(5-methylpyridin-2-yl)amino)methyl)-7,8-difluoroquinolin-

2(lH)-one

4-(((3-Chlorophenyl)(5-methylpyridin-2-yl)amino)methyl)-7,8-difluoroquinolin-2(lH)- one was synthesized as described in EXAMPLE 1 using 2-chloro-5-methylpyridine in Step 1 and N-(3-chlorophenyl)-5-methylpyridin-2-amine in Step 2. ¹H NMR (400 MHz, DMSO-de) δ 11.95 (s, IH), 8.01 (s, IH), 7.73-7.70 (m, IH), 7.41 (dd, IH), 7.35- 7.21 (m, 4H), 7.15 (dd, IH), 6.81 (d, IH), 6.23 (s, IH), 5.43 (s, 2H), 2.16 (s, 3H). LCMS: 412 (M+H)⁺.

EXAMPLE 12 4-(((3-Chlorophenyl)(phenyl)amino)methyl)-7,8-difluoroquinolin-2(lH)-one

4-(((3-Chlorophenyl)(phenyl)amino)methyl)-7,8-difluoroquinolin-2(lH)-one was synthesized as described in EXAMPLE 1 using bromobenzene in Step 1 and 3-chloro- N-phenylaniline in Step 2. ¹H NMR (400 MHz, DMSO-d₆) δ 11.98 (s, IH), 7.68-7.64 (m, IH), 7.37-7.19 (m, 6H), 7.09 (td, IH), 6.91-6.84 (m, 3H), 6.33 (s, IH), 5.27 (s, 2H). LCMS: 397 (M+H)⁺.

EXAMPLE 13

4-(((3-Chlorophenyl)(3-methylpyridin-2-yl)amino)methyl)-7,8-difluoroquinolin-

2(lH)-one

4-(((3-Chlorophenyl)(3-methylpyridin-2-yl)amino)methyl)-7,8-difluoroquinolin-2(lH)- one was synthesized as described in EXAMPLE 1 using 2-chloro-3-methylpyridine in Step 1 N-(3-chlorophenyl)-3-methylpyridin-2-amine in Step 2. ¹H NMR (400 MHz, DMSO-de) δ 11.98 (s, IH), 8.28 (d, IH), 7.73-7.71 (m, 2H), 7.28-7.17 (m, 3H), 6.89 (dd, IH), 6.66 (t, IH), 6.58 (dd, IH), 6.47 (s, IH), 5.37 (s, 2H), 2.02 (s, 3H). LCMS: 412 (M+H)⁺. EXAMPLE 14

4-(((3-Chlorophenyl)(3-methoxypyridin-2-yl)amino)methyl)-7,8-difluoroquinolin-

2(lH)-one

4-(((3-Chlorophenyl)(3-methoxypyridin-2-yl)amino)methyl)-7,8-difluoroquinolin- 2(lH)-one was synthesized as described in EXAMPLE 1 using 2-bromo-3- methoxypyridine in Step 1 and N-(3-chlorophenyl)-3-methoxypyridin-2-amine in Step 2. ¹H NMR (400 MHz, DMSO-d₆) δ 11.94 (s, IH), 8.00 (dd, IH), 7.72-7.69 (m, IH), 7.55 (dd, IH), 7.29-7.22 (m, 2H), 7.15 (t, IH), 6.84 (dd, IH), 6.61 (t, IH), 6.55 (dd, IH), 6.51 (s, IH), 5.40 (s, 2H), 3.74 (s, 3H). LCMS: 428 (M+H)⁺.

EXAMPLE 15 4-(((3-Chlorophenyl)(quinolin-2-yl)amino)methyl)-7,8-difluoroquinolin-2(lH)-one

4-(((3-Chlorophenyl)(quinolin-2-yl)amino)methyl)-7,8-difluoroquinolin-2(lH)-one was synthesized as described in EXAMPLE 1 using 2-chloroquinoline in Step 1 and N- (3-chlorophenyl)quinolin-2-amine in Step 2. ¹H NMR (400 MHz, DMSO-d₆) δ 11.95 (s, IH), 8.06 (d, IH), 7.81-7.75 (m, 2H), 7.56-7.54 (m, 2H), 7.50 (t, IH), 7.43 (t, IH), 7.34-7.27 (m, 4H), 6.96 (d, IH), 6.32 (s, IH), 5.61 (s, 2H). LCMS: 448 (M+H)⁺. EXAMPLE 16

4-(((3-Chlorophenyl)(6-(dimethylamino)pyrazin-2-yl)amino)methyl)-7,8- difluoroquinolin-2(lH)-one

4-(((3-Chlorophenyl)(6-(dimethylamino)pyrazin-2-yl)amino)methyl)-7,8- difluoroquinolin-2(lH)-one was synthesized as described in EXAMPLE 4 using 2,6- dichloropyrazine in Step 1, 6-chloro-N,N-dimethylpyrazin-2-amine in Step 2, and N2- (3-chlorophenyl)-N6,N6-dimethylpyrazine-2,6-diamine in Step 3. ¹H NMR (400 MHz, DMSO-d₆) δ 11.95 (s, IH), 7.76-7.73 (m, IH), 7.51 (s, IH), 7.47 (t, IH), 7.39 (t, IH), 7.33-7.23 (m, 4H), 6.28 (s, IH), 5.38 (s, 2H), 2.87 (s, 6H). LCMS: 442 (M+H)⁺.

EXAMPLE 17

4-(((3-Chlorophenyl)(pyrimidin-2-yl)amino)methyl)-7,8-difluoro-3- methylquinolin-2(lH)-one

4-(((3-chlorophenyl)(pyrimidin-2-yl)amino)methyl)-7,8-difluoro-3-methylquinolin- 2(lH)-one was synthesized as described in EXAMPLE 2 using 2-chloropyrimidine in Step 1 and N-(3-chlorophenyl)pyrimidin-2-amine and 4-(bromomethyl)-7,8-difluoro-3- methylquinolin-2(lH)-one (INTERMEDIATE 2) in Step 2. ¹U NMR (400 MHz, DMSO-de) δ 8.45 (d, 2H), 7.67 (m, IH), 7.21-7.14 (m, 4H), 6.85-6.80 (m, 2H), 5.53 (s, 2H), 1.85 (s, 3H). LCMS: 413 (M+H)⁺. EXAMPLE 18

4-(((3-Chlorophenyl)(pyridin-2-yl)amino)methyl)-7,8-difluoro-3-methylquinolin-

2(lH)-one

4-(((3-Chlorophenyl)(pyridin-2-yl)amino)methyl)-7,8-difluoro-3-methylquinolin- 2(lH)-one was synthesized as described in EXAMPLE 1 using 2-chloropyridine in Step 1 and N-(3-chlorophenyl)pyridin-2-amine and 4-(bromomethyl)-7,8-difluoro-3- methylquinolin-2(lH)-one (INTERMEDIATE 2) in Step 2. ¹U NMR (400 MHz, DMSO-de) δ 11.94 (s, IH), 8.31 (d, IH), 7.74 (m, IH), 7.44 (t, IH), 7.29-7.13 (m, 4H), 6.85-6.75 (m, 2H), 6.12 (d, IH), 5.51 (s, 2H), 1.85 (s, 3H). LCMS: 412 (M+H)⁺.

EXAMPLE 19

4-(((3-Chlorophenyl)(pyrimidin-2-yl)amino)methyl)-3,7,8-trifluoroquinolin-2(lH)- one

4-(((3-Chlorophenyl)(pyrimidin-2-yl)amino)methyl)-3,7,8-trifluoroquinolin-2(lH)-one was synthesized as described in EXAMPLE 2 using 2-chloropyrimidine in Step 1 and N-(3-chlorophenyl)pyrimidin-2-amine and 4-(bromomethyl)-3,7,8-trifluoroquinolin- 2(lH)-one (INTERMEDIATE 3) in Step 2. ¹U NMR (400 MHz, DMSO-d₆) δ 12.51 (s, IH), 8.45 (d, 2H), 7.73 (m, IH), 7.31-7.23 (m, 4H), 6.98 (d, IH), 6.86 (t, IH), 5.55 (s, 2H). LCMS: 417 (M+H)⁺. EXAMPLE 20 4-(((3-Chlorophenyl)(quinoxalin-2-yl)amino)methyl)-7,8-difluoroquinolin-2(lH)- one

4-(((3-Chlorophenyl)(quinoxalin-2-yl)amino)methyl)-7,8-difluoroquinolin-2(lH)-one was synthesized as described in EXAMPLE 1 using 2-chloroquinoxaline in Step 1 and N-(3-chlorophenyl)quinoxalin-2-amine in Step 2. ¹H NMR (400 MHz, DMSO-d₆) δ 11.95 (s, IH), 8.40 (s, IH), 7.83 (d, IH), 7.72-7.69 (m, IH), 7.66 (s, IH), 7.58 (d, 2H), 7.48-7.40 (m, 3H), 7.32-7.24 (m, 2H), 6.39 (s, IH), 5.53 (s, 2H). LCMS: 449 (M+H)⁺.

EXAMPLE 21

4-(((3-Chlorophenyl)(4-methylpyridin-2-yl)amino)methyl)-7,8-difluoroquinolin-

2(lH)-one

4-(((3-Chlorophenyl)(4-methylpyridin-2-yl)amino)methyl)-7,8-difluoroquinolin-2(lH)- one was synthesized as described in EXAMPLE 1 using 2-chloro-4-methylpyridine in Step 1 and N-(3-chlorophenyl)-4-methylpyridin-2-amine in Step 2. ¹H NMR (400 MHz, DMSO-d₆) δ 11.95 (s, IH), 8.03 (d, IH), 7.72-7.69 (m, IH), 7.40-7.36 (m, 2H), 7.30-7.20 (m, 3H), 6.67 (d, IH), 6.63 (s, IH), 6.24 (s, IH), 5.43 (s, 2H), 2.17 (s, 3H). LCMS: 412 (M+H)⁺.

EXAMPLE 22

4-(((3-Chlorophenyl)(4-methoxypyridin-2-yl)amino)methyl)-7,8-difluoroquinolin-

2(lH)-one

4-(((3-Chlorophenyl)(4-methoxypyridin-2-yl)amino)methyl)-7,8-difluoroquinolin- 2(lH)-one was synthesized as described in EXAMPLE 1 using 2-chloro-4- methoxypyridine in Step 1 and N-(3-chlorophenyl)-4-methoxypyridin-2-amine in Step 2. ¹H NMR (400 MHz, DMSO-d₆, HCl salt) δ 7.98 (d, IH), 7.62 (m, 2H), 7.48-7.30 (m, 4H), 6.70 (m, IH), 6.41 (m, 2H), 5.49 (s, 2H), 3.80 (s, 3H). LCMS: 428 (M+H)⁺.

EXAMPLE 23

4-(l-((3-Chlorophenyl)(pyrimidin-2-yl)amino)ethyl)-7,8-difluoroquinolin-2(lH)- one

4-(l-((3-Chlorophenyl)(pyrimidin-2-yl)amino)ethyl)-7,8-difluoroquinolin-2(lH)-one was synthesized as described in EXAMPLE 2 using 2-chloropyrimidine in Step 1 and N-(3-chlorophenyl)pyrimidin-2-amine and 4-(l-bromoethyl)-7,8-difluoroquinolin- 2(lH)-one (INTERMEDIATE 7) in Step 2. ¹U NMR (400 MHz, DMSO-d₆) δ 11.96 (s, IH), 8.44 (d, 2H), 7.58-7.55 (m, IH), 7.31-7.25 (m, 3H), 6.85-6.81 (m, 2H), 6.65- 6.59 (m, 2H), 6.18 (s, IH), 1.52 (d, 3H). LCMS: 413 (M+H)⁺.

EXAMPLE 24

4-(((3-Chlorophenyl)(pyridin-2-yl)amino)methyl)-3,7,8-trifluoroquinolin-2(lH)- one

4-(((3-Chlorophenyl)(pyridin-2-yl)amino)methyl)-3,7,8-trifluoroquinolin-2(lH)-one was synthesized as described in EXAMPLE 1 using 2-chloropyridine in Step 1 and N- (3-chlorophenyl)pyridin-2-amine and 4-(bromomethyl)-3,7,8-trifluoroquinolin-2(lH)- one (INTERMEDIATE 3) in Step 2. ¹H NMR (400 MHz, DMSO-d₆) δ 12.56 (s, IH), 8.29 (d, IH), 7.87-7.83 (m, IH), 7.47 (t, IH), 7.37-7.28 (m, 4H), 6.98 (dt, IH), 6.80 (m, IH), 6.27 (d, IH), 5.54 (s, 2H). LCMS: 416 (M+H)⁺.

EXAMPLE 25

4-(((3-Chlorophenyl)(pyrazin-2-yl)amino)methyl)-7,8-difluoro-3-methylquinolin-

2(lH)-one

4-(((3-Chlorophenyl)(pyrazin-2-yl)amino)methyl)-7,8-difluoro-3-methylquinolin- 2(lH)-one was synthesized as described in EXAMPLE 1 using 2-iodopyrazine in Step 1 and N-(3-chlorophenyl)pyrazin-2-amine and 4-(bromomethyl)-7,8-difluoro-3- methylquinolin-2(lH)-one (INTERMEDIATE 2) in Step 2. ¹H NMR (400 MHz, DMSO-d₆) δ 11.98 (s, IH), 8.29 (s, IH), 7.98 (d, IH), 7.63-7.59 (m, IH), 7.57 (s, IH), 7.35-7.28 (m, 3H), 7.21-7.14 (m, IH), 6.92 (dt, IH), 5.45 (s, 2H), 1.88 (s, 3H). LCMS: 413 (M+H)⁺.

EXAMPLE 26

4-(((3-Chlorophenyl)(3,5-dimethylpyrazin-2-yl)amino)methyl)-7,8- difluoroquinolin-2(lH)-one

4-(((3-Chlorophenyl)(3,5-dimethylpyrazin-2-yl)amino)methyl)-7,8-difluoroquinolin- 2(lH)-one was synthesized as described in EXAMPLE 1 using 2-chloro-3,5- dimethylpyrazine in Step 1 and N-(3-chlorophenyl)-3,5-dimethylpyrazin-2-amine in Step 2. ¹H NMR (400 MHz, DMSO-d₆, HCl salt) δ 11.96 (s, IH), 8.22 (s, IH), 7.75- 7.71 (m, IH), 7.31-7.23 (m, 2H), 6.99 (dd, IH), 6.85 (t, IH), 6.69 (dt, IH), 6.38 (s, IH), 5.40 (s, 2H), 2.34 (s, 3H), 2.12 (s, 3H). LCMS: 427(M+H)⁺.

EXAMPLE 27

4-(((3-Chlorophenyl)(pyrimidin-2-yl)amino)methyl)-3-ethyl-7,8-difluoroquinolin-

2(lH)-one

4-(((3-Chlorophenyl)(pyrimidin-2-yl)amino)methyl)-3-ethyl-7,8-difluoroquinolin- 2(lH)-one was synthesized as described in EXAMPLE 2 using 2-chloropyrimidine in Step 1 and N-(3-chlorophenyl)pyrimidin-2-amine and 4-(bromomethyl)-3-ethyl-7,8- difluoroquinolin-2(lH)-one (INTERMEDIATE 6) in Step 2. ¹H NMR (400 MHz, DMSO-de) δ 11.95 (s, IH), 8.45 (m, 2H), 7.65-7.62 (m, IH), 7.22-7.14 (m, 4H), 6.84 (t, IH), 6.79-6.76 (m, IH), 5.51 (s, 2H), 2.39 (qt, 2H), 0.81 (t, 3H). LCMS: 427(M+H)⁺.

EXAMPLE 28

4-(((3-Chlorophenyl)(pyrazin-2-yl)amino)methyl)-3,7,8-trifluoroquinolin-2(lH)- one

4-(((3-Chlorophenyl)(pyrazin-2-yl)amino)methyl)-3,7,8-trifluoroquinolin-2(lH)-one was synthesized as described in EXAMPLE 1 using 2-iodopyrazine in Step 1 and N-(3- chlorophenyl)pyrazin-2 -amine and 4-(bromomethyl)-3,7,8-trifluoroquinolin-2(lH)-one (INTERMEDIATE 3) in Step 2. ¹H NMR (400 MHz, DMSO-d₆) δ 12.49 (s, IH), 8.28 (s, IH), 8.00 (d, IH), 7.71-7.68 (m, 2H), 7.41-7.30 (m, 4H), 7.06 (dt, IH), 5.48 (s, 2H). LCMS: 417(M+H)⁺.

EXAMPLE 29

4-(((3-Chlorophenyl)(pyrazin-2-yl)amino)methyl)-3-ethyl-7,8-difluoroquinolin-

2(lH)-one

4-(((3-Chlorophenyl)(pyrazin-2-yl)amino)methyl)-3-ethyl-7,8-difluoroquinolin-2(lH)- one was synthesized as described in EXAMPLE 1 using 2-iodopyrazine in Step 1 and N-(3-chlorophenyl)pyrazin-2-amine and 4-(bromomethyl)-3-ethyl-7,8- difluoroquinolin-2(lH)-one (INTERMEDIATE 6) in Step 2. ¹H NMR (400 MHz, DMSO-de) δ 11.94 (s, IH), 8.30 (s, IH), 7.98 (d, IH), 7.57-7.53 (m, 2H), 7.36-7.29 (m, 3H), 7.19-7.12 (m, IH), 6.87 (dt, IH), 5.42 (s, 2H), 2.42 (qt, 2H), 0.82 (t, 3H). LCMS: 427(M+H)⁺.

EXAMPLE 30

4-(((3-Chlorophenyl)(pyrimidin-5-yl)amino)methyl)-7,8-difluoroquinolin-2(lH)- one

4-(((3-Chlorophenyl)(pyrimidin-5-yl)amino)methyl)-7,8-difluoroquinolin-2(lH)-one was synthesized as described in EXAMPLE 1 using 5-bromopyrimidine in Step 1 and N-(3-chlorophenyl)pyrimidin-5 -amine in Step 2. ¹H NMR (400 MHz, DMSO-d₆) δ 11.99 (s, IH), 8.77 (s, IH), 8.56 (s, 2H), 7.64-7.61 (m, IH), 7.36-7.31 (m, 3H), 7.19 (dd, IH), 7.11 (dd, IH), 6.36 (s, IH), 5.38 (s, 2H). LCMS: 399(M+H)⁺. EXAMPLE 31

4-(((3-Chlorophenyl)(5-fluoropyridin-2-yl)amino)methyl)-7,8-difluoroquinolin-

2(lH)-one

4-(((3-Chlorophenyl)(5-fluoropyridin-2-yl)amino)methyl)-7,8-difluoroquinolin-2(lH)- one was synthesized as described in EXAMPLE 1 using 2-bromo-5-fluoropyridine in Step 1 and N-(3-chlorophenyl)-5-fluoropyridin-2-amine in Step 2. ¹H NMR (400 MHz, DMSO-de) δ 11.96 (s, IH), 8.17 (d, IH), 7.71-7.67 (m, IH), 7.56-7.51 (m, IH), 7.42-7.38 (m, 2H), 7.31-7.19 (m, 3H), 6.88 (dd, IH), 6.26 (s, IH), 5.41 (s, 2H). LCMS: 416 (M+H)⁺.

EXAMPLE 32

4-(((3-Chlorophenyl)(5-chloropyridin-2-yl)amino)methyl)-7,8-difluoroquinolin-

2(lH)-one

4-(((3-Chlorophenyl)(5-chloropyridin-2-yl)amino)methyl)-7,8-difluoroquinolin-2(lH)- one was synthesized as described in EXAMPLE 1 using 2,5-dichloropyridine in Step 1 and 5-chloro-N-(3-chlorophenyl)pyridin-2-amine in Step 2. ¹H NMR (400 MHz, DMSO-de) δ 11.96 (s, IH), 8.18 (d, IH), 7.69-7.66 (m, IH), 7.62 (dd, IH), 7.48 (m, IH), 7.41 (t, IH), 7.35-7.25 (m, 3H), 6.77 (d, IH), 6.26 (s, IH), 5.41 (s, 2H). LCMS: 432 (M)⁺.

EXAMPLE 33

4-(((3-Chlorophenyl)(5-methoxypyridin-2-yl)amino)methyl)-7,8-difluoroquinolin-

2(lH)-one

4-(((3-Chlorophenyl)(5-methoxypyridin-2-yl)amino)methyl)-7,8-difluoroquinolin- 2(lH)-one was synthesized as described in EXAMPLE 1 using 2-bromo-5- methoxypyridine in Step 1 and N-(3-chlorophenyl)-5-methoxypyridin-2-amine in Step 2. ¹H NMR (400 MHz, DMSO-d₆) δ 11.95 (s, IH), 7.96 (d, IH), 7.73-7.70 (m, IH), 7.34-7.21 (m, 4H), 7.16 (dd, IH), 7.06 (dd, IH), 7.00 (d, IH), 6.26 (s, IH), 5.40 (s, 2H), 3.75 (s, 3H). LCMS: 428 (M+H)⁺.

EXAMPLE 34

4-(((3-Chlorophenyl)(6-methylpyridazin-3-yl)amino)methyl)-7,8-difluoroquinolin-

2(lH)-one

4-(((3-Chlorophenyl)(6-methylpyridazin-3-yl)amino)methyl)-7,8-difluoroquinolin- 2(lH)-one was synthesized as described in EXAMPLE 1 using 3-chloro-6- methylpyridazine in Step 1 and N-(3-chlorophenyl)-6-methylpyridazin-3 -amine in Step 2. ¹H NMR (400 MHz, DMSO-d₆) δ 11.99 (s, IH), 7.73-7.69 (m, IH), 7.46 (s, IH), 7.41 (t, IH), 7.32-7.24 (m, 4H), 7.09 (d, IH), 6.27 (s, IH), 5.52 (s, 2H), 2.45 (s, 3H). LCMS: 413 (M+H)⁺.

EXAMPLE 35

4-(((3-chlorophenyl)(pyrimidin-4-yl)amino)methyl)-3-ethyl-7,8-difluoroquinolin-

2(lH)-one

Step 1 : 6-Chloro-N-(3-chlorophenyl)pyrimidin-4-amine

6-Chloro-N-(3-chlorophenyl)pyrimidin-4-amine was synthesized as described in EXAMPLE 2, Step 1 using 4,6-dichloropyrimidine as a starting material. ¹H NMR (400 MHz, DMSO-de) δ 10.02 (s, IH), 8.53 (s, IH), 7.91 (s, IH), 7.45 (dd, IH), 7.35 (t, IH), 7.09 (dt, IH), 6.81 (s, IH).

Step 2: N-(3-Chlorophenyl)pyrimidin-4-amine

6-Chloro-N-(3-chlorophenyl)pyrimidin-4-amine (1 g, 4.19 mmol) in MeOH (10 mL) was hydrogenated for 45 min with a balloon of H₂ in the presence of Pd/C (cat.). The Pd/C was removed by filtration and the filtrate was evaporated to dryness to afford N- (3-chlorophenyl)pyrimidin-4-amine (800 mg) as a pale yellow solid. ¹H NMR (400 MHz, DMSO-de) δ 11.82 (s, IH), 8.97 (s, IH), 8.39 (d, IH), 7.94 (s, IH), 7.61 (dd, IH), 7.44 (t, IH), 7.28 (d, IH), 7.22 (d, IH).

Step 3: 4-(((3-Chlorophenyl)(pyrimidin-4-yl)amino)methyl)-3-ethyl-7,8- difluoroquinolin-2(lH)-one

4-(((3-chlorophenyl)(pyrimidin-4-yl)amino)methyl)-3-ethyl-7,8-difluoroquinolin- 2(lH)-one was synthesized as one regioisomer (other regioisomer: 4-((4-(3- chlorophenylimino)pyrimidin-l(4H)-yl)methyl)-3-ethyl-7,8-difluoroquinolin-2(lH)- one) as described in EXAMPLE 1, Step 2 using N-(3-chlorophenyl)pyrimidin-4-amine and 4-(bromomethyl)-3-ethyl-7,8-difluoroquinolin-2(lH)-one (INTERMEDIATE 6). ¹H NMR (400 MHz, DMSO-d₆) δ 11.97 (s, IH), 8.99 (s, IH), 8.24 (d, IH), 7.54-7.51 (m, IH), 7.42 (d, IH), 7.41-7.34 (m, 2H), 7.16 (m, IH), 6.82 (d, IH), 6.27 (d, IH), 5.57 (s, 2H), 2.39 (qt, 2H), 0.83 (t, 3H). LCMS: 427 (M+H)⁺.

EXAMPLE 36

4-(((3-Chlorophenyl)(2-chloropyridin-4-yl)amino)methyl)-7,8-difluoroquinolin-

2(lH)-one

Step 1 : 2-Chloro-N-(3-chlorophenyl)pyridin-4-amine

Sodium hydride (60% in mineral oil, 390 mg, 9.75 mmol) was added to a solution of 3- chloroaniline (1 g, 6.5 mmol) in DMF (20 mL) and the mixture was stirred at RT for 10 min. Solid 2-chloro-4-nitropyridine (990 mg, 7.8 mmol) was then added and it was stirred at RT for 30 min after which it was partitioned between EtOAc and brine. The organic layer was washed with brine (3x), dried, filtered, and evaporated to dryness. The residue was purified by flash chromatography on silica gel (eluting with 0 to 100% EtOAC/hexanes) to afford 2-chloro-N-(3-chlorophenyl)pyridin-4-amine as an orange solid.

Step 2: 4-(((3-Chlorophenyl)(2-chloropyridin-4-yl)amino)methyl)-7,8- difluoroquinolin-2(lH)-one

4-(((3-Chlorophenyl)(2-chloropyridin-4-yl)amino)methyl)-7,8-difluoroquinolin-2(lH)- one was synthesized as described in EXAMPLE 1, Step 2 using 2-chloro-N-(3- chlorophenyl)pyridin-4-amine as a starting material. ¹H NMR (400 MHz, DMSO-dβ) δ 12.04 (s, IH), 7.98 (d, IH), 7.61-7.58 (m, IH), 7.56 (m, IH), 7.48 (t, IH), 7.43-7.28 (m, 3H), 6.69 (s, IH), 6.66 (dd, IH), 6.31 (s, IH), 5.32 (s, 2H). LCMS: 432 (M+H)⁺. EXAMPLE 37 4-(((3-Chlorophenyl)(pyridin-4-yl)amino)methyl)-7,8-difluoroquinolin-2(lH)-one

4-(((3-Chlorophenyl)(pyridin-4-yl)amino)methyl)-7,8-difluoroquinolin-2(lH)-one was synthesized as described in EXAMPLE 35, Step 2 using 4-(((3-chlorophenyl)(2- chloropyridin-4-yl)amino)methyl)-7,8-difluoroquinolin-2(lH)-one as a starting material. ¹H NMR (400 MHz, DMSO-d₆) δ 12.05 (s, IH), 8.34 (d, 2H), 7.73 (s, IH), 7.61-7.51 (m, 4H), 7.33 (m, IH), 7.00 (d, 2H), 6.41 (s, IH), 5.49 (s, 2H). LCMS: 398 (M+H)⁺.

EXAMPLE 38

4-(((3-Chlorophenyl)(6-methoxypyridazin-3-yl)amino)methyl)-7,8- difluoroquinolin-2(lH)-one

4-(((3-Chlorophenyl)(6-methoxypyridazin-3-yl)amino)methyl)-7,8-difluoroquinolin- 2(lH)-one was synthesized as described in EXAMPLE 1 using 3-chloro-6- methoxypyridazine in Step 1 and N-(3-chlorophenyl)-6-methoxypyridazin-3 -amine in Step 2. ¹H NMR (400 MHz, DMSO-d₆) δ 11.99 (s, IH), 7.72-7.68 (m, IH), 7.42-7.25 (m, 5H), 7.22-7.19 (dt, IH), 7.06 (d, IH), 6.29 (s, IH), 5.48 (s, 2H), 3.89 (s, 3H). LCMS: 429 (M+H)⁺. EXAMPLE 39

4-(((3-Chlorophenyl)(6-methoxypyrimidin-4-yl)amino)methyl)-7,8- difluoroquinolin-2(lH)-one

N-(3-Chlorophenyl)-6-methoxypyrimidin-4-amine

A mixture of 6-chloro-N-(3-chlorophenyl)pyrimidin-4-amine (550 mg, 2.30 mmol) and sodium methoxide (25wt% in MeOH, 10 mL, 4.60 mmol) in MeOH (30 mL) was heated to 70⁰C for 2Oh. The solvent was removed and the residue was partitioned between H₂O and EtOAc. The organic layer was separated, dried, and evaporated to dryness to afford N-(3-chlorophenyl)-6-methoxypyrimidin-4-amine as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 8.39 (s, IH), 7.36 (t, IH), 7.29 (t, IH), 7.18-7.10 (m, 3H), 6.12 (s, IH), 3.94 (s, 3H).

Step 2: 4-(((3-Chlorophenyl)(6-methoxypyrimidin-4-yl)amino)methyl)-7,8- difluoroquinolin-2(lH)-one

4-(((3-Chlorophenyl)(6-methoxypyrimidin-4-yl)amino)methyl)-7,8-difluoroquinolin- 2(lH)-one was synthesized as described in EXAMPLE 1, Step 2 using N-(3- chlorophenyl)-6-methoxypyrimidin-4-amine as a starting material. ¹H NMR (400 MHz, DMSO-d₆) δ 11.95 (s, IH), 8.37 (s, IH), 7.67-7.63 (m, IH), 7.52 (t, IH), 7.44 (t, IH), 7.37-7.26 (m, 3H), 6.27 (s, IH), 5.79 (s, IH), 5.41 (s, 2H), 3.79 (s, 3H). LCMS: 429 (M+H)⁺.

EXAMPLE 40

4-(((3-Chlorophenyl)(pyrimidin-4-yl)amino)methyl)-7,8-difluoro-3- methylquinolin-2(lH)-one

4-(((3-Chlorophenyl)(pyrimidin-4-yl)amino)methyl)-7,8-difluoro-3-methylquinolin- 2(lH)-one was synthesized as described in EXAMPLE 1, Step 2 using N-(3- chlorophenyl)pyrimidin-4-amine and 4-(bromomethyl)-7,8-difluoro-3-methylquinolin- 2(lH)-one (INTERMEDIATE 2). ¹U NMR (400 MHz, DMSO-d₆) δ 12.05 (s, IH), 9.03 (s, IH), 8.26 (d, IH), 7.59-7.55 (m, IH), 7.43-7.40 (m, 2H), 7.34 (t, IH), 7.21- 7.16 (m, IH), 6.89 (d, IH), 6.35 (d, IH), 5.61 (s, 2H), 1.87 (s, 3H). LCMS: 412 (M+H)⁺.

EXAMPLE 41

4-(((3-Chlorophenyl)(pyridazin-3-yl)amino)methyl)-7,8-difluoroquinolin-2(lH)- one

4-(((3-Chlorophenyl)(pyridazin-3-yl)amino)methyl)-7,8-difluoroquinolin-2(lH)-one was synthesized as described in EXAMPLE 35 using 3,6-dichloropyridazine in Step 1, 6-chloro-N-(3-chlorophenyl)pyridazin-3 -amine in Step 2, and N-(3- chlorophenyl)pyridazin-3 -amine and 4-(bromomethyl)-7,8-difluoroquinolin-2(lH)-one in Step 3. ¹H NMR (400 MHz, DMSO-d₆) δ 11.97 (s, IH), 8.73 (d, IH), 7.72-7.68 (m, IH), 7.56 (s, IH), 7.47-7.29 (m, 5H), 7.12 (d, IH), 6.32 (s, IH), 5.54 (s, 2H). LCMS: 398 (M+H)⁺.

EXAMPLE 42

4-(((3-Chlorophenyl)(6-chloropyrimidin-4-yl)amino)methyl)-7,8-difluoroquinolin-

2(lH)-one

4-(((3-Chlorophenyl)(6-chloropyrimidin-4-yl)amino)methyl)-7,8-difluoroquinolin- 2(lH)-one was synthesized as described in EXAMPLE 2 using 4,6-dichloropyrimidine in Step 1 and 6-chloro-N-(3-chlorophenyl)pyrimidin-4-amine in Step 2. H₂O was added to quench the excess sodium hydride (no MeOH added). ¹H NMR (400 MHz, DMSO-d₆) δ 11.97 (s, IH), 8.49 (s, IH), 7.64-7.60 (m, 2H), 7.50-7.40 (m, 3H), 7.31- 7.24 (m, IH), 6.57 (s, IH), 6.36 (s, IH), 5.43 (s, 2H). LCMS: 433 (M+H)⁺.

EXAMPLE 43

4-(((3-Chlorophenyl)(pyrimidin-4-yl)amino)methyl)-7,8-difluoroquinolin-2(lH)- one

4-(((3-Chlorophenyl)(pyrimidin-4-yl)amino)methyl)-7,8-difluoroquinolin-2(lH)-one Was synthesized as described in EXAMPLE 35, Step 2 using 4-(((3-chlorophenyl)(6- chloropyrimidin-4-yl)amino)methyl)-7,8-difluoroquinolin-2(lH)-one as a starting material. ¹H NMR (400 MHz, DMSO-d₆) δ 11.95 (s, IH), 8.88 (s, IH), 8.34 (d, IH), 7.68 (s, IH), 7.64-7.60 (m, IH), 7.55-7.44 (m, 3H), 7.32-7.28 (m, IH), 6.76 (d, IH), 6.41 (s, IH), 5.52 (s, 2H). LCMS: 398 (M+H)⁺.

EXAMPLE 44

4-(((3-Chlorophenyl)(6-(dimethylamino)pyrimidin-4-yl)amino)methyl)-7,8- difluoroquinolin-2(lH)-one

4-(((3-Chlorophenyl)(6-(dimethylamino)pyrimidin-4-yl)amino)methyl)-7,8- difluoroquinolin-2(lH)-one was synthesized as described in EXAMPLE 5, Step 1 using 4-(((3-chlorophenyl)(6-chloropyrimidin-4-yl)amino)methyl)-7,8- difluoroquinolin-2(lH)-one as a starting material. ¹H NMR (400 MHz, DMSO-d₆) δ 11.99 (s, IH), 8.26 (s, IH), 7.66-7.62 (m, IH), 7.55 (s, IH), 7.45 (t, IH), 7.39-7.28 (m, 3H), 6.32 (s, IH), 5.69 (s, IH), 5.44 (s, 2H), 2.98 (s, 6H). LCMS: 442 (M+H)⁺.

EXAMPLE 45

4-(((3-Chlorophenyl)(4-(trifluoromethyl)pyridin-2-yl)amino)methyl)-7,8- difluoroquinolin-2(lH)-one

4-(((3-Chlorophenyl)(4-(trifluoromethyl)pyridin-2-yl)amino)methyl)-7,8- difluoroquinolin-2(lH)-one was synthesized as described in EXAMPLE 1 using 2- chloro-4-(trifluoromethyl)pyridine in Step 1 and N-(3-chlorophenyl)-4- (trifluoromethyl)pyridin-2-amine in Step 2. ¹H NMR (400 MHz, DMSO-d₆) δ 11.99 (s, IH), 8.40 (d, IH), 7.69-7.66 (m, IH), 7.58 (s, IH), 7.48-7.40 (m, 2H), 7.35-7.25 (m, 2H), 7.10 (d, IH), 6.84 (s, IH), 6.33 (s, IH), 5.47 (s, 2H). LCMS: 466 (M+H)⁺.

EXAMPLE 46

2-((3-Chlorophenyl)((7,8-difluoro-2-oxo-l,2-dihydroquinolin-4- yl)methyl)amino)isonicotinonitrile

N-(3-Chlorophenyl)-4-fluoropyridin-2-amine

N-(3-Chlorophenyl)-4-fluoropyridin-2-amine was synthesized as described in EXAMPLE 1, Step 1 using 2-chloro-4-fluoropyridine as a starting material. ¹H NMR (400 MHz, CDCl₃) δ 8.19-8.15 (m, IH), 7.41 (t, IH), 7.26 (t, IH), 7.18 (d, IH), 7.05 (d, IH), 6.84 (s, IH), 6.57-6.52 (m, 2H).

Step 2: 2-(3-Chlorophenylamino)isonicotinonitrile

A mixture of N-(3-chlorophenyl)-4-fluoropyridin-2-amine (500 mg, 2.25 mmol) and sodium cyanide (165 mg, 3.38 mmol) in NMP (10 mL) was heated to 190⁰C for 30 min in the microwave. The cooled reaction mixture was poured into EtOAc and the organic layer was washed with brine (3x), dried, and evaporated to dryness. The residue was purified by flash chromatography on silica gel (eluting with 0 to 40% EtOAc/Hexanes) to afford 2-(3-Chlorophenylamino)isonicotinonitrile as a yellow solid. LCMS: 230 (M+H)⁺.

Step 3: 2-((3-Chlorophenyl)((7,8-difluoro-2-oxo-l,2-dihydroquinolin-4- yl)methyl)amino)isonicotinonitrile

2-((3-Chlorophenyl)((7,8-difluoro-2-oxo-l,2-dihydroquinolin-4- yl)methyl)amino)isonicotinonitrile was synthesized as described in EXAMPLE 1 , Step 2 using 2-(3-chlorophenylamino)isonicotinonitrile as a starting material. ¹H NMR (400 MHz, DMSO-de) δ 11.99 (s, IH), 8.34 (d, IH), 7.67-7.63 (m, IH), 7.55 (s, IH), 7.47- 7.38 (m, 2H), 7.34-7.26 (m, 2H), 7.17 (d, IH), 7.09 (s, IH), 6.29 (s, IH), 5.43 (s, 2H). LCMS: 422 (M+H)⁺.

EXAMPLE 47

4-(((2-Chloro-6-methylpyrimidin-4-yl)(3-chlorophenyl)amino)methyl)-7,8- difluoroquinolin-2(lH)-one

4-(((2-Chloro-6-methylpyrimidin-4-yl)(3-chlorophenyl)amino)methyl)-7,8- difluoroquinolin-2(lH)-one was synthesized as described for EXAMPLE 2 using 2,4- dichloro-6-methylpyrimidine in Step 1 and 2-chloro-N-(3-chlorophenyl)-6- methylpyrimidin-4-amine in Step 2. ¹U NMR (400 MHz, DMSO-d₆) δ 11.99 (s, IH), 7.63-7.59 (m, IH), 7.58 (s, IH), 7.49-7.35 (m, 3H), 7.28 (m, IH), 6.38 (s, IH), 6.32 (s, IH), 5.37 (s, 2H), 2.21 (s, 3H). LCMS: 446 (M+H)⁺.

EXAMPLE 48

4-(((3-Chlorophenyl)(6-methylpyrimidin-4-yl)amino)methyl)-7,8-difluoroquinolin-

2(lH)-one

4-(((3-Chlorophenyl)(6-methylpyrimidin-4-yl)amino)methyl)-7,8-difluoroquinolin- 2(lH)-one was synthesized as described in EXAMPLE 35, Step 2 using 4-(((2-chloro- 6-methylpyrimidin-4-yl)(3-chlorophenyl)amino)methyl)-7,8-difluoroquinolin-2(lH)- one as a starting material. ¹H NMR (400 MHz, DMSO-d₆) δ 12.05 (s, IH), 8.87 (s, IH), 7.65 (s, IH), 7.61-7.49 (m, 3H), 7.42 (d, IH), 7.30 (m, IH), 6.74 (s, IH), 6.39 (s, IH), 5.51 (s, 2H), 2.37 (s, 3H). LCMS: 413 (M+H)⁺.

EXAMPLE 49

7,8-Difluoro-4-(((6-methylpyrimidin-4-yl)(phenyl)amino)methyl)quinolin-2(lH)- one

7,8-Difluoro-4-(((6-methylpyrimidin-4-yl)(phenyl)amino)methyl)quinolin-2(lH)-one was synthesized as a side product as described in EXAMPLE 35, Step 2 using 4-(((2- chloro-6-methylpyrimidin-4-yl)(3-chlorophenyl)amino)methyl)-7,8-difluoroquinolin- 2(lH)-one as a starting material. LCMS: 379 (M+H)⁺. EXAMPLE 50

4-(((3-Chlorophenyl)(2-methoxy-6-methylpyrimidin-4-yl)amino)methyl)-7,8- difluoroquinolin-2(lH)-one

4-(((3-Chlorophenyl)(2-methoxy-6-methylpyrimidin-4-yl)amino)methyl)-7,8- difluoroquinolin-2(lH)-one was synthesized as described in EXAMPLE 39, Step 1 using 4-(((2-chloro-6-methylpyrimidin-4-yl)(3-chlorophenyl)amino)methyl)-7,8- difluoroquinolin-2(lH)-one as a starting material. ¹H NMR (400 MHz, DMSO-d₆) δ 12.01 (s, IH), 7.66-7.62 (m, IH), 7.57 (s, IH), 7.51-7.43 (m, 2H), 7.34-7.26 (m, 2H), 6.33 (s, IH), 6.20 (s, IH), 5.46 (s, 2H), 3.80 (s, 3H), 2.23 (s, 3H). LCMS: 443 (M+H)⁺.

EXAMPLE 51

4-(((6-Chloro-2-methylpyrimidin-4-yl)(3-chlorophenyl)amino)methyl)-7,8- difluoroquinolin-2(lH)-one

4-(((6-Chloro-2-methylpyrimidin-4-yl)(3-chlorophenyl)amino)methyl)-7,8- difluoroquinolin-2(lH)-one was synthesized as described in EXAMPLE 2 using 4,6- dichloro-2-methylpyrimidine in Step 1 and 6-chloro-N-(3-chlorophenyl)-2- methylpyrimidin-4-amine in Step 2 (no MeOH used in work-up). ¹H NMR (400 MHz, DMSO-de) δ 11.99 (s, IH), 7.66-7.62 (m, IH), 7.58 (s, IH), 7.46 (t, IH), 7.41-7.35 (m, 2H), 7.29 (m, IH), 6.32 (s, IH), 6.31 (s, IH), 5.44 (s, 2H), 2.38 (s, 3H). LCMS: 446 (M+H)⁺.

EXAMPLE 52

4-(((3-Chlorophenyl)(2-methylpyrimidin-4-yl)amino)methyl)-7,8-difluoroquinolin-

2(lH)-one

4-(((3-Chlorophenyl)(2-methylpyrimidin-4-yl)amino)methyl)-7,8-difluoroquinolin- 2(lH)-one was synthesized as described in EXAMPLE 35, Step 2 using 4-(((6-chloro- 2-methylpyrimidin-4-yl)(3-chlorophenyl)amino)methyl)-7,8-difluoroquinolin-2(lH)- one as a starting material. ¹H NMR (400 MHz, DMSO-d₆) δ 12.03 (s, IH), 8.32 (d, IH), 7.68 (s, IH), 7.63-7.59 (m, IH), 7.56-7.50 (m, 2H), 7.43 (d, IH), 7.30 (m, IH), 6.66 (d, IH), 6.42 (s, IH), 5.56 (s, 2H), 2.55 (s, 3H). LCMS: 413 (M+H)⁺.

EXAMPLE 53

7,8-Difluoro-4-(((2-methylpyrimidin-4-yl)(phenyl)amino)methyl)quinolin-2(lH)- one

7,8-difluoro-4-(((2-methylpyrimidin-4-yl)(phenyl)amino)methyl)quinolin-2(lH)-one was synthesized as a side product as described in EXAMPLE 35, Step 2 using 4-(((6- chloro-2-methylpyrimidin-4-yl)(3-chlorophenyl)amino)methyl)-7,8-difluoroquinolin- 2(lH)-one as a starting material. LCMS: 379 (M+H)⁺.

EXAMPLE 54

4-(((3-Chloro-l,2,4-thiadiazol-5-yl)(3-chlorophenyl)amino)methyl)-7,8- difluoroquinolin-2(lH)-one

4-(((3-Chloro-l,2,4-thiadiazol-5yl)(3-chlorophenyl)amino)methyl)-7,8- difluoroquinolin-2(lH)-one was synthesized as described in EXAMPLE 2 using 3,5- dichloro-l,2,4-thiadiazole in Step 1 and 3-chloro-N-(3-chlorophenyl)-l,2,4-thiadiazol- 5-amine in step 2. ¹HNMR (400MHz, CDCl₃) δ 7.54-7.50 (m, IH), 7.43-7.38 (m, 2H), 7.35-7.32 (m, IH), 7.23-7.03 (m, IH), 7.14-7.00 (m, IH), 6.52 (s, IH), 5.37 (s, 2H). LCMS: 438.83 (M+H)⁺.

EXAMPLE 55

4-(((5-Bromopyrimidin-2-yl)(3-chlorophenyl)amino)methyl)-7,8-difluoroquinolin-

2(lH)-one

4-(((5-Bromopyrimidin-2yl)(3-chlorophenyl)amino)methyl)-7,8-difluoroquinolin- 2(lH)-one was synthesized as described in EXAMPLE 2 using 5-bromo-2- chloropyrimidine in Step 1 and 5-bromo-N-(3-chlorophenyl)pyrimidin-2-amine in step 2. ¹HNMR (400MHz, DMSO-d₆) δ 11.97 (s, IH), 8.56 (s, 2H), 7.67-7.60 (m, IH), 7.57 (s, IH), 7.41-7.37 (m, 2H), 7.35-7.25 (m, 2H), 6.27 (s, IH), 5.43 (s, 2H). LCMS: 477.83 (M+H)⁺.

EXAMPLE 56 4-(((3-Chlorophenyl)(thiazol-2-yl)amino)methyl)-7,8-difluoroquinolin-2(lH)-one

4-(((3-Chlorophenyl)(thiazol-2-yl)amino)methyl)-7,8-difluoroquinolin-2(lH)-one was synthesized as described in EXAMPLE 2 using 2-bromothiazole in Step 1 and N-(3- chlorophenyl)thiazol-2-amine in step 2. ¹HNMR (400MHz, DMSO-d₆) δ 11.97 (s, IH), 7.71-7.64 (m, 2H), 7.48-7.40 (m, 2H), 7.33-7.25 (m, 3H), 6.93 (d, IH), 6.31 (s, IH), 5.45 (s, 2H). LCMS: 403.93 (M+H)⁺.

EXAMPLE 57

4-(((3-Chlorophenyl)(4-(dimethylamino)-6-methylpyrimidin-2-yl)amino)methyl)-

7,8-difluoro quinolin-2(lH)-one

4-(((3-Chlorophenyl)(4-dimethylamino)-6-methylpyrimidin-2-yl)amino)methyl)-7,8- difluoroquinolin-2(lH)-one was synthesized as described in EXAMPLE 2 using 2- chloro-N,N,6-trimethylpyrimidin-4-amine in Step 1 and N²-(3-chlorophenyl)- N⁴, N⁴,6- trimethylpyrimidine-2,4-diamine in step 2. ¹HNMR (400MHz, DMSO-d₆) δ 11.93 (s, IH), 7.76-7.73 (m, IH), 7.51 (s, IH), 7.29-7.24 (m, 3H), 7.13-7.10 (m, IH), 6.16 (s, IH), 6.04 (s, IH), 5.47 (s, 2H), 2.84 (s, 6H), 2.09 (s, 3H). LCMS: 454.31 (M)⁺.

EXAMPLE 58

4-(((3-Chlorophenyl)(5-methyl-l,3,4-thiadiazol-2-yl)amino)methyl)-7,8- difluoroquinolin-2(lH)-one

4-(((3-Chlorophenyl)(5-methyl-l,3,4-thiadiazol-2-yl)amino)methyl)-7,8- difluoroquinolin-2(lH)-one was synthesized as described in EXAMPLE 2 using 2- bromo-5-methyl-l,3,4-thiadiazole in Step 1 and N-(3-chlorophenyl)-5-methyl-l,3,4- thiadiazol-2-amine in step 2. ¹HNMR (400MHz, DMSO-d₆) δ 11.96 (s, IH), 7.57-7.46 (m, 3H), 7.40-7.38 (m, IH), 7.30-7.27 (m, IH), 7.20-7.14 (m, IH), 6.38 (s, IH), 4.40 (s, 2H), 2.18 (s, 3H). LCMS: 419 (M+H)⁺.

EXAMPLE 59

4-(((3-Chlorophenyl)(4-phenylpyrimidin-2-yl)amino)methyl)-7,8-difluoroquinolin-

2(lH)-one

4-(((3-Chlorophenyl)(2-methylpyrimidin-4-yl)amino)methyl)-7,8-difluoroquinolin- 2(lH)-one was synthesized as described in EXAMPLE 2 using 4-chloro-2- phenylpyrimidine in Step 1 and N-(3-chlorophenyl)-2-phenylpyrimidin-4-amine in step 2. ¹HNMR (400MHz, DMSO-d₆) δ 11.99 (s, IH), 8.37 (d, IH), 8.18-8.14 (m, 3H), 7.78-7.71 (m, IH), 7.67-7.65 (m, IH), 7.57-7.38 (m, 5H), 7.33-7.26 (m, IH), 6.55 (d, IH), 6.39 (s, IH), 5.60 (s, 2H). LCMS: 475.23 (M+H)⁺.

EXAMPLE 60

4-(((3-Chlorophenyl)(thieno[3,2-d]pyrimidin-4-yl)amino)methyl)-7,8- difluoroquinolin-2(lH)-one

4-(((3-Chlorophenyl)(thieno[3,2-d]pyrimidin-4-yl)amino)methyl)-7,8-difluoroquinolin- 2(lH)-one was synthesized as described in EXAMPLE 2 using 4-chlorothieno[3,2- d]pyrimidine in Step 1 and N-(3-chlorophenyl)thieno[3,2-d]pyrimidin-4-amine in step 2. ¹HNMR (400MHz, DMSO-d₆) δ 11.97 (s, IH), 8.57 (s, IH), 7.73-7.68 (m, IH), 7.62 (s, IH), 7.48-7.43 (m, 3H), 7.40-7.35 (m, IH), 7.34-7.24 (m, IH), 6.35 (s, IH), 5.74 (d, IH), 5.59 (s, 2H). LCMS: 455.13 (M+H)⁺.

EXAMPLE 61

4-(((3-Chlorophenyl)(2-(dimethylamino)pyrimidin-4-yl)amino)methyl)-7,8- difluoroquinolin-2(lH)-one

Step 1 : 2-Chloro-N-(3-chlorophenyl)pyrimidin-4-amine

2-Chloro-N-(3-chlorophenyl)pyrimidin-4-amine was synthesized as described in EXAMPLE 2, Step 1 using 2,4-dichloropyrimidine as a starting material. LCMS: 240 (M+H)⁺.

Step 2: N4-(3-Chlorophenyl)-N2,N2-dimethylpyrimidine-2,4-diamine

N4-(3-Chlorophenyl)-N2,N2-dimethylpyrimidine-2,4-diamine was synthesized as described in EXAMPLE 4, Step 1 using 2-chloro-N-(3-chlorophenyl)pyrimidin-4- amine as a starting material. LCMS: 249 (M+H)⁺. Step 3 : 4-(((3-Chlorophenyl)(2-(dimethylamino)pyrimidin-4-yl)amino)methyl)- 7,8-difluoroquinolin-2(lH)-one

4-(((3-Chlorophenyl)(2-(dimethylamino)pyrimidin-4-yl)amino)methyl)-7,8- difluoroquinolin-2(lH)-one was synthesized as described in EXAMPLE 1, Step 2 using N⁴-(3-chlorophenyl)- N², N²,-dimethylpyrimidine-2,4-diamine as a starting material. ¹HNMR (400MHz, CD₃OD ) δ 7.74 (d, IH), 7.70-7.64 (m, IH), 7.56-7.48 (m, 3H), 7.36-7.31 (m, IH), 7.24-7.16 (m, IH), 6.52 (s, IH), 6.08-6.00 (m, IH), 5.54 (s, 2H), 3.14 (s,6H). LCMS: 442.83 (M+H)⁺.

EXAMPLE 62

4-(((3-Chlorophenyl)(2-isopropylquinazolin-4-yl)amino)methyl)-7,8- difluoroquinolin-2(lH)-one

4-(((3-Chlorophenyl)(2-isopropylquinazolin-4-yl)amino)methyl)-7,8-difluoroquinolin- 2(lH)-one was synthesized as described in EXAMPLE 2 using 4-chloro-2- isopropylquinazoline in Step 1 and N-(3-chlorophenyl)-2-isopropylquinazolin-4-amine in step 2. ¹HNMR (400MHz, CD₃OD) δ 7.86-7.81 (m, 2H), 7.76-7.68 (m, 2H), 7.42- 7.35 (m, 3H), 7.28-7.20 (m, 3H), 6.62 (s, IH), 5.72 (s, 2H), 3.09-3.03 (m, IH), 1.15 (d, 6H). LCMS: 491.25. (M+H)⁺. EXAMPLE 63

4-(((3-Chlorophenyl)(l-methyl-lH-imidazol-2-yl)amino)methyl)-7,8- difluoroquinolin-2(lH)-one

4-(((3-Chlorophenyl)(l -methyl- lH-imidazol-2-yl)amino)methyl)-7,8-difluoroquinolin- 2(lH)-one was synthesized as described in EXAMPLE 2 using 2-bromo-l -methyl- IH- imidazole in Step 1 and N-(3-chlorophenyl)-l -methyl- lH-imidazol-2-amine in Step 2. ¹H NMR (400 MHz, DMSO-d₆) δ 12.04 (br s, IH), 7.62-7.50 (m, IH), 7.51 (d, IH), 7.40-7.29 (m, 3H), 7.07 (dd, IH), 6.93 (s, IH), 6.74 (dd, IH), 6.52 (s, IH), 5.33 (s, 2H), 3.50 (s, 3H). LCMS: 401.3 (M+H)⁺.

EXAMPLE 64

4-(((3-Chlorophenyl)(l,5-dimethyl-lH-imidazol-2-yl)amino)methyl)-7,8- difluoroquinolin-2(lH)-one

4-(((3-Chlorophenyl)(l,5-dimethyl-lH-imidazol-2-yl)amino)methyl)-7,8- difluoroquinolin-2(lH)-one was synthesized as described in EXAMPLE 2 using 2- bromo-l,5-dimethyl-lH-imidazole in Step 1 and N-(3-chlorophenyl)-l,5-dimethyl-lH- imidazol-2-amine in Step 2. ¹U NMR (400 MHz, CD₃OD) δ 7.64 (ddd, IH), 7.24-7.16 (m, 2H), 6.91 (dd, IH), 6.71 (s, IH), 6.68 (s, IH), 6.60-6.57 (m, IH), 6.56-6.53 (m, IH), 5.18 (s, 2H), 4.87 (s, 3H), 2.21 (s, 3H). LCMS: 415.2 (M+H)⁺. EXAMPLE 65

4-(((3-Chlorophenyl)(l,4-dimethyl-lH-imidazol-2-yl)amino)methyl)-7,8- difluoroquinolin-2(lH)-one

4-(((3-Chlorophenyl)(l,4-dimethyl-lH-imidazol-2-yl)amino)methyl)-7,8- difluoroquinolin-2(lH)-one was synthesized as described in EXAMPLE 2 using 2- bromo-l,4-dimethyl-lH-imidazole in Step 1 and N-(3-chlorophenyl)-l,4-dimethyl-lH- imidazol-2-amine in Step 2. ¹H NMR (400 MHz, DMSO-d₆) δ 12.06 (br s, IH), 7.58 (dd, IH), 7.37-7.27 (m, 3H), 7.10 (d, IH), 6.98 (s, IH), 6.79 (d, IH), 6.46 (s, IH), 5.34 (s, 2H), 3.46 (s, 3H), 2.19 (s, 3H). LCMS: 415.1 (M+H)⁺.

EXAMPLE 66

4-(((3-Chlorophenyl)(4-(pyrrolidin-l-yl)pyrimidin-2-yl)amino)methyl)-7,8- difluoroquinolin-2(lH)-one

Step 1 : 2-chloro-4-(pyrrolidin-l-yl)pyrimidine

Pyrrolidine (600 μL, 7.31 mmol) and 2,4-dichloropyrimidine (1.0 g, 6.71 mmol) were mixed in THF (20 rnL). The reaction mixture was stirred at RT for 3h then dry loaded on silica gel and purified by flash chromatography (SiO₂, gradient eluent 0-50% ethyl acetate in hexanes) to afford 2-chloro-4-(pyrrolidin-l-yl)pyrimidine as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 7.99 (d, IH), 6.46 (d, IH), 3.43 (t, 2H), 3.32 (t, 2H), 2.0-1.84 (m, 4H). LCMS: 184.1 (M+H)⁺.

Step 2: 4-(((3-Chlorophenyl)(4-(pyrrolidin-l-yl)pyrimidin-2-yl)amino)methyl)- 7,8-difluoroquinolin-2(lH)-one

4-(((3-Chlorophenyl)(4-(pyrrolidin-l-yl)pyrimidin-2-yl)amino)methyl)-7,8- difluoroquinolin-2(lH)-one was synthesized as described in EXAMPLE 2 using 2- chloro-4-(pyrrolidin-l-yl)pyrimidine in Step 1 and N-(3-chlorophenyl)-4-(pyrrolidin-l- yl)pyrimidin-2-amine in Step 2. ¹H NMR (400 MHz, DMSO-d₆) δ 12.01 (br s, IH), 7.74-7.71 (m, 2H), 7.66-7.63 (m, IH), 7.53-7.43 (m, 3H), 7.33-7.26 (m, IH), 6.50 (s, IH), 6.36 (d, IH), 5.43 (s, 2H), 3.56-3.48 (m, 2H), 3.38-3.34 (m, 2H), 1.98-1.90 (m, 2H), 1.86-1.78 (m, 2H). LCMS: 468.2 (M+H)⁺.

EXAMPLE 67

4-(((3-Chlorophenyl)(4-(piperidin-l-yl)pyrimidin-2-yl)amino)methyl)-7,8- difluoroquinolin-2(lH)-one

4-(((3-Chlorophenyl)(4-(piperidin-l-yl)pyrimidin-2-yl)amino)methyl)-7,8- difluoroquinolin-2(lH)-one was synthesized as described in EXAMPLE 66 using piperidine in Step 1 and N-(3-chlorophenyl)-4-(piperidin-l-yl)pyrimidin-2-amine in Step 2. ¹H NMR (400 MHz, DMSO-d₆) δ 11.99 (br s, IH), 7.75 (d, IH), 7.72 (s, IH), 7.66-7.63 (m, IH), 7.51-7.43 (m, 3H), 7.32-7.26 (m, IH), 6.63 (d, IH), 6.50 (s, IH), 5.39 (s, 2H), 3.64-3.56 (m, 4H), 1.66-1.38 (m, 6H), 1.98-1.90 (m, 2H), 1.86-1.78 (m, 2H). LCMS: 482.2 (M+H)⁺.

EXAMPLE 68

4-(((3-chlorophenyl)(l-methyl-lH-pyrazolo[3,4-d]pyrimidin-4-yl)amino)methyl)-

7,8-difluoroquinolin-2(lH)-one

4-(((3-chlorophenyl)(l-methyl-lH-pyrazolo[3,4-d]pyrimidin-4-yl)amino)methyl)-7,8- difluoroquinolin-2(lH)-one was synthesized as described in EXAMPLE 1 using 4- chloro-1 -methyl- lH-pyrazolo [3, 4-d]pyrimidine in Step 1 and N-(3-chlorophenyl)-l- methyl- lH-pyrazolo [3, 4-d]pyrimidin-4-amine in Step 2. ¹H NMR (400 MHz, CD₃OD) δ 8.49 (s, IH), 7.81 (ddd, IH), 7.60-7.52 (m, 3H), 7.36-7.32 (m, IH), 7.21-7.14 (m, IH), 6.51 (s, IH), 6.11 (s, IH), 5.66 (s, 2H), 3.95 (s, 3H). LCMS: 453.2 (M+H)⁺.

EXAMPLE 69 4-(((3-Chlorophenyl)(pyrimidin-4-yl)amino)methyl)-8-fluoroquinolin-2(lH)-one

4-(((3-Chlorophenyl)(pyrimidin-4-yl)amino)methyl)-8-fluoroquinolin-2(lH)-one was synthesized as described in EXAMPLE 1, Step 2 using N-(3-chlorophenyl)pyrimidin- 4-amine and 4-(bromomethyl)-8-fluoroquinolin-2(lH)-one (INTERMEDIATE 5) as starting materials. ¹H NMR (400 MHz, CD₃OD) δ 8.93 (s, IH), 8.28 (d, IH), 7.63- 7.52 (m, 4H), 7.45-7.37 (m, 2H), 7.29-7.23 (m, IH), 6.78 (d, IH), 6.58 (s, IH), 5.68 (s, 2H). LCMS: 381.1 (M+H)⁺.

EXAMPLE 70 4-(((3-Chlorophenyl)(pyrimidin-4-yl)amino)methyl)quinolin-2(lH)-one

4-(((3 -Chlorophenyl)(pyrimidin-4-yl)amino)methyl)quinolin-2( 1 H)-one was synthesized as described in EXAMPLE 1, Step 2 using N-(3-chlorophenyl)pyrimidin- 4-amine and 4-(bromomethyl)quinolin-2(lH)-one (INTERMEDIATE 8) as starting materials. ¹H NMR (400 MHz, CD₃OD) δ 8.95 (s, IH), 8.28 (d, IH), 7.81 (d, IH), 7.62-7.53 (m, 3H), 7.41-7.36 (m, 2H), 7.32-7.28 (t, IH), 6.79 (d, IH), 6.54 (s, IH), 5.70 (s, 2H). LCMS: 363.1 (M+H)⁺.

EXAMPLE 71

4-(((3-Chlorophenyl)(l-methyl-lH-pyrazolo[3,4-d]pyrimidin-4-yl)amino)methyl)-

8-fluoroquinolin-2(lH)-one

4-(((3-Chlorophenyl)(l -methyl- lH-pyrazolo[3,4-d]pyrimidin-4-yl)amino)methyl)-8- fluoroquinolin-2(lH)-one was synthesized as described in EXAMPLE 2 using 4- chloro-1 -methyl- lH-pyrazolo [3, 4-d]pyrimidine in Step 1 and N-(3-chlorophenyl)-l- methyl-lH-pyrazolo[3,4-d]pyrimidin-4-amine and 4-(bromomethyl)-8-fluoroquinolin- 2(lH)-one (INTERMEDIATE 5) as starting materials in Step 2. ¹U NMR (400 MHz, DMSO-de) δ 11.74 (s, IH), 8.48 (s, IH), 7.68-7.66 (m, 2H), 7.59-7.52 (m, 2H), 7.46- 7.37 (m, 2H), 7.20-7.15 (m, IH), 6.41 (s, IH), 6.07 (s, IH), 5.59 (s, 2H), 3.88 (s, 3H). LCMS: 435.2 (M+H)⁺.

EXAMPLE 72

4-(((3-Chlorophenyl)(l-methyl-lH-pyrazolo[3,4-d]pyrimidin-4- yl)amino)methyl)quinolin-2(lH)-one

4-(((3 -Chlorophenyl)( 1 -methyl- 1 H-pyrazolo [3 ,4-d]pyrimidin-4- yl)amino)methyl)quinolin-2(lH)-one was synthesized as described in EXAMPLE 2 using 4-chloro-l -methyl- 1 H-pyrazolo [3, 4-d]pyrimidine in Step 1 and N-(3- chlorophenyl)- 1 -methyl- 1 H-pyrazolo [3 ,4-d]pyrimidin-4-amine and 4- (bromomethyl)quinolin-2(lH)-one (INTERMEDIATE 8) as starting materials in Step 2. ¹H NMR (400 MHz, DMSO-d₆) δ 11.72 (s, IH), 8.47 (s, IH), 7.84 (d, IH), 7.64 (t, IH), 7.59-7.49 (m, 3H), 7.40-7.37 (m, IH), 7.31 (d, IH), 7.17 (t, IH), 6.33 (s, IH), 6.08 (s, IH), 5.59 (s, 2H). LCMS: 417.2 (M+H)⁺.

EXAMPLE 73 7,8-Difluoro-4-((furo[3,2-c]pyridin-4-yl(phenyl)amino)methyl)quinolin-2(lH)-one

Step 1 : N-((7,8-Difluoro-2-methoxyquinolin-4-yl)methyl)aniline

4-(Bromomethyl)-7,8-difluoro-2-methoxyquinoline (INTERMEDIATE 4, 410 mg, 1.42 mmol) and aniline (300 μL, 3.29 mmol) were dissolved in DMSO (15 mL) and stirred at 50 ⁰C overnight. The crude reaction mixture was poured into H₂O and the desired product precipitated. The precipitate was filtered and washed with H₂O to afford N-((7,8-difluoro-2-methoxyquinolin-4-yl)methyl)aniline as an off-white solid. LCMS: 301.5 (M+H)+. Step 2: N-((7,8-Difluoro-2-methoxyquinolin-4-yl)methyl)-N-phenylfuro[3,2- c] pyridin-4-amine

N-((7,8-Difluoro-2-methoxyquinolin-4-yl)methyl)aniline (63 mg, 0.209 mmol), 4- chlorofuro[3,2-c]pyridine (38 mg, 0.247 mmol), 2-dicyclohexylphosphino-2',4',6'- triisopropylbiphenyl (18 mg, 0.038 mmol), Pd₂(dba)₃ (11 mg, 0.019 mmol), and NaOtBu (34 mg, 0.354 mmol) were mixed in freshly degassed toluene (2.5 mL) and heated in a microwave reactor to 15O⁰C for 10 min. The crude mixture was then dry loaded on silica gel and the desired product was purified by flash chromatography to afford N-((7,8-difluoro-2-methoxyquinolin-4-yl)methyl)-N-phenylfuro[3,2-c]pyridin- 4-amine as an off-white residue. ¹H NMR (400 MHz, CD₃OD) δ 8.00 (d, IH), 7.92 (ddd, IH), 7.43-7.22 (m, 7H), 7.03 (dd, IH), 6.85 (s, IH), 5.74 (s, 2H), 5.27-5.25 (m, IH), 3.99 (s, 3H). LCMS: 418.6 (M+H)⁺.

Step 3 : 7,8-Difluoro-4-((furo [3,2-c] pyridin-4-yl(phenyl)amino)methyl)quinolin- 2(lH)-one

N-((7,8-Difluoro-2-methoxyquinolin-4-yl)methyl)-N-phenylfuro[3,2-c]pyridin-4- amine (60 mg, 0.143 mmol) was stirred in a solution of THF (1 mL), cHCl (500 μL) and water (500 μL) overnight at 60 ⁰C. The desired product was purified by HPLC (semi preparative) to afford 7,8-difluoro-4-((furo[3,2-c]pyridin-4- yl(phenyl)amino)methyl)quinolin-2(lH)-one as a white solid. ¹H NMR (400 MHz, CD₃OD) δ 7.94 (d, IH), 7.73 (d, IH), 7.69 (ddd, IH), 7.59-7.52 (m, 5H), 7.39-7.37 (m, IH), 7.27-7.20 (m, IH), 6.69 (s, IH), 5.67 (s, 2H), 5.38-5.37 (m, IH). LCMS: 404.6 (M+H)⁺.

EXAMPLE 74 7,8-Difluoro-4-((phenyl(quinazolin-4-yl)amino)methyl)quinolin-2(lH)-one

7,8-Difluoro-4-((phenyl(quinazolin-4-yl)amino)methyl)quinolin-2(lH)-one was synthesized as described in EXAMPLE 73 using 4-chloroquinazoline in Step 2 and N- ((7,8-difluoro-2-methoxyquinolin-4-yl)methyl)-N-phenylquinazolin-4-amine in Step 3. ¹H NMR (400 MHz, CD₃OD) δ 8.93 (s, IH), 7.98-7.94 (m, IH), 7.85 (d, IH), 7.70 (ddd, IH), 7.59-7.55 (m, 5H), 7.37-7.32 (m, IH), 7.24-7.17 (m, IH), 7.02 (d, IH), 6.64 (s, IH), 5.91 (s, 2H). LCMS: 415.5 (M+H)⁺.

EXAMPLE 75 4-((Benzyl(6-chloropyrimidin-4-yl)amino)methyl)-7,8-difluoroquinolin-2(lH)-one

4-((Benzyl(6-chloropyrimidin-4-yl)amino)methyl)-7,8-difluoroquinolin-2( 1 H)-one was synthesized as described in EXAMPLE 2 using 4,6-dichloropyrimidine and phenylmethanamine as starting materials in Step 1 and N-benzyl-6-chloropyrimidin-4- amine in Step 2. LCMS: 413 (M+H)⁺.

EXAMPLE 76

4-((Benzyl(6-methoxypyrimidin-4-yl)amino)methyl)-7,8-difluoroquinolin-2(lH)- one

4-((Benzyl(6-methoxypyrimidin-4-yl)amino)methyl)-7,8-difluoroquinolin-2(lH)-one was synthesized as a byproduct (due to the MeOH work-up) as described in EXAMPLE 2 using 4,6-dichloropyrimidine and phenylmethanamine as starting materials in Step 1 and N-benzyl-6-chloropyrimidin-4-amine in Step 2. ¹H NMR (400 MHz, DMSO-de) δ 11.95 (s, IH), 8.29 (s, IH), 7.65-7.62 (m, IH), 7.33-7.21 (m, 6H), 6.01 (s, IH), 5.94 (s, IH), 5.06 (s, 2H), 4.82 (s, 2H), 3.78 (s, 3H). LCMS: 409 (M+H)⁺.

EXAMPLE 77 4-((Benzyl(pyrimidin-4-yl)amino)methyl)-7,8-difluoroquinolin-2(lH)-one

4-((benzyl(pyrimidin-4-yl)amino)methyl)-7,8-difluoroquinolin-2(lH)-one was synthesized as described in EXAMPLE 35, Step 2 using 4-((benzyl(6-chloropyrimidin- 4-yl)amino)methyl)-7,8-difluoroquinolin-2(lH)-one as a starting material. ¹H NMR (400 MHz, DMSO-de) δ 11.95 (s, IH), 8.53 (s, IH), 8.18 (d, IH), 7.67-7.64 (m, IH), 7.34-7.23 (m, 6H), 6.70 (s, IH), 6.01 (s, IH), 5.07 (s, 2H), 4.86 (s, 2H). LCMS: 379 (M+H)⁺.

EXAMPLE 78 7,8-Difluoro-4-(((2-methylbenzyl)(pyrazin-2-yl)amino)methyl)quinolin-2(lH)-one

7,8-Difluoro-4-(((2-methylbenzyl)(pyrazin-2-yl)amino)methyl)quinolin-2(lH)-one was synthesized as described in EXAMPLE 2 using 2-chloropyrazine and o- tolylmethanamine as starting materials in Step 1 and N-(2-methylbenzyl)pyrazin-2- amine in Step 2. ¹H NMR (400 MHz, DMSO-d₆) δ 11.95 (s, IH), 8.06 (m, IH), 7.97 (s, IH), 7.84 (d, IH), 7.66-7.63 (m, IH), 7.27-7.07 (m, 4H), 6.99 (d, IH), 6.16 (s, IH), 5.07 (s, 2H), 4.85 (s, 2H), 2.28 (s, 3H). LCMS: 393 (M+H)⁺.

EXAMPLE 79 7,8-Difluoro-4-(((3-methylbenzyl)(pyrazin-2-yl)amino)methyl)quinolin-2(lH)-one

7,8-Difluoro-4-(((3-methylbenzyl)(pyrazin-2-yl)amino)methyl)quinolin-2(lH)-one was synthesized as described in EXAMPLE 2 using 2-chloropyrazine and m- tolylmethanamine as starting materials in Step 1 and N-(3-methylbenzyl)pyrazin-2- amine in Step 2. ¹H NMR (400 MHz, DMSO-d₆) δ 11.95 (s, IH), 8.07-8.06 (m, 2H), 7.84 (d, IH), 7.68-7.65 (m, IH), 7.28-7.18 (m, 2H), 7.09-7.04 (m, 3H), 6.09 (s, IH), 5.09 (s, 2H), 4.85 (s, 2H), 2.24 (s, 3H). LCMS: 393 (M+H)⁺.

EXAMPLE 80 7,8-Difluoro-4-(((4-methylbenzyl)(pyrazin-2-yl)amino)methyl)quinolin-2(lH)-one

7,8-Difluoro-4-(((4-methylbenzyl)(pyrazin-2-yl)amino)methyl)quinolin-2(lH)-one was synthesized as described in EXAMPLE 2 using 2-chloropyrazine and p- tolylmethanamine as starting materials in Step 1 and N-(4-methylbenzyl)pyrazin-2- amine in Step 2. ¹U NMR (400 MHz, DMSO-d₆) δ 11.96 (s, IH), 8.06 (m, 2H), 7.83 (m, IH), 7.65 (m, IH), 7.26-7.11 (m, 5H), 6.08 (s, IH), 5.07 (s, 2H), 4.84 (s, 2H), 2.25 (s, 3H). LCMS: 393 (M+H)⁺.

EXAMPLE 81

4-(((6-Chloropyrimidin-4-yl)(pyridin-2-ylmethyl)amino)methyl)-7,8- difluoroquinolin-2(lH)-one

Step 1 : 6-Chloro-N-(pyridin-2-ylmethyl)pyrimidin-4-amine

A mixture of 4,6-dichloropyrimidine (2 g, 13.4 mmol), pyridin-2-ylmethanamine (I g, 8.9 mmol), and Et3N (2.6 mL, 17.9 mmol) in NMP (15 mL) was stirred at RT for Ih. The reaction mixture was poured into EtOAc and the organic layer was washed with brine (3x), dried, and evaporated to dryness. The residue was purified by flash chromatography on silica gel (eluting with 50 to 100% EtOAc/Hexanes) to afford 6- chloro-N-(pyridin-2-ylmethyl)pyrimidin-4-amine as a white solid. LCMS: 221 (M+H)+.

Step 2: 4-(((6-Chloropyrimidin-4-yl)(pyridin-2-ylmethyl)amino)methyl)-7,8- difluoroquinolin-2(lH)-one

4-(((6-Chloropyrimidin-4-yl)(pyridin-2-ylmethyl)amino)methyl)-7,8-difluoroquinolin- 2(lH)-one was synthesized as described in EXAMPLE 1, Step 2 using 6-chloro-N- (pyridin-2-ylmethyl)pyrimidin-4-amine as a starting material. LCMS: 414 (M+H)⁺.

EXAMPLE 82

7,8-Difluoro-4-(((pyridin-2-ylmethyl)(pyrimidin-4-yl)amino)methyl)quinolin-

2(lH)-one

7,8-Difluoro-4-(((pyridin-2-ylmethyl)(pyrimidin-4-yl)amino)methyl)quinolin-2(lH)- one was synthesized as described in EXAMPLE 35, Step 2 using 4-(((6- chloropyrimidin-4-yl)(pyridin-2-ylmethyl)amino)methyl)-7,8-difluoroquinolin-2(lH)- one as a starting material. ¹H NMR (400 MHz, DMSO-d₆) δ 11.96 (s, IH), 8.50 (m, 2H), 8.18 (d, IH), 7.73 (td, IH), 7.66-7.63 (m, IH), 7.33-7.25 (m, 3H), 6.75 (s, IH), 6.09 (s, IH), 5.14 (s, 2H), 4.90 (s, 2H). LCMS: 380 (M+H)⁺.

EXAMPLE 83

4-(((6-Chloropyrimidin-4-yl)(pyridin-4-ylmethyl)amino)methyl)-7,8- difluoroquinolin-2(lH)-one

4-(((6-Chloropyrimidin-4-yl)(pyridin-4-ylmethyl)amino)methyl)-7,8-difluoroquinolin- 2(lH)-one was synthesized as described in EXAMPLE 81 using pyridin-4- ylmethanamine in Step 1 and 6-chloro-N-(pyridin-4-ylmethyl)pyrimidin-4-amine in Step 2. LCMS: 414 (M+H)⁺.

EXAMPLE 84

4-(((6-Chloro-2-methylpyrimidin-4-yl)(pyridin-4-ylmethyl)amino)methyl)-7,8- difluoroquinolin-2(lH)-one

4-(((6-Chloro-2-methylpyrimidin-4-yl)(pyridin-4-ylmethyl)amino)methyl)-7,8- difluoroquinolin-2(lH)-one was synthesized as described as described in EXAMPLE 81 using pyridin-4-ylmethanamine and 4,6-dichloro-2-methylpyrimidine in Step 1 and 6-chloro-2-methyl-N-(pyridin-4-ylmethyl)pyrimidin-4-amine in Step 2. LCMS: 428 (M+H)⁺.

EXAMPLE 85

7,8-Difluoro-4-(((2-methylpyrimidin-4-yl)(pyridin-4- ylmethyl)amino)methyl)quinolin-2(lH)-one

7,8-Difluoro-4-(((2-methylpyrimidin-4-yl)(pyridin-4-ylmethyl)amino)methyl)quinolin- 2(lH)-one was synthesized as described in EXAMPLE 35, Step 2 using 4-(((6-chloro- 2-methylpyrimidin-4-yl)(pyridin-4-ylmethyl)amino)methyl)-7,8-difluoroquinolin- 2(lH)-one as a starting material. LCMS: 394 (M+H)⁺.

EXAMPLE 86

4-(((6-Chloro-2-methylpyrimidin-4-yl)(pyridin-2-ylmethyl)amino)methyl)-7,8- difluoroquinolin-2(lH)-one

4-(((6-Chloro-2-methylpyrimidin-4-yl)(pyridin-2-ylmethyl)amino)methyl)-7,8- difluoroquinolin-2(lH)-one was synthesized as described as described in EXAMPLE 81 using pyridin-2-ylmethanamine and 4,6-dichloro-2-methylpyrimidine in Step 1 and 6-chloro-2-methyl-N-(pyridin-2-ylmethyl)pyrimidin-4-amine in Step 2. LCMS: 428 (M+H)⁺. EXAMPLE 87

7,8-Difluoro-4-(((2-methylpyrimidin-4-yl)(pyridin-2- ylmethyl)amino)methyl)quinolin-2(lH)-one

7,8-Difluoro-4-(((2-methylpyrimidin-4-yl)(pyridin-2-ylmethyl)amino)methyl)quinolin- 2(lH)-one was synthesized as described in EXAMPLE 35, Step 2 using 4-(((6-chloro- 2-methylpyrimidin-4-yl)(pyridin-2-ylmethyl)amino)methyl)-7,8-difluoroquinolin- 2(lH)-one as a starting material. ¹U NMR (400 MHz, DMSO-d₆) δ 11.95 (s, IH), 8.48 (d, IH), 8.07 (d, IH), 7.73 (td, IH), 7.66 (m, IH), 7.30-7.24 (m, 3H), 6.52 (s, IH), 6.09 (s, IH), 5.13 (s, 2H), 4.87 (s, 2H), 2.33 (s, 3H). LCMS: 394 (M+H)⁺.

EXAMPLE 88

7,8-Difluoro-4-(((6-methoxy-2-methylpyrimidin-4-yl)(pyridin-2- ylmethyl)amino)methyl)quinolin-2(lH)-one

7,8-Difluoro-4-(((6-methoxy-2-methylpyrimidin-4-yl)(pyridin-2- ylmethyl)amino)methyl)quinolin-2(lH)-one was synthesized as described in EXAMPLE 39, Step 1 using 4-(((6-chloro-2-methylpyrimidin-4-yl)(pyridin-2- ylmethyl)amino)methyl)-7,8-difluoroquinolin-2(lH)-one as a starting material. LCMS: 424 (M+H)⁺. EXAMPLE 89

4-(((6-(Dimethylamino)-2-methylpyrimidin-4-yl)(pyridin-2- ylmethyl)amino)methyl)-7,8-difluoroquinolin-2(lH)-one

4-(((6-(Dimethylamino)-2-methylpyrimidin-4-yl)(pyridin-2-ylmethyl)amino)methyl)- 7,8-difluoroquinolin-2(lH)-one was synthesized as described in EXAMPLE 4, Step 1 using 4-(((6-chloro-2-methylpyrimidin-4-yl)(pyridin-2-ylmethyl)amino)methyl)-7,8- difluoroquinolin-2(lH)-one as a starting material. LCMS: 437 (M+H)⁺.

EXAMPLE 90 7,8-Difluoro-4-((phenethyl(pyrazin-2-yl)amino)methyl)quinolin-2(lH)-one

7,8-Difluoro-4-((phenethyl(pyrazin-2-yl)amino)methyl)quinolin-2(lH)-one was synthesized as described in EXAMPLE 2 using 2-chloropyrazine and 2- phenylethanamine as starting materials in Step 1 and N-phenethylpyrazin-2-amine in Step 2. ¹H NMR (400 MHz, DMSO-d₆) δ 11.94 (s, IH), 8.15 (s, IH), 8.04 (s, IH), 7.81 (d, IH), 7.61-7.58 (m, IH), 7.33-7.24 (m, 5H), 7.20-7.16 (m, IH), 6.04 (s, IH), 4.98 (s, 2H), 3.78 (t, 2H), 2.93 (t, 2H). LCMS: 393 (M+H)⁺. EXAMPLE 91

7,8-Difluoro-4-(((2-fluorobenzyl)(l-methyl-lH-pyrazolo[3,4-d]pyrimidin-4- yl)amino)methyl) quinolin-2(lH)-one

7,8-Difluoro-4-(((2-fluorobenzyl)( 1 -methyl- 1 H-pyrazolo[3 ,4-d]pyrimidin-4- yl)amino)methyl)quinolin-2(lH)-one was synthesized as described in EXAMPLE 2 using (2-fluorophenyl)methanamine and 4-chloro- 1 -methyl- lH-pyrazo Io [3,4- d]pyrimidine in Step 1 and N-(2-fluorobenzyl)-l-methyl-lH-pyrazolo[3,4-d]pyrimidin- 4-amine in Step 2. ¹HNMR (400MHz, MeOH) δ 8.43 (s, IH), 7.70-7.66 (m, 2H), 7.34- 7.29 (m, 2H), 7.24-7.07 (m, 3H), 6.31 (s, IH), 5.39 (s, 2H), 5.28 (s, 2H), 3.97 (s, 3H). LCMS: 451.23 (M+H)⁺.

EXAMPLE 92

7,8-Difluoro-4-(((2-fluor obenzyl)(thieno [2,3-d] pyrimidin-4- yl)amino)methyl)quinolin-2(lH)-one

7,8-Difluoro-4-(((2-fluorobenzyl)(thieno[2,3-d]pyrimidin-4-yl)amino)methyl)quinolin- 2(lH)-one was synthesized as described in EXAMPLE 2 using (2- fluorophenyl)methanamine and 4-chlorothieno[2,3-d]pyrimidine in Step 1 and N-(2- fluorobenzyl)thieno[2,3-d]pyrimidin-4-amine in Step 2. ¹HNMR (400MHz, DMSO- d₆) δ 11.96 (s, IH), 8.43 (s, IH), 7.68-7.65 (m, IH), 7.49 (d, IH), 7.35-7.20 (m, 4H), 7.15-7.12 (m, IH), 6.99-6.90 (m, IH), 6.28 (s, IH), 5.28 (s, 2H), 5.18 (s, 2H). LCMS: 453.18 (M+H)⁺.

EXAMPLE 93

7,8-Difluoro-4-(((2-fluorobenzyl)(thieno [3,2-d] pyrimidin-4- yl)amino)methyl)quinolin-2(lH)-one

7,8-Difluoro-4-(((2-fluorobenzyl)(thieno[3,2-d]pyrimidin-4-yl)amino)methyl)quinolin- 2(lH)-one was synthesized as described in EXAMPLE 2 using (2- fluorophenyl)methanamine and 4-chlorothieno[3,2-d]pyrimidine in Step 1 and N-(2- fluorobenzyl)thieno[3,2-d]pyrimidin-4-amine in Step 2. ¹HNMR (400MHz, CD₃OD) δ 8.82 (s, IH), 8.38 (d,lH), 7.69-7.65 (m, IH), 7.52 (d, IH), 7.45 (t, IH), 7.39-7.34 (m, IH), 7.26-7.14 (m, 3H), 6.38 (s, IH), 5.59 (s, 2H), 5.49 (s, 2H). LCMS: 453.18 (M+H)⁺.

EXAMPLE 94

7,8-Difluoro-4-(((l-methyl-lH-pyrazolo[3,4-d]pyrimidin-4-yl)(pyridin-2- ylmethyl)amino)methyl) quinolin-2(lH)-one

7, 8-Difluoro-4-(((l -methyl- lH-pyrazolo[3,4-d]pyrimidin-4-yl)(pyridin-2- ylmethyl)amino)methyl)quinolin-2(lH)-one was synthesized as described in EXAMPLE 2 using pyridin-2-ylmethanamine and 4-chloro- 1 -methyl- 1 H-pyrazolo [3, 4- d]pyrimidine in Step 1 and l-methyl-N-(pyridin-2-ylmethyl)-l H-pyrazolo [3, 4- d]pyrimidin-4-amine in Step 2. ¹HNMR (400MHz, DMSO-d₆) δ 8.97 (s, IH), 8.52- 8.51 (m, IH), 8.31 (s, IH), 7.77-7.23 (m, 2H), 7.49-7.23 (m, 3H), 6.22 (s, IH), 5.37 (s, 2H), 5.21 (s, 2H) 3.87 (s, 3H). LCMS: 434.53 (M+H)⁺.

EXAMPLE 95

8-Fluoro-4-(((l-methyl-lH-pyrazolo[3,4-d]pyrimidin-4-yl)(2- methylbenzyl)amino)methyl)quinolin-2(lH)-one

8-Fluoro-4-((( 1 -methyl- 1 H-pyrazolo [3 ,4-d]pyrimidin-4-yl)(2- methylbenzyl)amino)methyl)quinolin-2(lH)-one was synthesized as described in EXAMPLE 2 using o-tolylmethanamine and 4-chloro- 1 -methyl- 1 H-pyrazolo [3, 4- d]pyrimidine in Step 1 and l-methyl-N-(2-methylbenzyl)-l H-pyrazolo [3,4- d]pyrimidin-4-amine and 4-(bromomethyl)-8-fluoroquinolin-2( 1 H)-one (INTERMEDIATE 5) in Step 2. ¹HNMR (400MHz, DMSO-d₆) δ 8.32 (s, IH), 7.70- 7.60 (m, IH), 7.50-7.35 (m, 2H), 7.30-6.90 (m, 5H), 6.24 (s, IH), 5.28 (s, 2H), 5.10 (s, 2H), 3.86 (s, 3H), 2.32 (s, 3H). LCMS: 429.55. (M+H)⁺.

EXAMPLE 96 7,8-Difluoro-4-((isobutyl(pyrazin-2-yl)amino)methyl)quinolin-2(lH)-one

7,8-Difluoro-4-((isobutyl(pyrazin-2-yl)amino)methyl)quinolin-2(lH)-one was synthesized as described in EXAMPLE 2 using 2-methylpropan-l -amine and 2- chloropyrazine in Step 1 and N-isobutylpyrazin-2-amine in Step 2. ¹H NMR (400 MHz, DMSO-d₆) δ 11.95 (s, IH), 9.18 (d, IH), 8.02 (m, IH), 7.79 (d, IH), 7.68 (m, IH), 7.29 (m, IH), 5.92 (s, IH), 5.00 (s, 2H), 3.44 (d, 2H), 2.10 (m, IH), 0.93 (m, 6H). LCMS: 345 (M+H)⁺.

EXAMPLE 97 4-((Benzyl(pyrazin-2-yl)amino)methyl)-7,8-difluoroquinolin-2(lH)-one

4-((Benzyl(pyrazin-2-yl)amino)methyl)-7,8-difluoroquinolin-2(lH)-one was synthesized as described in EXAMPLE 2 using phenylmethanamine and 2- chloropyrazine in Step 1 and N-benzylpyrazin-2-amine in Step 2. ¹H NMR (400 MHz, DMSO-de) δ 11.98 (s, IH), 8.07 (m, 2H), 7.84 (m, IH), 7.66 (m, IH), 7.22-7.34 (m, 6H), 6.09 (s, IH), 5.10 (s, 2H), 4.89 (s, 2H). LCMS: 379 (M+H)⁺. EXAMPLE 98

7,8-Difluoro-4-((pyrazin-2-yl(pyridin-4-ylmethyl)amino)methyl)quinolin-2(lH)- one

7,8-Difluoro-4-((pyrazin-2-yl(pyridin-4-ylmethyl)amino)methyl)quinolin-2(lH)-one was synthesized as described in EXAMPLE 2 using pyridin-4-ylmethanamine and 2- chloropyrazine in Step 1 and N-(pyridin-4-ylmethyl)pyrazin-2-amine in Step 2. ¹H NMR (400 MHz, DMSO-d₆) δ 11.97 (s, IH), 8.49 (m, 2H), 8.08 (m, IH), 8.05 (m, IH), 7.87 (d, IH), 7.66 (m, IH), 7.28 (m, 3H), 6.12 (s, IH), 5.13 (s, 2H), 4.93 (s, 2H). LCMS: 380 (M+H)⁺.

EXAMPLE 99

7,8-Difluoro-4-((pyrazin-2-yl(pyridin-3-ylmethyl)amino)methyl)quinolin-2(lH)- one

7,8-Difluoro-4-((pyrazin-2-yl(pyridin-3-ylmethyl)amino)methyl)quinolin-2(lH)-one was synthesized as described in EXAMPLE 2 using pyridin-3-ylmethanamine and 2- chloropyrazine in Step 1 and N-(pyridin-3-ylmethyl)pyrazin-2-amine in Step 2. ¹H NMR (400 MHz, DMSO-d₆) δ 8.76 (m, IH), 8.69 (m, IH), 8.22 (m, IH), 8.14 (m, IH), 8.11 (m, IH), 7.91 (d, IH), 7.77 (m, IH), 7.61 (m, IH), 7.30 (m, IH), 6.07 (s, IH), 5.17 (s, 2H), 5.03 (s, 2H). LCMS: 380 (M+H)⁺. EXAMPLE 100

7,8-Difluoro-4-((pyrazin-2-yl(pyridin-2-ylmethyl)amino)methyl)quinolin-2(lH)- one

7,8-Difluoro-4-((pyrazin-2-yl(pyridin-2-ylmethyl)amino)methyl)quinolin-2(lH)-one was synthesized as described in EXAMPLE 2 using pyridin-2-ylmethanamine and 2- chloropyrazine in Step 1 and N-(pyridin-2-ylmethyl)pyrazin-2-amine in Step 2. ¹H NMR (400 MHz, DMSO-d₆) δ 8.64 (m, IH), 8.19 (m, IH), 8.06 (m, IH), 8.03 (m, IH), 7.88 (d, IH), 7.61 (m, IH), 7.56 (m, IH), 7.52 (m, IH), 7.27 (m, 1H)6.16 (s, IH), 5.18 (s, 2H), 5.05 (s, 2H). LCMS: 380 (M+H)⁺.

EXAMPLE 101

4-(((3-Chlorophenyl)(pyridin-2-ylmethyl)amino)methyl)-7,8-difluoroquinolin-

2(lH)-one

Step 1 : 3-Chloro-N-(pyridin-2-ylmethyl)aniline

Na (OAc)3BH (1.6g, 7.5 mmol) was added to a mixture of 2-pyridylaldehyde (590 mg, 5 mmol) and 3-chloroaniline (635 mg, 5 mmol) in dichloroethane (10 mL)/acetic acid (0.3 mL) at RT. After stirring at RT for 2h, the reaction mixture was quenched with NaHCO₃ (sat aq) and EtOAc. The mixture was then worked-up via EtOAcZH₂O extraction, dried over sodium sulfate and concentrated to 3-Chloro-N-(pyridin-2- ylmethyl)aniline as an orange oil which was used without any further purification.

Step 2: 4-(((3-Chlorophenyl)(pyridin-2-ylmethyl)amino)methyl)-7,8- difluoroquinolin-2(lH)-one

4-(((3-Chlorophenyl)(pyridin-2-ylmethyl)amino)methyl)-7,8-difluoroquinolin-2(lH)- one was synthesized as described in EXAMPLE 1, Step 2 using 3-Chloro-N-(pyridin- 2-ylmethyl)aniline as a starting material. ¹H NMR (400 MHz, DMSO-d₆) δ 8.72 (d, IH), 8.18 (m, IH), 7.51 (m, 3H), 7.30 (m, IH), 7.12 (dd, IH), 6.73 (m, IHO, 6.54 (m, IH), 6.12 (s, IH), 5.10 (s, 2H), 4.95 (s, 2H). LCMS: 412 (M+H)⁺.

EXAMPLE 102

4-((Benzo[d]oxazol-2-yl(3-chlorophenyl)amino)methyl)-7,8-difluoroquinolin-

2(lH)-one

4-((Benzo[d]oxazol-2-yl(3-chlorophenyl)amino)methyl)-7,8-difluoroquinolin-2(lH)- one was synthesized as described in EXAMPLE 2 using 2-chlorobenzo[d]oxazole and 3-chloroaniline in Step 1 and N-(3-chlorophenyl)benzo[d]oxazol-2-amine in Step 2. LCMS: 438 (M+H)⁺.

EXAMPLE 103

4-((Benzo[d]thiazol-2-yl(3-chlorophenyl)amino)methyl)-7,8-difluoroquinolin-

2(lH)-one

4-((Benzo[d]thiazol-2-yl(3-chlorophenyl)amino)methyl)-7,8-difluoroquinolin-2(lH)- one was synthesized as described in EXAMPLE 2 using 2-chlorobenzo[d]thiazole and 3-chloroaniline in Step 1 and N-(3-chlorophenyl)benzo[d]thiazol-2-amine in Step 2. LCMS: 454 (M+H)⁺.

EXAMPLE 104

4-(((3-Chlorophenyl)(6-methylbenzo[d]oxazol-2-yl)amino)methyl)-7,8- difluoroquinolin-2(lH)-one

4-(((3-Chlorophenyl)(6-methylbenzo[d]oxazol-2-yl)amino)methyl)-7,8- difluoroquinolin-2(lH)-one was synthesized as described in EXAMPLE 2 using 2- chloro-6-methylbenzo[d]oxazole and 3-chloroaniline in Step 1 and N-(3- chlorophenyl)-6-methylbenzo[d]oxazol-2-amine in Step 2. LCMS: 452 (M+H)⁺,

EXAMPLE 105

4-(((3-Chlorophenyl)(6-fluorobenzo[d]oxazol-2-yl)amino)methyl)-7,8- difluoroquinolin-2(lH)-one

4-(((3-Chlorophenyl)(6-fluorobenzo[d]oxazol-2-yl)amino)methyl)-7,8- difluoroquinolin-2(lH)-one was synthesized as described in EXAMPLE 2 using 2- chloro-6-fluorobenzo[d]oxazole and 3-chloroaniline in Step 1 and N-(3-chlorophenyl)- 6-fluorobenzo[d]oxazol-2-amine in Step 2. LCMS: 456 (M+H)⁺.

EXAMPLE 106

4-(((lH-Benzo[d]imidazol-2-yl)(3-chlorophenyl)amino)methyl)-7,8- difluoroquinolin-2(lH)-one

4-(((lH-Benzo[d]imidazol-2-yl)(3-chlorophenyl)amino)methyl)-7,8-difluoroquinolin- 2(lH)-one was synthesized as described in EXAMPLE 2 using 2-chloro-lH- benzo[d]imidazole and 3-chloroaniline in Step 1 and N-(3-chlorophenyl)-lH- benzo[d]imidazol-2-amine in Step 2. LCMS: 437 (M+H)⁺.

EXAMPLE 107

4-(((3-chlorophenyl)(5-methylbenzo[d]oxazol-2-yl)amino)methyl)-7,8- difluoroquinolin-2(lH)-one

4-(((3-chlorophenyl)(5-methylbenzo[d]oxazol-2-yl)amino)methyl)-7,8- difluoroquinolin-2(lH)-one was synthesized as described in EXAMPLE 2 using 2- chloro-5-methylbenzo[d]oxazole and 3-chloroaniline in Step 1 and N-(3- chlorophenyl)-5-methylbenzo[d]oxazol-2-amine in Step 2. LCMS: 452 (M+H)⁺.

EXAMPLE 108

4-(((3-Chlorophenyl)(6-methoxybenzo[d]thiazol-2-yl)amino)methyl)-7,8- difluoroquinolin-2(lH)-one

4-(((3-Chlorophenyl)(6-methoxybenzo[d]thiazol-2-yl)amino)methyl)-7,8- difluoroquinolin-2(lH)-one was synthesized as described in EXAMPLE 2 using 2- chloro-6-methoxybenzo[d]thiazole and 3-chloroaniline in Step 1 and N-(3- chlorophenyl)-6-methoxybenzo[d]thiazol-2-amine in Step 2. LCMS: 484 (M+H)⁴

EXAMPLE 109

4-(((3-Chlorophenyl)(oxazolo[4,5-b]pyridin-2-yl)amino)methyl)-7,8- difluoroquinolin-2(lH)-one

4-(((3-Chlorophenyl)(oxazolo[4,5-b]pyridin-2-yl)amino)methyl)-7,8-difluoroquinolin- 2(lH)-one was synthesized as described in EXAMPLE 2 using 2-chlorooxazolo[4,5- b]pyridine and 3-chloroaniline in Step 1 and N-(3-chlorophenyl)oxazolo[4,5-b]pyridin- 2-amine in Step 2. LCMS: 439 (M+H)⁺.

EXAMPLE 110

4-(((5-Chlorobenzo[d]oxazol-2-yl)(3-chlorophenyl)amino)methyl)-7,8- difluoroquinolin-2(lH)-one

4-(((5-Chlorobenzo[d]oxazol-2-yl)(3-chlorophenyl)amino)methyl)-7,8- difluoroquinolin-2(lH)-one was synthesized as described in EXAMPLE 2 using 2,5- dichlorobenzo[d]oxazole and 3-chloroaniline in Step 1 and 5-chloro-N-(3- chlorophenyl)benzo[d]oxazol-2-amine in Step 2. LCMS: 473 (M+H)⁺.

EXAMPLE 111 4-((Benzo[d]oxazol-2-yl(isopropyl)amino)methyl)-7,8-difluoroquinolin-2(lH)-one

4-((Benzo[d]oxazol-2-yl(isopropyl)amino)methyl)-7,8-difluoroquinolin-2(lH)-one was synthesized as described in EXAMPLE 81 using 2-chlorobenzo[d]oxazole and propan- 2-amine in Step 1 and N-isopropylbenzo[d]oxazol-2-amine in Step 2. LCMS: 370 (M+H)⁺.

EXAMPLE 112

4-((Benzo[d]oxazol-2-yl(cyclopropylmethyl)amino)methyl)-7,8-difluoroquinolin-

2(lH)-one

4-((Benzo[d]oxazol-2-yl(cyclopropylmethyl)amino)methyl)-7,8-difluoroquinolin- 2(lH)-one was synthesized as described in EXAMPLE 81 using 2- chlorobenzo[d]oxazole and cyclopropylmethanamine in Step 1 and N- (cyclopropylmethyl)benzo[d]oxazol-2-amine in Step 2. LCMS: 382 (M+H)⁺. EXAMPLE 113

4-((Benzo[d]oxazol-2-yl(cyclopropyl)amino)methyl)-7,8-difluoroquinolin-2(lH)- one

4-((Benzo[d]oxazol-2-yl(cyclopropyl)amino)methyl)-7,8-difluoroquinolin-2(lH)-one was synthesized as described in EXAMPLE 81 using 2-chlorobenzo[d]oxazole and cyclopropanamine in Step 1 and N-cyclopropylbenzo[d]oxazol-2-amine in Step 2. LCMS: 368 (M+H)⁺.

EXAMPLE 114 4-((Benzo[d]oxazol-2-yl(isobutyl)amino)methyl)-7,8-difluoroquinolin-2(lH)-one

4-((Benzo[d]oxazol-2-yl(isobutyl)amino)methyl)-7,8-difluoroquinolin-2(lH)-one was synthesized as described in EXAMPLE 81 using 2-chlorobenzo[d]oxazole and 2- methylpropan-1 -amine in Step 1 and N-isobutylbenzo[d]oxazol-2-amine in Step 2. LCMS: 384 (M+H)⁺. EXAMPLE 115 4-((Benzo[d]oxazol-2-yl(phenyl)amino)methyl)-7,8-difluoroquinolin-2(lH)-one

4-((Benzo[d]oxazol-2-yl(phenyl)amino)methyl)-7,8-difluoroquinolin-2(lH)-one was synthesized as described in EXAMPLE 2 using 2-chlorobenzo[d]oxazole and aniline in Step 1 and N-phenylbenzo[d]oxazol-2-amine in Step 2. LCMS: 404 (M+H)⁺.

EXAMPLE 116

4-((Benzo[d]oxazol-2-yl(3-methoxyphenyl)amino)methyl)-7,8-difluoroquinolin-

2(lH)-one

4-((Benzo[d]oxazol-2-yl(3-methoxyphenyl)amino)methyl)-7,8-difluoroquinolin-2(lH)- one was synthesized as described in EXAMPLE 2 using 2-chlorobenzo[d]oxazole and 3 -methoxy aniline in Step 1 and N-(3-methoxyphenyl)benzo[d]oxazol-2-amine in Step 2. LCMS: 434 (M+H)⁺. EXAMPLE 117 4-((Benzo[d]oxazol-2-yl(o-tolyl)amino)methyl)-7,8-difluoroquinolin-2(lH)-one

4-((Benzo[d]oxazol-2-yl(o-tolyl)amino)methyl)-7,8-difluoroquinolin-2(lH)-one was synthesized as described in EXAMPLE 2 using 2-chlorobenzo[d]oxazole and o- toluidine in Step 1 and N-o-tolylbenzo[d]oxazol-2-amine in Step 2. LCMS: 418 (M+H)⁺.

EXAMPLE 118 4-(((3-Chlorophenyl)(quinolin-3-yl)amino)methyl)-7,8-difluoroquinolin-2(lH)-one

4-(((3-Chlorophenyl)(quinolin-3-yl)amino)methyl)-7,8-difluoroquinolin-2(lH)-one was synthesized as described in EXAMPLE 1 using 3-bromoquinoline and 3- chloroaniline in Step 1 and N-(3-chlorophenyl)quinolin-3 -amine in Step 2. LCMS: 448 (M+H)⁺. EXAMPLE 119

4-(((3-Chlorophenyl)(2-methylpyridin-3-yl)amino)methyl)-7,8-difluoroquinolin-

2(lH)-one

4-(((3-Chlorophenyl)(2-methylpyridin-3-yl)amino)methyl)-7,8-difluoroquinolin-2(lH)- one was synthesized as described in EXAMPLE 1 using 3-bromo-2-methylpyridine and 3-chloroaniline in Step 1 and N-(3-chlorophenyl)-2-methylpyridin-3 -amine in Step 2. LCMS: 412 (M+H)⁺.

EXAMPLE 120

4-(((3-Chlorophenyl)(isoquinolin-4-yl)amino)methyl)-7,8-difluoroquinolin-2(lH)- one

4-(((3-Chlorophenyl)(isoquinolin-4-yl)amino)methyl)-7,8-difluoroquinolin-2(lH)-one was synthesized as described in EXAMPLE 1 using 4-bromoisoquinoline and 3- chloroaniline in Step 1 and N-(3-chlorophenyl)isoquinolin-4-amine in Step 2. LCMS: 448 (M+H)⁺. EXAMPLE 121

4-(((3-Chlorophenyl)(6-(pyrrolidin-l-yl)pyridin-3-yl)amino)methyl)-7,8- difluoroquinolin-2(lH)-one

4-(((3-Chlorophenyl)(6-(pyrrolidin-l-yl)pyridin-3-yl)amino)methyl)-7,8- difluoroquinolin-2(lH)-one was synthesized as described in EXAMPLE 1 using 5- bromo-2-(pyrrolidin-l-yl)pyridine and 3-chloroaniline in Step 1 and N-(3- chlorophenyl)-6-(pyrrolidin-l-yl)pyridin-3 -amine in Step 2. LCMS: 467 (M+H)⁺.

EXAMPLE 122 7,8-Difluoro-4-((pyrazin-2-yl(pyrimidin-4-yl)amino)methyl)quinolin-2(lH)-one

7,8-Difluoro-4-((pyrazin-2-yl(pyrimidin-4-yl)amino)methyl)quinolin-2(lH)-one was synthesized as described in EXAMPLE 1 using 2-iodopyrazine and pyrimidin-4-amine in Step 1 and N-(pyrazin-2-yl)pyrimidin-4-amine in Step 2. LCMS: 367 (M+H)⁺. EXAMPLE 123 7,8-Difluoro-4-((pyridin-2-yl(pyrimidin-4-yl)amino)methyl)quinolin-2(lH)-one

7,8-Difluoro-4-((pyridin-2-yl(pyrimidin-4-yl)amino)methyl)quinolin-2(lH)-one was synthesized as described in EXAMPLE 1 using 2-bromopyridine and pyrimidin-4- amine in Step 1 and N-(pyridin-2-yl)pyrimidin-4-amine in Step 2. LCMS: 366 (M+H)⁺.

EXAMPLE 124 7,8-Difluoro-4-((pyridin-3-yl(pyrimidin-4-yl)amino)methyl)quinolin-2(lH)-one

7,8-Difluoro-4-((pyridin-3-yl(pyrimidin-4-yl)amino)methyl)quinolin-2(lH)-one was synthesized as described in EXAMPLE 1 using 3-bromopyridine and pyrimidin-4- amine in Step 1 and N-(pyridin-3-yl)pyrimidin-4-amine in Step 2. LCMS: 366 (M+H)⁺. EXAMPLE 125 7,8-Difluoro-4-((pyrimidin-2-yl(o-tolyl)amino)methyl)quinolin-2(lH)-one

7,8-Difluoro-4-((pyrimidin-2-yl(o-tolyl)amino)methyl)quinolin-2(lH)-one was synthesized as described in EXAMPLE 2 using 2-chloropyrimidine and o-toluidine in Step 1 and N-o-tolylpyrimidin-2-amine in Step 2. LCMS: 379 (M+H)⁺.

EXAMPLE 126

7,8-Difluoro-4-(((2-fluorophenyl)(pyrimidin-2-yl)amino)methyl)quinolin-2(lH)- one

7,8-Difluoro-4-(((2-fluorophenyl)(pyrimidin-2-yl)amino)methyl)quinolin-2(lH)-one was synthesized as described in EXAMPLE 2 using 2-chloropyrimidine and 2- fluoroaniline in Step 1 and N-(2-fluorophenyl)pyrimidin-2-amine in Step 2. LCMS: 383 (M+H)⁺.

EXAMPLE 127 7,8-Difluoro-4-((pyridin-2-yl(pyrimidin-2-yl)amino)methyl)quinolin-2(lH)-one

7,8-Difluoro-4-((pyridin-2-yl(pyrimidin-2-yl)amino)methyl)quinolin-2(lH)-one was synthesized as described in EXAMPLE 2 using 2-chloropyrimidine and pyridine- amine in Step 1 and N-(pyridin-2-yl)pyrimidin-2-amine in Step 2. LCMS: 366 (M+H)⁺.

EXAMPLE 128 7,8-Difluoro-4-((pyrimidin-2-yl(m-tolyl)amino)methyl)quinolin-2(lH)-one

7,8-Difluoro-4-((pyrimidin-2-yl(m-tolyl)amino)methyl)quinolin-2(lH)-one was synthesized as described in EXAMPLE 2 using 2-chloropyrimidine and m-toluidine in Step 1 and N-m-tolylpyrimidin-2-amine in Step 2. LCMS: 379 (M+H)⁺.

EXAMPLE 129 7,8-Difluoro-4-(((3-fluorophenyl)(pyrimidin-2-yl)amino)methyl)quinolin-2(lH)- one

7,8-Difluoro-4-(((3-fluorophenyl)(pyrimidin-2-yl)amino)methyl)quinolin-2(lH)-one was synthesized as described in EXAMPLE 2 using 2-chloropyrimidine and 3- fluoroaniline in Step 1 and N-(3-fluorophenyl)pyrimidin-2-amine in Step 2. LCMS: 383 (M+H)⁺.

EXAMPLE 130

4-(((2-Chlorophenyl)(pyrimidin-2-yl)amino)methyl)-7,8-difluoroquinolin-2(lH)- one

4-(((2-Chlorophenyl)(pyrimidin-2-yl)amino)methyl)-7,8-difluoroquinolin-2(lH)-one was synthesized as described in EXAMPLE 2 using 2-chloropyrimidine and 2- chloroaniline in Step 1 and N-(2-chlorophenyl)pyrimidin-2-amine in Step 2. LCMS: 399 (M+H)⁺. EXAMPLE 131 7,8-Difluoro-4-((pyridin-3-yl(pyrimidin-2-yl)amino)methyl)quinolin-2(lH)-one

7,8-Difluoro-4-((pyridin-3-yl(pyrimidin-2-yl)amino)methyl)quinolin-2(lH)-one was synthesized as described in EXAMPLE 2 using 2-chloropyrimidine and pyridin-3- amine in Step 1 and N-(pyridin-3-yl)pyrimidin-2-amine in Step 2. LCMS: 366 (M+H)⁺.

EXAMPLE 132

7,8-Difluoro-4-(((3-methylpyridin-2-yl)(pyrimidin-2-yl)amino)methyl)quinolin-

2(lH)-one

7,8-Difluoro-4-(((3-methylpyridin-2-yl)(pyrimidin-2-yl)amino)methyl)quinolin-2(lH)- one was synthesized as described in EXAMPLE 2 using 2-chloropyrimidine and 3- methylpyridin-2-amine in Step 1 and N-(3-methylpyridin-2-yl)pyrimidin-2-amine in Step 2. LCMS: 380 (M+H)⁺. EXAMPLE 133

7,8-Difluoro-4-(((6-methylpyridin-2-yl)(pyrimidin-2-yl)amino)methyl)quinolin-

2(lH)-one

7,8-Difluoro-4-(((6-methylpyridin-2-yl)(pyrimidin-2-yl)amino)methyl)quinolin-2(lH)- one was synthesized as described in EXAMPLE 2 using 2-chloropyrimidine and 6- methylpyridin-2-amine in Step 1 and N-(6-methylpyridin-2-yl)pyrimidin-2-amine in Step 2. LCMS: 380 (M+H)⁺.

EXAMPLE 134

7,8-Difluoro-4-(((4-methylpyridin-2-yl)(pyrimidin-2-yl)amino)methyl)quinolin-

2(lH)-one

7,8-Difluoro-4-(((4-methylpyridin-2-yl)(pyrimidin-2-yl)amino)methyl)quinolin-2(lH)- one was synthesized as described in EXAMPLE 2 using 2-chloropyrimidine and A- methylpyridin-2-amine in Step 1 and N-(4-methylpyridin-2-yl)pyrimidin-2-amine in Step 2. LCMS: 380 (M+H)⁺. EXAMPLE 135 7,8-Difluoro-4-(((2-fluorobenzyl)(pyrazin-2-yl)amino)methyl)quinolin-2(lH)-one

7,8-Difluoro-4-(((2-fluorobenzyl)(pyrazin-2-yl)amino)methyl)quinolin-2( 1 H)-one was synthesized as described in EXAMPLE 2 using (2-fluorophenyl)methanamine and 2- chloropyrazine in Step 1 and N-(2-fluorobenzyl)pyrazin-2-amine in Step 2. LCMS: 397 (M+H)⁺.

EXAMPLE 136 7,8-Difluoro-4-(((3-fluorobenzyl)(pyrazin-2-yl)amino)methyl)quinolin-2(lH)-one

7,8-Difluoro-4-(((3-fluorobenzyl)(pyrazin-2-yl)amino)methyl)quinolin-2(lH)-one was synthesized as described in EXAMPLE 2 using (3-fluorophenyl)methanamine and 2- chloropyrazine in Step 1 and N-(3-fluorobenzyl)pyrazin-2-amine in Step 2. LCMS: 397 (M+H)⁺.

EXAMPLE 137 7,8-Difluoro-4-(((4-fluorobenzyl)(pyrazin-2-yl)amino)methyl)quinolin-2(lH)-one

7,8-Difluoro-4-(((4-fluorobenzyl)(pyrazin-2-yl)amino)methyl)quinolin-2( 1 H)-one was synthesized as described in EXAMPLE 2 using (4-fluorophenyl)methanamine and 2- chloropyrazine in Step 1 and N-(4-fluorobenzyl)pyrazin-2-amine in Step 2. LCMS: 397 (M+H)⁺.

EXAMPLE 138 7,8-Difluoro-4-(((2-chlorobenzyl)(pyrazin-2-yl)amino)methyl)quinolin-2(lH)-one

7,8-Difluoro-4-(((2-chlorobenzyl)(pyrazin-2-yl)amino)methyl)quinolin-2(lH)-one was synthesized as described in EXAMPLE 2 using (2-chlorophenyl)methanamine and 2- chloropyrazine in Step 1 and N-(2-chlorobenzyl)pyrazin-2-amine in Step 2. LCMS: 413 (M+H)⁺.

EXAMPLE 139 7,8-Difluoro-4-(((3-chlorobenzyl)(pyrazin-2-yl)amino)methyl)quinolin-2(lH)-one

7,8-Difluoro-4-(((3-chlorobenzyl)(pyrazin-2-yl)amino)methyl)quinolin-2(lH)-one was synthesized as described in EXAMPLE 2 using (3-chlorophenyl)methanamine and 2- chloropyrazine in Step 1 and N-(3-chlorobenzyl)pyrazin-2-amine in Step 2. LCMS: 413 (M+H)⁺.

EXAMPLE 140 7,8-Difluoro-4-(((4-chlorobenzyl)(pyrazin-2-yl)amino)methyl)quinolin-2(lH)-one

7,8-Difluoro-4-(((4-chlorobenzyl)(pyrazin-2-yl)amino)methyl)quinolin-2(lH)-one was synthesized as described in EXAMPLE 2 using (4-chlorophenyl)methanamine and 2- chloropyrazine in Step 1 and N-(4-chlorobenzyl)pyrazin-2-amine in Step 2. LCMS: 413 (M+H)⁺.

EXAMPLE 141 4-(((2-Chlorobenzyl)(pyrazin-2-yl)amino)methyl)-8-fluoroquinolin-2(lH)-one

4-(((2-Chlorobenzyl)(pyrazin-2-yl)amino)methyl)-8-fluoroquinolin-2(lH)-one was synthesized as described in EXAMPLE 2 using (2-chlorophenyl)methanamine and 2- chloropyrazine in Step 1 and N-(2-chlorobenzyl)pyrazin-2-amine and 4- (bromomethyl)-8-fluoroquinolin-2(lH)-one (INTERMEDIATE 5) in Step 2. LCMS: 395 (M+H)⁺.

EXAMPLE 142 8-Fluoro-4-(((2-fluorobenzyl)(pyrazin-2-yl)amino)methyl)quinolin-2(lH)-one

8-Fluoro-4-(((2-fluorobenzyl)(pyrazin-2-yl)amino)methyl)quinolin-2( 1 H)-one was synthesized as described in EXAMPLE 2 using (2-fluorophenyl)methanamine and 2- chloropyrazine in Step 1 and N-(2-fluorobenzyl)pyrazin-2-amine and 4- (bromomethyl)-8-fluoroquinolin-2(lH)-one (INTERMEDIATE 5) in Step 2. LCMS: 379 (M+H)⁺. EXAMPLE 143 8-Fluoro-4-(((3-fluorobenzyl)(pyrazin-2-yl)amino)methyl)quinolin-2(lH)-one

8-Fluoro-4-(((3-fluorobenzyl)(pyrazin-2-yl)amino)methyl)quinolin-2(lH)-one was synthesized as described in EXAMPLE 2 using (3-fluorophenyl)methanamine and 2- chloropyrazine in Step 1 and N-(3-fluorobenzyl)pyrazin-2-amine and 4- (bromomethyl)-8-fluoroquinolin-2(lH)-one (INTERMEDIATE 5) in Step 2. LCMS: 379 (M+H)⁺.

EXAMPLE 144

4-(((2,5-Difluorobenzyl)(pyrazin-2-yl)amino)methyl)-7,8-difluoroquinolin-2(lH)- one

4-(((2,5-Difluorobenzyl)(pyrazin-2-yl)amino)methyl)-7,8-difluoroquinolin-2(lH)-one was synthesized as described in EXAMPLE 2 using (2,5-difluorophenyl)methanamine and 2-chloropyrazine in Step 1 and N-(2,5-difluorobenzyl)pyrazin-2-amine in Step 2. LCMS: 415 (M+H)⁺. EXAMPLE 145

4-(((2,4-Difluorobenzyl)(pyrazin-2-yl)amino)methyl)-7,8-difluoroquinolin-2(lH)- one

4-(((2,4-Difluorobenzyl)(pyrazin-2-yl)amino)methyl)-7,8-difluoroquinolin-2(lH)-one was synthesized as described in EXAMPLE 2 using (2,4-difluorophenyl)methanamine and 2-chloropyrazine in Step 1 and N-(2,4-difluorobenzyl)pyrazin-2-amine in Step 2. LCMS: 415 (M+H)⁺.

EXAMPLE 146

4-(((2,6-Dichlorobenzyl)(pyrazin-2-yl)amino)methyl)-7,8-difluoroquinolin-2(lH)- one

4-(((2,6-Dichlorobenzyl)(pyrazin-2-yl)amino)methyl)-7,8-difluoroquinolin-2(lH)-one was synthesized as described in EXAMPLE 2 using (2,6-dichlorophenyl)methanamine and 2-chloropyrazine in Step 1 and N-(2,6-dichlorobenzyl)pyrazin-2-amine in Step 2. LCMS: 447 (M+H)⁺. EXAMPLE 147

4-(((5-Chloro-2-methylbenzyl)(pyrazin-2-yl)amino)methyl)-8-fluoroquinolin-

2(lH)-one

4-(((5-Chloro-2-methylbenzyl)(pyrazin-2-yl)amino)methyl)-8-fluoroquinolin-2(lH)- one was synthesized as described in EXAMPLE 2 using (5-chloro-2- methylphenyl)methanamine and 2-chloropyrazine in Step 1 and N-(5-chloro-2- methylbenzyl)pyrazin-2-amine and 4-(bromomethyl)-8-fluoroquinolin-2(lH)-one (INTERMEDIATE 5) in Step 2. LCMS: 409 (M+H)⁺.

EXAMPLE 148

8-Fluoro-4-(((5-fluoro-2-(trifluoromethyl)benzyl)(pyrazin-2- yl)amino)methyl)quinolin-2(lH)-one

8-Fluoro-4-(((5-fluoro-2-(trifluoromethyl)benzyl)(pyrazin-2- yl)amino)methyl)quinolin-2(lH)-one was synthesized as described in EXAMPLE 2 using (5-fluoro-2-(trifluoromethyl)phenyl)methanamine and 2-chloropyrazine in Step 1 and N-(5-fluoro-2-(trifluoromethyl)benzyl)pyrazin-2-amine and 4-(bromomethyl)-8- fluoroquinolin-2(lH)-one (INTERMEDIATE 5) in Step 2. LCMS: 447 (M+H)⁺. EXAMPLE 149

8-Fluoro-4-(((2-(furan-2-yl)benzyl)(pyrazin-2-yl)amino)methyl)quinolin-2(lH)- one

8-Fluoro-4-(((2-(furan-2-yl)benzyl)(pyrazin-2-yl)amino)methyl)quinolin-2(lH)-one was synthesized as described in EXAMPLE 2 using (2-(furan-2- yl)phenyl)methanamine and 2-chloropyrazine in Step 1 and N-(2-(furan-2- yl)benzyl)pyrazin-2-amine and 4-(bromomethyl)-8-fluoroquinolin-2( 1 H)-one (INTERMEDIATE 5) in Step 2. LCMS: 427 (M+H)⁺.

EXAMPLE 150

7,8-Difluoro-4-((pyrazin-2-yl((3-(trifluoromethyl)pyridin-2- yl)methyl)amino)methyl)quinolin-2(lH)-one

7,8-Difluoro-4-((pyrazin-2-yl((3-(trifluoromethyl)pyridin-2- yl)methyl)amino)methyl)quinolin-2(lH)-one was synthesized as described in EXAMPLE 2 using (3-(trifluoromethyl)pyridin-2-yl)methanamine and 2- chloropyrazine in Step 1 and N-((3-(trifluoromethyl)pyridin-2-yl)methyl)pyrazin-2- amine in Step 2. LCMS: 448 (M+H)⁺. EXAMPLE 151

7,8-Difluoro-4-((((3-methylpyridin-4-yl)methyl)(pyrazin-2- yl)amino)methyl)quinolin-2(lH)-one

7,8-Difluoro-4-((((3-methylpyridin-4-yl)methyl)(pyrazin-2-yl)amino)methyl)quinolin- 2(lH)-one was synthesized as described in EXAMPLE 2 using (3-methylpyridin-4- yl)methanamine and 2-chloropyrazine in Step 1 and N-((3-methylpyridin-4- yl)methyl)pyrazin-2-amine in Step 2. LCMS: 3948 (M+H)⁺.

EXAMPLE 152 8-Fluoro-4-((pyrazin-2-yl(pyridin-2-ylmethyl)amino)methyl)quinolin-2(lH)-one

8-Fluoro-4-((pyrazin-2-yl(pyridin-2-ylmethyl)amino)methyl)quinolin-2( 1 H)-one was synthesized as described in EXAMPLE 2 using pyridin-2-ylmethanamine and 2- chloropyrazine in Step 1 N-(pyridin-2-ylmethyl)pyrazin-2-amine and 4- (bromomethyl)-8-fluoroquinolin-2(lH)-one (INTERMEDIATE 5) in Step 2. LCMS: 362 (M+H)⁺. EXAMPLE 153

8-Fluoro-4-((pyrazin-2-yl(2-(trifluoromethyl)benzyl)amino)methyl)quinolin-

2(lH)-one

8-Fluoro-4-((pyrazin-2-yl(2-(trifluoromethyl)benzyl)amino)methyl)quinolin-2(lH)-one was synthesized as described in EXAMPLE 2 using (2- (trifluoromethyl)phenyl)methanamine and 2-chloropyrazine in Step 1 N-(2- (trifluoromethyl)benzyl)pyrazin-2-amine and 4-(bromomethyl)-8-fluoroquinolin- 2(lH)-one (INTERMEDIATE 5) in Step 2. LCMS: 429 (M+H)⁺.

EXAMPLE 154 8-Fluoro-4-(((2-methylbenzyl)(pyrazin-2-yl)amino)methyl)quinolin-2(lH)-one

8-Fluoro-4-(((2-methylbenzyl)(pyrazin-2-yl)amino)methyl)quinolin-2(lH)-one was synthesized as described in EXAMPLE 2 using o-tolylmethanamine and 2- chloropyrazine in Step 1 N-(2-methylbenzyl)pyrazin-2-amine and 4-(bromomethyl)-8- fluoroquinolin-2(lH)-one (INTERMEDIATE 5) in Step 2. LCMS: 375 (M+H)⁺. EXAMPLE 155 8-Fluoro-4-(((2-methoxybenzyl)(pyrazin-2-yl)amino)methyl)quinolin-2(lH)-one

8-Fluoro-4-(((2-methoxybenzyl)(pyrazin-2-yl)amino)methyl)quinolin-2( 1 H)-one was synthesized as described in EXAMPLE 2 using (2-methoxyphenyl)methanamine and 2-chloropyrazine in Step 1 and N-(2-methoxybenzyl)pyrazin-2-amine and 4- (bromomethyl)-8-fluoroquinolin-2(lH)-one (INTERMEDIATE 5) in Step 2. LCMS: 391 (M+H)⁺.

EXAMPLE 156

4-(((2-((Diethylamino)methyl)benzyl)(pyrazin-2-yl)amino)methyl)-7,8- difluoroquinolin-2(lH)-one

4-(((2-((Diethylamino)methyl)benzyl)(pyrazin-2-yl)amino)methyl)-7,8- difluoroquinolin-2(lH)-one was synthesized as described in EXAMPLE 2 using N-(2- (aminomethyl)benzyl)-N-ethylethanamine and 2-chloropyrazine in Step 1 and N-(2- ((diethylamino)methyl)benzyl)pyrazin-2-amine in Step 2. LCMS: 464 (M+H)⁺. EXAMPLE 157

8-Fluoro-4-(((2-((4-methylpiperazin-l-yl)methyl)benzyl)(pyrazin-2- yl)amino)methyl)quinolin-2(lH)-one

8-Fluoro-4-(((2-((4-methylpiperazin-l-yl)methyl)benzyl)(pyrazin-2- yl)amino)methyl)quinolin-2(lH)-one was synthesized as described in EXAMPLE 2 using (2-((4-methylpiperazin-l-yl)methyl)phenyl)methanamine and 2-chloropyrazine in Step 1 and N-(2-((4-methylpiperazin-l-yl)methyl)benzyl)pyrazin-2-amine and 4- (bromomethyl)-8-fluoroquinolin-2(lH)-one (INTERMEDIATE 5) in Step 2. LCMS: 473 (M+H)⁺.

EXAMPLE 158

8-Fluoro-4-(((2-(morpholinomethyl)benzyl)(pyrazin-2-yl)amino)methyl)quinolin-

2(lH)-one

8-Fluoro-4-(((2-(morpholinomethyl)benzyl)(pyrazin-2-yl)amino)methyl)quinolin- 2(lH)-one was synthesized as described in EXAMPLE 2 using (2- (morpholinomethyl)phenyl)methanamine and 2-chloropyrazine in Step 1 and N-(2- (morpholinomethyl)benzyl)pyrazin-2-amine and 4-(bromomethyl)-8-fluoroquinolin- 2(lH)-one (INTERMEDIATE 5) in Step 2. LCMS: 460 (M+H)⁺. EXAMPLE 159

7,8-Difluoro-4-(((2-((4-methylpiperazin-l-yl)methyl)benzyl)(pyrazin-2- yl)amino)methyl)quinolin-2(lH)-one

7,8-Difluoro-4-(((2-((4-methylpiperazin-l-yl)methyl)benzyl)(pyrazin-2- yl)amino)methyl)quinolin-2(lH)-one was synthesized as described in EXAMPLE 2 using (2-((4-methylpiperazin-l-yl)methyl)phenyl)methanamine and 2-chloropyrazine in Step 1 and N-(2-((4-methylpiperazin-l-yl)methyl)benzyl)pyrazin-2-amine in Step 2. LCMS: 491 (M+H)⁺.

EXAMPLE 160

7,8-Difluoro-4-(((2-(morpholinomethyl)benzyl)(pyrazin-2- yl)amino)methyl)quinolin-2(lH)-one

7,8-Difluoro-4-(((2-(morpholinomethyl)benzyl)(pyrazin-2-yl)amino)methyl)quinolin- 2(lH)-one was synthesized as described in EXAMPLE 2 using (2- (morpholinomethyl)phenyl)methanamine and 2-chloropyrazine in Step 1 and N-(2- (morpholinomethyl)benzyl)pyrazin-2-amine in Step 2. LCMS: 478 (M+H)⁺. EXAMPLE 161

4-(((6-Chloropyrimidin-4-yl)(pyridin-2-ylmethyl)amino)methyl)-8-fluoroquinolin-

2(lH)-one

4-(((6-Chloropyrimidin-4-yl)(pyridin-2-ylmethyl)amino)methyl)-8-fluoroquinolin- 2(lH)-one was synthesized as described in EXAMPLE 2 using pyridin-2- ylmethanamine and 4,6-dichloropyrimidine in Step 1 and 6-chloro-N-(pyridin-2- ylmethyl)pyrimidin-4-amine and 4-(bromomethyl)-8-fluoroquinolin-2(lH)-one (INTERMEDIATE 5) in Step 2. LCMS: 396 (M+H)⁺.

EXAMPLE 162

8-Fluoro-4-(((pyridin-2-ylmethyl)(pyrimidin-4-yl)amino)methyl)quinolin-2(lH)- one

8-Fluoro-4-(((pyridin-2-ylmethyl)(pyrimidin-4-yl)amino)methyl)quinolin-2(lH)-one was synthesized as described in EXAMPLE 35, Step2 using 4-(((6-chloropyrimidin-4- yl)(pyridin-2-ylmethyl)amino)methyl)-8-fluoroquinolin-2(lH)-one as a starting material. LCMS: 362 (M+H)⁺. EXAMPLE 163

4-(((6-Chloropyrimidin-4-yl)(pyridin-4-ylmethyl)amino)methyl)-8-fluoroquinolin-

2(lH)-one

4-(((6-Chloropyrimidin-4-yl)(pyridin-4-ylmethyl)amino)methyl)-8-fluoroquinolin- 2(lH)-one was synthesized as described in EXAMPLE 2 using pyridin-4- ylmethanamine and 4,6-dichloropyrimidine in Step 1 and 6-chloro-N-(pyridin-4- ylmethyl)pyrimidin-4-amine and 4-(bromomethyl)-8-fluoroquinolin-2(lH)-one (INTERMEDIATE 5) in Step 2. LCMS: 396 (M+H)⁺.

EXAMPLE 164

8-Fluoro-4-(((pyridin-4-ylmethyl)(pyrimidin-4-yl)amino)methyl)quinolin-2(lH)- one

8-Fluoro-4-(((pyridin-4-ylmethyl)(pyrimidin-4-yl)amino)methyl)quinolin-2(lH)-one was synthesized as described in EXAMPLE 35, Step2 using 4-(((6-chloropyrimidin-4- yl)(pyridin-4-ylmethyl)amino)methyl)-8-fluoroquinolin-2(lH)-one as a starting material. LCMS: 362 (M+H)⁺. EXAMPLE 165

4-(((6-Chloropyrimidin-4-yl)(2-methylbenzyl)amino)methyl)-8-fluoroquinolin-

2(lH)-one

4-(((6-Chloropyrimidin-4-yl)(2-methylbenzyl)amino)methyl)-8-fluoroquinolin-2(lH)- one was synthesized as described in EXAMPLE 2 using o-tolylmethanamine and 4,6- dichloropyrimidine in Step 1 and 6-chloro-N-(2-methylbenzyl)pyrimidin-4-amine and 4-(bromomethyl)-8-fluoroquinolin-2(lH)-one (INTERMEDIATE 5) in Step 2. LCMS: 409 (M+H)⁺.

EXAMPLE 166 8-Fluoro-4-(((2-methylbenzyl)(pyrimidin-4-yl)amino)methyl)quinolin-2(lH)-one

8-Fluoro-4-(((2-methylbenzyl)(pyrimidin-4-yl)amino)methyl)quinolin-2(lH)-one was synthesized as described in EXAMPLE 35, Step2 using 4-(((6-chloropyrimidin-4- yl)(2-methylbenzyl)amino)methyl)-8-fluoroquinolin-2(lH)-one as a starting material. LCMS: 375 (M+H)⁺. EXAMPLE 167

4-(((6-Chloropyrimidin-4-yl)(2-methylbenzyl)amino)methyl)-7,8-difluoroquinolin-

2(lH)-one

4-(((6-Chloropyrimidin-4-yl)(2-methylbenzyl)amino)methyl)-7,8-difluoroquinolin- 2(lH)-one was synthesized as described in EXAMPLE 2 using o-tolylmethanamine and 4,6-dichloropyrimidine in Step 1 and 6-chloro-N-(2-methylbenzyl)pyrimidin-4- amine in Step 2. LCMS: 427 (M+H)⁺.

EXAMPLE 168

7,8-Difluoro-4-(((2-methylbenzyl)(pyrimidin-4-yl)amino)methyl)quinolin-2(lH)- one

7,8-Difluoro-4-(((2-methylbenzyl)(pyrimidin-4-yl)amino)methyl)quinolin-2(lH)-one was synthesized as described in EXAMPLE 35, Step2 using 4-(((6-chloropyrimidin-4- yl)(2-methylbenzyl)amino)methyl)-7,8-difluoroquinolin-2(lH)-one as a starting material. LCMS: 393 (M+H)⁺.

[0152] The activity of the compounds in Examples 1-168 as iNOS inhibitors is illustrated in the following assays.

Biological Activity Assay Enzyme Source

[0153] The source of nitric oxide synthase (NOS) enzyme can be generated in several ways including induction of endogenous iNOS using cytokines and/or lipopolysaccharide (LPS) in various cell types known in the art. Alternatively, the gene encoding the enzyme can be cloned and the enzyme can be generated in cells via heterologous expression from a transient or stable expression plasmid with suitable features for protein expression as are known in the art. Enzymatic activity (nitric oxide production) is calcium independent for iNOS, while the constitutive NOS isoforms, nNOS and eNOS, become active with the addition of various cofactors added to cellular media or extract as are well known in the art. Enzymes specified in Table 1 were expressed in HEK293 cells transiently transfected with human iNOS. DAN Assay

[0154] A major metabolic pathway for nitric oxide is to nitrate and nitrite, which are stable metabolites within tissue culture, tissue, plasma, and urine (S Moncada, A Higgs, N Eng J Med 329, 2002 (1993)). Tracer studies in humans have demonstrated that perhaps 50% of the total body nitrate/nitrite originates from the substrate for NO synthesis, L-arginine (PM Rhodes, AM Leone, PL Francis, AD Struthers, S Moncada, Biomed Biophys Res. Commun. 209, 590 (1995); L. Castillo et al, Proc Natl Acad Sci USA 90, 193 (1993). Although nitrate and nitrite are not measures of biologically active NO, plasma and urine samples obtained from subjects after a suitable period of fasting, and optionally after administration of a controlled diet (low nitrate/low arginine), allow the use of nitrate and nitrite as an index of NO activity (C Baylis, P Vallance, Curr Opin Nephrol Hypertens 7, 59 (1998)).

[0155] The level of nitrate or nitrite in the specimen can be quantified by any method known in the art which provides adequate sensitivity and reproducibility. A variety of protocols have also been described for detecting and quantifying nitrite and nitrate levels in biological fluids by ion chromatography (e.g., SA Everett et al., J. Chromatogr. 706, 437 (1995); JM Monaghan et al., J. Chromatogr. 770, 143 (1997)), high-performance liquid chromatography (e.g., M KeIm et al., Cardiovasc. Res. 41, 765 (1999)), and capillary electrophoresis (MA Friedberg et al., J. Chromatogr. 781, 491 (1997)). For example, 2,3-diaminonaphthalene reacts with the nitrosonium cation that forms spontaneously from NO to form the fluorescent product lH-naphthotriazole. Using 2,3-diaminonaphthalene ("DAN"), researchers have developed a rapid, quantitative fluorometric assay that can detect from 10 nM to 10 μM nitrite and is compatible with a multi-well microplate format. DAN is a highly selective photometric and fluorometric reagent for Se and nitrite ion. DAN reacts with nitrite ion and gives fluorescent naphthotriazole (MC Carre et al., Analusis 27, 835-838 (1999)). Table 1 provides the test results of various compounds of the subject invention using the DAN assay.

[0156] A specimen can be processed prior to determination of nitrate or nitrite as required by the quantification method, or in order to improve the results, or for the convenience of the investigator. For example, processing can involve centrifuging, filtering, or homogenizing the sample. If the sample is whole blood, the blood can be centrifuged to remove cells and the nitrate or nitrite assay performed on the plasma or serum fraction. If the sample is tissue, the tissue can be dispersed or homogenized by any method known in the art prior to determination of nitrate or nitrite. It may be preferable to remove cells and other debris by centrifugation or another method and to determine the nitrate or nitrite level using only the fluid portion of the sample, or the extracellular fluid fraction of the sample. The sample can also be preserved for later determination, for example by freezing of urine or plasma samples. When appropriate, additives may be introduced into the specimen to preserve or improve its characteristics for use in the nitrate or nitrite assay.

[0157] The "level" of nitrate, nitrite, or other NO-related product usually refers to the concentration (in moles per liter, micromoles per liter, or other suitable units) of nitrate or nitrite in the specimen, or in the fluid portion of the specimen. However, other units of measure can also be used to express the level of nitrate or nitrite. For example, an absolute amount (in micrograms, milligrams, nanomoles, moles, or other suitable units) can be used, particularly if the amount refers back to a constant amount (e.g., grams, kilograms, milliliters, liters, or other suitable units) of the specimens under consideration. A number of commercially available kits can be used. In certain instances two regioisomers correspond to a single example #, whereby the example # is given in Table 1 with two hiNOS activity values respectively.

Table 1. Biological Activity

Pharmacokinetic Assay

Metabolic Stability of Compounds Following Incubation with Male Mouse Liver

Microsomes

[0158] Liver microsomes are subcellular fractions that contain drug-metabolizing enzymes including the cytochrome P450s (CYPs), flavin monooxygenases and UDP glucuronyl transferases. These enzymes require exogenous cofactors for activity in this test system. The co-factors used consist of an NADPH regenerating system (supporting Phase I oxidation) and UDP-GA (supporting Phase II glucuronidation). The following protocol, employing murine liver microsomes, may be used to determine the in vitro metabolic stability of compounds in terms of half life. Preparation:

[0159] Potassium phosphate buffer at pH 7.4 (incubation buffer) was prepared from 110 mL IM KPO₄ monobasic and 390 mL of IM KPO₄ dibasic (500 mL total volume), which was diluted with water to 100 mM prior to addition ofl mM EDTA, 3 mM MgCl₂ and 1.25 mM D-saccharic acid 1,4-lactone monohydrate. May be stored for up to one month at 4°C. One day prior to study, to 200 mL of incubation buffer was added 5 mg alamethicin and 0.21 g bovine serum albumin (BSA), with 2 min of sonication and several hours of stirring. In 15 mL polypropylene screw-cap tubes containing 8.5 mL incubation buffer, 40 μL of compound in DMSO at 1.25 mM was added to yield a 5.88 μM solution (test article). Liver microsomes (male CD-I mouse liver microsomes from, e.g., BD Gentest, Woburn, MA; may be stored at -70⁰C until use) at a concentration of 20 mg/mL were diluted to 5 mg/mL in incubation buffer in a separate tube.

[0160] A NADPH-generating system was prepared by combining one aliquot each of the following premade ingredients:

1. 0.5 mL/ aliquot of 10 mL of 600 mM of Glucose-6-phosphate stock solution in 100 mM phosphate buffer;

2. 0.5 mL/ aliquot of 10 mL of 120 mM of NADP stock solution in 100 mM phosphate buffer; and 3. 0.5 niL/ aliquot of 10 niL of 120 Units/ml Glucose-6-phosphate dehydrogenase stock solution in 100 mM phosphate buffer, with an equal volume of 200 mM UDP-GA in 10OmM phosphate buffer stock solution prepared the same day. Each of 1-3 may be stored at -8O⁰C in aliquot vial until use.

Half-life determination:

[0161] In an appropriate incubation tube, 425 μL of the incubation buffer containing compound test article at 5.88 μM was combined with 50 μL of the 5 mg/mL diluted liver microsomes and pre-incubated in a 37°C water bath for at least 5 minutes. 25 μL NADPH Generating System was added to the incubation vial, and a 100 μL aliquot immediately removed from each incubation tube and combined with 300 μL of chilled quench reagent (1 :2 water: acetonitrile) containing internal standard. At each subsequent incubation time point (15, 30 or 60 min), an additional 100 μL was removed and quenched. The final concentration of test articles were 5 μM, and final concentration of DMSO solvent in the incubation were 0.4% (v/v). [0162] Metabolic stability was determined based on disappearance half-life. The percent (%) test article remaining was determined at each incubation time-point, relative to the zero-time sample. These results were transformed by natural log, such that first-order decline of substrate concentrations with time produced a straight line. This line was fit with a standard linear regression algorithm, and the slope determined. If data points suggested higher order elimination kinetics (non linear), then the earliest data points were used for slope calculation. Disappearance half-life in minutes (Ty₂) was calculated by multiplying the inverse of this slope by the natural log of 2 {In∑). All data analysis was performed with Microsoft Excel (ver 2007). Results are reported in Table 2 below, in which A represents a half life of < 30 min, B represents a half life of >30 min but <120 min, and C represents a half life of > 120 min, wherein said values are generally representative of a mean value across several runs of the same test. Table 2. Metabolic Stability

In Vivo Assays

Murine LPS Challenge

[0163] Inhibition of induction of iNOS can be quantified via the LPS challenge. Inflammation, edema, and the onset of sepsis can be observed following an injection of lipopolysaccharide (LPS), a substance produced by Gram-negative bacteria. Injection of LPS has been shown to induce iNOS transcription, leading to measureable increases in both iNOS and NO. (Iuvone T et al., Evidence that inducible nitric oxide synthase is involved in LPS-mediated plasma leakage in rat skin through the activation of nuclear factor-κB, Br J Pharm 1998:123 1325-1330.) As described above, the level of nitric oxide in the specimen can be quantified by correlation with plasma nitrate or nitrite levels via chemiluminescence, fluorescence, spectophotometric assays, or by any method known in the art which provides adequate sensitivity and reproducibility, including those described above.

[0164] Male Lewis rats weighing 150-250 g are often used in the studies. Rats may be fasted for up to 16 hours prior to the administration of LPS. Free access to water is maintained. Test compounds are administered with LPS or alone. Compounds are dissolved in the vehicle of 0.5% methycele/0.025% Tween 20 or 20% encapsin for oral administration. For the intravenous dosing, compounds are dissolved in saline or 0.5-3%DMSO/20% encapsin. Compounds may also be dissolved in 10% stock solution of 90% PGE-400, 5% Tween 80, 5%PVP + 90% CMC. The dosing volumes are 1-2 ml for oral and 0.3-1 ml for intravenous administration. [0165] LPS is injected intravenously (under anesthesia) or intraperitoneally in sterile 0.9% saline (sodium chloride ) at a dose between 0.1-10 mg/kg in a volume not excess to 1 ml. The needle is 26-30 gauge. Following LPS injection, rats usually exhibit flu-like symptoms, principally involving lack of activity and diarrhea. In routine screening experiments, rats are sacrificed 1.5-6 hr after LPS injection and a terminal bleeding is performed under anesthesia to collect 1-3 ml blood samples and then animals are then euthanized by CO₂.

[0166] A protocol using mice instead of rats was adapted from the methods disclosed above, adjusting for species and weight differences, for example, using modifications well known in the art. Compounds were administered at 30 mpk. Results as percent inhibition are shown below in Table 3. Regarding Example 2: * indicates that the compound was formulated in 9% PGE-400, 0.5% Tween80, 0.5% PVP-k30 and 90% CMC; ** indicates that the compound was formulated in 1% DSMO/20% encapsain; and *** indicates that the compound was formulated in 0.5% MC/0.025% Tween 20. Table 3. Inhibition of Inflammation

[0167] From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of this invention, and without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions.

Claims

CLAIMSWhat is claimed is:

1. A compound of structural Formula II

II

R⁴ is selected from the group consisting of lower aryl and lower heteroaryl, either of which may be optionally substituted with one to three substituents selected from the group consisting of halogen, cyano, lower alkyl, lower haloalkyl, lower amino, lower aminoalkyl, lower alkoxy, and lower haloalkoxy;

R⁵ is selected from the group consisting of monocyclic lower heteroaryl, monocyclic lower aryl, monocyclic lower cycloalkyl, and lower alkyl, any of which may be optionally substituted with one to three substituents selected from the group consisting of halogen, cyano, lower alkyl, lower haloalkyl, lower amino, lower aminoalkyl, lower alkoxy, lower haloalkoxy, monocyclic lower aryl, monocyclic lower heteroaryl, and monocyclic lower heterocycloalkyl;

R⁶, R⁷, R⁸ and R⁹ are independently selected from the group consisting of hydrogen, lower alkyl, and halogen; and n is 0, 1, or 2.

2. The compound as recited in Claim 1, wherein R⁸ and R⁹ are hydrogen.

3. The compound as recited in Claim 2, wherein n is 0 or 1.

4. The compound as recited in Claim 3, wherein R⁶ is selected from the group consisting of methyl, methoxy, chlorine, fluorine, and hydrogen.

5. The compound as recited in Claim 4, wherein R⁶ is hydrogen.

6. The compound as recited in Claim 5, wherein R⁷ is fluorine.

7. The compound as recited in Claim 5, wherein R⁷ is hydrogen.

8. The compound as recited in Claim 5, wherein R⁵ is selected from the group consisting of isopropyl, t-butyl, cyclopentyl, cyclopropyl, phenyl, pyrimidine, pyrazine, pyridazine and pyridine, any of which may be optionally substituted with one or two substituents selected from the group consisting of halogen, cyano, lower alkyl, lower haloalkyl, lower amino, lower aminoalkyl, monocyclic lower heterocycloalkyl, lower alkoxy, and lower haloalkoxy.

9. The compound as recited in Claim 5, wherein R⁴ is selected from the group consisting of pyridine, pyridazine, pyrimidine, pyrazine, imidazole, thienopyrimidine, pyrazolopyrimidine, furopyridine, quinolone, isoquinoline, quinoxaline, quinazoline, benzimidazole, benzoxazole, and benzthiazole, any of which may be optionally substituted with one to three substituents selected from the group consisting of halogen, cyano, lower alkyl, lower haloalkyl, lower amino, lower aminoalkyl, monocyclic lower heterocycloalkyl, lower alkoxy, and lower haloalkoxy.

10. The compound as recited in Claim 9, wherein R⁵ is selected from the group consisting of isopropyl, t-butyl, cyclopentyl, cyclopropyl, cyclopropylmethyl, phenyl, and pyridine, any of which may be optionally substituted with one or two substituents selected from the group consisting of halogen, lower alkyl, trifluoromethoxy, and methoxy.

11. A compound selected from the group consisting of Examples 1 to 168.

12. A compound as recited in Claim 1 for use as a medicament.

13. A compound as recited in Claim 1 for use in the manufacture of a medicament for the prevention or treatment of a disease or condition ameliorated by the inhibition ofiNOS.

14. A pharmaceutical composition comprising a compound as recited in Claim 1 together with a pharmaceutically acceptable carrier.

15. A method of inhibition ofiNOS comprising contacting iNOS with a compound as recited in Claim 1.

16. A method of treatment of a iNOS-mediated disease comprising the administration of a therapeutically effective amount of a compound as recited in Claim 1 to a patient in need thereof.

17. The method as recited in claim 16, wherein said disease is selected from the group consisting of pain, an inflammatory disease, an autoimmune disease, and a respiratory disease.

18. The method as recited in claim 17, wherein said disease is selected from the group consisting of neuropathy, inflammatory pain, nerve injury, peripheral neuropathy, diabetic neuropathy, chronic pain, intractable cancer pain, complex regional pain syndrome, and entrapment neuropathy (carpel tunnel syndrome), neuropathic pain, acute herpes zoster (shingles), postherpetic neuralgia (PHN), , chemotherapy- induced neuropathy, HIV neuropathy, ocular pain, post-surgical pain, dental pain/dental extraction, pain resulting from dermal injury, lower back pain, headaches, migraine, tactile allodynia, and hyperalgesia.

19. The method as recited in claim 18, wherein said pain is inflammatory pain.

20. The method as recited in claim 18, wherein said pain is a result of dermal injury, and said dermal injury is a burn.

21. The method as recited in claim 18, wherein said disease is selected from the group consisting of neuropathic pain and postherpetic neuralgia.

22. The method as recited in claim 17, wherein said disease is is an inflammatory disease selected from the group consisting of sepsis, arthritis, rheumatoid arthritis, osteoarthritis, osteoporosis, systemic lupus erythematosus, reflux esophagitis, diarrhea, inflammatory bowel disease, Crohn's disease, gastritis, irritable bowel syndrome and ulcerative colitis, and psoriasis.

23. The method as recited in claim 17, wherein said disease is is a respiratory disease selected from the group consisting of asthma, chronic obstructive pulmonary disease, including chronic bronchitis, acute respiratory distress syndrome, pneumonia, pulmonary hypertension, and status asthamticus.

24. A method of treatment of a iNOS-mediated disease comprising the administration of: a. a therapeutically effective amount of a compound as recited in Claim 1; and b. another therapeutic agent.