NZ613181B2 - Heterocyclic compounds for the inhibition of pask - Google Patents

Abstract

Provided are quinoxaline derivative compounds of the general formula (I) where the variables are as described in the specification. Examples of the compounds are 3-(1,2,3,4-Tetrahydroquinolin-1(2H)-yl)-2-(4-fluorophenyl)quinoxaline-6-carboxylic acid, 2-(5-Fluoro-1-benzofuran-2-yl)-3-(6-methoxy-1,2,3,4-tetrahydroquinolin-1-yl)quinoxaline-6-carboxylic acid and 3-[2H,5H,6H,7H,8H-[1,3]Dioxolo[4,5-g]quinolin-5-yl]-2-(4-fluorophenyl)quinoxaline-6-carboxylic acid. The compounds are inhibitors of PAS kinase (PASK). The compounds may be useful in the treatment of cancer or metabolic diseases such as diabetes or hyperlipidemia. 3,4-tetrahydroquinolin-1-yl)quinoxaline-6-carboxylic acid and 3-[2H,5H,6H,7H,8H-[1,3]Dioxolo[4,5-g]quinolin-5-yl]-2-(4-fluorophenyl)quinoxaline-6-carboxylic acid. The compounds are inhibitors of PAS kinase (PASK). The compounds may be useful in the treatment of cancer or metabolic diseases such as diabetes or hyperlipidemia.

Description

CYCLIC COMPOUNDS FOR THE INHIBITION OF PASK This ation claims the benefit of ty of United States Provisional Applications No. 61/430,013, filed y 5, 2011 and No. 61/449,020, filed March 3, 2011, the disclosures of which are hereby incorporated by reference as if written herein in their entireties.

Disclosed herein are new heteroeyclic compounds and itions and their application as pharmaceuticals for the treatment of disease. Methods of inhibiting PAS Kinase (PASK) activity in a human or animal subject are also provided for the treatment of diseases such as diabetes mellitus.

The regulation of glycogen metabolism is critical for the nance of glucose and energy homeostasis in mammals. Glycogen, a large branched polymer of e, acts as a reserve of carbon and energy in a y of organisms. In mammals, the most important stores are found in the liver and al muscle (1). Liver glycogen is required to efficiently buffer blood glucose levels during fasting, whereas muscle glycogen is primarily used locally as a fuel for muscle contraction (2). Dysregulation of glycogen lism has been implicated in the development of many diseases, including Type 2 diabetes mellitus (3, 4).

The synthesis of glycogen is primarily controlled through regulation of the enzyme glycogen synthase (GYS, various isoforms), which catalyzes bulk glycogen sis (5, 6, 7).

The muscle m of glycogen se (GYSl) is inactivated by reversible phosphorylation that occurs at nine distinct sites within the enzyme (8, 9, 10). In the best characterized form of glycogen‘synthase, the phosphorylation sites are clustered at the N and C termini (14). Glycogen synthase kinase-3 (GSK-3), an insulin~dependent kinase which has long been implicated in the stepwise phosphorylation of four key sites in the C terminus of glycogen synthase including Ser- 640 (one of the most important endogenous regulatory phosphorylation sites in mammalian glycogen synthase (15, 32) and Ser—644 (10, 11—13, 24, 25). GSK-3, however, is not the sole kinase that orylates C-terminal regulatory sites; GSK—3—independent mechanisms also exist, since serine-to-alanine substitutions at Ser—7 and Ser—lO block GSK—3‘mediated phosphorylation of the important regulatory sites Ser-640 and Ser-644, and phosphorylation at these sites still occurs.

PASK (purine-analog sensitive kinase, PAS ) is a PAS domain-containing serinefthreonine kinase, and genetic experiments in S. cerevisiae yeast have implicated PASK as a physiological regulator of glycogen synthase and glycogen accumulation (16, 17). As with the WO 94462 PCT/U82012/020281 Attorney Docket No. BIOEOOO9-40l-PC entire glycogen synthase regulatory , PASK is highly conserved from yeast to man.

Human PASK (hPASK) phosphorylates glycogen synthase primarily at Ser—640, causing near complete inactivation. It is sting to note that the exact site of PASK-dependent orylation is r but not identical in yeast and mammalian glycogen synthase (l8, l9); yeast PASK orylates glycogen synthase at the site analogous to Ser—644, four residues C- terminal (18). It appears that the hPASK mid region (residues 444—95 5) is required for efficient phosphorylation of glycogen synthase in vitro and for interaction with glycogen synthase in cells: an hPASK mutant (A955) g the noncatalytic N terminus was unable to efficiently phosphorylate glycogen synthase. Since this region is not required for the orylation of generic, nonphysiological substrates, such as histories and synthetic peptides, it has been proposed that the mid region of hPASK is essential for substrate-targeting. A similar substrate region has been discovered in many protein kinases (26—29). Unlike GSK—3, the activity of hPASK has been shown to be independent of insulin and probably regulated d by a more direct metabolic signal (23). c and proteomic screens using yeast PASK fied a number of substrates and implicated this kinase in the regulation of carbohydrate metabolism and translation (18). It has previously been shown that yeast PASK phosphorylates glycogen synthase in vitro and that strains lacking the PASK genes (PSKJ and PSKZ) had elevated glycogen se activity and an approximately 5- to 10-fold lation of glycogen relative to wild-type strains, consistent with impaired ability to phosphorylatc glycogen synthase in vivo (18). Because glycogen sis and translation are two processes tightly regulated in response to nutrient availability and because PAS domains are frequently involved in metabolic sensing, a role for PASK in the cellular response to metabolic status has been proposed. Indeed, it was recently demonstrated that mammalian PASK plays a role in the cellular response to nutrients The catalytic activity of PASK in pancreatic islet B-cells is rapidly increased in se to glucose addition, and PASK is required for the glucose—responsive expression of some B—eell genes, including preproinsulin (23).

PASK catalytic activity is not responsive to glucose alone, however. The interaction between the hPASK ion and glycogen synthase is regulated by at least two factors. First, the PAS domain of PAS kinase plays a ve role in regulating this interaction. If the PAS domain is deleted or disrupted, hPASK associates more stably with glycogen synthase. PAS domain function is usually controlled by the metabolic status of the host cell, as has been suggested for the PASK PAS domain (23). This observation raises the intriguing possibility that the hPASK—glycogen synthase interaction is regulated by the metabolic status of the cell, thereby enabling an onal layer of lic regulation of glycogen synthesis. Second, glycogen PCT/U82012/020281 Attorney Docket No. BlOEOOO9-40l ~PC negatively regulates the hPAS K—glycogen synthase interaction, which would initially seem rintuitive, since glycogen would thereby stimulate its own continued synthesis. It is possible, however, that this mechanism exists to spatially coordinate the synthesis of glycogen. it is ng increasingly apparent that glycogen is synthesized in cells in a highly organized spatial pattern (30). Perhaps one function of hPASK is to maintain free, unlocalized glycogen synthase in a phosphorylated, inactive form until it is properly localized to an existing, properly organized en particle. These data strongly suggest that the hPASK ion plays an important role in targeting hPASK catalytic activity to specific substrates within the cell.

Since hPASK has been recently implicated in glucose~sensing and glucose-responsive transcription, it appears likely that glucose signaling by means of hPASK affects en metabolism in viva. It is well established that derangement in glycogen metabolism is one of the hallmarks of both Type 1 and Type 2 diabetes (’20) and related conditions (21), including a y of hreatening cardiovascular conditions (22). Using PASK] mice, it has further been demonstrated that PASK is indeed required for normal insulin secretion by pancreatic B cells, and that PASK deletion results in nearly complete resistance to the phenotypes caused by a high-fat diet, including obesity, insulin resistance and c fat accumulation. Therefore, PASK inhibition would se a system for the metabolic control of glucose utilization and storage in mammalian cells, and offer a new method to treat metabolic diseases including but not limited to diabetes and its complications, the metabolic syndrome, insulin ance, and various cardiovascular conditions.

Novel nds and pharmaceutical compositions, certain of which have been found to inhibit PASK have been discovered, together with methods of sizing and using the compounds including methods for the treatment of PASK-mediated diseases in a patient by administering the compounds.

In certain embodiments of the present invention, a compound has structural Formula (R19)n x3 o N N R1 N R3 or a pharmaceutically acceptable salt, ester, or prodrug thereof, wherein: 2012/020281 ey Docket No. BIOEOOO9-40l -PC R1 is chosen from aryl and heteroaryl, either of which may be ally tuted with one or more substitucnts chosen from hydrogen, halo, alkyl, alkenyl, alkynyl, cycloalkyl, kyl, aryl, aralkyl, heterocyclyl, heteroaryl, heterarylalkyl, CN, alkoxy, alkylamino, dialkylamino, NHSOZR12, NHSOzNHRn, NHCORn, NHCONHRIZ, CONHng, CONRnaRIZb, y, CF3, CHFZ. CHZF, SOan, SOZNHRIZ, OCF3, OCHFZ. and OCHZF; R3 is chosen from hydrogen and hydroxyl; R12, R123 and R121, are independently chosen from hydrogen, C1—C6 alkyl, aryl, heteroaryl, aralkyl and heteroaralkyl, or taken er, R123 and Rm, may form a heterocycloalkyl or heteroaryl, any of which may be optionally substituted; R19 is chosen from hydrogen, lower alkyl, l, l, hydroxy, alkoxy, CF3, CHFZ. CHZF, — COOH, OCF3, OCHFz. OCHgF halo, alkylsulfonyl, cyano, nitro, alkylamino, dialkylamino, NHSOZR 12, NHSOZNHR 12, NHCOR 12, NHCONHR12, CONI-IRIZ, CONRnaRlzb. SOgNngaRnb, aryl, and heteroaryl; X3 is chosen from CH2, NRIZ, and O; and n is an integer from 0 — 4. [01 1] Certain compounds disclosed herein may possess useful PASK modulating activity, and may be used in the treatment or prophylaxis of a disease or condition in which PASK plays an active role. Thus, in broad aspect, certain embodiments also provide pharmaceutical itions comprising one or more compounds disclosed herein together with a ceutically acceptable carrier, as well as methods of making and using the compounds and compositions. Certain embodiments provide methods for modulating PASK. Other embodiments provide methods for treating a PASK—mediated disorder in a patient in need of such treatment, comprising administering to said patient a therapeutically ive 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 cture of a medicament for the treatment of a disease or condition ameliorated by the inhibition of PASK.

In an embodiment, compounds of Formula I are provided wherein n is an integer from 0-2.

In an embodiment, compounds of Formula I are provided wherein R1 is phenyl.

In an embodiment, compounds of Formula I are ed wherein R1 is substituted with one or more halo substituents.

In an embodiment, compounds of Formula I are provided wherein said halo substitucnt is fluoro.

Attorney Docket No. B10E0009PC In an embodiment, compounds of Formula I are ed wherein R1 is 4— fluorophenyl.

In an embodiment, compounds of Formula I are ed wherein R3 is hydrogen.

In an embodiment, compounds of Formula 1 are provided n X3 is CH; r provided is a compound as disclosed above for use as a medicament.

Further provided is a compound as sed above for use in the manufacture of a medicament for the prevention or treatment of a e or condition ameliorated by the inhibition of PASK.

Further provided is a pharmaceutical ition comprising a nd as recited above together with a ceutically acceptable carrier.

Further provided is a method of inhibiting PASK comprising contacting PASK with a compound as sed above.

Further provided is a method of treatment of a disease comprising the administration of a therapeutically effective amount of a compound as disclosed above to a patient in need thereof.

Further provided is the method as recited above wherein said disease is chosen from cancer and a metabolic disease.

Further provided is the method as recited above wherein said disease is a metabolic disease.

Further provided is the method as recited above wherein said metabolic disease is chosen from metabolic syndrome, diabetes, dyslipidemia, fatty liver disease, non-alcoholic steatohepatitis. obesity, and insulin resistance. r provided is the method disclosed above wherein said diabetes is Type II diabetes.

Further provided is the method as disclosed above wherein said dyslipidemia is ipidemia.

Further provided is a method for achieving an effect in a patient comprising the administration of a therapeutically effective amount of a compound as disclosed above to a patient, wherein the effect is selected from the group consisting of reduction of triglycerides, reduction of cholesterol, and reduction of hemoglobin Ale.

Further provided is the method as disclosed above wherein said cholesterol is chosen from LDL and VLDL cholesterol.

Further provided is the method as disclosed above wherein said triglycerides are chosen from plasma triglycerides and liver triglycerides.

PCT/U52012/020281 Attorney Docket No. O9-40l —PC Further provided is a method of ent of a PASK—mediated disease comprising the administration of: a. a therapeutically effective amount of a compound as disclosed above; and b. another therapeutic agent.

As used herein, the temis below have the meanings indicated.

When ranges of values are disclosed, and the notation “from n1 to n;” is used, where n1 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 ing the end values. By way of example, the range “from 2 to 6 carbons” is intended to include two, three, four, five, and six s, since carbons come in integer units. Compare, by way of example, the range “from 1 to 3 uM (micromolar),” which is intended to include 1 uM, 3 uM, and everything in between to any number of significant figures (c.g., 1.255 uM, 2.1 uM, 2.9999 uM, etc.).

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 ular 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 tood 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. [03 6] The term ” as used , alone or in combination, refers to a yl attached to an alkenyl, alkyl, aryl, cycloalkyl, heteroaryl, heterocycle, or any other moiety were the atom attached to the carbonyl is carbon. An l” 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 methylearbonyl and ethylcarbonyl. Examples of acyl groups include formyl, alkanoyl and aroyl.

The term “alkenyl,” as used herein, alone or in combination, refers to a straight—chain or branched-chain hydrocarbon radical having one or more double bonds and containing from 2 to 20 carbon atoms. In n 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 ons such as ethenylene [(—CH=CH—), (—C::C—)]. Examples of suitable alkenyl radicals include ethenyl, propenyl, 2-methylpropenyl, 1,4—butadieny1 and the like. Unless otherwise specified, the term “alkenyl” may include “alkenylene” groups.

The term “alkoxy,” as used , alone or in combination, refers to an alkyl ether radical, wherein the term alkyl is as defined below. Examples of suitable alkyl ether radicals PCTHJS2012/020281 Attorney Docket No. BIOEOOO9-40l -PC include methoxy, ethoxy, n-propoxy, isopropoxy, n~butoxy, utoxy, sec—butoxy, tert-butoxy, and the like. [03 9] The term “alkyl,” as used herein, alone or in combination, refers to a straight-chain or branched-chain alkyl radical ning 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 radicals 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 ons, such as methylene (~CH2—).

Unless otherwise specified, the term “alkyl” may e ene” .

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, methy1amino, N,N-ethyhnethylamino and the like.

The term “alkylidene,” as used , 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.

The term “alkylthio,” as used herein, alone or in combination, refers to an alkyl thioether (R—S—) radical wherein the term alkyl is as d above and wherein the sulfur may be singly or doubly oxidized. Examples of suitable alkyl thioether radicals e methylthio, ethylthio, n—propylthio, isopropylthio, n-butylthio, iso—butylthio, sec-butylthio, ten—butylthio, methanesulfonyl, ethanesulfinyl, and the like.

The term yl,” as used , alone or in combination, refers to a straight-chain or branched chain hydrocarbon l having one or more triple bonds and containing from 2 to 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 “alkynylcnc” refers to a carbon-carbon triple bond attached at two positions such as ethynylene (—C:::C—, — CEC—). Examples of alkynyl radicals include ethynyl, propynyl, hydroxypropynyl, butyn-l—yl, butyn-Z-yl, pentyn—l-yl, 3—methylbutyn—l-yl, hexyn—Z—yl, and the like. Unless otherwise specified, the term “alkynyl” may include ylene” groups.

The terms “amido” and “carbamoyl,” as used herein, alone or in ation, refer to an amino group as described below attached to the parent molecular moiety h 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 Attorney Docket No. BiOEOOO9-40l -PC 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—). [045 J 'lhe term “amino,” as used , alone or in combination, refers to —NRR’, n R and R, are independently chosen from 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 ally substituted.

The term "aryl," as used , 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" es aromatic groups such as phenyl, naphthyl, anthracenyl, and phenanthryl.

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.

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.

The term “arylalkyl” or “aralkyl,” as used herein, alone or in ation, refers to an aryl group attached to the parent molecular moiety through an alkyl group.

The term “arylalkynyl” or “aralkynyl,” as used herein, alone or in ation, refers to an aryl group attached to the parent molecular moiety through an alkynyl group.

The term “arylalkanoyl” or “aralkanoyl” or “aroyl,” as used , alone or in combination, refers to an acyl radical derived from an aryl—substituted alkanecarboxylic acid such as benzoyl, napthoyl, phenylacetyl, 3—phenylpropionyl (hydrocinnamoyl), 4-phenylbutyryl, (2— naphthyl)acetyl, 4-chlorohydrocinnamoyl, and the like, The term aryloxy as used , alone or in combination, refers to an aryl group attached to the parent molecular moiety through an oxy.

The terms ” and “benz,” as used herein, alone or in ation, refer to the divalent radical C6H4= derived from benzene. Examples include benzothiophene and benzimidazole.

The term “carbamate,” as used herein, alone or in combination, refers to an ester of ic 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 d herein.

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.

PCT/USZOIZ/OZOZSI Attorney Docket No. BTOE0009PC 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.

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

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 .

The term “cyano,” as used herein, alone or in combination, refers to —CN.

The term “cycloalkyl,” or, atively, “carbocycle,” as used herein, alone or in combination, refers to a saturated or lly saturated monoeyclic, bicyclic or lic 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 ally substituted as defined herein. In certain embodiments, said cycloalkyl will comprise from 3 to 7 carbon atoms. Examples of such cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, tetrahydronapthyl, indanyl, octahydronaphthyl, 2,3-dihydro-1H-indenyl, adamantyl and the like.

“Bicyclic” and “tricyelic” as used herein are intended to e both fused ring systems, such as dronaphthalene, octahydronaphthalene as well as the multicyclic (multicentered) saturated or partially unsaturated type. The latter type of isomer is exemplified in general by, bicyclo[1, 1,1]pentane, camphor, adamantane, and bicyelo[3,2, l ]octane.

The term “ester,” as used herein, alone or in combination, refers to a carboxy group bridging two es linked at carbon atoms.

The term “ether,” as used , alone or in combination, refers to an oxy group bridging two moieties linked at carbon atoms.

The term “halo,” or “halogen,” as used herein, alone or in combination, refers to fluorine, chlorine, bromine, or iodine.

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.

The term “haloalkyl,” as used herein, alone or in combination, refers to an alkyl radical having the g as defined above wherein one or more hydrogens are replaced with a halogen. Specifically embraced are monohaloalkyl, dihaloalkyl and polyhaloalkyl radicals. A monohaloalkyl radical, for one example, may have an iodo, bromo, chloro or fluoro atom within the l. Dihalo and polyhaloalkyl radicals may have two or more of the same halo atoms or a combination of different halo radicals. es of haloalkyl radicals include fluoromethyl, difluoromethyl, trifluoromethyl, methyl, dichloromethyl, trichloromethyl, PCT/USZOIZ/OZOZSI Attorney Docket No. BlOEOOO9-40l -PC pentafluoroethyl, heptafluoropropyl, rochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl. “Haloalkylene” refers to a haloalkyl group attached at two or more positions, Examples include methylene (—CFH—), difluoromethylene (—Cb'z —), chloromethylene (—CHCl—) and the like.

The term "heteroalkyl," as used herein, alone or in combination, refers to a stable ht or ed chain hydrocarbon radical, or ations f, 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 chosen from O, N, and S, and wherein the nitrogen and sulfur atoms may ally be oxidized and the nitrogen heteroatom may optionally be substituted or 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, H— OCH3.

The term "heteroaryl," as used herein, alone or in combination, refers to a 3 to 7 membered unsaturated heteromonocyelic ring, or a fused monocyclic, bicyclic, or tricyelic ring system in which at least one of the fused rings is aromatic, which contains at least one atom chosen from O, S, and N. In certain ments, said heteroaryl will comprise from 5 to 7 carbon atoms. The term also embraces fused polycyclic groups wherein heterocyelic rings 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 yl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, pyranyl, fury], thienyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, isothiazolyl, indolyl, isoindolyl, indoliainyl, benzimidazolyl, yl, isoquinolyl, quinoxalinyl, quinazolinyl, indazolyl, benzotriazolyl, benzodioxolyl, benzopyranyl, azolyl, benzoxadiazolyl, benzothiazolyl, benzethiadiazolyl, benzofuryl, benzothienyl, chromonyl, coumarinyl, benzopyranyl, tetrahydroquinolinyl, tetrazolopyridazinyl, tetrahydroisoquinolinyl, thienopyridinyl, furopyridinyl, pyrrolopyridinyl and the like. Exemplary tricyclic heterocyelic groups include earbazolyl, benzidolyl, phenanthrolinyl, dibenzofuranyl, acridinyl, thridinyl, xanthenyl and the like.

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 heterocyelic group containing at least one heteroatom as a ring , wherein each said heteroatom may be independently chosen from nitrogen, oxygen, and sulfur In certain embodiments, said hetercycloalkyl will comprise from 1 to 4 heteroatoms as ring members. In further embodiments, said hetercycloalkyl will comprise from 1 to 2 heteroatoms as ring members. In n embodiments, said hetercycloalkyl will comprise from PCT/U82012/020281 Attorney Docket No. BlOEOOO9—40l -PC 3 to 8 ring members in each ring. In further embodiments, said hetercycloalkyl will comprise from 3 to 7 ring members in each ring. In yet further embodiments, said ycloalkyl will comprise from 5 to 6 ring members in each ring. ocycloalkyl” and “heterocycle” are intended to include sulfones, sulfoxides, N-oxides of tertiary nitrogen ring members, and carbocyclic fused and benzo fused ring s; additionally, both terms also include s where a heterocycle ring is fused to an aryl group, as defined herein, or an additional heterocycle group. Examples of cycle groups include aziridinyl, azetidinyl, 1,3-benzodioxoly1, dihydroisoindolyl, dihydroisoquinolinyl, dihydrocinnolinyl, dihydrobenzodioxinyl, dihydro[1,3]oxazolo[4,5-b]pyridinyl, benzothiazolyl, dihydroindolyl, dihy—dropyridinyl, 1,3— dioxanyl, 1,4-dioxanyl, l,3~dioxolany1, isoindolinyl, morpholinyl, piperazinyl, pyrrolidinyl, tetrahydropyridinyl, piperidinyl, rpholinyl, 3,4—rnethylenedioxyphenyl and the like. The heterocycle groups may be optionally substituted unless specifically prohibited.

The term “hydrazinyl” as used herein, alone or in combination, refers to two amino groups joined by a single bond, i.e., —N—N— and not embodied in a ring.

The term “hydroxy,” as used , alone or in combination, refers to —OH.

The term “hydroxyalkyl,” as used herein, alone or in combination, refers to a hydroxy group ed to the parent molecular moiety through an alkyl group.

The term “imino,” as used herein, alone or in combination, refers to =N—.

The term “iminohydroxy,” as used herein, alone or in combination, refers to =N(OH) and =N—O—.

The phrase “in the main chain” refers to the longest contiguous or adjacent chain of carbon atoms starting at the point of ment of a group to the compounds of any one of the formulas disclosed herein.

The term “isoeyanato” refers to a —NCO group.

The term “isothiocyanato” refers to a ~NCS group.

The phrase “linear chain of atoms” refers to the t straight chain of atoms independently selected from , nitrogen, oxygen and sulfur.

The term “lower,” as used , alone or in a combination, where not otherwise specifically defined, means containing from 1 to and including 6 carbon atoms.

The term “lower aryl,” as used , alone or in combination, means phenyl or naphthyl, which may be optionally substituted as provided.

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 said members may be heteroatoms chosen from O, S, and N, or 2) bieyclic heteroaryl, wherein each Attorney Docket No. 09-40l -PC of the fused rings comprises five or six ring members, comprising between them one to four heteroatoms chosen from O, S, and N.

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, entyl, and cyclohexyl. [082.] 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 chosen from O, S, and N. Examples of lower heterocycloalkyls include pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, and linyl.

Lower heterocycloalkyls may be unsaturated.

The term “lower amino,” as used herein, alone or in combination, refers to —NRR', wherein R and R, are independently chosen from 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 cycloalkyl, either of which may be optionally substituted.

The term “mercaptyl” as used herein, alone or in combination, refers to an RS— group, where R is as defined herein.

The term “nitro,” as used herein, alone or in ation, refers to —N02.

The terms “oxy” or “oxa,” as used herein, alone or in combination, refer to —O—.

The term “em,” as used , alone or in ation, refers to =0.

The term “perhaloalkoxy” refers to an alkoxy group where all of the hydrogen atoms are replaced by halogen atoms.

The term “perhaloalkyl” as used herein, alone or in ation, refers to an alkyl group where all of the hydrogen atoms are replaced by n atoms.

The terms “sulfonate,” “sulfonic acid,” and “sulfonic,” as used herein, alone or in combination, refer the —SO3H group and its anion as the sulfonic acid is used in salt formation.

The term “sulfanyl,” as used herein, alone or in combination, refers to —S—.

The term “sulfinyl,” as used herein, alone or in combination, refers to —S(O)—.

The term “sulfonyl,” as used herein, alone or in combination, refers to —S(O)2—.

The term “N-sulfonamido” refers to a RS(=O)2NR’- group with R and R’ as defined herein.

The term “S-sulfonamido” refers to a -S(=O)2NRR’, group, with R and R’ as defined herein.

PCT/U52012/020281 Attorney Docket No. BTOE0009-401 ~PC 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 sulfinyl and sulfonyl, are included in the definition of thia and thio.

[O97] 'lhe term “thiol,” as used herein, alone or in combination, refers to an —SH group.

The term “thiocarbonyl,” as used herein, when alone includes thioformyl —C(S)H and in combination is a —C(S)— group.

The term “N—thiocarbamyl” refers to an ROC(S)NR’— group, with R and R’as d herein.

The term “O-thiocarbamyl” refers to a —OC(S)NRR’, group with R and R’as defined herein.

The term “thiocyanato” refers to a —CNS group.

The term “trihalomethoxy” refers to a X3CO— group where X is a halogen.

Any definition herein may be used in combination with any other tion 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 le h an amide group, and the term alkyl would represent an alkoxy group attached to the parent molecule through an alkyl group.

When a group is defined to be “null,” what is meant is that said group is absent.

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 ular designated set of groups, alone or in combination: lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower heteroalkyl, lower heteroeycloalkyl, lower haloalkyl, lower haloalkenyl, lower kynyl, lower perhaloalkyl, lower perhaloalkoxy, lower cycloalkyl, phenyl, aryl, aralkyl, aryloxy, lower , lower haloalkoxy, oxo, lower acyloxy, carbonyl, carboxyl, lower alkylcarbonyl, lower yester, lower carboxamido, cyano, hydrogen, halogen, hydroxy, amino, lower alkylamino, arylamino, amido, nitro, thiol, lower alkylthio, lower haloalkylthio, lower perhaloalkylthio, io, sulfonate, sulfonic acid, stituted silyl, N3, SH, SCHg, C(O)CH3, COzCH3, COgH, pyridinyl, thiophene, furanyl, lower carbamate, and lower urea. Two substituents may be joined together to form a fused five-, six-, or membered carbocyclie or heterocyclic ring consisting of zero to three heteroatoms, for example forming methylenedioxy or ethylenedioxy. An optionally substituted group may be tituted (e.g., 3), fully substituted (e.g., —CF2CF3), monosubstitutcd (cg, - CHzCHzF) or substituted at a level anywhere iii-between fully substituted and monosubstituted PCT/USZOIZ/OZOZS] Attorney Docket No. BlOEOOO9-40l -PC (erg, —CH2CF3). Where tuents are d 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 d, often immediately following the phrase, “optionally substituted with.” The term R or the term R’, appearing by itself and t a number designation, unless otherwise defined, refers to a moiety chosen from hydrogen, alkyl, cycloalkyl, heteroalkyl, aryl, heteroaryl and heterocycloalkyl, any of which may be ally 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 R" where n=(1, 2, 3, ...n), every substituent, and every term should be understood to be independent of every other in terms of ion from a group. Should any variable, tuent, or term (cg. 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 r 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. tric 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, enantiomerie, and epimeric forms, as well as d-isomers and l-isomers, and mixtures thereof. Individual stereoisomers of compounds can be prepared synthetically from commercially available starting materials which n chiral centers or by preparation of mixtures of enantiomeric products followed by separation such as conversion to a mixture of reomers followed by separation or recrystallization, chromatographic techniques, direct tion of enantiomers on chiral chromatographic columns, or any other appropriate method known in the art. ng compounds of particular chemistry 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 en (Z) isomers as well as the appropriate mixtures thereof. Additionally, compounds may exist as tautomers; all tautomeric isomers are ed by this invention. Additionally, the compounds disclosed herein can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, PCT/U52012/020281 Attorney Docket No. BlOEOOO9—40l ~PC ethanol, and the like. In general, the solvated forms are considered equivalent to the unsolvated forms.

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 be single, double, or triple unless otherwise specified. A dashed line n two atoms in a drawing of a molecule tes that an additional bond may be t or absent at that position.

The term se” 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.

The term "combination therapy” means the administration of two or more therapeutic agents to treat a therapeutic condition or disorder described in the present sure. Such administration encompasses inistration 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 s of the drug combination in treating the conditions or disorders described herein. [01 l l] “PASK tor " as used herein refers to a compound that exhibits an (K350 / EC50) with t to PASK activity of no more than about 100 uM and more lly not more than about 50 uM, as measured in the PASK assay described generally hereinbelow. ICSO is that concentration of inhibitors which reduces the activity of PASK to half-maximal level. Certain compounds disclosed herein have been discovered to exhibit inhibition against PASK.

The phrase peutically ive” 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.

The term “therapeutically acceptable” refers to these compounds (or salts, prodrugs, tautomers, zwitterionic forms, etc.) which are suitable for use in t with the tissues of patients without undue toxicity, irritation, and ic response, are commensurate with a able benefit/risk ratio, and are effective for their intended use.

As used herein, reference to ment" 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.

WO 94462 PCT/U52012/020281 Attorney Docket No. BlOEOOO9-40l -PC 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 ysis in Drug and Prodrzrg Metabolism .' Chemistry, Biochemistry, and logy (Testa, Bernard and Mayer, m M. Wiley—VHCA, Zurich, Switzerland 2003). Prodrugs of the nds 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 nment. 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 ions, they may be easier to administer than the nd, or parent drug. They may, for instance, be ilable 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 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.

The compounds disclosed herein can exist as eutically 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- phamiaceutically 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).

The term “therapeutically acceptable salt,” as used herein, represents salts or zwitterionic forms of the compounds sed herein which are water or oil-soluble or dispersible and eutically acceptable as defined . The salts can be prepared during the final isolation and purification of the compounds or separately by reacting the appropriate nd in the form of the free base with a suitable acid. Representative acid addition salts include acetate, adipate, te, L—ascorbate, aspartate, benzoate, benzenesulfonate (besylate), bisulfate, butyrate, cainphorate, rsulfonate, e, digluconate, formate, fumarate, gentisate, glutarate, glycerophosphate, glycolatc, hemisulfate, hcptanoate, hexanoate, hippuratc, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethansulfonate (isethionate), lactate, Attorney Docket No. BlOEOOO9-40l ~PC maleate, malonate, delate, mesitylenesulfonate, esulfonate, naphthylenesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylproprionate, phosphonate, picrate, te, nate, pyroglutamate, succinate, sulfonate, tanrate, L- tartrate, trichloroacetate, trifluoroacetate, phosphate, glutamate, bicarbonate, para- esulfonate (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, es, 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 oric, and organic acids such as oxalic, maleic, succinic, and . 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.

Basic addition salts can be ed 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, ary, 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, N,N—dibenzylphenethylamine, l—ephenamine, and N,N‘-dibenzylethylenediamine.

Other representative organic amines useful for the formation of base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, and piperazine.

While it may be possible for the nds of the subject invention to be administered as the raw chemical, it is also possible to present them as a pharmaceutical ation. Accordingly, provided herein are pharmaceutical formulations which comprise one or more of certain compounds disclosed , or one or more pharmaceutically acceptable salts, esters, prodrugs, , or solvates f, together with one or more pharmaceutically acceptable carriers thereof and optionally one or more other therapeutic ingredients. The canier(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 stration chosen. Any of the well—known techniques, rs, and excipients may be used as suitable and as understood in the art; e.g., in Remington’s Pharmaceutical Sciences. The ceutical compositions disclosed herein may be manufactured in PCT/USZOIZ/OZOZSI Attorney Docket No. O9-40l -PC manner known in the art, e. g, by means of tional mixing, dissolving, granulating, dragee- making, levigating, emulsifying, encapsulating, entrapping or compression processes.

The formulations include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous, intraarticular, and intramedullary), intraperitoneal, transmucosal, transdermal, rectal and topical ding dermal, buccal, sublingual and intraocular) administration although the most suitable route may depend upon for e 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 cy.

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 ation the active ingredient with liquid carriers or finely divided solid carriers or both and then, if ary, shaping the product into the desired formulation.

Formulations of the compounds disclosed herein suitable for oral administration 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 on. The active ingredient may also be presented as a bolus, ary or paste.

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 ssing 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 g in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The s may optionally be coated or scored and be formulated so as to provide slow or controlled release of the active ingredient therein. All ations for oral administration should be in dosages suitable for such stration. The push-fit es can contain the active ingredients in admixture with filler such as lactose, binders such as es, and/or lubricants such as talc or ium stearate and, optionally, izers. In soft es, 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 PCT/U82012/020281 Attorney Docket No. BlOEOOO9—40l -PC sugar solutions may be used, which may optionally contain gum arable, talc, polyvinyl idone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer ons, 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.

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 es or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous es, 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 n—free water, ately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described. ations for parenteral administration include aqueous and non—aqueous (oily) sterile injection solutions of the active compounds which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation ic with the blood of the intended recipient; and aqueous and ueous sterile sions which may include suspending agents and thickening agents. Suitable ilic 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.

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 tation (for e subcutaneously or intramuscularly) or by intramuscular injection.

Thus, for example, the compounds may be ated with le 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.

For buccal or sublingual stration, the compositions may take the form of tablets, lozenges, pastilles, or gels formulated in conventional manner. Such compositions may comprise the active ient in a ed basis such as sucrose and acacia or tragacanth.

PCT/U52012/020281 Attorney Docket No. BTOE0009-40l -PC 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.

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 . In contrast, systemic administration refers to oral, intravenous, intraperitoneal and intramuscular administration.

Formulations suitable for topical administration include liquid or semi—liquid preparations le 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 se as much as 10% w/w. In other embodiments, it may comprise less than % w/w. In n ments, 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.

For administration by inhalation, compounds may be conveniently delivered from an insuftlator, 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 . Alternatively, for administration by inhalation or insufllation, 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. red unit dosage ations are those containing an effective dose, as herein below d, or an appropriate fraction thereof, of the active ient.

It should be understood that in addition to the ingredients particularly ned above, the formulations bed above may include other agents conventional in the art having regard to the type of ation in question, for example those suitable for oral administration may include flavoring agents. nds 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 PCT/U82012/020281 ey Docket No. BlOEOOO9-40l ~PC other forms of presentation provided in te units may conveniently contain an amount of one or more compounds which is ive at such dosage or as a multiple of the same, for instance, units ning 5 mg to 500 mg, usually around 10 mg to 200 mg. 'lhe amount of active ient that may be combined with the r materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.

The compounds can be administered in various modes, 6.3. orally, topically, or by injection. The precise amount of nd administered to a patient will be the responsibility of the attendant physician. The specific dose level for any particular patient will depend upon a y 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.

In certain instances, it may be riate to administer at least one of the compounds described herein (or a pharmaceutically acceptable salt, ester, or prodrug thereof) in combination with another eutic 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 nt (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 es involving administration of one of the compounds described herein, sed therapeutic benefit result by also providing the patient with another therapeutic agent for diabetes. In any case, less 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 istic benefit.

Specific, non-limiting es of possible combination therapies include use of a compound as disclosed herein, and at least one other agent selected from the group comprising: a) anti-diabetic agents such as insulin, insulin derivatives and mimetics; insulin secretagogues such as the sulfonylureas, e.g., Glipizide, glyburide and ; insulinotropic PCT/USZOIZ/OZOZSI Attorney Docket No. BlOEOOO9-40l -PC sulfonylurea or ligands such as meglitinides, e.g., nateglinide and repaglinide; insulin sensitizer such as n tyrosine atase-1B (FTP-1B) inhibitors such as FTP-112; GSK3 (glycogen synthase kinase—B) inhibitors such as SB-517955, SB-4l95052, SB-2l6763, NN 05441 and NN-57—05445; RXR ligands such as GW-O791 and AGN-194204; sodium-dependent glucose co—transporter inhibitors such as T-1095; glycogen phosphorylase A inhibitors such as BAY R3401; biguanides such as metforniin; alpha-glucosidase inhibitors such as se; GLP— l (glucagon like peptide-l), GLP—l analogs such as Exendin-4 and GLP-l cs; DPPIV tidyl peptidase IV) inhibitors such as DPP728, LAF237 (vildagliptin — Example 1 of WO 00/34241), l, iptin, GSK23A ; an AGE breaker; a thiazolidinedione derivative (glitazone) such as pioglitazone or rosiglitazone; and a non—glitazone type PPARES agonist eg. (31262570; b) hypolipidemic agents such as oxy—3~methyl-glutaryl coenzyme A (HMG-COA) rcductasc inhibitors, c.g., lovastatin, pitavastatin, simvastatin, pravastatin, statin, mevastatin, atin, fluvastatin, dalvastatin, atorvastatin, rosuvastatin and rivastatin; ne synthase inhibitors; FXR (farnesoid X receptor) and LXR (liver X receptor) ligands; cholestyramine; fibrates; nicotinic acid and aspirin; c) an anti-obesity agent or appetite regulating agent. such as phentermine, leptin, bromocriptine, dexamphetamine, amphetamine, feniluramine, dexfeniluramine, sibutramine, orlistat, dexfenfluramine, mazindol, phentermine, phendimetrazine, diethylpropion, fluoxetine, bupropion, mate, lpropion, benzphetamine, phenylpropanolamine or ecopipam, ephedrine, pseudoephedrine or cannabinoid or antagonists; d) anti—hypertensive agents, e.g., loop diuretics such as ethacrynic acid, furosemide and torsemide; diuretics such as thiazide derivatives, chlorothiazide, hydrochlorothiazide, aniiloride; ensin converting enzyme (ACE) inhibitors such as pril, captopril, enalapril, fosinopril, lisinopril, moexipril, perinodopril, quinapn'l, ramipril and trandolapril; inhibitors of the Na—K—ATPase membrane pump such as digoxin; neutral endopeptidase (NEP) inhibitors e. thiorphan, tertco—thiorphan, SQ29072; ECE inhibitors 0.g. SLV306; ACE/NEP inhibitors such as oniapatrilat, sampatrilat and fasidotril; angiotensin n antagonists such as candesartan, eprosartan, irbesartan, losartan, tehnisartan and valsartan, in particular valsartan; renin inhibitors such as ren, terlakiren, ditekiren, R0 2, RO l 168; B—adrenergic receptor blockers such as acebutolol, atenolol, betaxolol, bisoprolol, metoprolol, nadolol, propranolol, sotalo] and timolol; inotropic agents such as digoxin, dobutamine and milrinone; calcium channel blockers such as amlodipine, bepridil, diltiazem, felodipine, nicardipine, nimodipine, nifedipine, nisoldipine and verapamil; aldosterone receptor antagonists; and aldosterone synthase inhibitors; e) an HDL increasing compound; ey Docket No. BlOEOOO9PC f) cholesterol absorption modulator such as etizimibe and 1; g) Apo-Al analogues and mimetics; h) thrombin inhibitors such as Ximelagatran; i) aldosterone inhibitors such as anastrazole, fadrazole, and none; 3') inhibitors of platelet aggregation such as aspirin, and clopidogrel bisulfate; k) estrogen, testosterone, a selective estrogen or modulator, and a selective androgen receptor modulator; 1) a chemotherapeutic agent such as aromatase inhibitors e.g. femara, anti-estrogens, topoisomerase I inhibitors, topoisomerase II inhibitors, microtubule active agents, alkylating agents, antineoplastic tabolites, platin compounds, and compounds decreasing the protein kinase activity such as a PDGF receptor tyrosine kinase tor such as miatinib; and m) an agent interacting with a 5—HT3 receptor and/or an agent interacting with 5—HT4 receptor such as tegaserod described in the US patent No. 3 as example 13, tegaserod en maleate, cisapride, and cilansetron.

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, d 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 n the multiple doses may be any duration of time ranging from a few minutes to four weeks.

Thus, in another aspect, certain embodiments provide methods for treating PAS K- 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 t said disorder in the t, optionally in combination with at least one additional agent that is known in the art. In a related aspect, n embodiments provide therapeutic compositions comprising at least one nd disclosed herein in ation with one or more additional agents for the treatment of PAS K-mediated disorders.

Recent studies have found that elevated medium glucose trations caused post- translational activation of PASK. It has also been demonstrated that PASK activity is required for glucose—stimulated insulin expression, as shown by studies in PASKl mice. It has also been demonstrated that PASK deletion results in nearly complete resistance to the phenotypes caused by a high-fat diet, including obesity, insulin resistance and hepatic fat accumulation. It has been postulated that this protection may be due to an increase in AMPK expression in each of the relevant tissues. PASK deletion abrogates nearly all of the maladaptive phenotype associated PCT/U52012/020281 Attorney Docket No. BIOEOOO9-40l ~PC with a high-fat diet, possibly in part via maintenance of AMPK expression. Increasing AMPK ing is a proven therapeutic strategy, as illustrated by Metformin, which acts by increasing the phosphorylation and activation of AMPK. Inhibition of PASK signaling elicits similar beneficial s, but through a distinct mechanism. This complementary therapeutic strategy, either alone or in combination, can be efficacious in the treatment of metabolic diseases. In any case, it appears that PASK inhibition can provide an ive eutic gy for the treatment of diseases, for example Type 2 diabetes, insulin resistance in general, and the metabolic syndrome.

Metabolic me (also known as metabolic syndrome X) is characterized by having at least three of the following ms: insulin resistance; abdominal fat — in men this is defined as a 40 inch waist or larger, in women 35 inches or larger; high blood sugar levels - at least 110 milligrams per deciliter ) after g; high triglycerides - at least 150 mg/dL in the blood stream; low HDL— less than 40 mg/dL; pro—thrombotic state (cg. high fibrinogen or plasminogen activator tor in the blood); or blood pressure of 130/85 mmHg or higher. A connection has been found between metabolic syndrome and other conditions such as obesity, high blood pressure and high levels of LDL cholesterol, all of which are risk s for cardiovascular es. For example, an increased link between metabolic syndrome and atherosclerosis has been shown. People with metabolic syndrome are also more prone to developing Type 2 diabetes, as well as PCOS (polycystic ovarian syndrome) in women and prostate cancer in men.

As described above, insulin resistance can be manifested in several ways, including Type 2 diabetes. Type 2 diabetes is the condition most obviously linked to insulin resistance.

Compensatory hyperinsulinemia helps maintain normal glucose levels - often for decades, before overt diabetes develops. Eventually the beta cells of the pancreas are unable to overcome insulin ance through ecretion. Glucose levels rise, and a diagnosis of diabetes can be made.

Patients with Type 2 diabetes remain hyperinsulinemic until they are in an advanced stage of e. As described above, insulin ance can also correlate with hypertension. One half of patients with essential hypertension are insulin resistant and hyperinsulinemic, and there is evidence that blood pressure is linked to the degree of insulin resistance. Hyperlipidemia, too. is associated with insulin resistance. The lipid profile of patients with Type 2 diabetes includes increased serum very-low—density lipoprotein cholesterol and triglyceride levels and, mes, a decreased low-density lipoprotein cholesterol level. Insulin resistance has been found in persons with low levels of high-density lipoprotein. Insulin levels have also been linked to very- low-dcnsity lipoprotein synthesis and plasma triglyceride levels. 2012/020281 ey Docket No. BlOEOOO9-40l -PC Accordingly, also disclosed are s of treating insulin ance in a subject comprising selecting a subject in need of treatment for insulin resistance; and administering to the subject an effective amount of a nd that inhibits PAS K.

Specific es to be treated by the compounds, compositions, and methods disclosed herein are those ed at least in part by PASK, Accordingly, disclosed herein are methods: for reducing glycogen accumulation in a subject; for raising HDL or HDLc, lowering LDL or LDLc, shifting LDL particle size from small dense to normal LDL, lowering VLDL, lowering triglycerides, or inhibiting cholesterol absorption in a subject; for reducing insulin resistance, enhancing glucose utilization or lowering blood pressure in a subject; for reducing Visceral fat in a subject; for reducing serum transaminases in a subject; or for treating disease; all comprising the administration of a therapeutic amount of a compound as bed herein, to a patient in need thereof. In further embodiments, the e to be treated may be a metabolic disease. In further embodiment, the metabolic disease may be chosen from: obesity, diabetes s, especially Type 2 diabetes, hyperinsulinemia, glucose intolerance, metabolic syndrome X, dyslipidemia, hypertriglyceridemia, hypercholesterolemia, and hepatic steatosis. In other embodiments, the disease to be treated may be chosen from: cardiovascular diseases including vascular e, atherosclerosis, coronary heart. disease, ovascular disease, heart failure and peripheral vessel disease. In preferred embodiments, the methods above do not result in the induction or maintenance of a hypoglycemic state.

Additionally, the PASK modulators disclosed herein may be used to treat erative ers such as cancers. Hematological and non~hematological cancers which may be treated or ted 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), malignancies of the brain, head and neck, , lung, reproductive tract, upper digestive tract, pancreas, liver, renal, bladder, prostate and colon/rectum.

Besides being useful for human treatment, n compounds and formulations disclosed herein may also be useful for veterinary treatment of companion animals, exotic animals and farm animals, ing mammals, rodents, and the like. More preferred animals include horses, dogs, and cats.

PCT/USZOIZ/OZOZSI Attorney Docket No. BJOE0009PC References Cited The following is a list of references cited herein which, while not necessarily comprehensive, is provided for the convenience of the reader. All nces, patents, and patent applications cited herein are hereby incorporated by nce as if written herein in their entireties. When the teachings of these nces contradict the teachings presented expressly herein, the present disclosure controls.

Roach, P. J. et al. (2001) in The Endocrine Pancreas and Regulation of Metabolism, eds.

Chem'ngton. A. D. & Jefferson, L. S. (Oxford Univ. Press, New York), pp. 609—647. ix.) Bergstrom, J. et al. (1967) Acta Physiol. Scand. 71: 140—150. .0“ng Cline, G. W. et al. (1994) J. Clin. Invest. 94: 2369~2376.

Shulman, G. I. et a1. G. (1990) N. Engl. J. Med. 322: 223—228.

Cohcn, P. (1982) Nature 296: 613—620.

Roach, P. J. (1986) in The s, eds. Boyer, P. D. & Krebs, E. G. (Academic, Orlando, FL), Vol. 17: pp. 499—539.

Cohen, P. (1986) in The Enzymes. eds. Boyer, P. D. & Krebs, E. G. mic, Orlando, FL), Vol. 17: pp. 461—497.

Friedman, D. L. & , J. (1963) Biochemistry 128: 669—675.

Larner, J. (1990) Adv. anymol. Relat. Areas Mol. Biol. 63: 173—231.

. Roach, P. J. (1990) FASEB J. 4: 2961—2968.

. Skurat, A. V., et a1. (1994) J. Biol. Chem. 269: 25534—25542.

. Flotow. H. & Roach, P. J. (1989) J. Biol. Chem. 264: 9126—9128.

. Nakielny, 8., Campbell, D. G. & Cohen, P. (1991) Eur. J. Biochem. 199: 713422.

. Wilson WA et al., Proc Natl Acad Sci U S A. 2005 Nov 15 ;lO2(46): 16596-601, Fig. 6 . Skurat, A. V. & Roach, P. J. (1995) J. Biol. Chem. 270: 12491—12497.

. Hardy, T. A. & Roach, P. J. (1993) J. Biol. Chem. 268: 23799—23805 . is, J. & Parrou, J. L. (2001) FEMS Microbiol. Rcv. 25: 125—145.

. Rutter, J., Probst, B. L. & McKnight, S. L. (2002) Cell 111: 17—28.

. Rutter, J et a1. (2001) Proc. Natl. Acad. Sci. USA 98: 8991—8996.

. Roden M, Bernroider E: Best Pracr Res Clin Endocrinol Meta/7. 2003 7(3):365-83 . Van ergen W, Lanckmans Sz‘Int Journal Obes Reiar Metab Disorder 1995 Sept: 19 Suppl 3: 827-36.

. Arad M et al.. Circ Res. 2007 Mar 2;100(4):474—88 . da Silva Xavier, G. ct al. (2004) Proc. Natl. Acad. Sci. USA 101, 8319—8324. . 33Picton, C. et al. (1982) FEBS Lett. 150: 191—196.

PCT/USZOIZ/OZOZSI Attorney Docket No. BTOE0009-401—PC . DePaoli—Roach, A. A. at 211., (1983) J. Biol. Chem. 258: 10702—10709. 26. Elia, A. Bet a1. (2003) e 299:, 1228—1231. 27. Gao, T. et a]. (1997) Neuron 19:, 185—196. 28. Wilson, W. A. et a1. (1999) Mol. Cell. Biol. 19:, 7020—7030. 29. Yedovitzky, M. et a1. (1997) J. Biol. Chem. 272:, 1417—1420.

. Fernandez~NovelL J. M., et a1. (2002) FEBS Lett. 531:, 222—2_8.

PCT/U52012/020281 Attorney Docket No. BlOEOOO9PC l Synthetic Methods for Preparing Compounds The following schemes can lly be used to practice the present invention.

Scheme 1 NHZHCl ph)\n,o\ OZN SOC! I MeOH DIEA DMF PW“ Fe/NH4CI 0:11))?“ Ojfiko/ PBrOS MeOH dioxaQne MeCN Br /N]©/U\O/\N Step 1. S nthesis of meth l4-fluoro—3-nitrobenzoate. Thionyl chloride (6.5 g, 54.62 mmol, 1.01 equiv) was added dropwise, with stirring at 0°C, to a methanolic solution (60 mL) of 4—fluoronitrobenzoic acid (10 g, 5405 11111101, 1.00 equiv) in a 250-mL round~bottom flask, then stirred for 3 hr at reflux in an oil bath. The resulting mixture was concentrated under vacuum, diluted with 100 ml. of EtOAc, and the pH of the solution adjusted to 7—8 with aqueous NaHC03 (saturated). The solution was then extracted with 6x50 mL of ethyl acetate, the organic layers combined and dried over anhydrous sodium sulfate, and concentrated under , affording 12.42 g (crude) of methyl 4—fluoro—3—nitrobenzoate as a white solid.

Step 2. Synthesis of methyl 4—(2—methoxy~2-oxo-l—9henylethylamin02 nitrobenzoate. A solution of methyl 2-amino-Z—phenylacetate hydrochloride (2.5 g, 12.38 mmol, 1.00 equiv) in DMF (30 mL), methyl 4-fluoro~3-nitrobenzoate (5 g, 25.13 mmol, 2.00 equiv), and DTEA (5 g, 38.76 mmol, 3.13 equiv) was reacted overnight at 30°C in a 100-ml. round- bottom flask. 'lhe reaction was then ed by the addition of 200 mL of water, and the solids were collected by tion. Purification Via silica gel column (petroleum ether /EtOAc (50:1)) d 3.82 g (90%) of methyl 4-(2~methoxy-2—oxo—1-phenylethylamino)nitrobenzoate as a yellow solid. LC-MS (ES, m/z): 345 [M+Il]+. 2012/020281 ey Docket No. 1310130009401 -PC Step 3. §y_nthesis of methyl 3-oxophenyl-142,3.4-tetrahydroquinoxaline—6- carboxylate. Iron (34.89 g, 623.04 mmol, 5.00 equiv) was added nwise to a stirred solution of methyl 4-(2-methoxyoxo—1~phenylethy1amino)nitrobenzoate (42.87 g, 124.62 mmol, 1.00 equiv) and aqueous NH4C1 (32.1 g, 600.00 mmol, 5.00 equiv, 80 mL) in methanol (300 mL). The resulting solution was heated under reflux for 5 h. Upon g, the solids were filtered out. The resulting filtrate was concentrated under vacuum, affording 19.81 g (56%) of methyl 3-0x0-2~pheny1-1,2,3,4-tetrahydroquinoxalinecarboxy1ate as a yellow solid. LC—MS (ES, m/z): 283 [Ma-HF.

Step 4. Synthesis of methyl 3-oxopheny1—3.4-dihydroguinoxalinecarboxy1ate.

DDQ (21.25 g, 93.6 mmol, 2.62 equiv) was added to a stirred solution of methyl 3—oxopheny1- 1,2,3,4—tetrahydroquinoxaline~6—carboxy1ate (10.07 g, 35.7 mmol, 1.00 equiv) in dioxane (750 mL) and allowed to react, with stirring, overnight at room temperature. The solids were collected by filtration. The filter cake was washed with 2x500 mL of aqueous K2C03 (saturated). This resulted in 7.29 g (crude) of methyl 2—pheny1~3,4-dihydroquinoxa1ine-6—carboxylate as an off—white solid. LC-MS (ES. m/z): 281 [M+H]+.

Step 5. Synthesis of methyl 3-bromopheny1guinoxalinecarboxy1ate. A solution of methyl 3-oxo—2~pheny1-3,4—dihydroquinoxalinecarboxy1ate (2.1 g, 7.50 mmol, 1.00 equiv) and POBr3 (21.5 g, 74.91 mmol, 10.00 equiv) in CH3CN (120 mL) in a 1000-mL round-bottom flask was heated under reflux overnight in an oil bath. The resulting mixture was concentrated under vacuum; the pH value was adjusted to 7-8 with aqueous sodium bicarbonate (saturated), and the solution extracted with 4x100 mL of dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under , giving 2 g (78%) of methyl 3-bromo—2-phenquuinoxaline~6—carboxylate as a white solid. LC-MS (ES, m/z): 343 . 1H~NMR (300 MHz, DMSO—d5) 8620-8615 (d, z, 1H), 8.38-8.35 (q, J=3.3Hz, 1H), 8.28-8.25 (d, J=8.7Hz, 1H), 7.85-7.82 (q, J=6Hz. 2H), 7.60-7.58 (t, J=2.4Hz, 3H), 3.99 (s, 3H).

PCT/USZOIZ/OZOZSI Attorney Docket No. BIOEOOO9-40l ~PC Scheme 11 Br N\ COORB HNRsRs NR6R5 COOR3 R2 N I 1)N\/ NaOH NR6R5 I 13N\ COOH R2 N wherein R5 and R6 and R2 are each independently chosen from alkyl, lkyl, cycloalkyl, aryl, aryl, and amino any of which may be optionally substituted; and R3 is Chosen from hydrogen and optionally substituted alkyl.

Scheme III NHPMB HOWKQENO2F a H3COY©:NOZ b Haco\r(<j:No2NHPMBc H3COY<EENH2 0 0 EtO)J\n’OEt 0 0 H o o N e f I \; 0/ o N CiINUkO/O I}! CIIND/Ko/o N R1 R X \/ o o 1“ 2 ‘N ' N / / Reagents and conditions; (a) SOCIZ, MeOH, reflux. 3h, 93%; (b) PMBNHZ, DIEA, DMF. rt, 3h, 78%; (c) Pd/C, H2, MeOH, rt, 0.5h, 73%; (at) reflux, 3h, 74%; (e) POCI3, N,N— dimethylanaline, toluene, reflux, overnight, 72%; (f) HZSO4(conc), rt, 10mins; (9) 150°C, 3h, 42.6%; (h) TfZO, pyridine, DCM, rt, overnight; (1) K3P04, Pd(PPh3)4, dioxane, 90°C, 40 min; (j) NaOH, H20, MeOH, rt, overnight.

PCT/U52012/020281 Attorney Docket No. 09-40l —PC The invention is further illustrated by the ing examples, which can be made by the methods described herein or by one skilled in the art without undue experimentation, or can be purchased from commercial sources. Throughout. the experimental protocols, the ing abbreviations may be used. The list below is provided for convenience and is not intended to be inclusive iation/Acronym Ar Aryl Pd2(dba)3 Tris(dibenzylideneacetone)di nalladium(0) BINAP 2,2‘-bis(diphenylphosphino)-1 , l '—binaphthyl NaOt—Bu Sodium t—Butoxide PE Petroleum Ether EA Ethyl Acetate DCM Dichloromethane TFA Trifluoroacetic Acid ACOH Acetic Acid DMF N,N—Dimeth lformamide DIEA N,N-Diisopropylethylamine MeOH __J Methanol THF Tetrahydrofuran BOC N-t-butoxycarbonyl To] Toluene DMSO Dimeth l Sulfoxide PCy3 lohexylphosphine TLC Thin La er Chromatograh 2-Dicyclohexylphosphino—2’,4’,6’— X—Phos triisopropylbiphenyl DDQ 2,3~dichloro—5,6~dicyanobenzoguinone PCT/U52012/020281 Attorney Docket No. O9PC Intermediate 1.

Methyl 3-(3, 4-dihydroquinolin-1(2H)-yl)(trifluoromethylsulfonyloxy)quinoxaline carboxylate TfO N Step 1. Methyl 4-fluoro-3~nitrobenzoate /O‘n’ : Thionyl chloride (191.4 g, 1.61 mol) was added to a solution of 4-fluoro—3-nitrobenzoic acid (150.0 g, 810.81 mmol) in methanol (500 ml) at 0°C. The resulting solution was heated to reflux overnight, concentrated in vacuo, the product was precipitated by the addition of eum ether (200 ml), and the solids were collected by tion to afford methyl 4—fluoro—3—nitrobenzoate as a light yellow solid (150 g, 93%). 1H-NMR (300 MHz. CDC13) 5 8.74 - 8.77 (m, 1H), 8.31 - 8.37 (m, '1H), 7.37 - 7.43 (m, 1H), 3.99 (s, 3H).

Step 2. Methyl 4-(4—methoxybenzylamino)-3~nitrobenzoate NHPMB /O\n/ : :N02 DIEA (389.0 g, 3.02 mol) was added to a solution of methyl 4—fluoro-3—nitrobenzoate (200.0 g, 1.00 mol) in N,N—dimethylfonnarnide (2 L) at room temperature. Then (4- methoxyphenyl)methanamine (275 g, 2.00 mol) was added dropwise. After 2 h, the reaction was diluted with water (5 L), the solids were collected by filtration to afford methyl 4-(4— mcthoxybcnzylamino)-3—nitrobenzoatc as a yellow solid (250 g, 78 ‘70). 1H-NMR (300 MHZ, CDC13) 5 8.91 (d, J = 1.8 HZ, 1H), 8.64 (b, 1H), 8.02 - 8.06 (m, 1H), 7.26 — 7.30 (m, 2H), 6.88 - 6.95 (m, 3H), 4.53 (d, J: 5.4 Hz, 1H), 3.91 (s, 3H), 3.83 (s, 3H).

PCT/USZOIZ/OZOZSI Attorney Docket No. 1310130009401 -PC Step 3. Methyl 3-amino—4-(4—methoxybenzylamino)benzoate NHPMB A mixture of methyl 4-(4-mcthoxybcnzylamino)-3—nitrobcnzoatc (35.0 g, 110.65 mmol) and palladium on carbon (5 g) in methanol (3 L) was hydrogenated 30 mins at room ature.

The catalyst was removed by filtration and the filtrate was concentrated in vacuo to afford methyl 3-amino~4-(4—methoxybenzylamino) benzoate as a white solid (23.1 g, 76 %). 1H—NMR (300 MHZ, CDC13) 5 7.57 — 7.60 (m, 1H), 7.44 (d, J: 1.8 Hz, 1H), 7.28 - 7.33 (m, 2H), 6.90 - 6.94 (In, 2H), 6.63 (d, J = 8.1 Hz, 1H), 4.33 (s, 2H), 3.86 (S, 3H), 3.83 (s, 3H).

Step 4. Methyl 1—(4-methoxybenzyl)—2,3-dioxo-l,2,3,4—tetrahydroquinoxaline—6—carboxylate EDA“ A mixture of methyl 3-amino(4-methoxybenzylamino)benzoate (3 g, 10.48 mmol) and diethyl oxalate (100 ml) was stirred for 3h at reflux and then cooled with a water/ice bath, and diluted with ether (500 ml). Tthe product was collected by filtration to afford methyl l-(4- methoxybenzyl)-2,3—dioxo-l,2,3,4—tetrahydroquinoxaline-6—carboxylate as a green solid (2.64 g , 74 %). 1H-NMR (300 MHZ, DMSO) 5 12.22 (s, 1H), 7.80 (s, 1H), 7.61 ~ 7.62 (d, J: 1.8 Hz, 1H), 7.25 - 7.33 (m, 3H), 6.86 — 6.89 (d, J = 8.7 Hz, 1H), 5.31 (s, 2H), 3.83 (s, 3H), 3.70 (s, 3H).

Step 5. Methyl ro—l-(4-methoxybenzyl)~2—oxo—1,2-dihydroquinoxaline-6—carboxylate 011}!/N:©)LO/ POCl3 (2 g, 13.25 mmol) and N,N-dimethylbenzenamine (2.13 g, 17.60 mmol,) were added to a on of methyl 1—(4-methoxybenzyl)-2,3—dioxo—1,2,3,4-tetrahydroquinoxalinecarboxylate (3 g, 8.81 mmol) in toluene (100 ml). The resulting reaction was stirred overnight at 110°C and concentrated in vacuo. The residue was ated with methanol (50 ml) and collected by filtration to afford methyl 3-chloro-l-(4-meth0xybenzyl)oxo-1,2-dihydroquinoxaline—6- carboxylate as a green solid (2.27 g, 72 %).

PCT/U52012/020281 Attorney Docket No. BlOEOOOQ-401 —PC 1H—NMR (300 MHz, DMSO) 8 8.25 (d, J = 1.8 Hz, 1H), 8.07 - 8.11 (m, 1H), 7.61 (d, J: 9.0 Hz, 1H), 7.27 - 7.30 (d, J: 8.7 Hz, 2H), 6.86 — 6.90 (m, 2H), 5.46 (s, 2H), 3.83 (s, 3H), 3.71 (s, 3H).

Step 6. 3-Chlorooxo-1,2-dihydroquinoxalinecarboxylate _ /N]©/LKO/ Methyl 3-ch10ro(4—methoxybenzyl)—2-oxo—1,2-dihydroquinoxalinecarboxylate (13 g, 36.31 mmol) was added to sulfuric acid (cone, 15 ml) in l batches with stirring at room temperature and then stirred an additional 10 mins. The resulting solution was quenched with ice— water (100 m1), adjusted to PH=7 with aqueous sodium hydroxide (10 N), and extracted with l- butanol (3 x 200 ml). The organic layers were combined, dried over anhydrous magnesium e, and concentrated in vacuo to afford methyl 3-Chloro—2-oxo-l ,2—dihydroquinoxaline carboxylate as a yellow solid (12.4 g, crude). 1H—NMR (300 MHZ, CDC13): 5 13.20 (b, 1H), 8.21 (d, J: 1.8 Hz, 1H), 8.10 - 8.12 (m, 1H), 7.43 (d, J: 8.7 Hz, 1H), 3.88 (s, 3H).

Step 7. Methyl 3-(3, 4-dihydr0quinolin-1(21—l)—y1)-2—oxo-1, droquinoxaline-6—carboxylate Methyl 3-chloro—2—oxo-1, 2-dihydroquinoxalinc~6~carboxylatc (300 mg, 1.26 mmol) was added to 8 mL of 1, 2, 3, ahydr0quinoline and stirred for 3 h at 150°C. The reaction mixture was cooled to room temperature, the product was precipitated by the addition ethyl e, and the solids were collected by filtration to afford 3—(3, 4-dihydroquinolin—1(2H)—y1)—2-0x0-1, 2— dihydroquinoxaline-6—carboxylate as a light yellow solid (180 mg, 42.6%).

Calculated for C19H17N303: 335.13. (ES, m/z): [M+H]Jr 336.0. 1H—NMR (300 MHz, DMSO): 8 12.49 (s, 1H), 7.99 (d, J: 1.8 Hz, 1H ), 7.84 - 7.88 (m, 1H ), 7.30 (d, J = 8.4 Hz, 1H), 7.13 - 7.16 (111, 1H), 6.89 — 7.04 (m, 3H), 3.88 - 3.93 (t, J: 6.3 Hz, 2H), 3.85 (s, 3H), 2.73 - 2.78 (t. J: 6.6 Hz, 2H), 1.91 - 1.99 (m. 2H).

PCT/U52012/020281 Attorney Docket No. BIOE0009—401 -PC Step 8. Methyl 3-(3, droquinolin-l(2H)—yl)~2—(trifluoromethylsulfonyloxy)quinoxaline carboxylate Trifluoromethanesulfonic anhydride (315.6 mg, 1.12 mmol) was added to a on of methyl 3- (3, 4~dihydroquinolin—1(2H)-yl)-2—oxo-l, 2—dihydroquinoxalinecarboxylate (200.0 mg, crude) and pyridine (176.8 mg, 2.24 mmol) in dichloromethane (50 ml). After stirring overnight at room temperature, the reaction was quenched with water (50 ml) and extracted with dichloromethane (3 x 80 m1). Then the organic layers were combined dried over anhydrous magnesium sulfate, and concentrated in vacuo to afford methyl 3-(3, 4-dihydroquinolin—l(2H)- yl)—2-(trifluoromcthylsulfonyloxy)quinoxalinccarboxylatc as red oil (300 mg, crude), which was used directly in the next step.

EXAMPLE 1 ,3,4-Tetrahydroquinolin-1(2H)-yl)(4-fluorophenyl)quinoxalinecarboxylic acid N /N]£:H\OH\N PCT/U52012/020281 Attorney Docket No. 1310130009401 —PC Step 1. Methyl 3-(1.2,3,4-tetrahydroquinolin—1(2H)—yl)(4—lluorophenyl) quinoxaline carboxylate 4-fluorophenylb0r0nic acid (188.8 mg, 1.35 mmol), K3P04 (284.8 mg, 1.35 mmol) and Pd(PPh3)4 (25.9 mg, 0.02 mmol) were added to a solution of methyl 3-(1,2,3,4— tetrahydroquinolin- 1 (21I)~yl)-2—(trifluoromethylsulfonyloxy) quinoxalinecarb0xylate (Intermediate 1, 210mg, 0.45 11111101) in dioxane (5.0 111L) and three drops of water. The reaction was stirred for 1 h at 95°C while under an inert here of nitrogen in an oil bath. The reaction e was concentrated in vacuo and purified by flash column tography with 2 % ethyl acetate in petroleum to afford methyl 3-(1,2,3,4—tetrahydr0quinolin—l (2H)-yl)-2—(4- fluorophenyl)quin0xaline—6-carboxylate as a red solid (70 mg, 36 %).

Calculated for CZSHZOFN3OZ: 413.15. (ES, m/z): [M+H]+ 414.0 lH-NMR (300 MHz, CDCl3): 5 8.74 (s, 1H), 8.21 - 8.24 (dd, J]: 12 = 1.5 Hz, 1H), 8.12 (d, J = 8.4 Hz, 1H), 7.72 - 7.76 (m, 2H), 6.93 — 7.02 (m. 3H), 6.79 - 6.83 (m, 2H), 6.62 (s, 1H), 4.02 (s, 3H), 3.93 - 3.97 (t, J = 6.0 Hz, 2H), 2.79 - 2.84 (t, J: 6.3 Hz, 2H), 2.09 - 2.14 (t, J: 6.3 Hz, 2H) Step 2. 3-(1,2,3,4-Tetrahydroquinolin— 1 (2H)-y])—2—(4-f1uorophenyl)quinoxaline—6-carboxylic acid To a solution of methyl 3-(1,2,3,4—tetrahydr0quin01in—l(2H)—yl)~2-(4—flu0rophenyl)quinoxaline- 6—carboxylate (70 mg, 0.17 mmol) in water (1 mL) and ydrofuran (15 mL ) was added sodium hydroxide (27 mg, 0.68 11111101) with stirring overnight at 100111 temperature. The reaction mixture was concentrated under vacuum, ved in water (30 mL), adjusted to pH 4 with hydrogen chloride (3 N) to give the precipitation, which was collected by filtration to afford 3- PCT/U52012/020281 Attorney Docket No. 1310130009401 ~PC (1,2,3,4-tetrahydroquinolin—1(2H)-yl)—2-(4-fluorophenyl)quinoxalinccarboxylic acid as a light yellow solid (50 mg, 70%).

Calculated for C34H13FN302: 399.14 (ES, m/z): [M+H]+ 400.0 1H-NMR (300 MHz, DMSO): 5 8.36 (s, 1H), 8.09 (d, J = 2.10 Hz, 2H), 7.72 - 7.78 (m, 2H), 7.06 - 7.12 (t, J: 9.0 Hz, 2H), 6.98 - 7.00 (m, 1H), 6.69 - 6.73 (m, 2H), 6.57 — 6.59 (m, 1H), 3.81 — 3.85 (t, J: 6.3 Hz, 2H), 2.70 - 2.81 (t, J = 6.3 Hz, 2H), 1.98 - 2.02 (t, J = 6.3 Hz, 2H) 2-(Benzofuran-Z—yl)(1,2,3,4-tetrahydroquinolin-1(2H)-yl)quinoxalinecarboxylic acid Benzofuran-2—ylbor0nic acid (217.2 mg, 1.35 mmol). K3PO4 (284.8 mg, 1.35 mmol), Pd(PPh3)4 (25.9 mg, 0.02 mmol) and water (3 drops) were added to a solution of methyl ,3,4— tetrahydroquinolin- 1 (2H)-yl)—2—(triflu0romethylsulfonyloxy)quinoxalinecarboxylate (Intermediate 1, 210 mg, crudel) in dioxane (5.0 mL) and the reaction was stirred for l h at 95°C under an inert atmosphere of nitrogen in an oil bath. The reaction mixture was concentrated in vacuo and purified by silica gel column chromatography with 2 % ethyl acetate in petroleum to afford methyl 2—(benzofuran~2-yl)—3-(1,2,3,4—Tetrahydroquinolin-l(2H)-yl) quinoxaline—6- carboxylate as a red solid (60 mg).

Calculated for N303: 435.16. (ES, m/z): [M+H]+ 436.0 1H-NMR (300 MHZ, CDC13)I 5 8.75 (s, 1H), 8.18 - 8.28 (m, 2H), 7.35 - 7.42 (m, 2H), 7.17 - 7.20 (m, 1H), 7.04 - 7.07 (m, 2H), 6.74 - 6.76 (t, J = 4.5 Hz, 2H), 6.57 (s, 1H), 4.11 - 4.18 (m, 5H), 3.00 - 3.03 (t, J = 6.6 Hz, 2H), 2.22 - 2.26 (t, J = 6.0 Hz, 2H) PCT/U52012/020281 Attorney Docket No. 1310130009401 -PC Step 2. zofuran-2—yl)—3—(1,2,3,4—tetrahydroquinolin—1(2H)—yl)quinoxaline—6-carboxylic acid To a solution of methyl 2—(benzoturanyl)(1,2,3,4—tetrahydroquinolin—l(2H)—yl) quinoxaline- 6—carboxy1ate (60 mg, 0.14 mmol) in methanol (25 mL) and water (1 mL) was added sodium hydroxide (22 mg, 0.55 mmol) with stirring overnight at room temperature. The reaction mixture was concentrated under vacuum, dissolved in water (30 mL), adjusted to pH 4 with en chloride (3 N) to give the precipitation, which was collected by filtration to afford 2-(benzofuran- 2—yl)(1,2,3,4-tetrahydroquinolin—1(2H)-yl)quinoxalinecarboxylic acid as a red solid (45 mg, 74 %).

Calculated for C26H19N303: . (ES, m/z): [M+H]Jr 422.0 lH—NMR (300 MHz, DMSO) 8 8.36 (s, 1H), 8.16 - 8.20 (dd, J; = J2 = 1.8 Hz, 1H), 8.11(d, J: 8.7 Hz, 1H), 7.53 - 7.66 (111, 3H), 7.33 - 7.38 (m, 1H), 7.20 - 7.25 (m, 1H), 7.06 - 7.09 (m, 1H), 6.66 - 6.73 (m, 2H), 6.50 — 6.53 (dd, J; = J2 = 0.9 Hz, 1H ), 3.87 ~ 3.92 (t, J: 6.0 Hz, 2H), 2.90 - 3.00 (t, J: 6.3 Hz, 2H), 2.08 - 2.17 (m, 2H) EXAMPLE 3 3-(1,2,3,4-Tetrahydroquinolin-1(2H)«yl)-2—(5-f1uorobenzofuran-Z-yl)quin0xaline carboxylic acid PCT/USZOIZ/OZOZSI Attorney Docket No. BlOEOOO9-401 -PC Step 1. Methyl 2-(benzofuran-2—yl)—3—(1,2,3,4-tetrahydroquinolin—1(2H)-yl)methyl 3-(3, 4- dihydroquinolin-1(2H)—yl)—2-(5-fluorobenzofuranyl)quinoxalinecarboxylate F O -Huorobenzofuran—2-ylboronic acid (242.8 mg, 1.35 mmol), K3P04 (284.8 mg, 1.35 mmol), 3)4 (25.9 mg, 0.02 mmol) and water (3 drops) were added to a solution of methyl 3- ( 1 ,2,3,4—tetrahydroquinolin- l(2H)—yl)~2-(trifluoromethylsulfonyloxy)quinoxalinecarboxylate (Intermediare 1, 210 mg, 0.45 mmol,) in dioxane (5.0 mL). The reaction was d for 1 h at 95°C under an inert atmosphere of nitrogen in an oil bath. The reaction mixture was concentrated in vacuo and ed by a silica gel column chromatography with 2 % ethyl acetate in petroleum ether to afford methyl 3-(1 ,2,3,4-tetrahydroquinolin~ 1 l)-2—(5—fluorobenzofuran yl)quin0xalinecarboxylate as a red solid (70 mg, 33 %).

Calculated for C27H20FN3O3Z 453.15. (ES, m/z): [M+H]+ 454.0 1H-NMR (300 MHz, CDCI3): 5 8.65 (d, J: 1.5 Hz, 1H), 8.19 - 8.27 (m, 2H), 7.50 - 7.56 (m, 3H), 7.34 - 7.37 (m, 1H), 7.19 - 7.25 (111, 1H), 7.09 - 7.13 (m, 1H), 6.75 - 6.80 (m, 2H), 6.59 - 6.61 (m, 1H), 4.02 (s, 3H), 3.96 - 3.98 (t, J: 6.0 Hz, 2H), 3.00 - 3.04 (t, .1: 6.6 Hz, 2H), 2.19 - 2.24 (t, f: 6.0 Hz, 2H) Step 2. 3-(1,2,3,4-Tetrahydroquinolin— l l)-2—(5—fluorobenzofuranyl)quinoxaline-6— carboxylic acid Sodium hydroxide (24.7 mg, 0.62 mmol) was added to a solution of methyl 3-(1,2,3,4- tetrahydroquinolin-l (2H)—yl)-2—(5-fluorobenzofuran—2-yl)quinoxalinecarboxylate (70 mg, 0.15 mmol) in methanol (25 mL) and water ( 1 mL ). The reaction was stirred overnight at room temperature. The reaction mixture was concentrated in vacuo, dissolved in water (30 mL), adjusted to pH 4 with hydrogen chloride (3 N) to give the precipitate, which was collected by PCT/USZOIZ/020281 Attorney Docket No. BIOE0009-401 ~PC filtration to afford 3-(1,2,3,4-tetrahydroquinolin-1(2H)-yl)(5~fluorobenzofuran-2— yl)quinoxaline—6—carboxylic acid as a red solid (50 mg, 70 %).

Calculated for C26H13FN303: 439.13. (ES, m/z): [M+H]+ 440.0 IH-\IMR (300 MHz, DMSO) 8 12.40 (s, 1H), 8.36 (s, 1H), 8.15 (s, 2H), 7.44 - 7.59 (m, 3H), 7.17 - 7.22 (t, J: 6.9 Hz, 1H), 7.06 (d, J = 5.4 Hz, 1H ), 6.57 - 6.69 (m, 3H), 3.85 - 3.92 (m, 2H), 2.85 — 2.93 (m, 2H), 212 - 2.22 (m, 2H) EXAMPLE 4 2-(2, 3-Dihydr0-1,4—benz0dioxinyl)-3~(1, 2, 3, 4-tetrahydroquinolin—1-yl)quinoxaline ylic acid Step 1. Methyl 2—(2, 3—dihydro-1,4—bcnzodioxin-6—yl)-3—(l, 2, 3, 4-tctrahydroquinolin-1— y1)quinoxa1inecarboxylate A mixture of methyl 3-( l, 2, 3, 4-tetrahydroquinolin-l -yl)—2— L(trifluoromethane)sulfonyloxyjquinoxaline—6-Carboxy1ate (Intermediate 1, 300 mg, crude), (2, 3- dihydro—l, odi0xinyl)boronic acid (231.0 mg, 1.29 mmol), Pd(PPh3)4 (37.0 mg, 0.03 mmol) and K3PO4 (405.1 mg, 1.92 mmol) in dioxane (5.0 ml) and water (3 drops) was stirred for 40 min at 90°C under atmosphere of nitrogen. The reaction mixture was concentrated in vacuo and purified by silica gel column chromatography with 1 % ethyl acetate in eum ether to afford methyl 2-(2, 3-dihydro-1, 4—benzodioxin~6—yl)—3—( 1, 2, 3, 4-tetrahydroquinolin—1— yl)quinoxalinecarboxylate as a light yellow solid (65 mg, .

Calculated for C27H23N304: 453.17. (ES, m/z): [M+H]+ 454.0 Attorney Docket No. 1310130009401 ~PC 1H—NMR (300 MHZ, CDClg): 5 8.70 (s, 1H), 8.14 - 8.22 (m, 2H), 7.29 - 7.34 (m, 2H), 7.05 - 7.25 (m, 2H), 6.83 - 6.86 (m, 2H). 6.76 (d, J: 8.4 Hz - 4.25 (m, 4H), 4.01 , 1H), 4.21 (s, 3H), 3.87 - 3.91 (t, J = 6.3 Hz, 2H), 2.82 - 2.86 (t, J = 6.6 Hz, 07 - 2.11 (t, J = 6.0 Hz, 2H) Step 2. 2—(2, 3-dihydro-1,4-benzodioxin-6—yl)(1, 2, 3, 4—tetrahydroquinolin—1-yl)quinoxaline- 6—carb0xylic acid Sodium hydroxide (21.6 mg, 0.54 mmol) was added to a solution of methyl 2—(2, 3-dihydro-l, 4- benzodioxin-G-yl)-3—(1, 2, 3, 4~tetrahydr0quinolinyl)quin0xalinecarboxylate (65 mg, crude) in methanol (5 ml) and water (1 ml) and the reaction was stirred overnight at room temperature.

The reaction mixture was concentrated in mean, the residue was ved in water (30 ml), adjusted to pH=5 with hydrochloric acid (3 N), and the precipitate was collected by tion to afford 2-(2, 3-dihydr0-1, 4-benzodioxinyl)(1, 2, 3, 4-tetrahydroquinolinyl)quin0xaline- 6~carboxylic acid as a light yellow solid (31.8 mg).

Calculated for C26H21N3O4: 439.15. (ES,m/z): [M+H]+ 440.0 1H-NMR (300 MHz, DMSO): 5 13.25 05, 1H), 8.31 (d, J = 1.2 Hz, 1H), 8.03 — 8.11 (m, 2H), 7.25 — 7.30 (m, 2H), 7.02 - 7.05 (t, J: 3.6 Hz, 1H), 6.75 — 6.79 (m, 3H), 6.61 - 6.64 (m, 1H), 4.19 (d, J = 2.1 Hz, 4H), 3.70 — 3.74 (1., J = 6.0 Hz, 2H), 2.73 - 2.77 (t, J = 6.3 Hz, 2H), 1.94 - 1.98 (t, J = 6.0 Hz, 2H) PCT/U52012/020281 Attorney Docket No. BlOEOOO9PC EXAMPLE 5 2-(4-Fluorophenyl)(6-methoxy-l,2,3,4-tetrahydroquinolin—1-yl)quinoxalinecarboxylic acid Step 1. Methyl 3-(6-methoxy—1,2,3,4-tetrahydroquinolin—1—yl)—2-0xo-1,2-dihydroquinoxaline-6~ carboxylate O N To a solution of methyl 3-chlorooxo-1,2—dihydroquinoxaline-6—carboxylate (700 mg, crude) in NMP (2 mL) was added oxy-1,2,3,4-tctrahydroquinolinc (1.0 g, 6.13 mmol) with stirring for 3 h at 150°C. The reaction mixture was cooled to room temperature. The product was precipitated by the on ethyl acetate and the solids were collected by filtration to afford methyl 3-(6—n1ethoxy-1 ,2,3,4—tetrahydroquinoliny1)oxo-1,Z-dihydroquinoxaline—o- carboxylate as alight yellow solid (450mg), which was used to the next step without futher purification.

(ES, m/z): r 366.0 Step 2. Methyl 3—(6-methoxy-l,2,3,4—tetrahydroquinolin-l(2H)—yl)—2— (trifluoromothylsulfonyloxy)quinoxalinccarboxylatc 2012/020281 Attorney Docket No. BlOEOOO9-40l PC To a solution of methyl 3-(6-methoxy-1,2,3,4—tetrahydroquinolin~1—yl)-2—oxo-1,2- oquinoxaline-6—carboxylate (250 mg, 0.68 mmol) in dichloromethane (50 mL) was added pyridine (161.88 mg, 2.05 mmol) and mo (288.91 mg, 1.02 mmol) with stirring overnight maintained with an inert atmosphere of nitrogen at room ature. The reaction was then quenched with water (20 mL), ted with dichloromethane (3 X 20 mL), the organic layers combined and dried over anhydrous magnesium sulfate, concentrated under vacuum to afford methyl 3-(6-methoxy—1,2,3,4-tetrahydroquinolin-1—yl)~2— [(trifluoro111ethane)sulfonyloxylquinoxaline—6~carboxylate as red 0 mg, crude), which was used to the next step directly.

Step 3. Methyl 2-(4-fluorophenyl)-3~(6-methoxy~1 ,2,3,4-tetrahydroquinolin-1—y1)quinoxaline~6~ carboxylate To a solution of methyl 3-(6-1nethoxy—1,2,3,4-tetrahydroquinolinyl) [(trifluoromethane)sulf0nyloxy]quinoxaline-6—carb0xylate (350 mg, crude) in dioxane (5.0 mL) and water (three drops) was added 4-flu0rophenyl boronic acid (140.85 mg, 1.01 mmol), K3P04 (318.4 mg, 1.51 mmol) and Pd(PPh3)4 (29.02 mg, 0.03 mmol) with stirring for 1 h at 90°C maintained with an inert atmosphere of nitrogen in an oil bath. The reaction mixture was concentrated under vacuum to give a residue, which was purified by a silica gel column with 2% ethyl acetate in petroleum to afford methyl 2-(4—fluorophenyl)~3-(6-methoxy-12,3,4- tetrahydroquinolin-l-y1)quinoxaline~6-carboxylate as a red solid (80 mg).

LC/MS (ES, m/z): [M+H]+ 444.0 1H—NMR (300 MHz, CDCig) 8 8.76 (d, J = 1.8 Hz, 1H), 8.17 - 8.21 (dd, J1: J2 :18 Hz, 1H), 8.08 (d, J = 8.4 Hz, 1H), 7.68 - 7.73 (m, 2H), 6.93 — 6.99 (t, J: 8.7 Hz, 2H), 6.56 - 6.60 (m, 2H), 6.35 - 6.39 (m, 1H), 4.01 (s, 3H), 3.93 — 3.97 (t, J = 6.0 Hz, 2H), 2.75 — 2.79 (t, J: 6.6 Hz, 2H), 2.06 - 2.12 (m, 2H) PCT/USZOIZ/OZOZS] Attorney Docket No. 009401 -PC Step 4. 2-(4—Fluorophenyl)(6—inethoxy-1,2,3,4-tetrahydroquinolin—1-yl)quinoxaline carboxylic acid To a on of methyl 2-(4-fluorophenyl)(6—methoxy- 1 ,2,3,4-tetrahydroquinolin-1— yl)quinoxalinecarboxylate (80 mg, 0.18 mmol) in water (1 mL) and MeOH (15 mL ) was added sodium hydroxide (29 mg, 07211111101) with stirring overnight at room temperature. The reaction mixture was concentrated under vacuum, dissolved in water (30 mL), adjusted to pH 5 with hydrogen chloride (3 N) to give the precipitation, which was collected by filtration to afford 2-(4-fluoropheny1)(6-methoxy- 1,2,3,4-tetrahydroquinoliny1)quinoxaline—6-carboxy1ic acid as alight yellow solid (50 mg, 64.6 %).

LC/MS (ES, m/z): [M+H]+ 430.0 1H-NMR (300 MHz, DMSO) 5 8.31 (s, 1H), 8.04 (s, 2H), 7471 - 7.76 (m, 2H), 7.07 - 7.13 (t, J: 8.7 Hz, 2H), 6.57 - 6.62 (m, 2H), 6.30 - 6.33 (m, 2H), 3.74 - 3.79 (t, J: 6.6 Hz, 2H), 3.61 (S, 3H), 2.68 - 2.73 (t, J: 6.3 Hz, 2H), 1.94 - 1.99 (t, J: 6.3 Hz, 2H) EXAMPLE 6 3-(6-Flu0r0-1,2,3,4-tetrahydroquinolinyl)(4-fluorophenyl)quinoxaline-6—carboxylic acid N N COOH Attorney Docket No. 1310150009401 -PC Step 1. 6-Fluoro-1,2,3,4-tetrahydroquinoline FDC) Sodium cyanoborohydridc (6.45 g, 103 mmol ) was added gradually to the solution of 6-fluoro ine (5 g, 34 mmol) in glacial acetic acid (100 ml) at ambient temperature. After stirring for 12 h the reaction mixture was quenched in water and extracted with EtOAc (3 X 50 mL). The combined organic layers were washed with water, brine and dried over sodium sulfate, filtered and evaporated in vacuo, the residue was purified by a silica gel column with 1% to 5% ethyl acetate in petroleum ether to afford ro-1,2,3,4-tetrahydroquinoline as a light yellow liquid (3.65 g, 71.6 %).

LC/MS (ES, m/z): r 152.0 1H-NMR (300 MHZ, Z 8 6.68 - 6.74 (m, 2H), 6.43 - 6.48 (m, 1H), 3.27 - 3.31 (m, 2H), 2.74 - 2.79 (t, J = 6.6 Hz, 2H), 1.91 - 1.99(m, 211) Step 2. Methyl 3-(6-fluoro- l,2,3,4-tetrahydroquinolin-l(2H)-yl)—2-oxo—1,2-dihydroquinoxaline- 6~carboxylate To a solution of methyl 3—chloro-2—oxo~l,2-dihydroquinoxaline-6—carboxylate (500.0 mg, 2.10 mmol) in 6-fluoro—1,2,3,4~tetrahydroquinoline (1.5 g, 9.9 mmol) with stirring for 1 h at 150°C.

The on mixture was cooled to room temperature. The product was precipitated by the addition ethyl acetate and the solids were collected by filtration to afford methyl 3-(6-f1uoro- 1,2,3,4—tetrahydroquinolin-1(211)-yl)—2-oxo-1,2-dihydroquinoxalinecarboxylate (369.0 mg, 50%).

LC/MS (ES, m/z): [M+H]+ 354.0 1H-NMR (300 MHZ, DMSO) 5 12.50 (s, 1H), 7.98 (d, J: 1.5 HZ,1H), 7.83 — 7.87 (m, 1H), 7.31 (d, J: 8.7112, 111), 6.95 - 7.03 (In, 211), 6.83 - 6.89 (m, 111), 3.85 - 3.93 (m, 511), 2.73 - 2.77 (t, J = 6.6 Hz, 2H), 1.91 - 1.95 (1,]: 6.3 Hz, 2H) PCT/USZOIZ/OZOZS] Attorney Docket No. 810130009401 ~PC Step 3. Methyl uoro-1,2,3,4-tetrahydroquinolin-l(2H)-yl) oromethylsulfonyloxy)quinoxalinecarboxylate TfOIN/NUKO/ To a solution of methyl 3-(6—fluoro—1,2,3,4—tetrahydroquinolin-l—yl)-2—oxo-l,2— dihydroquinoxaline—6—carboxylate (200 mg, 0.54 mmol) in dichloromethane (40 mL) was added pyridine (180 mg, 2.28 mmol) and T130 (321 mg, 1.14 mmol) with stirring overnight maintained with an inert atmosphere of nitrogen at room ature. The reaction was then quenched with water (50 mL), extracted with dichloromethane (3 x 50 mL), the organic layers combined and dried over anhydrous magnesium sulfate, concentrated under vacuum to afford methyl 3~(6- fluoro-l ,2,3,4—tetrahydroquinolin-1(2H)-yl)~2-(trifluoromethylsulfonyloxy)quinoxaline—6- carboxylate (274 mg, crude), which was used to the next step ly.

Step 4. Methyl 3-(6-fluoro-l2,3,4-tetrahydroquinolin-l-yl)-2—(4-fluorophenyl)quinoxaline carboxylate To a solution of methyl 3-(6-fluoro—l,2,3,4-tetrahydroquinolin~l(2H)-y1) (trifluoromethylsulfonyloxy)quinoxaline—6-carboxylate (274 mg, crude) in dioxane (5.0 mL) and water (3 drops) was added 4—fluorophenylboronie acid (200 mg, 1.43 mmol), K3PO4 (360 mg, 1.71 mmol) and Pd(PPh3)4 (33 mg, 0.03 mmol) with ng for l h at 90°C maintained with an inert atmosphere of nitrogen in an oil bath. The reaction mixture was concentrated under vacuum to give a residue, which was purified by a silica gel column with 1% to 2% ethyl acetate in petroleum ether to afford methyl 3-(6-fluoro-1,2,3,4—tetrahydroquinolin-l-yl)-2—(4— fluorophenyl)quinoxalinecarboxylate as a yellow solid (88 mg).

LC/MS (ES, Iii/Z): [M+H]+ 432.0 PCT/USZOIZ/OZOZSI ey Docket No. 1310120009401 -PC 1H-NMR (300 MHZ, CDClg) 5 8.67 (s, 1H), 8.19 — 8.23 (m, 1H), 8.10 (d, J: 8.7 Hz, 1H), 7.72 - 7.77 (m, 2H), 6.96 - 7.14 (m, 2H), 6.74 — 6.78 (m, 1H), 6.49 - 6.60 (m, 2H), 4.02 (s, 3H), 3.86 - 3.90 (t, J: 6.0 Hz, 2H), 2.77 - 2.81 (t, J: 6.3 Hz, 2H), 2.07 - 2.11(t, J = 6.9 Hz, 2H) Step 5. 3-(6-Fluoro- l ,2,3.4—tetrahydroquinolin— l -yl)—2-(4-fluorophenyl)quinoxalinecarboxylic acid To a solution of methyl 3-(6-fluoro-l ,2,3,4—tetrahydroquinolin-l-yl)-2—(4- fluorophenyl)quinoxaline—6-carboxylate (88 mg, 0. l8 mmol) in methanol (25 mL) and water (1 mL ) was added sodium hydroxide (24.5 mg, 0.61 mmol) with stirring overnight at room temperature. The reaction mixture was concentrated under , dissolved in water (10 mL), adjusted to pH 4 with hydrochloric acid (3 N) to give the precipitation, which was collected by filtration to afford 3 -(6-fluoro-l ,2,3,4-tetrahydroquinolinyl)(4-fluorophenyl)quinoxaline carboxylic acid as a yellow solid (63 mg, 79%).

LC/MS (ES. m/z): [M+H]+ 418.0 1H-NMR (300 MHz, DMSO) 5 8.34 (d, J: 1.2Hz, 1H), 8.05 - 8.11 (m, 2H), 7.72 - 7.77 (m, 2H), 7.09 — 7.16 (m, 2H), 6.85 — 6.89 (m, 1H), 6.64 — 6.69 (m, 1H), 6.51 - 6.57 (m, 1H), 3.77 — 3.82 (t, J: 6.3 Hz, 2H), 2.71 — 2.76 (t, J: 6.6 Hz, 2H), 1.95 - 2.00 (t, J = 6.3 Hz. 2H) PCT/U82012/020281 Attorney Docket No. BlOEOOO9—40l —PC EXAMPLE 7 luorobenzofuranyl)(6-methoxy-1,2,3,4-tetrahydr0quinolinyl)quin0xaline- 6-carboxylic acid N fifikm \ N F 0 Step 1. Methyl 3—(1,2,3,4-tetrahydroquinolin—1(2[~I)-yl)-2— (uifluoromethylsulfonyloxy)quinoxaline—6-carboxylate To a solution of methyl 3-(6-methoxy-1 ,2,3,4-tetrahydroquinolin- 1-y1)-2—0x0-1,2- oquinoxaline-6—carboxylate (100 mg, 0.27 mmol) in dichloromethane (50 mL) was added pyridine (64.8 mg, 0.82 mmol) and ngO (1156 mg, 0.41 mmol) with stirring ght maintained with an inert atmosphere of nitrogen at room temperature. The reaction was then quenched with water (20 mL), extracted with dichloromethane (3 x 15 mL), the organic layers combined and dried over anhydrous magnesium sulfate, concentrated under vacuum to afford methyl 3-(6-methoxy—l [2,3,4—tetrahydroquinolin—1-yl) [(trifluoromethane)sulfonyloxy]quinoxalinecarboxylate as red oil(150mg, crude), which was used to the next step directly.

PCT/U52012/020281 Attorney Docket No. 1310130009401 —PC Step 2. Methyl 2—(5-fluoro-1~benzofurany1)—3-(6-methoxy—1 ,2,3,4-tetrahydroquinolin yl)quinoxaline-6—carboxylate N /N: : /U\O/ \ \ N F 0 To a solution of methyl 3-(6-methoxy—1,2,3,4-tetrahydroquinolin-1—yl)-2— [(trifluoromethane)sulfonyloxy]quinoxa1ine—6-carboxylate (150 mg, crude) in dioxane (5.0 mL) and water (three drops) was added (5-fluorobenzofuranyl)boronic acid (94 mg, 0.52 mmol), K3PO4 (165.8 g, 781.08 mmol) and Pd(PPh3)4 (15.3 mg, 13.08 mmol) with stirring for 1 h at 90°C maintained with an inert atmosphere of nitrogen in an oil bath. The reaction mixture was trated under vacuum to give the e, which was purified by a silica gel column with 2% ethyl acetate in petroleum to afford methyl 2-(5-fluoro—1-benzofuranyl)(6-methoxy- 1,2,3,4-tetrahydroquinolin-l~yl)quinoxaline-6—Carb0xylate as a red solid (40 mg).

(ES, m/z): [M—i-H]+ 484.0 1H-NMR (300 MHZ, CDC13) 8 8.61 (d, J: 1.8 Hz, 1H), 8.13 - 8.22 (m, 2H), 7.36 — 7.42 (m, 2H), 7.17 - 7.21 (m, III), 7.01 - 7.08 (m, 111), 6.65 (d, J = 2.7 Hz, 1H), 6.56 (d, J: 8.7112, 111), 6.33 — 6.37 (m, 1H), 4.01 (s, 3H), 3.95 - 3.99 (t, J: 6.3 Hz, 2H), 3.63 (s, 3H), 2.93 - 2.98 (t, J: 6.6 Hz, 2H), 2.13 - 2.21 (m, 2H) Step 3. 2—(5-F1uoro-1—benzofuranyl)(6~methoxy—1,2,3,4-tetrahydroquinolin—1— yl)quinoxaline—6—carboxylic acid N ’NfiOH \ N F 0 To a solution of methyl uorobenzofuran—2-yl)(6-methoxy-1,2,3,4-tetrahydroquinolin- 1-yl)quinoxaline—6-carboxylate (40 mg, 0.083 mmol) in methanol (20 mL) and water (three PCT/U52012/020281 Attorney Docket No. 1310130009401 -PC drops) was added sodium hydroxide (16.5 mg, 0.41 11111101) with ng overnight at room temperature. The reaction mixture was concentrated under vacuum, dissolved in water (30 mL), adjusted to pH 5 with hydrogen chloride (3 N) to give the precipitation, which was collected by filtration to afford 2-(5-fluoro-l-benzofurany1)(6-meth0xy-l ,2,3,4—tetrahydroquinolin-1— y1)quinoxaline-6—carboxylic acid as a light yellow solid (23 mg, 44 %).

LC/MS (ES, Iii/Z): [M+H]+ 470.0 1II—NMR (300 MHz, DMSO) 5 13.38 (s, 1H), 8.30 (s, 1H), 8.07 - 8.13 (t, J = 8.7 Hz, 2H), 7.55 - 7.59 (m, 1H), 7.42 - 7.46 (m, 2H), 7.16 - 7.23 (m, 1H), 6.67 (d, J: 2.7 HZ, 1H), 6.59 (d, J: 8.7 Hz, 1H), 6.30 - 6.34 (m, 1H), 3.84 - 3.88 (t, J: 6.3 Hz, 2H ), 3.53 (S, 3H), 2.87 - 2.91 (t, J: 6.3 Hz, 2H), 2.01 - 2.09 (m, 2H) 2-(S-Chlorobenzofuranyl)(6-flu0r0-1,2,3,4-tetrahydr0quinolinyl)quinoxaline carboxylic acid N N COOH \ N Cl 0 Step 1. Methyl 3—(6-fluoro~l,2,3,4—tetrahydroquinolin-1—y1)-2— (trifluoromethylsulfonyloxy)quinoxaline—6—carboxylate TfO N To a solution of methyl 3—(6-fluoro-1,2,3,4-tetrahydroquinolin—1-y1)—2—oxo—l,2- dihydroquinoxaline-é-carboxylate (150 mg, 0.43 mmol) in dichloromethane (40 mL) was added pyridine ( 136 mg, 11101) and ngO (242 mg, 0.86 mmol) with stirring overnight maintained with an inert atmosphere of nitrogen at room temperature. The reaction was then quenched with PCT/U52012/020281 Attorney Docket No. BTOE0009PC water (50 mL), extracted with dichloromethane (3 x 10 mL), the organic layers combined and dried over anhydrous magnesium sulfate, concentrated under vacuum to afford methyl 3-(6- fluoro- l ,2,3,4—tetrahydroquinolin-1—yl)—2—(trifluoromethylsulfonyloxy)quinoxalinecarboxylate (274 mg, crude), which was used to the next step directly.

Step 2. Methyl 2-(5-Chloro—1—benzofuranyl)(6—fluoro-1,2,3,4-tetrahydroquinolin-l- n0xaline—6-carboxy1ate N /N: : /U\O/ \ \ N Cl 0 To a solution of methyl luoro-l,2,3,4~tetrahydroquinolin- l—yl)-2— [(trifluoromethane)sulfonyloxy]quinoxaline—6-carboxylate (274 mg, crude) in dioxane (5.0 mL) and water (0.5 mL) was added (5-chlorobenzofurany1)boronic acid (210 mg, 1.07 mmol), K3PO4 (272 mg, 1.29 mmol) and Pd(PPh3)4 (25 mg, 0.0221an1) with stirring for 1 h at 90°C maintained with an inert atmosphere of nitrogen. The reaction mixture was concentrated under vacuum to give the residue, which was ed by a silica gel column with 1% to 5% ethyl acetate in petroleum ether to afford methyl 2-(5—chloro-l—benzofuran-2—yl)(6-fluoro-12,3,4— tetrahydroquinolin—l—yl)quinoxaline—6—carboxylate as a light red solid (53 mg).

(ES, m/z): [M+H]+ 488.0 1H-NMR (300 MHz, DMSO) 8 8.63 (d, J = 1.5 Hz, 1H), 8.18 - 8.26 (m, 2H), 7.53 (d, J: 2.1 Hz, 1H), 7.37 — 7.41 (t, J: 4.2 Hz, 2H), 7.30 (d, J: 2.1 Hz, 1H), 6.81 - 6.85 (m, 1H), 6.46 - 6.58 (m, 2H), 4.02 (s, 3H). 3.96 - 4.00 (m, 2H). 2.96 — 3.00 (t, J = 6.6 Hz. 2H), 2.15 — 2.24 (m, 2H) Attorney Docket No. 1310130009401 ~PC Step 3. 2-(5-Chloro~1-benzofuran—2-y1)—3-(6—fluoro-1,2,3,4-tetrahydroquinolinyl)quinoxaline~ 6-carboxy1ic acid Cl 0 To a solution of methyl 2-(5-chlorobenzofuranyl)-3—(6-f1uoro-1,2,3,4—tetrahydroquinolin-1~ yl)quinoxaline—6—carboxylate (53 mg, 0.11 mmol) in ol (25 mL) and water (1 mL ) was added sodium hydroxide (120 mg, 0.30 mmol) with stirring overnight at room temperature. The reaction mixture was concentrated under vacuum, dissolved in water (10 mL), adjusted pH to 5 with hydrogen chloride (3 N) to give the precipitation, which was collected by filtration to afford 2-(5 -ch10ro—1-benzofurany1)—3-(6~fluoro-1,2,3,4—tetrahydroquinolin~1-yl)quinoxaline carboxylic acid (37.5 mg, 73 ‘70).

(ES, m/z): [M+H]+ 374.0 11NMR (300 MHZ, DMSO) 5 8.30 (d, J = 1.5 Hz, 1H), 8.07 - 8.17 (m, 2H), 7.75 (d, J: 2.1 Hz, 1H), 7.61 (d, J: 9.0Hz, 1H), 7.49 (s, 1H), 7.36 - ,1H), 6.91 - 1, 1H), 6.52 - 6.68 (m, 1H), 3.85 - 3.89 (t, J: 6.0 Hz, 2H), 2.90 — 2.95 (t, J: 6.6 Hz, 2H), 2.05 — 2.10 (t, J: 6.0 Hz, 2H) EXAMPLE 9 2-(S-Chlor0benzofuran-Z-yl)~3-(6-methoxy—1,2,3,4~tetrahydroquinolin-l-yl)quinoxaline- 6-carb0xylic acid \ /NI>/‘kOHN CI 0 ZOIZ/OZOZSI Attorney Docket No. 1310130009401 ~PC Step 1. Methyl 2-(5—chloro-1—benzofurany1)(6-methoxy-1,2,3,4-tetrahydroquinolin—l- y1)quinoxalinecarboxylate N /N: : AO/\ \ N CI 0 To a solution of methyl 3~(6-methoxy~l ,2,3,4-tetrahydroquinolin-1—yl)-2— [(trilluoromeLhane)sulfonyloxy]quinoxalinecarboxylate (From Ex. 5, step 2, 130 mg, crude) in e (5.0 mL) and water (three drops) was added (5-chloro-1—benzofuranyl)boronic acid (103 mg, 0.52 mmol, K3PO4 (165.8 mg, 0.78 mmol) and Pd(PPh3)4 (15.2 mg, 0.01 mmol) with stirring for 1 h at 90°C maintained with an inert atmosphere of nitrogen in an oil bath. The reaction mixture was concentrated under vacuum to give the residue, which was purified by a silica gel column with 2% ethyl acetate in petroleum ether to afford methyl hloro-1— benzofuran-Z-yl)(6-methoxy-1,2,3,4-tetrahydroquinolinyl)quinoxa1inecarboxylate as a red solid (40 mg).

(ES, m/z): [M+H]+ 500.0 1H—NMR (300 MHz, CDC13) 5 8.61 (d, J: 1.5 Hz, 1H), 8.13 — 8.22 (m, 2H), 7.51 (d, J: 2.1 Hz, 1H), 7.25 — 7.40 (m, 3H), 6.65 (d, J = 2.7 Hz, 1H), 6.56 (d, J = 8.7 Hz, 1H), 6.32 — 6.36 (m, 1H), 4.01 (s, 3H), 3.96 — 3.99 (t, J = 6.3 Hz, 2H), 2.93 ~ 2.98 (t, J: 6.6 Hz, 2H), 2.13 - 2.21 (m, 2H) Step 2. 2—(5—Chlorobenzofuran—2~yl)(6-methoxy-1,2,3,4-tetrahydroquinolin~1— y1)quinoxaline-6—carboxylic acid \ N CI 0 To a solution of methyl 2-(5-chloro-l-benzofuran—2—y1)(6-methoxy-1,2,3,4- tetrahydroquinolin—l-y1)quinoxalinc-6—carboxylatc (40 mg, 0.08 mmol) in methanol (25 mL) and water ( 1 mL) was added sodium hydroxide (12.6 mg, 0.32 mmol) with stirring overnight at room Attorney Docket No. 810130009401 -PC temperature. The reaction mixture was concentrated under vacuum, dissolved in water (5 mL), ed to pH 5 with hydrochloric acid (3 N) to give the itation, which was collected by filtration to afford 2-(5-fluoro-l-benzofuranyl)(6-methoxy-1,2,3,4-tetrahydroquinolin-l- yl)quinoxalinecarboxylic acid as a light yellow solid (30.0 mg, 77 %).

LC/MS (ES, m/z): [M+H]+ 486.0 1H-NMR (300 MHZ, DMSO) 5 13.35 (s, 1H), 8.30 (d, J: 1.2 Hz, 1H), 8.09 (s, 1H), 7.71 (d, J = 2.1 Hz, 1H), 7.56 (d, J: 8.7 HZ, 1H), 7.42 (s, 1H), 7.34 - 7.38 (m, 1H), 6.67 (d, J: 2.7 Hz, 1H), 6.59 (d, J = 8.7 Hz, 1H), 6.29 - 6.33 (m, 1H), 3.84 - 3.88 (t, J = 6.3 Hz, 2H), 3.53 (s, 3H), 286 ~ 2.90 (t, J: 6.30 Hz, 2H), 2.03 — 2.09 (m, 2H).

EXAMPLE 10 2-Oxo(1, 2, 3, 4-tetrahydr0quinolin-l-yl)-1,2—dihydroquinoxalinecarboxylic acid ONINfikOHN 2-oxo(1, 2, 3, 4-tetrahydroquinolinyl)-1, 2-dihydroquinoxalinecarb0xylic acid To a solution of methyl 2—oxo(l, 2, 3, 4—tetrahydroquinolin—1-yl)-1 , 2-dihydroquinoxaline-6— carboxylate (50 mg, 0.15 mmol) in methanol (30 mL) was added potassium hydroxide (33.33 mg, 0.60 mmol) and water (1 mL) with stirring overnight at room temperature. The on mixture was concentrated under vacuum, dissolved in water (30 mL), ed to pH 4 with HCl (3 N) to give the precipitate, which was collected by filtration to afford 2—oxo(l, 2, 3, 4- tetrahydroquinolin-l—yl)—1, 2—dihydroquinoxalinecarboxylic acid as a light yellow solid (40.0 mg, 79 %).

(ES, m/z): [M+H]+ 322.0 1H—NMR (300 MHZ, DMSO) 7.98 (d, J = 1.5 Hz, 1H ), 7.83 - 7.86 (dd, J1: J2 = 1.80 H7, 1H ), 7.31 (d, J: 8.4 Hz, 1H), 7.13 - 7.15 (dd, J1: J2 :15 Hz, 1H), 6.87 — 7.04 (m, 3H), 3.88 - 3.92 (t, J = 6.3 HZ, 2H), 2.73 - 2.78 (t, J = 6.6Hz, 2H), 1.91 - 1.99 (s, 2H) PCT/U82012/020281 Attorney Docket No. BIOE0009—401—PC EXAMPLE 1] 3-(6-Fluoro-3,4-dihydroquinolin-l(2H)-yl)(S-fluorobenzofuran-Z-yl)quinoxaline carboxylic acid N JDJEH \ N F 0 Step 1. Methyl 2—(5-fluoro-l H—indenyl)~3-(6—fluoro-3,4—dihydroquinolin-1 (2H)- yl)quinoxalinecarboxylate \ N F 0 To a solution of methyl 3~(6-fluoro-3,4-dihydroquinolin-l(2H)-yl) (trifluoromethylsulfonyloxy)quinoxaline—6—carboxylate (From EX. 6, step 3, 200 mg, crude) in dioxane (5.0 mL) and three drops of water was added 5-fluorobenzofuran—2—ylboronic acid (210 mg, 1.07 mmol), K3PO4 (272 mg, 1.29 mmol) and Pd(PPh3)4 (25 mg, 0.02 mmol). The on was stirred for 1 h at 90°C under an inert atmosphere of nitrogen in an oil bath. The reaction mixture was concentrated under vacuum to give the e, which was purified by a silica gel column with 1 % to 5 % ethyl acetate in eum to afford methyl 2—(5-fluoro—1H~inden-2—yl)- 3-(6-fluoro-3,4-dihydroquinolin-l(2H)-yl)quinoxalinecarboxylate as a light red solid (59 mg).

LC/MS (ES, m/z): [M+H]+ 472.0 1H-NMR (300 MHz, CDCl3) 5 8.65 (d, J = 1.5 Hz, 1H), 8.16 - 8.27 (m, 2H), 7.37 - 7.43 (m, 2H), 7.19 — 7.23 (m, 1H), 7.03 - 7.10 (in, 1H), 6.80 - 6.84011, 1H), 6.47 — 6.59 (m, 2H), 4.02 (s, 3H), 3.98 - 4.00 (m, 2H), 2.96 - 3.01 (t, J: 6.6 Hz, 2H), 2.15 - 2.24 (m, 2H) PCT/U52012/020281 Attorney Docket No. BlOEOOO9-40l -PC Step 2. 3-(6-Fluoro-3,4-dihydroquinolin-1(2H)—yl)—2-(5-fluorobenzofuran—2—yl)quinoxaline carboxylic acid \ N F 0 Sodium hydroxide (15.6 mg, 0.39 mmol) was added to a solution of methyl uor0-1H~ inden—Z—yl)-3—(6-fluoro-3,4—dihydroquinolin~l(2H)-yl)quinoxalinecarboxylate (59 mg, 0. l3 mmol) in methanol (25 mL) and tetrahydrofuran (5 mL ). The reaction was stirred overnight at room ature, concentrated in vacuo, dissolved in water (30 mL), and adjusted to pH 5 with hydrogen chloride (3 N). The precipitate was collected by tion to afford 3-(6-fluoro—3,4- dihydroquinolin—1(2H)-y1)-2—(5—fluorobenzofuran~2-yl)quinoxalinecarboxylic acid (32.5 mg, 57 %).

LC/MS (ES,m/z): [M+H]+ 458.0 1H-NMR (300 MHz, DMSO) 5 8.33 (S, 1H), 8.10 - 8.17 (m, 2H), 7.57 - 7.62 (m,1H), 7.52 (s, 1H), 7.45 - 7.49 (m, 1H), 7.17 - 7.25 (m, 1H), 6.92 — 6.96 (m,1H), 6.66 — 6.71 (m, 1H), 6.53 - 6.59 (m, 1H), 3.85 — 3.90 (t, J: 6.0 Hz, 2H), 2.90 - 2.95 (t, J = 6.6 HZ, 2H), 2.06 — 2.09 (m, 2H) 3-(6-Cyano-1,2,39,4-tetrahydroquinolinyl)(4-flu0rophenyl)quinoxaline-6— carboxylic acid NC(:3 To a solution of methyl 3-(6-cyano-l,2,3,4—tetrahydroquinolinyl)(4- fluorophenyl)quinoxalinecarboxylate (From Ex 14, step 5, 50 mg, 0.11 mmol) in methanol (20 mL) and water (1 mL) was added lithiumol hydroxide (10 mg, 0.40 mmol) with stirring overnight at room temperature. The resulting e was concentrated under vacuum, dissolved in water (10 mL)and adjusted to 7 with AcOH, collected by filtration to give 3-(6-cyano-l,2,3,4- tetrahydroquinolin-l-y1)(4-flu0rophenyl)quinoxalinecarboxylic acid as a yellow solid (14.7 mg, 30 %).

[M+H]+ 425.1 1H-NMR (300 MHz, CDgOD) 5 8.56 (d, J= 1.2 Hz, 1H), 8.30 — 8.33 (m, 1H), 8.07 (d, J: 8.7 Hz, 1H), 7.77 — 7.82 (m, 2H), 7.33 (d, J: 1.8 Hz, 1H), 7.06 - 7.12 (m, 3H), 6.52 (d, J: 8.4 Hz, 1H), 3.92 — 3.96 (t, J: 6.0 Hz, 2H), 2.84 — 2.88 (t, J: 6.6 Hz, 2H), 2.08 — 2.12 (t, J: 6.0 Hz, 2H) EXAMPLE l3 7-(6—Bromo—1,2,3,4—tetrahydroquinolin-l-yl)—6-(4-flu0rophenyl)quinoxaline—Z-carboxylic acid To a solution of 1,2,3,4—tetrahydroquinoline (1.0 g, 7.51 mmol) in NMP (20 ml) was added methyl 3-chloro—2—oxo-l,2-dihydroquinoxaline—6-carboxylate (670 mg, 2.81 mmol) with stirring 3h at 130°C in an oil bath. The t was precipitated with water (80 m1), collected by filtration to afford methyl 2-oxo—3—(1,2,3,4-tetrahydroquinolinyl)—1,2-dihydr0quinoxaline—6— carboxylate as a yellow solid (700 mg 28 %).

PCT/U82012/02028l Attorney Docket No. BlOEOOO9-401—PC LC/MS (ES, m/z): [M+H]+ 338.0 lH-NMR (300 MHZ. DMSO) 5 10.67 (s, 1H), 8.41 (d, J: 2.1 Hz, 1H), 7.93 - 7.96 (m, 1H), 7.14 (d, J: 2.1 Hz, 1H), 7.02 - 7.09 (m, 3H), 6.88 - 6.93 (m, 1H), 4.10 - 4.14 (n1, 2H), 3.96 (s, 3H), 2.84 - 2.89 (t, J = 6.6 Hz, 2H), 1.99 - 2.15 (m, 2H).

Step 2. Methyl 3-(1,2,3,4—tetrahydroquinolinyl)—2- [(trifluoromethane)sulfonyloxy]quinoxaline—6-carb0xylate N /N 0/ To a solution of methyl 2—0xo-3—(1,2,3,4-tetrahydroquinolin-1—yl)—1,2—dihydr0quinoxaline—6- carboxylate (700 mg, 2.09 mmol) in dichloromethane (40 n11) was added pyridine (660 mg, 8.34 11111101) and then szO (1179 111g, 4.18 11111101) was added dropwise at 0 °C under an atmosphere of nitrogen . The reaction was stirred ght at room temperature and then quenched by the addition of ice-water (300 n11). The organic layers was separated and the aqueous layers was extracted with romethane (3 x 50 m1) and the organic layers combined, dried over anhydrous magnesium sulfate and concentrated in vacuo at low temperature to afford methyl 3- (1 ,2,3,4-tetrahydr0quinolin- 1-yl)—2-[(trifluoromethane)su1f0nyloxy]quinoxalinecarboxy1ate as a yellow solid (1.33 g, , which was used directly in the next step.

Step 3. Methyl 2—(4—fluorophenyl)(1,2,3,4-tetrahydr0quin01inyl)quinoxalinecarb0xylate To a solution of methyl 3-(1,2,3,4—tetrahydroquinolin-l-y1) [(trifluoromethane)sulfonyloxy]quinoxaline-6—carboxylate (1.33 g, crude in 1,4-dioxane (20 ml) and water (1 ml) was added (4-fluorophenyl)boronic acid (1.19 g, 8.55 mmol), K3PO4 (1.20 .65 01) and Pd(PPh3)4 (164 mg, 0.14 11111101) with stirring for 1 h at 90°C under atmosphere of en. The reaction mixture was concentrated to give a residue, which was purified by a silica gel column with 2 % ethyl acetate in petroleum ether to afford methyl 2-(4-fluorophenyl)— 3-(1,2,3,4—tetrahydroquinolin-1—yl)quinoxalinecarboxylate as a yellow solid (560 mg, 48% 2 steps).

LC/MS (ES, m/z): [M+H]+ 416 1H—NMR (300 MHz, CDC13)5 8.66 (d, J= 1.5 Hz 8.19 - 8.23 (m, 1H), 8.08 (d, J: 8.7 Hz , 1H), , 1H), 7.72 - 7.79 (m, 2H), 7.02 - 7.05 (m, 3H), 6.76 - 6.82 (m, 2H), 6.59 - 6.63 (m, 1H), 4.02 (s, 3H), 3.86 — 3.90 (m, 2H), 2.79 - 2.84 (t, J= 6.3 Hz, 2H), 2.08 - 2.12 (t, J= 6.3 Hz, 2H) Step 4. Methyl 3-(6—bromo-l,2,3,4-tetrahydroquinoliny1)(4-fluorophenyl)quinoxaline carboxylate To a solution of methyl 2—(4-fluorophenyl)-3—(l,2,3,4—tetrahydroquinolin—l-yl)quinoxaline-6— carboxylate (300 mg, 0.73 mmol) in N,N—dimethylformamide (20 ml) was added NBS (193 mg, 1.08 mmol) under an inert atmosphere of en. The resulting solution was stirred for 1.5 h at — °C. Then water (150 ml) was added and the reaction was extracted with ethyl acetate (3 x 50 ml). The organic layers were combined, dried over ous magnesium sulfate and concentrated in vacuo to give a residue, which was purified by silica gel chromatography eluting with 1 % — 2 % ethyl acetate in petroleum ether to afford methyl 3-(6-br0mo-1,2,3,4- tetrahydroquinolin-l-yl)(4-fluorophenyl)quinoxaline—6-carboxylate as a yellow solid (200 mg, 56%).

LC/MS(ES,m/z): [M+H]+ 495 1H-NMR (300 MHZ, CDC13) 8 8.64 (d, J= 1.8 Hz 8.22 - 8.25 (m, 1H), 8.09 (d, J= 8.7 Hz, , 1H), 1H), 7.76 - 7.81 (m, 2H), 7.18 (s, 1H), 7.00 — 7.05 (m, 2H), 6.92 — 6.95 (m, 1H), 6.51 (d, J: 8.7 Hz, 1H), 4.01 (s, 3H), 3.77 - 3.81 (t, J: 6.3 Hz, 2H), 2.78 — 2.79 (t, J= 6.6 Hz, 2H), 2.05 — 2.10 (m ,2H) Step 5. 7-(6-Bromo- l ,2,3 rahydroquinolin— l ~yl)-6—(4—fluorophenyl)quinoxaline—2- carboxylic acid Sodium hydroxide (39 mg, 0.97 mmol) was added to a solution of methyl 7-(6-bromo—l ,2,3,4— ydroquinolin-l -yl)—6—(4—fluorophenyl)naphthalenecarboxylate (120 mg, 0.24 mmol) in methanol (30 ml) and water (2 ml). The resulting solution was stirred overnight at room temperature and concentrated in vacuo. The residue was dissolved in water (20 ml) and adjusted to pH 4 with hydrochloric acid (3 N) to give the precipitation, which was collected by filtration to afford romo- l ,2,3 ,4—tetrahydroquinolinyl)—6—(4—fluorophenyl)quinoxaline-Z-carboxylic acid as a yellow solid (80 mg, 69 %).

LC/MS (BS, m/z): [M+H]+ 480.0 1H-NMR (300 MHZ, DMSO) 5 8.37 (s, 1H), 8.07 — 8.36 (m, 2H), 7.75 — 7.80 (m, 2H), 7.13 — 7.20 (m, 3H), 6.85 — 6.89 (m, 1H), 6.58 (d, J= 8.7 Hz, 1H), 3.76 — 3.80 (t, J: 6.0 Hz, 2H), 2.73 - 2.77 (t, J= 6.3 Hz, 2H), 1.95 — 1.99 (t, J= 6.0 Hz, 2H) EXAMPLE l4 3-(6-Carbamoyl—1,2,3,4-tetrahydr0quin01inyl)(4-flu0rophenyl)quinoxaline-6— carboxylic acid 0 NH2 Step 1. 6—Brom0-l,2,3,4«tetrahydroquinoline B'CO NBS (28 g, 158 mmol) was added to a on of 1,2,3,4-tetrahydroquinoline (20 g, 150.16 mmol) in carbon tetrachloride (200 mL). The resulting solution was stirred for 3 h at 0°C, extracted with dichloromethane(3 x 50 mL) and concentrated in vacuo to give a residue, which was applied onto a silica gel column with l % ethyl acetate in petroleum ether to give o— l,2,3,4-tetrahydroquinoline as a yellow solid (11 g, 35%).

LC/MS(ES, m/z):[M+H]+ 212.1 1H—NMR (300 MHZ, CDC13) 5 7.03 - 7.07 (m, 2H), 6.35 — 6.38 (m, 1H), 3.51 — 3.55 (m, 2H), 2.73 - 2.80 (m, 2H), 1.89 - 1.99 (m, 2H) Step 2. 1,2,3,4-Tetrahydroquinolinecarbonit1i1e NCCO PCT/U52012/020281 Attorney Docket No. 810130009401 -PC To a solution of 6—bromo-1,2,3,4—tetrahydroquinoline (10 g, 47.15 mmol) in N,N— dimethylformamide (80 mL) was added Pd(PPh3)4 (2.8 g, 2.42 mmol), and zincdicarbonitn’le (6.4 g, 54.49 mmol) and the reaction was stirred for 2 h at 120°C in an oil bath. The reaction was quenched by the addition of water (400 mL) and extracted with dichloromethane(3 x 50 mL), and concentrated in vacuo to give a residue, which was purified by a silica gel chromatography with 1 % — 20 % ethyl acetate in petroleum ether to give 1,2,3,4-tetrahydroquinoline~6-carbonitrile as a yellow solid (6 g, 80 %).

LC/MS (ES, iii/z): [M+HTr 159.1 1H—NMR (300 MHz, CDClg) 6 7.20 - 7.23 (m, 2H), 6.40 (d, J: 8.1 Hz, 1H), 3.36 — 3.40 (t, J = .7 Hz, 2H), 2.72 - 2.77 (t, J = 6.3 Hz, 2H), 1.90 - 1.97 (m, 2H) Step 3. Methyl 3-(6-cyano-l,2,3,4—tetrahydroquinolin—1—yl)—2—0xo-1,2—dihydroquinoxaline-6— carboxylate N Juflko/ To a solution of methyl 3-chloro0xo—l,2-dihydroquinoxaline-6—carboxylate (300 mg, 1.26 mmol) in NMP (0.5 mL) was added 4-tetrahydroquinolinecarbonitrile (597 mg, 3.77 mmol) with stirring for 1 h at 150°C in an oil bath. The resulting solution was diluted with water (100 mL) and the solids were collected by filtration to afford methyl 3-(6-cyano-1,2,3,4— ydroquinolin-l-yl)ox0-1,2—dihydroquinoxaline—6—carboxylate as a yellow solid (200 mg, 44 %).

ES, m/z): [M+H]+ 361.1 1H-NMR (300 MHz, DMSO) 8 12.67 (s, 1H), 8.07 (d, J: 1.8 Hz, 1H), 7.92 - 7.96 (m, 1H), 7.60 (d, J: 1.8 Hz, 1H), 7.35 - 7.43 (m, 2H), 7.04 (d, J = 8.7 Hz, 1H), 3.89 - 3.94 (m, 2H), 3.87 (s, 3H), 2.80 - 2.83 (t, J: 6.6 Hz, 2H), 1.95 - 1.99 (t, J: 6.9 Hz, 111) Step 4. Methyl 3-(6—cyan0—1,2,3,4-tetrahydroquinolin~1-yl)—2— [(trifluoromethane)sulfonyloxy]quinoxalinecarboxylate Attorney Docket No. 1310130009401 -PC To a solution of methyl 3-(6-cyano—1 ,2,3,4—tetrahydroquinolin-l~yl)oxo-1,2- dihydroquinoxaline—6-carboxylate (350 mg, 0.97 mmol) in dichloromethane (20 mL) was added pyridine (547 mg, 6.92 mmol) and then (trifluoromethane)sulfonyl tnfluoromethanesulfonate (307 mg, 1.09 mmol) and the on was stirred for 2 h at room temperature. The resulting e was concentrated in vacuo to provide a residue, which was purified by silica gel chromatography with 1 % — 6 % ethyl acetate in petroleum ether to give methyl 3—(6-cyano- 1,2,3,4—tetrahydroquinolinyl)—2-[(tn'fluoromethane)sulfonyloxy]quinoxaline~6—carboxylate as a yellow solid (440 mg, crude).

Step 5. Methyl yano-1 ,2,3,4-tetrahydroquinolin~1~y1)—2-(4—flu0ropheny1)quinoxaline~6~ carboxylate To a on of methyl 3-(6-cyano—l,2,3,4-tetrahydroquinolin-l-yl) L(trifluoromethane)sulfonyloxyj aline-é—carboxylate (440mg, crude) in 1,4-dioxane (8 mL), was added (4-flu0rophenyl)boronic acid (251 mg, 1.79 mmol), Pd(PPh3)4 (51 mg, 0.04 mmol), K3PO4 (377 mg, 1.79 mmol) with stirring for 2 h at 90°C in an oil bath. The reaction was then quenched by the addition water (30 mL ), extracted with chloromethane (3 x 20 mL) and concentrated under vacuum to give methyl 3-(6—cyano-l,2,3,4-tetrahydroquinolin-l—yl)—2—(4— fluorophenyl)quinoxaline-6~carboxylate as a yellow solid (200 mg, 47 % 2 steps).

LC/MS(ES, m/z): [M+H]+ 439.1 1H-NMR (300 MHz, CDCl3) 5 8.67 (d, J: 1.8 Hz, 1H), 8.30 ~ 8.33 (m, 1H), 8.15 (d, J: 8.7 Hz, 1H), 7.78 — 7.82 (m, 2H), 7.33 (s, 1H), 6.93 - 7.14 (m, 3H), 6.60 (d, J: 8.4 Hz, 1H), 4.13 (3, 31-1), 3.78 - 3.82 (t, J: 6.0 Hz, 2H), 2.84 - 2.88 (t, J = 6.6 Hz, 2H), 2.03 - 2.11 (m, 2H) Step 6. 3—(6—Carbamoyl-1,2,3,4-tetrahydroquinolin-1~yl)-2—(4-fluorophenyl)quinoxaline~6- carboxylic acid Attorney Docket No. BTOEOOO9-40l -PC 0 NH2 To a solution of methyl 3-(6-cyano-1,2,3,4-tetrahydroquinolin-1~y1)(4- fluorophenyl)quinoxalinecarboxylate (150 mg, 0.34 mmol) in DMSO (1.6 mL) and EtOl—l (6.4 mL) was added H202 (1.2 mL, 40%), NaOH (0.4 mL, 1M) with stirring ght at room temperature. The resulting mixture was concentrated under vacuum, diluted with water (1 5 mL), ed p11 to 7 with ACOII. The solids were collected by filtration to give 3—(6-carbam0y1- 1,2,3,4-tetrahydr0quinolin—1-yl)—2—(4—fluorophenyl)quinoxalinecarb0xylic acid as a solid (131 mg, 87 %).

(ES, mix): [M+H]+ 443.1 1H-NMR (300 MHz, DMSO) 5 8.40 (d, J = 1.2 Hz, 1H), 8.11 - 8.19 (m, 2H), 7.79 — 7.83 (m, 2H), 7.66 (s, 1H), 7.55 (d, J: 1.2 Hz, 1H), 7.27 - 7.30 (m, 1H), 7.12 - 7.18 (in, 2H), 7.03 (s, 1H), 6.61 (d, J: 8.4 Hz, 1H), 3.80 - 3.84 (t, J: 6.0 Hz, 2H), 2.74 - 2.81 (m, J: 6.6 Hz, 2H), 1.99 — 2.03 (m, J = 6.60 Hz. 2H) EXAMPLE 15 2-(4-Flu0r0phenyl)[6—[(morpholinyl)carbonyl]-1,2,3,4-tetrahydroquinolin yl]quinoxalinecarboxylic acid Attorney Docket No. BlOEOOO9-40l -PC Step 1. Methyl 2-(4-fluorophenyl)[6—[(morpholin-4—yl)carbonyll-1,2,3,4-tetrahydroquinolin- 1-y1]quinoxalinea6-carboxylate 0 0’ To a solution of methyl romo~1,2,3,4-tetrahydroquinolin-l-yl)—2—(4~ fluorophenyl)quinoxalinecarboxylate (130 mg, 0.26 mmol) in dioxane (25 ml) was added morpholine (35 mg, 0.40 mmol) and Pd(dpp02Clz (6.7 mg, 0.05mmol) with stirring overnight maintained with atmosphere of CO(g) at 100°C under 5Atm. The reaction mixture was concentrated under vacuum to give a e, which was applied onto a silica gel column with l % methanol in dichloromethane to afford methyl 2-(4-fluorophenyl)—3-[6—[(morpholin yl)carbonyl]—1,2,3,4—tetrahydroquinolinyl]quinoxaline—6-carboxylate as a yellow solid (107 mg, 77 %).

(ES, m/z): [M+H]+ 527.0 IH-VMR (300 MHz, DMSO): 5 8.43 (s, 1H), 8.13 (s, 2H), 7.68 - 7.73 (m, 2H), 7.04 — 7.12 (m, 3H), 6.69 (d, J: 8.4 Hz, 1H), 6.57 (d, J: 8.1 Hz, 1H ), 3.96 (s, 5H), 3.57 (s, 4H), 2.74 - 2.78 (t, J = 6.6 Hz, 2H), 2.02 — 2.06 (t, J: 5.7 Hz, 2H) Step 2. 2—(4—F1uorophenyl)—3-[6—[(morpholin—4—yl)carbonyl]-1,2,3,4—tetrahydroquinolin—1- yl]quinoxaline-6—carboxylic acid To a solution of methyl 2—(4-fluorophenyl)[6-[(morpholin-4—yl)carbonyl]—1,2,3,4- tetrahydroquinolinyl]quinoxalinecarboxylate (107 mg, 0.20 mmol) in methanol (30 ml) and water (2.0 ml) was added sodium ide (32 mg, 0.8 mmol) with stirring overnight at room temperature. The reaction mixture was concentrated under vacuum, ved in water (20 ml) and adjusted to pH 4 with hydrogen chloride (3 N). The solids were collected by filtration to PCTfU$2012/020281 Attorney Docket No. BlOEOOO9PC affordZ-(4-flu0ropheny1)—3-[6—[(morpholin—4-yl)carbonyl] - l ,2,3,4—tetrahydroquinolin-l — noxaline—6-carboxylic acid as a light yellow solid (90 mg, 86 %).

(ES, m/z): [M+H]+ 513.2 1H-’\IMR (300 MHz. DMSO): 5 8.41 (s, 1H), 8.12 (s, 2H), 7.66 - 7.71 (m, 2H), 7.02 - 7.10 (m, 3H), 6.68 (d, J: 6.6 Hz, 1H), 6.53 (d, J = 8.4 Hz, 1H), 3.93 ~ 3.97 (t, J = 6.3 Hz, 2H), 3.56 (s, 4H), 3.38 (s, 3H), 2.73 — 2.77 (m, 2H), 2.01 - 2.05 (m, 2H) EXAMPLE 16 3-[6-(Dimethylsulfam0yl)-1,2,3,4-tetrahydroquinolinyI](4-fluor0phenyl)quinoxaline carboxylic acid o=s=o Step 1. Methyl 3-[6-(chlorosulfonyl)-l,2,3,4-tetrahydr0quinolin-l-yl](4- fluoropheny1)quinoxalinecarboxylate To a solution of methyl luorophenyl)(1,2,3,4—tetrahydroquinolin-l-y1)quinoxaline carboxylate (300 mg, 0.73 mmol) in chloroform (50 mL) was added sulfuric acid (213.6 mg, 2.18 mmol) and thionyl chloride (514 mg, 4.36 mmol) dropwise with stirring at 85°C for 3 h in an oil bath. The reaction was then quenched by the addition of ice-water, ted with dichloromethane (3 X 80 mL).The organic layers combined and dried over magnesium sulfate, concentrated under vacuum to give the e, which was applied onto a silica gel column with 2 % ethyl acetate in petroleum to afford methyl 3-[6-(chlorosulfonyl)-1,2,3,4- tetrahydroquinolin-l-y1](4-flu0rophenyl)quinoxalineearboxylate as a yellow solid (260 mg, 70 %).

Attorney Docket No. 09PC (ES, m/z): [M+H]+ 512.0 1H—NMR (300 MHz,CDC13): 5 8.70 (d, J :15 Hz, 1H), 8.35 - 8.38 (m, 1H), 8.18 (d, J = 4.2 Hz, 1H), 7.77 - 7.82 (m, 2H), 7.71 (d, J = 2.1 Hz, 1H), 7.48 - 7.52 (m, 1H), 7.11 - 7.16 (m, 2H), 6.67 (d, J: 9.0 Hz, 1H), 4.04 (s, 3H), 3.76 - 3.80 (t, J: 6.0 Hz, 2H), 2.92 - 2.96 (t, J = 6.3 Hz, 2H), 2.07 - 2.12 (m, 2H) Step 2. Methyl 3-[6—(dimethylsulfa1110yl)—1,2,3,4—tetrahydroquinolinyl]-2—(4- henyl)quinoxaline-6—carboxylate o=s=o To a solution of dimethylamine hydrochloride (49.66 mg, 0.61 mmol) in dichloromethane (50 mL)was added and triethylamine (102 mg, 1.01 mmol) and stirred for 10min. Then methyl 3-[6- (chlorosulfonyl)- 1,2,3,4—tetrahydroquinoliny1]—2-(4-fluorophenyl)quinoxaline-6—carboxylate (260 mg, 0.51 mmol) in dichloromethane (20 mL) was added dropwise with stirring for 30 min at room ature. The reaction mixture was concentrated under vacuum to give the residue, which was applied onto a silica gel column with 2 % - 5 % ethyl acetate in petroleum ether to afford methyl 3—[6—(dimethylsulfamoyl)-1 ,2,3,4-tetrahydroquinolin-1—yl]-2—(4— fluorophenyl)quinoxaline—6-carboxylate as a yellow solid (240 mg, 91 %).

(ES, m/z): [M+H]+ 521.0 1H-NMR (300 MHz.CDC13):5 8.68 (d, J = 1.5 Hz, 1H), 8.28 — 8.31 (m, 1H), 8.14 (d, J: 5.7 Hz, 1H), 7.72 - 7.78 (m, 2H), 7.43 (d, J = 2.1 Hz, 1H), 7.15 — 7.19 (m, 1H), 6.96 - 7.02 (m, 2H), 6.57 (d, J: 8.4 Hz, 1H), 4.04 (s, 3H), 3.95 — 3.99 (t, J: 6.0 Hz, 2H), 2.87 - 2.91 (t, J: 6.9 Hz, 2H), 2.61 (s, 6H), 2.09 - 2.18 (m, 2H) Step 3. 3-[6—(Dimethylsulfamoyl)-1,2,3,4-tetrahydroquinolin-1~yl]-2—(4- lluorophenyl)quinoxalinecarboxylic acid 2012/020281 Attorney Docket No. BIOE0009PC o=é=o To a solution of methyl 3—[6—(dimethylsu1famoy1)—1,2,3,4—tetrahydroquinolin—l—y1]—2—(4— fluorophenyl)quinoxalinecarboxy1ate (120 mg, 0.23 mmol) in methanol (30 mL) and water (2 mL) was added sodium hydroxide (36.9 mg, 0.92 11111101) with stirring overnight at room temperature. The reaction mixture was concentrated under vacuum, dissolved in water (30 mL) and adjusted to pH 5 with hydrogen chloride (3 N). The solids were collected by filtration to afford 3— [6—(dimethylsu1famoyl)-1 ,2,3,4~tetrahydroquinoliny1j(4-fluorophenyl)quinoxaline- oxylic acid as a light yellow solid (43.5 mg, 37 %).

(ES, m/z): [M+H]+ 507.1 1H-NMR (300 MHz, DMSO): 5 8.43 (s, 1H), 8.22 - 8.25 (m, 1H), 8.04 (d, J: 8.4 Hz, 1H), 7.70 — 7.75 (111, 2H), 7.30 (d. J: 2.1 Hz, 1H), 7.08 - 7.14 (L, J: 9.0 Hz, 2H). 6.97 — 7.01 (111. 1H), 6.62 (d, J: 8.4 Hz, 1H), 3.99 - 4.03 (t, J: 6.0 Hz, 2H), 2.82 - 2.86 (t, J = 6.0 Hz, 2H), 2.51 (s, 6H), 2.04 - 2.18 (m, 2H) EXAMPLE 17 3-[6-(Dimethylamino)-1,2,3,4-tetrahydroquinolinyl](4—flu0rophenyl)quinoxaline carboxylic acid WO 94462 2012/020281 Attorney Docket No. 1310130009401 -PC To a solution of quinolinecarboxylic acid (5 g, 2887 11111101) in toluene (250 1111) was added uiethylamine (14.6 g, 144.28 mmol), DPPA (15.9 g, 57.78 mmol.) with stirring for 1 h at 0°C in water/ice bath. Then y1propan-2—ol (6.4 g, 86.34 mmol) was added with stirring overnight at 90°C in an oil bath and then diluted with water (300 m1), ted with dichloromethane (3 x 100 ml ), dried over anhydrous ium sulfate and concentrated under vacuum to give a residue, which was purified by a silica gel column with 1 % — 5 % ethyl acetate in petroleum ether to afford tert~buty1N-(quinolinyl)carbamate as a yellow solid (1.3 g, 18 %).

(ES, m/z):[M+H]Jr 245.1 IH-NMR (300 MHZ, CDC13) 8 8.80 - 8.82 (m, 1H), 8.01 ~ 8.14 (m, 2H), 7.47 - 7.51 (m, 1H), 7.30 - 7.38 (In, 1H), 6.90 — 7.10 (m, 1H), 1.56 (S, 9H) Step 2. Quinolin-6—amine \ NH2 To a solution of tert-butyl N-(quinolin—6-yl)carbamate (1.3 g, 5.32 mmol) in DCM (40 ml) was added TFA(10 ml) with stirn'ng overnight at room temperature. The resulting mixture was concentrated under vacuum, diluted with water (30 m1), adjusted pH to 8 with NaHC03 solution, extracted with dichloromethane (2 x 20 ml), dried over magnesium sulfate and concentrated in. vacuo to give quinolin»6-a1m’ne as a yellow solid (666 mg, 87 %).

LC/MS (ES, m/z):[M+H]+ 145.1 1H—NMR (300 MHz, CDC13) 5 8.67 - 8.69(m, 1H), 7.91 - 7.95(m, 2H), 7.28 - 7.31(m, 1H), 7.16 - 7.20(m, 1H), 6.92 (s, 1H), 3.96 (s, 2H) Step 3. MN—Dimcthquuinolin—6-aminc To a solution of quinolin-6—aminc (666 mg, 4.62 mmol) in CH30H(15 ml) was added 40% aqueous formaldehyde (1 m1), NaBHgCN (400 mg, 6.37 mmol) with stirring for 3 days at room ature and diluted with water (150 m1), extracted with ethyl acetate(3 x 30 ml), dried over magnesium sulfate and concentrated in vacuo to give a residue, which was purified by a silica gel column chromatography with 5 % — 20 % ethyl acetate in petroleum ether to give N,N— quuinolinamine as a soiid (400 mg, 50 %).

LC/MS (ES, m/z):[M+H]+ 173.1 1H-NMR (300 MHz, CDClg) 8 8.59 - 8.61 (m, 1H), 7.94 — 8.00 (hi, 2H), 7.37 - 7.41 (m, 1H), 7.27 - 7.32 (m, 1H), 6.81 (d, J = 2.7 Hz, 1H), 3.07 (s, 6H) PCT/U52012/020281 Attorney Docket No. 1310130009401 ~PC Step 4. N,N—Dimethyl- l ,2,3,4—tetrahydroquinolin—6-amine hydrochloride \ N\ HHCI To a solution of N,N—dimethquuinolin-6—amine (400 mg, 2.32 mmol) in methanol (20 ml), was added NO; (10 mg) and HCl (cone, 1 drop) under hydrogen and the reaction was stirred overnight at room temperature. The reaction was filtered and concentrated in vacuo to give N,N— dimethyl-1,2,3,4—tetrahydroquinolin~6-amine hydrochloride as a red oil (400 mg, crude).

LC/MS (ES, m/z):[M+H]+ 177.1 Step 5. Methyl dimethylamino)- 4-tetrahydroquinolin—l-yl]oxo—l,2- dihydroquinoxaline-6—carboxylate To a solution of methyl 3-chlorooxo—1,2-dihydroquinoxalinecarboxylate (420 mg, 1.76 mmol,) in NMP (3 mL) was added DIEA (343 mg, 2.65 mmol), MN-dimethyl-l,2,3,4- tetrahydroquinolinamine hydrochloride (400 mg, crude) and the reaction was stirred for 2 h at 130°C in an oil bath. The resulting on was diluted with water (100 mL), and the solids were collected by filtration to give methyl 3-[6—(dimethylamino)~1,2,3,4—tetrahydroquinolin—l-y1] oxo~1,2-dihydroquinoxalinc~6-carboxylatc as a red solid (260 mg, 39 %).

LC/MS(ES, m/z):[M+H]‘r 378.1 1H~NMR (300 MHz, CDC13) 5 10.29 (8,1H), 8.28 (d, J: 1.5 Hz, 1H), 7.84 - 7.91 (m, 1H), 7.02 - 7.07 (m, 1H), 6.85 (d, J 28.7 HZ, 1H), 6.62 (s, 2H), 4.06 - 4.16 (m, 2H), 3.95 (S, 3H), 2.98 , 2.81 - 2.91 (m, 2H), 2.38 - 2.41 (m, 2H) Step 6. Methyl 3-[6—(dimethylamino)-l ,2,3,4-tetrahydroquinolinle-2— [(trifluoromethane)sulfonyloxy] quinoxaline-6—carboxylate PCT/USZOlZ/OZOZSI Attorney Docket No. 1310130009401 -PC TfO/\\N To a solution of methyl 3-[6-(dimethylamino)-1,2,3,4~tetrahydroquinolin—1—yl]—2-0xo-1,2- dihydroquinoxaline—6-carboxylate (260 mg, 0.69 mmol) in dichloromethane (50 ml) was added pyridine (270 mg, 3.41 mmol) and (trifluoromethane)sulfonyl trifluoromethanesulfonate (390 mg, 1.38 01) and the reaction was stirred for 2 h at room temperature and then washed with water (100 ml), dried over anhydrous magnesium sulfate and concentrated in vacuo to give methyl 3-[6-(dimethylamino)-1,2,3,4-tetrahydroquinolin~1-yl]—2- uoromethane)sulfonyloxyjquinoxalinecarboxylate as a red solid (400 mg, crude).

Step 7. Methyl 3-[6-(dimethylamino)-l ,2,3,4~tetrahydroquinolinyl]—2—(4— fluorophenyl)quinoxaline-6—carboxylate To a solution of methyl 3-[6—(dimethylamino)-1,2,3,4-tetrahydroquinolin—1-le [(trifluoromethane)sulfonyloxy]quinoxalinecarboxylate (400 mg, 0.78 mmol) in oxane (3 ml) was added K3PO4 (331 mg, 1.56 mmol), 3)4 (45 mg, 0.04 mmol), and (4— fluorophenyl)boronic acid (214 mg, 1.53 mmol) and the reaction was stirred for 2 h at 90°C in a oil bath. The resulting solution was concentrated in vacuo to give a residue, which was purified by silica gel column chromatography with 1 % - 20 % ethyl acetate in petroleum ether to afford methyl 3-[6-(dimethylamino)- l ,2,3,4—tetrahydroquinolin—1~yl](4—fluorophenyl)quinoxaline—6- carboxylate as a red solid (30 mg, 8 %).

LC/MS (ES, I??/Z,)I[M+H]+ 456.1 1I-I—NMR (300 MHz, CDC13)I 5 8.56 (s, 1H), 8.13 — 8.20 (m, 1H), 8.02 — 8.05 (m, 1H), 7.73 - 7.85 (m, 2H), 6.91 - 6.99 (m, 3H), 6.75 - 6.85 (m, 1H), 6.30 - 6.40 (m, 2H), 4.01 - 4.03 (s, 3H), 3.75 - 3.80 (m, 2H). 2.86 (s, 6H), 2.75 - 2.79 (m, 2H), 2.02 - 2.06 (m, 2H) PCT/U82012/02028 1 Attorney Docket No. BlOEOOO9-401 -PC Step 8. 3—[6-(Dimethy1amino)—1,2,3,4—tetrahydr0quinolin—1-yl]-2—(4-fluor0phenyl)quinoxaline- oxylic acid To a solution of methyl 3—[6-(dimethylamino)-l,2,3,4-tetrahydroquinolin~1—yl]—2—(4— hcnyl)quinoxalinc-6—carboxylatc (30 mg, 0.07 mmol) in methanol (20 ml) and water (2 ml) was added sodium hydroxide (10 mg, 0.25 mmol) and the on was stirred overnight at room temperature. The resulting solution was diluted with water (100 ml), adjusted pH to 5 with AcOH, extracted with ethyl acetate (3 x 20 ml), dried over anhydrous magnesium sulfate and concentrated in vacuo to give 3—[6-(dimethylamin0)—1,2,3,4—tetrahydr0quinolin-l—yl](4- fluorophenyl)quinoxaline—6-carboxylic acid as a red solid (3 mg, 10 %).

LCMS (ES, m/z):[M+H]+ 443.1 1H-NMR (300 MHZ, CD3OD): 5 8.48 (s, 1H), 8.11 - 8.15 (m, 1H), 7.96 (d, J = 8.4 Hz, 1H), 7.67 — 7.71 (m, 2H), 6.91 — 6.97 (t, J: 9.0 Hz, 2H), 6.20 - 6.60 (m, 3H), 3.85 - 4.05 (m, 2H), 2.60 — 2.90 (m, 8H), 2.07 — 2.11 (t, J: 6.6 Hz, 2H) EXAMPLE 18 3-(6-Chloro-1,2,3,4-tetrahydroquinolinyl)—2-(4-fluorophenyl)quinoxalinecarboxylic acid N NKW PCT/U52012/020281 Attorney Docket No. BlOEOOO9PC Step 1. ro-1,2,3,4-tetrahydroquinoline To a solution of 6-chloroquinoline (1.5 g, 9.17 mmol) in CZHSOH (50 ml) was added PtOg (41.5 mg, 0.18 mmol) and concentrated HCl (0.1 ml) under an atmosphere of hydrogen gas. The reaction was stirred overnight at room temperature, then concentrated in. vacuo, d with water (100 ml), adjusted to pH 8 with s sodium bicarbonate. The resulting solution was extracted with dichloromcthanc (3 X 80 ml) and the organic layers were combined, dried over anhydrous magnesium e, concentrated in vacuo to afford 6-01110rO-1,2,3,4- tetrahydroquinoline as a colorless oil (1.2 g, 78 %).

LC/MS (ES, m/z): [M+H]+ 168.0 lH—\IMR (300 MHZ, CDC13) 5 6.90 ~ 6.98 (In, 2H), 6.39 - 6.42 (t, J: 1.2 Hz, 1H), 3.23 - 3.35 (m, 2H), 2.73 - 2.81 (m, 2H), 1.91 - 1.96 (m, 2H) Step 2. Methyl 3-(6-chloro-1,2,3,4-tetrahydroquinoliny1)oxo-1,2-dihydroquinoxaline carboxylate N N0A0, To a solution of methyl 3-chlorooxo-1,2-dihydroquinoxalineearboxylate ( 1.0 g, 4.19 mmol) in NMP (10.0 ml) was added 6-chloro-1,2,3,4—tetrahydroquinoline (1.20 g, 7.16 mmol) and the reaction was stirred for 1 h at 150°C in an oil bath. The reaction mixture was cooled down to room temperature, itated with water (100 ml). The solids were collected by filtration and dried in an oven under reduced pressure to afford methyl 3-(6-chloro—1,2,3,4—tetrahydroquinolin- l-yl)-2—oxo-l,2-dihydroquinoxaline~6—carboxylate as a gray solid (1.0 g, crude).

LC/MS (ES, m/z): [M+H]+ 370.0 2012/02028l Attorney Docket No. BIOE0009PC Step 3. Methyl 3-(6-chloro-1,2,3,4-tetrahydroquinolin—1—yl)-2— [(tril‘luoromethane)sulfonyloxquuinoxalinecarhoxylate To a solution of methyl 3—(6-chloro—l ,2,3,4-tetrahydroquinolin—1-yl)-2—oxo-1,2- dihydroquinoxaline—6—carboxylate (1.0 g, crude) in dichloromethane (80 1111) was added pyridine (850 mg, 10.75 mmol) and ngO (1.50 g, 5.32 mmol) with stirring overnight under an atmosphere of nitrogen at room ature. Then reaction mixture was quenched with water (100 ml), extracted with dichloromethane (3 x 20 ml), and the organic layers were combined and dried over anhydrous magnesium sulfate, The organics were trated in vacuo to afford methyl 3-(6- chloro— 1 ,2,3,4—tetrahydroquinolin— 1 —y1)-2~ [(trifluoromethane)sulfonyloxy]quinoxaline carboxylate as a yellow solid (1.0 g, crude), which was used to the next step directly.

Step 4. Methyl 3—(6-chloro-1,2,3,4-tetrahydroquinolin—l-yl)(4-fluorophenyl)quinoxaline-6— carboxylate To a solution of methyl 3—(6-chloro—l ,2,3,4-tetrahydroquinolin—l -yl)-2— [(trifluoromethane)sulfonyloxy] quinoxalinecarboxylate (400 mg, crude) in DME (5.0 ml) and water (1 ml) was added (4—fluorophenyl)boronic acid (134 mg, 0.96 mmol), Pd(PPh3)4 (45.5 mg, 0.04 mmol), N82CO3 (251 mg, -.37 mmol) with ng for 1h at 95°C under an atmosphere of nitrogen. The reaction mixture was concentrated in. vacuo to give a residue, which was purified by a silica gel column chromatography with 1 % ethyl acetate in petroleum ether to afford methyl hloro~1,2,3,4—tetrahydroquinolinyl)(4-f1uorophenyl)quinoxalinecarboxylate as a light yellow solid (125 mg).

LC/MS(ES, m/z): [M+HJ+ 448.0 2012/020281 Attorney Docket No. BlOEOOO9—401—PC 1H—NMR (300 MHZ, DMSO) 5 8.39 (s, 1H), 8.12 (d, J: 1.2 Hz, 2H), 7.75 - 7.80 (m, 2H), 7.07 - 7.18 (In, 3H), 6.65 — 6.77 (m, 2H), 3.95 (s, 3H), 3.79 - 3.92 (m, 2H), 2.72 - 2.77 (t, J: 6.6 Hz, 2H), 1.94 - 2.02 (m, 2H) Step 5. 3-(6—Chloro-l,2,3,4-tetrahydroquinolinyl)(4—fluorophenyl)quinoxaline carboxylic acid To a solution of methyl hloro-l ,2,3,4-tetrahydroquinolin—1~y1)-2—(4— fluorophenyl)quinoxalinecarboxylate (125 mg, 0.28 mmol) in methanol (30 ml) and water (1.0 ml) was added sodium hydroxide (44.6 mg, 1.11 mmol). The reaction was stirred ght at room temperature. Then the reaction mixture was concentrated in vacuo, dissolved in water (30 ml), adjusted to pH 5 with aqueous hydrochloric acid (3 N) to give a precipitate, which was collected by filtration to afford 3-(6-chloro-1,2,3,4—tetrahydroquinolin-l-yl)-2—(4- fluorophenyl)quinoxalinecarboxylic acid as a light yellow solid (90 mg, 74 %).

LC/MS (ES, Iii/z): [M+H]+ 434.0 1H—NMR (300 MHZ, DMSO) 5 8.37 (s, 1H), 8.05 - 8.16 (m, 2H), 7.75 - 7.79 (m, 2H), 7.07 - 7.19 (m, 3H), 6.62 - 6.70 (m, 1H), 6.73 — 6.77 (m, 1H), 3.77 ~ 3.81 (t, J = 6.0 Hz, 2H), 2.72 - 2.77 (t, J = 6.3 Hz, 211), 1.95 — 2.01 (In, 211) EXAMPLE 19 3-(7-Fluor0-1,2,3,4—tetrahydroquinolinyl)(4-fluor0phenyl)quinoxaline-G-carboxylic acid PCT/U52012/020281 Attorney Docket No. BlOEOOO9—401—PC Step 1. 5-Fluoroquinoline To a suspension of 5-aminoquinoline (10.0g, 0.069 mol) in 48% HBF4 (40 mL) at 0°C was added portionwise sodium nitrite. This was stirred for 1 hour and then poured into 1:1 ethyl acetatefdiethyl ether (50 mL). The resulting suspension was d and the solid dried. This solid was added portionwise to refluxing xylene (80 mL) and stirred for 2 hours then allowed to cool. The xylene was decanted off and the residue was dissolved in IN aqueous hydrochloric acid (100 mL). After neutralization with sodium carbonate, the mixture was extracted with ethyl acetate (3 x 80 mL). The extracts were dried over sodium e, filtered and the volatiles were d in vacuo. The residue was purified by silica gel column chromatography, eluting with 2% ethyl acetate in petroleum ether to afford 5-fluoroquinoline as a ess oil (2.5 g, 24.5%). 1H—NMR (300 MHz, CDCI3) 5 8.93 - 8.98 (m, 1H), 8.43 ~ 8.46 (m, H), 7.92 (d, J = 8.4 Hz, 1H), 7.62 — 7.78 (m, 1H), 7.41 — 7.49 (m, 1H), 7.22 — 7.26 (m, 1H) Step 2. 5-F1uoro-1,2,3,4-tetrahydroquinoline Palladium on carbon (10%, 1.25 g) was added to a so1ution of 5-fluoroquinoline (2.5 g, 16.99 mmol) in methanol and the reaction was overnight at room temperature under an atmosphere of en. The reaction mixture was filtered through Celite and concentrated in vacuo to afford S—fluoro-l ,2,3,4-tetrahydroquinoline as a colorless oil (1.80 g, 70 %).

LC/MS (ES, m/z): LM+HJ+ 152.0 1IrI-NMR (300 MHz, CDC13) 8 6.87 - 6.95 (m, 2H), 6.26 — 6.40 (m, 2H), 3.28 - 3.31 (m, 2H), 2.72 - 2.77 (t, J = 6.60 Hz, 2H), 1.92 - 1.98 (m, 2H) Step 3. Methyl 3—(5-fluoro—1,2,3,4-tetrahydroquinoliny1)ox0-1,2-dihydroquinoxa1ine carboxylate NINQAO/ O N To a solution of methyl 3—chloro—2—oxo—1,2-dihydroquinoxa1ine-6—carboxylate (1.0 g, 4.19 mmol) in NMP (10.0 mL) was added 5-fluoro—1,2,3,4—tetrahydroquinoline (1.5 g, 9.92 mmol) with PCT/U82012/020281 Attorney Docket No. 810130009401 ~PC stirring for 1 h at 150°C in an oil bath. The reaction mixture was cooled to room temperature, precipitated with water (100 mL). The solids were ted by filtration and dried in an oven under reduced pressure to afford methyl 3-(5-fluoro—l,2,3,4-tetrahydroquinolin- 1-y1)—2-oxo-1,2- dihydroquinoxalinecarboxylate as a gray solid (1.0 g, crude).

LC/MS (ES, m/z): [M+H]+ 354.0 Step 4. Methyl 3-(5—fluoro— l,2,3,4—tetrahydroquinolinyl)-2— [(trifluoromethane)sulfonyloxy]quinoxalinecarboxy1ate To a solution of methyl luoro-1,2,3,4~tetrahydroquinoliny1)~2-oxo—1,2- dihydroquinoxaline—6—carboxylate (1.0 g, crude) in dichloromethane (80 mL) was added ne (890 mg, 11.25 mmol) and H79 (1.58 g, 5.60 mmol) and the reaction was stirred ght under an atmosphere of nitrogen at room temperature. The reaction mixture was then quenched with water (50 mL), extracted with dichloromethane (3 x 80 mL). Then the organic layers were combined and dried over ous magnesium sulfate, concentrated in vacuo to afford methyl 3 -(5-t1uoro-1,2,3,4—tetrahydroquinolin—1 -yl) [(tritluoromethane)sulfonyloxy]quinoxaline carboxylate as a yellow solid (1.0 g), which was used directly in the next step.

Step 5. Methyl 3-(5-fluoro—1,2,3,4-tetrahydroquinolin-1—yl)-2—(4—fluorophenyl)quinoxaline-6— carboxylate To a solution of methyl 3-(5~fluoro-1,2,3,4-tetrahydroquinolin—1-yl) [(trifluoromethane)sulfonyloxy]quinoxaline—é-carboxylate (200 mg, 0.41 mmol) in dioxane (5.0 mL) and water (3 drops) was added (4-fluorophenyl)boronic acid (173 mg, 1.24 mmol), Pd(PPh3)4 (23.77 mg, 0.02 mmol), and K3PO4 (262 mg, 1.23 mmol). The reaction was stirred for 1h at 95°C under an atmosphere of nitrogen. The reaction mixture was concentrated in vacuo to give a residue, which was ed by a silica gel column chromatography with l % ethyl acetate in petroleum ether to afford methyl 3-(5-fluoro-1,2,3,4-tetrahydroquinolin-1—yl)—2—(4- fluorophenyl)quinoxalinecarboxylate as a light yellow solid (140 mg, 78 %).

LC/MS (ES, m/z): [M+H]+ 432.0 2012/020281 Attorney Docket No. 1310130009401 ~PC 1H—NMR (300 MHz. CDC13) 5 8.63 (d, J: 1.8 Hz. 1H), 8.22 — 8.26 (m, 1H), 8.09 ((1.1 = 2.7 Hz, 1H), 7.82 - 7.88 (m, 2H), 7.01 - 7.09 (m, 2H), 6.76 ~ 6.84 (m, 1H), 6.45 - 6.58 (m, 2H), 4.01 (s, 3H), 3.71 - 3.77 (m, 2H), 2.81 - 2.85 (t, J = 6.9 Hz, 2H), 2.02 - 2.10 (m, 2H) Step 6. lu0ro—1,2,3,4-tetrahydroquinolin-1—y1)(4—fluorophenyl)quinoxalinecarboxylic acid Sodium hydroxide (52.0 mg, 1.30 mmol) was added to a solution of methyl 3-(7-fluoro~1,2,3,4- tetrahydroquinolin-l-yl)—2-(4—fluorophenyl)quinoxaline~6—carboxylate (140 mg, 0.32 mmol) in methanol (30 mL) and water (1.0 mL). The reaction was stirred overnight at room temperature and then concentrated in vacuo, dissolved in water (30 mL), and ed to pH 5 with aqueous hydrochloric acid (3 N) to give a precipitate, which was collected by filtration to afford 3—(7— fluoro-l ,2,3,4-tetrahydroquinolin- l-y1)~2-(4-fluorophenyl)quinoxaline-6—carboxylic acid as a light yellow solid (100 mg, 74%).

LC/MS(ES, m/z): [M+H]+ 418.1 1I-I-NMR (300 MHz, DMSO) 8 8.54 (s, 1H), 8.09 - 8.38 (m, 2H), 7.81 - 7.90 (m, 2H), 7.16 - 7.22 (m, 2H), 6.73 - 6.80 (m, 1H), 6.46 - 6.59 (m, 2H), 3.73 - 3.76 (t, J: 6.0 Hz, 2H), 2.71 — 2.75 (t, J = 6.6 Hz, 2H), 1.97 - 2.06 (m, 2H) EXAMPLE 20 3-(6-Flu0ro-i1,2,3,4-tetrahydr0quinolinyl)-2~(2-methyl-1H-indolyl)quinoxaline carboxylic acid 2012/020281 Attorney Docket No. BlOE0009PC Step 1. Methyl 2—bromo—3 ~(6-fluoro-1,2,3,4-tetrahydroquinolinyl)quinoxalinecarb0xylate N /N: : /U\O/ BrIN I To a solution of methyl 3—(6—fluor0-l,2,3,4—tetrahydroquinolin- 1-yl) [(trifluoromethane)sulfonyloxy]quinoxalinecarboxylate (1.0, 2.06 mmol) in toluene (30 ml.) was added BU4NB1' (1.33 g, 4.12 mmol). The on was stirred for 5 h at 120°C under an inert atmosphere of nitrogen. The reaction mixture was concentrated in vacuo to give a residue, which was purified by a silica gel column with l % ethyl acetate in petroleum ether to afford methyl 2- bromo-3—(6-fluoro—l ,2,3,4—tetrahydroquinolin-1—yl)quinoxalinecarboxylate as a yellow solid (540 mg, 63%).

LC/MS(ES, m/z): [M+Hl+ 417.0 1H—NMR (300 MHz, CDC13)Z 5 8.60 (d, J = 1.5 Hz, 1H), 8.20 - 8.23 (m, 1H), 7.99 (d, J: 8.7 Hz, 1H), 6.93-6.98 (m, 1H), 6.78 - 6.85 (m, 1H), 6.57 (d, J: 4.8 HZ, 1H), 4.02(s, 3H), 3.92 - 3.96 (m, 2H), 2.87 - 2.92 (m, 2H), 2.13 - 2.17 (m, 2H) Step 2. Methyl 3—(6—fluor0—l ,2,3,4—tetrahydroquinolin- l—y])(2-methyl—lH—indol-S- yl)quinoxalinccarboxy1atc To a on of methyl 2-bromo-3—(6~f1uoro—l,2,3,4-tetrahydroquinolinyl)quinoxaline~6- carboxylate (200 mg, 0.48 mmol) in ethylene glycol yl ether (7 ml) was added 2-methyl-5— (4,4,5,5-tetramethyl—1,3,2-dioxaborolanyl)—lH—indole (124 mg, 0.48 mmol), sodium carbonate (101.8 mg, 09611111101) and Pd(PPh3)4 (28 mg, 0.02 mmol) and water (3 ml). The reaction was stirred for 40 min at 90°C. Then it was extracted with ethyl e (3 x 50 ml) and the organic layers were combined, dried over anhydrous magnesium sulfate and concentrated in vacuo to provide a residue, which was purified by a silica gel column chromatography with 2 % ethyl WO 94462 PCT/USZOIZ/020281 Attorney Docket No. BlOEOOO9—40l ~PC acetate in petroleum ether to afford methyl uoro-1,2,3,4-tetrahydroquinolin-l —yl)—2—(2— methyl-1H—indol-S—yl)quinoxalinecarboxylate as a light red solid (118 mg, 53 %).

LC/MS (ES, m/z): [M+H]+ 467.0 1H-NMR (300 MHz, CDC13): 5 8.62 (d, J = 1.5 Hz, 1H), 8.20 - 8.26 (m, 2H), 7.99 - 8.02 (m, 2H), 7.60 (d, J: 9.0 Hz, 1H), 7.22 (d, J = 6.6 Hz, 1H), 6.79 ~ 6.83 (m, 1H), 6.72 - 6.75 (m, 1H), 6.57 - 6.71 (m, 1H), 6.23 (s, 1H), 4.01(s, 3H), 3.68 — 3.72011, 2H), 2.72 - 2.83 (m, 2H), 2.46 (s, 3H), 1.98 - 2.02 (m, 2H) Step 3. 3—(6—Fluoro—1,2,3,4-tetrahydroquinolin—1—yl)-2—(2—methyl-1H—indol-S—yl)quinoxaline carboxylic acid N /ND)LOH / N To a solution of methyl 3-(6—fluoro—1,2,3,4—tetrahydroquinolin-l-yl)(2-methy1—lH-indol—S- yl)quinoxalinecarboxylate (118 mg, 0.25 mmol) in methanol (20 ml) and water (1.0 ml) was added sodium ide (40 mg, 1.00 mmol). The reaction was stirred overnight at room temperature. The reaction mixture was concentrated in vacuo, dissolved in water (20 mL) and adjusted to pH 4 with hydrogen chloride (3 N). The solids were collected by filtration to afford 3— (6-fluoro—1,2,3,4-tetrahydroquinolin-1~y1)(2—methyl-1H—indol~5-yl)quinoxaline—6—Carboxylic acid as alight yellow solid (81 mg, 71%).

LC/MS (ES, m/z): [M+H]+ 453.1 1HNMR (300 MHz, DMSO): 3 10.99 (s, 1H), 8.24 (s, 1H), 8.09 - 8.12 (m, 1H), 7.91 - 7.95 (m, 2H), 7.51 (d, J=1.5 Hz, 1H), 7.48 (d, J: 1.5 Hz, 1H), 6.81 - 6.85 (m, 1H), 6.71 — 6.75 (m, 1H), 6.56 — 6.62 (m, 1H), 6.15 (s, 1H), 3.61 - 3.68011, 2H), 2.74 - 2.81 (m, 2H), 2.49 (s, 3H), 1.92 - 1.95 (m,2H) PCT/USZOIZ/OZOZSI Attorney Docket No. O9~40l -PC EXAMPLE 2] 3-(6-Fluor0-1,2,3,4-tetrahydroquinolinyl)(1H-indazolyl)quinoxalinecarboxylic acid N N / IQJMH N‘/ N Step 1. Methyl 3-(6—fluoro-3,4-dihydroquinolin-l(2H)—yl)—2- (trifluoromethylsulfonyloxy)quinoxaline~6~carboxylate TfO N To a solution of methyl 3-(6-fluoro-3,4—dihydroquinolin-1 (2H)-yl)oxo—1,2— dihydroquinoxalinecarboxylate (150 mg, 0.43 mmol) in dichloromethane (30 mL) was added pyridine (136 mg, 1.72 mmol) and then "1330 (243 mg, 0.86 mmol) was added dropwise with stirring at 0°C. The resulting solution was stirred for 4 h at room temperature and then washed with water (3 x 50 mL), dried over anhydrous sodium sulfate and concentrated in. vacuo to afford methyl 3-(6-fluoro-3 ydroquinolin- l (2H)~yl)(trifluoromethylsulfonyloxy)quinoxaline carboxylate as red oil (200 mg, .

Step 2. Methyl 3—(6-fluoro- l 2,3,4-tetrahydroquinolin- l-yl)-2—( lH—indazol-S—y1)quinoxaline-6— carboxylate N /N 0/ PCT/U52012/020281 Attorney Docket No. BlOEOOO9—401—PC To a solution of methyl 3-(6—fluoro—1,2,3,4—tetrahydroquinolin-l-yl)—2— [(trifluoromethane)sulfonyloxy]quinoxalinecarboxylate (200 mg, crude) in ethylene glycol dimethyl ether (5 mL) was added tert—hutyl 5-(tetran1ethyl—1,3,2-dioxaborolanyl)-1H- indazole-l-carboxylate (282 mg, 0.82 mmol), 3)4 (24 mg, 0.02 mmol), sodium carbonate (109 mg, 1.03 mmol) and water (2 mL). The resulting solution was stirred for l h at 90°C and then quenched by the addition of CH2C12 (20 mL), washed with water (3 x 50 mL), dried over anhydrous sodium sulfate and concentrated in. vacuo to give a residue, which was ed by silica gel column chromatography with 5 % ethyl acetate in petroleum ether to afford methyl 3— (6-fluor0—1,2,3,4—tetrahydroquinolin—1-yl)(1H~indazol~5~yl)quinoxalinecarb0xylate as a yellow solid (60 mg).

LC/MS (ES, m/z):[M+H]Jr 454.0 1H-NMR (300 MHz, CDCl3): 8 8.61 (d, J = 1.8 Hz, 1H), 8.19 — 8.26 (m, 2H), 8.08 - 8.18 (m,2H), 7.87 - 7.95 (m, 1H), 7.43 - 7.49 (m, 1H), 6.66 ~ 6.71 (m, 2H), 6.47 ~ 6.53 (m, 1H), 4.02 (s, 3H), 3.76 - 3.80 (t, J: 6.0 Hz, 2H), 278 ~ 2.82 (t, J = 6.3 Hz, 2H), 2.01 — 2.09 (m, 2H) Step 3. 3—(6—fluoro- l ,2,3,4-tetrahydroquinolin-l -(lH—indazol—S-yl)quinoxaline—6-carboxylic acid N N / OH To a solution of methyl 3—(6-fluor0—1,2,3,4—tetrahydroquinolin~l-yl)—2-(1H-indazol—5~ yl)quin0xaline—6~carboxylate (60 mg, 0.13 mmol) in methanol (20 mL) was added sodium ide (15.8 mg, 0.40 mmol) and water (1 mL). The resulting solution was stirred for 3 h at room temperature and concentrated in vacuo. The e was dissolved in water (20 mL) and adjusted to pH 5 with hydrochloric acid (3 N). The solids were collected by filtration to afford 3- (6-fluoro—l,2.3,4-tetrahydroquinolin—1-y1)-2—(lH-indazol-5—yl)quinoxalinecarboxylic acid as a yellow solid (27 mg, 47 %).

LC/MS (ES, m/z): [M+H]+ 440.1 2012/020281 Attorney Docket No. 1310130009401 ~PC. lH—\IMR (300 MHz,DMSO)513.11(s, 1H), 8.33 (s, 1H), 8.20 (s, 1H), 8.05 - 8.10 , 7.74 - 7.77 (m, 1H), 7.46 (d. J: 8.7 Hz, 1H), 6.72 — 6.81 (m, 2H), 6.49 - 6.56 (m, 1H), 3.71 - 3.75 (t, J = 6.0 Hz, 2H), 2.74 - 2.78 (t, J: 6.3 Hz, 2H), 1.93 - 1.97 (t, J: 6.3 Hz, 21-1) 2-(4-Flu0r0phenyl)(7-methoxy-1,2,3,4-tetrahydroquinolin-l-yl)quinoxalinecarboxylic acid Step 1. 7-Methoxyquinoline To a solution of sodium hydride (5.5 g, 137.50 mmol, 60%) in N,N—dimethylformamide (150 ml) was added quinolinol (8 g, 55.11 mmol). The reaction was d for l h at 0°C in a water/ice bath. 'l‘hen CH31 (7.84 g, 55.23 mmol) was added and the solution was stirred for an additional 1 h at room temperature. The reaction was then quenched by the addition of water/ice (700 m1) and extracted with ethyl acetate (3 x 200 ml). The organic layers were combined. dried over anhydrous sodium sulfate, and concentrated in vacuo to give a residue, which was purified by a silica gel column with 6 % ethyl acetate in petroleum ether to afford 7—methoxyquinoline as a red oil (5.5 g, 63%).

LC/MS (ES, m/z): [M+H]+ 160.0 1H—NMR (300 MHz, CDC13): 5 8.84 - 8.86 (m, 1H), 8.07 - 8.11 (m, 11-1), 7.70 - 7.73 (t, J = 5.1 Hz, 1H), 7.44 (d, J: 2.4 Hz, 1H), 720 ~ 7.30 (m, 2H), 3.95 (s, 3H) Attorney Docket No. 0009401 -PC Step 2. 7-Methoxy-1,2,3,4-tetrahydroquinoline :N: : \o/ To a solution of 7—methoxyquinoline (2.0 g, 12.56 mmol) in methanol (60 ml) was added PtOz (180 mg, 0.79 mmol). H2 (g) was introduced into above solution and the reaction was stirred overnight at room temperature and then the solids were filtered off. The organics were concentrated in. vacuo to give a residue, which was purified by silica gel column chromatography with 3 % ethyl acetate in petroleum ether to afford oxy—1,2,3,4-tetrahydroquinoline as a light yellow oil (1.5 g, 73%).

LC/MS (ES, m/z): [M+H]+ 164.0 lH—’\IMR (300 MHZ, CD3OD): 5 6.76 (d, J: 8.4 HZ, 1H), 6.09 ~ 6.17 (m, 2H), 3.69 (s, 1H), 3.19 - 3.23 (m, 2H), 2.64 - 2.69 (t, J: 6.6 Hz, 2H), 1.85 - 1.93 (m, 2H) Step 3. Methyl 3-(7-methoxy-1,2,3,4—tetrahydroquinolinyl)—2—oxo-l,2—dihydroquinoxaline ylate NIN: : /U\O/ O N To a solution of 7-methoxy—1,2,3,4—tetrahydroquinoline (1.34 g, 8.21 mmol) in NMP (5 ml) was added methyl 3-chloro—2-oxo~1,2-dihydroquinoxaline—6—carboxylate (1.1 g, 4.61 mmol). The resulting solution was stirred for l h at 150°C in an oil bath and then diluted with water (300 ml).

The solids were collected by filtration to afford methyl 3—(7-methoxy—l ,2,3,4—tetrahydroquinolin- 2-oxo—1,2-dihydroquinoxaline—6-carboxylate as a red solid (844 mg, 28%).

LC/MS (ES, m/z): [M+H]Jr 366.1 1H—NMR (300 MHZ, CD30D): 5 8.21 (d, J: 1.8 HZ, 1H), 7.93 - 7.96 (m, 1H), 7.28 (d, J: 8.4 Hz, 1H), 7.05 (d, J: 8.4 Hz. 1H), 6.60 — 6.63 (m, 1H), 6.43 (d, J: 2.4 Hz, 1H), 3.92 — 4.02 (m, 1H), 3.88 (s, 3H), 3.69 (s, 3H), 2.76 — 2.81 (t, J = 6.6 Hz, 2H), 1.99 - 2.09 (m, 2H) Step 4. Methyl 3-(7-meth0xy-1,2,3,4—tetrahydroquinolinyl)—2- [(trifluoromethane)sulfonyloxy]quinoxalinecarboxylate PCT/U52012/020281 ey Docket No. BIOE0009-401—PC TfO N To a solution of methyl 3-(7-methoxy—l,2,3,4—tetrahydroquinolin—1—yl)—2noxo-1,2- dihydroquinoxalineca1b0xylate (690 mg, 1.89 11111101) in dichloromethane (80 ml) was added DIEA (1.5 g, 11.61 mmol). Then ngO (1.4 g, 4.96 mmol) was added dropwise. The resulting solution was stirred ght at room temperature and then ed by the addition of ice (100 ml), extracted with dichloromethane (3 X 20 ml). Then the organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated in. vacuo to give a residue, which was purified by a silica gel column chromatography with 2 % ethyl acetate in petroleum ether to afford methyl 3-(7-methoxy-12,3,4-tetrahydroquinoliml—y1)-2— uoromethane)su1fonyloxy]quinoxaline~6~carboxylate as a red oil (870 mg, 93%).

Step 5. Methyl 2-(4-fluoropheny1)(7—methoxy-1,2,3,4—tetrahydroquinoliny1)quinoxaline carboxylate To a solution of methyl 3-(7-methoxy-1,2,3,4—tetrahydroquinolin—1-y1)-2— [(trifluoromethane)sulfonyloxy] quinoxaline ~6-carboxy1ate (400 mg, 0.80 mmol) in 1,4—dioxane (3 ml) was added K3P04 (338 mg, 159 mmol), Pd(PPh3)4 (47 mg, 0.04 mmol), and (4- fluorophenyl)boronic acid (224 mg, 1.60 mmol). The resulting solution was stirred for 1 h at 90°C in an oil bath and then quenched by the addition of water (80 ml), extracted with dichloromethane (3 x 30 ml), the organic layers were combined and dried over anhydrous ium sulfate and concentrated in vacuo to give a residue, which was purified by a silica gel column chromatography with 5 % ethyl acetate in petroleum ether to afford methyl 2-(4- fluorophenyl)-3—(7—methoxy-1 ,2,3,4-tetrahydroquinoliny1)quinoxaline-6—carboxy1ate as a yellow solid (100 mg, 28%).

PCT/U52012/020281 Attorney Docket No. BlOEOOO9PC LC/MS(ES, 111/2): [M+Hl+ 444.0 1H-NMR (300 MHz, CD30D): 5 8.64 (d, J = 1.8 Hz, 1H), 8.19 - 8.23 (m, 1H), 8.08 (d, J = 2.1 Hz, 1H), 7.72 - 7.80 (m, 2H), 6.92 - 7.02 (m, 31-1), 6.35 - 6.39 (m, 1H), 6.13 (d, J = 2.4 Hz, 1H), 4.02 (s, 3H), 3.77 - 3.90 (m, 2H), 3.59 (s, 3H), 2.74 - 2.78 (t, J: 6.6 Hz, 2H), 2.02 - 2.11 (n1, 2H) Step 6. 2—(4—Fluorophenyl)—3—(7-methoxy—1,2,3,4—tetrahydroquinoliny1)quinoxaline—6— carboxylic acid To a on of methyl 2-(4-fluoropheny1)(7-n1ethoxy—1,2,3,4-tetrahydroquinolin y1)quinoxalinecarboxylate (88 mg, 0.20 11111101) in methanol (301111) was added sodium ide (32 mg, 0.80 mmol) and water (2 ml). The reaction was stirred for 2 days at room temperature. The resulting solution was diluted with water (15 ml), adjusted to pH 5 with ACOH, extracted with ethyl acetate (2 x 20 H11) and the organic layers were combined and concentrated in vaczto to afford 2-(4-fluoropheny1)—3-(7~methoxy—1,2,3,4-tetrahydroquinoliny1)quinoxaline- oxylic acid as a yellow solid (59 mg, 69%).

LC/MS (ES, m/z): [M+H]+ 430.1 1H~NMR (300 MHZ, DMSO): 5 8 8.37 (s, 1H), 8.10 (S, 1H), 7.73 — 7.78 (m, 2H), 7.08 — 7.14 (111, 2H), 6.87 (d, J: 8.4HZ, 1H), 6.28 - 6.31 (m, 1H), 6.13 (d, J: 2.4Hz, 1H), 3.80 — 3.85 (m, 2H), 3.47 (3,3H), 2.65 - 2.71 (111, 2H), 1.90 ~ 2.10 (m, 211) 3-(7-Fluor0-1,2,31,4-tetrahydroquinolinyl)-2—(4-f1u0rophenyl)quinoxalinecarboxylic acid 2 \Z OI PCT/U52012/020281 Attorney Docket No. 1310130009401 -PC Step 1. 3-Chloro-N—(3-fluorophenyl)propanamide To a solution of roaniline (10 g, 90.00 mmol) in acetone (40 ml) was added pyridine (18 g, 227.56 mmol) and 3-chlor0propanoyl chloride (13.73 g, 108.14 mmol) and the reaction was stirred for 3 h at 55°C. The resulting solution was extracted with ethyl acetate (3 x 50 ml) and the organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated in vacuo to afford 3—ch10ro—N-(3~fluorophenyl)propanamide as a yellow solid (13.21 g, 73 %).

LC/MS (ES, m/z): [M+Hl+ 202.0 1{Ll—NMR (300 MH2,CDC13): 8 7.51 - 7.62 (m, 1H), 7.31 - 7.41 (m, 1H), 7.16 (d, J: 8.1 Hz, 1H), 6.83 - 6.89 (m, 1H), 3.89 - 3.93 (m, 2H), 2.82 ~ 2.87 (m, 2H) Step 2. 7—Fluoro-1,2,3,4—tetrahydroquinolin—2-one To the solid of 3—chloro-N-(3-fluorophenyl)propanamide (3 g, 14.88 mmol) was added AlCl3 (6.3 g, 0.047 mmol) and maintained with an inert here of nitrogen with stirring for 511 at 120°C. The reaction was then quenched with ice—water, extracted with ethyl acetate (3 x 50 ml) and the organic layers were combined, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography with 4 % ethyl acetate in petroleum ether to afford ro-1,2,3,4-tetrahydroquinolinone as a white solid (1.5 g, 61 LCMS (ES, m/z): [M+H]+ 166.0 1H—NMR (300 MHZ, : 5 8.73 (s, 1H), 7.10 - 7.19 (m, 1H), 6.71 ~ 6.79 (m, 1H), 6.56 — 6.70 (m, 1H), 2.98 - 3.05 (m, 2H), 2.64 - 2.69 (m, 2H) Step 3. 7-Fluoro-1,2,3,4-tetrahydroquinoline QCL.

To a solution of 7—fluoro—1,2,3,4—tetrahydroquinolin-2‘one (1.5 g, 9.08 mmol) in tetrahydrofuran (50 ml) was dropwise B113 in TIIF (1M, 90 ml) ,the on was stirred for 24 h at 60°C. The reaction mixture was cooled and then quenched by the addition of methanol (15 1111) and HC] (cone) (5ml), then stirred for 1 h at 60°C. The reaction mixture was cooled to room temperature and adjusted to pH 12 with sodium hydroxide (4 mol/l.), extracted with (3 x 15 ml) of ethyl acetate and the organic layers were combined and dried over ous ium sulfate, PCT/USZOIZ/OZOZSI Attorney Docket No. BIOE0009PC concentrated in vacuo to give a residue, which was purified by a silica gel column tography with 3 % ethyl acetate in petroleum ether to afford 7«fluoro-l,2,3,4- tetrahydroquinoline as a yellow solid (0.9 g, 66%).

LC/MS (ES, m/z): [1Vl+lrlJ+ 152.0 1H—NMR (300 MHZ, CDC13)I 5 6.86 — 6.94 (111, 1H), 6.15 - 6.26 (m, 1H), 6.27 — 6.35 (m, 1H), 3.92 (s, 1H), 3.29 — 3.33 (111, 2H), 2.72 - 2.78 (111, 2H), 1.91 - 2.00 (111, 2H) Step 4. Methyl 3—(7—flu0ro-l ,2,3,4—tetrahydroquinolin—l—yl)oxo-1,2-dihydroquinoxaline carboxylate To a solution of 7-fluor0-l ,2,3,4—tetrahydroquinoline (1 g, 6.61 mmol) in NMP (30 ml) was added methyl 3—chlorooxo-1,2-dihydroquinoxaline-G-carboxylate (900 mg, 3.77 11111101) and then stirred for 2 h at 150°C. The resulting on was diluted with water ((900 ml). The solids were collected by filtration to afford methyl 3-(7-fluoro-l,2,3,4-tetrahydroquinolin-1~y])oxo- 1,2-dihydroquinoxalinecarboxylate as a brown solid (900 mg, 39 %).

Step 5. Methyl 3-(7-fluoro-l ,2,3,4—tetrahydroquinolin-1—yl)-2— [(trifluoromethane)sulfonyloxy]quinoxaline—6—carboxylate “r c 0/ TfO \N / To a solution of methyl lu0ro-l,2,3,4-tetrahydroquinolinyl)-2—oxo—l,2- dihydroquinoxalinecarboxylate (900 mg, 2.55 mmol) in dichloromethane (50 ml) was added pyridine (802 mg, 10.14 mmol) the reaction was cooled to 0°C. Then TfZO (2149 mg, 7.62 mmol) was added dropwise and the reaction was stirred overnight at room temperature. Then the mixture was washed with water ( 100 1111), dried over anhydrous magnesium sulfate, and concentrated in vacuo to afford a residue, which was purified by silica gel column chromatography with l % - 2 % ethyl acetate in petroleum ether to afford luoro-1,2,3,4— tetrahydroquinolin-l-yI)l(trifluoromethane)sulfonyloxyjquinoxalinecarboxylate as a yellow solid (819 mg, 66 ‘70). 2012/020281 Attorney Docket No. 1310130009401 -PC Step 6. Methyl 3—(7-fluoro-l,2,3,4-tetrahydroquinolin—1-yl)(4-fluorophenyl)quinoxaline carboxylate A solution of K3PO4 (682 mg, 3.21 mmol) in water (2 ml) was added to a solution of methyl 3~ (7-fluoro-1,2,3,4-tetrahydroquinolinyl)—2-[(trifluoromethane)sulfonyloxy]quinoxaline—6— carboxylate (500 mg, 1.03 mmol) (4—fluorophenyl)boronic acid (173 mg, 1.24 mmol), and in dioxane (25 ml). Then Pd(PPh3)4 (60 mg, 0.05 mmol) was added and the reaction was stirred for min at 90°C. The resulting mixture was concentrated in vacuo to give a residue, which was purified by a silica gel column tography with 1 % — 3 % ethyl acetate in petroleum ether to afford methyl 3-(7-fluoro—1,2,3,4—tetrahydroquinolin-1—yl)—2—(4—fluorophenyl) quinoxaline—6— carboxylatc as a yellow solid (200 mg, 45 %).

LC/MS (ES, m/z): [M+H]+ 432.0 1H—NMR (300 MHZ, CDC13): 5 8.67 (d, J: 1.8 Hz, 1H), 8.23 - 8.27 (m, 1H), 8.12 (d, J: 8.7 Hz, 1H), 7.76 - 7.81 (m, 2H), 6.93 — 7.05 (m, 2H), 6.46 - 6.53 (m, 1H), 6.28 - 6.33 (m, 1H), 4.03 (s, 3H), 3.81 - 3.85 (m, 2H), 2.76 « 2.81 (m, 2H), 2.03 - 2.11 (m, 2H) Step 7. 3-(7—fluoro-1,2,3,4—tetrahydroquinolin-1~yl)(4—fluoropheriyl)quinoxaline—6-carboxylic acid N /ND/LOH To a solution of methyl 3-(7-fluoro-1,2,3,4-tetrahydroquinolin—l-yl)~2—(4- fluorophenyl)quinoxaline-6—carhoxylate (120 mg, 0.28 mmol) in methanol (20 ml) was added a on of sodium hydroxide (44 mg, 1.10 mmol) in water (3 ml). The reaction was stirred overnight at room temperature. The resulting mixture was concentrated in vacuo to give a e, which was dissolved in water (20 ml) and adjusted to pH 4 with hydrogen chloride (3 N). The solids were collected by filtration to afford uoro-l ,2,3,4-tetrahydroquinolinyl)- 2-(4-fluorophenyl)quinoxaline—6—carboxylic acid as a yellow solid (101 mg, 87 %).

LC/MS (ES, m/z): [M+H]+ 418.1 Attorney Docket No. BlOEOOO9PC 1H—NMR (300 MHz, DMSO): 8 8.39 (d, J = 1.2 Hz, 1H), 8.09 — 8.17 (m, 2H), 7.76 - 7.81 (m, 2H), 7.14 - 7.20 (m, 2H), 6.98 ~ 7.03 (m, 1H), 6.49 - 6.54 (m, 2H), 6.75 - 6.79 (m, 2H), 2.70 — 2.74 (m, 2H), 1.94 - 1.98 (m, 2H) 3-[2H,5H,6H,7H,8H-[1,3]Dioxolo[4,S-g]quinolinyl](4-flu0rophenyl)quinoxaline carboxylic acid Step 1. Ethyl 2—(triphenyl-[5]-phosphanylidene)acetate Ph3PVkO/\ PPh3 (57 g, 217.32 mmol) was added to a solution of ethyl 2—bromoacetate (30 g, 179.64 mmol) in CH3CN (200 ml). The reaction was stirred overnight at 120°C. Then it was concentrated in. vacuo and the residue was ved in water (200 ml) and adjusted to pH 8 with sodium bicarbonate (aq), extracted with ethyl acetate (3 x 1501111), the c layers wee combined and concentrated in vacuo to afford ethyl 2-(triphenyl~ [5]-phosphanylidene)acetate as a light yellow solid (41 g, .

Step 2. (IQ-Ethyl 3—(6-nitrobenzo[d][1,3]dioxol—5-yl)acrylate Aom0> ON 0 To a solution of 6—nitro—2H—1,3-benzodioxole—5~carbaldehyde (10 g, 51.25 mmol) in benzene (100 ml) was added ethyl 2-(tripheny1—[5]~phosphanylidene)acetate (36 g, 103.34 mmol) and the reaction was stirred for 6 h at . The reaction mixture was concentrated in vacuo to provide a residue which was purified by silica gel column chromatography with 1% ethyl acetate in petroleum ether to afford (E)-ethyl 3-(6-nitrobenzo[d][1,3]dioxolyl)acrylate as a yellow solid (7.5 g, 55 %).

Attorney Docket No. BlOEOOO9-40l —PC LC/MS (ES, m/z): [M+H]+ 266.0 1H—NMR (300 MHZ, CD03) 5 8.10 (d, J: 15.9 Hz, 1H), 7.57 (S, 1H), 7.01 (S, 1H), 6.25 (Cl, J =15.6 Hz, 1H), 6.15 (d, J = 8.7 Hz, 2H), 4.27 - 4.34 (m, 2H), 1.34 - 1.39 (t, J = 7.2 Hz, 3H) Step 3. 2H,5H,6H,7H,8H—[l,3]Dioxolo[4,5-g]quinolin—6-one «$39 Palladium on carbon (340 mg) was added to a solution of (E)—ethyl 3-(6- nitrobenzo[d][l,3]di0xol~5-yl)acrylate (500 mg, 1.89 mmol) in ACOH (60 ml). Then H2 (g) was uced at 5 Atm and the reaction was stirred overnight at 70°C. The reaction mixture was adjusted to pH 8 with ted aqueous NaHC03 and extracted with ethyl acetate (3 x 80 ml).

The organic layers were combined, dried over anhydrous magnesium e, and concentrated in vacuo to afford 2H,5H,6H,7H,8H—[l,3]dioxolo[4,5-g]quinolinone as a brown solid (316 mg, crude).

LC/MS (ES, m/z): [M+H]+ 192.0 1H-NMR (300 MHZ, CD30D)C 5 6.69 (S, 1H), 6.45 (d, J: 5.4 Hz, lH), 5.90 (s, 2H), 2.83 — 2.88 (m, 2H), 2.49 — 2.55 (m, 2H) Step 4. 8—Tetrahydro-[l ,3]dioxolo[4,5-g]quinoline To a solution of 2H,5H,6H,7H,8H—[l,3]dioxolo[4,5*g]quinolinone (250 mg, crude) in tetrahydrofuran (50 ml) was dropwise BH3 in THF (1 N, 26 ml). The reaction was stirred at 60°C overnight. Then the reaction mixture was quenched with hydrogen chloride (3 N), adjusted to pH 8 with sodium bicarbonate, extracted with ethyl acetate (3 x 50 ml). The organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated in vacuo to afford 5,6,7,8- tetrahydro-[l,3]dioxolo[4,5-g]quinoline as a solid (180 mg).

LC/MS (ES, m/z): [M+H]+ 178.0 1H-NMR (300 MHZ, CDC]3)I 5 6.48 (S, 1H), 6.12 (s, 1H), 5.82 (S, 2H), 3.24 - 3.27 (m, 2H), 2.68 - 2.72 (t, J: 6.3 Hz, 2H), 1.88 - 1.96 (m, 2H) PCT/U52012/020281 Attorney Docket No. O9-401—PC Step 5. Methyl 3-[2H,5H,6H,7H,8H—[l,3ldioxolof4,5-g]quinolin-5—yll—2-oxo—1,2- dihydroquinoxaline-é—carboxylate O N To a solution of methyl 3—ch10ro—2-oxo-1,2—dihydroquinoxaline-6—carboxylate (161 mg, 0.67 mmol) in NMP (5 ml) was added the 6H,7H,8H—[1,3]dioxolo[4,5-g]quin01ine (180 mg, 1.02 mmol) and the reaction was stirred for 1h at 140°C. The reaction mixture was cooled to room temperature, and the product was precipitated by the addition of water and filtered off to afford methyl 3-[2H,5H,6H,7H,8H—[1,3]di0xolo[4,5-g]quinolin-5~yl]ox0-1,2— dihydroquinoxaline-6—carboxylate as a brown solid (140 mg, 55 %).

LC/MS (ES, m/z): [M+H]+ 380.0 1H~NMR (300 MHZ, CDC13): 510.31 (s, 1H), 8.30 ~ 8.36 (111, 1H), 7.92 - 9.95 (m, 1H), 7.06 (d, J = 8.7 Hz, 1H), 6.68 (d, J: 9.0 Hz, 1H), 6.50 (d, J: 7.5 Hz, 1H), 5.92 (s, 2H), 4.02 - 4.08 (m, 2H), 3.96 (s, 3H), 2.75 - 2.79 (t, J: 6.3 Hz, 2H), 2.00 - 2.08 (m, 2H) Step 6. Methyl 3—(7,8-dihydro—[1,3]dioxolo[4,5—g]quinolin-5(6H)—yl)~2~ (trifluoromethylsulfonyloxy)quinoxa line—6—carboxylate To a solution of methyl 3-[2H,5H,6H,7H,8H—[1,3]dioxolo[4,5—g]quinolin-S-yl]—2-oxo-l,2- dihydroquinoxalinecarboxylate (140 mg, 0.37 mmol) in dichloromethane (80 ml) was added pyridine (175 mg, 2.21 mmol) and szO (510 mg, 1.81 mmol). The reaction was stirred overnight under here of nitrogen at room temperature. Then the reaction mixture was quenched with water (200 ml), extracted with dichloromethanc (3 x 20 ml), the organic layers were combined, dried over anhydrous magnesium e, and concentrated in vacuo to afford methyl 3-(7,8-dihydrO-[1,3]diox010[4,5-g1quinolin—5(6H)-yl) ZOIZ/OZOZS] Attorney Docket No. BlOE0009~401 —PC (trifluoromethylsulfonyloxy)quinoxalinecarboxylate as a red 01] (150mg, crude), which was used directly in the next step.

Step 7. Methyl 3-(7,8-dihydro-[1,3ldioxolo[4,5-g]quinolin-5(6H)-yl)(4~ fluorophenyl)quinoxalinecarboxylate To a solution of methyl 3-[2H,5H,6H,7H,8H—[l,3]dioxolo[4,5-g]quinolinyl]-2— [(trifluoromethane)sulfonyloxy]quinoxalinecarboxy1ate (150 mg, crude) in e (5.0 ml) and water (3 drops) was added (4-fluorophcnyl)boronic acid (124 mg, 0.89 mmol), Pd(PPh3)4 (17 mg, 0.01 mmol), K3PO4 (186 mg, 0.88 mmol). The reaction was stirred for 40 min at 90°C under atmosphere of nitrogen. Then the reaction mixture was concentrated in vacuo to give a residue, which was purified by a silica gel column chromatography with 1% ethyl acetate in petroleum ether to afford methyl -dihydro-[l,3Idioxolo[4,5-g]quinolin-S(6H)-yl)(4- fluorophenyl)quinoxalinecarboxylate as a light yellow solid (100mg).

LC/MS (ES, m/z): [M+H]+ 458.0 1H-NMR (300 MHZ, CDC13): 8 8.69 (d, J: 1.5 Hz, 1H), 8.17 - 8.21 (m, 1H), 8.07 (d, J: 8.7 Hz, 1H), 7.72 — 7.76 (m, 2H), 6.98 — 7.04 (m, 2H), 6.53 (s, 1H), 6.19 (s,1H), 5.80 (s, 2H), 4.02 (s, 3H), 3.80 — 3.85 (t, J: 6.6 Hz, 2H), 2.68 - 2.73 (t, J = 6.3 Hz, 2H), 2.02 ~ 2.06 (t, J: 6.6 Hz, 2H) Step 8. 3-[2H,5H,6H,7H,8H—[1,3]dioxolo[4,5-glquinolin-5—yl]-2~(4-fluorophenyl)quinoxaline~6~ carboxylic acid Sodium hydroxide (35 mg, 0.88 mmol) was added to a solution of methyl 3-[2H,5H,6H,7H,8H- [1 ,3]dioxolo[4,5-g]quinoliny1]~2-(4-fluorophenyl)quinoxaline—6-carboxylate (100 mg, 0.22 mmol) in methanol (30 ml) and water (1.0 m1) and the reaction was stirred overnight at room Attorney Docket No. BIOEOOO9-40l ~PC temperature. The reaction mixture was concentrated in vacuo, dissolved in water (30 ml), and adjusted to pH 5 with hydrochloric acid (3 N) to give a precipitate which was collected by filtration to afford 3-[2H,5H,6H,7H,8H—[1,3]dioxolo[4,5-g]quinolinyl](4- fluorophenyl)quinoxaline-6~carboxylic acid as a light yellow solid (70.0 mg, 72 %).

LC/MS (ES, m/z): [M—tHrr 444.1 1H—NMR (300 MHZ, DMSO): 5 8.30 (s, 1H), 8.08 (01,]: 8.71 Hz, 1H), 7.98 (d, J = 8.4 Hz, 1H), 7.73 - 7.77 (m, 2H), 7.13 — 7.19 (m, 2H), 6.61 (s, 1H), 6.39 (s, 1H), 5.79 (s, 2H), 3.62 - 3.66 (t, J = 6.3 HZ, 2H), 2.61 — 2.66 (t, J: 6.3 HZ, 2H), 1.87 - 1.91 (t, J = 6.3 HZ, 2H) The following compounds can lly be made using the methods known in the art and described above. It is expected that these compounds when made will have activity r to those that have been made in the examples above.

ZOIZ/02028l Attorney Docket No. BIOEOOO9—401—PC 3”<3”° 13* 3rum/[L0H 3%»13*° :5333° :31 £9333° F1:213 :533” E3 PCT/U52012/020281 Attorney Docket No. BIOEOOO9-40l-PC OCH8 CI E O N N E N N COOH / ULOH ’ I} \ O N E \N H3CO O E O E N N COOH I)“ (1);“’ (I N N OCH3 E 5R N N \ UCOOH H3CO(DIN OCH3 (01);“I) N COOH PCT/U52012/020281 y Docket No. BIOEOOO9PC E EN N COOH E N N COOH / / COOH N /N COOH / N o OCH3 N N COOH \ \N N N COOH NH OCF3 N N nCOOH \ \N N N COOH NH 2012/020281 Attomey Docket No. BIOEOOO9PC OCH3 fig;Um fig;Um OCF3 fig;Um 52 ,COOH Clg? \N: : OCHCF2 £1:N:[::fi/COOH fig;Um fig;Um fig;Um. £1::Q/COOH fig;Um WO 94462 PCT/U82012/020281 Attorney Docket No. BIOEOOO9PC OCF3 Cl E EN N N / KW @611\N:[::}/COOH \ $waOCHFZ 0 go}w ©I:CH320* gay"H PCT/U52012/020281 Attomey Docket No. O9—401-PC CF3 .Q o 2 \ oI N N / 0H c:“<?/ <0 \N 0TI0.) 0 o N N Z / :[::j/fl\OH \Z oI \ 0 N Z/ F /—“‘\ CF3 TI o z 2 N N \ OI / :I::j/J\OH 0%/z \ OCH3 o 2 \ 0H N N E0 \N % o 00F3 00H3 N N / OH <3; (O \N (i3932 PCT/U52012/020281 Attomey Docket No. O9—401-PC OCHF2 Cl Z Z :20 \ OI 02/;z/ Q3;Q O \2 :: OI 0%2/ O'nw %_<<22>/\z2 O OCH3 2:2 o \ OI OCHF2 11OX0 z "1 5 0 :—<2:/\22 2012/020281 Attomey Docket No. BIOEOOO9—401—PC Cl -nQ3 2:; N COOH N: ,COOH \ /\ / ,2IZ\ \ N :: N COOH z N COOH \EZ/ 5%C? '1'] QC:NECOOH\ \E/z N COOH ’2 \ I2 \ Z/ QQ3 N COOH 2Q \ N COOH ’2 \ I2 \ z/ 9Q3 11Q3 NC?COOH N COOH \ IE; 3/z/ 2012/02028] Attorney Docket No. BIOEOOO9-401—PC .nQ3 F Z K) O \ oI / K/N /\ \ .nQ3 \Z O ; 0 o K/N 2/ F01\N 0 Q3;T]Z :=0 \ 0I 0%/Z m0/Q3 Z 22 0I 2 :20 'n 2/ Z :20 \ OI ‘n /EZ/ PCT/U52012/020281 ey Docket No. BIOE0009—401-PC The activity of the compounds in Examples 1— 24 as PASK modulators is illustrated in the following assays. The other compounds listed above, which have not. yet. been made and/or tested, are predicted to have activity in these assays as well. Compounds with activity in the following assay are expected to also have activity in other in vitro and in viva assays as indicated in , the disclosure of which is hereby incorporated by reference. mical Assay for hPASK Activity PAS Kinase FRET Assay The aim of the FRET assay is to determine the inhibition ial of test compounds on ed kinase. This assay platform provides a homogenous screening method for measuring kinase activity by quantitating the amount of phospho-substrate in on following a kinase reaction.

In the presence of kinase and ATP, the Might—peptide is phosphorylated and captured by an anti—phospho—substrate antibody, which brings the Eu chelate donor and Ulighr acceptor dyes into close proximity. Upon excitation at. 340 nm, the Eu ehelate transfers its energy to the Ulight dye, resulting in a fluorescent light emission at 665 nm.

Titration of kinase at 1 mM ATP was ed via the following protocol. After making serial fold dilutions of PASK (lnvitrogen) in reaction buffer across the plate; 5 p1 of kinase dilution and 5 pl substrate/ATP mix were added to the wells of the white Optiplate-384 (PerkinEhner). The contents of the plate were and incubated at RT for l h. The reaction was stopped by adding 5 ul of stop solution to each test well followed by mixing and incubation at RT for 10 minutes. 5 p1 of detection mix (detection dy diluted in detection ) was added; the contents of the plate were mixed and then incubated in the dark for 1 hour at RT. The signal was recorded at TR-FRET mode (665nm/615nm). The results were graphed to calculate the ECso.

Titration of ATP at the EC50 concentration of kinase to determine ATP Km,app. was performed using the following . After making serial dilutions of ATP (Invitrogen), 5 ul of ATP dilution and 5 ill substrate/kinase mix were added to the wells of the white Optiplate-3 84 (PerkinElmer). The contents of the plate were and incubated at RT for 1 h. The reaction was stopped by adding 5 it] of stop solution to each test well followed by mixing and incubation at RT for 10 minutes. 5 pl of ion mix tion antibody diluted in detection buffer) was added; the contents of the plate were mixed and then incubated in the dark for 1 hour at RT. The PCT/U52012/020281 Attorney Docket No. O9-40l —PC signal was recorded at TR—FRET mode (665nm/615nm). The results were graphed to calculate the ECso as the ATP Km,app.

Compound screening was done via the ing method. 10 mM stock solution of test compound in DMSO was prepared by dissolving test compound in DMSO at RT for 1 hour, and then sonicating at 100% output for 8 minutes. If compound is not soluble under this condition, it was d to 3 mM. Kinase reaction buffer was prepared containing 10 mM MgC12, 50 mM HEPES, 1 mM EGTA, 0.01% TWEEN—20, 2 mM DTT. Serial dilutions of the test compounds were prepared at 4 X final assay concentrations using Freedom EV0200® sing system as follows: 12x10"5 M, 4x105 M, 1.33x10‘5 M, 4.44x10'6 M, 0'6 M, 4.92x10‘7 M, 1.65x10‘7 M, 5.48x10'7 M, 1.82x10‘g M, 6.09x10‘9, 2.03x10‘9 M. Test compounds (2.5 pl at 4 x the final assay concentration) was added to wells using Freedom EV0200® dispensing system. As a positive control, 2.5 pl of positive compound was added to assay wells, and 2.5 pl of DMSO to assay wells as vehicle control. Kinase on was prepared in reaction buffer at 2 x final assay concentration. Kinase solution (5 pl) was added to each well of the assay plate. The substrate and ATP solution was prepared in kinase reaction buffer at 4 x final assay concentration. The kinase reaction was started by adding 2.5 pl of substrate + ATP mix solution to each well of the assay plate. The plate is mixed on a plate shaker; then covered and allowed to react for 2 hours in the dark at 25°C t shaking. The reaction was stopped by adding 5 pl of stop solution to each test well followed by mixing and incubation at RT for 10 minutes in the dark. 5 p1 of ion mix (detection antibody diluted in detection buffer) was added; the contents of the plate were mixed and then incubated in the dark for 1 hour at RT. The signal was recorded at TR-FRET mode (665n1u/615nm).

Results are shown below in Table l.

Table 1.

ICso Kinase Domain Example # + indicates 30 um - indicates >10 um ,_. 0 >—4 AU) r—Iy—A \IO\ Nw—A O\O t...

[UN WM N4’}.

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

Claims (12)

1. A compound chosen from 3 —( 1 ,2,3 ,4-Tetrahydroquin01in- 1 (2H)-y1)(4-fluorophenyl)quinoxalinecarboxy1ic acid; 2-(Benzofurany1)-3 -(1 ,2,3 ,4-tetrahydroquin01in- 1 (2H)-y1)quinoxaline—6—carb0xylic acid; 3 -(1,2,3 ,4-Tetrahydroquinolin-1(2H)—y1)~2-(5-fluor0benzofuran—Z-y1)quin0xa1ine-6— carboxylic acid; 2-(2, 3 —Dihydro-1 ,4—benzodioxin—6-y1)—3-( 1 3 , 2, , 4-tetrahydroquinolin~1—y1)quinoxalinc- 6-carboxy1ic acid; 2-(4—Fluoropheny1)-3 thoxy-1 ,2,3 ,4—tetrahydroquinolin- 1 —y1)quinoxa1ine—6— carboxylic acid; 3 ~(6-F1u0r0-1,2,3,4—tetrahydr0quin01in—1-y1)(4-fluoropheny1)quinoxa1inecarboxyiic acid; 2-(5-Fluor0— 1 -benzofi1rany1)—3~(6—methoxy—1 ,2,3 ,4-tetrahydroquin01in-1 — y1)quinoxa1ine—6—carboxylic acid; 2-(5-Chlor0benzofi1ran—2-y1)-3—(6-fluor0-1,2,3,4-tetrahydroquinoliny1)quinoxaline- 6-carboxy1ic acid; hloro—1 —benzofi1ran-2—y1)—3~(6-methoxy-1 ,2,3 ,4-tetrahydr0quinolin y1)quinoxaline—6—carboxylic acid; 2-Ox0-3 -(1, 2, 3 , 4-tetrahydr0quinolin-1—y1)—1,2-dihydroquinoxaline—6—carboxylic acid; 3—(6—Flu0ro-3 ,4—dihydroquin01in-1 (2H)—y1)(5—fluorobenzofiiran-Z—yl)quinoxa1ine ylic acid; 3-(6-Cyano-1 -tetrahydr0quinolin—1-y1)—2-(4—fluorophenyl)quinoxalinc—6-carboxylic acid; 7-(6~Bromo—1,2,3,4-tetrahydr0quinolin—1-y1)(4—fluorophenyl)quinoxaline—Z~carboxylic acid; 3-(6-Carbamoy1— 1 ,2,3,4-tetrahydroquino1in—1-y1)(4-fluoropheny1)quin0xa1ine-6— carboxylic acid; 2-(4—Fluor0pheny1)-3 -[6-[(morphoiiny1)carbonyl]-1 ,2,3 ,4-tetrahydroquinolin— 1 - yl]quinoxaline-6—carboxy1ic acid; 3 —[6-(Dimethylsulfamoyl)- l ,2,3 ,4-tetrahydroquinolinyl] ~2—(4- fluoropheny1)quinoxalinecarboxylic acid; 3 — [6-(Dimethylamino)—1 ,2,3 ,4—tetrahydroquinolin— l —yl] —2—(4—fluorophenyl)quinoxaline carboxylic acid; 3 -(6-Chloro— 1 -tetrahydroquinolin-l-yl)(4-fluoropheny1)quinoxalinecarboxy1ic acid; 3 —(7-Fluoro-l ,2 ,3 ,4-tetrahydroquinoliny1)—2-(4—fluorophenyl)quinoxaline—6-carboxylic acid; 3 -(6~Fluoro-l ,2,3 ,4-tetrahydroquinolin— l -yl)—2—(2-methyl- 1H—indol—5-y1)quinoxaline—6— carboxylic acid; 3 ~(6-Fluoro-1 ,2,3 ,4-tetrahydroquinolin- l —yl)-2—( lH-indazol-S-yl)quinoxaline carboxylic acid; 2-(4-Fluorophenyl)(7-methoxy—l ,2 ,3 ,4—tetrahydr0quinolin-l -yl)quinoxaline-6— carboxylic acid; 3 -(7-Fluor0-l ,2,3 ,4—tetrahydroquinolin- l -yl)-2—(4-fluorophenyl)quinoxaline—6-carboxylic acid; and 3 -[2H,5H,6H,7H,8H—[l ,3]Dioxolo[4,5-g]quinolin-S-yl]~2-(4-fluorophenyl)quinoxaline carboxylic acid. .

A ceutical ition comprising a compound as recited in Claim 1 er with a pharmaceutically acceptable carrier. .

Use of a compound as recited in Claim 1 in the manufacture of a medicament for the tion or treatment of a disease or ion rated by the tion of PASK. .

Use of a therapeutically effective amount of a compound as recited in Claim 1 in the manufacture of a medicament for treatment of a disease. .

The use as recited in Claim 4 wherein said disease is a metabolic disease. .

The use as recited in claim 5 wherein said metabolic disease is chosen from metabolic syndrome, diabetes, dyslipidemia, fatty liver disease, non—alcoholic steatohepatitis, obesity, and insulin resistance. .

The use as recited in Claim 6 wherein said diabetes is Type II diabetes. .

Use of: a. a therapeutically effective amount of a compound as recited in Claim 1; and b. another therapeutic agent in the manufacture of a medicament for treatment of a ediated disease.

The compound as recited in Claim 1, substantially as herein described with reference to any one of the Examples thereof.

10. The compound as recited in Claim 1, substantially as herein described.

11. The pharmaceutical composition as recited in Claim 2, substantially as herein bed.

12. The use as recited in any one of Claims 3 to 8, substantially as herein described.