NZ614610B2 - Heterocyclic compounds for the inhibition of pask - Google Patents

Heterocyclic compounds for the inhibition of pask Download PDF

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NZ614610B2
NZ614610B2 NZ614610A NZ61461012A NZ614610B2 NZ 614610 B2 NZ614610 B2 NZ 614610B2 NZ 614610 A NZ614610 A NZ 614610A NZ 61461012 A NZ61461012 A NZ 61461012A NZ 614610 B2 NZ614610 B2 NZ 614610B2
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methyl
acid
amino
quinoxaline
mmol
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NZ614610A
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NZ614610A (en
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Robert C Kelly
John M Mccall
Donna L Romero
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Bioenergenix
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Priority claimed from PCT/US2012/027423 external-priority patent/WO2012119046A2/en
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    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
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    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Abstract

Disclosed herein are new 3-Amino Quinoxaline-6-Carboxylic Acid compounds and compositions and their application as pharmaceuticals for the treatment of disease. Methods of inhibiting purine-analog sensitive kinase (PASK) activity in a human or animal subject, also provided for is the treatment of diseases such as diabetes mellitus. Compounds of the disclosure include: (R)-2-(4-Fluorophenyl)-3-(2-(trifluoromethyl)pyrrolidin-1-yl)quinoxaline-6-carboxylic acid, (R)-2-(Benzo[d][1,3]dioxol-5-yl)-3-(2-methylpyrrolidin-1-yl)quinoxaline-6-carboxylic acid, (S)-2-(1H-Indol-5-yl)-3-(3-methylmorpholino)quinoxaline-6-carboxylic acid, 3-(Azepan-1-yl)-2-(1H-indazol-5-yl)quinoxaline-6-carboxylic acid, and (S)-2-(4-Fluorophenyl)-3-(3-methylmorpholino)quinoxaline-6-carboxylic acid. seases such as diabetes mellitus. Compounds of the disclosure include: (R)-2-(4-Fluorophenyl)-3-(2-(trifluoromethyl)pyrrolidin-1-yl)quinoxaline-6-carboxylic acid, (R)-2-(Benzo[d][1,3]dioxol-5-yl)-3-(2-methylpyrrolidin-1-yl)quinoxaline-6-carboxylic acid, (S)-2-(1H-Indol-5-yl)-3-(3-methylmorpholino)quinoxaline-6-carboxylic acid, 3-(Azepan-1-yl)-2-(1H-indazol-5-yl)quinoxaline-6-carboxylic acid, and (S)-2-(4-Fluorophenyl)-3-(3-methylmorpholino)quinoxaline-6-carboxylic acid.

Description

PCT/U82012/027423 HETEROCYCLIC COMPOUNDS FOR THE INHIBITION OF PASK This application claims the benefit of priority of United States Provisional Applications No. 61/448,527, filed March 2, 2011, No. 61/449,009, filed March 3, 2011, and No. ,533, filed March 2, 2011, the disclosures of which are hereby incorporated by nce as if written herein in their entireties. sed herein are new heterocyclic compounds and compositions 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 maintenance of glucose and energy homeostasis in mammals. Glycogen, a large branched polymer of e, acts as a reserve of carbon and energy in a variety of organisms. In mammals, the most important stores are found in the liver and skeletal muscle (1). Liver en is required to efficiently buffer blood glucose levels during g, 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 ily controlled through tion of the enzyme glycogen synthase (GYS, various isoforms), which catalyzes bulk glycogen synthesis (5, 6, 7). The muscle isoform of glycogen synthase (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). en 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 nous regulatory phosphorylation sites in mammalian glycogen synthase (15, 32) and 4 (10, 11-13, 24, ). GSK—3, however, is not the sole kinase that phosphorylates C-terminal regulatory sites; GSK—B—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 0 and Ser-644, and phosphorylation at these sites still occurs.
PASK (purine-analog sensitive kinase, PAS kinase) is a PAS -containing serine/threonine kinase, and genetic ments in S. cerevisiae yeast have implicated PASK as a physiological regulator of glycogen synthase and glycogen accumulation (16, 17). As with the entire glycogen synthase regulatory system, PASK is highly conserved from yeast to WO 19046 PCT/U82012/027423 man. Human PASK (hPASK) phosphorylates glycogen synthase primarily at Ser—640, causing near complete inactivation. It is interesting to note that the exact site of PASK— dependent phosphorylation is similar but not cal in yeast and ian glycogen synthase (18, 19); yeast PASK phosphorylates glycogen synthase at the site analogous to Ser- 644, four residues C—terminal (18). It appears that the hPASK mid region (residues 444—955) is required for efficient phosphorylation of glycogen synthase in vitro and for interaction with glycogen synthase in cells: an hPASK mutant (A955) lacking the noncatalytic N terminus was unable to efficiently phosphorylate glycogen synthase. Since this region is not required for the phosphorylation of generic, nonphysiological substrates, such as histones 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 n kinases (26—29). Unlike GSK—3, the activity of hPASK has been shown to be independent of insulin and ly ted instead by a more direct metabolic signal (23).
Genetic and proteomic screens using yeast PASK identified 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 (PSKI and PSKZ) had elevated glycogen synthase ty and an imately 5- to 10-fold accumulation of glycogen relative to wild—type strains, consistent with impaired ability to phosphorylate glycogen synthase in vivo (18). Because glycogen synthesis and translation are two processes y regulated in response to nt availability and because PAS domains are ntly 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 ar response to nutrients. The catalytic activity of PASK in pancreatic islet B—cells is rapidly increased in response to glucose addition, and PASK is required for the glucose~ responsive expression of some B—cell genes, including preproinsulin (23).
PASK catalytic activity is not responsive to glucose alone, r. The interaction between the hPASK midregion and glycogen synthase is ted by at least two factors. First, the PAS domain of PAS kinase plays a ve role in ting 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 se interaction is regulated by the metabolic status of the cell, thereby enabling an additional layer of metabolic regulation of en sis. Second, glycogen negatively regulates the hPASK—glycogen synthase interaction, which would initially seem counterintuitive, since glycogen would thereby stimulate its own continued synthesis. It is possible, r, that this mechanism exists to lly coordinate the synthesis of en. It is becoming 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 ly localized to an existing, properly organized glycogen particle. These data strongly suggest that the hPASK midregion plays an important role in targeting hPASK catalytic activity to ic 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 glycogen metabolism in viva. It is well established that derangement in glycogen lism is one of the hallmarks of both Type 1 and Type 2 diabetes (20) and related conditions (21), ing a panoply of life—threatening cardiovascular conditions (22). Using PASKl 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 hepatic fat accumulation. Therefore, PASK inhibition would comprise a system for the metabolic control of glucose utilization and storage in mammalian cells, and offer a new method to treat metabolic es including but not limited to diabetes and its complications, the metabolic syndrome, insulin resistance, and various cardiovascular conditions.
The hallmarks of cancer, cellular overgrowth and hyperproliferation, require the rapid sis of all cellular materials, including protein and lipids. Both of these synthetic processes are controlled, to some extent, by PAS K. As a result of these observations, it is possible that tion of PASK could be a viable therapeutic strategy for many cancers. By ting the rapid synthesis of proteins and lipids, such an inhibitor should t the rapid and uncontrolled growth and division of cells that characterizes many cancers.
Novel nds and ceutical compositions, certain of which have been found to inhibit PASK have been discovered, together with methods of synthesizing and using the compounds including methods for the treatment of PASK—mediated diseases in a patient by administering the compounds.
PCT/U82012/027423 In certain embodiments of the present invention, a compound has structural Formula I: ‘36 0 N N R5/ / OH R1 N R3 or a salt, stereoisomer, ester or prodrug thereof, wherein: R1 is chosen from aryl and heteroaryl, which may be optionally substituted with one or more substituents chosen from hydrogen, halo, alkyl, alkenyl, alkynyl, lkyl, haloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, heterarylalkyl, CN, alkoxy, mino, dialkylamino, N02, oxo, amino, NHSOgng, NHSOgNHng, NHCORn, NHCONHRQ, CONHRlz, CONRnaRnb, hydroxy, , SOgNHRn, CF3, and haloalkoxy; R3 is chosen from hydrogen, hydroxyl, halo, C1—C5 alkyl, and C1-C5 alkoxy, any of which may be ally substituted; R5 and R6 are independently chosen from hydrogen, C1—C6 alkyl, C1-C7 cycloalkyl, C1-C7 heterocycloalkyl, C1—C6 alkenyl, C1-C6 alkynyl, aryl, heteroaryl, l, haloalkyl, and aralkyl, or taken together, R5 and R6 may form a heterocycloalkyl or heteroaryl, any of which may be optionally substituted; R12, R12a and R121, are independently chosen from hydrogen, C1—C6 alkyl, aryl, heteroaryl, aralkyl, CF3 and heteroaralkyl, any of which may be optionally substituted.
Certain compounds disclosed herein may possess useful PASK modulating activity, and may be used in the treatment or laxis of a disease or condition in which PASK plays an active role. Thus, in broad aspect, certain embodiments also provide pharmaceutical compositions comprising one or more compounds sed herein together with a ceutically acceptable carrier, as well as s 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 effective amount of a compound or ition according to the present invention. Also provided is W0 20121119046 PCT/U52012/027423 the use of certain compounds disclosed herein for use in the manufacture of a medicament for the treatment of a disease or condition ameliorated by the inhibition of PASK.
In further ments, compounds of Formula I are provided wherein R] is phenyl and has one or more substituents chosen from en, halo, alkyl, alkenyl, alkynyl, cycloalkyl, haloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, heterarylalkyl, CN, alkoxy, alkylamino, lamino, NHSOan, NHSOZNHRlz, NHCOR12,NHCONHR12, CONHRn, CONRuaR12b,hydroxy and OCF3; and R12, Rm and Rub are independently chosen from hydrogen, C1—C6 alkyl, aryl, aryl, l and heteroaralkyl, any of which may be optionally tuted.
In certain embodiments compounds of Formula I are provided wherein R5 and R6 are independently C1—C6 alkyl, cycloalkyl, heterocycloalkyl, and aryl, or taken together, R5 and R6 may form a heterocycloalkyl, any of which may be optionally substituted.
In certain embodiments compounds of Formula I are provided wherein R3 is hydrogen.
In certain embodiments compounds of Formula I are provided wherein R5 and R6 are independently C1-C6 alkyl, or taken together, R5 and R6 may form a heterocycloalkyl which may be optionally substituted.
In certain embodiments of the present ion, a compound has structural Formula II: (II) or a salt, stereoisomer, ester or g thereof, wherein: R1 is chosen from aryl which may be optionally substituted with one or more substituents chosen from hydrogen, halo, alkyl, alkenyl, alkynyl, cycloalkyl, haloalky], aryl, aralkyl, cyclyl, heteroaryl, heterarylalkyl, CN, alkoxy, alkylamino, dialkylamino, NHSOlez, NHSOzNHRlz, , NHCONHRIZ, CONHng, CONRnangb, hydroxy, CF3, SOleg, NHSOan, and OCF3; PCT/U82012/027423 R3 is chosen from hydrogen, hydroxyl, halo, C1—C5 alkyl, and C1-C5 alkoxy, any of which may be ally substituted; R12, Rm and Rm, are independently chosen from hydrogen, C1-C6 alkyl, aryl, heteroaryl, aralkyl and heteroaralkyl, any of which may be optionally substituted; R16 is chosen from null, hydrogen, alkyl, CORIS, SOles, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl any of which may be optionally subtituted; R17 is chosen from hydrogen, C1-C6 alkyl and C1~C5 haloalkyl, any of which may be optionally tuted; R13 is chosen from hydrogen, C1-C6 alkyl, C1-C6 cycloalkyl, C1-C6 heterocycloalkyl, aryl, and heteroaryl, any of which may be optionally substituted; and X3 is chosen from CH, N, O, and a bond.
In further embodiments, nds of Formula II are provided n R1 is , which may be ally substituted with one or more substituents chosen from hydrogen, halo, alkyl, alkenyl, alkynyl, cycloalkyl, haloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, heterarylalkyl, CN, alkoxy, alkylamino, dialkylamino, NHSOZRIZ, NHSOZNHRIZ, NHCORIZ, NHCONHRH, CONHRn, CONRnaRnb, hydroxy, CF3, SOan, NHSOan, and OCF3.
In further embodiments, compounds of Formula II are ed wherein R1 is phenyl ally substituted with one or more halo substituents.
In further embodiments, compounds of Formula II are provided wherein X3 is chosen from CH and N.
In further embodiments, compounds of Formula II are provided wherein R16 is In further embodiments, compounds of Formula II are provided wherein X3 is O and R16 is null.
In certain embodiments of the present invention, a compound has structural Formula III: R? 0 N N R5’ / OH R1 N (111) or a salt, stereoisomer, ester or prodrug thereof, wherein: R1 is chosen from aryl which may be optionally substituted with one or more substituents chosen from hydrogen, halo, alkyl, alkenyl, alkynyl, cycloalkyl, haloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, rylalkyl, CN, alkoxy, alkylamino, dialkylamino, NHSOgRu, NHSOZNHRIZ, NHCORn, NHCONHRIZ, CONHRIZ, CONngaRub, hydroxy, SOgR12,SOzNHR12, CF3, and OCF3; R5 and R6 are independently chosen from hydrogen, C1-C6 alkyl, C1—C7 lkyl, C1—C7 heterocycloalkyl, aryl, heteroaryl, aralkyl, and aralkyl, any of which may be optionally tuted; and R12, R123 and R12}, are independently chosen from hydrogen, C1—C6 alkyl, aryl, heteroaryl, aralkyl, CF3 and heteroaralkyl, any of which may be optionally substituted.
In another embodiment, compounds of Formula III are provided wherein R1 is phenyl, which may be optionally substituted with one or more substituents chosen from hydrogen, halo, alkyl, alkenyl, alkynyl, cycloalkyl, haloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, heterarylalkyl, CN, , alkylamino, lamino, NHSOZRlz, NHSOZNHRIZ, NHCORIZ, NHCONHRn, CONHRIZ, CONngaRnb, hydroxy, CF3, SOan, NHSOan, and OCF3.
In another embodiment, compounds of Formula III are ed wherein R1 is phenyl optionally substituted with one or more halo substituents.
In another embodiment, nds of Formula III are provided wherein R5 and R6 are independently chosen from hydrogen, C1-C6 alkyl, C1-C7 cycloalkyl, C1—C7 heterocycloalkyl, and aryl, any of which may be optionally substituted.
In another embodiment, compounds have structural Formula IV: $6 0 N N R5/ / OH R1 N R3 (IV) or a salt, ester, enantiomer or g thereof, wherein: R1 is heteroaryl, which may be optionally substituted with one or more substituents chosen from hydrogen, halo, alkyl, alkenyl, alkynyl, cycloalkyl,haloa]l<y1, aryl, aralkyl, cyclyl, heteroaryl, heterarylalkyl, CN, alkoxy, haloalkoxy, W0 2012I119046 oxo, alkylamino, dialkylamino, NHSOZRIZ, NHSOgNHRlz, NHCORlz, NHCONHRlz, CONHRn, CONngaRlzb, hydroxy, SOlez, and SO’ZNHR12, any of which may be optionally substituted; R3 is hydrogen; R5 and R6 are independently chosen from C1—C6 alkyl, C1—C6 branched alkyl, C1-C7 cycloalkyl, C1-C7 heterocycloalkyl, or taken together, R5 and R6 may form a heterocycloalkyl, any of which may be optionally substituted with one or more of C1—C6 alkyl, alkoxyalkyl, and C1~C5 haloalkyl; and R12, R12a and Rm, are independently chosen from hydrogen, C1-C6 alkyl, aryl, heteroaryl, aralkyl, CF3 and heteroaralkyl, any of which may be optionally substituted.
Further provided is a nd having structural Formula IV, wherein R5 and R5 are independently chosen from C1~C6 alkyl, C1-C6 branched alkyl, and C1-C7 cycloalkyl.
Further provided is a compound as disclosed above for use as a medicament.
Further provided is a compound as disclosed above for use in the cture of a medicament for the prevention or treatment of a e or condition ameliorated by the inhibition of PAS K.
Further provided is a compound as disclosed above for use in the manufacture of a ment for the prevention or treatment of a disease or condition ameliorated by the inhibition of PAS K.
Further provided is a pharmaceutical composition comprising a compound as d above together with a ceutically acceptable carrier. r provided is a method of inhibiting PASK comprising contacting PASK with a compound as disclosed 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 d above n said disease is chosen from cancer and a metabolic disease. r provided is the method as d 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 hyperlipidemia.
Further ed 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 Alc. r 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.
Further provided is a method of treatment of a PASK—mediated disease sing the administration of: a. a therapeutically effective amount of a compound as sed above; and b. another therapeutic agent.
Not to be bound by any theory or ism, the compounds disclosed herein can be used to treat or modulate metabolic e (including but not limited to diabetes, metabolic disorder, dyslipidemia, fatty liver disease, non—alcoholic steatohepatitis, y, and insulin resistance, as well as to reduce triglycerides, terol, and hemoglobin Ale) and cancer.
As used herein, the terms below have the meanings indicated.
When ranges of values are disclosed, and the notation “from n1 to n2” is used, where H1 and 112 are the numbers, then unless otherwise specified, this notation is intended to include the numbers themselves and the range between them. This range may be integral or continuous between and including the end values. By way of example, the range “from 2 to 6 carbons” is intended to include two, three, four, five, and six carbons, since carbons come in r 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 (e.g., 1.255 uM, 2.1 uM, 2.9999 uM, etc).
The term “about,” as used herein, is intended to y 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 ” should be understood to mean that range which PCT/U82012/027423 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.
The term “acyl,” 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 yl is carbon. An “acetyl” group refers to a —C(O)CH3 group. An “alkylcarbonyl” or “alkanoyl” group refers to an alkyl group attached to the parent molecular moiety through a carbonyl group. Examples of such groups include methylcarbonyl and ethylcarbonyl. Examples of acyl groups include formyl, alkanoyl and aroyl.
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 certain embodiments, said alkenyl will se 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- butadienyl and the like. Unless otherwise specified, the term “alkenyl” may include “alkenylene” groups.
The term “alkoxy,” as used herein, alone or in combination, refers to an alkyl ether radical, wherein the term alkyl is as defined below. Examples of le alkyl ether ls e methoxy, ethoxy, n-propoxy, isopropoxy, xy, iso-butoxy, sec-butoxy, tert-butoxy, and the like.
The term “alkyl,” as used herein, alone or in combination, refers to a straight- chain or branched—chain alkyl radical containing from 1 to 20 carbon atoms. In certain ments, said alkyl will comprise from 1 to 10 carbon atoms. In further embodiments, said alkyl will se from I to 6 carbon atoms. Alkyl groups may be ally substituted as defined herein. Examples of alkyl radicals include methyl, ethyl, n—propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, yl, hexyl, octyl, noyl and the like. The term “alkylene,” as used herein, alone or in combination, refers to a saturated aliphatic group d from a straight or branched chain saturated hydrocarbon attached at two or more positions, such as methylene (—CH2—). Unless otherwise specified, the term “alkyl” may include “alkylene” groups.
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 PCT/U82012/027423 groups may be mono- or dialkylated, forming groups such as, for example, N-methylamino, N-ethylamino, N,N—dimethylamino, N,N-ethylmethylamino and the like.
The term “alkylidene,” as used herein, alone or in combination, refers to an alkenyl group in which one carbon atom of the carbon—carbon double bond belongs to the moiety to which the alkenyl group is attached.
The term “alkylthio,” as used , alone or in ation, refers to an alkyl thioether (R—S—) radical wherein the term alkyl is as defined above and n the sulfur may be singly or doubly oxidized. Examples of suitable alkyl thioether radicals include methylthio, ethylthio, n—propylthio, isopropylthio, n—butylthio, iso-butylthio, sec—butylthio, tert-butylthio, methanesulfonyl, ethanesulfinyl, and the like.
The term “alkynyl,” as used herein, alone or in combination, refers to a straight- chain or ed chain arbon radical having one or more triple bonds and ning from 2 to 20 carbon atoms. In certain embodiments, said alkynyl comprises from 2 to 6 carbon atoms. In further embodiments, said alkynyl ses from 2 to 4 carbon atoms.
The term “alkynylene” refers to a carbon—carbon triple bond ed at two positions such as ethynylene (—C:::C—, —CEC—). Examples of alkynyl ls 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 e “alkynylene” .
The terms “amido” and “carbamoyl,” as used herein, alone or in combination, refer to an amino group as described below attached to the parent molecular moiety through a carbonyl group, or Vice versa. The term do” as used herein, alone or in combination, refers to a —C(=O)—NR2 group with R as defined herein. The term “N-amido” as used herein, alone or in combination, refers to a RC(=O)NH- group, with R as defined herein. The term "acylamino" as used , 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—).
The term “amino,” as used herein, alone or in combination, refers to ——NRR’, wherein R and R, are independently chosen from hydrogen, alkyl, acyl, heteroalkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl, any of which may themselves be optionally substituted. onally, R and R’ may combine to form heterocycloalkyl, either of which may be optionally substituted.
The term "aryl," as used herein, alone or in combination, means a carbocyclic aromatic system containing one, two or three rings wherein such polycyclic ring systems are fused together. The term "aryl" embraces aromatic groups such as phenyl, naphthyl, anthracenyl, and phenanthryl.
The term “arylalkenyl” or enyl,” 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 lar moiety through an alkoxy group.
The term lkyl” or “aralkyl,” as used herein, alone or in combination, refers to an aryl group attached to the parent molecular moiety through an alkyl group.
The term “arylalkynyl” or “aralkynyl,” as used , alone or in combination, refers to an aryl group attached to the parent molecular moiety through an alkynyl group.
The term “arylalkanoyl” or “aralkanoyl” or “aroyl,” as used herein, 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 herein, alone or in ation, refers to an aryl group attached to the parent molecular moiety through an oxy.
The terms “benzo” and ” as used , alone or in combination, refer to the divalent radical C6H4= derived from benzene. Examples include benzothiophene and idazole.
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 defined 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.
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 — group, where R is as defined . A “C-carboxy” group refers to a —C(O)OR groups where R is as defined herein.
The term “cyano,” as used , alone or in combination, refers to —CN.
The term “cycloalkyl,” or, alternatively, “carbocycle,” as used herein, alone or in ation, refers to a saturated or partially ted monocyclic, bicyclic or tricyclic alkyl group wherein each cyclic moiety contains from 3 to 12 carbon atom ring members and which may optionally be a benzo fused ring system which is optionally substituted as d 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- lH-indenyl, adamantyl and the like. “Bicyclic” and “tricyclic” as used herein are intended to include both fused ring systems, such as decahydronaphthalene, octahydronaphthalene as well as the multicyclic (multicentered) saturated or partially unsaturated type. The latter type of isomer is exemplified in general by, o[l,l ,l]pentane, camphor, adamantane, and bicyclo[3,2,l]octane.
The term “ester,” as used herein, alone or in combination, refers to a y group bridging two moieties linked at carbon atoms.
The term “ether,” as used herein, 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, e, or iodine.
The term “haloalkoxy,” as used herein, alone or in combination, refers to a haloalkyl group attached to the parent molecular moiety h an oxygen atom.
The term “haloalkyl,” as used herein, alone or in combination, refers to an alkyl radical having the meaning as defined above wherein one or more hydrogens are replaced with a halogen. Specifically ed are loalkyl, dihaloalkyl and polyhaloalkyl radicals. A monohaloalkyl radical, for one e, may have an iodo, bromo, chloro or fluoro atom within the radical. Dihalo and polyhaloalkyl radicals may have two or more of the same halo atoms or a combination of ent halo radicals. Examples of haloalkyl ls include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl.
“Haloalkylene” refers to a haloalkyl group attached at two or more positions. Examples include fluoromethylene (—CFH—), difluoromethylene (—CFz -—), chloromethylene (—CHCl—) and the like.
The term "heteroalkyl," as used , alone or in combination, refers to a stable straight or branched chain hydrocarbon radical, or combinations thereof, fully saturated or PCT/U82012/027423 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 en and sulfur atoms may optionally 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, —CHz—NHwOCH3.
The term "heteroaryl," as used herein, alone or in combination, refers to a 3 to 7 membered unsaturated heteromonocyclic ring, or a fused monocyclic, bicyclic, 0r tricyclic ring system in which at least one of the fused rings is ic, which ns at least one atom chosen from O, S, and N. In certain embodiments, said heteroaryl will comprise from 5 to 7 carbon atoms. The term also embraces fused polycyclic groups wherein heterocyclic rings are fused with aryl rings, wherein heteroaryl rings are fused with other heteroaryl rings, wherein heteroaryl rings are fused with heterocycloalkyl rings, or n heteroaryl rings are fused with cycloalkyl rings. Examples of heteroaryl groups include yl, pyrrolinyl, imidazolyl, lyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, pyranyl, furyl, thienyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, azolyl, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, quinoxalinyl, quinazolinyl, lyl, benzotriazolyl, benzodioxolyl, benzopyranyl, benzoxazolyl, adiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuryl, benzothienyl, chromonyl, coumarinyl, benzopyranyl, tetrahydroquinolinyl, tetrazolopyridazinyl, tetrahydroisoquinolinyl, thienopyridinyl, furopyridinyl, pyrrolopyridinyl and the like. Exemplary tricyclic heterocyclic groups include carbazolyl, benzidolyl, phenanthrolinyl, dibenzofuranyl, acridinyl, thridinyl, xanthenyl and the like.
The terms “heterocycloalkyl” and, hangeably, “heterocycle,” as used , alone or in combination, each refer to a ted, partially unsaturated, or fully unsaturated monocyclic, bicyclic, or tricyclic heterocyclic group containing at least one heteroatom as a ring member, wherein each said heteroatom may be independently 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 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 hetercycloalkyl will comprise from 5 t0 6 ring members in each ring. ocycloalkyl” and “heterocycle” are intended to include sulfones, sulfoxides, N—oxides PCT/U82012/027423 of tertiary nitrogen n'ng 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 heterocycle groups include aziridinyl, azetidinyl, 1,3—benzodioxolyl, dihydroisoindolyl, oisoquinolinyl, dihydrocinnolinyl, dihydrobenzodioxinyl, dihydro[l,3]oxazolo[4,5-b]pyridinyl, benzothiazolyl, dihydroindolyl, dihy—dropyridinyl, l,3~dioxanyl, 1,4—dioxanyl, 1,3— dioxolanyl, isoindolinyl, morpholinyl, piperazinyl, pyrrolidinyl, tetrahydropyridinyl, piperidinyl, thiomorpholinyl, 3,4—methylenedioxyphenyl and the like. The heterocycle groups may be ally 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 ed in a ring.
The term “hydroxy,” as used herein, alone or in combination, refers to ~OH.
The term “hydroxyalkyl,” as used herein, alone or in combination, refers to a hydroxy group attached to the parent molecular moiety through an alkyl group.
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 t contiguous or adjacent chain of carbon atoms starting at the point of attachment of a group to the compounds of any one of the formulas disclosed herein.
The term “isocyanato” refers to a —NCO group.
The term “isothiocyanato” refers to a ~NCS group.
The phrase r chain of atoms” refers to the longest straight chain of atoms independently selected from carbon, nitrogen, oxygen and sulfur.
The term “lower,” as used herein, alone or in a combination, where not otherwise specifically defined, means containing from 1 to and including 6 carbon atoms.
The term “lower aryl,” as used herein, alone or in ation, means phenyl or naphthyl, which may be ally 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) bicyclic heteroaryl, wherein each of the fused rings comprises five or six ring members, sing n them one to four heteroatoms chosen from O, S, and N.
PCT/U52012/027423 The term “lower cycloalkyl,” as used herein, alone or in combination, means a clic cycloalkyl having between three and six ring members. Lower cycloalkyls may be unsaturated. Examples of lower cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
The term “lower cycloalkyl,” 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 morpholinyl. 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 heterocycloalkyl, either of which may be optionally tuted.
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 combination, refers to —N02.
The terms “oxy” or “oxa,” as used herein, alone or in ation, refer to —O—.
The term “oxo,” as used herein, 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 loalkyl” as used herein, alone or in combination, refers to an alkyl group where all of the en atoms are replaced by halogen atoms.
The terms nate,” “sulfonic acid,” and “sulfonic,” as used herein, alone or in combination, refer the —SOgH group and its anion as the ic 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 —.
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/U52012/027423 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.
The term “thiol,” as used herein, alone or in combination, refers to an ~SH group.
The term “thiocarbonyl,” as used herein, when alone includes thiofomiyl —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 defined 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 definition to describe a composite structural group. By convention, the trailing t of any such definition is that which attaches to the parent moiety. For example, the composite group alkylamido would represent an alkyl group attached to the parent molecule through an amido group, and the term alkyl would represent an alkoxy group attached to the parent molecule through an alkyl group.
When a group is defined to be ” 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 nally substituted” group may include, without limitation, one or more substituents independently selected from the following groups or a particular designated set of groups, alone or in combination: lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower heteroalkyl, lower heterocycloalkyl, lower haloalkyl, lower kenyl, lower haloalkynyl, lower perhaloalkyl, lower perhaloalkoxy, lower cycloalkyl, phenyl, aryl, l, aryloxy, lower alkoxy, lower haloalkoxy, 0x0, lower y, carbonyl, carboxyl, lower arbonyl, lower yester, lower carboxamido, cyano, hydrogen, halogen, hydroxy, amino, lower alkylamino, arylamino, amido, nitro, thiol, lower alkylthio, lower haloalkylthio, lower perhaloalkylthio, arylthio, ate, sulfonic acid, trisubstituted silyl, N3, SH, SCH3, C(O)CH3, COgCHg, COZH, nyl, thiophene, furanyl, lower ate, and lower urea. Two substituents may be joined together to form a fused five-, six-, or seven-membered carbocyclic or heterocyclic ring consisting of zero to three atoms, for example forming methylenedioxy or ethylenedioxy. An optionally substituted group may be unsubstituted (e.g., -CH2CH3), fully W0 20122119046 tuted (e. g., —CF2CF3), monosubstituted (e. g., -CH2CH2F) or substituted at a level anywhere in-between fully substituted and monosubstituted (e.g., —CH2CF3). Where substituents are recited without qualification as to substitution, both substituted and unsubstituted fomis are encompassed. Where a substituent is qualified as “substituted,” the substituted form is specifically intended. Additionally, ent sets of optional tuents to a ular moiety may be defined as needed; in these cases, the optional substitution will be as defined, often immediately following the phrase, nally substituted with.” The term R or the term R’, appearing by itself and t a number designation, unless otherwise d, refers to a moiety chosen from hydrogen, alkyl, cycloalkyl, heteroalkyl, aryl, heteroaryl and heterocycloalkyl, any of which may be optionally substituted. Such R and R’ groups should be understood to be optionally substituted as defined herein. r an R group has a number designation or not, every R group, including R, R’ and Rn where n=(l, 2, 3, ...n), every substituent, and every term should be understood to be independent of every other in terms of selection from a group. Should any variable, substituent, or term (e. g. aryl, heterocycle, R, etc.) occur more than one time in a formula or generic structure, its definition at each occurrence is independent of the definition at every other ence. Those of skill in the art will further recognize that certain groups may be attached to a parent molecule or may occupy a position in a chain of elements from either end as written. Thus, by way of example only, an unsymmetrical group such as -C(O)N(R)— may be attached to the parent moiety at either the carbon or the en.
Asymmetric centers exist in the compounds disclosed herein. These centers are designated by the symbols “R” or “S,” depending on the configuration of substituents around the chiral carbon atom. It should be understood that the invention encompasses all stereochemical isomeric forms, including diastereomeric, enantiomeric, and epimeric forms, as well as d-isomers and 1—isomers, and mixtures thereof. Individual stereoisomers of nds can be prepared synthetically from commercially available ng materials which contain chiral centers or by preparation of mixtures of enantiomeric products followed by separation such as sion to a mixture of diastereomers followed by separation or recrystallization, chromatographic ques, direct separation of enantiomers on chiral chromatographic columns, or any other appropriate method known in the art. Starting compounds of particular stereochemistry are either commercially available or can be made and resolved by techniques known in the art. Additionally, the compounds disclosed herein may exist as geometric isomers. The present ion includes all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well as the appropriate mixtures thereof. 2012/027423 Additionally, compounds may exist as tautorners; all tautomeric isomers are provided by this invention. Additionally, the compounds disclosed herein can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like.
In general, the ed 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 may be single, double, or triple unless otherwise specified. A dashed line between two atoms in a drawing of a molecule indicates that an additional bond may be present or absent at that position.
The term “disease” as used herein is ed to be generally synonymous, and is used interchangeably with, the terms “disorder” and “condition” (as in medical condition), in that all reflect an abnormal ion of the human or animal body or of one of its parts that impairs normal functioning, is typically sted 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 eutic agents to treat a therapeutic condition or disorder described in the present disclosure. Such administration asses co-administration of these therapeutic agents in a substantially simultaneous manner, such as in a single capsule having a fixed ratio of active ingredients or in multiple, separate capsules for each active ingredient. In addition, such administration also encompasses use of each type of therapeutic agent in a sequential .
In either case, the treatment regimen will provide beneficial effects of the drug combination in treating the conditions or disorders described herein.
“PASK tor " as used herein refers to a compound that ts an (ICso / ECso) with respect to PASK activity of no more than about 100 uM and more typically not more than about 50 M, as measured in the PASK assay described lly hereinbelow.
IC50 is that concentration of inhibitors which reduces the activity of PASK to half—maximal level. Certain compounds sed herein have been discovered to exhibit inhibition against PASK.
The phrase ”therapeutically effective" is intended to qualify the amount of active ingredients used in the ent 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 those compounds (or salts, prodrugs, tautomers, zwitterionic forms, etc.) which are suitable for use in contact with the PCT/U82012/027423 tissues of patients without undue toxicity, irritation, and allergic response, are commensurate with a reasonable benefit/risk ratio, and are ive for their ed use.
As used , reference to "treatment“ of a patient is intended to include prophylaxis. The term “patient” means all mammals including humans. Examples of patients include , cows, dogs, cats, goats, sheep, pigs, and rabbits. Preferably, the patient is a human.
The term "prodrug" refers to a compound that is made more active in vivo.
Certain compounds disclosed herein may also exist as prodrugs, as described in Hydrolysis in Drug and g Metabolism : Chemistry, Biochemistry, and logy , Bernard and Mayer, Joachim M. Wiley-VHCA, Zurich, Switzerland 2003). Prodrugs of the compounds described herein are structurally modified forms of the compound that readily undergo chemical changes under physiological conditions to e the compound.
Additionally, prodrugs can be converted to the compound by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to a compound when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent. Prodrugs are often useful because, in some situations, they may be easier to administer than the compound, or parent drug. They may, for instance, be bioavailable by oral administration whereas the parent drug is not. The prodrug may also have improved lity in pharmaceutical compositions over the parent drug. A wide variety of prodrug tives 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 g would be a compound which is administered as an ester (the "prodrug"), but then is metabolically hydrolyzed to the carboxylic acid, the active entity. onal examples include peptidyl derivatives of a compound.
The compounds disclosed herein can exist as therapeutically acceptable salts. The present invention includes compounds listed above in the form of salts, including acid addition salts. le salts include those fOrmed with both organic and inorganic acids.
Such acid addition salts will normally be pharmaceutically acceptable. However, salts of non-pharmaceutically acceptable salts may be of utility in the preparation and cation of the nd 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. ch. Wiley—VCHA, Zurich, Switzerland, 2002).
The term “therapeutically acceptable salt,” as used herein, represents salts or zwitterionic forms of the compounds disclosed herein which are water or luble or dispersible and therapeutically able as defined herein. 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.
While it may be possible for the compounds of the t invention to be administered as the raw chemical, it is also possible to present them as a pharmaceutical formulation. Accordingly, provided herein are pharmaceutical formulations which comprise one or more of certain compounds disclosed herein, or one or more pharmaceutically acceptable salts, esters, prodrugs, amides, or solvates thereof, together with one or more pharmaceutically acceptable caniers thereof and optionally one or more other therapeutic ingredients. The cam'er(s) must be ”acceptable" in the sense of being compatible with the other ingredients of the ation and not deleterious to the recipient thereof. Proper formulation is dependent upon the route of administration chosen. Any of the well—known techniques, carriers, and excipients may be used as suitable and as understood in the art; e.g., in ton’s Pharmaceutical Sciences. The pharmaceutical compositions disclosed herein may be manufactured in any manner known in the art, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, ulating, entrapping or compression processes.
The formulations include those suitable for oral, parenteral (including aneous, intradermal, intramuscular, intravenous, intraarticular, and intramedullary), intraperitoneal, ucosal, transdermal, rectal and topical (including dermal, buccal, sublingual and intraocular) administration gh the most suitable route may depend upon for example the condition and disorder of the recipient. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Typically, these methods include the step of bringing into association a compound of the subject ion or a pharmaceutically acceptable salt, ester, amide, prodrug or solvate thereof (”active ingredient”) with the carrier which constitutes one or more accessory ingredients. In l, the formulations are prepared by uniformly and intimately bringing into association the active ient with liquid carriers or finely divided solid rs or both and then, if necessary, shaping the t into the desired ation.
Formulations of the nds disclosed herein suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a in-oil liquid emulsion. The active ingredient may also be presented as a bolus, electuary or paste.
Phamraceutical preparations which can be used orally include tablets, push-fit capsules made of n, as well as soft, sealed capsules made of gelatin and a cizer, such as glycerol or sorbitol. s may be made by compression or molding, optionally with one or more accessory ingredients. ssed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or es, optionally mixed with binders, inert diluents, or lubricating, surface active or dispersing agents. Molded tablets may be made by molding in a le machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ient n. All formulations for oral administration should be in s suitable for such administration. The push—fit capsules can contain the active ingredients in admixture with filler such as e, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added. Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.
The compounds may be ated for parenteral stration by injection, e.g., by bolus injection or uous infusion. Formulations for injection may be presented in unit dosage form, e. g. in ampoules or in multi-dose containers, with an added preservative.
The compositions may take such forms as suspensions, ons or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, izing and/or dispersing agents. The formulations may be presented in unit—dose or multi—dose containers, for example sealed ampoules and vials, and may be stored in powder form or in a freeze- dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, saline or sterile pyrogen-free water, immediately prior to use. Extemporaneous injection ons and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described. toIx.) Formulations for parenteral administration include aqueous and non-aqueous (oily) sterile injection solutions of the active compounds which may contain idants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non—aqueous sterile suspensions which may include suspending agents and thickening agents. Suitable lipophilic solvents or es include fatty oils such as sesame oil, or synthetic fatty acid , such as ethyl oleate or triglycerides, or liposomes. s injection suspensions may n 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 nds to allow for the preparation of highly concentrated solutions.
In addition to the formulations described previously, the nds may also be formulated as a depot preparation. Such long acting formulations may be stered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection.
Thus, for example, the compounds may be formulated with suitable polymeric or hydrophobic als (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for e, as a sparingly soluble salt.
For buccal or sublingual administration, the compositions may take the form of tablets, lozenges, pastilles, or gels formulated in conventional manner. Such compositions may comprise the active ingredient in a flavored basis such as sucrose and acacia or tragacanth.
The compounds may also be ated in rectal compositions such as suppositories or retention enemas, e. g., containing conventional itory 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 es the application of a compound disclosed herein externally to the mis or the buccal cavity and the instillation of such a compound into the ear, eye and nose, such that the compound does not significantly enter the blood stream.
In contrast, systemic administration refers to oral, intravenous, intraperitoneal and intramuscular administration.
Formulations suitable for topical stration include liquid or semi-liquid preparations suitable for ation 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, W0 2012!]19046 PCT/U52012/027423 from 0.001% to 10% w/w (by weight) of the formulation. In certain ments, the active ingredient may se as much as 10% w/w. In other embodiments, it may comprise less than 5% w/w. In n embodiments, the active ingredient may comprise from 2% w/w to % 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 insufflator, nebulizer pressurized packs or other convenient means of delivering an aerosol spray. rized packs may comprise a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon e or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. Alternatively, for administration by inhalation or insufflation, the compounds according to the invention may take the form of a dry powder composition, for example a powder mix of the nd and a suitable powder base such as lactose or starch. The powder composition may be presented in unit dosage form, in for example, es, cartridges, gelatin or blister packs from which the powder may be administered with the aid of an inhalator or insufflator.
Preferred unit dosage formulations are those containing an effective dose, as herein below recited, or an appropriate fraction thereof, of the active ingredient.
It should be understood that in addition to the ingredients particularly ned above, the formulations described 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.
Compounds may be administered orally or Via injection at a dose of from 0.1 to 500 mg/kg per day. The dose range for adult humans is generally from 5 mg to 2 g/day.
Tablets or other forms of presentation ed in discrete units may conveniently contain an amount of one or more compounds which is effective at such dosage or as a multiple of the same, for instance, units containing 5 mg to 500 mg, usually around 10 mg to 200 mg.
The amount of active ingredient that may be combined with the carrier als 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, e.g. orally, topically, or by injection. The precise amount of compound administered to a patient will be the responsibility of the attendant ian. 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 2012/027423 administration, rate of excretion, drug combination, the e 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 appropriate to administer at least one of the nds described herein (or a pharmaceutically acceptable salt, ester, or prodrug thereof) in combination with another therapeutic agent. By way of example only, if one of the side effects enced by a patient upon receiving one of the nds 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 ed by stration of an adjuvant (i.e., by itself the adjuvant may only have minimal eutic t, but in combination with another therapeutic agent, the overall therapeutic benefit to the patient is enhanced). Or, by way of example only, the benefit experienced by a patient may be increased by administering one of the compounds described herein with another eutic agent (which also includes a therapeutic regimen) that also has therapeutic t. By way of example only, in a treatment for diabetes involving administration of one of the compounds described herein, increased therapeutic benefit may result by also providing the patient with another therapeutic agent for diabetes. In any case, regardless of the disease, disorder or condition being treated, the overall benefit experienced by the patient may simply be ve of the two therapeutic agents or the patient may experience a synergistic benefit.
Specific, non—limiting examples of possible combination therapies include use of a nd 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; n secretagogues such as the sulfonylureas, e. g., Glipizide, glyburide and Amaryl; insulinotropic sulfonylurea receptor s such as meglitinides, e. g., nateglinide and repaglinide; insulin sensitizer such as protein tyrosine phosphatase—1B (FTP—1B) inhibitors such as FTP-112; GSK3 (glycogen synthase kinase-3) tors such as SB-517955, SB-4l95052, SB-216763, NN0544l and NN—57-05445; RXR ligands such as GW-079l and AGN—l94204; sodium-dependent glucose co-transporter inhibitors such as T—1095; glycogen phosphorylase A inhibitors such as BAY R3401; biguanides such as metformin; alpha-glucosidase inhibitors such as acarbose; GLP-l (glucagon like peptide-l), GLP-l analogs such as Exendin—4 and GLP—1 mimetics; DPPIV (dipeptidyl peptidase IV) inhibitors such as DPP728, LAF237 gliptin — Example 1 of WO 00/34241), MK—O43l, saxagliptin, PCT/U82012/027423 GSK23A ; an AGE breaker; a thiazolidinedione derivative (glitazone) such as pioglitazone or rosiglitazone; and a non-glitazone type PPAR5 agonist e.g. (ll-262570; b) hypolipidemic agents such as 3-hydroxymethyl-glutaryl coenzyme A (HMG- CoA) reductase inhibitors, e. g., lovastatin, pitavastatin, simvastatin, pravastatin, cerivastatin, mevastatin, velostatin, fluvastatin, dalvastatin, atorvastatin, rosuvastatin and rivastatin; ne se inhibitors; FXR (farnesoid X receptor), PXR (pregnane X receptor) and LXR (liver X receptor) s; cholestyramine; fibrates; nicotinic acid and aspirin; c) an anti-obesity agent or appetite regulating agent such as phentermine, leptin, bromocriptine, dexamphetamine, amphetamine, fenfluramine, dexfenfluramine, sibutramine, orlistat, dexfenfluramine, mazindol, phentermine, phendimetrazine, diethylpropion, ine, bupropion, topiramate, diethylpropion, benzphetamine, phenylpropanolamine or ecopipam, ephedrine, ephedrine or cannabinoid receptor antagonists; d) anti-hypertensive agents, e. g., loop diuretics such as ethacrynic acid, furosemide and torsemide; diuretics such as thiazide derivatives, thiazide, hydrochlorothiazide, amiloride; angiotensin converting enzyme (ACE) inhibitors such as benazepril, captopril, enalapril, fosinopril, lisinopril, ril, perinodopril, quinapril, ramipril and trandolapril; inhibitors of the Na~K-ATPase membrane pump such as digoxin; l endopeptidase (NEP) inhibitors e.g. thiorphan, terteo-thiorphan, SQ29072; ECE inhibitors e.g. SLV306; ACE/NEP inhibitors such as omapatrilat, sampatrilat and tril; angiotensin II antagonists such as artan, eprosartan, irbesartan, losartan, tehnisartan and tan, in particular valsartan; renin inhibitors such as aliskiren, terlakiren, ditekiren, R0 66—1132, RO—66-1168; nergic receptor blockers such as acebutolol, atenolol, betaxolol, bisoprolol, metoprolol, l, propranolol, sotalol and timolol; inotropic agents such as digoxin, dobutamine and milrinone; calcium channel blockers such as amlodipine, bepridil, diltiazem, felodipine, nicardipine, nimodipine, nifedipine, nisoldipine and mil; aldosterone receptor antagonists; and aldosterone synthase inhibitors; 6) an HDL increasing compound; f) cholesterol absorption modulator such as etizimibe and KT6—97l; g) Apo-Al analogues and mimetics; h) thrombin inhibitors such as Ximelagatran; i) aldosterone tors such as anastrazole, ole, and eplerenone; j) inhibitors of platelet aggregation such as aspirin, and clopidogrel bisulfate; PCT/U82012/027423 k) estrogen, testosterone, a selective estrogen receptor 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 ty such as a PDGF receptor tyrosine kinase inhibitor such as miatinib; 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. 5510353 as example 13, rod hydrogen maleate, cisapride, and cilansetron.
In any case, the le therapeutic agents (at least one of which is a compound disclosed herein) may be administered in any order or even simultaneously. If simultaneously, the multiple therapeutic agents may be provided in a single, unified form, or in multiple forms (by way of example only, either as a single pill or as two separate pills).
One of the therapeutic agents may be given in multiple doses, or both may be given as multiple doses. If not simultaneous, the timing between the multiple doses may be any duration of time ranging from a few minutes to four weeks.
Thus, in another aspect, certain embodiments provide methods for treating ediated disorders in a human or animal subject in need of such treatment comprising administering to said subject an amount of a compound disclosed herein effective to reduce or prevent said disorder in the subject, optionally in combination with at least one additional agent that is known in the art. In a related aspect, certain ments provide therapeutic compositions comprising at least one compound disclosed herein in combination with one or more additional agents for the treatment of ediated disorders.
Recent studies have found that elevated medium glucose concentrations caused ranslational 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 te resistance to the ypes caused by a high-fat diet, including obesity, insulin resistance and hepatic fat accumulation. It appears that PASK inhibition can provide an ive therapeutic strategy for the treatment of diseases, for example Type 2 diabetes, insulin resistance in general, and the metabolic syndrome. lic syndrome (also known as metabolic me X) is characterized by having at least three of the following ms: insulin resistance; abdominal fat — in men PCT/U82012/027423 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 (mg/dL) after fasting; high triglycerides — at least 150 mg/dL in the blood stream; 10w HDL— less than 40 mg/dL; pro-thrombotic state (eg. high fibrinogen or nogen activator inhibitor 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 factors for cardiovascular diseases. For example, an increased link n 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 me) in women and te cancer in men.
As described above, insulin resistance can be manifested in several ways, including Type 2 diabetes. Type 2 es is the condition most obviously linked to insulin resistance. Compensatory hyperinsulinemia helps in normal e levels - often for decades, before overt diabetes develops. ally the beta cells of the pancreas are unable to overcome insulin resistance through hypersecretion. 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 disease. As described above, insulin resistance can also ate 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 ated with insulin resistance. The lipid profile of patients with Type 2 diabetes includes sed serum very—low-density lipoprotein terol and triglyceride levels and, sometimes, a decreased low—density lipoprotein terol level. Insulin resistance has been found in persons with low levels of high-density lipoprotein. Increased insulin levels in insulin resistance have also been directly ated with high very—low—density lipoprotein synthesis and increased plasma triglyceride levels.
Accordingly, also disclosed are methods of treating insulin resistance in a subject sing ing a subject in need of treatment for insulin resistance; and administering to the subject an effective amount of a compound that ts PASK.
Specific diseases to be treated by the compounds, compositions, and methods disclosed herein are those mediated at least in part, directly or indirectly, 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 W0 20121119046 lowering blood pressure in a subject; for reducing visceral fat in a subject; for reducing serum transaminases in a t; for reducing hemoglobin A1c in a subject; or for treating disease; all comprising the administration of a therapeutic amount of a compound as described herein, to a patient in need thereof. In further embodiments, the e to be treated may be a metabolic disease. In further embodiments, the metabolic disease may be chosen from: obesity, diabetes melitus, especially Type 2 diabetes, hyperinsulinemia, glucose intolerance, metabolic me X, idemia, hypertriglyceridemia, hypercholesterolemia, and hepatic steatosis. In other embodiments, the disease to be treated may be chosen from: vascular diseases including vascular disease, atherosclerosis, coronary heart disease, cerebrovascular disease, heart failure and peripheral vessel disease. In preferred ments, the methods above do not result in the induction or maintenance of a hypoglycemic state.
In further embodiments, the metabolic e may be a neurological e known to be associated with metabolic disease and/or insulin resistance, such as Alzheimer’s disease.
Additionally, the PASK modulators sed herein may be used to treat erative disorders such as cancers. Hematological and non-hematological cancers which may be treated or prevented include but are not limited to le myeloma, acute and chronic leukemias including Acute cytic Leukemia (ALL), c Lymphocytic Leukemia (CLL), and Chronic enous Leukemia (CLL), lymphomas, ing Hodgkin’s lymphoma and non—Hodgkin’s lymphoma (low, intermediate, and high grade), malignancies of the brain, head and neck, breast, lung, reproductive tract, upper digestive tract, pancreas, liver, renal, bladder, prostate and colon/rectum.
Besides being useful for human treatment, certain compounds and ations disclosed herein may also be useful for veterinary treatment of companion animals, exotic animals and farm animals, including mammals, rodents, and the like. More preferred animals include horses, dogs, and cats.
References Cited This application incorporates by reference United States Non—Provisional Application No. 12/874,967, filed September 2, 2010, the disclosure of which is hereby incorporated by reference as if written herein in its entirety. The following is a list of references cited herein which, while not necessarily comprehensive, is provided for the convenience of the reader. All references, patents, and patent applications cited herein are WO 19046 hereby incorporated by reference as if written herein in their entireties. When the teachings of these references contradict the teachings presented expressly herein, the present disclosure controls.
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W0 19046 PCT/U82012/027423 General tic s for Preparing nds The following schemes can generally be used to practice the present invention.
Scheme I F/gim SOCI NHZHCI o N2 F/(jko/ Ph)\n/O\ O MeOH DIEA DMF ”Ar“ Fe/NH4CI PBrOa MeOH Ozfiko/ dioxaQne O:]©)\O/ MeCN Br /Nfio/ Step 1. S nthesis of meth l 4-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, 54.05 mmol, 1.00 equiv) in a 250-mL round—bottom flask, then stirred for 3 hr at reflux in an oil bath. The resulting e 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 soiution was then extracted with 6x50 mL of ethyl acetate, the organic layers combined and dried over anhydrous sodium sulfate, and concentrated under vacuum, affording 12.42 g (crude) of methyl 4—fluoro-3—nitrobenzoate as a white solid.
WO 19046 PCT/U82012/027423 Step 2. Synthesis of methyl ethoxy-2—oxo—lphenylethylamino)—3-nitrobenzoate. A solution of methyl o-2—phenylacetate hydrochloride (2.5 g, 12.38 mmol, 1.00 equiv) in DMF (30 mL), methyl 4—fluoronitrobenzoate (5 g, 25.13 mmol, 2.00 equiv), and DIEA (5 g, 38.76 mmol, 3.13 equiv) was reacted overnight at 30°C in a 100-mL round-bottom flask.
The reaction was then quenched by the addition of 200 mL of water, and the solids were collected by tion. Purification via silica gel column (petroleum ether iEtOAc (50:1)) yielded 3.82 g (90%) of methyl 4-(2-methoxyoxo-l-pheny1ethylamino)nitrobenzoate as a yellow solid. LC-MS (ES, m/z): 345 [M+H]+.
Step 3. Synthesis of methyl 3-oxo-2—phenyl-1,2,3,4-tetrahydroguinoxaline—6-carboxylate.
Iron (34.89 g, 623.04 mmol, 5.00 equiv) was added portionwise to a stirred solution of methyl 4—(2—methoxyoxopheny1ethy1amino)~3-nitrobenzoate (42.87 g, 124.62 mmol, 1.00 equiv) and s 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 cooling, the solids were filtered out. The resulting filtrate was concentrated under vacuum, affording 19.81 g (56%) of methyl 3-oxophenyl-1,2,3,4—tetrahydroquinoxa1inecarboxylate as a yellow solid. LC- MS (ES, m/z): 283 [M+H]+.
Step 4. Synthesis of methyl 3-oxophenyl-3,4—dihydroguinoxalinecarboxylate. DDQ (21.25 g, 93.6 mmol, 2.62 equiv) was added to a stirred solution of methyl 3-oxophenyl- 1,2,3,4—tetrahydroquinoxaline—6—carboxylate (10.07 g, 35.7 mmol, 1.00 equiv) in dioxane (750 mL) and allowed to react, with ng, 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 3-oxo-2—pheny1—3,4—dihydroquinoxaline- 6~carboxylate as an off-white solid. LC—MS (ES, m/z): 281 [M+H]+.
Step 5. Synthesis of methyl 3~bromo-2—pheny1guinoxalinecarboxylate. A solution of methyl 3-oxo—2—pheny1—3,4-dihydroquinoxalinecarboxylate (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-bromophenquuinoxalinecarboxylate as a white solid. LC-MS (ES, Iii/2,): 343 [M+H]+. 1H-NMR (300 MHz, DMSO-dg) 8.6208615 (d, J=1.5Hz, 1H), .35 (q, J=3.3Hz, 1H), 8.28-8.25 (d, J=8.7Hz, 1H), .82 (q, J=6Hz, 2H), 7.60-7.58 (t, J=2.4Hz, 3H), 3.99 (s, 3H).
W0 2012/119046 PCT/U82012/027423 Scheme II HoflF F PMBNHZ. NHPMB SOC|2.MeOH O7(©[ DlEA,DMF 07? N02 / reflux, 3h N02 / N02 0 O O NHPMB Pd/C,H2,MeOH 30HH03 rt, 0'5h 0 reflux 3h Poor3 NN——dimethylanaline ClDIN conc) CIINHjij/KOCH3 rt, 10mins toluene, reflux Scheme III 0 Rl‘N’R‘? F31 o DIEA,DMSO 0 u O 100°C,overnight u Tf20, Py Ra’NIN Ar——B(OH)2 DCM,0°C, 3h TfO N Pd(PPh3)4,K3PO4,dioxane 90°C1h R21,NN NaOH,H20,MeOHRZ’NI/NN]£>/1LOI-lR1rt, overnight Scheme IV NHzHCI o O 0\ OH 0 OZNDAO F e F DIEA, DMF o\ Noz N02 O O H H O Nfio/ O N / CI DDQ \ fio pBI—Q3 MeOH g dloxane N W R1 R1 or P0013 x= Cl Br R1 e.g.--F Scheme V B“ N\ COORS HNRsRe NRBRS N\ COOR3 R2 N I I) R2 N/ NaOH NR6R5I|::: ,COOH Scheme VI R1 N\ COORS HNRsRe R1 | 11>N\ COOR3 Br N R6R5N N NaOH ——_—>R5R5NI:Ijm W0 2012/119046 PCT/U82012/027423 wherein R1 and R2 are each independently chosen from alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and amino any of which may be optionally substituted; and R3 is chosen from hydrogen and optionally substituted alkyl.
Scheme VII F NHPMB PMBNH2,DIEA,DMF Pd/C,H2,MeOH /o —-———> o ———> N02 rt, 3h N02 rt,o.5h EOJKH/Nora NHPMB /oflNH2 O reflux 3h ZIZULO 0 PMB POClg,N,N-dimethy|ana|ine Cl /NI>)LO/__+“280’“ch_____>C;INNjgio/ toluene,reflux, ght I rt, 10mins 0 N Y“\ Y/N Pool3 /N N -————-—* /N::/U\O/ ———+ / : JLO/ DMSO reflux,overnight 0 I 70°C, 7h fl Cl ‘N Scheme VIII 0‘“ ° :INBn DMSO NINfiO/ L03, 0m” DCM 0 N fl én o" 0 o" 0 N ,N 0/ SOCI2,DMF N 1 J;/N 0/ Tot. o N Cl N 2012/027423 Scheme IX 31 O HET B(OH)2 , Pd(PPh3)4 , K3PO4 Rz/ / 0/ ’ \ K3PO4 dloxane.
Cl N 31 0 0 $1 ,N N NaOH aq, / RZ/N /N 1’ j; OH R2 O MeOH HET = heterocycie Scheme X R1\:R2$1R2 o DIEA,DMSO 0 100°C,overnight u szo Py 31 ”JiltZINDCM,,0°C 3h NUOLO/______’HET-B(OH)2 Pd(PPh3)4,K3PO4,dioxane 90°C,1 h IfiNaOH,H20,MeOH rt, overnight IDA HET = heterocycle The invention is further illustrated by the following examples, which can be made by the methods bed herein or by one skilled in the art without undue experimentation, or can be sed from commercial sources. Throughout the experimental protocols, the PCT/U82012/027423 ing abbreviations may be used. The list below is provided for convenience and is not intended to be inclusive.
Ar Aryl Pdg(dba)3 Tris(dibenzylideneacetone)dipalladium(0) BINAP 2,2'-bis(diphenylphosphino)-l,1'—binaphthyl —J NaOt—Bu Sodium t—Butoxide PB Petroleum Ether EA Ethyl e DCM Dichloromethane TFA Trifluoroacetic Acid AcOH Acetic Acid DMF N,N—Dimethy1formamide DIEA N,N—Diisopropylethylamine MeOH Methanol THF Tetrahydrofuran BOC N-t-butoxycarbonyl To] Toluene DMSO Dimethyl Sulfoxide PCy3 lohexylphosphine TLC Thin Layer Chromatography 2-Dicyclohexylphosphino-2’,4',6’- triisopropylbiphenyl DDQ 2,3—dichloro—5,6-dicyanobenzoquinone EXAMPLE 1 2-(Benzofuranyl)(isopropyl(methyl)amino)quinoxalinecarboxylic acid Y o /N /ND)}\OH Step 1. Methyl 2—(benzofuranyl)(isopropyl(methyl)amino)quinoxalinecarb0xylate Y o ,N / To a on of methyl 2—chloro(isopropy1(methyl)amino)quinoxaline-6—carboxy1ate (Scheme I, 150 mg, 0.51 mmol) in 1,4—dioxane (3 mL) was added 2—(benzofuranyl)— 4,4,5,5—tetramethyl-l,3,2—dioxaborolane (312 mg, 1.28 mmol), K3PO4 (326 mg, 1.53 mmol), Pd(PPh3)4 (30 mg, 0.03mmol) and water (3 drops). After stirring 40 min at 95°C under nitrogen atmosphere, the reaction mixture was dissolved in water (10 mL), ted with dichloromethane (3 x 30 mL), dried over anhydrous magnesium sulfate and concentrated under reduced re to afford a residue, which was purified by a silica gel column with 1% ethyl acetate in petroleum ether to afford methyl 2~(benzofuran-3—y1)—3— (isopropyl(methyl)amino)quinoxalinecarboxylate as a light yellow solid (110 mg, 57%).
LC/MS: (ES, m/z): [M+H]+ 376.0 1H—NMR (300 MHZ, DMSO) 5 8.75 (s, 1H), 8.25 - 8.31 (m, 2H), 7.98 - 8.06 (m, 2H), 7.72 - 7.75 (m, 1H), 7.41 - 7.46 (m, 2H), 4.24 - 4.28 (t, J = 6.6 Hz, 1H), 3.93 (s, 3H), 2.76 (s, 3H), 1.09 (d, J = 6.6 Hz, 6H) Step 2. 2—(Benzofuran—3—yl)—3-(isopropyl(methyl)amino)quinoxalinecarboxylic acid Y o /N /N]©)‘\OH To a solution of methyl zofuran—3-yl)—3-(isopropyl(methyl)amino)quinoxaline-6— carboxylate (100 mg, 0.27 mmol) in tetrahydrofuran (20 mL) and water (1 mL) was added sodium hydroxide (105 mg, 2.62 mmol). After stirring overnight at room temperature, the reaction mixture was concentrated under reduced pressure to afford a residue, which was dissolved in water (10 mL), the pH was adjusted to 6 with HCl (3N) and filtered to give 2- (benzofuranyl)(isopropy1(methyl)amino)quinoxalinecarboxylic acid as a light yellow solid (35.7 mg, 37%).
LC/MS (ES, m/z): [M+H]+ 362.0 PCT/U82012/027423 1H—NMR (300 MHZ, DMSO) 6 8.75 (s, 1H), 8.25 - 8.28 (t, J: 4.2 Hz, 2H), 8.00 (d, J = 7.2 Hz, 2H), 7.72 — 7.75 (t, J: 4.5 Hz, 1H), 7.41 — 7.46 (m, 2H), 4.17 - 4.23 (t, J = 6.6 Hz, 1H), 2.76 (s, 3H), 1.08 (d, J = 6.6 Hz, 6H) EXAMPLE 2 3-(Isopropyl(methyl)amino)—2—(1H-pyrazolyl)quinoxalinecarboxylic acid Y O HN@I“ Step 1. Methyl 3-(isopropy1(methyl)amino)(1H—pyrazol—4—yl)quinoxaline-6—carboxylate Y O H‘N“9/1” To a solution of methyl 2-chloro(isopropyl(methyl)amino)quinoxalinecarboxylate (Scheme 1, 200.0 mg, 0.68 mmol) in dioxane (3 mL) was added lH—pyrazol-4—ylboronic acid (172.0 mg, 1.54 mmol), K3PO4 (326.0 mg, 1.54 mmol), 3)4 (29.6 mg, 0.03 mmol) and 3 drops water. The resulting solution was d for 20 min at 90°C with an inert atmosphere of nitrogen and then diluted with water (20 mL), extracted with dichloromethane (4 x 20 mL), dried over anhydrous magnesium sulfate and concentrated under vacuum. The residue was d by a silica gel column with 2% - 10% ethyl acetate in petroleum ether to afford methyl 3-(isopropyl(methyl)amino)—2-(lH—pyrazolyl)quinoxaline~6~carboxylate as a yellow solid (130 mg, 58.6%).
LC/MS (ES, m/z): [M+H]Jr 326.0 1H—NMR (300 MHZ, DMSO), 5 13.2 (s, 1H) — 7.99 (m, 2H), , 8.26 (d, J: 1.5 Hz, 3H), 7.69 4.14 - 4.23 (m, 1H), 3.92 (s, 3H), 2.76 (s, 3H), 1.12 (d, J = 6.6 HZ, 2H) PCT/U82012/027423 Step 2. 3—(Isopropyl(methyl)amino)-2—(1H-pyrazol-4—y1)quinoxalinecarboxylic acid Y O /N /N OH N/ N To a solution of methyl 3~(isopropyl(methy1)amino)(1H-pyraz01—4-y1)quinoxaline carboxylate (130.0 mg, 0.40 mmol,) in methanol (20 mL) and water (1 mL) was added lithium hydroxide hydrate (50.0 mg, 1.12 mmol). The ing solution was stirred overnight at room temperature and then concentrated under vacuum. The residue was diluted with water (10 mL) and ed to pH 5 with citric acid (IN). The product were collected by filtration to afford 3-(isopropy1(methyl)amino)(1H—pyrazolyl)quinoxaline—6—carboxylic acid as yellow solid (64.7mg, 52%).
LC/MS (ES, m/z): [M+H]+ 312.0 1H—NMR (300 MHZ, DMSO), 13.2 (s, 1H) — 8.28 , 8.25 (t, J: 1.8 Hz, 3H), 7.96 — 7.99 (m, 1H), 7.87 (d, J: 8.7 Hz, 1H), 4.11 — 4.20 (m, 1H), 2.76 (s, 3H), 1.11 (d, J = 6.6 Hz, 2H).
EXAMPLE 3 3-(Isopr0pyl(methyl)amin0)(6-methoxypyridin-S-yl)quinoxaline—6-carboxylic acid Y 0 til“ \0 N/ Step 1. Methyl 3—(isopropyl(methyl)amino)(6-methoxypyridin~3~y1)quinoxaline-6— carboxylate Y O \ \N \ON/ PCT/U82012/027423 To a solution of methyl ro(isopropyl(methyl)amino)quinoxalinecarboxylate (Scheme I, 120 mg, 0.41 mmol) in dioxane (3 mL) was added K3PO4 (257 mg, 1.22 mmol), 6-methoxypyridinylboronic acid (187 mg, 1.22 mmol) and Pd(PPh3)4 (23.54 mg, 0.02 mmol) with stirring for 1 h at 90°C in an oil bath with an inert atmosphere of nitrogen. The reaction mixture was concentrated under vacuum to get a residue, which was purified by a silica gel column with 1% - 2% ethyl acetate in petroleum ether to afford methyl 3- (isopropyl(methyl)amin0)(6-methoxypyridinyl)quinoxalinecarboxylate as a light yellow solid (120 mg, 80%). 1H NMR (300 MHz,DMSO)513.01 (m, 1H), 8.27 (t, J: 1.2 Hz, 1H), 8.18 - 8.21 (m, 1H), 7.96 (m, 2H), 6.97 — 7.01 (m, 2H), 4.17 - 4.26 (m, 1H), 3.92 (t, 6H), 2.68 (s, 3H), 1.08 (d, J = 6.60 Hz, 6H) Step 2. 3-(Isopropy1(methyl)amino)~2~(6-methoxypyridin—3—yl)quinoxaline-6—carboxylic acid Y O /N fifiw 11/71” \0 N/ To a solution of methyl 3—(isopropyl(methyl)amino)—2-(6-methoxypyridinyl)quinoxaline- 6-carboxylate (140 mg, 0.38 mmol) in methanol (25 mL) was added sodium hydroxide (45.9 mg, 1.15 mmol) with stirring overnight at room temperature. The on e was concentrated under vacuum, dissolved in water (30 mL) and adjusted to pH 6 with HCl (3N).
The product were collected by ion to afford 3-(isopropyl(methyl)amino)(6— methoxypyridin—3—yl)quinoxaline—6—carboxylic acid as a light yellow solid (105 mg, 78%).
LC/MS (ES, m/z): [M+H]+ 352.0 1H-NMR (300 MHz, DMSO) 5 13.15 (s, 1H), 8.70 (d, J: 1.8 Hz, 1H), 8.18 - 8.27 (m, 2H), 7.95 (d, J: 1.20 Hz, 2H), 6.97 - 7.00 (m, 1H), 4.19 (m, 1H), 3.94 (s, 3H), 2.69 (s, 3H), 1.08 (d, J = 6.60 Hz, 6H) EXAMPLE 4 2-(1H-Indazolyl)(isopropyl(methyl)amino)quin0xalinecarboxylic acid Y O /N /N OH . H \ 4’)d Step 1. Methyl 2—(lH—indazol-6—yl)-3—(isopropyl(methyl)amino)quinoxaline-6—carboxylate To a solution of methyl 2—chloro—3—(isopropyl(methyl)amino)quinoxalinecarboxylate (Scheme 1, 200.0 mg, 0.68 mmol) in 1,4-dioxane (1 mL) was added 1H—indazol—6—ylboronic acid (386.0 mg, 2.38 mmol), K3PO4 (434.0 mg, 2.05 mmol), Pd(PPh3)4 (39.0 mg, 0.03 mmol) under nitrogen atmosphere. After stirring 20 min at 90°C, the reaction mixture was dissolved in dichloromethane (30 mL), washed with water (3 X 20 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure to afford a residue, which was purified by a silica gel column with 1% - 10% ethyl e in petroleum ether to afford methyl 2—(1H—indazolyl)(isopropy1(methyl)amino)quinoxaline-6—carb0xylate as a light yellow solid (200 mg, 78%).
LC/MS (ES, m/z): [M+H]+ 376.0 1H-NMR (300 MHZ, CDC13) 5 8.55 (S, 1H), 8.17 (s, 1H), 8.05 - 8.10 (m, 2H), 7.99 (d, J = 8.4 Hz, 1H), 7.87 (d, J: 8.4 Hz, 1H), 7.70 (d, J = 8.4 Hz, 1H), 7.48 — 7.65 (m, 1H), 4.27 — 4.31 (t, J: 6.6 Hz, 1H), 4.01 (s, 3H), 2.77 (s, 3H), 1.08 (d, J = 6.6 Hz, 6H) Step 2. 2—(1H—Indazol—6—yl)—3-(isopropyl(methy1)amino)quinoxaline—6—carboxylic acid Y O /N /N OH H \ To a on of methyl 2—(1H—indazol—6—yl)~3-(isopropyl(niethyl)amino)quinoxaline-6— carboxylate (195.0 mg, 0.52 mmol) in tetrahydrofuran (20 mL) was added LiOH‘HzO (25.0 mg, 1.04 mmol) and water (1 mL). After stirring overnight at room temperature, the reaction mixture was concentrated under d pressure to afford a residue, which was ved in water (30 mL) and adjusted to pH 6 with hydrochloric acid (3N) and filtered to give 2—(1H— indazol-6—yl)(isopropyl(methyl)amino)quinoxaline-6—carboxylic acid as a light yellow solid (121.5 mg, 65%).
LC/MS(ES, m/z): [M+H]+ 362.0 1H-NMR (300 MHz, DMSO) 5 13.23 (s, 1H), 8.28 (s, 1H), 8.16 (d, J = 0.6 Hz, 1H), 8.05 (d, J = 0.6 Hz, 1H), 7.89 - 7.99 (m, 3H), 7.57 - 7.62 (m, 1H), 4.17 - 4.22 (t, J: 6.8 Hz, 1H), 2.69 (s, 3H), 1.01 (d, J: 6.6 Hz, 6H) EXAMPLE 5 3-(Isopropyl(methyl)amino)—2—(l-methyl-IH—indazolyl)quinoxalinecarboxylic acid Y O N'N \N Step 1. Methyl 3-(isopropy1(methyl)amino)-2—(l-methyl-JH—indazolyl)quinoxaline—6- carboxylate Y O N'N \N To a solution of methyl 2-chloro-3—(isopropyl(methyl)amino)quinoxalinecarboxylate (Scheme 1, 180.0 mg, 0.61 mmol) in e (1 ml.) was added l-methyl-IH-indazol ylboronic acid (276.0 mg, 1.57 mmol), K3PO4 (391.2 mg, 1.85 mmol), and 3)4 (35.0 mg, 0.03 mmol) under nitrogen here. After stirring 20 min at 90°C, the reaction mixture was dissolved in dichloromethane (30 mL), washed with water (3 X 20 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure to afford a residue, which was purified by a silica gel column with 0.05% - 0.2% ethyl acetate in petroleum ether to afford methyl 3-(isopropyl(methyl)an1ino)—2—(1—methyl-JH—indazol—6- yl)quinoxaline—6—carboxylate as a light yellow solid (70 mg, 29%).
LC/MS (ES, m/z): [M+H]+ 390.0 1H—NMR (300 MHZ, CDC13)5 8.55 (d, J = 2.4 HZ, 1H), 7.99 - 8.09 (m, 4H), 7.82 — 7.85 (m, 1H), 7.65 - 7.68 (m, 1H), 4.25 - 4.32 (m, 1H), 4.18 (S, 3H), 4.01 (S, 3H), 2.77 (S, 3H), 1.08 (d, J: 6.6 Hz, 6H) W0 2012/119046 Step 2. 3-(Isopropyl(n1ethy1)amino)(1-methyl-1H—indazolyl)quinoxa1inecarboxylic acid Y O /N /NfiOH N’N \N To a solution of methyl 3—(isopropyl(methyl)amino)—2~(1-methyl-]H—indazol y1)quinoxaline-6—carboxylate (70 mg, 0.18 mmol) in tetrahydrofuran (20 mL) was added LiOH'HZO (9.0 mg, 0.36 mmol) and water (1 mL). After stirring overnight at room temperature, the reaction mixture was concentrated under reduced pressure to afford a residue, which was dissolved in water (30 mL), adjusted the pH to 6 with hloric acid (3N), and ed to give 3—(isopropyl(methy1)amino)(1-methyl~]H—indazol—6- yl)quinoxa1ine-6—carboxy1ic acid as a light yellow solid (20.5 mg, 30%).
LC/MS (ES, m/z): [M+H]+ 376.0 1H—NMR (300 MHZ, DMSO) 5 13.20 (s, 1H), 8.28 (s, 1H), 8.20 (d, J: 2.1 Hz, 2H), 7.88 - 7.99 (m, 2H), 7.59 (d, J = 9.6 Hz, 1H), 4.18 — 4.27 (m, 1H), 4.12 (s, 3H), 2.68 (s, 3H), 1.01 (d, J: 6.6 Hz, 6H) EXAMPLE 6 3—(Isopropyl(methyl)amino)(5-methoxy—IH-indolyl)quinoxalinecarb0xylic acid Y O \ N Step 1. Methyl 2-(1-(tert-butoxycarbony1)~5-methoxy-1H—indol~2—yl)—3- (isopropyl(n1ethyl)amino)quinoxalinecarboxylate Y O ffi/ZC\\ N To a on of methyl 2—chloro(isopropyl(methyl)amino)quinoxalinecarboxylate (200.0 mg, 0.68 mmol) in 1,4—dioxane (1 mL) was added t-butoxycarbonyl)—5-methoxy- JH-indolylboronic acid (320.0 mg, 1.40 mmol), K3PO4 (440.0 mg, 2.08 mmol), Pd(PPh3)4 (40.0 mg, 0.03 mmol) under nitrogen atmosphere. After stirring 1 h at 90°C, the reaction mixture was dissolved in dichloromethane (50 mL), washed with water (3 x 20 mL), dried over anhydrous magnesium sulfate and trated under reduced pressure to afford a residue, which was ed by a silica gel column with 0.1% — 1% ethyl acetate in petroleum ether to afford methyl 2—(1~(tert~butoxycarbonyl)—5-methoxy~1H-indol-2—yl)-3— (isopropyl(n1ethy1)amino)quinoxaline—6—carboxylate as a light yellow solid (280.0 mg, 81%).
LC/MS (ES, m/z): [M+H]+ 505.1 1H-NMR (300 MHZ, CDC13) 5 8.61 (d, J = 1.5 Hz, 1H), 8.05 — 8.13 (m, 2H), 7.95 (d, J: 8.4 Hz, 1H), 7.01 — 7.10 (m, 2H), 6.94 (s, 1H), 4.21 - 4.25 (t, J: 6.6 Hz, 1H), 4.01 (s, 3H), 3.90 (s, 3H), 2.82 (s, 3H), 1.28 (d, J: 7.5 Hz, 9H), 1.07 (d, J = 6.6 Hz, 6H) Step 2. Methyl 3-(isopropyl(methyl)amino)~2-(5-methoxy-]H—indol—2-yl)quinoxaline carboxylate Y O \ N /02$; A solution of methyl 2—(1—(tert—butoxycarbonyl)methoxy—]H—indol-2~yl)—3- (isopropyl(methyl) amino) quinoxaline—6-carboxylate (180.0 mg, 0.36 mmol) in 20% M (30 mL) was stirred overnight at room temperature and then quenched by the addition of water (100ml). The reaction mixture was adjusted to pH 7 with aq. sodium bicarbonate, extracted with chloroform, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by a silica gel column with 0. l % - 1% methanol in dichloromethane to afford methyl 3-(isopropyl(methyl)amino)—2—(5- methoxy-IH-indoly1)quinoxaline—6—carboxylate as a light yellow solid (100.0 mg, 69%).
LC/MS (ES, m/z): [M+H]+ 405.0 1H-NMR (300 MHz, DMSO) 5 11.64 (s, 1H), 8.29 (d, J = 1.2 Hz, 1H), 7.96 - 8.03 (m, 2H), 7.41 (d, J: 8.7 Hz, 1H), 7.24 (d, J: 8.7 Hz, 1H), 7.14 (d, J = 8.7 Hz, 1H), 6.85 - 6.88 (m, PCT/U82012/027423 1H), 4.28 - 4.33 (t, J = 6.8 Hz, 1H), 3.93 (s, 3H), 3.78 (s, 3H), 2.85 (s, 3H), 1.16 (d, J: 6.6 Hz, 6H) Step 3. 3-(Isopropy1(methyl)amino)—2-(5-methoxy-IH-indol—2-y1)quinoxalinecarboxylic acid Y O \ N To a solution of methyl 3-(isopropyl(methyl)amino)(5-methoxy~1H—indol yl)quinoxaline—6—carboxylate (100.0 mg, 0.25 mmol) in ol (30 mL) was added sodium hydroxide (20.0 mg, 0.50 mmol) in water (1 mL) and stirred overnight at room temperature.
The reaction mixture was concentrated under vacuum and ved in water (10 mL), adjusted to pH 6 with hydrochloric acid (3N). The solid was precipitated and filtered to afford 3—(isopropyl(methyl)amin0)—2-(5~methoxy—]H—indol~2—yl)quinoxaline—6—carboxylic acid as a light yellow solid as a light yellow solid (23.5 mg, 24%).
LC/MS (ES, m/z): [M+H]+ 391.0 1H-NMR (300 MHZ, DMSO) 8 11.55 (s, 1H), 8.25 (s 1H), 8.04 (d, J: 8.7 Hz, 1H), 7.84 (d, J = 7.5 Hz, 1H), 7.41 (d, J: 8.7 Hz, 1H), 7.23 (s, 1H), 7.13 (d, J: 1.8 Hz, 1H), 6.82 - 6.86 (m, 1H), 4.16 - 4.23 (m, 1H), 3.77 (s, 3H), 2.83 (s, 3H), 1.14 (d, J: 6.6 Hz, 6H) EXAMPLE 7 2-(5-Br0m0pyridin—3-yl)(isopr0pyl(methyl)amino)quinoxaline-G-carboxylic acid Y O Br\(fiI\N/ND/kmI , Step 1. Methyl 2-(5-bromopyridiny1)~3~(isopropyl(methyl)amino)quinoxaline carboxylate \ \N To a solution of 5—bromopyridinylboronic acid (288.0 mg, 1.43 mmol) in e (5 mL) was added methyl 2—chloro—3—(isopropyl(methyl)amino)quinoxalinecarboxylate (Scheme I, 140.0 mg, 0.48 mmol), K3PO4 (302.0 mg, 1.43 mmol), Pd(PPh3)4 (27.6 mg, 0.02 mmol) and three drops water. The reaction mixture was stirred for 1h at 90°C with an inert atmosphere of nitrogen and then concentrated under vacuum to give a residue, which was purified by a silica gel column with 1% ethyl e in petroleum ether to afford methyl 2-(5-bromopyridin y1)-3—(isopropyl(methyl)amino)quinoxalinecarboxylate(150.0 mg, 72%) as a light yellow solid.
LC/MS (ES, m/z): [M+H]+ 414.9 1H-NMR (300 MHz, DMSO) 5 9.02 (d, J: 1.8 Hz, 1H), 8.85 (d, J: 2.1 Hz, 1H), 8.50 ~ 8.51 (t, J = 2.1Hz, 1H), 8.31 (d, J: 1.50 Hz, 1H), 7.96 - 8.05 (m, 2H), 4.07 — 4.06 (m, 1H), 3.94 (s, 3H), 2.69 (s, 3H), 1.04 (d, J = 6.60 Hz, 6H) Step 2. 2—(5—Bromopyridinyl)-3—(isopropyl(methyl)amino)quinoxalinecarboxylic acid Y o /N /NfiOH To a solution of methyl 2—(5-bromopyridin-3—yl)—3—(isopropyl(methyl)amino)quinoxaline carboxylate (150.0 mg, 0.36 mmol) in methanol (30 mL) was added sodium hydroxide (43 mg, 1.08 mmol) and water (1 mL) The reaction e was stirred overnight at room temperature and trated under vacuum. The residue was dissolved in water (30 mL) and adjusted to PH 5 with HCl (3 N). The product were collected by filtration to afford 2-(5— bromopyridin—3—yl)(isopropyl(methyl)amino)quinoxaline—6—carboxylic acid as a light yellow solid (120.0 mg, 80%).
LC/MS (ES, m/z): [M+H]Jr 400.9 1H~NMR (300 MHz, DMSO) 8 13.24 (s, 1H), 9.02 (d, J: 1.8 Hz, 1H), 8.84 (d, J = 2.1 Hz, 1H), 8.51 - 8.52 (t, J = 2.1 Hz, 1H), 8.28 (d, J = 0.50 Hz, 1H), 7.96 — 8.03 (m, 2H), 4.02 - 4.11 (m, 1H), 2.70 (s, 3H), 1.20 (d, J: 6.6 Hz, 6H) WO 19046 EXAMPLE 8 2-(lH-Indazol-S-yl)(isopropyl(methyl)amino)quinoxalinecarboxylic acid Y O /N /N OH Step 1. Methyl 2—(1H—indazolyl)—3 —(isopropyl(methyl)amino)quinoxaline—6-carboxylate Y O / /N O/ To a solution of methyl ro(isopropyl(methyl)amino)quinoxalinecarboxylate (Scheme I, 200.0 mg, 0.68 mmol) in 1,4-dioxane (1 mL), was added 1H—indazolylboronic acid (386.0 mg, 2.38 mmol), K3PO4 (434.0 mg, 2.05 mmol), Pd(PPh3)4 (39.0 mg, 0.03 mmol) under nitrogen atmosphere and water (3 drops). After stirring for 20 min at 90°C, the reaction mixture was dissolved in water (30 mL), extracted with dichloromethane (3 x 20 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure to afford a residue, which was purified by a silica gel column with 2% - 10% ethyl acetate in eum ether to afford methyl 2—(1H—indazol-S-yl)—3-(isopropyl(methyl)amino)quinoxaline carboxylate as a light yellow solid (110.0 mg, 45%).
LC/MS (ES, m/z): [M+H]+ 376.0 1H-NMR (300 MHZ, DMSO) 5 13.27 (s, 1H), 8.29 (d, J: 9.6 Hz, 2H), 8.22 (s, 1H), 7.86 - 7.99 (m, 3H), 7.67 (d, J = 8.7 Hz, 1H), 4.19 - 4.23 (t, J: 6.6 Hz, 1H), 3.93 (s, 3H), 2.70 (s, 3H), 1.01 (d, J: 6.6 Hz, 6H) Step 2. 2-(1H—Indazol—S-yl)-3—(isopropyl(methyl)amino)quinoxaline—6-carboxylic acid \|/ O /N /N OH To a solution of methyl 2—(1H—indazol-5—yl)—3-(isopropyl(methyl)amino)quinoxaline carboxylate (110.0 mg, 0.29 mmol) in ol (20 mL) and water (1 mL), was added LiOH‘HZO (50 mg, 2.08 mmol, ). After stirring for 2 days at room temperature, the reaction mixture was concentrated under reduced pressure to afford a residue, which was dissolved in water (10 mL), adjusted to pH 6 with hydrochloric acid (1N) and filtered to give 2—(1H— l-S—y1)—3—(isopropyl(methy1)amino)quinoxaline—6-Carboxylic acid as a light yellow solid (47.4 mg, 45%).
LCMS (ES, m/z): [M+H]+ 362.0 1H-NMR (300 MHZ, DMSO) 5 13.27 (s, 1H), 8.21 - 8.32 (t, J: 16.2 Hz, 3H), 7.95 ~ 7.98 (t, J = 8.7 Hz, 1H), 7.87 (d, J: 9.0 Hz, 2H), 7.66 (d, J = 8.7 HZ, 1H), 4.12 - 4.16 (t, J = 6.6 Hz, 1H), 2.70 (s, 3H), 0.99 (d, J: 6.6 HZ, 6H) EXAMPLE 9 3-(Isopropyl(methyl)amino)(3-(trifluoromethyl)-1H-pyrazolyl)quinoxaline-G- carboxylic acid Step 1. Methyl 3—(isopropy1(methyl)amino)(3-(trifluoromethyl)-]H-pyrazol—4— yl)quinoxaline-6—carboxylate To a solution of 4—(4, 4, 5, 5—tetramethyl-l, 3, 2-dioxaborolanyl)(trifluoromethyl)-]H- pyrazole (536.0 mg, 2.05 mmol) in DME (5 mL) and water (0.5 mL) was added methyl 2- chloro(isopropyl(methy1)amino)quinoxalinecarboxylate (200.0 mg, 0.68 mmol), sodium ate (217.0 mg, 2.05 mmol) and Pd(PPh3)4 (39 mg, 0.03 mmol) with stirring for 0.5 h at 90°C in an oil bath with an inert atmosphere of nitrogen. The reaction mixture was concentrated under vacuum to get a e, which was purified by a silica gel column with PCT/U52012/027423 2% - 10% ethyl acetate in petroleum to afford methyl 3-(isopropyl (methyl) amino)(3- oromethyl)-]H—pyrazol-4—yl) aline—6-carboxylate as a light yellow solid (80 mg, %).
LC/MS (ES, m/z): [M+H]+ 394.0 1H-NMR (300 MHz, CDC13)I 5 8.54 (d, J: 1.8 Hz, 1H), 8.08 — 8.14 (m, 2H), 7.98 (d, J: 8.7 Hz, 1H), 4.13 - 4.24 (m, 1H), 4.01 (s, 3H), 2.76 (s, 3H), 1.13 (d, J: 6.6 Hz, 6H) Step 2. 3—(isopropyl(methyl)amino)(3~(trifluoromethyl)-]H—pyrazol—4—yl)quinoxaline carboxylic acid Y O / /N OH \ N To solution of methyl 3—(isopropyl(methyl)amino)-2—(3-(trifluoromethyl)-]H—pyrazol yl)quinoxaline—6-carboxylate (80.0 mg, 0.20 mmol) in methanol (30 mL) was added sodium hydroxide (24 mg, 0.60 mmol) and water (1 mL) with stirring overnight at room temperature.
The reaction e was concentrated under vacuum, dissolved in water (30 mL) and then adjusted to pH 5 with hydrochloric acid (3N). The solids were collected by filtration, dried in an oven under reduced pressure to afford 3-(isopropyl(methy1)amino)-2—(3—(trifluoromethyl)- IH—pyrazolyl)quinoxaline—6—carboxylic acid as a light yellow solid (64.0 mg, 79%).
LC/MS (ES, m/z): [M+H]+ 380.0 1H-NMR (300 MHZ, DMSO) 8 8.42 (s, 1H), 8.26 (d, J = 1.5 Hz, 1H), 7.94 - 7.98 (m, 1H), 7.86 (d, J: 8.7 Hz, 1H), 4.11 — 4.20 (m, 1H), 2.66 (s, 3H), 1.04 (d, J = 6.6 HZ, 6H) EXAMPLE 10 2-(6-(tert-Butoxycarbonylamino)pyridinyl)(isopropy1(methyl)amino)quinoxaline carboxylic acid Y o /N ”jg/MOP] x i 01“o \ PCT/U82012/027423 Step 1. Methyl 2-(6-(tert—butoxycarbonylamino)pyridin—3—yl)—3— (isopropyl(methyl)amino)quinoxalinecarboxy1ate Y 0 /N /Nflo/ a i OIo To a solution of 6—(tert-butoxycarbonylamino)pyridinylboronic acid (316.0 mg, 1.33 mmol) in dioxane (5 mL) was added methyl ro-3— (isopropyl(methyl)arnino)quinoxalinecarboxylate (130.0 mg, 0.44 mmol), K3PO4 (280.0 mg, 1.33 mmol) and 3)4 (25.6 mg, 0.02 mmol) and three drops water. The reaction mixture was stirred for l h at 90°C in an oil bath with an inert atmosphere of nitrogen and concentrated under vacuum to give a residue, which was purified by a silica gel column with 1% ethyl acetate in petroleum ether to afford methyl 2~(6-(rert-butoxycarbonylamino)pyridin- 3-yl)-3—(isopropyl(methyl)amino)quinoxaline—6—carboxylate as a light yellow solid (160 mg, 80%). 1H-NMR (300 MHz, CDC13) 6 8.95 (d, J = 2.4 Hz, 1H), 8.52 - 8.60 (m, 2H), 8.29 - 8.45 (m, 1H), 8.06 - 8.17 (m, 2H), 7.53 ~ 7.74 (m, 1H), 4.21 — 4.28 (m, 1H), 4.00 (s, 3H), 1.58 (s, 9H), 1.14 (d, J = 6.6 Hz, 6H) Step 2. 2—(6-(tert-Butoxycarbonylamino)pyridin—3-y1)—3- (isopropyl(methyl)amino)quinoxaline—6-carboxy1ic acid Y 0 /N /N:©)kOH >L 0 DINGig \ To a solution of methyl 2—(6-(tert—butoxycarbonylamino)pyridin—3—y1)—3- (isopropyl(methy1)amino)quinoxalinecarboxylate (160.0 mg, 0.35 mmol) in methanol (30 mL) was added sodium ide (43.0 mg, 1.06 mmol) and water (1 mL). The reaction mixture was stirred overnight at room temperature and trated under vacuum. The residue was dissolved in water (30 mL) and adjusted to pH 6 with HCl (3N). The solids were collected, dried in an oven under reduced pressure to afford 2-(6-(tert- W0 20121119046 butoxycarbonylamino)pyridinyl)(isopropyl(methyl)amino)quinoxalinecarboxylic acid as a light yellow solid (53.5 mg, 33%).
LC/MS (ES, m/z): [M+H]+ 438.0 1H-NMR (300 MHz, DMSO) 5 13.11 (s, 1H), 10.08 (s, 1H), 8.76 (t, J: 2.1 Hz, 1H), 8.22 — 8.26 (m, 2H), 7.95 — 7.98 (t, J: 1.2 Hz, 1H), 4.19 (t, J = 6.6 Hz, 1H), 2.69 (s, 3H), 1.50 (s, 9H), 1.08 (d, J: 6.6 Hz, 6H) EXAMPLE 11 2-(2—Fluoropyridinyl)(isopropyl(methyl)amin0)quinoxaline-6—carboxylic acid Y o /N /N:<:(U\0H Step 1. Methyl 2-(2—fluoropy1idinyl)(isopropyl(methyl)amino)quinoxaline carboxylate Y o /N /N]:>/U\O/ To a solution of methyl ro(isopropyl(methyl)amino)quinoxalinecarboxylate (300.0 mg, 1.02 mmol) in dioxane (5 mL) was added 2-fluoropyridinylboronic acid (289.0 mg, 2.06 mmol), K3PO4 (435.0 mg, 2.05 mmol), Pd(PPh3)4 (60 mg, 0.05 mmol) and three drops water under an inert atmosphere of nitrogen. The resulting on was stirred for l h at 90°C and then quenched by the addition of water (50 mL). The resulting solution was extracted with dichloromethane (5 X 20 mL) and the organic layers combined, dried over anhydrous magnesium 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 methyl 2—(2—fluoropyridin-4—yl)—3-(isopropyl(methyl)amino)quinoxaline—6-carboxylate as a yellow solid (250 mg, 69%).
LC/MS(ES, m/z):[M+H]+ 355.0 1H-NMR (300 MHZ, CDC13), 5 8.58 (d, J: 1.5 Hz, 1H), 8.38 (d, J = 5.1 Hz, 1H), 8.09 - 8.12 (m, 1H), 7.98 (d, J = 8.7 Hz, 1H), 7.72 - 7.74 (m, 1H), 7.51 (s, 1H), 4.22 - 4.26 (t, J = 6.6 Hz, 1H), 4.07 (s, 3H), 2.78 (s, 3H), 1.15 (d, J: 6.6 HZ, 6H) Step 2. luoropyridin—4—y1)—3-(isopropyl(methyl)amino)quinoxaline—6-carboxy1ic acid \Z_< 0 \ N To a solution of methyl 2—(2-fluoropyridin—4-y1)(isopropyl(1nethy1)an1in0)quinoxaline—6— carboxylate (125.0 mg, 0.35 mmol) in methanol (25 mL) and chloroform (10 mL) was added sodium hydroxide (56.0 mg, 1.40 mmol) in water (1 mL). The resulting solution was d overnight at room temperature and concentrated under vacuum. The residue was dissolved in water (20 mL) and adjusted to pH 6 with hydrochloric acid (1N). The product was precipitated and collected by filtration to afford 2-(2—fluoropyridin—4—yl)—3— (isopropyl(methyl)amino)quinoxalinecarboxylic acid as a yellow solid (50 mg, 42%).
LC/MS (ES, m/z):[M+H]+ 341.0 1H—NMR (300 MHz, DMSO), 8 8.44 (d, J = 8.1 Hz, 1H), 8.29 (d, J = 1.2 Hz, 1H), 7.95 — 8.02 (m, 2H), 7.77 — 7.79011, 1H), 7.60 (s, 1H), 4.17 — 4.21 (t, J: 6.6 Hz, 1H), 2.68 (s, 3H), 1.07 (d, J = 6.6 Hz, 6H) EXAMPLE 12 3-(Isopropyl(methyl)amin0)(6-(pyrrolidinyl)pyridinyl)quinoxaline-G-carboxylic acid Y OH Oil1 , WO 19046 Step 1. Methyl 3-(isopropyl(methyl)amino)~2—(6-(pyrrolidin-1—yl)pyridin—3—yl)quinoxaline carboxylate Y O 01“I / To a solution of 6—(pyrrolidinyl)pyridin—3—ylboronic acid (244.9 mg, 1.28 mmol) in MN- dimethylformamide (6 mL) was added 2-chloro—3~(isopropyl(methyl)amino)quinoxaline—6— carboxylate (170.0 mg, 0.58 mmol), )2 (17.2 mg, 0.03 mmol), DPPF (28.3 mg, 0.05 mmol), CuCl (50.5 mg, 0.51 mmol) and CS2CO3 (332.4 mg, 1.02 mmol) with stirring for 0.5 h at 100°C with an inert atmosphere of nitrogen. The on mixture was cooled and extracted with ethyl acetate (3 x 80 mL), dried over anhydrous magnesium sulfate and concentrated under vacuum. The residue was purified by a silica gel column with 2.5% ethyl acetate in petroleum ether to afford methyl 3-(isopropyl(methyl)amino)—2—(6—(pyrrolidin yl)pyridin—3-yl)quinoxaline—6-carboxylate as a light yellow solid (130.0 mg, 55%).
LC/MS (ES, m/z): [M+H]+ 406.0 1H—NMR (300 MHz, DMSO) 5 8.69 (d, J: 2.1 Hz, 1H), 8.24 (d, J: 0.9 Hz, 1H), 8.08 (d, J: 2.4 Hz, 1H), 7.91 — 7.99 (m, 1H), 7.66 - 7.70 (m, 1H), 6.59 (d, J: 9.0 Hz, 1H), 4.22 - 4.31 (m, 1H), 3.92 (s, 3H), 3.40 - 3.49 (m, 4H), 2.71 (s, 3H), 1.93 - 1.99 (m, 4H), 1.18 (d, J: 6.6 Hz, 3H), 1.09 (d, J: 6.6 Hz, 3H) Step 2. 3-(Isopropyl(methyl)amino)~2~(6-(pyrrolidin—1-yl)pyridinyl)quinoxaline—6- carboxylic acid Y OH /N /Nfio 01‘“I / d ..
To a solution of methyl 3-(isopropyl(methyl)amino)(6—(pyrrolidin—1-yl)pyridin-3— noxaline-6—carboxylate (130.0 mg, 0.32 mmol) in methanol (20 mL) was added sodium hydroxide (64.3 mg, 1.61 mmol) and water (1 mL) with stirring overnight at room temperature. The reaction mixture was concentrated under vacuum, dissolved in water (20 mL) and adjusted to pH 7 with hydrochloric acid (1N). The solids were collected to afford 3- (isopropyl(methyl)amino)(6-(pyrrolidinyl)pyridin-3—yl)quinoxaline-6—carboxylic acid as a light yellow solid (60.3 mg, 48%).
LC/MS (ES, m/z): [M+H]+ 392.1 1H—NMR (300 MHz, DMSO) 5 8.70 (d, J: 2.1 Hz, 1H), 8.22 (d, J: 1.2 Hz, 1H), 8.08 (d, J: 9.0 Hz, 1H), 7.87 - 7.95 (m, 2H), 6.60 (d, J = 8.7 Hz, 1H), 4.22 — 4.31 (m, 4H), 2.72 (s, 3H), 1.96 - 2.00 (t, J = 6.3 Hz, 4H), 1.09 (d, J = 6.6 Hz, 6H) EXAMPLE 13 2-(6-Flu0r0pyridinyl)(isopropyl(methyl)amin0)quinoxalinecarb0xylic acid Y O 01”/N]:>/U\OHI / F N Step 1. Methyl 2—(6—fluoropyridin—2—yl)-3—(isopropyl(methyl)amino)quinoxaline carboxylate Y O 01”| / F N To a solution of 6-fluoropyridin—2-ylboronic acid (289.0 mg, 2.05 mmol) in dioxane (1 mL) was added methyl 2-Chloro—3—(isopropyl(methyl)amino)quinoxaline—6-carboxylate (300.0 mg, 1.02 mmol), K3P04 (434.0 mg, 2.05 mmol), and Pd(PPh3)4 (27.6 mg, 0.02 mmol) under nitrogen here. After ng 1 h at 90°C, the reaction mixture was dissolved in water (50 mL), extracted with dichloromethane (3 x 20 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure to afford a residue, which was purified by a silica gel column with 0.05% - 0.2% ethyl acetate in petroleum ether to afford methyl 2-(6- fluoropyridin—2-yl)~3—(isopropy1(methyl)amino)quinoxalinecarboxylate as a light yellow solid (260.0 mg, 72%).
LC/MS (ES, m/z): [M+H]+ 355.0 1H-NMR (300 MHz, DMSO) 5 8.56 (s, 1H), 8.42 — 8.44 (t, J = 4.5 HZ, 1H), 8.29 (s, 1H), 7.94 - 8.01 (m, 2H), 7.32 - 7.39 (m, 1H), 4.12 - 4.21 (m, 1H), 3.93 (s, 3H), 2.67 (s, 3H), 1.05 (d, J: 6.6 Hz, 6H) Step 2. 2—(6-fluoropyridin—3—yl)—3—(isopropyl(methyl)amino)quinoxaline-6—carboxy1ic acid Y o /N /NOXOH F N/ To a solution of methyl 2—(6—fluoropyridin—3-yl)—3-(isopropyl(methyl)amino)quin0xaline carboxylate (130 mg, 0.37 mmol) in tetrahydrofuran (10 mL) was added LiOH'HzO (35 mg, 0.83 mmol) and water (1 mL). After stirring overnight at room temperature, the on e was concentrated under reduced pressure to afford a residue, which was dissolved in water (10 mL), adjusted the pH value to 6 with hydrochloric acid (1N). The solid was precipitated and filtered to afford 2-(6-fluoropyridiny1)~3- (isopropyl(methyl)amino)quinoxaline—6—carboxylic acid as a light yellow solid (81.6 mg, 65%).
LC/MS (ES, m/z): [M+H]+ 341.0 1H-NMR (300 MHZ, DMSO) 8 13.28 (s, 1H), 8.73 (d, J: 2.4 Hz, 1H), 8.42 — 8.48 (m, 1H), 8.28 (s, 1H), 7.98 (d, J = 0.9 Hz, 1H), 7.36 - 7.40 (m, 1H), 4.09 - 4.22 (m, 1H), 2.68 (S, 3H), 1.05 (d, J = 6.6 Hz, 6H) E 14 (S)(Benzofuranyl)(2-methylpyrrolidin-l-yl)quinoxalinecarb0xylic acid 0 ° N /N]©)\OH \ N Step 1. (S)—Methyl 3—(2-methy1pyrrolidin—1—yl)—2—oxo-1 ,2-dihydroquinoxaline—6-carboxylate o o N /N:©)\O/ To a solution of methyl 3-chlorooxo-1, 2-dihydroquinoxalinecarboxylate (500.0 mg, crude) in DMSO (6 mL) was added DIEA (543.0 mg, 4.20 mmol), and (S) methylpyrrolidine (268.0 mg, 3.15 mmol). The solution was stirred for 10 h at 100°C and then quenched by the addition of water (25 mL), extracted with ethyl acetate (3 x 80 mL), dried over anhydrous sodium sulfate and concentrated under vacuum The residue was purified by a silica gel column with 1% — 5% ethyl acetate in petroleum ether to afford (S)- methyl 3-(2-methylpyrrolidin—1—y1)—2-oxo-1,2—dihydroquinoxaline-6—carboxylate as a yellow solid (216.0 mg).
LC/MS (ES, m/z): [M+H]+ 288.0 1H-NMR (300 MHZ, CDC13) 5 10.87 (s, 1H), 8.24 (s, 1H), 7.77 — 7.81 (m, 1H), 7.11 (d, J = 8.4 Hz, 1H), 4.10 — 4.23 (m, 1H), 3.93 (s, 3H), 1.98 - 2.12 (m, 4H), 1.74 - 1.76 (m, 2H), 1.35 (d, J = 6.6 Hz, 3H) Step 2. thyl 3—(2-methylpyrrolidiny1)~2~(trifluoromethylsulfonyloxy)quinoxaline—6~ carboxylate o O TfOIN/N@0/ To a solution of (S)-methyl 3-(2—methylpyrrolidinyl)oxo-1,2-dihydroquinoxaline ylate (130.0 mg, 0.45 mmol) in dichloromethane (30 mL) was added ne (164.0 mg, 2.08 mmol) and then TfZO (293 mg, 1.04 mmol) was added se with stirring at 0°C. The resulting solution was stirred for 12 h at room temperature and then quenched by the addition of ice—water (50 mL), extracted with dichloromethane (3 x 20 mL), dried over anhydrous sodium sulfate and concentrated under vacuum to afford (S)~methyl 3—(2— pyrrolidin—l-yl)~2—(trifluoromethylsulfonyloxy)quinoxaline~6-carboxylate as red oil (200 mg, crude).
Step 3. (S)—Methyl 2—(benzofuran~2-yl)-3 —(2-methylpyrrolidin—1-yl)quinoxalinecarboxylate To a solution of (SD-methyl 3-(2-n1ethy1pyrro1idinyl)(tfifluoromethylsulfonyloxy) quinoxaline-6—carboxylate (200 mg, crude) in dioxane (6 mL) was added benzofuranu2— W0 2012/119046 ylboronic acid (113.0 mg, 0.70 mmol), K3PO4 (220.0 mg, 1.04 mmol), 3)4 (20.1 mg, 0.02 mmol) and water (3 drops). The resulting solution was stirred for 1 h at 90°C and then 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 (S)-methy12-(benzofuranyl)—3-(2- methylpyrrolidin-l-yl)quinoxaline—6—carboxylate as a red oil (100.0 mg).
LC/MS (ES, m/z):[M+H]+ 388.0 1H-NMR (300 MHZ, CDC13)I 5 9.27 (s, 1H), 8.16 (d, J: 8.4 Hz, 1H), 8.06 (d, J = 7.8 Hz, 1H), 7.75 (d, J: 2.7 Hz, 1H), 7.73 (d, J: 3.6 Hz, 1H), 7.35 - 7.67 (m, 4H), 5.10 (s, 1H), 4.02 (s, 3H), 3.69 — 3.77 (m, 1H), 3.41 - 3.51 (m, 1H), 2.31 - 2.37 (m, 2H), 1.77 - 1.98 (m, 2H), 1.42 - 1.69 (m, 3H) Step 4. (S)—2—(Benzofuran~2-yl)(2-methylpyrrolidin-1~yl)quinoxaline—6-carboxylic acid C O N /NfiOH \ N To a solution of (S)-methy1 2—(benzofuranyl)(2-methylpyrrolidin-1~yl) quinoxaline carboxylate (100.0 mg, 0.39 mmol) in MeOH (20 mL) was added sodium hydroxide (49.2 mg, 1.23 mmol) and water (1 mL). The resulting solution was stirred overnight at room temperature and concentrated under vacuum. The e was dissolved in water (20 mL) and adjusted to pH 6 with hydrochloric acid (1N). The solids were collected by filtration to afford (S)—2—(benzofuran—2-yl)(2—methylpyrrolidinyl)quinoxalinecarboxylic acid as a yellow solid (50.9 mg, 53%).
LC/MS (ES, M+H]+ 374.0 1H-NMR (300 MHz, DMSO) 8 8.23 (d, J = 1.8 Hz, 1H), 7.97 (d, J = 8.7 Hz, 1H), 7.88 - 7.92 (m, 1H), 7.71 - 7.79 (m, 2H), 7.39 — 7.45 (m, 2H), 7.30 - 7.35 (m, 1H), 4.29 — 4.35 (m, 1H), 3.31 — 3.33 (m, 1H), 3.04 - 3.10 (t, J = 8.1 Hz, 1H), 2.10 — 2.21 (m, 1H), 1.75 - 1.89 (m, 1H), 1.52 - l.67(m, 2H), 1.35 (d, J: 6.6 Hz, 3H) EXAMPLE 15 2-(Benzofuran-Z-yl)(cyclopropyl(methyl)amino)quinoxalinecarboxylic acid Y o C90;\\ N Step 1. Methyl 3—(Cyclopropyl(methyl)amino)~2-oxo-1,2-dihydroquinoxalinecarboxylate y o 01”/NI>/U\O/ To a solution of methyl 3-chlorooxo-l,2-dihydroquinoxaline—6-carboxylate (1.0 g, 4.20 mmol) in DMSO (6 mL) was added DIEA (1.35 g, 10.47 mmol) and N— methylcyclopropanamine hydrochloride (490 mg, 4.58 mmol) . The solution was stirred 10 mins at room temperature and 2 h at 75°C. Then the reaction was quenched by the on of water (100 mL) and the solids were collected by filtration to afford methyl 3— (Cyclopropyl(methyl)amino)-2—oxo-l,2-dihydroquinoxaline~6-carboxylate as a yellow solid (405 mg, 35%).
LC/MS (ES, m/z): [M+H]Jr 274.0 1H—NMR (300 MHz, DMSO) 5 12.25 (s, 1H), 7.96 (d, J: 1.8 Hz, 1H), 7.72 - 7.75 (m, 1H), 7.20 (d, J: 8.4 Hz, 1H), 3.85 (d, J: 5.4 Hz, 3H), 3.23 (s, 3H), 3.03 — 3.11 (m, 1H), 0.76 - 0.82 (m, 2H), 0.57 — 0.63 (m, 2H) Step 2. Methyl 3~(cyclopropyl(methy1)amino)~2~(trifluoromethylsulfonyloxy)quinoxaline carboxylate V o I/NDAO/ TfO N To a solution of methyl 3-(cyclopropyl(methyl)amino)—2-oxo-l,2-dihydroquinoxaline ylate (126.0 mg, 0.46 mmol) in dichloromethane (34 mL) was added pyridine (145.0 mg, 1.84 mmol) and then TfZO (259 mg, 0.92 mmol) was added dropwise with stirring at 0°C. The resulting solution was stirred for 3 h at room temperature and then quenched by the addition of ter (50 mL), extracted with dichloromethane (2 X 20 mL), dried over W0 2012(119046 anhydrous sodium sulfate and concentrated under vacuum to afford methyl 3- (cyclopropyl(methyl)amino)(trifluoromethylsulfonyloxy)quinoxaline~6~carboxylate as red oil (180mg, crude).
Step 3. Methyl 2—(benzofi1ran—2—yl)—3—(cyclopropy1(methyl)amino)quinoxaline—6-carboxylate V o /N /N]©)‘\O/ M\\ N To a solution of methyl lopropyl(methy1)amino) (trifluoromethylsulfonyloxy)quinoxaline—6-Carboxylate (180.0 mg, crude) in dioxane (6 mL) was added benzofuran-2—y1boronic acid (149.0 mg, 0.92 mmol), K3PO4 (195.0 mg, 0.92 mmol), Pd(PPh3)4 (30.0 mg, 0.03 mmol) and water (3 . The resulting on was stirred for 1 h at 90°C and then concentrated under vacuum to give a residue, which was purified by a silica gel column with 5% — 20% ethyl acetate in petroleum ether to afford methyl 2-(benzofuranyl)(cyclopropyl(methy1)amino)quinoxaline~6-carboxy1ate as a yellow solid (95.0 mg, 39% 2 steps).
LC/MS (ES, m/z): [M+H]+ 374.0 lH—NMR (300 MHz, DMSO) 6 8.68 (s, 1H), 8.08 — 8.16 (m, 2H), 7.63 — 7.72 (m, 2H), 7.50 (d, J = 0.6 Hz, 1H), 7.42 — 7.45 (m, 1H), 7.28 - 7.40 (m, 1H), 4.01 (s, 3H), 3.21 (s, 3H), 2.96 - 3.01 (m, 1H), 0.53 — 0.74 (m, 4H) Step 4. 2—(Benzofuran—2-yl)—3-(cyclopropyl(methyl)amino)quinoxalinecarboxylic acid V o C90;\\ N To a solution of methyl 3-(cyclopropyl(methyl)amino)(2,3-dihydro-1H—inden-2— yl)quinoxa1inecarb0xylate (95 .0 mg, 0.25 mmol) in methanol (15 mL) and CHC13 (10 mL) was added LiOH'HZO (35.0 mg, 0.83 mmol) and water (1 mL). The resulting solution was stirred overnight at room ature and concentrated under vacuum. The residue was dissolved in water (10 mL) and adjusted pH to 6 with hydrochloric acid (IN). The solids 2012/027423 were collected by filtration to afford 2—(benzofuran—2—y1)—3— (cyclopropyl(methyl)amino)quinoxalinecarboxylic acid as a yellow solid (43.6 mg ,48%).
LC/MS (ES, m/z):[M+H]+ 360.0 1H—NMR (300 MHz, DMSO) 5 8.28 (d, J = 1.2 Hz, 1H), 7.97 - 8.06 (m, 2H), 7.50 (d, J = 0.6 Hz, 1H), 7.42 — 7.45 (m, 1H), 7.28 — 7.40 (m, 2H), 7.75 - 7.80 (t, J: 8.4 Hz, 1H), 7.63 (s, 1H), 7.41 - 7.46 (t, J: 7.2 Hz, 1H),7.31 — 7.36 (t, J = 7.2Hz, 2H), 3.01 (s, 3H), 2.87 — 2.90 (t, J = 3.6 Hz, 1H), 0.51 — 0.55 (t, J: 7.2 HZ, 4H) EXAMPLE 16 2-(6-Aminopyridinyl)(isopropyl(methyl)amin0)quinoxalinecarboxylic acid Y O OI“1 / H2N N To a solution of rert-butoxycarbonylamino)pyridin—3—y1) opyl(methyl)amino)quinoxalinecarboxylic acid (140.0 mg, 0.32 mmol) in dichloromethane (50 mL)was added CF3COOH (182.6 mg, 1.60 mmol) with stirring overnight at room temperature. The reaction mixture was concentrated under vacuum, dissolved in water (10 mL) and adjusted to pH 6 with sodium bicarbonate. The product were collected by filtration to afford 2-(6-aminopyridin—3—yl)~3— (isopropyl(methyl)amino)quinoxalinecarboxylic acid as a light yellow solid (88.6mg, 78%).
LC/MS (ES, m/z): [M+H]+ 338.0 1H-NMR (300 MHz, DMSO) 8 8.54 (d, J = 1.8 Hz, 1H), 8.23 (d, J: 1.5 Hz, 1H), 7.87 - 7.98 (m, 3H), 6.51 — 6.59 (m, 3H), 4.18 - 4.25 (m, 1H), 2.73 (s, 3H), 1.08 (d, J = 6.6 Hz, 6H) W0 20121119046 PCT/U82012/027423 EXAMPLE 17 3-(Isopropyl(methyl)amino)(5-methoxybenzofuranyl)quinoxalinecarboxylic acid Y O /N /NI>)J\OH\ I \ N Step 1. 5-Methoxybenzofuranylboronic acid The solution of oxybenzofuran (1.0 g, 6.76 mmol) in dry ydrofuran (50 mL) was kept below -60°C under nitrogen, while BuLi (8.10 mmol, 2.5M solution in hexane) was added dropwise. It was warmed to —10°C during 45 min and stirred at this temperature for r 30 min. The mixture was cooled again below —60°C, followed by dropwise addition of triisopropyl borate (3.8 g, 20.21 mmol). After warming to room temperature the mixture was quenched with hydrochloric acid (30 mL, 2N) and stirred for 1 h. The alkaline aqueous layer was brought to pH 5 and extracted with ethyl acetate (3 X 80 mL). All organic layers were combined, dried over sodium sulfate, and concentrated in vacuo to give 5- methoxybenzofuran-Z-ylboronic acid (986 mg, 76%), which was used for the next step without further purification. 1H—NMR (300 MHZ, CDCl3): 5 8.52 (s, 2H), 7.45 (d, J: 9.0 Hz, 1H), 7.39 (d, J: 0.9 Hz, 1H), 7.18 (d, J: 2.7 Hz, 1H), 6.91 — 6.95 (m, 1H), 3.78 (s, 3H) Step 2. Methyl 3-(isopropyl(methyl)amino)~2—(5—methoxybenzofuran-2—yl)-4a,8a- dihydroquinoxalinecarboxylate Y O My;\\ N To a solution of 5-methoxybenzofuranylboronic acid (275.0 mg, 1.43 mmol) in dioxane (5.0 mL) was added ethyl 2—chloro—3-(isopropyl(methyl)amino)quinoxa1ine—6-carboxylate (140.0 mg, 0.48 mmol), K3PO4 (302.0 mg, 1.43 mmol) and Pd(PPh3)4 (27.5 mg, 0.02 mmol) and water (3 drops) with ng for 1 h at 90°C in an oil bath maintained with an inert atmosphere of nitrogen. The reaction mixture was concentrated under vacuum to give a residue, which was purified by a silica gel column with 1% ethyl acetate in petroleum ether to afford methyl 3-(isopropyl(methyl)amino)—2—(5-methoxybenzofuran—2—y1)—4a,8a— dihydroquinoxaline—6—carboxylate as a light yellow solid (150.0 mg, 73%).
LC/MS (ES, m/z): [M+H]+ 406.0 1H-NMR (300 MHz, CDC13)I 5 8.56 (d, J = 0.9 Hz, 1H), 8.05 — 8.12 (m, 2H), 7.54 — 7.58 (t, J: 9.3 Hz, 2H), 7.13 (d, J: 2.4 Hz, 1H), 7.01 - 7.05 (m, 1H), 4.32 - 4.36 (m, 1H), 4.01 (s, 3H), 390 (s, 3H), 2.93 (s, 3H), 1.23 (d, J = 6.6 Hz, 6H) Step 3. 3-(Isopropyl(methy1)amino)(5-methoxybenzofuran—2—yl)quinoxaline—6—carboxylic acid Y O /N /NflOH \ N \O 0 To a solution of methyl 3-(isopropyl(methyl)amino)(5-methoxybenzofuran yl)quinoxalinecarboxylate ( 150.0 mg, 0.37 mmol) in ol (30 mL) and water (1 mL) was added sodium hydroxide (44.4 mg, 1.11 mmol) with stirring overnight at room temperature. The reaction mixture was concentrated under vacuum, dissolved in water (30 mL) and adjusted to pH 5 with HCl (3N). The solids were collected by tion to afford 2- (5—fluorobenzofuran—2—yl)—3—(isopropyl(methyl)amino)quinoxaline—6-carboxylic acid as a light yellow solid (100.0 mg, 66%).
LC/MS (ES, m/z): [M+H]+ 392.1 1H-NMR (300 MHz, DMSO): 5 8.26 (s, 1H), 7.95 - 7.99 (m, 2H), 7.62 ~ 7.66 (t, J: 2.7 Hz, 2H), 7.30 (d, J = 2.4 Hz, 1H), 7.02 — 7.05 (m, 1H), 4.15 - 4.23 (m, 1H), 3.82 (s, 3H), 2.82 (s, 3H), 1.16 (d, J = 6.6 Hz, 6H) W0 2012(119046 EXAMPLE 18 2-(S-Fluorobenzofuran-Z-yl)(isopropyl(methyl)amino)quinoxalinecarboxylic acid Y O \ N Step 1. 1—(Diethoxymethoxy)~4-fluorobenzene /—Or0>j0@F To a suspension of sodium hydride (11.24 g, 281.00 mmol) in anhydrous N,N— dimethylformamide (500 mL) was added 4-fluorophenol (26.21 g, 233.96 mmol) at 0°C.
After hydrogen evolution had ceased, bromo—acetaldehyde diethyl acetal (55 g, 280.60 mmol) was added. The on was heated at 120°C overnight. The mixture was poured into ice- water, extracted with ethyl acetate (3 x 150 mL), washed with 1N sodium hydroxide (3 x 100 mL), and brine (3 x 100 mL). The c layer was dried over ous sodium e and filtered. The solvent was removed under vacuum to give the residue, which was purified by a silica gel column with 1% ethyl acetate in petroleum ether to afford 1-(diethoxymethoxy) fluorobenzene as oil (45 g , 84%). 1H—NMR (300 MHz, CDC13)I 5 6.84 — 7.01 (m, 4H), 4.81 - 4.85 (t, J = 5.1 Hz, 1H), 3.99 (d, J = 5.1Hz, 2H), 3.69 — 3.83 (m, 2H), 3.59 - 3.67 (m, 2H), 1.24 - 1.31 (m, 6H) Step 2. 5-Fluor0benzofuran F130 To a mixture of benzene (200 mL) ning polyphosphoric acid (80 g, 236.69 mmol) was added 2—(4—fluoro-phenoxy)—acetaldehyde diethyl acetal (45 g, 197.37 mmol). The mixture was stirred vigorously while being heated to reflux for 2.5 hours. The reaction mixture was cooled to room temperature and decanted from the polyphosphoric acid. The solvent was removed under vacuum to give the residue, which was purified by a silica gel column with 1% ethyl acetate in petroleum ether to afford S-fluorobenzofuran as colorless oil (14.0 g, crude).
PCT/U52012/027423 1H-NMR (300 MHZ, CDClg): 8 7.67 (d, J = 2.1 Hz, 1H), 7.44 - 7.48 (m, 1H), 7.27 - 7.30 (m, 1H), 7.01- 7.08 (m, 1H), 6.76 - 6.77 (m, 1H) Step 3. 5-Fluorobenzofuran~2-ylboronic acid To a solution of S—fluorobenzofuran (10 g, 73.53 mmol) in dry tetrahydrofuran (250 mL) were added tetramethylethylenediamine (10.2 g, 87.93 mmol). The solution was kept below - 60°C under nitrogen, while BuLi (93.75 mmlo, 2.5M on in hexane) was added se. It was warmed to —10°C during 45 min and stirred at this temperature for another min. The mixture was cooled again below —60°C ed by dropwise addition of triisopropyl borate (41.4 g, 220.21 mmol). After g to room temperature the mixture was quenched with hydrochloric acid (70 mL, 2N) and stirred for 1 h. The alkaline aqueous layer was brought to pH 5 and extracted with ethyl acetate (3 x 80 mL). All organic layers were combined, dried over sodium sulfate, and concentrated in vacuo to give 5— fluorobenzofuranylboronic acid (3.5 g, 26%) which was used for the next step without further purification. 1H-NMR (300 MHZ, CDClg): 5 8.63 (s, 2H), 7.58 - 7.62 (m, 1H), 7.44 — 7.49 (m, 2H), 7.15 - 7.22 (m, 1H) Step 4. Methyl 2—(5-fluorobenzofuranyl)(isopropy1(methyl)amino)quinoxaline carboxylate Y O \ N To a solution of 5-fluorobenzofuran—2—ylboronic acid (258.0 mg, 1.43 mmol) in dioxane (5.5 mL) was added ethyl 2—chloro-3—(isopropyl(methyl)amino)quinoxaline-6—carboxylate (140.0 mg, 0.48 mmol), K3PO4 (302.0 mg, 1.43 mmol) and Pd(PPh3)4 (27.5 mg, 0.02 mmol) and water (3 drops) with stirring for 1 h at 90°C in an oil bath maintained with an inert atmosphere of nitrogen. The on mixture was concentrated under vacuum to give a residue, which was purified by a silica gel column with 1% ethyl acetate in petroleum ether to afford methyl 2—(5—fluorobenzofuran-2—yl)(isopropyl(methyl)amino)quinoxaline—6— carboxylate as a light yellow solid (160.0 mg, 81%).
LC/MS (ES, m/z): [M+H]+ 394.0 1H-NMR (300 MHz, CDClg): 5 8.61 (d, J = 1.5 Hz, 1H), 8.05 - 8.14 (m, 2H), 7.57 - 7.62 (m, 2H), 7.34 - 7.37 (m, 1H), 7.11 — 7.18 (m, 1H), 4.29 - 4.38 (m, 1H), 4.01 (s, 3H), 2.94 (s, 3H), 1.21 (d, J = 6.6 Hz, 6H) Step 5. 2-(5-Fluorobenzofuran-2~yl)~3~(isopropyl(methy1)amino)quinoxaline-6—carboxylic acid Y O \ N To a solution of methyl 2-(5 benzofuran—2-y1)—3—(isopropyl(methyl)amino)quinoxaline- 6-carboxylate (160 mg, 0.41 mmol) in methanol (30 mL) and water (1 mL) was added sodium hydroxide (48.85 mg, 1.22 mmol) with stirring overnight at room temperature. The reaction mixture was concentrated under vacuum, dissolved in water (30 mL) and adjusted to pH 5 with HCl (3N). The solids were collected by filtration to afford 2-(5-fluorobenzofuran— 3-(isopropyl(methyl)amino)quinoxaline—6—carboxylic acid as a light yellow solid (120.0 mg, 74%).
LC/MS (ES, m/z): [M+H]+ 380.1 1H—NMR (300 MHZ, DMSO): 8 13.28 (s, 1H), 8.27 (s, 1H), 7.96 - 8.03 (m, 2H), 7.77 - 7.82 (m, 1H), 7.59 — 7.64 (m, 1H), 7.26 - 7.34 (m, 1H), 4.15 — 4.24 (m, 1H), 2.83 (s, 3H), 1.16 (d, J = 6.6 Hz, 6H) EXAMPLE 19 2-(5-Chlorobenzofuran-Z-yl)(isopropyl(methyl)amin0)quinoxaline~6-carb0xylic acid Y O /N /N:©/U\OH\ l \ N WO 2013119046 Step 1. 1—Chloro(2,2—diethoxyethoxy)benzene CI Crox/koA To a suspension of sodium hydride (11.24 g, 281 mmoi) in anhydrous N,N— dimethylformamide (500 mL) was added 4-chlorophenol (30 g, 234 mmol) at 0°C. After hydrogen ion had ceased, bromo—acetaldehyde diethyl acetal (55 g, 281 mmol) was added. The reaction was heated at 120°C overnight. The mixture was poured into ice—water, extracted with ethyl acetate (3 x 150 ml), washed with 1N sodium hydroxide (3 x 100 ml), and brine (3 x 100 ml). The organic layer was dried over anhydrous sodium sulfate and filtered. The t was removed under vacuum. The e was purified by a silica gel column with 1% ethyl acetate in petroleum ether to afford ro—4-(2,2- xyethoxy)benzene as oil (45 g , 75%). 1H-NMR (300 MHZ, CDC13)I 5 7.24 — 7.28 (m, 1H), 7.21 - 7.23 (m, 1H), 6.84 - 6.89(m, 2H), 4.81 - 4.85 (t, J: 5.1 HZ, 1H), 3.99 (d, J: 5.1 Hz, 2H), 3.69 - 3.83 (m, 2H), 3.59 - 3.67 (m, 2H), 1.23 - 1.30 (m, 6H) Step 2. 5-Chlorobenzofuran CICD) To a solution of 1~chloro-4—(2,2~diethoxyethoxy)benz.ene (45 g, 184 mmol,) in benzene (200 mL) was added polyphosphoric acid (25 g, 221 mmol) with stirring for 2.5 h at 90°C in an oil bath. The reaction mixture was cooled to room temperature and decanted from the polyphosphoric acid. The solvent was removed under vacuum. The residue was applied onto a silica gel column with 1% ethyl acetate in petroleum ether to afford 5~chlorobenzofuran as colorless oil (14.0 g, crude). 1H-NMR (300 MHZ, CDC13)Z 5 7.66 (d, J = 2.1 Hz, 1H), 7.59 (d, J = 2.1 Hz, 1H), 7.45 (d, J: 8.7 Hz, 1H), 7.26 — 7.29 (m, 1H), 6.73 - 7.75 (m, 1H) Step 3. robenzofuran—2—ylboronic acid / B C! \OH To a solution of 5-chlorobenzofuran (14 g, crude) in dry ydrofuran (250 mL) were added tetramethylethylenediamine (12.82 g, 110 mmol). The solution was kept below —60°C under argon, while the solution of butyllithium in hexane (44 ml, 2.5 M) was added dropwise.
It was warmed to —10°C during 45 min and stiired at this temperature for another 30 min. The mixture was cooled again below ~60°C followed by se addition of triisopropyl borate (51.88 g, 276 mmol). After warming to room ature the mixture was quenched with hydrochloric acid (70 ml, 2N) and stirred for 1 h. The alkaline aqueous layer was brought to pH 5 and extracted with ethyl acetate (3 x 80 m1). All organic layers were combined, dried over sodium sulfate, and concentrated in vacuo to give 5-chlorobenzofuran—2—ylboronic acid (7.5 g) which was used for the next step without further purification. lH—NMR (300 MHZ, DMSO): 5 8.66 (s, 2H), 7.78 (d, J = 2.1 Hz, 1H), 7.58 _ 7.71 (m, 1H), 7.42 — 7.44 (m, 1H), 7.27 — 7.37 (m, 1H) Step 4. Methyl 2-(5-chlorobenzofuran—2-yl)(isopropyl(methyl)amino)quinoxaline carboxylate Cl 0 To a solution of 5—chlorobenzofuranylboronic acid (281 mg, 1.43 mmol) in dioxane (6 mL) was added ethyl 2-chloro(isopropyl(methyl)amino)quinoxalinecarboxylate (140 mg, 0.48 mmol), K3PO4 (303 mg, 1.44 mmol), Pd(PPh3)4 (27.5 mg, 0.02 mmol) and water (3 drops) with stirring for 3 h at 90°C in an oil bath ined with an inert atmosphere of nitrogen. The reaction mixture was concentrated under vacuum to give a residue, which was applied onto a silica gel column with 1% ethyl acetate in petroleum ether to afford methyl 2- (5-chlorobenzofuranyl)(isopropyl(methyl)amino)quinoxaline—6-carboxylate as a light yellow solid (152 mg, 78%).
PCT/U82012/027423 1H—NMR (300 MHz, CDCl3)I 8 8.58 (s, 1H), 8.04 - 8.13 (m, 2H), 7.67 (d, J: 2.1 Hz, 1H), 7.56 - 7.60 (t, J = 8.7 Hz, 2H), 7.35 - 7.39 (m, 1H), 4.26 - 4.34 (m, 1H), 4.01 (s, 3H), 2.92 (s, 3H), 1.22 (d, J: 6.6 Hz, 6H) Step 5. 2—(5—Chlorobenzofuran—2—yl)—3—(isopropyl(methyl)amino)quinoxaline—6—carboxylic acid Y O /N /N©)kOH \ N To a solution of methyl 2-(5—chlorobenzofuranyl)-3—(isopropyl(methyl)amino)quinoxaline- 6-carboxylate (152 mg, 0.37 mmol) in tetrahydrofuran (30 mL) was added sodium hydroxide (48.6 mg, 1.22 mmol) and water(2 n11) with stirring overnight at room ature. The reaction mixture was concentrated under vacuum, dissolved in water (30 mL), and adjusted to pH 5 with HCl (3N). The solids were collected by filtration to afford 2-(5-chlorobenzofuran- 2—y1)-3—(isopropyl(methyl)amino)quinoxaline—6—carboxylic acid as a light yellow solid (60 mg, 41%).
LC/MS (ES, m/z): [M+H]+ 396.0 1H-NMR (300 MHz, DMSO): 5 13.28 (s, 1H), 8.26 — 8.27 (t, J: 1.2 Hz, 1H), 7.96 - 8.03 (m, 2H), 7.89 (d, J: 2.1 Hz, 1H), 7.80 (d, J = 8.7 Hz, 1H), 7.66 (d, J = 0.9 Hz, 1H), 7.45 - 7.48 (m, 1H), 4.14 — 4.23 (m, 1H), 2.82 (s, 3H), 1.16 (d, J: 6.6 Hz, 6H) EXAMPLE 20 2-(3,4-Dihydro-2H-benz0[b][1,4]dioxepinyl)(isopropyl(methyl)amino)quinoxaline- 6-carboxylic acid Y o Goldy Step 1. Methyl 2-(3,4-dihydro—2H—benzo[b][1,4]dioxepin-7—y1)—3— (isopropyl(methy1)amino)quinoxaline—6-carboxylate Y O {305$N / To a solution of 3,4-dihydro-2H—benzo[b][1,4]dioxepin-7—ylboronic acid (200.0 mg, 1.03 mmol in dioxane (5.0 mL) was added methyl 2-chloro (isopropy1(methy1)amino)quinoxaline—6—carboxylate (Scheme 1, 150.0 mg, 0.52 mmol), K3PO4 (325.9 mg, 1.54 mmol) and Pd(PPh3)4 (29.7 mg, 0.03 mmol) and 3 drops) with stirring for 1 h at 90°C in an oil bath maintained with an inert atmosphere of nitrogen. The reaction mixture was concentrated under vacuum to give a residue, which was purified by a silica gel column with 1% ethyl acetate in petroleum ether to afford methyl 2—(3,4-dihydro— 2H-benzo[b][1,4]dioxepin-7—yl)—3—(isopropyl(methy1)amino)quinoxaline—6-carboxylate as a light yellow solid (140.0 mg, 63%).
LC/MS (ES, m/z): [M+H]+ 408.0 1H-NMR (300 MHz, I 8 8.56 (d, J: 1.5 Hz, 1H), 8.03 - 8.07 (dd, J; = J2 = 1.8 Hz, 1H), 7.95 (d, J: 8.7 Hz, 1H), 7.56 (d, J: 2.4 Hz, 1H), 7.47 — 7.51 (n1,J1 = 2.4 Hz, 1H), 7.08 (d, J: 8.4 Hz, 1H), 4.23 - 2.29 — 4.31 (m, 5H), 3.99 (s, 3H), 390 (s, 3H), 2.79 (s, 3H), 2.24 (m, 2H), 1.22 (d, J: 6.6 Hz, 6H) Step 2. 2—(3,4-Dihydro-2H—benzo[b][1,4]dioxepin~7—y1)—3— (isopropyl(methy1)amino)quinoxaline—6-carboxy1ic acid Y 0 Cody To a solution of methyl 2—(3,4-dihydro-2H—benzo[b][1,4]dioxepin—7-yl)-3— (isopropyl(methy1)amino)quinoxaline-6—carboxy1ate (140.0 mg, 0.34 mmol) in methanol (30 mL) and water (1 mL) was added sodium hydroxide (42.0 mg, 1.03 mmol) with stirring overnight at room temperature. The reaction mixture was concentrated under vacuum, ved in water (30 mL) and adjusted to pH 5 with HCl (3N). The solids were ted by filtration to afford 2—(3,4—dihydro-2H—benzo[b][1,4]dioxepin—7—yl)—3— PCT/U52012/027423 (isopropyl(methyl)amino)quinoxaline-6—carboxylic acid as a light yellow solid (120.0 mg, 84%).
LC/MS(ES, m/z): [M+H]+ 392.1 1H-NMR (300 MHZ, DMSO): 5 8.23 — 8.24 (t, J = 1.2 Hz, 1H), 7.92 (s, 2H), 7.45 - 7.49 (m, 2H), 7.09 (d, J = 8.1 Hz, 1H), 4.17 - 4.22 (m, 5H), 2.69 (s, 3H), 2.13 - 2.17 (t, J = 5.1 Hz, 3H), 1.04 (d, J: 6.6 Hz, 6H) EXAMPLE 21 oman-6—yl)(isopropyl(methyl)amino)quinoxalinecarboxylic acid Y O 03?»: H Step 1. 2-(Chroman—6-yl)-4,4,5,5—tetramethyl-1,3,2—dioxaborolane BIO0)? ::: \ To a solution of 6-bromochroman (400 mg, 1.88 mmol) in MN—dimethylformamide (50 mL) was added ,4‘,5,5,5',5'-octamethyl—2,2'-bi(l,3,2-dioxaborolane) (620 mg, 2.44 mmol), KOAC (552.1 mg, 5.63 mmol) and Pd(dppf)Clz (155 mg, 0.19 mmol) with Stirling for 3 h at 95°C maintained with an inert atmosphere of nitrogen in an oil bath. The reaction mixture was diluted with water, extracted with ethyl acetate (80 mL x 3) and the organic layers combined, dried over anhydrous magnesium sulfate, concentrated under vacuum to give the e, which was applied onto a silica gel column with 1% ethyl acetate in petroleum ether to afford 2—(chromanyl)-4,4,5,5—tetramethyl-1,3,2—dioxaborolane as colorless oil (320 mg, 59%). 1H-NMR (300 MHz, CDC13)I 5 7.54 (d, J = 7.5 Hz, 2H), 6.78 (d, J = 8.4 Hz, 1H), 4.19 — 4.23 (t, J = 5.4 Hz, 2H), 2.78 — 2.83 (t, J = 6.3 Hz, 2H), 1.98 — 2.05 (m, 2H), 1.28 (s,12H) Step 2. Methyl 2-(chroman—6—yl)—3—(isopropyl(methyl)amino)quinoxaline—6-carboxylate To a solution of 2—(chroman—6—yl)-4,4,5,5~tetramethyl—l,3,2-dioxaborolane (320 mg, 1.23 mmol) in dioxane (5.0 mL) was added methyl ro (isopropyl(methyl)amino)quinoxaline—6~carboxylate (Scheme 1, 180 mg, 0.61 mmol), K3P04 (392 mg, 1.86 mmol), Pd(PPh3)4 (35.8 mg, 0.03 mmol) and water (3 drops) with ng for 4 h at 95°C maintained with an inert here of nitrogen in an oil bath. The reaction mixture was concentrated under vacuum to give the residue, which was applied onto a silica gel column with 2% ethyl acetate in petroleum ether to afford methyl 2-(chroman-6—yl)-3— (isopropyl(methyl)amino)quinoxalinecarboxylate as a light yellow solid (130 mg, 51%).
LC/MS(ES,m/z): [M+H]+ 392.0 1H-NMR (300 MHZ, CDClg): 5 8.76 (s, 1H), 8.07 — 8.16 (m, 2H), 7.71 (s, 1H), 7.62 (d, J = 8.7 Hz, 1H), 6.89 (d, J = 8.4 Hz, 1H), 4.42 - 4.47 (t, J: 6.6 Hz, 1H), 4.27 — 4.30 (t, J = 5.1 Hz, 2H), 4.00 (s, 3H), 2.88 — 2.94 (m, 5H), 2.05 — 2.12 (m, 2H), 1.16 (d, J: 6.60 Hz, 6H) Step 3. 2—(Chromanyl)-3—(isopropyl(methyl)amino)quinoxalinecarboxylic acid Y O /N /Nfio (DIN0 H To a solution of methyl 2—(chromanyl)-3—(isopropyl(methyl)amino)quinoxaline carboxylate (130 mg, 0.33 mmol) in water (1 mL) and tetrahydrofuran (5 mL) was added sodium hydroxide (53 mg, 1.33 mmol) with stirring overnight at room temperature. The reaction e was concentrated under vacuum, dissolved in water (30 mL), adjusted to pH 4 with HCl (3N) to give the precipitate, which was collected by filtration to afford 2- (chroman-6—yl)—3-(isopropyl(methyl)amino)quinoxalinecarboxylic acid as a light yellow solid (80 mg, 61%).
LC/MS (ES, m/z): [M+H]+ 378.0 1H-NMR (300 MHz, DMSO): 5 13.06 (s, 1H), 8.23 (s, 1H), 7.88 — 7.95 (m, 2H), 7.61 - 7.65 (t, J = 2.1 Hz, 1H), 6.85 (d, J = 8.4 Hz, 1H), 4.15 — 4.23 (m, 3H), 2.81 - 2.85 (t, J = 6.3 Hz, 2H), 2.70 (d, J = 7.8 Hz, 3H),l.95 - 2.01 (m, 2H), 1.05 (d, J = 6.6 Hz, 6H) EXAMPLE 22 z0[d]0xazolyl)(is0propyl(methyl)amin0)quinoxaline-G-carboxylic acid Y o /N 910/ka Step 1. Methyl 2—(benzo[d]oxazoly1)(isopropy1(methyl)amino)quinoxaline carboxylate Y 0 To a 10—mL sealed tube was placed methyl 2—chloro(isopr0pyl(methy1)amino)quinoxaline- 6—carb0xylate (Scheme 1, 400 mg, 1.36 mmol), 6,7—dihydrobenzo[d]0xazole (400 mg, 3.31 mmol), ACOK (268 mg, 3.31 mmol), and Pd(PPh3)4 (40 mg, 0.03 mmol) under nitrogen atmosphere. After stirring 2 h at 150°C, the reaction mixture was dissolved in water (10 mL), extracted with dichloromethane (3 x 30 mL), dried over anhydrous magnesium sulfate and concentrated under d re to afford a residue, which was purified by a silica gel column with 10% ethyl acetate in petroleum ether to afford methyl 2~(benz.0[d]oxazol-2—y1)— 3—(isopropy1(methy1)amin0)quinoxaline-6—carboxy1ate as a light yellow solid (100 mg, 21%).
LC/MS (ES, m/z): [M+H]+ 377.0 1H-NMR (300 MHZ, CDC13) 5 8.52 (d, J = 1.2 Hz, 1H), 8.03 - 8.11 (m, 2H), 7.87 — 7.90 (m, 1H), 7.69 — 7.72 (m, 1H), 7.41 — 7.46 (m, 2H), 4.37 - 4.46 (m, 1H), 4.00 (s, 3H), 2.87 (s, 3H), 1.23 (d, J = 6.6 Hz, 6H) W0 2012.1119046 2012/027423 Step 2. 2-(Benzo[d]oxazol—2-yl)—3-(isopropyl(methyl)amino)quinoxalinecarboxylic acid Y 0 To a solution of methyl 2—(benzo[d]oxazol-2—yl)—3-(isopropy1(methyl)amino)quinoxaline carboxylate (100 mg, 0.27 mmol) in tetrahydrofuran (20 mL) and water (2 mL) was added sodium hydroxide (21 mg, 0.53 mmol). After stirring ght at room temperature, the reaction mixture was concentrated under reduced pressure to afford a residue, which was dissolved in water (20 mL), adjusted the pH to 6 with hydrochloric acid (3N) and filtered to give 2—(benzo[d]oxazol—2-yl)(isopropy1(methyl)amino)quinoxaline-6—carboxy1ic acid as a light yellow solid (21.9 mg, 23%).
LC/MS (ES, m/z): [M+H]+ 363.0.0 1H-NMR (300 MHz, DMSO) 5 13.31 (s, 1H), 8.27 (d, J: 1.5 Hz, 1H), 8.04 (d, J = 8.7 Hz, 1H), 7.92 - 7.97 (m, 3H), 7.50 ~ 7.56 (m, 2H), 4.33 - 4.42 (m, 1H), 2.77 (s, 3H), 1.16 (d, J = 6.6 Hz, 6H) 2-(Benzo[b]thi0phenyl)(isopropyl(methyl)amino)quinoxalinecarboxylic acid INDCOOH Step 1. Methyl 6-(benzo[b]thiophen—2—yl)-7—(isopropyl(methyl)amino)-2—naphthoate Y O /N /N:©/u\o/ CQI\\ N To a on of benzo[b]thiophen-2—ylboronic acid (180 mg, 1.01 mmol) in dioxane (6 mL) was added methyl 6—chloro—7—(isopropyl(methyl)amino)-2—naphthoate (120 mg, 0.41 mmol), W0 19046 K3PO4 (259 mg, 1.23 mmol) , Pd(PPh3)4 (24.0 mg, 0.02 mmol) and water (3 drops) with stirring for 1 h at 90°C in an oil bath with an inert atmosphere of nitrogen. The reaction mixture was concentrated under vacuum and then purified by a silica gel column with 1% to 4% ethyl acetate in petroleum ether to afford methyl 6—(benzo[b]thiophen—2-yl)—7— (isopropyl(methyl)amino)—2—naphthoate as a light yellow solid (140 mg, 87.5%).
LC/MS (ES, m/z): [M+H]+ 392.0 1H-NMR (300 MHz,CDC13)5 8.57 (d, J: 1.2 Hz, 1H), 8.21(s, 1H), 8.09 - 8.13 (m, 1H), 8.00 (d, J: 8.4 Hz, 1H), 7.90 ~ 7.93 (m, 1H), 7.83 — 7.87 (m, 1H), 7.39 - 7.43 (m, 2H), 7.32 - 4.41 (m, 1H), 4.01 (s, 3H), 2.93 (s, 3H), 1.24 (d, J: 6.6 Hz, 6H) Step 2. 2—(Benzo[b]thiophen—2~yl)~3~(isopropyl(methyl)amino)quinoxaline-6—carboxylic acid INDCOOH To a solution of methyl 2-(benzo[b]thiophen—Z—yl)(isopropyl(methyl)amino)quinoxaline-6— carboxylate (140 mg, 0.36 mmol) in ydrofuran (25 mL) was added sodium hydroxide (43.2 mg, 1.08 mmol) and water(2 mL) with stirring overnight at room temperature. The on mixture was concentrated under vacuum, dissolved in water (20 mL) and adjusted to pH 5 with hydrochloric acid (3 N). The solids were ted by filtration to afford 2— (benzo[b]thiophen—2—yl)(isopropyl(methy1)amino)quinoxaline—6—carboxylic acid as a yellow solid (80 mg, 59%).
LC/MS (ES, m/z): [M+H]+ 378.1 1H—NMR (300 MHz, DMSO) 6 8.28 (s, 1H), 7.98 — 8.05 (m, 3H), 7.90 — 7.94 (m, 1H), 7.42 - 7.45 (m, 2H), 4.18 - 4.27 (m, 1H), 2.85 (s, 3H), 1.17 (d, J = 6.6 Hz, 6H) EXAMPLE 24 2-(5-Fluorobenzo[b]thiophen-Z-yl)(isopropyl(methyl)amino)quinoxalinecarboxylic acid 2012/027423 Step 1. Methyl 2—(5-fluorobenzo[b]thiophenyl)(isopropy1(methy1)amino)quinoxaline ylate Y O /N /N]©/lko/ \ N To a solution of 5-fluorobenzo[b]thiophen—2-ylboronic acid (202 mg, 1.03 mmol) in dioxane (6 mL) was added methyl 2—chloro~3-(isopropyl(methyl)amino)quinoxalinecarboxy1ate (120 mg, 0.41 mmol), K3PO4 (259 mg, 1.23 mmol) , Pd(PPh3)4 (24.0 mg, 0.02 mmol) and water (3 drops) with stirring for 0.5 h at 90°C in an oil bath with an inert here of nitrogen. The reaction mixture was concentrated under vacuum and then purified by a silica gel column with 1% to 2% ethyl acetate in petroleum ether to afford methyl 2—(5— fluorobenzo[b]thiophen—2-yl)(isopropyl(methyl)amino)quinoxaline—6—carboxy1ate as a light yellow solid (148 mg, 88%).
LC/MS (ES, m/z): [M+H]+ 410.0 1H-NMR (300 MHz, CDC13) 5 8.54 (d, J: 1.5 Hz, 1H), 8.10 - 8.15 (m, 2H), 8.00 (d, J = 8.4 Hz, 1H), 7.81 - 7.86 (m, 1H), 7.43 - 7.53 (m, 1H), 7.14 - 7.21 (m, 1H), 4.2? - 4.36 (m, 1H), 4.01 (s, 3H), 2.91 (s, 3H), 1.23 (d, J: 6.6 Hz, 6H) Step 2. 2—(5—Flu0r0benzo[b]thiophen—2-yl)—3—(isopropy1(methyl)amino)quinoxaline—6— carboxylic acid To a solution of methyl 2-(5-fluorobenzo[b]thiophen~2-yl)—3— (isopropyl(methyl)amino)quinoxaline-6—carboxylate (148 mg, 0.36 mmol) in tetrahydrofuran (25 mL) was added sodium hydroxide (43.4 mg, 1.08 mmol) and water(2 mL) with stirring overnight at room temperature. The reaction mixture was concentrated under vacuum, dissolved in water (20 mL) and adjusted to pH 5 with hydrochloric acid (3N). The solids were ted by filtration to afford 2-(5-fluorobenzo[b]thiopheny1) (isopropyl(methyl)amino)quinoxaline—6-carboxy1ic acid (69 mg, 49%).
LC/MS(ES, m/z): [M+H]+ 396.0 1H—NMR (300 MHz, DMSO) 5 8.29 (d, J: 1.5 Hz, 1H), 8.25 (s, 1H), 8.06 - 8.11 (m, 1H), 7.95 - 8.03 (m, 2H), 7.84 - 7.89 (dd, J: 2.7 Hz, J: 2.4 Hz, 1H), 7.31 - 7.38 (m, 1H), 4.19 - 4.28 (m, 1H), 2.84 (s, 3H), 1.17 (d, J = 6.3 Hz, 6H) E 25 3-(Isopropyl(methyl)amin0)-2—(1-methyl-IH-indazol-S-yl)quinoxaline-G-carboxylic acid /N /N COOH Step 1. Methyl 3-(isopropyl(methyl)amino)~2—(1—methyl—JH—indaz.olyl)quinoxaline-6— carboxylate Y O / /N O/ To a solution of 1-methyl—IH—indazol-S—ylboronic acid (180 mg, 1.02 mmol) in dioxane (3 mL) was added methyl 2-ch10r0—3-(isopropyl(methyl)amino)quinoxaline—6—carboxylate (Scheme 1, 109 mg, 0.37 mmol), K3PO4 (175 mg, 0.83 mmol) , Pd(PPh3)4 (29 mg, 0.03 mmol) and water (3 drops) with stirring for 1 h at 90°C in an oil bath with an inert atmosphere of nitrogen. The reaction mixture was concentrated under vacuum and then purified by a silica gel column with 10% ethyl e in petroleum ether to afford methyl 3- (isopropyl(methyl)amino)-2—(1~methyl-1H—indazol—5—yl)quinoxalinecarboxylate as a light yellow solid (110 mg, 76%).
LC/MS (ES, m/z): [M+H]+ 390.0 1H-NMR (300 MHZ, CDC13) 5 8.68 (s, 1H), 8.35 (d, J = 0.9 Hz, 1H), 8.07 - 8.11 (m, 3H), 7.96 - 8.00 (m, 1H), 7.52 (d, J: 6.0 Hz, 1H), 4.30 - 4.39 (m, 1H), 4.16 (s, 3H), 4.01 (s, 3H), 2.81 (s, 3H), 1.09 (d, J: 6.6 Hz, 6H) WO 19046 Step 2. 3-(Isopropyl(methyl)amino)—2-(l —methyl-1H—indazol-5—yl)quinoxalinecarboxylic acid /N /N\N: : COOH To a solution of methyl 3—(isopropyl(methy1)amino)(1-methyl—]H—indazol—5— yl)quinoxaline—6—carboxy1ate (110 mg, 0.28 mmol) in methanol (20 mL) and CHC13 (6 mL) was added sodium hydroxide (20 mg, 0.50 mmol) and water (1 mL). The resulting solution was stirred overnight at room temperature and concentrated under vacuum. The residue was dissolved in water (10 mL) and adjusted to pH 6 with hydrochloric acid (3N). The solids were collected by tion to afford propyl(methyl)amino)(l-methyl-JH—indazol—S- yl)quinoxalinecarboxy1ic acid (50 mg, 47%).
LC/MS (ES, m/z): [M+H]+ 376.1 1H-NMR (300 MHz, DMSO): 5 8.31 (d, J = 0.6 Hz, 1H), 8.27 - 8.28 (t, J = 1.2 Hz, 1H), 8.19 (d, J: 0.9 Hz, 1H), 7.91 - 7.95 (m, 3H), 7.79 (d, J: 8.7 Hz, 1H), 4.19 - 4.23 (m, 1H), 4.11 (s, 3H), 2.69(s, 3H), 1.01(d, J: 6.6 Hz, 6H) EXAMPLE 26 2-(1-Ethyl-1H-indazol-5—yl)-3~(isopr0pyl(methyl)amino)quinoxaline-fi-carboxylic acid whoCOOH Step 1. 5—Bromo— l-ethyl-IH-indazole To a solution of 5-bromo-JH-indazole (l g, 5.10 mmol) in tetrahydrofuran (30 mL) was added sodium hydride (330 mg, 8.25 mmol) at 0°C with stirring for 30 min, iodoethane WO 19046 (1.72 g, 11.04 mmol) was added dropwise. The reaction mixture was stirred overnight at room temperature. The reaction was then ed with water (50 mL), extracted with ethyl acetate (3 x 80 mL) and the organic layers combined, dried over anhydrous magnesium sulfate and concentrated under vacuum to give the residue, which was purified by a silica gel column with 1% to 5% ethyl acetate in petroleum ether to afford 5—bromo—1—ethyl-1H— le as yellow oil (598 mg, 52%).
LC/MS (ES, m/z): [M+H]Jr 225 1H-NMR (300 MHz, CDC13)Z 8 7.95 (d, J = 0.3 Hz, 1H), 7.88 - 7.89 (t, J: 1.2 Hz, 1H), 7.44 - 7.48 (m, 1H), 7.28 — 7.33 (m, 1H), 4.40 - 4.47(m, 2H), 1.48 — 1.55 (m, 3H) Step 2. 1-Ethyl—IH-indazol-S-ylboronic acid B(OH)2 A solution of 5-bromo—1-ethyl-1H—indazole (598 mg, 2.67 mmol) in dry tetrahydrofuran (30 mL) was cooled below -60°C. Then a solution of butyllithium in hexane (2.5 ml, 2.5M) was added dropwise. It was warmed to -10°C during 45 min and stirred at this temperature for another 30 min. The mixture was cooled again below -60°C followed by se addition of triisopropyl borate (1.5 g, 7.98 mmol). After g to room temperature the e was quenched with hydrochloric acid (3N) and stirred for 1 h. The alkaline aqueous layer was brought to pH 5 and extracted with ethyl acetate (3 x 80 ml). A11 organic layers were combined, dried over sodium sulfate, and concentrated in vacuum to give l-ethyl-IH— indazol-S—ylboronic acid (450 mg, 89%) which was used for the next step without further purification. 1H—NMR (300 MHZ, DMSO) 8 8.29(d, J: 1.5 Hz, 1H), 8.24 (s, 1H), 8.07 (d, J: 0.6 Hz, 1H), 7.77 - 7.80 (m, 1H), 7.59 (d, J = 8.4 Hz, 1H), 4.39 ~ 4.46 (in, 2H), 1.29 —1.41(m, 3H) Step 3. Methyl 2-(1-ethy1-JH—indazol—S—yl)-3—(isopropyl(methyl)amino)quinoxaline carboxylate Y O / /N N@0/ To a solution of l-ethy1-]H—indazol-S—ylboronic acid (196 mg, 1.03 mmol) in dioxane (6 mL) was added methyl 2—chloro—3-(isopropyl(methyl)amino)quinoxalinecarboxylate (Scheme I, 120 mg, 0.41 mmol), K3PO4 (259 mg, 1.23 mmol), Pd(PPh3)4 (20 mg, 0.02 mmol) and water (5drops) with stirring for 4 h at 90°C in an oil bath under an inert atmosphere of en. The reaction mixture was concentrated under vacuum and then purified by a silica gel column with 1% to 5% ethyl acetate in petroleum ether to afford methyl 2—(1—ethyl-IH— indazol-S-yl)(isopropyl(methyl)amino)quinoxaline~6—carboxylate as a light yellow solid (80 mg, 49%).
LC/MS (ES, m/z): [M+H]+ 404.0 1H-NMR (300 MHz, CDC13) 5 8.80 (s, 1H), 8.34 (s, 1H), 8.10 - 8.13 (m, 3H), 7.93 - 7.97 (m, 1H), 7.58 (d, J: 8.7 Hz, 1H), 4.42 ~ 4.55 (m, 3H), 4.01 (s, 3H), 2.87 (s, 3H), 1.55 —1.61 (t, J = 7.2 Hz, 3H), 1.13 (d, J: 6.6 Hz, 6H) Step 4. 2—(1-Ethy1-]H—indazol-5—yl)—3~(isopropyl(methyl)amino)quinoxalinecarboxylic acid DIDCOOH To a solution of methyl 2—(1—ethyl—JH—indazoly1)(isopropyl(methyl)amino)quinoxaline— oxylate (80 mg, 0.20 mmol) in tetrahydrofuran (25 mL) was added sodium hydroxide (34 mg, 0.85 mmol) and water (2 mL) with stirring overnight at room temperature. The reaction mixture was concentrated under vacuum, ved in water (20 mL) and adjusted to pH 5 with HCI (3N). The solids were collected by filtration to afford thyl—1H—indazol— -yl)—3—(isopropyl(methyl)amino)quinoxaline-6—carboxylic acid as yellow solid (18.6 mg, 24%).
LC/MS (ES, m/z): [M+H]+ 390.0 1H—NMR (300 MHz, DMSO) 5 8.32 (s, 1H), 8.26 (s, 1H), 8.20 (s, 1H), 7.79 - 7.98 (m, 4H), 4.46 - 4.53 (m, 2H), 4.13 - 4.21 (m, 1H), 2.69(s, 1H), 1.42 - 1.47 (t, J: 7.2 Hz, 3H), 1.01(d, J = 6.3 Hz, 6H) PCT/U52012/027423 EXAMPLE 27 enzofuran-Z-yl)(diethylamino)quinoxalinecarboxylic acid K o \ N Step 1. Methyl 3—(diethylamino)—2-hydroxyquinoxalinecarboxylate K o O N To a solution of methyl 3-chlorohydroxyquinoxaline-6—carboxylate (450 mg, crude) in DMSO (5 mL) was added diethylamine (550 mg, 7.52 mmol), DIEA (492 mg, 3.81 mmol).
After stirring for 2 h at 70°C, the resulting solution was diluted with water (50 mL), extracted with ethyl acetate (4 x 20 mL), dried over anhydrous magnesium sulfate and concentrated under reduced re to afford a residue, which was purified by a silica gel column with % ethyl acetate in petroleum ether to afford methyl 3—(diethylamino)~2-hydroxyquinoxaline- 6-carboxylate as a yellow solid (160 mg).
LC/MS (ES, m/z): [M+H]+ 276.0 1H-NMR (300 MHz, CDC13) 5 9.86 (s, 1H), 8.24 (s, 1H), 7.77 — 7.81 (m, 1H), 7.03 (d, J = 8.4 Hz, 1H), 3.92 (s, 1H), 3.85 — 3.89 (m, 4H), 1.29 — 1.34 (m, 6H) Step 2. Methyl 3—(diethylamino)—2-[(trifluoromethane)sulfonyloxy]quinoxaline—6*carboxylate K o \/N /NI>/U\O/ TfO N To a solution of methyl 3—(diethylamino)hydroxyquinoxalinecarboxylate (150 mg, 0.54 mmol) in dichloromethane (20 mL) was added pyridine (260 mg, 3.29 mmol) and ngO (460 mg, 1.63 mmol). After stirring overnight at room temperature, the reaction was quenched by the addition water/ice (50 mL), extracted with romethane (2 x 10 mL), dried over anhydrous magnesium sulfate and concentrated under vacuum to give methyl 3— PCT/U82012/027423 (diethylamino)—2—[(trifluoromethane)sulfonyloxy]quinoxaline—6—carboxylate as red oil (200 mg, crude).
Step 3. Methyl 2-(1-benzofuran-2—yl)(diethylamino)quinoxalinecarboxylate To a solution of methyl 3—(diethylamino)-2—[(trifluoromethane)su1fonyloxy]quinoxaline—6- carboxylate (200 mg, crude) in dioxane (4 mL) was added (l-benzofuran-2—yl)boronic acid (170 mg, 1.05 mmol), K3P04 (230 mg, 1.08 mmol), Pd(PPh3)4 (30 mg, 0.03 mmol) and water (3 drops) under nitrogen atmosphere. After stirring l h at 90°C, the reaction mixture was ved in water (40 mL), extracted with dichloromethane (3 x 20 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure to afford a residue, which was ed by a silica gel column with 2% ethyl e in petroleum ether to afford methyl 2-(1-benzofuran-2—yl)(diethylamino)quinoxaline-6—carboxylate as a light yellow solid (70 mg, 38%).
LC/MS (ES, m/z): [M+H]+ 376.0 1H—NMR (300 MHz, CDClg) 5 8.59 (s, 1H), 8.12 (d, J = 1.8 Hz, 2H), 7.68- 7.76 (m, 3H), 7.40- 7.45 (m, 1H), 7.30— 7.35 (t, J = 7.2 Hz, 1H), 3.99 (s, 3H), 3.49 — 3.56 (m, 4H), 1.18 - 1.22 (m, 6H) Step 4. 2-(1~Benzofuran—2—yl)—3—(diethylamino)quinoxaline—6-carboxylic acid K o \ /N1(>/U\OH\N To a solution of methyl 2—(1-benzofuran—2—yl)—3—(diethylamino)quinoxaline-6—carboxy1ate (65 mg, 0.17 mmol) in methanol (10 mL) and water (1 mL) was added sodium hydroxide (13 mg, 0.33 mmol). After stirring overnight at room ature, the reaction mixture was concentrated under reduced pressure to afford a residue, which was dissolved in water (10 W0 2012l119046 mL), adjusted the pH to 6 with 3N HCl and ed to give 2-(1-benzofuran-2—yl) (diethylamino)quinoxaline-6—carboxylic acid as a light yellow solid (32.2 mg, 51%).
LC/MS (ES, m/z): [M+H]+ 362.0 1H-NMR (300 MHZ, DMSO) 5 13.23 (s, 1H), 8.29 (s, 1H), 7.99 - 8.05 (m, 2H), 7.74— 7.83 (m, 3H), 7.43— 7.49 (m, 1H), 7.33- 7.38 (t, J = 7.2 Hz, 1H), 3.43 - 3.47 (m, 4H), 1.10 - 1.15 (m, 6H) EXAMPLE 28 2-(6-Fluoro-l-benzofuran-Z-yl)[(ZS)methylpiperidinyl]quinoxaline-fi-carboxylic acid 01 N COOH \ N Step 1. Methyl 3-[(2S)methylpiperidin-l-yl]oxo-1 ,2-dihydroquinoxalinecarboxylate 0..» O N NULO/ To a on of methyl 3~Chlorooxo-1, 2—dihydroquinoxaline-6—carboxylate (500 mg, crude) in DMSO (6 mL) was added DIEA (543 mg, 4.20 mmol), (2S)—2—methylpiperidine (104 mg, 1.05mmol). The solution was stirred for 6 h at 100°C. Then the reaction was quenched by the addition of water (50 mL). The resulting solution was extracted with ethyl acetate (4 x 30 mL) and the organic layers were concentrated under vacuum. The residue was purified by a silica gel column with 1% - 5% ethyl acetate in eum ether to afford methyl 3—[(2S)-2—methylpiperidiny1]oxo-l,2—dihydroquinoxaline—6—carboxylate as a yellow solid (98 mg).
LC/MS (ES, m/z): [M+H]+ 302.0 1H—NMR (300 MHZ, CDC13) 5 9.39 (s, 1H), 8.28 (s, 1H), 7.83 — 7.86 (m, 1H), 7.05 (d, J: 8.4 Hz, 1H), 5.36 - 5.40 (m, 1H), 4.88 (d, J=13.5 Hz, 1H), 3.94 (s, 1H), 3.16 - 3.25 (t, J: 13.2 Hz, 1H), 1.50 - 1.94 (m, 6H), 1.44 (d, J: 6.6 Hz, 3H) Step 2. (S)—Methyl 3—(2-methylpiperidin—1-yl)-2—(trifluoromethylsulfonyloxy)quinoxaline carboxylate ON 0 TfOIN/NDjko/ To a solution of methyl 3—[(2S)-2—methylpiperidinyl]oxo-1,2-dihydroquinoxaline~6~ carboxylate (98 mg, 0.33 mmol) in dichloromethane (30 mL) was added pyridine (104 mg, 1.31 mmol), and then ngO (186 mg, 0.66 mmol) was added dropwise with ng at 0°C.
The resulting on was stirred overnight at room temperature and then ed by the addition of ice-water (20 mL), extracted with dichloromethane (3 x 10 mL), dried over anhydrous sodium sulfate and concentrated under vacuum to afford (S)-methyl 3-(2- methylpipen'din-l~yl)(trifluoromethylsulfonyloxy)quinoxalinecarboxy1ate as red oil (200mg, crude).
Step 3. Methyl 2—(6—fluoro-IH—inden-Z-y1)—3—[(25)—2—methylpipe1idinyl]quinoxaline carboxylate \ N To a solution of methyl 3-[(2S)methylpiperidinyl] [(trifluoromethane)sulfonyloxy]quinoxalinecarboxylate (200 mg, crude) in dioxane (5 mL) was added 2—(6-fluoro—1—benzofuran—2—yl)—4,4,5,5—tetramethy1—1,3,2—dioxaborolane (250 mg, 0.95 mmol), Pd(PPh3)4 (27 mg, 0.02 mmol), K3PO4 (291 mg, 1.37 mmol) and water (5 drops) with ng 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 applied onto a silica gel column with 1% to 2% ethyl acetate in petroleum to afford methyl 2-(6— PCT/U52012/027423 -IH—inden—2—yl)-3—[(2S)methylpiperidin—1-yl]quinoxalinecarb0xylate as a yellow solid (50 mg).
LC/MS (ES,m/z): [M+H]+ 420.0 1H—NMR (300 MHZ, CDC13) 5 8.67 (s, 1H), 8.12 — 8.20 (m, 2H), 7.97 (s, 1H), 7.63 - 7.68(m,1H), 7.39 — 7.43 (m, 1H), 7.07 - ,1H), 4.19 (s, 1H), 4.02 (s, 3H), 3.39 (s, 1H), 1.65 — 1.85 (m, 6H),1.19(d, J: 6.3 Hz, 3H) Step 4. 2-(6—Fluorobenzofuranyl)-3~[(2S)methylpiperidin—1—yl]quin0xaline—6- carboxylic acid 01 N COOH \ N To a solution of methyl 2—(6-fluorobenzofuran—2—yl)-3—[(2S)-2—methylpiperidin-1— yl]quinoxalinecarboxylate (50 mg, 0.12 mmol) in methanol (25 mL) and water (5 mL) was added sodium hydroxide (14.4 mg, 0.36 mmol) with ng overnight at room temperature.
The reaction mixture was concentrated under vacuum, dissolved in water (30 mL), adjusted pH to 5 with HCl (3N) to give the precipitate, which was collected by filtration to afford 2-(6- fluoro-1—benzofuran—2—yl)—3-[(2S)—2—methylpiperidinyl]quinoxa1ine—6-carboxylic acid (36.6 mg, 76%).
LC/MS (ES, m/z): [M+H]Jr 406.0 1H—NMR (300 MHZ, DMSO) 5 8.29 (s, 1H), 8.03 (s, 2H), 7.96 (s, 1H), 7.81 — 7.86 (m,1H), 7.65 (d, J: 9.0 HZ, 1H), 7.18 - 7.25 (111,1H), 4.00 (d, J: 9.0 Hz, 1H), 3.27 (s, 1H),1.80 — 1.95 (m, 1H), 1.47 — 1.66 (m, 5H), 1.05 (d, J: 6.6 Hz, 3H) PCT/U82012/027423 EXAMPLE 29 3-(Cyclopropyl(methyl)amino)(1H-indazolyl)quinoxalinecarboxylic acid V O /N /N OH Step 1. Methyl 3—(cyclopropyl(methyl)amino)(trifluoromethylsulfonyloxy)quinoxaline—6- carboxylate Y o TfOIN/NDAO/ To a solution of methyl 3-(cyclopropyl(methyl)amino)-2—oxo-1,2—dihydroquinoxaline ylate (240 mg, 0.88 mmol) in DCM (50 mL) was added pyridine (280 mg, 3.54 mmol) and TfZO (496 mg, 1.76 mmol). The resulting solution was stirred 3h at room temperature and then dissolved in water/ice (100 mL), extracted with dichloromethane (3 x 20 mL), dried over anhydrous magnesium sulfate and concentrated under vacuum to afford methyl 3- (cyclopropyl(methyl)amino)-2—(trifluoromethylsulfonyloxy)quinoxalinecarboxylate as a red oil (300 mg , crude), which was used to the next step directly.
Step 2. lopropyl(methyl)amino)—2—(1H—indazol-S~yl)quinoxalinecarboxylate V 0 /N JuDJKO/ To a solution of methyl 3-(cyclopropyl(methyl)amino) (trifluoromethylsulfonyloxy)quinoxalinecarboxylate (300 mg, crude) in dioxane (10 mL), 1H—indazol-5~ylboronic acid (430 mg, 1.76 mmol), K3PO4 (370 mg, 1.76 mmol), and Pd(PPh3)4 (51mg, 0.04 mmol). The ing solution was stirred for 1h at 90°C. The ing mixture was concentrated under vacuum to give a residue, which was purified by a silica gel PCT/U52012/027423 column with 5% ~ 50% ethyl acetate in petroleum ether to afford methyl 3— (cyclopropyl(methyl)amino)(1H—indazol-S-yl)quinoxaline—6-carboxy1ate as a yellow solid (40 mg).
LC/MS (BS, m/z): [M+H]+ 374.0 1H—NMR (300 MHZ, CDC13) 5 8.96 (s, 1H), 8.28 (s, 2H), 8.10 — 8.18 (m, 2H), 7.88 (d, J = 7.8 Hz, 1H), 7.68 (d, J: 8.7 Hz, 2H), 4.02 (s, 3H), 2.70 — 2.80 (m, 1H), 0.83- 0.92 (m, 4H) Step 3. 3-(Cyclopropyl(methyl)amino)-2~(lH—indazol-5—yl)quinoxalinecarboxylic acid V 0 /N /N OH To a solution of lopropyl(methyl)amino)—2—(1H—indazol-5—y1)quinoxaline carboxylate (40.0 mg, 0.11 mmol,) in methanol (15 mL) and water (1 mL) was added a solution of NaOH (20 mg, 0.50 mmol). The resulting solution was stirred overnight at room temperature and concentrated under vacuum. The residue was dissolved in water (5 mL) and adjusted to pH 6 with hydrochloric acid (3N). The solids were collected by filtration to afford lopropy1(methyl)amino)-2—(1H—indazol—S—yl)quinoxaline—6—Carboxylic acid as a yellow solid (18?. mg, 47%).
LC/MS (ES, m/z): [M+H]+ 360.0 1H—NMR (300 MHz, CDgOD), 5 8.48 (d, J = 1.8 Hz, 1H), 8.27 (d, J = 0.3 Hz, 1H), 8.19 (d, J = 0.6 Hz, 1H), 8.05 — 8.08 (m, 1H), 7.91 — 7.99 (m, 2H), 7.68 (d, J = 8.7 Hz, 1H), 3.07 (s, 3H), 2.55 (d, J = 5.4 Hz, 1H), 0.50 (d, J = 5.4 Hz, 4H) EXAMPLE 30 2-(1-Benzofuranyl)[methyl(propan-Z-yl)amino]quinoxalinecarboxylic acid Y 0 CQIN\O Step 1. (l-Benzofuran—5-yl)boronic acid 1:00 (HO)2B The solution of 5—bromo-l-benzofuran (1.0 g, 5.08 mmol) in dry tetrahydrofuran (50 mL) was kept below —60°C under nitrogen, while BuLi (6.09n1mol, 2.5M solution in hexane) was added dropwise. It was warmed to -30°C during 45 min and stirred at this temperature for another 30 min. The mixture was cooled again below —60°C followed by dropwise addition of triisopropyl borate (1.44 g, 7.66 mmol). After g to room temperature the mixture was ed with hydrochloric acid (30 mL, 2N) and stirred for l h. The alkaline aqueous layer was brought to pH 5 and extracted with ethyl e (3 x 80 mL). All organic layers were ed, dried over sodium sulfate, and concentrated in. vacuo to give (l—benzofuran-S-yl) boronic acid (500 mg, crude), which was used for the next step without further purification.
Step 2. Methyl 2-(l—benzofuran-S-yl)-3—[methyl(propan—2—yl)amino]quinoxaline-6~ carboxylate Y o /N /N]©)LO/ To a solution of methyl ro—3—[methyl(propanyl)amino]quinoxaline-6—carboxylate (100 mg, 0.34 mmol) in dioxane (5.0 mL) was added (l-benzofuran—S—yl) boronic acid (215.6 mg, 1.33 mmol), K3P04 (280.6 mg, 1.33 mmol), Pd(PPh3)4 (25.56 mg, 0.02 mmol) and water (3 drops) with stirring for l h at 90°C in an oil bath under an inert atmosphere of nitrogen.
The reaction e was concentrated under vacuum to give a residue, which was purified by a silica gel column with 1% ethyl acetate in petroleum ether to afford methyl 2—(l- benzofuran—S—yl)[methyl(propanyl)amino]quinoxaline-6—carboxylate as a light yellow solid (105 mg, crude). LC/MS (ES, m/z): 376.0 Step 3. 2-(1-Benzofuranyl)[methyl(propany1)amino]quinoxaline—6-carboxylic acid Y 0 /N /NfiOH To a on of methyl 2—(1—benzofuranyl)—3-[methyl(propanyl)amino]quinoxaline—6— ylate (105 mg, crude) in methanol (30 mL) was added sodium hydroxide (59.7 mg, 1.49 mmol) with stirring overnight at room temperature. The reaction mixture was concentrated under vacuum, dissolved in water (30 mL) and adjusted to pH 5 with HCl (3N), extracted with ethyl acetate (3 x 80 mL) and the organic layers combined, dried over anhydrous magnesium sulfate and concentrated under vacuum to give the residue, which was purified by Prep-HPLC under the ing conditions [(Agilent 1200 prep HPLC): Column, SunFire Prep C18, 19 * 50 mm 5 um; mobile phase, water with 0.05% NH3‘HZO and CH3CN (10% CH3CN up to 45% in 10 min); Detector, UV 220nm] to afford enzofurany1)—3— [methyl(propanyl)amino]quinoxaline-6—carboxylic acid as a yellow solid (26.3 mg).
LC/MS (ES, m/z): [M+H]+ 362.0 1H-NMR (300 MHz, DMSO): 5 8.23 (d, J: 1.5 Hz, 1H), 8.17 (d, J = 1.5 Hz, 1H), 8.08 (d,J = 2.1 Hz, 1H), 7.95 — 7.98 (dd, 11 = 1.8 Hz,J2=1.5 Hz, 1H), 7.81 - 7.88 (m, 2H), 7.72 (d, J: 9.0 Hz, 1H), 7.08 - 7.09 (m, 1H), 4.09 — 4.16 (m, 1H), 2.69 (s, 3H), 1.00 (d, J = 6.6 Hz, 6H) EXAMPLE 31 2-(6-Chlorobenzofuranyl)[methyl(propanyl)amin0]quinoxalinecarb0xyiic acid Y o \ \N Step 1. Methyl 4—chlorohydroxybenzoate Cl0%“OH To a solution of 4-chloro-2—hydroxybenzoic acid (20 g, 115.90 mmol) in methanol (500 mL) was added l Chloride (26 mL). After refluxing for 3 h, the reaction mixture was trated under vacuum, dissolved in petroleum ether (300 mL) and filtered to give methyl 4-chloro—2—hydroxybenzoate as a white solid (21 g, 95%). 1H-NMR (300 MHz, CDC13) 5 10.88 (s, 1H), 7.77 (d, J: 8.4 Hz, 1H), 7.02 (d, J = 2.1 Hz, 1H), 6.86 - 6.90 (m, 1H), 3.97 (s, 3H) Step 2. Methyl ro-2—(2-ethoxyoxoethoxy)benzoate To a solution of methyl 4-chlorohydroxybenzoate (21 g, 112.55 mmol) in acetone (200 mL) was added ethyl 2-bromoacetate (28.3 g, 169.46 mmol) and potassium carbonate (23.4 g, 169.31 mmol). After refluxing for 3 h, the solids were collected by filtration. The resulting mixture was concentrated under vacuum, dissolved in petroleum ether (300 mL) and filtered to give methyl 4-chloro(2-ethoxyoxoethoxy)benzoate as a red solid (26 g, 85%).
Step 3. boxymethoxy)—4—chlorobenzoic acid Cldo”O/YOH To a solution of methyl 4—chloro~2—(2-ethoxy—2-oxoethoxy)benzoate (10 g, 36.67 mmol) in methanol (250 mL) and water (50 mL) was added potassium hydroxide (4 g, 71.43 mmol).
After stirring for 1.5 h at 25°C, the ing mixture was concentrated under vacuum, dissolved in water (50 mL), adjusted to pH 6 with HCl (3N) and filtered to give 2- (carboxymethoxy)~4-chlor0benzoic acid as a white solid (7 g, 80%). 1H—NMR (300 MHz, DMSO) 5 7.50 (d, J = 8.1 Hz, 1H), 7.39 (d, J = 1.8 Hz, 1H), 7.08 — 7.11 (m, 1H), 4.62 (s, 2H) WO 19046 PCT/U82012/027423 Step 4. 6-Methyl- 1 furanyl acetate CI1360 To a solution of 4—chloro(2,3-dioxobutoxy)benzoic acid (5 g, 19.48 mmol) in HOAC (80 mL) and AczO (100 mL) was added NaOAc (4.2 g, 51.22 mmol). After stirring for 3 h at 150°C, the resulting mixture was dissolved in water (1000 mL), extracted with ethyl e (3 x 200 mL), dried over anhydrous magnesium e and concentrated in vacuo to give 6— methyl-l—benzofuranyl acetate as off-white oil (3.8 g, 85%). 1H-NMR (300 MHZ, DMSO) 5 8.25 (s, 1H), 7.82 (d, J = 1.8 Hz, 1H),7.60 (d, J = 8.4 Hz, 1H), 7.35 — 7.39 (m, 1H), 2.38 (s, 3H) Step 5. 6-Methy1-2,3—dihydrobenzofuran—3-one A solution of 6-methyl-1—benzofuran-3—y1 acetate (3.8 g, 19.98 mmol) in HCl (4 mL, conc), methanol (160 mL), and water (40 mL) was heated under reflux for 1.5 h, the reaction mixture was cooled to room temperature, dissolved in water (200 mL) and filtered to give 6- methyl-2,3-dihydro-1—benzofuranone as a white solid (2.5 g, 82%). 1H-NMR (300 MHz, DMSO) 87.65 - 7.69 (t, J: 8.1 Hz, 1H), 7.50 (d, J: 1.5 Hz, 1H), 7.18 - 7.22 (m, 1H), 4.85 (s, 2H) Step 6. 6-Chloro—1—benzofuran Clco0 To a solution of 6-chloro-2,3—dihydro—1—benzofuran—3-one (2.5 g, 14.83 mmol) in methanol (50 mL) was treated with NaBH4 (1.2 g, 31.58 mmol) in four equivalent portions at room temperature, until the reaction was complete, as monitored by TLC (1 h). The reaction mixture was quenched by the addition of e (10 mL). This mixture was then treated with HCl (3N, 20 mL). After stirring for another 1 h, the resulting solution was extracted with PCT/U82012/027423 ethyl acetate (3 x 50 mL) dried over anhydrous ium sulfate and concentrated under vacuum to give 6-chlorobenzofuran as oil (2 g, crude).
Step 7. 2-(6-Chloro—1~benzofuran~2~yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane To a solution of 6—chlorobenzofuran (2 g, 13.11 mmol) in tetrahydrofuran (30 mL) was added n—BuLi (10 mL, 2.5N) at —78°C and stirred for 1.5h. Then 4,4,5,5—tetramethy1—2— (propan—2-yloxy)-1,3,2~dioxaborolane (4.4 g, 23.65 mmol) was added and d for 1.5 h.
The reaction solution was quenched by water (100 mL), extracted with ethyl acetate (3 x 50 mL), dried over anhydrous magnesium sulfate and concentrated under vacuum to give 2-(6- chloro-1~benzofuranyl)-4,4,5,5-tetramethy1-1,3,2—dioxaborolane as a h crude solid (3 g , crude).
Step 8. Methyl 2-(6—chlorobenzofuran—2—y1)[methyl(propan-2—y1)amino]quinoxaline-6— carboxylate Y o /N ,N@0/ To a solution of methyl ro—3—[methy1(propan—2—yl)amino]quinoxaline—6—carboxylate (100 mg, 0.34 mmol) in 1,4-dioxane (1 mL) was added 2—(6-chlorobenzofuran—2-yl)— 4,4,5,5-tetramethyl~1,3,2-dioxaborolane (300 mg, crude), and K3PO4 (140 mg, 0.66 mmol), Pd(PPh3)4 (20 mg, 0.02 mmol) under nitrogen atmosphere. After stirring l h at 95°C, the reaction mixture was ved in water (50 mL), extracted with dichloromethane (3 x 30 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure to afford a residue, which was purified by a silica gel column with 2% ethyl acetate in petroleum ether to afford methyl 2-(6-chloro-1—benzofuranyl)-3—[methy1(propan yl)amino]quinoxaline—6—carboxylate as a light yellow solid (60 mg, 43%).
LC/MS (ES, m/z): [M+H]+ 410.0 W0 2012;119046 PCT/U82012/027423 1H-NMR (300 MHz, CDCI3) 5 8.60 (d, J = 1.5 Hz, 1H), 8.04 — 8.13 (m, 2H), 7.60 — 7.67 (m, 3H), 7.30 - 7.33 (m, 1H), 4.31 - 4.35 (t, J: 6.6 Hz, 1H), 4.01 (s, 3H), 2.93 (s, 3H), 1.23 (d, J = 6.6 Hz, 6H) Step 9. 2-(6-Chloro— l -benzofuran-2—yl)-3—[methyl(propanyl)amino]quinoxaline-6— carboxylic acid Y O @510 O” \ \N To a solution of methyl 2~(6—chloro-l—benzofuranyl)—3—[methy1(propan—2— yl)amino]quinoxa1ine—6~carboxy1ate (60 mg, 0.15 mmol) in methanol (20 mL) and water (1 mL) was added sodium hydroxide (16 mg, 0.40 mmol). After stirring overnight at room temperature, the reaction mixture was trated under reduced pressure to afford a residue, which was ved in water (20 mL), adjusted the pH to 6 with 3N HCl and filtered to give 2-(6—chloro-l—benzofuranyl)[methy1(propan-2—yl)amino]quinoxaline—6— carboxylic acid as a light yellow solid (25.2 mg, 43%).
LC/MS (ES, m/z): [M+H]+ 396.0 1H—NMR (300 MHZ, DMSO) 5 8.28 (s, 1H), 7.96 — 8.00 (m, 3H), 7.81 (d, J: 8.4 Hz, 1H), 7.70 (d, J = 0.9 Hz, 1H), 7.38 — 7.42 (m, 1H), 4.16 - 4.21 (t, J = 6.6 Hz, 1H), 2.82 (s, 3H), 1.15 (d, J: 6.6 HZ, 6H) EXAMPLE 32 (S)(6-Fluorobenzofuranyl)(Z-methylpyrrolidin-l-yl)quinoxalinecarb0xylic acid PCT/U82012/027423 Step 1. (S)-Methyl 3—(2—methylpyrrolidin-l-y1)(trifluoromethylsulfonyloxy)quinoxaline—é- carboxylate 0 ° N ’Nfio/ TrolN To a solution of (.S')—methyl 3-(2-methylpy1rolidin—1-yl)—2—oxo-l ,2—dihydroquinoxaline carboxylate (200 mg, 0.70 mmol) in dichloromethane (30 mL) was added pyridine (220 mg, 2.78 mmol), followed by dropwise addition of ngO (393 mg, 1.39 mmol) with stirring at 0°C. The resulting solution was stirred overnight at room temperature and then quenched by the addition of ice—water (50 mL), extracted with dichloromethane (3 x 10 mL), dried over anhydrous sodium e and concentrated under vacuum to afford (S)—methy1 3—(2- methylpyrrolidin—l-yl)(trifluoromethylsulfonyloxy)quinoxalinecarboxy1ate as red oil (292 mg, crude).
Step 2. Methyl luorobenzofurany1)-3—[(2S)—2-methylpyrrolidin-l-y1]quinoxaline- 6-carboxy1ate To a solution of methyl 3-[(25)methylpyrrolidin-l-yl]~2~ [(trifluoromethane)sulfonyloxy]quinoxaline—6-carboxylate (292 mg, crude) in 1,2— oxyethane (6 mL) was added 2-(6—fluoro—l-benzofuran-2—yl)—4,4,5,5—tetramethyl- 1,3,2-dioxaborolane (365 mg, 1.39 mmol), Pd(PPh3)4 (40 mg, 0.03 mmol), K3PO4 (440 mg, 2.07 mmol) and water (5 drops) with stirring for l h at 90°C under an inert atmosphere of nitrogen in an oil bath. The reaction mixture was trated under vacuum to give the residue, which was applied onto a silica gel column with 1% to 5% ethyl acetate in eum to afford methyl 2-(6-fluoro-l -benzofuran—2—yl)—3—[(25)—2—methylpyrrolidin-l~y1]quinoxaline— 6-carboxylate as a yellow solid (78 mg).
LC/MS (ES, m/z): [M+H]+ 406.0 W0 2012/119046 PCT/U82012/027423 1H—NMR (300 MHz, CDClg) 5 8.52 (s, 1H), 8.04 (s, 2H), 7.60 — 7.65 (m, 1H), 7.37 - 7.41 (m, 1H), 7.29 (s, 1H), 7.06 - 7.13 (m, 1H), 4.44 - 4.53 (m, 1H), 4.01 (s, 3H), 3.51 - 3.60 (m, 1H), 3.06 - 3.12 (m, 1H), 2.22 - 2.32 (m, 1H), 1.89 — 1.94 (m, 1H), 1.70 — 1.73 (m, 2H), 1.45 (d, J: 6.0 Hz, 3H) Step 3. (S)—2—(6—Fluorobenzofuran—2-y1)—3—(2-methylpyrrolidin-1—yl)quinoxalinecarboxylic acid To a on of methyl 2-(6-fluoro—1—benzofuranyl)—3~[(2S)-2—methy1pyrrolidin yl]quinoxaline-é-carboxylate (78 mg, 0.19 mmol) in methanol (25 mL) and water (5 mL ) was added sodium hydroxide (23 mg, 0.57 mmol) with ng overnight at room temperature. The reaction mixture was concentrated under vacuum, dissolved in water (10 mL), adjusted to pH 5 with HCl (3N) to give the precipitate, which was collected by filtration to afford (S)—2-(6-fluorobenzofuran-Z-yl)(2-methylpyrrolidin-1~yl)quinoxa1ine carboxylic acid (37.3 mg, 52%).
LC/MS (ES, m/z): [M+H]+ 392.0 1H-NMR (300 MHZ, CD3OD) 5 8.39 (s, 1H), 8.02 - 8.14 (m, 1H), 7.93 (d, J = 8.4 Hz, 1H), 7.60 - 7.80 (m, 1H), 7.43 — 7.47 (m, 1H), 7.40 (s, 1H), 7.12 ~ 7.19 (m, 1H), 4.42 — 4.53 (m, 1H), 3.50 — 3.62 (m, 1H), 3.11 - 3.17 (m, 1H), 2.18 - 2.26 (m, 1H), 1.83 - 1.94 (m, 1H), 1.63 - 1.79 (m, 2H), 1.41(d, J: 6.0 Hz, 3H) PCT/U52012/027423 EXAMPLE 33 2-(5,6-Difluor0benzofuranyl)(isopropyl(methyl)amino)quinoxalinecarboxylic acid Y o /N /N o LC/MS (ES, m/z): [M+H]+ 398.0.
E 34 (S)(2,2-Diflu0robenzo[d][1,3]di0xolyl)(2-methylpyrrolidinyl)quinoxaline carboxylic acid 0 ° F \N LC/MS (ES, m/z): [M+H]+ 414.0 EXAMPLE 35 2-(1H-Indazolyl)(piperidinyl)quinoxalinecarb0xylic acid 0 O N /j:j)LoHN \ N LC/MS (ES, m/z): [M+H]+ 374.0 W0 2012/119046 E 36 3-(Azepanyl)(1H-indazolyl)quinoxalinecarboxylic acid O o N /N OH LC/MS (ES, m/z): [M+H]+ 388.0 EXAMPLE 37 3-(Azepanyl)(1H-indolyl)quinoxalinecarboxylic acid O O N /N CH / N LC/MS (ES, m/z): [M+H]+ 387.0 EXAMPLE 38 3-(Diethylamino)~2-(1H-indolyl)quinoxalinecarboxylic acid § 0 \/N ’NULLOH LC/MS (ES, m/z): [M+H]+ 361.0 W0 2012/119046 PCT/U82012/027423 EXAMPLE 39 3-(Azepanyl)(S-fiuorobenzofuranyl)quinoxalinecarboxylic acid 0 ° N /N:©/KOH F \ \N LC/MS (ES, m/z): [M+H]+ 406.0 EXAMPLE 4O (1H-Indol-S-yl)(2-methylpyrrolidinyl)quinoxalinecarboxylic acid 0““ ° N /N OH / N LC/MS (ES, m/z): [M+H]+ 373.0 EXAMPLE 41 (S)(5-Fluorobenzofuran-Z-yl)~3~(2-methylpyrrolidinyl)quinoxalinecarb0xylic acid 0 ° N /Nmic” F \ \N LC/MS (ES, m/z): [M+H]+ 392.0 W0 2012/119046 PCT/U82012/027423 EXAMPLE 42 2-(2,2-Difluorobenzo[d][1,3]dioxolyl)(isopropyl(methyl)amino)quinoxaline carboxylic acid Y O F o \N F><O LC/MS (ES, m/z): [M+H]+ 402.0 EXAMPLE 43 3-(Isopropyl(methyl)amino)(1H-pyrazolyl)quinoxalinecarb0xylic acid Y O N\NH LC/MS (ES, m/z): [M+H]+ 312.0 EXAMPLE 44 2-(3—Methyl-1H-indazolyl)~3-(isopropyl(methyl)amino)quinoxalinecarb0xylic acid Y O /N ,N OH Step 1. 5-Bromo—3—methy1-IH-indazole To a on of 4—br0mo-2—ethy1benzenamine (1.5 g, 7.50 mmol) in ACOH (20 mL) was added NaNOz (570 mg, 8.14 mmol). After stirring for 2.5 h at room temperature, the resulting PCT/U52012/027423 mixture was concentrated under reduced pressure to afford a e, which was purified by a silica gel column with 1% methanol in dichloromethane to afford 5-bromomethy1-1H- indazole as a light red solid (700 mg, 44%). 1H—NMR (300 MHZ, CDC13) 5 8.35 (s, 1H), 7.45 — 7.49 (m, 1H), 7.33 (d, J: 8.7 Hz, 1H), 2.59 (S, 3H) Step 2. 3—Methyl—5—(tetramethyl-l,3,2~dioxaborolanyl)-]H—indazole QLO,\B‘ 1 . O : \I To a on of 5—bromo—3~methyl—1H—indazole (400 mg, 1.90 mmol) in DMSO (10 mL) was added 4,4,5,5-tetramethy1—2~(tetramethyl—l,3,2—dioxaborolan—2—yl)-l ,3,2—dioxaborolane (959 mg, 3.78 mmol), KOAc (400 mg, 4.08 mmol), Pd(dppf)Clz (100 mg). After stirring for 6h at 85°C, the mixture was dissolved in water (50 mL), extracted with ethyl acetate (3 x 20 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure to afford a residue, which was purified by a silica gel column with 10% ethyl acetate in eum ether to afford 3-methyl(tetramethyl~l ,3,2-dioxaborolanyl)-JH—indazole as a off~white solid (700 mg, crude).
Step 3. Methyl 3-(isopropyl(methyl)amino)~2-(3 l-1H—indazol-5—yl)quinoxaline carboxylate Y O /N /N 0/ To a solution of methyl 2—chlor0—3—(isopropyl(methyl)amino)quinoxaline—6—carboxylate (180 mg, 0.61 mmol) in 1,4-dioxane (1 mL) was added 3—methyl(4,4,5,5-tetramethyl-1,3,2— dioxaborolan—Q-yl)-1H—indazole (440 mg, crude), K3PO4 (360 mg, 1.71 mmol), Pd(PPh3)4 (40 mg, 0.03 mmol) under nitrogen here. After stirring 4 h at 95°C, the reaction e was dissolved in water (50 mL), extracted with dichloromethane (3x30 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure to afford a residue, 2012/027423 which was purified by a silica gel column with 0.5% ol in dichloromethane to afford methyl 3—(isopropyl(methy1)amino)(3-methy1-JH—indazol—S—yl)quinoxalinecarboxy1ate as a light yellow solid (85 mg, 35%).
LC/MS (ES, m/z): [M+H]+ 390.0 1H-NMR (300 MHZ, DMSO) 5 12.85 (s, 1H), 8.26 - 8.29 (t, J: 2.1 Hz, 2H), 7.92 — 7.99 (m, 2H), 7.85 - 7.88 (m, 1H), 7.60 (d, J: 9.0 Hz, 2H), 4.18 - 4.24 (m, 1H), 3.93 (s, 3H), 2.72 (s, 3H), 2.54 (s, 3H), 0.88 (d, J = 6.6 Hz, 6H) Step 4. 2—(3—Methyl-JH—indazol-S-yl)-3—(isopropyl(methyl)amino)quinoxalinecarboxylic acid Y O /N /N CH To a solution of methyl 2-(3-methyl-]H-indazol—5-yl)—3-(3-methylbutan-2—yl)quinoxaline—6— carboxylate (85 mg, 0.22 mmol) in methanol (20 mL) and water (1 mL) was added sodium hydroxide (18 mg, 0.45 mmol). After stirring overnight at room temperature, the reaction mixture was concentrated under reduced pressure to afford a residue, which was dissolved in water (20 mL), adjusted the pH value to 6 with 3N HCl and filtered to give 2—(3 —methyl—JH- indazol-5—yl)—3—(isopropyl(methyl)amino)quinoxaline—6—carboxylic acid as a light yellow solid (50.1 mg, 61%).
LC/MS (ES, m/z): [M+H]Jr 376.0 1H—NMR (300 MHZ, DMSO) 5 8.27 (s, 2H), 7.85 — 7.94 (m, 3H), 7.57 ~ 7.60 (d, J: 9.3 Hz, 1H), 4.17 — 4.21 (t, J: 6.6 Hz, 1H), 2.72 (s, 3H), 2.54 (s, 3H), 1.02 (d, J: 6.6 Hz, 6H) W0 2012/119046 PCT/U82012/027423 EXAMPLE 45 2-(6-Fluoro-l-benzofuran-Z-yl)[methyl(propan-Z-yl)amino]quinoxalinecarboxylic acid Y O {Q0\\ N Step 1. 2~(2,2—Dibromoethenyl)fluorophenol To a solution of CBr4 (5.6 g, 17.1 mmoL) in romethane (100 mL) was added PPh3 (7 g, 26.69 mmol) at 0°C, 30 min later, NBt3 (4.3 g, 42.6 mmol) and 4-fluoro hydroxybenzaldehyde (1 g, 7.14 mmol) was added slowly. After stirring for 30 mins at room temperature, the resulting mixture was concentrated under reduced re to afford a residue, which was purified by a silica gel column with 5% ethyl acetate in petroleum ether to afford 2—(2,2—dibromoethenyl)—S—fluorophenol as a white solid (0.58 g, 27%). 1H—NMR (300 MHZ, CDC13) 5 7.47 — 7.72 (m, 4H) Step 2. 2-Bromo—6—fluoro-1—benzofuran F 0 To a solution of 2-(2,2—dibromoethenyl)-5—fluorophenol (580 mg, 1.96 mmol) in tetrahydrofuran (20 mL) was added CuI (30 mg, 0.16 mmol), K3P04 (800 mg, 3.77 mmol) under nitrogen atmosphere. After ng overnight at 80°C, the reaction mixture was dissolved in water (50 mL), extracted with dichloromethane (3x30 mL), dried over anhydrous magnesium sulfate and trated under reduced pressure to afford a residue, which was purified by a silica gel column with petroleum ether to afford 6-fluorobenzofuran as a white solid (0.16 g, 38%). 1H-NMR (300 MHZ, DMSO) 5 7.59 - 7.65 (m, 2H). 7.15 - 7.22 (m, 2H) PCT/U52012/027423 Step 3. 2—(6—Fluorobenzofuran—2—yl)-4,4,5,5—tetramethyl—1,3,2-dioxaborolane F o ‘0 To a solution of 2—bromo-6—fluoro—1—benzofuran (450 mg, 2.09 mmol) in DMSO (10 mL) was added KOAC (410 mg, 4.18 mmol), Pd(dppf)Clz (150 mg, 0.21 mmol), 15 min later was added 4,4,5,5—tetramethy1—2-(tetramethyl-l,3,2-dioxaborolan—2—yl)—1,3,2-dioxaborolane (1 g, 3.94 mmol) at room temperature. After ng for 2 h at 85°C, the reaction mixture was dissolved in water (100 mL), extracted with ethyl acetate (3 x 20 mL), dried over anhydrous ium sulfate and concentrated under reduced pressure to afford 2—(6—fluor0 benzofuranyl)-4,4,5,5—tetramethyl-1,3,2—dioxaborolane as a black solid (06 g, crude).
Step 4. Methyl 2-(6—fluorobenzofuranyl)—3-[methy1(propanyl)amino]quin0xaline—6- carboxylate Y O /N /Nfi0/ £931\\ N To a on of methyl 2—chloro[methyl(propan-2—y1)amino]quinoxaline-6—carboxylate (100 mg, 0.34 mmol) in dioxane (2 mL) was added 2-(6—fluorobenzofuran—2-yl)w4,4,5,5- tetramethyl—1,3,2—dioxaborolane (600 mg, crude), Pd(PPh3)4 (20 mg, 0.02 mmol), K3P04 (140 mg, 0.66 mmol) under nitrogen atmosphere. After stirring 40 min at 95°C, the on mixture was dissolved in water (50 mL), extracted with dichloromethane (3 x 20 mL), dried over anhydrous magnesium e and concentrated under reduced pressure to afford a residue, which was purified by a silica gel column with 2% ethyl acetate in petroleum ether to afford methyl 2—(6-fluoro-1—benzofuranyl)-3—[methyl(propan-2—yl)amino]quinoxaline—6- carboxylate as a light yellow solid (55 mg).
LC/MS (ES, m/z): [M+H]+ 394.0 1H-NMR (300 MHz, CDC13) 5 8.59 (s, 1H), 8.08 — 8.12 (m, 2H), 7.61 ~ 7.66 (m, 2H), 7.37 - 7.40 (t, J: 1.8 Hz, 1H), 7.10 (d, J: 2.1 Hz, 1H), 4.31 - 4.35 (t, J: 6.6 Hz, 1H), 4.01 (s, 3H), 2.93 (s, 3H), 1.26 (d, J = 6.6 Hz, 6H) Step 5. 2-(6—Fluoro—1-benzofuran-2—y1)—3-[methyl(propan—2-yl)amino]quinoxaline carboxylic acid Y O . @I\ \ N To a solution of methyl 2-(6~fluorobenzofuranyl)—3-[methyl(propan-2— yl)amino]quinoxalinecarboxy1ate (55 mg, 0.14 mmol) in methanol (20 mL) and water (1 mL) was added sodium hydroxide (12 mg, 0.30 mmol). After stirring overnight at room temperature, the reaction mixture was concentrated under reduced re to afford a residue, which was dissolved in water (10 mL), adjusted the pH value to 5 with 3N HCl and filtered to give 2-(6-fluorobenzofurany1)—3—[methyl(propan—2-yl)amino]quinoxaline ylic acid as a light yellow solid (28.8 mg, 54%).
LC/MS (ES, m/z): [M+H]+ 380.0 1H-NMR (300 MHZ, DMSO) 5 8.23 (s, 1H), 8.00 - 8103 (t, J = 4.5 Hz, 1H), 7.87 (d, J: 8.7 Hz, 1H), 7.80 — 7.82 (t, J: 2.7 Hz, 1H), 7.72 - 7.76 (m, 1H), 7.69 (s, 1H), 7.20 — 7.27 (m, 1H), 4.11 — 4.16 (t, J = 6.6 HZ, 1H), 2.82 (s, 3H),1.14 - 1.17 (d, J: 6.6 HZ, 6H) EXAMPLE 46 3-(Isopropyl(methyl)amino)(quinolinyl)quinoxalinecarboxylic acid Y O / N LC/MS (ES, m/z): [M+H]+ 373.00 E 47 2-(1H-Indazol-S-yl)[(ZS)methylpyrrolidinyl]quinoxalinecarboxylic acid 0’ O / N Step 1. tert-Butyl 5—bromo~JH-indazole—1—carboxylate corN Br To a solution of 5-bromo-JH-indazole (3 g, 15.23 mmol) in acetonitrile (40 mL) was added 4—din1ethylaminopyridine (373 mg, 3.05 mmol), (Boc)20 (3.67 g, 16.82 mmol) and triethylamine (1.55 g, 15.32 mmol). The solution was stirred overnight at room temperature and concentrated under . The residue was dissolved in ethyl acetate (200 mL), washed with water (3 x 50 mL) and the organic layers were dried over anhydrous magnesium sulfate, trated under vacuum. The residue was purified by a silica gel column with 1% - 2% ethyl acetate in eum ether to afford tert-butyl 5-bromo-1H~indazolecarboxylate as yellow oil (3.88 g, 86%). 1H—NMR (300 MHZ, CDC13) 5 8.08 - 8.13 (m, 2H), 7.89 — 7.90 (m, 1H), 7.61 — 7.65 (m, 1H), 1.74 (s, 9H) Step 2. tert-Butyl 5—(tetramethy1—1,3,2-dioxaborolan-2—yl)~JH—indazolecarboxylate é0)? NwN ‘0 To a solution of tert—butyl 5-bromo-JH—indazolecarboxylate (750 mg, 2.52 mmol) in DMSO (10 mL), was added KOAC (666 mg, 6.79 mmol) and Pd(dpp1)C12 (250 mg, 0.34 mmol). The solution was stirred for 15 mins at room temperature and then added 5- tetramethyl(tetramethyl-1,3,2—dioxaborolanyl)-1,3,2-dioxaborolane (1.72 g, 6.77 mmol). The resulting solution was stirred for 2.5 h at 85°C. Then the reaction was quenched by the addition of water (100 mL) and extracted with ethyl acetate (3 x 50 mL), dried over anhydrous sodium sulfate and concentrated under vacuum to give a residue, which was purified by a silica gel column with 1% - 2% ethyl e in petroleum ether to afford tert- butyl 5-(tetramethyl-l,3,2-dioxaborolanyl)-]H—indazole-l-carboxylate as a white solid(500 mg, crude). (300 MHz, CDCl3) 8 8.25 (s, 1H), 8.17 - 8.20 (m, 2H), 7.94 - 7.98 (m, 1H), 2.14 (s, 9H), 1.38 (s, 12H) Step 3. (S)—Methyl 3-(2—methylpyrrolidin—l-yl)—2-(trifluoromethylsu1fonyloxy)quinoxaline—6- carboxylate O o _ Tfol/ND25, To a on of (S)-methy1 3-(2-methylpyrrolidin-l-yl)—2-oxo-l ,2-dihydroquinoxaline—6- carboxylate (200 mg, 0.70 mmol) in dichloromethane (30 mL) was added pyridine (220 mg, 2.78 mmol), and then szO (393 mg, 1.39 mmol) was added dropwise with stirring at 0°C.
The ing on was stirred overnight at room temperature and then quenched by the addition of ice-water (20 mL), extracted with dichloromethane (2 x 20 mL), dried over anhydrous sodium sulfate and concentrated under vacuum to afford (S)-methyl 3—(2— methylpyrrolidin-l -yl)—2—(trifluoromethylsulfonyloxy)quinoxalinecarboxylate as red oil (292 mg, crude).
Step 4. Methyl 2—[ l —[(tert—butoxy)carbonyl]~1H—indazol—5—yl] [(2S)methylpyrrolidin— l - yl]quinoxaline-6—carboxylate To a solution of methyl 3—[(2S)—2-methylpyrrolidin—l—yl]-2— [(trifluoromethane)sulfonyloxy]quinoxalinecarboxy1ate (292 mg, crude) in dioxane (12 mL) was added tert-butyl 5-(tetramethyl- l,3,2-dioxaborolan-2~y1)-]H-indazolecarboxylate (300 mg), Pd(PPh3)4 (40 mg, 0.03 mmol), K3PO4 (221 mg, 1.05 mmol) and water (3 mL).
The resulting solution was stirred for 1 h at 90°C and then quenched by the addition of water (50 mL), extracted with dichloromethane (3 X 20 mL), dried over anhydrous sodium sulfate and concentrated under vacuum to give a residue, which was purified by a silica gel column with 25% ethyl acetate in eum ether to afford methyl 2-[1-[(tert-butoxy)carbonyl]-JH- indazol—S—yl][(ZS-Z-methylpyrrolidin—1~yl]quinoxaline—6—carboxylate as a yellow solid( 105 mg, crude).
LC/MS (ES, m/z):[M+H]+ 488.0 1H-NMR (300 MHz, : 5 8.63 (s, 1H), 8.29 — 8.34 (t, J = 8.7 Hz, 2H), 8.20 (s, 1H), 7.96 - 8.07 (m, 3H), 4.44 (d, J: 4.8 Hz, 1H), 4.01 (s, 3H), 3.09 (s, 1H), 2.97 (s, 1H), 2.20 (s, 1H), 1.78 (s, 9H), 1.38 — 1.44 (m, 3H), 1.25 — 1.30 (m, 3H) Step 5. Methyl indazol-S—yl)[(2S)—2—methylpyrrolidin—1—y1]quinoxaline—6- carboxylate To a solution of methyl 2-[1-[(tert—butoxy)earbony1]~1H-indazolyl][(ZS) methylpyrrolidin-l—yl]quinoxaline—6—carboxy1ate (105 mg, crude) in dichloromethane (20 mL) was added 2,2,2—trifluoroacetic acid (4 mL), The solution was stirred for 3h at room temperature and concentrated under vacuum. The residue was quenched by the addition of water (50 mL) and adjusted pH to 9 with NaHC03 (aq.), extracted with dichloromethane (3 x mL), dried over anhydrous sodium sulfate and concentrated under vacuum to afford methyl 2-(1H—indazol-5—yl)-3~[(QS)methylpyrrolidinyl]quinoxaline~6-earboxylate as a light yellow solid (69 mg, crude).
LC/MS (ES, M+H]+ 388.0 Step 6. 2—(1H—Indazolyl)-3~[(25’)-2—methylpyrrolidin-l-yl]quinoxaline—é—carboxylic acid PCT/U82012/027423 To a solution of methyl 2-(1H—indazol—S-yl)[(2S)-2—methylpyrrolidinyl]quinoxaline-6— carboxylate (69 mg, 0.18 mmol) in MeOH (20 mL) was added sodium hydroxide (21.6 mg, 0.54 mmol)and water (2 mL). The resulting solution was stirred overnight at room temperature and concentrated under vacuum. The residue was dissolved in water (5 mL) and adjusted pH to 5 with hydrochloric acid (IN). The solids were collected by filtration to afford 2-(1H—indazol—S—yl)—3—[(28)—2-methylpyrrolidin—1—yl]quinoxaline~6—carboxylic acid as a yellow solid (29 mg, 43%).
LC/MS (ES, m/z):[M+H]+ 374.0 1H—NMR (300 MHz, DMSO) 5 13.27 (s, 1H), 8.25 (d, J = 1.2 Hz, 1H), 8.22 (s, 1H), 8.15 (s, 1H), 7.86 — 7.95(m, 2H), 7.76 — 7.79 (1. J: 1.5 Hz, 1H), 7.67 (d, J: 8.7 Hz, 1H), 4.19 — 4.26 (m, 1H), 2.92 — 3.06 (m, 2H), 2.07 — 2.16 (m, 1H), 1.60 — 1.68 (m, 1H), 1.52 - 1.57 (m, 2H), 1.36 (d, J = 6.6 Hz, 3H) EXAMPLE 48 pan-l-yl)(6-fluorobenzofuran-Z-yl)quinoxalinecarboxylic acid 0 ° N /N@011 \ \N Step 1. Methyl 3-(azepan—1-yl)—2—oxo-1,2-dihydroquinoxaline-6—carboxylate C 0 O N To a solution of methyl 3-chloro-2—oxo-1,2—dihydroquinoxaline-6—carboxylate (500 mg, crude) in DMSO (6 mL) was added DIEA (543 mg, 4.20 mmol) and azepane (208 mg, ol). The solution was stirred overnight at 90°C. Then the reaction was quenched by the addition of water (50 mL), extracted with ethyl acetate (5 x 20 mL) and the organic layers were concentrated under vacuum to give a residue, which was purified by a silica gel column with 1% - 5% ethyl e in petroleum ether to afford methyl pany1)—2—oxo—1 ,2- dihydroquinoxaline—6-carboxylate as a yellow solid (165 mg).
PCT/U52012/027423 LC/MS (ES, m/z): [M+H]+ 302.0 1H-NMR (300 MHZ, CDC13) 8 9.74 (s, 1H), 8.16 (d, J: 1.5 Hz, 1H), 7.78 - 7.82 (m, 1H), 7.02 (d, J: 8.4 Hz, 1H), 4.04 (s, 4H), 3.94 (s, 3H), 1.91 (s, 4H), 1.54 - 1.66 (m, 4H) Step 2. Methyl 3—(azepan-1—yl)-2—(trifluoromethylsulfonyloxy)quinoxalinecarboxy1ate O O TfOIN/Nfio/ To a solution of methyl 3—(azepan—1—yl)—2—oxo—1,2-dihydroquinoxa1ine—6—carboxy1ate (100 mg, 0.33 mmol) in dichloromethane (30 mL) was added pyridine (104 mg, 1.31 mmol) and then ngO (186 mg, 0.66 mmol) was added dropwise with stirring at 0°C. The resulting solution was stirred overnight at room temperature and then quenched by the addition of ice- water (20 mL), ted with dichloromethane (3 X 10 mL), dried over anhydrous sodium sulfate and trated under vacuum to afford methyl 3-(azepanyl) (trifluoromethylsulfonyloxy)quinoxaline-6—carboxylate as red oil (200mg, crude).
Step 3. Methyl 3-(azepan-1 -y1)(6-fluorobenzofuranyl)quinoxalinecarboxylate To a solution of methyl 3-(azepan—1—y1)-2—[(trifluoromethane)sulfonyloxy]quinoxaline—6- carboxylate (200 mg, crude) in 1,2—dirnethoxyethane (5 mL) was added 2-(6-fluoro benzofuran—2—yl)-4,4,5,5~tetramethy1-1,3,2-dioxaborolane (250 mg, 0.95 mmol), Pd(PPh3)4 (27 mg, 0.02 mmol), K3PO4 (291 mg, 1.37 mmol) and water (5 drops) with ng for 1 h at 90°C maintained with an inert atmosphere of nitrogen in an oil bath. The on mixture was concentrated under vacuum to give the residue, which was applied onto a silica gel column with 1% to 2% ethy1 acetate in petroleum to afford methyl 3—(azepan-1—y1)(6- fluoro-l-benzofuranyl)quinoxaline-6~carboxylate as a yellow solid (73 mg).
LC/MS (ES, m/z): [M+H]+ 420.0 1H-NMR (300 MHZ, CDC13) 5 8.59 (s, 1H), 8.00 - 8.08 (m, 2H), 7.60 - 7.65 (m, 1H), 7.41 (s, 1H), 7.34 - 7.38 (m,1H), 7.06 - 7.13 (m, 1H), 4.01(s, 3H), 3.64 - 3.68 (t, J: 6.0 Hz, 4H), 1.83 - 1.90 (m, 4H), 1.60 - 1.76 (m, 4H) Step 4. pany1)-2—(6-fluoro—1—benzofuran-2—yl)quinoxaline-6—carboxylic acid To a solution of methyl 3-(azepanyl)-2—(6~fluor0benzofurany1)quinoxaline—6— carboxylate (73 mg, 0.17 mmol) in methanol (25 mL) and chloroform (5 mL ) was added sodium hydroxide (13.6 mg, 0.34 mmol) and water (2 mL) with stirring overnight at room ature. The reaction mixture was concentrated under vacuum, dissolved in water (15 mL), adjusted pH to 5 with HCl (3 N) to give the precipitate, which was collected by filtration to afford 3—(azepany1)—2-(6-fluorobenzofuranyl)quinoxaline-6—carboxylic acid (39 mg, 55%).
LCMS (ES, m/z): [M+H]+ 406.0 1H—NMR (300 MHz, CD30D) 5 8.38 (s, 1H), 8.01 — 8.04 (m, 1H), 7.93 (d, J = 8.4 Hz, 1H), 7.72 — 7.77 (111,111), 7.48 (s,1H), 7.41 — 7.45 (111,111), 7.12 — 7.19 (m, 1H), 3.62 — 3.66 (t, J: .7 Hz, 4H). 1.82 - 1.90 (m, 4H), 1.58 — 1.62 (m, 4H) EXAMPLE 49 3-(Cyclopropyl(methyl)amino)(6-fluor0benzofuranyl)quinoxalinecarb0xylic acid PCT/U82012/027423 Step 1. Methyl 3—(cyclopropyl(methyl)amino)—2—(trifluoromethylsulfonyloxy)quinoxaline carboxylate V 0 TfO N To a solution of methyl lopropyl(methyl)amino)—2—oxo—1,2-dihydroquinoxaline-6— yiate (120 mg, 0.44 mmol) in dichloromethane (10 mL) was added pyridine (135 mg, 1.71 mmol) and ngO (230 mg, 0.82 mmol)under nitrogen atmosphere. After stirring overnight at room temperature, the reaction was ed by the addition water/ice (50 mL), extracted with dichloromethane (2 x 10 mL), dried over ous magnesium sulfate and concentrated under vacuum to give methyl 3~(cyclopropyl(methyl)amino) (trifluoromethylsulfonyloxy)quinoxalinecarboxy1ate as red oil (130 mg, crude).
Step 2. Methyl 3-[cyclopropyl(methyl)amino]-2~(6-fluoro~1~benzofuran—2—yl)quinoxaline carboxylate V o /N /Nfio/ £9);\\ N To a solution of methyl 3-[cyclopropy1(methy1)amino]~2- [(trifluoromethane)sulfonyloxy]quinoxaline—6~carboxylate (130 mg, crude) in dioxane (2 mL) was added 2—(6—fluor0—2,3,5,6—tetrahydro~1~benzofuranyl)-4,4,5,5-tetramethy1—1,3,2— dioxaborolane (175 mg, 0.66 mmol), K3PO4 (140 mg, 0.66 mmol), Pd(PPh3)4 (20 mg, 0.02 mmol) and water (3 drops) under nitrogen atmosphere. After stirring 40 min at 90°C, the reaction mixture was dissolved in water (40 mL), extracted with romethane (3 x 20 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure to afford a residue, which was purified by a silica gel column with 2% ethyl acetate in petroleum ether to afford methyl 3-[cyclopropyl(methyl)amino]—2—(6-fluoro—l—benzofuran-Z- yl)quinoxalinecarboxy1ate as a yellow solid (55 mg).
LC/MS (ES, m/z): [M+H]+ 392.0 W0 2012!]19046 PCT/U52012/027423 lH—NMR (300 MHz, DMSO) 8 8.30 (d, J = 1.5 Hz, 1H), 7.98 - 8.08 (m, 2H), 7.73 — 7.83 (m, 2H), 7.65 (s, 1H), 7.20 - 7.27 (m, 1H), 3.94 (s, 3H), 3.09 (s, 3H), 2.89 (s, 1H), 0.51 - 0.57 (m, Step 3. 3-(Cyclopropyl(methyl)amino)—2—(6-fluorobenzofuran-2—yl)quinoxaline—6—carboxylic acid 7 o C9;\\ N To a on of methyl 3—[cyclopropyl(methyl)amino](6—fluoro-l-benzofuran—3~ yl)quinoxalinecarboxy1ate (55 mg, 0.15 mmol) in methanol (20 mL) and water (1 mL) was added sodium hydroxide (10 mg, 0.25 mmol). After stirring overnight at room temperature, the reaction mixture was concentrated under reduced re to afford a residue, which was dissolved in water (10 mL), adjusted the pH to 5 with 3N HC] and filtered to give 3— (cyclopropyl(methyl)amino)(6-fluorobenzofuran—2-yl)quinoxalinecarboxylic acid as a light yellow solid (28.7 mg, 50%).
LC/MS (ES, m/z): [M+H]+ 378.0 1H-NMR (300 MHZ, DMSO) 5 8.28 (s, 1H), 7.98 - 8.05 (m, 2H), 7.72 — 7.82 (m, 2H), 7.63 (s, 1H), 7.19 - 7.27 (m, 1H), 3.07 (s, 3H), 2.87 — 2.91 (m, 1H), 0.47 — 0.60 (m, 4H) EXAMPLE 50 2-(1,2-Benzoxazolyl)[methyl(propanyl)amin0]quinoxalinecarboxylic acid Y O /N /N OH PCT/U52012/027423 Step 1. 2-Hydroxy(tetramethy1-1,3,2—dioxaborolan—2—yl)benza1dehyde To a solution of 5—bromo-2—hydroxybenza1dehyde (5 g, 24.87 mmol) in 1,4-dioxane (20 mL) was added KOAc (6.2 g, 63.18 mmol) and Pd(dppf)Clz (1.6 g, 2.19 mmol). The solution was stirred for 15 min at room temperature and then 4,4,5,5-tetramethy1—2—(tetramethy1—1,3,2- dioxaborolan-2—yl)-l,3,2-dioxaborolane (7.7 g, 30.32 mmol) was added. The resulting solution was stirred for 2 h at 85°C. Then the reaction was quenched by the addition of water (300 mL). The resulting solution was extracted with ethyl acetate (4 x 60 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to give a e, which was purified by silica gel column chromatography eluting with petroleum ether to afford 2-hydroxy methyl-l,3,2-dioxaborolan-2—y1)benzaldehyde (4.8 g, 78%). 1H—NMR (300 MHz, CDC13)5 11.23 (s, 1H), 9.93 (s, 1H), 8.06 (d, J: 1.5 Hz, 1H), 7.94 — 7.97 (m, 1H), 6.98 (d, J: 8.4Hz, 1H), 1.36 (s, 12H) Step 2. (4-Methoxyphenyl)methy1 2-bromo[methyl(propan—2~yl)amino]quinoxaline carboxylate Y O Br N To a on of (4-methoxypheny1)methyl 3-[methyl(propan~2-yl)amino]~2— [(trifluoromethane)sulfonyloxy]quinoxaline-6—carboxylate (550 mg, 1.07 mmol) in toluene (10 mL) was added TBAB (350 mg, 1.17 mmol). The solution was stirred for 3 h at 110°C.
Then the reaction was quenched by the addition of water (100 mL). The resulting solution was extracted with dichloromethane (3 x 30 mL), dried over ous sodium sulfate and concentrated in vacuo to give a e, which was purified by silica gel column chromatography with dichloromethane to afford (4—n1ethoxyphenyl)methyl 2—bromo [methyl(propan—2-yl)amino]quinoxalinecarboxy1ate (400 mg, 84%). 1H-NMR (300 MHz, CDC13) 5 8.48 (d, J = 1.8 Hz, 1H), 8.07 - 8.11 (m, 1H), 7.88 (d, J = 8.7 Hz, 1H), 7.43 (d, J = 8.7 Hz, 2H), 6.94 (d, J = 8.7 Hz, 2H), 5.36 (s, 2H), 4.46 - 4.55 (m, 1H), 3.84 (s, 3H), 3.74 (s, 3H), 2.98 (s, 3H), 1.28 (d, J: 6.6 Hz, 6H) Step 3. (4-Methoxypheny1)methyl 2—(3—formy1—4-hydroxyphenyl)—3-[methyl(propan—2- yl)amino]quinoxaline-6—carboxy1ate Y O I NfiOPMB o/ N/ To a solution of (4-methoxypheny1)methyl 2-bromo~3-[methyl(propan—2- no]quinoxaline—6—carboxylate (400 mg, 0.90 mmol) in 1,2-di1nethoxyethane (10 mL) was added 2—hydroxy—5-(tetramethyl—l,3,2-dioxaborolanyl)benza1dehyde (444 mg, 2.26mmol), Et3N (273 mg, 2.7 mmol), Pd(dppf)Clz (58 mg, 0.08 mmol) and water (5 drops).
The resulting solution was stirred for 1 h at 90°C and maintained under an inert atmosphere of nitrogen in an oil bath. The reaction mixture was concentrated in vacuo to give the residue, which was purified by silica gel column chromatography eluting with 1% to 5% ethyl acetate in petroleum to afford hoxyphenyl)methy1 2-(3-formylhydroxyphenyl) [methyl(propan-2—y1)amino]quinoxalinecarboxylate as a yellow solid (190 mg, 43%).
LC/MS (ES, m/z): [M+H]+ 486.0 1H-NMR (300 MHz, CDC13)511.24(S, 1H), 10.03 (s, 1H), 8.57 (s, 1H), 8.31(s, 1H), 8.18 (d, J: 9.0 Hz, 1H), 8.10 (d, J: 8.7 Hz, 1H), 7.98 (d, J: 8.4 Hz, 1H), 7.38 -7.48 (m, 2H), 7.12 - 7.18 (m, 1H), 6.95 — 7.01 (m, 2H), 5.38 (s, 2H), 4.09 - 4.35 (m, 1H), 3.86 (s, 3H), 2.81 (s, 3H), 1.10 (d, J: 6.3 Hz, 6H) Step 4. (4~Methoxypheny1)methyl 2-(1,2-benzoxazol-5—yl)[methyl(propan—2- ino]quinoxalinecarboxylate Y O 1 NfiOPMB N\/ N To a solution of (4-methoxyphenyl)methyl 2—(3-formylhydroxyphenyl)-3—[methyl(propan- 2—y1)amino]quinoxalinecarboxylate (190 mg, 0.39 mmol) in water (5 mL) was added aminooxysulfonic acid (83 mg, 0.48 mmol) and methanol (5 mL). The resulting solution was stirred ght at 25°C. Then the reaction was quenched by the addition of water (200 mL) and extracted with ethyl acetate (3 x 50 mL), dried over ous sodium sulfate and concentrated in vacuo to give a e, which was purified by silica gel column chromatography eluting with 1% to 5% ethyl acetate in petroleum to afford (4— W0 2012I119046 methoxyphenyl)methyl 2-(1 ,2-benzoxazol-5 —y1) [methyl(propanyl)amino]quinoxa1ine carboxylate as a yellow solid (50 mg, 26%).
LC/MS (ES, m/z): [M+H]+ 483.0 1H—NMR (300 MHz, CDC13) 5 8.83 (s, 1H), 8.61 (s, 1H), 8.38 (s, 1H), 8.09 — 8.19 (m, 2H), 7.99 (d, J = 8.4 Hz, 1H), 7.75 (d, J: 7.8 Hz, 1H), 7.46 (d, J = 8.4 Hz, 1H), 6.93 - 6.98 (m, 2H), 5.39 (s, 2H), 4.15 - 4.21 (in, 1H), 3.86 (s, 3H), 2.79 (s, 3H), 1.10 (d, J: 6.6 Hz, 6H) Step 5. -Benzoxazol—5-y1)—3-[methyl(propan—2~yl)amino]quinoxaline-6—carboxylic acid Y O /N /N OH To a on of (4-methoxyphenyl)methyl 2—(1,2-benzoxazoly1)—3-[methyl(propan yl)amino]quinoxalinecarboxylate (50 mg, 0.10 mmol) in dichloromethane (10 mL) was added 2,2,2—trifluoroacetic acid (1 mL). The solution was stirred for 30 min at room temperature. Then the reaction was quenched by the addition of water (100 mL), extracted with dichloromethane (3 x 30 mL), dried over ous sodium sulfate and concentrated in vacuo to give a residue, which was purified by silica gel column chromatography eluting with % dichloromethane in methanol to afford 2—(1,2—benzoxazol—5-y1)—3-[methyl(propan—2- yl)amino]quinoxalinecarboxylic acid as a yellow solid (12.3 mg, 33%).
LC/MS (ES, m/z): [M+H]+ 363.0 1H-NMR (300 MHz, DMSO) 5 13.15 (s, 1H), 9.37 (s, 1H), 8.42 (d, J: 0.9 Hz, 1H), 8.29 (s, 1H),8.15 — 8.19 (m, 1H), 7.93 - 7.97 (m, 3H), 4.12 - 4.17 (m, 1H), 2.69 (s, 3H), 1.02 (d, J: 6.6 Hz, 6H) EXAMPLE 51 3-(Azepany1)(2,2-difluor0-2H-1,3-benzodi0xolyl)quin0xalinecarb0xylic acid ON I ‘1 \ F O / NfiOH PCT/U82012/027423 Step 1. Methyl 3—(azepan—1-yl)[(trifluoromethane)sulfonyloxy]quinoxaline—6-carboxylate O O TfONINfiO/\N To a solution of methyl 3—(azepan—l—yl)—2-oxo—1,2-dihydroquinoxaline—6-carboxylate(190 mg, 0.63 mmol) in dichloromethane (20 mL) was added pyridine (300 mg, 3.79 mmol) and TfZO (534 mg, 1.89 mmol) with stirring ght under atmosphere of nitrogen at room temperature. The resulting solution was diluted with water (50 mL), extracted with dichloromethane (3 X 20 mL) and the organic layers combined and dried over anhydrous sodium sulfate and concentrated in vacuo to afford methyl 3—(azepan—1—yl)-2— [(trifluoromethane)sulfonyloxy]quinoxaline—6—carboxylate as yellow oil (273 mg, crude).
Step 2. Methyl 3-(azepan—l-yl)-2—(2,2-difluoro—2H—l ,3-benzodioxol—5—yl)quinoxaline—6— carboxylate O O N \o/ F><O \N F 0 To a solution of methyl pan—1-y1)-2—[(trifluoromethane)sulfonyloxy]quinoxaline-6— carboxylate (273 mg, 0.63 mmol) in dioxane (5.0 mL) and water (3 drops) was added 2—(2,2- difluoro-ZH—l,3-benzodioxol~5—yl)-4,4,5,5-tetramethyl-l,3,2—dioxaborolane (358 mg, 1.26 mmol), Pd(PPh3)4 (37 mg, 0.03 mmol), K3PO4 (266 mg, 1.25 mmol) with stirring for 1 hour at 90°C under atmosphere of nitrogen. The resulting e was concentrated in vacuo to give a residue, which was d onto silica gel column chromatography eluting with 1% ethyl acetate in petroleum ether to give methyl 3-(azepan~1-yl)—2—(2,2-difluoro—2H—1,3- benzodioxol-S—yl)quinoxaline—6~carboxylate as a yellow solid(l 10 mg , 40%).
LC/MS (ES, m/z): [M+H]+ 4420 Step 3. 3—(Azepanyl)-2—(2,2—difluoro-2H~l,3—benzodioxol—5-yl)quinoxaline—6-carboxylic acid PCT/U52012/027423 To a solution of methyl 3—(azepanyl)(2,2—difluoro-2H—1,3-benzodioxol yl)quinoxalinecarb0xylate (110 mg, 0.25 mmol) in methanol (30 mL) and water (1 mL) was added sodium hydroxide (40 mg, 1.00 mmol) with stirring overnight at room temperature. The resulting mixture was concentrated in vacuo and dissolved in water (10 mL), adjusted to 6 with HCl (3 N) and collected by filtration to give 3-(azepan—1-yl)(2,2- difluoro-ZH—l,3-benzodioxol—5-yl)quinoxaline—6—carboxylic acid as a yellow solid (70 mg, 66%).
LC/MS (ES, m/z): [M+H]+ 428.0 1H—NMR (300 MHz, DMSO) 8 8.23 (s, 1H), 7.87 (d, J = 9.0 Hz, 2H), 7.82 (d, J = 0.9 Hz, 1H), 7.53 - 7.60 (m, 2H), 3.41 - 3.45 (m, 4H), 1.65 — 1.75 (m, 4H), 1.42 - 1.50 (s, 4H) EXAMPLE 52 hyl(propanyl)amin0](4-phenylfuranyl)quinoxalinecarb0xylic acid Y 0 Step 1. 3-Phenylfuran ©~C/ To a solution of phenylboronic acid (15 g, 123.02 mmol) in dioxane (150.0 mL) and water (3.0 mL) was added 3-bromofuran (16.3 g, 110.91 mmol), K3PO4 (43 g, 202.57 mmol) and 3)4 (6.0 g, 5.19 mmol) with ng for 2h at 90°C in an oil bath maintained with an inert atmosphere of nitrogen. The reaction mixture was concentrated under reduced pressure to give the residue, which was purified by silica gel column chromatography eluting with 1% ethyl acetate in petroleum ether to afford 3—phenylfuran as a white solid (15 g, 85%). 1H-NMR (300 MHz, CDC13): 5 7.76 (s, 1H), 7.51 - 7.54 (m, 3H), 7.40 - 7.47 (m, 2H), 7.29 — 7.38 (m, 1H), 6.73 (d, J: 0.9 Hz, 1H) Step 2. 4,4,5,5—Tetramethyl(4-phenylfuran-2—yl)-1,3,2-dioxaborolane W0 2012;119046 PCT/U82012/027423 A solution of n-BuLi (6.2 mL, 2.5 M on in hexane) was added drop-wise to a solution of 3-phenylfuran (1.5 g, 10.40 mmol) in dry tetrahydrofuran (100 mL) at —78°C under nitrogen. It was warmed slowly to -40°C over 45 min and stirred at this temperature for another 30 min. The mixture was cooled again to -78°C followed by the dropwise addition of —tetramethyl—2-(propan-2—yloxy)—1,3,2-dioxaborolane (3.72 g, 19.99 mmol). After warming to room temperature, the mixture was ed with NH4C1 (aq) and extracted with ethyl e (3 x 80 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the residue, which was precipitated by cooling to afford 4,4,5,5-tetramethy1—2-(3-phenylfuran~2—yl)—1,3,2—dioxaborone as a white solid (400 mg, 14.0%). The mother liquid was purified by silica gel column chromatography eluting with 2% ethyl acetate in eum ether to afford 4,4,5,5-tetramethyl—2-(4- phenylfuran-2—yl)—1,3,2—dioxaborolane (200 mg, crude), which was used to the next step without further purification.
Step 3. Methyl 3-[methyl(propanyl)amino]~2-(4—pheny1furan—2—yl)quinoxaline—6- carboxylate To a solution of 4,4,5,5—tetramethyl-2—(4—phenylfuran-2—yl)—1,3,2—dioxaborolane (200 mg, crude) in dioxane (5.5 mL) and water (3 drops) was added methyl ro-3— [methyl(propan—2—yl)amino]quinoxaline-6—carboxylate (72 mg, 0.25 mmol), K3PO4 (156 mg, 0.73 mmol) and Pd(PPh3)4 (14 mg, 0.01 mmol) with stirring for 1h at 95°C in an oil bath which was maintained under an inert atmosphere of nitrogen. The reaction mixture was concentrated under reduced re to give the residue, which was purified by silica gel column chromatography eluting with 2% ethyl acetate in petroleum ether to afford methyl 3- [methyl(propan—2-yl)amino]-2~(5-phenylfuranyl)quinoxaline—6-carboxy1ate as a light yellow solid (50 mg).
LC/MS (ES, m/z): [M+H]+ 401.0 1H-NMR (300 MHz, CDClg): 5 8.54 (s, 1H), 8.03 - 8.13 (m, 2H), 7.96 (s, 1H), 7.58 - 7.63 (m, 3H), 7.43 - 7.47 (m, 3H), 4.28 - 4.32 (m, 1H), 4.00 (s, 1H), 2.93 (s, 3H), 1.25 (d, J: 6.6 Hz, PCT/U52012/027423 Step 4. 3—[Methyl(propanyl)amino](4—phenylfuran—2—yl)quinoxaline—6-Carboxylic acid Y O \ N To a solution of methyl 3-[methyl(propanyl)amino](4-phenylfuran-2—yl)quinoxaline carboxylate (50 mg, 0.12 mmol) in ol (30 mL) and water (2 mL) was added sodium hydroxide (19.9 mg, 0.50 mmol) with stirring overnight at room temperature. The reaction mixture was concentrated in vacuo, dissolved in water (30 mL) and adjusted to pH 5 with HCl (3 N). The solids were collected by filtration to afford 3-[methyl(propan—2-yl)amino]~2— (5—phenylfuran—2—yl)quinoxalinecarboxylic acid as a light yellow solid (40 mg, 83%).
LC/MS (ES, m/z): [M+H]+ 388.0 1H-NMR (300 MHz, DMSO): 6 13.23 (s, 1H), 8.50 (s, 1H), 8.26 (s, 1H), 7.94 - 7.99 (m, 2H), 7.71 — 7.76 (m, 3H), 7.42 - 7.47 (m, 2H), 7.30 — 7.35 (m, 1H), 4.15 - 4.24 (m, 1H), 2.83 (s, 3H), 1.18 (d, J: 6.6 Hz, 6H) EXAMPLE 53 2-(Benzo[b]thiophen-2—yl)(piperidin-l-yl)quinoxaline-G-carboxylic acid Step 1. Methyl 3-(piperidinyl)—2-(trifluoromethylsulfonyloxy)quinoxaline-6—carboxylate O O N NfikO/ TfO N To a solution of methyl 2-oxo—3-(piperidin-1—y1)-l,2—dihydroquinoxaline-6—carboxylate (200 mg, 0.70 mmol) in romethane (30 mL) was added pyridine (220 mg, 2.8 mmol) and then TfZO (393 mg, 1.4 mmol) was added dropwise with stirring at 0°C. The resulting solution was d overnight at room temperature and then quenched by the addition of water (50 mL), extracted with dichloromethane (3 x 10 mL), dried over anhydrous sodium PCT/U52012/027423 sulfate and concentrated in vacuo to afford methyl 3-(piperidin—l—yl) (trifluoromethylsulfonyloxy)quinoxalinecarboxy1ate as red solid (280 mg, crude).
Step 2. Methyl 2-(benzo[b]thiopheny1)(piperidinyl)quinoxaline’6-carboxylate To a solution of methyl 3~(piperidin—l—yl)(trifluoromethylsulfonyloxy)quinoxaline-6— carboxylate (280 mg, crude) in dioxane (5 mL) was added benzo[b]thiophenylboronic acid (357 mg, 2.0 mmol), K3PO4 (425 mg, 2.0 mmol), Pd(PPh3)4 (39 mg, 0.033 mmol) and water (3 drops). The resulting solution was stirred for 1 h at 90°C and then trated in vacuo to give a e, which was purified by silica gel column tography eluting with 3.3% ethyl acetate in petroleum ether to afford methyl 2—(benzo[b]thiophen—2—yl) (piperidin-l—yl)quinoxaline-6—carboxy1ate as a yellow solid (100.0 mg, 37% 2 steps).
LC/MS (ES, m/z):[M+H]+ 404.0 1H-NMR (300 MHz, Z 5 8.75 (d, J: 1.5 Hz, 1H), 8.42 (s, 1H), 8.15 — 8.19 (m, 1H), 8.04 (d, J = 8.7 Hz, 1H), 7.88 - 7.94 (m, 2H), 7.37 - 7.47 (m, 2H), 4.01 (s, 3H), 3.50 — 3.47 (m, 4H), 1.82 - 1.71 (m, 6H) Step 3. 2-(Benzo[b]thiophen—2-yl)—3-(piperidiny1)quinoxalinecarboxylic acid To a solution of methyl 2—(benzo[b]thiophen—2—yl)~3-(piperidin—l—yl)quinoxaline—6— carboxylate (70 mg, 0.17 mmol) in MeOH (20 mL) was added sodium hydroxide (28 mg, 0.69 mmol) and water (1 mL). The resulting solution was stirred overnight at room temperature and concentrated in vacuo. The residue was dissolved in water (10 mL) and adjusted to pH 4 with HCl (IN). The solids were collected by filtration to afford 2- (benzo[b]thi0phen—2-yl)(piperidin-1—y1)quinoxaline-6—carb0xylic acid as a yellow solid (60 mg, 89%).
LC/MS (ES, m/z):[M+H]+ 390.0 1H-NMR (300 MHz, DMSO+ D20) 8 8.50 (s, 1H), 8.31 (d, J: 1.5 Hz, 1H), 7.96 — 8.06 (m, 4H), 7.43 - 7.46 (m, 2H), 3.38 - 3.32 (m, 4H), 1. 63 — 1.73 (m, 6H) PCT/U82012/027423 EXAMPLE 54 3-(Azepanyl)(benzo[b]thiophenyl)quinoxalinecarboxylic acid Step 1. Methyl 3—(azepan—l-yl)~2~(trifluoromethylsulfonyloxy)quinoxaline-6—carboxylate C O NINfiKO/' / TfO N To a solution of methyl 3-(azepan—1-yl)-2—oxo-1,2,4a,8a-tetrahydroquinoxaline—6-carboxy1ate (150.0 mg, 0.50 mmol) in dichloromethane (50 mL) was added pyridine (210 mg, 2.64 mmol) and ngO (375 mg, 1.32 mmol) with stirring overnight under atmosphere of nitrogen at room temperature. The on mixture was then quenched with water (50 mL), extracted with dichloromethane (3 x 15 mL), the organic layers combined and dried over anhydrous magnesium sulfate, trated in vacuo to afford methyl pan-l~yl) (trifluoromethylsulfonyloxy)quinoxalinecarboxy1ate as red oil (250 mg, , which was used directly in the next step.
Step 2. Methyl 3—(azepan- 1 —y1)-2—(benzo[b]thiophen—2—y1)quinoxa1ine-6—carboxy1ate To a solution of methyl 3-(azepan—1—y1)-2—(trifluoromethylsulfonyloxy)quinoxaline carboxylate (250 mg, crude) in dioxane (2 mL) was added benzo[b]thiopheny1boronic acid (180 mg, 1.00 mmol), K3PO4 (210 mg, 1.00 mmol) and Pd(PPh3)4 (29 mg, 0.025 mmol) under nitrogen atmosphere. After stirring 1h at 90°C, the reaction mixture was dissolved in water (25 mL), extracted with dichloromethane (3 x 30 mL), dried over anhydrous magnesium e and concentrated under reduced re to afford a residue, which was purified by silica gel column chromatography eluting with 2% ethyl acetate in petroleum ether to afford methyl 3-(azepanyl)(benzo[b]thiophen—Z-yl)quinoxalinecarboxy1ate as a light yellow solid (82 mg).
LC/MS (ES, m/z): [M+H]‘r 417.0 1H—NMR (300 MHz, CDC13) 8 8.65 (s, 1H), 8.06 - 8.10 (m, 1H), 7.98 (d, J: 5.4 Hz, 1H) 7.84 - 7.93 (m, 3H), 7.36 - 7.48 (m, 2H), 4.00 (s, 3H), 3.58 - 3.61 (t, J = 6.0 Hz, 4H), 1.82 - 1.90 (m, 4H), 1.52 - 1.65 (m, 4H) Step 3. 3—(Azepanyl)(benzo[b]thiophen—2—yl)quinoxaline-6—Carboxy1ic acid To a solution of methyl 3—(azepan—l~y1)(benzo[b]thiopheny1)quinoxaline—6—carboxylate (82 mg, 0.2 mmol) in methanol (lSmL) was added sodium hydroxide (80 mg, 2 mmol) and water (1 mL). After stirring overnight at room temperature, the reaction mixture was concentrated under reduced pressure to afford a residue, which was dissolved in water (10 mL), ed the pH value to 6 with HC1 (3 N) and filtered to give 3—(azepan—l—y1)—2- (benzo[b]thiophenyl)quinoxalinecarboxylic acid as a light yellow solid (70.1 mg, 88%).
LC/MS (ES, m/z): [M+H]+ 404.0 1H-NMR (300 MHZ, DMSO) 5 8.21 (s, 1H), 7.95 - 8.21 (m, 4H), 7.85 - 7.8? (m, 1H), 7.36 - 7.48 (m, 2H), 3.58 - 3.61 (t, J: 6.0 Hz, 4H), 1.74 - 1.80 (m, 4H), 1.45 - 1.55 (m, 4H) EXAMPLE 55 (S)(5-Flu0r0benzo[b]thi0phenyl)—3-(2-methylpyrrolidinyl)quin0xaline carboxylic acid Step 1. (S)—Methyl ethylpyrrolidin- l -yl)—2—(trifluoromethylsulfonyloxy)quinoxaline carboxylate 0““ 0 NINDflm/ TfO N To a solution of (S)-methyl ethylpyrrolidin-l-y1)-2~oxo-l,2-dihydroquinoxaline carboxylate (200 mg, 0.70 mmol) in dichloromethane (30 mL) was added pyridine (220 mg, 2.78 mmol) and then szO (393 mg, 1.39 mmol) was added dropwise with stirring at 0°C.
The resulting solution was stirred overnight at room temperature and then quenched by the on of ice-water (20 mL), extracted with dichloromethane (3 x 20 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to afford (S)-methyl 3-(2— methylpyrrolidin—l-yl)(trifluoromethylsulfonyloxy)quinoxaline-6—carboxylate as red oil (300mg, crude).
Step 2. (S)—Methyl 2—(5 —f1uorobenzo[b]thiopheny1)—3-(2~methylpyrr01idin—1— yl)quin0xalinecarboxy1ate To a solution of methyl 3—[(2S)methy1pyrrolidin-1—yl]—2- [(trifluoromethane)sulfonyloxy]quinoxalinecarboxylate (300 mg, crude) in 1,4- dioxane (6 mL) was added 5—fluorobenzo[b]thi0phenylboronic acid (176 mg, 0.90 mmol), Pd(PPh3)4 (21 mg, 0.018 mmol), K3PO4 (228 mg, 1.08 mmol) and water (5 drops) with stirring for l h at 90°C maintained with an inert atmosphere of nitrogen in an oil bath. The reaction mixture was concentrated in vacuo to give the residue, which was applied onto silica gel column chromatography eluting with 1% to 5% ethyl e in petroleum to afford thyl 2—(5- fluorobenzo[b]thiophenyl)-3 -(2—methylpyrrolidin-l-yl)quinoxaline—6—carboxylate as a yellow solid (89 mg).
LC/MS (ES, m/z): [M+H]+ 422.0 1H—NMR (300 MHz, CDC13) 5 8.60 (s, 1H), 7.98 - 8.08 (m, 2H), 7.82 - 7.86 (m, 1H), 7.71 (s, 1H), 7.49 - 7.54 (m, 1H), 7.15 ~ 7.22 (m, 1H), 4.54 - 4.61 (in, 1H), 4.01 (s, 3H), 3.54 - 3.63 (m, 1H), 3.03 — 3.09 (m, 1H), 2.28 - 2.3 (m, 1H), 1.89 - 1.95 (m, 1H), 1.65 — 1.78 (m, 2H),l.44 (d, J: 6.0 Hz, 3H) Step 3. (S)—2—(5 —F1uorobenzo [b]thiophen—2-y1)—3—(2—methy1pyrrolidin— 1 inoxa1ine—6- carboxylic acid To a solution of (S)-methyl 2—(5-fluorobenzo[b]thiophen—2-yl)—3-(2-methylpyrrolidin—l— yl)quinoxalinecarboxylate (89 mg, 0.21 mmol) in methanol (25 mL) and chloroform (5 mL ) was added sodium hydroxide (25.2 mg, 0.63 mmol) with stirring ght at room temperature. The reaction mixture was trated in vacuo, dissolved in water (15 mL), adjusted pH to 5 with HCl (3 N) to give the precipitate, which was collected by filtration to afford (S)—2—(5—fluorobenzo ophen-2—yl)(2—methy1pyrrolidin— 1 -yl)quinoxaline carboxylic acid (56 mg, 65%).
LC/MS (ES,m/z): [M+H]+ 408.0 1H—NMR (300 MHz, DMSO) 5 8.27 (s, 1H), 8.06 — 8.11 (m, 1H), 7.94 (s, 2H), 7.87 (s, 1H), 7.80 - 7.85 (m, 1H), 7.30 — 7.37 (m, 1H), 4.37 — 4.43 (m, 1H), 3.46 — 3.55 (m, 1H), 2.96 - 3.01 (t, J: 6.9 Hz, 1H), 2.22 - 2.67 (m, 1H), 1.50 - 1.68 (m, 2H), 1.39 (d, J: 6.0 Hz, 3H) EXAMPLE 56 2-(Benzo[d]thiazolyl)(isopropyl(methyl)amino)quinoxaline—é-carboxylic acid Y o «“1le/N]©/U\OH8 Step 1. Methyl 2—(benzo[d]thiazolyl)(isopropyl(methyl)amino)quinoxaline carboxylate Y O «MEGA,NU/KO/8 To a solution of methyl 3-(isopropyl(methyl)amino)—2— (trifluoromethylsulfonyloxy)quinoxalinecarboxylate (150 mg, 0.37 mmol) in dioxane (5 mL) was added ,5,5-tetramethyl-l,3,2-dioxaborolan—2—yl)benzo[d]thiazole (288 mg, 1.1 mmol), K3PO4 (234 mg, 1.1 mmol), Pd(PPh3)4 (21 mg, 0.018 mmol) and water (3 drops).
The resulting solution was stirred for 1 h at 90°C and then concentrated in. vacuo to give a residue, which was purified by silica gel column chromatography eluting with 2% - 5% ethyl e in petroleum ether to afford methyl 2-(benzo[d]thiazolyl) (isopropyl(methyl)amino)quinoxaline—6~carboxylate as a yellow solid (120 mg, 83%).
W0 2012(119046 LC/MS (ES, m/z):[M+H]+ 393.0 1H-NMR (300 MHz, CDC13)I 5 9.10 (s, 1H), 8.70 (d, J: 0.9 Hz, 1H), 8.63 (d, J = 1.5 Hz, 1H), 8.00 - 8.13 (m, 4H), 4.29 - 4.38 (m, 1H), 4.01 (s, 3H), 2.81 (s, 3H), 1.10 (d, J: 6.6 Hz, Step 2. 2—(Benzo[d]thiazol—S—yl)—3-(isopropy1(methyl)amino)quinoxaline-6—carboxylic acid Y 0 x” /N]©)LOH <1}8 To a solution of methyl 2-(benzo[d]thiazol—5—y1)-3~(isopropyl(methyl)amino)quinoxaline-6— ylate (120 mg, 0.31 mmol) in MeOH (10 mL) was added sodium hydroxide (49 mg, 1.2 mmol) and water (1 mL). The resulting solution was stirred ght at room temperature and concentrated in vacuo. The residue was dissolved in water (10 mL) and adjusted to pH 6 with HCl (1 N). The solids were collected by filtration to afford 2- (benzo[d]thiazolyl)-3—(isopropyl(methyl)amino)quinoxalinecarboxy1ic acid as a yellow solid (99 mg, 86%).
LC/MS (ES, m/z):[M+H]+ 379.1 1H-NMR (300 MHz, DMSO) 5 9.49 (s, 1H), 8.56 (d, J: 1.2 Hz, 1H), 8.29 - 8.35 (t, J = 8.4 Hz, 2H), 7.93 — 8.00 (m, 3H), 4.18 — 4.23 (m, 1H), 2.69 (s, 3H), 1.01 (d, J = 6.6 Hz, 6H) EXAMPLE 57 2-(1,3-Benzothiazolyl)[(ZS)methylpyrrolidin-l-yl]quinoxalinecarboxylic acid Step 1. Methyl 2—(1,3—benzothiazolyl)[(2S)—2—methylpyrrolidin—l—y1]quinoxaline—6- carboxylate To a solution of methyl 3—[(2S)—2—methylpyrrolidin-l—y1]-2— [(trifluoromethane)sulfonyloxy]quinoxalinecarboxylate (150 mg, 0.36 mmol) in dioxane (6 mL) was added 5-(tetramethyl-1,3,2-dioxaborolany1)-1,3-benzothiazole (280 mg, 1.07 mmol), Pd(PPh3)4 (21 mg, 0.02 mmol), K3PO4 (228 mg, 1.07 mmol) and water (5 drops). The resulting solution was stirred for 1 h at 90°C maintained with an inert atmosphere of nitrogen in an oil bath. The reaction mixture was trated in vacuo to give the e, which was applied onto silica gel column chromatography eluting with 1% to 5% ethyl acetate in petroleum to afford methyl 2—(1,3-benzothiazolyl)-3—[(2S)—2-methylpyrrolidin-1— yl]quinoxaline—6—carboxylate as a yellow solid (100 mg, 69%).
LC/MS (ES, m/z): [M+H]+ 405.0 1H-NMR (300 MHz, CDClg) 5 9.12 (s, 1H), 8.73 (s, 1H), 8.52 (s, 1H), 7.92 — 8.14 (m, 4H), 4.50 - 4.60 (m, 1H), 4.01 (s, 3H), 3.17 — 3.24 (m, 1H), 2.95 - 3.05 (m, 1H), 2.15 - 2.25 (m, 1H), 1.81 - 1.91 (m, 1H), 1.60 - 1.75 (m, 2H), 1.45 (d, J: 5.7 Hz, 3H) Step 2. 2-(1 ,3-Benzothiazolyl)—3—[(2S)methylpyrrolidin-1—yl]quinoxaline-6~carboxylic acid 0““ 0 I NDAOH <” / To a solution of methyl 2-(1,3-benzothiazol—5—y1)~3-[(2S)—2—methylpyrrolidin—1— yl]quinoxalinecarboxylate (100 mg, 0.25 mmol) in methanol (15 mL) was added sodium hydroxide (30.0 mg, 0.75 mmol) and water (1 mL). The resulting solution was stirred overnight at room ature and trated in vacuo. The residue was dissolved in water (15 mL) and adjusted pH to 5 with hydrochloric acid (3 N). The solids were collected by filtration to afford 2—(1,3-benzothiazoly1)-3—[(2S)~2~methylpyrrolidiny]]quinoxa1ine-6— carboxylic acid as a yellow solid (80 mg, 82%).
LC/MS (ES, m/z):[M+H]+ 391.0 1H—NMR (300 MHz, CD3OD) 8 9.37 (s, 1H), 8.43 — 8.48 (m, 2H), 8.25 (d, J = 8.4 Hz, 1H), 7.93 - 8.03 (m, 3H), 4.36 - 4.43 (m, 1H), 2.96 — 3.11 (m, 2H), 2.15 - 2.25 (m, 1H), 1.75 - 1.80 (m, 1H), 1.59 - 1.69 (m, 2H), 1.43 (d, J: 6.0 Hz, 3H) W0 2012/‘119046 EXAMPLE 58 -Benzothiazolyl)[methyl(propanyl)amino]quinoxalinecarboxylic acid Y O /N /N:©/U\OH Step 1. Methyl 2-(1,3—benzothiazolyl)[methyl(propan~2—yl)amino]quinoxaline—6— carboxylate Y o /N INfiO/ .31.
Into a 10-mL sealed was placed methyl ro[methy1(propan—2—yl)amino]quinoxaline- 6-carboxylate (400 mg, 1.36 mmol), 1,3-benzothiazole (368 mg, 2.72 mmol), Pd(PPh3)4 (80 mg, 0.06 mmol) and ACOK (272 mg, 2.72 mmol) under nitrogen atmosphere. After stirring 4 h at 150°C, the reaction mixture was purified by silica gel column chromatography g with 10% ethyl acetate in petroleum ether to afford methyl 2-(1,3-benzothiazolyl) [methyl(propan—2—yl)amino]quinoxaline—6-carboxylate as a light yellow solid (50 mg, 9.4%).
LC/MS (ES, m/z): [M+H]Jr 393.0 1H—NMR (300 MHz, CDC13) 5 8.81 (s, 1H), 8.01 — 8.19 (m, 4H), 7.51 - 7.63 (m, 2H), 4.51 — 4.64 (m, 1H), 4.02 (s, 3H), 3.08 (s, 3H), 1.31 (d, J = 6.6 Hz, 6H) Step 2. 2-(1,3—Benzothiazol-2—yl)—3—[n1ethyl(propan—2—yl)amino]quinoxalinecarboxylic acid Y O To a solution of methyl 2-(1,3—benzothiazolyl)—3—[methyl(propan—2-y1)amino]quinoxaline- 6-carboxy1ate (50 mg, 0.13 mmol) in methanol (30 mL), was added sodium hydroxide (50 mg, 1.25 mmol). After stirring overnight at room temperature, the reaction mixture was concentrated under reduced pressure to afford a e, which was dissolved in water (10 mL), adjusted the pH value to 6 with 3 N HCl and filtered to give -benzothiazolyl)- 3-[methyl(propanyl)amino]quinoxaline-6—carboxylic acid as a light yellow solid (19.4 mg, 40%).
LC/MS (ES, m/z): [M+H]+ 379.0 1H-NMR (300 MHz, DMSO) 5 8.20 — 8.27 (m, 2H), 8.12 (d, J = 7.5 Hz, 1H), 7.98 (s, 1H), 7.53 - 7.63 (m, 2H), 4.36 - 4.43 (m, 1H), 2.86 (s, 3H), 1.20 (d, J: 6.6 Hz, 6H) E 59 -Benz0thiazolyl)[(25)methylpyrrolidin-l-yl]quinoxalinecarboxylic acid Step 1. Methyl 2—chloro-3—[(2S)—2—methylpyrrolidin-1—yl]quinoxalinecarboxylate <1112*OCl N/ The solution of methyl )n1ethylpy1rolidin—1—yl]—2-oxo—1,2-dihydroquinoxaline-6— carboxylate (5.9 g, 20.54 mmol,) in phosphorus oxychloride (100 mL) was stirred overnight at 120°C in an oil bath. The reaction mixture was concentrated in vacuo and diluted with dichloromethane (500 mL) and ice—water (500 mL), adjusted to pH 7 with NaHC03 solution.
The solution was extracted with dichloromethane (3 X 200 mL) and the organic layers combined , dried over anhydrous sodium sulfate and concentrated in vacuo to give a residue, which was purified by silica gel column chromatography eluting with 2% ethyl acetate in petroleum ether to afford methyl 2-chloro~3—[(2S)methylpyrrolidin—1—yl]quinoxaline carboxylate as a yellow solid (5 g, 80%).
LC/MS (ES, m/z): [M+H]+306.1 1H-NMR (300 MHZ, CDC13) 5 8.46 (d, J: 1.5 Hz, 1H), 7.98 - 8.02 (m, 1H), 7.82 (d, J = 8.7 Hz, 1H), 4.62 - 6. 69 (m, 1H), 4.04 - 4.14 (m, 1H), 3.99 (s, 3H), 3.78 - 3.88 (m, 1H), 2.20 - 2.29 (m, 1H), 2.03 — 2.12 (m, 1H),1.81— 1.95 (m, 1H), 1.72 - 1.79 (m, 1H), 1.32 - 1.42 (m, W0 2012/‘119046 Step 2. Methyl 2-(1,3 -benzothiazolyl)-3 -[(2S)—2—methylpyrrolidin- l -yl]quinoxaline-6— carboxylate 0"“ 0 8%.N\ O/ To a solution of methyl 2-chloro—3—[(2S)methy1pyrrolidin-1—yl]quinoxaline—6-carboxylate (300 mg, 0.98 mmol) in nzothiazole (266 mg, 1.97 mmol) was added Pd(PPh3)4 (57 mg, 0.05 mmol,) and potassium acetate (193 mg, 1.97 mmol) under an atmosphere of nitrogen. The resulting solution was stirred for 2 h at 170°C and then quenched by the on of NH4C1 solution (150 mL), extracted with dichloromethane (3 X 20 mL) and the organic layers combined and dried over anhydrous sodium sulfate and concentrated in vacuo to give a residue, which was purified by silica gel column chromatography eluting with 1% - % ethyl acetate in petroleum ether to afford methyl 2—(1,3—benzothiazol-2—y1)—3—[(2S) methylpyirolidin—l-yl]quinoxaline-6—carboxylate as a yellow solid (80 mg, 20%). 1H-NMR (300 MHz, CDC13) 8 8.55 (s, 1H), 8.16 (d, J = 7.5 Hz,1H), 7.98 - 8.02 (m, 3H), 7.47 — 7.59 (m, 2H), 4.53 — 4.60 (m, 1H), 4.01 (s, 3H), 3.68 — 3.77 (m, 1H), 2.26 - 2.31 (m, 1H), 1.92 — 1.93 (m, 1H), 1.75 - 1.77 (m, 2H), 1.45 (d, J: 6.0 Hz, 3H).
Step 3. 2—(1,3—Benzothiazol—2—yl)-3—[(28)-2—methylpyrrolidin-1—yl]quinoxaline-6—carboxylic acid <7” 0 I NfiOH S N/ To a solution of methyl 2-(1,3-benzothiazolyl)[(2S)—2-methylpyrrolidin—l— yl]quinoxalinecarboxylate (80 mg, 0.20 mmol) in tetrahydrofuran (20 mL) was added NaOH (23.8 mg, 0.60 mmol) and water(1 mL). The ing solution was stirred overnight at room temperature and then concentrated in vacuo, adjusted the pH to 7 with HCl (3 N).
The product was collected and d to afford 2—(1,3-benzothiazolyl)—3-[(2S)-2— methylpyrrolidin-l-yl]quinoxaline-é-carboxylic acid as a light yellow solid (43.8 mg, 57%).
LC/MS (ES, m/z): [M+H]+ 391.0 PCT/U52012/027423 1H-NMR (300 MHZ, CD3OD) 5 8.40 (d, J = 1.2 Hz, 1H), 8.10 — 8.14 (m, 2H), 7.92 — 8.02 (m, 2H), 7.51 - 7.62 (m, 2H), 4.49 - 4.55 (m, 1H), 3.60 - 3.69 (m, 1H), 3.05 - 3.10 (m, 1H), 2.25 - 2.31 (m, 1H), 1.91 - 1.92 (m, 1H),1.65 - 1.80 (m, 2H) ,1.42 (d, J: 6.0 Hz , m, 3H) EXAMPLE 60 3-(Isopropyl(methyl)amino)-2,7'-biquinoxalinecarboxylic acid Y O Step 1. Methyl 3~(isopropyl(methyl)amino)-2,7'-biquinoxalinecarboxylate Y O ENDIN/Nj:j)l\o/\N To a solution of methyl 3-[methyl(propanyl)amino] [(trifluoromethane)sulfonyloxy]quinoxaline—6-carboxylate (150 mg, 0.37 mmol) in dioxane (5 ml) was added 6—(tetramethyl-1,3,2—dioxaborolanyl)quinoxaline (141.5 mg, 0.55 mmol), 3)4 (21.3 mg, 0.02 mmol), K3PO4 (155.5 mg, 0.73 mmol) and water (3 drops) under a nitrogen here. After stirring 1 h at 90°C, the reaction mixture was concentrated in vacuo and purified by silica gel column chromatography eluting with 2% - 10% ethyl acetate in petroleum ether to afford methyl 3—(isopropyl(methyl)amino)-2,7'-biquinoxaline-6— carboxylate as a light yellow solid (90 mg, 63%).
LC/MS (ES, m/z): [M+H]+ 388.0 1H-NMR (300 MHz, DMSO) 5 9.00 - 9.04 (m, 2H), 8.58 (d, J: 1.8 Hz, 1H), 8.25 — 8.39 (m, 3H), 7.96 - 8.07 (m, 2H), 4.20 - 4.26 (m, 1H), 3.95 (s, 3H), 2.70 (s, 3H), 1.06 (d, J = 6.6 Hz, W0 2012fll9046 Step 2. 3-(Isopropy1(methyl)amino)—2,7‘—biquinoxa1ine—6-carboxylic acid Y O / /NUKOH To a solution of methyl 3-(isopropyl(methy1)amino)—2,7’-biquinoxaline—6—carboxylate (90 mg, 0.23 mmol) in methanol (30 mL) and water (1 ml), was added sodium hydroxide (54 mg, 1.35 mmol). After stirring overnight at room temperature, the reaction mixture was concentrated under reduced pressure to afford a e, which was dissolved in water (10 m1), adjusted the pH value to 6 with HCl (3N) and filtered to give 3- (isopropyl(methyl)amino)-2,7'-biquinoxaline~6—carboxy1ic acid as a light yellow solid (43.6 mg, 50%).
LC/MS (ES, m/z): [M+H]+ 374.0 1H—NMR (300 MHz, DMSO) 5 8.57 (d, J = 2.1 Hz, 2H), 8.57 (d, J: 4.2 Hz, 1H), 8.26 - 8.38 (m, 3H), 7.96 - 8.04 (m, 2H), 4.17 - 4.26 (m, 1H), 2.71 (s, 3H), 1.03 (d, J = 6.6 HZ, 6H) E 61 3-[Cyclopropyl(methyl)amino]—2-(5-flu0r0benzofuranyl)quinoxalinecarboxylic acid Step 1. Methyl 3—(cyclopropyl(methy1)amino)(trifluoromethylsulfonyloxy)quinoxa1ine carboxylate V o TfO N WO 19046 PCT/U82012/027423 To a solution of methyl 3-(cyclopropyl(methy1)amino)-2—oxo—1,2-dihydroquinoxaline-6— ylate (120 mg, 0.44 mmol) in romethane (10 mL) was added pyridine (139 mg, 1.76 mmol) and mo (248 mg, 0.88 mmol)under a nitrogen atmosphere After stirring overnight at room temperature, the reaction was ed by the addition water/ice (50 mL), extracted with dichloromethane (2 x 10 mL), dried over anhydrous magnesium sulfate and concentrated in vacuo to give methyl 3-(cyclopropyl(methyl)amino) (trifluoromethylsulfonyloxy)quinoxaline—6-carboxy1ate as red oil (150 mg, crude).
Step 2. Methyl 3-[cyclopropyl(methy1)amino](5-fluoro—1—benzofuranyl)quinoxaline-6— carboxylate To a solution of methyl 3-[cyclopropyl(methy1)amino] [(trifluoromethane)su1f0nyloxy]quinoxaline—6—carboxylate (150 mg, crude) in dioxane (5 mL) was added (5-fluorobenzofuranyl)boronic acid (167 mg, 0.93 mmol), K3PO4 (234 mg, 1.11 mmol), Pd(PPh3)4 (22 mg, 0.02 mmol) under a nitrogen atmosphere. After stirring 1 h at 90°C, the reaction mixture was dissolved in water (10 mL), extracted with dichloromethane (3 x 30 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure to afford a residue, which was purified by silica gel column chromatography eluting with 2% ethyl acetate in petroleum ether to afford methyl 3—[cyclopropyl(methyl)amino]-2— ro—1-benzofuranyl)quinoxa1inecarboxylate as a yellow solid (79 mg).
LC/MS (ES, m/z): [M+H]+ 392.0 1H~NMR (300 MHz, CDC13) 5 8.61 (s, 1H), 8.07 - 8.15 (m, 2H), 7.58 — 7.63 (m, 1H), 7.44 (s, 1H), 7.33 — 7.36 (m, 1H), 7.07 - 7.17 (m, 1H), 4.01 (s, 3H), 3.19 (s, 3H), 2.84 - 2.94 (m, 1H), 0.61 — 0.70 (m, 2H), 0.54 - 0.55 (m, 2H) Step 3. 3-[Cyclopr0py1(methy1)amino]~2-(5-f1uorobenzofuranyl)quinoxa1ine—6- carboxylic acid PCT/U82012/027423 To a solution of methyl 3-[cyclopropy1(methyl)amino]~2—(5—fluorobenzofuran-2— yl)quinoxalinecarboxy1ate (79 mg, 0.20 mmol) in methanol (15 mL) and water (1 mL) was added sodium hydroxide (24 mg, 0.60 mmol). After stirring overnight at room temperature, the reaction mixture was concentrated under reduced pressure to afford a residue, which was dissolved in water (20 mL), adjusted the pH value to 5 with 3N HCl and filtered to give 3- [cyclopropyl(methyl)amino](5—fluorobenzofuran-2—y1)quinoxalinecarboxy1ic acid as a light yellow solid (60 mg, 79%).
LC/MS (ES, m/z): [M+H]+ 378.0 1H-NMR (300 MHz, DMSO) 6 13.25 (s, 1H), 8.28 (s, 1H), 7.98 — 8.05 (m, 2H), 7.78 - 7.83 (m, 1H), 7.56 — 7.60 (m, 2H), 7.24 - 7.32 (m, 1H), 3.10 (s, 3H), 2.87 — 2.95 (m, 1H), 0.50 - 0.55 (m, 4H) EXAMPLE 62 2-(5-Fluorobenzofurany1)(pyrrolidinyl)quinoxalinecarboxylic acid C‘ O N /N@OH \ N F 0 Step 1. Methyl 2-oxo-3—(pyrrolidin-l—yl)-1,2—dihydroquinoxaline—6-carboxylate C O O N To a solution of methyl 3—chloro-2—oxo-1,2~dihydroquinoxaline—6—carboxylate (200 mg, 0.84 mmol) in DMSO (2 mL) was added pyrrolidine (90 mg, 1.27 mmol) and DIEA (163 mg, 1.26 mmol). After ng overnight at 70°C, the reaction mixture was ved in water (50 mL), then filtered to afford methyl 2—oxo(pyrrolidin—1-y1)—1,2-dihydroquinoxalinecarboxylate as a light yellow solid (200 mg, 87%).
LC/MS (ES, m/z): [M+H]+ 274.0 1H—NMR (300 MHz, DMSO) 5 12.15 (s, 1H), 7.82 (d, J: 1.8 Hz, 1H), 7.61 (d, J = 8.4 Hz, 1H), 7.13 (d, J: 8.4 Hz, 1H), 3.83 (s, 3H), 3.35 — 3.40 (m, 4H), 1.85 — 1.95 (m, 4H) Step 2. Methyl rolidin—1-yl)[(trifluoromethane)sulfonyloxy]quinoxaline-6— carboxylate C O TfO N To a solution of methyl Z—oxo—3-(pyrrolidin-1—yl)-1,2—dihydroquinoxaline—6-carboxy1ate (200 mg, 0.73 mmol) in dichloromethane (40 mL) was added pyridine (400 mg, 5.06 mmol) and szO (400 mg, 1.42 mmol), which was added dropwise with stirring at 0°C. After stirring overnight at room temperature under a nitrogen atmosphere, the reaction mixture was dissolved in water (100 mL), ted with dichloromethane (3 x 20 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure to afford methyl 3- (pyrrolidin—1-y1)—2—[(trifluoromethane)sulfonyloxy]quinoxaline—6—carboxylate as a light yellow solid (500 mg, crude).
Step 3. Methyl 2—(5 -fluorobenzofuran—2—yl)—3-(pyrrolidin-1—yl)quinoxaline—6—carboxylate To a solution of methyl 3—(pyrrolidin-1—yl)—2-[(trifluoromethane)sulfonyloxy]quinoxaline-6— carboxylate (500 mg, crude) in dioxane (2 mL) was added robenzofuran—2— yl)boronic acid (264 mg, 1.47 mmol), Pd(PPh3)4 (309 mg, 0.27 mmol), K3PO4 (42 mg, 0.20 mmol), and water (5 drops). After stirring 40 min at 90°C under nitrogen atmosphere, the reaction mixture was dissolved in water (100 mL), extracted with dichloromethane (3 x 30 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure to afford a residue, which was purified by silica gel column chromatography g with 2% ethyl e in petroleum ether to afford methyl 2-(5—fluoro—1—benzofuran—2—yl) (pyrrolidinyl)quinoxaline-6—carboxylate as a light yellow solid (150 mg).
LC/MS (ES, m/z): [M+H]+ 392.0 1H—NMR (300 MHz, CDC13) 5 8.58 (s, 1H), 7.98 - 8.06 (m, 2H), 7.55 - 7.62 (m, 1H), 7.33 - 7.37 (m, 1H), 7.26 (s, 1H), 7.09 - 7.16 (m, 1H), 4.00 (s, 3H), 3.53 — 3.57 (m, 4H), 1.93 - 1.97 (m. 4H) W0 20121119046 Step 4. 2-(5—Fluoro—l-benzofuranyl)-3—(pyrrolidin—1—yl)quinoxalinecarboxy1ic acid C‘ O \ N F 0 To a solution of methyl 2—(5—fluoro—1—benzofuranyl)—3—(pyrrolidin-l-yl)quinoxaline—6— carboxylate (150 mg, 0.38 mmol) in methanol (50 mL) was added sodium hydroxide (150 mg, 3.75 mmol) and water (2 mL). After stirring overnight at room temperature, the on mixture was concentrated under reduced pressure to afford a residue, which was dissolved in water (10 mL), adjusted to pH 6 with HCl (3N) and filtered to give 2-(5-fluoro—l-benzofuran— 2-yl)-3—(pyrrolidin—1-yl)quinoxalinecarboxylic acid as a light yellow solid (36.5 mg, 25%).
LC/MS (ES, m/z): [M+H]+ 378.0 1H—NMR (300 MHz, CDC13) 5 8.77 (s, 1H), 8.02 - 8.10 (m, 2H), 7.56 - 7.62 (m, 1H), 7.35 - 7.38 (m, 1H), 7.31 (s, 1H), 7.11 - 7.18 (m, 1H), 3.55 - 3.61 (m, 4H), 1.97 — 2.05 (m, 4H) EXAMPLE 63 2-(1H-Benzo[d]imidazolyl)(isopropyl(methyl)amin0)quinoxalinecarb0xy1ic acid Y O / N N The mixture of methyl 2~chloro(isopropyl(methyl)amino)quinoxaline—6—carboxylate (200 mg, 0.68 mmol), 1H—benzo[d]imidazole (500 mg, 4.24 mmol), ACOK (200 mg, 2.05 mmol) and Pd(PPh3)4 (39 mg, 0.03 mmol) was stirred for 3 h at 170°C and then ed by silica gel Chromatography eluting with 2% —5% methanol in dichloromethane to afford 2-(1H- benzo[d]imidazol—l-yl)-3—(isopropyl(methyl)amino)quinoxaline-6—carboxylic acid as a yellow solid (18.0 mg, 7%).
LC/MS (ES, m/z):[M+H]+ 362.0 WO 19046 1H—NMR (300 MHz, CDC13)I 5 8.69 (d, J = 9.0 HZ, 2H), 8.20 (d, J = 8.1 Hz, 1H), 7.92 — 8.03 (m, 3H), 7.44 - 7.47 (t, J = 4.2 Hz, 2H), 4.13 - 4.17 (m, 1H), 2.69 (s, 3H), 1.15 (d, J: 6.3 Hz, EXAMPLE 64 3-[Cyclopropyl(methyl)amino]—2-(lH-indol-S-yl)quinoxalinecarboxylic acid ‘7 o mil“' him/“\OH Step 1. Methyl 3—[cyclopropyl(methyl)amin0]—2-oxo-1,2~dihydroquinoxaline—6—carboxylate 7 o /N /Nj©/u\o/ To a solution of methyl 3-chlorooxo-1,2-dihydroquinoxalinecarboxylate (300 mg, 1.26 mmol) in DMSO (2 mL), was added ylcyclopropanamine hydrochloride (175 mg, 1.63 mmol) and DlEA (325 mg, 2.52 mmol) with stirring for 2h at 75°C in an oil bath. Then the reaction was quenched by the addition of water (10 mL) to give the precipitate, which was collected by filtration to afford methyl 3-[cyclopropy1(methyl)amino]ox0-1,2— dihydroquinoxaline—6-carboxylate as an off-white solid (297 mg, 86%).
LC/MS (ES, m/z): 273.0 1H-NMR (300 MHz, DMSO) 5 12.26 (s, 1H), 7.92 (d, J: 1.8 Hz 1H), 7.71 - 7.75 (m, 1H), 7.19 (d, J = 10.5 Hz, 1H), 3.85 (s, 3H), 3.23 (s, 3H), 3.05 - 3.12 (m, 1H), 0.76 — 0.82 (m, 2H), 0.60 - 0.63 (m, 1H) Step 2. Methyl 3-[cyclopropyl(methyl)amino]—2- [(trifluoromethane)sulfonyloxy]quinoxaline—6-carb0xylate i O TfO N To a solution of methyl 3—[cyclopropyl(methyl)amino]oxo-1,2-dihydroquinoxaline carboxylate (150 mg, 0.55 mmol) in dichloromethane (30 mL) was added pyridine (173.8 mg, 2.20 mmol) under an inert atmosphere of nitrogen. This was followed by the addition of PCT/U52012/027423 ngO (316 mg, 1.12 mmol) with stirring overnight at room temperature. The reaction mixture was then quenched with water (50 mL), extracted with dichloromethane (3 x 20 mL), the organic layers combined and dried over anhydrous magnesium e, and concentrated in vacuo to afford methyl 3—[cyclopropyl(methyl)amino] [(trifluoromethane)sulfonyloxy]quinoxaline-6—carboxylate as a yellow oil (200 mg, crude).
Step 3. Methyl 3-[cyclopropy1(methyl)amino]—2—(1H—indolyl)quinoxalinecarboxylate V o /” IND” CCFN’ To a solution of methyl 3-[cyclopropyl(methyl)amino]~2~ [(trifluoromethane)sulfonyloxy]quinoxaline-é—carboxylate (200 mg, crude) in 1,4—dioxane (4.0 mL) and water (three drops) was added (1H—indol—5—yl)boronic acid (238 mg, 1.48 mmol), K3PO4 (312 mg, 1.47 mmol) and Pd(PPh3)4 (28 mg, 0.02 nmiol) with stirring for 1 h at 90°C maintained under an inert atmosphere of en in an oil bath. The reaction mixture was concentrated in vacuo to give the residue, which was purified by silica gel column tography eluting with 2% - 10% ethyl acetate in eum to afford methyl 3— [cyclopropyl(methyl)amino](1H—indol—S-yl)quinoxaline—6—carboxylate as a yellow solid (71 mg, 35% 2 steps).
LC/MS (ES, m/z): [M+H]+ 372.0 1H-NMR (300 MHz, DMSO) 811.29 (s, 1 H), 8.29 (s, 1H), 7.92 - 8.04 (m, 3H), 7.62 — 7.71 (m, 1H), 7.48 - 7.59 (m, 1H), 7.41 — 7.48 (m, 1H), 6.60 - 6.84 (m, 1H), 6.21 — 6.22 (m, 1H), 4.02 — 4.07 (m, 1H), 3.93 (s, 3H), 2.96 (s, 3H), 0.43 ~ 0.45 (m, 4H) Step 4. 3—[Cyclopropyl(methyl)amino]—2—(1H—indol-S-yl)quinoxaline—6—carboxylic acid Y o witI NfikOH W0 20121119046 To a solution of methyl 3-[cyclopropyl(methyl)amino](lH—indol-S-yl)quinoxaline-6— carboxylate (71 mg, 0.19 mmol) in methanol (20 mL) and water (1.0 mL) was added sodium hydroxide (22.9 mg, 0.57 mmol) with stirring overnight at room temperature. The reaction mixture was concentrated in vacuo, dissolved in water (10 mL), adjusted pH to 4 with HCl (3N) to give the precipitate, which was collected by filtration to afford 3- [cyclopropyl(methyl)amino]—2-(1H—indol-S-yl)quinoxalinecarboxylic acid of as a yellow solid (20.4 mg, 30%).
LC/MS (ES, m/z): [M+H]+ 358.0 1H—NMR (300 MHz, CD3OD) 5 8.47 (d, J: 1.8 Hz, 1H), 8.03 - 8.06 (m, 2H), 7.94 (d, J: 8.4 Hz, 1H), 7.59 — 7.63 (m, 1H), 7.41 (d, J: 9.3 Hz, 1H), 7.33 (d, J: 3.3 Hz, 1H), 6.58 (d, J: 6.6 Hz, 1H), 3.01 (s, 3H), 2.55 — 2.59 (m, 1H), 0.51 — 0.54 (m, 4H) E 65 2-(1H-Indolyl)(piperidinyl)quinoxalinecarb0xylic acid 0 O I NUAOH / N Step 1. Methyl eridin—l-y1)—2—(trifluoromethylsulfonyloxy)quinoxaline—6—carboxylate o O NINDJkO/l / TfO N To a solution of methyl 2—oxo—3—(piperidin—1—yl)-l,2-dihydroquinoxaline~6—carboxylate (180 mg, 0.63 mmol) in romethane (50 mL) was added pyridine (220 mg, 2.8 mmol) and then szO (393 mg, 1.4 mmol) was added dropwise with stirring at 0°C. The resulting solution was stirred overnight 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-(piperidin— l-yl)(trifluoromethylsulfonyloxy)quinoxaline—6—carboxylate as yellow oil (290 mg, crude).
W0 2012I119046 Step 2. Methyl 2-(1H—indol-S—yl)(piperidiny1)quinoxaline-6—carboxy1ate To a solution of methyl 3—(piperidiny1)(trifluoromethylsulfonyloxy)quinoxaline-6— carboxylate (290 mg, crude) in dioxane (5 mL) was added ol—S-ylboronic acid (337 mg, 2.1 mmol), K3PO4 (443 mg, 2.1 mmol), Pd(PPh3)4 (40 mg, 0.03 mmol) and water (0.5 mL). The resulting solution was stirred for 1 h at 90°C and then quenched by the on of CHzClz (100 mL), washed with water (3 x 50 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to give a residue, which was purified by silica gel column chromatography eluting with 5% ethyl acetate in petroleum ether to afford methyl 2-(1H- indol-5—yl)(pipe1idin—l—yl)quinoxaline-6—carboxy1ate as a yellow solid (90.0 mg, 33%).
LC/MS (ES, m/z):[M+H]+ 387.0 1H-NMR (300 MHz, CDC13)Z 88.55 (d, J: 1.8 Hz, 1H), 8.39 (s, 1H), 8.30 (s, 1H). 8.06 - 8.09 (m, 1H), 7.99 (d, J = 8.7 Hz, 1H), 7.90 — 7.93 (m, 1H), 7.50 (d, J = 8.7 Hz, 1H), 7.29 - 7.31 (m, 1H), 6.67 - 6.69 (t, J: 2.4 Hz, 1H), 4.00 (s, 3H), 3.25 - 3.31 (m, 4H), 1.55 - 1.62 (m, Step 3. 2-(1H—Indol-S-yl)—3-(piperidin-l~yl)quinoxalinecarboxylic acid 0 ° I NDAOH / N T0 a solution of methyl 2—(1H—indol—5-y1)—3-(piperidin~1~yl)quinoxaline—6—carboxylate (90 mg, 0.23 mmol) in MeOH (20 mL) was added sodium hydroxide (40 mg, 0.93 mmol) and water (2 mL). The resulting solution was stirred overnight at room temperature and concentrated in vacuo. The e was dissolved in water (5 mL) and adjusted to pH 6 with hydrochloric acid (1N). The solids were collected by filtration to afford 2-(1H—indol—5—yl)-3— (piperidinyl)quinoxaline-6—carboxy1ic acid as a brown solid (65.8 mg, 76%).
LC/MS (ES, M+H]+ 373.0 1H—NMR (300 MHz, DMSO) 511.32(s, 1H), 8.27 (d, J = 0.6 Hz, 1H), 7.92 - 7.99 (m, 2H), 7.77 - 7.81 (m, 1H), 7.51 (d, J: 8.4 Hz, 1H), 7.42 (d, J: 2.7 Hz, 1H), 6.58 (s, 1H), 3.15 — 3.24 (m, 4H), 1.45 - 1.53 (m, 6H) PCT/U82012/027423 EXAMPLE 66 (S)(1H-Indolyl)(3-methylmorpholino)quinoxalinecarboxylic acid o/fim“ 0 K/N /ND/kOH / N Step 1. (S)—Methyl 3—(3—methylmorpholino)oxo—1,2-dihydroquinoxalinecarboxylate o/fi'“ o K/N AD/KO/ To a solution of (3S)—3-methylmorpholine (127 mg, 1.26 mmol) in DMSO (2 mL) was added methyl 3—chloro-2—hydroxyquinoxaline-6~carboxylate (200 mg, 0.84 mmol) and DIEA (217 mg, 1.68 mmol). The resulting solution was stirred at 70°C for 3 h and then quenched by water (10 mL). The solids were collected by filtration to afford (S)—methy1 3—(3- methylmorpholino)oxo—1,2—dihydroquinoxaline-6—carboxylate as a light yellow solid (200 mg, crude).
LC/MS (ES, m/z): [M+H]+ 304.0 1H—NMR (300 MHz, CDC13) 5 9.29 (s, 1H), 8.22 (d, J: 1.5 Hz, 1H), 7.87 — 7.90011, 1H), 7.04 (d, J = 8.4 Hz, 1H), 5.21 - 5.23 (m, 1H), 4.69 - 4.74 (m, 1H), 3.95 — 4.02 (m, 4H), 3.67 - 3.88 (m, 3H), 3.46 — 3.55 (m, 1H), 1.42 (d, J: 6.6 Hz, 3H) Step 2. (S)-Methyl 3-(3—methylmorpholino)(trifluoromethylsulfonyloxy)quinoxaline carboxylate o o K/NINDAO/\TfO N To a on of (S)-methyl 3—(3-methylmorpholino)-2—oxo-l ,2—dihydroquinoxaline—6— carboxylate (200 mg, crude) in dichloromethane (30 mL) was added ne (79 mg, 2.64 mmol). Then ngO (372 mg, 1.32 mmol) was added and stirred overnight at room temperature. The reaction was then ed by the addition of ice-water (100 mL ) and extracted with dichloromethane ( 3 x 15 mL), the organic layers combined and dried over anhydrous magnesium sulfate and concentrated in vacuo to afford (S)-methy1 3-(3- methylmorpholino)—2—(trifluoromethylsulfonyloxy)quinoxaline—6-carboxy1ate as red oil (250 mg, crude).
Step 3. (S)-Methyl indol—S-y1)-3—(3—methylmorpholino)quinoxalinecarboxylate o/fi‘“\\ o K/N /N]::)ko/ / N To a solution of (S)—methyl 3—(3—methylmorpholino) (trifluoromethylsulfonyloxy)quinoxaline—6-carboxylate (250 mg, crude) in dioxane (5 mL) was added Pd(PPh3)4 (33 mg, 0.03 mmol), lH-indol-S-ylboronic acid (230 mg, 1.43 mmol), K3P04 (361 mg, 1.71 mmol) and water (5 drops). The resulting on was stirred for 1 h at 90°C under an inert atmosphere of nitrogen and then concentrated in vacuo to give a residue, which was purified by silica gel column chromatography eluting with 1% - 10% ethyl acetate in petroleum ether to afford (S)—methyl 2-(1H—indol-5—yl)-3—(3- methylmorpholino)quinoxaline—6-carboxylate as a yellow solid (110 mg).
LC/MS (ES, m/z): [M+H]+ 403.0 1H-NMR (300 MHz, CDC13) 5 8.56 (d, J: 1.5 Hz, 1H), 8.36 (d, J: 0.9 Hz, 1H), 8.34 (s, 1H), 8.02 - 8.14 (m, 2H), 7.87 — 7.91 (m, 1H), 7.52 (d, J = 8.7 Hz, 1H), 7.30 - 7.33 (t, J = 2.7 Hz, 1H), 6.68 — 6.70 (t, J: 2.1 Hz, 1H), 4.01 (s, 3H), 3.91 - 3.96 (m, 1H), 3.81 - 3.86 (m, 1H), 3.64 — 3.76 (m, 2H), 3.41 — 3.51 (m, 3H), 1.17 (d, J: 6.6 Hz, 3H) Step 4. (S)—2—(1H-Indol—S—y1)—3—(3-methylmorpholino)quinoxalinecarb0xylic acid o/fi'f‘ o R \DAOHN /N / N To a solution of (S)-methyl 2—(lH-indol-S-y1)(3—methylmorpholino)quinoxaline—6- carboxylate (110 mg, 0.27 mmol) in methanol (15 mL) and CHC13 (5 mL) was added NaOH (32.4 mg, 0.81 mmol) and water (1 mL). The resulting on was stirred overnight at room temperature and trated in vacuo. The residue was dissolved in water (15 mL) and adjusted to pH 5 with hydrochloric acid (1N). The solids were collected by tion to afford (S)—2-(1H—indol-S-yl)(3-methylmorpholino)quinoxalinecarboxylic acid as a yellow solid (81 mg, 76%).
LC/MS (ES, m/z): [M+H]+ 389.0 1H-NMR (300 MHz, DMSO) 5 11.28 (s, 1H), 8.29 (s, 1H), 8.24 (s, 1H), 7.95 - 8.01 (m, 2H), 7.74 - 7.77 (m, 1H), 7.53 (d, J = 8.7 Hz, 1H), 7.40 - 7.43 (t, J = 2.4 HZ, 1H), 6.59 (d, J = 2.4 Hz, 1H), 3.76 - 3.82 (m, 2H), 3.53 — 3.60 (m, 2H), 3.26 - 3.42 (m, 02 (d, J: 6.6 Hz, EXAMPLE 67 2-(1H-Indolyl)[(2R)(methoxymethyl)pyrrolidinyl]quinoxalinecarb0xylic acid ‘ O Q. O ,N OH / N Step 1. Methyl 3—[(2R)~2—(methoxymethyl)py1rolidin-l-yl]—2-oxo-1,2—dihydroquinoxaline carboxylate \\\O o 0 O N To a solution of methyl 3—chloro-2—oxo—1, 2—dihydroquinoxalinecarboxylate (600 mg, 2.51 mmol) in DMSO (8 mL) was added DIEA (650 mg, 5.03 mmol), and (2R)—2— hoxymethyl)pyrrolidine (318 mg, 2.76 mmol). The solution was stirred for 4 h at 75°C.
Then the reaction was quenched by the addition of water (50 mL) to give the precipitate, which was collected by filtration to afford methyl 3-[(2R)~2-(methoxymethyl)pyrrolidin—1~ yl]—2—oxo-1,2—dihydroquinoxalinecarboxylate as a gray solid (650 mg, 81%).
LC/MS (ES, m/z):[M+H]+ 317.0 1H-NMR (300 MHz, CDC13) 8 11.09 (s, 1H), 8.18 (s, 1H), 7.79 - 7.82 (m, 1H), 7.11 (d, J = 8.4 Hz, 1H), 4.11 - 4.20 (m, 1H), 3.91 - 4.01 (m, 4H), 3.67 - 3.72 (m, 1H), 3.41 - 3.46 (m, 4H), 2.65 (s, 4H), 1.96 - 2.12 (m, 4H) Step 2. Methyl 3-[(2R)—2-(methoxymethyl)py1rolidin-l—yl]—2- luoromethane)sulfonyloxy]quinoxaline-6—carboxy1ate “\\O/ O O TfO N To a solution of methyl 3-[(2R)—2—(methoxymethyl)pyrrolidinyl]—2-oxo-1,2- dihydroquinoxalinecarboxy1ate (600 mg, 1.89 mmol) in dichloromethane (120 mL) was added pyridine (598 mg, 7.56 mmol) and szO (1.06 g, 3.76 mmol) with stirring ght maintained under an inert atmosphere of nitrogen at room temperature. The on was then quenched with water (100 mL), extracted with dichloromethane (3 x 50 mL), the organic layers combined and dried over anhydrous magnesium sulfate, and concentrated in vacuo to afford methyl 3-[(2R)(methoxymethyl)py1rolidiny1] [(trifluoromethane)sulfonyloxy]quinoxaline—6—carboxylate as red oil(850mg, crude), which was used to the next step directly.
Step 3. Methyl 2—(1H—indol—5—yl)—3—[(2R)—2~(methoxymethyl)pyrrolidin—1—yl]quinoxaline carboxylate \\\° 0“ 0 / N To a solution of methyl 3—[(2R)—2—(methoxymethyl)pyrrolidin-1—yl] uoromethane)sulfonyloxy]quinoxaline—6-carboxylate (425 mg, crude) in dioxane (5.0 mL) and water (three drops) was added (1H—indol-5—yl)boronic acid (350 mg, 2.17 mmol), K3PO4 (458 mg, 2.16 mmol) and Pd(PPh3)4 (41.5 mg, 0.04 mmol) with stirring for 1 h at 90°C under with an inert atmosphere of nitrogen in an oil bath. The reaction mixture was trated in vacuo to give the residue, which was purified by silica gel column chromatography eluting with 2% ethyl acetate in petroleum to afford methyl 2-(1H—indol yl)[(2R)(methoxymethyl)pyrrolidin-1—yl]quinoxaline—6-carboxylate as a red solid (200 mg).
LC/MS (BS, m/z): [M+H]+ 417.0 1H-NMR (300 MHz, CDC13) 8 8.51 (s, 1H), 8.37 (s, 1H), 8.10 (s, 1H), 7.97 - 8.04 (m, 2H), 7.65 - 7.68 (m, 1H), 7.48 (d, J: 8.7 Hz, 1H), 7.30 (d, J = 3.0 Hz, 1H), 6.65 - 6.66 (m, 1H), 4.67 - 4.69 (m, 1H), 4.01 (s, 3H), 3.82 - 3.86 (m, 1H), 3.62 — 3.81 (m, 1H), 3.46 (s, 3H), 2.96 -3.09 (m, 2H), 2.12 — 2.17 (m, 1H), 1.87 — 1.94 (m, 2H), 1.75 — 1.79 (m, 1H) Step 4. 2—(1H—Indol-S-y1)—3-[(2R)~2~(methoxyn1ethy1)pyrrolidin—1-yl]quinoxaline carboxylic acid \x\° 0“ 0 N /Nj©flkOH / N To a solution of methyl 2-(1H—indol-5—yl)—3—[(2R)~2-(methoxymethyl)pyrrolidin—1- yl]quinoxalinecarboxylate (200 mg, 0.48 mmol) in methanol (35.0 mL) and water (1.0 mL ) was added sodium hydroxide (76.9 mg, 1.92 mmol) with stirring overnight at room temperature. The reaction mixture was concentrated in vacuo, dissolved in water (30.0 mL), ed pH to 4 with HCl (3N) to give the precipitate, which was collected by ion to afford 2-(1H—indol—S-yl)—3-[(2R)—2—(methoxymethyl)pyrrolidin—1-yl]quinoxaline—6—carboxylic acid (80 mg, 41%).
LC/MS (ES, m/z): [M+H]+ 403.0 1H-NMR (300 MHz, DMSO) 5 11.32 (s, 1H), 8.24 (s, 1H), 7.86 — 8.24 (m, 3H), 7.43 - 7.55 (m, 3H), 6.54 — 6.56 (t, J: 2.1 Hz, 1H), 4.45 - 4.50 (m, 1H), 3.67 — 3.71 (m, 1H), 3.49 - 3.55 (m, 1H), 3.32 (s, 1H), 2.93 - 2.99 (m, 2H), 2.00 — 2.08 (m, 1H), 1.81 - 1.93 (m, 2H), 1.56 - 1.69 (m, 1H) W0 2012/‘119046 EXAMPLE 68 luorobenzofuranyl)[(2R)(methoxymethyl)pyrrolidinyl]quinoxaline- 6-carboxylic acid Step 1. Methyl 2—(5—fluoro—1-benzofuranyl)-3—[(2R)(methoxymethyl)pyrrolidin—1- yl]quinoxaline—6—carboxylate ‘x\O O 0 N Nfio/ \ N To a solution of methyl 3—[(2R)(methoxymethyl)pyrrolidin-l-yl] [(trifluoromethane)sulfonyloxy]quinoxaline—6-carboxylate (325 mg, 0.72 mmol) in dioxane (5.0 mL) and water (three drops) was added (5-fluoro-l-benzofuranyl)boronic acid (391 mg, 2.17 mmol), Pd(PPh3)4 (41.7 mg, 0.04 mmol), and K3PO4 (458.0 mg, 2.16 mmol) with stirring for 1 h at 90°C under an inert atmosphere of nitrogen in an oil bath. The on mixture was cooled down to room temperature, concentrated in vacuo to give the residue, which was purified by silica gel column chromatography eluting with 1% ethyl acetate in petroleum ether to afford methyl 2—(5-fluorobenzofuran—2—yl)-3—[(2R)~2- (methoxymethyl)pyrrolidin-l—yl]quinoxalinecarboxylate as a yellow solid (135 mg).
LC/MS (ES, m/z): [M+H]+ 436.0 1H-NMR (300 MHz, CDCl3) 8 8.50 (s, 1H), 8.06 (s, 2H), 7.58 - 7.62 (m, 1H), 7.31 - 7.37 (m, 2H), 7.10 - 7.17 (m, 1H), 4.78 - 4.80 (m, 1H), 4.15 (s, 3H), 3.77 — 3.81 (m, 1H), 3.63 ~ 3.68 (m, 1H), 3.50 — 3.56 (m, 1H), 3.48 (s, 3H), 3.05 — 3.10 (m, 1H), 2.17 - 2.21 (m, 1H), 1.92 - 2.01 (m, 2H), 1.59 - 1.71 (m, 1H) W0 19046 PCT/U82012/027423 Step 2. 2-(5-F1uoro— l —benzofuranyl)[(2R)—2-(methoxymethyl)py1rolidin- 1- yl]quinoxalinecarboxylic acid .~“\O C O \ /N:©/U\OH\N F 0 To a solution of methyl 2—(5—fluoro—l-benz.ofuran—2-yl)—3-[(2R)-2~ (methoxymethyl)pyrrolidin—1—y1]quinoxalinecarboxylate (135 mg, 0.31 mmol) in methanol (35.0 mL) and water (1.0 mL) was added sodium hydroxide (55 mg, 1.38 mmol) with stining overnight at room temperature. The reaction mixture was concentrated in vacuo, dissolved in water (30.0 mL), ed pH to 4 with HCl (3N) to give the precipitate, which was collected by filtration to afford 2—(5~fluoro—l—benzofuran—2—yl)—3—[(2R)—2- (methoxymethyl)pyrrolidin-1—y1]quinoxaline~6~carboxylic acid (100 mg, 77%).
LC/MS (ES, m/z): [M+H]+ 422.0 1H-NMR (300 MHz, DMSO) 5 13.21 (s, 1H), 8.26 (s, 1H), 7.93 - 8.02 (1n, 2H), 7.77 - 7.81 (m, 1H), 7.58 - 7.63 (m, 1H), 7.44 (s, 1H), 7.26 - 7.33 (m, 1H), 4.59 - 4.64 (m, 1H), 3.68 - 3.72 (m, 1H), 3.47 - 3.52 (m, 1H), 3.36 - 3.43 (m, 1H), 3.10 - 3.16 (m, 1H), 2.17 ~ 2.27 (m, 1H), 1.81 - 1.93 (m, 2H), 1.56 - 1.71 (m, 1H) EXAMPLE 69 (S)(sec-Butyl(methyl)amino)(5-fluorobenz0furanyl)quinoxaline—6-carb0xylic acid R o \ N Step 1. (S)-methyl 3-(sec-butylan1ino)oxo-1,2—dihydroquinoxaline—6—carboxy1ate Hi‘\\\ 0 HNIND/KO/o N PCT/U82012/027423 To a solution of methyl ro-2—oxo-1,2-dihydroquinoxaline—6—carboxylate (200 mg, 0.84 mmol) in DMSO (2 mL) was added tanamine (93 mg, 1.27 mmol) and DIEA (163 mg, 1.26 mmol). The ing solution was stirred for 3 hours at 70°C and then quenched by the addition of water (10 mL). The solids were collected by filtration to afford (S)-methyl 3— (sec-butylamino)—2—oxo-1,2-dihydroquinoxalinecarboxylate as light yellow solid(150 mg, 65%).
LC/MS (ES, m/z):[M+H]+ 2760 Step 2. (S)—Methyl 3-(sec-butylamino)—2~(trifluoromethylsulfonyloxy)quinoxaline-6— carboxylate H““‘ O TfOHNrNfiO/\N To a solution of (S)—methy1 3-(sec—buty1amino)-2—oxo-1 ,2-dihydroquinoxalinecarboxylate (300 mg, 1.10 mmol) in dichloromethane (40 mL) was added pyridine (344 mg, 4.36 mmol).
Tf20 (615 mg, 2.18 mmol) was added drop—wise with stirring at 0°C. The resulting on was stirred for 2h at room temperature and then washed with water (3 x 50 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to afford (S)-methyl 3-(sec-butylamino)- 2-(trifluoromethylsulfonyloxy)quinoxaline—6—carboxylate as red oil (390 mg, crude).
Step 3. (S)—Methyl 3-(sec—butylamino)-2—(5—fluorobenzofuran-2—yl)quinoxaline—6— carboxylate H‘““ O HN /N: : /U\O/ \ \ N To a solution of (S)—methy1 3-(sec-buty1amino)(trifluoromethylsulfonyloxy)quinoxaline—6— carboxylate (390 mg, crude) in dioxane (6 mL) was added 5-fluorobenzofuran—2—y1boronic acid (353 mg, 1.96 mmol), K3PO4 (416 mg, 1.96 mmol), Pd(PPh3)4 (64 mg, 0.06 mmol) and water (5 drops). The resulting solution was stirred for 1 h at 90°C and then quenched by the on of dichloromethane (100 mL). The resulting mixture washed with water (3 x 50 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to give a residue, which was purified by silica gel column chromatography g with 3.3% ethyl acetate in petroleum W0 2012(119046 2012/027423 ether to afford (S)-methyl 3—(sec-butylamino)—2—(5—fluorobenzofuran—2-y1)quinoxaline—6— carboxylate as a red solid (130.0 mg, 30% 2 steps).
LC/MS (ES, m/z):[M+H]+ 394.1 1H—NMR (300 MHz, CDC13)I 5 8.59 (s, 1H), 8.01 — 8.04 (m, 1H), 7.91 (d, J: 8.7 Hz, 1H), 7.79 (s, 1H), 7.55 - 7.59 (m, 1H), 7.39 - 7.42 (m, 1H), 6.95 — 7.22 (m, 1H), 4.56 - 4.60 (m, 1H), 4.00 (S, 3H), 1.71 - 1.85 (m, 2H), 1.40 (d, J: 6.6 Hz, 3H), 1.08 - 1.13 (t, J: 7.2 HZ, 3H) Step 4. (S)—3—(sec—Butyl(methyl)amino)(5-fluorobenzofuran—2-yl)quinoxalinecarboxylic acid R o \ N To a solution of (S)—methyl 3-(sec—butylamino)(5-fluorobenzofuran-2—yl)quinoxaline-6— carboxylate (130 mg, 0.33 mmol) in THF (20 mL) was added NaH (52 mg, 1.32 mmol) and CH3I (188 mg, 1.32 mmol). The resulting solution was stirred overnight at room temperature and then the reaction mixture was poured into water/ice solution (20 mL). The mixture was evaporated until about 10mL of water remained and adjusted to pH 5 with hydrochloric acid (IN). The product was ted by filtration to afford (S)—3—(sec-buty1(methyl)amino)—2-(5 — benzofuran-Z-yl)quinoxaline—6—carboxylic acid as a yellow solid (34.4 mg, 27%).
LC/MS (ES, m/z):[M+H]+ 3940 1H—NMR (300 MHz, DMSO): 5 8.22 (s, 1H), 7.92 — 7.99 (m, 2H), 7.74 — 7.78 (m, 1H), 7.60 — 7.63 (m, 2H), 7.25 — 7.32 (m, 1H), 3.89 — 3.96 (m, 1H), 2.81 (s, 3H), 1.61 — 1.70(m, 1H), 1.42 — 1.51 (m, 1H), 1.17 (d, J = 6.6 Hz, 3H), 0.69 — 0.71 (t, J = 7.2 Hz, 3H) EXAMPLE 70 2-(1-Benzofuranyl)[(propan-Z-yl)amino]quinoxalinecarboxylic acid Y O \ N W0 2012I119046 Step 1. Methyl 3—[(propan-2—yl)amino]—l,2—dihydroquinoxalinecarboxylate Y o HN /N:©)1\O/ To a solution of methyl 3—chloro-2—oxo—1,2-dihydroquinoxaline—6—carboxylate (500 mg, 2.1 mmol) in DMSO (2 mL) was added propan-2—amine (186 mg, 3.15 mmol) and DIEA (540 mg, 3.15 mmol). After stirring for overnight at 50°C, the reaction mixture was dissolved in water (20 mL), then filtered to afford methyl 2-ox0[(propan—2—yl)amino]—1 ,2- dihydroquinoxalinecarboxylate as a white solid (430 mg, 78%).
LC/MS (ES, m/z): [M+H]+ 262.0 1H—NMR (300 MHz, DMSO) 5 12.42 (s, 1H), 7.88 (d, J: 1.8 Hz, 1H), 7.66 — 7.70 (m, 1H), 7.34 (d, J: 8.1 Hz, 1H), 7.34 (d, J: 8.4 Hz, 1H), 4.21 - 4.30 (m, 1H), 3.84 (s, 3H), 1.22 (d, J = 6.6 Hz, 6H) Step 2. Methyl 3-[(prOpanyl)amino]-2—[(trifluoromethane)sulfonyloxy]quinoxaline—6— carboxylate Y O TfO N To a solution of methyl 2—oxO[(propan-Z—yl)amino]~l ,2—dihydroquinoxalinecarboxylate (330 mg, 1.26 mmol) in dichloromethane (50 mL) was added pyridine (600 mg, 7.59 mmol) and szO (1100 mg, 3.90 mmol), which was added dropwise with stirring at 0°C. After stirring 3h at room temperature under nitrogen atmosphere, the reaction mixture was dissolved in water (100 mL), ted with dichloromethane (2 x 20 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure to afford methyl 3- [(propan-2—yl)amino]-2—[(trifluoromethane)sulfonyloxy]quinoxalinecarboxylate as a light yellow solid (650 mg, crude).
Step 3. Methyl 2-(1-benzofuran—2-yl)-3~[(pr0pan—2-yl)amino]quinoxaline—6-carboxylate Y O C90}/N: : JLO/\\ N To a on of methyl 3-[(Propan-2—yl)amino]—2- PCT/U52012/027423 [(trifluoromethane)sulfonyloxy]quinoxaline-6—carboxylate (650 mg, crude) in dioxane (5 mL) was added (1-benzofuranyl)boronic acid (537 mg, 3.32 mmol), K3PO4 (700 mg, 3.30 mmol) and Pd(PPh3)4 (95 mg, 0.08 mmol). After stirring 40 min at 95°C under a nitrogen atmosphere, the reaction mixture was dissolved in water (10 mL), extracted with dichloromethane (3 x 30 mL), dried over anhydrous ium sulfate and concentrated under reduced pressure to afford a residue, which was purified by silica gel column chromatography eluting with 2% ethyl acetate in petroleum ether to afford methyl 2—(1— benzofuran—2—yl)—3—[(prOpan—2—yl)amino]quinoxalinecarboxylate as a light yellow solid (60 mg).
LC/MS (ES, m/z): [M+H]+ 362.0 1H—NMR (300 MHz, DMSO) 5 8.17 (d, J = 1.5 Hz, 1H), 7.80 - 7.96 (m, 5H), 7.47 - 7.53 (m, 1H), 7.36 - 7.42 (m, 1H), 7.13 (d, J: 7.2 Hz, 1H), 4.39 - 4.50 (m, 1H), 3.92 (s, 3H), 1.34 (d, J = 6.6 Hz, 6H) Step 4. enzofuranyl)[(prOpan—2-yl)amino]quinoxalinecarboxylic acid Y O \ /Nj:)/D\OH\N To a solution of methyl 2-(1—benzofuran—2-y1)[(Propan—2-yl)amino]quinoxaline—6- carboxylate (60 mg, 0.17 mmol) in methanol (30 mL) was added sodium hydroxide (60 mg, 1.50 mmol). After ng overnight at room temperature, the reaction mixture was trated under reduced pressure to afford a residue, which was dissolved in water (10 mL), adjusted pH to 6 with HCl (3N) and filtered to give 2-(1-benzofuran-2—y1)—3—[(propan~2- yl)amino]quinoxaline—6—carboxylic acid as a light yellow solid (30.1 mg, 52%).
LC/MS (ES, m/z): [M+H]+ 348.1 1H-NMR (300 MHz, DMSO) 5 8.15 (d, J: 1.5 Hz, 1H), 7.80 - 7.94 (m, 5H), 7.47 - 7.53 (m, 1H), 7.36 - 7.42 (m, 1H), 7.10 (d, J = 7.5 Hz, 1H), 4.42 - 4.51 (m, 1H), 1.34 (d, J = 6.6 Hz, EXAMPLE 71 3-[Methyl(propanyl)amino][5-(trifluoromethy1)benzofuranyl]quin0xaline carboxylic acid Y O /N ”jg/Km F3C£§OI l \ \ N Step 1. l-(2,2-Diethoxyethoxy)—4-(trifluoromethyl)benzene <0_/ To a suspension of sodium e (12.0 g, 500.00 mmol) in anhydrous DMF (500 mL) was added 4—(trifluoromethyl)phenol (35.0 g, 215.90 mmol) at 0°C. After hydrogen evolution had ceased, 2—bromo—l,l-diethoxyethane (55.0 g, 279.09 mmol) was added. The reaction was heated at 120°C overnight. The mixture was poured into ice—water (2 L), extracted with ethyl acetate (3 x 150 mL), washed with 1N sodium ide (3 x 100 mL) and brine (3 x 100 mL). The c layer was dried over anhydrous sodium sulfate and filtered. The solvent was removed under vacuum to give the residue, which was ed by silica gel column chromatography eluting with 1% ethyl acetate in petroleum ether to afford 1-(2,2— diethoxyethoxy)—4—(trifluoromethyl)benzene as oil (8.0 g, 13%). 1H-NMR (300 MHz, CDClg): 5 7.54 (d, J = 8.4 Hz, 2H), 6.99 (d, J = 8.4 Hz, 2H), 4.85 - 4.88 (t, J = 5.10 Hz, 1H), 4.06 (d, J = 5.10 Hz, 2H), 3.69 - 3.85 (m, 4H), 1.22 — 1.29 (m, 6H) Step 2. 5-(Trifluoromethy1)—1~benzofuran F3C 0 To a mixture of benzene (100 mL) containing polyphosphoric acid (19.45 g, 57.54 mmol) was added l-(2,2-diethoxyethoxy)~4~(trifluoromethyl)benzene (8.0 g, 28.75 mmol). The mixture was stirred vigorously while being heated to reflux for 2.5 hours. The reaction mixture was cooled to room temperature and ed from the osphoric acid. The solvent was removed under vacuum to give the residue, which was purified by silica gel column chromatography eluting with 1% ethyl acetate in petroleum ether to afford 5- (trifluoromethyl)-l-benzofuran (5.0 g, crude) as colorless oil.
W0 2012/‘119046 1H—NMR (300 MHz, CDC13)Z 8 7.93 (s, 1H), 7.75 (d, J = 2.4 Hz, 1H), 7.56 - 7.64 (m, 2H), 6.87 - 6.88 (m, 1H) Step 3. [5-(Trifluoromethyl)-l-benzofuranyl]boronic acid flewB(OH)2\ To a solution of 5—(trifluoromethyl)—1-benzofuran (5.0 g, 26.86 mmol) in dry tetrahydrofuran (120 mL) were added tetramethylethylenediamine (3.74 g, 32.2 mmol). The solution was kept below ~60°C. under nitrogen, while n-BuLi (12.8 mL, 32.2 mmol, 2.5 M solution in hexane) was added dropwise. The solution was warmed to -10°C over 45 min and stirred at this temperature for another 30 min. The e was cooled again below 60°C followed by dropwise addition of triisopropyl borate (10.0 g, 53.19 mmol). After warming to room temperature the mixture was quenched with hloric acid (70 mL, 2N) and stirred for 1 h. The alkaline aqueous layer was brought to pH 5 and extracted with ethyl acetate (3 x 80 mL). All organic layers were combined, dried over sodium sulfate, and concentrated in vacuo to give [5—(trifluoromethyl)benzofuran~2—yl]boronic acid (2.0 g, crude) as light yellow oil; which was used for the next step without further purification.
Step 4. Methyl 3-[methyl(propany1)amino][5-(trifluoromethyl)- l-benzofuran noxaline—6-carboxylate Y O \ N To a solution of [5-(trifluoromethyl)—1-benzofuran-2—yl]boronic acid (305.1 mg, 1.33 mmol) in e (5.0 mL) and water (3 drops) was added methyl 3-[methyl(propan—2-yl)amino]—2- [(trifluoromethane)sulfonyloxy]quinoxaline—6—carboxy1ate (180 mg, 0.44 mmol), K3PO4 (279 mg, 1.31 mmol) and Pd(PPh3)4 (25.38 mg, 0.02 mmol) with stirring for 1 h at 90°C in an oil bath under an inert atmosphere of en. The reaction mixture was concentrated in vacuo to give a residue, which was purified by silica gel column chromatography eluting with 1% ethyl acetate in petroleum ether to afford methyl 3-[methyl(propanyl)amino]~2-[5- oromethyl)benzofuranyl]quinoxalinecarboxylate as alight yellow solid (135mg, 71%).
LC/MS (ES, m/z): [M+H]+ 444.0 1H-NMR (300 MHz, CDC13): 8 8.54 (d, J: 1.2 Hz, 1H), 7.97 — 8.14 (m, 3H), 7.72 - 7.78 (m, 1H), 7.63 - 7.69 (m, 2H), 4.26 - 4.35 (m, 1H), 4.02 (s, 3H), 2.91 (s, 3H), 1.26 (d, J: 6.6 Hz, Step 5. 3-[Methyl(propan-2—yl)amino]—2—[5~(tn'fluoromethyl)benzofuran yl]quinoxalinecarboxylic acid Y O F3C‘<;Q)I | \ N To a solution of methyl hy1(propan—2-yl)amino]~2~[5—(trifluoromethyl)-l-benzofuran- 3-yl]quinoxaline-6~carboxylate (135 mg, 0.30 mmol) in methanol (30 mL) and water (1.0 mL) was added sodium hydroxide (48.8 mg, 1.22 mmol) with ng overnight at room temperature. The reaction mixture was concentrated in vacuo, dissolved in water (20 mL) and adjusted to pH 5 with HCl (3N). The solids were collected by filtration to afford 3- [methyl(propan~2—yl)amino][5-(tn'fluoromethyl)—l—benzofuranyl]quinoxaline carboxylic acid as a light yellow solid (42.6 mg, 33%).
LC/MS (ES, m/z): [M+H]+ 430.0 1H—NMR (300 MHz, DMSO): 5 8.27 — 8.28 (t, J: 0.6 Hz, 2H), 7.98 — 8.05 (m, 3H), 7.77 ~ 7.81 (m, 2H), 4.17 - 4.26 (m, 1H), 2.83 (s, 3H), 1.17 (d, J: 6.6 Hz, 6H) EXAMPLE 72 2-(1-Benzofuranyl)[(2S)methylpyrrolidin~1—yl]quinoxalinecarboxylic acid F3C 0 Step 1. Methyl 3—[(2S)—2—methylpyrrolidinyl][6-(trif1uoromethy1)-1—benzofuran yl]quinoxalinecarboxy1ate F3C 0 PCT/U82012/027423 To a on of 3-[(2S)methy1pyrrolidin—1-y1]—2- uoromethane)sulfonyloxy]quinoxalinecarboxylate (200 mg, 0.48 mmol) in dioxane (3.0 mL) and water (2 drops) was added [6-(trifluoromethyl)benzofuranyl]boronic acid (331 mg, 1.44 mmol) Pd(PPh3)4 (28 mg, 0.02 mmol), K3PO4 (304mg, 1.43 mmol) with stirring for 2 hour at 90°C under an atmosphere of nitrogen. The resulting mixture was concentrated in vacuo to give a residue, which was purified by silica gel column chromatography eluting with 1% ethyl acetate in petroleum ether to give methyl methyl 3- [(2.S)-2—methylpyrrolidin— 1 -y1] [6-(trifluoromethyl)benzofuranyl]quinoxaline carboxylate (150 mg, 69%) as a yellow solid.
LC/MS (ES, m/z): r 456.1 1H-NMR (300 MHz, CDCL3) 6 8.52 - 8.53 (t, J = 0.9 Hz, 1H), 8.01 - 8.06 (m, 3H), 7.76 (d, J = 8.7 Hz, 1H), 7.65 - 7.69 (m, 1H), 7.36 (d, J: 0.6 Hz, 1H), 4.46 — 4.53 (m, 1H), 4.02 (s,3H), 3.49 — 3.55 (m, 1H), 3.06 - 3.11 (m, 1H), 2.27 - 2.31 (m, 1H), 1.92 — 1.94 (m, 1H), 1.67 - 1.74 (m, 2H), 1.44 - 1.48 (d, J: 6.0 Hz, 3H) Step 2. 2—(1-Benzofuran-3~y1)—3-[(2S)—2—methylpyrrolidin—1—yl]quinoxaline—6—carboxylic acid C" O \ N F3C 0 To a solution of methyl 3—[(2S)~2-methy1pyrrolidin~1 -y1][5-(trifluoromethyD—1— benzofuran~2-yl]quinoxaline—6-carboxylate (150 mg, 0.33 mmol) in methanol (30 mL) and water (1 mL) was added sodium hydroxide (53 mg, 1.33 mmol) with stirring overnight at room ature. The resulting mixture was concentrated in vacuo and dissolved in water (15mL), adjusted to pH 7 with HCl (3N). The product was collected by filtration to give 3— [(2S)—2-methylpyrrolidiny1][5-(trifluoromethyl)—1-henzofuran—2—yl]quinoxaline carboxylic acid as a yellow solid (72.8 mg, 50%).
LC/MS (ES, m/z): [M+H]+ 442.0 1H-NMR (300 MHz, DMSO) 5 8.24 - 8.27 (t, J = 1.5 HZ, 2H), 7.92 - 8.06 (m, 3H), 7.77 - 7.80 (m, 1H), 7.59 (s, 1H), 4.33 - 4.40 (m, 1H), 3.34 - 3.44 (m, 1H), 3.11 ~ 3.13 (m, 1H). 2.15 — 2.20 (m, 1H), 1.85 - 1.90 (m, 1H), 1.60 — 1.70 (m, 2H), 1.38 (d, J: 6.0 Hz, 3H) W0 20121119046 PCT/U52012/027423 iEXAMPLE 73 (S)(lH-Indol-S-yl)(2-methylpiperidinyl)quinoxalinecarboxylic acid / N Step 1. (S)—Methyl 3—(2—methylpiperidin—1—y1)—2—oxo-1,2—dihydroquinoxaline—6—carboxylate Om“ O N /Nj©/U\O/ To a solution of methyl ro-2—oxo-1,2-dihydroquinoxaline—6-carboxylate (200 mg, 0.84 mmol) in DMSO (2 mL) was added (S)—2—methy1piperidine (166 mg, 1.7 mmol) and DIEA (217 mg, 1.7 mmol). The resulting solution was stirred at 70°C for 3 h and then quenched by water (10 mL), the solids were collected by filtration to afford (S)-methyl 3-(2- methylpipen'din-l~y1)oxo-1,2-dihydroquinoxa1inecarboxy1ate as a light yellow solid (200 mg, 79%).
LC/MS (ES, M+H]+ 302.0 1H—NMR (300 MHz, CDC13): 5 10.11 (s, 1H), 8.29 (s, 1H), 7.83 - 7.86 (m, 1H), 7.09 (d, J: 8.4 Hz, 1H), 5.39 - 5.41 (m, 1H), 4.86 (d, J: 13.8 Hz, 1H), 3.94 (s, 3H), 3.18 - 3.26 (t, J: 12.6 Hz, 1H), 1.65 — 1.94 (m, 6H), 1.35 (d, J: 6.9 Hz, 3H) Step 2. (S)—Methy1 3~(2-methylpiperidin—1~y1)—2-(trifluoromethylsulfonyloxy)quinoxaline—6— carboxylate TfO N To a solution of (S)—methyl 3-(2—methy1piperidin—1-y1)-2—oxo-1,2-dihydroquinoxaline carboxylate (200 mg, 0.66 mmol) in dichloromethane (30 mL) was added pyridine (208 mg, 2.64 mmol). Then ngO (372 mg, 1.32 mmol) was added and stirred overnight at room ature. The reaction was then quenched by the addition of ice—water (100 mL ) and extracted with dichloromethane ( 3 x 15 mL), the organic layers ed and dried over anhydrous magnesium sulfate and concentrated in vacuo to afford (S)-methyl 3-(2- methylpiperidin—l—yl)(trifluoromethylsulfonyloxy)quinoxalinecarboxylate as red oil (250 mg, crude).
Step 3. (S)-Methyl 2-(1H—indolyl)(2-methy1piperidin-1~yl)quinoxalinecarboxylate To a on of (S)-methyl 3-(2-methy1piperidinyl) (trifluoromethylsulfonyloxy)quinoxaline—6—carboxylate (250 mg, crude) in dioxane (5 mL) was added 3)4 (33 mg, 0.03 mmol), 1H—indol—5-ylboronic acid (234 mg, 1.45 mmol), K3PO4 (367 mg, 1.74 mmol) and water (5 drops). The resulting solution was stirred for 1 h at 90°C with an inert atmosphere of nitrogen and then concentrated in vacuo to give a residue, which was purified by silica gel column chromatography eluting with 1% - 10% ethyl acetate in eum ether to afford (S)-methyl 2-(1H—indol—5-y1)—3—(2-methylpiperidin yl)quinoxalinecarboxylate as a yellow solid (79 mg).
LC/MS (ES, m/z): [M+H]+ 401.0 1H-NMR (300 MHz, CDC13) 5 8.53 (d, J: 1.5 Hz, 1H), 8.38 (s, 1H), 8.29 (s, 1H), 8.05 - 8.08 (d, J: 1.8 Hz, 2H), 7.98 (d, J = 8.7 Hz, 1H), 7.88 - 7.92 (m, 1H), 7.50 (d, J = 8.7 Hz, 1H), 7.30 (d, J: 3.0 Hz, 1H), 6.67 (d, J: 2.1 Hz, 1H), 4.17 - 4.21 (m, 1H), 4.00 (s, 3H), 3.58 — 3.63 (m, 1H), 3.12 - 3.16 (m, 1H), 1.60 - 1.76 (m, 4H), 1.28 - 1.39 (m, 2H), 1.10 (d, J: 6.9 Hz, 3H) Step 4. (S)—2-(1H—indol—S—yl)(2-methylpiperidin—1-yl)quinoxalinecarboxylic acid 0 0 / N To a solution of (S)-methyl 2-(1H~indolyl)—3-(2-methylpiperidin-1—yl)quinoxaline—6— carboxylate (79 mg, 0.20 mmol) in methanol (15 mL) and CHC13 (5 mL) was added NaOH (24 mg, 0.60 mmol) and water(1 mL). The resulting solution was stirred overnight at room temperature and concentrated in vacuo. The residue was dissolved in water (15 mL) and adjusted to pH 5 with hydrochloric acid (IN). The solids were ted by filtration to afford (S)(lH-indol-S-yl)(2-methylpiperidin—1—yl)quinoxaline—6—carboxylic acid as a yellow solid (70 mg, 92%).
LC/MS (ES, m/z): [M+H]+ 387.0 1H-NMR (300 MHz, DMSO) 5 11.33 (s, 1H), 8.28 (d, J = 16.2 Hz, 2H), 7.89 — 7.98 (m, 2H), 7.77 (d, J: 8.4 Hz, 1H), 7.53 (d, J: 8.4 Hz, 1H), 7.44 (s, 1H), 6.57 (s, 1H), 4.05 - 4.11 (m, 1H), 3.54 (d, J: 12.3 Hz, 1H), 3.04 - 3.08 (m, 1H), 1.54 — 1.64 (m, 5H), 1.32 (d, J: 8.7 Hz, 1H), 1.02 (d, J: 6.6 Hz, 3H) EXAMPLE 74 (R)(sec-Butyl(methyl)amin0)(5-fluor0benzofuranyl)quinoxalinecarboxylic acid N N / / fiOH F \ \N Step 1. (R)-Methyl 3-(sec-butylamino)oxo-1 ,2-dihydroquinoxalinecarboxy1ate R/ o HN /N:©/U\O/ To a solution of methyl 3—Chlorooxo-1,2-dihydroquinoxalinecarboxylate (0.5 g, 2.1 mmol) in DMSO (10 mL) was added (R)-butan—2-amine (570 mg, 7.79 mmol) and DIBA (850 mg, 6.58mmol). The resulting solution was stirred for 4 hours at 70°C and then ed by the addition of water (50 mL). The solids were collected by filtration to afford (R)—methyl 3-(sec-butylamino)oxo-1,2-dihydroquinoxalinecarboxylate as a white solid (425 mg, 75%).
LC/MS (ES, m/z): [M+H]+ 276.0 1H-NMR (300 MHz, DMSO): 812.43 (s, 1H), 7.87 (d, J = 1.8 Hz, 1H), 7.66 - 7.70 (m, 1H), 7.33 (d, J: 8.4 Hz, 1H), 7.20 (d, J: 8.4 Hz, 1H), 4.04 - 4.14 (m, 1H), 3.85 (s, 3H), 1.51 - 1.71 (m, 2H), 1.19 (d, J: 6.6 Hz, 3H), 0.88 - 0.91 (t, J: 7.5 Hz, 3H) Step 2. thyl 3-(sec-butylamino)~2—(trifluoromethylsulfonyloxy)quinoxaline-6— carboxylate kg 0 TfOlN/ND/MO/ To a solution of (R)—methy1 3—(sec—butylamino)oxo-1,2-dihydroquinoxaline—6—carboxy1ate (300 mg, 1.10 mmol) in romethane (40 mL) was added pyridine (344 mg, 4.36 mmol) and then szO (615 mg, 2.18 mmol) was added dropwise with stirring at 0°C. The resulting on was stirred for 2h at room temperature and then washed with water (3 x 50 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to afford (R)-methyl 3—(sec— butylamino)—2-(trifluoromethylsulfonyloxy)quinoxaline—6-carboxylate as red oil (400 mg, crude).
Step 3. (R)—Methyl -butylamino)-2—(5—f1uorobenzofuran-2—yl)quinoxaline—6— carboxylate V O HN /N. : JLO/ FM\l\ N To a solution of (R)—methyl 3-(sec—butylamino)(trifluoromethylsulfonyloxy)quinoxaline ylate (400 mg, crude) in dioxane (5 mL) was added 5~fluorobenzofuranylboronic acid (441 mg, 2.45 mmol), K3PO4 (620 mg, 2.94 mmol), and Pd(PPh3)4 (57 mg, 0.05 mmol).
The resulting solution was stirred for 1 h at 90°C and then quenched by the addition of dichloromethane (200 mL) and washed with water (3 X 50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo to give a residue, which was purified by silica gel column chromatography (5% ethyl acetate in petroleum ether) to afford (R)-methyl 3—(sec-butylamino)~2-(5-fluorobenzofuran—2—y1)quinoxaline—6-carboxylate as a yellow solid (100 mg, 24% 2 steps).
LC/MS (ES, m/z):[M+H]+ 394.1 1H-NMR (300 MHz, CDC13): 5 8.53 (s, 1H), 8.02 (d, J: 8.1 Hz, 1H), 7.93 (d, J = 8.7 Hz, 1H), 7.78 (s, 1H), 7.55 - 7.59 (m, 1H), 7.39 - 7.43 (m, 1H), 6.87 (s, 1H), 4.53 - 4.55 (m, 1H), 4.01 (s, 3H), 1.73 — 1.85 (m, 2H), 1.40 (d, J: 6.6 Hz, 3H), 1.08 - 1.13 (t, J: 7.5 Hz, 3H) PCT/U52012/027423 Step 4. (R)—3-(sec—Buty1(methyl)amino)(5-fluorobenzofuranyl)quinoxaline—6— carboxylic acid /N /N:©)‘\OH F \ \N To a solution of (R)~methyl 3—(sec-butylamino)—2~(5~fluorobenzofuran-2—yl)quinoxaline—6- carboxylate (100 mg, 0.33 mmol) in THF (20 mL) was added NaH (90 mg, 2.24 mmol) and CH3]: (159 mg, 1.12 mmol). The resulting solution was stirred overnight at room temperature and concentrated in vacuo. The residue was dissolved in water (10 mL) and adjusted to pH 5 with hydrochloric acid (1N).The ing solution was extracted with dichloromethane (3 x mL), dried over anhydrous sodium sulfate and then trated in vaczgo to give a residue, which was purified by silica gel column chromatography eluting (10% dichloromethane in methanol) to afford (R)—3-(sec—butyl(rnethyl)amino)-2—(5- fluorobenzofuranyl)quinoxalinecarboxylic acid as a yellow solid (25 mg, 23%).
LC/MS (ES, M+H]+ 394.1 1H-NMR (300 MHz, CDClg): 5 8.38 (s, 1H), 8.06 (d, J: 8.7 Hz, 1H), 7.92 (d, J = 8.4 Hz, 1H), 7.59 — 7.63 (m, 1H), 7.55 (s, 1H), 7.44 - 7.48 (m, 1H), 7.15 - 7.23 (m, 1H), 3.97 - 4.05 (m, 1H), 2.89 (s, 3H), 1.70 — 1.80 (m, 1H), 1.48 — 1.57 (m, 1H), 1.23 (d, J = 6.6 Hz, 3H), 0.75 — 0.81 (t, J = 7.5 Hz, 3H) EXAMPLE 75 2-(2-Methyl-1H—indolyl)[(2S)methylpyrrolidin-l-yl]quinoxalinecarboxylic acid Step 1. 5-Bromo-2—methy1-JH—indole mN Br To a solution of 2-methyl-JH—indole (5.0 g, 38.12 mmol) in sulfuric acid (80 mL) was added Ag2S04 (12.5 g, 40.06 mmol) with ice cooling, and the solution was stirred for 30 min. Then Er; (6.4 g, 40.05 mmol) was added to the solution dropwise over 30 min. After the solution was stirred for 4 h at room ature, the reaction was then quenched by the addition of water/ice (300 mL). The reaction e was extracted with dichloromethane (3 x 200 mL) and the organic layers ed, dried over anhydrous sodium sulfate and trated in vacuo to afford 5~bromo~2~methyl-]H-indole as a light brown solid (6 g, 75%).
LC/MS (ES, m/z): [M+H]+ 211.0 1H—NMR (300 MHz, CDClg): 8 11.23 (s, 1H), 7.56 (s, 1H), 7.21 (d, J = 8.7 Hz, 1H), 7.07 — 7.09 (m, 1H), 6.11 (s, 1H), 2.38 (s, 3H) Step 2. 2-Methyl—6—(tetramethy1—1,3,2—dioxaborolan—2-yl)-1H—indole 028QC)-/ To a solution of 6—bromo—2—methy1-1H—indole (2.0 g, 9.52 mmol) in dry tetrahydrofuran (100 mL) was added sodium hydride (381 mg, 9.53 mmol ) with ice-cooling. After stirring for about 30 min a solution of n-BuLi (15 mL, 2.5 M solution in hexane) was added dropwise with stirring at —78°C under nitrogen. It was warmed slowly to —40°C during 45 min and stirred at this temperature for another 30 min. The mixture was cooled again below ~78°C followed by dropwise addition of 4,4,5,5—tetramethyl~2~(propan—2—yloxy)—1,3,2— dioxaborolane (3.54 g, 19.03 mmol). After warming to room temperature, the mixture was quenched with NH4Cl (aq) and extracted with ethyl e (3 x 80 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the residue, which was purified by silica gel column chromatography (2% ethyl acetate in petroleum ether) to afford 2-methyl-6—(tetramethyl- 1,3,2—dioxaborolan—2—yl)-1H—indole (1.2 g, 49%). 1H-NMR (300 MHz, CDC13)I 5 8.06 (s, 1H), 7.91(s, 1H), 7.58 - 7.60 (t, J: 7.5 Hz, 1H), 7.31 (d, J: 8.1 Hz, 1H), 6.24 (s, 1H), 2.46 (s, 3H), 1.39 (s, 12H) PCT/U82012/027423 Step 3. Methyl 2-(2-methyl-JH—indol—S-yl)-3—[(25')-2—methylpyrrolidinyl]quinoxaline-6— carboxylate To a solution of 2—methyl(tetramethyl-1,3,2-dioxaborolan-2—yl)-]H—indole (378 mg, 1.47 mmol) in ethylene glycol dimethyl ether (5.5 mL) and water (3 drops) was added methyl 2— chloro[(2S)-2—methylpyrrolidin-1—yl]quinoxaline—6~carboxylate (150 mg, 0.49 mmol), sodium carbonate (156 mg, 1.47 mmol) and Pd(PPh3)4 (29 mg, 0.03 mmol) with stirring for 2h at 90°C in an oil bath under an inert atmosphere of nitrogen. The reaction e was concentrated under reduced pressure to give the residue, which was purified by silica gel column chromatography (2% ethyl acetate in petroleum ether) to afford methyl ethyl— olyl)—3—[(2S)-2—methylpyrrolidin—1—yl]quinoxalinecarboxylate as light yellow solid (140 mg, 71%).
LC/MS (ES, m/z): [M+H]+ 401.0 1H-NMR (300 MHz, CDC13): 8 8.92 (s, 1H), 8.13 (s, 1H), 8.06 (s, 2H), 7.89 (s, 1H), 7.48 (d, J = 8.4 Hz, 1H), 7.39 (d, J: 8.40 Hz, 1H), 6.34 (s, 1H), 4.72 (s, 1H), 4.01 (s, 1H), 3.06 - 3.19 (m, 2H), 2.51 (s, 3H), 2.21 — 2.25 (m, 1H), 1.73 - 1.80 (m, 1H), 1.55 - 1.62 (m, 2H), 1.43 — 1.49 (m, 3H) Step 4. 2-(2—Methy1-1H~indol~5~yl)[(2S)—2—methylpyrrolidin-l-yl]quinoxaline-6— carboxylic acid <7 0 “ WI)“ / N To a solution of methyl 2—(2-methyl—JH—indol—5—yl)[(2S)—2-methylpyrrolidin-l— noxalinecarboxylate (140 mg, 0.35 mmol) in methanol (30 mL) and water (2 mL) was added sodium hydroxide (56 mg, 1.40 mmol) with stirring overnight at room temperature. The reaction mixture was concentrated in vacuo, dissolved in water (30 mL) and adjusted to pH 5 with acetic acid. The solids were collected by filtration to afford 2-(2— methyl-IH—indol-S—yl)—3—[(2S)-2—methylpyrrolidin-1—yl]quinoxalinecarboxylic acid as a light yellow solid (100 mg, 74%).
LC/MS (ES,m/z): [M+H]+ 387.1 1H-NMR (300 MHz, DMSO): 513.05(s, 1H), 11.14 (s, 1H), 8.23 (s, 1H), 7.81 - 7.88 (m, 3H), 7.36 - 7.44 (m, 2H), 6.25 (s, 1H), 4.19 - 4.21 (m, 1H), 2.96 - 3.32 (m, 2H), 2.42 (s, 3H), 2.09 — 2.21 (m, 1H), 1.69 - 1.72 (m, 1H), 1.51 ~ 1.54 (m, 2H), 1.31 (d, J: 6.0 Hz, 3H) E 76 3-[Methyl(propanyl)amino]—2-(Z-methyl-IH-indolyl)quinoxalinecarboxylic acid Y o / NND/[LOH Step 1. Methyl 3-[methyl(propan—2-yl)amino]-2—(2-methyl-]H—indolyl)quinoxaline—6- carboxylate To a solution of methyl 2—chloro—3—[methyl(propanyl)amino]quinoxaline—6-carb0xylate (200 mg, 0.68 mmol ) in DME (5.0 mL) and water (2 drops) was added 2~methyl~6~ (tetramethyl—l,3,2-dioxaborolan—2—yl)~JH—indole (352 mg, 1.37 mmol), Pd(PPh3)4 (39 mg, 0.03 mmol), and K2CO3 (189 mg, 1.37 mmol) with stirring for 1 hour at 90°C under atmosphere of nitrogen. The resulting mixture was concentrated in vacuo to give a residue, which was ed by silica gel column chromatography (1% ethyl acetate in petroleum ether) to give methyl 3-[methyl(propan-2—yl)amino]-2—(2—methyl-1H—indolyl)quinoxaline— 6-carboxylate as a light yellow solid (180 mg, 68%).
LC/MS (ES, m/z): [M+H]+ 389.1 1H-NMR (300 MHz, DMSO) 8 11.14 (s, 1H), 8.27 (s, 1H), 7.93 - 7.97 (m, 3H), 7.54 - 7.57 (m, 1H), 7.37 (d, J: 9.0 Hz ,1H), 6.25 (s, 1H), 4.21 - 4.25 (m, 1H), 3.93 (s, 3H), 2.70 (s, 3H), 2.42 (s, 3H), 1.00 - 1.02 (d, J: 6.6 Hz, 6H) Step 2. 3—[Methyl(propanyl)amino]~2-(2-methyl-JH—indol—5—yl)quinoxalinecarboxylic acid To a solution of methyl 3—[methyl(propan~2~y1)amino]—2—(2-methyl-1H—indol-5— y1)quinoxa1ine—6-carboxylate (120 mg, 0.31 mmol) in methanol (20 mL) and water (1 mL) was added sodium hydroxide (66 mg, 1.65 mmol) with stirring 1h at reflux. The ing e was concentrated in vacuo and ved in water (30 ml), adjusted to pH 7 with HCl (3N), and collected by filtration to give 3—[methyl(propan-2—yl)amino]—2—(2-methyl—1H—indol- —yl)quinoxaline-6—carboxylic acid as a light yellow solid (50.1 mg, 43%).
LC/MS (ES, m/z): [M+H]+ 375.1 1H—NMR (300 MHz, DMSO) 8 13.00 (s, 1H), 11.13 (s, 1H), 8.25 (s,1H),7.91 - 7.97 (m, 3H), 7.54 - 7.57 (m, 1H), 7.37 (d, J: 8.4 Hz, 1H), 6.25 (s, 1H), 4.21 - 4.31 (m, 1H), 2.70 (s, 3H), 2.50 (s, 3H), 1.00 (d, J = 6.6 Hz, 6H) 3-[Methyl(propanyl)amino](5-phenylfuran-Z-yl)quinoxalinecarb0xy1ic acid Y O O \N \ I Step 1. 2—Pheny1furan To a solution of (furanyl)boronic acid (3.0 g, 26.81 mmol) in dioxane (50.0 mL) and water (1.0 mL) was added bromobenzene (2.10 g, 13.38 mmol), K3PO4 (9.3 g, 43.81 mmol) and Pd(PPh3)4 (767 mg, 0.66 mmol) with stirring for 3h at 95°C in an oil bath under an inert atmosphere of nitrogen. The reaction mixture was concentrated under reduced pressure to give the residue, which was purified by silica gel column chromatography (1% ethyl acetate in petroleum ether) to afford ylfuran as colorless oil (1.20g, 62%).
PCT/U82012/027423 1H—NMR (300 MHz, CDC13): 5 7.69 - 7.72 (m, 2H), 7.50 (d, J = 0.6 Hz, 1H), 7.38 - 7.49 (m, 2H), 7.26 - 7.31 (m, 2H), 6.68 V» 6.69 (m, 1H), 6.47 - 6.49 (m, 1H) Step 2. 4,4,5,5-Tetramethyl(5-phenylfurany1)-1,3,2-dioxaborolane %P\/ on To a solution of 2—phenylfuran (1.20 g, 8.32 mmol) in dry tetrahydrofuran (100 mL) was added a solution of n—BuLi (4.9 mL, 2.5 M solution in hexane) dropwise with stirring at - 78°C under nitrogen. The resulting solution was warmed slowly to ~40°C during 45 min and stirred at this temperature for another 30 min. The e was cooled again below -78°C ed by dropwise addition of 4,4,5,5-tetramethyl(propan~2~yloxy)-l ,3,2— orolane (3.10 g, 16.66 mmol). After warming to room temperature, the mixture was quenched with NH4C1 (aq) and extracted with ethyl acetate (3 x 80 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the residue, which was purified by silica gel column chromatography (2% ethyl acetate in petroleum ether) to afford 4,4,5,5-tetramethyl-2—(5- phenylfuranyl)-1,3,2-dioxaborolane (560 mg, 25%). 1H—NMR (300 MHz, CDC13)I 5 7.79 - 7.83 (m, 2H), 7.37 — 7.43 (m, 2H), 7.30 - 7.33 (m, 1H), 7.16 (d, J = 3.6 Hz, 1H), 6.71 (d, J = 3.3 Hz, 1H), 1.34 - 1.42 (m, 12H) Step 3. Methyl 3—[methyl(propan—2—yl)amino]-2—(5~phenylfuran-2—yl)quinoxaline carboxylate To a solution of 4,4,5,5-tetramethyl—2-(5—phenylfuran-2~yl)-l ,3,2—dioxaborolane (553 mg, 2.05 mmol) in dioxane (5.5 mL) and water (3 drops) was methyl 2-chloro—3-[methyl(propan- 2-yl)amino]quinoxalinecarboxylate (200 mg, 0.68 mmol), K3PO4 (430 mg, 2.03 mmol) and Pd(PPh3)4 (39.3 mg, 0.03 mmol) with stirring for 1h at 95°C in an oil bath under an inert atmosphere of nitrogen. The reaction e was concentrated under d pressure to give the residue, which was ed by silica gel column chromatography (2% ethyl acetate in petroleum ether) to afford methyl 3-[methyl(propanyl)amino](5-pheny1furan noxaline—6-carboxylate as light yellow solid (150 mg, 55%).
LC/MS (ES, m/z): [M+H]Jr 401.0 2012/027423 1H-NMR (300 MHz, I 8 8.51 (s, 1H), 8.02 - 8.09 (m, 2H), 7.80 — 7.99 (m, 2H), 7.48 — 7.56 (m, 2H), 7.42 - 7.46 (m, 2H), 6.87 (d, J: 3.6 Hz, 1H), 4.41 - 4.47 (m, 1H), 4.00 (s, 1H), 2.88 (s, 3H), 1.26 (d, J = 6.6 Hz, 6H) Step 4. 3—[Methyl(propany1)amino](5-pheny1furan-2—yl)quinoxalinecarboxylic acid Y o N /NE©)\OH \O \ To a solution of methyl 3—[methyl(propan-2—yl)amino](5-pheny1furan—2—y1)quinoxaline—6— carboxylate (150 mg, 0.37 mmol) in methanol (30 mL) and water (2 mL) was added sodium hydroxide (59.8 mg, 1.50 mmol) with stirring overnight at room temperature. The reaction mixture was concentrated in vacuo, dissolved in water (30 mL) and adjusted to pH 5 with HCl (3N). The solids were collected by filtration to afford 3~[methyl(propan—2—yl)amino] (5-phenylfuranyl)quinoxaline-6—carboxylic acid as a light yellow solid (100 mg, 69%).
LC/MS (ES, m/z): [M+H]+ 388.0 1H-NMR (300 MHz, DMSO): 5 8.24 (d, J: 1.5 Hz, 1H), 7.87 - 8.01 (m, 4H), 7.51 - 7.62 (m, 2H), 7.36 ~ 7.48 (m, 2H), 7.25 (d, J: 3.3 Hz, 1H), 4.25 - 4.33 (m, 1H), 2.80 (s, 3H), 1.17 (d, J = 6.6 Hz, 6H) EXAMPLE 78 2-(Furanyl)[(25)methylpyrrolidin-l-yl]quinoxalinecarb0xylic acid 0““ 0 N INDAOH /’ N Step 1. Methyl 2—(furanyl)~3~[(2S)~2-methylpyrrolidin~1-yl]quinoxaline—6—carboxylate o“ 0 / N To a on of methyl 3-[(ZS)-2—methy1pyrrolidin—1-yl] [(trifluoromethane)sulfonyloxy]quinoxalinecarboxylate (200 mg, 0.48 mmol) in 1,4- dioxane (4.0 mL) and water (3 drops) was added (furan-3—yl)boronic acid (116 mg, 1.04 PCT/U52012/027423 mmol), K3PO4 (304 mg, 1.43 mmol) and Pd(PPh3)4 (28 mg, 0.02 mmol) with stirring for l h at 90°C under an inert atmosphere of nitrogen in an oil bath. The reaction mixture was concentrated in vacuo to give the residue, which was ed by silica gel column chromatography (2% ethyl acetate in petroleum ether) to afford methyl 2-(furan—3—yl)—3- [(2S)—2-methy1pyrrolidin—1-yl]quinoxaline—6—carboxylate as a light yellow solid (111 mg, 69%).
LC/MS (ES, m/z): [M+H]+ 337.0 1H—NMR (300 MHz, CDC13) 8 8.51 (d, J =: 1.8 Hz, 1H), 7.93 — 8.06 (m, 3H), 7.54 - 7.55 (t, J = 0.9 Hz, 1H), 7.00 (d, J: 0.6 Hz 4.44 - 4.51 (m, 1H), 4.00 (s, 3H), 3.51 —3.60 (m, , 1H), 1H), 3.02 — 3.08 (m, 1H), 2.20 - 2.26 (m, 1H), 1.90 - 1.95 (m, 1H), 1.60 - 1.66 (m, 2H), 1.24 - 1.29 (m, 3H) Step 2. an—3-yl)-3—[(2S)-2—methylpyrrolidin—l—yl]quinoxaline-6—carb0xylic acid 0' .
/ N To a solution of methyl 2-(furanyl)[(25)—2-methylpyrrolidin-l-yl]quin0xaline carboxylate (111 mg, 0.33 mmol) in methanol (20 mL) and water (1.0 mL) was added sodium hydroxide (52.9 mg, 1.32 mmol) with stirring overnight at room temperature. The reaction mixture was concentrated in vacuo, dissolved in water (10 mL), adjusted pH to 4 with HCl (3N) to give the itate, which was collected by filtration to afford 2-(furan—3—yl)-3—[(2S)— 2-methylpyrrolidin—1—y1]quinoxaline—6-carboxylic acid as a light yellow solid (72 mg, 68%).
LC/MS (ES, m/z): [M+H]+ 323.0 1H—NMR (300 MHz, DMSO) 8 8.23 (s, 2H), 7.84 ~ 7.94 (m, 3H), 7.01 — 7.02 (m,1H), 4.31 — 4.38 (m,1H), 3.47 — 3.50 (m, 2H), 2.98 — 3.04 (n1, 1H), 2.10 — 2.17 (m, 1H), 1.80 — 1.90011, 1H), 1.58 — 1.64 (m, 2H), 1.29 (d, J: 6.0 Hz, 3H) WO 2012119046 3-(Isopropyl(methyl)amino)(4-phenylfuranyl)quinoxalinecarboxylic acid Y O O \N \ I Step 1. l-Phenyl-4—(tetrahydro-2H—pyran—2-yloxy)but-2~yn- 1 ~01 OTHP To a solution of 2-(propynyloxy)~tetrahydro—2H—pyran (10.0g, 71.4 mmol) in THF (40 mL) was added Iz-BuLi (2.5M, 31.4 mL, 78.6 mmol) at -78°C. The reaction e was kept for 1h at -78°C and then benzaldehyde (8.3 g, 78.6 mmol) was added at -78°C. The reaction mixture was stirred for 2h and then slowly warmed to —30°C. before being poured into NaHC03 (aq., 500 mL), extracted with ethyl acetate (3 x 200 mL), dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 1-phenyl(tetrahydro-2H—pyran-2— yloxy)but—2-yn—1—ol as a ess oil (17.0 g, crude). 1H—NMR (300 MHz, CDCI3) 8 7.54 — 7.57 (m, 2H), 7.40 - 7.43 (m, 3H), 5.43 (s, 1H), 4.83 - 4.85 (m, 1H), 4.36 — 4.38 (m, 2H), 3.80 - 3.90 (m, 1H), 3.45 - 3.56 (m, 1H), 1.54 - 1.84 (m, Step 2. l—Phenyl—4—(tetrahydro~2H~pyran~2~yloxy)but~2—yn— 1 —one OTHP To a solution of 1-phenyl(tetrahydro~2H-pyran—2—yloxy)but—2—yn—l-ol (3.0 g, 12.2 mmol) in DCM (50 mL) was added DMP (10.0 g, 24.4 mmol). The ing solution was stirred for 30min at room temperature and then the reaction mixture was poured into NaHC03/Na8203 solution and stirred for overnight, extracted with DCM (3 x 150 mL), dried over anhydrous sodium sulfate and then concentrated in vacuo to give a residue. The residue was purified by silica gel column chromatography (3% ethyl acetate in eum ether) to afford 1~phenyl (tetrahydro-2H—pyran—2—yloxy)butynone as a light yellow oil (2.4 g).
W0 2012i119046 1H-NMR (300 MHz, CDCI3)I 5 8.14 - 8.17 (m, 2H), 7.61 — 7.66 (m, 1H), 7.48 — 7.53 (m, 1H), 4.90 - 4.92 (m, 1H), 4.57 (s, 2H), 3.86 - 3.92 (m, 1H), 3.58 - 3.61 (m, 1H), 1.55 - 1.86 (m, Step 3. 4—Hydr0xy—l -phenylbut—2—yn—l-one To a solution of (l-phenyl(tetrahydro-ZH-pyran-Z-yloxy)but~2~yn-1—one (3.0 g, 12.3 mmol) in EtOH (20 mL) was added pyridinium enesulfonate (0.62 g, 2.5 mmol). The resulting solution was stirred for lh at 50°C and then the reaction mixture was poured into water (150 mL), extracted with EtzO (3 x 50 mL), dried over ous sodium sulfate and then concentrated in. vacuo to afford 4-hydroxy-1~phenylbut—2—yn—1-one as a dark red oil (3.2 g, crude).
Step 4 . 4—Bromo—2-phenylfuran 0// Br To a solution of 4—hydroxy—1—phenylbut—2—ynone (3.2 g, crude) in e (60 mL) was added HBr (40%, 15 mL). The resulting solution was stirred for 40min at 50°C and then the reaction mixture was poured into water (300 mL), extracted with EtzO (4 x 100 mL), dried over anhydrous sodium sulfate and then concentrated in vacuo to give a residue, which was purified by silica gel column chromatography (petroleum ether) to afford 4—bromo—2— phenylfuran as a yellow solid (1.3 g, 50%). 1H—NMR (300 MHz, CDClg): 8 7.63 - 7.66 (m, 2H), 7.48 (s, 1H), 7.41 ~ 7.46 (m, 2H), 7.28 - 7.34 (m, 1H), 6.70 (s, 1H) Step 5. 4,4,5,5-Tetramethyl(5~phenylfuranyl)~1,3,2-dioxaborolane O / 9’0 To a on of 4-bromophenylfuran (1.3 g, 5.8 mmol) in THF (15 mL) was added n-BuLi (2.5M, 2.8 mL, 7.0 mmol) at —78°C. The reaction mixture was kept at -55°C for 15 min and PCT/U52012/027423 then 2—isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.3 g, 7.0 mmol) was added at - 78°C. The reaction mixture was stirred for 1.5h and then poured into water/ice solution, extracted with petroleum ether (3 x 50 mL), dried over anhydrous sodium sulfate and then concentrated in vacuo to give a residue, which was purified by silica gel column tography (1 % ethyl acetate in petroleum ether) to afford 5—tetramethyl—2—(5— phenylfuran—3-yl)-1,3,2—dioxaborolane as a red oil (300 mg, 19%). 1H—NMR (300 MHz, CDC13)Z 5 7.81 (s, 1H), 7.67 - 7.70 (m, 2H), 7.37 — 7.42 (t, J: 7.5 Hz, 2H), 7.24 — 7.29 (m, 1H), 6.87 (s, 1H), 1.36 (s, 12H) Step 6. Methyl 3—(isopr0pyl(methyl)amino)~2-(4-phenylfuran—2—y1)quinoxaline—6-carboxy1ate To a on of methyl 2—chloro—3—(isopropyl(methyl)amino)quinoxaline—6—carb0xylate (150 mg, 0.51 mmol) in dioxane (5 mL) was added 4,4,5,5-tetramethyl(5-phenylfuranyl)- 1,3,2-dioxaborolane (276 mg, 1.02 mmol), Na2C03 (54 mg, 0.51 mmol), 3)4 (30 mg, 0.03 mmol). The resulting solution was stirred for 1 h at 90°C and then concentrated in vacuo to give a residue, which was purified by silica gel column chromatography (3.3% ethyl acetate in petroleum ether) to afford methyl 3—(isopropyl(methyl)amino)(4-phenylfuran yl)quin0xaline~6—carb0xylate as a red solid (140 mg, 68%).
LC/MS (ES, m/z):[M+HTr 402.0 1H-NMR (300 MHz, CDCl3): 5 8.55 (d, J: 0.9 Hz, 1H), 8.30 (s, 1H), 8.10 - 8.13 (m, 1H), 7.98 - 8.00 (d, J: 8.4 Hz, 1H), 7.77 - 7.80 (m, 2H), 7.40 - 7.48 (m, 4H), 4.27 — 4.31 (m, 1H), 4.00 (s, 3H), 2.89 (s, 3H), 1.20 - 1.22 (d, J: 6.6 Hz, 6H) Step 7. 3—(Isopr0pyl(rnethy1)amin0)—2-(4—phenylfuran—2—y1)quinoxaline-6—carboxylic acid Y O O \N \ l WO 20121119046 To a on of methyl 3-(isopropy1(methyl)amino)(4—pheny1furany1)quinoxaline—6- carboxylate (70 mg, 0.17 mmol) in MeOH (20 mL) was added sodium hydroxide (28 mg, 0.70 mmol) and water (2 mL). The resulting solution was stirred overnight at room temperature and concentrated in vacuo. The residue was dissolved in water (3 mL) and adjusted to pH 6 with HCl (1N). The solids were collected by filtration to afford 3— (isopropyl(methy1)amino)-2—(4-pheny1furan~2—yl)quinoxa1ine~6—carboxy1ic acid (43 mg, 64%).
LC/MS (ES, M+H]+ 388.1 1H-NMR (300 MHz, DMSO): 5 8.48 (s, 1H), 8.27 (d, J = 1.5 Hz, 2H), 7.99 — 8.03 (m,1H), 7.91 — 7.94 (d, J: 8.7 Hz, 1H), 782 ~ 7.85 (d, J: 7.5Hz, 2H), 7.56 (s, 1H), 7.46 — 7.51 (m, 2H), 7.34 — 7.39(m, 1H), 4.19 ~ 4.23 (m, 1H), 2.81 (s, 3H), 1.14 — 1.16 (d, J: 6.6 Hz, 6H) EXAMPLE 80 3-[(ZS)methylpyrrolidinyl](1H—pyrr01—3-yl)quinoxalinecarboxylic acid C O I NUAOH / N Step 1. Methyl 3—[(2S)methylpyrrolidin—1—y1]—2—[1—[t1is(propanyl)silyl]—1H-pyrrol—3— yl]quinoxaline—6—carboxylate 0,1121)” To a solution of methyl 2-chloro-3—[(2S)-2~methy1pyrrolidin~1~yl]quinoxaline—6—carboxy1ate (180 mg, 0.59 mmol) in ethylene glycol dimethyl ether (6 ml) and water (2 ml) was added 3- (tetramethyl—l ,3,2-dioxaborolan~2—yl)—1-[tris(propan—2—yl)si1yl]—]H—pyrrole (618 mg, 1.77 mmol), sodium carbonate (188 mg, 1.77 mmol) and Pd(PPh3)4 (34 mg, 0.03 mmol) with stirring for 1 h at 95°C in an oil bath maintained under an inert atmosphere of nitrogen. The reaction e was concentrated under vacuum to give a residue, which was purified via silica gel tography (2% ethyl acetate in petroleum ether) to afford methyl 3-[(2S) methylpyrrolidin—l—yl]-2—[1~[tris(propan-2—yl)silyl]~1H—pyrrol—3—yl]quinoxaline-6—carboxylate as a light yellow solid (150 mg, 52%).
LC/MS (ES, m/z): [M+H]+ 493.0 1H-NMR (300 MHz, CDC13)I 5 8.47 (d, J: 1.2 Hz, 1H), 7.91 - 8.01 (m, 2H), 7.43 (s, 1H), 6.92 (s, 1H), 6.84 - 6.86 (m, 1H), 4.42 — 4.45 (m, 1H), 3.98 (s, 3H), 3.53 - 3.60 (m, 1H), 3.06 — 3.09 (m, 1H), 2.20 — 2.22 (m,1H), 1.85 — 1.87 (m, 1H), 1.64 - 1.85 (m, 2H), 1.50 - 1.60 (m, 4H), 1.25 — 1.31 (m, 3H), 1.07 — 1.18 (m, 18H) Step 2. Methyl 3-[(2S)—2—methylpyrrolidin-1—yl](1H—pyrroly1)quinoxaline-6— carboxylate To a solution of methyl 3-[(2S)methylpyrrolidin—1-yl]—2—[1-[tris(propan-2—yl)silyl]-]H— pyrrolyl]quinoxalinecarboxylate (150 mg, 0.30 mmol) in tetrahydrofuran (30 ml) was added Tetra-n-butylammonium fluoride (TBAF) (80 mg, 0.31 mmol) with stirring for 10 min at room temperature. The on was then quenched with water (10 ml). The resulting on was extracted with dichloromethane (3 x 10 m1) and the organic layers combined and dried over anhydrous magnesium sulfate, concentrated under vacuum to afford methyl 3- [(2S)—2—methy1pyrrolidin—1-y1]-2—(1H—pyrrol—3—yl)quinoxaline-6—carboxylate as a light yellow solid (100 mg, 98%).
LC/MS (ES, m/z): [M+H]+ 337.0 1H-NMR (300 MHz, CDCl3)I 5 8.71 (s, 1H), 8.48 (d, J: 1.5 Hz, 1H), 7.92 - 8.02 (m, 2H), 7.50 (s, 1H), 6.81 — 6.88 (m, 2H), 4.45 - 4.48 (m, 1H), 3.98 (s, 3H), 3.56 — 3.58 (m, 1H), 3.08 — 3.10 (m, 1H), 2.15 ~ 2.25 (m, 1H), 1.82 - 1.93 (m, 1H), 160 — 1.69 (m, 2H), 1.33 (d, J: 6.0 Hz, 3H) Step 3. 3—[(2S)Methylpyrrolidin-1—yl](1H—pyrrolyl)quinoxaline—6—carboxylic acid C‘ O I NDAOH / N To a solution of methyl )-2—methylpyrrolidin—1—yl]—2-(1H—pyrrolyl)quinoxaline carboxylate (100 mg, 0.30 mmol) in methanol (30 m1) and water (2.0 ml) was added sodium PCT/U52012/027423 hydroxide (48 mg, 1.20 mmol) with stirring overnight at room ature. The reaction mixture was concentrated under vacuum, dissolved in water (30 le) and ed to pH 4 with HCl (3 N). The solids were collected by filtration to afford 3-[(ZS)methy1pyrrolidin- 1—yl]-2—(1H—pyrrol—3-yl)quinoxalinecarboxylic acid as a light yellow solid (70 mg, 73%).
LC/MS (ES, m/z): [M+H]”r 323.0 1H-NMR (300 MHz, CDC13)Z 8 11.25 (s, 1H), 8.18 (s, 1H), 7.79 - 7.88 (m, 2H), 7.41 — 7.42 (t, J: 1.2 Hz, 1H). 6.87 - 6.89 (m, 1H), 6.65 (d, J: 1.5 Hz, 1H), 4.31 - 4.38 (m, 1H), 3.48 — 3.54 (m, 1H), 2.95 — 3.00 (m, 1H), 2.11 ~ 2.19 (m, 1H), 1.81 - 1.85 (m, 1H), 1.56 — 1.62 (m, 2H), 1.27 (d, J: 6.0 Hz, 3H) EXAMPLE 81 3-[Methyl(propanyl)amino](1H-pyrroly1)quinoxalinecarb0xylic acid Y O (El/ /NDAOH Step 1. Methyl 3-[methyl(propanyl)amino][1-[tris(propanyl)sily1]~IH-pyrrol noxaline—6-carboxy1ate 72D” ,JiiN To a solution of methyl 2—chlor0—3-[methyl(propanyl)amino]quinoxaline—6—carboxylate (150 mg, 0.51 mmol) in 1,4—dioxane (5.0 mL) and water (3 drops) was added 3—(tetramethyl— 1,3,2—dioxaborolanyl)—1-[tris(propan-2—yl)silyl]—]H—pyrrole (356 mg, 1.02 mmol), Pd(PPh3)4 (29.4 mg, 0.03 mmol), and sodium carbonate (108.1 mg, 1.01 mmol) with stirring for 1 hour at 90°C under an atmosphere of en. The resulting mixture was concentrated under vacuum to give a residue, which was purified by silica gel chromatography (1% ethyl acetate in petroleum ether) to give methyl 3-[methyl(propanyl)amino][1-[tris(propan y1)silyl]~]H—pyrrolyl]quinoxalinecarboxy1ate as a yellow solid (130 mg , 53%).
LC/MS (ES, m/z): [M+H]+ 481.0 WO 19046 PCT/U82012/027423 Step 2. Methyl 3—[methyl(propan~2—yl)amino]—2-(1H—pyrrol—3-y1)quinoxalinecarboxylate To a solution of 3-[methy1(propan-2—yl)amino][1-[tris(propan—2—yl)si1y1]—1H—pyrrol-3— yl]quinoxaline—6-carboxylate (130 mg, 0.27 mmol) in THF (10 mL) was added TBAF (71 mg, 0.27 mmol) with ng for 10 min at room temperature. The ing mixture was concentrated under vacuum, diluted with water (30 mL), and extracted with ethyl acetate(2 x mL). The organic layers were combined, dried over anhydrous sodium sulfate, and the solids were collected via filtration. The resulting mixture was concentrated under vacuum to give methyl 3-[methyl(propan-2—yl)amino]-2—(lH—pyrrol—3~y1)quinoxaline-6—carboxy1ate (70 mg, 80%) as yellow oil.
LC/MS (ES, m/z): [M+H]+ 325.0 1H-NMR (300 MHz, DMSO) 5 11.26 (s, 1H), 8.24 (d, J: 1.8 Hz, 1H), 7.92 - 8.23 (m, 1H), 7.83 (d, J: 8.4 Hz,1H), 7.61 - 7.62 (t, J: 0.9 Hz, 1H), 6.87 - 6.90(m, 1H), 6.77 - 6.78 (t, J: 1.5 Hz, 1H), 4.25 - 4.34 (m, 1H), 3.92 (s, 1H), 2.73 - 2.78 (s, 3H), 1.09 - 1.12 (m, 6H) Step 3. 3~[Methyl(propan—2-yl)amino]—2-(lH—pyrrol—3-y1)quinoxalinecarboxy1ic acid \l/ O (fN/NI>/U\OH\ To a solution of methyl 3-[methyl(propanyl)amino]-2~(1H—pyrrol-3—y1)quinoxa1ine—6- carboxylate (70 mg, 0.22 mmol) in methanol (40 mL) was added NaOH (34.6 mg, 0.87 mmol) with stirring for 2 h at room temperature. The resulting mixture was concentrated under vacuum and extracted with romethane (20 mL). The aqueous layers were combined, adjusted to pH 6 with HCl (3 N), and the product was collected by filtration to give 3-[methy1(pr0panyl)amino]—2-(1H—pyrrol—3-y1)quinoxaline—6-carboxylic acid as a yellow solid (18.6 mg, 28%).
LC/MS (ES, m/z): [M+H]+ 311.0 1H-NMR (300 MHz,DMSO)811.26(s, 1H), 8.21 (d, J: 1.5 Hz, 1H), 7.91 ~ 7.95 (m, 1H), 7.81 (d, J: 8.7 Hz, 1H), 7.62 (s, 1H), 6.88 (t, J: 2.4 Hz, 1H), 6.77 (d, J: 1.5 Hz, 1H), 4.25 - 4.30 (t, J = 6.6 Hz, 1H), 2.78 (s, 3H), 1.10 (d, J: 6.6 Hz, 6H) W0 20121119046 PCT/U82012/027423 2-(1-Benzofuranyl)[(ZS)methylpyrrolidin-l-yl]quinoxalinecarboxylic acid Step 1. Methyl 2-(1—benzofuranyl)-3 -[(23)methylpyrrolidin— 1 -yl]quinoxaline—6— carboxylate To a solution of 3-[(2S)methylpyrrolidin~1~yl] [(trifluoromethane)sulfonyloxy]quinoxaline—6-Carboxylate (150 mg, 0.36 mmol) in dioxane (5.0 mL) and water (3 drops) was added 2—(1—benzofuran-3—yl)-4,4,5,5—tetramethy1-1,3,2- dioxaborolane (174.7 mg, 0.72 mmol), Pd(PPh3)4 (20.7 mg, 0.02 mmol), and K3PO4 (151 mg, 0.71 mmol) with stirring for 1 hour at 90°C under an atmosphere of nitrogen. The resulting mixture was concentrated under vacuum to give a residue, which was purified via silica gel chromatography (1% ethyl acetate in petroleum ether) to give methyl 2-(1-benzofuran—3—y1)~ )-2—methy1pyrrolidin—1—yl]quinoxaline~6~carboxylate as a yellow solid (97 mg, 70%).
LC/MS (ES, m/z): [M+H]+ 388.0 1H-NMR (300 MHz, CDCL3) 5 8.54 (d, J = 1.5 Hz, 1H), 8.14 (d, J = 2.4 Hz, 1H), 8.12 (d, J = 1.8 Hz, 1H), 7.98 — 8.07 (m, 2H), 7.59 (d, J: 1.8 Hz, 1H), 7.35 ~ 7.58 (m, 2H), 4.43 - 4.50 (m,1H), 4.01 (s, 3H), 3.33 - 3.38 (m,lH), 3.07 - 3.13 (m, 1H), 2.16 - 2.21 (m,1H),1.80 - 1.85 (m, 1H), 1.58 - 1.71 (m, 2H), 1.40 (d, J: 6.0 Hz, 3H) Step 2. enzofuranyl)[(2S)methylpyrrolidin~1~yl]quinoxaline—6—carboxylic acid To a solution of methyl 2-(1-benzofurany1)[(2S)methylpyrrolidinyl]quinoxaline- 6-carboxylate (80 mg, 0.21 mmol) in methanol (40 mL) and water (1 mL) was added sodium hydroxide (33 mg, 0.83 mmol) with ng overnight at room ature. The resulting W0 19046 mixture was trated under vacuum, dissolved in water (50ml) adjusted to pH 6 with HCl (3N), and collected by filtration to give 2—(1-benzofuranyl)[(2S) methylpyrrolidin-l-yl]quinoxaline-G-carboxylic acid as a yellow solid (60.1 mg, 78%).
LC/MS (ES, m/z): [M+H]+ 374.0 1H-NMR (300 MHz, DMSO) 5 8.52 (s, 1H), 8.27 (s, 1H), 8.08 — 8.11 (t, J: 1.5 Hz,1H), 7.92 - 7.98 (t, J: 8.4 Hz, 1H), 7.72 (d, J = 7.2 Hz,1H), 7.38 - 7.47 (m, 2H), 4.30 — 4.37 (m, 24 — 3.32 (m, 1H) ,3.03 — 3.09 (m,1H), 2.04 — 2.14 (m, 1H), 1.78 - 1.85 (m, 1H),1.53 - 1.63 (m, 2H), 1.33 (d, J = 6.0Hz ,3H) EXAMPLE 83 3—[Methyl(propan-Z-yl)amino](3-phenylfuran-2—yl)quinoxalinecarboxylic acid Y o /N /N©)J\OH Step 1. Methyl hyl(propany1)amino]—2-(3-phenylfuranyl)quinoxa1ine carboxylate To a solution of methyl 2-chloro—3-[methyl(propan—2~yl)amino]quinoxaline—6—carboxy1ate (140 mg, 0.48 mmol) in dioxane (5.0 mL) and water (3 drops) was added 4,4,5,5- tetramethyl-2—(3-phenylfuran—2—yl)—1,3,2—dioxaborolane (270 mg, 1.00 mmol), K3PO4 (211 mg, 0.99 mmol) and Pd(PPh3)4 (28 mg, 0.02 mmol) with stirring for l h at 95°C in an oil bath maintained under an inert atmosphere of nitrogen. The reaction mixture was concentrated under vacuum to give a residue, which was purified by silica gel chromatography (2% ethyl acetate in petroleum ether) to afford methyl 3-[methyl(propan-2—yl)amino](3-phenylfuran- 2-y1)quinoxa1inecarboxylate as a light yellow solid (140.0 mg, 73%).
LC/MS (ES, m/z): [M+H]+ 402.0 1H-NMR (300 MHz, CDC13): 5 8.47 (t, J: 1.2 Hz, 1H), 8.00 - 8.05 (m, 2H), 7.70 (d, J = 2.1 Hz, 2H), 7.28 - 7.31 (m, 2H), 7.19 - 7.27 (m, 2H), 6.80 (d, J: 1.8 Hz 1H), 4.24 - 4.28 (m, 1H), 4.00 (s, 3H), 2.44 (s, 3H), 0.85 (d, J = 6.6 Hz,6H) Step 2. 3—[Methyl(propan-2~y1)amino]—2—(3-phenylfuran—2—yl)quinoxaline-6—Carboxylic acid Y o To a solution of methyl 3—[methyl(propanyl)amino]—2—(3-phenylfuran-2—y1)quinoxaline-6~ carboxylate (140 mg, 0.35 mmol) in methanol (35 mL) and water (2.0 mL) was added sodium hydroxide (55 mg, 1.38 mmol) with stirring overnight at room ature. The reaction mixture was concentrated under vacuum, ved in water (30 mL) and adjusted to pH 4 with HCl (3N). The solids were collected by filtration to afford 3—[methy1(propan yl)amino]—2-(3 -phenylfuran—2—y1)quinoxalinecarboxylic acid as a light yellow solid (100 mg, 74%).
LC/MS (ES, m/z): [M+H]+388.0 1H—NMR (300 MHz, DMSO): 5 8.23 (s, 1H), 8.02 (d, J = 1.8 Hz, 1H), 7.89 — 7.95 (m, 2H), 7.22 — 7.35 (m, 5H), 7.06 (d, J = 1.8 Hz, 1H), 4.15 - 4.24 (m, 1H), 2.66 (s, 3H), 2.43 (s, 1H), 0.85 (d, J = 6.6 Hz, 6H) EXAMPLE 84 2-[5-(4-Fluorophenyl)furanyl]~3-[methyl(pr0panyl)amino]quinoxaline-G- carboxylic acid W0 2012/119046 PCT/U82012/027423 Step 1. 2-(4—Fluorophenyl)furan To a solution of l-bromofluorobenzene (3.0 g, 17.14 mmol) in dioxane (100.0 mL) and water (3.0 mL) was added (furan—Z-yl)boronic acid (5.76 g, 51.48 mmol), K3PO4 (10.76 g, 50.69 mmol) and Pd(PPh3)4 (980 mg, 0.85 mmol) with stirring for 2h at 90°C in an oil bath ined under an inert atmosphere of en. The reaction mixture was concentrated under reduced pressure to give the residue, which was purified Via silica gel chromatography (1% ethyl acetate in petroleum ether) to afford 2-(4-fluorophenyl)furan as colorless oil (2.5g, 90%). 1H-NMR (300 MHz, CDClg): 5 7.66 — 7.71 (m, 2H), 7.45 - 7.48 (m, 1H), 7.11 - 7.14 (m, 2H), 6.60 - 6.61 (m, 1H), 6.48 - 6.49 (m, 1H) Step 2. 2-[5-(4-Fluorophenyl)furan-2—yl]-4,4,5,5-tetramethyl-l ,3,2—dioxaborolane o ,0 l / on To a solution of 2-(4-fluorophenyl)furan (1.50 g, 9.25 mmol) in dry tetrahydrofuran (100 mL) was added a solution of n—BuLi (4.4 mL, 2.5M solution in hexane) se with stirring at - 78°C under nitrogen. The resulting solution was warmed slowly to —40°C over 45 min and stirred at this temperature for another 30 min. The mixture was cooled again below —78°C followed by dropwise addition of 4,4,5,5—tetramethyl-2—(propan-Z—yloxy)—1,3,2— dioxaborolane (3.42 g, 18.38 mmol). After warming to room temperature, the mixture was quenched with NH4Cl (aq) and extracted with ethyl acetate (3 x 80 mL). The combined c layers were dried over ous sodium sulfate, filtered and concentrated under reduced pressure to give the residue (120 g , which was used to the next step without further purification.
Step 3. Methyl 4-fluorophenyl)furanyl]-3—[methyl(propanyl)amino]quinoxaline- 6-carboxylate To a solution of 2—[5—(4-fluorophenyl)furan-2—yl]—4,4,5,5-tetramethyl-1,3,2—dioxaborolane (442 mg, crude) in dioxane (5.5 mL) and water (3 drops) was added methyl 2—chloro—3— [methyl(propan-2—y1)amino]quinoxaline-6—carboxylate (150 mg, 0.51 mmol), K3PO4 (324.9 mg, 1.53 mmol) and Pd(PPh3)4 (29.5 mg, 0.03 mmol) with stirring for 40 min at 90°C in an oil bath maintained under an inert atmosphere of nitrogen. The reaction mixture was concentrated under reduced pressure to give the residue, which was purified via silica gel chromatography (2% ethyl acetate in eum ether) to afford methyl 2-[5—(4- fluorophenyl)furanyl][methyl(propanyl)amino]quinoxalinecarboxylate as light yellow solid (150 mg, 55%).
LC/MS (ES, m/z): [M+H]+ 420.0 1H-NMR (300 MHz, CDC13)I 5 8.50 (d, J: 1.8 Hz, 1H), 8.06 - 8.09 (m, 1H), 7.98 (d, J: 8.7 Hz, 1H), 7.75 — 7.82 (m, 2H), 7.36 (d, J = 3.3 Hz, 1H ), 7.15 - 7.19 (m, 2H), 6.80 (d, J: 3.6 Hz, 1H), 4.35 - 4.44 (m, 1H), 4.00 (s, 3H), 2.88 (s, 3H), 1.26 (d, J: 6.6 Hz, 6H) Step 4. 4—Fluorophenyl)furan-2—yl][methyl(propan—2-yl)amino]quinoxaline-6— carboxylic acid To a solution of methyl 2-[5-(4-f1uorophenyl)furanyl]~3-[methyl(propan yl)amino]quinoxaline-6~carboxylate (110 mg, 0.26 mmol) in methanol (30 mL) and water (2 mL) was added sodium hydroxide (42 mg, 1.05 mmol) with stirring overnight at room W0 20121119046 temperature. The reaction mixture was concentrated under , dissolved in water (30 mL) and adjusted to pH 5 with HCl (3N). The solids were collected by filtration to afford 3- [methyl(propanyl)amino](5-phenylfurany1)quinoxalinecarboxylic acid as a light yellow solid (19.3 mg, 18%).
LC/MS (ES, m/z): [M+H]Jr 406.1 1H NMR (300 MHz, DMSO): 8 8.58 (d, J = 1.8 Hz, 1H), 8.48 (d, J = 1.5 Hz, 1H), 8.12 — 8.17 (m, 1H), 7.80 — 7.99 (m, 2H), 7.38 (d, J: 3.6 Hz, 1H), 7.12 — 7.19 (m, 2H), 6.81 (d, J = 3.6 Hz, 1H ), 4.37 — 4.46 (m, 1H), 2.89 (s, 3H), 1.24 (d, J: 6.6 Hz, 6H) EXAMPLE 85 3-[Methyl(propany1)amin0](3-methyl-l-benzofuran-S-yl)quinoxalinecarboxylic acid Y o (1:8/N:©/U\OH\0 Step 1. Ethyl cety1—4-bromophenoxy)acetate %O\/U\O/\ To a solution of 1—(5—bromo-2—hydroxyphenyl)ethan~1—one (10 g, 46.50 mmol) in MN— dimethylformamide (80 mL) was added sodium hydroxide (2.23 g, 92.92 mmol) and then stirred for 1 hour at room temperature. Ethyl 2—bromoacetate (8.24 g, 49.34 mmol) was added se and stirred ght at room temperature. The reaction mixture was quenched by the addition of water (200 mL), adjusted to pH 5 with HCl (3N), extracted with ethyl acetate (50 mL x 3), dried over anhydrous sodium sulfate, and concentrated under vacuum to give a residue which was purified by silica gel chromatography (5% ethyl acetate in petroleum ether) to afford ethyl 2-(2-acetylbromophenoxy)acetate as a light yellow oil (8.9 g, 64%). 1H-NMR (300 MHz, CDC13) 8 7.87 (d, J = 2.7 Hz, 1H), 7.52 - 7.55 (m, 1H), 6.74 (d, J = 8.7 Hz, 1H), 4.72 (s, 2H), 4.24 - 4.30 (m, 2H), 2.71 (s, 3H), 1.28 - 1.36 (m, 3H) W0 20121’119046 PCT/U52012/027423 Step 2. cetyl-4—bromophenoxy)acetic acid To a on of ethyl 2—(2-acetyl—4—bromophenoxy)acetate (8.9 g, 29.56 mmol) in THF (60 mL) was added sodium hydroxide (1.43 g, 35.75 mmol) and water(10 mL). The resulting solution was stirred overnight at room temperature and concentrated under vacuum. The residue was dissolved in water (30 mL) and adjusted to pH 2 with HCl (3N). The solids were collected by filtration to afford 2—(2—acetyl-4—bromophenoxy)acetic acid as a light yellow solid (6.3 g, 78%). 1H-NMR (300 MHz, CDCl3) 8 7.62 - 7.69 (m, 2H), 7.10 (d, J = 8.7 Hz, 1H), 4.86 (s, 2H), 2.63 (s, 3H) Step 3. 5-Bromomethyl-l-benzofuran To a solution of 2—(2-acety1—4—bromophenoxy)acetic acid (5.3 g, 19.41 mmol) in acetic anhydride (100 mL) was added NaOAc (3.19 g, 38.90 mmol). The resulting solution was heated to reflux ght. The pH value of the resulting on was adjusted to 7 with sodium aqueous sodium hydroxide, extracted with ether (50 mL x 3), dried over anhydrous sulfate and concentrated under vacuum to give a residue, which was purified by silica gel chromatography (petroleum ether) to afford 5—bromo~3—Inethyl-l~benzofuran as a light yellow oil (3.8 g, 93%). 1H-NMR (300 MHz, CDC13) 8 7.67 (d, J = 1.8 Hz, 1H), 7.33 — 7.43(rn, 3H), 2.28 (d, J: 1.5 HZ, 3H) Step 4. 4,4,5,5~Tetramethyl—2—(3~niethyl-l-benzofuran-S-yl)-1,3,2—dioxaborolane To a on of 5-bromomethylbenzofuran (1.9 g, 9.00 mmol) in 1,4-dioxane (30 mL) was added KOAC (2.2 g, 22.42 mmol) and Pd(dppf)Clz (600 mg, 0.82 mmol). The solution was stirred for 15 minutes at room temperature and then 4,4,5,5-tetramethyl—2-(tetramethyl- W0 2012!]19046 1,3,2—dioxaborolan—2—yl)—1,3,2-dioxaborolane (2.7 g, 10.63 mmol) was added. The resulting solution was d overnight at 85°C, followed by quenching via the on of water (100 mL). The resulting solution was extracted with ethyl acetate (3 x 30 mL), dried over anhydrous sodium sulfate and concentrated under vacuum to give a residue, which was purified by silica gel chromatography (petroleum ether) to afford 4,4,5,5-tetramethyl-2—(3— methylbenzofuran-5—yl)—1,3,2-dioxaborolane as a light yellow solid (1.5 g, 65%). 1H-NMR (300 MHz, CDC13) 5 8.05 (s, 1H), 7.76 - 7.79 (m, 1H), 7.41 - 7.48 (m, 2H), 2.28 (d, J: 1.5 Hz, 3H), 1.39 (s,12H) Step 5. Methyl 3—[methy1(propan—2—yl)amino]~2—(3—methylbenzofuran-5~y1)quinoxaline-6— carboxylate Y O To a solution of methyl 2-chloro—3-[methyl(propan—2-yl)amino]quinoxaline—6-carboxylate (150 mg, 0.36 mmol) in 1,4- dioxane (6 mL) was added 4,4,5,5-tetramethy1(3-methyl benzofuran-S-yl)-1,3,2-dioxaborolane (350 mg, 1.36 mmol), Pd(PPh3)4 (40 mg, 0.034 mmol), K3PO4 (430 mg, 2.04 mmol) and water (5 drops) with stirring for 5 h at 90°C under an inert atmosphere of nitrogen in an oil bath. The reaction e was concentrated under vacuum to give the residue, which was purified via silica gel chromatography (1% to 5% ethyl acetate in petroleum ether) to afford methyl 3—[methyl(propanyl)amino]-2—(3-methyl—1- benzofuran-S—yl)quinoxalinecarboxylate as a yellow solid (110 mg, 63%).
LC/MS (ES, m/z): [M+H]+ 390.0 1H-NMR (300 MHz, CDC13) 5 8.56 (d, J: 1.5 Hz, 1H), 7.99 - 7.86 (m, - 8.12 (m, 3H), 7.83 1H), 7.49 — 7.62 (m, 2H), 4.25 - 4.39 (m, 1H), 4.00 (s, 3H), 3.00(s, 3H), 2.54 (s, 3H), 1.08 (d, J = 6.6 Hz, 6H) Step 6. hyl(propan—2~yl)amino]—2—(3—methyl—1-benzofuran~5—yl)quinoxaline—6— carboxylic acid Y o /N /N:©/ILOH PCT/U52012/027423 To a solution of methyl 3—[methy1(propan—2-yl)amino](3-methyl-l-benzofuran—5— y1)quinoxa1inecarboxylate (110 mg, 0.28 mmol) in methanol (25 mL) and chloroform (5 mL ) was added sodium hydroxide (468 mg, 1.17 mmol) and water (2 mL) with ng for 3h at room temperature. The on mixture was concentrated under vacuum, dissolved in water (15 mL), and adjusted pH to 5 with HCl (3N) to give the precipitate, which was collected by filtration to afford 3—[methyl(propan-2—yl)amino]—2—(3 ~methyl—l-benzofuran-5— yl)quinoxaline-6~carboxylic acid (62 mg, 59%).
LC/MS (ES, m/z): [M+H]+ 376.1 1H—NMR (300 MHz, DMSO) 5 8.28 (t, J = 0.9 Hz, 1H), 8.12 (d, J = 1.5 Hz, 1H), 7.96 (s, 2H), 7.81 - 4.20 (m, 1H), 2.69 (s, 3H), 2.28 (s, — 7.87 (m, 2H), 7.68 (d, J: 8.4 Hz, 1H), 4.16 3H), 1.02 (d, J = 6.6 Hz, 6H) EXAMPLE 86 3-(Isopropyl(methyl)amino)(3-methyl-1H-indol-S-yl)quinoxaline-é-carboxylic acid Y 0 / N Step 1. 5-Bromo-]H—indole—3—carba1dehyde To a solution of POC13 (8.58 g, 55.96 mmol) in MN-dimethylformamide (14.9 g, 203.9 mmol) was added a solution of 5-bromo-1H—indole (10.0 g, 51.0 mmol) in MN— dimethylformamide (100 mL) dropwise at 0-10°C. The reaction mixture was d for 1h at 0-35°C and then poured into water/ice solution, adjusted the pH to 10 with aqueous sodium hydroxide and filtered to afford 5—bromo-JH—indole-3~carba1dehyde as a white solid (8.0 g, 70%). 1H—NMR (300 MHz, CD30D): 5: 9.90 (s, 1H), 8.32 (s, 1H), 8.14 (s, 1H), 7.38 - 7.44 (m, 2H) WO 19046 PCT/U52012/027423 Step 2. 5—Bromo-3—methyl-1H—indole THF (80 mL) was To a solution of 5—bromo-1H—indole-3—carbaldehyde (5.0 g, 22.3 mmol) in added LiAlH4 (1.70 g, 44.6 mmol). The resulting solution was stirred for 2h under reflux, then poured into 1N NaOH solution (150 mL), extracted with ethyl acetate (3 x 100 mL), dried over anhydrous sodium sulfate, and then concentrated under vacuum to give a residue, which was purified via silica gel chromatography (3% ethyl e in petroleum ether) to afford 5—bromo-3—methyl~IH-indole as a white solid (3.4 g, 73%).
IH—NMR (300 MHz, : 8:7.91 (s, 1H), 7.72 - 7.73 (t, J: 0.9 Hz, 1H), 7.21 - 7.30 (m, 2H), 6.99 (d, J: 0.9 Hz, 1H), 2.31 (s, 3H) Step 3. 3—Methyl—5-(4,4,5,5-tetramethyl— l ,3,2-dioxaborolan-2—yl)~1H—indole To a solution of 5—bromomethy1—1H—indole (1.5 g, 7.14 mmol) in dioxane (40 mL) was ACOK added 4,4,4',4',5,5,5’,5'-octamethyl—2,2'—bi(1,3,2-dioxaborolane) (2.18 g, 8.57 mmol), stirred (1.40 g, 14.3 mmol) and Pd(dppf)C12 (262 mg, 0.36 mmol). The resulting solution was with overnight at 90°C. The reaction mixture was poured into water (200 mL), extracted under vacuum to DCM (3 x 100 mL), dried over anhydrous sodium sulfate, and concentrated give a residue, which was ed via silica gel chromatography (3% ethyl acetate petroleum ether) to afford 3-methyl-5—(4,4,5,5—tetramethy1-l,3,2—dioxaborolan—2—yl)-]H— indole as a white solid(1.1 g, 60%). 1H—NMR (300 MHz, CDC13)I 8: 8.14 (s, 1H), 7.95 (s, 1H), 7.65 — 7.37 - 7.68 (m, 1H), 7.34 (m, 1H), 6.97 (d, J: 0.9Hz, 2H), 2.37 (s, 3H), 1.40 (s, 12H) Step 4. Methyl 3-(isopropy1(methyl)amino)—2-(3—methyl—1H-indol—5 -yl)quinoxa1ine-6— carboxylate PCT/U52012/027423 To a solution of methyl 2—chloro—3-(isopropyl(methyl)amino)quinoxaline-6—carboxylate (150 added 3-methy1(4,4,5,5-tetramethy1-1,3,2- mg, 0.51 mmol) in dioxane (5 mL) was dioxaborolanyl)-JH—indole (395 mg, 1.54 mmol), K2CO3 (106 g, 0.77 mmol), Pd(PPh3)4 (30 mg, 0.03 mmol) and water (5 drops). The resulting solution was d for 5h at 90°C, and then poured into water (100 mL). extracted with DCM (4 X 50 mL), dried over anhydrous sodium sulfate and then concentrated under vacuum to give a residue. The residue was purified via silica gel chromatography (25% ethyl acetate in petroleum ether) to afford methyl propyl(methyl)amino)—2-(3-methyl-1H—indolyl)quinoxaline-6—carboxylate as a yellow solid (80 mg, 45%). 1H—NMR (300 MHz, CDC13)I 5 8.96 — 8.22 (m, 3H), - 8.61 (m, 2H), 8.15 - 9.09 (m, 1H), 8.51 7.62 2.41 - 7.70 (m, 1H), 4.60- 4.70 (m, 1H), 4.03 (s, 3H), 2.95 (s, 3H), (s, 3H), 1.99 (s, 6H) Step 5. 3-(Isopropy1(methy1)amino)—2-(3-methyl~IH—indol-S-yl)quinoxaline—6-carboxylic acid /N /Nj©/U\OH\ / N To a solution of methyl 3—(isopr0pyl(methy1)amino)-2—(3-methyl—JH—indol—5—yl)quinoxaline- 6-carboxylate (80 mg, 0.21 mmol) in MeOH (10 mL) was added sodium hydroxide (52 mg, 0.29 mmol) and water (1 mL). The resulting solution was stirred for 2h at room temperature and trated under vacuum. The residue was dissolved in water (3 mL) and adjusted to pH 6 with hydrochloric acid (1N). The solids were collected by filtration to afford 3- (isopropyl(methyl)amino)-2—(3-methyl~1H—indol-S-y1)quinoxaline—6-carboxylic acid as a yellow solid (45.8 mg, 59%).
LC/MS (ES, m/z): [M+H]+ 375.1 1H-NMR (300 MHz, DMSO): 513.05 (s, 1H), 10.98 (s, 1H), 8.25 (s, 1H), 8.08 (s, 1H), 7.93 (s, 2H), 7.64 — 7.68 (m, 2H), 7.44 - 4.29 (m, 1H), - 7.46 (d, J = 8.4 Hz,1H), 7.20 (s, 1H), 4.20 2.71 (s, 3H), 2.31 (s, 3H),1.10 — 1.13 (d, J: 6.6 Hz, 6H) WO 19046 PCT/U52012/027423 EXAMPLE 87 (R)(Benzo[d][1,3]dioxolyl)(2-methylpyrrolidinyl)quinoxalinecarboxylic acid To a solution of methyl 3-chloro-2~oxo-1,2—dihydroquinoxaline—6—carboxylate (250 mg, 1.05 mmol) in DMSO (2 mL) was added DIEA (850 mg, 4.2 mmol), and (R)—2-methylpyrrolidine hydrochloride (300 mg, 2.35 mmol), and the resulting mixture was stirred for 3 h at 70°C.
Then the reaction was quenched by the addition of water (10 mL). The solids were collected by filtration to afford (R)—methy1 3-(2-methy1pyrrolidin-l-yl)oxo-1,2-dihydroquinoxaline- 6—carboxylate as a light yellow solid (216 mg, 72%).
LC/MS (ES, m/z):[M+H]+ 288.0 Step 2. thy1 3-(2-methy1pyrrolidiny1)—2-(trifluoromethylsu1fonyloxy)quinoxaline—6— carboxylate To a solution of thy1 3-(2—methylpyrrolidin—1-y1)—2-oxo-1,2-dihydroquinoxaline—6— carboxylate (200 mg, 0.70 mmol) in dichloromethane (30 mL) was added pyridine (221 mg, 2.79 mmol) and then TfZO (395 mg, 1.40 mmol) dropwise with stirring at 0°C. The resulting solution was stirred overnight at room ature, then quenched by the addition of ice- water (50 mL), extracted with dichloromethane (3 x 20 mL), dried over anhydrous sodium sulfate and concentrated under vacuum to afford (R)-methyl 3-(2-methylpyrrolidinyl) (trifluoromethylsulfonyloxy)quinoxaline—6-carboxylate as red oil (250 mg, crude).
PCT/U52012/027423 Step 3. (R)—Methyl 2—(benzo[d][1,3]dioxol—5-yl)—3-(2—methylpyrrolidin-1—yl)quin0xaline-6— carboxylate To a solution of (R)-methy1 3-(2~methylpyrrolidin—1-yl)~2-(trifluoromethylsulfonyloxy) aline-6—carboxy1ate (250 mg, crude) in dioxane (5 mL) was added 2- (benzo[d][1,3]dioxol—5—y1)—4,4,5,5-tetramethyl-1,3,2—dioxaborolane (250 mg, 1.51 mmol), K3PO4 (380 mg, 1.79 mmol), Pd(PPh3)4 (35 mg, 0.03 mmol) and water (5 drops). The resulting solution was stirred for 1 h at 90°C and then concentrated under vacuum to give a residue, which was purified Via silica gel chromatography (1% - 5% ethyl e in petroleum ether) to afford thyl 2~(benzo[d][1,3]dioxolyl)-3—(2—methylpyrrolidin—l- yl)quinoxaline—6—carboxylate as a yellow solid (120 mg).
LC/MS (ES, m/z):[M+H]+ 392.0 1H-NMR (300 MHz, CDC13)C 8 8.56 (s, 1H), 7.93 - 7.32 (s, 2H), 6.93 (d, - 8.03 (m, 2H), 7.28 J = 7.8 Hz, 1H), 6.07 (s, 2H), 4.35 - 4.42 (m, 1H), 4.00 (s, 3H), 3.25 (d, J: 6.3 Hz, 1H), 2.95 — 1.70 - 1.91 (m, 1H), 1.53 - 2.25 (m, 1H), 1.86 - 3.04 (m, 1H), 2.15 (m, 2H), 1.39 (d, J: 5.4 Hz, 3H) Step 4. (R)—2—(Benzo[d][1,3]dioxol-S-yl)—3-(2~methylpyrrolidinyl)quinoxaline—6— carboxylic acid Cl/ 0 <0 \N To a solution of (R)-methyl 2-(benz0[d][1,3]dioxolyl)-3—(2~methylpyrrolidin yl)quinoxalinecarboxy1ate (120 mg, 0.31 mmol) in methanol (25 mL) was added sodium hydroxide (37.2 mg, 0.93 mmol) and water (2 mL). The resulting solution was stirred overnight at room temperature and concentrated under vacuum. The residue was ved in water (20 mL) and adjusted pH to 5 with hydrochloric acid (3N). The solids were collected by filtration to afford (R)(benzo[d][1,3]dioxoly1)(2-methy1pyrrolidin yl)quinoxaline—6—carboxylic acid as a yellow solid (90 mg , 78%).
LC/MS (ES, m/z,):[M+H]+ 378.1 1H—NMR (300 MHz, CD3OD) 6 8.38 (d, J = 1.8 Hz, 1H), 7.96 - 7.99 (m, 1H), 7.86 (d, J = 8.7 Hz, 1H), 7.26 - 7.29 (m, 2H), 6.98 (d, J: 8.4 Hz, 1H), 6.06 - 6.08 (m, 2H), 4.32 - 4.87 (m, 1H), 3.19 - 3.33 (m, 1H), 3.01 - - 1.87 (m, 1H), 1.59 - 2.22 (m, 1H), 1.83 — 3.07 (m, 1H), 2.18 1.70 (m, 2H), 1.37 (d, J = 6.6 Hz, 3H) EXAMPLE 88 (S)(2-Methyl-1H-ind0lyl)(2-methylpiperidinyl)quinoxaline-é-carboxylic acid Step 1. (S)-Methyl 3—(2—methylpiperidin~l -y1)—2~oxo- l ,2—dihydroquinoxaline-6—carboxylate O N To a on of methyl 3—chlorooxo-1,2-dihydroquinoxalinecarboxylate (1 g, 4.2 mmol) in DMSO (20 ml) was added (S)-2—methylpiperidine (500 mg, 5.04 mmol) and DIEA (1.09 g, 8.4 mmol). The resulting solution was stirred for 2 hours at 80°C and then quenched by the addition of water (100 ml). The product was ted by filtration to afford (S)-methyl 3—(2-methy1piperidin-1—yl)—2—oxo~1 ,2-dihydroquinoxaline—6-carboxy1ate as white solid (840 mg, 66%).
LC/MS (ES, m/2:)2[M+H]+ 302.0 1H—NMR (300 MHz, CDCl3): 8 10.11 (s, 1H), 8.29 (s, 1H), 7.83 — 7.86 (m, 1H), 7.09 (d, J: 8.4 Hz, 1H), 5.39 — 3.26 ~ 4.91 (m 1H), 3.94 (s, 3H), 3.18 - 5.41 (m, 1H), 4.86 (t, J: 12.6 Hz, 1H), 1.65 — 1.94 (m, 6H), 1.35 (d, J: 6.9 Hz, 3H) Step 2. (S)-Methyl ethy1piperidin- 1 ~y1)—2—(trifluoromethylsulfonyloxy)quinoxaline—6- carboxylate TfO N To a solution of (S)-methyl 3—(2—methylpiperidiny1)-2—oxo-1,2—dihydroquinoxaline-6— carboxylate (840 mg, 2.79 mmol) in dichloromethane (60 ml) was added pyridine (1.19 g, 14.98 mmol) and then TfZO (2.12 g, 7.52 mmol) dropwise with stirring at 0°C. The ing solution was stirred ght at room temperature, then washed with water (3 x 50 ml), dried which was over anhydrous sodium sulfate and concentrated under vacuum to give a residue, purified Via silica gel chromatography (1% to 2% ethyl acetate in petroleum ether) to afford (S)—methyl 3—(2—methylpiperidin-1—yl)—2—(trifluoromethylsulfonyloxy)quinoxaline—6- carboxylate as red oil (990 mg, crude).
Step 3. (S)—Methy1 2—bromo-3—(2—methylpiperidin—1—yl)quinoxa1ine-6~carboxylate I /N\ O/ Br N To a solution of (S)-methyl 3-(2-methylpiperidin-1—yl)-2— oromethylsulfonyloxy)quinoxalinecarboxylate (990 mg, crude) in toluene (30 ml) The resulting solution was added Bu4NBr (1.3 g, 4.05 mmol) with stirring for 5 h at 120°C. ed and dried was extracted with ethyl acetate (3 x 50 ml), and the organic layers were over anhydrous magnesium sulfate and concentrated under vacuum to give (S)-methyl bromo(2-methylpiperidiny1)quinoxaline-6»carboxylate as a yellow solid (900 mg).
LC/MS (ES, m/z): [M+H]+ 364.0 Step 4. (S)-Methyl 2—(2-methyl-JH—indol-5—yl)-3—(2-methylpiperidin— 1 -yl)quinoxaline carboxylate To a solution of (S)—methyl 2-bromo(2—methylpiperidin~1-yl)quinoxaline—6—carboxylate (200 mg, 0.55 mmol) in ethylene glycol dimethyl ether (7 ml) was added y1 (tetramethyl—l,3,2—dioxaborolan-2—yl)-JH—indole (141 mg, 0.55 mmol), sodium carbonate (116 mg, 1.09 mmol), water (2 mL), and Pd(PPh3)4 (32 mg, 0.03 mmol). The resulting solution was stirred for 3 h at 90°C and concentrated under vacuum to give a residue, which to afford was purified via silica gel chromatography (2% ethyl acetate in petroleum ether) (S)-methyl 2-(2-methyl-JH-indol-5 -y1)(2—methylpiperidinyl)quinoxalinecarboxylate as a light yellow solid (142.1 mg, 62%).
LC/MS (ES, m/z): [M+H]+ 415.0 W0 2012/119046 2012/027423 1H—NMR (300 MHz, : 5 8.67 (s, 1H), 8.15 — — 8.11 (m, 1H), 7.73 - 8.30 (m, 4H), 8.08 7.77 (m, 1H), 7.37 (d, J = 8.7 Hz, 1H), 6.32 (s, 1H), 4.22 - 4.35 (m, 1H), 4.01 (s, 3H), 3.62 - 3.70 (m, 1H), 3.11 - 1.45 (m, 2H), 1.12 — 1.72 (m, 4H), 1.38 - 3.30 (m, 1H), 2.67 (s, 3H), 1.62 (d, J = 6.6 Hz, 3H) Step 5. (S)—2—(2-Methyl—JH-indol-5 -yl)—3-(2—methylpiperidin—1—yl)quinoxaline—6-carboxylic acid I ND/KOH / N To a solution of (S)-1nethyl 2-(2-methy1-JH—indol—5-yl)~3-(2-methylpiperidin—l- yl)quinoxaline-6—carboxylate (142.1 mg, 0.34 mmol) in methanol (30 m1) was added NaOH (55 mg, 1.38 mmol) and water(2 ml). The resulting solution was stirred overnight at room dissolved in water temperature and concentrated under vacuum to give a residue, which was (20 m1), and the pH adjusted to 4 with HCl (3N). The solids were collected by filtration to afford (S)-2—(2-methyl-1H-indol-5 -y1)(2—methylpiperidinyl)quinoxalinecarboxylic acid as a yellow solid (11.9 mg, 9%).
LC/MS (ES, m/z): [M+H]+ 401.1 1H—NMR (300 MHz, CDC13)I 5 8.44 (d, J: 1.5 Hz, 1H), 8.03 — 8.09 (m, 2H), 7.91 (d, J: 8.7 Hz, 1H), 7.63 - 4.21 (m, 1H), 3.50 - 7.67 (m, 1H), 7.40 (d, J: 8.4 Hz, 1H ), 6.26 (s, 1H), 4.14 - 1.37 (m, 2H), - 1.72 (m, 4H), 1.32 — 3.22 (m, 1H), 2.48 (s, 3H), 1.62 - 3.64 (m, 1H), 3.09 1.12 (d, J: 6.6 Hz, 3H) EXAMPLE 89 3-[Cyclopropyl(methyl)amino}2-(2-methyl-1H-indol-S-yl)quinoxalinecarboxylic acid Step 1. Methyl 3-(cyclopropyl(methyl)amino)—2—oxo—1,2—dihydroquinoxaline—6-carboxylate v o /N O/ To a solution of methyl 3-chlorooxo-1,2-dihydroquinoxalinecarboxylate (750 mg, 3.14 mmol) in DMSO (5 ml) was added DlEA (812.7 mg, 6.29 mmol), N- methylcyclopropanamine hydrochloride (450 mg, 4.18 mmol) with stirring for 3 h at 75°C in an oil bath. The resulting solution was diluted with water (200 ml), and the t was collected by filtration to give methyl 3-[cyclopropy1(methyl)amino]oxo-1 ,2- dihydroquinoxaline—6-carboxylate as a solid (780 mg, 91%).
LC/MS (ES, m/z):[M+H]+ 274.1 1H-NMR (300 MHz, DMSO) 6 12.17(s, 1H), 7.93 (d, J = 1.8 Hz, 1H), 7.67 — 7.75 (m, 1H), 7.20 (d, J: 8.4 Hz, 1H), 3.85 (s, 3H), 3.23(s, 3H), 3.05 — 3.11 (m, 1H), 0.76 — 0.82 (m, 2H), 0.50 - 0.63 (m, 2H) Step 2. Methyl 3-[cyclopropyl(methyl)amino]-2—[(trifluoromethane)sulfonyloxy]quinoxaline- 6-carboxylate V o TfO N To a solution of methyl 3-[cyclopropyl(methyl)amino]oxo-1,2-dihydroquinoxaline—6— carboxylate (780 mg, 2.85 mmol) in dichloromethane (100 ml) was added pyridine (900 mg, 11.38 mmol), szO (1645 mg, 5.83 mmol) with stirring under an inert atmosphere of nitrogen for 2 h at room temperature. The resulting solution was d with water (300 m1), extracted with dichloromethane (2 X 50 ml), dried over anhydrous magnesium sulfate and concentrated under vacuum to give a residue, which was purified via silica gel chromatography (1% - 5% ethyl acetate in petroleum ether) to give methyl 3—[cyclopropyl(methyl)amino]—2- [(trifluoromethane)sulfonyloxy]quinoxaline-6—carboxylate as a yellow solid (700 mg, 61%).
Step 3. Methyl 2-bromo[cyclopropyl(methyl)amino]quinoxalinecarboxylate Y o Br N WO 19046 To a solution of methyl 3-[cyclopropyl(methyl)amino] [(trifluoromethane)sulfonyloxy]quinoxalinecarboxylate (700 mg, 1.73 mmol) in toluene (80 mL) was added tetrabutylammonium bromide (TBAB) (668 mg, 2.07 mmol) with stirring overnight at 120°C in an oil bath. The resulting solution was diluted with water (300 ml), extracted with dichloromethane (3 x 30 n11) dried over anhydrous ium sulfate, concentrated under vacuum to get residue, which was purified via silica gel chromatography (1% - 10% ethyl acetate in eum ether) to give methyl 2—bromo—3- [cyclopropyl(methy1)amino]quinoxalinecarboxylate as a yellow solid (480 mg, 82%).
LC/MS (ES, m/z):[M+H]’r 336.1.0 1H—NMR (300 MHz, DMSO) 8 8.26 (d, J: 1.5 Hz, 2H), 7.98 - 8.01 (m, 1H), 7.88 (d, J: 8.7 Hz, 1H), 3.93 (s, 3H), 3.19 (s, 3H), 3.10 - 3.18 (m, 1H), 0.70 - 0.90 (m, 4H) Step 4. Methyl 3-[cyclopropyl(methy1)amino]—2-(2-methy1-1H—indolyl)quinoxaline ylate To a solution of methyl 2—bromo[cyclopropyl(methyl)amino]quinoxaline-6—carboxylate (200 mg, 0.59 mmol) in DME (5 m1) and water (2 ml) was added Pd(PPh3)4 (35 mg, 0.03 mmol), ium carbonate (164 mg, 1.19 mmol), 2-methy1—5-(tetramethyl-1,3,2- dioxaborolan-Z-yl)-]H-indole (305 mg, 1.19 mmol) with stirring for 2 h at 90°C in an oil bath. The resulting solution was diluted with water (150 ml), extracted with dichloromethane(2 x 40 ml) under , dried over anhydrous sodium sulfate, then concentrated vacuum to give a residue, which was purified via silica gel chromatography (1 % - 20% ethyl acetate in petroleum ether) to give methyl 3-[cyclopropyl(methyl)amino]-2—(2-methy1-1H— indoly1)quinoxaline-6—carboxylate as a yellow solid(74.4 mg, 32%).
LC/MS (ES, m/z): [M+H]+ 387.1 1H-NMR (300 MHz, CDSOD) 5 8.46 (d, J: 1.5 Hz, 1H), 8.01 — 8.05 (m, 1H), 7.90 - 7.96 (m, 1H), 7.89 (s, 1H), 7.49 - 7.52 (m, 1H), 7.37 - 7.40 (m, 1H), 6.25 (s, 1H), 4.00 (s, 3H), 3.01 (s, 3H), 2.55 - 2.59 (m, 1H), 2.46 (s, 3H), 0.47 — 0.55 (m, 4H) WO 19046 Step 5. 3-[Cyclopropyl(methyl)amino]—2—(2-methyl—1H—indolyl)quinoxalinecarboxylic acid V o /N /N:©/U\0H\ / N To a solution of methyl 3-[cyclopropyl(methyl)amino](2-methy1—]H—indol—5— yl)quinoxalinecarboxylate (74.7 mg, 0.19 mmol) in methanol (30 ml) was added NaOH (32 mg, 0.80 mmol), water (1 ml) with stirring overnight at room temperature. The resulting solution was extracted ethyl acetate (2 x 50 ml), and adjusted pH to 5 with AcOH. The resulting solution was extracted with ethyl acetate (3 x 30 ml) sodium , dried over anhydrous sulfate, concentrated under vacuum to give a e, which was purified via silica gel chromatography (20% methanol in ethyl acetate) to afford lopropyl(methyl)amino]-2— (2—methy1—JH—indol—5-y1)quinoxaline—6—carboxylic acid as a yellow solid (13.6 mg, 19%).
LC/MS (ES, m/z): [M+H]+ 373.1 1H—NMR (300 MHZ, CD3OD) 8 8.46 (d, J: 1.8 Hz, 1H), 8.02 - 8.06 (m, 1H), 7.89 - 7.95 (m, 2H), 7.49 — 7.53 (m, 1H), 7.38 — 7.40 (m, 1H), 6.25 (s, 1H), 3.00 (s, 3H), 2.57 - 2.60 (m, 1H), 2.47 (s, 3H), 1.32 (m, 1H), 0.50 — 0.55 (m, 4H) EXAMPLE 90 3-[Methyl(propan-Z-yl)amino](1-methyl-1H-pyrazolyl)quinoxalinecarboxylic acid Y O /N /N OH \ N Step 1. Methyl 3-[methyl(propanyl)amino](1—methyl—1H—pyrazolyl)quinoxaline-6— carboxylate Y O /N /N O/ \ N W0 2012/119046 2012/027423 To a solution of methyl 3-[methy1(propan—2-yl)amino] [(trifluoromethane)su1fonyloxy]quinoxalinecarboxylate (200 mg, 0.49 mmol) in ethylene glycol yl ether (3 mL ) was added Pd(PPh3)4 (28 mg, 0.02 mmol), 1-methy1—4— (tetramethyl-l ,3,2-dioxaborolan—2-y1)-]H—pyrazole (205 mg, 0.99 mmol), Na2C03 (130 mg, 1.23 mmol) and water (5 drops). The resulting solution was stirred for 1 h at 90°C under an inert atmosphere of nitrogen, and then concentrated under vacuum to give a e. The residue was purified via silica gel chromatography (1% - 10% ethyl acetate in petroleum ether) to afford methyl 3-[methyl(propany1)amino](1—methy1-]H-pyrazol—4— y1)quinoxa1ine-6—carboxylate as a yellow solid (80 mg, 48%).
LC/MS (ES, m/z): [M+H]+ 340.0 1H-NMR (300 MHz, CDC13) 5 8.52 (d, J = 1.8 Hz, 1H), 8.21(d, J: 6.3 Hz, 2H), 8.07 - 8.11 (m, 1H), 7.94 (d, J: 8.7 Hz, 1H), 4.18 - 4.27 (m, 1H), 4.00 (d, J: 6.6 Hz, 6H), 2.85 (s, 3H), 1.18 (d, J: 6.6 Hz, 6H) Step 2. 3—[Methyl(propan—2-yl)amino]( l -methy1—1H—pyrazol-4—y1)quinoxa1ine carboxylic acid.
Y o /N /N:©)LOH \Nf/j/INN’ To a solution of methyl 3-[methyl(propan—2—yl)amino]—2-(l-methyl-IH—pyrazol y1)quinoxa1inecarboxylate (80 mg, 0.24 mmol) in methanol (20 mL) and CHC13 (5 mL) was added sodium hydroxide (75 mg, 0.72 mmol) and water(1 mL). The resulting solution was stirred for overnight at room temperature and concentrated under vacuum. The residue was dissolved in water (15 mL) and ed to pH 5 with hydrochloric acid (3N). The solids were collected by filtration to afford 3-[methyl(propanyl)amino](l-methyl-IH-pyrazol- 4—yl)quinoxa1ine-6—carboxylic acid as a yellow solid (70 mg, 91%).
LC/MS (ES, m/z): [M+H]+ 326.1 1H-NMR (300 MHz, DMSO) 8 13.10 (s, 1H), 8.41 (s, 1H), 8.25 (d, J: 1.8 Hz, 1H), 8.08 (s, 1H), 7.95 — 7.99 (m, 1H), 7.88 (d, J = 8.7 Hz, 1H), 4.11 - 4.20 (m, 1H), 3.95 (s, 3H), 2.74 (s, 3H), 1.13 (d, J: 6.6 Hz, 6H) EXAMPLE 91 3-[Methyl(propanyl)amino](1-phenyl-1H-pyrazolyl)quinoxalinecarboxylic acid Y O /N /N OH \ N O N’N\ Step 1. Methyl 3-[methyl(propanyl)amino](1H—pyrazolyl)quinoxalinecarboxy1ate Y o HN‘\/j/\[\N/NQAO/N’ To a solution of methyl 2—chloro-3—[methyl(propan-2—yl)amino]quinoxaline—6—carboxylate (170 mg, 0.58 mmol) in 1,4—dioxane (6 ml) was added (1H—pyrazol—4—yl)boronic acid (130 mg, 1.16 mmol), Pd(PPh3)4 (34 mg, 0.029 mmol), K3PO4 (367 mg, 1.74 mmol) and water (5 drops) with stirring for 1 h at 90°C under an inert here of nitrogen in an oil bath. The reaction mixture was concentrated under vacuum to give the residue, which was purified Via silica gel chromatography (1% to 10% ethyl acetate in petroleum ether) to afford methyl 3- [methyl(propan-2—yl)amino]—2-(1H—pyrazoly1)quinoxaline-6—carboxy1ate as a yellow solid (150 mg, 79%).
LC/MS (ES, m/z): [M+H]+ 326.0 1H-NMR (300 MHZ, CDC13) 8 8.53 (d, J = 1.8 Hz, 1H), 8.40 (s, 2H), 8.08 - 8.12 (m, 1H), 7.94 (d, J: 8.4 Hz, 1H), 4.16 — 4.25 (m, 1H), 4.00 (s, 3H), 2.85 (m, 3H), 1.19 (d, J: 6.6 Hz, Step 2. Methyl 3-[methyl(propanyl)amin0](1-pheny1-IH—pyrazol-4—y1)quinoxa1ine carboxylate Y O /N / To a on of methyl 3-[methyl(propany1)amino](1H—pyrazolyl)quinoxaline carboxylate (150 mg, 0.46 mmol) in dioxane (10 mL) was added phenylboronic acid (112 mg, 0.92 mmol), Cu(OAc)2 (123 mg, 0.68 mmol), pyridine (31 mg, 0.39 mmol) and Et3N (310 mg,2.3 mmol). The resulting solution was stirred for 36 h at room temperature and concentrated under vacuum. The residue was purified via silica gel tography (1% to % ethyl acetate in petroleum ether) to afford methyl 3-[methyl(propanyl)amino](l- phenyl-JH—pyrazo1—4-y1)quinoxa1inecarboxylate as a yellow solid (80 mg, 43%).
LC/MS (ES, m/z): [M+H]+ 402.0 1H-NMR (300 MHz, CDC13) 6 8.77 (s, 1H), 8.55 (d, J: 1.8 Hz, 1H), 8.45 (s, 1H), 8.10 - 8.13 (m, 1H), 7.97 (d, J: 8.7 Hz, 1H), 7.82 (d, J: 7.8 Hz, 2H), 7.50 - 7.56 (m, 2H), 7.34 - 7.40 (m, 1H), 4.22 - 4.31(m, 1H), 4.00 (s, 3H), 2.90 (s, 3H), 1.22 (d, J: 6.6 Hz, 6H) Step 3. 3-[Methyl(propany1)amino](1-pheny1-JH-pyrazoly1)quinoxaline carboxylic acid Y O /N xNflkOH To a solution of methyl 3-[methyl(propan—2—yl)amino]-2—(l—phenyl—JH—pyrazol—4— yl)quinoxalinecarboxylate (80 mg, 0.20 mmol) in methanol (25 m1) and chloroform (5 ml) was added sodium hydroxide (24 mg, 0.60 mmol) with ng ght at room temperature. The reaction mixture was concentrated under vacuum, dissolved in water (15 ml), and the pH ed to 5 with HCl (3N) to give the precipitate, which was collected by filtration to afford 3—[methyl(propan-2—yl)amino](1-pheny1-1H—pyrazolyl)quinoxaline— 6—carboxylic acid (56 mg, 73%).
LC/MS (ES, m/z): [M+H]+ 388.1 1H-NMR (300 MHz, CDC13) 6 9.11 (s, 1H), 8.37 (s, 1H), 8.28 (d, J: 1.8 Hz, 1H), 7.92 - 8.03 (m, 4H), 7.53 — 7.59 (t, J: 7.8 Hz, 2H), 7.36 - 7.41 (t, J: 7.5 Hz, 1H), 4.15 - 4.24 (m, 1H), 2.82 (s, 3H), 1.14 (d, J: 6.6 Hz, 6H) W0 2012/119046 EXAMPLE 92 (1H-indazolyl)(2-methyl(pyridiny1)piperazinyl)quinoxaline ylic acid Step 1. (S)—tert—Butyl 2—methy1(pyridinyl)piperazine-l—carboxylate To a solution of tert-butyl (2S)-2—methy1piperazine-1—carboxylate (8 g, 39.94 mmol) in DMSO (25 ml) was added 2-bromopyridine (6.594 g, 41.74 mmol), and DIEA (15.48 g, 119.78 mmol). After ng 2 days at 120°C, the resulting solution was quenched by the addition of DCM (200 ml), washed with water (3 x 300 m1), dried over anhydrous magnesium sulfate and concentrated under reduced pressure to afford a residue, which was purified via silica gel chromatography (3% ethyl acetate in petroleum ether) to afford (S)-tert- butyl 2-methyl—4—(pyridin—2—yl)piperazine—l—carboxylate as a red oil (5.2 g, 47%).
LC/MS (ES, m/z): [M+H]+ 278.0 1H-NMR (300 MHz, CDC13) 6 8.18 - 8.20 (t, J = 1.8 Hz, 1H), 7.46 - 7.52 (m, 1H), 6.60 - 6.64 (m, 2H), 4.33 - 4.35 (m, 1H), 4.08 - 4.15 (m, 1H), 3.91 - 4.00 (m, 2H), 3.19 - 3.31 (m, 2H), 2.92 - 3.01 (m, 1H), 1.50 (s, 9H), 1.27 — 1.30 (t, J: 4.5 Hz, 3H) Step 2. (S)—3-Methy1(pyridiny1)piperazine To a solution of (S)—tert—butyl 2-methy1—4-(pyridin-2—yl)piperazine-l—carboxylate (5.2 g, 18.75 mmol,) in dichloromethane (30 ml) was added trifluoroacetic acid (5 ml). After stirring 2012/027423 overnight at room temperature, the pH was adjusted to 8 with an aqueous sodium carbonate solution, ted with dichloromethane (3 x 150 m1), dried over anhydrous magnesium sulfate and concentrated under vacuum to afford (S)methyl—1—(pyridinyl)piperazine as yellow oil (3.1 g, 93%).
LC/MS (ES, m/z): [M+H]+ 178.0 Step 3. thy1 ethy1—4-(pyridinyl)piperazin—l—yl)—2—oxo—l,2- dihydroquinoxaline—6—carboxylate 61\N N o o N To a solution of (S)methy1-1—(pyridinyl)piperazine (748 mg, 4.22 mmol) in NMP (5 ml), was added methyl 3-chlorooxo-1,2-dihydroquinoxa1inecarboxy1ate (1 g, 4.19 mmol). After stirring 1h at 140°C, the resulting solution was quenched by the addition of water (100 m1) and filtered to give (S)-methy1 3—(2-methy1(pyridin-2—y1)piperazin-l—yl)—2— oxo-1,2-dihydroquinoxalinecarboxylate as a yellow solid (1.07 g, 67%).
LC/MS (ES, m/z): [M+H]+ 380 1H-NMR (300 MHz, CDC13) 6 9.86 (s, 1H), 8.24 (d, J = 1.2 Hz, 2H), 7.87 - 7.91 (m, 1H), 7.51 - 7.56 (m, 1H), 7.08 (d, J: 8.4 Hz, 2H), 6.64 - 6.70 (t, J = 8.7 Hz, 2H), 5.40 (s, 1H), 4.89 — 4.50 (m, 1H), 4.15 — 4.25 (m, 1H), 4.07 - 4.14 (m, 1H), 3.96 (s, 3H), 3.63 - 3.72 (m, 1H), 3.45 - 3.50 (m, 1H), 3.20 — 3.25 (m, 1H), 1.41 (d, J: 6.6 Hz, 3H) Step 4. (S)-Methy1 3-(2-methy1(pyridinyl)piperaziny1) (trifluoromethylsulfonyloxy)quinoxalinecarboxylate N Ng-‘ 0 “EMTfO\N To a solution of (S)-methy1 3-(2-methyl(pyridin—2—y1)piperaziny1)oxo-1,2- dihydroquinoxaline-6—carboxy1ate (800 mg, 2.11 mmol) in romethane (20 m1) under an inert atmosphere of nitrogen, was added TEA (958 mg, 9.47 mmol) followed by addition of TfZO (1.19 g, 4.22 mmol) dropwise at —60°C. After stirring 5 min at this temperature, the reaction was quenched by the addition of water (100 ml), extracted with dichloromethane (2 x 30 m1), dried over anhydrous ium sulfate and concentrated under vacuum to give a residue, which was purified via silica gel tography (2% ethyl acetate in petroleum ether) to afford (S)—methy1 3-(2—methy1—4—(pyridin—2-yl)piperazinyl)—2- (trifluoromethylsulfonyloxy)quinoxaline-6—carboxy1ate as red oil (0.9 g, 83.4%).
Step 5. (S)-Methyl tert—butoxycarbonyl)-IH—indazol-S-y1)(2—methyl(pyridin-2— y1)piperaziny1)quinoxaline-6—carboxylate \N N/fi‘“ 0 RN /Nj©)%/ / N To a solution of (S)-methyl 3-(2-methyl(pyridinyl)piperazinyl)-2— (trifluoromethylsulfonyloxy)quinoxalinecarboxylate (240 mg, 0.38 mmol) in ethylene glycol dimethyl ether (20 ml) was added Pd(PPh3)4 (27 mg, 0.02 mmol), sodium ate (74.3 mg, 0.69 mmol) in water(6 ml), and tert-butyl 5—(tetramethyl-1,3,2-dioxaborolanyl)- IH—indazole—l—carboxylate (300 mg, 0.87 mmol). After stirring 90 minutes at 90°C in an oil bath, the reaction was then quenched by the addition of water (200 ml), extracted with dichloromethane (3 x 30 ml), dried over anhydrous magnesium sulfate and concentrated under vacuum to afford a residue, which was ed Via silica gel chromatography (20% ethyl acetate in petroleum ether) to afford (S)-methy1 2-(1-(tert-butoxycarbonyl)-1H—indazol- -y1)-3—(2—methyl(pyridin—2-yl)piperaziny1)quinoxalinecarboxylate as a yellow solid (134 mg, 60%).
LC/MS (ES, m/z): [M+H]+ 580 1H-NMR (300 MHz, CDC13) 6 8.59 (d, J = 1.5 Hz, 1H), 8.49 (s, 1H), 8.19 - 8.29 (m, 3H), 8.14 - 8.18 (m, 2H), 8.03 (d, J = 8.7 Hz, 1H), 7.50 - 7.51 (m, 1H), 6.63 - 6.66 (m, 2H), 4.13 - 4.18 (t, J: 7.2 Hz, 2H), 4.06 (s, 3H), 3.78 - 3.85 (m, 1H), 3.61 - 3. 70 (m, 1H), 3.40 - 3.55 (m, 1H), 3.10 — 3.35 (m, 2H), 1.78 (s, 9H), l.21(d, J: 6.3 Hz, 3H) Step 6. (S)-Methyl 2-(1H—indazol—S-y1)(2-methy1—4—(pyridiny1)piperazin yl)quinoxalinecarboxy1ate To a solution of (S)-methy1 2-(1-(tert-butoxycarbonyl)-1H—indazol-S-yl)-3—(2—methy1—4— (pyridin—2—y1)piperazinyl)quinoxa1ine—6-carboxylate (112 mg, 0.19 mmol) in dichloromethane (20 ml), was added trifluoroacetic acid (2 ml). After stirring 100 min at room temperature, the pH was adjusted to 8 with saturated sodium onate, ted with dichloromethane (3x20 mL), dried over anhydrous magnesium sulfate and concentrated under vacuum to afford a residue, which was purified via silica gel chromatography (30% petroleum ether in ethyl acetate) to afford (S)-methy1 2-(1H—indazolyl)(2-methy1 inyl)piperaziny1)quinoxa1ine—6-carboxy1ate as a yellow solid (78 mg, 84%).
LC/MS (ES, m/z): [M+H]+ 480.1 1H-NMR (300 MHZ, CDC13) 5 8.58 (d, J = 1.5 Hz, 1H), 8.53 (s, 1H), 8.13 - 8.19 (m, 3H), 8.03 (d, J = 8.7 Hz, 1H), 7.63 (d, J: 8.1 Hz, 1H), 7.45 - 7.60 (m, 1H), 6.66 (d, J: 6.0 Hz, 2H), 4.20 (s, 1H), 4.08 (s, 1H), 4.02 (s, 3H), 3.80 - 3.85 (m, 1H), 3.65 - 3.69 (m, 1H), 3.43 - 3.51 (m, 1H), 3.19 — 3.32 (m, 2H), 1.22 — 1.28 (m, 3H) Step 7. (S)(1H—Indazol—S-yl)-3—(2—methy1-4—(pyridin—2—y1)piperazin—1—yl)quinoxa1ine carboxylic acid To a solution of (S)—methy1 2-(1H—indazoly1)—3-(2-methyl(pyridin-2—y1)piperazin—1— yl)quinoxa1ine-6—carboxy1ate (47 mg, 0.10 mmol) in methanol (15 ml) was added NaOH (15.6 mg, 0.39 mmol) and water(l mL). After stirring 6 h at room temperature, the reaction mixture was concentrated under reduced pressure to afford a residue, which was dissolved in water (10 ml), adjusted to pH 6 with HCl (3N). The solids were ed to give (S)-2—(1H— indazoly1)(2—methyl-4—(pyridin—Z—yl)piperazin-l-yl)quinoxalinecarboxylic acid as a yellow solid (40 mg, 88%).
LC/MS (ES, m/z): [M+H]+ 466.2 1H-NMR (300 MHz, CDgOD) 8 8.52 (d, J: 1.8 Hz, 2H), 8.23 (s, 1H), 7.87 - 8.17 (m, 5H), 7.74 (d, J: 8.7 Hz, 1H), 7.21 (d, J: 9.0 Hz, 1H), 6.89 - 6.93 (t, J: 6.3 Hz, 1H), 4.29 - 4.32 (m, 1H), 3.97 - 4.01 (m, 1H), 3.73 - 3.86 (m, 2H), 3.34 - 3.59 (m, 3H), 1.21 (d, J: 6.6 Hz, EXAMPLE 93 (S)Hydroxy(1H-indazolyl)(2-methylpyrrolidin-l-yl)quinoxalinecarboxylic acid Step 1. thyl 2-(1—(tert—butoxycarbonyl)-IH—indazolyl)methoxy(2- methylpyrrolidin— 1 —yl)quinoxaline-6—carboxylate 300’ To a solution of methyl oxy—3-[(2S)methylpyrrolidin—1-yl] [(trifluoromethane)sulfonyloxy]quinoxalinecarboxylate (359 mg, 0.80 mmol) in DME (4 ml) and water (1 ml) was added tert-butyl 5-(tetramethyl-1 ,3,2-dioxaborolan—2—yl)-JH- indazole—l—carboxylate (275 mg, 0.80 mmol), sodium carbonate (200 mg, 1.87 mmol) and Pd(PPh3)4 (43 mg, 0.04 mmol) under nitrogen atmosphere. After ng 30 min at 90°C, the reaction mixture was dissolved in water (100 ml), extracted with romethane (3 x 30 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure to afford a residue, which was purified via silica gel chromatography (2% ethyl acetate in petroleum ether) to afford (S)—methyl 2—(1-(tert-butoxycarbonyl)-IH-indazol—S-yl)—7- methoxy—3—(2—methylpyrrolidin—1-yl)quinoxaline-6—carboxylate as a light yellow solid (310 mg, crude).
W0 2012/119046 LC/MS (ES, m/z): [M+H]+ 518.0 Step 2. (S)-Methy1 2—(1H—indazol—5—y1)—7-methoxy(2-methylpyrrolidin—l—yl)quinoxaline carboxylate o ° N /Nflay \ / N\/ N O To a solution of (S)—methy1 2-(l-(tert—butoxycarbony])—]H-indazol—5—yl)—7-methoxy(2- methylpyrrolidin-l-yl)quinoxaline~6-carboxylate (310 mg, crude) in dichloromethane (32 ml) was added roacetic acid (8 ml). After stirring overnight at room temperature, the pH value was adjusted to 7 with aqueous sodium bicarbonate and extracted with dichloromethane (2 x 25 ml). The organic layers were combined, dried over anhydrous magnesium sulfate and concentrated under vacuum to give a residue, which was purified Via silica gel chromatography (10% ethyl acetate in petroleum ether) to give (S)-methyl 2-(1H—indazol—5- yl)methoxy(2-methylpyrrolidin—1-yl)quinoxa1inecarboxylate (240 mg) as yellow solid.
LC/MS (ES, m/z): [M+H]+ 418.1 1H—NMR (300 MHZ, CDC13) 5 8.28 (s, 1H), 8.20 - 8.22 (m, 2H), 7.87 - 7.90 (m, 1H), 7.60 (d, J = 8.7 Hz, 1H), 7.43 (s, 1H), 4.28 — 4.39 (m, 1 H), 4.00 (s, 6H), 3.05 - 3.15 (m, 1H), 2.89 - 2.96 (m, 1H), 2.10 — 2.20 (m, 1H), 1.59 - 1.76 (m, 3H), 1.48 (d, J: 6.9 Hz, 3H) Step 3. (S)-Methy1 7—hydroxy—2—(1H—indazol—S—yl)—3—(2—methylpyrrolidin—1-yl)quinoxaline carboxylate C ° N /N O/ N" OH To a solution of (S)-methyl indazol-S-yl)—7—methoxy—3—(2-methylpyrrolidin-l- y1)quinoxaline-6—carboxylate (208 mg, 0.50 mmol) in dichloromethane (20 ml) was added BBr3 (0.37 g, 0.75 mmol) at -60°C. The resulting solution was stirred for 0.5 h at -60°C. The reaction was then quenched by the addition of ice (200 m1), extracted with dichloromethane (4X 50 ml), and the organic layers combined, dried over anhydrous ium e, and concentrated under vacuum to give the residue, which was purified via silica gel chromatography (10% ethyl acetate in petroleum ether) to afford (S)—methyl 7- hydroxy(1H—indazol-S—yl)-3—(2—methy1pyrrolidinyl)quinoxalinecarboxy1ate as a yellow solid (180 mg, 90%).
LC/MS (ES, m/z): [M+H]+ 404.0 1H-NMR (300 MHz, CDC13) 810.46 (s, 1H), 8.43 (s, 1H), 8.25 (d, J = 0.6 Hz, 1H), 8.20 (s, 1H), 7.90 - 7.94 (m 1H), 7.60 (d, J: 8.7 Hz, 1H), 7.48 (s, 1H), 4.26 - 4.33 (m, 1H), 4.00 (s, 3H), 3.04 - 3.13 (m, 1H), 2.89 - 2.96 (m, 1H), 2.14 (d, J: 6.9 Hz, 1H), 1.50 - 1.80 (m, 3H), 1.38 (d, J: 6.0 Hz, 3H) Step 4. (S)Hydroxy(1H—indazol-S-y1)(2-methylpyrrolidinyl)quinoxaline ylic acid To a solution of (S)—methyl 7—hydroxy—2—(1H—indazol-S-yl)(2—methy1pyrrolidin- 1— y1)quinoxaline-6—carboxylate (120 mg, 0.30 mmol) in ol (10 ml) was added NaOH (48 mg, 1.27 mmol) and water (1 ml). The resulting solution was stirred overnight at room temperature and concentrated under vacuum. The e was dissolved in water (15 ml) and adjusted to pH 5 with hydrochloric acid (IN). The solids were collected by filtration to afford (S)—7—hydroxy( 1H-indazoly1)-3 -(2-methylpyrrolidin— 1 -y1)quinoxalinecarboxy1ic acid as a yellow solid (65.6 mg, 56%).
LC/MS (ES, m/z): [M+H]+ 390.1 lH-NMR (300 MHz, DMSO) 8 13.24 (s, 1H), 8.21 (s, 1H), 8.16 (d, J: 3.3 Hz, 1H), 7.77 - 7.80 (m, 1H), 7.64 (d, J: 8.7 Hz,lH), 7.13 (s, 1H), 4.12- 4.18 (m, 1H), 2.87 - 3.01 (m, 1H), 2.72 — 2.84 (m, 1H), 2.01 - 2.18 (m, 1H), 1.69 - 1.80 (m, 1H), 1.47- 1.57 (m, 2H), 1.30 (s, 3H) EXAMPLE 94 Benzo[d][1,2,3]triazolyl)(isopropyl(methyl)amin0)quinoxaline—6-carboxylic acid Y 0 I NfiOH .N N/ Step 1. 2—Nitro—4—(4,4,5,5—tetramethyl—1,3,2—dioxaborolan-2—yl)aniline OZN Bco9? WU To a solution of 4—bromonitrobenzenamine (4 g, 18.43 mmol) in 1,4-dioxane (100 mL) was added KOAc (5.4 g, 55.02 mmol), Pd(dppf)C12 (405 mg, 0.55 mmol), dppf (307 mg, 0.55 mmol) and 4,4,4‘,4‘,5,5,5‘,5'-octamethyl-2,2'-bi( 1,3,2-dioxaborolane (5.15 g, 20.28 mmol). The resulting on was stirred overnight at 85°C. Then the reaction was quenched by the addition of water (200 mL), extracted with ethyl acetate (3 x 80 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum to give a residue, which was purified via silica gel chromatography (petroleum ether) to afford 2—nitro(4,4,5,5— tetramethyl-1,3,2-dioxaborolan-2—yl)aniline as a yellow solid (4.2 g, 86%). 1H—NMR (300 MHz, CDC13) 8 8.60 (d, J = 0.9 Hz, 1H), 7.72 - 7.75 (m, 1H), 6.79 (d, J = 8.4 Hz, 1H), 6.24 (s, 2H), 1.35 (s, 12H) Step 2. Methyl 2-(4-aminonitrophenyl)(isopropyl(methyl)amino)quinoxaline carboxylate Y o /N Nfio/ To a on of methyl 3-(isopropyl(methy1)amino)—2- (trifluoromethylsulfonyloxy)quinoxalinecarboxylate (1.0 g, 2.46 mmol) in DME (10 mL) was added 2—nitro(4,4,5,5-tetramethyl-l,3,2-dioxaborolan—2—yl)aniline (0.97 g, 3.69 mmol), 3)4 (90 mg, 0.12 mmol), Na2C03 (781 mg, 7.38 mmol) and water (2 mL) with stirring for 40 minutes at 90°C under an inert atmosphere of nitrogen in an oil bath. The reaction e was concentrated under vacuum to give the e, which was purified Via silica gel tography (1% to 5% ethyl acetate in eum ether) to afford methyl 2-(4— aminonitrophenyl)—3—(isopropy1(methyl)amino)quinoxaline—6—carboxylate as a yellow solid (900 mg, 93%).
LC/MS (ES, m/z): [M+H]+396.0 1H-NMR (300 MHz, DMSO) 8 8.89 (d, J: 1.8 Hz, 1H), 8.54 (d, J: 1.8 Hz, 1H), 8.06 - 8.14 (m, 2H), 7.96 (d, J = 8.7 Hz, 1H), 6.90 - 6.98 (m, 1H), 6.32 (s, 2H), 4.23 — 4.32 (m, 1H), 4.00 (s, 3H), 2.82 (s, 3H), 1.15 (d, J = 6.6 Hz, 6H) Step 3. Methyl 2-(3,4—diaminophenyl)—3—(isopropyl(methyl)amino)quinoxaline—6-carboxy1ate Y O /N N\ O/ H2NHZNDIN/ To a solution of methyl 2-(4-amino—3-nitrophenyl)(isopropyl(methy1)amino)quinoxaline— oxylate (900 mg, 2.28 mmol) in methanol (40 mL) was added iron (1.28 g, 22.8 mmol) and NH4C1 (1.81 g, 34.2 mmol). After stirring for 6 h at 60°C, the solids were filtered out.
The filtrate was concentrated under vacuum to give a residue which was dissolved in water (200 mL), extracted with dichloromethane (3 x 50 mL), dried over anhydrous sodium sulfate and concentrated under vacuum to afford methyl 2-(3,4-diaminopheny1)-3— (isopropyl(methyl)amino)quinoxalinecarboxylate as yellow solid (635 mg, crude).
LC/MS (ES, m/z): [M+H] + 366.0 Step 4. Methyl 2—(lH—benzo[d][1,2,3]t:riazolyl)(isopropyl(methy1)amino)quinoxaline carboxylate Y O N / N: DIN To a solution of methyl 2-(3,4-diaminophenyl)(isopropyl(methy1)amino)quinoxaline—6— carboxylate (635 mg, crude) in HCl (IN, 150 mL) was added sodium nitrite (132 mg, 1.91 mmol) in water (1 mL) at 0°C. After stirring for 15 min at 0°C, the reaction mixture was extracted with dichloromethane (3 x 50 mL), dried over anhydrous sodium sulfate and concentrated under vacuum to give a residue, which was purified via silica gel chromatography (3% methanol in dichloromethane) to afford methyl 2-(1H- WO 19046 benzo[d][1,2,3]triazolyl)-3—(isopropyl(methyl)amino)quinoxalinecarboxylate as a yellow solid (140 mg).
LC/MS (ES, m/z): [M+H]+377.1 1H-NMR (300 MHz, DMSO) 8 8.40 (s, 1H), 8.31 (d, J: 1.2 Hz, 1H), 7.94 - 8.03 (m, 4H), 4.16 - 4.25 (m, 1H), 3.94 (s, 3H), 2.67 (s, 3H), 1.02 (d, J: 6.6 Hz, 6H) Step 5. 2-(1H-Benzo[d][1,2,3]triazolyl)(isopropy1(methyl)amino)quinoxaline carboxylic acid Y o /N N0}OH N\,NDIN/ To a solution of methyl 2—(1H—benzo[d][1,2,3]triazolyl)-3— (isopropyl(methy1)amino)quinoxaline-6—Carboxylate (140 mg, 0.37 mmol) in methanol (25 mL) and water (5 mL) was added sodium ide (45 mg, 1.11 mmol) with stirring for overnight at room temperature. The reaction mixture was concentrated under vacuum, dissolved in water (20 mL), and adjusted to pH 5 with HCl (3N) to give the precipitate, which was collected by filtration to afford benzo[d][1,2,3]triazolyl)—3- (isopropyl(methyl)amino)quinoxaline—6-carboxylic acid as a yellow solid (110 mg, 82%).
LC/MS (ES, m/z): [M+H]+ 363.1 1H-NMR (300 MHz, CD3OD) 8 8.46 (d, J = 1.5 Hz, 2H), 7.95 - 8.08 (m, 4H), 4.19 - 4.28 (m, 1H), 2.79 (s, 3H), 1.08 (d, J: 6.6 Hz, 6H) EXAMPLE 95 3-(Isopropyl(methyl)amino)(l-methyl-IH-benzold][1,2,3]triazolyl)quinoxaline carboxylic acid Step 1. 4-Bromo—N—methyl—2-nitroaniline 02N Br \N: : To a solution of 4-bromo-l-fluoronitrobenzene (6 g, 27.27 mmol) in dichloromethane (100 ml) was added potassium carbonate (7.5 g, 54.27 mmol). This was followed by the on of CH3NH2 (20 ml, 33% aqueous), which was added dropwise with stirring at room temperature. The resulting solution was stirred for 2 h at room temperature, extracted with dichloromethane (2 x 200 ml), and the organic layers combined and concentrated under vacuum to afford 4-bromo-N—methylnitroaniline as a red solid (6.1 g, 97%).
LC/MS (ES, m/z): [M+H]+ 231.1 1H—NMR (300 MHz, CDC13) 6 8.34 (d, J = 2.4 Hz, 1H), 8.05 (s, 1H), 7.47 - 7.56 (m, 1H), 6.79 (d, J: 3.3 Hz, 1H), 3.03 (d, J: 8.1 Hz, 3H) Step 2. 4-Bromo-N1-methy1benzene-1 ,2-diamine HZN: : ,Br To a solution of 4-bromo-N-methyl-2—nitroaniline (6 g, 25.97 mmol) in ethanol (100 ml) was added SnC12'2H20 (29 g, 128.52 mmol). The resulting solution was stirred for 3 h at 70°C, adjusted to pH 8 with potassium hydroxide (4M), extracted with ethyl acetate (2 x 200 ml), and the c layers combined and trated under vacuum to afford 4-bromo-N1- methylbenzene-1,2-diamine as a white solid (5 g, 96%).
LC/MS (ES, m/z): [M+H]+ 202.1 1H—NMR (300 MHz, CDClg) 8 6.93 — 6.96 (m, 1H), 6.84 (d, J = 2.1 Hz, 1H), 6.50 (d, J = 8.4 Hz, 1H), 2.85 (s, 3H) Step 3. 5-Bromo—1—methy1—1H—benzo[d][l,2,3]triazole To a solution of 4—bromo-N1-methy1benzene-1,2—diamine (4.2 g, 21 mmol) in hydrochloric acid (2N, 50 ml) was added a solution of NaNOg (1.52 g, 22 mmol) in water (5 ml) at 0°C.
The resulting solution was stirred for 4 h at 0—10°C, ed to pH 8 with potassium hydroxide (3N), extracted with romethane (2 x 200 m1), and the organic layers combined and concentrated under vacuum to give a residue, which was purified via silica gel chromatography (50% dichloromethane in petroleum ether) to afford 5—bromo—1—methyl-1H— d][1,2,3]t1iazole as a red solid (1.5 g , 31%).
LC/MS (ES, m/z): [M+H]+.213.1 1H—NMR (300 MHZ, CDC13) 5 8.24 - 8.25 (m, 1H), 7.60 - 7.63 (m, 1H), 7.42 - 7.46 (m, 1H), 4.32 (d, J = 5.4 Hz, 3H) Step 4. 1-Methy1(4,4,5,5-tetramethyl—l,3,2—dioxaborolan-2—y1)-JH-benzo[d][1,2,3]triazole To a solution of 5-bromomethyl-1H—benzo[d][1,2,3]triazole (600 mg, 2.84 mmol) in dioxane (20 ml) was added Pd(dppflClz (86 mg, 0.12 mmol), AcOK (0.575 g, 5.86 mmol), and 4,4,4',4',5,5,5',5’-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (658 mg, 2.59 mmol) under an N2 atmosphere. The resulting on was stirred for 12 h at 90°C and then trated under vacuum to give a residue, which was purified via silica gel chromatography (2% ethyl acetate in petroleum ether) to afford yl(4,4,5,5—tetramethy1—1,3,2—dioxaborolan—2— y1)-]H—benzo[d][l,2,3]triazole as a white solid (0.56 g, 74%).
LC/MS (ES, m/z): .260.1 1H—NMR (300 MHz, CDC13) 5 8.57 (s, 1H), 7.90 - 7.93 (m, 1H), 7.50 — 7.55 (m, 1H), 4.33 (s, 3H), 1.36 (s, 12H) Step 5. Methyl 3—(isopropy1(methy1)amino)(1-methy1-]H-benzo[d][1,2,3]triazol—5- yl)quinoxaline—6-carboxylate Y O /N N\ o/ To a solution of 1-methy1(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan—2—y1)-1H— benzo[d][1,2,3]triazole (168 mg, 0.65 mmol) in dioxane (10 ml) was added K3PO4 (316 mg, 1.49 mmol), Pd(PPh3)4 (28 mg, 0.02 mmol), and methyl 3-[methyl(propan-2—y1)amino] [(trifluoromethane)su1fonyloxy]quinoxalinecarboxylate (203.5 mg, 0.50 mmol). The resulting solution was stirred for 1 h at 90°C under an N2 atmosphere. The resulting mixture was concentrated under vacuum to give a residue, which was purified via silica gel chromatography (50% dichloromethane in petroleum ether) to afford methylp3- (isopropyl(methyl)amino)( 1 -methy1-]H-benzo[d] [1 ,2,3]triazol-5—yl)quinoxaline—6— carboxylate as a yellow solid (110 mg, 56%).
LC/MS (ES, m/z): [M+H]+ 391.1 2012/027423 1H-NMR (300 MHz, CDC13) 8 8.65 (s, 1H), 8.55 (d, J: 1.8 Hz, 1H), 7.98 — 8.17 (m, 3H), 7.65 (d, J: 8.7 Hz, 1H), 4.39 (s, 3H), 4.24 - 4.28 (m, 1H), 4.01 (s, 3H), 2.76 (s, 3H), 1.08 (d, J = 6.6 Hz, 6H) Step 6. 3-(Isopropyl(methy1)amino)(1-methy1-1H-benzo[d][1,2,3]triazoly1)quinoxa1ine- 6-carboxylic acid Y O ,N N/ To a solution of methyl 3-(isopropyl(methyl)amino)—2-(1-methyl-JH-benzo[d][1,2,3]triazol- —y1)quinoxaline—6-carboxy1ate (110 mg, 0.28 mmol) in methanol (10 ml) was added sodium ide (45 mg, 1.12 mmol) and water (2 ml). The resulting solution was stirred for 2 h at room temperature and concentrated under vacuum, diluted with water (10 ml), and the pH adjusted to 4 with HCl (3N). The solid was collected by filtration to afford 3— (isopropy1(methy1)amino)—2-( 1 -methy1—1H—benzo[d] [ l ,2,3]triazol-5—yl)quinoxa1ine carboxylic acid as a yellow solid (56.2 mg, 53%).
LC/MS (ES, m/z): [M+H]+ 377.1 1H-NMR (300 MHz, DMSO) 813.1 (s, 1H), 8.51 (s, 1H), 8.29 (s, 1H), 7.94 — 8.08 (m, 4H), 4.38 (s, 3H), 4.15 - 4.24 (m, 1H), 2.68 (s, 3H), 1.01 (d, J: 6.6 Hz, 6H) EXAMPLE 96 (S)(1H-Benzo[d][1,2,3]triazolyl)(2-methylpyrrolidinyl)quinoxaline carboxylic acid Step 1. (S)—Methyl 2—(4—aminonitrophenyl)—3-(2-methy1pyrrolidiny1)quinoxa1ine carboxylate To a solution of 2-nitr0—4—(4,4,5,5-tetramethyl-1,3,2-dioxaborolan—2-yl)aniline (1.30 g, 4.92 mmol) in ethylene glycol dimethyl ether (100 mL) was added (S)-methy1 2—chloro(2— methylpyrrolidin-l-yl)quinoxaline—6—carboxy1ate (1.0 g, 3.27 mmol), sodium carbonate (1.05 g, 9.91 mmol), and Pd(dppf)2C12 (0.12 g, 0.17mmol). The resulting solution was stirred for 40 min at 90°C under an N2 here, and then concentrated under vacuum to give a residue, which was purified via silica gel tography (2% to 10% ethyl acetate in petroleum ether) to afford (S)-methyl 2-(4-aminonitropheny])—3-(2-methy1pyrrolidin-1— yl)quinoxa1inecarboxylate as an orange solid (1.0 g, 57%).
LC/MS (ES, m/z): [M+H] +408.0 1H-NMR (300 MHz, CDC13) 6 8.68 (d, J = 2.1 Hz, 1H), 8.50 (d, J = 1.5 Hz, 1H), 7.93 - 7.98 (m, 2H), 6.94 (d, J: 8.7 Hz, 1H), 6.30 (s, 1H), 4.37 - 4.44 (m, 1H), 3.94 (s, 3H), 3.23 - 3.32 (m, 1H), 2.97 - 3.03 (m, 1H), 2.15 - 2.25 (m, 1H), 1.82 - 1.90 (m, 1H), 1.58 - 1.68 (m, 2H), 1.40 (d, J = 6.0 Hz, 3H).
Step 2. (S)-Methy1 2—(3,4-diaminophenyl)—3-(2-methylpyrrolidin-1—y1)quinoxa1ine carboxylate To a solution of thy1 2—(4—aminonitropheny1)(2-methy1pyrrolidin yl)quinoxalinecarboxy1ate (1.0 g, 2.45 mmol) in ol (40 mL) was added Fe (1.38 g, 24.6 mmol) and NH4C1 (1.3 g, 24.30 mmol). After the resulting solution was stirred for 6 h at 60°C, the solids were filtered out. The filtrate was concentrated under vacuum and dissolved in water (200 mL), extracted with romethane (3 x 80 mL), dried over anhydrous sodium sulfate and concentrated under vacuum to afford (S)-methy1 2-(3,4-diaminopheny1)—3- (2-methy1pyrrolidin—1-yl)quinoxaline-6—carboxylate as yellow solid (970 mg, crude).
LC/MS (ES, m/z): [M+H]+ 378.0 Step 3. (S)-Methyl 2-(lH-benzo[d][1,2,3]triazol-S-yl)—3-(2-methy1pyrrolidin—1- y1)quinoxa1inecarboxy1ate To a solution of (S)-methy1 2-(3,4-diaminopheny1)(2-methy1pyrrolidiny1)quinoxa1ine—6- carboxylate (600 mg, crude) in HCl (60 mL, 2N) was added sodium nitrite (164.7 mg, 2.39 mmol) in water(1 mL) dropwise at 0-5°C. The resulting solution was stirred for 15 min at 0°C, then diluted with water (150 mL), extracted with dichloromethane (3 x 80 mL), dried over anhydrous sodium sulfate and concentrated under vacuum to give a e, which was purified via silica gel chromatography (1.25% methanol in dichloromethane) to afford (S)— methyl 2—(1H—benzo[d][1,2,3]triazol-S-yl)(2—methy1pyrrolidin-1—y1)quinoxaline—6- ylate (130 mg).
LC/MS (ES, m/z): [M+H]+ 389.0 1H—NMR (300 MHz, DMSO) 5 8.29 (d, J: 1.5 Hz, 1H), 7.98 — 8.25 (m, 3H), 7.90 - 7.94 (m, 2H), 7.80 - 7.90 (m, 1H), 4.25 — 4.27 (m, 1H), 3.94 (s, 3H), 2.89 — 2.95 (m, 2H), 2.05 - 2.15 (m, 1H), 1.65 - 1.73 (m, 1H), 1.45 — 1.57 (m, 2H), 1.37 (d, J: 6.0 Hz, 3H) Step 4. (S)(1H-Benzo[d] [1 ,2,3]triazolyl)(2-methy1py1rolidin— 1 —y1)quinoxaline-6— carboxylic acid To a solution of (S)—methy12—(1H—benzo[d][1,2,3]triazol—S—yl)—3—(2—methy1pyrrolidin yl)quinoxa1inecarboxy1ate (130 mg, 0.33 mmol) in methanol (30 mL) was added sodium hydroxide (40.2 mg, 1.00 mmol) and water (1 mL) with stirring for ght at room temperature. The resulting mixture was trated under vacuum and dissolved in water (25 mL), and ed to pH 4 with HCl (3N) to give the precipitate, which was collected by filtration to afford (S)(1H—benzo[d][1,2,3]triazol—5—yl)—3—(2—methy1pyrrolidin y1)quinoxaline—6-Carboxy1ic acid as a yellow solid (90.3 mg, 72%).
LC/MS (ES, m/z): [M+H]+ 375.1 W0 2012/119046 PCT/U32012/027423 lH-NMR (300 MHz, CD30D) 6 8.27 (d, J = 1.5 Hz, 1H), 8.24 (s, 1H), 8.04 (d, J = 8.7 Hz, 1H), 7.90 — 7.98 (m, 2H), 7.83 (d, J = 8.4 Hz, 1H), 4.22 — 4.29 (m, 1H), 2.93 — 2.97 (m, 2H), 2.05 — 2.16 (m, 1H), 1.68 — 1.72 (m, 1H), 1.45 — 1.60 (m, 2H), 1.36 (d, J: 6.0 Hz, 3H) EXAMPLE 97 3-(Benzyl(methyl)amino)(lH-indazol-S-yl)quinoxalinecarboxylic acid Step 1. Methyl 3-(benzyl(methyl)amino)—2-ox0—1,2-dihydroquinoxaline—6—carboxylate Q 0 /N ,NDXO/ To a solution of methyl 3-chloro—2—oxo-1,2—dihydroquinoxaline—6—carboxylate (500 mg, 2.10 mmol) in DMSO (6 mL) was added benzyl(methyl)amine (305 mg, 2.52 mmol), and DIEA (542 mg, 4.19 mmol). The resulting solution was d for 2 h at 85°C, then water (50 mL) was added, causing a precipitate to form which was collected by filtration to afford methyl 3— (benzyl(methyl)amino)—2-oxo-1,2-dihydroquinoxalinecarboxylate as a yellow solid (0.55 g, 81%).
LC/MS (ES, m/z): [M+H]+ 324.0 1H—NMR (300 MHZ, CDC13): 6 10.01 (s, 1 H), 8.23 (d, J: 1.8 Hz, 1 H), 7.81 — 7.84 (m, 1 H), 7.25 - 7.37 (m, 5 H), 6.68 (d, J: 8.1 Hz, 1 H), 5.21 (s, 2 H), 3.95 (s, 3 H), 3.34 (s, 3 H) Step 2. Methyl 3-(benzyl(methyl)amino)-2—(tn'fluoromethylsulfonyloxy)quinoxaline carboxylate W0 2012/119046 To a solution of methyl 3—[benzyl(methyl)amino]-2—oxo-1,2-dihydroquinoxaline carboxylate (200 mg, 0.62 mmol) in dichloromethane (30 mL) was added pyridine (196 mg, 2.48 mmol), followed by TfZO (349 mg, 1.24 mol) at room temperature. The mixture was d overnight at room temperature, then quenched with water (100 mL), extracted with dichloromethane (3 x 20 le), and the c layers ed and dried over anhydrous magnesium sulfate and concentrated under vacuum to afford methyl 3— (benzyl(methyl)amino)(trifluoromethylsulfonyloxy)quinoxa1ine-6~carboxylate as a red solid (300 mg, crude).
Step 3. Methyl 3-(benzyl(methyl)amino)(1—(tert-butoxycarbonyl)—1H—indazol—5— yl)quinoxalinecarboxylate To a solution of methyl 3—(benzyl(methy1)amino)(trifluoromethylsulfonyloxy)quinoxaline- 6—carboxylate (300 mg, crude) in ethylene glycol dimethyl ether (7 mL) was added tert-butyl -(4,4,5,5-tetramethyl-l,3,2-dioxaborolanyl)-IH-indazole-l-carboxylate (181 mg, 0.53 mmol), sodium carbonate (93 mg, 0.88 mmol), and Pd(PPh3)4 (25 mg, 0.02 mmol). The resulting solution was stirred for 1 h at 90°C under an inert atmosphere of nitrogen, quenched with water (100 mL) and extracted with dichloromethane (3 x 50mL), dried over anhydrous magnesium sulfate, and concentrated under vacuum to give a residue, which was purified via silica gel tography (3% ethyl acetate in petroleum ether) to afford methyl 3- (benzyl(methy1)amino)(1-(tert-butoxycarbonyl)-JH-indazol-S-y])quinoxaline ylate as a yellow solid (120 mg).
LC/MS (ES, m/z): [M+H]+ 524.0 Step 4. Methyl 3-(benzyl(methy1)amino)(1H-indazol-S-yl)quinoxaline-6—carboxylate To a on of methyl 3-(benzy1(methyl)amino)—2-(1—(tert—butoxycarbonyl)-JH-indazol noxalinecarboxylate (120 mg, 0.23 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (0.5 mL). The resulting solution was stirred for 2 h at room temperature, adjusted to pH 7 with saturated aqueous sodium bicarbonate, extracted with dichloromethane (3 x 50mL), and the organic layers combined and concentrated under vacuum to give a residue, which was purified via silica gel chromatography (4% ethyl acetate in eum ether) to afford methyl 3-(benzyl(methyl)amino)(lH—indazolyl)quinoxaline-6— carboxylate as a yellow solid (70 mg, 72%).
LC/MS (ES, m/z): [M+H]+ 424.0 1H-NMR (300 MHz, CDC13): 6 8.58 (d, J: 1.2 Hz, 1 H), 8.38 (s, 1 H), 8.18 (s, 1 H), 8.01 - 8.12 (m, 3 H), 7.62 (d, J: 8.7 Hz, 1 H), 7.21 - 7.33 (m, 4 H), 4.60 (s, 2 H), 4.01 (s, 3 H), 2.76 (s, 3 H) Step 5. 3—(Benzyl(methy1)amino)—2—(1H—indazol-S—yl)quinoxaline-6—carboxylic acid To a solution of methyl 3—(benzyl(methyl)amino)(1H-indazolyl)quinoxaline—6— carboxylate (70 mg, 0.17 mmol) in methanol (20 ml) was added sodium hydroxide (33 mg, 0.82 mmol) in water(5 ml). The resulting solution was d overnight at room temperature and then concentrated under vacuum to give a residue, which was dissolved in water (20 ml), and adjusted to pH 4 with HCl (3N). The solids were collected by filtration to afford 3- (benzyl(methyl)amino)—2-(lH—indazolyl)quinoxa1inecarboxylic acid as a yellow solid (64.1 mg, 89%).
LC/MS (ES, m/z): [M+H]+ 410.1 1H-NMR (300 MHz, DMSO): 5 8.47 (d, J: 1.8 Hz, 1 H), 8.36 (s, l H), 8.15 (s, l H), 8.06 - 8.10 (m, 1 H), 7.95 - 7.99 (m, 2 H), 7.68 (d, J: 8.7 Hz, 1 H), 7.18 - 7.30 (m, 5 H), 4.54 (s, 2 H), 2.81 (s, 3 H) W0 2012/119046 EXAMPLE 98 (S)(lH-Indazolyl)(methyl(1-phenylethyl)amino)quinoxalinecarboxy1ic acid Step 1. (S)-Methyl 3-(methyl(1-pheny1ethyl)amino)oxo-1,2—dihydroquinoxaline carboxylate /N /Nfio/ To a solution of methyl 3—chloro—2—oxo—1,2-dihydroquinoxaline-6—carboxylate (300 mg, 1.26 mmol) in DMSO (2 mL) was added DIEA (244 mg, 1.89 mmol), and (S)—N—methyl phenylethanamine (204 mg, 1.51 mmol) with stirring for 3 h at 85°C in an oil bath. The reaction was then quenched by the addition of water (50 mL). The product was precipitated Via the addition of water and collected by filtration to give (S)-methy1 3-(methyl(1— phenylethyl)amino)—2-oxo-1,2—dihydroquinoxalinecarboxylate as a gray solid (323 mg, 76%).
LC/MS (ES, M+H]+ 338.1 1H-NMR (300 MHz, CDgOD) 5 8.09 (d, J: 1.8 Hz, 1H), 7.79 - 7.82 (m, 1H), 7.33 — 7.43 (m, 5H), 7.19 - 7.29 (m, 1H), 6.66 - 6.73 (m, 1H), 3.92 (s, 3H), 2.94 (s, 3H), 1.66 (d, J: 6.9 Hz, Step 2. thyl 3-(methy1(l-phenylethyl)amino) (trifluoromethylsu1fonyloxy)quinoxalinecarboxy1ate Q““‘ 0 /N Nfiko/ TfO N To a solution of (S)-methyl hy1(1-pheny1ethy1)amino)—2—oxo-l,2-dihydroquinoxaline- 6-carboxylate (320 mg, 0.95 mmol) in dichloromethane (30 mL) was added pyridine (313 2012/027423 mg, 3.96 mmol), and szO (559 mg, 1.98 mmol). The resulting solution was stirred ght at room temperature and then concentrated under vacuum to get a residue, which was purified via silica gel chromatography (1% to 5% ethyl acetate in petroleum ether) to give (S)—methy1 3—(methyl(1 -pheny1ethyl)amino)(trifluoromethylsulfonyloxy)quinoxalinecarboxylate as a yellow solid (432 mg, crude).
Step 3. (S)-Methyl 2—(lH—indazol-5—y1)—3—(methyl(1-pheny1ethyl)amino)quinoxaline—6— carboxylate To a solution of (S)-methyl 3-(methy1(1-phenylethyl)amino)—2- (trifluoromethylsu1fonyloxy)quinoxalinecarboxylate (432 mg, crude) in ethylene glycol dimethyl ether (5 mL) was added tert-butyl 5-(4,4,5,5—tetramethyl—1,3,2—dioxaborolanyl)- JH-indazole-l-carboxylate (201 mg, 0.58 mmol), K2C03 (55 mg, 0.40 mmol), Pd(PPh3)4 (392 mg, 0.34 mmol) and water (1.5 mL) with stirring overnight at 90°C in an oil bath. The resulting mixture was concentrated under vacuum, dissolved in water (100 mL), ted with ethyl acetate (3 x 30 mL), dried over anhydrous sodium sulfate and trated under vacuum to give a e, which was purified via silica gel chromatography (10% ethyl acetate in petroleum ether) to afford (S)-methyl 2-(1H—indazol-S-yl)(methyl(1- phenylethyl)amino)quinoxaline—6-carboxylate as a yellow solid (144 mg).
LC/MS (ES, m/z) : [M+H]+ 438.1 1H-NMR (300 MHZ, CD30D) 5 8.43 (d, J = 1.8 Hz, 1H), 8.34 (s, 1H), 8.15 (s, 1H), 7.93 - 8.08 (m, 3H), 7.68 (d, J: 8.7 Hz, 1H), 7.21 - 7.30 (m, 5H), 5.51 - 5.53 (m, 1H), 4.00 (s, 3H), 2.60 (s, 3H), 1.50 (d, J: 6.9 Hz, 3H) Step 4. (S)(lH—Indazolyl)(methyl(1-phenylethyl)amino)quinoxalinecarboxylic acid PCT/U82012/027423 To a solution of (S)-methyl 2—(1H—indazol—5—yl)—3—(methyl(l—phenylethy1)amino)quinoxaline— 6—carboxylate (100 mg, 0.23 mmol) in methanol (20 mL) was added NaOH (37 mg, 0.93 mmol) and water (1 mL) with stirring for 1 day at room temperature. The resulting e was concentrated under vacuum, diluted with water (20 mL), and adjusted to pH 5 with HCl (3N). The product was precipitated from solution via the addition of water and collected by tion to give (S)—2—(lH—indazol—5—yl)(methyl(1-phenylethy1)amino)quinoxaline—6— ylic acid as a yellow 48.9 mg, 51%).
LC/MS (ES, m/z):[M+H]Jr 424.2 1H—NMR (300 MHz, CDgOD) 8 8.40 (d, J = 1.5 Hz, 1H), 8.33 (s, 1H), 8.15 (d, J: 0.6 Hz, 1H), 8.06 - 8.10 (m, 1H), 7.91 - 7.96 (m, 2H), 7.67 - 7.70 (m, 1H), 7.19 - 7.26 (m, 5H), 5.43 - .45 (m, 1H), 2.59 (s, 3H), 1.48 (d, J: 6.9 Hz, 3H) EXAMPLE 99 (S)(2-Methyl-1H-indolyl)(2-methyl(pyridin—Z-yl)piperazinyl)quinoxaline- 6-carb0xylic acid Step 1. (S)-Methyl 2—bromo(2—methyl(pyridinyl)piperaziny1)quinoxa1ine—6- carboxylate \ \“ N " 0 Br N/ To a solution of (S)—methyl 3—(2—methy1(pyridiny1)piperaziny1)-2— (trifluoromethylsulfonyloxy)quinoxaline—6—carboxylate (900 mg, 1.76 mmol) in toluene (25 ml) was added Bu4NBr (0.85 g, 2.64 mmol). The resulting solution was stirred for 2 h at 110°C. Then the mixture was concentrated under vacuum to give a residue, which was purified via silica gel chromatography (2.5% ethyl acetate in petroleum ether) to afford (S)- methyl 2—bromo(2-methy1-4—(pyridin—2—yl)piperazin—l—yl)quinoxalinecarboxylate as a yellow solid (632 mg, 81%).
LC/MS (ES, m/z): [M+H]+ 442.0 Step 2. (S)-Methyl 2-(2-methyl-1H—indol-5—y1)-3—(2-methy1(pyridiny1)piperazin yl)quinoxalinecarboxylate To a solution of (S)-methy1 2-bromo(2-methyl(pyridinyl)piperaziny1)quinoxaline- 6-carboxy1ate (200 mg, 0.45 mmol) in dioxane (7 ml) was added 2-methyl(4,4,5,5- tetramethyl-1,3,2—dioxaborolan-2—yl)-IH-indole (140 mg, 0.54 mmol), K3PO4 (190 mg, 0.90 mmol), and Pd(PPh3)4 (26 mg, 0.02 mmol). The resulting solution was stirred for 2 h at 90°C.
Then the e was concentrated under vacuum, and the residue was purified via silica gel column chromatography (5% ethyl acetate in petroleum ether) to afford thyl 2-(2- —1H—indoly1)-3—(2—methy1—4—(pyridin—Z—yl)piperaziny1)quinoxalinecarboxy1ate as a yellow solid (202 mg, 91%).
LC/MS (ES, m/z): [M+H]+ 493.0 1H—NMR (300 MHz, DMSO) 6 11.19 (s, 1H), 8.32 (t, J: 1.2 Hz, 1H), 8.14 (s, 1H), 8.07 - 8.09 (m, 1H), 7.99 (s, 2H), 7.70 - 7.73 (m, 1H), 7.50 - 7.60 (m, 1H), 7.40 - 7.45 (m, 1H), 6.80 - 6.83 (m, 1H), 6.63 - 6.64 (m, 1H), 6.30 (s, 1H), 3.99 — 4.02 (m, 2H), 3.94 (s, 3H), 3.33 - 3.38 (m, 1H), 2.99 - 3.20 (m, 2H), 3.19 - 3.25 (m, 1H), 2.49 - 2.52 (m, 3H), 1.05 (t, J: 6.6 Hz, 3H) Step 3. (S)-2—(2-Methyl-JH—indol-5—y1)—3—(2—methyl—4—(pyridin-Z-yl)piperazin yl)quinoxalinecarboxy1ic acid To a solution of (S)-methyl 2-(2-methyl-1H—indol—5-yl)(2-methyl(pyridin y1)piperazinyl)quinoxa1ine—6—carboxylate (150 mg, 0.30 mmol) in methanol (20 ml) was added sodium hydroxide (36 mg, 0.90 mmol) and water (1 ml) The resulting solution was d overnight at room temperature and the mixture was concentrated under vacuum 2012/027423 dissolved in water (30 ml), adjusted to pH 5 with hydrochloric acid (3N) to give the precipitate, which was collected by filtration to afford (S)(2-methy1-]H—indoly1)(2— methyl(pyridin-2—yl)piperazin-1—yl)quinoxaline—6-carboxylic acid as a yellow solid (44 mg, 30%).
LC/MS (ES, m/z): [M+H]+ 479.2 1H-NMR (300 MHz, CD3OD) 8 8.48 (d, J = 1.5 Hz, 1H), 8.06 - 8.47 (m, 3H), 7.95 (d, J = 8.7 Hz, 1H), 7.67 - 7.70 (m, 1H), 7.51 - 7.57 (m, 1H), 7.43 - 7.46 (m, 1H), 6.79 - 6.82 (m, 1H), 6.64 - 6.68 (m, 1H), 6.28 (s, 1H), 4.18 - 4.21 (m, 1H), 3.98 - 4.03 (m,1H), 3.70 - 3.75 (m, 2H), 3.31 - 3.34 (m, 1H), 3.12 - 3.23 (m, 2H), 2.48 (s, 3H),1.13 (d, J: 6.6 Hz, 3H) EXAMPLE 100 (S)(S-Fluorobenzofuranyl)(2-methylpiperidin-l-yl)quinoxalinecarboxylic acid Step 1. (S)—Methyl 3 —(2-methylpiperidin— 1 —y1)—2—oxo- 1 ,2—dihydroquinoxaline—6-carboxy1ate Ow“ O N /N:©)ko/ To a solution of methyl 3-chlorooxo-1,2-dihydroquinoxaline—6-carboxylate (150 mg, 0.63 mmol) in DMSO (2 mL) was added (S)—2—methylpiperidine (166 mg, 1.7 mmol) and DIEA (217 mg, 1.7 mmol). The ing solution was stirred for 3 hours at 80°C and then quenched by the addition of water (250 mL), extracted with dichloromethane (3 X 100 mL), dried over anhydrous sodium sulfate, and then trated under vacuum to give a residue, which was purified via silica gel column chromatography (9% ethyl acetate in petroleum ether) to afford thy1 3—(2—methylpiperidin—1-yl)—2-oxo—1,2—dihydroquinoxaline-6—carboxylate as white solid(l65 mg, 87%).
(ES, m/z):[M+H]+ 302.0 1H-NMR (300 MHz, CDC]3)I 8 10.11 (s, 1H), 8.29 (s, 1H), 7.83 — 7.86 (m, 1H), 7.09 (d, J: 8.4 Hz, 1H), 5.39 - 5.41 (m, 1H), 4.86 - 4.91 (m 1H), 3.94 (s, 3H), 3.18 - 3.26 (t, J = 12.6 Hz, 1H), 1.65 - 1.94 (m, 6H), 1.35 (d, J: 6.9 Hz, 3H) W0 2012/119046 Step 2. (S)—Methyl 3-(2-methylpiperidinyl)-2—(trifluoromethylsulfonyloxy)quinoxaline carboxylate N ND/KO/ TfO N To a on of (S)—methyl 3—(2-methylpiperidin—1—yl)—2—oxo—l,2—dihydroquinoxaline carboxylate (165 mg, 0.55 mmol) in dichloromethane (40 mL) was added pyridine (231 mg, 2.92 mmol) followed by the addition of szO (412 mg, 1.46 mmol) dropwise with stirring at 0°C. The resulting solution was stirred overnight at room temperature and then washed with water (3 x 50 mL), dried over ous sodium sulfate and concentrated under vacuum to afford (S)-methyl 3-(2—methylpiperidin—1—yl)—2—(trifluoromethylsulfonyloxy)quinoxaline-6— ylate as red oil (240 mg, crude).
Step 3. (S)-Methyl 2—(5-fluorobenzofuran—2—yl)(2-methylpiperidin- l —y1)quinoxaline ylate N Nfiko/ \ N F 0 To a solution of (S)-methyl 3-(2—methylpiperidin-1—y1)-2— (trifluoromethylsulfonyloxy)quinoxaline—6-carboxylate (240 mg, crude) in dioxane (5 mL) was added 5—fluorobenzofuran—2—ylboronic acid (337 mg, 1.87 mmol), K3PO4 (397 mg, 1.87 mmol), Pd(PPh3)4 (36 mg, 0.03 mmol) and water (5 drops). The resulting solution was stirred for 1 hour at 90°C and then concentrated under vacuum to give a residue, which was purified via silica gel column tography (2% ethyl acetate in petroleum ether) to afford (S)- methyl 2-(5-fluorobenzofuran—2—y1)—3—(2—methy1piperidinyl)quinoxaline—6—carboxylate as a yellow solid (135.0 mg, 59% 2 steps).
(ES, m/z):[M+H]+ 420.1 1H-NMR (300 MHz, CDC13): 8 8.71 (d, J: 1.2 Hz, 1H), 8.12 - 8.21 (m, 2H), 7.91 (s, 1H), 7.60 - 7.65 (m, 1H), 7.36 - 7.40 (m, 1H), 7.13 — 7.19 (m, 1H), 4.21- 4.25 (m, 1H), 4.02 (s, 3H), 3.40 - 3.43 (m, 2H), 1.95 - 2.06 (m, 1H), 1.59 - 1.90 (m, 1H), 1.19 (d, J: 6.6 Hz, 3H) W0 2012/119046 Step 4. (S)(5-Fluorobenzofurany1)(2-methy1piperidinyl)quinoxalinecarboxylic acid N INDXOH \ N F 0 To a solution of (S)—methyl 2-(5-fluorobenzofurany1)—3-(2—methy1piperidin yl)quinoxaline—6—carboxy1ate (120 mg, 0.29 mmol) in MeOH (20 mL) was added sodium hydroxide (46 mg, 1.15 mmol) and water (3 mL). The resulting on was stirred overnight at room ature and concentrated under vacuum. The residue was dissolved in water (10 mL) and adjusted to pH 5 with hloric acid (IN). The solids were collected by filtration to afford (S)—2—(5-fluorobenzofuran—2—y1)—3-(2-methylpiperidinyl)quinoxalinecarboxylic acid as a yellow solid (113 mg, 97%).
(ES, m/z):[M+H]+ 406.0 1H-NMR (300 MHz, DMSO + D20) 5 8.30 (s, 1H), 8.01 - 8.08 (m, 2H), 7.93 (s, 1H), 7.76 - 7.81 (m, 1H), 7.63 - 7.67 (m, 1H), 7.26 - 7.33 (m, 1H), 4.04 — 4.06 (m,1H), 3.22 - 3.36 (m, 2H), 1.80 — 1.90 (m, 1H), 1.49 -1.75(m,5H),1.08(d,J= 6.6 Hz, 3H) EXAMPLE 101 (R)(4-Fluorophenyl)(2-(trifluoromethyl)pyrrolidinyl)quinoxalinecarboxylic acid Step 1. (R)-Methyl 2-(4-fluoropheny1)(2—(trifluoromethyl)pyrrolidinyl)quinoxaline-6— carboxylate 2012/027423 To a solution of methyl 3-chloro(4-fluorophenyl)quinoxaline—6—carboxylate (270 mg, 0.85 mmol) in DMSO (1 mL) was added (R)(trifluoromethyl)pyrrolidine (275 mg, 1.99 mmol).
The resulting solution was stirred 7 days at 130°C and then evaporated in vacuo. The residue was diluted with eum ether (15 mL) and filtered. The filtrate was concentrated and purified by a silica gel column chromatography with 2 % - 10 % ethyl acetate in petroleum ether to afford (R)-methyl 2-(4-fluorophenyl)—3—(2—(trifluoromethyl)pyrrolidin yl)quinoxa1inecarboxylate as a yellow solid (35 mg, crude).
LC/MS (ES, m/z):[M+H]+ 420.0 Step 2. (R)(4-Fluorophenyl)(2-(tfifluoromethyl)pyrrolidiny1)quinoxaline carboxylic acid To a solution of (R)—methyl 2-(4-fluorophenyl)(2-(trifluoromethyl)pyrrolidin yl)quinoxaline-6—carboxylate (35 mg, crude) in methanol (15 mL) was added a on of sodium hydroxide (10 mg, 0.25 mmol) in water (1 mL). The resulting solution was stirred ght at room temperature and then concentrated in vacuo. The residue was dissolved in water (5 mL) and adjusted to pH 6 with aqueous hydrochloric acid (IN). The product was collected by filtration and purified by Prep-HPLC under the following ions: Column, silica gel 19mm* 100mm; mobile phase, A:B=0.05% TFA:ACN B%= 35%~100% 0~8mins; or, Sum. 18.2 mg. (R)(4-Fluorophenyl)(2-(trifluoromethyl)pyrrolidin yl)quinoxalinecarboxylic acid was obtained as a yellow solid (2 steps yield = 5.3 %).
LC/MS (ES, m/z):[M+H]+ 406.1 1H—NMR (300 MHz, CD3OD) 8 8.48 (d, J: 1.5 Hz, 1H), 8.11 — 8.14 (m, 1H), 8.00 (d, J: 8.7 Hz, 1H), 7.29 - 7.35 (t, J: 8.7 Hz, 2H), 5.73 - 5.81 (m, 1H), 3.00 — 3.17 (m, 2H), 2.26 - 2.34 (m, 1H), 2.05 - 2.17 (m, 1H), 1.89 - 1.95 (m, 1H), 1.71 — 1.80 (m, 1H) EXAMPLE 102 luorophenyl)(methyl(tetrahydro-2H-pyranyl)amino)quinoxaline carboxylic acid g) 0 OI“| \ Step 1. Methyl 2—(4-fluorophenyl)-3~(tetrahydro-2H—pyran—4-ylamino)quinoxaline-6— carboxylate Q 0 OI”/N: : JKO/\ | F To a solution of methyl 3-chloro(4-fluorophenyl)quinoxaline—6—carboxylate (200.0 mg, 0.63 mmol) in DMSO (1.5 mL) was added tetrahydro-2H—pyran-4—amine (127.8 mg, 1.26 mmol), DIEA (163.3 mg, 1.27 mmol) under nitrogen atmosphere. After stirring overnight at 100°C, the reaction mixture was dissolved in dichloromethane (30 mL), washed with water (3 x 10 mL), dried over ous magnesium sulfate and trated under reduced pressure to afford a residue, which was purified by a silica gel column with 0.01% - 0.1% ethyl acetate in petroleum ether to afford methyl 2-(4-fluorophenyl)—3—(tetrahydro—2H—pyran-4— ylamino)quinoxalinecarboxylate as a light yellow solid (180.0 mg, 75%).
(ES, m/z): [M+H]+ 382.0 1H—NMR (300 MHz, DMSO) 5 8.17 (d, J: 1.2 Hz, 1H), 7.82 - 7.89 (m, 4H), 7.37 - 7.43 (m, 2H), 6.65 (d, J: 7.5 Hz, 1H),4.24 - 4.34 (m, 1H), 3.86 - 3.91 (m, 5H), 3.42 - 3.49 (m, 2H), 1.86 - 1.92 (m, 2H), 1.57 - 1.68 (m, 2H) W0 2012/119046 PCT/U82012/027423 Step 2. Methyl 2-(4—fluoropheny1)(methyl(tetrahydro—2H—pyran—4—yl)amino)quinoxaline carboxylate Q 0 /N /Nfio/ (DIN1 \ To a solution of ethyl 2-(4-fluoropheny1)(tetrahydro-2H-pyranylamino)quinoxaline carboxylate (180.0 mg, 0.47 mmol) in tetrahydrofuran (20 mL) was added sodium e (22.7 mg, 0.95 mmol) at 0°C and stirred for 1 h at room temperature. Then CH3I (134.0 mg, 0.94 mmol) was added at 0°C and stirred overnight at room temperature. The on mixture was quenched by the addition of NH4C1 on (100ml) and adjusted to pH 6 with hydrochloric acid (1N), extracted with dichloromethane (3 x 30 mL), dried over anhydrous magnesium sulfate and concentrated under vacuum to afford methyl 2-(4—fluoropheny1)—3— (methyl(tetrahydro—2H—pyran—4—yl)amino)quin0xa1ine-6—carboxylate as yellow oil (100mg, crude).
(ES, m/z): [M+H]+ 395.0 Step 3. 2-(4-Flu0rophenyl)(methyl(tetrahydro-2H—pyranyl)amino)quinoxaline—6— carboxylic acid Q 0 OI“/N]:>)LOH\ l F To a solution of methyl 2-(4-fluor0phenyl)(methyl(tetrahydro-2H—pyran—4- yl)amino)quinoxaline-6—carboxylate (100 mg) in ol (20 mL) was added sodium hydroxide (40 mg, 1.00 mmol) and water (1 mL). After stirring overnight at room temperature, the reaction mixture was concentrated under d pressure to afford a residue, which was dissolved in water (10 mL), adjusted the pH value to 6 with hydrochloric acid (3 N) and the product was precipitated to afford 2-(4—fluorophenyl) (methy1(tetrahydro-2H—pyranyl)amino)quinoxaline—6-carboxylic acid as a light yellow solid (52 mg).
(ES, m/z): [M+H]+ 382.0 1H—NMR (300 MHz, DMSO) 8 8.27 (s, 1H), 7.85 - 7.95 (m, 4H), 7.35 — 7.41 (t, J = 9.0 Hz, 2H), 3.98 — 4.06 (m, 1H), 3.83 - 3.88 (m, 2H), 3.11 - 3.18 (t, J = 10.5 Hz, 2H), 2.69 (s, 3H), 1.69 - 1.82 (m, 2H), 1.5 (d, J: 10.5 Hz, 1H) EXAMPLE 103 2—(4-Fluorophenyl)(methyl(piperidinyl)amino)quinoxalinecarboxylic acid Q 0 /N NfiOH DI“l / Step 1. Methyl 3-(1—(tert-butoxycarbonyl)piperidin-4—ylamino)(4-fluorophenyl) quinoxaline—6—carboxylate I300 Q 0 I ND/ko/ FOI” To a solution of methyl 3-chloro(4-fluorophenyl)quinoxa1inecarboxy1ate (300.0 mg, 0.95 mmol) in DMSO (2 mL) was added tert—buty] opiperidine—l-carboxylate (227.0 mg, 1.14 mmol), DIEA (367.0 mg, 2.82 mmol). The resulting solution was stirred overnight at 100°C and then diluted with water (10 mL), extracted with dichloromethane (3 X 10 mL), dried over anhydrous magnesium e and concentrated in vacuo. The residue was purified by a silica gel colunm tography with 20% — 50% ethyl acetate in petroleum ether to afford methyl 3-(1-(tert—butoxycarbonyl)piperidin—4—ylamino)—2—(4— fluorophenyl)quinoxaline—6—carboxylate as a yellow solid (200 mg, 44 %).
LC/MS (ES, m/z): [M+H]+481.0 1H—NMR (300 MHz, CDC13) 5 8.47 (d, J: 1.8 Hz, 1H), 8.01 - 8.04(m, 1H), 7.92 (d, J: 8.7 Hz, 1H), 4.15 (m, 2H), 4.00 (s, 3H), 3.00 — 3.08 (t, J: 12 Hz, 2H), 2.12 — 2.17 (m, 2H), 1.51 (s, 9H), 1.34 — 1.48 (m, 2H) Step 2. 3-((1-(tert—Butoxycarbonyl)piperidin—4—y1)(methy1)amino)—2—(4- fluorophenyl)quinoxalinecarboxylate 1'30c Q 0 OI”I / F To a solution of methyl 3-(1-(tert—butoxycarbonyl)piperidin—4—ylamino)-2—(4- fluorophenyl)quinoxalinecarboxy1ate (200.0 mg, 0.42 mmol) in tetrahydrofuran (10 mL)was added sodium e (50.0 mg, 2.08 mmol) at 0°C and stirred for 30 minutes at room temperature. Subsequently, iodomethane (350.0 mg, 2.47 mmol) was added and stirred overnight at room temperature. The reaction mixture was then quenched by the addition of NH4C1 solution (100 mL), extracted with dichloromethane (3 x 15 mL), dried over anhydrous ium sulfate and concentrated in vacuo to afford methyl 3-((l-(tert— butoxycarbonyl)piperidin—4—yl)(methyl)amino)(4-fluorophenyl)quinoxalinecarboxylate as a yellow solid (210 mg, crude).
(ES, m/z): [M+H]+495.0 Step 3. Methyl 2-(4—fluoropheny1)(methyl(piperidinyl)amino)quinoxa1ine-6— ylate Q o /N Nfio/ {DINl / F The solution of methyl 3—((1—(tert—butoxycarbonyl)piperidin—4-yl)(methyl)amino)(4- fluorophenyl)quinoxalinecarboxylate (210 mg, crude) in hydrogen chloride(g)/MeOH (50 mL) was stirred overnight at room temperature and then trated in vacuo. The residue was dissolved in water (50 mL) and ed to pH 8 with sodium bicarbonate, extracted with dichloromethane (5 x 30 mL), dried over anhydrous magnesium sulfate and concentrated in vacuo. The t was precipitated by the addition ether (20 mL) to afford methyl 2—(4— fluorophenyl)(methyl(piperidin—4—yl)amino)quinoxalinecarboxylate as a yellow solid (100 mg ).
LC/MS (ES, m/z): [M+H]+ 395.0 lH-NMR (300 MHz, DMSO) 8 8.33 (s, 1H), 7.89 - 7.96(m, 2H), 7.99 (d, J: 8.4 Hz, 1H), 7.35 - 7.41(t, J: 8.7 Hz, 2H), 4.15 - 4.22 (t, J: 9.3 Hz, 1H), 3.94 (s, 3H), 2.82 - 2.89 (t, J: 11.8 Hz, 2H), 2.61 (s, 2H), 1.84 — 2.00 (m, 4H) Step 4. 2—(4—F1uorophenyl)—3-(methyl(piperidin—4—yl)amino)quinoxalinecarboxylic acid Q 0 FOI“ To a solution of 3—((1—(tert-butoxycarbonyl)piperidin—4-yl)(methyl)amino)(4- fluorophenyl)quinoxaline—6-carboxylic acid (90.0 mg, 0.23 mmol) in MeOH (20 mL) was added sodium hydroxide (50 mg, 1.25 mol) and water (1 mL). The resulting on was stirred overnight at room temperature and concentrated in vacuo. The residue was dissolved in water (5 mL) and adjusted to pH 6 with hydrochloric acid (1N) and concentrated in vacuo.
The crude product was purified by Prep-HPLC with the following conditions (3#-Agi1ent 1200 prep HPLC): Column, X—Bridge Prep Cl8,19*150mm; mobile phase, water with 0.5 % TFA : CH3CN =(25%-37% CH3CN in 9.0 min); Detector, 5pm to afford 2-(4-fluoropheny1)— hyl(piperidin-4—yl)amino)quinoxaline—6—carboxylic acid as a yellow solid ( 22 mg, 25 LC/MS (ES, m/z):[M+H]+ 380.9 1H—NMR (300 MHZ, CD30D) 8 8.48 (s, 1H), 8.09 (d, J: 6.3 HZ, 1H), 7.96 - 8.00 (t, J: 5 Hz, 3H), 7.29 - 7.33(t, J: 6 Hz, 2H), 4.31 (s, 1H), 3.50 (d, J: 9 Hz, 2H), 3.07 — 3.15 (m, 2H), 2.73 (s, 3H), 2.11 (s, 4H) EXAMPLE 104 (sec-Butyl(methyl)amino)(4-fluorophenyl)quinoxalinecarboxylic acid 0 0 l NDAOH FOI” Step 1. (S)-Methyl 3-(sec-butylamino)(4-fluorophenyl)quinoxaline—6-carboxylate Q 0 DINI NDAO// F To a solution of methyl 3—chloro-2—(4-fluoropheny1)quinoxa1ine—6-carboxylate (400.0 mg, 1.26 mmol) in DMSO (3 mL) was added (S)-butan-2—amine (200 mg, 2.74 mmol). The resulting solution was stirred overnight at 90°C and then diluted with water (50 mL), extracted with dichloromethane (5 x 20 mL), dried over anhydrous magnesium sulfate and trated in vacuo. The residue was purified by a silica gel column chromatography with 2% ethyl acetate in petroleum ether to afford (S)-methy1 3-(seq-butylamino)—2—(4— fluorophenyl)quinoxalinecarboxylate as a yellow solid (280.0 mg, 63 %).
LC/MS (ES, m/z): [M+H]+ 354.0 1H—NMR (300 MHz, CDC13), 8 8.60 (s, 1H), 8.01 — 8.04 (m, 1H), 7.92 (d, J: 8.7 Hz, 1H), 7.73 - 7.78 (m, 2H), 7.23 - 7.33 (m, 2H), 4.43 — 4.48 (t, J: 6.9Hz, 1H), 4.00 (s, 3H), 1.59 - 1.68 (m, 2H), 1.23-1.32 (m, 3H), 0.90 - 1.01 (m, 3H) Step 2. (sec-Butyl(methy1)amino)-2—(4—fluorophenyl)quinoxaline—6—carboxylic acid Q 0 /N NfiOH OI“l / F To a solution of (S)-methy1 3-(sec-butylamino)(4—fluorophenyl)quinoxaline-6—carboxylate (280.0 mg, 0.79 mmol) in tetrahydrofuran (30 mL) was added sodium hydride (127 mg, 3.17 mmol) and stirred for 1h at room temperature. Subsequently, iodomethane (570 mg, 3.97 mmol) was added and stirred overnight at room temperature. The reaction was trated in vacuo and then quenched by the addition of water (20 mL), adjusted to pH 5 with hydrochloric acid (IN). The solids were collected by filtration to afford (S)(sec- buty1(methyl)amino)(4-fluorophenyl)quinoxaline—6-carboxylic acid as a yellow solid (124.3 mg, 44 %).
LC/MS (ES, m/z): [M+H]+ 354.0 1H-NMR (300 MHz, CDCl3), 8 8.58 (s, 1H), 8.08 (d, J: 8.4 Hz, 1H), 7.97 (d, J = 8.4 Hz, 1H), 7.86 — 7.91 (m, 2H), 7.18 - 7.28 (m, 2H), 4.04 (d, J: 6.9 Hz, 1H), 2.74 (s, 3H), 1.56— 1.65 (m, 2H), 1.09 (d, J: 6.6 Hz, 3H), 0.73 - 0.78 (t, J: 7.5 Hz, 3H) E 105 (S)(4-Fluorophenyl)(3-methylmorpholino)quinoxalinecarboxylic acid o/fi‘“ o N /N Step 1. (S)-Methyl 3-(3-methylmorpholino)oxo-1 ,2—dihydroquinoxaline—6-carboxylate O/fi‘” o O N To a on of (3S)methylmorpholine (200 mg, 1.98 mmol) in DMSO (10 mL) was added methyl 3-chlorohydr0xyquinoxalinecarboxylate (700 mg, 2.93 mmol), DIEA (510 mg, 3.95 mmol). The resulting solution was stirred ght at 70°C and then dissolved in water (100 mL), extracted with dichloromethane (4 x 30 mL), dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by a silica gel column chromatography with 5% ~ 50% ethyl acetate in petroleum ether to afford methyl 2- hydroxy[(3S)methylmorpholinyl]quinoxa1inecarboxy1ate as a light yellow solid (210.0 mg).
LC/MS (ES, m/z): [M+H]+ 304.0 W0 2012/119046 1H-NMR (300 MHZ, CDC13), 5 9.34 (s, 1H), 8.22 (d, J = 1.5 Hz, 1H), 7.87 — 7.90 (m, 1H), 7.04 (d, J = 8.1 Hz, 1H), 3.95 — 4.03 (m, 4H), 3.67 - 3.87 (m, 3H), 3.50 — 3.56 (m, 1H), 1.43 (d, J: 6.6 Hz, 3H) Step 2. Methyl 3-[(3S)—3-methylmorpholin—4—yl]—2— [(trifluoromethane)sulfonyloxy]quinoxaline—6—carboxylate o o >*\TfO N To a solution of methyl 3-[(3S)methylmorpholiny1]oxo-1,2-dihydroquinoxaline carboxylate (210 mg, 0.69 mmol) in romethane (50 mL) was added pyridine (220 mg, 2.78 mmol), ed by szO (390 mg, 1.38 mmol), and the resulting mixture was stirred overnight at room temperature. The reaction was then quenched by the addition of ice—water (100 mL) and extracted with dichloromethane (2 x 20 mL), the organic layers were combined and dried over anhydrous magnesium sulfate and concentrated in vacuo to afford methyl 3-[(35)—3-methylmorpholin-4—yl]—2— [(trifluoromethane)sulfonyloxy]quinoxaline—6— carboxylate as red oil (300 mg, crude).
Step 3. Methyl 2—(4—fluorophenyl)[(3S)methylmorpholin-4—yl]quinoxaline—6- carboxylate o/fi“ o K/N /N\ND/‘ko/ To a solution of methyl 3-[(3S)methylmorpholinyl] uoromethane)sulfonyloxy]quinoxalinecarboxylate (300 mg,crude) in dioxane (10 mL) was added Pd(PPh3)4 (40 mg, 0.03 mmol), (4-fluorophenyl)boronic acid (200 mg, 1.43 mmol), K3PO4 (292 mg, 1.38 mmol) and water (1 mL). The resulting on was stirred for 1 h at 90°C with an inert atmosphere of nitrogen, and then concentrated in vacuo to give a residue, which was purified by a silica gel column chromatography (2% — 4% ethyl acetate in petroleum ether) to afford methyl 2-(4-fluorophenyl)-3—[(3S)methylmorpholin-4— yl]quinoxaline—6—carboxylate as a yellow solid (140 mg).
LC/MS (ES, m/z): [M+H]+ 382.0 WO 19046 2012/027423 1H-NMR (300 MHz, CDClg), 8 8.56 (d, J = 1.8 Hz, 1H), 8.00 - 8.16 (m, 4H), 7.20 - 7.26 (m, 2H), 4.01 (s, 3H), 3.84 - 3.89 (m, 2H), 3.64 - 3.76 (m, 2H), 3.31 - 3.56 (m, 3H), 1.17(d, J: 6.6 Hz, 3H) Step 4. (S)—2—(4-Fluorophenyl)(3-methylmorpholino)quinoxalinecarboxylic acid o/fi‘” o K/ \NfiOHN /N To a solution of (SD-methyl 2-(4-fluorophenyl)—3-(3-methylmorpholino)quinoxaline carboxylate (140.0 mg, 0.37 mmol,) in methanol (15 mL) and CHC13 (5 mL) was added a solution of NaOH (45 mg, 1.12 mmol) in water (1 mL). The resulting solution was stirred overnight at room temperature and concentrated in vacuo. The residue was dissolved in water (10 mL) and adjusted to pH 6 with hydrochloric acid (IN). The solids were collected by filtration to afford (S)—2—(4-fluorophenyl)(3-methylmorpholino)quinoxalinecarboxylic acid as a yellow solid (91.2 mg, 68 %).
(ES, m/z): [M+H]+ 368.0 1H—NMR (300 MHZ, DMSO), 8 8.31 (d, J: 0.6 Hz, 1H), 8.01 - 8.09 (m, 4H), 7.37 - 7.43 (t, J = 8.7 Hz, 2H), 3.75 — 3.79 (m, 2H), 3.45 — 3.64 (m, 4H), 3.26 - 3.33 (m, 1H), 1.08 (d, J: 6.6 Hz, 3H) EXAMPLE 106 2-(4-Fluorophenyl)[(2R)(trifluoromethyl)piperidinyl]quinoxalinecarboxylic acid Ono\ F3 O N /ND)J\OH 2012/027423 Step 1. (R)—2-(4—Fluoropheny1)-3 -(2—(trifluoromethyl)piperidiny1)quinoxaline—6—carboxy1ic acid OI‘\CF3 O N /N1©)LO/ To a on of methyl 3—chloro—2—oxo-1,2—dihydroquinoxa1ine-6—carboxylate (1 g, crude) in NMP (1 mL) was added (2R)—2—(trifluoromethyl)piperidine (700 mg, 4.57 mmol). The resulting solution was stirred for 5 h at 160°C and then purified by a silica gel column chromatography (5% ethyl acetate in petroleum ether) to afford (R)(4-fluoropheny1)(2- (trifluoromethy1)piperidiny1)quinoxalinecarboxy1ic acid as a yellow solid (55 mg, crude).
LC/MS (ES, m/z): [M+H]+ 356.0 Step 2. Methyl 2-[(trifluoromethane)sulfonyloxy][(2R)(trifluoromethyl)piperidin—1 — yl]quinoxalinecarboxylate O_‘\CF3 O TfO N To a solution of methyl 2—oxo—3-[(2R)—2-(trifluoromethy1)piperidin—1—yl]-1,2- dihydroquinoxalinecarboxylate (55 mg, crude) in dichloromethane (30 mL) was added pyridine (58 mg, 0.73 mmol) and Tf20 (103 mg, 0.37 mmol). The resulting solution was stirred overnight at room ature, and then quenched by the addition of water/ice (50 mL) and extracted with dichloromethane (2 x 20 mL). The organic layers were combined and dried over anhydrous magnesium sulfate and trated in vacuo to afford methyl 2- [(trifluoromethane)sulfonyloxy]-3 -[(2R)-2—(trifluoromethyl)piperidiny1]quinoxa1ine carboxylate as red oil (80 mg, crude).
Step 3. Methyl 2-(4—fluorophenyl)-3—[(2K)—2—(tlifluoromethyl)piperidin—1-y1]quinoxaline—6- carboxylate To a solution of methyl 2-[(trifluoromethane)sulfonyloxy][(2R) (trifluoromethyl)piperidin—1-yl]quinoxalinecarboxylate (80 mg, crude) in dioxane (2 mL) was added (4-fluoropheny1)boronic acid (69 mg, 0.49 mmol), K3PO4 (69 mg, 0.33 mmol), and Pd(PPh3)4 (9 mg, 0.01 mmol). The resulting solution was stirred for 1 h at 90°C and then concentrated in vacuo. The residue was purified by a silica gel column chromatography (1%- % ethyl acetate/petroleum ether) to afford methyl 2-(4-fluorophenyl)[(2R)—2— (trifluoromethyl)piperidin-l-y1]quinoxalinecarboxylate as yellow oil (15mg, crude).
LC/MS (ES, m/z): [M+H]+ 434.0 Step 4. 2-(4—Fluorophenyl)-3—[(2R)(trifluoromethyl)piperidin-1—y1]quinoxaline carboxylic acid O“‘CF3 O To a solution of methyl 2-(4-fluoropheny1)~3—[(2R)~2—(t1ifluoromethyl)piperidin—1- yl]quinoxalinecarboxy1ate (15 mg, crude) in methanol (15 mL) was added sodium hydroxide (10 mg, 0.25 mmol) in water (1 mL). The ing on was stirred ght at room temperature and concentrated in vacuo. The residue was dissolved in water (5 mL) and adjusted pH to 6 with HCl (1N), then extracted with dichloromethane (4 x 10 mL) and the organic layers combined and dried over anhydrous magnesium sulfate and concentrated in vacuo to give a residue. Purification via PLC under the following ions [(Agilent 1200 prep HPLC): Column, SunFire Prep C18, 19 * 50 mm 5 um; mobile phase, water with 0.05 % NH3 and CH3CN (10 % CH3CN up to 45 % in 7 min); Detector, UV 220nm] afforded 2—(4—fluorophenyl)[(2R)(trifluoromethyl)piperidin—1-yl]quinoxalinecarboxylic acid as a yellow solid (9 mg).
W0 2012/119046 LC/MS (ES, m/z):[M+H]+ 420.0 1H-NMR (300 MHZ, DMSO), 5; 8.47 (d, J: 1.5 Hz, 1H), 8.13 - 8.17 (m, 1H) 7.95 - 8.03 (m, 1H), 7.28 - 7.36 (m, 2H), 4.93 — 4.99 (m, lH),3.50 - 3.56 (m, 1H), 3.16 - 3.25 (m, 1H), 1.94 - 2.00 (m, 2H), 1.66 - 1.71 (m, 3H), 1.51 — 1.55 (m, 1H) EXAMPLE 107 3-(tert-Butyl(methyl)amino)(4-fluorophenyl)quinoxalinecarboxylic acid \*/ O /N /NI>JKOH OI”\ F Step 1. Methyl 3-(tert-butylamino)—2—(4-fluorophenyl)quinoxaline—6-carboxylate \’/ O HN ”jg/[KO OI“\ I To a solution of methyl 3-chloro-2—(4-fluorophenyl) quinoxaline—6—carboxylate (200 mg, 0.63 mmol) in DMSO (10 mL) was added DIEA (163 mg, 1.26 mmol) and 2-methy1propan amine (461.3 mg, 6.32 mmol) with stirring overnight at 90°C in an oil bath. The on mixture was cooled to room temperature, diluted with H20 (150 mL), extracted with ethyl acetate (3 x 80 mL). The organic layers were combined, dried over magnesium sulfate, and concentrated in vacuo to give the residue, which was ed by silica gel column chromatography (1% ethyl e in petroleum ether) to afford methyl 3—(tert—butylamino) (4-fluorophenyl)quinoxalinecarboxylate as a light yellow solid (115 mg, 51 %).
(ES, m/z): [M+H]+ 354.0 1H-NMR (300 MHz, CDC13)I 6 8.46 (d, J = 1.5 Hz, 1H), 7.93 - 8.01 (m, 2H), 7.73 - 7.78 (m, 2H), 7.25 - 7.31 (m, 2H), 5.09 (s, 1H), 4.02 (s, 3H), 1.54 (s, 9H) WO 19046 Step 2. 3—(tert—Buty1(methy1)arnino)(4—fluorophenyl)quinoxaline—6-carboxylic acid \1/ O DI\N F To a solution of methyl 3-(tert-butylamino)(4-fluorophenyl)quinoxaline—6—carboxylate (115 mg, 0.33 mmol) in ydrofuran (30 mL) was added sodium hydride (65 mg, 2.71 mol) at 0°C and then stirred for 10 minutes at room temperature. Methyliodide (185 mg, 1.30 mmol) was then added with stirring, and the reaction was allowed to proceed overnight at room temperature. The reaction was quenched with water (50 mL), ed to pH 5 with HCl (3N), extracted with ethyl acetate (3 x 80 mL) and the organic layers combined, dried over anhydrous magnesium sulfate and concentrated in vacuo to give the residue. Purification Via Prep-HPLC under the following conditions [(Agilent 1200 prep HPLC): Column, SunFire Prep C18, 19 * 50 mm 5 um; mobile phase, water with 0.05 % TFA and CH3CN (10 % CH3CN up to 45 % in 10 min); Detector, UV 220nm] afforded t—buty1(methyl)amino)- 2-(4-fluoropheny1)quinoxaline—6-carboxylic acid as alight yellow solid (8.20 mg, 7.13%).
LC/MS (ES, m/z): [M+H]+ 354.0 1H-NMR (300 MHz, DMSO): 3 8.29 (d, J: 1.2 Hz, 1H), 7.99 - 8.29 (m, 4H), 7.34 - 7.40 (t, J = 9.0 Hz, 2H), 2.46 (s, 3H), 1.52 (s, 9H) EXAMPLE 108 3-(Cyclohexyl(methyl)amino)—2-(4-fluorophenyl)quinoxalinecarboxylic acid ; O {DIN\ F PCT/U$2012/027423 Step 1. Methyl 3—(cyclohexylamino)-2—(4—f1uorophenyl)quinoxa1ine-6—carboxylate HN /N]:>)ko/ . | FEDI” To a solution of methyl 3-chloro—2-(4-fluorophenyl)quinoxalinecarboxylate (200 mg, 0.63 mmol) in DMSO (10 mL) was added DIEA (163.3 mg, 1.27 mmol) and cyclohexanamine (250.7 mg, 2.53 mmol), and the reaction was allowed to proceed with stirring overnight at 90°C in an oil bath. The reaction mixture was cooled down to room temperature and d with water (150 mL). The mixture was extracted with ethyl acetate (3 x 80 mL), the organic layers combined and dried over magnesium sulfate, concentrated in vacuo to give the residue, which was purified by a silica gel column chromatography (1 % ethyl acetate in petroleum ether) to afford methyl 3-(cyclohexylamino)—2—(4—fluorophenyl)quinoxaline—6—carboxylate as a light yellow solid (200 mg, 83 %).
LC/MS (ES, m/z): [M+H]+ 380.0 1H—NMR (300 MHz, CDC13): 5 8.52 (s, 1H), 7.98 (d, J: 8.4 Hz, 1H), 7.90 (d, J = 8.4 Hz, 1H), 7.72 _ 7.76 (t, J = 5.7 Hz, 2H), 7.26 — 7.31 (t, J = 7.5 Hz, 2H), 5.10 (s, 1H), 4.24 (s, 1H), 3.99 (s, 3H), 2.14 (d, J = 7.5 Hz, 2H), 1.66 — 1.76 (m, 3H), 1.53 — 1.56 (d, J = 7.8 Hz, 2H), 1.16 (s, 3H) Step 2. 3-(Cyclohexyl(methyl)amino)(4-fluorophenyl)quinoxalinecarboxylic acid A o /N ”DAM OI“\ F To a solution of methyl 3-(cyclohexylamino)—2—(4—fluorophenyl)quinoxalinecarboxylate (200 mg, 0.53 mmol) in tetrahydrofuran (30 mL) was added sodium hydride (105.5 mg, 4.40 mmol) and CH3I (299.9 mg, 2.11 mmol), and the reaction was allowed to d with stirring overnight at room ature. The reaction was then quenched by the addition of water (50 mL), ed pH to 5 with HCl (3N). The resulting solution was extracted with 2012/027423 ethyl acetate (3 x 80 mL) and the organic layers combined, dried over anhydrous magnesium e, and concentrated in vacuo to give the crude product. The crude product was re— crystallized from ethyl acetatezpetroleum ether (1:5) to afford 3-(cyclohexyl(methyl)amino)- 2—(4-fluorophenyl)quinoxalinecarboxylic acid (100 mg, 48 %) as a light yellow solid.
LC/MS (ES, m/z): [M+H]+ 380.1 1H—NMR (300 MHz, DMSO): 5 13.19 (s, 1H), 8.24 - 8.25 (t, J = 1.20 Hz, 1H), 7.85 — 7.94 (m, 4H), 7.34 — 7.40 (t, J = 8.7 Hz, 2H), 3.63 - 3.71 (m, 1H), 2.72 (s, 3H), 1.64 (d, J: 9.6 Hz, 2H), 1.40 — 1.60 (m, 5H), 0.99 - 1.05 (t, J: 7.80 Hz, 3H) EXAMPLE 109 2-(4-Fluorophenyl)(methyl(0-tolyl)amino)quinoxalinecarboxylic acid ; \ o /N xNfiOH 9*\ F Step 1. Methyl 3—(0—toluidino)-2—(4-fluorophenyl)quinoxaline—6-carboxylate : 145°C three days©jNHZF/©I: Methyl 3-chloro(4-fluoropheny1)quinoxalinecarboxy1ate (300 mg, 0.95 mmol) was stirred in o—toluidine (10 mL) at 145°C for 3 days in an oil bath. The reaction mixture was concentrated in vacuo to give a residue, which was purified by a silica gel column chromatography (1% ethyl acetate in petroleum ether) to afford methyl 3—(0—toluidino)-2—(4— fluorophenyl)quinoxalinecarboxylate as a light yellow solid (145 mg, 37 %).
LC/MS (ES, m/z): [M+H]+ 388.0 1H-NMR (300 MHz, CDC13)Z 6 8.55 (d, J = 1.8 Hz, 2H), 8.49 (d, J = 8.1 Hz, 2H ), 8.08 - 8.12 (dd, J: 1.8 Hz, 2H ), 7.98 (d, J = 8.7 Hz, 2H), 7.83 - 7.88 (m, 4H), 7.32 - 7.38 (m, 5H), 7.22 W0 2012/119046 PCT/U52012/027423 (d, J: 6.9 Hz, 2H), 7.09 - 7.12 (t, J = 0.9 Hz, 2H), 6.98 (s, 2H), 4.00 - 4.03 (t, J = 5.4 Hz, 6H), 2.13 (s, 6H) Step 2. 2—(4—Fluorophenyl)(methyl(o-tolyl)amino)quinoxalinecarboxylic acid ; ‘ O /N /NfiOH DI”\ F To a solution of methyl 3-(o-toluidino)—2~(4—flu0rophenyl)quinoxalinecarboxylate (145 mg, 0.37 mmol) in tetrahydrofuran (30 mL) was added sodium hydride (74.9 mg, 3.12 mol) at 0°C with stin‘ing for 30 min, followed by the addition of CH3I (1.5 mL) dropwise. The reaction mixture was stirred overnight at room temperature. The reaction was then quenched with water (50 mL), adjusted to pH 5 with HCl (3N), and extracted with ethyl acetate (3 x 80 mL). The organic layers were combined, dried over anhydrous magnesium sulfate and concentrated in vacuo to give the residue, which was purified by Prep-HPLC under the following conditions ent 1200 prep HPLC): , SunFire Prep C18, 19 * 50 mm 5 um; mobile phase, water with 0.05 % TFA and CH3CN (25 % CH3CN up to 67 % in 10 min); Detector, UV 220nm] to afford 2-(4-fluorophenyl)—3—(methyl(0-tolyl)amino)quinoxaline—6- carboxylic acid as a light yellow solid (46.5 mg, 30%).
LC/MS (ES, m/z): [M+H]+ 388.0 1H-NMR (300 MHz, DMSO): 5 8.39 (d, J: 1.2 Hz, 1H), 7.96 - 8.03 (m, 2H), 7.28 - 7.33 (m, 2H), 6.87 - 6.98 (m, 5H), 6.63 - 6.65 (t, J: 3.6 Hz, 1H), 3.32 (s, 6H), 2.07 (s, 3H) EXAMPLE 1 10 t-Butylamino)(4-fluorophenyl)quinoxalinecarb0xylic acid \l/ O - /N]©)J\OH\N To a solution of methyl t-butylamino)(4-fluorophenyl)quinoxaline—6—carboxylate (120 mg, 0.34 mmol) in THF (20 mL) and water (2 mL) was added sodium hydroxide (54.39 PCT/U52012/027423 mg, 1.36 mmol) with stirring overnight at room temperature. The reaction mixture was concentrated in vacuo, dissolved in water (30 mL), adjusted to pH 4 with HCl (3N) to give the precipitate, which was collected by filtration to afford 3-(tert—buty1amino)(4- henyl)quinoxalinecarboxylic acid as a light yellow solid (80 mg, 66 %).
(ES, m/z): [M+H]+ 340.0 1H-NMR (300 MHz, DMSO): 8 8.18 (d, J = 0.9 Hz, 1H), 7.84 — 7.89 (m, 4H), 7.38 - 7.44 (m, 2H), 5.77 (s, 1H), 4.02 (s, 3H), 1.49 (s, 9H) EXAMPLE 1 11 3-(Ethyl(isopropyl)amino)(4-fluorophenyl)quinoxaline-6—carboxylic acid Y O Step 1. Methyl 2-(4-fluorophenyl)(isopropylamino)quinoxalinecarboxylate \l/ O 01“/NQAO/l\ F To a solution of methyl 3-chloro(4-fluorophenyl)quinoxaline—6—carboxy1ate (200 mg, 0.63 mmol) in DMSO (10 mL) was added DIEA (489 mg, 3.79 mmol) and propan—2-amine (149.4 mg, 2.53 mmol) under en atmosphere. After stirring overnight at 70°C, the reaction mixture was ved in water (100 mL), extracted with dichloromethane (3 x 80 mL), dried over anhydrous magnesium sulfate and concentrated under d pressure to afford a residue. Purification via silica gel column chromatography (2% ethyl acetate in petroleum ether) afforded methyl 2—(4—fluorophenyl)(isopropylamino)quinoxaline—6—carboxy1ate as a light yellow solid (100 mg, 44 %).
LC/MS (ES, m/z): [M+H]+ 368.0 1H-NMR (300 MHZ, CDC13) 5 8.57 (s, 1H), 8.00 - 8.04 (m, 1H), 7.92 (d, J: 8.7 Hz, 1H), 7.73 - 7.78 (m, 2H), 7.26 — 7.32 (m, 2H), 5.07 (s, 1H), 4.54 (d, J: 6.6 Hz, 1H), 4.00 (s, 3H), 1.30 (d, J: 6.6 Hz, 6H) Step 2. 3—(Ethyl(isopropyl)amino)(4-fluorophenyl)quinoxaline—6-carboxylic acid Y O To a solution of methyl 2-(4-fluorophenyl)-3—(isopropylamino)quinoxalinecarboxylate (95 mg, 0.28 mmol) in tetrahydrofuran (20 mL) was added sodium hydride (23 mg, 0.96 mmol) and stirred for 10 minutes. Subsequently, iodoethane (43.7 mg, 0.28 mmol) was added and stirred overnight at room temperature. The reaction mixture was trated under reduced re to afford a residue, which was dissolved in water (25 mL) and the pH ed to 6 with hydrochloric acid (3N). The product precipitated and was filtered to afford 3- (ethyl(isopropyl)amino)-2—(4—fluorophenyl)quinoxalinecarb0xylic acid as a light yellow solid (28.4 mg, 29%).
LC/MS (ES, m/z): [M+H]+ 354.0 1H—NMR (300 MHz, CDC13) 5 8.63 (s, 1H), 7.95 - 8.11 (m, 3H), 7.15 — 7.21 (m, 3H), 3.81 (s, 1H), 3.36 (s, 2H), 1.18 (s, 3H), 0.96 (d, J = 6.6 Hz, 6H) EXAMPLE 112 3-[Cyclohexyl(ethyl)amino](4-fluorophenyl)quinoxalinecarboxylic acid To a solution of methyl 3—(cyclohexylamino)(4-fluorophenyl)quinoxalinecarboxylate (130 mg, 0.34 mmol) in tetrahydrofuran (20 mL) was added sodium hydride (28 mg, 60%) and stirred for 10 minutes, followed by the addition of iodoethane (107 mg, 0.69 mmol).
W0 19046 PCT/U82012/027423 After stirring overnight at room ature, the reaction e was concentrated under reduced pressure to afford a residue, which was dissolved in water (10 mL), and the pH adjusted to 6 with hydrochloric acid (3N). The product precipitated and was filtered to afford 3-[cyclohexyl(ethyl)amino]—2-(4-fluorophenyl)quinoxaline-6—carboxylic acid as a light yellow solid (50.9 mg, 38 %).
LC/MS (ES, m/z): [M+H]+ 394.0 1H-NMR (300 MHz,CDC13)8 8.61 (s, 1H), 8.09 (s, 1H), 7.90 — 7.97 (m, 3H), 7.16 — 7.22 (t, J = 8.1 Hz, 1H), 3.43 (d, J: 6.6 Hz, 3H), 1.63 (d, J = 6.6 Hz, 2H), 1.39 — 1.49 (m, 5H), 1.19 — 1.27 (m, 3H), 0.85 - 0.97 (m, 3H) EXAMPLE 1 l3 3-(Diethylamino)(4-fluorophenyl)quinoxalinecarboxylic acid K o Step 1. Methyl 3-(diethylamino)-2—(4—fluorophenyl)quinoxalinecarboxylate To a solution of methyl 3-chloro—2—(4-fluoropheny])quinoxalinecarboxylate (150 mg, 0.47 mmol) in DMSO (2 mL) was added diethylamine (173 mg, 2.37 mmol) and DIEA (170 mg, 1.32 mmol). The resulting solution was stirred ght at 70°C and then quenched by the addition of water/ice (40 mL), extracted with ethyl acetate (3 x 20 mL), the organic layers combined and dried over anhydrous magnesium sulfate and concentrated in vacuo to give a residue. Purification via silica gel column chromatography (0.5% - 4% ethyl acetate in petroleum ether) afforded methyl 3-(diethylamino)(4-fluorophenyl)quinoxaline carboxylate as a yellow solid (100 mg, 60%).
LC/MS (ES, m/z): [M+H]+ 354.0 W0 2012/119046 1H-NMR (300 MHz, CDC13), 8 8.68 (d, J = 1.5 Hz, 1H), 8.11 (d, J = 1.8 Hz, 1H), 8.08 (d, J = 1.8 Hz, 1H), 7.99 (d, J: 8.4 Hz, 1H), 7.90 — 7.95 (m, 1H), 7.19 — 7.25 (m, 2H), 4.01 (s, 3H), 3.38 - 3.45 (m, 4H), 1.10 — 1.150, J: 6.9 Hz, 6H) Step 2. 3-(Diethylamino)—2—(4—fluorophenyl)quinoxaline-6—carboxylic acid K o OI“| \ To a solution of methyl 3-(diethylamino)(4-fluoropheny1)quinoxalinecarboxy1ate (95.0 mg, 0.27 mmol,) in methanol (20 mL) was added a solution of NaOH (20 mg, 0.50 mmol) in water (1 mL). The resulting on was stirred ght at room temperature and concentrated in vacuo. The residue was dissolved in water (5 mL) and adjusted to pH 5 with hydrochloric acid (IN). The solids were collected by filtration to afford thy1amino)—2- (4-fluorophenyl)quinoxa1inecarboxy1ic acid as a yellow solid (50 mg, 55 %).
(ES, m/z): [M+H]+ 340.0 1H—NMR (300 MHZ, DMSO), 8 13.21 (s, 1H), 8.28 (t, J = 1.2 Hz, 1H), 7.89 - 7.96 (m, 4H), 7.35 - 7.42 (t, J = 9.0 Hz, 2H), 3.26 - 3.33 (m, 4H), 1.00 - 1.04 (m, 3H) EXAMPLE 114 2—(4-Fluorophenyl)[(ZS)methylpiperazin-l-yl]quinoxalinecarboxylic acid HN/fi-N‘ o K/N /N\ND/KOH Step 1. Methyl 3-[(2S)[(tert—butoxy)carbonyl]methy1piperaziny1]oxo-1,2- dihydroquinoxaline—6—carboxylate BOC\N/fi‘,\\‘ O “El/gift PCT/U52012/027423 To a on of methyl 3-chlorooxo-1,2-dihydroquinoxaline-6—carboxylate (1.0 g, crude) in DMSO (10 mL) was added tert—butyl-(3S)methylpiperazinecarboxylate (1.0 g, 4.99 mmol) and DIEA (1.0 g, 7.74 mmol). The resulting on was stirred overnight at 80°C in an oil bath and then diluted with water (100 mL), extracted with ethyl acetate (4 x 40 mL) and the organic layers combined and dried over anhydrous magnesium sulfate. The solids were filtered out and filtrate was concentrated in vacuo to give a residue, which was purified by a silica gel column chromatography (2% ethyl acetate in petroleum ether) to afford methyl 3-[(2S)—4- [(tert—butoxy)carbonyl]—2—methylpiperazin— 1 —oxo- 1 ,2— dihydroquinoxaline—6—carboxylate as a light yellow solid (310 mg).
LC/MS(ES, m/z): [M+H]+ 403.0 1H-NMR (300 MHz, CDC13) 5 8.43 (s, 1H), 8.26 (d, J: 1.5 Hz, 1H), 7.87 — 7.91 (m, 1H), 7.07 (d, J: 2.1 Hz, 1H), 4.79 - 4.84 (m, 1H), 3.94 - 4.01 (m, 5H), 3.45 - 3.46 (m, 1H), 3.25 - 3.41 (m, 3H), 1.52 (s, 9H), 1.24 (d, J: 5.7 Hz, 3H) Step 2. Methyl 3-[(2.S’)[(tert—butoxy)carbonyl]-2—methylpiperazin—l-yl]-2— uoromethane)sulfonyloxy]quinoxaline-6—carboxylate Boc\ NGINfiO/o TfO \N To a solution of methyl 3—[(2S)—4—[(tert-butoxy)carbonyl]methylpiperazinyl]—2—oxo—l,2— dihydroquinoxaline—6—carboxylate (300 mg, 0.75 mmol,) in dichloromethane (80 mL) was added pyridine (235.8 mg, 2.98 mmol) dropwise with stirring followed by TfZO (420.7 mg, 1.49 mmol), and the reaction was stirred overnight at room temperature. The resulting solution was diluted with water (50 mL), extracted with romethane (3 x 20 mL), the organic layers combined and dried over anhydrous magnesium sulfate and concentrated in vacuo to afford methyl 3-[(2S)-4—[(tert-butoxy)carbonyl]methylpiperazin—l—yl]—2- [(trifluoromethane)su1fonyloxy]quinoxaline—6-carboxylate as red oil (500 mg, crude).
Step 3. Methyl 3—[(2S)—4-[(tert—butoxy)carbonyl]-2—methy1piperazinyl]—2—(4- fluorophenyl)quinoxa1ine—6-carboxy1ate BORN/w” 0 To a solution of methyl 3—[(2S)—4-[(tert—butoxy)carbonyl]~2—methylpiperazin—1—y1]—2— [(trifluoromethane)sulfonyloxy]quinoxaline—6—carboxylate (500 mg, crude) in dioxane (5 mL) and water (0.5 mL) was added 4-fluorophenyl)boronic acid (188.6 mg, 1.35 mmol), Pd(PPh3)4 (38.89 mg, 0.03 mmol,), and K3PO4 (426.6 mg, 2.01 rnmol). The ing solution was d for 1 h at 90°C with an inert atmosphere of nitrogen and then concentrated in vacuo to give a residue. Purification via silica gel column chromatography (2% - 5% ethyl acetate in petroleum ether) afforded methyl 3-[(ZS)[(tert—butoxy)carbonyl] methylpiperazin-l-y1](4-fluorophenyl)quinoxa1ine—6—carboxylate as a light yellow solid (260 mg).
LC/MS (ES, m/z): [M+H]+ 481.0 1H-NMR (300 MHz, CDCl3) 6 8.57 (d, J = 1.8 Hz, 1H), 8.12 - 8.16 (m, 1H), 8.01 - 8.09 (m, 3H), 7.20 - 7.25 (m, 2H), 3.99 - 4.02 (m, 5H), 3.46 - 3.50 (m, 1H), 3.30 — 3.35 (m, 1H), 3.14 - 3.27 (m, 2H), 1.47 (s, 9H), 1.10 (d, J = 6.6 Hz, 3H) Step 4. 2—(4-F1uorophenyl)—3—[(2S)methylpiperazinyl]quinoxaline—6-carboxylic acid HN/fi-N‘ o K/N /N]::/lkOH\N To a solution of methyl 3-[(2S)—4-[(tert—butoxy)carbonyl]methylpiperazin—1—yl](4— fluorophenyl)quinoxaline—6—carboxy1ate (260 mg, 0.54 mmol) in dichloromethane (30 mL) was added CF3COOH (2 mL). The resulting on was stirred overnight at room ature and then concentrated in vacuo. The residue was dissolved in ol (15 mL), and sodium hydroxide (20 mg, 0.50 mmol) in water (1 mL) was added. The resulting solution was stirred overnight at room temperature and concentrated in vacuo. The residue was dissolved in water (3 mL), the pH adjusted to 6, and the resulting solution concentrated in WO 19046 2012/027423 vacuo. The crude product (40 mg) was purified by Prep-HPLC with the following conditions (AGILENT Pre-HPLC(MS-Directed)): Column, 1#-PrepC—001(XBridge Shield RP18 19* 150 186002987 111130103113 03), N; mobile phase, WATER WITH 0.03% NH3H20 and CH3CN (10% CH3CN up to 22% in 7 min, hold 100% in 2 min, hold 10% in 2 min); Detector, UV 220 nm) to afford 2-(4-fluoropheny1)[(ZS)methylpiperazin-l- yl]quinoxa1ine-6—carboxylic acid as a yellow solid (31 mg, 59%).
LC/MS (ES, m/z): [M+H]+ 367.0 1H—NMR (300 MHz, CD30D) 6 8.42 (d, J = 1.5 Hz, 1H), 8.05 — 8.14 (m, 3H), 7.89 (d, J = 8.4 Hz, 3H), 7.26 - 7.32 (m, 2H), 3.79 - 3.82 (t, J: 3.3 Hz, 1H), 3.26 - 3.30 (t, J: 6.0 Hz, 2H), 2.94 - 3.00 (m, 1H), 2.84 - 2.88 (d, J = 7.8 Hz, 2H), 2.61 - 2.66 (m, 1H), 1.14 (d, J = 6.6 Hz, 3H) EXAMPLE 115 (S)(2,4-Difluorophenyl)(2-methylpyrrolidin-l-yl)quinoxalinecarboxylic acid O O \/N]:>)kOH F F Step 1. (S)—Methyl 2—(2,4—difluoropheny1)(2—methylpyrrolidinyl)quinoxaline ylate F F To a solution of (S)-methy1 3-(2-methy1pyrrolidin—1-y1) (trifluoromethylsulfonyloxy)quinoxa1inecarboxylate (150 mg, 0.36 mmol) in e (5 mL) was added 2,4-difluorophenylboronic acid (113 mg, 0.72 mmol), K3PO4 (152 mg, 0.72 mmol), Pd(PPh3)4 (20 mg, 0.02 mmol) and water (3 drops). The resulting solution was stirred for 1 hour at 90°C and then concentrated in vacuo to give a residue, which was purified by silica gel column chromatography (5% ethyl acetate in petroleum ether) to afford (S)-methyl 2—(2,4-difluorophenyl)—3-(2—methylpyrrolidin-l—yl)quinoxaline—6-carboxylate as a yellow solid (115 mg, 84 %).
LC/MS (ES, m/z): [M+H]+ 384.0 1H-NMR (300 MHz, : 5 8.66 (s, 1H), 8.02 - 8.05 (m, 1H), 7.94 (d, J: 8.7 Hz, 1H), 7.65 - 7.80 (m, 1H), 7.04 - 7.10 (t, J: 8.1 Hz, 1H), 6.92 - 6.99 (t, J: 9.9 Hz, 1H), 4.51 - 4.53 (m, 1H), 4.00 (s, 3H), 3.05 - 3.08 (m, 2H), 2.17 - 2.21 (m, 1H), 1.85 - 1.95 (m, 1H), 1.65 - 1.75 (m, 2H), 1.41 - 1.47 (m, 3H) Step 2. (S)—2—(2,4—Difluorophenyl)(2-methylpyrrolidiny1)quinoxaline-6—carboxy1ic acid C‘ O N /N©)kOH F F To a solution of (S)—methyl 2—(2,4—difluorophenyl)-3—(2-methylpyrrolidiny1)quinoxaline—6— carboxylate (100 mg, 0.39 mmol) in MeOH (20 mL) was added sodium hydroxide (63 mg, 1.57 mmol) and water (2 mL). The resulting solution was stirred ght at room temperature and concentrated in vacuo. The residue was dissolved in water (2 mL) and adjusted to pH 6 with hydrochloric acid (IN). The solids were collected by filtration to afford (S)—2-(2,4—difluorophenyl)(2-methylpyrrolidin—1—yl)quinoxaline—6-carboxylic acid as a brown solid (82.4 mg, 86 %).
LC/MS (ES, m/z):[M+H]+ 370.0 1H-NMR (300 MHz, CD3OD)I 6 8.41 (d, J: 1.8 Hz, 1H), 7.97 - 8.01 (m, 1H), 7.89 (d, J: 8.4 Hz, 1H), 7.75 - 7.85 (m, 1H), 7.12 - 7.21 (m, 2H), 4.37 - 4.40 (m, 1H), 3.02 - 3.10 (m, 2H), 2.16 — 2.20 (m, 1H), 1.84 - 1.86 (m, 1H), 1.61 — 1.76 (m, 2H), 1.30 - 1.36 (t, J = 6.0 Hz, EXAMPLE 1 16 (S)(2,4-Difluorophenyl)(2-methylpiperidinyl)quinoxalinecarb0xylic acid N /N]:>)}\OH\N Step 1. (S)~Methy1 2-(2,4-difluorophenyl)—3-(2—methy1piperidin- 1-yl)quinoxaline-6— carboxylate F F To a solution of (2,4-difluorophenyl)boronic acid (218.9 mg, 1.39 mmol) in e (5.0 mL) and water (3 drops) was added (S)-methy13—(2—methylpiperidin—l—yl) oromethylsulfonyloxy)quinoxaline-6—carboxy1ate (300 mg, 0.69 mmol), K3PO4 (293 mg, 1.38 mmol) and Pd(PPh3)4 (39.97 mg, 0.03 mmol) with stirring for 1 hour at 95°C in an oil bath under an inert atmosphere of nitrogen. The reaction mixture was concentrated in vacuo to give a residue, which was ed via silica gel column chromatography (2% ethyl acetate in petroleum ether) to afford (S)—methy1 2—(2,4—difluorophenyl)(2-methylpiperidin- 1-y1)quinoxalinecarboxylate as a light yellow solid (192.0 mg, 70 %) LC/MS (ES, m/z): [M+H]+ 398.0 1H—NMR (300 MHz, CDClg): 8 8.56 (d, I: 1.50 Hz, 1H), 8.08 - 8.11 (m, 1H), 7.98 (d, J = 8.70 Hz, 1H), 7.67 - 7.75 (m, 1H), 6.95 - 7.10 (m, 2H), 4.11 - 4.17 (m, 1H), 4.01 (s, 3H), 3.46 — 3.50 (m, 1H), 3.09 - 3.17 (m, 1H), 1.41 - 1.76 (m, 6H), 1.13 (d, J: 6.60 Hz, 3H) Step 2. (S)—2—(2,4-Difluoropheny1)-3—(2—methy1piperidinyl)quinoxaline—6-carboxylic acid F F To a solution of (S)-methy1 2-(2,4-difluorophenyl)—3-(2-methylpiperidinyl)quinoxaline carboxylate (100 mg, 0.25 mmol) in methanol (30 mL) and water (1.0 mL) was added sodium hydroxide (40 mg, 1.00 mmol) with stirring overnight at room temperature. The reaction mixture was concentrated in vacuo, dissolved in water (10 mL) and ed to pH 5 with HCl (3N). The solids were collected by filtration to afford (S)(2,4-difluorophenyl)(2— methylpiperidin—l—yl)quinoxaline—6—carboxylic acid as a light yellow solid (55.5 mg, 57.5 %).
LC/MS (ES, m/z): [M+H]+ 366.0 1H-NMR (300 MHz, DMSO): 5 8.29 (d, J: 1.5 Hz 1H), 7.99 - 8.03 (m, 1H), 7.92 (d, J: 8.4 Hz, 1H), 7.80 - 7.88 (m, 1H), 7.43 - 7.50 (m, 1H), 7.28 - 7.34 (m, 1H), 4.01- 4.02 (m, 1H), 3.56 - 3.59 (m, 1H), 3.03 — 3.09 (m, 1H), 1.37 - 1.58 (m, 6H), 1.15 (d, J: 6.6 Hz, 3H) E 117 (S)(4-Fluor0methylphenyl)(2-methylpyrrolidinyl)quinoxaline carboxylic acid C ° Step 1. (4—Fluoro-2—methylpheny1)boronic acid B(OH)2 To a solution of 1—bromo—4—fluoro—2—methy1benzene (5 g, 26.45 mmol) in THF (100 mL) was added n-butyllithium (12.7 mL) dropwise at —78°C. Tris(propan—2-y1)borate (10 g, 53.17 mmol) was added dropwise and the reaction was stirred overnight at -78°C in a liquid nitrogen bath. The resulting solution was diluted with s sodium hydroxide (IN, 30 mL) and extracted with ether (2 x 50 mL). The aqueous layers were combined and adjusted to pH 3 with HCl (3N), extracted with ethyl acetate (3 x 50 mL), and the organic layers were combined and concentrated in vacuo to give ro—2—methylphenyl)boronic acid as a white solid (2.1 g, 52 %).
Step 2. (S)-Methyl 2-(4-fluoromethylphenyl)—3-(2-methy1pyrrolidin—1—y1)quinoxaline carboxylate To a solution of (S)—methy1 ethylpyrrolidin—1-yl)—2— (trifluoromethylsulfonyloxy)quinoxalinecarboxy1ate (150 mg, 0.41 mmol) in dioxane (5.0 mL) and water (3 drops) was added (4-fluoro—2—methy1phenyl)boronic acid (101 mg, 0.66 mmol), 3)4 (19.0 mg, 0.02 mmol), and K3PO4 (138.3 mg, 0.65 mmol). The reaction was stirred for 1 hour at 90°C under a nitrogen atmosphere. The resulting solution was concentrated in vacuo, and then purified by silica gel colunm chromatography (1% ethyl W0 2012/119046 2012/027423 acetate in petroleum ether) to provide (S)-methyl 2-(4-fluoro-2—methylphenyl)-3—(2— methylpyrrolidin-l-y1)quinoxaline—6-carboxylate as a yellow solid (120 mg, 78 %).
LC/MS (ES, m/z): [M+H]+ 380.0 1H-NMR (300 MHz, DMSO) 6 8.27 (s, 1H), 7.87 - 7.95 (m, 2H), 7.66 (s, 1H), 7.20 — 7.30 (m, 2H), 4.23 (d, J: 6.9 Hz, 1H), 3.93 (s, 3H), 3.00 - 3.05 (m,1H), 2.73 — 2.80 (m, 1H), 2.30 - 2.40 , 1.99 - 2.12 (m, 3H), 1.75 - 1.85 (m, 1H), 1.46 - 1.65 (m, 2H), 1.18 - 1.30 (m, Step 3. (S)-2—(4-Fluoromethylphenyl)-3 -(2-methy1pyrrolidiny1)quinoxaline carboxylic acid 0' ° To a solution of (S)—methy1 2—(4—fluoro-2—methylphenyl)—3 -(2-methylpyrrolidin-1— yl)quinoxaline-6—carboxylate (120 mg, 0.32 mmol) in methanol (20 mL) and water (1 mL) was added sodium hydroxide (50.7 mg, 1.27 mmol,) and the reaction was d overnight at room temperature. The resulting mixture was concentrated in vacuo, adjusted to pH 6 with aqueous HCl (3N), collected by filtration to afford (S)(4-fluoro-2—methylphenyl)—3—(2- methylpyrrolidin-l-yl)quinoxaline-6—carboxylic acid as a yellow solid (85.7 mg, 74 %).
LC/MS (ES, m/z): [M+H]+ 366.0 1H-NMR (300 MHz, DMSO) 6 8.25 (s, 1H), 7.89 (s, 2H), 7.64 (s, 1H), 7.10 - 7.30 (m, 2H), 4.24 - 4.34 (m, 1H), 3.01 - 3.10 (m, 1H), 2.68 - 2.74 (m, 1H), 2.30 - 2.40 (m, 1H), 2.04 - 2.09 (m, 3H), 1.74 - 1.90 (m, 1H), 1.48 - 1.63 (111,2H), 1.27 (d, J: 6.0 Hz , 3H) EXAMPLE 1 18 2-(4-Fluor0methylphenyl)—3—(isopropyl(methyl)amino)quinoxalinecarboxylic acid Y O I)?”/Nj:>)\0H\ | F Step 1. Methyl uoro—2-methylphenyl)-3—(isopropyl(methy1)amino)quinoxa1ine carboxylate Y O D?“| \ To a solution of (4-fluoromethylphenyl)boronic acid (158 mg, 1.03 mmol) in dioxane (5.0 mL) and water (3 drops) was added methyl 2—chloro[methyl(propan no]quinoxalinecarboxylate (100 mg, 0.34 mmol), K3PO4 (215 mg, 1.01 mmol) and Pd(PPh3)4 (20 mg, 0.02 mmol), and the reaction was stirred for 1 hour at 95°C under an inert atmosphere of nitrogen. The reaction mixture was concentrated in vacuo to provide a residue, which was purified via silica gel column chromatography (2% ethyl acetate in petroleum ether) to afford methyl 2-(4-fluoromethylphenyl)-3—(isopropyl(methyl)amino)quinoxaline- 6—carboxylate as a light yellow solid (53.0 mg, 42 %).
LC/MS (ES, m/z): [M+H]+ 368.0 1H—NMR (300 MHz, CDC13): 5 8.55 (d, J = 1.8 Hz, 1H), 8.04 — 8.08 (m, 1H), 7.95 (d, J = 8.7 Hz, 1H), 7.43 — 7.49 (m, 1H), 7.02 - 7.07 (m, 2H), 4.21 — 4.30 (m, 1H), 4.01 (s, 3H), 2.69 (s, 3H), 2.30 (s, 3H), 1.09 (d, J = 6.6 Hz, 6H) Step 2. 2-(4-Fluoromethylpheny1)(isopropy1(methyl)amino)quinoxaline—6—carboxylic acid Y O /N /Nj:>)L0H\ | FIf” To a solution of methyl 2-(4-fluoromethylphenyl) (isopropyl(methyl)amino)quinoxaline—6—carboxylate (45 mg, 0.12 mmol) in methanol (35 mL) and water (2.0 mL) was added sodium hydroxide (20 mg, 0.50 mmol) and 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 s HCl (3N). The solids were collected by filtration to afford 2-(4-fluoro-2—methy1phenyl) (isopropyl(methyl)amino)quinoxalinecarboxylic acid as a light yellow solid (36 mg, 83 %).
LC/MS (ES, m/z): [M+H]+ 354.0 lH-NMR (300 MHz, DMSO): 5 13.12 (s, 1H), 8.27 (s, 1H), 7.90 — 7.97 (m, 2H), 7.51 — 7.56 (m, 1H), 7.16 — 7.26 (m, 2H), 4.13 — 4.22 (m, 1H), 2.61 (s, 3H), 2.22 (s, 3H), 0.99 (d, J: 6.6 Hz, 6H) EXAMPLE 1 19 arbamoylphenyl)(isopropyl(methyl)amino)quinoxalinecarboxylic acid Y O Step 1. Methyl 2—(4—carbamoylpheny1)—3—(isopropyl(methyl)amino)quinoxaline-6—carboxylate Y O HZNYQJ:I / N To a solution of methyl 2—chloro-3—(isopropyl(methyl)amino)quinoxalinecarboxylate (120 mg, 0.49 mmol) in dioxane (5 mL) was added 4-carbamoy1pheny1boronic acid (169 mg, 1.02 mmol), K3PO4 (217 mg, 1.02 mmol), Pd(PPh3)4 (30 mg, 0.03 mmol) and water (5 drops). The resulting solution was stirred for 1 hour at 90°C and then concentrated in vacuo to give a residue, which was purified Via silica gel column chromatography (9% ethyl acetate in eum ether) to afford methyl 2-(4-carbam0ylphenyl)—3— (isopropy1(methyl)amino)quinoxalinecarboxylate as a yellow solid (103 mg, 66 %).
LC/MS (ES, m/z):[M+H]+ 379.0 1H—NMR (300 MHz, DMSO): 8 8.28 (d, J: 1.2 Hz, 1H), 8.09 (s, 1H), 8.01 (d, J: 8.4 Hz, 2H), 7.96 - 7.98 (m, 2H), 7.89 - 7.94 (m, 2H), 7.48 (s, 1H), 4.18 - 4.27 (m, 1H), 3.93 (s, 3H), 2.66 (s, 3H), 1.04 (d, J: 6.6 Hz, 3H) PCT/U52012/027423 Step 2. 2-(4-Carbamoylphenyl)—3—(isopropyl(methy1)amino)quinoxalinecarboxylic acid Y O To a solution of methyl 2-(4—carbamoylphenyl)(isopropyl(methyl)amino)quinoxaline carboxylate (103 mg, 0.27 mmol) in MeOH (20 mL) was added sodium hydroxide (68 mg, 1.69 mmol) and water (2 mL). The resulting on was stirred overnight at room temperature and concentrated in vacuo. The residue was dissolved in water (2 mL) and adjusted to pH 5 with hydrochloric acid (1N). The solids were ted by filtration to afford 2-(4-carbamoylphenyl)(isopropyl(methy1)amino)quinoxalinecarboxy1ic acid as a brown solid (57.9 mg, 58 %).
LC/MS (ES, m/z):[M+H]+ 365.0 1H—NMR (300 MHz, DMSO): 5 13.18 (s, 1H), 8.27 (s, 1H), 8.10 (s, 1H), 8.01 (d, J = 8.4 Hz, 2H), 7.90 — 7.98 (m, 4H), 7.48 (s, 1H), 4.18 — 4.22 (m, 1H), 2.66 (s, 3H), 1.03 (d, J = 6.6 Hz, EXAMPLE 120 2-(4-Fluorophenyl)hydroxy(isopropyl(methyl)amino)quinoxalinecarb0xylic acid Y O FDIN Step 1. Methyl 2,4-difluorobenzoate ACE” F F To a solution of fluorobenzoic acid (50.0 g, 316.25 mmol) in methanol (500 mL) was added sulfuryl dichloride (112 g, 949.15 mmol) at 0°C. The resulting solution was heated to reflux overnight and concentrated in vacuo to afford methyl 2,4-difluorobenzoate as a colorless oil (50 g, 92%). 1H-NMR (300 MHz, CDClg) 5 7.96 — 8.04 (m, 1H), 6.86 - 6.98 (m, 2H), 3.94 (s, 3H) Step 2. Methyl 4-fluoromethoxybenzoate To a solution of methyl 2,4—difluorobenzoate (50 g, 290 mmol) in dioxane (300 mL) was added sodium methoxide (18.0 g, 333.21 mmol) and the reaction was d for 48 hours at 100°C in an oil bath. The reaction mixture was cooled to room temperature and diluted with H20 (200 mL). The e was extracted with ethyl acetate (3 x 150 mL). The organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated in vacuo to afford methyl 4—fluoromethoxybenzoate as colorless oil (50.0 g, 92 %). 1H—NMR (300 MHz, CDClg) 5 7.84 — 7.89 (m, 1H), 6.66 - 6.72 (m, 2H), 3.86 — 3.91 (m, 6H) Step 3. Methyl 4—fluoro—2—methoxynitrobenzoate 021:0“NF 0/ To a solution of methyl 4—fluoro—2—methoxybenzoate (50 g, 271.50 mmol) in sulfuric acid (150 mL) was added a solution of potassium nitrate (35.6 g, 352.48 mmol) in sulfuric acid (30 mL) se with stirring for 45 min at 0—25°C in an ice/water bath. The reaction was then quenched by the addition of water/ice. The solids were ted by filtration to afford methyl 4-fluoro—2—methoxy—5—nitrobenzoate as a white solid (40.0 g, 64 %). 1H-NMR (300 MHz, CDClg) 5 8.46 - 8.51 (m, 1H), 7.43 (d, J = 13.8 Hz, 1H), 4.08 (s, 3H), 3.84 (s, 3H) Step 4. Methyl 2-methoxy(4-methoxybenzylamino)-5—nitrobenzoate PMBHN 0/ To a solution of methyl 4—fluoro-2—methoxy—5—nitrobenzoate (40 g, 174.55 mmol) in MN- dimethylformamide (1000 mL) was added DIEA (45.2 g, 349.74 mmol). Then (4- methoxyphenyl)methanamine (31.1 g, 226.71 mmol) was added dropwise with ng for 1 hour at 25°C. The reaction mixture was diluted with water (2L). The solids were collected by filtration to afford methyl 2—methoxy—4—(4—methoxybenzylamino)nitrobenzoate as a yellow solid (44 g, 75 %).
W0 19046 1H—NMR (300 MHz, CDC13) 8 8.97 — 9.01 (t, J: 5.4 Hz, 1H), 8.55 (d, J = 6.0 Hz, 1H), 7.36 (d, J: 8.7 Hz, 2H), 6.92 - 6.96 (m, 2H), 6.35 (s, 1H), 4.62 (d, J: 5.7 HZ, 2H), 3.72 — 3.81 (m, Step 5. Methyl 5—aminomethoxy(4—methoxybenzylamino)benzoate H2Nmay PMBHN 0/ To a solution of methyl 2-methoxy(4-methoxybenzylamino)nitrobenzoate (544 g, 144.37 mmol) in methanol (1500 mL) was added palladium on carbon (15 g). The on was allowed to react for 2h at room temperature under an atmosphere of H2 (g). The solids were filtered from the resulting solution, and the filtrate was concentrated in vacuo to afford methyl 5-amino-2—methoxy(4-methoxybenzylamino)benzoate as a white solid (30.0 g, 75 1H-NMR (300 MHz, DMSO) 5 7.30 (d, J = 8.7 Hz, 2H), 7.04 (d, J = 4.5 Hz, 1H), 6.88 - 6.93 (m, 2H), 6.07 (s, 1H), 5.89 - 5.92 (t, J: 5.7 Hz, 1H), 4.40 (s, 2H), 4.31 (d, J: 5.7 Hz, 2H ), 3.71 (s, 3H), 3.83 (s, 3H), 3.65 (s, 1H) Step 6. Methyl 7-methoxy-l-(4-methoxybenzyl)-2,3-dioxo—1,2,3,4—tetrahydroquinoxaline—6— carboxylate o n I If", 0 I}: o/ The solution of methyl 5—amino—2-methoxy—4—(4—methoxybenzylamino)benzoate (30 g, 94.83 mmol) in diethyl oxalate (100 mL) was stirred for 3h at reflux and then cooled with a water/ice bath and d with ether (500 mL). The product was collected by filtration to afford methyl 7-methoxy- l - [(4-methoxyphenyl)methyl] -2,3-dioxo— l ,2,3 ,4- tetrahydroquinoxaline—6—carboxylate as a light yellow solid (25.0 g 71 %). 1H—NMR (300 MHz, DMSO) 5 12.03 (s, 1H), 7.56 (d, J = 3.3 Hz, 1H), 7.32 (d, J: 8.7 Hz, 2H), 6.88 - 6.92 (m, 3H), 5.38 (s, 2H), 3.91 (s, 3H), 3.71 - 3.79 (m, 6H) PCT/U82012/027423 Step 7. Methyl 3—chloromethoxy(4-methoxybenzy1)—2-oxo-1,2-dihydroquinoxa1ine—6— carboxylate Cl Nfio/ o u o/ To a solution of methyl 7—methoxy—l—[(4-methoxyphenyl)methyl]-2,3-dioxo—l,2,3,4— tetrahydroquinoxaline-6—carboxylate (24 g, 64.80 mmol) in toluene (300 mL) was added POC13 (14.8 g, 96.52 mmol) and MN—dimethylanaline (15.7 g, 129.75 mmol). The resulting solution was stirred overnight at 110°C and concentrated in vacuo. The product was precipitated by the addition of methanol (150 mL) and ted by filtration to afford methyl 3-chloromethoxy(4-methoxybenzyl)—2—oxo—1,2-dihydroquinoxalinecarboxylate as a green solid (17 g, 65 %). 1H-NMR (300 MHz, DMSO) 6 8.02 (s, 1H), 7.34 (d, J = 8.7 Hz, 2H), 7.03 (s, 1H), 6.88 - 6.92 (m, 2H), 5.52 (s, 2H), 3.85 (s, 3H), 3.81 (s, 3H), 3.72 (s, 3H) Step 8. Methyl 3-chloromethoxyoxo-1,2-dihydroquinoxa1ine-6—carboxylate CIIdeLO/o n 0/ Methyl 3—chloromethoxy— 1 -(4-methoxybenzyl)—2—oxo—1 ydroquinoxaline carboxylate (6.0 g, 15.43 mmol) was added to sulfuric acid (conc, 15 mL) in several s with stirring at room temperature and then stirred for 10 minutes. The resulting solution was diluted with ice-water (100 mL) and extracted with ethyl acetate (3 x 200 mL). The organic layers were combined and dried over anhydrous magnesium sulfate and concentrated in vacuo to afford methyl 3-chloromethoxyoxo-1,2-dihydroquinoxalinecarboxylate as a yellow solid (2.5, 60 %). 1H—NMR (300 MHz, DMSO) 8 12.9 (s, 1H), 7.98 — 8.02 (m, 1H), 7.03 (s, 1H), 3.92 (s, 3H), 3.85 (s, 3H) Step 9. Methyl 3-(isopropyl(methy1)amino)methoxy—2-oxo-1,2-dihydroquinoxa1ine ylate Y o /03:”,NDEMO/ To a solution of methyl romethoxy—2-oxo-1,2—dihydroquinoxalinecarboxylate (1.2 g, 4.47 mmol) in DMSO (20 mL) was added DIEA (1.16 g, 8.98 mmol) and methyl(propan—2—yl)amine (490 mg, 6.70 mmol) with stirring at 85°C overnight. The reaction mixture was cooled to room temperature. The product was precipitated by the addition water and the solids were collected by filtration to afford methyl 3— (isopropyl(methyl)amino)—7—methoxy—2—oxo-1,2—dihydroquinoxaline-6—carboxylate as a light yellow solid (1.0 g, 73 %).
LC/MS (ES, m/z): [M+H]+ 306.0 1H-NMR (300 MHz, DMSO) 8 12.10 (s, 1H), 7.69 (d, J = 6.3 Hz, 1H), 6.78 (s, 1H), 5.14 - .22 (m, 1H), 3.71 (s, 6H), 2.99 (s, 3H), 1.21 (d, J = 6.6 Hz, 6H) Step 10. Methyl 3—(isopropyl(methy1)amino)—7-methoxy-2— (trifluoromethylsulfonyloxy)quinoxaline—6—carboxylate Y o TfOIN/N@0/0/ To a solution of methyl 3-(isopropyl(methyl)amino)—7-methoxyoxo-1,2- dihydroquinoxaline-6—carboxylate (2.0 g, 6.55 mmol) in dichloromethane (80 mL) was added pyridine (2.0 g, 25.28 mmol) and szO (3.66 g, 12.97 mmol) with stirring overnight under an atmosphere of en at room temperature. The reaction e was then quenched with water (50 mL) and extracted with dichloromethane (3 x 80 mL). The organic layers were combined and dried over anhydrous ium e and concentrated in vacuo to afford methyl 3-(isopropyl(methyl)amino)—7-meth0xy—2—(trifluoromethylsulfonyloxy)quinoxaline carboxylate as red oil (2.50g, crude), which was used in the next step directly.
Step 11. Methyl 2-(4-fluorophenyl)(isopropy1(methyl)amino)methoxyquinoxaline-6— carboxylate Y o DIN/Nka/0/ To a solution of methyl 3-(isopropyl(methyl)amino)—7—meth0xy—2— (trifluoromethylsulfonyloxy)quinoxalinecarboxylate (2.5 g, crude) in dioxane (5.0 mL) and water (3 drops) was added (4—fluorophenyl)boronic acid (2.40 g, 17.15 mmol), Pd(PPh3)4 (320 mg, 0.28 mmol), and K3PO4 (3.58 g, 16.87 mmol) with stirring for 1.5h at 95°C under an atmosphere of nitrogen. The on mixture was concentrated in vacuo to give a e, which was purified via silica gel column chromatography (1% ethyl acetate in petroleum ether) to afford methyl uoropheny1)—3-(isopropyl(methy1)amino) methoxyquinoxa1inecarboxylate as a light yellow solid (09 g, 36% 2 steps).
LC/MS (ES, m/z): [M+H]+ 384.0 1H-NMR (300 MHz, DMSO) 8 7.81 - 7.86 (m, 3H), 7.47 (s, 1H), 7.33 - 7.41 (m, 2H), 3.95 - 4.02 (m, 1H), 3.92 (s, 3H), 3.87 (s, 3H), 2.66 (s, 3H), 0.99 (d, J: 6.6 Hz, 6H) Step 12. Methyl 2-(4-fluorophenyl)hydroxy(isopropyl(methyl)amino)quinoxaline carboxylate Y O QIN\ OH To a solution of methyl 2—(4—fluorophenyl)(isopropy1(methyl)amino)—7- methoxyquinoxaline—6-carboxylate (500 mg, 1.31 mmol) in dichloromethane (80 mL) was added BBr3 (2.0 mL) dropwise with stirring at -78°C for 30 minutes. The reaction was then quenched by the addition of water/ice. The resulting solution was ted with dichloromethane (3 x 80 mL), and the organic layers combined, dried over anhydrous magnesium sulfate, and concentrated in vacuo to give the residue, which was purified via silica gel column chromatography (2% ethyl acetate in petroleum ether) to afford methyl 2— (4-f1uoropheny1)hydroxy(isopropy1(methyl)amino)quinoxalinecarboxylate as a yellow solid (145 mg, 30%).
LC/MS (ES, m/z): r 370.0 1H-NMR (300 MHz, DMSO) 8 10.35 (s, 1H), 8.15 (s, 1H), 7.91 - 8.14 (m, 2H), 7.33 - 7.39 (m, 3H), 3.89 - 4.04 (m, 4H), 2.65 (s, 3H), 0.95 (d, J: 6.6 Hz, 6H) Step 13. 2-(4-Fluoropheny1)hydroxy-3—(isopropyl(methyl)amino)quinoxalinecarboxylic acid Y O OIN/N:©:lkOH\ OH To a solution of methyl 2-(4-fluorophenyl)—7-hydroxy—3- (isopropyl(methy1)amino)quinoxalinecarboxylate (45 mg, 0.12 mmol) in methanol (30 mL) and water (1.0 mL) was added sodium hydroxide (19.5 mg, 0.49 mmol) with stirring overnight at room temperature. The reaction mixture was concentrated in vacuo, dissolved in water (30 mL), adjusted to pH 5 with hydrochloric acid (3N) to give the precipitate, which was collected by filtration to afford 2-(4—fluorophenyl)—7-hydroxy (isopropyl(methyl)amino)quinoxaline—6-carboxylic acid as a light yellow solid (38.2 mg, 88 LC/MS (ES, m/z): [M+H]+ 356.1 1H-NMR (300 MHz, DMSO) 8 8.17 (s, 1H), 7.92 - 7.97 (m, 2H), 7.32 - 7.37 (t, J: 9.0 Hz, 2H), 7.12 (s, 1H), 3.79 - 3.88 (m, 1H), 2.65 (s, 3H), 0.95 (d, J: 6.6 Hz, 6H) EXAMPLE 1 21 (R)(4-Fluorophenyl)(2-methylpiperidinyl)quinoxalinecarboxylic acid N /N]:>)\0H\N Step 1. Methyl 3—(2—methy1piperidin-l-yl)-2—oxo-1,2-dihydroquinoxalinecarboxylate U ° N IN@0/ To a solution of methyl 3-chloro—2—oxo—l,2-dihydroquinoxalinecarboxylate (600 mg, 2.51 mmol) in DMSO (10 ml) was added 2-methy1piperidine (500 mg, 5.04 mmol) and DIEA (650 mg, 5.03 mmol). The resulting on was stirred at 80°C for 2 hours and then ed by water (50 ml). The solids were collected by filtration to afford methyl 3—(2—methylpiperidin— 2-oxo—1,2—dihydroquinoxaline—6-carboxylate as a light yellow solid (520 mg, 69%). 1H-NMR (300 MHz, DMSO) 8 12.31 (s, 1H), 7.89 (d, J: 1.8 Hz, 1H), 7.70 - 7.73 (m, 1H), 7.20 (d, J = 8.4 Hz, 1H), 5.20 - 5.30 (m, 1H), 4.71 - 4.76 (m, 1H), 3.84 (s, 3H), 3.01-3.10(m, 1H), 1.62 —1.74 (m, 6H), 1.25 (d, J = 6.6 Hz, 3H) Step 2. Methyl 3-(2—methy1piperidiny1)-2—(trifluoromethylsulfonyloxy)quinoxaline—6— carboxylate 0 ° TfO N To a solution of methyl 3-(2-methylpiperidinyl)oxo-1,2-dihydroquinoxaline-6— carboxylate (520 mg, 1.73 mmol) in dichloromethane (60 ml) was added pyridine (690 mg, 8.72 mmol) followed by the addition of TfZO (1.22 g, 4.32 mmol), and the resulting solution was stirred overnight at room temperature. The reaction was quenched by the addition of ice- water (200 ml) and extracted with dichloromethane (2 x 30 ml). The organic layers were combined, dried over anhydrous magnesium sulfate and concentrated in vacuo to afford methyl 3—(2—methylpiperidinyl)(trifluoromethylsulfonyloxy)quinoxalinecarboxylate as red oil (880 mg, .
Step 3. Methyl 2—(4—fluorophenyl)—3—(2-methylpiperidin—1-yl)quinoxaline—6—carboxylate To a solution of methyl 3-(2-methylpiperidinyl) oromethylsulfonyloxy)quinoxalinecarboxylate (880 mg, crude) in dioxane (25 ml) was added Pd(PPh3)4 (100 mg, 0.09 mmol), 4—fluorophenylboronic acid (485 mg, 3.47 mmol), K3PO4 (735 mg, 3.46 mmol) and water (3 ml). The resulting solution was stirred for 1 hour at 90°C under an inert atmosphere of nitrogen, and then concentrated in vacuo to give a residue, which was purified via silica gel column chromatography (1% - 10% ethyl acetate in eum ether) to afford methyl 2-(4-fluorophenyl)(2-methylpiperidinyl)quinoxaline- 6—carboxylate as a yellow solid (330 mg).
LC/MS (ES, m/z): [M+H]+ 380.0 1H—NMR (300 MHz, CDC13) 8 8.53 (d, J: 1.5 Hz, 1H), 7.95 — 8.10 (m, 4H), 7.17 — 7.28 (m, 2H), 4.06 — 4.10 (m, 1H), 4.00 (s, 3H), 3.47 - 3.51 (m, 1H), 3.11 - 3.19 (m, 1H), 1.55 - 1.76 (m, 6H), 1.11 (d, J: 6.6 Hz, 3H) 2012/027423 Step 4. (R)—2—(4-Fluorophenyl)(2-methy1piperidin—1—y1)quinoxalinecarboxy1ic acid To a solution of methyl 2—(4-fluorophenyl)(2-methylpiperidinyl)quinoxaline-6— carboxylate (330 mg, 0.87 mmol) in methanol (15 ml) was added NaOH (104.4 mg, 2.61 mmol) and water (1 ml). The resulting solution was stirred ght at room temperature and concentrated in vacuo. The residue was dissolved in water (15 ml) and adjusted to pH 5 with hydrochloric acid (3N) to yield a precipitate that was collected to afford yellow solid (250 mg). The solids was purified by Chiral—Prep-HPLC to afford (R)(4-fluorophenyl)(2- methylpiperidin—l-yl)quinoxaline—6—carboxylic acid as a yellow solid (53.2 mg, 17 %).
LC/MS (ES, m/z): [M+H]+ 366.1 1H-NMR (300 MHz, DMSO) 6 8.45 (s, 1H), 8.03 - 8.09 (m, 3H), 7.94 (d, J = 8.7 Hz, 1H), 7.26 - 7.32 (t, J = 8.7 Hz, 2H), 4.05 - 4.06 (m, 1H), 3.48 — 3.53 (m, 1H), 3.16 - 3.24 (m, 1H), 1.30 - 1.81 (m, 6H), 1.12 (d, J = 6.6 Hz, 3H) EXAMPLE 122 2-(4-Fluorophenyl)methoxy[methyl(propanyl)amino]quinoxalinecarboxylic acid Y O To a solution of methyl 2—(4—fluoropheny1)methoxy[methyl(propan yl)amino]quinoxalinecarboxylate (120 mg, 0.31 mmol) in methanol (30 mL) and water (1.0 mL) was added sodium hydroxide (50 mg, 1.25 mmol) with stirring overnight at room temperature. The reaction mixture was concentrated in vacuo, dissolved in water (30 mL), and ed to pH 5 with hydrochloric acid (3N) to give the precipitate, which was collected by filtration to afford 2-(4-fluorophenyl)methoxy[methyl(propan no]quinoxalinecarboxylic acid as a light yellow solid (38.2 mg, 88 %).
LC/MS (ES, m/z): [M+H]’r 370.1 2012/027423 1H-NMR (300 MHz, DMSO) 3 7.91 - 7.97 (m, 3H), 7.34 - 7.43 (m, 3H), 3.93 - 3.99 (m, 1H), 3.92 (s, 3H), 2.73 (s, 1H), 0.98 (d, J: 6.6 Hz, 6H) EXAMPLE 123 7-Fluoro(4-fluorophenyl)[methyl(propanyl)amino]quinoxalinecarboxylic acid Y O /N /N©\)kOH OI”\ F Step 1. Methyl 2,4—difluoro-5—nitrobenzoate To a solution of methyl 2,4—difluorobenzoate (50.0 g, 290.48 mmol, 1.00 equiv) in sulfuric acid (150 ml) was added a solution of potassium nitrate (35.23 g, 348.81 mmol) in sulfuric acid (30 ml) se in an ice-water bath with stirring for 1h at 0—25°C. The reaction was then quenched by the addition of ice-water. The solids were collected by filtration to afford methyl 2,4—difluoro—5—nitrobenzoate as a white solid (40.0 g, 63 %). 1H—NMR (300 MHz, DMSO) 5 8.61 - 8.66 (m, 1H), 7.88 - 7.95 (m, 1H), 3.92 (s, 3H) Step 2. Methyl 2-fluoro(4—methoxybenzylamino)nitrobenzoate zN:©\)J\O/F To a solution of methyl 2,4-difluoronitrobenzoate (35 g, 161.20 mmol) in MN- dimethylformamide (1000 ml) was added DIEA (41.3 g, 319.56 mmol). Then (4- methoxybenzylamine (28.72 g, 209.64 mmol) was added dropwise with stirring for 1 hour at °C. The reaction mixture was diluted with water (2 L). The solids were collected by filtration to afford methyl 2—flu0r0(4-methoxybenzylamino)nitrobenzoate as a yellow solid (44 g, 82 %). 1H—NMR (300 MHz, DMSO) 8 9.05 - 9.12 (m, 1H), 8.62 — 8.70 (m, 2H), 7.30 — 7.35 (m, 2H), 6.90 — 6.95 (m, 2H), 4.59 (d, J = 6.0 Hz, 2H), 3.88 (s, 3H), 3.81 (s, 3H) Step 3. Methyl 5—amino—2-fluoro-4—(4—methoxybenzylamino)benzoate H2Nfl0/ PMBHN F To a solution of methyl 2-fluoro—4—(4-methoxybenzylamino)nitrobenzoate (50.0 g, 149.57 mmol) in methanol (1500 ml) was added palladium on carbon (15 g). The mixture was allowed to react for 2 hours at room temperature under an atmosphere of H2 (g). The solids were filtered out and the filtrate was concentrated in vacuo to afford methyl o—2- (4-methoxybenzylamino)benzoate as a gray solid (30.0 g, 66 %). 1H-NMR (300 MHz, DMSO) 8 7.27 (d, J = 8.7 Hz, 2H), 7.04 (d, J = 7.5 Hz, 1H), 6.88 - 6.93 (m, 2H), 6.12 - 6.21 (m, 2H), 4.72 (s, 2H), 4.30 (d, J = 5.7 Hz, 2H), 3.68 — 3.73 (m, 6H) Step 4. Methyl 7—fluoro-l-(4-methoxybenzyl)—2,3-dioxo-1,2,3,4—telrahydroquinoxaline carboxylate o n 1 Dodo/ O I}! F The solution of methyl 5—aminofluoro(4-methoxybenzylamino)benzoate (30 g, 98.58 mmol) in diethyl oxalate (100 ml) was d for 3h at reflux and then cooled with a water/ice bath, diluted with ether (500 ml). The t was collected by filtration to afford methyl 7-fluoro- 1-(4-methoxybenzyl)-2,3-dioxo-1 ,2,3 ,4—tetrahydroquinoxa1ine—6—carboxylate as a light yellow solid (35.0 g , 99 %). 1H-NMR (300 MHZ, DMSO) 8 12.19 (s, 1H), 7.69 (d, J: 6.9 Hz, 1H), 7.20 - 7.31 (m, 3H), 6.87 - 6.92 (m, 2H), 5.30 (s, 2H), 3.84 (s, 3H), 3.81 (s, 3H) Step 5. Methyl 3 -chlorofluoro(4-methoxybenzyl)—2—oxo-1 ,2-dihydroquinoxaline carboxylate CI N@0/ O I}! F Methyl 7-fluoro- l ~(4—methoxybenzyl)—2,3—dioxo— l ,2,3 ,4-tetrahydroquinoxaline—6—carboxylate (35.0 g, 98 mmol) was added to POC13 with stirring overnight at 130°C and concentrated in vacuo. The product was precipitated via the addition of methanol (150 ml) and collected by W0 2012/119046 filtration to afford methyl rofluoro—1-(4—methoxybenzyl)—2-oxo—1,2- dihydroquinoxalinecarboxylate as a yellow solid (25.0 g, 68%). 1H-NMR (300 MHz, DMSO) 8 8.21 (d, J = 7.5 Hz, 1H), 7.50 — 7.55 (m, 1H), 7.23 - 7.32 (m, 2H), 6.88 - 6.92 (m, 2H), 5.43 (s, 2H), 3.96 (s, 3H), 3.74 (s, 3H) Step 6. Methyl 3-chlorofluorooxo—1,2-dihydroquinoxaline-6—carboxylate CIINfio/ O M F Methyl 3-chloroflu0ro- 1-(4-methoxybenzy1)—2—oxo— 1 ,2~dihydroquinoxalinecarboxy1ate (4.0 g, 10.62 mmol) was added to sulfuric acid (conc, 15 ml) in several s with stirring at room temperature, and then stirred for 10 minutes. The ing solution was diluted with ice-water (100 ml) and extracted with ethyl acetate (3 x 200 ml). The organic layers were combined and dried over anhydrous ium sulfate and concentrated in vacuo to afford methyl 3—chloro—7—fluorooxo—1,2—dihydroquinoxalinecarboxylate as a yellow solid (2.0 g, crude), which was used in the next step without further purification.
Step 7. Methyl 7-fluoro[methyl(propanyl)amin0]-2—oxo-1,2-dihydroquinoxa1ine—6— carboxylate Y o /N /N]©:KO/ 01” F To a solution of methyl 3-chlorofluoro—2—oxo—1,2-dihydroquinoxaline-6—carboxylate (2.0 g, crude) in DMSO (20 ml) was added DIEA (2.0 g, 15.48 mmol) and methyl(propan yl)amine (790 mg, 10.80 mmol) with stirring at 85°C overnight. The reaction mixture was cooled to room temperature. The product was itated by the addition water and the solids were collected by filtration to afford methyl 7-fluoro-3—[methyl(propan—2-y1)amino]-2— oxo—l,2-dihydroquinoxalinecarboxylate as a light yellow solid (800 mg).
LC/MS (ES, m/z): [M+H]+294.0 1H-NMR (300 MHZ, DMSO) 8 12.28 (s, 1H), 7.78 (d, J: 7.5 Hz, 1H), 6.91 (d, J: 11.4 Hz, 1H), 5.22 — 5.29(m, 1H), 3.84 (s, 3H), 3.04 (s, 3H), 1.17 (d, J = 6.6 Hz, 6H) WO 19046 Step 8. Methyl 7-fluoro—3-[methyl(propan—2—yl)amino] [(trifluoromethane)sulfonyloxy]quinoxaline—6-carboxylate Y o /N /Nfio/ TfOI\N F To a solution of methyl 7-fluoro-3—[methy1(propanyl)amino]oxo-1,2- dihydroquinoxalinecarboxylate (800 mg, 2.73 mmol) in dichloromethane (80 ml) was added pyridine (863 mg, 10.91 mmol) and ngO (1.5 g, 5.32 mmol) with stirring overnight under atmosphere of nitrogen at room temperature. The reaction mixture was then quenched with water (50 ml), extracted with dichloromethane (3 x 80 ml), and the organic layers ed and dried over anhydrous magnesium sulfate and trated in vacuo to afford methyl 7-fluoro[methy1(propanyl)amino] [(trifluoromethane)sulfonyloxy]quinoxaline—6—carboxylate as yellow oil (600 g, crude), which was used in the next step directly.
Step 9. Methyl 7-fluoro—2—(4—fluorophenyl)—3—[methy1(propanyl)amino]quinoxa1ine—6- carboxylate Y O DI”\ F To a solution of methyl o[methy1(propanyl)amino] [(trifluoromethane)sulfonyloxy]quinoxa1inecarboxylate (400 mg, crude) in dioxane (5.0 m1) and water (3 drops) was added (4-fluorophenyl)boronic acid (389 mg, 2.78 mmol), Pd(PPh3)4 (163 mg, 0.14 mmol), and K3PO4 (595 mg, 2.80 mmol) with stirring for 40min at 90°C under an atmosphere of nitrogen. The on mixture was concentrated in vacuo to give a residue, which was purified via silica gel column chromatography (1% ethyl acetate in petroleum ether) to afford methyl 7—fluoro—2—(4—fluorophenyl)[methy1(propan—2- yl)amino]quinoxalinecarboxy1ate as a light yellow solid (150 mg).
LC/MS (ES, m/z): [M+H]+ 372.0 1H—NMR (300 MHz, DMSO) 8 8.46 (d, J = 7.2 Hz, 1H), 7.91 - 7.96 (m, 2H), 7.64 (d, J: 11.1 Hz, 1H), 7.18 — 7.24 (m, 2H), 4.15 — 4.24 (m, 1H), 4.02 (s, 3H), 2.75 (s, 3H), 1.09 (d, J = 6.6 Hz, 6H) Step 10. 7-Fluoro-2—(4—fluorophenyl)[methyl(propan—2—yl)amino]quinoxalinecarboxylic acid Y O /N ”QEKOH DI“\ F To a solution of methyl o-2—(4-fluoropheny1)—3-[methyl(propan—2— yl)amino]quinoxaline—6—carboxylate (150 mg, 0.40 mmol) in tetrahydrofuran (30 ml) and water (1.0 ml) was added m hydroxide (38.8 mg, 1.62 mmol) with stirring overnight at room temperature. The reaction mixture was concentrated in vacuo, dissolved in water (30 ml), and ed to pH 5 with hydrochloric acid (3N) to give the precipitate, which was collected by filtration to afford 7-fluoro—2—(4-fluorophenyl)-3~[methyl(propan yl)amino]quinoxalinecarboxylic acid as a light yellow solid (120 mg, 83 %).
LC/MS (ES, m/z): [M+H]+ 358.1 1H-NMR (300 MHz, DMSO) 5 8.16 (d, J = 7.5 Hz, 1H), 7.89 — 7.94 (m, 2H), 7.72 (d, J: 11.1 Hz, 1H), 7.35 - 7.41 (m, 2H), 4.07 — 4.16 (m, 1H), 2.66 (s, 3H), 1.02 (d, J = 6.6 Hz, 6H) EXAMPLE 124 2-(4-Fluor0phenyl)[methyl(2,2,2-trifluoroethyl)amino]quinoxalinecarboxylic acid j 0 Step 1. Methyl 2-(4-fluoropheny1)[(2,2,2-trifluoroethyl)arrrino]quinoxalinecarboxylate j 0 HN Nfio/ To a solution of methyl 3—chloro(4-fluorophenyl)quinoxalinecarboxylate (500 mg, 1.58 mmol) in DMSO (23 ml) was added 2,2,2—trifluoroethan—1—amine (188 mg, 1.90 mmol) and DIEA (407 mg, 3.15 mmol,) with stirring, and the resulting mixture was allowed to react for 4 days at 110°C in an oil bath. The reaction mixture was diluted with water (80 ml), extracted WO 19046 PCT/U52012/027423 with romethane (4 x 15 m1), dried over anhydrous sodium sulfate, and concentrated in vacuo to give the residue, which was purified via silica gel column chromatography (2% ethyl acetate in petroleum ether) to afford methyl 2-(4-fluorophenyl)—3-[(2,2,2— trifluoroethyDamino]quinoxaline—6-carboxylate as a yellow solid(400 mg, 67 %).
LC/MS (ES, m/z): [M+H]+ 380.1 1H—NMR (300 MHz, CDC13) 8 8.52 (d, J = 1.8 Hz, 1H), 8.08 — 812 (m, 1H), 7.99 (d, J = 8.7 Hz, 1H), 7.76 - 7.82 (m, 2H), 7.28 - 7.35 (m, 2H), 5.33 - 5.37 (m, 1H), 4.33 — 4.44 (m, 2H), 4.02 (s, 3H) Step 2. 2—(4-Fluorophenyl)—3-[methy1(2,2,2-tn’fluoroethyl)amino]quinoxaline—6-carboxylic acid F30W o I NfikOH To a solution of methyl 2-(4-fluorophenyl)[(2,2,2—trifluoroethyl)amino]quinoxaline—6- carboxylate (400 mg, 1.05 mmol) in tetrahydrofuran (30 ml) was added sodium hydride (101 mg, 4.21 mol) at 0°C with stirring for 40 minutes and then iodomethane (899 mg, 6.33 mmol) was added to the reaction mixture, and the resulting mixture was allowed to react with stirring overnight at room temperature. The reaction mixture was adjusted pH to 4 with HCl to give the solid, which was ted by filtration to afford 2-(4-fluorophenyl) [methyl(2,2,2—trifluoroethyl)amino]quinoxa1ine—6-carboxylic acid as a yellow solid (80.6 mg, %).
LC/MS (ES, m/z):[M+H]+ 380.0 1H-NMR (300 MHZ, DMSO) 8 11.19 (s, 1H), 8.35 (s, 1H), 8.04 (s, 2H), 7.84 - 7.89 (m, 2H), 7.41 - 7.47 (m, 2H), 4.49 — 4.52 (m, 2H), 2.84 (s, 3H) W0 2012/119046 EXAMPLE 125 2-(4-Fluor0phenyl)(((1r,4r)hydroxycyclohexyl)(methyl)amino)quinoxaline carboxylic acid /N /Nj©)‘\OH\ FQI“ Step 1. Methyl 2~(4-fluorophenyl)(((1r,4r) hydroxycyclohexyl)(methyl)amino)quinoxaline~6-carboxylate : o /N /N:©)‘\O/ OI”\ To a solution of methyl 3—chloro-2—(4-fluorophenyl)quinoxalinecarboxy1ate (408 mg, 1.29 mmol) in DMSO (20 ml) was added trans-4—(methy1amino)cyclohexan—l—ol (200 mg, 1.55 mmol) and DIEA (499 mg, 3.86 mmol), and the on mixture was allowed to react with stirring ght at 100°C in an oil bath. The reaction e was diluted with water (200 ml), extracted with dichloromethane (4 x 50 ml). The organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated in vacuo to give the residue, which was purified via silica gel column chromatography (5% ethyl acetate in petroleum ether) to afford methyl 2—(4-fluoropheny1)((( 1 r,4r)—4—hydroxycyclohexyl)(methyl)amino)quinoxa1ine carboxylate as a yellow solid (130 mg, 25 %).
LC/MS (ES, m/z): [M+H]+410.0 1H-NMR (300 MHz, DMSO) 5 8.27 (s, 1H), 7.93 - - 7.99 (m, 2H), 7.85 - 7.90 (m, 2H), 7.36 7.41 (t, J = 8.4 Hz, 2H), 3.93 (s, 3H), 3.65 - 3.69 (m, 1H), 3.26 - 3.29 (m, 1H), 2.74 (s, 3H), 1.76 - 1.79 (m, 2H), 1.51 - 1.58 (m, 4H), 0.97 - 1.01 (m, 2H) PCT/U52012/027423 Step 2. 2-(4—Pluorophenyl)(((1r,4r)hydroxycyclohexyl)(methyl)amino)quinoxaline-6— carboxylic acid : o OI“\ F To a solution of methyl 2-(4-fluorophenyl)(((1r,4r) hydroxycyclohexyl)(methyl)amino)quinoxalinecarboxylate (130 mg, 0.32 mmol) in tetrahydrofuran (30 ml) and water (1.0 ml) was added sodium hydroxide (51.3 mg, 1.28 mmol), and the reaction mixture was allowed to react with stirring ght at room temperature. The reaction mixture was concentrated in vacuo, dissolved in water (30 ml), and adjusted to pH 5 with hydrochloric acid (3N) to give the itate, which was collected by filtration to afford 2-(4—fluorophenyl)(((1r,4r)—4- hydroxycyclohexyl)(methyl)amino)quinoxaline—6—carboxylic acid as a light yellow solid (100 mg, 80 %).
LC/MS (ES, m/z): [M+H]+ 396.1 1H-NMR (300 MHZ, DMSO) 8 8.25 (s, 1H), 7.94 (s, 2H), 7.83 - 7.88 (m, 2H), 7.34 - 7.39 (t, J: 8.7 Hz, 2H), 3.65 — 1.79 (m, 2H), - 3.69 (m, 1H), 3.26 - 3.29 (m, 1H), 2.69 (s, 3H), 1.75 1.49 - 1.60 (m, 4H), 0.91 - 0.97 (m, 2H) EXAMPLE 126 2-(4-Fluorophenyl)(methyl((1r,4r)(methylamino)cyclohexyl)amino)quinoxaline carboxylic acid Hr)!" ; O DI”\ F PCT/U82012/027423 Step 1. Methyl 3—(((1r,4r)((tert-butoxycarbonyl)amino)cyclohexyl)amino)-2—(4— henyl)quinoxalinecarboxylate lngBoc HN ”IQ/[Rf 01”\ F To a solution of methyl 3-chloro—2—(4-fluorophenyl)quinoxalinecarboxy1ate (1.45 g, 4.74 mmol) in DMSO (25 ml) was added DIEA (1.22 g, 5.69 mmol), and tert—butyl (1r,4r) aminocyclohexylcarbamate (1.3 g, 6 mmol). After stirring ght at 100°C in an oil bath, the reaction was quenched by the addition of water/ice (200 ml). The solids were collected via filtration and purified via silica gel column chromatography (1% - 10% ethyl acetate in petroleum ether) to afford methyl 3-(((1r,4r)-4—((tert— carbonyl)amino)cyclohexy1)amino)—2-(4—fluoropheny1)quinoxalinecarboxylate as a light yellow solid (0.91 g, 42 %).
LC/MS (ES, m/z):[M+H]+ 495.0 Step 2. Methyl 3-(((1r,4r)—4-((tert- carbonyl)(methyl)amino)cyclohexyl)(methyl)amino)(4-fluorophenyl)quinoxaline carboxylate \NBoc ; O QI”/N:©/u\o/\ To a solution of methyl 3—(((1r,4r)((tert-butoxycarbonyl)amino)cyclohexyl)amino)—2-(4- fluorophenyl)quinoxalinecarboxy1ate (400 mg, 0.81 mmol) in tetrahydrofuran (20 ml) was added sodium hydride (140 mg, 5.83 mmol) and d for 10 minutes. Iodomethane (947 mg, 6.67 mmol) was added dropwise at 0°C. After stirring overnight, the reaction was quenched by the addition of NH4C1 solution (100 m1), extracted with ethyl acetate (3 x 30 ml), dried over anhydrous magnesium sulfate, and concentrated in vacuo to afford methyl 3- (((1r,4r)((tert—butoxycarbonyl)(methyl)amino)cyclohexyl)(methyl)amino)-2—(4- henyl)quinoxaline-6—carboxylate as a yellow solid (360 mg, crude).
LC/MS (ES, m/z):[M+H]+ 523.1 Step 3. Methyl 2—(4—fluorophenyl)(methyl((1r,4r) (methylamino)cyclohexyl)amino)quinoxalinecarboxylate ; O /N /N:©)ko/ DI“\ Methyl 3-(((l r,4r)((tert—butoxycarbonyl)(methyl)amino)cyclohexyl)(methyl)amino)—2-(4- fluorophenyl)quinoxalinecarboxylate (360 mg, crude) in methanol (50 ml) was stirred for 4 hours at room temperature under an atmosphere of HCl (g). Then the reaction was concentrated in vacuo and the residue was dissolved in water (50 mL), adjusted pH to 8 with saturated sodium bicarbonate, ted with dichloromethane (3 x 30 m1), dried over anhydrous magnesium sulfate, and trated in vacuo to afford methyl 2-(4- fluorophenyl)—3-(methyl((1r,4r)(methylamino)cyclohexyl)amino)quinoxa1ine-6— carboxylate as a yellow solid (120 mg, 35 % 2 steps).
LC/MS (ES, m/z):[M+H]+ 423.2 1H-NMR (300 MHz, CDCl3) 8 8.50 (d, J = 1.8 Hz, 1H), 8.05 - 8.09 (m, 1H), 7.95 (d, J: 8.7 Hz, 1H), 7.86 - 7.91 (m, 2H), 7.18 - 7.23 (t, J: 8.7 Hz, 2H), 4.00 (s, 3H), 3.86 - 3.94 (m, 1H), 2.81 (s, 3H), 2.43 - 2.60 (m, 4H), 2.14 - 2.18 (m, 2H), 1.80 — 1.90 (m, 2H), 1.60 - 1.75 (m, 2H), 1.27 - 1.38 (m, 2H) Step 4. 2—(4-Fluorophenyl)—3-(methyl((1r,4r)-4— (methylamino)cyclohexyl)amino)quinoxalinecarboxylic acid ; O /N ”fikw DI“\ F To a solution of methyl 2-(4-fluorophenyl)(methyl((lr,4r)—4- (methylamino)cyclohexyl)amino)quinoxalinecarboxylate (120 mg, 0.28 mmol) in methanol (40 ml) was added a solution of NaOH (34 mg, 0.85 mmol) in water (4 ml). After stirring overnight at room temperature, the ing mixture was concentrated in vacuo. The residue was dissolved in water (10 ml) and adjusted pH to 6 with HCl (3N). The solids were collected by filtration to afford 2—(4-fluorophenyl)(methyl((1r,4r) (methylamino)cyclohexyl)amino)quinoxaline-6—carboxylic acid as a yellow solid (64 mg, 43 LC/MS (ES, M+H]+ 409.1 1H-NMR (300 MHz, DMSO) 5 8.27 (s, 1H), 7.93 (d, J = 9.0 Hz, 2H), 7.86 - 7.91 (m, 2H), 7.36 — 7.42 (t, J: 9.0 Hz, 2H), 3.65 - 3.75 (m, 1H), 2.83 - 2.92 (m, 1H), 2.71 (s, 3H), 2.01 - 2.05 (m, 2H), 1.60 - 1.68 (m, 4H), 1.12 - 1.18 (m, 2H) EXAMPLE 127 3-(((1r,4r)Acetamidocyclohexyl)(methyl)amino)(4-fluorophenyl)quinoxaline-6— carboxylic acid ; O II ~33ka/ Step 1. Methyl 3-(((1r,4r)((tert-butoxycarbonyl)amino)cyclohexyl)(methyl)amino)(4- fluoropheny1)quinoxaline-6—carboxy1ate NHBoc ; O 0;”I / F W0 2012/119046 To a solution of methyl 3-((l r,4r)(tert-butoxycarbonylamino)cyclohexy1amino)—2-(4- fluorophenyl)quinoxaline-6—carboxylate (300 mg, 0.61 mmol) in DMF (18 ml) was added methyl iodide (300 mg), and t-BuOK (135 mg, 1.20 mmol), and the reaction mixture was d for 3 hours at room temperature. The resulting solution was quenched with water (100 ml) and extracted with ethyl acetate (3 x 50 mL). The organic layers were combined and dried over anhydrous magnesium sulfate and concentrated in vacuo to give a residue, which was ed via silica gel column chromatography (1% to 2% ethyl acetate in petroleum ether) to afford methyl 3—(((lr,4r)((tert- butoxycarbonyl)amino)cyclohexyl)(methy1)amino)-2—(4—fluorophenyl)quinoxaline carboxylate as a yellow solid (250 mg, 81 %).
LC/MS (ES, m/z): [M+H]+ 509.0 1H—NMR (300 MHz, CDClg): 5 8.50 (d, J: 1.5 Hz, 1H), 8.05 - 8.08 (m, 1H), 7.95 - 8.00 (m, 1H), 7.86 — 7.91 (m, 2H), 7.18 - 7.28 (m, 2H), 4.01 (s, 3H), 3.75 - 3.40 — 3.85 (m, 1H), 3.25 (m, 1H), 2.75 (s, 3H), 1.55 - 0.90 (m, 2H) - 1.76 (m, 6H), 1.45 (s, 9H), 0.85 Step 2. Methyl 3-(((1r,4r)aminocyclohexyl)(methyl)amino)(4- fluorophenyl)quinoxalinecarboxy1ate ; O /N Nfio/ iii“| / F To a solution of methyl 3-(((lr,4r)((tert— butoxycarbonyl)amino)cyclohexyl)(methyl)amino)~2-(4-fluorophenyl)quinoxaline ylate (250 mg, 0.49 mmol) in romethane (30 ml) was added trifluoroacetic acid (6 ml) and stirred for 3 hours at room temperature. The resulting solution was trated in vacuo to give a residue, which was dissolved in water (100 ml), adjusted to pH 8 with NaHC03 solution, and extracted with ethyl acetate (3 x 50 ml). The organic layers were combined, dried over anhydrous ium sulfate, and concentrated under reduced pressure to afford methyl 3-(((lr,4r)aminocyclohexyl)(methyl)amino)—2-(4— fluoropheny1)quinoxalinecarboxylate as a yellow solid (150 mg, crude).
LC/MS (ES, m/z): [M+H]+409.1 Step 3. Methyl 3-(((1r,4r)acetamidocyclohexy1)(methy1)amino)(4- heny1)quinoxaline-6—carboxy1ate A solution of methyl 3-(((1r,4r)aminocyclohexyl)(methyl)amino)(4- fluorophenyl)quinoxa1ine-6~carboxylate (150 mg, crude) in acetic anhydride (30 ml) was stirred for 2 hours at room temperature. The resulting on was diluted with water (200 mL) and stirred for 30 minutes. The pH was adjusted to 8 with sodium bicarbonate (3N) and extracted with ethyl acetate (3 x 50 ml). The organic layers combined and concentrated in vacuo to give a residue, which was purified via silica gel column chromatography (0.5% to 1% ol in dichloromethane) to afford methyl 3—(((1r,4r)—4- acetamidocyclohexyl)(methyl)amino)—2—(4-fluorophenyl)quinoxaline-6—carboxy1ate as a yellow solid (142 mg).
LC/MS (ES, m/z): [M+H]+ 451.0 1H-NMR (300 MHz, CDC13)I 8 8.28 (s, 1H), 7.96 — 7.97 (d, J = 1.5 Hz, 2H), 7.87 - 7.89 (m, 2H), 7.64 - 7.66 (d, J = 8.4 Hz, 1H), 7.36 - 7.42 (m, 2H), 3.94 (s, 3H), 3.67 (s, 1H), 3.34 (s, 1H), 2.74 (s, 3H), 1.76 (s, 5H), 1.65 (s, 4H) Step 4. 3—(((1r,4r)—4—Acetamidocyclohexy1)(methyl)amino)(4-fluoropheny1)quinoxaline- 6-carboxylic acid ; O 01“l Nj:>).k0H/ F To a solution of methyl 3—(((1r,4r)—4—acetamidocyclohexyl)(methy1)amino)(4— fluoropheny1)quinoxalinecarboxylate (142 mg, 0.32 mmol) in methanol (25 ml) was added solution of NaOH (51 mg, 1.28 mmol) in water(5 ml), and the resulting mixture was stirred overnight at room temperature. The resulting on was concentrated in vacuo to give a residue, which was dissolved in water (10 ml) and adjusted to pH 4 with HCl (3N). The product was precipitated from water and filtered to afford 3-(((1r,4r) acetamidocyclohexyl)(methyl)amino)—2-(4—fluorophenyl)quinoxalinecarboxylic acid as a yellow solid (115.7 mg, 81%).
LC/MS (ES, m/z): 437.1 1H—NMR (300 MHz, DMSO): 5 8.26 (s, 1H), 7.87 — 7.95 (m, 4H), 7.63 (d, J: 8.8 Hz, 1H), 7.36 - 7.42 (m, 2H), 3.60 - 3.67 (m, 1H), 3.40 — 3.44 (m, 1H), 2.74 (s, 3H), 1.68 - 1.80 (m, 5H), 1.56 - 1.64 (m, 4H), 0.87 - 0.98 (m, 2H) EXAMPLE 128 3—(4-Acetylpiperazinyl)(4-fluorophenyl)quinoxalinecarboxylic acid Step 1. Methyl 2-(4-fluorophenyl)(piperazinyl)quinoxaline—6-carboxylate HN/fi o K/N / \Nfio/ To a solution of methyl 3-chloro(4-fluorophenyl)quinoxaline-6~carboxylate (632 mg, 2.00 mmol) in DMSO (10 ml) was added DIEA (516 mg, 3.99 mmol) and piperazine (688 mg, 7.99 mmol). The resulting solution was stirred for 3 hours at 80°C and then quenched by the addition of water (100 ml). The solids were ted by filtration to afford methyl 2-(4- fluorophenyl)-3—(piperazin-l-yl)quinoxa1inecarboxylate as a yellow solid (540 mg, 74 %).
LC/MS (ES, m/z): [M+H]+ 367.0 1H-NMR (300 MHz, CDC13) 5 8.56 (d, J = 1.5 Hz, 1H), 7.99 - 8.56 (m, 4H), 7.19 - 7.28 (m, 2H), 4.01 (s, 3H), 3.30 - 3.33 (t, J = 4.5 Hz, 2H), 2.93 — 2.96 (t, J = 4.8 Hz, 2H) Step 2. Methyl 3-(4-acetylpiperazinyl)(4—fluoropheny1)quinoxalinecarboxylate 010» To a solution of methyl 2—(4-fluorophenyl)(piperaziny1)quinoxalinecarboxylate (180 mg, 0.49 mmol) in dichloromethane (10 ml) was added Eth (59 mg, 0.59 mmol) and then acetyl chloride (39 mg, 0.59 mmol) was added dropwise. The ing on was stirred for 1 hour at room temperature and then quenched by the addition of ice-water (100 m1) and extracted with dichloromethane (3 x 15 ml). The organic layers were combined and dried over anhydrous magnesium sulfate and concentrated in vacuo to afford methyl 3—(4— acetylpiperaziny1)—2-(4-f1uoropheny1)quinoxaline-6—carboxylate as a yellow solid (103 mg, 51 %).
LC/MS (ES, m/z): [M+H]+ 409.0 1H-NMR (300 MHz, CDC13) 8 8.57 (d, J: 1.5 Hz, 1H), 8.15 — 8.18 (m, 1H), 8.01 - 8.10 (m, 3H), 6.93 — 7.28 (m, 2H), 4.02 (s, 3H), 3.64 — 3.68 (t, J: 5.4 Hz, 2H), 3.54 - 3.57 (t, J: 5.7 Hz, 2H), 3.36 - 3.40 (t, J: 4.8 Hz, 2H), 3.26 — 3.29 (t, J: 5.1 Hz, 2H), 2.13 (s, 3H) Step 3. 3—(4—Acetylpiperazin—1—y1)—2-(4—fluoropheny1)quinoxaline—6—carboxy1ic acid To a solution of methyl 3-(4-acetylpiperazin-l-yl)(4-fluorophenyl)quinoxa1ine carboxylate (103 mg, 0.25 mmol) in methanol (10 ml) was added NaOH (48 mg, 1.27 mmol).
The resulting solution was stirred overnight at room temperature and concentrated in vacuo.
The residue was dissolved in water (15 ml) and adjusted to pH 5 with hydrochloric acid (IN).
The solids were collected by tion to afford 3—(4-acetylpiperazin—1—yl)(4- fluorophenyl)quinoxalinecarboxy1ic acid as a yellow solid (20.8 mg, 21 %).
LC/MS (ES, m/z): [M+H]+ 395.1 1H-NMR (300 MHz, DMSO) 8 8.32 (s, 1H), 8.07 - 8.12 (m, 2H), 8.02 (d, J: 1.8 Hz, 2H) 7.37 — 7.43 (m, 2H), 3.50 - 3.60 (m, 4H), 3.20 — 3.30 (m, 4H), 2.00 (s, 3H) W0 2012/119046 PCT/U52012/027423 E 129 3—(4-Benz0ylpiperazinyl)(4-fluorophenyl)quinoxalinecarboxylic acid @G J'DJLOH Step 1. Methyl 3—(4—benzoylpiperazinyl)-2—(4-fluorophenyl)quinoxaline—6—carboxylate (32,0.
To a solution of methyl 2—(4—fluoropheny1)—3-(piperazinyl)quinoxalinecarboxylate (180 mg, 0.49 mmol) in dichloromethane (10 ml) was added Et3N (200 mg, 2 mmol) followed by benzoyl chloride (170 mg, 1.18 mmol) dropwise. The resulting solution was stirred for 1 hour at room ature and then ed by the addition of ice-water (150 ml) and extracted with dichloromethane ( 3 X 30 ml). The organic layers were combined, dried over anhydrous magnesium sulfate and concentrated in vacuo to afford methyl 3-(4-benzoylpiperazinyl)—2- (4-fluorophenyl)quinoxaline-6—carboxylate as a yellow solid (130 mg, 56%). 1H—NMR (300 MHz, CDClg) 8 8.57 (d, J = 1.8 Hz, 1H), 8.02 - 8.56 (m, 4H), 7.40 — 7.48 (m, 5H), 7.20 - 7.28 (m, 2H), 4.05 (s, 3H), 3.20- 3.90(m, 8H) Step 2. 3-(4-Benzoylpiperaziny1)(4-fluorophenyl)quinoxalinecarboxylic acid ono info/flofiw Di To a solution of methyl 3-(4-benzoylpiperazinyl)(4—fluorophenyl)quinoxaline—6— carboxylate (130 mg, 0.27 mmol) in methanol (15 ml) was added NaOH (37 mg, 0.93 mmol) in water (1 ml). The ing solution was stirred overnight at room temperature and concentrated in vacuo. The residue was dissolved in water (15 ml) and adjusted to pH 5 with hloric acid (1N). The solids were collected by filtration to afford 3—(4- benzoylpiperazinyl)(4-fluorophenyl)quinoxalinecarboxylic acid as a yellow solid (53.0 mg, 42 %).
LC/MS (ES, m/z): [M+H]+ 457.1 1H-NMR (300 MHz, DMSO) 8 8.30 (s, 1H), 7.90 - 8.01 (m, 4H), 7.35 - 7.43 (m, 7H), 3.55- 3.82 (m, 2H), 3.10 - 3.52 (m, 6H) EXAMPLE 130 luorophenyl)(4-(methylsulfonyl)piperazinyl)quinoxalinecarboxylic acid o" N’W 0 K/N /N:©)L0H Step 1. Methyl 2-(4—fluorophenyl)—3—(4-(methylsulfonyl)piperazin—l—yl)quinoxaline—6— carboxylate To a solution of methyl 2—(4—fluorophenyl)~3—(piperazin—1—yl)quinoxaline—6-carboxy1ate (180 mg, 0.59 mmol) in dichloromethane (10 ml) was added Et3N (202 mg, 2 mmol) and methanesulfonyl chloride (110 mg, 0.98 mmol). The resulting solution was stirred for 1 hour at room temperature. The reaction was then ed by the addition of ice—water (20 ml) and extracted with dichloromethane (3 x 15 ml). The organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated in vacuo to afford methyl 2-(4- fluorophenyl)(4-(methylsulfonyl)piperazinyl)quinoxa1inecarboxylate as a yellow solid (0.14g, 7O %).
LC/MS (ES, m/z): [M+H]+ 445.0 1H-NMR (300 MHz, CDClg) 6 8.35 (d, J = 1.2 Hz, 1H), 8.03 — 8.12 (m, 4H), 7.37 - 7.44 (m, 2H), 3.94 (s, 3H), 3.32 - 3.35 (m, 4H), 3.18 - 3.20 (m, 4H), 2.92 (s, 3H) W0 2012/119046 Step 2. 2-(4—Fluorophenyl)—3—(4—(methylsulfony1)piperazinyl)quinoxalinecarboxylic acid \3/9 0" ‘Nfi 0 K/N /Nfi0H To a solution of methyl 2-(4-fluoropheny1)-3—(4—(methy1sulfonyl)piperazin—1-y1)quinoxaline- 6-carboxylate (100 mg, 0.22 mmol) in methanol (10 ml) was added NaOH (36 mg, 0.9 mmol) and water (1 ml). The resulting solution was stirred overnight at room temperature and concentrated in vacuo. The residue was dissolved in water (15 ml) and adjusted to pH 5 with hydrochloric acid (IN). The solids were ted by filtration to afford 2—(4-fluorophenyl) (4-(methylsulfonyl)piperazin-l-yl)quinoxalinecarboxylic acid as a yellow solid (25.0 mg, %).
LC/MS (ES, m/z): [M+H]+ 431.1 1H—NMR (300 MHz, DMSO) 8 8.33 (d, J = 1.2 Hz, 1H), 7.99 - 8.11 (m, 4H), 7.37 - 7.43 (m, 2H), 3.30 — 3.34 (m, 4H), 3.18 - 3.20 (m, 4H), 2.91 (s, 3H) EXAMPLE 1 3 1 luorophenyl)[4-(pyridin-Z-yl)piperidin-l-yl]quinoxalinecarboxylic acid To a solution of diisopropylamine (14.5 mL, 2.00 equiv) in THF (100 ml) was added n-BuLi (36.1 mL, 2.4M) dropwise at —78°C. The mixture was then stirred for 15 min and followed by the addition of a solution of tert—butyl 4-oxopiperidine-l-carboxylate (10 g, 50.19 mmol) in tetrahydrofuran (100 ml). The mixture was d for 1 hour at this temperature and then trifluoro-N—phenyl—N—(trifluoromethane)sulfonylmethane sulfonamide (23 g, 64.38 mmol) was added dropwise. The mixture was stirred overnight at room temperature and extracted with ethyl acetate (3 x 50 ml), dried over anhydrous magnesium sulfate, and trated in vacuo to give a residue, which was purified via silica gel column chromatography (1 % ethyl acetate in petroleum ether) to afford tert—butyl 4— [(trifluoromethane)sulfonyloxy]—1,2,3,6-tetrahydropyridine-l-carboxylate as red oil (12 g, 72%).
Step 2. tert-Butyl 4-(4,4,5,5-tetramethy1-1,3,2-dioxaborolanyl)-5,6-dihydropyridine- 1(2H)-carboxylate To a solution of tert-butyl 4-[(trifluoromethane)sulfonyloxy]—1 ,2,3,6-tetrahydropyridine carboxylate (9 g, 27.16 mmol) in dioxane (150 ml) was added 4,4,4',4‘,5,5,5',5'-octamethyl- 2,2‘-bi(1,3,2-dioxaborolane) (7.6 g, 29.93 mmol), AcOK (7.9 g, 80.6 mmol), Pd(dppf)2C12 (0.59 g, 0.81 mmol), and dppf (450 mg, 0.81 mmol). The resulting on was stirred overnight at 80°C under an inert atmosphere of nitrogen, and then diluted with water (500 ml), extracted with ethyl e (4 x 100 ml), and the organic layers combined, dried over ous magnesium sulfate, and concentrated in vacuo to give a residue, which was purified via silica gel column chromatography (1% to 4% ethyl acetate in petroleum ether) to afford tert-butyl 4-(4,4,5,5-tetramethy1—1,3,2—dioxaborolany1)-5,6-dihydropyridine-1(2H)- carboxylate as a pink solid (6.6 g, 79%). 1H-NMR (300 MHz, CDC13): 6 6.47 (s, 1H), 3.95 - 3.98 (m, 2H), 3.43 — 3.47 (t, J: 5.7 Hz, 2H), 2.21 — 2.26 (m, 2H), 1.451 (s, 9H), 1.25 (s, 12H) Step 3. tert—Butyl 4-(pyridin—2—yl)—5,6—dihydropyridine—1(2H)-carboxylate To a solution of tert-butyl ,5,5-tetramethyl-1,3,2—dioxaborolanyl)-5,6- dihydropyridine-1(2H)-carboxylate (1 g, 3.23 mmol) in dioxane (35 m1) and water (2.0 ml) was added 2—bromopyridine (2.9 g, 18.35 mmol), K3PO4 (3.8 g, 17.90 mmol) and Pd(PPh3)4 (350 mg, 0.30 mmol), and the resulting mixture was allowed to react with stirring for 3 hours at 90°C. The reaction mixture was diluted with water (180 ml) and extracted with ethyl acetate (3 x 50 ml). The c layers were combined, dried over anhydrous magnesium sulfate, and trated under reduced pressure to give the residue, which was purified via silica gel column chromatography (2% ethyl acetate in petroleum ether) to afford tert—butyl 4— (pyridinyl)—5,6—dihydropyridine—1(2H)-carboxy1ate as pink oil (1.1 g , 70 %).
LC/MS (ES, m/z): [M+H]+261.0 1H—NMR (300 MHz, CDC13)I 5 8.58 (d, J: 3.9 Hz, 1H), 7.65 — 7.71 (m, 1H), 7.38 (d, J: 7.8 Hz, 1H), 7.16 - 7.19 (m, 1H), 6.63 (s, 1H), 4.13 - 4.17 (m, 2H), 3.65 - 3.69 (t, J: 5.7 Hz, 2H), 2.65 — 2.69 (m, 2H), 1.51 (s, 9H) Step 4. 2-(1,2,3,6-Tetrahydropyridinyl)pyridine To a solution of tert-butyl 4-(pyridinyl)-5,6-dihydropyridine-1(2H)-carboxylate (1.1 g, 4.23 mmol) in dichloromethane (50 ml) was added trifluoroacetic acid (4 ml), and the reaction e was allowed to react with stirring overnight at room temperature. The reaction mixture was concentrated in vacuo to afford 2—(1,2,3,6—tetrahydropyridin yl)pyridine as a crude yellow oil (600 mg).
LC/MS (ES, m/z): [M+H]+ 161.0.
W0 2012/119046 2012/027423 Step 5. Methyl 2—(4-fluorophenyl)-3—(4—(pyridinyl)-5,6-dihydropyridin—l(2H)— yl)quinoxaline-6—carboxylate To a solution of methyl 3-chloro(4-fluorophenyl)quinoxalinecarboxylate (450 mg, 1.42 mmol) in DMSO (5.0 ml) was added 2-(1,2,3,6-tetrahydropyridin—4-y1)pyridine (300 mg, 1.87 mmol) and DIEA (361 mg, 2.79 mmol), and the reaction mixture was stirred overnight at 90°C. The reaction mixture was extracted with ethyl acetate (3 x 50 ml), and the organic layers combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the residue, which was purified by preparative silica gel plate chromatography (dichloromethane: ethyl acetate: petroleum ether (4021212)) to afford methyl 2—(4—fluorophenyl)—3 —(4—(pyridin-2—y1)-5,6—dihydropyridin—1(2H)—yl)quinoxaline—6— carboxylate as a yellow solid (410 mg).
LC/MS (ES, m/z): [M+H]+441.0 1H-NMR (300 C13): 8 8.58 (d, J: 1.8 Hz, 2H), 7.99 - 8.14 (m, 4H), 7.63 - 7.72 (m, 1H), 7.42 (d, J: 8.1 Hz, 1H), 7.17 - 7.26 (m, 3H), 6.78 (s, 1H), 4.15 - 4.16 (m, 2H), 4.02 (s, 3H), 3.52 - 3.55 (t, J: 5.7 Hz, 2H), 2.63 - 2.66 (m, 2H) Step 6. Methyl 2-(4-fluorophenyl)[4-(pyridinyl)piperidin—l-yl]quinoxaline-6— carboxylate To a solution of methyl 2-(4—fluorophenyl)—3—(4—(pyridin—2-yl)-5,6-dihydropyridin-1(2H)- yl)quinoxalinecarboxylate (150 mg, 0.34 mmol) in ethyl acetate (30 ml) was added PtOz (38 mg) and the reaction mixture was stirred at room temperature for 2 hours under an atmosphere of H2(g). The reaction mixture was added to water (100 ml), extracted with romethane (3 x 30 mL), and the organic layers ed, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the residue, which was WO 19046 PCT/U52012/027423 purified via silica gel column chromatography (2% ethyl acetate in eum ether) to afford methyl 2-(4-flu0rophenyl)—3—[4—(pyridin—2—yl)piperidin-1—y1]quinoxalinecarboxylate as a yellow solid (84 mg, 56 %).
LC/MS (ES, m/z): [M+H]+443.0 1H-NMR (300 MHz, CDC13)Z 6 8.57 - 8.60 (t, J: 6.6 Hz, 2H), 8.09 - 8.14 (m, 3H), 7.99 (d, J = 8.7 Hz, 1H), 7.67 — 7.72 (m, 1H), 7.18 - 7.27 (m, 4H), 4.01 (s, 3H), 3.96 - 3.99 (m, 2H), 2.91 - 3.00 (m, 3H), 1.84 - 2.08 (m, 4H) Step 7. 2-(4-Fluorophenyl)[4-(pyridin—2—yl)piperidin-1—y1]quinoxaline-6—carboxylic acid To a solution of methyl 2—(4-fluorophenyl)[4-(pyridinyl)piperidiny1]quinoxaline—6— carboxylate (84 mg, 0.19 mmol) in methanol (30 ml) and water (1.0 ml) was added sodium hydroxide (30 mg, 0.75 mmol), and the reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated in vacuo, dissolved in water (10 ml), and adjusted to pH 5 with hydrochloric acid (3N) to give the precipitate, which was collected by filtration to afford 2-(4-fluorophenyl)[4-(pyridinyl)piperidinyl]quinoxaline carboxylic acid as a light yellow solid (61.1 mg, 75 %).
LC/MS (ES, m/z): [M+H]+429.1 1H-NMR (300 MHz, DMSO): 6 8.50 (d, J = 4.8 Hz, 1H), 8.32 (s, 1H), 8.08 — 8.13 (m, 2H), 8.01 (s, 2H), 7.72 - 7.77 (m, 1H), 7.38 - 7.44 (m, 2H), 7.33 (d, J: 7.5 Hz, 1H), 7.22 — 7.26 (m, 1H), 3.85 - 3.89 (m, 2H), 2.88 - 2.96 (m, 3H), 1.78 - 1.85 (m, 4H) EXAMPLE 132 (S)(4-Fluorophenyl)hydroxy(2-methylpyrrolidinyl)quinoxalinecarboxylic acid Step 1. (S)—Methy1 7-methoxy(2-methy1pyrrolidin-1 —yl)—2-oxo— 1 ydroquinoxaline—6- ylate o m 0/ To a solution of methyl 3—chloromethoxyoxo-1,2-dihydroquinoxalinecarboxylate (1.2 g, 4.47 mmol) in DMSO (20 ml) was added DIEA (1.16 g, 8.98 mmol) and methylpyrrolidine hydrochloride (650 mg, 5.35 mmol), and the on was stirred at 85°C overnight. The reaction mixture was cooled to room temperature. The product was precipitated by the addition water, and the solids were collected by filtration to afford (S)- methyl 7-methoxy-3 -(2-methylpyrrolidin— 1 -yl)oxo-1 ,2-dihydroquinoxaline-6—carboxylate as a light yellow solid (1.0 g, 71 %).
LC/MS (ES, m/z): [M+H]+ 318.0 1H-NMR (300 MHz, DMSO) 8 12.04 (s, 1H), 7.63 — 7.67 (t, J: 5.7 Hz, 1H), 6.76 (s, 1H ), 4.73 - 4.78 (In, 1H), 3.91 - 3.96 (m, 1H), 3.83 (s, 6H), 2.53 - 2.54 (m, 1H), 1.87 - 1.99 (m, 3H), 1.63 - 1.65 (m, 1H), 1.12 (d, J: 6.0 Hz, 3H) Step 2. (S)—Methyl 7-methoxy-3—(2—methylpyrrolidinyl) (trifluoromethylsulfonyloxy)quinoxaline—6—carboxylate 0““ ° TfO \N 0/ To a solution of (S)-methyl 7-methoxy(2—methy1pyrrolidin—1-y1)-2—oxo-1,2- oquinoxalinecarboxylate (1.0 g, 3.15 mmol) in dichloromethane (80 ml) was added pyridine (990 mg, 12.52 mmol) and mo (1.69 g, 5.99 mmol), and the reaction was stirred overnight under an here of nitrogen at room temperature. The reaction mixture was then quenched with water (200 ml), extracted with dichloromethane (3 x 30 mL), the organic layers combined, dried over anhydrous magnesium sulfate, and concentrated in vacuo to afford (S)-methyl 7-methoxy—3—(2—methylpyrrolidin-1—yl) (trifluoromethylsulfonyloxy)quinoxalinecarboxylate as red oil (1.20 g, crude), which was used in the next step directly.
Step 3. (S)-Methyl 2—(4-fluorophenyl)—7-methoxy(2—methylpyrrolidin—l-yl)quinoxaline—6— carboxylate To a solution of (S)-methyl 7-methoxy-3—(2—methylpyrrolidinyl) (trifluoromethylsulfonyloxy)quinoxalinecarboxy1ate (300 mg, crude) in dioxane (5 ml) and water (3 drops) was added (4-fluorophenyl)boronic acid (280.6 mg, 2.01 mmol), Pd(PPh3)4 (38.5 mg, 0.03 mmol), and K3PO4 (422 mg, 1.99 mmol), and the reaction was stirred for 40 s at 95°C under an atmosphere of nitrogen. The reaction mixture was concentrated in vacuo to give a residue, which was purified via silica gel column chromatography (1% ethyl e in petroleum ether) to afford (S)-methyl 2—(4- fluorophenyl)—7—methoxy(2—methylpyrrolidin—l-yl)quinoxalinecarboxylate as a light yellow solid (200 mg).
LC/MS (ES, m/z): [M+H]+ 396.1 1H—NMR (300 MHz, DMSO) 5 8.27 (s, 1H), 7.78 - 7.83 (m, 2H), 7.48 (s, 1H), 7.14 — 7.23 (m, 2H), 4.31 — 4.35 (m, 1H), 3.98 (s, 6H), 3.19 - 3.24 (m, 1H), 2.85 - 2.92 (m, 1H), 2.18 — 2.25 (m, 1H), 1.81 — 1.86 (m, 1H), 1.55 - 1.69 (m, 3H), 1.36 (d, J: 6.0 Hz, 3H) Step 4. (S)-methyl 2—(4—fluorophenyl)hydroxy(2-methylpyrrolidinyl)quinoxaline carboxylate To a solution of (S)—methyl uorophenyl)—7-methoxy—3—(2—methylpyrrolidin—l— yl)quinoxaline-6—carboxylate (200 mg, 0.51 mmol) in dichloromethane (80 ml)was added BBI'3 (2.0 m1) dropwise with stirring at -78°C, and the reaction was allowed to proceed for 40 minutes. The reaction was then quenched by the on of water/ice. The ing solution was extracted with romethane (3 X 80 ml), and the organic layers combined, dried over anhydrous magnesium sulfate, and concentrated in vacuo to give the residue, which was purified via silica gel column chromatography (2% ethyl acetate in petroleum ether) to afford W0 2012/119046 (S)-methyl 2-(4-fluoropheny1)hydroxy(2-methylpyrrolidin- l -yl)quinoxaline carboxylate as a yellow solid (150 mg, 78 %).
LC/MS (ES, m/z): [M+H]+ 382.0 Step 5. (S)—2-(4-F1uorophenyl)hydroxy—3—(2-methylpyrrolidin—l-yl)quinoxa1ine—6— carboxylic acid To a solution of (S)-methy1 2-(4-fluorophenyl)~7-hydroxy~3-(2-methylpyrrolidin yl)quinoxaline-6—carboxylate (150 mg, 0.39 mmol) in ol (30 ml) and water (1 ml) was added sodium hydroxide (19.5 mg, 0.49 mmol), and the reaction was d overnight at room temperature. The reaction mixture was concentrated in vacuo, ved in water (30 mL), and adjusted to pH 5 with hydrochloric acid (3N) to give the precipitate, which was collected by filtration to afford (S)(4-fluorophenyl)hydroxy(2—methylpyrrolidin yl)quinoxaline—6—carboxy1ic acid as a light yellow solid (100 mg, 69 %).
LC/MS (ES, m/z): [M+H]Jr 368.1 1H—NMR (300 MHZ, DMSO) 5 8.18 (s, 1H), 7.78 - 7.83 (m, 2H), 7.32 - 7.39 (m, 2H), 7.26 (s, 1H), 4.12 — 4.22 (m, 1H), 2.99 - 3.11 (m, 1H), 2.86 - 2.95 (m, 1H), 2.07 - 2.14 (m, 1H), 1.69 — 1.76 (m, 1H), 1.55 - 1.59 (m, 2H),l.25 (d, J: 6.60 Hz, 3H) EXAMPLE 133 3-[Benzyl(methyl)amino](4-fluorophenyl)quinoxalinecarboxylic acid W0 2012/119046 Step 1. Methyl 3-[benzyl(methyl)amino]~2—(4-fluorophenyl)quinoxaline—6—carboxylate To a solution of methyl 3-chloro-2—(4-fluorophenyl)quinoxalinecarboxylate (200 mg, 0.63 mmol) in DMSO (4 mL) was added benzyl(methyl)amine (92 mg, 0.76 mmol), and DIEA (163 mg, 1.26 mmol). The resulting solution was stirred for 2 hours at 85°C. Then the mixture was quenched of water (100 mL) and ted with dichloromethane (3 x 50 mL) The organic layers were combined and concentrated in vacuo to give a residue, which was purified via silica gel column chromatography (2% ethyl acetate in petroleum ether) to afford methyl 3-[benzyl(methyl)amino](4-fluorophenyl)quinoxalinecarboxylate as yellow oil (100 mg, 39%).
LC/MS (ES, m/z): [M+H]+402.0.
Step 2. 3—[Benzyl(methyl)amino]-2—(4-fluorophenyl)quinoxaline—6-carboxylic acid To a solution of methyl 3-[benzyl(methyl)amino](4—fluorophenyl)quin0xaline carboxylate (100 mg, 0.25 mmol) in methanol (20 mL) was added sodium hydroxide (60 mg, 1.50 mmol) in water (5 mL). The resulting solution was stirred overnight at room temperature and the mixture was concentrated in vacuo to give a residue, which was ved in water (5 mL), and ed to pH to 5 with HCl (2N). The solids were collected by filtration and dried in an oven under reduced pressure to afford 3-[benzyl(methyl)amino](4- fluorophenyl)quinoxaline—6-carboxylic acid as a yellow solid (58.3 mg, 61 %).
LC/MS (ES, m/z): [M+H]+ 388.1 1H-NMR (300 MHz, DMSO): 8 8.26 (s, 1H), 7.92 - 7.98 (m, 4H), 7.22 - 7.39 (m, 7H), 4.55 (s, 2H), 2.70 (s, 3H) EXAMPLE 134 2-(4-Fluorophenyl)[methyl(pyridinylmethyl)amino]quinoxalinecarboxylic acid To a solution of methyl 3—chloro(4-fluorophenyl)quinoxalinecarboxy1ate (200 mg, 0.95 mmol) in DMSO (5 mL) was added DIEA (245 mg, 1.90 mmol) and pyridin-Z— ylmethanamine (124 mg, 1.15 mmol), and the reaction was stirred ght at 90°C in an oil bath. The solids were precipitated from water (50 mL), collected by filtration, washed with AcOEt (10 mL), and dried to afford methyl 2-(4-fluorophenyl)—3-[(pyridin-2— ylmethyl)amino]quinoxaline—6—carboxylate as a yellow solid (200 mg, 81%).
LC/MS (ES, m/z): [M+H]+ 389.1 1H-NMR (300 MHz, DMSO) 5 8.51 (d, J: 4.2 Hz, 1H), 8.09 (s, 1H), 7.95 - , 4H), 7.72 — 7.76 (m, 1H), 7.57 - 7.61 (t, J: 5.4 Hz, 1H), 7.43 - 7.49 (t, J: 9.0 Hz, 1H), 4.75 (d, J = 5.7 Hz, 2H), 3.90 (s, 3H) Step 2. Methyl 2-(4—fluorophenyl)[methyl(pyridiny1methyl)amino]quinoxaline carboxylate To a solution of methyl 2—(4—fluoropheny1)—3—[(pyridin-2—ylmethyl)amino]quinoxaline carboxylate (200 mg, 0.51 mmol) in tetrahydrofuran (50 mL) was added NaH (107 mg, 4.65 mol) at 0°C, and the reaction mixture was stirred for 30 minutes. Iodomethane (954 mg, 6.72 mmol) was added, and the reaction mixture was stirred overnight at room temperature.
The resulting solution was diluted with NH4C1 solution (80 mL), extracted with ethyl e (3 x 40 mL), dried over anhydrous magnesium sulfate, and concentrated in vacuo to give methyl 2—(4—fluoropheny1)[methy1(pyridin-2—ylmethyl)amino]quinoxaline—6—carboxylate as a yellow solid (120 mg, 57 %).
LC/MS (ES, m/z):[M+H]+ 403.1 1H—NMR (300 MHz, CDC13) 6 8.54 (d, J = 4.5 Hz, 1H), 8.50 (d, J: 1.8 Hz, 1H), 8.07 - 8.10 (m, 1H), 7.93 - 8.00 (m, 3H), 7.63 - 7.67 (t, J: 7.5 Hz, 1H), 7.21 - 7.30 (m, 1H), 7.14 - 7.20 (m, 3H), 4.75 (s, 2H), 4.00 (s, 3H), 2.90(s, 3H) Step 3. luorophenyl)—3-[methyl(pyridiny1methyl)amino]quinoxaline—6-carboxylic acid N O /N NfioH To a on of methyl uoropheny1)—3-[methyl(pyridin—2—ylmethyl)amin0]quinoxaline- 6—carboxylate (120 mg, 0.30 mmol) in methanol (30 mL) was added sodium hydroxide (48 mg, 1.20 mmol), and the reaction mixture was stirred overnight at room temperature. The resulting mixture was concentrated in vacuo, diluted with water (20 mL), and adjusted to pH 6 with HCl (2N). The solids were collected by filtration to give 2-(4-fluoropheny1) [methyl(pyridin-2—ylmethy1)amino]quinoxaline-6—carboxylic acid as a yellow solid (66 mg, 57 %).
LC/MS (ES, m/z): [M+H]+ 389.1 1H—NMR (300 MHz, CD3OD) 6 8.41 - 8.47 (m, 2H), 8.06 - 8.09 (m, 1H), 7.94 - 7.98 (m, 3H), 7.77 — 7.82 (m, 1H), 7.42 (d, J = 7.8 Hz, 1H), 7.20 - 7.33 (m, 3H), 4.70 (s, 2H), 2.89 (s, 3H) W0 2012/119046 EXAMPLE 135 3-(Cyclopentyl(methyl)amino)(4-fluorophenyl)quinoxalinecarboxylic acid O OI“' ND/lLOH/ F Step 1. Methyl 3-(cyclopentylamino)(4-fluorophenyl) quinoxalinecarboxylate DI“| NU/ILO// F To a solution of methyl 3—chloro(4-fluoropheny1) quinoxaline-6—carboxylate (250 mg, 0.79 mmol) in DMSO (3 mL) was added cyclopentylamine (402.6 mg, 4.73 mmol), and the resulting solution was stirred overnight at 100°C. The resulting mixture was d with water (15 mL) and extracted with dichloromethane (3 x 10 mL), and the organic layers combined, dried over anhydrous ium sulfate, and concentrated in vacuo to give a residue, which was purified Via silica gel column chromatography (2% - 5% ethyl e in petroleum ether) to afford methyl 3-(cyclopentylamino)(4-fluorophenyl)quinoxaline—6— carboxylate as a yellow solid (240 mg, 69%).
LC/MS (ES, m/z):[M+H]+ 366.0 1H—NMR (300 MHz, CDC13) 5 8.50 (d, J = 1.8 Hz, 1H), 7.99 — 8.02(m, 1H), 7.91 (d, J = 8.4 Hz, 1H), 7.25 - 7.31 (m, 2H), 4.50 - 4.57 (m, 1H), 4.00 (s, 3H), 2.17 - 2.23 (m, 2H), 1.67 - 1.76 (m, 4H), 1.44 - 1.51 (m, 2H) Step 2. Methyl 3-(cyclopentyl(methyl)amino)—2—(4-fluorophenyl)quinoxalinecarboxylate OI“l / F To a solution of methyl 3-(cyclopentylamino)—2—(4—fluorophenyl)quinoxalinecarboxylate (200 mg, 0.55 mmol) in tetrahydrofuran (15 mL) was added sodium hydride (96 mg, 4.00 mol) at 0°C. After stirring for 1h at room ature, iodomethane (141.94 mg, 1.00 mmol) was added at 0°C and the reaction mixture was stirred overnight .The reaction was then quenched by the addition of water (3 mL), ted with romethane (3 x 15 mL), and the organic layers combined, dried over anhydrous magnesium e, and concentrated in vacuo to give methyl 3—(cyclopenty1(methy1)amino)(4—fluorophenyl)quinoxaline-6— carboxylate as a yellow oil (120 mg, .
LC/MS (ES, m/z): [M+H]+ 380.0 Step 3. 3-(Cyclopentyl(methyl)amino)(4—fluoropheny1)quinoxaline—6—carboxylic acid DI”I ND/LKOH/ F To a solution of methyl 3-(cyclopentyl(methyl)amino)(4-fluorophenyl)quinoxaline—6- carboxylate (120.0 mg, crude) in methanol (20 mL) was added sodium hydroxide (50.0 mg, 1.25 mmol) in water (1 mL). The resulting solution was stirred overnight at room temperature and then concentrated in vacuo. The residue was dissolved in water (15 mL) and adjusted to pH 6 with hydrochloric acid (IN). The product was precipitated and filtered to afford 3- (cyclopenty1(methyl)amino)(4-fluorophenyl)quinoxalinecarboxylic acid (20 mg).
LC/MS (ES, m/z): [M+H]+ 366.0 1H—NMR (300 MHz, CDClg) 8 8.61(d, J = 1.8 Hz, 1H), 8.11 — 8.14(m, 1H), 7.95 - 7.99 (m, 2H), 7.18 - 7.24 (m, 2H), 4.31 - 4.36 (t, J = 7.8 Hz, 1H), 2.77 (s, 3H), 1.54 - 1.81 (m, 8H) EXAMPLE 136 3-(Isopropyl(methyl)amino)(4-(trifluoromethyl)phenyl)quinoxalinecarboxylic acid /N ”UCOOH DI”\ Step 1. Methyl 3-(isopropyl(methyl)amino)(4-(trifluoromethyl)phenyl)quinoxaline carboxylate Y O /N /N:©)LO/ DI”\ To a on of 4-(trifluoromethyl)phenylboronic acid (273 mg, 1.44 mmol) in dioxane (6 mL) was added methyl 2-chloro(isopropyl(methyl)amino)quinoxaline—6-carboxylate (140 mg, 0.48 mmol), K3PO4 (303 mg, 1.44 mmol), Pd(PPh3)4 (27.6 mg, 0.02 mmol) and water (3 drops), and the reaction mixture was stirred for 4 hours at 90°C in an oil bath under an inert here of nitrogen. The reaction mixture was concentrated in vacuo and then purified via silica gel column chromatography (2% - 10% ethyl acetate in petroleum ether) to afford methyl 3—(isopropy1(methyl)amino)—2-(4-(trifluoromethyl)phenyl)quinoxaline-6—carboxylate as a light yellow solid (158 mg, 82 %).
LC/MS (ES, m/z): [M+H]+ 404.0 1H—NMR (300 MHz, CDC13) 8 8.54 (d, J = 1.8 Hz, 1H), 7.96 - 8.09 (m, 4H), 7.62 — 7.79 (m, 2H), 4.21 — 4.30 (m, 1H), 4.01 (s, 3H), 2.74 (s, 3H), 1.12 (d, J = 6.6 Hz, 6H) Step 2. 3~(Isopropy1(methyl)amino)(4-(trifluoromethyl)phenyl)quinoxaline-6—carboxylic acid ’“ ”UCOOH OI“\ To a solution of methyl 3-(isopropyl(methyl)amino)—2—(4— (trifluoromethyl)phenyl)quinoxalinecarboxylate (158.0 mg, 0.39 mmol) in tetrahydrofuran (20 mL) was added sodium hydroxide (47.0 mg, 1.18 mmol) and water (2 mL), and the reaction mixture was stirred overnight at room ature. The reaction mixture was concentrated in vacuo, ved in water (20 mL) and adjusted to pH 5 with hydrochloric acid (IN). The solids were collected by filtration to afford 3-(isopropy1(methyl)amino)—2—(4— (trifluoromethyl)phenyl)quinoxalinecarboxylic acid as a light yellow solid (89 mg, 58%).
LC/MS (ES, m/z): [M+H]+ 390.0 W0 19046 1H—NMR (300 MHZ, DMSO) 8 8.27 — 8.28 (t, J: 1.2 Hz, 1H), 8.06 (d, J: 8.1 Hz, 2H), 7.89 - 7.96 (m, 4H), 4.18 (t, J: 6.6 Hz, 1H), 2.65 (s, 3H), 1.04 — 1.11 (m, 6H) EXAMPLE 137 3-[(1-Ethylpiperidinyl)(methyl)amino](4-fluorophenyl)quinoxalinecarboxylic acid [9 o /N NfiOH OI“| / F Step 1. Methyl 3-[( l -ethylpipen'diny1)(methyl)amino]-2—(4-fluorophenyl)-l ,4- dihydroquinoxalinecarboxylate Q 0 DI“I Nfiko// To a solution of methyl 2-(4—fluorophenyl)-3—[methyl(piperidinyl)amino]quinoxaline-6— carboxylate (100 mg, 0.25 mmol) in MN—dimethylformamide (30 mL) was added potassium carbonate (157.6 mg, 1.14 mmol) and CH3CH21 (71.32 mg, 0.46 mmol), and the reaction mixture was stirred overnight at room temperature. The reaction mixture was then diluted with water (200 mL) and extracted with romethane (4 x 50 mL). The organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography (1% ol in dichloromethane) to afford methyl 3-[( l -ethylpiperidinyl)(methyl)amino](4—fluorophenyl)-l ,4— dihydroquinoxaline—6—carboxylate as light yellow oil (53 mg, 46 %).
LC/MS (ES, m/z): [M+H]+423.0 1H-NMR (300 MHz, CDCl3) 6 8.49 (d, J: 1.8 Hz, 1H), 8.05 - 8.09 (m, 1H), 7.95 (d, J = 8.4 Hz, 1H), 7.87 - 7.92 (m, 2H), 7.18 - 7.23 (m, 2H), 4.01 (s, 3H), 3.95 — 3.98 (m, 1H), 3.07 - 3.15 (m, 2H), 2.77 (s, 3H), 2.41 — 2.49 (m, 2H), 1.82 - 2.01 (m, 4H), 1.74 — 1.78 (m, 2H), 0.85 — 0.89 (t, J: 6.6 Hz, 3H) Step 2. 3-[(l-Ethylpiperidin—4-yl)(methyl)amino](4-fluorophenyl)quinoxaline carboxylic acid Q 0 DI”I NfikOH/ F To a on of methyl 3—[(1—ethylpiperidin—4-yl)(methy1)amino]—2-(4- fluorophenyl)quinoxa1ine—6—carboxy1ate (53 mg, 0.12 mmol) in methanol (30 mL) was added sodium hydroxide (26.5 mg, 0.66 mmol), and the resulting mixture was stirred overnight at room temperature. The reaction mixture was concentrated in vacuo, dissolved in water (10 mL), and ed to pH 5 with HCl (3N) to give the precipitate, which was collected by filtration to afford 3-[(l-ethy1pipen'din—4-y1)(methyl)amino]—2-(4—fluorophenyl)quinoxa1ine- 6-carboxy1ic acid as a light yellow solid (35.2 mg, 69 %).
LC/MS (ES, m/z): [M+H]+ 409.0 1H—NMR (300 MHZ, DMSO) 5 8.47 (d, J: 1.8 Hz, 1H), 8.02 - 8.12 (m, 1H), 7.94 - 7.99 (m, 3H), 7.28 — 7.34 (t, J: 8.7 Hz, 2H), 4.31 - 4.36 (t, J: 7.5 Hz, 1H), 3.66 - 3.98 (m, 2H), 3.20 (d, J: 6.9 Hz, 2H), 3.06 - 3.09 (t, J: 6.9 Hz, 2H), 2.72 (s, 3H), 2.18 (s, 4H), 1.36 - 1.41 (t, J = 7.5 Hz, 3H) EXAMPLE 138 (S)(4-Ethyl-Z-methylpiperazin-l-yl)(4-fluorophenyl)quinoxalinecarboxy1ic acid AN/fi“ 0 | NfiLOH Step 1. (S)-Methyl 3—(4-ethy1—2-methy1piperazin- 1 —y1)—2—(4-fluorophenyl)quinoxaline carboxylate /\Nfi“0‘ O N N To a solution of (S)—methy1 2-(4-fluoropheny1)(2-methy1piperazin—1—y1)quinoxa1ine carboxylate (160 mg, 0.42 mmol) in MN—dimethylformamide (30 mL) was added potassium carbonate (174 mg, 1.26 mmol) and CH3CH2I (68.8 mg, 0.44 mmol), and the reaction was stirred overnight at room temperature. The reaction on was diluted with water (150 mL), extracted with dichloromethane (3 x 30 mL), and the organic layers ed, dried over anhydrous magnesium e, and concentrated in vacuo. The residue was purified by silica gel column chromatography (1% methanol in dichloromethane) to afford (S)—methy1 3- (4-ethy1—2—methy1piperaziny1)(4-fluoropheny1)quinoxalinecarboxy1ate as light yellow oil (80 mg, crude).
LC/MS (ES, m/z): [M+H]+ 408.0 Step 2. (S)—3 —(4—Ethy1—2-methy1piperazin-1 -y1)—2-(4-fluoropheny1)quinoxaline—6—carboxy1ic acid To a solution of (S)-methy1 3-(4-ethy1methylpiperazinyl)(4- fluoropheny1)quinoxa1inecarboxylate (80 mg, crude) in ol (30 mL) was added sodium ide (31.0 mg, 0.78 mmol) and water (1 mL), and the on was stirred overnight at room temperature. The reaction mixture was concentrated in vacuo, dissolved in water (30 mL), and adjusted to pH 5 with HCl (3N) to give the precipitate, which was purified by Prep—HPLC with the following conditions [(Agilent 1200 prep HPLC): Column, SunFire Prep C18, 19 * 50 mm 5 um; mobile phase, water with 0.05 % NH3‘H20 and CH3CN (10 % CH3CN up to 45% in 10 min); Detector, UV 220nm] to afford (S)-3—(4—ethyl—2— methylpiperazin-l-y1)(4-fluorophenyl)quinoxalinecarboxy1ic acid (40 mg, 52.0%).
LC/MS (ES, m/z): [M+H]Jr 395.0 1H—NMR (300 MHz, DMSO) 8 8.28 (d, J = 1.50 Hz, 1H), 7.94 — 8.00 (m, 4H), 7.34 — 7.39 (t, J = 9.00 Hz, 2H), 3.87 _ 3.89 (t, J = 3.30 Hz, 1H), 3.36 — 3.41 (m, 1H), 3.20 — 3.24 (m, 1H), 2.71 — 2.74 (m, 1H), 2.19 — 2.38 (m, 4H), 1.06 (d, J = 6.60 Hz, 3H), 0.96 - 1.01 (t, J = 6.90 Hz, 3H) EXAMPLE 139 3-[Ethyl(propyl)amino](4-fluorophenyl)quinoxalinecarboxylic acid H o Step 1. Methyl 2-(4-fluorophenyl)(propylamino)quinoxalinecarboxylate To a solution of methyl 3-chloro-2—(4-fluoropheny1) alinecarboxylate (150 mg, 0.47 mmol) in DMSO (10 mL) was added DIEA (182 mg, 1.41 mmol) and propan—l—amine (56 mg, 0.95 mmol), and the reaction was stirred overnight at 80°C in an oil bath. The reaction mixture was cooled to room temperature, diluted with water (150 mL), extracted with ethyl acetate (3 x 50 mL), and the c layers combined, dried over magnesium e, and concentrated in vacuo to give the residue, which was purified via silica gel column chromatography (1% ethyl acetate in petroleum ether) to afford 2-(4-fluorophenyl) (propylamino)quinoxalinecarboxylate as a light yellow solid (70 mg, 45.0%).
LC/MS (ES, m/z): [M+H]+ 340.0 1H-NMR (300 MHz,CDC13): 8 8.51 (d, J = 1.50 Hz, 1H), 7.91 - 8.02 (m, 2H), 7.73 — 7.79 (m, 2H), 7.25 - 7.32 (m, 2H), 5.20 (s, 1H), 4.00 (s, 3H), 3.54 - 3.60 (m, 2H), 1.64 - 1.76 (m, 2H), 0.95 - 1.54 (m, 3H) Step 2. 3—(Ethyl(propyl)amino)(4-fluorophenyl)quinoxalinecarboxylic acid fl 0 NM N\ OH To a solution of methyl 2-(4—fluorophenyl)—3—(propylamino)quinoxaline—6-carboxylate (70 mg, 0.21 mmol) in tetrahydrofuran (30 mL) was added sodium hydride (32 mg, 1.32 mmol) and CH3CHZI (1.5 mL), and the reaction was stirred overnight at room temperature. The reaction was then quenched with water (50 mL), adjusted to pH 5 with HCl (3N), and extracted with ethyl acetate (3 x 40 mL). The organic layers were combined, dried over ous magnesium sulfate, and concentrated in vacuo to give the residue, which was purified by PLC under the following conditions [(Agilent 1200 prep HPLC): Column, SunFire Prep C18, 19 * 50 mm 5 um; mobile phase, water with0.03% NH3H20 and CH3CN (10 % CH3CN up to 35 % in 8 min); Detector, UV 220nm] to afford 3-(ethyl(propyl)amino)- uoropheny1)quinoxalinecarboxylic acid as alight yellow solid (45.0 mg, 62.0%).
LC/MS (ES, m/z): [M+H]+ 354.0 1H—NMR (300 MHz, DMSO): 5 8.21(d,J= 1.20 Hz, 1H), 7.83 — 7.98 (m, 4H), 7.34 — 7.40 (m, 2H), 3.36 - 3.39 (m, 2H), 3.27 - 3.32 (t, J = 7.20 Hz, 2H), 1.45 - 1.52 (m, 2H), 0.98 — 1.02 (t, J: 6.90 Hz, 3H), 0.69 - 0.74 (t, J = 7.50 Hz, 3H) EXAMPLE 140 3-(Dipropylamino)(4-fluorophenyl)quinoxalinecarboxylic acid H o I Nj:>)LOH Step 1. Methyl 3-(dipropy1amino)(4-fluorophenyl)quinoxaline-6—carboxy1ate To a on of methyl 3—chloro(4-fluorophenyl)quinoxalinecarboxylate (100 mg, 0.32 mmol) in DMSO (3 mL) was added dipropylamine (100 mg, 0.99 mmol) and DIEA (100 mg, 0.77 mmol). The resulting solution was stirred overnight at 85°C and then diluted with water (50 mL), ted with ethyl acetate (3 x 20 mL), and the organic layers combined, dried over anhydrous magnesium sulfate, and concentrated in vacuo to give a residue, which was W0 2012/119046 PCT/U52012/027423 purified Via silica gel column chromatography (2.5% - 4% ethyl acetate in petroleum ether) to afford methyl 3-(dipropylamino)—2-(4-fluorophenyl)quinoxalinecarboxylate as a yellow solid (50 mg, 41 %).
LC/MS (ES, m/z):[M+H]+ 382.0 1H—NMR (300 MHz, CDC13), 6 8.60 (d, J = 1.5 Hz ,lH), 8.06 - 8.09 (m, 1H), 7.91 (d, J: 8.4 Hz, 1H), 7.86 - 7.91 (m, 2H), 7.18 - 7.24 (m, 2H), 4.00 (s, 3H), 3.26 - 3.31 (t, J = 7.2 Hz, 4H), 1.51 — 1.63 (m, 4H), 0.77 - 0.82 (t, J: 7.2 Hz, 6H) Step 2. ropylamino)—2-(4-fluorophenyl)quinoxalinecarboxylic acid H o /\/N I ND/LkOH To a solution of methyl 3—(dipropylamino)-2—(4—fluorophenyl)quinoxaline—6—carb0xylate (50 mg, 0.13 mmol) in methanol (15 mL) was added a solution of sodium hydroxide (10 mg, 0.25 mmol) in water (1 mL). The resulting solution was stirred overnight at room temperature and then concentrated in vacuo. The e was dissolved in water (20 mL) and adjusted to pH 5 with hydrochloric acid (3N). The resulting solution was extracted with dichloromethane (4 x mL), and the organic layers combined, dried over anhydrous magnesium e, and concentrated in vacuo to afford 3—(dipropylamino)—2-(4—fluoropheny1)quinoxaline ylic acid as a yellow solid (22.4 mg, 46 %).
LC/MS (ES, m/z): [M+H]Jr 368.0 1H-NMR (300 MHz, CD3OD), 8 8.42 (d, J: 1.5 Hz,lH), 8.03 - 8.06 (m, 1H), 7.88 - 7.94 (m, 3H), 7.29 — 7.33 (m, 2H), 3.26 (d, J: 7.5 Hz, 4H), 1.51 - 1.63 (m, 4H), 0.77 - 0.82 (t, J: 7.2 Hz, 6H) EXAMPLE 1 41 2-(4-Fluorophenyl)(isobutyl(methyl)amino)quinoxalinecarboxylic acid J} O N OI/ /NULOH \ Step 1. Methyl 2-(4-fluorophenyl)(isobutyl(methyl)amino)quinoxalinecarboxy1ate /% O OI“\ F To a solution of methyl 3-chloro(4-fluorophenyl)quinoxalinecarboxylate (100 mg, 0.32 mmol) in DMSO (3 mL) was added DIEA (81.5 mg, 0.63 mmol) and isobuty1(methyl)amine (41 mg, 0.47 mmol), and the reaction was stirred overnight at 70°C in an oil bath. The reaction mixture was cooled to room temperature, diluted with water (50 mL), and extracted with ethyl acetate (3 x 20 mL). The organic layers were combined, dried over magnesium sulfate, and concentrated in vacuo to give the residue, which was purified via silica gel column tography (1% ethyl acetate in petroleum ether) to afford methyl 2—(4- fluorophenyl)-3—(isobutyl(methy1)amino)quinoxaline—6—carboxylate as a light yellow solid (80 mg, 69%).
LC/MS (ES, m/z): [M+H]+ 368.0 1H—NMR (300 MHz, CDC13)I 5 8.54 (d, J = 1.5 Hz, 1H), 8.04 - 8.08 (m, 1H), 7.96 (d, J: 8.7 Hz, 1H), 7.86 — 7.91 (m, 2H), 7.19 — 7.28 (m, 2H), 4.00 (s, 3H), 3.16 (d, J = 7.2 Hz, 2H), 2.89 (s, 3H), 1.99 - 2.09 (m, 1H), 0.82 (d, J: 6.6 Hz, 6H) Step 2. luorophenyl)-3 —(isobutyl(methyl)amino)quinoxaline—6—carboxylic acid )fi 0 OI“/N:©/U\OH\ To a solution of methyl 2-(4-fluorophenyl)(isobuty1(methyl)amino)quinoxaline carboxylate (80 mg, 0.22 mmol) in methanol (20 mL) and water (1 mL) was added sodium hydroxide (34.8 mg, 0.87 mmol l), and the reaction was d overnight at room temperature. The on mixture was concentrated in vacuo, dissolved in water (10 mL), and adjusted to pH 5 with HCl (3N) to give the precipitate, which was collected by filtration to afford 2—(4—fluorophenyl)—3—(isobutyl(methyl)amino)quinoxalinecarboxylic acid as a light yellow solid (50.0 mg, 65 %).
LC/MS (ES, m/z): [M+H]+ 354.0 1H—NMR (300 MHz, DMSO) 5 13.19 (s, 1H), 3 8.25 (s, 1H), 7.83 — 7.96 (m, 4H), 7.36 — 7.42 (t, J: 8.7 Hz, 2H), 3.09 (d, J: 7.2 Hz, 2H), 2.84 (s, 3H), 1.92 - 2.01 (m, 1H), 0.71 (d, J: 6.6 Hz, 6H) EXAMPLE 142 thylpiperidin— l -yl)(4-fluoropheny1)quinoxalinecarboxy1ic acid To a solution of methyl 3-chlorooxo-1,2-dihydroquinoxa1ine—6—carboxy1ate (500 mg, crude) in DMSO (5 mL) was added 2-ethy1piperidine (475 mg, 4.20 mmol) and DIEA (542 mg, 4.19 mmol). The resulting solution was stirred ght at 80°C in an oil bath and then quenched by the addition of water (50 mL), ted with dichloromethane (5 x 20 mL). The organic layers were combined, dried over magnesium sulfate, and concentrated in vacuo to give a residue, which was purified via silica gel column chromatography (1% - 10% ethyl acetate in petroleum ether) to afford methyl 3-(2-ethy1piperidiny1)-2—oxo—1,2- dihydroquinoxaline-6—carboxy1ate as yellow oil (150 mg).
LC/MS (ES, m/z): [M+H]+ 316.0 1H-NMR (300 MHz, CDC13), 6 9.78 (s,l H), 9.27 (s, 1H), 7.82 - 7.86 (m, 1H), 7.06 (d, J = 8.4 Hz, 1H), 5.27 (s, 1H), 4.86 - 4.91 (s,1H), 3.94 (s, 3H), 3.14 — 3.19 (m, 1H), 1.60 - 1.80 (m, 6H), 0.92 - 0.98 (m, 3H) W0 19046 Step 2. Methyl 3-(2-ethylpiperidin—l—yl)—2—[(trifluoromethane)sulfonyloxy]quinoxaline carboxylate TfONINfiO/\N To a solution of methyl 3-(2-ethylpipen'dinyl)oxo-1,2—dihydroquinoxaline—6— carboxylate (150 mg, 0.48 mmol) in dichloromethane (20 mL) was added pyridine (151 mg, 1.91 mmol) and mo (270 mg, 0.96 mmol,). The resulting solution was stirred overnight at room temperature, and then washed with water (30 mL), dried over anhydrous magnesium e, and concentrated in vacuo to afford methyl 3-(2-ethylpiperidin—1-yl) [(trifluoromethane)sulfonyloxy]quinoxalinecarboxylate as yellow oil (210 mg .
Step 3. Methyl 3-(2-ethylpiperidin—1-y1)(4-fluorophenyl)quinoxaline—6-carboxylate To a solution of methyl 3-(2-ethylpiperidin-l-yl)—2- [(trifluoromethane)sulfonyloxy]quinoxalinecarboxy1ate (210 mg, crude) in dioxane (5 mL) was added (4—fluorophenyl)boronic acid (133 mg, 0.95 mmol), K3PO4 (200 mg, 0.94 mmol), Pd(PPh3)4 (27 mg, 0.02 mmol) and water (5 drops). The resulting solution was stirred for 1 hour at 90°C under an inert atmosphere of nitrogen and then concentrated in vacuo to give a residue, which was purified via silica gel column chromatography (2% - 10% ethyl acetate in eum ether) to afford methyl 3-(2-ethylpiperidinyl)-2—(4-fluorophenyl)quinoxaline carboxylate as a yellow solid (140 mg).
LC/MS (ES, m/z): [M+H]+ 394.0 Step 4. 3—(2—Ethylpiperidin-l-yl)(4-fluorophenyl)quinoxaline—6—carboxylic acid W0 2012/119046 To a solution of methyl 3-(2-ethylpiperidin—1-yl)(4-fluorophenyl)quinoxaline—6- carboxylate (45 mg, 0.11 mmol) in methanol (15 mL) was added sodium hydroxide (10 mg, 0.25 mmol) in water (1 mL). The resulting solution was stirred overnight at room ature and concentrated in vacuo. The residue was dissolved in water (3 mL), adjusted to pH 5 with hloric acid (3M), and collected by filtration to afford 3—(2—ethy1piperidinyl)(4- fluorophenyl)quinoxalinecarboxylic acid as a yellow solid (23.3 mg, 54%).
LC/MS (ES, m/z): [M+H]+ 380.0 1H-NMR (300 MHz, DMSO), 68.57 (d, J: 1.2 Hz, 1H), 8.09 — 8.13 (m, 1H), 7.98 — 8.04 (m, 3H), 7.19 - 7.28 (m, 1H), 3.80 - 3.90 (m, 1H), 3.68 - 3.72 (m, 1H), 3.08 - 3.18 (m, 1H), 1.60 - 1.73 (m, 6H), 0.66 - 0.71 (t, J: 7.5 Hz, 3H) EXAMPLE 143 (S)(4-Fluorophenyl)(methyl(1-phenylethyl)amino)quinoxalinecarboxylic acid The solution of methyl 3—chloro—2—(4—fluorophenyl)quinoxalinecarboxy1ate (180 mg, 0.57 mmol) in (S)-1—pheny1ethanamine (2 mL) was stirred overnight at 95°C, and then purified via silica gel column tography (1% - 2% ethyl acetate in petroleum ether) to afford (S)- methyl 2—(4-fluorophenyl)—3-(1-phenylethylamino)quinoxalinecarboxylate as yellow oil (100 mg, 44 %).
LC/MS (ES, m/z): [M+H]+ 402.0 1H—NMR (300 MHz, CDC13), 6 8.27 - 8.28 (t, J: 1.5 Hz, 1H), 7.82 - 7.95 (m, 4H), 7.44 - 7.47 (t, J = 7.8 Hz, 1H), 7.30 - 7.38 (m, 4H), 7.21 - 7.24 (m, 1H), 5.45 (d, J: 4.8 Hz, 1H), 3.97 (s, 3H), 1.57 (d, J: 6.9 Hz, 3H) Step 2. (S)(4-Fluorophenyl)(methy1(1-phenylethyl)amino)quinoxaline-6—carboxylic acid To a solution of (S)—methyl 2—(4—fluorophenyl)—3—(1—phenylethylamino)quinoxaline carboxylate (100 mg, 0.25 mmol) in tetrahydrofuran (15 mL) was added sodium hydride (30 mg, 0.75 mmol), and the reaction mixture was stirred for 10 minutes. CH31 (106 mg, 0.75 mmol) was added, and the ing mixture was stirred overnight. The reaction was then quenched by the on of NH4C1 solution (50 mL) and adjusted pH to 5 with hydrochloric acid (3N). The solids were collected by filtration to afford (S)(4-fluorophenyl)—3— (methyl(1-pheny1ethyl)amino)quinoxaline-6—carboxylic acid as a yellow solid (47.5 mg, 48 LC/MS (ES, m/z): [M+H]+ 402.0 1H-NMR (300 MHZ, CD30D), 6 8.40 (d, J = 1.8 Hz, 1H), 8.05 - 8.08 (m, 1H), 7.90 — 7.95 (In, 3H), 7.20 - 7.28 (m, 7H), 5.43 — 5.50 (m, 1H), 2.58 (s, 3H), 1.53 (d, J: 6.9 Hz, 3H) EXAMPLE 144 2-(4-Fluorophenyl)(pyrrolidin-l-yl)quinoxalinecarboxylic acid To a solution of methyl ro(4-fluoropheny1)quinoxalinecarboxylate (130 mg, 0.41 mmol) in DMSO (2 mL) was added pyrrolidine (58 mg, 0.82 mmol) and DIEA (106 mg, 0.82 mmol). After stirring 2h at 70°C, the reaction mixture was dissolved in water (100 mL), extracted with romethane (3 x 30 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure to afford a residue, which was purified via silica gel column chromatography (2% romethane in petroleum ether) to afford methyl 2—(4— fluorophenyl)—3—(pyrrolidin—1-yl)quinoxa1ine-6—carboxy1ate as a light yellow solid (72 mg, 50 LC/MS (ES, m/z): [M+H]+ 352.0 1H-NMR (300 MHz, CDC13) 6 8.69 (s, 1H), 7.94 - 8.05 (m, 2H), 7.71 - 7.76 (m, 2H), 7.19 - 7.28 (m, 2H), 4.02 (s, 3H), 3.32 - 3.40 (m, 4H), 1.88 — 1.93 (m, 4H) Step 2. 2-(4-F1uoropheny1)(pyrrolidin—1-y1)quinoxa1ine-6—carboxy1ic acid C O I NDAOH To a solution of methyl 2—(4-fluorophenyl)-3—(pyrrolidin—1—yl)quinoxalinecarboxylate (72 mg, 0.20 mmol) in methanol (20 mL) was added sodium ide (50 mg, 1.25 mmol).
After stirring overnight at room temperature, the reaction mixture was concentrated under reduced pressure to afford a residue, which was dissolved in water (10 mL), adjusted to pH 6 with hydrochloric acid (3N). The product formed a precipitate and was filtered to give 2-(4- henyl)—3-(pyrrolidinyl)quinoxaline—6-carboxylic acid as a light yellow solid (41.5 mg, 60%).
LC/MS (ES, m/z): [M+H]+ 338.0 1H—NMR (300 MHz, DMSO) 8 8.23 (s, 1H), 7.85 - 7.92 (m, 2H), 7.73 - 7.76 (m, 2H), 7.34 - 7.38 (t, J = 6.6 Hz, 2H), 3.23 (s, 4H), 1.80 (s, 4H) EXAMPLE 145 3-(Azetidinyl)(4-fluorophenyl)quinoxaline—6-carboxylic acid C‘ O I ”ID/kw Step 1. Methyl 3—(azetidin-l-yl)—2—(4-fluoropheny1)quinoxalinecarboxylate C 0 N N\ O/ To a solution of methyl 3-chloro(4-fluorophenyl)quinoxalinecarboxylate (100 mg, 0.32 mmol) in DMSO (2 mL) was added azetidine (37 mg, 0.65 mmol) and DIEA (81 mg, 0.63 mmol). After stirring for 2 hours at 70°C, the reaction mixture was dissolved in water (50 mL), extracted with dichloromethane (3 x 30 mL), dried over anhydrous ium sulfate, and concentrated under reduced pressure to afford a residue, which was purified Via silica gel column chromatography (2% dichloromethane in petroleum ether) to afford methyl 3- (azetidin-l-yl)(4-fluoropheny1)quinoxalinecarboxylate as a light yellow solid (60 mg, 56 %).
LC/MS (ES, m/z): [M+H]+ 338.0 1H-NMR (300 MHz, DMSO) 5 8.24 (s, 1H), 7.88 - 7.95 (m, 2H), 7.75 - 7.80 (m, 2H), 7.34 - 7.48 (m, 2H), 3.97 (s, 3H), 3.70 - 3.85 (t, J = 7.5 Hz, 4H), 2.13 - 2.23 (m, 2H) Step 2. 3-(Azetidin-1—yl)(4—fluorophenyl)quinoxalinecarboxylic acid I NUAOH W0 2012/119046 2012/027423 To a solution of methyl tidiny1)—2-(4-fluorophenyl)quinoxaline—6—carboxylate (60 mg, 0.18 mmol) in methanol (20 mL) was added sodium hydroxide (50 mg, 1.25 mmol) and water (1 mL). After ng overnight at room temperature, the reaction mixture was concentrated under reduced pressure to afford a residue, which was dissolved in water (10 mL), adjusted to pH 6 with hydrochloric acid (3N), and the product was precipitated and filtered to give 3-(azetidin-l-yl)(4-fluorophenyl)quinoxaline—6-carboxylic acid as a light yellow solid (35.3 mg, 61 %).
LC/MS (ES, m/z): [M+H]+ 324.0 1H-NMR (300 MHz, DMSO) 5 8.24 (s, 1H), 7.88 ~ 7.95 (m, 2H), 7.75 - 7.80 (m, 2H), 7.34 - 7.50 (t, J = 8.7 Hz, 2H), 3.70 - 3.85 (t, J: 7.5 Hz, 4H), 2.13 - 2.23 (m, 2H) EXAMPLE 146 3-(Cyclobutyl(methyl)amino)(4—fluorophenyl)quinoxaline—6-carboxylic acid £31”l / F Step 1. Methyl 3—(cyclobutylamino)-2—(4—fluorophenyl)quinoxalinecarboxylate A O oi“!l NDJkO// F To a solution of methyl 3-chloro(4-fluorophenyl)quinoxalinecarboxylate (100 mg, 0.32 mmol) in DMSO (1 mL) in was added cyclobutanamine (100 mg, 1.41 mmol) and DIEA (110 mg, 0.85 mmol). The ing solution was stirred for 2 hours at 70°C, and then quenched by the addition of water (50 mL) and extracted with dichloromethane (4 x 20 mL).
The organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated in vacuo to give a residue, which was purified via silica gel column chromatography (2% - 10% ethyl acetate in petroleum ether) to afford methyl 3- (cyclobutylamino)-2—(4-fluorophenyl)quinoxaline—6—carboxylate as a yellow solid (67 mg, 58%) LC/MS (ES, m/z): [M+H]+ 352.0 1H-NMR (300 MHz, CDClg) 8 8.59 (s, 1H), 8.02- 8.05 (m, 1H), 7.92 (d, J = 8.4 Hz, 1H), 7.28 - 7.33 (m, 2H), 4.81 - 4.83 (m, 1H), 4.00 (s, 3H), 2.55 — 2.57 (m, 2H), 1.84 - 1.92 (m, Step 2. Methyl 3-[cyclobutyl(methy1)amino]—2—(4-fluorophenyl)quinoxaline—6-carboxylate i O /N Nfio/ OI”I / F To a solution of methyl 3-(cyclobutylamino)—2—(4-fluorophenyl)quinoxa1inecarboxy1ate (67 mg, 0.19 mmol) in tetrahydrofuran (20 mL) was added sodium hydride (30 mg, 60%) and CH3I (135 mg, 0.95 mmol). The resulting solution was stirred overnight at 10°C. The reaction was then ed by the addition of NH4C1 solution (50 mL), extracted with ethyl acetate (4 x 20 mL), and the organic layers combined, dried over anhydrous magnesium sulfate, and trated in vacuo to give a residue, which was purified via silica gel column chromatography (2% - 10% ethyl acetate in petroleum ether) to afford methyl 3— butyl(methyl)amino](4-fluorophenyl)quinoxalinecarboxylate as a yellow solid (70 mg, crude).
LC/MS (ES, m/z): [M+H]+ 366.0 Step 3. 3—(Cyclobutyl(methyl)amino)-2—(4-fluorophenyl)quinoxalinecarboxylic acid.
FQI” To a solution of methyl 3—(cyclobutyl(methyl)amino)(4-fluorophenyl)quinoxaline—6- ylate (70.0 mg, crude) in MeOH (15 mL) was added sodium hydroxide (18.0 mg, 0.45 mmol) and water (0.5 mL). The resulting solution was stirred overnight at room temperature and concentrated in vacuo. The residue was dissolved in water (10 mL) and adjusted to pH 3 with hydrochloric acid (1N). The solids were collected by filtration to afford 3— (cyclobutyl(methyl)amino)~2—(4—fluorophenyl)quinoxaline—6-carboxylic acid as a yellow solid (30 mg).
LC/MS (ES, m/z): [M+H]+ 352.0 1H-NMR (300 MHz, DMSO) 3 8.24 (d, J = 1.8 Hz, 1H), 7.99 _ 7.89 (m, 4H), 7.41 — 7.39 (t, J = 9.0 Hz, 2H), 4.19 — 4.08 (m, 1H), 2.68 (s, 3H), 2.14 — 2.04 (m, 4H), 1.62 — 1.56 (m, 2H) EXAMPLE 147 2-(2,4-Difluorophenyl)[methyl(propanyl)amino]quinoxalinecarboxylic acid Y O /N N\ OH F F Step 1. Methyl 2-(2,4-difluorophenyl)[methyl(propanyl)amino]quinoxaline carboxylate Y O /N Nfio/ For“ F To a solution of methyl 3-[methyl(propan—2-y1)amino]-2— [(trifluoromethane)sulfonyloxy]quinoxalinecarboxy1ate (200 mg, 0.49 mmol) in dioxane (5.0 mL) and water (3 drops) was added (2,4—difluoropheny1)boronic acid (233 mg, 1.48 mmol), Pd(PPh3)4 (28.3 mg, 0.02 mmol), and K3PO4 (310 mg, 1.46 mmol), and the reaction mixture was stirred for 40 min at 90°C under an atmosphere of nitrogen. The reaction mixture was concentrated in vacuo to give a residue, which was ed via silica gel column chromatography (2% ethyl acetate in petroleum ether) to afford methyl - difluorophenyl)—3—[methyl(propan—2—yl)amino]quinoxalinecarboxylate as a light yellow solid (150 mg, 82 %).
LC/MS (ES, m/z): [M+H]+ 372.0 1H-NMR (300 MHz, CDC13) 5 8.54 (d, J = 1.5 Hz,1H), 8.04 — 8.07 (m, 1H), 7.95 (d, J = 8.4 Hz, 1H), 7.66 - 7.73 (m, 1H), 7.04 - 7.11 (m, 1H), 6.93 - 7.00 (m, 1H), 4.29 - 4.36 (m, 1H), 4.01 (s, 3H), 2.72 (s, 3H), 1.09 (d, J: 6.6 Hz, 6H) Step 2. 2—(2,4—Difluorophenyl)[methy1(propany1)amino]quinoxaline—6-carboxylic acid Y O if“l , F F W0 2012/119046 To a solution of methyl 2-(2,4-difluorophenyl)—3-[methy1(propanyl)amino]quinoxaline carboxylate (150 mg, 0.40 mmol) in methanol (25 mL) and water (1 mL) was added sodium hydroxide (64.7 mg, 1.62 mmol), and the reaction e was stirred overnight at room temperature. The reaction e was concentrated in vacuo, and then dissolved in water (30 mL), and adjusted to pH 4 with hydrochloric acid (3N) to give the precipitate, which was collected by filtration to afford -difluorophenyl)[methyl(propan-2— yl)amino]quinoxaline-6—carboxylic acid as a light yellow solid (100 mg, 69 %).
LC/MS (ES, m/z): [M+H]+ 358.0 1H-NMR (300 MHz, DMSO) 5 13.25 (s, 1H), 8.27 (s, 1H), 7.92 - 7.97 (m, 2H), 7.79 - 7.87 (m, 1H), 7.41 — 7.48 (m, 1H), 7.28 - 7.34 (m, 1H), 4.19 - 4.28 (m, 1H), 2.64 (s, 3H), 1.01 (d, J = 6.6 Hz, 6H) EXAMPLE 148 (S)(3,4-Difluorophenyl)(2—methylpyrrolidin-l-yl)quinoxaline-fi-carboxylic acid 0‘“ ° N /NfioH Step 1. (S)—Methyl 3-(2—methylpyrrolidin-1—yl)—2—(trifluoromethylsulfonyloxy)quinoxaline carboxylate Cs“‘ 0 N Nfio/ I I \ TfO N To a solution of methyl 3-((S)methylpyrrolidinyl)oxo-1,2,4a,8a- tetrahydroquinoxaline-6—carboxylate (140.0 mg, 0.48 mmol) in dichloromethane (50 mL) was added pyridine (152 mg, 1.92 mmol) and TfZO (271mg, 0.96 mmol), and the reaction mixture was stirred overnight under an atmosphere of nitrogen at room temperature. The reaction mixture was then quenched with water (50 mL), extracted with dichloromethane (3 x 15 mL), and the organic layers combined, dried over anhydrous magnesium sulfate, and concentrated in vacuo to afford thyl ethy1pyrrolidinyl) (trifluoromethylsulfonyloxy)quinoxaline—6-carboxylate as red oil (195 mg, crude), which was used in the next step directly.
Step 2. thyl 2—(3,4-difluoropheny1)—3-(2—methylpyrrolidin-l—yl)quinoxa1ine carboxylate To a solution of (S)—methyl 3-(2—methylpyrrolidin-1—yl)-2— (trifluoromethylsulfonyloxy)quinoxa1ine—6—carboxylate (195mg, crude) in dioxane (3 mL), was added 3,4-difluorophenylboronic acid (130 mg, 0.80 mmol), K3PO4 (180 mg, 0.8 mmol), Pd(PPh3)4 (28 mg, 0.024 mmol) and water (5 drops) under a nitrogen atmosphere. After stirring lh at 90°C, the reaction mixture was dissolved in water (100 mL), extracted with dichloromethane (3 x 30 mL), dried over anhydrous magnesium sulfate, and trated under d pressure to afford a residue, which was purified via silica gel column chromatography (2% ethyl acetate in petroleum ether) to afford (S)-methyl 2-(3,4— difluorophenyl)(2-methylpyrrolidinyl)quinoxalinecarboxylate as a light yellow solid (86.0 mg).
LC/MS (ES, m/z): [M+H]+ 384.0 1H-NMR (300 MHz, CDCl3) 8 = 1.5 Hz, 1H), 7.92 — 8.28 (m, 2H), 7.76 — 7.82 (m, . 8.27 (d, J 1H), 7.56 — 7.62(m, 2H), 4.21— 4.28 (m, 1H), 3.90 (s, 3H), 2.96 - 3.01 (m, 2H), 2.10 - 2.20 (m, 1H), 1.70 — 1.79 (m, 1H), 1.55 - 1.60 (m, 2H), 1.33 (d, J: 6.0 Hz, 3H) Step 3. (3 uorophenyl)—3—(2—methylpyrrolidin-1—yl)quinoxaline—6-carboxylic acid 0‘“ ° N /ND/KOH To a solution of (S)—methyl 2-(3,4—difluorophenyl)-3—(2—methy1pyrrolidin—1—yl)quinoxaline carboxylate (80 mg, 0.23 mmol) in methanol (10mL) was added sodium hydroxide (40 mg, 1 mmol). After stirring overnight at room temperature, the reaction mixture was concentrated under reduced pressure to afford a residue, which was dissolved in water (10 mL), adjusted the pH to 6 with 3N HCl, and filtered to give (S)—2—(3,4—difluorophenyl)(2— methylpyrrolidin-l-yl)quinoxalinecarboxylic acid as a light yellow solid (44.5 mg, 58 %).
W0 2012/119046 LC/MS (ES, m/z): [M+H]+ 370.0 1H-NMR (300 MHz, DMSO) 8 8.25 (d, J: 1.5 Hz,1H), 7.91 - 7.95 (m, 2H), 7.80 — 7.90 (m, 1H), 7.58 - 7.61 (m, 2H), 4.21 — 4.28 (m, 1H), 2.93 - 3.04 (m, 2H), 2.05 - 2.13 (m, 1H), 1.70 - 1.79 (m, 1H), 1.55 - 1.60 (m, 2H), 1.32 (d , J: 6.0 Hz, 3H) EXAMPLE 149 2-(4-Acetamidopheny1)[methyl(propan-Z-yl)amin0]quinoxaline—6-carb0xylic acid Y o /N xN:©)LOH 0 01" Step 1. N—(4-Bromopheny1)acetamide ONE“ A on of 4-bromoaniline (10 g, 58.13 mmol) in acetic anhydride (50 mL) was stirred for minutes at room ature, and then collected by filtration to give N—(4- bromophenyl)acetamide (12 g, 96 %) as a white solid. 1H-NMR (300 MHz, CDC13) 8 7.42 - 7.48(m, 4H), 2.20 (s, 3H) Step 2. N-(4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolanyl)pheny1)acetamide .,r>“r To a solution of N-(4-bromophenyl)acetamide (5 g, 23.36 mmol) in dioxane (50 mL) was added 4,4,4‘,4',5,5,5',5'-octamethy1—2,2'-bi(1,3,2-dioxaborolane) (7.13 g, 28.08 mmol), KOAc (4.6 g, 46.87 mmol) and Pd(dppf)C12 (1.5 g, 2.05 mmol), and the reaction mixture was stirred overnight under an atmosphere of en at 100°C in an oil bath. The resulting mixture was concentrated in vacuo, diluted with water (300 mL), and extracted with dichloromethane(3 x 50 mL), and the organic layers ed, dried over anhydrous sodium sulfate, and concentrated in vacuo to give a residue, which was purified via silica gel column chromatography (14% ethyl acetate in petroleum ether) to give N—(4—(4,4,5,5—tetramethyl— 1,3,2-dioxaborolan—2—yl)phenyl)acetamide (6 g, 98 %) as a white solid.
LC/MS (ES, m/z): 262.0 1H-NMR (300 MHz, CDClg) 5 7.77 (d, J = 8.4 Hz, 2H), 7.52 (d, J = 8.1 Hz, 2H), 7.23 (d, J = .6 Hz, 1H), 2.20 (s, 3H), 1.35 (s, 12H) Step 3. Methyl 2—(4-acetamidopheny1)—3-[methyl(propan—2—yl)an1ino]quinoxaline carboxylate Y 0 /N /N:©)k0/ . loo To a solution of methyl 3-[methyl(propany1)amino] [(trifluoromethane)sulfonyloxy]quinoxaline—6-carboxylate (150 mg, 0.37 mmol) in dioxane (5.0 mL) and water (3 drops) was added N-(4-(4,4,5,5-tetramethyl-1,3,2—dioxaborolan yl)phenyl)acetamide (293 mg, 1.12 mmol), Pd(PPh3)4 (21 mg, 0.02 mmol), and K3PO4 (165 mg, 0.78 mmol), and the reaction mixture was d for 1 hour at 90°C under an atmosphere of nitrogen. The resulting mixture was concentrated in vacuo to give a residue, which was purified via silica gel column chromatography (9% ethyl acetate in petroleum ether) to give methyl cetamidophenyl)[methyl(propanyl)amino]quinoxalinecarboxylate as a yellow solid (110 mg, 76 %).
LC/MS (ES, m/z): [M+H]+ 393.0 1H—NMR (300 MHz, DMSO) 5 10.20 (s, 1H), 8.25 (d, J = 1.2 Hz, 1H), 7.94 (s, 2H), 7.81 (d, J = 8.7 Hz, 2H), 7.72 (d, J = 8.7 Hz, 2H), 4.21 — 4.26 (m,1H), 3.92 (s, 3H), 2.68 (s,3H), 2.09 (s, 3H), 1.04 (d, J: 6.0 Hz, 6H) Step 4. 2-(4-Acetamidophenyl)[methy1(propany1)amino]quinoxalinecarboxylic acid Y 0 /NI>)J\OHN /U\N£31 To a on of methyl 2—(4-acetamidophenyl)—3-[methyl(propanyl)amino]quinoxaline carboxylate (110 mg, 0.28 mmol) in methanol (30 mL) and water (1 mL) was added sodium hydroxide (45 mg, 1.12 mmol), and the reaction mixture was stirred overnight at room temperature. The resulting mixture was concentrated in vacuo, dissolved in water (50ml), adjusted to pH 6 with HCl (1N), and collected by filtration to give 2—(4-acetamidophenyl) [methyl(propanyl)amino]quinoxalinecarboxylic acid as a yellow solid (70 mg, 66 %).
LC/MS (ES, m/z): [M+H]+ 379.0 1H—NMR (300 MHz, DMSO) 8 10.18 (s, 1H), 8.24 (s, 1H),7.96 (s, 2H), 7.92 (d, J: 8.1 Hz, 2H), 7.81 (d, J = 8.7 Hz, 2H), 7.73 (d, J = 8.7 Hz, 2H), 4.16 - 4.25 (m, 1H), 2.68 (d, J: 6.0 Hz,3H), 2.09 (s, 3H), 1.03 (d, J = 6.6 Hz, 6H) EXAMPLE 150 (R)(4-Fluorophenyl)(2-methylpyrrolidin-l-yl)quinoxalinecarboxylic acid To a solution of methyl 3-chloro—2—(4—fluorophenyl)quinoxalinecarboxy1ate (150 mg, 0.47 mmol) in DMSO (2 mL), was added (R)methy1pyrrolidine hydrochloride (61 mg, 0.50 mmol) and DIEA (92 mg, 0.71 mmol). After stirring ght at 70°C, the reaction mixture was ved in water (100 mL), extracted with dichloromethane (3 x 30 mL), dried over anhydrous magnesium sulfate, and trated under reduced pressure to afford a residue, which was purified Via silica gel column chromatography (2% ethyl acetate in petroleum ether) to afford (R)-methyl 2-(4-fluorophenyl)(2-methylpyrrolidin-l-yl)quinoxaline carboxylate as a light yellow solid (95 mg, 55 %).
LC/MS (ES, m/z): [M+H]+ 366.0 1H—NMR (300 MHz, CDC13) 8 8.61 (s, 1H), 7.95 — 8.06 (m, 2H), 7.77 - 7.82 (m, 2H), 7.18 - 7.24 (t, J = 8.4 Hz, 2H), 4.04 - 4.47 (m, 1H), 4.00 (s, 3H), 3.11 - 3.20 (m, 1H), 2.93 — 2.99 (m, 1H), 2.19 — 2.23 (m, 1H), 1.79 - 1.85 (m, 1H), 1.55 - 1.69 (m, 2H), 1.38 (d, J: 6.0 Hz, 3H) Step 2. (R)-2—(4—Fluorophenyl)-3 -(2—methy1pyrrolidin—l—yl)quinoxaline—6—carboxy1ic acid 0 ”IO“/N To a on of (R)-methyl 2—(4-fluorophenyl)(2-methylpyrrolidin—1-yl)quinoxaline carboxylate (95 mg, 0.26 mmol) in methanol (50 mL) was added sodium hydroxide (95 mg, 2.38 mmol) and water (2 mL). After stirring overnight at room ature, the reaction mixture was concentrated under reduced pressure to afford a residue, which was dissolved in water (10 mL), adjusted to pH 6 with HCl (3N), and filtered to give (R)(4-fluoropheny1) (2-methylpyrrolidinyl)quinoxalinecarboxylic acid as a light yellow solid (29.2 mg, 32 LC/MS (ES, m/z): [M+H]+ 352.0 1H-NMR (300 MHz, DMSO) 8 8.24 (s, 1H), 7.90 (s, 2H), 7.77 - 7.82 (m, 2H), 7.34 - 7.39 (t, J = 9.0 Hz, 2H), 4.20 - 4.25 (m, 1H), 2.94 - 3.03 (m, 2H), 2.13 - 2.20 (m, 1H), 1.70 — 1.80 (m, 1H), 1.49 - 1.54 (m, 2H), 1.31 (d, J = 6.0 Hz, 3H) The following compounds can generally be made using the methods known in the art and described above. It is ed that these compounds when made will have activity similar to those that have been made in the examples above. 0 ° Q ° F \ \N H3CO FSigrid“ H3COgiffiiou 0/} o 0/} o 516*" U for" H3CO WO 19046 PCT/U82012/027423 WO 19046 W0 2012/119046 PCTfUS2012/027423 )fi 0 O?”/N OH\ F F V o £11"/N xNflLOH\ F F Y o <96/NUL“IN \N Y o /N /N OH F \ \N WO 19046 2012/027423 The activity of the compounds in Examples 1- 150 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.
W0 2012/119046 Biochemical Assay for hPASK Activity PASK ATP Radiochemical Assay Purified PASK (UniProt #Q96RG2; human inant N—terminal GST tagged construct, es 879-1323) from insect cells (final concentration 5 nM) is added to freshly prepared Base Reaction Buffer containing 20 mM HEPES (pH 7.5), 10 mM MgC12, 1 mM EGTA, 0.02% Brij35, 0.02 mg/ml BSA, 0.1 mM Na3V04, 2 mM DTT, 1% DMSO and Myelin Basic Protein (20 ”M final). Test compounds in DMSO are then added and the mixture, followed by delivery of 33P—ATP (specific activity 0.01 uCi/ul final) to initiate the reaction. The kinase reaction is incubated for 120 min at room temperature. The entire reaction e is washed through onto a P81 Phosphocellulose paper and washed three times for 10 minutes in 75 mM phosphoric acid and once in methanol prior to drying and scintillation counting. s for this assay are shown below in Table 1.
Table 1. _C50KinaseDomain Example # + indicates <10 um in—dicates- >10 m _AUt —4;00 _O\O\O\UIUI #03\lUI 2012/027423 n16 — 7 + oo + __++ n21 ++++ 111111111 23444445 150670090 W0 2012/119046 PAS Kinase FRET Assay The aim of the FRET assay is to determine the inhibition potential of test compounds on targeted kinase. This assay platform provides a homogenous screening method for measuring kinase activity by quantitating the amount of phospho—subslrate in on following a kinase reaction.
In the presence of kinase and ATP, the Ulight—peptide is phosphorylated and captured by an anti-phospho-substrate antibody, which brings the Eu chelate donor and Ulight acceptor dyes into close proximity. Upon excitation at 340 nm, the Eu chelate transfers its energy to the Ulight dye, ing in a fluorescent light emission at 665 nm.
Titration of kinase at 1 mM ATP was achieved via the following protocol. After making serial three-fold ons of PASK (Invitrogen) 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 (PerkinElmer). The contents of the plate were incubated at RT for l h. The reaction was stopped by adding 5 pl of stop solution to each test well ed by mixing and incubation at RT for 10 minutes. 5 341 of detection. mix (detection antibody diluted in ion 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 ’l‘R-FRET mode (fitStSSnny’tSlSnm). 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 method. After making serial dilutions of ATP (Invitrogen), 5 pl of ATP dilution and 5 p1 substrate/kinase mix were added to the wells of the white ate—384 (PerkinElmer). The contents of the plate were and incubated at RT for 1 h. The reaction was stopped by adding 5 u] of stop solution to each test well ed by mixing and incubation at RT for 10 minutes. 5 pl 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 (665nm/615nm). The results were graphed to calculate the ECW as the A’l‘l’ K111313131 Compound screening was done via the following 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 ion, it was diluted to 3 mM. Kinase reaction buffer was prepared containing 10 mM. lVlgClz~ 50 mM I’IEPES, 1 111M ESTA, ().0l% TWEEN—ZO, 2 mM DTT. Serial ons of the test compounds were prepared at 4 3.x: final assay trations using Freedom EVOZOOG’D dispensing systen't as follows: 12x10‘5 M, 4x104" M, 0"5 M, 4.44x10‘6 M, 1.48x10‘6 M, PCT/U82012/027423 4.92x10" M, 1.65x10‘7 M, 5.48x10'7 M, iszxio4g M, 0'9, 2.03x1tl'9 M. Test compounds (2.5 511 at 4 x the final assay tration) was added to wells using Freedom EV0200® sing system. As a positive control, 2.5 til of positive. compound was added to assay wells, and 2.5 til of DMSO to assay wells as vehicle control. Kinase solution 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 bullier at 4 X final assay concentration. The icinase 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 without g. The reaction was stopped by adding 5 [.ll of stop on to each test well followed by mixing and incubation at RT for 10 minutes in the dark. 5 ill of detection 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 "FR-FRET mode (665nm/615nin).
Results are shown below in Table 2.
Table 2.
IC50 Kinase Domain e # + indicates 510 um - indicates >10 m )-ll—|l—|l—| UIADJN 2012/027423 1111122222222332333333334444444444555555678901234569017234567890123456789012345 PCT/U82012/027423 5555 67009 6666612345 777788888 012345678912345 0000 700 99999 112345 PCT/U82012/027423 1111111111111 000000000 1234567009 111 111 234 111111111111 2222222222333333 0123456789012345 Pharmacokinetics of a PASK inhibitor The in Vivo pharmacokinetics of Examples 14, 15, 18, 105 were evaluated in the Sprague Dawley rat. The test compounds were formulated in polyethylene glycol and beta cyclodextrin in water for administration at 1 mg/kg for Example 105, and at 3mg/kg for Example 14, 15, and 18 for intravenous administration via the tail vein and 10 mg/kg for oral administration by gavage. Blood samples were collected at 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours and the samples were analyzed for test compounds content using LC/MS/MS. The data was submitted to pharmacokinetic analysis using WinNonLin software and the ed and calculated pharmacokinetic parameters are shown in Table 3 for each compound.
Table 3.
C] t1/2 V85 Tmax (ml/min/kg) (hr) (L/kg) (%) (hr) 1.72 3.68 0.362 63.4 1 4 3.39 0.347 1.33 7.72 0.366 74.8 05 0.712 7.72 0.407 74.8 C1 = clearance; tl/z = half-life; VSS = volume of distribution; F = oral bioavailability; Tmax = Time to maximum blood concentration after an oral dose The data in Table 3 indicate that Example 105 has a low volume of distribution and good half-life of more than 7 hours. The compound also exhibits high oral bioavailability of more than 74%. Examples 14, 15, and 18 have a low volume of distribution and reasonable half-life of 3 hours or more, and t high oral bioavailability of 63% or more. Thus, the pharmacokinetic parameters ofthese nds suggest that they will display suitable drug ties to support efficacy in human clinical trials.
From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of this ion, and t departing from the range and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions. This description may contain subject matter that falls outside the scope of the claims. This subject matter is included to aid understanding of the invention.

Claims (1)

  1. CLAIMS 1 . A compound chosen from (R)—2-(4-F1uorophenyl)(2-(trifluoromethyl)pyrrolidin- 1 —y1)quinoxa1ine carboxylic acid, (R)(4-F1uoropheny1)—3 -(2-methy1pipcridiny1)quinoxaline-6—carboxylic acid, (R)(4-F1uorophenyl)—3 -(2-methylpyrrolidiny1)quinoxalinecarboxy1ic acid. (R)—2-(Benzo [d] [1 ,3 ] dioxol-S-y1)-3 -(2-methylpyrrolidin-1 -y1)quinoxaline-6— carboxylic acid, (R)(sec-Butylimethyl)amino)(5-fluorobenzofilran-Z-y1)quinoxa1inecarboxylic acid, (S)(1H-Benzo[d][1,2,3]triazol—5-y1)—3—(2-methylpyrrolidin-1—y1)quin0xa1ine carboxylic acid, (S)(1H—indazol-S-y1)-3 -(2-methy1—4-(pyridin—2-y1)piperaziny1)quinoxaline ylic acid, (S)(1H-Indazol—S-y1)(methy1(1 -phenylethy1)amin0)quinoxalinecarboxylic acid, ( 1 H-Indol-S-y1)-3 -(2-methy1piperidiny1)quinoxa1inecarboxy1ic acid, (S)—2-(1H-IIid01-5—yl)-3 -(2-methylpyrrolidin—1-y1)quinoxaline—6-carboxylic acid, (S)—2-(1H-Ind01—5-yl)-3 -(3-methylmorpholino)quinoxa1inecarboxy1ic acid, (S)—2—(2,2—Difluorobenzo[d] [1 ,3]dioxol-5—yl)—3 -(2-methy1pyrrolidiny1)quinoxaline— 0xy1ic acid, (S)(2,4—Difluorophenyl)—3-(2-methy1piperidin-1 —y1)quinoxaline-6—carboxylic acid, (S)(2,4-Difluoropheny1)(2-methylpyrrolidin-1 inoxalinecarboxy1ic acid, (S)—2-(2-Methy1—1H—ind01—5-y1)—3-(2—methy1(pyridiny1)piperazin yl)quinoxa1inecarboxy1ic acid, (S)—2-(2-Methy1-1H-indol-S-y1)—3—(2—methy1piperidin—1 -y1)quinoxalinecarb0xy1ic acid, (S)(3 ,4—Difluoropheny1)(2-methy1pyrr01idin-1 —y1)quinoxa1inecarb0xylic acid, (S)'(4-F1uoromethy1pheny1)(2-methy1pyrrolidiny1)quinoxaline—6— carboxylic acid, (S)—2-(4-F1uor0pheny1)-3 -(3-methylmorpho1ino)quinoxalinecarboxy1ic acid, (S)—2-(4-F1u0ropheny1)(methy1(1 -phenylethy1)amino)quin0xaline—6-carboxylic acid, (4-Fluoropheny1)hydroxy—3-(2-methy1pyrrolidiny1)quinoxa1ine carboxylic acid, (S)(5-F1uorobenzo[b]thiophenyl)—3—(2—methy1pyrrolidin—1-y1)quinoxa1ine carboxylic acid, (S)—2-(5-F1uorobenzofuranyl)—3-(2-methylpiperidin- 1 inoxa1inecarboxy1ic acid, (S)(5-F1uorobenzofurany1)-3—(2-methy1pyrrolidin—1-y1)quinoxa1ine-6—carboxy1ic acid, (S)—2-(6-Flu0robenzofuran-Z-yl)(2-methy1pyrrolidin-1 -y1)quinoxa1ine—6—carboxylic acid, (S)-3 -(4-Ethy1methy1piperaziny1)(4-fluorophenyl)quinoxalinecarboxylic acid, (S)(sec—Buty1(methy1)amino)—2—(5-flu0robenzofuran—Z-y1)quinoxalinecarboxylic acid, (S)—7-Hydroxy(1H—indazol-S-y1)—3—(2-methy1pyrrolidin-1 -y1)quinoxa1ine—6- carboxylic acid, 2-(1 ,2-Benzoxazol-5—yl)[methyl(propany1)amino]quinoxalinecarboxylic acid, 2-(1,3 -Benzothiazoly1)-3 -[(ZS)methy1pyrrolidiny1] quinoxalinecarboxy1ic acid, 2-(1 ,3 -Benzothiazolyl)-3 -[methyl(propan—2-y1)amino]quinoxalinecarboxy1ic acid, 2-(1 ,3 -Benzothiazoly1)-3 -[(ZS)methy1pyrrolidiny1]quinoxalinecarboxy1ic acid, 2-(1 -Benzofuranyl)(diethylamino)quinoxaline-6~carboxylic acid, 2—(1-Benzofurany1)[(propan~2-yl)amino]quinoxaline—6-carboxylic acid, 2-(1-Benzofuran-3 -y1)[(ZS)—2—methylpyrrolidin—1—y1]quinoxaline—6-carboxylic acid, 2-(1 -Benzofi.1rany1)—3 - [methyl(propan—2-yl)amino]quinoxalinecarboxylic acid, 2-(1 -Ethy1— 1 H—indazol-S-y1)-3 -(isopropy1(methyl)amino)quinoxalinecarboxy1ic acid, 2-(1H-Benzo[d] [1 riazoly1)(isopropy1(methyl)amino)quinoxaline—6- carboxylic acid, 2-(1H-Benzo[d]imidazol-1—y1)-3—(isopropy1(methyl)amino)quinoxaline-6—carboxy1ic acid, 2-(1H-Indazolyl)-3 -(pipen'din-1 -yl)quinoxa1inecarboxy1ic acid, 2-(1H-Indazoly1)[(ZS)—2-methylpyrr01idin-1—y1]quinoxaline—6-carboxylic acid, 2-(1H—Indolyl)(piperidinyl)quinoxa1inecarboxylic acid, 2-(1H—Ind01y1)-3 —[(2R)-2—(methoxymethy1)pyrrolidin— 1 —y1]quinoxa1ine-6— carboxylic acid, 2-(2,2-Diflu0r0benzo [d] [ 1 ,3 ] dioxol-S—yl)-3 -(isopropy1(methy1)amino)quinoxaline-6— carboxylic acid, 2-(2,4—Difluoropheny1)-3 -[methy1(propanyl)amino]quinoxaline—6-carboxylic acid, 2-(2-F1uoropyridin—4-yl)(isopropy1(methyl)amino)quinoxa1inecarboxylic acid, 2-(2-Methyl-1H-indoly1)[(2S)methy1pyrrolidin- l -y1]quin0xaline carboxylic acid, 2—(3 ydro-2H-benzo [b] [1 ,4] dioxepiny1)-3 - (isopropy1(methyl)amino)quin0xaline-6—carb0xy1ic acid, 2-(3 -Methy1—1H—indazoly1)-3—(isopropyl(methyl)amin0)quinoxaline-6—carboxy1ic acid, 2-(4-Acetamidophenyl)[methyl(propan-2—y1)amino]quinoxalinecarboxylic acid, 2-(4-Carbamoylpheny1)(is0propy1(methyl)amino)quinoxa1ine—6-carboxy1ic acid, 2-(4—F1uoromethylpheny1)—3-(isopropyl(methy1)amino)quinoxa1ine—6-carboxylic acid, 1uorophenyl)-3—(((1r,4r)hydroxycyclohexyl)(methyl)amino)quinoxaline carboxylic acid, 2-(4-F1u0r0phenyl)-3 -(4-(methylsulfonyl)piperaziny1)quin0xaline-6—carboxy1ic acid, 2-(4-F1uoropheny1)(isobutyl(methyl)amin0)quinoxalinecarboxy1ic acid, 2-(4-Fluorophenyl)-3 -(methy1((1r,4r) (methylamino)cyclohexyl)amino)quinoxaline-6—carboxy1ic acid, 2—(4-Fluor0pheny1)-3 -(methy1(0-tolyl)amino)quinoxalinecarboxylic acid, 2-(4-Fluor0phenyl)-3 -(pyrr01idin— 1 -yl)quin0xa1ine—6-carb0xy1ic acid, 2-(4-F1uorophenyl)-3 -[(2R)—2-(trifluoromethyl)piperidin— 1 -y1]quinoxa1ine—6- ylic acid, 1uoropheny1)-3 -[(ZS)methylpiperazin-1 —y1]quinoxalinecarboxylic acid, 2-(4-F1uorophenyl)-3 -[4—(pyridinyl)piperidin— 1 -y1]quinoxaline—6-carboxylic acid, 1uoropheny1)-3 -[methyl(2,2,2—trifluoroethyl)amino]quinoxaline—6-carboxylic acid, 2-(4-F1u0r0pheny1)[methyl(pyridiny1methy1)amin0]quinoxalinecarboxylic acid, 2—(4—Fluoropheny1)hydroxy—3-(isopropy1(methyl)amino)quinoxalinecarboxylic acid, 2-(4-F1uoropheny1)—7-methoxy—3-[methyl(propan-Z-y1)amino]quinoxaline-6— carboxylic acid, 2-(5,6-Difluorobenzofuranyl)(isopropyl(methyl)amino)quinoxaline carboxylic acid, 2—(5—F1uorobenzofuran—2-y1)(pyrrolidiny1)quinoxa1inecarboxylic acid, 2-(5-Fluoro—1-benzofurany1)[(2R)(methoxymethyl)pyrrolidin yl]quinoxalinecarboxy1ic acid, 2-(5-F1uorobenzo[b]thiophen—2—y1)(isopr0pyl(methy1)amin0)quinoxaline carboxylic acid, 2-(6-Aminopyridin-3 -y1)(isopropyl(methyl)amino)quinoxalinecarboxylic acid, hloro—1-benzofurany1)[methyl(propan-Z-y1)amino]quinoxaline carboxylic acid, 2—(6-F1uorobenzofurany1)[(ZS)methylpiperidiny1]quin0xaline-6— carboxylic acid, 2—(6-F1u0ro—1-benzofuran—2—yl)—3-[methyl(propanyl)amino]quinoxaline carboxylic acid, 2—(Benzo[b]thiophenyl)(isopropy1(methy1)amino)quinoxa1inecarboxylic acid, 2-(Benzo[b]thi0phen—2-y1)—3-Q)iperidin-1 -y1)quinoxa1inecarboxylic acid, 2-(Benzo[d]oxazol—2—y1)(isopropyl(methyl)amin0)quinoxalinecarboxy1ic acid, zo[d]thiazoly1)(isopropyl(methyl)amino)quinoxalinecarboxy1ic acid, 2-(Benzofi1ran-3 —(isopropy1(methyl)amino)quinoxaline—6-carboxy1ic acid, 2-(Chroman—6-y1)(isopropy1(methyl)amino)quinoxaline-6—carboxylic acid, 2-(Furan—3 -y1)-3 -[(ZS)methy1pyrrolidin-1 -y1] quinoxalinecarboxy1ic acid, 2-[5-(4-Flu0rophenyl)fi1ranyl][methyl(propanyl)amino]quinoxaline carboxylic acid, 3-(((1r,4r)Acetamidocyclohexyl)(methy1)amin0)(4—fluoropheny1)quinoxaline carboxylic acid, 3-(2-Ethy1piperidiny1)(4-fluorophenyl)quinoxalinecarboxylic acid, 3 -(4-Acety1piperazin-1 -y1)-2—(4-fluoropheny1)quinoxaline—6-carb0xy1ic acid, 3 -(4-Benzoy1piperazin— 1 -y1)—2—(4-fluorophenyl)quinoxaline-6—carboxylic acid, 33 1 3-(Azepan— 1 -y1)( 1 zo'ly1)quinoxa1ine—6-carboxylic acid, 3-(Azepan-1 -y1)(1H-indoly1)quinoxa1ine—6—carboxy1ic acid, 3 —(Azepan—1-y1)-2—(2,2-difluoro-2H-1,3—benzodioxol-5—y1)quinoxaline-6—carboxylic acid, 3-(Azepan-1 -y1)(5-fluorobenzofuran—2-y1)quinoxa1inecarboxy1ic acid, pan-1 -y1)(6-fluorobenzofurany1)quinoxa1inecarboxy1ic acid, 3-(Azepan-1 -y1)(benzo[b]thi0pheny1)quinoxaline—6-carboxy1ic acid, 3 -(Azetidiny1)(4-fluorophenyl)quinoxaline—6-carboxy1ic acid, 3 -(Benzy1(methy1)amino)( 1 H-indazol-S-y1)quinoxalinecarboxy1ic acid, 3-(Cyclobuty1(methy1)amino)(4-flu0rophenyl)quinoxalinecarboxylic acid, 3-(Cyc10hexy1(methyl)amino)(4-flu0r0phenyl)quinoxalinecarboxy1ic acid, 3 -(Cyclopropy1(methy1)amino)—2-(1H-indazoly1)quinoxalinecarboxy1ic acid, 3 -(Cyclopropy1(methyl)amino)—2-(6—fluorobenzofuran—Z-y1)quinoxa1inecarboxylic acid, 3 -(Diethylamino)(1H-indol-S-y1)quin0xa1ine—6-carboxylic acid, 3-(Diethy1amino)(4-fluorophenyl)quinoxalinecarboxy1ic acid, 3-(Dipropy1amin0)-2—(4-fluorophenyl)quinoxaline-6—carboxy1ic acid, 3-(Ethyl(isopropyl)amino)(4-fluorophenyl)quinoxalinecarboxylic acid, 3 ropy1(methyl)amino)(1 H-pyrazol—‘S-y1)quinoxa1ine-6—carboxylic acid, 3 -(Isopropy1(methyl)amino)-2—(1—methy1-1H-benzo[d][1,2,3]triazoly1)quinoxalinc- 6-carboxy1ic acid, 3-(Isopropy1(methyl)amino)( 1 -methyl-1H-indazol-5—y1)quinoxa1inecarboxylic acid, 3-(Isopropy1(methyl)amino)-2—(3-methyl-1 H—indol-S-y1)quinoxa1ine—6-carboxylic acid, 3-(Isopropyl(methyl)amin0)(4-(trifluoromethyl)phenyl)quinoxalinecarboxylic acid, 3-(Isopropy1(methyl)amin0)(4-pheny1filran—Z—yl)quin0xalinecarboxy1ic acid, 3—(Isopropy1(methyl)amino)—2-(5-meth0xybenzofuran—Z-y1)quinoxalinecarboxy1ic acid, 3-(Isopropy1(methyl)amino)(quinoliny1)quinoxalinecarboxy1ic acid, 3—(Isopr0py1(methy1)amin0)-2,7'-biquinoxalinecarboxylic acid, 3-(tert—Butyl(methy1)amin0)—2-(4-fluoropheny1)quinoxalinecarb0xy1ic acid, 3-(tert—Buty1amino)(4-fluorophenyl)quinoxaline—6-carboxylic acid, 3 -[(l -Ethylpiperidinyl)(methyl)amino](4—fluorophenyl)quinoxaline—6-carboxy1ic acid, 3 -[(28)—2—methy1pyrrolidiny1]—2-(1H—pyrrol-3 -yl)quinoxaline-6—carboxylic acid, 3 -[(ZS)methy1pyrrolidin-1 -y1][5-(trifluoromethyl)— 1 -benzofuran—2- yl]quinoxaline—6-carboxylic acid 3-[Benzyl(methyl)amino](4-fluorophenyl)quinoxaline—6-carboxylic acid, 3-[Cyclohexy1(ethyl)amino](4-fluorophenyl)quinoxalinecarboxylic acid, 3—[Cyclopropyl(methyl)amino](lH—indol—S-yl)quinoxaline—6-carboxylic acid, lopropy1(methyl)amino](2-methy1—lH-indol-5—y1)quinoxaline—6-carboxylic acid, 3-[Cyclopropyl(methy1)amino]~2-(5-fluorobenzofuran—2-y1)quinoxaline carboxylic acid, 3-[Ethyl(propyl)amino](4—fluorophenyl)quinoxaline—6-carboxylic acid, 3-[Methyl(propan—2—yl)amino]-2—(lH-pyrrolyl)quinoxa1ine-6—carboxylic acid, 3-[Methyl(propan—2-yl)amino] (1 —methy1—1H-pyrazoly1)quinoxaline—6— carboxylic acid, 3 -[Methy1(propan—2-y1)amino] -2—(1 l- 1 H-pyrazolyl)quinoxa1ine—6-carboxylic acid, 3-[Methyl(propanyl)amino]—2-(2-methyl—1H-indol-5—yl)quinoxaline—6-carboxylic acid, 3 - [Methyl(propan—2-yl)amino](3-methy1-1 —benzofurany1)quinoxaline—6— carboxylic acid, 3-[Methyl(propanyl)amino](3-phenylfiiran—Z-yl)quinoxalinecarboxy1ic acid, 3-[Methy1(propanyl)amino](4-phenylfuran-Z-yl)quinoxalinecarboxy1ic acid, 3-[Methyl(propan—2-y1)amino](5—pheny1furan-Z-yl)quinoxaline—6-carboxylic acid, 3 — l(propanyl)amino]-2— [5—(trifluoromethyl)— 1 —benzofi.1ran-3 -y1] quinoxaline- oxylic acid, and 7-Fluoro—2-(4-fluorophenyl)[methy1(propan—2-yl)amino]quinoxalinecarboxylic acid. A compound as recited in Claim 1, wherein said compound is (S)(4-Fluorophenyl)(3-methy1morpholino)quinoxaline—6-carboxylic acid. . A compound as recited in Claim 1 for use as a medicament. 1 for use in the manufacture of a medicament for the . A compound as recited in Claim prevention or treatment of a disease or condition ameliorated by the inhibition of PASK. A pharmaceutical composition comprising a compound as recited in Claim 1 together with a pharmaceutically acceptable carrier. Use of a compound as recited in Claim 1 in the manufacture of a medicament for inhibiting PASK. Use of a therapeutically ive 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 7 wherein said disease is chosen from cancer and a metabolic disease. The use as recited in Claim 7 wherein said disease is a lic disease. 10. The use as recited in claim 9 wherein said metabolic disease‘is chosen from metabolic syndrome, diabetes, dyslipidemia, fatty liver disease, non-alcoholic hepatitis, y, and insulin resistance. 11. The use of claim 10 wherein said diabetes is Type II diabetes. 12. The use of claim 10 wherein said dyslipidemia is hyperlipidemia. 13. Use of a therapeutically effective amount of a compound as recited in Claim 1 in the manufacture of a medicament for ing an effect in a patient, wherein the effect is selected from the group consisting of reduction of triglycerides, reduction of cholesterol, and reduction ofhemoglobin A1 c. 14. The use of Claim 13 wherein said cholesterol is chosen from LDL and VLDL cholesterol. 15. The use of Claim 13 wherein said triglycerides are chosen from plasma triglycerides and liver triglycerides. 16. Use of a therapeutically effective amount of a compound as recited in Claim 1 in the manufacture of a medicament for the treatment of a PASK-mediated disease, wherein the medicament is adapted for administration with another eutic agent. 17. The compound as d in Claim 1, substantially as herein described with reference to any one of the Examples thereof. 18. The compound as recited in Claim 1 0r 2, substantially as herein described. 19. The use as recited in any one of claims 3 to 16, ntially as herein described.
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