Quinoxaline derivatives as anticancer drugs

Abstract

The present invention relates to azachinolone compounds of formula (I), and their use in medicine.

Description

[0001] The present disclosure relates to substituted azquinoline compounds and pharmaceutically acceptable salts thereof which inhibit the poly(ADP-ribose) polymerase (PARP) family of enzymes. The present disclosure also relates to the use of these compounds and pharmaceutically acceptable salts thereof in medicine, for example in the treatment of diseases in which inhibition of PARP1 or PARP1 function has therapeutic significance. The present disclosure also relates to methods of treatment and methods of manufacturing medicaments using the compounds according to the present disclosure.

[0002] The PARP family of enzymes plays an important role in many cellular processes such as replication, recombination, chromatin remodelling and DNA damage repair (O’Connor MJ, Mol Cell (2015) 60(4): 547-60).

[0003] Examples of PARP inhibitors and their mechanism of action are taught in, for example, WO 2004 / 080976.

[0004] PARP1 and PARP2 are the PARPs that are most widely studied for their role in DNA damage repair. PARP1 is activated by DNA damage breaks and acts to catalyse the addition of poly(ADP-ribose) (PAR) chains to target proteins. This post-translational modification, known as PARylation, mediates the recruitment of additional DNA repair factors to the DNA damage.

[0005] Upon completion of this recruitment task, the auto-PARylation of PARP triggers the release of the bound PARP from the DNA, allowing other DNA repair proteins to be used to complete repair. Thus, the binding of PARP to the damaged site, its catalytic activity and ultimately its release from the DNA are all important steps in the response of cancer cells to DNA damage caused by chemotherapeutic agents and radiotherapy (Bai P. Biology of poly(ADP-ribose) polymerases: the factotums of cell maintenance. Mol Cell 2015; 58: 947-58.).

[0006] Inhibition of PARP family enzymes has been used as a strategy to selectively kill cancer cells by inactivating the complementary DNA repair pathway. A number of preclinical and clinical studies have shown that tumor cells bearing deleterious alterations in BRCA1 or BRCA2, key tumor suppressor proteins involved in the repair of double-stranded DNA breaks (DSBs) through homologous recombination (HR), are selectively sensitive to small molecule inhibitors of the PARP family of DNA repair enzymes. Such tumors have a defective homologous recombination repair (HRR) pathway and their survival depends on the function of PARP enzymes. Although PARP inhibitor therapy primarily targets BRCA-mutant cancers, PARP inhibitors have been clinically tested in non-BRCA-mutant tumors that exhibit homologous recombination deficiency (HRD) (Turner N, Tutt A, Ashworth A. Hallmarks of 'BRCAness' in sporadic cancers. Nat Rev Cancer 2004; 4: 814-9).

[0007] It is believed that PARP inhibitors with increased selectivity for PARP1 compared to other clinical PARP1 / 2 inhibitors can result in improved efficacy and reduced toxicity. It is also believed that strong inhibition of PARP1 will result in PARP1 trapping on DNA, which leads to DNA double-strand breaks (DSBs) by collapsing replication forks in S phase. It is also believed that PARP1-DNA trapping is an effective mechanism to selectively kill tumor cells with HRD.

[0008] Accordingly, there is an unmet medical need for effective and safe PARP inhibitors. In particular, PARP inhibitors with selectivity for PARP1.

[0009] Applicants have discovered that the azanquinolones described herein surprisingly have PARP inhibitory activity and are therefore useful in the treatment of diseases and conditions in which PARP function has pharmacological significance. Furthermore, the azanquinolones described herein have unexpectedly high selectivity for PARP1 over other PARP family members, such as PARP2, PARP3, PARP5a, and PARP6.

[0010] Applicants have also discovered that the azanquinolone compounds described herein surprisingly are able to penetrate the blood brain barrier (BBB). Accordingly, the azanquinolones described herein are useful in the treatment of diseases and conditions that occur in central nervous system tissue, such as the brain and spinal cord.

[0011] In one aspect, Applicants provide a class of compounds having the formula (I):

[0012]

[0013] wherein:

[0014] R 1 is independently selected from H, C 1-4 alkyl, C 3-6 cycloalkyl, C 1-4 fluoroalkyl, and C 1-4 alkyloxy;

[0015] R 2 is independently selected from H, halogen, C 1-4 alkyl, and C 1-4 fluoroalkyl; and

[0016] R 3 is H or C 1-4 alkyl;

[0017] R 4 is halogen or C 1-4 alkyl,

[0018] or a pharmaceutically acceptable salt thereof.

[0019] In another aspect, the Applicant provides a class of compounds having formula (I):

[0020]

[0021] wherein:

[0022] R 1 is independently selected from H, C 1-4 alkyl, C 1-4 fluoroalkyl, and C 1-4 alkyloxy;

[0023] R 2 is independently selected from H, halogen, C 1-4 alkyl, and C 1-4 fluoroalkyl; and

[0024] R 3 is H or C 1-4 alkyl;

[0025] R 4 is halogen or C 1-4 alkyl,

[0026] or a pharmaceutically acceptable salt thereof.

[0027] In one aspect, R 1 is selected from any one of methyl, ethyl, isopropyl, cyclopropyl, 1,1-difluoroethyl, 1-fluoroethyl, trifluoromethyl, difluoromethyl, and methoxy. In a particular aspect, R 1 is methyl or ethyl.

[0028] In one aspect, R2 is selected from any one of H, chloro, fluoro, methyl, and difluoromethyl. In one aspect, R 2 is fluoro or methyl.

[0029] In one aspect, R 3 is methyl or ethyl.

[0030] In one aspect, R 4 is selected from any one of chloro, fluoro, and methyl. In a particular aspect, R 4 is fluoro.

[0031] In one aspect, there is provided a compound of Formula I, wherein R 1 is C 1-4 alkyl, R 2 is halo, R 3 is C 1-4 alkyl, R 4 is halo or C 1-4 alkyl, or a pharmaceutically acceptable salt thereof.

[0032] In a further aspect, there is provided a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable diluent, excipient, or inert carrier.

[0033] In a further aspect, there is provided a compound of Formula I, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of diseases and conditions in which inhibition of PARP1 is beneficial. In one aspect, the present specification provides a compound of Formula I, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer. In one aspect, the cancer is breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, a hematological cancer, a gastrointestinal cancer such as gastric cancer and colorectal cancer, or a lung cancer such as small cell or non-small cell lung cancer. In one aspect, the cancer is breast cancer, ovarian cancer, pancreatic cancer, or prostate cancer. In one aspect, the cancer is a brain cancer, for example a glioma or a glioblastoma. In one aspect, the brain cancer is a metastatic cancer arising from a tumor in another part of the body, for example breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, a hematological cancer, a gastrointestinal cancer such as gastric cancer and colorectal cancer, or a lung cancer such as small cell or non-small cell lung cancer.

[0034] In further aspects, there are provided methods of treating a disease or disorder in which inhibition of PARP1 is beneficial, the method comprising administering to a patient in need thereof an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof. In one aspect, the disease or disorder is cancer. In one aspect, the cancer is breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, a hematological cancer, a gastrointestinal cancer such as gastric cancer and colorectal cancer, or a lung cancer such as small cell or non-small cell lung cancer. In one aspect, the cancer is breast cancer, ovarian cancer, pancreatic cancer, or prostate cancer. In one aspect, the cancer is a brain cancer, for example a neuroglioma or glioblastoma. In one aspect, the brain cancer is a metastatic cancer arising from a tumor in another part of the body, for example breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, a hematological cancer, a gastrointestinal cancer such as gastric cancer and colorectal cancer, or a lung cancer such as small cell or non-small cell lung cancer.

[0035] In further aspects, there are provided compounds of Formula I, or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for the treatment of a disease or disorder in which inhibition of PARP1 is beneficial. In one aspect, the cancer is breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, a hematological cancer, a gastrointestinal cancer such as gastric cancer and colorectal cancer, or a lung cancer such as small cell or non-small cell lung cancer. In one aspect, the cancer is breast cancer, ovarian cancer, pancreatic cancer, or prostate cancer. In one aspect, the cancer is a brain cancer, for example a neuroglioma or glioblastoma. In one aspect, the brain cancer is a metastatic cancer arising from a tumor in another part of the body, for example breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, a hematological cancer, a gastrointestinal cancer such as gastric cancer and colorectal cancer, or a lung cancer such as small cell or non-small cell lung cancer.

[0036] In further aspects, there are provided uses of a compound of Formula I, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disease or disorder in which inhibition of PARP1 is beneficial. In one aspect, the cancer is breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, a hematological cancer, a gastrointestinal cancer such as gastric cancer and colorectal cancer, or a lung cancer such as small cell or non-small cell lung cancer. In one aspect, the cancer is breast cancer, ovarian cancer, pancreatic cancer, or prostate cancer. In one aspect, the cancer is a brain cancer, for example a neuroglioma or glioblastoma. In one aspect, the brain cancer is a metastatic cancer arising from a tumor in another part of the body, for example breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, a hematological cancer, a gastrointestinal cancer such as gastric cancer and colorectal cancer, or a lung cancer such as small cell or non-small cell lung cancer.

[0037] In a further aspect, there is provided a compound of Formula I capable of penetrating the blood brain barrier (BBB). In one aspect, the ratio of the compound that penetrates the BBB is > 0.1, where 1 is complete BBB penetration and 0 is no penetration. In one aspect, the ratio of the compound that penetrates the BBB is > 0.2. In one aspect, the ratio of the compound that penetrates the BBB is > 0.3. In one aspect, the ratio of the compound that penetrates the BBB is measured using the rat kpuu assay. In one aspect, the compound of Formula I has a ratio of > 0.3 (i.e., from 0.3 to 1) as determined in the rat kpuu assay.

[0038] In a further aspect, there is provided a compound of Formula I, or a pharmaceutically acceptable salt thereof, for use in medicine.

[0039] In a further aspect, the compound of Formula I is in free base form.

[0040] In a further aspect, there is provided a compound of Formula I, or a pharmaceutically acceptable salt thereof, for use as a medicament.

[0041] In a further aspect, there is provided an example disclosed herein.

[0042] In one aspect, there is provided a compound of Formula I which is 5-[4-[(2-ethyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N,6-dimethyl-pyridine-2- carboxamide or a pharmaceutically acceptable salt thereof.

[0043] In one aspect, there is provided a compound of Formula I which is 6-fluoro-5-[4-[(5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2- carboxamide or a pharmaceutically acceptable salt thereof.

[0044] In one aspect, there is provided a compound of Formula I which is 6-fluoro-5-[4-[(5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2- carboxamide crystalline Form B or a pharmaceutically acceptable salt thereof.

[0045] In one aspect, there is provided a compound of Formula I which is 6-fluoro-5-[4-[(5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2- carboxamide crystalline Form D or a pharmaceutically acceptable salt thereof.

[0046] In one aspect, there is provided a compound of Formula I which is 6-fluoro-5-[4-[(5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N- methyl-pyridine-2-carboxamide mesylate, optionally in crystalline Form C.

[0047] Further aspects will be apparent to those skilled in the art from reading the present specification.

[0048] It is well known that blockade of the cardiac ion channel encoded by the human ether-à-gogo related gene (hERG) is a risk factor in drug discovery and development. Blockade of hERG can cause safety issues such as cardiac arrhythmias. Advantageously, the compound of Formula I has low hERG activity. In one aspect, there is provided a compound of Formula I having an IC50> 10 mM. In one aspect, there is provided a compound of Formula I having an IC50> 20 mM.

[0049] To minimise the risk of off-target effects, it is desirable for a drug molecule to have selectivity for a particular target. The compound of Formula I advantageously has selectivity for PARP1 over other members of the PARP family, including PARP2, PARP3, PARP5a and PARP6. Advantageously, the compound of Formula I has selectivity for PARP1 over PARP2. In one aspect, there is provided a compound of Formula I having a selectivity for PARP1 that is 10 times that of PARP2. In one aspect, there is provided a compound of Formula I having a selectivity for PARP1 that is 100 times that of PARP2.

[0050] Another aspect provides the use of a compound of Formula I in the manufacture of a medicament for use as an adjunct to cancer therapy or for enhancing treatment of tumour cells with ionising radiation or a chemotherapeutic agent or an antibody-based therapy (such as immuno-oncology or antibody-drug conjugates).

[0051] Other further aspects provide the treatment of a disease ameliorated by inhibition of PARP1 (including administration of a therapeutically effective amount of a compound of Formula I, preferably in the form of a pharmaceutical composition, to a subject in need of treatment) and the treatment of cancer (including administration of a therapeutically effective amount of a compound of Formula I, preferably in the form of a pharmaceutical composition, to a subject in need of treatment, concurrently or sequentially with ionising radiation or a chemotherapeutic agent).

[0052] In a further aspect, a compound of Formula I can be used in the manufacture of a medicament for treating a cancer deficient in homologous recombination (HR)-dependent DNA DSB repair activity, or for treating a patient with a cancer deficient in HR-dependent DNA DSB repair activity (including administration of a therapeutically effective amount of the compound to the patient).

[0053] The HR-dependent DNA DSB repair pathway repairs double-strand breaks (DSBs) in DNA via homologous mechanisms to reestablish a continuous DNA helix (K. K. Khanna and S. P. Jackson, Nat. Genet. 27(3):247-254 (2001)). Components of the HR-dependent DNA DSB repair pathway include, but are not limited to, ATM (NM_000051), RAD51 (NM_002875), RAD51L1 (NM_002877), RAD51C (NM_002876), RAD51L3 (NM_002878), DMC1 (NM_007068), XRCC2 (NM_005431), XRCC3 (NM_005432), RAD52 (NM_002879), RAD54L (NM_003579), RAD54B (NM_012415), BRCA1 (NM_007295), BRCA2 (NM_000059), RAD50 (NM_005732), MRE11A (NM_005590), and NBS1 (NM_002485). Other proteins involved in the HR-dependent DNA DSB repair pathway include regulatory factors such as EMSY (Hughes-Davies et al., Cell, 115, pp. 523-535). HR components are also described in Wood et al., Science, 291, 1284-1289 (2001).

[0054] A cancer deficient in HR-dependent DNA DSB repair can comprise or consist of one or more cancer cells having a reduced or eliminated ability to repair DNA DSBs by this pathway relative to normal cells, i.e., the activity of the HR-dependent DNA DSB repair pathway can be reduced or eliminated in the one or more cancer cells.

[0055] The activity of one or more components of the HR-dependent DNA DSB repair pathway can be eliminated in the one or more cancer cells of an individual having a cancer deficient in HR-dependent DNA DSB repair. Components of the HR-dependent DNA DSB repair pathway are well characterized in the art (see, e.g., Wood et al., Science, 291, 1284-1289 (2001)) and include the components listed above.

[0056] On the one hand, cancer cells can exhibit a BRCA1 and / or BRCA2 deficiency phenotype, meaning that BRCA1 and / or BRCA2 activity is reduced or eliminated in cancer cells. Cancer cells with this phenotype have BRCA1 and / or BRCA2 defects, meaning that the expression and / or activity of BRCA1 and / or BRCA2 can be reduced or eliminated in cancer cells, for example, through mutations or polymorphisms in the encoding nucleic acids, or through amplification, mutation, or polymorphism in genes encoding regulatory factors (e.g., the EMSY gene encoding a BRCA2 regulatory factor) (Hughes-Davies et al., Cell, 115, 523-535).

[0057] BRCA1 and BRCA2 are known tumor suppressor factors, and their wild-type alleles are frequently lost in tumors of heterozygous carriers (Jasin M., Oncogene, 21(58), 8981-93 (2002); Tutt et al., Trends in Molecular Medicine, 8(12), 571-6 (2002)). The association between BRCA1 and / or BRCA2 mutations and breast cancer is well characterized in the field (Radice, PJ, Exp Clin Cancer Res., 21(3 Supplement), 9-12 (2002)). Amplification of the EMSY gene, which encodes the BRCA2 binding factor, is also known to be associated with breast and ovarian cancer. Carriers of mutations in BRCA1 and / or BRCA2 also have a higher risk of developing certain cancers, including breast, ovarian, pancreatic, prostate, hematologic malignancies, gastrointestinal, and lung cancers.

[0058] In one aspect, the individual is heterozygous for one or more variations (e.g. mutations and polymorphisms) in BRCA1 and / or BRCA2 or a modulator thereof. Detection of variations in BRCA1 and BRCA2 is well known in the art and is described, for example, in EP 699 754, EP 705 903, Neuhausen, S.L. and Ostrander, E.A., Genet. Test, 1, 75-83 (1992); Chappnis, P.O. and Foulkes, W.O., Cancer Treat Res, 107, 29-59 (2002); Janatova M. et al., Neoplasma, 50(4), 246-505 (2003); Jancarkova, N., Ceska Gynekol., 68{1), 11-6 (2003). Determination of amplification of the BRCA2 binding factor EMSY is described in Hughes-Davies et al., Cell, 115, 523-535.

[0059] Mutations and polymorphisms associated with cancer can be detected at the nucleic acid level by detecting the presence of a variant nucleic acid sequence, or at the protein level by detecting the presence of a variant (i.e. mutant or allelic variant) polypeptide.

[0060] Definitions

[0061] Alkyl groups and moieties are straight-chain or branched, for example C 1-8 Alkyl, C 1-6 Alkyl, C 1-4 Alkyl or C 5-6 Alkyl. Examples of alkyl groups are methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, n-pentyl, n-hexyl, n-heptyl and n-octyl, such as methyl or n-hexyl.

[0062] Cycloalkyl is a saturated cyclic alkyl group. C 3-6 Cycloalkyl is a saturated cyclic alkyl group having 3 to 6 carbon atoms. C 3-6 Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. C 3-6 Cycloalkyl includes C 3-5 Cycloalkyl and C 3-4 Cycloalkyl.

[0063] Fluoroalkyl groups are alkyl groups in which one or more H atoms are replaced by one or more fluorine atoms, for example C 1-8 Fluoroalkyl, C 1-6 Fluoroalkyl, C 1-4 Fluoroalkyl or C 5-6Fluoroalkyl. Examples include fluoromethyl (CH2F-), difluoromethyl (CHF2-), trifluoromethyl (CF3-), 2,2,2-trifluoroethyl (CF3CH2-), 1,1-difluoroethyl (CH3CHF2-), 2,2-difluoroethyl (CHF2CH2-), 1-fluoroethyl (CH3CHF-), and 2-fluoroethyl (CH2FCH2-).

[0064] Halo means fluoro, chloro, bromo, and iodo. In one aspect, halo is fluoro or chloro.

[0065] Alkylcarbonyloxy is an alkyl group attached to the remainder of the molecule through an oxygen atom. Suitable C 1-4 Examples of alkylcarbonyloxy groups include acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, and pentanoyloxy.

[0066] In this specification, unless otherwise indicated, the term "pharmaceutically acceptable" as used herein means those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit / risk ratio.

[0067] In this specification, unless otherwise indicated, the phrase "effective amount" means an amount of a compound or composition sufficient to significantly and positively alter the condition and / or disorder to be treated (e.g., to provide a positive clinical response). The effective amount of an active ingredient in a pharmaceutical composition will vary with the particular condition being treated, the severity of the condition, the duration of the treatment, the nature of concurrent therapy, the particular active ingredient(s) employed, the particular pharmaceutical acceptable excipient(s) / carrier(s) employed, and like factors within the knowledge and expertise of the attending physician.

[0068] The term "treatment" as used herein, unless otherwise indicated, means reversing, alleviating, or preventing a disorder or condition to which such term applies, or one or more symptoms of such disorder or condition, inhibiting the progress of such disorder or condition, delaying the onset of such disorder or condition, unless otherwise indicated, the term "treatment" as used herein means the act of treating as defined above. The term "treatment" also includes adjuvant and neoadjuvant treatment of a subject. For the avoidance of doubt, reference herein to "treatment" includes reference to curative, palliative and prophylactic treatment and administration of a medicament for such treatment.

[0069] The compounds of Formula I can form stable pharmaceutically acceptable acid or base salts and administration of the compound as a salt can be appropriate in such cases. Examples of salts of acidic groups include acetate, adipate, ascorbate, benzoate, besylate, bicarbonate, bisulfate, butyrate, camphorate, camphorsulfonate, choline, citrate, cyclohexylsulfamate, diethylamine, ethanesulfonate, fumarate, glutamate, glycolate, hemisulfate, 2-hydroxyethanesulfonate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, hydroxymaleate, lactate, malate, maleate, methanesulfonate (mesylate), meglumine, 2-naphthalenesulfonate, nitrate, oxalate, pamoate, persulfate, phenylacetate, phosphate, hydrogen phosphate, picrate, pivalate, propionate, quinate, salicylate, stearate, succinate, sulfamate, sulfanilate, sulfate, tartrate, tosylate (p-toluenesulfonate), trifluoroacetate, and undecanoate. Although other salts can be useful, e.g., in isolating or purifying the product, non-toxic physiologically acceptable salts are preferred.

[0070] These salts can be formed by conventional means, e.g., by reacting the free base form of the product with one or more equivalents of the appropriate acid in a solvent or medium, the salt then formed either being isolated or used directly in the next step of the chain without isolation. The salt can also be formed by freeze-drying of a solution of the product in the presence of the desired salt, or by cation exchange on a suitable ion exchange resin.

[0071] The compounds of Formula I can have more than one chiral center and it is to be understood that the application encompasses all individual stereoisomers, enantiomeric pairs and diastereomeric pairs of the compounds of Formula I, and mixtures thereof. Thus, it is to be understood that the present application encompasses any and all prodrugs, geometric isomers, racemic mixtures, enantiomeric pairs, diastereomeric pairs, and diastereomeric mixtures that can be formed by administration of a compound of Formula I. The present application encompasses all such compounds within the scope of the application.

[0072] Thus, throughout this specification, where reference is made to a compound of Formula I, it is to be understood that such reference includes diastereomers, mixtures of diastereomers, and enantiomers that are PARP1 inhibitors.

[0073] It is also understood that certain compounds of Formula I and pharmaceutically acceptable salts thereof can exist in solvated as well as unsolvated forms (e.g., hydrated forms and anhydrous forms). It is understood that the compounds herein encompass all such solvated forms. For the purposes of clarity, this includes both solvated (e.g., hydrated) forms of the compounds in free form as well as solvated (e.g., hydrated) forms of salts of the compounds.

[0074] Formula I as described herein is intended to encompass all isotopes of the constituent atoms thereof. For example, H (or hydrogen) includes any isotope form of hydrogen, including 1 H, 2 H(D), and 3 H(T); C includes any isotope form of carbon, including 12 C, 13 C, and 14 C; O includes any isotope form of oxygen, including 16 O, 17 O, and 18 O; N includes any isotope form of nitrogen, including 13 N, 14 N, and 15 N; F includes any isotope form of fluorine, including 19 F, and 18 F; and the like. In one aspect, compounds of Formula I include isotopes of the atoms encompassed herein in amounts corresponding to their natural abundance. In certain instances, however, it can be desirable to enrich one or more atoms in a particular isotope that would not normally exist in a lower abundance. For example, H 1 H is present in greater than 99.98% abundance; however, in one aspect, compounds of any of the chemical formulas set forth herein can be enriched in one or more positions where H is present with 2 H, or 3 H. In another aspect, when a compound of any of the chemical formulas set forth herein is enriched in a radioactive isotope (e.g., 3 H, and 14 C), the compound can be used in drug and / or substrate tissue distribution assays. It is understood that the present application encompasses all such isotopic forms.

[0075] Compounds of Formula I or pharmaceutically acceptable salts thereof will generally be administered via the oral route in pharmaceutical formulations comprising the active ingredient or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such salt, in a pharmaceutically acceptable dosage form. Depending on the disorder and patient to be treated, the composition can be administered in different dosages.

[0076] Pharmaceutical formulations of compounds having Formula I described above can be prepared for oral administration, specifically in tablet or capsule form, and particularly relate to techniques aimed at providing drug release targeting the colon (Patel, MM Expert Opin. Drug Deliv. [Expert Opinion on Drug Delivery] 2011, 8(10), 1247-1258).

[0077] Pharmaceutical formulations of compounds having Formula I described above can be conveniently administered in unit dosage forms and can be prepared by any method known in the pharmaceutical field, such as that described in Remington's Pharmaceutical Sciences, 17th edition, Mack Publishing Company, Easton, PA. (1985).

[0078] Pharmaceutical formulations suitable for oral administration may contain one or more physiologically compatible carriers and / or excipients and may be in solid or liquid form. Tablets and capsules may be prepared using binders, fillers, lubricants, and / or surfactants (such as sodium lauryl sulfate). Liquid compositions may contain conventional additives such as suspending agents, emulsifiers, and / or preservatives. Liquid compositions may be encapsulated in, for example, gelatin to provide unit dosage forms. Solid oral dosage forms include tablets, two-piece hard-shell capsules, and soft elastic gelatin (SEG) capsules. Such two-piece hard-shell capsules may be prepared, for example, by filling a compound having formula (I) into a gelatin or hydroxypropyl methylcellulose (HPMC) shell.

[0079] Dry-shell formulations typically contain about 40% to 60% w / w gelatin, about 20% to 30% plasticizers (such as glycerin, sorbitol, or propylene glycol), and about 30% to 40% water. Other materials may also be present, such as preservatives, dyes, opacifiers, and flavorings. Liquid filler materials include solid drugs that have been dissolved, solubilized, or dispersed (using suspending agents such as beeswax, hydrogenated castor oil, or polyethylene glycol 4000) or liquid drugs in a medium or a combination of mediums (such as mineral oil, vegetable oil, triglycerides, glycols, polyols, and surfactants).

[0080] When used for therapeutic treatment in humans, a suitable daily dose of a compound having formula I or a pharmaceutically acceptable salt thereof is about 0.0001-100 mg / kg body weight.

[0081] Oral formulations are preferred, particularly tablets or capsules, which can be formulated by methods known to those skilled in the art to provide a dose of the active compound in the range of 0.1 mg to 1000 mg. Attached Figure Description

[0082] Figure 1 X-ray powder diffraction pattern showing 6-fluoro-5-[4-[(5-fluoro-2-methyl-3-oxo-4H- quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2-carboxamide Form B

[0083] Figure 2 DSC trace showing 6-fluoro-5-[4-[(5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2-carboxamide Form B

[0084] Figure 3 X-ray powder diffraction pattern showing 6-fluoro-5-[4-[(5-fluoro-2-methyl-3-oxo-4H- quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2-carboxamide Form D

[0085] Figure 4 Single crystal structure showing 6-fluoro-5-[4-[(5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6- yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2-carboxamide Form D (ORTEP 50)

[0086] Figure 5 X-ray powder diffraction pattern showing 6-fluoro-5-[4-[(5-fluoro-2-methyl-3-oxo-4H- quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2-carboxamide MSA salt Form C

[0087] Figure 6 DSC trace showing 6-fluoro-5-[4-[(5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2-carboxamide MSA salt Form C

[0088] Examples

[0089] The compounds of the application will now be further explained by reference to the following non-limiting examples.

[0090] General Experimental Conditions

[0091] Bruker 300 MHz, 400 MHz or 500 MHz spectrometer at 27°C using 1 H NMR spectra; chemical shifts are expressed in parts per million (ppm, δ units) and are referenced to residual solvent 1H isotopes (CHCl3: 7.24 ppm; CHDCl2: 5.32 ppm; CD3S(=O)CD2H: 2.49 ppm). Coupling constants are given in Hertz (Hz). Splitting modes describe apparent multiplicity and are designated as s (singleton), d (doublet), t (triplet), q (quartet), m (multiplet), and brs (broad peak). LC-MS was performed using a Waters UPLC equipped with a Waters SQD mass spectrometer or a Shimadzu LC-20AD, LC-20XR, or LC-30AD equipped with a Shimadzu 2020 mass spectrometer. Unless otherwise specified, the reported molecular ion corresponds to [M+H]+; for molecules with multiple isotopic modes (Br, Cl, etc.), unless otherwise specified, the reported values ​​are those obtained for the lowest isotopic mass.

[0092] The following rapid chromatography method was used: [from Biotage] TM SP1 TM On the purification system, from ISCO Rf or on Gilson from Thermo Fisher Scientific, using positive silicon dioxide FLASH+ TM (40M, 25M or 12M) or SNAP IM KP-Sil cartridges (340, 100, 50, or 10), Agela's fast column silica-CS column, straight-phase fast chromatography using a C18 fast column, or standard fast chromatography. Typically, all solvents used are commercially available and analytical grade. Anhydrous solvents are routinely used for the reactions. The phase separator used in these examples is... Phase separation column. The intermediates and examples listed below are named using ACD / Name 12.01 from Advanced Chemistry Development, Inc. (ACD / Laboratory). Starting materials were obtained from commercial sources or prepared via literature routes.

[0093] X-ray powder diffraction (XRPD) analysis

[0094] XRPD analysis was performed using a Bruker D8 diffractometer, which is commercially available from Bruker AXS Inc. TM(Madison, Wisconsin). The XRPD spectrum is obtained by mounting a sample of the material for analysis (about 10 mg) on a single silicon crystal wafer holder (e.g., a Bruker silicon zero background X-ray diffraction sample holder) and spreading the sample into a thin layer with the aid of a microscope slide. The sample is rotated at 30 revolutions per minute (to improve counting statistics) and illuminated with X-rays having a wavelength of 1.5406 Angstroms (i.e., about 1.54 Angstroms) generated by a long fine focus tube made of copper operating at 40 kV and 40 mA. The sample is exposed for 1 second per 0.02° 2-theta increment in the theta-theta mode over a range of 2-theta from 5° to 40° (continuous scan mode). The run time for the D8 is 15 min.

[0095] XRPD 2 theta values can vary within a reasonable range, for example within ±0.2°, and XRPD intensities can vary when measurements are made on essentially the same crystalline form for a variety of reasons, including, for example, preferred orientation. The principles of XRPD are described in publications such as Giacovazzo, C. et al. (1995), Fundamentals of Crystallography, Oxford University Press; Jenkins, R. and Snyder, R.L. (1996), Introduction to X-Ray Powder Diffractometry, John Wiley & Sons, New York; and Klug, H.P. & Alexander, L.E. (1974), X-ray Diffraction Procedures, John Wiley and Sons, New York.

[0096] DSC analysis

[0097] For samples prepared according to standard methods, DSC analysis is performed using a Q2000 TA Instruments® DSC calorimeter. A sample (about 2 mg) is weighed into an aluminum sample pan and transferred to the DSC. The instrument is purged with nitrogen at 50 mL / min and data is collected between 22 °C and 300 °C using a dynamic heating rate of 10 °C / minute. Thermal data is analyzed using standard software (e.g., Universal Analysis v. 4.5A from TA Instruments®). M Q1000 DSC calorimeter. A sample (about 2 mg) is weighed into an aluminum sample pan and transferred to the DSC. The instrument is purged with nitrogen at 50 mL / min and data is collected between 22 °C and 300 °C using a dynamic heating rate of 10 °C / minute. Thermal data is analyzed using standard software (e.g., Universal Analysis v. 4.5A from TA Instruments®).

[0098] ​​The following abbreviations were used: AcOH = acetic acid; aq = aqueous; BAST = bis(2-methoxyethyl)aminosulfur trifluoride; Boc2O = ditert-butyl dicarbonate; Boc = tert-butoxycarbonyl; CDCl3 = deuterated chloroform; CD3OD = deuterated methanol; CH3NO2 = nitromethane; DAST = diethylaminosulfur trifluoride; DCE = 1,2-dichloroethane; DCM = dichloromethane; DDQ = 2,3-dichloro-5,6-dicyano-1,4-benzoquinone; DEA = diethylamine; DEAD = diethyl azodicarbonate; Dys-Martin periodoyl alkyl = 1,1,1-tris(acetyloxy)-1,1-dihydro-1 2-Benzoyl-3-(1H)-one; DIPEA = N,N-diisopropylethylamine; DMAP = 2,6-dimethylaminopyridine; DMF = N,N-dimethylformamide; DMSO = dimethyl sulfoxide; DMSO-d6 = deuterated dimethyl sulfoxide; DPPA = diphenyl azidophosphate; dppf = 1,1′-bis(biphenylphosphino)ferrocene; DIAD = di-isopropyl(E)-diazepine-1,2-dicarboxylate; DSC = differential scanning calorimetry; DTAD = di-tert-butyl(E)-diazepine-1,2-dicarboxylate; ee = enantiomer excess; eq. = equivalent; ESI or ES = electroinjection Ionization; Et2O = diethyl ether; EtOAc or EA = ethyl acetate; EtOH = ethanol; FA = formic acid; Grubbs catalyst (1,3-ditrimethylimidazoline-2-yl) (tricyclohexylphosphine) ruthenium dichloride; h = hours; HATU = (dimethylamino)-N,N-dimethyl(3-oxo-1H-[1,2,3]triazolo[4,5-b]pyridyl)methylimine ion hexafluorophosphate; HCl = hydrochloric acid; H2O2 = hydrogen peroxide; HP = high pressure; IPA = isopropanol; KF = potassium fluoride; LC = liquid chromatography; LiClO4 = lithium perchlorate; mmol = millimoles; mCPBA = m-chloroperoxybenzoic acid; MeOH = methanol; min = minutes; MeCN or CH3CN or ACN = acetonitrile; MeNO2 = nitromethane; MS = mass spectrometry; NBS = N-bromosuccinimide; NH4Cl = ammonium chloride; NMP = N-methyl-2-pyrrolidone; NMR = nuclear magnetic resonance; Pd / C = palladium on carbon; Pd2dba3 = tris(diphenylmethyleneacetone)dipalladium(0); PdCl2(dppf) = 1,1′-bis(di-tert-butylphosphino)ferrocene palladium dichloride; PE = petroleum ether; PPh3 = triphenylphosphine; rt = room temperature; Rt or RT = retention time; Ruphos Pd G3 = (2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)[2-(2′-amino-1,1′biphenyl)]palladium(II) methanesulfonate; Pd-PEPPSI TM- IPent = Dichloro[l,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3- chloropyridyl)palladium(II), [l,3-bis(2,6-di-3-pentylphenyl)imidazol-2- ylidene](3-chloropyridyl)dichloropalladium(II), [l,3-bis(2,6-di-3-pentylphenyl)imidazol- 2-ylidene](3-chloropyridyl)dichloropalladium(II); Xphos Pd G2 = Chloro(2- dicyclohexylphosphino-2',4',6'-triisopropyl-l,r-biphenyl)[2-(2'-amino-l,r- biphenyl)]palladium(II), X-Phos Aminobiphenyl Palladium Chloride; CataCXium A-Pd-G2 = Chloro[(di(l-adamantyl)-N-butylphosphine)-2-(2- aminobiphenyl)]palladium(II); sat = saturated; SFC = supercritical fluid chromatography; T3P = 2,4,6-tripropyl-l,3,5,2,4,6-trioxatriphosphinane 2,4,6- trioxide; PPh3O = triphenylphosphine oxide; TBTU = 2-(lH-benzo[d][l,2,3]thiazol-l- yl)-l,l,3,3-tetramethylisouronium tetrafluoroborate; TFA = trifluoroacetic acid; THF = tetrahydrofuran; TLC = thin layer chromatography; TMS = trimethylsilyl; Xantphos = 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; CBr4 = carbon tetrabromide; HBr = hydrobromic acid; Cs2CO3 = cesium carbonate; MgSO4 = magnesium sulfate; NaHCO3 = sodium bicarbonate; DDQ = 2,3-dichloro-5,6-dicyano-l,4-benzoquinone; SOCl2 = thionyl chloride; DIBAL-H = diisobutylaluminum hydride; NH4HCO3 = ammonium bicarbonate; BINAP = 2,2'-bis(diphenylphosphino)-l,l'-binaphthalene; SM = starting material; CH2Cl2 = dichloromethane; Et3N = triethylamine; HCO2H = formic acid; LCMS = liquid chromatography-mass spectrometry; N2 = nitrogen; Na2SO4 = sodium sulfate; NH4CO3 = ammonium carbonate; UV = ultraviolet; XPhos Pd G2 = chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-l,r- biphenyl)[2-(2'-amino-l,r-biphenyl)]palladium(II); Pd(OAc)2 = palladium(II) acetate, ppt = precipitate.

[0099] Preparation of Examples

[0100]

[0101] Intermediate 2: l-Bromo-4-fluoro-2-methyl-3-nitro-benzene

[0102] To a solution of 1-fluoro-3-methyl-2-nitro-benzene (10.7 g, 68.98 mmol) (Intermediate 1) in TFA (50 mL) was added slowly at 0 °C concentrated H2SO4 (20 mL) followed by portionwise addition of NBS (13.50 g, 75.87 mmol). After the addition, the mixture was stirred at room temperature for 4 h. The resulting mixture was poured onto ice, the precipitate formed was collected by filtration, washed with water and dried under vacuum to give 1-bromo-4-fluoro-2-methyl-3-nitrobenzene (Intermediate 2) as a white solid (14.80 g, 92%).1H NMR (500 MHz, Chloroform-d) 2.43 (3H, s), 7.03 (1H, t), 7.68 (1H, dd).

[0103] Intermediate 3: 2-(4-Bromo-3-methyl-2-nitro-anilino)propionic acid

[0104] A mixture of 1-bromo-4-fluoro-2-methyl-3-nitro-benzene (13.8 g, 58.97 mmol) (Intermediate 2), alanine (6.30 g, 70.76 mmol) and potassium carbonate (24.45 g, 176.90 mmol) in DMF (15 mL) was stirred at 100 °C for 5 h, then the temperature was raised to 110 °C and stirred for 5 h. The mixture was poured onto ice and quenched slowly at 0 °C with 1 M aqueous HC1 (ca. 300 ml) to give a yellow suspension. The solid was collected by filtration, washed with water and dried in a vacuum oven at 50 °C for 2 days to give 2-(4-bromo-3-methyl-2-nitro-anilino)propanoic acid (14.03 g, 78%) (Intermediate 3) as a yellow solid (some impurities present).1H NMR (500 MHz, DMSO-d6) 1.39 (3H, d), 2.28 (3H, s), 4.20 (1H, quin), 6.12 (1H, br d), 6.68 (1H, d), 7.58 (1H, d), 12.98 (1H, br s); m / z (ES+) [M+H] 303.0. + [M+H] + = 303.

[0105] Intermediate 4: Methyl 2-[4-bromo-3-methyl-2-nitro-anilino)propionate

[0106] To a solution of 2-(4-bromo-3-methyl-2-nitro-anilino)propanoic acid (14.9 g, 49.16 mmol) (Intermediate 3) in MeOH (150 mL) was added dropwise thionyl chloride (10.76 mL, 147.47 mmol) at 0 °C and the mixture was stirred at room temperature overnight. LCMS indicated complete conversion. The reaction mixture was slowly quenched with saturated aqueous NaHC03solution (about 300 ml) at 0 °C to give an orange suspension. The solid was collected by filtration, washed with water and dried to give the crude product (14.6 g). The solid was purified on a silica gel column (eluted with 0 to 25% ethyl acetate in hexanes) to give 2-(4-bromo-3-methyl-2-nitro-anilino)propanoic acid methyl ester (Intermediate 4) as a bright orange solid (12.74 g, 82%).1H NMR (500 MHz, Chloroform-d) 1.52 (3H, d), 2.43 (3H, s), 3.76 (3H, s), 4.14 (1H, quin), 5.83 (1H, br d), 6.45 (1H, d), 7.48 (1H, d); m / z (ES+) [M+H] 317.0. + [M+H] + = 317.

[0107] Intermediate 5: 7-Bromo-3,8-dimethyl-3,4-dihydro-lH-quinoxalin-2-one

[0108] To a stirred mixture of 2-(4-bromo-3-methyl-2-nitro-anilino)propanoic acid methyl ester (11.6 g, 36.58 mmol) (Intermediate 4), zinc (23.91 g, 365.77 mmol), ammonium chloride (19.56 g, 365.77 mmol) in MeOH (100 mL) was added small ice pieces (exotherm) at 0 °C. The reaction mixture was then stirred at 0 °C (ice bath) for 15 min. Water (2 mL) was added and the resulting mixture was stirred at room temperature for 15 min. The bright orange color disappeared. The mixture was filtered through filter paper, washed with methanol and the filtrate was concentrated in vacuo. The residue was diluted with ethyl acetate and washed successively with water and brine. The organic layer was dried (Na2S04, anhydrous), filtered and concentrated to give a mixture of 2-(2-amino-4-bromo-3-methyl-anilino)propanoic acid methyl ester and 7-bromo-3,8-dimethyl-3,4-dihydro-1H-quinoxalin-2-one (9.8 g).

[0109] To a solution of the above solid in MeOH (100 mL) was added 2 ml of a 4M solution of HCI in dioxane at room temperature and the mixture stirred at room temperature for 10 minutes. A further 100 ml of methanol was added (forming a free suspension) and the resulting suspension stirred at room temperature for 1 hour. The mixture was diluted with ether (approximately 200 ml) and the solid collected by filtration and washed with ether. The filtrate was concentrated until a solid precipitated which was collected by filtration. This procedure was repeated several times to yield a first portion of product 7.2 g. The filtrate was concentrated and purified on a silica gel column (eluting with 0 to 100% ethyl acetate in hexane) and the product fractions concentrated and the resulting material combined with the above material to yield 7-bromo-3,8-dimethyl-3,4-dihydro-1 H- quinoxalin-2-one as an off-white solid (9.10 g, 98%) (Intermediate 5).1H NMR (500 MHz, DMSO-d6) 1.23 (3H, d), 2.24 (3H, s), 3.68 (1H, q), 3.75 (br, 1H), (6.54 (1H, d), 7.00 (1H, d), 9.77 (1H, s); m / z (ES + )[M+H] + = 255.

[0110] Intermediate 6: 7-Bromo-3,8-dimethyl-lH-quinoxalin-2-one

[0111] DDQ (8.91 g, 39.24 mmol) was added to a suspension of 7-bromo-3,8-dimethyl-3,4- dihydro-1 H-quinoxalin-2-one (9.1 g, 35.67 mmol) (Intermediate 5) in CH2CI2(400 mL) at room temperature and the mixture stirred overnight. LCMS indicated complete conversion. The solvent was removed under reduced pressure, a saturated NaHC03solution (approximately 300 ml) was added and the yellow suspension stirred at room temperature for 4 hours. The solid was collected by filtration and washed with water. The solid was slurred in saturated NaHC03(100 ml) and stirred at room temperature for 1 hour. The solid was filtered, washed with water and ether in turn and dried to yield 7-bromo-3,8-dimethyl-1 H-quinoxalin-2-one as an off-white solid (7.29 g, 81%) (Intermediate 6).1H NMR (500 MHz, DMSO-d6) 2.40 (3H, s), 2.50 (3H, s) (overlapping with DMSO-d6 peak), 7.32-7.65 (2H, m), 11.76 (1H, br s); m / z (ES + )[M+H] + = 253.

[0112] Intermediate 7: 7-(Hydroxymethyl)-3,8-dimethyl-lH-quinoxalin-2-one

[0113] A mixture of (tributylstannyl)methanol (1142 mg, 3.56 mmol), 7-bromo-3,8- dimethyl-1H-quinoxalin-2-one (600 mg, 2.37 mmol) (Intermediate 6) and Xphos Pd G2 (280 mg, 0.36 mmol) in 1,4-dioxane (40 mL) was stirred at 80 °C for 18 h. The solvent was removed under reduced pressure and the residue was purified on a silica gel column eluting with 0-15% methanol in DCM to give 7-(hydroxymethyl)-3,8-dimethyl-1H-quinoxalin-2-one (225 mg, 46%) as an off-white solid (Intermediate 7).1H NMR (500 MHz, DMSO-d6) 2.31 (3H, s), 2.40 (3H, s), 4.58 (2H, d), 5.22 (1H, t), 7.33 (1H, d), 7.52 (1H, d), 11.53 (1H, br s); m / z (ES+) [M+H] 205.0. + [M+H] + = 205.

[0114] Intermediate 8: 7-(Bromomethyl)-3,8-dimethyl-lH-quinoxalin-2-one

[0115] 7-(hydroxymethyl)-3,8-dimethyl-1H-quinoxalin-2-one (223 mg, 1.09 mmol) (Intermediate 7) in HBr (15 ml, 132.59 mmol) (48 w% in water) was stirred at 80 °C for 3.5 h. The solvent was removed under reduced pressure and diethyl ether was added to the residue, the mixture was sonicated and the solid was collected to yield 7-(bromomethyl)-3,8-dimethyl-1H-quinoxalin-2-one (408 mg, 107%) as a yellow solid (Intermediate 8).1H NMR (500 MHz, DMSO-d6) 2.36-2.45 (6H, m), 4.83 (2H, s), 7.34 (1H, d), 7.53 (1H, d), 11.63 (1H, br s); m / z (ES+) [M+H] 267, 269. + [M+H] + = 267, 269.

[0116] Example 1: 5-[4-[(2,5-Dimethyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-l-yl]-6- fluoro-N-methyl-pyridine-2-carboxamide Example 2: 5-[4-[(2,5-Dimethyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-l-yl]-N- methyl-pyridine-2-carboxamide

[0117] To a suspension of 7-(bromomethyl)-3,8-dimethyl-lH-quinoxalin-2-one, HBr (37 mg, 0.10 mmol) (Intermediate 8) was added ACN (5 ml), 6-fluoro-N-methyl-5-(piperazin-l- yl)picolinamide, 2HCI (31.5 mg, 0.10 mmol) (Intermediate 32) and DIPEA (79 μΐ, 0.45 mmol) and the reaction mixture was stirred at 70 °C for 1 hour to give a light yellow suspension. The suspension was cooled to room temperature, 1 drop of water was added, the solid was collected by filtration, washed with acetonitrile three times and dried to give 5-[4-[(2,5-dimethyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-l-yl]-6-fluoro-N-methyl- pyridine-2-carboxamide as a yellow solid (0.016 g, 33%) (Example 1).1H NMR (500 MHz, DMSO-d6) 2.07 (3H, br s), 2.42 (3H, br d), 2.56 (4H, br s), 2.76 (3H, br s), 3.14 (4H, br s), 3.61 (2H, br s), 7.23 (IH, br d), 7.42-7.67 (2H, m), 7.83 (IH, br d), 8.38 (IH, br s), 11.13-11.97 (IH, m); m / z (ES+) [M+H] 425.2. + [M+H] + = 425.

[0118]

[0119] Example 3: 6-Chloro-5-[4-[(2,5-dimethyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-l- yl]-N-methyl-pyridine-2-carboxamide Example 4: 5-[4-[(2,5-Dimethyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-l-yl]-N,6- di-methyl-pyridine-2-carboxamide

[0120] To a suspension of 7-(bromomethyl)-3,8-dimethylquinoxalin-2(lH)-one, HBr (240 mg, 0.69 mmol) (Intermediate 8), N-methyl-5-piperazin-l-yl-pyridine-2-carboxamide, 2HCl (202 mg, 0.69 mmol) (Intermediate 31) in acetonitrile (13 mL) was added DIPEA (0.723 mL, 4.14 mmol) and the resulting mixture was stirred at 70 °C for 3 hours. The mixture was concentrated and purified on reverse phase (C18 column eluting with 0 to 100% ACN / water (0.2% ammonium hydroxide)) to give the product as a brown solid. The solid was suspended in a mixture of DCM and MeOH (2:1), concentrated to remove DCM, the solid was filtered and washed with methanol. The solid was suspended in ACN (3 ml), 0.8 ml of 1M aqueous HC1 was added, diluted with water (about 3 ml) and lyophilized to give the HC1 salt of 5-[4-[(2,5-dimethyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-l-yl]-N-methyl-pyridine-2-carboxamide (0.033 g, 11%) (Example 2).1H NMR (500 MHz, DMSO-d6) 2.45 (3H, s), 2.54 (3H, s), 2.81 (3H, br d), 3.24-3.56 (6H, m), 3.88-4.02 (2H, m), 4.54 (2H, br s), 7.48-7.71 (3H, m), 7.97 (IH, br d), 8.33 (IH, br d), 8.59 (IH, br s), 11.28 (IH, br s), 11.48-11.95 (IH, m); m / z (ES+) [M+H] = 407. + [M+H] + = 407.

[0121]

[0122] Intermediate 10: Methyl 5-bromo-6-fluoro-pyridine-2-carboxylate Intermediate 11: 4-(2-Fluoro-6-methoxycarbonyl-3-pyridyl)piperazine-1-carboxylic acid tert-butyl ester

[0123] HBr in AcOH (2 mL, 0.18 mmol) (33 wt%) was added to a solution of 7- (hydroxymethyl)-3,8-dimethyl-1H-quinoxalin-2-one (36 mg, 0.18 mmol) (Intermediate 7) in NMP (2 mL). The resulting mixture was stirred at 100 °C for 1 h. The solvent was removed under reduced pressure. DIPEA (0.25 mL, 1.43 mmol) was added to a solution of 6-chloro-N-methyl-5- (piperazin-1-yl)picolinamide (48 mg, 0.19 mmol) (Intermediate 30) in NMP (2 mL). The resulting mixture was stirred at 100 °C for 18 h. The crude product was purified by preparative HPLC (Column: YMC-Actus Triart C18, 30*250, 5 μm; Mobile Phase A: Water (0.05% NH3H2O), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 41B to 61B in 7 min; 254; 220 nm. Fractions containing the desired compound were evaporated to dryness to give 6-chloro-5-[4-[(2,5-dimethyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N- methyl-pyridine-2-carboxamide (33.0 mg, 42%) (Example 3) as a white solid.1H NMR (400 MHz, DMSO-d6) 2.41 (3H, s), 2.43 (3H, s), 2.54-2.62 (4H, m), 2.78 (3H, d), 3.05-3.11 (4H, m), 3.62 (2H, s), 7.24 (1H, d), 7.51 (1H, d), 7.65 (1H, d), 7.92 (1H, d), 8.41-8.45 (1H, m), 11.56 (1H, s); m / z (ES+) [M+H] 441.2. + [M+H] + = 441.

[0124]

[0125] Intermediate 12: Methyl 6-fluoro-5-piperazin-l-yl-pyridine-2-carboxylate Intermediate 13: Methyl 5-[4-[(2,5-dimethyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-l- yl]-6-fluoro-pyridine-2-carboxylate

[0126] A solution of HBr in AcOH (2 mL, 12.15 mmol) (33 wt%) was added to a solution of 7-(hydroxymethyl)-3,8-dimethyl-lH-quinoxalin-2-one (43 mg, 0.21 mmol) (Intermediate 7) in NMP (2 mL). The resulting mixture was stirred at 80 °C for 1 hour. The solvent was removed under reduced pressure. To a solution of the resulting solid in NMP (3 mL) was added DIPEA (0.25 mL, 1.43 mmol) and N,6-dimethyl-5-(piperazin-l-yl)picolinamide (42 mg, 0.18 mmol) (Intermediate 33). The resulting mixture was stirred at 100 °C for 18 hours. The crude product was purified by preparative HPLC (Column: YMC-Actus Triart C18, 30*250, 5 μm; using water in acetonitrile (0.05% NH4OH. Fractions containing the desired compound were evaporated to dryness to give 5-[4-[(2,5-dimethyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-l-yl]-N,6-dimethyl- pyridine-2-carboxamide (Example 4) as a white solid (18.40 mg, 24%).1H NMR (400 MHz, DMSO-c / 6) 2.40 (3H, s), 2.43 (3H, s), 2.48 (3H, s), 2.55-2.63 (4H, m), 2.79 (3H, d), 2.87-2.94 (4H, m), 3.62 (2H, s), 7.24 (IH, d), 7.46 (IH, d), 7.51 (IH, d), 7.78 (IH, d), 8.39-8.44 (IH, m), 11.56 (IH, s); m / z (ES+) [M+H] 421.2. + [M+H] + = 421.

[0127]

[0128] Example 5: 5-[4-[(2,5-Dimethyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-l-yl]-6-fluoro- pyridine-2-carboxamide

[0129] A dry flask was charged with methyl 5-bromopicolinate (intermediate 9) (24 g, 111.09 mmol) in acetonitrile (300 ml), silver (II) fluoride (50 g, 342.78 mmol) was added and the mixture was stirred at room temperature under N2for 1 day. LCMS indicated about 70% conversion. Another batch of AgF2(16 g) was added and the resulting mixture was continued to stir at room temperature overnight. The mixture was filtered through celite, washed with acetonitrile and DCM in turn, the filtrate was concentrated to give a light brown solid. The residue was partitioned between DCM and saturated NH4CI solution to give a white suspension. The solid was filtered off and discarded. The filtrate was transferred to a separatory funnel, the organic layer was separated, the aqueous layer was extracted with ethyl acetate (150 ml x 3). The organics were combined, dried (Na2SO4), filtered and concentrated until solid precipitated out. The solid was collected by filtration, washed with ether and dried to give a plate-like off-white solid. The combined filtrate was concentrated again, the solid was collected by filtration to give a combined 19.96 g of product. The remaining filtrate was concentrated and purified on a silica gel column (eluted with 0 to 25% ethyl acetate in hexanes) to give a second portion of the desired product 3.5 g as a white plate-like solid. All the materials were combined to give methyl 5-bromo-6-fluoro-pyridine-2-carboxylate (23.46 g, 90%) (intermediate 10).1H NMR (500 MHz, DMSO-d6) 3.89 (3H, s), 7.93 (1H, d), 8.51 (1H, t); m / z (ES+) [M+H] = 234. + [M+H] + = 234.

[0130] Intermediate 15: 4-(6-Methoxycarbonyl-2-methyl-3-pyridyl)piperazine-l-carboxylic acid tert-butyl ester

[0131] A mixture of piperazine-1-carboxylic acid tert-butyl ester (28.0 g, 150.37 mmol), methyl 5-bromo-6-fluoro-pyridine-2-carboxylate (Intermediate 10) (23.46 g, 100.25 mmol), RuPhos Pd G3 (5.45 g, 6.52 mmol) and Cs2CO3 (82 g, 250.61 mmol) in 1,4-dioxane (400 mL) was stirred at 80 °C under N2 overnight. The reaction mixture was diluted with water (250 ml) and extracted with ethyl acetate (250 ml). The organic layer was washed with brine, the aqueous layer was extracted with ethyl acetate (100 ml x 1), the organics were dried (Na2SO4 anhydrous), filtered and concentrated, the residue was purified on a silica gel column (eluted with 0 to 50% ethyl acetate in hexanes) to give the product as a yellow solid, the solid was recrystallized from ethyl acetate / hexanes, filtered, washed with hexanes, dried to give the product as a crystalline white solid (24.8 g); the filtrate was concentrated and purified on a silica gel column again to produce more product 1.9 g. Total 4-(2-fluoro-6-methoxycarbonyl-3-pyridyl)piperazine-1-carboxylic acid tert-butyl ester (Intermediate 11) (26.7 g, 78%).1H NMR (500 MHz, Chloroform-d) 1.51 (9H, s), 3.12 - 3.28 (4H, m), 3.48 - 3.67 (4H, m), 3.98 (3H, s), 7.27 (1H, d), 7.99 (1H, dd); m / z (ES+) [M+H] = 340. + [M+H] + = 340.

[0132] Intermediate 16: Methyl 6-methyl-5-piperazin-l-yl-pyridine-2-carboxylate

[0133] To a mixture of 4-(2-fluoro-6-methoxycarbonyl-3-pyridyl)piperazine-1-carboxylic acid tert-butyl ester (1.9 g, 5.60 mmol) (Intermediate 11) in MeOH (10 ml) was added HCl 4M in dioxane (10 mL, 40.00 mmol) at room temperature and the resulting mixture was stirred at room temperature for 1 hour. The mixture was diluted with ether, the solid was collected by filtration, washed with ether and dried under vacuum to give 6-fluoro-5-piperazin-1-yl-pyridine-2-carboxylic acid methyl ester (1.360 g, 78%) (Intermediate 12) as a white solid.1H NMR (500 MHz, DMSO-d6) 3.24 (4H, br s), 3.46 (4H, br s), 3.84 (3H, s), 7.65 (1H, br t), 7.94 (1H, br d), 9.43 (2H, br s); m / z (ES+) [M+H] = 240. + [M+H] + = 240.

[0134] Example 6: 5-[4-[(5-Fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-l-yl]-6- methyl-pyridine-2-carboxamideIntermediate 19: Methyl 5-[4-[(2,5-dimethyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-l- yl]-6-methyl-pyridine-2-carboxylate

[0135] A solution of 7-(hydroxymethyl)-3,8-dimethylquinoxalin-2(lH)-one (223 mg, 1.09 mmol) (Intermediate 7) in HBr (15 ml, 132.59 mmol) (48w% in water) was stirred at 80 °C for 3.5 hours. The solvent was removed under reduced pressure, DCM was added to the residue and concentrated to give 7-(bromomethyl)-3,8-dimethylquinoxalin-2(lH)-one as a yellow solid.

[0136] To a solution of the above solid in acetonitrile (20 ml) at room temperature was added 6-fluoro-5-piperazin-l-yl-pyridine-2-carboxylic acid methyl ester, 2HCI (260 mg, 0.83 mmol) (Intermediate 12) and DIPEA (1.907 ml, 10.92 mmol) and the reaction mixture was stirred at 70 °C for 2 hours. The mixture was cooled to room temperature, 0.5 ml water was added, the solid was collected by filtration and washed with acetonitrile. The solid was dried to give 5-[4-[(2,5-dimethyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-l-yl]-6-fluoro-pyridine-2-carboxylic acid methyl ester (0.371 g, 80%) (Intermediate 13) as an off-white solid.1H NMR (500 MHz, DMSO-d6) 2.42 (6H, m), 2.52-2.59 (4H, m), 3.20 (4H, br d), 3.61 (2H, s), 3.82 (3H, s), 7.23 (IH, d), 7.41-7.59 (2H, m), 7.91 (IH, d), 11.55 (IH, s); m / z (ES+) [M+H] 426.2. + [M+H] + 426.

[0137] Example 7: 5-[4-[(2,5-Dimethyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-l-yl]-6-methyl- pyridine-2-carboxamide ​

[0138] A sealed 40 ml vial was charged with 5-[4-[(2,5-dimethyl-3-oxo-4H- quinoxalin-6-yl)methyl]piperazin-1-yl]-6-fluoro-pyridine-2-carboxylic acid methyl ester (360 mg, 0.85 mmol) (Intermediate 13) and ammonia (15 ml, 105.00 mmol, 7N in methanol) and the mixture stirred at 50 °C overnight. LCMS indicated that some starting material remained. The mixture was concentrated, 10 ml of 7N ammonia in methanol was added to the solid and the mixture stirred at 50 °C for 4 hours to give a white suspension. The solid was collected by filtration, washed with hexane and dried to give 5-[4-[(2,5-dimethyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-6-fluoro-pyridine-2-carboxylic acid amide (Example 5) as a white solid (340 mg, 98%).1H NMR (500 MHz, DMSO-d6) 2.40 (3H, s), 2.43 (3H, s), 2.56 (4H, br s), 3.14 (4H, br s), 3.61 (2H, s), 7.23 (1H, d), 7.46 (1H, br s), 7.48-7.58 (2H, m), 7.76 (1H, br s), 7.84 (1H, br d), 11.11-11.70 (1H, m); m / z (ES+) 411.2 [M+H]. + [M+H] + = 411.

[0139]

[0140] ​

[0141] A 40 mL vial equipped with a septum cap was charged with methyl 5-bromo-6- methylpicolinic acid (Intermediate 14) (2 g, 8.69 mmol), piperazine-1-carboxylic acid tert-butyl ester (3.24 g, 17.39 mmol), Cs2CO3(5.66 g, 17.39 mmol), and Ruphos Pd G3 (0.727 g, 0.87 mmol). The reaction vial was evacuated under vacuum and filled with nitrogen. 1,4-Dioxane (20 mL) was added, and the reaction vial was placed in a heating block preheated to 80 °C and stirred for 16 h. The reaction mixture was cooled, diluted with water and extracted with ethyl acetate, the organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated. The residue was purified on a silica gel column eluting with 0 to 50% ethyl acetate in hexanes to give tert-butyl 4-(6-methoxycarbonyl-2-methyl-3-pyridyl)piperazine-1-carboxylate (Intermediate 15) as a light yellow solid (2.090 g, 72%).1H NMR (500 MHz, Methanol-d4) 1.49 (9H, s), 2.59 (3H, s), 2.88 - 3.00 (4H, m), 3.55 - 3.65 (4H, m), 3.92 (3H, s), 7.32 (1H, d), 7.92 (1H, d); m / z (ES+) [M+H] = 336. + [M+H] + = 336.

[0142] ​

[0143] 4M Hydrogen chloride in 1,4-dioxane (31.2 ml, 124.63 mmol) was added to a stirred solution of tert-butyl 4-(6-(methoxycarbonyl)-2-methylpyridin-3-yl)piperazine-1- carboxylate (Intermediate 15) (4.18 g, 12.46 mmol) in DCM (30 mL) and the resulting solution was stirred at room temperature for 18 h. The solvent was removed in vacuo and the resulting solid was slurry in diethyl ether, the solid was collected by filtration to give methyl 6-methyl-5-piperazin-1-yl-pyridine-2-carboxylate (Intermediate 16) as a light yellow solid (3.80 g, 99%); m / z (ES+) [M+H] = 236. + [M+H] + = 236.

[0144] ​ ​

[0145] Triphenylphosphine (1.584 g, 6.04 mmol) (add 4.4 g, based on 1.6 mmol / g loading of PPh3) was added to a stirred slurry of 8-fluoro-7-(hydroxymethyl)-3- methylquinoxalin-2(lH)-one (419 mg, 2.01 mmol) (Intermediate 17) and perbromo methane (1.335 g, 4.03 mmol) in DCM (40 mL) at room temperature. The resulting mixture was stirred for 1 h. The reaction mixture was filtered, washed with DCM and THF, and the filtrate was concentrated in vacuo to give 7-(bromomethyl)-8-fluoro-3-methylquinoxalin-2(lH)-one as a light yellow solid.

[0146] To a slurry of the above freshly prepared 7-(bromomethyl)-8-fluoro-3-methylquinoxalin- 2(lH)-one in acetonitrile (25 mL) was added 6-methyl-5-piperazin-l-yl-pyridine-2-carboxylic acid methyl ester, 2HCI (590 mg, 1.91 mmol) (Intermediate 16) and N-ethyl-N- isopropylpropan-2-amine (1754 μΐ, 10.07 mmol) and the reaction was heated to 70 °C for 1 h. The reaction mixture was cooled to room temperature, concentrated, and quenched with saturated aqueous NaHC03and stirred for 1 h. The solid was isolated by filtration and washed with water. The crude solid was purified on a silica gel column chromatography (using 0-10% MeOH in DCM) to give 5-[4-[(5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-l-yl]-6- methyl-pyridine-2-carboxylic acid methyl ester (Intermediate 18) (0.263 g, 31%).1H NMR (500 MHz, DMSO-d6) 2.40-2.49 (6H, m), 2.62 (4H, br s), 2.97 (4H, br s), 3.72 (2H, s), 3.83 (3H, s), 7.30 (1H, t), 7.44 (1H, d), 7.52 (1H, d), 7.85 (1H, d), 12.45 (1H, br s);19F NMR (471 MHz, DMSO-d6) -135.54 (1F, s); m / z (ES+) [M+H] 426.2. + [M+H] + = 426.

[0147] ​ ​

[0148] 7N ammonia in methanol (16.47 ml, 115.26 mmol) was added to 5-[4-[(5-fluoro-2- methyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-6-methyl-pyridine-2-carboxylic acid methyl ester (Intermediate 18) (0.2452 g, 0.58 mmol) in a 40 mL scintillation vial, sealed and stirred at room temperature for 18 hours. Further 7N NH3solution (15 mL) was added to the reaction mixture and stirred at 50 °C overnight. The reaction was concentrated in vacuo, slurry in 5 mL MeOH. The solid was filtered off, washed with methanol and dried to give 5-[4-[(5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-6-methyl-pyridine-2-carboxamide (Example 6) as an off-white solid (0.151 g, 64%).1H NMR (500 MHz, DMSO-c / 6) 2.42 (3H, s), 2.45 - 2.49 (3H, m), 2.52 - 2.69 (4H, m), 2.94 (4H, br s), 3.71 (2H, s), 7.29 (1H, t), 7.40 - 7.54 (3H, m), 7.77 - 7.84 (2H, m), 12.43 (1H, br s);19F NMR (471 MHz, DMSO-c / 6) -135.53 (1F, s); m / z (ES+) [M+H] 411.2. + [M+H] + = 411.

[0149]

[0150] ​ ​

[0151] 7-(hydroxymethyl)-3,8-dimethylquinoxalin-2(1H)-one (Intermediate 7) (223 mg, 1.09 mmol) in HBr (15 ml, 132.59 mmol) (48 w% in water) was stirred at 80 °C for 4 hours. The solvent was removed under reduced pressure, DCM was added to the residue, the mixture was sonicated and concentrated to give 7-(bromomethyl)-3,8-dimethylquinoxalin-2(1H)-one as a yellow solid.

[0152] To the slurry above in acetonitrile (20 ml) was added 6-methyl-5-piperazin-l-yl- pyridine-2-carboxylic acid methyl ester, 2HCI (Intermediate 16) (337 mg, 1.09 mmol) and DIPEA (1.907 ml, 10.92 mmol). The reaction mixture was stirred at 70 °C for 2 hours to give a clear solution. The resulting mixture was cooled to room temperature, half the solvent removed, and 0.5 ml water added. The solid was collected by filtration, washed with acetonitrile and dried to give a yellow solid. This solid was purified on a silica gel column (eluting with 0-20% methanol in DCM) to give 5-[4-[(2,5-dimethyl-3-oxo-4H- quinoxalin-6-yl)methyl]piperazin-l-yl]-6-methyl-pyridine-2-carboxylic acid methyl ester (Intermediate 19) as an off-white solid (213 mg, 46%).1H NMR (500 MHz, DMSO-d6) 2.41 (3H, s), 2.43 (3H, s), 2.47 (3H, s), 2.58 (4H, br s), 2.95 (4H, br s), 3.63 (2H, s), 3.82 (3H, s), 7.24 (IH, d), 7.43 (IH, d), 7.51 (IH, d), 7.84 (IH, d), 11.55 (IH, s). m / z (ES+) [M+H] = 422. + [M+H] + = 422.

[0153] ​ ​

[0154] A sealed 40 ml vial was charged with 5-[4-[(2,5-dimethyl-3-oxo-4H- quinoxalin-6-yl)methyl]piperazin-1-yl]-6-methyl-pyridine-2-carboxylic acid methyl ester (Intermediate 19) (210 mg, 0.50 mmol) and ammonia (15 ml, 105.00 mmol, 7N in methanol) and the reaction stirred at 50 °C overnight. The reaction was incomplete. The mixture was concentrated and to the solid was added 10 ml of 7N ammonia in methanol. The vial was capped and stirred at 50 °C for 4 hours to give a white suspension. The mixture was cooled to room temperature and the solid was collected by filtration, washed with hexanes and dried to give 5-[4-[(2,5-dimethyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-6-methyl-pyridine-2-carboxamide (Example 7) as a white solid (191 mg, 94%).1H NMR (500 MHz, DMSO-d6) 2.41 (3H, s), 2.44 (3H, s), 2.49 (3H, s), 2.58 (4H, br s), 2.92 (4H, br s), 3.63 (2H, br s), 7.24 (1H, br d), 7.42 (1H, br s), 7.46 (1H, br d), 7.51 (1H, br d), 7.79 (2H, br d), 10.53-11.23 (1H, m); m / z (ES+) [M+H] = 407. + [M+H] + = 407.

[0155]

[0156] Intermediate 21 : methyl 2-aminobutanoate

[0157] A slurry of 2-aminobutyric acid (Intermediate 20) (5 g, 48.49 mmol) in methanol (35 mL) was cooled in an ice bath. Thionyl chloride (11 mL, 150.72 mmol) was added dropwise to the above mixture at 0 °C. The reaction was allowed to warm to room temperature and stirred overnight. The clear solution was concentrated to dryness to give a residue. The resulting solid was suspended in ether, filtered, washed with ether and dried to give methyl 2-aminobutyrate.HCl (Intermediate 21) as a white solid as the HCl salt (7.35 g, 99%).1H NMR (500 MHz, DMSO-d6) 0.92 (3H, t), 1.76-1.93 (2H, m), 3.75 (3H, s), 3.95-4.05 (1H, m), 8.53 (3H, br s).

[0158] Intermediate 23: methyl 2-(4-bromo-3-chloro-2-nitro-anilino)butanoate

[0159] A flask was charged with methyl 2-aminobutanoate, HC1 (Intermediate 21) (1.811 g, 11.79 mmol), 1-bromo-2-chloro-4-fluoro-3-nitrobenzene (Intermediate 22) (2.0 g, 7.86 mmol) in 1,4-dioxane (30 mL), added DIPEA (8.24 mL, 47.16 mmol) and the mixture was stirred at 105 °C for 24 h. The mixture was concentrated and the residue was purified on a silica gel column (eluted with 0 to 50% ethyl acetate in hexanes) to give methyl 2-(4-bromo-3-chloro-2-nitro-anilino)butanoate (Intermediate 23) (2.100 g, 76%) as a bright yellow oil which turned to yellow solid upon standing.1H NMR (500 MHz, Chloroform-d) 0.99 (3H, t), 1.78 - 1.89 (1H, m), 1.91 - 2.02 (1H, m), 3.77 (3H, s), 4.04 (1H, q), 5.63 (1H, br d), 6.55 (1H, d), 7.52 (1H, d); m / z (ES+) [M+H] 351.0. + [M+H] + = 351.

[0160] Intermediate 24: 7-bromo-8-chloro-3-ethyl-3,4-dihydro-1 H-quinoxalin-2-one

[0161] Sodium hydrosulfite (3.05 g, 17.49 mmol) was added to a stirred mixture of methyl 2-(4-bromo-3-chloro-2-nitro-anilino)butanoate (Intermediate 23) (2.05 g, 5.83 mmol) in DMSO (50 mL) and the mixture was stirred at 120 °C for 3 h. The mixture was quenched with water and extracted with ethyl acetate (50 ml x 2). The organic layer was dried (Na2S04), filtered, concentrated and the residue was purified on a silica gel column (0 to 55% ethyl acetate in hexanes) to give Peak 1, 7-bromo-8-chloro-3-ethyl-1H-quinoxalin-2-one (Intermediate 25) as a light yellow solid (0.319 g, 19%).1H NMR (500 MHz, Methanol-d4) 1.31 (3H, t), 2.89 (2H, q), 7.56 - 7.67 (2H, m); m / z (ES+) [M+H] 287, 289. + [M+H] + = 287, 289

[0162] and peak 2, 7-bromo-8-chloro-3-ethyl-3,4-dihydro-1 H-quinoxalin-2-one (intermediate 24) as a yellow oil (0.895 g, 53%) which turned to a yellow solid upon standing.1H NMR (500 MHz, Chloroform-d) 1.04 (3H, t), 1.75 - 1.84 (1H, m), 1.85 - 1.93 (1H, m), 3.89 (1H, dd), 6.51 (1H, d), 7.12 (1H, d), 7.82 (1H, br s). m / z (ES+) [M+H] = 289, 291. + [M+H] + = 289, 291.

[0163] Intermediate 25: 7-bromo-8-chloro-3-ethyl-1 H-quinoxalin-2-one

[0164] DDQ (772 mg, 3.40 mmol) was added to a mixture of 7-bromo-8-chloro-3-ethyl-3,4- dihydro-1 H-quinoxalin-2-one (intermediate 24) (895 mg, 3.09 mmol) in 1,4-dioxane (20 mL) at room temperature and the resulting suspension was stirred at room temperature for 3 hours. LCMS indicated complete conversion. The solvent was removed under reduced pressure and the residue was treated with saturated NaHC03solution and stirred at room temperature for 2 hours. The solid was collected by filtration, washed with saturated NaHC03solution, water and dried to give 7-bromo-8-chloro-3-ethyl-1 H-quinoxalin-2-one (intermediate 25) as an off-white solid (780 mg, 88%).1H NMR (500 MHz, Methanol-d4) 1.31 (3H, t), 2.89 (2H, q), 7.56 - 7.67 (2H, m); m / z (ES+) [M+H] = 287, 289. + [M+H] + = 287, 289.

[0165] Intermediate 26: 8-chloro-3-ethyl-7-vinyl-1 H-quinoxalin-2-one

[0166] A mixture of 7-bromo-8-chloro-3-ethyl-1 H-quinoxalin-2-one (intermediate 25) (1.05 g, 3.65 mmol), tributyl(vinyl)stannane (1.737 g, 5.48 mmol) and Pd(PPh3)4(0.422 g, 0.37 mmol) in toluene (50 mL) was stirred at 110 °C under N2for 2 hours. LCMS indicated about 44% of starting material remained. The mixture was continued to stir at this temperature for 4.5 hours and then at 80 °C overnight. The mixture was concentrated and purified on a silica gel column (eluted with 0 to 100% ethyl acetate in hexanes) to give the desired product 8-chloro-3-ethyl-7-vinyl-1 H-quinoxalin-2-one (intermediate 26) as a light yellow solid (0.850 g, 99%). m / z (ES+) [M+H] = 225. +)[M+H] + = 235 (product contaminated with PPh3O).

[0167] Intermediate 27: 5-chloro-2-ethyl-3-oxo-4H-quinoxalin-6-carbaldehyde

[0168] Osmium tetroxide in H20 (0.568 mL, 0.07 mmol) was added to a solution of 8-chloro-3-ethyl-7-vinyl-1H-quinoxalin-2-one (Intermediate 26) (850 mg, 3.62 mmol), 2,6-dimethylpyridine (0.844 mL, 7.24 mmol) and sodium periodate (3099 mg, 14.49 mmol) in THF (50 mL) / water (10 mL) / tert-butanol (3.46 mL, 36.22 mmol) and stirred at room temperature overnight to give a yellow suspension. The reaction was concentrated, partitioned between water, saturated NH4Cl solution and DCM and the layers separated. The aqueous layer was extracted with DCM and the combined organic layers dried (Na2S04), filtered and concentrated. The residue was purified on a silica gel column (eluting with 0 to 50% ethyl acetate in hexane) to give 5-chloro-2-ethyl-3-oxo-4H-quinoxalin-6-carbaldehyde (Intermediate 27) as a light yellow solid (808 mg, 94%).1H NMR (500 MHz, chloroform-d) 1.34 - 1.42 (3H, m), 3.03 (2H, q), 7.88 (2H, d), 8.99 - 9.38 (1H, m), 10.54 (1H, s); m / z (ES+) [M+H] 235.0. + [M+H] + = 237.

[0169] Intermediate 28: 8-chloro-3-ethyl-7-(hydroxymethyl)-1 H-quinoxalin-2-one

[0170] A solution of 5-chloro-2-ethyl-3-oxo-4H-quinoxaline-6-carboxylic acid (Intermediate 1) (1.00 g, 4.20 mmol) in DMF (20 mL) was cooled to 0 °C and then sodium hydride (60% in mineral oil, 0.20 g, 5.04 mmol) was added in one portion. The reaction mixture was stirred at 0 °C for 30 min. Then iodomethane (0.30 mL, 4.80 mmol) was added in one portion and the reaction mixture was stirred at 0 °C for 1 h. LCMS indicated complete conversion. The reaction mixture was quenched with 1 mL of water and concentrated. The residue was purified on a silica gel column (eluted with 0 to 50% ethyl acetate in hexanes) to give 5-chloro-2-ethyl-3-oxo-4H-quinoxaline-6-carbaldehyde (Intermediate 2) (0.80 g, 79%) as a yellow solid. 1H NMR (500 MHz, Chloroform-d) 1.22 (3H, t), 2.82 (2H, q), 7.48 (1H, d), 7.68 (1H, d), 8.02 (1H, s); m / z (ES+) [M+H]=220.0. + [M+H] + = 239.

[0171] Intermediate 29: 7-(bromomethyl)-8-chloro-3-ethyl-1 H-quinoxalin-2-one

[0172] A solution of 5-chloro-2-ethyl-3-oxo-4H-quinoxaline-6-carboxylic acid (Intermediate 1) (1.00 g, 4.20 mmol) in DMF (20 mL) was cooled to 0 °C and then sodium hydride (60% in mineral oil, 0.20 g, 5.04 mmol) was added in one portion. The reaction mixture was stirred at 0 °C for 30 min. Then iodomethane (0.30 mL, 4.80 mmol) was added in one portion and the reaction mixture was stirred at 0 °C for 1 h. LCMS indicated complete conversion. The reaction mixture was quenched with 1 mL of water and concentrated. The residue was purified on a silica gel column (eluted with 0 to 50% ethyl acetate in hexanes) to give 5-chloro-2-ethyl-3-oxo-4H-quinoxaline-6-carbaldehyde (Intermediate 2) (0.80 g, 79%) as a yellow solid. 1H NMR (500 MHz, Chloroform-d) 1.22 (3H, t), 2.82 (2H, q), 7.48 (1H, d), 7.68 (1H, d), 8.02 (1H, s); m / z (ES+) [M+H]=220.0. + [M+H] + = 301, 303.

[0173] Example 8: 6-chloro-5-[4-[(5-chloro-2-ethyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]- N-methyl-pyridine-2-carboxamide

[0174] DIPEA (0.058 mL, 0.33 mmol) was added to a stirred suspension of 7- (bromomethyl)-8-chloro-3-ethyl-1H-quinoxalin-2-one (Intermediate 29) (25 mg, 0.08 mmol) and 6-chloro-N-methyl-5-piperazin-1-yl-pyridine-2-carboxamide, 2HCI (Intermediate 30) (27.2 mg, 0.08 mmol) in acetonitrile (4 mL) and the resulting mixture was stirred at 70 °C for 1.5 hours to give a suspension. LCMS indicated complete conversion. The solvent was removed under reduced pressure and an analytical purification group was performed, which upon purification gave 6-chloro-5-[4-[(5-chloro-2-ethyl-3-oxo-4H- quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2-carboxamide (Example 8) as a yellow solid (24.00 mg, 61 %). Purification conditions (non-chiral): Column (Xbridge C18 19mm x 100mm 5μm, Mobile Phase A: H2O with 0.2% NH4OH pH 10, Mobile Phase B: Acetonitrile; Gradient B%: 13%-95% B over 8 minutes; Flow rate: 20 ml / min; Concentration: 35 mg / ml in DMSO; Load (mg / injection): 15; Column temperature: room temperature.1H NMR (500 MHz, DMSO-d6) 1.23 (3H, t), 2.66 (4H, br s), 2.76-2.92 (5H, m), 3.13 (4H, br s), 3.77 (2H, s), 7.44 (1H, d), 7.69 (2H, dd), 7.94 (1H, d), 8.43 (1H, q), 10.75-11.45 (1H, m); m / z (ES+) [M+H] 475.2. + 475.2. + 475.2.

[0175]

[0176] Example 9: 5-[4-[(5-chloro-2-ethyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-6-fluoro- N-methyl-pyridine-2-carboxamide

[0177] DIPEA (0.116 mL, 0.66 mmol) was added to a stirred suspension of 6-fluoro-N- methyl-5-piperazin-1-yl-pyridine-2-carboxamide, 2HCI (Intermediate 32) (51.6 mg, 0.17 mmol) and 7-(bromomethyl)-8-chloro-3-ethylquinoxalin-2(1 H)-one (Intermediate 29) (50 mg, 0.17 mmol) in acetonitrile (4 mL) and the resulting mixture was stirred at 70 °C for 1.5 hours. LCMS indicated complete conversion. The solvent was removed under reduced pressure and the residue was purified on a silica gel column (eluting with 0 to 20% methanol in DCM) to give a mixture of product and PPh3O. The material was submitted for analytical group purification which upon purification gave 5-[4-[(5-chloro-2-ethyl-3-oxo-4H- quinoxalin-6-yl)methyl]piperazin-1-yl]-6-fluoro-N-methyl-pyridine-2-carboxamide (Example 9) as a yellow solid (47.0 mg, 62%). Purification conditions (non-chiral): Column (Xbridge CI 8 19 mm x 100 mm 5 μm, mobile phase A: H2O with 0.2% NH4OH pH 10, mobile phase B: acetonitrile; gradient B%: 13%-95% B over 8 minutes; flow rate: 20 ml / min; concentration: 35 mg / ml in DMSO; loading (mg / injection): 15; column temperature: room temperature.

[0178] 1H NMR (500 MHz, DMSO-c / 6) 1.22 (3H, t), 2.63 (4H, br s), 2.76 (3H, d), 2.82 (2H, q), 3.19 (4H, br s), 3.75 (2H, s), 7.43 (1H, d), 7.52-7.64 (1H, m), 7.70 (1H, d), 7.84 (1H, d), 8.39 (1H, q), 11.17-11.55 (1H, m); m / z (ES + [M+H] + = 459.

[0179]

[0180] Example 10: 5-[4-[(5-chloro-2-ethyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methyl- pyridine-2-carboxamide

[0181] DIPEA (0.081 mL, 0.46 mmol) was added to a stirred suspension of N-methyl-5- (piperazin-1-yl)picolinamide, 2HCI (Intermediate 31) (34.0 mg, 0.12 mmol) and 7- (bromomethyl)-8-chloro-3-ethylquinoxalin-2(1H)-one (Intermediate 29) (35 mg, 0.12 mmol) in acetonitrile (4 mL) and the resulting mixture was stirred at 70 °C for 1.5 hours. LCMS indicated complete conversion. The solvent was removed under reduced pressure and the resulting residue was sent to the analytical group for purification which upon purification gave 5-[4-[(5-chloro-2-ethyl-3-oxo-4H- quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2-carboxamide (Example 10) as a white solid (13.00 mg, 20%). Purification conditions (non-chiral) Column (Xbridge CI 8 19 mm x 100 mm 5 μm, Mobile Phase A: H20 with 0.2% NH4OH pH 10, Mobile Phase B: Acetonitrile; Gradient B% over 8 minutes 13%-95% B; Flow rate: 20 ml / min; Concentration: 35 mg / ml in DMSO; Load (mg / injection): 15; Column temperature: room temperature.1H NMR (500 MHz, DMSO-d6) 1.24 (3H, t), 2.79 (3H, d), 2.86 (2H, q), 3.22-3.37 (8H, m, merged into water peak), 4.39-4.65 (2H, m), 7.46 (1H, dd), 7.57 (1H, br d), 7.79-7.90 (2H, m), 8.32 (1H, d), 8.43 (1H, br d), 11.87-12.21 (1H, m). m / z (ES+) [M+H] = 441. + [M+H] + = 441.

[0182]

[0183] Example 11 : 5-[4-[(5-chloro-2-ethyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N6-dimethyl- pyridine-2-carboxamide

[0184] DIPEA (0.111 mL, 0.64 mmol) was added to a stirred suspension of N,6-dimethyl-5- piperazin-1-yl-pyridine-2-carboxamide, 2HCI (Intermediate 33) (48.9 mg, 0.16 mmol) and 7-(bromomethyl)-8-chloro-3-ethyl-1H-quinoxalin-2-one (Intermediate 29) (48 mg, 0.16 mmol) in acetonitrile (10 mL) and the resulting mixture stirred at 70 °C for 2 hours to give a suspension. LCMS indicated complete conversion. The mixture was cooled to room temperature, the solids collected by filtration, washed with water and dried to give 5-[4-[(5-chloro-2-ethyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N,6-dimethyl- pyridine-2-carboxamide (Example 11) as a white solid (42.0 mg, 58%).1H NMR (500 MHz, DMSO-c / 6) 1.22 (3H, t), 2.65 (4H, br s), 2.78-2.88 (5H, m), 2.95 (4H, br s), 3.38 (3H, s, overlapped with water peak), 3.76 (2H, s), 7.47 (2H, dd), 7.71 (1H, d), 7.79 (1H, d), 8.42 (1H, br d), 11.59-11.99 (1H, m); m / z (ES+) [M+H] 455.3. + [M+H] + 455.3.

[0185]

[0186] Intermediate 35: 1 -bromo-2,4-difluoro-3-nitro-benzene

[0187] A mixture of 1,3-difluoro-2-nitrobenzene (Intermediate 34) (19.5 g, 122.57 mmol) and NBS (26.2 g, 147.08 mmol) in sulfuric acid (150 mL) was stirred at 80 °C overnight. LCMS indicated complete conversion. The mixture was cooled to room temperature and poured slowly onto ice. The mixture was extracted with ethyl acetate (200 ml), the organic layer was washed with water (50 ml x 2), saturated NaHC03solution (50 ml x 2), brine, dried (anhydrous Na2S04), filtered and concentrated. The residue was purified on a silica gel column (eluted with 0 to 20% ethyl acetate in hexane) to give 1-bromo-2,4-difluoro-3-nitro-benzene (Intermediate 35) as a light yellow oil (26.8 g, 92%).1H NMR (500 MHz, DMSO-c / 6) 7.42-7.73 (1H, m), 8.06-8.26 (1H, m); m / z (ES+) [M+H] 238.0. + [M+H] + 238.0.

[0188] Intermediate 36: methyl 2-(4-bromo-3-fluoro-2-nitro-anilino)-3-hydroxy-butanoate

[0189] DIPEA (8.56 mL, 48.99 mmol) was added slowly to a stirred solution of 1-bromo-2,4- difluoro-3-nitro-benzene (Intermediate 35) (5.3 g, 22.27 mmol) and methyl 2-amino-3- hydroxybutanoate HC1 (4.53 g, 26.72 mmol) in 1,4-dioxane (50 mL) at room temperature and the resulting mixture was stirred at 40 °C for 3 h. LCMS indicated some starting material remained. To the mixture was added 800 mg of DL-threonine methyl ester HC1 salt and the mixture was continued to stir at 40 °C overnight. The solvent was removed under reduced pressure and the residue was purified on a silica gel column (eluting with 0 to 30% ethyl acetate in hexanes) to give methyl 2-(4-bromo-3-fluoro-2-nitro- phenylamino)-3-hydroxy-butanoate (Intermediate 36) (4.69 g, 60%) as a bright orange solid. (HNMR indicated it was a mixture of diastereomers).1H NMR (500 MHz, chloroform-d) 1.30 - 1.44 (3H, m), 3.81 (3H, s), 4.00 - 4.22 (1H, m), 4.22 - 4.48 (1H, m), 6.32 - 6.68 (1H, m), 7.40 - 7.66 (2H, m); m / z (ES+) [M+H] 351, 353. + [M+H] + = 351, 353.

[0190] Intermediate 37: methyl 2-(4-bromo-3-fluoro-2-nitro-anilino)-3-fluoro-butanoate

[0191] DAST (0.919 mL, 6.95 mmol) was added slowly to a mixture of 2-(4-bromo-3- fluoro-2-nitro-anilino)-3-hydroxy-butyric acid methyl ester (Intermediate 36) (2.22 g, 6.32 mmol) in CH2Cl2(40 mL) at 0 °C over 10 minutes and the mixture was stirred at 0 °C for 20 minutes. LCMS and TLC showed starting material remaining. To the mixture was added 0.4 ml DAST and the reaction was stirred for a further 10 minutes. The mixture was quenched with saturated NaHCO3solution and extracted with DCM. The organic layer was dried (Na2SO4, anhydrous), filtered and concentrated to give a yellow oil. The resulting residue was purified on a silica gel column (eluting with 0 to 30% ethyl acetate in hexanes) to give peak 2 as 2-(4-bromo-3-fluoro-2-nitro-anilino)-3-fluoro-butyric acid methyl ester (1.110 g, 50%) (Intermediate 37) as a yellow oil and peak 4 as starting material 2-((4-bromo-3-fluoro-2-nitrophenyl)amino)-3-hydroxybutyric acid methyl ester (0.300 g, 13%) along with other by-products.1H NMR (500 MHz, Chloroform-d) 1.37-1.51 (3H, m), 2.80-2.93 (0.5H, m), 3.00 (0.5H, br d), 3.75 (1.5H, s), 3.85 (1.5H, s), 4.40-4.56 (0.5H, m), 5.01-5.23 (0.5H, m), 6.43-6.58 (0.5H, m), 6.71-6.74 (0.5H, m), 7.38-7.69 (2H, m). m / z (ES+) [M+H] 353.0. + [M+H] + = 353.

[0192] Intermediate 38: 7-bromo-8-fluoro-3-(1 -fluoroethyl)-3,4-dihydro-1 H-quinoxalin-2-one

[0193] To a mixture of 2-(4-bromo-3-fluoro-2-nitro-anilino)-3-fluoro-butyric acid methyl ester (Intermediate 37) (1.11 g, 3.14 mmol), zinc (2.466 g, 37.72 mmol) and ammonium chloride (3.36 g, 62.87 mmol) in MeOH (20 mL) was added water (2 mL) and the mixture was stirred at room temperature for 10 minutes. The orange colour disappeared (exothermic) and LCMS showed complete conversion. The mixture was filtered, the solid was washed with methanol and the filtrate was concentrated. The resulting residue was dissolved in DCM, the organic layer was washed with water, dried (Na2SO4, anhydrous), filtered and concentrated to give the crude product. The residue was purified on a silica gel column (0 to 30% ethyl acetate in hexanes) to give 2-((2-amino-4-bromo-3-fluorophenyl)amino)-3-fluorobutyric acid methyl ester as a light yellow solid (0.533 g, 52%).

[0194] The above yellow solid was dissolved in 15 ml of methanol, 0.51 M HC1 in methanol was added and the reaction was stirred at room temperature for 4 hours. LCMS indicated complete conversion. The solvent was removed and the residue was diluted with DCM / methanol (5:1). The organic layer was washed once with 50% NaHC03solution, dried (anhydrous Na2S04) and concentrated. The residue was purified on a silica gel column (eluted with 0 to 31% ethyl acetate in hexanes) to give 7-bromo-8-fluoro-3-(1-fluoroethyl)-3,4-dihydro-1 H- quinoxalin-2-one (Intermediate 38) as a white solid (0.337 g, 37%).1H NMR (500 MHz, Methanol-d4) 1.27-1.46 (3H, m), 4.26 (1H, dd), 4.90-5.12 (1H, m), 6.50 (1H, dd), 6.97 (1H, dd). m / z (ES+) [M+H] = 291, 293. + [M+H] + = 291, 293.

[0195] Intermediate 39: 7-bromo-8-fluoro-3-(1 -fluoroethyl)-1 H-quinoxalin-2-one

[0196] DDQ (289 mg, 1.27 mmol) was added to a slurry of 7-bromo-8-fluoro-3-(1-fluoroethyl)-3,4-dihydro-1 H- quinoxalin-2-one (Intermediate 38) (337 mg, 1.16 mmol) in CH2CI2(10 mL) and the mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure, the residue was diluted with saturated NaHC03solution (about 20 ml) and the suspension was stirred at room temperature for 3 hours. The solid was collected by filtration, washed with water and dried to give 7-bromo-8-fluoro-3-(1-fluoroethyl)-1 H- quinoxalin-2-one (Intermediate 39) as a white solid (333 mg, 100%).1H NMR (500 MHz, Methanol-d4) 1.65-1.84 (3H, m), 5.87-6.18 (1H, m), 7.50-7.60 (1H, m), 7.61-7.78 (1H, m). m / z (ES+) [M+H] = 289, 291. + [M+H] + = 289, 291.

[0197] Intermediate 40: 8-fluoro-3-(1 -fluoroethyl)-7-(hydroxymethyl)-1 H-quinoxalin-2-one

[0198] Pd-PEPPSI TMA mixture of IPent catalyst (26 mg, 0.03 mmol), (tributylstannyl)methanol (1638 mg, 5.10 mmol) and 7-bromo-8-fluoro-3-(l-fluoroethyl)-lH-quinoxalin-2-one (intermediate 39) (590 mg, 2.04 mmol) in 1,4-dioxane (25 mL) was degassed, backfilled with N2and the mixture stirred at 80 °C for 17 h. The mixture was concentrated and the residue purified on a silica gel column eluting with 0 to 50% ethyl acetate in hexanes (to recover remaining SM) then 0 to 20% methanol in DCM to give 8-fluoro-3-(l-fluoroethyl)-7-(hydroxymethyl)-lH-quinoxalin-2-one (intermediate 40) (282 mg, 57%).1H NMR (500 MHz, DMSO-d6) 1.58-1.81 (3H, m), 4.67 (2H, br d), 5.46 (1H, br t), 5.87-6.24 (1H, m), 7.33-7.48 (1H, m), 7.65 (1H, br d), 12.65-12.83 (1H, m); m / z (ES+) [M+H] 241.0. + [M+H] + = 241.

[0199] Intermediate 41 : 7-(bromomethyl)-8-fluoro-3-(1 -fluoroethyl)-1 H-quinoxalin-2-one

[0200] A suspension of triphenylphosphine (1223 mg, 4.66 mmol) and 8-fluoro-3-(l- fluoroethyl)-7-(hydroxymethyl)-lH-quinoxalin-2-one (280 mg, 1.17 mmol) (intermediate 40) in CH2CI2(15 mL) was cooled to 0 °C, carbon tetrabromide (1546 mg, 4.66 mmol) was added and the mixture immediately turned clear purple, the mixture was stirred at this temperature for a further 10 min, the mixture turned to a yellow solution, which indicated complete conversion by LCMS check (not very clean), the mixture was concentrated and purified on a silica gel column eluting with 0 to 20% methanol in DCM to give the main peak as 7-(bromomethyl)-8-fluoro-3-(l-fluoroethyl)-lH-quinoxalin-2-one (intermediate 41) which was contaminated with some impurities. Concentration gave 2.5 g of solid (theoretical mass 353 mg assuming 100% yield available for next step). m / z (ES+) [M+H] 303, 305. + [M+H] + = 303, 305.

[0201] Example 12 and Example 13: 6-fluoro-5-[4-[[5-fluoro-2-[(1 S and 1 R)-1 -fluoroethyl]-3-oxo-4H- quinoxalin-6-yl]methyl]piperazin-1 -yl]-N-methyl-pyridine-2-carboxamide Example 14 and Example 15: 5-[4-[[5-fluoro-2-[(1 S and 1 R)-1 -fluoroethyl]-3-oxo-4H-quinoxalin-6- yl]methyl]piperazin-1 -yl]-N,6-dimethyl-pyridine-2-carboxamide

[0202] DIPEA (0.265 mL, 1.52 mmol) was added to a mixture of 7-(bromomethyl)-8- fluoro-3-(1-fluoroethyl)-1H-quinoxalin-2-one (Intermediate 41) (115 mg, 0.38 mmol) and 6-fluoro-N-methyl-5-(piperazin-1-yl)picolinamide, 2HCI (94 mg, 0.30 mmol) (Intermediate 32) in acetonitrile (20 mL) and the resulting mixture was stirred at 70 °C for 1 hour. LCMS indicated complete conversion. The mixture was concentrated, the residue was dissolved in DMSO (~4 ml) and purified on a C18 reverse phase column (eluted with 0 to 100% ACN / water / 0.1% TFA). Fractions containing product were combined and lyophilized. The material was re-purified on a Gilson (eluted with 0 to 80% ACN / water / 0.1% TFA) to give the product 6-fluoro-5-[4-[[5-fluoro-2-[(1S and 1R)-1-fluoroethyl]-3-oxo-4H- quinoxalin-6-yl]methyl]piperazin-1-yl]-N-methyl-pyridine-2-carboxamide. The enantiomers were separated by chiral column. Chiral purification conditions: Column info: chiralpak OD 4.6 mm x 100 mm 5 μm, mobile phase A: CO2 (100%), mobile phase B: methanol with 0.2% NH4OH, isocratic 25% B over 6 min, flow rate: 4.0 ml / min, diluent: methanol, column temperature: room temperature, outlet pressure (SFC): N / A.

[0203] Peak 1 : The white solid was diluted with water and ACN. 0.1 mL of 0.5 M aqueous HC1 was added and the mixture was lyophilized to give isomer 1, 6-fluoro-5-[4-[[5-fluoro-2-[(1S or 1R)-1-fluoroethyl]-3-oxo-4H-quinoxalin-6-yl]methyl]piperazin-1-yl]-N-methyl-pyridine-2-carboxamide (Example 12, absolute stereochemistry not determined) (5.42 mg, 10.90 μmol, 3%) as the HC1 salt as a yellow solid.1H NMR (500 MHz, DMSO-d6) 1.54 - 1.73 (3H, m), 2.70 - 2.87 (3H, m), 3.53 - 3.90 (8H, m), 4.57 (2H, br s), 5.79 - 6.21 (1H, m), 7.59 - 7.81 (3H, m), 7.87 (1H, d), 8.43 (1H, br d), 11.40 - 11.85 (1H, m), 12.78 - 13.14 (1H, m); m / z (ES+) [M+H] 461, >95% ee. + [M+H] + = 461, >95% ee.

[0204] Peak 2: Dilute the white solid with water and ACN. Add 0.1 mL of 0.5 M aqueous HC1 and lyophilize the mixture to give isomer 2,6-fluoro-5-[4-[[5-fluoro-2-[(1S or 1R)-1- fluoroethyl]-3-oxo-4H-quinoxalin-6-yl]methyl]piperazin-1-yl]-N-methyl-pyridine-2- carboxamide as the HC1 salt (Example 13, absolute stereochemistry not determined).1H NMR (500 MHz, DMSO-d6) 1.49-1.83 (3H, m), 2.77 (3H, br d), 3.46-3.91 (8H, m), 4.56 (2H, br s), 5.80-6.26 (1H, m), 7.52-7.80 (3H, m), 7.87 (1H, br d), 8.43 (1H, br d), 11.44-11.82 (1H, m), 12.77-13.24 (1H, m); m / z (ES+) 461, >95% ee. + [M+H] + = 461, >95% ee.

[0205]

[0206] Intermediate 43: methyl 2-(4-bromo-3-chloro-2-nitro-anilino)propanoate Intermediate 44: 7-bromo-8-chloro-3-methyl-3,4-dihydro-1 H-quinoxalin-2-one

[0207] To a suspension of 7-(bromomethyl)-8-fluoro-3-(1-fluoroethyl)quinoxalin-2(1H)-one (Intermediate 41) (138 mg, 0.41 mmol) and N,6-dimethyl-5-(piperazin-1-yl)picolinamide, 2HC1 (126 mg, 0.41 mmol) (Intermediate 33) in acetonitrile (13 mL) was added DIPEA (429 μΐ, 2.46 mmol) and the resulting mixture was stirred at 70 °C for 3 hours. LCMS indicated complete conversion. The reaction was concentrated and the residue was purified on a silica gel column (eluting with 0 to 20% methanol in DCM) to give racemic product 5-[4-[[5-fluoro-2-[(1S / 1R)-1-fluoroethyl]-3-oxo-4H-quinoxalin-6-yl]methyl]piperazin-1-yl]-N,6-dimethyl-pyridine-2-carboxamide as a light yellow solid (169 mg). The enantiomers were separated by chiral separation. Chiral purification conditions: Column info: chiralpak OD 21.2 mm x 250 mm 5 μm, mobile phase A: CO2 (100%), mobile phase B: methanol with 0.2% NH4OH, isocratic: 25% B in 12 min, flow rate: 70.0 ml / min, concentration: 8.45 mg / ml solution in methanol, loading: 4.23 mg / injection, column temperature: room temperature, outlet pressure (SFC): N / A.

[0208] After chiral separation, each isomer was further purified on a reverse phase column (eluting with 0-60% ACN / water / 0.2% ammonium hydroxide) to give;

[0209] Peak 1 : 5-[4-[[5-fluoro-2-[(1 S or 1 R)-1 -fluoroethyl]-3-oxo-4H-quinoxalin-6- yl]methyl]piperazin-1 -yl]-N,6-dimethyl-pyridine-2-carboxamide, Isomer 1 (Example 14, absolute stereochemistry not determined) as a white solid (30.7 mg, 0.067 mmol, 16%).1H NMR (500 MHz, DMSO-d6) 1.40-1.70 (3H, m), 2.48 (3H, s), 2.54-2.69 (4H, m), 2.79 (3H, d), 2.94 (4H, br s), 3.74 (2H, s), 5.83-6.22 (1 H, m), 7.17-7.41 (1 H, m), 7.47 (1 H, d), 7.65 (1 H, d), 7.78 (1 H, d), 8.40 (1 H, br d), 1 1.65-12.88 (1 H, m); m / z (ES+) [M+H] 457.2; >98% ee. + [M+H] + = 457; >98% ee.

[0210] Peak 2: 5-[4-[[5-fluoro-2-[(1 S or 1 R)-1 -fluoroethyl]-3-oxo-4H-quinoxalin-6- yl]methyl]piperazin-1 -yl]-N,6-dimethyl-pyridine-2-carboxamide, Isomer 2 (Example 15, absolute stereochemistry not determined) as a white solid (37 mg, 0.081 mmol, 20%).1H NMR (500 MHz, Chloroform-d) 1.68-1.88 (3H, m), 2.51 (3H, s), 2.71 (4H, br s), 2.86-3.12 (7H, m), 3.81 (2H, s), 5.92-6.29 (1 H, m), 7.34 (1 H, d), 7.44 (1 H, t), 7.76 (1 H, d), 7.95 (1 H, br d), 7.99 (1 H, d), 10.24 (1 H, br s); m / z (ES+) [M+H] 457.2; 94.5% ee. + [M+H] + = 457; 94.5% ee.

[0211]

[0212] Intermediate 45: 7-bromo-8-chloro-3-methyl-1 H-quinoxalin-2-one

[0213] A flask was charged with alanine methyl ester, HC1 (Intermediate 42) (1.851 g, 13.26 mmol) and 1-bromo-2-chloro-4-fluoro-3-nitrobenzene (Intermediate 22) (2.25 g, 8.84 mmol) in 1,4-dioxane (70 mL). DIPEA (9.27 mL, 53.06 mmol) was added and the mixture was stirred at 105 °C for 24 h to give a brown solution. LCMS showed the reaction was complete. The mixture was concentrated and the residue was purified on a silica gel column (eluted with 0 to 30% ethyl acetate in hexanes) to give 2-(4-bromo-3-chloro-2-nitro-anilino)propanoic acid methyl ester (Intermediate 43) (2.120 g, 71%) as a bright yellow oil which turned to yellow solid upon standing.1H NMR (500 MHz, Chloroform-d) 1.52 (3H, d), 3.77 (3H, s), 6.53 (1H, d), 7.15 (1H, t), 7.53 (1H, d), 7.78 (1H, dd); m / z (ES+) [M+H] = 337. + [ M + H ] + = 337.

[0214] ​

[0215] Sodium hydrosulfite (3.28 g, 18.84 mmol) was added to a stirred solution of 2-(4-bromo-3-chloro-2-nitro-anilino)propanoic acid methyl ester (Intermediate 43) (2.12 g, 6.28 mmol) in DMSO (50 mL) and the mixture was stirred at 120 °C for 5 h. LCMS and TLC indicated complete conversion. The mixture was quenched with water and extracted with ethyl acetate (50 ml x 2). The organic layer was dried (Na2S04), filtered, concentrated and the residue was purified on a silica gel column (0 to 55% ethyl acetate in hexanes) to give 7-bromo-8-chloro-3-methyl-1H-quinoxalin-2-one (Intermediate 45) (0.055 g, 3%) and 7-bromo-8-chloro-3-methyl-3,4-dihydro-1H-quinoxalin-2-one (Intermediate 44) (0.190 g, 11%). m / z (ES+) [M+H] = 273, 275 and 275, 277. + [ M + H ] + = 275, 277.

[0216] ​

[0217] DDQ (157 mg, 0.69 mmol) was added to a mixture of 7-bromo-8-chloro-3-methyl-3,4- dihydro-1H-quinoxalin-2-one (Intermediate 44) (190 mg, 0.69 mmol) in 1,4-dioxane (10 mL) and the resulting mixture was stirred at room temperature overnight, LCMS indicated complete conversion. The mixture was concentrated and the residue was treated with saturated NaHC03solution. The mixture was stirred at room temperature for 4, the solid was isolated by filtration, washed with saturated NaHC03solution and water. The solid was then purified on a silica gel column (eluted with 0 to 20% methanol in DCM) to give 7-bromo-8-chloro-3-methyl-1H-quinoxalin-2-one (Intermediate 45) as a yellow solid (122 mg, 65%). m / z (ES+) [M+H] = 273, 275. + [M+H] + = 273, 275.

[0218] INTERMEDIATE 46: 8-Chloro-3-methyl-7-vinyl-lH-quinoxalin-2-one

[0219] A mixture of 7-bromo-8-chloro-3-methyl-1H-quinoxalin-2-one (Intermediate 45) (122 mg, 0.45 mmol), tetrakis(triphenylphosphine)palladium(0) (51.5 mgs, 0.04 mmol) and tributyl(vinyl)stannane (212 mg, 0.67 mmol) in toluene (15 ml) was stirred at 110 °C under N2for 16 hours. LCMS indicated the reaction was complete. The mixture was concentrated and the residue was purified on a silica gel column (eluted with 0 to 16% methanol in DCM) to give 8-chloro-3-methyl-7-vinyl-1H-quinoxalin-2-one (Intermediate 46) as a brown solid (98 mg, 100%). (contaminated with PPh30). m / z (ES+) [M+H] = 221. + [M+H] + = 221.

[0220] INTERMEDIATE 47: 5-Chloro-2-methyl-3-oxo-4H-quinoxalin-6-carboxaldehyde

[0221] Sodium periodate (543 mg, 2.54 mmol) was added to a solution of 8-chloro-3-methyl-7-vinyl-1 H- quinoxalin-2-one (140 mg, 0.63 mmol) (Intermediate 46), 2,6-dimethylpyridine (0.148 ml, 1.27 mmol) and sodium periodate (543 mg, 2.54 mmol) in THF (10 mL) / water (2 mL) / tert-butanol (0.607 mL, 6.34 mmol) and stirred at room temperature overnight to give a yellow suspension. LCMS and TLC indicated that there was still starting material remaining. To the mixture was added THF (10 ml) / water (2.000 ml), 200 mg sodium periodate, 0.3 ml osmium tetroxide and the mixture was continued to stir at room temperature for 5 hours. LCMS indicated complete conversion. The reaction was diluted with water, saturated NH4CI solution was added and extracted with DCM. The combined organic layers were dried (Na2S04), filtered and concentrated. The residue was purified on a silica gel column (eluted with 0 to 20% methanol in DCM) to give 5-chloro-2-methyl-3-oxo-4H-quinoxalin-6-carbaldehyde (Intermediate 47) as a yellow solid (141 mg, 100%). (Not very pure, carry on to next step). m / z (ES+) [M+H] = 223. + + = 223.

[0222] INTERMEDIATE 48: 8-Chloro-7-(hydroxymethyl)-3-methyl-lH-quinoxalin-2-one

[0223] Sodium borohydride (23.96 mg, 0.63 mmol) was added to a cooled solution of 5-chloro-2-methyl-3-oxo-4H-quinoxalin-6-carbaldehyde (Intermediate 47) (141 mg, 0.63 mmol) in a mixture of MeOH (16 mL) and DCM (8.00 mL) cooled to 0 °C and the mixture was continued to stir at 0 °C for 1 hour. LCMS indicated complete conversion. To the mixture was added 1 ml water, concentrated, the residue was purified on a silica gel column (eluted with 40 to 100% ethyl acetate in hexane; then 0 to 20% methanol in DCM) to give 8-chloro-7-(hydroxymethyl)-3-methyl-1 H-quinoxalin-2-one (Intermediate 48) as a yellow solid (142 mg, 100%);1H NMR (500 MHz, DMSO-d6) 2.42 (3H, s), 4.65 (2H, br d), 5.53 (1H, br t), 7.46 (1H, br d), 7.69 (1H, br d), 11.77 (1H, br s); m / z (ES+) [M+H] = 225. + = 225.

[0224] INTERMEDIATE 49: 7-(Bromomethyl)-8-chloro-3-methyl-lH-quinoxalin-2-one

[0225] ​Cool 8-chloro-7-(hydroxymethyl)-3-methyl-1H-quinoxalin-2-one (Intermediate 48) (142 mg, 0.63 mmol) and triphenylphosphine (332 mg, 1.26 mmol) in CH2Cl2(20 ml) to 0 °C. Add perbromo methane (419 mg, 1.26 mmol) in one portion and stir the mixture at 0 °C for 1 hour and at room temperature for 2 hours. LCMS indicates no progress. Add a second portion of triphenylphosphine (332 mg, 1.26 mmol) and perbromo methane (419 mg, 1.26 mmol) to the mixture at room temperature and stir the mixture for 1 hour. LCMS indicates complete conversion. Remove the solvent under reduced pressure and purify the residue on a silica gel column (eluting with 0 to 100% ethyl acetate in hexanes) to give the product 7-(bromomethyl)-8-chloro-3-methyl-1H-quinoxalin-2-one (Intermediate 49) (32 mg, 18%) as a yellow solid. Further elution with 20% methanol in DCM gives a second portion of 100 mg (55%) of the product (47% purity) as a brown solid. m / z (ES+) 287, 289.1H NMR (400 MHz, DMSO-d6) δ 8.62 (s, 1H), 7.87 (s, 1H), 4.62 (s, 2H), 3.89 (s, 3H), 3.62 (s, 2H). + [M+H] + = 287, 289.

[0226] Example 16: 5-[4-[(5-Chloro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin- 1-yl]-N-methyl-pyridine-2-carboxamide Example 17: 5-[4-[(5-Chloro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin- 1-yl]-6-fluoro-N-methyl-pyridine-2-carboxamide

[0227] DIPEA (0.053 mL, 0.31 mmol) was added to a mixture of N-methyl-5-(piperazin-l- yl)picolinamide, 2HCI (22.43 mg, 0.08 mmol) (Intermediate 31) and 7-(bromomethyl)-8- chloro-3-methyl-lH-quinoxalin-2-one (Intermediate 49) (22 mg, 0.08 mmol) in acetonitrile (4 mL) and the resulting suspension stirred at 70 °C for 1 hour. LCMS indicated complete conversion. The mixture was concentrated, the residue dissolved in DMSO and purified on a reverse phase C18 column (eluting with 0 to 100% ACN / water / 0.1% TFA). Fractions containing pure product were lyophilized to give 5-[4-[(5-chloro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-l-yl]-N- methyl-pyridine-2-carboxamide (20 mg, 56%). 1 mL of 2M HCI in ether was added, the solvent removed in vacuo to give the corresponding HCI salt as a yellow solid (Example 16).1H NMR (500 MHz, Methanol-d4) 2.96 - 3.03 (3H, m), 3.48 - 3.86 (6H, m), 4.04 - 4.41 (2H, m), 4.78 (2H, s), 4.86 (3H, d, merged into water peak), 7.74 (1H, d), 7.84 (1H, d), 8.14 (1H, dd), 8.31 (1H, d), 8.47 (1H, d); m / z (ES+) [M+H] 427.2. + [ M + H ] + = 427.

[0228]

[0229] Example 18: 5-[4-[(5-Chloro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin- 1-yl]-N6-dimethyl-pyridine-2-carboxamide INTERMEDIATE 50: 7-Bromo-8-fluoro-3-(l-hydroxyethyl)-3,4-dihydro-lH- quinoxalin-2-one

[0230] DIPEA (0.061 mL, 0.35 mmol) was added to a mixture of 6-fluoro-N-methyl-5- (piperazin-l-yl)picolinamide, 2HCI (Intermediate 32) (27.1 mg, 0.09 mmol) and 7- (bromomethyl)-8-chloro-3-methyl-lH-quinoxalin-2-one (Intermediate 49) (50 mg, 0.09 mmol) (about 50% purity) in acetonitrile (5 mL) and the resulting solution was stirred at 70 °C for 1 hour. LCMS indicated complete conversion. The mixture was concentrated, the residue was dissolved in DMSO and purified on a reverse phase C18 column (eluted with 0 to 100% ACN / water / 0.1% TFA) then purified a second time on a reverse phase C18 column (eluted with 0 to 100% ACN / water / 0.1% TFA). The material was finally purified a third time on a reverse phase column (eluted with 0 to 100% ACN / water / ammonium hydroxide, pH ~ 10) to give 5-[4-[(5-chloro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-l-yl]-6- fluoro-N-methyl-pyridine-2-carboxamide (Example 17) as a white solid (16.50 mg, 43%).1H NMR (500 MHz, DMSO-d6) 2.37-2.47 (3H, m), 2.63 (4H, br s), 2.76 (3H, d), 3.13-3.23 (4H, m), 3.74 (2H, s), 7.45 (IH, d), 7.57 (IH, dd), 7.68 (IH, d), 7.84 (IH, d), 8.39 (IH, br d), 10.71-12.11 (IH, m); m / z (ES+) [M+H] 445.2. + 445.2. + 445.2.

[0231]

[0232] INTERMEDIATE 51: 7-Bromo-8-fluoro-3-(l-hydroxyethyl)-lH-quinoxalin-2-one INTERMEDIATE 52: 3-Acetyl-7-bromo-8-fluoro-lH-quinoxalin-2-one

[0233] DIPEA (0.061 mL, 0.35 mmol) was added to a mixture of N,6-dimethyl-5-(piperazin- 1-yl)picolinamide, 2HCI (Intermediate 33) (26.7 mg, 0.09 mmol) and 7-(bromomethyl)-8- chloro-3-methyl-lH-quinoxalin-2-one (50 mg, 0.09 mmol) (Intermediate 49, -50% purity) in acetonitrile (5 mL) and the resulting solution was stirred at 70 °C for 1 h. LCMS indicated complete conversion. The mixture was concentrated, the residue was dissolved in DMSO and the residue was purified on a reverse phase C18 column (eluted with 0 to 100% ACN / water / 0.1% TFA). After concentration of fractions, the residue was purified again on a reverse phase C18 column (eluted with 0 to 100% ACN / water / ammonium hydroxide, pH ~10). The pure fractions were lyophilized to dryness to give 5-[4-[(5-chloro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-l-yl]-N,6-dimethyl- pyridine-2-carboxamide (Example 18) as a free base (18.4 mg, 48%). 1H NMR (500 MHz, Methanol-d4) 2.53 (6H, d), 2.76 (4H, br s), 2.94 (3H, s), 3.04 (4H, br t), 3.86 (2H, s), 7.48 (1H, d), 7.51-7.60 (1H, m), 7.69 (1H, d), 7.86 (1H, d); m / z (ES+) [M+H] 441.2. + [M+H] + = 441.

[0234]

[0235] INTERMEDIATE 53: 7-Bromo-3-(l,l-difluoroethyl)-8-fluoro-lH-quinoxalin-2-one

[0236] Ammonium chloride (6.70 g, 125.31 mmol) was added to a suspension of methyl 2-((4-bromo-3-fluoro-2-nitrophenyl)amino)-3-hydroxybutanoate (Intermediate 36) (4.4 g, 12.53 mmol) and zinc (8.19 g, 125.31 mmol) in MeOH (65 mL) at 0 °C. To this was added water (2 mL) and the mixture was stirred at 0 °C for 60 min. Disappearance of orange color indicated complete conversion, LCMS indicated completion of reaction. The mixture was filtered, washed with methanol and the filtrate was concentrated. The residue was diluted with ethyl acetate / methanol (10 / 1), the organic layer was washed with water (-20 ml), brine, dried (anhydrous Na2SO4) and concentrated to give methyl 2-((2-amino-4-bromo-3-fluorophenyl)amino)-3-hydroxybutanoate.

[0237] The above solid was slurried in methanol (about 30 ml), added a solution of 4M HCI in dioxane (about 1 ml) and the mixture stirred at room temperature for 2 hours. LCMS indicated complete conversion. The mixture was concentrated and the residue purified on a silica gel column (eluting with 0 to 100% ethyl acetate in hexane) to give 7-bromo-8-fluoro-3-(1 -hydroxyethyl)-3,4-dihydro-1 H-quinoxalin-2-one (Intermediate 50) as a yellow solid (3.20 g, 88%). (mixture of diastereomers). m / z (ES+) [M+H] = 287, 289. + [M+H] + = 287, 289.

[0238] INTERMEDIATE 54: 3-(l,l-Difluoroethyl)-8-fluoro-7-(hydroxymethyl)-lH-quinoxalin- 2-one

[0239] DDQ (432 mg, 1.90 mmol) was added to a suspension of 7-bromo-8-fluoro-3-(1- hydroxyethyl)-3,4-dihydro-1 H-quinoxalin-2-one (Intermediate 50) (500 mg, 1.73 mmol) in CH2CI2(30 mL) and the mixture stirred at room temperature overnight. LCMS indicated complete conversion. The solvent was removed under reduced pressure, a saturated NaHC03solution (about 100 ml) was added and the mixture stirred at room temperature for 3 hours. The solid was collected by filtration, washed with water and dried to give 7-bromo-8-fluoro-3-(1 -hydroxyethyl)-1 H-quinoxalin-2-one (Intermediate 51) (439 mg, 88%).1H NMR (500 MHz, DMSO-d6) 1.39 (3H, d), 4.78 - 5.31 (2H, m), 7.39 - 7.71 (2H, m), 12.72 (1 H, br s); m / z (ES+) [M+H] = 287, 289. + [M+H] + = 287, 289.

[0240] INTERMEDIATE 55: 7-(Bromomethyl)-3-(l,l-difluoroethyl)-8-fluoro-lH-quinoxalin- 2-one

[0241] A solution of DMSO (0.651 mL, 9.17 mmol) in DCM was added dropwise to a stirred solution of oxalyl chloride (3.06 mL, 6.12 mmol) (2M in DCM) in dichloromethane (20 ml) at -78°C. A solution of 7-bromo-8-fluoro-3-(1 -hydroxyethyl)- 1 H-quinoxalin-2-one (Intermediate 51) (439 mg, 1.53 mmol) was added slowly to the above reaction mixture and the resulting slurry was stirred at -78°C for 15 minutes. Triethylamine (1.279 mL, 9.17 mmol) was added dropwise and the resulting slurry was stirred at 0°C for a further 30 minutes. LCMS indicated formation of the desired product. Water (30 ml) was added and the mixture was extracted with dichloromethane / MeOH (5:1) (2 x 50 ml). The organic phases were combined and dried over magnesium sulfate. The solvent was removed in vacuo and the residue was purified by reverse phase C18 column (eluted with 0 to 100% ACN / water / 0.1% TFA) to give 3-acetyl-7-bromo-8-fluoro- 1 H-quinoxalin-2-one (Intermediate 52) as a yellow solid (85 mg, 19%).1H NMR (500 MHz, DMSO-d6) 2.52-2.66 (3H, m), 7.42-7.76 (2H, m), 13.03 (1H, br s). m / z (ES+) [M+H] = 285, 287. + [M+H] + = 285, 287.

[0242] Example 19: 5-[4-[[2-(l,l-Difluoroethyl)-5-fluoro-3-oxo-4H-quinoxalin-6-yl]methyl] piperazin- 1-yl]-N,6-trimethyl-pyridine-2-carboxamide

[0243] DAST (0.148 mL, 1.12 mmol) was added to a suspension of 3-acetyl-7-bromo-8-fluoro- 1 H-quinoxalin-2-one (Intermediate 52) (80 mg, 0.28 mmol) in CH2Cl2(20 mL) at room temperature and the resulting suspension was stirred at room temperature for 24 hours. LCMS showed 42% product formation. The mixture was left to stir over the weekend. Water was added to the mixture and extracted with DCM. The organic layer was dried (Na2SO4), filtered and concentrated. The residue was purified on a silica gel column (eluted with 0 to 20% methanol in DCM) to give 7-bromo-3-(1,1 - difluoroethyl)-8-fluoro- 1 H-quinoxalin-2-one (Intermediate 53) as a light yellow solid (65.0 mg, 75%). m / z (ES+) [M+H] = 307, 309. (Material not very pure, proceed to next step). + [M+H] + = 307, 309. (Material not very pure, proceed to next step).

[0244] INTERMEDIATE 56: Methyl 2-(4-bromo-3-fluoro-2-nitro-anilino)propanoate

[0245] A mixture of (tributylstannyl)methanol (102 mg, 0.32 mmol), Xphos Pd G2 (24.98 mg, 0.03 mmol) and 7-bromo-3-(1,1 -difluoroethyl)-8-fluoro-1 H- quinoxalin-2-one (Intermediate 53) (65 mg, 0.21 mmol) in 1,4-dioxane (10 mL) was stirred at 80 °C under N2atmosphere for 6 h. LCMS indicated complete conversion. The solvent was removed in vacuo and the residue was purified on a silica gel column (eluted with 0 to 20% methanol in DCM) to give 3-(1,1 -difluoroethyl)-8-fluoro-7-(hydroxymethyl)- 1 H-quinoxalin-2-one (Intermediate 54) (55.0 mg, 100%) as a brown solid. m / z (ES+) [M+H] 259.0 Rf= 0.23 (9:1 dichloromethane:methanol). + [M+H] + = 259.

[0246] INTERMEDIATE 57: 7-Bromo-8-fluoro-3-methyl-3,4-dihydro-lH-quinoxalin-2-one

[0247] CBr4(129 mg, 0.39 mmol) was added to a mixture of 3-(1,1 -difluoroethyl)-8-fluoro-7- (hydroxymethyl)-1 H-quinoxalin-2-one (Intermediate 54) (67 mg, 0.26 mmol) and triphenylphosphine (102 mg, 0.39 mmol) in CH2CI2(6 mL) at 0 °C and the resulting mixture was stirred at room temperature overnight. LCMS indicated complete conversion. The solvent was removed in vacuo and the residue was purified on a silica gel column (eluted with 0 to 100% ethyl acetate in hexane) to give 7-(bromomethyl)-3-(1,1 -difluoroethyl)-8-fluoro-1 H-quinoxalin-2-one (Intermediate 55) (56.0 mg, 67%) as a white solid. m / z (ES+) [M+H] 321, 323. + [M+H] + = 321, 323.

[0248] INTERMEDIATE 58: 7-Bromo-8-fluoro-3-methyl-lH-quinoxalin-2-one INTERMEDIATE 17: 8-Fluoro-7-(hydroxymethyl)-3-methyl-lH-quinoxalin-2-one

[0249] To a suspension of 7-(bromomethyl)-3-(l,l-difluoroethyl)-8-fluoro-lH-quinoxalin-2- one (Intermediate 55) (56 mg, 0.16 mmol) and N,6-dimethyl-5-(piperazin-l-yl)picolinamide, 2HCI (Intermediate 33) (48.2 mg, 0.16 mmol) in acetonitrile (4 mL) was added DIPEA (0.164 mL, 0.94 mmol) and the resulting mixture was stirred at 70 °C for 1.5 hours. LCMS indicated complete conversion. The mixture was concentrated and the residue was purified on a reverse phase Gilson column (eluting with 0 to 70% ACN / water / 0.1% TFA). Pure fractions were combined, 0.5 ml 1M aqueous HC1 was added to the combined fractions and lyophilized to dryness to give 5-[4-[[2-(l,l-difluoroethyl)-5-fluoro-3-oxo-4H-quinoxalin-6-yl]methyl]piperazin-l-yl]-N,6-dimethyl-pyridine-2-carboxamide as the HCI salt (Example 19) as a yellow solid (35.0 mg, 44%).1H NMR (500 MHz, DMSO-d6) 2.08 (3H, br t), 2.52 (3H, s), 2.80 (3H, br d), 3.02 - 3.54 (8H, m), 4.61 (2H, br s), 7.57 (IH, br d), 7.67 - 8.04 (3H, m), 8.52 (IH, br d), 11.74 (IH, br s), 12.77 - 13.55 (IH, m); m / z (ES+) [M+H] 475.3. + 475.3. + 475.3.

[0250]

[0251] Example 20: 6-Fluoro-5-[4-[(5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl] piperazin- 1-yl]-N-methyl-pyridine-2-carboxamide

[0252] DIPEA (151 ml, 867.27 mmol) was added slowly to a stirred solution of 1-bromo-2,4- difluoro-3-nitrobenzene (Intermediate 35) (68.8 g, 289.09 mmol) and methyl alaninate, HC1 (40.4 g, 289.09 mmol) in DMF (300 mL). The resulting solution was stirred at room temperature for 18 hours (complete conversion to the desired product by LCMS). The reaction mixture was concentrated using a rocket evaporator system, diluted with water and extracted with ethyl acetate. The organic layer was washed thoroughly with water, dried over sodium sulfate, filtered and concentrated in vacuo. To the above orange solid was added 100 mL of DCM, the suspension was stirred at room temperature for 30 minutes, the solid was filtered to give methyl 2-(4-bromo-3-fluoro-2-nitro- phenylamino)propanoate as a bright orange solid (24.00 g, 26%) (Intermediate 56).1H NMR (500 MHz, Methanol-d4) 1.52 - 1.62 (3H, m), 3.80 (3H, s), 4.28 (1H, quin), 6.49 (1H, dd), 7.19 - 7.39 (1H, m), 7.54 (1H, dd);19F NMR (471 MHz, Methanol-d4) -109.49 (1F, s); m / z (ES+) [M+H] 321, 323. + [M+H] + = 321, 323.

[0253] 6-(Difluoromethyl)-5-[4-[(5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl] piperazin- 1-yl]-N-methyl-pyridine-2-carboxamide

[0254] Zinc (78 g, 1195.88 mmol) was added in portions to a mixture of methyl 2-(4-bromo-3-fluoro-2-nitro-phenylamino)propanoate (Intermediate 56) (48 g, 149.49 mmol) and ammonium chloride (64.0 g, 1195.88 mmol) in MeOH (720 ml) and water (16 ml) at 0 °C (exothermic reaction) and the mixture was stirred at room temperature for 2 hours (complete disappearance of orange colour indicated completion of the reaction). The solids were filtered off and the solid filter cake was washed with 20% MeOH in DCM. The filtrate was concentrated, water was added to the crude product and the product was extracted with ethyl acetate. The organic layer was dried and concentrated in vacuo to give an oil. m / z (ES+) [M+H] 291, 293. + [M+H] + = 291, 293.

[0255] The material was slurried in ethyl acetate (50 mL) and methanol (50 mL), 2 mL of 4N HC1 in dioxane was added and the mixture was stirred for 1 hour. The reaction mixture was concentrated to give the crude product 7-bromo-8-fluoro-3-methyl-3,4-dihydro-1 H- quinoxalin-2-one (Intermediate 57) as a grey solid (38.7 g). The crude product (38.7 g) was used in the next step without any further purification assuming 100% yield of the reaction. m / z (ES + [M+H] + = 259.

[0256] INTERMEDIATE 61: Methyl 6-fluoro-5-[4-[(5-fluoro-2-methyl-3-oxo-4H- quinoxalin-6-yl)methyl]piperazin- 1-yl]pyridine-2-carboxylate

[0257] DDQ (21.55 g, 94.95 mmol) was added in one portion to a stirred solution of 7-bromo-8-fluoro-3-methyl-3,4-dihydro-1 H-quinoxalin-2-one (Intermediate 57) (20.5 g, 79.13 mmol) in DCM (200 mL) to give a very thick off-white slurry, additional dichloromethane (800 mL) was added. The resulting slurry was stirred at room temperature for 2 hours (complete conversion to the desired product by LCMS). The reaction mixture was concentrated in vacuo and quenched with saturated aqueous sodium bicarbonate solution (about 500 mL, the quenching caused vigorous frothing). The above slurry was stirred at room temperature overnight and the solid was filtered off, washed thoroughly with water and the solid was dried on the filter overnight. The solid was washed with diethyl ether and dried for 30 minutes to give 7-bromo-8-fluoro-3-methyl-1 H-quinoxalin-2-one (Intermediate 58) as an off-white solid (16.28 g, 80%).19F NMR (471 MHz, DMSO-d6) - 124.18 (1 F, s);1H NMR (500 MHz, DMSO-d6) 2.41 (3H, s), 7.45 - 7.54 (2H, m), 12.60 (1 H, br s); m / z (ES + [M+H] + = 257.

[0258] Example 22: 6-Fluoro-5-[4-[(5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl] piperazin- 1-yl]pyridine-2-carboxamide

[0259] A mixture of (tributylstannyl)methanol (15.39 g, 47.93 mmol), 7-bromo-8-fluoro-3- methyl-1H-quinoxalin-2-one (Intermediate 58) (11.2 g, 43.57 mmol) and Xphos Pd G2 (1.714 g, 2.18 mmol) in 1,4-dioxane (200 mL) was stirred at 80 °C for 7 h. LCMS indicated complete conversion. The solvent was removed under reduced pressure and the residue was purified on a silica gel column (eluting with 0 to 15% methanol in DCM). The fractions were concentrated to a slurry, diluted with ether, the solid was collected by filtration and dried to give 8-fluoro-7-(hydroxymethyl)-3-methyl-1H-quinoxalin-2-one (Intermediate 17) as a white solid (8.10 g, 89%).1H NMR (500 MHz, DMSO-d6) 2.41 (3H, s), 4.63 (2H, br d), 5.39 (1H, t), 7.31 (1H, br t), 7.51 (1H, d), 12.41 (1H, br s). m / z (ES+) [M+H] 209.0. + [M+H] + = 209.

[0260] ​ ​

[0261] A mixture of (tributylstannyl)methanol (15.39 g, 47.93 mmol), 7-bromo-8-fluoro-3- methyl-1H-quinoxalin-2-one (Intermediate 58) (11.2 g, 43.57 mmol) and Xphos Pd G2 (1.714 g, 2.18 mmol) in 1,4-dioxane (200 mL) was stirred at 80 °C for 7 h. LCMS indicated complete conversion. The solvent was removed under reduced pressure and the residue was purified on a silica gel column (eluting with 0 to 15% methanol in DCM). The fractions were concentrated to a slurry, diluted with ether, the solid was collected by filtration and dried to give 8-fluoro-7-(hydroxymethyl)-3-methyl-1H-quinoxalin-2-one (Intermediate 17) as a white solid (8.10 g, 89%).1H NMR (500 MHz, DMSO-d6) 2.41 (3H, s), 4.63 (2H, br d), 5.39 (1H, t), 7.31 (1H, br t), 7.51 (1H, d), 12.41 (1H, br s). m / z (ES+) [M+H] 209.0. +)[M+H] + = 271, 273.

[0262] To a flask containing 7-(bromomethyl)-8-fluoro-3-methylquinoxalin-2(lH)-one (Intermediate 59) (22.76 g) and 6-fluoro-N-methyl-5-(piperazin-l-yl)picolinamide, 2HCI (Intermediate 32) (24.24 g, 77.9 mmol) in acetonitrile (350 ml) at room temperature was added DIPEA (38.0 ml, 217.59 mmol) and the resulting mixture was stirred at 70 °C for 4 hours. The reaction was not complete. To the mixture was added 5 g of KI and 2 g of Nal and the mixture was stirred at 50 °C for 20 hours. More 540 mg (about 0.03 eq) of 6-fluoro-N-methyl-5-(piperazin-l-yl)picolinamide 2HCI (Intermediate 32) was added to the mixture and stirring was continued at 50 °C for 2 hours. The solids from the reaction suspension were collected by filtration, washed with acetonitrile and dried. The resulting material was then suspended in water (about 400 ml), slurried at room temperature for 20 minutes, filtered and dried (LCMS purity 97%). The solids were then dissolved into a mixture of DCM / MeOH (3 / 1) (about 1.5 L) at reflux, filtered through a pad of silica gel, most of the DCM was removed until the solids precipitated out and the mixture was left at room temperature for 20 minutes. The solids were collected by filtration, the procedure was repeated on the filtrate and the solids were combined to give the product 6-fluoro-5-[4-[(5-fluoro-2-methyl-3-oxo-4H- quinoxalin-6-yl)methyl]piperazin-l-yl]-N-methyl-pyridine-2-carboxamide (Example 20) as a light yellow solid (26 g, 84%).1H NMR (500 MHz, DMSO-d6) 2.41 (3H, s), 2.57 - 2.69 (4H, m), 2.76 (3H, d), 3.16 (4H, br s), 3.70 (2H, s), 7.29 (1H, br t), 7.40 - 7.60 (2H, m), 7.83 (1H, d), 8.38 (1H, br d), 12.44 (1H, br s); m / z (ES+) [M+H] 429.2. + )[M+H] + = 429.

[0263]

[0264] Example 21 : ​ ​

[0265] DIPEA (0.052 mL, 0.30 mmol) was added to a stirred mixture of 7-(bromomethyl)-8- fluoro-3-methylquinoxalin-2(lH)-one (Intermediate 59) (40 mg, 0.15 mmol) and 6- (difluoromethyl)-N-methyl-5-(piperazin-l-yl)picolinamide, 2HCI (Intermediate 60) (50.6 mg, 0.15 mmol) in acetonitrile (mL) and the resulting mixture was stirred at 70 °C for 2 hours. After the reaction was concentrated, it was submitted for analytical group purification (purification conditions: the residue was purified by reverse phase C18 column (eluted with 0 to 100% ACN / water / 0.1% NH4OH), which gave 6-(difluoromethyl)-5-[4-[(5-fluoro-2-methyl-3-oxo-4H- quinoxalin-6-yl)methyl]piperazin-l-yl]-N-methyl-pyridine-2-carboxamide (Example 21) as a white solid (15 mg, 22%). 1H NMR (500 MHz, DMSO-d6) 2.37 (3H, s), 2.64 (4H, br s), 2.84 (3H, d), 3.01 (4H, br d), 3.70 (2H, s), 7.00-7.28 (2H, m), 7.42 (1H, br d), 7.86 (1H, d), 8.09 (1H, d), 8.39 (1H, q), 12.24-12.63 (1H, m); m / z (ES+) [M+H] 461.2. + [M+H] + = 461.

[0266]

[0267] ​ ​

[0268] Polymer supported triphenylphosphine (1.512 g, 5.76 mmol) (add 3.4 g, based on 1.6 mmol / g PPh3 loading) was added to a stirred slurry of 8-fluoro-7-(hydroxymethyl)-3- methylquinoxalin-2(lH)-one (Intermediate 17) (400 mg, 1.92 mmol) and perbromo methane (1.274 g, 3.84 mmol) in DCM (40 mL) at room temperature. The resulting mixture was stirred at 23 °C for 1 hour. The reaction was incomplete. Additional polymer bound -PPh3 (1 g) was added to complete the reaction. The reaction mixture was filtered, washed with DCM, THF, the filtrate was concentrated in vacuo to give 7-(bromomethyl)-8-fluoro-3-methylquinoxalin-2(lH)-one as a light yellow solid.

[0269] To the above freshly prepared 7-(bromomethyl)-8-fluoro-3-methylquinoxalin-2(lH)-one was added 6-fluoro-5-(piperazin-l-yl)picolinic acid methyl ester, 2HCI (Intermediate 12) (600 mg, 1.92 mmol), acetonitrile (25 mL) and N-ethyl-N-isopropyl-2-amine (1674 μΐ, 9.61 mmol) and the reaction mixture heated to 70 °C for 1 hour. The reaction mixture was cooled to room temperature, concentrated and the crude solid purified by normal phase chromatography using 0-10% MeOH in DCM to give 6-fluoro-5-[4-[(5-fluoro-2-methyl-3-oxo-4H- quinoxalin-6-yl)methyl]piperazin-l-yl]pyridine-2-carboxylic acid methyl ester (Intermediate 61) as an off-white solid (0.484 g, 59%).1H NMR (500 MHz, DMSO-c / 6) 2.34-2.49 (3H, m), 2.52-2.62 (4H, m), 3.08-3.28 (4H, m), 3.70 (2H, s), 3.83 (3H, s), 7.29 (IH, t), 7.44-7.54 (2H, m), 7.91 (IH, dd), 12.45 (IH, s);19F NMR (471 MHz, DMSO-c / 6) -135.50 (IF, s), -70.49 (IF, s). m / z (ES+) [M+H] = 430. + [M+H] + = 430.

[0270] ​ ​

[0271] Ammonia (7N ammonia in MeOH) (31.3 ml, 218.90 mmol) was added to 6-fluoro-5-[4-[(5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]pyridine-2- carboxylic acid methyl ester (Intermediate 61) (0.470 g, 1.09 mmol) in a 40 mL scintillation vial, sealed and stirred at room temperature for 18 hours. Complete conversion to the desired product by LCMS. The white solid was filtered to give 103 mg of pure product. The filtrate was concentrated in vacuo, the resulting off-white solid was slurried in ~5 mL of methanol and filtered to give additional pure product 298 mg. The two batches were combined to give 6-fluoro-5-[4-[(5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]pyridine-2-carboxamide (Example 22) (0.401 g, 88%).1H NMR (500 MHz, DMSO-d6) 2.42 (3H, s), 2.59 (4H, br s), 3.09-3.27 (4H, m), 3.70 (2H, s), 7.29 (1H, br t), 7.46 (1H, br s), 7.49-7.58 (2H, m), 7.76 (1H, br s), 7.85 (1H, br d), 12.35 (1H, br s);19F NMR (471 MHz, DMSO-d6) -135.49 (1F, s), -72.40 (1F, s); m / z (ES+) [M+H] 415.2. + [M+H] + = 415.

[0272]

[0273] Intermediate 62: Methyl 2-(4-bromo-3-fluoro-2-nitro-anilino)butanoate

[0274] DIPEA (165 ml, 942.91 mmol) was added slowly to a stirred solution of 1-bromo-2,4- difluoro-3-nitrobenzene (Intermediate 35) (74.8 g, 314.30 mmol) and methyl 2- aminobutanoate, HC1 (48.3 g, 314.30 mmol) in DMF (733 mL) and the resulting solution stirred at room temperature for 18 hours. The DMF was removed on a rotoevaporator, diluted with water and extracted with ethyl acetate. After concentration, the crude material was purified by flash silica chromatography eluting with a gradient of 0 to 70% EtOAc / hexane. Concentration of the product fractions under reduced pressure afforded methyl 2-(4-bromo-3-fluoro-2-nitro-anilino)butanoate (Intermediate 62) as a red solid (49.4 g, 47%).1H NMR (500 MHz, DMSO-c / 6) 0.82 - 0.98 (3H, m), 1.77 - 1.93 (2H, m), 3.70 (3H, d), 4.38 - 4.54 (1H, m), 6.77 (1H, br d), 7.28 (1H, br d), 7.64 - 7.80 (1H, t); m / z (ES+) [M+H] 335.0. + [M+H] + = 335.

[0275] Intermediate 63: 7-Bromo-3-ethyl-8-fluoro-3,4-dihydro-1 H-quinoxalin-2-one

[0276] Zinc (44.1 g, 674.07 mmol) was added portionwise (exothermic reaction) to a mixture of methyl 2-(4-bromo-3-fluoro-2-nitro-anilino)butanoate (Intermediate 62) (50.2 g, 149.79 mmol) and ammonium chloride (64.1 g, 1198.34 mmol) in MeOH (468 mL). The mixture was stirred at room temperature for 1 hour. The solids were filtered off and washed with 20% MeOH in DCM. This material was dissolved in methanol (120 mL) and 4N HC1 in dioxane (10 mL) was added and the reaction stirred for 30 minutes. The solvent was removed under vacuum, diluted with ethyl acetate and basified with saturated NaHC03solution. The organic layer was separated, washed with water, dried over sodium sulfate and concentrated to give the crude product. The solid was triturated with 100 mL of methanol, stirred for 10 minutes, the light brown solid was filtered off to give 7-bromo-3-ethyl-8-fluoro-3,4-dihydro-1H-quinoxalin-2-one (Intermediate 63) (39.8 g, 97%) product.1H NMR (500 MHz, DMSO-c / 6) 0.92 (3H, t), 1.49 - 1.77 (2H, m), 3.57 - 3.87 (1H, m), 6.24 - 6.62 (2H, m), 6.99 (1H, dd), 10.44 (1H, s); m / z (ES+) [M+H] 273.0. + [M+H] + = 273.

[0277] Intermediate 64: 7-Bromo-3-ethyl-8-fluoro-1 H-quinoxalin-2-one

[0278] DDQ (29.7 g, 130.94 mmol) was added in one portion to a stirred solution of 7-bromo-3- ethyl-8-fluoro-3,4-dihydro-1H-quinoxalin-2-one (Intermediate 63) (29.8 g, 109.12 mmol) in DCM (546 mL) and the resulting solution was stirred at room temperature for 2 hours. The solvent was removed in vacuo and the solid was slurred with 150 mL of methanol and stirred for 30 minutes. The solid was filtered off and washed with 30 mL of methanol. The solid was transferred to a 2 litre round bottom flask; 200 mL of water was added followed by the slow addition of 300 mL of sodium bicarbonate. After the addition was complete, the mixture was stirred at room temperature overnight to give a pale yellow slurry. Stirring was stopped and the aqueous layer was removed. The solid was collected by filtration and washed thoroughly with water to give 7-bromo-3-ethyl-8-fluoro-1H-quinoxalin-2-one (Intermediate 64) as a yellow solid (24.45 g, 83%).1H NMR (500 MHz, DMSO-d6) 1.22 (3H, t), 2.81 (2H, q), 7.27 - 7.69 (2H, m), 12.59 (1H, br s); m / z (ES+) [M+H] 271.0. + [M+H] + = 271.

[0279] Intermediate 65: 3-Ethyl-8-fluoro-7-(hydroxymethyl)-1 H-quinoxalin-2-one

[0280] Xphos Pd G2 (1.121 g, 1.43 mmol) was added to a stirred degassed solution of 7-bromo-3- ethyl-8-fluoro-1H-quinoxalin-2-one (Intermediate 64) (7.727 g, 28.50 mmol) and (tributylstannyl)methanol (10.98 g, 34.20 mmol) in 1,4-dioxane (143 mL). The resulting solution was stirred at 80 °C for 6 hours. The solvent was removed in vacuo, 100 mL of diethyl ether was added and the slurry was stirred for 30 minutes. The solid was filtered off and washed with 50 mL of diethyl ether to give 3-ethyl-8-fluoro-7-(hydroxymethyl)-1H-quinoxalin-2-one (5.88 g, 93%) as an off-white solid (Intermediate 65).1H NMR (500 MHz, DMSO-d6) 1.22 (3H, t), 2.82 (2H, q), 4.64 (2H, br d), 5.40 (1H, t), 7.32 (1H, br t), 7.55 (1H, d), 12.40 (1H, br s); m / z (ES+) [M+H] 223.0. + [M+H] + = 223.

[0281] Intermediate 66: 7-(Bromomethyl)-3-ethyl-8-fluoro-1 H-quinoxalin-2-one

[0282] Triethylphosphine (19.94 ml, 135.00 mmol) was added dropwise to a stirred solution of 3-ethyl-8-fluoro-7-(hydroxymethyl)-1 H-quinoxalin-2-one (Intermediate 65) (10 g, 45.00 mmol) and CBr4(49.2 g, 148.50 mmol) in DCM (355 mL) at 0 °C under nitrogen over a period of 5 minutes. The reaction was stirred at room temperature for 1 hour. The DCM was removed under vacuum and the residue was slurry in 150 mL diethyl ether. The white ppt was filtered off and washed with 50 mL diethyl ether. The solid was slurry with water (200 mL) and stirred for 30 minutes. The solid was filtered off and washed thoroughly with water. The solid was dried under vacuum overnight to give 7-(bromomethyl)-3-ethyl-8-fluoroquinoxalin-2(1 H)-one (Intermediate 66) as a light brown solid (11.38 g, 89%).1H NMR (500 MHz, DMSO-d6) 1.22 (3H, t), 2.83 (2H, q), 4.81 (2H, s), 7.37 (1 H, br t), 7.55 (1 H, d), 12.53 (1 H, br s); m / z (ES+) 285.0 [M+H]. + [M+H] + = 285.

[0283]

[0284] Example 23: 5-[4-[(2-Ethyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N,6- dimethyl-pyridine-2-carboxamide

[0285] DIPEA (20.90 mL, 119.64 mmol) was added to a stirred slurry of 7-(bromomethyl)-3- ethyl-8-fluoroquinoxalin-2(lH)-one (Intermediate 66) (11.37 g, 39.88 mmol) and N,6-dimethyl-5- piperazin-l-yl-pyridine-2-carboxamide, 2HCI (Intermediate 33) (14.09 g, 45.86 mmol) in acetonitrile (178 mL). The resulting solution was stirred at 50 °C for 2 hours. The reaction was complete. Half of the solvent was removed by evaporation, 10 mL of saturated sodium bicarbonate was added and the mixture was stirred for 15 minutes. The solid was filtered off, washed with water and then with 50 mL of acetonitrile. The solid was dissolved in DCM / methanol (about 9 / 1) and filtered through a bed of silica gel. The filtrate was concentrated to give a light yellow solid. This material was triturated with about 120 mL of methanol, the solid was filtered off and dried. LCMS still showed about 2.1% of impurity (possibly from reagent). The material was triturated again with acetonitrile and then with 3% methanol in acetonitrile to give about 14 g of white solid. Methanol (40 mL) was added and stirred for 3 hours. The solid was filtered off to give the pure product 5-[4-[(2-ethyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-l-yl]-N,6-dimethyl-pyridine-2- carboxamide (Example 23) (12.26 g, 70%).1H NMR (500 MHz, DMSO-d6) 1.23 (3H, t), 2.48 (3H, s), 2.62 (4H, br s), 2.76-2.88 (5H, m), 2.95 (4H, br s), 3.73 (2H, s), 7.31 (IH, t), 7.47 (IH, d), 7.56 (IH, d), 7.79 (IH, d), 8.41 (IH, q), 12.44 (IH, s); m / z (ES+) [M+H] = 439. + [M+H] + = 439.

[0286]

[0287] Example 24: 6-(Difluoromethyl)-5-[4-[(2-ethyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin- 1-yl]-N-methyl-pyridine-2-carboxamide

[0288] DIPEA (0.049 mL, 0.28 mmol) was added to a stirred mixture of 7-(bromomethyl)-3- ethyl-8-fluoroquinoxalin-2(lH)-one (Intermediate 66) (40 mg, 0.14 mmol) and 6-(difluoromethyl)-N-methyl-5-(piperazin-l-yl)picolinamide, 2HCI (Intermediate 60) (48.1 mg, 0.14 mmol) in acetonitrile (2 mL) and the resulting mixture was stirred at 70 °C for 2 hours. After concentration of the reaction, it was submitted for purification (purification conditions: the residue was purified by reverse phase C18 column (eluted with 0 to 100% ACN / water / 0.1% NH4OH), which gave 6-(difluoromethyl)-5-[4-[(2-ethyl-5-fluoro-3-oxo-4H-quinoxalin-6- yl)methyl]piperazin-l-yl]-N-methyl-pyridine-2-carboxamide (Example 24) (56.0 mg, 84%). 1H NMR (500 MHz, DMSO-c / 6) 1.23 (3H, t), 2.65 (4H, br d), 2.77-2.86 (5H, m), 2.97-3.06 (4H, m), 3.73 (2H, s), 7.00-7.26 (1H, t), 7.30 (1H, br d), 7.55 (1H, br d), 7.86 (1H, d), 8.09 (1H, d), 8.39 (1H, q), 12.45 (1H, br d); m / z (ES+) [M+H] = 475. + [M+H] + = 475.

[0289]

[0290] Intermediate 67: Methyl 5-[4-[(2-ethyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]pyridine- 2-carboxylate

[0291] DIPEA (246 μΐ, 1.41 mmol) was added to a stirred slurry of 7-(bromomethyl)-3-ethyl-8- fluoro-lH-quinoxalin-2-one (Intermediate 66) (134 mg, 0.47 mmol) and methyl 5- (piperazin-l-yl)picolinate hydrochloride, 2HCI (Intermediate 119) (138 mg, 0.47 mmol) in acetonitrile (2 mL). The resulting solution was stirred at 50 °C for 2 hours. The solvent was removed under vacuum and the resulting residue was purified by flash silica chromatography (elution gradient 0 to 20% MeOH in DCM). Concentration of the product fractions under reduced pressure afforded methyl 5-[4-[(2-ethyl-5-fluoro-3-oxo-4H-quinoxalin-6- yl)methyl]piperazin-l-yl]pyridine-2-carboxylate (Intermediate 67) (0.142 g, 71.0%) as a white solid; m / z (ES+) [M+H] = 426. + [M+H] + = 426.

[0292] Example 25: 5-[4-[(2-Ethyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]pyridine-2- carboxamide

[0293] A solution of ammonia (7N) in methanol (3 mL, 6.00 mmol) was added to methyl 5-[4-[(2-ethyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1- yl]pyridine-2-carboxylate (Intermediate 67) (130 mg, 0.31 mmol). The resulting suspension was stirred at 50 °C for 24 hours (sealed tube). The solvent was removed and the resulting residue was purified by flash silica chromatography eluting with a gradient of 0 to 35% MeOH in DCM. Product fractions were concentrated under reduced pressure to give 5-[4-[(2-ethyl-5-fluoro-3-oxo-4H-quinoxalin-6- yl)methyl]piperazin-1-yl]pyridine-2-carboxamide (Example 25) as a light yellow solid (0.079 g, 63%).1H NMR (500 MHz, DMSO-c / 6) 1.23 (3H, t), 2.54-2.61 (4H, m), 2.83 (2H, q), 3.32-3.40 (4H, m), 3.70 (2H, s), 7.24-7.34 (2H, m), 7.38 (1H, dd), 7.56 (1H, d), 7.76 (1H, br d), 7.84 (1H, d), 8.27 (1H, d), 12.44 (1H, br s); m / z (ES+) [M+H] 411.2. + [M+H] + = 411.

[0294]

[0295] Intermediate 68: Methyl 5-[4-[(2-ethyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-6- methyl-pyridine-2-carboxylate

[0296] Triethylphosphine (0.399 ml, 2.70 mmol) was added dropwise to a stirred solution of 3-ethyl-8-fluoro-7-(hydroxymethyl)quinoxalin-2(1H)-one (Intermediate 65) (0.2 g, 0.90 mmol) and CBr4(0.985 g, 2.97 mmol) in DCM (7.10 mL) at 0 °C over a period of 5 minutes. The reaction was stirred at room temperature for 1 hour. The DCM was removed in vacuo and the resulting solid was slurred in diethyl ether. The white ppt was filtered under vacuum and washed with water and then ether. The solid was dried under vacuum overnight (without heating) to give 7-(bromomethyl)-3-ethyl-8-fluoroquinoxalin-2(1H)-one as a light brown solid.

[0297] To the above crude product was added 6-methyl-5-(piperazin-l-yl)picolinic acid methyl ester, 2HCI (Intermediate 16) (278 mg, 0.90 mmol), acetonitrile (10 mL) and N- ethyl-N-isopropylpropan-2-amine (785 μΐ, 4.51 mmol) and heated to 70 °C for 1 h. The reaction mixture was cooled, concentrated, quenched with aqueous NaHC03solution (1 mL) and stirred at room temperature for 1 h. Water (3 mL) was added to the above mixture and stirred for 10 min. The precipitate was filtered and washed with water (50 mL). The solid was purified by normal phase chromatography using 0-10% MeOH in DCM. The isolated product was 89% pure according to LCMS. The above solid was further purified using mass guided preparative HPLC using 20-40% acetonitrile in water and NH4OH modifier to give 5-[4-[(2-ethyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-l-yl]-6-methyl- pyridine-2-carboxylic acid methyl ester (Intermediate 68) as a white solid (115 mg, 0.262 mmol, 29%) with 93% LCMS purity.1H NMR (500 MHz, DMSO-c / 6) 1.23 (3H, t), 2.45-2.49 (3H, m), 2.53-2.69 (4H, m), 2.83 (2H, q), 2.98 (4H, br s), 3.73 (2H, s), 3.83 (3H, s), 7.31 (1H, t), 7.45 (1H, d), 7.56 (1H, d), 7.86 (1H, d), 12.44 (1H, br s);19F NMR (471 MHz, DMSO-c / 6) -135.54 (1F, s). m / z (ES+) [M+H] = 440. + [M+H] + = 440.

[0298] Example 26: 5-[4-[(2-Ethyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-6-methyl-pyridine- 2-carboxamide

[0299] A 7N ammonia solution in methanol (6.40 ml, 44.78 mmol) was added to 5-[4-[(2-ethyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-6-methyl- pyridine-2-carboxylic acid methyl ester (Intermediate 68) (0.0984 g, 0.22 mmol) in a 40 mL scintillating vial, sealed and stirred at room temperature for 18 hours. The reaction was concentrated under vacuum, additional ammonia (6.40 ml, 44.78 mmol) solution was added and stirred at 50 °C for 16 hours. The reaction was concentrated under vacuum and additional NH3methanol solution was added and stirred at room temperature over the weekend. The reaction was complete according to LCMS. The reaction mixture was concentrated under vacuum, the resulting solid was slurry in diethyl ether. The solid was filtered and washed with additional ether and methanol to give 5-[4-[(2-ethyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-6-methyl-pyridine-2-carboxamide (Example 26) as a white solid (0.095 g, 100%);1H NMR (500 MHz, DMSO-c / 6) 1.22 (3H, br t), 2.45 - 2.49 (3H, m), 2.52 - 2.68 (4H, m), 2.82 (2H, q), 2.94 (4H, br s), 3.72 (2H, br s), 7.30 (1H, br t), 7.38 - 7.51 (2H, m), 7.55 (1H, br d), 7.80 (2H, br d), 12.41 (1H, br s);19F NMR (471 MHz, DMSO-c / 6) -135.53 (1F, s); m / z (ES+) [M+H] 425.2. + 425.2. + 425.2.

[0300]

[0301] Intermediate 69: 2-Ethyl-5-fluoro-3-oxo-4H-quinoxalin-6-carbaldehyde

[0302] Dess-Martin periodinane (458 mg, 1.08 mmol) was added to 3-ethyl-8-fluoro-7- (hydroxymethyl)-1H-quinoxalin-2-one (intermediate 65) (contaminated with its regioisomer 3-ethyl-8-fluoro-5-(hydroxymethyl)-1H-quinoxalin-2-one) (160 mg, 0.72 mmol) in DCM (5 mL). The resulting mixture was stirred at room temperature for 4 h. The solvent was evaporated to give a crude product which was purified by flash C18-fast chromatography eluting with a gradient of 5% to 30% MeCN in water (0.4% FA). The pure fractions were evaporated to dryness to give 2-ethyl-5-fluoro-3-oxo-4H-quinoxalin-6-carbaldehyde (contaminated with its regioisomer 3-ethyl-8-fluoro-2-oxo-1H-quinoxalin-5-carbaldehyde) (intermediate 69) as a yellow solid (110 mg, 69%). m / z (ES+) 221.0 [M+H]. + [M+H] + = 221.

[0303] Example 27: 5-[4-[(2-Ethyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-6-fluoro-N-methyl- pyridine-2-carboxamide

[0304] Titanium isopropoxide (64.5 mg, 0.23 mmol) was added to 2-ethyl-5-fluoro-3-oxo-4H- quinoxaline-6-carboxaldehyde (Intermediate 69) (contaminated with its regioisomer 3-ethyl-8- fluoro-2-oxo-lH-quinoxaline-5-carboxaldehyde) (50 mg, 0.23 mmol) and 6-fluoro-N- methyl-5-(piperazin-l-yl)picolinamide (54.1 mg, 0.23 mmol) in THF (3 mL). The resulting mixture was stirred at room temperature for 2 minutes. Sodium triacetoxyborohydride (Intermediate 32) (192 mg, 0.91 mmol) was added. The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with MeOH (0.1 mL). The solvent was evaporated to provide a crude product. The crude residue was purified by preparative HPLC (Column: Xselect CSH OBD Column 30*150mm 5um; Mobile Phase A: Water (0.05% TFA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 10% B to 20% B in 10 minutes; 254; 220 nm) and (Column: XBridge Shield RP18 OBD Column, 19*250mm, 10um; Mobile Phase A: Water (10 MMOL / L NH4HCO3 + 0.1% NH3.H2O), Mobile Phase B: ACN; Flow rate: 20 mL / min; Gradient: 21B to 95B in 7 minutes; 254 / 220 nm. Fractions containing the desired compound were evaporated to dryness to give 5-[4-[(2-ethyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-l-yl]-6-fluoro-N- methyl-pyridine-2-carboxamide (Example 27) as a white solid (6 mg, 6%). 1H NMR (400 MHz, DMSO-c / 6) 1.22 (3H, t), 2.56 - 2.64 (4H, m), 2.76 (3H, d), 2.82 (2H, q), 3.14 - 3.20 (4H, m), 3.71 (2H, s), 7.27 - 7.33 (1H, m), 7.53 - 7.59 (2H, m), 7.82 - 7.86 (1H, m), 8.38 - 8.45 (1H, m), 12.46 (1H, s);19F NMR (376 MHz, DMSO-c / 6) -72.58, -135.51; m / z (ES+) [M+H] = 443. + [M+H] + 443.

[0305]

[0306] Example 28: 6-Chloro-5-[4-[(2-ethyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methyl- pyridine-2-carboxamide

[0307] Titanium isopropoxide (51.6 mg, 0.18 mmol) was added to 2-ethyl-5-fluoro-3-oxo-4H- quinoxaline-6-carboxaldehyde (Intermediate 69) (contaminated with its regioisomer 3-ethyl-8- fluoro-2-oxo-lH-quinoxaline-5-carboxaldehyde) (40 mg, 0.18 mmol) and 6-chloro-N- methyl-5-(piperazin-l-yl)picolinamide (Intermediate 30) (50 mg, 0.20 mmol) in THF (3 mL). The resulting mixture was stirred at room temperature for 2 minutes. Sodium triacetoxyborohydride (154 mg, 0.73 mmol) was added. The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with MeOH (0.1 mL) and evaporated to give the crude product. The crude product was purified by preparative HPLC (Column: XBridge Shield RP18 OBD Column, 30*150mm, 5um; Mobile Phase A: Water (0.05% NH3H2O), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 21B to 41B in 7 minutes; 254 / 220 nm. Fractions containing the desired compound were evaporated to dryness to give 6-chloro-5-[4-[(2-ethyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-l-yl]-N- methyl-pyridine-2-carboxamide (Example 28) as a white solid (37.5 mg, 45%). 1H NMR (400 MHz, DMSO-c / 6) 1.22 (3H, t), 2.57 - 2.65 (4H, m), 2.76 - 2.86 (5H, m), 3.05 - 3.15 (4H, m), 3.72 (2H, s), 7.29 (1H, t), 7.55 (1H, d), 7.65 (1H, d), 7.93 (1H, d), 8.40 - 8.45 (1H, m), 12.45 (1H, s);19F NMR (376 MHz, DMSO-c / 6) -135.46; m / z (ES+) [M+H] = 459. + [M+H] + = 459.

[0308]

[0309] Example 29: 5-[4-[(2-Ethyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methyl-pyridine- 2-carboxamide

[0310] Titanium isopropoxide (51.6 mg, 0.18 mmol) was added to 2-ethyl-5-fluoro-3-oxo-4H- quinoxaline-6-carboxaldehyde (intermediate 69) (contaminated with its regioisomer 3-ethyl-8- fluoro-2-oxo-lH-quinoxaline-5-carboxaldehyde) (40 mg, 0.18 mmol) and N-methyl-5- (piperazin-l-yl)picolinamide (intermediate 31) (50 mg, 0.23 mmol) in THF (3 mL). The resulting mixture was stirred at room temperature for 2 minutes. Sodium triacetoxyborohydride (154 mg, 0.73 mmol) was added. The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with MeOH (0.1 mL) and concentrated to give the crude product. The crude product was purified by preparative HPLC (column: Xselect CSH OBD column 30*150mm 5um, n; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 6B to 17B in 7 minutes; 254; 220 nm. Fractions containing the desired compound were evaporated to dryness to give 5-[4-[(2-ethyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-l-yl]-N- methyl-pyridine-2-carboxamide (example 29) as a white solid (17.29 mg, 22%). 1H NMR (400 MHz, DMSO-c / 6) 1.22 (3H, t), 2.53 - 2.63 (4H, m), 2.74 - 2.87 (5H, m), 3.05 - 3.15 (4H, m, merged into water peak), 3.69 (2H, s), 7.29 (1H, t), 7.37 (1H, dd), 7.54 (1H, d), 7.81 (1H, d), 8.25 (1H, d), 8.35 - 8.42 (1H, m), 12.44 (1H, s);19F NMR (376 MHz, DMSO-c / 6) -135.49; m / z (ES+) [M+H] = 425. + [M+H] + = 425.

[0311]

[0312] Intermediate 70: 5-Fluoro-2-methyl-3-oxo-4H-quinoxalin-6-carbaldehyde

[0313] Dess-Martin periodinane (1.34 g, 3.16 mmol) was added to 8-fluoro-7- (hydroxymethyl)-3-methyl-1H-quinoxalin-2-one (intermediate 17) (contaminated with 8-fluoro-5-(hydroxymethyl)-3-methyl-1H-quinoxalin-2-one) (0.33 g, 0.79 mmol) in DCM (20 ml). The resulting mixture was stirred at room temperature for 6 hours. The reaction mixture was evaporated to give a crude product. The crude product was purified by flash C18 flash chromatography (elution gradient of 5 to 30% MeCN in water (0.4% FA)). The pure fractions were evaporated to dryness to give 5-fluoro-2-methyl-3-oxo-4H-quinoxaline-6- carboxaldehyde (contaminated with 8-fluoro-3-methyl-2-oxo-1H-quinoxaline-5- carboxaldehyde) (intermediate 70) as an off-white solid (0.300 g, 92%). m / z (ES+) 207.0 [M+H]. + [M+H] + = 207.

[0314] Example 30: 6-Chloro-5-[4-[(5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methyl- pyridine-2-carboxamide

[0315] Titanium isopropoxide (89 mg, 0.31 mmol) was added to 5-fluoro-2-methyl-3-oxo-4H-quinoxaloline-6-carboxaldehyde (contaminated with 8-fluoro-3-methyl-2-oxo-1H-quinoxaloline-5-carboxaldehyde) (intermediate 70) (150 mg, 0.36 mmol) and 6-chloro-N-methyl-5-piperazin-1-ylpyridin-2-carboxamide (intermediate 30) (80 mg, 0.31 mmol) in THF (3 mL). The resulting mixture was stirred at room temperature for 20 minutes. Sodium triacetoxyborohydride (266 mg, 1.26 mmol) was added. The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with MeOH (0.1 mL) and concentrated to provide the crude product. The crude product was purified by preparative HPLC (column: XBridge Shield RP18 OBD column, 19*250 mm, 10 μm; mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3·H2O), mobile phase B: MeOH- preparative; flow rate: 20 mL / min; gradient: 57 B to 80 B over 7 min; 254 / 220 nm). The fraction containing the desired compound was evaporated to dryness to give 6-chloro-5-[4-[(5-fluoro-2-methyl-3-oxo-4H-quinoxalo-6-yl)methyl]piperazin-1-yl]-N-methyl-pyridin-2-carboxamide (Example 30) (35.6 mg, 25%) as a white solid. 1H NMR (400MHz, DMSO-d6) 2.42 (3H, s), 2.58-2.66 (4H, m), 2.79 (3H, d), 3.06-3.16 (4H, m), 3.72 (2 19F NMR(376MHz, DMSO-d6)-135.45; m / z(ES + [M+H] + =445.

[0316]

[0317] Example 31: 5-[4-[(5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N6-dimethyl-pyridine-2-carboxamide

[0318] Titanium isopropoxide (105 mg, 0.37 mmol) was added to 5-fluoro-2-methyl-3-oxo- 4H-quinoxaline-6-carboxaldehyde (contaminated with 8-fluoro-3-methyl-2-oxo-1H- quinoxaline-5-carboxaldehyde) (intermediate 70) (150 mg, 0.36 mmol) and N,6-dimethyl- 5-piperazin-1-yl-pyridine-2-carboxamide, HC1 (intermediate 33) (100 mg, 0.37 mmol) in THF (3 mL). The resulting mixture was stirred at room temperature for 2 minutes. Sodium triacetoxyborohydride (313 mg, 1.48 mmol) was added. The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with MeOH (0.1 mL) and evaporated to provide crude product. The crude product was purified by preparative HPLC (Column: XBridge Shield RP18 OBD Column, 30*150mm, 5um; Mobile Phase A: Water (0.05% NH3H2O), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 19B to 39B in 7 minutes; 254 / 220 nm. Fractions containing the desired compound were evaporated to dryness to give 5-[4-[(5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N,6-dimethyl- pyridine-2-carboxamide (Example 31) as an off-white solid (12.39 mg, 8%).1H NMR (400 MHz, DMSO-c / 6) 2.42 (3H, s), 2.48 (3H, s), 2.57 - 2.67 (4H, m), 2.80 (3H, d), 2.90 - 2.98 (4H, m), 3.72 (2H, s), 7.30 (1H, t), 7.47 (1H, d), 7.52 (1H, d), 7.79 (1H, d), 8.39 - 8.46 (1H, m), 12.46 (1H, s);19F NMR (376 MHz, DMSO-c / 6) -135.52; m / z (ES+) [M+H] = 425. + [M+H] + = 425.

[0319]

[0320] Example 32: 5-[4-[(5-Fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methyl-pyridine- 2-carboxamide

[0321] Titanium isopropoxide (103 mg, 0.36 mmol) was added to 5-fluoro-2-methyl-3-oxo- 4H-quinoxaline-6-carboxaldehyde (contaminated with 8-fluoro-3-methyl-2-oxo-1H- quinoxaline-5-carboxaldehyde) (150 mg, 0.36 mmol) and N-methyl-5-(piperazin-1- yl)picolinamide (intermediate 31) (80 mg, 0.36 mmol) in THF (3 mL). The resulting mixture was stirred at room temperature for 2 minutes. Sodium triacetoxyborohydride (308 mg, 1.45 mmol) was added. The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with MeOH (0.1 mL). The reaction mixture was evaporated to give a crude product. The crude product was purified by preparative HPLC (Column: Xbridge Phenyl OBD column, 5um, 19*150mm; mobile phase A: water (0.05% TFA), mobile phase B: MeOH - preparative; flow rate: 20 mL / min; gradient: 24B to 32B in 12 min; 254 / 220 nm and (Column: XBridge Shield RP18 OBD column, 19*250mm, 10um; mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3.H2O), mobile phase B: ACN; flow rate: 20 mL / min; gradient: 15B to 30B in 10 min; 254 / 220 nm. Fractions containing the desired compound were evaporated to dryness to give 5-[4-[(5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N- methyl-pyridine-2-carboxamide as a white solid (12.4 mg, 8%).1H NMR (400 MHz, DMSO-d6) 2.42 (3H, s), 2.55-2.60 (4H, m), 2.78 (3H, d), 2.90-2.98 (4H, m, merged into water peak), 3.70 (2H, s), 7.30 (1H, t), 7.38 (1H, dd), 7.52 (1H, d), 7.82 (1H, d), 8.26 (1H, d), 8.38-8.43 (1H, m), 12.47 (1H, s);19F NMR (376 MHz, DMSO-d6) -135.48; m / z (ES+) [M+H] = 411. + [ M + H ] + = 411.

[0322]

[0323] Intermediate 72: 4-Bromo-3-fluoro-benzene-1,2-diamine

[0324] Iron powder (5.2 g, 93.11 mmol) was added to 4-bromo-3-fluoro-2-nitro- aniline (Intermediate 71) (7.3 g, 31.06 mmol) and HCI (10 mL, 100.00 mmol) (10 M) in MeOH (30 mL). The resulting mixture was stirred at room temperature for 18 hours. The solvent was removed under reduced pressure. The reaction mixture was basified with saturated Na2C03solution (100 mL). The aqueous layer was extracted with EtOAc (2 x 100 mL). The organic layer was dried over Na2S04, filtered and evaporated to yield 4-bromo-3-fluoro-benzene-1,2-diamine (Intermediate 72) (6.05 g, 95%) as a black solid.1H NMR (400 MHz, DMSO-d6) 4.66 (2H, s), 4.94 (2H, s), 6.30 (1H, dd), 6.56 (1H, dd); m / z (ES+) [M+H] = 205, 207. + [ M + H ] + = 205, 207.

[0325] Intermediate 73: 7-Bromo-8-fluoro-1 H-quinoxalin-2-one

[0326] Ethyl 2-oxoacetate (6.41 g, 31.39 mmol) in toluene was added to 4-bromo-3-fluoro- benzene-1,2-diamine (Intermediate 72) (4.46 g, 21.75 mmol) in toluene (30 mL). The resulting mixture was stirred at 100 °C for 30 minutes. The solvent was removed under reduced pressure. The reaction mixture was diluted with (PE: 10 mL and EA: 2 mL). The precipitate was collected by filtration, washed with EtOAc (5 mL) and dried under vacuum to yield 7-bromo-8-fluoro-1H-quinoxalin-2-one (Intermediate 73) (contaminated with 6-bromo-5-fluoro-1H-quinoxalin-2-one) (2.75 g, 52%) as an off-white solid. m / z (ES+) [M+H] = 243. + [ M + H ] + = 243.

[0327] Intermediate 74: 8-Fluoro-7-(hydroxymethyl)-1 H-quinoxalin-2-one

[0328] CataCXium A-Pd-G2 (0.12 g, 0.18 mmol) was added to (tributylstannyl)methanol (1.25 g, 3.89 mmol) and 7-bromo-8-fluoro-1H-quinoxalin-2-one (intermediate 73) (1 g, 2.06 mmol) (contaminated with 6-bromo-5-fluoro-1H-quinoxalin-2-one) in 1,4-dioxane (30 mL). The resulting mixture was stirred at 100 °C under nitrogen for 18 h. The reaction mixture was quenched with saturated KF (10 mL), filtered and evaporated to provide the crude product. The crude product was purified by flash C18 flash chromatography (elution gradient of 3 to 30% MeCN in water (0.1% formic acid). The pure fractions were evaporated to dryness to give 8-fluoro-7-(hydroxymethyl)-1H-quinoxalin-2-one (intermediate 74) (260 mg, 69%) as an off-white solid (contaminated with 5-fluoro-6-(hydroxymethyl)-1H-quinoxalin-2-one). m / z (ES+) 225.0 [M+H]. + [M+H] + = 195.

[0329] Example 33: 5-[4-[(5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin- 1 -yl] -N- methyl-pyridine-2-carboxamide Example 34: 6-chloro-5-[4-[(5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin- 1 -yl] -N- methyl-pyridine-2-carboxamide

[0330] SOCl2(0.3 mL, 4.11 mmol) was added to 8-fluoro-7-(hydroxymethyl)-1H- quinoxalin-2-one (intermediate 74) (158 mg, 0.41 mmol) (contaminated with 5-fluoro-6- (hydroxymethyl)-1H-quinoxalin-2-one) in DCM (3 mL). The resulting mixture was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure. DIPEA (0.25 mL, 1.43 mmol) and N-methyl-5-piperazin-1-yl-pyridine-2-carboxamide (intermediate 31) (141 mg, 0.64 mmol) were added to the mixture in NMP (3.00 mL). The resulting mixture was stirred at 80 °C for 1 hour. The crude product was purified by preparative HPLC (column: XBridge Prep OBD C18 Column, 19*250mm, 5um; mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3.H2O), mobile phase B: ACN; flow rate: 20 mL / min; gradient: 18B to 24B in 9 minutes; 254; 220 nm). Fractions containing the desired compound were evaporated to dryness to give 5-[4-[(5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methyl- pyridine-2-carboxamide (example 33) as a white solid (13.00 mg, 8%).1H NMR (400 MHz, DMSO-d6) 2.55-2.60 (4H, m), 2.77 (3H, d), 3.28-3.33 (4H, m), 3.71 (2H, s), 7.30-7.42 (2H, m), 7.61 (1H, d), 7.82 (1H, d), 8.20 (1H, s), 8.25 (1H, d), 8.37-8.42 (1H, m);19F NMR (376 MHz, DMSO-d6) -129.26; m / z (ES+) [M+H] 397.2. + [M+H] + = 397.

[0331]

[0332] Example 35: 5-[4-[(5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin- 1 -yl] -N,6- dimethyl-pyridine-2-carboxamide Example 36: 6-fluoro-5-[4-[(5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin- 1 -yl] -N- methyl-pyridine-2-carboxamide

[0333] SOCl2(0.3 mL, 4.11 mmol) was added to 8-fluoro-7-(hydroxymethyl)-1H- quinoxalin-2-one (intermediate 74) (contaminated with 5-fluoro-6- (hydroxymethyl)-1H-quinoxalin-2-one) (143 mg, 0.37 mmol) in DCM (3 mL). The resulting mixture was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure. DIPEA (0.25 mL, 1.43 mmol) and 6-chloro-N-methyl-5-piperazin-1-yl- pyridine-2-carboxamide (intermediate 30) (101 mg, 0.40 mmol) were added to the mixture in NMP (3.00 mL). The resulting mixture was stirred at 80 °C for 1 hour. The crude product was purified by preparative HPLC (column: XBridge Prep OBD C18 Column, 19*250mm, 5um; mobile phase A: water (10 MMOL / L NH4HCO3 + 0.1% NH3.H2O), mobile phase B: ACN; flow rate: 20 mL / min; gradient: from 25B to 28B in 9 minutes; 254 / 220 nm. Fractions containing the desired compound were evaporated to dryness to give 6-chloro-5-[4-[(5-fluoro-3-oxo-4H- quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2-carboxamide (Example 34) as a white solid (23.0 mg, 14%).1H NMR (400 MHz, DMSO-d6) 2.58-2.65 (4H, m), 2.78 (3H, d), 3.07-3.14 (4H, m), 3.73 (2H, s), 7.35 (1H, dd), 7.61 (1H, d), 7.65 (1H, d), 7.93 (1H, d), 8.20 (1H, s), 8.41-8.45 (1H, m), 12.58 (1H, s);19F NMR (376 MHz, DMSO-d6) -135.18; m / z (ES+) [M+H] 431.2. + [M+H] + 431.

[0334]

[0335] Example 37: 5-[4-[[2-(difluoromethyl)-5-fluoro-3-oxo-4H-quinoxalin-6-yl]methyl]piperazin- 1 -yl] -N,6-dimethyl-pyridine-2-carboxamide Intermediate 72: 4-bromo-3-fluoro-benzene- 1,2-diamine

[0336] SOCl2(0.3 mL, 4.11 mmol) was added to 8-fluoro-7-(hydroxymethyl)-1H- quinoxalin-2-one (intermediate 74) contaminated with 5-fluoro-6-(hydroxymethyl)- 1H-quinoxalin-2-one (143 mg, 0.37 mmol) in DCM (3 mL) (153 mg, 0.39 mmol). The resulting mixture was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure. DIPEA (0.25 mL, 1.43 mmol) and N,6-dimethyl-5-piperazin-1-yl-pyridine-2- carboxamide (intermediate 33) (137 mg, 0.58 mmol) in NMP (3 mL) were added to the mixture. The resulting mixture was stirred at 80 °C for 1 hour. The crude product was purified by preparative HPLC (column: XBridge Prep OBD C18 Column, 19*250mm, 5um; mobile phase A: water (10 MMOL / L NH4HCO3 + 0.1% NH3.H2O), mobile phase B: ACN; flow rate: 20 mL / min; gradient: from 24B to 28B in 9 minutes; 254 / 220 nm. Fractions containing the desired compound were evaporated to dryness to give 5-[4-[(5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N,6-dimethyl- pyridine-2-carboxamide (example 35) as a white solid (13.0 mg, 8%).1H NMR (400 MHz, DMSO-d6) 2.48 (3H, s), 2.56-2.65 (4H, s), 2.79 (3H, d), 2.92-2.97 (4H, m), 3.73 (2H, s), 7.31-7.39 (1H, m), 7.47 (1H, d), 7.61 (1H, d), 7.78 (1H, d), 8.19 (1H, s), 8.39-8.44 (1H, m), 12.55 (1H, s);19F NMR (376 MHz, DMSO-d6) -135.25; m / z (ES+) [M+H] = 411. + [M+H] + = 411.

[0337]

[0338] Intermediate 75: 7-bromo-8-fluoro-3-methoxy-lH-quinoxalin-2-one Intermediate 76: 8-fluoro-7-(hydroxymethyl)-3-methoxy-lH-quinoxalin-2-one

[0339] SOCl2(0.3 mL, 4.11 mmol) was added to 8-fluoro-7-(hydroxymethyl)-1 H- quinoxalin-2-one (contaminated with 5-fluoro-6-(hydroxymethyl)-1 H-quinoxalin-2-one) (144 mg, 0.37 mmol) in DCM (3 mL). The resulting mixture was stirred at room temperature for 1 h. The solvent was removed under reduced pressure. DIPEA (0.25 mL, 1.43 mmol) and 6-fluoro-N-methyl-5-piperazin-1 -yl-pyridine-2- carboxamide (Intermediate 32) (94 mg, 0.39 mmol) were added to the mixture in NMP (3.00 mL). The resulting mixture was stirred at 80 °C for 1 h. The crude product was purified by preparative HPLC (Column: XBridge Prep OBD C18 Column, 19*250mm, 5um; Mobile Phase A: Water (10 MMOL / L NH4HCO3 + 0.1% NH3.H2O), Mobile Phase B: ACN; Flow Rate: 20 mL / min; Gradient: 23B to 25B in 9 min; 254 / 220 nm; RT1: 6.9, 8.46. Fractions containing the desired compound were evaporated to dryness to give 6-fluoro-5-[4-[(5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2-carboxamide (Example 36) as a white solid (16.0 mg, 10%).1H NMR (400 MHz, DMSO-c / 6) 2.56-2.62 (4H, m), 2.76 (3H, d), 3.13-3.20 (4H, m), 3.71 (2H, d), 7.33 (1H, dd), 7.55 (1H, t), 7.61 (1H, d), 7.83 (1H, dd), 8.19 (1H, s), 8.37-8.43 (1H, m), 12.56 (1H, br s);19F NMR (376 MHz, DMSO-c / 6) -72.57, -135.21 ; m / z (ES+) [M+H] = 415. + [M+H] + = 415.

[0340]

[0341] Intermediate 77: 7-(chloromethyl)-8-fluoro-3-methoxy-lH-quinoxalin-2-one Example 38: 5-[4-[(5-fluoro-2-methoxy-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin- 1 -yl] -N- methyl-pyridine-2-carboxamide

[0342] A solution of iron(ll) chloride (6.18 mg, 0.05 mmol) and zinc(ll) difluoromethanesulfinate (86 mg, 0.29 mmol) in water (0.5 mL) was added portionwise to a stirred solution of 5-[4-[(5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N,6-dimethyl-pyridine-2-carboxamide (Example 35) (40.0 mg, 0.10 mmol) and TFA (7.51 μΐ, 0.10 mmol) in DMSO (3 mL) at room temperature. Subsequently, tert-butyl hydroperoxide (9.44 μΐ, 0.10 mmol) was added and the resulting mixture was stirred at room temperature for 2 hours. The crude product was purified by preparative HPLC (column, column: XBridge Prep OBD C18 Column, 30 x 150 mm, 5 um; mobile phase A: water (0.05% NH3H20), mobile phase B: ACN; flow rate: 60 mL / min; gradient: from 12% B to 32% B in 7 minutes; 254 / 220 nm; Rt: 6.07 min. Fractions containing the desired compound were evaporated to dryness to give 5-[4-[[2-(difluoromethyl)-5-fluoro-3-oxo-4H-quinoxalin-6-yl]methyl]piperazin-1-yl]-N,6-dimethyl-pyridine-2-carboxamide (Example 37) as a light yellow solid (2.2 mg, 5%).1H NMR (400 MHz, DMSO-d6) 2.49 (3H, s), 2.60-2.65 (4H, m), 2.80 (3H, d), 2.92-2.99 (4H, m), 3.76 (2H, s), 7.08 (1H, t), 7.39 (1H, t), 7.48 (1H, d), 7.70 (1H, d), 7.79 (1H, d), 8.42 (1H, q), 13.01 (1H, s);19F NMR (376 MHz, DMSO-d6) -124.324, -134.183; m / z (ES+) [M+H] = 461. + [ M + H ] + = 461.

[0343]

[0344] Example 39: 6-fluoro-5-[4-[(5-fluoro-2-methoxy-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin- 1 -yl] -N- methyl-pyridine-2-carboxamide

[0345] Iron powder (3.56 g, 63.83 mmol) was added to 4-bromo-3-fluoro-2-nitro- aniline (Intermediate 71) (3.00 g, 12.77 mmol), concentrated hydrogen chloride (10.64 ml, 127.65 mmol) in MeOH (30 ml) at room temperature. The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with water (100 ml) and extracted with ethyl acetate (100 ml x 3). The organic layer was dried over MgS04, filtered and evaporated to give 4-bromo-3-fluoro-benzene-1,2-diamine (Intermediate 72) (2.5 g, 96%).1H NMR (400 MHz, DMSO-c / 6) 4.66 (2H, s), 4.94 (2H, s), 6.30 (dd, 1 H), 6.56 (dd, 1 H); m / z (ES+) [M+H] = 205. + [ M + H ] + = 205.

[0346] Example 40: 5-[4-[(5-fluoro-2-methoxy-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin- 1 -yl] -N,6- dimethyl-pyridine-2-carboxamide

[0347] Methyl 2,2,2-trimethoxyacetate (2.402 g, 14.63 mmol) was added to 4-bromo-3- fluorobenzene-1,2-diamine (Intermediate 72) (1.500 g, 7.32 mmol), ytterbium tris(((trifluoromethyl)sulfonyl)oxy) (0.454 g, 0.73 mmol) in toluene (20 ml) at room temperature. The resulting mixture was stirred at 100 °C for 5 hours. The solvent was removed under reduced pressure. The crude product was purified by reverse phase chromatography on a C18 column eluting with a gradient of 5% to 70% MeCN in water. The pure fractions were evaporated to dryness to give 7-bromo-8-fluoro-3-methoxy-1 H-quinoxalin-2-one (Intermediate 75) (0.650 g, 32%) as a white solid.1H NMR (300 MHz, DMSO-c / 6) 3.97 (3H, s), 7.31 (1 H, dd), 7.45 (1 H, dd); m / z (ES+) [M+H] = 273. + [ M + H ] + = 273.

[0348] Example 41 : 6-chloro-5-[4-[(5-fluoro-2-methoxy-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin- 1 -yl] -N- methyl-pyridine-2-carboxamide

[0349] (triphenylphosphoranylidene)propanedinitrile (1.0 g, 3.3 mmol) was added to a stirred solution of 7-bromo-8-fluoro-3-methoxyquinoxalin-2(lH)-one (intermediate 75) (300.0 mg, 1.1 mmol) in 1,4-dioxane (20 mL) at room temperature under nitrogen. The resulting mixture was stirred at 100 °C for 16 h. The reaction mixture was quenched with saturated KF (10 mL) and then filtered. The solvent was removed under reduced pressure. The crude product was purified by reverse phase chromatography on a C18 column eluting with a gradient of 5% to 100% MeOH in water. Pure fractions were evaporated to dryness to give 8-fluoro-7-(hydroxymethyl)-3-methoxy-lH-quinoxalin-2-one (intermediate 76) (130 mg, 53%) as a white solid.1H NMR (300 MHz, DMSO-c / 6) 3.97 (3H, s), 4.88 (2H, d), 5.36 (1H, s), 7.27-7.32 (1H, m), 7.36 (1H, d), 12.45 (1H, s); m / z (ES+) [M+H] = 225. + [M+H] + = 225.

[0350] Intermediate 78: 2-(4-bromo-3-methyl-2-nitro-anilino)butanoic acid

[0351] SOCl2(8 ml, 109.62 mmol) was added to 8-fluoro-7-(hydroxymethyl)-3-methoxy-lH- quinoxalin-2-one (intermediate 76) (50.0 mg, 0.22 mmol) in diethyl ether (50 mL) at room temperature. The resulting mixture was stirred at room temperature for 16 h. The solvent was removed under reduced pressure to give 7-(chloromethyl)-8-fluoro-3-methoxy-lH- quinoxalin-2-one (intermediate 77) (66.7 mg, 122%, crude) as a yellow oil. This product was used directly in the next step without further purification.1H NMR (300 MHz, DMSO-c / 6) 3.97 (3H, s), 4.88 (2H, s), 7.27-7.42 (2H, m), 12.60 (1H, s) m / z (ES+) [M+H] = 243. + [M+H] + = 243.

[0352] Intermediate 79: 7-bromo-3-ethyl-8-methyl-3,4-trihydro-lH-quinoxalin-2-one Intermediate 80: 7-bromo-3-ethyl-8-methyl-lH-quinoxalin-2-one

[0353] N-methyl-5-piperazin-1-yl-pyridine-2-carboxamide (Intermediate 31) (150 mg, 0.68 mmol) was added to 7-(chloromethyl)-8-fluoro-3-methoxy-1H-quinoxalin-2-one (Intermediate 77) (198 mg, 0.82 mmol), DIPEA (0.595 mL, 3.40 mmol) in MeCN (10 mL) at room temperature. The resulting mixture was stirred at 60 °C for 16 h. The solvent was removed under reduced pressure. The crude product was purified by flash C18-fast chromatography (elution gradient 5% to 70% MeCN in water). The pure fractions were evaporated to dryness to give the product as a yellow solid (103.0 mg) (UV purity 80%). Repurification by flash C18-fast chromatography with an elution gradient 5% to 70% MeCN in water. The pure fractions were evaporated to dryness to give 5-[4-[(5-fluoro-2-methoxy-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2-carboxamide (Example 38) as a yellow solid (36.0 mg, 12%).1H NMR (300 MHz, DMSO-c / 6) 2.51 - 2.60 (4H, m), 2.77 (3H, d), 3.18 - 3.45 (4H, m), 3.66 (2H, s), 3.95 (3H, s), 7.10 - 7.27 (1H, m), 7.27 - 7.42 (2H, m), 7.81 (1H, d), 8.25 (1H, d), 8.39 (1H, q), 12.30 (1H, s);19F NMR (282 MHz, DMSO-c / 6) -134.783; m / z (ES+) [M+H] 427.2. + 427. + 427.

[0354]

[0355] Intermediate 81 : 3-ethyl-7-(hydroxymethyl)-8-methyl-lH-quinoxalin-2-one Example 42: 5-[4-[(2-ethyl-5-methyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin- 1 -yl] -N6- dimethyl-pyridine-2-carboxamide

[0356] SOCl2(0.065 mL, 0.89 mmol) was added to 8-fluoro-7-(hydroxymethyl)-3- methoxy-1 H-quinoxalin-2-one (Intermediate 76) (0.040 g, 0.18 mmol) in diethyl ether (10 mL) at room temperature. The resulting mixture was stirred at room temperature for 16 hours. The solvent was removed under reduced pressure. 6-Fluoro-N-methyl-5-piperazin-1-yl- pyridine-2-carboxamide (Intermediate 32) (0.043 g, 0.18 mmol) and DIPEA (0.156 mL, 0.89 mmol) in MeCN (10.00 mL) were added to the above solid at room temperature. The resulting mixture was stirred at 60 °C for 16 hours. The solvent was removed under reduced pressure. The crude product was purified by preparative HPLC column, Column: XBridge Shield RP18 OBD Column, 19*250mm, 10um; Mobile Phase A: Water (10mmol / L NH4HCO3 + 0.1% NH3.H2O), Mobile Phase B: ACN; Flow rate: 20 mL / min; Gradient: 34B to 48B in 7 minutes; 254 / 220 nm; RT1: 5.9. Fractions containing the desired compound were evaporated to dryness to give 6-fluoro-5-[4-[(5-fluoro-2-methoxy-3-oxo-4H- quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2-carboxamide (Example 39) (0.020 g, 25%) as a white solid.1H NMR (300 MHz, DMSO-d6) 2.55-2.61 (4H, m), 2.75 (3H, d), 3.11-3.19 (4H, m), 3.67 (2H, s), 3.96 (3H, s), 7.18-7.29 (1H, m), 7.35 (1H, d), 7.55 (1H, dd), 7.79-7.88 (1H, m), 8.41 (1H, d), 12.50 (1H, s);19F NMR (282 MHz, DMSO-d6) -72.581, -134.799; m / z (ES+) [M+H] 445.2. + [M+H] + 445.2.

[0357]

[0358] Example 43: 5-[4-[(2-ethyl-5-methyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin- 1 -yl] -6- fluoro-N-methyl-pyridine-2-carboxamide Example 44: 5-[4-[(2-ethyl-5-methyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin- 1 -yl] -N- methyl-pyridine-2-carboxamide

[0359] N,6-Dimethyl-5-piperazin-1-ylpyridin-2-carboxamide (intermediate 33) (0.097 g, 0.41 mmol) was added to 7-(chloromethyl)-8-fluoro-3-methoxyquinoxaline-2(1H)-one (intermediate 77) (0.100 g, 0.41 mmol) and DIPEA (0.360 mL, 2.06 mmol) in MeCN (10 mL) at room temperature. The resulting mixture was stirred at 60 °C for 16 hours. The solvent was removed under reduced pressure. The crude product was purified by preparative HPLC using an XBridge Prep OBD C18 column (30 × 150 mm 5 μm) and mobile phase A: water (0.05% NH3H2). O Mobile phase B: ACN; flow rate: 60 mL / min; gradient: from 10B to 30B over 7 minutes; 254 / 220 nm. The fraction containing the desired compound was evaporated to dryness to give 5-[4-[(5-fluoro-2-methoxy-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N,6-dimethyl-pyridine-2-carboxamide (Example 40) (0.063 g, 35%) as a white solid. 1H NMR (400MHz, DMSO-d6) 2.48 (3H, s), 2.58-2.63 (4H, m), 2.80 (3H, d), 2.92-2.96 (4H, m), 3.69 (2H, s 19F NMR(376MHz, DMSO-d6)-134.815; m / z(ES + [M+H] + =441.

[0360]

[0361] ​ ​

[0362] SOCl2(0.065 mL, 0.89 mmol) was added to 8-fluoro-7-(hydroxymethyl)-3- methoxy-1 H-quinoxalin-2-one (Intermediate 76) (0.040 g, 0.18 mmol) in diethyl ether (10 mL) at room temperature. The resulting mixture was stirred at room temperature for 16 hours. The solvent was removed under reduced pressure to give crude 7-(chloromethyl)-8- fluoro-3-methoxy-1 H-quinoxalin-2-one (0.045 g, 0.18 mmol). To the above solid was added MeCN (10.00 mL) followed by 6-chloro-N-methyl-5-piperazin-1-yl- pyridine-2-carboxamide (Intermediate 30) (0.045 g, 0.18 mmol) and DIPEA (0.156 mL, 0.89 mmol). The resulting mixture was stirred at 80 °C for 16 hours. The solvent was removed under reduced pressure. The crude product was purified by preparative HPLC column: YMC-Actus Triart C18, 30*250,5um; Mobile Phase A: Water (0.05% NH3H2O), Mobile Phase B: ACN; Flow Rate: 60 mL / min; Gradient: 21B to 41B in 7 minutes; 254, 220 nm; RT1: 6.18. Fractions containing the desired compound were evaporated to dryness to give 6-chloro-5-[4-[(5-fluoro-2-methoxy-3-oxo-4H- quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2-carboxamide (Example 41) as a white solid (0.041 g, 50%).1H NMR (300 MHz, DMSO-d6) 2.56-2.66 (4H, m), 2.79 (3H, d), 3.06 3.16 (4H, m), 3.70 (2H, s), 3.97 (3H, s), 7.19-7.30 (m, 1H), 7.36 (d, 1H), 7.66 (d, 1H), 7.93 (d, 1H), 8.44 (d, 1H), 12.47 (s, 1H);19F NMR (282 MHz, DMSO-d6) -134.746; m / z (ES+) [M+H] 461.2. + [M+H] + = 461.

[0363]

[0364] ​

[0365] Intermediate 78 (1.4 g, 74%) as a yellow solid (not very pure, used directly in the next step without further purification). m / z (ES+) [M+H] 317.0 Rf = 0.45 (Dichloromethane). + [M+H] + = 317.

[0366] ​

[0367] Iron powder (1.585 g, 28.38 mmol) was added slowly to 2-(4-bromo-3-methyl-2-nitro- anilino)butanoic acid (Intermediate 78) (1.800 g, 5.68 mmol), concentrated hydrogen chloride (4.73 ml, 56.76 mmol) in MeOH (100 ml) at room temperature. The resulting mixture was stirred at room temperature for 7 hours. The reaction mixture was filtered. The solvent was removed under reduced pressure. The reaction mixture was quenched with saturated Na2CO3(40 ml) and extracted with EtOAc (3 x 50 ml). The organic layer was dried over Na2SO4, filtered and evaporated to give a brown solid. The crude product was purified by flash C18-fast chromatography (elution gradient 5% to 50% MeCN in water). The pure fractions were evaporated to dryness to give 7-bromo-3-ethyl-8-methyl-3,4-dihydro-1H- quinoxalin-2-one (Intermediate 79) (650 mg, 43%) as a white solid.1H NMR (300 MHz, DMSO-d6) 0.90 (3H, t), 1.43 - 1.72 (2H, m), 2.22 (3H, s), 3.56 (1H, ddd), 6.16 (1H, d), 6.56 (1H, d), 6.97 (1H, d), 9.76 (1H, s); m / z (ES+) [M+H] 269.0 Rf = 0.45 (Dichloromethane). + [M+H] + = 317.

[0368] ​

[0369] DDQ (1.316 g, 5.80 mmol) was added to 7-bromo-3-ethyl-8-methyl-3,4-dihydro-1H- quinoxalin-2-one (Intermediate 79) (1.300 g, 4.83 mmol) in 1,4-dioxane (150 mL) at room temperature. The resulting mixture was stirred at room temperature for 3 hours. The solvent was removed under reduced pressure. The reaction mixture was quenched with saturated NaHC03(150 mL). The precipitate was collected by filtration. The solid was washed with water (10 mL x 3) and dried under vacuum to give the desired product 7-bromo-3-ethyl-8-methyl-1H- quinoxalin-2-one (Intermediate 80) as a yellow solid (1.2 g, 93%).1H NMR (300 MHz, DMSO-c / 6) 1.20 (3H, t), 2.44 - 2.53 (3H, m), 2.78 (2H, q), 7.48 (2H, s), 11.74 (1H, s); m / z (ES+) [M+H] 267.0. + [M+H] + = 267.

[0370] ​

[0371] (tri-n-butylstannyl)methanol (1202 mg, 3.74 mmol) was added to 7-bromo-3-ethyl-8- methylquinoxalin-2(1H)-one (Intermediate 80) (400 mg, 1.50 mmol), Pd(PPh3)4(173 mg, 0.15 mmol) in 1,4-dioxane (40 mL) at room temperature under nitrogen. The resulting mixture was stirred at 60 °C for 16 hours. The reaction mixture was quenched with KF (10 mL) and the solid was filtered off. The solvent was removed under reduced pressure. The crude product was purified by flash C18-fast chromatography eluting with a gradient of 5% to 100% MeOH in water. The pure fractions were evaporated to dryness to give 3-ethyl-7-(hydroxymethyl)-8-methyl-1H- quinoxalin-2-one (Intermediate 81) as a white solid (100 mg, 31%).1H NMR (400 MHz, DMSO-c / 6) 1.22 (3H, t), 2.32 (3H, s), 2.81 (2H, q), 4.59 (2H, d), 5.25 (1H, s), 7.33 (1H, d), 7.55 (1H, d); m / z (ES+) [M+H] 219.0. + [M+H] + = 219.

[0372] ​ ​

[0373] A solution of HBr in AcOH (1 ml, 6.08 mmol) (33 w%) was added to 3-ethyl-7- (hydroxymethyl)-8-methylquinoxalin-2(lH)-one (Intermediate 81) (65.0 mg, 0.30 mmol) at room temperature. The resulting mixture was stirred at 60 °C for 2 hours. The solvent was removed under reduced pressure. N,6-dimethyl-5-piperazin-l-yl-pyridine-2-carboxamide (Intermediate 33) (69.8 mg, 0.30 mmol) and DIPEA (0.156 ml, 0.89 mmol) in NMP (3 mL) were added to the above solid at room temperature. The resulting mixture was stirred at 60 °C for 2 hours. The crude product was purified by preparative HPLC (column, column: Sunfire prep C18 column, 30*150, 5um; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 9B to 20B in 7 minutes; 254 / 220 nm; RT1: 5.15; fractions containing the desired compound were evaporated to dryness to give 5-[4-[(2-ethyl-5-methyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-l-yl]-N,6-dimethyl-pyridine-2-carboxamide (Example 42) as a light yellow solid (0.049 g, 38%).1H NMR (300 MHz, DMSO-c / 6) 1.20 (3H, t), 2.42 (3H, s), 2.50 (3H, s), 2.53-2.59 (4H, m), 2.73-2.86 (5H, m), 2.87-2.93 (4H, m), 3.61 (2H, s), 7.23 (IH, d), 7.45 (IH, d), 7.52 (IH, d), 7.76 (IH, d), 8.39 (IH, d), 11.52 (IH, s); m / z (ES+) [M+H] 435.3. + [M+H] + = 435.

[0374]

[0375] ​ ​

[0376] A solution of HBr in AcOH (1 ml, 6.08 mmol) (33 w%) was added to 3-ethyl-7- (hydroxymethyl)-8-methyl-lH-quinoxalin-2-one (intermediate 81) (65.0 mg, 0.30 mmol) at room temperature. The resulting mixture was stirred at 60 °C for 2 hours. The solvent was removed under reduced pressure. 6-Fluoro-N-methyl-5-(piperazin-l-yl)picolinamide (intermediate 32) (71.0 mg, 0.30 mmol) was added to the above solid at room temperature followed by the addition of DIPEA (0.156 ml, 0.89 mmol) in NMP (3 mL). The resulting mixture was stirred at 60 °C for 2 hours. The crude product was purified by preparative HPLC (column, column: XBridge Prep OBD C18 Column, 30 x 150 mm, 5 um; mobile phase A: water (0.05% NH3H20), mobile phase B: ACN; flow rate: 60 mL / min; gradient: from 31 B to 51 B in 7 minutes; 254 / 220 nm; RT1: 6.27; fractions containing the desired compound were evaporated to dryness to give 5-[4-[(2-ethyl-5-methyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-l-yl]-6-fluoro-N- methyl-pyridine-2-carboxamide (example 43) as a light yellow solid (0.043 g, 33%).1H NMR (300 MHz, DMSO-c / 6) 1.20 (3H, t), 2.41 (3H, s), 2.49 - 2.59 (4H, m), 2.70 - 2.81 (5H, m), 3.08 - 3.16 (4H, m), 3.59 (2H, s), 7.22 (1H, d), 7.47 - 7.60 (2H, m), 7.82 (1H, dd), 8.37 (1H, d), 11.52 (1H, s);19F NMR (282 MHz, DMSO-c / 6) -72.539; m / z (ES+) [M+H] 439.2. + [M+H] + = 439.

[0377]

[0378] ​ Methyl-pyridine-2-carboxamide

[0379] A solution of HBr in AcOH (1 ml, 18.42 mmol) (33 wt%) was added to 3-ethyl-7- (hydroxymethyl)-8-methyl-lH-quinoxalin-2-one (Intermediate 81) (65.0 mg, 0.30 mmol) at room temperature. The resulting mixture was stirred at 60 °C for 2 hours. The solvent was removed under reduced pressure. N-methyl-5-(piperazin-l-yl)picolinamide (Intermediate 31) (65.6 mg, 0.30 mmol) and DIPEA (0.156 ml, 0.89 mmol) were added to the above solid in NMP (3 mL) at room temperature. The resulting mixture was stirred at 60 °C for 2 hours. The crude product was purified by preparative HPLC (Column: Sunfire prep C18 column, 30*150, 5um; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 9B to 20B in 7 minutes; 254 / 220 nm; RT1: 5.15; Fractions containing the desired compound were evaporated to dryness to give 5-[4-[(2-ethyl-5-methyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-l-yl]-N- methyl-pyridine-2-carboxamide (Example 44) as a light yellow solid (0.014 g, 10%).1H NMR (400 MHz, DMSO-c / 6) 1.16-1.26 (3H, m), 2.41 (3H, s), 2.49-2.59 (4H, m), 2.70-2.81 (5H, m), 3.30-3.35 (4H, m, merged into water peak), 3.61 (2H, s), 7.25 (1H, d), 7.38 (1H, d), 7.55 (1H, d), 7.82 (1H, d), 8.26 (1H, s), 8.38 (1H, s), 11.53 (1H, s); m / z (ES+) [M+H] 421.2. + [M+H] + = 421.

[0380]

[0381] Intermediate 82: tert-Butyl 4-[6-(ethylcarbamoyl)-2-fluoro-3-pyridyl]piperazine-1- carboxylate

[0382] tert-Butyl 4-(2-fluoro-6-methoxycarbonyl-3-pyridyl)piperazine-1 -carboxylate (Intermediate 11) (500 mg, 1.47 mmol) was added to an aqueous solution of ethylamine (10 mL, 1.47 mmol) (65 wt%). The resulting mixture was stirred at room temperature for 2 hours. The reaction was complete. The precipitate was collected by filtration, washed with water (2 mL x 3) and dried under vacuum to afford tert-butyl 4-[6-(ethylcarbamoyl)-2-fluoro-3-pyridyl]piperazine-1 -carboxylate (Intermediate 82) as an off-white solid (0.515 g, 99%).1H NMR (400 MHz, DMSO-c / 6) 1.09 (3H, t), 1.42 (9H, s), 3.11 (4H, t), 3.23-3.30 (2H, m), 3.49 (4H, t), 7.59 (1H, dd), 7.85 (1H, d), 8.45 (1H, t); m / z (ES+) [M+H] = 353. + [ M + H ] + = 353.

[0383] Intermediate 83: N-Ethyl-6-fluoro-5-piperazin-1-yl-pyridine-2-carboxamide

[0384] tert-Butyl 4-[6-(ethylcarbamoyl)-2-fluoro-3-pyridyl]piperazine-1 -carboxylate (Intermediate 82) (536 mg, 1.52 mmol) was added to a solution of HC1 in 1,4-dioxane (5 mL, 20.00 mmol). The resulting mixture was stirred at room temperature for 1 hour. DIPEA (5 mL) was added and the resulting mixture was stirred at room temperature for 15 minutes. The reaction mixture was evaporated to give a crude product. The crude product was purified by flash C18-fast chromatography (eluting with a gradient of 5% to 50% MeCN in water (0.1 % NH4HCO3)). The pure fractions were evaporated to dryness to give N-ethyl-6-fluoro-5-piperazin-1 -yl-pyridine-2-carboxamide (Intermediate 83) as a yellow solid (0.368 g, 96%). The sample was impure and used directly in the next step without further purification; m / z (ES+) [M+H] = 253. + [ M + H ] + = 253.

[0385] Example 45: N-Ethyl-6-fluoro-5-[4-[(5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]pyridine-2-carboxamide Intermediate 84: 5-Bromo-N-ethyl-6-methyl-pyridine-2-carboxamide

[0386] Ph3P (94 mg, 0.36 mmol) was added to CBr4 (119 mg, 0.36 mmol), 8-fluoro-7- (hydroxymethyl)-3-methylquinoxalin-2(lH)-one (Intermediate 17) (50 mg, 0.24 mmol) in CH2CI2 (3 mL). The resulting mixture was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure. N-ethyl-6-fluoro-5-piperazin-l-yl- pyridine-2-carboxamide (Intermediate 83) (60 mg, 0.24 mmol) and DIPEA (1.5 mL, 8.59 mmol) in NMP (3 mL) were added to the mixture. The resulting mixture was stirred at 80 °C for 2 hours. The solvent was removed under reduced pressure. The crude product was purified by flash C18 flash chromatography (eluting with a gradient of 0 to 25% MeCN in water (NH4HCO3)). The pure fractions were evaporated to dryness to give N-ethyl-6-fluoro-5-[4-[(5-fluoro-2-methyl-3-oxo-4H- quinoxalin-6-yl)methyl]piperazin-l-yl]pyridine-2-carboxamide (Example 45) (2.60 mg, 3%) as a white solid.1H NMR (300 MHz, DMSO-c / 6) 1.09 (3H, t), 2.40 (3H, s), 2.52-2.62 (4H, m), 3.17-3.27 (4H, m), 3.25 (2H, q), 3.68 (2H, s), 7.28 (1H, t), 7.48-7.59 (2H, m), 7.82 (1H, d), 8.41 (1H, t), 12.48 (1H, s);19F NMR (282 MHz, DMSO-c / 6) -72.58, -135.52; m / z (ES+) [M+H] 443.2. + 443.2. + 443.2.

[0387]

[0388] Intermediate 85: tert-Butyl 4-[6-(ethylcarbamoyl)-2-methyl-3-pyridyl]piperazine-1- carboxylate

[0389] A H2O solution of ethylamine (3 mL, 2.20 mmol) (65 wt%) was added to methyl 5-bromo-6-methyl-pyridine-2-carboxylate (Intermediate 14) (505 mg, 2.20 mmol). The resulting mixture was stirred at room temperature for 18 hours. The solvent was removed under reduced pressure to give 5-bromo-N-ethyl-6-methyl-pyridine-2-carboxamide (Intermediate 84) (0.500 g, 94%) as a yellow solid.1H NMR (300 MHz, DMSO-c / 6) 1.13 (3H, t), 2.66 (3H, s), 3.26-3.39 (2H, m), 7.76 (1H, d), 8.18 (1H, d), 8.67-8.72 (1H, m); m / z (ES+) [M+H] 245.0. +)[M+H] + = 243.

[0390] Intermediate 86: N-Ethyl-6-methyl-5-piperazin-1-yl-pyridine-2-carboxamide

[0391] Cs2CO3(1.340 g, 4.11 mmol) was added to 5-bromo-N-ethyl-6-methyl- pyridine-2-carboxamide (Intermediate 84) (0.5 g, 2.06 mmol), piperazine-1- carboxylic acid tert-butyl ester (0.575 g, 3.09 mmol), BINAP (0.128 g, 0.21 mmol) and Pd(OAc)2(0.046 g, 0.21 mmol) in 1,4-dioxane (5 mL). The resulting mixture was stirred at 100 °C under nitrogen for 18 h. The reaction mixture was diluted with EtOAc (10 mL) and washed sequentially with water (10 mL x 2) and brine (10 mL x 1). The organic layer was dried over Na2SO4, filtered and evaporated to give a crude product. The crude product was purified by flash silica chromatography (elution gradient 0 to 40% EtOAc in petroleum ether). The pure fractions were evaporated to dryness to give 4-[6-(ethylcarbamoyl)-2-methyl-3-pyridyl]piperazine-1- carboxylic acid tert-butyl ester (Intermediate 85) as a yellow solid (0.481 g, 67%).1H NMR (300 MHz, Chloroform-d) 1.26 (3H, t), 1.49 (9H, s), 2.54 (3H, s), 2.85-2.98 (4H, m), 3.49 (2H, qd), 3.56-3.65 (4H, m), 7.32 (1H, d), 7.91-8.01 (2H, m); m / z (ES+) [M+H] 391.3. + )[M+H] + = 349.

[0392] Example 46: N-Ethyl-5-[4-[(5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-6-methyl-pyridine-2-carboxamide

[0393] A solution of HC1 in 1,4-dioxane (4 ml, 16.00 mmol, 4M) was added to tert- butyl 4-[6-(ethylcarbamoyl)-2-methyl-3-pyridyl]piperazine-1 -carboxylate (Intermediate 85) (0.481 g, 1.38 mmol) in MeOH (10 mL). The resulting mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure. The reaction mixture was basified with a solution of DIPEA (1 mL) in MeOH (3 mL). The solvent was removed under reduced pressure. The crude product was purified by flash C18 flash chromatography eluting with a gradient of 0 to 20% MeCN in water (NH4HCO3). Pure fractions were evaporated to dryness to give N-ethyl-6-methyl-5-piperazin-1 -yl-pyridine-2-carboxamide (Intermediate 86) as a yellow oil (0.189 g, 55%).1H NMR (400 MHz, DMSO-c / 6) 1.12 (3H, t), 2.81 -2.92 (8H, m), 3.27-3.36 (5H, m), 7.46 (1 H, d), 7.81 (1 H, d), 8.43 (1 H, t); m / z (ES+) [M+H] 249.0. + [M+H] + 249.0.

[0394] Intermediate 87: 7-Bromo-8-fluoro-3-(trifluoromethyl)-1 H-quinoxalin-2-one Intermediate 88: 8-Fluoro-7-(hydroxymethyl)-3-(trifluoromethyl)-1 H-quinoxalin-2-one

[0395] Ph3P (299 mg, 1.14 mmol) was added to 8-fluoro-7-(hydroxymethyl)-3- methylquinoxalin-2(lH)-one (158 mg, 0.76 mmol) (Intermediate 17), CBr4(378 mg, 1.14 mmol) in CH2Cl2(3.00 mL). The resulting mixture was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure. N-ethyl-6-methyl-5-piperazin-l-yl-pyridine-2-carboxamide (Intermediate 86) (188 mg, 0.76 mmol) and DIPEA (1.5 mL, 8.59 mmol) were added to the mixture in NMP (3 mL). The resulting mixture was stirred at 80 °C for 2 hours. The solvent was removed under reduced pressure. The crude product was purified by flash C18 flash chromatography (eluting with a gradient of 0 to 25% MeCN in water (NH4HCO3)). The pure fractions were evaporated to dryness to give N-ethyl-5-[4-[(5-fluoro-2-methyl-3-oxo-4H- quinoxalin-6-yl)methyl]piperazin-l-yl]-6-methyl-pyridine-2-carboxamide (Example 46) as a white solid (7.40 mg, 2%).1H NMR (300 MHz, DMSO-c / 6) 1.10 (3H, t), 2.40 (3H, s), 2.50 (3H, s), 2.54-2.64 (4H, m), 2.87-2.97 (4H, m), 3.30 (2H, q), 3.70 (2H, s), 7.28 (1H, t), 7.47 (1H, d), 7.52 (1H, d), 7.77 (1H, d), 8.42 (1H, t), 12.44 (1H, s);19F NMR (282 MHz, DMSO-c / 6) -135.54; m / z (ES+) [M+H] 439.2. + [M+H] + = 439.

[0396]

[0397] Example 47: 5-[4-[[5-Fluoro-3-oxo-2-(trifluoromethyl)-4H-quinoxalin-6-yl]methyl]piperazin-1-yl]-N,6-dimethyl-pyridine-2-carboxamide

[0398] Ethyl 3,3,3-trifluoro-2-oxopropionate (2.30 g, 13.52 mmol) was added to 4-bromo-3-fluoro-phenyl-1,2-diamine (intermediate 72) (2.20 g, 10.73 mmol) in toluene (10 mL). The resulting mixture was stirred at 100 °C for 18 hours. The solvent was removed under reduced pressure. The crude product was purified by rapid C18 chromatography (eluting in water (0.1% NH4HCO3) with an elution gradient of 3% to 70% MeCN). The purified fraction was evaporated to dryness to give 7-bromo-8-fluoro-3-(trifluoromethyl)-1H-quinoxalin-2-one (intermediate 87) as a grayish-white solid (contaminated with 6-bromo-5-fluoro-3-(trifluoromethyl)-1H-quinoxalin-2-one) (3.40 g, 501%). m / z (ES + [M+H] + =311.

[0399] Example 48: 6-Fluoro-5-[4-[[5-fluoro-3-oxo-2-(trifluoromethyl)-4H-quinoxalin-6-yl]methyl]piperazin-1-yl]-N-methyl-pyridine-2-carboxamide

[0400] CataCxium APd G2 (53 mg, 0.08 mmol) was added to 7-bromo-8-fluoro-3-(trifluoromethyl)-1H-quinoxalin-2-one (intermediate 87) (contaminated with 6-bromo-5-fluoro-3-(trifluoromethyl)-1H-quinoxalin-2-one) (0.5 g, 0.80 mmol) and (tributyltinyl)methanol (0.5 mL, 0.80 mmol) in 1,4-dioxane (15 mL). The resulting mixture was stirred at 80 °C for 18 hours under nitrogen. The reaction mixture was quenched with saturated KF (1.25 mL). The reaction solution was collected by filtration and washed with dioxane (2.5 mL). The solvent of the combined organic layers was removed under reduced pressure. The crude product was purified by rapid C18 chromatography (elution gradient of 3 to 40% MeCN (0.1% TFA) in water). The pure fraction was evaporated to dryness to give 8-fluoro-7-(hydroxymethyl)-3-(trifluoromethyl)-1H-quinoxalin-2-one (intermediate 88) as a grayish-white solid (contaminated with 5-fluoro-6-(hydroxymethyl)-3-(trifluoromethyl)-1H-quinoxalin-2-one) (0.217 g, 51%). m / z (ES + [M+H] + =263.

[0401] Example 49: 6-Chloro-5-[4-[[5-fluoro-3-oxo-2-(trifluoromethyl)-4H-quinoxalin-6-yl]methyl]piperazin-1-yl]-N-methyl-pyridine-2-carboxamide Example 50: 5-[4-[[5-Fluoro-3-oxo-2-(trifluoromethyl)-4H-quinoxalin-6-yl]methyl]piperazin-1-yl]-N-methyl-pyridine-2-carboxamide

[0402] SOCl2(0.5 mL, 6.85 mmol) was added to 8-fluoro-7-(hydroxymethyl)-3- (trifluoromethyl)-1H-quinoxalin-2-one (Intermediate 88) (contaminated with 5- fluoro-6-(hydroxymethyl)-3-(trifluoromethyl)-1H-quinoxalin-2-one) (160 mg, 0.31 mmol) in Et2O (5 mL). The resulting mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure. DIPEA (4 mL, 22.90 mmol) and N,6-dimethyl-5-piperazin-1-yl-pyridine-2-carboxamide (Intermediate 33) (134 mg, 0.57 mmol) were added to the mixture in MeCN (10 mL). The resulting mixture was stirred at room temperature for 24 hours. The crude product was purified by preparative HPLC (Column: XBridge BEH C18 OBD Prep Column, 5 pm, 19 mm 250 mm; Mobile Phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3.H2O), Mobile Phase B: ACN; Flow Rate: 20 mL / min; Gradient: 24B to 33B in 10 minutes; 254 / 220 nm; RT1: 8.2 / 9.5) Fractions containing the desired compound were evaporated to dryness to give 5-[4-[[5-fluoro-3-oxo-2-(trifluoromethyl)-4H-quinoxalin-6-yl]methyl]piperazin-1-yl]- N,6-dimethyl-pyridine-2-carboxamide (Example 47) as a white solid (8.8 mg, 6%).1H NMR (400 MHz, DMSO-d6) 2.50 (3H, s), 2.58 - 2.66 (4H, m), 2.79 (3H, d), 2.90 - 2.99 (4H, m), 3.77 (2H, s), 7.41 (1H, t), 7.47 (1H, d), 7.72 (1H, d), 7.78 (1H, d), 8.39 - 8.44 (1H, m), 13.21 (1H, br s);19F NMR (376 MHz, DMSO-d6) -68.50, -133.81; m / z (ES+) [M+H] = 479. + [M+H] + = 479.

[0403]

[0404] Intermediate 90: Methyl 2-(4-bromo-3-fluoro-2-nitro-anilino)-3-methyl-butanoate Intermediate 91 : 7-Bromo-8-fluoro-3-isopropyl-3,4-dihydro-1 H-quinoxalin-2-one

[0405] SOCl2(0.4 mL, 5.48 mmol) was added to 8-fluoro-7-(hydroxymethyl)-3- (trifluoromethyl)-lH-quinoxalin-2-one (intermediate 88) (contaminated with 5- fluoro-6-(hydroxymethyl)-3-(trifluoromethyl)-lH-quinoxalin-2-one) (120 mg, 0.23 mmol) in Et2O (5 mL). The resulting mixture was stirred at room temperature for 2 h. The solvent was removed under reduced pressure. DIPEA (2 mL, 11.45 mmol) and 6-fluoro-N-methyl-5-piperazin-l-yl-pyridine-2- carboxamide (intermediate 32) (156 mg, 0.65 mmol) were added to the mixture in MeCN (10 mL). The resulting mixture was stirred at room temperature for 24 h. The crude product was purified by preparative HPLC (column: XBridge BEH C18 OBD Prep Column, 5 pm, 19 mm 250 mm; mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3.H2O), mobile phase B: ACN; flow rate: 20 mL / min; gradient: from 25B to 37B in 10 min; 254 / 220 nm; RT1: 7.58 / 8.97). Fractions containing the desired compound were evaporated to dryness to give 6-fluoro-5-[4-[[5-fluoro-3-oxo-2- (trifluoromethyl)-4H-quinoxalin-6-yl]methyl]piperazin-l-yl]-N-methyl-pyridine-2- carboxamide (example 48) as a white solid (8.9 mg, 8%).1H NMR (400 MHz, DMSO-c / 6) 2.58-2.65 (4H, m), 2.76 (3H, d), 3.14-3.21 (4H, m), 3.75 (2H, s), 7.39 (1H, t), 7.56 (1H, dd), 7.71 (1H, d), 7.84 (1H, dd), 8.37-8.43 (1H, m), 13.39 (1H, br s);19F NMR (376 MHz, DMSO-c / 6) -68.48, -72.59, -133.78; m / z (ES+) [M+H] = 483. + [M+H] + = 483.

[0406]

[0407] Intermediate 92: 7-Bromo-8-fluoro-3-isopropyl-1 H-quinoxalin-2-one Intermediate 93: 8-Fluoro-7-(hydroxymethyl)-3-isopropyl-1 H-quinoxalin-2-one

[0408] SOCl2(0.4 mL, 5.48 mmol) was added to 8-fluoro-7-(hydroxymethyl)-3- (trifluoromethyl)-lH-quinoxalin-2-one (intermediate 88) (contaminated with 5- fluoro-6-(hydroxymethyl)-3-(trifluoromethyl)-lH-quinoxalin-2-one) (120 mg, 0.23 mmol) in Et2O (5 mL). The resulting mixture was stirred at room temperature for 2 h. The solvent was removed under reduced pressure. DIPEA (2 mL, 11.45 mmol) and 6-fluoro-N-methyl-5-piperazin-l-yl-pyridine-2- carboxamide (intermediate 32) (156 mg, 0.65 mmol) were added to the mixture in MeCN (10 mL). The resulting mixture was stirred at room temperature for 24 h. The crude product was purified by preparative HPLC (column: XBridge BEH C18 OBD Prep Column, 5 pm, 19 mm 250 mm; mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3.H2O), mobile phase B: ACN; flow rate: 20 mL / min; gradient: from 25B to 37B in 10 min; 254 / 220 nm; RT1: 7.58 / 8.97). Fractions containing the desired compound were evaporated to dryness to give 6-fluoro-5-[4-[[5-fluoro-3-oxo-2- (trifluoromethyl)-4H-quinoxalin-6-yl]methyl]piperazin-l-yl]-N-methyl-pyridine-2- carboxamide (example 48) as a white solid (8.9 mg, 8%).1H NMR (400 MHz, DMSO-c / 6) 2.58-2.65 (4H, m), 2.76 (3H, d), 3.14-3.21 (4H, m), 3.75 (2H, s), 7.39 (1H, t), 7.56 (1H, dd), 7.71 (1H, d), 7.84 (1H, dd), 8.37-8.43 (1H, m), 13.39 (1H, br s);19F NMR (376 MHz, DMSO-c / 6) -68.48, -72.59, -133.78; m / z (ES ol) to 8-fluoro-7-(hydroxymethyl)-3-(trifluoromethyl)-lH-quinoxalin-2-one (Intermediate 88) (contaminated with 5-fluoro-6-(hydroxymethyl)-3-(trifluoromethyl)-lH-quinoxalin-2-one) (120 mg, 0.23 mmol) in Et20 (5 mL). The resulting mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure. DIPEA (2 mL, 11.45 mmol) and 6-chloro-N-methyl-5-piperazin-l-yl-pyridine-2-carboxamide (Intermediate 30) (157 mg, 0.62 mmol) were added to the mixture in MeCN (10 mL). The resulting mixture was stirred at room temperature for 24 hours. The crude product was purified by preparative HPLC (column: XBridge Shield RP18 OBD Column, 19*250mm, 10um; mobile phase A: water (10M HMOL / L NH4HCO3 + 0.1% NH3.H20), mobile phase B: ACN; flow rate: 20 mL / min; gradient: from 45B to 57B in 10 minutes; 254 / 220 nm). The fractions containing the desired compound were evaporated to dryness to give 6-chloro-5-[4-[[5-fluoro-3-oxo-2-(trifluoromethyl)-4H- quinoxalin-6-yl]methyl]piperazin-l-yl]-N-methyl-pyridine-2-carboxamide (Example 49) as a white solid (18 mg, 16%). ¾ NMR (400 MHz, DMSO-c / 6) 2.60-2.68 (4H, m), 2.78 (3H, d), 3.07-3.16 (4H, m), 3.77 (2H, s), 7.40 (1H, t), 7.66 (1H, d), 7.72 (1H, d), 7.93 (1H, d), 8.40-8.43 (1H, m), 13.25 (1H, br s);19F NMR (376 MHz, DMSO-c / 6) -68.51, -133.73; m / z (ES+) [M+H] 499.2. + [M+H] + = 499.

[0409]

[0410] Intermediate 94: 7-(Bromomethyl)-8-fluoro-3-isopropyl-1 H-quinoxalin-2-one Example 51 : 6-Fluoro-5-[4-[(5-fluoro-2-isopropyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2-carboxamide

[0411] SOCl2(0.4 mL, 5.48 mmol) was added to 8-fluoro-7-(hydroxymethyl)-3- (trifluoromethyl)-1H-quinoxalin-2-one (Intermediate 88) (contaminated with 5- fluoro-6-(hydroxymethyl)-3-(trifluoromethyl)-1H-quinoxalin-2-one) (120 mg, 0.23 mmol) in Et2O (5 mL). The resulting mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure. DIPEA (2 mL, 11.45 mmol) and N-methyl-5-piperazin-1-yl-pyridine-2-carboxamide (Intermediate 31) (259 mg, 1.18 mmol) were added to the mixture in MeCN (10 mL). The resulting mixture was stirred at room temperature for 24 hours. The crude product was purified by preparative HPLC (column: XBridge Shield RP18 OBD column, 19*250mm, 10um; mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3.H2O), mobile phase B: ACN; flow rate: 20 mL / min; gradient: from 15B to 35B in 10 minutes; 254 / 220 nm; RT1: 10.18 / 11.2). Fractions containing the desired compound were evaporated to dryness to give 5-[4-[[5-fluoro-3-oxo-2-(trifluoromethyl)-4H-quinoxalin-6-yl]methyl]piperazin-1-yl]-N-methyl-pyridine-2-carboxamide (Example 50) as a white solid (6 mg, 6%).1H NMR (400 MHz, DMSO-d6) 2.51-2.57 (4H, m), 2.76 (3H, d), 3.25-3.34 (4H, m), 3.72 (2H, s), 7.30 (1H, t), 7.39 (1H, dd), 7.65 (1H, d), 7.83 (1H, d), 8.27 (1H, d), 8..36-8.41 (1H, m);19F NMR (376 MHz, DMSO-d6) -68.34, -133.80; m / z (ES+) [M+H] 465.2. + [M+H] + = 465.

[0412]

[0413] Example 52: 5-[4-[(5-Fluoro-2-isopropyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N,6-dimethyl-pyridine-2-carboxamide

[0414] DIPEA (2.202 mL, 12.61 mmol) was added slowly to a stirred solution of 1-bromo-2,4-difluoro-3-nitrobenzene (Intermediate 35) (1 g, 4.20 mmol) and valine methyl ester, HC1 (Intermediate 89) (0.704 g, 4.20 mmol) in DMF (6 mL). The resulting solution was stirred at room temperature for 18 hours (complete conversion to desired product by LCMS). The reaction mixture was concentrated, diluted with water and extracted with ethyl acetate, the organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by normal phase chromatography with hexane: ethyl acetate to give 2-(4-bromo-3-fluoro-2-nitro-phenylamino)-3-methyl- butyric acid methyl ester (0.763 g, 52.0%) (Intermediate 90) as a bright orange solid.1H NMR (500 MHz, Methanol-d4) 1.00 - 1.14 (6H, m), 2.20 - 2.35 (1H, m), 3.78 (3H, s), 4.06 (1H, dd), 6.52 (1H, br d), 7.39 (1H, br d), 7.52 (1H, dd);19F NMR (471 MHz, Methanol-d4) -109.33 (1F, s); m / z (ES+) [M+H] 349.0. + [M+H] + = 349.

[0415] Example 53: 5-[4-[(5-Fluoro-2-isopropyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2-carboxamide

[0416] Zinc dust (1.143 g, 17.48 mmol) was added portionwise to a mixture of 2-(4-bromo-3-fluoro-2-nitro-phenylamino)-3-methyl-butyric acid methyl ester (0.763 g, 2.19 mmol) (Intermediate 90) and ammonium chloride (0.935 g, 17.48 mmol) in MeOH (12 mL) and water (0.3 mL) at 0 °C (exothermic reaction), the mixture was stirred at room temperature for 2 hours (no SM remaining, complete disappearance of orange colour indicated completion of reaction). The Zn was filtered off, the solid filter cake was washed with 20% MeOH in DCM, the filtrate was concentrated in vacuo. Water was added to the above crude product and the product was extracted into the ethyl acetate layer. The organic layer was dried and concentrated in vacuo to give a colourless oil. The crude product was slurry in 1 : 1 ethyl acetate: methanol, 0.5 mL of 4N HC1 in dioxane was added and the reaction was stirred for 1 hour (no uncyclized product remaining). The reaction mixture was concentrated to give 7-bromo-8-fluoro-3-isopropyl-3,4-dihydro-1H- quinoxalin-2-one (Intermediate 91). Assuming 100% yield for this reaction, the crude product was subjected to the reagents for the next step without any further purification. m / z (ES+) [M+H]+= 287. + [M+H]

[0417] ​

[0418] To a stirred solution of 4,5-dichloro-3,6-dioxocyclohexa-1,4-diene-1,2-dicarbonitrile (595 mg, 2.62 mmol) was added in one portion to a stirred solution of 7-bromo-8-fluoro-3-isopropyl-3,4-dihydroquinoxalin-2(1 H)-one (627 mg, 2.18 mmol) (Intermediate 91 ) in DCM (20 mL). The resulting slurry was stirred at room temperature for 2 hours (complete conversion to desired product by LCMS). The reaction mixture was concentrated in vacuo and quenched with saturated aqueous sodium bicarbonate solution. The slurry was stirred at room temperature overnight and the solid was filtered off. The filtered solid was washed thoroughly with water followed by diethyl ether and dried to give 7-bromo-8-fluoro-3-isopropyl-1 H-quinoxalin-2-one as an off-white solid (0.425 g, 68.3%) (Intermediate 92).1H NMR (500 MHz, DMSO-c / 6) 1.22 (6H, d), 3.36 - 3.52 (1 H, m), 7.45 - 7.58 (2H, m), 12.62 (1 H, br s);19F NMR (471 MHz, DMSO-c / 6) -124.16 (1 F, s).; m / z (ES+) [M+H] 285.0. + [M+H] + = 285.

[0419] ​

[0420] Xphos Pd G2 (103 mg, 0.13 mmol) was added to a stirred degassed solution of 7-bromo-8-fluoro-3-isopropylquinoxalin-2(1 H)-one (375 mg, 1.32 mmol) (Intermediate 92) and (tributylstannyl)methanol (507 mg, 1.58 mmol) in 1,4-dioxane (6.58 mL). The resulting solution was stirred at 80 °C for 16 hours. The reaction mixture was concentrated in vacuo and purified by normal phase chromatography using 0-10% MeOH in DCM to give 8-fluoro-7-(hydroxymethyl)-3-isopropyl-1 H-quinoxalin-2-one as a white solid (0.255 g, 82%) (Intermediate 93).1H NMR (500 MHz, DMSO-c / 6) 1.22 (6H, d), 3.39 - 3.52 (1 H, m), 4.64 (2H, d), 5.41 (1 H, t), 7.33 (1 H, s), 7.55 (1 H, d), 12.42 (1 H, br s).;19F NMR (471 MHz, DMSO-c / 6) -137.71 (1 F, s).; m / z (ES+) [M+H] 237.0. + [M+H] + = 237.

[0421] ​

[0422] Triethylphosphine (0.477 ml, 3.23 mmol) was added dropwise to a stirred solution of 8-fluoro-7-(hydroxymethyl)-3-isopropylquinoxalin-2(lH)-one (0.2541 g, 1.08 mmol) (Intermediate 93) and CBr4(1.177 g, 3.55 mmol) in DCM (8.49 ml) at 0 °C under nitrogen over a period of 5 minutes. The reaction mixture was stirred at room temperature for 1 hour, the DCM was removed under vacuum and the resulting solid was slurred in diethyl ether. The white ppt was filtered under vacuum, washed with water and then ether. The solid was dried under vacuum overnight (without heating) to give 7-(bromomethyl)-8-fluoro-3-isopropyl-lH-quinoxalin-2-one (0.313 g, 97%) as a light brown solid (Intermediate 94). m / z (ES+) 299.0 [M+H] + [M+H] + = 299.

[0423] ​ ​

[0424] To 7-(bromomethyl)-8-fluoro-3-isopropylquinoxalin-2(lH)-one (100 mg, 0.33 mmol) (Intermediate 94) was added 6-fluoro-N-methyl-5-piperazin-l-yl-pyridine-2-carboxamide, 2HCI (104 mg, 0.33 mmol) (Intermediate 32), acetonitrile (5 mL) and N-ethyl-N-isopropylpropan-2-amine (291 μί, 1.67 mmol) and heated to 70 °C. LCMS indicated complete disappearance of SM after 1 h and formation of desired product. The reaction mixture was cooled, concentrated, quenched with aqueous NaHC03solution (1 mL) and stirred at room temperature for 1 h. Water (3 mL) was added to the above mixture and stirred for 10 min. The precipitate was filtered and washed with copious amount of water (50 mL). The solid was purified by normal phase chromatography using 0-10% MeOH in DCM to give 6-fluoro-5-[4-[(5-fluoro-2-isopropyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-l-yl]-N-methyl-pyridine-2-carboxamide (0.050 g, 32.8%) as a white solid (Example 51).1H NMR (500 MHz, DMSO-c / 6) 1.22 (6H, d), 2.53 - 2.65 (4H, m), 2.77 (3H, d), 3.12 - 3.24 (4H, m), 3.36 - 3.52 (1H, m), 3.71 (2H, s), 7.30 (1H, t), 7.52 - 7.59 (2H, m), 7.84 (1H, d), 8.36 - 8.41 (1H, m), 12.46 (1H, br s).;19F NMR (471 MHz, DMSO-c / 6) -135.53 (1F, s), -72.59 (1F, s).; m / z (ES+) [M+H] 457.2. + [M+H] + = 457.

[0425]

[0426] ​ , ​

[0427] To 7-(bromomethyl)-8-fluoro-3-isopropylquinoxalin-2(lH)-one (109 mg, 0.36 mmol) (Intermediate 94) was added N,6-dimethyl-5-(piperazin-l-yl)picolinamide, 2HCI (112 mg, 0.36 mmol) (Intermediate 33), acetonitrile (5 mL) and N-ethyl-N-isopropylpropan-2-amine (317 ul, 1.82 mmol) and heated to 70 °C. LCMS indicated complete disappearance of SM after 1 hour and formation of desired product. The reaction mixture was cooled, concentrated, quenched with aqueous NaHC03solution (1 mL) and stirred at room temperature for 1 hour. Water (3 mL) was added to the above mixture and stirred for 10 minutes. The precipitate was filtered and washed with copious amount of water (50 mL). The solid was purified by normal phase chromatography using 0-10% MeOH in DCM to give 5-[4-[(5-fluoro-2-isopropyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-l-yl]-N,6-dimethyl-pyridine-2-carboxamide (0.057 g, 34.6%) as a white solid (Example 52).1H NMR (500 MHz, DMSO-c / 6) 1.22 (6H, d), 2.46-2.49 (3H, m), 2.52-2.68 (4H, m), 2.80 (3H, d), 2.94 (4H, br s), 3.36-3.52 (1H, m), 3.73 (2H, s), 7.30 (1H, t), 7.47 (1H, d), 7.56 (1H, d), 7.79 (1H, d), 8.37-8.44 (1H, m), 12.46 (1H, s).;19F NMR (471 MHz, DMSO-c / 6) -135.55 (1F, s).; m / z (ES+) [M+H] 453.3. + [M+H] + = 453.

[0428]

[0429] Example 53: 5-[4-[(5-fluoro-2-isopropyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin- 1-yl]-N-methyl-pyridine-2-carboxamide Example 53: 5-[4-[(5-fluoro-2-isopropyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin- 1-yl]-N-methyl-pyridine-2-carboxamide

[0430] To 7-(bromomethyl)-8-fluoro-3-isopropylquinoxalin-2(lH)-one (100 mg, 0.33 mmol) (Intermediate 94) was added N-methyl-5-(piperazin-l-yl)picolinamide, 2HCI (98 mg, 0.33 mmol) (Intermediate 31), acetonitrile (5 mL) and N-ethyl-N-isopropylpropan-2-amine (291 μΐ, 1.67 mmol) and heated to 70 °C. LCMS indicated complete disappearance of SM after 1 h and formation of desired product. The reaction mixture was cooled, concentrated, quenched with aqueous NaHC03solution (1 mL) and stirred at room temperature for 1 h. Water (3 mL) was added to the above mixture and stirred for 10 min. The precipitate was filtered and washed with copious amount of water (50 mL). The solid was purified by normal phase chromatography using 0-10% MeOH in DCM to give 5-[4-[(5-fluoro-2-isopropyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-l-yl]-N- methyl-pyridine-2-carboxamide (0.052 g, 35.5%) (Example 53) as a white solid.1H NMR (500 MHz, DMSO-c / 6) 1.22 (6H, d), 2.52 - 2.61 (4H, m), 2.78 (3H, d), 3.26 - 3.30 (4H, m), 3.36 - 3.52 (1H, m), 3.70 (2H, s), 7.31 (1H, t), 7.38 (1H, dd), 7.56 (1H, d), 7.82 (1H, d), 8.26 (1H, d), 8.38 (1H, br d), 12.45 (1H, br s).;19F NMR (471 MHz, DMSO-c / 6) -135.54 (1F, s).; m / z (ES+) [M+H] 439.2. + 439.2 + 439.2

[0431]

[0432] Intermediate 96: 2-(4-bromo-3-fluoro-2-nitro-anilino)-2-cyclopropyl-acetic acid methyl ester

[0433] DIPEA (2.202 mL, 12.61 mmol) was added slowly to a stirred solution of 1-bromo-2,4-difluoro-3-nitrobenzene (Intermediate 35) (1 g, 4.20 mmol) and methyl 2-amino-2-cyclopropylacetate, HC1 (Intermediate 95) (0.696 g, 4.20 mmol) in DMF (6 mL). The resulting solution was stirred at room temperature for 18 hours (complete conversion to desired product by LCMS). The reaction mixture was concentrated, diluted with water and extracted with ethyl acetate, the organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by normal phase chromatography (using hexanes and ethyl acetate) to give methyl 2-(4-bromo-3-fluoro-2-nitro-phenylamino)-2-cyclopropyl-acetate as a bright orange solid (0.635 g, 43.5%) (Intermediate 96).1H NMR (500 MHz, Chloroform-d) 0.39 - 0.49 (1H, m), 0.54 (1H, td), 0.64 - 0.75 (2H, m), 1.25 - 1.39 (1H, m), 3.74 - 3.83 (4H, m), 6.45 (1H, dd), 7.34 (1H, br d), 7.52 (1H, dd).19F NMR (471 MHz, Chloroform-d) -109.53 (1F, s).; m / z (ES+) [M+H] 397.0. + [M+H] + = 347.

[0434] Intermediate 97: 7-bromo-3-cyclopropyl-8-fluoro-3,4-dihydro-1H-quinoxalin-2-one

[0435] Zinc dust (957 mg, 14.63 mmol) was added portionwise to a mixture of methyl 2-((4-bromo-3-fluoro-2-nitrophenyl)amino)-2-cyclopropylacetate (635 mg, 1.83 mmol) (Intermediate 96) and ammonium chloride (783 mg, 14.63 mmol) in MeOH (12 mL) and water (0.3 mL) at 0 °C (exothermic reaction), the mixture was stirred at room temperature for 2 hours (no SM remaining, complete disappearance of orange colour indicates completion of reaction). The Zn was filtered off and the solid cake was washed with 20% MeOH in DCM. The filtrate was concentrated, the crude material showed a large degree of uncyclized product. To the above crude product was added water and the product was extracted into the ethyl acetate layer. The organic layer was dried and concentrated in vacuo to give an oil. This material was slurred in 1 : 1 ethyl acetate:methanol, 0.5 mL of 4N HC1 in dioxane was added and the reaction mixture was stirred for 1 hour (no uncyclized product remaining). The reaction mixture was concentrated to yield 7-bromo-3-cyclopropyl-8-fluoro-3,4-dihydro-1H-quinoxalin-2-one as a grey solid (Intermediate 97). Assuming 100% yield for this reaction, the crude product was subjected to the reagents for the next step without any further purification. m / z (ES+) [M+H] 307.0. +)[M+H] + = 285.

[0436] Intermediate 97: 7-bromo-3-cyclopropyl-8-fluoro-3,4-dihydro-1H-quinoxalin-2-one

[0437] To a stirred solution of 7-bromo-3-cyclopropyl-8-fluoro-3,4-dihydroquinoxalin-2(lH)-one (522 mg, 1.83 mmol) (Intermediate 97) in DCM (20 mL) was added 4,5-dichloro-3,6-dioxocyclohexa-l,4-diene-l,2-dicarbonitrile (499 mg, 2.20 mmol) in one portion. The resulting slurry was stirred at room temperature for 2 hours (complete conversion to desired product by LCMS). The reaction mixture was concentrated in vacuo and quenched with saturated aqueous sodium bicarbonate solution. The slurry was stirred at room temperature overnight and the solid was filtered off. The solid was washed thoroughly with water followed by diethyl ether and dried to give 7-bromo-3-cyclopropyl-8-fluoro-lH-quinoxalin-2-one (0.382 g, 73.7%) as an off-white solid (Intermediate 98). m / z (ES+) [M+H] 285.0 C12H9BrFNO2requires 285.0. + )[M+H] + = 283.

[0438] Intermediate 97: 7-bromo-3-cyclopropyl-8-fluoro-3,4-dihydro-1H-quinoxalin-2-one

[0439] To a stirred degassed solution of 7-bromo-3-cyclopropyl-8-fluoroquinoxalin-2(lH)-one (332 mg, 1.17 mmol) (Intermediate 98) and (tributylstannyl)methanol (452 mg, 1.41 mmol) in 1,4-dioxane (5.86 mL) was added Xphos Pd G2 (92 mg, 0.12 mmol) and the resulting mixture was stirred at 80 °C for 16 hours. The reaction mixture was concentrated in vacuo and purified by normal phase chromatography using 0-10% MeOH in DCM to give 3-cyclopropyl-8-fluoro-7-(hydroxymethyl)-lH-quinoxalin-2-one (0.224 g, 82%) as a white solid (Intermediate 99).1H NMR (500 MHz, DMSO-c / 6) 1.02 - 1.14 (4H, m), 2.52 - 2.73 (1H, m), 4.62 (2H, d), 5.38 (1H, t), 7.29 (1H, t), 7.43 (1H, d), 12.43 (1H, br s).;19F NMR (471 MHz, DMSO-c / 6) -137.67 (1F, s).; m / z (ES+) [M+H] 235.0 C10H9FNO3requires 235.2. + )[M+H] + = 235.

[0440] Intermediate 97: 7-bromo-3-cyclopropyl-8-fluoro-3,4-dihydro-1H-quinoxalin-2-one

[0441] Triethylphosphine (0.422 ml, 2.86 mmol) was added dropwise to a mixture of 3-cyclopropyl-8-fluoro-7-(hydroxymethyl)quinoxalin-2(lH)-one (0.223 g, 0.95 mmol) (Intermediate 99) and CBr4(1.043 g, 3.14 mmol) in DCM (7.52 ml) at 0 °C under nitrogen over a period of 5 minutes. The reaction was stirred at room temperature for 1 hour. The DCM was removed in vacuo and the resulting solid was slurred in diethyl ether. The pale greenish-white ppt was filtered under vacuum and washed with water and then ether. The solid was dried in vacuo overnight (without heating) to give 7-(bromomethyl)-3-cyclopropyl-8-fluoro-lH-quinoxalin-2-one as a pale green solid (0.193 g, 68.2 %) (Intermediate 100).1H NMR (500 MHz, DMSO-c / 6) 1.03 - 1.17 (4H, m), 2.63 - 2.76 (1H, m), 4.79 (2H, s), 7.33 (1H, t), 7.43 (1H, d), 12.55 (1H, br s);19F NMR (471 MHz, DMSO-c / 6) -133.65 (1F, s); m / z (ES+) [M+H] 297.0. + [M+H] + = 297.

[0442] Example 54: 5-[4-[(2-cyclopropyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin- 1-yl]-6-fluoro-N-methyl-pyridine-2-carboxamide Example 54: 5-[4-[(2-cyclopropyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin- 1-yl]-6-fluoro-N-methyl-pyridine-2-carboxamide

[0443] To 7-(bromomethyl)-3-cyclopropyl-8-fluoroquinoxalin-2(lH)-one (75 mg, 0.25 mmol) (Intermediate 100) was added 6-fluoro-N-methyl-5-(piperazin-l- yl)picolinamide, 2HCI (79 mg, 0.25 mmol) (Intermediate 32), acetonitrile (5 mL) and N-ethyl-N-isopropylpropan-2-amine (220 μΐ, 1.26 mmol) and heated to 70 °C. LCMS indicated complete disappearance of SM after 1 hour and formation of desired product. The reaction mixture was cooled, concentrated, quenched with aqueous NaHC03solution (1 mL) and stirred at room temperature for 1 hour. Water (3 mL) was added to the above mixture and stirred for 10 minutes. The precipitate was filtered and washed with copious amount of water (50 mL). The solid was purified by normal phase chromatography using 0-10% MeOH in DCM to give 5-[4-[(2-cyclopropyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-l-yl]-6-fluoro-N-methyl-pyridine-2-carboxamide (0.048 g, 41.8%) as a white solid (Example 54).1H NMR (500 MHz, DMSO-c / 6) 1.04 - 1.13 (4H, m), 2.52 - 2.63 (4H, m), 2.71 (1H, s), 2.77 (3H, d), 3.12 - 3.21 (4H, m), 3.69 (2H, s), 7.26 (1H, t), 7.43 (1H, d), 7.55 (1H, dd), 7.84 (1H, d), 8.39 (1H, br d), 12.46 (1H, br s).;19F NMR (471 MHz, DMSO-c / 6) -135.52 (1F, s), -72.58 (1F, s).; m / z (ES+) [M+H] 455.2. + [M+H] + = 455.

[0444]

[0445] Example 54: 5-[4-[(2-cyclopropyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin- 1-yl]-6-fluoro-N-methyl-pyridine-2-carboxamide , Example 54: 5-[4-[(2-cyclopropyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin- 1-yl]-6-fluoro-N-methyl-pyridine-2-carboxamide

[0446] To 7-(bromomethyl)-3-cyclopropyl-8-fluoroquinoxalin-2(lH)-one (75 mg, 0.25 mmol) (Intermediate 100) was added N,6-dimethyl-5-(piperazin-l- yl)picolinamide, 2HCI (78 mg, 0.25 mmol) (Intermediate 33), acetonitrile (5 mL) and N-ethyl-N-isopropylpropan-2-amine (220 μL, 1.26 mmol) and heated to 70 °C. LCMS indicated complete conversion to the desired product after 1 hour. The reaction mixture was cooled, concentrated, quenched with aqueous NaHC03solution (1 mL) and stirred at room temperature for 1 hour. Water (3 mL) was added to the above mixture and stirred for 10 minutes. The precipitate was filtered and washed with copious amounts of water (50 mL). The solid was purified by normal phase chromatography using 0-10% MeOH in DCM to give 5-[4-[(2-cyclopropyl-5-fluoro-3-oxo-4H- quinoxalin-6-yl)methyl]piperazin-l-yl]-N,6-dimethyl-pyridine-2-carboxamide as a white solid (0.049 g, 43.1%) (Example 55).1H NMR (500 MHz, DMSO-d6) 1.03-1.15 (4H, m), 2.46-2.49 (3H, m), 2.52-2.65 (4H, m), 2.65-2.75 (1H, m), 2.80 (3H, d), 2.94 (4H, br s), 3.71 (2H, s), 7.26 (1H, t), 7.40-7.50 (2H, m), 7.79 (1H, d), 8.37-8.44 (1H, m), 12.46 (1H, s).;19F NMR (471 MHz, DMSO-d6) -135.54 (1F, s).; m / z (ES+) [M+H] 451.2. + [ M + H ] + = 451.

[0447]

[0448] Intermediate 102: 7-bromo-3-methoxy-8-methyl-1H-quinoxalin-2-one Intermediate 102: 7-bromo-3-methoxy-8-methyl-1H-quinoxalin-2-one

[0449] To 7-(bromomethyl)-3-cyclopropyl-8-fluoroquinoxalin-2(lH)-one (43 mg, 0.14 mmol) (Intermediate 100) was added N-methyl-5-(piperazin-l-yl)picolinamide, 2HCI (42.4 mg, 0.14 mmol) (Intermediate 31), acetonitrile (5 mL) and N-ethyl-N-isopropylpropan-2-amine (126 μΐ, 0.72 mmol) and heated to 70 °C. LCMS indicated complete disappearance of SM after 1 hour and formation of desired product. The reaction mixture was cooled, concentrated, quenched with aqueous NaHC03solution (1 mL) and stirred at room temperature for 1 hour. Water (3 mL) was added to the above mixture and stirred for 10 minutes. The precipitate was filtered and washed with copious amount of water (25 mL). The solid was purified by normal phase chromatography using 0-10% MeOH in DCM to give 5-[4-[(2-cyclopropyl-5-fluoro-3-oxo-4H-quinoxalin-6- yl)methyl]piperazin-l-yl]-N-methyl-pyridine-2-carboxamide (0.020 g, 31.7%) as a white solid (Example 56).1H NMR (500 MHz, DMSO-c / 6) 1.03 - 1.16 (4H, m), 2.53 - 2.60 (4H, m), 2.65 - 2.80 (5H, m), 3.68 (2H, s), 7.25 (1H, br t), 7.38 (1H, dd), 7.42 (1H, d), 7.82 (1H, d), 8.25 (1H, d), 8.35 - 8.40 (1H, m), 12.38 - 12.51 (1H, m) (missing 3H possibly overlapped with DMSO peak);19F NMR (471 MHz, DMSO-c / 6) -135.52 (1F, s).; m / z (ES+) [M+H] 437.2 (Example 57) + [M+H] + = 437

[0450]

[0451] Intermediate 102: 7-bromo-3-methoxy-8-methyl-1H-quinoxalin-2-one

[0452] A mixture of 4-bromo-3-methylbenzene-1,2-diamine (1.75 g, 8.70 mmol) (Intermediate 101 ), methyl 2,2,2-trimethoxyacetate (2.86 g, 17.41 mmol) and ytterbium(III) trifluoromethanesulfonate (0.540 g, 0.87 mmol) in toluene (10 mL) in a sealed tube was degassed, backfilled with N2, stirred at 100 °C overnight to give a brown suspension, LCMS indicated formation of desired product, the mixture was cooled to room temperature, the solid was collected by filtration, washed with methanol, dried to give 7-bromo-3-methoxy-8-methyl-1 H-quinoxalin-2-one (1.2 g, 51.2 %) (Intermediate 102) as a yellow solid (contaminated with ca. 8% of its regioisomer 6-bromo-3-methoxy-5-methylquinoxalin-2(1 H)-one).1H NMR (500 MHz, DMSO-c / 6) 2.50 (3H, br s), 3.97 (3H, s), 7.32 (1 H, d), 7.45 (1 H, d), 11.79 (1 H, br s); (m / z) (ES+) 289.0 [M+H]. + [M+H] + = 269.

[0453] Example 57: 5-[4-[(2-methoxy-5-methyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1- yl]-N,6-dimethyl-pyridine-2-carboxamide

[0454] A mixture of (tributylstannyl)methanol (1.844 g, 5.74 mmol), 7-bromo-3-methoxy-8-methyl-1 H-quinoxalin-2-one (1.03 g, 3.83 mmol) (Intermediate 102) and Xphos Pd G2 (0.452 g, 0.57 mmol) in 1,4-dioxane (40 mL) was stirred at 80 °C under N2overnight to give a dark mixture, LCMS showed near complete conversion. The solvent was removed under reduced pressure, the residue was purified on a silica gel column (eluting with 0 to 20% methanol in DCM), the fractions were concentrated to a yellow solid, the solid was checked by LCMS, it was not very pure, then the product was slurry in 20 mL of methanol, the solid was collected by filtration, dried to give the product with 55% purity (contaminated with 30% starting material and 9.5% debromination side product) as a yellow solid.

[0455] The above obtained solid was charged into a dry flask with 1,4-dioxane (40 mL), to the flask was added 900 mg (tributylstannyl)methanol and 300 mg xphos Pd G2, the mixture was degassed, then stirred at 80 °C under N2 overnight. The solvent was removed under reduced pressure, the mixture was purified on a silica gel column (eluted with 0 to 20% methanol in DCM), to give 7-(hydroxymethyl)-3-methoxy-8-methyl-1H-quinoxalin-2-one (800 mg, 95%) as a yellow solid (Intermediate 103) with 80% purity by LCMS.1H NMR (500 MHz, DMSO-d6) 2.32 (3H, s), 3.91 - 4.01 (3H, m), 4.56 (2H, d), 5.15 (1H, t), 7.27 (1H, d), 7.37 (1H, d), 11.57 (1H, br s); (m / z) (ES+) 221.0 [M+H]. + [M+H] + = 221.

[0456] Example 57: 5-[4-[(2-methoxy-5-methyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1- yl]-N,6-dimethyl-pyridine-2-carboxamide

[0457] Triethylphosphine (294 μl, 2.04 mmol) was added dropwise to a suspension of 7-(hydroxymethyl)-3-methoxy-8-methyl-1H-quinoxalin-2-one (300 mg, 1.36 mmol) (Intermediate 103) and 1,1,2,2-tetrabromo-1,2-dichloroethane (875 mg, 2.11 mmol) in CH2Cl2(20 mL) at 0 °C under N2, then the resulting mixture was stirred at room temperature for 3.5 hours, the solvent was removed under reduced pressure, the residue was suspended in ether (10 mL), filtered, the solid was washed with ether (10 mL x 2), then the solid was suspended in water (20 mL), filtered, washed with water (5 mL x 3), dried to give 7-(bromomethyl)-3-methoxy-8-methyl-1H-quinoxalin-2-one (0.250 g, 64.8%) as a light yellow solid (Intermediate 104). (m / z) (ES+) 285.0 [M+H]. + [M+H] + = 285.

[0458] Example 57: 5-[4-[(2-methoxy-5-methyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1- yl]-N,6-dimethyl-pyridine-2-carboxamide Intermediate 106: 6-bromo-5-fluoro-pyridine-2-carboxylic acid methyl ester

[0459] To a suspension of N,6-dimethyl-5-(piperazin-l-yl)picolinamide, 2HCI (83 mg, 0.27 mmol) (Intermediate 33) and 7-(bromomethyl)-3-methoxy-8-methyl-lH- quinoxalin-2-one (85 mg, 0.27 mmol) (Intermediate 104) in acetonitrile (6 mL) was added DIPEA (236 μL, 1.35 mmol) and the resulting mixture was stirred at 70 °C for 2 hours to give a clear solution. The mixture was cooled to room temperature to give a suspension, the solid was collected by filtration, washed with water, acetonitrile and dried to give 5-[4-[(2-methoxy-5-methyl-3-oxo-4H- quinoxalin-6-yl)methyl]piperazin-l-yl]-N,6-dimethyl-pyridine-2-carboxamide as a white solid (0.064 g, 54.3%) (Example 57).1H NMR (500 MHz, DMSO-c / 6) 2.43 (3H, s), 2.49 (3H, s), 2.57 (4H, br s), 2.80 (3H, d), 2.91 (4H, br s), 3.60 (2H, s), 3.95 (3H, s), 7.18 (IH, d), 7.35 (IH, d), 7.46 (IH, d), 7.78 (IH, d), 8.40 (IH, q), 11.58 (IH, br s); (m / z) (ES+) 5 / 2 460.3 [M+H]. + [M+H] + = 437

[0460]

[0461] Intermediate 107; 4-(2-bromo-6-methoxycarbonyl-3-pyridyl)piperazine-1-carboxylic acid tert-butyl ester Intermediate 107; 4-(2-bromo-6-methoxycarbonyl-3-pyridyl)piperazine-1-carboxylic acid tert-butyl ester

[0462] To a suspension of 6-fluoro-N-methyl-5-(piperazin-l-yl)picolinamide, 2HCI (84 mg, 0.27 mmol) (Intermediate 32) and 7-(bromomethyl)-3-methoxy-8-methyl-lH- quinoxalin-2-one (85 mg, 0.27 mmol) (Intermediate 104) in acetonitrile (6 mL) was added DIPEA (236 μL, 1.35 mmol) and the resulting mixture was stirred at 70 °C for 2 h to give a suspension, the mixture was cooled to room temperature, the solid was collected by filtration, washed with water, acetonitrile, dried, the solid was suspended in acetonitrile, filtered and dried to give 6-fluoro-5-[4-[(2-methoxy-5-methyl-3-oxo-4H- quinoxalin-6-yl)methyl]piperazin-l-yl]-N-methyl-pyridine-2-carboxamide as a beige solid (0.073 g, 61.3 %) (Example 58).1H NMR (500 MHz, DMSO-c / 6) 2.42 (3H, s), 2.55 (4H, br s), 2.76 (3H, d), 3.14 (4H, br s), 3.58 (2H, s), 3.95 (3H, s), 7.17 (IH, br d), 7.35 (IH, br d), 7.50-7.63 (IH, m), 7.83 (IH, br d), 8.38 (IH, br d), 11.58 (IH, s); (m / z) (ES+) 442.2 [M+H]. + [M+H] + = 442.

[0463]

[0464] Intermediate 107; 4-(2-bromo-6-methoxycarbonyl-3-pyridyl)piperazine-1-carboxylic acid tert-butyl ester

[0465] Sulfuric acid (1.5 mL, 28.14 mmol) was added slowly to a mixture of 6-bromo-5- fluoropicolinic acid (500 mg, 2.27 mmol) (Intermediate 105) in MeOH (8 mL). The mixture was stirred at room temperature for 3 h to give a white suspension. LCMS indicated complete conversion, the mixture was poured into saturated aqueous NaHC03solution, extracted with DCM (40 mL x 2), the organic layer was dried (anhydrous Na2S04), filtered and concentrated to give 6-bromo-5-fluoro- picolinic acid methyl ester as a white solid (532 mg, 100%) (Intermediate 106) which was used in the next step without further purification.1H NMR (500 MHz, Chloroform-d) 4.01 (3H, s), 7.55 (IH, t), 8.15 (IH, dd); (m / z) (ES+) 236.0 [M+H]. + [M+H] + = 236.

[0466] Intermediate 107; 4-(2-bromo-6-methoxycarbonyl-3-pyridyl)piperazine-1-carboxylic acid tert-butyl ester

[0467] A mixture of piperazine-1-carboxylic acid tert-butyl ester (8.21 g, 44.06 mmol), methyl 6-bromo-5-fluoro-pyridine-2-carboxylate (6.065 g, 25.92 mmol) (Intermediate 106) and potassium carbonate (4.66 g, 33.69 mmol) in DMF (60 mL) was stirred at 110 °C for 5 h, LCMS indicated complete conversion. The mixture was cooled to room temperature, diluted with DCM and water, the layers were separated, the aqueous layer was extracted twice with DCM, the organic layers were combined, dried (Na2SO4, anhydrous), filtered and concentrated, the residue was purified on a silica gel column (eluted with 0 to 50% ethyl acetate in hexanes, UV wavelength 221 nm, 310 nm) to give the desired product 4-(2-bromo-6-methoxycarbonyl-3-pyridyl)piperazine-1-carboxylic acid tert-butyl ester (7.68 g, 74.1%) as a white solid (Intermediate 107).1H NMR (500 MHz, Chloroform-d) 1.51 (9H, s), 3.14 (4H, br t), 3.60 - 3.71 (4H, m), 3.99 (3H, s), 7.32 (1H, d), 8.08 (1H, d); (m / z) (ES+) 402.2 [M+H]. + [M+H] + = 402.

[0468] Intermediate 107; 4-(2-bromo-6-methoxycarbonyl-3-pyridyl)piperazine-1-carboxylic acid tert-butyl ester

[0469] A mixture of 4-(2-bromo-6-methoxycarbonyl-3-pyridyl)piperazine-1-carboxylic acid tert-butyl ester (7.67 g, 19.16 mmol) (Intermediate 107) in methylamine (100 mL, 19.16 mmol) (33% in ethanol) in a sealed vessel was stirred at 60 °C for 4.5 h, LCMS indicated complete conversion, the mixture was cooled to room temperature, concentrated, the residue was dissolved in DCM, washed with saturated NH4Cl solution, dried (Na2SO4, anhydrous), filtered and concentrated to give 4-[2-bromo-6-(methylcarbamoyl)-3-pyridyl]piperazine-1-carboxylic acid tert-butyl ester (7.48 g, 98%) as a white solid (Intermediate 108).1H NMR (500 MHz, Chloroform-d) 1.50 (9H, s), 3.02 (3H, d), 3.08 (4H, br t), 3.60 - 3.71 (4H, m), 7.36 (1H, d), 7.68 (1H, br d), 8.11 (1H, d); (m / z) (ES+) 401.2 [M+H]. + [M+H] + = 401.

[0470] Intermediate 107; 4-(2-bromo-6-methoxycarbonyl-3-pyridyl)piperazine-1-carboxylic acid tert-butyl ester

[0471] A mixture of tert-butyl 4-[2-bromo-6-(methylcarbamoyl)-3-pyridyl]piperazine- 1 -carboxylate (1.344 g, 3.37 mmol) (Intermediate 108), tributyl(vinyl)stannane (1.174 g, 3.70 mmol) and Xphos Pd G2 (0.132 g, 0.17 mmol) in 1,4-dioxane (25 ml) was stirred at 100 °C under N2for 2.5 hours, LCMS showed complete conversion. The mixture was diluted with DCM, washed with saturated NH4CI, the organic layer was dried (Na2SO4), filtered and concentrated, the residue was purified on a silica gel column (0 to 80% ethyl acetate in hexanes, UV wavelength 226 nm, 293 nm) to give tert-butyl 4-[6-(methylcarbamoyl)-2-vinyl-3-pyridyl]piperazine-1- carboxylate (0.961 g, 82%) as a white solid (Intermediate 109).1H NMR (500 MHz, Chloroform-d) 1.50 (9H, s), 2.90 - 3.01 (4H, m), 3.05 (3H, d), 3.55 - 3.68 (4H, m), 5.54 (1H, dd), 6.42 (1H, dd), 7.10 (1H, dd), 7.39 (1H, d), 7.98 (1H, br d), 8.07 (1H, d); m / z (ES+) [M+H] = 346.6, 348.5. + [M+H] + = 346.6, 348.5.

[0472] Intermediate 60: 6-(difluoromethyl)-N-methyl-5-piperazin-1-yl-pyridine-2-carboxamide, 2HCl

[0473] A solution of osmium tetraoxide in H20 (0.0435 mL, 6.00 μmol) was added to a solution of tert-butyl 4-[6-(methylcarbamoyl)-2-vinyl-3-pyridyl]piperazine-1 - carboxylate (960 mg, 2.77 mmol) (Intermediate 109), 2,6-dimethylpyridine (646 μΐ, 5.54 mmol) and sodium periodate (2371 mg, 11.08 mmol) in THF (25 mL) / water (5 mL) / tert-butanol (2650 μΐ, 27.71 mmol) and stirred at room temperature overnight to give a yellow suspension. LCMS and TLC indicated complete conversion. The reaction was diluted with water and extracted with ethyl acetate. After concentration, the crude material was purified by a silica column (eluted with 0 to 100% ethyl acetate in hexanes, UV at 226 nm, 310 nm) to give tert-butyl 4-[2-formyl-6-(methylcarbamoyl)-3-pyridyl]piperazine-1 -carboxylate as a yellow solid (0.732 g, 76%) (Intermediate 110).1H NMR (500 MHz, Chloroform-d) 1.50 (9H, s), 3.07 (3H, d), 3.15-3.30 (4H, m), 3.63-3.79 (4H, m), 7.48 (1H, d), 7.85 (1H, br d), 8.28 (1H, d), 10.10 (1H, s); (m / z) (ES+) 429.2 [M+H]. + [M+H] + = 349.

[0474] Example 59: 6-(difluoromethyl)-5-[4-[(2-methoxy-5-methyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2-carboxamide ​

[0475] tert-Butyl 4-[2-formyl-6-(methylcarbamoyl)-3-pyridyl]piperazine-1 -carboxylate (730 mg, 2.10 mmol) (Intermediate 110) in CH2CI2(10 mL) was cooled to 0 °C, DAST (692 μL, 5.24 mmol) in DCM (5 mL) was added to the mixture, the resulting mixture was stirred at room temperature for 4 hours, TLC and LCMS indicated complete conversion. The reaction mixture was quenched by dropwise addition of saturated aqueous NaHC03solution, extracted with DCM, the organics were dried (Na2S04, anhydrous), filtered and concentrated, the residue was purified on a silica gel column (eluted with 0 to 100% ethyl acetate in hexanes, UV wavelength 254 nm, 293 nm) to give tert-butyl 4-[2-(difluoromethyl)-6-(methylcarbamoyl)-3-pyridyl]piperazine-1 - carboxylate (0.666 g, 86%) as a white solid (Intermediate 111).1H NMR (500 MHz, Chloroform-d) 1.50 (9H, s), 2.93 - 3.02 (4H, m), 3.05 (3H, d), 3.57 - 3.72 (4H, m), 6.99 (1H, t), 7.62 (1H, d), 7.92 (1H, br d), 8.27 (1H, d); (m / z) (ES+) [M+H] 371.2. + [M+H] + = 371.

[0476] ​

[0477] HCl 4M in dioxane (7 mL, 28.00 mmol) was added to a flask containing tert-butyl 4-[2-(difluoromethyl)-6-(methylcarbamoyl)-3-pyridyl]piperazine-1 -carboxylate (665 mg, 1.80 mmol) (Intermediate 111) and a stir bar, the mixture was stirred at room temperature for 1 hour to give a yellow suspension. The solvent was removed, the residue was diluted with ether, the solid was collected by filtration, dried to give 6-(difluoromethyl)-N-methyl-5-piperazin-1-yl-pyridine-2-carboxamide, 2HCI as an orange solid (0.617 g, 100%) (Intermediate 60). (m / z) (ES+) [M+H] 272.2. + [M+H] + = 272.

[0478] ​ [6-(dimethylcarbamoyl)-3-pyridyl]piperazin-1-yl]-N-methyl-pyridine-2-carboxamide

[0479] To a suspension of 6-(difluoromethyl)-N-methyl-5-piperazin-l-yl-pyridine-2- carboxamide, 2HCI (87 mg, 0.25 mmol) (Intermediate 60) and 7-(bromomethyl)-3- methoxy-8-methyl-lH-quinoxalin-2-one (80 mg, 0.25 mmol) (Intermediate 104) in acetonitrile (6 mL) was added DIPEA (222 μL, 1.27 mmol) and the resulting mixture was stirred at 70 °C for 2 hours to give a clear solution, the mixture was cooled to room temperature to give a suspension, the solid was collected by filtration, washed with acetonitrile, water and dried to give 6-(difluoromethyl)-5-[4-[(2-methoxy-5-methyl-3-oxo-4H- quinoxalin-6-yl)methyl]piperazin-l-yl]-N-methyl-pyridine-2-carboxamide as a white solid (0.070 g, 58.3%) (Example 59).1H NMR (500 MHz, DMSO-c / 6) 2.43 (3H, s), 2.59 (4H, br s), 2.83 (3H, br d), 2.98 (4H, br s), 3.60 (2H, s), 3.95 (3H, s), 6.92 - 7.29 (2H, m), 7.35 (1H, d), 7.85 (1H, br d), 8.08 (1H, d), 8.38 (1H, br d), 11.58 (1H, br s); ((m / z) (ES+) 473.2 [M+H]. + [M+H] + = 473.

[0480]

[0481] Example 60: 6-(difluoromethyl)-5-[4-[(2,5-dimethyl-3-oxo-4H- quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2-carboxamide [6-(dimethylcarbamoyl)-3-pyridyl]piperazin-1-yl]-N-methyl-pyridine-2-carboxamide

[0482] A mixture of 7-(bromomethyl)-3,8-dimethyl-1H-quinoxalin-2-one (196 mg, 0.73 mmol) (Intermediate 8), a mixture of 6-(difluoromethyl)-N-methyl-5-piperazin-1-yl-pyridine-2- carboxamide, 2HCI (252 mg, 0.73 mmol) (Intermediate 60) and Et3N (0.614 mL, 4.41 mmol) in acetonitrile (25 mL) was stirred at 70 °C for 2 hours to give a clear solution, LCMS indicated complete conversion. The mixture was allowed to cool to room temperature overnight. A solid crystallized from the mixture which was collected by filtration, washed with acetonitrile, water and dried to give the first portion of product 141 mg, the filtrate was concentrated and purified on reverse phase Gilson (eluting with 5% to 80% ACN / water / 0.1% TFA) to give the second portion of product as a TFA salt 92 mg. Total: 6-(difluoromethyl)-5-[4-[(2,5-dimethyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N- methyl-pyridine-2-carboxamide as an off-white solid (0.233 g, 64.0%) (Example 60).1H NMR (500 MHz, DMSO-d6) 2.40 (3H, s), 2.43 (3H, s), 2.60 (4H, br s), 2.83 (3H, d), 2.98 (4H, br d), 3.63 (2H, s), 6.95 - 7.22 (1H, m), 7.23 - 7.29 (1H, m), 7.51 (1H, d), 7.85 (1H, d), 8.08 (1H, d), 8.38 (1H, br d), 11.54 (1H, br s); (m / z) (ES+) 457.2 [M+H]. + [M+H] + = 457.

[0483]

[0484] Intermediate 113: methyl 6-chloro-5-(piperazin-1-yl)picolinic acid

[0485] Piperazine (1.0 g, 11.61 mmol) was added to methyl 6-chloro-5-fluoropicolinic acid (Intermediate 112, 1.0 g, 5.28 mmol) in MeCN (30 mL). The resulting mixture was stirred at 80 °C for 18 hours. The solvent was removed under reduced pressure. The crude product was purified by reverse phase chromatography (elution gradient 5% to 60% MeCN in water (0.1% NH4HCO3)). The pure fractions were evaporated to dryness to give methyl 6-chloro-5-(piperazin-1-yl)picolinic acid (Intermediate 113, 1.28 g, 95%) as a red oil. 1H NMR (400 MHz, DMSO-d6) δ 2.81 - 2.91 (4H, m), 3.04 - 3.08 (4H, m), 3.85 (3H, s), 7.61 (1H, d), 8.00 (1H, d) (NH proton not shown); m / z (ES+) [M+H] 256.0. + [M+H] + = 256.

[0486] Intermediate 30: 6-chloro-N-methyl-5-(piperazin-1-yl)picolinamide

[0487] A 2M solution of methylamine in THF (40 mL, 80.00 mmol) was added to methyl 6-chloro-5-(piperazin-1-yl)picolinate (Intermediate 113, 1.26 g, 4.93 mmol). The resulting mixture was stirred at 80 °C for 18 h. The solvent was removed under reduced pressure. The crude product was purified by reverse phase chromatography (elution gradient 5% to 60% MeCN in water (0.1% NH4HCO3)). Pure fractions were evaporated to dryness to give 6-chloro-N-methyl-5-(piperazin-1-yl)picolinamide (Intermediate 30, 1.12 g, 89%) as a light yellow oil. 1 H NMR (300 MHz, DMSO-d6) δ 2.79 (3H, d), 2.85 - 2.89 (4H, m), 2.97 - 3.02 (4H, m), 7.63 (1H, d), 7.94 (1H, d), 8.45 (1H, q) (piperazine - NH proton not shown); m / z (ES+) [M+H] 255.0. + [M+H] + = 255.

[0488]

[0489] Intermediate 114: tert-butyl 4-[2-fluoro-6-(methylcarbamoyl)-3-pyridyl]piperazine-1- carboxylate

[0490] tert-Butyl 4-(2-fluoro-6-methoxycarbonyl-3-pyridyl)piperazine-1 -carboxylate (Intermediate 11, 12.49 g, 36.80 mmol) in methylamine (120 mL, 36.80 mmol, 33 wt% in ethanol) was stirred at room temperature for 24 h (sealed tube). The solvent was removed under reduced pressure. The residue was dissolved in DCM and filtered through a bed of silica gel and washed with ethyl acetate. The filtrate was concentrated and dried under vacuum to give tert-butyl 4-[2-fluoro-6-(methylcarbamoyl)-3-pyridyl]piperazine-1 -carboxylate (Intermediate 114, 12.45 g, 100%) as a yellow solid.1H NMR (500 MHz, DMSO-c / 6) 1.42 (9H, s), 2.77 (3H, d), 3.04-3.16 (4H, m), 3.43-3.56 (4H, m), 7.59 (1 H, dd), 7.80-7.93 (1 H, m), 8.41 (1 H, q); m / z (ES+) [M+H] 340.2. + [M+H] + = 340.

[0491] Intermediate 32: 6-fluoro-N-methyl-5-piperazin-1-yl-pyridine-2-carboxamide

[0492] HCl (4M in dioxane, 100 ml, 400.00 mmol) was added to a solution of tert-butyl 4-[2-fluoro-6-(methylcarbamoyl)-3-pyridyl]piperazine-1 -carboxylate (Intermediate 114, 12.5 g, 36.94 mmol) in 1,4-dioxane (50 mL) at 0 °C. The reaction was stirred for 5 h during which time the temperature was allowed to warm to room temperature to give a yellow suspension. The suspension was diluted with diethyl ether and the solid filtered off and washed with diethyl ether. This solid was dried under vacuum to give 6-fluoro-N-methyl-5-piperazin-1 -yl-pyridine-2-carboxamide, 2HCI (Intermediate 32, 11.42 g, 99%) as a light yellow solid.1H NMR (500 MHz, DMSO-c / 6) δ ppm 2.8 (d, J=4.6 Hz, 3 H) 3.3 (br s, 4 H) 3.4 (br d, J=4.4 Hz, 4 H) 7.6-7.7 (m, 1 H) 7.9 (d, J=8.1 Hz, 1 H) 8.4 (br d, J=4.4 Hz, 1 H) 9.0-9.3 (m, 2 H); m / z (ES+) [M+H] 239.2. + [M+H] + = 239

[0493]

[0494] Intermediate 115: 5-bromo-N,6-dimethylpicolinamide

[0495] A 2M solution of methylamine in THF (20 mL, 40.00 mmol) was added to methyl 5-bromo-6-methylpicolinate (Intermediate 14, 2.0 g, 8.69 mmol) and the resulting mixture stirred at 80 °C for 18 hours. The solvent was removed under reduced pressure. The crude product was purified by reverse phase chromatography (elution gradient 5% to 80% MeOH in water (0.1% NH4HCO3)). Pure fractions were evaporated to dryness to give 5-bromo-N,6-dimethylpicolinamide (Intermediate 115, 1.5 g, 75%) as a light yellow solid. 1 H NMR (400 MHz, DMSO-c / 6) δ 2.65 (3H, s), 2.82 (3H, d), 7.75 (1H, d), 8.17 (1H, d), 8.57-8.76 (1H, m); m / z (ES + )[M+H] + = 229

[0496] Intermediate 116: tert-butyl 4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazine-1- carboxylate

[0497] tert-Butyl piperazine-1 -carboxylate (0.894 g, 4.80 mmol), BINAP (0.272 g, 0.44 mmol), Pd(OAc)2(0.098 g, 0.44 mmol) and Cs2CO3(3.56 g, 10.91 mmol) in toluene (20 mL). The resulting mixture was stirred at 80 °C for 16 hours. The solvent was removed under reduced pressure. The crude product was purified by reverse phase chromatography (elution gradient 5% to 30% MeOH in water (0.4% HCO2H)). Pure fractions were evaporated to dryness to give tert-butyl 4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazine-1 -carboxylate (Intermediate 116, 1.2 g, 82%) as a brown solid. 1 H NMR (300 MHz, CD3OD) δ 1.50 (9H, s), 2.58 (3H, s), 2.92-3.00 (7H, m), 3.62 (4H, m), 7.50 (1H, d), 7.88 (1H, d); m / z (ES + )[M+H] + = 335.

[0498] Intermediate 33: N,6-dimethyl-5-(piperazin-1-yl)picolinamide

[0499] tert-Butyl 4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazine-1 -carboxylate (Intermediate 115, 1.18 g, 3.53 mmol) was added to a solution of 4M HCI in 1,4-dioxane (10 mL, 329.15 mmol). The resulting mixture was stirred at room temperature for 1 hour. The precipitate was collected by filtration, washed with petroleum ether (5 mL x 2), Et20 (5 mL x 2) and dried under vacuum to give N,6-dimethyl-5-(piperazin-1-yl)picolinamide (Intermediate 33, 0.77 g, 81 %) as a yellow solid. 1 H NMR (300 MHz, CD3OD) δ 2.86 (3H, s), 3.02 (3H, s), 3.42-3.54 (8H, m), 8.29 (2H, d); m / z (ES + [M+H] + = 235.

[0500]

[0501] Intermediate 117: tert-butyl 4-(6-methoxycarbonyl-3-pyridyl)piperazine-1-carboxylate

[0502] Ruphos Pd G3 (4.07 g, 4.86 mmol) was added to a degassed mixture of methyl 5-bromopyridine-2-carboxylate (Intermediate 9, 30 g, 138.87 mmol), tert-butyl piperazine-1 -carboxylate (27.2 g, 145.81 mmol), Cs2C03(90 g, 277.73 mmol) in 1,4-dioxane (200 mL) and the mixture was stirred at 110 °C under N2atmosphere for 6 hours. The mixture was then cooled to room temperature, diluted with water, extracted with ethyl acetate (150 ml x 3). The combined organic layers were dried over anhydrous Na2S04and filtered. To this filtrate was added 3-(diethylenetriaminyl)propyl functionalized silica gel (12 g, 1.3 mmol / g loading) and the mixture was stirred at room temperature for 1 hour. The mixture was filtered and the filtrate was concentrated to about 100 mL. The crystallized yellow solid was filtered off, washed with diethyl ether and dried under vacuum to give tert-butyl 4-(6-methoxycarbonyl-3-pyridyl)piperazine-1 -carboxylate (Intermediate 117, 26.36 g, 82 mmol, 59.1 %) as a yellow solid.1H NMR (500 MHz, Chloroform-d) 1.50 (9H, s), 3.31 - 3.42 (4H, m), 3.56 - 3.68 (4H, m), 3.98 (3H, s), 8.04 (1H, d), 8.37 (1H, d); m / z (ES + [M+H] + = 322.

[0503] Intermediate 118: tert-butyl 4-[6-(methylcarbamoyl)-3-pyridyl]piperazine-1-carboxylate

[0504] Methanamine (100 ml, 1155.26 mmol, 40% in water) was added to a solution of tert-butyl 4-(6-methoxycarbonyl-3-pyridyl)piperazine-1 -carboxylate (Intermediate 117, 36 g, 112.02 mmol) in MeOH (100 ml) and the reaction stirred at room temperature for 4 hours to give a white suspension. The mixture was concentrated, the residue partitioned between saturated NH4CI solution and DCM, the layers separated. The aqueous layer was extracted with DCM, the organic layers combined, washed with brine, dried over Na2S04, filtered and concentrated to give tert-butyl 4-[6-(methylaminocarbonyl)-3-pyridyl]piperazine-1 -carboxylate (Intermediate 118, 35.9 g, 100%) as a yellow solid.1H NMR (500 MHz, Chloroform-d) 1.49 (9H, s), 3.02 (3H, d), 3.26-3.35 (4H, m), 3.58-3.67 (4H, m), 7.23 (1 H, dd), 7.81 (1 H, br d), 8.07 (1 H, d), 8.16 (1 H, d); m / z (ES+) [M+H]+= 321.0. + [M+H] + = 321.

[0505] Intermediate 119: methyl 5-(piperazin-1-yl)picolinic acid

[0506] HCl 4M in dioxane (20 ml, 576.01 mmol) was added to a mixture of tert-butyl 4-(6-(methoxycarbonyl)pyridin-3-yl)piperazine-1 -carboxylate (Intermediate 117, 1.55 g, 4.82 mmol) in MeOH (2 ml) at 0 °C, the reaction stirred at room temperature for 2 hours to give a suspension, LCMS indicated complete conversion, the mixture was diluted with ether (ca. 80 ml), the solid collected by filtration, washed with ether, dried to give methyl 5-(piperazin-1 -yl)pyridinecarboxylate (Intermediate 119) as a yellow solid (1.384 g, 98%).1H NMR (500 MHz, DMSO-d6) 3.21 (4H, br s), 3.66 (4H, br d), 3.83 (3H, s), 7.43-7.55 (1 H, m), 7.95 (1 H, br d), 8.43 (1 H, br s), 9.49 (2H, br s); (m / z) (ES+) [M+H]+= 223.0.

[0507] Intermediate 31: formate N-methyl-5-piperazin-1-yl-pyridine-2-carboxamide

[0508] HCI (4 M in dioxane, 150 mL, 600.00 mmol) was added to a suspension of tert-butyl 4-[6-(methylcarbamoyl)-3-pyridyl]piperazine-1 -carboxylate (Intermediate 118, 35.9 g, 112.05 mmol) in MeOH (50 mL) and the resulting orange suspension was stirred at room temperature for 4 hours. About 80 mL of solvent was removed under reduced pressure and the mixture was diluted with diethyl ether and hexanes (200 ml, 1 / 1). The solids were collected by filtration, washed with hexanes, dried and dried under vacuum to give N-methyl-5-piperazin-1-yl-pyridine-2-carboxamide 2 HCI salt (Intermediate 31, 37.0 g, 100%) as a yellow solid.1H NMR (500 MHz, DMSO-d6) 2.79 (3H, d), 3.22 (4H, br s), 3.53-3.67 (4H, m), 7.51 (1 H, dd), 7.91 (1 H, d), 8.33 (1 H, d), 8.50 (1 H, br s), 9.19-9.49 (2H, m); m / z (ES+) [M+H] = 221. + [M+H] + = 221.

[0509] Example 61 : Preparation of 6-fluoro-5-[4-[(5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6- yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2-carboxamide crystalline Form B (anhydrous form)

[0510] Method 1

[0511] A suspension of 43 mg (0.10 mmol) of 6-fluoro-5-[4-[(5-fluoro-2-methyl-3-oxo-4H- quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2-carboxamide (from e.g. Example 20) in 1.0 ml MeOH was prepared and 0.11 ml of a 1 M aqueous methanesulfonic acid (MSA) solution was added to obtain a clear solution. To this solution, 0.11 ml of a 1 N aqueous NaOH solution was added. Upon completion of the NaOH solution addition, a white solid started to precipitate. The slurry was stirred at room temperature for 1 day. 36 mg of white solid was filtered and dried in air. The XRPD showed that the solid was pure 6-fluoro-5-[4-[(5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2-carboxamide Form B.

[0512] Method 2

[0513] Pyridine (93.5 g) was added to a solution of pure 6-fluoro-5-[4-[(5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2-carboxamide mesylate (4.67 kg, prepared by the method of Example 63) in water (47.9 kg) and ethanol (38.0 kg) at 75 ± 5 °C, followed by the addition of 6-fluoro-5-[4-[(5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2-carboxamide Form B seed (4.7 g) prepared according to Method 1. The slurry was stirred at 75 ± 5 °C for 40 minutes, then a solution of pyridine (651 g) in 50:50 v:v water:ethanol (4.2 kg) was added gradually over 3 hours 40 minutes. The slurry was stirred at 75 ± 5 °C for 50 minutes, then a solution of 4-methylmorpholine (900 g) in 50:50 v:v water:ethanol (4.1 kg) was added gradually over 3 hours 50 minutes. The slurry was stirred at 75 ± 5 °C for 1 hour 10 minutes, cooled to 25 ± 5 °C over 4 hours 50 minutes, stirred at 25 ± 5 °C for 15 hours, then filtered. The resulting solid was washed twice with 50:50 v:v water:ethanol (12.5 kg x 2), then dried under vacuum at between 25 °C and 50 °C for 1 day to give pure 6-fluoro-5-[4-[(5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2-carboxamide Form B (3.54 kg) in 93% yield.

[0514] Form B from Method 1 was analyzed by XRPD and the results are listed below (Table 1) and shown in Figure 1 .

[0515] Table 1. XRPD peaks for Form B

[0516]

[0517]

[0518] Form B is characterized by providing at least one of the following 2-theta values measured using Cu K alpha radiation: 6.2°, 14.3°, and 15.6°.

[0519] Form B (Method 1) was analyzed by thermal techniques. DSC analysis indicated that Form B has a melting point that begins at 275 °C and reaches a peak at 276 °C. TGA indicated that Form B exhibits a mass loss of about 0.2% upon heating from about 25 °C to about 100 °C. A representative DSC / TGA thermogram of Form B is shown in Figure 2 .

[0520] Example 62: Preparation of 6-fluoro-5-[4-[(5-fluoro-2-methyl-3-oxo-4H- quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2-carboxamide crystalline Form D (anhydrous form).

[0521] A sample of 5-6 mg of 6-fluoro-5-[4-[(5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6- yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2-carboxamide (Example 20) was dissolved in a mixed solvent of MeOH / DCM / H2O (0.50 ml / 0.50 ml / 0.20 ml) and the clear solution was slowly evaporated to give a white solid at ambient conditions. XRPD showed that the resulting white solid was 6-fluoro-5-[4-[(5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2-carboxamide Form D.

[0522] Form D was analyzed by XRPD and the results are listed in the table below (Table 2) and shown in Figure 3 .

[0523] Table 2. XRPD peaks of Form D

[0524] Angle (2Θ ± 0.2°) Intensity (%) 9.6 100.0 18.4 43.0 13.1 32.0 19.9 17.9 27.1 17.3 9.2 15.9 21.7 14.0 23.4 11.2 24.5 9.6 19.3 8.8 16.8 8.7 22.2 8.3 16.3 8.0 18.8 7.6 25.4 6.9 10.2 6.6 33.0 6.3 22.5 5.8 12.6 5.7 7.9 4.5

[0525] Form D is characterized by providing at least one of the following 2-theta values measured using CuK alpha radiation: 7.9°, 13.1° and 16.3°.

[0526] Single crystals of Form D were obtained from the evaporation of a DMF solution (or DMF / H2O) of 6-fluoro-5-[4-[(5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2-carboxamide. Single crystal structure analysis confirmed that Form D is an anhydrous form. The molecular structure of 6-fluoro-5-[4-[(5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2-carboxamide Form D is shown in Figure 4 . Crystallographic data: space group monoclinic P21 / c, unit cell dimensions: β = 92.609(1)°,

[0527] Example 63: Preparation of 6-fluoro-5-[4-[(5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6- yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2-carboxamide MSA crystalline salt Form C (anhydrous form).

[0528] Method 1

[0529] Example 20) was suspended in 8.0 ml of MeOH. To the suspension was added 1.1 ml of a 1.0 M aqueous solution of MS A (1.1 mmol) to give a clear solution. The resulting solution was filtered and the solvent of the clear solution was removed. The resulting solid was suspended in 1.0 ml of EtOH and 2.0 ml of THF to give a slurry. The slurry was stirred at room temperature for 1 day. The solid was collected by filtration and air dried. 452 mg of off-white solid was obtained. XRD showed that 6-fluoro-5-[4-[(5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6- yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2-carboxamide MSA salt Form C was obtained.

[0530] Method 2

[0531] (750 mL) at 25 °C. The resulting suspension was stirred at 25 °C for 16 hours, then filtered. The solid was washed with 4:1 v:v THF:ethanol (300 mL), then dried under vacuum at 35 °C to give 6-fluoro-5-[4-[(5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6- yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2-carboxamide mesylate Form C (90.3 g) in 98% yield.

[0532] MSA-Form C from Method 1 was analyzed by XRPD and the results are listed below (Table 3) and shown in Figure 5 .

[0533] Table 3. XRPD peaks for MSA-Form C

[0534]

[0535] MSA-Form C obtained from Method 1 was analyzed by thermal techniques. DSC analysis indicated that MSA-Form C began to melt and decompose at this temperature with an onset temperature of 254 °C and a peak at 258 °C. TGA indicated that MSA-Form C exhibited a mass loss of about 0.3% upon heating from about 25 °C to about 100 °C. A representative DSC / TGA thermogram of MSA-Form C is shown in Figure 6 .

[0536] Biological Assay

[0537] The following test procedure can be employed to determine the inhibitory properties of the compounds described herein.

[0538] PARP fluorescence anisotropy binding assay

[0539] Recombinant full-length 6HIS tagged PARP1 protein was diluted to 6 nM in 50 mM Tris pH 8, 0.001% Triton X100, 10 mM MgCl2, 150 mM NaCl and incubated with an equal volume of 2 nM fluorescent probe (diluted in 50 mM Tris pH 8, 0.001% Triton X100, 10 mM MgCl2, 150 mM NaCl) for four hours. The final DMSO concentration of the probe was kept below 1% (v / v).

[0540] Recombinant full-length PARP2 protein was diluted to 6 nM in 50 mM Tris pH 8, 0.001% Triton X100, 10 mM MgCl2, 150 mM NaCl and incubated with an equal volume of 2 nM fluorescent probe (diluted in 50 mM Tris pH 8, 0.001% Triton X100, 10 mM MgCl2, 150 mM NaCl) for four hours. The final DMSO concentration of the probe was kept below 1% (v / v).

[0541] Recombinant full-length PARP3 protein was diluted to 100 nM in 50 mM Tris pH 8, 0.001% Triton X100, 10 mM MgCl2, 150 mM NaCl and incubated with an equal volume of 6 nM fluorescent probe (diluted in 50 mM Tris pH 8, 0.001% Triton X100, 10 mM MgCl2, 150 mM NaCl) for four hours. The final DMSO concentration of the probe was kept below 1% (v / v).

[0542] Recombinant PARP5a binding domain was diluted to 160 nM in 50 mM Tris pH 8, 0.001% Triton X100, 10 mM MgCl2, 150 mM NaCl and incubated with an equal volume of 6 nM fluorescent probe (diluted in 50 mM Tris pH 8, 0.001% Triton X100, 10 mM MgCl2, 150 mM NaCl) for four hours. The final DMSO concentration of the probe was kept below 1% (v / v).

[0543] Recombinant full-length GST-tagged PARP6 protein was diluted to 160 nM in 50 mM Tris pH 8, 0.001% Triton X100, 10 mM MgCl2, 150 mM NaCl and incubated with an equal volume of 6 nM fluorescent probe (diluted in 50 mM Tris pH 8, 0.001% Triton X100, 10 mM MgCl2, 150 mM NaCl) for four hours. The final DMSO concentration of the probe was kept below 1% (v / v).

[0544] In the presence of test compounds or solvent controls, the fluorescence anisotropy of the probe when bound to the protein was measured using a BMG Pherastar The fluorescence anisotropy of the probe when bound to the protein was measured in the presence of test compounds or solvent controls using a BMG Pherastar 50 The % inhibition values for different concentrations of test compounds were calculated and fitted to a four parameter log plot to determine the IC i values. If necessary, compound K 50 values were determined using the Munson Rodbard equation defined in Anal Biochem. 1980 Sep 1;107(1):220-39 and are based on the known K D determined for the probe binding to the relevant PARP protein.

[0545] PARP proliferation assay (7 day compound dosing)

[0546] DLD1 cells and BRCA2- / -) DLD1 cells at a density of 5000 cells / ml and 2.5E4 cells / ml respectively were harvested in complete medium and seeded at 40 pL / well into 384 well plates (Greiner, Kremsmunster, Austria; 781090) using a Multidrop Combi and then incubated overnight at 37°C, 5% C02. The next day (day 1), sytox green (5ul, 2uM) and saponin (10ul, 0.25% stock) were added to day 0 plates using a Multidrop Combi, plates were sealed using black adhesive caps and incubated at room temperature for >3 hours. Cells were imaged using a Cell Insight (Thermo Fisher) fitted with a 4x objective. Test compounds were added using an Echo 555 and placed in an incubator kept at 37°C, 5% C02and incubated for 7 days. On day 8, sytox green (5ul, 2uM) was added to the plates followed by saponin (10ul, 0.25% stock), plates were sealed using black adhesive caps and incubated at room temperature for >3 hours. All cells on the Cell Insight were read using a 4x objective. Proliferation rates in Genedata were determined by assessing the total cell number from Cell Insight output for day 0 and day 8 plates.

[0547] Human transporter efflux in vitro

[0548] MDCKII cells expressing MDR1 and BCRP were seeded at a density to form confluent cell monolayers on the polyethylene membrane of a 96-well Transwell insert system. Test and reference compounds were diluted in transport buffer (HBSS HEPES pH 7.4) to a concentration of 1 or 0.1 mM. The final volume percentage of organic solvent was less than 1%. Permeation of test compounds from A to B direction and from B to A direction was determined after 90 min incubation at 37°C and 5% C02and 95% relative humidity. At the end of the incubation, samples were taken from the apical side and from the basolateral side and then precipitated with cold acetonitrile containing an internal standard. After centrifugation at 4000 rpm, the supernatant was diluted with 0.1% aqueous formic acid and quantified with LC-MS / MS. The integrity of the cell monolayer was confirmed by using the marker fluorescent yellow.

[0549] The permeability coefficient (1 x 10-6cm / s) was calculated using the following equation

[0550] Papp= (dCr / dt) x Vr / (A x Co)

[0551] The efflux ratio was calculated using the following equation

[0552] Efflux ratio = Papp(B to A) / Papp(A to B)

[0553] (2) where dCr / dt is the cumulative concentration of compound in the receiver chamber as a function of time (in μΜ / s); Vr is the volume of solution in the receiver chamber (0.1 ml apical side and 0.3 ml basolateral side); A is the transport surface area, i.e., the monolayer area is 0.11 cm2; and Co is the initial concentration in the donor chamber (in μΜ).

[0554] Determination of unbound fraction in plasma

[0555] The fraction unbound was determined using the RED device.

[0556] Compounds were prepared as 10 mM solutions in DMSO. A 1 mM working stock was prepared by mixing up to 9 test compounds (4 uL of each) and 1 control (uL). If fewer than 9 test compounds were included, a volume of blank DMSO was added to make up the volume to 40 uL.

[0557] Frozen plasma was thawed in a 37 °C water bath. The plasma was then centrifuged at 4,000 rpm for 2 minutes to remove clots and the supernatant was collected into a new tube. The pH of the plasma was checked and only used if in the range of pH 7 to pH 8. 3 uL of working solution per cassette was added to 597 uL of blank plasma and vortexed at 1000 rpm for 5 minutes. The final volume percent of organic solvent was 0.5% and the final concentration of test compound was 5 uM. 50 uL of the spiked plasma suspension was immediately transferred to a 96 well plate as the T=0 control sample. The samples were treated the same as the samples after incubation. The remaining plasma was kept at 37 °C until the start of dialysis.

[0558] The insert was placed into the well of the base plate. 300 uL of the spiked plasma sample was added to the sample chamber, indicated by the red ring. 500 uL of phosphate buffered saline (pH 7.4) was added to the buffer chamber. The device was capped with a gas permeable lid and incubated at 37 °C for 18 hours on an orbital shaker in a CO2 incubator at 300 rpm and 5% CO2. At the end of the incubation, the lid was removed and 50 uL of post-dialysis sample was removed from the buffer and plasma chambers, respectively, into separate 96 well plates for analysis.

[0559] Samples were matrix-matched by adding 50 pL of blank rat plasma to the buffer samples and an equal volume of PBS to the collected plasma samples and vortex mixed. 400 pL of acetonitrile containing the appropriate internal standard (IS) was added to precipitate the proteins and release the compounds and mixed by vortexing the plate for 10 minutes and then centrifuged at 4,000 rpm for 30 minutes. 250 pL of supernatant was transferred to a new 96-well plate and centrifuged again (4,000 rpm for 30 minutes). 100 pL of supernatant was then transferred to a new 96-well plate and mixed with 100 pL of distilled water by vortexing at 1,000 rpm for 5 minutes into each sample. Samples were analyzed by LC-MS / MS and drug concentrations were determined relative to a calibration curve generated from spiked blank plasma, typically ranging from 1-7500 nM.

[0560] The % unbound was determined as % unbound = (buffer chamber concentration / plasma chamber concentration) x 100%. The fraction unbound was determined as % unbound / 100.

[0561] Determination of unbound fraction in brain sections

[0562] The principle of the method for determining the volume of unbound in brain slices has been published previously (Development of a High-Throughput Brain Slice Method for Studying Drug Distribution in the Central Nervous System; Fridén et al; Drug Metabolism and Disposition, 2009, 37(6) 1226-1233). Briefly:

[0563] A stock solution of the compound was prepared at a concentration of 10 mM in DMSO. A 1 mM working stock was prepared by mixing up to 9 test compounds (4 uL of each) and 1 control (4 uL). If fewer than 9 test compounds were included, blank DMSO was added to make up the volume to 40 uL. On the day of the experiment, 4 ul was diluted in 40 mL of ECF buffer to give a 100 nM solution of each test compound which was then pre-warmed to 37 °C before the start of incubation.

[0564] To prepare brain sections, rats weighing approximately 300 g were terminally anesthetized by inhalation of isoflurane, the brains were carefully removed and immersed in ice-cold oxygenated ECF buffer. The rat brains were transferred to a dish containing ice-cold, O2-supplied ECF buffer and trimmed with a razor blade before being glued to the tray of a microtome, the brain was placed in the center of the tray with the dorsal cut surface facing down. Ice-cold ECF buffer was added to harden the glue and to wet the brain. The tray was placed in the microtome and sections of 100-400 pm were cut using an appropriate cutting speed until the striatal region appeared. Four to six coronal sections, 300 pm thick, of the striatal region were cut from each brain and placed in ice-cold, O2-supplied buffer until incubation. Six sections were transferred to an incubation tray containing 40 mL of pre-warmed (37 °C) cassette cocktail. The time from removal of the brain to the sections entering the cocktail was a maximum of 20 min. The incubation tray was covered with a gas-permeable lid, placed in a 37 °C water bath, pumped with O2, and incubated for 5 h with a shaking frequency of 45 rpm.

[0565] Before incubation, 200 pL of the unincubated cassette solution was saved as a T=0 sample. Then 200 pL was mixed with 200 pL of blank brain homogenate in ECF buffer (4 volumes (w / v)). The pH value in the cassette solution was measured and recorded after incubation, the pH value must be higher than 7.3. 200 pL from the surface of the cassette solution was transferred to a tube containing 200 pL of blank brain homogenate (4 volumes (w / v)) in ECF buffer. Each brain section was dried on filter paper and weighed in a 2 mL eppendoff tube. After adding 9 volumes (w / v) of ECF buffer, the sections were homogenized with an ultrasonicator. The samples were precipitated and diluted as follows.

[0566] An aliquot of 50 pL from each sample and 3 x 50 pL from each cassette solution (mixed with blank homogenate) was transferred to 0.6 mL centrifuge tubes. The samples were precipitated with 200 pL ice-cold acetonitrile containing internal standard and vortexed at 2,000 rpm for 3 min and then centrifuged at 14,000 rpm for 15 min at 4 °C. 100 pL of supernatant was transferred to a new 96-well plate for analysis, 100 pL of distilled water was transferred to each sample, and the plate was shaken at 1,000 rpm for 2 min for LC-MS / MS analysis.

[0567] The mixed slice samples were then further diluted in two steps, 10-fold and 100-fold. Double blank samples were prepared by homogenizing 150 μL of blank brain in ECF buffer (4 volumes (w / v)) and transferring the homogenate to a 1.5 mL centrifuge tube containing 150 μL of ECF buffer. The samples were vortexed at 2,000 rpm for 2 min. The samples were then precipitated with 1200 μL of ice-cold acetonitrile and vortexed at 2,000 rpm for 3 min, followed by centrifugation at 14,000 rpm at 4 °C for 15 min. 100 μL of the supernatant was then transferred to a new 96-well plate for analysis. 100 μL of distilled water was added to each sample to obtain double blank samples.

[0568] Unbound brain volume (V) u，脑 ) Calculated as V u =(C 切片 -V0*C ECF ) / (1-V0)*C ECF

[0569] Where C 切片 C ECF V0 and V0 represent the amount of drug in the slice, the drug concentration in the ECF (representing the drug concentration in the brain ECF, i.e., the free concentration), and the water attachment in the brain slice (0.0931), respectively.

[0570] Unbound fraction f in the brain u，脑 =1 / V u，脑

[0571] Determination of Kpuu in rats

[0572] The ratio of total / unbound drug in plasma to total / unbound drug in the brain (Kp / Kpuu) was determined as follows.

[0573] The compound was prepared as a mixture in a 1:1:1 ratio of tetraethylene glycol:dimethylacetamide:water at a concentration of 0.5 mM each, and administered to Han Wistar rats via intravenous infusion at a rate of 4 mL / kg at a rate of 2 μmol / kg / h. Animals were sacrificed 4 hours later, and brain and blood samples were collected. Plasma was prepared from blood, and all samples were frozen at -20°C until analysis. Brain samples were homogenized in purified water at a ratio of 1:3 (w / v) and frozen at -20°C until analysis.

[0574] Plasma and brain samples were analyzed by protein precipitation followed by LC-MS / MS, with concentrations determined based on calibration curves generated by spiked blank rat plasma or brain homogenates with appropriate concentration ranges of the drug. Residual blood brain concentration was corrected by subtracting 0.8% of the plasma concentration from the total brain concentration.

[0575] Kp was calculated as follows: Kp = ((4*[brain homogenate]) - (0.008*[plasma])) / [plasma]

[0576] Kpuu was calculated as follows: Kpuu = Kp * (fraction unbound in brain sections / fraction unbound in plasma)

[0577] Biological data

[0578]

[0579]

[0580]

[0581] Table 4

Claims

1. A compound having formula I or a pharmaceutically acceptable salt thereof, in: R 1 Independently selected from H and C 1-4 Alkyl, C 3-6 cycloalkyl, C 1-4 fluoroalkyl or C 1-4 Alkyloxy; R 2 Independently selected from H, halogen, C 1-4 Alkyl or C 1-4 fluoroalkyl; and R 3 Is it H or C? 1-4 alkyl; R 4 Is it halogen or C? 1-4 alkyl.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 It is selected from any one of methyl, ethyl, isopropyl, cyclopropyl, 1,1-difluoroethyl, 1-fluoroethyl, trifluoromethyl, difluoromethyl and methoxy.

3. The compound of claim 2 or a pharmaceutically acceptable salt thereof, wherein R 1 It is methyl or ethyl.

4. The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein R 2 It is selected from any one of H, chlorine, fluorine, methyl and difluoromethyl.

5. The compound of claim 4 or a pharmaceutically acceptable salt thereof, wherein R 2 It is either fluorine or methyl.

6. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein R 3 It is methyl or ethyl.

7. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R 4 It is selected from any one of chlorine, fluorine, and methyl.

8. The compound of claim 7 or a pharmaceutically acceptable salt thereof, wherein R 4 It's fluorine.

9. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 It is C 1-4 Alkyl, R 2 It's halogen, R 3 It is C 1-4 Alkyl, R 4 Is it halogen or C? 1-4 alkyl.

10. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 Independently selected from H and C 1-4 Alkyl, C 1-4 fluoroalkyl or C 1-4 Alkyloxy group.

11. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from: 5-[4-[(2,5-dimethyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-6-fluoro-N-methylpyridin-2-carboxamide, 5-[4-[(2,5-dimethyl-3-oxo-4H-quinoxalo-6-yl)methyl]piperazin-1-yl]-N-methylpyridin-2-carboxamide, 6-Chloro-5-[4-[(2,5-dimethyl-3-oxo-4H-quinoxalo-6-yl)methyl]piperazin-1-yl]-N-methylpyridin-2-carboxamide, 5-[4-[(2,5-dimethyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N,6-dimethylpyridin-2-carboxamide, 5-[4-[(2,5-dimethyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-6-fluoro-pyridine-2-carboxamide, 5-[4-[(5-fluoro-2-methyl-3-oxo-4H-quinoxalo-6-yl)methyl]piperazin-1-yl]-6-methylpyridin-2-carboxamide, 5-[4-[(2,5-dimethyl-3-oxo-4H-quinoxalo-6-yl)methyl]piperazin-1-yl]-6-methylpyridin-2-carboxamide, 6-Chloro-5-[4-[(5-chloro-2-ethyl-3-oxo-4H-quinoxalo-6-yl)methyl]piperazin-1-yl]-N-methylpyridin-2-carboxamide, 5-[4-[(5-chloro-2-ethyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-6-fluoro-N-methylpyridin-2-carboxamide, 5-[4-[(5-chloro-2-ethyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methylpyridin-2-carboxamide, 5-[4-[(5-chloro-2-ethyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N,6-dimethylpyridin-2-carboxamide, 6-Fluoro-5-[4-[[5-Fluoro-2-[(1S and 1R)-1-fluoroethyl]-3-oxo-4H-quinoxalin-6-yl]methyl]piperazin-1-yl]-N-methylpyridin-2-carboxamide, 5-[4-[[5-fluoro-2-[(1S and 1R)-1-fluoroethyl]-3-oxo-4H-quinoxalin-6-yl]methyl]piperazin-1-yl]-N,6-dimethylpyridine-2-carboxamide, 5-[4-[(5-chloro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methylpyridin-2-carboxamide, 5-[4-[(5-chloro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-6-fluoro-N-methylpyridin-2-carboxamide, 5-[4-[(5-chloro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N,6-dimethylpyridin-2-carboxamide, 5-[4-[[2-(1,1-difluoroethyl)-5-fluoro-3-oxo-4H-quinoxalin-6-yl]methyl]piperazin-1-yl]-N,6-dimethylpyridin-2-carboxamide, 6-Fluoro-5-[4-[(5-fluoro-2-methyl-3-oxo-4H-quinoxalo-6-yl)methyl]piperazin-1-yl]-N-methylpyridin-2-carboxamide, 6-(difluoromethyl)-5-[4-[(5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methylpyridin-2-carboxamide, 6-Fluoro-5-[4-[(5-fluoro-2-methyl-3-oxo-4H-quinoxalo-6-yl)methyl]piperazin-1-yl]pyridine-2-carboxamide, 5-[4-[(2-ethyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N,6-dimethylpyridin-2-carboxamide, 6-(difluoromethyl)-5-[4-[(2-ethyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methylpyridin-2-carboxamide, 5-[4-[(2-ethyl-5-fluoro-3-oxo-4H-quinoxalo-6-yl)methyl]piperazin-1-yl]pyridine-2-carboxamide, 5-[4-[(2-ethyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-6-methylpyridin-2-carboxamide, 5-[4-[(2-ethyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-6-fluoro-N-methylpyridin-2-carboxamide, 6-Chloro-5-[4-[(2-ethyl-5-fluoro-3-oxo-4H-quinoxalo-6-yl)methyl]piperazin-1-yl]-N-methylpyridin-2-carboxamide, 5-[4-[(2-ethyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methylpyridin-2-carboxamide, 6-Chloro-5-[4-[(5-fluoro-2-methyl-3-oxo-4H-quinoxalo-6-yl)methyl]piperazin-1-yl]-N-methylpyridin-2-carboxamide, 5-[4-[(5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N,6-dimethylpyridin-2-carboxamide, 5-[4-[(5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methylpyridin-2-carboxamide, 5-[4-[(5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methylpyridin-2-carboxamide, 6-Chloro-5-[4-[(5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methylpyridin-2-carboxamide, 5-[4-[(5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N,6-dimethylpyridin-2-carboxamide, 6-Fluoro-5-[4-[(5-Fluoro-3-oxo-4H-quinoxalo-6-yl)methyl]piperazin-1-yl]-N-methylpyridin-2-carboxamide, 5-[4-[[2-(difluoromethyl)-5-fluoro-3-oxo-4H-quinoxalin-6-yl]methyl]piperazin-1-yl]-N,6-dimethylpyridin-2-carboxamide, 5-[4-[(5-fluoro-2-methoxy-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methylpyridin-2-carboxamide, 6-Fluoro-5-[4-[(5-fluoro-2-methoxy-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methylpyridin-2-carboxamide, 5-[4-[(5-fluoro-2-methoxy-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N,6-dimethylpyridine-2-carboxamide, 6-Chloro-5-[4-[(5-fluoro-2-methoxy-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methylpyridin-2-carboxamide, 5-[4-[(2-ethyl-5-methyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N,6-dimethylpyridin-2-carboxamide, 5-[4-[(2-ethyl-5-methyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-6-fluoro-N-methylpyridin-2-carboxamide, 5-[4-[(2-ethyl-5-methyl-3-oxo-4H-quinoxalo-6-yl)methyl]piperazin-1-yl]-N-methylpyridin-2-carboxamide, N-Ethyl-6-fluoro-5-[4-[(5-fluoro-2-methyl-3-oxo-4H-quinoxalo-6-yl)methyl]piperazin-1-yl]pyridine-2-carboxamide, N-Ethyl-5-[4-[(5-fluoro-2-methyl-3-oxo-4H-quinoxalo-6-yl)methyl]piperazin-1-yl]-6-methylpyridin-2-carboxamide, 5-[4-[[5-fluoro-3-oxo-2-(trifluoromethyl)-4H-quinoxalin-6-yl]methyl]piperazin-1-yl]-N,6-dimethylpyridin-2-carboxamide, 6-Fluoro-5-[4-[[5-Fluoro-3-oxo-2-(trifluoromethyl)-4H-quinoxalo-6-yl]methyl]piperazin-1-yl]-N-methylpyridin-2-carboxamide, 6-Chloro-5-[4-[[5-fluoro-3-oxo-2-(trifluoromethyl)-4H-quinoxalin-6-yl]methyl]piperazin-1-yl]-N-methylpyridin-2-carboxamide, 5-[4-[[5-fluoro-3-oxo-2-(trifluoromethyl)-4H-quinoxalin-6-yl]methyl]piperazin-1-yl]-N-methylpyridin-2-carboxamide, 6-Fluoro-5-[4-[(5-fluoro-2-isopropyl-3-oxo-4H-quinoxalo-6-yl)methyl]piperazin-1-yl]-N-methylpyridin-2-carboxamide, 5-[4-[(5-fluoro-2-isopropyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N,6-dimethylpyridin-2-carboxamide, 5-[4-[(5-fluoro-2-isopropyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methylpyridin-2-carboxamide, 5-[4-[(2-cyclopropyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-6-fluoro-N-methylpyridin-2-carboxamide, 5-[4-[(2-cyclopropyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N,6-dimethylpyridine-2-carboxamide, 5-[4-[(2-cyclopropyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methylpyridin-2-carboxamide, 5-[4-[(2-methoxy-5-methyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N,6-dimethylpyridine-2-carboxamide, 6-Fluoro-5-[4-[(2-methoxy-5-methyl-3-oxo-4H-quinoxalo-6-yl)methyl]piperazin-1-yl]-N-methylpyridin-2-carboxamide, 6-(difluoromethyl)-5-[4-[(2-methoxy-5-methyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methylpyridin-2-carboxamide, or 6-(difluoromethyl)-5-[4-[(2,5-dimethyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methylpyridine-2-carboxamide.

12. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is: 6-Fluoro-5-[4-[(5-Fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methylpyridine-2-carboxamide.

13. The compound according to claim 1, wherein the compound is: 6-Fluoro-5-[4-[(5-Fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methylpyridine-2-carboxamide.

14. A pharmaceutical composition comprising a compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient or inert carrier.

15. The pharmaceutical composition of claim 14, wherein the excipient comprises at least one pharmaceutically acceptable diluent.

16. Use of any compound of claims 1 to 13 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating or preventing a disease or condition in which inhibition of PARP1 is beneficial, wherein the disease or condition is cancer, wherein the cancer is selected from any one of breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, blood cancer, gastrointestinal cancer, lung cancer, and brain cancer.

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