PARP1 inhibitors

Abstract

The present invention relates to azaquinolone compounds of formula (I) and their use in medicine. [Formula 1] TIFF2022541483000071.tif33160

Description

[Technical field]

[0001] The present disclosure relates to substituted azaquinolone compounds and pharma- ceutically acceptable salts thereof that inhibit the poly(ADP-ribose) polymerase (PARP) family of enzymes. The present disclosure also relates to the use of these compounds and pharma- ceutically acceptable salts thereof in medical therapy, for example, in the treatment of diseases in which inhibition of PARP1 or PARP1 function is of therapeutic importance. The present disclosure also relates to methods of treatment using the compounds according to the present disclosure, and methods of making medicaments. [Background technology]

[0002] PARP family enzymes play important roles in many cellular processes such as replication, recombination, chromatin remodeling, and DNA damage repair (Non-Patent Document 1).

[0003] Examples of PARP inhibitors and their mechanism of action are taught, for example, in US Pat. No. 5,399,633.

[0004] PARP1 and PARP2 are the most widely studied PARPs for their role in DNA damage repair. PARP1 is activated by DNA damage breaks and functions to catalyze 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 lesion.

[0005] Once this recruitment role is completed, auto-PARylation of PARP triggers the release of bound PARP from DNA and access to other DNA repair proteins to complete the repair. Thus, the binding of PARP to the damaged site, its catalytic activity, and final release from DNA are all important steps for cancer cells to respond to DNA damage caused by chemotherapy and radiation therapy (Non-Patent Document 2).

[0006] Inhibition of PARP family enzymes has been exploited as a strategy to selectively kill cancer cells by inactivating complementary DNA repair pathways. Numerous preclinical and clinical studies have demonstrated that tumor cells with deleterious alterations in BRCA1 or BRCA2, key tumor suppressor proteins involved in double-stranded DNA break (DSB) repair by homologous recombination (HR), are selectively sensitive to small molecule inhibitors of the PARP family of DNA repair enzymes. Such tumors are defective in the homologous recombination repair (HRR) pathway and depend on the function of the PARP enzyme for survival. Although PARP inhibitor therapy primarily targets BRCA-mutated cancers, PARP inhibitors are being tested in clinical trials in non-BRCA-mutated tumors, i.e., tumors that exhibit homologous recombination deficiency (HRD) (Non-Patent Document 3).

[0007] PARP inhibitors with improved selectivity for PARP1 are believed to have improved efficacy and reduced toxicity compared to other clinical PARP1 / 2 inhibitors. Selective and strong inhibition of PARP1 is believed to trap PARP1 in DNA, leading to DNA double-strand breaks (DSBs) caused by the collapse of replication forks in the S phase. PARP1-DNA trapping is believed to be an effective mechanism for selectively killing tumor cells with HRD.

[0008] Thus, there is an unmet medical need for effective and safe PARP inhibitors, particularly those with selectivity for PARP1. [Prior art documents] [Patent documents]

[0009] [Patent Document 1] International Publication No. 2004 / 080976 Brochure [Non-patent literature]

[0010] [Non-Patent Document 1] O'Connor MJ, Mol Cell (2015)60(4):547-60 [Non-Patent Document 2] Bai P.Biology of poly(ADP-ribose)polymerases:the factotums of cell maintenance.Mol Cell 2015;58:947-58 [Non-Patent Document 3] Turner N, Tutt A, Ashworth A. Hallmarks of'BRCAness' in sporadic cancers. Nat Rev Cancer 2004;4:814-9. Summary of the Invention [Means for solving the problem]

[0011] The applicant has discovered that the azaquinolones described herein surprisingly have PARP inhibitory activity and thus may be useful in treating diseases and conditions in which PARP function has pharmacological significance.Furthermore, the azaquinolones described herein have surprisingly high selectivity for PARP1 over other PARP family members such as PARP2, PARP3, PARP5a, and PARP6.Furthermore, the azaquinolones described herein advantageously have low hERG activity.

[0012] In one aspect of the present invention, the applicant provides a compound of formula (I): [ka] [In the formula, X 1 and X 2 are each independently selected from N and C(H); X 3 are independently N and C(R 4 ) (where R 4 is H or fluoro; R 1 is C 1~4 Alkyl or C 1~4 is a fluoroalkyl; R 2 are independently H, halo, and C 1~4 Alkyl and C 1~4 fluoroalkyl; R 3 is H or C 1~4 is alkyl] or a pharma- ceutically acceptable salt thereof (however, X 1 When N, X 2 is C(H) and X 3 is C(R 4 ) and X 2 When N, X 1 is C(H), X 3 is C(R 4 ) and; X 3 When N, X 1 and X 2 are all C(H) Make available.

[0013] In yet another aspect, there is provided a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I), or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable diluent, excipient, or inert carrier.

[0014] In another aspect, the compound of formula (I) or its pharmaceutically acceptable salt is provided for use in the treatment or prevention of diseases and conditions in which inhibition of PARP1 is beneficial.In an embodiment, the present disclosure provides a compound of formula I or its pharmaceutically acceptable salt for use in the treatment of cancer.In an embodiment, the cancer is breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, blood cancer, gastrointestinal cancer such as gastric cancer and colon cancer, or lung cancer.In an embodiment, the cancer is breast cancer, ovarian cancer, pancreatic cancer, or prostate cancer.

[0015] In another aspect, a method for treating a disease or condition that would benefit from inhibition of PARP1 is provided, comprising administering to a patient in need of treatment a therapeutically effective amount of a compound of formula I or a pharma- ceutically acceptable salt thereof.In one embodiment, the disease or condition is cancer.In an embodiment, the cancer is breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, blood cancer, gastrointestinal cancer such as gastric cancer and colon cancer, or lung cancer.In an embodiment, the cancer is breast cancer, ovarian cancer, pancreatic cancer, or prostate cancer.

[0016] In another aspect, the compound of formula I or its pharma- ceutically acceptable salt is provided for use in preparing a medicament for treating a disease or condition that would benefit from the inhibition of PARP1.In an embodiment, the cancer is breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, blood cancer, gastrointestinal cancer such as gastric cancer and colon cancer, or lung cancer.In an embodiment, the cancer is breast cancer, ovarian cancer, pancreatic cancer, or prostate cancer.

[0017] In another aspect, there is provided the use of the compound of formula I or its pharma- ceutically acceptable salt in the manufacture of a medicament for use in the treatment of a disease or condition that would benefit from the inhibition of PARP1.In an embodiment, the cancer is breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, blood cancer, gastrointestinal cancer such as gastric cancer and colon cancer, or lung cancer.In an embodiment, the cancer is breast cancer, ovarian cancer, pancreatic cancer, or prostate cancer.

[0018] In yet another aspect, there is provided a compound of formula I, or a pharma- ceutically acceptable salt thereof, for use in medicine.

[0019] In yet another embodiment, the compound of formula I in the free base form.

[0020] In yet another aspect, there is provided a compound of formula I, or a pharma- ceutically acceptable salt thereof, for use as a medicament.

[0021] In a further aspect, there is provided an embodiment of the present disclosure.

[0022] In one aspect, there is provided a compound of formula I which is 5-[(4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2-carboxamide, or a pharma- ceutically acceptable salt thereof.

[0023] In one embodiment, there is provided a compound of formula I which is 5-[(4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2-carboxamide.

[0024] Further aspects of the present specification will become apparent to those skilled in the art from reading the present specification.

[0025] It is well known that blocking the cardiac ion channel encoded by the human delayed rectifier potassium ion channel gene (hERG) is a risk factor in drug discovery and development. Blocking hERG may cause safety issues such as cardiac arrhythmia. Advantageously, compounds of formula I have low hERG activity. In one embodiment, compounds of formula I are provided with IC50 greater than 10 μM. In one embodiment, compounds of formula I are provided with IC50 greater than 20 μM.

[0026] To minimize 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 embodiment, a compound of formula I is provided that has 10-fold selectivity for PARP1 over PARP2. In one embodiment, a compound of formula I is provided that has 100-fold selectivity for PARP1 over PARP2.

[0027] Another further aspect provides the use of a compound of formula I in the preparation of a medicament for use as an adjuvant in cancer therapy, or for treatment with ionizing radiation or chemotherapeutic agents, or for antibody-based therapy such as immuno-oncology or antibody-drug conjugates, to enhance the effect on tumor cells.

[0028] Other further aspects provide for the treatment of a disease ameliorated by inhibition of PARP1, comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound of formula I, preferably in the form of a pharmaceutical composition, and for the treatment of cancer, comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound of formula I in combination with ionizing radiation or a chemotherapeutic agent, preferably in the form of a pharmaceutical composition, either simultaneously or sequentially.

[0029] In yet another aspect, the compounds of formula I may be used in the preparation of a medicament for the treatment of a cancer in which homologous recombination (HR)-dependent DNA DSB repair activity is deficient, or in the treatment of a patient with a cancer in which HR-dependent DNA DSB repair activity is deficient, comprising administering to the patient a therapeutically effective amount of a compound.

[0030] The HR-dependent DNA DSB repair pathway repairs DNA double-strand breaks (DSBs) by a homologous mechanism and reforms the continuous DNA helix (KK Khanna and SP Jackson, Nat. Genet. 27(3):247-254(2001)). Components of the HR-dependent DNA DSB repair pathway include ATM (NM_000051), RAD51 (NM_002875), RAD51L1 (NM_002877), RAD51C (NM_002876), RAD51L3 (NM_002878), DMC1 (NM_007068), XRCC2 (NM_005431), XRCC3 (NM_005432), and RA. These include, but are not limited to, D52 (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 regulators such as EMSY (Hughes-Davies, et al., Cell, 115, pp523-535). HR components are also described in Wood et al., Science, 291, 1284-1289 (2001).

[0031] A cancer that is deficient in HR-dependent DNA DSB repair may comprise or consist of one or more cancer cells that have a reduced or abolished ability to repair DNA DSBs through that pathway compared to normal cells, i.e. activity of the HR-dependent DNA DSB repair pathway may be reduced or abolished in one or more cancer cells.

[0032] The activity of one or more components of the HR-dependent DNA DSB repair pathway may be lost in one or more cancer cells of an individual with a cancer that is defective in HR-dependent DNA DSB repair. Components of the HR-dependent DNA DSB repair pathway have been well characterized in the art (see, for example, Wood, et al., Science, 291, 1284-1289 (2001)), and include the components listed above.

[0033] In some embodiments, cancer cells may have a BRCA1 and / or BRCA2-deficient phenotype. That is, BRCA1 and / or BRCA2 activity is reduced or eliminated in cancer cells. Cancer cells with this phenotype may be BRCA1 and / or BRCA2-deficient. That is, BRCA1 and / or BRCA2 expression and / or activity may be reduced or eliminated in cancer cells, for example, by mutation or polymorphism in coding nucleic acid, or by amplification, mutation or polymorphism in gene coding regulator, for example, EMSY gene coding BRCA2 regulator (Hughes-Davies, et al., Cell, 115, 523-535).

[0034] BRCA1 and BRCA2 are known tumor suppressors whose wild-type alleles are frequently lost in tumors of heterozygous carriers (Jasin M., Oncogene, 21(58), 8981-93 (2002); Tutt, et al., Trends Mol Med., 8(12), 571-6 (2002)). The association of mutations in BRCA1 and / or BRCA2 with breast cancer has been well characterized in the art (Radice, PJ, Exp Clin Cancer Res., 21(3 Suppl), 9-12 (2002)). Amplification of the EMSY gene, which encodes a BRCA2 binding factor, is also known to be associated with breast and ovarian cancer. Carriers of mutations in BRCA1 and / or BRCA2 are also at increased risk of certain cancers, including breast, ovarian, pancreatic, prostate, hematological, gastrointestinal and lung cancers.

[0035] In some embodiments, the individual is heterozygous for one or more variations (e.g., mutations and polymorphisms) in BRCA1 and / or BRCA2 or regulators thereof. Detection of variations in BRCA1 and BRCA2 is well known in the art and described, for example, in EP 699 754; EP 705 903; Neuhausen, SL and Ostrander, EA, Genet. Test, 1, 75-83 (1992); Chappnis, PO and Foulkes, WO, 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).

[0036] Cancer-associated mutations and polymorphisms may 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.

[0037] definition Alkyl groups and moieties may be straight or branched chain, e.g., C 1~8 Alkyl, C 1~6 Alkyl, C 1~4 Alkyl or C 5~6 Examples of alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl, n-hexyl, n-heptyl and n-octyl, e.g. methyl or n-hexyl.

[0038] A fluoroalkyl group is an alkyl group in which one or more H atoms are replaced by one or more fluoro atoms, e.g., C 1~8 Fluoroalkyl, C 1~6 Fluoroalkyl, C 1~4Fluoroalkyl or C 5~6 Fluoroalkyl. Examples include fluoromethyl (CH 2 F-), difluoromethyl (CHF 2 -), trifluoromethyl (CF 3 -), 2,2,2-trifluoroethyl (CF 3 CH 2 -), 1,1-difluoroethyl (CH 3 CHF 2 -), 2,2-difluoroethyl (CHF 2 CH 2 -) and 2-fluoroethyl (CH 2 FCH 2 -) are mentioned.

[0039] Halo means fluoro, chloro, bromo and iodo, hi one embodiment, halo is fluoro or chloro.

[0040] As used herein, unless otherwise indicated, the term "pharmacologically acceptable" refers to compounds, materials, compositions, and / or dosage forms that 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.

[0041] In this specification, unless otherwise specified, the phrase "effective amount" refers to an amount of a compound or composition that is sufficient to significantly and positively alter the symptoms and / or condition to be treated (e.g., provide a benign clinical response). The effective amount of the active ingredient to be used in the pharmaceutical composition will vary within the knowledge and expertise of the attending physician depending on the particular condition being treated, the severity of the condition, the duration of treatment, the nature of concurrent therapy, the particular active ingredient being used, the particular pharma- ceutically acceptable excipients / carriers used, and similar factors.

[0042] The term "treating" as used herein, unless otherwise indicated, means to ameliorate, alleviate, inhibit progression, delay progression, delay onset, or prevent the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition. The term "treatment" as used herein, unless otherwise indicated, refers to the act of treating as "treating" is defined immediately above. The term "treating" also includes administering adjuvant and neoadjuvant treatment to a subject. For the avoidance of doubt, references to "treatment" herein include references to curative, palliative, and prophylactic treatment, as well as the administration of medicaments for use in such treatment.

[0043] Compounds of formula (I) may form stable pharma- ceutically acceptable acid or base salts, and in such cases, it may be appropriate to administer the compounds as salts. Examples of acid addition salts include acetate, adipate, ascorbate, benzoate, benzenesulfonate, bicarbonate, bisulfate, butyrate, camphorate, camphorsulfonate, choline, citrate, cyclohexylsulfamate, diethylenediamine, ethanesulfonate, fumarate, glutamate, glycolate, hemisulfate, 2-hydroxyethylsulfonate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, hydroxamate, and the like. Examples of suitable salts include leic acid salts, lactate salts, malate salts, maleate salts, methanesulfonate salts, meglumine salts, 2-naphthalenesulfonate salts, nitrate salts, oxalate salts, pamoate salts, persulfate salts, phenylacetate salts, phosphate salts, diphosphate salts, picrate salts, pivalate salts, propionate salts, quinate salts, salicylates, stearates, succinates, sulfamates, sulfanilate salts, sulfate salts, tartrate salts, tosylates (p-toluenesulfonates), trifluoroacetates, and undecanoates. Non-toxic physiologically acceptable salts are preferred, although other salts may be useful, for example, in isolating or purifying the product.

[0044] These salts can be formed by conventional means, for example, by reacting the free base form of the product with one or more equivalents of the appropriate acid in a solvent or medium in which the salt is insoluble or in a solvent such as water, and removing the solvent in vacuo or by lyophilization, or by exchanging the anion of an existing salt for another anion with a suitable ion exchange resin.

[0045] It should be understood that the compounds of formula I may have two or more chiral centers, and the present application encompasses all individual stereoisomers, enantiomers and diastereoisomers, as well as mixtures thereof.Thus, to the extent that the compounds of formula I may exist in optically active or racemic forms due to one or more asymmetric carbon atoms, it should be understood that the present application encompasses all such optically active or racemic forms that have the activity previously defined in the present application.The present application encompasses all such stereoisomers that have the activity defined herein.

[0046] Thus, throughout this specification, when referring to a compound of formula (I), it should be understood that the term compound includes diastereoisomers, mixtures of diastereoisomers, and enantiomers that inhibit the activity of being PARP1 inhibitors.

[0047] It should also be understood that certain compounds of formula (I) and pharmaceutical salts thereof can exist in solvated and non-solvated forms, for example, hydrated and anhydrous forms.It should also be understood that the compounds described herein encompass all such solvated forms.For clarity, this includes both the solvated (e.g., hydrated) form of the free form of the compound and the solvated (hydrated) form of the salt of the compound.

[0048] Formula I as described herein is intended to include all isotopes of its constituent atoms. For example, H (or hydrogen) is 1 H, 2 H(D) and 3 H(T), including all isotopic forms of hydrogen; 12 C. 13 C and 14Includes all isotopic forms of carbon, such as C; 16 O. 17 O and 18 O includes all isotopic forms of oxygen, such as O; N includes 13 N, 14 N and 15 N includes all isotopic forms of nitrogen; F includes all isotopic forms of nitrogen, such as 19 F and 18 and the like, including all isotopic forms of fluorine, such as F. In one embodiment, the compounds of formula I contain isotopes of the atoms contained therein in amounts corresponding to their naturally occurring amounts. However, in certain instances, it may be desirable to enrich one or more atoms of a particular isotope that is normally present in a lesser amount. For example, 1 H is typically present in abundance greater than 99.98%, but in one aspect, a compound of any formula provided herein may have at least one H at one or more positions where H is present. 2 H or 3 In another embodiment, the compounds of any of the formulae presented herein may be enriched with radioactive isotopes, e.g. 3 H and 14 When enriched in C, the compounds may be useful in drug and / or substrate tissue distribution assays. It is to be understood that the present application encompasses all such isotopic forms.

[0049] The compound of formula (I) or a pharma- ceutically acceptable salt thereof will usually be administered by oral route in the form of a pharmaceutical preparation containing the active ingredient or a pharma- ceutically acceptable salt or solvate thereof, or a solvate of such a salt, in a pharma- ceutically acceptable dosage form. Depending on the disease and the patient to be treated, the compound may be administered in various doses.

[0050] Pharmaceutical formulations of the compounds of formula I above can be prepared for oral administration, particularly in the form of tablets or capsules, using techniques aimed at providing targeted drug release, particularly to the colon (Patel, MM Expert Opin. Drug Deliv. 2011, 8(10), 1247-1258).

[0051] The pharmaceutical formulations of the compounds of formula (I) described above can conveniently be administered in unit dosage form and can be prepared by any of the methods well known in the pharmaceutical art, for example, as described in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., (1985).

[0052] 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 (e.g., sodium lauryl sulfate). Liquid compositions may contain conventional additives such as suspending agents, emulsifying agents and / or preservatives. Liquid compositions may be encapsulated, for example, with gelatin to provide a unit dosage form. 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 made, for example, by filling the compound of formula (I) into a gelatin or hydroxypropylmethylcellulose (HPMC) shell.

[0053] Dry shell formulations typically contain gelatin at a concentration of about 40%-60% w / w, a plasticizer (such as glycerin, sorbitol or propylene glycol) at a concentration of about 20%-30%, and water at a concentration of about 30%-40%. Other materials such as preservatives, dyes, opacifiers and flavorings may also be included. Liquid fill materials include dissolved, solubilized or dispersed solid drugs (with suspending agents such as beeswax, hydrogenated castor oil or polyethylene glycol 4000) or liquid drugs in a vehicle or combination of vehicles such as mineral oils, vegetable oils, triglycerides, glycols, polyols and surfactants.

[0054] A suitable daily dose of a compound of formula I or a pharma- ceutically acceptable salt thereof in the therapeutic treatment of humans is about 0.0001 to 100 mg / kg of body weight.

[0055] Oral formulations are preferred, particularly tablets or capsules which may be formulated by methods known to those skilled in the art to provide dosages of active compound in the range of 0.1 mg to 1000 mg. [Brief description of the drawings]

[0056] [Figure 1] 1 shows the powder X-ray diffraction of Example 4 Form A. [Diagram 2] 1 shows a DSC trace of Example 4 Form A. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0057] The present invention includes the following aspects. [1] Formula I [ka] [In the formula, X 1 and X 2 are each independently selected from N and C(H); X 3 are independently N and C(R 4 ) (where R 4 is H or fluoro; R 1 is C 1~4 Alkyl or C 1~4 is a fluoroalkyl; R 2 are independently H, halo, and C 1~4 Alkyl and C 1~4 fluoroalkyl; R 3 is H or C 1~4 is alkyl] or a pharma- ceutically acceptable salt thereof (however, X1 When N, X 2 is C(H), X 3 is C(R 4 ) and X 2 When N, X 1 is C(H), X 3 is C(R 4 ) and; X 3 When N, X 1 and X 2 are both C(H). [2] R 3 is C 1~4 Item 3. The compound according to item 1, [3] R 3 is methyl. [4] R 1 The compound according to any one of items 1 to 3, wherein is ethyl. [5] Formula (Ia)

change

change

[10] R 1 is ethyl, and R 2 is selected from H, chloro and fluoro; R 3 Item 10. The compound according to item 9, wherein is methyl.

[11] Formula (Ic)

change

[12] R 1 are independently ethyl, n-propyl, trifluoromethyl, 1,1-difluoroethyl, selected from 2,2-difluoroethyl, 2-fluoroethyl and 2,2,2-trifluoroethyl; R 2 is independently selected from H, methyl, ethyl, trifluoromethyl, difluoromethyl, fluoromethyl, fluoro, and chloro; R 3 is H or methyl, R 4 is H, Item 12. The compound according to item 11.

[13] 5-[4-[(3-ethyl-2-oxo-1H-1,6-naphthyridine-7-yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2-carboxamide, 5-[4-[(3-ethyl-2-oxo-1H-1,6-naphthyridin-7-yl)methyl]piperazin-1-yl]-6-fluoro-N-methyl-pyridine-2-carboxamide, 6-chloro-5-[4-[(3-ethyl-2-oxo-1H-1,6-naphthyridine-7-yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2-carboxamide, 5-[4-[(7-ethyl-6-oxo-5H-1,5-naphthyridine-3-yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2-carboxamide, 5-[4-[(7-ethyl-6-oxo-5H-1,5-naphthyridine-3-yl)methyl]piperazin-1-yl]-6-fluoro-N-methyl-pyridine-2-carboxamide, 6-chloro-5-[4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2-carboxamide, 5-[4-[(7-ethyl-6-oxo-5H-1,5-naphthyridine-3-yl)methyl]piperazin-1-yl]pyridine-2-carboxamide, 6-ethyl-5-[4-[(2-ethyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2-carboxamide, 5-[4-[(2-ethyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methyl-6-(trifluoromethyl)pyridine-2-carboxamide, 6-(difluoromethyl)-5-[4-[(2-ethyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2-carboxamide, 5-[4-[(2-ethyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2-carboxamide, 5-[4-[(2-ethyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-6-fluoro-N-methyl-pyridine-2-carboxamide, 5-[4-[(2-ethyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N,6-dimethyl-pyridine-2-carboxamide, 6-chloro-5-[4-[(2-ethyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2-carboxamide, N-methyl-5-[4-[[3-oxo-2-(trifluoromethyl)-4H-quinoxalin-6-yl]methyl]piperazin-1-yl]pyridine-2-carboxamide, 6-chloro-N-methyl-5-[4-[[3-oxo-2-(trifluoromethyl)-4H-quinoxalin-6-yl]methyl]piperazin-1-yl]pyridine-2-carboxamide, 6-fluoro-N-methyl-5-[4-[[3-oxo-2-(trifluoromethyl)-4H-quinoxalin-6-yl]methyl]piperazin-1-yl]pyridine-2-carboxamide, N-methyl-5-[4-[(3-oxo-2-propyl-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]pyridine-2-carboxamide, 6-chloro-N-methyl-5-[4-[(3-oxo-2-propyl-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-pyridine-2-carboxamide, 6-fluoro-N-methyl-5-[4-[(3-oxo-2-propyl-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-pyridine-2-carboxamide, 5-[4-[(2-ethyl-7-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-6-fluoro-N-methyl-pyridine-2-carboxamide, 5-[4-[[2-(1,1-difluoroethyl)-3-oxo-4H-quinoxalin-6-yl]methyl]piperazin-1-yl]-N-methyl-pyridine-2-carboxamide, 5-[4-[[2-(2,2-difluoroethyl)-3-oxo-4H-quinoxalin-6-yl]methyl]piperazin-1-yl]-N-methyl-pyridine-2-carboxamide, 5-[4-[[2-(2,2-difluoroethyl)-3-oxo-4H-quinoxalin-6-yl]methyl]piperazin-1-yl]-6-fluoro-N-methyl-pyridine-2-carboxamide, 5-[4-[[2-(2-fluoroethyl)-3-oxo-4H-quinoxalin-6-yl]methyl]piperazin-1-yl]-N-methyl-pyridine-2-carboxamide, 6-fluoro-5-[4-[[2-(2-fluoroethyl)-3-oxo-4H-quinoxalin-6-yl]methyl]piperazin-1-yl]-N-methyl-pyridine-2-carboxamide, N-methyl-5-[4-[[3-oxo-2-(2,2,2-trifluoroethyl)-4H-quinoxalin-6-yl]methyl]piperazin-1-yl]pyridine-2-carboxamide, and 6-Fluoro-N-methyl-5-(4-((3-oxo-2-(2,2,2-trifluoroethyl)-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)picolinamide The compound according to item 1, selected from or a pharma- ceutically acceptable salt thereof.

[14] The compound according to item 1, which is 5-[4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2-carboxamide. or a pharma- ceutically acceptable salt thereof.

[15] 6-(difluoromethyl)-5-[4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2-carboxamide, 5-[4-[(7-ethyl-6-oxo-5H-1,5-naphthyridine-3-yl)methyl]piperazin-1-yl]-N-methyl-6(trifluoromethyl)pyridine-2-carboxamide, 5-[4-[(7-ethyl-6-oxo-5H-1,5-naphthyridine-3-yl)methyl]piperazin-1-yl]-N,6-dimethyl-pyridine-2-carboxamide, N-Ethyl-5-[4-[(7-ethyl-6-oxo-5H-1,5-naphthyridine-3-yl)methyl]piperazin-1-yl]pyridine-2-carboxamide The compound according to item 1, selected from or a pharma- ceutically acceptable salt thereof.

[16] A pharmaceutical composition comprising the compound according to any one of items 1 to 15 or a pharma- ceutically acceptable salt thereof, and at least one pharma- ceutically acceptable diluent, excipient or inert carrier.

[17] The compound or a pharma- ceutically acceptable salt thereof according to any one of items 1 to 15 for use as a medicament.

[18] The compound or a pharma- ceutically acceptable salt thereof according to any one of items 1 to 15 for use in the treatment of cancer.

[19] The compound according to item 18, wherein the cancer is defective in the HR-dependent DNA DSB repair pathway.

[20] The compound according to item 18, wherein the cancer comprises one or more cancer cells that have a reduced or lost ability to repair DNA DSBs by HR compared to normal cells.

[21] The compound according to item 18 or 19, wherein the cancer cells have a BRCA1 or BRCA2 deficient phenotype.

[22] The compound according to item 21, wherein the cancer cells are deficient in BRCA1 or BRCA2.

[23] The compound according to any one of items 19 to 22, wherein the individual is heterozygous for a mutation in a gene encoding a component of the HR-dependent DNA DSB repair pathway.

[24] The compound of paragraph 23, wherein the individual is heterozygous for a mutation in BRCA1 and / or BRCA2.

[25] The compound according to any one of items 18 to 24, wherein the cancer is selected from any one of breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, blood cancer, gastrointestinal cancer, and lung cancer.

[26] A method for treatment, comprising administering a therapeutically effective amount of the compound or a pharma- ceutically acceptable salt thereof according to any one of items 1 to 15 to a patient in need of treatment.

[27] The method of treatment described in paragraph 26, wherein the patient in need of the treatment has cancer.

[28] The method of claim 27, wherein the cancer is defective in the HR-dependent DNA DSB repair pathway.

[29] The method of paragraph 27, wherein the cancer comprises one or more cancer cells that have a reduced or lost ability to repair DNA DSBs by HR compared to normal cells.

[30] The method of paragraph 28 or 29, wherein the cancer cells have a BRCA1 or BRCA2 defective phenotype.

[31] The method of claim 30, wherein the cancer cells are deficient in BRCA1 or BRCA2.

[32] The method according to any one of items 28 to 31, wherein the individual is heterozygous for a mutation in a gene encoding a component of the HR-dependent DNA DSB repair pathway.

[33] The method of paragraph 32, wherein the individual is heterozygous for a mutation in BRCA1 and / or BRCA2.

[34] The method according to any one of items 27 to 33, wherein the cancer is selected from any one of breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, blood cancer, gastrointestinal cancer, and lung cancer.

[35] The compound according to any one of items 1 to 15 or a pharma- ceutically acceptable salt thereof for use in the treatment or prevention of a disease or pathology in which inhibition of PARP1 is beneficial.

[36] The compound according to item 35, wherein the disease or condition is cancer.

[37] The compound according to item 36, wherein the cancer is selected from any one of breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, blood cancer, gastrointestinal cancer, and lung cancer. Working Example The compounds of the present application are further described with reference to the following non-limiting examples.

[0058] General experimental conditions 1 1 H NMR spectra were recorded at 27° C. on a Bruker 300 MHz, 400 MHz or 500 MHz spectrometer unless otherwise stated, chemical shifts are expressed in parts per million (ppm, δ units) and are independent of residual solvent shifts. 1 H isotopologues are used as the standard (CHCl 3 :7.24ppm;CHDCl 2 :5.32ppm;CD 3 S(=O)CD 2 H: 2.49 ppm). Coupling constants are given in units of Hertz (Hz). Splitting patterns represent apparent multiplicities and are designated as s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet) and br s (broad singlet). LC-MS was performed using a Waters UPLC equipped with a Waters SQD mass spectrometer or a Shimadzu LC-20AD LC-20XR LC-30AD equipped with a Shimadzu 2020 mass spectrometer. Molecular ions reported correspond to [M+H]+ unless otherwise stated; for molecules with multiple isotopic patterns (Br, Cl, etc.), the value reported is that obtained for the lowest isotopic mass unless otherwise stated.

[0059] Flash chromatography was performed using Biotage TM From SP1 TM Purification systems, CombiFlash® Rf from ISCO or Gilson systems from Thermo Fisher, using normal-phase silica FLASH+ TM (40M, 25M or 12M) or SNAP TMDirect phase flash chromatography was performed using KP-Sil cartridges (340, 100, 50 or 10), flash column silica-CS columns from Agela, C18 flash columns, or standard flash chromatography. In general, all solvents used were of analytical grade available commercially. Anhydrous solvents were routinely used for reactions. Phase separators used in the examples are ISOLUTE® Phase Separator columns. Intermediates and examples referred to below are named with ACD / Name 12.01 from Advanced Chemistry Development, Inc. (ACD / Labs). Starting materials were obtained from commercial sources or prepared by literature routes.

[0060] X-ray powder diffraction (XRPD) analysis XRPD analysis was performed using a Bruker D8 diffractometer commercially available from Bruker AXS Inc™ (Madison, Wisconsin). XRPD spectra were obtained by mounting a sample (approximately 10 mg) of the material for analysis on a silicon single crystal wafer mount (e.g., a Bruker silicon zero background X-ray diffraction sample holder) and spreading the sample into a thin layer using a microscope slide. The sample was spun at 30 revolutions per minute (to improve counting statistics) and irradiated with X-rays produced by a copper long fine focus tube operated at 40 kV and 40 mA with a wavelength of 1.5406 angstroms (i.e., approximately 1.54 angstroms). The sample was exposed in theta-theta mode over a range of 5 degrees to 40 degrees 2-theta for 1 second per 0.02 degree 2-theta increment (continuous scan mode). Run time was approximately 15 min on the D8.

[0061] XRPD 2θ values ​​may vary within reasonable limits, e.g., within ±0.2°, and XRPD intensities may vary for a variety of reasons, including, e.g., preferred orientation, when measured on essentially the same crystalline form. The principles of XRPD are described in publications such as, e.g., Giacovazzo, C. et al. (1995), Fundamentals of Crystallography, Oxford University Press; Jenkins, R. and Snyder, RL (1996), Introduction to X-Ray Powder Diffractometry, John Wiley & Sons, New York; and Klug, HP & Alexander, LE (1974), X-ray Diffraction Procedures, John Wiley and Sons, New York.

[0062] DSC analysis DSC analysis was performed using a Q SERIES™ Q1000 DSC calorimeter available from TA INSTRUMENTS® (New Castle, Delaware) on samples prepared according to standard methods. Samples (approximately 2 mg) were weighed into aluminum sample pans and transferred to the DSC. The instrument was purged with nitrogen at 50 mL / min and data was collected between 22° C. and 300° C. using a dynamic heating rate of 10° C. / min. Thermal data was analyzed using standard software, such as Universal v.4.5A from TA INSTRUMENTS®.

[0063] The following abbreviations are used: AcOH = acetic acid; aq = aqueous; BAST = bis(2-methoxyethyl)aminosulfur trifluoride; Boc 2 O = di-tert-butyl dicarbonate; Boc = t-butyloxycarbonyl; CDCl 3 = deuterated chloroform; CD 3 OD = deuterated methanol; CH 3 NO 2= Nitromethane;DCE = 1,2-Dichloroethane;DCM = Dichloromethane;DEA = Diethylamine;DEAD = Diethyl azodicarboxylate;Dess-Martin periodinane = 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one;DIPEA = N,N-Diisopropylethylamine;DMAP = 2,6-Dimethylaminopyridine;DMF = N,N-Dimethylformamide;DMSO = Dimethylsulfoxide;DMSO-d 6 = deuterated dimethylsulfoxide; DPPA = diphenylphosphoroazidate; dppf = 1,1'-bis(diphenylphosphino)ferrocene; DIAD = diisopropyl (E)-diazene-1,2-dicarboxylate; DSC = differential scanning calorimetry; DTAD = di-tert-butyl (E)-diazene-1,2-dicarboxylate; ee = enantiomeric excess; eq. = equivalents; ESI = electrospray ionization; Et 2 O = diethyl ether EtOAc or EA = ethyl acetate; EtOH = ethanol; FA = formic acid; Grubbs' catalyst (1,3-dimesitylimidazolin-2-ylidene)(tricyclohexylphosphine)ruthenium dichloride; h = hours; HATU = (dimethylamino)-N,N-dimethyl(3-oxido-1H-[1,2,3]triazolo[4,5-b]pyridinyl)methaniminium hexafluorophosphate; HCl = hydrochloric acid; H 2 O 2 = hydrogen peroxide; HP = high pressure; IPA = isopropyl alcohol; LC = liquid chromatography; LiClO 4 = lithium perchlorate; mmol = millimolar; mCPBA = metachloroperbenzoic acid; MeOH = methanol; min = minutes; MeCN or CH3CN = acetonitrile; MeNO 2 = nitromethane; MS = mass spectrometry; NMP = N-methyl-2-pyrrolidone; NMR = nuclear magnetic resonance; Pd / C = palladium / carbon; Pd 2 dba 3 = Tris(dibenzylideneacetone)dipalladium(0); PdCl 2(dppf) = 1,1'-bis(di-tert-butylphosphino)ferrocene palladium dichloride; PE = petroleum ether; PPh 3 = 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; sat=saturated; SFC=supercritical fluid chromatography; T3P=2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide; TBTU=2-(1H-benzo[d][1,2,3]triazol-1-yl-1,1,3,3-tetramethylisouronium tetrafluoroborate; TFA=trifluoroacetic acid; THF=tetrahydrofuran; TLC=thin layer chromatography; TMS=trimethylsilyl; Xantphos=4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; CBr4=carbon tetrabromide; HCl=hydrochloric acid; HBr=hydrobromic acid; Cs2CO3 = cesium carbonate; MgSO4 = magnesium sulfate; NaHCO3 = sodium bicarbonate; DDQ = 2,3-dichloro-5,6-dicyano-1,4-benzoquinone; SOCl2 = thionyl chloride; DIBAL-H = diisobutylaluminum hydride; NH4HCO3 = ammonium bicarbonate; BINAP = 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl.

[0064] Synthesis of Starting Materials and Intermediates [ka]

[0065] Intermediate 2: 7-Bromo-3-ethyl-1H-1,6-naphthyridin-2-one Butyryl chloride (0.143 mL, 1.37 mmol) was dissolved in CH 3 Cl 2 at 0 °C with 4-amino-6-bromo-pyridine-3-carbaldehyde (Intermediate 1 250 mg, 1.24 mmol), DIPEA (1.086 mL, 6.22 mmol) and DMAP (30.4 mg, 0.25 mmol).2 Cl 2 (5 mL) was added to the stirred solution. The resulting solution was stirred at rt for 4 h. 2 eq more of butyryl chloride was added and the reaction was continued for another 24 h. The reaction was diluted with water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated to give the crude product. 1.5 mL of MeOH was added and the solid (product) was filtered and washed with 1 mL of MeOH to give 7-bromo-3-ethyl-1H-1,6-naphthyridin-2-one (Intermediate 2, 167 mg, 53.1%) as a white solid. 1H NMR (DMSO-d6) 1.17 (3H,t), 2.45-2.50 (2H,m, overlap with solvent DMSO peak), 7.35 (1H,s), 7.82 (1H,s), 8.63 (1H,s), 12.09 (1H,br s); m / z (ES + ) [M+H] + =252

[0066] Intermediate 3: 3-Ethyl-7-vinyl-1H-1,6-naphthyridin-2-one PdCl 2 (dppf) (37.6 mg, 0.05 mmol) was dissolved in 1,4-dioxane (4 mL) / water (1.333 mL) with 7-bromo-3-ethyl-1,6-naphthyridin-2-one (Intermediate 2, 130 mg, 0.51 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborane (0.105 mL, 0.62 mmol) and K 2 CO 3 (213 mg, 1.54 mmol) was added to the stirred mixture and the resulting mixture was stirred at 90° C. for 1 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layers were combined, dried over sodium sulfate and concentrated to give the crude product. The resulting residue was purified by flash silica chromatography, eluent gradient 0 to 20% MeOH in DCM. The product fractions were concentrated to dryness under reduced pressure to give 3-ethyl-7-vinyl-1H-1,6-naphthyridin-2-one (Intermediate 3, 93 mg, 90%) as a yellow solid. 1H NMR (DMSO-d6) 1.18 (3H,t), 2.53 (2H,m, overlapped with solvent DMSO peak), 5.49 (1H,dd), 6.27 (1H,dd), 6.84 (1H,dd), 7.15 (1H,s), 7.81 (1H,s), 8.78 (1H,s), 12.00 (1H,br s); m / z (ES + ) [M+H] + =201

[0067] Intermediate 4: 3-Ethyl-2-oxo-1H-1,6-naphthyridine-7-carbaldehyde To a solution of 3-ethyl-7-vinyl-1H-1,6-naphthyridin-2-one (Intermediate 3, 30 mg, 0.15 mmol), 2,6-lutidine (0.035 mL, 0.30 mmol) and sodium periodate (128 mg, 0.60 mmol) in THF (1 mL) / water (0.200 mL) was added H 2 Osmium tetroxide (0.024 mL, 3.00 μmol) in O was added and stirred at rt overnight. The reaction was diluted with water, extracted with ethyl acetate, and the filtrate was concentrated to dryness. The resulting residue was purified by flash silica chromatography, eluent gradient 0 to 15% MeOH in DCM. The product fractions were concentrated under reduced pressure to give 3-ethyl-2-oxo-1H-1,6-naphthyridine-7-carbaldehyde (Intermediate 4, 24.00 mg, 79%) as a pale yellow foam. 1H NMR (DMSO-d6) 1.20 (3H,t), 2.55-2.62 (2H,m, overlapped with solvent DMSO peak), 7.73 (1H,s), 7.95 (1H,s), 9.03 (1H,s), 10.00 (1H,s), 12.32 (1H,br s); m / z (ES + ) [M+H] + =203

[0068] Intermediate 5: 3-Ethyl-7-(hydroxymethyl)-1H-1,6-naphthyridin-2-one Sodium borohydride (61.4 mg, 1.62 mmol) was added slowly to a stirred solution of 3-ethyl-2-oxo-1H-1,6-naphthyridine-7-carbaldehyde (Intermediate 4, 82 mg, 0.41 mmol) in methanol (2 mL) at 0° C., and the resulting mixture was stirred at room temperature for 1 h. Methanol was removed under vacuum, and the resulting residue was purified by flash silica chromatography, eluent gradient 0 to 35% MeOH in DCM. The product fractions were concentrated under reduced pressure to give 3-ethyl-7-(hydroxymethyl)-1H-1,6-naphthyridine-2-one (Intermediate 5, 68.0 mg, 82%) as a pale yellow solid. 1H NMR (500MHz, DMSO-d6) 1.18 (3H,t), 2.52-2.55 (2H,m, overlapped with solvent DMSO peak), 4.59 (2H,br s), 5.52 (1H,br s), 7.33 (1H,s), 7.80 (1H,s), 8.71 (1H,s), 12.01 (1H,br s; m / z (ES + ) [M+H] + =205

[0069] Intermediate 6: 7-(bromomethyl)-3-ethyl-1H-1,6-naphthyridin-2-one CBr4 (928 mg, 2.80 mmol) was added to a stirred solution of 3-ethyl-7-(hydroxymethyl)-1H-1,6-naphthyridin-2-one (Intermediate 5, 381 mg, 1.87 mmol) and triphenylphosphine (734 mg, 2.80 mmol) in CHCl2 (18.656 ml) at 0° C., and the resulting solution was stirred at 0° C. for 2 h. The reaction was concentrated and the resulting residue was purified by flash silica chromatography, eluent gradient 0 to 15% MeOH in DCM. The product fractions were concentrated under reduced pressure to give 7-(bromomethyl)-3-ethyl-1H-1,6-naphthyridin-2-one (Intermediate 6, 386 mg, 77%) as a white solid (contains triphenylphosphine oxide, difficult to separate). This compound was taken to the next step without further purification. m / z(ES + ),[M] + =267

[0070] Example 1: 5-[4-[(3-ethyl-2-oxo-1H-1,6-naphthyridine-7-yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2-carboxamide [ka] DIPEA (0.059 mL, 0.34 mmol) was added to a stirred solution of 7-(bromomethyl)-3-ethyl-1H-1,6-naphthyridine-2-one (Intermediate 6, 30 mg, 0.11 mmol) and N-methyl-5-piperazin-1-yl-pyridine-2-carboxamide, 2HCl (Intermediate 13, 42.8 mg, 0.15 mmol) in acetonitrile (1 mL) at 20° C. The resulting solution was stirred at 70° C. for 2 h. The solvent was removed under vacuum and the resulting crude material was further purified by reverse phase chromatography (RediSep Rf Gold® C18, 0 to 90% acetonitrile in water, 0.1% NH4OH as additive). The product fractions were concentrated to dryness under reduced pressure to give 5-[(4-[(3-ethyl-2-oxo-1H-1,6-naphthyridine-7-yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2-carboxamide (Example 1, 23.60 mg, 51.7%) as a pale yellow solid. 1H NMR (500MHz, DMSO-d6) 1.18 (3H, br t), 2.54 (2H, m, overlapped with solvent DMSO peak), 2.67 (4H, br s), 2.79 (3H, br d), 3.38 (4H, br s), 3.75 (2H, br s), 7.34 (1H, s), 7.42 (1H, br dd), 7.77-7.88 (2H, m), 8.29 (1H, br d), 8.40 (1H, br d), 8.75 (1H, s), 11.60-12.11 (1H, m); m / z (ES + ) [M+H] + =407

[0071] Example 2: 5-[4-[(3-ethyl-2-oxo-1H-1,6-naphthyridine-7-yl)methyl]piperazin-1-yl]-6-fluoro-N-methyl-pyridine-2-carboxamide [ka] DIPEA (0.082 mL, 0.47 mmol) was added to a stirred solution of 7-(bromomethyl)-3-ethyl-1H-1,6-naphthyridin-2-one (Intermediate 6, 25 mg, 0.09 mmol) and 6-fluoro-N-methyl-5-piperazin-1-yl-pyridine-2-carboxamide, HCl (Intermediate 23, 28.3 mg, 0.10 mmol) in acetonitrile (2 mL) at 20° C. The resulting solution was stirred at 70° C. for 2 h. The solvent was removed under vacuum. The resulting residue was purified by flash silica chromatography, eluent gradient 0 to 20% MeOH in DCM. The product fractions were concentrated under reduced pressure to give 5-[(4-[(3-ethyl-2-oxo-1H-1,6-naphthyridin-7-yl)methyl]piperazin-1-yl]-6-fluoro-N-methyl-pyridine-2-carboxamide (Example 2, 17.00 mg, 42.8%) as a pale yellow solid. 1H NMR (500MHz, DMSO-d6) 1.18 (3H,t), 2.52-2.55 (2H,m, overlapped with solvent DMSO peak), 2.64 (4H,br s), 2.77 (3H,d), 3.20 (4H,br s), 3.70 (2H,s), 7.32 (1H,s), 7.59 (1H,dd), 7.80 (1H,s), 7.86 (1H,d), 8.31-8.49 (1H,m), 8.73 (1H,s), 11.93 (1H,br s); m / z (ES + ) [M+H] + =425

[0072] Example 3: 6-Chloro-5-[4-[(3-ethyl-2-oxo-1H-1,6-naphthyridine-7-yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2-carboxamide [ka] DIPEA (0.082 mL, 0.47 mmol) was added to a stirred solution of 7-(bromomethyl)-3-ethyl-1H-1,6-naphthyridin-2-one (Intermediate 6, 25 mg, 0.09 mmol) and 6-chloro-N-methyl-5-piperazin-1-yl-pyridine-2-carboxamide, 2HCl (Intermediate 47, 33.7 mg, 0.10 mmol) in acetonitrile (2 mL) at 20° C. The resulting solution was stirred at 70° C. for 2 h. The solvent was removed under vacuum. The resulting residue was purified by flash silica chromatography, eluent gradient 0 to 20% MeOH in DCM. The product fractions were concentrated under reduced pressure to give 6-chloro-5-[(4-[(3-ethyl-2-oxo-1H-1,6-naphthyridin-7-yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2-carboxamide (Example 3, 19.20 mg, 46.5%) as a white solid. 1H NMR (500MHz, DMSO-d6) 1.18 (3H,t), 2.53 (2H,m, overlapped with solvent DMSO peak), 2.66 (4H,br s), 2.80 (3H,d), 3.15 (4H,br s), 3.72 (2H,s), 7.33 (1H,s), 7.68 (1H,d), 7.81 (1H,s), 7.95 (1H,d), 8.43 (1H,br d), 8.74 (1H,s), 11.93 (1H,s); m / z (ES + ) [M+H] + =441. [ka]

[0073] Intermediate 8: Ethyl 6-formyl-5-nitro-pyridine-3-carboxylate A mixture of ethyl 6-methyl-5-nitro-pyridine-3-carboxylate (Intermediate 7, 10 g, 47.58 mmol) and selenium dioxide (7.92 g, 71.36 mmol) in 1,4-dioxane (50 mL) was stirred at 110° C. for 20 h. The reaction mixture was cooled to room temperature and filtered through a pad of celite, washing with ethyl acetate. The combined filtrate was concentrated to give a residue that was purified by flash silica chromatography, eluent gradient 0 to 70% ethyl acetate in hexanes. The product fractions were concentrated under reduced pressure to give ethyl 6-formyl-5-nitro-pyridine-3-carboxylate (Intermediate 8, 9.70 g, 91%) as a brown oil. 1H NMR (500MHz, chloroform-d) 1.48 (3H,t), 4.54 (2H,q), 8.81 (1H,d), 9.51 (1H,d), 10.32 (1H,s); m / z (ES + )[M] + =224.

[0074] Intermediate 9: Ethyl 6-[(E)-2-ethoxycarbonylbut-1-enyl]-5-nitro-pyridine-3-carboxylate (E / Z isomer mixture) To a stirred solution of sodium hydride (9.63 g, 240.89 mmol) (60% in mineral oil) in anhydrous THF (100 mL) was added ethyl 2-(diethoxyphosphoryl)butanoate (60.8 g, 240.89 mmol) dropwise using an addition funnel at 0° C. to give a grey mixture. The resulting mixture was stirred at 0° C. for 10 min, warmed to room temperature over 10 min, and stirred at 40° C. for 5 min. The reaction mixture was cooled to −78° C., and then a solution of ethyl 6-formyl-5-nitro-pyridine-3-carboxylate (Intermediate 8, 22.5 g, 100.37 mmol) in 100 mL of THF was slowly added to the cooled reaction mixture. The mixture was cooled to sat.NH 4 The reaction was quenched with Cl solution and extracted with ethyl acetate. The combined organic layers were washed with Na 2 SO 4Dried over sodium, filtered and concentrated to give the crude product. The resulting residue was purified by flash silica chromatography, eluent gradient 0 to 50% ethyl acetate in hexanes. The product fractions were concentrated under reduced pressure to give ethyl 6-[(E)-2-ethoxycarbonylbut-1-enyl]-5-nitro-pyridine-3-carboxylate (Intermediate 9, 24.30 g, 75%) as a yellow oil (1:1 and mixture of E / Z isomers). 1H NMR(500MHz,chloroform-d)1.13(3H,t),1.18(3H,t),1.23(3H,t),1.37(3H,t),1.45(6H,q),2.57(2H,qd),2.66(2H,q),4.1 1-4.24(2H,m),4.32(2H,q),4.45-4.56(4H,m),7.08(1H,s),7.85(1H,s),8.86(2H,dd),9.26(1H,d),9.43(1H,d);m / z(ES + )[M] + =322

[0075] Intermediate 10: Ethyl 7-ethyl-6-oxo-7,8-dihydro-5H-1,5-naphthyridine-3-carboxylate A mixture of ethyl 6-[(E)-2-ethoxycarbonylbut-1-enyl]-5-nitro-pyridine-3-carboxylate (1:1 mixture of E / Z isomers) (Intermediate 9, 3.75 g, 11.63 mmol), Pd / C (1.857 g, 1.75 mmol) (10%) in ethanol (30 mL) was degassed and charged with H2 (balloon) and the reaction was stirred under H2 atmosphere at room temperature overnight. The mixture was filtered through a bed of celite and the bed of celite was washed with ethanol. After concentration, 4M HCl in dioxane (15 ml) was added to the resulting residue and the mixture was stirred at room temperature for 30 min. The mixture was diluted with ether and the solid was filtered off, washed with diethyl ether and dried under vacuum to give ethyl 7-ethyl-6-oxo-7,8-dihydro-5H-1,5-naphthyridine-3-carboxylate (Intermediate 10, 2.260 g, 78%) as a white solid. 1H NMR (500 MHz, DMSO-d6) 0.94 (3H,t), 1.33 (3H,t), 1.41-1.51 (1H,m), 1.69-1.81 (1H,m), 2.41-2.48 (1H,m), 2.94 (1H,dd), 3.20 (1H,dd), 4.35 (2H,t), 7.67 (1H,d), 8.61 (1H,d), 10.32 (1H,s); m / z (ES + ) [M+H] + =249.

[0076] Intermediate 11: Ethyl 7-ethyl-6-oxo-5H-1,5-naphthyridine-3-carboxylate Ethyl 7-ethyl-6-oxo-7,8-dihydro-5H-1,5-naphthyridine-3-carboxylate (Intermediate 10, 2.26 g, 9.10 mmol) was dissolved in 1,4-dioxane (40 mL), DDQ (2.273 g, 10.01 mmol) was added, and the mixture was stirred under reflux for 3 h. The solvent was removed under reduced pressure, and sat. NaHCO 3 The solution was added and the residue was stirred at room temperature for 1 hour. The solid was filtered off and washed with water followed by 10 ml of diethyl ether. The solid obtained was dried under vacuum to give ethyl 7-ethyl-6-oxo-5H-1,5-naphthyridine-3-carboxylate (Intermediate 11, 1.738 g, 78%) as a light brown solid. m / z(ES + ) [M+H] + =247.

[0077] Intermediate 12: 3-Ethyl-7-(hydroxymethyl)-1H-1,5-naphthyridin-2-one Lithium aluminum hydride 2M in THF (29.2 mL, 58.47 mmol) was added dropwise to ethyl 7-ethyl-6-oxo-5H-1,5-naphthyridine-3-carboxylate (Intermediate 11, 7.2 g, 29.24 mmol) in tetrahydrofuran (150 mL) under nitrogen over 45 min at 0° C. The resulting mixture was stirred at 0° C. for 1.5 h. The reaction mixture was quenched by dropwise addition of 1M aqHCl (29 mL). The reaction mixture was concentrated and the solid was diluted with water (about 150 ml) and 29 ml of 1M HCl solution to give a yellow suspension. The solid was collected by filtration, washed with water, diethyl ether and dried to give the crude product as a yellow solid (contaminated by some inorganic salts). The solid was suspended in a mixture of methanol and DCM (2:1) (400 ml) and heated to reflux. The solid was filtered off. The solid was resuspended in a methanol / DCM mixture and the procedure was repeated five times to obtain most of the product from the mixture. The combined filtrate was then concentrated to about 100 ml, and the solid was collected by filtration, washed with ether, and dried under vacuum to obtain 3-ethyl-7-(hydroxymethyl)-1H-1,5-naphthyridin-2-one (Intermediate 12, 4.35 g, 72.8%) as a yellow solid. 1H NMR (500 MHz, DMSO-d6) 1.18 (3H,t), 2.52-2.56 (2H,m), 4.61 (2H,d), 5.44 (1H,t), 7.61 (1H,s), 7.74 (1H,s), 8.37 (1H,s), 11.87 (1H,br s); m / z (ES+) [M+H]+ = 205.3

[0078] Example 4: 5-[4-[(7-ethyl-6-oxo-5H-1,5-naphthyridine-3-yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2-carboxamide [ka] Thionyl chloride (6.41 mL, 88.14 mmol) was added dropwise to a suspension of 3-ethyl-7-(hydroxymethyl)-1,5-naphthyridin-2(1H)-one (Intermediate 12, 3 g, 14.69 mmol) and N,N-dimethylformamide (0.114 mL, 1.47 mmol) in CHCl (60 mL) at 0° C., and the resulting solution was stirred at room temperature for 6 h. The mixture was concentrated to dryness to give crude 7-(chloromethyl)-3-ethyl-1H-1,5-naphthyridin-2-one (Intermediate 17).

[0079] DIPEA (12.83 mL, 73.45 mmol) was added to a stirred solution of 7-(chloromethyl)-3-ethyl-1H-1,5-naphthyridin-2-one (Intermediate 17, crude from above), potassium iodide (0.488 g, 2.94 mmol) and N-methyl-5-piperazin-1-yl-pyridine-2-carboxamide, 2HCl (Intermediate 13, 4.31 g, 14.69 mmol) in acetonitrile (50.00 mL) at 20° C. The resulting solution was stirred at 80° C. for 2 h. The solvent was removed under vacuum. The crude material was diluted with water, basified with aq. NaHCO3 solution and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated to give the crude product. The resulting residue was purified by flash silica chromatography, eluent gradient 0 to 15% MeOH in DCM. The product fractions were concentrated under reduced pressure to give 5-[(4-[(7-ethyl-6-oxo-5H-1,5-naphthyridine-3-yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2-carboxamide (Example 4, 3.93 g, 65.8%) as an off-white partially crystallized solid. NMR(500MHz,DMSO-d6)1.19(3H,t),2.53-2.59(6H,m),2.79(3H,d),3.33-3.39(4H,m),3.66(2H,s),7.39(1H, m / z(ES + )[M] + =406. [ka]

[0080] Intermediate 14: 7-(bromomethyl)-3-ethyl-1H-1,5-naphthyridin-2-one CBr4 (219 mg, 0.66 mmol) was added to a stirred solution of 3-ethyl-7-(hydroxymethyl)-1H-1,5-naphthyridin-2-one (Intermediate 12, 90 mg, 0.44 mmol) and triphenylphosphine (173 mg, 0.66 mmol) in CHCl2 (4 mL) at 0 °C. The resulting solution was stirred at 0 °C for 2 h. The reaction was concentrated in vacuo and the resulting residue was purified by flash silica chromatography, eluent gradient 0 to 15% MeOH in DCM. The product fractions were concentrated under reduced pressure to give 7-(bromomethyl)-3-ethyl-1H-1,5-naphthyridin-2-one (Intermediate 14, 84 mg, 71.4%) (contains triphenylphosphine oxide, difficult to separate). This compound was taken to the next step without further purification. m / z(ES + )[M] + =267

[0081] Example 5: 5-[4-[(7-ethyl-6-oxo-5H-1,5-naphthyridine-3-yl)methyl]piperazin-1-yl]-6-fluoro-N-methyl-pyridine-2-carboxamide [ka] DIPEA (0.082 mL, 0.47 mmol) was added to a stirred solution of 7-(bromomethyl)-3-ethyl-1H-1,5-naphthyridin-2-one (Intermediate 14, 25 mg, 0.09 mmol) and 6-fluoro-N-methyl-5-piperazin-1-yl-pyridine-2-carboxamide, 2HCl (Intermediate 23, 32.0 mg, 0.10 mmol) in acetonitrile (2 mL) at 20° C. The resulting solution was stirred at 70° C. for 2 h. The solvent was removed under vacuum. The resulting residue was purified by flash silica chromatography, eluent gradient 0 to 20% MeOH in DCM. The product fractions were concentrated under reduced pressure to give 5-[(4-[(7-ethyl-6-oxo-5H-1,5-naphthyridine-3-yl)methyl]piperazin-1-yl]-6-fluoro-N-methyl-pyridine-2-carboxamide (Example 5, 13.00 mg, 33%) as a pale yellow solid. 1H NMR (500 MHz, DMSO-d6) 1.19 (3H,t), 2.55 (2H,m, overlapped with solvent DMSO peak), 2.58 (4H,br d), 2.77 (3H,d), 3.19 (4H,br s),3.67(2H,s),7.57(1H,dd),7.63(1H,s),7.76(1H,s),7.85(1H,d),8.32-8.49(2H,m),11.85(1H,s);m / z(ES + ) [M+H] + =425.

[0082] Example 6: 6-Chloro-5-[4-[(7-ethyl-6-oxo-5H-1,5-naphthyridine-3-yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2-carboxamide [ka] DIPEA (0.082 mL, 0.47 mmol) was added to a stirred solution of 7-(bromomethyl)-3-ethyl-1H-1,5-naphthyridin-2-one (Intermediate 14, 25 mg, 0.09 mmol) and 6-chloro-N-methyl-5-piperazin-1-yl-pyridine-2-carboxamide (Intermediate 48, 26.2 mg, 0.10 mmol) in acetonitrile (2 mL) at 20° C. The resulting solution was stirred at 70° C. for 2 h. The solvent was removed under vacuum. The resulting residue was purified by flash silica chromatography, eluent gradient 0 to 20% MeOH in DCM. The product fractions were concentrated under reduced pressure to give 6-chloro-5-[(4-[(7-ethyl-6-oxo-5H-1,5-naphthyridine-3-yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2-carboxamide (Example 6, 19.80 mg, 48.0%) as a pale yellow solid. 1H NMR (500 MHz, DMSO-d6) 1.19 (3H,t), 2.55 (2H,m, overlapped with solvent DMSO peak), 2.58-2.65 (4H,m), 2.79 (3H,d), 3.13 (4H,br s),3.68(2H,s),7.63(1H,d),7.67(1H,d),7.76(1H,s),7.94(1H,d),8.34-8.50(2H,m),11.85(1H,s);m / z(ES + ) [M+H] + =441. [ka]

[0083] Intermediate 16: Methyl 5-piperazin-1-ylpyridine-2-carboxylate HCl in dioxane (4.67 mL, 18.67 mmol) was added to a stirred solution of tert-butyl 4-(6-methoxycarbonyl-3-pyridyl)piperazine-1-carboxylate (Intermediate 15, 600 mg, 1.87 mmol) in MeOH (1 mL) and the resulting solution was stirred at rt for 18 h. The solvent was removed in vacuo to give methyl 5-piperazin-1-ylpyridine-2-carboxylate, 2HCl (Intermediate 16, 543 mg, 99%) as a pale yellow solid. 1H NMR(500MHz,DMSO-d6)3.20(4H,br s),3.71(4H,br s),3.85(3H,s),7.58(1H,br d),7.99(1H,br d),8.43(1H,br s),9.73(2H,br),11.29-11.75(1H,br);m / z(ES + ) [M+H] + =222

[0084] Intermediate 18: 5-[4-[(7-ethyl-6-oxo-5H-1,5-naphthyridine-3-yl)methyl]piperazin-1-yl]pyridine-2-carboxylate methyl DIPEA (944 μl, 5.40 mmol) was added to a stirred solution of 7-(chloromethyl)-3-ethyl-1H-1,5-naphthyridine-2-one, HCl (Intermediate 17, 200 mg, 0.77 mmol), sodium iodide (11.57 mg, 0.08 mmol) and methyl 5-piperazin-1-ylpyridine-2-carboxylate, 2HCl (Intermediate 16, 250 mg, 0.85 mmol) in acetonitrile (6774 μl) at 20° C. The resulting solution was stirred at 80° C. for 3 h. The solvent was removed under vacuum and 0.4 mL of saturated sodium bicarbonate solution and 1.5 mL of acetonitrile were added and the reaction was stirred for 10 min. The solid was filtered off and washed with 2 mL of water followed by 1 mL of acetonitrile to give methyl 5-[(4-[(7-ethyl-6-oxo-5H-1,5-naphthyridine-3-yl)methyl]piperazin-1-yl]pyridine-2-carboxylate (Intermediate 18, 158 mg, 50.2%) as an off-white solid. 1H NMR (500 MHz, DMSO-d6) 1.19 (3H, br t), 2.54-2.61 (6H, m), 3.40 (4H, br s), 3.66 (2H, s), 3.81 (3H, s), 7.35 (1H, br dd), 7.62 (1H, s), 7.75 (1H, s), 7.88 (1H, br d), 8.28-8.47 (2H, m), 12.03 (1H, br); m / z (ES + ) [M+H] + =408

[0085] Example 7: 5-[4-[(7-ethyl-6-oxo-5H-1,5-naphthyridine-3-yl)methyl]piperazin-1-yl]pyridine-2-carboxamide [ka] Ammonia in methanol (4 mL, 28.00 mmol) was added to methyl 5-[(4-[(7-ethyl-6-oxo-5H-1,5-naphthyridine-3-yl)methyl]piperazin-1-yl]pyridine-2-carboxylate (Intermediate 18, 60 mg, 0.15 mmol) and the resulting solution was heated at 50° C. for 24 h (sealed tube). The reaction was cooled to room temperature and the solid was filtered off and washed with 2 mL of methanol to give 5-[(4-[(7-ethyl-6-oxo-5H-1,5-naphthyridine-3-yl)methyl]piperazin-1-yl]pyridine-2-carboxamide (Example 7, 88 mg, 90%) as a light brown solid. 1H NMR (500MHz, DMSO-d6) 1.19 (3H,t), 2.56 (6H,m, overlapped with solvent DMSO peak), 3.35 (4H,br d), 3.66 (2H,s), 7.30 (1H,br s), 7.40 (1H,dd), 7.64 (1H,s), 7.76 (2H,s), 7.85 (1H,d), 8.28 (1H,d), 8.41 (1H,d), 11.61-11.98 (1H,m); m / z (ES + ) [M+H] + =393. [ka]

[0086] Intermediate 20: 5-Bromo-6-fluoro-pyridine-2-carboxylate methyl An oven-dried flask was charged with methyl 5-bromopyridine-2-carboxylate (Intermediate 19, 6 g, 27.77 mmol) in acetonitrile (60 mL). Silver(II) fluoride (14.18 g, 97.21 mmol) was added and the mixture was stirred at room temperature overnight. The reaction mixture was filtered through filter paper and washed with DCM. The filtrate was concentrated to give a light brown solid. The residue was diluted with DCM and sat.NH 4The white suspension was filtered. The organic layer was separated and the aqueous layer was extracted with DCM (100 mL x 2). The combined organic layers were washed with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated. The resulting residue was purified by flash silica chromatography, eluent gradient 0 to 25% EtOAc in hexanes. The product fractions were concentrated to dryness under reduced pressure to give methyl 5-bromo-6-fluoro-pyridine-2-carboxylate (Intermediate 20, 5.98 g 90% yield). 1 H NMR (500 MHz, chloroform-d) 4.01 (3H,s), 7.93 (1H,d), 8.15 (1H,t); m / z (ES + )[M] + =234.

[0087] Intermediate 21: tert-butyl 4-(2-fluoro-6-methoxycarbonyl-3-pyridyl)piperazine-1-carboxylate tert-Butyl piperazine-1-carboxylate (13.11 g, 70.41 mmol), methyl 5-bromo-6-fluoro-pyridine-2-carboxylate (Intermediate 20, 10.985 g, 46.94 mmol), RuphosPd-G3 (2.5 g, 2.99 mmol) and Cs in 1,4 dioxane (200 mL). 2 CO 3 (38 g, 116.63 mmol) was mixed with N 2 The mixture was stirred at 80° C. under reduced pressure overnight. The mixture was diluted with water and ethyl acetate, and the layers were separated. The aqueous layer was extracted with DCM (100 mL×2). The combined organic layers were washed with Na 2 SO 4The mixture was dried at 40° C., filtered and concentrated. The resulting residue was purified by flash silica chromatography, eluent gradient 0 to 100% EtOAc in hexanes. The product fractions were concentrated to dryness under reduced pressure to give tert-butyl 4-(2-fluoro-6-methoxycarbonyl-3-pyridyl)piperazine-1-carboxylate (Intermediate 21, 14.00 g, 88%) as a yellow solid; 1H NMR (500 MHz, chloroform-d) 1.51 (9H,s), 3.16-3.32 (4H,m), 3.58-3.72 (4H,m), 3.98 (3H,s), 7.29-7.34 (1H,m), 8.00 (1H,d); m / z (ES + ) [M+H] + =340.

[0088] Intermediate 22: tert-Butyl 4-[2-fluoro-6-(methylcarbamoyl)-3-pyridyl]piperazine-1-carboxylate tert-Butyl 4-(2-fluoro-6-methoxycarbonyl-3-pyridyl)piperazine-1-carboxylate (Intermediate 21, 12.49 g, 36.80 mmol) in methylamine (120 mL, 36.80 mmol, 33 wt% in ethanol) was stirred at rt 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, washing 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 22, 12.45 g, 100%) as a yellow solid. m / z(ES + ) [M+H] + =340.

[0089] Intermediate 23: 6-Fluoro-N-methyl-5-piperazin-1-yl-pyridine-2-carboxamide 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 22, 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 ether and the solid was filtered off and washed with ether. The solid was dried under vacuum to give 6-fluoro-N-methyl-5-piperazin-1-yl-pyridine-2-carboxamide, 2HCl (Intermediate 23, 11.42 g, 99%) as a pale yellow solid. 1H NMR(500MHz,DMSO-d6)δ ppm 2.8(d,J=4.6Hz,3H)3.3(br s,4H)3.4(br d,J=4.4Hz,4H)7.6-7.7(m,1H)7.9(d,J=8.1Hz,1H)8.4(br d,J=4.4Hz,1H)9.0-9.3(m,2H);m / z(ES + ) [M+H] + =239 [ka]

[0090] Intermediate 15: tert-Butyl 4-(6-methoxycarbonyl-3-pyridyl)piperazine-1-carboxylate Ruphos Pd G3 (4.07 g, 4.86 mmol) was dissolved in 1,4-dioxane (200 mL) with methyl 5-bromopyridine-2-carboxylate (Intermediate 19, 30 g, 138.87 mmol), tert-butyl piperazine-1-carboxylate (27.2 g, 145.81 mmol), Cs 2 CO 3 (90 g, 277.73 mmol) was added to the combined and degassed mixture, and the mixture was then heated under N 2 The mixture was stirred at 110° C. for 6 hours under atmospheric conditions. The mixture was then cooled to room temperature, diluted with water, and extracted with ethyl acetate (150 ml×3). The combined organic layer was washed with anhydrous Na 2 SO 4The filtrate was dried at 40° C. and filtered. To the filtrate was added 3-(diethylenetriamino)propyl-functionalized silica gel (12 g, 1.3 mmol / g loading) and the mixture was stirred at rt for 1 h. The mixture was filtered and the filtrate was concentrated to about 100 mL. The crystalline yellow solid was filtered off, washed with ether and dried under vacuum to give tert-butyl 4-(6-methoxycarbonyl-3-pyridyl)piperazine-1-carboxylate (Intermediate 15, 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.

[0091] Intermediate 24: tert-Butyl 4-[6-(methylcarbamoyl)-3-pyridyl]piperazine-1-carboxylate Methylamine (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 15, 36 g, 112.02 mmol) in MeOH (100 ml) and the reaction was stirred at room temperature for 4 hours to give a white suspension. The mixture was concentrated and the residue was dissolved in sat.NH 4 Partition between Cl solution and DCM and separate the layers. The aqueous layer was extracted with DCM and the organic layers were combined, washed with brine and added Na 2 SO 4 Drying at 40° C., filtration and concentration afforded tert-butyl 4-[6-(methylcarbamoyl)-3-pyridyl]piperazine-1-carboxylate (Intermediate 24, 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 (1H,dd), 7.81 (1H,br d), 8.07 (1H,d), 8.16 (1H,d); m / z (ES + ) [M+H] + =321.

[0092] Intermediate 13: Carboxylic acid N-methyl-5-piperazin-1-yl-pyridine-2-carboxamide HCl (4M in dioxane, 150 ml, 600.00 mmol) was added to a suspension of tert-butyl 4-[6-(methylcarbamoyl)-3-pyridyl]piperazine-1-carboxylate (Intermediate 24, 35.9 g, 112.05 mmol) in MeOH (50 ml) and the resulting orange suspension was stirred at rt for 4 h. Approximately 80 ml of solvent was removed under reduced pressure and the mixture was diluted with ether and hexane (200 ml, 1 / 1). The solid was collected by filtration, washed with hexane, dried and concentrated under vacuum to give N-methyl-5-piperazin-1-yl-pyridine-2-carboxamide, diHCl salt (Intermediate 13, 37.0 g, 100%) as a yellow solid. 1H NMR(500MHz,DMSO-d6)2.79(3H,d),3.22(4H,br s),3.53-3.67(4H,m),7.51(1H,dd),7.91(1H,d),8.33(1H,d),8.50(1H,br s),9.19-9.49(2H,m);m / z(ES + ) [M+H] + =221 [ka]

[0093] Intermediate 26: Methyl 4-(1-methoxycarbonylpropylamino)-3-nitro-benzoate Sodium bicarbonate (27.0 g, 321.39 mmol) was added portionwise to a stirred mixture of methyl 4-fluoro-3-nitrobenzoate (Intermediate 25, 16 g, 80.35 mmol) and methyl 2-aminobutanoate, HCl (14.81 g, 96.42 mmol) in THF (100 mL). The reaction mixture was stirred at room temperature overnight. The reaction was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with saturated aq. NaHCO 3 The organic layer was washed with MgSO 4The mixture was dried at 400 rpm and concentrated to dryness to give methyl 4-(1-methoxycarbonylpropylamino)-3-nitrobenzoate (Intermediate 26, 22.86 g, 96%) as a bright yellow solid. 1H NMR (500 MHz, DMSO-d6) 0.91 (3H, t), 1.75-2.12 (2H, m), 3.75 (3H, s), 3.85 (3H, s), 4.63-4.82 (1H, m), 7.15 (1H, d), 8.00 (1H, dd), 8.52-8.76 (2H, m).

[0094] Intermediate 27: 2-Ethyl-3-oxo-2,4-dihydro-1H-quinoxaline-6-carboxylate methyl Pd / C (4.15 g, 3.90 mmol) was added in portions to a stirred solution of methyl 4-(1-methoxycarbonylpropylamino)-3-nitrobenzoate (Intermediate 26, 23.1 g, 77.97 mmol) in MeOH (300 mL) and the resulting slurry was diluted with H 2 Stirred at room temperature under atmosphere for 30 h. Methanol was removed under vacuum, 150 mL of DMF was added and the mixture was stirred for 10 min. Palladium catalyst was filtered off through ceilite and washed with 50 mL of DMF (material has very low solubility in organic solvents such as MeOH / DCM / EtOAc). The filtrate was concentrated in Genevac to give methyl 2-ethyl-3-oxo-2,4-dihydro-1H-quinoxaline-6-carboxylate (Intermediate 27, 15.80 g, 87%) as a grey solid. Material was analyzed by NMR and carried to the next step without purification. 1H NMR(500MHz,DMSO-d6)0.91(3H,t),1.63-1.73(2H,m),3.75(3H,s),3.90(1H,t d),6.71(1H,d),6.84(1H,s),7.33(1H,d),7.41(1H,dd),10.39(1H,s);m / z(ES + )[M] + =235.

[0095] Intermediate 28: 2-Ethyl-3-oxo-4H-quinoxaline-6-carboxylate methyl DDQ (15.87 g, 69.92 mmol) was added to a suspension of methyl 2-ethyl-3-oxo-2,4-dihydro-1H-quinoxaline-6-carboxylate (Intermediate 27, 15.6 g, 66.59 mmol) in 1,4-dioxane (150 mL). The reaction mixture was stirred at room temperature overnight. This mixture was diluted with saturated aqNaHCO 3 The solution (approximately 500 ml) was slowly added and stirred at room temperature for 20 min. The precipitate was filtered, washed with water (100 ml) and dried to give methyl 2-ethyl-3-oxo-4H-quinoxaline-6-carboxylate (Intermediate 28, 11.40 g, 73.7%). 1H NMR (500 MHz, DMSO-d6) 1.23 (3H, t), 2.83 (2H, q), 3.89 (3H, s), 7.73-7.86 (2H, m), 7.89 (1H, d), 12.45 (1H, s); m / z (ES + ) [M+H] + =233.

[0096] Intermediate 29: 3-Ethyl-7-(hydroxymethyl)-1H-quinoxalin-2-one Lithium aluminum hydride, 2M in THF (49.1 mL, 98.17 mmol) was added dropwise to a slurry of methyl 2-ethyl-3-oxo-4H-quinoxaline-6-carboxylate (Intermediate 28, 11.4 g, 49.09 mmol) in tetrahydrofuran (350 mL) under nitrogen atmosphere at 0° C. over a period of 50 min. The resulting mixture was stirred at 0° C. for 1.5 h. The reaction mixture was slowly poured into 1M aqHCl (300 mL) at 0° C. The reaction mixture was extracted with ethyl acetate (ca. 300 ml×2) followed by DCM / methanol (5:1) (150 ml×3). The combined organic layers were concentrated to 300 ml and diluted with ether (200 ml) to give a suspension. The solid was collected by filtration, washed with ether, and dried under vacuum to give 3-ethyl-7-(hydroxymethyl)-1H-quinoxalin-2-one (Intermediate 29, 8.00 g, 80%). 1H NMR (500 MHz, DMSO-d6) 1.22 (3H, t), 2.80 (2H, q), 4.59 (2H, s), 5.19-5.61 (1H, m), 7.19 (1H, dd), 7.28 (1H, s), 7.66 (1H, d), 12.28 (1H, br s); m / z (ES + ) [M+H] + =205.

[0097] Intermediate 30: 7-(Bromomethyl)-3-ethyl-1H-quinoxalin-2-one Hydrogen bromide (60 ml, 48% by weight in water) was added to 3-ethyl-7-(hydroxymethyl)-1H-quinoxalin-2-one (Intermediate 29, 7.8 g, 38.19 mmol) (resulting in a clear brown solution), the mixture was stirred at 80° C. for 8 hours, the reaction mixture was cooled to room temperature and poured into 150 mL of ice water to give an off-white precipitate. The solid was filtered under vacuum, washed with water followed by diethyl ether and dried to give 7-(bromomethyl)-3-ethyl-1H-quinoxalin-2-one as a beige solid (Intermediate 30, 11.10 g, 84%) in 80% purity. 1H NMR(500MHz,DMSO-d6)1.20(3H,t),2.79(2H,q),4.79(2H,s),7.27-7.38(2H,m),7.69(1H,d),12.34(1H,br s);m / z(ES +)[M] + =267.0. [ka]

[0098] Intermediate 32: tert-Butyl 4-(2-bromo-6-methoxycarbonyl-3-pyridyl)piperazine-1-carboxylate A mixture of tert-butyl piperazine-1-carboxylate (Intermediate 31, 2.57 g, 13.80 mmol), methyl 6-bromo-5-fluoro-pyridine-2-carboxylate (1.9 g, 8.12 mmol) and potassium carbonate (1.459 g, 10.55 mmol) in DMF (20 mL) was stirred at 110° C. for 5 h, LCMS showed complete conversion. The mixture was cooled to rt, diluted with DCM and water and the layers were separated. The aqueous layer was extracted twice with DCM and the combined organic layers were purified by anhydrous NaCl. 2 SO 4 The mixture was dried at 40° C., filtered and concentrated. The resulting residue was purified by flash silica chromatography, eluent gradient 0 to 50% EtOAc in hexanes. The product fractions were concentrated to dryness under reduced pressure to give tert-butyl 4-(2-bromo-6-methoxycarbonyl-3-pyridyl)piperazine-1-carboxylate (Intermediate 32, 2.200 g, 67.7%) as a pale yellow solid. 1H NMR (500 MHz, chloroform-d) 1.50 (9H,s), 3.05-3.20 (4H,m), 3.58-3.72 (4H,m), 3.98 (3H,s), 7.31 (1H,d), 8.06 (1H,d); m / z (ES + ) [M+H] + =400.

[0099] Intermediate 33: tert-Butyl 4-[2-bromo-6-(methylcarbamoyl)-3-pyridyl]piperazine-1-carboxylate A sealed pressure vessel was charged with tert-butyl 4-(2-bromo-6-methoxycarbonyl-3-pyridyl)piperazine-1-carboxylate (Intermediate 32, 2.2 g, 5.50 mmol) and methylamine (22 ml, 176.72 mmol) (33 wt % in ethanol) and the mixture was heated at 60° C. for 2 h, LCMS showed complete conversion. The mixture was concentrated and the resulting residue was purified by flash silica chromatography, eluent gradient 0 to 80% EtOAc in hexanes. The product fractions were concentrated to dryness under reduced pressure to give tert-butyl 4-[2-bromo-6-(methylcarbamoyl)-3-pyridyl]piperazine-1-carboxylate (Intermediate 33, 2.200 g, 100%) as a white solid. 1H NMR (500MHz, chloroform-d) 1.50 (9H,s), 3.02 (3H,d), 3.05-3.14 (4H,m), 3.56-3.74 (4H,m), 7.36 (1H,d), 7.68 (1H,br d), 8.11 (1H,d); m / z (ES + ) [M+H] + =399.

[0100] Intermediate 34: tert-Butyl 4-[6-(methylcarbamoyl)-2-vinyl-3-pyridyl]piperazine-1-carboxylate A mixture of tert-butyl 4-[2-bromo-6-(methylcarbamoyl)-3-pyridyl]piperazine-1-carboxylate (Intermediate 33, 200 mg, 0.50 mmol), tributyl(vinyl)stannane (0.161 ml, 0.55 mmol) and XPhos Pd cycle 2 (19.71 mg, 0.03 mmol) in 1,4-dioxane (5 ml) was stirred at 100 °C under N2 for 2.5 h, LCMS showed complete conversion. This mixture was diluted with DCM and sat.NH 4 The organic layer was washed with Cl and dried (anhydrous Na 2 SO 4), filtered and concentrated. The resulting residue was purified by flash silica chromatography, eluent gradient 0 to 80% EtOAc in hexanes. The product fractions were concentrated to dryness under reduced pressure to give tert-butyl 4-[6-(methylcarbamoyl)-2-vinyl-3-pyridyl]piperazine-1-carboxylate (Intermediate 34, 174 mg, 100%) as a white solid. m / z (ES + ) [M+H] + =347

[0101] Intermediate 35: tert-Butyl 4-[2-ethyl-6-(methylcarbamoyl)-3-pyridyl]piperazine-1-carboxylate Pd / C (53.5 mg, 0.05 mmol) (10 wt % dry basis, wet loading) was added to a solution of tert-butyl 4-[6-(methylcarbamoyl)-2-vinyl-3-pyridyl]piperazine-1-carboxylate (Intermediate 34, 174 mg, 0.50 mmol) in MeOH (6 mL). The flask was degassed and cooled with H 2 (balloon). The mixture was stirred at rt overnight. LCMS showed the reaction was not complete. Additional Pd / C (53.5 mg, 0.05 mmol) was added and the resulting mixture was stirred at rt under H2 atmosphere for 5 h. The mixture was filtered through a pad of celite, washed with methanol, and the filtrate was concentrated to dryness to give tert-butyl 4-[2-ethyl-6-(methylcarbamoyl)-3-pyridyl]piperazine-1-carboxylate (Intermediate 35, 172 mg, 98%) as a colorless residue. 1H NMR (500MHz, chloroform-d) 1.37 (3H,t), 1.51 (9H,s), 2.82-2.95 (6H,m), 3.05 (3H,d), 3.57-3.73 (4H,m), 7.39 (1H,d), 7.93-8.13 (2H,m); m / z (ES + )[M] + =348

[0102] Intermediate 36: 6-Ethyl-N-methyl-5-piperazin-1-yl-pyridine-2-carboxamide A mixture of tert-butyl 4-[2-ethyl-6-(methylcarbamoyl)-3-pyridyl]piperazine-1-carboxylate (Intermediate 35, 172 mg, 0.49 mmol) in HCl (4M in dioxane, 8 ml, 32.00 mmol) was stirred at room temperature for 1 h to give a white suspension. The mixture was diluted with ether and the solid was filtered off and dried under vacuum to give 6-ethyl-N-methyl-5-piperazin-1-yl-pyridine-2-carboxamide, 2HCl (Intermediate 36, 159 mg, 100%) as a pale yellow solid. 1H NMR (500MHz, DMSO-d6) 1.31 (3H, t), 2.74-2.86 (5H, m), 3.00-3.14 (4H, m), 3.24 (4H, br s), 7.57 (1H, d), 7.82 (1H, d), 8.43 (1H, br d), 9.20 (2H, br s);m / z(ES + )[m+H]+=249.

[0103] Example 8: 6-Ethyl-5-[4-[(2-ethyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2-carboxamide [ka] DIPEA (0.203 mL, 1.17 mmol) was added to a suspension of 6-ethyl-N-methyl-5-piperazin-1-yl-pyridine-2-carboxamide, 2HCl (Intermediate 36, 75 mg, 0.23 mmol) and 7-(bromomethyl)-3-ethyl-1H-quinoxalin-2-one (Intermediate 30, 69.3 mg, 0.23 mmol) in acetonitrile (3 mL). The resulting mixture was stirred at 60° C. for 3 h, at which time LCMS showed complete conversion. The mixture was cooled to rt, concentrated, and the residue was purified on a Gilson reverse phase column (eluted with 0-95% ACN / water / 0.1% TFA, run for 15 min, collected between 5-9 min). The product-containing fractions were concentrated, and then the residue was dissolved in methanol and DCM. 300 mg of tetraalkylammonium carbonite, polymer bound (40-90 mesh, 2.5-3.5 mmol / g) and the mixture was stirred at rt for 10 min. The mixture was then filtered and washed with methanol. The filtrate was concentrated and redissolved in a water / CAN mixture and the mixture was lyophilized to give 6-ethyl-5-[4-[(2-ethyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2-carboxamide (Example 8, 60.0 mg, 59.1%) as a pale yellow solid. 1H NMR(500MHz,DMSO-d6)1.22(3H,t),1.30(3H,t),2.54-2.69(2H,m),2.72-2.86(7H,m),2.93(4H,br m / z(ES) + ) [M+H] + =435. [ka]

[0104] Intermediate 37: tert-Butyl 4-[6-(methylcarbamoyl)-2-(trifluoromethyl)-3-pyridyl]piperazine-1-carboxylate To a well-stirred mixture of silver(I) fluoride (176 mg, 1.39 mmol) in DMF (2 mL) was added trimethyl(trifluoromethyl)silane (0.247 mL, 1.67 mmol) at room temperature. The mixture was stirred for 20 min, followed by the addition of copper powder (133 mg, 2.09 mmol). After stirring for 4 h, the reaction mixture turned blue (CuCF 3 Indication of formation). tert-Butyl 4-(2-bromo-6-methoxycarbonyl-3-pyridyl)piperazine-1-carboxylate (Intermediate 33, 150 mg, 0.38 mmol) was added to the mixture and the resulting dark mixture was stirred at 90° C. for 18 h to give a brown suspension. LCMS showed complete conversion. The mixture was diluted with ethyl acetate and the solids were filtered off. The filtrate was washed with water followed by brine. Anhydrous Na 2 SO 4 The organic layer was dried over 1000 cc, filtered and concentrated. The resulting residue was purified by flash silica chromatography, eluent gradient 0 to 70% EtOAc in hexanes. The product fractions were concentrated to dryness under reduced pressure to give tert-butyl 4-[6-(methylcarbamoyl)-2-(trifluoromethyl)-3-pyridyl]piperazine-1-carboxylate (Intermediate 37, 146 mg, 100%) as a yellow residue. 1H NMR (500 MHz, chloroform-d) 1.50 (9H,s), 2.93-3.03 (4H,m), 3.05 (3H,d), 3.55-3.69 (4H,m), 7.71 (1H,d), 7.81 (1H,br d), 8.33 (1H,d); m / z (ES + ) [M+H] + =389.

[0105] Intermediate 38: N-methyl-5-piperazin-1-yl-6-(trifluoromethyl)pyridine-2-carboxamide A mixture of tert-butyl 4-[6-(methylcarbamoyl)-2-(trifluoromethyl)-3-pyridyl]piperazine-1-carboxylate (Intermediate 37, 146 mg, 0.38 mmol) in HCl (4M in dioxane, 8 ml, 32.00 mmol) was stirred at rt for 2 h. LCMS showed complete conversion. The solvent was concentrated to a volume of 2 ml and the mixture was diluted with ether / hexane (15 ml, 5 / 1). The solid was filtered off and dried under vacuum to give N-methyl-5-piperazin-1-yl-6-(trifluoromethyl)pyridine-2-carboxamide, 2HCl (Intermediate 38, 127 mg, 94%) as a pink solid. 1H NMR(500MHz,DMSO-d6)2.83(3H,d),3.21(8H,br s),8.09(1H,d),8.23(1H,d),8.46(1H,br d),9.08(2H,br d);m / z(ES + ) [M+H] + =289.

[0106] Example 9: 5-[4-[(2-ethyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methyl-6-(trifluoromethyl)pyridine-2-carboxamide [ka] DIPEA (0.121 mL, 0.69 mmol) was added to a suspension of N-methyl-5-piperazin-1-yl-6-(trifluoromethyl)pyridine-2-carboxamide, 2HCl (Intermediate 38, 50 mg, 0.14 mmol) and 7-(bromomethyl)-3-ethylquinoxalin-2(1H)-one (Intermediate 30, 46.2 mg, 0.14 mmol) in acetonitrile (3 mL) and the mixture was stirred at 60° C. for 3 h. The mixture was cooled to rt, concentrated and the residue was purified on a Gilson reverse phase column (eluted with 0-95% ACN / water / 0.1% TFA). The product-containing fractions were concentrated at room temperature. The residue was then dissolved in methanol and DCM, followed by the addition of 250 mg of tetraalkylammonium carbonate, polymer bound (40-90 mesh, 2.5-3.5 mmol / g) and the mixture was stirred at room temperature for 10 min. The solid was then filtered off, washed with methanol and the filtrate was concentrated to give a solid. This solid was then redissolved in a mixture of water / CH3CN and lyophilized to give 5-[(4-[(2-ethyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methyl-6-(trifluoromethyl)pyridine-2-carboxamide (Example 9, 40.0 mg, 60.9%) as a white solid. 1H NMR (500 MHz, chloroform-d) 1.40 (3H,t), 2.70 (4H,br s), 2.98-3.08 (5H,m), 3.12 (4H,br s), 3.72 (2H,br s),7.29-7.32(1H,m),7.37(1H,dd),7.74(1H,d),7.79-7.88(2H,m),8.33(1H,d),11.06(1H,br s);m / z(ES + ) [M+H] + =475. [ka]

[0107] Intermediate 39: tert-Butyl 4-[2-formyl-6-(methylcarbamoyl)-3-pyridyl]piperazine-1-carboxylate H 2Osmium tetroxide (0.050 mL, 6.35 μmol) in O was added to a solution of tert-butyl 4-[6-(methylcarbamoyl)-2-vinyl-3-pyridyl]piperazine-1-carboxylate (Intermediate 34, 110 mg, 0.32 mmol), 2,6-lutidine (0.074 mL, 0.64 mmol) and sodium periodate (272 mg, 1.27 mmol) in THF (5 mL) / water (1 mL) / tert-butanol (0.304 mL, 3.18 mmol) and the mixture was stirred at rt overnight to give a yellow suspension. LCMS and TLC showed complete conversion. The reaction was diluted with water and extracted with ethyl acetate. After concentration, the resulting residue was purified by flash silica chromatography, eluent gradient 0 to 100% EtOAc in hexanes. The product fractions were concentrated to dryness under reduced pressure to give tert-butyl 4-[2-formyl-6-(methylcarbamoyl)-3-pyridyl]piperazine-1-carboxylate (Intermediate 39, 100 mg, 90%) as a yellow solid. 1H NMR (500 MHz, chloroform-d) 1.50 (9H,s), 3.07 (3H,d), 3.14-3.29 (4H,m), 3.66-3.79 (4H,m), 7.49 (1H,d), 7.86 (1H,br d), 8.28 (1H,d), 10.10 (1H,s). m / z (ES + ) [M+H] + =349.

[0108] Intermediate 40: tert-Butyl 4-[2-(difluoromethyl)-6-(methylcarbamoyl)-3-pyridyl]piperazine-1-carboxylate CH 2 Cl 2 tert-Butyl 4-[2-formyl-6-(methylcarbamoyl)-3-pyridyl]piperazine-1-carboxylate (Intermediate 39, 99 mg, 0.28 mmol) in (2 mL) was cooled to 0° C., DAST (0.710 mL, 0.71 mmol) (1 M in DCM) was added, and the resulting mixture was stirred at room temperature for 3 h. TLC and LCMS showed complete conversion. The reaction was treated with sat.NaHCO 3 The reaction was quenched dropwise with ethyl acetate and extracted with DCM. The combined organics were washed with anhydrous Na 2SO 4 The mixture was dried at 40° C., filtered and concentrated to give the crude product. The resulting residue was purified by flash silica chromatography, eluent gradient 0 to 100% EtOAc in hexanes. The product fractions were concentrated to dryness under reduced pressure to give tert-butyl 4-[2-(difluoromethyl)-6-(methylcarbamoyl)-3-pyridyl]piperazine-1-carboxylate (Intermediate 40, 94 mg, 89%) as an off-white solid. 1H NMR (500 MHz, chloroform-d) 1.51 (9H,s), 2.89-3.03 (4H,m), 3.06 (3H,d), 3.54-3.73 (4H,m), 6.82-7.16 (1H,m), 7.64 (1H,d), 7.94 (1H,br d), 8.29 (1H,d); m / z (ES + ) [M+H] + =371.

[0109] Intermediate 41: 6-(difluoromethyl)-N-methyl-5-piperazin-1-yl-pyridine-2-carboxamide A mixture of tert-butyl 4-[2-(difluoromethyl)-6-(methylcarbamoyl)-3-pyridyl]piperazine-1-carboxylate (Intermediate 40, 92 mg, 0.25 mmol) in 4 M HCl in 1,4-dioxane (6 ml, 24.00 mmol) was stirred at rt for 1.5 h to give an orange suspension, which was diluted with ether, filtered, and the solid redissolved in methanol and concentrated to dryness to give 6-(difluoromethyl)-N-methyl-5-piperazin-1-yl-pyridine-2-carboxamide, 2HCl (Intermediate 41, 56.0 mg, 65.7%) as an orange solid. 1H NMR(500MHz,DMSO-d6)2.83(3H,d),3.03-3.23(5H,m),3.30(4H,br s),7.06-7.49(1H,m),7.92(1H,d),8.13(1H,d),8.43(1H,br d),9.00(2H,br d);m / z(ES + ) [M+H] + =271.

[0110] Example 10: 6-(Difluoromethyl)-5-[4-[(2-ethyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2-carboxamide [ka] DIPEA (0.127 mL, 0.73 mmol) was added to a suspension of 6-(difluoromethyl)-N-methyl-5-piperazin-1-yl-pyridine-2-carboxamide, 2HCl (Intermediate 41, 50 mg, 0.15 mmol) and 7-(bromomethyl)-3-ethylquinoxalin-2(1H)-one (Intermediate 30, 48.6 mg, 0.15 mmol) in acetonitrile (3 mL). The resulting mixture was stirred at 60° C. for 3 h, at which time LCMS showed complete conversion. The mixture was concentrated and the residue was purified on a Gilson reverse phase column (eluted with 0-95% ACN / water / 0.1% TFA). The product-containing fractions were concentrated at room temperature. The residue was then dissolved in methanol and DCM, followed by the addition of 250 mg of tetraalkylammonium carbonite polymer bound (40-90 mesh, 2.5-3.5 mmol / g) and the mixture was stirred at room temperature for 10 min. The solid was then filtered off, washed with methanol and the filtrate was concentrated to give a solid. This solid was then redissolved in a mixture of water / CH3CN and lyophilized to give 6-(difluoromethyl)-5-[4-[(2-ethyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2-carboxamide (Example 10, 50.0 mg, 75%) as a yellow solid. 1H NMR(500MHz,chloroform-d)1.40(3H,t),2.72(4H,br s),2.97-3.17(9H,m),3.73(2H,s),6.84-7.15(1H,m),7.32(1H,s),7.37(1H,d),7.64(1H,d),7.83(1H,d),7.95(1H,br d),8.29(1H,d),11.32-11.62(1H,m);m / z(ES + ) [M+H] + =457. [ka]

[0111] Example 11: 5-[4-[(2-ethyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2-carboxamide [ka] To a 20 mL vial was added 7-(bromomethyl)-3-ethylquinoxalin-2(1H)-one (Intermediate 30, 0.147 g, 0.55 mmol) and N-methyl-5-piperazin-1-yl-pyridine-2-carboxamide, 2HCl (Intermediate 13, 0.161 g, 0.55 mmol). The vial was sealed, evacuated, and flushed with N 2 The vial was refilled with acetonitrile (3 mL) and DIPEA (0.481 mL, 2.75 mmol) were added and placed in a heating block preheated to 70 °C. The reaction mixture was stirred at the same temperature for 2 h and cooled to room temperature. The volume of the reaction was reduced to ⅓ of its initial volume under vacuum and NaHCO 3 Aqueous solution (2 mL) was added. The reaction mixture was stirred for 30 min, filtered, and the solid was washed with water (50 mL). The crude product was purified by flash silica chromatography using 0 to 30% MeOH in DCM to give 5-[(4-[(2-ethyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2-carboxamide (Example 11, 93.0 mg, 41.6%) as a pale yellow solid. 1 H NMR (500MHz, DMSO-d 6 ) 1.22 (3H,t), 2.52-2.60 (4H,m), 2.73-2.85 (5H,m), 3.30 (4H,m, overlapping with water peak), 3.62 (2H,s), 7.22-7.31 (2H,m), 7.39 (1H,dd), 7.69 (1H,d), 7.83 (1H,d), 8.23-8.31 (1H,m), 8.39 (1H,br d), 12.13-12.36 (1H,m); m / z (ES + ) [M+H] + =407. [ka]

[0112] Example 12: 5-[4-[(2-ethyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-6-fluoro-N-methyl-pyridine-2-carboxamide [ka] 7-(Bromomethyl)-3-ethylquinoxalin-2(1H)-one (Intermediate 30, 150 mg, 0.56 mmol) was added to 6-fluoro-N-methyl-5-piperazin-1-yl-pyridine-2-carboxamide (Intermediate 23, 60 mg, 0.25 mmol) and DIPEA (0.270 mL, 1.55 mmol) in NMP (2 mL). The resulting mixture was stirred at 80° C. for 2 h. The solvent was removed under reduced pressure. The crude product was purified by preparative HPLC (Column: XBridge Shield RP18 OBD column, 5 μm, 19×150 mm; Mobile phase A: water (10 mmol / L NH 4 HCO 3 , 0.1%NH 3 H 2 0), mobile phase B: ACN; flow rate: 20 mL / min; gradient: 28% B to 38% B in 8 min; 254; 220 nm; RT: 8.02 min). Fractions containing the desired compound were evaporated to dryness to give 5-[(4-[(2-ethyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-6-fluoro-N-methyl-pyridine-2-carboxamide (Example 12, 9 mg, 42.9%) as a white solid. 1 H NMR (400MHz, CD 3 OD)δ 1.33(3H,t),2.65-2.72(4H,m),2.87-2.95(5H,m),3.26-3.30(4H,m),3 .71(2H,s),7.33-7.41(2H,m),7.52(1H,dd),7.76(1H,d),7.90(1H,dd); 19 F NMR (376MHz, CD 3 OD) δ -73.40; m / z(ES + ) [M+H]+ =425. [ka]

[0113] Intermediate 43: 5-Bromo-N,6-dimethylpicolinamide A 2M solution of methylamine in THF (20 mL, 40.00 mmol) was added to methyl 5-bromo-6-methylpicolinate (Intermediate 42, 2.0 g, 8.69 mmol) and 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, eluent gradient 5 to 80% MeOH in water (0.1% NH 4 HCO 3 )) The pure fractions were evaporated to dryness to afford 5-bromo-N,6-dimethylpicolinamide (intermediate 43, 1.5 g, 75%) as a pale yellow solid. 1 H NMR (400MHz, DMSO-d 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

[0114] Intermediate 44: tert-Butyl 4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazine-1-carboxylate 5-Bromo-N,6-dimethylpicolinamide (Intermediate 43, 1.0 g, 4.37 mmol) was dissolved in toluene (20 mL) and tert-butyl piperazine-1-carboxylate (0.894 g, 4.80 mmol), BINAP (0.272 g, 0.44 mmol), Pd(OAc) 2 (0.098g, 0.44mmol) and Cs 2 CO 3 (3.56 g, 10.91 mmol) was added under nitrogen. The resulting mixture was stirred at 80° C. for 16 h. The solvent was removed under reduced pressure. The crude product was purified by reverse phase chromatography, eluent gradient 5 to 30% MeOH (water (0.4% HCO 2Purified by HPLC under H) Pure fractions were evaporated to dryness to afford tert-butyl 4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazine-1-carboxylate (Intermediate 44, 1.2 g, 82%) as a brown solid. 1 H NMR (300MHz, CD 3 OD)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.

[0115] Intermediate 45: N,6-Dimethyl-5-(piperazin-1-yl)picolinamide tert-Butyl 4-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)piperazine-1-carboxylate (Intermediate 44, 1.18 g, 3.53 mmol) was added to a 4 M solution of HCl in 1,4-dioxane (10 mL, 329.15 mmol). The resulting mixture was stirred at room temperature for 1 h. The precipitate was collected by filtration and dissolved in petroleum ether (5 mL x 2), Et 2 O (5 mL×2) and dried under vacuum to give N,6-dimethyl-5-(piperazin-1-yl)picolinamide (Intermediate 45, 0.77 g, 81%) as a yellow solid. 1 H NMR (300MHz, CD 3 OD)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.

[0116] Example 13: 5-[4-[(2-ethyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N,6-dimethyl-pyridine-2-carboxamide [ka] 7-(Bromomethyl)-3-ethylquinoxalin-2(1H)-one (Intermediate 30, 100 mg, 0.37 mmol) was added to N,6-dimethyl-5-(piperazin-1-yl)picolinamide (Intermediate 45, 90 mg, 0.33 mmol) and DIPEA (0.36 mL, 2.05 mmol) in NMP (2 mL). The resulting mixture was stirred at 80° C. for 2 h. The solvent was removed under reduced pressure. The crude product was purified by preparative HPLC (Column: XBridge Prep OBD C18 column, 30×150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH 4 HCO 3 ), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 30% B to 40% B in 7 min; 254; 220 nm; RT: 6.43 min). Fractions containing the desired compound were evaporated to dryness to give 5-[(4-[(2-ethyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N,6-dimethyl-pyridine-2-carboxamide (Example 13, 68.7 mg, 43.6%) as an off-white solid. 1 H NMR (400MHz, CD 3 OD)δ 1.33(3H,t),2.55(3H,s),2.71(4H,s),2.87-2.99(5H,m),3.05(4H,t),3.73(2H,s ),7.35(1H,s),7.38(1H,d),7.49(1H,d),7.77(1H,d),7.87(1H,d);m / z(ES+)[M+H] + =421. [ka]

[0117] Intermediate 47: 6-chloro-5-(piperazin-1-yl)picolinate methyl ester Piperazine (1.0 g, 11.61 mmol) was added to methyl 6-chloro-5-fluoropicolinate (Intermediate 46, 1.0 g, 5.28 mmol) in MeCN (30 mL). 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, eluent gradient 5 to 60% MeCN (water (0.1% NH4 HCO 3 ) in hexanes). Pure fractions were evaporated to dryness to afford methyl 6-chloro-5-(piperazin-1-yl)picolinate (intermediate 47, 1.28 g, 95%) as a red oil. 1 H NMR (400MHz, DMSO-d 6 ) 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 protons not shown); m / z (ES + ) [M+H] + =256.

[0118] Intermediate 48: 6-Chloro-N-methyl-5-(piperazin-1-yl)picolinamide A 2M solution of methylamine in THF (40 mL, 80.00 mmol) was added to methyl 6-chloro-5-(piperazin-1-yl)picolinate (Intermediate 47, 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, eluent gradient 5 to 60% MeCN in water (0.1% NH 4 HCO 3 ) in hexanes). Pure fractions were evaporated to dryness to give 6-chloro-N-methyl-5-(piperazin-1-yl)picolinamide (Intermediate 48; 1.12 g, 89%) as a pale yellow oil. 1 H NMR (300MHz, DMSO-d 6 ) 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 protons not shown); m / z (ES + ) [M+H] + = 255.

[0119] Example 14: 6-Chloro-5-[4-[(2-ethyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2-carboxamide [ka] 7-(Bromomethyl)-3-ethylquinoxalin-2(1H)-one (Intermediate 30, 200 mg, 0.75 mmol) was added to 6-chloro-N-methyl-5-(piperazin-1-yl)picolinamide (Intermediate 48, 100 mg, 0.39 mmol) and DIPEA (0.358 mL, 2.05 mmol) in NMP (2 mL). The resulting mixture was stirred at 80° C. for 2 h. The solvent was removed under reduced pressure. The crude product was purified by preparative HPLC (Column: XBridge Prep OBD C18 column, 30×150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH 4 HCO 3 ), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 30% B to 40% B in 8 min; 254; 220 nm; RT: 7.3 min). Fractions containing the desired compound were evaporated to dryness to give 6-chloro-5-[4-[(2-ethyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2-carboxamide (Example 14, 52.6 mg, 30.4%) as a white solid. 1 HNMR (400MHz, CD 3 OD)δ m / z(ES) + ) [M+H] + =441. [ka]

[0120] Intermediate 50: 7-Bromo-3-(trifluoromethyl)quinoxalin-2(1H)-one 4-Bromobenzene-1,2-diamine (Intermediate 49, 0.9 g, 4.81 mmol) was added to methyl 3,3,3-trifluoro-2-oxopropanoate (0.9 g, 5.77 mmol) in toluene (10 mL). The resulting mixture was stirred at 100° C. for 60 min. The solvent was removed under reduced pressure. The crude product was purified by flash silica chromatography, eluent gradient: 0 to 50% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to give a regioisomeric mixture of 7-bromo-3-(trifluoromethyl)quinoxalin-2(1H)-one and 6-bromo-3-(trifluoromethyl)quinoxalin-2(1H)-one (Intermediate 50+Intermediate 51, 1.28 g, 45.4%) as an off-white solid. The mixture of regioisomers was isolated, 1 H NMR spectra were not interpreted; m / z (ES + ) [M+H] + =295.

[0121] Intermediate 52: 7-(hydroxymethyl)-3-(trifluoromethyl)quinoxalin-2(1H)-one Pd(Ph 3 P) 4 (0.3 g, 0.26 mmol) was added to a mixture of 7-bromo-3-(trifluoromethyl)quinoxalin-2(1H)-one and 6-bromo-3-(trifluoromethyl)quinoxalin-2(1H)-one (Intermediate 50 + Intermediate 51, 1.2 g, 2.05 mmol) and (tributylstannyl)methanol (1.2 g, 3.74 mmol) in 1,4-dioxane (40 mL). The resulting mixture was stirred at 100° C. under nitrogen for 18 h. The solvent was removed under reduced pressure. The crude product was purified by reverse phase chromatography, eluent gradient 5 to 50% MeOH in water (0.1% HCO 2 The pure fractions were evaporated to dryness to afford 7-(hydroxymethyl)-3-(trifluoromethyl)quinoxalin-2(1H)-one (intermediate 52, 0.32 g, 64.0%) as an off-white solid. 1 H NMR (300MHz, DMSO-d 6,)δ 4.63(2H,d),5.52(1H,t),7.30(1H,dd),7.38(1H,d),7.83(1H,d),13.05(1H,s);m / z(ES + ) [M+H] + =245.

[0122] Example 15: N-Methyl-5-[4-[[3-oxo-2-(trifluoromethyl)-4H-quinoxalin-6-yl]methyl]piperazin-1-yl]pyridine-2-carboxamide [ka] A 33% HBr solution in AcOH (3 mL, 18.23 mmol) was added to 7-(hydroxymethyl)-3-(trifluoromethyl)quinoxalin-2(1H)-one (Intermediate 52, 111 mg, 0.45 mmol). The resulting mixture was stirred at 80° C. for 1 h. The solvent was removed under reduced pressure. DIEA (0.5 mL, 2.86 mmol) and N-methyl-5-(piperazin-1-yl)picolinamide (Intermediate 13, 100 mg, 0.45 mmol) were added to the above mixture in NMP (3 mL). The resulting mixture was stirred at 80° C. for 1 h. The solvent was removed under reduced pressure. The crude product was purified by preparative HPLC (Column: XBridge Prep OBD C18 column, 30×150 mm 5 μm; Mobile phase A: water (10 mmol / L NH 4 HCO 3 ), mobile phase B: MeCN; flow rate: 60 mL / min; gradient: 22B to 32B in 7 min; 254; 220 nm; RT: 5.77). Fractions containing the desired compound were evaporated to dryness to give N-methyl-5-[4-[3-oxo-2-(trifluoromethyl)-4H-quinoxalin-6-yl]methyl]piperazin-1-yl]pyridine-2-carboxamide (Example 15, 44.0 mg, 21.71%) as a white solid. 1 H NMR (400MHz, DMSO-d 6)δ 2.55-2.62(m,4H),2.78(d,3H),3.34-3.38(t,4H),3.69(s,2H),7.34-7.4 4(m,3H),7.80-7.91(m,2H),8.27(d,1H),8.36-8.41(m,1H),12.97(s,1H); 19 F NMR (376MHz, DMSO-d 6 ) δ -68.36; m / z(ES + ) [M+H] + =447. [ka]

[0123] Example 16: 6-Chloro-N-methyl-5-[4-[[3-oxo-2-(trifluoromethyl)-4H-quinoxalin-6-yl]methyl]piperazin-1-yl]pyridine-2-carboxamide [ka] 33% HBr in AcOH (3 mL, 18.23 mmol) was added to 7-(hydroxymethyl)-3-(trifluoromethyl)quinoxalin-2(1H)-one (Intermediate 52, 43.1 mg, 0.18 mmol). The resulting mixture was stirred at 80° C. for 1 h. The solvent was removed under reduced pressure. DIPEA (0.5 mL, 2.86 mmol) and 6-chloro-N-methyl-5-(piperazin-1-yl)picolinamide (Intermediate 48, 45 mg, 0.18 mmol) were added to the above mixture in NMP (5 mL). The resulting mixture was stirred at 80° C. for 1 h. The solvent was removed under reduced pressure. The crude product was purified by preparative HPLC (Column: XBridge Prep OBD C18 column, 30×150 mm 5 μm; Mobile phase A: Water (10 mmol / L NH 4 HCO 3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 10B to 50B in 7 min; 254; 220 nm; RT: 6.75). Fractions containing the desired compound were evaporated to dryness to give 6-chloro-N-methyl-5-[4-[[3-oxo-2-(trifluoromethyl)-4H-quinoxalin-6-yl]methyl]piperazin-1-yl]pyridine-2-carboxamide (Example 16, 22.00 mg, 25.9%) as an off-white solid. 1 H NMR (400MHz, DMSO-d 6 )δ 2.56-2.64(s,4H),2.79(d,3H),3.09-3.17(m,4H),3.71(s,2H),7.36-7.42(m ,2H),7.67(d,1H),7.88(d,1H),7.94(d,1H),8.39-8.44(m,1H),12.89(s,1H); 19 F NMR(376MHz,DMSO)δ -68.41;m / z(ES+)[M+H] + =481. [ka]

[0124] Example 17: 6-Fluoro-N-methyl-5-[4-[[3-oxo-2-(trifluoromethyl)-4H-quinoxalin-6-yl]methyl]piperazin-1-yl]pyridine-2-carboxamide [ka] 33% HBr in AcOH (3 mL, 55.25 mmol) was added to 7-(hydroxymethyl)-3-(trifluoromethyl)quinoxalin-2(1H)-one (Intermediate 52, 102 mg, 0.42 mmol). The resulting mixture was stirred at 80° C. for 1 h. The solvent was removed under reduced pressure. 6-Fluoro-N-methyl-5-(piperazin-1-yl)picolinamide (Intermediate 23, 100 mg, 0.42 mmol) and DIPEA (0.5 mL, 2.86 mmol) were added to the above mixture in NMP (5 mL). The resulting mixture was stirred at 80° C. for 1 h. The solvent was removed under reduced pressure. The crude product was purified by preparative HPLC (Column: XBridge Prep OBD C18 column, 30×150 mm 5 μm; Mobile phase A: Water (10 mmol / L NH 4 HCO 3 ), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 15B to 40B in 8 min; 254; 220 nm; RT: 7.2). Fractions containing the desired compound were evaporated to dryness to give 6-fluoro-N-methyl-5-[4-[[3-oxo-2-(trifluoromethyl)-4H-quinoxalin-6-yl]methyl]piperazin-1-yl]pyridine-2-carboxamide (Example 17, 66.0 mg, 33.9%) as a white solid. 1 H NMR (400MHz, DMSO-d 6 )δ 2.55-2.69(m,4H),2.77(d,3H),3.15-3.23(m,4H),3.69(s,2H),7.33-7.46 (m,2H),7.58(dd,1H),7.78-7.93(m,2H),8.37-8.42(m,1H),12.99(s,1H); 19 F NMR (376MHz, DMSO-d 6 ) δ -68.36, -72.52; m / z(ES + ) [M+H] + =465. [ka]

[0125] Intermediate 54: Methyl 2-aminopentanoate hydrochloride SOCl2 (17 mL, 232.94 mmol) was added dropwise to 2-aminopentanoic acid (Intermediate 53, 10.0 g, 85.36 mmol) in MeOH (200 mL) at 0° C. The resulting mixture was stirred at room temperature for 18 h. The solvent was removed under reduced pressure to give methyl 2-aminopentanoate hydrochloride (Intermediate 54; 15.78 g, 110%) as a white solid. 1 H NMR (DMSO-d 6 ,400MHz)δ 0.88(3H,t),1.19-1.51(2H,m),1.67-1.83(2H,m),3.74(3H,s),3.89-3.93(1H,m),8.64(3H,s);m / z(ES+)[M+H] + =132.

[0126] Intermediate 55: Methyl 4-(1-methoxy-1-oxopentan-2-ylamino)-3-nitrobenzoate Sodium bicarbonate (20.0 g, 238.08 mmol) was added to methyl 2-aminopentanoate hydrochloride (Intermediate 54, 15.57 g, 92.88 mmol) and methyl 4-fluoro-3-nitrobenzoate (9.0 g, 45.19 mmol) in THF (160 mL). The resulting mixture was stirred at room temperature for 18 h. The solvent was removed under reduced pressure. The reaction mixture was diluted with EtOAc (150 mL) and washed with water (100 mL x 1), saturated NaHCO 3 The organic layer was washed with saturated aqueous solution of sodium chloride (100 mL × 1) and saturated brine (100 mL × 1) in turn. 2 SO 4 Drying at 40° C., filtration and evaporation afforded methyl 4-(1-methoxy-1-oxopentan-2-ylamino)-3-nitrobenzoate (Intermediate 55, 14.09 g, 100%) as a yellow oil. 1 H NMR (400MHz, DMSO-d 6 )δ 0.89(3H,t),1.26-1.41(2H,m),1.84-1.94(2H,m),3.73(3H,s),3.83(3H,s),4.68 -4.75(1H,m),7.12(1H,d),8.00(1H,d),8.60(1H,d),8.63(1H,d);m / z(ES+)[M+H] + =311.

[0127] Intermediate 56: 3-Oxo-2-propyl-1,2,3,4-tetrahydroquinoxaline-6-carboxylate methyl Pd(OH) 2 A solution of 1.58 g (20 wt %) / C (2.25 mmol) was added to methyl 4-((1-methoxy-1-oxopentan-2-yl)amino)-3-nitrobenzoate (Intermediate 55, 14.05 g, 45.28 mmol) in MeOH (300 mL). The resulting mixture was subjected to H 2 The mixture was stirred at room temperature under reduced pressure for 30 hours. The reaction mixture was filtered. The precipitate was washed with DMF (100 mL) and the filtrate was evaporated to dryness to give the crude product. The crude product was washed with DCM (10 mL) and dried under vacuum to give methyl 3-oxo-2-propyl-1,2,3,4-tetrahydroquinoxaline-6-carboxylate (intermediate 56, 9.12 g, 81%) as a white solid. 1 H NMR (400MHz, DMSO-d 6 )δ 0.87(3H,t),1.32-1.46(2H,m),1.57-1.64(2H,m),3.74(3H,s),3.88-3.93(1H ,m),6.70(1H,d),6.83(1H,d),7.32(1H,d),7.40(1H,dd),10.38(1H,s);m / z(ES + ) [M+H] + =249.

[0128] Intermediate 57: 3-Oxo-2-propyl-3,4-dihydroquinoxaline-6-carboxylate methyl DDQ (9.42 g, 41.50 mmol) was added to methyl 3-oxo-2-propyl-1,2,3,4-tetrahydroquinoxaline-6-carboxylate (Intermediate 56, 9.12 g, 36.73 mmol) in 1,4-dioxane (200 mL). The resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with saturated NaHCO 3(200 mL). The resulting mixture was stirred at room temperature for 0.5 h. The precipitate was collected by filtration, washed with water (1000 mL) and dried under vacuum to give methyl 3-oxo-2-propyl-3,4-dihydroquinoxaline-6-carboxylate (Intermediate 57, 7.86 g, 87%) as an off-white solid. 1 H NMR (400MHz, DMSO-d 6 )δ 0.98(3H,t),1.68-1.80(2H,m),2.75-2.83(2H,m),3.89(3H,s),7.73-7.85(2H,m),7.88(1H,d),12.45(1H,s);m / z(ES + ) [M+H] + =247.

[0129] Intermediate 58: 7-(hydroxymethyl)-3-propylquinoxalin-2(1H)-one A 1M solution of DIBAL-H in THF (100 mL, 100.00 mmol) was added dropwise to methyl 3-oxo-2-propyl-3,4-dihydroquinoxaline-6-carboxylate (Intermediate 57, 7.81 g, 31.71 mmol) in THF (200 mL) at 0° C. The resulting mixture was stirred at room temperature for 18 h. The reaction mixture was quenched with MeOH (5 ml) and saturated aqueous sodium potassium tartrate tetrahydrate (20 ml) and the organic layer was evaporated to give 7-(hydroxymethyl)-3-propylquinoxalin-2(1H)-one (Intermediate 58, 1.2 g, 17.34%) as a white solid. 1 H NMR (400MHz, DMSO-d 6 )δ m / z(ES) + ) [M+H] + =219.

[0130] Intermediate 59: 7-(bromomethyl)-3-propylquinoxalin-2(1H)-one 33% HBr in AcOH (74.6 μl, 1.37 mmol) was added to 7-(hydroxymethyl)-3-propylquinoxalin-2(1H)-one (Intermediate 58, 300 mg, 1.37 mmol). The resulting mixture was stirred at 80° C. for 1 h. The solvent was removed under reduced pressure to give 7-(bromomethyl)-3-propylquinoxalin-2(1H)-one (Intermediate 59, 600 mg, 155%) as a brown solid (the crude product was not pure and contained AcOH and other impurities). The product was used in the next step without further purification. 1 The H NMR spectrum was unclear and was not interpreted; m / z (ES + ) [M+H] + =282.

[0131] Example 18: N-Methyl-5-[4-[(3-oxo-2-propyl-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]pyridine-2-carboxamide [ka] To 7-(bromomethyl)-3-propylquinoxalin-2(1H)-one (Intermediate 59, 200 mg, 0.71 mmol) and N-methyl-5-(piperazin-1-yl)picolinamide (Intermediate 13, 80 mg, 0.36 mmol) in NMP (3 mL) was added DIPEA (200 μL, 1.15 mmol). The resulting mixture was stirred at 80° C. for 1 h. The solvent was removed under reduced pressure. 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 NH 4 HCO 3 , 0.1%NH 3 .H 210C), mobile phase B: ACN; flow rate: 20 mL / min; gradient: 38B to 50B in 7 min; 254 / 220 nm; RT: 6.20). Fractions containing the desired compound were evaporated to dryness to give N-methyl-5-[4-[(3-oxo-2-propyl-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]pyridine-2-carboxamide (Example 18, 71.0 mg, 46.5%) as a white solid. 1 H NMR (400MHz, DMSO-d 6 )δ 0.97(3H,t),1.66-1.80(2H,m),2.55-2.61(4H,m),2.73-2.85(5H,m),3.33-3.40(4H,m),3.62(2H,s),7.19-7.3 1(2H,m),7.40(1H,dd),7.68(1H,d),7.83(1H,d),8.27(1H,d),8.35-8.45(1H,m),12.26(1H,s);m / z(ES+)[M+H] + =421. [ka]

[0132] Example 19: 6-Chloro-N-methyl-5-[4-[(3-oxo-2-propyl-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-pyridine-2-carboxamide [ka] To 7-(bromomethyl)-3-propylquinoxalin-2(1H)-one (Intermediate 59, 200 mg, 0.71 mmol) and 6-chloro-N-methyl-5-(piperazin-1-yl)picolinamide (Intermediate 48, 80 mg, 0.31 mmol) in NMP (3 mL) was added DIPEA (200 μL, 1.15 mmol). The resulting mixture was stirred at 80° C. for 1 h. The solvent was removed under reduced pressure. The crude product was purified by preparative HPLC (Column: XBridge Shield RP18 OBD column, 19×250 mm, 10 μm; Mobile phase A: water (0.1% HCO 2H), mobile phase B: ACN; flow rate: 20 mL / min; gradient: 18B to 30B in 7 min; 254 / 220 nm; RT: 5.93). Fractions containing the desired compound were evaporated to dryness to give 6-chloro-N-methyl-5-[4-[(3-oxo-2-propyl-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-pyridine-2-carboxamide (Example 19, 52.0 mg, 36.4%) as a white solid. 1 H NMR (400MHz, DMSO-d 6 )δ 0.97(3H,t),1.66-1.79(2H,m),2.55-2.65(4H,m),2.71-2.85(5H,m),3.06-3.12(4H,m),3.64(2 H,s),7.20-7.32(2H,m),7.64-7.72(2H,m),7.94(1H,d),8.40-8.50(1H,m),12.27(1H,s);m / z(ES + ) [M+H] + =455. [ka]

[0133] Example 20: 6-Fluoro-N-methyl-5-[4-[(3-oxo-2-propyl-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-pyridine-2-carboxamide [ka] DIPEA (500 μl, 2.86 mmol) was added to 7-(bromomethyl)-3-propylquinoxalin-2(1H)-one (Intermediate 59, 200 mg, 0.71 mmol) and 6-fluoro-N-methyl-5-(piperazin-1-yl)picolinamide, 2HCl (Intermediate 23, 100 mg, 0.32 mmol) in NMP (3 mL). The resulting mixture was stirred at 80° C. for 1 h. The solvent was removed under reduced pressure. The crude product was purified by preparative HPLC (Column: SunFire C18 OBD preparative column, 100 Å, 5 μm, 19 mm×250 mm; Mobile phase A: water (0.1% HCO 2H), mobile phase B: ACN; flow rate: 25 mL / min; gradient: 10B to 20B in 13 min; 254 / 220 nm; RT: 12.13). Fractions containing the desired compound were evaporated to dryness to give 6-fluoro-N-methyl-5-[4-[(3-oxo-2-propyl-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-pyridine-2-carboxamide (Example 20, 71.0 mg, 50.4%) as a white solid. 1 H NMR (400MHz, DMSO-d 6 )δ 0.97(3H,t),1.66-1.78(2H,m),2.54-2.60(4H,m),2.71-2.83(5H,m),3.14-3.25(4H,m),3.62(2H ,s),7.19-7.33(2H,m),7.57(1H,dd),7.68(1H,d),7.85(1H,dd),8.37-5.43(1H,m),12.27(1H,s); 19 F NMR (376MHz, DMSO-d 6 ) δ -72.51; m / z(ES + ) [M+H] + =439. [ka]

[0134] Intermediate 61: Methyl 2-aminobutanoate hydrochloride SOCl 2 (17 mL, 232.94 mmol) was added dropwise to 2-aminobutanoic acid (Intermediate 60, 10.0 g, 96.97 mmol) in MeOH (100 mL) at 0° C. The resulting mixture was stirred at room temperature for 18 h. The solvent was removed under reduced pressure to give methyl 2-aminobutanoate hydrochloride (Intermediate 61, 14.84 g, 100%) as a white solid. 1 H NMR (400MHz, DMSO-d 6 )δ 0.91(3H,t),1.75-1.95(2H,m),3.73(3H,s),3.93(1H,t),8.72(3H,s);m / z(ES + ) [M+H] + =118

[0135] Intermediate 62: 2-Fluoro-4-(1-methoxy-1-oxobutan-2-ylamino)-5-nitrobenzoate methyl DIPEA (4.02 mL, 23.03 mmol) was added to methyl 2,4-difluoro-5-nitrobenzoate (1.0 g, 4.61 mmol) and methyl 2-aminobutanoate hydrochloride (Intermediate 61, 0.707 g, 4.61 mmol) in NMP (10 mL). The resulting mixture was stirred at rt for 5 h. The crude product was purified by reverse phase chromatography, eluent gradient 5 to 80% MeOH (water (0.1% NH 4 HCO 3 ) in hexanes). Pure fractions were evaporated to dryness to afford methyl 2-fluoro-4-(1-methoxy-1-oxobutan-2-ylamino)-5-nitrobenzoate (Intermediate 62, 1.2 g, 83%) as a black solid. 1 H NMR (400MHz, DMSO-d 6 )δ 0.88(3H,t),1.78-2.03(2H,m),3.75(3H,s),3.83(3H,s),4.73-4.80(1H,m),7.06(1H,d),8.66-8.72(2H,m);m / z(ES + ) [M+H] + =315.

[0136] Intermediate 63: 2-Ethyl-7-fluoro-3-oxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylate methyl Methyl 2-fluoro-4-((1-methoxy-1-oxobutan-2-yl)amino)-5-nitrobenzoate (Intermediate 62, 1.15 g, 3.66 mmol) was reacted with 20 wt% Pd(OH) in MeOH (300 mL) and ethyl acetate (50 mL) under hydrogen. 2 (500 mg, 0.71 mmol). The resulting mixture was stirred at room temperature for 3 days. The reaction was not complete. The reaction mixture was filtered. The organic layer was evaporated to give the crude product, methyl 2-ethyl-7-fluoro-3-oxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylate (Intermediate 63, 0.780 g, 85%) as a brown gum. This crude product was used in the next step without further purification. The crude product was not clean,1 H NMR spectra were uninterpreted; m / z (ES + ) [M+H] + =253.

[0137] Intermediate 64: 2-Ethyl-7-fluoro-3-oxo-3,4-dihydroquinoxaline-6-carboxylate methyl Methyl 2-ethyl-7-fluoro-3-oxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylate (Intermediate 63, 760 mg, 3.01 mmol) was added to DDQ (821 mg, 3.62 mmol) in DCM (20 mL). The resulting mixture was stirred at room temperature for 2 hours. The reaction was complete. The resulting mixture was concentrated under reduced pressure to give a brown solid. aqNaHCO 3 A saturated aqueous solution (10 mL) was added to the solid and stirred at room temperature for 1 h. The precipitate was filtered and additional aqNaHCO 3 The solid was dried under vacuum to give methyl 2-ethyl-7-fluoro-3-oxo-3,4-dihydroquinoxaline-6-carboxylate (Intermediate 64, 750 mg, 99%) as a brown solid. 1 H NMR (300MHz, DMSO-d 6 )δ 1.20(3H,t),2.82(2H,q),3.87(3H,s),7.65(1H,d),7.76(1H,d),12.42(1H,s);m / z(ES + ) [M+H] + =251.

[0138] Intermediate 65: 3-Ethyl-6-fluoro-7-(hydroxymethyl)quinoxalin-2(1H)-one A 1M solution of diisobutylaluminum hydride in THF (15.35 mL, 15.35 mmol) was added portionwise to methyl 2-ethyl-7-fluoro-3-oxo-3,4-dihydroquinoxaline-6-carboxylate (Intermediate 64, 640 mg, 2.56 mmol) in THF (300 mL). The resulting mixture was stirred at room temperature for 16 h. The reaction was complete. The reaction mixture was quenched with saturated aqueous sodium potassium tartrate (20 mL) and MeOH (10 mL) at 0° C. The resulting mixture was stirred at room temperature for 1 h. The reaction mixture was filtered and washed with THF (50 mL×3). The organic layer was evaporated to dryness to give the crude product. The crude product was purified by reverse phase chromatography, eluent gradient 5 to 60% MeOH (water (0.4% HCO 2 The pure fractions were evaporated to dryness to afford 3-ethyl-6-fluoro-7-(hydroxymethyl)quinoxalin-2(1H)-one (intermediate 65, 110 mg, 19.37%) as an off-white solid. 1 H NMR (400MHz, DMSO-d 6 )δ 1.21(3H,t),2.80(2H,q),4.63(2H,d),5.49(1H,t),7.41(1H,d),7.49(1H,d),12.36(1H,s);m / z(ES + ) [M+H] + =223.

[0139] Example 21: 5-[4-[(2-ethyl-7-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-6-fluoro-N-methyl-pyridine-2-carboxamide [ka] 3-Ethyl-6-fluoro-7-(hydroxymethyl)quinoxalin-2(1H)-one (Intermediate 65, 50 mg, 0.23 mmol) was added to 33% HBr in AcOH (2 mL, 12.15 mmol). The resulting mixture was stirred at 80° C. for 2 h. The reaction mixture was evaporated under vacuum to give 7-(bromomethyl)-3-ethyl-6-fluoroquinoxalin-2(1H)-one (crude product). This product was used directly in the next step without further purification. To 7-(bromomethyl)-3-ethyl-6-fluoroquinoxalin-2(1H)-one and 6-fluoro-N-methyl-5-(piperazin-1-yl)picolinamide (Intermediate 23, 70 mg, 0.29 mmol) in NMP (2 mL) was added DIPEA (0.196 mL, 1.13 mmol). The resulting mixture was stirred at 80° C. for 2 h. The resulting mixture was subjected to preparative HPLC (column: Sunfire preparative C18 column, 30 × 150 mm, 5 μm; mobile phase A: water (0.1% HCO 2 H), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 10B to 35B in 8 min; 254 / 220 nm; RT: 7.37). Fractions containing the desired compound were evaporated to dryness to give 5-[4-[(2-ethyl-7-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-6-fluoro-N-methyl-pyridine-2-carboxamide (Example 21, 55.0 mg, 53.7%) as an off-white solid. 1 H NMR (400MHz, DMSO-d 6 )δ 1.21(3H,t),2.61(4H,m),2.73-2.85(5H,m),3.18(4H,m),3.68(2H,s),7.38(1H, d),7.51-7.61(2H,m),7.84(1H,dd),8.13(0.29H,s),8.38(1H,m),12.29(1H,s); 19 F NMR (376MHz, DMSO-d 6 )δ -72.53,-124.31;m / z(ES+)[M+H] + =443. [ka]

[0140] Intermediate 67: Methyl 4-(3-hydroxy-1-methoxy-1-oxobutan-2-ylamino)-3-nitrobenzoate To methyl 4-fluoro-3-nitrobenzoate (2.0 g, 10.04 mmol) and methyl 2-amino-3-hydroxybutanoate hydrochloride (Intermediate 66, 2.04 g, 12.05 mmol) in DMF (20 mL) was added DIPEA (8.77 mL, 50.22 mmol). The resulting mixture was stirred at rt for 16 h. The reaction mixture was diluted with EtOAc (100 mL) and saturated NaH 4 The organic layer was washed successively with aqueous Cl (100 mL x 1) and brine (100 mL x 4). 2 SO 4 Drying at 40° C., filtration and evaporation afforded the desired product, methyl 4-((3-hydroxy-1-methoxy-1-oxobutan-2-yl)amino)-3-nitrobenzoate (Intermediate 67, 2.9 g, 92%) as a yellow solid. 1 H NMR (400MHz, DMSO-d 6 )δ 1.15-1.27(3H,m),3.64-3.74(3H,m),3.83(3H,s),4.08-4.44(1H,m),4.61-4.72(1H,m),5.39-5.60 (1H,m),7.03-7.15(1H,m),7.90-8.03(1H,m),8.62-8.69(1H,m),8.73-8.89(1H,m);m / z(ES+)[M+H] + =313.

[0141] Intermediate 68: 2-(1-hydroxyethyl)-3-oxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylate methyl 20% Pd(OH) 2 / C (0.648 g, 0.92 mmol) was added to methyl 4-(((3-hydroxy-1-methoxy-1-oxobutan-2-yl)amino)-3-nitrobenzoate (Intermediate 67, 2.88 g, 9.22 mmol) in MeOH (300 mL) under hydrogen. The resulting mixture was stirred at room temperature for 16 h. The reaction was complete. The reaction mixture was filtered through celite. The organic layer was evaporated to give methyl 2-(1-hydroxyethyl)-3-oxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylate (Intermediate 68, 2.290 g, 99%) as a grey solid. 1 H NMR (400MHz, DMSO-d 6 )δ 1.07(3H,m),2.81(1H,d),3.72(1H,m),3.74(3H,s),4.78(1H,d),6.70-6.86(2H,m),7.27(1H,d),7.37(1H,dd),10.38(1H,d);m / z(ES + ) [M+H] + =251.

[0142] Intermediate 69: 2-(1-hydroxyethyl)-3-oxo-3,4-dihydroquinoxaline-6-carboxylate methyl DDQ (2.265 g, 9.98 mmol) was added to methyl 2-(1-hydroxyethyl)-3-oxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylate (Intermediate 68, 2.27 g, 9.07 mmol) in DCM (100 mL). The resulting mixture was stirred at room temperature for 1 h. The reaction was complete. The reaction mixture was concentrated under reduced pressure to give a brown solid. aqNaHCO 3 A saturated aqueous solution (100 mL) was added to the solid and stirred at room temperature for 1 h. The precipitate was filtered and additional aqNaHCO 3 The solid was dried under vacuum to give methyl 2-(1-hydroxyethyl)-3-oxo-3,4-dihydroquinoxaline-6-carboxylate (Intermediate 69, 2.24 g, 99%) as a grey solid. 1 H NMR (400MHz, DMSO-d 6) δ 1.40 (3H, d), 3.88 (3H, s), 4.94 (1H, q), 7.69 (1H, dd), 7.77 (1H, d), 7.90 (1H, d) (2 protons not shown); m / z (ES + ) [M+H] + =249.

[0143] Intermediate 70: 2-Acetyl-3-oxo-3,4-dihydroquinoxaline-6-carboxylate methyl Dess-Martin periodinane (2.56 g, 6.04 mmol) was added to methyl 2-(1-hydroxyethyl)-3-oxo-3,4-dihydroquinoxaline-6-carboxylate (Intermediate 69, 1.0 g, 4.03 mmol) in DCM (30 mL). The resulting mixture was stirred at room temperature for 3 h. The reaction mixture was evaporated to give the crude product. The crude product was purified by reverse phase chromatography, eluent gradient 5 to 30% MeCN (water (0.4% HCO 2 H)) The pure fractions were evaporated to dryness to give methyl 2-acetyl-3-oxo-3,4-dihydroquinoxaline-6-carboxylate (Intermediate 70; 0.62 g, 62.5%) as a pale yellow solid. 1 H NMR (400MHz, DMSO-d 6 )δ 2.58(3H,s),3.91(3H,s),7.84(1H,dd),7.91-8.03(2H,m),12.86(1H,s);m / z(ES + ) [M+H] + =247.

[0144] Intermediate 71: 2-(1,1-difluoroethyl)-3-oxo-3,4-dihydroquinoxaline-6-carboxylate methyl BAST (1.35 mL, 7.31 mmol) was added to methyl 2-acetyl-3-oxo-3,4-dihydroquinoxaline-6-carboxylate (Intermediate 70, 600 mg, 2.44 mmol) in DCM (20 mL). The resulting mixture was stirred at room temperature for 16 h. The reaction mixture was evaporated to give the crude product. The crude product was purified by reverse phase chromatography, eluent gradient 5 to 30% MeCN in water (0.4% HCO 2H)) Pure fractions were evaporated to dryness to afford methyl 2-(1,1-difluoroethyl)-3-oxo-3,4-dihydroquinoxaline-6-carboxylate (Intermediate 71, 174 mg, 26.6%) as an off-white solid. 1 H NMR (400MHz, DMSO-d 6 )δ 2.07(3H,t),3.91(3H,s),7.84(1H,dd),7.92-7.99(2H,m),12.90(1H,s); 19 F NMR (376MHz, DMSO-d 6 ) δ -93.26; m / z(ES + ) [M+H] + =269.

[0145] Intermediate 72: 3-(1,1-difluoroethyl)-7-(hydroxymethyl)quinoxalin-2(1H)-one A 1M solution of diisobutylaluminum hydride in THF (2.39 mL, 2.39 mmol) was added to methyl 2-(1,1-difluoroethyl)-3-oxo-3,4-dihydroquinoxaline-6-carboxylate (Intermediate 71, 160 mg, 0.60 mmol) in THF (50 mL) at 0° C. The resulting mixture was stirred at room temperature for 16 h. The reaction mixture was quenched with saturated aqueous sodium potassium tartrate (3 mL) and MeOH (1 mL) at 0° C. The resulting mixture was stirred for 1 h. The reaction mixture was filtered and washed with THF (10 mL×3). The organic layer was evaporated to give the crude product, 3-(1,1-difluoroethyl)-7-(hydroxymethyl)quinoxalin-2(1H)-one (Intermediate 72, 120 mg, 84%). This product was used directly in the next step without further purification. 1 H NMR (400MHz, DMSO-d 6 )δ 2.06(3H,t),4.63(2H,s),5.47(1H,s),7.26(1H,dd),7.35(1H,d),7.78(1H,d),12.75(1H,br s);m / z(ES+)[M+H] + =241.

[0146] Example 22: 5-[4-[[2-(1,1-difluoroethyl)-3-oxo-4H-quinoxalin-6-yl]methyl]piperazin-1-yl]-N-methyl-pyridine-2-carboxamide [ka] 3-(1,1-difluoroethyl)-7-(hydroxymethyl)quinoxalin-2(1H)-one (Intermediate 72, 60 mg, 0.25 mmol) was added to 33% HBr in acetic acid (2 mL, 12.15 mmol). The resulting mixture was stirred at 80° C. for 2 h. The reaction mixture was evaporated under vacuum to give 7-(bromomethyl)-3-(1,1-difluoroethyl)quinoxalin-2(1H)-one (crude product). This product was used in the next step without further purification. DIPEA (0.218 mL, 1.25 mmol) was added to 7-(bromomethyl)-3-(1,1-difluoroethyl)quinoxalin-2(1H)-one (crude product) and N-methyl-5-(piperazin-1-yl)picolinamide (Intermediate 13, 60 mg, 0.27 mmol) in NMP (3 mL). The resulting mixture was stirred at 80° C. for 1 h. The reaction mixture was concentrated and purified by preparative HPLC (column: XBridge Shield RP18 OBD column, 30×150 mm, 5 μm; mobile phase A: water (0.05% NH 3 H 2 0), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 13B to 33B in 7 min; 254; 220 nm; RT: 5.70). Fractions containing the desired compound were evaporated to dryness to give 5-[4-[[2-(1,1-difluoroethyl)-3-oxo-4H-quinoxalin-6-yl]methyl]piperazin-1-yl]-N-methyl-pyridine-2-carboxamide (Example 22, 47.8 mg, 43.2%) as a yellow solid. 1 H NMR (400MHz, DMSO-d 6)δ 2.06(3H,t),2.52-2.62(4H,m),2.78(3H,d),3.30-3.40(4H,m),3.67(2H,s),7.3 2-7.42(3H,m),7.80-7.86(2H,m),8.27(1H,d),8.34-8.42(1H,m),12.70(1H,s); 19 F NMR (376MHz, DMSO-d 6 ) δ -92.74; m / z(ES + ) [M+H] + =443. [ka]

[0147] Intermediate 74: Methyl 4-(4,4-difluoro-1-methoxy-1-oxobutan-2-ylamino)-3-nitrobenzoate To methyl 4-fluoro-3-nitrobenzoate (2.0 g, 10.04 mmol) and methyl 2-amino-3-hydroxybutanoate hydrochloride (Intermediate 73, 2.0 g, 10.55 mmol) in DMF (20 mL) was added DIPEA (8.77 mL, 50.22 mmol). The resulting mixture was stirred at 40° C. for 8 h. The reaction mixture was diluted with EtOAc (100 mL) and saturated NaH 4 The organic layer was washed with NaCl (100 mL x 1) and brine (100 mL x 4) in sequence. 2 SO 4 Drying at 40° C., filtration and evaporation afforded the desired product, methyl 4-((4,4-difluoro-1-methoxy-1-oxobutan-2-yl)amino)-3-nitrobenzoate (Intermediate 74, 2.5 g, 74.9%) as a yellow solid. 1 H NMR (300MHz, DMSO-d 6 )δ 2.50-2.76(2H,m),3.71(3H,s),3.82(3H,s),4.95(1H,q),6.22(1H,tt),7.18(1H,d),7.99(1H,dd),8.63(1H,d),8.66(1H,d);m / z(ES+)[M+H] + =333.

[0148] Intermediate 75: 2-(2,2-difluoroethyl)-3-oxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylate methyl 20% Pd(OH) 2 / C (0.465 g, 0.66 mmol) was added to methyl 4-((4,4-difluoro-1-methoxy-1-oxobutan-2-yl)amino)-3-nitrobenzoate (Intermediate 74, 2.2 g, 6.62 mmol) in MeOH (300 mL) under hydrogen. The resulting mixture was stirred at room temperature for 16 h. The reaction mixture was filtered through celite. The filtrate was evaporated to give methyl 2-(2,2-difluoroethyl)-3-oxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylate (Intermediate 75, 1.64 g, 92%) as a yellow solid. 1 H NMR (400MHz, DMSO-d 6 )δ m / z(ES) + ) [M+H] + =271.

[0149] Intermediate 76: 2-(2,2-difluoroethyl)-3-oxo-3,4-dihydroquinoxaline-6-carboxylate methyl DDQ (1.478 g, 6.51 mmol) was added to methyl 2-(2,2-difluoroethyl)-3-oxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylate (Intermediate 75, 1.6 g, 5.92 mmol) in DCM (100 mL). The resulting mixture was stirred at room temperature for 3 hours. The resulting mixture was removed under reduced pressure to give a brown solid. aqNaHCO 3 A saturated aqueous solution (100 mL) was added to the solid and stirred at room temperature for 1 h. The precipitate was filtered and additional aqNaHCO 3The solid was dried under vacuum to give methyl 2-(2,2-difluoroethyl)-3-oxo-3,4-dihydroquinoxaline-6-carboxylate (Intermediate 76, 1.58 g, 99%) as an off-white solid. 1 H NMR (400MHz, DMSO-d 6 )δ 3.46(2H,td),3.90(3H,s),6.57(1H,t),7.79-7.92(3H,m),12.68(1H,s);m / z(ES + ) [M+H] + =269.

[0150] Intermediate 77: 3-(2,2-difluoroethyl)-7-(hydroxymethyl)quinoxalin-2(1H)-one A 1M solution of diisobutylaluminum hydride in THF (22.37 mL, 22.37 mmol) was added portionwise to methyl 2-(2,2-difluoroethyl)-3-oxo-3,4-dihydroquinoxaline-6-carboxylate (Intermediate 76, 1.0 g, 3.73 mmol) in THF (100 mL) at 0° C. The resulting mixture was stirred at room temperature for 16 h. The reaction mixture was quenched with saturated aqueous sodium potassium tartrate (20 mL) and MeOH (10 mL) at 0° C. The resulting mixture was stirred for 1 h. The reaction mixture was filtered and washed with THF (30 mL×3). The organic layer was evaporated to give 3-(2,2-difluoroethyl)-7-(hydroxymethyl)quinoxalin-2(1H)-one (0.72 g, 80%) as a red solid (crude product). The crude product was purified by reverse phase chromatography, eluent gradient 5 to 60% MeOH (in water (0.4% HCO 2 The pure fractions were evaporated to dryness to give 3-(2,2-difluoroethyl)-7-(hydroxymethyl)quinoxalin-2(1H)-one (intermediate 77, 500 mg, 69.4%) as a red solid. 1 H NMR (300MHz, DMSO-d 6)δ 3.42(2H,td),4.61(2H,s),5.42(1H,brs),6.56(1H,tt),7.23(1H,dd),7.32(1H,d),7.71(1H,d),12.55(1H,s);m / z(ES+)[M+H] + =241.

[0151] Intermediate 78: 2-(2,2-difluoroethyl)-3-oxo-3,4-dihydroquinoxaline-6-carbaldehyde Dess-Martin periodinane (530 mg, 1.25 mmol) was added to 3-(2,2-difluoroethyl)-7-(hydroxymethyl)quinoxalin-2(1H)-one (Intermediate 77, 200 mg, 0.83 mmol) in DCM (5 mL). The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was evaporated to give the crude product. The crude product was purified by reverse phase chromatography, eluent gradient 5 to 30% MeCN (water (0.4% HCO 2 The pure fractions were evaporated to dryness to afford 2-(2,2-difluoroethyl)-3-oxo-3,4-dihydroquinoxaline-6-carbaldehyde (intermediate 78, 160 mg, 81%) as a yellow solid. 1 H NMR (400MHz, DMSO-d 6 )δ 3.47(2H,td),6.58(1H,tt),7.77-7.85(2H,m),7.90-7.98(1H,m),10.09(1H,s),12.79(1H,s);m / z(ES + ) [M+H] + =239.

[0152] Example 23: 5-[4-[[2-(2,2-difluoroethyl)-3-oxo-4H-quinoxalin-6-yl]methyl]piperazin-1-yl]-N-methyl-pyridine-2-carboxamide [ka] To 2-(2,2-difluoroethyl)-3-oxo-3,4-dihydroquinoxaline-6-carbaldehyde (Intermediate 78, 55 mg, 0.23 mmol) and N-methyl-5-(piperazin-1-yl)picolinamide (Intermediate 13, 60 mg, 0.23 mmol) in THF (2 mL) was added titanium isopropoxide (65.6 mg, 0.23 mmol). The resulting mixture was stirred at room temperature for 2 min. Sodium triacetoxyborohydride (196 mg, 0.92 mmol) was added. The resulting mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with MeOH (0.1 mL). The reaction mixture was evaporated to give the crude product, which was purified by preparative HPLC (Column: XBridge Shield RP18 OBD column, 30×150 mm, 5 μm; Mobile phase A: Water (0.05% NH 3 H 2 0), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 13B to 33B in 7 min; 254; 220 nm; RT: 5.70). Fractions containing the desired compound were evaporated to dryness to give 5-[4-[[2-(2,2-difluoroethyl)-3-oxo-4H-quinoxalin-6-yl]methyl]piperazin-1-yl]-N-methyl-pyridine-2-carboxamide (Example 23, 8.76 mg, 8.57%) as a yellow solid. 1 H NMR (400MHz, DMSO-d 6 )δ 2.56(4H,m),2.78(3H,d),3.32-3.48(6H,m),3.64(2H,s),6.55(1H,tt),7.27-7.33(2 H,m),7.39(1H,dd),7.73(1H,d),7.83(1H,d),8.26(1H,d),8.37(1H,m),12.49(1H,s); 19 F NMR (376MHz, DMSO-d 6 ) δ -114.29; m / z(ES + ) [M+H] + =443. [ka]

[0153] Example 24: 5-[4-[[2-(2,2-difluoroethyl)-3-oxo-4H-quinoxalin-6-yl]methyl]piperazin-1-yl]-6-fluoro-N-methyl-pyridine-2-carboxamide [ka] To 2-(2,2-difluoroethyl)-3-oxo-3,4-dihydroquinoxaline-6-carbaldehyde (intermediate 78, 50 mg, 0.21 mmol) and 6-fluoro-N-methyl-5-(piperazin-1-yl)picolinamide (intermediate 23, 50.0 mg, 0.21 mmol) in THF (2 mL) was added titanium isopropoxide (59.7 mg, 0.21 mmol). The resulting mixture was stirred at room temperature for 2 min. Sodium triacetoxyborohydride (178 mg, 0.84 mmol) was added. The resulting mixture was stirred at room temperature for 1 h. The reaction was complete. The reaction mixture was quenched with MeOH (0.1 mL). The reaction mixture was evaporated to give the crude product. The crude product was purified by preparative HPLC (column: Sunfire preparative C18 column, 30×150, 5 μm; mobile phase A: water (0.1% HCO 2 H), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 2B to 27B in 7 min; 254 / 220 nm; RT: 6.78). Fractions containing the desired compound were evaporated to dryness to give 5-[4-[[2-(2,2-difluoroethyl)-3-oxo-4H-quinoxalin-6-yl]methyl]piperazin-1-yl]-6-fluoro-N-methyl-pyridine-2-carboxamide (Example 24, 21.72 mg, 22.13%) as a yellow solid. 1 H NMR (400MHz, DMSO-d 6 )δ 2.54-2.61(4H,m),2.76(3H,d),3.14-3.22(4H,m),3.41(2H,td),3.64(2H,s),6.39-6.71(1H,m),7.26- 7.33(2H,m),7.57(1H,dd),7.73(1H,d),7.82-7.86(1H,m),8.13(0.16H,s),8.37(1H,m),12.49(1H,s); 19 F NMR (376MHz, DMSO-d6 ) δ -72.52, -114.29; m / z(ES + ) [M+H] + =461. [ka]

[0154] Intermediate 80: Methyl 4-(4-fluoro-1-methoxy-1-oxobutan-2-ylamino)-3-nitrobenzoate To methyl 4-fluoro-3-nitrobenzoate (2.0 g, 10.04 mmol) and methyl 2-amino-4-fluorobutanoate hydrochloride (Intermediate 79, 1.81 g, 10.55 mmol) in DMF (20 mL) was added DIPEA (8.77 mL, 50.22 mmol). The resulting mixture was stirred at 40° C. for 8 h. The reaction mixture was diluted with EtOAc (100 mL) and saturated NaH 4 The organic layer was washed with NaCl (100 mL x 1) and brine (100 mL x 4) in sequence. 2 SO 4 Drying at 40° C., filtration and evaporation afforded the desired product, methyl 4-((4-fluoro-1-methoxy-1-oxobutan-2-yl)amino)-3-nitrobenzoate (Intermediate 80, 2.5 g, 79%) as a yellow solid. 1 H NMR (300MHz, DMSO-d 6 )δ 2.25-2.35(1H,m),2.35-2.45(1H,m),3.71(3H,s),3.82(3H,s),4.36-4.58(1H,m),4.56-4.74( 1H,m),4.84(1H,q),7.14(1H,d),7.99(1H,dd),8.63(1H,d),8.67(1H,d);m / z(ES+)[M+H]+=315.

[0155] Intermediate 81: 2-(2-fluoroethyl)-3-oxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylate methyl 20% Pd(OH) 2 / C (0.547 g, 0.78 mmol) was added to methyl 4-((4-fluoro-1-methoxy-1-oxobutan-2-yl)amino)-3-nitrobenzoate (Intermediate 80, 2.45 g, 7.80 mmol) in MeOH (300 mL) under hydrogen. The resulting mixture was stirred at room temperature for 16 h. The reaction was complete. The reaction mixture was filtered through celite. The filtrate was evaporated to give methyl 2-(2-fluoroethyl)-3-oxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylate (Intermediate 81, 1.9 g, 97%) as a grey solid. 1 H NMR (400MHz, DMSO-d 6 )δ1.91-2.19(2H,m),3.75(3H,s),4.03(1H,m),4.49-4.73(2H,m),6.73(1H,d),6.91(1H,d),7.35(1H,d),7.42(1H,dd),10.46(1H,s);m / z(ES + ) [M+H] + =253.

[0156] Intermediate 82: 2-(2-fluoroethyl)-3-oxo-3,4-dihydroquinoxaline-6-carboxylate methyl DDQ (1.83 g, 8.07 mmol) was added to methyl 2-(2-fluoroethyl)-3-oxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylate (Intermediate 81, 1.85 g, 7.33 mmol) in DCM (100 mL). The resulting mixture was stirred at room temperature for 3 h. The resulting mixture was removed under reduced pressure to give a brown solid. aq. aqueous NaHCO 3 A saturated aqueous solution (100 mL) was added to the solid and stirred at room temperature for 1 h. The precipitate was filtered and additional aqNaHCO 3 The solid was dried under vacuum to give methyl 2-(2-fluoroethyl)-3-oxo-3,4-dihydroquinoxaline-6-carboxylate (Intermediate 82, 1.8 g, 98%) as a grey solid. 1 H NMR (400MHz, DMSO-d 6)δ 3.23(2H,dt),3.89(3H,s),4.90(2H,dt),7.76-7.85(2H,m),7.88(1H,d),12.55(1H,s);m / z(ES + ) [M+H] + =251.

[0157] Intermediate 83: 3-(2-fluoroethyl)-7-(hydroxymethyl)quinoxalin-2(1H)-one A 1M solution of diisobutylaluminum hydride in THF (15.99 mL, 15.99 mmol) was added portionwise to methyl 2-(2-fluoroethyl)-3-oxo-3,4-dihydroquinoxaline-6-carboxylate (Intermediate 82, 1.0 g, 4.00 mmol) in THF (100 mL) at 0° C. The resulting mixture was stirred at room temperature for 16 h. The reaction mixture was quenched with saturated aqueous potassium sodium tartrate (20 mL) and MeOH (10 mL) at 0° C. The resulting mixture was stirred at room temperature for 1 h. The reaction mixture was filtered and washed with THF (30 mL×3). The organic layer was evaporated to give the crude product. The crude product was purified by reverse phase chromatography, eluent gradient 5 to 60% MeOH (water (0.4% HCO 2 The pure fractions were evaporated to dryness to afford 3-(2-fluoroethyl)-7-(hydroxymethyl)quinoxalin-2(1H)-one (intermediate 83, 0.49 g, 55.2%) as a brown solid. 1 H NMR (300MHz, DMSO-d 6 )δ 3.20(2H,dt),4.60(2H,d),4.90(2H,dt),5.41(1H,t),7.21(1H,dd),7.30(1H,d),7.68(1H,d),12.42(1H,s);m / z(ES+)[M+H] + =223.

[0158] Intermediate 84: 2-(2-fluoroethyl)-3-oxo-3,4-dihydroquinoxaline-6-carbaldehyde Dess-Martin periodinane (229 mg, 0.54 mmol) was added to 3-(2-fluoroethyl)-7-(hydroxymethyl)quinoxalin-2(1H)-one (Intermediate 83, 100 mg, 0.45 mmol) in DCM (3 mL). The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was evaporated to give the crude product. The crude product was purified by reverse phase chromatography, eluent gradient 5 to 30% MeCN (water (0.4% HCO 2 The pure fractions were evaporated to dryness to give 2-(2-fluoroethyl)-3-oxo-3,4-dihydroquinoxaline-6-carbaldehyde (intermediate 84, 93 mg, 94%) as a yellow solid. 1 H NMR (300MHz, DMSO-d 6 )δ 3.20-3.28(2H,m),4.90(2H,dt),7.74-7.80(2H,m),7.91(1H,d),10.06(1H,s),12.66(1H,s);m / z(ES+)[M+H] + =221.

[0159] Example 25: 5-[4-[[2-(2-fluoroethyl)-3-oxo-4H-quinoxalin-6-yl]methyl]piperazin-1-yl]-N-methyl-pyridine-2-carboxamide [ka] To 2-(2-fluoroethyl)-3-oxo-3,4-dihydroquinoxaline-6-carbaldehyde (Intermediate 84, 50 mg, 0.23 mmol) and N-methyl-5-(piperazin-1-yl)picolinamide (Intermediate 13, 50.0 mg, 0.23 mmol) in THF (3 mL) was added titanium isopropoxide (64.5 mg, 0.23 mmol). The resulting mixture was stirred at room temperature for 2 min. Sodium triacetoxyborohydride (192 mg, 0.91 mmol) was added. The resulting mixture was stirred at room temperature for 2 h. This was repeated with another batch and the two batches were combined for purification. The combined reaction mixture was purified by preparative HPLC (Column: XBridge Prep OBD C18 column, 30×150 mm, 5 μm; Mobile phase A: Water (10 mmol / L NH4 HCO 3 ), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 20B to 35B in 7 min; 254 / 210 nm; RT: 6.38). Fractions containing the desired compound were evaporated to dryness to give 5-[4-[[2-(2-fluoromethyl)-3-oxo-4H-quinoxalin-6-yl]methyl]piperazin-1-yl]-N-methyl-pyridine-2-carboxamide (Example 25, 4.83 mg, 2.54%) as a white solid. 1 H NMR (400MHz, DMSO-d 6 )δ 2.53-2.59(4H,m),2.78(3H,d),3.17(1H,t),3.23(1H,t),3.32-3.38(4H,m),3.63(2H,s),4.83(1H,t),4.95 (1H,t),7.25-7.32(2H,m),7.39(1H,dd),7.71(1H,d),7.83(1H,d),8.26(1H,d),8.37(1H,d),12.36(1H,s); 19 F NMR (376MHz, DMSO-d 6 ) δ -217.70; m / z(ES + ) [M+H] + =425. [ka]

[0160] Example 26: 6-Fluoro-5-[4-[[2-(2-fluoroethyl)-3-oxo-4H-quinoxalin-6-yl]methyl]piperazin-1-yl]-N-methyl-pyridine-2-carboxamide [ka] To 2-(2-fluoroethyl)-3-oxo-3,4-dihydroquinoxaline-6-carbaldehyde (Intermediate 84, 70 mg, 0.32 mmol) and 6-fluoro-N-methyl-5-(piperazin-1-yl)picolinamide (Intermediate 23, 76 mg, 0.32 mmol) in THF (3 mL) was added titanium isopropoxide (90 mg, 0.32 mmol). The resulting mixture was stirred at room temperature for 2 min. Sodium triacetoxyborohydride (269 mg, 1.27 mmol) was added. The resulting mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with MeOH (0.1 mL). The reaction mixture was evaporated to give the crude product. The crude product was purified by preparative HPLC (Column: XBridge Prep OBD C18 column, 30×150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH 4 HCO 3 ); mobile phase B: ACN; flow rate: 60 mL / min; gradient: 28B to 35B in 8 min; 254 / 210 nm; RT: 7). Fractions containing the desired compound were evaporated to dryness to give the crude product. The crude product was further purified by preparative HPLC (column: Xselect CSH OBD column 30 × 150 mm 5 μm, n; mobile phase A: water (0.1% HCO 2 H), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 5B to 20B in 7 min; 254; 220 nm; RT: 6.83). Fractions containing the desired compound were evaporated to dryness to give 6-fluoro-5-[4-[[2-(2-fluoroethyl)-3-oxo-4H-quinoxalin-6-yl]methyl]piperazin-1-yl]-N-methyl-pyridine-2-carboxamide (Example 26, 3.79 mg, 2.65%) as a yellow solid. 1 H NMR (400MHz, DMSO-d 6 )δ 2.55-2.60(4H,m),2.76(3H,d),3.14-3.25(6H,m),3.63(2H,s),4.89(2H,dt),7.24-7.31(2 H,m),7.57(1H,dd),7.70(1H,d),7.84(1H,d),8.24(0.174H,s),8.38(1H,d),12.37(1H,s); 19 F NMR (376MHz, DMSO-d6 ) δ -72.51,-217.71;(ES + ) [M+H] + =443. [ka]

[0161] Intermediate 86: 3-nitro-4-(4,4,4-trifluoro-1-methoxy-1-oxobutan-2-ylamino)benzoic acid methyl ester To methyl 4-fluoro-3-nitrobenzoate (2.0 g, 10.04 mmol) and methyl 2-amino-4,4,4-trifluorobutanoate hydrochloride (Intermediate 85, 2.2 g, 10.55 mmol) in DMF (20 mL) was added DIPEA (8.77 mL, 50.22 mmol). The resulting mixture was stirred at 50° C. for 10 h. The reaction mixture was diluted with EtOAc (100 mL) and saturated NaH 4 The organic layer was washed successively with aqueous Cl (100 mL x 1) and brine (100 mL x 4). 2 SO 4 Drying at 40° C., filtration and evaporation afforded the desired product, methyl 3-nitro-4-((4,4,4-trifluoro-1-methoxy-1-oxobutan-2-yl)amino)benzoate (Intermediate 86, 3.0 g, 85%) as a yellow solid. 1 H NMR (400MHz, DMSO-d 6 )δ 2.99-3.28(2H,m),3.73(3H,s),3.84(3H,s),5.18(1H,td),7.28(1H,d),8.01(1H,dd),8.65(1H,d),8.71(1H,d);m / z(ES + ) [M+H] + =351.

[0162] Intermediate 87: 3-Oxo-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroquinoxaline-6-carboxylate methyl 20% Pd(OH) 2 / C (0.601 g, 0.86 mmol) was added to methyl 3-nitro-4-((4,4,4-trifluoro-1-methoxy-1-oxobutan-2-yl)amino)benzoate (Intermediate 86, 3.0 g, 8.57 mmol) in MeOH (300 mL) under hydrogen. The resulting mixture was stirred at room temperature for 16 h. The reaction mixture was filtered through celite. The filtrate was evaporated to dryness to give methyl 3-oxo-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroquinoxaline-6-carboxylate (Intermediate 87, 2.3 g, 93%) as an off-white solid. 1 H NMR (400MHz, DMSO-d 6 )δ 2.64-2.83(2H,m),3.76(3H,s),4.32-4.37(1H,m),6.78(1H,d),6.90(1H,d),7.37(1H,d),7.43(1H,dd),10.64(1H,s);m / z(ES + ) [M+H] + =289.

[0163] Intermediate 88: 3-Oxo-2-(2,2,2-trifluoroethyl)-3,4-dihydroquinoxaline-6-carboxylate methyl DDQ (1.975 g, 8.70 mmol) was added to methyl 3-oxo-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroquinoxaline-6-carboxylate (Intermediate 87, 2.28 g, 7.91 mmol) in DCM (100 mL). The resulting mixture was stirred at room temperature for 3 hours. The resulting mixture was removed under reduced pressure to give a brown solid. aq. aqueous NaHCO 3 A saturated aqueous solution (100 mL) was added to the solid and stirred at room temperature for 1 h. The precipitate was filtered and additional aqNaHCO 3 The solid was dried under vacuum to give methyl 3-oxo-2-(2,2,2-trifluoroethyl)-3,4-dihydroquinoxaline-6-carboxylate (Intermediate 88, 2.2 g, 97%) as a brown solid. 1 H NMR (400MHz, DMSO-d 6)δ 3.88-3.98(5H,m),7.81(1H,dd),7.86-7.94(2H,m),12.75(1H,s);m / z(ES + ) [M+H] + =287.

[0164] Intermediate 89: 7-(hydroxymethyl)-3-(2,2,2-trifluoroethyl)quinoxalin-2(1H)-one A 1M solution of diisobutylaluminum hydride in THF (20.96 mL, 20.96 mmol) was added portionwise to methyl 3-oxo-2-(2,2,2-trifluoroethyl)-3,4-dihydroquinoxaline-6-carboxylate (Intermediate 88, 1.0 g, 3.49 mmol) in THF (100 mL) at 0° C. The resulting mixture was stirred at room temperature for 16 h. The reaction mixture was quenched with saturated aqueous potassium sodium tartrate (20 mL) and MeOH (10 mL) at 0° C. The resulting mixture was stirred for 1 h. The reaction mixture was filtered and washed with THF (30 mL×3). The organic layer was evaporated to give an off-white solid, which was purified by flash silica chromatography, eluent gradient 5 to 55% MeOH in water (0.4% HCO 2 The pure fractions were evaporated to dryness to afford 7-(hydroxymethyl)-3-(2,2,2-trifluoroethyl)quinoxalin-2(1H)-one (intermediate 89, 650 mg, 72.2%) as a yellow solid. 1 H NMR (300MHz, DMSO-d 6 )δ 3.88(2H,q),4.62(2H,d),5.45(1H,t),7.24(1H,dd),7.33(1H,d),7.73(1H,d),12.62(1H,s);m / z(ES + ) [M+H] + =259.

[0165] Example 27: N-Methyl-5-[4-[[3-oxo-2-(2,2,2-trifluoroethyl)-4H-quinoxalin-6-yl]methyl]piperazin-1-yl]pyridine-2-carboxamide [ka] 7-(hydroxymethyl)-3-(2,2,2-trifluoroethyl)quinoxalin-2(1H)-one (Intermediate 89, 50 mg, 0.19 mmol) was added to 33% HBr in AcOH (2 mL, 12.15 mmol). The resulting mixture was stirred at 80° C. for 2 h. The reaction mixture was evaporated in vacuum to give 7-(bromomethyl)-3-(2,2,2-trifluoroethyl)quinoxalin-2(1H)-one (crude product). This product was used directly in the next step without further purification. DIPEA (0.169 mL, 0.97 mmol) was added to 7-(bromomethyl)-3-(2,2,2-trifluoroethyl)quinoxalin-2(1H)-one (crude product) and N-methyl-5-(piperazin-1-yl)picolinamide (intermediate 13, 50 mg, 0.23 mmol) in NMP (2 mL). The resulting mixture was stirred at 80° C. for 1 h. The reaction mixture was concentrated and purified by preparative HPLC (column: Sunfire preparative C18 column, 30×150 mm, 5 μm; mobile phase A: water (0.1% HCO 2 H), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 10B to 25B in 7 min; 254 / 220 nm; RT: 6.57). Fractions containing the desired compound were evaporated to dryness to give N-methyl-5-[4-[[3-oxo-2-(2,2,2-trifluoroethyl)-4H-quinoxalin-6-yl]methyl]piperazin-1-yl]pyridine-2-carboxamide (Example 27, 41.5 mg, 46.6%) as an off-white solid. 1 H NMR (400MHz, DMSO-d 6 )δ 2.56(4H,m),2.78(3H,d),3.35(4H,m),3.65(2H,s),3.88(2H,q),7.29- 7.42(3H,m),7.79(2H,m),8.25-8.30(1H,m),8.38(1H,m),12.60(1H,br s); 19 F NMR (376MHz, DMSO-d 6 ) δ -61.53; m / z(ES + ) [M+H] + =461. [ka]

[0166] Example 28: 6-Fluoro-N-methyl-5-[4-[[3-oxo-2-(2,2,2-trifluoroethyl)-4H-quinoxalin-6-yl]methyl]piperazin-1-yl]pyridine-2-carboxamide [ka] 7-(hydroxymethyl)-3-(2,2,2-trifluoroethyl)quinoxalin-2(1H)-one (intermediate 89, 60 mg, 0.23 mmol) was added to 33% HBr in AcOH (2 mL, 12.15 mmol). The resulting mixture was stirred at 80° C. for 2 h. The reaction mixture was evaporated in vacuum to give 7-(bromomethyl)-3-(2,2,2-trifluoroethyl)quinoxalin-2(1H)-one (crude product). This product was used directly in the next step without further purification. DIPEA (0.203 mL, 1.16 mmol) was added to 7-(bromomethyl)-3-(2,2,2-trifluoroethyl)quinoxalin-2(1H)-one (crude product) and 6-fluoro-N-methyl-5-(piperazin-1-yl)picolinamide (intermediate 23, 60 mg, 0.25 mmol) in NMP (2 mL). The resulting mixture was stirred at 80° C. for 2 h. The resulting mixture was purified by preparative HPLC (column: Sunfire preparative C18 column, 30×150, 5 μm; mobile phase A: water (0.1% HCO 2 H), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 12B to 30B in 7 min; 254 / 220 nm; RT: 6.25). Fractions containing the desired compound were evaporated to dryness to give 6-fluoro-N-methyl-5-[4-[[3-oxo-2-(2,2,2-trifluoroethyl)-4H-quinoxalin-6-yl]methyl]piperazin-1-yl]pyridine-2-carboxamide (Example 28, 49.0 mg, 43.3%) as an off-white solid. 1 H NMR (400MHz, DMSO-d 6)δ 2.53-2.63(4H,m),2.76(3H,d),3.15-3.22(4H,m),3.65(2H,s),3.88(2H,q),7.28-7.35(2H ,m),7.57(1H,dd),7.76(1H,d),7.84(1H,dd),8.17(0.185H,s),8.38(1H,m),12.57(1H,s); 19 F NMR (376MHz, DMSO-d 6 ) δ -61.54, -72.52; m / z (ES + ) [M+H] + =479.

[0167] Example 29: 6-(Difluoromethyl)-5-[4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2-carboxamide [ka] DIPEA (330 μl, 1.89 mmol) was added to a stirred solution of 7-(chloromethyl)-3-ethyl-1,5-naphthyridine-2(1H)-one, HCl (Intermediate 17, 70 mg, 0.27 mmol), sodium iodide (4.05 mg, 0.03 mmol) and 6-(difluoromethyl)-N-methyl-5-piperazin-1-yl-pyridine-2-carboxamide, 2HCl (Intermediate 41, 102 mg, 0.30 mmol) in acetonitrile (2.4 mL) at 20° C., and the resulting solution was stirred at 50° C. for 3 h. The solvent was removed under vacuum and 50 mL of water followed by 3 mL of satNaHCO 3 was added. 3 was added. The mixture was extracted with ethyl acetate. After concentration, the resulting residue was purified by flash silica chromatography, eluent gradient 0 to 30% MeOH in DCM. The product fractions were concentrated to dryness under reduced pressure to give 6-(difluoromethyl)-5-[(4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2-carboxamide (Example 29, 52.0 mg, 42%) as a pale yellow solid. 1 H NMR (500MHz, DMSO-d 6)1.19(3H,t),2.54-2.58(2H,m),2.63(4H,br s),2.84(3H,d),3.03(4H,br m / z(ES + ) [M+H] + =457.

[0168] Example 30: 5-[4-[(7-ethyl-6-oxo-5H-1,5-naphthyridine-3-yl)methyl]piperazin-1-yl]-N-methyl-6(trifluoromethyl)pyridine-2-carboxamide [ka] DIPEA (330 μl, 1.89 mmol) was added to a stirred solution of 7-(chloromethyl)-3-ethyl-1,5-naphthyridine-2(1H)-one, HCl (Intermediate 17, 70 mg, 0.27 mmol), sodium iodide (4.05 mg, 0.03 mmol) and N-methyl-5-piperazin-1-yl-6-(trifluoromethyl)pyridine-2-carboxamide, 2HCl (Intermediate 38, 107 mg, 0.30 mmol) in acetonitrile (2.4 mL) at 20° C., and the resulting solution was stirred at 50° C. for 3 h. The solvent was removed under vacuum and 50 mL of water followed by 3 mL of satNaHCO 3 was added. The mixture was extracted with ethyl acetate. After concentration, the resulting residue was purified by flash silica chromatography, eluent gradient 0 to 30% MeOH in DCM. The product fractions were concentrated to dryness under reduced pressure to give 5-[4-[(7-ethyl-6-oxo-5H-1,5-naphthyridine-3-yl)methyl]piperazin-1-yl]-N-methyl-6(trifluoromethyl)pyridine-2-carboxamide (Example 30, 58.0 mg, 45%) as a pale yellow solid. 1 H NMR (500MHz, DMSO-d 6)1.19(3H,t),2.54-2.62(6H,m),2.83(3H,d),3.04(4H,br m / z(ES) + ) [M+H] + =475.

[0169] Example 31: 5-[4-[(7-ethyl-6-oxo-5H-1,5-naphthyridine-3-yl)methyl]piperazin-1-yl]-N,6-dimethyl-pyridine-2-carboxamide [ka] DIPEA (0.366 mL, 2.10 mmol) was added to a stirred solution of 7-(bromomethyl)-3-ethyl-1,5-naphthyridin-2(1H)-one (Intermediate 14, 80 mg, 0.30 mmol) and N,6-dimethyl-5-piperazin-1-yl-pyridine-2-carboxamide, 2HCl (Intermediate 45, 101 mg, 0.33 mmol) in acetonitrile (2 mL) at 20° C., and the resulting solution was stirred at 70° C. for 3 h. The solvent was removed under vacuum and 50 mL of water followed by 3 mL of satNaHCO 3 was added. The mixture was extracted with ethyl acetate. After concentration, the resulting residue was purified by flash silica chromatography, eluent gradient 0 to 30% MeOH in DCM. The product fractions were concentrated to dryness under reduced pressure to give 5-[(4-[(7-ethyl-6-oxo-5H-1,5-naphthyridine-3-yl)methyl]piperazin-1-yl]-N,6-dimethyl-pyridine-2-carboxamide (Example 31, 36.0 mg, 29%) as a pale yellow solid. 1 H NMR (500MHz, DMSO-d 6)1.19(3H,t),2.50(3H,s),2.54-2.57(2H,m),2.57-2.64(4H,m),2.81(3H,d),2.96(4H,br m / z(ES) + ) [M+H] + =421. [ka]

[0170] Intermediate 90: tert-Butyl 4-[6-(ethylcarbamoyl)-3-pyridyl]piperazine-1-carboxylate Ethanolamine in methanol (7 M, 7.78 mL, 15.56 mmol) was added to a solution of tert-butyl 4-(6-(methoxycarbonyl)pyridin-3-yl)piperazine-1-carboxylate (Intermediate 15, 500 mg, 1.56 mmol) and the resulting solution was stirred for 18 hours at 50° C. The solvent was removed under vacuum and the sample was further dried to give tert-butyl 4-[6-(ethylcarbamoyl)-3-pyridyl]piperazine-1-carboxylate (Intermediate 90, 0.495 g, 95%). 1 H NMR(500MHz,DMSO-d6)1.11(3H,t),1.43(9H,s),3.27-3.32(6H,m),3.44-3.52(4H,m),7.42(1H,dd),7.85(1H,d),8.28(1H,d),8.44(1H,br t).

[0171] Intermediate 91: N-Ethyl-5-piperazin-1-yl-pyridine-2-carboxamide HCl (0.473 mL, 15.58 mmol) in dioxane was added slowly to a stirred solution of tert-butyl 4-(6-(ethylcarbamoyl)pyridin-3-yl)piperazine-1-carboxylate (Intermediate 90, 521 mg, 1.56 mmol) in methanol (10 mL). The resulting solution was stirred at rt for 17 h. The reaction was concentrated and the solid was dried to give N-ethyl-5-piperazin-1-yl-pyridine-2-carboxamide, 2HCl (Intermediate 91, 421 mg, 88%); m / z (ES + ) [M+H] + =235

[0172] Example 32: N-Ethyl-5-[4-[(7-ethyl-6-oxo-5H-1,5-naphthyridine-3-yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2-carboxamide [ka] DIPEA (0.320 mL, 1.83 mmol) was added to a stirred solution of 7-(bromomethyl)-3-ethyl-1,5-naphthyridin-2(1H)-one (Intermediate 14, 70 mg, 0.26 mmol) and N-ethyl-5-piperazin-1-yl-pyridine-2-carboxamide, 2HCl (Intermediate 91, 89 mg, 0.29 mmol) in acetonitrile (2 mL) at 20° C., and the resulting solution was stirred at 70° C. for 3 h. The solvent was removed under vacuum and 50 mL of water followed by 3 mL of satNaHCO 3 was added. The mixture was extracted with ethyl acetate. After concentration, the crude product was purified by reverse phase chromatography (column: Xbrid C18) with an eluent gradient of 20 to 50% MeCN in water (containing 0.2% NH4OH). Pure fractions were evaporated to dryness to give N-ethyl-5-[4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl]pyridine-2-carboxamide (Example 32, 28.0 mg, 25%) as a white solid. 1 H NMR (500MHz, DMSO-d 6)1.10(3H,t),1.19(3H,t),2.52-2.55(2H,m),2.55-2.59(4H,m),3.26-3.30(2H,m),3.34(4H,br m / z(ES + )[M] + =420.

[0173] Example 4 - Form A In Example 4, 5-[4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2-carboxamide was obtained as a partially crystallized solid by evaporation of the methanol / dichloromethane solution under reduced pressure. The crystalline material thus obtained was characterized as crystalline Form A.

[0174] In cases where the degree of crystallinity was low, crystalline Form A was obtained by suspending 20 mg of the crude sample in 0.20 ml of water, methanol, ethanol, acetone, acetonitrile, tetrahydrofuran, ethyl acetate or other solvents at ambient temperature or 50° C. for 1 day.

[0175] Form A was analyzed by XRPD and the results are tabulated below (Table 1) and shown in FIG.

[0176] [Table 1]

[0177] Form A is characterized by exhibiting at least one of the following 2θ values ​​as measured using CuKα radiation: 8.3, 12.4, and 19.4°.

[0178] Form A was analyzed by thermal techniques. DSC analysis showed that Form A has a melting point with an onset at 254° C. and a peak at 255° C. A representative DSC trace of Form A is shown in FIG.

[0179] Biological assays The following test procedures can be used to determine the inhibitory properties of the compounds described herein.

[0180] PARP fluorescence anisotropy binding assay Recombinant full-length 6HIS-tagged PARP1 protein was incubated with 50 mM Tris pH 8, 0.001% TritonX100, 10 mM MgCl 2 Dilute to 6 nM in 150 mM NaCl, 50 mM Tris pH 8, 0.001% TritonX100, 10 mM MgCl 2 The mixture was incubated for 4 h with an equal volume of 2 nM fluorescent probe diluted in 150 mM NaCl. The final DMSO concentration of the probe was less than 1% (v / v).

[0181] Recombinant full-length PARP2 protein was incubated in 50 mM Tris pH 8, 0.001% TritonX100, 10 mM MgCl 2 Dilute to 6 nM in 150 mM NaCl, 50 mM Tris pH 8, 0.001% TritonX100, 10 mM MgCl 2 The mixture was incubated for 4 h with an equal volume of 2 nM fluorescent probe diluted in 150 mM NaCl. The final DMSO concentration of the probe was less than 1% (v / v).

[0182] Recombinant full-length PARP3 protein was incubated with 50 mM Tris pH 8, 0.001% TritonX100, 10 mM MgCl 2 Dilute 100 with 150 mM NaCl, 50 mM Tris pH 8, 0.001% TritonX100, 10 mM MgCl 2 The mixture was incubated for 4 h with an equal volume of 6 nM fluorescent probe diluted in 150 mM NaCl. The final DMSO concentration of the probe was less than 1% (v / v).

[0183] Recombinant full-length PARP5a protein was incubated with 50 mM Tris pH 8, 0.001% TritonX100, 10 mM MgCl 2 Dilute to 160 nM with 150 mM NaCl, 50 mM Tris pH 8, 0.001% TritonX100, 10 mM MgCl 2 The mixture was incubated for 4 h with an equal volume of 6 nM fluorescent probe diluted in 150 mM NaCl. The final DMSO concentration of the probe was less than 1% (v / v).

[0184] Recombinant full-length GST-tagged PARP6 protein was incubated with 50 mM Tris pH 8, 0.001% TritonX100, 10 mM MgCl 2 Dilute to 160 nM with 150 mM NaCl, 50 mM Tris pH 8, 0.001% TritonX100, 10 mM MgCl 2 The mixture was incubated for 4 h with an equal volume of 6 nM fluorescent probe diluted in 150 mM NaCl. The final DMSO concentration of the probe was less than 1% (v / v).

[0185] The fluorescence anisotropy of the probes when bound to the protein was measured using a BMG Pherastar FS© in the presence of test compounds or solvent controls and the effect on anisotropy was determined. 50 To determine the value, the % inhibition values ​​for the different test compound concentrations were calculated and fitted to a four parameter logistic plot. i is calculated using the Munson Rodbard equation defined in Anal Biochem. 1980 Sep 1;107(1):220-39. 50 The K value can be determined from the known K of the probe that binds to the relevant PARP protein. D Based on

[0186] hERG electrophysiological assay Electrophysiological recordings (all performed at RT) from stably transfected CHO hKv11.1 cells were obtained using a Nanion Syncropatch 768PE. Test compounds, vehicle or positive controls were added at different concentrations using six compound plates to allow for cumulative dosing of cells (10 mM, 3.167 mM, 1 mM, 0.3167 mM, 0.1 mM, 0.03167 mM). 600 μl of compound was resuspended in 90 μl of reference buffer (in mM: NaCl 80, KCl 4, CaCl 5, MgCl 1, NMDG Cl 60, D-glucose monohydrate 5, HEPES 10 (pH 7.4 HCl, 298 mOsm) to give final compound concentrations of 39.6 μM, 13.2 μM, 4.4 μM, 1.46 μM, 0.48 μM, 0.16 μM. For each Nanion Syncropatch 768PE run, extracellular solution (in mM: NaCl 80, KCl 4, CaCl 5, MgCl 1, NMDG Cl 60, D-glucose monohydrate 5, HEPES Current amplitudes in each cell in the presence of HBPS 10 (pH 7.4 HCl, 298 mOsm) are measured with all liquid additions made using the Syncropatch liquid handling system. 40 μL of external solution (in mM: HBPS, CaCl2 2, MgCl2 1 (pH 7.4, NaOH)) is added to a 384-well multi-hole medium-resistant recording chip and internal buffer (in mM: KF 130, KCl 20, MgCl2 1, EGTA 10, HEPES 10, Escin 25 (all Sigma-Aldrich; pH 7.2-7.30, 10 M KOH, 320 mOsm) is perfused over the bottom of the plate. 20 μL of cells maintained at approximately 9 °C are dispensed into each well of the chip at a density of 1e6 cells / ml, followed by 20 μL of seal enhancer (in mM: NaCl 80, KCl 3, CaCl Dispense 40 μL of compound concentration 1 (0.16 μM) and perform a "real-time" recording, exposing for 3 minutes, followed by removal of 40 μL. Dispense 40 μL of compound concentration 1 (0.16 μM) and perform a "real-time" recording, allowing 3 minutes of exposure, followed by removal of 40 μL. Dispense 40 μL of compound concentration 1 (0.16 μM) and perform a "real-time" recording, allowing 3 minutes of exposure, followed by removal of 40 μL.This process is repeated for five additional subsequent compound plates to generate a cumulative curve analysis. All data is leak subtracted and 2 pulses to -80 mV 100 ms with a 100 ms delay. Outward K+ currents are then elicited by a voltage step from a holding potential of -90 mV to +60 mV, with each pulse delivered at a frequency of 2 Hz with an interpulse interval of 15 s.

[0187] PARP proliferation test (4-day compound administration) DLD1 and BRCA2(- / -) DLD1 cells were harvested in complete medium at a density of 1.875E4 cells / ml and 6.25E4 cells / ml, respectively, and seeded at 40 μL / well into 384-well plates (Greiner, Kremsmunster, Austria; 781090) using a Multidrop Combi, then incubated at 37°C, 5% CO 2 The next day (day 1), sytox green (5 μl, 2 μM) and saponin (10 μl, 0.25% stock) are added to the day 0 plates using a Multidrop Combi, the plates are sealed using black adhesive lids, and incubated at RT for >3 h. Cells were imaged using a Cell Insight (Thermo Fisher) fitted with a 4× objective. Test compounds were added using an Echo 555 and incubated at 37° C., 5% CO. 2 Place in an incubator maintained at 4°C for 4 days. On day 5, add sytox green (5 μl, 2 μM) followed by saponin (10 μl, 0.25% stock) to the plate and seal the plate using a black adhesive lid and incubate at RT for >3 hours. Read all cells on a Cell Insight with a 4× objective. Proliferation rate is determined in Genedata by evaluating the total cell number output from Cell Insight for day 0 and day 5 plates.

[0188] [Table 2]

[0189]

Table 3

Claims

1. Formula (Ia) 【Chemistry 1】 (In the formula, R １ is C １～４ is alkyl, R ２ H, halo, C １～４ Alkyl and C １～４ fluoroalkyl; R ３ is H or C １～４ is alkyl, R ４ is H) or a pharma- ceutically acceptable salt thereof.

2. R ２ or a pharma- ceutically acceptable salt thereof, according to claim 1, wherein R is selected from difluoromethyl, trifluoromethyl, or methyl.

3. R ２ is H or halo, or a pharma- ceutically acceptable salt thereof.

4. R １ is ethyl, R ２ is selected from H, chloro and fluoro; R ３ or a pharma- ceutically acceptable salt thereof.

2. The compound of claim 1, wherein:

5. 5-[4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2-carboxamide, 5-[4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl]-6-fluoro-N-methyl-pyridine-2-carboxamide, 6-chloro-5-[4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2-carboxamide, and 5-[4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl]pyridine-2-carboxamide The compound according to claim 1, selected from or a pharma- ceutically acceptable salt thereof.

6. The compound has the following structure: The compound of claim 1, which is 5-[4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2-carboxamide having the formula: or a pharma- ceutically acceptable salt thereof.

7. The compound has the following structure:

2. The compound of claim 1, which is 5-[4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2-carboxamide having the formula:

8. 6-(difluoromethyl)-5-[4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2-carboxamide, 5-[4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl]-N-methyl-6(trifluoromethyl)pyridine-2-carboxamide, 5-[4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl]-N,6-dimethyl-pyridine-2-carboxamide, and N-Ethyl-5-[4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl]pyridine-2-carboxamide The compound according to claim 1, selected from or a pharma- ceutically acceptable salt thereof.

9. A pharmaceutical composition comprising a compound according to any one of claims 1 to 8 or a pharma- ceutically acceptable salt thereof and at least one pharma- ceutically acceptable diluent, excipient or inert carrier.

10. A pharmaceutical agent comprising the compound according to any one of claims 1 to 8 or a pharma- ceutically acceptable salt thereof.

11. The method of claim 10 for treating cancer in a cancer patient.

12. The agent of claim 11, wherein the cancer is deficient in the homologous recombination (HR)-dependent DNA double-strand break (DSB) repair pathway.

13. The method of claim 11 , wherein the cancer comprises one or more cancer cells that have a reduced or lost ability to repair DNA DSBs by HR compared to normal cells.

14. The method of claim 11 or 12, wherein the cancer cells have a BRCA1 or BRCA2 deficient phenotype.

15. The method of claim 14, wherein the cancer cells are deficient in BRCA1 or BRCA2.

16. The method of any one of claims 12 to 15, wherein the patient is heterozygous for a mutation in a gene encoding a component of the HR dependent DNA DSB repair pathway.

17. The method of claim 16, wherein the patient is heterozygous for a mutation in BRCA1 and / or BRCA2.

18. The drug according to any one of claims 11 to 17, wherein the cancer is selected from any one of breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, blood cancer, gastrointestinal cancer, and lung cancer.

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