Polycyclic mthfd2 inhibitors and uses thereof

Abstract

The present invention relates to novel polycyclic compounds of general Formula (I) wherein X represents N-R5, O, S, or S(O)2; Y represents optionally substituted aryl or heteroaryl; and R1, R2, R3, R4 and R5 represent various groups. The compounds of the invention are useful as inhibitors of the MTHFD2 enzyme, in particular for use in the treatment of diseases associated with MTHFD2 enzyme such as, for example, auto-immune diseases, inflammatory diseases, and proliferative diseases.

Description

POLYCYCLIC MTHFD2 INHIBITORS AND USES THEREOFFIELD OF INVENTION

[0001] The present invention relates to novel polycyclic compounds useful as inhibitors of the MTHFD2 enzyme, in particular for use in the treatment of diseases associated with MTHFD2 enzyme such as, for example, an auto-immune disease, an inflammatory disease, or a proliferative disease.BACKGROUND OF INVENTION

[0002] One-carbon metabolism is a central pathway in both physiological and pathological contexts. This pathway consists of a complex set of compartmentalized reactions primarily localized in the cytosol and mitochondria. It is essential for the synthesis of metabolites required for multiple biological processes, such as de novo purine and pyrimidine biosynthesis, amino acid homeostasis, synthesis of S-adenosylmethionine (SAM) required for DNA and histone methylation, and the maintenance of the redox state of the cell. The one-carbon (1-C) folate pathway generates 1-C units from serine, which are used for de novo purine synthesis, thymidine and methionine production. Folic acid derivatives act as carriers for transfer of the 1-C Units between the enzymes involved in the metabolic transformations. MTHFD2, is a bifunctional enzyme localized to the mitochondria which catalyses two reactions in the mitochondrial 1-C pathway. The dehydrogenase step converts the substrate methylenetetrahydrofolate to methenyltetrahydrofolate, upon generation of NAD(P)H from NAD(P)+. The subsequent cyclohydrolase step generates NIO-formyl-tetrahydrofolate from methenyltetrahydrofolate by a hydrolytic ring cleavage reaction.

[0003] Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) is overexpressed in cancer cells and barely expressed in most healthy adult tissues except some immune cells. MTHFD2 is highly upregulated across many cancers relative to normal tissues and genetic silencing of MTHFD2 slows proliferation across a number of cancer cell lines independent of tissue of origin. MTHFD2 is overexpressed in breast cancer andassociated with poor clinical characteristics and promotes cellular features connected with metastatic disease, thus implicating MTHFD2 as a potential target to block breast cancer cell migration and invasion. The overexpression of MTHFD2 could provide the basis for biosynthesis of pyrimidine and purine during rapid proliferation of cancer cells which is widely needed for the growth of many tumours: colorectal, leukaemia, and prostate. Inhibition of MTHFD2 leads to imbalance of NADPH and redox homeostasis, which inhibits tumorigenic proliferation and growth and increases cancer cell death under hypoxia. The knockdown of MTHFD2 leads to decreased expression of cell cycle genes suggesting interference with cell cycle progression.

[0004] Current treatments for cancer are not effective for all patients with a diagnosed disease. This also includes a large proportion of patients that experience adverse effects from treatments with current standard of care therapy or where resistance to therapy exist already at start of treatment or is developed over time. There is therefore a clear need for alternative treatments for cancers which may overcome the limitations of current treatments.

[0005] Because of the low expression of MTHFD2 in most adult tissues, targeting MTHFD2 is unlikely to produce significant side effects and MTHFD2 could be a highly effective and safe therapeutic strategy to reduce cancer cell growth and survival.

[0006] On the other hand, recent research found that MTHFD2 was consistently overexpressed in many inflammatory diseases, including ulcerative colitis, Celiac’s disease, systemic lupus erythematosus (SLE), psoriatic arthritis, Sjogren’s syndrome, and multiple sclerosis (MS). Inhibition of MTHFD2 promotes regulatory CD4 T cell (Treg) activity, which suppresses the immune response. MTHFD2 has been shown to regulate de novo purine synthesis and signal transduction in activated T cells, promoting proliferation and the production of inflammatory cytokine. MTHFD2 deficiency can reduce disease degree in various inflammatory condition models. T-cell dependent Delayed Type Hypersensitivity (DTH) mouse models trials showed that MTHFD2 inhibitors did not increase inflammatory symptoms in mice, and increase animal weight, suggesting that inhibiting MTHFD2 has a protective effect on inflammation extending to B cell function. In another different model of inflammatorybowel disease (IBD) mice receptor of CD4AMthfd2 T cells continued gaining body weight and the number and frequency of CD4AMthfd2 T cells in spleen and mesenteric lymph nodes (MLNs) were significantly reduced. Multiple sclerosis (MS) is an inflammatory demyelinating disease originating in the central nervous system. Compared to control group, Experimental Autoimmune Encephalomyelitis (EAE) model using with MTHFD2 inhibitors (MTHFD2i) resulted in significantly lower disease degree and cumulative clinical score. The infiltration of CD4st, CD4+ and CD8+ cells in the spinal cord of mice was significantly reduced after MTHFD2i treatment.

[0007] Similarly, the treatment of autoimmune conditions, such as rheumatoid arthritis (RA), is not effective for all patients with diagnosed disease. This includes a large proportion of patients that experience adverse side-effects from treatments with biological agents, as represented by the therapy with TNF-a inhibitors, or from treatment with methotrexate and COX-2 inhibitors. The cause and pathology of autoimmune and (hyper) inflammatory conditions, including multiple sclerosis (MS), inflammatory bowel disease (IBD) and the majority of less prevalent autoimmune conditions, are far from understood and many patients suffer from a disease that current treatments do not have the capacity to treat or ameliorate. In autoimmune conditions it is vital to control the activated auto- reactive lymphocytes while preferably preserving their normal counterparts. The sensitivity of T-cell to MTHFD2 inhibition might provide an efficacious strategy of immunotherapy for CD4+ T-cell-driven inflammation and in general inflammatory diseases and produce fewer adverse reactions than presently usable therapeutics. Therefore, there is a clear need for new treatment that can overcome the present limitation of existing drugs and ameliorates the patient life. This is why targeting MTHFD2 by small molecules inhibitor could represent a promising novel therapy for inflammatory diseases either as monotherapy or in combination with other drugs that are currently on the market.

[0008] Previous findings suggest that targeting of MTHFD2 by small molecule inhibitors could be a useful as therapeutic agent. MTHFD2 inhibitors or their use have been recently reviewed (CUTHBERTSON, C. et al . “A Review of Small-Molecule Inhibitors of One-Carbon Enzymes: SHMT2 and MTHFD2 in the Spotlight”, ACSPharmacology & Translational Science, 2021, Vol. 4, pp. 624-646) or described in the following patents and papers. International patent application WO 2017 / 106352 Al (RAZE THERAPEUTICS INC) describes inhibitors of MTHFD2 based on a caffeine- derived core and uses thereof. International patent application WO 2017 / 023894 Al (RAZE THERAPEUTICS INC) describes indole derivatives as MTHFD2 inhibitors and uses thereof. International patent application WO 2019 / 201991 Al (THOMAS HELLED AYS STIFTELSE FOER MEDICINSK FORSKNING) describes 2,6-diamino- 3,4-dihydropyrimidin-4-one as effective inhibitors of MTHFD2. GUSTAFSSON, R. et al. (“Crystal Structure of the Emerging Cancer Target MTHFD2 in Complex with a Substrate-Based Inhibitor.”, Cancer Research, 2017, Vol. 77, No. 4, pp. 937-948) describes the MTHFD1 inhibitor “LY345899” as an MTHFD2 inhibitor. BONAGAS, N. et al. (“Pharmacological targeting of MTHFD2 suppresses acute myeloid leukemia by inducing thymidine depletion and replication stress.”, Nature Cancer, 2022, Vol. 3, pp. 156-172. doi: 10.1038 / s43018-022-00331-y) and CHANG, H.-H. et al (“Development of Potent and Selective Inhibitors of Methylenetetrahydrofolate Dehydrogenase 2 for Targeting Acute Myeloid Leukemia: SAR, Structural Insights, and Biological Characterization.”, Journal of Medicinal Chemistry, 2024, doi.org / 10.1021 / acs.jmedchem.4c01775) report 2,6-diamino-3,4-dihydropyrimidin-4- one inhibitors with activities against acute leukaemia cell lines. KAWAI, J. et al. (Kawai, J. et al. : “Discovery of a Potent, Selective, and Orally Available MTHFD2 Inhibitor (DS 18561882) with in Vivo Antitumor Activity.”, Journal of Medicinal Chemistry, 2019, Vol. 62, pp. 10204-10220; Kawai, J. et al “Structure-Based Design and Synthesis of an Isozyme-Selective MTHFD2 Inhibitor with a Tricyclic Coumarin Scaffold.”, ACS Medicinal Chemistry Letters, Vol. 10, pp. 893-898) describes tricyclic coumarins with activities against breast cancer cell lines.SUMMARY

[0009] It was surprisingly found out by the inventors that novel polycyclic compounds of formula (I) as described herein are potent inhibitors of the MTHFD2 enzyme, and therefore useful for the treatment of diseases associated with MTHFD2 enzyme.

[0010] The present invention relates to a compound of formula (I)or a pharmaceutically acceptable salt and / or solvate thereof; wherein R1, R2, R3, R4, X and Y are each independently as defined hereinafter or in the claims.

[0011] The present invention further relates to pharmaceutical composition comprising a compound according to the invention and at least one pharmaceutically acceptable carrier.

[0012] The present invention further relates to a compound according to the invention or a pharmaceutical composition according to the invention for use as a medicament. The present invention further relates to a compound according to the invention or a pharmaceutical composition according to the invention for use in the treatment of an auto-immune disease, an inflammatory disease, or a proliferative disease.

[0013] The present invention further relates to a process for manufacturing a compound according to the invention comprising a step of reaction of a bromophenyl-imino-piperidine-carboxylate with a / V-acetyl-oxopiperidine-carboxylate in acidic conditions.DEFINITIONS

[0014] In the present invention, the following terms have the following meanings.Chemical definitions

[0015] Where chemical substituents are combinations of chemical groups, the point of attachment of the substituent to the molecule is by the last chemical group recited on the right of the name of the substituent. For example, an arylalkyl substituent is linked to the rest of the molecule through the alkyl moiety and it may by represented as follows: “aryl-alkyl-”. Unless otherwise indicated, the compounds were named using Marvin Sketch (ChemAxon Ltd, Hungary).

[0016] The definitions herein referring to the optional or mandatory substitution of a specified group apply both to the substituted group considered as such or to the same group comprised in another chemical moiety, which can both be substituted as set forth herein. For example, / U represents hydrogen, (Ci-Cs) alkyl, (Ci-Cs) alkyl-O- or cycloalkyl-(Ci-Cs) alkyl-NH-; wherein the alkyl is optionally substituted by at least one I " means that any alkyl group present in the structure of Rxmay optionally substituted by at least one F, including said (Ci-Cs) alkyl as such (e.g., CF3), the alkyl comprised in said (Ci-Cs) alkyl-O- (e.g., OCF3) and the alkyl comprised in said cycloalkyl-(Ci-C8) alkyl-NH- (e.g., cyclopropyl-CH2-CHF-CH2-NH-).

[0017] “Alkoxy” refers to any -O-alkyl group.

[0018] “Alkyl” refers to a saturated linear or branched hydrocarbon chain, typically comprising from 1 to 16 carbon atoms, preferably from 1 to 12 carbon atoms, more preferably from 1 to 8 carbon atoms, furthermore preferably from 1 to 6 carbon atoms, furthermore preferably from 1 to 4 carbon atoms. Alkyl groups may be monovalent or polyvalent (i.e., “alkylene” groups, which are divalent alkyl groups, are encompassed in “alkyl” definition). Non-limiting examples of alkyl groups include methyl, ethyl, / / -propyl, z-propyl, / / -butyl, z-butyl, .s-butyl and Lbutyl, pentyl and its isomers (e.g., / / -pentyl, / .w-pentyl), and hexyl and its isomers (e.g., / / -hexyl, / .w-hexyl). Particular examples of alkyl groups include methyl, ethyl, / / -propyl, / -propyl, / / -butyl, s-butyl and Lbutyl (including methylene, ethylene, / / -propylene, / / -butylene and / / -butylene).

[0019] “Alkenyl” refers to a monovalent unsaturated linear or branched hydrocarbyl group comprising at least one carbon-carbon double bond(s); and typically comprising from 2 to 6 carbon atoms, preferably from 2 to 4 carbon atoms, still more preferably 2 or 3 carbon atoms. Non-limiting examples of alkenyl groups include ethenyl, 2-propenyl,2-butenyl, 3-butenyl, 2-pentenyl and its isomers, 2-hexenyl and its isomers, and2.4-pentadienyl.

[0020] “Alkynyl” as used herein refers to a monovalent unsaturated hydrocarbyl group comprising at least one carbon-carbon triple bond(s); and typically comprising from 2 to 6 carbon atoms, preferably from 2 to 4 carbon atoms, still more preferably 2 or 3 carbon atoms. Non-limiting examples of alkynyl groups include ethynyl, 2-propynyl, 2-butynyl,3-butynyl, 2-pentynyl and its isomers, 2-hexynyl and its isomers-and the like.

[0021] “Aryl” refers to a cyclic, polyunsaturated, aromatic hydrocarbyl group comprising at least one aromatic ring and comprising from 5 to 12 carbon atoms, preferably from 6 to 10 carbon atoms. Aryl groups may be monovalent or polyvalent (e.g., divalent). Aryl groups may have a single ring (e.g., phenyl) or multiple aromatic rings fused together (e.g., naphthyl) or linked covalently. The aromatic ring may optionally include one to two additional rings (either cycloalkyl, heterocycloalkyl or heteroaryl) fused thereto. This definition of “aryl” encompasses the partially hydrogenated derivatives of the carbocyclic systems enumerated herein, as long as at least one ring is aromatic. Non-limiting examples of aryl groups include phenyl, biphenyl, biphenylenyl, 5- or 6-tetralinyl, naphthalen-1- or -2-yl, 4-, 5-, 6 or 7-indenyl, 1- 2-, 3-, 4- or 5-acenaphthylenyl, 3-, 4- or 5-acenaphthenyl, 1- or 2-pentalenyl,4- or 5-indanyl, 5-, 6-, 7- or 8-tetrahydronaphthyl, 1,2,3,4-tetrahydronaphthyl,1.4-dihydronaphthyl, and 1-, 2-, 3-, 4- or 5-pyrenyl. A particular example of aryl group is phenyl.

[0022] “Cycloalkyl” refers to a cyclic alkyl group, typically comprising from 3 to 15 carbon atoms, preferably from 3 to 12 carbon atoms, more preferably from 3 to 8 carbon atoms, further more preferably from 3 to 6 carbon atoms. Cycloalkyl groups may be monovalent or polyvalent (e.g., divalent). This definition of “cycloalkyl” encompasses polycyclic cycloalkyls (e.g., bicycles) and bridged cycloalkyl structures, including cycles bound together through one atom (“spiro”) or through two atoms. This definition of“cycloalkyl” encompasses cycloalkyls including a cyclic alkyl group substituted by at least one non-cyclic alkyl, such as, for example, a (Ci-Cs) alkyl (preferably, (C1-C4) alkyl, (e.g., methyl). Non-limiting examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycoheptyl, cyclooctanyl, cyclononanyl, cyclodecanyl, norbomyl, adamantyl, bicyclo[2.2.2]octanyl, bicyclo[4.4.0]decanyl, bicyclo[3.2.1]octanyl, bicyclo[3.3.1]nonanyl, bicyclo[2.1.1]hexane,2,3-dihydro-lH-indenyl, 1,2,3,4-tetrahydronaphthalenyl, decahydronaphthalenyl,1,2,3,4-tetrahydronaphthalenyl, and octahydropentalenyl.

[0023] “Cx-Cy” or “(Cx-Cy)” preceding the name of a group means that the group comprises from x to y carbon atoms, in accordance to common terminology in the chemistry field.

[0024] “Haloalkyl” refers to an alkyl substituted by at least one halogen. Typically, the halogen is fluorine. Non-limiting examples of haloalkyl groups include trifluoromethyl, difluoromethyl, and fluoromethyl.

[0025] “Halogen” or “halo” are synonyms and refer to a fluorine, chlorine, bromine, or iodine atom.

[0026] “Heteroaryl” refers to aromatic rings or aromatic ring systems comprising from 5 to 15 carbon atoms, preferably from 4 to 12 carbon atoms, more preferably from 3 to 10 carbon atoms, having one or two rings that are fused together or linked covalently, wherein at least one ring is aromatic, and wherein one or more carbon atoms in one or more of these rings is replaced by oxygen, nitrogen and / or sulphur atoms. Heteroaryl groups may be monovalent or polyvalent (e.g., divalent). The nitrogen and sulphur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quaternized (e.g., the heteroatom is substituted by oxo (=0) for sulphur atom or (— >0) for nitrogen atom). This definition of “heteroaryl” encompasses the partially hydrogenated derivatives of the carbocyclic systems enumerated herein, as well as ring systems including one or more fused non-aromatic cycloalkyl and / or heterocycloalkyl ring(s), as long as at least one ring is aromatic. The heteroaryl can be bound to another group or molecule through a carbon atom, i.e., the binding atom is not selected among the heteroatoms included therein. Alternatively, the heteroaryl can be bound to another groupor molecule through one of the heteroatoms included therein. When substituted by one or more other group(s), an heteroaryl may be substituted either through a carbon atom or through a heteroatom (e.g., nitrogen), unless otherwise specified. Non-limiting examples of heteroaryl groups include pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, oxatriazolyl, thiatriazolyl, pyridinyl, pyrimidyl, pyrazinyl, pyridazinyl, oxazinyl, dioxinyl, thiazinyl, triazinyl, tetrazinyl, imidazo[2,l-b][l,3]thiazolyl, thieno[3,2-b]furanyl, thieno[3,2-b]thiophenyl, thieno[2,3-d][l,3]thiazolyl, thieno[2,3-d]imidazolyl, tetrazolo[l,5-a]pyridinyl, indolyl, indolizinyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, isobenzothiophenyl, indazolyl, benzimidazolyl, 1,3-benzoxazolyl, 1,2-benzisoxazolyl, 2,1-benzisoxazolyl,1.3 -benzothiazolyl, 1,2-benzoisothiazolyl, 2,1 -benzoisothiazolyl, benzotriazolyl,1.2.3-benzoxadiazolyl, 2,1,3-benzoxadiazolyl, 1,2,3-benzothiadiazolyl,2.1.3-benzothiadiazolyl, thienopyridinyl, purinyl, imidazo[l,2-a]pyridinyl,6-oxo-pyridazin- 1 (6H)-yl, 2-oxopyridin- 1 (2H)-yl, 6-oxo-pyridazin- 1 (6H)-yl, 2-oxopyridin-l(2H)-yl, 1,3-benzodioxolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl and quinoxalinyl. Non-limiting examples of heteroaryl groups comprising at least one fused non-aromatic ring include 2,3-dihydrobenzofuranyl, benzo / t / / [l,3]dioxolyl, indolinyl, 2,3-dihydrobenzo / >7[l,4]dioxinyl,3.4-dihydro-2Z7-benzo Z>7[l,4]oxazinyl, 1,2,3,4-tetrahydroquinoxaline,3.4-dihydro-2J / -benzo[b] [ 1 ,4] thi azine and 2,3 -dihydrobenzofb] [ 1 ,4]oxathiine.

[0027] “Heterocycloalkyl” refers to non-aromatic, fully saturated or partially unsaturated cyclic groups that have at least one heteroatom in at least one carbon atom-containing ring, typically comprising from 2 to 15 carbon atoms, preferably from 2 to 11 carbon atoms, more preferably from 2 to 7 carbon atoms, furthermore preferably from 2 to 6 carbon atoms. Heterocycloalkyl groups may be monovalent or polyvalent (e.g., divalent). Heterocycloalkyl groups are typically 3- to 7-membered, preferably 5- or 6-membered. Heterocycloalkyl are typically monocyclic or bicyclic, preferably monocyclic. This definition encompasses polycyclic heterocycloalkyls (e.g., bicycles) and bridged heterocycloalkyl structures, including cycles bound together through one atom (“spiro”) or through two atoms. The nitrogen and sulphur heteroatoms mayoptionally be oxidized and the nitrogen heteroatoms may optionally be quatemized (e.g., the heteroatom is substituted by oxo (=0) for sulphur atom or (— >0) for nitrogen atom). The heterocycloalkyl can be bound to another group or molecule through a carbon atom, i.e., the binding atom is not selected among the heteroatoms included therein. Alternatively, the heterocycloalkyl can be bound to another group or molecule through one of the heteroatoms included therein. When substituted by one or more other group(s), an heterocycloalkyl may be substituted either through a carbon atom or through a heteroatom (e.g., nitrogen), unless otherwise specified. Non-limiting examples of heterocycloalkyl include aziridine, pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, azepane, azocane, octahydro-777-isoindole, decahydroisoquinoline, tetrahydrofuran, tetrahydropyran, tetrahydroisoquinoline(e.g., 1,2,3,4-tetrahydroisoquiline), hexahydropyridazine, hexahydropyrazine, hexahydropyrimidine, decahydroquinoline, octahydropyrrolo[3,4-c]pyrrole, isoindoline, 1,2,3,4-tetrahydroquinoline, oxetane,3-phenyl-4,5-dihydro-l,2,4-oxadiazol-5-one, 4,4-dimethyl-2-phenyl-4,5-dihydro-777- imidazol-5-one, 5-methyl-5-phenylimidazolidine-2, 4-dione,2,3-dihydro-l,3-benzoxazol-2-one, dimethyl(phenylimino)-k6-sulfanone, 2,5-dimethyl- 5-phenyl-4,5-dihydro-777-imidazol-4-one, 2,5-dimethyl-5-phenyl-4,5-dihydro-lH- imidazol -4-one, 4-phenyl-2,3-dihydro-l,3-thiazol-2-one, [cyclopropyl(phenyl)imino-k6- sulfanyl]one, methyl [methyl(oxo)phenyl-k6-sulfanylidene]amine, and1 ,3 -dihydro-2-benzofuran- 1 -one.

[0028] “Prodrug” refers to a pharmacologically acceptable derivative of a therapeutic agent (e.g., a compound according to the invention) whose in vivo biotransformation product is the therapeutic agent (active drug). Prodrugs are typically characterized by increased bioavailability and are readily metabolized in vivo into the active compounds. Non-limiting examples of prodrugs include amide prodrugs and carboxylic acid ester prodrugs.

[0029] “Solvate” refers to a molecular complex comprising a compound of the invention and contains stoichiometric or sub-stoichiometric amounts of one or more pharmaceutically acceptable solvent molecule such as ethanol. The term “hydrate” refers to when said solvent is water.General definitions

[0030] “About” is used herein to mean approximately, roughly, around, or in the region of. The term “about” preceding a figure means plus or less 10 % of the value of the figure. When the term “about” is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the numerical values set forth by 10%.

[0031] “Administration”, or a variant thereof (e.g., “administering”), means providing the active agent or active ingredient, alone or as part of a pharmaceutically acceptable composition, to the patient in whom / which the condition, symptom, or disease is to be treated or prevented.

[0032] “Comprise” or a variant thereof (e.g., “comprises”, “comprising”) is used herein according to common patent application drafting terminology. Hence, “comprise” preceded by an object and followed by a constituent means that the presence of a constituent in the object is required (typically as a component of a composition), but without excluding the presence of any further constituent(s) in the object. Moreover, any occurrence of “comprise” or a variant thereof herein also encompasses narrower expression “substantially consist of’, further narrower expression “consist of’ and any variants thereof (e.g., “consists of’, “consisting of’), and may be replaced thereby, unless otherwise stated.

[0033] “Human” refers to a male or female human subject at any stage of development, including neonate, infant, juvenile, adolescent and adult.

[0034] “Patient” refers to a subject who / which is awaiting the receipt of, or is receiving medical care or was / is / will be the object of a medical procedure, or is monitored for the development of the targeted disease or condition.

[0035] “Pharmaceutically acceptable carrier” refers to an excipient that does not produce an adverse, allergic or other untoward reaction when administered to an animal, preferably a human. It includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. For human administration, preparations should meet sterility, pyrogenicity, general safetyand purity standards as required by regulatory offices, such as, for example, FDA Office or EMA.

[0036] “Pharmaceutically acceptable” means that the ingredients of a composition are compatible with each other and not deleterious to the subject to which / whom it is administered.

[0037] “Pharmaceutical composition” refers to a composition comprising at least one therapeutic agent (e.g., a compound according to the present invention) and at least one pharmaceutically acceptable carrier.

[0038] “Pharmaceutical vehicle” refers to a carrier or inert medium used as solvent or diluent in which the pharmaceutically active agent is formulated and / or administered. Non-limiting examples of pharmaceutical vehicles include creams, gels, lotions, solutions and liposomes.

[0039] “Selected from” is used herein according to common patent application drafting terminology, to introduce a list of elements among which one or more item(s) is (are) selected. Any occurrence of “selected from” in the specification may be replaced by “selected from the group comprising or consisting of’ and reciprocally without changing the meaning thereof.

[0040] “Subject” refers to an animal, typically a warm-blooded animal, preferably a mammal, more preferably a primate, furthermore preferably a human. In one embodiment, the subject is a “patient” as defined herein. In one embodiment, the subject is affected, preferably is diagnosed, with a disease. In one embodiment, the subject is at risk of developing a disease. Examples of risks factor include, but are not limited to, genetic predisposition, or familial history of the disease.

[0041] “Therapeutic agent”, “active pharmaceutical ingredient” and “active ingredient” refer to a compound for therapeutic use and relating to health. Especially, a therapeutic agent may be indicated for treating a disease. An active ingredient may also be indicated for improving the therapeutic activity of another therapeutic agent.

[0042] “Therapeutically effective amount” (or more simply an “effective amount”) refers to the amount of active agent or active ingredient that is sufficient to achieve the desired therapeutic or prophylactic effect in the patient to which / whom it is administered.

[0043] “Treating” or “treatment” or “alleviation” refers to both therapeutic treatment and prophylactic or preventative measures; wherein the object is to prevent or slow down (lessen) the targeted pathologic condition or disorder. Those in need of treatment include those already with the disorder as well as those prone to have the disorder or those in whom the disorder is to be prevented. A subject or mammal is successfully "treated" for an infection if, after receiving a therapeutic amount of an antibody according to the methods of the present invention, the patient shows observable and / or measurable reduction in or absence of one or more of the following: reduction in the number of pathogenic cells; reduction in the percent of total cells that are pathogenic; and / or relief to some extent, one or more of the symptoms associated with the specific disease or condition; reduced morbidity and mortality, and improvement in quality of life issues. The above parameters for assessing successful treatment and improvement in the disease are readily measurable by routine procedures familiar to a physician.DETAILED DESCRIPTIONCompoundGeneral formulaFormula (I)

[0044] This invention relates to a compound of Formula (I)or a pharmaceutically acceptable salt and / or solvate thereof; whereinR1represents hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, hydroxyl, -O-alkyl, or halogen; wherein the alkyl in R1is optionally substituted by at least one group selected from NR1*^11, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cyano, hydroxy, (C1-C4) alkoxy, and halogen; the cycloalkyl in R1is optionally substituted by at least one group selected from (C1-C4) alkyl, cyano, and halogen; the heterocycloalkyl in R1is optionally substituted by at least one group selected from NR10Rn, (C1-C4) alkyl, cyano, (C1-C4) haloalkyl, hydroxy, (C1-C4) alkoxy, oxo (=0), and halogen;the aryl in R1is optionally substituted by at least one group selected from NR10Rn, (C1-C4) alkyl, cyano, (C1-C4) haloalkyl, hydroxyl, (C1-C4) alkoxy, and halogen; and the heteroaryl in R1is optionally substituted by at least one group selected from NR1ORU, (C1-C4) alkyl, cyano, (C1-C4) haloalkyl, hydroxyl, (C1-C4) alkoxy, and halogen;R2represents hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, hydroxy, -O-alkyl, -O-aryl, or halogen; wherein the alkyl in R2is optionally substituted by at least one group selected from NR10Rn, cyano, cycloalkyl, aryl, heteroaryl, hydroxy, (C1-C4) alkoxy, and halogen; the cycloalkyl in R2is optionally substituted by at least one group selected from NR10Rn, (C1-C4) alkyl, (C1-C4) haloalkyl, cyano, hydroxy, (C1-C4) alkoxy, and halogen; the aryl in R2is optionally substituted by at least one group selected from NR10Rn, (C1-C4) alkyl, (C1-C4) haloalkyl, cyano, hydroxy, (C1-C4) alkoxy, and halogen; and the heteroaryl in R2is optionally substituted by at least one group selected from NR10Rn, (C1-C4) alkyl, (C1-C4) haloalkyl, cyano, hydroxy, (C1-C4) alkoxy, and halogen;R3represents hydrogen, -NRARB, alkyl, cycloalkyl, -alkenyl-C(O)2-R12, alkynyl, heterocycloalkyl, aryl, heteroaryl, -O-alkyl, -O-cycloalkyl, -O-(Ci-C4) alkyl-NR10Ru, or halogen; wherein the alkyl in R3is optionally substituted by at least one group selected from NR10Rn, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cyano, hydroxy, (C1-C4) alkoxy, and halogen;wherein the heterocycloalkyl (z.e., the heterocycloalkyl that is part of the substituents of the alkyl that constitute the base structure of R3) is optionally substituted by at least one group selected from (C1-C4) alkyl, (C1-C4) alkyl-NR10R11, cyano, hydroxy, (C1-C4) alkoxy, and halogen; the cycloalkyl in R3is optionally substituted by at least one group selected from NR1ORU, cyano, heterocycloalkyl, hydroxy, (C1-C4) alkoxy, and halogen; wherein the heterocycloalkyl (z.e., the heterocycloalkyl that is part of the substituents of the cycloalkyl that constitute the base structure of R3) is optionally substituted by at least one -(C1-C4) alkyl-NR1*^11; the alkynyl in R3is optionally substituted by at least one group selected from NR10Rn, heterocycloalkyl, hydroxy, and (C1-C4) alkoxy; the heterocycloalkyl in R3is optionally substituted by at least one group selected from NR10Rn, -NR10-C(O)-R12, -NR10-C(O)2-R12, alkyl, cycloalkyl, heterocycloalkyl, cyano, (C1-C4) haloalkyl, -C(O)2-R12, -C(O)-NR10R11, hydroxyl, -O-alkyl, oxo (=0), and halogen; wherein the alkyl, cycloalkyl or heterocycloalkyl (z.e., the alkyl, cycloalkyl or heterocycloalkyl that are part of the substituents of the heterocycloalkyl that constitute the base structure of R3) is optionally substituted by at least one group selected from NR10Rn, (C1-C4) alkyl, cyano, C(O)2R12, hydroxyl, (C1-C4) alkoxy, and halogen; the aryl in R3is optionally substituted by at least one group selected from NR10Rn, (C1-C4) alkyl, cycloalkyl, heterocycloalkyl, -(C1-C4) alkyl- NR10Rn, cyano, hydroxyl, (C1-C4) alkoxy, and halogen; the heteroaryl in R3is optionally substituted by at least one group selected from NR10Rn, (C1-C4) alkyl, cycloalkyl, heterocycloalkyl, -(C1-C4) alkyl-NR10Rn, cyano, hydroxyl, (C1-C4) alkoxy, and halogen; andRAand RBeach independently represents hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -C(0)-Rc, or -C(0)2-Rc;whereinRcrepresents alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; and the alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl in RA, RBor Rcis optionally substituted by at least one group selected from NR1ORU, (C1-C4) alkyl, cycloalkyl, cyano, (C1-C4) haloalkyl, hydroxy, (C1-C4) alkoxy, oxo (=0), and halogen;R4represents hydrogen or halogen;X represents N-R5, O, S, or S(0)2; wherein R5represents hydrogen, alkyl, or cycloalkyl; wherein the alkyl in R5is optionally substituted by at least one group selected from NR10Rn, cyano, (C1-C4) haloalkyl, hydroxy, (C1-C4) alkoxy, and halogen; and the cycloalkyl in R5is optionally substituted by at least one group selected from NR10Rn, (C1-C4) alkyl, cyano, hydroxy, (C1-C4) alkoxy, and halogen;Y represents aryl or heteroaryl; wherein the aryl or heteroaryl in Y is optionally substituted by at least one REgroup; wherein RErepresents NR10Rn, -NR10-S(O)2-RE, -N=S(O)R10R11, B(0H)2, alkyl, heterocycloalkyl, heteroaryl, cyano, -C(O)NH-S(O)2-NR10R11, -C(O)2-R12, hydroxy, -O-alkyl,-S(0)2-NRERG, -S(O)2-RE, -S(O)(=NR10)-R12, -P(0)(0R)2, or halogen; wherein the alkyl, heterocycloalkyl or heteroaryl in REis optionally substituted by at least one group selected from-NR10-S(O)-R12, -C(O)-NR10R11, -C(O)2H, -S(O)2-NR10Rn, S(O)2-R12, and halogen; and wherein RFand RGeach independently represents hydrogen, alkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl or heterocycloalkyl in RFor RGis optionally substituted by at least on group selected from (C1-C4) alkyl, -CH2-(CI-C4) alkoxy, cycloalkyl, cyano, hydroxy, (C1-C4) alkoxy, and halogen.R10and R11each independently represents hydrogen, (C1-C4) alkyl, or cycloalkyl; wherein the alkyl or cycloalkyl in R10or R11is optionally substituted by at least one group selected from cyano, hydroxy, (C1-C4) alkoxy, and halogen; orR10and R11form together with the nitrogen atom to which they are bound a 3-membered to 6-membered heterocycloalkyl; wherein the heterocycloalkyl is optionally substituted by at least one group selected from (C1-C4) alkyl, (C1-C4) haloalkyl, hydroxy, (C1-C4) alkoxy, oxo (=0), and halogen; andR12represents hydrogen, (C1-C4) alkyl, or cycloalkyl; wherein the alkyl or cycloalkyl in R12is optionally substituted by at least one group selected from cyano, hydroxy, (C1-C4) alkoxy, and halogen.R1embodiments

[0045] According to some embodiments, R1represents hydrogen, alkyl, heterocycloalkyl, aryl, heteroaryl, hydroxyl, -O-alkyl, or halogen; wherein the alkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted as defined under Formula (I) herein.

[0046] According to some preferred embodiments, R1represents hydrogen, heteroaryl, hydroxyl, -O-alkyl, or halogen; wherein the alkyl or heteroaryl is optionally substituted as defined under Formula (I) herein. In some preferred embodiments, R1is selected from hydrogen, pyridinyl, hydroxy, methoxy, or F.

[0047] In some preferred embodiments, R1is hydrogen.

[0048] In some embodiments, R1represents an heteroaryl, wherein the heteroaryl is optionally substituted as defined under Formula (I) herein. In some preferred embodiments, R1is pyridinyl.

[0049] In some embodiments, R1represents hydroxyl or -O-alkyl, wherein the alkyl is optionally substituted as defined under Formula (I) herein. In some preferred embodiments, R1is selected from hydroxy and methoxy. In some further preferred embodiments, R1represents hydroxy. In some further preferred embodiments, R1is methoxy.

[0050] In some embodiments, R1represents halogen. In some preferred embodiments, R1is F.R2embodiments

[0051] According to some embodiments, R2represents hydrogen, alkyl, cycloalkyl, heteroaryl, -O-aryl, or halogen; wherein the alkyl, cycloalkyl, aryl or heteroaryl is optionally substituted as defined under Formula (I) herein.

[0052] According to some preferred embodiments, R2represents hydrogen or halogen. In some preferred embodiments, R2is selected from hydrogen, Cl, and F. In some preferred embodiments, R2is hydrogen. In some embodiments, R2represents halogen. In some preferred embodiments, R2is selected from Cl and F.R3embodiments

[0053] According to some embodiments, R3represents hydrogen, -NRARB, alkyl, cycloalkyl, -alkenyl-C(O)2-R12, alkynyl, heterocycloalkyl, aryl, heteroaryl, -O-alkyl, -O-cycloalkyl, -O-(Ci-C4) alkyl-NR10Rn, or halogen; wherein the cycloalkyl, alkynyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted as defined under Formula (I) herein.

[0054] According to some preferred embodiments, R3represents hydrogen, -NRARB, alkyl, cycloalkyl, -alkenyl-C(O)2-R12, alkynyl, heterocycloalkyl, aryl, heteroaryl, -O-(Ci-C4) alkyl-NR10Ru, or halogen; wherein the cycloalkyl, alkynyl, heterocycloalkyl, heteroaryl or aryl is optionally substituted as defined under Formula (I) herein.

[0055] In some preferred embodiments, R3is selected from: hydrogen;-NH-pyrrolidinyl, -NH-cyclobutylamino, Nl-substituted-cyclobutane-l,3-diamine, {3 -[(substituted amino)methyl]azetidin-3-yl}methanol, N-substituted piperidine-3- carboxamide, N-substituted azeti din-3 -amine, N-substituted cyclohexanamine, diethyl[2-(substituted amino)ethyl]amine, 1-methyl-N-substituted piperidine-4- carboxamide, and N-substituted piperidine-3 -carboxamide; methylamino and l-[l-(2-substituted ethyl)pyrrolidin-3-yl]methanamine;3-substituted cyclohexan-1 -amine, 3-substituted cyclobutan-1 -amine, 3-substituted cyclopentan- 1 -amine, N,N-diethyl-3-substituted cyclobutan-1 -amine, and 3 -sub stituted cyclohex-3 -en- 1 -amine;3-substituted prop-2-enoic acid;(NH2)-propynyl, Me2N-propynyl, MeNH-propynyl, 2-methyl-4-substituted but-3- yn-2-ol, and 2-methyl-4-substituted-but-3-yn-2-amine;2-methyl-6-substituted 2,6-diazaspiro[3.4]octane, l-methyl-4-substituted 1, 2,3,6- tetrahydropyridine, l-methyl-4-substituted piperidine, 3 -(aminomethyl)- 1- substituted azeti din-3 -ol, 2-substituted 5-oxa-2,7-diazaspiro[3.4]octan-6-one,1-substituted azeti din-3 -amine, 6-substituted l,6-diazaspiro[3.3]heptane, 1-methyl-4-substituted piperazine, 8-methyl-3-substituted 3,8-diazabicyclo[3.2.1]octane,2-methyl-5-substituted 2,5-diazabicyclo[4.1.0]heptane, l-methyl-3-substituted pyrrolidine, 2-methyl-5-substituted 2,5-diazabicyclo[2.2.2]octane, 3-methyl-l- substituted piperi din-3 -amine, 2-substituted pyrrolidine, 5-substituted 2,5-diazaspiro[3.4]octan-7-ol, 2-substituted octahydropyrrolo[l,2-a]pyrazin-7-ol, l'-substituted 1,3 '-bipyrrolidine, 1-substituted piperi din-3 -amine, 8-substituted octahydropyrazino[2, l-c][l,4]oxazine, 1-substituted azepan-4-amine,l,2-dimethyl-4-substituted piperazine, 2-substituted 2,5-diazaspiro[3.4]octan-6- one, 5-substituted 2,5-diazaspiro[3.4]octane, 7-substituted1.7-diazaspiro[4.4]nonan-2-one, l,2,6-trimethyl-4-substituted piperazine,7.7-difluoro-2-substituted octahydropyrrolo[l,2-a]pyrazine, l-cyclopropyl-2- methyl-4-substituted piperazine, 2-methyl-4-substituted-l -(2,2,2)- trifluoroethyl)piperazine, 4-substituted azepane, l-methyl-4-substituted piperidine, 2,2,6,6-tetramethyl-4-substituted piperidine, l-ethyl-4-substituted piperidine, 6-(2-methoxyethyl)-2-substituted 2,6-diazabicyclo[3.2. l]octane, 1-substituted pyrrolidin-3-amine, N-methyl-l-substituted pyrrolidin-3 -amine, 6-methyl-2- substituted 2,6-diazabicyclo[3.2.1]octane, N-methyl-l-substituted piperidin-3- amine, l-methyl-4-substituted 1,2,3,6-tetrahydropyridine, 4-substituted 1, 2,3,6- tetrahydropyridine, 2-substituted 2,7-diazaspiro[3.5]nonane, 3-substituted 3-azabicyclo[3.1.0]hexan-l-amine, 3-substituted 3-azabicyclo[3.1.0]hexan-6- amine, N-[-3-substituted 3-azabicyclo[3.1.0]hexan-6-yl]acetamide, 1-substituted pyrrolidine-3 -carboxamide, 2-ethyl-l-methyl-4-substituted piperazine, l-methyl-2- (propan-2-yl)-4-substituted piperazine, 4-methyl-7-substituted4.7-diazaspiro[2.5]octane, 6-substituted 2,6-diazaspiro[3.4]octane, {2-methyl-7- substituted 2,7-diazaspiro[3.5]nonan-5-yl}methanol, 5-methyl-2-substituted2.5-diazaspiro[3.4]octane, [2-(hydroxymethyl)-l-methyl-4-substituted piperazin-2-yl]methanol, (4-amino- 1-substituted piperidin-4-yl)methanol, 8-substituted3-oxa-l,8-diazaspiro[4.5]decan-2-one, l-[ 1-substituted pyrrolidin-3- yl]methanamine, 1-substituted piperidin-4-amine, 1 -(1-substituted piperidin-4- yl)methanamine, 2-methyl-7-substituted 2,7-diazaspiro[3.5]nonane, 2-substituted2.6-diazaspiro[3.3]heptane, N- [3 -substituted 3-azabicyclo[3.1.0]hexan-6- yl]acetamide, 1-substituted piperidine-3 -carboxamide, 1-substituted piperidin-3-ol,4-substituted piperazine-2-carboxamide, l-ethoxy-3-(4-substituted piperazin-1- yl)propan-2-ol, 3-substituted piperidine, 7-substituted l,7-diazaspiro[4.4]nonane, 2-substituted 2,6-diazaspiro[3.4]octane, 6-substituted 2,6-diazaspiro[3.4]octane,1-substituted l,7-diazaspiro[4.4]nonane, 2-substituted 2,7-diazaspiro[4.4]nonane,2-substituted 2,7-diazaspiro[4.4]nonan-l-one, l-methyl-4-substituted-2-(trifluoromethyl)piperazine, 2-(fluoromethyl)-l-methyl-4-substituted piperazine, 1 -substituted -4-(2,2,2-trifluoroethyl)piperazine, [ l-methyl-4-substitutedpiperazin-2-yl]methanol, l-(2-fluoroethyl)-4-substituted piperazine,8-cyclopropyl-3-substituted 3,8-diazabicyclo[3.2. l]octane, (6-methyl-3- substituted 3,6-diazabicyclo[3.1. l]heptane, l-cyclopropyl-4-substituted piperazine, and 2-methyl-4-substituted piperidine; dimethyl[(4-substituted phenyl)methyl]amine;3,5-dimethyl-4-substituted / / / -pyrazole;-O-CH2CH2-NMe2; andBr.

[0056] In some preferred embodiments, R3is hydrogen.

[0057] In some embodiments, R3represents -NRARB, wherein RAand RBare each independently as defined under Formula (I) herein. In some preferred embodiments, R3is selected from -NH-pyrrolidinyl, -NH-cyclobutylamino, Nl-substituted-cyclobutane- 1,3-diamine, {3 -[(substituted amino)methyl]azetidin-3-yl}methanol, N-substituted piperidine-3 -carboxamide, N-substituted azeti din-3 -amine, N-substituted cyclohexanamine, diethyl[2-(substituted amino)ethyl]amine, 1-methyl-N-substituted piperidine-4-carboxamide, and N-substituted piperidine-3-carboxamide.

[0058] In some embodiments, R3represents alkyl, wherein the alkyl is optionally substituted as defined under Formula (I) herein. In some preferred embodiments, R3is selected from -methylamino and l-[l-(2-substituted ethyl)pyrrolidin-3-yl]methanamine.

[0059] In some embodiments, R3represents cycloalkyl, wherein the cycloalkyl is optionally substituted as defined under Formula (I) herein. In some preferred embodiments, R3is selected from 3-substituted cyclohexan-1 -amine, 3-substituted cyclobutan-1 -amine, 3-substituted cyclopentan- 1 -amine, N,N-diethyl-3-substituted cyclobutan-1 -amine, and 3-substituted cyclohex-3 -en-1 -amine.

[0060] In some embodiments, R3represents -alkenyl-CO2-R12, wherein the alkenyl is optionally substituted as defined under Formula (I) herein and R12is as defined under Formula (I) herein. In some preferred embodiments, R3is 3-substituted prop-2-enoic acid.

[0061] In some embodiments, R3represents alkynyl, wherein the alkynyl is optionally substituted as defined under Formula (I) herein. In some preferred embodiments, R3is selected from (NH2)-propynyl, Me2N-propynyl, MeNH-propynyl, 2-methyl-4-substituted but-3-yn-2-ol, and 2-methyl-4-substituted-but-3-yn-2-amine.In some embodiments, R3represents heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted as defined under Formula (I) herein. In some preferred embodiments, R3is selected from 2-methyl-6-substituted 2,6-diazaspiro[3.4]octane, l-methyl-4-substituted 1,2,3,6-tetrahydropyridine, l-methyl-4-substituted piperidine,3-(aminomethyl)-l-substituted azeti din-3 -ol, 2-substituted 5-oxa-2,7- diazaspiro[3.4]octan-6-one, 1-substituted azetidin-3 -amine, 6-substituted1.6-diazaspiro[3.3]heptane, l-methyl-4-substituted piperazine, 8-methyl-3-substituted3,8-diazabicyclo[3.2.1]octane, 2-methyl-5-substituted 2,5-diazabicyclo[4.1.0]heptane, l-methyl-3-substituted pyrrolidine, 2-methyl-5-substituted2.5-diazabicyclo[2.2.2]octane, 3-methyl-l-substituted piperi din-3 -amine, 2-substituted pyrrolidine, 5-substituted 2,5-diazaspiro[3.4]octan-7-ol, 2-substituted octahydropyrrolo[l,2-a]pyrazin-7-ol, 1 '-substituted l,3'-bipyrrolidine, 1-substituted piperi din-3 -amine, 8-substituted octahydropyrazino[2,l-c][l,4]oxazine, 1-substituted azepan-4-amine, l,2-dimethyl-4-substituted piperazine, 2-substituted2.5-diazaspiro[3.4]octan-6-one, 5-substituted 2,5-diazaspiro[3.4]octane, 7-substituted1.7-diazaspiro[4.4]nonan-2-one, l,2,6-trimethyl-4-substituted piperazine, 7,7-difluoro-2- substituted octahydropyrrolof 1 ,2-a]pyrazine, 1 -cyclopropyl-2-methyl-4-substituted piperazine, 2-methyl-4-substituted -l-(2,2,2)-trifluoroethyl)piperazine, 4-substituted azepane, l-methyl-4-substituted piperidine, 2,2,6,6-tetramethyl-4-substituted piperidine, 1 -ethyl-4-substituted piperidine, 6-(2-methoxyethyl)-2-substituted2.6-diazabicyclo[3.2.1]octane, 1-substituted pyrrolidin-3 -amine, N-methyl- 1-substituted pyrrolidin-3 -amine, 6-methyl-2-substituted 2,6-diazabicyclo[3.2.1]octane, N-methyl-1- substituted piperi din-3 -amine, l-methyl-4-substituted 1,2,3,6-tetrahydropyridine,4-substituted 1,2,3,6-tetrahydropyridine, 2-substituted 2,7-diazaspiro[3.5]nonane, 3-substituted 3-azabicyclo[3.1.0]hexan-l-amine, 3-substituted 3-azabicyclo[3.1.0]hexan- 6-amine, N-[-3-substituted 3-azabicyclo[3.1.0]hexan-6-yl]acetamide, 1-substituted pyrrolidine-3 -carboxamide, 2-ethyl-l-methyl-4-substituted piperazine, l-methyl-2-(propan-2-yl)-4-substituted piperazine, 4-methyl-7-substituted4,7-diazaspiro[2.5]octane, 6-substituted 2,6-diazaspiro[3.4]octane, {2-methyl-7- substituted 2,7-diazaspiro[3.5]nonan-5-yl}methanol, 5-methyl-2-substituted2.5-diazaspiro[3.4]octane, [2-(hydroxymethyl)-l-methyl-4-substituted piperazin-2- yl]methanol, (4-amino-l-substituted piperidin-4-yl)methanol, 8-substituted 3-oxa-l,8-diazaspiro[4.5]decan-2-one, 1-[1 -substituted pyrrolidin-3-yl]methanamine, 1 -substituted piperidin-4-amine, 1-(1 -substituted piperidin-4-yl)methanamine, 2-methyl- 7-substituted 2,7-diazaspiro[3.5]nonane, 2-substituted 2,6-diazaspiro[3.3]heptane, N-[3-substituted 3-azabicyclo[3.1.0]hexan-6-yl]acetamide, 1-substituted piperidine-3- carboxamide, 1-substituted piperi din-3 -ol, 4-substituted piperazine-2-carboxamide,1-ethoxy-3-(4-substituted piperazin- l-yl)propan-2-ol, 3-substituted piperidine,7-substituted l,7-diazaspiro[4.4]nonane, 2-substituted 2,6-diazaspiro[3.4]octane, 6-substituted 2,6-diazaspiro[3.4]octane, 1-substituted l,7-diazaspiro[4.4]nonane,2-substituted 2,7-diazaspiro[4.4]nonane, 2-substituted 2,7-diazaspiro[4.4]nonan-l-one, l-methyl-4-substituted -2-(trifluoromethyl)piperazine, 2-(fluorom ethyl)- l-methyl-4- substituted piperazine, 1-substituted -4-(2,2,2-trifluoroethyl)piperazine, [l-methyl-4- substituted piperazin-2-yl]methanol, l-(2-fluoroethyl)-4-substituted piperazine,8-cyclopropyl-3-substituted 3,8-diazabicyclo[3.2. l]octane, (6-methyl-3-substituted3.6-diazabicyclo[3.1.1]heptane, l-cyclopropyl-4-substituted piperazine, and 2-methyl-4- substituted piperidine.

[0062] In some embodiments, R3represents aryl, wherein the aryl is optionally substituted as defined under Formula (I) herein. In some preferred embodiments, R3is dimethyl [(4-substituted phenyl)methyl]amine (or “4-[(dimethylamino)methyl]phenyl”).

[0063] In some embodiments, R3represents heteroaryl, wherein the heteroaryl is optionally substituted as defined under Formula (I) herein. In some preferred embodiments, R3is 3,5-dimethyl-4-substituted / 77-pyrazole.

[0064] In some embodiments, R3represents -O-(Ci-C4) alkyl-NR10Ru, wherein the alkyl is optionally substituted as defined under Formula (I) herein and R10and R11are each independently as defined under Formula (I) herein. In some preferred embodiments, R3is -O-CH2CH2-NMe2.

[0065] In some embodiments, R3represents halogen. In some preferred embodiments, R3is Br.B4embodiments

[0066] According to some embodiments, R4represents hydrogen or halogen. According to some preferred embodiments, R4is hydrogen.X embodiments

[0067] According to some embodiments, X represents N-R5or O; wherein R5is as defined under Formula (I) herein. According to some preferred embodiments, X represents N-R5, wherein R5is as defined under Formula (I) herein; in these embodiments, Formula (I) is identified as “Formula (I-a)”.

[0068] According to some preferred embodiments, X represents N-R5or O, wherein R5is selected from hydrogen, methyl, ethyl, propyl (preferably, isopropyl), cyclopropyl, trifluoromethyl, difluoromethyl, and -CH2CH2OH.

[0069] In some preferred embodiments, X represents N-R5, wherein R5is selected from hydrogen, methyl, ethyl, propyl (preferably, isopropyl), cyclopropyl, trifluoromethyl, difluoromethyl, or -CH2CH2OH. In some more preferred embodiments, X is selected from NH and N-CH3 (N-Me). In some further preferred embodiments, X is NH. In some further preferred embodiments, X is N-CH3.

[0070] In some preferred embodiments, X is O.Y embodiments

[0071] According to some preferred embodiments, Y is selected from:2,2,2-trifluoro- 1 -phenylethan- 1 -ol, phenylmethanol, 3 -phenyl-4, 5-dihydro- 1 ,2,4- oxadiazol-5-one, 4,4-dimethyl-2-phenyl-4,5-dihydro-7J / -imidazol-5-one, phenol, 2,6-difluorobenzoic acid, ethyl benzoate, 2-phenylacetic acid, 5-methyl-5- phenylimidazolidine-2, 4-dione, methanesulfonylbenzene,(methanesulfonylmethyl)benzene, N-methylbenzenesulfonamide,2-(trifluoromethoxy)aniline, 2-chloroaniline, 2,3-dihydro-l,3-benzoxazol-2-one, N-phenylaminosulfonamide, dimethyl(phenylimino)-lambda6-sulfanone,2.5-dimethyl-5-phenyl-4,5-dihydro-777-imidazol-4-one, 2,5-dimethyl-5-phenyl-4.5-dihydro-777-imidazol-4-one, 4-phenyl-2,3-dihydro-l,3-thiazol-2-one,[cyclopropyl(phenyl)imino-lambda6-sulfanyl]one, 2-phenylacetic acid, methyl[methyl(oxo)phenyl-lambda6-sulfanylidene]amine, 5-phenyl-277-l,2,3,4- tetrazole, 2,5-dimethylbenzoic acid, 3 -hydroxybenzoic acid, phenylphosphonic acid, pyridine-3 -carboxylic acid, pyridine-2-carboxylic acid, l,3-dihydro-2- benzofuran-l-one, 2-aminobenzoic acid, 2-methylbenzoic acid, 2-chlorobenzoic acid, 3 -methoxybenzoic acid, 3 -chlorobenzoic acid, 2-methoxybenzoic acid,2-fluorobenzoic acid, 3 -fluorobenzoic acid, pyrazine-2-carboxylic acid,3 -methylbenzoic acid, 2,6-difluorobenzoic acid, 5-chloropyridine-3-carboxylic acid, naphthalene- 1 -carboxylic acid, 2-methylpyridine-3 -carboxylic acid, 6-hydroxypyridine-2-carboxylic acid, and phenylboronic acid; and1-(l,2-oxazol-5-yl)cyclopropane-l-carboxylic acid, 2-(l,2-oxazol-5-yl)propanoic acid, 2-(777-pyrazol-l-yl)acetic acid, 2-methyl-2-(l,2-oxazol-5-yl)propanoic acid, (75,25)-2-(777-pyrazol- 1 -yl)cyclopropane- 1 -carboxylic acid, (77?,27?)-2-(777- pyrazol-l-yl)cyclopropane-l -carboxylic acid, 2-(777-pyrazol-l-yl)acetic acid, N-[(l,2-oxazol-5-yl)methyl]methanesulfonamide, 2-(l,2-oxazol-5-yl)acetic acid, N-methyl-l-(l,2-oxazol-5-yl)methanesulfonamide, 2-[(l,3-oxazol-2- yl)amino]acetic acid, l-(l,3-oxazol-2-yl)piperidine-2-carboxylic acid,2-[l-(777-pyrazol-l-yl)cyclopropyl]acetic acid, 2-methyl-2-(l,2-oxazol-5- yl)propanoic acid, 2-methyl-2-(l,2-oxazol-5-yl)propanoic acid, thiophene-3- carboxylic acid, thiophene-2-carboxylic acid, thiophene-2-carboxylic acid, N-[(thiophen-2-yl)methyl]methanesulfonamide, 2-(l,2-oxazol-5-yl)acetic acid, and 3-(777-pyrazol-l-yl)propanoic acid.

[0072] According to some preferred embodiments, Y represents aryl, wherein the aryl is optionally substituted as defined under formula (I) herein. In these embodiments, Formula (I) is identified as “Formula (I- 1)”. In some preferred embodiments, Y is selected from2,2,2-trifluoro- 1 -phenylethan- 1 -ol, phenylmethanol, 3 -phenyl-4, 5-dihydro- 1 ,2,4-oxadi azol -5 -one, 4,4-dimethyl-2-phenyl-4,5-dihydro-777-imidazol-5-one, phenol, 2,6-difluorobenzoic acid, ethyl benzoate, 2-phenylacetic acid, 5-methyl-5- phenylimidazolidine-2, 4-dione, methanesulfonylbenzene,(methanesulfonylmethyl)benzene, N-methylbenzenesulfonamide,2-(trifluoromethoxy)aniline, 2-chloroaniline, 2,3-dihydro-l,3-benzoxazol-2-one,N-phenylaminosulfonamide, dimethyl(phenylimino)-lambda6-sulfanone, 2,5-dimethyl-5-phenyl-4,5-dihydro-777-imidazol-4-one, 2,5-dimethyl-5-phenyl-4,5-dihydro-777- imidazol -4-one, 4-phenyl-2,3-dihydro-l,3-thiazol-2-one, [cyclopropyl(phenyl)imino- lambda6-sulfanyl]one, 2-phenylacetic acid, methyl[methyl(oxo)phenyl-lambda6- sulfanylidene]amine, 5-phenyl-277-l,2,3,4-tetrazole, 2,5-dimethylbenzoic acid,3 -hydroxybenzoic acid, phenylphosphonic acid, pyridine-3 -carboxylic acid, pyridine-2- carboxylic acid, l,3-dihydro-2-benzofuran-l-one, 2-aminobenzoic acid, 2-methylbenzoic acid, 2 -chlorobenzoic acid, 3 -methoxybenzoic acid, 3 -chlorobenzoic acid, 2 -methoxybenzoic acid, 2-fluorobenzoic acid, 3 -fluorobenzoic acid, pyrazine-2- carboxylic acid, 3 -methylbenzoic acid, 2,6-difluorobenzoic acid, 5-chloropyridine-3- carboxylic acid, naphthalene- 1 -carboxylic acid, 2-methylpyridine-3 -carboxylic acid,6-hydroxypyridine-2-carboxylic acid, and phenylboronic acid.

[0073] According to some embodiments, Y represents heteroaryl, wherein the heteroaryl is optionally substituted as defined under Formula (I) herein. In some preferred embodiments, Y is selected from l-(l,2-oxazol-5-yl)cy cl opropane-1 -carboxylic acid, 2-(l,2-oxazol-5-yl)propanoic acid, 2-(777-pyrazol-l-yl)acetic acid, 2-methyl-2-(l,2- oxazol-5-yl)propanoic acid, (75, 25)-2-(777-pyrazol-l-yl)cy cl opropane-1 -carboxylic acid, (77?,27?)-2-(777-pyrazol- 1 -yl)cyclopropane- 1 -carboxylic acid, 2-(777-pyrazol- 1 -yl)acetic acid, N-[(l,2-oxazol-5-yl)methyl]methanesulfonamide, 2-(l,2-oxazol-5-yl)acetic acid, N-methyl-l-(l,2-oxazol-5-yl)methanesulfonamide, 2-[(l,3-oxazol-2-yl)amino]acetic acid, l-(l,3-oxazol-2-yl)piperidine-2-carboxylic acid, 2-[l-(777-pyrazol-l- yl)cyclopropyl]acetic acid, 2-methyl-2-(l,2-oxazol-5-yl)propanoic acid, 2-methyl-2- (l,2-oxazol-5-yl)propanoic acid, thiophene-3 -carboxylic acid, thiophene-2-carboxylic acid, thiophene-2-carboxylic acid, N-[(thiophen-2-yl)methyl]methanesulfonamide, 2-(l,2-oxazol-5-yl)acetic acid, and 3-(777-pyrazol-l-yl)propanoic acid.

[0074] In some preferred embodiments, Y represents aryl or heteroaryl; wherein the aryl or heteroaryl is substituted by at least one -S(O)2-NRFRG; wherein RFand RGare as defined under formula (I) herein. Advantageously, in these embodiments, the compound of formula (I) is especially potent as MTHFD2 inhibitor.

[0075] In some preferred embodiments, the aryl or heteroaryl in Y is optionally substituted by at least one RE, wherein REis selected from -CO2H, 3-phenyl-4,5-dihydro- l,2,4-oxadiazol-5-one, 4,4-dimethyl-2-phenyl-4,5-dihydro-777-imidazol-5-one, 5- methyl-5-phenylimidazolidine-2, 4-dione, 2,3-dihydro-l,3-benzoxazol-2-one, dimethyl(phenylimino)-lambda6-sulfanone,2,5-dimethyl-5-phenyl-4,5-dihydro-777-imidazol-4-one, 2,5-dimethyl-5-phenyl-4,5- dihydro-777-imidazol -4-one, 4-phenyl-2,3-dihydro-l,3-thiazoL2-one,[cyclopropyl(phenyl)imino-k6-sulfanyl]one, methyl [methyl(oxo)phenyl-k6- sulfanylidene]amine, and l,3-dihydro-2-benzofuran-l-one.Further general formulae

[0076] According to some preferred embodiments, the compound is a compound of Formula (La-1)or a pharmaceutically acceptable salt and / or solvate thereof; wherein R1, R2, R3, R4and R5are each independently as defined under formula (I) herein; each REis independently as defined under formula (I) herein; and p is an integer ranging from 0 to 5.

[0077] In some embodiments, p an integer ranging from 1 to 5, preferably ranging from 1 to 4, more preferably ranging from 1 to 3. In some preferred embodiments, p is 1 or 2,i.e. , the phenyl has exactly one or two REsubstituent(s) as defined herein. In some embodiments, p is 1, i.e., the phenyl has exactly one REsubstituent as defined herein.

[0078] In some preferred embodiments, one of the REsubstituent(s) is on meta or para position towards the amide group. In some further preferred embodiments, one of the REsubstituent(s) is on para position towards the amide group.Individual compounds

[0079] According to some embodiments, the compound according to the invention is selected from the compound of Table 1 below.Table 1and pharmaceutically acceptable salts and / or solvates thereof.Alternative forms of the compounds

[0080] All references to compounds of Formula (I) include references to salts, solvates, multi-component complexes and / or liquid crystals thereof. All references to compounds of Formula (I) include references to polymorphs and / or crystal habits thereof. All references to compounds of Formula (I) include references to pharmaceutically acceptable prodrugs thereof. All references to compounds of Formula (I) include references to isotopically-labelled compounds of Formula (I), including deuterated compounds of Formula (I).

[0081] The compounds of Formula (I) and subformulae thereof may contain at least one asymmetric centre(s) and thus may exist as different stereoisomeric forms. Accordingly, all references to compounds of Formula (I) include references to all possible stereoisomers and includes not only the racemic compounds but the individual enantiomers and their non-racemic mixtures as well. When a compound is desired as a single enantiomer, such single enantiomer may be obtained by stereospecific synthesis, by resolution of the final product or any convenient intermediate, or by chiralchromatographic methods as each are known in the art. Resolution of the final product, an intermediate, or a starting material may be carried out by any suitable method known in the art. Bonds from an asymmetric carbon in compounds are generally depicted using a solid line ( - ),a solid wedge ( M), or a dotted wedge ( ).The use of either a solid or dotted wedge to depict bonds from an asymmetric carbon atom is meant to indicate that only the stereoisomer shown is meant to be included.

[0082] The compounds of the invention may be in the form of pharmaceutically acceptable solvates. Pharmaceutically acceptable solvates of the compounds of Formula (I) include hydrates thereof.

[0083] The compounds of the invention may be in the form of pharmaceutically acceptable salts. Pharmaceutically acceptable salts of the compounds of Formula (I) include the acid addition and base salts thereof. Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include the acetate, adipate, aspartate, benzoate, besylate, bicarbonate / carbonate, bi sulphate / sulphate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate and xinafoate salts. Suitable base salts are formed from bases which form non-toxic salts. Examples include the aluminium, arginine, benzathine, calcium, choline, diethylamine, 2-(diethylamino)ethanol, diolamine, ethanolamine, glycine, 4-(2-hydroxyethyl)- morpholine, lysine, magnesium, meglumine, morpholine, olamine, potassium, sodium, tromethamine and zinc salts. Hemisalts of acids and bases may also be formed, for example, hemisulphate and hemicalcium salts. When the compounds of Formula (I) contain an acidic group as well as a basic group the compounds of the invention may also form internal salts, and such compounds are within the scope of the invention. When the compounds of the invention contain a hydrogen-donating heteroatom (e.g., NH), the invention also covers salts and / or isomers formed by transfer of said hydrogen atom to abasic group or atom within the molecule. Pharmaceutically acceptable salts of compounds of Formula (I) may be prepared by one or more of these methods: (i) by reacting the compound of Formula (I) with the desired acid; (ii) by reacting the compound of Formula (I) with the desired base; (iii) by removing an acid- or base-labile protecting group from a suitable precursor of the compound of Formula (I) or by ring-opening a suitable cyclic precursor, e.g., a lactone or lactam, using the desired acid; and / or (iv) by converting one salt of the compound of Formula (I) to another by reaction with an appropriate acid or by means of a suitable ion exchange column. All these reactions are typically carried out in solution. The salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent. The degree of ionization in the salt may vary from completely ionized to almost non-ionized.Pharmaceutical

[0084] This invention also relates to a pharmaceutical composition comprising a compound according to the invention, as described hereinabove, and at least one pharmaceutically acceptable carrier.

[0085] According to a first embodiment, the pharmaceutical composition comprises the compound according to the invention as sole therapeutic agent. According to a second embodiment, the pharmaceutical composition further comprises at least another therapeutic agent. In some embodiments, the other therapeutic agent is suitable for treating an auto-immune disease, an inflammatory disease, or a proliferative disease.Medical use and methods of treatment

[0086] This invention also relates to a compound according to the invention, as described hereinabove, for use as a medicament.

[0087] This invention also relates to a compound according to the invention, as described hereinabove, for use in the treatment of an auto-immune disease, an inflammatory disease, or a proliferative disease.

[0088] This invention also relates to the use of a compound according to the invention, as described hereinabove, in the manufacture of a medicament for the treatment of anauto-immune disease, an inflammatory disease, or a proliferative disease. This invention also relates to the use of a compound according to the invention, as described hereinabove, in the treatment of an auto-immune disease, an inflammatory disease, or a proliferative disease. This invention also relates to a method for the treatment of an autoimmune disease, an inflammatory disease, or a proliferative disease in a subject in need thereof, comprising a step of administrating to said subject a therapeutically effective amount of a compound according to the invention, as described hereinabove.

[0089] According to some embodiments, the auto-immune or inflammatory disease is selected from inflammatory bowel diseases, Crohn's disease, ulcerative colitis, rheumatoid arthritis, osteoarthritis, juvenile idiopathic arthritis, psoriasis, psoriatic arthritis, allergic airway diseases : asthma, rhinitis, chronic obstructive pulmonary disease (COPD), endotoxin-driven disease states, sepsis, systemic lupus erythematosus (SLE), cutaneous lupus erythematosus, lupus nephritis, dermatomyositis, Sjogren's syndrome, multiple sclerosis, psoriasis, dry eye disease, type I diabetes mellitus and complications associated therewith, atopic eczema (atopic dermatitis), thyroiditis (Hashimoto's and autoimmune thyroiditis), contact dermatitis and further eczematous dermatitis, atherosclerosis and amyotrophic lateral sclerosis, bone resorption, graft vs. host reaction, atherosclerosis, osteoarthritis. However, the inflammatory diseases and autoimmune diseases susceptible to be treated by the compound of the invention are not limited thereto.

[0090] According to some embodiments, the proliferative disease is selected from lung cancer, gastrointestinal cancer (colon, colorectal, stomach), ovarian cancer, uterine cancer, breast cancer, prostate cancer, liver cancer, head and neck cancer, pancreatic cancer, kidney cancer, skin cancer, malignant melanoma, glioblastoma, a retinoblastoma, testicular tumour, sarcoma; acute myelogenous leukaemia, malignant lymphoma, leukaemia : acute myeloid leukaemia (AML), and acute lymphoblastic leukaemia (ALL) and chronic lymphoblastic leukaemia (CLL), T -cell lymphoma, retinoblastoma, neuroblastoma or sarcoma; myeloproliferative disorders polycythaemia vera, essential thrombocytosis and myelofibrosis. However, the proliferative diseases susceptible to be treated by the compound of the invention are not limited thereto. According to some embodiments, the proliferative disease is a cancer.

[0091] According to a first embodiment, the compound according to the invention is to be administrated to the subject as sole therapeutic agent. According to a second embodiment, the compound according to the invention is to be administrated to the subject in combination with at least another therapeutic agent. In some embodiments, the other therapeutic agent is suitable for treating an auto-immune disease, an inflammatory disease, or a proliferative disease.

[0092] The compound according to the invention, as described hereinabove, can be prepared by any suitable synthetic method known in the art.

[0093] However, this invention also relates to process for manufacturing a compound according to the invention, as described hereinabove, comprising a step of reaction in acidic conditions of a bromophenyl-imino-piperidine-carboxylate with a A-acetyl- oxopiperidine-carboxylate. According to some embodiments, the acid is polyphosphoric acid. According to some embodiments, the reaction is carried out at elevated temperature (such as about 150 °C).

[0094] According to some embodiments, the process further comprises a step of formation of an amide bond then cross-coupling, thereby obtaining a compound wherein at least one of R’-R4(typically R3) comprises an amine derivative (typically a cyclic amine such as, for example piperazinyl). According to some embodiments, the process further comprises a step of cross-coupling then formation of an amide bond, thereby obtaining a compound wherein Y comprise a least one sulphonamide derivative.EXAMPLES

[0095] The present invention is further illustrated by the following examples.Example 1: Synthetic exampleGeneral synthetic schemes Intermediate synthesis

[0096] To synthesize tricyclic core, an oxopiperidine-carboxylate was mixed with an organic based (such as triethylamine) and acetic anhydride in an organic solvent (such as dichloromethane) to give an N-acetyl-oxopiperidine-carboxylate, which was reacted with bromoaniline and acetic acid (such as ethanol) to give a bromophenyl-imino-piperidine- carboxylate. This product was finally cyclized in acidic conditions (such as polyphosphoric acid) at elevated temperature (such as 150° C) to yield tricyclic scaffold.Amide bond formation then cross coupling

[0097] To synthesize compounds with amino derivatives in the left-hand part of the molecule, an unprotected bromo-tricyclic intermediate was coupled with(tert-butoxy)carbonyl]benzoic acid using an amide-coupling reagent (such as propanephosphonic acid anhydride) with an organic base (such as N,N- diisopropylethylamine) in an organic solvent (such as dichloromethane). Then Br- function was reacted in Buchwald-type conditions with methylpiperazine using Pd11source (such as Pd2dbas) and a phosphine-based ligand (such as 2,2'- bis(diphenylphosphino)-l,l'-binaphtyl) using an inorganic based (such as cesium carbonate) in an organic solvent (such as toluene) at elevated temperature (such as 90° C).Cross coupling then amide bond formation

[0098] To synthesize compounds with sulphonamide derivatives in the right-hand part of the molecule, a protected bromo-tricyclic intermediate was cross-coupled in Buchwald-type conditions with methylpiperazine using Pd11source (such as Pd2dbas) and a phosphine-based ligand (such as 2,2'-bis(diphenylphosphino)-l,l'-binaphtyl) using an inorganic based (such as caesium carbonate) in an organic solvent (such as toluene) at elevated temperature (such as 90° C). Amino-protected with te / 7-butyl-carbamate protecting group was cleaved in acidic conditions (such as chlorohydric acid in dioxane solution), then coupled with methanesulfonamidobenzoic acid using an amide-coupling reagent (such as propanephosphonic acid anhydride) with an organic base (such as N,N-diisopropylethylamine) in an organic solvent (such as dichloromethane).Analytical methods

[0099] HPLC (method A) was conducted on an X-Select CSH C18 XP column (2.5 pm 30 x 4.6 mm id) eluting with 0.1% formic acid in water (solvent A) and 0.1% formic acid in acetonitrile (solvent B), using the following elution gradient 0-3 minutes: 5% to 100% B, 3-4 minutes 100% B, at a flow rate of 1.8 ml / minute at 40 °C. HPLC (method B) wasconducted on an X-Select CSH C18 XP column (2.5 pm 30 x 4.6 mm id) eluting with (NH4)2CO3 aq. 2g / L in water (solvent A) and acetonitrile (solvent B), using the following elution gradient 0-3 minutes: 5% to 100% B, 3-4 minutes 100% B, at a flow rate of 1.8 ml / minute at 40 °C. HPLC (method C) HPLC method for final compounds, H2O + (0.1% formic acid) / ACN gradient. HPLC (method D) HPLC method for final compounds, H2O + (0.1% TFA) / ACN gradient. HPLC (method E) HPLC method for final compounds, H2O + (0.1% Ammonium Bicarbonate) / ACN gradient.Synthesis of intermediatesIntermediate A

[0100] Step 1. To a mixture of methyl 4-oxopiperidine-3 -carboxylate (50 g, 258.23 mmol, HC1 salt) in DCM (500 mL) was added triethylamine (52.26 g, 516.46 mmol) at 20 °C and then acetic anhydride (29.00 g, 284.05 mmol) was added dropwise into the mixture at 20 °C. The mixture was stirred at 20 °C for 16 hours. The reaction mixture was poured into water (500 mL), extracted with ethyl acetate (600 mL><2), the combined organic layers were washed with brine (400 mL><2), dried over Na2SO4, filtered and concentrated to afford methyl l-acetyl-4-oxopiperidine-3 -carboxylate (55 g) as a red oil.

[0101] Step 2. To a mixture of methyl l-acetyl-4-oxopiperidine-3 -carboxylate (10 g, 50.20 mmol) and 3 -bromoaniline (8.64 g, 50.20 mmol) in EtOH (80 mL) was added 4A MS (12 g, 50.20 mmol) and AcOH (3.01 g, 50.20 mmol). The mixture was stirred at 80 °C for 16 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to afford methyl (4E)-l-acetyl-4-[(3-bromophenyl)imino]piperidine-3- carboxylate (34 g) as a red solid.

[0102] Step 3. The mixture of methyl (4E)-l-acetyl-4-[(3- bromophenyl)imino]piperidine-3-carboxylate (8 g, 22.65 mmol) in PPA (80 mL) was stirred at 150 °C for 2 hours. The reaction mixture was cooled to room temperature andpoured into water (1000 mL). Then adjusted with aqueous solution NaOH to pH = 7. Then a quantity of gum was formed, the gum was collected. The crude product was triturated with petroleum ether (200 mL) and H2O (200 mL) to afford 2-acetyl-7-bromo- lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridin-10-one (4.5 g, 62% yield) as a yellow solid. 1H NMR: DMSO-d6400 MHz 5 11.77 (br s, 1H), 8.00 (m, 1H), 7.67 (m, 1H), 7.42 (tm, 1H), 4.34-4.27 (m, 2H), 3.74-3.69 (m, 2H), 2.86 (s, 1H), 2.74 (s, 1H), 2.09 (s, 3H).

[0103] Step 4. The mixture of 2-acetyl-7-bromo-lH,2H,3H,4H,5H,10H-benzo[b]l,6- naphthyridin- 10-one (3 g, 9.34 mmol) in aqueous solution HC1 (40 mL, 20% purity) was stirred at 100 °C for 12 hours. After cooling to room temperature, the reaction mixture was filtered and the filter cake was washed by H2O (30 mL) for 3 times to afford 7- bromo-lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridin-10-one (1 g, 33%, HC1 salt) as a brown solid.

[0104] Step 5. To a mixture of 7-bromo-lH,2H,3H,4H,5H,10H-benzo[b]l,6- naphthyridin- 10-one (1 g, 3.17 mmol) and compound 3 (704.19 mg, 3.17 mmol) in DMF (30 mL) was added DIPEA (1.64 g, 12.67 mmol, 2.21 mL) and HATU (1.81 g, 4.75 mmol), the mixture was stirred at 25 °C for 16 hours. The reaction mixture was filtered and the filter cake was concentrated under reduced pressure to afford tert-butyl 4-{7- bromo- 10-oxo- 1H,2H,3H,4H,5H, 10H-benzo[b] 1 ,6-naphthyridine-2-carbonyl (benzoate (1.19 g) as a brown solid. 1H NMR: DMSO-d6 400 MHz 5 11.79 (br s, 1H), 8.03-7.98 (m, 3H), 7.68-7.41 (m, 4H), 4.51 (m, 1H), 4.23 (m, 1H), 3.95 (m, 1H), 3.56 (m, 1H), 2.88- 2.85 (m, 1H), 1.57 (s, 9H).Intermediate B

[0105] Step 1. To the mixture of 7-bromo-2,4-dihydro-lH-3,l-benzoxazine-2, 4-dione (CAS 76561-16-5, 10 g, 41.32 mmol) in DMF (100 mL) was added NaH (2.48 g, 61.98 mmol, 60% purity) portion-wise at 0 °C under N2. The mixture was stirred at 20 °C for1 hour. Then to the reaction mixture was added benzyl bromide (10.60 g, 61.98 mmol) and the mixture was stirred at 20 °C for 16 hours. The mixture was poured into ice water (1000 mL) and stirred at 20 °C for 0.5 hours. After filtered, the filter cake was washed by water (100 mL) and petroleum ether (100 mL). The filter cake was dried under reduced pressure to afford l-benzyl-7-bromo-2,4-dihydro-lH-3,l-benzoxazine-2, 4-dione (10.4 g, 76%) as a brown solid. 1H NMR: DMSO-d6 400 MHz 5 7.94 (d, J = 8.4 Hz, 1H), 7.51- 7.35 (m, 7H), 5.32 (s, 2H).

[0106] Step 2. The mixture of l-benzyl-7-bromo-2,4-dihydro-lH-3,l-benzoxazine-2,4- dione (10 g, 30.11 mmol) and tert-butyl 4-oxopiperidine-l -carboxylate (12.6 g, 63.22 mmol) in toluene (100 mL) was cooled to 0 °C under N2 and then LiHMDS (1 M, 69.25 mL, 69.25 mmol) was added dropwise into the reaction mixture at 0 °C. The mixture was stirred at 80 °C for 3 hours. After the reaction mixture was cooled to room temperature, the mixture was quenched by aqueous solution NH4C1 (150 mL) and extracted with ethyl acetate (150 mL><3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude was triturated with petroleum ether / ethyl acetate (3 / 1, 50 mL) at 20 °C for 16 hours. After filtered, the filter cake was dried under reduced pressure to afford tert-butyl 5-benzyl-7-bromo-10- oxo-lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridine-2-carboxylate (7.5 g, 53% yield) as a white solid. 1H NMR: DMSO-d6 400 MHz 5 8.14 (d, J = 8.4 Hz, 1H), 7.82 (s, 1H), 7.51 (d, J = 7.2 Hz, 1H), 7.38-7.29 (m, 3H), 7.07 (d, J = 7.2 Hz, 2H), 5.60 (s, 2H), 4.33 (s, 2H), 3.59 (br s, 2H), 2.84 (br s, 2H), 1.43 (s, 9H).

[0107] Step 3. Synthesis of 5-benzyl-7-bromo-lH,2H,3H,4H,5H,10H-benzo[b]l,6- naphthyridin- 10-one: To a mixture of tert-butyl 5-benzyl-7-bromo-10-oxo- lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridine-2-carboxylate (3.5 g, 7.46 mmol) in MeOH (10 mL) was added HCl / dioxane (4 M, 30 mL), then the mixture was stirred at 20 °C for 0.5 hours. The reaction mixture was concentrated under reduced pressure to afford 5-benzyl-7-bromo-lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridin-10-one (3.4 g, HC1 salt) as a white solid. 1H NMR: DMSO-d6 400 MHz 5 9.73 (br s, 2H), 8.13 (d, J = 8.4 Hz, 1H), 7.88 (s, 1H), 7.55 (d, J = 8.8 Hz, 1H), 7.38-7.31 (m, 3H), 7.13 (d, J = 7.2 Hz, 2H), 5.66 (s, 2H), 4.02 (s, 2H), 3.39 (m, 2H), 3.16-3.08 (m, 2H).Intermediate C

[0108] Step 1. To a solution of methyl l-acetyl-4-oxopiperidine-3-carboxylate (5 g, 25.1 mmol) and 3-bromo-4-fluoroaniline (4.77 g, 25.1 mmol) in EtOH (38 mL) was added HO Ac (263 mg, 4.37 mmol) and 4A MS (10 g, 25.1 mmol) at 20 °C. The mixture was stirred at 80 °C for 3 hours. After cooling to room temperature, the reaction mixture was filtered and filtrate was concentrated under reduced pressure. The residue was dissolved in PPA (100 mL) and stirred at 150 °C for 2 hours. After cooling to room temperature, the reaction mixture was poured into water (400 mL) and adjusted with NaOH aqueous solution (100 mL) to pH = 7.0 at 0 °C. The mixture was filtered and the filter cake was concentrated to afford 2-acetyl-7-bromo-8-fluoro-lH,2H,3H,4H,5H,10H-benzo[b]l,6- naphthyridin- 10-one (6 g, crude) as a yellow solid.

[0109] Step 2. A mixture of 2-acetyl-7-bromo-8-fluoro-lH,2H,3H,4H,5H,10H- benzo[b]l,6-naphthyri din- 10-one (3 g, 8.85 mmol) in aqueous solution HC1 (40 mL, 20% purity) was stirred at 100 °C for 12 hours. The reaction mixture filtered and the filter cake was washed with H2O (30 mL) for 3 times to afford 7-bromo-8-fluoro- lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridin-10-one (1.8 g, 61%, HC1 salt) as an off- white solid. 1H NMR: DMSO-d6 400 MHz 5 12.59-12.43 (m, 1H), 9.45 (s, 2H), 7.98- 7.82 (m, 1H), 7.67 (m, 1H), 3.93 (m, 2H), 3.42 (m, 2H), 3.04-3.01 (m, 2H).

[0110] Step 3. To a mixture of 7-bromo-8-fluoro-lH,2H,3H,4H,5H,10H-benzo[b]l,6- naphthyridin- 10-one (1.8 g, 5.40 mmol) and 4-[(tert-butoxy)carbonyl]benzoic acid (1.2 g, 5.40 mmol) in DMF (30 mL) was added HATU (2.46 g, 6.48 mmol) and DIPEA (2.79 g, 21.60 mmol). The mixture was stirred at 25 °C for 16 hours. The reaction mixture was filtered and the filter cake was dried under reduced pressure to afford tert-butyl 4-{7- bromo-8-fluoro-10-oxo-lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridine-2-carbonyl (benzoate (2.1 g, crude) as a white solid. 1HNMR: DMSO-d6400 MHz 5 11.89 (s, 1H), 7.99 (d, J = 7.6 Hz, 2H), 7.62-7.55 (m, 4H), 4.49 (m, 1H), 4.18 (m, 1H), 3.94 (m, 1H), 3.54 (m, 1H), 2.89-2.82 (m, 2H), 1.57 (s, 9H).

[0111] Step 4. To the mixture of tert-butyl 4-{7-bromo-8-fluoro-10-oxo- lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridine-2-carbonyl}benzoate (1.2 g, 2.39 mmol) and K2CO3 (661 mg, 2.39 mmol) in DMF (15 mL) was added BnBr (614 mg, 3.59 mmol) in one portion at 20 °C under N2. The mixture was heated to 80 °C and stirred for 16 hours under N2. After cooling to room temperature, the reaction mixture was poured into water (30 mL), extracted with ethyl acetate (50 mL><2). The combined organic, , , , , , naphthyridin- 10-one (Intermediate B, 3 g, 7.39 mmol, HC1 salt) and 4-[(tert- butoxy)carbonyl]benzoic acid (1.64 g, 7.39 mmol) in DMF (30 mL) was added DIPEA (3.82 g, 29.58 mmol, 5.15 mL) in one portion at 20 °C. Then HATU (4.22 g, 11.09 mmol) was added into the stirred solution. The mixture was stirred at 20 °C for 16 hours. The reaction mixture was poured into water (300 mL), extracted with ethyl acetate (100 mL><2). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified bycolumn chromatography to afford tert-butyl 4-{5-benzyl-7-bromo-10-oxo- lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridine-2-carbonyl}benzoate (5.6 g) as a red solid. 1H NMR: DMSO-d6 400 MHz 5 8.16 (m, 1H), 8.03-7.95 (m, 3H), 7.59-7.50 (m, 3H), 7.38-7.29 (m, 3H), 7.10 (m, 2H), 5.61 (br s, 2H), 4.65 (br s, 1H), 4.33 (s, 1H), 3.92 (br s, 1H), 3.67-3.60 (m, 1H), 3.16-3.12 (m, 1H), 2.96 (m, 1H), 1.56 (s, 9H).Intermediate E

[0113] To a suspension of 7-bromo-5-[(2,4-dimethoxyphenyl)methyl]- lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridin-10-one hydrochloride (1 eq., 2.06 g, 3.98 mmol) in DMF (13.25 mL) were added at RT 4-[(tert-butoxy)carbonyl]benzoic acid (1.1 eq., 0.97 g, 4.37 mmol), DIPEA (4.6 eq., 2.36 g, 3.19 mL, 18.29 mmol) and HATU (1.3 eq., 1.97 g, 5.17 mmol). The reaction mixture was stirred at RT for 16 hours then was diluted with water (80 mL). The resulting precipitate was filtered, washed with water (3 x 20 mL), dissolved in DCM (100 mL), dried over Na2SO4, filtered and concentrated to dryness to afford tert-butyl 4-{7-bromo-5-[(2,4-dimethoxyphenyl)methyl]-10-oxo- lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridine-2-carbonyl}benzoate (2.59 g) as an orange solid which was used in the next step without further purification.Intermediate F

[0114] To a solution of tert-butyl 5-[(2,4-dimethoxyphenyl)methyl]-7-(4- methylpiperazin- 1 -yl)- 10-oxo- 1H,2H,3H,4H,5H, 10H-benzo[b] 1 ,6-naphthyridine-2- carboxylate (1 eq., 1.74 g, 3.17 mmol) in DCM (15.7 mL) was added TFA (66.5 eq., 24g, 15.66 mL, 210.82 mmol) at RT. The reaction mixture was stirred at RT for 2 hours. The reaction mixture was concentrated to dryness. The residue was diluted with EtOAc (50 mL) and washed with a saturated solution of NaHCO3 (35 mL). The aqueous layer was extracted with EtOAc (2 x 50 mL). The aqueous layer was extracted with CHC13 / MeOH (9 / 1, 4 x 100 mL). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated to dryness to afford 5-[(2,4- dimethoxyphenyl)methyl]-7-(4-methylpiperazin-l-yl)-lH,2H,3H,4H,5H,10H- benzo[b]l,6-naphthyri din- 10-one (1.28 g) as an off-white solid. LC / MS (Method E): Rt= 1.30 min, [M+H]+ = 449.7Intermediate G

[0115] To a solution of tert-butyl 7-[(3S)-3,4-dimethylpiperazin-l-yl]-5-methyl-10-oxo- lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridine-2-carboxylate (1 eq., 2.82 g, 6.61 mmol) in 1,4-di oxane (30 mL) was added HC1 4M in dioxane (18.15 eq., 30 mL, 120 mmol) at RT and the resulting mixture was stirred at RT for 16 h. Et2O (50 mL) was added to the reaction mixture. The precipitate was filtered on a glass-frit. The resulting solid was washed with Et2O (3 x 50 mL) affording 7-[(3S)-3,4-dimethylpiperazin-l-yl]- 5-methyl-lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridin-10-one (3.55 g, di HC1 salt) as a brown solid.Intermediate H

[0116] Step 1. To a solution of 7-bromo-2,4-dihydro-lH-3,l-benzoxazine-2, 4-dione (1 eq., 1.5 g, 6.2 mmol) in DMA (2 mL) were added at RT DIPEA (2 eq., 1.602 g, 2.16 mL, 12.4 mmol) and iodomethane (3 eq., 2.64 g, 1.16 mL, 18.59 mmol). The mixture wasstirred at RT for 18 h. The mixture was cooled at 0 °C and water (20 mL) was slowly added. The solid that precipitated was collected by filtration, washed with water (3 x 50 mL) and dried under vacuum overnight to afford 7-bromo-l-methyl-2,4-dihydro-lH-3,l- benzoxazine-2, 4-dione (1.5 g) as a yellow solid.

[0117] Step 2. Boc-piperidone (2.1 eq., 2.45 g, 12.31 mmol) and LiHMDS (2.3 eq., 13.48 mL, 13.48 mmol) in toluene (11.9 mL) were stirred at 0 °C for 20 min. 7-bromo-l- methyl-2,4-dihydro-lH-3,l-benzoxazine-2, 4-dione (1 eq., 1.5 g, 5.86 mmol) was slowly added to the mixture (by portion) at 0 °C. The resulting mixture was heated at 80 °C for 16 h. The mixture was cooled to room temperature and concentrated under reduced pressure. The crude product was triturated with Et2O (100 mL) for 30 min. The reaction mixture was filtered, washed with Et2O (2 x 100 mL) and concentrated under reduced pressure. The residue was dissolved in EtOAc (1 mL), precipitated with Et2O (5 mL), centrifuged and the supernatant was discarded (process done twice). The remaining solid was dried under reduced pressure. The residue was diluted with NH4C1 aq (5 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated to dryness. The crude material was purified by flash chromatography over silica gel (DCM / (DCM / MeOH: 9 / 1) 100 / 0 to 70 / 30) to afford tert-butyl 7-bromo-5-methyl-10-oxo-lH,2H,3H,4H,5H,10H- benzo[b]l,6-naphthyridine-2-carboxylate (633 mg) as a yellow solid.

[0118] Step 3. To a suspension of tert-butyl 7-bromo-5-methyl-10-oxo- lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridine-2-carboxylate (1 eq., 740 mg, 1.88 mmol) in dioxane (11.069 mL) was added HC1 4N in dioxane (5 eq., 2.35 mL, 9.408 mmol). The reaction mixture was stirred at RT for 4 hours. HC1 4 N in dioxane (5 eq., 2.35 mL, 9.408 mmol) was then added at RT and the reaction mixture was stirred at RT for 2 hours. The reaction mixture was concentrated to dryness at 30 °C and co-evaporated with DCM (2 x 40 mL) to afford 7-bromo-5-methyl-lH,2H,3H,4H,5H,10H-benzo[b]l,6- naphthyridin- 10-one (679 mg, quantitative yield, HC1 salt) as a beige solid used as such for the next step.Intermediate I

[0119] To a suspension of 7-bromo-5-methyl-lH,2H,3H,4H,5H,10H-benzo[b]l,6- naphthyridin- 10-one (1 eq., 620 mg, 1.71 mmol) in DMF (5.7 mL) were added at RT 4- [(tert-butoxy)carbonyl]benzoic acid (1.1 eq., 418 mg, 1.88 mmol), DIPEA (4.6 eq., 1.02 g, 1.37 mL, 7.87 mmol) and HATU (1.3 eq., 846 mg, 2.23 mmol). The reaction mixture was stirred at RT for 16 hours. The reaction mixture was diluted with water (100 mL). The resulting precipitate was filtered and washed with water (3 x 50 mL) and Et20 (3 x 50 mL). The solid concentrated to dryness to afford tert-butyl 4-{7-bromo-5-methyl-10- oxo- 1H,2H,3H,4H, 5H, 10H-benzo[b] 1 ,6-naphthyridine-2-carbonyl (benzoate (827 mg, 98% yield) as a beige solid used as such for the next step.Intermediate J

[0120] Step 1. To an Argon-purged mixture of tert-butyl 7-bromo-5-methyl-10-oxo- lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridine-2-carboxylate (1 eq., 4 g, 10.17 mmol), (2S,6S)-l,2,6-trimethylpiperazine (1.2 eq., 1.56 g, 12.205 mmol) and Cs2CO3 (2 eq., 6.63 g, 20.34 mmol) in toluene (78.24 mL) were added Pd2(dba)3 (0.05 eq., 0.47 g, 0.509 mmol) and BINAP (0.05 eq., 0.32 g, 0.509 mmol) at RT and the resulting mixture was stirred at 100 °C for 16 h. The reaction mixture was filtered over Celite, washed with MeOH (3 x 80 mL) and concentrated to dryness. The crude material was purified by flash chromatography over silica gel (DCM / (MeOH + 5% NH4OH) 95 / 5 to 85 / 15) to afford tert-butyl 5-methyl-10-oxo-7-[(3S,5S)-3,4,5-trimethylpiperazin-l-yl]- lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridine-2-carboxylate (1.68 g) as a brown solid.

[0121] Step 2. To a solution of tert-butyl 5-methyl-10-oxo-7-[(3S,5S)-3,4,5- trimethylpiperazin-l-yl]-lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridine-2- carboxylate (0.62 eq., 1.68 g, 3.81 mmol) in DCM (27 mL) was added at RT HC1 4N in dioxane (17 eq., 27 mL, 109.4 mmol). The reaction mixture was stirred at RT for 3 hours., , , DIPEA (1 eq., 6.46 g, 8.71 mL, 50 mmol). The reaction mixture was heated to 110 °C and stirred for 16 hours. The reaction mixture was cooled to RT, diluted with water (50 mL) and extracted with EtOAc (3 x 60 mL). The combined organic layers were washed with brine (3 x 50 mL), dried over Na2SO4, filtered and concentrated to dryness to afford 4-bromo-2-(cy cl opropylamino)benzonitrile (13.83 g) as a brown solid used as such for the next step.

[0123] Step 2. To a solution of 4-bromo-2-(cyclopropylamino)benzonitrile (1 eq., 13.83 g, 50 mmol) in EtOH (21 mL) and H2O (4.4 mL) was added at RT KOH (3.5 eq., 9.82 g, 174.99 mmol). The reaction mixture was heated to 80 °C and stirred for 16 hours. The reaction mixture was cooled to RT and acidified to pH 3-4 with HC1 3M at 0 °C. The resulting solid was filtered, washed with H2O (3 x 50 mL), with Et2O (50 mL) then coevaporated with CH3CN (3 x 100 mL).The filtrate was concentrated until evaporation of Et2O, filtered, washed with water (3 x 50 mL) and co-evaporated with CH3CN (3 x 100 mL) to afford 4-bromo-2-(cyclopropylamino)benzoic acid (5.44 g) as a brown solid.

[0124] Step 3. To a solution of 4-bromo-2-(cyclopropylamino)benzoic acid (1 eq., 2 g, 7.809 mmol) in THF (13.9 mL) cooled to 0 °C, was added portion-wise triphosgene (0.38 eq., 0.88 g, 0.49 mL, 2.97 mmol). The reaction mixture was stirred at 0 °C for 30 minutes then warmed to RT and stirred for 16 hours. The reaction mixture was diluted with Et2O (50 mL), filtered and washed with Et2O (2 x 15 mL).The filtrate was concentrated to dryness and the residue was triturated in Et2O (30 mL), filtered and washed with Et2O (3 x 15 mL) to afford after drying under vacuum 7-bromo-l-cyclopropyl-2,4-dihydro- lH-3,l-benzoxazine-2, 4-dione (1.49 g) as a beige solid.

[0125] Step 4. To a mixture of 7-bromo-l-cyclopropyl-2,4-dihydro-lH-3,l- benzoxazine-2, 4-dione (1 eq., 1.92 g, 6.806 mmol) and Boc-piperidone (2.1 eq., 2.85 g, 14.29 mmol) in toluene (13.4 mL) was added dropwise at 0 °C LiHMDS 1 M in THF (2.3 eq., 15.65 mL, 15.65 mmol). The reaction mixture was stirred at 0 °C for 20 minutes, then heated to 80 °C and stirred for 16 hours. The reaction mixture was cooled to RT and concentrated to dryness. The crude material was purified by flash chromatography over silica gel (DCMZEtOAc 10 / 0 to 6 / 4) to afford tert-butyl 7-bromo-5-cyclopropyl-10-oxo- lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridine-2-carboxylate (1.59 g) as a yellow solid.

[0126] Step 5. To a solution of tert-butyl 7-bromo-5-cyclopropyl-10-oxo- lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridine-2-carboxylate (1 eq., 0.25 g, 0.56 mmol) in dioxane (3.3 mL) was added HC1 4N in dioxane (10 eq., 1.403 mL, 5.61 mmol) at RT. The reaction mixture was stirred at RT for 16 hours. The reaction mixture was concentrated to dryness and co-evaporated with DCM / MeOH (9 / 1 ; 20 mL) thenDCM (20 mL) to afford 7-bromo-5-cyclopropyl-lH,2H,3H,4H,5H,10H-benzo[b]l,6- naphthyridin- 10-one (231 mg) as an orange solid used as such for the next step.Synthesis of the example compoundsCpd 1

[0127] Step 1. To a solution of 5-bromo-2-chloroaniline (20 g, 96.87 mmol) in EtOH (200 mL) was added ethyl l-benzyl-4-oxopiperidine-3 -carboxylate (34.61 g, 116.24 mmol, HC1 salt), AcOH (5.82 g, 96.87 mmol, 5.54 mL), 4A MS (50 g) at 20 °C and then the mixture was stirred at 80 °C for 16 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure. The crude product (40 g, 88.93 mmol) was stirred in polyphosphoric acid (250 mL) at 150 °C for 3 hours. After cooling to room temperature, the mixture was dissolved in water (500 mL). The mixture was adjusted to pH = 6-7 with aqueous NaOH (6 M), filtered and triturated with MeOH (50 mL) at 20 °C for 0.5 hour to afford 2-benzyl-9-bromo-6-chloro-lH,2H,3H,4H,5H,10H-benzo[b]l,6- naphthyridin- 10-one (10 g, 28% yield) as a brown solid.

[0128] Step 2. To a solution of 2-benzyl-9-bromo-6-chloro-lH,2H,3H,4H,5H,10H- benzo[b]l,6-naphthyri din- 10-one (1 g, 2.48 mmol) in dioxane (10 mL) and H2O (2.5 mL) was added (pyri din-3 -yl)boronic acid (274.03 mg, 2.23 mmol), Pd(dppf)C12 (181.25 mg, 247.71 pmol), K3PO4 (1.58 g, 7.43 mmol) at 20 °C and the mixture was stirred at 80 °C for 16 hours under N2. After cooling to room temperature, the mixture was poured into water (40 mL) and extracted with ethyl acetate (50 mL><3). The combined organic layer was washed with brine (30 mL><3), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, CH2C12 / MeOH=99 / l to 95 / 5) to afford 2-benzyl-6-chloro-9-(pyridin-3-yl)- lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridin-10-one (350 mg, 35% yield) as brown oil.

[0129] Step 3. To a mixture of 2-benzyl-6-chloro-9-(pyridin-3-yl)- lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridin-10-one (320 mg, 796.2 pmol) and cone. HC1 (12 M, 199 pL) in EtOH (10 mL) was added Pd / C (100 mg, 10% wt Pd) and Pd(OH)2 / C (100 mg, 10% wt Pd). The reaction mixture was stirred at 20 °C for 17 hours under H2 atmosphere. The reaction mixture was filtered and Pd / C (100 mg, 10% wt Pd)and Pd(OH)2 / C (100 mg, 10% wt Pd) were added. The reaction mixture was stirred at 40 °C for 2 hours under H2 atmosphere. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to afford 6-chl oro-9-(pyri din-3 -yl)- lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridin-10-one (300 mg) as a yellow solid.

[0130] Step 4. To a mixture of 6-chloro-9-(pyridin-3-yl)-lH,2H,3H,4H,5H,10H- benzo[b]l,6-naphthyri din- 10-one (250 mg, 901.5 pmol) and 4-[(tert- butoxy)carbonyl]benzoic acid (200.3 mg, 901.5 pmol) in DMF (3 mL) were added DIPEA (349.5 mg, 2.70 mmol, 471 pL) and HATU (514.2 mg, 1.35 mmol). The mixture was stirred at 20 °C for 16 hours. The reaction mixture was poured into brine (50 mL), extracted with ethyl acetate (50 mL><2). The combined organic layers were washed with brine (50 mL><2), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, CH2C12 / MeOH=10 / l) to afford tert-butyl 4-[6-chloro- 10-oxo-9-(pyri din-3 -yl)- 1H,2H,3H,4H, 5H, 10H- benzo[b]l,6-naphthyridine-2-carbonyl]benzoate (210 mg, 49% yield) as a black brown solid.

[0131] Step 5. To a mixture of tert-butyl 4-[6-chloro-10-oxo-9-(pyridin-3-yl)- lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridine-2-carbonyl]benzoate (180 mg, 373.8 pmol) in DCM (3 mL) was added TFA (4.62 g, 40.5 mmol). The mixture was stirred at 25 °C for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC to afford 4-[6-chloro-10-oxo-9-(pyridin-3-yl)- lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridine-2-carbonyl]benzoic acid (77.9 mg, 45% yield, TFA salt) as a white solid. LCMS: [M+H]+ = 426.3. 'H NMR (400 MHz, Methanol-d4) 5 8.83-8.68 (m, 2H), 8.48-8.37 (m, 1H), 8.16-7.92 (m, 3H), 7.80-7.72 (m, 2H), 7.56-7.54 (m, 2H), 7.24-7.22 (m, 1H), 4.62 (s, 1H), 4.32 (s, 1H), 4.10 (m, 1H), 3.73 (m, 1H), 3.05-2.99 (m, 2H) (7 labile H not visible)' .Cpd 2

[0132] Step 1. To a mixture of Intermediate A (500 mg, 1.03 mmol) and tert-butyl 3- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2,5-dihydro-lH-pyrrole-l-carboxylate (305.35 mg, 1.03 mmol) in dioxane (5 mL) and H2O (1 mL) was added Pd(dppf)C12 (75.7 mg, 103.4 pmol) and K2CO3 (285.9 mg, 2.07 mmol). The mixture was stirred at100 °C for 16 hours under N2. After cooling to room temperature, the reaction mixture was poured into water (300 mL), extracted with ethyl acetate (200 mL*2). The combined organic layers were washed with brine (50 mL><2), dried over Na2SO4, filtered and concentrated. The residue was purified by prep-TLC to afford tert-butyl 3-(2-{4-[(tert- butoxy)carbonyl]benzoyl}-10-oxo-lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridin-7- yl)-2,5-dihydro-lH-pyrrole-l-carboxylate (340 mg, 58% yield) as a brown solid.

[0133] Step 2. To a mixture of tert-butyl 3-(2-{4-[(tert-butoxy)carbonyl]benzoyl}-10- oxo-lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridin-7-yl)-2,5-dihydro-lH-pyrrole-l- carboxylate (340 mg, 594.8 pmol) in MeOH (6 mL) was added Pd / C (200 mg, 10% wt Pd). The mixture was stirred at 40 °C for 4 hours under H2 atmosphere. After cooling to room temperature, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure to afford tert-butyl 3-(2-{4-[(tert-butoxy)carbonyl]benzoyl}-10- oxo-lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridin-7-yl)pyrrolidine-l -carboxylate (240 mg, 70% yield) as a brown solid.

[0134] Step 3. To a mixture of tert-butyl 3-(2-{4-[(tert-butoxy)carbonyl]benzoyl}-10- oxo-lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridin-7-yl)pyrrolidine-l -carboxylate (240 mg, 418.4 pmol) in dichloromethane (3 mL) was added TFA (3 mL). The mixture was stirred at 20 °C for 1 hour. The reaction mixture was concentrated under reduced pressure to afford 4-[10-oxo-7-(pyrrolidin-3-yl)-lH,2H,3H,4H,5H,10H-benzo[b]l,6- naphthyridine-2-carbonyl]benzoic acid (320 mg, crude) as a brown solid.

[0135] Step 4. To a mixture of 4-[10-oxo-7-(pyrrolidin-3-yl)-lH,2H,3H,4H,5H,10H- benzo[b]l,6-naphthyridine-2-carbonyl]benzoic acid (300 mg, 718.6 pmol) and HCHO (255 mg) in dichloromethane (3 mL) and MeOH (2 mL) were added AcOH (86.3 mg, 1.44 mmol) and NaBH3CN (135.5 mg, 2.16 mmol). The mixture was stirred at 35 °C for 16 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC and lyophilized to afford 4-[7-(l-methylpyrrolidin-3-yl)- 10-oxo-lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridine-2-carbonyl]benzoic acid (8.7 mg, 3% yield, HC1 salt) as an off-white solid. LCMS: [M+H]+ = 432.3. 'H NMR (400 MHz, DMSO-d6) 5 12.67-12.37 (m, 1H), 11.48-11.36 (m, 1H), 8.19-8.01 (m, 3H), 7.62- 7.30 (m, 4H), 4.57 (s, 1H), 4.29 (s, 1H), 3.95-3.87 (m, 2H), 3.70-3.52 (m, 4H), 3.28-3.13 (m, 2H), 2.95 (m, 2H), 2.87 (s, 3H), 2.18-1.98 (m, 1H).Cpd 3

[0136] Step 1. To a mixture of Intermediate B (1.2 g, 3.25 mmol) in DCM (10 mL) was added TEA (986.5 mg, 9.75 mmol, 1.36 mL) and methyl 4-(chlorocarbonyl)benzoate (645.4 mg, 3.25 mmol). The mixture was stirred at 20 °C for 2 hours. The reaction mixture was filtered and the filter cake was triturated with petroleum ether (25 mL) and H2O (25 mL) for 1 hour to afford methyl 4-{5-benzyl-7-bromo-10-oxo-lH,2H,3H,4H,5H,10H- benzo[b]l,6-naphthyridine-2-carbonyl (benzoate (1.49 g, 86% yield) as a white solid.

[0137] Step 2. To a mixture of methyl 4-{5-benzyl-7-bromo-10-oxo- lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridine-2-carbonyl}benzoate (750 mg, 1.41 mmol) and 2-(2-ethoxyethenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (559.1 mg, 2.82 mmol) in dioxane (5 mL) and H2O (1 mL) was added K2CO3 (585.2 mg, 4.23 mmol) and Pd(dppf)C12 (103.3 mg, 141.14 pmol). The mixture was heated to 80 °C and stirred for 16 hours under N2. The reaction mixture was poured into water (50 mL), extracted with ethyl acetate (50 mL><2). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure and purified by column chromatography (SiO2, Dichloromethane / Methanol = 10 / 1, Rf = 0.48) to afford methyl 4-[5-benzyl-7-(2-ethoxy ethenyl)- 10-oxo- 1H, 2H, 3H, 4H, 5H, 10H- benzo[b]l,6-naphthyridine-2-carbonyl]benzoate (460 mg, crude) as a yellow solid.

[0138] Step 3. To a solution of methyl 4-[5-benzyl-7-(2-ethoxyethenyl)-10-oxo- lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridine-2-carbonyl]benzoate (460 mg, 880.2 pmol) in DCM (5 mL) was added TFA (8.50 g, 74.55 mmol, 5.5 mL) dropwise at 0 °C and the mixture was stirred at 0 °C for 1 hour. The reaction mixture was adjusted to pH = 8~9 with aqueous NaHCO3. The combined organic layers were concentrated to afford methyl 4-[5-benzyl-10-oxo-7-(2-oxoethyl)-lH,2H,3H,4H,5H,10H-benzo[b]l,6- naphthyridine-2-carbonyl]benzoate (350 mg, crude) as yellow oil.

[0139] Step 4. To a solution of methyl 4-[5-benzyl-10-oxo-7-(2-oxoethyl)- lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridine-2-carbonyl]benzoate (167.6 mg, 707.7 pmol, HC1) in DCM (3 mL) was added TEA (190.8 mg, 1.89 mmol) at 20 °C. The mixture was stirred at 20 °C for 0.5 hour. To the reaction mixture was added tert-butyl N-{[(3R)-pyrrolidin-3-yl]methyl}carbamate (350 mg, 707.7 pmol) and AcOH (34.0 mg,707.7 pmol, 20 pL). The mixture was stirred at 20 °C for 2 hours. To the reaction mixture was added NaBH(OAc)3 (375.0 mg, 1.77 mmol). The reaction mixture was stirred at 20 °C for 16 hours. The reaction mixture was adjusted to pH = 8~9 with aqueous NaHCO3, extracted with ethyl acetate (30 mL><3). The combined organic layers were washed with brine (30 mL><2), dried over Na2SO4, filtered and concentrated to afford methyl 4-(5- benzyl-7-{2-[(3S)-3-({[(tert-butoxy)carbonyl]amino}methyl)pyrrolidin-l-yl]ethyl}-10- oxo-lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridine-2-carbonyl)benzoate (400 mg, 83% yield) as yellow oil.

[0140] Step 5. To a mixture of methyl 4-(5-benzyl-7-{2-[(3S)-3-({[(tert- butoxy)carbonyl]amino}methyl)pyrrolidin- 1 -yl] ethyl }- 10-oxo- 1H,2H,3H,4H,5H, 10H- benzo[b]l,6-naphthyridine-2-carbonyl)benzoate (400 mg, 589.26 pmol) in MeOH (4 mL) was added Pd / C (500 mg, 10% wt Pd) and Pd(OH)2 / C (500 mg, 10% wt Pd). The mixture was stirred at 40 °C for 16 hours under H2 (15 Psi). The reaction mixture was filtered and concentrated under reduced pressure to afford methyl 4-(7-{2-[(3S)-3-({[(tert- butoxy)carbonyl]amino}methyl)pyrrolidin- 1 -yl] ethyl }- 10-oxo- 1H,2H,3H,4H,5H, 10H- benzo[b]l,6-naphthyridine-2-carbonyl)benzoate (180 mg, 52% yield) as yellow oil.

[0141] Step 6. To a mixture of methyl 4-(7-{2-[(3S)-3-({[(tert- butoxy)carbonyl]amino}methyl)pyrrolidin- 1 -y 1 ] ethyl }- 10-oxo- 1H,2H,3H,4H,5H, 10H- benzo[b]l,6-naphthyridine-2-carbonyl)benzoate (180 mg, 305.76 pmol) in DCM (3 mL) was added TFA (4.62 g, 40.52 mmol, 3.00 mL) and the mixture was stirred at 20 °C for 0.5 hour. The reaction mixture was concentrated under reduced pressure to afford methyl 4-(7- { 2- [(3 S ) -3 -(aminomethyl)pyrrolidin- 1 -y 1 ] ethyl } - 10-oxo- 1 H,2H, 3H,4H, 5H, 10H- benzo[b]l,6-naphthyridine-2-carbonyl)benzoate (250 mg, crude) as yellow oil.

[0142] Step 7. To a mixture of methyl 4-(7-{2-[(3S)-3-(aminomethyl)pyrrolidin-l- yl] ethyl } - 10-oxo- 1H,2H,3H,4H,5H, 10H-benzo[b] 1 ,6-naphthyridine-2- carbonyl)benzoate (250 mg, in MeOH (2 mL), THF (1 mL) and H2O (2 mL) was added LiOH.H2O (226.8 mg, 5.40 mmol) and the mixture was stirred at 20 °C for 1 hour. The reaction mixture was concentrated under reduced pressure and purified by preparative HPLC to afford 4-(7-{2-[(3S)-3-(aminomethyl)pyrrolidin-l-yl]ethyl}-10-oxo- lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridine-2-carbonyl)benzoic acid (13 mg, 4% yield, TFA salt). LCMS: [M+H]+ = 475.2. *H NMR (400 MHz, DMSO-d6) 5 11.91 (s,1H), 10.72 (br s, 1H), 8.09-7.97 (m, 6H), 7.61-7.55 (m, 2H), 7.38 (m, 1H), 7.24-7.20 (m, 1H), 4.53 (s, 1H), 4.27 (s, 1H), 3.95 (s, 1H), 3.58-3.47 (m, 6H), 3.09-2.91 (m, 8H), 2.50- 2.07 (m, 1H), 1.89-1.70 (m, 1H).Cpd 4

[0143] Step 1. To a 15 mL vial equipped with a stir bar was added tert-butyl 4-{7-bromo- 5-[(4-methoxyphenyl)methyl]-10-oxo-lH,2H,3H,4H,5H,10H-benzo[b]l,6- naphthyridine-2-carbonyl}benzoate (100 mg, 165.70 pmol), tert-butyl N-(3- iodocyclobutyl)carbamate (98.5 mg, 331.40 pmol), Ir[dF(CF3)ppy]2(dtbpy)(PF6) (1.9 mg, 1.66 pmol), NiC12.dtbbpy (0.99 ug, 2.49 pmol), TTMSS (41.2 mg, 165.70 pmol, 51.12 pL) and Na2CO3 (35.1 mg, 331.40 pmol) in DME (2 mL). The reaction was stirred under N2 and irradiated with a 10 W blue LED lamp (3 cm away), with cooling water to keep the reaction temperature at 25 °C for 14 hours. The reaction mixture was poured into water (10 mL), extracted with ethyl acetate (5 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by prep-TLC to afford tert-butyl 4-[7-(3-{[(tert-butoxy)carbonyl]amino}cyclobutyl)-5-[(4- methoxyphenyl)methyl]-10-oxo-lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridine-2- carbonyl]benzoate (150 mg) as a yellow solid.

[0144] Step 2. The mixture of tert-butyl 4-[7-(3-{[(tert- butoxy)carbonyl]amino}cyclobutyl)-5-[(4-methoxyphenyl)methyl]-10-oxo- lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridine-2-carbonyl]benzoate (130 mg, 187.4 pmol) in TFA (3 mL) was stirred at 80 °C for 32 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC to afford 4-[7-(3-aminocyclobutyl)-10-oxo-lH,2H,3H,4H,5H,10H-benzo[b]l,6- naphthyridine-2-carbonyl]benzoic acid (10.9 mg, 11% yield, TFA salt) as a white solid. LCMS: [M+H]+ = 418.3. 'H NMR (400 MHz, DMSO-d6) MHz 5 8.25-8.14 (m, 3H), 7.62-7.60 (m, 2H), 7.41-7.33 (m, 2 H), 4.80 (s, 1H), 4.51 (s, 1H), 4.13 (s, 1H), 3.97-3.55 (m, 3H), 3.06-2.99 (m, 2 H) 2.88-2.69 (m, 4 H).Cpd 5

[0145] Step 1. To a solution of 2-amino-4-bromobenzoic acid (10 g, 46.29 mmol) in DCM (100 mL) was added 2,4-dimethoxybenzaldehyde (9.23 g, 55.55 mmol) and AcOH(1.39 g, 23.14 mmol) at 20 °C. The mixture was stirred at 40 °C for 1 hour then cooled to 0 °C and NaBH(OAc)3 (29.43 g, 138.87 mmol) was added in portions under N2. The mixture was stirred at 20 °C for 16 hours. To the reaction mixture was added NaBH3CN (8.73 g, 138.87 mmol) and the mixture was stirred at 40 °C for 16 hours. The mixture was poured into water (200 mL) and extracted with ethyl acetate (300 mL x 3). The combined organic layers were washed with brine (100 mL><3), dried over Na2SO4, filtered and concentrated under reduced pressure and triturated with a petroleum ether / ethyl acetate (4 / 1, 100 mL) to afford 4-bromo-2-{[(2,4-dimethoxyphenyl)methyl]amino}benzoic acid (14.5 g, 86% yield) as a brown solid.1H NMR (400 MHz, DMSO-d6) 5 12.80 (br s, 1H), 8.29 (br s, 1H), 7.68 (d, J = 8.4 Hz, 1H), 7.16 (d, J = 8.0 Hz, 1H), 6.89 (d, J = 2.0 Hz, 1H), 6.70-6.68 (m, 1H), 6.60 (m, 1H), 6.51-6.49 (m, 1H), 4.29 (m, 2H), 3.83 (s, 3H), 3.75 (s, 3H).

[0146] Step 2. To the solution of 4-bromo-2-{[(2,4- dimethoxyphenyl)methyl]amino}benzoic acid (14.5 g, 39.60 mmol) in THF (150 mL) was added triphosgene (4.46 g, 15.05 mmol) in portions at 0 °C under N2. The mixture was stirred at 20 °C for 16 hours. The mixture was filtered and the filter cake was washed with ethyl acetate (10 mL) and dried under reduced pressure to afford 7-bromo-l-[(2,4- dimethoxyphenyl)methyl]-2,4-dihydro-lH-3,l-benzoxazine-2, 4-dione (12 g, 77% yield) as a white solid. 'H NMR (400 MHz, DMSO-d6) 5 7.93 (d, J = 8.4 Hz, 1H), 7.51-7.49 (m, 1H), 7.44 (d, J = 1.2 Hz, 1H), 7.16 (d, J = 8.4 Hz, 1H), 6.64 (m, 1H), 6.48-6.45 (m, 1H), 5.09 (s, 2H), 3.90 (s, 3H), 3.75 (s, 3H).

[0147] Step 3. To a solution of 7-bromo-l-[(2,4-dimethoxyphenyl)methyl]-2,4-dihydro- lH-3,l-benzoxazine-2, 4-dione (6 g, 15.30 mmol) and benzyl 4-oxopiperidine-l- carboxylate (7.85 g, 33.66 mmol) in toluene (100 mL) was added LiHMDS (1 M, 35.2 mL) dropwise at 0 °C under N2. The mixture was stirred at 80 °C for 16 hours. After cooling to room temperature, the mixture was poured into water (100 mL) and extracted with ethyl acetate (200 mL><3). The combined organic layers were washed with brine (50 mL><3), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude mixture was triturated with petroleum ether / ethyl acetate (3 / 1, 40 mL) at 20 °C for 16 hours to afford benzyl 7-bromo-5-[(2,4-dimethoxyphenyl)methyl]-10-oxo- lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridine-2-carboxylate (8.5 g, 99% yield) as abrown solid. 'H NMR (400 MHz, DMSO-d6) 5 8.13 (d, J = 8.8 Hz, 1H), 7.65 (d, J = 1.6 Hz, 1H), 7.52-7.50 (m, 1H), 7.40-7.37 (m, 5H), 6.68 (m, 1H), 6.45-6.39 (m, 2H), 5.32 (s, 2H), 5.13 (s, 2H), 4.40 (m, 2H), 3.90 (s, 3H), 3.73 (s, 3H), 3.70-3.67 (m, 2H), 2.87 (m, 2H).

[0148] Step 4. To a mixture of benzyl 7-bromo-5-[(2,4-dimethoxyphenyl)methyl]-10- oxo-lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridine-2-carboxylate (3 g, 5.32 mmol) and B2Pin2 (1.62 g, 1.2 eq) in dioxane (30 mL) was added Pd(dppf)C12 (389.6 mg, 532.45 pmol) and KO Ac (1.05 g, 10.65 mmol) in one portion at 20 °C. The mixture was stirred at 90 °C under N2 for 2 hours. After cooling to room temperature, the reaction mixture was filtered and the filter cake was washed with ethyl acetate (20 mL><3) and dried under reduced pressure to afford benzyl 5-[(2,4-dimethoxyphenyl)methyl]-10-oxo-7-(4, 4,5,5- tetram ethyl- 1 ,3 ,2-dioxaborolan-2-yl)- 1H,2H,3H,4H, 5H, 10H-benzo[b] 1,6- naphthyridine-2-carboxylate (6 g, crude) as brown oil.

[0149] Step 5. To a mixture of benzyl 5-[(2,4-dimethoxyphenyl)methyl]-10-oxo-7- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH,2H,3H,4H,5H,10H-benzo[b]l,6- naphthyridine-2-carboxylate (6 g, 9.83 mmol) and tert-butyl N-[3- (trifluoromethanesulfonyloxy)cyclohex-2-en-l-yl]carbamate (1.70 g, 4.91 mmol) in dioxane (40 mL) and H2O (8 mL) were added K2CO3 (1.36 g, 9.83 mmol) and Pd(dppf)C12 (179.8 mg, 245.70 pmol). The mixture was stirred at 100 °C under N2 for 16 hours. The reaction mixture was poured into water (300 mL), extracted with ethyl acetate (200 mL x 2). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude mixture was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 3 / 1) to afford benzyl 7-(3-{[(tert-butoxy)carbonyl]amino}cyclohex-l-en-l-yl)-5-[(2,4- dimethoxyphenyl)methyl]- 10-oxo- 1H,2H,3H,4H, 5H, 10H-benzo[b] 1 ,6-naphthyridine-2- carboxylate (2.86 g, 86% yield) as a yellow solid.

[0150] Step 6. To a solution of benzyl 7-(3-{[(tert-butoxy)carbonyl]amino}cyclohex-l- en-l-yl)-5-[(2,4-dimethoxyphenyl)methyl]-10-oxo-lH,2H,3H,4H,5H,10H-benzo[b]l,6- naphthyridine-2-carboxylate (500 mg, 735.51 pmol) in ethyl acetate (10 mL) was added Pd / C (250 mg, 10% wt Pd). The mixture was stirred at 40 °C for 48 hours under H2 (15 Psi) pressure. The reaction mixture was filtered and the filtrate was concentrated underreduced pressure to as afford tert-butyl N-(3-{5-[(2,4-dimethoxyphenyl)methyl]-10-oxo- lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridin-7-yl}cyclohexyl)carbamate (130 mg, 81% yield) as a yellow solid.

[0151] Step 7. To a mixture of tert-butyl N-(3-{5-[(2,4-dimethoxyphenyl)methyl]-10- oxo-lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridin-7-yl}cyclohexyl)carbamate (130 mg, 237.36 pmol) and 4-(2H-l,2,3,4-tetrazol-5-yl)benzoic acid (45.1 mg, 237.36 pmol) in DMF (2 mL) were added DIPEA (61.4 mg, 474.73 pmol) and HATU (135.4 mg, 356.05 pmol). The mixture was stirred at 20 °C for 1 hour. The reaction mixture was poured into water (20 mL), extracted with ethyl acetate (20 mL><2). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude mixture was purified by prep-TLC (SiO2, dichloromethane / methanol = 5 / 1) to afford tert-butyl N-(3-{5-[(2,4- dimethoxyphenyl)methyl]-10-oxo-2-[4-(2H-l,2,3,4-tetrazol-5-yl)benzoyl]- lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridin-7-yl}cyclohexyl)carbamate (80 mg, 47% yield) as a yellow solid.

[0152] Step 8. To a solution of tert-butyl N-(3-{5-[(2,4-dimethoxyphenyl)methyl]-10- oxo-2-[4-(2H-l,2,3,4-tetrazol-5-yl)benzoyl]-lH,2H,3H,4H,5H,10H-benzo[b]l,6- naphthyridin-7-yl}cyclohexyl)carbamate (80 mg, 111.14 pmol) in MeOH (3 mL) was added HCl / dioxane (4 M, 4.4 mL). The mixture was stirred at 20 °C for 1 hour. The reaction mixture was concentrated under reduced pressure to afford 7-(3- aminocyclohexyl)-5-[(2,4-dimethoxyphenyl)methyl]-2-[4-(2H-l,2,3,4-tetrazol-5- yl)benzoyl]-lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridin-10-one (60 mg, 87% yield) as a yellow solid.

[0153] Step 9. A solution of 7-(3-aminocyclohexyl)-5-[(2,4-dimethoxyphenyl)methyl]- 2-[4-(2H-l,2,3,4-tetrazol-5-yl)benzoyl]-lH,2H,3H,4H,5H,10H-benzo[b]l,6- naphthyridin- 10-one (60 mg, 96.82 pmol) in TFA (20 mL) was stirred at 80 °C for 16 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC to afford 7-(3-aminocyclohexyl)-2-[4-(2H-l,2,3,4-tetrazol- 5-yl)benzoyl]-lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridin-10-one (16.6 mg, 17% yield, di-TFA salts) as a white solid. LCMS: [M+H]+ = 470.0. 'H NMR (400 MHz, DMSO-d6) 5 12.90-12.52 (m, 1H), 8.22-8.06 (m, 3H), 7.91-7.87 (m, 3H), 7.71 (m, 2H),7.49-7.28 (m, 2H), 4.69 (m, 1H), 4.43 (m, 1H), 3.99-3.98 (m, 1H), 3.68-3.53 (m, 2H), 3.21-3.03 (m, 4H), 1.98-1.21 (m, 9H).Cpd 6

[0154] Step 1. To a solution of tert-butyl 4-[10-(benzyloxy)-7-bromo-8-fluoro- lH,2H,3H,4H-benzo[b]l,6-naphthyridine-2-carbonyl]benzoate (300 mg, 507.21 pmol) in dioxane (5 mL) was added (3 'S)- 1,3 '-bipyrrolidine (167 mg, 1.19 mmol), RuPhos Pd G3 (42.4 mg, 50.72 pmol) and t-BuONa (146.2 mg, 1.52 mmol) and the mixture was stirred at 100 °C for 16 hours under N2. After cooling to room temperature, the mixture was poured into water (20 mL) and extracted with ethyl acetate (50 mLx3). The combined organic layer was washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC (CH2C12 / MeOH=10 / l) to afford tert-butyl4-[10-(benzyloxy)-7-[(3'S)-[l,3'- bipyrrolidin]-l'-yl]-8-fluoro-lH,2H,3H,4H-benzo[b]l,6-naphthyri dine-2- carbonyl]benzoate (200 mg, 61% yield) as brown oil.

[0155] Step 2. To a solution of tert-butyl 4-[10-(benzyloxy)-7-[(3'S)-[l,3'-bipyrrolidin]- l'-yl]-8-fluoro-lH,2H,3H,4H-benzo[b]l,6-naphthyridine-2-carbonyl]benzoate (169.5 mg, 260.42 pmol) and cone. HC1 (12 M, 28.5 mg) in MeOH (10 mL) was added Pd / C (50 mg, 10% wt Pd) and Pd(OH)2 / C (50 mg, 10% wt Pd). The reaction mixture was stirred at 20 °C for 1 hour under H2 pressure (15 psi). The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to afford tert-butyl 4-{7-[(3'S)-[l,3'- bipyrrolidin]- 1 '-yl]-8-fluoro- 10-oxo- 1H,2H,3H,4H, 5H, 10H-benzo[b] 1 ,6-naphthyridine- 2-carbonyl (benzoate (200 mg) as yellow oil.

[0156] Step 3. To a solution of tert-butyl 4-{7-[(3'S)-[l,3'-bipyrrolidin]-l'-yl]-8-fhioro- 10-oxo-lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridine-2-carbonyl(benzoate (170 mg, 303.22 pmol) in DCM (5 mL) was added TFA (7.70 g, 67.53 mmol, 5 mL). The mixture was stirred at 20 °C for 0.5 hour. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (TFA conditions) to afford 4- {7-[(3'S)-[l,3'-bipyrrolidin]-l'-yl]-8-fluoro-10-oxo-lH,2H,3H,4H,5H,10H-benzo[b]l,6- naphthyridine-2-carbonyl (benzoic acid (65.6 mg, 35% yield, TFA salt) as an off-white solid. LCMS: [M+H]+ = 505.2. *H NMR (400 MHz, Methanol-d4) 5 8.14-8.12 (m, 2H),7.75-7.58 (m, 3H), 6.64 (d, J = 7.6 Hz, 1H), 4.73 (s, 1H), 4.46 (s, 1H), 4.08-4.05 (m, 2H), 3.90-3.71 (m, 6H), 3.56-3.50 (m, 1H), 3.25-3.13 (m, 2H), 2.99-2.92 (m, 2H), 2.59-2.54 (m, 1H), 2.33-2.28 (m, 1H), 2.19-2.09 (m, 4H).Cpd 7

[0157] Step 1. To a mixture of tert-butyl 4-{7-bromo-5-[(4-methoxyphenyl)methyl]-10- oxo-lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridine-2-carbonyl (benzoate (200 mg, 331.40 pmol) and tert-butyl N-[(3R)-piperidin-3-yl]carbamate (132.7 mg, 662.80 pmol) in t-Amyl-OH (4 mL) was added Ruphos Pd G4 (50 mg) and Cs2CO3 (216.0 mg, 662.80 pmol). The mixture was stirred at 100 °C for 16 hours under N2. After cooling to room temperature, the reaction mixture was purified by prep-TLC to afford tert-butyl 4-{7- [(3R)-3-{[(tert-butoxy)carbonyl]amino(piperidin-l-yl]-5-[(4-methoxyphenyl)methyl]- 10-oxo-lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridine-2-carbonyl(benzoate (200 mg, 83%) as a yellow solid.

[0158] Step 2. To a mixture of tert-butyl 4-{7-[(3R)-3-{[(tert- butoxy)carbonyl]amino(piperidin-l-yl]-5-[(4-methoxyphenyl)methyl]-10-oxo- lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridine-2-carbonyl (benzoate (200 mg, 276.68 pmol) in DCM (3 mL) was added TFA (3 mL). The mixture was stirred at 20 °C for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC and lyophilized to afford 4-{7-[(3R)-3- aminopiperidin- 1 -yl]-5-[(4-methoxyphenyl)methyl]- 10-oxo- 1H,2H,3H,4H,5H, 10H- benzo[b]l,6-naphthyridine-2-carbonyl (benzoic acid (130 mg, 69%, TFA salt) as ayellow solid. 'HNMR: DMSO-d6 400 MHz 5 13.14 (s, 1H), 8.10-7.97 (m, 6H), 7.58 (d, J =8.0 Hz, 2H), 7.07-7.6.91 (m, 5H), 6.75 (s, 1H), 5.45 (s, 2H), 4.56 (s, 1H), 4.32 (s, 1H), 3.55 (s, 2H), 3.86 (s, 1H), 3.64 (s, 1H), 3.55 (s, 1H), 3.43-3.40 (m, 1H), 3.27 (s, 1H), 3.07-2.97 (m, 4H), 1.91-1.90 (m, 21), 1.75-1.74 (m, 1H), 1.57-1.50 (m, 2H).

[0159] Step 3. The mixture of 4-{7-[(3R)-3-aminopiperidin-l-yl]-5-[(4- methoxyphenyl)methyl]-l 0-oxo- 1H,2H,3H,4H,5H, 10H-benzo[b]l, 6-naphthyri dinercarbonyl (benzoic acid (130 mg, 191.0 pmol, TFA salt) in TFA (20 mL) was stirred at 80 °C for 42 hours. The reaction mixture was concentrated under reduced pressure and purified by preparative HPLC and lyophilized to afford 4-{7-[(3R)-3-aminopiperidin-l-y 1 ] - 10-oxo- 1H,2H,3H,4H,5H, 10H-benzo[b] 1 ,6-naphthyridine-2-carbonyl (benzoic acid (52.9 mg, 50% yield, TFA salt) as a yellow solid. LCMS: [M+H]+ = 447.2. 'HNMR (400 MHz, Methanol-d4) 5 8.14-7.98 (m, 3H), 7.59 (m, 2H), 7.14-7.08 (m, 1H), 6.83 (s, 1H), 4.75 (s, 1H), 4.46 (s, 1H), 4.09 (m, 1H), 3.73 (m, 2H), 3.48-3.44 (m, 2H), 3.31-3.28 (m, 2H), 2.99-2.92 (m, 2H), 2.11-1.97 (m, 2H), 1.82-1.75 (m, 2H) (2 labile H not visible).Cpd 8

[0160] Step 1. To a mixture of tert-butyl 4-{7-bromo-5-[(4-methoxyphenyl)methyl]-10- oxo-lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridine-2-carbonyl (benzoate (200 mg, 331.40 pmol) and tert-butyl N-[(3S)-piperidin-3-yl]carbamate (132.7 mg, 662.80 pmol) in t-Amyl-OH (4 mL) was added Ruphos Pd G4 (40 mg) and Cs2CO3 (216.0 mg, 662.80 pmol). The mixture was stirred at 100 °C for 16 hours under N2. After cooling to room temperature, the reaction mixture was purified by prep-TLC (SiO2, dichloromethane / methanol = 15 / 1) to afford tert-butyl 4-{7-[(3S)-3-{[(tert- butoxy)carbonyl]amino(piperidin-l-yl]-5-[(4-methoxyphenyl)methyl]-l 0-oxo- lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridine-2-carbonyl(benzoate (160 mg, 67%) as a white solid. ‘H NMR (400 MHz, DMSO-d6) 5 8.00-7.88 (m, 3H), 7.61-7.57 (m, 2H), 7.10-7.09 (m, 2H), 7.03-6.90 (m, 4H), 6.75 (m, 1H), 5.45 (m, 2H), 4.62-4.51 (m, 1H), 4.30 (m, 1H), 4.00-3.84 (m, 1H), 3.72-3.67 (m, 5H), 3.56-3.53 (m, 1H), 3.37 (m, 2H), 3.04-2.77 (m, 3H), 1.79 (m, 1H), 1.64-1.57 (m, 11H), 1.43 (s, 9H).

[0161] Step 2. A solution of tert-butyl 4-{7-[(3S)-3-{[(tert- butoxy)carbonyl]amino}piperidin-l-yl]-5-[(4-methoxyphenyl)methyl]-l 0-oxo- 1H,2H,3H,4H, 5H, 10H-benzo[b] 1 ,6-naphthyridine-2-carbonyl (benzoate (160 mg,221.34 pmol) in TFA (20 mL) and the mixture was stirred at 80 °C for 72 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC and lyophilized to afford 4-{7-[(3S)-3- aminopiperi din- 1 -yl]-l 0-oxo- 1H,2H,3H,4H,5H, 10H-benzo[b]l,6-naphthyri dinercarbonyl (benzoic acid (51.7 mg, 42% yield, TFA salt) as a yellow solid. LCMS: [M+H]+ = 447.3. ‘H NMR (400 MHz, DMSO-d6) 5 13.18 (br s, 1H), 11.48 (s, 1H), 8.02 (d, J = 8.0 Hz, 4H), 7.97-7.82 (m, 1H), 7.61-7.54 (m, 2H), 7.02-6.97 (m, 1H), 6.76 (s, 1H), 4.49 (s, 1H), 4.23 (s, 1H), 3.93 (s, 1H), 3.70-3.68 (m, 1H), 3.55 (m, 1H), 3.45-3.44 (m, 1H),3.33 (m, 1H), 3.10-3.04 (m, 2H), 2.84-2.83 (m, 2H), 1.98-1.86 (m, 2H), 1.66-1.56 (m, 2H).Cpd 9

[0162] Step 1. To a mixture of Intermediate A (200 mg, 413.78 pmol) and K2CO3 (114.4 mg, 827.55 pmol) in DMF (4 mL) was added benzyl bromide (106.2 mg, 620.66 pmol). The mixture was stirred at 80 °C for 16 hours. After cooling to room temperature, the reaction mixture was poured into water (20 mL), extracted with ethyl acetate (20 mL><2). The combined organic layers were washed with brine (40 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=l / l) to afford tert-butyl 4- [10-(benzyloxy)-7-bromo-lH,2H,3H,4H-benzo[b]l,6-naphthyridine-2- carbonyl]benzoate (100 mg) as a yellow oil.JH NMR (400 MHz, DMSO-d6) 5 8.19 (s, 1H), 8.04-7.98 (m, 3H), 7.71-7.59 (m, 5H), 7.24-7.15 (m, 3H), 5.24 (m, 1H), 4.97-4.88 (m, 2H), 4.68 (m, 1H), 4.04-4.00 (m, 1H), 3.67 (m, 1H), 3.21 (m, 1H), 3.13 (m, 1H), 1.58 (s, 9H).

[0163] Step 2. To a mixture of tert-butyl 4-[10-(benzyloxy)-7-bromo-lH,2H,3H,4H- benzo[b]l,6-naphthyridine-2-carbonyl]benzoate (90 mg, 156.94 pmol) and N- methylpiperazine (31.4 mg, 313.9 pmol, 34.82 pL) in dioxane (5 mL) was added t- BuONa (45.3 mg, 470.81 pmol) and RuPhos Pd G3 (26.3 mg, 31.39 pmol). The mixture was stirred at 100 °C for 16 hours under N2. The reaction mixture was poured into water (20 mL), extracted with dichloromethane (20 mL><2). The combined organic layers were concentrated under reduced pressure. The residue was purified by preparative HPLC to afford 4-[7-(4-methylpiperazin-l-yl)-10-oxo-lH,2H,3H,4H,5H,10H-benzo[b]l,6- naphthyridine-2-carbonyl]benzoic acid (6.1 mg, 8% yield, HC1 salt) as an off-white solid. LCMS: [M+H]+ = 447.2. 'H NMR (400 MHz, DMSO-d6 + D2O) 5 8.04-8.02 (m, 3H), 7.61-7.55 (m, 2H), 7.14-7.07 (m, 1H), 6.80-6.79 (m, 1H), 4.51 (s, 1H), 4.24 (s, 1H), 3.97- 3.94 (m, 3H), 3.55 (d, J=8.0 Hz, 3H), 3.22-3.10 (m, 4H), 2.86 (m, 5H) (2 labile H not visible).Cpd 10

[0164] Step 1. To a mixture of Intermediate A (200 mg, 413.78 pmol) and l-methyl-4- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,2,3,6-tetrahydropyridine (277 mg, 1.24 mmol) in dioxane (5 mL) and H2O (1 mL) was added K2CO3 (171.6 mg, 1.24 mmol) and Pd(dppf)C12 (30.3 mg, 41.38 pmol). The mixture was stirred at 100 °C for 16 hours. The reaction mixture was poured into water (20 mL), extracted with dichloromethane / methanol=10 / l (20 mL><2). The combined organic layers were washed with brine (40 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to afford tert-butyl 4-[7-(l-methyl-l,2,3,6-tetrahydropyridin-4-yl)-10-oxo- lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridine-2-carbonyl]benzoate (200 mg, 97% yield) as a yellow solid. 'H NMR (400 MHz, DMSO-d6) 5 11.70 (d, J = 16.0 Hz, 2H), 8.06-7.90 (m, 3H), 7.62-7.54 (m, 2H), 7.43 (s, 2H), 6.36 (s, 1H), 4.52 (s, 1H), 4.23 (s, 1H), 3.95 (s, 1H), 3.55 (s, 1H), 3.07 (s, 2H), 2.89-2.85 (m, 2H), 2.60-2.59 (m, 2H), 2.42 (m, 2H), 2.30 (s, 3H), 1.57 (s, 9H).

[0165] Step 2. To a mixture of tert-butyl 4-[7-(l-methyl-l,2,3,6-tetrahydropyridin-4-yl)- 10-oxo-lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridine-2-carbonyl]benzoate (170 mg, 340.27 pmol) in MeOH (8 mL) was added Pd / C (80 mg, 10% wt Pd) under H2 atmosphere. The mixture was stirred at 25 °C for 18 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to afford tert-butyl 4-[7- (1 -methylpiperidin-4-yl)- 10-oxo- 1H,2H,3H,4H,5H, 10H-benzo[b] 1 ,6-naphthyridine-2- carbonyl]benzoate (100 mg, 59% yield) as a yellow solid.

[0166] Step 3. To a mixture of tert-butyl 4-[7-(l-methylpiperidin-4-yl)-10-oxo- lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridine-2-carbonyl]benzoate (100 mg, 199.36 pmol) in DCM (5 mL) was added TFA (7.70 g, 67.53 mmol, 5.00 mL). The mixture was stirred at 20 °C for 1 hour. The reaction mixture was concentrated in vacuum to afford the residue. The residue was purified by preparative HPLC to afford 4-[7-(l- methylpiperidin-4-yl)-l 0-oxo- 1H,2H,3H,4H,5H, 10H-benzo[b]l, 6-naphthyridine-2- carbonyl]benzoic acid (24.3 mg, 22% yield, TFA salt) as an off-white solid. LCMS: [M+H]+ = 446.0.XH NMR (400 MHz, Methanol-d4) 5 8.14-8.10 (m, 3H), 7.60-7.59 (m, 2H), 7.42-7.28 (m, 2H), 4.78 (s, 1H), 4.49 (s, 1H), 4.11 (br s, 1H), 3.73-3.64 (m, 3H), 3.23-3.17 (m, 2H), 3.04-2.94 (m, 6H), 2.22-2.02 (m, 4H) (2 labile H not visible).Cpd 11

[0167] Step 1. To a mixture of tert-butyl 4-[10-(benzyloxy)-7-bromo-8-fluoro- lH,2H,3H,4H-benzo[b]l,6-naphthyridine-2-carbonyl]benzoate (50 mg, 84.54 pmol) and tert-butyl (3 S)-3 -aminopyrrolidine- 1 -carboxylate (63.0 mg, 338.14 pmol) in dioxane (1 mL) was added t-BuONa (16.3 mg, 169.07 pmol), BrettPhos Pd G3 (7.7 mg, 8.45 pmol) and BrettPhos (4.5 mg, 8.45 pmol). The mixture was heated to 100 °C and stirred for 2 hours under N2. After cooling to room temperature, the reaction mixture was poured into water (30 mL), extracted with ethyl acetate (20 mLx2). The combined organic layers were washed with brine (10 mLx2), dried over Na2SO4, filtered and concentrated to afford tert-butyl (3S)-3-{[10-(benzyloxy)-2-{4-[(tert-butoxy)carbonyl]benzoyl}-8-fluoro- lH,2H,3H,4H-benzo[b]l,6-naphthyridin-7-yl]amino}pyrrolidine-l -carboxylate (200 mg, crude) as a yellow solid.

[0168] Step 2. To the mixture of tert-butyl (3S)-3-{[10-(benzyloxy)-2-{4-[(tert- butoxy)carbonyl]benzoyl}-8-fluoro-lH,2H,3H,4H-benzo[b]l,6-naphthyri din-7- yl]amino}pyrrolidine-l -carboxylate (120 mg, 232.27 pmol) in MeOH (4 mL) was added Pd / C (30 mg, 10% wt Pd). The mixture was stirred at 20 °C for 2 hours under H2 balloon. The reaction mixture was filtered and the filtrate was concentrated to afford tert-butyl (3S)-3-[(2-{4-[(tert-butoxy)carbonyl]benzoyl}-8-fluoro-10-oxo-lH,2H,3H,4H,5H,10H- benzo[b]l,6-naphthyridin-7-yl)amino]pyrrolidine-l-carboxylate (100 mg, crude) as a yellow solid.

[0169] Step 3. To the mixture of tert-butyl (3S)-3-[(2-{4-[(tert- butoxy)carbonyl]benzoyl } -8-fluoro- 10-oxo- 1H,2H,3H,4H, 5H, 10H-benzo[b] 1 ,6- naphthyridin-7-yl)amino]pyrrolidine-l -carboxylate (100 mg, 164.83 pmol) in CH2C12 (2 mL) was added TFA (2 mL, 27.01 mmol). The mixture was stirred at 20 °C for 0.5 hour. The reaction mixture was concentrated under reduced pressure. The residue was purified by prepaative HPLC and lyophilized to afford 4-(8-fluoro-10-oxo-7-{[(3S)-pyrrolidin-3- yl]amino}-lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridine-2-carbonyl)benzoic acid (3.9 mg, 5% yield) as a white solid.. LCMS: [M+H]+ = 451.4. 'H NMR (400 MHz, Methanol-d4) 5 8.12 (m, 2H), 7.74-7.57 (m, 3H), 6.60 (d, J = 3.2 Hz, 1H), 4.73 (s, 1H), 4.45 (s, 1H), 4.38-4.34 (m, 1H), 4.08 (m, 1H), 3.63 (m, 1H), 3.60-3.45 (m, 4H), 2.98-2.91 (m, 1H), 2.47-2.41 (m, 1H), 2.29 (m, 1H) (4 labile H not visible).Cpd 12

[0170] Step 1. To a mixture of Intermediate C (300 mg, 507.71 pmol) in dioxane (5 mL) were added (3 'S)- 1,3 '-bipyrrolidine (179.2 mg, 1.01 mmol), RuPhos Pd G3 (42.4 mg, 50.72 pmol) and t-BuONa (146.2 mg, 1.52 mmol). The mixture was stirred at 100 °C for 16 hours under N2. After cooling to room temperature, the reaction mixture was poured into water (30 mL), extracted with ethyl acetate (50 mLx2). The combined organic layers were washed with brine (30 mLx2), dried over Na2SO4, filtered and concentrated. The residue was purified by Prep-TLC (CH2C12 / MeOH= 10 / 1, Rf = 0.4) to afford tert-butyl4- [10-(benzyloxy)-7-[(3'S)-[l,3'-bipyrrolidin]-l'-yl]-8-fluoro-lH,2H,3H,4H-benzo[b]l,6- naphthyridine-2-carbonyl]benzoate (120 mg, 36% yield) as a brown solid.

[0171] Step 2. To a mixture of tert-butyl 4-[10-(benzyloxy)-7-[(3'S)-[l,3'-bipyrrolidin]- T-yl]-8-fhioro-lH,2H,3H,4H-benzo[b]l,6-naphthyridine-2-carbonyl]benzoate (120 mg, 184.39 pmol) in MeOH (4 mL) was added Pd / C (40 mg, 10% wt Pd). The mixture was stirred at 20 °C for 4 hours under H2 atmosphere. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to afford tert-butyl 4-{7-[(3'S)-[l,3'- bipyrrolidin]- 1 '-yl]-8-fluoro- 10-oxo- 1H,2H,3H,4H, 5H, 10H-benzo[b] 1 ,6-naphthyridine- 2-carbonyl (benzoate (100 mg, 97% yield) as a yellow solid.

[0172] Step 3. To a mixture of tert-butyl 4-{7-[(3'S)-[l,3'-bipyrrolidin]-l'-yl]-8-fluoro- 10-oxo- 1H,2H,3H,4H,5H, 10H-benzo[b] 1 ,6-naphthyridine-2-carbonyl (benzoate (100 mg, 178.36 pmol) in DCM (2 mL) was added TFA (2 mL, 27.01 mmol). The mixture was stirred at 20 °C for 0.5 hour. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC and lyophilized to afford 4-{7- [(3'S)-[l,3'-bipyrrolidin]-r-yl]-8-fhioro-10-oxo-lH,2H,3H,4H,5H,10H-benzo[b]l,6- naphthyridine-2-carbonyl(benzoic acid (20.1 mg, 22% yield) as an off-white solid.. LCMS: [M+H]+ = 505.1. *HNMR (400 MHz, DMSO-d6) 5 11.40 (m, 1H), 8.01 (d, J = 8.0 Hz, 2H), 7.59-7.43 (m, 3H), 6.52 (d, J = 7.2 Hz, 1H), 4.47 (s, 1H), 4.21 (s, 1H), 3.92 (s, 1H), 3.64 (s, 1H), 3.54 (m, 2H), 3.47 (m, 2H), 3.84, (m, 2H), 3.07 (m, 1H), 2.81-2.69 (m, 4H), 2.18 (m, 1H), 1.98-1.93 (m, 1H), 1.76 (m, 4H) (7 labile H not visible)' .Cpd 13

[0173] Step 1. To a mixture of Intermediate C (100 mg, 169.07 pmol) in dioxane (2 mL) was added tert-butyl (3R)-3 -aminopyrrolidine- 1 -carboxylate (126.0 mg, 676.29 pmol), BrettPhos Pd G1 (30 mg, 16.91 pmol), BrettPhos (9.1 mg, 16.91 pmol), and t-BuONa (32.5 mg, 338.14 pmol). The mixture was stirred at 100 °C for 2 hours under N2. After cooling to room temperature, the reaction mixture was poured into water (50 mL), extracted with ethyl acetate (30 mL><2). The combined organic layers were washed with brine (30 mL><2), dried over Na2SO4, filtered and concentrated to afford tert-butyl (3R)-3-{[10-(benzyloxy)-2-{4-[(tert-butoxy)carbonyl]benzoyl}-8-fluoro-lH,2H,3H,4H- benzo[b]l,6-naphthyridin-7-yl]amino}pyrrolidine-l -carboxylate (250 mg, crude) as a brown solid.

[0174] Step 2. To a mixture of tert-butyl (3R)-3-{[10-(benzyloxy)-2-{4-[(tert- butoxy)carbonyl]benzoyl}-8-fluoro-lH,2H,3H,4H-benzo[b]l,6-naphthyri din-7- yl]amino}pyrrolidine-l -carboxylate (250 mg, 358.78 pmol) in MeOH (5 mL) was added Pd / C (150 mg, 10% wt Pd). The mixture was stirred at 20 °C for 16 hours under H2 atmosphere. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to afford tert-butyl (3R)-3-[(2-{4-[(tert-butoxy)carbonyl]benzoyl}-8- fhioro-10-oxo-lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridin-7- yl)amino]pyrrolidine-l -carboxylate (250 mg, crude) as a brown solid.

[0175] Step 3. To a mixture of tert-butyl (3R)-3-[(2-{4-[(tert- butoxy)carbonyl]benzoyl } -8-fluoro- 10-oxo- 1H,2H,3H,4H, 5H, 10H-benzo[b] 1 ,6- naphthyridin-7-yl)amino]pyrrolidine-l-carboxylate (250 mg, 412.08 pmol) in dichloromethane (3 mL) was added TFA (3 mL, 50.65 mmol) in one portion at 20 °C. The mixture was stirred at 20 °C for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC and lyophilized to afford4-(8-fluoro- 10-oxo-7- { [(3R)-pyrrolidin-3 -yl] amino } - 1 H,2H, 3H,4H, 5H, 10H- benzo[b]l,6-naphthyridine-2-carbonyl)benzoic acid (20.1 mg, 11% yield) as a white solid. LCMS: [M+H]+ = 451.2. 'H NMR (400 MHz, D2O) 5 7.97-7.91 (m, 2H), 7.55- 7.46 (m, 3H), 6.50-6.46 (m, 1H), 4.59 (s, 1H), 4.45 (s, 1H), 4.00-3.96 (m, 2H), 3.61-3.58 (m, 1H), 3.11-2.95 (m, 1H), 2.94-2.73 (m, 5H), 2.19-2.14 (m, 1H), 1.70-1.67 (m, 1H) (4 labile H not visible).Cpd 14

[0176] Step 1. To a mixture of Intermediate A (150 mg, 310.33 pmol) and tert-butyl 4- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2,3,6,7-tetrahydro-lH-azepine-l- carboxylate (120.4 mg, 372.40 pmol) in dioxane (4 mL) and H2O (0.8 mL) were added K2CO3 (128.7 mg, 931.00 pmol) and Pd(dppf)C12 (22.7 mg, 31.03 mmol) under N2, the mixture was stirred at 100 °C for 16 hours. The reaction mixture was poured into water (20 mL), extracted with Dichloromethane (20 mL><2). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC to afford tert-butyl 4-(2-{4-[(tert- butoxy)carbonyl]benzoyl } - 10-oxo- 1H,2H,3H,4H,5H, 10H-benzo[b] 1 ,6-naphthyridin-7- yl)-2,3,6,7-tetrahydro-lH-azepine-l-carboxylate (200 mg) as a yellow solid.

[0177] Step 2. To a mixture of tert-butyl 4-(2-{4-[(tert-butoxy)carbonyl]benzoyl}-10- oxo-lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridin-7-yl)-2,3,6,7-tetrahydro-lH- azepine-1 -carboxylate (200 mg, 333.49 pmol) in EtOH (10 mL) was added Pd / C (200 mg, 333.49 pmol, 10% wt Pd) and stirred at 40 °C for 1 hours under H2 atmosphere. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to afford tert-butyl 4-(2-{4-[(tert-butoxy)carbonyl]benzoyl}-10-oxo- lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridin-7-yl)azepane-l -carboxylate (140 mg, 70% yield) as a yellow solid. 'H NMR(400 MHz, DMSO-d6) 5 11.72 (br s, 1H), 8.02- 7.90 (m, 3H), 7.62-7.53 (m, 2H), 7.26 (s, 1H), 7.14-7.10 (m, 1H), 4.51 (s, 1H), 4.23 (s, 1H), 3.94 (s, 1H), 3.63-3.59 (m, 2H), 3.54-3.42 (m, 2H), 3.40-3.26 (m, 1H), 2.89-2.84 (m, 2H), 2.84 (s, 1H), 1.90-1.89 (m, 2H), 1.86 (m, 1H), 1.70 (m, 1H), 1.65-1.64 (m, 2H), 1.44 (s, 9H), 1.43 (s, 9H).

[0178] Step 3. To a mixture of tert-butyl 4-(2-{4-[(tert-butoxy)carbonyl]benzoyl}-10- oxo-lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridin-7-yl)azepane-l -carboxylate (140 mg, 232.66 pmol) in DCM (4 mL) was added TFA (6.16 g, 54.02 mmol) and stirred at 20 °C for 16 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC to afford 4-[7-(azepan-4-yl)-10-oxo- lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridine-2-carbonyl]benzoic acid (77.8 mg, 60% yield, TFA salt) as a white solid. LCMS: [M+H]+ = 446.1. 'H NMR(400 MHz, DMSO-d6) 5 11.47 (s, 1H), 8.68 (br s, 2H), 8.02 (d, J = 8.0 Hz, 3H), 7.56 (d, J = 8.0 Hz,2H), 7.31 (s, 1H), 7.18 (d, J = 8.4 Hz, 1H), 4.04 (s, 2H), 3.79 (br s, 2H), 3.34-3.29 (m, 2H), 3.22-3.20 (m, 2H), 2.89 (m, 1H), 2.88-2.87 (m, 2H), 2.09-1.80 (m, 6H).Cpd 15

[0179] Step 1. A solution of l-methyl-2,4-dihydro-lH-3,l-benzoxazine-2, 4-dione (1 g, 5.64 mmol) and tert-butyl 4-oxopiperidine-l -carboxylate (2.36 g, 11.85 mmol) in toluene (10 mL) was cooled to 0 °C under N2, then LiHMDS (IM, 13.0 mL) was added dropwise into the reaction mixture. The mixture was stirred at 80 °C for 2 hours. The mixture was quenched with aqueous NH4C1 (30 mL) and extracted with ethyl acetate (50 mL*3). The combined organic layer was washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography to afford tert-butyl 5-methyl-10-oxo-lH,2H,3H,4H,5H,10H- benzo[b]l,6-naphthyridine-2-carboxylate (1.7 g, 96% yield) as a brown solid.

[0180] Step 2. To a solution of tert-butyl 5-methyl-10-oxo-lH,2H,3H,4H,5H,10H- benzo[b]l,6-naphthyridine-2-carboxylate (1.7 g, 5.41 mmol) in MeOH (10 mL) was added HCl / dioxane (4 M, 9.0 mL). The mixture was stirred at 20 °C for 2 hours. The reaction mixture was concentrated to afford 5-methyl-lH,2H,3H,4H,5H,10H- benzo[b]l,6-naphthyri din- 10-one (1.5 g, HC1 salt) as a yellow solid.JH NMR(400 MHz, DMSO-d6) 5 9.81 (s, 2H), 8.21 (d, J = 8 Hz, 1H), 7.85 (d, J = 8.8 Hz, 1H), 7.78-7.76 (m, 1H), 7.44-7.40 (m, 1H), 3.98 (s, 2H), 3.76 (s, 3H), 3.40-3.39 (m, 2H), 3.22-3.19 (m, 2H).

[0181] Step 3. To a mixture of 5-methyl-lH,2H,3H,4H,5H,10H-benzo[b]l,6- naphthyridin- 10-one (200 mg, 797.69 pmol) and 4-[(tert-butoxy)carbonyl]benzoic acid (177.3 mg, 797.69 pmol) in DMF (8 mL) was added HATU (333.6 mg, 877.46 pmol) and DIEA (412.4 mg, 3.19 mmol). The mixture was stirred at 20 °C for 16 hours. The reaction mixture was extracted with ethyl acetate (20 mL><2), washed with brine (10 mL><2), dried over Na2SO4, filtered and concentrated. The residue was purified by prep- TLC to afford tert-butyl 4-{5-methyl-10-oxo-lH,2H,3H,4H,5H,10H-benzo[b]l,6- naphthyridine-2-carbonyl (benzoate (180 mg, 54% yield) as a yellow solid.

[0182] Step 4. To a mixture of tert-butyl 4-{5-methyl-10-oxo-lH,2H,3H,4H,5H,10H- benzo[b]l,6-naphthyridine-2-carbonyl (benzoate (170 mg, 406.23 pmol) in DCM (3 mL) was added TFA (3 mL). The mixture was stirred at 20 °C for 0.5 hour. The reactionmixture was concentrated under reduced pressure. The crude product was triturated with DMSO (5 mL) for 15 min at 20 °C. After filtered, the filter cake was washed with MeCN (2 mL) to afford 4-{5-methyl-10-oxo-lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridine-2-carbonyl (benzoic acid (112.3 mg, 76% yield) as a white solid. LCMS: [M+H]+ = 363.0.JH NMR(400 MHz, D2O) 5 7.90-7.71 (m, 3H), 7.51-7.41 (m, 3H), 7.33-7.28 (m, 1H), 7.24-7.12 (m. 1H), 4.24 (m, 2H), 3.87-3.84 (m, 1H), 3.50-3.47 (m, 1H), 3.36 (m, 3H), 2.83-2.80 (m, 1H), 2.68-2.65 (m, 1H).Cpd 16

[0183] Step 1. To a mixture of methyl 4-oxopiperidine-3 -carboxylate (50 g, 258.23 mmol, HC1 salt) in DCM (500 mL) was added TEA (52.26 g, 516.46 mmol) at 20 °C and then acetic anhydride (29.00 g, 284.05 mmol) was added dropwise into the mixture. The mixture was stirred at 20 °C for 16 hours then poured into water (500 mL), extracted with ethyl acetate (600 mL><2). The combined organic layers were washed with brine (400 mL><2), dried over Na2SO4, filtered and concentrated to afford methyl l-acetyl-4- oxopiperidine-3 -carboxylate (55 g) as red oil.

[0184] Step 2. To a mixture of methyl l-acetyl-4-oxopiperidine-3 -carboxylate (10 g, 50.20 mmol) and 3 -bromoaniline (8.64 g, 50.20 mmol) in EtOH (80 mL) was added 4A MS (12 g, 50.20 mmol) and AcOH (3.01 g 50.20 mmol). The mixture was stirred at 80 °C for 16 hours. The reaction mixture was filtered and concentrated under reduced pressure to afford methyl (4E)-l-acetyl-4-[(3-bromophenyl)imino]piperidine-3- carboxylate (34 g) as a red solid.

[0185] Step 3. A solution of methyl (4E)-l-acetyl-4-[(3-bromophenyl)imino]piperidine-3-carboxylate (8 g, 22.65 mmol) in PPA (80 mL) was stirred at 150 °C for 2 hours. The reaction mixture was cooled to room temperature, poured into water (1000 mL) and adjusted with aqueous NaOH to pH = 7. The precipitate was collected and triturated with petroleum ether (200 mL) and H2O (200 mL) to afford 2-acetyl-7-bromo- lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridin-10-one (4.5 g, 62% yield) as a yellow solid. 'H NMR (400 MHz, DMSO-d6) 5 11.77 (br s, 1H), 8.00 (m, 1H), 7.67 (m, 1H), 7.42 (tm, 1H), 4.34-4.27 (m, 2H), 3.74-3.69 (m, 2H), 2.86 (s, 1H), 2.74 (s, 1H), 2.09 (s, 3H).

[0186] Step 4. To a mixture of 2-acetyl-7-bromo-lH,2H,3H,4H,5H,10H-benzo[b]l,6- naphthyridin- 10-one (1 g, 3.11 mmol) and l-methyl-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-l,2,3,6-tetrahydropyridine (694.7 mg, 3.11 mmol) in dioxane (10 mL) and H2O (2 mL) were added Pd(dppf)C12 (227.8 mg, 311.36 pmol) and K2CO3 (1.29 g, 9.34 mmol) under N2. The mixture was stirred at 100 °C for 2 hours. The reaction mixture was cooled to room temperature, filtered and the filter cake was concentrated to afford 2-acetyl-7-(l -methyl- 1,2, 3, 6-tetrahydropyridin-4-yl)-lH,2H,3H,4H,5H,10H- benzo[b]l,6-naphthyri din- 10-one (360 mg, 34% yield) as a yellow solid.JH NMR (400 MHz, DMSO-d6) 5 8.01-7.98 (m, 1H), 7.41 (s, 1H), 7.36 (d, J = 8.4 Hz, 1H), 6.29 (s, 1H), 4.36 (m, 2H), 3.73-3.68 (m, 3H), 3.03 (s, 2H), 2.86 (m, 1H), 2.73 (m, 1H), 2.58-2.55 (m, 2H), 2.50 (m, 1H), 2.28 (s, 3H), 2.09 (m, 3H).

[0187] Step 5. To a mixture of 2-acetyl-7-(l-methyl-l,2,3,6-tetrahydropyridin-4-yl)- lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridin-10-one (350 mg, 1.04 mmol) in MeOH (15 mL) was added Pd / C (0.2 g, 10% wtPd). The reaction was stirred at 20 °C for 2 hours under H2 atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to afford 2-acetyl-7-(l-methylpiperidin-4-yl)-lH,2H,3H,4H,5H,10H- benzo[b]l,6-naphthyri din- 10-one (320 mg, 91% yield) as a yellow solid. 'H NMR (400 MHz, DMSO-d6) 5 8.00-7.97 (m, 1H), 7.29 (s, 1H), 7.14 (d, J = 8.4 Hz, 1H), 4.34 (d, J =10.8 Hz, 2H), 3.73-3.67 (m, 2H), 2.87 (m, 3H), 2.74-2.73 (m, 1H), 2.53-2.50 (m, 1H), 2.19 (s, 3H), 2.09 (m, 3H), 1.99-1.94 (m, 2H), 1.77 (m, 2H), 1.70-1.67 (m, 2H).

[0188] Step 6. A solution of 2-acetyl-7-(l-methylpiperidin-4-yl)- lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridin-10-one (320 mg, 942.76 pmol) in aqueous HC1 (20 mL) was stirred at 100 °C for 16 hours. The reaction mixture was lyophilized under reduced pressure to afford 7-(l-methylpiperidin-4-yl)- lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridin-10-one (330 mg, 95% yield, di-HCl salts) as a yellow solid. *H NMR (400 MHz, DMSO-d6) 5 12.65 (s, 1H), 11.06 (s, 1H),9.8 (s, 2H), 8.14 (d, J = 8.4 Hz, 1H), 7.48 (s, 1H), 7.21 (d, J = 8.0 Hz, 1H), 3.94 (s, 2H), 3.49-3.38 (m, 4H), 3.10-3.08 (m, 4H), 2.95-2.75 (m, 1H), 2.75-2.74 (m, 3H), 2.11-1.98 (m, 4H).

[0189] Step 7. To a mixture of 7-(l-methylpiperidin-4-yl)-lH,2H,3H,4H,5H,10H- benzo[b]l,6-naphthyri din- 10-one (150 mg, 504.38 pmol, 2 HC1 salts) in DCM (5 mL)were added DMAP (6.2 mg, 50.44 pmol) and TEA (102.1 mg, 1.01 mmol, 140.41 pL). A solution of 4-methanesulfonamido-3-(trifluoromethoxy)benzoic acid (160.2 mg, 504.38 pmol) in DCM (1 mL) was then added dropwise to the above mixture at 0 °C. The mixture was stirred at 20 °C for 16 hours then was concentrated under reduced pressure. The crude product was triturated with MeCN (10 mL) to afford N-{4-[7-(l- methylpiperidin-4-yl)-10-oxo-lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridine-2- carbonyl]-2-(trifluoromethoxy)phenyl}methanesulfonamide (39.9 mg, 14% yield) as an off-white solid. LCMS: [M+H]+ = 579.3. 'H NMR (400 MHz, DMSO-d6) 5 11.63 (s, 1H), 9.86 (br s, 1H), 7.98 (d, J = 7.6 Hz, 1H), 7.58 (d, J = 8.8 Hz, 1H), 7.43 (d, J = 6.4 Hz, 2H), 7.29 (s, 1H), 7.19 (d, J = 8.4 Hz, 1H), 4.41 (s, 1H), 3.77 (br s, 2H), 3.07-3.01 (m, 3H), 2.88 (m, 2H), 2.67 (m, 1H), 2.37 (s, 3H), 2.32-2.26 (m, 2H), 1.88-1.85 (m, 2H), 1.73-1.70 (m, 2H).Cpd 17

[0190] Step 1. Under N2 atmosphere, a solution of LiHMDS (1 M, 12.7 mL) was added to THF (10 mL) and was cooled to -78 °C. To the mixture was added tert-butyl N-(3- oxocyclopentyl)carbamate (1 g, 5.02 mmol) in THF (5 mL) over 10 minutes. Thereafter, 1,1,1-trifluoro-N-phenyl-N-trifluorom ethanesulfonylmethanesulfonamide (2.16 g, 6.03 mmol) in THF (5 mL) was added and the mixture was stirred at 0 °C for 10 minutes. The reaction mixture was quenched by water (10 mL), toluene (20 mL) and aqueous NaOH (5M, 10 mL). The mixture was extracted with toluene (30 mL><3). The combined organic layers were washed with aqueous Na2SO3 (50 mL), aqueous NaHCO3 (50 mL) and brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography to afford tert-butyl N-[3- (trifluoromethanesulfonyloxy)cyclopent-3-en-l-yl]carbamate (840 mg, 51%) as a white solid.XH NMR (400 MHz, DMSO-d6) 57.29-7.21 (m, 1H), 5.77-5.73 (m, 1H), 4.55-4.15 (m, 1H), 2.83-2.62 (m, 2H), 2.48-1.72 (m, 2H), 1.38 (s, 9H).

[0191] Step 2. To a mixture of tert-butyl N-[3-(trifluoromethanesulfonyloxy)cyclopent- 3 -en-l-yl] carbamate (800 mg, 2.41 mmol) and B2pin2 (919.8 mg, 3.62 mmol in DMF (5 mL) were added Pd(dppf)C12.CH2C12 (98.6 mg, 120.73 pmol) and KOAc (355.5 mg, 3.67 mmol). The mixture was stirred at 80 °C for 14 hours under N2. After cooling toroom temperature the mixture was poured into water (100 mL), extracted with ethyl acetate (50 mL><2) and the combined organic layers were concentrated under reduced pressure. The residue was purified by column chromatography to afford tert-butyl N-[3- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)cyclopent-3-en-l-yl]carbamate (600 mg, 80% yield) as yellow oil.

[0192] Step 3. To a mixture of tert-butyl N-[3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan- 2-yl)cyclopent-3-en-l-yl]carbamate (323.5 mg, 1.05 mmol) and Intermediate D (500 mg, 871.88 pmol) in dioxane (5 mL), H2O (0.5 mL) were added Pd(dppf)C12 (63.8 mg, 87.19 pmol) and K2CO3 (241.0 mg, 1.74 mmol), then the mixture was stirred at 80 °C for 16 hours under N2. The reaction mixture was cooled to room temperature and poured into water (80 mL), extracted with Ethyl acetate (30 mL><2), the combined organic layers were washed with brine (80 mL><2), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography to afford tertbutyl 4-[5-benzyl-7-(4-{[(tert-butoxy)carbonyl]amino}cyclopent-l-en-l-yl)-10-oxo- lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridine-2-carbonyl]benzoate (450 mg, 76% yield) as a yellow solid.

[0193] Step 4. To a mixture of tert-butyl 4-[5-benzyl-7-(4-{[(tert- butoxy)carbonyl]amino}cyclopent-l-en-l-yl)-10-oxo-lH,2H,3H,4H,5H,10H- benzo[b]l,6-naphthyridine-2-carbonyl]benzoate (450 mg, 665.87 pmol) inMeOH (5 mL) was added Pd / C (1 g, 10% wt Pd) and Pd(OH)2 / C (1 g, 10% wt Pd), then the mixture was stirred at 40 °C for 1 hours under H2 atmosphere. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography to afford tert-butyl 4-[7-(3-{[(tert- butoxy)carbonyl]amino}cyclopentyl)-10-oxo-lH,2H,3H,4H,5H,10H-benzo[b]l,6- naphthyridine-2-carbonyl]benzoate (100 mg, 26% yield) as a white solid.JH NMR (400 MHz, DMSO-d6) 5 11.62 (m, 1H), 7.92 (m, 3H), 7.62-7.54 (m, 2H), 7.30-7.01 (m, 3H), 4.51 (s, 1H), 4.23 (s, 1H), 3.94 (s, 2H), 3.55 (s, 1H), 3.11 (s, 1H), 2.86 (m, 2H), 2.68 (m, 1H), 2.37-2.28 (m, 3H), 1.57 (s, 9H), 1.39 (s, 9H).

[0194] Step 5. To a mixture of tert-butyl 4-[7-(3-{[(tert- butoxy)carbonyl]amino}cyclopentyl)-10-oxo-lH,2H,3H,4H,5H,10H-benzo[b]l,6- naphthyridine-2-carbonyl]benzoate (100 mg, 170.15 pmol) in DCM (3 mL) was addedTFA (4.62 g, 40.52 mmol). The mixture was stirred at 20 °C for 0.5 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC to afford 4-[7-(3-aminocyclopentyl)-10-oxo-lH,2H,3H,4H,5H,10H- benzo[b]l,6-naphthyridine-2-carbonyl]benzoic acid (45.7 mg, 50% yield, TFA salt) as an off-white solid. LCMS: [M+H]+ = 432.1. 'HNMR (400 MHz, DMSO-d6) 5 13.02 (br s, 1H), 11.74 (m, 1H), 8.04-7.97 (m, 6H), 7.61-7.55 (m, 2H), 7.33-7.20 (m, 2H), 4.52 (s, 1H), 4.26 (s, 1H), 3.95 (s, 1H), 3.77-3.20 (m, 3H), 2.89 (m, 2H), 2.10-2.07 (m, 3H), 1.82- 1.62 (m, 3H).Cpd 18

[0195] Step 1. A mixture of Intermediate D (300 mg, 523.13 pmol), 2,2,6,6-tetramethyl- 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,2,3,6-tetrahydropyridine (208.1 mg, 784.69 pmol), Pd(dppf)C12 (38.3 mg, 52.31 pmol) and K2CO3 (144.6 mg, 1.05 mmol) in dioxane (5 mL) and H2O (1 mL) was stirred at 80 °C for 2 hours under N2. The residue was purified by prep-TLC (SiO2, CH2C12 / MeOH = 10 / 1) to afford tert-butyl 4-[5-benzyl- 10-oxo-7-(2,2,6,6-tetramethyl-l,2,3,6-tetrahydropyridin-4-yl)-lH,2H,3H,4H,5H,10H- benzo[b]l,6-naphthyridine-2-carbonyl]benzoate (170 mg, 51% yield) as an off-white solid. 'H NMR (400 MHz, DMSO-d6) 5 8.18-8.05 (dd, J = 7.6, 8.0 Hz, 1H), 7.98 (m, 2H), 7.60 (s, 2H), 7.47-7.41 (m, 2H), 7.35 (m, 2H), 7.29 (m, 1H), 7.19 (m, 2H), 6.13 (s, 1H), 5.62 (s, 2H), 4.62 (s, 1H), 4.35 (s, 1H), 3.95 (s, 1H), 3.58 (s, 1H), 3.04 (s, 2H), 2.18- 2.12 (m, 2H), 1.56 (s, 9H), 1.21 (s, 6H), 1.12 (s, 6H).

[0196] Step 2. A mixture of tert-butyl 4-[5-benzyl-10-oxo-7-(2,2,6,6-tetramethyl- l,2,3,6-tetrahydropyridin-4-yl)-lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridine-2- carbonyl]benzoate (100 mg, 158.28 pmol) in MeOH (1 mL) was added Pd / C (30 mg, 10% wt Pd), Pd(OH)2 / C (30 mg, 10% wt Pd) and cone. HC1 (12 M, 2.3 mL) under N2. The mixture was stirred under H2 atmosphere at 25 °C for 3 hours. The reaction mixture was filtered and the filtrate was concentrated to afford tert-butyl 4-[10-oxo-7-(2, 2,6,6- tetramethylpiperidin-4-yl)-lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyri dinercarb onyl]benzoate (80 mg, 93% yield) as a yellow solid.

[0197] Step 3. A mixture of tert-butyl 4-[10-oxo-7-(2,2,6,6-tetramethylpiperidin-4-yl)- lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridine-2-carbonyl]benzoate (70 mg, 128.75pmol) in CH2C12 (2 mL) was added TFA (598.9 mg, 5.25 mmol), then the mixture was stirred at 25 °C for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC to afford 4-[10-oxo-7-(2,2,6,6- tetramethylpiperidin-4-yl)-lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridine-2- carbonyl]benzoic acid (14.2 mg, 22% yield) as a white solid. LCMS: [M+H]+ = 488.4. 'H NMR (400 MHz, DMSO-d6 + CF3COOH) 5 12.15-12.03 (m, 1H), 8.71-8.68 (m, 1H), 8.15-8.02 (m, 3H), 7.83-7.80 (m 1H), 7.61-7.57 (m, 2H), 7.47-7.36 (m, 1H), 7.33-7.25 (m, 1H), 4.58 (s, 1H), 4.30 (s, 1H), 3.96 (s, 1H), 3.60 (s, 1H), 3.44-3.36 (m, 1H), 2.93 (m, 2H), 1.93-1.92 (m, 2H), 1.71-1.62 (m, 2H), 1.50 (s, 6H), 1.40 (s, 6H).Cpd 19

[0198] Step 1. To a mixture of Intermediate D (2.5 g, 4.36 mmol) and tert-butyl 4- (4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)- 1 ,2,3,6-tetrahydropyridine- 1 -carboxylate (2.7 g, 8.72 mmol) in dioxane (30 mL) and H2O (6 mL) were added Pd(dppf)C12 (319.0 mg, 435.94 pmol) and K2CO3 (1.20 g, 8.72 mmol). The mixture was stirred at 100 °C for 2 hours under N2. After cooling to room temperature, the reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (100 mL><2). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography to afford tert-butyl 4-(5-benzyl-2-{4-[(tert-butoxy)carbonyl]benzoyl}-10-oxo-1H, 2H,3H,4H,5H,10H-benzo[b]l,6-naphthyri din-7-yl)-l, 2,3, 6-tetrahydropyri dine- 1- carboxylate (2.9 g, 98% yield) as a brown solid. 'H NMR (400 MHz, DMSO-d6) 5 8.20- 7.98 (m, 3H), 7.59-7.58 (m, 2H), 7.48 (m, 2H), 7.35-7.21 (m, 3H), 7.15 (m, 2H), 6.26 (m, 1H), 5.64 (br s, 2H), 4.61-4.35 (m, 2H), 3.93 (s, 3H), 3.60-3.48 (m, 3H), 3.00 (m, 2H), 2.36 (m, 2H), 1.40 (s, 9H), 1.07 (s, 9H).

[0199] Step 2. To a mixture of tert-butyl 4-(5-benzyl-2-{4-[(tert- butoxy)carbonyl]benzoyl } - 10-oxo- 1H,2H,3H,4H,5H, 10H-benzo[b] 1 ,6-naphthyridin-7- yl)-l,2,3,6-tetrahydropyridine-l-carboxylate (2.4 g, 3.55 mmol) in MeOH (30 mL) was added Pd / C (1 g, 10% wt Pd), Pd(OH)2 / C (1 g, 10% wt Pd) and cone. HC1 (12 M, 62 pL). The mixture was stirred at 25 °C for 16 hours under H2 atmosphere (30 Psi). The reaction mixture was filtered and concentrated to afford tert-butyl 4-(2-{4-[(tert-butoxy)carbonyl]benzoyl } - 10-oxo- 1H,2H,3H,4H,5H, 10H-benzo[b] 1 ,6-naphthyridin-7- yl)piperidine-l -carboxylate (1.6 g, crude) as a black brown solid.

[0200] Step 3. To a mixture of tert-butyl 4-(2-{4-[(tert-butoxy)carbonyl]benzoyl}-10- oxo- 1H,2H,3H,4H, 5H, 10H-benzo[b] 1 ,6-naphthyridin-7-yl)piperidine- 1 -carboxylate (330 mg, 561.51 pmol) in DCM (3 mL) was added TFA (4.6 g, 40.52 mmol, 3 mL). The mixture was stirred at 20 °C for 0.5 hours then concentrated under reduced pressure to afford 4-[10-oxo-7-(piperidin-4-yl)-lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridine- 2-carbonyl]benzoic acid (300 mg, crude, TFA salt) as brown oil.

[0201] Step 4. To a mixture of 4-[10-oxo-7-(piperidin-4-yl)-lH,2H,3H,4H,5H,10H- benzo[b]l,6-naphthyridine-2-carbonyl]benzoic acid (100 mg, 213.70 pmol, HC1) and acetaldehyde (47.1 mg, 427.40 pmol, 59.96 ul, 40% purity) in DCM (2 mL) and MeOH (0.4 mL) was added NaBH3CN (53.7 mg, 854.80 pmol), then the mixture was stirred at 35 °C for 16 hours. The reaction mixture was poured into water (20 mL), extracted with ethyl acetate (20 mL><2). The combined organic layers were washed with brine (40 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The product was purified by preparative HPLC to afford 4-[7-(l-ethylpiperidin-4-yl)-10-oxo- lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridine-2-carbonyl]benzoic acid (27 mg, 26% yield, HC1 salt) as an off-white solid. LCMS: [M+H]+ = 460.0. 'H NMR (400 MHz, DMSO-d6) 5 12.44-12.26 (m, 1H), 10.72 (br s, 1H), 8.15-7.98 (m, 3H), 7.62-7.55 (m, 2H), 7.48-7.43 (m, 1H), 7.25-7.18 (m, 1H), 4.56 (s, 2H), 4.29 (s, 1H), 3.95 (s, 1H), 3.56 (m, 2H), 3.13-2.93 (m, 7H), 2.13-2.03 (m, 4H), 1.29 (m, 3H).Cpd20

[0202] Step 1. To a mixture of 2-amino-6-bromobenzoic acid (10 g, 46.29 mmol) and 4- methoxybenzaldehyde (7.56 g, 55.55 mmol) in DCM (100 mL) was added HO Ac (1.39 g, 23.14 mmol) in one portion at 20 °C. The mixture was stirred at 40 °C for 0.5 hour and then to the solution was added NaBH(OAc)3 (29.43 g, 138.87 mmol) in portions at 0 °C. The reaction mixture was warmed to 20 °C and stirred for 16 hours. The reaction mixture was poured into water (300 mL), extracted with ethyl acetate (220 mL><2), the combined organic layers were washed with brine (70 mL><2), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by columnchromatography (SiO2, Petroleum ether / Ethyl acetate=l / 0 to 2 / 1) to afford 2-bromo-6- {[(4-methoxyphenyl)methyl]amino}benzoic acid (13.2 g, 85% yield) as a red solid. 'H NMR (400 MHz, DMSO-d6) 5 13.39 (br s, 1H), 7.24 (d, J = 8.4 Hz, 2H), 7.01 (m, 1H), 6.88 (d, J = 6.8 Hz, 2H), 6.87-6.80 (m, 1H), 6.55 (d, J = 8.4 Hz, 1H), 4.28 (s, 2H), 3.71 (s, 3H).

[0203] Step 2. To a mixture of 2-bromo-6-{[(4-methoxyphenyl)methyl]amino}benzoic acid (5 g, 14.87 mmol) in THF (50 mL) was added triphosgene (1.68 g, 5.65 mmol) in portions at 0 °C under N2. The mixture was stirred at 20 °C for 16 hours. The reaction mixture was filtered and the filter cake was washed with petroleum ether (40 mL) to afford 5-bromo-l-[(4-methoxyphenyl)methyl]-2,4-dihydro-lH-3,l-benzoxazine-2,4- dione (3.6 g, 67%) as a white solid. 'HNMR (400 MHz, DMSO-d6) 57.57-7.54 (m, 2H), 7.35 (d, J = 8.8 Hz, 2H), 7.5-7.4 (m, 1H), 6.89 (d, J = 8.8 Hz, 2H), 5.21 (s, 2H), 3.72 (s, 3H).

[0204] Step 3. To a mixture of 5-bromo-l-[(4-methoxyphenyl)methyl]-2,4-dihydro-lH- 3, l-benzoxazine-2, 4-dione (3.6 g, 9.94 mmol) and tert-butyl 4-oxopiperidine-l- carboxylate (4.16 g, 20.87 mmol) in toluene (50 mL) was added LiHMDS (1 M, 22.9 mL) dropwise at 0 °C under N2. The mixture was stirred at 80 °C for 19 hours. The mixture was poured into aqueous solution NH4C1 (200 mL) and stirred at 0 °C for 0.5 hours. The mixture was extracted with ethyl acetate (200 mL><2). The combined organic layers were washed with brine (100 mL><2), dried over Na2SO4, filtered and concentrated under reduced pressure to afford crude (7 g) as yellow oil. To a mixture of crude (7 g) in toluene (70 mL) was added TsOH (233.0 mg, 1.35 mmol) in one portion at 20 °C. The mixture was stirred at 120 °C for 3 hours. The reaction mixture was cooled to room temperature and poured into water (100 mL), extracted with ethyl acetate (50 mL><2), the combined organic layers were washed with brine (50 mL><2), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was triturated with petroleum ether (45 mL) and ethyl acetate (15 mL) for 15 min, filtered and the filter cake was washed with petroleum ether (15 mL><2) to afford tert-butyl 9-bromo-5-[(4-methoxyphenyl)methyl]- 10-oxo-lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridine-2-carboxylate (3.62 g) as a yellow solid. 'H NMR (400 MHz, DMSO-d6) 5 7.58-7.54 (m, 2H), 7.43-7.38 (m, 1H),6.99 (d, J = 8.4 Hz, 2H), 6.90 (d, J = 8.8 Hz, 2H), 5.46 (s, 2H), 4.28 (br s, 2H), 3.70 (s, 3H), 3.58 (s, 2H), 2.84 (br s, 2H), 1.43 (s, 9H).

[0205] Step 4. To a mixture of tert-butyl 9-bromo-5-[(4-methoxyphenyl)methyl]-10- oxo-lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridine-2-carboxylate (3 g, 6.01 mmol) in DCM (30 mL) was added TFA (9.24 g, 81.04 mmol), then the mixture was stirred at 20 °C for 0.5 hours. The reaction mixture was poured into water (50 mL), adjusted with Na2CO3 aq. to pH = 8~9, extracted with ethyl acetate (40 mL><3). The combined organic layers were washed with brine (30 mL><2), dried over Na2SO4, filtered and concentrated under reduced pressure to afford 9-bromo-5-[(4-methoxyphenyl)methyl]- lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridin-10-one (2.13 g, 89% yield) as a yellow solid. 'H NMR (400 MHz, DMSO-d6) 5 7.56-7.34 (m, 3H), 6.98-6.88 (m, 4H), 5.44 (s, 2H), 3.70 (s, 3H), 3.63 (s, 2H), 2.92 (br s, 2H), 2.67 (m, 2H).

[0206] Step 5. To a solution of 9-bromo-5-[(4-methoxyphenyl)methyl]- lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridin-10-one (2.13 g, 5.33 mmol), 4-[(tert- butoxy)carbonyl]benzoic acid (1.19 g, 5.33 mmol) and DIPEA (2.07 g, 16.00 mmol, 2.8 mL) in DMF (25 mL) was added HATU (2.23 g, 5.87 mmol). The mixture was stirred at 20 °C for 16 hours. The reaction mixture was poured into water (60 mL), extracted with ethyl acetate (40 mL><2), the combined organic layers were washed with brine (80 mL><2), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography to afford tert-butyl tert-butyl 4-{9-bromo-5-[(4- methoxyphenyl)methyl]-10-oxo-lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyri dinercarbonyl (benzoate (2.1 g, 65% yield) as a light yellow solid.1HNMR(400 MHz, DMSO- d6) 5 8.00-7.96 (m, 2H), 7.60-7.58 (m, 4H), 7.42-7.38 (m, 1H), 7.03 (d, J = 8.0 Hz, 2H), 6.91 (d, J = 7.6 Hz, 2H), 5.47 (s, 2H), 4.55 (br s, 1H), 4.29 (s, 1H), 3.89 (br s, 1H), 3.71 (s, 3H), 3.53 (s, 1H), 2.94 (br s, 2H), 1.57 (s, 9H).

[0207] Step 6. To a mixture of tert-butyl tert-butyl 4-{9-bromo-5-[(4- methoxyphenyl)methyl]-10-oxo-lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyri dinercarbonyl (benzoate (200 mg, 331.40 pmol) and (pyrimidin-5-yl)boronic acid (82.1 mg, 662.80 pmol) in dioxane (3 mL) and H2O (0.3 mL) were added K2CO3 (91.6 mg, 662.80 pmol) and Pd(dppf)C12 (24.3 mg, 33.14 pmol). The mixture was heated to 100 °C and stirred for 16 hours under N2. The reaction mixture was cooled to room temperature andpoured into water (60 mL), extracted with dichloromethane (30 mL*j). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, Dichloromethane / Methanol / Ethyl acetate= 10 / 1 / 11) to afford tert-butyl 4-{5-[(4-methoxyphenyl)methyl]-10-oxo-9-(pyrimidin-5-yl)- lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridine-2-carbonyl}benzoate (150 mg, 75% yield) as a red solid.

[0208] Step 7. A solution of tert-butyl tert-butyl 4-{5-[(4-methoxyphenyl)methyl]-10- oxo-9-(pyrimidin-5-yl)-lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyri dinercarbonyl (benzoate (130 mg, 215.70 pmol) in TFA (15 mL) was stirred at 80 °C for 16 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC to afford 4-[10-oxo-9-(pyrimidin-5-yl)- lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridine-2-carbonyl]benzoic acid (69.4 mg, 59% yield, TFA salt) as a yellow solid. LCMS: [M+H]+ = 427.2. 'H NMR (400 MHz, DMSO-d6) 5 13.14 (br s, 1H), 11.93 (m 1H), 9.07 (m, 1H), 8.62 (m, 2H), 8.03-7.97 (m, 2H), 7.48-7.75 (m, 4H), 7.13-7.07 (m, 1H), 4.39 (s, 1H), 4.14 (s, 1H), 3.94 (s, 1H), 3.56 (m, 1H), 2.91-2.90 (m, 2H).Cpd 21

[0209] Step 1. To a solution of tert-butyl (lR,5S)-2,6-diazabicyclo[3.2.1]octane-2- carboxylate (200 mg, 942.12 pmol) in MeCN (4 mL) was added l-bromo-2-m ethoxyethane (196.4 mg, 1.41 mmol), K2CO3 (260.4 mg, 1.88 mmol) at 20 °C and then the mixture was stirred at 80 °C for 16 hours. After cooling to room temperature, the mixture was diluted with CH2C12 (10 mL) and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, Dichloromethane / Methanol=5 / 1) to afford tert-butyl (lR,5S)-6-(2-methoxyethyl)-2,6- diazabicyclo[3.2.1]octane-2-carboxylate (210 mg, 82% yield) as a brown oil. 'H NMR (400 MHz, CDC13) 54.80-4.62 (m, 1H), 3.94-3.84 (m, 1H), 3.54-3.51 (m, 2H), 3.41-3.39 (m, 4H), 3.12-2.84 (m, 5H), 1.86-1.76 (m, 2H), 1.59-1.56 (m, 2H), 1.47 (s, 9H).

[0210] Step 2. A solution of tert-butyl (lR,5S)-6-(2-methoxyethyl)-2,6- diazabicyclo[3.2.1]octane-2-carboxylate (200 mg, 739.74 pmol) in HCl / dioxane (4 M, 5mL) was stirred at 20 °C for 1 hour. The mixture was concentrated under reduced pressure to afford (lR,5S)-6-(2-methoxyethyl)-2,6-diazabicyclo[3.2.1]octane (183 mg, crude, di- HC1 salts) as a brown oil.

[0211] Step 3. To a solution of (lR,5S)-6-(2-methoxyethyl)-2,6- diazabicyclo[3.2.1]octane (300 mg, 523.13 pmol) and Intermediate D (165.4 mg, 680.06 pmol) in t-Amyl-OH (5 mL) were added Xphos Pd G4 (45.0 mg, 52.31 pmol) and Cs2CO3 (852.2 mg, 2.62 mmol), then the mixture was stirred at 100 °C for 16 hours under N2. After cooling to 20 °C, the mixture was poured into water (20 mL) and extracted with ethyl acetate (50 mL><3). The combined organic layers were washed with brine (20 mL><3), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC (SiO2, Ethyl acetate) to afford tert-butyl 4-{5- benzyl-7-[(lR,5S)-6-(2-methoxyethyl)-2,6-diazabicyclo[3.2.1]octan-2-yl]-10-oxo- lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridine-2-carbonyl}benzoate (240 mg, 69% yield) as a brown solid.

[0212] Step 4. To a solution of tert-butyl 4-{5-benzyl-7-[(lR,5S)-6-(2-methoxyethyl)- 2,6-diazabicyclo[3.2.1]octan-2-yl]-10-oxo-lH,2H,3H,4H,5H,10H-benzo[b]l,6- naphthyridine-2-carbonyl}benzoate (150 mg, 226.31 pmol) in MeOH (10 mL) were added Pd / C (100 mg, 10% wt Pd), Pd(OH)2 / C (100 mg, 10% wt Pd) and cone. HC1 (12 M, 19 pL). The mixture was stirred under H2 atmosphere at 20 °C for 24 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure to afford tert-butyl 4-{7-[(lR,5S)-6-(2-methoxyethyl)-2,6-diazabicyclo[3.2.1]octan-2-yl]-10-oxo- lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridine-2-carbonyl}benzoate (100 mg, crude) as a brown solid.

[0213] Step 5. To a solution of tert-butyl 4-{7-[(lR,5S)-6-(2-methoxyethyl)-2,6- diazabicyclo[3.2.1]octan-2-yl]-10-oxo-lH,2H,3H,4H,5H,10H-benzo[b]l,6- naphthyridine-2-carbonyl}benzoate (100 mg, 174.61 pmol) in CH2C12 (1 mL) and MeOH (1 mL) was added TFA (2 mL) at 20 °C and then the mixture was stirred at 20 °C for 16 hours. The mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC to afford 4-{7-[(lR,5S)-6-(2-methoxyethyl)-2,6- diazabicyclo[3.2.1]octan-2-yl]-10-oxo-lH,2H,3H,4H,5H,10H-benzo[b]l,6- naphthyridine-2-carbonyl (benzoic acid (3.8 mg, 4% yield, HC1 salt) as a yellow solid..LCMS: [M+H]+ = 517.1. 'HNMR (400 MHz, Methanol-d4) 5 8.30-8.17 (m, 3H), 7.65- 7.64 (m, 2H), 7.53-7.44 (m, 1H), 6.97-6.94 (m, 1H), 5.07-5.05 (m, 1H), 4.98-4.93 (m, 2H), 4.65-4.44 (m, 1H), 4.17 (m, 1H), 3.90-3.78 (m, 5H), 3.63-3.62 (m, 2H), 3.50-3.46 (m, 2H), 3.22 (s, 3H), 3.22 (m, 2H), 2.48-2.23 (m, 4H) (2 labile H not visible).Cpd 22

[0214] Step 1. To a mixture of tert-butyl 4-{5-benzyl-7-bromo-10-oxo- lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridine-2-carbonyl (benzoate (400 mg, 697.50 pmol) and tert-butyl N-[(3S)-pyrrolidin-3-yl]carbamate (259.8 mg, 1.40 mmol) in tert-amyl alcohol (5 mL) was added XantPhos Pd G3 (66.2 mg, 69.75 pmol) and Cs2CO3 (454.9 mg, 1.40 mmol). The mixture was stirred at 100 °C for 16 hours under N2. After cooling to room temperature, the reaction mixture was purified by prep-TLC to afford tert-butyl 4-{5-benzyl-7-[(3S)-3-{[(tert-butoxy)carbonyl]amino(pyrrolidin-l-yl]-10- oxo-lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridine-2-carbonyl (benzoate (300 mg, 63% yield) as a brown solid.

[0215] Step 2. To a mixture of tert-butyl 4-{5-benzyl-7-[(3S)-3-{[(tert- butoxy)carbonyl]amino(pyrrolidin- 1 -yl]- 10-oxo- 1H,2H,3H,4H, 5H, 10H-benzo[b] 1 ,6- naphthyridine-2-carbonyl(benzoate (170 mg, 331.40 pmol) in MeOH (4 mL) was added HC1 aqueous solution (IM, 823 pL), Pd / C (80 mg, 10% wt Pd) and Pd(OH)2 / C (80 mg, 20% wt Pd). The mixture was stirred at 40 °C for 13 hours under H2 atmosphere. After cooling to room temperature, the reaction mixture was filtered and concentrated. The residue was purified by prep-TLC to afford tert-butyl 4-{7-[(3S)-3-{[(tert- butoxy)carbonyl]amino(pyrrolidin- 1 -yl]- 10-oxo- 1H,2H,3H,4H, 5H, 10H-benzo[b] 1 ,6- naphthyridine-2-carbonyl(benzoate (50 mg, 34%) as a white solid.

[0216] Step 3. To a mixture of tert-butyl 4-{7-[(3S)-3-{[(tert- butoxy)carbonyl]amino(pyrrolidin- 1 -yl]- 10-oxo- 1H,2H,3H,4H, 5H, 10H-benzo[b] 1 ,6- naphthyridine-2-carbonyl(benzoate (50 mg, 84.93 pmol) in dichloromethane (18 mL) was added TFA (2 mL) in one portion at 20 °C. The mixture was stirred at 20 °C for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC and lyophilized to afford 4-{7-[(3S)-3-aminopyrrolidin-l- yl]- 10-oxo- 1H,2H,3H,4H,5H, 10H-benzo[b] 1 ,6-naphthyridine-2-carbonyl (benzoic acidI l l(15.3 mg, 32% yield, TFA salt) as a yellow solid. LCMS: [M+H]+ = 433.2. 'HNMR (400 MHz, DMSO-d6) 5 13.17 (br s, 1H), 11.33 (m, 1H), 8.10-8.02 (m, 4H), 7.96-7.81 (m, 1H), 7.61-7.55 (m, 2H), 6.72-6.64 (m, 1H), 6.36 (s, 1H), 4.49 (s, 1H), 4.22 (s, 1H), 4.01 (s, 1H), 3.93 (s, 1H), 3.66-3.62 (m, 2H), 3.55 (s, 1H), 3.39-3.38 (m, 2H), 2.83-2.80 (m, 2H), 2.37-2.36 (m, 1H), 2.12 (m, 1H).Cpd 23

[0217] Step 1. To a mixture of tert-butyl 4-{7-bromo-5-[(4-methoxyphenyl)methyl]-10- oxo-lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridine-2-carbonyl (benzoate (200 mg, 331.40 pmol) and tert-butyl N-methyl-N-[(3S)-pyrrolidin-3-yl]carbamate (132.7 mg, 662.80 pmol) in t-Amyl-OH (3 mL) was added Ruphos Pd G4 (40 mg) and Cs2CO3 (216.0 mg, 662.80 pmol). The mixture was stirred at 100 °C for 16 hours under N2. After cooling to room temperature, the reaction mixture was poured into water (30 mL), extracted with ethyl acetate (20 mL><2). The combined organic layers were washed with brine (10 mL><2), dried over Na2SO4, filtered and concentrated. The residue was purified by prep-TLC to afford tert-butyl 4-{7-[(3S)-3-{[(tert- butoxy)carbonyl](methyl)amino(pyrrolidin-l-yl]-5-[(4-methoxyphenyl)methyl]-10- oxo-lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridine-2-carbonyl (benzoate (200 mg, 84% yield) as a brown solid. 'H NMR (400 MHz, DMSO-d6) 5 8.03-7.98 (m, 3H), 7.89 (m, 2H), 7.10-7.08 (m, 2H), 6.92-6.88 (m, 2H), 6.70-6.64 (m, 1H), 6.27 (s, 1H), 5.41 (m, 2H), 4.69-4.55 (m, 2H), 4.28 (s, 1H), 3.92 (br s, 1H), 3.71 (s, 3H), 3.53 (s, 1H), 3.38 (s, 1H), 3.17-3.16 (m, 3H), 2.95 (m, 2H), 2.71 (s, 3H), 2.08-2.06 (m, 2H), 1.56 (s, 9H), 1.39 (s, 9H).

[0218] Step 2. A mixture of tert-butyl 4-{7-[(3S)-3-{[(tert- butoxy)carbonyl](methyl)amino(pyrrolidin-l-yl]-5-[(4-methoxyphenyl)methyl]-10- oxo-lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridine-2-carbonyl (benzoate (180 mg, 249.01 pmol) in TFA (18 mL) was stirred at 80 °C for 64 hours. The reaction mixture was concentrated under reduced pressure, purified by preparative HPLC and lyophilized to afford 4-{7-[(3S)-3-(methylamino)pyrrolidin-l-yl]-10-oxo-lH,2H,3H,4H,5H,10H- benzo[b]l,6-naphthyridine-2-carbonyl (benzoic acid (61.7 mg, 45% yield, TFA salt) as a yellow solid. LCMS: [M+H]+ = 447.2. 'H NMR (400 MHz, DMSO-d6) 5 13.23 (br s,1H), 11.42 (m, 1H), 8.90 (m, 2H), 8.03 (d, J = 4.0 Hz, 2H), 7.97-7.81 (m, 1H), 7.61-7.55 (m, 2H), 6.74-6.67 (m, 1H), 6.39 (m, 1H), 4.50 (s, 1H), 4.23 (s, 1H), 3.94 (s, 2H), 3.66- 3.65 (m, 1H), 3.55-3.53 (m, 3H), 3.39 (m, 1H), 2.82 (m, 2H), 2.68 (s, 3H), 2.44-2.38 (m, 1H), 3.22-3.21 (m, 1H).Cpd 24

[0219] The mixture of 4-[7-(3-aminocyclobutyl)-10-oxo-lH,2H,3H,4H,5H,10H- benzo[b]l,6-naphthyridine-2-carbonyl]benzoic acid (30 mg, 71.86 pmol) and acetaldehyde (7.9 mg, 71.86 pmol, 40% purity) in CH2C12 (2 mL) and MeOH (0.2 mL) was stirred at 20 °C for 2 hours. Then NaBH3CN (18.1 mg, 287.46 pmol) was added and the mixture was stirred at 20 °C for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC to afford 4-{7-[3- (diethylamino)cyclobutyl]- 10-oxo- 1H,2H,3H,4H, 5H, 10H-benzo[b] 1 ,6-naphthyri dinercarbonyl (benzoic acid (1.6 mg, 5% yield) as a white solid. LCMS: [M+H]+ = 474. 'H NMR (400 MHz, Methanol-d4) 5 8.26-8.23 (m, 1H), 8.07 (d, J = 6.8 Hz, 2H), 7.30 (m, 4H), 4.76 (s, 1H), 4.34 (s, 1H), 4.06 (m, 1H), 3.69 (m, 1H), 3.48 (m, 1H), 3.31 (m, 1H), 3.18-3.13 (m, 4H), 2.95-2.88 (m, 4H), 2.48 (m, 2H), 1.32 (m, 6H) (2 labile H not visible).Cpd 25

[0220] Step 1. To a solution of tert-butyl (lR,5S)-2,6-diazabicyclo[3.2.1]octane-2- carboxylate (200 mg, 942.12 pmol) in CH2C12 (4 mL) was added Cbz-Cl (192.9 mg, 1.13 mmol) and DIPEA (365.3 mg, 2.83 mmol). The mixture was stirred at 20 °C for 16 hours. The mixture was concentrated under reduced pressure. The residue was purified by prep- TLC (Petroleum ether / Ethyl acetate = 1 / 1) to afford 6-benzyl 2-tert-butyl (lR,5S)-2,6- diazabicyclo[3.2.1]octane-2,6-dicarboxylate (260 mg, 80% yield) as colorless oil. 'H NMR (400 MHz, CDC13) 5 7.29-7.25 (m, 5H), 5.08-5.07 (m, 2H), 4.79-4.63 (m, 1H), 4.32-4.23 (m, 1H), 3.86-3.80 (m, 1H), 3.49-3.44 (m, 1H), 3.40-3.33 (m, 1H), 2.96 (m, 1H), 1.84-1.75 (m, 2H), 1.61-1.50 (m, 2H), 1.38 (s, 9H).

[0221] Step 2. To a solution of 6-benzyl 2-tert-butyl (lR,5S)-2,6- diazabicyclo[3.2.1]octane-2,6-dicarboxylate (250 mg, 721.67 pmol) in CH2C12 (2 mL) was added TFA (3.08 g, 27.01 mmol, 2 mL) at 20 °C and then the mixture was stirred at 20 °C for 0.5 hours. The mixture was concentrated under reduced pressure to affordbenzyl (lR,5S)-2,6-diazabicyclo[3.2.1]octane-6-carboxylate (270 mg, TFA salt) as brown oil.

[0222] Step 3. To a solution of tert-butyl 4-{7-bromo-5-[(4-methoxyphenyl)methyl]-10- oxo-lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridine-2-carbonyl (benzoate (300 mg, 497.10 pmol) in t-Amyl-OH (5 mL) was added benzyl (lR,5S)-2,6- diazabicyclo[3.2.1]octane-6-carboxylate (268.7 mg, 745.65 pmol, TFA salt), Xphos Pd G4 (42.8 mg, 49.71 pmol) and Cs2CO3 (809.8 mg, 2.49 mmol). Then the mixture was stirred at 100 °C for 16 hours under N2. After cooling to room temperature, the mixture was poured in water (20 mL) and extracted with ethyl acetate (50 mL><3). The combined organic layers were washed with brine (20 mL><3), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC (Dichloromethane / Methanol = 10 / 1) to afford benzyl (lR,5S)-2-(2-{4-[(tert- butoxy)carbonyl]benzoyl ( -5-[(4-methoxyphenyl)methyl]- 10-oxo- lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridin-7-yl)-2,6-diazabicyclo[3.2.1]octane-6- carboxylate (200 mg, 52% yield) as a brown solid.JH NMR (400 MHz, DMSO-d6 + D2O) 5 8.02-7.98 (m, 3H), 7.60-7.59 (m, 3H), 7.38-7.31 (m, 4H), 7.08-7.01 (m, 3H), 6.90 (m, 2H), 6.64 (s, 1H), 5.52-5.44 (m, 2H), 5.10-5.04 (m, 2H), 4.59-4.58 (m, 2H), 4.30- 4.23 (m, 2H), 4.02-3.83 (m, 1H), 3.72-3.54 (m, 4H), 3.37 (m, 3H), 3.00-2.96 (m, 3H), 1.92-1.74 (m, 4H), 1.57 (s, 9H).

[0223] Step 4. To a solution of benzyl (lR,5S)-2-(2-{4-[(tert- butoxy)carbonyl]benzoyl ( -5-[(4-methoxyphenyl)methyl]- 10-oxo- lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridin-7-yl)-2,6-diazabicyclo[3.2.1]octane-6- carboxylate (170 mg, 221.10 pmol) in MeOH (5 mL) was added Pd / C (150 mg, 10% wt Pd) and cone. HC1 (12 M, 18 pL). The mixture was stirred at 20 °C for 16 hours under H2 atmosphere. The mixture was concentrated under reduced pressure. The residue was purified by prep-TLC (Dichloromethane / Methanol / NH3.H2O = 5 / 1 / 0.01) to afford tertbutyl 4-{7-[(lR,5S)-2,6-diazabicyclo[3.2.1]octan-2-yl]-5-[(4-methoxyphenyl)methyl]- 10-oxo-lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridine-2-carbonyl (benzoate (70 mg) as a brown solid.

[0224] Step 5. To a solution of tert-butyl 4-{7-[(lR,5S)-2,6-diazabicyclo[3.2.1]octan-2- yl]-5-[(4-methoxyphenyl)methyl]- 10-oxo- 1H,2H,3H,4H, 5H, 10H-benzo[b] 1 ,6-naphthyridine-2-carbonyl(benzoate (70 mg, 110.28 pmol) in CH2C12 (3 mL) was added CH2O (9.9 mg, 330.83 pmol) and NaBH(OAc)3 (116.9 mg, 551.39 pmol) at 20 °C. The mixture was stirred at 20 °C for 16 hours. The mixture was diluted with ethyl acetate (100 mL). The organic layer was washed with brine (20 mL><3), dried over Na2SO4, filtered and concentrated under reduced pressure to afford tert-butyl 4-{5-[(4- methoxyphenyl)methyl]-7-[(lR,5S)-6-methyl-2,6-diazabicyclo[3.2.1]octan-2-yl]-10- oxo-lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridine-2-carbonyl (benzoate (58 mg, 81% yield) as a brown solid.

[0225] Step 6. A solution of tert-butyl 4-{5-[(4-methoxyphenyl)methyl]-7-[(lR,5S)-6- methyl-2,6-diazabicyclo[3.2.1]octan-2-yl]-10-oxo-lH,2H,3H,4H,5H,10H-benzo[b]l,6- naphthyridine-2-carbonyl(benzoate (48 mg, 73.98 pmol) in TFA (1 mL) was stirred at 80 °C for 16 hours. The reaction mixture was concentrated under reduced pressure and purified by preparative HPLC to afford 4-{7-[(lR,5S)-6-methyl-2,6- diazabicyclo[3.2.1]octan-2-yl]-10-oxo-lH,2H,3H,4H,5H,10H-benzo[b]l,6- naphthyridine-2-carbonyl (benzoic acid (10.8 mg, 29% yield, HC1 salt) as a yellow solid. LCMS: [M+H]+ = 473.4. 1H NMR (400 MHz, Methanol-d4) 5 8.29-8.13 (m, 3H), 7.65- 7.63 (m, 2H), 7.49-7.40 (m, 1H), 6.97-6.94 (m, 1H), 5.07-5.06 (m, 1H), 4.95-4.92 (m, 1H), 4.72 (m, 1H), 4.19 (m, 2H), 3.97-3.93 (m, 3H), 3.43-3.37 (m, 2H), 3.20 (m, 2H), 3.10-3.06 (m, 3H), 2.50-2.21 (m, 4H) (2 labile H not visible).Cpd26

[0226] Step 1. To a mixture of tert-butyl 4-{7-bromo-5-[(4-methoxyphenyl)methyl]-10- oxo-lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridine-2-carbonyl (benzoate (200 mg, 331.40 pmol) and tert-butyl N-methyl-N-[(3R)-piperidin-3-yl]carbamate (142.04 mg, 662.80 pmol) in t-Amyl-OH (4 mL) was added Ruphos Pd G4 (40 mg) and Cs2CO3 (216.0 mg, 662.80 pmol) in one portion at 20 °C under N2. The mixture was stirred at 100 °C for 16 hours under N2. After cooling to room temperature, the reaction mixture was purified by prep-TLC to afford tert-butyl 4-{7-[(3R)-3-{[(tert- butoxy)carbonyl](methyl)amino(piperidin-l-yl]-5-[(4-methoxyphenyl)methyl]-10-oxo- lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridine-2-carbonyl(benzoate (170 mg, 83% yield) as awhite solid. 'H NMR (400 MHz, DMSO-d6) 58.03-7.88(m, 3H), 7.58-7.56(m,2H), 7.07-6.98 (m, 3H), 6.90 (m, 2H), 6.72 (br s, 1H), 5.44 (br s, 2H), 4.58-4.53 (m, 1H), 4.29 (s, 1H), 3.79-3.70 (m, 6H), 3.53 (m, 2H), 2.96-2.84 (m, 3H), 2.72-2.67 (m, 4H), 1.70-1.67 (m, 4H), 1.56 (s, 9H), 1.39 (s, 9H).

[0227] Step 2. The mixture of tert-butyl 4-{7-[(3R)-3-{ [(tert- butoxy)carbonyl](methyl)amino}piperidin-l-yl]-5-[(4-methoxyphenyl)methyl]-10-oxo- lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridine-2-carbonyl (benzoate (170 mg, 230.70 pmol) in TFA (20 mL) was stirred at 80 °C for 41 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC and lyophilized to afford 4-{7-[(3R)-3-(methylamino)piperidin-l-yl]-10-oxo- lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridine-2-carbonyl(benzoic acid (63.6 mg, 48% yield, TFA salt) as a yellow solid. LCMS: [M+H]+ = 461.2. 'H NMR (400 MHz, D2O) 5 8.04-7.83 (m, 3H), 7.44 (d, J = 7.6 Hz, 2H), 7.12-7.05 (m, 1H), 6.93 (s, 1H), 4.67 (s, 1H), 4.47 (s, 1H), 3.95-3.92 (m, 1H), 3.67-3.56 (m, 1H), 3.55-3.53 (m, 2H), 2.95-2.93 (m, 1H), 2.80-2.77 (m, 1H), 2.60-2.53 (m, 2H), 2.37-2.28 (m, 4H), 1.93-1.90 (m, 1H), 1.72-1.71 (m, 1H), 1.57 (m, 1H), 1.11-1.05 (m, 1H) (3 labile H not visible).Cpd 27

[0228] Step 1. To a mixture of tert-butyl 4-{7-bromo-5-[(4-methoxyphenyl)methyl]-10- oxo-lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridine-2-carbonyl (benzoate (200 mg, 331.40 pmol) and (3 'S)- 1,3 '-bipyrrolidine (141 mg, 662.80 pmol, di-HCl salts) in t-Amyl- OH (5 mL) was added Ruphos Pd G4 (50 mg) and Cs2CO3 (432 mg, 1.33 mmol). The mixture was stirred at 100 °C for 16 hours under N2. After cooling to room temperature, the reaction mixture was purified by prep-TLC to afford tert-butyl 4-{7-[(3'S)-[l,3'- bipyrrolidin]-l'-yl]-5-[(4-methoxyphenyl)methyl]-10-oxo-lH,2H,3H,4H,5H,10H- benzo[b]l,6-naphthyridine-2-carbonyl (benzoate (170 mg, 77% yield) as a white solid. 'H NMR (400 MHz, DMSO-d6) 5 7.99-7.86 (m, 3H), 7.58 (m, 2H), 7.11 (m, 2H), 6.91 (m, 2H), 6.67-6.61 (m, 1H), 6.23 (s, 1H), 5.39 (s, 2H), 4.55 (br s, 1H), 4.28 (s, 1H), 4.20- 4.13 (m, 1H), 3.92 (br s, 3H), 3.71 (s, 1H), 3.54 (m, 1H), 3.38 (m, 2H), 3.20 (s, 1H), 3.08 (s, 2H), 2.96 (s, 1H), 2.89 (s, 2H), 2.80 (s, 1H), 2.41 (m, 2H), 2.11 (m, 1H), 1.92-1.83 (m, 1H), 1.70 (s, 4H), 1.56 (s, 9H).

[0229] Step 2. The mixture of tert-butyl 4-{7-[(3'S)-[l,3'-bipyrrolidin]-l'-yl]-5-[(4- methoxyphenyl)methyl]-10-oxo-lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridine-2- carbonyl [benzoate (170 mg, 256.48 pmol) in TFA (20 mL) was stirred at 80 °C for 40 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (TFA condition) and lyophilized to afford 4-{7-[(3'S)-[l,3'- bipyrrolidin]-l'-yl]-10-oxo-lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyri dinercarbonyl (benzoic acid (55.2 mg, 36% yield, TFA salt) as a yellow solid. LCMS: [M+H]+ = 487.4. ‘HNMR (400 MHz, Methanol-d4) 5 8.16-8.01 (m, 3H), 7.61 (d, J = 7.6 Hz, 2H), 6.94-6.85 (m, 1H), 6.50 (s, 1H), 4.79 (s, 1H), 4.49 (s, 1H), 4.14-4.10 (m, 2H), 3.92-3.70 (m, 6H), 3.53-3.51 (m, 1H), 3.37 (m, 1H), 3.28 (m, 1H), 3.02-2.96 (m, 2H), 2.65-2.64 (m, 1H), 2.39-2.36 (m, 1H), 2.22-2.13 (m, 4H) (3 labile H not visible).Cpd 28

[0230] Step 1. To a mixture of tert-butyl 4-{7-bromo-5-[(4-methoxyphenyl)methyl]-10- oxo-lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridine-2-carbonyl (benzoate (200.0 mg, 331.40 pmol) and (3 'R)- 1,3 '-bipyrrolidine (141.3 mg, 662.80 pmol) in t-Amyl-OH (5 mL) was added Ruphos Pd G4 (50 mg, 1.66 pmol) and Cs2CO3 (431.9 mg, 1.33 mmol). The mixture was stirred at 100 °C for 16 hours under N2. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-TLC (SiO2, dichloromethane / methanol = 10 / 1) to afford tert-butyl 4-{7-[(3'R)-[l,3'-bipyrrolidin]-l'- yl]-5-[(4-methoxyphenyl)methyl]- 10-oxo- 1H,2H,3H,4H, 5H, 10H-benzo[b] 1 ,6- naphthyridine-2-carbonyl(benzoate (180 mg, 82% yield) as a yellow solid. *HNMR (400 MHz, DMSO-d6) 5 7.99-7.97 (m, 3H), 7.59-7.57 (m, 2H), 7.10 (s, 2H), 6.92-6.90 (m, 2H), 6.66-6.60 (m, 1H), 6.23 (s, 1H), 5.75 (s, 1H), 5.39 (s, 2H), 4.55 (s, 1H), 4.28 (s, 1H), 3.92 (s, 1H), 3.71 (s, 3H), 3.54 (s, 1H), 3.37 (s, 1H), 3.19-2.67 (m, 6H), 2.10 (s, 1H), 1.91- 1.87 (m, 1H), 1.69 (s, 4H), 1.56 (s, 9H).

[0231] Step 2. A mixture of tert-butyl 4-{7-[(3'R)-[l,3'-bipyrrolidin]-l'-yl]-5-[(4- methoxyphenyl)methyl]-l 0-oxo- 1H,2H,3H,4H,5H, 10H-benzo[b]l, 6-naphthyri dinercarbonyl (benzoate (180 mg, 271.57 pmol) in TFA (30 mL) was stirred at 80 °C for 64 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC to afford 4-{7-[(3'R)-[l,3'-bipyrrolidin]-l'-yl]-10-oxo-lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridine-2-carbonyl}benzoic acid (77.2 mg, 47% yield, TFA salt) as a yellow solid. LCMS: [M+H]+ = 487.3 'H NMR (400 MHz, DMSO-d6) 5 13.16 (br s, 1H), 11.34 (s, 1H), 10.00 (br s, 1H), 8.03-7.81 (m, 3H), 7.61- 7.55 (m, 2H), 6.74-6.67 (m, 1H), 6.38 (s, 1H), 4.48 (s, 1H), 4.22 (m, 1H), 4.07-4.05 (m, 2H), 3.93 (m, 1H), 3.77-3.76 (m, 1H), 3.64 (m, 5H), 3.55 (m, 1H), 3.19-3.3.15 (m, 2H), 2.82-2.79 (m, 2H), 2.25 (m, 1H), 2.07 (m, 2H), 1.90-1.89 (m, 2H) (2 labile H not visible).Cpd 29

[0232] To a stirred solution of 7-(l-methylpiperidin-4-yl)-l, 3,4,5- tetrahydrobenzo[b][l,6]naphthyridin-10(2H)-one dihydrochloride (27 mg, 73 pmol) and 3-(l,l-dioxidoisothiazolidin-2-yl)benzoic acid (23 mg, 95 pmol) in MeCN / DMA (9: 1, 1.5 mL) was added DIPEA (63 pL, 365 pmol). After stirring for 5 minutes, T3P (69 pL, 102 pmol) was added and the reaction mixture was stirred for 16 h at room temperature. The reaction mixture was evaporated under reduced pressure and the crude residue was purified by preparative HPLC to afford 2-{3-[7-(l-methylpiperidin-4-yl)-10-oxo- lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridine-2-carbonyl]phenyl}-lX6,2- thiazolidine-l,l-dione (41 mg, 88% yield, TFA salt) as a pale yellow thick oil. LCMS: [M+H]+ = 521.5. 'H NMR (500 MHz, DMSO-d6) 5 11.79 (br s, 1H), 9.57 (br s, 1H), 8.09 (d, J = 7.6 Hz, 0.55H) + 7.97 (d, J = 7.6 Hz, 0.45H), 7.49 (br s, 1H), 7.14-7.41 (m, 5H), 4.51 (br s, 1H), 4.30 (br s, 1H), 3.94 (br s, 1H), 3.79 (br s, 2H), 3.62 (br s, 1H), 3.52- 3.60 (m, 4H), 3.06-3.17 (m, 2H), 2.85-2.96 (m, 3H), 2.83-2.84 (m, 3H), 2.36-2.46 (m, 2H), 2.03-2.12 (m, 2H), 1.80-1.92 (m, 2H).Cpd 30

[0233] Step 1. To a mixture of tert-butyl 4-{7-bromo-5-[(4-methoxyphenyl)methyl]-10- oxo-lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridine-2-carbonyl (benzoate (200 mg, 331.40 pmol) and tert-butyl N-methyl-N-[(3S)-piperidin-3-yl]carbamate (142.0 mg, 662.80 pmol) in t-Amyl-OH (4 mL) were added Ruphos Pd G4 (40 mg) and Cs2CO3 (216.0 mg, 662.80 pmol). The mixture was stirred at 100 °C for 16 hours under N2. After cooling to room temperature, the reaction mixture was purified by prep-TLC (SiO2, dichloromethane / methanol = 15 / 1) to afford tert-butyl 4-{7-[(3S)-3-{[(tert- butoxy)carbonyl](methyl)amino}piperidin-l-yl]-5-[(4-methoxyphenyl)methyl]-10-oxo-lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridine-2-carbonyl(benzoate3 (200 mg, 82% yield) as a white solid. 'H NMR (400 MHz, DMSO-d6) 5 8.00-7.89 (m, 3H), 7.61-7.57 (m, 2H), 7.09-6.99 (m, 3H), 6.91-6.88 (m, 2H), 6.73 (m, 1H), 5.46-5.45 (s, 2H), 4.56 (m, 1H), 4.30 (s, 1H), 3.81-3.54 (m, 8H), 2.96 (m, 3H), 2.73 (m, 3H), 1.71-1.69 (m, 4H), 1.57 (s, 9H), 1.41 (s, 9H).

[0234] Step 2. A solution of tert-butyl 4-{7-[(3 S)-3-{ [(tert- butoxy)carbonyl](methyl)amino}piperidin-l-yl]-5-[(4-methoxyphenyl)methyl]-10-oxo- lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridine-2-carbonyl (benzoate (200 mg, 271.41 pmol) in TFA (20 mL) was stirred at 80 °C for 48 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC and lyophilized to afford 4-{7-[(3S)-3-(methylamino)piperidin-l-yl]- 10-oxo- 1H,2H,3H,4H,5H, 10H-benzo[b] 1 ,6-naphthyridine-2-carbonyl (benzoic acid(81.7 mg, 52% yield, TFA salt) as a yellow solid. LCMS: [M+H]+ = 461.3.1HNMR (400 MHz, DMSO-d6) 5 13.16 (br s, 1H), 11.50 (s, 1H), 8.70 (br s, 2H), 8.03 (d, J = 8.0 Hz, 2H), 7.97-7.82 (m, 1H), 7.61-7.55 (m, 2H), 7.09-7.02 (m, 1H), 6.80 (m, 1H), 4.49 (s, 1H), 4.23 (s, 1H), 3.94 (s, 1H), 3.78 (m, 1H), 3.56-3.45 (m, 2H), 3.28-3.07 (m, 3H), 2.85 (m, 2H), 2.67 (s, 3H), 2.06-1.84 (m, 2H), 1.70-1.64 (m, 2H).Cpd 31

[0235] Step 1. A solution of 2-fluorobenzonitrile (5 g, 41.28 mmol), cyclopropylamine (7.66 g, 134.08 mmol) and DIPEA (5.34 g, 41.28 mmol) in NMP (16 mL) was stirred at 110 °C for 34 hours. The reaction mixture was cooled to room temperature. The reaction mixture was poured into water (100 mL), extracted with ethyl acetate (80 mL><3). The combined organic layers were washed with brine (20 mL><2), dried over Na2SO4, filtered and concentrated to afford 2-(cyclopropylamino)benzonitrile (9 g, crude) as yellow oil.

[0236] Step 2. To a mixture of 2-(cyclopropylamino)benzonitrile (4.5 g, 28.45 mmol) in EtOH (12 mL) and H2O (2.5 mL) was added KOH (5.59 g, 99.56 mmol), then the mixture was stirred at 80 °C for 24 hours. The mixture was cooled to room temperature and adjusted with aqueous solution HC1 to pH = 4 at 0 °C. After filtration, the filter cake was dried under reduced pressure to afford 2-(cyclopropylamino)benzoic acid (2 g, 40% yield) as a light yellow solid. 'H NMR (400 MHz, DMSO-d6) 5 12.63 (br s, 1H), 7.89 (m, 1H),7.78-7.76 (m, 1H), 7.43-7.39 (m, 1H), 7.11-7.08 (m, 1H), 6.64-6.60 (m, 1H), 2.48-2.44 (m, 1H), 0.81-0.77 (m, 2H), 0.46-0.45 (m, 2H).

[0237] Step 3. To a solution of 2-(cyclopropylamino)benzoic acid (2 g, 11.29 mmol) in THF (20 mL) was added triphosgene (1.27 g, 4.29 mmol) in portions under 0 °C. Then the mixture was stirred at 25 °C for 16 hours. The reaction mixture was concentrated under reduced pressure. The crude product was triturated with petroleum ether (20 mL) for 30 min. The reaction mixture was filtered to get the filter cake. The filter cake was dried under reduced pressure to afford l-cyclopropyl-2,4-dihydro-lH-3,l-benzoxazine- 2, 4-dione (1.6 g, 70%yield ) as a yellow solid. 'H NMR (400 MHz, DMSO-d6) 5 7.99- 7.97 (m, 1H), 7.88-7.84 (m, 1H), 7.70-7.68 (m, 1H), 7.35-7.32 (m, 1H), 2.97-2.91 (m, 1H), 1.21-1.18 (m, 2H), 0.87-0.84 (m, 2H).

[0238] Step 4. To the mixture of l-cyclopropyl-2,4-dihydro-lH-3,l-benzoxazine-2,4- dione (1.6 g, 7.87 mmol) and tert-butyl 4-oxopiperidine-l -carboxylate (3.29 g, 16.54 mmol) in toluene (16 mL) was added LiHMDS (1 M, 18.1 mL) dropwise under 0 °C and then the mixture was stirred at 80 °C for 16 hours under N2. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The crude product was triturated with petroleum ether (20 mL) for 30 min. The reaction mixture was filtered to get the filter cake. The filter cake was concentrated under reduced pressure to afford tert-butyl 5-cyclopropyl-10-oxo-lH,2H,3H,4H,5H,10H-benzo[b]l,6- naphthyridine-2-carboxylate (600 mg, 22% yield) as a yellow solid.1H NMR (400 MHz, DMSO-d6) 5 8.15-8.01 (m, 2H), 7.72-7.69 (m, 1H), 7.37-7.33 (m, 1H), 4.25 (m, 2H), 3.57 (m, 2H), 3.39-3.36 (m, 1H), 3.13-3.11 (m, 2H), 1.45 (s, 9H), 1.36-1.35 (m, 2H), 0.92 (m, 2H).

[0239] Step 5. To a solution of tert-butyl 5-cyclopropyl-10-oxo-lH,2H,3H,4H,5H,10H- benzo[b]l,6-naphthyridine-2-carboxylate (500 mg, 1.47 mmol) in CH2C12 (5 mL) was added TFA (1.54 g, 13.51 mmol), then the mixture was stirred at 25 °C for 2 hours. The reaction mixture was concentrated under reduced pressure to afford 5-cyclopropyl- lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridin-10-one (350 mg, 67% yield, TFA salt) as yellow oil. 'H NMR (400 MHz, DMSO-d6) 5 9.06 (m, 1H), 8.16-8.13 (m, 1H), 8.06- 8.04 (m, 1H), 7.78-7.74 (m, 1H), 7.41-7.37 (m, 1H), 4.03-4.02 (m, 2H), 3.45-3.32 (m, 5H), 1.44-1.41 (m, 2H), 0.88-0.87 (m, 2H).

[0240] Step 6. To the mixture of 5-cyclopropyl-lH,2H,3H,4H,5H,10H-benzo[b]l,6- naphthyridin- 10-one (350 mg, 987.80 pmol, TFA salt) and 4-[(tert- butoxy)carbonyl]benzoic acid (219.5 mg, 987.80 pmol) in DMF (5 mL) were added DIEA (383.0 mg, 2.96 mmol) and HATU (563.4 mg, 1.48 mmol), then the mixture was stirred at 25 °C for 16 hours. Then to the reaction mixture was added 4-[(tert- butoxy)carbonyl]benzoic acid (43.9 mg, 197.56 pmol), DIEA (191.5 mg, 1.48 mmol) and HATU (187.8 mg, 493.90 pmol), then the mixture was stirred at 25 °C for 2 hours. The reaction mixture was poured into water (20 mL), extracted with ethyl acetate (15 mL><3). The combined organic layers were washed with brine (5 mL><2), dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 1 / 1) to afford tert-butyl 4-{5-cyclopropyl-10-oxo- lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridine-2-carbonyl(benzoate (600 mg) as a yellow solid.

[0241] Step 7. To the mixture of tert-butyl 4-{5-cyclopropyl-10-oxo- lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridine-2-carbonyl (benzoate (300 mg, 674.88 pmol) in CH2C12 (3 mL) was added TFA (1.54 g, 13.51 mmol), then the mixture was stirred at 25 °C for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC to afford 4-{5-cyclopropyl-10- oxo-lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridine-2-carbonyl (benzoic acid (109.1 mg, 41% yield) as an off-white solid. LCMS: [M+H]+ = 389.0. 'H NMR (400 MHz, DMSO-d6 + CF3COOH) 400 MHz 5 8.21-8.03 (m, 4H), 7.76-7.69 (m, 1H), 7.62-7.57 (m, 2H), 7.42-7.33 (m, 1H), 4.58-4.54 (m, 1H), 4.30 (s, 1H), 3.90-3.80 (m, 1H), 3.52 (m, 1H), 3.40-3.38 (m, 1H), 3.23 (m, 2H), 1.38 (m, 2H), 0.92 (m, 2H) (7 labile H not visible).Cpd 32

[0242] Step 1. To a mixture of tert-butyl 4-{7-bromo-5-[(4-methoxyphenyl)methyl]-10- oxo-lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridine-2-carbonyl (benzoate (200 mg, 331.40 pmol) and tert-butyl N-[(3R)-pyrrolidin-3-yl]carbamate (123.5 mg, 662.80 pmol) in t-Amyl-OH (4 mL) were added Ruphos Pd G4 (40 mg) and Cs2CO3 (216.0 mg, 662.80 pmol). The mixture was stirred at 100 °C for 16 hours under N2. After cooling to room temperature, the reaction mixture was purified by prep-TLC (SiO2,dichloromethane / methanol = 10 / 1) to afford tert-butyl 4-{7-[(3R)-3-{[(tert- butoxy)carbonyl]amino}pyrrolidin-l-yl]-5-[(4-methoxyphenyl)methyl]-10-oxo- lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridine-2-carbonyl(benzoate (200 mg, 85% yield) as a white solid.

[0243] Step 2. A solution of tert-butyl 4-{7-[(3R)-3-{[(tert- butoxy)carbonyl]amino(pyrrolidin-l-yl]-5-[(4-methoxyphenyl)methyl]-10-oxo- lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridine-2-carbonyl (benzoate (200 mg,282.15 pmol) in TFA (20 mL) was stirred at 80 °C for 56 hours. The reaction mixture was concentrated under reduced pressure, purified by preparative HPLC and lyophilized to afford 4-{7-[(3R)-3-aminopyrrolidin-l-yl]-10-oxo-lH,2H,3H,4H,5H,10H- benzo[b]l,6-naphthyridine-2-carbonyl (benzoic acid (67.3 mg, 44% yield, TFA salt) as a yellow solid. LCMS: [M+H]+ = 433.1. 'H NMR (400 MHz, DMSO-d6) 5 13.20 (br s, 1H), 11.38 (s, 1H), 8.11-8.01 (m, 5H), 7.96-7.80 (m, 1H), 7.61-7.55 (m, 2H), 6.71-6.64 (m, 1H), 6.36 (d, J = 6.8 Hz, 1H), 4.49 (s, 1H), 4.22 (s, 1H), 4.00-3.93 (m, 3H), 3.43-3.35 (m, 4H), 2.83-2.80 (m, 2H), 2.38-2.33 (m, 1H), 2.11 (m, 1H).Cpd 33

[0244] Step 1. To a solution of tert-butyl 4-aminobenzoate (200 mg, 1.03 mmol) in CH2C12 (4 mL) was added pyridine (98.2 mg, 1.24 mmol). After cooled it down to 0 °C, difluoromethanesulfonyl chloride (171.4 mg, 1.14 mmol) was added into the mixture. Then, the solution was stirred at 20 °C for 2 hours. The reaction mixture was quenched by H2O (40 mL), extracted with dichloromethane (20 mL><2). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 5 / 1) to afford tert-butyl 4-(difluoromethanesulfonamido)benzoate (300 mg, 94% yield) as a red solid. 'H NMR (400 MHz, DMSO-d6) 5 11.39 (br s, 1H), 7.88 (d, J = 8.8 Hz, 2H), 7.34-7.08 (m, 3H), 1.53 (s, 9H).

[0245] Step 2. To a solution of tert-butyl 4-(difluoromethanesulfonamido)benzoate (300 mg, 976.20 pmol) in DCM (3 mL) was added TFA (4.62 g, 40.52 mmol). The mixture was stirred at 20 °C for 16 hours. The solution was adjusted with aqueous solution NaHCO3 to pH = 7. The reaction mixture was poured into water (20 mL), extracted withethyl acetate (20 mL><2). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to afford 4- (difluoromethanesulfonamido)benzoic acid (200 mg, 82% yield) as a yellow solid.JH NMR (400 MHz, DMSO-d6) 5 7.87 (d, J = 8.8 Hz, 2H), 7.28 (d, J = 8.8 Hz, 2H), 7.21- 6.95 (m, 1H).

[0246] Step 3. To a mixture of 4-(difluoromethanesulfonamido)benzoic acid (50 mg, 199.04 pmol) and tert-butyl N-(3-{5-[(4-methoxyphenyl)methyl]-10-oxo- lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridin-7-yl}cyclohexyl)carbamate (103.0 mg, 199.04 pmol) in DMF (1 mL) were added DIPEA (77.2 mg, 597.12 pmol) and HATU (90.8 mg, 238.85 pmol). The mixture was stirred at 20 °C for 16 hours. The reaction mixture was poured into water (20 mL), extracted with di chloromethane (10 mL><2). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, dichloromethane / methanol = 10 / 1) to afford tert-butyl N-(3-{2- [4-(difluoromethanesulfonamido)benzoyl]-5-[(4-methoxyphenyl)methyl]-10-oxo- lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridin-7-yl}cyclohexyl)carbamate (24 mg, 16% yield) as a white solid.

[0247] Step 4. A mixture of ert-butyl N-(3-{2-[4- (difluoromethanesulfonamido)benzoyl]-5-[(4-methoxyphenyl)methyl]-10-oxo- lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridin-7-yl}cyclohexyl)carbamate (24 mg, 31.96 pmol) in TFA (3 mL) was stirred at 80 °C for 18 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC to afford N-{4-[7-(3-aminocyclohexyl)-10-oxo- 1H,2H,3H,4H, 5H, 10H-benzo[b] 1 ,6-naphthyridine-2-carbonyl]phenyl } - 1 , 1 - difluoromethanesulfonamide (4.6 mg, 21% yield, TFA salt) as a yellow oil. LCMS: [M+H]+ = 531.3. 'H NMR (400 MHz, Methanol-d4) 5 8.13 (m, 1H), 7.52-7.50 (m, 2H), 7.40-7.38 (m, 3H), 7.32-7.30 (m, 1H), 6.86-6.60 (m, 1H), 4.73-4.56 (m, 2H), 4.07-3.65 (m, 3H), 3.08-2.88 (m, 3H), 2.21-1.63 (m, 8H) (4 labile H not visible).Cpd 34

[0248] Step 1. To a mixture of 4-[(tert-butoxy)carbonyl]benzoic acid (900 mg, 4.05 mmol) in CH2C12 (30 mL) was added cyclopropanesulfonamide (638.3 mg, 4.05 mmol), EDCI (1.55 g, 8.10 mmol) and DMAP (1.98 g, 16.20 mmol). The mixture was stirred at 20 °C for 1 hour. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by column chromatography (SiO2, petroleum / ether ethyl acetate = 10 / 1) to afford tert-butyl 4-[(cyclopropanesulfonyl)carbamoyl]benzoate (1 g, 76% yield) as a white solid.JH NMR (400 MHz, DMSO-d6) 5 8.02-8.00 (m, 2H), 7.86-7.84 (m, 2H), 1.74-1.71 (m, 1H), 0.83- 0.67 (m, 4H).

[0249] Step 2. To a mixture of tert-butyl 4-[(cyclopropanesulfonyl)carbamoyl]benzoate (1 g, 3.07 mmol) in CH2C12 (10 mL) was added TFA (3.09 g, 27.01 mmol), then the mixture was stirred at 25 °C for 18 hours. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by prep-HPLC to afford 4- [(cyclopropanesulfonyl)carbamoyl]benzoic acid (220 mg, 27% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) 5 13.37 (s, 1H), 12.30 (br s, 1H), 8.08-8.01 (m, 4H), 3.17- 3.11 (m, 1H), 1.16-1.12 (m, 4H).

[0250] Step 3. To a mixture of tert-butyl N-(3-{5-[(4-methoxyphenyl)methyl]-10-oxo- lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridin-7-yl}cyclohexyl)carbamate (96.1 mg, 185.68 pmol) and 4-[(cyclopropanesulfonyl)carbamoyl]benzoic acid (50 mg, 185.68 pmol) in DMF (1 mL) were added DIPEA (72 mg, 557.04 pmol) and HATU (77.7 mg, 204.25 pmol), then the mixture was stirred at 20 °C for 16 hours. The reaction mixture was poured into water (30 mL), extracted with ethyl acetate (20 mL><2). The combined organic layers were washed with brine (10 mL><2), dried over Na2SO4, filtered and concentrated. The residue was purified by prep-TLC (SiO2, ethyl acetate) to afford tertbutyl N-[3-(2-{4-[(cyclopropanesulfonyl)carbamoyl]benzoyl}-5-[(4- methoxyphenyl)methyl]-10-oxo-lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyri din-7- yl)cyclohexyl]carbamate (32 mg, 22% yield) as a white solid.

[0251] Step 4. A solution of tert-butyl N-[3-(2-{4-[(cyclopropanesulfonyl)carbamoyl]benzoyl}-5-[(4-methoxyphenyl)methyl]-10-oxo-lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridin-7-yl)cyclohexyl]carbamate (32 mg,41.62 pmol) in TFA (20 mL) was stirred at 80 °C for 64 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC and lyophilized to afford 4-[7-(3-aminocyclohexyl)-10-oxo- lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridine-2-carbonyl]-N- (cyclopropanesulfonyl)benzamide (10.4 mg, 38% yield, TFA salt) as a white solid.. LCMS: [M+H]+ = 549.3. 'HNMR (400 MHz, Methanol-d4) 5 8.22-7.98 (m, 3H), 7.64-7.62 (m, 2H), 7.41-7.28 (m, 2H), 4.78 (m, 1H), 4.48 (s, 1H), 4.13-4.10 (m, 1H), 3.73-3.65 (m, 1H), 3.18-3.14 (m, 1H), 3.07-2.97 (m, 3H), 2.60-1.38 (m, 9H), 1.33-1.31 (m, 2H), 1.18-1.15 (m, 2H) (4 labile H not visible).Cpd 35

[0252] Step 1. To a solution of methyl 4-oxopiperidine-3 -carboxylate (10 g, 51.7 mmol) in DCE (100 mL) was added DIPEA (6.67 g, 51.65 mmol) and then stirred at 25°C for 15 min. To the reaction mixture was added benzaldehyde (5.48 g, 51.65 mmol) and then stirred at 25°C for another 15 min. NaBH(OAc)3 (14.23 g, 67.14 mmol) was added to the mixture and the reaction mixture was stirred at 25°C for 2 h. The reaction mixture was poured into ice water (200 ml), extracted with dichloromethane (200 mLx2). The combined organic layers were washed with aqueous solution NaHCO3 (400 mL), then concentrated under reduced pressure. The residue was purified by column chromatography to afford methyl l-benzyl-4-oxopiperidine-3 -carboxylate (9.5 g, 74% yield) as colourless oil.

[0253] Step 2. (reaction run in two identical batches) A mixture of methyl l-benzyl-4- oxopiperidine-3 -carboxylate (1 g, 4.04 mmol) and aniline (376.6 mg, 4.04 mmol) in PPA (20 mL) was stirred at 150 °C for 4 h. After cooling to room temperature, the reaction mixture was poured into water (200 mL) and adjusted to pH=7 with aqueous NaOH. After filtration, the filter cake was collected to afford 2-benzyl-lH,2H,3H,4H,5H,10H- benzo[b]l,6-naphthyri din- 10-one (2 g) as a yellow solid. 'H NMR (400 MHz, DMSO- d6) 5 11.62 (s, 1H), 8.02 (d, J = 8, 1H), 7.58-7.60 (m, 1H), 7.47-7.49 (m, 1H), 7.33-7.36 (m, 4H), 7.23-7.29 (m, 2H), 3.69 (s, 2H), 3.31 (s, 2H), 2.81-2.83 (m, 2H), 2.73-7.74 (m, 2H).

[0254] Step 3. A solution of 2-benzyl-lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridin- 10-one (200 mg, 688 pmol) and Pd / C (100 mg, 10% wtPd) in MeOH (10 mL) was stirred at 25°C for 19 h under H2 balloon. The reaction mixture was filtered and the filtrate was concentrated to lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridin-10-one (230 mg, 42% yield) as a yellow solid.

[0255] Step 4. To a solution of lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridin-10-one (111 mg, 500 pmol) and HATU (228 mg, 600 pmol) in DMF (3 mL) was added 4-[(tert- butoxy)carbonyl]benzoic acid (100 mg, 500 pmol) and DIPEA (194 mg, 1.50 mmol). The mixture was stirred at 25°C for 16 h. The reaction mixture was poured into water (20 mL), extracted with ethyl acetate (20 mLx2). The combined organic layers were washed with brine (40 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography to afford tert-butyl 4-{ 10-oxo- lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridine-2-carbonyl}benzoate (90 mg, 45% yield) as a yellow solid.

[0256] Step 5. To a solution of tert-butyl 4-{ 10-oxo-lH,2H,3H,4H,5H,10H- benzo[b]l,6-naphthyridine-2-carbonyl (benzoate (80 mg, 198 pmol) in DCM (5 mL) was added TFA (1.54 g, 13.51 mmol), the mixture was stirred at 25 °C for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC to afford 4-{ 10-oxo-lH,2H,3H,4H,5H,10H-benzo[b]l,6- naphthyridine-2-carbonyl (benzoic acid (33.6 mg, 49% yield) as a white solid. LCMS: [M+H]+ = 349.1. 'H NMR (400 MHz, DMSO-d6) 5 7.97-8.10 (m, 3H), 7.51-7.62 (m, 4H), 7.28 (br s, 1H), 4.52 (s, 1H), 4.29 (s, 1H), 3.95 (s, 1H), 3.59 (s, 1H), 2.89 (m, 2H).Cpd 36

[0257] Step 1. A mixture of methyl 4-oxopiperidine-3 -carboxylate (1.4 g, 7.03 mmol) and 4-chloroaniline (896.6 mg, 7.03 mmol) in PPA (30 mL) was stirred at 150 °C for 2 hours. After cooling to room temperature, poured into water (100 mL). The solution was neutralized with NaOH to pH = 7. The precipitate was filtered and dried under reduced pressure to afford 2-acetyl-8-chloro-lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridin- 10-one (340 mg) as a brown solid. 'H NMR (400 MHz, DMSO-d6) 5 11.92-11.87 (m,1H), 8.02-8.00 (m, 1H), 7.68-7.64 (m, 1H), 7.56-7.53 (m, 1H), 4.36-4.34 (m, 2H), 3.76- 3.69 (m, 2H), 2.89-2.87 (m, 1H), 2.77-2.74 (m, 1H), 2.10 (s, 3H).

[0258] Step 2. A mixture of 2-acetyl-8-chloro-lH,2H,3H,4H,5H,10H-benzo[b]l,6- naphthyridin- 10-one (190 mg, 686.62 pmol) in aqueous solution HC1 (12 mL, 20% wt) was stirred at 100 °C for 12 hours. The reaction mixture was filtered and the filtrate was dried under reduced pressure to afford 8-chloro-lH,2H,3H,4H,5H,10H-benzo[b]l,6- naphthyridin- 10-one (150 mg, HC1 salt) as a yellow solid.1HNMR (400 MHz, Methanol - d4) 5 8.2 (d, J = 2 Hz, 1H), 7.75-7.72 (m, 1H), 7.62-7.60 (m, 1H), 4.23 (s, 2H), 3.63-3.60 (m, 2H), 3.22-3.18 (m, 2H).

[0259] Step 3. To a mixture of 8-chloro-lH,2H,3H,4H,5H,10H-benzo[b]l,6- naphthyridin- 10-one (50 mg, 184.41 pmol) and 4-[(tert-butoxy)carbonyl]benzoic acid (54.2 mg, 243.82 pmol) in pyridine (3 mL) was added EDCI (93.5 mg, 487.64 pmol). The mixture was stirred at 50 °C for 16 hours. The reaction mixture was poured into water (20 mL), extracted with ethyl acetate (20 mL><2). The combined organic layers were washed with brine (40 mL) and concentrated in vacuum to afford tert-butyl 4-{8-chloro- 10-oxo-lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridine-2-carbonyl (benzoate (150 mg, crude) as a yellow solid.

[0260] Step 4. A mixture of tert-butyl 4-{8-chloro-10-oxo-lH,2H,3H,4H,5H,10H- benzo[b]l,6-naphthyridine-2-carbonyl (benzoate (150 mg, 341.76 pmol) in DCM (7.5 mL) in TFA (7.5 mL, 101.30 mmol) was stirred at 25 °C for 1 hour. The reaction mixture was filtered, concentrated and purified by preparative HPLC to afford 4-{8-chloro-10- oxo-lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridine-2-carbonyl(benzoic acid (10 mg, 8% yield) as a white solid. LCMS: [M+H]+ = 383.0. 'H NMR (400 MHz, DMSO-d6) 5 7.99-7.97 (m, 3H), 7.67-7.49 (m, 4H), 4.52-4.29 (m, 2H), 3.94-3.60 (m, 2H), 2.90 (br s, 2H) (2 labile H missing).Cpd 37

[0261] Step 1. To a solution of 2, 4-dihydro-lH-3,l-benzoxazine-2, 4-dione (2 g, 12.26 mmol) in DMF (20 mL) was added NaH (382.5 mg, 9.56 mmol, 60% purity) slowly at 0 °C under N2 and then the mixture was stirred at 20 °C for 1 hour. To the reaction mixture was added 2-iodopropane (3.13 g, 18.39 mmol) and the mixture was stirred at 20 °C foranother 16 hours. The mixture was quenched by NH4C1 aq. (50 mL) and extracted with ethyl acetate (100 mL><3). The combined organic layer was washed with brine (80 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography to afford 1 -(propan-2 -yl)-2, 4- dihydro-lH-3,l-benzoxazine-2, 4-dione (400 mg, 16% yield) as a brown solid. 'H NMR (400 MHz, DMSO-d6) 5 8.03-8.01 (m, 1H), 7.85-7.82 (m, 1H), 7.66-7.63 (m, 1H), 7.35- 7.31 (m, 1H), 4.89-4.84 (m, 1H), 1.49 (d, J = 6.8 Hz, 6H).

[0262] Step 2. To the mixture of l-(propan-2-yl)-2,4-dihydro-lH-3,l-benzoxazine-2,4- dione (400 mg, 1.95 mmol) and tert-butyl 4-oxopiperidine-l -carboxylate (815.6 mg, 4.09 mmol) in toluene (5 mL) was added LiHMDS (IM, 4.5 mL) dropwise at 0 °C under N2 and then the reaction mixture was stirred at 80 °C for 2 hours. The mixture was quenched by NH4C1 aq. (30 mL) and extracted with ethyl acetate (50 mL><3). The combined organic layer was washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was triturated with ethyl acetate (20 mL) for 1 hour at 20 °C to afford tert-butyl 10-oxo-5-(propan-2-yl)-lH,2H,3H,4H,5H,10H-benzo[b]l,6- naphthyridine-2-carboxylate (400 mg, 20% yield) as a yellow solid.1H NMR (400 MHz, DMSO-d6) 5 8.22-8.20 (m, 1H), 7.95 (d, J =8.8 Hz, 1H), 7.68-7.64 (m, 1H), 7.35-7.32 (m, 1H), 5.04-5.00 (m, 1H), 4.28 (m, 2H), 3.60-3.58 (m, 2H), 2.99-2.96 (m, 2H), 1.63 (d, J =6.8 Hz, 6H), 1.44 (s, 9H).

[0263] Step 3. To the mixture of tert-butyl 10-oxo-5 -(propan-2 -yl)- lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridine-2-carboxylate (80 mg, 233.62 pmol) in MeOH (1 mL) was added HCl / dioxane (4 M, 2 mL) in one portion at 20 °C and then the mixture was stirred at 20 °C for 1 hour. The reaction mixture was concentrated to afford 5-(propan-2-yl)-lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridin-10-one (80 mg, HC1 salt) as a yellow solid. 'H NMR (400 MHz, DMSO-d6) 59.54 (s, 2H), 8.23-8.21 (m, 1H), 8.01 (d, J = 8.8 Hz, 1H), 7.71 (m, 1H), 7.41-7.37 (m, 1H), 5.11-5.04 (m, 1H), 4.00- 3.98 (m, 2H), 3.38 (m, 2H), 3.22-3.20 (m, 2H), 1.65 (d, J =6.8 Hz, 6H).

[0264] Step 4. To the mixture of 5-(propan-2-yl)-lH,2H,3H,4H,5H,10H-benzo[b]l,6- naphthyridin- 10-one (80 mg, 286.97 pmol) and 4-[(tert-butoxy)carbonyl]benzoic acid (63.8 mg, 286.97 pmol) in DMF (2 mL) was added HATU (120.0 mg, 315.67 pmol) and DIEA (148.4 mg, 1.15 mmol) in one portion at 20 °C. The mixture was stirred at 20 °Cfor 16 hours. The reaction mixture was extracted with ethyl acetate (20 mL*2), washed with brine (10 mL><2), dried over Na2SO4, filtered and concentrated. The residue was triturated with MeCN (2 mL) for 30 min at 20 °C and filtered to afford tert-butyl 4-[10- oxo-5-(propan-2-yl)-lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyri dine-2- carbonyl]benzoate (55 mg, 43% yield) as a white solid.JH NMR (400 MHz, CDC13) 5 8.43 (d, J = 7.6 Hz, 1H), 8.05 (d, J = 7.6 Hz, 2H), 7.76 (d, J = 8.8 Hz, 1H), 7.62-7.59 (m, 1H), 7.56 (d, J = 8.0 Hz, 2H), 7.35-7.32 (m, 1H), 4.98 (m, 1H), 4.56 (m, 2H), 4.06 (m, 2H), 3.05 (s, 2H), 1.76 (d, J = 6.8 Hz, 6H), 1.62 (s, 9H).

[0265] Step 5. To the mixture of tert-butyl 4-[10-oxo-5-(propan-2-yl)- lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridine-2-carbonyl]benzoat (50 mg, 111.97 pmol) in di chloromethane (2 mL) was added TFA (2 mL) in one portion at 20 °C. The mixture was stirred at 20 °C for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC to afford 4-[10-oxo-5- (propan-2-yl)-lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridine-2-carbonyl]benzoic acid (29.7 mg, 53% yield) as a white solid. LCMS: [M+H]+ = 391.0JH NMR (400 MHz, DMSO-d6) 5 13.20 (br s, 1H), 8.26-8.12 (m, 1H), 8.04-7.96 (m, 3H), 7.66-7.59 (m, 3H), 7.36-7.32 (m, 1H), 5.01 (br s, 1H), 4.55 (s, 1H), 4.32 (s, 1H), 3.92 (s, 1H), 3.55 (s, 1H), 3.09 (s, 2H), 1.65 (d, J = 6.8 Hz, 6H).Cpd 38

[0266] Step 1. To a stirred solution of 8-fhioro-lH,2H,3H,4H,5H,10H-benzo[b]l,6- naphthyridin- 10-one (28 mg, 0.20 mmol) and 4-[(tert-butoxy)carbonyl]benzoic acid (58 mg, 0.26 mmol) in DCM (2.0 mL) was added DIPEA (173 pL, 1.0 mmol). After stirring for 5 minutes, T3P (187 pL, 0.28 mmol) was added and the reaction mixture was stirred for 16 h at room temperature. The reaction mixture was evaporated under reduced pressure and the crude residue was purified by flash column chromatography (5% to 100% EtOAc in hexane). Additional purification was performed using HPLC to afford tert-butyl 4- { 8-fluoro- 10-oxo- 1H,2H,3H,4H, 5H, 10H-benzo[b] 1 ,6-naphthyri dinercarbonyl [benzoate (81 mg, 96% yield) as a white powder. LCMS: [M+H]+ = 551.4

[0267] Step 2. To a stirred solution of tert-butyl 4-{8-fluoro-10-oxo- lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridine-2-carbonyl}benzoate (81 mg, 0.19mmol) in dioxane (0.6 mL) was added 4N HC1 in dioxane (0.6 mL) and the reaction mixture was stirred for 16 h at room temperature. Et20 (10 mL) was added and the solids were filtered off and dried to afford 4-{8-fluoro-10-oxo-lH,2H,3H,4H,5H,10H- benzo[b]l,6-naphthyridine-2-carbonyl (benzoic acid (76 mg, 98% yield, HC1 salt) as an off-white powder. LCMS: [M+H]+ = 395.2. 'H NMR (500 MHz, DMSO-d6) 5 8.03 (d, J = 8.3 Hz, 2H), 7.57 (br s, 2H), 4.48 (br s, 1H), 4.21 (br s, 1H), 3.90-4.07 (m, 3H), 3.40- .353 (m, 5H), 2.72 (m, 2H), 2.20-2.29 (m, 4H).Cpd 39

[0268] Step 1. The mixture of 2, 4-dihydro-lH-3,l-benzoxazine-2, 4-dione (2 g, 12.26 mmol) in DMF (15 mL) was cooled to 0 °C under N2, then NaH (897.4 mg, 22.44 mmol, 60% wt) was added slowly into the mixture at 0 °C. The mixture was stirred at 20 °C for1 hour. To the reaction mixture was added ethyl iodide (2.10 g, 13.49 mmol) dropwise over 5 mins at 0 °C under N2 and then the mixture was stirred at 20 °C for 16 hours. The reaction mixture was poured into ice water (100 mL) and then stirred at 0 °C for 1 hour. After filtered, the filter cake was washed with petroleum ether (10 mL) to afford 1-ethyl- 2, 4-dihydro-lH-3,l-benzoxazine-2, 4-dione (800 mg, 34% yield) as an off-white solid. 'H NMR (400 MHz, DMSO-d6) 5 8.02-8.00 (m, 1H), 7.87-7.83 (m, 1H), 7.50 (d, J = 8.4 Hz, 1H), 7.33 (m, 1H), 4.09-4.04 (m, 2H), 1.25-1.21 (m, 3H).

[0269] Step 2. The mixture of l-ethyl-2,4-dihydro-lH-3,l-benzoxazine-2, 4-dione (800 mg, 4.18 mmol) and tert-butyl 4-oxopiperidine-l -carboxylate (1.75 g, 8.78 mmol) in toluene (8 mL) was cooled to 0 °C under N2, then LiHMDS (IM. 9.6 mL) was added dropwise into the reaction mixture at 0 °C under N2. The mixture was stirred at 80 °C for2 hours. The mixture was quenched with aqueous NH4C1 (50 mL) and stirred at 0 °C for 10 min. Then extracted with ethyl acetate (50 mL><2), the combined organic layers were washed with brine (50 mL><3), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography to afford tertbutyl 5-ethyl-10-oxo-lH,2H,3H,4H,5H, 10H-benzo[b] l,6-naphthyridine-2-carboxylate (750 mg, 55% yield) as a white solid. 'H NMR (400 MHz, DMSO-d6) 5 8.22-8.20 (m, 1H), 7.88 (d, J = 8.8 Hz, 1H), 7.74-7.70 (m, 1H), 7.38-7.34 (m, 1H), 4.31-4.26 (m, 4H), 3.65-3.62 (m, 2H), 2.97-2.94 (m, 2H), 1.44 (s, 9H), 1.32-1.29 (m, 3H).

[0270] Step 3. To a solution of tert-butyl 5-ethyl-10-oxo-lH,2H,3H,4H,5H,10H- benzo[b]l,6-naphthyridine-2-carboxylate (750 mg, 2.28 mmol) in MeOH (2 mL) was added HCl / dioxane (4 M, 5 mL). The mixture was stirred at 20 °C for 1 hour. The reaction mixture was concentrated to afford 5-ethyl-lH,2H,3H,4H,5H,10H-benzo[b]l,6- naphthyridin- 10-one (640 mg, HC1 salt) as a yellow solid.JH NMR (400 MHz, DMSO- d6) 5 9.65 (br s, 2H), 8.23-8.21 (m, 1H), 7.88 (d, J = 8.8 Hz, 1H), 7.80-7.78 (m. 1H), 7.44-7.40 (m, 1H), 4.37-4.32 (m, 2H), 4.01-3.98 (m, 2H), 3.42 (m, 2H), 3.22-3.19 (m, 2H), 1.32-1.29 (m, 3H).

[0271] Step 4. To a mixture of 5-ethyl-lH,2H,3H,4H,5H,10H-benzo[b]l,6- naphthyridin- 10-one (200 mg, 755.43 pmol, HC1 salt) and 4-[(tert- butoxy)carbonyl]benzoic acid (167.9 mg, 755.43 pmol) in DMF (3 mL) were added HATU (316.0 mg, 830.97 pmol) and DIEA (390.5 mg, 3.02 mmol). The mixture was stirred at 20 °C for 16 hours. The reaction mixture was filtered, the filter cake was washed with MeCN (10 mL) and concentrated under reduced pressure to afford tert-butyl 4-{5- ethyl- 10-oxo- 1H,2H,3H,4H, 5H, 10H-benzo[b] 1 ,6-naphthyridine-2-carbonyl (benzoate (140 mg, 43% yield) as a white solid. 'H NMR (400 MHz, DMSO-d6) 5 8.25-8.12 (m, 1H), 7.99 (d, J = 6.8 Hz, 2H), 7.74 (m, 1H), 7.65 (m, 1H), 7.64-7.56 (m, 2H), 7.39-7.36 (m, 1H), 4.57 (s, 1H), 4.31 (m, 3H), 3.98 (s, 1H), 3.59 (s, 1H), 3.08 (m, 2H), 1.58 (s, 9H), 1.34 (m, 3H).

[0272] Step 5. To a mixture of tert-butyl 4-{5-ethyl-10-oxo-lH,2H,3H,4H,5H,10H- benzo[b]l,6-naphthyridine-2-carbonyl (benzoate (140 mg, 323.69 pmol) in CH2C12 (2 mL) was added TFA (3 mL). The mixture was stirred at 20 °C for 1 hour. The reaction mixture was concentrated under reduced pressure. The crude product was triturated with MeCN (5 mL) to afford 4-{5-ethyl-10-oxo-lH,2H,3H,4H,5H,10H-benzo[b]l,6- naphthyridine-2-carbonyl(benzoic acid (98.5 mg, 81% yield) as a white solid. LCMS: [M+H]+ = 377.3. 'H NMR (400 MHz, DMSO-d6) 5 13.18 (s, 1H), 8.27-8.12 (m, 1H), 8.03 (d, J = 7.6 Hz, 2H), 7.83 (d, J = 8.8 Hz, 1H), 7.74 (m, 1H), 7.65-7.57 (m, 2H), 7.39- 7.36 (m, 1H), 4.57 (s, 1H), 4.33 (m, 3H), 3.98 (s, 1H), 3.61 (s, 1H), 3.09 (m, 2H), 1.34 (m, 3H).Cpd 40

[0273] Step 1. To a stirred solution of 4-amino-3-trifluoromethoxybenzoic acid (5.0 g, 23 mmol, CAS# 175278-22-5) in MeOH (113 mL) at -20 °C was added thionyl chloride (3.3 mL, 45 mmol) dropwise while warming up to room temperature. The reaction mixture was stirred for 3 h at 60 °C after which, LC-MS showed complete conversion to the desired ester. Volatiles were evaporated under reduced pressure and the crude residue was azeotroped one more time with MeOH (100 mL). The residual pale brown solid containing methyl 4-amino-3-(trifluorom ethoxy )benzoate was used in the following step without further purification.

[0274] Step 2. To a stirred solution of methyl 4-amino-3-(trifluoromethoxy)benzoate (5.32 g, 22.6 mmol) in DCM (113 mL) at -20 °C were successively added triethylamine (15.8 mL, 113 mmol) and methanesulfonyl chloride (3.8 mL, 49.7 mmol) dropwise. The reaction mixture was slowly warmed up to room temperature and stirred for 3 h after which, LC-MS showed complete conversion to the desired product. The reaction mixture was cooled down to -18 °C and the solids were removed by filtration and washed with a minimum amount of cold DCM. The filtrate was washed with IN aq. HC1 (2x 100 mL), sat. aq. NaCl (100 mL), dried over Na2SO4, filtered through a pad of silica (eluting with more DCM) and solvents were evaporated under reduced pressure. The crude residue, containing methyl 4-(N-(methylsulfonyl)methylsulfonamido)-3-(trifluoromethoxy)benzoate (and methyl 4-(methylsulfonamido)-3- (trifluoromethoxy)benzoate) as a pale yellow powder, was used in the next step without further purification. LCMS: [M-H]- = 312.1, 390.2

[0275] Step 3. To a stirred solution of methyl 4-(N- (methylsulfonyl)methylsulfonamido)-3-(trifluoromethoxy)benzoate (8.85 g, 22.6 mmol) in THF (151 mL) and MeOH (23 mL) was added IN aq. NaOH (57 mL) at room temperature. The reaction mixture was stirred for 15 min, after which LC-MS showed complete mono de-mesylation. Solid NaOH (3.39 g, 84.8 mmol) was then added and stirring was extended for 16 h. The reaction mixture was diluted with water (100 mL) and acidified to pH 3 with 2N aq. HC1 (~85 mL). The white precipitate that formed was filtered off, washed with water (50 mL) and diethylether (50 mL) to afford 4-(methylsulfonamido)-3-(trifluoromethoxy)benzoic acid (4.42 g, 65% yield) as a white powder. LCMS: [M-H]- = 298.1

[0276] Step 4. To a stirred solution of 4-(methylsulfonamido)-3- (trifluoromethoxy)benzoic acid (77 mg, 0.26 mmol) in DCM (2.0 mL) were successively added DIPEA (173 pL, 1.0 mmol) and 8-fluoro-l, 3,4,5- tetrahydrobenzo[b][l,6]naphthyridin-10(2H)-one dihydrochloride (58 mg, 0.20 mmol). After stirring for 5 minutes, T3P (240 pL, 0.36 mmol) was added and the reaction mixture was stirred for 16 h at room temperature. Upon completion of the coupling, as judged by LC-MS, the reaction mixture was diluted with sat. aq. NaHCO3 (3 mL) and passed through a ChemElut® cartridge using DCM to elute the organic materials. Volatiles were evaporated under reduced pressure and the crude residue was purified by flash column chromatography (0% to 10% MeOH in DCM) to afford N-(4-(8-fluoro-10-oxo- l,2,3,4,5,10-hexahydrobenzo[b][l,6]naphthyridine-2-carbonyl)-2- (trifluoromethoxy)phenyl)m ethanesulfonamide (38 mg, 38% yield) as a white powder. LCMS: [M+H]+ = 500.2. 'H NMR (500 MHz, DMSO-d6) 5 11.94 (s, 1H), 10.05 (s, 1H), 7.63-7.80 (m, 1H), 7.65 (d, J = 8.5 Hz, 1H), 7.50-7.63 (m, 4H), 4.51 (br s, 1H), 4.36 (br s, 1H), 3.16 (s, 3H), 2.91-2.93 (m, 1H).

[0277] General procedure for synthesis using Chemspeed Robot: Reactions are performed in Isynth reactors of a SWING workstation Chemspeed Robot. The 96 reactor wells are 8 mL glass vials placed in the two independent Isynth reactors. Both contain 48 reaction positions, are able to be heated up to 150 °C, cooled down to -10 °C using a Cryostat, and equipped with a Reflux system. The robot can be put under an inert atmosphere using N2 gas. All volumetric transfers are performed using the Chemspeed 4-Needle Head tool, with a capacity of 10 mL for each needle, and a rinsing step between each transfer of different solvent or solution. All solid dispenses are performed using the Chemspeed Gravimetric Dispense Unit (GDU-Pfd), connected to a 0.1 mg precision balance. Theworkflow is divided into the following steps.

[0278] Preparation of reactors: Building blocks dissolution: the appropriate solvents are added into 2 mL vials containing pre-weighted quantities of desired building blocks. The custom rack is shaken at 600 rpm and heated at 35-50 °C for 10 min, to allow dissolution of building blocks. Building blocks dispense into corresponding reactor vials.To note: Some substrates are already in reactor vials, if insoluble materials or intermediates prepared in a previous step. Powders dispense into reactors, using GDU- Pfd tool. Stock solutions dispense using 4-Needle Head tool, to add prepared solutions of reactants unable to be added as a powder. Solvents addition using 4-Needle Head tool, to reach desired reaction concentration.

[0279] Reaction time: stirring and heating / cooling of Isynths: The 2 reactors of 48 vials are independent for duration (t, hours) and temperature (T, °C). Reactions are stirred at 400 rpm in Isynths under reflux and inert atmosphere. After cooling down reactors to 20 °C and an optional work-up process, reaction mixtures are transferred into barcoded vials.

[0280] Work-up (all steps are optional): Quenching using appropriate solvent. Dilution of reaction mixtures. Filtration of reaction mixture using 1 mL or 3 mL SPE cartridge, containing 50 mg or 200 mg of either Silica or metal-scavenger pad. Rinsing of reaction vial, followed by another filtration in the same SPE position.

[0281] Transfer of crudes: Transfer of filtrates after SPE into barcoded 8 mL vials, OR, Direct transfer of reaction mixtures without filtration step.

[0282] Evaporation in Genevac system: Concentrations of crude mixtures before purifications are made using a Genevac EZ-2 Elite Personal Evaporator containing 48 positions for 8 mL glass vials. Automatic preloaded methods are used to evaporate under vacuum diverse solvent groups, having very low, low or high boiling points. In general use, the maximal sample temperature is set at 40°C. “Low BP mix” method is chosen in a first attempt, then followed by “High + Low BP” or even “High BP” methods for remaining liquid mixtures.

[0283] The mass spectra (MS) were recorded on a Waters ZQ mass spectrometer (scan 200-900 uma) using electrospray positive ionisation [ES+ to give MH+ molecular ions] or electrospray negative ionisation [ES- to give (M-H)- molecular ions] modes with a 20 V cone voltage.

[0284] General procedures for Purifications and final QC analysis:

[0285] Purification: Autopurify Waters system equipped with an injector collector Waters 2767, an at-column pump Waters 515, a gradient pump 2545, a 1 / 5000 splitter, amake-up pump Waters 515, a diode array detector Waters 2996 and a quadripolar mass spectrometer Waters QDa (electrospray ion source). Column: Waters XSelect Cl 8 CSH 50*30mm, 5pm, T: RT flow rate: 60mL / min, at-column dilution: ACN with flow rate of ImL / min, make-up dilution: MeOH + 0.1% HCOOH with a flow rate of ImL / min, elution in gradient mode, mobile phase: focused gradients with HCOOH lOmM or NH4OH 10mM / ACN in 5 min.

[0286] QC analysis of final products: UHPLC / MS Waters Acquity HClass coupled with a diode array detector Waters Acquity, a quadripolar mass spectrometer Waters 3100 (electrospray ion source) and a charged aerosol detector Thermo Corona Ultra RS. Column: Waters XSelect C18 CSH 50*2.1mm, 2.5pm, T: 45°C, flow rate: ImL / min, elution in gradient mode, mobile phase: Ammonium formate lOmM pH7.4 95% / ACN 5% to Ammonium formate lOmM pH7.4 2% / ACN 98% in 2.17 min.

[0287] General procedures for Robotic synthesis

[0288] Two general cases regarding the crudes: Crudes of final products are all sent to purification; OR Crudes of intermediates are concentrated and used in the next step without further purification. They are directly preloaded in the reactors.

[0289] Procedure Pl: TFA-TIS deprotection: To a pre-loaded Substrate (1 eq.) was added a mixture of TFA / TIS (10 / 1 v / v, 0.1 M). The reaction was heated at 80 °C for 4 to 16 hours. After cooling down Isynth to room temperature, 1 mL of MeOH was added to the reaction mixture for quenching, then concentrated under reduced pressure in Genevac to give the crude product.

[0290] Procedure P2: TFA deprotection: To a pre-loaded Substrate (1 eq.) was added TFA (0.1 M). The reaction was heated at 80 °C for 4 to 16 hours. After cooling down Isynth to room temperature, 1 mL of MeOH was added to the reaction mixture for quenching, then concentrated under reduced pressure in Genevac to give the crude product.

[0291] Procedure P3: TFA-DCM deprotection: To a Substrate (1 eq.) dissolved in DCM or pre-loaded if intermediate, were added DCM and TFA to reach a volumetric ratio TFA / DCM of 1 / 1 (v / v, 0.05 M). The reaction was stirred at 25 °C for 2 to 16 hours. 1 mLof MeOH was added to the reaction mixture for quenching, then concentrated under reduced pressure in Genevac to give the crude product.

[0292] Procedure P4: Ester hydrolysis: To a Substrate (1 eq.) dissolved in THF or pre- loaded if intermediate, was added a LiOH.EEO (1.2-4.0 eq.) as a stock solution in H2O. THF, MeOH and H2O were added to reach a volumetric ratio THF / MeOH / H2O of 4 / 1 / 1 (v / v, 0.05 M). The reaction was stirred at 25-40 °C for 16 hours. The reaction mixture was directly concentrated under reduced pressure in Genevac to give the crude product.

[0293] Procedure P5: Peptidic coupling: To a mixture of Amine substrate (1.0 eq.) and RCOOH Substrate (1.5 eq.) dissolved in DMF or pre-loaded if intermediate, were added HATU (1.5 eq.) as a powder, and a stock solution of DIPEA (4 eq.) in DMF. Optional addition of DMF was performed, to reach a reaction concentration of 0.05 M. The reaction was stirred at 25-40 °C for 16 hours. The reaction mixture was directly concentrated under reduced pressure in Genevac to give the crude product.

[0294] Procedure P6: Hydroxy to Methoxy: To a solution of ArOH substrate (1.0 eq.) dissolved in DMF or pre-loaded if intermediate, was added a stock solution of CH3I (1.5 eq.) in DMF, followed by Cs2CO3 (2.0 eq.) as a powder. Optional addition of DMF was performed, to reach a reaction concentration of 0.05 M. The reaction was stirred at 50 °C for 16 hours. After cooling down Isynth to room temperature, the reaction mixture was filtered on Silica SPE cartridge. After additional rinsing with DCM / MeOH (9 / 1 v / v), the filtrate was concentrated under reduced pressure in Genevac to give the crude product.

[0295] Procedure P7: Suzuki coupling - protocol 1 (using RB(0H)2) : To a mixture of ArBr / ArCl substrate (1.0 eq.) and RB(OH)2 substrate (1.2 eq.) dissolved in degassed DME / EtOH / H2O (2 / 2 / 1 v / v) or pre-loaded if intermediate, were added Pd catalyst Si- DPP-Pd (5 mol%, purchased from Silicycle) and CS2CO3 (2.0 eq.) as powders. Optional addition of DMEZEtOH / H2O (2 / 2 / 1 v / v) was performed, to reach a reaction concentration of 0.1 M. The reaction was stirred at 60-80 °C for 16 hours. After cooling down Isynth to room temperature, the reaction mixture was diluted using 1 mL of DCM / MeOH (9 / 1 v / v), filtered on Si-thiol SPE cartridge. After additional rinsing with DCM / MeOH (9 / 1 v / v), the filtrate was concentrated under reduced pressure in Genevac to give the crude product.

[0296] Procedure P8: Suzuki coupling - protocol 2 (using RBpin)'. To a mixture of ArBr / ArCl substrate (1.0 eq.) and RBpin substrate (1.2 eq.) dissolved in degassed DME / EtOH / lhO (2 / 2 / 1 v / v) or pre-loaded if intermediate, were added Pd catalyst Si- DPP-Pd or PdC12(dppf) (5 mol%) and CS2CO3 (3.0 eq.) as powders. Optional addition of DME / EtOEI / EhO (2 / 2 / 1 v / v) was performed, to reach a reaction concentration of 0.1 M. The reaction was stirred at 60-80 °C for 16 hours. After cooling down Isynth to room temperature, the reaction mixture was diluted using 1 mL of DCM / MeOH (9 / 1 v / v), filtered on Si-thiol SPE cartridge. After additional rinsing with DCM / MeOH (9 / 1 v / v), the filtrate was concentrated under reduced pressure in Genevac to give the crude product.

[0297] Procedure P9: Sonogashira coupling: To a mixture of ArBr substrate (1.0 eq.) and Alkyne substrate (2.0 eq.) dissolved in MeCN or pre-loaded if intermediate, were added PdC12(dtbpf) (5 mol%) and CS2CO3 (2.0 eq.) as powders. Optional addition of MeCN was performed to reach a reaction concentration of 0.05 M. The reaction was stirred at 80 °C for 16 hours. After cooling down Isynth to room temperature, the reaction mixture was diluted using 1 mL of DCM / MeOH (9 / 1 v / v), filtered on Si-thiol SPE cartridge. After additional rinsing with DCM / MeOH (9 / 1 v / v), the filtrate was concentrated under reduced pressure in Genevac to give the crude product.

[0298] Procedure P10: SN2 - N-alkylation: To a mixture of Pyrazole substrate (1.0 eq.) and Alkyl-Br / Alkyl-Cl substrate (2.0 eq.) dissolved in MeCN or pre-loaded if intermediate, was added CS2CO3 (2.0 eq.) as a powder. Optional addition of MeCN was performed, to reach a reaction concentration of 0.1 M. The reaction was stirred at 50 °C for 18 hours. After cooling down Isynth to room temperature, the reaction mixture was filtered on Silica SPE cartridge. After additional rinsing with DCM / MeOH (9 / 1 v / v), the filtrate was concentrated under reduced pressure in Genevac to give the crude product.

[0299] Procedure PH: C~N coupling between ArX and Amide: To a mixture of ArBr substrate (1.0 eq.) and Amide substrate (1.5 eq.) dissolved in degassed Dioxane, were added Pd pre-catalyst XantPhos Pd G4 (5 mol%) and CS2CO3 (2.0 eq.) as powders. Optional addition of Dioxane was performed, to reach a reaction concentration of 0.05 M. The reaction was stirred at 100 °C for 16 hours. After cooling down Isynth to room temperature, the reaction mixture was diluted using 1 mL of DCM / MeOH (9 / 1 v / v),filtered on Si-thiol SPE cartridge. After additional rinsing with DCM / MeOH (9 / 1 v / v), the filtrate was concentrated under reduced pressure in Genevac to give the crude product.

[0300] Procedure P12: Buchwald-Hartwig amination - protocol 1: To a mixture of ArBr substrate (1.0 eq.) and Amine substrate (2.0 eq.) dissolved in degassed Dioxane or pre- loaded if intermediate, were added (Amphos^PdCh (5 mol%) and NaOtBu (3 eq.) as powders. Optional addition of Dioxane was performed, to reach a reaction concentration of 0.05 M. The reaction was stirred at 100 °C for 16 hours. After cooling down Isynth to room temperature, the reaction mixture was diluted using 1 mL of DCM / MeOH (9 / 1 v / v), filtered on Si-thiol SPE cartridge. After additional rinsing with DCM / MeOH (9 / 1 v / v), the filtrate was concentrated under reduced pressure in Genevac to give the crude product.

[0301] Procedure P13: Buchwald-Hartwig amination - protocol 2 (for primary amines)'. To a mixture of ArBr substrate (1.0 eq.) and Amine substrate (2.0 eq.) dissolved in degassed Dioxane or pre-loaded if intermediate, were added BrettPhos Pd G3 (5 mol%) and NaOtBu (3-4 eq.) as powders. Optional addition of Dioxane was performed, to reach a reaction concentration of 0.05 M. The reaction was stirred at 100 °C for 16 hours. After cooling down Isynth to room temperature, the reaction mixture was diluted using 1 mL of DCM / MeOH (9 / 1 v / v), filtered on Si-thiol SPE cartridge. After additional rinsing with DCM / MeOH (9 / 1 v / v), the filtrate was concentrated under reduced pressure in Genevac to give the crude product.

[0302] Procedure P14: Buchwald-Hartwig amination - protocol 3 (for secondary amines '. To a mixture of ArBr substrate (1.0 eq.) and Amine substrate (2.0 eq.) dissolved in degassed Dioxane or pre-loaded if intermediate, were added Pd pre-catalyst Ruphos Pd G4 (5 mol%) and NaOtBu (3-7 eq.) as powders. Optional addition of Dioxane was performed, to reach a reaction concentration of 0.05 M. The reaction was stirred at 100 °C for 16 hours. After cooling down Isynth to room temperature, the reaction mixture was diluted using 1 mL of DCM / MeOH (9 / 1 v / v), filtered on Si-thiol SPE cartridge. After additional rinsing with DCM / MeOH (9 / 1 v / v), the filtrate was concentrated under reduced pressure in Genevac to give the crude product.

[0303] Procedure P15: Miyaura borylation: To a mixture of ArBr substrate (1.0 eq.) and B2pin2 (1.5 eq.) dissolved in degassed Dioxane or pre-loaded if intermediate, were addedSi-DPP-Pd (5 mol%) and KO Ac (3.0 eq.) as powders. Optional addition of Dioxane was performed, to reach a reaction concentration of 0.05 M. The reaction was stirred at 80 °C for 16 hours. Work-up: After cooling down Isynth to room temperature, the reaction mixture was diluted using 1 mL of DCM / MeOH (9 / 1 v / v), filtered on Si-thiol SPE cartridge. After additional rinsing with DCM / MeOH (9 / 1 v / v), the filtrate was concentrated under reduced pressure in Genevac to give the crude product.

[0304] Procedure P16: Heck coupling: To a mixture of ArBr substrate (1.0 eq.) and Alkene substrate (1.2 eq.) dissolved in NMP or pre-loaded if intermediate, were added PdC12(dtbpf) (5 mol%). Then Cy2NMe (1.5 eq.) was added as a stock solution in NMP, followed by an optional addition of NMP to reach a reaction concentration of 0.05 M. The reaction was stirred at 100 °C for 16 hours. Work-up: After cooling down Isynth to room temperature, the reaction mixture was diluted using 1 mL of DCM / MeOH (9 / 1 v / v), filtered on Si-thiol SPE cartridge. After additional rinsing with DCM / MeOH (9 / 1 v / v), the filtrate was concentrated under reduced pressure in Genevac to give the crude product.

[0305] Representative preparation using standardized Robotic protocols.Cpd 41

[0306] Step 1. Methyl 2-(3-{5-[(2,4-dimethoxyphenyl)methyl]-7-(4-methylpiperazin-l- yl)- 10-oxo- 1H,2H,3H,4H,5H, 10H-benzo[b] 1 ,6-naphthyridine-2-carbonyl } - 1 ,2-oxazol- 5-yl)acetate was prepared following Procedure P5 (Peptidic coupling) using Intermediate F dihydrochloride (Intermediate F, 52 mg, 0.1 mmol) and 5-(2-methoxy-2-oxoethyl)-l,2- oxazole-3 -carboxylic acid (19 mg, 0.1 mmol). The crude mixture was forwarded to the next step without further purification.

[0307] Step 2. 2-(3-{5-[(2,4-dimethoxyphenyl)methyl]-7-(4-methylpiperazin-l-yl)-10- oxo-lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridine-2-carbonyl}-l,2-oxazol-5- yl)acetic acid was prepared following Procedure P4 (Ester hydrolysis) from crude methyl 2-(3 - { 5-[(2,4-dimethoxyphenyl)methyl]-7-(4-methylpiperazin- 1 -yl)- 10-oxo- lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridine-2-carbonyl}-l,2-oxazol-5-yl)acetate. The crude mixture was forwarded to the next step without further purification.

[0308] Step 3. Crude 2-(3-{5-[(2,4-dimethoxyphenyl)methyl]-7-(4-methylpiperazin-l- yl)- 10-oxo- 1H,2H,3H,4H,5H, 10H-benzo[b] 1 ,6-naphthyridine-2-carbonyl } - 1 ,2-oxazol-5-yl)acetic acid was engaged in Procedure Pl (TFA-TIS deprotection). The crude material was purified by prep-HPLC (method 1) to afford 2-{3-[7-(4-methylpiperazin-l- yl)- 10-oxo- 1H,2H,3H,4H,5H, 10H-benzo[b] 1 ,6-naphthyridine-2-carbonyl]- 1 ,2-oxazol- 5-yl}acetic acid (8.5 mg, 19% yield). LC / MS (method B): tR = 0.34 min, [M+H]+ = 452.2 Cpd 42 to Cpd 97

[0309] Other examples prepared in a similar manner using Robotic synthesis are described in the table below.

[0310] All reactions were run on a 0.1 mmol scale for the first step with no intermediate purification step. Yields reported below are therefore not optimized. For detailed procedures, refer to the general protocols for robotic synthesis described above.

[0311] General procedures for synthesis

[0312] Procedure P17: Buchwald-Hartwig amination - protocol 4. To an Argon-purged mixture of ArBr intermediate (1.0 eq.), Amine substrate (1.5 eq.) and Cs2CO3 (3 eq.) in dioxane were added Pd2(dba)3 (0.05 eq.) and Xantphos (0.1 eq.) at RT. The resulting mixture was purged with Argon and stirred at 100 °C for 24 h. The reaction mixture was cooled to RT, diluted with water (15 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (15 mL), dried over Na2SO4, filtered and concentrated to dryness to afford a crude product. This resulting crude material was material purified by flash chromatography over silica gel to yield the expected product.

[0313] Procedure P18: Buchwald-Hartwig amination - protocol 5. To an Argon-purged mixture of ArBr intermediate (1.0 eq.), Amine substrate (1.5 eq.) and Cs2CO3 (6 eq.) in dioxane was added Pd2(dba)3 (0.05 eq.) and Xantphos (0.1 eq.) at RT. The reaction mixture was purged with Argon, heated to 100 °C and stirred for 2 to 18 h then cooled to RT, diluted with MeOH (10 mL) and filtered on a pad of Celite. The pad was rinsed with MeOH and the filtrate was concentrated under reduced pressure. The resulting crude material was purified by flash chromatography over silica gel to yield the expected product.

[0314] Procedure P19: Buchwald-Hartwig amination - protocol 6. To an Argon-purged mixture of ArBr intermediate (1.0 eq.), Amine substrate (1.5 eq.) and Cs2CO3 (5 eq.) in tert-amyl alcohol was added RuPhos Pd G4 (0.05 eq.) at RT. The reaction mixture was purged with Argon, heated to 100 °C and stirred for 2 to 16 hours. The reaction mixture was cooled to RT, diluted with water (15 mL) and extracted with DCM (3 x 20 mL). The combined organic layers were washed with brine (15 mL), dried over Na2SO4, filtered and concentrated to dryness to afford a crude product. This resulting crude material was material purified by flash chromatography over silica gel to yield the expected product.

[0315] Procedure P20: Protecting-group cleavage (TFA / TIS). To a solution of protected starting material (1 eq.) in TFA (0.1 M) was added triisopropylsilane (5 eq.) at RT and the resulting mixture was stirred at 70 °C for 16-18 h. The reaction mixture was precipitated with Et2O (5 mL) and centrifuged. The supernatant was discarded. The solid was dissolved in CH3CN (1 mL), precipitated with Et2O (3 x 5 mL), centrifuged and the supernatant was discarded. The remaining solid was dried under vacuo to afford a crude product. This crude was purified by flash chromatography over silica gel or by preparative LC / MS to yield the expected product.

[0316] Procedure P21: Protecting-group cleavage (TFA). A solution of protected starting material (1 eq.) in TFA (1.6 mL) was stirred at RT for 1 h. The reaction mixture was precipitated with Et2O (5 mL) and centrifuged. The solid was dissolved in CH3CN (1 mL), precipitated with Et2O (2 x 5 mL), centrifuged and the supernatant was discarded. The remaining solid was dried under vacuo to afford a crude product. This crude was purified by flash chromatography over silica gel or by preparative LC / MS to yield the expected product.

[0317] Procedure P22: Protecting-group cleavage (TFA / DCM 1 :4). To a solution of protected starting material (1 eq.) in TFA was added DCM (1 :4 v / v) at RT. The reaction mixture was stirred at RT for 1 h. The reaction mixture was precipitated with Et2O (5 mL) and centrifuged. The supernatant was discarded. The solid was suspended in Et2O (5 mL), centrifuged and the supernatant was discarded. The solid was dissolved in MeOH (1 mL), precipitated with Et2O (5 mL), centrifuged and the supernatant was discarded. The resulting crude product was purified by flash chromatography over silica gel or by preparative LC / MS to yield the expected product.Cpd 98 to Cpd 123Cpd 124

[0318] Step 1. To an Argon-purged mixture of Intermediate E (1 eq., 150 mg, 0.24 mmol), tert-butyl N-(azeti din-3 -yl)carbamate (2 eq., 82 mg, 0.47 mmol) and sodium tert- butoxide (3 eq., 68 mg, 0.71 mmol) in toluene (5 mL) were added Pd2(dba)3 (0.05 eq., 10.8 mg, 0.012 mmol) and BINAP (0.1 eq., 14.7 mg, 0.024 mmol) at RT. The resulting mixture was heated at 100 °C under microwave irradiation for 0.5 h. The reaction mixture was concentrated under reduced pressure, solubilized with EtOAc (15 mL) and washed with an aqueous saturated solution of NH4C1 (20 mL). The aqueous layer was extractedwith EtOAc (2 x 15 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated to dryness. The resulting crude material was purified by flash chromatography over silica gel (DCM / MeOH 100 / 0 to 90 / 10) to afford tert-butyl 4-[7-(3-{[(tert-butoxy)carbonyl]amino}azetidin-l-yl)-5-[(2,4- dimethoxyphenyl)methyl]- 10-oxo- 1H,2H,3H,4H, 5H, 10H-benzo[b] 1 ,6-naphthyri dine-2- carbonyl]benzoate (38 mg, 22% yield) as an orange solid.

[0319] Step 2. To a solution of tert-butyl 4-[7-(3-{[(tert- butoxy)carbonyl]amino}azetidin-l-yl)-5-[(2,4-dimethoxyphenyl)methyl]-10-oxo- lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridine-2-carbonyl]benzoate (1 eq., 36 mg, 0.05 mmol) in TFA (0.98 mL) was added triisopropylsilane (5 eq., 39.3 mg, 51 pL, 0.25 mmol) at RT and the mixture was stirred at 70 °C for 16 h. The mixture was diluted with ACN (4 mL) and concentrated under reduced pressure. The residue was dissolved in ACN (3 mL) and concentrated under reduced pressure (x 2). The residue was dissolved in ACN (1 mL) and Et2O (3 mL) was added at RT. The resulting precipitate was centrifugated (4000 rpm, 3 min) and the supernatant was removed. The crude material was purified by preparative HPLC (XBridge prep C18, 150 x 30 mm, 5 pm, 43 ml / min, liquid loading, mobile phase gradient: water+0.2% TFA / ACN from 90 / 10 to 75 / 25 over 18 min) and lyophilized in 3 mL of water to afford 4-[7-(3-aminoazetidin-l-yl)-10-oxo- lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridine-2-carbonyl]benzoic acid (11.9 mg, 0.022 mmol, 45% yield, TFA salt) as a light yellow solid. LC / MS (Method C): Rt= 4.28 min, [M+H]+= 533.8. 'HNMR (400 MHz, DMSO-d6) 5 13.15 (brs, 1H), 11.42 - 11.26 (m, 1H), 9.21 (d, J = 8.2 Hz, 1H), 8.08 - 7.49 (m, 6H), 6.80 - 6.43 (m, 3H), 6.39 (s, 1H), 4.94 (s, 2H), 4.48 (s, 1H), 4.24 - 4.17 (m, 1H), 4.09 - 4.00 (m, 1H), 3.91 (s, 1H), 3.36 - 3.18 (m, 3H), 2.81 (s, 2H).Cpd l25

[0320] Step 1. To a suspension of 5-methyl-lH,2H,3H,4H,5H,10H-benzo[b]l,6- naphthyridin- 10-one (1 eq., 620 mg, 1.71 mmol) in DMF (5.7 mL) were added at RT 4- [(tert-butoxy)carbonyl]benzoic acid (1.1 eq., 418 mg, 1.88 mmol), DIPEA (4.6 eq., 1.018 g, 1.37 mL, 7.87 mmol) and HATU (1.3 eq., 846 mg, 2.23 mmol). The reaction mixture was stirred at RT for 16 hours. The reaction mixture was diluted with water (100 mL).The resulting precipitate was filtered and washed with water (3 x 50 mL) and Et2O (3 x 50 mL). The solid concentrated to dryness to afford tert-butyl 4-{7-bromo-5-methyl-10- oxo-lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridine-2-carbonyl (benzoate (827 mg, 98% yield) as a beige solid used as such for the next step.

[0321] Step 2. To an Argon-purged mixture of tert-butyl 4-{7-bromo-5-methyl-10-oxo- lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridine-2-carbonyl(benzoate (1 eq., 80 mg, 0.16 mmol), l-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,2,3,6- tetrahydropyridine (1.5 eq., 53.8 mg, 0.24 mmol) and K2CO3 (2.5 eq., 56 mg, 0.402 mmol) in 1,4-dioxane (1.6 mL) and H2O (0.33 mL) was added Pd(dppf)C12.DCM (0.05 eq., 6.6 mg, 0.008 mmol) at RT. The reaction mixture was stirred at 100°C for 16 h. The RM was concentrated under reduced pressure and purified by flash chromatography over silica gel (50 pm, 12 g, DCM / MeOH from 100:0 to 60:40 in 40 min to afford tert-butyl 4-[5-methyl-7-(l -methyl- 1,2, 3, 6-tetrahydropyridin-4-yl)-10-oxo- lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridine-2-carbonyl]benzoate (33 mg, 40% yield) as a brown solid.

[0322] Step 3. To a solution of tert-butyl 4-[5-methyl-7-(l-methyl-l, 2,3,6- tetrahydropyridin-4-yl)- 10-oxo- 1H,2H,3H,4H, 5H, 10H-benzo[b] 1 ,6-naphthyridine-2- carbonyl]benzoate (1 eq., 33 mg, 0.064 mmol) in DCM (0.5 mL) was added TFA (50 eq., 366 mg, 0.24 mL, 3.21 mmol) at RT and the mixture was stirred for 4 h. Et2O (5 mL) was added and the resulting precipitate was centrifuged. The supernatant was discarded. The residue was dissolved in CH3CN (1 mL), precipitated with Et2O (5 mL), centrifuged and the supernatant was discarded. The residue was dissolved in MeOH (1 mL), precipitated with Et2O (5 mL), centrifuged and the supernatant was discarded to afford 4- [5-methyl-7-(l -methyl- 1,2, 3, 6-tetrahydropyridin-4-yl)-l 0-oxo- 1H,2H,3H,4H,5H,1 OH- benzo[b]l,6-naphthyridine-2-carbonyl]benzoic acid (29.5 mg, 98% yield, TFA salt) as a light brown solid. LC / MS (Method C) Rt= 3.65 min [M+H]+ = 458.3. 'H NMR (400 MHz, DMSO-d6) 5 13.17 (s, 1H), 9.78 (s, 1H), 8.28 - 8.07 (m, 1H), 8.03 (d, J = 7.7 Hz, 2H), 7.74 (s, 1H), 7.68 - 7.47 (m, 3H), 6.48 (s, lH), 4.57 (s, 1H), 4.33 (s, 1H), 4.15 - 3.79 (m, 4H), 3.79 (s, 3H), 3.69 - 3.49 (m, 3H), 3.09 (s, 2H), 3.00 - 2.83 (m, 4H).Cpd 126

[0323] Step 1. To an Argon-purged mixture of intermediate G (1 eq., 130 mg, 0.26 mmol), l-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,2,3,6- tetrahydropyridine (1.5 eq., 87.5 mg, 0.39 mmol) and K2CO3 (2.5 eq., 90.3 mg, 0.65 mmol) in 1,4-dioxane (2.7 mL) and H2O (0.5 mL) was added Pd(dppf)C12.DCM (0.05 eq., 10.7 mg, 0.013 mmol) at RT. The reaction mixture was purged with Ar, heated to 100 °C and stirred for 16 hours. The mixture was concentrated under reduced pressure and purified by flash chromatography over silica gel (DCM / MeOH 100:0 to 65:35) to afford tert-butyl 4-[5-methyl-7-(l-methyl-l,2,3,6-tetrahydropyridin-4-yl)-10-oxo- lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridine-2-carbonyl]benzoate (100 mg, 75% yield) as a brown solid.

[0324] Step 2. To an Argon-purged mixture of tert-butyl 4-[5-methyl-7-(l-methyl- 1 ,2,3 ,6-tetrahydropyridin-4-yl)- 10-oxo- 1H,2H,3H,4H, 5H, 10H-benzo[b] 1 ,6- naphthyridine-2-carbonyl]benzoate (1 eq., 96 mg, 0.19 mmol) in MeOH (3.8 mL) was added Pd / C 10% (0.15 eq., 29.8 mg, 0.028 mmol). The reaction mixture was purged with H2 and stirred at RT under atmospheric pressure of hydrogen for 72 h. The reaction mixture was purged with Argon, filtered over a PTFE filter, rinsed with MeOH (2 x 2 mL), concentrated to dryness and purified by flash chromatography over silica gel (DCM / MeOH 100:0 to 35:65) to afford tert-butyl 4-[5-methyl-7-(l-methylpiperidin-4- yl)- 10-oxo- 1H,2H,3H,4H,5H, 10H-benzo[b] 1 ,6-naphthyridine-2-carbonyl]benzoate (35 mg, 36% yield) as a light yellow solid.

[0325] Step 3. A solution of tert-butyl 4-[5-methyl-7-(l-methylpiperidin-4-yl)-10-oxo- lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridine-2-carbonyl]benzoate (1 eq., 31 mg, 0.06 mmol) in TFA (1.2 mL) was stirred at RT for 1 h. The reaction mixture was cooled to 0 °C and Et2O (5 mL) was added. The mixture was centrifugated and the supernatant was removed. The resulting solid was dissolved in a minimum of MeOH (0.5 mL), precipitated with Et2O (5 mL), centrifuged and the supernatant was discarded. The resulting crude material was dissolved in a minimum of MeOH (0.5 mL), precipitated with Et2O (5 mL), centrifuged and the supernatant was discarded to afford 4-[5-methyl- 7-(l-methylpiperidin-4-yl)-10-oxo-lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridine- 2-carbonyl]benzoic acid (20.2 mg, 59% yield, TFA salt) as a white solid aftervacuum-drying at 40 °C for 3 h. LC / MS (Method C): Rt= 3.67 min, [M+H]+ = 460.4. 'H NMR (400 MHz, DMSO-d6) 5 8.25 - 8.06 (m, 1H), 8.03 (d, J = 7.7 Hz, 2H), 7.66 - 7.49 (m, 3H), 7.35 - 7.22 (m, 1H), 4.56 (s, 1H), 4.31 (s, 1H), 3.94 (s, 1H), 3.75 (s, 3H), 3.58 (s, 1H), 3.50 - 3.43 (m, 2H), 3.11 - 2.94 (m, 5H), 2.79 (s, 3H), 2.10 - 1.89 (m, 4H), (two labile protons missing).Cpd 127

[0326] Step 1. To an Argon-purged mixture of tert-butyl 4-{7-bromo-5-methyl-10-oxo- lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridine-2-carbonyl}benzoate (1 eq., 150 mg, 0.302 mmol), tert-butyl N-[(3-hydroxyazetidin-3-yl)methyl]carbamate (1.5 eq., 91.5 mg, 0.45 mmol) and Cs2CO3 (3 eq., 295 mg, 0.905 mmol) in 1,4-dioxane (2.5 mL) were added Pd2(dba)3 (0.05 eq., 13.8 mg, 0.015 mmol) and Xantphos (0.1 eq., 17.5 mg, 0.0302 mmol) at RT and the resulting mixture was stirred at 70 °C for 16 h. The reaction mixture was concentrated to dryness under reduced pressure. The crude material was purified by flash chromatography over silica gel (DCM / MeOH from 100 / 0 to 90 / 10). The fractions containing compound were combined, evaporated in vacuo and co-evaporated with DCM affording tert-butyl 4-{7-[3-({[(tert-butoxy)carbonyl]amino}methyl)-3-hydroxyazetidin- l-yl]-5-methyl-10-oxo-lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyri dinercarbonyl (benzoate (65.7 mg, 39% yield) as a yellow solid. LC / MS (Method C): Rt= 1.53 min, [M+H]+ = 619.7

[0327] Step 2. To a solution of tert-butyl 4-{7-[3-({[(tert- butoxy)carbonyl]amino}methyl)-3-hydroxyazetidin-l-yl]-5-methyl-10-oxo- lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridine-2-carbonyl}benzoate (1 eq., 65.7 mg, 0.106 mmol) in DCM (0.8 mL) was added TFA (0.2 mL) and the resulting mixture was stirred at RT for 2 h. The reaction mixture was cooled to 0 °C and Et2O (5 mL) was added. The mixture was centrifugated and the supernatant was removed. The resulting solid was solubilized with ACN (minimum amount) and precipitated with Et2O (5 mL). The mixture was centrifugated and the supernatant was removed (process done twice). The residual solid was triturated with Et2O (5 mL) then solubilized with MeOH (minimum amount) and precipitated with Et2O (5 mL). The mixture was centrifugated and the supernatant was removed (process done twice). The residual solid was trituratedwith Et2O (5 mL) and dried under high-vacuum at 40 °C affording 4-{7-[3- (aminomethyl)-3-hydroxyazetidin-l-yl]-5-methyl-10-oxo-lH,2H,3H,4H,5H,10H- benzo[b]l,6-naphthyridine-2-carbonyl (benzoic acid (39.7 mg, 65% yield, TFA salt) as a yellow solid. LC / MS (Method D): Rt= 3.52 min, [M+H]+ = 463.3. 'H NMR (400 MHz, DMSO-d6) 5 8.84 (br s, 2H), 8.14 - 7.81 (m, 4H), 7.66 - 7.48 (m, 2H), 6.60 - 6.49 (m, 1H), 6.37 - 6.31 (m, 1H), 4.50 (br s, 1H), 4.27 (br s, 1H), 4.09 (d, J = 8.4 Hz, 2H), 3.96 - 3.80 (m, 3H), 3.65 - 3.52 (m, 4H), 3.18 (s, 2H), 3.00 (br s, 2H).Cpd 128

[0328] Step 1. To an Argon-purged mixture of Intermediate I (1 eq., 150 mg, 0.302 mmol), tert-butyl N-[(3-hydroxyazetidin-3-yl)methyl]carbamate (1.5 eq., 92 mg, 0.45 mmol) and Cs2CO3 (3 eq., 295 mg, 0.905 mmol) in 1,4-dioxane (2.5 mL) were added Pd2(dba)3 (0.05 eq., 13.8 mg, 0.015 mmol) and Xantphos (0.1 eq., 17.5 mg, 0.0302 mmol) atRT and the resulting mixture was stirred at 100 °C for 16 h. The reaction mixture was concentrated to dryness under reduced pressure and the residue was purified by flash chromatography over silica gel (DCM / MeOH 100 / 0 to 60 / 40). The fractions containing compound were combined, evaporated in vacuo and co-evaporated with DCM affording tert-butyl 4-(5-methyl-10-oxo-7-{6-oxo-5-oxa-2,7-diazaspiro[3.4]octan-2-yl}- lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridine-2-carbonyl)benzoate (38.1 mg) as a yellowish solid.

[0329] Step 2. To a solution of tert-butyl 4-(5-methyl-10-oxo-7-{6-oxo-5-oxa-2,7- diazaspiro[3.4]octan-2-yl}-lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridine-2- carbonyl)benzoate (1 eq., 33 mg, 0.061 mmol) in DCM (0.4 mL) was added TFA (0.1 mL) and the resulting mixture was stirred at RT for 6 h. The reaction mixture was cooled to 0 °C and Et2O (5 mL) was added. The mixture was centrifugated and the supernatant was removed. The resulting solid was solubilized with ACN (minimum amount) and precipitated with Et2O (5 mL). The mixture was centrifugated and the supernatant was removed (process done twice). The residual solid was triturated with Et2O (5 mL) and dried under high-vacuum at 40 °C affording 4-(5-methyl-10-oxo-7-{6-oxo-5-oxa-2,7- diazaspiro[3.4]octan-2-yl}-lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridine-2- carbonyl)benzoic acid (21.8 mg, 74% yield) as a yellow solid. LC / MS (Method D): Rt=4.16 min, [M+H]+=489.3. 'H NMR (400 MHz, DMSO-d6) 5 13.18 (br s, 1H), 8.08 - 7.90 (m, 3H), 7.76 (s, 1H), 7.64 - 7.50 (m, 2H), 6.65 - 6.52 (m, 1H), 6.43 (s, 1H), 4.52 (s, 1H), 4.30 - 4.17 (m, 5H), 3.94 - 3.90 (m, 1H), 3.79 (s, 2H), 3.64 (s, 3H), 3.59 - 3.51 (m, 1H), 3.01 (br s, 2H).Cpd 129

[0330] Step 1. To an Argon-purged mixture of Intermediate E (1 eq., 150 mg, 0.24 mmol), tert-butyl N-(azetidin-3-yl)carbamate (2 eq., 81.6 mg, 0.47 mmol) and sodium tert-butoxide (3 eq., 68.3 mg, 0.71 mmol) in toluene (5 mL) were added Pd2(dba)3 (0.05 eq., 10.8 mg, 0.012 mmol) and BINAP (0.1 eq., 14.7 mg, 0.024 mmol) at RT. The resulting mixture was heated at 100 °C under microwave irradiation for 0.5 h. The reaction mixture was concentrated under reduced pressure, solubilized with EtOAc (15 mL) and washed with an aqueous saturated solution of NH4C1 (20 mL). The aqueous layer was extracted with EtOAc (2 x 15 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, concentrated to dryness and purified by flash chromatography over silica gel (DCM / MeOH 100 / 0 to 90 / 10) to afford tert-butyl 4- [7-(3-{[(tert-butoxy)carbonyl]amino}azetidin-l-yl)-5-[(2,4-dimethoxyphenyl)methyl]- 10-oxo- 1H,2H,3H,4H,5H, 10H-benzo[b] 1 ,6-naphthyridine-2-carbonyl]benzoate (38 mg, 0.052 mmol, 22% yield) as an orange solid.

[0331] Step 2. To a solution of tert-butyl 4-[7-(3-{[(tert- butoxy)carbonyl]amino}azetidin-l-yl)-5-[(2,4-dimethoxyphenyl)methyl]-10-oxo- lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridine-2-carbonyl]benzoate (1 eq., 36 mg, 0.05 mmol) in TFA (0.98 mL) was added triisopropylsilane (5 eq., 39.3 mg, 50.9 pL, 0.25 mmol) at RT and the RM was stirred at 70 °C for 16 h. The mixture was diluted with ACN (4 mL) and concentrated under reduced pressure to afford a purple residue (this operation was repeated three times). The residue was dissolved in a minimum of ACN (1 mL) and Et2O (3 mL) was added at RT. The resulting precipitate was centrifugate (4000 rpm, 3 min) and the supernatant was removed. The resulting crude material was purified by preparative HPLC (XBridge prep Cl 8, 150 x 30 mm, 5 pm, 43 ml / min, liquid loading, mobile phase gradient: water+0.2% TFA / ACN from 90 / 10 to 75 / 25 over 18 min) and lyophilized in 3 mL of water to afford 4-[7-(3-aminoazetidin-l-yl)-10-oxo-lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridine-2-carbonyl]benzoic acid (11.9 mg, 45% yield, TFA salt) as a light yellow solid. LC / MS (Method C): Rt= 3.13 min, [M+H]+= 419.5.XH NMR (400 MHz, DMSO-d6) 5 13.14 (brs, 1H), 11.25 (s, 1H), 8.02 (d, J = 7.9 Hz, 2H), 7.93 (s, 2H), 7.79 (dd, J = 51.7, 8.7 Hz, 1H), 7.65 - 7.48 (m, 2H), 6.72 - 6.38 (m, 3H), 5.39 (s, 1H), 4.47 (s, 1H), 4.21 (s, 1H), 3.92 (s, 1H), 3.63 - 3.52 (m, 2H), 3.38 - 3.19 (m, 3H), 2.87 - 2.73 (m, 2H).Cpd 130

[0332] Step 1. To an argon-purged solution of tert-butyl 7-bromo-5-[(2,4- dimethoxyphenyl)methyl]- 10-oxo- 1H,2H,3H,4H, 5H, 10H-benzo[b] 1 ,6-naphthyridine-2- carboxylate (1 eq., 0.5 g, 0.94 mmol), l-methyl-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-l,2,3,6-tetrahydropyridine (1.5 eq., 0.32 g, 1.42 mmol) and K2CO3 (2.5 eq., 0.33 g, 2.36 mmol) in dioxane (9 mL) and H2O (1.8 mL) was added Pd(dppf)C12.DCM (0.05 eq., 0.039 g, 0.047 mmol) atRT and the resulting mixture was stirred at 100 °C for 18 h. The reaction was poured into water (30 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated to dryness under reduced pressure The crude material was purified by flash chromatography over silica gel (DCM / MeOH from 100 / 0 to 90 / 10). The fractions containing compound were combined, evaporated in vacuo and co-evaporated with DCM affording tert-butyl 5-[(2,4-dimethoxyphenyl)methyl]-7- (1 -methyl- 1 ,2,3 ,6-tetrahydropyridin-4-yl)- 10-oxo- 1H,2H,3H,4H,5H, 10H-benzo[b] 1 ,6- naphthyridine-2-carboxylate (0.402 g, 0.74 mmol, 78%) as a brown solid.

[0333] Step 2. To a solution of tert-butyl 5-[(2,4-dimethoxyphenyl)methyl]-7-(l- methyl- 1 ,2,3 ,6-tetrahydropyridin-4-yl)- 10-oxo- 1H,2H,3H,4H, 5H, 10H-benzo[b] 1,6- naphthyridine-2-carboxylate (1 eq., 0.4 g, 0.73 mmol) in MeOH (9 mL), previously purged with argon was added Pd / C (0.2 eq., 0.16 g, 0.15 mmol). A further purge with argon was proceeded (3x) followed by H2 (3x). The reaction was performed under H2 atmosphere at RT for 17 h. The reaction mixture was filtered on a PTFE filter and washed with MeOH (20 mL). The filtrate was evaporated in vacuo and co-evaporated with DCM affording tert-butyl 5-[(2,4-dimethoxyphenyl)methyl]-7-(l-methylpiperidin-4-yl)-10-oxo-lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridine-2-carboxylate (0.47 g) as a yellow gum.

[0334] Step 3. To a solution of methyl 3-chloro-4-methanesulfonamidobenzoate (1 eq., 2.27 g, 8.075 mmol) in THF (20 mL) was added a solution of LiOH (2 eq., 0.68 g, 16.15 mmol) in water (6 mL) and the reaction mixture was stirred at 70 °C for 2.5 h. Additional LiOH (1 eq., 0.34 g, 0.24 mL, 8.075 mmol) was added and the resulting mixture was stirred at 70 °C for 16.5 h. THF was removed under reduced pressure. The resulting solution was acidified with an aq. HC1 IM solution (40 mL, pH: 1) and extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated to dryness under reduced pressure affording crude 3-chloro-4- methanesulfonamidobenzoic acid (1.57 g, 6.29 mmol, 78%) as a white solid.

[0335] Step 4. To a solution of tert-butyl 5-[(2,4-dimethoxyphenyl)methyl]-7-(l- methylpiperidin-4-yl)-10-oxo-lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridine-2- carboxylate (1 eq., 0.47 g, 0.69 mmol) in 1,4-di oxane (5 mL) was added HC1 4M in dioxane (10 eq., 1.72 mL, 6.87 mmol) at RT and the resulting mixture was stirred at RT for 17 h. The reaction mixture was concentrated to dryness and co-evaporated with Et2O (x2) affording crude 5-[(2,4-dimethoxyphenyl)methyl]-7-(l-methylpiperidin-4-yl)- lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridin-10-one (0.54 g, di-HCl salt) as ayellow solid.

[0336] Step 5. To an argon-purged solution of 5-[(2,4-dimethoxyphenyl)methyl]-7-(l- methylpiperidin-4-yl)-lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridin-l 0-one (1 eq., 150 mg, 0.19 mmol) and DIPEA (5 eq., 123 mg, 0.17 mL, 0.95 mmol) in DMF (1 mL) were added 3-chloro-4-methanesulfonamidobenzoic acid (1.5 eq., 71 mg, 0.29 mmol) and TBTU (2 eq., 122 mg, 0.38 mmol) at RT and the resulting mixture was stirred for 41 h. The reaction was poured into water (15 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (3 x 20 mL), dried over Na2SO4, filtered and concentrated to dryness. The crude material was purified by flash chromatography over silica gel (DCM / MeOH from 100 / 0 to 70 / 30). The fractions containing compound were combined, evaporated in vacuo and co-evaporated with DCM affording N-(2-chloro-4-{5-[(2,4-dimethoxyphenyl)methyl]-7-(l-methylpiperidin-4-yl)-10-oxo-lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridine-2- carbonyl}phenyl)methanesulfonamide (70.9 mg) as a beige solid.

[0337] Step 6. To a solution of N-(2-chloro-4-{5-[(2,4-dimethoxyphenyl)methyl]-7-(l- methylpiperidin-4-yl)-10-oxo-lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridine-2- carbonyl}phenyl)methanesulfonamide (1 eq., 129 mg, 0.17 mmol) in TFA (1.9 mL) was added triisopropylsilane (5 eq., 135 mg, 0.17 mL, 0.85 mmol) at RT and the resulting mixture was stirred at 70 °C for 16 h. The reaction mixture was cooled to 0 °C and Et2O (5 mL) was added. The mixture was centrifugated and the supernatant was removed. The resulting solid was solubilized with ACN (minimum amount) and precipitated with Et2O (5 mL). The mixture was centrifugated and the supernatant was removed (process done twice). The crude material was purified by reverse phase preparative HPLC (XBridge prep Cl 8, 150 x 30 mm, 5 pm, 43 mL / min, liquid loading, mobile phase gradient: water+0.1% TFA / MeCN from 90 / 10 to 75 / 25 over 20 min). The fractions containing compound were combined, evaporated in vacuo and freeze-dried using water affording N- {2-chloro-4-[7-( 1 -methylpiperidin-4-yl)- 10-oxo- 1H,2H,3H,4H,5H, 10H-benzo[b] 1 ,6- naphthyridine-2-carbonyl]phenyl}methanesulfonamide (58.7 mg, 54% yield, TFA salt) as a white solid. LC / MS (Method D): Rt= 3.84 min, [M+H]+=529.4. 'H NMR (400 MHz, DMSO-d6) 5 11.71 (s, 1H), 9.64 (s, 1H), 9.40 (br s, 1H), 8.15 - 7.90 (m, 1H), 7.64 (s, 1H), 7.56 (d, J = 8.2 Hz, 1H), 7.50 - 7.41 (m, 1H), 7.31 (s, 1H), 7.23 - 7.13 (m, 1H), 4.54 - 4.44 (m, 1H), 4.37 - 4.27 (m, 1H), 3.91 (br s, 1H), 3.71 - 3.46 (m, 3H), 3.17 - 3.01 (m, 5H), 2.97 - 2.78 (m, 6H), 2.13 - 2.01 (m, 2H), 1.93 - 1.77 (m, 2H).Cpd 131

[0338] Step 1. To an Argon-purged mixture of Intermediate G (1 eq., 150 mg, 0.302 mmol), 3-methyl butynol (2 eq., 50.7 mg, 0.059 mL, 0.603 mmol) and triethylamine (3 eq., 92 mg, 0.13 mL, 0.905 mmol) in DMF (2.5 mL) were added Pd(PPH3)2C12 (0.3 eq., 63.5 mg, 0.09 mmol) and Cui (0.3 eq., 17 mg, 0.09 mmol) at RT and the resulting mixture was stirred at 90 °C for 16 h. The reaction was poured into water (30 mL) and extracted with EtOAc (2 x 30 mL). The combined organic layers were washed with brine (3 x 30 mL), dried over Na2SO4, filtered and concentrated to dryness under reduced pressure The crude material was purified by flash chromatography over silica gel (DCM / MeOHfrom 100 / 0 to 90 / 10). The fractions containing compound were combined, evaporated in vacuo and co-evaporated with DCM affording tert-butyl 4-[7-(3-hydroxy-3-methylbut-l- yn-l-yl)-5-methyl-10-oxo-lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridine-2- carbonyl]benzoate (85.1 mg, 0.17 mmol, 56% yield) as a brown solid.

[0339] Step 2. To a solution of tert-butyl 4-[7-(3-hydroxy-3-methylbut-l-yn-l-yl)-5- methyl-10-oxo-lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridine-2-carbonyl]benzoate (1 eq., 85 mg, 0.17 mmol) in DCM (0.6 mL) was added TFA (0.6 mL) and the resulting mixture was stirred at RT for 6 h. The reaction mixture was cooled to 0 °C and Et2O (5 mL) was added. The mixture was centrifugated and the supernatant was removed. The resulting solid was solubilized with ACN (minimum amount) and precipitated with Et2O (5 mL) then was purified by flash chromatography over silica gel (DCM / MeOH from 100 / 0 to 80 / 20). The fractions containing compound were combined, evaporated in vacuo and co-evaporated with DCM then repurified by reverse phase preparative HPLC (XBridge prep C18, 150 x 30 mm, 5 pm, 43 mL / min, liquid loading, mobile phase gradient: water+0.1% TFA / MeCN from 65 / 35 to 50 / 50 over 20 min). The fractions containing compound were combined, evaporated in vacuo and freeze-dried using water affording 4- [7-(3 -hydroxy-3 -methylbut- 1 -yn- 1 -yl)-5-methyl- 10-oxo- lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridine-2-carbonyl]benzoic acid (9.5 mg, 0.022 mmol, 13% yield) as a yellowish solid. LC / MS (Method D): Rt= 4.83 min, [M+H]+=445.3. 'H NMR (400 MHz, DMSO-d6) 5 13.14 (br s, 1H), 8.26 - 7.97 (m, 3H), 7.78 (s, 1H), 7.63 - 7.51 (m, 2H), 7.33 (br s, 1H), 5.55 (s, 1H), 4.55 (br s, 1H), 4.32 (br s, 1H), 3.93 (br s, 1H), 3.74 (s, 3H), 3.58 (br s, 1H), 3.06 (br s, 2H), 1.50 (s, 6H).Cpd 132

[0340] Step 1. An oven-dried vial was charged with [Ir{dF(CF3)ppy}2(dtbpy)]PF6 (0.01 eq., 2.82 mg, 0.0025 mmol), Intermediate G (1 eq., 125 mg, 0.25 mmol), tert-butyl N-(3-bromocyclobutyl)carbamate (1.5 eq., 94.29 mg, 0.38 mmol), tris(trimethylsilyl)silane (2 eq., 124.98 mg, 0.16 mL, 0.503 mmol) and Na2CO3 (2 eq., 53.27 mg, 0.503 mmol). The vial was purged with Argon and DMA (1.5 mL) / toluene (1.5 mL) were added. 245 pL of the pre-catalyst stock solution (NiC12.glyme (0.005 eq., 0.28 mg, 0.0013 mmol) + dtbbpy (0.005 eq., 0.34 mg, 0.0013 mmol) weresyringed into the first vial. The reaction mixture was degassed by bubbling argon stream for 5 min, then irradiated with one 18 W blue LED lamps (450 nm) (at approximately 2 cm away from the light source, hepatochem system) at ~30 °C for 1.5 h. The reaction mixture was concentrated under reduced pressure and purified by flash chromatography over silica gel (DCM:MeOH from 1 / 0 to 90 / 10) to afford tert-butyl 4-[7-(3-{[(tert- butoxy)carbonyl]amino}cyclobutyl)-5-methyl-10-oxo-lH,2H,3H,4H,5H,10H- benzo[b]l,6-naphthyridine-2-carbonyl]benzoate (75 mg, 0.13 mmol, 51% yield) as alight yellow solid. Pre-catalyst stock solution preparation: To a separate vial were added NiC12.glyme (2.32 mg, 0.0106 mmol) and dtbbpy (2.84 mg, 0.0106 mmol). The vial was purged with Ar and DME (2 mL) was added. The precatalyst solution was sonicated for 5 min.

[0341] Step 2. A solution of tert-butyl 4-[7-(3-{[(tert- butoxy)carbonyl]amino}cyclobutyl)-5-methyl-10-oxo-lH,2H,3H,4H,5H,10H- benzo[b]l,6-naphthyridine-2-carbonyl]benzoate (1 eq., 75 mg, 0.13 mmol) in TFA (2 mL) was stirred at RT for 1.5 h. The reaction mixture was precipitated in Et2O (5 mL) and centrifuged. The supernatant was discarded (process done twice). The solid was dissolved in MeOH (0.5 mL), precipitated with Et2O (5 mL), centrifuged and the supernatant was discarded (process done twice). The remaining solid was dried under vacuum at 40 °C to afford 4-[7-(3-aminocyclobutyl)-5-methyl-10-oxo- lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridine-2-carbonyl]benzoic acid (43.3 mg, 0.079 mmol, 62% yield, TFA salt) as a white solid (cis:trans mixture 58:42). LC / MS (Method D): Rt= 3.65-3.70 min, [M+H]+ = 432.3. 'H NMR (400 MHz, DMSO-d6) 5 13.17 (brs, 1H), 8.37 - 7.80 (m, 6H), 7.74 - 7.45 (m, 3H), 7.42 - 7.28 (m, 1H), 4.56 (s, 1H), 4.32 (s, 1H), 3.99 - 3.85 (m, 2H), 3.76 (s, 3H), 3.58 (s, 1H), 3.51 - 3.42 (m, 1H), 3.07 (s, 2H), 2.73 - 2.66 (m, 1H), 2.61 - 2.55 (m, 2H), 2.34 - 2.25 (m, 1H).Cpd 133

[0342] Step 1. In a flask, a solution of 4-carbomethoxybenzaldehyde (1 eq., 500 mg, 3.046 mmol) in THF (anhydrous) (20 mL) was cooled down to 0 °C. TBAF (IM in THF) (1 eq., 3.046 mL, 3.046 mmol) was added at 0 °C. Then, TMSCF3 (0.5M in THF) (1.1 eq., 476.34 mg, 0.5 mL, 3.35 mmol) was added dropwise over 5 minutes (Caution: reactsstrongly with the reaction mixture). The reaction mixture was stirred at 0 °C for 1 h. The reaction mixture was warmed up to rt and stirred for 2.5 h. Then, TMSCF3 (0.8 eq., 4.87 mL, 2.44 mmol) was added at rt and the reaction mixture was stirred for 2 h. Then, TBAF (IM in THF) (0.8 eq., 2.44 mL, 2.44 mmol) was added at rt and the reaction mixture was stirred for 16 h. Then, TBAF (IM in THF) (1 eq., 3.046 mL, 3.046 mmol) and TMSCF3 (0.6 eq., 259.86 mg, 0.27 mL, 1.83 mmol) were added and the reaction mixture was stirred at rt for 1 h. The reaction was quenched with water (50 mL) and diluted with EtOAc (50 mL). The organic layer was washed with brine (50 mL), dried over anhydrous sodium sulphate, filtered and concentrated under vacuum The crude material was purified by flash chromatography over silica gel (CyH / EtOAc 10:0 to 8:2) to afford methyl 4-(2,2,2- trifluoro-1 -hydroxy ethyl)benzoate (200 mg, 25% yield) as a pale yellow oil.

[0343] Step 2. In a vial, methyl 4-(2,2,2-trifluoro-l -hydroxy ethyl)benzoate (1 eq., 200 mg, 0.85 mmol) was dissolved in MeOH (2 mL) and H2O (2 mL) at rt. Then, NaOH (IN in H2O) (1.2 eq., 1.025 mL, 1.025 mmol) was added and the reaction mixture was stirred at rt for 18 h. The reaction mixture was acidified to pH -2 with IN HC1 (~1.3 mL). DCM (20 mL) and water (10 mL) were added. The aqueous layer was extracted with DCM (3x20 mL), DCM / MeOH (8:2, 3x20 mL) and CHC13 / i-PrOH (8:2, 3x20 mL). The organic layers were combined, concentrated under vacuum, and co-evaporated with MeCN (3x2 mL). The crude material was purified by silica gel chromatography (DCM / MeOH 10:0 to 8:2) to afford 4-(2,2,2-trifluoro-l -hydroxy ethyl)benzoic acid (131 mg, 70% yield) as a white solid.

[0344] Step 3. To a solution of tert-butyl 7-[(3S)-3,4-dimethylpiperazin-l-yl]-5-methyl- 10-oxo-lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridine-2-carboxylate (1 eq., 2.82 g, 6.61 mmol) in 1,4-dioxane (30 mL) was added HC1 4M in dioxane (18.15 eq., 30 mL, 120 mmol) at RT and the resulting mixture was stirred at RT for 16 h. Et2O (50 mL) was added to the reaction mixture. The precipitate was filtered on a glass-frit. The resulting solid was washed with Et2O (3 x 50 mL) affording 7-[(3S)-3,4-dimethylpiperazin-l-yl]- 5-methyl-lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridin-10-one (3.55 g, di HC1 salt) as a brown solid.

[0345] Step 4. In a vial, 7-[(3S)-3,4-dimethylpiperazin-l-yl]-5-methyl- lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridin-10-one dihydrochloride (1 eq., 135 mg,0.25 mmol) and 4-(2,2,2-trifluoro-l -hydroxy ethyl)benzoic acid (1.2 eq., 66 mg, 0.30 mmol) were suspended in DMF (1.42 mL) at rt. Then, DIPEA (5 eq., 162 mg, 0.22 mL, 1.25 mmol) and T3P (50 wt% in EtOAc) (2 eq., 318 mg, 0.3 mL, 0.500 mmol) were added in that order. The reaction mixture was stirred at rt for 1.5 h. The reaction mixture was diluted with DCM (20 mL) and sat. aq. NaHCO3 (15 mL). The aqueous layer was extracted with DCM (2x10 mL). The organic layers were dried over anhydrous sodium sulphate, filtered and concentrated under vacuum. The crude material was purified by silica gel flash chromatography (DCM / MeOH (+5% aq. NH3) 100:0 to 8:2). 50 mg of the resulting beige solid were dissolved in DCM (1 mL) at rt. TFA (0.1 mL) were added at rt and the mixture was stirred for 10 minutes. Et2O (7 mL) was added to precipitate the product. The suspension was centrifugated (4000 rpm, 4 min) and the supernatant was removed. The yellow solid was suspended in MeCN (1 mL) and Et2O (7 mL). The suspension was centrifugated (4000 rpm, 4 min) and the supernatant was removed (this process was repeated once more). The yellow solid was dissolved in MeOH (1 mL) and precipitated with Et2O (7 mL). The suspension was centrifugated (4000 rpm, 4 min) and the supernatant was removed. The solid was freeze-dried afford 7-[(3S)-3,4- dimethylpiperazin-l-yl]-5-methyl-2-[4-(2,2,2-trifluoro-l -hydroxy ethyl)benzoyl]- lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridin-10-one (55.6 mg, 92% yield, TFA salt) as a pale yellow solid. LC / MS (Method D): Rt= 4.03 min, [M+H]+= 529.4. 'H NMR (400 MHz, DMSO-d6) 5 10.15 - 9.55 (m, 1H), 8.12 - 7.91 (m, 1H), 7.63 - 7.46 (m, 4H), 7.13 (br s, 1H), 6.95 (d, J = 5.2 Hz, 2H), 5.26 (br s, 1H), 4.66 - 4.03 (m, 4H), 3.91 (br s, 1H), 3.74 - 3.51 (m, 5H), 3.17 - 2.97 (m, 3H), 2.97 - 2.72 (m, 4H), 1.41 - 1.20 (m, 3H). Two missing protons under solvent peaks.Cpd 134

[0346] Step 1. To an Argon-purged mixture of tert-butyl 4-{7-bromo-5-methyl-10-oxo- lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridine-2-carbonyl}benzoate (1 eq., 150 mg, 0.302 mmol), 8-methyl-3,8-diazabicyclo[3.2.1]octane dihydrochloride (1.5 eq., 90.074 mg, 0.45 mmol) and Cs2CO3 (6 eq., 589.55 mg, 1.809 mmol) in dioxane (3.016 mL) was added Pd2(dba)3 (0.05 eq., 13.808 mg, 0.015 mmol) and Xantphos (0.1 eq., 17.45 mg, 0.0302 mmol) at RT. The reaction mixture was purged with Argon, heated to 100 °C and stirred for 16 h. The reaction mixture was cooled to RT, diluted with water (10 mL) andextracted with EtOAc (3 x 15 mL) (emulsion: addition of some drops of EtOH). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated to dryness. The resulting crude material was purified by flash chromatography over silica gel (DCM / (Me0H:NH40H, 95:5) 100 / 0 to 90 / 10) then purified as second time by flash chromatography over silica gel (DCM / premix (premix = DCM / MeOH 8 / 2) 10 / 0 to 0 / 10) to afford tert-butyl 4-(5-methyl-7-{8-methyl-3,8- diazabicyclo[3.2.1 ]octan-3 -y 1 } - 10-oxo- 1H,2H,3H,4H,5H, 10H-benzo[b] 1 ,6- naphthyridine-2-carbonyl)benzoate (17 mg) as an orange solid.

[0347] Step 2. To a solution oftert-butyl 4-(5-methyl-7-{8-methyl-3,8- diazabicyclo[3.2.1 ]octan-3 -y 1 } - 10-oxo- 1H,2H,3H,4H,5H, 10H-benzo[b] 1 ,6- naphthyridine-2-carbonyl)benzoate (1 eq., 17 mg, 0.028 mmol) in DCM (222.63 microL) was added TFA (55.66 microL) at RT. The reaction mixture was stirred at RT for 2 hours. The reaction mixture was precipitated with Et2O (5 mL) and centrifuged. The supernatant was discarded. The solid was suspended in CH3CN (1 mL), precipitated with Et2O (5 mL), centrifuged and the supernatant was discarded. The solid was dissolved in MeOH (1 mL), precipitated with Et2O (5 mL), centrifuged and the supernatant was discarded. The remaining solid was suspended in water (2 mL) and CH3CN (200 pL) and freeze-dried to afford 4-(5-methyl-7-{8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl}-10- oxo-lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridine-2-carbonyl)benzoic acid (7.7 mg, 57% yield, TFA salt) as a beige solid. LCMS (Method D): Rt= 3.71 min, [M+H]+= 487.31H NMR (400 MHz, DMSO-d6) 5 13.16 (br. s, 1H), 8.11 - 7.89 (m, 3H), 7.67 - 7.50 (m, 2H), 7.11 - 6.97 (m, 1H), 6.84 (s, 1H), 4.58 - 4.46 (m, 1H), 4.33 - 4.24 (m, 1H), 4.07 - 3.84 (m, 5H), 3.67 (s, 3H), 3.60 - 3.51 (m, 1H), 3.09 - 2.96 (m, 2H), 2.81 - 2.68 (m, 3H), 2.27 - 2.09 (m, 2H), 2.02 - 1.88 (m, 2H). 3 protons are missing (overlaps with water or DMSO-d6).Cpd 135

[0348] Step 1. To a solution of LiHMDS IM in THF (2.5 eq., 23.4 mL, 23.44 mmol) in THF (24 mL) was added at -78 °C over 5 minutes a solution of tert-butyl N-(3- oxocyclohexyl)carbamate (1 eq., 2 g, 9.38 mmol) in THF (8 mL). The reaction mixture was stirred at -78 °C for 10 minutes, then a solution of N-phenyltrifluoromethanesulfonimide (1 eq., 3.35 g, 9.38 mmol) in THF (8 mL) was added at -78 °C over 5 minutes. The reaction mixture was warmed to 0 °C and stirred for 15 minutes. The reaction mixture was quenched with water (30 mL) and with NaOH 3M (30 mL). The mixture was stirred for 15 minutes, then extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with a saturated solution of NH4C1 (50 mL), with brine (50 mL), dried over Na2SO4, filtered and concentrated to dryness. The crude material was purified by flash chromatography over silica gel (CyH / EtOAc 10 / 0 to 6 / 4) to afford tert-butyl N-[3-(trifluoromethanesulfonyloxy)cyclohex-2-en-l-yl]carbamate (2.61 g, 81% yield) as a white solid.

[0349] Step 2. To an argon-purged solution of tert-butyl N-[3- (trifluoromethanesulfonyloxy)cyclohex-2-en-l-yl]carbamate (1 eq., 2.36 g, 6.83 mmol), bis(pinacolato)diboron (1.5 eq., 2.60 g, 10.25 mmol) and KO Ac (1.5 eq., 1.01 g, 10.25 mmol) in DMF (12 mL) was added Pd(dppf)C12.DCM (0.05 eq., 0.28 g, 0.34 mmol) at RT and the resulting mixture was stirred at 85 °C for 16 h. The reaction was poured into water (120 mL) and extracted with EtOAc (2 x 150 mL). The combined organic layers were washed with brine (3 x 150 mL), dried over Na2SO4, filtered and concentrated to dryness under reduced pressure. The crude material was purified by ELSD flash chromatography over silica gel (CyH / EtOAc from 100 / 0 to 80 / 20 over 40 min). The fractions containing compound were combined, evaporated in vacuo and co-evaporated with DCM affording tert-butyl N-[3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)cyclohex-2-en-l-yl]carbamate (1.49 g, 4.61 mmol, 68% yield) as a yellow gum. LC / MS (Method C): Rt= 1.83 min, [M+H]+ = 224.3

[0350] Step 3. To an argon-purged solution of Intermediate I (1 eq., 1.8 g, 2.84 mmol), tert-butyl N-[3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)cyclohex-2-en-l- yl]carbamate (1.49 eq., 1.84 g, 4.24 mmol) and K2CO3 (2.5 eq., 0.98 g, 7.103 mmol) in dioxane (28.8 mL) and H2O (5.76 mL) was added Pd(dppf)C12.DCM (0.05 eq., 0.12 g, 0.14 mmol) at RT and the resulting mixture was stirred at 100 °C for 15 h. The reaction was poured into water (100 mL) and extracted with EtOAc (3 x 150 mL). The combined organic layers were washed with brine (150 mL), dried over Na2SO4, filtered and concentrated to dryness. The crude material was purified by flash chromatography over silica gel (DCM / MeOH 100 / 0 to 94 / 6). The fractions containing desired productwere combined, evaporated in vacuo and co-evaporated with DCM affording tert-butyl 4-[7-(3 - { [(tert-butoxy)carbonyl]amino} cyclohex- 1 -en- 1 -yl)-5-m ethyl- 10-oxo- lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridine-2-carbonyl]benzoate (1.79 g) as a green solid.

[0351] Step 4. To an Argon-purged mixture of tert-butyl 4-[7-(3-{[(tert- butoxy)carbonyl]amino}cyclohex-l-en-l-yl)-5-methyl-10-oxo-lH,2H,3H,4H,5H,10H- benzo[b]l,6-naphthyridine-2-carbonyl]benzoate (1 eq., 99 mg, 0.15 mmol) (in mixture with S2) in MeOH (3.32 mL) was added Pd / C 10% (0.43 eq., 66.38 mg, 0.062 mmol). The reaction mixture was purged with H2 and stirred at RT under atmospheric pressure of hydrogen for 64 hours. The reaction mixture was purged with Argon, filtered over a ptfe filter, rinsed with MeOH (2 x 2 mL) and concentrated to dryness. The crude material was purified by flash chromatography over silica gel (DCM / premix (premix = DCM / MeOH 8 / 2) 10 / 0 to 7 / 3) to afford tert-butyl 4-[7-(3-{[(tert- butoxy)carbonyl]amino}cyclohexyl)-5-methyl-10-oxo-lH,2H,3H,4H,5H,10H- benzo[b]l,6-naphthyridine-2-carbonyl]benzoate as a white solid (60 mg).

[0352] Step 5. A solution of tert-butyl 4-[7-(3-{[(tert- butoxy)carbonyl]amino}cyclohexyl)-5-methyl-10-oxo-lH,2H,3H,4H,5H,10H- benzo[b]l,6-naphthyridine-2-carbonyl]benzoate (1 eq., 60 mg, 0.073 mmol) in TFA (1.45 mL) was stirred at RT for 1 h. The reaction mixture was precipitated with Et2O (5 mL) and centrifuged. The supernatant was discarded. The solid was dissolved in CH3CN (1 mL), precipitated with Et2O (5 mL), centrifuged and the supernatant was discarded (process done twice). The remaining solid was dried under vacuum at 40 °C to afford 4- [7-(3-aminocyclohexyl)-5-methyl-10-oxo-lH,2H,3H,4H,5H,10H-benzo[b]l,6- naphthyridine-2-carbonyl]benzoic acid (23 mg, 54% yield, TFA salt) as a white solid. LCMS (Method D): Rt= 3.87 / 3.92 min, [M+H]+= 460.4. 'H NMR (400 MHz, DMSO- d6) 5 13.17 (br. s, 1H), 8.29 - 7.95 (m, 3H), 7.95 - 7.70 (m, 3H), 7.67 - 7.48 (m, 3H), 7.34 - 7.16 (m, 1H), 4.66 - 4.22 (m, 2H), 4.03 - 3.85 (m, 1H), 3.74 (s, 3H), 3.64 - 3.49 (m, 1H), 3.26 - 2.79 (m, 4H), 2.16 - 1.27 (m, 8H).Cpd 136

[0353] Step 1. To an Argon-purged mixture of Intermediate G (1 eq., 130 mg, 0.26 mmol), tert-butyl N-(3-aminocyclobutyl)carbamate (2 eq., 97.36 mg, 0.52 mmol) and Cs2CO3 (4 eq., 340.63 mg, 1.045 mmol) in dioxane (2.61 mL) was added Pd2(dba)3 (0.05 eq., 11.97 mg, 0.013 mmol) and Xantphos (0.1 eq., 15.12 mg, 0.026 mmol) at RT. The reaction mixture was purged with Argon, heated to 100 °C and stirred for 16 hours. The reaction mixture was cooled to RT, diluted with water (15 mL) and extracted with DCM (3 x 20 mL). The combined organic layers were washed with brine (15 mL), dried over Na2SO4, filtered and concentrated to dryness and purified by flash chromatography over silica gel (DCM / premix (DCM / MeOH 9 / 1) 10 / 0 to 0 / 10) to afford tert-butyl 4-{7-[(3-{[(tert-butoxy)carbonyl]amino}cyclobutyl)amino]-5-methyl- 10-oxo-lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridine-2-carbonyl}benzoate (99 mg) as an orange solid.

[0354] Step 2. A solution of tert-butyl 4-{7-[(3-{[(tert- butoxy)carbonyl]amino}cyclobutyl)amino]-5-methyl-10-oxo-lH,2H,3H,4H,5H,10H- benzo[b]l,6-naphthyridine-2-carbonyl (benzoate (1 eq., 50 mg, 0.083 mmol) in TFA (1.64 mL) was stirred at RT for 1 h. The reaction mixture was precipitated with Et2O (5 mL) and centrifuged. The supernatant was discarded. The solid was dissolved in CH3CN (1 mL), precipitated with Et2O (5 mL), centrifuged and the supernatant was discarded (process done twice). The remaining solid was dried under vacuum overnight to afford 4- {7-[(3-aminocyclobutyl)amino]-5-methyl-10-oxo-lH,2H,3H,4H,5H,10H-benzo[b]l,6- naphthyridine-2-carbonyl}benzoic acid (41 mg, 88% yield, TFA salt) as a yellow solid. LC / MS (Method D): Rt= 3.59-3.62 min, [M+H]+= 447.4. 'H NMR (400 MHz, DMSO- d6) 5 13.11 (brs, 1H), 8.17 - 7.76 (m, 6H), 7.69 - 7.45 (m, 2H), 6.89 (s, 1H), 6.72 - 6.54 (m, 1H), 6.35 (d, J = 26.6 Hz, 1H), 4.51 (s, 1H), 4.28 - 4.19 (m, 2H), 3.91 (s, 1H), 3.85 - 3.76 (m, 1H), 3.65 - 3.43 (m, 5H), 3.00 (s, 2H), 2.88 - 2.73 (m, 1H), 2.31 - 2.22 (m, 1H), 2.08 - 1.88 (m, 1H).Cpd 137

[0355] Step 1. An oven-dried vial was charged with Intermediate G (1 eq., 150 mg, 0.302 mmol), l-[(tert-butoxy)carbonyl]pyrrolidine-2-carboxylic acid (1.5 eq., 97.4 mg, 0.45mmol), phthalimide (1 eq., 44.4 mg, 0.302 mmol), 2 -tert-butyl- 1,1, 3, 3- tetramethylguanidine (BTMG,1.5 eq., 77.5 mg, 0.45 mmol), [Ir{dF(CF3)ppy}2(dtbpy)]PF6 (0.01 eq., 3.4 mg, 0.003 mmol), NiC12.glyme (0.05 eq., 3.3 mg, 0.015 mmol), dtbbpy (0.05 eq., 4.1 mg, 0.015 mmol) in DMSO (3.0 mL) at RT. The reaction mixture was degassed by bubbling argon stream for 20 min, then irradiated with two 18 W blue LED lamps (450 nm) (at approximately 2 cm away from the light source). The mixture was stirred for 16 h After then, DMSO (3.0 mL), 1 -[(tert- butoxy)carbonyl]pyrrolidine-2-carboxylic acid (1.5 eq., 97.4 mg, 0.45 mmol), phthalimide (1 eq., 44.4 mg, 0.302 mmol), BTMG (1.5 eq., 77.49 mg, 0.45 mmol), [Ir{dF(CF3)ppy}2(dtbpy)]PF6 (0.01 eq., 3.4 mg, 0.003 mmol), NiC12.glyme (0.05 eq., 3.3 mg, 0.015 mmol) and dtbbpy (0.05 eq., 4.1 mg, 0.015 mmol) were added to the mixture. The reaction mixture was degassed by bubbling argon stream for 20 min, then irradiated with two 18 W blue LED lamps (450 nm) (at approximately 2 cm away from the light source). The mixture was stirred for 24 h at rt. The reaction mixture was diluted with saturated aqueous NaHCO3 solution (20 mL), extracted with Et20 (3 x 100 mL). The combined organic extracts were washed with water (100 mL) and brine (100 mL), dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography over silica gel (DCM / (DCM / MeOH 9: 1) from 10 / 0 to 7 / 3) to afford tert-butyl 2-(2-{4-[(tert-butoxy)carbonyl]benzoyl}-5-methyl-10-oxo- lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridin-7-yl)pyrrolidine-l -carboxylate (44 mg) as a yellow solid.

[0356] Step 2. A solution of tert-butyl 2-(2-{4-[(tert-butoxy)carbonyl]benzoyl}-5- methyl- 10-oxo- 1H,2H,3H,4H, 5H, 10H-benzo[b] 1 ,6-naphthyridin-7-yl)pyrrolidine- 1 - carboxylate (1 eq., 35 mg, 0.0503 mmol) in TFA (0.99 mL) was stirred at RT for 1 h. The reaction mixture was precipitated with Et2O (5 mL) and centrifuged. The supernatant was discarded. The solid was dissolved in CH3CN (1 mL), precipitated with Et2O (3 x 5 mL), centrifuged and the supernatant was discarded. The crude material was purified by preparative LC / MS (Eluant: Water + 0.1% TFA / Acetonitrile Gradient : from 10 to 25% acetonitrile in water + 0.1% TFA Column : XBridge C18 (30xl50(5pm)) Flow Rate : 43 mL / min). The residual solid was freeze-dried with water (5 mL) then dissolved in MeOH (500 pL) and loaded onto an ISOLUTE PE-AX cartridge. The SPE cartridge was rinsedwith DCM (3 x 3 mL). The filtrate was discarded. The SPE cartridge was then washed with aqueous IM HC1 (2 x 2 mL). The filtrate was concentrated freeze-dried to afford 4- [5-methyl-10-oxo-7-(pyrrolidin-2-yl)-lH,2H,3H,4H,5H,10H-benzo[b]l,6- naphthyridine-2-carbonyl]benzoic acid (6 mg, 26% yield, HC1 salt) as a beige solid. LC / MS (Method D): Rt= 3.67 min, [M+H]+= 432.3. 'H NMR (400 MHz, DMSO-d6) 5 13.27 (brs, 1H), 10.13 (brs, 1H), 9.38 (brs, 1H), 8.32 - 7.95 (m, 4H), 7.69 - 7.41 (m, 3H), 4.72 (s, 1H), 4.57 (s, 1H), 4.32 (s, 1H), 3.95 (s, 1H), 3.81 (s, 3H), 3.59 (s, 1H), 3.52 - 3.40 (m, 1H), 3.37 - 3.26 (m, 1H), 3.15 - 3.03 (m, 2H), 2.23 - 1.94 (m, 4H).Cpd 138

[0357] Step 1. To a suspension of Intermediate K (1 eq., 1.81 g, 4.75 mmol) in DMF (15.83 mL) were added atRT 4-[(tert-butoxy)carbonyl]benzoic acid (1.1 eq., 1.16 g, 5.22 mmol), DIPEA (4.6 eq., 2.82 g, 3.805 mL, 21.84 mmol) and HATU (1.3 eq., 2.35 g, 6.17 mmol). The reaction mixture was stirred at RT for 16 hours. The reaction mixture was diluted with water (150 mL). The resulting precipitate was filtered, washed with water (3 x 50 mL) and dissolved in DCM (100 mL). The organic layer was washed with brine (100 mL), dried over Na2SO4, filtered and concentrated to dryness then purified by flash chromatography over silica gel (DCM / MeOH 100 / 0 to 95 / 5) to afford tert-butyl 4-{7- bromo-5-cyclopropyl- 10-oxo- 1H,2H,3H,4H,5H, 10H-benzo[b] 1 ,6-naphthyri dinercarbonyl [benzoate (2.33 g) as an orange solid. LC / MS (Method C): Rt= 1.65 min, [M+H]+ = 523.5 / 525.4. 'H NMR (400 MHz, DMSO-d6) 5 8.04 - 7.89 (m, 4H), 7.67 - 7.45 (m, 4H), 4.24 (s, 1H), 4.08 - 3.67 (m, 1H), 3.55 - 3.33 (m, 2H), 3.26 - 3.10 (m, 2H), 1.65 - 1.48 (m, 9H), 1.44 - 1.30 (m, 2H), 1.06 - 0.91 (m, 2H).

[0358] Step 2. To an argon-purged solution of tert-butyl 4-{7-bromo-5-cyclopropyl-10- oxo-lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridine-2-carbonyl}benzoate (1 eq., 200 mg, 0.32 mmol), tert-butyl N-[3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)cyclohex- 3-en-l-yl]carbamate (1.49 eq., 156.4 mg, 0.48 mmol) and K2CO3 (2.5 eq., 112.2 mg, 0.81 mmol) in dioxane (3.3 mL) and H2O (0.7 mL) was added Pd(dppf)C12.DCM (0.05 eq., 13.3 mg, 0.016 mmol) at RT and the resulting mixture was stirred at 100 °C for 24 h. The reaction was poured into water (15 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filteredand concentrated to dryness under reduced pressure. The crude material was purified by flash chromatography over silica gel (DCM / premix (DCM / MeOH 9 / 1) 100 / 0 to 7 / 3) to afford tert-butyl 4-[7-(3-{[(tert-butoxy)carbonyl]amino}cyclohex-l-en-l-yl)-5- cyclopropyl- 10-oxo- 1H,2H,3H,4H, 5H, 10H-benzo[b] 1 ,6-naphthyridine-2- carbonyl]benzoate (73 mg) as a brownish solid.

[0359] Step 3. To an Argon-purged mixture of tert-butyl 4-[7-(3-{ [(tertbutoxy )carb onyl ] amino } cy cl ohex- 1 -en- 1 -yl)-5-cyclopropyl- 10-oxo- lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridine-2-carbonyl]benzoate (1 eq., 70 mg, 0.109 mmol) in MeOH (2.5 mL) was added Pd / C 10% (0.43 eq., 50 mg, 0.047 mmol). The reaction mixture was purged with H2 and stirred at RT under atmospheric pressure of hydrogen for 42 hours. The reaction mixture was purged with Argon, filtered on celite, rinsed with MeOH (3 x 5 mL) and concentrated to dryness. The crude material was purified by flash chromatography over silica gel (DCM / premix (DCM / MeOH 9 / 1) 10 / 0 to 0 / 10) to afford tert-butyl 4-[7-(3-{[(tert-butoxy)carbonyl]amino}cyclohexyl)-5- cyclopropyl- 10-oxo- 1H,2H,3H,4H, 5H, 10H-benzo[b] 1 ,6-naphthyri dine-2- carbonyl]benzoate (39 mg) as a white solid.

[0360] Step 4. A solution of tert-butyl 4-[7-(3-{[(tert- butoxy)carbonyl]amino}cyclohexyl)-5-cyclopropyl-10-oxo-lH,2H,3H,4H,5H,10H- benzo[b]l,6-naphthyridine-2-carbonyl]benzoate (1 eq., 36 mg, 0.056 mmol) in TFA (1.1 mL) was stirred at RT for 1 h. The reaction mixture was precipitated with Et2O (5 mL) and centrifuged. The solid was dissolved in CH3CN (1 mL), precipitated with Et2O (2 x 5 mL), centrifuged and the supernatant was discarded. The remaining solid was dried under vacuum overnight to afford 4-[7-(3-aminocyclohexyl)-5-cyclopropyl-10-oxo- lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridine-2-carbonyl]benzoic acid (29 mg, 87% yield, TFA salt) as a white solid. LC / MS (Method D): Rt= 4.11 / 4.16 min, [M+H]+ = 486.4. ‘H NMR (400 MHz, DMSO-d6) 5 13.17 (br s, 1H), 8.17 - 7.97 (m, 3H), 7.97 - 7.75 (m, 4H), 7.61 (dd, J = 17.2, 7.9 Hz, 2H), 7.25 (d, J = 11.6 Hz, 1H), 4.52 (br s, 1H), 4.27 (s, 1H), 3.55 (br s, 2H), 3.26 - 3.09 (m, 3H), 2.98 - 2.78 (m, 1H), 2.19 - 1.81 (m, 4H), 1.81 - 1.60 (m, 3H), 1.59 - 1.31 (m, 4H), 0.96 (br s, 2H).Cpd 139

[0361] Step 1. To a solution of LiHMDS IM in THF (2.5 eq., 6.27 mL, 6.27 mmol) in THF (6.5 mL) was added dropwise a solution of tert-butyl N-(3- oxocyclopentyl)carbamate (1 eq., 0.5 g, 2.509 mmol) in THF (2 mL). The reaction mixture was stirred at -78 °C for 10 minutes, then a solution of N- phenyltrifluoromethanesulfonimide (1 eq., 0.9 g, 2.509 mmol) in THF (2 mL) was added dropwise at -78 °C. The resulting mixture was warmed to 0 °C and stirred for 15 minutes. The reaction mixture was quenched with water (10 mL) and NaOH 3M (10 mL). The mixture was stirred for 15 minutes, then extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with a saturated solution of NH4C1 (20 mL), brine (20 mL), dried over Na2SO4, filtered and concentrated to dryness. The crude material was purified by flash chromatography over silica gel (CyH / EtOAc 100 / 0 to 0 / 100). The fractions containing compound were combined, evaporated in vacuo and co-evaporated with DCM affording tert-butyl N-[3-(trifluoromethanesulfonyloxy)cyclopent-2-en-l-yl]carbamate (0.98 g) as a yellow oil.

[0362] Step 2. To an argon-purged solution of tert-butyl N-[3- (trifluoromethanesulfonyloxy)cyclopent-2-en-l-yl]carbamate (1 eq., 0.98 g, 2.48 mmol), bis(pinacolato)diboron (1.5 eq., 0.95 g, 3.73 mmol) and KOAc (1.5 eq., 0.37 g, 3.73 mmol) in DMF (4.4 mL) was added Pd(dppf)C12.DCM (0.05 eq., 0.101 g, 0.12 mmol) at RT and the resulting mixture was stirred at 85 °C for 17 h. The reaction was poured into water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with brine (3 x 50 mL), dried over Na2SO4, filtered and concentrated to dryness under reduced pressure. The crude material was purified by ELSD flash chromatography over silica gel (CyH / EtOAc from 100 / 0 to 70 / 30). The fractions containing compound were combined, evaporated in vacuo and co-evaporated with DCM affording tert-butyl N-[3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)cyclopent-2-en-l- yl]carbamate (0.23 g, 0.73 mmol, 29% yield) as a yellow gum.

[0363] Step 3. To an argon-purged solution of Intermediate G (1 eq., 0.25 g, 0.49 mmol), tert-butyl N-[3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)cyclopent-2-en-l- yl]carbamate (1.5 eq., 0.29 g, 0.74 mmol) and K2CO3 (2.5 eq., 0.17 g, 1.23 mmol) in dioxane (5 mL) and H2O (1 mL) was added Pd(dppf)C12.DCM (0.05 eq., 20mg, 0.025 mmol) at RT and the resulting mixture was stirred at 100 °C for 17 h. The reaction was poured into water (20 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated to dryness under reduced pressure. The crude material was purified by flash chromatography over silica gel (DCM / MeOH from 100 / 0 to 92 / 8). The fractions containing compound were combined, evaporated in vacuo and co-evaporated with DCM affording tert-butyl 4-[7-(3-{[(tert-butoxy)carbonyl]amino}cyclopent-l-en-l-yl)-5- methyl-10-oxo-lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridine-2-carbonyl]benzoate (0.29 g) as a brown solid.

[0364] Step 4. To a solution of tert-butyl 4-[7-(3-{[(tert- butoxy)carbonyl]amino}cy cl opent- 1-en-l -yl)-5-methyl-l 0-oxo-lH,2H,3H, 4H,5H,10H- benzo[b]l,6-naphthyridine-2-carbonyl]benzoate (1 eq., 0.29 g, 0.49 mmol) in MeOH (5 mL), previously purged with argon was added Pd / C (0.2 eq., 0.104 g, 0.098 mmol). A further purge with argon was proceeded (3x) followed by H2 (3x). The reaction was performed under H2 atmosphere at RT for 19 h. The reaction mixture was filtered on a PTFE filter and washed with MeOH (10 mL). The filtrate was evaporated in vacuo, coevaporated with MeOH (x3) and purified by flash chromatography over silica gel (DCM / MeOH from 100 / 0 to 94 / 6). The fractions containing compound were combined, evaporated in vacuo and co-evaporated with DCM affording tert-butyl 4-[7-(3-{[(tert- butoxy)carbonyl]amino}cyclopentyl)-5-methyl-10-oxo-lH,2H,3H,4H,5H,10H- benzo[b]l,6-naphthyridine-2-carbonyl]benzoate (0.19 g) as a yellowish solid.

[0365] Step 5. A solution of tert-butyl 4-[7-(3-{[(tert- butoxy)carbonyl]amino}cyclopentyl)-5-methyl-10-oxo-lH,2H,3H,4H,5H,10H- benzo[b]l,6-naphthyridine-2-carbonyl]benzoate (1 eq., 70 mg, 0.104 mmol) in TFA (0.9 mL) was stirred at RT for 1 h. The reaction mixture was cooled to 0 °C and Et2O (5 mL) was added. The mixture was centrifugated and the supernatant was removed. The resulting solid was solubilized with ACN (minimum amount) and precipitated with Et2O (5 mL). The mixture was centrifugated and the supernatant was removed (process done twice). The residual solid was triturated with Et2O (5 mL) and dried under high-vacuum at 40 °C affording 4-[7-(3-aminocyclopentyl)-5-methyl-10-oxo-lH,2H,3H,4H,5H,10H- benzo[b]l,6-naphthyridine-2-carbonyl]benzoic acid (53.3 mg, 92% yield, TFA salt) as awhite solid. LC / MS (Method D): Rt= 3.79; 3.82 min, [M+H]+ = 446.3. 'H NMR (400 MHz, DMSO-d6) 5 13.18 (s, 1H), 8.23 - 8.00 (m, 3H), 7.98 - 7.78 (m, 3H), 7.67 - 7.50 (m, 3H), 7.40 - 7.23 (m, 1H), 4.56 (s, 1H), 4.31 (s, 1H), 3.94 (s, 1H), 3.74 (s, 3H), 3.70 - 3.63 (m, 1H), 3.58 (s, 2H), 3.32 - 3.23 (m, 1H), 3.07 (s, 2H), 2.26 - 1.79 (m, 4H), 1.75 - 1.61 (m, 1H).Cpd 140

[0366] Step 1. To a solution of 3-butyn-l-ol (1 eq., 1 g, 1.08 mL, 14.27 mmol) in EtOH (7.509 mL) was added ethyl 2-nitroacetate (2.0 eq., 3.802 g, 28.56 mmol) and DABCO (0.1 eq., 0.16 g, 0.14 mL, 1.43 mmol) at RT. The RM was stirred in a sealed tube vessel at 80 °C for 20 h. The RM was quenched with water (50 mL), extracted with EtOAc (2 x 25 mL), the combined organic layer was washed with brine (50 mL), dried overNa2SO4, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography over silica gel (CyH / EtOAc from 100 / 0 to 20 / 80). The fractions containing compound were combined and evaporated in vacuo affording ethyl 5-(2- hydroxy ethyl)- l,2-oxazole-3 -carboxylate (2.46 g, 13.28 mmol, 93% yield) as a light yellow oil.

[0367] Step 2. To a solution of ethyl 5-(2-hydroxyethyl)-l,2-oxazole-3-carboxylate (1 eq., 2.36 g, 12.74 mmol) in acetone (29 mL) was added Jones reagent (1.21 eq., 11.91 mL, 15.46 mmol) dropwise at 0 °C. The mixture was stirred at RT for 3 h. The mixture was diluted with acetone (80 mL), filtered over celite, the filter cake was rinsed with acetone (10 mL) and the filtrate was concentrated under reduced pressure to afford 2-[3- (ethoxy carbonyl)- l,2-oxazol-5-yl]acetic acid (1.88 g, 74% yield) as a colourless oil. LC / MS (Method C): Rt= 1.14 min, [M+H]+= 200.2

[0368] Step 3. A solution of 2-[3-(ethoxycarbonyl)-l,2-oxazol-5-yl]acetic acid (1 eq., 1.85 g, 9.29 mmol) in thionyl chloride (44.76 eq., 49.46 g, 30.16 mL, 415.77 mmol) was stirred at 70 °C for 1 h. The mixture was concentrated under reduced pressure, then tertbutanol (30 mL) and Et3N (5.73 eq., 5.39 g, 7.4 mL, 53.24 mmol) were added and the mixture was stirred at RT for 2 h. The mixture was quenched with H2O (100 mL) and Et2O (80 mL) was added. The phases were separated and the aqueous layer was extracted with Et2O (1 x 50 mL). The combined organic layer was washed with water (150 mL),brine (150 mL), dried over Na2SO4, filtered and concentrated under reduced pressure The crude material was purified by flash chromatography over silica gel (CyH / EtOAc from 10 / 0 to 8 / 2 over 40 min) to afford ethyl 5-[2-(tert-butoxy)-2-oxoethyl]-l,2-oxazole- 3-carboxylate (1.33 g, 5.21 mmol, 56% yield) as a colourless oil.

[0369] Step 4. To a solution of ethyl 5-[2-(tert-butoxy)-2-oxoethyl]-l,2-oxazole-3- carboxylate (1 eq., 300 mg, 1.18 mmol) in DMF (5.4 mL) was added NaH 60% in oil (2.2 eq., 103.4 mg, 2.59 mmol) at RT and the reaction mixture was stirred at RT for 15 min. 1,2-dibromoethane (2.2 eq., 485.72 mg, 0.22 mL, 2.59 mmol) in DMF (1.08 mL) was added dropwise at 0 °C and the RM was stirred at RT for 18 h. The mixture was quenched with an aqueous solution of saturated NH4C1 (50 mL) and extracted with Et2O (2 x 50 mL). The combined organic layer was washed with water (100 mL), brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography over silica gel (CyH / EtOAc from 10 / 0 to 85 / 15) to afford ethyl 5-{ l-[(tert-butoxy)carbonyl]cyclopropyl}-l,2-oxazole-3- carboxylate (169 mg, 0.60 mmol, 51% yield) as a colourless oil.

[0370] Step 5. To a solution of ethyl 5-{ l-[(tert-butoxy)carbonyl]cyclopropyl}-l,2- oxazole-3 -carboxylate (1 eq., 169 mg, 0.6008 mmol) in MeOH (14.14 mL) was added a solution of NaOH (1.5 eq., 36.0 mg, 0.901 mmol) in H2O (3.53 mL) at RT. The RM was stirred at RT for 1.5 h. The organic solvent was removed under reduced pressure. The residue was dissolved in water (20 mL), cooled to 0 °C and acidified with a IN aq. solution of HC1 to pH 4 and extracted with DCM (2 x 10 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to afford 5-{ l-[(tert-butoxy)carbonyl]cyclopropyl}-l,2-oxazole-3-carboxylic acid (144 mg, 0.57 mmol, 95% yield) as a white solid.

[0371] Step 6. To a suspension of 7-[(3S)-3,4-dimethylpiperazin-l-yl]-5-methyl- lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridin-10-one (1 eq., 117.2 mg, 0.22 mmol) in DMF (1.73 mL) were added DIPEA (5 eq., 140.3 mg, 0.19 mL, 1.086 mmol) at 0 °C followed by 5-{ l-[(tert-butoxy)carbonyl]cyclopropyl}-l,2-oxazole-3-carboxylic acid (1.2 eq., 66 mg, 0.26 mmol), and TBTU (2.5 eq., 174.3 mg, 0.54 mmol). The reaction mixture was stirred at RT for 16 h. The reaction was diluted with water (30 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with water(60 mL), brine (60 mL), dried over Na2SO4, filtered and concentrated to dryness. The crude material was purified by flash chromatography over silica gel (DCM / (Me0H:NH40H, 9:1) 10 / 0 to 85 / 15) to afford tert-butyl l-(3-{7-[(3S)-3,4- dimethylpiperazin- 1 -yl]-5-methyl- 10-oxo- 1H,2H,3H,4H, 5H, 10H-benzo[b] 1 ,6- naphthyridine-2-carbonyl}-l,2-oxazol-5-yl)cyclopropane-l-carboxylate (38 mg) as an orange solid.

[0372] Step 7. To a solution of tert-butyl l-(3-{7-[(3S)-3,4-dimethylpiperazin-l-yl]-5- methyl- 10-oxo- 1H,2H,3H,4H, 5H, 10H-benzo[b] 1 ,6-naphthyridine-2-carbonyl } - 1 ,2- oxazol-5-yl)cyclopropane-l -carboxylate (1 eq., 37 mg, 0.066 mmol) in DCM (0.53 mL) was added TFA (50 eq., 376 mg, 0.24 mL, 3.29 mmol) at RT and the mixture was stirred for 2.5 h. Et2O (5 mL) was added and the resulting precipitate was centrifuged. The supernatant was discarded. The residue was dissolved in CH3CN (1 mL), precipitated with Et2O (5 mL), centrifuged and the supernatant was discarded. The residue was dissolved in MeOH (1 mL), precipitated with Et2O (5 mL), centrifuged and the supernatant was discarded to afford l-(3-{7-[(3S)-3,4-dimethylpiperazin-l-yl]-5-methyl- 10-oxo- 1H,2H,3H,4H,5H, 10H-benzo[b] 1 ,6-naphthyridine-2-carbonyl } - 1 ,2-oxazol-5- yl)cyclopropane-l -carboxylic acid (30.1 mg, 74% yield, TFA salt) as a light yellow solid. LC / MS (Method D): Rt= 3.87 min, [M+H]+ = 506.3. 'H NMR (400 MHz, DMSO-d6) 5 13.02 (brs, 1H), 9.67 (brs, 1H), 8.03 (dd, J = 25.0, 9.0 Hz, 1H), 7.14 (td, J = 8.8, 2.1 Hz, 1H), 6.97 - 6.91 (m, 1H), 6.83 - 6.75 (m, 1H), 4.54 (d, J = 4.1 Hz, 2H), 4.12 (brs, 2H), 3.96 - 3.86 (m, 2H), 3.69 (d, J = 4.7 Hz, 3H), 3.55 - 3.44 (m, 1H), 3.20 - 3.02 (m, 5H), 2.93 - 2.72 (m, 4H), 1.68 - 1.61 (m, 2H), 1.56 - 1.49 (m, 2H), 1.36 - 1.27 (m, 3H).Cpd 141

[0373] To a suspension of Intermediate G (1 eq., 100 mg, 0.19 mmol) and 3-chloro-4- methanesulfonamidobenzoic acid (1.5 eq., 77.105 mg, 0.28 mmol) in DMF (1.87 mL) were added DIPEA (5 eq., 119.75 mg, 0.16 mL, 0.93 mmol), EDC.HC1 (1.5 eq., 53.28 mg, 0.28 mmol) and HOBt (1.5 eq., 37.56 mg, 0.28 mmol) at 0 °C. The reaction mixture was stirred at RT for 72 h. The reaction was diluted with water (15 mL) and extracted with DCM / MeOH (8 / 2 ; 2 x 20 mL). The combined organic layers were washed with water (20 mL), brine (20 mL), dried over Na2SO4, filtered and concentrated todryness. The crude material was purified by flash chromatography over silica gel (DCM / (MeOH + 5% NH40H) 100 / 0 to 8 / 2). The desired fractions were concentrated under reduced pressure and the residue was dissolved in DCM (1 mL), TFA (15 eq., 153.5 mg, 0.1 mL, 1.35 mmol) was added at RT and the RM was stirred for 5 min. Et2O (5 mL) was added and the resulting precipitate was centrifuged. The supernatant was discarded. The residue was dissolved in CH3CN (1 mL), precipitated with Et2O (5 mL), centrifuged and the supernatant was discarded. The residue was dissolved in MeOH (1 mL), precipitated with Et2O (5 mL), centrifuged and the supernatant was discarded. The crude material was purified by preparative HPLC (Eluant: Water + 0.1% TFA / Acetonitrile Gradient : from 10 to 25% acetonitrile in water + 0.1% TFA Column : XBridge C18 (30xl50(5pm)) Flow Rate : 43 mL / min). The remaining solid was freeze-dried using water (4 mL) to afford to afford pure N-(2-chloro-4-{7-[(3S)-3,4-dimethylpiperazin-l- yl]-5-methyl-10-oxo-lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyri dinercarbonyl }phenyl)methanesulfonamide (52.5 mg, 86% yield, TFA salt) as a light yellow solid. LC / MS (Method D): Rt= 3.82 min, [M+H]+ = 558.4. 'H NMR (400 MHz, DMSO- d6) 5 9.74 - 9.54 (m, 2H), 8.11 - 7.93 (m, 1H), 7.63 (brs, 1H), 7.58 - 7.52 (m, 1H), 7.50 - 7.40 (m, 1H), 7.18 - 7.07 (m, 1H), 6.96 (brs, 1H), 4.50 - 4.44 (m, 1H), 4.37 - 4.29 (m, 1H), 4.25 - 4.13 (m, 2H), 3.88 (brs, 1H), 3.69 (brs, 3H), 3.65 - 3.54 (m, 2H), 3.48 - 3.32 (m, 1H), 3.29 - 3.18 (m, 1H), 3.12 (s, 4H), 3.06 - 2.98 (m, 2H), 2.94 - 2.78 (m, 4H), 1.40 - 1.28 (m, 3H).Cpd 142

[0374] Step 1. To a solution of Intermediate I (1 eq., 200 mg, 0.78 mmol) in DMF (5.26 mL) was added potassium tert-butylate (0.9 eq., 79 mg, 0.705 mmol) at 0 °C and the mixture was stirred at RT for 15 min. Mel (0.9 eq., 100 mg, 0.044 mL, 0.705 mmol) was added dropwise and the solution was stirred at RT for 16 h. The mixture was quenched with an aqueous solution of saturated NH4C1 (50 mL) and extracted with Et2O (2 x 30 mL). The combined organic layer was washed with water (2 x 30 mL), brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography over silica gel (CyHZEtOAc from 10 / 0 to 9 / 1) to afford ethyl 5-[l-(tert-butoxy)-l-oxopropan-2-yl]-l,2-oxazole-3-carboxylate (73.7 mg, 0.27 mmol, 39% yield) as a colourless oil.

[0375] Step 2. To a solution of ethyl 5-[l-(tert-butoxy)-l-oxopropan-2-yl]-l,2-oxazole- 3-carboxylate (1 eq., 48 mg, 0.18 mmol) in MeOH (4.19 mL) was added a solution of NaOH (1.5 eq., 10.7 mg, 0.27 mmol) in H2O (1.048 mL) at RT. The mixture was stirred at RT for 1.5 h. The organic solvent was removed under reduced pressure. The residue was dissolved in water (20 mL), cooled to 0 °C and acidified with a IN aq. solution of HC1 to pH 4 and extracted with DCM (2 x 10 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to afford 2-[3-(ethoxycarbonyl)-l,2-oxazol-5-yl]propanoic acid (40.7 mg, 0.17 mmol, 95% yield) as a colourless oil.

[0376] Step 3. To a suspension of Intermediate G (1 eq., 72.7 mg, 0.13 mmol) in DMF (1.07 mL) were added DIPEA (5 eq., 87 mg, 0.12 mL, 0.67 mmol) at 0 °C followed by 2-[3-(ethoxycarbonyl)-l,2-oxazol-5-yl]propanoic acid (1.2 eq., 39 mg, 0.16 mmol), and TBTU (2.5 eq., 108.14 mg, 0.34 mmol). The reaction mixture was stirred at RT for 16 h. The reaction was diluted with water (30 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with water (60 mL), brine (60 mL), dried over Na2SO4, filtered and concentrated to dryness. The crude material was purified by flash chromatography over silica gel (DCM / MeOH 10 / 0 to 65 / 35) to afford tert-butyl 2-(3-{7- [(3S)-3,4-dimethylpiperazin-l-yl]-5-methyl-10-oxo-lH,2H,3H,4H,5H,10H- benzo[b]l,6-naphthyridine-2-carbonyl}-l,2-oxazol-5-yl)propanoate (41.5 mg) as an orange solid.

[0377] Step 4. To a solution of tert-butyl 2-(3-{7-[(3S)-3,4-dimethylpiperazin-l-yl]-5- methyl- 10-oxo- 1H,2H,3H,4H, 5H, 10H-benzo[b] 1 ,6-naphthyridine-2-carbonyl } - 1 ,2- oxazol-5-yl)propanoate (1 eq., 39 mg, 0.071 mmol) in DCM (0.57 mL) was added TFA (25 eq., 202.25 mg, 0.13 mL, 1.77 mmol) at RT and the solution was stirred for 2.5 h (RM2). Et2O (5 mL) was added and the resulting precipitate was centrifuged. The supernatant was discarded. The residue was dissolved in CH3CN (1 mL), precipitated with Et2O (5 mL), centrifuged and the supernatant was discarded. The residue was dissolved in MeOH (1 mL), precipitated with Et2O (5 mL), centrifuged and the supernatant was discarded to afford 2-(3-{7-[(3S)-3,4-dimethylpiperazin-l-yl]-5-methyl- 10-oxo- 1H,2H,3H,4H,5H, 10H-benzo[b] 1 ,6-naphthyridine-2-carbonyl } - 1 ,2-oxazol-5- yl)propanoic acid (31.2 mg, 72% yield, TFA salt) as a light yellow solid. LC / MS (MethodD): Rt= 3.76 min, [M+H]+ = 494.3. 'H NMR (400 MHz, DMSO-d6) 5 12.97 (brs, 1H), 9.65 (brs, 1H), 8.03 (dd, J = 26.0, 9.1 Hz, 1H), 7.15 (td, J = 9.1, 2.0 Hz, 1H), 6.98 - 6.90 (m, 1H), 6.73 - 6.62 (m, 1H), 4.59 - 4.47 (m, 2H), 4.27 - 4.02 (m, 3H), 3.97 - 3.85 (m, 2H), 3.69 (d, J = 5.0 Hz, 3H), 3.56 - 3.45 (m, 2H), 3.19 - 2.99 (m, 4H), 2.95 - 2.70 (m, 4H), 1.54 - 1.44 (m, 3H), 1.37 - 1.23 (m, 3H).Cpd 143

[0378] Step 1. To an Argon-purged mixture of Intermediate G (1 eq., 150 mg, 0.302 mmol), (7R,8aS)-octahydropyrrolo[l,2-a]pyrazin-7-ol dihydrochloride (1.5 eq., 97.3 mg, 0.45 mmol) and Cs2CO3 (4.5 eq., 442 mg, 1.36 mmol) in tert-amyl alcohol (2.59 mL) was added RuPhos Pd G4 (0.1 eq., 25.6 mg, 0.03 mmol) at RT. The reaction mixture was purged with Argon, heated to 100 °C and stirred for 16 h. The reaction mixture was diluted in a mixture of DCM:MeOH and filtered over a pad of celite. The filter cake was rinsed with DCMMeOH and the filtrate was concentrated under reduced pressure. The crude residue was purified by flash chromatography over silica gel (DCM:MeOH from 98 / 2 to 80 / 20) to afford tert-butyl 4-{7-[(7R,8aS)-7-hydroxy-octahydropyrrolo[l,2- a]pyrazin-2-yl]-5-methyl-10-oxo-lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyri dinercarbonyl (benzoate (81.6 mg, 0.15 mmol, 48% yield) as a light brown solid.

[0379] Step 2. To a solution of tert-butyl 4-{7-[(7R,8aS)-7-hydroxy- octahydropyrrolo[ 1 ,2-a]pyrazin-2-yl]-5-m ethyl- 10-oxo- 1H,2H,3H,4H,5H, 10H- benzo[b]l,6-naphthyridine-2-carbonyl (benzoate (1 eq., 80 mg, 0.14 mmol) in DCM (1.14 mL) was added TFA (50 eq., 816.38 mg, 0.53 mL, 7.16 mmol) at RT and the RM was stirred for 4 h. Et2O (5 mL) was added and the resulting precipitate was centrifuged. The supernatant was discarded. The residue was dissolved in CH3CN (1 mL), precipitated with Et2O (5 mL), centrifuged and the supernatant was discarded. The residue was dissolved in MeOH (1 mL), precipitated with Et2O (5 mL), centrifuged and the supernatant was discarded to afford a light brown solid. The remaining solid was freeze- dried using water (4 mL) to afford 4-{7-[(7R,8aS)-7-hydroxy-octahydropyrrolo[l,2- a]pyrazin-2-yl]-5-methyl-l 0-oxo- 1H,2H,3H,4H,5H, 10H-benzo[b]l,6-naphthyri dinercarbonyl (benzoic acid (75.2 mg, 85% yield, TFA salt) as a light yellow solid. LC / MS (Method D): Rt= 3.57 min, [M+H]+= 503.4. 'H NMR (400 MHz, DMSO-d6) 5 13.10(brs, 1H), 13.06 (brs, 1H), 10.54 - 9.81 (m, 1H), 8.11 - 7.90 (m, 3H), 7.65 - 7.48 (m, 2H), 6.98 (brs, 1H), 6.72 (brs, 1H), 5.57 (s, 1H), 4.57 - 4.44 (m, 2H), 4.28 (brs, 1H), 4.13 (brs, 1H), 4.07 - 3.98 (m, 1H), 3.93 (brs, 1H), 3.68 (brs, 5H), 3.60 - 3.39 (m, 4H), 3.12 - 2.87 (m, 3H), 2.16 - 1.93 (m, 2H).Cpd 144

[0380] Step 1. To an Argon-purged mixture of Intermediate G (1 eq., 150 mg, 0.302 mmol), (7S,8aS)-octahydropyrrolo[l,2-a]pyrazin-7-ol; oxalic acid (1.5 eq., 105 mg, 0.45 mmol) and Cs2CO3 (4 eq., 393 mg, 1.206 mmol) in tert-amyl alcohol (2.59 mL) was added RuPhos Pd G4 (0.1 eq., 25.6 mg, 0.0302 mmol) at RT. The reaction mixture was purged with Argon, heated to 100 °C and stirred for 16 hours. The reaction mixture was diluted in a mixture of DCM:MeOH and filtered over a pad of celite. The filter cake was rinsed with DCM:MeOH and the filtrate was concentrated under reduced pressure. The crude material was purified by flash chromatography over silica gel (12 g column, 50 pm, dry loading, DCM:MeOH from 98 / 2 to 80 / 20 over 40 min) to afford tert-butyl 4-{7- [(7S,8aS)-7-hydroxy-octahydropyrrolo[l,2-a]pyrazin-2-yl]-5-methyl-10-oxo- lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridine-2-carbonyl}benzoate (55.8 mg, 0.1 mmol, 33% yield) as a light brown solid.

[0381] Step 2. To a solution of tert-butyl 4-{7-[(7S,8aS)-7-hydroxy- octahydropyrrolo[ 1 ,2-a]pyrazin-2-yl]-5-m ethyl- 10-oxo- 1H,2H,3H,4H,5H, 10H- benzo[b]l,6-naphthyridine-2-carbonyl (benzoate (1 eq., 50 mg, 0.089 mmol) in DCM (0.71 mL) was added TFA (50 eq., 510 mg, 0.33 mL, 4.47 mmol) at RT and the RM was stirred for 4 h. Et2O (5 mL) was added and the resulting precipitate was centrifuged. The supernatant was discarded. The residue was dissolved in CH3CN (1 mL), precipitated with Et2O (5 mL), centrifuged and the supernatant was discarded. The residue was dissolved in MeOH (1 mL), precipitated with Et2O (5 mL), centrifuged and the supernatant was discarded . The crude material was purified by preparative HPLC (Eluant: Water + 0.1% TFA / Acetonitrile Gradient : from 10 to 25% acetonitrile in water + 0.1% TFA Column : XBridge C18 (30xl50(5pm)) Flow Rate : 43 mL / min). The solid was freeze-dried using water (4 mL) to afford 4-{7-[(7S,8aS)-7-hydroxy- octahydropyrrolo[ 1 ,2-a]pyrazin-2-yl]-5-m ethyl- 10-oxo- 1H,2H,3H,4H,5H, 1 OH-benzo[b]l,6-naphthyridine-2-carbonyl (benzoic acid (33 mg, 60% yield, TFA salt) as a light yellow solid. LC / MS (Method D): Rt= 3.58 min, [M+H]+= 503.3. 'H NMR (400 MHz, DMSO-d6) 5 13.15 (s, 1H), 10.31 - 10.06 (m, 1H), 8.12 - 7.91 (m, 3H), 7.65 - 7.50 (m, 2H), 7.20 - 7.02 (m, 1H), 6.99 - 6.83 (m, 1H), 5.64 (s, 1H), 4.57 - 4.46 (m, 2H), 4.43 - 4.37 (m, 1H), 4.31 - 4.21 (m, 2H), 3.99 - 3.83 (m, 3H), 3.78 - 3.53 (m, 6H), 3.49 - 3.40 (m, 1H), 3.36 - 3.10 (m, 3H), 3.08 - 2.99 (m, 2H), 1.89 - 1.52 (m, 1H).Cpd 145

[0382] To a solution of Intermediate G (1 eq., 100 mg, 0.19 mmol), 4- (hydroxymethyl)benzoic acid (1.5 eq., 42.3 mg, 0.28 mmol) and DIPEA (5 eq., 119.8 mg, 0.15 mL, 0.93 mmol) in DMF (0.62 mL) was added at 0 °C Propylphosphonic anhydride (50 wt% in EtOAc) (2 eq., 235.8 mg, 0.22 mL, 0.37 mmol). The reaction mixture was allowed to warm slowly to RT and stirred for 1 h. The reaction mixture was diluted with sat. NaHCO3 (10 mL) and extracted with DCM / MeOH (8 / 2; 3 x 20 mL). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated to dryness. The crude material was purified by flash chromatography over silica gel (DCM / MeOH 100 / 0 to 60 / 40). The fractions were combined and evaporated in vacuo. The residue was dissolved in DCM (0.89 mL) and TFA (0.22 mL) was added at RT. The mixture was stirred at RT for 10 minutes then precipitated with Et2O (2 mL) and centrifuged. The supernatant was discarded. The solid was dissolved in CH3CN (0.5 mL), precipitated with Et2O (2 mL), centrifuged and the supernatant was discarded (process done twice). The remaining solid was dried under vacuum then dissolved in water (1 mL) and freeze-dried to afford 7-[(3S)-3,4-dimethylpiperazin-l-yl]-2-[4- (hydroxymethyl)benzoyl]-5-methyl-lH,2H,3H,4H,5H,10H-benzo[b]l,6-naphthyridin- 10-one (37.7 mg, 35% yield, TFA sa...

Claims

CLAIMS1. A compound of Formula (I)or a pharmaceutically acceptable salt and / or solvate thereof; whereinR1represents hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, hydroxyl, -O-alkyl, or halogen; wherein the alkyl in R1is optionally substituted by at least one group selected from NR10Rn, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cyano, hydroxy, (C1-C4) alkoxy, and halogen; the cycloalkyl in R1is optionally substituted by at least one group selected from (C1-C4) alkyl, cyano, and halogen; the heterocycloalkyl in R1is optionally substituted by at least one group selected from NR10Rn, (C1-C4) alkyl, cyano, (C1-C4) haloalkyl, hydroxy, (C1-C4) alkoxy, oxo (=0), and halogen; the aryl in R1is optionally substituted by at least one group selected from NR10Rn, (C1-C4) alkyl, cyano, (C1-C4) haloalkyl, hydroxyl, (C1-C4) alkoxy, and halogen; and the heteroaryl in R1is optionally substituted by at least one group selected from NR1ORU, (C1-C4) alkyl, cyano, (C1-C4) haloalkyl, hydroxyl, (C1-C4) alkoxy, and halogen;R2represents hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, hydroxy, -O-alkyl, -O-aryl, or halogen; wherein the alkyl in R2is optionally substituted by at least one group selected from NR10Rn, cyano, cycloalkyl, aryl, heteroaryl, hydroxy, (C1-C4) alkoxy, and halogen; the cycloalkyl in R2is optionally substituted by at least one group selected from NR10Rn, (C1-C4) alkyl, (C1-C4) haloalkyl, cyano, hydroxy, (C1-C4) alkoxy, and halogen; the aryl in R2is optionally substituted by at least one group selected from NR1*^11, (C1-C4) alkyl, (C1-C4) haloalkyl, cyano, hydroxy, (C1-C4) alkoxy, and halogen; and the heteroaryl in R2is optionally substituted by at least one group selected from NR10Rn, (C1-C4) alkyl, (C1-C4) haloalkyl, cyano, hydroxy, (C1-C4) alkoxy, and halogen;R3represents hydrogen, -NRARB, alkyl, cycloalkyl, -alkenyl-C(O)2-R12, alkynyl, heterocycloalkyl, aryl, heteroaryl, -O-alkyl, -O-cycloalkyl, -O-(Ci-C4) alkyl-NR10Ru, or halogen; wherein the alkyl in R3is optionally substituted by at least one group selected from NR10Rn, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cyano, hydroxy, (C1-C4) alkoxy, and halogen; wherein the heterocycloalkyl is optionally substituted by at least one group selected from (C1-C4) alkyl, (C1-C4) alkyl-NR10Ru, cyano, hydroxy, (C1-C4) alkoxy, and halogen; the cycloalkyl in R3is optionally substituted by at least one group selected from NR1ORU, cyano, heterocycloalkyl, hydroxy, (C1-C4) alkoxy, and halogen;wherein the heterocycloalkyl is optionally substituted by at least one -(C1-C4) alkyl-NR10Rn; the alkynyl in R3is optionally substituted by at least one group selected from NR10Rn, heterocycloalkyl, hydroxy, and (C1-C4) alkoxy; the heterocycloalkyl in R3is optionally substituted by at least one group selected from NR10Rn, -NR10-C(O)-R12, -NR10-C(O)2-R12, alkyl, cycloalkyl, heterocycloalkyl, cyano, (C1-C4) haloalkyl, -C(O)2-R12, -C(O)-NR10R11, hydroxyl, -O-alkyl, oxo (=0), and halogen; wherein the alkyl, cycloalkyl or heterocycloalkyl is optionally substituted by at least one group selected from NR10Rn, (C1-C4) alkyl, cyano, C(O)2R12, hydroxyl, (C1-C4) alkoxy, and halogen; the aryl in R3is optionally substituted by at least one group selected from NR10Rn, (C1-C4) alkyl, cycloalkyl, heterocycloalkyl, -(C1-C4) alkyl-NR10Rn, cyano, hydroxyl, (C1-C4) alkoxy, and halogen; the heteroaryl in R3is optionally substituted by at least one group selected from NR10Rn, (C1-C4) alkyl, cycloalkyl, heterocycloalkyl, -(C1-C4) alkyl-NR10Rn, cyano, hydroxyl, (C1-C4) alkoxy, and halogen; andRAand RBeach independently represents hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -C(0)-Rc, or -C(0)2-Rc; whereinRcrepresents alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; and the alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl in RA, RBor Rcis optionally substituted by at least one group selected from NR1ORU, (C1-C4) alkyl, cycloalkyl, cyano, (C1-C4) haloalkyl, hydroxy, (C1-C4) alkoxy, oxo (=0), and halogen;R4represents hydrogen or halogen;X represents N-R5, O, S, or S(O)2; wherein R5represents hydrogen, alkyl, or cycloalkyl; wherein the alkyl in R5is optionally substituted by at least one group selected from NR10Rn, cyano, (C1-C4) haloalkyl, hydroxy, (C1-C4) alkoxy, and halogen; and the cycloalkyl in R5is optionally substituted by at least one group selected from NR10Rn, (C1-C4) alkyl, cyano, hydroxy, (C1-C4) alkoxy, and halogen;Y represents aryl or heteroaryl; wherein the aryl or heteroaryl in Y is optionally substituted by at least one REgroup; wherein RErepresents NR10Rn, -NR10-S(O)2-RE, -N=S(O)R10R11, B(OH)2, alkyl, heterocycloalkyl, heteroaryl, cyano, -C(O)NH-S(O)2- NR10Rn, -C(O)2-R12, hydroxy, -O-alkyl, -S(O)2-NRERG, -S(O)2-RE, -S(O)(=NR10)-R12, -P(O)(OR)2, or halogen; wherein the alkyl, heterocycloalkyl or heteroaryl in REis optionally substituted by at least one group selected from -NR10-S(O)-R12, -C(O)-NR10R11, -C(O)2H, -S(O)2-NR10Rn, S(O)2-R12, and halogen; and wherein REand RGeach independently represents hydrogen, alkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl or heterocycloalkyl in REor RGis optionally substituted by at least on group selected from (C1-C4) alkyl, -CH2-(Ci-C4) alkoxy, cycloalkyl, cyano, hydroxy, (C1-C4) alkoxy, and halogen.R10and R11each independently represents hydrogen, (C1-C4) alkyl, or cycloalkyl; wherein the alkyl or cycloalkyl in R10or R11is optionally substituted by at least one group selected from cyano, hydroxy, (C1-C4) alkoxy, and halogen; orR10and R11form together with the nitrogen atom to which they are bound a 3-membered to 6-membered heterocycloalkyl; wherein the heterocycloalkyl is optionally substituted by at least one group selected from (C1-C4) alkyl, (C1-C4) haloalkyl, hydroxy, (C1-C4) alkoxy, oxo (=0), and halogen; andR12represents hydrogen, (C1-C4) alkyl, or cycloalkyl; wherein the alkyl or cycloalkyl in R12is optionally substituted by at least one group selected from cyano, hydroxy, (C1-C4) alkoxy, and halogen.

2. The compound according to claim 1, wherein R1represents hydrogen, heteroaryl, hydroxyl, -O-alkyl, or halogen; wherein the alkyl or heteroaryl is optionally substituted as defined in claim 1; preferably R1is selected from hydrogen, pyridinyl, hydroxy, methoxy, and F.

3. The compound according to claim 1 or claim 2, wherein R2represents hydrogen or halogen; preferably R2is selected from hydrogen, Cl, and F.

4. The compound according to any one of claims 1 to 3, wherein R3represents hydrogen, -NRARB, alkyl, cycloalkyl, -alkenyl-C(O)2-R12, alkynyl, heterocycloalkyl, aryl, heteroaryl, -O-(Ci-C4) alkyl-NR10Rn, or halogen; wherein the alkyl, cycloalkyl, alkynyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted as defined in claim 1.

5. The compound according to any one of claims 1 to 4, wherein R4is hydrogen.

6. The compound according to any one of claims 1 to 5, wherein X represents N-R5, wherein R5is as defined in claim 1; preferably R5is selected from hydrogen, methyl, ethyl, propyl, cyclopropyl, trifluoromethyl, difluoromethyl, and -CH2CH2OH.

7. The compound according to claim 6, wherein R5is selected from hydrogen and methyl.

8. The compound according to any one of claims 1 to 7, wherein Y represents aryl or heteroaryl; wherein the aryl or heteroaryl is substituted by at least one -S(0)2-NRFRG; wherein RFand RGare as defined in claim 1; preferably RFandRGrepresent hydrogen or alkyl.

9. The compound according to claim 1, wherein the compound is of Formula (I-a-1)or a pharmaceutically acceptable salt and / or solvate thereof; wherein:R1, R2, R3, R4and R5are each independently as defined in claim 1; each REis independently as defined in claim 1; and p is an integer ranging from 0 to 5.

10. The compound according to claim 9, wherein p an integer ranging from 1 to 5, preferably p is an integer ranging from 1 to 3, more preferably p is 1 or 2.

11. The compound according to claim 1, wherein the compound is selected from:and pharmaceutically acceptable salts and / or solvates thereof.

12. A pharmaceutical composition comprising a compound according to any one of claims 1 to 11 and at least one pharmaceutically acceptable carrier.

13. A compound according to any one of claims 1 to 11 or a pharmaceutical composition according to claim 12 for use as a medicament.

14. A compound according to any one of claims 1 to 11 or a pharmaceutical composition according to claim 12 for use in the treatment of an auto-immune disease, an inflammatory disease, or a proliferative disease.

15. A process for manufacturing a compound according to any one of claims 1 to 11 comprising a step of reaction in acidic conditions of a bromophenyl-imino- piperidine-carboxylate with a A-acetyl-oxopiperidine-carboxylate.

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