RU2804468C2 - Dihydronaphthyridines and related compounds suitable as kinase inhibitors for the treatment of proliferative diseases - Google Patents

Abstract

FIELD: medicine; oncology.

SUBSTANCE: method of treating a disease caused by the kinase activity of c-KIT, its oncogenic forms or polymorphs, where the disease is a stromal tumor of the gastrointestinal tract, including the administration of a therapeutically effective amount of a dihydronaphthyridine derivative are proposed.

EFFECT: effectiveness against a wide range of primary and secondary c-KIT mutations with high therapeutic value for the treatment of patients with resistant GIST.

12 cl, 4 tbl, 184 ex

Description

State of the art

[0001] c-KIT (also known as KIT, CD117 and stem cell factor receptor) is a 145 kDa transmembrane protein tyrosine kinase that acts as a type III receptor (Pereira et al. J. Carcin. 2005, 4, pg. 19 ). The c-KIT proto-oncogene, located on chromosome 4q11-21, encodes the c-KIT receptor, the ligand of which is stem cell factor (SCF, steel factor, kit ligand, mast cell growth factor, Morstyn, G. et al. Oncology 1994, 57(2 ), pg. 205; Yarden, Y et al. Embo. J, 1987, (6(11), pg. 3341). This receptor has protein tyrosine kinase activity, and binding of the CSF ligand leads to autophosphorylation of c-KIT and its association with substrates such as phosphatidylinositol 3-kinase (PI3K).Tyrosine phosphorylation by protein tyrosine kinases is particularly important in cellular signaling pathways and can mediate signaling in important cellular processes such as proliferation, survival, differentiation, apoptosis, attachment, invasiveness and migration.Defects in c-KIT cause pinto, a genetic autosomal dominant developmental pigmentation disorder characterized by the presence at birth of patches of white skin and hair that lack melanocytes. Gain-of-function mutations in the c-KIT gene and expression of constitutively phosphorylated c-KIT are found in most gastrointestinal stromal tumors (GISTs) and mastocytosis. In addition, almost all gonadal seminomas/dysgerminomas show membranous c-KIT staining, and several reports have reported that c-KIT gene mutation occurs in some cases (10-25%) (Sakuma, Y. et al. Cancer Sci 2004, 95(9), pg. 716). Defects in c-KIT have also been associated with testicular tumors, including germ cell tumors (GCT) and testicular germ cell tumors (TGCT).

[0002] Studies have been conducted on the effect of c-KIT expression in hematological and solid tumors, such as types of acute leukemia (Cortes, J. et al. Cancer 2003, 97(11), pg. 2760) and GIST (Fletcher, J. et al Hum Pathol 2002, 33(5), pg. 459). The clinical relevance of c-KIT expression in malignant tumors was revealed in studies using Gleevec ^® (imatinib mesylate, STI571 (signal transduction inhibitor no. 571), Novartis Pharma AG Basel, Switzerland), which specifically inhibits receptor tyrosine kinases (Lefevre, G. et al. J Biol Chem 2004, 279(30), pg 31769). In addition, a clinically important discovery was the determination of the antitumor effect of the specified compound in GIST, a group of tumors generally considered resistant to conventional chemotherapy (de Silva, S.M., Reid, R. Pathol. Oncol. Res. 2003, 9(1 ), pp. 13-19). In most GISTs, primary activating mutations of genes encoding RTKs closely related to c-KIT (in 75-80% of GIST cases) or PDGFRα (in 8% of GIST cases without c-KIT mutations) are observed. c-KIT and PDGFRα mutations are mutually exclusive in GIST (Rubin et al. Lancet 2007, 369, pg. 1731). The majority of primary c-KIT mutations causing GIST affect the juxtamembrane (JM) region of the protein encoded by exon 11 (i.e., V560D) and involve in-frame deletions or insertions or missense mutations. Exon 11 c-KIT mutations have been identified as primary mutations in approximately 75% of GIST cases. These JM domain mutations disrupt the autoinhibitory mechanism of c-KIT kinase, which leads to constitutive kinase activity and cell transformation events that cause GIST (Chen, LL et al. Clin. Cancer Res. 2005, 11, pg. 3668-3677; Mol, CD, et al J Biol Chem 2004, 279, pg 31655-31663).

[0003] An increasing number of cases of GISTs resistant to Gleevec® are being reported, and small molecule targeted therapies targeting secondary c-KIT mutations have not been well studied. In patients with GIST who relapse after treatment with Gleevec® or Sutent®, the disease continues to be defined by c-KIT mutations. These secondary mutations occur on the same alleles as the primary JM region mutations and thus represent even more aggressive activated forms of c-KIT compared to the original primary mutation. These secondary c-KIT mutations found in GIST lead to acquired drug resistance. Secondary mutations were found in the extracellular domain of c-KIT (exon 9, i.e. AY501-502 duplication/insertion), ATP-binding pocket (exon 13, i.e. K642E, V654A; exon 14, i.e. T670I) and the activating loop (exon 17, i.e. N822K, D816H, D816V, D820A). There are descriptions of these various secondary c-KIT mutations: Heinrich, M.C et al. J. Clin. Oncol. 2006, 24, pg. 4764-4774; Debiec-Rychter, M. et al. Gastroenterology 2005, 128, pg. 270-279; Wardelmann, E. et al. Lancet Oncol. 2005, 6, pg. 249-251; Antonescu, C. R., et al. Clin. Cancer Res. 2005, 11, pg. 4182-4190. Sunitinib malate (Sutent™, Pfizer) is an inhibitor of several RTKs, particularly in the context of the present invention c-KIT and PDGFRα, and has been shown to be effective against certain imatinib-resistant c-KIT mutants, such as ATP- binding pocket V654A and T670I. Certain Gleevec ^® -resistant mutants, such as D816H and D816V, which are located in the activation loop of the c-KIT catalytic domain encoded by exon 17 (Corless et al. J. Clin. Oncol. 2004, 22, pg. 3813; Heinrich et al. J. Clin. Oncol. 2008, 26, pg. 5352; Gajiwala et al. Proc. Natl. Acad. Sci. USA 2009, 106:1542) are also resistant to sunitinib. The average survival after disease progression due to resistance to Gleevec ^® remains relatively short.

[0004] It has been demonstrated that various complex multiple secondary c-KIT mutations can occur in individual patients, such as changes in c-KIT mutational status, as shown in biopsy specimens obtained from various advanced metastases taken from each patient (Wardelmann, E., et al. Lancet Oncol. 2005, 6, pg. 249-251; Fletcher, J. A. and Rubin, B. P., Curr. Opin in Genetics & Develop., 2007, 17, pg. 3-7). This complex mutational heterogeneity of c-KIT in each individual patient highlights the unmet medical need to identify c-KIT kinase inhibitors that are effective against a wide range of primary and secondary c-KIT mutations. This broad spectrum c-KIT inhibitor may have high therapeutic value for the treatment of patients with refractory GISTs.

Brief description of the invention

[0005] The present invention provides the unexpected use of compounds that inhibit c-KIT kinase with a wide range of c-KIT mutations, including complex manifestations of primary mutations (KIT exons 9 or 11) and secondary KIT mutations (exons 13, 14, 17 and 18) which may occur in selected patients with refractory GISTs. Also unexpected is the use of the compounds of the present invention to inhibit the difficult to treat exon 17 c-KIT mutation D816V, for which there is currently no effective therapy. D816 mutations in c-KIT have been demonstrated to cause mastocytosis, mast cell leukemia, seminomas, dysgerminomas, lymphomas, and intracranial teratomas (Ning, A.Q., Li, J., and Arceci, R.J. Leuk Lymphoma, 2001, 41, pg. 513-522 ; Beghini, A. et al. Blood, 2000, 95, pg. 726-727; Tian, Q., et al. Am J. Pathol. 1999, 154, pg. 1643-1647; Nagata, H. et al. Proc. Natl. Acad. Sci. USA, 1995, 92, 10560-10564; Longley, B. J., et al. Nat. Genet., 1996, 12, pg. 312-314). The present invention also provides new compounds for the treatment of diseases caused by c-KIT mutation, including new compounds for the treatment of resistant GIST, mast cell leukemia or mastocytosis.

[0006] According to one aspect of the present invention, there is provided a method of treating a disease caused by the kinase activity of c-KIT, its oncogenic forms, aberrant chimeric proteins or polymorphs of the specified kinase, comprising the administration of a compound of formula Ia

or a pharmaceutically acceptable salt thereof,

Where:

A is selected from the group consisting of phenyl, naphthyl and benzothienyl;

G1 is heteroaryl selected from the group consisting of pyrrolyl, furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyrazinyl, pyridazinyl, triazinyl, pyridinyl and pyrimidinyl;

G4 is heterocyclyl selected from the group consisting of oxetanyl, azetadinyl, tetrahydrofuranyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, imidazolonyl, pyranyl, tetrahydropyranyl, dioxalinyl, piperidinyl and morpholinyl;

if A contains one or more sp2-hybridized carbon atoms, which may have substituents, then each corresponding sp2-hybridized carbon atom may optionally be substituted with a Z3 substituent;

Z1 is selected from the group consisting of -NH(R4) and -NHCOR8;

if Z1 contains an alkyl or alkylene fragment, then these fragments can be additionally replaced by one or more C1-C6 alkyls;

each Z2 is independently individually selected from the group consisting of hydrogen, C1-C6 alkyl, C3-C8 carbocyclyl, C1-C6 alkoxy, hydroxyl, hydroxy-C1-C6 alkyl, cyano, (R3) _2N- and -( _CH2 ) _n R5;

if Z2 contains an alkyl or alkylene fragment, then these fragments can be additionally replaced by one or more C1-C6 alkyls;

each Z3 is independently individually selected from the group consisting of H, methyl, ethyl, isopropyl, C3-C4 carbocyclyl, halogen, cyano, -(CH ₂ ) _k -N(R3) ₂ and -(CH ₂ ) _k -R5;

R1 is selected from the group consisting of C1-C4 alkyl, branched C3-C5 alkyl and C3-C5 carbocyclyl;

each R2 is independently individually selected from the group consisting of hydrogen, methyl, ethyl, halogen, fluoroalkyl, where the alkyl moiety may be partially or fully fluorinated, cyano and C2-C3 alkynyl;

each R3 is independently individually selected from the group consisting of H, C1-C6 alkyl, branched C3-C7 alkyl and C3-C8 carbocyclyl;

each R4 is independently individually selected from the group consisting of H, C1-C6 alkyl, hydroxy-C2-C6 alkyl, C1-C6 alkoxy-C2-C6 alkyl, branched C3-C7 alkyl, branched hydroxy-C2-C6 alkyl, branched C1-C6 alkoxy-C2-C6 alkyl, -(CH ₂ ) _q -N(R7) ₂ , -(CH ₂ ) _q -R5, -(CH ₂ ) _n C(O)R5, C3-C8 carbocyclyl, hydroxyl-substituted C3-C8 carbocyclyl, alkoxy-substituted C3-C8 carbocyclyl and -(CH ₂ ) _n -R17;

each R5 is independently individually selected from the group consisting of

where the symbol (##) indicates the attachment site of the R5 fragment;

each R5 may be optionally substituted with one or two R10 substituents;

each R7 is independently individually selected from the group consisting of H, C1-C6 alkyl, hydroxy-C2-C6 alkyl, C1-C6 alkoxy-C2-C6 alkyl, branched C3-C7 alkyl, branched hydroxy-C2-C6 alkyl, branched C1-C6 alkoxy-C2-C6 alkyl, -(CH ₂ ) _q -R5, -(CH ₂ ) _n -C(O)R5, -(CH ₂ ) _n -C(O)OR3, C3-C8 carbocyclyl, hydroxyl-substituted C3-C8 carbocyclyl, alkoxy-substituted C3-C8 carbocyclyl and -(CH ₂ ) _n -R17;

each R8 is independently individually selected from the group consisting of hydrogen, C1-C6 alkyl, branched C3-C7 alkyl, fluoroalkyl where the alkyl moiety is partially or fully fluorinated, C3-C8 carbocyclyl, Z3-substituted phenyl, Z3-substituted G1, Z3-substituted G1-C1-C6 alkyl, Z2-substituted G4, Z2-substituted G4-C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkoxy-C1-C6 alkyl, cyano-C1-C6 alkyl, -N( R4) ₂ and R5;

each R10 is independently individually selected from the group consisting of CO ₂ H, CO ₂ -C1-C6 alkyl, CO-N(R4) ₂ , OH, C1-C6 alkoxy, C1-C6 alkyl and -N(R4) ₂ ;

each R17 is selected from the group consisting of phenyl, naphthyl, pyrrolyl, furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyrazinyl, pyridazinyl, triazinyl, oxetanyl, azetadinyl, tetrahydrofuranyl, oxazolin yl, oxazolidinyl , pyranyl, thiopyranyl, tetrahydropyranyl, dioxalinyl, pyrrolidinyl and piperidinyl;

wherein R17 may be further substituted by one or more Z2 or Z3 moieties;

wherein two fragments R3 or R4 are independently selected from the group consisting of C1-C6 alkyl and branched C3-C6 alkyl, hydroxyalkyl and alkoxyalkyl, and are attached to one nitrogen atom, wherein these fragments can be cyclized to form C3-C7 heterocyclyl ring;

and k is 1 or 2; n is 0-6; p is equal to 1-4; q is 2-6; r is 0 or 1; t is 1-3.

[0007] In one embodiment, the invention provides a method of treating a disease caused by the kinase activity of c-KIT, its oncogenic forms, aberrant chimeric proteins or polymorphs of the specified kinase, where c-KIT has a missense mutation, insertion mutation or deletion mutation encoded by exons, including exon 9, exon 11, exon 13, exon 14, exon 17 or exon 18, present alone or in combination, comprising administering a compound of formula Ia or a pharmaceutically acceptable salt thereof.

[0008] According to a second aspect of the present invention, there is provided a method for treating a disease selected from gastrointestinal stromal tumors, ovarian cancer, pancreatic cancer, prostate cancer, lung cancer, breast cancer, melanoma, kidney cancer, liver cancer, cervical carcinomas, metastases from primary tumor sites, papillary thyroid carcinoma, non-small cell lung cancer, mesothelioma, hypereosinophilic syndrome, colon cancers, acute myeloid leukemia, seminoma or dysgerminoma germ cell tumors, teratomas, mastocytosis or mast cell leukemia, comprising administering to the patient therapeutically an effective amount of a compound of formula Ia or a pharmaceutically acceptable salt thereof.

[0009] According to a third aspect of the present invention, there is provided a pharmaceutical composition containing a compound of formula Ia or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier, provided that the compound is not 1-(5-(1-ethyl-7-(methylamino)- 2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoro-4-methylphenyl)-3-(naphthalene-1-yl)urea, 1-(5-(1-ethyl) -7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-(naphthalene-1-yl)urea, 1-(4-chloro -5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea, 1-(4-chloro -5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-(2,3-difluorophenyl)urea , 1-(2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)phenyl)-3-phenylurea, 1- (4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-(naphthalene-1 -yl)urea, 1-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)phenyl )-3-phenylurea, 1-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl) phenyl)-3-(naphthalene-1-yl)urea, 1-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydro-1, 6-naphthyridin-3-yl)phenyl)-3-(3-cyanophenyl)urea or 1-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1, 2-dihydro-1,6-naphthyridin-3-yl)phenyl)-3-(2,3-difluorophenyl)urea.

[0010] According to a fourth aspect of the present invention, there is provided the use of a compound of formula Ia or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of a disease selected from gastrointestinal stromal tumors, ovarian cancer, pancreatic cancer, prostate cancer, lung cancer, cancer breast diseases, melanoma, kidney cancers, liver cancers, cervical carcinomas, metastases from primary tumor sites, papillary thyroid carcinoma, non-small cell lung cancer, mesothelioma, hypereosinophilic syndrome, colon cancers, acute myeloid leukemia, seminoma germ cell tumors or dysgerminomas, teratomas, mastocytosis or mast cell leukemia.

[0011] According to a fifth aspect of the present invention, there is provided a compound of formula Ia

or a pharmaceutically acceptable salt thereof,

Where:

A is selected from the group consisting of phenyl, naphthyl and benzothienyl;

G1 is heteroaryl selected from the group consisting of pyrrolyl, furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyrazinyl, pyridazinyl, triazinyl, pyridinyl and pyrimidinyl;

G4 is heterocyclyl selected from the group consisting of oxetanyl, azetadinyl, tetrahydrofuranyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, imidazolonyl, pyranyl, tetrahydropyranyl, dioxalinyl, piperidinyl and morpholinyl;

if A contains one or more sp2-hybridized carbon atoms, which may have substituents, then each corresponding sp2-hybridized carbon atom may optionally be substituted with a Z3 substituent;

Z1 is selected from the group consisting of -NH(R4) and -NHCOR8;

in case Z1 contains an alkyl or alkylene moiety, these moieties may be further substituted with one or more C1-C6 alkyls;

each Z2 is independently individually selected from the group consisting of hydrogen, C1-C6 alkyl, C3-C8 carbocyclyl, C1-C6 alkoxy, hydroxyl, hydroxy-C1-C6 alkyl, cyano, (R3) _2NH- ( _CH2 ) _n R5;

in case Z2 contains an alkyl or alkylene moiety, said moieties may be further substituted with one or more C1-C6 alkyls;

each Z3 is independently individually selected from the group consisting of H, methyl, ethyl, isopropyl, C3-C4 carbocyclyl, halogen, cyano, -(CH ₂ ) _k -N(R3) ₂ and -(CH ₂ ) _k -R5;

R1 is selected from the group consisting of C1-C4 alkyl, branched C3-C5 alkyl and C3-C5 carbocyclyl;

each R2 is independently individually selected from the group consisting of hydrogen, methyl, ethyl, halogen, fluoroalkyl, where the alkyl moiety may be partially or fully fluorinated, cyano and C2-C3 alkynyl;

each R3 is independently individually selected from the group consisting of H, C1-C6 alkyl, branched C3-C7 alkyl and C3-C8 carbocyclyl;

each R4 is independently individually selected from the group consisting of H, C1-C6 alkyl, hydroxy-C2-C6 alkyl, C1-C6 alkoxy-C2-C6 alkyl, branched C3-C7 alkyl, branched hydroxy-C2-C6 alkyl, branched C1-C6 alkoxy-C2-C6 alkyl, -(CH ₂ ) _q -N(R7) ₂ , -(CH ₂ ) _q -R5, -(CH ₂ ) _n C(O)R5, C3-C8 carbocyclyl, hydroxyl-substituted C3-C8 carbocyclyl, alkoxy-substituted C3-C8 carbocyclyl and -(CH ₂ ) _n -R17;

each R5 is independently individually selected from the group consisting of

where the symbol (##) indicates the attachment site of the R5 fragment;

each R5 may be optionally substituted with one or two R10 substituents;

each R7 is independently individually selected from the group consisting of H, C1-C6 alkyl, hydroxy-C2-C6 alkyl, C1-C6 alkoxy-C2-C6 alkyl, branched C3-C7 alkyl, branched hydroxy-C2-C6 alkyl, branched C1-C6 alkoxy-C2-C6 alkyl, -(CH ₂ ) _q -R5, -(CH ₂ ) _n -C(O)R5, -(CH ₂ ) _n -C(O)OR3, C3-C8 carbocyclyl, hydroxyl-substituted C3-C8 carbocyclyl, alkoxy-substituted C3-C8 carbocyclyl and -(CH ₂ ) _n -R17;

each R8 is independently individually selected from the group consisting of hydrogen, C1-C6 alkyl, branched C3-C7 alkyl, fluoroalkyl where the alkyl moiety is partially or fully fluorinated, C3-C8 carbocyclyl, Z3-substituted phenyl, Z3-substituted G1, Z3-substituted G1-C1-C6 alkyl, Z2-substituted G4, Z2-substituted G4-C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkoxy-C1-C6 alkyl, cyano-C1-C6 alkyl, -N( R4) ₂ and R5;

each R10 is independently individually selected from the group consisting of CO ₂ H, CO ₂ -C1-C6 alkyl, CO-N(R4) ₂ , OH, C1-C6 alkoxy, C1-C6 alkyl and -N(R4) ₂ ;

each R17 is selected from the group consisting of phenyl, naphthyl, pyrrolyl, furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyrazinyl, pyridazinyl, triazinyl, oxetanyl, azetadinyl, tetrahydrofuranyl, oxazolin silt, oxazolidinyl , pyranyl, thiopyranyl, tetrahydropyranyl, dioxalinyl, pyrrolidinyl and piperidinyl;

wherein R17 may be further substituted by one or more Z2 or Z3 moieties;

wherein two fragments R3 or R4 are independently selected from the group consisting of C1-C6 alkyl and branched C3-C6 alkyl, hydroxyalkyl and alkoxyalkyl, and are attached to one nitrogen atom, wherein these fragments can be cyclized to form C3-C7 heterocyclyl ring;

and k is 1 or 2; n is 0-6; p is equal to 1-4; q is 2-6; r is 0 or 1; t is 1-3;

provided that the compound is not 1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoro-4- methylphenyl)-3-(naphthalene-1-yl)urea, 1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl) -2-fluorophenyl)-3-(naphthalene-1-yl)urea, 1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6 -naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea, 1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6 -naphthyridin-3-yl)-2-fluorophenyl)-3-(2,3-difluorophenyl)urea, 1-(2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1, 2-dihydro-1,6-naphthyridin-3-yl)phenyl)-3-phenylurea, 1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro -1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-(naphthalene-1-yl)urea, 1-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino )-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)phenyl)-3-phenylurea, 1-(4-chloro-2-fluoro-5-(1-methyl-7-( methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)phenyl)-3-(naphthalene-1-yl)urea, 1-(4-chloro-2-fluoro-5- (1-methyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)phenyl)-3-(3-cyanophenyl)urea or 1-(4-chloro- 2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)phenyl)-3-(2,3-difluorophenyl)urea .

[0012] According to any of the above aspects:

[0013] In one embodiment, the compound of formula Ia is a compound wherein: A is phenyl; or a pharmaceutically acceptable salt thereof.

[0014] In one embodiment, the compound of formula Ia is a compound wherein: A is naphthyl; or a pharmaceutically acceptable salt thereof.

[0015] In one embodiment, the compound of formula Ia is a compound wherein: A is benzothienyl; or a pharmaceutically acceptable salt thereof.

[0016] In one embodiment, the compound of Formula Ia is a compound wherein: R1 is selected from the group consisting of C1-C4 alkyl, C3-C5 branched alkyl and C3-C5 carbocyclyl; or a pharmaceutically acceptable salt thereof.

[0017] In one embodiment, the compound of formula Ia is a compound wherein: R1 is C1-C4 alkyl; or a pharmaceutically acceptable salt thereof.

[0018] In one embodiment, the compound of formula Ia is a compound wherein: R1 is a branched C3-C5 alkyl; or a pharmaceutically acceptable salt thereof.

[0019] In one embodiment, the compound of formula Ia is a compound wherein: R1 is a C3-C5 carbocyclyl; or a pharmaceutically acceptable salt thereof.

[0020] In one embodiment, the compound of formula Ia is a compound wherein: Z1 is selected from the group consisting of -NH(R4) and -NHCOR8; or a pharmaceutically acceptable salt thereof.

[0021] In one embodiment, the compound of Formula Ia is the compound wherein: Z1 is -NH(R4); or a pharmaceutically acceptable salt thereof.

[0022] In one embodiment, the compound of formula Ia is a compound wherein: Z1 is -NH(R4) and R4 is H or C1-C6 alkyl; or a pharmaceutically acceptable salt thereof.

[0023] In one embodiment, the compound of formula Ia is a compound wherein: Z1 is -NH(R4) and R4 is H; or a pharmaceutically acceptable salt thereof.

[0024] In one embodiment, the compound of formula Ia is a compound wherein: Z1 is -NH(R4) and R4 is C1-C6 alkyl; or a pharmaceutically acceptable salt thereof.

[0025] In one embodiment, the compound of formula Ia is a compound wherein: Z1 is -NH(R4) and R4 is methyl; or a pharmaceutically acceptable salt thereof.

[0026] In one embodiment, the compound of Formula Ia is the compound wherein: Z1 is -NR4COR8; or a pharmaceutically acceptable salt thereof.

[0027] In one embodiment, the compound of Formula Ia is the compound wherein: Z1 is -NHCOR8; or a pharmaceutically acceptable salt thereof.

[0028] In one embodiment, the compound of Formula Ia is a compound wherein: Z1 is -NHCOR8 and R8 is hydrogen, C1-C6 alkyl, C3-C7 branched alkyl, C3-C8 carbocyclyl, -N(R4) ₂ or R5; or a pharmaceutically acceptable salt thereof.

[0029] In one embodiment, the compound of formula Ia is a compound wherein: Z1 is -NHCOR8 and R8 is C1-C6 alkyl; or a pharmaceutically acceptable salt thereof.

[0030] In one embodiment, the compound of formula Ia is a compound wherein: Z1 is -NHCOR8 and R8 is a C3-C7 branched alkyl; or a pharmaceutically acceptable salt thereof.

[0031] In one embodiment, the compound of formula Ia is a compound wherein: Z1 is -NHCOR8 and R8 is a C3-C8 carbocyclyl; or a pharmaceutically acceptable salt thereof.

[0032] In one embodiment, the compound of formula Ia is a compound wherein: Z1 is -NHCOR8 and R8 is -N(R4)2; or a pharmaceutically acceptable salt thereof.

[0033] In one embodiment, the compound of formula Ia is a compound wherein: Z1 is -NHCOR8 and R8 is R5; or a pharmaceutically acceptable salt thereof.

[0034] In one embodiment, the compound of formula Ia is a compound wherein: each R2 is independently hydrogen, methyl or halogen and t is 2; or a pharmaceutically acceptable salt thereof.

[0035] In one embodiment, the compound of formula Ia is a compound of formula Ib

Where:

R2 is hydrogen, methyl or halogen; or a pharmaceutically acceptable salt thereof.

[0036] In one embodiment, the compound of formula Ia is a compound of formula Ib, wherein: R2 is hydrogen; or a pharmaceutically acceptable salt thereof.

[0037] In one embodiment, the compound of formula Ia is a compound of formula Ib, wherein: R2 is methyl; or a pharmaceutically acceptable salt thereof.

[0038] In one embodiment, the compound of formula Ia is a compound of formula Ib, wherein: R2 is halogen; or a pharmaceutically acceptable salt thereof.

[0039] In one embodiment, the compound of formula Ia is a compound of formula Ib, where: A is phenyl, R1 is C1-C4 alkyl, C3-C5 branched alkyl or C3-C5 carbocyclyl, R2 is hydrogen, methyl or halogen and Z1 is -NH(R4) or -NHCOR8; or a pharmaceutically acceptable salt thereof.

[0040] In one embodiment, the compound of formula Ia is a compound of formula Ib, where: A is phenyl, R1 is C1-C4 alkyl, R2 is methyl or halogen, and Z1 is -NH(R4) or - NHCOR8; or a pharmaceutically acceptable salt thereof.

[0041] In one embodiment, the compound of formula Ia is a compound of formula Ib wherein: A is phenyl, R1 is ethyl, R2 is methyl or halogen, and Z1 is -NH(R4) or -NHCOR8; or a pharmaceutically acceptable salt thereof.

[0042] In one embodiment, the compound of formula Ia is a compound of formula Ib, where: A is phenyl, R1 is ethyl, R2 is methyl or halogen, Z1 is -NH(R4), and R4 is methyl ; or a pharmaceutically acceptable salt thereof.

[0043] In one embodiment, the compound of formula Ia is a compound of formula Ib wherein: A is phenyl, R1 is ethyl, R2 is methyl, Z1 is -NH(R4), and R4 is methyl; or a pharmaceutically acceptable salt thereof.

[0044] In one embodiment, the compound of formula Ia is a compound of formula Ib wherein: A is phenyl, R1 is ethyl, R2 is halogen, Z1 is -NH(R4), and R4 is methyl; or a pharmaceutically acceptable salt thereof.

[0045] In one embodiment, the compound of formula Ia is a compound of formula Ib, where: A is naphthyl, R1 is C1-C4 alkyl, C3-C5 branched alkyl or C3-C5 carbocyclyl, R2 is hydrogen, methyl or halogen and Z1 is -NH(R4) or -NHCOR8; or a pharmaceutically acceptable salt thereof.

[0046] In one embodiment, the compound of formula Ia is a compound of formula Ib, where: A is naphthyl, R1 is C1-C4 alkyl, R2 is methyl or halogen, and Z1 is -NH(R4) or - NHCOR8; or a pharmaceutically acceptable salt thereof.

[0047] In one embodiment, the compound of formula Ia is a compound of formula Ib where: A is naphthyl, R1 is ethyl, R2 is methyl or halogen, and Z1 is -NH(R4) or -NHCOR8; or a pharmaceutically acceptable salt thereof.

[0048] In one embodiment, the compound of formula Ia is a compound of formula Ib, where: A is naphthyl, R1 is ethyl, R2 is methyl or halogen, Z1 is -NH(R4), and R4 is methyl ; or a pharmaceutically acceptable salt thereof.

[0049] In one embodiment, the compound of formula Ia is a compound of formula Ib where: A is naphthyl, R1 is ethyl, R2 is methyl, Z1 is -NH(R4), and R4 is methyl; or a pharmaceutically acceptable salt thereof.

[0050] In one embodiment, the compound of formula Ia is a compound of formula Ib, where: A is naphthyl, R1 is ethyl, R2 is halogen, Z1 is -NH(R4), and R4 is methyl; or a pharmaceutically acceptable salt thereof.

[0051] In one embodiment, the compound of formula Ia is a compound of formula Ib, where: A is benzothienyl, R1 is C1-C4 alkyl, C3-C5 branched alkyl or C3-C5 carbocyclyl, R2 is hydrogen, methyl or halogen and Z1 is -NH(R4) or -NHCOR8; or a pharmaceutically acceptable salt thereof.

[0052] In one embodiment, the compound of formula Ia is a compound of formula Ib, where: A is benzothienyl, R1 is C1-C4 alkyl, R2 is methyl or halogen, and Z1 is -NH(R4) or - NHCOR8; or a pharmaceutically acceptable salt thereof.

[0053] In one embodiment, the compound of formula Ia is a compound of formula Ib wherein: A is benzothienyl, R1 is ethyl, R2 is methyl or halogen, and Z1 is -NH(R4) or -NHCOR8; or a pharmaceutically acceptable salt thereof.

[0054] In one embodiment, the compound of formula Ia is a compound of formula Ib, where: A is benzothienyl, R1 is ethyl, R2 is methyl or halogen, Z1 is -NH(R4), and R4 is methyl ; or a pharmaceutically acceptable salt thereof.

[0055] In one embodiment, the compound of formula Ia is a compound of formula Ib, where: A is benzothienyl, R1 is ethyl, R2 is methyl, Z1 is -NH(R4), and R4 is methyl; or a pharmaceutically acceptable salt thereof.

[0056] In one embodiment, the compound of formula Ia is a compound of formula Ib, where: A is benzothienyl, R1 is ethyl, R2 is halogen, Z1 is -NH(R4), and R4 is methyl; or a pharmaceutically acceptable salt thereof.

[0057] In some embodiments, the present invention provides a method of treating a disease caused by c-KIT kinase, including gastrointestinal stromal tumors, ovarian cancer, melanoma, cervical carcinomas, acute myeloid leukemia, germ cell tumors, seminomas or dysgerminomas, teratomas, mastocytosis or mast cell leukemia, the method comprising administering to the patient a therapeutically effective amount of a compound selected from 1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridine -3-yl)-2-fluoro-4-methylphenyl)-3-(naphthalene-1-yl)urea, 1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2- dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-(naphthalene-1-yl)urea, 1-(4-chloro-5-(1-ethyl-7-(methylamino)-2 -oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea, 1-(4-chloro-5-(1-ethyl-7-(methylamino)-2 -oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-(2,3-difluorophenyl)urea, 1-(2-fluoro-5-(1-isopropyl- 7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)phenyl)-3-phenylurea, 1-(4-chloro-5-(1-ethyl-7-( methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-(naphthalene-1-yl)urea, 1-(4-chloro-2-fluorine) -5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)phenyl)-3-phenylurea, 1-(4-chloro-2- fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)phenyl)-3-(naphthalene-1-yl)urea, 1 -(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)phenyl)-3-(3 -cyanophenyl)urea, 1-(4-chloro-2-fluoro-5-(1-metal-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)phenyl )-3-(2,3-difluorophenyl)urea, 1-(4-chloro-3-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridine-3 -yl)phenyl)-3-(3-cyanophenyl)urea, 1-(3-cyanophenyl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1 ,6-naphthyridin-3-yl)-2-fluorophenyl)urea, 1-(benzo[b]thiophen-3-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7- (methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)phenyl)urea, 1-(benzo[b]thiophen-3-yl)-3-(2,4-difluoro -5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)phenyl)urea, 1-(5-(1-ethyl-7- (methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2,4-difluorophenyl)-3-(3-fluorophenyl)urea, 1-(5-(1-ethyl -7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2,4-difluorophenyl)-3-phenylurea, 1-(3-chlorophenyl)-3-( 5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2,4-difluorophenyl)urea, 1-(3-cyanophenyl)- 3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2,4-difluorophenyl)urea, 1-(benzo[ b]thiophen-3-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2,4- difluorophenyl)urea, 1-(5-(7-amino-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-4-chloro-2-fluorophenyl)-3- (3-fluorophenyl)urea, 1-(5-(7-amino-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-4-chloro-2-fluorophenyl) -3-phenylurea, 1-(4-chloro-2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)phenyl )-3-phenylurea, 1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoro-4-methylphenyl )-3-phenylurea, 1-[4-chloro-5-(1-ethyl-7-methylamino-2-oxo-1,2-dihydro[1,6]naphthyridin-3-yl)-2-fluorophenyl]- 3-(3-fluorophenyl)urea, 1-[4-chloro-5-(1-ethyl-7-methylamino-2-oxo-1,2-dihydro[1,6]naphthyridin-3-yl)-2- fluorophenyl]-3-(2-fluorophenyl)urea, 1-(4-chloro-3-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridine-3- yl)-2-fluorophenyl)-3-phenylurea, 1-(4-chloro-5-(1-ethyl-7-(2-methoxyethylamino)-2-oxo-1,2-dihydro-1,6-naphthyridine- 3-yl)-2-fluorophenyl)-3-phenylurea, 1-(4-chloro-5-(1-ethyl-7-(2-methoxyethylamino)-2-oxo-1,2-dihydro-1,6- naphthyridin-3-yl)-2-fluorophenyl)-3-(3-fluorophenyl)urea, 1-(4-chloro-5-(7-(2-(dimethylamino)ethylamino)-1-ethyl-2-oxo- 1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea, 1-(4-chloro-5-(7-(3-(dimethylamino)propylamino)-1-ethyl -2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea, 1-(4-bromo-5-(1-ethyl-7-(methylamino) -2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea, 1-(benzo[b]thiophen-3-yl)-3-(4- chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2,4a,8a-tetrahydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)urea, 1-(4 -chloro-3-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)phenyl)-3-phenylurea, 1-(4-chloro- 5-(1-ethyl-7-(2-methoxystylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-(4-fluorophenyl)urea, 1-(4-chloro-5-(1-ethyl-7-(2-methoxyethylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3- (2-fluorophenyl)urea, 1-(5-(1-ethyl-7-(2-methoxyethylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2,4- difluorophenyl)-3-phenylurea, 1-(5-(1-ethyl-7-(2-methoxyethylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoro- 4-methylphenyl)-3-phenylurea, 1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoro- 4-methylphenyl)-3-(2-fluorophenyl)urea, 1-(4-chloro-5-(1-ethyl-7-(3-methoxypropylamino)-2-oxo-1,2-dihydro-1,6- naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea, 1-(2,4-difluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydro-1, 6-naphthyridin-3-yl)phenyl)-3-(3-fluorophenyl)urea, 1-(2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydro- 1,6-naphthyridin-3-yl)-4-methylphenyl)-3-(3-fluorophenyl)urea, 1-(4-chloro-5-(1-ethyl-2-oxo-7-(tetrahydro-2H- pyran-4-ylamino)-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea, (S)-1-(4-chloro-5-(1-ethyl) -7-(1-methoxypropan-2-ylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea, 1-(5-(1 -ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoro-4-methylphenyl)-3-(3-fluorophenyl)urea, 1- (5-(7-(cyclopropylamino)-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoro-4-methylphenyl)-3-(3-fluorophenyl )urea, 1-(4-chloro-5-(1-ethyl-7-(1-methylpiperidin-4-ylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)- 2-fluorophenyl)-3-phenylurea, 1-(4-chloro-5-(1-ethyl-2-oxo-7-(THF-3-ylamino)-1,2-dihydro-1,6-naphthyridine-3 -yl)-2-fluorophenyl)-3-phenylurea, 1-(4-chloro-5-(1-ethyl-7-(2-(methylsulfonyl)ethylamino)-2-oxo-1,2-dihydro-1, 6-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea, 1-(4-chloro-5-(1-ethyl-7-(1-methylpyrrolidin-3-ylamino)-2-oxo-1, 2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea, 1-(4-bromo-5-(1-ethyl-7-(methylamino)-2-oxo-1, 2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-(3-fluorophenyl)urea, 1-(4-bromo-5-(1-ethyl-7-(2-methoxyethylamino) -2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea, 1-(4-bromo-5-(1-ethyl-7-(2- (methylsulfonyl)ethylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea, 1-(5-(7-acetamido-1-ethyl- 2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-4-bromo-2-fluorophenyl)-3-phenylurea, 1-(5-(7-acetamido-1-ethyl-2- oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-4-chloro-2-fluorophenyl)-3-phenylurea, 1-(4-chloro-5-(1-ethyl-7-(methylamino )-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-(3,5-difluorophenyl)urea, 1-(4-bromo-2-fluoro- 5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)phenyl)-3-phenylurea, 1-(5-(7-amino- 1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-4-bromo-2-fluorophenyl)-3-phenylurea, 1-(5-(7-amino-1- ethyl 2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoro-4-methylphenyl)-3-(3-fluorophenyl)urea, 1-(benzo[b]thiophene- 3-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoro-4-methylphenyl) urea, 1-(3,5-difluorophenyl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2 -fluoro-4-methylphenyl)urea, 1-(2,5-difluorophenyl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridine -3-yl)-2-fluoro-4-methylphenyl)urea, 1-(2,5-difluorophenyl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2, 4a,8a-tetrahydro-1,6-naphthyridin-3-yl)-2,4-difluorophenyl)urea, 1-(3,5-difluorophenyl)-3-(5-(1-ethyl-7-(methylamino) -2-oxo-1,2,4a,8a-tetrahydro-1,6-naphthyridin-3-yl)-2,4-difluorophenyl)urea, N-(3-(2-bromo-4-fluoro-5- (3-phenylureido)phenyl)-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)-2-cyanoacetamide, N-(3-(2-chloro-4-fluoro -5-(3-phenylureido)phenyl)-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)-2-cyanoacetamide, 1-(5-(7-acetamido- 1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2,4-difluorophenyl)-3-phenylurea, N-(3-(2-chloro-5-(3 -(3,5-difluorophenyl)ureido)-4-fluorophenyl)-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)acetamide, 1-(4-chloro-5 -(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-(2,5-difluorophenyl)urea, 1 -(3-chloro-5-fluorophenyl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2- fluoro-4-methylphenyl)urea, 3-(3-(2-chloro-4-fluoro-5-(3-phenylureido)phenyl)-1-ethyl-2-oxo-1,2-dihydro-1,6- naphthyridin-7-yl)-1,1-dimethylurea, 1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridine-3 -yl)-2-fluorophenyl)-3-(3-chloro-5-fluorophenyl)urea, 1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2- dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-(3-fluoro-5-methylphenyl)urea, methyl ester (3-(2-chloro-4-fluoro-5-(3- phenylureido)phenyl)-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)carbamic acid, N-(3-(2-chloro-4-fluoro-5-(3 -phenylureido)phenyl)-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)-2-methoxyacetamide, 2-cyano-N-(3-(2,4-difluoro -5-(3-phenylureido)phenyl)-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)acetamide, 1-(4-cyano-5-(1-ethyl) -7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea, 1-(4-chloro-2-fluoro-5- (1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)phenyl)-3-(3-fluorophenyl)urea, N-(1-ethyl- 3-(4-fluoro-5-(3-(3-fluorophenyl)ureido)-2-methylphenyl)-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)acetamide, 1-( 4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-(3-(( 4-methylpiperazin-1-yl)methyl)phenyl)urea, N-(1-ethyl-3-(4-fluoro-2-methyl-5-(3-phenylureido)phenyl)-2-oxo-1,2- dihydro-1,6-naphthyridin-7-yl)acetamide, N-(3-(2-chloro-4-fluoro-5-(3-phenylureido)phenyl)-1-ethyl-2-oxo-1,2- dihydro-1,6-naphthyridin-7-yl)-3-hydroxyazetidin-1-carboxamide, 1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6 -naphthyridin-3-yl)-2-fluoro-4-methylphenyl)-3-(3-((4-methylpiperazin-1-yl)methyl)phenyl)urea, 1-(4-bromo-5-(1- ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-(3-((4-methylpiperazin-1-yl)methyl )phenyl)urea, (R)-N-(3-(2-chloro-4-fluoro-5-(3-phenylureido)phenyl)-1-ethyl-2-oxo-1,2-dihydro-1,6 -naphthyridin-7-yl)-3-(dimethylamino)pyrrolidine-1-carboxamide, (S)-N-(3-(2-chloro-4-fluoro-5-(3-phenylureido)phenyl)-1-ethyl -2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)pyrrolidin-2-carboxamide, N-(3-(2-chloro-4-fluoro-5-(3-phenylureido)phenyl) -1-isopropyl-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)acetamide, 1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo -1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-(4-fluoro-3-((4-methylpiperazin-1-yl)methyl)phenyl)urea, 1- (4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-(3-fluoro -5-((4-methylpiperazin-1-yl)methyl)phenyl)urea, 1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridine -3-yl)-2-fluoro-4-methylphenyl)-3-(4-fluoro-3-((4-methylpiperazin-1-yl)methyl)phenyl)urea, 1-(5-(1-ethyl- 7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2,4-difluorophenyl)-3-(4-fluoro-3-((4-methylpiperazine-1 -yl)methyl)phenyl)urea, 1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)- 2-fluorophenyl)-3-(3-cyanophenyl)urea, 1-(4-chloro-5-(1-ethyl-7-((3-morpholinopropyl)amino)-2-oxo-1,2-dihydro-1 ,6-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea, 1-(5-(7-amino-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3 -yl)-2-fluoro-4-methylphenyl)-3-(4-fluoro-3-((4-methylpiperazin-1-yl)methyl)phenyl)urea, 1-(4-chloro-5-(1- ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-(3-((dimethylamino)methyl)-4-fluorophenyl) urea, 1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3- (4-fluoro-3-(morpholinomethyl)phenyl)urea, (S)-N-(3-(2-chloro-4-fluoro-5-(3-phenylureido)phenyl)-1-ethyl-2-oxo- 1,2-dihydro-1,6-naphthyridin-7-yl)-3-(dimethylamino)pyrrolidine-1-carboxamide, 1-(4-chloro-5-(1-ethyl-7-(methylamino)-2- oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-(4-fluoro-3-(pyrrolidin-1-ylmethyl)phenyl)urea, 3-(3-( 2-chloro-4-fluoro-5-(3-(3-fluorophenyl)ureido)phenyl)-1-isopropyl-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)-1, 1-dimethylurea, N-(3-(2-chloro-4-fluoro-5-(3-(3-fluorophenyl)ureido)phenyl)-1-isopropyl-2-oxo-1,2-dihydro-1,6 -naphthyridin-7-yl)acetamide, N-(1-ethyl-3-(4-fluoro-5-(3-(4-fluoro-3-((4-methylpiperazin-1-yl)methyl)phenyl)ureido )-2-methylphenyl)-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)formamide, 3-(1-ethyl-3-(4-fluoro-2-methyl-5-( 3-phenylureido)phenyl)-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)-1,1-dimethylurea, N-(3-(2-chloro-4-fluoro-5- (3-phenylureido)phenyl)-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)-3-(dimethylamino)azetidine-1-carboxamide, 3-(3-( 2-chloro-4-fluoro-5-(3-phenylureido)phenyl)-1-isopropyl-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)-1,1-dimethylurea, 3 -(3-(5-(3-(benzo[b]thiophen-3-yl)ureido)-4-fluoro-2-methylphenyl)-1-ethyl-2-oxo-1,2-dihydro-1,6 -naphthyridin-7-yl)-1,1-dimethylurea, 3-(3-(2-bromo-4-fluoro-5-(3-phenylureido)phenyl)-1-ethyl-2-oxo-1,2- dihydro-1,6-naphthyridin-7-yl)-1,1-dimethylurea, 3-(1-ethyl-3-(4-fluoro-5-(3-(3-fluorophenyl)ureido)-2-methylphenyl) -2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)-1,1-dimethylurea, N-(3-(2-chloro-4-fluoro-5-(3-(4- fluoro-3-(morpholinomethyl)phenyl)ureido)phenyl)-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)formamide, 3-(3-(5-(3 -(3,5-difluorophenyl)ureido)-4-fluoro-2-methylphenyl)-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)-1,1-dimethylurea , N-(3-(4-fluoro-2-methyl-5-(3-phenylureido)phenyl)-1-isopropyl-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)azetidine -1-carboxamide, N-(1-ethyl-3-(4-fluoro-2-methyl-5-(3-phenylureido)phenyl)-2-oxo-1,2-dihydro-1,6-naphthyridine-7 -yl)azetidin-1-carboxamide, 1-(5-(1-ethyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridin- 3-yl)-2-fluoro-4-methylphenyl)-3-phenylurea, 3-(3-(2,4-difluoro-5-(3-phenylureido)phenyl)-1-ethyl-2-oxo-1, 2-dihydro-1,6-naphthyridin-7-yl)-1,1-dimethylurea, 3-(dimethylamino)-N-(1-ethyl-3-(4-fluoro-2-methyl-5-(3- phenylureido)phenyl)-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)azetidin-1-carboxamide, 1-(5-(1-ethyl-7-(methylamino)-2-oxo -1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoro-4-iodophenyl)-3-phenylurea and 1-(5-(1-ethyl-7-((1-methyl-1H -pyrazol-4-yl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoro-4-methylphenyl)-3-phenylurea; or a pharmaceutically acceptable salt thereof.

[0058] In some embodiments, the present invention includes a compound selected from the group consisting of 1-(4-chloro-3-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydro-1, 6-naphthyridin-3-yl)phenyl)-3-(cyanophenyl)urea, 1-(3-cyanophenyl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2- dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)urea, 1-(benzo[b]thiophen-3-yl)-3-(2-fluoro-4-methyl-5-(1-methyl -7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)phenyl)urea, 1-(benzo[b]thiophen-3-yl)-3-(2, 4-difluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)phenyl)urea, 1-(5-(1-ethyl -7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2,4-difluorophenyl)-3-(3-fluorophenyl)urea, 1-(5-( 1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2,4-difluorophenyl)-3-phenylurea, 1-(3-chlorophenyl)- 3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2,4-difluorophenyl)urea, 1-(3- cyanophenyl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2,4-difluorophenyl)urea, 1- (benzo[b]thiophen-3-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2 ,4-difluorophenyl)urea, 1-(5-(7-amino-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-4-chloro-2-fluorophenyl) -3-(3-fluorophenyl)urea, 1-(5-(7-amino-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-4-chloro-2 -fluorophenyl)-3-phenylurea, 1-(4-chloro-2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridine-3- yl)phenyl)-3-phenylurea, 1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoro- 4-methylphenyl)-3-phenylurea, 1-[4-chloro-5-(1-ethyl-7-methylamino-2-oxo-1,2-dihydro[1,6]naphthyridin-3-yl)-2- fluorophenyl]-3-(3-fluorophenyl)urea, 1-[4-chloro-5-(1-ethyl-7-methylamino-2-oxo-1,2-dihydro[1,6]naphthyridin-3-yl) -2-fluorophenyl]-3-(2-fluorophenyl)urea, 1-(4-chloro-3-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridine -3-yl)-2-fluorophenyl)-3-phenylurea, 1-(4-chloro-5-(1-ethyl-7-(2-methoxyethylamino)-2-oxo-1,2-dihydro-1,6 -naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea, 1-(4-chloro-5-(1-ethyl-7-(2-methoxyethylamino)-2-oxo-1,2-dihydro-1 ,6-naphthyridin-3-yl)-2-fluorophenyl)-3-(3-fluorophenyl)urea, 1-(4-chloro-5-(7-(2-(dimethylamino)ethylamino)-1-ethyl-2 -oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea, 1-(4-chloro-5-(7-(3-(dimethylamino)propylamino)- 1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea, 1-(4-bromo-5-(1-ethyl-7- (methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea, 1-(benzo[b]thiophen-3-yl)-3- (4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2,4a,8a-tetrahydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)urea, 1 -(4-chloro-3-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)phenyl)-3-phenylurea, 1-(4 -chloro-5-(1-ethyl-7-(2-methoxyethylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-(4-fluorophenyl )urea, 1-(4-chloro-5-(1-ethyl-7-(2-methoxyethylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl) -3-(2-fluorophenyl)urea, 1-(5-(1-ethyl-7-(2-methoxyethylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2 ,4-difluorophenyl)-3-phenylurea, 1-(5-(1-ethyl-7-(2-methoxyethylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2 -fluoro-4-methylphenyl)-3-phenylurea, 1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2 -fluoro-4-methylphenyl)-3-(2-fluorophenyl)urea, 1-(4-chloro-5-(1-ethyl-7-(3-methoxypropylamino)-2-oxo-1,2-dihydro-1 ,6-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea, 1-(2,4-difluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydro -1,6-naphthyridin-3-yl)phenyl)-3-(3-fluorophenyl)urea, 1-(2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2 -dihydro-1,6-naphthyridin-3-yl)-4-methylphenyl)-3-(3-fluorophenyl)urea, 1-(4-chloro-5-(1-ethyl-2-oxo-7-(tetrahydro -2H-pyran-4-ylamino)-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea, (S)-1-(4-chloro-5-( 1-ethyl-7-(1-methoxypyran-2-ylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea, 1-(5 -(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoro-4-methylphenyl)-3-(3-fluorophenyl)urea , 1-(5-(7-(cyclopropylamino)-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoro-4-methylphenyl)-3-( 3-fluorophenyl)urea, 1-(4-chloro-5-(1-ethyl-7-(1-methylpiperidin-4-ylamino)-2-oxo-1,2-dihydro-1,6-naphthyridine-3- yl)-2-fluorophenyl)-3-phenylurea, 1-(4-chloro-5-(1-ethyl-2-oxo-7-(THF-3-ylamino)-1,2-dihydro-1,6- naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea, 1-(4-chloro-5-(1-ethyl-7-(2-(methylsulfonyl)ethylamino)-2-oxo-1,2-dihydro -1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea, 1-(4-chloro-5-(1-ethyl-7-(1-methylpyrrolidin-3-ylamino)-2-oxo -1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea, 1-(4-bromo-5-(1-ethyl-7-(methylamino)-2-oxo -1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-(3-fluorophenyl)urea, 1-(4-bromo-5-(1-ethyl-7-(2 -methoxyethylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea, 1-(4-bromo-5-(1-ethyl-7- (2-(methylsulfonyl)ethylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea, 1-(5-(7-acetamido-1 -ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-4-bromo-2-fluorophenyl)-3-phenylurea, 1-(5-(7-acetamido-1-ethyl -2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-4-chloro-2-fluorophenyl)-3-phenylurea, 1-(4-chloro-5-(1-ethyl-7 -(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-(3,5-difluorophenyl)urea, 1-(4-bromo-2 -fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)phenyl)-3-phenylurea, 1-(5-(7 -amino-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-4-bromo-2-fluorophenyl)-3-phenylurea, 1-(5-(7-amino -1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoro-4-methylphenyl)-3-(3-fluorophenyl)urea, 1-(benzo[b ]thiophen-3-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoro-4 -methylphenyl)urea, 1-(3,5-difluorophenyl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl )-2-fluoro-4-methylphenyl)urea, 1-(2,5-difluorophenyl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1, 6-naphthyridin-3-yl)-2-fluoro-4-methylphenyl)urea, 1-(2,5-difluorophenyl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1 ,2,4a,8a-tetrahydro-1,6-naphthyridin-3-yl)-2,4-difluorophenyl)urea, 1-(3,5-difluorophenyl)-3-(5-(1-ethyl-7- (methylamino)-2-oxo-1,2,4a,8a-tetrahydro-1,6-naphthyridin-3-yl)-2,4-difluorophenyl)urea, N-(3-(2-bromo-4-fluoro -5-(3-phenylureido)phenyl)-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)-2-cyanoacetamide, N-(3-(2-chloro- 4-fluoro-5-(3-phenylureido)phenyl)-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)-2-cyanoacetamide, 1-(5-(7 -acetamido-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2,4-difluorophenyl)-3-phenylurea, N-(3-(2-chloro-5 -(3-(3,5-difluorophenyl)ureido)-4-fluorophenyl)-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)acetamide, 1-(4- chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-(2,5-difluorophenyl) urea, 1-(3-chloro-5-fluorophenyl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl) -2-fluoro-4-methylphenyl)urea, 3-(3-(2-chloro-4-fluoro-5-(3-phenylureido)phenyl)-1-ethyl-2-oxo-1,2-dihydro-1 ,6-naphthyridin-7-yl)-1,1-dimethylurea, 1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6- naphthyridin-3-yl)-2-fluorophenyl)-3-(3-chloro-5-fluorophenyl)urea, 1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1 ,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-(3-fluoro-5-methylphenyl)urea, methyl ester (3-(2-chloro-4-fluoro-5- (3-phenylureido)phenyl)-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)carbamic acid, N-(3-(2-chloro-4-fluoro-5 -(3-phenylureido)phenyl)-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)-2-methoxyacetamide, 2-cyano-N-(3-(2, 4-difluoro-5-(3-phenylureido)phenyl)-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)acetamide, 1-(4-cyano-5-( 1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea, 1-(4-chloro-2-fluoro) -5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)phenyl)-3-(3-fluorophenyl)urea, N-(1 -ethyl-3-(4-fluoro-5-(3-(3-fluorophenyl)ureido)-2-methylphenyl)-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)acetamide, 1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-(3 -((4-methylpiperazin-1-yl)methyl)phenyl)urea, N-(1-ethyl-3-(4-fluoro-2-methyl-5-(3-phenylureido)phenyl)-2-oxo-1 ,2-dihydro-1,6-naphthyridin-7-yl)acetamide, N-(3-(2-chloro-4-fluoro-5-(3-phenylureido)phenyl)-1-ethyl-2-oxo-1 ,2-dihydro-1,6-naphthyridin-7-yl)-3-hydroxyazetidin-1-carboxamide, 1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro- 1,6-naphthyridin-3-yl)-2-fluoro-4-methylphenyl)-3-(3-((4-methylpiperazin-1-yl)methyl)phenyl)urea, 1-(4-bromo-5- (1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-(3-((4-methylpiperazine-1- yl)methyl)phenyl)urea, (R)-N-(3-(2-chloro-4-fluoro-5-(3-phenylureido)phenyl)-1-ethyl-2-oxo-1,2-dihydro- 1,6-naphthyridin-7-yl)-3-(dimethylamino)pyrrolidine-1-carboxamide, (S)-N-(3-(2-chloro-4-fluoro-5-(3-phenylureido)phenyl)- 1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)pyrrolidin-2-carboxamide, N-(3-(2-chloro-4-fluoro-5-(3-phenylureido )phenyl)-1-isopropyl-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)acetamide, 1-(4-chloro-5-(1-ethyl-7-(methylamino)- 2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-(4-fluoro-3-((4-methylpiperazin-1-yl)methyl)phenyl)urea , 1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-( 3-fluoro-5-((4-methylpiperazin-1-yl)methyl)phenyl)urea, 1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1, 6-naphthyridin-3-yl)-2-fluoro-4-methylphenyl)-3-(4-fluoro-3-((4-methylpiperazin-1-yl)methyl)phenyl)urea, 1-(5-(1 -ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2,4-difluorophenyl)-3-(4-fluoro-3-((4- methylpiperazin-1-yl)methyl)phenyl)urea, 1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridine-3- yl)-2-fluorophenyl)-3-(3-cyanophenyl)urea, 1-(4-chloro-5-(1-ethyl-7-((3-morpholinopropyl)amino)-2-oxo-1,2- dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea, 1-(5-(7-amino-1-ethyl-2-oxo-1,2-dihydro-1,6- naphthyridin-3-yl)-2-fluoro-4-methylphenyl)-3-(4-fluoro-3-((4-methylpiperazin-1-yl)methyl)phenyl)urea, 1-(4-chloro-5- (1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-(3-((dimethylamino)methyl)-4 -fluorophenyl)urea, 1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl) -3-(4-fluoro-3-(morpholinomethyl)phenyl)urea, (S)-N-(3-(2-chloro-4-fluoro-5-(3-phenylureido)phenyl)-1-ethyl-2 -oxo-1,2-dihydro-1,6-naphthyridin-7-yl)-3-(dimethylamino)pyrrolidine-1-carboxamide, 1-(4-chloro-5-(1-ethyl-7-(methylamino) -2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-(4-fluoro-3-(pyrrolidin-1-ylmethyl)phenyl)urea, 3-( 3-(2-chloro-4-fluoro-5-(3-(3-fluorophenyl)ureido)phenyl)-1-isopropyl-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl) -1,1-dimethylurea, N-(3-(2-chloro-4-fluoro-5-(3-(3-fluorophenyl)ureido)phenyl)-1-isopropyl-2-oxo-1,2-dihydro- 1,6-naphthyridin-7-yl)acetamide, N-(1-ethyl-3-(4-fluoro-5-(3-(4-fluoro-3-((4-methylpiperazin-1-yl)methyl) phenyl)ureido)-2-methylphenyl)-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)formamide, 3-(1-ethyl-3-(4-fluoro-2-methyl- 5-(3-phenylureido)phenyl)-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)-1,1-dimethylurea, N-(3-(2-chloro-4-fluoro -5-(3-phenylureido)phenyl)-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)-3-(dimethylamino)azetidine-1-carboxamide, 3-( 3-(2-chloro-4-fluoro-5-(3-phenylureido)phenyl)-1-isopropyl-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)-1,1- dimethylurea, 3-(3-(5-(3-(benzo[b]thiophen-3-yl)ureido)-4-fluoro-2-methylphenyl)-1-ethyl-2-oxo-1,2-dihydro- 1,6-naphthyridin-7-yl)-1,1-dimethylurea, 3-(3-(2-bromo-4-fluoro-5-(3-phenylureido)phenyl)-1-ethyl-2-oxo-1 ,2-dihydro-1,6-naphthyridin-7-yl)-1,1-dimethylurea, 3-(1-ethyl-3-(4-fluoro-5-(3-(3-fluorophenyl)ureido)-2 -methylphenyl)-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)-1,1-dimethylurea, N-(3-(2-chloro-4-fluoro-5-(3- (4-fluoro-3-(morpholinomethyl)phenyl)ureido)phenyl)-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)formamide, 3-(3-(5 -(3-(3,5-difluorophenyl)ureido)-4-fluoro-2-methylphenyl)-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)-1, 1-dimethylurea, N-(3-(4-fluoro-2-methyl-5-(3-phenylureido)phenyl)-1-isopropyl-2-oxo-1,2-dihydro-1,6-naphthyridine-7- yl)azetidine-1-carboxamide, N-(1-ethyl-3-(4-fluoro-2-methyl-5-(3-phenylureido)phenyl)-2-oxo-1,2-dihydro-1,6- naphthyridin-7-yl)azetidin-1-carboxamide, 1-(5-(1-ethyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,2-dihydro-1,6 -naphthyridin-3-yl)-2-fluoro-4-methylphenyl)-3-phenylurea, 3-(3-(2,4-difluoro-5-(3-phenylureido)phenyl)-1-ethyl-2-oxo -1,2-dihydro-1,6-naphthyridin-7-yl)-1,1-dimethylurea, 3-(dimethylamino)-N-(1-ethyl-3-(4-fluoro-2-methyl-5- (3-phenylureido)phenyl)-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)azetidin-1-carboxamide, 1-(5-(1-ethyl-7-(methylamino)- 2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoro-4-iodophenyl)-3-phenylurea and 1-(5-(1-ethyl-7-((1- methyl-1H-pyrazol-4-yl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoro-4-methylphenyl)-3-phenylurea; or a pharmaceutically acceptable salt thereof.

[0059] For convenience, certain terms used in the description, examples, and claims are set forth below. Unless otherwise defined, all technical and scientific terms used in this specification have the meanings commonly understood by those skilled in the art to which the present invention belongs. The original definition given for a group or term proposed herein applies to that group or term used alone or as part of the description of another group herein, unless otherwise indicated.

[0060] The compounds of the present invention include any and all of their possible isomers, stereoisomers, enantiomers, diastereomers, tautomers, pharmaceutically acceptable salts and solvates, as well as crystalline polymorphic forms of the present compounds and any and all of their possible isomers, stereoisomers, enantiomers, diastereomers, tautomers, pharmaceutically acceptable salts and solvates. Thus, the terms "compound", "compounds", "test compound" or "test compounds" as used herein refer to the compounds of the present invention and to any and all possible isomers, stereoisomers, enantiomers, diastereomers, tautomers thereof , pharmaceutically acceptable salts, solvates and crystalline polymorphs.

Definitions

[0061] The term "alkyl" as used herein refers to linear alkyl, where the length of the alkyl chain is indicated by a numerical range. In exemplary embodiments, “alkyl” refers to an alkyl chain, as defined above, containing 1, 2, 3, 4, 5, or 6 carbon atoms (ie, C1-C6 alkyl). Examples of alkyls include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl and hexyl.

[0062] The term “branched alkyl” as used herein refers to an alkyl chain where chain branching is present and the total number of carbon atoms in the chain is indicated as a numerical range. In exemplary embodiments, “branched alkyl” refers to an alkyl chain, as defined above, containing 3, 4, 5, 6, or 7 carbon atoms (ie, C3-C7 branched alkyl). Examples of branched alkyls include, but are not limited to, isopropyl, isobutyl, sec-butyl, t-butyl, 2-pentyl, 3-pentyl, 2-hexyl and 3-hexyl.

[0063] The term "alkoxy" as used herein refers to -O-(alkyl), where "alkyl" is as defined above.

[0064] The term "branched alkoxy" as used herein refers to -O-(branched alkyl), where "branched alkyl" is as defined above.

[0065] The term "alkylene" as used herein refers to an alkyl moiety sandwiched between two other atoms. In exemplary embodiments, “alkylene” refers to an alkyl moiety, as defined above, containing 1, 2, or 3 carbon atoms. Examples of alkylene groups include, but are not limited to, -CH ₂ -, -CH ₂ CH ₂ - and -CH ₂ CH ₂ CH ₂ -. In typical embodiments, the alkylene groups are branched.

[0066] The term "alkynyl" as used herein refers to a carbon chain containing one carbon-carbon triple bond. In exemplary embodiments, “alkynyl” refers to a carbon chain, as defined above, containing 2 or 3 carbon atoms (ie, C2-C3 alkynyl). Examples of alkynyl groups include, but are not limited to, ethyn and propyne.

[0067] The term "aryl" as used herein refers to a cyclic hydrocarbon where the ring is characterized by delocalized π electrons (aromaticity) distributed throughout the ring members, where the number of atoms in the ring is indicated as a numerical range. In exemplary embodiments, “aryl” refers to a cyclic hydrocarbon, such as described above, containing 6, 7, 8, 9 or 10 ring atoms (ie, C6-C10 aryl). Examples of aryl groups include, but are not limited to, benzene, naphthalene, tetralin, indene and indane.

[0068] The term “cycloalkyl” as used herein refers to a monocyclic saturated carbon ring, where the number of atoms in the ring is specified as a numerical range. In exemplary embodiments, “cycloalkyl” refers to a carbon ring, such as defined above, containing 3, 4, 5, 6, 7, or 8 ring atoms (ie, C3-C8 cycloalkyl). Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

[0069] The term “halogen” or “halo-” as used herein refers to fluorine, chlorine, bromine and iodine.

[0070] The term “heterocycle” or “heterocyclyl” as used herein refers to a cyclic hydrocarbon wherein at least one of the ring atoms is O, N or S, wherein the number of ring atoms is specified as a numerical range . Heterocyclyl moieties, as defined above, are linked to the moiety of the molecule through C or N atoms. For example, in some embodiments, the atom through which the heterocyclyl moiety is linked to the moiety of the molecule is the N atom of the heterocyclyl ring. In exemplary embodiments, “heterocyclyl” refers to a cyclic hydrocarbon, such as described above, containing 4, 5, or 6 ring atoms (ie, C4-C6 heterocyclyl). Examples of heterocyclic groups include, but are not limited to, aziridine, oxirane, thiirane, azetidine, oxetane, thietane, pyrrolidine, tetrahydrofuran, pyran, thiopyran, thiomorpholine, thiomorpholine S-oxide, thiomorpholine S-dioxide, oxazoline, tetrahydrothiophene, piperidine, tetrahydropyran, tian, imidazolidine, oxazolidine, thiazolidine, dioxolane, dithiolane, piperazine, oxazine, dithiane and dioxane.

[0071] The term “heteroaryl” as used herein refers to a cyclic hydrocarbon in which at least one of the ring atoms is O, N or S, where the ring is characterized by delocalized π electrons (aromaticity) distributed throughout members of the ring, with the number of atoms in the ring indicated as a numerical range. Heteroaryl moieties, as defined herein, are linked to the moiety of the molecule through C or N atoms. For example, in some embodiments, the atom through which the heteroaryl moiety is linked to the moiety of the molecule is the N atom of the heteroaryl ring. In exemplary embodiments, “heteroaryl” refers to a cyclic hydrocarbon, such as described above, containing 5 or 6 ring atoms (ie, C5-C6 heteroaryl). Examples of heteroaryl groups include, but are not limited to, pyrrole, furan, thiene, oxazole, thiazole, isoxazole, isothiazole, imidazole, pyrazole, oxadiazole, thiadiazole, triazole, tetrazole, pyridine, pyrimidine, pyrazine, pyridazine, and triazine.

[0072] The term "substituted" relative to a moiety, as used herein, refers to an additional substituent attached to the moiety at any suitable location on the moiety. Unless otherwise specified, moieties may be attached via carbon, nitrogen, oxygen, sulfur, or any other suitable atom.

[0073] The term “salts” as used herein includes pharmaceutically acceptable salts conventionally used for the preparation of alkali metal salts and free acids, as well as for the preparation of free base addition salts. The nature of the salt is not important as long as it is pharmaceutically acceptable. Suitable pharmaceutically acceptable acid addition salts can be prepared from an inorganic acid or an organic acid. Exemplary pharmaceutical salts are described in Stahl, R.N., Wermuth, C.G., Eds. Handbook of Pharmaceutical Salts: Properties, Selection and Use; Verlag Helvetica Chimica Acta/Wiley-VCH: Zurich, 2002, the contents of which are incorporated herein by reference in their entirety. Specific non-limiting examples of inorganic acids include hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric acids. Suitable organic acids include, without limitation, aliphatic, cycloaliphatic, aromatic, arylaliphatic and heterocyclyl-containing carboxylic acids and sulfonic acids, for example, formic, acetic, propanoic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, grape, aspartic, glutamic, benzoic, anthranilic, mesyl, stearic, salicylic, n-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic) acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, pantothenic acid, toluenesulfonic acid, 2-hydroxyethanesulfonic acid , sulfanilic acid, cyclohexylaminosulfonic acid, alginic, 3-hydroxybutyric, galactaric or galacturonic acids. Suitable pharmaceutically acceptable salts of the compounds containing free acid groups provided herein include, without limitation, metal salts and organic salts. Exemplary metal salts include, but are not limited to, the corresponding alkali metal (Group Ia), alkaline earth metal (Group IIa) and other physiologically acceptable metal salts. These salts can be obtained from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc. Typical organic salts can be prepared from primary amines, secondary amines, tertiary amines and quaternary ammonium salts, for example tromethamine, diethylamine, tetra-N-methylammonium, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N -methylglucamine) and procaine.

[0074] The terms “administer”, “injected” or “administration” as used herein refer to administering to a subject the compound itself or a pharmaceutically acceptable salt of the compound or composition.

[0075] The term "carrier" as used herein includes carriers, excipients and diluents and refers to a material, composition or carrier such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material involved in transfer or transportation pharmaceutical agent from one organ or part of the body to another organ or part of the body.

[0076] Unless otherwise indicated, the term “disorder” is used herein in the same sense as the terms disease, condition, or illness, and interchangeably with those terms.

[0077] The terms “effective amount” and “therapeutically effective amount” are used interchangeably herein and refer to an amount of a compound that, when administered to a subject, is capable of providing relief from a symptom of a disorder in the subject. The actual amount that contains an "effective amount" or a "therapeutically effective amount" may vary depending on a number of conditions, including, but not limited to, the particular disorder being treated, the severity of the disorder, the size and medical condition of the patient, and the route of administration. A skilled physician can easily determine the appropriate amount using methods known in the medical field.

[0078] The terms “isolated” and “purified” as used herein refer to a component that is separated from other components of the reaction mixture or natural source. In certain embodiments, the isolated component comprises at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or at least about 98% of the compound or pharmaceutically acceptable salt of the compound, by weight of the isolated component.

[0079] The phrase "pharmaceutically acceptable" as used herein refers to compounds, substances, compositions and/or dosage forms that, based on careful medical evaluation, are suitable for use in contact with human and animal tissues without causing excessive toxicity, irritation , allergic response or other problem or complication, and have an acceptable benefit/risk ratio.

[0080] As used herein, the terms “patient” or “subject” include, without limitation, a human or animal. Typical animals include, but are not limited to, mammals such as mouse, rat, guinea pig, dog, cat, horse, cow, pig, monkey, chimpanzee, baboon or rhesus macaque.

[0081] "Therapeutically effective amount" or "effective amount" means the dosage of a compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula I as provided, or a pharmaceutically acceptable salt thereof, required to inhibit c-KIT signaling in a patient with cancer and kill target cancer cells or slowing or stopping the progression of cancer in a patient. The exact dosage required to treat a patient and the duration of treatment is determined by the attending physician, taking into account the stage and severity of the disease, as well as the specific requirements and response of each patient and the specific compound administered. Although dosage is expressed as an amount administered per day, the dosage schedule can be adjusted to provide more optimal therapeutic benefit to the patient. In addition to daily administration, twice daily (BID) and three times daily (TID) administration may be suitable schedules. Administration of BID is preferred according to the present invention.

[0082] The terms “treating,” “treating,” and “cure” are intended to include the full range of methods for controlling a cancer from which a patient is suffering, such as administering an active compound to attenuate, slow, or reverse one or more symptoms and to delaying the progression of cancer, even if the cancer is not actually eliminated. Treatment may be a cure, amelioration, or at least partial amelioration of the disorder. The patient being treated is a mammal, in particular a human.

[0083] The term “hydrate” as used herein refers to a compound as provided herein that is associated with water in molecular form, i.e. with a water molecule in which the H-OH bond is not broken, and can be represented, for example, by the formula R⋅H ₂ O, where R represents the compound proposed in the present description. A given compound can form more than one hydrate, including, for example, monohydrates (R⋅H ₂ O), dihydrates (R⋅2H ₂ O), trihydrates (R⋅3H ₂ O), etc.

[0084] The term “solvate” as used herein refers to a compound as provided herein that is associated with a solvent in molecular form, i.e. wherein the solvent is linked through coordination bonds, and can be represented, for example, by the formula R⋅(solvent), where R represents a compound as provided herein. A given compound may form more than one solvate, including, for example, monosolvates (R⋅(solvent)) or polysolvates (R⋅n(solvent)), where n is an integer greater than 1), including, for example, disolvates (R⋅2 (solvent)), trisolvates (R⋅3(solvent)), etc., or hemisolvates such as, for example, R⋅n/2(solvent), R⋅n/3(solvent), R⋅n/ 4(solvent), etc., where n is an integer. Solvents herein include mixed solvents, such as methanol/water, and as such, solvates may include one or more solvents within the solvate.

[0085] The term "acid hydrate" as used herein refers to a complex that can be formed by the association of a compound having one or more basic moieties with at least one compound having one or more acidic moieties, or by association of a compound having one or more acidic moieties with at least one compound having one or more basic moieties, wherein said complex is further associated with water molecules to thereby produce a hydrate, wherein said hydrate is as defined above, and R is is the complex described above in this application.

[0086] Structural, chemical and stereochemical definitions are generally taken from the IUPAC recommendations, more specifically from the Glossary of Terms Used in Physical Organic Chemistry (IUPAC Recommendations 1994), summarized in , R. Pure Appl. Chem. 1994, 66, pp. 1077-1184, and basic stereochemistry terminology (IUPAC 1996 recommendations) summarized in Moss, GP Pure Appl. Chem. 1996, 68, pp. 2193-2222.

[0087] Atropoisomers are defined as a subclass of conformers that can be distinguished as individual chemical species that are formed as a result of limited rotation about a single bond.

[0088] Regioisomers or structural isomers are defined as isomers in which the same atoms have different arrangements.

[0089] Enantiomers are defined as one of a pair of molecular species that are mirror images of each other, but which cannot be combined with each other.

[0090] Diastereomers or diastereoisomers are defined as stereoisomers other than enantiomers. Diastereomers or diastereoisomers are stereoisomers that are not mirror images. Diastereoisomers are characterized by different physical properties and some differences in chemical behavior with respect to achiral as well as chiral reagents.

[0091] The term "tautomer" as used herein refers to compounds resulting from the phenomenon in which a proton from one atom of a molecule is shifted to another atom. See March, Advanced Organic Chemistry: Reactions, Mechanisms and Structures, 4th Ed., John Wiley & Sons, pp. 69-74 (1992). Tautomerism is defined as isomerism, which can be expressed by the general formula

where isomers (called tautomers) easily convert into each other; the atoms connecting the groups X, Y and Z are generally any atoms selected from C, H, O or S, and G is a group which is converted to an electrofuge or nucleofuge by isomerization. The most common case in which the electrofuge is H ⁺ is also known as "prototropy". Tautomers are defined as isomers resulting from tautomerism, regardless of whether said isomers can be isolated or not.

[0092] The compounds of the present invention are preferably formulated into a pharmaceutical composition using a pharmaceutically acceptable carrier and administered through a variety of routes. Preferably, said compositions are for oral administration. These pharmaceutical compositions and methods for their preparation are well known in the art. See, for example, REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY (A. Gennaro, et al., eds., ^19th ed., Mack Publishing Co., 1995). In a specific embodiment, the pharmaceutical composition contains 1-(3,3-dimethylbutyl)-3-{2-fluoro-4-methyl-5-[7-methyl-2-(methylamino)pyrido[2,3-d]pyrimidin- 6-yl]phenyl}urea or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier and optionally other therapeutic ingredients, particularly suitable for the treatment of cancer in general or a specific type of cancer.

[0093] The compounds of the present invention are capable of reacting with a variety of inorganic and organic acids to form pharmaceutically acceptable acid addition salts. These pharmaceutically acceptable salts and the traditional methodology for their preparation are well known in the art. See, for example, P. Stahl, et al., HANDBOOK OF PHARMACEUTICAL SALTS: PROPERTIES, SELECTION AND USE, (VCHA/Wiley-VCH, 2002); S.M. Berge, et al., "Pharmaceutical Salts," Journal of Pharmaceutical Sciences, Vol. 66, No. 1, January 1977.

[0094] Compounds of formula Ia or pharmaceutically acceptable salts thereof can be prepared using various methods known in the art, as well as those described below. Specific synthetic steps can be combined in various ways to produce compounds of formula Ia or pharmaceutically acceptable salts thereof.

[0095] The compounds useful as starting materials for the synthesis of compounds of formula Ia are well known and, if not commercially available, can be readily synthesized according to the specific references cited, using standard methods conventionally used by those skilled in the art. , or listed in general reference books.

[0096] Examples of known procedures and methods include those described in general references such as Comprehensive Organic Transformations, VCH Publishers Inc., 1989; Compendium of Organic Synthetic Methods, Volumes 1-10, 1974-2002, Wiley Interscience; Advanced Organic Chemistry, Reactions Mechanisms, and Structure, ^5th Edition, Michael B. Smith and Jerry March, Wiley Interscience, 2001; Advanced Organic Chemistry, ^4th Edition, Part B, Reactions and Synthesis, Francis A. Carey and Richard J. Sundberg, Kluwer Academic / Plenum Publishers, 2000, etc., as well as in the references given in these works.

[0097] ChemDraw version 10 or 12 (CambridgeSoft Corporation, Cambridge, MA) was used to generate structure names for intermediates and proposed compounds.

[0098] As used herein, the following abbreviations are used and are defined as follows: "ADP" is adenosine diphosphate, "AIBN" is azobisisobutyronitrile, "ATP" is adenosine triphosphate, "BippyPhos" is 5-(di-tert-butylphosphino )-1',3',5'-triphenyl-1'H-[1,4']bipyrazole, "BrettPhos Palladacycle" is chloro[2-(dicyclohexylphosphino)-3,6-dimethoxy-2'-4'-6'-triisopropyl-1,1'-biphenyl][2-(2-aminoethyl)phenyl] palladium (II), "conc." means concentrated, "DBU" is 1,8-diazabicyclo[5.4.0]undec-7-ene, "DCM" is dichloromethane, "DIEA" is N,N-diisopropylethylamine, "DMA" is N,N -dimethylacetamide, "DMAP" is (dimethylamino)pyridine, "DMF" is N,N-dimethylformamide, "DMSO" is dimethyl sulfoxide, "DPPA" is diphenylphosphoryl azide, "DTT" is dithiothreitol, "IER" is electron sputter ionization, "Et ₂ O" represents diethyl ether, "EtOAc" represents ethyl acetate, "EtOH" represents ethanol, "GST" represents glutathione S-transferase, "h" represents hour or hours, "hex ." represents hexane, "IC ₅₀ " represents the half-maximal inhibition concentration, "IPA" refers to isopropyl alcohol, "KF/Al ₂ O ₃ " represents potassium fluoride on alumina, "mCPBA" represents 3-chloroperbenzoic acid, "MeCN " represents acetonitrile, "MeOH" represents methanol, "MHz" represents megahertz, "min" represents minute or minutes, "MS" represents mass spectrometry, "MTBE" represents methyl tert-butyl ether, ""NADP" is nicotinamide adenine dinucleotide, "NBS" is N-bromosuccinimide, "NMP" is 1-methyl-2-pyrrolidinone, "NMR" is nuclear magnetic resonance, "PBS" is phosphate buffered saline, "Pd" is C" represents palladium on carbon, "Pd(OAc) ₂ " represents palladium (II) acetate, "Pd ₂ (dba) ₃ " represents tris(dibenzylideneacetone) dipalladium (0), "pet. ether" represents petroleum ether, "prep-HPLC" is preparative high performance liquid chromatography, "prep-TLC" is preparative thin layer chromatography, "RT" is room temperature, also called "ambient temperature", which is understood to include the range normal laboratory temperatures 15-25°C, “sat.” is saturated, "tert-butyl-X-Phos" is 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl, "TEA" is triethylamine, "TFA" is trifluoroacetic acid, ""THF" is tetrahydrofuran, "Tris" is tris(hydroxymethyl)aminomethane, "Xantphos" is 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, and "X-Phos" is 2-dicyclohexylphosphino-2 ',4',6'-triisopropylbiphenyl.

General chemical methods

[0099] Compounds of formula Ia (1) are prepared using the general synthetic methods illustrated in the schemes below and in the accompanying examples. Suitable reaction conditions for the steps indicated in the above schemes are well known in the art, and appropriate changes in solvents and auxiliary reagents are within the competence of those skilled in the art. Those skilled in the art will appreciate that synthetic intermediates can be isolated and/or purified by well-known methods as needed or desired, and various intermediates can be used directly in subsequent synthetic steps with little or no purification. In addition, those skilled in the art will appreciate that in some cases the order in which the fragments are introduced is not important. The specific order of steps required to prepare the compounds of formula 1 depends on the particular compound being synthesized, the starting compound, and the relative lability of the substituted moieties, as is also well understood by those skilled in the art. All substituents, unless otherwise noted, are as defined above.

[00100] Compounds of formula Ia (1) often contain -NH moieties at the Z1 position. Those skilled in the art will appreciate that in some cases, during synthesis, it may be effective to use an amino protecting group to temporarily mask one or more -NH moieties. The specified protecting group can be removed from any subsequent intermediate, resulting in compound 1, under standard conditions that promote the removal of the specified protective group, where these conditions are known to specialists in the art. Unless specifically indicated in the diagram, it will be appreciated by those skilled in the art that moiety Z1 shown in the diagrams below may optionally contain a standard NH protecting group, which can be removed at any appropriate time in any of the synthesis reaction sequences. For example, intermediates where Z1 is aminomethyl can be prepared directly by including methylamine in the synthesis scheme or alternatively by including a "protected" form of methylamine, such as 1-(4-methoxyphenyl)-N-methylmethanamine, to provide intermediates where Z1 is 1-(4-methoxyphenyl)-N-methylmethanamino. Even if not specifically depicted, the following schemes implicitly include the steps of deprotecting any protected Z1 moiety immediately after introduction or optionally at any subsequent synthesis step.

[00101] Scheme 1 illustrates general methods for preparing compounds of formula 1 from 7-chloronaphthyridinone 2. Conversion of chloride 2 to Z1-substituted intermediate 3 can be accomplished using a variety of methods known to those skilled in the art, the choice of which is dictated by the nature of the particular Z1. Additional conversion of intermediate 3 to ureas of formula 1 is carried out using one of three methods. In one embodiment, reacting 3 with isocyanates of formula 4 provides ureas of formula 1. Many isocyanates (4) are commercially available, and those that are not can be easily prepared from the corresponding amines (9) by reacting said amines with phosgene or its equivalent such as triphosgene or carbonyldiimidazole. Conditions for the conversion of 3 to 1 include treating 3 with 4 in an aprotic solvent such as DCM, THF or EtOAc, optionally in the presence of a base such as pyridine, and optionally by heating said mixtures. In a second embodiment, reacting 3 with carbamates of formula 5 also produces ureas of formula 1. Conditions for achieving the conversion of 3 to 1 include treating 3 with 5 in an aprotic solvent such as 1,4-dioxane, THF or DMSO in the presence of a base , for example, N-methylpyrrolidine, diisopropylethylamine or triethylamine, and heating the resulting mixture. Suitable carbamates (5) include isopropenyl, 2,2,2-trichloroethyl and phenyl (or substituted phenyl) carbamates. Said carbamates 5 can be easily prepared by reacting amines 9 with the corresponding chloroformate, as is known to those skilled in the art. In a third embodiment, carboxylic acids of formula 5 can undergo a Curtius rearrangement in the presence of amine 3 to provide ureas of formula 1. Conditions for carrying out this transformation include combining amine 3, carboxylic acid 5 and diphenylphosphoryl azide (DPPA) and a base, such as triethylamine, and heating said mixture in an aprotic solvent such as 1,4-dioxane, at a temperature in the range of 50-120°C to effect rearrangement.

[00102] In addition to these methods, compound 3 can also be converted to 1 using a two-step method by first converting 3 to carbamate 8 and then reacting carbamate 8 with amine 9. As above, carbamates (8) include isopropenyl-, 2,2 ,2-trichloroethyl and phenyl (or substituted phenyl) carbamates. Said carbamates 8 can be easily prepared by reacting the amine 3 with the corresponding chloroformate 11 (eg R=2-propenyl, 2,2,2-trichloroethyl or phenyl). In one embodiment, reacting amine 3 with isopropenyl chloroformate and sodium bicarbonate in a mixed solvent containing EtOAc and water provides carbamate 8 (R=2-propenyl). Further treatment of carbamate 8 using amine 9 in an aprotic solvent such as 1,4-dioxane, THF or DMSO in the presence of a base such as N-methylpyrrolidine, diisopropylethylamine or triethylamine and heating the resulting mixture is provided by compounds of formula 1.

[00103] Similar to the conversion of 3 to 1 or 3 to 8, 7-chloronaphthyridinone 2 can also be converted to urea 7 or carbamate 10, respectively. Urea 7 is then further converted to urea 1 by reacting 7 with the appropriate amine, amide, urea or carbamic acid Z1 in the presence of a palladium catalyst (Buchwald coupling), as further illustrated below.

[00104] Scheme 2 illustrates an example of the preparation of compounds of formula 15, compounds of formula 1, where Z1 is -NHR4. In one embodiment, 7-chloronaphthyridinone 2 is reacted with amine 12a (P=H) or 12b (P is a conventional amino protecting group such as 4-methoxybenzyl or t-butoxycarbonyl) to provide 13 or 14, respectively. Conditions for the conversion of 2 to 13 or 14 involve heating the amine of formula 12a or 12b with chloride 2, optionally in the presence of an additional base, for example DBU (1,8-diazabicyclo[5.4.0]undec-7-ene), and optionally using microwave radiation . If "P" represents a protecting group, then said group can be removed from compound 14 under suitable conditions known to those skilled in the art, for example by treatment with TFA if "P" is 4-methoxybenzyl, to provide 13. Using one of of the three methods described for Scheme 1, compound 13 or 14 can be converted to ureas 15 or 16, respectively. If "P" represents a protecting group, then said group can be removed from compound 16 under suitable conditions known to those skilled in the art to provide 15. Alternatively, as described in Scheme 1, amines 13 or 14 can be converted to carbamates 17 or 18. Additional reaction of these carbamates with amine 9 provides ureas 15 or 16. Finally, ureas 15 or 16 can also be prepared from chloride 7 (Scheme 1) by reaction with amine 12a or 12b in the presence of a suitable palladium catalyst, e.g. derived from Pd(OAc) ₂ or Pd ₂ ((dba) ₃ [tris(dibenzylideneacetone)dipalladium] and a ligand such as Xantphos [4,5-bis(diphenylphosphino)-9,9-dimethylxanthene] or BippyPhos [5-( di-tert-butylphosphino)-1',3',5'-triphenyl-1'H-[1,4']bipyrazole], in the presence of a base, for example K ₂ CO ₃ .

[00105] Scheme 3 illustrates an example of the preparation of 21, a compound of Formula 1 wherein Z1 is -N(R4)COR8. Using the methods described in Scheme 2, treatment of chlorides 2 or 7 with the appropriate carbonylamine 19 in the presence of a suitable palladium catalyst provides amides, ureas or carbamates (depending on the R8 moiety) of formula 20 or 21, respectively. Additional conversion of 20 to 21 is carried out as described above by treating 20 with 4, 5 or 6. Alternatively, 20 can be converted first to carbamate 22. As described above, additional treatment of 22 with amine 9 provides urea 21.

[00106] Scheme 4 illustrates alternative examples for the preparation of 21, 27 and 28 using intermediate 15 (Scheme 2) as a starting material. Treatment of 15 with carbonylation agent 23 under conditions known to those skilled in the art produces urea 21. The X moiety in 23 represents the leaving group as a whole. Examples of X-(CO)R8 in 23 include acid chlorides (X=Cl, R8 = alkyl) or anhydrides (X=O(CO)R8) and chloroformates (X=Cl, R8 = alkoxy). Those skilled in the art will appreciate that when R8 is -NHR4, isocyanates of the formula R4-NCO can be used in place of 23. Additionally, if R8 is an amine, the final ureas 27 and 28 can be prepared by reacting a suitable carbamate 24 with amine 25 or heterocyclic amine 26, respectively. Suitable carbamates include alkyl, isopropenyl, 2,2,2-trichloroethyl and phenyl (or substituted phenyl) carbamates. These carbamates 24 can be easily prepared by reacting the amine 15 with the corresponding chloroformate 11 (eg R=2-propenyl, 2,2,2-trichloroethyl or phenyl).

[00107] Scheme 5 illustrates a general example for the preparation of 7-chloronaphthyridinones 2. Treatment with 4,6-dichloronicotinic acid ethyl ester (29, see Example C3) using R1-NH ₂ 30 provides 4-aminopyridine 31. Conditions for this conversion include polar solvents such as DMF, THF, acetonitrile, dioxane, water or mixtures thereof, in the presence of optionally added bases such as triethylamine, at a temperature of from 0°C to 100°C. Reduction of 31, for example, by treatment with lithium aluminum hydride in THF at temperatures ranging from 0°C to room temperature provides alcohol 32. Oxidation of 32 using manganese dioxide provides aldehyde 33. Condensation of 33 with phenylacetate 34 provides common intermediate 2. Conditions for this transformation involve combining 33 and 34 in DMF or DMAc in the presence of potassium carbonate or cesium carbonate, optionally with heating (30-150°C) for a period of time ranging from 1 hour to 4 days. Alternative conditions include combining 33, 34 and potassium fluoride on an alumina support in DMAc with stirring and/or optionally using sonication and/or optionally heating (30-150°C) for a period of 10 minutes to 48 hours.

[00108] Scheme 6 illustrates a general example of the preparation of ester 34. Nitration of R2-substituted phenylacetic acid 35, for example by treatment with nitric acid and sulfuric acid, provides 36. Acid 36 is in turn converted to ethyl ester 37, for example by heating in EtOH in the presence of an acid such as sulfuric acid. Finally, reduction of the nitro group provides 34. Conditions suitable for this transformation include hydrogenation over a palladium or nickel catalyst or reduction using iron or zinc powder in the presence of a source of protons, for example, HCl in ethanol, acetic acid or ammonium formate. It will be appreciated by those skilled in the art that there are many alternative methods for preparing phenylacetic acid total ethyl ester 34. One additional method can be illustrated by the conversion of benzyl alcohol 38 to mesylate 39, homologation of mesylate 39 using cyanide to give benzonitrile 40 and conversion of nitrile 40 into ethyl ester 34 by treatment with EtOH and HCl. Alcohol 38 can be prepared by reduction of a suitable substituted benzoic acid or aldehyde, an exemplary method for the preparation of which is disclosed below (Example A45).

Examples

[00109] The invention is further illustrated by the following examples, which should not be construed as limiting the scope or spirit of the present invention to the specific methods described. It should be understood that the examples are provided to illustrate certain embodiments and are not intended to limit the scope of the invention. It should also be understood that various other embodiments, modifications and equivalents thereof may be made by those skilled in the art without departing from the spirit of the present invention and/or the scope of the appended claims.

[00110] General Method A: In a stirred solution of carboxylic acid (0.50 mmol, 1.00 eq.) and DPPA (0.75 mmol, 1.50 eq.) in 1,4-dioxane (5.0 ml) at RT, TEA (1.5 mmol, 3.00 eq) was added. After stirring for 30 minutes at RT, the appropriate amine (0.76 mmol, 1.50 eq.) was added and the mixture was heated to 100°C. After 2 hours, the reaction mixture was cooled to RT, diluted with brine and extracted with EtOAc (2×). The combined organic layers were washed with 3M HCl (1×), sat. NaHCO ₃ (2×) and brine (1×), dried (MgSO ₄ ), concentrated in vacuo to obtain the crude product, which was purified by flash column chromatography to obtain the target urea.

[00111] General Method B: Into a stirred suspension of isocyanate (0.51 mmol, 1.00 eq.) and pyridine (0.0418 mL, 0.51 mmol, 1.00 eq.) in DCM (5 mL) at RT the appropriate amine (0.51 mmol, 1.00 eq.) was added. Gradually a thick suspension formed. After 3.5 hours, the solids were collected by filtration, washed thoroughly with DCM and filter dried to obtain the target urea.

[00112] Example A1: Compound of Example A6 (1.61 g, 4.85 mmol), 4-methoxy-N-methylbenzylamine (1.10 g, 7.28 mmol) and DBU (1.09 ml, 7. 28 mmol) were mixed in NMP (20 ml) and heated at 180°C in an Ar atmosphere overnight. The mixture was cooled to RT, poured into H ₂ O (200 ml), the resulting solids were collected by filtration and washed thoroughly with H ₂ O. The solids were filter dried until wet, dissolved in EtOAc, dried (MgSO ₄ ) and evaporated to give 3-(5-amino-4-fluoro-2-methylphenyl)-1-ethyl-7-((4-methoxybenzyl)(methyl)amino)-1,6-naphthyridin-2(1H)-one (2.06 d) in the form of brittle brown foam with a small content of EtOAc and NMP impurities. It was used for the next interaction.

[00113] Example A2: Using a method similar to Example A8, the compound of Example A1 (2.06 g, 4.61 mmol) was converted to 3-(5-amino-4-fluoro-2-methylphenyl)- 1-ethyl-7-(methylamino)-1,6-naphthyridin-2(1H)-one (1.16 g, 73% yield in 2 steps). ^1H NMR (400 MHz, DMSO- _d6 ): δ 8.36 (s, 1H), 7.58 (s, 1H), 6.94-6.92 (m, 1H), 6.83 (d , J=12.0 Hz, 1H), 6.57 (d, J=9.6 Hz, 1H), 4.87 (lat.s, 2H), 4.12 (q, J=6.8 Hz , 2H), 2.84 (d, J=4.8 Hz, 3H), 1.94 (s, 3H), 1.19 (t, J=7.2 Hz, 3H); MS (ESI) m/z: 327.2 [M+H] ⁺ .

[00114] Example A3: A mixed suspension of the compound of Example B1 (3.5 g, 0.019 mol), the compound of Example C2 (4.4 g, 0.019 mol) and KF/Al ₂ O ₃ (10 g) in DMA was stirred at RT for 10 minutes, poured into water and extracted with EtOAc (3×). The combined organic phases were washed with brine, dried (Na ₂ SO ₄ ), concentrated in vacuo and purified by silica gel chromatography to give 3-(5-amino-2-chloro-4-fluorophenyl)-7-chloro-1-ethyl- 1,6-naphthyridin-2(1H)-one (4 g, 60% yield). ^1H NMR (400 MHz, DMSO- _d6 ): δ 8.75 (s, 1H), 8.01 (s, 1H), 7.72 (s, 1H), 7.24 (d, J=10 .8 Hz, 1H), 6.76 (d, J=9.2 Hz, 1H), 5.40 (s, 2H), 4.26-4.24 (m, 2H), 1.18 (t , J=6.8 Hz, 3H); MS (ESI) m/z: 352.1 [M+H] ⁺ .

[00115] Example A4: A mixture of the compound of Example A3 (3 g, 8.5 mmol) and 1-(4-methoxyphenyl)-N-methylmethanamine (20 ml) was placed in a sealed vessel, and then the mixture was heated at 200° C. in during the night. The volatiles were removed and the residue was purified by column chromatography to give 7-((4-methoxybenzyl)(methyl)amino)-3-(5-amino-2-chloro-4-fluorophenyl)-1-ethyl-1,6- naphthyridin-2(1H)-one (3 g, 73% yield). ^1H NMR (400 MHz, DMSO- _d6 ): δ 8.47 (s, 1H), 7.70 (s, 1H), 7.18-7.17 (m, 3H), 6.86 (d , J=8.4 Hz, 2H), 6.73 (d, J=9.6 Hz, 1H), 6.30 (s, 1H), 5.31 (s, 2H), 4.84 (s , 2H), 4.17 (q, J=7.1 Hz, 2H), 3.70 (s, 3H), 3.12 (s, 2H), 1.11 (t, J=7.0 Hz , 3H); MS (ESI) m/z: 467.2 [M+H] ⁺ .

[00116] Example A5: To a solution of the compound of Example A4 (3 g, 6.2 mmol) in DCM (100 ml) was added TFA (20 ml) at RT and the resulting mixture was stirred at RT for 6 hours. The mixture was extracted with water (2×) and the combined aqueous layers were neutralized with NH ₃ ⋅H ₂ O. The resulting precipitate was collected by filtration and dried to give 3-(5-amino-2-chloro-4-fluorophenyl)-1-ethyl-7- (methylamino)-1,6-naphthyridin-2(1H)-one (1 g, 44% yield). ^1H NMR (400 MHz, DMSO- _d6 ): δ 8.46 (s, 1H), 7.75 (s, 1H), 7.1 (d. J=11.2 Hz, 1H), 7. 0 (m, 1H), 6.73 (d, J=9.6 Hz, 1H), 6.43 (s, 1H), 4.95 (lat s, 2H), 4.14 (m, 2H ), 2.92 (s, 3H), 1.14 (t, J=6.8 Hz, 3H); MS (ESI) m/z: 347.2 [M+H] ⁺ .

[00117] Example A6: Compound of Example C1 (1.32 g, 6.25 mmol, 1.00 eq), Compound of Example B1 (1.15 g, 6.25 mmol, 1.00 eq) and KF/Al ₂ O ₃ (40.00 wt.%, 9.08 g, 62.5 mmol, 10.00 eq.) was mixed in DMA (35 ml) and sonicated for 2 hours. Solids were removed by filtration through diatomaceous earth and washed with EtOAc. The combined filtrates were washed with H ₂ O (3×) and the combined aqueous layers were re-extracted with EtOAc (1×). The combined organic layers were washed with brine (2×), dried (MgSO ₄ ), evaporated and purified by silica gel chromatography (EtOAc/hex) to give 3-(5-amino-4-fluoro-2-methylphenyl)-7- chloro-1-ethyl-1,6-naphthyridin-2(1H)-one (1.61 g, 78% yield) as a brittle foam. MS (ESI) m/z: 332.0 [M+H] ⁺ .

[00118] Example A7: A solution of the compound of Example A18 (22 g, 65.7 mmol), (4-methoxybenzyl)methylamine (14.9 g, 98.5 mmol) and DBU (15 g, 98.5 mmol) in NMP (120 ml) was heated at 160°C for 5 hours. The mixture was poured into 200 ml of water with stirring, the resulting solids were collected by filtration, washed with water, dried and then washed with Et ₂ O to obtain 3-(5-amino-2,4-difluorophenyl)-1-ethyl-7-[ (4-methoxybenzyl)methylamino]-1H-[1,6]naphthyridin-2-one (25 g, 85% yield). ^1H NMR (300 MHz, DMSO- _d6 ): δ 8.51 (s, 1H), 7.80 (s, 1H), 7.19-7.17 (d, J=8.7 Hz, 2H ), 7.06 (t, J=10.2 Hz, 1H). 6.90-6.81 (m, 3H), 6.32 (s, 1H), 5.02 (s, 2H), 4.86 (s, 2H), 4.19 (q, J=6, 9 Hz, 2H), 3.72 (s, 3H), 3.14 (s, 3H), 1.14 (t, J=6.9 Hz, 3H); MS (ESI): m/z 451.1 [M+H] ⁺ .

[00119] Example A8: TFA (3.64 g, 32.0 mmol) was added to the compound of Example A7 (0.48 g, 1.06 mmol) and the mixture was stirred for 90 minutes at RT. Water (50 ml) was added and the reaction mixture was carefully treated with solid Na ₂ CO ₃ until it became slightly alkaline. The product was extracted with EtOAc (3×), the combined organic layers were washed with water (1×), then brine and dried (Na ₂ SO ₄ ) to obtain the crude product, which was stirred with DCM (2 ml) for 2 hours. The resulting suspension was filtered, washed with DCM and dried to give 3-(5-amino-2,4-difluorophenyl)-1-ethyl-7-(methylamino)-1,6-naphthyridin-2(1H)-one as an off-white solid. substances (0.28 g, yield 60%). ^1H NMR (400 MHz, DMSO- _d6 ): δ 8.39 (s, 1H), 7.73 (s, 1H), 7.06-7.01 (m, 2H), 6.79 (dd , J=10.0, 7.6 Hz, 1H), 6.21 (s, 1H), 4.99 (s, 2H), 4.12 (q, J=7.2 Hz, 2H), 2 .84 (d, J=5.2 Hz, 3H), 1.19 (t, J=7.2 Hz, 3H); MC (IEP) m/z: 331.0 [M+H] ⁺ .

[00120] Example A9: A solution of the compound of Example A3 (1.90 g, 5.39 mmol), 4-methoxybenzylamine (1.110 g, 8.09 mmol) and DBU (1.232 g, 8.09 mmol) in NMP (15 ml) heated at 150°C overnight. After cooling to RT, the mixture was diluted with EtOAc (100 ml) and water (100 ml). The organic phase was washed with water, then with brine, dried (Na ₂ SO ₄ ), concentrated in vacuo and purified by reverse phase chromatography (MeCN/H ₂ O with 0.1% TFA) to obtain the TFA salt and 7-(4- methoxybenzylamino)-3-(5-amino-2-chloro-4-fluorophenyl)-1-ethyl-1,6-naphthyridin-2(1H)-one. Salt treated us. NaHCO ₃ (15 ml), left to settle, the resulting solid was collected by filtration, washed with water and dried in vacuo to give 7-(4-methoxybenzylamino)-3-(5-amino-2-chloro-4-fluorophenyl)-1 -ethyl-1,6-naphthyridin-2(1H)-one (901 mg, 36% yield). ^1H NMR (400 MHz, DMSO- _d6 ): δ 1.10 (t, 3H), 3.69 (s, 3H), 4.05-4.00 (m, 2H), 4.50-4 .45 (s, 2H), 5.30 (s, 2H), 6.28 (s, 1H), 6.71-6.69 (m, 1H), 6.87-6.85 (m, 2H ), 7.18-7.15 (m, 1H), 7.28-7.26 (m, 2H), 7.52 (s, 1H), 7.64 (s, 1H), 8.36 ( s, 1H); MS (IER-AD) m/z: 453.2 [M+H] ⁺ .

[00121] Example A10: Compound of Example B2 (0.701 g, 3.53 mmol), Compound of Example C2 (0.817 g, 3.53 mmol) and 40% KF on alumina (3.59 g, 24.7 mmol ) were combined in DMA (5 ml) and the mixture was sonicated for 2 hours. The mixture was diluted with EtOAc (10 ml), solids were removed by filtration through diatomaceous earth and washed with EtOAc. The filtrate was washed with water (2×) and brine, dried (Na ₂ SO ₄ ), concentrated in vacuo and purified by silica gel chromatography (EtOH/hex) to give 3-(5-amino-2-chloro-4-fluorophenyl )-7-chloro-1-isopropyl-1,6-naphthyridin-2(1H)-one (0.99 g, 77% yield) as a white foam. ^1H NMR (400 MHz, DMSO- _d6 ): δ 8.87 (s, 1H), 8.10 (s, 1H), 7.96 (s, 1H), 7.38 (d, J=11 ,2 Hz, 1H), 6.89 (d, J=9.2 Hz, 1H), 5.55 (s, 2H), 5.23 (lat s, 1H), 1.65 (d, J =6.4 Hz, 6H); MS (ESI) m/z: 366.0 [M+H] ⁺ .

[00122] Example A11: 4-(methoxyphenyl)-N-methylmethanamine (0.56 g, 3.75 mmol) and DBU (0.52 mL, 3.75 mmol) were added to a solution of the compound of Example A10 (0.98 g, 2.68 mmol) in NMP (10 ml) and the mixture was heated in an Ar atmosphere at 155°C for 24 hours. The mixture was cooled to RT, poured into water (50 ml) and extracted with EtOAc (2×). The combined organic layers were washed with brine, dried (Na ₂ SO ₄ ), concentrated in vacuo and purified by chromatography (EtOAc/DCM) to give 7-((4-methoxybenzyl)(methyl)amino)-3-(5-amino- 2-chloro-4-fluorophenyl)-1-isopropyl-1,6-naphthyridin-2(1H)-one (0.78 g, 60% yield) as a white foam. MS (ESI) m/z: 481.0 [M+H] ⁺ .

[00123] TFA (5.55 g, 48.7 mmol) was added to 7-((4-methoxybenzyl)(methyl)amino)-3-(5-amino-2-chloro-4-fluorophenyl)-1-isopropyl -1,6-naphthyridin-2(1H)-one (0.78 g, 1.62 mmol) and the reaction mixture was stirred for 90 minutes at RT. Water (50 ml) was added and the reaction mixture was carefully treated with solid Na ₂ CO ₃ until it became slightly alkaline. The solution was extracted with EtOAc (2×) and the combined organic layers were washed with brine, dried (Na ₂ SO ₄ ), concentrated in vacuo and purified by silica gel chromatography (MeOH/DCM) to give 3-(5-amino-2-chloro- 4-fluorophenyl)-1-isopropyl-7-(methylamino)-1,6-naphthyridin-2(1H)-one (0.42 g, 72% yield) as a white amorphous solid. ^1H NMR (400 MHz, DMSO- _d6 ): δ 8.34 (s, 1H), 7.60 (s, 1H), 7.17 (d, J=11.2 Hz, 1H), 6, 95 (q, J=4.8 Hz, 1H), 6.71 (d, J=9.6 Hz, 1H), 6.41 (s, 1H), 5.30 (s, 2H), 5, 08 (lat s, 1H), 2.84 (d, J=4.8 Hz, 3H), 1.49 (d, J=6.8 Hz, 6H); MS (ESI) m/z: 361.0 [M+H] ⁺ .

[00124] Example A12: A suspension of the compound of Example A3 (1.50 g, 4.26 mmol) in 2-methoxyethylamine (3 mL, 34.51 mmol) was heated at 120° C. for 12 hours. The reaction mixture was diluted with water and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried (Na ₂ SO ₄ ) and concentrated to give 3-(5-amino-2-chloro-4-fluorophenyl)-1-ethyl-7-(2-methoxyethylamino)-1,6- naphthyridin-2(1H)-one (1.56 g, 94% yield) as a white solid. ^1H NMR (400 MHz, DMSO- _d6 ): δ 8.36 (s, 1H), 7.65 (s, 1H), 7.18 (d, J=11 Hz, 1H), 7.03 ( m, 1H), 6.72 (d, J=9.5 Hz, 1H), 6.38 (s, 1H), 5.30 (s, 2H), 4.07 (m, 2H), 3, 47 (m, 4H), 3.25 (s, 3H), 1.20 (s, 3H); MS (ESI) m/z: 391.1 [M+H] ⁺ .

[00125] Example A13: A mixture of Example C5 (2.191 g, 7.94 mmol), Example B1 (1.538 g, 8.33 mmol) and KF on alumina (40 wt%) (9.22 g , 63.5 mmol) in DMA (40 ml) was treated with ultrasound for 2 hours. The mixture was filtered through a thin pad of silica gel and washed thoroughly with EtOAc. The filtrate was washed out for us. NaHCO ₃ (1×), 5% LiCl (2×), then brine (1×), dried (MgSO ₄ ) and concentrated to dryness to give 3-(5-amino-2-bromo-4-fluorophenyl)-7 -chloro-1-ethyl-1,6-naphthyridin-2(1H)-one (2.793 g, 89% yield) as a brown solid. ^1H NMR (400 MHz, DMSO- _d6 ): δ 8.77 (s, 1H), 8.00 (s, 1H), 7.74 (s, 1H), 7.37 (d, 1H), 6.77 (d, 1H), 5.45 (s, 2H), 4.27 (q, 2H), 1.20 (t, 3H); MS (ESI) m/z: 398.0 [M+H] ⁺ .

[00126] Example A14: A suspension of the compound of Example A13 (1.50 g, 3.78 mmol) in dioxane (15 ml) was treated with methylamine (40% in water) (26.4 ml, 303 mmol) in a test tube resistant to pressure and heated to 100°C overnight. The mixture was cooled to RT, treated with more saline, then diluted with EtOAc until all solids were completely dissolved. The layers were separated, the aqueous layer was further extracted with EtOAc (1×) and the combined organic layers were washed. NaHCO ₃ (1×), dried (MgSO ₄ ) and concentrated to dryness. The resulting solid was suspended in MeCN/H ₂ O, frozen and lyophilized to give 3-(5-amino-2-bromo-4-fluorophenyl)-1-ethyl-7-(methylamino)-1,6-naphthyridine-2( 1H)-one (1.32 g, 89% yield) as a light brown solid. ^1H NMR (400 MHz, DMSO- _d6 ): δ 8.37 (s, 1H), 7.62 (s, 1H), 7.30 (d, 1H), 6.99 (q, 1H), 6.73 (d, 1H), 6.21 (s, 1H), 5.33 (s, 2H), 4.11 (q, 2H), 2.84 (d, 3H), 1.19 (t , 3H); MS (ESI) m/z: 393.0 [M+H] ⁺ .

[00127] Example A15: To a solution of the compound of Example A3 (1.00 g, 2.84 mmol) in DMF (10 ml) was added N,N-dimethylethanediamine (0.250 g, 2.84 mmol) and the resulting reaction mixture was heated at 100°C for 36 hours. The reaction mixture was diluted with water and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried (MgSO ₄ ) and the solvent was evaporated. The residue was crystallized from IPA to give 3-(5-amino-2-chloro-4-fluorophenyl)-7-(2-(dimethylamino)ethylamino)-1-ethyl-1,6-naphthyridin-2(1H)-one ( 0.98 g, 85% yield) as a white solid. ^1H NMR (400 MHz, DMSO- _d6 ): δ 8.36 (s, 1H), 7.64 (s, 1H), 7.17 (d. J=11 Hz, 1H), 6.84 ( m, 1H), 6.72 (d, J=9 Hz, 1H), 6.37 (s, 1H), 5.30 (s, 2H), 4.08 (m, 2H), 3.40 ( m, 2H), 2.41 (t, J=6 Hz, 2H), 2.20 (s, 6H), 1.18 (t, J=6 Hz, 3H); MS (IER) m/z: 404.2 [M+H] ⁺ .

[00128] Example A16: To a solution of the compound of Example A3 (1.00 g, 2.84 mmol) in DMF (10 ml) was added N,N-dimethylpropanamine (0.870 g, 8.52 mmol) and the resulting reaction mixture was heated at 100°C for 36 hours. The mixture was diluted with water and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried (MgSO ₄ ) and the solvent was evaporated to give 3-(5-amino-2-chloro-4-fluorophenyl)-7-(3-(dimethylamino)propylamino)-1-ethyl-1. 6-naphthyridin-2(1H)-one (1.10 g, 93% yield) as an orange foam. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 8.36 (s, 1H), 7.64 (s, 1H), 7.20 (d, J=11 Hz, 1H), 7.03 ( m, 1H), 6.76 (d, J=9 Hz, 1H), 6.27 (s, 1H), 5.30 (s, 2H), 4.08 (m, 2H), 3.30 ( m, 2H), 2.26 (t, J=6 Hz, 2H), 2.05 (m, 6H), 1.66 (m, 2H), 1.18 (t, J=6 Hz, 3H) ; MS (ESI) m/z: 418.2 [M+H] ⁺ .

[00129] Example A17: A solution of the compound of Example A3 (0.25 g, 0.710 mmol) in THF (6 ml) was treated with dimethylamine (2M in THF, 2.84 ml, 5.68 mmol) and heated at 80°C in during the night. Further dimethylamine (2M in THF, 5.68 mL, 11.36 mmol) was added for 3 days and the reaction mixture was heated at 80°C. The mixture was separated into DXM and us. NaHCO ₃ and extracted with DCM (3×). The combined organic extracts were dried (MgSO ₄ ) and evaporated. The crude product was purified by silica gel chromatography (EtOAc/hex) to give 3-(5-amino-2-chloro-4-fluorophenyl)-7-(dimethylamino)-1-ethyl-1,6-naphthyridine-2(1H )-she (0.21 g, yield 82%). ^1H NMR (400 MHz, DMSO- _d6 ): δ 8.45 (s, 1H), 7.69 (s, 1H), 7.18 (d, 1H), 6.73 (d, 1H), 6.29 (s, 1H), 5.31 (br.s, 2H), 4.21 (q, 2H), 3.14 (s, 6H), 1.18 (t, 3H); MS (ESI) m/z: 361.1 [M+H] ⁺ .

[00130] Example A18: To a solution of the compound of Example B1 (19 g, 103.3 mmol) and the compound of Example C4 (20.3 g, 103.3 mmol) in DMF (150 ml) was added K ₂ CO ₃ (28 .5 g, 206.6 mmol) and the reaction mixture was heated at 90°C overnight. The mixture was poured into water (300 ml), stirred at RT for 10 minutes and the resulting precipitate was collected by filtration, washed with water and dried to give 3-(5-amino-2,4-difluorophenyl)-7-chloro-1-ethyl -1H-[1,6]naphthyridin-2-one (22 g, 65% yield). ^1H NMR (400 MHz, DMSO- _d6 ): δ 8.76 (s, 1H), 8.07 (s, 1H), 7.71 (s, 1H), 7.11 (t, J=10 .4 Hz, 1H), 8.84 (dd, J=10.0, 7.6 Hz, 1H), 5.09 (s, 2H), 4.25 (q, J=6.8 Hz, 2H ), 1.19 (t, J=6.8 Hz, 3H).

[00131] Example A19: To a suspension of the compound of Example A18 (0.180 g, 0.536 mmol) in dioxane (5 ml) was added 2-methoxyethylamine (0.462 ml, 5.36 mmol) and the mixture was heated at 100°C for 20 hours. The solvent from the reaction mixture was evaporated and the residue was stirred with water (50 ml). The solids were filtered, washed and dried to give 3-(5-amino-2,4-difluorophenyl)-1-ethyl-7-(2-methoxyethylamino)-1,6-naphthyridin-2(1H)-one (0.185 g , yield 92%) as a white solid. MS (ESI) m/z: 375.1 [M+H] ⁺ .

[00132] Example A20: A mixture of the compound of example B2 (5 g, 25 mmol), the compound of example C1 (5.3 g, 25 mmol) and Cs ₂ CO ₃ (21.4 g, 66 mmol) in DMF (50 ml) heated at 100°C overnight. The solid was removed by filtration and the precipitate was washed with DMF. The organic layers were concentrated and the residue was purified by silica gel chromatography (EtOAc/pet ether) to give 3-(5-amino-4-fluoro-2-methylphenyl)-7-chloro-1-isopropyl-1,6-naphthyridine- 2(1H)-one (1.7 g, 20% yield). ^1H NMR (400 MHz, DMSO- _d6 ): δ 8.69 (s, 1H), 7.84 (s, 1H), 7.78 (s, 1H), 6.87-6.84 (d , J=12.4 Hz, 1H), 6.61-6.58 (d, J=9.6 Hz, 1H), 5.11-5.08 (lat.s, 1H), 4.93 ( s, 2H), 1.93 (s, 3H), 1.50-1.48 (d, J=6.8 Hz, 6H); MS (ESI) m/z: 346 [M+H] ⁺ .

[00133] Example A21: A mixture of the compound of Example A20 and (4-methoxybenzyl)methylamine (4.5 g, 30 mmol) was heated to 180° C. under N ₂ atmosphere for 8 hours. Excess (4-methoxybenzyl)methylamine was removed under reduced pressure to obtain the crude product, which was suspended in 50% aqueous acetic acid and stirred for 30 minutes. The mixture was extracted with EtOAc (3×) and the combined organic layers were washed with brine, dried (MgSO ₄ ) and concentrated to give 7-((4-methoxybenzyl)(methyl)amino)-3-(5-amino-4-fluoro-2 -methylphenyl)-1-isopropyl-1,6-naphthyridin-2(1H)-one (1.0 g, 76.9% yield), which was used in the next step without further purification.

[00134] Into a solution of 7-((4-methoxybenzyl)(methyl)amino)-3-(5-amino-4-fluoro-2-methylphenyl)-1-isopropyl-1,6-naphthyridine-2(1H)- she (1.0 g, 2.2 mmol) in DCM (10 ml) added TFA (3 ml) at RT. The resulting mixture was stirred at RT for 6 hours, then washed with H ₂ O (6×). The combined aqueous layers were neutralized with NH ₃ ⋅H ₂ O, extracted with DCM (3×) and the combined organic layers were washed with brine, dried (Na ₂ SO ₄ ), filtered and concentrated to give 3-(5-amino-4-fluoro-2 -methylphenyl)-1-isopropyl-7-(methylamino)-1,6-naphthyridin-2(1H)-one (0.5 g, 66.8% yield). ^1H NMR (400 MHz, DMSO- _d6 ): δ 8.41 (s, 1H), 7.60 (s, 1H), 6.95 (m, 1H), 6.90 (d, J=12 ,4 Hz, 1H), 6.65 (d, J=9.2 Hz, 1H), 6.50 (s, 1H), 5.21 (lat s, 1H), 4.95 (s, 2H ), 2.92 (d, J=4.8 Hz, 3H), 2.02 (s, 3H), 1.58 (d, J=6.8 Hz, 6H); MS (ESI) m/z: 341.2 [M+H] ⁺ .

[00135] Example A22: Example A3 (0.50 g, 1.420 mmol), 4-aminotetrahydropyran (0.431 g, 4.26 mmol) and TEA (0.394 mL, 2.84 mmol) were combined in NMP (5 mL) and the mixture was heated at 180°C under microwave irradiation for 6 hours. Additionally, 4-aminotetrahydropyran (0.2 ml) was added and the mixture was heated at 180°C under microwave irradiation for an additional 3 hours. The reaction was quenched with water and the mixture was extracted with EtOAc (3×). The organic layers were washed with 5% LiCl, then brine, dried (Na ₂ SO ₄ ), concentrated to dryness and purified by silica gel column chromatography (MeOH/DCM) to give 3-(5-amino-2-chloro-4-fluorophenyl) -1-ethyl-7-(tetrahydro-2H-pyran-4-ylamino)-1,6-naphthyridin-2(1H)-one (0.31 g, 52% yield). MS (ESI) m/z: 417.1 [M+H] ⁺ .

[00136] Example A23: The compound of Example A3 (0.4 g, 1.14 mmol) and 3-methoxypropylamine (0.5 g, 5.69 mmol) were combined in NMP (5 ml) and heated at 120°C in within 24 hours. The mixture was poured into water, extracted with EtOAc (2×) and the combined organic layers were washed with brine, dried (Na ₂ SO ₄ ), concentrated to dryness and purified by silica gel chromatography (MeOH/DCM) to give 3-(5-amino-2 -chloro-4-fluorophenyl)-1-ethyl-7-(3-methoxypropylamino)-1,6-naphthyridin-2(1H)-one (409 mg, 89% yield) as an orange solid. ^1H NMR (400 MHz, DMSO- _d6 ): δ 8.36 (s, 1H), 7.64 (s, 1H), 7.18 (d, J=11.2 Hz, 1H), 7. 04 (t, J=5.6 Hz, 1H), 7.20 (d, J=8.8 Hz, 1H), 6.27 (s, 1H), 5.30 (s, 2H), 4, 09 (q, J=6.8 Hz, 2H), 3.41-3.30 (m, 4H), 3.23 (s, 3H), 1.80-1.73 (m, 2H), 1 .18 (t, J=6.8 Hz, 3H); MS (ESI) m/z: 405.1 [M+H] ⁺ .

[00137] Example A24: A solution of the compound of Example C4 (5 g, 23.2 mmol), the compound of Example B2 (4.6 g, 23.2 mmol) and Cs ₂ CO ₃ (15 g, 2 eq.) in DMF was heated at 80°C overnight. The mixture was poured into water and extracted with EtOAc. The combined organic layers were washed with brine, dried (Na ₂ SO ₄ ), concentrated to dryness and purified by silica gel chromatography to give 3-(5-amino-2,4-difluorophenyl)-7-chloro-1-isopropyl-1,6 -naphthyridin-2(1H)-one (4 g, 49% yield). MS (ESI) m/z: 350.2 [M+H] ⁺ .

[00138] Example A25: A mixture of the compound of Example A24 (4 g, 11.5 mmol) and methylamine (30 ml) was heated to 100° C. in a sealed vessel for 12 hours, then cooled to RT. Concentrate the mixture and wash the residue with EtOAc to give 3-(5-amino-2,4-difluorophenyl)-1-isopropyl-7-(methylamino)-1,6-naphthyridin-2(1H)-one (3.5 g , yield 90%). ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 8.40 (s, 1H), 7.70 (s, 1H), 7.05 (t, J=10 Hz, 1H), 6.98 ( m, 1H), 6.81 (t, J=7.6 Hz, 1H), 6.45 (s, 1H), 5.10 (lat s, 1H), 5.06 (s, 2H). 2.87 (d, J=4.8 Hz, 3H), 1.53 (d, J=6.8 Hz, 6H); MS (ESI) m/z: 345.1 [M+H] ⁺ .

[00139] Example A26: The compound of Example A3 (0.150 g, 0.426 mmol) and (S)-(+)-1-methoxy-2-propylamine (0.228 g, 2.56 mmol) were combined in NMP (4 ml) and heated under microwave irradiation at 180°C for 18 hours. After cooling, the reaction mixture was diluted with us. LiCl and extracted with EtOAc (2×). The combined organic layers washed us successively. LiCl (1×), H ₂ O (1×) and brine (1×), dried (MgSO ₄ ), filtered and evaporated. The crude product was purified by silica gel chromatography (EtOAc/hex) to give (S)-3-(5-amino-2-chloro-4-fluorophenyl)-1-ethyl-7-(1-methoxypropan-2-ylamino) -1,6-naphthyridin-2(1H)-one (0.13 g, 75% yield). MS (ESI) m/z: 405.1 (M+H ⁺ ), 407.1 (M+2+H ⁺ ).

[00140] Example A27: A solution of the compound of Example A6 (500 mg, 1.507 mmol) and cyclopropylamine (860 mg, 15.07 mmol) in EtOH (15 ml) was heated at 100° C. in a sealed vessel. After 20 hours, the reaction mixture was further treated with cyclopropylamine (860 mg, 15.07 mmol) and a catalytic amount of DMAP (10 mg) and heated at 100°C for 23 hours, then at 115°C for 10 days. The mixture was cooled to RT, concentrated to dryness and the resulting residue was dissolved in EtOAc (30 ml) and washed successively with water (30 ml), sat. NaHCO ₃ (30 ml) and saline (30 ml). The organic phase was dried over Na ₂ SO ₄ , concentrated to dryness and purified by reverse phase chromatography (MeCN/H ₂ O with 0.1% TFA). We were treated with an aqueous solution. NaHCO ₃ (5 ml) and left to settle. A solid formed and was collected by filtration to give 3-(5-amino-4-fluoro-2-methylphenyl)-7-(cyclopropylamino)-1-ethyl-1,6-naphthyridin-2(1H)-one (124 mg, yield 23%). ^1H NMR (400 MHz, DMSO- _d6 ): δ 8.36 (s, 1H), 7.60 (s, 1H), 7.28 (s, 1H), 6.83 (d, 1H), 6.58 (d, 1H), 6.38 (s, 1H), 4.87 (s, 2H), 4.18-4.12 (m, 2H), 2.59 (m, 1H), 1 .94 (s, 3H), 1.21 (t, 3H), 0.75 (m, 2H), 0.47 (m, 2H); MS (IER-AD) m/z: 353.1 [M+H] ⁺ .

[00141] Example A28: To a suspension of the compound of Example A6 (0.500 g, 1.507 mmol) in dioxane (10 ml) was added 2-methoxyethylamine (2 ml, 23.22 mmol) and the mixture was heated at 100°C for 40 hours. The solvent from the reaction mixture was evaporated and the residue was diluted with water (50 ml) and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried and the solvent was evaporated to give 3-(5-amino-4-fluoro-2-methylphenyl)-1-ethyl-7-(2-methoxyethylamino)-1,6-naphthyridine-2(1H )-one (405 mg, 73% yield) as an orange-yellow solid. MS (ESI) m/z: 371.2 [M+H] ⁺ .

[00142] Example A29: A solution of the compound of Example A13 (0.500 g, 1.261 mmol) and 2-methoxyethylamine (0.947 g, 12.61 mmol) in NMP (5 ml) was heated at 120°C. After 4 hours, the reaction mixture was cooled and partitioned in EtOAc and water. The organic layer was separated and the aqueous layer was further extracted with EtOAc (1×). The combined organic layers were washed with brine, dried and the solvent was evaporated to give 3-(5-amino-2-bromo-4-fluorophenyl)-1-ethyl-7-(2-methoxyethylamino)-1,6-naphthyridine-2(1H )-she (0.486 g, yield 89%) in the form of a brownish mass. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 8.37 (s, 1H), 7.62 (s, 1H), 7.30 (d, J=12 Hz, 1H), 7.04 ( m, 1H), 6.72 (d, J=10 Hz, 1H), 6.39 (s, 1H), 5.33 (s, 2H), 4.08 (m, 2H), 3.50 ( m, 4H), 3.27 (s, 3H), 1.18 (t, J=6 Hz. 3H); MS (ESI) m/z 435.1/437.1 [M+H] ⁺ .

[00143] Example A30: To a solution of the compound of Example A3 (2.0 g, 5.7 mmol) in NMP (10 ml) was added tetrahydrofuran-3-ylamine (1.5 g, 17.2 mmol) and DBU (1 .7 g, 11.4 mmol). Nitrogen was purged through the mixture for 5 minutes, then it was heated under microwave irradiation at 180°C for 1 hour. The reaction mixture was cooled to RT, poured into water and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , concentrated under reduced pressure and purified by silica gel chromatography to give 3-(5-amino-2-chloro-4-fluorophenyl)-1-ethyl-7-(tetrahydrofuran -3-ylamino)-1,6-naphthyridin-2(1H)-one (0.57 g, 25% yield). ^1H NMR (400 MHz, DMSO- _d6 ): δ 8.39 (s, 1H), 7.66 (s, 1H), 7.27 (d, J=6.4 Hz, 1H), 7. 18 (d, J=11.2 Hz, 1H), 6.72 (d, J=9.6 Hz, 1H), 6.33 (s, 1H), 5.31 (s, 2H), 4, 46-4.42 (m, 1H), 4.08 (q, J=6.8 Hz, 2H), 3.89-3.81 (m, 2H), 3.75-3.69 (m, 1H) , 3.55-3.52 (m, 1H), 2.22-2.17 (m, 1H), 1.83-1.79 (m, 1H), 1.20 (t, J=6, 8 Hz, 3H).

[00144] Example A31: The compound of Example A13 (0.165 g, 0.416 mmol) and 2-(thiomethyl)ethylamine (0.38 g, 4.16 mmol) were combined in NMP (2 ml) and the solution was heated under microwave irradiation at 180 °C for 5 hours. The mixture was poured into water (30 ml) and the resulting suspension was filtered, washed with water and dried to give 3-(5-amino-2-bromo-4-fluorophenyl)-1-ethyl-7-(2-(methylthio)ethylamino)- 1,6-naphthyridin-2(1H)-one (0.19 g, 100% yield) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 8.37 (s, 1H), 7.62 (s, 1H), 7.30 (d, J=10.8 Hz, 1H), 7. 15 (t, J=6.8 Hz, 1H), 7.32 (d, J=8.8 Hz, 1H), 6.33 (s, 1H), 5.33 (s, 2H), 4, 09 (q, J=7.2 Hz, 2H), 3.53 (q, J=7.2 Hz, 2H), 2.66 (t, J=6.8 Hz, 2H), 2.10 ( s, 3H), 1.18 (t, J=7.2 Hz, 3H); MS (ESI) m/z: 451.1 [M+H] ⁺ .

[00145] Example A32: Combine Example A13 (2.5 g, 6.35 mmol) and 4-methoxybenzylamine (50 ml) and heat at 140°C overnight. The reaction mixture was cooled to RT, then poured into water. The resulting solid was collected by filtration, dried and purified by silica gel chromatography (EtOAc/pet. ether) to give 7-(4-methoxybenzylamino)-3-(5-amino-2-bromo-4-fluorophenyl)-1-ethyl -1,6-naphthyridin-2(1H)-one (2.5 g, 81% yield). ^1H NMR (400 MHz, DMSO- _d6 ): δ 8.35 (s, 1H), 7.59 (s, 1H), 7.51-7.48 (t, J=5.6 Hz, 1H ), 7.29 (s, 1H), 7.26 (d, J=8.4 Hz, 2H), 6.85 (d, J=8.4 Hz, 2H), 6.70 (d, J =9.6 Hz, 1H), 6.27 (s, 1H), 5.31 (s, 2H), 4.45 (d, J=5.6 Hz, 2H), 4.06-4.01 (q, J=6.8 Hz, 2H), 3.53 (s, 3H), 1.10-1.07 (t, J=6.8 Hz, 3H).

[00146] Example A33: The compound of Example A32 (2.5 g, 13.8 mmol) in TFA (30 ml) was stirred at 50-60°C for 2 days. The mixture was concentrated, dissolved in EtOAc (100 ml) and washed. NaHCO ₃ (3×), then saline (3×). The organic layer was dried with Na ₂ SO ₄ and concentrated to obtain the crude product. Hydrochloric acid (6M, 100 ml) was added to the residue and the solution was washed with EtOAc (3×). The water layer neutralized us. NaHCO ₃ and then extracted with EtOAc (3×). The organic layers were washed with brine (1×), dried and concentrated to give 7-amino-3-(5-amino-2-bromo-4-fluorophenyl)-1-ethyl-1,6-naphthyridine-2(1H)- she (1 g, yield 53%). ^1H NMR (400 MHz, DMSO- _d6 ): δ 8.56 (s, 1H), 7.79 (s, 1H), 7.73 (s, 2H), 7.37 (d, J=10 .8 Hz, 1H), 6.77 (s, 1H), 6.73 (d, J=7.6 Hz, 1H), 5.89-5.03 (lat.s, 2H), 4.14 -4.08 (q, J=6.8 Hz, 2H), 1.25-1.21 (t, J=6.8 Hz, 3H).

[00147] Example A34: A solution of the compound of Example A6 (2.5 g, 7.5 mmol) and 4-methoxybenzylamine (30 ml) was refluxed at 140°C for 2 hours. After cooling to RT, the reaction mixture was poured into 20% aq. acetic acid solution and stirred for 0.5 hours. The mixture was filtered to obtain 7-(4-methoxybenzylamino)-3-(5-amino-4-fluoro-2-methylphenyl)-1-ethyl-1,6-naphthyridin-2(1H)-one.

[00148] A solution of 7-(4-methoxybenzylamino)-3-(5-amino-4-fluoro-2-methylphenyl)-1-ethyl-1,6-naphthyridin-2(1H)-one in DCM (10 ml ) TFA (2 ml, 26.9 mmol) was added and the reaction mixture was refluxed at 50°C for 2 hours. After cooling to RT, the reaction mixture was washed with water and the combined aqueous layers were neutralized. _NaHCO3 . The aqueous layer was extracted with EtOAc (3×) and the extracts were dried (Na ₂ SO ₄ ) and concentrated to give 7-amino-3-(5-amino-4-fluoro-2-methylphenyl)-1-ethyl-1,6-naphthyridine -2(1H)-one (0.9 g, yield 46% in 2 stages). ^1H NMR (300 MHz, DMSO- _d6 ): δ 8.30 (s, 1H), 7.56 (s, 1H), 6.83 (d, J=12.3 Hz, 1H), 6, 57 (d, J=9.6 Hz, 1H), 6.40 (s, 2H), 6.32 (s, 1H), 4.85 (s, 2H), 4.07 (q, J=6 .9 Hz, 2H), 1.94 (s, 1H), 1.19 (t, J=6.9 Hz, 3H); MS (ESI) m/z: 313.3 [M+H] ⁺ .

[00149] Example A35: The compound of Example A9 (2 g, 4.4 mmol) was stirred in TFA (10 ml) at 60°C overnight, cooled to RT, added to water (10 ml) and extracted with EtOAc (3 ×). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , concentrated in vacuo and purified by silica gel chromatography to give 7-amino-3-(5-amino-2-chloro-4-fluorophenyl)-1-ethyl-1 ,6-naphthyridin-2(1H)-one (870 mg, 59% yield). ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 8.35 (s, 1H), 7.68 (s, 1H), 7.21 (d, J=10.8 Hz, 1H), 6, 75 (d, J=9.6 Hz, 1H), 6.52 (s, 2H), 6.35 (s, 1H), 5.33 (s, 2H), 4.09 (q, J=6 ,8 Hz, 2H), 1.22 (t, J=6.8 Hz, 3H); MS (ESI) m/z: 333.2 [M+H] ⁺ .

[00150] Example A36: A solution of the compound of Example A18 (1 g, 3 mmol) in (4-methoxyphenyl)methanamine (10 ml) was heated at 130°C overnight. The mixture was cooled to RT, poured into a 1:1 mixture of acetic acid and water (10 ml), stirred for 30 minutes and extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and the filtrate was concentrated to give the crude product, which was purified by silica gel chromatography to give 7-(4-methoxybenzylamino)-3-(5-amino-2,4- difluorophenyl)-1-ethyl-1,6-naphthyridin-2(1H)-one (1 g, 69% yield). ^1H NMR (400 MHz, DMSO- _d6 ): δ 8.40 (s, 1H), 7.74 (s, 1H), 7.57-7.54 (m, 1H), 7.30 (d , J=8.4 Hz, 2H), 7.08-7.03 (m, 1H), 6.90 (d, J=4.4 Hz, 2H), 6.78-6.72 (m, 1H), 6.30 (s, 1H), 5.02 (s, 2H), 4.49 (d, J=6.0 Hz, 2H), 4.11-4.09 (q, J=7 .2 Hz, 2H), 3.72 (s, 3H), 1.14-1.11 (t, J=6.8 Hz, 3H).

[00151] Example A37: To a solution of the compound of Example B3 (1 g, 5.5 mmol) and the compound of Example C5 (1.53 g, 5.5 mmol) in DMA (10 ml) was added KF/Al ₂ O ₃ (3 g) and the mixture was stirred at RT for 10 minutes. The reaction mixture was filtered, the filtrate was concentrated, and the residue was poured into water. The resulting solid was collected by filtration, washed with water, dried in vacuo and washed with MTBE to give 3-(5-amino-2-bromo-4-fluorophenyl)-7-chloro-1-methyl-1H-[1,6]naphthyridine -2-ona (1.5 g, 67% yield). ^1H NMR (400 MHz, DMSO- _d6 ): δ 8.76 (s, 1H), 7.99 (s, 1H), 7.66 (s, 1H), 7.37 (d, J=11 ,2, 1H), 6.75 (d, J=9.6 Hz, 1H), 5.44 (s, 2H), 3.62 (s, 3H).

[00152] Example A38: Solution of the compound of Example B1 (6.0 g, 0.033 mol), 2-(3-amino-4-fluorophenyl)acetic acid ethyl ester (6.4 g, 0.033 mol) and K ₂ CO ₃ (9.17 g, 0.066 mol) in DMF (100 ml) was heated to 80°C overnight. The reaction mixture was poured into water and extracted with EtOAc (3×). The combined extracts were washed with saline (3x), dried (MgSO ₄ ), concentrated in vacuo and purified by chromatography to give 3-(3-amino-4-fluorophenyl)-7-chloro-1-ethyl-1,6-naphthyridine -2(1H)-one (7.0 g, 68% yield). ^1H NMR (400 MHz, DMSO- _d6 ): δ 8.75 (s, 1H), 8.07 (s, 1H), 7.67 (s, 1H), 7.13 (dd, J=8 ,8, 2.0 Hz, 1H), 7.02 (dd, J=11.6, 8.4 Hz, 1H), 6.80 (m, 1H), 5.20 (s, 2H), 4 .25 (q, J=6.8 Hz, 2H), 1.19 (t, J=6.8 Hz, 3H); MS (ESI) m/z: 318.2 [M+H] ⁺ .

[00153] Example A39: Using the 2-step method of Example A4 and A5, the compound of Example A38 (0.85 g, 2.7 mmol) and 4-methoxybenzylmethylamine (10 ml) was combined to give 3-(3-amino- 4-fluorophenyl)-1-ethyl-7-(methylamino)-1,6-naphthyridin-2(1H)-one (0.45 g, 32% yield, 2 steps). ^1H NMR (300 MHz, DMSO- _d6 ): δ 8.40 (s, 1H), 7.77 (s, 1H), 7.11 (d, J=9.0 Hz, 1H), 6, 95 (m, 2H), 6.76 (m, 1H), 6.19 (s, 1H), 5.09 (s, 2H), 4.14 (m, 2H), 2.85 (br.s , 3H), 1.20 (t, J=6.0, 3H); MS (ESI) m/z (M+H ⁺ ): 313.3.

[00154] Example A40: To a solution of the compound of Example B2 (6 g, 30 mmol) and (3-amino-4-fluorophenyl)acetic acid ethyl ester (6 g, 30 mmol) in DMA (80 ml) was added KF/Al ₂ O ₃ (40 wt.%, 10 g, 69 mmol) and stirred at RT for 1 hour. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was poured into water, the precipitate was collected by filtration, washed with Et ₂ O and dried in vacuo to give 3-(3-amino-4-fluorophenyl)-7-chloro-1-isopropyl-1,6-naphthyridine-2(1H) -ona (7 g, yield 70%). ^1H NMR (400 MHz, DMSO- _d6 ): δ 8.71 (s, 1H), 8.00 (s, 1H), 7.76 (s, 1H), 7.11 (dd, J=9 ,2, 2.4 Hz, 1H), 7.05 (dd, J=11.6, 8.4 Hz, 1H), 6.76 (m, 1H), 5.18 (s, 2H), 5 .15 (m, 1H), 1.52 (d, J=7.2 Hz, 1H); MS (ESI) m/z: 332.0 [M+H] ⁺ .

[00155] Mixture of 3-(3-amino-4-fluorophenyl)-7-chloro-1-isopropyl-1,6-naphthyridin-2(1H)-one (4 g, 12.1 mmol) and (4-methoxybenzyl )methylamine (15 ml) was degassed under reduced pressure, then heated to 180°C under N ₂ for 4 hours. After cooling, the reaction mixture was diluted with Et ₂ O. The precipitate was filtered off, washed with Et ₂ O and dried in vacuum to obtain 3-(3-amino-4-fluorophenyl)-1-isopropyl-7-[(4-methoxybenzyl)methylamino]-1H -[1,6]naphthyridin-2-one (5.3 g) as a solid with impurities of HCl salt of (4-methoxybenzyl)methylamine.

[00156] 3-(3-Amino-4-fluorophenyl)-1-isopropyl-7-[(4-methoxybenzyl)methylamino]-1H-[1,6]naphthyridin-2-one (5.3 g) obtained above mixed with TFA (50 ml) in DCM (150 ml) and heated at reflux temperature overnight. Volatiles were removed under reduced pressure and the residue was dissolved in 10% HCl and washed with EtOAc (3×). The aqueous layer was made basic (pH=11), extracted with EtOAc and the combined organic layers were dried (Na ₂ SO ₄ ) and concentrated to give 3-(3-amino-4-fluorophenyl)-1-isopropyl-7-methylamino-1H-[1 ,6]naphthyridin-2-one (1.26 g, 32% yield in two steps). ^1H NMR (400 MHz, DMSO- _d6 ): δ 8.36 (s, 1H), 7.70 (s, 1H), 7.06 (dd, J=8.4, 2.0 Hz, 1H ), 6.94 (dd, J=11.6, 8.4 Hz, 1H), 6.88 (m, 1H), 6.72 (m, 1H), 6.39 (s, 1H), 5 .07 (m, 1H), 5.06 (s, 2H), 2.83 (d, J=4.8 Hz, 1H), 1.51 (d, J=6.8 Hz, 6H); MS (ESI) m/z: 327.1 [M+H] ⁺ .

[00157] Example A41: Compound of Example C2 (3 g, 12.9 mmol), Compound of Example B3 (2.2 g, 12.9 mmol) and KF/Al ₂ O ₃ (40%, 6 g, 41 mmol) were combined in DMA (40 ml) and the resulting mixture was stirred at RT for 1 hour. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was washed with Et ₂ O to give 3-(5-amino-2-chloro-4-fluorophenyl)-7-chloro-1-methyl-1,6-naphthyridin-2(1H)-one (2.6 g, yield 60%). ^1H NMR (300 MHz, DMSO- _d6 ): δ 8.74 (s, 1H), 8.00 (s, 1H), 7.63 (s, 1H), 7.23 (d, J=11 .2 Hz, 1H), 6.75 (d, J=9.2 Hz, 1H), 5.40 (s, 2H), 3.60 (s, 3H); MS (ESI) m/z: 338.1 [M+H] ⁺ .

[00158] Mixture of 3-(5-amino-2-chloro-4-fluorophenyl)-7-chloro-1-methyl-1,6-naphthyridin-2(1H)-one (2.5 g, 7.4 mmol ) and 4-methoxy-N-methylbenzylamine (4 ml) were heated to 180°C under N ₂ for 3 hours. After cooling, the reaction mixture was diluted with Et ₂ O. The precipitate was filtered off, washed with water and dried to obtain 7-((4-methoxybenzyl)(methyl)amino)-3-(5-amino-2-chloro-4-fluorophenyl)-1- methyl-1,6-naphthyridin-2(1H)-one (3 g, 89% yield). ^1H NMR (400 MHz, DMSO- _d6 ): δ 8.47 (s, 1H), 7.77 (s, 1H), 7.22 (m, 2H), 7.17 (d, J=8 ,0 Hz, 2H), 6.86 (d, J=8.4 Hz, 2H), 5.86 (d, J=9.6 Hz, 1H), 6.30 (s, 1H), 5, 32 (s, 2H), 4.87 (s, 1H), 3.72 (s, 3H), 3.52 (s, 3H), 3.09 (s, 3H); MS (ESI) m/z: 453.2 [M+H] ⁺ .

[00159] 7-((4-methoxybenzyl)(methyl)amino)-3-(5-amino-2-chloro-4-fluorophenyl)-1-methyl-1,6-naphthyridin-2(1H)-one solution (3 g, 6.6 mmol) in DCM (50 ml) was treated with TFA (20 ml) and the mixture was heated at reflux overnight. The mixture was concentrated under reduced pressure, the residue was dissolved in 10% HCl (50 ml), washed with EtOAc, neutralized. NaHCO ₃ and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo to give 3-(5-amino-2-chloro-4-fluorophenyl)-1-methyl-7-(methylamino)-1,6- naphthyridin-2(1H)-one (1.6 g, 72% yield). ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 8.36 (s, 1H), 7.66 (s, 1H), 7.17 (d, J=10.8 Hz, 1H), 7. 05 (m, 1H), 6.71 (d, J=9.6 Hz, 1), 6.15 (s, 1H), 5.30 (s, 2H), 3.47 (s, 3H), 3.42 (s, 1H), 2.84 (d, J=4.4 Hz, 3H); MS (ESI) m/z: 333.1 [M+H] ⁺ .

[00160] Example A42: Compound of Example B3 (3.2 g, 18.8 mmol), Compound of Example C6 (4.0 g, 18.8 mmol) and Cs ₂ CO ₃ (12.3 g, 37, 6 mmol) were combined in DMF (80 ml) and heated to 80°C for 4 hours. The reaction mixture was poured into water (600 ml) and the precipitate was collected by filtration and dried under reduced pressure to give 3-(5-amino-2-chlorophenyl)-7-chloro-1-methyl-1,6-naphthyridine-2(1H )-she (5.0 g, yield 83%). ^1H NMR (400 MHz, DMSO- _d6 ): δ 8.74 (s, 1H), 7.97 (s, 1H), 7.63 (s, 1H), 7.09 (d, J=8 ,4 Hz, 1H), 6.57 (dd, J=8.4 Hz, 2.8 Hz, 1H), 6.52 (s, 1H), 5.31 (s, 2H), 3.60 ( s, 3H).

[00161] A mixture of 3-(5-amino-2-chlorophenyl)-7-chloro-1-methyl-1,6-naphthyridin-2(1H)-one (5 g, 15.67 mmol), 4-methoxybenzylmethylamine ( 3.6 g, 23.5 mmol) and DBU (3.7 g, 23.5 mmol) in NMP (80 ml) were heated at 180°C under N ₂ for 4 hours. The reaction mixture was cooled to RT and poured into water (600 ml). The precipitate was collected by filtration and dried in vacuo to give 7-((4-methoxybenzyl)(methyl)amino)-3-(5-amino-2-chlorophenyl)-1-methyl-1,6-naphthyridine-2(1H) -ona (6.5 g, yield 95%). ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 8.46 (s, 1H), 7.68 (s, 1H), 7.16 (d, J=8.8 Hz, 2H), 7. 06 (d, J=8.4 Hz, 1H), 6.85 (d, J=8.8 Hz, 2H), 6.54-6.51 (m, 2H), 6.29 (s, 1H ), 5.23 (s, 2H), 4.85 (s, 2H), 3.69 (s, 3H), 3.51 (s, 3H), 3.07 (s, 3H).

[00162] Into a solution of 7-((4-methoxybenzyl)(methyl)amino)-3-(5-amino-2-chlorophenyl)-1-methyl-1,6-naphthyridin-2(1H)-one (4 g , 9.2 mmol) in DCM (50 ml) was added TFA (10 ml, 134 mmol) and heated at the reflux temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, dissolved in HCl, washed with EtOAc (3×), neutralized. Na ₂ CO ₃ and extracted with EtOAc (3×). The combined extracts were washed with saline, dried over Na ₂ SO ₄ , concentrated under reduced pressure and purified by chromatography to give 3-(5-amino-2-chlorophenyl)-1-methyl-7-(methylamino)-1,6-naphthyridine -2(1H)-one (1.7 g, 58% yield). ^1H NMR (400 MHz, DMSO- _d6 ): δ 8.36 (s, 1H), 7.63 (s, 1H), 7.06-7.00 (m, 2H), 6.54-6 .50 (m, 2H), 6.14 (s, 1H), 5.21 (s, 2H), 3.48 (s, 3H), 2.84 (d, J=4.8 Hz, 3H) ; MS (ESI) m/z: 314.9 [M+H] ⁺ .

[00163] Example A43: A solution of the compound of Example B3 (2 g, 11.8 mmol) in DMA (40 ml) was treated with the compound of Example C1 (2.5 g, 11.8 mmol), then KF/Al ₂ O ₃ (40 wt.%, 10 g, 68 mmol) and stirred at RT for 2 hours. The mixture was filtered, the filtrate was poured into water and the precipitate was collected by filtration and dried to give 3-(5-amino-4-fluoro-2-methylphenyl)-7-chloro-1-methyl-1,6-naphthyridine-2(1H) -ona (2.5 g, yield 69%). ^1H NMR (300 MHz, DMSO- _d6 ): δ 8.72 (s, 1H), 7.90 (s, 1H), 7.62 (s, 1H), 6.88 (d, J=12 .3 Hz, 1H), 6.60 (d, J=6 Hz, 1H), 4.95 (s, 2H), 3.60 (s, 3H), 1.95 (s, 3H); MS (ESI) m/z: 318.0 [M+H] ⁺ .

[00164] 3-(5-amino-4-fluoro-2-methylphenyl)-7-chloro-1-methyl-1,6-naphthyridin-2(1H)-one (1.36 g, 4.28 mmol, 1, 00 eq), 4-methoxy-N-methylbenzylamine (0.971 g, 6.42 mmol, 1.50 eq) and DBU (0.960 mL, 6.42 mmol, 1.50 eq) were combined in NMP (20 mL ) and heated at 180°C in an Ar atmosphere overnight. The mixture was cooled to RT and poured into H ₂ O (200 ml). The resulting solids were collected by filtration, washed very thoroughly with H ₂ O, filter dried to form a wet solid, and then dissolved in EtOAc. The solution was dried (MgSO ₄ ), filtered and evaporated to give 7-((4-methoxybenzyl)(methyl)amino)-3-(5-amino-4-fluoro-2-methylphenyl)-1-methyl-1,6- naphthyridin-2(1H)-one (1.86 g, 100% yield) as a brittle brown foam, which was used as such for the next reaction. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 8.45 (s, 1H), 7.63 (s, 1H), 7.16 (d, J=8.8 Hz, 2H), 6, 85 (d, J=8.8 Hz, 2H), 6.86-6.82 (m, 1H), 6.57 (d, J=9.6 Hz, 1H), 6.29 (s, 1H ), 4.88 (broads, 2H), 4.85 (s, 2H), 3.69 (s, 3H), 3.52 (s, 3H), 3.07 (s, 3H), 1 .94 (s, 3H); MS (ESI) m/z: 433.3 [M+H] ⁺ .

[00165] Combined 7-((4-methoxybenzyl)(methyl)amino)-3-(5-amino-4-fluoro-2-methylphenyl)-1-methyl-1,6-naphthyridin-2(1H)-one (1.86 g, 4.3 mmol) and TFA (9.5 ml, 121 mmol) and stirred at RT overnight. The mixture was slowly treated with 2M Na ₂ CO ₃ until a slightly alkaline mixture was obtained, then stirred at RT for 1 hour. The solids were collected by filtration, washed thoroughly with H ₂ O, partially air dried, and then under high vacuum at 65°C. The crude product was purified by flash column chromatography (THF/EtOAc) to give 3-(5-amino-4-fluoro-2-methylphenyl)-1-methyl-7-(methylamino)-1,6-naphthyridine-2(1H )-she (0.86 g, 64% yield) as a whitish solid. ^1H NMR (400 MHz, DMSO- _d6 ): δ 8.35 (s, 1H), 7.58 (s, 1H), 6.99 (q, J=4.8 Hz, 1H), 6, 56 (d, J=12.0 Hz, 1H), 6.56 (d, J=9.2 Hz, 1H), 6.15 (s, 1H), 4.87 (lat.s, 2H), 3.48 (s, 3H), 2.84 (d, J=5.2 Hz, 3H), 1.94 (s, 3H); MS (ESI) m/z: 313.2 [M+H] ⁺ .

[00166] Example A44: Compound of Example B3 (2 g, 9.3 mmol), Compound of Example C4 (1.6 g, 9.3 mmol) and KF/Al ₂ O ₃ (40%, 5 g, 34 .4 mmol) were combined in DMA and stirred for 10 minutes. The reaction mixture was poured into water and extracted with EtOAc. The combined organic layers were washed with brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo. The residue was purified by chromatography to give 3-(5-amino-2,4-difluorophenyl)-7-chloro-1-methyl-1,6-naphthyridin-2(1H)-one (2 g, 68% yield). ^1H NMR (300 MHz, DMSO- _d6 ): δ 8.41 (s, 1H), 7.73 (s, 1H), 7.06-7.03 (m, 1H), 6.81-6 .75 (m, 1H), 6.15 (s, 1H), 4.98 (s, 2H), 3.48 (s, 3H); MS (ESI) m/z: 322.7 [M+H] ⁺ .

[00167] 3-(5-amino-2,4-difluorophenyl)-7-chloro-1-methyl-1,6-naphthyridin-2(1H)-one (2.4 g, 7.5 mmol) and 4 -methoxy-N-methylbenzylamine (10 ml) was combined in a sealed vessel and heated to 200°C overnight. Volatiles were removed in vacuo and the residue was purified by column chromatography to give 7-((4-methoxybenzyl)(methyl)amino)-3-(5-amino-2,4-difluorophenyl)-1-methyl-1,6- naphthyridin-2(1H)-one (3 g, 91% yield), which was used in the next step without further purification.

[00168] A solution of 7-((4-methoxybenzyl)(methyl)amino)-3-(5-amino-2,4-difluorophenyl)-1-methyl-1,6-naphthyridin-2(1H)-one (3 g, 6.8 mmol) in DCM (100 ml) was treated with TFA (20 ml) and stirred at RT for 6 hours. The mixture was extracted with water and the combined aqueous layers were neutralized with NH ₃ ⋅H ₂ O. The precipitate was collected by filtration and dried to give 3-(5-amino-2,4-difluorophenyl)-1-methyl-7-(methylamino)-1,6 -naphthyridin-2(1H)-one (661 mg, 30% yield). ^1H NMR (300 MHz, DMSO- _d6 ): δ 8.39 (s, 1H), 7.78 (s, 1H), 7.08-6.93 (m, 2H), 6.80 (dd , J=10.2, 8.1 Hz, 1H), 6.16 (s, 1H), 5.00 (s, 2H), 3.50 (s, 3H), 2.84 (d, J= 4.8 Hz, 3H); MS (ESI) m/z: 317.0 [M+H] ⁺ .

[00169] Example A45: A solution of 4-chloro-2-fluoroaniline (5.0 g, 34.3 mmol) in acetic acid (3 ml) was treated with acetic anhydride (6.45 ml, 68.7 mmol) and stirred at RT within 2 hours. The mixture was poured into ice water, stirred for 2 hours and the resulting solid was collected by filtration and dried to give N-(4-chloro-2-fluorophenyl)acetamide (6.12 g, 95% yield). ^1H NMR (400 MHz, DMSO- _d6 ): δ 9.80 (s, 1H), 7.91 (t, J=8.7 Hz, 1H), 7.45 (dd, J=10.8 , 2.4 Hz, 1H), 7.22 (d, J=8.9 Hz, 1H), 2.07 (s, 3H).

[00170] A solution of N-(4-chloro-2-fluorophenyl)acetamide (2.00 g, 10.66 mmol) in THF (40 mL) at -78°C under Ar was treated with butyllithium (16.66 mL, 26 .7 mmol), stirred at -78°C for 2.5 hours, slowly treated with DMF (1.651 ml, 21.32 mmol), stirred for 15 minutes at -78°C and warmed slowly to RT. The mixture was stirred for 2 hours, treated with sat.NH ₄ Cl, the layers were separated and the aqueous layer was extracted with EtOAc (1×). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , concentrated to dryness and purified by silica gel chromatography (EtOAc/hex) to give N-(4-chloro-2-fluoro-3-formylphenyl)acetamide (1,1 g, yield 48%) as a whitish solid. MS (ESI) m/z: 216.0 [M+H] ⁺ .

[00171] A solution of N-(4-chloro-2-fluoro-3-formylphenyl)acetamide (1.1 g, 5.10 mmol) in MeOH (10 ml) at 0° C. was treated portionwise with sodium borohydride (0.193 g, 5.10 mmol), stirred at 0°C for 0.5 hour, then warmed to RT and concentrated to dryness. The residue was treated with water, extracted with EtOAc (2×) and the combined organic layers were washed with brine, dried over Na ₂ SO ₄ and concentrated to dryness to give N-(4-chloro-2-fluoro-3-(hydroxymethyl)phenyl)acetamide (1 .05 g, yield 95%) as a white solid. MS (ESI) m/z: 218.0 [M+H] ⁺ .

[00172] At 0°C N-(4-chloro-2-fluoro-3-(hydroxymethyl)phenyl)acetamide (1.05 g, 4.82 mmol) and TEA (1.003 mL, 7.24 mmol) in DCM (30 ml) was slowly treated with methanesulfonyl chloride (0.414 ml, 5.31 mmol), warmed to RT and stirred for 2 hours. The mixture was treated to us. NaHCO ₃ , extracted with DCM (2×) and the combined organic layers were washed with brine, dried over Na ₂ SO ₄ and concentrated to dryness to give 3-acetamido-6-chloro-2-fluorobenzylmethanesulfonate (1.31 g, 74% yield) in as a whitish solid. MS (ESI) m/z: 296.0 [M+H] ⁺ .

[00173] A solution of 3-acetamido-6-chloro-2-fluorobenzylmethanesulfonate (1.31 g, 3.54 mmol) in DMSO (10 mL) was treated with sodium cyanide (0.868 g, 17.72 mmol), stirred at RT for overnight, treated with water and extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , concentrated to dryness and purified by silica gel chromatography (EtOAc/hex) to give N-(4-chloro-3-(cyanomethyl)-2-fluorophenyl)acetamide (630 mg, yield 78%) as a yellow solid. MS (ESI) m/z: 227.0 [M+H] ⁺ .

[00174] EtOH (30 ml) was bubbled with HCl gas at 0°C, added to N-(4-chloro-3-(cyanomethyl)-2-fluorophenyl)acetamide (0.28 g, 1.235 mmol) and heated at 80° C for 7 hours. The mixture was cooled to RT, concentrated to dryness, and the residue was neutralized with NaHCO ₃ . The mixture was extracted with EtOAc (2×) and the combined organic layers were washed with brine, dried over Na ₂ SO ₄ and purified by silica gel chromatography (EtOAc/hex) to give 2-(3-amino-6-chloro-2- ethyl ester fluorophenyl)acetic acid (250 mg, 87% yield) as a whitish solid. MS (ESI) m/z: 232.1 [M+H] ⁺ .

[00175] A solution of 2-(3-amino-6-chloro-2-fluorophenyl)acetic acid ethyl ester (0.252 g, 1.089 mmol) in DMA (5 ml) was treated with the compound of Example B1 (0.201 g, 1.089 mmol) and KF on alumina (40%, 1.107 g, 7.62 mmol) and sonicated for 1 hour. The mixture was diluted with EtOAc, filtered through diatomaceous earth and washed thoroughly with EtOAc. The filtrate was washed with water, then brine, dried over Na ₂ SO ₄ and concentrated to dryness to obtain crude 3-(3-amino-6-chloro-2-fluorophenyl)-7-chloro-1-ethyl-1,6-naphthyridine- 2(1H)-one (450 mg, 117% yield) as a white amorphous solid, which was used without further purification. MS (ESI) m/z: 352.0 [M+H] ⁺ .

[00176] A solution of 3-(3-amino-6-chloro-2-fluorophenyl)-7-chloro-1-ethyl-1,6-naphthyridin-2(1H)-one (0.45 g, 1.150 mmol) in dioxane (5 ml) was treated with methylamine (40% in water, 7.14 g, 92 mmol) and heated at 100°C overnight. The mixture was cooled to RT, treated with brine and extracted with EtOAc (2×). The combined organic layers were dried over Na ₂ SO ₄ , concentrated to dryness and purified by silica gel chromatography (MeOH/DCM) to give 3-(3-amino-6-chloro-2-fluorophenyl)-1-ethyl-7-(methylamino) -1,6-naphthyridin-2(1H)-one (350 mg, 88% yield) as a white amorphous solid. ¹ H NMR (500 MHz, DMSO-d ₆ ): δ 8.41 (s, 1H), 7.74 (s, 1H), 7.07 (q, J=4.9 Hz, 1H), 7. 03 (dd, J=8.7, 1.3 Hz, 1H), 6.77 (t, J=9.0 Hz, 1H), 6.25 (s, 1H), 5.30 (s, 2H ), 4.15-4.13 (q, J=7.0 Hz, 2H), 2.87 (d, J=4.9 Hz, 3H), 1.21 (t, J=7.0 Hz , 3H); MS (ESI) m/z: 347.1 [M+H] ⁺ .

[00177] Example A46: Using the three-step process of Example A42, compound of Example B1 (3.5 g, 18.8 mmol), compound of Example C6 (4.0 g, 18.8 mmol), Cs ₂ CO ₃ ( 12.3 g, 37.6 mmol), 4-methoxybenzylmethylamine (3.6 g, 23.5 mmol) and TFA (10 mL, 134 mmol) were combined to give 3-(5-amino-2-chlorophenyl)-1 -ethyl-7-(methylamino)-1,6-naphthyridin-2(1H)-one (1.68 g, 27% yield in 3 steps). ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 8.36 (s, 1H), 7.62 (s, 1H), 7.05 (dd, J=7.2, 2.0 Hz, 1H ), 6.96 (q, J=4.8 Hz, 1H), 6.54-6.50 (m, 2H), 6.21 (s, 1H), 5.21 (s, 2H), 4 .11 (q, J=7.2 Hz, 2H), 2.84 (d, J=4.8 Hz, 3H), 1.18 (t, J=7.2 Hz, 3H); MS (ESI) m/z: 329.2 [M+H] ⁺ .

[00178] Example A47: A biphasic mixture of the compound of Example A4 (1.00 g, 2.142 mmol) in EtOAc (25 ml) and sat. NaHCO ₃ (25 ml) was treated with isopropenyl chloroformate (516 mg, 4.28 mmol) and stirred vigorously at RT for 3 hours. Hexane (10 ml) was added and the resulting solid was collected by filtration and dried. The filtrate layers were separated, the organic layer was washed with brine, dried over Na ₂ SO ₄ , concentrated to dryness and combined with the above solid to give prop-1-en-2-yl ether (4-chloro-5-(1-ethyl- 7-((4-methoxybenzyl)(methyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)carbamic acid (1.168 g, 98% yield). MS (ESI) m/z: 551.2 [M+H] ⁺ .

[00179] Example A48: Biphasic solution of the compound of Example A2 (300 mg, 0.919 mmol) in EtOAc (10 ml) and sat. NaHCO ₃ (10 ml) was treated with isopropenyl chloroformate (138 mg, 1.149 mmol) and stirred at RT for 6 hours. Additionally, isopropenyl chloroformate (50 μl) was added and the mixture was stirred at RT overnight. The layers were separated, the organic layer was washed with brine, dried over Na ₂ SO ₄ and concentrated to dryness to give prop-1-en-2-yl ester (5-(1-ethyl-7-(methylamino)-2-oxo-1, 2-dihydro-1,6-naphthyridin-3-yl)-2-fluoro-4-methylphenyl)carbamic acid (378 mg, 100% yield). MS (ESI) m/z: 411.2 [M+H] ⁺ .

[00180] Example A49: A solution of the compound of Example A14 (0.75 g, 1.917 mmol) in a biphasic mixture of EtOAc/THF/sat. NaHCO ₃ 1:1:1 (90 ml) at 0°C was treated with isopropenyl chloroformate (0.220 ml, 2.013 mmol), left to warm to RT and stirred overnight. Additional isopropenyl chloroformate (0.220 mL, 2.013 mmol) was added and the mixture was stirred at RT for 3 hours, then placed in the refrigerator overnight. The mixture was extracted with EtOAc (2×) and the combined organic layers were washed with brine, dried over Na ₂ SO ₄ and concentrated to dryness to give prop-1-en-2-yl ether (4-bromo-5-(1-ethyl-7- (methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)carbamic acid (960 mg, 105% yield). ^1H NMR (400 MHz, DMSO- _d6 ): δ 9.81 (s, 1H), 8.39 (s, 1H), 7.72-7.61 (m, 3H), 7.04 (m , 1H), 6.23 (s, 1H), 4.72 (d, J=9.5 Hz, 2H), 4.13 (m, 2H), 2.85 (d, J=4.8 Hz , 3H), 1.91 (s, 3H). 1.20 (t, J=7.0 Hz, 3H); MS (ESI) m/z: 475.1 [M+H] ⁺ .

[00181] Example A50: A solution of the compound of Example 21 (0.1 g, 0.221 mmol) in pyridine (5 ml) was treated with isopropenyl chloroformate (0.027 ml, 0.243 mmol) and stirred at RT overnight. Water was added and the resulting solid was collected by filtration and dried to give prop-1-en-2-yl ester (3-(2-chloro-4-fluoro-5-(3-phenylureido)phenyl)-1-ethyl-2 -oxo-1,2-dihydro-1,6-naphthyridin-7-yl)carbamic acid (105 mg, 89% yield). ^1H NMR (400 MHz, DMSO- _d6 ): δ 10.82 (s, 1H), 9.10 (s, 1H), 8.72 (d, J=2.6 Hz, 1H), 8. 70 (s, 1H), 8.23 (d, J=8.6 Hz, 1H), 7.99 (s, 1H), 7.91 (s, 1H), 7.57 (d, J=11 ,0 Hz, 1H), 7.41 (dd, J=8.2, 1.2 Hz, 2H), 7.26 (m, 2H), 6.97 (t, J=7.4 Hz, 1H ), 4.80-4.79 (m, 2H), 4.21 (q, J=7.1 Hz, 2H), 1.96 (s, 3H), 1.25 (t, J=7, 1 Hz, 3H); MS (ESI) m/z: 536.1 [M+H] ⁺ .

[00182] Example A51: A suspension of the compound of Example A5 (0.154 g, 0.444 mmol) in EtOAc (2.5 ml) was treated with sat. NaHCO ₃ (2.5 ml) and isopropenyl chloroformate (0.046 ml, 0.422 mmol) and the biphasic mixture was intensively stirred at RT for 3.5 hours. Additionally, isopropenyl chloroformate (20 μl) was added and the mixture was stirred at RT overnight. The mixture was further diluted with EtOAc and us. NaHCO ₃ and the layers were separated. The organic layer was washed with brine, dried over MgSO ₄ and concentrated to dryness. The resulting residue was dissolved in pyridine (1.5 ml), cooled to 0°C, treated with isopropenyl chloroformate (15 μl) and left to warm to RT. The mixture was re-cooled to 0°C, further treated with isopropenyl chloroformate (7 μl) and allowed to warm to RT. The mixture was cooled again to 0°C, treated with isopropenyl chloroformate (5 μl), left to warm to RT and stirred overnight. The mixture was concentrated to dryness, treated with brine and extracted with EtOAc (2×). The combined organic layers were dried over MgSO ₄ , concentrated to dryness and purified by silica gel chromatography (EtOAc/hex) to give prop-1-en-2-yl ester (4-chloro-5-(1-ethyl-7-(methylamino )-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)carbamic acid (141 mg, 74% yield). ^1H NMR (400 MHz, DMSO- _d6 ): δ 9.80 (s, 1H), 8.40 (s, 1H), 7.75 (s, 1H), 7.64 (s, 1H), 7.55 (d, J=10.5 Hz, 1H), 7.05 (d, J=5.0 Hz, 1H), 6.23 (s, 1H), 4.73 (m, 2H), 4.13 (q, J=7.1 Hz, 2H), 2.85 (d, J=4.9 Hz, 3H), 1.91 (s, 3H), 1.20 (t, J=7 ,0 Hz, 3H); MS (ESI) m/z: 431.1 [M+H] ⁺ .

[00183] Example A52: A mixture of the compound of Example A10 (200 mg, 0.546 mmol) and pyridine (173 mg, 2.184 mmol) in THF (5 ml) was treated with 3-fluorophenyl isocyanate (90 mg, 0.655 mmol) and stirred at RT for nights. The mixture was treated with water and EtOAc and most of the aqueous layer was removed. DMF was added, the mixture was concentrated to dryness and purified by reverse phase chromatography (MeCN/H ₂ O with 0.1% TFA). Organic matter was removed under reduced pressure and the aqueous residue was treated with us. NaHCO ₃ and left to settle at RT. The resulting solid was collected by filtration and dried to give 1-(4-chloro-5-(7-chloro-1-isopropyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2 -fluorophenyl)-3-(3-fluorophenyl)-urea (153 mg, 56% yield). ^1H NMR (400 MHz, DMSO- _d6 ): δ 9.31 (s, 1H), 8.80 (s, 1H), 8.76 (s, 1H), 8.20 (d, J=8 .4 Hz, 1H), 8.04 (s, 1H), 7.84 (s, 1H), 7.59 (d, J=10.9 Hz, 1H), 7.46 (d, J=11 ,9 Hz, 1H), 7.29 (m, 1H), 7.07 (d, J=8.2 Hz, 1H), 6.79 (m, 1H), 5.12 (m, 1H), 1.52 (d, J=6.6 Hz, 6H); MS (ESI) m/z: 503.1 [M+H] ⁺ .

[00184] Example A53: A suspension of the compound of Example A6 (0.161 g, 0.485 mmol) in EtOAc (2.5 ml) was treated with us. NaHCO ₃ (2.5 ml), then isopropenyl chloroformate (0.080 ml, 0.728 mmol) and the two-phase mixture was stirred vigorously at RT for 2 hours. The layers were separated, the organic layer was washed with brine, dried over MgSO ₄ and concentrated to dryness to give prop-1-en-2-yl ether (5-(7-chloro-1-ethyl-2-oxo-1,2-dihydro- 1,6-naphthyridin-3-yl)-2-fluoro-4-methylphenyl)carbamic acid (expected overall yield 100%). MS (ESI) m/z: 416.1 [M+H] ⁺ .

[00185] Example A54: A solution of the compound of Example A6 (0.200 g, 0.603 mmol) and TEA (0.126 mL, 0.904 mmol) in THF (6 mL) was treated with phenyl isocyanate (0.066 mL, 0.603 mmol) and stirred at RT overnight. The resulting solid was collected by filtration and dried to give 1-(5-(7-chloro-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoro-4 -methylphenyl)-3-phenylurea (211 mg, 78% yield). ^1H NMR (400 MHz, DMSO- _d6 ): δ 9.01 (s, 1H), 8.77 (s, 1H), 8.51 (d, J=2.3 Hz, 1H), 8. 01-7.98 (m, 2H), 7.73 (s, 1H), 7.41 (dd, J=8.3, 1.2 Hz, 2H), 7.25 (dd, J=8, 5, 7.3 Hz, 2H), 7.17 (d, J=12.2 Hz, 1H), 6.97-6.90 (m, 1H), 4.27 (q, J=7.1 Hz, 2H), 2.07 (s, 3H), 1.21 (t, J=7.0 Hz, 3H); MS (ESI) m/z: 451.1 [M+H] ⁺ .

[00186] Example A55: A mixture of the compound of Example A10 (700 mg, 1.911 mmol) and pyridine (605 mg, 7.65 mmol) in THF (15 ml) was treated with phenyl isocyanate (250 mg, 2.103 mmol) and stirred at RT for 7 p.m. The mixture was diluted with EtOAc and washed. NaHCO ₃ , then brine, dried over Na ₂ SO ₄ , concentrated to dryness and purified by reverse phase chromatography (MeCN/H ₂ O with 0.1% TFA). Organic substances were removed under reduced pressure, and the aqueous residue was treated with us. NaHCO ₃ and left to settle at RT. The resulting solid was collected by filtration and dried to give 1-(4-chloro-5-(7-chloro-1-isopropyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2 -fluorophenyl)-3-phenylurea (325 mg, 35% yield). ^1H NMR (400 MHz, DMSO- _d6 ): δ 9.10 (s, 1H), 8.76 (s, 1H), 8.73 (m, 1H), 8.23 (d, J=8 .6 Hz, 1H), 8.04 (s, 1H), 7.84 (s, 1H), 7.58 (d, J=11.0 Hz, 1H), 7.41 (d, J=8 ,0 Hz, 2H), 7.27 (t, J=7.9 Hz, 2H), 6.97 (t, J=7.4 Hz, 1H), 5.11 (m, 1H), 1, 52 (d, J=6.7 Hz, 6H); MS (ESI) m/z: 485.1 [M+H] ⁺ .

[00187] Example A56: A solution of Example A6 (0.200 g, 0.603 mmol) and TEA (0.126 mL, 0.904 mmol) in THF (6 mL) was treated with 3-fluorophenyl isocyanate (0.083 mL, 0.723 mmol) and stirred at RT for 4 hours. The mixture was concentrated to dryness and purified by chromatography on silica gel (EtOAc/hex). The substance was treated with DCM and the solid was collected by filtration. The filtrate was concentrated to dryness, purified again by silica gel chromatography (MeOH/DCM) and combined with the isolated solid to give 1-(5-(7-chloro-1-ethyl-2-oxo-1,2-dihydro-1,6 -naphthyridin-3-yl)-2-fluoro-4-methylphenyl)-3-(3-fluorophenyl)urea (88 mg, 31% yield). ^1H NMR (400 MHz, DMSO- _d6 ): δ 9.23 (s, 1H), 8.77 (s, 1H), 8.58 (d, J=2.3 Hz, 1H), 8. 00 (s, 1H), 7.97 (d, J=8.4 Hz, 1H), 7.73 (s, 1H), 7.46 (dt, J=12.0, 2.3 Hz, 1H ), 7.28 (m, 1H), 7.18 (d, J=12.2 Hz, 1H), 7.05 (ddd, J=8.2, 2.0, 0.9 Hz, 1H) , 6.77 (td, J=8.3, 2.5 Hz, 1H), 4.27 (q, J=7.1 Hz, 2H), 2.07 (s, 3H), 1.21 ( t, J=7.0 Hz, 3H); MS (ESI) m/z: 469.1 [M+H] ⁺ .

[00188] Example A57: A mixture of Example A34 (0.3 g, 0.960 mmol), phenyl isocyanate (0.137 g, 1.153 mmol) and TEA (0.134 mL, 0.960 mmol) in THF (5 mL) was stirred at RT for 4 hours. The mixture was treated with 30% EtOAc/hex, stirred for several minutes and the resulting solid was collected by filtration and dried to give 1-(5-(7-amino-1-ethyl-2-oxo-1,2-dihydro-1,6- naphthyridin-3-yl)-2-fluoro-4-methylphenyl)-3-phenylurea (350 mg, 84% yield). ^1H NMR (400 MHz, DMSO- _d6 ): δ 9.01 (s, 1H), 8.47 (s, 1H), 8.34 (s, 1H), 7.93 (d, J=8 .5 Hz, 1H), 7.65 (s, 1H), 7.41 (dd, J=8.3, 1.2 Hz, 2H), 7.24-7.26 (m, 2H), 7 .12 (d, J=12.2 Hz, 1H), 6.95 (t, J=7.4 Hz. 1H), 6.47 (s, 2H), 6.34 (s, 1H), 4 .09 (q, J=7.3 Hz, 2H), 2.06 (s, 3H), 1.20 (t, J=7.0 Hz, 3H); MS (ESI) m/z: 432.1 [M+H] ⁺ .

[00189] 1-(5-(7-Amino-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoro-4-methylphenyl)-3- solution phenylurea (0.35 g, 0.811 mmol) in pyridine (5 ml) was treated with isopropenyl chloroformate (0.147 g, 1.217 mmol) and stirred at RT for 1 hour. Water was added, the mixture was stirred for 10 minutes and the resulting solid was collected by filtration and dried to give prop-1-en-2-yl ether (1-ethyl-3-(4-fluoro-2-methyl-5-(3 -phenylureido)phenyl)-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)carbamic acid (360 mg, 86% yield). MS (ESI) m/z: 516.2 [M+H] ⁺ .

[00190] Example B1: A solution of the compound of Example C3 (4.4 g, 20 mmol) in MeCN (50 ml) at 0°C was treated dropwise with a 65% solution of ethylamine in water (2.7 g, 39 mmol), heated to RT and stirred. The reaction mixture was concentrated and the residue was washed with water to give 6-chloro-4-(ethylamino)nicotinic acid ethyl ester (3.9 g, 91% yield). ^1H NMR (400 MHz, DMSO- _d6 ): δ 8.51 (s, 1H), 8.08 (s, 1H), 6.53 (m, 1H), 4.19 (q, J=7 ,2 Hz, 2H), 2.78 (q, J=7.2 Hz, 2H), 1.28 (t, J=7.2 Hz, 3H), 1.13 (t, J=7.2 Hz, 3H); MS (ESI) m/z: 229.1 [M+H] ⁺ .

[0019] [A solution of 6-chloro-4-(ethylamino)nicotinic acid ethyl ester (3.9 g, 17 mmol) in THF (50 ml) at -50°C was treated with LiAlH ₄ (3.6 g, 95 mmol) , left to warm to 0°C and stirred for 1 hour. The reaction was quenched with 10% NaOH (3.6 ml), filtered, and the filtrate was treated with water and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried (MgSO ₄ ) and concentrated in vacuo to give (6-chloro-4-(ethylamino)pyridin-3-yl)methanol (2.5 g, 79% yield). ^1H NMR (400 MHz, DMSO- _d6 ): δ 7.84 (s, 1H), 6.55 (s, 1H), 6.17 (m, 1H), 5.25 (t, J=5 ,2 Hz, 1H), 4.44 (q, J=7.2 Hz, 2H), 3.23 (m, 2H), 1.23 (t, J=7.2 Hz, 3H).

[00192] To a solution of (6-chloro-4-(ethylamino)pyridin-3-yl)methanol (2.5 g, 13.4 mmol) in DCM (30 ml) was added MnO ₂ (5.8 g, 67 mmol ) and the reaction mixture was stirred at RT overnight. The reaction mixture was filtered and the filtrate was concentrated in vacuo to give 6-chloro-4-(ethylamino)nicotinaldehyde (2.2 g, 89% yield). ^1H NMR (400 MHz, CDCl ₃ ): δ 9.82 (s, 1H), 8.51 (brs, 1H), 8.27 (s, 1H), 6.56 (s, 1H), 3.28 (m, 2H), 1.31 (t, J=7.2 Hz, 3H); MS (IER) m/z: 185.0 [M+H] ⁺ .

[00193] Example B2: Using the three-step process of Example B1, Example C3 (20 g, 91 mmol) and isopropylamine (60% in water, 18 g, 182 mmol) were converted to 6-chloro-4-(isopropylamino)nicotinaldehyde (16 g, yield 81%). ^1H NMR (400 MHz, DMSO- _d6 ): δ 9.82 (s, 1H), 8.43-8.39 (m, 2H), 6.83 (s, 1H), 3.84 (m , 1H), 1.17 (d, J=6.4 Hz, 6H).

[00194] Example B3: A solution of 4,6-dichloronicotinic acid ethyl ester (5 g, 22.8 mmol) in MeCN (30 ml) at 0° C. was treated dropwise with aqueous methylamine (65%, 5.2 g, 45. 6 mmol), heated to RT and stirred for 8 hours. The mixture was concentrated to dryness, the residue was suspended in H ₂ O and extracted with EtOAc (3×). The combined extracts were washed with brine, dried (MgSO ₄ ) and concentrated to give 6-chloro-4-(methylamino)nicotinic acid ethyl ester (4 g, 82% yield), which was used in the next step without further purification. ^1H NMR (300 MHz, DMSO- _d6 ): δ 8.48 (s, 1H), 8.04 (d, J=4.5 Hz, 1H), 6.71 (s, 1H), 4, 27 (q, J=6.9 Hz, 2H), 2.85 (d, J=5.1 Hz, 3H), 1.29 (t, J=6.9 Hz, 3H).

[00195] A solution of 6-chloro-4-(methylamino)nicotinic acid ethyl ester (4 g, 18.7 mmol) in THF (40 ml) at 0° C. was treated portionwise with LiAlH ₄ (1.4 g, 37.4 mmol) in an atmosphere of N ₂ , stirred for 20 minutes, then carefully treated with water, after which 2N. NaOH. The suspension was filtered and the filtrate was concentrated to give (6-chloro-4-(methylamino)pyridin-3-yl)methanol (2.9 g, 91% yield), which was used in the next step without purification. ^1H NMR (400 MHz, DMSO- _d6 ): δ 7.96 (s, 1H), 6.63 (s, 1H), 6.46 (s, 1H), 5.04 (s, 1H), 4.39 (m, 2H), 2.81-2.68 (m, 3H).

[00196] A mixture of (6-chloro-4-(methylamino)pyridin-3-yl)methanol (2.9 g, 16.7 mmol) and MnO ₂ (11.7 g, 133.6 mmol) in anhydrous DCM ( 25 ml) was stirred at 30°C for 6 hours. The reaction mixture was cooled to RT and filtered. The filtrate was concentrated in vacuo to give 6-chloro-4-(methylamino)nicotinaldehyde (2.5 g, 87% yield). ^1H NMR (400 MHz, DMSO- _d6 ): δ 9.83 (s, 1H), 8.52 (brs, 1H), 8.40 (s, 1H), 6.75 (s, 1H ), 2.87 (d, J=5.8 Hz, 3H); MS (ESI) m/z: 171.0 [M+H] ⁺ .

[00197] Example C1: 4-Fluoro-2-methylphenylacetic acid (15 g, 89.2 mmol) was added portionwise to stirred fuming HNO ₃ (90 wt.%, 30.0 ml, 643 mmol) at -15°C. , so that the internal temperature does not exceed -10°C. After addition was complete, the reaction mixture was stirred while heating to 5°C for 15 minutes. The mixture was poured into ice (400 g), stirred vigorously until the ice completely melted and the resulting solid was collected by filtration, washed thoroughly with H ₂ O and dried on a filter to obtain 2-(4-fluoro-2-methyl-5-nitrophenyl)acetic acid. acid (18.43 g, 97% yield) as a pale yellow solid. ¹ H NMR (400 MHz, acetone-d ₆ ): δ 8.06 (d, J=7.6 Hz, 1H), 7.36 (d, J=12.0 Hz, 1H), 3.84 ( s, 2H), 2.44 (s, 3H).

[00198] 2-(4-fluoro-2-methyl-5-nitrophenyl)acetic acid (18.43 g, 86.5 mmol) and conc. H ₂ SO ₄ (4.00 ml) was combined in EtOH (300 ml) and heated at 85°C for 2.5 hours. The mixture was cooled to RT, concentrated, the residue was dissolved in MTBE and washed with H ₂ O (2×), then with brine (2×), dried (MgSO ₄ ) and evaporated to give 2-(4-fluoro-2-methyl) ethyl ester -5-nitrophenyl)acetic acid (16.79 g, 81% yield) as a dark orange oily liquid, which was used without further purification. MS (ESI) m/z: 242.0 (M+H) ⁺ .

[00199] A solution of 2-(4-fluoro-2-methyl-5-nitrophenyl)acetic acid ethyl ester (16.79 g, 69.6 mmol) in EtOH (60 ml) was treated with 10% Pd/C (50% wet ., 7.41 g, 3.48 mmol) and hydrogenated (3.5 atm) for 2 hours. Solids were removed by filtration through diatomaceous earth, washed with EtOH, and the filtrate was concentrated to give 2-(5-amino-4-fluoro-2-methylphenyl)acetic acid ethyl ester (13.18 g, 90% yield) as a brown oil. . ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 6.80 (d, J=12.4 Hz, 1H), 6.59 (d, J=9.6 Hz, 1H), 4.86 ( s, 2H), 4.05 (q, J=7.2 Hz, 2H), 3.46 (s, 2H), 2.05 (s, 3H), 1.17 (t, J=7.2 Hz, 3H); MS (ESI) m/z: 212.2 (M+H) ⁺ .

[00200] Example C2: A solution of 2-(2-chloro-4-fluorophenyl)acetic acid (16.9 g, 89.6 mmol) in conc. H ₂ SO ₄ (60 ml) was added dropwise at -10°C with HNO ₃ (10.35 g, 98.6 mmol), stirred at 0°C for 10 minutes, then carefully poured into ice water. The whitish solid was collected by filtration and dried to give 2-(2-chloro-4-fluoro-5-nitrophenyl)acetic acid (20.5 g, 98% yield). ^1H NMR (400 MHz, DMSO- _d6 ): δ 12.71 (brs, 1H), 8.33 (d, J=8.0 Hz, 1H), 7.92 (d, J=11 .2 Hz, 1H), 3.85 (s, 2H).

[00201] A solution of 2-(2-chloro-4-fluoro-5-nitrophenyl)acetic acid (20.5 g, 88 mmol) in EtOH (150 ml) at 0°C was treated with sulfuryl dichloride (21 g, 0.17 mol ), then heated to reverse condensation temperature for 1 hour. The reaction mixture was concentrated under reduced pressure and treated with us. Na ₂ CO ₃ to pH 7-8. The resulting mixture was extracted with EtOAc (3×) and the combined organic layers were washed with brine, dried (MgSO ₄ ) and concentrated to give 2-(2-chloro-4-fluoro-5-nitrophenyl)acetic acid ethyl ester (22.5 g, yield 98%). ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 8.32 (d, J=8.0 Hz, 1H), 7.91 (d, J=11.2 Hz, 1H), 4.09 ( q, J=7.2 Hz, 2H), 3.92 (s, 2H), 1.17 (t, J=7.2 Hz, 3H).

[00202] A solution of 2-(2-chloro-4-fluoro-5-nitrophenyl)acetic acid ethyl ester (22.5 g, 86.2 mmol) in EtOH (200 ml) was stirred with Raney Ni (20% suspension in water , 5.0 g, 17 mmol) under hydrogen atmosphere (30 psi (207 kPa)) for 5 hours. The catalyst was removed by filtration and the filtrate was concentrated to give 2-(5-amino-2-chloro-4-fluorophenyl)acetic acid ethyl ester (19 g, 95% yield). ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 7.10 (d, J=11.2 Hz, 1H), 6.71 (d, J=9.2 Hz, 1H), 5.27 ( s, 2H), 4.05 (q, J=6.8 Hz, 2H), 3.57 (s, 2H), 1.14 (t, J=6.8 Hz, 3H); MS (ESI) m/z: 232.0 [M+H] ⁺ .

[00203] Example C3: 3-Oxopentanedioic acid diethyl ester (101 g, 0.5 mmol), triethyl orthoformate (81.4 g, 0.55 mol) and acetic anhydride (102 g, 1 mol) were combined and heated to 120 °C for 2 hours. The resulting mixture was cooled to RT and dissolved in DCM (1 L). After further cooling to 0°C, ammonia (30%, 80 ml) was added and the reaction mixture was left to warm to RT overnight. The product was extracted with water (2×) and the aqueous layer was acidified to pH 5 using conc. HCl. The precipitate was collected by filtration to give 4,6-dihydroxynicotinic acid ethyl ester (60.0 g, 60% yield). ^1H NMR (400 MHz, DMSO- _d6 ): δ 7.99 (s, 1H), 5.58 (s, 1H), 4.23 (q, J=6.8, 14.0 Hz, 2H ), 1.25 (t, J=7.2 Hz, 3H); MS (ESI) m/z: 184.1 [M+H] ⁺ .

[00204] 4,6-Dihydroxynicotinic acid ethyl ester (60 g, 0.328 mol) was slowly added to POCl ₃ (500 mL), then heated to reflux temperature for 2 hours. The resulting mixture was distilled under reduced pressure to remove excess POCl ₃ . The residue was poured into ice water and stirred for 30 minutes, after which it was extracted with EtOAc (3×). The combined extracts were washed with brine, dried (MgSO ₄ ) and concentrated in vacuo to give 4,6-dichloronicotinic acid ethyl ester (65 g, 90% yield). ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 8.80 (s, 1H), 7.95 (s, 1H), 4.34 (q, J=6.9 Hz, 2H), 1, 31 (t, J=6.9 Hz, 3H); MS (ESI) m/z: 220.1 [M+H] ⁺ .

[00205] Example C4: A solution of (2,4-difluorophenyl)acetic acid (14.5 g, 0.084 mol) in H ₂ SO ₄ (60 ml) at 0°C was treated dropwise with 69% HNO ₃ (6 ml), stirred at 0°C for 35 minutes, then poured into ice water. The aqueous layer was extracted with EtOAc, the organic extracts were washed with brine, dried (Na ₂ SO ₄ ), concentrated in vacuo and purified by silica gel chromatography to give (2,4-difluoro-5-nitrophenyl)acetic acid (16 g, 88% yield). ). ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 8.30 (t, J=8.0 Hz, 1H), 7.68 (m, 1H), 3.75 (s, 2H).

[00206] A solution of (2,4-difluoro-5-nitrophenyl)acetic acid (16 g, 74 mmol) in EtOH (200 ml) and 98% H ₂ SO ₄ (14 ml) was refluxed at 80°C in for 2.5 hours in an N ₂ atmosphere. The reaction mixture was poured into ice water and the resulting solution was extracted with Et ₂ O. The combined organic extracts were washed with brine, dried (Na ₂ SO ₄ ), concentrated in vacuo and purified by silica gel chromatography to give 2-(2,4-difluoro ethyl ester -5-nitrophenyl)acetic acid (16 g, 89% yield). ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 8.22 (t, J=8.1 Hz, 1H), 7.55 (t, J=11.1 Hz, 1H), 4.06 ( m, 2H), 3.77 (s, 2H), 1.13 (t, J=6.9 Hz, 3H).

[00207] A mixture of 2-(2,4-difluoro-5-nitrophenyl)acetic acid ethyl ester (16 g, 130 mmol) and 10% Pd/C (1.6 g, 1.5 mmol) in EtOAc was hydrogenated (30 psi (207 kPa)) at CT for 12 hours. The catalyst was filtered off and the filtrate was evaporated. The residue was purified by column chromatography to give 2-(5-amino-2,4-difluorophenyl)acetic acid ethyl ester (14 g, 99% yield). ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 6.98 (t, J=9.9 Hz, 1H), 6.70 (t, J=7.8 Hz, 1H), 4.50 ( s, 2H), 4.06 (m, 2H), 3.53 (s, 2H), 1.16 (t, J=6.9 Hz, 3H); MS (ESI) m/z: 216.2 [M+H] ⁺ .

[00208] Example C5: Nitric acid (16.00 mL, 322 mmol) was cooled to -15°C and treated portionwise with 2-bromo-4-fluorophenylacetic acid (10.00 g, 42.9 mmol) while maintaining internal temperature from -10°C to -5°C. After addition was complete, the mixture was heated to 5°C for ~15 minutes, poured into ice (200 ml), stirred vigorously until the ice completely melted, and then filtered and washed with water. The resulting solid was dissolved in EtOAc, washed with brine, dried (MgSO ₄ ) and concentrated to dryness to give 2-(2-bromo-4-fluoro-5-nitrophenyl)acetic acid (10.93 g, 92% yield) as bright yellow solid. ^1H NMR (400 MHz, DMSO- _d6 ): δ 8.29 (d, 1H), 8.04 (d, 1H), 3.85 (s, 2H).

[00209] A solution of 2-(2-bromo-4-fluoro-5-nitrophenyl)acetic acid (5.00 g, 17.98 mmol) in EtOH (100 mL) was treated with concentrated sulfuric acid (0.999 mL, 17.98 mmol ) and heated at 85°C overnight. The mixture was cooled to RT and EtOH was removed under reduced pressure. The resulting oily liquid was dissolved in MTBE, washed with water (2×), then brine (2×), dried (MgSO ₄ ) and concentrated to dryness. The material was purified by chromatography on silica gel (EtOAc/hex) to give 2-(2-bromo-4-fluoro-5-nitrophenyl)acetic acid ethyl ester (2.679 g, 49% yield) as a yellow oily liquid. ^1H NMR (400 MHz, DMSO- _d6 ): δ 8.33 (d, 1H), 8.08 (d, 1H), 4.12 (q, 2H), 3.96 (s, 2H), 1.20 (t, 3H); MS (ESI) m/z: 308.0 [M+H] ⁺ .

[00210] A solution of 2-(2-bromo-4-fluoro-5-nitrophenyl)acetic acid ethyl ester (2.127 g, 6.95 mmol) in EtOH (70 ml) was treated with iron powder (3.88 g, 69.5 mmol) and us. ammonium chloride (14.48 ml, 69.5 mmol) and heated to 55°C for 1 hour. The mixture was cooled to RT, filtered through a pad of diatomaceous earth, washed thoroughly with EtOH, and the organics were concentrated under reduced pressure. The resulting aqueous residue was processed for us. NaHCO ₃ , extracted with EtOAc (2×) and the combined organic layers were washed with water, dried (MgSO ₄ ) and concentrated to give 2-(5-amino-2-bromo-4-fluorophenyl)acetic acid ethyl ester (1.792 g, 93% yield) %) in the form of an amber oily liquid. ^1H NMR (400 MHz, DMSO- _d6 ): δ 7.25 (d, 1H), 6.76 (d, 1H), 5.35 (s, 2H), 4.08 (q, 2H), 3.61 (s, 2H), 1.18 (t, 3H); MS (ESI) m/z 278.0 [M+H] ⁺ .

[00211] Example C6: Mixture of (2-chlorophenyl)acetic acid (15 g, 88 mmol) in conc. H ₂ SO ₄ (100 ml) was cooled to -20°C and treated dropwise with conc. HNO ₃ (9.4 g, 97 mmol). The resulting mixture was stirred at -20°C for 0.5 hour, poured into ice water and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ and concentrated in vacuo to give (2-chloro-5-nitrophenyl)acetic acid (15 g, 79% yield). ^1H NMR (400 MHz, DMSO- _d6 ): δ 8.58 (s, 1H), 8.35 (m, 1H), 7.96 (m, 1H), 4.12 (s, 2H).

[00212] Thionyl chloride (16.7 g, 0.14 mol) was added dropwise to a solution of (2-chloro-5-nitrophenyl)acetic acid (15 g, 0.07 mol) in EtOH (300 ml) at 0° C. and the resulting mixture was heated at reflux temperature overnight. The reaction mixture was concentrated under reduced pressure, the residue was poured into ice water and extracted with EtOAc (2×). The combined organic layers were washed with saline, then with us. NaHCO ₃ , dried over Na ₂ SO ₄ and concentrated in vacuo to give 2-(2-chloro-5-nitrophenyl)acetic acid ethyl ester (17 g, 99% yield). ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 8.35 (d, J=2.8 Hz, 1H), 8.12 (dd, J=8.4, 2.8 Hz, 1H), 7.72 (d, J=8.4 Hz, 1H), 4.10 (q, J=7.2 Hz, 2H), 3.96 (s, 2H), 1.15 (t, J=7 ,2 Hz, 3H).

[00213] In a solution of 2-(2-chloro-5-nitrophenyl)acetic acid ethyl ester (8 g, 4.68 mmol) and conc. HCl (12M, 3.9 mL, 46.8 mmol) in EtOH (100 mL) was added portionwise to iron powder (2.5 g, 44.7 mmol). The resulting mixture was heated at 50°C for 2 hours. The mixture was filtered, and the precipitate was washed with us. Na ₂ CO ₃ to pH 8. The precipitate was further washed with EtOAc and the combined filtrates were separated in EtOAc and water. The organic layer was dried over Na ₂ SO ₄ and concentrated in vacuo to give 2-(5-amino-2-chlorophenyl)acetic acid ethyl ester (5.6 g, 56% yield). ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 7.00 (d, J=8.4 Hz, 1H), 6.50 (s, J=2.8 Hz, 1H), 6.44 ( dd, J=8.4 Hz, 2.8 Hz, 1H), 5.20 (s, 2H), 4.05 (q, J=7.2 Hz, 2H), 3.56 (s, 2H) , 1.15 (t, J=7.2 Hz, 3H).

[00214] Example D1: A mixture of N-methylpiperazine (233 μl, 2.097 mmol) and DIEA (452 mg, 3.49 mmol) in THF (12 ml) at -20°C was treated dropwise with a solution of tert-butyl ether (3- bromomethyl)phenylcarbamic acid (500 mg, 1.747 mmol) in THF (3 ml) and stirred overnight after removing the cooling bath. The mixture was diluted with EtOAc and washed. NaHCO ₃ then brine, dried over Na ₂ SO ₄ and concentrated to dryness to give (3-((4-methylpiperazin-1-yl)methyl)phenyl)carbamic acid tert-butyl ester (544 mg, 102% yield). MS (ESI) m/z: 306.2 [M+H] ⁺ .

[00215] A solution of (3-((4-methylpiperazin-1-yl)methyl)phenyl)carbamic acid tert-butyl ester (544 mg, 1.781 mmol) in dioxane (10 ml) was treated with HCl (g) for 10 minutes, then stirred at RT for 3 hours. The mixture was concentrated to dryness to give crude 3-((4-methylpiperazin-1-yl)methyl)aniline trihydrochloride (505 mg, 90% yield), which was used without further purification. MS (ESI) m/z: 306.2 [M+H] ⁺ .

[00216] Example D2: A mixture of 2-fluoro-5-nitrotoluene (0.750 g, 4.83 mmol), NBS (1.549 g, 8.70 mmol) and AIBN (0.159 g, 0.967 mmol) in trifluorotoluene (15 ml) was heated at reverse condensation temperature overnight. The mixture was cooled to RT, solids were removed by filtration, and the filtrate was concentrated to dryness and purified by silica gel chromatography (EtOAc/hex) to give 2-(bromomethyl)-1-fluoro-4-nitrobenzene (956 mg, 63% yield). with a purity of ~80%.

[00217] A solution of 2-(bromomethyl)-1-fluoro-4-nitrobenzene (0.956 g, 3.27 mmol, ~80% purity) in THF (10 mL) was slowly added dropwise to a solution of 1-methylpiperazine (0.393 g, 3.92 mmol) and DIEA (1.142 ml, 6.54 mmol) in THF (20 ml) at -20°C, the mixture was allowed to warm slowly to RT and stirred overnight. The resulting solid was removed by filtration and the filtrate was concentrated to dryness and purified by silica gel chromatography (EtOAc, MeOH/DCM) to give 1-(2-fluoro-5-nitrobenzyl)-4-methylpiperazine (577 mg, 70% yield). ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 8.28 (dd, J=6.2, 3.0 Hz, 1H), 8.21 (ddd, J=9.0, 4.4, 3.0 Hz, 1H), 7.47 (t, J=9.1 Hz, 1H), 3.60 (s, 2H), 2.48-2.25 (latm, 8H), 2, 14 (s, 3H); MS (ESI) m/z: 254.1 [M+H] ⁺ .

[00218] A solution of 1-(2-fluoro-5-nitrobenzyl)-4-methylpiperazine (0.577 g, 2.278 mmol) in EtOH (7 ml) was treated with us. NH ₄ Cl (4.75 ml, 22.78 mmol), then iron (powder) (1.272 g, 22.78 mmol) and the mixture was heated at 55°C overnight. The mixture was cooled to RT and filtered by gravity through filter paper, washing thoroughly with MeOH and DCM. The filtrate was concentrated to dryness. The residue was treated with EtOAc and water, then concentrated again to dryness. The resulting substance was treated with THF (20 ml), ultrasound for several hours, and the solvent was decanted from the solids. The solids were further treated with THF (20 mL), sonicated again, and the solvent was decanted. The solids were treated a third time with THF (20 ml), stirred vigorously overnight, then the liquid was decanted. The combined decanted liquids were concentrated to dryness, treated with DCM, filtered to remove solids, and concentrated to dryness to give the highly hygroscopic 4-fluoro-3-((4-methylpiperazin-1-yl)methyl)aniline (382 mg, 75% yield). ^1H NMR (400 MHz, DMSO- _d6 ): δ 6.81 (m, 1H), 6.49 (m, 2H), 4.99 (s, 2H), 3.44 (s, 2H), 3.32 (s, 8H), 2.69 (s, 3H); MS (ESI) m/z: 224.2 [M+H] ⁺ .

[00219] Example D3: A mixture of 1-fluoro-2-methyl-4-nitrobenzene (2.5 g, 16.12 mmol) and NBS (3.16 g, 17.73 mmol) in trifluorotoluene (45 ml) was treated with AIBN (66 mg, 0.403 mmol) and heated at 80°C overnight. The mixture was cooled to RT, solids were removed by filtration, and the filtrate was concentrated to dryness. The residue was dissolved in EtOAc, washed with water, then brine, dried over Na ₂ SO ₄ , concentrated to dryness and purified by silica gel chromatography (EtOAc/hex) to give 2-(bromomethyl)-1-fluoro-4-nitrobenzene (1.915 g, yield 50%). ^1H NMR (400 MHz, DMSO- _d6 ): δ 8.53-8.52 (m, 1H), 8.28 (ddd, J=9.1, 4.4, 3.0 Hz, 1H) , 7.55 (t, J=9.2 Hz, 1H), 4.80 (s, 2H).

[00220] A mixture of D1EA (552 mg, 4.27 mmol) and morpholine (242 mg, 2.78 mmol) in THF (5 ml) at -20°C was treated dropwise with a solution of 2-(bromomethyl)-1-fluoro- 4-nitrobenzene (500 mg, 2.137 mmol) in THF (5 ml) and stirred overnight after removing the ice bath. The mixture was treated with EtOAc, washed with water, then brine, dried over Na ₂ SO ₄ and concentrated to dryness to give 4-(2-fluoro-5-nitrobenzyl)morpholine (414 mg, 81% yield). ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 8.30 (dd, J=6.2, 3.0 Hz, 1H), 8.21 (ddd, J=9.0, 4.4, 3.0 Hz, 1H), 7.48 (t, J=9.1 Hz, 1H), 3.61 (s, 2H), 3.56 (t, J=4.6 Hz, 4H), 2 .40 (t, J=4.4 Hz, 4H); MS (ESI) m/z: 241.1 [M+H] ⁺ .

[00221] A mixture of 4-(2-fluoro-5-nitrobenzyl)morpholine (414 mg, 1.723 mmol) in EtOAc (15 ml) was treated with 10% Pd/C (100 mg) and hydrogenated (1 atm) for 3 hours. Solids were removed by filtration, washed with EtOAc, and the filtrate was concentrated to dryness to give 4-fluoro-3-(morpholinomethyl)aniline (200 mg, 55% yield). MS (ESI) m/z: 211.1 [M+H] ⁺ .

[00222] Example 1: Using General Method B, 1-isocyanate naphthalene (0.051 g, 0.3 mmol) and Example A2 (0.1 g, 0.3 mmol) were combined to give 1-(5-(1- ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoro-4-methylphenyl)-3-(naphthalene-1-yl)urea in the form white solid (0.115 g, 77% yield). ^1H NMR (400 MHz, DMSO- _d6 ): δ 9.16 (s, 1H), 9.05 (s, 1H), 8.45 (s, 1H), 8.19 (d, J=8 ,4 Hz, 1H), 8.08-8.04 (m, 2H), 7.96 (d, J=7.6 Hz, 1H), 7.72 (s, 1H), 7.67-7 .58 (m, 3H), 7.47 (t, J=8.0 Hz, 1H), 7.21 (d, J=12.4 Hz, 1H), 7.05-7.02 (m, 1H), 6.28 (s, 1H), 4.21-4.16 (m, 2H), 2.89 (d, J=4.8 Hz, 3H), 2.12 (s, 3H), 1.25 (t, J=6.8 Hz, 3H); MS (ESI) m/z: 496.3 [M+H] ⁺ .

[00223] Example 2: Using General Method B, 1-isocyanate naphthalene (0.045 g, 0.26 mmol) and Example A39 (0.1 g, 0.3 mmol) were combined to give 1-(5-(1- ethyl 7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-(naphthalene-1-yl)urea as a white solid ( 0.062 g, yield 48%). ^1H NMR (400 MHz, DMSO- _d6 ): δ 9.23 (s, 1H), 9.14 (s, 1H), 8.56-8.54 (m, 1H), 8.52 (s , 1H), 8.23 (d, J=8.4 Hz, 1H), 8.11 (d, J=7.6 Hz, 1H), 8.09 (d, J=7.6 Hz, 1H ), 7.93 (s, 1H), 7.71-7.59 (m, 3H), 7.53 (t, J=8.0 Hz, 1H), 7.36-7.34 (m, 2H), 7.10-7.07 (m, 1H), 6.29 (s, 1H), 4.23 (q, J=6.8 Hz, 2H), 2.92 (d, J=4 ,8 Hz, 3H), 1.28 (t, J=7.2 Hz, 3H); MS (ESI) m/z: 482.0 [M+H] ⁺ .

[00224] Example 3: Using General Method B, 1-isocyanatobenzene (0.05 g, 0.420 mmol) and Example A5 (0.146 g, 0.420 mmol) were combined to give 1-(4-chloro-5-(1- ethyl 7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea (0.180 g, 92% yield). ^1H NMR (400 MHz, DMSO- _d6 ): δ 9.16 (s, 1H), 8.75 (s, 1H), 8.45 (s, 1H), 8.22 (d, J=9 Hz, 1H), 7.78 (s, 1H), 7.58 (d, J=10.5 Hz, 1H), 7.46 (s, 1H), 7.44 (s, 1H), 7, 30 (m, 2H), 7.08 (m, 1H), 7.00 (s, 1H), 6.27 (s, 1H), 4.18 (q, J=5 Hz, 2H), 2, 89 (d, J=5 Hz, 3H), 1.24 (t, J=6 Hz, 3H); MS (ESI) m/z: 466.0 [M+H] ⁺ .

[00225] Example 4: Using General Method A, 2,3-difluorobenzoic acid (0.100 g, 0.633 mmol) and Example A5 (0.219 g, 0.633 mmol) were combined to give 1-(4-chloro-5-(1 -ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-(2,3-Difluorophenyl)urea (0.172 g, yield 54%). ^1H NMR (400 MHz, DMSO- _d6 ): δ 9.27 (s, 1H), 9.24 (s, 1H), 8.45 (s, 1H), 8.22 (d, J=10 Hz, 1H), 7.96 (m, 1H), 7.77 (s, 1H), 7.58 (d, J=12 Hz, 1H), 7.18-7.00 (m, 3H), 6.27 (s, 1H), 4.17 (q, J=6 Hz, 2H), 2.90 (d, J=5.5 Hz, 3H), 1.24 (t, J=6 Hz, 3H); MS (ESI) m/z: 502.0 [M+H] ⁺ .

[00226] Example 5: Using General Method B, phenyl isocyanate (0.036 g, 0.302 mmol) and Example A40 (0.1 g, 0.302 mmol) were combined to give 1-(2-fluoro-5-(1-isopropyl- 7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)phenyl)-3-phenylurea (0.94 g, 70% yield). ^1H NMR (400 MHz, DMSO- _d6 ): δ 9.03 (s, 1H), 8.62 (s, 1H), 8.49 (s, 1H), 8.42 (d, J=8 Hz, 1H), 7.86 (s, 1H), 7.52 (s, 1H), 7.50 (s, 1H), 7.32 (m, 4H), 7.03 (m, 2H), 6.50 (br.s, 1H), 3.40 (s, 1H), 2.91 (d, J=6 Hz, 3H), 1.60 (d, J=6 Hz, 6H); MS (ESI) m/z: 446.3 [M+H] ⁺ .

[00227] Example 6: Using General Method B, 1-isocyanate naphthalene (0.05 g, 0.29 mmol) and Example A5 (0.1 g, 0.29 mmol) were combined to give 1-(4-chloro -5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-(naphthalene-1-yl)urea as a white solid (0.121 g, 79% yield). ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 9.26 (br.s, 2H), 8.48 (s, 1H), 8.32 (d, J=8.8 Hz, 1H), 8.21 (d, J=8.8 Hz, 1H), 8.05 (dd, J=7.6 Hz, 0.8 Hz, 1H), 7.98 (d, J=8.4 Hz, 1H), 7.81 (s, 1H), 7.71-7.58 (m, 4H), 7.51 (t, J=8.0 Hz, 1H), 7.11 (q, J=4 ,8 Hz, 1H), 6.30 (s, 1H), 4.20 (q, J=6.8 Hz, 2H), 2.92 (d, J=4.8 Hz, 3H), 1, 27 (t, J=6.8 Hz, 3H); MS (ESI) m/z: 516.0 [M+H] ⁺ .

[00228] Example 7: Using General Method B, phenyl isocyanate (0.050 g, 0.420 mmol) was reacted with Example A41 (0.070 g, 0.210 mmol) in EtOAc (2 ml) for 13 hours to give 1-(4- chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)phenyl)-3-phenylurea (0.080 g, yield 84%). ^1H NMR (400 MHz, DMSO- _d6 ): δ 9.08 (s, 1H), 8.68 (brs, 1H), 8.40 (s, 1H), 8.17 (d, J =9 Hz, 1H), 7.74 (s, 1H), 7.53 (d, J=11.5 Hz, 1H), 7.41 (m, 1H), 7.26 (m, 1H), 7.10 (m, 1H), 6.96 (m, 1H), 6.15 (s, 1H), 3.49 (s, 3H), 2.86 (d, J=5 Hz, 3H); MS (ESI) m/z: 452.0 [M+H] ⁺ .

[00229] Example 8: Using General Method B, 1-isocyanatonaphthalene (0.050 g, 0.296 mmol) was reacted with Example A41 (0.070 g, 0.210 mmol) in EtOAc (2 mL) at RT for 13 hours to give 1 -(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)phenyl)-3-(naphthalene -1-yl)urea (0.07 g, yield 67%). ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 9.18 (s, 2H), 8.40 (s, 1H), 8.26 (d, J=9 Hz, 1H), 8.14 ( d, J=9 Hz, 1H), 7.98 (d, J=7 Hz, 1H), 7.90 (d, J=8 Hz, 1H), 7.74 (s, 1H), 7.60 (m, 3H), 7.43 (t, J=8 Hz, 1H), 7.11 (m, 1H), 7.26 (m, 1H), 6.16 (s, 1H), 3.49 (s, 3H), 2.86 (d, J=5 Hz, 3H); MS (ESI) m/z: 502.0 [M+H] ⁺ .

[00230] Example 9: Using General Method B, 3-isocyanatobenzonitrile (0.050 g, 0.347 mmol) was reacted with Example A41 (0.070 g, 0.210 mmol) in EtOAc (2 mL) for 13 hours to give 1-( 4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)phenyl)-3-(3-cyanophenyl )urea (0.090 g, yield 90%). ^1H NMR (400 MHz, DMSO- _d6 ): δ 9.42 (s, 1H), 8.86 (brs, 1H), 8.44 (s, 1H), 8.17 (d, J =9 Hz, 1H), 7.99 (m, 1H), 7.77 (s, 1H), 7.63 (m, 1H), 7.58 (d, J=11.5 Hz, 1H), 7.51 (t, J=7 Hz, 1H), 7.45 (m, 1H), 7.14 (m, 1H), 6.19 (s, 1H), 3.52 (s, 3H), 2.86 (d, J=5 Hz, 3H); MS (ESI) m/z: 477.0 [M+H] ⁺ .

[00231] Example 10: Using General Method A, 2,3-difluorobenzoic acid (0.071 g, 0.449 mmol), TEA (0.091 g, 0.898 mmol), DPPA (0.124 g, 0.449 mmol) and the compound of Example A41 (0.100 g , 0.299 mmol) were combined to give 1-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl )phenyl)-3-(2,3-difluorophenyl)urea (0.070 g, 48% yield). ^1H NMR (400 MHz, DMSO- _d6 ): δ 9.26 (brs, 1H), 9.22 (brs, 1H), 8.42 (s, 1H), 8.20 (d , J=10 Hz, 1H), 7.94 (m, 1H), 7.77 (s, 1H), 7.57 (d, J=12 Hz, 1H), 7.12 (m, 2H), 7.04 (m, 1H), 6.18 (s, 1H), 3.51 (s, 3H), 2.86 (d, J=5 Hz, 3H); MS (ESI) m/z: 488.0 [M+H] ⁺ .

[00232] Example 11: Using General Method B, 3-isocyanatobenzonitrile (0.070 g, 0.486 mmol) was reacted with Example A42 (0.070 g, 0.222 mmol) in EtOAc (2 ml) for 13 hours to give 1-( 4-chloro-3-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)phenyl)-3-(3-cyanophenyl)-urea ( 55 mg, yield 54%). ^1H NMR (400 MHz, DMSO- _d6 ): δ 9.13 (s, 1H), 9.07 (s, 1H), 8.45 (s, 1H), 8.00 (m, 1H), 7.79 (s, 1H), 7.69 (m, 1H), 7.59 (m, 1H), 7.52 (m, 1H), 7.47-7.44 (m, 3H), 7 .17 (m, 1H), 6.22 (s, 1H), 3.55 (s, 3H), 2.90 (d, J=4.8 Hz, 3H); MS (ESI) m/z: 459.0 [M+H] ⁺ .

[00233] Example 12: Using General Method B, 3-isocyanatobenzonitrile (0.032 g, 0.224 mmol) was reacted with Example A39 (0.070 g, 0.224 mmol) in EtOAc (5 mL) for 20 hours to give 1-( 3-cyanophenyl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)urea (17 mg , yield 17%). ^1H NMR (400 MHz, DMSO- _d6 ): δ 9.39 (s, 1H), 8.71 (d, J=2.3 Hz, 1H), 8.46 (s, 1H), 8. 36 (dd, J=8.0, 2.2 Hz, 1H), 8.00 (t, J=1.8 Hz, 1H), 7.87 (s, 1H), 7.63 (ddd, J =8.2, 2.2, 1.2 Hz, 1H), 7.49 (t, J=7.9 Hz, 1H), 7.43 (dt, J=7.6, 1.4 Hz, 1H), 7.34-7.22 (m, 2H), 7.03 (m, 1H), 6.22 (s, 1H), 4.16 (q, J=7.0 Hz, 2H), 2.85 (d, J=4.8 Hz, 3H), 1.22 (t, J=7.0 Hz, 3H); MS (ESI) m/z: 457.2 [M+H] ⁺ .

[00234] Example 13: Using General Method A, benzothiophene-3-carboxylic acid (103 mg, 0.576 mmol), TEA (194 mg, 1.921 mmol), DPPA (165 mg, 0.600 mmol) and the compound of Example A43 (0.100 g , 0.299 mmol) were combined to give 1-(benzo[b]thiophen-3-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1 ,2-dihydro-1,6-naphthyridin-3-yl)phenyl)urea (140 mg, 59% yield). ^1H NMR (400 MHz, DMSO- _d6 ): δ 9.42 (s, 1H), 8.85 (s, 1H), 8.40 (s, 1H), 8.03 (d, J=8 .5 Hz, 1H), 7.95 (d, J=8.0 Hz, 1H), 7.88 (d, J=8.1 Hz, 1H), 7.68 (d, J=6.5 Hz, 2H), 7.48 (m, 1H), 7.41 (m, 1H), 7.16 (d, J=12.3 Hz, 1H), 7.03 (m, 1H), 6, 18 (s, 1H), 3.51 (s, 3H), 2.86 (d, J=4.4 Hz, 3H), 2.08 (s, 3H); MS (ESI) m/z: 488.1 [M+H] ⁺ .

[00235] Example 14: Using General Method A benzo[b]thiophene-3-carboxylic acid (0.101 g, 0.569 mmol), TEA (0.144 g, 1.423 mmol), DPPA (0.196 g, 0.711 mmol) and the compound of Example A44 (0.150 g, 0.474 mmol) was combined to give 1-(benzo[b]thiophen-3-yl)-3-(2,4-difluoro-5-(1-methyl-7-(methylamino)-2-oxo -1,2-dihydro-1,6-naphthyridin-3-yl)phenyl)urea (177 mg, 76% yield). ^1H NMR (400 MHz, DMSO- _d6 ): δ 9.39 (s, 1H), 8.85 (s, 1H), 8.43 (s, 1H), 8.26 (t, J=8 .5 Hz, 1H), 7.96 (d, J=8.1 Hz, 1H), 7.87 (d, J=8.0 Hz, 1H), 7.84 (s, 1H), 7. 69 (s, 1H), 7.49 (t, J=7.6 Hz, 1H), 7.44-7.36 (m, 2H), 7.12-7.10 (m, 1H), 6 .17 (s. 1H), 3.51 (s, 3H), 2.86 (d, J=4.8 Hz, 3H); MS (ESI) m/z: 492.0 [M+H] ⁺ .

[00236] Example 15: 3-fluorophenyl isocyanate (81 mg, 0.444 mmol) was added to a solution of the compound of Example A7 (200 mg, 0.444 mmol) in THF (5 ml) and the mixture was stirred at RT overnight. The reaction mixture was further treated with isocyanate (10 mg) and stirred at RT for another 4 hours. The mixture was diluted with EtOAc, washed successively with water, sat. NaHCO ₃ and brine, dried (Na ₂ SO ₄ ), concentrated in vacuo, purified by reverse phase chromatography (MeCN/water with 0.1% TFA) and partially concentrated to an aqueous solution. The solution was diluted for us. NaHCO ₃ , extracted with EtOAc (2×) and the combined organic layers were washed with brine, dried (Na ₂ SO ₄ ) and evaporated under reduced pressure to give 1-(5-(7-((4-methoxybenzyl)(methyl)amino) -1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2,4-difluorophenyl)-3-(3-fluorophenyl)urea (207 mg, 79% yield, purity -75%) as a light yellow solid, which was used without further purification. MS (IER-AD) m/z: 588.2 [M+H] ⁺ .

[00237] 1-(5-(7-((4-methoxybenzyl)(methyl)amino)-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2 solution ,4-difluorophenyl)-3-(3-fluorophenyl)urea (267 mg, 0.421 mmol) in TFA (3 ml) was stirred at RT for 40 minutes. The mixture was evaporated under reduced pressure, dissolved in EtOAc, and washed. NaHCO ₃ then brine, dried (Na ₂ SO ₄ ), concentrated in vacuo, purified by reverse phase chromatography (MeCN/water with 0.1% TFA) and partially concentrated to an aqueous solution. The aqueous solution was diluted for us. NaHCO ₃ and left to settle. The white solid was collected by filtration, washed with water and dried in vacuo to give 1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl )-2,4-difluorophenyl)-3-(3-fluorophenyl)urea (83 mg, 50% yield). ^1H NMR (400 MHz, DMSO- _d6 ): δ 9.50 (brs, 1H), 8.80 (brs, 1H), 8.42 (s, 1H), 8.10-8 .00 (m, 1H), 7.82 (s, 1H), 7.48 (d, 1H), 7.40-7.30 (m, 2H), 7.15-7.05 (m, 2H ), 6.80-6.70 (m, 1H), 5.99 (s, 1H), 4.13 (m, 2H), 2.85 (s, 3H), 1.21 (m, 3H) ; MS (IER-AD) m/z: 468.1 [M+H] ⁺ .

[00238] Example 16: Phenyl isocyanate (58 mg, 0.488 mmol) was added to a solution of Example A7 (200 mg, 0.444 mmol) and pyridine (140 mg, 1.776 mmol) in THF (5 ml) and the mixture was stirred at RT for nights. The mixture was diluted with EtOAc, water and us. _NaHCO3 ; the resulting precipitate was collected by filtration, washed with EtOAc and dried in vacuo to give 1-(5-(7-((4-methoxybenzyl)(methyl)amino)-1-ethyl-2-oxo-1,2-dihydro-1. 6-naphthyridin-3-yl)-2,4-difluorophenyl)-3-phenylurea (219 mg, 87% yield). MS (IER-AD) m/z: 570.2 [M+H] ⁺ .

[00239] 1-(5-(7-((4-methoxybenzyl)(methyl)amino)-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2 solution ,4-difluorophenyl)-3-phenylurea (219 mg, 0.384 mmol) in TFA (2.0 ml) was stirred at RT for 1 hour. The mixture was concentrated in vacuo, dissolved in EtOAc, and washed. NaHCO ₃ and saline, dried (Na ₂ SO ₄ ), heated to recondensation temperature in MeOH (5 ml) using a desiccant, filtered the desiccant (hot), concentrated in vacuo and treated with 4M HCl/dioxane (0. 2 ml). The mixture was evaporated under reduced pressure and then triturated with Et ₂ O. The solid was collected by filtration, purified by reverse phase chromatography (MeCN/water with 0.1% TFA) and concentrated in vacuo to give an aqueous residue. We were treated with an aqueous solution. NaHCO ₃ and left to settle. The solid was collected by filtration, washed with water and dried in vacuo to give 1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl) -2,4-difluorophenyl)-3-phenylurea (87 mg, 50% yield). ^1H NMR (400 MHz, DMSO- _d6 ): δ 9.01 (s, 1H), 8.52 (s, 1H), 8.42 (s, 1H), 8.12 (m, 1H), 7.81 (s, 1H), 7.42-7.24 (m, 5H), 7.05-6.94 (m, 2H), 6.23 (s, 1H), 4.13 (m, 2H), 2.85 (s, 3H), 1.20 (m, 3H); MS (IER-AD) m/z: 450.1 [M+H] ⁺ .

[00240] Example 17: Using a method similar to that described in Example 16, the compound of Example A7 (200 mg, 0.444 mmol) and 3-chlorophenyl isocyanate (58 mg, 0.488 mmol) were combined to give 1-(5-(7-( (4-methoxybenzyl)(methyl)amino)-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2,4-difluorophenyl)-3-(3-chlorophenyl) urea (229 mg, yield 85%). MS (IER-AD) m/z: 604.2 [M+H] ⁺ .

[00241] Using a method similar to that described in Example 16, 1-(5-(7-((4-methoxybenzyl)(methyl)amino)-1-ethyl-2-oxo-1,2-dihydro-1,6 -naphthyridin-3-yl)-2,4-difluorophenyl)-3-(3-chlorophenyl)urea (219 mg, 0.384 mmol) was converted to 1-(3-chlorophenyl)-3-(5-(1-ethyl- 7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2,4-difluorophenyl)urea (98 mg, 53% yield). ^1H NMR (400 MHz, DMSO- _d6 ): δ 9.20 (brs, 1H), 8.65 (brs, 1H), 8.42 (s, 1H), 8.08 (t , 1H), 7.82 (s, 1H), 7.70 (s, 1H), 7.38-7.19 (m, 3H), 7.05 (s, 1H), 7.01-6, 99 (m, 1H), 6.21 (s, 1H), 4.14 (q, 2H), 2.85 (s, 3H), 1.19 (t, 3H); MS (IER-AD) m/z: 488.1 [M+H] ⁺ .

[00242] Example 18: Using a method similar to that described in Example 16, the compound of Example A7 (200 mg, 0.444 mmol) and 3-cyanophenyl isocyanate (70 mg, 0.488 mmol) were combined to give 1-(5-(7-( (4-methoxybenzyl)(methyl)amino)-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2,4-difluorophenyl)-3-(3-cyanophenyl) urea (240 mg, yield 91%). MS (IER-AD) m/z: 595.2 [M+H] ⁺ .

[00243] Using a method similar to that described in Example 16, 1-(5-(7-((4-methoxybenzyl)(methyl)amino)-1-ethyl-2-oxo-1,2-dihydro-1,6 -naphthyridin-3-yl)-2,4-difluorophenyl)-3-(3-cyanophenyl)urea (219 mg, 0.384 mmol) was converted to 1-(3-cyanophenyl)-3-(5-(1-ethyl- 7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2,4-difluorophenyl)urea (108 mg, 56% yield). ^1H NMR (400 MHz, DMSO- _d6 ): δ 9.05 (brs, 2H), 8.42 (s, 1H), 8.06 (m, 1H), 7.96 (s, 1H ), 7.81 (s, 1H), 7.63-7.60 (m, 1H), 7.49-7.33 (m, 3H), 7.05 (br.s, 1H), 6, 23 (s, 1H), 4.14 (q, 2H), 2.85 (s, 3H), 1.20 (t, 3H); MS (IER-AD) m/z: 475.2 [M+H] ⁺ .

[00244] Example 19: Using General Method A benzo[b]thiophene-3-carboxylic acid (113 mg, 0.636 mmol), TEA (245 mg, 2.422 mmol), DPPA (200 mg, 0.727 mmol) and the compound of Example A8 (200 mg, 0.605 mmol) was combined and purified by precipitation to give 1-(benzo[b]thiophen-3-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1 ,2-dihydro-1,6-naphthyridin-3-yl)-2,4-difluorophenyl)urea (153 mg, 50% yield). ^1H NMR (400 MHz, DMSO- _d6 ): δ 9.51 (s, 1H), 8.94 (s, 1H), 8.43 (s, 1H), 8.23 (t, 1H), 7.96-7.91 (m, 2H), 7.83 (s, 1H), 7.68 (s, 1H), 7.49-7.35 (m, 3H), 7.07-7, 05 (m, 1H), 6.23 (s, 1H), 4.14 (q, 2H), 2.85 (s, 3H), 1.21 (t, 3H); MS (IER-AD) m/z: 506.1 [M+H] ⁺ .

[00245] Example 20: DMF (0.2 mL) and 3-fluorophenyl isocyanate (67 mg, 0.486 mmol) were added to a suspension of Example A9 (200 mg, 0.442 mmol) and pyridine (140 mg, 1.766 mmol) in THF ( 5 ml) and the mixture was stirred at RT overnight. The mixture was diluted with EtOAc and water, heated, then cooled to rt and the resulting solid was collected by filtration. The solid was washed with EtOAc and dried in vacuo to give 1-(5-(7-(4-methoxybenzylamino)-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-4 -chloro-2-fluorophenyl)-3-(3-fluorophenyl)urea (206 mg, 79% yield). MS (IER-AD) m/z: 590.2 [M+H] ⁺ .

[00246] Using a method similar to that described in Example 15, 1-(5-(7-(4-methoxybenzylamino)-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl )-4-chloro-2-fluorophenyl)-3-(3-fluorophenyl)urea (204 mg, 0.346 mmol) was converted to 1-(5-(7-amino-1-ethyl-2-oxo-1,2- Dihydro-1,6-naphthyridin-3-yl)-4-chloro-2-fluorophenyl)-3-(3-fluorophenyl)urea (66 mg, 40% yield). ^1H NMR (400 MHz, DMSO- _d6 ): δ 9.29 (s, 1H), 8.74 (s, 1H), 8.35 (s, 1H), 8.13 (d, 1H), 7.77 (s, 1H), 7.53 (d, 1H), 7.47-7.43 (m, 1H), 7.32-7.26 (m, 1H), 7.07-7, 04 (m, 1H), 6.81-6.76 (m, 1H), 6.54 (s, 2H), 6.33 (s, 1H), 4.08 (q, 2H), 1.20 (t, 3H); MS (IER-AD) m/z: 470.1 [M+H] ⁺ .

[00247] Example 21: DMF (0.2 ml) and phenyl isocyanate (58 mg, 0.486 mmol) were added to a suspension of the compound of Example A9 (200 mg, 0.442 mmol) and pyridine (140 mg, 1.766 mmol) in THF (5 ml ) and the mixture was stirred at RT overnight. The mixture was diluted with EtOAc and water and heated. The organic phase was separated, washed with brine, dried (Na ₂ SO ₄ ), concentrated in vacuo, purified by reverse phase chromatography (MeCN/water with 0.1% TFA) and concentrated to give an aqueous residue. The watery residue was treated for us. NaHCO ₃ and left to settle. The solid was collected by filtration, washed with water and dried in vacuo to give 1-(5-(7-(4-methoxybenzylamino)-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridine-3- yl)-4-chloro-2-fluorophenyl)-3-phenylurea (56 mg, 22% yield). MS (IER-AD) m/z: 572.2 [M+H] ⁺ .

[00248] Using a method similar to that described in Example 15, 1-(5-(7-(4-methoxybenzylamino)-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl )-4-chloro-2-fluorophenyl)-3-phenylurea (109 mg, 0.191 mmol) was converted to 1-(5-(7-amino-1-ethyl-2-oxo-1,2-dihydro-1,6 -naphthyridin-3-yl)-4-chloro-2-fluorophenyl)-3-phenylurea (45 mg, 53% yield). MS (IER-AD) m/z: 452.1 [M+H] ⁺ .

[00249] Into a solution of 1-(5-(7-amino-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-4-chloro-2-fluorophenyl)-3 α-phenylurea (45 mg, 0.100 mmol) in DCM (4 ml), a 25 mg/ml solution of methanesulfonic acid in DCM (0.424 ml, 0.110 mmol) was added, the mixture was stirred for 15 minutes and then evaporated under reduced pressure to obtain a solid. The solid was dissolved in MeCN and water, frozen and lyophilized to give 1-(5-(7-amino-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-4 methanesulfonate -chloro-2-fluorophenyl)-3-phenylurea (1.4 eq.) (53 mg, 97% yield). ^1H NMR (400 MHz, DMSO- _d6 ): δ 9.12 (s, 1H), 8.76 (s, 1H), 8.56 (s, 1H), 8.21 (d, 1H), 7.92 (s, 1H), 7.90 (br.s, 2H), 7.60-7.56 (m, 1H), 7.42-7.40 (m, 2H), 7.28- 7.24 (m, 2H), 6.98-6.95 (m, 1H), 6.74 (s, 1H), 4.12 (q, 2H), 2.34 (s, ~4H), 1.23 (t, 3H); MS (IER-AD) m/z: 452.1 [M+H] ⁺ .

[00250] Example 22: Example A11 (0.12 g, 0.33 mmol), TEA (0.046 mL, 0.33 mmol) and phenyl isocyanate (0.044 g, 0.36 mmol) were combined in THF (4 mL) , stirred at RT for 20 hours, concentrated in vacuo and purified by silica gel chromatography (EtOAc/DCM) to give 1-(4-chloro-2-fluoro-5-(1-isopropyl-7-(methylamino)-2 -oxo-1,2-dihydro-1,6-naphthyridin-3-yl)phenyl)-3-phenylurea (97 mg, 61% yield) as a white solid. ^1H NMR (400 MHz, DMSO- _d6 ): δ 9.07 (s, 1H), 8.67 (d, J=2.0 Hz, 1H), 8.37 (s, 1H), 8. 16 (d, J=8.8 Hz, 1H), 7.67 (s, 1H), 7.51 (d, J=10.8 Hz, 1H), 7.41 (d, J=7.6 Hz, 2H), 7.28-7.24 (m, 2H), 6.98-6.94 (m, 2H), 6.44 (s, 1H), 5.31-4.82 (br. s, 1H), 2.85 (d, J=4.8 Hz, 3H), 1.51 (d, J=7.2 Hz, 6H); MS (ESI) m/z: 480.2 [M+H] ⁺ .

[00251] Example 23: A solution of pyridine (0.248 ml, 3.06 mmol) and phenyl isocyanate (0.100 ml, 0.919 mmol) in DMF (0.4 ml) was added to a solution of the compound of Example A2 (0.25 g, 0.766 mmol) in THF (5 ml) and the mixture was stirred at RT. After 14 hours, the solid was filtered, washed with THF and dried in vacuo to give 1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl )-2-fluoro-4-methylphenyl)-3-phenylurea (280 mg, 79% yield). ^1H NMR (400 MHz, DMSO- _d6 ): δ 9.00 (s, 1H), 8.46 (d, J=2.0 Hz, 1H), 8.40 (s, 1H), 7. 93 (d, J=8.4 Hz, 1H), 7.66 (s, 1H), 7.40 (m, 2H), 7.25 (m, 2H), 7.12 (d, J=12 .4 Hz, 1H), 6.96 (m, 2H), 6.24 (s, 1H), 4.14 (q, J=6.8 Hz, 2H), 2.85 (d, J=4 ,8 Hz, 3H), 2.06 (s, 3H), 1.21 (t, J=6.8 Hz, 3H); MS (ESI) m/z: 446.2 [M+H] ⁺ .

[00252] Example 24: A solution of the compound of Example A5 (200 mg, 0.58 mmol) and pyridine (68 mg, 0.87 mmol) in THF (20 ml) at 0° C. was treated with 1-fluoro-3-isocyanatobenzene ( 80 mg, 0.58 mmol), heated to RT and stirred for 3 hours. The mixture was concentrated in vacuo and purified by preparative HPLC to give 1-[4-chloro-5-(1-ethyl-7-methylamino-2-oxo-1,2-dihydro-[1,6]naphthyridin-3-yl) -2-fluorophenyl]-3-(3-fluorophenyl)urea (193 mg, 69% yield). ^1H NMR (400 MHz, DMSO- _d6 ): δ 9.34 (s, 1H), 8.78 (s, 1H), 8.51 (s, 1H), 8.19 (d, J=8 ,4 Hz, 1H), 7.85 (s, 1H), 7.87-7.49 (broads, 1H), 7.59 (d, J=10.8 Hz, 1H), 7.48 (d, J=11.6 Hz, 1H), 7.33 (m, 1H), 7.08 (m, 1H), 6.83 (m, 1H), 6.44 (s, 1H), 4 .18 (m, 2H), 2.94 (s, 3H), 1.24 (t, J=6.8 Hz, 3H); MS (ESI): m/z 484.1 [M+H] ⁺ .

[00253] Example 25: Using a method similar to that described in Example 24, the compound of Example A5 (400 mg, 1.16 mmol) and 1-fluoro-2-isocyanatobenzene (158 mg, 1.16 mmol) were converted to 1- [4-chloro-5-(1-ethyl-7-methylamino-2-oxo-1,2-dihydro-[1,6]naphthyridin-3-yl)-2-fluorophenyl]-3-(2-fluorophenyl) urea (144 mg, yield 26%). ^1H NMR (400 MHz, DMSO- _d6 ): δ 9.22 (s, 1H), 9.10 (s, 1H), 8.52 (s, 1H), 8.25 (d, J=8 ,4 Hz, 1H), 8.12 (t, J=8 Hz, 1H), 7.87-7.57 (lat.s, 1H), 7.86 (s, 1H), 7.59 (d , J=11.2 Hz, 1H), 7.26 (m, 1H), 7.13 (m, 1H), 7.04 (m, 1H), 6.47 (s, 1H), 4.18 (m, 2H), 2.95 (s, 3H), 1.24 (t, J=6.8 Hz, 3H); MS (ESI): m/z 484.1 [M+H] ⁺ .

[00254] Example 26: A solution of the compound of Example A45 (0.09 g, 0.260 mmol) in THF (3 mL) was treated with TEA (0.036 mL, 0.260 mmol) and phenyl isocyanate (0.034 g, 0.285 mmol) and stirred at RT for nights. Additional phenyl isocyanate (0.034 g, 0.285 mmol) was added and the mixture was heated at 60°C for 5 hours. The mixture was concentrated to dryness and purified by silica gel chromatography (MeOH/DCM) to give 1-(4-chloro-3-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6- naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea (101 mg, 84% yield) as a white solid. ^1H NMR (500 MHz, DMSO- _d6 ): δ 9.08 (s, 1H), 8.65 (d, J=2.7 Hz, 1H), 8.44 (s, 1H), 8. 20 (t, J=8.7 Hz, 1H), 7.86 (s, 1H), 7.46-7.45 (m, 2H), 7.35 (dd, J=9.0, 1, 4 Hz, 1H), 7.30 (t, J=7.8 Hz, 2H), 7.13 (q, J=4.9 Hz, 1H), 7.00 (t, J=7.4 Hz , 1H), 6.28 (s, 1H), 4.16 (q, J=7.0 Hz, 2H), 2.88 (d, J=4.9 Hz, 3H), 1.23 (t , J=7.0 Hz, 3H); MS (ESI): m/z 466.1 [M+H] ⁺ .

[00255] Example 27: A suspension of Example A12 (0.300 g, 0.768 mmol) in EtOAc (6 mL) was treated with phenyl isocyanate (0.091 g, 0.768 mmol), stirred at RT for 13 hours, and the resulting solid collected by vacuum filtration . White solids were stirred in boiling MeCN for 20 minutes, then stirred at RT for 1 hour. The solids were collected by vacuum filtration, washed and dried to give 1-(4-chloro-5-(1-ethyl-7-(2-methoxyethylamino)-2-oxo-1,2-dihydro-1,6-naphthyridine- 3-yl)-2-fluorophenyl)-3-phenylurea (0.233 g, 60% yield) as a white solid. MS (ESI) m/z: 510.2 [M+H] ⁺ .

[00256] A suspension of 1-(4-chloro-5-(1-ethyl-7-(2-methoxyethylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl )-3-phenylurea (0.233 g, 0.457 mmol) in MeCN (10 ml) was treated with methanesulfonic acid (0.044 g, 0.457 mmol). The crystallized solids were filtered off, washed and dried to give 1-(4-chloro-5-(1-ethyl-7-(2-methoxyethylamino)-2-oxo-1,2-dihydro-1,6-naphthyridine-3 methanesulfonate -yl)-2-fluorophenyl)-3-phenylurea as a white solid (0.210 g, 76% yield). ^1H NMR (400 MHz, DMSO- _d6 ): δ 9.13 (s, 1H), 8.70 (s, 1H), 8.54 (s, 1H), 8.22 (d, J=9 Hz, 2H), 7.90 (s, 1H), 7.58 (d, J=12 Hz, 1H), 7.42 (d, J=8 Hz, 2H), 7.26 (t, J= 8 Hz, 2H), 6.97 (t, J=8.5 Hz, 1H), 6.74 (s, 1H), 4.16 (m, 2H), 3.57 (m, 4H), 3 .29 (s, 3H), 2.34 (s, 3H), 1.20 (t, J=6 Hz, 3H); MS (ESI) m/z: 510.2 [M+H] ⁺ .

[00257] Example 28: To a suspension of the compound of Example A12 (0.300 g, 0.768 mmol) in EtOAc (6 ml) was added 3-fluorophenyl isocyanate (0.105 g, 0.768 mmol). The mixture was stirred at RT for 13 hours and solids were collected from the reaction mixture by vacuum filtration. White solids were stirred in boiling MeCN for 20 minutes, then stirred at RT for 1 hour. The solids were filtered, washed and dried to give 1-(4-chloro-5-(1-ethyl-7-(2-methoxyethylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl )-2-fluorophenyl)-3-(3-fluorophenyl)urea (0.300 g, 74% yield) as a white solid. MS (ESI) m/z: 528.2 [M+H] ⁺ .

[00258] Into a suspension of 1-(4-chloro-5-(1-ethyl-7-(2-methoxyethylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2- fluorophenyl)-3-(3-fluorophenyl)urea (0.300 g, 0.568 mmol) in MeCN (10 ml) was added methanesulfonic acid (0.055 g, 0.568 mmol). After stirring at RT for 1 hour, the solvent was completely evaporated and the residue was crystallized from EtOH to give 1-(4-chloro-5-(1-ethyl-7-(2-methoxyethylamino)-2-oxo-1,2- methanesulfonate Dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-(3-fluorophenyl)urea as a white solid (0.295 g, 83% yield). ^1H NMR (400 MHz, DMSO- _d6 ): δ 9.37 (s, 1H), 8.84 (s, 1H), 8.55 (s, 1H), 8.30 (s, 1H), 8.18 (d, J=8 Hz, 1H), 7.91 (s, 1H), 7.59 (d, J=11 Hz, 1H), 7.47 (m, 1H), 7.29 ( m, 1H), 7.07 (m, 1H), 6.77 (m, 2H), 4.15 (m, 2H), 3.56 (m, 4H), 3.30 (s, 3H), 2.37 (s, 3H), 1.20 (t, J=6 Hz, 3H); MS (ESI) m/z: 528.2 [M+H] ⁺ .

[00259] Example 29: To a suspension of the compound of Example A15 (0.300 g, 0.743 mmol) in EtOAc (6 ml) was added phenyl isocyanate (0.088 g, 0.743 mmol) and the mixture was stirred at RT for 13 hours. The solids were filtered, washed and dried to give 1-(4-chloro-5-(7-(2-(dimethylamino)ethylamino)-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridine- 3-yl)-2-fluorophenyl)-3-phenylurea (320 mg, 82% yield) as a white solid. MS (ESI) m/z: 524.2 [M+H] ⁺ .

[00260] Into a suspension of 1-(4-chloro-5-(7-(2-(dimethylamino)ethylamino)-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl) -2-fluorophenyl)-3-phenylurea (0.260 g, 0.497 mmol) in MeOH (1 ml), HCl (1.25 M in MeOH) (0.875 ml, 1.094 mmol) was added and the mixture was stirred at RT for 1 hour. The reaction mixture was diluted with EtOAc, the remaining solid was filtered off, washed and dried to give 1-(4-chloro-5-(7-(2-(dimethylamino)ethylamino)-1-ethyl-2-oxo-1,2-dihydro dihydrochloride -1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea (267 mg, 90% yield) as a white solid. ^1H NMR (400 MHz, DMSO- _d6 ): δ 9.37 (s, 1H), 8.83 (s, 1H), 8.44 (s, 1H), 8.17 (d, J=9 Hz, 1H), 7.78 (m, 1H), 7.52 (d,.1=11 Hz, 1H), 7.42 (m, 2H), 7.25 (m, 3H), 6.95 (t, J=8 Hz, 1H), 6.42 (s, 1H), 4.13 (m, 2H), 3.63 (m, 2H), 3.02 (s, 2H), 2.64 (s, 6), 1.20 (t, J=6 Hz, 3H); MS (ESI) m/z: 523.2 [M+H] ⁺ .

[00261] Example 30: To a suspension of the compound of Example A16 (0.320 g, 0.766 mmol) in EtOAc (6 ml) was added phenyl isocyanate (0.091 g, 0.766 mmol) and the mixture was stirred at RT for 13 hours. The residue obtained after evaporation of the solvent was purified by silica gel chromatography (THF/EtOAc) to give 1-(4-chloro-5-(7-(3-(dimethylamino)propylamino)-1-ethyl-2-oxo-1, 2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea (132 mg, 32% yield) as a white solid. MS (ESI) m/z: 537.2 [M+H] ⁺ .

[00262] Into a suspension of 1-(4-chloro-5-(7-(3-(dimethylamino)propylamino)-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl) -2-fluorophenyl)-3-phenylurea (0.130 g, 0.242 mmol) in MeOH (1 ml), HCl (1.25 M in MeOH, 0.426 ml, 0.533 mmol) was added and the mixture was stirred at RT for 1 hour. The reaction mixture was diluted with EtOAc, filtered, washed and dried to give 1-(4-chloro-5-(7-(3-(dimethylamino)propylamino)-1-ethyl-2-oxo-1,2-dihydro-1 dihydrochloride, 6-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea (118 mg, 80% yield) as a white solid. ^1H NMR (400 MHz, DMSO- _d6 ): δ 9.44 (s, 1H), 8.86 (s, 1H), 8.43 (s, 1H), 8.17 (d, J=9 Hz, 1H), 7.76 (s, 1H), 7.52 (d, J=9 Hz, 1H), 7.42 (m, 2H), 7.25 (m, 3H), 6.96 ( t, J=7 Hz, 1H), 6.34 (s, 1H), 4.12 (m, 2H), 3.42 (m, 2H), 3.10 (m, 2H), 2.75 ( s, 6H), 1.93 (m, 2H), 1.18 (t, J=6 Hz, 3H); MS (ESI) m/z: 537.2 [M+H] ⁺ .

[00263] Example 31: A mixture of Example A14 (0.120 g, 0.307 mmol) and TEA (0.043 mL, 0.307 mmol) in THF (3.0 mL) was treated with phenyl isocyanate (0.040 g, 0.337 mmol) and stirred at RT for 4 hours. Over the next 4 days, the mixture was further treated with phenyl isocyanate (0.056 ml) and stirred at RT. The resulting solid was filtered, washed with THF, then triturated with MeOH to give 1-(4-bromo-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridine- 3-yl)-2-fluorophenyl)-3-phenylurea (101 mg, 64.5% yield) as a bright white solid. ^1H NMR (400 MHz, DMSO- _d6 ): δ 9.09 (s, 1H), 8.68 (s, 1H), 8.41 (s, 1H), 8.17 (d, 1H), 7.70 (s, 1H), 7.65 (d, 1H), 7.41 (d, 2H), 7.27 (m, 2H), 7.03 (m, 1H), 6.96 (t , 1H), 6.23 (s, 1H), 4.13 (q, 2H), 2.86 (d, 3H), 1.20 (t, 3H); MS (ESI) m/z: 510.1 [M+H] ⁺ .

[00264] Example 32: The compound of Example A5 (0.2 g, 0.577 mmol), benzothiophene-3-carboxylic acid (0.134 g, 0.750 mmol) and TEA (0.322 ml, 2.307 mmol) were suspended in dioxane (5 ml), treated with DPPA (0.186 ml, 0.865 mmol) and heated to 100°C for 3 hours. The mixture was cooled to RT and the precipitate was filtered and dried to give 1-(benzo[b]thiophen-3-yl)-3-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo- 1,2,4a,8a-tetrahydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)urea (215 mg, 71% yield), which was suspended in boiling MeCN (6 ml). Methanesulfonic acid (0.027 ml, 0.412 mmol) was added, then MeOH (1 ml) was added. The mixture was cooled to RT, left to settle for 2 hours, treated with Et ₂ O (3 ml) and ultrasound for 5 minutes. The resulting solid was collected by filtration and dried to give 1-(benzo[b]thiophen-3-yl)-3-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1 mesylate ,2,4a,8a-tetrahydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)urea (209 mg, 82% yield). ^1H NMR (400 MHz, DMSO- _d6 ): δ 9.48 (s, 1H), 9.06 (s, 1H), 8.54 (s, 1H), 8.32 (d, 1H), 8.01 (br.s, 1H), 7.96 (d, 1H), 7.91 (s, 1H), 7.86 (d, 1H), 7.68 (s, 1H), 7.62 (d, 1H), 7.49 (t, 1H), 7.42 (t, 1H), 6.55 (s, 1H), 4.17 (q, 2H), 2.96 (s, 3H) , 2.30 (s, 3H), 1.22 (t, 3H); MS (ESI) m/z: 522.1 [M+H] ⁺ .

[00265] Example 33: A solution of the compound of Example A46 (0.12 g, 0.365 mmol) in pyridine (3 ml) was treated with phenyl isocyanate (0.044 ml, 0.401 mmol) and stirred at RT overnight. The mixture was concentrated to dryness, the residue was treated with MeCN then sonicated and the resulting solid was collected by filtration and dried to give 1-(4-chloro-3-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro -1,6-naphthyridin-3-yl)phenyl)-3-phenylurea (166 mg, 102% yield). MS (ESI) m/z: 448.1 [M+H] ⁺ .

[00266] 1-(4-chloro-3-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)phenyl)-3-phenylurea suspension (0.166 g, 0.371 mmol) in boiling MeCN (5 ml) was treated with methanesulfonic acid (0.026 ml, 0.408 mmol), cooled to RT, treated with water, frozen and lyophilized. The resulting material was treated with EtOAc, then sonicated and collected by filtration to give 1-(4-chloro-3-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridine-methanesulfonate 3-yl)phenyl)-3-phenylurea (172 mg, 85% yield). ^1H NMR (400 MHz, DMSO- _d6 ): δ 8.96 (s, 1H), 8.81 (s, 1H), 8.54 (s, 1H), 8.08 (brs, 1H ), 7.89 (s, 1H), 7.62 (t, J=1.4 Hz, 1H), 7.45-7.39 (m, 4H), 7.25 (t, J=7, 8 Hz, 2H), 6.95 (t, J=7.3 Hz, 1H), 6.57 (s, 1H), 4.18 (q, J=7.1 Hz, 2H), 2.97 (s, 3H), 2.33 (s, 3H), 1.22 (t, J=7.0 Hz, 3H); MS (ESI) m/z: 448.1 [M+H] ⁺ .

[00267] Example 34: To a suspension of the compound of Example A12 (0.200 g, 0.512 mmol) in EtOAc (5 ml) was added 1-fluoro-4-isocyanatobenzene (0.093 g, 0.681 mmol) and the mixture was stirred at RT for 16 hours. The solids were filtered, washed and dried to give 1-(4-chloro-5-(1-ethyl-7-(2-methoxyethylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl )-2-fluorophenyl)-3-(4-fluorophenyl)urea (0.220 g, 81% yield) as a white solid. MS (ESI) m/z: 528.2 [M+H] ⁺ .

[00268] A suspension of 1-(4-chloro-5-(1-ethyl-7-(2-methoxyethylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl )-3-(4-fluorophenyl)urea (0.220 g, 0.417 mmol) in MeCN (10 ml) was treated with methanesulfonic acid (0.044 g, 0.458 mmol) and stirred at RT for 20 hours. The solids were filtered, washed and dried to give 1-(4-chloro-5-(1-ethyl-7-(2-methoxyethylamino)-2-oxo-1,2-dihydro-1,6-naphthyridine-3- yl)-2-fluorophenyl)-3-(4-fluorophenyl)urea (212 mg, 74% yield) as a white solid. ^1H NMR (400 MHz, DMSO- _d6 ): δ 9.16 (s, 1H), 8.75 (s, 1H), 8.54 (s, 1H), 8.28 (brs, 1H ), 8.19 (d, J=9 Hz, 1H), 7.89 (s, 1H), 7.58 (d, J=11 Hz, 1H), 7.43 (m, 2H), 7, 10 (m, 2H), 6.74 (s, 1H), 4.14 (m, 2H), 3.56 (m, 4H), 3.30 (s, 3H), 2.34 (s, 3H ), 1.20 (t, J=6 Hz, 3H); MS (ESI) m/z: 528.2 [M+H] ⁺ .

[00269] Example 35: To a suspension of the compound of Example A12 (0.200 g, 0.512 mmol) in EtOAc (5 ml) was added 1-fluoro-2-isocyanatobenzene (0.093 g, 0.681 mmol) and the mixture was stirred at RT for 16 hours. The solids were filtered, washed and dried to give 1-(4-chloro-5-(1-ethyl-7-(2-methoxyethylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl )-2-fluorophenyl)-3-(2-fluorophenyl)urea (0.220 g, 81% yield) as a white solid. MS (ESI) m/z: 528.1 [M+H] ⁺ .

[00270] A suspension of 1-(4-chloro-5-(1-ethyl-7-(2-methoxyethylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl )-3-(2-fluorophenyl)urea (0.220 g, 0.417 mmol) in MeCN (10 ml) was treated with methanesulfonic acid (0.040 g, 0.417 mmol) and stirred at RT for 20 hours. The solids were filtered, washed and dried to give 1-(4-chloro-5-(1-ethyl-7-(2-methoxyethylamino)-2-oxo-1,2-dihydro-1,6-naphthyridine-3-methanesulfonate yl)-2-fluorophenyl)-3-(2-fluorophenyl)urea (205 mg, 79% yield) as a white solid. ^1H NMR (400 MHz, DMSO- _d6 ): δ 9.22 (s, 1H), 9.10 (s, 1H), 8.54 (s, 1H), 8.25 (d, J=9 Hz, 1H), 8.18 (lat.s, 1H), 8.10 (m, 1H), 7.89 (s, 1H), 7.60 (d, J=11 Hz, 1H), 7, 23 (m, 1H), 7.10 (m, 1H), 7.00 (m, 1H), 6.72 (s, 1H), 4.14 (m, 2H), 3.56 (m, 4H ), 3.30 (s, 3H), 2.31 (s, 3H), 1.20 (t, J=6 Hz, 3H); MS (ESI) m/z: 528.2 [M+H] ⁺ .

[00271] Example 36: To a suspension of the compound of Example A19 (0.200 g, 0.534 mmol) in EtOAc (5 ml) was added phenyl isocyanate (0.085 g, 0.710 mmol) and the mixture was stirred at RT for 16 hours. The solids were filtered, washed and dried to give 1-(5-(1-ethyl-7-(2-methoxyethylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2, 4-difluorophenyl)-3-phenylurea (201 mg, 76% yield) as a white solid. MS (ESI) m/z: 494.2 [M+H] ⁺ .

[00272] Into a suspension of 1-(5-(1-ethyl-7-(2-methoxyethylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2,4-difluorophenyl) -3-phenylurea (0.200 g, 0.405 mmol) in MeCN (10 ml), methanesulfonic acid (0.039 g, 0.405 mmol) was added and the mixture was stirred at RT for 1 hour. The solvent was evaporated and the residue was crystallized from MeCN to give 1-(5-(1-ethyl-7-(2-methoxyethylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)- methanesulfonate 2,4-difluorophenyl)-3-phenylurea (190 mg, 80% yield) as a white solid. ^1H NMR (400 MHz, DMSO- _d6 ): δ 9.22 (s, 1H), 9.10 (s, 1H), 8.64 (s, 1H), 8.56 (s, 1H), 8.15 (t, J=8 Hz, 1H), 8.00 (s, 1H), 7.42 (m, 3H), 7.26 (m, 2H), 6.96 (t, J=7 Hz, 1H), 6.73 (s, 1H), 4.14 (m, 2H), 3.56 (m, 4H), 3.30 (s, 3H), 2.35 (s, 3H), 1.20 (t, J=6 Hz, 3H); MS (ESI) m/z: 494.2 [M+H] ⁺ .

[00273] Example 37: To a suspension of the compound of Example A28 (0.400 g, 1.080 mmol) in EtOAc (10 ml) was added phenyl isocyanate (0.171 g, 1.436 mmol) and the mixture was stirred at RT for 16 hours. The solids were filtered, washed and dried to give 1-(5-(1-ethyl-7-(2-methoxyethylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2- fluoro-4-methylphenyl)-3-phenylurea (500 mg, 95% yield) as a white solid. MS (ESI) m/z: 490.2 [M+H] ⁺ .

[00274] Into a suspension of 1-(5-(1-ethyl-7-(2-methoxyethylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoro-4- methylphenyl)-3-phenylurea (0.500 g, 1.021 mmol) in MeCN (10 ml), methanesulfonic acid (0.098 g, 1.021 mmol) was added and the mixture was stirred at RT for 1 hour. The solids were filtered, washed and dried to give 1-(5-(1-ethyl-7-(2-methoxyethylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2 methanesulfonate -fluoro-4-methylphenyl)-3-phenylurea as a white solid (468 mg, 78% yield). ^1H NMR (400 MHz, DMSO- _d6 ): δ 9.07 (s, 1H), 8.54 (m, 2H), 8.30 (brs, 1H), 7.98 (d, J =9 Hz, 1H), 7.83 (s, 1H), 7.42 (m, 2H), 7.25 (m, 2H), 7.16 (d, J=12 Hz, 1H), 6, 94 (t, J=8 Hz, 1H), 6.77 (s, 1H), 4.18 (m, 2H), 3.60 (m, 4H), 3.30 (s, 3H), 2, 31 (s, 3H), 2.07 (s, 3H), 1.20 (t, J=6 Hz, 3H); MS (ESI) m/z: 490.2 [M+H] ⁺ .

[00275] Example 38: To a suspension of Example A2 (0.09 g, 0.276 mmol) and TEA (0.038 mL, 0.276 mmol) in THF (3 mL), 2-fluorophenyl isocyanate (0.042 g, 0.303 mmol) was added and the mixture was stirred. with CT within 16 hours. The solvent was removed and the resulting crude product was purified by silica gel chromatography (MeOH/DCM) to give 1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridine -3-yl)-2-fluoro-4-methylphenyl)-3-(2-fluorophenyl)urea (61 mg, 48% yield) as a white solid. ^1H NMR (400 MHz, DMSO- _d6 ): δ 8.97 (brs, 2H), 8.40 (s, 1H), 8.10 (td, J=8.0 Hz, 1.6 Hz, 1H), 7.95 (d, J=8.4 Hz, 1H), 7.66 (s, 1H), 7.24-7.18 (m, 1H), 7.14-7.07 (m, 2H), 7.00-6.95 (m, 2H), 6.23 (s, 1H), 4.14 (q, J=6.8 Hz, 2H), 2.85 (d, J=6.4 Hz, 3H), 2.06 (s, 3H), 1.20 (t, J=6.8 Hz, 3H); MS (ESI) m/z: 464.2 [M+H] ⁺ .

[00276] Example 39: To a solution of Example A23 (0.105 g, 0.26 mmol) and TEA (0.036 mL, 0.26 mmol) in THF (3 mL) was added phenyl isocyanate (0.04 g, 0.337 mmol) and the suspension was stirred at RT for 2 hours. Filter the suspension, wash with EtOAc and dry to give 1-(4-chloro-5-(1-ethyl-7-(3-methoxypropylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl )-2-fluorophenyl)-3-phenylurea (0.12 g, 88% yield) as a white solid. ^1H NMR (400 MHz, DMSO- _d6 ): δ 9.08 (s, 1H), 8.68 (d, J=2.0 Hz, 1H), 8.40 (s, 1H), 8. 17 (d, J=8.8 Hz, 1H), 7.72 (s, 1H), 7.53 (d, J=11.2 Hz, 1H), 7.42-7.40 (m, 2H ), 7.28-7.24 (m, 2H), 7.08 (t, J=5.6 Hz, 1H), 6.96 (t, J=7.2 Hz, 1H), 6.29 (s, 1H), 4.11 (q, J=6.8 Hz, 2H), 3.41-3.31 (m, 4H), 3.23 (s, 3H), 1.81-1, 75 (m, 2H), 1.19 (t, J=6.8 Hz, 3H); MS (ESI) m/z: 524.2 [M+H] ⁺ .

[00277] Example 40: To a suspension of the compound of Example A25 (0.300 g, 0.871 mmol) in EtOAc (5 ml) was added 3-fluorophenyl isocyanate (0.119 g, 0.871 mmol) and the mixture was stirred at RT for 2 hours. The solids were filtered, washed and dried to give 1-(2,4-difluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl )phenyl)-3-(3-fluorophenyl)urea (0.364 g, 87% yield) as an off-white solid. ^1H NMR (400 MHz, DMSO- _d6 ): δ 9.24 (s, 1H), 8.60 (s, 1H), 8.40 (s, 1H), 8.07 (t, J=8 Hz, 1H), 7.76 (s, 1H), 7.46 (m, 1H), 7.31 (m, 2H), 7.07 (m, 1H), 7.00 (m, 1H), 6.77 (m, 1H), 6.43 (s, 1H), 5.19 (lat s, 1H), 2.84 (lat s, 3H), 1.50 (d, J=6 Hz , 6H); MS (ESI) m/z: 482.2 [M+H] ⁺ .

[00278] Example 41: Example A21 (0.20 g, 0.588 mmol) and 3-fluorophenyl isocyanate (0.081 g, 0.588 mmol) were combined in THF (5 ml), treated with TEA (0.163 ml, 1.175 mmol) and stirred at CT scan overnight. The solvent was removed and the residue was purified by reverse phase column chromatography (MeCN/H ₂ O with 0.1% TFA). The pure fractions were combined and concentrated with MeOH, and the remaining aqueous solution was treated with NaHCO ₃ and extracted with EtOAC. The organic layers were washed with brine, dried (Na ₂ SO ₄ ), filtered, concentrated and dried in vacuo to give 1-(2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2 -dihydro-1,6-naphthyridin-3-yl)-4-methylphenyl)-3-(3-fluorophenyl)urea. The substance was suspended in MeCN (3 ml), treated with methanesulfonic acid (1 M in DCM, 0.369 ml, 0.369 mmol), heated to reflux temperature and allowed to cool to RT. The solvent was then removed, Et ₂ O was added, the solid was filtered off and washed with Et ₂ O to give 1-(2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydro- 1,6-naphthyridin-3-yl)-4-methylphenyl)-3-(3-fluorophenyl)urea (190 mg, 57% yield). ^1H NMR (400 MHz, DMSO- _d6 ): δ 9.26 (s, 1H), 8.60 (s, 1H), 8.49 (s, 1H), 8.11 (brs, 1H ), 7.95 (d, J=8.4 Hz, 1H), 7.77 (s, 1H), 7.47 (m, 1H), 7.28 (m, 1H), 7.17 (d , J=12.4 Hz, 1H), 7.05 (m, 1H), 6.77 (m, 2H), 3.36 (m, 1H), 2.96 (s, 3H), 2.30 (s, 3H), 2.06 (s, 3H), 1.52 (d, J=6.8 Hz, 6H); MS (ESI) m/z: 478.2 [M+H] ⁺ .

[00279] Example 42: The compound of Example A22 (0.15 g, 0.360 mmol) and phenyl isocyanate (0.051 g, 0.432 mmol) were combined in THF (5 ml), treated with TEA (0.100 ml, 0.720 mmol) and stirred at RT in during the night. The solid was filtered, washed with EtOAc and dried in vacuo to give 1-(4-chloro-5-(1-ethyl-2-oxo-7-(tetrahydro-2H-pyran-4-ylamino)-1,2-dihydro- 1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea (0.135 g, 70% yield). ^1H NMR (400 MHz, DMSO- _d6 ): δ 9.08 (s, 1H), 8.68 (s, 1H), 8.40 (s, 1H), 8.17 (d, J=8 ,8 Hz, 1H), 7.72 (s, 1H), 7.52 (d, J=10.8 Hz, 1H), 7.41 (d, J=8.0 Hz, 2H), 7, 26 (m, 3H), 7.07 (d, J=7.6 Hz, 1H), 6.96 (t, J=7.2 Hz, 1H), 6.34 (s, 1H), 4, 10 (q, J=6.8 Hz, 2H), 3.86 (m, 2H), 3.42 (m, 2H), 1.88 (m, 2H), 1.44 (m, 2H), 1.20 (t, J=6.8 Hz, 3H); MS (ESI) m/z: 536.2 [M+H] ⁺ .

[00280] Example 43: The compound of Example A26 (0.13 g, 0.321 mmol) was dissolved in EtOAc (10 ml), treated with phenyl isocyanate (0.037 ml, 0.337 mmol) and stirred at RT overnight. The precipitated solids were collected by filtration, washed with EtOAc and filter dried to give (S)-1-(4-chloro-5-(1-ethyl-7-(1-methoxypropan-2-ylamino)-2-oxo-1 ,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea (0.138 g, 82% yield) as a white solid. ^1H NMR (400 MHz, DMSO- _d6 ): δ 9.03 (s, 1H), 8.68 (brs, 1H), 8.39 (s, 1H), 8.17 (d, 1H , J=8.4 Hz), 7.72 (s, 1H), 7.52 (d, 1H, J=10.8 Hz), 7.42-7.40 (m, 2H), 7.28 -7.24 (m, 2H), 6.98-6.92 (m, 2H), 6.39 (s, 1H), 4.26-4.20 (m, 1H), 4.09 (q , 2H, J=7.6 Hz), 3.40 (dd, 1H, J=4.0, 9.2 Hz), 3.34 (s, 3H), 3.34-3.28 (m, 1H), 1.19 (t, 3H, J=7.6 Hz), 1.15 (d, 3H, J=6.4 Hz); MS (ESI) m/z: 524.2 [M+H] ⁺ .

[00281] Example 44: A solution of the compound of Example A2 (300 mg, 0.919 mmol) in pyridine (5 ml) was treated dropwise with 3-fluorophenyl isocyanate (139 mg, 1.011 mmol) and stirred at RT. The mixture was diluted with EtOAc and water, and the remaining solid was collected by filtration, washed with water and EtOAc, and purified by reverse phase chromatography (MeCN/water with 0.1% TFA). Organic matter was removed under reduced pressure and the aqueous residue was treated with us. NaHCO ₃ (10 ml) and left to settle. The solid was collected by filtration, washed with water and dried to give 1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2 -fluoro-4-methylphenyl)-3-(3-fluorophenyl)urea (214 mg, 50% yield). ^1H NMR (400 MHz, DMSO- _d6 ): δ 9.23 (s, 1H), 8.54 (s, 1H), 8.41 (s, 1H), 7.90 (d, 1H), 7.67 (s, 1H), 7.45 (d, 1H), 7.30-7.24 (m, 1H), 7.14-7.03 (m, 3H), 6.78-6, 74 (m, 1H), 6.28 (s, 1H), 4.17-4.12 (m, 2H), 2.85 (s, 3H), 2.05 (s, 3H), 1.20 (t, 3H); MS (IER-AD) m/z: 463.9 [M+H] ⁺ .

[00282] Example 45: A solution of the compound of Example A27 (124 mg, 0.352 mmol) in pyridine (4 ml) was treated dropwise with 3-fluorophenyl isocyanate (51 mg, 0.369 mmol) and stirred at RT. The mixture was diluted with EtOAc and water, the remaining solid was collected by filtration, washed with Et ₂ O, dried and purified by reverse phase chromatography (MeCN/water with 0.1% TFA). Organic matter was removed under reduced pressure and the aqueous residue was treated with us. NaHCO ₃ and extracted with hot EtOAc (2×). The combined organic layers were dried under heat over Na ₂ SO ₄ and evaporated under reduced pressure to give a white solid, which was dried under reduced pressure to give 1-(5-(7-(cyclopropylamino)-1-ethyl-2-oxo- 1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoro-4-methylphenyl)-3-(3-fluorophenyl)urea (75 mg, 43% yield). ^1H NMR (400 MHz, DMSO- _d6 ): δ 9.22 (s, 1H), 8.53 (s, 1H), 8.40 (s, 1H), 7.91 (d, 1H), 7.68 (s, 1H), 7.47-7.44 (m, 1H), 7.34-7.26 (m, 2H), 7.15-7.11 (m, 1H), 7. 06-7.03 (m, 1H), 6.80-6.72 (m, 1H), 6.41 (s, 1H), 4.21-4.15 (m, 2H), 2.20 ( m, 1H), 2.06 (s, 3H), 1.23 (t, 3H), 0.79-0.74 (m, 2H), 0.50-0.47 (m, 2H); MS (IER-AD) m/z: 490.2 [M+H] ⁺ .

[00283] Example 46: To a solution of the compound of Example A3 (2.1 g, 5.96 mmol) in NMP (10 ml) was added 1-methylpiperidin-4-ylamine (1.36 g, 11.9 mmol) and DBU (1.7 g, 11.4 mmol). Nitrogen was purged through the mixture for 5 minutes and then heated at 180°C for 12 hours. The reaction mixture was cooled to RT, poured into water and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , concentrated under reduced pressure, and the residue was purified by silica gel chromatography to give 3-(5-amino-2-chloro-4-fluorophenyl)-1-ethyl-7- (1-methylpiperidin-4-ylamino)-1,6-naphthyridin-2(1H)-one (0.50 g, 19.5% yield), which was 70% pure (30% demethylated by-product), and its used without further purification.

[00284] Solution of 3-(5-amino-2-chloro-4-fluorophenyl)-1-ethyl-7-(1-methylpiperidin-4-ylamino)-1,6-naphthyridin-2(1H)-one (200 mg, 0.465 mmol) and pyridine (70 mg, 0.95 mmol) in DCM (5 ml) were treated dropwise with phenyl isocyanate (112 mg, 0.93 mmol) and stirred at RT under nitrogen overnight. The reaction was quenched with MeOH (5 ml), the mixture was concentrated under reduced pressure and purified by pre-TLC separation to give 1-(4-chloro-5-(1-ethyl-7-(1-methylpiperidin-4-ylamino)-2 -oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea (120 mg, 47% yield). ^1H NMR (400 MHz, DMSO- _d6 ): δ 9.16 (s, 1H), 8.72 (s, 1H), 8.39 (s, 1H), 8.17 (d, J=8 ,8 Hz, 1H), 7.71 (s, 1H), 7.51 (d, J=10.8 Hz, 1H), 7.42 (s, 1H), 7.40 (s, 1H), 7.26 (t, J=8.0 Hz, 2H), 7.02-6.94 (m, 2H), 6.33 (s, 1H), 4.11-4.05 (m, 2H) , 3.81-3.78 (m, 1H), 2.78-2.75 (m, 2H), 2.20 (s, 3H), 2.12-2.05 (m, 2H), 1 .90-1.88 (m, 2H), 1.52-1.47 (m, 2H), 1.21-1.18 (m, 3H); MS (ESI) m/z: 549.3 [M+H] ⁺ .

[00285] Example 47: A solution of Example A30 (150 mg, 0.37 mmol) and pyridine (59 mg, 0.74 mmol) in DCM (3 mL) was treated dropwise with phenyl isocyanate (53 mg, 0.44 mmol) and stirred at RT under nitrogen atmosphere overnight. The mixture was filtered and the precipitate was purified by pre-HPLC separation to give 1-(4-chloro-5-(1-ethyl-2-oxo-7-(THF-3-ylamino)-1,2-dihydro-1, 6-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea (49 mg, 25% yield). ^1H NMR (400 MHz, CDCl ₃ ): δ 8.36 (s, 1H), 8.21 (s, 1H), 7.94 (d, J=8.4 Hz, 1H), 7.77 ( s, 1H), 7.68 (s, 1H), 7.40 (d, J=7.6 Hz, 2H), 7.22-7.18 (m, 2H), 6.97-6.91 (m, 2H), 6.14 (s, 1H), 5.08 (d, J=7.6 Hz, 1H), 4.46 (lat s, 1H), 4.33 (q, J= 6.4 Hz, 2H), 4.01-3.95 (m, 2H), 3.88-3.83 (m, 1H), 3.75 (dd, J=9.2 Hz, 2.8 Hz, 1H), 2.39-2.32 (m, 1H), 1.98-1.87 (m, 1H), 1.40 (t, J=6.4 Hz, 3H); MS (ESI) m/z: 522.1 [M+H] ⁺ .

[00286] Example 48: 2-methylsulfanylethylamine (5 ml) and the compound of Example A3 (500 mg, 1.42 mmol) were added to a sealed tube and the mixture was heated at 130°C overnight. The reaction mixture was concentrated in vacuo, treated with water and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried (Na ₂ SO ₄ ) and concentrated to give 3-(5-amino-2-chloro-4-fluorophenyl)-1-ethyl-7-(2-(methylthio)ethylamino)-1 ,6-naphthyridin-2(1H)-one (400 mg, 69% yield), which was used directly without further purification.

[00287] In a solution of 3-(5-amino-2-chloro-4-fluorophenyl)-1-ethyl-7-(2-(methylthio)ethylamino)-1,6-naphthyridin-2(1H)-one (400 mg, 0.99 mmol) to DCM (20 ml) was added phenyl isocyanate (200 mg, 1.68 mmol) and the mixture was stirred overnight. The reaction was quenched with MeOH and the mixture was concentrated under reduced pressure. The residue was washed with Et ₂ O to give 1-(4-chloro-5-(1-ethyl-7-(2-(methylthio)ethylamino)-2-oxo-1,2-dihydro-1,6-naphthyridine-3- yl)-2-fluorophenyl)-3-phenylurea (200 mg, 39% yield).

[00288] Into a solution of 1-(4-chloro-5-(1-ethyl-7-(2-(methylthio)ethylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl) -2-fluorophenyl)-3-phenylurea (200 mg, 0.38 mmol) in DCM (20 ml) was added with 85% mCPBA (169 mg, 0.84 mmol) at RT. The mixture was stirred for 2 hours and then further mCPBA (84 mg, 0.42 mmol) was added. The mixture was stirred for 1 hour and we were washed successively. Na ₂ SO ₃ , sat. NaHCO ₃ and saline, dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was dissolved in MeOH and THF and NH ₄ Cl (222 mg, 4.2 mmol) was added, followed by Zn powder (273 mg, 4.2 mmol) and the mixture was stirred for 30 minutes. The mixture was filtered, the filtrate was concentrated to dryness, treated with water, extracted with 10% MeOH/DCM, and the organic layer was concentrated and purified by pre-HPLC to give 1-(4-chloro-5-(1-ethyl-7-(2-(methylsulfonyl) )ethylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea (96 mg, 45% yield in two steps). ^1H NMR (400 MHz, DMSO- _d6 ): δ 9.75 (s, 1H), 9.03 (s, 1H), 8.45 (s, 1H), 8.15 (d, J=8 ,4 Hz, 1H), 7.77 (s, 1H), 7.49 (d, J=10.8 Hz, 1H), 7.43 (d, J=8.0 Hz, 2H), 7, 30 (m, 1H), 7.24 (m, 2H), 6.94 (m, 1H), 6.44 (s, 1H), 4.10 (q, J=7.2 Hz, 2H), 3.76 (m, 2H), 3.39 (t, J=6.4 Hz, 2H), 3.01 (s, 3H), 1.19 (t, J=6.8 Hz, 3H); MS (ESI): m/z 557.8 [M+H] ⁺ .

[00289] Example 49: Solution of Example A3 (500 mg, 1.42 mmol), 1-methylpyrrolidin-3-ylamine (170 mg, 1.7 mmol) and DBU (383 mg, 2.84 mmol) in NMP (5 ml) was heated under microwave irradiation at 160°C for 2 hours. After cooling to RT, the mixture was purified by silica gel chromatography to give 3-(5-amino-2-chloro-4-fluorophenyl)-1-ethyl-7-(1-methylpyrrolidin-3-ylamino)-1,6-naphthyridine- 2(1H)-one (500 mg, 85% yield) as a yellow oily liquid.

[00290] Into a solution of 3-(5-amino-2-chloro-4-fluorophenyl)-1-ethyl-7-(1-methylpyrrolidin-3-ylamino)-1,6-naphthyridin-2(1H)-one ( 500 mg, 1.20 mmol) and pyridine (140 mg, 1.8 mmol) in DCM (20 ml) was added phenyl isocyanate (215 mg, 1.8 mmol). The mixture was stirred at RT overnight, concentrated and purified by pre-HPLC separation to give 1-(4-chloro-5-(1-ethyl-7-(1-methylpyrrolidin-3-ylamino)-2-oxo-1 ,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea (53 mg, 8.4% yield) as a pale yellow solid. ^1H NMR (400 MHz, DMSO- _d6 ): δ 9.08 (s, 1H), 8.67 (s, 1H), 8.40 (s, 1H), 8.17 (d, J=8 ,8 Hz, 1H), 7.73 (s, 1H), 7.53 (d, J=11.2 Hz, 1H), 7.41 (d, J=7.6 Hz, 2H), 7, 28-7.23 (m, 3H), 6.98-6.95 (m, 1H), 6.35 (s, 1H), 4.39 (s, 1H), 4.11-4.09 ( m, 2H), 2.77-2.71 (m, 1H), 2.65-2.61 (m, 1H), 2.44-2.36 (m, 2H), 2.26 (s, 3H), 2.23-2.20 (m, 1H), 1.68-1.62 (m, 1H), 1.64 (t, J=7.2 Hz, 3H).

[00291] Example 50: A suspension of Example A14 (0.150 g, 0.383 mmol) and TEA (0.053 mL, 0.383 mmol) in THF (2.5 mL) was treated with 3-fluorophenyl isocyanate (0.048 mL, 0.422 mmol) and stirred at RT in an Ar atmosphere overnight. Additional 3-fluorophenyl isocyanate (0.024 mL, 0.55 eq.) was added, the mixture was stirred at RT for 6 hours, then treated again with 3-fluorophenyl isocyanate (1 drop) and the mixture was stirred at RT overnight. Filter the resulting solid, wash with a little THF and dry to give 1-(4-bromo-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridine-3 -yl)-2-fluorophenyl)-3-(3-fluorophenyl)urea (166 mg, 82% yield) as a white solid. ^1H NMR (400 MHz, DMSO- _d6 ): δ 9.30 (s, 1H), 8.74 (s, 1H), 8.41 (s, 1H), 8.14 (d, 1H), 7.70 (s, 1H), 7.66 (d, 1H), 7.75 (m, 1H), 7.29 (q, 1H), 7.05 (m, 2H), 6.78 (m , 1H), 6.24 (s, 1H), 4.13 (q, 2H), 2.86 (d, 3H), 1.21 (t, 3H); MS (ESI) m/z: 528.1 [M+H] ⁺ .

[00292] Example 51: To a solution of the compound of Example A29 (0.131 g, 1.103 mmol) in DCM (5 ml) was added phenyl isocyanate (0.480 g, 1.103 mmol) and the reaction mixture was stirred at RT. After 2 hours, the solvent was completely evaporated and the residue was crystallized from MeCN to give 1-(4-bromo-5-(1-ethyl-7-(2-methoxyethylamino)-2-oxo-1,2-dihydro-1,6- naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea (0.433 g, 70.8% yield) as a white solid. MS (ESI) m/z: 554.1/556.1 [M+H] ⁺ .

[00293] Into a suspension of 1-(4-bromo-5-(1-ethyl-7-(2-methoxyethylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2- fluorophenyl)-3-phenylurea (0.200 g, 0.361 mmol) in MeCN (4 ml), methanesulfonic acid (0.035 g, 0.361 mmol) was added and the mixture was stirred at RT for 30 minutes. The solvent was completely evaporated, and the residue was crystallized from MeCN to obtain 1-(4-bromo-5-(1-ethyl-7-(2-methoxyethylamino)-2-oxo-1,2-dihydro-1,6-naphthyridine-methanesulfonate 3-yl)-2-fluorophenyl)-3-phenylurea (0.160 g, 67% yield) as a white solid. ^1H NMR (400 MHz, DMSO- _d6 ): δ 9.23 (s, 1H), 9.04 (s, 1H), 8.53 (s, 1H), 8.22 (d, J=9 Hz, 2H), 7.87 (s, 1H), 7.70 (d, J=11 Hz, 1H), 7.41 (d, J=9 Hz, 2H), 7.26 (t, J= 7 Hz, 2H), 6.96 (t, J=7 Hz, 1H), 6.72 (s, 1H), 4.13 (m, 2H), 3.56 (m, 4H), 3.30 (s, 3H), 2.33 (s, 3H), 1.21 (d, J=6 Hz, 3H); MS (ESI) m/z: 554.1/556.1 [M+H] ⁺ .

[00294] Example 52: To a solution of Example A31 (0.19 g, 0.43 mmol) and TEA (0.09 g, 0.87 mmol) in THF (3 mL) was added phenyl isocyanate (0.067 g, 0. 56 mmol) and stirred at RT for 1 hour. The resulting suspension was diluted with MTBE (3 ml), filtered, washed with MTBE and dried to give 1-(4-bromo-5-(1-ethyl-7-(2-(methylthio)ethylamino)-2-oxo-1,2- dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea as a white solid (0.18 g, 74% yield). ^1H NMR (400 MHz, DMSO- _d6 ): δ 9.08 (s, 1H), 8.68 (s, 1H), 8.41 (s, 1H), 8.17 (d, J=8 ,4 Hz, 1H), 7.70 (s, 1H), 7.65 (d, J=10.4 Hz, 1H), 7.41 (d, J=8.4 Hz, 2H), 7, 28-7.17 (m, 3H), 6.96 (t, J=8.4 Hz, 1H), 6.35 (s, 1H), 4.11 (q, J=6.4 Hz, 2H ), 3.55 (q, J=6.0 Hz, 2H), 2.66 (t, J=6.8 Hz, 2H), 2.10 (s, 3H), 1.20 (t, J =6.8 Hz, 3H); MS (ESI) m/z: 570.1 [M+H] ⁺ .

[00295] Into a suspension of 1-(4-bromo-5-(1-ethyl-7-(2-(methylthio)ethylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl) -2-fluorophenyl)-3-phenylurea (0.18 g, 0.31 mmol) in DCM (25 ml), 70-75% mCPBA (0.14 g, 0.63 mmol) was added and the suspension was stirred at RT for 15 minutes. The mixture was diluted with 10% Na ₂ SO ₃ solution (30 ml) and the layers were separated, the organic layer was washed with us. NaHCO ₃ solution, then saline solution, dried (Na ₂ SO ₄ ) and concentrated. The crude product was purified by silica gel chromatography (MeOH/DCM) to give 1-(4-bromo-5-(1-ethyl-7-(2-(methylsulfonyl)ethylamino)-2-oxo-1,2-dihydro-1 ,6-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea (115 mg, 61% yield) as a white solid. ^1H NMR (400 MHz, DMSO- _d6 ): δ 9.08 (s, 1H), 8.69 (s, 1H), 8.46 (s, 1H), 8.18 (d, J=8 ,4 Hz, 1H), 7.74 (s, 1H), 7.66 (d, J=10.8 Hz, 1H), 7.41 (d, J=7.6 Hz, 2H), 7, 28-7.24 (m, 3H), 6.96 (t, J=7.6 Hz, 1H), 6.42 (s, 1H), 4.12 (q, J=6.8 Hz, 2H ), 3.77 (q, J=6.4 Hz, 2H), 3.39 (t, J=6.8 Hz, 2H), 3.02 (s, 3H), 1.20 (t, J =6.8 Hz, 3H); MS (ESI) m/z: 602.1 [M+H] ⁺ .

[00296] Example 53: A suspension of the compound of Example A32 (0.278 g, 0.559 mmol) in THF (6 ml) was treated with TEA (0.097 ml, 0.699 mmol), then phenyl isocyanate (0.061 ml, 0.559 mmol) and stirred at RT overnight . The resulting solids were collected by filtration, washed with THF and dried in vacuo to give 1-(5-(7-(4-methoxybenzylamino)-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridine-3 -yl)-4-bromo-2-fluorophenyl)-3-phenylurea (0.256 g, 74% yield). ^1H NMR (400 MHz, DMSO- _d6 ): δ 9.08 (s, 1H), 8.68 (d, 1H, J=2.4 Hz), 8.4 (s, 1H), 8. 16 (d, 1H, J=8.8 Hz), 7.69 (s, 1H), 7.65 (d, 1H, J=10.8 Hz), 7.56-7.53 (m, 1H ), 7.42-7.39 (m, 2H), 7.30-7.24 (m, 4H), 6.96 (m, 1H), 6.89-6.86 (m, 2H), 6.31 (broads, 1H), 4.49-4.47 (m, 2H), 4.07 (q, 2H, J=8.0 Hz), 3.70 (s, 3H), 1 ,12 (t, 3H, J=8.0 Hz); MS (ESI) m/z: 616.2 (M+H ⁺ ), 618.2 (M+2+H ⁺ ).

[00297] 1-(5-(7-(4-methoxybenzylamino)-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-4-bromo-2-fluorophenyl) -3-phenylurea (0.256 g, 0.415 mmol) was dissolved in TFA (4 mL, 51.9 mmol) and stirred at RT. After 4 hours, the reaction mixture was concentrated to dryness, the residue was diluted with MeOH, and the precipitated solids were removed by filtration. The filtrate was processed for us. NaHCO ₃ and the resulting solid was collected by filtration, washed with H ₂ O, dried in vacuo and purified by reverse phase chromatography (MeCN/H2O with 0.1% TFA). Organic substances were removed under reduced pressure, and the aqueous residue was treated with us. The NaHCO ₃ and resulting solids were collected by filtration, washed with H ₂ O and dried to give 1-(5-(7-amino-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridine-3- yl)-4-bromo-2-fluorophenyl)-3-phenylurea (90 mg, 44% yield). ^1H NMR (400 MHz, DMSO- _d6 ): δ 9.08 (s, 1H), 8.68 (d, 1H, J=2.4 Hz), 8.36 (s, 1H), 8. 17 (d, 1H, J=8.8 Hz), 7.70 (s, 1H), 7.65 (d, 1H, J=10.8 Hz), 7.42-7.40 (m, 2H ), 7.28-7.24 (m, 2H), 6.98-6.95 (m, 1H), 6.54 (br.s, 2H), 6.34 (s, 1H), 4, 08 (q, 2H, J=7.2 Hz), 1.20 (t, 3H, J=7.2 Hz); MS (ESI) m/z: 496.1 (M+H ⁺ ), 498.1 (M+2+H ⁺ ).

[00298] 1-(5-(7-amino-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-4-bromo-2-fluorophenyl)-3-phenylurea (90 mg, 0.181 mmol) was suspended in acetic anhydride (5 ml, 52.9 mmol) and heated at 110°C for 4 hours. The reaction mixture was cooled to RT, poured into ice (15 g) and stirred overnight. The solids were collected, washed thoroughly with H ₂ O, air dried, then suspended in MeCN (2-3 ml) and heated at 80°C overnight. The solids were collected by filtration, washed with MeCN and dried in vacuo to give 1-(5-(7-acetamido-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-4 -bromo-2-fluorophenyl)-3-phenylurea (56 mg, 57% yield). ^1H NMR (400 MHz, DMSO- _d6 ): δ 10.84 (s, 1H), 9.10 (s, 1H), 8.73 (d, J=2.4 Hz, 1H), 8. 71 (s, 1H), 8.26 (s, 1H), 8.22 (d, J=8.4 Hz, 1H), 7.95 (s, 1H), 7.7 (d, J=6 .8 Hz, 1H), 7.42-7.40 (m, 2H), 7.28-7.24 (m, 2H), 6.98-6.95 (m, 1H), 4.19 ( q, J=6.8 Hz, 2H), 2.15 (s, 3H), 1.25 (t, J=6.8 Hz, 3H); MS (ESI) m/z: 538.1 [M+H] ⁺ .

[00299] Example 54: Example A35 (0.200 g, 0.601 mmol) was dissolved in THF (6 mL) at RT and treated with TEA (0.109 mL, 0.781 mmol), then phenyl isocyanate (0.066 mL, 0.601 mmol). After 2 hours, the precipitated solids were collected by filtration and washed with THF to give 1-(5-(7-amino-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-4 -chloro-2-fluorophenyl)-3-phenylurea (200 mg, 74% yield). ^1H NMR (400 MHz, DMSO- _d6 ): δ 9.12 (s, 1H), 8.7 (s, 1H), 8.35 (s, 1H), 8.16 (d, J=8 ,4 Hz, 1H), 7.73 (s, 1H), 7.52 (d, J=11.8 Hz, 1H), 7.43-7.40 (m, 2H), 7.28-7 .24 (m, 2H), 6.96-6.94 (m, 1H), 6.54 (broads, 2H), 6.34 (s, 1H), 4.08 (q, J=7 ,2 Hz, 2H), 1.20 (t, J=7.2 Hz, 3H); MS (ESI) m/z: 452.1 (M+H ⁺ ), 454.1 (M+2+H ⁺ ).

[00300] 1-(5-(7-amino-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-4-chloro-2-fluorophenyl)-3-phenylurea (0.100 g, 0.221 mmol) was suspended in acetic anhydride (5 ml, 53.0 mmol) and stirred while gradually heating to 110°C. After 5 hours, the mixture was cooled to RT and diluted with MeCN (15 ml). The solids were collected by filtration, washed with MeCN and dried to give 1-(5-(7-acetamido-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-4-chloro -2-fluorophenyl)-3-phenylurea (107 mg, 98% yield). ^1H NMR (400 MHz, DMSO- _d6 ): δ 10.84 (s, 1H), 9.13 (s, 1H), 8.74 (d, J=2.0 Hz, 1H), 8. 71 (s, 1H), 8.26 (s, 1H), 8.22 (d, J=8.8 Hz, 1H), 7.97 (s, 1H), 7.57 (d, J=4 ,0 Hz, 1H), 7.42-7.40 (m, 2H), 7.28-7.24 (m, 2H), 6.98-6.95 (m, 1H), 4.19 ( q, J=7.2 Hz, 2H), 2.14 (s, 3H), 1.25 (t, J=7.2 Hz, 3H); MS (IER) m/z: 494.1 [M+H] ^- .

[00301] Example 55: A solution of the compound of Example A5 (200 mg, 0.58 mmol) and pyridine (91 mg, 1.16 mmol) in DCM (4 ml) at 0° C. was treated dropwise with 1,3-difluoro- 5-isocyanatobenzene (98 mg, 0.64 mmol) and stirred at RT overnight after removing the cooling bath. The mixture was concentrated to dryness and purified by pre-HPLC. The resulting solution was treated with HCl (1 ml) and lyophilized to give 1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridine-3 hydrochloride -yl)-2-fluorophenyl)-3-(3,5-difluorophenyl)urea (74 mg, 26% yield). ^1H NMR (400 MHz, DMSO- _d6 ): δ 9.94 (s, 1H), 9.03 (s, 1H), 8.54 (s, 1H), 8.14 (brs, 1H ), 8.13 (d, J=8.8 Hz, 1H), 7.88 (s, 1H), 7.57 (d, J=11.2 Hz, 1H), 7.16-7.12 (m, 2H), 6.78 (t, J=8.8 Hz, 1H), 6.57 (s, 1H), 4.16-4.13 (m, 2H), 2.96 (s, 3H), 1.19 (t, J=6.8 Hz, 3H); MS (ESI) m/z: 502.3 [M+H] ⁺ .

[00302] Example 56: A mixture of the compound of Example A37 (1.3 g, 3.4 mmol), methylamine (25%, 30 ml) and EtOH (5 ml) was heated at 120°C in a pressure-resistant vessel in within 1 day. The mixture was cooled to RT, the solids were collected by filtration, and the peter was washed. ether and dried to give 3-(5-amino-2-bromo-4-fluorophenyl)-1-methyl-7-methylamino-1H-[1,6]naphthyridin-2-one (1.06 g, yield 82, 8%).

[00303] A solution of 3-(5-amino-2-bromo-4-fluorophenyl)-1-methyl-7-methylamino-1H-[1,6]naphthyridin-2-one (420 mg, 1.16 mmol) in DCM (25 ml) was treated with phenyl isocyanate (0.19 g, 1.62 mmol) and TEA (0.326 g, 3.23 mmol) and stirred at RT for 12 hours. The mixture was concentrated under reduced pressure and washed with MTBE (1×). The crude product was purified by pre-HPLC separation (MeCN/H ₂ O with 0.1% TFA) to give 1-(4-bromo-2-fluoro-5-(1-methyl-7-(methylamino)-2- oxo-1,2-dihydro-1,6-naphthyridin-3-yl)phenyl)-3-phenylurea (245 mg, 44% yield). ^1H NMR (400 MHz, DMSO- _d6 ): δ 9.08 (s, 1H), 8.67 (s, 1H), 8.40 (s, 1H), 8.17 (d, J=8 ,8 Hz, 1H), 7.70 (s, 1H), 7.64 (d, J=10.8 Hz, 1H), 7.40 (d, J=7.6 Hz, 2H), 7, 28-7.24 (t, J=7.6 Hz, 2H), 7.04-7.03 (m, 1H), 6.98-6.94 (t, J=8 Hz, 1H), 6 .17 (s, 1H), 3.50 (s, 3H), 2.85 (d, J=4.8 Hz, 3H).

[00304] Example 57: To a solution of the compound of Example A33 (300 mg, 0.798 mmol) in DCM (20 ml) was added phenyl isocyanate (284 mg, 2.39 mmol) and TEA (241.7 mg, 2.39 mmol). The mixture was stirred at RT for 3 days and then concentrated and purified by HPLC separation (MeCN/H ₂ O with 0.1% TFA) to give 1-(5-(7-amino-1-ethyl-2-oxo -1,2-dihydro-1,6-naphthyridin-3-yl)-4-bromo-2-fluorophenyl)-3-phenylurea (20 mg, 5% yield). ^1H NMR (400 MHz, DMSO- _d6 ): δ 9.17 (s, 1H), 8.72 (s, 1H), 8.33 (s, 1H), 8.15 (d, J=8 ,4 Hz, 1H), 7.68 (s, 1H), 7.63 (d, J=10.8 Hz, 1H), 7.41 (s, 1H), 7.39 (s, 1H), 7.26-7.22 (t, J=8.0 Hz, 2H), 6.96-6.93 (t, J=7.2 Hz, 1H), 6.52 (s, 2H), 6 .32 (s, 1H), 4.09-4.06 (q, J=5.2 Hz, 2H), 1.20-1.17 (t, J=5.2 Hz, 3H).

[00305] Example 58: Isopropenyl chloroformate (0.564 g, 4.68 mmol) and NaHCO ₃ ( 1.31 g, 15.6 mmol) and the mixture was stirred at RT overnight. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were concentrated to dryness and purified by silica gel chromatography (EtOH/hex) to give 3-fluorophenylcarbamic acid prop-1-en-2-yl ester (125 mg, 21% yield) as a white solid. ^1H NMR (400 MHz, DMSO- _d6 ): δ 10.14 (s, 1H), 7.35 (m, 1H), 7.31 (m, 1H), 7.21 (m, 1H), 6.83 (m, 1H), 4.74 (m, 2H), 1.92 (s, 3H).

[00306] A solution of 3-fluorophenylcarbamic acid prop-1-en-2-yl ester (0.094 g, 0.480 mmol) and the compound of Example A34 (0.100 g, 0.320 mmol) in THF (3 ml) was treated with a catalytic amount (1 drop) 1-methylpyrrolidine and the mixture was heated at 60°C overnight. Additionally, 1-methylpyrrolidine (2 drops) was added and heating at 60°C was continued for another 24 hours. The mixture was cooled to RT, the solid was collected by filtration, washed with THF and dried to give 1-(5-(7-amino-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl )-2-fluoro-4-methylphenyl)-3-(3-fluorophenyl)urea (123 mg, 85% yield) as a white solid. ^1H NMR (400 MHz, DMSO- _d6 ): δ 9.22 (s, 1H), 8.53 (s, 1H), 8.34 (s, 1H), 7.89 (d, 1H), 7.65 (s, 1H), 7.46 (m, 1H), 7.27 (q, 1H), 7.13 (d, 1H), 7.04 (d, 1H), 6.76 (m , 1H), 6.47 (s, 2H), 6.34 (s, 1H), 4.09 (q, 2H), 2.06 (s, 3H), 1.20 (t, 3H); MS (ESI) m/z: 450.2 [M+H] ⁺ .

[00307] Example 59: A mixture of 1-benzothiophenecarboxylic acid (0.131 g, 0.735 mmol) and TEA (0.188 mL, 1.348 mmol) in toluene (3.0 mL) was treated with DPPA (0.198 mL, 0.919 mmol), stirred at RT for 0.5 hours, treated with the compound according to example A2 (0.200 g, 0.613 mmol) and heated at 90°C for 3 days. The mixture was cooled to RT, concentrated to dryness, treated with MeCN (5 ml) and heated at 70°C for 5 minutes. The solid was collected by filtration, washed with MeCN, treated with MeOH, heated at 50°C and collected by filtration. The substance was purified by reverse phase chromatography (MeCN/water with 0.1% TFA). Water and NaHCO ₃ were added to the purified product and the resulting precipitate was filtered and dried to obtain 1-(benzo[b]thiophen-3-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo- 1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoro-4-methylphenyl)urea (69 mg, 21% yield) as a white solid. ^1H NMR (400 MHz, DMSO- _d6 ): δ 9.39 (s, 1H), 8.83 (s, 1H), 8.45 (s, 1H), 8.06 (d, 1H), 7.96 (d, 1H), 7.87 (d, 1H), 7.73 (s, 1H), 7.67 (s, 1H), 7.45 (m, 3H), 7.17 (d , 1H), 6.36 (s, 1H), 4.16 (m, 2H), 2.90 (d, 3H), 2.08 (s, 3H), 1.21 (t, 3H); MS (ESI) m/z: 502.2 [M+H] ⁺ .

[00308] Example 60: A suspension of the compound of Example A2 (0.096 g, 0.29 mmol) in THF (3 ml) was treated with TEA (0.041 ml, 0.294 mmol) and 3,5-difluorophenyl isocyanate (0.114 g, 0.735 mmol) and stirred with CT within 6 hours. The mixture was treated with 60% EtOAc/hex, stirred for 5 minutes and the resulting solid was collected by filtration and dried to give 1-(3,5-difluorophenyl)-3-(5-(1-ethyl-7-(methylamino) )-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoro-4-methylphenyl)urea (0.11 g, 73% yield) as a white solid. ^1H NMR (400 MHz, DMSO- _d6 ): δ 9.37 (s, 1H), 8.61 (s, 1H), 8.40 (s, 1H), 7.85 (d, J=8 ,4 Hz, 1H), 7.66 (s, 1H), 7.13 (dd, J=10.0 Hz, 2.4 Hz, 3H), 6.98 (q, J=4.8 Hz, 1H), 6.80-6.75 (m, 1H), 6.23 (s, 1H), 4.14 (q, J=6.8 Hz, 2H), 2.85 (d, J=4 ,8 Hz, 3H), 2.06 (s, 3H), 1.20 (t, J=6.8 Hz, 3H); MS (ESI) m/z: 482.2 [M+H] ⁺ .

[00309] Example 61: A suspension of the compound of Example A2 (0.096 g, 0.29 mmol) in THF (3 ml) was treated with TEA (0.041 ml, 0.294 mmol) and 2,5-difluorophenyl isocyanate (0.055 g, 0.353 mmol) and stirred with CT within 2 hours. The mixture was treated with 60% EtOAc/hex, stirred for 5 minutes and the resulting solid was collected by filtration and dried to give 1-(2,5-difluorophenyl)-3-(5-(1-ethyl-7-(methylamino) )-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoro-4-methylphenyl)urea (0.12 g, 85% yield) as a white solid. ^1H NMR (400 MHz, DMSO- _d6 ): δ 9.18 (s, 1H), 9.06 (s, 1H), 8.40 (s, 1H), 8.02-7.97 (m , 1H), 7.94 (d, J=8.4 Hz, 1H), 7.66 (s, 1H), 7.30-7.24 (m, 1H), 7.14 (d, J= 12.4 Hz, 1H), 6.98 (q, J=4.8 Hz, 1H), 6.81-6.77 (m, 1H), 6.23 (s, 1H), 4.14 ( q, J=6.8 Hz, 2H), 2.85 (d, J=4.8 Hz, 3H), 2.06 (s, 3H), 1.20 (t, J=6.8 Hz, 3H); MS (ESI) m/z: 482.2 [M+H] ⁺ .

[00310] Example 62: A solution of the compound of Example A7 (0.12 g, 0.266 mmol) in dioxane (5 ml) was treated with 2,5-difluorophenyl isocyanate (0.034 ml, 0.293 mmol) and stirred at RT overnight. The resulting solid was collected by filtration and dried to give 1-(5-(7-((4-methoxybenzyl)(methyl)amino)-1-ethyl-2-oxo-1,2,4a,8a-tetrahydro-1. 6-naphthyridin-3-yl)-2,4-difluorophenyl)-3-(2,5-difluorophenyl)-urea (129 mg, 80% yield). ^1H NMR (400 MHz, DMSO- _d6 ): δ 9.19 (s, 1H), 9.10 (s, 1H), 8.52 (s, 1H), 8.16 (t, 1H), 8.01-7.98 (m, 1H), 7.86 (s, 1H), 7.38 (t, 1H), 7.31-7.27 (m, 1H), 7.18 (d, 2H), 6.87 (d, 2H), 6.82-6.80 (m, 1H), 6.32 (s, 1H), 4.85 (s, 2H), 4.19 (q, 2H ), 3.70 (s, 3H), 3.13 (s, 3H), 1.13 (t, 3H); MS (ESI) m/z: 606.3 [M+H] ⁺ .

[00311] Solution of 1-(5-(7-((4-methoxybenzyl)(methyl)amino)-1-ethyl-2-oxo-1,2,4a,8a-tetrahydro-1,6-naphthyridine-3- yl)-2,4-difluorophenyl)-3-(2,5-difluorophenyl)urea (0.129 g, 0.213 mmol) and anisole (0.233 ml, 2.130 mmol) in DCM (2 ml) were treated with TFA (2 ml, 26, 0 mmol) and stirred at RT overnight. The mixture was concentrated to dryness, treated with EtOAc and us. NaHCO ₃ was stirred for 1 hour and the resulting solid was collected by filtration and dried to give 1-(2,5-difluorophenyl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1 ,2,4a,8a-tetrahydro-1,6-naphthyridin-3-yl)-2,4-difluorophenyl)urea (84 mg, 81% yield). The substance was suspended in MeCN (2 ml), treated with 0.5 N. HCl (2.076 ml, 0.208 mmol), diluted with water (2 ml), frozen, lyophilized, triturated with Et ₂ O and the resulting solid was collected by filtration and dried to give 1-(2,5-difluorophenyl)-3-( hydrochloride 5-(1-ethyl-7-(methylamino)-2-oxo-1,2,4a,8a-tetrahydro-1,6-naphthyridin-3-yl)-2,4-difluorophenyl)urea (85 mg, yield 94%). ^1H NMR (400 MHz, DMSO- _d6 ): δ 9.24 (s, 1H), 9.18 (s, 1H), 8.53 (s, 1H), 8.18 (t, 1H), 8.02-7.97 (m, 1H), 7.94 (s, 1H), 7.90 (br.s, 1H), 7.42 (t, 1H), 7.32-7.26 ( m, 1H), 6.84-6.80 (m, 1H), 6.48 (s, 1H), 4.19 (q, 2H), 2.94 (s, 3H), 1.21 (t , 3H); MS (ESI) m/z: 486.2 [M+H] ⁺ .

[00312] Example 63: A solution of the compound of Example A7 (0.12 g, 0.266 mmol) in dioxane (5 ml) was treated with 3,5-difluorophenyl isocyanate (0.038 ml, 0.320 mmol) and stirred at RT overnight. Additional 3,5-difluorophenyl isocyanate (0.038 mL, 0.320 mmol) was added and the mixture was stirred for 4 hours. The resulting precipitate was collected by filtration and dried to give 1-(5-(7-((4-methoxybenzyl)(methyl)amino)-1-ethyl-2-oxo-1,2,4a,8a-tetrahydro-1,6 -naphthyridin-3-yl)-2,4-difluorophenyl)-3-(3,5-difluorophenyl)urea (112 mg, 69% yield). ^1H NMR (400 MHz, DMSO- _d6 ): δ 9.38 (s, 1H), 8.67 (s, 1H), 8.52 (s, 1H), 8.05 (t, 1H), 7.86 (s, 1H), 7.38 (t, 1H), 7.19-7.14 (m, 4H), 6.86 (d, 2H), 6.80-6.77 (m, 1H), 6.32 (s, 1H), 4.85 (s, 2H), 4.19 (q, 2H), 3.70 (s, 3H), 3.12 (s, 3H), 1, 13 (t, 3H); MS (ESI) m/z: 606.3 [M+H] ⁺ .

[00313] A solution of 1-(5-(7-((4-methoxybenzyl)(methyl)amino)-1-ethyl-2-oxo-1,2,4a,8a-tetrahydro-1,6-naphthyridine-3- yl)-2,4-difluorophenyl)-3-(3,5-difluorophenyl)urea (0.112 g, 0.185 mmol) and anisole (0.202 ml, 1.849 mmol) in DCM (2 ml) were treated with TFA (2 ml, 26, 0 mmol) and stirred at RT overnight. The mixture was concentrated to dryness, treated with EtOAc and us. NaHCO ₃ was stirred for 1 hour and the resulting solid was collected by filtration and dried to give 1-(3,5-difluorophenyl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1 ,2,4a,8a-tetrahydro-1,6-naphthyridin-3-yl)-2,4-difluorophenyl)urea (57 mg, 64% yield). The substance was dissolved in MeCN (2 ml), treated with 0.1 N. HCl (1.17 ml, 0.117 mmol), diluted with water (3 ml), frozen, lyophilized, triturated with Et ₂ O and the resulting solid was collected by filtration and dried to give 1-(3,5-difluorophenyl)-3 hydrochloride -(5-(1-ethyl-7-(methylamino)-2-oxo-1,2,4a,8a-tetrahydro-1,6-naphthyridin-3-yl)-2,4-difluorophenyl)urea (57 mg , yield 96%). ^1H NMR (400 MHz, DMSO- _d6 ): δ 9.95 (s, 1H), 8.80 (s, 1H), 8.51 (s, 1H), 8.07 (t, 1H), 7.92 (s, 1H), 7.70 (br.s, 1H), 7.40 (t, 1H), 7.15 (d, 2H), 6.82-6.77 (m, 1H) , 6.43 (s, 1H), 4.15 (q, 2H), 2.91 (s, 3H), 1.21 (t, 3H); MS (ESI) m/z: 486.2 [M+H] ⁺ .

[00314] Example 64: A suspension of the compound of Example 57 (135 mg, 0.272 mmol) in ethyl cyanoacetate (2.307 g, 20.40 mmol) was heated at 105°C for 4.5 hours, then at 125°C for 2 days . The mixture was treated with NMP (0.3 ml), heated at 125°C for 5 hours, then cooled to RT and purified by silica gel chromatography (EtOAc/hex). The substance was purified again by chromatography on silica gel (THF/hex.), dissolved in MeCN/H ₂ O 4:1, frozen and lyophilized. The material was treated with MTBE and the resulting solid was collected by filtration and dried to give N-(3-(2-bromo-4-fluoro-5-(3-phenylureido)phenyl)-1-ethyl-2-oxo-1,2- dihydro-1,6-naphthyridin-7-yl)-2-cyanoacetamide (13 mg, 8.5% yield) as an off-white solid. ^1H NMR (400 MHz, DMSO- _d6 ): δ 11.17 (s, 1H), 9.10 (s, 1H), 8.74 (m, 2H), 8.23 (d, J=8 .5 Hz, 1H), 8.17 (s, 1H), 7.98 (s, 1H), 7.70 (d, J=10.7 Hz, 1H), 7.41 (d, J=8 ,1 Hz, 2H), 7.26 (t, J=7.8 Hz, 2H), 6.97 (t, J=7.4 Hz, 1H), 4.22 (q, J=7.2 Hz, 2H), 4.05 (s, 2H), 1.26 (t, J=6.8 Hz, 3H); MS (ESI) m/z: 565.1 [M+H] ⁺ .

[00315] Example 65: A suspension of the compound of Example 21 (0.180 g, 0.398 mmol) in ethyl cyanoacetic acid (3 mL, 28.1 mmol) was heated at 125°C overnight. The mixture was treated with NMP (0.3 ml), heated at 125°C for 24 hours, then cooled to RT and purified by silica gel chromatography (EtOAc/hex). The material was purified again by chromatography on silica gel (THF/hex), dissolved in MeSM/H ₂ O 4:1, frozen and lyophilized, treated with MTBE and the resulting solid collected by filtration and dried to give N-(3-(2 -chloro-4-fluoro-5-(3-phenylureido)phenyl)-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)-2-cyanoacetamide (22 mg, yield 11%) as a whitish solid. ^1H NMR (400 MHz, DMSO- _d6 ): δ 11.17 (s, 1H), 9.10 (s, 1H), 8.75 (s, 1H), 8.73 (s, 1H), 8.23 (d, J=8.6 Hz, 1H), 8.17 (s, 1H), 8.01 (s, 1H), 7.58 (d, J=11.0 Hz, 1H), 7.41 (d, J=8.0 Hz, 2H), 7.26 (t, J=7.8 Hz, 2H), 6.97 (t, J=7.0 Hz, 1H), 4, 22 (q, J=7.1 Hz, 2H), 4.05 (s, 2H), 1.26 (t, J=7.0 Hz, 3H); MS (ESI) m/z: 519.1 [M+H] ⁺ .

[00316] Example 66: A solution of the compound of Example A36 (1 g, 2.3 mmol) in TFA (10 ml) was stirred at 60°C overnight. The solvent was removed and the crude product was processed for us. NaHCO ₃ and extracted with EtOAc (2×). The combined organic extracts were washed with brine, dried over Na ₂ SO ₄ and evaporated to give 7-amino-3-(5-amino-2,4-difluorophenyl)-1-ethyl-1,6-naphthyridine-2(1H)- she (600 mg, 83% yield), which was used in the next step without purification.

[00317] A solution of 7-amino-3-(5-amino-2,4-difluorophenyl)-1-ethyl-1,6-naphthyridin-2(1H)-one (500 mg, 1.58 mmol) and TEA ( 638 mg, 6.32 mmol) in DCM (5 ml) was treated dropwise with phenyl isocyanate (503 mg, 4.8 mmol) and stirred at RT overnight. The mixture was concentrated to dryness and purified by chromatography on silica gel (EtOAc/pet. ether) to give 1-(5-(7-amino-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridine-3- yl)-2,4-difluorophenyl)-3-phenylurea (500 mg, 73% yield). ^1H NMR (400 MHz, DMSO- _d6 ): δ 9.03 (s, 1H), 8.55 (s, 1H), 8.38 (s, 1H), 8.13 (m, 1H), 7.83 (s, 1H), 7.43 (d, J=7.6 Hz, 2H), 7.39-7.34 (m, 1H), 7.29-7.25 (m, 2H) , 6.99-6.95 (m, 1H), 6.58 (s, 2H), 6.34 (s, 1H), 4.13-4.08 (q, J=0.8 Hz, 2H ), 1.22 (t, J=6.8 Hz, 3H).

[00318] 1-(5-(7-Amino-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2,4-difluorophenyl)-3-phenylurea solution ( 150 mg, 0.344 mmol) and TEA (174.2 mg, 1.72 mmol) in THF (3 ml) were treated dropwise with acetyl chloride (81 mg, 1.03 mmol) at RT. The resulting mixture was stirred for 2 hours and the solvent was removed to obtain the crude product. It was diluted, washed with saline, dried over Na ₂ SO ₄ , concentrated under reduced pressure and purified by silica gel chromatography to give N-acetyl-N-{3-[2,4-difluoro-5-(3-phenylureido)phenyl ]-1-ethyl-2-oxo-1,2-dihydro-[1,6]naphthyridin-7-yl}acetamide (150 mg, 84% yield). ^1H NMR (400 MHz, DMSO- _d6 ): δ 10.86 (s, 1H), 9.41 (s, 1H), 8.79 (s, 1H), 8.74 (s, 1H), 8.27 (s, 1H), 8.20-8.16 (m, 1H), 8.08 (s, 1H), 8.00 (s, 1H), 7.46-7.39 (m, 3H), 7.29-7.25 (m, 2H), 6.98-6.95 (m, 1H), 4.25-4.22 (t, J=7.2 Hz, 3H), 2 .16 (s, 3H), 1.27 (s, 3H).

[00319] Into a solution of N-acetyl-N-{3-[2,4-difluoro-5-(3-phenylureido)phenyl]-1-ethyl-2-oxo-1,2-dihydro-[1,6] naphthyridin-7-yl}acetamide (100 mg, 0.19 mmol) in MeOH (2 ml) was added K ₂ CO ₃ (79 mg, 0.57 mmol) and water (1 ml) and the mixture was stirred overnight at RT . MeOH was removed under reduced pressure and the residue was diluted with water (8 ml). The mixture was extracted with EtOAc to give the crude product, which was purified by pre-HPLC to give 1-(5-(7-acetamido-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl) -2,4-difluorophenyl)-3-phenylurea (32 mg, 23% yield). ^1H NMR (400 MHz, DMSO- _d6 ): δ 10.85 (s, 1H), 9.08 (s, 1H), 8.74 (s, 1H), 8.61 (s, 1H), 8.27 (s, 1H), 8.21-8.16 (m, 1H), 8.07 (s, 1H), 7.45-7.40 (m, 3H), 7.30-7, 26 (m, 2H), 7.00-6.96 (m, 1H), 4.24-4.18 (q, J=6.8 Hz, 2H), 2.16 (s, 3H), 1 ,28-1.25 (t, J=6.8 Hz, 3H); MS (ESI) m/z: 478.3 [M+H] ⁺ .

[00320] Example 67: A solution of the compound of Example A3 (0.20 g, 0.568 mmol) in THF (6 ml) was treated with TEA (0.098 ml, 0.710 mmol), then 3,5-difluorophenyl isocyanate (0.092 g, 0.596 mmol) and stirred at RT for 2 hours. Additional 3,5-difluorophenyl isocyanate (0.14 g, 0.903 mmol) was added and the mixture was stirred at RT overnight. 3,5-difluorophenyl isocyanate (0.25 g, 1.61 mmol) was added again and the mixture was stirred at RT for 24 hours. The mixture was cooled to 0°C and the solids were collected by filtration and dried. The filtrate was concentrated to dryness and purified by silica gel chromatography (THF/hex) and combined with the isolated solid to give 1-(4-chloro-5-(7-chloro-1-ethyl-2-oxo-1,2-dihydro -1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-(3,5-difluorophenyl)urea (177 mg, 61% yield). ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 9.27 (br.s, 2H), 8.79 (s, 1H), 8.15 (d, J=8.5 Hz, 1H), 8.08 (s, 1H), 7.74 (s, 1H), 7.57 (d, J=10.9 Hz, 1H), 7.16 (m, 2H), 6.77 (m, 1H ), 4.27 (q, J=7.0 Hz, 2H), 1.20 (t, J=7.0 Hz, 3H); MS (ESI) m/z: 507.1 [M+H] ⁺ .

[00321] A mixture of 1-(4-chloro-5-(7-chloro-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3- (3,5-difluorophenyl)urea (178 mg, 0.351 mmol), Xantphos (20.30 mg, 0.035 mmol), Cs ₂ CO ₃ (229 mg, 0.702 mmol) and acetamide (104 mg, 1.754 mmol) in dioxane ( 3.5 ml) was purged with Ar for 10 minutes, treated with Pd ₂ (dba) ₃ (16.07 mg, 0.018 mmol) and heated at 100°C overnight. The mixture was cooled to RT, treated with THF, solids were removed by filtration through diatomaceous earth and washed thoroughly with THF. The filtrate was washed with brine (3×), dried over MgSO ₄ , concentrated to dryness and purified by silica gel chromatography (EtOAc/hex). The substance was suspended in MeCN/H ₂ O 4:1, frozen and lyophilized; the resulting solid was triturated with MTBE, collected by filtration and dried to give N-(3-(2-chloro-5-(3-(3,5-difluorophenyl)ureido)-4-fluorophenyl)-1-ethyl-2- oxo-1,2-dihydro-1,6-naphthyridin-7-yl)acetamide (9 mg, 4.8% yield). ^1H NMR (400 MHz, DMSO- _d6 ): δ 10.86 (s, 1H), 9.48 (s, 1H), 8.89 (s, 1H), 8.74 (s, 1H), 8.29 (s, 1H), 8.17 (d, J=8.5 Hz, 1H), 8.01 (s, 1H), 7.63 (d, J=10.9 Hz, 1H), 7.17 (m, 2H), 6.84-6.83 (m, 1H), 4.22 (q, J=7.2 Hz, 2H), 2.17 (s, 3H), 1.27 (t, J=7.1 Hz, 3H); MS (ESI) m/z: 530.1 [M+H] ⁺ .

[00322] Example 68: A solution of the compound of Example A4 (250 mg, 0.535 mmol) in pyridine (2 ml) was treated with 2,5-difluorophenyl isocyanate (91 mg, 0.589 mmol) and stirred at RT overnight. Additional 2,5-difluorophenyl isocyanate (30 μL, 0.256 mmol) was added and stirred at RT for 4 hours. The mixture was concentrated to near dryness, treated with EtOAc and brine, the resulting solid was collected by filtration and dried to give 1-(4-chloro-5-(1-ethyl-7-((4-methoxybenzyl)(methyl)amino)-2 -oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-(2,5-difluorophenyl)urea (314 mg, 94% yield). ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 9.31 (s, 2H), 8.51 (s, 1H), 8.19 (d, J=8.6 Hz, 1H), 7. 98 (m, 1H), 7.78 (s, 1H), 7.56 (d, J=10.9 Hz, 1H), 7.29 (m, 1H), 7.18 (d, J=8 ,4 Hz, 2H), 6.89-6.78 (m, 3H), 6.33 (s, 1H), 4.85 (s, 2H), 4.19 (q, J=7.1 Hz , 2H), 3.70 (s, 3H), 3.13 (s, 3H), 1.13 (t, J=7.0 Hz, 3H); MS (ESI) m/z: 622.2 [M+H] ⁺ .

[00323] A mixture of 1-(4-chloro-5-(1-ethyl-7-((4-methoxybenzyl)(methyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridine-3- yl)-2-fluorophenyl)-3-(2,5-difluorophenyl)urea (314 mg, 0.505 mmol) and anisole (273 mg, 2.52 mmol) were treated with TFA (3.0 ml, 51.9 mmol) and stirred at RT for 2.5 hours. The mixture was concentrated to near dryness and treated with EtOAc. NaHCO ₃ , the resulting solid was collected by filtration and dried to give 1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridine-3 -yl)-2-fluorophenyl)-3-(2,5-difluorophenyl)urea (233 mg, 92% yield). ^1H NMR (400 MHz, DMSO- _d6 ): δ 9.24 (m, 2H), 8.40 (s, 1H), 8.17 (d, J=8.7 Hz, 1H), 7, 97 (m, 1H), 7.73 (s, 1H), 7.54 (d, J=11.0 Hz, 1H), 7.27 (m, 1H), 7.02 (m, 1H), 6.80 (m, 1H), 6.23 (s, 1H), 4.12 (q, J=7.1 Hz, 2H), 2.85 (d, J=4.9 Hz, 3H), 1.19 (t, J=7.0 Hz, 3H); MS (ESI) m/z: 502.2 [M+H] ⁺ .

[00324] Example 69: Biphasic solution of the compound of Example A1 (0.15 g, 0.336 mmol) in EtOAc (5 ml) and sat. NaHCO ₃ (4.2 ml) was treated with isopropenyl chloroformate (0.061 g, 0.504 mmol) and stirred at RT for 2 hours. The layers were separated, the aqueous layer was extracted with EtOAc (1x), and the combined organic layers were washed with brine, dried over Na ₂ SO ₄ and concentrated to dryness. The solid was dissolved in THF (2 ml), treated with 1-methylpyrrolidine (0.011 g, 0.134 mmol) and 3-chloro-5-fluoroaniline (0.098 g, 0.672 mmol) and heated at 55°C for 20 hours. The mixture was cooled to RT, concentrated to dryness and purified by silica gel chromatography (EtOAc/hex) to give 1-(3-chloro-5-fluorophenyl)-3-(5-(1-ethyl-7-((4-methoxybenzyl) )(methyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoro-4-methylphenyl)urea (105 mg, 51% yield). MS (ESI) m/z:618.2[M+H] ⁺ .

[00325] Solution of 1-(3-chloro-5-fluorophenyl)-3-(5-(1-ethyl-7-((4-methoxybenzyl)(methyl)-amino)-2-oxo-1,2-dihydro -1,6-naphthyridin-3-yl)-2-fluoro-4-methylphenyl)urea (0.105 g, 0.170 mmol) in TFA (3 ml) was treated with anisole (0.093 ml, 0.849 mmol) and stirred at RT for 4 hours. The mixture was concentrated to dryness and purified by reverse phase chromatography (MeCN/H ₂ O with 0.1% TFA). The united factions neutralized us. NaHCO ₃ , extracted with EtOAc (2×) and the combined organic layers were washed with water, then brine, dried over Na ₂ SO ₄ and concentrated to dryness to give 1-(3-chloro-5-fluorophenyl)-3-(5-(1 -ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoro-4-methylphenyl)urea (62 mg, 73% yield). ^1H NMR (400 MHz, DMSO- _d6 ): δ 9.54 (s, 1H), 8.69 (s, 1H), 8.40 (s, 1H), 7.85 (d, J=8 .4 Hz, 1H), 7.66 (s, 1H), 7.35 (s, 1H), 7.27 (dt, J=11.3, 2.1 Hz, 1H), 7.14 (d , J=12.1 Hz, 1H), 7.00-6.95 (m, 2H), 6.24 (s, 1H), 4.14 (q, J=7.1 Hz, 2H), 2 .85 (d, J=4.9 Hz, 3H), 2.07 (s, 3H), 1.21 (t, J=7.0 Hz, 3H); MS (ESI) m/z: 498.2 [M+H] ⁺ .

[00326] Example 70: A solution of the compound of Example A50 (0.105 g, 0.196 mmol) in dioxane (4 ml) was treated with dimethylamine (2M in THF, 4 ml, 8.0 mmol) and stirred at RT overnight. 1-Methylpyrrolidine (0.1 ml) was added and the mixture was stirred at RT for 24 hours. Additional 1-methylpyrrolidine (0.1 ml) and dimethylamine (2M in THF, 2 ml, 4.0 mmol) were added and the mixture was stirred at RT for 3 days, then heated at 40°C for 24 hours. The mixture was cooled to RT and the solid was collected by filtration and dried to give 3-(3-(2-chloro-4-fluoro-5-(3-phenylureido)phenyl)-1-ethyl-2-oxo-1,2- Dihydro-1,6-naphthyridin-7-yl)-1,1-dimethylurea (80 mg, 73% yield). ^1H NMR (400 MHz, DMSO- _d6 ): δ 9.19 (s, 1H), 9.08 (s, 1H), 8.70 (m, 1H), 8.65 (s, 1H), 8.21 (d, J=8.6 Hz, 1H), 8.01 (s, 1H), 7.94 (s, 1H), 7.56 (d, J=11.0 Hz, 1H), 7.43-7.41 (m, 2H), 7.26 (m, 2H), 6.97 (t, J=7.4 Hz, 1H), 4.17 (q, J=7.0 Hz , 2H), 2.97 (s, 6H), 1.24 (t, J=7.0 Hz, 3H); MS (ESI) m/z: 523.2 [M+H] ⁺ .

[00327] Example 71: A mixture of the compound of Example A47 (200 mg, 0.363 mmol), DIEA (188 mg, 1.452 mmol) and 3-chloro-5-fluoroaniline (211 mg, 1.452 mmol) in dioxane (5 ml) was heated at 80°C overnight. The mixture was cooled to RT, treated with EtOAc and us. NaHCO ₃ and the resulting solid were collected by filtration and dried to give crude 1-(4-chloro-5-(1-ethyl-7-((4-methoxybenzyl)(methyl)amino)-2-oxo-1,2- Dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-(3-chloro-5-fluorophenyl)urea (91 mg, 39% yield), which was used in the next step without further purification. MS (ESI) m/z: 638.2 [M+H] ⁺ .

[00328] A mixture of 1-(4-chloro-5-(1-ethyl-7-((4-methoxybenzyl)(methyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridine-3- yl)-2-fluorophenyl)-3-(3-chloro-5-fluorophenyl)urea (91 mg, 0.143 mmol) and anisole (77 mg, 0.713 mmol) were stirred in TFA (3 ml) at RT for 3 hours. The mixture was concentrated to near dryness, dissolved in EtOAc and treated with us. _NaHCO3 . The layers were separated, the organic layer was washed with brine and dried over Na ₂ SO ₄ . A solid precipitated, then THF, MeOH and DMF were added and the mixture was heated until a clear solution was obtained, then filtered to remove salts. The filtrate was concentrated to dryness and purified by reverse phase chromatography (MeCN/H ₂ O with 0.1% TFA). Organic substances were removed under reduced pressure, and the aqueous residue was neutralized. NaHCO ₃ , extracted with warm EtOAc (2×), the combined organic layers were washed with brine, dried over Na ₂ SO ₄ and concentrated to dryness to give 1-(4-chloro-5-(1-ethyl-7-(methylamino)-2 -oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-(3-chloro-5-fluorophenyl)urea (55 mg, 74% yield). ^1H NMR (400MHz, DMSO- _d6 ): δ 9.43 (s, 1H), 8.83 (s, 1H), 8.41 (s, 1H), 8.09 (d, J=8, 6 Hz, 1H), 7.74 (s, 1H), 7.55 (d, J=10.9 Hz, 1H), 7.36 (s, 1H), 7.27 (dt, J=11, 2, 2.1 Hz, 1H), 7.06-6.98 (m, 2H), 6.24 (s, 1H), 4.14 (q, J=7.1 Hz, 2H), 2, 86 (d, J=4.8 Hz, 3H), 1.20 (t, J=7.0 Hz, 3H); MS (ESI) m/z: 518.1 [M+H] ⁺ .

[00329] Example 72: A mixture of the compound of Example A47 (200 mg, 0.363 mmol), DIEA (188 mg, 1.452 mmol) and 3-chloro-5-methylaniline (182 mg, 1.452 mmol) in dioxane (5 ml) was heated at 80°C overnight. The mixture was cooled to RT, treated with EtOAc and us. NaHCO ₃ and the resulting solid were collected by filtration and dried to give crude 1-(4-chloro-5-(1-ethyl-7-((4-methoxybenzyl)(methyl)amino)-2-oxo-1,2- Dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-(3-fluoro-5-methylphenyl)urea (197 mg, 88% yield). MS (ESI) m/z: 618.2 [M+H] ⁺ .

[00330] A mixture of 1-(4-chloro-5-(1-ethyl-7-((4-methoxybenzyl)(methyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridine-3- yl)-2-fluorophenyl)-3-(3-fluoro-5-methylphenyl)urea (197 mg, 0.319 mmol) and anisole (172 mg, 1.594 mmol) were stirred in TFA (4 ml) at RT for 3 hours. The mixture was concentrated to near dryness and treated with EtOAc. NaHCO ₃ and the resulting solid was collected by filtration and dried to give 1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridine- 3-yl)-2-fluorophenyl)-3-(3-fluoro-5-methylphenyl)urea (113 mg, 71% yield). ^1H NMR (400 MHz, DMSO- _d6 ): δ 9.18 (brs, 1H), 8.80 (brs, 1H), 8.41 (s, 1H), 8.14 (d , J=8.15 Hz, 1H), 7.73 (s, 1H), 7.52 (d, J=10.8 Hz, 1H), 7.22 (d, J=11.5 Hz, 1H ), 7.03 (br.s, 1H), 6.92 (s, 1H), 6.67-6.59 (m, 1H), 6.24 (s, 1H), 4.14 (q, J=7.1 Hz, 2H), 2.86 (s, 3H), 2.25 (s, 3H), 1.21 (t, J=7.3 Hz, 3H); MS (ESI) m/z: 498.1 [M+H] ⁺ .

[00331] Example 73: A mixture of the compound of Example 21 (100 mg, 0.221 mmol) in pyridine (3 ml) was treated dropwise with methyl chloroformate (23 mg, 0.243 mmol) and stirred at RT for 4 hours. Additional methyl chloroformate (50 μl) was added and the mixture was stirred overnight. The mixture was further treated with methyl chloroformate (100 μl) and stirred for another 2 days. The mixture was concentrated to dryness, treated with EtOAc and water, and the resulting solid was collected by filtration. The substance was purified by reverse phase chromatography (MeCN/H ₂ O with 0.1% TFA); the organic matter was removed under reduced pressure and the aqueous mixture was neutralized. _NaHCO3 . The resulting solid was collected by filtration, washed with water and dried to give (3-(2-chloro-4-fluoro-5-(3-phenylureido)phenyl)-1-ethyl-2-oxo-1,2-dihydro methyl ester -1,6-naphthyridin-7-yl)carbamic acid (101 mg, 87% yield). ^1H NMR (400 MHz, DMSO- _d6 ): δ 10.56 (brs, 1H), 9.31-8.78 (m, 2H), 8.67 (s, 1H), 8.20 (d, J=8.6 Hz, 1H), 7.96 (s, 2H), 7.56 (d, J=11.0 Hz, 1H), 7.42 (d, J=8.0 Hz, 2H ), 7.26 (t, J=7.8 Hz, 2H), 6.96 (t, J=7.4 Hz, 1H), 4.20 (q, J=7.2 Hz, 2H), 3.71 (s, 3H), 1.25 (t, J=7.1 Hz, 3H); MS (ESI) m/z: 510.1 [M+H] ⁺ .

[00332] Example 74: A mixture of the compound of Example 21 (90 mg, 0.199 mmol) and pyridine (79 mg, 0.996 mmol) in THF (4 ml) was treated dropwise with methoxyacetyl chloride (27 mg, 0.249 mmol) and stirred at RT for 22 hours. Additional methoxyacetyl chloride (30 μL, 0.328 mmol) was added and the mixture was heated at 40°C for 6 hours, then cooled to RT and stirred overnight. The mixture was treated with EtOAc and water, stirred for 1 hour, the resulting solid was collected by filtration and dried to give N-(3-(2-chloro-4-fluoro-5-(3-phenylureido)phenyl)-1-ethyl- 2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)-2-methoxy-acetamide (76 mg, 72% yield). ^1H NMR (400 MHz, DMSO- _d6 ): δ 10.39 (s, 1H), 9.09 (s, 1H), 8.73 (m, 2H), 8.27-8.20 (m , 2H), 8.00 (s, 1H), 7.58 (d, J=10.9 Hz, 1H), 7.41 (d, J=8.0 Hz, 2H), 7.26 (t , J=7.7 Hz, 2H), 6.97 (t, J=7.3 Hz, 1H), 4.21 (q, J=7.1 Hz, 2H), 4.12 (s, 2H ), 3.38 (s, 3H), 1.26 (t, J=7.1 Hz, 3H); MS (ESI) m/z: 524.2 [M+H] ⁺ .

[00333] Example 75: A mixture of the compound of Example A18 (752 mg, 9.0 mmol), Cs ₂ CO ₃ (2.0 g, 6.0 mmol) and Xantphos (173 mg, 0.3 mmol) in dioxane ( 10 ml) was purged with N ₂ , treated with Pd ₂ (dba) ₃ (165 mg, 0.18 mmol), purged again with N ₂ and heated at 100°C overnight. The mixture was cooled to RT, poured into water and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , concentrated to dryness and purified by silica gel chromatography to give N-(3-(5-amino-2,4-difluorophenyl)-1-ethyl-2-oxo-1 ,2-dihydro-1,6-naphthyridin-7-yl)-2-cyanoacetamide (500 mg, 44% yield). ^1H NMR (400 MHz, DMSO- _d6 ): δ 11.15 (s, 1H), 8.71 (s, 1H), 8.14 (s, 1H), 7.98 (s, 1H), 7.06-7.11 (m, 1H), 6.80-6.85 (m, 1H), 5.06 (s, 2H), 4.22-4.18 (m, 2H), 4. 08 (s, 2H), 1.25-1.22 (t, J=7.2 Hz, 3H).

[00334] N-(3-(5-amino-2,4-difluorophenyl)-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)-2-cyanoacetamide solution ( 0.5 g, 1.3 mmol) and K ₂ CO ₃ (448 mg, 3.25 mmol) in THF (4 ml) were treated dropwise with phenylchloroformate (408 mg, 2.6 mmol) and heated at 60 ° C in during the night. The mixture was cooled to RT, concentrated to dryness, treated with water and extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , concentrated and purified by silica gel chromatography to give phenyl ester (5-(7-(2-cyanoacetamido)-1-ethyl-2-oxo-1,2-dihydro -1,6-naphthyridin-3-yl)-2,4-difluorophenyl)carbamic acid (400 mg, 61% yield).

[00335] (5-(7-(2-cyanoacetamido)-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2,4-difluorophenyl)carbamine phenyl ester solution acid (400 mg, 0.80 mmol) and aniline (158 mg, 1.6 mmol) in DMSO (3 ml) were heated at 60°C overnight and purified by reverse phase chromatography (MeCN/H ₂ O with 0 .1% TFA) to give 2-cyano-N-(3-(2,4-difluoro-5-(3-phenylureido)phenyl)-1-ethyl-2-oxo-1,2-dihydro-1,6 -naphthyridin-7-yl)acetamide (50 mg, 13% yield). ^1H NMR (400 MHz, DMSO- _d6 ): δ 11.23 (s, 1H), 8.92 (s, 1H), 8.78 (s, 1H), 8.20-8.16 (m , 2H), 8.11 (s, 1H), 7.49-7.39 (m, 4H), 7.29-7.25 (m, 2H), 6.96 (t, J=7.2 Hz, 1H), 4.26-4.21 (q, J=6.8 Hz, 2H), 4.09 (s, 2H), 1.30-1.26 (t, J=6.8 Hz , 3H); MS (ESI) m/z: 503.2 [M+H] ⁺ .

[00336] Example 76: A solution of the compound of Example C5 (3 g, 10.9 mmol) in DMF (50 ml) was treated with ZnCN ₂ (l.7 g, 16.4 mmol) and Pd(PPh ₃ ) ₄ (1, 26 g, 1.09 mmol), purged with N ₂ and heated at 100°C for 12 hours. The mixture was cooled to RT, treated with water and extracted with EtOAc (3×). The combined organic layers were washed with brine (3×), dried over Na ₂ SO ₄ , concentrated to dryness and purified by silica gel chromatography (EtOAc/pet. ether) to give 2-(5-amino-2-cyano-4- ethyl ester). fluorophenyl)acetic acid (600 mg, 25% yield). ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.19 (d, J=2.4 Hz, 1H), 6.67 (d, J=8.4 Hz, 1H), 4.13-4, 11 (q, J=6.8 Hz, 2H), 3.66 (s, 2H), 1.23-1.19 (t, J=6.8 Hz, 3H).

[00337] A solution of 2-(5-amino-2-cyano-4-fluorophenyl)acetic acid ethyl ester (400 mg, 1.80 mmol) and the compound of Example B1 (281 mg, 1.80 mmol) in DMF (20 ml) was treated with Cs ₂ CO ₃ (1.17 g, 3.60 mmol) and stirred at RT for 1 hour. The resulting solid was collected by filtration, washed with water and dried to give 4-amino-2-(7-chloro-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-5 -fluorobenzonitrile (420 mg, yield 68%). ^1H NMR (400 MHz, DMSO- _d6 ): δ 8.88 (s, 1H), 8.26 (s, 1H), 7.83 (s, 1H), 7.69 (d, J=11 .6 Hz, 1H), 6.92 (d, J=8.8 Hz, 1H), 6.43 (s, 2H), 4.38-4.33 (q, J=6.4 Hz, 2H ), 1.30-1.26 (t, J=6.4 Hz, 3H).

[00338] Mixture of 4-amino-2-(7-chloro-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-5-fluorobenzonitrile (420 mg, 1.23 mmol) and methylamine (25%, 50 ml) were heated at 120°C in a pressure-resistant vessel for 1 day. The mixture was cooled to RT, the solid was collected by filtration and purified by silica gel chromatography (EtOAc/pet. ether) to give 4-amino-2-(1-ethyl-7-(methylamino)-2-oxo-1,2- Dihydro-1,6-naphthyridin-3-yl)-5-fluorobenzonitrile (250 mg, 61% yield). ^1H NMR (400 MHz, DMSO- _d6 ): δ 8.42 (s, 1H), 7.81 (s, 1H), 7.72 (s, 1H), 7.53 (d, J=11 ,6 Hz, 1H), 7.09-7.08 (m, 1H), 6.81 (d, J=8.4 Hz, 1H), 6.23 (s, 2H), 4.16-4 .11 (q, J=6.8 Hz, 2H), 2.85 (d, J=4.8 Hz, 3H), 1.22-1.18 (t, J=6.8 Hz, 3H) .

[00339] 4-Amino-2-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-5-fluorobenzonitrile solution (100 mg, 0.296 mmol) in DCM at -70°C, treated dropwise with n-BuLi (0.47 ml, 1.17 mmol), stirred at -60°C for 40 minutes, treated with phenyl isocyanate (70.6 mg, 0.593 mmol), heated to RT and stirred for 12 hours. The mixture was concentrated and purified by HPLC to give 1-(4-cyano-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2 -fluorophenyl)-3-phenylurea (22 mg, 16% yield). ^1H NMR (400 MHz, DMSO- _d6 ): δ 9.28 (s, 1H), 9.08 (s, 1H), 8.46 (s, 1H), 8.42 (d, J=8 .0 Hz, 1H), 7.94 (s, 1H), 7.91 (s, 1H), 7.45-7.43 (m, 2H), 7.31-7.27 (m, 2H) , 7.18-7.13 (q, J=4.8 Hz, 1H), 7.02-6.98 (m, 1H), 6.26 (s, 1H), 4.16 (q, J -7.2 Hz, 2H), 2.87 (d, J=4.8 Hz, 3H), 1.22 (t, J=7.2 Hz, 3H); MS (ESI) m/z: 457.3 [M+H] ⁺ .

[00340] Example 77: Mixture of Example A52 (153 mg, 0.304 mmol), tert-butyl-X-phos (6.45 mg, 0.015 mmol), Cs ₂ CO ₃ (198 mg, 0.608 mmol), Pd ₂ (dba) ₃ (28 mg, 0.030 mmol) and methylamine (2.0 N in THF, 2.0 ml, 4.0 mmol) in dioxane (3 ml) were purged with Ar and heated at 80°C for 4. 5 o'clock. The mixture was cooled to RT, treated with EtOAc and DCM, and solids were removed by filtration through diatomaceous earth. The filtrate was concentrated to dryness and purified by reverse phase chromatography (MeCN/H ₂ O with 0.1% TFA). Organics were removed under reduced pressure and the aqueous layer was neutralized with NaHCO ₃ . The mixture was extracted with EtOAc (2×) and the combined organic layers were washed with brine, dried over Na ₂ SO ₄ and concentrated to dryness to give 1-(4-chloro-2-fluoro-5-(1-isopropyl-7-(methylamino)- 2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)phenyl)-3-(3-fluorophenyl)urea (22 mg, 14% yield). MS (ESI) m/z: 498.1 [M+H] ⁺ .

[00341] Mixture of 1-(4-chloro-2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)phenyl) -3-(3-fluorophenyl)urea (22 mg, 0.042 mmol) in MeCN (1.5 ml) was treated with 0.1 N. HCl (464 µl, 0.046 mmol), frozen and lyophilized to give 1-(4-chloro-2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydro-1 hydrochloride ,6-naphthyridin-3-yl)phenyl)-3-(3-fluorophenyl)urea (19 mg, 84% yield). ^1H NMR (400 MHz, DMSO- _d6 ): δ 9.58 (s, 1H), 8.90 (s, 1H), 8.50 (s, 1H), 8.18 (d, J=8 .6 Hz, 1H), 7.83 (s, 1H), 7.56 (d, J=10.9 Hz, 1H), 7.50-7.38 (m, 2H), 7.32-7 .25 (m, 1H), 7.07 (dd, J=8.2, 1.9 Hz, 1H), 6.82-6.73 (m, 2H), 5.12 (m, 1H), 2.96 (s, 3H), 1.52 (d, J=6.9 Hz, 6H); MS (ESI) m/z: 498.2 [M+H] ⁺ .

[00342] Example 78: A mixture of Example A56 (88 mg, 0.188 mmol), Cs ₂ CO ₃ (122 mg, 0.375 mmol) and acetamide (55.4 mg, 0.938 mmol) in dioxane (2 ml) was purged with Ar in for 15 minutes, treated with Pd ₂ (dba) ₃ (8.59 mg, 9.38 µmol) and Xantphos (10.86 mg, 0.019 mmol), again purged with Ar and heated to 100°C for 2.5 hours. The mixture was cooled to RT, treated with 10% MeOH/DCM and solids were removed by filtration through diatomaceous earth. The filtrate was concentrated to dryness and purified by silica gel chromatography (EtOAc/hex). The material was repurified by reverse phase chromatography (MeCN/H ₂ O with 0.1% TFA); organic matter was removed under reduced pressure, and the aqueous residue was frozen and lyophilized. The resulting material was treated with MTBE, the solid was collected by filtration and dried to give N-(1-ethyl-3-(4-fluoro-5-(3-(3-fluorophenyl)ureido)-2-methylphenyl)-2-oxo- 1,2-dihydro-1,6-naphthyridin-7-yl)acetamide (12 mg, 13% yield). ^1H NMR (400 MHz, DMSO- _d6 ): δ 10.80 (s, 1H), 9.23 (s, 1H), 8.70 (s, 1H), 8.57 (s, 1H), 8.26 (s, 1H), 7.95 (d, J=8.4 Hz, 1H), 7.89 (s, 1H), 7.46 (dt, J=12.0, 2.3 Hz , 1H), 7.28 (m, 1H), 7.17 (d, J=12.2 Hz, 1H), 7.05 (d, J=8.3 Hz, 1H), 6.77 (td , J=8.5, 2.6 Hz, 1H), 4.20 (q, J=7.0 Hz, 2H), 2.14 (s, 3H), 2.08 (s, 3H), 1 .25 (t, J=7.1 Hz, 3H); MS (ESI) m/z: 492.2 [M+H] ⁺ .

[00343] Example 79: Mixture of Example D1 (155 mg, 0.493 mmol), DIEA (146 mg, 1.126 mmol), 1-methylpyrrolidine (24 mg, 0.281 mmol) and Example A47 (155 mg, 0.281 mmol) in dioxane (4 ml) was heated at 80°C for 20 hours. The mixture was cooled to RT, treated with EtOAc, washed with NaHCO ₃ then brine, dried over Na ₂ SO ₄ , concentrated to dryness and purified by reverse phase chromatography (MeCN/H ₂ O with 0.1% TFA). Organic matter was removed under reduced pressure, and the aqueous residue was treated with us. NaHCO ₃ and left to settle at RT. The resulting solid was collected by filtration, washed with water and dried to give 1-(4-chloro-5-(1-ethyl-7-((4-methoxybenzyl)(methyl)amino)-2-oxo-1,2-dihydro -1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-(3-((4-methylpiperazin-1-yl)methyl)phenyl)urea (79 mg, 40% yield). ^1H NMR (400 MHz, DMSO- _d6 ): δ 9.16 (s, 1H), 8.73 (s, 1H), 8.51 (s, 1H), 8.17 (d, J=8 ,6 Hz, 1H), 7.78 (s, 1H), 7.52 (d, J=10.9 Hz, 1H), 7.39 (s, 1H), 7.27 (m, 1H), 7.20-7.15 (m, 3H), 6.91-6.84 (m, 3H), 6.32 (s, 1H), 4.85 (s, 2H), 4.19 (q, J=7.0 Hz, 2H), 3.70 (s, 3H), 3.37 (s, 2H), 3.13 (s, 3H), 2.40-2.19 (m, 8H), 2.11 (s, 3H), 1.13 (t, J=6.9 Hz, 3H); MS (ESI) m/z: 698.3 [M+H] ⁺ .

[00344] A mixture of 1-(4-chloro-5-(1-ethyl-7-((4-methoxybenzyl)(methyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridine-3- yl)-2-fluorophenyl)-3-(3-((4-methylpiperazin-1-yl)methyl)-phenyl)urea (78 mg, 0.112 mmol) and anisole (60 mg, 0.559 mmol) were stirred in TFA (2 ml) at CT within 2 hours. The mixture was concentrated to dryness and purified by reverse phase chromatography (MeCN/H ₂ O with 0.1% TFA). Organic matter was removed under reduced pressure and the aqueous residue was treated with us. _NaHCO3 . The mixture was extracted with EtOAc (2×) and the combined organic layers were washed with brine, dried over Na ₂ SO ₄ and concentrated to dryness to give 1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo- 1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-(3-((4-methylpiperazin-1-yl)methyl)phenyl)urea (50 mg, 76% yield) . MS (ESI) m/z: 578.2 [M+H] ⁺ .

[00345] A mixture of 1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)- 3-(3-((4-methylpiperazin-1-yl)methyl)phenyl)urea in MeCN (4 ml) was treated with 0.1 N. HCl (1.77 mL, 0.177 mmol), frozen and lyophilized to give 1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6) dihydrochloride -naphthyridin-3-yl)-2-fluorophenyl)-3-(3-((4-methylpiperazin-1-yl)methyl)phenyl)urea (53 mg, 91% yield). ^1H NMR (400 MHz, DMSO- _d6 ): δ 9.46 (s, 1H), 8.89 (s, 1H), 8.42 (s, 1H), 8.14 (d, J=8 .6 Hz, 1H), 7.75 (s, 1H), 7.50 (m, 2H), 7.35-7.19 (m, 3H), 6.96 (s, 1H), 6.33 (s, 1H), 4.10 (q. J=7.0 Hz, 2H), 3.66-3.21 (m, 8H), 3.09-2.94 (br.s, 2H), 2.86 (s, 3H), 2.68 (s, 3H), 1.16 (t, J=7.0 Hz, 3H); MS (ESI) m/z: 578.3 [M+H] ⁺ .

[00346] Example 80: Mixture of Example A54 (0.211 g, 0.468 mmol), Bippyphos (0.024 g, 0.047 mmol), acetamide (0.332 g, 5.62 mmol) and K ₃ PO ₄ (0.397 g, 1.872 mmol) in dioxane (5 ml) was purged with Ar for 15 minutes, treated with Pd ₂ (dba) ₃ (0.021 g, 0.023 mmol) and heated at 80°C overnight. The mixture was cooled to RT, diluted with EtOAc and solids removed by filtration. The filtrate was concentrated to dryness, dissolved in EtOAc/THF, washed with brine (2×), dried over MgSO ₄ and concentrated to dryness. The substance was treated with acetone, the solid was collected by filtration and dried. The filtrate was concentrated to dryness, purified by silica gel chromatography (MeOH/DCM) and combined with the isolated solid. The material was repurified by reverse phase chromatography (MeCN/H ₂ O with 0.1% TFA); the combined fractions were partially concentrated, then frozen and lyophilized to give N-(1-ethyl-3-(4-fluoro-2-methyl-5-(3-phenylureido)phenyl)-2-oxo-1,2-dihydro-1 ,6-naphthyridin-7-yl)acetamide (24 mg, 11% yield). ^1H NMR (400 MHz, DMSO- _d6 ): δ 10.79 (s, 1H), 9.01 (s, 1H), 8.70 (s, 1H), 8.50 (s, 1H), 8.26 (s, 1H), 7.98 (d, J=8.2 Hz, 1H), 7.89 (s, 1H), 7.41 (d, J=7.8 Hz, 2H), 7.25 (t, J=7.5 Hz, 2H), 7.16 (dd, J=12.3 Hz, 1H), 6.99-6.89 (m, 1H), 4.25-4 .14 (m, 2H), 2.14 (s, 3H), 2.08 (s, 3H), 1.30-1.20 (m, 3H); MS (ESI) m/z: 474.2 [M+H] ⁺ .

[00347] Example 81: A suspension of the compound of Example A50 (0.202 g, 0.377 mmol) and 3-hydroxyazetidine hydrochloride (0.045 g, 0.415 mmol) in THF (4 ml) was treated with 1-methylpyrrolidine (0.050 ml, 0.471 mmol) and heated at 55°C overnight. Additionally, 3-hydroxyazetidine hydrochloride (0.150 g) and 1-methylpyrrolidine (0.30 ml) were added and the mixture was heated at 55°C for another 24 hours. The mixture was cooled to RT, diluted with water, and the remaining solid was collected by filtration, washed with THF and dried. The solid was purified by reverse phase chromatography (MeCN/H ₂ O with 0.1% TFA); organic substances were removed under reduced pressure, the aqueous residue was neutralized. NaHCO ₃ was then concentrated as an azeotrope with IPA to dryness. The residue was suspended in water, the solid was collected by filtration and dried to give N-(3-(2-chloro-4-fluoro-5-(3-phenylureido)phenyl)-1-ethyl-2-oxo-1,2- Dihydro-1,6-naphthyridin-7-yl)-3-hydroxyazetidin-1-carboxamide (26 mg, 13% yield). ^1H NMR (400 MHz, DMSO- _d6 ): δ 9.47 (s, 1H), 9.10 (s, 1H), 8.72 (s, 1H), 8.64 (s, 1H), 8.21 (d, J=8.6 Hz, 1H), 8.11 (s, 1H), 7.94 (s, 1H), 7.56 (d, J=11.0 Hz, 1H), 7.41 (d, J=8.0 Hz, 2H), 7.26 (t, J=7.7 Hz, 2H), 6.97 (t, J=6.9 Hz, 1H), 5, 64 (d, J=6.3 Hz, 1H), 4.47-4.37 (m, 1H), 4.26-4.09 (m, 4H), 3.81-3.72 (m, 2H), 1.25-1.23 (m, 3H); MS (IER) 551.2 [M+H] ⁺ .

[00348] Example 82: A mixture of the compound of Example D1 (250 mg, 0.794 mmol), DIEA (252 mg, 1.949 mmol) and 1-methylpyrrolidine (41 mg, 0.487 mmol) in dioxane (4 ml) was treated with the compound of Example A48 ( 200 mg, 0.487 mmol), heated at 80°C for 4 hours, then cooled to RT for 3 days. The mixture was diluted with EtOAc, washed with 50% sat. NaHCO ₃ then brine, dried over Na ₂ SO ₄ , concentrated to dryness and purified by reverse phase chromatography (MeCN/H ₂ O with 0.1% TFA). Organic matter was removed under reduced pressure and the aqueous residue was treated with NaHCO ₃ and left to settle at RT. The resulting solid was collected by filtration, washed with water and dried to give 1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)- 2-fluoro-4-methylphenyl)-3-(3-((4-methylpiperazin-1-yl)methyl)phenyl)urea (62 mg, 22% yield). ^1H NMR (400 MHz, DMSO- _d6 ): δ 9.03 (s, 1H), 8.45-8.41 (m, 2H), 7.93 (d, J=8.5 Hz, 1H ), 7.66 (s, 1H), 7.41 (s, 1H), 7.28-7.16 (m, 2H), 7.12 (d, J=12.6 Hz, 1H), 6 .97 (m, 1H), 6.87 (m, 1H), 6.24 (s, 1H), 4.14 (m, 2H), 3.39 (s, 2H), 2.86 (d, J=5.2 Hz, ZN), 2.43-2.26 (widthm, 8H), 2, (s, 3H), 2.06 (s, 3H), 1.21 (t, J= 7.9 Hz, 3H); MS (ESI) m/z: 558.3 [M+H] ⁺ .

[00349] Example 83: A mixture of the compound of Example D1 (250 mg, 0.794 mmol), DIEA (218 mg, 1.683 mmol) and 1-methylpyrrolidine (36 mg, 0.421 mmol) in dioxane (4 ml) was treated with the compound of Example A49 ( 200 mg, 0.421 mmol), heated at 80°C for 4 hours, then cooled to RT for 3 days. The mixture was treated with EtOAc and DCM, washed with 50% sat. NaHCO ₃ then brine, dried over Na ₂ SO ₄ , concentrated to dryness and purified by reverse phase chromatography (MeCN/H ₂ O with 0.1% TFA). Organic substances were removed under reduced pressure, and the aqueous residue was treated with us. NaHCO ₃ and extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ and concentrated to dryness to give 1-(4-bromo-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1, 6-naphthyridin-3-yl)-2-fluorophenyl)-3-(3-((4-methylpiperazin-1-yl)methyl)-phenyl)urea (57 mg, 21% yield). MS (ESI) m/z: 622.2 [M+H] ⁺ .

[00350] A suspension of 1-(4-bromo-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)- 3-(3-((4-methylpiperazin-1-yl)methyl)phenyl)urea (55 mg, 0.088 mmol) in MeCN (4 ml) was treated with 0.1 N. HCl (1.81 mL, 0.181 mmol), frozen and lyophilized to give 1-(4-bromo-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6) dihydrochloride -naphthyridin-3-yl)-2-fluorophenyl)-3-(3-((4-methylpiperazin-1-yl)methyl)phenyl)urea (60 mg, 93% yield). MS (ESI) m/z: 622.2 [M+H] ⁺ .

[00351] Example 84: A solution of the compound of Example A50 (0.098 g, 0.183 mmol) in THF (3 ml) was treated with (3R)-(+)-3-(dimethylamino)pyrrolidine (0.047 g, 0.549 mmol) and 1-methylpyrrolidine (2.088 mg, 0.018 mmol) and heated at 55°C for 16 hours. The mixture was concentrated to dryness and purified by silica gel chromatography (MeOH/DCM) to give (R)-N-(3-(2-chloro-4-fluoro-5-(3-phenylureido)phenyl)-1-ethyl-2- oxo-1,2-dihydro-1,6-naphthyridin-7-yl)-3-(dimethylamino)pyrrolidine-1-carboxamide (48 mg, 45% yield). ^1H NMR (400 MHz, DMSO- _d6 ): δ 9.10 (s, 1H), 9.08 (s, 1H), 8.72 (s, 1H), 8.65 (s, 1H), 8.21 (d, J=8.6 Hz, 1H), 8.11 (s, 1H), 7.94 (s, 1H), 7.57 (d, J=11.0 Hz, 1H), 7.41 (dd, J=8.3, 1.2 Hz, 2H), 7.26 (t, J=7.8 Hz, 2H), 6.97 (t, J=7.4 Hz, 1H ), 4.18 (q, J=7.2 Hz, 2H), 3.68 (m, 2H), 3.39 (m, 1H), 3.20 (m, 1H), 2.19 (shir .s, 6H), 2.07 (m, 2H), 1.72 (m, 1H), 1.24 (t, J=7.1 Hz, 3H); MS (ESI) m/z: 592.2 [M+H] ⁺ .

[00352] Example 85: A solution of Example A3 (500 mg, 1.420 mmol) and pyridine (449 mg, 5.68 mmol) in THF (20 mL) was treated with phenyl isocyanate (186 mg, 1.562 mmol) and stirred at RT for 20 o'clock. The mixture was accidentally treated with a few drops of SOCl ₂ ; EtOAc, water and us were added. NaHCO ₃ and the mixture was stirred at RT for 2 hours. The resulting solid was collected by filtration and dried. The filtrate layers were separated, the organic layer was washed with brine, dried over Na ₂ SO ₄ and concentrated to dryness. The material was treated with EtOAc then sonicated for 2 minutes, collected by filtration and combined with the isolated solid above to give 1-(4-chloro-5-(7-chloro-1-ethyl-2-oxo-1,2-dihydro -1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea (366 mg, 54% yield). ^1H NMR (400 MHz, DMSO- _d6 ): δ 9.10 (s, 1H), 8.79 (s, 1H), 8.74 (s, 1H), 8.24 (d, J=8 .6 Hz, 1H), 8.09 (s, 1H), 7.75 (s, 1H), 7.60 (d, J=11.0 Hz, 1H), 7.41 (d, J=8 ,0 Hz, 2H), 7.26 (t, J=7.8 Hz, 2H), 6.97 (t, J=7.3 Hz, 1H), 4.27 (q, J=7.1 Hz, 2H), 1.20 (t, J=7.0 Hz, 3H).

[00353] A mixture of 1-(4-chloro-5-(7-chloro-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3- phenylurea (185 mg, 0.393 mmol), Pd ₂ (dba) ₃ (18 mg, 0.020 mmol), Bippyphos (20 mg, 0.039 mmol), K ₃ PO ₄ (333 mg, 1.570 mmol) and LN-1-BOC- prolinamide (673 mg, 3.14 mmol) in dioxane (9 ml) was purged with Ar, heated at 90°C for 4 hours, then cooled to RT and stirred overnight. The mixture was cooled to RT, treated with EtOAc, water and DMF, and solids were removed by filtration through diatomaceous earth. The filtrate layers were separated, the organic layer was washed with brine, dried over Na ₂ SO ₄ , concentrated to dryness and purified by reverse phase chromatography (MeCN/H ₂ O with 0.1% TFA). Organics were removed under reduced pressure and the aqueous residue was treated with sat. NaHCO ₃ and extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ and concentrated to dryness to give (S)-tert-butyl 2-((3-(2-chloro-4-fluoro-5-(3-phenylureido)phenyl) -1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)carbamoyl)pyrrolidine-1-carboxylic acid (105 mg, 41% yield). MS (ESI) m/z: 648.9 [M+H] ⁺ .

[00354] A mixture of (S)-tert-butyl 2-((3-(2-chloro-4-fluoro-5-(3-phenylureido)-phenyl)-1-ethyl-2-oxo-1,2- Dihydro-1,6-naphthyridin-7-yl)carbamoyl)pyrrolidine-1-carboxylic acid (115 mg, 0.177 mmol) in dioxane (3 ml) was treated with 1.25 N. HCl in MeOH (2.8 ml, 3.5 mmol) and heated at 50°C for 2 hours. The mixture was concentrated to dryness and processed for us. NaHCO ₃ and extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , concentrated to dryness and purified by reverse phase chromatography (MeCN/H ₂ O with 0.1% TFA). Organics were removed under reduced pressure and the aqueous residue was treated with sat. NaHCO ₃ and extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ and concentrated to dryness to give (S)-N-(3-(2-chloro-4-fluoro-5-(3-phenylureido)phenyl)-1-ethyl- 2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)pyrrolidin-2-carboxamide (27 mg, 30% yield). MS (ESI) m/z: 549.2 [M+H] ⁺ .

[00355] Mixture of (S)-N-(3-(2-chloro-4-fluoro-5-(3-phenylureido)phenyl)-1-ethyl-2-oxo-1,2-dihydro-1,6- naphthyridin-7-yl)pyrrolidin-2-carboxamide (43 mg, 0.078 mmol) in MeCN (3 ml) was treated with 0.1 N. HCl (aq) (1.56 ml, 0.156 mmol), frozen and lyophilized. The material was treated with MTBE then sonicated, the solid was collected by filtration and dried to give (S)-N-(3-(2-chloro-4-fluoro-5-(3-phenylureido)phenyl)-1-ethyl-2 dihydrochloride -oxo-1,2-dihydro-1,6-naphthyridin-7-yl)pyrrolidin-2-carboxamide (31 mg, 63% yield). MS (ESI) m/z: 549.2 [M+H] ⁺ .

[00356] Example 86: Mixture of compound according to example A55 (320 mg, 0.659 mmol), Pd ₂ (dba) ₃ (30 mg, 0.033 mmol), Bippyphos (33 mg, 0.066 mmol), K ₃ PO ₄ (560 mg, 2.64 mmol) and acetamide (389 mg, 6.59 mmol) in dioxane (8 ml) were purged with Ar and heated to 90°C for 22 hours. The mixture was cooled to RT, diluted with DMF, stirred for 1 hour, and solids were removed by filtration through diatomaceous earth. The filtrate was concentrated to dryness and purified by reverse phase chromatography (MeCN/H ₂ O with 0.1% TFA). Organic substances were removed under reduced pressure, and the aqueous residue was treated with us. NaHCO ₃ and extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ and concentrated to dryness. The material was purified again by chromatography on silica gel (EtOAc/hex) to give N-(3-(2-chloro-4-fluoro-5-(3-phenylureido)phenyl)-1-isopropyl-2-oxo-1,2 -dihydro-1,6-naphthyridin-7-yl)acetamide (33 mg, yield 9.8%). MS (ESI) m/z: 508.2 [M+H] ⁺ .

[00357] A mixture of N-(3-(2-chloro-4-fluoro-5-(3-phenylureido)phenyl)-1-isopropyl-2-oxo-1,2-dihydro-1,6-naphthyridine-7- yl)acetamide (33 mg, 0.065 mmol) in MeCN (3 ml) was treated with 0.1 N. HCl (0.650 ml, 0.065 mmol), frozen and lyophilized. The material was treated with Et ₂ O, the solid was collected by filtration and dried to give N-(3-(2-chloro-4-fluoro-5-(3-phenylureido)phenyl)-1-isopropyl-2-oxo-1 hydrochloride. 2-dihydro-1,6-naphthyridin-7-yl)acetamide (17 mg, 47% yield). ^1H NMR (400 MHz, DMSO- _d6 ): δ 10.82 (s, 1H), 9.16 (s, 1H), 8.75 (s, 1H), 8.69 (s, 1H), 8.53 (s, 1H), 8.22 (d, J=8.6 Hz, 1H), 7.93 (s, 1H), 7.56 (d, J=11.0 Hz, 1H), 7.42 (d, J=8.0 Hz, 2H), 7.26 (t, J=7.7 Hz, 2H), 6.97 (t, J=7.3 Hz, 1H), 3, 71 (m, 1H), 2.15 (s, 3H), 1.56 (d, J=7.0 Hz, 6H); MS (ESI) m/z: 508.2 [M+H] ⁺ .

[00358] Example 87: A mixture of the compound of Example A51 (0.138 g, 0.320 mmol) and the compound of Example D2 (0.100 g, 0.448 mmol) in dioxane (4 ml) was treated with 1-methylpyrrolidine (6.73 μl, 0.064 mmol) and heated to 80°C overnight. The mixture was cooled to RT, further treated with a small amount of dioxane and the solids were collected by filtration and dried to give 1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro- 1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-(4-fluoro-3-((4-methylpiperazin-1-yl)methyl)phenyl)urea (141 mg, 74% yield). ¹ H NMR (400 MHz, CD ₃ OD): δ 8.38 (s, 1H), 8.14 (d, J=8.5 Hz, 1H), 7.75 (s, 1H), 7.68 (dd, J=6.5, 2.8 Hz, 1H), 7.35 (d, J=10.8 Hz, 1H), 7.18 (m, 1H), 7.04 (t, J= 9.2 Hz, 1H), 6.35 (s, 1H), 4.29 (q, J=7.2 Hz, 2H), 3.68 (s, 2H), 2.98 (s, 3H) , 3.46-2.95 (latm, 8H), 2.83 (s, 3H), 1.34 (t, J=7.1 Hz, 3H); MS (ESI) m/z: 596.2 [M+H] ⁺ .

[00359] Example 88: A solution of 3-fluoro-5-nitrotoluene (1.0 g, 6.45 mmol) in trifluorotoluene (15 ml) was treated with NBS (1.721 g, 9.67 mmol) and AIBN (0.212 g, 1.289 mmol ) and heated at 105°C overnight. The mixture was cooled to RT, solids were removed by filtration, and the filtrate was concentrated to dryness to give 1-(bromomethyl)-3-fluoro-5-nitrobenzene (95 mg, 63% yield).

[00360] A solution of 1-(bromomethyl)-3-fluoro-5-nitrobenzene (0.95 g, 4.06 mmol) and DIEA (1.418 mL, 8.12 mmol) in THF (20 mL) at -20°C treated dropwise with a solution of 1-methylpiperazine (0.488 g, 4.87 mmol) in THF (10 ml) and stirred at RT overnight after removing the cooling bath. The solid was removed by filtration and the filtrate was concentrated to dryness and purified by silica gel chromatography (MeOH/DCM) to give 1-(3-fluoro-5-nitrobenzyl)-4-methylpiperazine (820 mg, 80% yield). ^1H NMR (400 MHz, DMSO- _d6 ): δ 8.01 (s, 1H), 7.97 (dt, J=8.6, 2.3 Hz, 1H), 7.64 (dd, J =9.2, 2.2 Hz, 1H), 3.60 (s, 2H), 2.41 (s, 8H), 2.21 (s, 3H); MS (ESI) m/z: 254.1 [M+H] ⁺ .

[00361] A solution of 1-(3-fluoro-5-nitrobenzyl)-4-methylpiperazine (0.15 g, 0.592 mmol) in MeOH (5 ml) was treated with 10% Pd-C (dry) (0.063 g, 0.059 mmol) and hydrogenated (1 atm) for 3 hours. The solids were removed by filtration, washed with MeOH, and the filtrate concentrated to dryness to give 3-fluoro-5-((4-methylpiperazin-1-yl)methyl)aniline (expected 100% yield). MS (ESI) m/z: 224.1 [M+H] ⁺ .

[00362] A mixture of 3-fluoro-5-((4-methylpiperazin-1-yl)methyl)aniline (0.13 g, 0.582 mmol), the compound of Example A51 (0.167 g, 0.388 mmol) and 1-methylpyrrolidine (4 .08 µl, 0.039 mmol) in dioxane (5 ml) was heated at 60°C for 2 days. The mixture was cooled to RT, concentrated to dryness and the residue was treated with Et ₂ O. The solid was collected by filtration, treated with EtOAc, stirred at RT for 2 hours, then collected by filtration. The resulting solid was treated with dioxane, stirred at RT overnight, collected by filtration and dried to give 1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro- 1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-(3-fluoro-5-((4-methylpiperazin-1-yl)methyl)phenyl)urea (84 mg, 36% yield). ^1H NMR (400 MHz, pyridine): δ 10.20 (s, 1H), 9.16 (s, 1H), 8.85 (d, J=8.6 Hz, 1H), 8.61 (s , 1H), 7.91 (d, J=11.3 Hz, 1H), 7.71 (s, 1H), 7.55 (s, 1H), 7.48 (s, 1H), 7.36 (d, J=10.8 Hz, 1H), 6.87 (d, J=9.3 Hz, 1H), 6.26 (s, 1H), 4.21 (q, J=7.0 Hz , 2H), 3.36 (s, 2H), 3.08 (s, 3H), 2.70-2.50 (m, 8H), 2.35 (s, 3H), 1.19 (t, J=7.0 Hz, 3H); MS (ESI) m/z: 596.3 [M+H] ⁺ .

[00363] Example 89: A mixture of the compound of Example D2 (0.060 g, 0.269 mmol) and the compound of Example A48 (0.085 g, 0.207 mmol) in dioxane (2 ml) was treated with 1-methylpyrrolidine (2 drops) and heated to 80°C during the night. The mixture was concentrated to dryness, treated with EtOAc and the resulting solid was collected by filtration and purified by reverse phase chromatography (MeCN/H ₂ O with 0.1% TFA). Organic substances were removed under reduced pressure, and the aqueous residue was treated with us. NaHCO ₃ , extracted with EtOAc (2×) and the combined organic layers were washed with brine, dried over MgSO ₄ and concentrated to dryness to give 1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2- Dihydro-1,6-naphthyridin-3-yl)-2-fluoro-4-methylphenyl)-3-(4-fluoro-3-((4-methylpiperazin-1-yl)methyl)phenyl)urea (39 mg, yield 33%). ^1H NMR (400 MHz, DMSO- _d6 ): δ 9.84 (s, 1H), 8.87 (s, 1H), 8.73 (d, J=8.43 Hz, 1H), 8. 62 (s, 1H), 7.96 (dd, J=6.5, 2.8 Hz, 1H), 7.79 (ddd, J=8.9, 4.5, 2.8 Hz, 1H) , 7.65 (s, 1H), 7.58 (s, 1H), 7.15 (t, J=9.2 Hz, 1H), 7.08 (d, J=12.0 Hz, 1H) , 6.32 (s, 1H), 4.26 (q, J=7.1 Hz, 2H), 3.58 (s, 2H), 3.13 (d, J=4.8 Hz, 3H) , 2.53 (bir.m, 4H), 2.31 (m, 7H), 2.13 (s, 3H), 1.24 (t, J=7.0 Hz, 3H); MS (ESI) m/z: 576.2 [M+H] ⁺ .

[00364] Example 90: A suspension of the compound of Example A8 (0.078 g, 0.236 mmol) in EtOAc (1.5 ml) was treated with us. NaHCO ₃ (1.5 ml), then isopropenyl chloroformate (0.036 ml, 0.331 mmol) and the two-phase mixture was stirred vigorously at RT overnight. The layers were separated, the organic layer was washed with brine, dried over MgSO ₄ and concentrated to dryness to give prop-1-en-2-yl ester (5-(1-ethyl-7-(methylamino)-2-oxo-1,2- Dihydro-1,6-naphthyridin-3-yl)-2,4-difluorophenyl)carbamic acid (86 mg, 88% yield). ^1H NMR (400 MHz, DMSO- _d6 ): δ 9.64 (s, 1H), 8.41 (s, 1H), 7.83 (s, 1H), 7.61 (s, 1H), 7.36 (t, J=10.2 Hz, 1H), 7.06 (m, 1H), 6.23 (s, 1H), 4.71 (d, J=7.9 Hz, 2H), 4.13 (q, J=7.1 Hz, 2H), 2.85 (d, J=4.9 Hz, 3H), 1.91 (s, 3H), 1.20 (t, J=7 ,1 Hz, 3H); MS (ESI) m/z: 415.1 [M+H] ⁺ .

[00365] A mixture of the compound of Example D2 (0.060 g, 0.269 mmol) and prop-1-en-2-yl ether (5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro- 1,6-naphthyridin-3-yl)-2,4-difluorophenyl)carbamic acid (0.086 g, 0.208 mmol) in dioxane (2 ml) was treated with 1-methylpyrrolidine (2 drops) and heated at 80°C overnight. The mixture was concentrated to dryness, treated with EtOAc and the resulting solid was dried by filtration and purified by reverse phase chromatography (MeCN/H ₂ O with 0.1% TFA). The organics were removed under reduced pressure, the aqueous residue was treated with NaHCO ₃ , extracted with EtOAc (2×), and the combined organic layers were washed with brine, dried over MgSO ₄ and concentrated to dryness to give 1-(5-(1-ethyl-7 -(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2,4-difluorophenyl)-3-(4-fluoro-3-((4-methylpiperazin-1- yl)methyl)phenyl)urea (37 mg, 31% yield). ^1H NMR (400 MHz, DMSO- _d6 ): δ 9.82 (s, 1H), 8.94 (s, 1H), 8.86 (t, J=8.5 Hz, 1H), 8. 59 (s, 1H), 7.93 (dd, J=6.5, 2.8 Hz, 1H), 7.76 (m, 2H), 7.62 (s, 1H), 7.13 (t , J=9.5 Hz, 2H), 6.25 (s, 1H), 4.19 (q, J=7.1 Hz, 2H), 3.55 (s, 2H), 3.08 (d , J=4.9 Hz, 3H), 2.50 (lat.s, 4H), 2.30 (lat.s, 4H), 2.10 (s, 3H), 1.18 (t, J= 7.1 Hz, 3H); MS (ESI) m/z: 580.2 [M+H] ⁺ .

[00366] Example 91: A suspension of the compound of Example A3 (0.250 g, 0.710 mmol) in THF (10 ml) was treated with 3-cyanophenyl isocyanate (0.102 g, 0.710 mmol), then pyridine (0.011 g, 0.142 mmol) and stirred at RT in within 2 days. The mixture was concentrated to dryness and the residue was treated with MeCN. The solid was collected by filtration, treated with MeOH, and the resulting solid was collected by filtration and dried to give 1-(4-chloro-5-(7-chloro-1-ethyl-2-oxo-1,2-dihydro-1, 6-naphthyridin-3-yl)-2-fluorophenyl)-3-(3-cyanophenyl)urea (212 mg, 60% yield). ^1H NMR (400 MHz, DMSO- _d6 ): δ 9.39 (s, 1H), 8.89 (s, 1H), 8.79 (s, 1H), 8.20 (d, J=8 .5 Hz, 1H), 8.09 (s, 1H), 7.97 (t, J=1.8 Hz, 1H), 7.75 (s, 1H), 7.61 (d, J=10 ,6 Hz, 2H), 7.44 (m, 2H), 4.27 (q, J=7.1 Hz, 2H), 1.20 (t, J=7.0 Hz, 3H); MS (ESI) m/z: 496.1 [M+H] ⁺ .

[00367] A mixture of 1-(4-chloro-5-(7-chloro-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3- (3-cyanophenyl)urea (0.210 g, 0.423 mmol), tert-butyl-X-Phos (0.020 g, 0.047 mmol), Pd ₂ (dba) ₃ (0.020 g, 0.022 mmol), Cs ₂ CO ₃ (0.400 g , 1.228 mmol) and methylamine (2.0 M in THF, 4.0 ml, 8.0 mmol) in dioxane (5 ml) were heated at 90°C for 5 hours, then cooled to RT and stirred overnight. Solids were removed by filtration, washed with DCM, then MeCN, and the filtrate was concentrated to dryness and purified by silica gel chromatography (EtOAc/DCM) to give 1-(4-chloro-5-(1-ethyl-7-(methylamino)-2 -oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-(3-cyanophenyl)urea (33 mg, 15% yield). ^1H NMR (400 MHz, DMSO- _d6 ): δ 9.40 (s, 1H), 8.83 (s, 1H), 8.41 (s, 1H), 8.13 (d, J=8 .6 Hz, 1H), 7.97 (t, J=1.8 Hz, 1H), 7.74 (s, 1H), 7.61-7.45 (m, 4H), 7.05 (d , J=5.1 Hz, 1H), 6.24 (s, 1H), 4.14 (d, J=7.4 Hz, 2H), 2.86 (d, J=4.9 Hz, 3H ), 1.21 (t, J=7.0 Hz, 3H); MS (ESI) m/z: 491.1 [M+H] ⁺ .

[00368] Example 92: A suspension of the compound of Example A3 (0.200 g, 0.568 mmol) in 3-morpholinopropan-1-amine (1 ml) was microwaved at 160° C. for 30 minutes. The mixture was cooled to RT, treated with water, and the aqueous layer was decanted. The material was treated with MTBE and the resulting solid was collected by filtration to give 3-(5-amino-2-chloro-4-fluorophenyl)-1-ethyl-7-((3-morpholinopropyl)amino)-1,6-naphthyridine-2 (1H)-one (150 mg, yield 57%). MS (ESI) m/z: 460.1 [M+H] ⁺ .

[00369] Solution of 3-(5-amino-2-chloro-4-fluorophenyl)-1-ethyl-7-((3-morpholinopropyl)-amino)-1,6-naphthyridin-2(1H)-one (0.140 g, 0.304 mmol) in pyridine (4 ml) was treated with phenyl isocyanate (0.040 g, 0.336 mmol) and stirred at RT for 1 hour. The mixture was concentrated to dryness, treated with MeOH and the resulting solid collected by filtration to give 1-(4-chloro-5-(1-ethyl-7-((3-morpholinopropyl)amino)-2-oxo-1,2-dihydro- 1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea (120 mg, 61% yield). ^1H NMR (400 MHz, DMSO- _d6 ): δ 9.08 (s, 1H), 8.68 (s, 1H), 8.40 (s, 1H), 8.17 (d, J=8 ,7 Hz, 1H), 7.72 (s, 1H), 7.52 (d, J=11.0 Hz, 1H), 7.41 (d, J=8.0 Hz, 2H), 7, 26 (t, J=7.8 Hz, 2H), 7.10 (t, J=5.6 Hz, 1H), 6.97 (t, J=7.4 Hz, 1H), 6.28 ( s, 1H), 4.06 (m, 2H), 3.56 (t, J=4.5 Hz, 4H), 3.34 (m, 2H), 2.34 (d, J=6.8 Hz, 6H), 1.70 (t, J=7.0 Hz, 2H), 1.20 (t, J=7.0 Hz, 3H); MS (ESI) m/z: 579.2 [M+H] ⁺ .

[00370] Example 93: A solution of the compound of Example A34 (0.200 g, 0.640 mmol) in pyridine (0.5 ml) was cooled to 0° C. and slowly treated with isopropenyl chloroformate (0.073 ml, 0.672 mmol). The mixture was stirred at 0°C for 0.5 hour, warmed to RT, concentrated to dryness and purified by silica gel chromatography (EtOAc/hex) to give prop-1-en-2-yl ester (5-(7-amino -1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoro-4-methylphenyl)-carbamic acid (244 mg, 96% yield). ^1H NMR (400 MHz, DMSO- _d6 ): δ 9.54 (s, 1H), 8.33 (s, 1H), 7.66 (s, 1H), 7.35 (m, 1H), 7.13 (d, J=11.7 Hz, 1H), 6.48 (s, 2H), 6.33 (s, 1H), 4.69 (d, J=8.4 Hz, 2H), 4.08 (q, J=7.3 Hz, 2H), 2.08 (s, 3H), 1.90 (s, 3H), 0.84 (t, J=7.0 Hz, 3H); MS (ESI) m/z: 397.1 [M+H] ⁺ .

[00371] A mixture of the compound of Example D2 (0.100 g, 0.448 mmol) and prop-1-en-2-yl ester (5-(7-amino-1-ethyl-2-oxo-1,2-dihydro-1, 6-naphthyridin-3-yl)-2-fluoro-4-methylphenyl)carbamic acid (0.142 g, 0.358 mmol) in dioxane (3 ml) was treated with 1-methylpyrrolidine (3 drops) and heated at 80°C overnight. The mixture was treated with DMSO (2 drops) and heated at 80°C for another 24 hours. The mixture was cooled to RT, concentrated to dryness and purified by reverse phase chromatography (MeCN/H ₂ O with 0.1% TFA). Organic substances were removed under reduced pressure, and the aqueous residue was treated with us. NaHCO ₃ , extracted with EtOAc (2×) and the combined organic layers were washed with brine, dried over MgSO ₄ and concentrated to dryness to give 1-(5-(7-amino-1-ethyl-2-oxo-1,2-dihydro- 1,6-naphthyridin-3-yl)-2-fluoro-4-methylphenyl)-3-(4-fluoro-3-((4-methylpiperazin-1-yl)methyl)phenyl)urea (44 mg, yield 22 %). ^1H NMR (400 MHz, pyridine- _d5 ): δ 9.87 (s, 1H), 8.89 (s, 1H), 8.71 (m, 1H), 8.60 (s, 1H), 7.97 (dd, J=6.5, 2.8 Hz, 1H), 7.79 (dt, J=8.7, 3.6 Hz, 1H), 7.64 (s, 1H), 7 .26 (s, 2H), 7.15 (t, J=9.2 Hz, 1H), 7.07 (d, J=12.0 Hz, 1H), 6.56 (s, 1H), 4 .17 (q, J=7.1 Hz, 2H), 3.58 (s, 2H), 2.53 (s, 4H), 2.30 (m, 7H), 2.13 (s, 3H) , 1.16 (t, J=7.1 Hz, 3H); MS (ESI) m/z: 562.2 [M+H] ⁺ .

[00372] Example 94: Mixture of 1-fluoro-2-methyl-4-nitrobenzene (2.5 g, 16.12 mmol), NBS (5.02 g, 28.2 mmol) and AIBN (265 mg, 1.612 mmol ) in trifluorotoluene (45 ml) was heated to reflux temperature overnight. The mixture was cooled to rt, filtered to remove solids, and the filtrate was concentrated to dryness. The residue was dissolved in Et ₂ O, washed with water, then with brine, dried over Na ₂ SO ₄ , concentrated to dryness and purified by silica gel chromatography (EtOAc/hex) to give 2-(bromomethyl)-1-fluoro-4-nitrobenzene (698 mg, yield 18%). ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 8.53 (dd, J=6.4, 3.0 Hz, 1H), 8.28 (ddd, J=9.1, 4.4, 3.0 Hz, 1H), 7.55 (t, J=9.2 Hz, 1H), 4.80 (s, 2H).

[00373] A solution of DIEA (771 mg, 5.97 mmol) and dimethylamine (2.0 M in THF, 1.94 mL, 3.88 mmol) in THF (5 mL) at -20°C was treated dropwise with solution 2 -(bromomethyl)-1-fluoro-4-nitrobenzene (698 mg, 2.98 mmol) in THF (5 ml) and stirred at RT overnight after removing the cooling bath. The mixture was treated with EtOAc, washed with water, then brine, dried over Na ₂ SO ₄ and concentrated to dryness to give 1-(2-fluoro-5-nitrophenyl)-N,N-dimethylmethanamine (494 mg, 84% yield). MS (ESI) m/z: 199.1 [M+H] ⁺ .

[00374] A mixture of us. NH ₄ Cl (5.19 ml) in EtOH (8 ml) was treated with 1-(2-fluoro-5-nitrophenyl)-N,N-dimethylmethanamine (494 mg, 2.49 mmol), then iron powder (1.39 g, 24.93 mmol) and heated at 55°C overnight. The mixture was cooled to RT, solids were removed by filtration through diatomaceous earth and washed with 10% MeOH/DCM. The filtrate was concentrated to dryness, the residue was treated with DCM, then sonicated, and the resulting solid was collected by filtration, washed with THF and dried to give 3-((dimethylamino)methyl)-4-fluoroaniline (305 mg, 72% yield). MS (ESI) m/z: 169.1 [M+H] ⁺ .

[00375] A mixture of the compound of Example A47 (200 mg, 0.363 mmol), 3-((dimethylamino)methyl)-4-fluoroaniline (300 mg, 1.815 mmol) and 1-methylpyrrolidine (31 mg, 0.363 mmol) in dioxane (4 ml) heated at 80°C overnight. The mixture was cooled to RT, treated with EtOAc and us. NaHCO ₃ was heated to near reflux temperature and the resulting solid was collected by filtration and dried to give 1-(4-chloro-5-(1-ethyl-7-((4-methoxybenzyl)(methyl)amino)-2- oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-(3-((dimethylamino)methyl)-4-fluorophenyl)urea (174 mg, 72% yield). ^1H NMR (400 MHz, DMSO- _d6 ): δ 9.21 (brs, 1H), 8.80 (brs, 1H), 8.50 (s, 1H), 8.14 (d , J=9.1 Hz, 1H), 7.77 (s, 1H), 7.56-7.48 (m, 2H), 7.25 (m, 1H), 7.18 (d, J= 8.3 Hz, 2H), 7.04 (m, 1H), 6.86 (d, J=8.4 Hz, 2H), 6.32 (s, 1H), 4.85 (s, 2H) , 4.18 (q, J=7.0 Hz, 2H), 3.70 (s, 3H), 3.36 (s, 2H), 3.13 (s, 3H), 2.13 (s, 6H), 1.13 (t, J=7.0 Hz, 3H); MS (ESI) m/z: 661.2 [M+H] ⁺ .

[00376] A mixture of 1-(4-chloro-5-(1-ethyl-7-((4-methoxybenzyl)(methyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridine-3- yl)-2-fluorophenyl)-3-(3-((dimethylamino)methyl)-4-fluorophenyl)urea (174 mg, 0.263 mmol) in TFA (2.0 ml) was stirred at RT for 2.5 hours. The mixture was concentrated to dryness, treated with EtOAc and us. NaHCO ₃ was stirred for 0.5 hour and the resulting solid was collected by filtration and dried to give 1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro -1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-(3-((dimethylamino)methyl)-4-4)torphenyl)urea (111 mg, 78% yield). ^1H NMR (400 MHz, DMSO- _d6 ): δ 9.12 (s, 1H), 8.63 (s, 1H), 8.41 (s, 1H), 8.15 (d, J=8.7 Hz, 1H), 7.74 (s, 1H), 7.54-7.50 (m, 2H), 7.23 (m, 1H), 7.09-7.01 (m, 2H), 6 .23(s, 1H). 4.13 (q, J=6.8 Hz, 2H), 3.37 (s, 2H), 2.86 (d, J=4.4 Hz, 3H), 2.13 (s, 6H), 1, 20 (t, J=7.0 Hz, 3H); MS (ESI) m/z: 541.1 [M+H] ⁺ .

[00377] Example 95: A mixture of the compound of Example A47 (200 mg, 0.363 mmol) and the compound of Example D3 (95 mg, 0.454 mmol) in dioxane (5 ml) was treated with 1-methylpyrrolidine (31 mg, 0.363 mmol) and heated at 70°C overnight. The mixture was cooled to RT, treated with EtOAc and 50% sat. NaHCO ₃ and stirred for 0.5 hour. The resulting solid was collected by filtration and dried to give 1-(4-chloro-5-(1-ethyl-7-((4-methoxybenzyl)(methyl)amino)-2-oxo-1,2-dihydro-1. 6-naphthyridin-3-yl)-2-fluorophenyl)-3-(4-fluoro-3-(morpholinomethyl)phenyl)urea (152 mg, 60% yield). ^1H NMR (400 MHz, DMSO- _d6 ): δ 9.12 (s, 1H), 8.62 (m, 1H), 8.50 (s, 1H), 8.16 (d, J=8 .7 Hz, 1H), 7.77 (s, 1H), 7.53 (d, J=11.0 Hz, 1H), 7.47 (m, 1H), 7.30 (m, 1H), 7.18 (m, 2H), 7.07 (t, J=9.2 Hz, 1H), 6.87 (m, 2H), 6.32 (s, 1H), 4.85 (s, 2H ), 4.19 (q, J=7.0 Hz, 2H), 3.70 (s, 3H), 3.54-3.53 (m, 4H), 3.45 (s, 2H), 3 .13 (s, 3H), 2.35 (m, 4H), 1.13 (t, J=7.0 Hz, 3H); MS (ESI) m/z: 703.2 [M+H] ⁺ .

[00378] A mixture of 1-(4-chloro-5-(1-ethyl-7-((4-methoxybenzyl)(methyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridine-3- yl)-2-fluorophenyl)-3-(4-fluoro-3-(morpholinomethyl)phenyl)urea (152 mg, 0.216 mmol) in TFA (3 ml) was stirred under Ar for 3 hours. The mixture was concentrated to dryness, treated with EtOAc and us. NaHCO ₃ and stirred for 0.5 hour. The resulting solid was collected by filtration and dried to give 1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl) -2-fluorophenyl)-3-(4-fluoro-3-(morpholinomethyl)phenyl)-urea (111 mg, 76% yield). ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 9.12 (s, 1H), 8.63 (d, J=2.5 Hz, 1H), 8.41 (s, 1H), 8. 15 (d, J=8.7 Hz, 1H), 7.73 (s, 1H), 7.53 (d, J=11.0 Hz, 1H), 7.47 (dd, J=6.5 , 2.8 Hz, 1H), 7.30 (ddd, J=8.9, 4.5, 2.8 Hz, 1H), 7.10-7.01 (m, 2H), 6.24 ( s, 1H), 4.14 (q, J=7.1 Hz, 2H), 3.53 (t, J=4.4 Hz, 4H), 3.44 (s, 2H), 2.86 ( d, J=4.9 Hz, 3H), 2.35 (m, 4H), 1.20 (t, J=7.0 Hz, 3H); MS (ESI) m/z: 583.2 [M+H] ⁺ .

[00379] Example 96: A mixture of the compound of Example A50 (0.12 g, 0.224 mmol), (3S)-(+)-3-(dimethylamino)pyrrolidine (0.077 g, 0.672 mmol) and 1-methylpyrrolidine (9.53 mg, 0.112 mmol) in THF (3 ml) was heated at 60°C overnight. The mixture was cooled to RT, concentrated to dryness and purified by silica gel chromatography (MeOH/DCM) to give (S)-N-(3-(2-chloro-4-fluoro-5-(3-phenylureido)phenyl)-1- ethyl 2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)-3-(dimethylamino)pyrrolidine-1-carboxamide (67 mg, 51% yield). ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 9.05 (s, 2H); 8.67(s, 1H); 8.61(s, 1H); 8.17 (d, J=8.6 Hz, 1H); 8.06(s, 1H); 7.90(s, 1H); 7.52 (d, J=11.0 Hz, 1H); 7.37 (d, J=8.1 Hz, 2H); 7.21 (t, J=7.8 Hz, 3H); 6.92 (m, 1H); 4.13 (q, J=6.9 Hz, 2H); 3.65 (m, 2H); 3.38(m, 1H); 2.15 (m, 3H); 1.19 (t, J=6.9 Hz, 3H); MS (ESI) m/z: 592.2 [M+H] ⁺ .

[00380] Example 97: A mixture of DIEA (552 mg, 4.27 mmol) and pyrrolidine (152 mg, 2.137 mmol) in THF (5 ml) at -20°C was treated dropwise with a solution of 2-(bromomethyl)-1-fluoro -4-nitrobenzene (500 mg, 2.137 mmol) in THF (5 ml), left to warm to RT and stirred for 6 hours. The mixture was treated with EtOAc, washed with water, then brine, dried over Na ₂ SO ₄ and concentrated to dryness to give 1-(2-fluoro-5-nitrobenzyl)pyrrolidine (450 mg, 94% yield). MS (ESI) m/z: 225.1 [M+H] ⁺ .

[00381] A mixture of 1-(2-fluoro-5-nitrobenzyl)pyrrolidine (450 mg, 2.007 mmol) in EtOAc (15 ml) was treated with 10% Pd/C (107 mg) and hydrogenated (1 atm) for 3 hours. Additional 10% Pd/C (100 mg) was added and the mixture was hydrogenated (1 atm) overnight. Solids were removed by filtration through diatomaceous earth, washed with EtOAc. and the filtrate was washed with water, then with brine, dried over Na ₂ SO ₄ and concentrated to dryness to give 4-fluoro-3-(pyrrolidin-1-ylmethyl)aniline (282 mg, 72% yield). ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 6.75 (dd, J=10.0, 8.7 Hz, 1H), 6.56 (dd, J=6.4, 2.9 Hz , 1H), 6.39 (ddd, J=8.7, 4.3, 2.9 Hz, 1H), 4.85 (s, 2H), 3.44 (d, J=1.5 Hz, 2H), 2.40 (m, 4H), 1.66 (m, 4H); MS (ESI) m/z: 195.1 [M+H] ⁺ .

[00382] A mixture of the compound of Example A47 (200 mg, 0.363 mmol) and 4-fluoro-3-(pyrrolidin-1-ylmethyl)aniline (88 mg, 0.454 mmol) in dioxane (5 ml) was treated with 1-methylpyrrolidine (31 mg , 0.363 mmol) and heated at 70°C overnight. The mixture was cooled to RT, treated with EtOAc and 50% sat. NaHCO ₃ and stirred for 0.5 hour. The resulting solid was collected by filtration and dried to give 1-(4-chloro-5-(1-ethyl-7-((4-methoxybenzyl)(methyl)amino)-2-oxo-1,2-dihydro-1. 6-naphthyridin-3-yl)-2-fluorophenyl)-3-(4-fluoro-3-(pyrrolidin-1-ylmethyl)phenyl)-urea (135 mg, 54% yield). ^1H NMR (400 MHz, DMSO- _d6 ): δ 9.11 (s, 1H), 8.61 (d, J=2.5 Hz, 1H), 8.50 (s, 1H), 8. 16 (d, J=8.7 Hz, 1H), 7.78 (s, 1H), 7.53 (d, J=11.0 Hz, 1H), 7.49 (dd, J=6.5 , 2.8 Hz, 1H), 7.27 (m, 1H), 7.18 (d, J=8.5 Hz, 2H), 7.05 (t, J=9.3 Hz, 1H), 6.87 (d, J=8.6 Hz, 2H), 6.32 (s, 1H), 4.85 (s, 2H), 4.19 (q, J=7.1 Hz, 2H), 3.70 (s, 3H), 3.55 (s, 2H), 3.13 (s, 3H), 2.43 (m, 4H), 1.66 (m, 4H), 1.13 (t , J=7.0 Hz, 3H); MS (ESI) m/z: 687.2 [M+H] ⁺ .

[00383] A mixture of 1-(4-chloro-5-(1-ethyl-7-((4-methoxybenzyl)(methyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridine-3 -yl)-2-fluorophenyl)-3-(4-fluoro-3-(pyrrolidin-1-ylmethyl)phenyl)-urea (135 mg, 0.196 mmol) in TFA (3 ml) was stirred at RT for 3 hours. The mixture was concentrated to dryness, treated with EtOAc and us. NaHCO ₃ and stirred for 15 minutes. The resulting solid was collected by filtration and dried to give 1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl) -2-fluorophenyl)-3-(4-fluoro-3-(pyrrolidin-1-ylmethyl)phenyl)urea (98 mg, 88% yield). ^1H NMR (400 MHz, DMSO- _d6 ): (9.19 (brs, 1H), 8.71 (brs, 1H), 8.41 (s, 1H), 8.13 (m , 1H), 7.73 (s, 1H), 7.54-7.48 (m, 2H), 7.27 (m, 1H), 7.04 (m, 2H), 6.23 (s, 1H), 4.13 (q, J=7.2 Hz, 2H), 3.54 (s, 2H), 2.86 (s, 3H), 2.42 (m, 4H), 1.66 ( m, 4H), 1.20 (t, J=6.9 Hz, 3H); MS (ESI) m/z: 567.2 [M+H] ⁺ .

[00384] Example 98: A mixture of the compound of Example A52 (0.27 g, 0.536 mmol), Cs ₂ CO ₃ (0.524 g, 1.609 mmol), N,N-dimethylurea (0.236 g, 2.68 mmol) and Xantphos ( 0.093 g, 0.161 mmol) in dioxane (10 ml) was flushed with Ar, treated with Pd ₂ (dba) ₃ (0.074 g, 0.080 mmol), flushed with Ar again and heated at 100°C overnight. The mixture was cooled to RT and the solid was removed by filtration and washed with EtOAc. The filtrate was washed with brine (2×), dried over Na ₂ SO ₄ , concentrated to dryness and purified by silica gel chromatography (EtOAc/hex). The material was re-purified by reverse phase chromatography (MeCN/H ₂ O with 0.1% TFA); organic matter was removed under reduced pressure, and the aqueous residue was treated with NaHCO ₃ . The mixture was extracted with EtOAc (3×) and the combined organic layers were washed with brine, dried over Na ₂ SO ₄ and concentrated to dryness to give 3-(3-(2-chloro-4-fluoro-5-(3-(3-fluorophenyl )ureido)phenyl)-1-isopropyl-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)-1,1-dimethylurea (65 mg, 22% yield). ^1H NMR (400 MHz, DMSO- _d6 ): δ 9.31 (s, 1H), 9.17 (s, 1H), 8.77 (s, 1H), 8.62 (s, 1H), 8.30 (s, 1H), 8.17 (d, J=8.6 Hz, 1H), 7.89 (s, 1H), 7.58 (m, 1H), 7.48 (m, 1H ), 7.30 (m, 1H), 7.07 (d, J=8.3 Hz, 1H), 6.79 (m, 1H), 2.97 (s, 6H), 1.55 (d , J=7.0 Hz, 6H); MS (ESI) m/z: 555.1 [M+H] ⁺ .

[00385] Example 99: A solution of Example A10 (0.16 g, 0.437 mmol) in NMP (3 mL) was treated with DBU (0.079 mL, 0.524 mmol) and 4-methoxybenzylamine (0.150 g, 1.092 mmol) and heated at 150 °C overnight. Additionally, 4-methoxybenzylamine (0.05 ml) was added and the mixture was heated at 150°C for 24 hours. The mixture was cooled to RT, treated with brine and extracted with EtOAc (3×). The combined organic layers were dried over Na ₂ SO ₄ , concentrated to dryness and purified by silica gel chromatography (EtOAc/hex) to give 3-(5-amino-2-chloro-4-fluorophenyl)-1-isopropyl-7-(( 4-methoxybenzyl)amino)-1,6-naphthyridin-2(1H)-one (110 mg, 54% yield). MS (ESI) m/z: 467.1 [M+H] ⁺ .

[00386] A solution of 3-(5-amino-2-chloro-4-fluorophenyl)-1-isopropyl-7-((4-methoxybenzyl)-amino)-1,6-naphthyridin-2(1H)-one (0 .11 g, 0.236 mmol) in THF (5 ml) was treated with TEA (0.1 ml) and 3-fluorophenyl isocyanate (0.032 ml, 0.259 mmol) and stirred at RT for 5 hours. The mixture was concentrated to dryness, treated with DCM, and the solid was collected by filtration and dried to give 1-(4-chloro-2-fluoro-5-(1-isopropyl-7-((4-methoxybenzyl)amino)-2-oxo- 1,2-dihydro-1,6-naphthyridin-3-yl)phenyl)-3-(3-fluorophenyl)urea (94 mg, 66% yield). MS (ESI) m/z: 604.1 [M+H]+.

[00387] Mixture of 1-(4-chloro-2-fluoro-5-(1-isopropyl-7-((4-methoxybenzyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridine-3 -yl)phenyl)-3-(3-fluorophenyl)urea (0.094 g, 0.156 mmol) and anisole (0.085 mL, 0.778 mmol) were stirred in TFA (1 mL) at RT for 3 hours. The mixture was concentrated to dryness, treated with EtOAc and us. NaHCO ₃ and stirred for 1 hour. The resulting solid was collected by filtration and dried to give 1-(5-(7-amino-1-isopropyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-4-chloro-2 -fluorophenyl)-3-(3-fluorophenyl)urea (70 mg, 93% yield). MS (ESI) m/z: 484.1 [M+H] ⁺ .

[00388] Solution of 1-(5-(7-amino-1-isopropyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-4-chloro-2-fluorophenyl)-3- (3-fluorophenyl)urea (0.07 g, 0.145 mmol) in pyridine (2 ml) was treated with acetyl chloride (0.011 ml, 0.159 mmol) and stirred at RT for 2 hours. The mixture was concentrated to dryness, treated with EtOAc and washed with brine, dried over Na ₂ SO ₄ and concentrated to dryness. The material was treated with Et ₂ O and the solid was collected by filtration to give N-(3-(2-chloro-4-fluoro-5-(3-(3-fluorophenyl)ureido)phenyl)-1-isopropyl-2-oxo- 1,2-dihydro-1,6-naphthyridin-7-yl)-acetamide (65 mg, 84% yield). ^1H NMR (400 MHz, DMSO- _d6 ): δ 10.81 (s, 1H), 9.31 (s, 1H), 8.78 (s, 1H), 8.68 (s, 1H), 8.54 (s, 1H), 8.18 (d, J=8.6 Hz, 1H), 7.93 (s, 1H), 7.58 (d, J=11.0 Hz, 1H), 7.46 (dt, J=11.9, 2.3 Hz, 1H), 7.29 (m, 1H), 7.06 (m, 1H), 6.79 (td, J=8.5, 2.6 Hz, 1H), 5.36 (m, 1H), 2.14 (s, 3H), 1.56 (d, J=7.0 Hz, 6H); MS (ESI) m/z: 526.1 [M+H] ⁺ .

[00389] Example 100: A solution of the compound of Example D2 (0.117 g, 0.524 mmol) and the compound of Example A53 (0.182 g, 0.437 mmol) in dioxane (4.5 ml) was treated with a catalytic amount of 1-methylpyrrolidine (2 drops) and the mixture heated at 80°C overnight. The mixture was cooled to RT, concentrated to dryness and purified by silica gel chromatography (MeOH/DCM) to give 1-(5-(7-chloro-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridine- 3-yl)-2-fluoro-4-methylphenyl)-3-(4-fluoro-3-((4-methylpiperazin-1-yl)methyl)phenyl)urea (123 mg, 49% yield). ^1H NMR (400 MHz, DMSO- _d6 ): δ 9.06 (s, 1H), 8.77 (s, 1H), 8.47 (s, 1H), 8.00-7.95 (m , 2H), 7.73 (s, 1H), 7.45 (m, 1H), 7.31-7.26 (m, 1H), 7.17 (d, J=12.2 Hz, 1H) , 7.05 (t, J=9.2 Hz, 1H), 4.27 (q, J=7.1 Hz, 2H), 3.44 (s, 2H), 2.38 (lat.s, 8H), 2.17 (s, 3H), 2.07 (s, 3H), 1.20 (t, J=7.0 Hz, 3H); MS (ESI) m/z: 581.2 [M+H] ⁺ .

[00390] A mixture of 1-(5-(7-chloro-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoro-4-methylphenyl)-3- (4-fluoro-3-((4-methylpiperazin-1-yl)methyl)phenyl)urea (0.120 g, 0.207 mmol), formamide (0.041 ml, 1.033 mmol) and K ₂ CO ₃ (0.057 g, 0.413 mmol) in dioxane (3 ml) was flushed with Ar, treated with BrettPhos Palladacycle (8.05 mg, 10.33 µmol), flushed with Ar again and heated to 100°C for 1 hour. The mixture was cooled to RT, treated with EtOAc and us. NaHCO ₃ was filtered to remove insoluble matter and the layers were separated. The organic layer was washed with brine, dried over MgSO ₄ and concentrated to dryness. The substance was treated with a small amount of DCM, left to settle at RT, and the resulting solid was collected by filtration and dried. The filtrate was concentrated to dryness, separated into layers using a small amount of DCM and left to settle at RT overnight. The resulting solid was collected by filtration and combined with the isolated solid above to give N-(1-ethyl-3-(4-fluoro-5-(3-(4-fluoro-((4-methylpiperazin-1-yl)methyl )phenyl)ureido)-2-methylphenyl)-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)formamide (53 mg, 44% yield). ^1H NMR (400 MHz, DMSO- _d6 ): δ 9.38 (m, 1H), 9.05 (s, 1H), 8.69 (d, J=18.4 Hz, 1H), 8. 44 (s, 1H), 8.21 (s, 1H), 7.96 (d, J=8.4 Hz, 1H), 7.90 (s, 1H), 7.43 (dd, J=6 ,5, 2.8 Hz, 1H), 7.30 (ddd, J=8.9, 4.4, 2.8 Hz, 1H), 7.16 (d, J=12.2 Hz, 1H) , 7.05 (t, J=9.3 Hz, 1H), 6.96 (s, 1H), 4.19 (m, 2H), 3.42 (s, 2H), 2.41-2, 19 (m, 8H), 2.10 (s, 3H), 2.07 (s, 3H), 1.24 (m, 3H); MS (ESI) m/z: 590.2 [M+H] ⁺ .

[00391] Example 101: Mixture of the compound of Example A54 (308 mg, 0.665 mmol), Cs ₂ CO ₃ (650 mg, 1.996 mmol), N,N-dimethylurea (293 mg, 3.33 mmol) and Xantphos (115 mg , 0.20 mmol) in dioxane (10 ml) was purged with Ar, treated with Pd ₂ (dba) ₃ (91 mg, 0.100 mmol) and heated at 100°C overnight. The mixture was cooled to RT, treated with EtOAc and DMF, solids were removed by filtration through diatomaceous earth and washed with water and EtOAc. The filtrate layers were separated, and the organic layer was washed. NaHCO ₃ , then brine, dried over Na ₂ SO ₄ , concentrated to dryness and purified by reverse phase chromatography (MeCN/H ₂ O with 0.1% TFA). Organic matter was removed under reduced pressure, and the aqueous residue was treated with us. _NaHCO3 . The resulting solid was collected by filtration and dried to give 3-(1-ethyl-3-(4-fluoro-2-methyl-5-(3-phenylureido)phenyl)-2-oxo-1,2-dihydro-1. 6-naphthyridin-7-yl)-1,1-dimethylurea (35 mg, 10% yield). ^1H NMR (400 MHz, DMSO- _d6 ): δ 9.18 (s, 1H), 9.01 (s, 1H), 8.64 (s, 1H), 8.50 (s, 1H), 8.01 (s, 1H), 7.98 (d, J=8.4 Hz, 1H), 7.86 (s, 1H), 7.41 (d, J=8.0 Hz, 2H), 7.25 (t, J=7.7 Hz, 2H), 7.15 (d, J=12.2 Hz, 1H), 6.95 (t, J=7.3 Hz, 1H), 4, 18 (q, J=7.2 Hz, 2H), 2.97 (s, 6H), 2.08 (s, 3H), 1.24 (t, J=7.1 Hz, 3H); MS (ESI) m/z: 503.2 [M+H] ⁺ .

[00392] Example 102: A suspension of N,N-dimethylazetidin-3-amine dihydrochloride (0.071 g, 0.410 mmol) and N-methylpyrrolidine (0.070 g, 0.821 mmol) in dioxane (4 ml) was heated at 55°C for 10 minutes , were treated with the compound according to example A50 (0.11 g, 0.205 mmol) and heated at 55°C for 16 hours. The mixture was concentrated to dryness and purified by silica gel chromatography (MeOH/DCM) to give N-(3-(2-chloro-4-fluoro-5-(3-phenylureido)phenyl)-1-ethyl-2-oxo-1, 2-dihydro-1,6-naphthyridin-7-yl)-3-(dimethylamino)azetidine-1-carboxamide (68 mg, 57% yield). ^1H NMR (400 MHz, DMSO- _d6 ): δ 9.49 (s, 1H), 9.09 (s, 1H), 8.71 (d, J=2.6 Hz, 1H), 8. 65 (s, 1H), 8.21 (d, J=8.6 Hz, 1H), 8.09 (s, 1H), 7.94 (s, 1H), 7.57 (d, J=11 ,0 Hz, 1H), 7.41 (dd, J=8.2, 1.2 Hz, 2H), 7.26 (t, J=7.8 Hz, 2H), 6.97 (t, J =7.3 Hz, 1H), 4.17 (q, J=7.3 Hz, 2H), 4.06-4.01 (m, 2H), 3.86-3.77 (m, 2H) , 3.04 (m, 1H), 2.09 (s, 6H), 1.24 (t, J=7.0 Hz, 3H); MS (ESI) m/z: 578.2 [M+H] ⁺ .

[00393] Example 103: Mixture of the compound of Example A55 (0.2 g, 0.412 mmol), Cs ₂ CO ₃ (0.403 g, 1.236 mmol), N,N-dimethylurea (0.182 g, 2.060 mmol) and Xantphos (0.072 g , 0.124 mmol) in dioxane (10 ml) was flushed with Ar, treated with Pd ₂ (dba) ₃ (0.057 g, 0.062 mmol), flushed with Ar again and heated at 100°C overnight. The mixture was cooled to RT and solids were removed by filtration and washed with water and EtOAc. The filtrate layers were separated, the organic layer was washed with brine, dried over Na ₂ SO ₄ , concentrated to dryness and purified by silica gel chromatography (EtOAc/hex). The substance was repurified by reverse phase chromatography (MeCN/H ₂ O with 0.1% TFA). Organic matter was removed under reduced pressure and the aqueous residue was treated with us. _NaHCO3 . The resulting solid was collected by filtration and dried to give 3-(3-(2-chloro-4-fluoro-5-(3-phenylureido)phenyl)-1-isopropyl-2-oxo-1,2-dihydro-1. 6-naphthyridin-7-yl)-1,1-dimethylurea (25 mg, 6% yield). ^1H NMR (400 MHz, DMSO- _d6 ): δ 9.16 (s, 1H), 9.11 (s, 1H), 8.73 (s, 1H), 8.62 (s, 1H), 8.30 (s, 1H), 8.20 (d, J=8.6 Hz, 1H), 7.89 (s, 1H), 7.55 (d, J=11.0 Hz, 1H), 7.42 (m, 2H), 7.26 (t, J=7.8 Hz, 2H), 6.97 (t, J=7.3 Hz, 1H), 5.32 (m, 1H), 2.97 (s, 6H), 1.55 (d, J=7.0 Hz, 6H); MS (ESI) m/z: 537.1 [M+H] ⁺ .

[00394] Example 104: A solution of benzo[b]thiophene-3-carboxylic acid (0.129 g, 0.723 mmol) in toluene (5 ml) was treated with TEA (0.167 ml, 1.206 mmol) and DPPA (0.195 ml, 0.904 mmol), stirred at RT for 5 minutes, treated with the compound according to example A6 (0.20 g, 0.603 mmol) and heated at 100°C for 2 hours. The mixture was cooled to RT and the resulting solid was collected by filtration to give 1-(benzo[b]thiophen-3-yl)-3-(5-(7-chloro-1-ethyl-2-oxo-1,2- Dihydro-1,6-naphthyridin-3-yl)-2-fluoro-4-methylphenyl)urea (230 mg, 75% yield). ^1H NMR (400 MHz, DMSO- _d6 ): δ 9.40 (s, 1H), 8.86 (s, 1H), 8.78 (s, 1H), 8.11 (d, J=8 ,4 Hz, 1H), 8.02 (s, 1H), 7.96 (d, J=8.0 Hz, 1H), 7.87 (d, J=8.1 Hz, 1H), 7, 74 (s, 1H), 7.67 (s, 1H), 7.48 (m, 1H), 7.41 (m, 1H), 7.20 (m, 1H), 4.28 (q, J =7.1 Hz, 2H), 2.08 (s, 3H), 1.21 (t, J=7.0 Hz, 3H); MS (ESI) m/z: 507.1 [M+H] ⁺ .

[00395] A mixture of 1-(benzo[b]thiophen-3-yl)-3-(5-(7-chloro-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridine-3- yl)-2-fluoro-4-methylphenyl)urea (0.23 g, 0.454 mmol), Cs ₂ CO ₃ (0.443 g, 1.361 mmol), N,N-dimethylurea (0.200 g, 2.268 mmol) and Xantphos (0.079 g, 0.136 mmol) in dioxane (10 ml) was flushed with Ar, treated with Pd ₂ (dba) ₃ (0.062 g, 0.068 mmol), flushed with Ar again and heated at 100°C overnight. The mixture was cooled to RT and solids were removed by filtration and washed with water and EtOAc. The filtrate layers were separated, the organic layer was washed with brine, dried over Na ₂ SO ₄ and concentrated to dryness. The material was treated with DCM, the solid was removed by filtration and the filtrate was purified by silica gel chromatography (EtOAc/hex) to give 3-(3-(5-(3-(benzo[b]thiophen-3-yl)ureido)- 4-fluoro-2-methylphenyl)-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)-1,1-dimethylurea (25 mg, 9% yield). ^1H NMR (400 MHz, DMSO- _d6 ): δ 9.34 (s, 1H), 9.13 (s, 1H), 8.79 (s, 1H), 8.60 (s, 1H), 8.03 (d, J=8.4 Hz, 1H), 7.97 (s, 1H), 7.91 (d, J=8.0 Hz, 1H), 7.83 (m, 2H), 7.62 (s, 1H), 7.45-7.40 (m, 1H), 7.36 (t, J=7.5 Hz, 1H), 7.15 (d, J=12.3 Hz , 1H), 4.14 (d, J=8.0 Hz, 2H), 2.93 (s, 3H), 1.20 (m, 3H); MS (IER) m/z: 559.2 [M+H] ⁺ .

[00396] Example 105: A solution of the compound of Example A13 (0.300 g, 0.756 mmol) in pyridine (8 ml) was cooled to 0°C, slowly treated with phenyl isocyanate (0.086 ml, 0.794 mmol), stirred at 0°C for 20 minutes , then heated to RT for 45 minutes. The solids were collected by filtration, washed with a small amount of DCM and dried; the filtrate was processed for us. NaHCO ₃ and extracted with DCM. The organic layer was washed with brine, dried over MgSO ₄ , concentrated to dryness, triturated with DCM, the solid was collected by filtration and combined with the solid isolated above to give 1-(4-bromo-5-(7-chloro-1-ethyl- 2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea (170 mg, 44% yield). ^1H NMR (400 MHz, DMSO- _d6 ): δ 9.11 (s, 1H), 8.79 (s, 1H), 8.75 (d, J=2.5 Hz, 1H), 8. 24 (d, J=8.5 Hz, 1H), 8.06 (s, 1H), 7.75 (s, 1H), 7.71 (d, J=10.8 Hz, 1H), 7, 41 (dd, J=8.2, 1.2 Hz, 2H), 7.26 (t, J=7.8 Hz, 2H), 6.97 (t, J=7.4 Hz, 1H), 4.27 (q, J=7.1 Hz, 2H), 1.20 (t, J=7.0 Hz, 3H); MS (ESI) m/z: 515.0 [M+H] ⁺ .

[00397] A suspension of 1-(4-bromo-5-(7-chloro-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3- phenylurea (0.360 g, 0.698 mmol), N,N-dimethylurea (0.307 g, 3.49 mmol) and Cs ₂ CO ₃ (0.682 g, 2.094 mmol) in dioxane (8 ml) purged with Ar, treated with Xantphos (0.121 g, 0.209 mmol) and Pd ₂ (dba) ₃ (0.096 g, 0.105 mmol), again purged with Ar and heated at 100°C overnight. The mixture was cooled to RT and solids were removed by filtration and washed with EtOAc. The filtrate was treated with brine, filtered again to remove solids, and the layers were separated. The organic layers were washed a second time with brine, dried over MgSO ₄ , concentrated to dryness and purified by reverse phase chromatography (MeCN/H ₂ O with 0.1% TFA). Organic substances were removed under reduced pressure, and the aqueous residue was treated with us. NaHCO ₃ and stirred for 1 hour. The resulting solid was collected by filtration and dried to give 3-(3-(2-bromo-4-fluoro-5-(3-phenylureido)phenyl)-1-ethyl-2-oxo-1,2-dihydro-1. 6-naphthyridin-7-yl)-1,1-dimethylurea (37 mg, 9% yield). ^1H NMR (400 MHz, DMSO- _d6 ): δ 9.21 (s, 1H), 9.10 (s, 1H), 8.72 (s, 1H), 8.65 (s, 1H), 8.21 (d, J=8.5 Hz, 1H), 8.01 (s, 1H), 7.91 (s, 1H), 7.69 (d, J=10.8 Hz, 1H), 7.42 (m, 2H), 7.26 (m, 2H), 6.97 (t, J=7.4 Hz, 1H), 4.18 (q, J=7.1 Hz, 2H), 2.97 (s, 6H), 1.24 (t, J=7.1 Hz, 3H); MS (ESI) m/z: 567.1 [M+H] ⁺ .

[00398] Example 106: Mixture of the compound of Example A56 (320 mg, 0.682 mmol), Cs ₂ CO ₃ (667 mg, 2.047 mmol), N,N-dimethylurea (301 mg, 3.41 mmol) and Xantphos (118 mg , 0.205 mmol) in dioxane (5 ml) was purged with Ar, treated with Pd ₂ (dba) ₃ (94 mg, 0.102 mmol) and heated at 100°C overnight. The mixture was cooled to RT, treated with EtOAc and DMF, solids were removed by filtration through diatomaceous earth and washed with water and EtOAc. The filtrate layers were separated, and the organic layer was washed. NaHCO ₃ , then brine, dried over Na ₂ SO ₄ , concentrated to dryness and purified by reverse phase chromatography (MeCN/H ₂ O with 0.1% TFA). Organic substances were removed under reduced pressure, and the aqueous residue was treated with us. NaHCO ₃ and stirred for 1 hour. The resulting solid was collected by filtration and dried to give 3-(1-ethyl-3-(4-fluoro-5-(3-(3-fluorophenyl)ureido)-2-methylphenyl)-2-oxo-1,2- Dihydro-1,6-naphthyridin-7-yl)-1,1-dimethylurea (30 mg, 8% yield). ^1H NMR (400 MHz, DMSO- _d6 ): δ 9.27 (s, 1H), 9.17 (s, 1H), 8.66-8.58 (m, 2H), 8.01 (s , 1H), 7.93 (m, 1H), 7.86 (s, 1H), 7.47 (m, 1H), 7.29 (m, 1H), 7.17 (m, 1H), 7 .06 (m, 1H), 6.76 (m, 1H), 4.18 (q, 2H), 2.97 (s, 6H), 2.08 (s, 3H), 1.24 (t, 3H); MS (ESI) m/z: 521.2 [M+H] ⁺ .

[00399] Example 107: A biphasic mixture of the compound of Example A3 (250 mg, 0.710 mmol) in EtOAc (10 ml) and sat. NaHCO ₃ (15 ml) was treated with isopropenyl chloroformate (120 mg, 0.984 mmol) and stirred at RT for 2 hours. The layers were separated, the organic layer was washed with water, then with brine, dried over Na ₂ SO ₄ and concentrated to dryness to give prop-1-en-2-yl ether (4-chloro-5-(7-chloro-1-ethyl-2 -oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-carbamic acid (292 mg, 94% yield). MS (ESI) m/z: 436.0 [M+H] ⁺ .

[00400] Prop-1-en-2-yl ether mixture (4-chloro-5-(7-chloro-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl) -2-fluorophenyl)carbamic acid (182 mg, 0.416 mmol) and compound according to example D3 (105 mg, 0.454 mmol) in dioxane (5 ml) were treated with 1-methylpyrrolidine (35 mg, 0.416 mmol) and heated at 70°C in during the night. The mixture was cooled to RT, treated with EtOAc and 50% sat. NaHCO ₃ and stirred for 0.5 hour. The resulting solid was collected by filtration and dried. The filtrate layers were separated, the organic layer was washed with brine, dried over Na ₂ SO ₄ , concentrated to dryness and purified by reverse phase chromatography (MeCN/H ₂ O with 0.1% TFA). Organic substances were removed under reduced pressure, and the aqueous residue was treated with us. NaHCO ₃ and stirred for 1 hour. The resulting solid was collected by filtration and combined with the isolated solid above to give 1-(4-chloro-5-(7-chloro-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridine-3 -yl)-2-fluorophenyl)-3-(4-fluoro-3-(morpholinomethyl)phenyl)urea (155 mg, 63% yield). ^1H NMR (400 MHz, DMSO- _d6 ): δ 9.14 (s, 1H), 8.79 (s, 1H), 8.68 (s, 1H), 8.22 (d, J=8 .6 Hz, 1H), 8.09 (s, 1H), 7.75 (s, 1H), 7.59 (d, J=11.0 Hz, 1H), 7.48 (dd, J=6 .5, 2.8 Hz, 1H), 7.30 (m, 1H), 7.07 (t, J=9.2 Hz, 1H), 4.27 (q, J=7.1 Hz, 2H ), 3.56-3.51 (m, 4H), 3.44 (s, 2H), 2.35 (m, 4H), 1.20 (t, J=7.0 Hz, 3H); MS (ESI) m/z: 588.1 [M+H] ⁺ .

[00401] A mixture of 1-(4-chloro-5-(7-chloro-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3- (4-fluoro-3-(morpholinomethyl)phenyl)urea (155 mg, 0.263 mmol), K ₂ CO ₃ (73 mg, 0.570 mmol) and formamide (59 mg, 1.317 mmol) in dioxane (3 ml) were purged with Ar, treated with BrettPhos Palladacycle (10 mg, 13 μmol) and heated at 100°C for 2 hours. The mixture was cooled to RT, treated with EtOAc, DMF and 50% sat. NaHCO ₃ and solid were collected by filtration. The filtrate layers were separated, the organic layer was washed with brine, dried over Na ₂ SO ₄ , concentrated to dryness, combined with the isolated solid and treated by reverse phase chromatography (MeCN/H ₂ O with 0.1% TFA). Organic substances were removed under reduced pressure, and the aqueous residue was treated with us. NaHCO ₃ and stirred for 1 hour. The resulting solid was collected by filtration, dried and repurified by reverse phase chromatography (MeCN/H ₂ O with 0.1% TFA). Organic substances were removed under reduced pressure, and the aqueous residue was treated with us. NaHCO ₃ and extracted with EtOAc (3×). The combined organic layers were dried over Na ₂ SO ₄ and concentrated to dryness to give N-(3-(2-chloro-4-fluoro-5-(3-(4-fluoro-3-(morpholinomethyl)phenyl)ureido)phenyl)- 1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)formamide (33 mg, 20% yield). MS (ESI) m/z: 597.2 [M+H] ⁺ .

[00402] A suspension of N-(3-(2-chloro-4-fluoro-5-(3-(4-fluoro-3-(morpholinomethyl)phenyl)-ureido)phenyl)-1-ethyl-2-oxo-1 ,2-dihydro-1,6-naphthyridin-7-yl)formamide (33 mg, 0.055 mmol) in MeCN (2 ml) was treated with 0.1 N. HCl (580 µl, 0.058 mmol), frozen and lyophilized to give N-(3-(2-chloro-4-fluoro-5-(3-(4-fluoro-3-(morpholinomethyl)phenyl)ureido)phenyl) hydrochloride -1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)formamide (34 mg, 91% yield). MS (ESI) m/z: 597.2 [M+H] ⁺ .

[00403] Example 108: A mixture of the compound of Example A53 (400 mg, 0.962 mmol) and 3,5-difluoroaniline (186 mg, 1.443 mmol) in dioxane (5 ml) was treated with 1-methylpyrrolidine (123 mg, 1.443 mmol) and heated at 70°C for 20 hours. The mixture was cooled to RT, treated with EtOAc and 50% sat. NaHCO ₃ and stirred for 1 hour. The resulting solid was collected by filtration and dried to give 1-(5-(7-chloro-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoro-4 -methylphenyl)-3-(3,5-difluorophenyl)urea (287 mg, 61% yield). MS (ESI) m/z: 487.1 [M+H] ⁺ .

[00404] A mixture of 1-(5-(7-chloro-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoro-4-methylphenyl)-3- (3,5-difluorophenyl)urea (287 mg, 0.589 mmol), Cs ₂ CO ₃ (576 mg, 1.768 mmol), N,N-dimethylurea (260 mg, 2.95 mmol) and Xantphos (102 mg, 0.177 mmol ) in dioxane (5 ml) was purged with Ar, treated with Pd ₂ (dba) ₃ (81 mg, 0.088 mmol) and heated at 100°C overnight. The mixture was cooled to RT, treated with water, EtOAc and DMF and solids were removed by filtration through diatomaceous earth. The filtrate layers were separated, the organic layer was washed with brine, dried over Na ₂ SO ₄ , concentrated to dryness and purified by reverse phase chromatography (MeCN/H ₂ O with 0.1% TFA). Organic substances were removed under reduced pressure, and the aqueous residue was treated with us. NaHCO ₃ and stirred overnight. The resulting solid was collected by filtration and dried to give 3-(3-(5-(3-(3,5-difluorophenyl)ureido)-4-fluoro-2-methylphenyl)-1-ethyl-2-oxo-1. 2-dihydro-1,6-naphthyridin-7-yl)-1,1-dimethylurea (18 mg, 5% yield). ^1H NMR (400 MHz, DMSO- _d6 ): δ 9.41 (s, 1H), 9.17 (s, 1H), 8.65 (m, 2H), 8.01 (s, 1H), 7.90 (d, J=8.3 Hz, 1H), 7.86 (s, 1H), 7.20-7.11 (m, 3H), 6.78 (m, 1H), 4.18 (q, J=7.1 Hz, 2H), 2.97 (s, 6H), 2.08 (s, 3H), 1.24 (t, J=7.1 Hz, 3H); MS (ESI) m/z: 539.2 [M+H] ⁺ .

[00405] Example 109: A mixture of Example A20 (0.345 g, 0.998 mmol), phenyl isocyanate (0.143 g, 1.197 mmol) and TEA (0.138 mL, 0.998 mmol) in THF (5 mL) was stirred at RT for 3 hours. The mixture was treated with 30% EtOAc/hex, stirred for several minutes and the resulting solid was collected by filtration and dried to give 1-(5-(7-chloro-1-isopropyl-2-oxo-1,2-dihydro-1, 6-naphthyridin-3-yl)-2-fluoro-4-methylphenyl)-3-phenylurea (350 mg, 75% yield). MS (ESI) m/z: 465.1 [M+H] ⁺ .

[00406] Solution of 1-(5-(7-chloro-1-isopropyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoro-4-methylphenyl)-3- phenylurea (0.35 g, 0.753 mmol) in dioxane (4 ml) and DMF (1 ml) was purged with Ar, treated with N-tert-butylcarbamate (0.441 g, 3.76 mmol), Cs ₂ CO ₃ (0.368 g, 1.129 mmol), X-Phos (0.036 g, 0.075 mmol) and Pd ₂ (dba) ₃ (0.034 g, 0.038 mmol) and the mixture was heated at 80°C for 16 hours. The mixture was cooled to RT, treated with THF and solids were removed by filtration through diatomaceous earth. The filtrate was washed with brine, dried over Na ₂ SO ₄ and concentrated to dryness. The residue was suspended in EtOAc/hex. 1:1, sonicated and the solid collected by filtration to give tert-butyl ether (3-(4-fluoro-2-methyl-5-(3-phenylureido)phenyl)-1-isopropyl-2-oxo-1. 2-dihydro-1,6-naphthyridin-7-yl)carbamic acid (205 mg, 50% yield). ^1H NMR (400 MHz, DMSO- _d6 ): δ 10.10 (s, 1H), 9.02 (s, 1H), 8.61 (s, 1H), 8.50 (s, 1H), 8.13 (s, 1H), 7.97 (d, J=8.4 Hz, 1H), 7.82 (s, 1H), 7.41 (d, J=8.0 Hz, 2H), 7.25 (t, J=7.8 Hz, 2H), 7.15 (d, J=12.2 Hz, 1H), 6.95 (t, J=7.4 Hz, 1H), 5, 28 (m, 1H), 2.07 (s, 3H), 1.57 (d, J=7.0 Hz, 6H), 1.49 (s, 9H); MS (ESI) m/z: 546.2 [M+H] ⁺ .

[00407] (3-(4-Fluoro-2-methyl-5-(3-phenylureido)phenyl)-1-isopropyl-2-oxo-1,2-dihydro-1,6-naphthyridine-tert-butyl ether solution 7-yl)carbamic acid (0.2 g, 0.367 mmol) in MeOH (3 ml) was treated with HCl in dioxane (4 M, 0.916 ml, 3.67 mmol) and stirred at RT for 16 hours. The mixture was concentrated to dryness, treated with pyridine (3 ml) and isopropenyl chloroformate (0.066 g, 0.550 mmol) and stirred at RT for 1 hour. Water was added, the mixture was stirred for several minutes, extracted with 20% THF/EtOAc (2×) and the combined organic layers were washed with brine, dried over Na ₂ SO ₄ and concentrated to dryness. The residue was treated with 30% EtOAc/hex, then sonicated, and the resulting solid was collected by filtration to give prop-1-en-2-yl ester (3-(4-fluoro-2-methyl-5-(3-phenylureido) phenyl)-1-isopropyl-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)carbamic acid (175 mg, 90% yield). ^1H NMR (400 MHz, DMSO- _d6 ): δ 10.77 (s, 1H), 9.02 (s, 1H), 8.66 (s, 1H), 8.50 (s, 1H), 8.15 (s, 1H), 7.98 (d, J=8.5 Hz, 1H), 7.85 (s, 1H), 7.41 (d, J=8.0 Hz, 2H), 7, 25 (t, J=7.8 Hz, 2H), 7.15 (d, J=12.2 Hz, 1H), 6.95 (t, J=7.3 Hz, 1H), 5.33 ( m, 1H), 4.81 (s, 1H), 4.77 (s, 1H), 2.07 (s, 3H), 1.96 (s, 3H), 1.56 (d, J=7 ,0 Hz, 6H); MS (ESI) m/z: 530.2 [M+H] ⁺ .

[00408] A suspension of prop-1-en-2-yl ether (3-(4-fluoro-2-methyl-5-(3-phenylureido)-phenyl)-1-isopropyl-2-oxo-1,2-dihydro -1,6-naphthyridin-7-yl)carbamic acid (0.1 g, 0.189 mmol) in dioxane (3 ml) was treated with azetidine hydrochloride (0.071 g, 0.755 mmol) and 1-methylpyrrolidine (0.129 g, 1.511 mmol) and heated at 70°C for 16 hours, then cooled to RT and stirred for 24 hours. The mixture was concentrated to dryness and purified by reverse phase chromatography (MeCN/H ₂ O with 0.1% TFA). The factions neutralized us. NaHCO ₃ , extracted with EtOAc (2×), and the combined organic layers were washed with brine, dried over Na ₂ SO ₄ and concentrated to dryness to give N-(3-(4-fluoro-2-methyl-5-(3-phenylureido) phenyl)-1-isopropyl-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)azetidin-1-carboxamide (43 mg, 43% yield). ^1H NMR (400 MHz, DMSO- _d6 ): δ 9.34 (s, 1H), 9.01 (s, 1H), 8.60 (s, 1H), 8.49 (s, 1H), 8.38 (s, 1H), 7.97 (d, J=8.4 Hz, 1H), 7.80 (s, 1H), 7.41 (d, J=8.0 Hz, 2H), 7.25 (t, J=7.8 Hz, 2H), 7.14 (d, J=12.2 Hz, 1H), 6.95 (t, J=7.4 Hz, 1H), 5, 35 (m, 1H), 4.02 (t, J=7.5 Hz, 4H), 2.17 (t, J=7.7 Hz, 2H), 2.07 (s, 3H), 1, 55 (d, J=7.0 Hz, 6H); MS (ESI) m/z: 529.2 [M+H] ⁺ .

[00409] Example 110: A suspension of the compound of Example A57 (0.15 g, 0.291 mmol) in THF (4 ml) was treated with azetidine hydrochloride (0.109 g, 1.164 mmol) and 1-methylpyrrolidine (0.248 g, 2.91 mmol) and heated at 60°C for 16 hours. The mixture was concentrated to dryness and purified by reverse phase chromatography (MeCN/H ₂ O with 0.1% TFA). The factions neutralized us. NaHCO ₃ , extracted with EtOAc (2×), and the combined organic layers were washed with brine, dried over Na ₂ SO ₄ and concentrated to dryness to give N-(1-ethyl-3-(4-fluoro-2-methyl-5-( 3-phenylureido)phenyl)-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)azetidin-1-carboxamide (53 mg, 35% yield). ^1H NMR (400 MHz, DMSO- _d6 ): δ 9.37 (s, 1H), 9.05 (s, 1H), 8.63 (s, 1H), 8.52 (s, 1H), 8.10 (s, 1H), 7.97 (d, J=8.4 Hz, 1H), 7.85 (s, 1H), 7.41 (d, J=8.1 Hz, 2H), 7.25 (t, J=7.8 Hz, 2H), 7.15 (d, J=12.2 Hz, 1H), 6.95 (t, J=7.4 Hz, 1H), 4, 17 (q, J=7.5 Hz, 2H), 4.02 (t, J=7.5 Hz, 4H), 2.17 (t, J=7.7 Hz, 2H), 2.07 ( s, 3H), 1.24 (t, J=7.0 Hz, 3H); MS (ESI) m/z: 515.2 [M+H] ⁺ .

[00410] Example 111: Mixture of compound according to example A54 (222 mg, 0.492 mmol), Pd(OAc) ₂ (6 mg, 0.026 mmol), Xantphos (31 mg, 0.053 mmol), K ₂ CO ₃ (73 mg, 0.527 mmol) and 3-amino-6-methylpyridine (171 mg, 1.582 mmol) in dioxane (4 ml) were purged with Ar and heated at 90°C for 4 hours. The mixture was cooled to RT, treated with EtOAc and 50% sat. NaHCO ₃ and solids were removed by filtration through diatomaceous earth. The filtrate layers were separated, the organic layer was washed with brine, dried over Na ₂ SO ₄ , concentrated to dryness and purified by reverse phase chromatography (MeCN/H ₂ O with 0.1% TFA). Organic substances were removed under reduced pressure, and the aqueous residue was treated with us. NaHCO ₃ and stirred. The resulting solid was collected by filtration and dried to give 1-(5-(1-ethyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridine -3-yl)-2-fluoro-4-methyl-phenyl)-3-phenylurea (87 mg, 33% yield). ^1H NMR (400 MHz, DMSO- _d6 ): δ 9.47 (s, 1H), 9.08 (s, 1H), 8.64 (d, J=2.7 Hz, 1H), 8. 57 (s, 1H), 8.55 (s, 1H), 8.07 (dd, J=8.4, 2.7 Hz, 1H), 7.96 (d, J=8.4 Hz, 1H ), 7.79 (s, 1H), 7.41 (dd, J=8.2, 1.2 Hz, 2H), 7.25 (t, J=7.8 Hz, 2H), 7.16 (t, J=8.7 Hz, 2H), 6.94 (t, J=7.3 Hz, 1H), 6.73 (s, 1H), 4.16 (q, J=7.1 Hz , 2H), 2.40 (s, 3H), 2.08 (s, 3H), 1.25 (t, J=7.0 Hz, 3H); MS (ESI) m/z: 523.2 [M+H] ⁺ .

[00411] Example 112: A mixture of Example A18 (400 mg, 1.191 mmol) and pyridine (471 mg, 5.96 mmol) in THF (10 ml) was treated dropwise with phenyl isocyanate (170 mg, 1.43 mmol) and stirred with CT scan overnight. The mixture was treated with EtOAc and 50% us. NaHCO ₃ and stirred for 2 hours. The resulting solid was collected by filtration and dried to give 1-(5-(7-chloro-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2,4-difluorophenyl )-3-phenylurea (211 mg, yield 38%). ^1H NMR (400 MHz, DMSO- _d6 ): δ 9.07 (brs, 1H), 8.80 (s, 1H), 8.64 (brs, 1H), 8.22-8 .15 (m, 2H), 7.74 (s, 1H), 7.46-7.39 (m, 3H), 7.26 (t, J=7.8 Hz, 2H), 6.96 ( t, J=7.3 Hz, 1H), 4.27 (q, J=7.1 Hz, 2H), 1.20 (t, J=7.0 Hz, 3H); MS (ESI) m/z: 455.1 [M+H] ⁺ .

[00412] A mixture of 1-(5-(7-chloro-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2,4-difluorophenyl)-3-phenylurea ( 211 mg, 0.464 mmol), Cs ₂ CO ₃ (453 mg, 1.392 mmol), N,N-dimethylurea (204 mg, 2.319 mmol) and Xantphos (81 mg, 0.139 mmol) in dioxane (5 ml) purged with Ar, treated Pd(dba) ₃ (64 mg, 0.070 mmol) and heated at 100°C for 4 hours. The mixture was cooled to RT, treated with EtOAc, DMF and 50% sat. NaHCO ₃ and solids were removed by filtration through diatomaceous earth. The filtrate layers were separated, the organic layer was washed with brine, dried over Na ₂ SO ₄ , concentrated to dryness and purified by reverse phase chromatography (MeCN/H ₂ O with 0.1% TFA). Organic substances were removed under reduced pressure, and the aqueous residue was treated with us. NaHCO ₃ and stirred. The resulting solid was collected by filtration and dried to give 3-(3-(2,4-difluoro-5-(3-phenylureido)phenyl)-1-ethyl-2-oxo-1,2-dihydro-1,6- naphthyridin-7-yl)-1,1-dimethylurea (47 mg, 33% yield). ^1H NMR (400 MHz, DMSO- _d6 ): δ 9.21 (s, 1H), 9.03 (s, 1H), 8.66 (s, 1H), 8.57 (s, 1H), 8.17 (dd, J=9.1, 7.8 Hz, 1H), 8.01 (d, J=2.1 Hz, 2H), 7.45-7.38 (m, 3H), 7 .26 (t, J=7.8 Hz, 2H), 6.96 (t, J=7.4 Hz, 1H), 4.18 (q, J=7.3 Hz, 2H), 2.97 (s, 6H), 1.24 (t, J=7.1 Hz, 3H); MS (ESI) m/z: 507.2 [M+H] ⁺ .

[00413] Example 113: A suspension of the compound of Example A57 (0.210 g, 0.407 mmol) in MeCN (8 ml) was treated with N,N-dimethylazetidine-3-amine hydrochloride (0.300 g, 1.733 mmol), then 1-methylpyrrolidine (0.150 g , 1.762 mmol) and heated at 70°C for 3 hours. The mixture was cooled to RT, concentrated to dryness and purified by silica gel chromatography (MeOH/DCM) to give 3-(dimethylamino)-N-(1-ethyl-3-(4-fluoro-2-methyl-5-(3-phenylureido) )phenyl)-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)azetidin-1-carboxamide (160 mg, 70% yield). ^1H NMR (400 MHz, DMSO- _d6 ): δ 9.56 (s, 1H), 9.48 (s, 1H), 8.72 (s, 1H), 8.64 (s, 1H), 8.08 (s, 1H), 7.96 (d, J=8.4 Hz, 1H), 7.86 (s, 1H), 7.42 (dd, J=8.2, 1.2 Hz , 2H), 7.24 (t, J=7.8 Hz, 2H), 7.14 (d, J=12.2 Hz, 1H), 6.93 (t, J=7.4 Hz, 1H ), 4.21-3.91 (m, 6H), 3.32 (m, 1H), 2.73 (s, 6H), 2.07 (s, 3H), 1.24 (t, J= 7.1 Hz, 3H); MS (ESI) m/z: 558.3 [M+H] ⁺ .

[00414] Example 114: A solution of the compound of Example A39 (0.600 g, 1.921 mmol) in dioxane (4 ml) and pyridine (4 ml) was treated with iodine (1.463 g, 5.76 mmol) and stirred at RT for 2 days. The mixture was treated to us. Na ₂ S ₂ O ₃ , stirred for a few minutes and extracted with DCM (4×). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ and concentrated to dryness. The residue was treated with MeOH and the resulting solid was collected by filtration and dried to give 3-(5-amino-4-fluoro-2-iodophenyl)-1-ethyl-7-(methylamino)-1,6-naphthyridine-2(1H )-ona (312 mg, yield 37%). MS (ESI) m/z: 439.0 [M+H] ⁺ .

[00415] A suspension of 3-(5-amino-4-fluoro-2-iodophenyl)-1-ethyl-7-(methylamino)-1,6-naphthyridin-2(1H)-one (0.310 g, 0.707 mmol) in DCM (10 ml) was treated with phenyl isocyanate (0.100 g, 0.839 mmol), then pyridine (0.060 g, 0.759 mmol) and stirred at RT for 3 hours. The mixture was concentrated to dryness and purified by silica gel chromatography (EtOAc/hex) to give 1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridine-3 -yl)-2-fluoro-4-iodophenyl)-3-phenylurea (120 mg, 29% yield). ^1H NMR (400 MHz, DMSO- _d6 ): δ 9.08 (s, 1H), 8.66 (s, 1H), 8.41 (s, 1H), 8.14 (d, J=8 ,3 Hz, 1H), 7.77 (d, J=10.6 Hz, 1H), 7.64 (s, 1H), 7.41 (d, J=8.0 Hz, 2H), 7, 26 (t, J=7.7 Hz, 2H), 7.05 (m, 2H), 6.24 (s, 1H), 4.14 (d, J=8.1 Hz, 2H), 2, 86 (d, J=4.8 Hz, 3H), 1.22 (t, J=7.0 Hz, 3H); MS (ESI) m/z: 558.1 [M+H] ⁺ .

[00416] Example 115: Mixture of compound according to example A54 (255 mg, 0.566 mmol), Pd(OAc) ₂ (6.4 mg, 0.028 mmol), Xantphos (33 mg, 0.057 mmol), K ₂ CO ₃ (117 mg , 0.848 mmol) and 4-amino-1-methylpyrazole (60 mg, 0.622 mmol) in dioxane (4 ml) were purged with Ar and heated at 99°C overnight. The mixture was cooled to RT, treated with EtOAc and DMF, and solids were removed by filtration through diatomaceous earth. The filtrate was concentrated to dryness and purified by reverse phase chromatography (MeCN/H ₂ O with 0.1% TFA). Organic substances were removed under reduced pressure, and the aqueous residue was treated with us. NaHCO ₃ and extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ and concentrated to dryness to give 1-(5-(1-ethyl-7-((1-methyl-1H-pyrazol-4-yl)amino)-2-oxo -1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoro-4-methylphenyl)-3-phenylurea (14 mg, 4% yield). ^1H NMR (400 MHz, DMSO- _d6 ): δ 9.11 (s, 1H), 8.96 (s, 1H), 8.47 (s, 1H), 8.43 (s, 1H), 7.92-7.88 (m, 2H), 7.69 (s, 1H), 7.41 (s, 1H), 7.36 (d, J=8.0 Hz, 2H), 7.20 (t, J=7.8 Hz, 2H), 7.08 (d, J=12.3 Hz, 1H), 6.90 (t, J=7.3 Hz, 1H), 6.46 (s , 1H), 4.07 (q, J=7.1 Hz, 2H), 3.76 (s, 3H), 2.02 (s, 3H), 1.17 (t, J=7.0 Hz , 3H); MS (ESI) m/z: 512.2 [M+H] ⁺ .

[00417] The following studies show that certain compounds of formula Ia inhibit C-KIT kinase and its mutations in enzyme assays, and also inhibit cKIT kinase in GIST cell lines.

c-KIT kinase study

[00418] The activity of c-KIT kinase (Seq ID No. 1) was determined by assessing the production of ADP in the kinase reaction due to communication with the pyruvate kinase/lactate dehydrogenase system (eg, Schindler et al. Science (2000) 289: 1938-1942). In this study, NADP oxidation (measured by the decrease in absorbance at 340 nm) was monitored continuously spectrophotometrically. The reaction mixture (100 μl) contained c-KIT (residues cKIT T544-V976, 6 nM), polyE4Y (1 mg/ml), MgCl ₂ (10 mmol), pyruvate kinase (4 units), lactate dehydrogenase (0.7 units), phosphoenolpyruvate (1 mM) and NADP (0.28 mM) in 90 mM Tris buffer containing 0.2% octyl glucoside and 1% DMSO, pH 7.5. Test compounds were incubated with c-KIT (Seq ID No. 1) and other reagents at 22°C for ~30 minutes, after which ATP (200 μM) was added to initiate the reaction. The absorbance at 340 nm was continuously monitored on a Synergy 2 (BioTeK) for 2 hours at 30°C. The reaction rate was calculated for the interval from 0 to 1 hour. Percentage inhibition was determined by comparing the reaction rate with a control (ie, an experiment where the test compound was not used). IC ₅₀ values were calculated from a set of determined percent inhibition values over a range of inhibitor concentrations using standard software tools such as those included in the GraphPad Prism software package.

c-KIT protein sequence (Seq ID #1)

[00419] The protein construct was prepared at deCODE Biostructures using methods known in the art. The construct contained cKit residues T544-V976, an N-terminal tag, a GST inclusion sequence, and a TEV cleavage site.

c-KIT V654A Kiase Study

[00420] The activity of c-KIT V654A kinase (Seq ID No. 2) was determined by assessing the production of ADP in the kinase reaction due to communication with the pyruvate kinase/lactate dehydrogenase system (eg, Schindler et al. Science (2000) 289: 1938-1942). In this study, NADP oxidation (measured by the decrease in absorbance at 340 nm) was monitored continuously spectrophotometrically. The reaction mixture (100 μl) contained c-KIT V654A (residues T544-V976 with GST inclusion at the N-terminus, 47 nM), polyE4Y (1 mg/ml), MgCl ₂ (10 mmol), pyruvate kinase (4 units), lactate dehydrogenase (0.7 units), phosphoenolpyruvate (1 mM) and NADP (0.28 mM) and ATP (200 μM) in 90 mM Tris buffer containing 0.2% octyl glucoside and 1% DMSO, pH 7.5. Reaction inhibition was initiated by mixing serially diluted test compound with the above reaction mixture. Absorbance at 340 nm was monitored continuously on a Synergy 2 plate analyzer (BioTech) for 6 hours at 30°C. Reaction rates over approximately 3 to 5 hours were used to calculate % inhibition values from which IC ₅₀ values were determined using GraphPad Prism.

c-KIT protein sequence (V654A) (Seq ID #2)

[00421] The protein construct was prepared at deCODE Biostructures using methods known in the art. The construct contained cKit residues T544-V976, an N-terminal tag, a GST inclusion sequence, and a TEV cleavage site. The specified construct was identical to the sequence of Seq ID No. 1 with the exception of the V654A mutation.

Study of c-KIT D816H kinase

[00422] The c-KIT D816H kinase assay (Seq ID #3) was performed under the conditions described above for the c-KIT V654A assay, except that 10 nM c-KIT D816H was used.

Protein sequence c-KIT (D816H) (Seq ID No. 3)

[00423] The protein construct was prepared at deCODE Biostructures using methods known in the art. The construct contained cKit residues T544-V976, an N-terminal tag, a GST inclusion sequence, and a TEV cleavage site. The specified construct was identical to the sequence of Seq ID No. 1 with the exception of the D816H mutation.

c-KIT D816V kinase study

[00424] The activity of c-KIT D816V kinase (Seq ID No. 4) was determined by assessing the production of ADP in the kinase reaction due to communication with the pyruvate kinase/lactate dehydrogenase system (eg, Schindler et al. Science (2000) 289: 1938-1942). In this study, NADP oxidation (measured by the decrease in absorbance at 340 nm) was monitored continuously spectrophotometrically. The reaction mixture (100 μl) contained c-KIT D816V (residues T544-V976 with GST inclusion at the N-terminus, 16 nM), polyE4Y (1 mg/ml), ATP (200 μM), MgCl ₂ (10 mM), pyruvate kinase (4 units), lactate dehydrogenase (0.7 units), phosphoenolpyruvate (1 mM) and NADP (0.28 mM) in 90 mM Tris buffer containing 0.001% Triton X-100 and 1% DMSO, pH 7.5. Reaction inhibition was initiated by mixing serially diluted test compound with the above reaction mixture. Absorbance at 340 nm was monitored continuously on a Synergy 2 plate analyzer (BioTech) for 5 hours at 30°C. Reaction rates over approximately 3 to 4 hours were used to calculate % inhibition values from which IC ₅₀ values were determined using GraphPad Prism.

Protein sequence c-KIT (D816V) (Seq ID No. 4)

[00425] The protein construct was prepared at deCODE Biostructures using methods known in the art. The construct contained cKit residues T544-V976, an N-terminal tag, a GST inclusion sequence, and a TEV cleavage site. The specified construct was identical to the sequence of Seq ID No. 1 with the exception of the D816V mutation.

cKIT-VVDV kinase study

[00426] c-KIT-VVDV is a c-KIT mutant with residues V559 and V560 deleted and the D816V mutation. The kinase assay for c-KIT VVDV (Seq ID #5) was performed under the conditions described above for the C-K1T-D816V assay, except that 16 nM c-KIT-VVDV was used.

VVDV c-KIT protein sequence (Seq ID #5)

[00427] The protein construct was prepared at deCODE Biostructures using methods known in the art. The construct contained residues T544-V976 of cKit (except for the presence of the D816V mutation and the absence of residues V559 and V560), an N-terminal tag, a GST inclusion sequence, and a TEV cleavage site. This construct was identical to the sequence of Seq ID No. 1 with the exception of the D816V mutation and the absence of residues V559 and V560.

c-KIT T670I kinase study

[00428] The c-KIT T670I kinase assay (Seq ID #6) was performed under the conditions described above for the KIT-D816V assay, except that 25 nM Kit T670I was used in the assay.

Protein sequence C-KIT-T670I (Seq ID No. 6)

[00429] The protein construct was prepared at deCODE Biostructures using methods known in the art. The construct contained cKit residues T544-V976, an N-terminal tag, a GST inclusion sequence, and a TEV cleavage site. The specified construct was identical to the sequence of Seq ID No. 1 with the exception of the T670I mutation.

[00430] According to the enzyme assay protocols described above, compounds of Formula Ia were shown to be inhibitors in studies that measured the kinase activity of KIT kinase, V654A KIT kinase, D816H KIT kinase, D816V KIT kinase, V559 deletion mutant KIT kinase +V560 and the D816V (KIT-VVDV), and T670I KIT kinase mutation, as shown below in Table 1.

NI: not studied; +: IC ₅₀ >1 µM; ++: 0.1 µM <IC ₅₀ ≤1 µM; +++; 0.01 µM <IC ₅₀ ≤0.1 µM; ++++: IC ₅₀ ≤0.01 µM

GIST cell culture

[00431] GIST48, GIST430 and GIST882 cells were obtained from J. Fletcher (Brigham and Women's Hospital, Boston, MA). GIST T1 cells were obtained from B. Rubin (Cleveland Clinic, Cleveland, ON) and Professor Takahiro Taguchi (Takahiro Taguchi, Kochi Medical School, Nankoku, Kochi, Japan). Briefly, GIST48 and GIST882 cells were grown in RPMI 1640 medium supplemented with 15% characterized fetal bovine serum (Invitrogen, Carlsbad, CA), 1 U/ml penicillin G, 1 μg/ml streptomycin, and 0.29 mg/ml L-glutamine. at 37°C, 5% CO ₂ and 95% humidity. GIST430 cells were grown in Ham's F10 medium supplemented with 15% characterized fetal bovine serum (lnvitrogen, Carlsbad, CA), 30 mg/L bovine pituitary extract (BD Biosciences, San Jose, CA), 0.5% Mito+ serum vehicle (BD Biosciences , San Jose, CA), 1 U/ml penicillin G, 1 μg/ml streptomycin, and 0.29 mg/ml L-glutamine, at 37°C, 5% CO ₂ , 95% humidity. GIST T1 cells were grown in DMEM supplemented with 10% characterized fetal bovine serum (Invitrogen, Carlsbad, CA), 1 U/ml penicillin G, 1 μg/ml streptomycin, and 0.29 mg/ml L-glutamine at 37°C. , 5% CO ₂ and 95% humidity. Cells were allowed to grow until 70-95% confluent, at which point they were subcultured or harvested for use in the study.

Western blot KIT GIST48

[00432] Two hundred fifty thousand cells were added to the wells of a 24-well tissue culture plate. The cells were then incubated overnight at 37°C, 5% CO ₂ , 95% humidity. The medium was aspirated, the cells were washed with PBS, and serum-free RPMI1640 medium was added. Serially diluted test compound was added to plates containing cells, and the plates were incubated for 4 hours at 37°C, 5% CO ₂ , 95% humidity. Cells were washed with PBS and then lysed. Cell lysates were separated by SDS-PAGE and transferred to PVDF. Phospho-KIT (Tyr719) was detected using an antibody obtained from Cell Signaling Technology (Beverly, MA), ECL Plus detection reagent (GE Healthcare, Piscataway, NJ) on a Molecular Devices Storm 840 phosphor imager in fluorescence mode. Blots were collected and probes were assayed for total KIT content using an antibody obtained from Santa Cruz Biotech (Santa Cruz, CA). IC ₅₀ values were calculated using Prism software (Graphpad, San Diego, CA).

Western blot KIT GIST430

[00433] One hundred and fifty thousand cells were added to the wells of a 24-well tissue culture plate. The cells were then incubated overnight at 37°C, 5% CO ₂ , 95% humidity. The medium was aspirated, the cells were washed with PBS, and Ham's F10 medium containing serum was added. Serially diluted test compound was added to plates containing cells, and the plates were incubated for 4 hours at 37°C, 5% CO ₂ , 95% humidity. Cells were washed with PBS and then lysed. Cell lysates were separated by SDS-PAGE and transferred to PVDF. Phospho-KIT (Tyr719) was detected using an antibody obtained from Cell Signaling Technology (Beverly, MA), ECL Plus detection reagent (GE Healthcare, Piscataway, NJ) on a Molecular Devices Storm 840 phosphor imager in fluorescence mode. Blots were collected and probes were assayed for total KIT content using an antibody obtained from Santa Cruz Biotech (Santa Cruz, CA). IC ₅₀ values were calculated using Prism software (Graphpad, San Diego, CA).

GIST 430 Cell Proliferation Study

[00434] Serially diluted test compound was placed in a 384-well black clear bottom plate (Corning, Corning, NY). Two thousand five hundred cells were added to the wells in 50 μl of complete nutrient medium. The plates were incubated for 115 hours at 37°C, 5% CO ₂ , 95% humidity. Upon completion of incubation, 10 μl of a 440 μM solution of resazurin (Sigma, St. Louis, MO) in PBS was added to each well and incubated for an additional 5 hours at 37°C, 5% CO ₂ , 95% humidity. The plates were examined on a Synergy2 analyzer (Biotek, Winooski, VT) using an excitation wavelength of 540 nm and an emission wavelength of 600 nm. To calculate IC ₅₀ values, data were analyzed using Prism software (Graphpad, San Diego, CA).

Western blot KIT GIST882

[00435] Two hundred fifty thousand cells were added to the wells of a 24-well tissue culture plate. The cells were then incubated overnight at 37°C, 5% CO ₂ , 95% humidity. The medium was aspirated, the cells were washed with PBS, and serum-free RPMI1640 medium was added. Serially diluted test compound was added to plates containing cells, and the plates were incubated for 4 hours at 37°C, 5% CO ₂ , 95% humidity. Cells were washed with PBS and then lysed. Cell lysates were separated by SDS-PAGE and transferred to PVDF. Phospho-KIT (Tyr719) was detected using an antibody obtained from Cell Signaling Technology (Beverly, MA), ECL Plus detection reagent (GE Healthcare, Piscataway, NJ) on a Molecular Devices Storm 840 phosphor imager in fluorescence mode. Blots were collected and probes were assayed for total KIT content using an antibody obtained from Santa Cruz Biotech (Santa Cruz, CA). IC ₅₀ values were calculated using Prism software (Graphpad, San Diego, CA).

Western blot KIT GIST T1

[00436] One hundred twenty-five thousand cells were added to the wells of a 24-well tissue culture plate. The cells were then incubated overnight at 37°C, 5% CO ₂ , 95% humidity. The medium was aspirated, the cells were washed with PBS, and serum-free DMEM was added. Serially diluted test compound was added to plates containing cells, and the plates were incubated for 4 hours at 37°C, 5% CO ₂ , 95% humidity. Cells were washed with PBS and then lysed. Cell lysates were separated by SDS-PAGE and transferred to PVDF. Phospho-KIT (Tyr719) was detected using an antibody obtained from Cell Signaling Technology (Beverly, MA), ECL Plus detection reagent (GE Healthcare, Piscataway, NJ) on a Molecular Devices Storm 840 phosphor imager in fluorescence mode. Blots were collected and probes were assayed for total KIT content using an antibody obtained from Santa Cruz Biotech (Santa Cruz, CA). IC ₅₀ values were calculated using Prism software (Graphpad, San Diego, CA).

GIST T1 Cell Proliferation Study

[00437] Serially diluted test compound was placed in a 384-well black clear bottom plate (Corning, Corning, NY). One thousand two hundred and fifty cells were added to the wells in 50 μl of complete nutrient medium. The plates were incubated for 68 hours at 37°C, 5% CO ₂ , 95% humidity. Upon completion of incubation, 10 μl of a 440 μM solution of resazurin (Sigma, St. Louis, MO) in PBS was added to each well and incubated for an additional 4 hours at 37°C, 5% CO ₂ , 95% humidity. The plates were examined on a Synergy2 analyzer (Biotek, Winooski, VT) using an excitation wavelength of 540 nm and an emission wavelength of 600 nm. To calculate IC ₅₀ values, data were analyzed using Prism software (Graphpad, San Diego, CA).

[00438] In the cellular studies described above, compounds of Formula Ia were demonstrated by Western blot analysis to reduce the level of phospho-KIT (autophosphorylation) in one or more GIST cell lines, as shown in Table 2. In addition or as alternative compounds of Formula Ia have antiproliferative effects against GIST cell lines, as measured by the reduction in cell proliferation shown in Table 2.

NI: not studied; +: IC ₅₀ >1 µM; ++: 0.1 µM<IC ₅₀ ≤1 µM; +++: 0.01 µM<IC ₅₀ ≤0.1 µM; ++++: IC ₅₀ ≤0.01 µM

Cell culture CHO K1

[00439] CHO K1 cells (Cat. No. CCL-61) were obtained from the American Type Culture Collection, Manassas, VA. Briefly, cells were grown in RPMI 1640 supplemented with 10% characterized fetal bovine serum and 1% penicillin-streptomycin-L-glutamine solution (Invitrogen, Carlsbad, CA), at 37 degrees Celsius, 5% CO ₂ , 95% rel. ow. Cells were allowed to grow until 70–95% confluent, at which point they were subcultured or harvested for use in the study.

ELISA Phospho-KIT CHO K1

[00440] Forty thousand cells in RPMI 1640 supplemented with 10% characterized fetal bovine serum and 1% MEM nonessential amino acids (Invitrogen Carlsbad, CA) were added to each well of a 24-well tissue culture plate (Nunc, Rochester, NY). The cells were then incubated overnight at 37°C, 5% CO ₂ , 95% RH. ow. The pcDNA3.2 V5 DEST expression vector containing the KIT variant and suitable for transfection, Lipofectamine LTX reagent and PLUS reagent (Invitrogen Carlsbad, CA) were diluted in Opti-MEM® I medium (Invitrogen, Carlsbad, CA). The tube was incubated at room temperature to form DNA-Lipofectamine LTX complexes. The mixture containing the DNA-Lipofectamine LTX complex was added directly to each well and mixed gently. Eighteen hours after transfection, the medium was replaced with serum-free RPMI medium. Serially diluted test compound was added and the plates were incubated for 4 hours at 37°C, 5% CO ₂ , 95% RH. ow. Cell lysates were prepared and phospho-c-KIT (Tyr719) levels were measured using a human phospho-c-KIT ELISA kit (Cell Signaling, Beverly, Calif.). To calculate IC ₅₀ values, data were analyzed using Prism software (GraphPad, San Diego, CA).

Plasmid DNA constructs (expression vector pcDNA 3.2 V5 DEST)

duplication AY502/N882K KIT

duplication AY502/D820E KIT

duplication AY502/D816G KIT

duplication AY502/D820G KIT

duplication AY502/N822Y KIT

duplication AY502/N822H KIT

WKV557-559 deletion/C557/D820Y insertion

WKV557-559 deletion/C557/D820A insertion

V560D/N822K

V560D/Y823D

Western blot of phospho-KIT CHO K1

[00441] One hundred thousand cells in RPMI 1640 supplemented with 10% characterized fetal bovine serum and 1% MEM nonessential amino acids (Invitrogen Carlsbad, CA) were added to each well of a 24-well tissue culture plate (Nunc, Rochester, NY). The cells were then incubated overnight at 37°C, 5% CO ₂ , 95% rel. ow. The expression vector pcDNA3.2 V5 DEST, containing the KIT variant and suitable for transfection, and the Lipofectamine LTX reagent (Invitrogen Carlsbad, CA) were diluted in Opti-MEM® I medium (Invitrogen, Carlsbad, CA). The tube was incubated at room temperature to form DNA-Lipofectamine LTX complexes. The mixture containing the DNA-Lipofectamine LTX complex was added directly to each well and mixed gently. Eighteen hours after transfection, the medium was replaced with serum-free RPMI medium. Serially diluted test compound was added and the plates were incubated for 4 hours at 37°C, 5% CO ₂ , 95% RH. ow. Cells were washed with PBS and then lysed. Cell lysates were separated by SDS-PAGE and transferred to PVDF. Phospho-KIT (Tyr719) was detected using an antibody obtained from Cell Signaling Technology (Beverly, MA), ECL Plus detection reagent (GE Healthcare, Piscataway, NJ) on a Molecular Devices Storm 840 phosphor imager in fluorescence mode. Blots were collected and probes were assayed for total KIT content using an antibody obtained from Santa Cruz Biotech (Santa Cruz, CA). IC ₅₀ values were calculated using Prism software (Graphpad, San Diego, CA).

Plasmid DNA constructs (expression vector pcDNA 3.2 V5 DEST)

D816V KIT

D820A KIT

Deletion VV559-560/D816V KIT

[00442] There are increasing numbers of GISTs becoming resistant to Gleevec® (imatinib), and small molecule therapies targeting molecular targets that target secondary c-KIT mutations have not been well studied. In patients with GIST who relapse after treatment with Gleevec® (imatinib) or Sutent® (sunitinib), the disease continues to be defined by c-KIT mutations. These secondary mutations occur on the same alleles as the primary mutations of the JM region, and. thus represent even more aggressive activated forms of c-KIT than the original primary mutations. In the CHO K1 cell studies described above, it was demonstrated that certain compounds of the present invention inhibit a variety of mutant forms of cKIT kinase that are identified in GIST patients with acquired resistance to treatment with imatinib or sunitinib (Table 3).

NI: not studied; +: IC ₅₀ >1 µM; ++: 0.1 µM<IC ₅₀ ≤1 µM; +++: 0.01 µM<IC ₅₀ ≤0.1 µM; ++++: IC ₅₀ ≤0.01 µM

[00443] The compounds described in the present invention, suitable for the treatment of diseases mediated by c-KIT kinase, have similar structures to the compounds previously proposed in the publication of international patent application WO 2008/034008 as inhibitors of the RAF-MEK-ERK pathway, more specifically as RAF kinase inhibitors. The use of the compounds proposed in WO 2008/034008 as c-KIT kinase inhibitors, however, was unexpected, and thus was not proposed in WO 2008/034008. Thus, the unexpected ability of the compounds to inhibit c-KIT, and also, more importantly, the oncogenic mutant forms of c-KIT kinase described in this application, determines the novelty of the invention. Additionally, the fact that RAF kinase inhibitors can also potently inhibit c-KIT kinase, as evidenced by the data below illustrating the different kinase inhibition profiles of the marketed cKIT inhibitors imatinib® and sunitinib® and the marketed BRAF inhibitor vemurafenib®, does not is obvious.

--->

LIST OF SEQUENCES

<110> Flynn, Daniel L.

Kaufman, Michael D.

<120> DIHYDRONAPHTHYRIDINES AND RELATED COMPOUNDS, SUITABLE

AS KINASE INHIBITORS FOR THE TREATMENT OF PROLIFERATIVE

DISEASES

<130> DECP-060/00US

<160> 6

<170> Patent In version 3.5

<210> 1

<211> 676

<212>PRT

<213> Artificial sequence

<220>

<223> c-KIT with N-terminal GST insert

<400> 1

Leu Gly Tyr Trp Lys Ile Lys Gly Leu Val Gln Pro Thr Arg Leu Leu

1 5 10 15

Leu Glu Tyr Leu Glu Glu Lys Tyr Glu Glu His Leu Tyr Glu Arg Asp

20 25 30

Glu Gly Asp Lys Trp Arg Asn Lys Lys Phe Glu Leu Gly Leu Glu Phe

35 40 45

Pro Asn Leu Pro Tyr Tyr Ile Asp Gly Asp Val Lys Leu Thr Gln Ser

50 55 60

Met Ala Ile Ile Arg Tyr Ile Ala Asp Lys His Asn Met Leu Gly Gly

65 70 75 80

Cys Pro Lys Glu Arg Ala Glu Ile Ser Met Leu Glu Gly Ala Val Asp

85 90 95

Ile Arg Tyr Gly Val Ser Arg Ile Ala Tyr Ser Lys Asp Phe Glu Thr

100 105 110

Leu Lys Val Asp Phe Leu Ser Lys Leu Pro Glu Met Leu Lys Met Phe

115 120 125

Glu Asp Arg Leu Cys His Lys Thr Tyr Leu Asn Gly Asp His Val Thr

130 135 140

His Pro Asp Phe Met Leu Tyr Asp Ala Leu Asp Val Val Leu Tyr Met

145 150 155 160

Asp Pro Met Cys Leu Asp Ala Phe Pro Lys Leu Val Cys Phe Lys Lys

165 170 175

Arg Ile Glu Ala Ile Pro Gln Ile Asp Lys Tyr Leu Lys Ser Ser Lys

180 185 190

Tyr Ile Trp Pro Leu Gln Gly Trp Gln Ala Thr Phe Gly Gly Gly Asp

195 200 205

His Pro Pro Lys Ser Asp Leu Val Pro Arg His Asn Gln Thr Ser Leu

210 215 220

Tyr Lys Lys Ala Gly Ser Ala Ala Ala Val Leu Glu Glu Asn Leu Tyr

225 230 235 240

Phe Gln Gly Thr Tyr Lys Tyr Leu Gln Lys Pro Met Tyr Glu Val Gln

245 250 255

Trp Lys Val Val Glu Glu Ile Asn Gly Asn Asn Tyr Val Tyr Ile Asp

260 265 270

Pro Thr Gln Leu Pro Tyr Asp His Lys Trp Glu Phe Pro Arg Asn Arg

275 280 285

Leu Ser Phe Gly Lys Thr Leu Gly Ala Gly Ala Phe Gly Lys Val Val

290 295 300

Glu Ala Thr Ala Tyr Gly Leu Ile Lys Ser Asp Ala Ala Met Thr Val

305 310 315 320

Ala Val Lys Met Leu Lys Pro Ser Ala His Leu Thr Glu Arg Glu Ala

325 330 335

Leu Met Ser Glu Leu Lys Val Leu Ser Tyr Leu Gly Asn His Met Asn

340 345 350

Ile Val Asn Leu Leu Gly Ala Cys Thr Ile Gly Gly Pro Thr Leu Val

355 360 365

Ile Thr Glu Tyr Cys Cys Tyr Gly Asp Leu Leu Asn Phe Leu Arg Arg

370 375 380

Lys Arg Asp Ser Phe Ile Cys Ser Lys Gln Glu Asp His Ala Glu Ala

385 390 395 400

Ala Leu Tyr Lys Asn Leu Leu His Ser Lys Glu Ser Ser Cys Ser Asp

405 410 415

Ser Thr Asn Glu Tyr Met Asp Met Lys Pro Gly Val Ser Tyr Val Val

420 425 430

Pro Thr Lys Ala Asp Lys Arg Arg Ser Val Arg Ile Gly Ser Tyr Ile

435 440 445

Glu Arg Asp Val Thr Pro Ala Ile Met Glu Asp Asp Glu Leu Ala Leu

450 455 460

Asp Leu Glu Asp Leu Leu Ser Phe Ser Tyr Gln Val Ala Lys Gly Met

465 470 475 480

Ala Phe Leu Ala Ser Lys Asn Cys Ile His Arg Asp Leu Ala Ala Arg

485 490 495

Asn Ile Leu Leu Thr His Gly Arg Ile Thr Lys Ile Cys Asp Phe Gly

500 505 510

Leu Ala Arg Asp Ile Lys Asn Asp Ser Asn Tyr Val Val Lys Gly Asn

515 520 525

Ala Arg Leu Pro Val Lys Trp Met Ala Pro Glu Ser Ile Phe Asn Cys

530 535 540

Val Tyr Thr Phe Glu Ser Asp Val Trp Ser Tyr Gly Ile Phe Leu Trp

545 550 555 560

Glu Leu Phe Ser Leu Gly Ser Ser Pro Tyr Pro Gly Met Pro Val Asp

565 570 575

Ser Lys Phe Tyr Lys Met Ile Lys Glu Gly Phe Arg Met Leu Ser Pro

580 585 590

Glu His Ala Pro Ala Glu Met Tyr Asp Ile Met Lys Thr Cys Trp Asp

595 600 605

Ala Asp Pro Leu Lys Arg Pro Thr Phe Lys Gln Ile Val Gln Leu Ile

610 615 620

Glu Lys Gln Ile Ser Glu Ser Thr Asn His Ile Tyr Ser Asn Leu Ala

625 630 635 640

Asn Cys Ser Pro Asn Arg Gln Lys Pro Val Val Asp His Ser Val Arg

645 650 655

Ile Asn Ser Val Gly Ser Thr Ala Ser Ser Ser Gln Pro Leu Leu Val

660 665 670

His Asp Asp Val

675

<210> 2

<211> 469

<212>PRT

<213> Artificial sequence

<220>

<223> c-KIT (V654A)

<400> 2

Met Ser Tyr Tyr His His His His His Asp Tyr Asp Ile Pro Thr

1 5 10 15

Thr Glu Asn Leu Tyr Phe Gln Gly Ala Met Leu Val Pro Arg Gly Ser

20 25 30

Pro Trp Gly Ser Thr Tyr Lys Tyr Leu Gln Lys Pro Met Tyr Glu Val

35 40 45

Gln Trp Lys Val Val Glu Glu Ile Asn Gly Asn Asn Tyr Val Tyr Ile

50 55 60

Asp Pro Thr Gln Leu Pro Tyr Asp His Lys Trp Glu Phe Pro Arg Asn

65 70 75 80

Arg Leu Ser Phe Gly Lys Thr Leu Gly Ala Gly Ala Phe Gly Lys Val

85 90 95

Val Glu Ala Thr Ala Tyr Gly Leu Ile Lys Ser Asp Ala Ala Met Thr

100 105 110

Val Ala Val Lys Met Leu Lys Pro Ser Ala His Leu Thr Glu Arg Glu

115 120 125

Ala Leu Met Ser Glu Leu Lys Val Leu Ser Tyr Leu Gly Asn His Met

130 135 140

Asn Ile Ala Asn Leu Leu Gly Ala Cys Thr Ile Gly Gly Pro Thr Leu

145 150 155 160

Val Ile Thr Glu Tyr Cys Cys Tyr Gly Asp Leu Leu Asn Phe Leu Arg

165 170 175

Arg Lys Arg Asp Ser Phe Ile Cys Ser Lys Gln Glu Asp His Ala Glu

180 185 190

Ala Ala Leu Tyr Lys Asn Leu Leu His Ser Lys Glu Ser Ser Cys Ser

195 200 205

Asp Ser Thr Asn Glu Tyr Met Asp Met Lys Pro Gly Val Ser Tyr Val

210 215 220

Val Pro Thr Lys Ala Asp Lys Arg Arg Ser Val Arg Ile Gly Ser Tyr

225 230 235 240

Ile Glu Arg Asp Val Thr Pro Ala Ile Met Glu Asp Asp Glu Leu Ala

245 250 255

Leu Asp Leu Glu Asp Leu Leu Ser Phe Ser Tyr Gln Val Ala Lys Gly

260 265 270

Met Ala Phe Leu Ala Ser Lys Asn Cys Ile His Arg Asp Leu Ala Ala

275 280 285

Arg Asn Ile Leu Leu Thr His Gly Arg Ile Thr Lys Ile Cys Asp Phe

290 295 300

Gly Leu Ala Arg Asp Ile Lys Asn Asp Ser Asn Tyr Val Val Lys Gly

305 310 315 320

Asn Ala Arg Leu Pro Val Lys Trp Met Ala Pro Glu Ser Ile Phe Asn

325 330 335

Cys Val Tyr Thr Phe Glu Ser Asp Val Trp Ser Tyr Gly Ile Phe Leu

340 345 350

Trp Glu Leu Phe Ser Leu Gly Ser Ser Pro Tyr Pro Gly Met Pro Val

355 360 365

Asp Ser Lys Phe Tyr Lys Met Ile Lys Glu Gly Phe Arg Met Leu Ser

370 375 380

Pro Glu His Ala Pro Ala Glu Met Tyr Asp Ile Met Lys Thr Cys Trp

385 390 395 400

Asp Ala Asp Pro Leu Lys Arg Pro Thr Phe Lys Gln Ile Val Gln Leu

405 410 415

Ile Glu Lys Gln Ile Ser Glu Ser Thr Asn His Ile Tyr Ser Asn Leu

420 425 430

Ala Asn Cys Ser Pro Asn Arg Gln Lys Pro Val Val Asp His Ser Val

435 440 445

Arg Ile Asn Ser Val Gly Ser Thr Ala Ser Ser Ser Gln Pro Leu Leu

450 455 460

Val His Asp Asp Val

465

<210> 3

<211> 620

<212>PRT

<213> Artificial sequence

<220>

<223> c-KIT (D816H)

<400> 3

Met Ser Pro Ile Leu Gly Tyr Trp Lys Ile Lys Gly Leu Val Gln Pro

1 5 10 15

Thr Arg Leu Leu Leu Glu Tyr Leu Glu Glu Lys Tyr Glu Glu His Leu

20 25 30

Tyr Glu Arg Asp Glu Gly Asp Lys Trp Arg Asn Lys Lys Phe Glu Leu

35 40 45

Gly Leu Glu Phe Pro Asn Leu Pro Tyr Tyr Ile Asp Gly Asp Val Lys

50 55 60

Leu Thr Gln Ser Met Ala Ile Ile Arg Tyr Ile Ala Asp Lys His Asn

65 70 75 80

Met Leu Gly Gly Cys Pro Lys Glu Arg Ala Glu Ile Ser Met Leu Glu

85 90 95

Gly Ala Val Leu Asp Ile Arg Tyr Gly Val Ser Arg Ile Ala Tyr Ser

100 105 110

Lys Asp Phe Glu Thr Leu Lys Val Asp Phe Leu Ser Lys Leu Pro Glu

115 120 125

Met Leu Lys Met Phe Glu Asp Arg Leu Cys His Lys Thr Tyr Leu Asn

130 135 140

Gly Asp His Val Thr His Pro Asp Phe Met Leu Tyr Asp Ala Leu Asp

145 150 155 160

Val Val Leu Tyr Met Asp Pro Met Cys Leu Asp Ala Phe Pro Lys Leu

165 170 175

Val Cys Phe Lys Lys Arg Ile Glu Ala Ile Pro Gln Ile Asp Lys Tyr

180 185 190

Leu Lys Ser Ser Lys Tyr Ile Ala Trp Pro Leu Gln Gly Trp Gln Ala

195 200 205

Thr Phe Gly Gly Gly Asp His Pro Pro Lys Ser Asp Leu Glu Val Leu

210 215 220

Phe Gln Gly Pro Glu Phe Lys Gly Leu Arg Arg Gln Thr Tyr Lys Tyr

225 230 235 240

Leu Gln Lys Pro Met Tyr Glu Val Gln Trp Lys Val Val Glu Glu Ile

245 250 255

Asn Gly Asn Asn Tyr Val Tyr Ile Asp Pro Thr Gln Leu Pro Tyr Asp

260 265 270

His Lys Trp Glu Phe Pro Arg Asn Arg Leu Ser Phe Gly Lys Thr Leu

275 280 285

Gly Ala Gly Ala Phe Gly Lys Val Val Glu Ala Thr Ala Tyr Gly Leu

290 295 300

Ile Lys Ser Asp Ala Ala Met Thr Val Ala Val Lys Met Leu Lys Pro

305 310 315 320

Ser Ala His Leu Thr Glu Arg Glu Ala Leu Met Ser Glu Leu Lys Val

325 330 335

Leu Ser Tyr Leu Gly Asn His Met Asn Ile Val Asn Leu Leu Gly Ala

340 345 350

Cys Thr Ile Gly Gly Pro Thr Leu Val Ile Thr Glu Tyr Cys Cys Tyr

355 360 365

Gly Asp Leu Leu Asn Phe Leu Arg Arg Lys Arg Asp Ser Phe Ile Cys

370 375 380

Ser Lys Gln Glu Asp His Ala Glu Ala Ala Leu Tyr Lys Asn Leu Leu

385 390 395 400

His Ser Lys Glu Ser Ser Cys Ser Asp Ser Thr Asn Glu Tyr Met Asp

405 410 415

Met Lys Pro Gly Val Ser Tyr Val Val Pro Thr Lys Ala Asp Lys Arg

420 425 430

Arg Ser Val Arg Ile Gly Ser Tyr Ile Glu Arg Asp Val Thr Pro Ala

435 440 445

Ile Met Glu Asp Asp Glu Leu Ala Leu Asp Leu Glu Asp Leu Leu Ser

450 455 460

Phe Ser Tyr Gln Val Ala Lys Gly Met Ala Phe Leu Ala Ser Lys Asn

465 470 475 480

Cys Ile His Arg Asp Leu Ala Ala Arg Asn Ile Leu Leu Thr His Gly

485 490 495

Arg Ile Thr Lys Ile Cys Asp Phe Gly Leu Ala Arg His Ile Lys Asn

500 505 510

Asp Ser Asn Tyr Val Val Lys Gly Asn Ala Arg Leu Pro Val Lys Trp

515 520 525

Met Ala Pro Glu Ser Ile Phe Asn Cys Val Tyr Thr Phe Glu Ser Asp

530 535 540

Val Trp Ser Tyr Gly Ile Phe Leu Trp Glu Leu Phe Ser Leu Gly Ser

545 550 555 560

Ser Pro Tyr Pro Gly Met Pro Val Asp Ser Lys Phe Tyr Lys Met Ile

565 570 575

Lys Glu Gly Phe Arg Met Leu Ser Pro Glu His Ala Pro Ala Glu Met

580 585 590

Tyr Asp Ile Met Lys Thr Cys Trp Asp Ala Asp Pro Leu Lys Arg Pro

595 600 605

Thr Phe Lys Gln Ile Val Gln Leu Ile Glu Lys Gln

610 615 620

<210> 4

<211> 698

<212>PRT

<213> Artificial sequence

<220>

<223> c-KIT (D816V)

<400> 4

Met Glu His His His His His His His Glu Tyr Met Pro Met Glu

1 5 10 15

Met Ala Pro Ile Leu Gly Tyr Trp Lys Ile Lys Gly Leu Val Gln Pro

20 25 30

Thr Arg Leu Leu Leu Glu Tyr Leu Glu Glu Lys Tyr Glu Glu His Leu

35 40 45

Tyr Glu Arg Asp Glu Gly Asp Lys Trp Arg Asn Lys Lys Phe Glu Leu

50 55 60

Gly Leu Glu Phe Pro Asn Leu Pro Tyr Tyr Ile Asp Gly Asp Val Lys

65 70 75 80

Leu Thr Gln Ser Met Ala Ile Ile Arg Tyr Ile Ala Asp Lys His Asn

85 90 95

Met Leu Gly Gly Cys Pro Lys Glu Arg Ala Glu Ile Ser Met Leu Glu

100 105 110

Gly Ala Val Leu Asp Ile Arg Tyr Gly Val Ser Arg Ile Ala Tyr Ser

115 120 125

Lys Asp Phe Glu Thr Leu Lys Val Asp Phe Leu Ser Lys Leu Pro Glu

130 135 140

Met Leu Lys Met Phe Glu Asp Arg Leu Cys His Lys Thr Tyr Leu Asn

145 150 155 160

Gly Asp His Val Thr His Pro Asp Phe Met Leu Tyr Asp Ala Leu Asp

165 170 175

Val Val Leu Tyr Met Asp Pro Met Cys Leu Asp Ala Phe Pro Lys Leu

180 185 190

Val Cys Phe Lys Lys Arg Ile Glu Ala Ile Pro Gln Ile Asp Lys Tyr

195 200 205

Leu Lys Ser Ser Lys Tyr Ile Ala Trp Pro Leu Gln Gly Trp Gln Ala

210 215 220

Thr Phe Gly Gly Gly Asp His Pro Pro Lys Ser Asp Leu Val Pro Arg

225 230 235 240

His Asn Gln Thr Ser Leu Tyr Lys Lys Ala Gly Ser Ala Ala Ala Val

245 250 255

Leu Glu Glu Asn Leu Tyr Phe Gln Gly Thr Tyr Lys Tyr Leu Gln Lys

260 265 270

Pro Met Tyr Glu Val Gln Trp Lys Val Val Glu Glu Ile Asn Gly Asn

275 280 285

Asn Tyr Val Tyr Ile Asp Pro Thr Gln Leu Pro Tyr Asp His Lys Trp

290 295 300

Glu Phe Pro Arg Asn Arg Leu Ser Phe Gly Lys Thr Leu Gly Ala Gly

305 310 315 320

Ala Phe Gly Lys Val Val Glu Ala Thr Ala Tyr Gly Leu Ile Lys Ser

325 330 335

Asp Ala Ala Met Thr Val Ala Val Lys Met Leu Lys Pro Ser Ala His

340 345 350

Leu Thr Glu Arg Glu Ala Leu Met Ser Glu Leu Lys Val Leu Ser Tyr

355 360 365

Leu Gly Asn His Met Asn Ile Val Asn Leu Leu Gly Ala Cys Thr Ile

370 375 380

Gly Gly Pro Thr Leu Val Ile Thr Glu Tyr Cys Cys Tyr Gly Asp Leu

385 390 395 400

Leu Asn Phe Leu Arg Arg Lys Arg Asp Ser Phe Ile Cys Ser Lys Gln

405 410 415

Glu Asp His Ala Glu Ala Ala Leu Tyr Lys Asn Leu Leu His Ser Lys

420 425 430

Glu Ser Ser Cys Ser Asp Ser Thr Asn Glu Tyr Met Asp Met Lys Pro

435 440 445

Gly Val Ser Tyr Val Val Pro Thr Lys Ala Asp Lys Arg Arg Ser Val

450 455 460

Arg Ile Gly Ser Tyr Ile Glu Arg Asp Val Thr Pro Ala Ile Met Glu

465 470 475 480

Asp Asp Glu Leu Ala Leu Asp Leu Glu Asp Leu Leu Ser Phe Ser Tyr

485 490 495

Gln Val Ala Lys Gly Met Ala Phe Leu Ala Ser Lys Asn Cys Ile His

500 505 510

Arg Asp Leu Ala Ala Arg Asn Ile Leu Leu Thr His Gly Arg Ile Thr

515 520 525

Lys Ile Cys Asp Phe Gly Leu Ala Arg Val Ile Lys Asn Asp Ser Asn

530 535 540

Tyr Val Val Lys Gly Asn Ala Arg Leu Pro Val Lys Trp Met Ala Pro

545 550 555 560

Glu Ser Ile Phe Asn Cys Val Tyr Thr Phe Glu Ser Asp Val Trp Ser

565 570 575

Tyr Gly Ile Phe Leu Trp Glu Leu Phe Ser Leu Gly Ser Ser Pro Tyr

580 585 590

Pro Gly Met Pro Val Asp Ser Lys Phe Tyr Lys Met Ile Lys Glu Gly

595 600 605

Phe Arg Met Leu Ser Pro Glu His Ala Pro Ala Glu Met Tyr Asp Ile

610 615 620

Met Lys Thr Cys Trp Asp Ala Asp Pro Leu Lys Arg Pro Thr Phe Lys

625 630 635 640

Gln Ile Val Gln Leu Ile Glu Lys Gln Ile Ser Glu Ser Thr Asn His

645 650 655

Ile Tyr Ser Asn Leu Ala Asn Cys Ser Pro Asn Arg Gln Lys Pro Val

660 665 670

Val Asp His Ser Val Arg Ile Asn Ser Val Gly Ser Thr Ala Ser Ser

675 680 685

Ser Gln Pro Leu Leu Val His Asp Asp Val

690 695

<210> 5

<211> 696

<212>PRT

<213> Artificial sequence

<220>

<223> cKIT-VVDV

<400> 5

Met Glu His His His His His His His Glu Tyr Met Pro Met Glu

1 5 10 15

Met Ala Pro Ile Leu Gly Tyr Trp Lys Ile Lys Gly Leu Val Gln Pro

20 25 30

Thr Arg Leu Leu Leu Glu Tyr Leu Glu Glu Lys Tyr Glu Glu His Leu

35 40 45

Tyr Glu Arg Asp Glu Gly Asp Lys Trp Arg Asn Lys Lys Phe Glu Leu

50 55 60

Gly Leu Glu Phe Pro Asn Leu Pro Tyr Tyr Ile Asp Gly Asp Val Lys

65 70 75 80

Leu Thr Gln Ser Met Ala Ile Ile Arg Tyr Ile Ala Asp Lys His Asn

85 90 95

Met Leu Gly Gly Cys Pro Lys Glu Arg Ala Glu Ile Ser Met Leu Glu

100 105 110

Gly Ala Val Leu Asp Ile Arg Tyr Gly Val Ser Arg Ile Ala Tyr Ser

115 120 125

Lys Asp Phe Glu Thr Leu Lys Val Asp Phe Leu Ser Lys Leu Pro Glu

130 135 140

Met Leu Lys Met Phe Glu Asp Arg Leu Cys His Lys Thr Tyr Leu Asn

145 150 155 160

Gly Asp His Val Thr His Pro Asp Phe Met Leu Tyr Asp Ala Leu Asp

165 170 175

Val Val Leu Tyr Met Asp Pro Met Cys Leu Asp Ala Phe Pro Lys Leu

180 185 190

Val Cys Phe Lys Lys Arg Ile Glu Ala Ile Pro Gln Ile Asp Lys Tyr

195 200 205

Leu Lys Ser Ser Lys Tyr Ile Ala Trp Pro Leu Gln Gly Trp Gln Ala

210 215 220

Thr Phe Gly Gly Gly Asp His Pro Pro Lys Ser Asp Leu Val Pro Arg

225 230 235 240

His Asn Gln Thr Ser Leu Tyr Lys Lys Ala Gly Ser Ala Ala Ala Val

245 250 255

Leu Glu Glu Asn Leu Tyr Phe Gln Gly Thr Tyr Lys Tyr Leu Gln Lys

260 265 270

Pro Met Tyr Glu Val Gln Trp Lys Glu Glu Ile Asn Gly Asn Asn Tyr

275 280 285

Val Tyr Ile Asp Pro Thr Gln Leu Pro Tyr Asp His Lys Trp Glu Phe

290 295 300

Pro Arg Asn Arg Leu Ser Phe Gly Lys Thr Leu Gly Ala Gly Ala Phe

305 310 315 320

Gly Lys Val Val Glu Ala Thr Ala Tyr Gly Leu Ile Lys Ser Asp Ala

325 330 335

Ala Met Thr Val Ala Val Lys Met Leu Lys Pro Ser Ala His Leu Thr

340 345 350

Glu Arg Glu Ala Leu Met Ser Glu Leu Lys Val Leu Ser Tyr Leu Gly

355 360 365

Asn His Met Asn Ile Val Asn Leu Leu Gly Ala Cys Thr Ile Gly Gly

370 375 380

Pro Thr Leu Val Ile Thr Glu Tyr Cys Cys Tyr Gly Asp Leu Leu Asn

385 390 395 400

Phe Leu Arg Arg Lys Arg Asp Ser Phe Ile Cys Ser Lys Gln Glu Asp

405 410 415

His Ala Glu Ala Ala Leu Tyr Lys Asn Leu Leu His Ser Lys Glu Ser

420 425 430

Ser Cys Ser Asp Ser Thr Asn Glu Tyr Met Asp Met Lys Pro Gly Val

435 440 445

Ser Tyr Val Val Pro Thr Lys Ala Asp Lys Arg Arg Ser Val Arg Ile

450 455 460

Gly Ser Tyr Ile Glu Arg Asp Val Thr Pro Ala Ile Met Glu Asp Asp

465 470 475 480

Glu Leu Ala Leu Asp Leu Glu Asp Leu Leu Ser Phe Ser Tyr Gln Val

485 490 495

Ala Lys Gly Met Ala Phe Leu Ala Ser Lys Asn Cys Ile His Arg Asp

500 505 510

Leu Ala Ala Arg Asn Ile Leu Leu Thr His Gly Arg Ile Thr Lys Ile

515 520 525

Cys Asp Phe Gly Leu Ala Arg Val Ile Lys Asn Asp Ser Asn Tyr Val

530 535 540

Val Lys Gly Asn Ala Arg Leu Pro Val Lys Trp Met Ala Pro Glu Ser

545 550 555 560

Ile Phe Asn Cys Val Tyr Thr Phe Glu Ser Asp Val Trp Ser Tyr Gly

565 570 575

Ile Phe Leu Trp Glu Leu Phe Ser Leu Gly Ser Ser Pro Tyr Pro Gly

580 585 590

Met Pro Val Asp Ser Lys Phe Tyr Lys Met Ile Lys Glu Gly Phe Arg

595 600 605

Met Leu Ser Pro Glu His Ala Pro Ala Glu Met Tyr Asp Ile Met Lys

610 615 620

Thr Cys Trp Asp Ala Asp Pro Leu Lys Arg Pro Thr Phe Lys Gln Ile

625 630 635 640

Val Gln Leu Ile Glu Lys Gln Ile Ser Glu Ser Thr Asn His Ile Tyr

645 650 655

Ser Asn Leu Ala Asn Cys Ser Pro Asn Arg Gln Lys Pro Val Val Asp

660 665 670

His Ser Val Arg Ile Asn Ser Val Gly Ser Thr Ala Ser Ser Ser Gln

675 680 685

Pro Leu Leu Val His Asp Asp Val

690 695

<210> 6

<211> 469

<212>PRT

<213> Artificial sequence

<220>

<223> cKIT-T670I

<400> 6

Met Ser Tyr Tyr His His His His His Asp Tyr Asp Ile Pro Thr

1 5 10 15

Thr Glu Asn Leu Tyr Phe Gln Gly Ala Met Leu Val Pro Arg Gly Ser

20 25 30

Pro Trp Gly Ser Thr Tyr Lys Tyr Leu Gln Lys Pro Met Tyr Glu Val

35 40 45

Gln Trp Lys Val Val Glu Glu Ile Asn Gly Asn Asn Tyr Val Tyr Ile

50 55 60

Asp Pro Thr Gln Leu Pro Tyr Asp His Lys Trp Glu Phe Pro Arg Asn

65 70 75 80

Arg Leu Ser Phe Gly Lys Thr Leu Gly Ala Gly Ala Phe Gly Lys Val

85 90 95

Val Glu Ala Thr Ala Tyr Gly Leu Ile Lys Ser Asp Ala Ala Met Thr

100 105 110

Val Ala Val Lys Met Leu Lys Pro Ser Ala His Leu Thr Glu Arg Glu

115 120 125

Ala Leu Met Ser Glu Leu Lys Val Leu Ser Tyr Leu Gly Asn His Met

130 135 140

Asn Ile Val Asn Leu Leu Gly Ala Cys Thr Ile Gly Gly Pro Thr Leu

145 150 155 160

Val Ile Ile Glu Tyr Cys Cys Tyr Gly Asp Leu Leu Asn Phe Leu Arg

165 170 175

Arg Lys Arg Asp Ser Phe Ile Cys Ser Lys Gln Glu Asp His Ala Glu

180 185 190

Ala Ala Leu Tyr Lys Asn Leu Leu His Ser Lys Glu Ser Ser Cys Ser

195 200 205

Asp Ser Thr Asn Glu Tyr Met Asp Met Lys Pro Gly Val Ser Tyr Val

210 215 220

Val Pro Thr Lys Ala Asp Lys Arg Arg Ser Val Arg Ile Gly Ser Tyr

225 230 235 240

Ile Glu Arg Asp Val Thr Pro Ala Ile Met Glu Asp Asp Glu Leu Ala

245 250 255

Leu Asp Leu Glu Asp Leu Leu Ser Phe Ser Tyr Gln Val Ala Lys Gly

260 265 270

Met Ala Phe Leu Ala Ser Lys Asn Cys Ile His Arg Asp Leu Ala Ala

275 280 285

Arg Asn Ile Leu Leu Thr His Gly Arg Ile Thr Lys Ile Cys Asp Phe

290 295 300

Gly Leu Ala Arg Asp Ile Lys Asn Asp Ser Asn Tyr Val Val Lys Gly

305 310 315 320

Asn Ala Arg Leu Pro Val Lys Trp Met Ala Pro Glu Ser Ile Phe Asn

325 330 335

Cys Val Tyr Thr Phe Glu Ser Asp Val Trp Ser Tyr Gly Ile Phe Leu

340 345 350

Trp Glu Leu Phe Ser Leu Gly Ser Ser Pro Tyr Pro Gly Met Pro Val

355 360 365

Asp Ser Lys Phe Tyr Lys Met Ile Lys Glu Gly Phe Arg Met Leu Ser

370 375 380

Pro Glu His Ala Pro Ala Glu Met Tyr Asp Ile Met Lys Thr Cys Trp

385 390 395 400

Asp Ala Asp Pro Leu Lys Arg Pro Thr Phe Lys Gln Ile Val Gln Leu

405 410 415

Ile Glu Lys Gln Ile Ser Glu Ser Thr Asn His Ile Tyr Ser Asn Leu

420 425 430

Ala Asn Cys Ser Pro Asn Arg Gln Lys Pro Val Val Asp His Ser Val

435 440 445

Arg Ile Asn Ser Val Gly Ser Thr Ala Ser Ser Ser Gln Pro Leu Leu

450 455 460

Val His Asp Asp Val

465

<---

Claims (12)

1. A method of treating a disease caused by the kinase activity of c-KIT, its oncogenic forms or polymorphs, where the disease is gastrointestinal stromal tumors, comprising administering a therapeutically effective amount of a compound selected from the group consisting of 1-(5-(1 -ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoro-4-methylphenyl)-3-(naphthalene-1-yl)urea, 1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-(naphthalene-1-yl )urea, 1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3 -phenylurea, 1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3 -(2,3-difluorophenyl)urea, 1-(2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl) phenyl)-3-phenylurea, 1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2- fluorophenyl)-3-(naphthalene-1-yl)urea, 1-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydro-1, 6-naphthyridin-3-yl)phenyl)-3-phenylurea, 1-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydro-1 ,6-naphthyridin-3-yl)phenyl)-3-(naphthalene-1-yl)urea, 1-(4-chloro-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo -1,2-dihydro-1,6-naphthyridin-3-yl)phenyl)-3-(3-cyanophenyl)urea, 1-(4-chloro-2-fluoro-5-(1-methyl-7-( methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)phenyl)-3-(2,3-difluorophenyl)urea, 1-(4-chloro-3-(1-methyl -7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)phenyl)-3-(3-cyanophenyl)urea, 1-(3-cyanophenyl)-3-( 5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)urea, 1-(benzo[b]thiophene-3 -yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)phenyl) urea, 1-(benzo[b]thiophen-3-yl)-3-(2,4-difluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydro-1, 6-naphthyridin-3-yl)phenyl)urea, 1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2 ,4-difluorophenyl)-3-(3-fluorophenyl)urea, 1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl )-2,4-difluorophenyl)-3-phenylurea, 1-(3-chlorophenyl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6 -naphthyridin-3-yl)-2,4-difluorophenyl)urea, 1-(3-cyanophenyl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro- 1,6-naphthyridin-3-yl)-2,4-difluorophenyl)urea, 1-(benzo[b]thiophen-3-yl)-3-(5-(1-ethyl-7-(methylamino)-2 -oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2,4-difluorophenyl)urea, 1-(5-(7-amino-1-ethyl-2-oxo-1,2- dihydro-1,6-naphthyridin-3-yl)-4-chloro-2-fluorophenyl)-3-(3-fluorophenyl)urea, 1-(5-(7-amino-1-ethyl-2-oxo-1 ,2-dihydro-1,6-naphthyridin-3-yl)-4-chloro-2-fluorophenyl)-3-phenylurea, 1-(4-chloro-2-fluoro-5-(1-isopropyl-7-( methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)phenyl)-3-phenylurea, 1-(5-(1-ethyl-7-(methylamino)-2-oxo- 1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoro-4-methylphenyl)-3-phenylurea, 1-[4-chloro-5-(1-ethyl-7-methylamino-2- oxo-1,2-dihydro[1,6]naphthyridin-3-yl)-2-fluorophenyl]-3-(3-fluorophenyl)urea, 1-[4-chloro-5-(1-ethyl-7-methylamino) -2-oxo-1,2-dihydro[1,6]naphthyridin-3-yl)-2-fluorophenyl]-3-(2-fluorophenyl)urea, 1-(4-chloro-3-(1-ethyl- 7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea, 1-(4-chloro-5-(1-ethyl- 7-(2-methoxyethylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea, 1-(4-chloro-5-(1- ethyl-7-(2-methoxyethylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-(3-fluorophenyl)urea, 1-(4- chloro-5-(7-(2-(dimethylamino)ethylamino)-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea, 1-(4-chloro-5-(7-(3-(dimethylamino)propylamino)-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl) -3-phenylurea, 1-(4-bromo-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl) -3-phenylurea, 1-(benzo[b]thiophen-3-yl)-3-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2,4a,8a -tetrahydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)urea, 1-(4-chloro-3-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro- 1,6-naphthyridin-3-yl)phenyl)-3-phenylurea, 1-(4-chloro-5-(1-ethyl-7-(2-methoxyethylamino)-2-oxo-1,2-dihydro-1 ,6-naphthyridin-3-yl)-2-fluorophenyl)-3-(4-fluorophenyl)urea, 1-(4-chloro-5-(1-ethyl-7-(2-methoxyethylamino)-2-oxo- 1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-(2-fluorophenyl)urea, 1-(5-(1-ethyl-7-(2-methoxyethylamino)-2 -oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2,4-difluorophenyl)-3-phenylurea, 1-(5-(1-ethyl-7-(2-methoxyethylamino)-2 -oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoro-4-methylphenyl)-3-phenylurea, 1-(5-(1-ethyl-7-(methylamino)-2 -oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoro-4-methylphenyl)-3-(2-fluorophenyl)urea, 1-(4-chloro-5-(1- ethyl 7-(3-methoxypropylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea, 1-(2,4-difluoro-5 -(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)phenyl)-3-(3-fluorophenyl)urea, 1-(2-fluoro -5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-4-methylphenyl)-3-(3-fluorophenyl)urea, 1 -(4-chloro-5-(1-ethyl-2-oxo-7-(tetrahydro-2H-pyran-4-ylamino)-1,2-dihydro-1,6-naphthyridin-3-yl)-2- fluorophenyl)-3-phenylurea, (S)-1-(4-chloro-5-(1-ethyl-7-(1-methoxypropan-2-ylamino)-2-oxo-1,2-dihydro-1,6 -naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea, 1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridine-3 -yl)-2-fluoro-4-methylphenyl)-3-(3-fluorophenyl)urea, 1-(5-(7-(cyclopropylamino)-1-ethyl-2-oxo-1,2-dihydro-1, 6-naphthyridin-3-yl)-2-fluoro-4-methylphenyl)-3-(3-fluorophenyl)urea, 1-(4-chloro-5-(1-ethyl-7-(1-methylpiperidin-4- ylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea, 1-(4-chloro-5-(1-ethyl-2-oxo -7-(THF-3-ylamino)-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea, 1-(4-chloro-5-(1-ethyl -7-(2-(methylsulfonyl)ethylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea, 1-(4-chloro-5 -(1-ethyl-7-(1-methylpyrrolidin-3-ylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea, 1- (4-bromo-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-(3-fluorophenyl )urea, 1-(4-bromo-5-(1-ethyl-7-(2-methoxyethylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl) -3-phenylurea, 1-(4-bromo-5-(1-ethyl-7-(2-(methylsulfonyl)ethylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl) -2-fluorophenyl)-3-phenylurea, 1-(5-(7-acetamido-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-4-bromo-2 -fluorophenyl)-3-phenylurea, 1-(5-(7-acetamido-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-4-chloro-2-fluorophenyl )-3-phenylurea, 1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl )-3-(3,5-difluorophenyl)urea, 1-(4-bromo-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6 -naphthyridin-3-yl)phenyl)-3-phenylurea, 1-(5-(7-amino-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-4 -bromo-2-fluorophenyl)-3-phenylurea, 1-(5-(7-amino-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoro -4-methylphenyl)-3-(3-fluorophenyl)urea, 1-(benzo[b]thiophen-3-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1 ,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoro-4-methylphenyl)urea, 1-(3,5-difluorophenyl)-3-(5-(1-ethyl-7-(methylamino )-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoro-4-methylphenyl)urea, 1-(2,5-difluorophenyl)-3-(5-(1 -ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoro-4-methylphenyl)urea, 1-(2,5-difluorophenyl)- 3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2,4a,8a-tetrahydro-1,6-naphthyridin-3-yl)-2,4-difluorophenyl)urea, 1 -(3,5-difluorophenyl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2,4a,8a-tetrahydro-1,6-naphthyridin-3-yl)- 2,4-difluorophenyl)urea, N-(3-(2-bromo-4-fluoro-5-(3-phenylureido)phenyl)-1-ethyl-2-oxo-1,2-dihydro-1,6- naphthyridin-7-yl)-2-cyanoacetamide, N-(3-(2-chloro-4-fluoro-5-(3-phenylureido)phenyl)-1-ethyl-2-oxo-1,2-dihydro-1 ,6-naphthyridin-7-yl)-2-cyanoacetamide, 1-(5-(7-acetamido-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2 ,4-difluorophenyl)-3-phenylurea, N-(3-(2-chloro-5-(3-(3,5-difluorophenyl)ureido)-4-fluorophenyl)-1-ethyl-2-oxo-1, 2-dihydro-1,6-naphthyridin-7-yl)acetamide, 1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6- naphthyridin-3-yl)-2-fluorophenyl)-3-(2,5-difluorophenyl)urea, 1-(3-chloro-5-fluorophenyl)-3-(5-(1-ethyl-7-(methylamino) -2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoro-4-methylphenyl)urea, 3-(3-(2-chloro-4-fluoro-5-(3 -phenylureido)phenyl)-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)-1,1-dimethylurea, 1-(4-chloro-5-(1-ethyl -7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-(3-chloro-5-fluorophenyl)urea, 1-(4 -chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-(3-fluoro-5 -methylphenyl)urea, methyl ester (3-(2-chloro-4-fluoro-5-(3-phenylureido)phenyl)-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridine-7 -yl)carbamic acid, N-(3-(2-chloro-4-fluoro-5-(3-phenylureido)phenyl)-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridine- 7-yl)-2-methoxyacetamide, 2-cyano-N-(3-(2,4-difluoro-5-(3-phenylureido)phenyl)-1-ethyl-2-oxo-1,2-dihydro-1 ,6-naphthyridin-7-yl)acetamide, 1-(4-cyano-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl )-2-fluorophenyl)-3-phenylurea, 1-(4-chloro-2-fluoro-5-(1-isopropyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridine -3-yl)phenyl)-3-(3-fluorophenyl)urea, N-(1-ethyl-3-(4-fluoro-5-(3-(3-fluorophenyl)ureido)-2-methylphenyl)-2 -oxo-1,2-dihydro-1,6-naphthyridin-7-yl)acetamide, 1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro -1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-(3-((4-methylpiperazin-1-yl)methyl)phenyl)urea, N-(1-ethyl-3-(4- fluoro-2-methyl-5-(3-phenylureido)phenyl)-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)acetamide, N-(3-(2-chloro-4- fluoro-5-(3-phenylureido)phenyl)-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)-3-hydroxyazetidin-1-carboxamide, 1-(5- (1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoro-4-methylphenyl)-3-(3-((4- methylpiperazin-1-yl)methyl)phenyl)urea, 1-(4-bromo-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridine-3- yl)-2-fluorophenyl)-3-(3-((4-methylpiperazin-1-yl)methyl)phenyl)urea, (R)-N-(3-(2-chloro-4-fluoro-5-( 3-phenylureido)phenyl)-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)-3-(dimethylamino)pyrrolidine-1-carboxamide, (S)-N-( 3-(2-chloro-4-fluoro-5-(3-phenylureido)phenyl)-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)pyrrolidin-2-carboxamide , N-(3-(2-chloro-4-fluoro-5-(3-phenylureido)phenyl)-1-isopropyl-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)acetamide , 1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-( 4-fluoro-3-((4-methylpiperazin-1-yl)methyl)phenyl)urea, 1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2- dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-(3-fluoro-5-((4-methylpiperazin-1-yl)methyl)phenyl)urea, 1-(5-(1 -ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoro-4-methylphenyl)-3-(4-fluoro-3-(( 4-methylpiperazin-1-yl)methyl)phenyl)urea, 1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl) -2,4-difluorophenyl)-3-(4-fluoro-3-((4-methylpiperazin-1-yl)methyl)phenyl)urea, 1-(4-chloro-5-(1-ethyl-7-( methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-(3-cyanophenyl)urea, 1-(4-chloro-5-(1- ethyl 7-((3-morpholinopropyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea, 1-(5-(7 -amino-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoro-4-methylphenyl)-3-(4-fluoro-3-((4- methylpiperazin-1-yl)methyl)phenyl)urea, 1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridine-3- yl)-2-fluorophenyl)-3-(3-((dimethylamino)methyl)-4-fluorophenyl)urea, 1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo- 1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-(4-fluoro-3-(morpholinomethyl)phenyl)urea, (S)-N-(3-(2- chloro-4-fluoro-5-(3-phenylureido)phenyl)-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)-3-(dimethylamino)pyrrolidin-1- carboxamide, 1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3- (4-fluoro-3-(pyrrolidin-1-ylmethyl)phenyl)urea, 3-(3-(2-chloro-4-fluoro-5-(3-(3-fluorophenyl)ureido)phenyl)-1-isopropyl -2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)-1,1-dimethylurea, N-(3-(2-chloro-4-fluoro-5-(3-(3- fluorophenyl)ureido)phenyl)-1-isopropyl-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)acetamide, N-(1-ethyl-3-(4-fluoro-5-( 3-(4-fluoro-3-((4-methylpiperazin-1-yl)methyl)phenyl)ureido)-2-methylphenyl)-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl )formamide, 3-(1-ethyl-3-(4-fluoro-2-methyl-5-(3-phenylureido)phenyl)-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl )-1,1-dimethylurea, N-(3-(2-chloro-4-fluoro-5-(3-phenylureido)phenyl)-1-ethyl-2-oxo-1,2-dihydro-1,6- naphthyridin-7-yl)-3-(dimethylamino)azetidine-1-carboxamide, 3-(3-(2-chloro-4-fluoro-5-(3-phenylureido)phenyl)-1-isopropyl-2-oxo- 1,2-dihydro-1,6-naphthyridin-7-yl)-1,1-dimethylurea, 3-(3-(5-(3-(benzo[b]thiophen-3-yl)ureido)-4- fluoro-2-methylphenyl)-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)-1,1-dimethylurea, 3-(3-(2-bromo-4- fluoro-5-(3-phenylureido)phenyl)-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)-1,1-dimethylurea, 3-(1-ethyl- 3-(4-fluoro-5-(3-(3-fluorophenyl)ureido)-2-methylphenyl)-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)-1,1- dimethylurea, N-(3-(2-chloro-4-fluoro-5-(3-(4-fluoro-3-(morpholinomethyl)phenyl)ureido)phenyl)-1-ethyl-2-oxo-1,2- dihydro-1,6-naphthyridin-7-yl)formamide, 3-(3-(5-(3-(3,5-difluorophenyl)ureido)-4-fluoro-2-methylphenyl)-1-ethyl-2- oxo-1,2-dihydro-1,6-naphthyridin-7-yl)-1,1-dimethylurea, N-(3-(4-fluoro-2-methyl-5-(3-phenylureido)phenyl)-1 -isopropyl-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)azetidin-1-carboxamide, N-(1-ethyl-3-(4-fluoro-2-methyl-5-( 3-phenylureido)phenyl)-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)azetidin-1-carboxamide, 1-(5-(1-ethyl-7-((6-methylpyridine -3-yl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoro-4-methylphenyl)-3-phenylurea, 3-(3-(2, 4-difluoro-5-(3-phenylureido)phenyl)-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)-1,1-dimethylurea, 3-(dimethylamino) -N-(1-ethyl-3-(4-fluoro-2-methyl-5-(3-phenylureido)phenyl)-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)azetidine -1-carboxamide, 1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoro-4-iodophenyl) -3-phenylurea and 1-(5-(1-ethyl-7-((1-methyl-1H-pyrazol-4-yl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridine- 3-yl)-2-fluoro-4-methylphenyl)-3-urea. 2. The method according to claim 1, characterized in that the kinase activity of c-KIT, its oncogenic forms or polymorphs, wherein c-KIT contains a missense mutation, insertion mutation or deletion mutation encoded by exons, including exon 9, exon 11, exon 13, exon 14, exon 17 or exon 18, present alone or in combination. 3. The method according to claim 1, characterized in that the compound is selected from the group consisting of 1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridine -3-yl)-2-fluoro-4-methylphenyl)-3-(naphthalene-1-yl)urea, 1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo- 1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea, 1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo- 1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-(2,3-difluorophenyl)urea, 1-(5-(1-ethyl-7-(methylamino)-2 -oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2,4-difluorophenyl)-3-phenylurea, 1-(benzo[b]thiophen-3-yl)-3-(5- (1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2,4-difluorophenyl)urea, 1-(5-(7-amino- 1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-4-chloro-2-fluorophenyl)-3-(3-fluorophenyl)urea, 1-(5-(7 -amino-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-4-chloro-2-fluorophenyl)-3-phenylurea, 1-(5-(1-ethyl -7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoro-4-methylphenyl)-3-phenylurea, 1-[4-chloro-5- (1-ethyl-7-methylamino-2-oxo-1,2-dihydro-[1,6]naphthyridin-3-yl)-2-fluorophenyl]-3-(3-fluorophenyl)urea, 1-(4- bromo-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea, 1-(benzo[ b]thiophen-3-yl)-3-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2,4a,8a-tetrahydro-1,6-naphthyridine-3 -yl)-2-fluorophenyl)urea, 1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoro -4-methylphenyl)-3-(3-fluorophenyl)urea, 1-(5-(7-amino-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)- 4-bromo-2-fluorophenyl)-3-phenylurea, 1-(benzo[b]thiophen-3-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2 -dihydro-1,6-naphthyridin-3-yl)-2-fluoro-4-methylphenyl)urea, 3-(3-(2-chloro-4-fluoro-5-(3-phenylureido)phenyl)-1- ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)-1,1-dimethylurea, N-(1-ethyl-3-(4-fluoro-5-(3-(3 -fluorophenyl)ureido)-2-methylphenyl)-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)acetamide, N-(1-ethyl-3-(4-fluoro-2-methyl) -5-(3-phenylureido)phenyl)-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)acetamide and 3-(1-ethyl-3-(4-fluoro-2-methyl) -5-(3-phenylureido)phenyl)-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)-1,1-dimethylurea. 4. The method according to claim 3, characterized in that the compound is 1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl )-2-fluoro-4-methylphenyl)-3-(naphthalene-1-yl)urea. 5. The method according to claim 3, characterized in that the compound is 1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridine -3-yl)-2-fluorophenyl)-3-(2,3-difluorophenyl)urea. 6. The method according to claim 3, characterized in that the compound is 1-(4-bromo-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridine -3-yl)-2-fluorophenyl)-3-phenylurea. 7. The method according to claim 3, characterized in that the compound is 1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl )-2-fluoro-4-methylphenyl)-3-phenylurea. 8. The method according to claim 3, characterized in that the compound is 1-(benzo[b]thiophen-3-yl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1 ,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoro-4-methylphenyl)urea. 9. The method according to claim 3, characterized in that the compound is 1-[4-chloro-5-(1-ethyl-7-methylamino-2-oxo-1,2-dihydro-[1,6]naphthyridine- 3-yl)-2-fluorophenyl]-3-(3-fluorophenyl)urea. 10. The method according to claim 3, characterized in that the compound is 1-(5-(7-amino-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)- 4-bromo-2-fluorophenyl)-3-phenylurea. 11. The method according to claim 3, characterized in that the compound is 1-(5-(7-amino-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)- 4-chloro-2-fluorophenyl)-3-phenylurea. 12. The method according to claim 3, characterized in that the compound is 1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridine -3-yl)-2-fluorophenyl)-3-phenylurea.