Title of Invention

KINASE INHIBITIRS USEFUL FOR THE TREATMENT OF PROLIFERATIVE DISEASES

Abstract The present invention relates to novel kinase inhibitors and modulator compounds useful for the treatment of various diseases. More particularly, the invention is concerned with such compounds, kinase/compound adducts, methods of treating diseases, and methods of synthesis of the compounds. Preferrably, the compounds are useful for the modulation of kinase activity of Raf kinases and disease polymorphs thereof. Compounds of the present invention find utility in the treatment of mammalian cancers and especially human cancers including but not limited to malignant melanoma, colorectal cancer, ovarian cancer, papillary thyroid carcinoma, non small cell lung cancer, and mesothelioma. Compounds of the present invention also find utility in the treatment of rheumatoid arthritis and retinopathies including diabetic retinal neuropathy and macular degeneration.
Full Text FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES, 2003
COMPLETE SPECIFICATION
(See section 10, rule 13)
"KINASE INHIBITORS USEFUL FOR THE TREATMENT OF PROLIFERATIVE DISEASES"

DECIPHERA PHARMACEUTICALS LLC, a Limited Liability Company, having a principal place of business at 4950 Research Park Way, City of Lawrence. State of Kansas 66047, United States of America.
The following specification particularly describes the invention and the manner in which it is to be performed.


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KINASE INHIBITORS USEFUL FOR THE TREATMENT OF PROLIFERATIVE
DISEASES
Cross-Reference to Related Applications
This application claims the benefit of Provisional Application 60/844552 filed September 14,
2006. This application is incorporated by reference herein.
Field of the Invention
The present invention relates to novel kinase inhibitors and modulator compounds useful for the treatment of various diseases. More particularly, the invention is concerned with such compounds, kinase/compound adducts, methods of treating diseases, and methods of syntliesis of the compounds. Preferrably, the compounds are useful for the modulation of kinase activity of Raf kinases and disease polymorphs thereof.
Background of the invention
Several members of the protein kinase family have been clearly implicated in the patliogenesis of various proliferative diseases and thus represent important targets for treatment of these diseases. Some of the proliferative diseases relevant to this invention include cancer, rheumatoid arthritis, atherosclerosis, and retinopathies. Important examples of kinases which have been shown to cause or contribute to the pathogensis of these diseases including, but not limited to. BRaf, CRaf, Abl, KDR(VEGF), EGFR/HER1, HER2, HER3, cMET, FLT-3, PDGFR-a, PDGFR-b, p38, cKIT, JAK2.
A major signaling pathway downstream of cell surface growth factor receptor activation is the Ras-RAF-MEK-ERK-MAP kinase pathway (Peyssonnaux, C. et al, Biol. Cell (2001) 93: 53-62, Cancers arise when mutations occur in one or more of the proteins involved in this signaling cascade. Cell proliferation and differentiation become dysregulated and cell survival mechanisms are activated which allow unregulated cancer cells to override protective programmed cell death surveillance. Mutations in die p21-Ras protein have been shown to be a major cause of dysregulation of this signaling pathway, leading to the development of human cancers. P21-Ras mutations have been identified in approximately 30% of human cancers (Bolton et al, Ann. Rep. Med. Cfiem. (1994) 29: 165-174). Cancer-causing mutations in the P21-

Ras fStein lead to a constituitively active signaling cascade, causing unregulated activation of the downstream components of the RAF-MEK-ERJC-MAP kinase pathway (Magnuson el al, Semin.Cancer Biol. (1994) 5: 247-253). The three RAF kinases which participate in this signaling cascade are known as ARAF, BRAF, and CRAF (Peyssonnaux, C. et al, Biol Cell (2001) 93: 53-62; Avruch, J., Recent Prog. Norm. Res. (2001) 56: 127-155; Kolch, W., Biochem. J. (2000) 351: 289-305). These RAF kinase isoforms are all activated by Ras, and thus arc activated in cancers that result from mutated and upregulated p21-Ras protein activity. In addition to activation of this signaling cascade at the initial p2l-Ras protein level, mutations have also been found in BRAF kinase which results in activation of the cascade downstream from p21-Ras (Davies, H., et al, Nature (2002) 417: 949-954). A dominant single site mutation at position 600 in the BRAF kinase was shown to be particularly aggressive and linked to approximately 80% of the observed human malignant melanomas. This mutation substitutes the negatively charged amino acid glutamic acid for the normally occurring neutral amino acid valine. This single site mutation is sufficient to render the mutated BRAF kinase constituitively active, resulting in signaling pathway dysregulation and human cancer. Hence small molecule inhibitors of BRAF kinase are a rational approach to the treatment of human malignancy, whether the signaling mutation is at the level of the upstream p21-Ras protein or at the level of BRAF kinase.
The majority of small molecule kinase inhibitors that have been reported have been shown to bind in one of three ways. Most of the reported inhibitors interact with the ATP binding domain of the active site and exert their effects by competing with ATP for occupancy. Other inhibitors have been shown to bind to a separate hydrophobic region of the protein known as the "DFG-in-conformation" pocket, and still others have been shown to bind to both the ATP domain and the "DFG-in-conformation" pocket. Examples specific to inhibitors of RAF kinases can be found in Lowinger et al, Current Pharmaceutical Design (2002) 8: 2269-2278; Dumas, J. et al, Current Opinion in Drug Discovery & Development (2004) 7: 600-616; Dumas, J. et al WO 2003068223 Al (2003); Dumas, J., et al, WO 9932455 Al (1999), and Wan, P.T.C., et al, Ce//(2004) 116:855-867.
Physiologically, kinases are regulated by a common activation/deactivation mechanism wherein a specific activation loop sequence of the kinase protein binds into a specific pocket on the same protein which is referred to as the switch control pocket (Flynn, D. et at WO 2004 / 061084 for


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further details). Such binding occurs when specific amino acid residues of the activation loop are modified for example by phosphorylation, oxidation, or nitrosylation. The binding of the activation loop into the switch pocket results in a conformational change of the protein into its rcSwe fovm H\KA, M. sad Kuriyan, I. Ceil (109} 27S-2&2.V
Summary of the Invention
Compounds of the present invention find utility in the treatment of mammalian cancers and especially human cancel's including but not limited to malignant melanoma, colorectal cancer, ovarian cancer, papillary thyroid carcinoma, lung cancers, kidney cancers, pancreatic cancer, glioblastomas, myeloproliferative diseases, and mesothelioma. Compounds of the present invention also find utility in the treatment of inflammatory diseases including rheumatoid arthritis, retinopathies including diabetic retinal neuropathy and macular degeneration, cardiovascular disease and metabolic diseases.

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Description of the Preferred Embodiments
The following descriptions refer to various compounds and moieties thereof.
Carbocyclyl refers to carbon rings taken from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptanyl, cyclooctanyl, norboranyl, norborenyl, bicyclo[2.2.2joctanyl, and bicyclo[2.2.2]octenyl;
Halogen refers to fluorine, chlorine, bromine and iodine;
Aryl refers to monocyclic or fused bicyclic ring systems characterized by delocalized TC electrons (aromaticity) shared among the ring carbon atoms of at least one carbocyclic ring; preferred aryl rings are taken from phenyl, naphthyl, tetrahydronaphthyl, indenyl, and indanyl;
Heteroaryl refers to monocyclic or fused bicyclic ring systems characterized by delocalized K
electrons (aromaticity) shared among (he ring carbon or heteroatoms including nitrogen, oxygen,
or sulfur of at least one carbocyclic or heterocyclic ring; heteroaryl rings are taken from, but not
limited to, pyrrolyl. furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, imidazolyl.
pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl,
pyridazinyl, triazinyl, indolyl, indolinyl, isoindolyl, isoindolinyl, indazolyl, benzofuranyl,
benzothienyl, benzothiazoly!, benzothiazolonyl, benzoxazolyl, benzoxazolonyl, benzisoxazolyl,
benzisothiazolyl, benzimidazolyl, benzimidazolonyl, benztriazolyl, imidazopyridinyl,
pyrazolopyridinyl. imidazolonopyridinyl, thiazolopyridinyl, thiazolonopyridinyl,
oxazolopyridinyl, oxazolonopyridinyl, isoxazolopyridinyl, isothiazolopyridinyl,
triazolopyridinyl, imidazopyrimidinyl. pyrazolopyrimidinyl, imidazolonopyrimidinyl, tliiazolopyridiminyl, thiazolonopyrimidinyl, oxazolopyridiminyl, oxazolonopyrimidinyl, isoxazolopyrimidinyl, isothiazolopyrimidinyl, triazolopyrimidinyl, dihydropurinonyl, pyrrolopyrimidinyl, purinyl, pyrazolopyrimidinyl, phthalimidyl, phthalimidinyl, pyrazinylpyridinyl, pyridinopyrimidinyl, pyrimidinopyrimidinyl, cinnolinyl, quinoxalinyl, quinazolinyl, quinolinyl, isoquinolinyl, phthalazinyl, benzodioxyl, benzisothiazoline-1,1,3-

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trionyl, dihydroquinolinyi, tetrahydroquinolinyl, dihydroisoquinolyl, tetrahydroisoquinolinyl, benzoazepinyl, benzodiazepinyl, benzoxapinyl, or benzoxazepinyl;
Heterocyclyl refers to monocyclic rings containing carbon and heteroatoms taken from oxygen, nitrogen, or sulfur and wherein there is not delocalized TC elections (aromaticity) shared among the ring carbon or heteroatoms; heterocyclyl rings include, but are not limited to, oxetanyl, azetadinyl, tetrahydrofuranyl, pyrroiidinyl, oxazolinyl, oxazolidinyl, thiazolinyl, thiazolidinyl, pyranyl, thiopyranyl, tetrahydropyranyl, dioxalinyl, piperidlnyl, morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholmyl S-dioxide, piperazinyl, azepinyl, oxepinyl, diazepinyl, tropanyl, and homotropanyl;
Poly-aryl refers to two or more monocyclic or fused aryl bicyclic ring systems characterized by delocalized n electrons (aromaticity) shared among the ring carbon atoms of at least one carbocyclic ring wherein the rings contained therein are optionally linked together;
Poly-heteroaryl refers to two or more monocyclic or frised bicyclic systems characterized by delocalized % electrons (aromaticity) shared among the ring carbon or heteroatoms including nitrogen, oxygen, or sulfur of at least one carbocyclic or heterocyclic ring wherein the rings contained therein are optionally linked together, wherein at least one of the monocyclic or fused bicyclic rings of the poly-heteroaryl system is taken from heteroaryl as defined broadly above and the otlier rings are taken from either aryl, heteroaryl, or heterocyclyl as defined broadly above;
Poly-heterocyclyl refers to two or more monocyclic or fused bicyclic ring systems containing carbon and heteroatoms taken from oxygen, nitrogen, or sulfur and wherein there is not delocalized K electrons (aromaticity) shared among the ring carbon or heteroatoms wherein the rings contained therein are optionally linked, wherein at least one of the monocyclic or fused bicyclic rings of the poly-heteroaryl system is taken from heterocyclyl as defined broadly above and the other rings are taken from either aryl, heteroaryl, or heterocyclyl as defined broadly above;

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Lower alkyl refers to straight or branched chain C1-C6alkyls;
Substituted in connection with a moiety refers to the fact that a fisher substituent may be attached to the moiety to any acceptable location on the moiety.
The terra salts embraces pharmaceutically acceptable salts commonly used to form alkali metal salts of free acids and to form addition salts of free bases. The "ature of the salt is not critical, provided that it is pharmaceutically-acceptable. Suitable pnarmaceutically-acceptable acid addition salts may be prepared from an inorganic acid or from ari organic acid. Examples of such inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric acid. Appropriate organic acids may be selected from aliphatic, cycloalipharic, aromatic, arylaliphatic, and heterocyclyl containing carboxylic adids and sulfonic acids, examples of which are formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, stearic, salicylic, p-hydroxybenzoic, phenylacetic, maudelic, embonic (pamoic), methanesulfonic, ethanesulfonic, 2-hydroxyethanesulfonic benzenesulfonic, pantothenic, toluenesulfonic, 2-hydroxyethanesulfonic, sulfanilic, cyclohwlaminosulfonic algenic, 3-hydroxybutyric, galactaric and galacturonic acid. Suitable pharmaceutically-acceptable salts of free acid-containing compounds of the invention include metallic salts and organic salts. More preferred metallic salts include, but are not limited to appropriate alkali metal (group la) salts, alkaline earth metal (group TIa) salts and other physiological acceptable metals. Such salts can be made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc. Preferred organic salts can be made from primary amines, secondary amines, tertiary amines and quaternary ammonium salts, including in part, trometh^ine, diethyl amine, (etra-'N-methylammonium, N,N'-dibenzylcthylenediamine, chioroprocaine choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine.
The term prodrug refers to derivatives of active compounds which revert in vivo into the active form. For example, a carboxylic acid form of an active drug may be esterifled to create a prodrug, and the ester is subsequently converted in vivo to revert to the cafboxylic acid form. See Ettmayer

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et. al, J. Med Chem, 2004, 47(10), 2393-2404 and Lorenzi et. al, J. Pharm. Exp. Therpeutics, 2005,883-8900 for reviews.
1. First aspect of the invention — Compounds, Preparations and Methods
In the first aspect of the invention, compounds are of the formula la
wherein El is selected from the group consisting cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidiriyl piperidinyl, phenyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, pyrrolyl, pyi'azolyl, oxadiazolyl, thiadiazolyl, furyl, imidazolyl, pyridyl, pyrimidinyl and naphthyl;
wherein A is selected from the group consisting of phenyl, naphthyl, C3-C8carbocyclyl, indanyl, tetralinyl, indenyl, Gl, G2, G3, G4 and -CHR4R8;
Gl is a heteroaryl taken from tlie group consisting of pyrrolyl, furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyrazinyl, pyridazinyl, triazinyl, pyridinyl, and pyrimidinyl;
G2 is a fused bicyclic heteroaryl taken from the group consisting of indolyl, indolinyl, isoindolyl,
isoindolinyl, indazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzothiazolonyl,
benzoxazolyl, benzoxazolonyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyt
benzimidazolonyl, benztriazolyl, imidazopyridinyi, pyrazolopyridinyl, imidazolonopyridinyl,
thiazolopyridinyl, thiazolonopyridinyl, oxazolopyridinyl, oxazolonopyridinyl.
isoxazolopyridiny], isothiazolopyridinyl, triazolopyridinyl, imidazopyrimidinyl,
pyrazolopyi'imidinyl, imidazolonopyrimidinyl, thiazolopyridiminyl, thiazolonopyrimidinyl, oxazolopyridiminyl, oxazolonopyrimidinyl, isoxazolopyrimidinyl, isothiazolopyrimidinyi, triazolopyrimidinyl, dihydropurinonyl, pyrrolopyrimidinyl, purinyl, pyrazolopyi'imidinyl, phthalimidyl, phthaliinidinyl, pyrazinylpyridinyl, pyridinopyrimidinyi, pyrimidinopyrimidinyl, cinnolinyl, quinoxalinyl, quinazolinyl, quinolinyl, isoquinolinyl, phthalazinyl, benzodioxyl,

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benzisothiazoline-l,l,3-trionyl, dihydroquinolinyl, tetrahydroquinolinyl, dihydroisoquinolyl, tetrahydroisoquinolinyl, benzoazepinyl, benzodiazepinyl, benzoxapinyl, and benzoxazepinyl;
G3 is a non-fused bicyclic heteroaryl taken from the group consisting of pyridylpyridimmy]
pyrimidinylpyrimidinyl, oxazolylpyrimidinyl, thiazolylpyrimidinyl, imidazolylpyrimidinyl,
isoxozolylpyrimidinyl, isothiazolylpyrimidinyl, pyrazofylpyrirmdiny], triazolylpyrimidinyl,
oxadiazoylpyrimidinyl, thiadiazoylpyrimidinyl, morpholinylpyrimidinyl,
dioxothiomorpholinylpyrimidinyl, and thiomorpholinylpyrimidinyl;
G4 is a heterocyclyl taken from the group consisting of oxetanyl, azetadinyl, tetrahydrofuranyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, imidazolonyl, pyranyl, thiopyranyl, tetrahydropyranyl, dioxalinyl, piperidinyl, morpholinyl, tniomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S-dioxide, piperazinyl, azepinyl, oxepinyl, diazepinyl, tropanyl, and homotropanyl;
the A ring may be optionally substituted with one or more -XI -Al moieties:
XI is selected from the group consisting of -(CH2)n-(0)r-(CH2)n-, -(CH2)n-(NR3)r(CH2)n-, -(CH2)n-(S)r(CH2)n-, -(CH2)n-(O0)r(CH2)n-, -(CH2)„-(C(=0)-NR3)r-(CH2)n-, and -(CH2)n-(S02-NR3V(CH2)n-, wherein any of the alkylenes may be straight or branched chain;
X2 is selected from the group consisting of CJ -C6alkyl, branched C2-C6alkyl, and a direct bond wherein El is directly linked to the NR3 group of formula la;
Al is selected from the group consisting of hydrogen, aryl, Gl, G2, G3, G4, C1-C6 alkyl, branched C3-C8alkyK R19 substituted C3-C8carbocyclyl, fluoroCl-C6alkyl wherein the alkyl is fully or partially fluorinated, halogen, cyano, hydroxyl, -N(R4)2, -R5, -C(0)N(R4)2, C(0)R5, Cl-C6alkoxy, and fluoroCl-C6alkoxy wherein the alkyl group is fully or partially fluorinated;
When A and Al have one or more substitutable sp2-hybridized carbon atom, each respective sp2 hybridized carbon atom may be optionally substituted with a Zl or Z3 substituent;

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when A and Al have one or more substitutable sp3-hybridized carbon atom, each respective sp3 hybridized carbon atom may be optionally substituted with a Z2 or R3 substituent;
when A and Al have one or more substitutable nitrogen atom, each respective nitrogen atom may be optionally substituted with a 24 substituent:
each Zl is independently and individually selected from the group consisting of hydrogen, hydroxyCl-C6aIkyl, Cl-C6alkoxy, Cl-C6alkoxyCl-C6aIkyi, (R4)2NC1-C6alkyl, (R4)2NC2-C6alkylN(R4)-(CH2)n, (R4)2NC2-C6alkytO- in the event that Zl contains an aikyl or alkylene moiety, such moieties may be further substituted with one or more Cl-C6alky3s;
each Z2 is independently and individually selected from the group consisting of hydrogen, aryl, Cl-C6alkyi, C3-C8carbocyclyl, hydroxy], hydroxyCl-C6alkyl-, cyano, (R3)2N-, (R4)2N-, (R4)2NC1-C6a!kyl-, (R4)2NC2-C6alkylN(R4)-(CH2V, (R4)2NC2-C6aIkylO-(CH2)n-, (R3)2N-C(=0)-, (R4)2N-C(=0)-, (R4)2N-CO-Cl-C6alkyl-, carboxyl, carboxyCl-C6alkyI, Cl-C6alkoxycarbonyl, Cl-C6alkoxycarbonylCl-C6alkyl, (R3)2NS02-, (R4)2NS02-, -S02R5, -S02R8, -(CH2)nN(R4)C(0)R8, -C(0)R8, =0, =NOH, =N(OR6), -(CH2)n-Gi, -(CH2)n-G4, -(CH2VO-(CH2)„-Gl, -(CH2)n-0-(CH2)n-G4, -(CH2)n-NR3-(CH2)„-aryl, -(CH2)n-NR3-(CH2)n-Gl, -(CH2)n-NR3-(CH2)n-G4, -(CH2)nNHC(0)NHS(0)2R8, -(CH2)nNHS(0)2NHC(0)R8, -

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C(0}NHS(0)2R8, -(CH2)NHC in the event that Z2 contains an alkyl or alkylene moiety, such moieties may be further substituted with one or more Cl-C6alkyls;
each Z3 is independently and individually selected from the group consisting of H, Cl~C6alkyi, branched CS-CTalkyl, C3-C8carbocyclyl, halogen, fluoroalky! wherein the alkyl moiety can be partially or fully fluorinated, cyano, hydroxy!, methoxy, oxo, (R3)2N-C(=0)-, (R4)2N-C(=0)-, -N(R4)-C(=0}R8, (R3)2NS02-, (R4)2NS02-, -N(R4)S02R5, -N(R4)S02RS, -(CH2)n-N(R3)2, -(CH2)n-N(R4)2) -0-(CH2)q-N(R4)2, -CHCH^-O-alkyl, -N(R3)-(CH2)q-0-alkyl, -N(R3HCH2)q -N(R4)2, -0-(CH2)q-R5, -N(R3)-(CH2)q-R5, -C(=0)R5, -C(=0)R8, and nitro;
in the event that Z3 contains an alkyl or alkylene moiety, such moieties may be further substituted with one or more Cl-C6alkyls;
each Z4 is independently and individually selected from the group consisting of H, Cl-C6a!kyl, hydroxyC2-C6alkyi, Ci-C6alkoxyC2-C6alkyl) (R4)2N-C2-C6~alkyi, (R4}2N-C2-C6aIkyIN(R4)-C2-C6alkyl, (R4)2N-C2-C6aIkyl-0-C2-C6alkyl, (R4)2N-CO-Cl-C6alkyI, carboxyCl-C6alkyl, Cl-C6a1koxycarbony]Cl-C6aJkyl, -C2-C6alkylN(R4)C(0)R8,R8-C(=NR3X -S02R8, -COR8, -(CH2)„-GL -(CH2)n-G4, -(CH2)q-0-(CH2)n-Gl, -(CH2)q-0-(CH2VG4, -{CH^-NRS-CCHa^-Gl, -(CH2)q-NR3-(CH2)n-G4, -(CH2)qNHC(0)(CH2)nR5, -(CH2)qC(0)NH(CH2)qR5, -(CH2)qC(0)R5, -(CH2)qOC(0)R5, -(CH2)qR5, -(CH2)qNR4(CH2)qR5, and -(CH2)qO(CH2)qR5;
in the event that Z4 contains an alkyl or alkylene moiety, such moieties may be further substituted with one or more Cl-CGalkyls;
each Z6 is independently and individually selected from die group consisting of B, Cl-C6alkyl, branched C3-C7alkyl, hydroxyl, Cl-C6alkoxy, -OR4, Cl-C6alkylthio, (R3)2N-, (R4)ZN-, -R5, -N(R3)COR8, -N(R4)COR8, -N(R3)S02R6-, -CON(R3)2) -CON(R4)2, -COR5, -S02N(R4)2, halogen, fluoroCl-C6alkyl wherein die alkyl is fully or partially fluorinated, cyano, fluoroCl-

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C6aIkoxy wherein the alkyl is fully or partially fluorinated, .0^(CH2)q-N(R4)2? -N(R3)-(CH2)q-N(R4)2, -0-(CH2)q-0-alky], -N(R3)-(CH2)q-0-alkyl, -0-(CH2)q-R5, -N(R3)-(CH2)q-R5, -(NR3)r (CH2)Q-R17, -(OVR17, -(SVR17, and -(CH2)rR17;
in the event that Z6 contains an alkyl or alkylene moiety, such moieties may be further substituted with one or more Cl-C6alkyls;
wherein each R3 is independently and individually selected from the group consisting of H. Cl-CSalkyl, branched C3-C7alkyl, CS-Cgcarbocyclyl, and Z3-substituted phenyl;
each R4 is independently and individually selected from the group consisting of H, Cl-C6alkyl. hydroxyCl-C6alkyI, dihydroxyCl-C6alkyl, CJ-C6aIkoxyCl-C6alkyl, branched C3-C7alkyL branched hydroxyCl-C6alkyl, branched Cl-C6alkoxyCl-C6alkyl; branched dihydroxyCl-C6alky}, -(CTbV^k -ICH2)P-R5, -(CH2)p-CtO)>5(R7)2, -lCH2)nC{0)R5, -(CH2)n-C(0)OR3, C3-C8carbocyclyl, hydroxyl substituted C3-C8carbocyclyl, alkoxy substituted C3-C8carbocyclyl, dihydroxy substituted C3-C8carbocyclyl. and -(CH2)„-R17;
each R5 is independently and individually selected from the group consisting of

and wherein the symbol (##) is the point of attachment of the R5 moiety;
each R6 is independently and individually selected from the group consisting of Cl-C6alkyl, branched C3-C7alkyl, C3-C8carbocyclyL phenyl, Gl, and G4;
each R7 is independently and individually selected from the group consisting of H, Cl-C6alkyl, hydroxyC2-C6alkyl, dihydroxyC2-C6alkyl, CI-C6alkoxyC2-C6alkyl, branched C3-C7alkyl, branched hydroxyC2-C6 alkyl, branched Cl-C6alkoxyC2-C6alkyl, branched dihydroxyC2-C6alkyl, ~(CH2)q-R5, -(CH2)n-C(0}R5, -(CH2)n-C(0)OR3, C3-CScarbocyclyl, hydroxyl

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substituted C3-C8carbocycIyl, aikoxy substituted C3-C8carbocyclyl, dihydroxy substituted C3-C8carbocyclyi, and -(CH2)„-R17;
each R8 is independently and individually selected from the group consisting of Cl-C6alkyl, branched C3-C7alkyl, fluoroalkyi wherein the alkyl moiety is partially or fully fluorinated, C3-CScarbocyclyl, Z3-substituted phenyl, Z3-substituted phenyl Cl-C6alkyl, Z3-substituted Gl, Z3-substituted Gl-Cl-C6alkyl, Z2-substituted G4, Z2-substituted G4-Cl-C6alkyl, OH, Cl-C6alkoxy, N(R3)2, N(R4h, and R5;
each R10 is independently and individually selected from the group consisting of C02H, C02C1-C6alkyl, CO-N(R4)2, OH, Cl~C6alkoxy, and -N(R4)2;
R16 is independently and individually selected from the group consisting of hydrogen, Ci-C6alkyl, branched C3-C7alkyl, C3-C8carbocyclyl, halogen, fluoroalkyi wherein the alkyl moiety can be partially or fully fluorinated, cyana, hydroxyl, Cl-C6alkoxy., Cl-C6fluoroalkoxy wherein the alkyl moiety can be partially or fully fluorinated, -N(R3)2, -N(R4)2, C2-C3alkynyl, and nitro;
each Rl 7 is taken from the group comprising phenyl, naphthyl, pyrrolyl, furyl, tliienyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, Jetrazolyl, pyrazinyl, pyridazinyl, triazinyl, oxetanyl, azetadinyl, tetrahydTofurany], oxazolinyi, oxazolidinyl, pyranyl, thiopyranyl, tetrahydropyranyl, dioxalinyl, azepinyl, oxepinyl, diazepinyl, pyrrolidinyl, and piperidinyl;
wherein R17 can be further substituted with one or more Z2, Z3 or Z4 moieties;
R19 is HorC1-C6 alkyl;
wherein two R3 or R4 moieties are independently and individually taken from the group consisting of Cl-C6alkyl and branched C3-C6alkyl3 hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen atom, said moieties may cyclize to form a C3-C7 heterocyclyl ring;

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and k is \ or 2; n is 0-6; p is 1-4; q is 2-6; r is 0 or 1; t is 1-3.
1. 1 Compounds of Formula la which exemplify preferred El ^2 moieties
In an embodiment of section I, preferred compounds have the structures of formula lb



1.2 Compounds of Formula la which exemplify preferred A Moieties
In an embodiment of section 7.7, preferred compounds have the structures of formula Ic



1.3 Compounds of Formula la which exemplify preferred A1 Moieties
In an embodiment of section 7,2, preferred compounds have the structures of formula Id

wherein Al is selected from the group consisting of branched C3-C8alkyl, R19 substituted C3-CScarbocyclyl, Cl-C6alkyl, fluoroCl-C6alkyl wherein the alkyl is fully or partially fluorinated, Z3-substituted phenyl, and Z3-substituted Gl;
and wherein R16 is CI -Coalkyl, cyano, -CCH, or halogen.
1.3a Compounds of Formula Id which exemplify more preferred X2-E1 moieties
In an embodiment of section 1.3, preferred compounds have the structures of formula Ie


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J. 3b Additional compounds of Formula Id which exemplify more preferred X2-E1 moieties In another embodiment of section 1.3, preferred compounds have the structures of fonnula If

wherein Rl 6 is methyl, cyano, -CCH, fluorine or chlorine.
1.4 Compounds of Formula la which exemplify additionalpreferredAt moieties
In a different embodiement of section 1.2, additional preferred compounds have the structures of
formula Ig

wherein Al is selected from the group consisting of branched C3-CSalkyl, R19 substituted C3-C8carbocyclyl, Cl-CealkyI, f!uoroCl-C6alkyl wherein the alkyl js fully or partially fluorinated, 23-substttuted phenyl, and Z3-substituted Gl;
and wherein R16 is Cl-C6alkyl, cyano, -CCH, or halogen.
1.4a Additional compounds of Formula Ig which exemplify mtjre preferred X2-E1 moieties In an embodiment of section 1.4, preferred compounds have the structures of formula Ih

J.4b Additional compounds of Fonnula Jg which exemplify more preferred X2-E1 moieties In another embodiment of section 1.4. preferred comoounds havt-thp stmr.fiirps of Formula li


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wherein R16 is Cl-C6alkyl, cyano, -CCH, fluorirte or chlorine.
L5 Compounds of Formula la which exemplify additionaly preferred A Moieties
In a different embodiment of section 7.7, additional preferred compounds have the structures of
formula Ij

wherein AI is selected from die group consisting of branched Z2-substitued C3-C8alkyl, R19 substituted C3-C8carbocyclyl, Z2-substituted Cl-C6alkyl, fluoroCl-C6a!kyl wherein the alkyl is fully or partially fluorinated, Z3-substituted phenyl, and Z3-substituted Gl;
and wherein R16 is Cl-C6alkyl, cyano, -CCH, or halogen.
1.5a Additional compounds of Formula Ij which exemplify more preferred X2-EI moieties In an embodiment of section 1.5, preferred compounds have the structures of formula Ik
1.5b Additional compounds of Formula Ij which exemplify more preferred X2-E1 moieties In annther errVhndinient of section 7. J. preferred comnounds have the structures of formula II

wherein R16 is Cl-C6alkyl, cyano, -CCH, fluorine or chlorine.
1.6 Compounds ofFormida la which exemplify additional)'prefeired A Moieties
In a different embodiment of section 1.1, additional preferred compounds have the structures of
formula Im

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wherein Al is selected from the group consisting of hydrogen, Z2-substituted branched C3-C8alkyl, R19 substituted C3-C8carbocyclyI, Z2-substituted Cl-C6alkyl, fluoroCl-C6alkyl wherein the alkyl is fully or partially fluorinated, Z3-substituted phenyl, and Z3-substituted Gl;
and wherein R16 is Cl-C6alkyl, cyano, -CCH, or halogen.
1.6a Additional compounds of Formula Im which exemplify more prefen-ed X2-E1 moieties In an embodiment of section L6y preferred compounds have the structures of formula In

J.6b Additional compounds of Formula Im which exemplify more preferred X2-E1 moieties In another embodiment of section i.6. Drefcrred comrjounds have the structures of formula In



wherein R16 is Cl-C6alkyl, cyano, -CCH, fluorine or chlorine.
/. 7 Compounds of Formula la which exemplify additionaly preferred A Moieties
In a different embodiment of section 1.1, additional preferred compounds have the structures of
formula Ip


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wherein Al is selected from the group consisting of Z2-subsrituted branched C3-C8alkyl, R19 substituted C3-C8carbocyclyl, Z2-substituted Cl~C6aIkyl, fluoroCl-C6alkyl wherein the alkyl is fully or partially fluorinated, Z3-substituted phenyl, and Z3-substituted GI;
and wherein R16 is Cl-C6alkyl, cyano, -CCH, or halogen.
/. 7a Additional compounds of Formula Ip which exemplify more prefen'ed X2-E1 moieties hi an embodiment of section 1.7, preferred compounds have the structures of formula Iq

1.7b Additional compounds of Formula Ip which exemplify more prefeired X2-E1 moieties In another embodiment of section 1.7, preferred compounds have the structures of formula Ir

and wherein R16 is Cl-C6alkyl, cyano, -CCH, fluorine or chlorine.
/. 8 Compounds of Formula la which exemplify additional)' preferred A Moieties
In a different embodiment of section /./, additional preferred compounds have the structures of
formula Is
wherein the hashed bond is a saturated or unsaturated bond;
and wherein Al is selected from the group consisting of hydrogen. Z2-substituted branched C3-CSalkyL R19 substituted C3-C8carbocyclyl, Z2-substituted Cl-C6alkyl, halogen, cyano, Cl-C6alkoxy, fluoroCI-C6aIkoxy, fluoroCl-C6alkyl wherein the alkyl is fully or partially fluorinated, Z3-substituted phenyl, and Z3-substituted Gl;

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and wherein R16 is Cl-C6alkyl, cyano, -CCH, or halogen.

1.8a Additional compounds of Formula Is which exemplify more preferred X2-E1 moieties In an embodiment of section 1.8, preferred compounds have the structures of formula It
1.8b Additional compounds of Formula Is which exemplify more preferred X2-E1 moieties In another embodiment of section 1.8, preferred compounds have the structures of formula lu

wherein R16 is Cl-C6alkyl, cyano, -CCH, fluorine or chlorine.
1.9 Compounds of Formula la which exemplify additional)'preferred A Moieties
In a different embodiment of section 7,/s additional preferred compounds have the structures of
formula Iv

wherein the hashed bond is a saturated or unsaturated bond:
and wherein Al is selected from the group consisting of hydrogen, Z2-substituted branched C3-C8alkyl, RI9 substituted C3-C8carbocycly], Z2-substituted Cl-C6alkyl, halogen, cyano, Cl-C6alkoxy, fluoroCl-C6aikoxy, fluoroCl-C6alkyI wherein the alkyl is fully or partially fluorinated, Z3-substituted phenyl, and Z3-substituted Gl;
and wherein R16 is Cl~C6alkyi, cyano, -CCH, or halogen.

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7.9a Additional compounds of Formula Iv which exemplify more preferred X2-E1 moieties In an embodiment of section 1.9, preferred compounds have the structures of formula lw


1.9b Additional compounds of Formula Iv which exemplify' more preferred X2-E7 moieties In another embodiment of section 1.9, preferred compounds have the structures of formula Ix

and wherein R16 is Cl-C6alkyl, cyano, -CCH, fluorine or chlorine.
1.10 Compounds of Formula la which exemplify additionaly preferredA Moieties
In a different embodiment of section 1.1, additional preferred compounds have the structures of
formula Iy

wherein Al is selected from the group consisting of Z2-substituted branched C3-C8alkyl, R19 substituted C3-C8carbocycIyL Z2-substituted Cl-C6alkyl, fluoroCl-C6alkyl wherein the alky! is fully or partially fluorinated, 23-substituted phenyl, and Z3-substituted Gl;
and wherein R16 is CI -C6alkyl, cyano, -CCH, or halogen.
1.10a Additional compounds of Formula Iy which exemplify more preferred X2-El moieties In an embodiment of section 1.10, preferred compounds have the structures of formula Lz


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1.10b Additional compounds of Formula ly which exemplify more preferred X2-E1 moieties In another embodiment of section 1.10, preferred compounds have the structures of formula Iaa



wherein R16 is CI-C6alkyl, cyano, -CCH, fluorine or chlorine.
1.11 Compounds of Formula la which exemplify additional)? preferred A Moieties
In a different embodiment of section 1.1, additional preferred compounds have the structures of
formula Ibb

wherein R16 is Cl-C6alkyl, cyano, -CCH, or halogen.
1.11a Additional compounds of Formula Ibb which exemplify more preferred X2-El moieties In an embodiment of section 1.11, preferred compounds have the structures of formula Ice

1.11b Additional compounds of Formula Ibb which exemplify more preferred X2-El moieties In another embodiment of section 1.11, preferred compounds have the structures of formula Idd

wherein R16 is Cl-C6alkyl, cyano, -CCH, fluorine or chlorine.
1.12 Compounds of Formula la which exemplify additionaly preferred A Moieties
In a different embodiment of section 1.1, additional preferred compounds have the structures of
formula lee

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wherein Ql and Q2 are individually and independently taken from the group consisting of N and CH;
and wherein R16 is Cl-C6alkyl, cyano, -CCH, or halogen.
],I2a Additional compounds of Formula Jee which exemplify more preferred X2-EI moieties In an embodiment of section /. 12 preferred compounds have the structures of formula Iff

1.12b Additional compounds of Formula lee which exemplify more preferred X2-E1 moieties In another embodiment of section 1.12, preferred compounds have the structures of formula Igfi

wherein R16 is Cl-C6alkyl, cyano, -CCH, fluorine or chlorine.
1.J3 Compounds of Formula la which exemplify additionaly preferred A Moieties
In a different embodiment of section 1.1, additional preferred compounds have the structures of
formula Ihh
R3 R4 ° fl> f
R4
and wherein R16 is Cl-C6alkyl, cyano, -CCHor halogen.
/. 13a Additional compounds of Formula Ihh which exemplify more preferred X2-E1 moieties

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In an embodiment of section 1.13, preferred compounds have the structures of formula Iii


1.13b Additional compounds of Formula Ihh which exemplify more preferred X2-E1 moieties In another embodiment of section 1.13, preferred compounds have the structures of formula Ijj

and wherein RI6 is methyl, cyano, -CCH, fluorine or chlorine.
1.14 Compounds of Formula la which exemplify additionally preferred A Moieties
In a different embodiment of section /./, additional preferred compounds have the structures of
formula Ikk

wherein Q6 is N or C-Al;
wherein Al is selected from the group consisting of hydrogen, Z2-substituted branched C3-C8alkyl, R19 substituted C3-C8carbocyclyI, Z2-substituted Cl-C6alkyl, fluoroCl-C6aIkyl wherein the alkyl is fully or partially fluorinated, Z3-substituted phenyl, and Z3-substituted Gl;
and wherein R16 is Cl-C6alkyl. cyano, -CCH, or halogen.
1.14a Additional compounds of Formula Ikk which exemplify more preferred X2-El moieties In an embodiment of section 1,14, preferred compounds have the structures of formula 111

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U4b Additional compounds of Formula Ikk which exemplify move preferred X2-E1 moieties In another embodiment of section 1.14, preferred compounds have the structures of formula Imm

wherein R16 is Cl-C6alkyl, cyano, -CCH, fluorine or chlorine.
/. 15 Compounds of Formula la which exemplify additionally preferred A Moieties
In a different embodiment of section 1.1, additional preferred compounds have the structures of
formula Inn
wherein Al is selected from the group consisting of hydrogen, Z2-substituted branched C3-C8alkyl, R19 substituted C3-C8carbocyclyl, Z2-substituted Cl-C6alkyl, fluoroCl-C6alkyl wherein the alkyl is fully or partially fluorinated, Z3-substituted phenyl, and 23-substituted Gl;
and wherein Rl 6 is C1 -C6alkyl, cyano, -CCH, or halogen.
1.15a Additional compounds of Formula Inn which exemplify more preferred X2-E1 moieties In an embodiment of section 1.15, preferred compounds have the structures of formula loo


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1.15b Additional compounds of Formula Inn which exemplify more preferred X2-E1 moieties In another embodiment of section 1.15, preferred compounds have the structures of formula Ipp

wherein R16 is Cl-C6alkyl, cyano, -CCH, fluorine or chlorine.
1.16 Compounds of Formula la which exemplify additionally prefetred A Moieties
In a different embodiment of section /./, additional preferred compounds have the structures of
formula Iqq

wherein Q3, Q4 and Q5 are selected from the group consisting of N-Al and C-Al, and only one ofQ3,Q4,orQ5isN-Al;
wherein Al is selected from the group consisting of hydrogen, Z2-substituted branched C3-C8alkyl, R19 substituted C3-C8carbocyclyl, Z2-substituted C1-C6alkyl, fiuoroCl-C6alkyl wherein the alkyl is fully or partially fluorinated, Z3-substituted phenyl, and Z3-substituted Gl;
wherein R16 is Cl-C6alkyl, cyano, -CCH, or halogen.

1.16a Additional compounds of Formula Iqq which exemplify more preferred X2-El moieties In an embodiment of section 1.16, preferred compounds have the structures of fonnula Irr
1.16b Additional compounds of Formula Iqq which exemplify more preferred X2-EI moieties In another embodiment of section 1.16, preferred compounds have the structures of fonnula Iss

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wherein R16" is Cl-C6alkyl, cyano, -CCH, fluorine or chlorine.
LI 7 Methods
1.17a Methods of Protein Modulation
The invention includes methods of modulating kinase activity of RAF kinases and other kinases in the RAS-RAF-MEK-ERK-MAP kinase pathway including, but not limited to, A-Raf, B-Raf, and C-Raf. The kinases may be wildtype kinases, oncogenic forms tliereof, aberrant fusion proteins tliereof or polymorphs of any of the foregoing. The method comprises the step of contacting the kinase species with compounds of the invention and especially those set forth in sections IJ-I.I6. The kinase species may be activated or unmotivated, and the species may be modulated by phosphorylations, sulfation, fatty acid acylations glycosylalions, nitrosylation, cystinylation (i.e. proximal cysteine residues in the kinase react with each other to form a disulfide bond) or oxidation. The kinase activity may be selected from the group consisting of catalysis of phospho transfer reactions, kinase cellular localization, and recruitment of other proteins into signaling complexes through modulation of kinase conformation.
1.17b Treatment Methods
The methods of the invention, especially those of sections 1.1-].16, also include treating individuals suffering from a condition selected from the group consisting of chronic myelogenous leukemia, acute lymphocytic leukemia, gastrointestinal stromal tumors, hypereosinophillic syndrome, glioblastomas, ovarian cancer, pancreatic cancer, prostate cancer, lung cancers, breast cancers, kidney cancers, cervical carcinomas, metastasis of primary solid tumor secondary sites, ocular diseases characterized by hyperproliferation leading to blindness including various retinopathies including diabetic retinopathy and age-related macular degeneration, rheumatoid arthritis, melanomas, colon cancer, thyroid cancer, a disease caused by a mutation in the RAS-RAF-MEK-ERK-MAP kinase pathway, human inflammation, rheumatoid spondylitis, ostero-arthritis, asthma, gouty arthritis, sepsis, septic shock, endotoxic shock, Gram-

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negative sepsis, toxic shock syndrome, adult respiratory distress syndrome, stroke, repertusion injury, neural trauma, neural ischemia, psoriasis, restenosis, chronic obstructive pulmonary disease, bone resorptive diseases, graft-versus-host reaction, Chron's disease, ulcerative colitis, inflammatory bowel disease, pyresis, and combinations thereof,
1. 18 Pharmaceutical Preparations
The compounds of the invention, especially those of sections 1.1-1.16, may form a part of a pharmaceutical composition by combining one or more such compounds with a pharamaceutically acceptable carrier. Additionally, the compositions may include an additive selected from the group consisting of adjuvants, excipients, diluents, and stablilizers.
A pharmaceutical composition of the present invention comprising a compound such as herein described and salts thereof, together with a pharmaceutical ly acceptable carrier including an additive selected from the group including adjuvants, excipients, diluents, and stabilizers showed surprising and enhanced effects. Therefore, the said composition is synergistic in nature,
2. Second aspect of the invention ~ Compounds, Methods, Preparations and Adducts
Compounds of the formula Lla

wherein one of QI and Q2 is N and the other is CR3;
wherein El is selected from the group consisting cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl piperidinyl, phenyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl. pyrrolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, furyl, imidazolyl, pyridyl, pyrimidinyl and naphthyl;
wherein A is selected from the group consisting of phenyl, naphthyl, C3-C8carbocyclyl, indanyl, tetralinyl, indenyl, Gl, G2, G3, G4 and -CHR4R8;
Gl is a heteroaryl taken from the group consisting of pyrrolyl, furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, tliiadiazolyl, triazolyl, tetrazolyl, pyrazinyl, pyridazinyl, triazinyl, pyridinyl, and pyrimidinyl;

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G2 is a fused bicyciic heteroaryl taken from the group consisting of indolyl, indolinyl, isoindolyl,
isoindolinyl, indazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzothiazolonyl,
benzoxazolyl, benzoxazolonyl, benzisoxazolyl, benzisothiazolyl, benzhnidazolyl,
benzimidazolonyl, benztriazolyl, imidazopyridinyl, pyrazolopyridinyl, imidazolonopyridinyl,
thiazolopyridinyl, thiazolonopyridinyl, oxazolopyridinyl, oxazolonopyridinyl,
isoxazolopyridinyl, isothiazolopyridinyl, triazolopyridinyl, imidazopyrimidinyl.
pyrazolopyrimidinyl, imidazolonopyrimidinyl. thiazolopyridiminyl, thiazolonopyrirnidinyl. oxazolopyridiminyl, oxazolonopyrimidinyl, isoxazolopyrimidinyl, isothiazolopyrimidinyl, triazolopyrimidinyl, dihydropurinonyl, pyrrol opyrimidinyl, purinyl, pyrazolopyrimidinyl, phthalimidyl, phthalimidinyl, pyrazinylpyridinyl, pyridinopyrirnidinyl, pyrimidinopyrirnidinyl, cinnolinyl, quinoxalinyl, quinazolinyl, quinolinyl, isoquinolinyl, phthalazinyl, benzodioxyl, benzisotliiazoline-1,1,3-trionyl, dihydroquinolinyl, tetrahydroquinolinyl. dihydroisoquinolyl, tetrahydroisoquinolinyl, benzoazepinyl, benzodiazepinyl, benzoxapinyl, and benzoxazepinyl;
G3 is a non-fused bicyciic heteroaryl taken from the group consisting of pyridylpyridiminyl
pyrimidinylpyrimidinyl, oxazolylpyrimidinyl, tliiazolylpyrifliidinyl, imidazolylpyrimidinyl,
isoxazolylpyrimidinyl, isothiazolylpyrimidinyl, pyi^olylpyrimidinyl, triazolylpyrimidinyl,
oxadiazoylpyrimidinyl, thiadiazoylpyrimidinyl. morpholinylpyrimidinyl,
dioxothiomorpholinylpyrimidinyl, and thiomorpholinylpyrimidinyl;
G4 is a heterocyclyl taken from the group consisting of oxetanyl, azetadinyl, tetrahydrofuranyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, imidazolonyl, pyranyl, thiopyranyl, tetrahydropyranyl, dioxalinyl, piperidinyl, morpholinyl, thiomorpholiiiyl, thiomorpholinyl S-oxide, thiomorpholiiiyl S-dioxide, piperazinyl, azepinyl, oxepinyl, diazepinyl, tropanyl, and homotropanyl;
the A ring may be optionally substituted with one or more -XI -Al moieties;
XI is selected from the group consisting of -(CH2)AO)r(CH2)a-, -(CH2)n-(NR3MCH2)n-, -(CH2)n-(S)r(CH-,)n-, -(CH2)AC=0)r{CH2)n-, -(CH;0n-(CK)-ni3MCH2)n-, and -(CH2)n-(S02-NR3)r(CH2)n-, wherein any of the alkylenes may be straight or branched chain;

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X2 is selected from the group consisting of Cl~C6alkyl, branched C2-C6a1kyl: and a direct bond wherein EI is directly linked to the NR3 group of formula la;
Al is selected from the group consisting of hydrogen, aryl, Gl, G2, G3, G4, C1-C6 alkyl, branched C3-C8alkyl, R19 substituted C3-C8carbocyclyI, fluoroCl-C6alkyl wherein the allcyl is folly or partially fluorinated, halogen, cyano, hydroxyl, -N(R4)2, -R5, -C(0)N(R4)2, C(0)R5, Cl-C6alkoxy, and fluoroCl-C6alkoxy wherein the alkyl group is iully or partially fluorinated;
When A and Al have one or more substitutable sp2-hybridized carbon atom, each respective sp2 hybridized carbon atom may be optionally substituted with a 21 or Z3 substituent;
when A and Al have one or more substitutable sp3-hybridized carbon atom, each respective sp3 hybridized carbon atom may be optionally substituted with a Z2 or R3 substituent;
when A and Al have one or more substitutable nitrogen atom, each respective nitrogen atom may be optionally substituted with a Z4 substituent;
each Zl is independently and individually selected from the group consisting of hydrogen, hydroxyCl-C6a!kyl, Cl-C6alkoxy, Cl-C6alkoxyCl-C6alkyl, (R4)2NCl-C6aUcyl, (R4)2NC2-C6alkylN(R4MCH2)„, (R4)2NC2-C6a]kylO-(CH2)n, (R3)2N-C(=0)-, (R4)2N-C(=0>, (R4)2N-CO-Cl-C6alkyI-, Cl-C6alkoxycarbonyl-, -carboxyCl-C6alkyl, Cl-C6alkoxycarbonylCl-C6alkyL (R3)2NS02-, -SOR3, (R4)2NS02-, -S02R3, -SOR4, -C(=0)R6, -C(=NOH)R6, -C(=NOR3)R6, -(CH2)nN(R4)C(0)R8,-(CH2)n-Gl, -(CH2)n-G4, phenoxy, -(CH2)n-0-(CH2)n-Gl, -(CH2)n-0-(CH2)n-G4, -(CH2)irNR3-(CH2)n-aryl, -(CH2)n-NR3-(CH2)n-Gl, -(CH2),rNR3-(CH2),r G4, -S(0)2R5, -N=S(0)R6R8, -S(0)(=NR3)R6, -(CH2)nNHC(0)NHS(0)2R8, (CH2)nNHS(0)2NHC(0)R8, -C(0)NHS(0)2R8, -S(0)2NHC(0)R8, -(CH2)nNHC(0)(CH2)11R57 -(CH^NHSfOHCHz), -(CH2)nC(0)NH(CH2)qR5, -(CH2)nC(0)R5, -(CH2)nOC(0)R5, -(CH2)nS(0)2NH(CH2)qR5, -CH
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in the event that Zl contains an alkyl or alkyiene moiety, such moieties may be further substituted with one or more Cl-C6alkyls;
each Z2 is independently and individually selected from the group consisting of hydrogen, aryl, Cl-C6alkyl, C3-C8carbocyclyl, hydroxyl, hydroxyCl-C6alkyl-, cyano, (R3)2N-, (R4)2N-, (R4)2NCl-C6alkyI-5 (R4)2NC2-C6alkylN(R4)-(CH2)n-, (R4)2NC2-C6alkylO-(CH2)r-, (R3)2N-C(=0)-, (R4)2N-C{^0)-5 (R4)2N-CO-C 1 -CSalkyl-, carboxyl, carboxyC 1 -C6alkyl, C1 -C6alkoxycarbonyl, Cl-C6alkoxycarbonylC3-C6alkyl, (R3)2NS02-, (R4)2NS02-, -S02R5, -S02R8, -(CH2)„N(R4)C(0)R8, -C(0)R8, =0, =NOH, =N(OR6)T -(CH2)n-Gl, -(CH2)n-G4, -(CH2)n-0-(CH2)irGl, -(CH2)n-0-(CH2VG4) -(CH2)n-NR3-(CH2)n-aryl, -(CH2)n-NR3-(CH2)n-Gl, -(CH2)„-NR3-(CH2)Il-G4, -(CH2)nNHC in the event that Z2 contains an alkyl or alkyiene moiety, such moieties may be further substituted with one or more Cl-C6alkyls;
each Z3 is independently and individually selected from the group consisting of H, Cl-C6alkyl, branched C3-C7alkyl, C3-C8carbocyclyl, halogen, fluoroalkyl wherein the alkyl moiety can be partially or fully fluorinated, cyano, hydroxyl, methoxy, oxo, (R3)2N-C(=0)-? (R4)2N-C(=0)-T -N(R4)-C(=0)R8; (R3)2NS02-5 (R4)2NSO--, -N(R4)S02R5, -N(R4)S02R8, -(CH2)I1-N(R3)2, -(CH2)n-N(R4)2) -0-(CH2)q-N(R4)2, -0-(CH2)q-0-alkyK -N(R3)-(CH2)Q-0-alkyl, -N(R3)-(CH2)q -N(R4)2, -0-(CH2)v-X$, -N(R3)-(C}l?)q-R5, -C(=0)R57 -C(=0)RS, and nitro;
in the event that Z3 contains an alkyl or alkyiene moiety, such moieties may be further substituted with one or more C1 -C6alkyls;
each Z4 is independently and individually selected from the group consisting of H, Cl-C6alkyl) hydroxyC2-C6alkyl, Cl-C6alkoxyC2-C6alkyl, (R4)2N-C2-C6alkyl, (R4)2N-C2-C6alkylN(R4)-C2-C6alkyl, (R4)2N-C2-C6alkyl-0-C2-C6alkyl, (R4)2N-CO-Cl-C6alkyl, carboxyCl-C6alkyl, Cl-C6alkoxycarbonylCl-C6alkyl, -C2-C6alkylN(R4)C(0)R8,R8"C(=NR3, ~S02R8, -COR8, -

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(CH2)n-Gl, -(CH2)n-G4, -(CH2)q-0-(CH2)n-Gl, -(CH2)q-0-(CH2)n-G4, -(CH2)q-NR3-(CH2)n-Gl, -(CH2)q-NR3-(CH2)„-G4, -(CH2)qNHC(0)(CH2)BR5, -(CH2)qC(0)NH(CH2)qR5: -(CH2)qC(0)R5, -(CH2)qOC(0)R5, »(CH2)qR5, -(CH2)qNR4(CH2)qR5, and -(CH2)qO(CH2)qR5;
in the event that Z4 contains an alkyl or alkylene moiety, such moieties may be further substituted with one or more Cl-C6alkyls;
each Z6 is independently and individually selected from the group consisting of H, Cl-C6alkyl, branched C3-C7atkyt, hydroxy!, CI-C6alkoxy, -OR4, Cl-C6alkylthio, (R3)2N-, (R4)2N-, -R5, -N(R3)COR8, -N(R4)COR8, -N(R3)S02R6-, -CON(R3)2, -CON(R4)2, -COR5, -S02N(R4)2, halogen, f!uoroCl-C6alkyI wherein the alkyl is fully or partially fluorinated, cyano, fluoroCl-C6alkoxy wherein the alkyl is fully or partially fluorinated, -0-(CH2)q-N(R4)2, -N(R3)-(CH2)q-N(R4)2, -0-(CH2)q-0-aLkyI, -N(R3)-(CH2VO-aIkyl, -0-(CH2)q-R5, -N(R3)-(CH2)q-R5, -(NR3)r (CH2)n-R17T -(0)rR17, -(S)r-R17, and -(CH2)rR17;
in the event that Z6 contains an alkyl or alkylene moiety, such moieties may be further substituted with one or more Cl-C6alkyls;
wherein each R3 is independently and individually selected from the group consisting of H, Cl-C6alkyl, branched C3-C7alkyl, C3-C8carbocyclyl, and Z3-substituted phenyl;
each R4 is independently and individually selected from the group consisting of H, Cl-C6alkyl, hydroxyCl-C6alkyl, dihydroxyCl-C6alkyl, Cl-C6alkoxyCNC6alkyl, branched C3-C7alkyl, branched hydroxyCl-C6alkyl, branched Cl-C6alkoxyCl-C6alkyl, branched dihydroxyCl-C6alkyl, -(CH2)P-N(R7)2, -(CH2)P-R5, -(CH2)P-C(0)N(R7)2, -(CH2)nC(0)R5, -{CH2)n-C(0)OR3, CS-CScarbocyclyl, hydroxyl substituted C3-C8carbocyclyl, alkoxy substituted C3-C8carbocycIyl, dihydroxy substituted C3-C8carbocyclyl, and -(CH2)n-R17;
each R5 is independently and individually selected from the group consisting of

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and wherein the symbol (##) is the point of attachment of the R5 moiety;
each R6 is independently and individually selected from the group consisting of Cl-C6alkyl, branchedC3-C7alkyl, C3-C8carbocydyl, phenyl, Gl, and G4;
each R7 is independently and individually selected from the group consisting of H, CI -C6alkyl, hydroxyC2-C6alkyl, dihydroxyC2-C6alkyl, Cl-C6alkoxyC2-C6alkyI, branched C3-C7alkyl, branched hydroxyC2-C6 alkyl, branched Cl-C6alkoxyC2-C6alkyl3 branched dihydroxyC2-C6alkyl, -(CH2)q-R5, -(CH2)n-C(0)R53 -(CH2)n-C(0)OR3, C3-C8carbocyclyl, hydroxyl substituted C3-C8carbocycly], alkoxy substituted C3-C8carbocycly], dihydroxy substituted C3-C8carbocyclyl, and -(CH2)H-R17;
each R8 is independently and individually selected from the group consisting of Cl-C6alky{, branched C3-C7alkyl, fluoroalkyl wherein the alkyl moiety is partially or fully fluorinated, C3-CScarfaocycIyl, Z3-substituted phenyl, Z3-substituted phenyl CI-C6aIkyl, Z3-substituted GI, Z3-substituted Gl-CI-C6alkyl, Z2-substituted G4, Z2-substituted G4-Cl-C6alkyl, OH, Cl-C6alkoxy, N(R3)2, N(R4)2, and R5;
each R10 is independently and individually selected from the group consisting of C02H, C02C1-C6alkyl, CO-N(R4)2, OH, Cl-C6alkoxy; and -N(R4)2;
R16 is independently and individually selected from the group consisting of hydrogen, CI-C6alkyl, branched C3-C7alkyl, C3-C8carbocyclyl, halogen, fluoroalkyl wherein the alkyl moiety can be partially or fully fluorinated, cyano, hydroxyl, Cl-C6alkoxy, Cl-C6fluoroalkoxy wherein the alkyl moiety can be partially or fully fluorinated, -N(R3)2) -N(R4)2, C2-C3alkynyl, and nitro;
each R17 is taken from the group comprising phenyl, naphthyl, pyrrolyl, furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl,

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tetrazolyl, pyrazinyl, pyridazinyl, triazinyl, oxetanyl, azetadinyl, tetrahydrofuranyl, oxazolinyl, oxazolidinyl, pyranyl, thiopyranyl, tetrahydropyranyl, dioxalinyl, azepinyl, oxepinyl, diazepinyl, pyrrolidinyl, and piperidinyl;
wherein R17 can be further substituted with one or more Z2, Z3 or Z4 moieties;
R19isHorCl-C6alkyl;
wherein two R3 or R4 moieties are independently and individually taken from the group consisting of Cl-C6alkyl and branched C3-C6alkyl, hydroxyalkyi, and alkoxyalkyl and are attached to the same nitrogen atom, said moieties may cyclize to form a C3-C7 heterocyclyl ring;
and k is 1 or 2; n is 0-6; p is 1-4; q is 2-6; risOor 1; t is 1-3.
2.1 Compounds of Formula Ha which exemplify preferred El ~X2 moieties
In an embodiment of section 2, preferred compounds have the structures of formula lib

2.2 Compounds of Formula Ua which exemplify prefen-ed A Moieties
In an embodiment of section 2.1, preferred compounds have the structures of formula He

2.3 Compounds of Formula Ha which exemplify preferred A1 Moieties
In an embodiment of section 2.2, preferred compounds have the structures of formula Hd


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wherein Al is selected from the group consisting of branched C3-C8alkyl, R19 substituted C3-CScarbocyclyl, Cl-C6alkyl, fluoroCl-C6alkyl wherein the alkyl is fully or partially fluorinated, Z3-substituted phenyl, and Z3-substituted Gl;
and wherein R16 is Cl-C6alkyl, -CCH, cyano, halogen.
2.3a Compounds of Formula lid which exemplify more preferred X2~EI moieties
In an embodiment of section 2.3, preferred compounds have the structures of formula He



2.3b Additional compounds of Formula Hd which exemplify more preferred X2-EJ moieties hi another embodiment of section 2.3, preferred compounds have the structures of formula Ilf



wherein R16 is methyl, cyano, -CCH, fluorine or chlorine.
2.4 Compounds of Formula Ha which exemplify additional preferred A1 moieties
In a different embodiment of section 2.2, additional preferred compounds have the structures of
formula Ilg

wherein A3 is selected from the group consisting of branched CS-CSaiky). R19 substituted C3-CScarbocyclyl, Cl-C6alkyl, fluoroCl~C6alkyl wherein the alkyl is fully or partially fluorinated, Z3-substituted phenyl, and Z3-substituted Gl;

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and wherein R16 is Cl-C6alkyl, cyano, -CCH, or halogen.
2.4a Additional compounds of Formula Ilg which exemplify more preferred X2-E1 moieties In an embodiment of section 2.4, preferred compounds have the structures of formula IHi

2.4b Additional compounds of Formula Ilg which exemplify more preferred X2-E7 moieties In anotiier embodiment of section 2.4, preferred compounds have the structures of formula Hi

wherein R16 is methyl, cyano, -CCH, fluorine or chlorine.
2,5 Compounds of Formula Ila which exemplify additional)' preferred A Moieties
In a different embodiment of section 2. J, additional preferred compounds have the structures of
formula IIj
,(R16),

wherein Al is selected from the group consisting of branched Z2-substitued C3-C8alkyl, R19 substituted C3-C8carbocyclyl, Z2-substituted Cl-C6alkyl, fluoroCl-C6alkyl wherein the alkyl is fully or partially fhiorinated, Z3-substituted phenyl, and Z3-substituted G1;
and wherein R16 is Cl-C6alkyl, cyano, -CCH, or halogen.
2.5a Additional compounds of Formula IIj which exemplify more prefen'edX2-E1 moieties In an embodiment of section 2.5, preferred compounds have the structures of formula Ilk

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2.5b Additional compounds of Formula Hj which exemplify more preferred X2-E1 moieties In another embodiment of section 2.5. preferred comDounds have the structures of formula III

wherein R16 is methyl, cyano, ~CCH, fluorine or chlorine.
2.6 Compounds of Formula Ha which exemplify additional)? preferred A Moieties
In a different embodiment of section 2.1, additional preferred compounds have the structures of
formula Ilm

wherein Al is selected from the group consisting of hydrogen, Z2-substituted branched C3-C8alkyl, R19 substituted C3-C8carbocyclyl, 22-substituted Cl-C6alkyl, fluoroCl-C6alkyl wherein the alkyl is fully or partially fluorinated, Z3-substituted phenyl, and Z3-substituted Gl;
and wherein R16 is Cl-C6alkyl, cyano, -CCH, or halogen.
2.6a Additional compounds of Formula Urn which exemplify more preferred X2-E1 moieties In an embodiment of section 2.6, preferred compounds have the structures of formula Iln

2.6b Additional compounds of Formula llm which exemplify more prefetred X2-EI moieties In another embodiment of section 2.6, preferred compounds have the structures of formula IIo

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wherein Rl 6 isCl-C6alkyl, cyano, -CCH, fluorine or chlorine.
2.7 Compounds of Formula Ila which exemplify additionaly preferred A Moieties
In a different embodiment of section 2.J, additional preferred compounds have the structures of
formula Up

wherein Al is selected 'from the group consisting of Z2-substituted branched C3-C8alkyl, R19 substituted C3-C8carbocyclyl, Z2-substituted Cl-C6alkyl, fluoroCl-C6alkyl wherein the alkyl is fully or partially fluorinated, Z3-substituted phenyl, and Z3-substituted Gl;
and wherein R16 is Cl-C6alkyl; cyano, -CCH, or halogen.
2.7a Additional compounds of Formula lip which exemplify more preferred X2-El moieties In an embodiment of section 2,7, preferred compounds have the structures of formula Ilq


2.76 Additional compounds of Formula Up which exemplify more preferred X2-E1 moieties In another embodiment of section 2,7, preferred compounds have the structures of formula Ilr

and wherein R16 is methyl, cyano, -CCH, fluorine or chlorine.

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2,8 Compounds of Formula lla which exemplify additional}'preferred A Moieties
In a different embodiment of section 2.1, additional preferred compounds have the structures of
formula lis

wherein the hashed bond is a saturated or unsaturated bond;

and wherein Al is selected from the group consisting of hydrogen, Z2-substituted branched C3-C8alkyl, R19 substituted C3-C8carbocyclyl, Z2-substituted Cl-C6alkyl, halogen, cyano, Cl-C6alkoxyT fluoroC 1 -C6alkoxy, fluoroCl-C6alkyl wherein the alkyl is fully or partially fiuorinated, Z3~substituted phenyl, and Z3-substituted Gl;
and wherein R16 is CI -C6alkyl, cyano, -CCH, or halogen.
2.8a Additional compounds of Formula lis which exemplify more preferred X2-E1 moieties In an embodiment of section 2.8, preferred compounds have the structures of formula lit

2.8b Additional compounds of Formula lis which exemplify more preferred XI-El moieties in another embodiment of section 25, preferred compounds have the structures of formula IIu

and wherein R16 is CI -C6alkyl, cyano, -CCH, fluorine or chlorine.
2.9 Compounds of Formula lla which exemplify additionaly preferred A Moieties
In a different embodiment of section 2.1, additional preferred compounds have the structures of
formula IIv

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wherein the hashed bond is a saturated or unsaturated bond;
and wherein Al is selected from the group consisting of hydrogen, Z2-substituted branched C3-C8alkyl, R19 substituted C3-C8carbocyclyl, Z2-substituted Cl-C6a!kyi, halogen, cyano: Cl-C6alkoxy, fluoroCl-C6alkoxy, fluoroCl~C6aIkyl wherein the alkyl is fully or partially fluorinated, Z3-substituted phenyl, and Z3-substituted Gl;
and wherein R16 is Cl-C6alkyl, cyano, -CCH, or halogen.
2.9a Additional compounds of Formula IIv which exemplify more preferred X2-EI moieties In an embodiment of section 2,9, preferred compounds have the structures of formula llw

2.9b Additional compounds of Formula IIv which exemplify more preferred X2-E1 moieties In another embodiment of section 2.9, preferred compounds have the structures of formula IIx

and wherein R16 is C1 -C6alkyl, cyano, -CCH, fluorine or chlorine.
2.10 Compounds of Formula Ha which exemplify additional)'prefeired A Moieties
In a different embodiment of section 2.1, additional preferred compounds have the structures of
formula Ily

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wherein Al is selected from the group consisting of Z2-substituted branched C3-C8alkyl3 R19 substituted C3-C8carbocyclyl, Z2-substituted Cl-C6alkyi, fluoroCl-C6alkyl wherein the alkyl is fully or partially fiuorinated, Z3-substituted phenyl, and Z3-substituted Gl;
and wherein R16 is CI-C6alkyl, cyano, -CCH, or halogen.
2.10a Additional compounds of Formula Ily which exemplify more preferred X2-E1 moieties In an embodiment of section 2.10, preferred compounds have the structures of formula IIz

2,10b Additional compounds of Formula Ily which exemplify more preferred X2-E1 moieties In another embodiment of section 2.10, preferred compounds have the structures of formula Ilaa



wherein R16 is methyl, cyano, -CCH, fluorine or chlorine.
2.11 Compounds of Formula Ha which exemplify additionaly preferred A Moieties
In a different embodiment of section 2.1, additional preferred compounds have the structures of
formula Ilbb

wherein R16 is Cl-C6alkyl, cyano, -CCH, or halogen.
2.11a Additional compounds of Formula Ilbb which exemplify more preferred X2-E1 moieties

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In an embodiment of section 2.//, preferred compounds have the structures of formula Hcc

2. lib Additional compounds of Formula Ilbb which exemplify more preferred X2-E1 moieties lii another embodiment of section 2.11, preferred compounds have the structures of formula Ildd



wherein R16 is Cl-C6alkyl, cyano, -CCH, fluorine or chlorine.
2.12 Compounds of Formula Ha which exemplify additionaly preferred A Moieties
In a different embodiment of section 2.1, additional preferred compounds have the structures of
formula Ilee

wherein Ql and Q2 are individually and independently taken from the group consisting of N and CH;
and wherein R16 is Cl-C6alkyl, cyano, -CCH, or halogen.
2.12a Additional compounds of Formula llee which exemplify more preferred X2-E1 moieties In an embodiment of section 2.12 preferred compounds have the structures of formula Ilff

2.12b Additional compounds of Formula lee which exemplify more preferred X2-E1 moieties In another embodiment of section 2.12, preferred compounds have the structures of formula Ilgg

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wherein R16 is Cl-C6allcyls cyano, -CCH, fluorine or chlorine.
2.13 Compounds of Formula Ila which exemplify additional)) preferred A Moieties
In a different embodiment of section 2.1, additional preferred compounds have the structures of
formula Ilhh

and wherein R16 is Cl-C6alkyl, cyano, -CCH, or halogen.
2.13a Additional compounds of Formula Ilhh which exemplify more preferred X2-El moieties In an embodiment of section 2.13 ^ preferred compounds have the structures of forrmila Ilii

2.13b Additional compounds of Formula Ilhh which exemplify more preferred X2-EI moieties In another embodiment of section 2.13, preferred compounds have the structures of formula II jj

and wherein Rl 6 is methyl, cyano, -CCH, fluorine or chlorine.
2.14 Compounds of Formula lla which exemplify additionally preferred A Moieties
In a different embodiment of section 2.1, additional preferred compounds have the structures of
formula Ilkk

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wherein Q6 is N or C-Al;
wherein Al is selected from the group consisting of hydrogen, Z2-substituted branched C3-CSalkyl, R19 substituted C3-C8carbocyclyl, Z2-substituted Cl-C6alkyl, fluoroCl-C6alkyl wherein the alkyl is flilly or partially fluorinated, Z3-substituted phenyl, and Z3-substituted G1;
and wherein R16 is Cl-C6alkyl, cyano, -CCH, or halogen.
2.14a Additional compounds of Formula Ilkkwhich exemplify more preferred X2-El moieties In an embodiment of section 2.14, preferred compounds have the structures of formula Ml


mi


2.14b Additional compounds of Formula Ilkk which exempUjy more preferred X2-El moieties In another embodiment of section 2.14, preferred compounds have the structures of formula [[mm
A1 c - .R16
wherein R16 is Cl-C6alkyl, cyano, -CCH, fluorine or chlorine.
2.15 Compounds of Formula Ha which exemplify additionally preferred A Moieties
In a different embodiment of section 2.1, additional prefened compounds have the structures of
formula linn

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i
R4
wherein Al is selected from the group consisting of hydrogen, Z2-substituted branched C3-CSalkyh R19 substituted C3-C8carbocyclyl, Z2-substituted Cl-C6alkyl, fluoroCl-Cfialkyl wherein the alkyl is fully or partially fluorinated, Z3-substituted phenyl, and Z3-substituted Gl;
and wherein Rl6 is Cl-C6alkyl, cyano, -CCH, or halogen.
2.15a Additional compounds of Formula linn which exemplify more preferred X2-E1 moieties In an embodiment of section 2.15, preferred compounds have the structures of formula Iloo

2.15b Additional compounds of Formula Ilnn which exemplify more preferred X2-E1 moieties Fn another embodiment of section 2.15, preferred compounds have the structures of formula IIpp



wherein R16 is CI-C6aIkyl, cyano, -CCH, fluorine or chlorine.
2.16 Compounds of Formula Ila which exemplify additionally preferred A Moieties
In a different embodiment of section 2.1, additional preferred compounds have the structures of
formula Ilqq


"Iqi

wherein Q3, Q4 and Q5 are selected from the group consisting of N-Al and C-Al, and only one ofQ3,Q4,orQ5isN~Al;

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wherein Al is selected from the group consisting of hydrogen, Z2-substituted branched C3-CSalkyl, R19 substituted C3-C8carbocyclyl, Z2-substituted Cl-C6alkyl, fluoroCl-C6alkyl wherein the alkyl is fully or partially fluorinated, Z3-substituted phenyl, and Z3-substituted Gl;
and wherein R16 is Cl-C6alkyl, cyano, -CCH, or halogen.
2.16a Additional compounds of Formula Ilqq which exemplify more preferred X2-E J moieties In an embodiment of section 2.16, preferred compounds have the structures of formula Ilrr

2.16b Additional compounds of Formula llgg which exemplify more preferred X2-E1 moieties In another embodiment of section 2.16, preferred compounds have the structures of formula llss

wherein R16 is Cl-C6alkyl, cyano, -CCH, fluorine or chlorine.
2.17 Methods
2.17a Methods of Protein Modulation
The invention includes methods of modulating kinase activity of RAF kinases and other kinases
in the RAS-RAF-MEK.-ERK-MAP kinase pathway including, but not limited to, A-Raf, B-Raf,
and C-Raf. The kinases may be wildtype kinases, oncogenic forms thereof, aberrant fusion
proteins thereof or polymorphs of any of the foregoing. The method comprises the step of
contacting the kinase species with compounds of the invention, and especially those set forth in
sections 2J-2.16. The kinase species may be activated or unactivaied, and the species may be
modulated by phosphorylations, sulfation, fatty acid acylations glycosylations, nitrosylation,
cystinylatioii (i.e. proximal cysteine residues in the kinase react with each other to form a
disulfide bond) or oxidation. The kinase activity may be selected from the group consisting of

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catalysis of phospho transfer reactions, kinase cellular localization, and recruitment of other proteins into signaling complexes through modulation of kinase conformation.
2.17b Treatment Methods
The methods of the invention, especially those of sections 2.1-2.16, also include treating individuals suffering from a condition selected from the group consisting of chronic myelogenous leukemia, acute lymphocytic leukemia, gastrointestinal stromal tumors, hypereosinophillic syndrome, glioblastomas, ovarian cancer, pancreatic cancer, prostate cancer, lung cancers, breast cancers, kidney cancers, cervical carcinomas, metastasis of primary solid tumor secondary sites, ocular diseases characterized by hyperproliferation leading to blindness including various retinopathies including diabetic retinopathy and age-related macular degeneration, rheumatoid arthritis, melanomas, colon cancer, thyroid cancer, a disease caused by a mutation in the RAS-RAF-MEK.-ERK-MAP kinase pathway, human inflammation, rheumatoid spondylitis, ostero-arthritis, asthma, gouty arthritis, sepsis, septic shock, endotoxic shock, Gram-negative sepsis, toxic shock syndrome, adult respiratory distress syndrome, stroke, reperfusion injury, neural trauma, neural ischemia, psoriasis, restenosis, chronic obstructive pulmonary disease, bone resorptive diseases, graft-versus-host reaction, Chron's disease, ulcerative colitis, inflammatory bowel disease, pyresis, and combinations thereof,
2.18 Pharmaceutical Preparations
The compounds of the invention, especially those of sections 2.1-2.16, may form a part of a pharmaceutical composition by combining one or more such compounds with a pharamaceutically acceptable carrier. Additionally, the compositions may include an additive selected from the group consisting of adjuvants, excipients, diluents, and stablilizers.
3. Synthesis of compounds ofthe present invention
The compounds of Formulae la and Ha are prepared by the general synthetic methods illustrated
in the Schemes below and the accompanying examples.

.-*

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Compounds of Formula la are prepared as indicated in Scheme 1. In step 1, a suitable chloropyrimidine ester 1 is reacted with an R4-substituted amine to provide compounds of formula 2. Preferred conditions for Scheme 1, step 1, include polar solvents such as DMF, THF, acetonitrile, dioxane, water or mixtures thereof in the presence of optionally added bases such as triethylamine at temperatures between 0 °C and 100 °C. Reduction of ester 2 provides alcohol 3. Preferred reagents for the transformation of step 2 include lithium aluminum hydride in THF at temperatures ranging from 0 °C to room temp. As shown in step 3, aldehyde 4 can be prepared by oxidation of alcohol 3 with oxidants such as manganese dioxide. Condensation of aldehyde 4 with ester 5 (step 4) provides pyridopyrimidinone 6. Preferred conditions for step 4 include optional heating (30-150°C) in DMF or DMAc in the presence of potassium carbonate or cesium

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carbonate for a period of time ranging from 1 h to 4 days. Other preferred conditions for Scheme 1, step 4 include combining aldehyde 4, ester 5 and alumina-supported potassium fluoride in DMAc with stirring and optional sonication and/or optional heating (30-150°C) for a period of 30 min to 48 h. The group "P" in formula 5-8 represents a hydrogen atom or an optional amine protecting group, such as tert-butyl carbamate (Boc), benzyl carbamate (Cbz), acetamide or the like. It is understood by those skilled in the art that the moiety R3-N-P-X2 in formulae 5-8. might also represent an amino surrogate such as nitro or cyano that can be converted to an amino group or aminomethyl group in step 7 by reduction under suitable conditions.
In Scheme 1, step 5, the thiomethyl moiety of 6 can be oxidized to a sulfoxide or sulfone to provide 1_, Preferred reagents for such transformations include peroxybenzoic acids, oxone, oxaziridines, or other oxidants that will be recognized as standard oxidants of sulfur atoms by those skilled in the art. In practice, mixtures of sulfoxides and sulfones can be used in step 6 without prior separation. In step 6, the sulfone or sulfoxide moiety of 7 can be converted to a Z6 moiety that is linked to the pyridopyrimidinone through a heteroatom to provide 8. by the contacting of 7 with moieties of Z6-H [for example NH(R4)i, HOR4 or HSR4] optionally in the presence of a base such as potassium ter/-butoxide, sodium hydride or the tike or, alternatively, in the presence of a strong acid such as hydrochloric acid. Preferred solvents for such transformations include dioxane, DMF, THF, alcoholic solvents or neat Z6-H at temperatures ranging from 0 °C to 200 °C. Those skilled in the art will recognize that in certain instances. compounds of formula % can be prepared directly from compounds of formula 6 using die conditions of step 6. hi the instance that Z6 is hydrogen, preferred methods include exposure of compounds of fonnula 6 or 7 to hydrogen gas in the presence of a suitable hydrogenation catalyst, for example Raney Nickel® or Pd on carbon in a suitable solvent such as ethanoi, methanol, ethyl acetate or THF.
In Scheme 1, step 7, the optional protecting group P of formula 8, can be removed, if necessary, by appropriate de-protection conditions (for example, acidic hydrolysis for a Boc or hydrogenation for a Cbz) to provide compounds of formula 9. Step 7 may also encompass the conversion of amine surrogates (such as nitro) into amines by appropriate chemistries (for example, reduction of a nitro group with Zn/ammonium chloride or by hydrogenation with a Pd catalyst). Finally, the conversion of compounds of fonnula 9 to compounds of formula 10, an aspect of formula la. can be accomplished in step 8 by reaction with isocyanates of formula A-

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NCO, 11. It will be understood that the isocycantes JJ. may be either introduced into the reaction directly or may be prepared in situ, tor example, by the decomposition of acyl azides (Curtius rearrangement) in the presence of 9. It will be further understood by those skilled in the art that certain carbamates, for example rrichloroethyl carbamates (12) and isopropenyl carbamates (13) also function as isocyanate equivalents and will find use in step 8.
An alternative preparation of intermediate 6 is shown in Scheme 2. Treatment of aldehyde 4 from Scheme 1 with ethyl (triphenylphosphoranylidene)acetate provides compounds of formula _14. Brornination of 14 with N-bromosuccinimde (step 2) provides bromide 15. In step 3, Suruki-type couplings of 15 with boronic acids 16 in the presence of palladium catalysts provide compounds of formula 6, useful for the preparation of compounds of formula 10 as illustrated in Scheme I.

Non-commercially available pyrimidines 1 can be readily prepared from known intermediate 17 [See Seto, et al Biorg, Med. Client. Lett. 2005, 7J, 1485], (Scheme 3) Thus, lithiation of J_7 with LDA followed by CO? quench provides acid jji. Conversion of acid J_8 to ester 19 provides a scaffold to introduce Z6 groups of the invention. When the Z6 moiety is attached to the pyrimidine ring through a Z6~ nitrogen atom, a Z6 oxygen atom or a Z6 sulfur atom, compounds of formula 1 can be prepared by contacting the amine Z6-H, the alcohol Z6-H or the thiol Z6-H with compound 19. either neat (Z6-H as solvent) or in a suitable solvent such as DMF, DMSO or an alcoholic solvent at temperatures ranging from -78 °C to 200 °C in the presence of suitable base such as triethylamine, potassium carbonate, or potassium tert-butoxide, When the Z6 moiety is attached to the pyrimidine through a Z6 carbon atom, preferred methods include contacting compound 19 with a species of formula Z6-M in the presence of a palladium

cat4f£rst, wherein M is a species that participates in transition-metal catalyzed cross-coupling reactions. Examples of suitable M groups include but are not limited to, boronic acids and boronic esters, zinc, copper, tin, silicon, magnesium, lithium, and aluminum.
Scheme 3

1 Compounds of both Formulae la and Ila can be prepared by the additional methods in Scheme 4, below. As shown in step 1, reaction of R4-substituted amines with 5-bromo-2,6-dichloropyrimidine (22, commercially available), 3-bromo-2,6-dichloropyridine (21, available by the procedure of Pierrat et al. J. Comb. Chem. 2005, 7, 879-886) or 5-bromo-2,4-dichloropyridine 20, available by the procedure of Schlosser et al, J. Org. Chem. 2005, 70, 2494-2502) provides compounds 23-25 respectively. In step 2, treatment of bromides 23-25 with tri butyl vinyl tin in the presence of a palladium catalyst provides compounds of formula 26-28. In step 3, oxidative cleavage of the olefin moiety provides aldehydes of formula 29-31-

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In Scheme 4, step 4, condensation of 29-31 with ester 5 provides 32-34. Preferred conditions for step 4 include optional heating (30-150°C) in DMF or DMAc in the presence of potassium carbonate or cesium carbonate for a period of time ranging from 1 h to 4 days. Other preferred conditions for Scheme 4, step 4 include combining aldehyde 29-31, ester 5 and alumina-supported potassium fluoride in DMAc with stirring and optional sonication and/or optional heating (30-150°C) for a period of 30 min to 48 h. As described in Scheme 1, the group "P" present in formulas 32-37 represents a hydrogen atom or an optional amine protecting group,

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such as tert-butyl carbamate (Boc), benzyl carbamate (Cbz), acetamide or the like. It is understood by those skilled in the art that the moiety R3-N-P-X2 in formula 32-37 might also represent an amino surrogate such as nitro or cyano that can be converted to an amino group or an aminomethyl group in step 6 by reduction under suitable conditions.
As shown in Scheme 4, step 5, compounds of formula 32-34 can be converted to compounds of formula 35-37 by replacement of the chloride moiety of 32-34 with a Z6 moiety. There are several methods through which this can be accomplished, depending on the nature of the Z6. When the Z6 moiety is attached to the Ql-containing ring through a Z6 nitrogen atom, preferred methods include heating compounds of formula 32-34 with an excess of the amine Z6-H either neat or in a solvent such as N-methylpyrrolidinone, DMF, DMSO or an alcoholic solvent at temperatures ranging from room temp to 200 °C, For the case of aryl and heteroaryl amines Z6-H, additional preferred methods include the heating of compounds 32-34 with an excess of the amine Z6-H and an acid catalyst (for example, TsOH, HC1, HOAc or die like) in a suitable solvent such as DMF, DMSO or an alcoholic solvent. Additional preferred methods for aryl and heteroaryl amines Z6-H include heating with compounds ^32-34 in the presence of a transition metal catalyst such as a palladium catalyst in a suitable solvent like 1,4-dioxane or DMF. When the Z6 moiety is attached to the Q-containing ring through a Z6 oxygen or sulfur atom, preferred methods include heating 32-34 with alcohol or thiol Z6-H in the presence of a strong base (for example, NaH or potassium tert-butoxide) either neat using Z6-H as the solvent, or in a polar solvent such as DMF or DMSO at temperatures ranging from room temp to 200 °C. When the Z6 moiety is attached to the pyridopyrimidine through a Z6 carbon atom, preferred methods include contacting compounds 32-34 with a species of fonnula Z6-M in the presence of a palladium catalyst, wherein M is a species that participates in transition-metal catalyzed cross-coupling reactions. Examples of suitable M groups include but are not limited to, boronic acids and boronic esters, zinc, tnalkykin, silicon, magnesium, lithium, and aluminum. In the instance that Z6 is hydrogen, preferred methods include exposure of compounds of formula 32-34 to hydrogen gas in the presence of a suitable hydrogenation catalyst, for example Raney Nickel® or Pd on carbon in a suitable solvent such as ethanol, ethyl acetate or THF.
As shown in Scheme 4, step 6, removal of the optional protecting group P provides compounds of formula 38-40. which can be further converted (step 7) to compounds of formula 41-43, examples of Formula la and Ila, by the methods described in Scheme 1.

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Scheme 5 illustrates an alternate, preferred method for die preparation of chloropyridine aldehydes 29, useful for the preparation of amines 32 and compounds of general formula 11a. Thus, by analogy to Scheme 1, ethyl 4,6-dichloronicotinate (44) is reacted with an R4-substituted amine to provide a compound of formula 45. Preferred conditions for Scheme 5, step 1, include polar solvents such as DMF, THF, acetonitrile, dioxane, water or mixtures thereof in the presence of optionally added bases such as triethylamine at temperatures between 0 DC and 100 °C. Reduction of ester 45 provides alcohol 46. Preferred reagents for the transformation of step 2 include lithium aluminum hydride in THF at temperatures ranging irom 0 °C to room temp. As shown in step 3, aldehyde 29 can be prepared by oxidation of alcohol 46 with oxidants such as manganese dioxide. Condensation of aldehyde 29 with ester 5 according to Scheme 4 provides 32, useful for the preparation of compounds of Formula Ha.
Scheme 5

It will be recognized in the above Schemes and the accompanying examples that some Z6 moieties may be introduced with protecting groups that will require additional de-protection steps. For example, Scheme 6 shows a preferred route to preparing pyridopyridines of fonnula 48 wherein Z6 is NHMe. In Scheme 6, step ], chloropyridine 32 is reacted with (4-methoxybenzyljm ethyl amine to provide 47. Step 1 may be performed in neat (4-methoxybenzyl}methylamine at temperatures between 150 °C and 200 °C. Or more preferably. step 1 can be conducted using only a slight excess of (4-methoxybenzyl)methylamine and DBU (l,8-diazabicyclo[5.4.0]undec-7-ene) in N-methylpyrrolidinone at temperatures between 150 °C and 200 °C In step 2, removal of the 4-methoxybenzyI protecting group from 47 with trifluoroacetic acid provides amine 48.

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In addition to the methods of urea formation described in Schemes 1 and 4 above, ureas of formulae la and Ilamay also be prepared as shown in Scheme 7. In Scheme 7, step 1, amines of formulae 49-51 are reacted with isopropenyi cMorofbrmate to afford the corresponding isopropenyl carbamates 52-54- In step 2, carbamates 51-54 are reacted with amines of formula A-NHR3 (55) to provide ureas of formula 56-58. hi the event that R3 is not H, the mono-substituted ureas 56-58 can be optionally further transformed into bis-R3-substituted ureas 59-61. Thus, in step 3, exposure of the NH-ureas 56-58 to alkyl halides in the presence of a base, for example potassium carbonate, NaH, potassium t-butoxide or BEMP, in a suitable solvent such as DMF provides ureas 59-61 wherein the newly incorporated R3 group is alkyl.
Alternatively, exposure of ureas 56-58 to copper(II) acetate and phenylboronic acids [See: Chan et.ai, Tetrahedron Lett. 2003, 44, 3863-3865; Chan et.al, Tetrahedron Lett 1998, 39, 2933-2936; Chan, D. M. T. Tetrahedron Lett. 1996, 37, 9013-9016] provides the analogous compounds 59-61 wherein the newly incorporated R3 is phenyl.



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General method A: To a solution of the starting pyrazole amiiie (1 eq) in EtOAc were added 2,2,2-trichloroethylchloroformate (1.1 eq) and saturated NaHC03 (2-3 eq) at 0 °C. After stirring for 3h at RT, the layers were separated and the aqueous layer extracted with EtOAc. The combined organic extracts were washed with brine, dried (Na2S4) and concentrated in vacuo to yield the crude TROC carbamate of the pyrazole amine. To the carbamate (1 eq) in DMSO were added diisopropyl ethyl amine (2 eq), the appropriate amine (2 ecp and the mixture was stirred at 60 °C for 16h or until all the starting carbamate was consumed. Water was added to the mixture and the product was extracted with EtOAc (2x25 mL). The combined organic extracts were washed with brine solution, dried (Na2S04) and concentrated ifl vacuo to yield crude product, which was purified by column chromatography to yield the target compound.
General method B: To a suspension of the amine (usually 0.6'? mmol) in EtOAc (2 mL) was added aqueous IN NaOH. The reaction mixture was cooled to 0 °C and treated with isopropenyl chloroformate (0.1 mL, 0.94 mmol) over 30 sec. The reaction mixture was stirred 15 min at 0 °C and 1 h at RT. The reaction was poured into THF-EtOAc (1: J; 40 mL) and washed with H20 (2x10 mL) and brine (2x10 mL). The organics were dried (Na2$04), concentrated in vacuo and the residue purified via column chromatography to provide the target (prop-l-en-2-yl)carbamate. To the carbamate (usually 0.26 mmol) was added the appropriate amine (usually 0.26 mmol) in THF (2 mL) and 1-methylpyrrolidine (Catalytic amount) at 60 °C for 18h. The mixture was diluted with CH2C12 (2 mL) and hexane (0.5 mL) solution, and Stirred for 10 min. The resultant solid was filtered and dried and the resulting solid converted to the amine hydrochloride salt by treatment with 0.1 N HCI solution and lyophilizarion.
General Method C: To a stirring solution of amine (2 mmol, 1 -00 eq) and pyridine (4 mmol, 2.00 eq) in CH2C12 (18 ml) at RT was added Troc-Cl (1.87 mrool, 1.05 eq). After 4 hours the reaction was washed with 3M HCl (lx), satd. NaHC03 (lx), dried (Na2S04), filtered and evaporated to afford the target 2,2,2-trichloroethyl carbamate. TN material was used as is in the next reaction.
The 2,2,2-trichloroediyi carbamate (0.7 mmol, 1.00 eq), the appropriate (0,7 mmol, 1.00 eqjand iPr2NEt (1.54 mmol, 2.20 eq) were combined in DMSO (3 ml) arid stirred with heating at 70 °C.


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After 18 h, the completed reaction was diluted with brine (30 ml) and extracted with EtOAc (3x). The combined organics were washed with brine (2x), dried (MgSGi), filtered and evaporated to give the crude product which was purified via flash column chromatography.
General Method D: To a stirring 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 was added Et3N (1.5 mmol, 3.00 eq). After stimng for 30 min at RT, the appropriate amine (0.76 mmol, 1.50 eq) was added and the mixture was heated at 100 °C. After 2 h, the completed reaction was cooled to RT, diluted with brine and extracted with EtOAc (2x). The combined organics were washed with 3M HC1 (lx), satd. NaHCOa (2x), and brine (lx), dried (MgSCU), filtered and evaporated to give the crude product which was purified by flash column chromatography to afford the target urea.
General Method E; To a solution of aryl sulfone and/or aryl sulfoxide (0.4 mmol) in THF added the appropriate amine (2 mmol, 5eq) and the reaction was stirred for 2h at RT. The mixture was diluted with EtOAc (3 mL) and resultant solid filtered, washed and dried to provide the desired product aryl amine.
General Method F: To a stirring suspension of isocyanate (0.51 mmol, 1.00 eq) and pyridine (0.0418 ml, 0.51 mmol, 1.00 eq) in CH2C12 (5 ml) at RT was added the appropriate amine (0.51 mmol, 1.00 eq). A thick suspension gradually formed. After 3.5 h, the solids were collected by filtration, rinsed well with CH2CI2 and dried on the filter to afford the desired urea.
General Method G: To a solution of amine (11 mmol) in THF (100 mL) was added LiHMDS (22 mmol) at -78 °C under Ar. After 20 min, prop-l-en-2-yl carbonochloridate (11 mmol) was added and the reaction was stirred for 30 min. The mixture was quenched with 2N HC1 (15 mL) at -78 °C and warmed to RT. It was diluted with brine (50 mL) and EtOAc (50 mL), the organic layer was separated and washed with brine, dried (Na2S04) and concentrated in vacuo. Purification by silica gel chromatography or recrystallization provided the appropriate prop-1 -en-2-yl carbamate.
To the carbamate (usually 0.26 mmol) was added the appropriate amine (usually 0.26 mmol) in THF (2 mL) and 1-methylpyrrolidine (Catalytic amount) at 60 °C for 18h. The mixture

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was diluted with CH2CI2 (2 mL) and hexane (0.5 mL) solution, and stirred for 10 min. The resultant solid was filtered and dried and the resulting solid converted to the amine hydrochloride salt by treatment with 0.1 N HC1 solution and lyophilization.
Example Al: To a solution of Example A3 (6.0 g, 19 mmol) in CH2O2 (50 mL) was added m-chloroperoxybenzoic acid (mCPBA, 6.5 g, 38 mmol) in one portion. After stirring for 2h at RT, sat. aq NaHCCh and aq NaHSC3 solution were added and stirring was continued for a few minutes. The combined organic layer was washed with brine, dried and concentrated in vacuo. The residue was dissolved in DMSO (5 mL) and ammonia in dioxane (2 M, 200 mL, 400 mmol) was added. The resultant reaction mixture was stirred overnight at RT. The solvent was removed under reduced pressure and the residue was purified by reverse phase prep-HPLC to provide 2-amino-6-(3-amino-4-fluorophenyl)-8-methylpyrido[2,3-d3pyrimidin-7(8H)-one (1.9 g, 35% yield). lH NMR (300 MHz, DMSO-40, 6 8.63 (s, 1 H), 7.80 (s, 1 H), 7.39 (br s, 2 H), 7.12 (d, J= 6.0 Hz, 1 H), 7.03 (t, J =12.0 Hz, 1 H), 6.80 (m, 1 H), 3.53 (s, 3 H); MS (ESI) m/z: 286,2 (M+H%
Example A2: Using a procedure analogous to Example Al, Example A9 (3.50 g, 10.6 mmol) was oxidized with mCPBA (2.87 g, 11.7 mmol, 70% wt) to afford the intermediate 6-(3-amino-4-fluorophenyl>8-ethyl"2-(methylsulfinyl)pyrido[2,3-d]pyrimidin-7(8H)-one (2.35 g, 61% yield). The intermediate (1.40 g, 3.86 mmol) and 0.5 M ammonia in dioxane (15.5 mL, 2 eq) were combined and purified by silica gel column chromatography to obtain 2-amino-6-(3-anuno-4-fIuorophenyI)-8-ethyIpyrido[2t3-d]pyrimidin-7(8H)-one (0.65 g, 56% yield). 'H NMR (400 MHz, DMSO-rfe): 8 8.63 (5, 1H): 7.79 (s, IH), 7.27 (s, IH), 7.10 (dd,J= 2.4, 8.8 Hz, IH ), 7.00 (dd, 7=8.8, 11.6 Hz, IH), 6.75 (m, IH), 5.14 (s, 2H), 4.31 (q, J= 6.8 Hz, 2H), 1.18 (t, 7-6.8 Hz, 3H); LC-MS (EI) m/z: 300.0 (M+H+).
Example A3: A mixture of Example CI (15 g, 82 mmol), ethyl 2-(3-amino-4-fluorophenyl)acetate (19.4 g, 98 mmol; prepared by the method of Kuse et al. Tetrahedron (2005), 61, 5754-5762) and K2CO3 (34.0 g, 246 mmol) in DMF (100 mL) was heated at 110 °C overnight. The mixture was poured into water and product was extracted with ethyl acetate (3 x 200 mL). The combined organics were washed with brine, dried (Na2SO4) and concentrated in

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vacuo. Purification by silica gel chromatography provided 6-(3-amino-4-f!uorophenyl)-8-methyl^2-(methylthio)pyrido[2J3-d]pyrimidin-7(SH)-one (13.0 g, 50% yield). 'H NMR (300 MHz, DMSO-4), 6 8.91 (s, 1 H), 7.99 (s, 1 H), 7.15 (dd, J = 8.7, 2.1 Hz, 1 H), 7.04 (dd, J = 11.4, 8.4,1 H), 6.80 (m, 1 H), 5.21 (br s, 2 H), 3.65 (s, 3 H), 2.60 (s, 3 H); MS (ESI) m/z: 317.2 (M+H+).
Example A4: Using general method E, 6-(3-amino-4-fluorophenyl)-8-ethyl-2-
(methylsultinyI)p}Tido[2J3-d]pyrimidin-7(8H)-one from Example 2 (0.94 g, 2.73 mmol) and 2.0 M methylamineTHF (2.73 mL, 5.5 mmol) were stirred overnight at RT. Water (50 mL) was added and the product was extracted with EtOAc (2 x 30 mL). The combined organic layers were washed with brine, dried (Na2SO4) and concentrated to afford crude product. This crude product was stirred with 60%) CCh/hexane solution (10 mL) for 10 mm. The resultant solid was filtered and washed with 60% CCh/hexane solution and dried to afford 6-(3-amino-4-fluorophenyl)-8-ethyl-2-(methylamino)pyrido[2,3-d]pyrimidin-7(8H)-one (0.32 g, 37% yield) as a solid. 'H NMR (400 MHz, DMSO-f6): 8 8.62 (s, 1H), 7.82-7.77 (m, 2H), 7.11 (dd, J= 8.8 Hz, 1.6 Hz, LH), 7.00 (dd, J = 11.2 Hz, 8.0 Hz, 1H), 6.78-6.74 (m, 1H), 5.14 (s, 2H), 4.39-4.35 (m, 2H), 2.89 (d, 7 = 4.4 Hz, 3H), 1.26-1.22 (m, 3H); MS (ESI) m/z: 314.3 (M+H*).
Example A5: Using a two-step procedure analogous to Example A27, Example A55 (1.3 g, 3.2 mmol) and 4-Methoxybenzylamine (10 mL) were converted to 7-amino-3-(3-amino-4-fluorophenyl)-l-metiiyl-l,6-naphmyridin-2(lH)-one (0.55 g, 54%, yield, two steps). ]H NMR (400MHz, DMSO-Jtf): 68.34 (s, 1 H), 7.77 (s, 1 H), 7.07 (dd, J= 9.2, 2.4 Hz, 1 H), 6.97 (m, 1 H), 6.75 (m, 1 H), 6.50 (s, 2 H), 6.24 (s, 1H), 5.10 (s, 2H),, 3.47 (s, 3 H), MS (ESI) m/z (M+rT): 2S5.3.
Example A6: Using a procedure analogous to Example Al, Example A10 (0.200g, 0.605 mmol) and N,N-dimethylethylenediamine (0.334 ml, 3.03 mmol) were combined to afford 6-(5-amino-4-fluoro-2-memyIphenyl)-2-(2-(dimeUiylammo)ethylamino)-8-metliylpyrido[2^-d]p>'rimidm-7(8//)-one (0.095 g, 42% yield) as a yellow foam. !H NMR (400 MHz, CDC13) 8 8.40 (s, 1H), 7.36 (s, 1H), 6.85 (d, .7=11.6 Hz, 1H), 6.62 (d, J = 9.2 Hz, 1H), 6.11 (s, 1H), 3.79 (s, 3H), 3.57

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(q, J = 5.6 Hz, 2H), 2.56 (t, / = 6.0 Hz, 2H), 2.29 (s, 6H), 2.07 (s, 3H); MS (ESI) m/z: 371.2 (M+H*).
Example A7: The mixture of Example AII (0.050 g, 0.16 mmol) and N,N-dimethylethane-f ,2-diamine (2.0 mL, 18 mmol) was heated at 175 °C under N2 overnight. The reaction was cooled down to RT and solvent was removed under reduced pressure. The residue was quenched with satd. NaHC03 (6 mL) and extracted with EtOAc (2x10 mL). The combined organic layers were washed with brine (6 mL), dried (MgSO,*) and concentrated to afford 3-(5-amino-4-fluoro-2-methylphenyl)-7-(2-(dimetliylamino)elhylamino)»l -methyl-1,6-naphfhyridin-2(lH)-one (0.050 g, 86% yield) as a light yellow foam. !H NMR (400 MHz, CDCI3), 5 8.28 (s, IH), 7.43 (s, IH), 6.86 (d, J= 12.0 Hz, IH), 6.64 (d, J= 9.2 Hz, IH), 6.06 (s, IH), 5.58 (m, IH), 3.60 (s, 3H), 3.40 (q, J = 5.2 Hz, 2H), 2.60 (I, J = 6.0 Hz, 2H), 2.28 (s, 6H), 2.09 (s, 3H); MS (EST) m/z: 370.2 (M+H4).
Example A8: Using procedures analogous to Example C2 and Example A2, ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate, cyclopropyl amine, ethyl 2-(3-amino-4-fluorophenyl)acetate (prepared by the method of Kuse et al. Tetrahedron (2005), 61, 5754-5762) and 0.5 M ammonia in dioxane (2 ml) were combined to afford 2-amino-6-(3-amino-4-fluorophenyI)-8-cycJopropyIpyrido[2,3-d]pyrimidin-7(8H)-oneas an off-white solid (67 mg). JH NMR (400 MHz, DMSO-rf6): 5 8.57 (s, IH), 7.73 (s, IH), 7.15 (brs, IH), 7.06 (dd, / = 9.2 Hz, 2.4 Hz, IH), 6.99 (6d,J= 11.2 Hz, 11.6 Hz, IH), 6.75-6.71 (m, IH), 2.88-2.82 (rn, IH), 1.18-1.13 (m, 2H), 0.83-0.78 (m, 2H); MS (ESI) m/z: 312.0 (M+H*).
Example A9: Method 1: To a solution of Example C2 (8.0 g, 0.041 mol) and ethyl 2-(3-amino-4-fluorophenyl)acetate (8.0 g, 0.041 mol) in DMAc (200 mL) was added KF on AI203 (40 wt %, 40 g, 0.275 mol) and the mixture was stirred at RT for In. The reaction mixture was filtered and the filtrate was concentrated to dryness. The residue was washed with ethyl ether to provide 6-(3-aniino-4-fiuorophenyl)-8-ethyI-2-(methylthio)pyrido[2,3-d]pyrimidm-7(8H)-one (10.9 g, 81 % yield). 'H NMR (400 MHz, DMSO-d6): 5 S.S8 (s, 1 H), 7.96 (s, 1 H), 7.10 (dd, J= 9.2, 2.4 Hz, 1 H), 7.00 (dd, J = 11.4, 8.6 Hz, 1 H), 6.76 (m, 1 H), 5.17 (s, 2 H), 4.36 (q,y= 6.8 Hz, 2 H), 2.57 (s, 3 H), 1.22 (t, J= 6.8 Hz,3H); MS (ESI) m/z: 331.1 [M + H]+.

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Method 2: The compound from Example C2 (2.08 g, 10.5 mmol), ethyl 2-(3-amino-4-fluorophenyl)acetate (2.29 g, 11.6 mmol) and powdered K2CO3 (4.37 g, 31.6 mmol) were combined in DMF (15 mL) and vigorously stirred with heating at 110 °C under a N2 atmosphere. The completed reaction was cooled partially and diluted with H2O (60 mL) to precipitate product. The suspension was chilled thoroughly in ice. The solid was filtered and washed with water (100 mL) to obtain the crude product, 6-(3-arnino-4-f3uorophenyl)-8-ethyl-2-(memy1fm^)pyrido[2^-d]pyrimidin-7(8H)-one(3.50g, 100% yield).
Example A10: Nitrogen was bubbled though a solution of Example D4 (2 g, 8.0 mmol), 6-
bromo-8-memyl-2-(mediylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (2.5 g, 8.8 mmol) and
potassium carbonate (3.3 g, 23.9 mmol) in DMF (10 mL) for 20 min, then tetrakis(triphenyl
phosphine) palladium (460 mg, 0.4 mmol) was added and the nitrogen was continued for 30
min. The resulting mixture was heated at 80 °C for 16 h. The excess DMF was removed under
reduced pressure and tlie residue was partitioned between water and EtOAc. The organic layer
was washed with brine, dried, filtered concentrated and purified by silica gel column
chromatography to give 6~(5-amino~4-fluoro-2-methylphenyl)-8-methyl-2-
(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (1.1 g, 42.3% yield). *H NMR (400 MHz, DMSO-rfd): 6 8.86 (s, 1 H), 7.80 (s,l H), 6.87 (d,J= 12.0 Hz, 1 H), 6.58 (d, J = 8.0 Hz, 1 H), 4.96 (br s, 2 H ), 3.62 (s, 3H), 2.59 (s, 3 H), 1.95 (s, 3 H). MS (ESI) m/z: 331.2 (M+H+).
Method 2: Example CI (3 g, 16.4 mmol) and Example Dl (3.46 g, 16.4 mmol) were combined in DMAc (30 mL). KF/AI2O3 (40 wt %, 19 g. 130 mmol) was added and resulting slurry was stirred vigorously at RT for 30 min. The solids were removed by filtration and the filter cake was washed with DMAc. The combined organics were concentrated in vacuo to give a residue which was slurried with water and filtered to provide 6-(5-amino-4-fluoro-2-methylphenyl)-8-methyl-2-(methylthio)pyrido[2,3-d]pyriraidin-7(8H)-one(700 mg, 13% yield).
Method 3: Cs2C03 (40.0 g, 123 mmol) was added to a solution of Example Dl (10.00 g, 47 mmol, leq ) and Example CI (S.Og, 44 mmol, 0.92eq) in DMF (100 mL). The reaction mixture was stirred at RT for 15 hours. Water (800 mL) was added with stirring. The precipitate was filtered and washed with water to provide the crude product. The crude product was slurried
in methanol with heating to 50°C for 20 minutes. The hot suspension was filtered and the

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collected solids were dried in vacuo to provide 6-(5-amino-4-fluoro-2-metliylphenyl)-8-metliyl-2-(methyiaiio)pyrido[2,3-d]pyrimidin-7(8H}-one (11.4 g, 73 % yield).
Example All: To a solution of Example C3 (2 g, 11.8 mmof) in DMAc (40 mL) was added Example Dl (2.5 g, 11.8 mmol}, followed by KF/AI2O3 (40 wt %, 10 g, 68 mmol). The reaction mixture was stirred at RT for 2 hours. The reaction mixture was filtered and 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-chloio-l-methyl-l,6-naphthyridin-2(lH)-one (2.5 g, 69% yield). *H NMR (300 MHz, DM$0-rf6): S 8.72 (s, 1 H), 7.90 (s, I H), 7.62 (s, 1 H), 6.88 (d, J= 12.3 Hz, 1 H), 6.60 (d, J = 6 Hz, 1 H), 4.95 (s, 2 H), 3.60 (s, 3 H), 1.95 (s, 3 H); MS (ESI) m/z: 318.0 [M + H]+.
Example A12: Using a procedure analogous to Example Al, Example A3 (4.0g, 12.6 mmol), mCPBA (3.43 g, 13.9mmol) and metiiylamine hydrochloride (1.73g, 25.3mmol) were combined to afford 6-(3-amino-4-fluorophenyl)-8-methyl-2-(methylamino)pyrido[2,3-d]pyrimidin-7(8H)-one as a yellow solid ( 3.00 g, 79% yield). 1H NMR (400 MHz, DMSO-d6) 5 8.70 and 8.62 (br s, 1 H), 7.81 (s, lH),7.78(m, 1 H), 7.11 (dd, J = 8.8, 2.0 Hz, 1 H), 7.00 (dd, J = 11.6, 8.0 Hz, 1 H), 6.77 (m, 1 H), 5.13 (s, 2 H), 3.59 and 3.54 (s, 3 H), 2.91 (d, J = 4.4 Hz, 3 H); MS (ESI) m/z: 300.3 [M + H]+.
Example A13: A solution of Example A3 (2.5 g, 7.9 mmol) in EtOH (30 ml) was treated with Raney Nickel (50% slurry in water, 10 g, 85 mmol) and the mixture was refmxed for 3h. The cooled reaction was filtered and the filtrate was concentrated to give the crude product, which was washed with cold MeOH (2 mL) to give 6-(3-amino-4-fluoro-phenyl)-8-methyl-SH-pyrido[2,3-d] pyrimidm-7-one (1.0 g, 47 % yield). 'H NMR (300 MHz, DMSO-6) 6 9.10 (s, H), 9.07 (s, 1 H), 8.06 (s, 1 H), 7.14 (dd, ./= 8.7, 2.1 Hz, 1 H), 7.05 (dd, J= 11.4, 8.4 Hz, 1 H), 6.82 (m, 1 H), 5.22 (s, 2 H), 3.68 (s, 3 H); MS (ESI) m/z: 271.3 (M+H+).
Example Al 4: A solution of Example A10 (500 mg, 1,5 mmol) in dioxane(l mL) andNH3~H20 (5 mL) was heated to 180°C in a steel bomb for 3 h. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to afford 2-amino-6-

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(5-ammo^-fluoro-2-mediylphenyl)-8-methylpyrido[2,3-d]pyrirnidin-7(8H)-one (110 mg, 24% yield). 'H NMR (300 Hz, DMSO-d6)\ S 8.58 (s, 1 H), 7.59 (s, 1 H), 7.25 (s, 2 H), 6,85 (d, J = 12.6 Hz, 1 H), 6.57 (d, J = 9.3 Hz, 1 H), 4.88 (s, 2 H), 3.53 (s, 3 H), 1.95 (s, 3 H); MS (ESI) m/z: 300.3 [M+Hf.
Example A15: By analogy to Example A3, 4-ammo-2-(methylthio)pyrimidine-5-carbaldehyde (1 g , 5.9 mmol, prepared according to Barvian etal. J. Med. Chem. (2000), 43, 4606-4616), K.2CO3 (2.4 g, 17.4 mmol) and (3-amino-4-fluoro-phenyl)-acid ethyl ester (1.4 g, 7.1 mmol) were combined to provide 6-(3-amino-4-fluorophenyl)-2-(methyIthio)pyrido[2,3-d]pyrimidin-7(8H)-one ( 1.1 g , 56%, yield). [H NMR (300 MHz, DMSO-rfe), S 12.51 (br s, 1 H), 8.87 (s, 1 H), 7.95 (s, 1 H), 7.12 (dd, 7=9.0, 2.1 Hz, 1 H), 7.02 (dd,J= 11.4, 8.4 Hz, 1 H), 6.80 (m, 1 H),5.19(s,2 H), 2.55 (s, 3 H); MS (ESI) m/z: 303.2 [M-H]+.
Example Al 6: A mixture of Example CI (2.4 g, 13 mmol), Example D2 (2.8 g, 13 mmol) and KF/A1203 (40 wt %, 10 g, 69 mmol) in DMAc was stirred at RT for 10 min. The reaction mixture was poured into water and the mixture was extracted with EtOAc (3x). The combined organic extracts were washed with brine, dried (Na2S04), concentrated in vacuo and chromatographed to give 6-(5-amino-2,4-difluorophenyl)-8-methyl-2~(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (2.5 g, 58 % yield). 'H NMR (300 MHz, DMSO-d6): S 8.91 (s, 1 H), 7.98 Example A17: To a solution of Example D3 (3 g, 13 mmol) and Example CI (2.4 g: 13 mmol) in DMAc (50 mL) was added KF/AUO3 (40 wt %, 10 g, 69 mmol). The resultant mixture was stirred at RT for 1 hour. The reaction was filtered and the filtrate was concentrated in vacuo and poured into water. The precipitate was collected by filtration and washed with Et20 to provide 6-(5-ammo-2-chloro-4-fiuoro-phenyl)-8-methyl-2-methylsiilfanyl-8H-pyrido[2,3-d]pyrimidin-7-one (2.9 g, 64% yield). !H NMR (400MHz, CDCI3): 5 8.59 (s, 1 H), 7.58 (s, 1 H), 7.09 (d, J = 10.4 Hz, 1 H), 6.73 (d, J= 9.2 Hz, 1 H), 3.75 (s, 3 H), 3.72 (br s, 2 H), 2.62 (s, 3 H); MS (ESI) m/z: 351.2 [M+H]+.

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Example Al 8: A solution of Example C2 (2.0 g, 10.2 mmol), Example D3 (2.3 g, 10.2 mmol) and KF/A1203 (40 wt% 4 g, 27 mmol) in anliydrous DMAc (50 mL) was stirred at RT for 10 min. The reaction mixture was poured into water and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine, dried (NaiSCU), concentrated in vacuo and purified by silica gel chromatography to give 6-(5-amino-2-crnoro-4-fluorophenyI)-8-ethyl-2~ (methylthio)pyrido[2J-d3pyrimidhv7(8H)-one (2.5 g, 67.6% yield). 'H NMR (300 MHz, DMSO-40, S 8.89 (s, 1 H), 7.91 (s, 1 H), 7.23 (ds 7=11.1 Hz, 1 H), 6.75 (d, 7 = 9.3 Hz, 1 H), 5.40 (s, 2 H), 4.35 (q, 7 = 6.6 Hz, 2 H); 2.59 (s, 3 H), 1.22 (t, 7 = 6.6 Hz, 3 H); MS (ESI) m/z: 365.2 [M+Hf.
Example A19: Example C4 (1 g, 4.2 mmol) in DMAc (10 mL), ethyl (3-amino-4-fluoro-phenyl)-acetate (0.83 g, 4.2 mmol) and KF/A1203 (40 wt %, 2 g, 34 mmol) in DMAc (10 mL) were combined by the procedure of Example A17 to provide 6-(3-amino-4-fluorophenyl)-8-cycl op entyl-2-(methyl thio)pyrido[23-d]pyrimidin-7(8H)-one (1 g, 64% yield). !H NMR (400MHz,CDCl3): S 8.63 (s, 1 H),7.60 (s, 1 H), 7.13 (dd, 7 = 8.4, 2.0 Hz, 1 H), 7.03 (dd, 7= 10.8, 8.4 Hz, 1 H), 6.92 (m, 1 H), 6.05 (m,l H), 2.64 (5, 3 H), 2.41-2.32 (m, 2 H), 2.13-2.05 (in, 2 H), 1.95-1.87 (m, 2 H), 1.72-1.65 (m, 2 H); MS (ESI) m/z: 371.0 [M+H]+.
Example A20: To a solution of Example A10 (1.30 g, 3.93 mmol) in ethanol (20 mL) was placed Raney Nickel® (50% slurry in water, 5.08 g, 43.3 mmol). The reaction mixture was refluxed overnight. The mixture was filtered through Celite and washed with EtOH. The combined filtrates were evaporated. The residue was treated with EtOAc and the solid was filtered to obtain 6-(5-amino-4-fiuoro-2-methylphenyl)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one (0.65 g, 58% yield). 'H NMR (400 MHz, DMSO-d6): 5 9.10 (s, 1H), 9.08 (s3 1H), 7.91 (s, 1H), 6.90 (d, J = 12.8 Hz, 1H), 6.61 (d, J =92 Hz, 1H), 4.00 (brs, 2H), 3.67 (s, 3H), 1.97 (s, 3H); MS (ESI) m/z: 285.0 (M+H+).
Example A21: Example C4 (2 g, 8.4 mmol) and Example Dl (1.78 g, 8.4 mmol) were combined by the procedure of Example A19 to give 6-(5-amino-4-fluoro-2-methylphenyl)-8-cyclopentyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7{8H)-one (0.9 g, 27 % yield). lH NMR (400 MHz, CDCh): £8.53(s, 1 H),7.39(s,lH),6.82(d,J=11.6Hz, 1 H), 6.59 (d, J = 8.8 Hz, 1 H), 5.98 (m, 1 H),

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2.57 (s, 3 H), 2.26 (m, 2 H), 2.03-1.97 (m, 5 H), 1.85-1.83 (m, 2 H), 1.62-1.60 (m, 2 H); MS (ESI) m/z: 385.0 [M+Hf.
Example A22: Example A25 (2.0 g, 6.3 mmol) in methanol (50 mL) was hydrogenated (45 psi) overnight at 50 °C in the presence of 10% Pd(OH)2 (Pearlman's catalyst, 0.5 g, 0.35 mmoi). The reaction mixture was filtered, concentrated under reduced pressure and purified by silica gel column chromatography to provide 3-(3-amino-4-fluorophenyl)-l-emyl-l,6-naphthyridin-2(lH)-one (0.81 g, 45 % yield). 'H NMR (400 MHz, DM$0~d6): 8 8.91 (s, 1 H), 8.54 (d, 7= 6.0 Hz, 1 H), 8.06 (s, 1 H), 7.51 (d, 7= 6.4 Hz, 1 H), 7.14 (dd, J = 8.8, 2.0 Hz, 1 H), 7.02 (dd, 7 = 11.6, 8.4 Hz, 1 H), 6.81 (m, 1 H), 5.18 (s, 2 H), 4.27(q, 7.2 Hz, 2 H), 1.21 (t, 7=7.2 Hz, 3 H), MS (ESI) m/z (M+H+): 284.2.
Example A23: A steel bomb was charged with Example A25 (2.5 g, 7.8 mmol) and 4-methoxy-benzylamine (20 mL). The bomb was sealed and the mixture was heated to 180 °C for 6 hours. The cooled reaction mixture was poured into a solution of AcOH (15 mL) in ice-water (100 mL) and then extracted with EtOAc (3 x 100 mL). The combined extracts were washed with brine (3 x 50 mL), dried (MgSO,}) and concentrated in vacuo. The crude product was purified by silica gel column chromatography to provide 7-(4-methoxybenzylamino)-3-(3-amino-4-fluorophenyl)-l-ethyl-l,6-naphthyridin-2(lH)-one (2.8 g, 85 % yield). *H NMR (400 MHz, DMSO-d*): 6 8.39 (s, 1 H), 7.76 (s, 7 = 6.0 Hz, 1 H), 7.45 (br s, 1 H), 7.28 (d, 7 = 7.6 Hz, 2 H), 7.07(d, J= 8.0 Hz, 1 H), 6.96 (in, 1 H), 6.86 (d, 7 = 8.4 Hz, 2H), 6.74 (m, 1 H), 6.27 (s, 1 H), 5.08 (s, 2 H), 4.46 (d, 7 = 5.6 Hz, 2 H), 4.08 (q, 7=7.2, 14.0 Hz, 2 H), 3.69 (s, 3 H), 1.12 (t, 7=7.2 Hz, 3 H), MS (ESI) m/z419.3(M+H+).
To a solution of TFA in CH2C12 (10 %, 50 mL) was added 3-(3-amino-4-fluoro-phenyl)-l-ethyl-7-(4-methoxy-benzylamino)-lH-[l,6]naphthyridin-2-one (2.0 g, 4.78 mmol). The resulting mixture was stirred at 50 °C overnight. The reaction mixture was poured saturated aq NaHCC>3 solution (100 mL), and was extracted with CH2Cl2 (3 x75 mL). Tlie comhined organic layer was dried (MgS04) and concentrated in vacuo. The residue was purified by silica gel column chromatography to give 7-amino-3-(3-amino-4-fluorophenyl)-l-ethyI-l,6-naphthyridin-2(lH)-one (0.45 g, 32 % yield). *H NMR (300 MHz, DMSO-d6): 5 8.35 (s, 1 H), 7.76 (s, 1 H), 7.09 (dd, J = 9.0, 2.1 Hz, 1 H), 6.97 (dd, J = 11.4, 8.4 Hz, 1 H), 6.75 (m, 1 H), 6.44 (s, 2 H), 6.31

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(s, 1 H), 5.09 (s, 2 H),4.0S (q, J = 7.2 Hz, 2 H), 1.20 (t, J= 7.2 Hz, 3 H), MS (ESI) m/z (M+H+): 299.3.
Example A24: Using the 2-step procedure of Example A23, Example A25 (0.85 g, 2.7 mmol} and 4-methoxybenzyImethylamine (10 mL) were combined to provide 3-(3-amino-4-fiuorophenyl)-l-ethyl-7-(methylamino)-l,6-naphthyridin-2(lH)-one (0.45 g, 32 % yield, 2 steps). lH NMR (300MHz, DMSO-flfc): 58.40 (s, 1 H), 7.77 (ss 1 H), 7.11 (d, J- 9.0 Hz, 1 H), 6.95 (m, 2 H), 6.76 (m, 1 H), 6.19 (s, 1 H), 5.09 (s, 2H), 4.14 (m, 2 H), 2.85 (br s, 3 H), 1.20 (t, J =6.0, 3H); MS (ESI) m/z (M+H+): 313.3.
Example A25: A solution of Example C5 (6.0 g, 0.033 mol), ethyl 2-(3-amino-4-fluorophenyl)acetate (6.4 g, 0.033 mol) and K2C03 (9.17 g, 0.066mol) in DMF (100 mL) was heated to 80 °C overnight. The reaction mixture was poured into the water and extracted with EtOAc- (3 x 200 mL). The combined extracts were washed with saturated brine (3 x 100 mL). dried (MgSC>4), concentrated in vacuo and purified by chromatography to provide 3-(3-amino-4-fluorophenyl)-7-chloro-l-ethyl-l,6-naphthyridin-2(lH)-one (7.0 g, 67.9% yield). JH NMR (400MHz, DMSO-4,}: 6 8.75 (s, 1 H), 8.07 (s, 1 H), 7.67 (s, 1 H), 7.13 (dd,J= 8.8,2.0 Hz, 1 H), 7.02 (dd, J = 11.6, 8.4 Hz, 1 H), 6.80 (m, 1H), 5.20 (s, 2 H), 4.25 (q, J = 6.8 Hz, 2H), 1.19 (t, J = 6.8 Hz, 3H; MS (ESI) m/z: 318.2 [M+H]+.
Example A26: Example All (1.36 g, 4.28 mmol, 1.00 eq), 4-methoxy-N-methyIbenzylamine (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 stirred with heating at 180 °C under Ar overnight. The completed reaction was cooled to RT and poured onto H2O (200 ml). Solids immediately separated which were collected by filtration and rinsed very well with H2O. The solids were dried on the filter to dampness and then dissolved in EtOAc. The solution was dried (MgSCU), filtered and evaporated to afford 7-((4-methoxybenzyl)(methyl)amino)-3-(5-amino-4-fluoro-2-metliylphenyl)-l-methyl-l,6-naphthyridin~2(lH)-one(1.86 g, 100% yield) as a brittle brown foam wliich was used as is in the next reaction. 'H NMR (400 MHz, DMSO-d6): 5 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 (brs,

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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*).
7-((4-methoxybeiizyl)(methyl)amirio)-3-(5-ainino-4-fluoro-2-rnethylphenyl)-l -methyl-l,6-naphthyridin-2(lH)-one (1.86 g, 4.3 mmol, 1.0 eq) and CF3C02H (9.5 ml, 13.8 g, 121 mmol, 28 eq) were combined and stirred at RT overnight. The completed reaction was treated slowly with 2M Na2CC3 until the mixture was just faintly basic. Tlie resulting suspension was stirred at RT for Ih. Tlie solids were collected by filtration, washed thoroughly with H2O, dried partially in the air and then under high vacuum at 65 °C. The crude product was purified by flash column chromatography (100% EtOAc to 25% THF/EtOAc) to afford 3-(5-arnino-4-fluoro-2-memylphenyl)-l-methyl-7-(methylamino)-l,6-naphthyridin-2(lH)-one (0.86 g, 64% yield) as an off-white solid. 'H NMR (400 MHz, DMSO-rftf): 5 8.35 (s, IH), 7.58 (s, IH), 6.99 (q, J = 4.8Hz, IH), 6.56 (d, J = 12.0 Hz, IH), 6.56 (d, J - 9.2 Hz, IH), 6.15 (s, IH), 4.87 (brs, 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*).
Example A27: A solution of Example All (2.2 g, 6.9 mmol) in 4-methoxybenzylamine (30 ml) was refluxed at 140 DC for two hours. After cooling to RT, tlie reaction mixture was poured into 20% aq. solution of acetic acid and stirred for 30 min. The mixture was filtered to provide 7-(4-methoxybenzy]amino)-3-(5-amino-4-fluoro-2-methylphenyl)-l-methyl-3J6-naphthyridin-2(IH)-one (2.3 & 79% yield). 'H NMR (300 MHz, DMSO- Trifluoroacetic acid (2 mL, 26.9 mmol) was added to a solution of 7-(4-medioxybenzylamino)-3-(5-aininO"4-fluoro-2-methylphenyl)-l-methyl-l,6-naphthyridin-2(lH)-one (0.8 g, 1.9 mmol) in DCM (10 mL) and tlie reaction mixture was refluxed at 50 °C for 2 hour. After cooling to RT, the reaction mixture was washed with water and the combined aqueous layers were neutralized with saturated aq NaHC03 to pH 7-8. Then tlie aqueous layer was extracted with EtOAc (3 X 50 mL), tlie extracts were dried (Na2S04) and concentrated to give 7-amino-3-(5-amino-4-fluoro-2-methylphenyl)-1 -methyl-1,6-naphthyridin-2(l H)-one (0.3 g, 53% yield). 'H NMR (300 MHz, DMSO-4): S 8.29 (s, 1 H), 7.57 (s, 1 H), 6.83 (d, J= 12.4

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Hz, 1 H), 6.56 (d, J= 9.6 Hz, 1 H), 6.48 (s, 2 H), 6.24 (s, 1 H), 4.87 (s, 2 H), 3.45 (s: 3 H), 1.94 (s, 3 H); MS (ESI) m/z: 299.0 [M + H]+.
fa-ampte A28: Example D3 (3 g, 12.9 mmol), Example C3 (2.2 g, 12.9 mmol) acid KF/A1203 (40 %, 6 g, 41 mmol) were combined in DMAc (40 mL) and die resultant mixture was stirred "at RT for about 1 hour. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was washed with Et20 to give 3-(5-amino-2-chJoro-4-fluorophenyl)-7-chloro-l-methyl-I,6-naphthyridin-2(lH)-one (2.6 g, 59.6 % yield).'H NMR (300MHz, DMSO-d6): 5 8.74 (s, 1 H), 8.00 (s, 1 H), 7.63 (s, 1 H), 7.23 (d, J = 11.2 Hz, 1 H), 6.75 (d, J= 9.2 Hz, 1 H), 5.40 (s, 2 H), 3.60 (s, 3 H); MS (ESI) m/z: 338.1[M+H]A mixture of 3-(5-amino-2-cliloro-4-fluorophenyI)-7-ch3oro-l -methyl-1,6-naphthyridin-2(lH)-one (2.5 g, 7.4 mmol) and 4-methoxy-N-methylbenzylamine (4 mL) was heated to 180 °C under NT for about 3 hour. After cooling, the reaction mixture was diluted with Et20. The precipitate was filtered, washed with water, and dried to give 7-((4-methoxybenzyl)(methyl)amino)-3-(5-amino-2-cl-iloro-4»fluorophenyl)-1 -mediyl-1,6-naphthyridin-2(lH)-one (3 g, 89 % yield). 'H NMR (400MHz, DM$0-d6): S 8.47 (s, 1 H), 7,77 (s, 1 H) 7.22 (m, 2 H), 7.17 (d, J = 8.0 Hz, 2 H), 6.86 (d, J - 8.4 Hz, 2 H), 5.86 (d, J= 9.6 Hz,l H), 6.30 (s, 1 H), 5.32 (Sj 2 H) 4.87 (s, 1 H), 3.72 (s, 3 H), 3.52 (s, 3 H), 3.09 (s, 3 H); MS (ESI) m/z: 453.2[M+Hj*.
A solution of 7-((4-metlioxybenzyl)(methyl)amino)-3-(5-amino-2-chloro-4-fIuorophenyl)-l-methyI-l,6-naphthyridin-2(lH)-one (3 g, 6.6 mmol) in CH2O2 (50 mL) was treated with TFA (20 mL) and the mixture was heated to reflux overnight. The mixture was concentrated under reduced* pressure, the residue was dissolved in IC % aq. of HCl (50 mL) and the aqueous layer was washed with EtOAc. The aqueous layer was neutralized with NaHCC>3 aq. solution to pH 8, and dien extracted with EtOAc (3 x 50 mL). The combined organics were washed witir brine, dried (NaaSO.*) and concentrated in vacuo to give 3-(5-amino-2-chloro-4-fluorophenyl)-l-methyl-7-(methylammo)-l,6-naphthyridin-2(lH)-one (1.6 g, 72 % yield) JH NMR (300MHz, DMSO-4s): S S.36(s, 1 H), 7.66 (s, 1 H), 7.17 (d, J - 10.8 Hz, I H), 7.05 (m, 1 H), 6.71 (d, J = 9.6 Hz, 1), 6.15 (s, 1 H), 5,30 (s, 2 H), 3.47 (s, 3 H), 3.42 (s, 1 H), 2.84 (d, J = 4.4 Hz, 3 H); MS (ESI) m/r. 333.1 [M+H]+

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Example A29: Example C3 (2 g; 9.3 mmol), Example D2 (1.6 g, 9.3 mmol) and KF/A1203 (40 %, 5 g, 34.4 mmol) were combined in DMAc and stirred for 10 min. The reaction mixture was poured into water and extracted with ediyl acetate. The combined organic layers were washed with brine, dried (NaSCXjJ and concentrated in vacuo. The residue was purified by chromatography to give 3-(5-amino-2>4-difluorophenyl)-7-chloro-l-methyI-l,6-naphthyridin-2(lH)-one (2 g, 68 % yield). ]H NMR (300 MHz, DMSO-d6): 5 8.41 (s, 1 H), 7.73 (s, 1 H), 7.06-7.03 (m, 1 H), 6.81-6.75 (m, 1 H), 6.15 (s,l H), 4.98 (s, 2 H), 3.48 (s, 3 H); MS (ESI) m/z: 322.7 [M+Hf.
3-(5-Amino-2,4-difluorophenyl)-7-chloro-l-metliyl-l,6-naphthyridin-2(lH)-one (2.4 g, 7.5 mmol) and 4-methoxy-N-methylbenzylamine (10 mL) were combined in a sealed vessel and heated to 200 °C overnight The volatiles were removed in vacuo and the residue was purified by column chromatography to give 7-((4-methoxybenzyl)(memyl)ammo)-3-(5-arnino-2,4-difluorophenyl)-l-methyl-l,6-naphthyridin-2(lH)-one (3 g, 91% yield), which was used in the next step without further purification.
To a solution of 7-((4-methoxybenzyl)(methyl)amino)-3-(5-amino-2,4"difluorophenyI)-l-methyl-l,6-naphmyridin-2(lH)-one (3 g, 6.8 mmol) in DCM (100 mL) was added CF3COOH (20 mL) and the resulting mixture was stirred at 25 °C for 6 h. Water was added and the mixture was extracted with water. The combined aqueous layers were neutralized with NH3H2O to pH 7. The precipitate was collected by filtration and dried to give 3-(5-amino-2,4-difluorophenyI)-l-methyl-7-(methylamino)-l,6-naphthyridin-2(lH)-one (661 mg, 30% yield). JH NMR (300 MHz, DMSO-d6): 5 8.39 (s, 1 H), 7.78 (s, 1 H), 7.08-6.93 (m, 2 H), 6.80 (dd, J = 10.2, 8.1 Hz, 1 H), 6.16 (s, 1 H), 5.00 (s, 2 H), 3.50 (s, 3 H), 2.84 (d, J= 4.8 Hz, 3 H); MS (ESI) m/z: 317,0 [M+Hf.
Example A30: In a manner analogous to that described for the preparation of Example A26, Example A34 (1.61 g, 4.85 mmol) was converted to 3-(5-amino-4-fluoro-2-methylphenyl)-l-ethyl-7-(methylamino)-l,6-naphthyridin-2(lH)-one (1.16 g, 73% yield for two steps). 'H NMR (400 MHz, DMSO^r): 6 8.36 (s, IH), 7.58 (s, IH), 6.94-6.92 (bnn, IH), 6.83 (d, J = 12.0 Hz, IH), 6.57 (d, J - 9.6 Hz, IH), 4.87 (brs, 2H): 4.12 (q, J = 6.8 Hz, 2H), 2.84 (d, J = 4.8 Hz, 3H), 1.94 (s, 3H), 1.185 (t, J = 7.2 Hz, 3H); MS (ESI) m/z: 327.2(M+H).

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Example A31: Example A34 (2.5 g, 7.5 mmol) and 4-methoxybenzylamine (30 ml) were combined by the 2-step procedure of Example A27 to provide 7-amino-3-(5"amino-4-fluoro-2-methyIphenyI)-l-emyl4,6-naphthyridin-2(lH)-one (0.9 g, 46% yield, 2 steps). 'H-NMR (300 MHz, DMSO-rf6): d 8.30 (s, I H), 7.56 (s, 1 H), 6.83 (d, 7=12.3 Hz, 1 H), 6.57 (d, J = 9.6 Hz, 1 H), 6.40 (s, 2 H), 6.32 (s, 1 H), 4.85 (s, 2 H), 4.07 (q, J= 6.9 Hz, 2 H), 1.94 (s, 3 H), 1.19 (t,J= 6.9 Hz, 3 H); MS (ESI) m/z: 313.3 [M + H]+.
Example A32: Example C5 (3.5 g, 19 mmol), Example D3 (4.4 g, 19 mmol) and KF/A1203 (40 wt %, 10 g, 69 mmol) were combined by the procedure of Example A17 to give 3-(5-amino-2-cliloro-4-fluorophenyl)-7-chloro-l-ethyl-l36-naphthyridin-2(lH)-one (4 g, 60% yield). 'H NMR (400 MHz, DMSO-40: S 8.75 (s, 1 H), 8.01 (s, 1 H), 7.72 (s, 1 H), 7.24 (d, J= 10.8 Hz, 1 H), 6.76 (d, J= 9.2 Hz.1 H), 5.40 (s, 2 H), 4.26-4.24 (m, 2 H), 1.18 (t, J= 6.8 Hz, 3 H); MS (ESI) m/z: 352.1 [M+H]+,
Example A3 3: Using the procedure of Example A28, steps 2 and 3, Example A32 (3g, 8.5mmol) was converted to 3-(5-amino-2-chloro-4-fluorophenyl)-l-etliyl-7-(methylamino)-l,6-naphthyridin-2(lH)-one (1 g, 32% yield over two steps). 'HNMR (400 MHz, DMSO-rf,,): 5 8.46 (s, 1H), 7.75(s, 1 H), 7.1 {d,J= 11.2 Hz, 1 H), 6.73 (d, J =9.6 Hz, 1 H), 6.43 (s, 1 H), 4.95 (br s, 1 H), 4.14 (m, 2 H), 2.92 (s, 3 H), 1.14 (t, /= 6.8 Hz, 3 H); MS (ESI) m/z: 347.2 [M+H]+.
Example A34: Example Dl (1.32 g, 6.25 mmol, 1.00 eq), Example C5 (1.15 g, 6.25 mmol, 1.00 eq) and KF/A1203 (40.00 wt%, 9.08 g, 62.5 mmol, 10.00 eq) were combined in DMAc (35 ml) and sonicated for 2h. The completed reaction was filtered through Celite, rinsing forward with EtOAc (3 x 35 ml). The combined filtrates were washed with H2O (3x 50-75ml). The combined aqueous layers were extracted with EtOAc (Ix). The combined organics were washed with brine (2x), dried (MgSG*), filtered and evaporated. The crude product was purified by flash column chromatography (5% EtOAc/hexanes to 100% EtOAc) to afford 3-{5-amino-4-fluoro-2-methylphenyl)"7-chloro-l-ethyl-l,6-naphthyridin-2(lH)-one (1.61 g. 78% yield) as a brittle foam. MS (ESI) m/z: 332.0 (M+H)a 334.0 (M+2+H).

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Example A35: A solution of ethyl 4,6-dichloronicotinate (16 g, 73 mmol), aniline (8.2 g, 88 mmol) and cone. HCI (0.5 mL) in EtOH (100 mL) was heated at reflux overnight. The solvent was removed under reduced pressure. Water was added and the solution was basified to pH 8 and extracted with EtOAc. The combined extracts were washed with brine, dried (MgS04). and concentrated in vacuo. The residue was purified by chromatography to give ethyl 6-chloro-4-(phenylamino)nicotinate (10 g, 50 % yield). 'H NMR (40 MHz, DMSO-^): S 9.73 (s, 1 H), 8.67 (s, 1 H), 7.50-7.46 (m, 2 H), 7.36-7.31 (m, 3 H), 6.78 (s, 1 H), 4.37 (q, J= 7.2 Hz, 2 H), 1.35 (t, J = 7.2 Hz, 3 H).
A solution of ethyl 6-chloro-4-(phenylamino)nicotinate (19 g, 89 mmol) in anhydrous THF (40 mL) was added dropwise to a 0 °C suspension of L1AIH4 (8.5 g, 223 mmol) in anhydrous THP (80 mL). After complete addition, the reaction mixture was stirred at RT for 3 h. The mixture was quenched by the addition of 10% aq NaOH (8.5 mL) and water (8.5 mL). The solids were removed by filtration and the organic phase was concentrated in vacuo to provide (6-cliloro-4-(phenylamino)pyridm-3-y))methanol (12 g, 80% yield). [H NMR (400 MHz, DMSO-d6): 3 8.09 (s, 1 H), 8.08 (s, 1 H), 7.39-7.10 (m, 5H), 6.73 (s, 1 H), 5.37 (s, 1 H), 4.52 (s, 2 H).
M11O2 (39 g, 448 mmol) was added to a solution of (6-chloro-4-phenylamino-pyridin-3-yl)-methanol (13 g, 56 mmol) in CH2CI2 (100 ml) and die mixture was stirred at RT overnight. The solids was removed by filtration and the filtrate was concentrated to give 6-chloro-4-(phenylamino)nicotinaldehyde (11 g, 86% yield). 'H-NMR (400 MHz, DMSO-^j): S 10.18 (s, 1 H), 9.99 (s, 1 H), 8.62 (s, 1 H), 7.49-7.31 (m, 5 H), 6.80 (s, 1 H).
A mixture of 6-Chloro-4-(phenylamino)nicotmaldehyde (3 g, 13 mmol), ethyl 2-(3-amino-4-fluorophenyl)acetate (2.6 g, 13 mmol), and KF/AI2O3 (40 wt %, 10 g, 69 mmol) in DMAc (30 mL) was stin-ed at RT for 2 hours. The solids were removed by filtration and the filtrtate was concentrated in vacuo. RecrystaHization (EtOAc) provided 3-(3-amino-4-fluorophenyJ)-7-chloro-l-phenyI-l,6-naphtliyiidin-2(lH)-one (2.6 g, 55% yield). lH NMR (400 MHz, DMSO-d6); S 8.81 (s, 1 H), 8.20 (s, 1 H), 7.62-7.56 (m, 3 H), 7.40 (d, 7= 7.2 Hz, 2 H), 7.13 (d, J = 7.6 Hz, I H), 7.02 (t, J = 10.0 Hz, 1 H), 6.82 (m, 1 H), 6.26 (s, 1 H), 5.19 (s, 2 H); MS (ESI) m/z: 366.2 [M + Hf.
Example A36: A suspension of Example A35 (2.5 g. 7 mmol) in 4-metlioxybenzylmethylamine (5 mL) was heated at 160°C for 3 h. The reaction mixture was cooled to RT and diluted with

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ether. The resultant white precipitate was collected by filtration and dried to obtained 7-((4-methoxybenzyl)(methyl)amino)'3-(3-amino-fluorophenyl)-I-Phenyl-l,6-naphmyridin-2(lH)-one (3 g, 77%), which was used in the next step without farther purification. A suspension of 7-((4-methoxyberizyI)(metiiyl)aimno)
l,6-naphthyridin-2(lH)-one (3.0 g, 6 mmol) in mixture of CF3C02H and CH2C12 (3 : 7, 30 mL) was heated at reflux overnight. Then the solvent was removed under reduced pressure and the residue was recrystallized (EtOAc-petroleum ether) to give 3-(3-amino-4-fluorophenyl)-7-(methylamino)-l-phenyl-lJ6-naphthyridin-2(lH)-one (1 g, 45% yield). (H NMR (400 MHz, DMSO-4;): 6 8.43 (s, 1 H), 7.88 (s, 1 H), 7.60-7.50 (m, 3 H), 7,31-7.29 (ra, 2 H), 7.10-6.75 (m, 4 H), 5.26 (s, 1 H), 5.08 (s, 2 H), 2.63 (br s, 3 H); MS (ESI) m/z: 361.3 [M + H]+.
Example A37: A mixture of Example A60 (1.1 g, 3.7 mmol) and 28% ammonium hydroxide (6.0 mL) in a sealed-vessel was heated at 160 °C for 2h. After cooling to RT, the reaction mixture was filtered and the solid was washed with cold £tOAc to provide 2-amino-6-(3-aminophenyl)-8-methylpyrido[2J3-d]pyrimidin-7(8H)-one (440 mg7 45 % yield). ]H NMR (300 MHz, DMSO-rfrf): 8.61 (s, 1 H), 7.77 (s, 1 H), 7.24 (brs, 2 H), 7.02 (t, J = 8.0 Hz, 1 H), 6.84 (s, 1 H), 6.73 (d, J = 7.8 Hz, 1 H), 6.51 (d, J = 8.0 Hz, I H), 5.05 (br s7 2 H), 3.54 (s, 3 H). MS (ESI)m/z:268.1(M+H4).
Example A38: Using a procedure analogous to Example A28, Example A55 was converted to 3-(3-amino-4-fluorophenyl)-l-methyl-7-(methylamino)-l,6-naphtliyridin-2(lH)-one (1.6 g, 59 % yield). 'HNMR (300 MHz, DMSO-d6): 8 8.39 (s, 1 H), 7.78 {$ 1 H), 7.07 (d, J = 8.7 Hz, 1 H), 7.05-6.93 (m, 2 H), 6.75 (m, 1 H), 6.13 (s, 1 H), 5.10 (s, 2 H), 3.50 (s, 3 H), 2.84 (d, J = 4.8 Hz, 3 H); MS (ESI) m/z; 299.2(M+H*).
Example A39: Using a procedure analogous to Example AI, Example AI0 (1.500 g, 4.54 mmol, 1.0 eq), 3-chloroperbenzoic acid (70 wt%, 269 mg, 1.090 mmol, 1.20 eq) and 2.0M Me"NH2 in THF (11.400 ml, 22.80 mmol, 5.00 eq) were combined to afford crude 6-(5-amino-4-fluoro-2-metliylphenyl)-8-methyl-2-(melhylamino)pyrido[2,3-d]pyrimidin-7(8H)-one (1.56 g, 105% yield) as an orange foam which was used as is. MS (ESI) m/z: 314.3 (M+H).

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Example A4Q: In dimethylacetamide (30 mL) was placed 4-aminonicotinaIdehyde (1.50 g, 12.3 mmol) and ethyl 2-(3-amino-4-fluorophenyl)acetate (2.42 g, 12.3 mmol). To this was added 40% KPValumina (8.92 g, 61.4 mmol) and the mixture was stirred at RT for 48 hrs. The mixture was filtered through a Celite pad and the pad was washed with ethyl acetate (2 x 30 mL). The filtrate was diluted with water (100 mL) and the biphasic mixture was set aside to precipitate. The solid was collected by filtration, washed with water (2 x 25 mL) and dried on high vac line at 65 °C for 3 hrs in the abderhalden and identified as 3-(3-amino-4-fluorophenyl)-l(6-naphthyridin-2(lH)-one (1.55 g, 49% yield). Used as is. MS (ESI) m/z: 256.0 (M+H4).
Example A41: Example C2 (5.0 g, 25 mmol), Example Dl (5.8 g, 27 mmol) and Cs2C03 (22.7 g, 70 mmol) were combined DMF (150 mL) and stirred at 60 °C overnight. The resulting mixture was concentrated under reduced pressure and the residue was washed with ethyl ether to give 6-(5-amfoo-4-fluoro-2-methyIphmyI)-8-
one (3.59 g; 42 % yield). !H NMR (400 MHz, DMSO-4,): S 8.88 (s, 1 H), 7.82 (s, 1 H), 6.89 (d, J- 12.4 Hz, 1 H), 6.61 (d, /= 9.6 Hz, 1 H), 4.96 (s, 2 H), 4.38 (q, /= 6.8 Hz, 2 H), 2.61 (s, 3 H), 1.96 (s, 3 H), 1.24 (t, J= 6.8 Hz, 3 H); MS (ESI) m/z: 345.2 [M + Hf.
Example A42: Example C6 (4.2 g, 19.9 mmol), Example Dl (4.2 g, 20 mmol), and Cs2C03 (16.86 g, 51.74 mmol) were combined in DMF (80 mL) and heated at reflux overnight. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The combined extracts were washed with brine, dried (Na2$04), and concentrated in vacuo. Purification by chromatography on silica gel gave 6-(5-amino-4-fluoro-2-methyIphenyl)-8-isopropyI-2-(methyltlu'o)pyrido{2,3-d]pyrimidin-7(8H)-one (1.47 g, 20 % yield). lH NMR (400 MHz, DMSO-4,): S 8.83 (s, 1 H), 7.75 (s, 1 H), 6.86 (d,J = 12.4 Hz, 1 H), 6.58 (d, J= 9.2 Hz, 1 H), 5.71 (m, 1 H), 4.92 (s, 2 H), 2.58 (s, 3 H), 1.93 (s, 3 H), 1.53 (d, J =7.2 Hz, 6 H); MS (ESI) m/z: 359.0 [M + H]+.
Example A43: Using a procedure analogous to Example Al, Example A10 (0.200g, 0.605 mmol) and N\N'-dimethylpropane-l,3Hiiamine (0.378 ml, 3.03 mmol) were combined to afford 6-(5-amino-4-fluoro-2-memylphenyl)-2-(3-(dmiethyIaiTiino)propylamino)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one (0.076 g, 33% yield) as yellow solid. MS (ESI) m/z: 385.2 (M+H*)

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Example A44: In methylene chloride (50 mL) was placed 2-methyI-5-nitrobenzoic acid (3.00 g, 16.6 mmol) and 1 microdrop of dimethylfonnamide. The solution was cooled to 0 °C and to tin's was added oxalyl chloride (3.15 g, 24.8 mmol). After 15 minutes the mixture was allowed to warm to RT and stirred a further 2 hours. The mixture evaporated at reduced pressure. Tins residue was dissolved in THF (60 mL) and cooled to 0 °C. To this was added the 2.00N TMS-diazomethane (18.6 mL, 37.3 mmol) and the mixture stirred at 0 °C for 5 lirs. The solution was evaporated at reduced pressure and the new residue was treated with benzyl alcohol (15 mL) and 2,4,6-collidine (10 mL) and wanned to 180 °C for 15 min. After cooling to RT and diluting with ethyl acetate (100 mL), the resulting solution was washed successively with water (2 x 100 mL), 5% citric acid (100 mL, till pH of aqueous phase is acidic), water (100 mL) and brine (100 mL). The solvent was removed at reduced pressure and the resultant oil was dried on the high vacuum line at 65 °C to remove most excess benzyl alcohol. The oil was purified by chromatography (Biotage Si-40 column, 10-40% ethyl acetate/Hex - 1398 mL) to give benzyl 2-(2-methyl-5-nitrophenyl)acetate as an oil (2.465 g, 52% yield) which was used as is.
In a solution of THF:ethanol (1:1, 100 mL) was placed the crude benzyl 2-(2-methyl-5~ nitrophenyl)acetate (2.46 g, 8.62 mmol) and ammonium chloride (4.61 g, 86.2 mmol). To this was added zinc dust (5.64 g, 86.2 mmol) and the resulting slurry was stirred at RT for 4 hrs. The slurry was filtered through Celite and washed with ethanol (2 x 50 mL). The combined filtrates were evaporated at reduced pressure to give an oily mass. This was dissolved in a mixture of ethyl acetate (75 mL) and brine (75 mL). The organic phase dried (Na2S04) and evaporated at reduced pressure to give benzyl 2-(5-ammo-2-merhy]phenyl)acetate as an oil. which appears to be 6:4 mix of product: non-homologated compound. Used as is.
In dimethylacetamide (35 mL) was placed Example Cl (1.31 g, 7.13 mmol) and the crude benzyl 2-(5~amino~2-methy]phenyl)acetate (2.00 g, 5.09 mmol). To this was added KF/Alumina (11.1 g, 76.4 mmol) and the mixture sonicated at RT for 1.5 hrs. The reaction mixture was diluted with CH2CI2 (100 mL) and filtered free of insolubles. The filtrate was washed with water (]00 mL) and brine (100 mL), dried (NaiSO) and concentrated in vacuo to remove dimethylacetamide to give an oil. The oil was treated with ethyl acetate (30 mL), forming a precipitate overnight. The solid was collected by filtration, washed with ethyl acetate (2x10 mL) and then dried in vacuo. The isolated solid was warmed to reflux in methanol (15

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mL), filtered and dried on high vacuum line to give 6-(5-amino-2-methylphenyl)-8-methyI-2-(memylmio)pyrido[2,3-djpyrimidiii-7(8H)-one (879 mg, 55% yield). lH NMR (300. MHz, DMSO-d6): 5 1.93 (s, 3 H), 2.48 (s, 3 H), 2.60 (s, 3 H), 4.89 (br. s, 1 H), 6.39 (s, 1 H), 6.48-6.50 (m, 1 H), 6.86-6.88 (m, 1 H), 7.79 (s, 1 H), 8.87 (s, 2 H); MS (ESI) m/z: 313.0 (M+H*).
Example A45: Following the procedure of Example A60, Example C2 (0.42 g, 2.1 mmol), ethyl 2-(3-aminophenyl) acetate (0.38 g, 2.1 mmol), and K2CO3 (0.44 g, 3.2 mmol) were combined to give 6"(3-aminophenyl)-8"ethyl-2-(methylthio)pyrido[2J3-d]pyiimidin-7(8H)-one (0.44 g, 66 % yield). lH NMR (400 MHz, DMSO-): 8 8.93 (s, 1 H), 7.99 (s, 1 H), 7.08 (t, J = 8.0 Hz, 1 H), 6.91 (t, J = 2.0 Hz, 1 H), 6.78 (dt, J = 7.6, 1.2 Hz, 1 H), 6.60 (m, 1 H), 5.14 (s, 2 H), 4.04 (q, J = 7.2 Hz, 2 H), 2.62 (s, 3 H), 1.26 (t,J = 3H); MS (ESI) m/z: 313.2 [M + H]+.
Example A46: To stirring fuming HNOj (15 mL) at -15 °C was added 2-bromo-4-fluorophenylacetic acid (10 g, 43 mmol) in portions such that the internal temperature remained below -10 °C. After completing the addition the reaction was stirred with warming to +5 °C over 15 min. The mixture was poured onto ice (500 g). Product separated as a slightly sticky solid which on manipulation with a spatula became powdery. The suspension was stirred vigorously until the ice had completely melted. While still very cold, the solids were collected by filtration, rinsed very well with H2O (1L). The solid was dried under vacuum to afford 2-(2-bromo-4-fluoro-5-nitrophenyl) acetic acid (6.04 g, 51%) yield) as a pale yellow solid which was used as is in the next reaction.
2-(2-bromo-4-fluoro-5-nitrophenyl)acetic acid (6.04 g, 21.7 mmol) and cone. H2SO4 (1.2 mL) were combined in EtOH (100 mL) and stirred with heating at 85 °C. After 1.5 h, the completed reaction was cooled to RT and concentrated as completely as possible. The residue was dissolved in MTBE (50 mL) and washed with H2O (2x), and brine (2x), dried (MgSO^), filtered and evaporated to afford a dark orange oil. The crude was purified by silica gel column chromatography to obtain ethyl 2-(2-bromo-4-fluoro-5-nitrophenyl)acetate (5.S g, 87% yield).
Ethyl 2-(2-bromo-4-fluoro-5-nitrophenyl)acetate (1.00 g, 3.27 mmol), PdCl2(PPh3)2 (115 mg, 0.16 mmol), Cul (44 nig. 0.23 mmol), and trimethylsilylacetylene (0.7 mL, 4.9 mmol) were dissolved in Et3N (5 mL). The mixture was immediately degassed by vacuum, and the flask was charged with N2. The mixture was heated overnight at 50 °C. Water was added and then the

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solution was extracted with EtOAc (3x). The organic was washed with NH4CI, brine and dried (MgSO.*). The solvent was removed and then the residue was purified by silica gel column chromatography to obtain ethyl 2-(4-fluoro-5-nitro-2-(2-(trimediylsiIyl)etIiynyl)phenyl)ace£ate (0.66g, 62% yield).
To a stirring suspension of ethyl 2-(4-fluoro-5-nitro-2-(2-
(trimethylsilyl)ethynyl)phenyl)acetate (0.66 g, 2.04 mmol) in MeOH/THF (1:1, 20 mL) was added NH4CI (1.09 g, 20.4 mmol), followed by Zn dust (1.33 g, 20.4 mmol). After stirring 3.5 h, the mixture was filtered through Celite, and rinsed forward with MeOH. The combined filtrates were concentrated, diluted with brine and extracted with THF (2x). The combined organic layers were washed with brine (lx), dried (MgS04). filtered and concentrated to afford ethyl 2-(5-amino-4-fluoro-2-(2-(trimethylsilyl)ethynyl)phenyl)acetate (0.54 g, 90% yield). [H NMR (400 MHz, DMSO-db): 8 6.86 (d, J = 12.0 Hz, IH), 6.47 (d, J= 8.8 Hz, IH), 5.47 (brs, 2H), 3.88 (d, J = 6.S Hz, 2H), 3.43 (s, 2H), i.00 (d, J= 6.$ Hz, 3H), 0.00 (s, 9H); MS (ESI) m/z: 294.0 (M+H+).
To a solution of ethyl 2-(5-amino-4-fluoro-2-(2-(trimethylsilyl)ethynyl)pheny])acetate (0.30 g, 1.02 mmol) and Example CI (0.19 g, 1.02 mmol) in 4 mL of DMF was added cesium carbonate (0.87 g, 2.66 mmol) and then the reaction mixture was stirred overnight at RT. The mixture was diluted with water (50 ml) stirred, filtered and washed with water to provide the crude product. The crude was filtered and dried under vacuum to provide 6-(5-amino-2-ethynyl-4-fluorophenyl)-8-memyl-2-(me%ltlno)pyrido[2,3-d]pyriinidin-7(8H)-one (300 mg, 71% yield) which was used for the next reaction. 'H NMR (400 MHz, DMSO-o^)-' 6 8.87 (s, IH), 7.90 (s, IH), 7.15 (d,y= 12.0 Hz, 1H)3 6.69 (d,J = 9.2 Hz, IH), 5.65 (s, 2H), 3.77 (s, IH), 3.60 (s, 3H); 2.57 (s, 3H); MS (ESI) m/z: 341.0 (M+H^.
Using a procedure analogous to Example Al, 6-(5-amino-2-ethynyl-4-fluorophenyl)-8-methyl-2-(metliyltliio)pyrido[2,3-d]pyrimidin-7(SH)-one (0.250 g, 0.734 mmol), MCPBA (0.217 g, 0.881 mmol) and 2 M methylamine (1.5 mL, 2.95 mmol) were combined to obtain 6~(5-ammo-2-emynyl-4-fluorophenyl)--8--metliyl-2-(methylamino)pyrido[2,3-d]pyrirnidin-7(8H)-one (140 mg, 59% yield). 'H NMR (400 MHz, DMSO-d6): 8 8.59 (s, IH), 7.82 (m, IH), 7.73 (s, lH),7.15(d,J= 12.0 Hz, IH), 6.71 (d,J=9.2Hz; IH), 5.61 (s, 2H), 3.78 (s, IH), 3.58 (s, 3H), 2.90 (d, J=4.4 Hz, IH); MS (ESI) m/z: 324.2 (M+H+).

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Example A47: Ethyl 2-(4-fluoro-5-nitro-2-(2-(trimethyIsilyl)ethynyl)phenyl)acetate (0.85 g, 2.6 mmol) and K2C03 (3.6 g) were dissolved in THF/MeOH (5:1, 30 mL) and the mixture was stirred overnight at RT. The reaction mixture was diluted with EbO and washed with sat'd NH4CI solution. The organic layer was dried (MgSQ*), filtered, and concentrated. The residue was purified by silica gel column chromatography to obtain ethyl 2-(2~ethynyl-4-fluoro-5-nitrophenyl)acetic acid.
Ethyl 2"(2-ethynyl-4-fiuoro-5-nitrophenyl)acetic acid and cone. H2SO4 were combined in EtOH (5 mL) and stirred with heating at 85 °C. After 4 h, the completed reaction was cooled to RT and concentrated as completely as possible. The residue was dissolved in MTBE (50 mL) and washed with H2O (2x), and brine (2x), dried (MgS04), filtered and evaporated to afford desired product as a dark orange oil. The crude was purified by silica gel column chromatography to obtain ethyl 2-(2-etliynyL4-fluoro-5-nitrophenyl)acetate (160 mg, 21% yield). MS (ESI) m/z: 252.0 (M+H+).
Ethyl 2-(2- ethynyl -4-fiuoro-5-nitrophenyl)acetate (160 mg, 0.64 mmol) was dissolved in MeOH (5 mL) and EtOAc (5 mL) and then Pd-C (20 mg) was added. The reaction mixture was shaken in a Parr hydrogenator (46 psi) overnight at RT. The reaction mixture was filtered, washed with methanol, and concentrated to obtain ethyl 2-(5-amino-2-ethyl-4-fluorophenyl)acetate (135 mg, 93% yield). MS (ESI) m/z: 226.2 (M+H+).
To a solution of ethyl 2-(5-amino~2-ethyl-4-fluorophenyl)acetate (135 mg, 0.6 mmol) and Example CI (110 mg, 0.6 mmol) in DMF (2 mL) was added cesium carbonate (500 mg, 1.5 mmol) and slirred overnight at RT. The reaction mixture was diluted with water (50 mL) stirred, filtered and washed to provide the crude product. The crude product was stirred in EtOH overnight at RT. The solid was filtered, washed and dried to provide 6-(5-amino-2-ethyl-4-fluorophenyl)-8-metIiyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (100 mg, 48% yield). fH NMR (400 MHz, DMSO-rf6, major isomers): 5 8.87 (s, 1H), 7.81 (s, 1H), 6.91 (d, J = 12.8 Hz, 1H), 6.54 (d, J= 9.2 Hz, 1H), 4.98 (s, 2H), 3.63 (s, 3H), 2.60 (s, 3H), 2.26 (q, y= 7.2 Hz, 2H), 0.97 (t, J= 12 Hz, 3H), MS (ESI) m/z: 345.0 (M+H+).
Example A48: Ethyl 2-(2-bromo-4-fluoro-5-nitrophenyl)acetate (1.0 g, 3.27 mmol) and zinc cyanide (0.77 g, 6.54 mmol) were combined in DMF (8 mL), de-gassed under vacuum and backfilled with argon (4 x). Palladium te£rakis(triphenylphosphzne) (380 mg, 0.32 mmol) was

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added and the reaction was heated at 160 °C under microwave for 30 min. The solution was diluted with EtOAc and then the solid was filtered. The filtrate was washed with brine (3x) and dried (Na2S04), concentrated in vacuo and the residue was purified by silica gel column chromatography to obtain ethyl 2-(2-cyano-4-fluoro-5-nitrophenyI)acetate (0.3 g, 37% yield).
To a solution of ethyl 2-(2-cyano-4-fluoro-5-nitrophenyl)acetate in meuianol and EtOAc (1:1, lOmL) was added 10% Pd/C. The solution was stirred under H2 (1 atm) at RT for 3 days. The solution was filtered and evaporated to obtain ethyl 2-(5-amino-2-cyano-4-fIuorophenyl)acetate (0.21 g, 81% yield).
To a solution of ethyl 2-(5-amino-2-cyano-4-fluorophenyl)acetate (0.21 g, 0.95 mmol) and Example CI ( 0.17 g, 0.95 mmol) in 4 mL of DMF was added cesium carbonate (0.80 g, 2.46 mmol) and then the reaction mixture was stirred overnight at RT. The reaction mixture was diluted with water (50 ml) stirred, filtered and washed with water to provide the crude product. The crude was filtered and dried under vacuum to provide 4-amino-5-fluoro-2-(8-methyI-2-(methyltliio)-7"Oxo-7,8-dihydropyrido[2J3-d]pyrimidin-6-yl)benzonitrile (125 mg, 39% yield). lHNMR(400MHz,DMSO-4i): 5 8.94 (s, IH), 8.07 (s, IH), 7.61 (d, J= 11.6 Hz, lH),6.82(d, J= 8.8 Hz, IH), 6.35 (s, 2H), 3.65 (s, 3H), 2.62 (s, 3H); MS (ESI) m/z: 342.0 (M+rf).
Example A49: Using a procedure analogous to example Al, Example A59 (0.18 g, 0.52 mmol), MCPBA (0.1 g, 0.57 mmol) and 2 M Methylamine in THF (1 ml) were combined to afford 6-(3~ ammo-4-fluorophenyl)-8-isopropy!-2-(methylamino)pyrido[2,3-d]pyrimidin-7(8H)-one as a light yellow solid (105 mg, 61% yield). lH NMR (400 MHz, DMSCW6): 5 8.57 (s, IH), 7.72 (s; IH), 7.06 (dd, J= 8.8 Hz, 2.0 Hz, IH), 6.97 (dd, J = 11.2 Hz, 8.4 Hz, IH), 6.72-6.68 (m, IH), 5.77-5.74 (m, IH), 5.11 (brs, 2H), 2.88 (d, J= 4.8 Hz, 3H), 1.57-1.51 (m, 6H); MS (ESI) m/z: 328.3 (M+H!").
Example A50: Using a procedure analogous to Example Al, Example A41 (0.6 g, 1.7 mmol) and 2M methylamine in THF (3 eq) were combined to afford 6-(5-amino-4-fluoro-2-merhylphenyl)-S-ethyl-2-(methylamino)pyrido[2,3-d]pyrimidin-7(8H)-one as a white solid (0.31, 54% yield). ]H NMR (400 MHz, Acetone-rf6): 5 8.53 (s, IH), 7.55 (s, IH), 6.85-6.82 (m, 2H), 6.70 (d, J= 9.6 Hz, IH), 4.46-4.43 (m, 2H), 3.05 (d, J = 4.8 Hz, 3H), 1.314.27 (m, 3H); MS (ESI) m/z: 328.0 (M+H+).

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Example A51: Using a procedure analogous to Example Al, Example A42 (0.5, 1.4 mmol), MCPBA (0.26 g, 1.5 mmol) and 2 M methyl amine in THF (3 eq) were combined to provide 6-(5-ainmo-4-fluoro-2-me[hylphenyl)-S-isopropyi-2-(memyIamino)pyrido[2,3-d]pyrimidiii-7(8H)-one as a foam (0.33 g, 69% yield). ]H NMR (400 MHz, DMSO-4,): 8 8.62-8.54 (m, IH), 7.72-7.69 (m, IH), 7.54 (s, IH), 6.84 (d, ./= 12.0 Hz, IH), 6.57 (d, J = 9.6 Hz, IH), 5.74 (brs, 2H), 4.90 (brs, 2H), 2.88 (d, J = 4.4 Hz, IH), 1.94 (s, 3H), 1.56-1.50 (m, 6H); MS (ESI) m/z: 342.0 (M+H+).
Example A52: To a degassed solution of 6-bromo-8-isopropyI-2-(methylthio)pyrido[2,3-d]pyiimidin-7(8H)-one (0.78 g, 2 mmol; J. Med. Chem., 48, 2371, 2005) in DME (10 ml) was added Pd(PPh3)4 (0.1 g. 5% mol), 4-fluoro-3-nitrophenylboronic acid (0.5 g, 3 mmol) and 2M Na2COi solution (3 ml, 6 mmol) and the mixture was heated to 80 °C for 16h. The mixture was poured into water (40 ml), and product was extracted with EtOAc (3x25 mL). The combined organics were washed with brine, dried (Na2S04) and concentrated in vacuo afforded crude product. Purification by silica gel chromatography provided 6-(4-fluoro-3-nitrophenyl)-8-isopropyl-2-(methyUhio)pyrido[2,3-d]pyrimidm-7(8H)-one as off-white solid (0.82 g, 88% yield). 'H NMR (400 MHz, DMSO-of6): 5 8.94 (s, IH), 8.52 (dd,7 = 7.2 Hz, 2.4 Hz, IH), 8.28 (s, IH), 8.15-8.12 (m, IH), 7.70 (dd, J= 11.6 Hz, 8.8 Hz, IH), 5.81-5.78 (m, IH), 2.63 (s, 3H), 1.60 (d, J- 6.8 Hz, 6H); MS (ESI) m/z: 375.0 (M+H*).
Using a procedure analogous to Example Al, 6-(4-fluoro~3~mtrophenyl)-8-isopropyi-2-(metliylthio)pyrido[2J3-d3pyrimidin-7(8H)-one (0.82 g, 2.2 mmol), MCPBA (0.38 g, 2.2 mmol) and 0.5 M ammonia in dioxane (8 mL) were combined to afford 2-amino-6-(4~fluoro-3-nitrophenyl)-8-isopropylpyrido[2,3-d]pyrimidin-7(8H)-one as a yellow solid (0.52 g, 69% yield). ]H NMR (400 MHz, MeOH-d4): 5 8.61 (s, IH), 8.44 (dd, J= 7,6 Hz, 2.4 Hz, IH), 8.03-8.00 (m, 1H),7.95 (s, IH), 7.48 (dd, J= 10.8 Hz, 7.6 Hz, IH), 5.96-5.92 (m, IH), 2.63 (s, 3H), 1.64 (d,7 = 6.4 Hz, 6H); MS (ESI) m/z: 344.3 (M+H*).
To a solution of 2-amino-6-(4-fluoro-3-nitrophenyl)-8-isopropylpyrido[2,3-d]pyiimidin-7(8H)-one (0.52 g, 1.5 mmol) in EtOAc and methanol (5:1, 30 mL) was added palladium on carbon (50 mg of 10% mol) and mixture was stirred under a hydrogen atmosphere at RT for 16h. The mixture was filtered over a Celite pad and the pad was washed with EtOAc (2x10 mL). The

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combined filtrate was concentrated in vacuo to provide crude product. Purification by silica gel
chromatography afforded 2-amino-6-(3-amino-4-fluorophenyl)-8-isopropylpyrido[2,3-
d]pyrimidin-7(8H)-one as an off-white solid (0.34 g, 72% yield). *H NMR (400 MHz, DMSO-d6): 5 8.60 (s, 1H), 7.73 (s, IH), 7.22 (s, 2H), 7.08 (dd, J = 9.2 Hz, 1.2 Hz, IH), 6.99 (dd, / = 10.8 Hz, 8.4 Hz, IH), 6.74-6.70 (m, IH), 5.78-5.76 (m, IH), 5.13 (s, 2H), 1.53 (d, J= 6.8 Hz, 6H); MS (ESI) m/z: 314.0 (M+H4).
Example A53: Using a procedure analogous to Example A7, N,N-dimethylpropane-l,3-diamine (3.27 g, 32 mmol) and Example All (100 mg, 0,32 nuiiol) were combined to provide 3-{5-amino-4-fluoro-2-methylphenyl)-7-(3-(dimethylamino)propylamino)-1 -methyl-l,6-naphthyridin-2(lH)-one (93 mg? 77 % yield). MS (ESI) m/z; 384.2 (M+H4).
Example A54: A solution of Example Al 1 (0.200 g, 0.629 mmol), KOAc (0.093 g, 0.944 mmol) and 10% Pd/C (0.33 g, 0.031 mmol) in THF/MeOH (2:1, 15 mL) was stirred at RT under a H2 atmosphere overnight The mixture was filtered on Celite and rinsed forward with MeOH. The combined filtrates were concentrated, diluted with satd. NaHCCH and extracted with EtOAc (2x). The combined organic layers were washed with brine (lx); dried (MgS04), filtered and concentrated to afford 3-(5-amino-4-fl"uoro-2-methylphenyl)-l-methyl-1,6-naphthyridin-2(lH)-one (0.161 g, 90%) as a yellow solid. MS (ESI) m/z: 284.0 (M+H4).
Example A55: A mixture of ethyl (3-amino-4-fluorophenyl)acetate (3.5 g, 17.6 mmol) and K2C03 (6.1 g, 44.1 mmol) in DMF (20 mL) was stirred at RT for 30 min. Example C3 (2.5 g, 14.7 mmol) was added to the above mixture and the resulting mixture was stirred at 80 °C for 10 h. The DMF was removed under reduced pressure and the crude residue was suspended in H20 and extracted with EtOAc (3 x 20 mL). The organics were washed with brine, dried (MgSCU) and concentrated to give 3-(3-amino-4-fluoropbenyl)-7-chloro-l-methyl-l)6-naphthyridin-2(lH)-one (4 g, 90 % yield). 'H NMR (300 MHz, DMSCWtf): 6 8.75 (s, 1 H), 8.07 (s, 1 H), 7.61 (s, 1 H), 7.13-7.00 (m, 2 H), 6.80 (m, 1 H), 5.21 (s, 2 H), 3.61 (s, 3 H). MS (ESI) m/z: 304.2 (M+H4).
Example A56: Using a procedure analogous to Example A7, N,N-dimethylemane-l,2-diamine (6.0 mL, 55 mmol) and Example A55 (150 mg, 0.49 mmol) were combined to afford 3-(3-

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amino-fluorophenyl)-7-(2-(dimethylainino)ethylamino)-l-methyI-l)6-naphthyridin-2(lH)-one (151 mg, 86% yield) as a yellow solid. MS (ESI) m/z: 356.3 (M+H+).
Example A57: A mixture of Example A60 (1.1 g, 3.7 mmol) and 25% CH3NH2/EtOH solution (10 mL) was heated at 160 °C in a steel bomb for 2h. The cooled reaction mixture was filtered and the solid was recrystallized (EtOH) to give 6-(3-ammo-phenyI)-8-memyL2-mefhy!amino~ 8H-pyrido[2,3-d]pyrimidin-7-one (610 mg, 59% yield). 'H NMR (300 MHz, DIVISOR): 8.69 and 8.61 (s, 1 H), 7.78 (m, 2 H), 7.01 (t, J= 7.8 Hz, 1 H), 6.85 (br s, 1 H), 6.73 (d, J= 7.8 Hz, 1 H), 6.51 (d, J = 7.8 Hz, 1 H), 5.05 (br s, 2 H), 3.56 and 3.52 (s, 3 H), 2.88 (m, 3 H). MS (ESI) m/z: 282.2 (M-HH+).
Example A58; KF/A1203 (40 wt %, 10 g, 69 mmol) was added to a solution of Example C7 (6 g, 30 mmol) and ethyl (3-amino-4-fluorophenyI)acetate (6 g, 30 mmol) in DMAc (80 mL). The reaction mixture was stirred at RT for 1 hour. The mixture was filtered and the filtrate was concentrated under vacuum. The residue was poured into water, and the precipitate was collected by filtration, washed with ethyl ether, and dried in vacuo to give 3-(3-amino-4-fluorophenyl)-7-chloro-l-isopropyl-l,6-naphthyridin-2(IH)-one (7 g, 70 % yield). 'H NMR (400 Hz, DMSO-4,): S 8.71 (s, 1 H), 8.00 (s, 1 H), 7.76 (s, 1 H), 7.11 (dd, J = 9.2, 2.4 Hz, 1 H), 7.05 (dd,J= 11.6, 8.4 Hz, 1 H), 6.76 (m, 1 H), 5.18 (s, 2 H), 5.15 (m, 1 H), 1.52 (d, 7=7.2 Hz, 1 H); MS (ESI) m/z: 332.0 [M+H]+.
A mixture of 3-(3-amino-4-fluorophenyl)-7-chlora-l-isopropyl-l,6-naphthyridin-2(lH)-one (4 g, 12.1 mmol) and (4-methoxybenzyl)methylamine (15 mL) was degassed under reduced pressure and heated to 180 °C under N2 for 4 h. After cooling, the reaction mixture was diluted with EtnO. The precipitate was filtered, washed with ether and dried in vacuo to give 3-(3-amino-4-fluoro-phenyl)-1 -isopropyl-7-[(4-medioxybenzyl)-methyl-amino]-1H-[l,6jnaphthyridin-2-one (5.3 g) as a solid contaminated with (4-metlioxybenzyl)methylamine HC1 salt.
The above prepared 3-(3-amino-4-fluoro-phenyi)-l -isopropyl-7-[(4-methoxy-benzyi)-methyl-amino]-lH-[l,6]naphtJiyridin-2-one (5.3 g) was combined in DCM (150 mL) with TEA (50 mL) and the resultant mixture was heated at reflux overnight. The volatiles were removed under reduced pressure, and the residue was dissolved in 10% HC1 aqueous solution. The

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aqueous layer was washed with EtOAc (3 x 100 mL) and the aqueous layer was basified to pH 11, and extracted with EtOAc. The combined extracts were dried (NEI2SO4) and concentrated to give 3-(3-amino-4-fluoro-phenyl)-l-isopropyl-7-memylamino-lH-[lJ6]naphtliyridin-2- one (1.26 g, 32 % yield for two steps). ]H NMR (400 MHz, DMSO-d6): 6 8.36 (s, 1 H), 7.70 (s, 1 H), 7.06 (dd, J = 8.4, 2.0 Hz, 1 H), 6.94 (dd, J= 11.6, 8.4 Hz, 1 H), 6.88 (m, 1 H), 6.72 (m, 1 H), 6.39 (s, 1 H), 5.07 (m, 1 H), 5.06 (s, 2 H), 2.83 (d, J = 4.8 Hz, 1 H), 1.51 (d, J = 6.8 Hz, 6 H); MS (ESI) m/z: 327.1 [M+H]+.
Example A59: Method 1: To a solution of Example A15 (0.5 g, 1.7 mmol) in DMF (5 mL) was added NaH (0.048 g, 2.0 mmol) at RT. After stirring for 30 min, 2-iodopropane (0.56 g, 3.3 mmol) was added and the mixture was stirred for 3h at RT. Sat NH4CI solution was added, and the product was extracted with ethylacetate (2x35 mL). The combined organics were washed with brine solution, dried (Na2S04) and concentrated in vacuo to provide crude residue. Purification by silica gel chromatography provided 6-(3-amino-4~fluorophenyl)-8-isopropyl-2~ (methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one as a light orange solid (0.18 g, 32% yield). lH NMR (400 MHz, DMSCW6): 5 8.88 (s, IH), 7.93 (s, 1H), 7.10 (dd, J = 8.8 Hz, 2.0 Hz, 1H), 7.02 (dd, J = 11.2 Hz, 8.4 Hz, IH), 6.77-6.73 (m, IH), 5.78-5.74 (m, IH), 5.19 (br s, 2H), 2.60 (s, 3H), 1.56 (d, /= 7.2 Hz, 6H); MS (ESI) m/z: 345.2 (M+H*).
Method 2: Example C6 (3.0 g, 14.2 mmol), ethyl 2-(3-ainino-4-fluorophenyl)acetate (2.8 g, 14.2 mmol), and KF/AI2O3 (40 wt %. 9 g, 62 mmol) were combined in DMAc (30 mL) and stirred at RT for 12 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure, washed with ethyl ether and dried in vacuo to give 6-(3-amino-4-fluorophenyl)-8-isopropyl-2-(methyIthio)pyrido[2,3-d]pyrimidin-7(8H)-one (2.1 g, 42.9% yield).
Example A60: Chlorotrimethylsilane (13.3 g, 122 mmol was added to a solution of 2-(3-nitrophenyl)acetonitrile (10 g, 61.2 minol) in EtOH (100 mL) and the mixture was refluxed overnight. The reaction mixture was concentrated under reduced pressure. Water was added and the mixture was neutralized to pH = 7 with saturated aq NaiCOa solution and extracted with EtOAc (3 x 70 mL). The combined organics were washed with brine, dried (MgS04) and concentrated to give ethyl 2-(3-nitrophenyl)acetate (12 g, 94 % yield). *H NMR (400 MHz,

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DMSO-d6):5 8,15(s, 1H), 8.10 (d, J= 8.4 Hz, 1 H), 7.71 (d, J = 7.6 Hz, 1 H), 7.61 (=8.0 Hz, 1 H), 4.06 (q, J= 7.2 Hz, 2 H), 3,85 (s, 2 H), 1.15 (t, J= 7.2 Hz, 3 H).
A mixture of ethyl 2-(3-nitrophenyl)acetate (12 g, 57.4 mmol) and Pd/C (1.2 g, 10%) in methanol (100 mL) was hydrogenated (45 psi) at RT for 12 h. The mixture was filtered and the filtrate was concentrated to afford ethyl 2-(3-aminophenyl)acetate (10 g, 97 % yield). 'H NMR (400 MHz, DMSO-d6):S 6.91 (t,J=7.6Hz, 1 H), 6.42-6.40 (m, 2 H), 6.35 (d, J = 1.6 Hz, 1 H), 5.00 (s, 2 H), 4.03 (q, /= 7.2 Hz, 2 H), 3.41 (s, 2 H), 1.15 (t, J = 12 Hz, 3 H).
Example CI (5.1 g, 27.9 mmol), ethyl 2-(3-aminophenyl)acetate (5.0 g, 29.3 mmol), and K2CO3 (7.7 g, 55.8 mmol) were combined in DMF (60 rnL) and the resulting mixture was stirred at 100 °C for 10 hours. The reaction mixture was concentrated under reduced pressure, diluted with water (100 mL), and the aqueous layer was extracted with EtOAc (3 x 70 mL). The combined organic layers were washed with brine, dried (MgSCU) and concentrated in vacuo. The residue was purified by column chromatography on silica gel to give 6-(3-aniinophenyl)-8-methyl-2-(methylthio)pyrido[2,3-d]pyrimidiri-7(8H)-one (5.2 g; 62.7% yield). *H NMR (400 MHz, DMSO-4;): S 8.89 (s, 1 H), 7.97 (s, 1 H), 7.05 (t, J= 8.0 Hz, 3 H), 6.S7 (s, I H), 7.76 (d, J = 7.6 Hz, 1 H), 6.57 (d, J= 8.4 Hz, 1 H), 5.11 (s, 2 H), 3.64 (s, 3 H), 2.59 (s, 3 H); MS (ESI) m/z: 299.2 [M + Hf.
Example A61: Example C3 (3.2 g, 18.8 mmol), Example D6 (4.0 g, 18.8 mmol) and Cs2C03 (12.3 g, 37.6 mmol) were combined in DMF (80 mL) and heated to 80°C with stirring for 4 h. The reaction mixture was poured into water (600 mL) and precipitate was collected by filtration and dried under reduced pressure to give 3-(5-amino-2-chIorophenyl)-7-chIoro-l -methyl-1,6-naphthyridin-2(lH)-one (5.0 g, 83 % yield). lH-NMR (400 MHz, DMSO-rf&): 6 8.74 (s, 1 H), 7.97 (s, 1 H), 7.63 (s, 1H), 7.09 (d, J= 8.4 Hz, 1 H), 6.57 (dd, J= 8.4 Hz, 2.8 Hz, 1 H), 6.52 (s, 1 H),5.31(s,2H),3.60(s, 3 H).
A mixture of 3-(5-amino-2-chIorophenyl)-7-chloro-l-methyl-l,6-naphtliyridin--2(lH)-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) was heated at 180 °C under N2 for 4 h. The reaction was cooled to room temperature and poured into water (600 mL). The precipitate was collected by filtration and dried in vacuo to give 7-((4-methoxybenzyl)(methyi)amino)-3-(5-amino-2-chIoropheny!)-l-methyl-l,6-naphtliyridin-2(lH)-one (6.5 g, 95 % yield), !H NMR (400 MHz, DMSO-d6): S 8.46

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(s, 1 H), 7.68 (s, 1 H), 7.16 (d, J = 8.8 Hz, 2 H), 7.06 (d, J= 8.4 Hz, 1 H), 6.85 (d, J= 8.8 Hz, 2 H), 6.54-6.51 (m, 2 H), 6.29 (s, 1 H), 5.23 (s, 2 H), 4.85 (s, 2 H), 3.69 (s, 3 H)? 3.51 (s, 3 H), 3.07 (s, 3 H).
Trifluoroacetic acid (10 mL, 134 mmol) was added to a solution of 7-((4-metlioxybenzyl)(methyl)amino)-3-(5-amino-2-chlorophenyI)-l-methyl-l,6-naphth)Tidiii-2(lH)-one (4 g, 9.2 mmol) in CH2CI2 (50 mL). The mixture was heated to reflux for 3 hrs. The reaction mixture was concentrated under reduced pressure, dissolved in aq HC1 solution and washed with EtOAc (3 x 50 mL). The aqueous layer was neutralized with saturated Na2C03 solution to pH 8, and was extracted with EtOAc (3 x 50 mL). The combined extracts were washed with brine, dried over Na2S04 and concentrated under reduced pressure. The residue was purified by chromatography to give 3-(5-amino-2-dilorophenyl)-l-methyl-7-(memylarnino)-l,6-naphthyridin-2(lH)-one (1.7 g, 58% yield). !H NMR (400 MHz, DMSO-rf6): & 8.36 (s, 1 H), 7.63 {s, 1 HI 7.06-7.00 (m, 2 H), 6.54-6.50 (m, 2 H), 6.14 (a, } H), 5.21 (s, 2 H), 3.48 (s, 3 H), 2.84 (d, J= 4.8 Hz, 3 H); MS (ESI) m/z: 314.9 [M + H]4.
Example A62: Using the Ihree-step procedure of Example 61, Example C5 (3.5 g. 18.8 mmol), Example D6 (4.0 g, 18.8 mmol), CS2CO3 (12.3 g, 37.6 mmol), 4-methoxybenzyl methyl amine (3.6 g, 23.5 mmol) and trifluoroacetic acid (10 mL, 134 mmol) were combined to provide 3-(5-amino-2-chlorophenyl)-l -ethyl-7-(methylamino)-1,6-naphthyridin-2(l H)-one (1.68 g, 27 % yield over 3 steps). 'H NMR (400 MHz, DMSO-^): 5 8.36 Example A63: Using a procedure analogous to Example Al. Example AT 8 (1.01 g. 2.77 mmol) and 2M Methylamine in THF (6 mLl) were combined and purified by silica gel chromatography to afford 6-(5-amino-2-chloro-4-fluorophenyl)-8-ethyl-2-(methylamino)pyrido[2,3-d]pyrimidin-
7(8H)-one as orange colored solid (0.55 g, 57% yield). !H NMR (400 MHz, DMSO-J6)-' $ S.59 (s, 1H), 7.84-7.81 (m, 1H), 7.67 (s, 1H), 6.20 (d, 7- 11.2 Hz, 1H), 6.72 (d, J= 9.6 Hz, IH), 5.33 (s, 2H), 4.35-4.30 (m, 2H), 2.89 (d, J= 6.0 Hz, 3H), 1.21 (t, 7 = 6.8 Hz, 3H); MS (ESI) m/z: 348.0 (M+HH~).

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Example A64: Example D6 (1.0 g, 4.68 mmol), Example CI (0.858 g, 4.68 mmol) and Cs2C03 (3.96 g, 12.2 mmol) were combined in DMF(lSmL) by the procedure of Example A10, method 3, to provide 6-(5-aminO"2-chlorophenyl)-8-metriyl-2-(metriylthio)p>Tido[2,3-d]pyrimidin-7(8H)-one (1.37 g, 88 % yield). 'H NMR (400 MHz, DMSOd6): 5 8.90 (s, 1H), 7.90 (s, 1H), 7.10 (d, J = 8.0 Hz, 1H), 6.58 (dd, J = 8.8, 2.4 Hz, 1H), 6.53 (d, J = 2.4 Hz, 1H), 5.33 (s, 2H), 3.64 (s, 3H), 2.61 (s, 3H); MS (ESI) m/z: 330.0 (M+H4).
6-(5-amino-2-chlorophenyl)-8-memyl-2-(memylmio)pyrido[213-d]pyriniidin-7(8H)--one (0.500 g, 1.5 mmol), mCPBA (0.481 g, 1.953 mmol) and methylamine (0.76 mL. 2.0 M in THF, 1.52 mmol) were combined by analogy to Example Al to provide 6-(5-amino-2-chlorophenyI)-8-methyl-2-(methylamino)pyrido[2,3-d]pyrimidin-7(8H)-one (0.378 g, 80 % yield). MS (ESI) m/z: 316.0 (M+H+).
Example A65: Example C5 (1.8 g, 10 mmol) and ethyl 2-(5-amino-2-methylphenyl)acetate (1.9 g, 10 mmol, and KF/A1203 (40%, 5.4 g, 37 mmol) were combined in DMAc (40 mL) by the procedure of Example All to give 3-(5-amino-2~memylphenyl)-7-chloro-l-ethyl-l,6-naphthyridin-2(lH)-one (1.9 g, 61 % yield). 'H NMR (400 MHz, DMS(W6): S 8.73 (s, 1 H),
7.88 (s, 1 H), 7.68 (s, 1 H), 6.87 (d, J= 8.4 Hz, 1 H), 6.49 (d, J= 8.4 Hz, 1 H), 6.41 (m, 1 H),
4.88 (s, 2 H), 4.24 (q, .7=7.2 Hz, 2 H), 1.92 (s, 3 H), 1.16(t, J=7.2Hz, 3 H).
Using a procedure analogous to Example A26, 3-(5-amino-2-methylphenyl)-7-chloro-l-ethyl-l,6-naphthyridin-2(lH)-one (1.9 g, 6.4 mmol), 4-methoxybenzylmemylamine (1.5 g, 9.6 mmol), DBU (1.6 g, 9.6 mmol), and trifluoroacetic acid (10 mL, 134 mmol) were combined to give 3-(5-ammo-2-memylphenyl)-l-emyl-7-(meU]ylannno)-l,6-riaphtliyridin-2(lH)-one (0.84 g, 43 % yield, 2 steps). ]H NMR (300 MHz, DMSO-^): 8 8.36 (s, 1 H), 7.56 (s, 1 H), 6.91-6.82 (m, 2 H), 6.47-6.39 (m, 2 H), 6.22 (s; 1 H), 4.80 (s, 2 H), 4.13 (q, / = 6,9 Hz, 2 H), 2.84 (d, J = 4.8 Hz, 3 H), 1.92 (s, 3 H), 1.19 (t, /= 6.9 Hz, 3H); MS (ESI) m/z: 308.9 [M + H]+.
Example B1; Phenyl hydrazine and 4,4-dimethyl-3-oxopentanenitrile were combined according to literature procedures to yield 3-tert-butyl-l-phenyI-lH-pyrazol-5-amine. See WO 20067071940.

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Example B2: Methyl hydrazine and 4,4-dimethyl-3-oxopentanenitrile were combined according to literature procedures to yield 3-tert-buty]-l-methyl-lH-pyrazol-5-amine, See WO 2006/071940.
Example B3: 3-(2-amino-2-oxoethyl)phenyl hydrazine and 4,4-dimethyl-3-oxopentanenitrile were combined according to literature procedures to yield 2-(3-(5-amino-3-tert-butyl-lH-pyrazol-l-yl)phenyl)acetamide. See WO 2006/071940.
Example B4: A mixture of 5-nitro-lH-indazole (25 g, 0.153 mmol) and 10% Pd/C (2.0 g) in MeOH was stirred under H^ (1 arm) overnight. After filtration, the filtrate was concentrated to yield lH-indazol-5-ylamine (20 g, 97% yield) as a yellow solid. lH NMR (300 MHz, DMSO-rf6):5 12.50 (bra, 1H), 7.70 (s, 1H), 7.21 (d, J -8.7 Hz, 1H), 6.77 (d, J= 8.7 Hz, lH)?6.74(s, 1H),4.71 (brs, 1H), 3.15 (d, 7=4.8 Hz, 2H); MS (ESI) m/z: 134(M+H+).
To a solution of lH-indazol-5-ylamine (20 g, 153 mmol) in cone. HC1 (50 mL) was added an aqueous solution (50 mL) of NaN02 (19 g, 158 mmol) at 0 °C and the resulting mixture was stirred for Ih. A solution of SnCl2*2H20 (90 g, 306 mmol) in cone. HC1 (70 mL), pre-cooled to 0 °C, was then added. The reaction solution was stirred for 2h at RT. The precipitate was filtered and washed with ether to yield (lH-indazol-5-yl)-hydrazine hydrochloride as a yellow solid, which was used for the next reaction without further purification.
A mixture of (1 H-indazoI-5-yl)-hydrazine hydrochloride and 4,4-dimethyl-3-oxo-pentanenitrile(19 g, 1.05eq)in EtOH (200 mL) was heated at reflux overnight. The reaction was concentrated and the residue purified by column chromatography to yield 3-t-butyl-l-(lH-indazo!-5-yl)-lH-pyra2ol-5-amine (23 g, 60% for two steps). 'H NMR (300 MHz, DMSO-6): 5 8.24 (s, 1 H), 8.06 (s, 1 H), 7.75 (d, J = 9.0 Hz, 1 H), 7.45 (dd, J= 9.0 Hz, 1.8 Hz, 1 H), 5.7 (s, 1 H), 1.31 (s, 9 H); MS (ESr) m/z: 256 (M+H*).
To a solution of 3-t-butyl-l-(lH-indazol-5-yI)-lH-pyrazol-5-amine (14 g, 48 mmol) in dioxane (100 mL) was added 10% NaOH (50 mL) at RT and the mixture stirred for 0.5h. Boc anhydride (12 g, 1.2eq) was added to the mixture and the solution stirred for 3h. The mixture was extracted with CH2CI2 (3*100 mL). The combined organic extracts were concentrated and purified by column chromatography to yield t-butyl 5-(5-amino-3-t-butyl-lH-pyrazol-l-yl)-lH-indazoIe-l-

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carboxylate (7.8 g, 46%). !H NMR (300 MHz, DMSO-^): 8.44 (s, 1 H), 8.10 (d, J= 9.0 Hz, I H), 8.00 (s, 1 H), 7.82 (d, /= 9.0 Hz, 1 H), 5.39 (s, 1 H), 5.24 (br s, 2 H), 1.65 (s, 9 H), 1.21 (s, 9 H): MS (ESI) m/z: 356 (M+H+).
Example B5: Phenyl hydrazine and 3-oxo-3-(tniophen-2-yl)propanenitrile were combined according to literature procedures to yield l-phenyl-3-(thiophen-2-yl)-lH-pyrazol-5-amine. See WO 2006/071940.
Example B6: Methyl hydrazine (0.35 g, 7.6 mmol) and 2-thionyl acetonitrile (1.1 g, 7.6 mmol) were heated to 80 °C in ethanol in the presence of cone. HCl (1 drop) for 18h. Solvents were removed; sat. NaHC03 solution (35 ml) was added and the product was extracted with ethyl acetate (2x30 ml). The combined organic layers were washed with brine, dried (Na2SO Example B7: 3-FIuoropheryylboronic acid (0.70 g, 5.0 mmol), ethyl 3-tert-butyl-lH-pyrazole-5-carboxylate (0.981 g, 5.0 mmol), Cu(OAc)2 (0.908 g, 5.0 mmol), pyridine (2.45 ml, 30 mmol)
and 4A MS (1.9 g) were combined in CH2CI2 (48 ml) and stirred open to air at RT for 4 d. The reaction mixture was diluted with EtOAc (150 mL), washed with 3M HCl (2x50 mL), H20 (50 mL) and brine (50 mL), dried (MgS04) and concentrated in vacuo. The crude product was purified by chromatography to afford ethyl 3-tert-butyl~l-(3-fluorophcnyl)-lH-pyrazole-5-carboxylate (0.786 g, 54% yield) as colorless oil. MS (EST) m/z: 291 (M+H+).
To a stirring solution of ethyl 3-tert-butyl-l-(3-fluorophenyl)-lH-pyrazole-5-carboxylate (0.786g, 2.71 mmol) in 1:1:1 THF/EtOH/H20 (36 ml) at RT was added LiOHH20 (0.568g, 13.5 mmol). After stirring at RT overnight, the reaction mixture was diluted with 3M HCl (30 mL) and extracted with EtOAc (3x50 mL). The combined organic layers were washed with brine (2x30 mL), dried (MgSO) and concentrated to afford 3-tert-butyl-l-(3-fluorophenyl)-lH-pyrazole-5-carboxylic acid (0.602 g, 85% yield) as white solid. MS (ESI) m/z: 263 (M+H4).

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To a stirring solution of 3-tert-butyl-l-(3-fluorophenyl)»lH-pyrazole-5-carboxylic acid (0.26 g, 0.60 mmol) and TEA (0.13 ml, 0.90 mmol) in 1,4-dioxane (9 ml) was added DPPA (0.16 ml, 0.75 mmol), After stirring for 30 min at RT, 2,2,2-rrichloroethanol (0.5S ml, 6.0 mmol) was added and the reaction was heated at 100 °C for 2 h. The reaction mixture was diluted with brine (10 ml) and extracted with EtOAc (3x20 ml). The combined organic phases were washed with 5% citric acid (10 ml), satd. NaHC03 (10 ml), dried (MgSO^), filtered and evaporated. The crude product was purified by chromatography to afforded 2,2,2-trichloroethyl 3-tert-butyl-l -(3-fluoropheny])-lH-pyrazol-5-ylcarbamate (0.180 g, 73% yield) as colorless oil. MS (ESI) m/z: 410(M+H+).
Example B8: Method 1: To a solution of quinolin-6-ylamine (5 g, 35 mmol) in cone. HC1 (12 mL) was added dropwise an aqueous solution (4 mL) of NaN02 (2.42 g, 35 mmol) at 0 °C. The resulting mixture was stirred for In and then treated dropwise with a solution of SnCh,2H20 (15.8 g, 70 mmol) in cone. HC1 (15 mL) at 0 QC. The reaction mixture was stirred for 2h at RT. The precipitate was collected and washed with EtOH and Ei20 to yield 1 -(quinolin-6-yl)hydrazine hydrochloride (4.3 g, 77% yield) as a yellow powder, which was used for the next reaction without further purification.
A mixture of l-(quinolin-6-yl)hydrazine hydrochloride (4.0 g, 20.5 mmol) and 4,4-dimethyl-3-oxo-pentanenitrile (3.6 g, 30 mol) in EtOH (50 mL) and cone. HC1 (5 mL) was heated at reflux overnight. After removal of the solvent, the residue was purified by column ciiromatography to yield 3-t-butyl-l-(quinolin-6-yl)-l//-pyrazol-5-amine (2.8 g, 51% yield). ]H NMR (300 MHz, DMSO-rfd): 5 8.84 (d, J = 4.2 Hz, IH), 8.37 (d, J = 7.5 Hz, IH), S.09 (s, IH), 8.04 (s, 2H), 7.52(m, IH), 5.46 (s, IH), 5.40 (brs, 2H), 1.29 (s, 9H). MS (ESI) m/z (M+H*): 267.2.
Method 2: A solution of triflic anhydride (42.8 g, 0.15 mol) in methylene chloride (lOOmL) was added dropwise to a 0 °C solution of 6-hydroxyquinoline (20.00 g, 0.138 mol) and pyridine (23 g, 0.277 mol) in methylene chloride (500 mL). The cooling bath was removed and the resulting solution was stirred at RT for 4 h. The reaction mixture was washed with water (3 x 300 mL) and the organics were dried (MgS04) and concentrated under vacuum to afford crude quinolin-6-yl trifluoromethanesulfonate (40g , >100% yield) as an oil. 'H-NMR (400 MHz,

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DMSO-4): 5 9.00 (d, 1 H, 7 = 2.8 Hz), 8.50 (d, 1R7 = 8.0 Hz), 8.21 (d, 7 = 2.8 Hz, 1H), 8.18 (d, 7= 9.2 Hz, 1H), 7.80 (m, 1 H), 7.64 (m, 1 H); MS (ESI) m/z: 277.9 (M+H*).
To a suspension of quinolin-6-yl trifluoromethanesulfonate (40 g, 0.14 mol), benzophenone hydrazone (35.6 g, 0.18 mol), cesium carbonate (74 g, 0.23 mol) and 1,1'-bis(diphenylphosphino)ferrocene (2.5 g5 4.5 mmol) in degassed toluene (1 L) was added palladium acetate (0.013 g, 0.058 mmol). The resultant mixture was heated to 90 °C under a nitrogen atmosphere. After 16 h, the mixture was concentrated in vacuo and the residue was purified through silica gel column chromatography (20-30% EtOAc in pet ether) lo provide 1-(diphenylmethylene)-2-(quinolin-6-yl)hydrazine (32 g, 68.6% yield). 'H-NMR (300 MHz, DMSO-40: S 9.22 (s, 1 H), 8.58 (t, 7= 1.8 Hz, 1 H), 8.13 (d, 7 = 3.6 Hz, 1 H), 7.80 (d, 7= 3.6 Hz, 1 H), 7.61 (d, 7 = 3.9 Hz, 1 H), 7.59-7.51 (m, 4 H), 7.50 (d, 7 = 3.6 Hz, 2 H), 7.33-7.39 (m, 6 H); MS (ESI) m/z: 324 (M+H*).
A solution of l-(diphenylmethylene)-2-(quinolin-6-yl)hydrazine (32 g, 99 mmol) and 4,4-dimethyl-3-oxo-pentanenitrile (26 g, 0.15 mol) in ethanol (500 mL) was treated with cone HC1 (80 ml, 12 N, 0.96 mol) and the mixture was heated to reflux overnight. The cooled reaction mixture was concentrated under vacuum and the residue was washed with Et20 to remove the diphenylketone. The crude product was dissolved in EtOAc and neutralized (pH 8) with saturated Na2C03 solution. The organic layer was dried (Na2SO,j) and concentrated in vacuo. The residue was further purified by silica gel chromatography to give 3-t-butyI-l-(quinolii]-6-yl)-l//-pyrazol-5-amine (23 g, 87% yield). 'H-NMR (300 MHz, DMSCW*): 5 8.86 (m, 1 H), 8.39 (d, 7= 5.7 Hz, I H), 8.11-8.02 (m, 3 H), 7,54 (m, 1 H), 5.46 (s, 1 H), 5.42 (br s, 2 H), 1.23 (s, 9 H); MS (ESI) m/z (M+H4): 267.2.
Example B9: Methyl hydrazine (0.46, 10 mmol) and 2-fluorophenyl acetonitrile (1.63 g, 10 mrnol) were heated to 80 °C in presence of cone. HC1 (1 drop) in ethanol (30 mL) for 18h. Solvents were removed; sat. NaHC03 solution (35 ml) was added and the product was extracted with ethyl acetate (2x30 mL). The combined organic layers were washed with brine, dried (Na2SO4) and concentrated to afford crude product which was purified by chromatography (methanoI/CH2Cl2) to afford 3-(2-fluorophenyl)~l-methyl-lH-pyrazol-5-amine (1.25 g, 65% yield) as a thick residue. !H NMR (400 MHz, DMSO-rf6): 5 7.86 (td, 7 = 8.8 Hz, 2.4 Hz, 1H),

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7.28-7.15 (m, 3H), 5.71 (d, J = 4.4 Hz, 1H), 5.28 (brs, 2H), 3.58 (s, 3H); MS (ESI) m/z: 192.0 (M+H4).
To a triphasic solution of 3-(2-fluoropheny1)-l-memyl-lH-pyrazoI-5-arnine (1.19 g, 6.22 mmol) in ethyl acetate (30 mL) and NaHC03 solution (30 mL) was added isopropenylchloroformate (1.28 g, 10.6 mmol) and mixture was stirred at RT for 24h. Both layers were separated; the aqueous layer was extracted with ethyl acetate (1x30 mL) and the combined organic layers were washed with brine, dried (Na2SO4) and concentrated to afford crude product which was purified by chromatography (ethyl acetate/hexane) to afford prop-1-en-2-yl 3-(2-fluorophenyl)-l-methyl-lH-pyrazoI-5-ylcarbamate (1.15 g, 82% yield) as a pasty mass. 'H NMR (400 MHz, DMSCWfi): 6 10.09 (brs, 1H), 7.90 (td, 7= 8.0 Hz, 1.6 Hz, 1H), 7.38-7.22 (m, 3H), 6.54 (d, J = 3,6 Hz, 1H), 4.79-4.77 (m, 2H), 3.76 (s, 3H); 1.96 (s, 3H); MS (ESI) m/z: 276.0 (M+rT).
Example B10: A mixture of 5-hydrazinyI~2~methylpyridine hydrochloride from Example B27 (5.0 g, 31.4 mmol) and 4, 4-dimethyl-3-oxopentanenitrile (8.3 g, 66.3 mmol) in EtOH (50 mL) was heated at reflux overnight. The reaction was concentrated and the residue was dissolved in EtOAc and neutralized with saturated Na2CO3 solution. The organic layer was dried (Na^SO4), concentrated in vacuo and purified by column chromatography to yield 3-tert-butyJ-1-(6-memylpyridin-3-yl)-lH-pyrazol-5-amine (5.2 g, 71 % yield). ]HNMR (400 MHz, CDC13) 8 8.72 (s, 1 H), 7.81 (dd,7= 8.0; 2.4Hz, 1 H), 7.23 (d, J= 8.4 Hz, 1 H), 5.54 (s, 1 H), 3.71 (brs, 1 H), 2.58 (s, 3 H), 1.29 (s, 9 H); MS (ESI) m/z: 231.2 (M+H+).
Example Bll: To a stirring solution of Example B35, 0.240 g, 0.86 mmol) in dry THF (8.0 mL) at RT was added LiAlHj (1.0 M in THF. 2.6 mL, 2.6 mmol) and the resulting mixture was stirred at RT for Ih. The reaction was carefully quenched by the addition of H20 (0.10 mL), 3M NaOH (0.10 mL) and H20 (0.20 mL), and the mixture was stirred at RT overnight. The suspension was filtered through Celite and rinsed with EtOAc (20 mL). The filtrate was dried (MgS04) and concentrated to afford 2-(5-amino-l-phenyl-lH-pyrazoI-3-yl)-2-methylpropan-l-ol (0.208, 105% yield) as a yellow oil. MS (ESI) m/z: 232.2 (M+H+).
To a solution of 2-(5-amino-l-phenyl-lH-pyrazol-3-yl)-2-methylpropan-l-ol (0.208 g, 0.85 mmol) in DMF (2.0 mL) was added imidazole (0.32 g, 4.7 mmol) and TBSC1 (0.39 g, 2.6

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mmol). Tlie resulting mixture was stirred at RT for 5 h. Solvent was removed under reduced pressure. The residue was diluted with H2O (10 mL) and extracted with EtOAc (2x20 mL). Tlie combined organic layers were dried (MgSOj) and concentrated. The crude product was purified by chromatography to afford 3-(l-(tert-butyIdimethylsilyIoxy)-2-metIiyIpropan-2-yl)-l-phenyl-lH-pyrazot-5-amine (0.125 g, 42% yield) as a light yellow oil. MS (ESI) m/z: 346.3 (M+H4).
Example B12: Using a procedure analogous to Example Bl 1, Example B36 was converted to 3-(1 -(tert-butyIdi'melhylsilyloxy)-2-methyJpropan-2-yl)-1 -methyl-1 H-pyrazol-5-amine in 42% yield. *H NMR (400 MHz, CDCI3): 5 5.59 (s, 1H), 3.69 (s, 3H), 3.55 (s, 2H), 1.26 (s, 6H), 0.89 (s, 9H), 0.00 (s, 6H); MS (ESI) m/z: 284.2 (M+H1).
Example B13: Potassium t-butoxide (0.51 g, 4.5 mmol) was dissolved in DMSO (10 mL) and lo this solution was added ethyl 3-(thiophen-2-yl)-lH-pyrazole-5-carboxylate (1.01 g, 4.5 mmol) in small portions and stirred under Ar for 15 min. To this solution was added 2-todopropane (1.2 g, 6.8 mmol) slowly and stirred for lh at RT. Sat. NH4CI solution was added, the product was extracted with EtOAc (2x40 mL). The combined organics were washed with brine, dried (Na2S04 and concentrated in vacuo. Purification by silica gel chromatography provided ethyl 1 -isopropyI-3-(thiophen-2-yl)-lH-pyi-azole-5-carboxylate as a pasty mass (0.88 g, 73% yield). ]H NMR (400 MHz, Acetone^): 6" 7.47 (dd, J = 3.2 Hz, 1.2 Hz, 1H), 7.42 (dd, J= 4.8 Hz, 1.2 Hz, 1H), 7.12-7.09 (m, 2H), 5.57-5.51 (m, 1H), 4.37 (q,J= 7.2 Hz, 2H), 1.50 (d, 7 = 6.8 Hz, 6H), 1.38 (t, J= 7.2 Hz, 3H); MS (ESI) m/z: 265.0 (M+H*).
To a solution of ethyl l-isopropyL3-(thiophen-2-yl)-lH-pyrazole-5-carboxylate (0.88 g, 3.3 mmol) in THF (10 mL) was added aq. LiOH solution (0.42 g, 10 mmol, 5 mL) and tlie mixture was stirred for I6h at RT. Solvents were removed and the thick liquid was diluted with water (5 mL) and acidified with 3M HC1 solution to pH 4 - 5. The product precipitated and was filtered, washed with water and dried to afford l-isopropyI-3-(thiophen-2-yl)-lH-pyrazole-5-carboxylic acid as a white solid (0.69 g, 88% yield).
To a solution of l-isopropyl-3-(thiophen-2-yl)-lH-pyrazole-5-carboxylic acid (0.68 g, 2.9 mmol) in dioxane (10 mL) was added with triethylamine (0.44 g, 4.3 mmol), diphenylphosphorylazide (0.95 g, 3.5 mmol) and trichloroethanol (0.86 g, 5.8 mmol) and the
o
mixture was heated to 90 C for 4h, The mixture was poured into 3 M HCI (40 mL) solution and

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the product was extracted with EtOAc (2x40 mL). The combined organics were washed with brine, dried (NaiSCXj) and concentrated in vacuo. Purification by silica gel chromatography provided 2,2,2-trichloro ethyl l-isopropyl-3-(thiophen-2-yl)-lH-pyrazol-5-ylcarbamate (0.S8 g, 80% yield) as a white solid. ]H NMR (400 MHz, Acetone-^): 5 7.36-7.34 (m, 3H), 7.07 (dd, J = 5.6 H2, 4.0 Hz, lH),6.52(s, IH), 5.83 (t,J= 7.2 Hz, 3H), 4.95 (s;2H), 4.66-4.62 (m, IH), 1.45 (d,./ = 6.8 Hz, 6H); MS (ESI) tn/z: 3S2.0 (M+H*).
Example B14: In a procedure analogous to Example B8 (method 1), 2-methylquinoIiiie-6-amine (l.OOg, 6.32 mmol) and 4,4-dimethy]-3-oxopentanenitriIe (1.03 g, 8.22 mmol) were combined to provide 3-tert~buryl-l-(2-memylquinolm~6-y])-lH-pyrazol-5-amme (428 mg, 24% yield) as a solid. lH NMR (300 MHz, DMSO-40, 5 1.24 (s, 9 H), 2.66 (s, 3 H), 5.37 (s, 2 H), 5.43 (s, 1 H), 7.44 (d, J = 8.4, 1 H), 7.97 (s, 2 H), 8.05 (s, 1 H), 8.28 (d, J= 8.4, 1 H); MS (ESI) m/z: 281.2 (M+H+).
Example B15; To a suspension of KCN (1.90 g, 29.1 mmol) in MeOH (35 mL) was added dropwisely 3-bronio-l,l,l-trifluoropropan-2-one oxime (5.00 g, 24.3 mmol) in MeOH (72 mL) at RT. The reaction mixture was stirred at RT for 3 hours. The solution was evaporated and then the residue was dissolved in EtOAc and stirred at RT. The solid was filtered and the filtrate was evaporated to obtain the crude product. The crude product was purified by silica gel column chromatography (Biotage: 25M, 10% to 60% EtOAc/hexane: 550 mL) to obtain 3-(trifluoromethyl)isoxazol-5-amine (1.38 g, 37% yield). MS (ESI) m/z: 153.0 (M+H*).
Using general method G, 3-(trifluoromethyl)isoxazol-5-amine (1.38 g, 9.1 mmol) and isopropenyl chIoroformate(I.1 g. 9.1 mmol) in presence of LiHMDS (I. OM, I8mL, 18.2 mmol) were combined to afford prop-l-en-2-yl 3-(trifluoromelhyl)isoxazol-5-ylcarbamate (0.82 g, 38% yield). ). lH NMR (400 MHz, DMSO-d6): 6 12.3 (s, IH), 6.48 (s, 1H), 4.83 (m, IH), 4.80 (m, 1H), 1.93 (s, 31-1); MS (ESI) m/z: 237.0 (M+H+).
Example B16: Potassium t-butoxide (0.29 g, 2.5 mmol) was dissolved in DMSO (5 mL) and to this solution was added Example B37 (0.50 g, 2.5 mmol) in small portions under argon atmosphere. After 15 minutes, 2-iodoethane (0.31 mL, 3.8 mmol) was added slowly. After stirring for 1.5 hours, LC-MS showed disappearance of starting material and formation of

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product. Sat. NH4CI solution was added, product was extracted with etliyl acetate (2x40 ml), the combined organic layers were washed with brine, dried (NasSO and concentrated to afford crude product. The crude product was purified by silica gel column chromatography (Biotage: 25M, 5% to 35% EtOAc/hexane: 340 mL, 35% to 100% EtOAc/hexane: 300 mL) to afford ethyl 3-tert-butyl-l-ethyl-lH-pyi-azole-5-carboxylate (0.35 g, 61% yield). MS (ESI) m/z: 225.3 (M+H*).
To a solution of etliyl 3-tert-butyl-l -ethyl-lH-pyrazole-5-carboxylate (0.35 g, 1.6 mmol) in a mixture of ethanol:dioxane:water (1:1:1, 6 mL) was added lithium hydroxide (0.15 g, 6.2 mmol). The reaction mixture was stirred overnight at RT. The solution diluted with EtOAc (50 mL) and 5% citric acid (50 mL). The organic phase separated, washed with brine (20 mL), dried (Na2SO-0 and evaporated under reduced pressure to afford 3-tert-butyl-]-ethyl-lH-pyrazole-5-carboxylic acid (0.30 g, 98% yield) as a yellow solid. 'H NMR (400 MHz, DMSO-d6): 5 6.64 (s, 1H), 4.40 (q, J = 7.2 Hz; 2H), 1.27 (t, J = 7.2 Hz, 3H), 1.22 (s, 9H); MS (ESD m/z: 197.3 (M+H*).
Example B17: Potassium t-butoxide (2.6 g, 23 mmol) was dissolved in DMSO (10 mL) and to this solution was added Example B37 (4.5 g, 23 mmol) in small portions and stirred under Ar for 15 min. To this solution was added t-butyl-bromoacetate (5.4 g. 28 mmol) slowly at 0 °C with stirring for for 45 min at RT. Sat. NH4CI solution was added and product was extracted with ethylacetate (3x50 mL). The combined organic layers were washed with brine, dried (NanSO) and concentrated to afford (7.0 g) coupled product as a pasty mass. The above pasty mass was dissolved in TFA (10 mL) and stirred for 3h at RT. Solvents were removed, to the residue water (100 mL) was added and product was extracted with DCM (3x50 ml). The combined organic extracts were washed with brine solution, dried (Na2S04) and concentrated to yield 2-(3-tert-butyl-5-(emoxycarbonyl)-lH-pyra2ol-l-yI)acetic acid (5.8 gm, 100%) as a pasty mass. 'H NMR (400 MHz, Acetone-d6): 5 6.78 (s, 1H), 5.25 (s, 2H), 4.30 (q, J= 7.2 Hz, 2H), 1.35-1.30 (m, 12H); MS (ESI) m/z: 255.2 (M+H*).
To a solution of acid (0.41 g, 1.6 mmol) in DMF (5 mL) was added PyBop (0.84 g, 1.6 mmol), DIEA (0.42 g, 3,2 mmol) and dimethylamine hydrochloride (0.26 g, 3.2 mmol). After stirring the mixture for lh at RT, water (50 mL) was added, and the product was extracted with ethylacetate (2x30 ml). The combined organic layers were washed with 3M HC1 solution (1x30

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mL), dried (Na2SO0 and concentrated to afford crude product which was purified by chromatography (EtOAc/DCM) to afford ethyl 3-tert-butyI-l-(2-(dimethylamino)-2-oxoethyI)-lH-pyrazole-5-carboxylate (0.25 g, 55%) as a thick paste. fH NMR (400 MHz, Acetone-^): 6 6.73 (s, 1H), 5.35 (s, 2H), 4.27 (q, J- 7.2 Hz, 2H), 3.15 (s, 3H), 2,90 (s, 3H), 1.33-1.28 (m, 12H); MS (ESI) m/z: 282.3 (M+H*).
To a solution of ethyl 3-tert-butyl-l-(2-(dimethylamino)-2-oxoethyl)-lH-pyrazoIe-5-carboxylate (1.16 g, 4 mmol) in THF (10 mL) was added 1M borane/THF (12 ml, 12 mrnol) at 0 °C under Ar and stirring continued for 12h at 60 °C. The mixture was cooled to 0 °C, quenched with 3M HC1 solution and heated to 60 °C for 30 min. The mixture was basified with solid NaHC03 to pH around 8 and the product was extracted with CHCI3 (2x30 ml). The combined organics were washed with brine, dried (Na2S04) and concentrated in vacuo provided crude product. Purification by silica gel chromatography provided ethyl 3-tert-butyl-l-(2-(dimethylamino)ethyl)-l H-pyrazole-5-carboxylate as a pasty mass (0.47 g, 43% yield). lH NMR (400 MHz, MeOH-rf4): §6.73 (s, 1H), 4.66 (t, J= 6.8 Hz, 2H), 4.35 (q, J= 7.2 Hz, 2H), 2.80 (t, J = 12 Hz, 2H), 2.34 (s, 6H), 1.38 (t, J= 7.2 Hz, 3H), 1.31 (s, 9H); MS (ESI) m/z: 268.2 (M+H*).
To a solution of ethyl 3-tert-butyl-l-(2-(dimethylamino)ethyl)~lH-pyrazole-5-carboxylate (0.47 g, 1.8 mmol) in THF (10 mL) was added aqueous LiOH (0.22 g, 5.3 mmol, 5 mL) and mixture was stirred for 16h at RT. Solvents were removed, the thick liquid was diluted with water (5 mL) and acidified with 50% aq. acetic acid solution to pH 5- 6. The product was extracted with EtOAc (2x50 ml) and the combined organics were washed with brine, dried (Na2S04) and concentrated in vacuo to afford 3-tert-butyl-l-(2-(dimethyIamino)ethyl)-lH-pyrazo3e-5-carboxylic acid as a pasty mass (0.12 g, 29% yield). lH NMR (400 MHz, DMSO-^)-' 56.56 (s, 1H), 4.66 (t,/= 6.0 Hz, 2H), 3.17 (t, J= 6.0 Hz, 2H), 2.53 (s, 6H), 1.17 (s, 9H); MS (ESI) m/z: 240.3 (M+H+).
Example B18: 3-t-butylisoxazol-5-amine was prepared according to the method disclosed in WO 99/32111, 0.250.
Example B19: A mixture of l,l,3,3-tetramethoxypropane(37 g, 226 mmol), tert-butyl-hydrazine hydrochloride (28 g, 226 mmol) and cone HC1 (60 mL, 720 mmol) in EtOH (300 mL) was heated at reflux overnight. The mixture was pouTed into water and the resulting mixture was

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extracted with ether. The combined organics were washed with brine, dried (MgS04) and concentrated in vacuo to give 1-tert-butyl-lH-pyrazole (25 g, 89% yield). 'H NMR (400 MHz, DMSO-40: 57.73 (s, 1 H), 7.38 (s, I H), 6.17 (s, 1 H), 1.47 (s, 9 H); MS (ESI) m/z: 125.1 [M+Hf.
HNO3 (11.7 g, 185 mmol)was added dropwise to a mixture of 1-tert-butyMH-pyrazole (23 g, 185 mmol) in cone. H2SO4 (30 raL) at 0°C. The resulting mixture was stirred at 0nC for 30 min and was poured onto crashed ice. The aqueous mixture was extracted with EtOAc. The combined organics were washed with brine, dried (MgSC4) and concentrated in vacuo to give 1-lert-butyl-4-nitro-lH-pyrazole (20g, 64 % yield). lH NMR (400 MHz, DMSO-rf*): (58.85 {s, 1 H),8.23(s, lH),1.52(s,9H).
A mixture of l-tert-butyl-4-rritro-lH-pyrazole (20 g, 118 mmol) and Pd/C {10 %, 2 g, 1.9 mmol) in MeOH (100 mL) was hydrogenated under 1 atmosphere of hydrogen at RT for 16 h. The reaction mixture was filtered and the filtrate was concentrated in vacuo to give 1 -tert-butyl-lH-pyrazol-4-ylamine (15 g, 93%). lH NMR (400 MHz, DMSO-d6): 8 7.08 (s, 1 H), 6.90 (s, 1 H), 3.70 (s, 2 H), 1.41 (s, 9 H); MS (ESI) m/z: 140.1 [M+H]+.
Example B20: Prepared according to the method disclosed in WO 99/32111.
Example B21: 4J4,4-Trifluoro-3-oxo-butyronitrile and phenylhydrazine were combined by the procedure of Example B22 to provide l-phenyl-3-(trifluorometliyl)-lH-pyrazol-5-amine. ]H-NMR (400 MHz, DMSO-d6) 5 7.59-7.50 (m, 4 H), 7.42 (m, 1 H), 5.78 (s, 1 H), 5.73 (br s, 2 H).
Example B22: A solution of etliyl trifluoro acetate (14.2 g, 0.1 mol) and anhydrous acetonitrile (5.0 g , 0.12 mol) in THF (lOOmL) was added dropwise to a suspension of NaH (60%, 6.0 g, 0.15 mol) in THF (lOOmL) at 80 °C. The resulting mixture was heated to reflux overnight, and then cooled to RT. The reaction mixture was concentrated in vacuo and the residue was diluted with EtOAc and 10 % aq HC1. The organic layer was washed with water and brine, dried (MgSO,*) and concentrated in vacuo to yield crude 4,4,4-Trifluoro-3-oxo-butyronitrile (15 g), which was used without further purification.
A solution of methylhydrazine (5.0 g, 60 mmol) and 4,4,4-trifluoro-3-oxo-butyronitrile (9.8 g, 71 mmol) in EtOH (50 mL) was treated with cone. HC1 (5 mL) and the resultant mixture

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was heated to reflux overnight. The solvent was removed in vacuo and the crude product was dissolved in EtOAc washed with saturated aq. NaC03 solution until the washings were pH 8. The organics were concentrated and purified by pre-HPLC to provide 2-methyl-5-trifluoromethyI-2H-pyrazoI-3-yIamine (2.07 g, 21 % yield). *HNMR (300 MHz, DMSO-dS), 6 5.57 (s, 1 H), 5.54 (br s, 2 H), 3.55 (s, 3 H); MS (EST) m/z: 166.1 (M+H*).
Example B23: Example B37 (3.3 g, 17 mmol) was added to a solution of potassium t-butoxide (1.9 g, 17 mmol) in DMSO (40 mL) and the reaction was stirred under argon for 15 min. 2-Bromopropane (2.9 g, 24 mmol) was added and the reaction was stirred 2 h at RT. Water was then added and the solution was extracted with EtOAc (3 x 50 mL). The organics were washed widi water and brine, dried (MgSCXO and concentrated under reduced pressure. Chromatography provided ethyl 3-tert-butyl-l-isopropyMH-pyrazole-5-carboxylate (1.65 g, 41% yield). 3H NMR (400 MHz, DMSO-d6)\ 6.64 (s, 1 H), 5.31 (m, 1 H), 4.22 (q,y= 7.2 Hz, 2 H), 1.37 (d, J = 6.4 Hz, 6 H), 1.24 (t, J= 7.2 Hz, 3 H), 1.14 (s, 9 H). MS (ESI) m/z: (M+H*) 239.2.
A solution comprised of LiOH (2.3 g, 9 mmol) in water (12 mL) was added to a solution of ethyl 3-fcrr-butyl-l-isopropyl-lH-pyrazole-5-carboxylate (2.3 g. 9 mmol) in THF (24 mL) and the reaction mixture was heated to 50 °C overnight. The reaction was concentrated under reduced pressure and diluted with water. The solution pH was adjusted to pH 5 and the solution was extracted with EtOAc. The organics were washed with water and brine, dried (MgS04) and concentrated under reduced pressure to give 3-/er/-butyl-l-i5opropyl-lH-pyrazole-5-carboxylic acid (1.S5 g, 93 % yield). ]H NMR (300 MHz, DMSO-^6): 6.62 (s, 1 H), 5.37 (m, 1 H), 1.35 (d, 7= 6.6 Hz, 6 H), 1.22 (s, 9 H). MS (ESI) m/z: (M+H*) 211.2
To a stirring solution of 3-/e?-/-butyl-l-isopropyl-lH-pyrazoie-5-carboxylic acid (7.92 g, 38 mmol) and triethylamine (5.7 g, 56 mmol) in 1,4-dioxane (80 mL) was added diphenylphosplioryl azide (12 g, 44 mmol). The resultant reaction mixture was stirred 30 min at RT. 2,2,2-Trichloroethanol (78 g, 527 mmol) was added and the reaction was heated to 100 °C. After 4 h, the completed reaction was diluted with brine and extracted with EtOAc. The organic layer was washed with water, dried (MgS04), and concentrated in vacuo. Purification of the residue by chromatography provided 2,2,2-trichloroethyl 3-tert-butyl-l-isopropyl-lH-pyrazol-5-ylcarbamate (4,0 g, 31% yield). lH-NMR (400 MHz, DMSCW6): 9.85 (s, 1 H), 5.94 (s, 1 H).

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4.90 (s, 2 H), 4.37 (m, 1 H), 1.27 (d, J = 7.2 Hz, 6 H), 1.18 (s, 9 H). MS (ESI) m/z: 356.1
(M+tfy
Example B24: 4-Fluorophenylboronic acid (1.0 g, 7.15 mmol) was reacted with Example B38
(1.56 g, 10.7 mmol) in presence of copper (II) acetate (1.95 g, 10.7 mmol) at 80°Cfor 3 hours in pyridine (15 mL) to provide the product, ethyl l-(4-fluorophenyl)-3-isopropyl-lH-pyrazole-5-
carboxylate (0.95g, 48% yield). !HNMR (400 MHz, DMSO-d6): 5 7.45 (m, 2H), 7.30 (m, 2H),
6.9 (s, lH),4.17(q,J = 6Hz,2H), 2.9 (m, 1H), 1.25 (d, J = 6 Hz , 6H), 1.18 (d, J = 6Hz, 3H): MS(ESI) nVz : 277.0 (M+H4). The ethyl esler (0.9g, 3.3 mmol) was hydrolyzed with lithium hydroxide monohydrate (0.67g. 16.0 mmol) in a THF/ethanol/water mixture to provide l-(4-
fluorophenyl)-3-isopropyl-lH-pyrazole-5-carboxylic acid (0.71g, 88% yield). *H NMR (400 MHz, DMSO-d6): 5 7.47 (m, 2H), 7.30 (m, 2H), 6.89 (s, ]H), 2.97 (m, 1H), 1.25 (d, J =6Hz ,
6H), 1.17 (t, J = 6Hz, 3H); MS(ESI) m/z : 249.0 (M+H*).
Example B25: 3-Cyanophenylboronic acid (0.4 g, 2.74 mmol), was reacted with Example B38
(0.5 g, 2.74 mmol) in the presence of copper (II) acetate (0.5 g, 2.74 mmol) at 80 °C for 3 hours in pyridine (3.5 ml) to provide ethyl l-(3-cyanophenyl)-3-isopropyI-lH-pyrazoIe-5-carhoxy]ate
(0.18g, 24% yield). ]H NMR (400 MHz, DMSO-d6): 6 8.06 (m, 1H), 7.92 (m, 1H), 7.83 (m,
1H), 7.69 (m, 1H), 7.02 (s , 1H), 4.20 (q, J =6Hz , 1H), 3.00 (m, 1H), 1.26 (d, J=6Hz, 6H), 1.20 (t, J = 6Hz, 3H); MS(ESI) m/z : 284.2 (M+H*). Hydrolysis of the ester with lithium hydroxide monohydrate provided l-(3-cyanophenyl)-3-isopropyl-lH-pyrazole-5-carboxylic acid in 94%
yield. !H NMR (400 MHz, DMSO-d6): 5 8.02 (m, 1H), 7.89 (m, 1H), 7.83 (m, 1H), 7.67 (m,
1H), 6.97 (s , 1H), 3.00 (m, 1H), 1.26 (q, J=6Hz, 6H); MS(ESI) m/z : 256.0 (M+H4).
Example B26: 6-(2-(Diphenylmethylene)hydrazinyl)quinoline (4.0 g, 12.3 mmol) and 4-methyl-3-oxo-penLanenitrile (1.5 g, 13.5 mmol) were combined by the procedure of Example B8 (method 2) to give 5-isopropyl-2-quinolin-6-yI-2H-pyrazol-3-ylamine (1.1 g, 35.5% yield). lH NMR (400 MHz, CDC13) 5 8.93 (dd, /= 4,4, 1.6 Hz, 1 H), 8.21-8.18 (m, 2 H), 8.05-8.02 (m, 2

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H), 7.44 (dd, J = 8.4, 4.4 Hz, 1 H), 5.56 (s, 1 H), 3.S5 (br s, 2 H), 2.97 (m, 1 H), 1.31 (d, /= 6.8 Hz, 6 H); MS (ESI) m/z: 253.2 (M+H+).
Example B27: To a 0 °C solution of 6-methylpyridin-3-amine (12 g, 0.11 mol) in cone HC1 (40 mL) was added a solution of NaN02 (7.7 g, 110 mmol) in water (30 mL) and the resulting mixture was stirred at 0 °C for 1 h. A solution of SnCI2 (50 g, 0.22 mol) in cone HC1 (60 mL) was added at 0 °C. The reaction solution was warmed to RT and stirred for 2 hours. The precipitate was collected by filtration to provide 5-hydrazinyl-2-methylpyridine hydrochloride (10 g, 57% yield) which was used without further purification.
A mixture of 5-hydrazinyI-2-methylpyridine hydrochloride (5.0 g, 31 mmol) and 4,4,4-trifluoro-3-oxo-butyronitrile (9.0 g, 65 mmol) in ethanol (50 mL) was treated with cone HO (5.0 mL, 60 mmol) and the resultant mixture was heated to reflux overnight. The solvent was removed in vacuo and the residue was dissolved in EtOAc and neutralized with saturated Na2C03 solution. The organic layer was dried (Na2SO^), concentrated in vacuo and purified by pre-HPLC to give 2-(6-methyl-pyridin-3-yl)-5-trifluoromethyl-2H--pyrazol-3-ylamine (1.3 g, i 0% yieJd over 2 steps). 'HNMR (400 MHz, CDC]3) 5 9.17 (d, J = J .6 Hz, 1 H), 8.40 (dd, J = 8.4, 2.4 Hz, 1 H), 7.62 (d, J = 8.4 Hz, 1 H), 5.97 (s, 1 H), 2.80 (s, 3 H); MS (ESI) m/z: 243.2 (M+H*).
Example B28: A solution of etliyl cyclopentanecarboxylate (prepared by esterifi cation of commercially available cyclop en tantecarboxylic acid, 30 g, 0.21 mol) and acetonitirle (10.1 g, 0.25 mol) in dry THF (80 mL) was added dropwise to a suspension of NaH (12.5 g, 0.31 mol) in dry THF (80 mL) and the resulting mixture was refluxed overnight. The reaction mixture was concentrated under reduced pressure and partitioned between water and EtOAc. The aqueous layer was separated, adjusted to pH 8 and extracted with EtOAc. The combined extracts were washed with brine, dried (MgS04), and concentrated to give 3-cyclopentyl-3-oxopropanenitrile (26 g, 90% yield), which was used in the next step without further purification. [H NMR (400 MHz, DMSO-d6): J4.06 (s, 2 H), 2.92 (m, 1 H), 1.41-1.77 (m, 8 H).
Hydroxylamine hydrochloride (6 g, 86 mmol) and 3-cyclopentyl-3-oxopropanenitrile (10 g, 73 mmol) were added to a solution of NaOH (9 g, 225 mmol) in water (100 mL) and the resulting mixture was heated at 50 °C overnight. The precipitate was collected by filtration,

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washed with water, and dried to give 3-cyclopentylisoxazol-5-amine (6.7 g, 61% yield). 'H NMR (400 MHz, DMSO-rftf): 6 6.43 (s, 2 H), 4.77 (s, 1 H), 2.84 (m, 1 H), 3.87- 1.51 (m, 8 H); MS (ESI) m/z: 153. J (M+H*).
Example B29: A solution of nBuLi in hexanes (242 mL. 387 mmol) was added to a -78 °C solution of diisopropylamine (39.1 g, 387 mmol) in anhydrous THF (300 mL) and the resultant mixture was stirred for 30 min at -78 °C. A solution of ethyl cyclopentanecarboxylate (50 g. 352 mmol) in anhydrous THF (150 mL) was added dropwise into the mixture and the reaction mixture was stirred at -78 °C for 1 h. Iodomethane (79.2 g. 558 mmol) was added dropwise and the resulting mixture was warmed to RT and stirred overnight. The mixture was poured into water and extracted with ethyl ether. The combined extracts were washed with brine, dried (MgSC4) and concentrated in vacuo to give ethyl 1-methylcyclopentanecarboxylate (47 g, 85%). *H NMR (300 MHz, DMSO-d6): S 4.03 (q, J = 7.2 Hz, 2 H), 1.37 - 2.03 (m, 8 H), 1.15-1.12 (m, 6H).
Ethyl 1-methylcyclopentanecarboxylate (47 g, 301 mmol), acetonitrile (14.5 g. 363mmol). NaH (18 g, 450 mmol), NaOH (6.8 g, 170 mmol) and hydroxylamine hydrochloride (4 g, 57 mmol) were sequentially combined by a procedure analogous to Example B28 to provide 3-(l-methylcycIopentyl)isoxazol-5-amine (7 g, 70 % yield over 2 steps). 'H NMR (400 MHz, DMSCWfi): 8 6.41 (s, 2 H), 4.81 (s, 1 H), 1.91-1.86 (m, 2 H), 1.67-1.48 (m, 6 H), 1.19 (s, 3 H); MS (ESI) m/z: 167.1 (M+H+).
Example B30: To a suspension of Na2C03 (36 g, 339 mmol) in CHiCOO mL) was added 1-f-butyl-lH-pyrazole from Example B19 (21 g. 170 mmol) and Br2 (9 mL), and the resulting mixture was stirred at RT overnight. The solid was removed by filtration and the filter cake was washed with CH2CI2. The filtrates were washed with water and brine, dried (MgSO4), and concentrated to give crude 4-bromo-l- r-butyl-lH-pyrazole (29 g, 85%), used without further purification. 'H NMR (300 MHz, CDC13: 8 7.49 (s, 1 H), 7.45 (s, 1 H), 1.53 (s, 9 H); MS (ESI) m/z: 203 [M+H]+.
To a -78 DC solution of 4-bromo-I-j'-butyl-lH-pyrazole (15 g, 74.3 mmol) in anhydrous THF (100 mL) was added n-BuU (2.5 M in hexane, 53 mL, 132 mmol) under N2, and the resulting mixture was stirred at -78°C for 30 min. Excess dry ice was added at -78 °C, and the

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mixture was warmed slowly to RT and stirred overnight. The reaction was concentrated in vacuo, water was added and the pH was adjusted to pH 3 by the addition of 2N aq HC1. The aqueous solution was extracted with EtOAc. The extracts were washed with brine, dried (MgSC>4) and concentrated in vacuo. The residue was recrystallized (EtOAc-pet. ether) to give l-/-butyl-lH-pyrazole-4-carboxylic acid (8.0 g, 67 % yield). lH NMR (300 MHz, CDC13): S 8.10 (s, I H), 8.03 (s, 1 H), 1.64 (s, 9 H); MS (ESI) m/z: 168.9 [M+Hf.
Example B31: Cyclopentyl-3-oxopropanenitrile (8 g. 0.058 mol), methylhydrazine (40 % aqueous, 32.5 g , 0.29 mol) and cone. HC1 (40 mL, 0.48 mol) were combined in EtOH (200 mL) and the reaction mixture was heated at reflux overnight. The mixture was concentrated in vacuo, poured into water and washed with EtOAc (3 x 100 mL). The aqueous portion was basified to pH 8 with aq NaHC03 and the mixture was extracted with EtOAc (3 x 100 mL). The extracts were washed with brine, dried (Na2S04) and concentrated in vacuo. Crystallization from EtOAc afforded 5-cyclopentyt-2~methyl-2H-pyrazol~3~ylamine (2.1 g, 22 % yield). fHNMR (400 MHz, DMSO-dfi): 5 5.05 (s, 1 H), 4.95 (s, 2 H), 3.39 (s, 3 H), 2.75 (in, 1 H), 1.78 (m, 2 H), 1.62-1.50 (m, 6 H); MS (ESI) m/z; 166.2 [M + Hf.
Example B32: In a mixture of saturated sodium bicarbonate:toluene:ethanol (1:2:1) (20 mL) was dissolved methyl 2-tert-buty!-4-chloropyrimidine-5-carboxylate (2.71 g, 11.85 mmol), phenylboronic acid (2.88 g, 23.7 mmol) and to this was added tetrakis-(triphenylphosphine)paUadium(O) (300 nig). The reaction stirred at 75 °C, under Ar, overnight. After dilution with ethyl acetate (75 mL) and water (75 mL), the mixture was filtered through Celite and the organic phase separated. The organic phase was washed with 5% citric acid (75 mL), brine (75 mL), dried (Na2SO0 and evaporated at reduced pressure to give a semi solid/oil. The solid was purified by chromatography (Biotage Si-40 column, 5-30% ethyl acetate/Hex -900 mL) to give a clear thick oil, which solidified to a white solid identified as methyl 2-tert-butyi-4-phenylpyrimidine-5-carboxylate (2.58 g, 81% yield). *H NMR (300 MHz, DMSO-J6), 5 1.39 (s, 9 H), 3.70 (s, 3 H), 7.49-7.52 (m, 3 H), 7.61-7.63 (m, 2 H), 9.04 (s, 1 H); MS (ESI) m/z: 271.3 (M+H*).
In a 1:1:1 mix of methanol:dioxane:water (15 mL) was placed* methyl 2-tert-butyl-4-phenylpyrimidine-5-carboxylate (2.58 g, 9.54 mmol) and lithium hydroxide hydrate (1.20 g, 28.6

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mraol). The solution was stirred at RT overnight. The mix was diluted with ethyl acetate (70 mL) and washed with 5% citric acid (100 mL). The organic phase washed with brine, dried (NaiSCU) and evaporated at reduced pressure to give a white solid, identified as 2-tert-butyI-4-phenyIpyrimidine-5-carboxyIic acid (2.31 g, 94%yield). 'H NMR (300 MHz, DMSO- Example B33: In ethanol (25 mL) was placed pivalamidine hydrochloride (1.138 g, 8.33 mmol). This was treated with 21% sodium ethoxide in ethanol (2.70 g, 8.33 mmol) and stirred at RT for 15 min. To this was added ethyl 2-(ethoxymethylene)-4,4,4~trifluoro-3-oxobutanoate (2.00 g. 8.33 mmol) in ethanol (10 mL) and stirred at RT overnight. The mix was wanned to reflux for 1 kr, cooled to RT and evaporated at reduced pressure to give a slurry. The slurry was dissolved in a mix of ethyl acetate (75 mL) and 5% citric acid (75 mL). The organic phase was washed with brine, dried (Na2S0.4) and evaporated at reduced pressure to give a thick oil identified as ethyl 2-tert-butyl-4-(crifluorometliyl)pyriiTiidme-5-carboxylate (1.67 g, 72% yield). MS (ESI) m/z: 277.0 (M+H+).
Example B34: Using a procedure analogous to Example B32, methyl 2-tert-buryl-4-chloropyrimidine-5-carboxylate (0.849 g, 3.71 mmol), N-methylindole-5-boronic acid (1.30 g,
7.43 mmol) and tetrakis-(triphenylphosphine)palladium(0) (86 rng) were combined to give methyl 2"tert-butyl-4-(l-methyl-lH-indol-5-yl)pyriiTiidine-5-carboxyIate (898 mg, 74% yield). 'H NMR (300 MHz, DMSO-J6): 6 1.40 (s, 9 H), 3.70 (s, 3 H), 3.82 (s, 3 H), 6.57 (s, 1 H), 7.41-
7.44 (m, 2 H), 7.53 (d, J= S.6 Hz, 1 H), 7.92 (s: 1 H), 8.94 (s, 1 H); MS (ESI) m/z: 324.0 (M+H+).
Using a procedure analogous to Example B32, methyl 2-tert-butyl-4-(l-methyI-lH-indol-5-yl)pyrirnidine-5-carboxyIate (898 mg, 2.78 mmol) and lithium hydroxide hydrate (466 mg, 11.11 mmol) were combined to give 2-tert-butyl-4-(l"iTiethyl-lH-indol-5-yl)pyrimidine-5-carboxylic acid (833 mg, 97% yield). [H NMR (300 MHz, DMSO-
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Example B35: A solution of anhydrous acetonitrile (2.3 g, 56 mmol) in THF (100 mL) was added dropwise at 80 °C to a mixture of NaH (60%, 2.8 g, 70 mmol) and methyl 2-cyano-2-methylpropanoate (6 g, 47 mmol Jin THF (100 mL). The resultant reaction mixture was heated at reflux for 8 hours. The solvent was removed in vacuo and the residue was diluted with EtOAc and washed with 10 % HCl, water and brine. The organics were dried (MgSO-i) and concentrated in vacuo to obtain crude 2,2-diniethyl-3-oxopentanedinitrile (4 g), which was used for the next step reaction without further purification.
A solution of 2,2-dimethyl-3-oxopentanedmitrile (4.0 g, 29 mmol) and phenyl-hydrazine HCl salt (4.6 g, 31 mmol) in EtOH (50 mL) was treated with 2 N HCl solution (10 mL, 20 mmol). The reaction mixture was heated at reflux for 4h. After cooling down, the mixture was neutralized with NaHCC>3 to pH 7-8 and then extracted with EtOAc (3 x 100 mL). The organics were concentrated mid the residue was purified by chromatography to give 2-(5-amino-l-phenyi-lH-pyrazol-3-yI)-2-methylpropanenitriIe (3.5 g, 33% yield, 2 steps). !HNMR (300 MHz, DMSO-40: 5 7.56-7.31 (m, 5 H), 5.52 (s, 1 H), 5.45 (br s, 2 H), 1.61 (s, 6 H); MS (ESI) m/z: 227.1(M+H*).
A solution of 2-(5-ainino-l-pheiiyl-lH-pyrazol-3-yl)-2-methyLpropionitrile (1.0 g, 7.4 mmol) and aq NaOH (2 M, 11 mL, 22 mmol) in EtOH (10 mL) was heated to 70 °C for 12h. The reaction mixture was partitioned between ether and water and the aqueous solution was acidified with HCl to pH 4-5. The aqueous was extracted with EtOAc (3 x 50 mL) and the extracts were concentrated in vacuo to give crude 2-(5-amino-l-phenyl-lH-pyrazol-3-yl)-2-methylpropanoic acid (0.7 g, 39% yield) which was used without further purification.
Cone. H2SO4 (0.5 mL) was added to a solution of 2-(5-amino-l-phenyl-lH-pyrazol-3-yl)-2-methylpropanoic acid (0.7 g, 28.5 mmmol) in EtOH (10 mL) and the reaction was heated at 45 °C for 2 h. The reaction solution was neutralized with aq NaHC03 and then extracted with EtOAc (3 x 20 mL). The combined extracts were washed with aq NaHC03 solution, dried (Na2S04), and concentrated in vacuo to give ethyl 2-(5-amino-l-phenyl-lH-pyrazol-3-yl)-2-methylpropanoate (710 mg, 91% yield). *H NMR (400 MHz, DMSO-rffi): 5 7.62 (d, J= 7.6 Hz, 2 H), 7.52 (t, J= 7.6 Hz, 2 H), 7.35 (t, J= 7.6 Hz, I H), 5.47 (s, 1 H), 5.35 (br s, 2 H), 4.12 (q, J = 7.2 Hz, 2 H), 1.50 (s, 6 H), 1.22 (t, J= 7.2 Hz, 3 H); MS (ESI) m/z: 274.KM+H4).

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Example B36: A solution of 2,2-dimethyI-3-axo~pentanedmitrile (9 g, 66 mmol) and methyl-hydrazine (3 g, 66 mmoi) in EtOH (100 mL) was treated with cone HC1 (16.5 mL, 198 mmol) and the resulting mixture was refluxed overnight. The solvent was removed under reduced pressure and the residue was purified by chromatography to give 2-(5-amino-l-melhyl-lH-pyrazol-3-yl)-2-methylpropanenitriIe (2.7 g, 25% yield). LH NMR (300 MHz, CDC13): 5 5.56 (s, 1 H), 3.63 (s, 3 H), 1.67 (s, 6 H); MS (ESI) m/z: 165.2 [M+H]+.
A mixture of 2'(5-amino-l-methyl-lH-pyrazol-3-yl)-2-methylpropanenitrile (1.4 g, 8.5 mmol) in EtOH (30 mL) was treated with cone. H7SO4 (3 mL) and the resulting mixture was refluxed for 10 days. The reaction mixture was neutralized with saturated aq NaHCC>3 solution, and the mixture was extracted with EtOAc, The organics were washed with brine, dried (MgS04) and concentrated in vacuo. Recrystallization (EtOAc/petroleum ether) provided ethyl 2-(5-aminO"I-methyl-lH~pyrazol-3-yl)-2-metliylpropanoate (0.8 g: 44% yield). 'H NMR (300 MHz, DMSO-d6): 55.13 (s, 1 H), 5.04 (s, 2 H)s 4.00 (q, J= 6.9 Hz, 2 H), 3.41 (s, 3 H), 1.11 (t J = 6.9 Hz, 6 H); MS (ESI) m/z: 212.0 [M+Hf.
Example B37: Sodium metal (13.8 g, 0.5 mol) was added portionwise to ice-cold anhydrous EtOH (700 mL). After complete dissolution of the Na, a mixture of 3,3-dimethylbutan-2-one (50 g, 0.5 mol) and oxalic acid diethyl ester (77 ml, 0.5 mol) was added drop-wise. The reaction mixture was stirred in ice-salt bath and until TLC indicated completion of the reaction. Acetic acid (38.1 ml, 0.5 mol) was added and the mixture was stirred at RT for 30 min. The reaction mixture was cooled in an ice-salt bath and treated with hydrazine hydrate (29.4 g, 0.5 mol). After complete addition, the mixture was warmed to RT and stirred until judged complete by TLC. The reaction mixture was concentrated under reduced pressure and re-dissolved in EtOAc. The EtOAc solution was washed with NaHC03, brine and water, dried (MgSO,}) and concentrated in vacuo. The resultant solid was washed with cold petroleum ether to give ethyl 3-tert-butyl-tH-pyrazole-5-carboxylate (49 g, 50% yield over two steps) as a white solid. *H NMR (400 MHz, CDCI3): 5 6.65 (s, 1 H), 4.38 (q, J= 6.8 Hz, 2 H), 1.39 (t, J = 6.8 Hz, 3 H), 1.35 (s, 1 H); MS (ESI) m/z: 197.2 (M+H+).
Example B38: Using a procedure analogous to Example B37, 3-methylbutan-2-one (100 g, 1.16 mol) was converted to ethyl 3-isopropyl-lH-pyrazoIe-5-carboxylate (90 g, 42 % yield, two steps)

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as an off-white solid. !H NMR (300 MHz, CDC13): 5 12.00 (s, 1 H), 6.57 (s, 1 H), 4.30 (q, J = 12 Hz, 2 H), 3.00 (m, 1 H), 1.46 (t, J = 7.2 Hz, 3 H), 1.28 (d, J = 6.8 Hz, 6 H); MS (ESI) m/z: 183.3 (M+H+).
Example B39: Nitric acid (2 mL) was added to a stirred solution of indazole (5.0 g, 42 mmol) in acetic acid (40 mL) at 0°C. The resulting mixture was stirred at RT for 30min. Acetic anhydride (6 mL) was added in one portion and the mixture was stirred at RT overnight. The solvent was removed under reduced pressure and the residue was purified by chromatography to give 3-nitro-lH-indazole (3.4 g, 49% yield). *H NMR (400 MHz, DMSO-rffi): S 14.46 (s, 1 H), 8.12 (m, 1 H), 7.76 (m, 1 H), 7.57 (m, 1 H), 7.48 (m, 1 H).
Cone. H2SO4 (2 mL) was added to a suspension of 3-nitro-lH-indazole (3.4 g, 21 mmol) in 2-methyl-propan-2-ol (30 mL) and the resulting mixture was heated to 180 °C in a steel bomb. The reaction mixture was cooled to RT and diluted with EtOAc. The organic phase was washed with brine, dried (MgSO,}) and concentrated to give l-tert-butyl-3-nitro-lH-indazole (3.4 g, 76%). 'H NMR (400 MHz, DMSO-d6): 8 8.18-8.15 (m, 2 H), 7.59-7.49 (m, 2 H), 1.76 (s, 9 H).
A mixture of l-tert-butyl-3-nitro-lH-indazole (3.0 g, 14 mmol) and PdVC (1 g) in MeOH (50 mL) was hydrogenated (1 atm) at RT for 2 h. The reaction mixture was filtered and the filtrate was concentrated and purified by chromatography to give l-tert-bulyl-lH-indazol-3-ylamine (1.7 g, 68% yield). 'H NMR (400 MHz, DMSO-rftf): S 7.67 (m, 1 H), 7.52 (m, 1 H), 7.19 (m, 1 H), 6.89 (m, 1 H), 5.32 (s, 2 H), 1.58 (s, 9 H); MS (ESI) m/z: 190.1 [M+H+].
Example B40: In ethanol (40 mL) was placed t-butylcarbarnidine hydrochloride (3.71 g, 27.2 mmol). Tliis was treated with 21 % sodium emoxide in ethanol (8.80 g, 27.2 mmol) and stirred at RT for 15 min. To this was added the diethyl ethoxymethylenemalonate (5.87 g, 27.2 mmol) and the reaction mixture was stirred overnight at RT. The reaction mixture was refluxed for 1 hour and then cooled to RT. The solution was evaporated and the residue was dissolved in water (100 mL) and the pH adjusted to 3-4 (wet litmus) with acetic acid. The mixture formed a precipitate. The solid collected by filtration, washed with water (50 mL) and dried under vacuum to obtain ethyl 2-tert-butyl~4-hydroxypyrimidine-5-carboxylate (2.18 g, 36% yield). ]H NMR (400 MHz, DMSO-rf6): 5 12.6 (brs, 1H), 8.44 (s, 1H), 4.20 (q, J = 7.2 Hz, 2H), 1.25 (s, 9H), 1.23 (t, J = 7.2 Hz, 3H); MS (ESI) m/z: 225.0 (M+H*).

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In cold (-0 °C) POCI3 (20 mL) was dropped triethylamine (0.55 mL) with stirring. To this was added in parts of ethyl 2-tert-butyl-4-hyd^xypyrimidine-5-carboxylate (2.18 g, 9.72 mmol). The mixture then warmed to 40 °C and stirred under Argon for 1 hour. The mixture was evaporated until free of POG3, diluted with CHCI3 (100 mL) and poured carefully into ice (300 mL). The solution was stirred at RT to melt. The organic phase was separated, washed with sodium bicarbonate (100 mL), water (100 mL) and dried (NaaSdj). The solvents evaporated to give ethyl 2-tert-butyl-4~cmoropyrimidine-5-carboxylate (2.0 g, 85% yield). lH NMR (400 MHz, DMSO-d6): 5 9.12 (s, 1H), 4.34 (q, J= 6.8 Hz, 2H), 1.33 (s, 9H), 111 (t, J= 6.8 Hz, 3H); MS (ESI) m/z: 243.0 (M+H4).
To a solution of ethyl 2-tert-butyl-4-chloropyrimidine-5-carboxylate (0.30g, 1.24 mmol) in NMP (3 mL) was added morpholine (0.54 g. 6.16 mmol) and it was heated at 80 °C for 1.5 hour. The reaction was checked by LC-MS, water was added and the solution was extracted with ethyl acetate (3x). The organic layer was washed with brine, dried (Na2SO:j) and solvent was removed to obtain tert-butyl 4-(5-(3-tert-butyl-5»(ethoxycarbonyl)-lH-p>razol-I-yl)pyridin-2-yl)piperazine-l-carboxylate. MS (ESI) m/z: 294.0 (M+H").
To a stirring suspension of ethyl 2-tert-butyI-4-morphohnopyrimidine-5-carboxylate (0.36 g, 1.24 mmol) in t: I: I THF/EtOH/H20 (9 ml) at RT was added LiOH-H20 (130 mg, 4.95 mmol) and the mixture was stirred overnight at RT. The reaction mixture was checked by LC-MS and the completed reaction was concentrated to an aqueous residue, acidified (pH 3-4) with 3M HC1 and the solution was extracted with EtOAc (3x). The combined organics were washed with brine (Ix), dried (MgS04), filtered and concentration. The crude was dissolved in isopropanol and the solid (LiCI and NaCl) was filtered and washed with isopropanol. Tie filtrate was concentrated to obtain the desired product 2-tert-butyI-4-morphoIinopyrimidine-5-carboxylic acid (0.15 g, 46% yield). MS (ESI) m/z: 266.0 (M+H*).
Example B4I: In a mix of sat'd NaHCC>3:toluene:ethanol (1:2:1) (8 mL) was dissolved ethyl 2-tert-butyi-4~chloropyrimidine-5-earboxylate from Example B40 (300 mg, 1,24 mmol), 3-fluorophenylboronic acid (350 mg, 2.47 mmol) and to this was added tetralds(triphenylphosphine)palladium(0) (29 mg). TJie mixture was heated overnight at 75 °C under Ar. The mixture was diluted with EtOAc (25 mL) and water (25 mL). The mixture was filtered to remove insolubies and the organic phase separated, washed with 5% citric acid (25

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mL), then saturated soium bicarbonate (25 mL) and brine (25 mL). The solvents evaporated at reduced pressure and the residue purified by silica gel column chromatography (Biotage: 25M. 5-50% EtOAc/Hex - 550 mL) to give ethyl 2-tert-butyl-4-(3-fluoropheiiyl)pyrimidine-5-carboxylate (0.27 g, 72% yield).
Using a procedure to Example B40, 2-tert-butyl-4-(3-fluorophenyl)pyrimidine-5-carboxylate (0.27 g, 0.89 mmol) was treated with LiOH-H20 (86 mg, 3.57 mmol) to afford 2-tert-butyI-4-moiphoIinopyrimidine-5-carboxylic acid (0.23 g, 92% yield). MS (ESI) m/z: 275.0 (M+H+).
Example B42: Using a procedure analogous to Example B41, ethyl 2-tert-butyl-4-chloropyrimidine-5-carboxylate from Example B40 (0.30 g, 1-24 mmol) and pyridin-3-ylboronic acid (1.8 g, 1.48 mmol) in presence of tetrakis(triphenylphosphine)palladium(0) (71 mg, 0.062 mmol) were combined lo aiford ethyl 2-tert-butyl-4-(pyridin-3-yl)pyrimidine~5-carboxylate (0.10 g, 28% yield).
Using a procedure analogous to Example B39, ethyl 2-tert-butyl-4-(pyridin-3-yl)pyrimidine-5-carboxylate (0.17 g, 0.60 mmol) was treated with LiOHH20 (57 mg, 2.38 mmol) to afford 2-tert-butyl-4-(pyridin-3-yl)pyrimidine-5-carboxylic acid (0.11 g, 72% yield). MS (ESI) m/z: 258.0 (M+H+).
Example B43: Using a procedure analogous to Example B40, ethyl 2-tert-butyl-4-chloropyrimidine-5-carboxylate from Example B40 (0.30g, 1.24 mmo) and 1-methylpiperazine (0.62 g, 6.18 mmol) in presence of NMP (catalytic amount) were combined to afford 2-tert-butyI-4-(4-methy]piperazin-l-yI)pyrimidine-5-carboxylic acid (0.11 g, 32% yield). MS (ESI) m/z: 279.0 (M+H+).
Example B44: Using a procedure analogous to Example B40,2-tert-butyl-4-chloropyrimidiiie-5-carboxylate from Example B40 (0.30g, 1.24 mmo) and tert-butyl piperazine-1-carboxylate (1.15 g, 6.18 mmol) in presence of NMP (catalytic amount) were combined to afford 4-(4-(tert-butoxycarbonyl)piperazin-l-yl)-2-tert-butyipyrimidine-5-carboxylic acid (0.36 g, S0% yield). MS (ESI) m/z: 365.0 (M+H+).

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Example B45: In ethanol (10 mL) was placed the tert-butylhydrazine hydrochloride (1.35 g, 10,8 mmol) and ethyl 2-((dimethylamino)methylene)-3-oxobutanoate (2.00 g, 10.8 mmol). The mixture warmed to reflux and stirred for 2 hrs, cooled to RT and stirred overnight. The mixture was evaporated at reduced pressure to give an oil which was dissolved in ether (25 mL) and washed successively with water (25 mL), saturated sodium bicarbonate (25 mL) and brine (25 mL), dried (Na2S04), evaporated at reduced pressure and purified by chromatography (Biotage Sl-25 column, 10-40% ethyl acetate/Hex) to give ethyl l-tert-butyl-5-memyl-lH-pyrazole-4-carboxylate (1.48 g, 65% yield) as an oil. MS (ESI) m/z: 211.0 (M+H+).
In a mixture of ethanol:water:dioxane (1:1:1, 21 mL) was placed ethyl l-tert-butyl-5-methyl-lH-pyrazole-4-carboxylate (1.48 g, 7.04 mmol) and lithium hydroxide hydrate (886 mg. 21.12 mmol). The reaction was stirred at 40 °C for 3 hrs and then at RT overnight. The reaction was diluted with water (25 mL) and ether (25 mL). The ether layer was discarded and the aqueous phase made acidic (pH~=4) with IN HCI. The acidic phase was then extracted with ethyl acetate (2 x 25 mL) and the combined ethyl acetate layers were washed with brine, dried (NaiSO), evaporated at reduced pressure to give l-tert-butyl-5-methyl-lH-pyrazole-4-carboxylic acid as a white solid (1.12 g, 87% yield). !H NMR (300 MHz, DMSO-d6): 5 1.56 (s, 9 H), 2.67 (s, 3 H), 7.65 (s, I H), 12.13 (s, I H); MS (ESI) m/z: 183.0 (M+H+).
Example B46: Using a procedure analogous to Example B45, ethyl l-tert-butyl-5-(trifluoromethyl)-lH-pyrazole-4-carboxylate (750 mg, 2.84 mmol) was converted to 1-tert-butyl-5-(trifluoromethyl)-lH-pyrazole-4-carboxyiic acid (646 mg, 94% yield) using lithium hydroxide hydrate (357 mg, 8.51 mmol). 'H NMR (300 MHz, DMSO- Example B47: Using a procedure analogous to Example B17, I-(2-(dimetiiylamino)-2-oxoethyl)-5-isopropyMH-pyrazole-3-carboxylic acid was synthesized from ethyl 3-isopropyl-lH-pyrazoIe-5-carboxylate as a white solid (0.35 g). ]H NMR (400 MHz, DMS
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Example B48: NaH (6.8 g, 0.17 mol) was added portionwise to a 0 DC solution of lH-pyrazole (10 g, 0.15 mol) in DMF (150 mL) and the resulting mixture was stirred at room temperature for 30 min. 2-Iodopropane (30 mL 0.3 mol) was added dropwise to the above mixture at 0 °C, then the reaction mixture was stirred at room temperature for 10 h. H2O was added and the mixture was extracted with ethyl ether (3 x 100 mL). The combined organic layers were washed with brine, dried over Na2S04, and concentrated in vacuo. The residue was distilled "under reduced pressure to afford 1-isopropyl-lH-pyrazole (6.6 g, 40 % yield). *H NMR (400 MHz, DMSO-^):
5 7.68 (d, J= 1.6 Hz, 1 H), 7.38 (d, J = 1.2 Hz, 1 H), 6.17 (t, /= 2.0 Hz, 1 H), 4.46 (m, 1 H),
1.37(d,7=6.8Hz;6H).
To a solution of 1-isopropyl-lH-pyrazole (5 g, 45.5 mmol) in concHoSC (50 mL) was added KNO3 (5.0 g, 50 mmol) portion wise at 0 °C. After the addition, the resulting mixture was heated to 50 0 °C for 8 h. The reaction mixture was cooled to room temperature and poured into ice water, and the mixture was extracted with EtOAc. The combined organics were washed with saturated NaCOs solution, brine, and were dried over NaoSO,}, and concentrated in vacuo. Chromatography on silica gel provided l-isopropyl-4-nitro-lH-pyrazole (3.2 g. 46 % yield). !H NMR (400 MHz, DMSCWrt): A solution of I-isopropyl-4-nitro-lH-pyrazole (3 g, 19 mmol) in EtOH (30 mL) was stirred under a hydrogen atmosphere for 2 h in the presence of 10 % Pd/C (300 mg). The catalyst was removed by filtration and the filtrate was concetrated under reduced pressure to afford HsopropyI-lH-pyrazol-4-yiarnirje (l.S g, 75.0% yield). lH NMR (400 MHz, DMSCW*):
6 6.99 (s, 1 H), 6.84 (s, 1 H), 4.23 (m, 1 H), 3.70 (s, 2 H), 1.28 (d, J = 6.8 Hz, 6 H); MS (ESI)
m/z: 126.2[M+H]".
Example B49: In cold (-0 °C) phosphorous oxychloride (40 mL) was carefully added triethylamine (1.87 mL) with stirring. To this was added, in parts, ethyl 4-hydroxy-2-iriethylpyrimidine-5-carboxylate (5.00 g, 27.4 mmol). The mixture then warmed to 40 °C and stirred under Argon for 2 hours. The mixture was evaporated free of phosphorous oxychloride, diluted with chloroform (150 mL) and poured carefully into ice (~400 mL) and allowed to warm to RT. The organic phase was separated, washed with saturated sodium bicarbonate (75 mL), then brine (100 mL) and dried over sodium sulfate. The solvents evaporated to give a thick oil

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which was purified by chromatography (Biotage Si-40 column, 15-40% ethyl acetate/hexane) to give ethyl 4-chloro-2-methylpyrimidine-5-carboxylate as a clear oil (2.96 g,53% yield), 'H NMR (400 MHz, DMSO-d6): 6 1.31 (t, 3 H), 2.66 (s, 3 H), 4.34 (q, 2 H), 9.06 (s, 1 H); MS (ESI) m/z: 201.0 (M+H4).
In a mixture of saturated NaHC03:toIuene:ethanol (1:2:1) (12 mL) was dissolved ethyl 4-chloro-2-methylpyrimidine-5-carboxyIate (500 mg, 2.49 mmol), N-methylindole-5-boronic acid (872 mg, 4.98 mmol) and to this was added tetrakis(tjiphenylphosphme)-palladium(0) (58 rng). The reaction stirred at 75 °C, under Ar, overnight. The reaction was allowed to cooled to RT, diluted with ethyl acetate (25 mL) and water (25 mL) and filtered free of insolubles. The organic phase was washed with 5% citric acid (25 mL), saturated sodium bicarbonate (25 mL) and brine (25 mL), evaporated at reduced pressure to give a reddish thick foam, and purified by chromatography (Biotage Si-25 column, 15-40% ethyl acetate/hexane) to give ethyl 2-methyl-4-(l-methyl-lH-indoL5-yI)pyrimidine-5-carboxylate as a thick clear oil. The oil solidified overnight (391 mg, 53% yield). MS (ESI) m/z: 296.0 (M+H+).
In a mix of ethanoI:water:dioxane (1:1:1, 9 mL) was placed ethyl 2-methyl-4-(l-methyl-lH-mdoI-5-yl)pyrirnidine-5-carboxylate (391 mg, 1.324 mmol) and lithium hydroxide hydrate (222 mg, 5.30 mmol). The mix stirred at RT overnight. The mix was diluted with ethyl acetate (25 mL) and 5% citric acid (20 mL). The organic phase was separated, washed with brine (20 mL) and dried over sodium sulfate. The solvent was evaporated at reduced pressure to give 2-methyl-4-(l-methyl-lH-indol-5-yl)pyrimidine-5~carboxylic acid as a tan solid (132 mg, 37% yield). MS (ESI) m/z: 268.0 (M+H+).
Example B5Q: A mixture of 1,1,3,3-tetramethoxypropane ^3^ gs 83 mmol) and N2-cyclopentyl-Nl-(tert-butoxycarbonyl)hydrazine (16.6 g, 83 mmol, see Ranatunge et al„ J. Med. Chem. (2004), 47, p2180-2193) hi water (150 mL) was treated with cone. HC1 (21 mL, 252 mmol). The resulting mixture was heated at reflux overnight. The compJeted reaction mixture was extracted with ether and the extracts were washed with brine, dried over anhydrous MgS04, and concentrated in vacuo to give 1-cyclopentyl-lH-pyrazole (8.0 g, 71 % yield. *H NMR (400 MHz, CDC13): S 7.52 (s, 1 H), 7.43 (s, 1 H), 6.24 (s, 1 H), 4.68 (m, 1 H), 2.20-1.71 (m, 8 H). MS (ESI) m/z: 137.1 [M+H4].

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To a suspension of N&2CO3 (13 g, 124 mmol) in CH2CL2 (100 mL) was added 1-cyclopentyl-1 H-pyrazole (8.35 g, 62 mmol) and Br2 (3.2 mL). Tlie resulting mixture was stirred at RT overnight. The solid was removed by filtration and the filter cake was washed with DCM. The combined filtrates were washed with water, brine and dried over anhydrous MgSOd. The solvent was concentrated to dryness to give 4-bromo-l-cyclopentyl-l H-pyrazole (14 g, 93%). 'H NMR (300 MHz, CDChy. 37.46 (s, I H), 7.44 (s, I H), 4.64 (m: 1 H), 2.18-1.67(m, 8 H); MS (ESI) m/z: 215.0 [M+H]+.
Using the procedure of Example B30, 4-bromo-l-cyclopentyl-lH-pyrazole (9.0 g, 42 mmol), n-BuLi (2.5 M, 18.5 mL, 46.2 mmol) and C02 were combined to provide 1-cyclopentyl-lH-pyrazole-4-carboxylic acid (3.5 g, 47 % yield). !H NMR (400 MHz, DMSO-d6): & 8.31 (s, 1 H), 7.85 (s, 1 H), 4.78 (m, 1 H), 1.70- 2.56 (m, 8 H); MS (ESI) m/z: 181.1 [M+Hj +.
Example C1: A solution of ethyl 4-chloro-2-(methyIthio)pyrimidine-5-carboxylate (42 g, 181 mmol) in EtOH (400 mL) was treated with a solution of methylamme (12.3 g, 397 mmol) in EtOH (100 mL) at 0 °C and the mixture was stirred for 3 h. The mixture was concentrated and then partitioned between H2O (200 mL) and CH2CI2 (500 mL). The organic layer was washed with brine, dried (Na2S04) and concentrated in vacuo to give ethyl 4-(methylamino)-2-(methylthio)pyrimidine-5-carboxylate as a white solid (36.0 g, 88% yield). fH NMR (300 MHz, CDC13): 8.59 (s, 1 H),8.18(brs, 1 H),4.31 (q, J = 7.2 Hz, 2 H), 3.05 (d, J = 4.8 Hz, 3 H), 2.52 (s, 3 H), 1.34 (t, J = 7.2 Hz, 3 H); MS (ESI) m/z: 228.1 (M+H*).
To a solution of ethyl 4-(methylamino)-2-(methylthio)pyrimidme-5-carboxylate (30 g, 132 mmol) in THF (300 mL) was added L1AIH4 (7.5 g, 198 mmol). The reaction mixture was stirred for Ih at RT. The reaction was carefully quenched with 10 mL water and 7 mL of 10% aq NaOH. The mixture was stirred for 1 h, filtered and the filtrate was concentrated to give (4-(methylamino)-2-(methylthio)pyrimidin-5-yl)methanol (22.0 g, 90% yield). lH NMR (300 MHz, DMSO-dg): 7.79 (s, 1 H), 6.79 (m, 1 H), 5.04 (t, J = 5.4 Hz, l.H), 4.27 (d, J - 5.4 Hz, 2 H), 2.83 (d,J = 4.8 Hz, 3 H), 2.40 (s, 3 H). MS (ESI) m/z: 186.1 (M+H+).
A mixture of (4-(methylamino)-2-(methylthio)pyrimidin-5-yl)methanol (22.0 g, 119 mmol) and MnO^ (44 g, 506 mmol) in CHCI3 (300 mL) was stirred at RT for 3 h. The reaction was filtered and the filtrate was concentrated to give 4-(methyIamino)-2-(methylthio)pyrimidine-5-carbaldehyde as a pale solid (20 g, 92% yield). !H NMR {400 MHz, DMSO-rffi): 9.71 (s, 1 H),

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8.60 (br s, 1 H), 8.49 (s, 1 H), 2.96 (d, J = 4.8 Hz, 3H), 2.48 (s, 3 H) MS (ESI) m/z: 184.0 (M+H*).
Example C2: To a 0 °C solution of ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxyIate (19 g, 82 mmol) in CH3CN (100 mL) was added a solution of aqueous ethylamine (70 %, 8.1 g, 126 mmol). The resulting mixture was stirred at RT for 8 h. The organic solution was removed under reduced pressure, and the residue was partitioned between EtOAc and H2O. The aqueous layer was extracted with ethyl acetate (3*30 mL) and the combined organics were washed with brine, dried (MgSO,*) and concentrated to give ethyl 4-(etliylamino)-2-(raethyltliio)pyrimidine-5-carboxylate (19.5 g, 99.1 % yield). lH NMR (400 MHz, DMSO-i6): S 8.49 (s, 1 H), 8.26 (t, J = 4,8 Hz, 1 H), 4.23 (q, J= 7.2 Hz, 2 H), 3.48 (q, /= 7.2 Hz, 2 H), 2.44 (s, 3 H), 1.26 (t, J = 7.2 Hz,3H), 1.13 (t, 7-7.2 Hz, 3 H).
To a solution of ethyl 4-(ethyIamino)-2-(methyltliio)pyrimidine-5-carboxylate (19.5 g. 81.9 mmol) in anhydrous THF (100 mL) was added UAIH4 (12.3 g, 327.6 mmol) in portions at 0 °C under N2 atmosphere. After stirring for 30 min, the reaction was quenched with water and then 2N aqueous NaOH as added. The suspension was filtered and the filtrate was concentrated to afford (4-(ethylamino)-2-(methyltliio)pyrimidin-5-yl)methano! (15 g, 92.0% yield). 'H NMR (400 MHz, DMSO-efc): 5 7.78 (s, 1 H), 6.74 (t, J = 4.8 Hz, 1 H), 5.05 (t, J = 5.2 Hz, 1 H), 4.26 (d, .7=5.2 Hz, 2 H), 3.36 (m, 2 H), 2.37 (s, 3 H), 1.10 (m, 3 H).
Activated MDOT (52 g, 0.6 mol) was added to a solution of (4-(ethylamino)-2-(methylthio)pyrimidin-5-yl)methanol (15 g, 0.075 mol) in CH2CL1 (300 mL) and the reaction mixture was stirred overnight at RT. The reaction solution was filtered and the filtrate was concentrated to give 4-(ethylamino)-2-(methylthio)pyrimrdine-5-carbaldehyde (14 g, 93% yield). 'H NMR (300 MHz, DMSO-t/rt): S 9.71 (s, I H), 8.67 (br s, 1H), 8.49 (s, 1 H), 3.51 (m, 2 H), 2.48 (s, 3 H), 1,17 (t, J= 7.2 Hz, 3 H).
Example C3: To a solution of ethyl 4,6-dichloronicotinate (5 g, 22.8 mmol) in CH3CN (30 mL) was added dropwise aqueous methylamine (65%, 5.2 g, 45.6 mmol) at 0 °C The resulting mixture was stirred at RT for 8 h. The organic solution was removed under reduced pressure to give the crude product, which was suspended in H2O and extracted with EtOAc (3 x 20 mL). The combined extracts were washed with brine, dried (MgSO-O and concentrated to give ethyl 6-

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chloro-4-(methylamino)nicotinate (4 g, 82 % yield), which was used in the next step without further purification. 'HNMR (300 MHz, DMSO-d6): 6 8.48 (s, 1 H), 8.04 (d, J = 4.5 Hz, 1 H), 6.71 (s3 I H), 4.27 (q, J= 6.9 Hz, 2 H), 2.85 (d, J= 5.1 Hz, 3 H), 1.29 (L /- 6.9 Hz, 3 H).
To a 0 °C solution of ethyl 6-chloro-4-(memylamino)nicotinate (4 g, 18.7 mmol) in THF (40 mL) was added LiAJH* (1.4 g. 37.4 mmol) portionwise under N2 atmosphere. After stirring for 20 min, the reaction was quenched by cautious addition of water followed by aqueous solution of 2 N NaOH. The suspension was filtered and the filtrate was concentrated to afford (6-chloro-4-(methylamtno)pyiidin-3-yl)methanol (2.9 g, 90.6% yield), which was used in next step without purification. 1HNMR (400 MHz, DMSO-d6): 5 7.96 (s, 1 H), 6.63 (s, 1 H), 6.46 (s, 1 H), 5.04 (s, 1 H), 4.39 (m, 2 H), 2.81-2.68 (m, 3 H).
A mixture of (6-clilorO"4-(methylammo)pyridin-3-yl)methanol (2.9 g, 16.7 mmol) and Mn02 (11.7 g, 133.6 mmol) in anhydrous DCM (25 mL) was stirred at 30 °C for 6 h. The reaction mixture was cooled to RT, and filtered. The filtrate was concentrated in vacuo to give 6-cliloro-4-(metiiyIamino)nicotinaldehyde (2.5 g, 87 % yield). 'HNMR (400 MHz, DMSO-^): 5 9.83 (s, 1 H), 8.52 (br s, 1 H), 8.40 (s, 1 H), 6.75 (s, 1 H)> 2.87 (d, J = 5.8 Hz, 3 H); MS (ESI) m/z: 171.0 [M+H]+.
Example C4: Ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (17 g, 73 mmol) and cyclopentyl amine (12.4 g, 146 mmol) were combined by the 3-step procedure of Example CI to provide 4-cyclopentylamino-2-methylsu1fanyl-pyrimidine-5-carbaIdehyde (8.5 g, 49% yield over 3 steps). ]H NMR (400 MHz, DMSO-^): S 9.73 (s, 1 H), 8.55 (d, J = 6.4 Hz, 1 H), 8.51 (s, 1 H), 4.43 (m, 1 H), 2,50 (s5 3 H, obscured by DMSO), 2.03-1.98 (m, 2 H), 1.69-1.48 (m, 6 H); MS (ESI) m/z: 238.3 [M+H]+.
Example C5: To a solution of ethyl 4,6-dichloronicotinate (4.4 g, 20 mmol) in CH3CN (50 mL) was added dropwise a solution of ethyiamine in water (65 %, 2.7 g, 39 mmol) at 0 °C. then the resulting mixture was stirred at RT overnight. The reaction was concentrated and the residue was washed with water to give ethyl 6-cliloro-4-(ethylamino)nicotinate (3.9 g, 91% yield). 'H NMR (400MHz, DMSO-d6): 5 8.51 (s, 1 H), 8.08 (s, I H), 6.53 (m, 1 H), 4.19 (q, .7=7.2 Hz, 2 H), 2.78 (q, .7=7.2 Hz, 2 H), 1.28 (t, J= 12 Hz, 3 H), 1.13 (t, J = 7.2 Hz, 3H); MS (ESI) m/z: 229.1[M+Hf.

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To a solution of ethyl 6-chloro-4-(ethylamino)nicotinate (3.9 g, 17 mmol) in anhydrous THF (50 mL) was added L1AIH4 (3.6 g, 95 mmol) at -50 °C, then the resulting mixture was allowed to warm to 0 °C and stirred for 1 h. Then the mixture was quenched by the addition of 30% aq NaOH solution (3.6 mL). The mixture was filtered and the filtrate was partitioned between water and EtOAc. The aqueous layer was extracted with EtOAc (3 x 100 mL). The combined organics were washed with brine, dried (MgSO,}) and concentrated in vacuo to provide to (6-chloro-4-(ethylamino)pyridin-3-yl)methanol (2.5 g, 79% yield). !H NMR (400MHz, DMSO-de): § 7.84 (s, 1 H), 76.55 (s, 1 H), 6.17 (m, 1 H), 5.25 (t, J- 5.2 Hz, 1 H), 4.44 (q, J = 12 Hz, 2 H), 3.23 (m, 2H), 1.23 (t,J= 12 Hz, 3H).
To a solution of (6-cliIoro-4-(emylamino)pyridin-3-yl)methanol (2.5 g, 13.4 mmol) in DCM (30 mL) was added MnCh (5,8 g, 67 mmol), then 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). 'H-NMR (400 MHz, CDC13): Example C6: To a solution of ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxyIate (15 g, 64.7 mmol) in CH3CN (100 mL) was added dropwise a solution of isopropylamine in water (7.6 g, 0.13 mol) at 0 °C. The resulting mixture was stirred at RT for 8 h. The organic solution was removed under reduced pressure and the residue was partitioned between water and EtOAc, and the aqueous layer was extracted with EtOAc (3 *50 mL). The combined organic layers were washed with brine, dried (MgS04) and concentrated to give ethyl 4-(isopropylamino)-2-(methylthio)pyrimidiiie-5-carboxylate (16.4 g, 99.6% yield), which was used in the next step without further purification. !H NMR (400 MHz, DMSO-rf«): S 8.51 (s, 1 H), 8.05 (d, J= 7.6 Hz, 1 H), 4.31-4.22 (m, 3 H), 2.46 (s, 3 H), 1.27 (t,./ = 7.2 Hz, 3 H), 1.20 (d, J= 6.4 Hz, 6 H).
To a solution of ethyl 4-(isopropylamino)-2-(methylthio)pyrimidme-5-carboxyIate (16.4 g, 64.4 mmol) in anhydrous THF (100 mL) was added LAH (6.1 g, 0.16 mol) in portions at 0 °C under N2 atmosphere, then the reaction mixture was stirred at r.t. for 30 min. The reaction was quenched by the addition of water (6 mL) followed by aqueous solution of 2N NaOH (6 mL). The suspension was filtered and the filtrate was concentrated to give (4-(isopropylamino)-2-(methylmio)pyrimidin-5-y])methanol (13.5 g, 98.4% yield), which was used in next step without

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further purification. ]HNMR (400 MHz, DMSO-^): 3 7.79 (s, 1 H), 6.37 (d, J = 7.6 Hz, 1 H), 5.10 (t, /= 5.6 Hz, 1 H), 4.28-4.20 (m, 3 H), 2.38 (s, 3 H), 1.13 (d, /= 6.4 Hz, 6 H).
To a solution of (4-(isopropylamino)-2-(memylmio)pyrimidin-5-yl)methanol (13.5 g, 63.4 mmol) in DCM (100 mL) was added manganese(rV) oxide (45 g, 0.5 mol), and the mixture was stirred at RT overnight The reaction mixture was filtered and the filtrate was concentrated to give the 4-(isopropylaraino)-2-(methylthio)pyrimidme-5-carbaldehyde (12.2 g, 91% yield), which was used in the next step without further purification. 'HNMR (400 MHz, DMSO-ds): S 9,71 (s, 1 H), S.50(s, 1 H),8.41 (d,/=7.2 Hz, 1 H), 4.33 (m, 1 H), 2.47 (s3 3 H), 1.21 (d,/=6.4 Hz,6H).
Example C7: Using the three-step procedure of Example C5, ethyl 4,6-dichloronicotinate (20 g, 91 mmol) and isopropylamine (60 % in water, 18 g, 182 mmol) were converted to 6-chloro-4-(isopropylamino)nicotinaldehyde (16 g, 81 % yield). 'H NMR (400 MHz, DMSO-^): 6 9.82 (s, 1 H), 8.43-8.39 (m, 2 H), 6.83 (s, 1 H), 3.84 (m, 1 H), 1.17 (d,J= 6.4 Hz, 6 H).
Example Dl: To stirring fuming HNO3 (90.00 wt%, 30.0 ml, 45 g, 643 mmol, 7.21 eq) al -15 °C was added 4-fluoro-2-methy!phenyIacetic acid (15.00 g, 89.2 mmol, 1.00 eq) in portions such that the internal temperature remained below -10 °C. After completing the addition the reaction was stirred with warming to -f5 °C over 15 min. The mixture was poured onto ice (400 g). Product separated as a slightly sticky solid which on manipulation widi a spatula became powdery. The suspension was stirred vigorously until the ice had completely melted. While still very cold, the solids were collected by filtration, rinsed very well with H2O and dried on the filter to afford crude 2-(4-ffuoro-2-methyI-5-nitrophenyl)acetic acid (18.43 g, 97% yield) as a pale yellow solid which was used as is in the next reaction. lH NMR (400 MHz, acetone-^): 5 8.06 (d, J = 7.6 Hz, 1H), 7.36 (d, J = 12.0 Hz), 3.84 (s, 2H), 2.44 (s, 3H)
2-(4-Fluoro-2-methyl-5-nitrophenyl)acetic acid (18.43 g, 86.5 mmol, 1.00 eq) and cone. H2S04 (4.00 ml) were combined in EtOH (300 ml) and stirred with heating at 85 DC. After 2.5 h, the completed reaction was cooled to RT and concentrated as completely as possible. The residue was dissolved in MTBE (250 ml) and washed with H20 (2x) and brine (2x). dried (MgSCU), filtered and evaporated to afford ethyl 2-(4-fluoro-2-methyl-5-nitrophenyl)acetate

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(16.79 g, 81% yield) as a dark orange oil which was used as is in the next reaction. MS (ESI) ra/z: 242.0 (M+H)+.
Ethyl 2-(4-fluoro-2-methyl-5-nitrophenyl)acetate (16.79 g, 69.6 mmol, 1.00) in EtOH (60 ml) was shaken with 10% Pd/C (50% H20) (7.41 g, 3.48 mmol, 0.050 eq) under H2 (3.5 arm) at RT for 2h until Hj uptake was complete. The completed reaction was filtered on Celite, rinsing forward with EtOH. The cake was washed well witli EtOH and the combined filtrates were concentrated and pumped on to afford ethyl 2-(5-amino-4-fluoro-2-methylphenyl)acetate (13.18 g, 90% yield) as a brown oil. - 'ii NMR (400 MHz, DMSO-d6): 3 6.80 (d, 7=12.4 Hz, 1 H), 6,59 (d, J = 9.6 Hz, 1 H), 4.86 (s, 2H), 4.05 (q,J= 7.2 Hz, 2 H), 3.46 (s, 2 H), 2.05 (s, 3 I-I), 1.17 (UJ= 7.2 Hz, 3 H); MS (ESI) in/z: 212.2 (M+H)+.
Example D2: To a solution of (254-difluoro-phenyl)acetic acid (14.5 g, 0.084 mol) in H2S04 (60 mL) at 0°C was added dropwise 69% HNOj (6 mL). After stirring at 0°C for 35 min, the reaction mixture was poured into ice water. The aqueous layer was extracted with EtOAc, and the organic extracts were washed with brine, dried (Na2S04), and concentrated in vacuo. The residue was purified by chromatography to give (2,4~difluoro-5-nitro-phenyl) acetic acid (16 g, 87.5 % yield). lH NMR (400 MHz, DMSO-4): S 8.30 (t, J= 8.0 Hz, 1 H), 7.68 (m, i H), 3.75 (s,2H).
A solution of (2,4-difluoro-5-nitro-pheny!)acetic acid (16 g , 74 mmol ) in EtOH (200 mL) and 98% H2S04 (14 mL) was refluxed at 80 °C for 2.5 h under a N2 atmosphere. The reaction mixture was poured into ice-water, and the resultant solution was extracted with ether. The combined organic extracts were washed with brine, dried (NazSO.*) and concentrated in vacuo. The residue was purified by column chromatography to give ethyl 2-(2,4-difluoro-5-nitrophenyl)acetate (16 g, 89 % yield). lH NMR (300 MHz, DMSO-c/6): 5 8.22 (t, J - 8.1Hz, 1 H), 7.55 {X,J= 11.1 Hz, 1 H),4.06(m,2H),3.77(s,2H), 1.13 (t, 7=6.9 Hz, 3 H),
A mixture of ethyl 2~(2!4-difluoro-5-nitrophenyI)acetate (16 g, 130 mmol) and 10 % Pd/C (1.6 g, 1.5 mmol) in EtOAc was hydrogenated at 30 psi at RT for 12h. The catalyst was filtered off and die filtrate was evaporated. Then the residue was purified by column chromatography to give ethyl 2-(5-amino-2,4-difluorophenyl)acetate (14 g, 99% yield ). H NMR (300 MHz, DMSO-d6): 5 6.98 (t, J = 9.9 Hz, 1 H), 6.70 (t, J= 7.8 Hz, 1 H), 4.50 (s, 2 H), 4.06 (m, 2 H), 3.53 (s, 2 H), 1.16 (t, J= 6.9 Hz, 3 H); MS (ESI) m/z: 216.2 [M+H]+.

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Example D3: HNO3 (10.35 g, 98.6 mmol) was added dropwsie to a stirred solution of 2-(2-chloro-4-fluorophenyl)acetic acid (16.9 g, 89.6 minol) in conc.H2S04 (60 mL) at -10 °C. After complete addition, the resulting mixture was stirred at 0 °C for 10 min, and was carefully poured into ice water. The ofT-white solid was collected by filtration and dried to give 2-(2-chloro-4-fluoro-5-nitrophenyl)aceticacid (20.5 g, 98.2% yield). 1HNMR (400 Hz, DMSO-^); S 12.71 (br s, 1 H), 8.33 (d, J = 8.0 Hz, 1 H), 7.92 (d, J= 11.2 Hz, 1 H), 3.85 (s, 2 H).
A solution of 2-(2-chloro-4-rluoro-5-nitrophenyi)aceric acid (20.5 g, SS mmol) in ethanol (150 mL) was treated with sulfuryl dichloride (21 g, 0.17 mol) at 0 °C, then die mixture was heated to reflux for 1 h. The reaction mixture was concentrated under reduced pressure and the pH was adjusted to between pH 7-8 by addition of saturated Na2COj solution. Then resultant mixture was extracted with EtOAc (3 x 100 mL) and the combined organic layers were washed with brine, dried (MgS04) and concentrated to give ethyl 2-(2-chloro-4-fluoro-5-nitrophenyl)acetate (22.5 g, 97.8%). ]HNMR (400 Hz, DMSO-rftf): 3 8.32 (d, J = 8.0 Hz, 1 H), 7.91 (d!y=11.2Hz, 1 H),4.09(q,./=7.2Hz,2H),3.92(s,2H), 1.17 (t, 7=7.2 Hz, 3 H).
A solution of ethyl 2-(2-chIoro-4-fluaro-5-nitrophenyl)acelale (22.5 g, 86.2 mmol) in ethanol (200 mL) was stirred with Raney Ni (20% slurry in water, ~5.0 g, 17 mmol) under a hydrogen atmosphere (30 psi) for 5 h. The catalyst was removed by filtration and the filtrate was concentrated to give ethyl 2-(5-amino-2-chloro-4-fluorophenyl)acetate (19 g, 95 % yield). *H NMR (400 MHz, DMSO-^j): S 7.10 (d, J= 11.2 Hz, 1 H), 6.71 (d, J = 9,2 Hz, 1 H), 5.27 (s, 2 H), 4.05 (q, J = 6.8 Hz, 2 H), 3.57 (s, 2 H), 1.14 (t, J = 6.8 Hz, 3 H); MS (ESI) m/z: 232.0 [M + H]+.
Example D4: To a stirred solution of 1-bromo-4-fluoro-2-methylbcnzene (30 g. 0.16 mol) in cone. H2SO4 (200 mL) was added KNO3 (16.1 g, 0.16 mol) at 0 °C portion wise. After the resulting mixture was stirred at 0 °C for 30 min, the reaction was poured into ice water and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with saturated Na^COs solution and brine, dried, filtered and concentrated to give l-bromo-4~fluoro-2-methyI-5-nitrobenzene (20 g, 53.6% yield). !HNMR (300 Hz, DMSO~d6): S 8,15 (d, J = 7.2 Hz, 1 H), 7.52 (d, J= 12 Hz, 1 H), 2.35 (s, 3 H).

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To a solution of l-bromo-4-fluoro-2-methyI-5-nitrobenzene (20 g, 85.8 mmol) in methanol (300 mL) was added Raney Ni (20%/w, -2.0 g, suspension in water, washed with acetone for several times), then the resulting mixture was hydrogenated under hydrogen atmosphere for 2 h. The catalyst was filtered, concentrated, and the residue was recrystallized (petroleum ether) to afford 5-bromo-2-fluoro-4-methylphenylamine (10 g, 57.5% yield). !HNMR (400 MHz, DMSO-^): 5 7.12 (d,J= 10.2 Hz, 1 H), 6.78 (d, J= 10.9 Hz, 1 H), 4.85 (s, 2 H), 2.29 (s, 3 H), 1.26 (s, 12 H). Nitrogen was bubbled though a solution of 5-bromo-2-fluoro-4-methylphenylamine (3.5 g, 37.2 mrnol), bis(pinacolato)diboron (3.9 g, 15.5 mmol), and KOAc (4.2 g, 51.6 mmol) in DMF (10 mL) for20min. To the above mixture was added dppf(954mg, 1.7 mmol) and PdCl^ (151 mg, 0.86 mmol), then nitrogen was continued to bubble for 30min., and the resulting mixture was heated to 80 °C under nitrogen for 16 h. The excess DMF was removed under reduced pressure, and the residue was partitioned between water and EtOAc. The organic layer was wash with brine, dried, filtered and concentrated and purified by silica gel column chromatography to give 2-fiuoro-4-methyl-5-(4,4,5,5-tetramethyl-l 33,2-dioxaborolan-2-yl)phenylamine (2 g, 47 % yield). ]H NMR (400 MHz, DMSO-^): S 7.10 (d, J = 10.4 hz, 1 H), 6,76 (d, J = 12.8 Hz, 1 H), 4.85 (s, 2 H), 2.27 (s, 3 H), 1.24 (s, 12 H); MS (ESI) m/z: 252.i[M+HJ+.
Example D5: 3-Oxo-pentanedioic acid (101 g, 0.5 mmol), diethyl ester, triethyl orthoformate (81.4 g, 0.55mol) and acetic anhydride (102 g, 1 mol) were combined and heated to 120 °C for 2 h. The resulting mixture was cooled to RT and dissolved in DCM (1000 mL). After further cooling to 0 °C, ammonia (30%, 80 mL) was added and the reaction mixture was allowed to warm to RT overnight. The product was extracted with water (2 x 1000 mL). Then the aqueous layer was acidified to pH 5 with cone HC1. The precipitate was collected by filtration to afford ethyl 4,6-dihydroxynicotinate (60.0 g, 60 % yield). !H NMR (400 MHz, DMSO-4,): 8 7.99 (s, 1 H), 5.58 (s, 1 H), 4.23 (q, J = 6.8, 14.0 Hz, 2 H), 1.25 (t, J= 7.2 Hz, 3 H). MS (ESI) m/z: 184.1 (M+H").
Ethyl 4,6-dihydroxynicotinate (60 g, 0.328 mol) was added slowly to a 2 L flask containing POCl3 (500 mL). After complete addition, the reaction mixture was heated to reflux for 2 hours. The resulting mixture was distilled to remove POCU under reduced pressure. The residue was poured into ice-water and stirred for 30 minutes before extracting with EtOAc (3 x

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500 mL). The combined extracts were washed with brine (300 mL), dried (MgS04) and concentrated in vacuo to give ethyl 4,6-dichloronicotinate (65 g, 90.1%, yield). lH NMR (300 MHz, DMSO-d6); 5 S.80 (s, 1 H), 7.95 (s, 1 H), 4.34 (q, .7=6.9 Hz, 2 H), 1.31 (t, 7= 6.9 Hz, 3 H). MS (ESI) m/z: 220.1(M+H+).
Example D6: A mixture of (2-chlorophenyl)acetic acid (15 g, 88 mmol) in cone. H2SO4 (100 mL) was cooled to -20°C and treated (drop wise) with cone. HNOi (9.4 g, 97 mmol). The resulting mixture was stirred at -20 DC for an additional 30 min. The reaction mixture was poured into the ice-water, and the mixture was extracted with EtOAc (3 x 200 mL), the combined organics were washed with brine, dried over Na2S04 and concentrated in vacuo to give (2-chloro-5-mtrophenyl)acetic acid (15 g, 79 % yield). lH NMR (400 MHz, DMSO-rf6): 5 8.58 (s, 1 H), 8.35 (m, 1 H), 7.96 (m, 1H), 4.12 (s, 2 H).
Thionyl chloride (16.7 g, 0.14 mol) was added dropwise to a 0 °C solution of (2-chloro-5-nitro-phenyl)acetic acid (15 g, 0.07 mol) in EtOH (300 mL) and the resultant mixture was heated at reflux overnight. The reaction mixture was concentrated under reduced pressure and the residue was poured into ice water, and extracted with EtOAc (2 x 300 mL). The combined organics were washed with brine and saturated NaHC03 solution, were dried over Na2S04, and were concentrated in vacuo to give ethyl 2-(2-chloro-5-nitrophenyl)acetate (17 g, 99% yield). 'H NMR (400 MHz, DMSO-4): S 8.35 (d, J= 2.8 Hz, 1 H), 8.12 (dd, J= 8.4, 2.8 Hz, 1 H), 7.72 (d, J - 8.4 Hz, 1 H), 4.10 (q, .7= 7.2 Hz, 2 H), 3.96 (s, 2 H), 1.15 (t,/= 7.2 Hz, 3 H).
Iron powder (2.5 g, 44.7 mmol) was added portion wise to a solution of ethyl 2-(2-chloro-5-nitrophenyl)acetate (8 g, 4.68 mmol) and cone. HC1 ((2 M, 3.9 mL, 46.8 mmol) in EtOH (100 mL). The resultant mixture was heated at 50 °C for 2 hour. The mixture was filtered and the filtrate cake was washed with saturated aqueous NajCOj until pH 8. The filter cake was further washed with EtOAc and the combined filtrates were partitioned between EtOAc and water. The organics were dried over Na2S04 and concentrated in vacuo to provide ethyl 2-(5-amino-2-chlorophenyl)acetate (5.6 g, 56 % yield). 'H NMR (400 MHz, DMSO-6): S 7.00 (d, J= 8.4 Hz, 1 H), 6.50 (s, J= 2.8 Hz, 1 H), 6.44 (dd, J= 8.4 Hz, 2.8 Hz, 1H), 5.20 (s, 2 H), 4.05 (q, J= 7.2 Hz, 2 H), 3.56 (s, 2 H), 1.15 (t, J= 12 Hz, 3 H).

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Example I: Using general method A, Example Bl (0.16 g, 0.42 mmol) and Example Al (0.12 g, 0.42 mmol) were combined to afford l-(5-(2-amino-8-memyl-7-oxo-7,8-dihydropyrido[2,3~ d]pyrimidin-6-yl)»2-fluorophenyl)-3-(3-tert-butyl-l-phenyl-lH-pyrazol-5"yl)urea as the amine hydrochloride salt (85 mg, 38% yield). (H NMR (400 MHz, DMSO-d6): 5 9.03 (s, 1H), 8.94 (s, IH), 8,71 (s, IH), 8.42 (d, J= 7.6 Hz, 1H), 7.89 (s, IH), 7.58-7.52 (m, 4H), 7.45-7.42 (m, 1H), 7.28 (d,./= 8.8 Hz, IH), 6.41 (s, IH), 3.73 (s, 3H), 1.28 (s, 9H); MS (ESI) m/z: 527.2 (M+H+).
Example 2: Using general method A, Example B2 (0.15 g, 0.46 mmo\) and Example A1 (0.13 g, 0.46 mmol) were combined to afford l-(5-(2-amino-8-methyl-7-oxo-7)8"dihydropyrido(2,3-d]pyrimidin-6-yI)-2-fliiorophenyI)-3-(3-tert-butyi-l-methyl-lH-pyrazol-5-yl)urea as the amine hydrochloride salt (80 mg, 37% yield). 'H NMR (400 MHz, DMSO-rf6): 5 8.99 (brs, IH), 8.87 (s, IH), 8.68 (s, IH), 8.43 (d, J = 8.4 Hz, IH), 7.88 (s, IH), 7.41-7.38 (m, 2H), 7.31-7.29 (m, 2H), 6.12 (s, IH), 3.63 (s, 3H), 3.57 (s, 3H), 1.21 (s, 9H); MS (ESI) m/z: 465.2 (M+H+).
Example 3: Using general method A, Example B3 (0.075 g, 0.17 mmol) and Example Al (0.05 g, 0.17 mmol) were combined to afford l-(l-(3-(2-amino-2-oxoethyl)phenyl)-3-tert-butyl-lH-pyrazoI-5-yl)-3-(5»(2-amino-S-methyl-7-oxo-7,8-dmydrapyrido[2,3-d]pyrimidin-6-yl)-2-fluorophenyl)urea as amine hydrochloride salt (41 mg, 42% yield). ]H NMR (400 MHz, DMSO-rf«): 5 9.03 (s, IH), 8.95 (s, IH), 8.72 (s, IH), 8.44-8.42 (m, IH), 7.90 (s, IH), 7.54 (brs, IH), 7.49-7.42 (m, 2H), 7.38-7.26 (m, 4H), 6.94 (brs, 1H)3 6.41 (s, IH), 3.58 (s, 3H), 3.48 (s, 211), 1.28 (s, 9H); MS (ESI) m/z: 584.2 (M+H*).
Example 4: Using general method A, Example B4 (0.075 g, 0.14 mmol) and Example Al (0.04 g, 0.14 mmol) were combined and then deprotected with HC1 in dioxane solution to afford l-(5-(2-ammo-8-memyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-2-fluorophenyl)-3-(3-tert-buryi-l-(lH-indazol-5-yl)-lH-pyrazol-5-yI)urea as the amine hydrochloride salt. !H NMR (400 MHz, DMSO-d6): 8 9.01 (s, IH), 8.90 (s, 1H): 8.74 (s, IH), 8.45-8.42 (m, IH), 8.20 (s, IH), 7.90 (s, 2H), 7.70 (d? J = 8.8 Hz, IH), 7.45 (dd, J= 8.8 Hz, 2.0 Hz, IH), 7.28-7.25 (m, 2H), 6.42 (s, IH), 3.58 (s, 3H), 1.28 (s, 9H); MS (ESI) m/z: 567.3 (M+H+).

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.ample 5: Using general method B, 3-isopropyl-l-phenyl-lH-pyrazol-5-amine (0.071 g. 0.19 mmol) and Example Al (0.054 g, 0.19 mmol) were combined to afford l-(5-(2-amino-8-methyl-7-oxo-7,8-dihydropyrido[233-d]pyrimidin-6-yl)-2-fluorophenyl)-3-(3-isopropyl"l-phenyl-lH-pyrazol-5-yl)urea as the amine hydrochloride salt (36 mg, 38% yield). lH NMR (400 MHz, DMSO-rffr): 8 9.05 (s, 1H), 8.97 (s, IH), 8.74 (s, IH), 8.42 {d,J= 7.2 Hz, 1H), 7.91 (s, 1H), 7.57-7.44 (m, 5H), 7.28 (d, J = 8.0 Hz, IH), 6.37 (s, IH), 3.62 (s, 3H), 2.89-2.86 (m, IH), 1.23 (s, J= 12 Hz, IH); MS (ESI) m/z: 513.3 (M+H4).
Example 6: To a solution of ethyl 3-tert-butyl-l-(2-(dimethylamino)-2-oxoethyl)-lH-pyrazole-5-carboxylate from example B17 (0.48 g, 1.7 mmol) in THF (10 mL) was added a solution of lithium hydroxide (0.21 g, 5,1 mmol) in water (5 mL) and the mixture was stirred for 16h at RT. Solvents were removed and the residue was acidified with 3M HC1 and the product was extracted with EtOAc (2x30 ml). The combined organic extracts were washed with brine, dried (Na2S04) and concentrated to afford 3-tert-butyl-l-(2-(dunethylamino)-2-oxoethyl)-lH-pyrazoIe-5-carboxylic acid (0.4, 93% yield) as a pasty mass. 'H NMR (400 MHz, DMSO-rf6): & 6.69 (s, IH), 5.30 (s, 2H), 3.02 (s, 3H), 2.82 (s, 3H), 1.24 (m, 9H); MS (ESI) m/z: 254.0 (M+H4). Using general method D, 3-tert-butyl-l-(2-(dimethylamino)-2-oxoethyl)-lH-pyrazole-5-carboxylic acid (0.055 g, 0.22 mmol) and Example Al (0.23 g, 0.88 mmol) were combined to afford l-(5-(2-amino-8-methyl-7-oxo-7,8-dihydropyrido[23-d]pyrimidin-6-yl)-2-fluorophenyl)-3-(3-tert-butyl-l-(2-(dimethylamino)-2-oxoethyl)-lH-pyrazol-5-yl)urea as the amine hydrochloride salt (81 mg, 70% yield). 'H NMR (400 MHz, DMSO-d6): 5 9.55 (brs, IH), 9.16 (s, IH), 8.78 (s, IH), 8.47-8.42 (m, IH), 7.32-7.30 (m, 2H), 6.28 (s, IH), 5.10 (s, 2H), 3.58 (s, 3H), 3.07 (s, 3H), 2.88 (s, 3H), 1.24 (m, 9H); MS (ESI) m/z: 536.2 (M+H+).
Example 7: Using general method Bf the carbamate of Example B21 (0.055 g, 0.18 mmol) and Example Al (0.05 g, 0.18 mmol) were combined to afford l-(5-(2-amino-8-metiiyl-7-oxO"7,8-dihydropyrido[2,3-d]pyrimidin-6-yI)-2-fluorophenyl)"3-(l-phenyl~3-(trifluoromethyl)-lH-pyrazoI-5-yl)urea as the amine hydrochloride salt (55 mg, 58% yield). 'H NMR (400 MHz, DMSO-d6): 5 9.24 (s, IH), 9.16 (s, IH), 8.71 (s, IH), 8.41-8.39 (m, IH), 7.89 (s, IH), 7.65-7.56 (m, 5H), 7.31-7.28 (m, 2H), 6.90 (s, IH), 3,65 (s, 3H); MS (ESI) m/z: 539.0 (M+H').

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Example 8: Using general method A, Example B2 (0.075 g, 0.23 mmol) and Example A2 (0.07 g, 0.23 mmol) were combined to afford l-(5-(2-amino-8-emyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-2-fluorophenyl)-3-(3-tert-butyl-1 -methyl-1 H-pyrazol-5-yl)urea as the amine hydrochloride salt (32 mg, 29% yield). lH NMR (400 MHz, DMSO-rffi): 5 9.31 (s, 1H), 9.01 (s, 1H), S.73 (s, IH), 8.41 (d, J = 8.4 Hz, 1H), 7.91 (s, 1H), 7.31 (d, J= 8.4 Hz, IH), 6.17 (s, IH), 4.32 (q, 7=6.8 Hz, IH), 3.67 (s, 3H), 1.24-1.20 (m, 12H); MS (ESI) m/z: 479.2 (M+H+).
Example 9: Using general method C, Example B5 (400 mg, 0.96 mmol) and Example Al (288 mg, 2.88 mmol) were combined to afford l-(5-(2-amtno-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-2-fluorophenyl)-3-(l-phenyl-3-(thiophen-2-yl)-lH-pyrazol-5-yl)urea (208 mg, 39% yield) as the HC1 salt. 'H-NMR (DMSO-d*) S 3.58 (s, 3H), 6.87 (s, IH), 7.10-7.12 (m, IH), 7.28-7.31 (m, 2H), 7.47-7.61 (m, 7H), 7.91 (s, IH), 7.70-8.30 (br s, 2H), 8.43 (d, IH), 8.80 (s, IH), 9.19 (s, 2H); MS (ESI) m/z: 553.0 (M+H4).
Example 10: Using general method A, Example B6 (0.071 g, 0.2 mmol) and Example Al (0.057 g, 0.2 mmol) were combined to afford l-(5-(2-amino-8~methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-2-fluorophenyl)-3-(l-methyl-3-(tliiophen-2-yl)-lH-pyrazol-5-yl)urea as the amine hydrochloride salt (25 mg, 25% yield). *H NMR (400 MHz, DMSCW6): 5 9.39 (s, IH), 9.06 (s, IH), 8.74 (s, IH), 8.45-8.43 (m, IH), 7.93 (s, IH), 7.42 (d, J = 4.8 Hz, IH), 7.34-7.31 (m, 3H), 7.06 (dd, J = 4.8 Hz, 3,6 Hz, IH), 6.60 (s, IH), 3.58 (s, 3H); MS (ESI) m/z: 491.0 (M+H+).
Example 11: Using general method A, Example Bl (0.075 g, 0.25 mmol) and Example A2 (0.075 g) were combined to afford l-(5-(2-amino-8-etliyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-2-fluorophenyl)-3-(3-tert-butyl-l-phenyl-lH-pyra2ol"5-yl)urea as the amine hydrochloride salt (56 mg, 41% yield). ]H NMR (400 MHz, DMSO-4,): 5 9.04 (s, IH), 8.94 (s, IH), 8.73 (s, IH), 8.42-8.40 (m, IH), 7.89 (s, IH), 7.58-7.52 (m, 4H), 7.46-7.42 (m, IH), 7.29-7.27 (m 2H), 6.41 (s, IH), 4.32 (q, J = 6.8 Hz, IH), 1.28 (s, 9H), 1.22 (t, J = 6.8 Hz, 3H); MS (ESI) m/z: 541.3 (M+H*).

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Example 12: Using general method A, Example B2 (0.500 g, 3.3 mmol) and Example A3 (0.382 g, 1.21 mmol) were combined and purified by flash column chromatography (12-100% EtOAc/hexanes) to afford 1-(3-t-butyl-1-methyl-lH-pyrazol-5-yl)-3-(2-fluoro-5-(8-methyl-2-(methyl(hio)-7-oxo-7,S-dihydropyrido[2,3-d]pyrimidin-6-yl)plienyl)urea (0.180 g, 30Vo yield) as a foam. MS (ESI) m/z: 496.0 (M+H+).
Using a procedure analogous to Example Al, l-(3-t-butyl-l-methyl-lH-pyrazol-5-yl)-3-(2-fluoro-5-(8-memyl-2-(memylmio)-7-oxo-718-dihydropyiido[23-^]pyrimidin-6-yl)phenyl)urea (0.180 g, 0.363 mmol) and MeNH2-HCl (0.0502 g, 0.743 mmol, 2.00 eq) were combined to afford l-(3-t-butyl-l-memyl-lH"pyrazol-5-yl)-3-(2-fluoro-5-(8-mediyl-2-(memylaniino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrioiidin-6-yl)phenyl)urea (0.0451 g, 24% yield) as the HCl salt. *H NMR (400 MHz, DMSO-rf«): 6 9.49 (bis, IH), 9.07 (s, 1H), 8.44-8.41 (m, IH), 7.97 (brs, 1H), 7.92 (s, IH), 7.33-7.27 (m, 2H), 6.23 (s, IH), 3.71 (s, 3H), 3.63 (brs, 3H), 2.94 (s, 3H), 1.24 (s, 9H); MS (ESI) m/z: 479.2 (M+H4).
Example 13: Using general method A, Example B7 (0.180 g, 0.444 mmol) and Example Al (0.138 g, 0.484 mmol) were combined to afford l-(5-(2-amino-8-metliyl-7-oxo-7,8-dihydropyrido[2)3-d]pyrimidin-6-yl)-2-fluorophenyl)-3-(3-tert-butyl-l-(3-fluorophenyl)-lH--pyrazoI-5-yl)urea (0.08 g, 33% yield) as a white foam. This was converted to corresponding HCl salt by reacting with HCL ]H NMR (DMSO-rffi): 5 9.15 (s, 2H)> 8.81 (s, IH), 8.39 (d, J = 7.8 Hz, IH), 7.94 (s, IH), 7.59-7.56 (m, IH), 7.45-7.41 (m, 2H), 7.30-7.26 (m, 3H), 6.42 (s, IH), 3.57 (s, 3H), 1.28 (s, 9H); MS (ESI) m/z: 545 (M+H+).
Example 14: Using general method A, Example B8 (0.10 g. 0.23 mmol) and Example Al (65 mg, 0.23 mmol) were combined to afford l-(5-(2-amino-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyiimidin-6-yl)-2-fluorophenyl)-3-(3-tert-butyl-1 -(quinolin-6-yl)-l H-pyrazol-5-yl)urea as the HCl salt (43 mg, 32% yield). lH NMR (400 MHz, DMSO-d6): B 9.08 (brs, IH), 9.02 (dd, J = 1.2, 3.6 Hz , IH), 8.97 (m, IH), 8.69 (s, IH), 8.60 (m, IH), 8.40 (dd, J = 1.6, 8.0 Hz , IH), 8.21 (m , 2H), 8.02 (dd, J= 2.4, 8.4 Hz , IH), 7.86 (s, IH), 7.69 (dd, J = 4.0, 8.4 Hz , IH), 7.39 (ban, IH), 7.27 (m, 2H), 6.49 (s, IH), 3.58 (s, 3H), 1.32 (s, 9H); LC-MS (EI) m/z: 578.3 (M+H*).

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Example 15: Using general method B, Example B9 (0.071 g, 0.26 mmol) and Example Al (0.074 g, 0.26 mmol) were combined to afford l-(5-(2-amino-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)"2-fiuorophenyl)-3-(3-(2-fluorophenyl)-l-metliyl-lH-pyrazoi-5-yI)urea (49 mg, 38% yield). This solid was converted to the amine hydrochloride salt by treating with 0.1 N HCl solution. 'H NMR (400 MHz, DMSO- Example 16: Using general method A, Example B10 (85 m g, 0.21 mmol) and Example A2 (63
mg, 0.21 mmol) were combined to obtain l-(5-(2-amino-8-ethyI-7-oxo-7,8-dihydropyrido[2,3-
d]pjrimidin-6-yl)-2-fluorophenyl)-3-(3-tert-b^
as the HCl salt (68 mg, 54% yield). lH NMR (400 MHz, DMSO- 1H), 8.85 (d, ./= 2.0 Hz, IH), 8.74 (s, IH), 8.35 (dd, /= 1.6, 8.4 Hz, IH), 8-25 (m , IH), 7.90 (s,
IH), 7.74 (d, /= 8.4 Hz, IH), 7.71 (brs, IH), 7.29 (m, 2H), 6.46 (s, IH), 4.31 (q,J= 7.2 Hz, 2H),
2.66 (s, 3H), 1.29 (s, 9H), 1.22 (t, J= 7.2 Hz, 3H); LC-MS (El) m/z: 556.3 (M+H *).
Example 17: Using general method A, the TROC carbamate of Example B2 (0.071 g, 0.23 mmol) and Example A4 (0.071 g, 0.23 mmol) were combined to afford l-(3-tert-butyl-l-methyl-lH-pyrazol-5-yl)-3-(5-(8-ethyl-2-(memylamino)-7-oxo-7,8HJihydropyrido[2,3-d]pyrimidin-6-yl)-2-fluorophenyl)urea (45 mg, 40% yield). ]H NMR (400 MHz, DMSO-rf6): 5 9.60 (s, IH), 9.12 (s, IH), 8.72 (bra, IH), 8.40 (6,J= 8.4 Hz, IH), 7.98 (brs, IH), 7.9] (s, IH), 7.33-7.27 (m, 2H), 6.24 (s, IH), 4.36 (brs, 2H), 3.79 (s, 3H), 2.93 (s, 3H), 1.24 (s, 12H); MS (ESI) m/z: 493.2 (M+H+).
Example 18: Using a procedure analogous to Example 12, Example B10 (0.051 g, 0,23 mmol), Example A3 (0.072 g, 0.23 mmol) and methylamine were combined to afford l-(3-tert-butyl-I-(6-methylpyridin-3-yl)-lH-pyrazol--5-yI)-3-(2-fluoro-5-(8-methyI-2-(methylaiTiino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (57 mg, 46% yield). lH NMR (400 MHz, DMSCW6):5 9.17(s, IH), 9.04 (s, IH), 8.79 (d, J = 2.0 Hz, IH), 8.69 (brs, IH), 8.38(dd,/ = 2.0, and 5.6 Hz, IH), 8.15 (m , IH), 7.SS (s, IH), 7.67 (d, J= 8.8 Hz, IH), 7.29 (m, 2H), 6.46 (s, IH), 3.60 (brm, 3H), 2.93 (brs, 3H), 2.64 (s, 3H), 1.29 (s, 9H); LC-MS (EI) m/z: 556.3 (M+H+).

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Example 19: Using general method B, the carbamate of 3-isopropyM-methyl-1 H-pyrazoI-5-amine (0.051 gT 0.23 mmol) and Example A4 (0.072 g, 0.23 mmol) were combined to afford 1-(5-(8-ethyl-2-(methylamino)- 7-oxo-7,8 -dihydropyrido [2,3-d] pyrirnidin-6-yl)-2-fluorophenyl)-3~ (3-isopropyl-l-methyl-lH-pyrazol-5-y])urea (78 mg, 71% yield) as a white solid. !H NMR (400 MHz, DMSO-4,): 5 9.10 (s, 1H), 9.06 (s, 1H), 8.71 (brs, 1H), 8.40 (d, J= 8.8 Hz, 1H); 7.96-7.87 (m, 2H), 7.35-7.27 (m, 2H), 6.19 (d, J = 7.6 Hz, 1H), 4.37 (brs, 2H), 3.69 (dT J = 5.2 Hz, 3H), 2.92 (s, 3H), 2,85-2.81 (m, 1H), 1.25-1.17 (m, 9H); MS (ESI) m/z: 479.2 (M+H+).
Example 20: To a solution of 2-(3-tert-butyl-5-(ethoxycarbonyI)-lH-pyrazo]-l-yl)acetic acid from Example B17 (0.77 g, 3.02 mmol) in DMF (5 mL) were added EDC (0.75 g, 3.93 mmol), HOBt (0.55 g, 3.62 mmol) and morpholine (0.39 g, 4.53 mmol). After stirring the mixture for 4h at RT, water (50 mL) and 3M HC1 (5 mL) were added and the product was extracted with EtOAc (3x30 mL). The combined organic layers were washed with aq. LiCl, dried (NazSC^), concentrated and purified by chromatography (EtOAc/CHiCfe) to afford ethyl 3-tert-butyI-I-(2-morpholino-2-oxoethyI)-lH-pyrazole-5-carboxylate (0.67 g, 69% yield) as a solid. !H NMR (400 MHz, Acetone-rf6): 5 6.74 (s, 1H), 5.40 (s, 2H), 4.27 (q, J = 12 Hz, 2H), 3,73 (brs, 2H), 3.65-3.62 (m, 4H), 3.51 (brs, 2H), 1.32 (t,J=7.2 Hz, 3U), 1.29 (s, 9H); MS (ESI) m/z: 324.2 (M+H4).
To a solution of ethyl 3-tert-butyl-l-(2-morphoIino-2-oxoemyl)-lH-pyrazole-5-carboxylate (0.34 g, 1 mmol) in THF (10 mL) was added borane in THF (4 mi of 1M solution, 4 mmol) at 0 °C under an Ar atmosphere and the mixture was stirred at 60 °C for 12h. The mixture was cooled to 0 °C and quenched with 3M HC1 solution and heated to 60 °C for 30 min. The mixture was basified with solid NaHCOs to pH -8 and the product was extracted with CHCI3 (2x30 ml) and the combined organic layers were washed with brine, dried (Na2S04) and concentrated to afford ethyl 3-tert-butyl-l-(2-morpholinoethyl)-lH-pyrazole-5-carboxylate amine (0.25 g, 76% yield) as a pasty mass. 'H NMR (400 MHz, Acetone-^): 5 6.69 (s, 1H), 4.60 (t, J= 6.4 Hz, 2H), 4.33 (q,J= 7.2 Hz, 2H), 3,59-3.53 (m, 4H), 2.69 (t, J= 6.4 Hz, 2H), 2.43-2.38 (m, 4H), 1.36 (t,/= 7.2 Hz, 3H), 1.29 (s, 9H): MS (ESI) m/z: 310.3 (M+H+).
To a solution of ethyl 3-tert-butyl-l-(2-raorpholinoetbyl)-IH-pyrazole-5-carboxyIate amine (0.43 g, 1.4 mmol) in THF (5 mL) was added a solution of LiOH (0.17 g, 4.2 mmol) in

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water (2 mL) and the mixture was stirred for 16h at RT. Solvents were removed, and then the thick liquid was diluted with water (5 mL) and the pH was adjusted to 4-5 with 50% aq.acetic acid. The product was extracted with EtOAc (3x25 ml) and the combined organic layers were washed with brine, dried (NaS04) and concentrated to afford 3-tert-butyl-l-(2-morpholinoethyl)-lH-pyrazole-5-carboxylic acid (0.16 g, 41% yield) as a pasty mass. 'H NMR (400 MHz, DMSO-4,): 5 6.65 (s, 1H), 4.54 (t, J= 6.4 Hz, 2H), 3.58-3.52 (m, 4H), 2.69 (t, J = 6.4 Hz, 2H), 2.44 (brs, 4H), 1.28 (s, 9H); MS (ESI) m/z; 282.3 (M+H+).
Using general method D, 3-tert-butyl-l-(2-morpholinoethyl)-lH-pyrazole-5-carboxylic acid (0.048 g, 0.17 rnmol), Example Al (0.097 g, 0.34 mmol), triethylamine (0.035 g, 0.34 mmol) and diphenylphospharyl azide (0.07 g, 0.26 rnmol) were combined to afford l-{5-{2-amino-8-methyl-7--oxo-7,8-dihydropTido[2.3-d]pyrimidin-6-yl)-2-fluorophenylV3-(3-tert-butyl-l-(2-morpholinoethyl)-lH-pyi'azol-5-yl)urea (38 mg, 40% yield) as the amine hydrochloride salt. 'H NMR (400 MHz, DMSO-s): 5 9.90 (s, 1H), 9.20 (s, JH), 8.73 (s, JH), S.4J (d: J = 8.S Hz, 1H), 7.92 (s, 1H), 7.30 (d, J = 8.4 Hz, 2H), 6.18 (s, 1H), 4.50-4.48 (m, 2H), 3.89-3.80 (m, 4H), 3.57 (s, 3H), 3.33-3.30 (m, 4H), 1.24 (m, 9H); MS (ESI) m/z: 564.3 (M+H*).
Example 21: Using a procedure analogous to Example 20, 2-(3-tert-butyl-5-(ethoxycarbonyl)-lH-pyrazol-l-yl)acetic acid from Example B17, benzyl piperazine-1-carboxylate and Example Al were combined to afford benzyl 4-(2~(5-(3-(5-(2-amino-8-methyl-7~oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-2-fluorophenyl)ureido)-3-tert-butyl-lH-pyrazol-l-yl)ethyl)piperazine-l-carboxylate (117 mg) as a solid. lH NMR (400 MHz, DMSO-&): 5 8.88 (s, 1H), 8.32 (s, 1H): 8.67 (s, 1H), 8.42-8.40 (m, 1H), 7.86 (s, 1H), 7.38-7.28 (m, 9H), 6.11 (s, 1.H), 5.05 (s, 2H), 4.04 (t, J= 6.8 Hz, 2H), 3.57 (s, 3H), 3.36 (brs, 4H), 2.68 (t, J= 6.8 Hz, 2H), 2.40 (brs, 2H), 1.18 (s, 9H); MS (ESI) m/z: 697.0 (M+H4).
To a solution of benzyl 4-(2-(5-{3-(5-(2-amino-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-2-iIuorophenyl)ureido)-3-tert-butyl-lH-pyrazol-l-yl)etliyl)piperazine-l-carboxylate (0.11 g, 0.16 mmol) in EtOAc (] 0 mL) was added palladium hydroxide (10% of 10 mg) and the mixture was stirred under a H2 atmosphere for 18h at RT. Then the mixture was filtered through a Celite pad, the pad was washed with EtOAc (2x5 ml). The filtrate was concentrated to afford a solid which was purified by chromatography using acetonitrile and water as eluents to afford l-(5-(2-arriino--8--methyl-7-oxo-7,8-dihydropyrido[2!3-d]pyrimidin--6-

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yl)-2-fluorophenyI)-3-(3-tert-butyl-l-(2-(piperazin-l-yl)ethyl)-lH-pyrazol-5-yl)urea as the amine hydrochloride salt (62 mg, 70% yield). lH NMR {400 MHz, DMSO-4): 5 9.20 (brs, IH), 9.16 (s, IH), 8.71 (s, IH), 8.41-8.39 (m, IH), 7.91 (s, IH), 7.31-7.29 (m, 2H), 6.18 (s, IH), 4.44 (brs, 2H), 3,57 (s, 3H), 3.52-3.39 (m, 8H), 1.23 (s, 9H); MS (ESI) m/z; 562.8 (M+H4).
Example 22: Using general method E, l-(3-t-butyl-l-methyl-1H-pyrazol-5-yl)-3-(2-fluoro-5-(8-
methyl-2"(memylsulfinyI)-7-oxo-7,8-dihydropyrido[2J3-d]pyrimidm-6-yl)phenyl)ui*ea from
Example 12 (0.199 g, 0.389 mmol) and N'^'-dimethylethane-l-diamine (0.214 ml, 1,94 mmol, 5.00 eq) were combined to afford l-(3-t-butyI-I-methyI-IH-pyrazoI-5-yI)-3-(5-(2-{2-(dimethylamino)ethylamino)-8-methyl-7-oxc-7)8-dihydropyrido[2.3-d]pyrimidin-6-yl)"2-fluorophenyl)urea which was subsequently treated with HCl to afford hydrochloride salt (20.8 mg, 10% yield) as a wliite solid. 'H NMR (400 MHz, DMSO-rfrt): 5 9.07 (s, IH), 8.91 (brs, IH), 8.80-8.75 (brs, IH), 8.47-8.44 (m, IH), 8.01 (brs, IH), 7.97 (s, IH), 7.33-7.27 (m, 2H), 6.10 (s, IH), 3.77-3.72 (m, 2H), 3.63 (s, 3H), 3.51 (brs, 3H), 3.37-3.33 (brm, 2H), 2.86 (m, 6H), 1.21 (s, 9H); MS (ESI) m/z: 536.2 (M+H*).
Example 23: Using general method F, Example Al (76 mg, 0.27 mmol) and l-isocyanato-3-(trifluoromethyl)benzene (80 mg, 0.43 mmol) were combined to provide l-(5-(2-amino-8-inethyl-7-oxo-7,8-dihydropyrido[2,3-d]pyi'imidin-6-yl)-2-fluorophenyl)-3-(3-(trifIuoromethyl)phenyI)urea (67 mg, 53 % yield). !H NMR (400 MHz, DMSO-d6): 5 9.43 (s, 1 H), 8.69 (s, 2 H), 8.41 (m, 1 H), 8.07 (s, 1 H), 7.90 (s, 1 H), 7.53 (m, 2 H), 7.35-7.25 (m, 5 H), 3.59 (s, 3 H); MS (ESI) m/z: 473.0 (M+H+).
Example 24: Using general method D, Example B17 (0.051 g, 0.21 mmol) and Example Al (0.12 g, 0.43 mmol) in presence of tri ethyl amine (0.032 g, 0.32 mmol) and diphenylphospharyl azide (0.07 g, 0.26 mmol) were combined to afford l-(5-(2-amino-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrirnidm-"6-yl)-2-fluorophenyi)-3-(3-tert-butyl-l-(2-(dimethylamino)ethyl)-lH-pyrazol-5-yl)urea as the amine hydrochloride salt (0.036 g, 32% yield). 'H NMR (400 MHz, DMSO-6): 69.63 (brs, IH), 9.44 (s, IH), 9.02 (s, IH), 8.67 (s, IH), 8.41-8.38 (m, IH), 7.88 (s, IH), 7.36-7.27 (m, 3H), 7,18-7.15 (m, IH), 6.18 (s, IH), 4.37 (t, J =

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6.4 Hz, 2H)S 3.55-3.51 (m, 2H), 2.84 (s, 3H), 2.82 (s, 3H), 1.23 (s, 9H); MS (ESI) m/z: 522.2 (M+H+).
Example 25: Using general method A, Example B2 (0.071 g, 0.22 mmol) and Example A8 (0.067 g, 0.22 mmol) were combined to afford l-(5-(2-amino-8-cyclopropyl-7-oxo-7.8-dihydropyrido[2,3-d]pyrimidin-6-yl)-2-fluorophenyl)-3-(3-tert-butyl-1 -methyl-1 H-pyrazol-5-yl)urea as the hydrochloride salt (0.062 g, 59% yield). 'H NMR (400 MHz, DMSO-rf6): 5 9.12 (s, IH), 8.92 (s, IH), 8.66 (s, IH), 8.38-8.36 (m, IH), 7.30-7.28 (m, 2H), 6.13 (s, IH), 3.64 (s, 3H), 2.89-2.84 (m, IH), 1.21 (s, 9H), 1.19-1.14 (m, 2H), 0.85-0.81 (m, 2H); MS (ESI) m/z: 491.2 (M+H+).
Example 26: Using general method F, Example Al (75 mg, 0.26 mmol) and l-fluoro-2-isocyanato-4-methylbenzene (0.050 mL, 0.39 mmol) were combined to provide l-(5-(2-amino-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d3pyrimidin-6-yl)-2-fluorophenyl)-3-(2-fIuoro-5-methylphenyl)urea (46 mg, 40% yield). [H NMR {400 MHz, DMSO-d6): 8 9.08 (d, J = 1.8 Hz, I H), 9.00 (d, J = 2.2 Hz, 1 H), 8.69 (s, 1 H), 8.48 (m, 1 H), 8.03 (dd, J = 7.9,1.6 Hz, 1 H), 7.89 (s, 1 H), 7.34-7.25 (m, 4 H), 7.12 (dd, J = 11.4, 8.6 Hz, 1 H), 6.81 (m, 1 H), 3.58 (s, 3 H), 2.27 (s, 3 H); MS (ESI) m/z: 437.3 (M+H%
Example 27: Using general method C, Example B13 (0.081 g, 0.21 mmol) and Example A2 (0.063 g, 0.21 mmol) were combined to afford l-(5-(2-amino-8-ethyl-7-oxo-7,8-dihydropyrido[2,3-d]pyiimidin-6-yl)-2-fluorophenyl)-3-(l-isopropyl-3-(tliiophen-2*-yl)-lH-pyrazol-5-yl)urea as die hydrochloride salt (0,059 g, 52% yield). !H NMR (400 MHz, DMSO-d6): 5 9.13 (s, IH), 8.94 (s, IH), 8.70 (s, IH), 8.42-8.40 (m, IH), 7.89 (s, IH), 7.41 (dd, J = 5.2 Hz, 1.2 Hz, IH), 7.34-7.30 (m, 3H), 7.06 (dd, /= 5.2 Hz, 3.2 Hz, IH), 6.57 (s, IH), 4.54^1.49 (m, IH), 4.32 (q, J= 12 Hz, 2H), 1.42 (d, ./= 6.4 Hz, 6H), 1.22 (t, J = 7.2 Hz, 3H); MS (ESI) m/z: 533.3 (M+H*).
Example 28: Using general method A, Example BI3 (0.081 g, 0.21 mmol) and Example Al (0.060 g, 0.21 mmol) were combined to afford l-(5-(2-amino-8-methyl-7-oxo-7,8-dihydropyrido[2J3-d]pyrimidin-6-yl)-2-fluorophenyl)--3-(l-isopropyl-3-(miophen-2-yl)-lH-

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pyrazol-5-yI)urea as the hydrochloride salt (0.049 g, 45% yield). 'H NMR (400 MHz, DMSO-d6): 5 9.23 (s, 1H), 8.99 (s, 1H), 8.72 (s, 1H), 8.44-8.41 (HL lH), 7.91 (s, 1H), 7.41 (dd, ./= 5.2 Hz, 1.2 Hz, 1H), 7.34-7.30 (m, 3H), 7.06 (dd,7= 5.2 Hz, 4.0 Hz, 1H), 6.57 (s, 1H), 4.52 (q, J = 6.0 Hz, 1H), 3.58 (s, 3H), 1.42 (d, J= 6.0 Hz, 6H);MS (ESI) m/z: 519.0 (M+H*).
Example 29: Using general method B, Example B9 (0.61 g, 0.22 mmol) and Example A2 (0.066 g, 0.22 mmol) were combined to afford l-(5- Example 30: Using general method F, 4-chloro-2-isocyanato-l-methylbenzene (0.112 g, 0.668 mmol) and Example A2 (0.100 g, 0.334 mmol) were combined in ethyl acetate to provide l-(5-(2-amino-8-ethyl-7"Oxo-7,8-dihydropvrido[2,3-d]pyrimidin-6-yt)-2-flLtorophenyl)-3-(5-chloro-2-
methylphenyl)urea, which was converted to tlie hydrochloride salt (120 mg, 77% yield) *H NMR (400 MHz, DMSO-d6): 5 9.38 (s, 1H), 8.78 (brs, 1H), S-66 (s: 1H), 8.45 (d, J = 8.0 Hz,
1H), 8.07 (m, 1H), 7.94 (m, 1H), 7.31 (d, J = 8.0 Hz, 1H), 7.20 (d, J = 8.0 Hz, 1H), 6.98 (d, J = 8.0 Hz, 1H), 4.30 (q, J = 6.0 Hz, 2H), 2.26 (s, 3H), 1.22 {U J =6.0 Hz, 3H); MS(ES1, m/z: 467.0, M+H*).
Example 31: Using general method F, 4-ch]oro-l-isocyanato-2-methylbenzene (0.112 g, 0.668 mmol) and Example A2 (0.100 g, 0.334 mmol) were combined in ethyl acetate to provide l-(5-(2-amino-8-emyl-7-oxo-7J8-dihydropyrido[2s3Hd]pyrimidin-6-yl)-2-fiuorophenyl)"3-(4-chloro-2-
methylphenyl)urea; which was converted to tlie hydrochloride salt (125 mg, 80% yield) *H NMR (400 MHz, DMSO-d6): 8 9.16 (m, 1H), 8.74 (s, 1H), 8.54 (s, 1H), 8.46-8.43 (m, 2H), 7.93
(s, 1H), 7.91 (m, 1H), 7.31-7.27 (m, 3H), 7.20 (dd, J = 8,0, 2.5 Hz, 1H), 4.32 (q, J = 6.0 Hz, 2H), 2.26 (s, 3H), 1.22 (t, J =6.0 Hz, 3H); MS(ESI, m/z: 467.0, M+H+).

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Example 32: Using general method F, 1-isocyanatonaphthalene (0.112 g, 0,668 minol) and Example A2 (0.100 g, 0.334 mmol) were combined in ethyl acetate to provide l-(5-(2-amino-8-etliyl-7-oxo-7,8-dihydropyrido[2J3-d]pyrimidin-6-yl)-2-fluorophenyl)-3-(naphthalen-l-yl)urea,
which was converted to the hydrochloride salt (130 mg, 83% yield) *H NMR (400 MHz, DMSO-dg): 89.36 (s, 1H), 9.26 (s, 1H), 8.77(m, 1H), 8.50 (d, J= 8 Hz, 1H), 8.23 (d, J = 8
Hz,lH), 8.06 (d, J = 8 Hz,lH),, 7.94 (m, 1H), 7.66-7-46 (m, 4H), 7.31 (m, 4H) , 4.32 (q, J = 6.0 Hz, 2H), 2.26 (s, 3H), 1.22 (t, J =6.0 Hz, 3H); MS(ESI, m/z: 469.0, M+H*).
Example 33: Using general method F, l-chloro-3-isocyanato-2-methyIbenzene (0.112 g, 0.668 mmol) and Example A2 (0.100 g, 0.334 mmol) were combined in ethyl acetate to provide l-(5-(2-amino-8-e£hyJ - 1-oxo-l, 8-dihydropyrido[2,3 -d] pyrimidin-6-yl )-2-fl uorophenyl )-3 -(3 -chloro-2 -
methylphenyl)urea, which was converted to the hydrochloride salt (128 mg, 82% yield). *H NMR (400 MHz, DMSO-d6): 5 9.12 (s, 1H), 8.74 (m, 1H), 8.66 (s, 1H), 8.43 (d, J= 8Hz, 1H),
7.90 (m, 1H), 7.78 (m, 1H), .29 (m, 2H), 7.17 (m, 1H), 4.32 (q, J = 6.0 Hz, 2H), 2.26 (s, 3H), 1.22 (t, J =6.0 Hz, 3H); MS(ESI, m/z: 467.0, M+H+).
Example 34: A solution of 4-(l,3,4-oxadiazol-2-yl)pheno! (1.05 g, 6.48 mmol) and triethylamine (1.82 mL, 13.0 mmol) in CH2CI2 (12 mL) was cooled to 0 °C and treated with trifiic chloride (0.83 mL, 7.77 mmol). The resultant orange-colored reaction was stirred 30 min at 0 °C and 30 min at RT. The reaction was poured into EtOAc (50 mL), washed with water (20 mL), satd aq NaHC03 (20 mL) and brine (20 mL), dried (NaiSO and concentrated in vacuo to provide 4-(l,3,4-OxadiazoI-2-yl)phenyl trifluoromethanesulfonate (1.94 gT 102 % yield) as a beige-colored solid. !H NMR (400 MHz, DMSO-d6): 8 9.43 (s, 1 H), 8.22 (d, J = 8.6 Hz, 2 H), 7.78 (d, J = 8,6 Hz, 2 H).
4-(l,3,4-Oxadiazol-2-yI)phenyl trifluoromethanesulfonate (0.645 g, 2.19 mmol), bis(pinacolato)diboron (0.72 g, 2.85 mol), and potassium acetate (0.645 g, 6.58 mmol) were combined in DMF (4 mL). The resultant mixture was de-gassed under vacuum, backfilling with argon (repeated 4x). Pd(dppf)Cl2 (96 mg, 0.12 mmol) was added and the reaction warmed to 95°C overnight. The reaction was diluted with EtOAc (50 mL), washed with water (2 x 15 mL) and brine (2x10 mL), dried (MgSO**) and concentrated in vacuo. Silica gel chromatography

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provided 2-(4-(414,5,5-terxamethyI-l)3,2-dioxaborolan-2-yl)phenyl)-l,3,4-oxadiazole (504 mg, 86 % yield) as a white solid. fH NMR (400 MHz, DMSO-4): 6 8.50 (s, I H); S.10 (d, J = 8.0 Hz, 2 H), 7.97 (d, J = 8.0 Hz, 2 H), 1.39 (s, 12 H).
A solution of 2-(4-(4,4,5,5-tetrainethyl-l ,3,2-dioxaborolan-2-yl)phenyI)-] ,3,4-oxadiazole (0.504 g, 1.85 mmol) in THF (] 0 mL) and water (5 mL) was treated with sodium periodate (1.19 g, 5.56 mmol). The resultant slurry was stirred at RT for 5 h. Glacial acetic acid (0.21 mL, 3.7 mmol) was added and the mixture was stirred for 1 h and filtered. The filtered solid was washed with ethyl acetate (75 mL) and THF-metbanoI (1:1, 100 mL) and the filtrates were concentrated in vacuo to a white solid. The solid was suspended in THF (75 mL) and 10 mL of 0.1 M aq HC1 and was sonicated to promote dissolution. The trace of insolubles were filtered and the organic layer was diluted with ethyl acetate (25 mL), washed with 0.1 M NaiS203 (2 x 20 mL), water (2 x 20 mL) and brine (20 mL), dried (Na2S04) and concentrated in vacuo to provide 4-( 1,3,4-oxadiazol-2-yl)phenylboronic acid (304 mgr 86% yield) as a white powder. ' H NMR (400 MHz. DMSCW6): 5 9.37 (s, 1 H), 8.32 (s, 2 H), 7.99 (s, 4 H).
A mixture of 4-(l,3,4-oxadiazol-2-yl)phenylboronic acid (303 mg. 1.60 mmol) and powdered 4A molecular sieves (300 mg) in CH2CU (6 mL) was heated to reflux for 2 h. Ethyl 3-tert-butyl-lH-pyrazole-5-carboxylate (310 mg, 1.6 mmol), pyridine (0.13 mL, 1.6 mmol) and copper (II) acetate (290 mg, 1.6 mmol) were added and the reaction mixture was refluxed for 24 h. The reaction was filtered and the solid was washed with EtOAc (40 mL) and MeOH (40 mL). The combined filtrtate and washings were concentrated in vacuo and partitioned between EtOAc (40 mL) and water (20 mL). The organics were washed with water (20 mL), satd aq NaHCOs (20 mL), water (20 mL), and brine (20 mL), dried (Na2S04) and concentrated in vacuo. The oily residue was chromatographed to provide ethyl I-(4-(I,3,4-oxadiazol-2-yl)phenyl)-3-tert-butyI-lH-pyrazole-5-carboxylate (440 mg, > 100 % yield) as a visocus oil contaminated with the starting ester. The mixture was used without further purification.
A solution of ethyl 1 ~(4-( 1,3,4-oxadiazol-2-yl)phenyl)-3 -tert-butyl-1 H-pyrazole-5-carboxylate (440 mg, 1.29 mmol) in a mixture comprised of THF (3 mL), methanol (1 mL) and water (I mL) was cooled to 0 °C and treated with lithium hydroxide (62 mg, 2.59 mmol). Hie reaction mixture was stirred 3 h at 0 °C and was then allowed to warm to RT over 4 h. Water (15 mL) was added and the mixture was extracted with ether (2 x 10 mL). The aqueous portion was acidified by addition of 1 M aq HC1 (2.5 mL, 2.5 mmol) and was extracted with EtOAc (3 x

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20 mL). The organics were dried (Na2S04) and concentrated in vacuo to provide 1-{4-( 1,3,4-oxadia2ol-2-yl)phenyI)-3-tert-hutyl-lH-pyrazole-5-carboxyIic acid (355 mg, 88 % yield). H NMR (400 MHz, DMSO-4): 5 13.35 (or s, 1 H), 9.40 (d, J = 3.4 Hz, 1 H), 8.11 (m, 2 H), 7.69 (m, 2 H), 7.01 (d, J = 3.2 Hz, 1 H), 1.32 (s, 9 H); MS (ESI) m/z: 313.0 (M+H+).
Using general method D, l-(4-(I,3,4-oxadia2ol-2-yI)phenyl)-3-tert-butyl-lH-pyrazole-5-carboxylic acid (95 mg, 0.30 mmol), Example Al ( 87 mg, 0.30 mmol) and pyridine (0.015 mL, 0.19 mmol) were combined to afford crude product product. The product was chromatographed on silica gel (100% EtOAc) and farther crystallized from EtOAc to provide l-(l-(4-(l,3.4-oxadiazol-2-yl)phenyl)-3-tert-butyl-lH-pyrazol-5-yl)-3-(5-(2-amino-8-methyl-7-oxo-7J8-dihydropyrido[2,3-d]pyiimidin-6-yl)-2-fluorophenyl)urea. ]H NMR (400 MHz, DMSO-rf6): 8 9.39 (s, 1 H), 9.03 (brs, 1 H), 8.99 (brs, 1 H), 8.67 (s, 1 H), 8.39 (dd, J = 8.0 , 2.0 Hz3 1 H), 8.19 (d, J = 8.6 Hz, 2 H), 7.86 (s, 1 H), 7.83 (s, 1 H), 7.82 (d, J = 8.6 Hz, 2 H), 7.33-7.24 (m, 4 H), 6.47 (s, 1 H), 3,57 Example 35: Using general method A, the troc carbamate of pyrazole amine of Example 37 (0.2g, 0.53 mmol ) and Example A2 (0.160g, 0.53 mmol) were combined to provide l-(5-(2-amino-8-ethyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-2-fluorophenyl)-3-(3-isopropyl-l-phenyl-lH-pyrazol-5-yl)urea which was converted to the hydrochloride salt (140 mg, 50 %
yield). *H NMR (400 MHz, DMSO-d6): 59.10 (s, IH), 9.05 (s, IH), 8.79 (s, IH), 8.40 (d, J=
8Hz, IH), 7.90 (s, IH), 7.54(m, 4H), 7.43 (m, IH).. 7.27 (d, J= 8Hz, IH), 6.36 (s, IH), 4.32 (q; J = 6.0Hz,2H), 2.89 (m,lH), 1.22 (m, 9H); MS(ESI, m/z: 527.2., M+H+).
Example 36: Using general method C, Example B14 (420 mg, 1.50 mmol) was converted to
73% mono-Troc, 2,2,2-trichloroethyI 3-tert-butyI-l-(2-methylquinolin-6-yl)-lH-pyrazol-5-
ylcarbamate and 16% bis-Troc, based on LC analysis, and which was used without further
purification in the next reaction (667 mg). MS (ESI) m/z: 456.5 (M+H*).
Example Al (J36mg, 0.475 mmol) and the above Troc mixture (200 mg, 0.453 mmol) were
combined to afford I-(5-(2-amino-8~methyI-7-oxo-7,8-dihydi'opyrido[2,3-d]pyrimidin-6-yl)-2-
fluorophenyl)-3-(3-tert-butyl-l-(2-mediylquinolin-6-yl)-lH-pyrazol-5-yl)urea as the
hydrochloride salt (22 mg, 8% yield). 'H NMR (300 MHz, DMSO-rf6), 5 1.32 (s, 9 H), 2.96 (s, 3 H), 3.56 (s, 3 H), 6.49 (s, 1 H), 7.26-7.28 (m, 2 H), 7.70 (or. s, 2 H), 7.88 (s, 1 H), 7.95 (d, J =

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8.7, 1 H), 8.31-8.35 (m, 2 H), 8.42-8.44 (m, 1 H), 8.50 (m, 1 H), 8.74 (s; 1 H), 9.01 (m, 1 H), 9.17 (s, 1 H), 9.46 (s, 1 H); MS (ESI) m/z: 592.3 (M+H*).
Example 37: Using general method B, the carbamate of 3-isopropyl-l-phenyl-lH-pyrazol-5-amine (1.01 g, 5.02 mmol) and Example A12 (0.69 g, 2.3 mmol) were combined to afford l-(2-fluoro-5-(8-memyI-2-(memylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yi)phenyl)-3-(3-isopropyl-l-phenyl-lH-pyrazol-5-yl)urea as an off-white solid (0.75 g, 62%, yield). *H NMR (400 MHz, DMSO-4): 6 8.99 (s, IH), 8.90 (s, IH), 8.75-8.66 (m, IH), 8.42 (dd, J= 8.0 Hz, 1.6 Hz, IH), 7.87 (s, IH), 7.83-7.81 (m, IH), 7.58-7.51 (m, 4H), 7.46-7.41 (m, IH), 7.32-7.23 (m, 2H), 6,37 (s, IH), 3.63-3.56 (m, 3H), 2.93-2.87 (m, 4H), 1.23 (d, J= 6.8 Hz, 6H); MS (ESI) m/z: 527.2 (M+H*).
Example 38 Using general method B, Example Bl(1.01 g, 4.69 mmol) and Example A12 (1.25 g, 4.18 mmol) were combined to afford l-(3-tert-butyl-l-phenyl-lH-pyrazol-5-yl)-3-(2-fluoro-5-(8-metliyl-2-(methyIamino)-7-oxo-7,8-dihydropyrido[2s3-d]pyrimidin-6-yl)phenyl)urea as off-white solid (1.39 g, 62%, yield). 'H NMR (400 MHz, DMSO~6): 5 9.00 (s, IH), 8.89 (s, IH), 8.75-8.67 (m, IH), 8.42 (dd, J- 8.0 Hz, 1.6 Hz, IH), 7.88 (s, IH), 7.83-7.81 (m, IH), 7.58-7.51 (m, 4H), 7.46-7.41 (m, IH), 732-7.23 (m, 2H), 6.41 (s, IH), 3.63-3.56 (m, 3H)S 2.92 (d, J = 4.0 Hz, 3H), 1.28 (s, 9H); MS (ESI) m/z: 541.3 (M+H4).
Example 39: Using general method B, Example B9 (0.61 g, 0.22 mmol), and Example A12 (0.066 g, 0.22 mmol) were combined to afford l-(2-fluoro-5-(8-methyl-2-(methylamino)-7-oxo-7J8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)-3-(3-(2-fluorophenyl)-l-metliyl-lH-pyrazol-5-yl)urea as the hydrochloride salt (0.071 g, 62%, yield). *H NMR (400 MHz, DMSO-rf6): 6 9.33 (s, IH), 9.01 (s, IH), 8.70 (s, IH), 8.44-8.41 (m, IH), 7.94-7.90 (m, 2H), 7.35-7.21 (m, 5H), 6.67 (d, J = 4.4 Hz, IH), 3.80 (s, 3H), 3.62 (s, 3H), 2.93 (s, 3H); MS (ESI) m/z: 517.3 (M+H*).
Example 40: Using general method F, 4-bipheny!yl isocyanate (0.100 g, 0.512 mmol, 1.00 eq) and Example A3 (0.162 g, 0.512 mmol, 1.00 eq) were combined to afford l-(2-fluoro-5-(8-methyI-2-(methyltm^)-7-oxo-7,8-dmydropyrido[2.3-d]pyrnnidui-6-yl)phenyi)-3-(4-biphenyl)urea (0.1884 g, 72% yield) as a peach-colored solid which was used as is in the next

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step. *H NMR (400 MHz, DMSO-rfa): 5 9.22 (s, IH), 8.98 (s, IH), 8.68 (brs, IH), 8.54-8.51 (m, IH), 8.10 (s, IH), 7.66-7.56 (m, 7H), 7.46-7.42 (m, 2H), 7.36-7.30 (m, 3H), 3.69 (s, 3H), 2.63 (s, 3H); MS (ESI) m/z: 512.3 (M+H+), 534.0 (M+Na+).
Using a procedure analogous to Example AI, I-(2-fluoro-5-(8-methyl-2-(methylthio)-7-oxo-7,8-dihydropyrido[213-d]pyrimidin"6"y])phenyl)-3-(4-biphenyl)urea and MeN^-HCl were combined to afford l-(2-flnoro-5-(8-methyl-2-(methylamino)-7-oxo-7,8-dihydropyi-ido[2,3-d]pyrimidin-6-yl)phenyl)-3-(4-biphenyl)urea (59.9 mg) as a pale yellow solid which was subsquentually converted to the HCl salt (56.7 mg). ]H NMR (400 MHz, DMSO-4*): 5 9.30 (s, IH), 8.71 (brs, IH), 8.67 (brs, IH), 8.48 (dd, IH, J = 2.0 and H.Q Hz), 7.92 (s, IH), 7.657.56 (m, 7H), 7.46-7.41 (m, 2H), 7.34-7.26 (m, 3H), 3.64 (brs, 3H), 2.94 (brs, 3H); MS (ESI) m/z; 495.0 (M+H*).
Example 41: Using general method D, Example B17 (0.061 g? 0.25 minol) and Example A37 (0.14 g, 0.51 mmoi) in presence of triethyiamine (0.077 g, 0.76 mmol) and diphenylphospharyl azide (0.077 g, 0.28 mmol) were combined to afford l-(3-(2-amino-8-methyl-7-o.xo-7,8-dihydropyrido[2]3-d]pyrimidin-6-yl)phenyl)-3-(3-tert-butyI-l-(2-(dimethylainino)ethyl)-lH-pyrazol-5-yl)urea as the hydrochloride salt (0.063 g, 49% yield). lH NMR (400 MHz, DMSO-d6): 59.62 (brs, IH), 9.46 (s, IH), 9.24 (s, IH), 8.67 (s, IH), 7.89 (s, IH), 7.45 (d, J= 8.0 Hz, IH), 7.36-7.31 (m, 4H), 7.17-7.12 (m, IH), 6.15 (s, IH), 4.38 (t, J = 6.4 Hz, 2H), 3.58 (s, 3H), 3.55-3.51 (m, 2H), 2.84 (s, 3H), 2.83 (s, 3H), 1.24 (s, 9H); MS (ESI) m/z: 504.2 (M+H+).
Example 42: Using general method F, Example Al (72 mg, 0.25 mmol) and l-isocyanato-3-methylbenzene (0.049 mL, 0.38 mmol) were combined to provide l-(5-(2-amino-8-methyl-7-oxo~7,8-dihydropyridof2,3-d]pyrimidin-6-yl)-2-fluorophenyl)-3-m-tolylurca (57 rag, 52 % yield). ]H NMR (400 MHz, DMSCW6): 59.01(br s, 1 H), 8.69 (s, 1 H), 8.57 (d, J = 2.5 Hz, 1 H), 8.45 (m, 1 H), 7.89 (s, 1 H), 7.34-7.27 (m, 4 H), 7.22-7.14 (m, 3 H), 6.81 (d, J = 7.1 Hz, 1 H), 3.58 (s, 3 H), 2.29 (s, 3 H); MS (ESI) m/z: 419.2 (M+H+).
Example 43: Using general method C, Example Bl8 (0.250 g, 1.78 mmol, 1.00eq)astheTROC carbamate and Example A3 (0.211 g, 0.665 mmol, 1.00 eq) were combined to afford l-(3-t-butylisoxazol-5-yl)-3-(2-fluoro-5-(8-memyl-2-(memylthio)-7-oxo-7,8-dihydropyrido[2,3--

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d]pyrimidin-6-yl)phenyl)urea (0.180 g, 56% yield) as an oil. lH NMR (400 MHz. acetone-^): 5 9.64 (brs, 1H), 8.91 (s, 1H), 8.62 (m, 1H), 8.35 (brs, 1H), 8.06 (s, 1H), 7.49 (m, 1H), 7.26 (m, 1H), 6.17 (s, 1H), 3.77 (s, 3H), 2.69 (s, 3H), 1.32 (s, 9H); MS (ESI) m/z: 483.3 (M+H4).
Using a procedure analogous to Example Al, l-(3-t-butylisoxa2oI-5-yl)-3-(2-fluoro-5-(8-methyl-2»(methylthio)-7-oxo-7,8-dihydropyrido[2,3^]pyriniidin-6-yl)phenyl)urea (0.180 g, 0.373 mmol, 1.00 eq) was oxidized with MCPBA (70.00 wt%, 0.276 g, 1.12 mmol, 3.00 eq) and then subjected to MeNHrHCI (0.019 g, 0.28 mmol, 2.00 eq) to afford afford I-(3-t-butylisoxazol-5-yl)-3-(2-fluoro-5-(8-methyl-2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (0.0346 g, 53% yield) as an off-white solid. The free base thus obtained converted to the hydrochloride (32.3 mg) as a pale yellow solid. 'H NMR (400 MHz, DMSO-rf6): 5 10.45 (s, 1H), 8.840 (s, 1H), 8.69 (brs, 1H), 8.42 (dd, J = 8.0, 2.0 Hz, 1H), 7.92 (s, IB), 7.90 (brs, 1H), 7.39-7.29 (m, 2H), 6.09 (s, 1H), 3.64 (brs, 3H), 2.93 (brs, 3H), 1.26 (s, 9H): MS (ESI) m/z: 466.2 (M+H+).
Example 44: Using general method D, Example B25 (0.1 g, 0.39 mmol) and Example A2 (0.234g, 0.78 mmol ) were combined to provide I-(5-(2-ammo-S-etIiyl-7-oxo-7,8-diliydropyrido[2,3-d]pyrimidin-6-yl)-2-fluorophenyl)-3-(l-(3-cyanophenyl)-3-isopropyl-lH-
pyrazoK5-yl)urea. which was converted to the hydrochloride salt (52 mg, 24% yield)'. *H NMR (400 MHz, DMSO-d6) 69.18 (s, 1H), 9.10 (brs, 1H), 8.79 (s, 1H), 8.34 (d, J = 8.0 Hz, 1H), 8.05
(m, 1H), 7.90 (m, 3H), 7.73 (t, J= 8.5 Hz, 1H), 7.30 (d, J= 8.5 Hz , 1H), 6.40 (s, 1H), 4.31(q, J= 8 Hz, 2H), 2,90 (m,lH), 1.22 (m, 9H); MS(ESI, m/z: 552.2, M+H+).
Example 45: Using general procedure D, biphenyl-3-carboxylic acid (0.100 g, 0.504 mmol, i .00 eq) and Example A3 (0.239 g, 0.757 mmol, 1.50 eq) were combined to afford 1 -(2-fluoro-5-(8-memyl-2-(mediylthio)-7-oxo-7J8-dihydropyrido[2,3-d]pyrimidin-6-yI)phenyl)-3-(3--biphenyl)urea (0.110 g, 43% yield) as a foam. 'H NMR (400 MHz, acetone-^*); 5 9.23 (s. 1H), 8.97 (s, 1H), 8.69 (dd, J = 8.0, 2.4 Hz), 8.64 (brs, 1H), 8.09 (s, 1H), 7.93 (m, 1H), 7.68-7.65 (m, 2H), 7.50-7.46 (m, 3H)S 7.43-7.36 (m, 3H), 7.30-7.24 (m, 2H), 3.76 (s, 3H), 2.67 (s, 3H); MS (ESI) m/z: 512.0 (M+H*).
Using a procedure analogous to example Al, l-(2-fluoro-5-(8-methyl-2-(metliylthio)-7-oxo-7)8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)-3-(3-biphenyl)urea (0.110 g, 0.215 mmol, 1.00 eq)

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was oxidized with MCPBA (70.00 wt%, 0.159 g, 0.645 mmol, 3.00 eq) and then subjected to MeNHrHCl (0.00870 g, 0.129 mmol, 2.00 eq) to afford l-(2-fluoro-5-(8-methyl-2-(metiiyIamino)-7-oxo-7,8-dihydropyrido[2J3-d]pyrimidin-6-yl)phenyl)-3-(3-biphenyl)urea (0.0227 g, 71% yield). This was converted to the HC1 salt (0.021 g) as an off-white solid. (H NMR (400 MHz, DMSO-d6): 5 9.29 (brs, IH), 8.71 (brs, IH), 8.69 (brs, IH), 8.44 (m, IH), 7.92 (s, IH), 7.84 (s, IH), 7.64-7.61 (m, 2H), 7.50-7.46 (m, 2H), 7.40-7.36 (m, 3H), 7.31-7.26 (m, 3H), 3.64 (brs, 3H), 2.93 (brs, 3H); MS (ESI) m/z: 495.2 (M+H+).
Example 46: Using general method F, Example Al (80 mg. 0.28 mmol) and 4-chloro-3-(trifluoromemyl)phenyl isocyanate (93 mg, 0.42 mmol) were combined to provide l-(5-(2-amino-8-methyl-7-oxo-7 J8-dihydropyrido[2,3-d]pyrimidin-6-yl)-2-fluorophenyl)-3-(4-cliloro-3-(trifluoromethyl)phenyl)urea (62 mg, 44 % yield). 'H NMR (400 MHz: DMSO-d6): d 9.52 (s, 1 H), 8.71 (d, J = 2.3 Hz, 1 H), 8.68 (s, 1 H), 8.37 (dd, J -8.2,1.9 Hz, 1 H), 8.14 (d, J = 2.2 Hz, 1 H), 7.90 (s, 1 H), 7.65-7.58 (m, 2 H), 7.36-7.26 (m, 4 H), 3.58 (s, 3 H); MS (ESI) m/z: 507.0 (M+rT).
Example 47: 6-t-Butyl-lH-thieno[312-d]tl3]oxazine-2,4-dione (0.075 g, 0.33 mmol, 1.0 eq; prepared according to the method disclosed in WO 99/32111) and Example A12 (0.100 g, 0.33 mmol, 1.0 eq) were combined in DMSO (3.3 ml) and stirred with heating at 70 °C for 16 h and at 110 °C for 24 h. The completed reaction was cooled to RT, diluted with brine and extracted with EtOAc (3x). The combined organics were washed with brine (2x), dried (Na3S04), filtered, concentrated in vacuo and purified by flash column chromatography (10% EtOAc/hexanes-100% EtOAc) to afford I -(54-burylthiophen-3-yl)-3-(2-fluoro-5-(8-methyl-2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yi)phenyI)urea (0.060 g, 38% yield) as a creamy yellow solid. 'H NMR (400 MHz, DMSO-40: 8 9.18 (s, IH), 8.67 (brs, IH), 8.49 (m, IH), 8.42 (m, IH), 7.89 (s, IH), 7.82 (brs, IH), 7.28-7.25 (m, 2H), 7.02 (d, J = 1.6 Hz, IH), 6.82 (d, J = 1.6 Hz, IH), 3.639 (brs, 3H), 2.93 (d, J = 4.1 Hz, 3H); MS (ESI) m/z: 481.2 (M+H*).
Example 48: Using general method B, the carbamate of l-phenyI-3-(trifluoromethyl)-lH-pyrazol-5-amine (1.01 g, 3.24 mmol) and Example A12 (0.97 g, 3.24 mmol) were combined to afford l-(2-fluoro-5-(8-metliyl-2-(methylamino)-7-oxo-7,8-dihydropyrido[213-d3pytimidin-6-

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yl)pheny])-3-(l-phenyl-3-(trifluoromethyl)-lH-pyrazol-5-3)urea as an off-white solid (1.41 g, 79%, yield). 'H NMR (400 MHz, DMSO-4;): 8 9.16 (s, IH), 9.08 (s, IH), 8.72 (s, IH), 8.37 (dd, J= 8.0 Hz, 1.6 Hz, IH), 7.92 (s, IH), 7.85 (brs, IH), 7.64-7.54 (m, 5UI 7.32-7.20 (in, 2H), 6.87 (s, IH), 3.60-3.57 (m, 3H), 2.89 (d, J= 4.8 Hz, 3H); MS (ESI) m/z: 556.3 (M+H*).
Example 49: Using general method D, 3-ter£-butyl-l-methyl-lH-pyrazole-5-carboxylic acid (0.041 g, 0.24 mmol) and Example A52 (0.085 g, 0.27 mmol) were combined in presence of triethylamine (0.046 g, 0.45 mmol) and diphenylphospharyl azide (0.093 g, 0.34 mmol) to afford l-(5-(2-ammo-S-isopropyl-7-oxo-7i8-dihydropyrido[233-d]pyrimidin-6-yl)-2-fluorophenyl)-3-(3-tert-butyl-l-memyI-lH-pyrazol-5-yl)urea as a white solid (0.068 g, 61% yield). *H NMR (400 MHz, DMSO-c/6): 5 8.92 (s, IH), 8.82 (s, IH), 8.64 (a, IH), 8.37-8.35 (m, IH), 7.80 (s, IH), 7.29-7.26 (m, 4H), 6.01 (s, IH), 5.80-5.76 (m, IH), 3.62 (s, 3H), 1.54 (d, J= 6.8 Hz, 6H), 1.21 (s, 9H); MS (ESI) m/z: 493.2 (M+H*).
Example 50 Using general method D, Example B24 (0.150 g. 0.403 mmol) and Example A2 (0.271 g. 0.906 mmol) were combined to provide l-(5-(2-amino-8-ethyl-7-oxo-7,8-dihydropyTido[2,3-d]pyrimidin-6-yl)-2-fluorophenyl)-3-(l-(4-tluorophenyl)»3-isopropyl-lH-
pyrazoI-5-yI)urea, which was converted to the mesylate salt (184 mg, 63% yield ).*H NMR (400 MHz, DMSO-d6): 59.06 (brs, IH), 8.96 (s, IH), 8.78 (s, IH), 8.39 (d, J = 9Hz, IH), 7.92
(s, IH), 7.59 (m, IH), 7.42 (m,2H), 7.29 (m, 2H), 6.39 (s, IH), 4.31 (q, J = 7 Hz, 2H), 2.90 (m, IH), 2.37 (s, 6H), 1.24 (m, 9H); MS (ESI, m/z: 545.3, M+H+).
Example 51: Using general method D, example B25 (0.150 g, 0.588 mmol) and Example Al (0.2 g, 0.705 mmol) were combined to provide l-(5-(2-amino-8-methyl-7-oxo-7,8-dihydrop>Tido[2,3-d]pyriiTiidin-6-yl)-2-fluorophenyl)-3-(l-(3-cyanophenyl)-3-isopropyl-lH-
pyrazol-5-yl)urea which was converted to the mesylate salt (78 mg, 51% yield). 'HNMR(400 MHz, DMSO-d6) 59.00 (brs, IH), 8.96 (s, IH), 8.75 (s, IH), 8.39 (d, J = 8Hz, IH), 8.05 (s, IH),
7.93-7.85 (m, 3H), 7.75 (m, IH), 7.29 (d, J = 8Hz, 2H), 6.41 (s, IH), 3.50 (s, 3H), 2.90 (in, IH), 2.37 (s, 6H), 1.24 (d, J = 7Hz, 6H); MS (ESI, m/z: 538.3, M+H*).

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Example 52: Using general method D, l-(3-fluorophenyl)-3-isopropyl-lH-pyrazole-5-carboxylic acid (0.10 g, 0.403 mmol) and Example A2 (0.241 g, 0.806 mmol) were combined to provide l-(5-(2-amino-8-emyl-7-oxo-7)8-dihydropyrido[2,3-d]pyrimidin-6-yl)-2-f]uoropheny])--3-(l-(3-fluorophenyl)-3-isopropyl-lH-pyrazol-5-yl)urea, which was converted to the mesylate
salt (70 mg, 63 % yield). lH NMR (400 MHz, DMSO-d6): 59.06 (brs, IH), 8.96 (s, IH), 8.78 (s,
IH), 8.39 (d, J = 9Hz, IH), 7.92 (s, IH), 7.59 (m, IH), 7.42 (m, 2H), 7.29 (m, 2H), 6.39 (s, IH), 4.31 (q, J = 7 Hz, 2H), 2.90 (m, IH), 2.37 (s, 6H), 1.24 (m, 9H); MS (ESI, m/z: 545.3, M+H*).
Example 53: To a stirring solution of Example A45 (0.460 g, 1.5 mmol, 1.0 eq) and (Boc)20 (0.70 g, 3.2 mmol, 2.200 eq) in THF (15 ml) at 22 °C was added DMAP (0.040 g, 0.30 mmol, 0.20 eq). The mixture was heated at reflux for lh. The completed reaction was cooled to RT, concentrated to a residue and purified by flash column chromatography (0-35% EtOAc in hexanes) to afford bis-tert-butyl 3-(8-ethyl-2-(memylmio)-7-oxo-7,8-diftydropyrido[2;3-d]pyrimidin-6-yl)phenylcarbamate (0.54 g, 70% yield) as an oil that solidified under high vacuum. lH NMR (400 MHz, acetone-^): 5 8.89 (s, IH), 8.11 (s, IH), 7.74 (ddd, J = 1.2, 1.6, and 8.0 Hz, IH), 7.68 (t, J = 2.4 Hz, 1H)? 7.48 (t, J = 7.6 Hz, IH), 7.26 (ddd, J = 1.2,2.0 and 8.0 Hz, IH), 4.54 (q, J = 6.8 Hz, 2H), 2.67 (s, 3H), 1.4S (s, 18H), 1.35 (t, J = 6.8 Hz, 3H); MS (ESI) m/z: 513.3 (M+H4"), 535,2 (M+Na+).
Using a procedure analogous to Example Al, bis-tert-butyl 3-(8-ethyl-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenylcarbamate (0.540 g, 1.1 mmol) in CH2CI9 (11 ml), MCPBA (70.00 wt%, 0.31 g, 1.3 mmol) and 0.5M NH3 in 1,4-dioxane (11 ml, 5.3 mmol) were combined to afford desired product (0.50 g, 99% yield) as a brittle foam which was used as is in die next reaction. 'H NMR (400 MHz, acetone-^): 8 8.66 (s, IH), 7.94 (s, 1H); 7.70 (m; 1H): 7.65 (m, IH), 7.44 (m, IH), 7.19 (m, IH), 6.65 (brs, 2H), 4.42 (q, J = 6.S Hz), 1.47 (s, I8H), 1.27 (t, J = 6.8 Hz, 3H); MS (ESI) m/z: 482.2(M+fT).
To a stirring solution of bis-t-butyl 3-(2-ammo-8~ethyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenylcarbamate (0.500 g, 1.04 mmol, 1.00 eq) in MeOH (5.00 ml) at 22 °C was added 3M HCI (5.00 ml, 15.0 mmol, 14.4 eq). After 3 d, the completed reaction was concentrated to remove the MeOH and excess HCI. The aqueous residue was diluted with MeCN/H20, frozen and lyophilized to afford 2-amino-6-(3-ammophenyl)-8-etiiylpyrido[2,3-d]pyrimidin-7(8H)-one hydrochloride (0.330 g, 100% yield) which was used as is in the next

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reaction. !H NMR (400 MHz, DMSO-): 6 8.79 (s, 1H), 8.02 (s, IH), 7.52 (t, J = 2.0 Hz, IH), 7.64 (dt, J = 1.2 and 8,0 Hz, IH), 7.56 (t, J = 7.6 Hz, IH), 7.39 (ddd, J = 1.2, 2.0, and 8.0 Hz, IH), 4.33 (q, J = 7.2 Hz, 2H), 1.23 (t, J = 7.2 Hz, 3H); MS (ESI) m/z: 282.3 (M+H+).
Using general method C, the TROC carbamate of Example B26 (0.304 g, 0.711 mmol) and 2-amino-6-(3-ammophenyl)-8-ethylpyrido[2,3-d]pyrimidm-7(8H)-one hydrochloride (0.226 g, 0.711 mmol) were combined to afford impure product (0.300 g) as a yellowish solid. This was triturated with CHjCh at 0 °C. The solids were collected by filtration, rinsed with ice-cold CH2CI2 and dried on the filter to afford desired product (0.1584, 40% yield) as an off-white solid. The solid was treated with MsOH to afford l-(3-(2-ammo-8-ethyl-7-oxo-7,8-dihyaVopyrido[2,3-d]pyrimidin-6-yl)phenyI)-3-(3-isopropyI-l-(quinolm-6-yl)-lH-pyrazoI-5-yl)urea (0.1793 g) as the bis-mesylate salt. lH NMR (400 MHz, DMSO-^): 5 9.19 (s, IH), 9.15 (dd, J - 1.2 and 4.40 Hz, IH), 8.87 (d, J - 8.8 Hz, IH), 8.73-8.71 (m, 2H), 8.38 (d, J = 2.0 Hz, IH), 8.27 (d, J = 8.8 Hz, IH), 8.19 (dd; J = 2.0 and 8.8 Hz, IH), 7.91 (s, IH), 7.88 (dd, J = 4.4 and 8.4 Hz, IH), 7.74 (dd, J = 2.0 and 4.0 Hz, IH), 7.41 (m, IH), 7.31 (t, J = S.O Hz, IH), 7.22 (m, IH), 6.44 (s, IH), 4.31 (q, J = 6.8 Hz, 2H), 2.96 (septet, J = 6.8 Hz, IH), 2.36 (s, 6H), 1.28 (d, J = 6.8 Hz, 6H), 1.21 (t, J = 6.8 Hz, 3H); MS (ESI) m/z: 560.2 (M+H+).
Example 54: Using General Method A, Example A22 (197 mg, 0.697 mmol) and the 2,2,2-trichloroethyl carbamate of Example B18 (200 mg, 0.634 mmol) were combined to afford l-(3-terl-butylisoxazol-5-yl)-3-(5-(l -ethyl-2-oxo-l ,2-dihydro-l ,6-naphthyridin-3-yl)-2-fluorophenyl)urea (98 mg, 34% yield) as the hydrochloride salt. *H NMR (300 MHz, DMSO-d6) 5 1.25 (s, 9 H), 1.26-1.30 (d, 3 H), 4.39 (q, 2 H), 6.06 (s, 1 H), 7.40-7.43 (m, 2 H), 7.98-8.00 (m, I H), 8.34 (s, 1 H), 8,49-8.51 (m, 1 H), 8.78-8.80 (m, 1 H), 9.07 (s, 1 H), 9.28 (s, 1 H), 10.6 (s, 1 H); MS (ESI) m/z: 450.2 (M+H*).
Example 55: Using general method A, the TROC carbamate of Eample B18 (0.083 g, 0.26 mmol) and Example A52 (0.082 g, 0.26 mmol) were combined to afford l-(5-(2-amino-8-isopropyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-2-fluoropbeny])-3-(3-tert-butylisoxazol~5-yl)urca as an off-white solid (0.051 mg, 40% yield). 'H NMR (400 MHz, DMSO-rf6): 8 10.37 (s, IH), 8.75 (s, IH), 8.64 (s, IH), 8.34 (dd,7= 7.6 Hz, 1.6 Hz, 1H),7.82 (s,

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IH), 7.35-7.27 (m, 4H), 6.09 (s, IH), 5.82-5.76 (m, IH), 1.55 (d, J~ 7.2 Hz, 6H), 1.25 (s, 9H); MS (ESJ) m/z: 480.2 (M+H+).
Example 56: Using general method B, prop-l-en-2-y[ 3-tert-buty[phenyIcarbamate (0.18 g, 0.75 mmol) and Example A12 (0.090g, 0.30 mmol) were combined to afford l-(3-tert-butylphenyl)-3-(2-fluoro-5-(8-methyI-2-(methylarnino)-7-oxo-7.8-dihydropyrido[2,3-d]pyriTnidin-6-yl)phenyl)urea (0.057 g, 40% yield) as a yellow solid. ]H NMR (400 MHz, DMSO-d6): 8 9.07 (s, IH), 8.68 (s, IH), 8.52 (s, IH), 8.42 (dd, J = 7.6,2.4 Hz, IH), 7.90 (s, IH), 7.83 (s, IH), 7.45 (s, IH), 7.32-7.19 (m, 4H), 7.03 (d, J= 4.4 Hz, IH), 3.67(m, 3H), 3.32 Example 57: To a stirring solution of l-(3-t-butylisoxazol-5-yl)-3-(2-fluoro-5-(8-methyl-2-(methylsulfinyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea from Example 43 (0.125 g, 0.251 mmol, 1.00 eq) in DMF (2,50 ml) at 0 °C was added unsym-dhnethyl ethyl en edi amine (0.138 ml, 1,25 mmol, 5.00 eq). After 1 h, die completed reaction was diluted with brine (5 ml) and left to stir overnight. The solids were collected by filtration, rinsed well with H2O and dried on the filter to afford crude desired product (76 mg) as a pale pink solid. The crude product was purified by reverse phase chromatography (5-40% MeCN (w/ 0.1% TFA)/ H20 (w/ 0.1% TFA)) to afford l-(3-t-butylisoxazol-5-yl)-3-(5~(2-(2-(dimethylamino)etliylamino)-8-methyl-7-oxo-7,8-dihydropyrido [2,3-d] pyrimidin-6-yl)-2-fluorophenyl)urea (37.3 mg, 0.059 mmol) as the TFA salt following lyophilization. The TFA salt thus obtained was treated with MP-Cafbonate resin and certified 0.1N HCI (1.0 eq), frozen and lyophilized to afford the HCI salt. 'H NMR (400 MHz, DMSO-d6): 8 10.44 (s, IH), 9.56 (brs, IH), 8.85 (brs, IH), 8.76 (brs, IH), 8.41 (dd, J = 2.0 and 7.6 Hz, IH), 8.01 (brs, IH), 7.95 (s, IH), 7.37-7.28 (m, 2H), 6.05 (s, IH), 3.73 (m, 2H), 3.58 (brs, 3H), 3.41 (brs, 2H), 2.85 (brs, 6H), 1.24 (s, 9H); MS (ESI) m/z: 523.2 (M+H4-).
Example 58: Using General Method A, Example A24 (400 mg, 1.28 mmol) and die TROC carbamate of Example BI8 (421 mg, 1.28 mmol) were combined to afford l-(3-tert-butylisoxazol-5-yl)-3-(5-(l-ethyl-7-(methylamino)-2-oxo-l,2-dihydTo-l,6-naphthyridin-3-y!)-2-fluorophenyl)urea (242 mg) as a foam. The foam was treated with methanesulfonic acid (47 mg,

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0.492 mmol) and isolated as the methanesulfonic acid salt (248 mg, 87% yield). fH NMR (300 MHz, DMSO-d6): 5 1.20-1.28 (m, 3 H), 1.22 (ss 9 H), 2.28 (s, 3 H), 2.94 (s, 3 H), 4.15-4.18 (q, 2 H), 6.04 (s, 1 H), 6.51 (s, 1 H), 7.31-7.33 (m, 2 H), 7.98 (s, 1 H), 8.37-8.39 (m, 1 H), 8.55 (s, 1 H), 8.77 (s, 1 H), 10.3 (s, 1 H), acid proton missing; MS (ESI) m/z: 479.2 (M+H4).
Example 59: Using general method A, Example A14 (54 mg, 0.18 mmol) and the TROC carbamate of Example B18 (57mg, 0.18 mmol) were combined to provide l-(5-(2-amino-8-methyl-7-oxo-7,8-dihydropyrido[2.3-d]pyrimidm-6-yl)-2-fluoro-4-methylphenyl)-3-(3-tert-bittylisoxazol-5-yl)urea (45 mg, 54% yield). 'H NMR (400 MHz, DMSO-6): 5 10.30 (s, 1 H), 8.68 (s, 1 H), 8.63 (s, 1 H), 7.90 (d, J = 8.6 Hz, 1 H), 7.69 (s, 1 H), 7.32 (s, 2 H), 7.19 (d, J = 12.2 Hz, 1 H), 6.03 (s, 1 H), 3.56 (s, 3 H), 2.10 (s, 3 H), 1.24 (s, 9 H); MS (ESI) m/z: 466.2 (M+H*).
Example 60: Using general method A. Example Al (54 mg, 0.18 mmol) and the TROC carbamate of Example B18 (57 mg, 0.18 mmol) were combined to provide l-(5-(2-amino-8-methyl-7-oxo-7,8-dihydropyrido[2.3-d]pyrimidin-6-yl)-2-fliiorophenyl)-3-(3-tert-butylisoxazol-5-yl)urea. !H NMR (400 MHz, DMSO-J6): 6 10.37 (s, 1 H), 8.77 (d, J = 2.0 Hz, 1 H), 8.68 (s, 1 H), 8.42 (dd, J = 8.0, 2.0 Hz, 1 H), 7.90 (s, 1 H), 7.38-7.28 (m, 4 H), 6.09 (s, 1 H), 3.58 (s, 3 H), 1.27 (s, 9 H); MS (ESI) m/z: 452.2 (M+H+).
Example 61: Using a procedure analogous to Example Al, Example A3 (1.00 g, 3.16 mmol) and unsym-dimethylethylenediamine (1.74 ml, 15.8 mmol) were combined to afford 6-(3-amino-4-fluorophenyl)-2-(2-(dimeUiyIamino)ethylamino)-8Mnemylpyrido[2,3-d]pyrimidin-7(8H)-one (0.8640 g, 77% yield) as a tan solid which was used as is in the next reaction. JH NMR (400 MHz, DMSO-40: 8 8.62 (s, IH), 7.80 (s, IH), 7.71 (brt, IH), 7.10 (dd, J = 2.0 and 9.2 Hz, IH), 7.00 (dd, J = 8.4 and 11.2 Hz, IH), 6.76 (ddd, J = 2.0, 4.40, and S.40 Hz, IH), 5.14 (brs, 2H), 3.58 (brs, 3H), 3.47 (q, J = 6.4 Hz, 2H), 2.47 (brrn, 2H), 2.20 (s, 6H); MS (ESI) m/z: 357.2 (M+H+).
Using general method F, 6-(3-amino-4-fluorophenyl)-2-(2-(dimethylamino)ethy!amino)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one (0.1000 g, 0.281 mmol, 1.00 eq) and a,a,a-trifluoro-m-tolyl isocyanate (0.0589 ml, 0.421 mmol, 1.50 eq) were combined to afford crude product. The crude residue was purified by reverse phase chromatography and isolated as the HCl salt of

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l-(5-(2-(2-(dimethylamino)ethylamino)-8-methyi-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-2-fluorophenyl)"3-(3-(trifluoromethyl)phenyl)urea (63 mg). 'H NMR (400 MHz, DMSO-40: 5 9.62 (brs, 1H), 9.59 (s, 1H), 8.78 (brs, 1H), 8.75 (s, 1H), 8.40 (m, 1H), 8.05 (s, 1H), 7.99 (brs, 1H), 7.95 (s, 1H), 7.51-7.49 (m, 2H), 7.33-7.25 (m, 3H), 3.75-3.70 (m, 2H), 3.62 (brs, 3H), 3.32 (brs, 2H), 2.83 (brs, 6H), MS (ESI) m/z: 544.2 (M+H+).
Example 62: Using general procedure A, Example B3 (0.3000 g, 1.1 mmol, 1.0 eq) and 6-(3-ammo-4-fluorophenyl)-2-(2-(dimethylamiiio)emylmimio)-8~memylpyrido[2,3-d]pyrimidin-7(8H)-one from Example 61 (0.0796 g, 0.223 mmol, 1.00 eq) were combined to to give the target crude product. The crude product was purified by reverse phase cliromatography to afford die TFA salt (34.2 mg) following lyophilization. The TFA salt thus obtained was converted to the HC1 of desired product, l-(l-(3-(2-amino-2-oxoethyl)phenyl)-3-t-butyl-lH-pyrazol-5-yl)-3-(5-(2-(2-(dimethylamino)ethylammo)-8-methyl-7-oxo-7.8-dihydropyrido[2,3-d]pyrimidin-6-yi)-2-fluorophenyl)urea (30 mg). ]H NMR (400 MHz, DMSO-d6): 5 9.87 (brs, 1H), 9.05 (s, 1H), 8.97 (s, 1H), 8.77 (brs, 1H), 8.45 (m, 1H), 8.05 (brs, 1H), 7.95 (s, 1H), 7.55 (brs, 1H), 7.50-7.44 (m, 2H)S 7.39-7.25 (m, 4H), 6.94 (brs, 1H), 6.40 (s, 1H), 3.76 (brm, 2H), 3.66 (brs, 3H): 3.48 (s, 2H), 3.34 (brm, 2H), 2.85 (brs, 6H), 1.28 (s, 9H); MS (ESI) m/z: 655.2 (M+H+).
Example 63: Using general method C, Example B27 (400 mg, 1.7 mmol) was converted to the bis (2,2,2-trichloroethyl) carbamate of l-(6-methylpyridin-3-yl)-3-(trifluoromethyl)-lH-pyrazol-5-amine (435 mg, 43% yield). MS (ESI) m/z: 592.7/594.8 (M+H+).
A solution of the bis (2,2,2-trichloroethyl) carbamate of l-(6-methylpyridin-3-yl)-3-(trifluoromerliyI)-lH-pyrazol-5-amine (433 mg, 0.7 mmol) and trichloroethanol (1 mL, 10 mmol) in acetonitrile (5 mL) was treated with K2CO3 (9 mg, 0.07 mmol ). The resultant reaction mixture was stirred at RT for 7 h. The reaction mixture was diluted with ethyl acetate (30 mL), washed with water and brine, dried (MgSCU) and concentrated in vacuo. Chromatography provided 2,2,2-trichloroethyl l-(6-methylpyridin-3-yl)-3-(trifluoromethyl)-1H-pyrazol-5-ylcarbamate (270 mg, 89 % yield) as a white foam. 'H NMR (400 MHz, DMSO-d6): 6 10.56 (br s, 1 H), S.61 (d, J = 2.5 Hz, 1 H), 7.87 (dd, J = 8.3, 2.8 Hz, 1 H), 7.47 (d, J = 8.3 Hz, 1 H), 6.95 (s, 1 H), 4.89 (s, 2 H), 2.56 (s, 3 H); MS (ESI) m/z: 417.0/419.0 (M+H+).

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Using general method A, Example AI (69 mg, 0.24 mmol) and 2,2,2-trichloroethyl l-(6-methylpyridin-3-yl)-3'(trifluoromethyl)-lH-pyrazol-5- ylcarbamate (98 mg, 0.23 mmol) were combined to provide impure desired product. The residue was chromatographed and triturated with boiling CHjCfe to provide l-(5^2-amino-8-met1iyl-7-oxo-7$-d!hydropyrido[2> d]pyrimidin-6-yl)-2-fltiorophenyI)-3-(l-(6~methyIpyridin-3-yl)-3^trifluorome 5-yl)urea (35 mg, 27% yield). !B NMR (400 MHz, DMSO-A): 5 9.21 (br s, 1 H), 9.02 (m, 1 H), 8.70 (d, J = 2.4 Hz, 1 H), 8.65 (s, 1 H), 8.37 (dd, J = 8.0, 1-2 Hz, 1 H), 7.96 (dd, J = 8.0,2.6 Hz, 1 H), 7.84 (s, 1 H), 7.51 (d, J = 8.0 Hz, 1 H), 7.31-7.22 (m, 4 H), 6.89 (s, 1 H), 3.55 (s, 3 H), 2.58 (s, 3 H); MS (ESI) m/z: 554.0 (M+H+).
Example 64: Using general method A, l-(5-(2-(2-(dimethyIamino)ethylamino)-S-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-2-fluorophenyl)-3-(3-i5opropylisoxazol-5-yl)urea hydrochloride (210 mg, 45% yield) was prepared from the Troc carbamate of Example B20 (0.300 g, 0.995 mmol, 1.00 eq) and 6-(3-amino-4-fluorophenyl)-2-(2-(dimethylamino)ethylamino)-8-memylpyrido[2,3-d3pyrimidin-7(8H)-one from Example 61
(0.355 g, 0.995 mmol, 1.00 eq). !H NMR (400 MHz, DMSO-): 5 10.40 (s, 1H), 9.43 (brs, 1H), 8.82 (d, J = 2.4 Hz, 1H), 8.75 (brs, 1H), 8.39 (dd, J = 2.0 and 7.6 Hz, 1H), 7.99 (brs, 1H), 7.95 (s, 1H), 7.37-7.28 (m, 2H), 6.01 (s, 1H), 3.73 (brm, 2H), 3.63 (brs, 3H), 3.32 (brm, 2H), 2.89 (septet, J = 6.8 Hz, 1H), 2.85 (brs, 6H), 1.18 (d, J = 6.8 Hz, 6H); MS (ESI) m/z: 509.2 (M+H+).
Example 65: Using a modified general method B, the carbamate of Example BI9 (0.3 g, 1.36 mmol) and Example A3 (0.43 g, 1.36 mmol) in presence of l-methyl pyrrolidine (catalytic amount) were heated at 120 °C for 1.5h under microwave irradiation to afford 1 -(1 -tert-butyl-1 H-pyrazol^-yl)-3-(2-fluoro-5-(8-methyl-2-(memylthio)~7-oxo-7,8'dihydropyrido[2,3-d]pyriimdin-6-yl)phenyl)urea (0.3 g, 47% yield). 'H NMR (400 MHz, DM.SO-d6): S 8.95 .(s, 1H), 8.72 (brs, 1H), 8.54 (d,y= 2.0 Hz, 1H), 8.48-S.46 (m, 1H), 8.05 (s, 1H), 7.81 (s, Iti), 7.39 (s, 1H), 7.29-7.26 (m, 2H), 3.66 (s, 3H), 2.60 (s, 3H), 1.47 (s, 9H); (ESI) m/z: 482.2 (M+H*).
Using a procedure analogous to Example Al, K(l-tert-butyl-lH-pyrazoI-4-yl)-3-(2-fluoro-5-(8-memyl-2-(methylmioH-oxo-7,8-dmydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (0.3 g, 0.63 mmol) and methyl amine (1.3 ml of 1M solution, 1.3 mmol) were combined to afford ]-(]-tert-butyl-lH-pyrazo]-4-yl)-3-(2-fluoro-5-(8-methyl-2"(methylamino)-7-oxo-7,8-

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dmydropyrido[2,3-d]pyriniidin-6-yl)phenyl}urea as a white solid (0.135 g3 66% yield). *H NMR (400 MHz, DM3CM;): 5 S.73-8.70 (m, IH), 8.65 (s, IH), 8.48 (d, ./=* 2.0 Hz, IH), 8.4I-S.39 (m, IH), 7.85 (s, IH), 7.81 (bis, 2H), 7.38 (s, IH), 7.24-7.22 (m, 2H), 3.61-3.57 (m, 3H), 2.90 (d, J-= 4.0 Hz, IH), 2.60 (s, 3H), 1.46 (s, 9H); (ESI) m/z: 465.2 (M+H*).
Example 66: Using general method B, the carbamate of B2 (0.045 g, 0.19 mmol) and Example A14 (0.057 g, 0.19 mmol) were combined to afford l-(5-(2-amino-8-methyl-7-oxO"7,8-dihydropyrido[2J3-d]pyrimidin-6-yI)-2-fluoro-4-methylphenyl)-3-(3-tert~butyl-l-methyl-lH-pyrazol-5-yl)urea (0.076 g, 84% yield). ]H NMR (400 MHz, DMSO-c/6): 5 8.85 (s, IH), 8.71 (m, IH), 8.60 (s, IH), 7.92 (d, 7 = 8.8 Hz, IH), 7.65 (s, IH), 7.28 (s, 2H), 7.14 (d, J= 12.4Hz, IH), 6.04 (s, IH), 3.58 (s, 3H), 3.54 (s, 3H), 2.05 (s, 3H), 1.16 (s, 9H); MS (ESI) m/z: 479.2 (M+H*).
Example 67: Using general method F, Example A3 (500 mg, 1.58 mmol) and l-isocyanato-3-(trifluoromethyl)benzene (311 mg, 1.66 mmol) were combined in the presence of pyridine (500 mg, 6.32 mmol) to afford I-(2-fluoro-5-(8-methyI-2-(memyltlu*o)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyi)-3-(3-(trifluoromethyl)phenyl)urea (440 mg, 55% yield). 'H NMR (300 MHz, DMSO-t/fj): 5 2.60 (s, 3 H), 3.65 (s, 3 H), 7.29-7.34 (in, 3 H), 7.50-7.51 (m, 2 H), 8.04-8.08 (m, 2 H), 8.43-8.46 (m, 1 H), 8.69 (s, 1 H), 8.95 (s, 1 H), 9.42 (s, 1 H); MS (ESI) m/z: 504.0 (M+H+).
Using a procedure analogous to Example Al, l-(2-fIuoro-5-(8-metIiyI-2-(metIiyIthio)-7-oxo-7,8-dihydropyrido[2,3-d3pyrimidin-6-yl)phenyI)-3-(3-(trifluorometliyl)phenyl)urea (436 mg, 0.866 mmol) and 2.00N methylamine in THF (1.93 mL, 3.85 mmol) were combined to provide l-(2-fluoro-5-(8-med]yl-2-(mediylamino)-7-oxo-7.8-dihydropyrido[2,3-d]pyrirnidin"6-yl)phenyI)-3-(3-(trifluoromethyl)phenyl)urea (141 mg, 75% yield). *H NMR (300 MHz, DMSO-d6): 5 2.89 (s, 3 H), 3.53-3.61 (m, 3 H), 7.24-7.31 (m; 3 H), 7.49-7.51 (m, 2 H), 7.65-7.75 (br. m, 1 H), 7.79 (m, 1 H), 8.03 (s, 1 H), 8.37-8.39 (m, 1 H), 8.65-8.73 (m, 2 H), 9.40 (s, 1 H); MS (ESI) m/z: 487.0 (M+H+).
Example 68: Using general method C, 2,2)2-trichloroethyl-(2-phenyI)phenylcarbamate (0.10 g, 0.29 mmol) and Example A38 (87 mg, 0.29 mmol) were combined to afford l-(2-fluoro-5-(l-methyI-7-(methylamino)-2-oxo-l,2"dihydro-l,6-naphthyridin-3-yl)phenyI)-3-(2-

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phenyl)phenylurea The product was treated with MsOH to obtain l-(2-fluoro-5-(l-methyl-7-(methyIamino)-2-oxo-l,2-dihydro-lJ6-naphthyridin-3-yl)phenyI)-3-(2-phenyl)phenyIurea mesylate salt (33 mg, 19% yield). 'H NMR (400 MHz, DMSO-rf6): □ S.90 (m, IH), 8.48 (s, IH), 8.41 (m, IH), 8.18 (s, IH), 7.89 (s, IH), 7.84 (m, IH), 7.1-7.5 (m, 11H), 6.29 (brs, IH), 2.S9 (brs, 3H), 2.27 (s, 3H), 2.05 (s, 3H); MS (ESI) m/z: 494.3 (M+jT).
Example 69: Using general method B, the carbamate of Example Bl (0.081 g, 0.27 mmol) and Example A38 (0.081 g, 0.27 mmol) were combined to afford l-(3-tert~butyl-l-phenyl- 1H-pyrazoi-5-yl)-3-(2-fluoro-5-(l -methyl-7-(methylamino)-2-oxo-1,2-dihydro-1 ,6-naphthyridin-3-yl)phenyl)urea as the methane sulfonic acid salt (0.105 g, 72% yield). !H NMR (400 MHz, DMSOd6): 5 9.00 (s, IH), 8.87 (s, IH), 8.52 (s, IH), 8.40 (d, J= 8.8 Hz, IH), 7.93 (s, IH), 7.55-7.48 £m, 4H), 7.43-7.39 (m, IH), 7.27-7.25 (m, 2H), 6.40 (brs, IH), 6.38 (s, IH), 3.53 (s, 3H); 2.98 (s, 3H), 2.27 (s, 3H), 1.25 (s, 9H); MS (ESI) m/z: 540.3 (M+Hl.
Example 70: Using general method B, the carbamate of 3-isopropyl-l-phenyl-lH-pyrazoI-5-amine (0.081 g, 0.28 mmol), and Example A38 (0.085 g, 0.28 mmol) were combined to afford 1 -(2-fiuoro-5-(l -methyl-7-(methylamino)-2 -oxo-1,2-dihydro-1 ,6-naphthyridin-3-yI)phenyl)-3-(3-isopropyl-I-phenyl-lH-pyrazoI-5-yl)urea as methane sulfonic acid salt (0.095 g, 64% yield). 'H NMR (400 MHz, DMSO-rf6): 5 9.00 (s, 1H), 8.89 (s, IH), 8.53 (s, IH), 8.40 (d, J= 8.8 Hz, IH), 7.93 (s, IH), 7.55-7.49 (m, 4H), 7.43-7.40 (m, IH), 7.27-7.25 (m, 2H), 6.40 (brs,.lH), 6.34 (s, IH), 3.54 (s, 3H), 2.93 (s, 3H), 2.90-2.83 (m, IH), 2.28 (s, 3K), 1.20 (d, J = 6.8 Hz, 6H); MS (ESI) m/z: 526.2 (M+H*>
Example 71: Using general method B, prop-l-en-2-yl 3-tert-butyIphenylcarbamate (0.18 g, 0.75 mmol) and Example A38 (0.090g, 0.30 mmol) were combined to afford l-(3-tert-butylphenyl)-3-(2-fluoro-5-(l-methyl-7-(methylamino)-2-oxo-l)2-diliydro-l16-naphthyridin-3-yl)phenyl)urea (0.103 g, 72% yield) as a light yellow solid. 'H NMR (400 MHz, DMSO-dfl): 5 9.05 (s, IH), 8.50 (d, J = 2.0 Hz, IH), 8.45 (s, IH), 8.40 (dd, J = 6.8, 2.0 Hz, IH), 7,86 (s, IH), 7.44 (t, J = 2.0 Hz, IH), 7.28-7.24 (m, 3H), 7.20 (t, J = 8.0 Hz, IH), 7.03-7.00 (m, 2H), 6.16 (s, IH), 3.53 (s, 3H), 2.86 (d,7= 5.2 Hz, 3H), 1.26 (s, 9H); MS (ESI) m/z: 474.2 (M+H4).

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Example 72: Using general method A, the TROC carbonate of Example B20 (0.250g, 0.83mmol) and Example A12 (0.248g, 0.83 mmol) were combined to provide l-(2-fluoro-5-(8-memyl-2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrirriidin-6-yl)phenyl)-3-(3-
isopropyhsoxazol-5-yI)urea (ISO mg, 48% yield). ]H NMR t400 MHz> DMSO-d6): 510.33 (s, IH), 8.75 (brs, IH), 8.64 (brs, IH), 8.38 (brd, J = 8Hz, IH), 7-90 (s; IH), 7.80 (brs, IH), 7.36-7.25 (m, 2H), 6.04 (s, IH), 3.6I (brs, 3H), 2,89 (brs, 3H), 1.23 (s, 6H); MS (ESI, m/z: 452.2, M+H*).
Example 73: Using general method A, the TROC carbamate of Example Bl 8 (0.170 g, 0,54 mmol) and Example A38 (0.160 g, 0.54 mmol) were combined to provide l-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-5-(l-methyl-7-(methylamino)4-oxo-l12"dihydro-l,6-
naphthyridin-3-yl)phenyl)urea (81 mg, 32% yield). *H NMR (400 MHz, DMSO-d6): 510.32 (s, IH), 8.72 (brs, IH), 8.43 (s, IH), 8.38 (dd, J = 8.0,2.0 Hz, IH), 7.85 (s, IH), 7.35-7.23 (m, 2H), 7.03 (m, IH), 6.15 (brs, IH), 6.06 (s, IH), 3.51 (s, 3H), 2.85 (d, J = 5 Hz, 3H), 1.22 (s, 9H); MS(ESI, m/z: 465.2, M+H4).
Example 74: Using general method B, the carbamate of 3-isopropyl-l-phenyl-lH-pyrazol-5-amine (0.1 OOg, 0.35 mmol) and Example A4 (0.1 lOg, 0.35 rnriioi) were combined to provide 1-(5K8-ethyI-2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin~6-yl)-2-fluorophenyl)-3-
(3-isopropyl-l-phenyl-lH-pyrazol-5-yl)urea (130 mg, 68 % yield). ]H NMR(400 MHz, DMSO-d6): 5 8.95 (s, IH), 8.86 (s, IH), 8.66 (brs, IH), 8.38 (brd, J = 8-0 Hz, IH), 7.83 (brs, IH), 7.78
(brs, IH), 7.50 (m, 4H), 7.40 (m, IH), 7.30-7.20 (m, 2H), 6.34 (brs, IH), 4.40 (brs, 2H), 2.85 (m, 4H), 1.22 (m, 9H); MS (ESI, m/z: 541.3, M+H+).
Example 75: Using general method F, l-isocyanato-3-(trifluofomethyl)benzene (0.125 g, 0.668 mmol) and Example A2 (0.2 g, 0.668 mmol) were combined in ethyl acetate to provide l-(5-(2-amino-8-emy]-7-oxo~7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-2-fluorophenyI)-3-(3-
(trifluoromethyl)phenyl)urea (188 mg, 58% yield) *H NMR (400 MHz, DMSO-d6: 8 9.46 (s,

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IH), 8.72 (s, IH), 8.70 (brd, J = 8Hz, IH), 8.42 (dd, J = 8.0, 2.0 Hz , IH), 8.08 (s, IH), 7.57 (m, 2H), 7.35 (m, 5H), 4.37 (q, J = 6 Hz, 2H), 1.25 (t, J = 6 Hz, 3H); MS (ESI, m/z: 487.2, M+H4).
Example 76: Using general method B, prop-l-en-2-yl 3-tert-butylphenylcarbamate (0.100g. 0.43 mmol) and Example A4 (0.134g, 0.43 mmol) were combined to provide l-(3-tert-butylphenyI)-3-(5-(8-ethyl-2-(methylamino)-7-oxo-7,8-dihydropyrido[2)3-d]pyrimidin-6-yl)-2-
f]uorophenyl)urea (50 mg, 24% yield). !H NMR (400 MHz, DMSO-d6): 89.04 (s, IH), 8.65
(brs, IH), 8.50 (d, J = 2.4Hz, IH), 8.35 (brd, J = 8.0 Hz, IH), 7.86 (s, IH), 7.78 (brs, IH), 7.41 (m, IH), 7.30-7.20 (m, 3H), 7.07 (brd, J = 8Hz, IH), 4.37 (brs, 2H), 2.89 (d, J = 5Hz, 3H), 1.25 (s, 12H); MS (ESI, m/z: 489.2, M+H*).
Example 77: Using general method A, the TROC carbamate of Example B21 (O.lOOg, 0.25 mmol) and Example A4 (0.078g, 0.25 mmol) were combined to provide l-(5-(8-ethyl-2-(methylmnino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin~6-yl)-2-fluorophenyI)-3-(l-pheny!--3-
(trifluoromethyl)-IH-pyrazol-5-yl)urea (98 mg, 70% yield). lH NMR (400 MHz, DMSO-d6):
^9.16 (s, IH), 9.08 (s, IH), 8.68 (brs, IH), 8.35 (brd, J = 8.0 Hz, IH), 7.S3 (s, IH), 7.78 (brs, IH), 7.63-7.50 (m, 5H), 7.30-7.20 (m, 2H), 6.87 (brs, IH), 4.33 (brs, 2H), 3.54 (s, 3H), 2.88 (d, J - 5Hz, 3H); MS (ESI, m/z: 567.3, M+H*).
Example 78: Using general method D, Example B16 (0,050 g, 0.25 mmol) and Example A12 (0.099 g, 0.33 mmol) were combined to afford l-(3-tert-butyl-l-ethyMH-pyrazol-5-yl)-3-(2-f]uoro-5-(8-methyI-2-(memylamino)"7-oxo-7,8-diliydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (33 mg, 26% yield). !H NMR (400 MHz, DMSO-4, major rotomer): 5 8.83 (s, 1H), 8.79 (d, J = 2.0 Hz, IH), 8.64 (s, IH), 8.41 (dd, J= 2.0, and 8.4 Hz, IH), 7.86 (s, IH), 7.79 (m, IH), 7,27 (m, 2H), 6.08 (s, IH), 3.93 (q, /= 7.2 Hz, 2H), 3.61 (s, 3H), 2.89 (brd, J = 4.0 Hz, 3H), 1.26 (t, J = 7.2 Hz, 3H), 1.18 (s, 9H); MS (ESI) m/z: 493.2 (M+H+).
Example 79: Using General Method F, Example A3 (150 mg, 0.474 mmol) and l-chloro-4-isocyanato-2-(trifluoromethyl)benzene (110 mg, 0.498 mmol) were combined in the presence of pyridine (150 mg, 1.90 mmoJ) to provide l-(4-chloro-3-(trifluoromethyl)phenyl)-3-(2-fEuoro-5-

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2thyl-2-(methylthio)»7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (0.055 g, 22% yield). MS (ESI) m/z: 538.0 (M+H+).
Using a procedure analogous to Example Al, l-(4-chloro-3-(trifluoromethyl)phenyl)-3-(2 -fluoro-5-(8-methyI-2-(methyl thio)- 7-oxo-7,8-dihyaropyrido[2,3-d]pyrimidin-6-yI)phenyI) urea (55 mg, 0.100 mmol) and 2.00N methylamine in THF (4.00 mL, 8.0 mmol) were combined to provide H4-cliloro-3-(trifluoromethyl)phenyl)-3-(2-fluoro-5-(S-metliyl-2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (36 mg, 67% yield). [H NMR (300 MHz, DMSCM): 5 2.90 (s, 3 H), 3.53-3.6} (m, 3 H), 7.26-7.31 (m, 2 H), 7.58-7.59 (m, 2 H), 7.60-7.75 (br. m, 1 H), 7.88 (s, 1 H), 8.10 (s, 1 H), 8.33-8.35 (m, 1 H), 8.64-8.77 (m, 2 H), 9.49 (s, 1 H); MS (ESI) m/z: 521.0 (M+H4).
Example 80: Using the procedure in Example 57, l-(3-t-butylisoxazol-5-yl)-3-(2-fluoro-5-{8-
methyl-2-(methylsuIfinyl)-7-oxo-7,8-dihydropyrido[2)3-d]pyrimidin-6-yl)phenyl)urea from
Example 43 (0.150 g, 0.311 mmol, 1.00 eq) and L-alaninol (48.4 uL, 0.622 mmol, 2.00 eq) were combined to afford (S)-1 -(3-t-butylisoxazol-5-yl)-3-(2-fluoro-5-(2-( 1 -hydroxypropan-2-ylamino)-8-metliyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (72 mg, 46% yield) as an off-white solid. ]H NMR (400 MHz, DMSO-tf6): 6 10.34 (s, 1H), 8.73 (brs, 1H), 8.65 (brs, 1H), 8.39 (dd, J = 2.4 and 8.0 Hz, 1H), 7.87 (s, 1H), 7.60-7.57 (m, 1H), 7.35-7.25 (m, 2H), 6.06 (s, 1H), 4.70 (t, J = 6.0 Hz, 1H), 4.09 (brs, 1H), 3.58-3.49 (m, 4H), 3.35 (brs, 1H), 1.23 (s, 9H), 1.17-1.15 (m, 3H); MS (ESI) m/z: 510.2 (M+H4).
Example 81: Using general method B, the carbamate of Example B21 (0.071 g. 0.23 mmol) and Example A3 8 (0.068 g, 0.23 mmol) were combined to afford l-(2-fluoro-5-(l-methyl-7-(methylamino)-2-oxo-l,2-dihydro-l,6-naphthyi-idin-3-yl)phenyl)-3-(l-plienyl-3-(lrifluorometliyl)-lH-pyrazoI-5-yl)urea as the methane sulfonic acid salt (0.076 g, 60% yield). 'H NMR (400 MHz, DMSO-^)"- 6 9.18 (s, 1H), 9.11 (s, 1H), 8.50 (s, 1H), 8.38-8.36 (m, 1H), 7.92 (s, IH), 7.64-7.56 (m, 6H)T 7.29-7.26 (m, 2H), 6.88 (s, 1H), 6.35 (brs, IH), 3.53 (s, 3H), 2.91 (s, 3H)3 2.27 (s, 3H); (EST) m/z: 552.2 (M+H*).
Example 82: Using general method D, 3-tert-butyl-l-methyl-lH-pyrazole-5-carboxylic acid (0.051 g, 0.28 mmol) and Example A38 (0.1 g, 0.34 mmol) were combined to afford 1-(3-tert-

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butyl-1 -methyl-1 H-pyrazoI-5-yl)-3-(2-fluoro-5-(I ~methyl-7-(methylamino)-2-oxo-1,2-dihydro-l,6-naphthyridiii-3-yl)phenyl)urea as the methane sulfonic acid salt (0.089 g, 67% yield). ]H NMR (400 MHz, DUSO-d6): 5 8.94 (s, IH), 8.85 (d, J= 2.4 Hz, IH), 8.53 (s, IH), 8.41 (dd, J = 8.0 Hz, 2.0 Hz, IH), 7.95 (s, IH), 7.30-7.27 (m, 2H), 6.42 (brs, IH), 6.08 (s, IH), 3.60 (s, 3H), 3.54 (s, 3H), 2.93 (s, 3H), 2.28 (s, 3H), 1.18 (s, 9H); (ESI) m/z: 478.3 (M+H4).
Example 83: Using general method C, the carbamate of Example B20 (2.70 g, 21.4 mmol, 1.00 eq) and Example A3 (0.525 g, 1.66 mmol, 1.00 eq) were combined to afford l-(2-fluoro-5-(8-memyl-2-(metJiyltruo)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)-3-(3-isopropylisoxazol-5-yI)urea (0.344 g, 44% yield) as a pale yellow foam. 'H NMR (400 MHz, DMSO-rffi): 8 10.35 (s, IH), 8.93 (s, IH), 8.79 (d, J = 2.0 Hz, IH), 8.44 (dd, J = 2.00 and 8.0 Hz, IH), 8.07 (s, IH), 7.40-7.31 (m, 2H), 6.02 (s, IH), 3.66 (s, 3H), 2.89 (septet, J - 6.8 Hz, IH), 2.60 (s, 3H), 1.18 (d, J = 6.8 Hz, 6H); MS (ESI) m/z: 469.0 (M+H*).
Using a procedure analogous to Example Al, l-(2-fluoro-5-(8-methyl-2-(methylthio)-7- '
oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)"3-(3-isopropylisoxazol-5-yl)urea (0.150 g,
0.322 mmol, 1.00 eq) was oxidized and reacted with L-alaninol (41,4 pL, 0.533 mmol, 2.00 eq)
to afford (S)-l -(2-fluoro-5-(2-(l -hydroxypropan-2-ylamino)-8-methyl-7-oxo-7,8-
dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)-3-(3-isopropylisoxazol-5-yl)urea (67 mg, 51% yield) as an off-white solid. ]H NMR (400 MHz, DMSO-4,}: 5 10.34 (s, IH), 8.73 (brs, IH), 8.65 (brs, IH), 8.39 (dd, J = 2.4 and 8.0 Hz, IH), 7.87 (s, IH), 7.60-7.57 (m, IH), 7.35-7.25 (m, 2H), 6.06 (s, IH), 4.70 (t, J = 6.0 Hz, IH), 4.09 (bra, IH), 3.58-3.49 (m, 4H), 3.35 (brs, IH), 2.89 (m, IH), 1.23 (s, 9H), 1.17-1.15 (m, 9H); MS (ESI) m/z: 496.3 (M+H+).
Example 84: Pivalonitrile (2.75 g, 33.1 mmol), water (20 mL), dioxane (20 mL), sodium hydrogensulfide hydrate (14.7 g, 198 mmol) and diethyl amine hydrochloride (21.8 g, 198 mmol) were combined and mixture was stirred at 55 °C for 48h. Water (150 mL) and EtOAc (60 mL) were added, the organic layer was separated and the aqueous layer was extracted with EtOAC (1x60 mL). The combined organics were washed with brine, dried (Na2S04) and concentrated in vacuo to afford 2,2-dimethylpropanethioarnide as off-white solid (3.00 g, 89% yield).

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Ethyl 3-bromo-2-oxopropanoate (1,95 g, 10 mmol) and 2,2-dimethylpropanethioamide (1.17 g, 10 mmol) were combined in ethanol (20 mL) and solution was stirred at RT for 48h. Solvent was removed and to the residue Sat. NaHC03 solution was added and product was extracted with EtOAc (2x30 mL). The combined organics were washed with brine, dried (Na2S04)h concentrated in vacuo and purification by silica gel chromatography afforded ethyl 2-tert-butylthiazole-5-carboxylate (1.16 g, 55%) as a colorless liquid (1.16 g, 55% yield). MS (ESI) m/z: 214.0 (M+H+).
To a solution of ethyl 2-tert-butylthiazoIe-5-carboxylate (1.16 g, 5.44 mmol) in THF (10 mL) was added lithium hydroxide (0.45 g, 10.9 mmol) in water (5 mL) and the mixture was stirred for 16h at RT. Solvents were removed under vacuum, and the thick liquid was diluted with water (5 mL) and acidified with 2M HC1 solution to pH 4 to 5. The product precipitated, was filtered, washed with water (2x5 mL) and dried to provide 2-tert~butylthiazole-5-carboxylic acid as white solid (0.55 g, 55% yield). 'H NMR (400 MHz, DMSO-rf6): 8 8.32 (s, 1H), 1.39 (s, 9H); MS (ESI) m/z: 186.0 (M+H*).
To a solution of 2-tert-butylthiazole-5-carboxylic acid (0.46 g, 2.52 mmoi) in dioxane (10 mL) was added with triethylamine (0.76 g, 7.55 mmol), Diphenylphosphorylazide (1,04 g, 3.77
0
mmol) and trichloroethanol (1.13 g, 7.55 mmol) and mixture was heated to 90 C for 3h. Sat. NaHCO} solution (30 mL) was added and the product was extracted with EtOAc (2x30 mL). The combined organics were washed with brine, dried (SOi), concentrated in vacua and purificatied by silicagel chromatography provided 2,2,2-trichloroethyl 2-tert-butylthiazol-5-ylcarbamate as a pasty mass (0.55 g, 66% yield), *H NMR (400 MHz, Acetone-^): 5 8.44 (s, 1H), 4.94 (s, 2H), 1.38 (s, 9H); MS (ESI) m/z: 333.0 (M+H+).
Using general method C, 2,2,2-trichloroethyl 2-tert-butyIthiazol-5-y I carbamate (0.081 g, 0.24 mmol) and Example A12 (0.73 g, 0.24 mmol) were combined to afford I-(2-tert-butylthi^ol-5-yl)-3-(2-fluoro-5-(8-mediyl-2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea as an off-white solid {0.025 g, 21% yield). *H NMR (400 MHz, DMSCW6): 5 9.88 (s, 1H), 8.64 (s, 1H), 8.44 (d, /= 8.4 Hz, 1H)5 7.87 (s, 1H), 7.S8 (brs, 1H), 7.26-7.22 (m, 2H), 7.04 (s, 1H), 3.60 (s, 3H), 2.89 (d, J= 4.4 Hz, 3H), L35 (s, 9H); MS (ESI) m/z: 482.2 (M+H+).

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Example 85: Using general method B, the carbamate of Example B22 (0.10 g, 0.40 mmol) and
Example A4 (0.10 g, 0.32 mmol) were combined to afford l-(5-(8-ethyl-2-{methylarnino)-7-oxo-
7,8-dmydropyrido[2,3-d]pyruTiidm-6-yl)-2-iluoropte
pyrazol-5-yl)nrea (0.12 g, 61% yield). 'H NMR (400 MHz, DMSO-rffi, major rotomer): 6 9.27 (s,
IH), 8.94 (brs,IH), 8.64 (s, IH), 8.36 (dd, 7 = 2.0, 8.0 Hz, 1H), 7.85 (s, 1H), 7.79 (m, 1H), 7.2-
7.4 (m, 2H), 6.61 (s, IH), 4.35 (q,J = 5.6 Hz, 2H), 3.77 (s, 3H), 2.88 (d, J= 4.4 Hz, 3H), 1.23 (t,
J= 6.8 Hz, 3H); MS (ESI) m/z: 505.2 (M+H+).
Example 86: Using general method B, the carbamate of B15 (0.05 g, 0.21 mmol) and Example A12 (0.063 g, 0.21 mmol) were combined to afford l-(5-(8-ethyl-2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-y])-2-fluorophenyl)-3-(l-methyl-3-(trifluoromethyl)-]H-pyrazoi-5-yl)urea (55 mg, 55% yield). *H NMR (400 MHz, DMSO-rf6, major rotomer): 5 11.0 (s, 1H),8.91 (brs, lH),8.64(s, 1H), 8.33 (dd,J = 1.6, and 6.4 Hz, IH), 7.90 (s, 1H),7.83 (m, IH), 7.2-7.4 (m, 2H), 6.52 (s, 1H), 3.61 (brs, 3H), 2.90 (brd, J - 4.8 Hz, 3H); MS (ESI) m/z: 478.0 (M+H+).
Example 87: Using general method B, prop-l-en-2-yl 3-tert-butyl-l-methyl-lH-pyrazol-5-ylcarbamate(0.12 g, 0.51 mmol) and Example A24 (O.I6g, 0,51 mmol) were combined to afford l-(3-tert-butyl-l-methyl-lH-pyi*azol-5-yl)-3-(5-(l-ethyl-7-(metliylamino)-2-oxo-l,2-dihydro-l)6-naph£hyridin-3-yI)-2-fluorophenyl)urea as the mesylate salt (130 mg, 47% yield). !H NMR (400 MHz, DMSO-4): 5 8.98 (s, 1H), 8.87 (brs, IH), 8.57 (dd, J= 2.0, and 8.0 Hz, IH), 7.88 (s, IH), 7.2-7.4 (m, 2H), 6.55 (brs, IH), 6.09 (s, IH), 4.18 (m, 2H), 3.61 (s, 3H), 2.96 (brs, 3H), 2.30 (s, 3H), 1.22 (t, J= 6.4 Hz, 3H), 1.18 (s, 9H); MS (ESI) m/z: 492.3 (M+H+).
Example 88: Using general method B, prop-l-en-2-yl 3-lert-butylphenylcarbamate (0.545 g, 2.34 mmol) and Example A3 (0.592g, 01.87 mmol) were combined to afford l-(3-tert-butylphenyl)-3-(2-fluoro-5-(8-methyI-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (0.574 g, 62% yield) as a light yellow solid. MS (ESI) m/z: 475.2 (M+H*).
Using a procedure analogous to Example Al, I-(3»tert-bntylphenyl)-3-(2-fIuoro-5-(8-methyl-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (0.200 g, 0.407 mmol) and N,N-dimethy]ethylenediamine (0.181 mL, 1.65 mmol) were combined to

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afford l-(3-tert-butyIphenyl)-3-(5~(2-(2-(dimethylamino)ediylamino)-8-methyl-7-oxo-7,8-
dihydropyrido[23-d]pyrimidin-6-yl)-2-fluorophenyl)urea (0.150 g, 86% yield) as a light yellow solid. It was converted to corresponding HCl salt by reacting with HCl (4.0 M HCl in dioxane, 1.0 eq.). 'H NMR (400 MHz, DMSO-d6): 59.28 (s, IH), 8.73 (s, 1H), 8.64 (d, J= 1.6 Hz, IH), 8.39 (d, J= 7.6 Hz, 1H), 8.04 (s, 1H), 7.93 (s, 1H), 7.43 (s, IH), 7.28-7.24 (m, 3H), 7.18 (£, J = 8.0 Hz, 1H), 6.99 (tt, J= 7.6, 0.8 Hz, IH), 3.74 (broad, 2H), 3.63 (s, 3H), 3.30 (broad, 2H), 2.81 (d, J-4.8 Hz, 6H), 1.25 (s, 9H); MS (ESl)m/z: 532.3 (M+H+).
Example 89: Using a procedure analogous to Example Al, l-(4-chloro-3-
(trifluoromemyl)phenyl)-3-(2-fluoro-5-(8-me%
d]pyrirnidin-6-yl)phenyl)urea from Example 67 (55 mg, 0.100 mmol) and 2-amino-l-propanol (249 mg, 3.31 mmol) were combined to provide l-(2-fluoro-5-(2-(l-hydroxypropan-2-ylamino)-8-methyl -7-oxo- 7,8 -dihydropyri do [2,3 -d]pyrimidin-6-yl)phenyl)-3-(3-
(trifluoromethyl)phenyl)urea (489 mg, 22% yield). *H NMR (300 MHz, DMSO-c/6), S 1.15 (s, 3 H), 3.37-3.56 (m, 4 H), 3.90-4.15 (m, 1 H), 4.69 (s, 1 H), 7.22-7.55 (m, 6 H), 7.84 (s, 1 H), 8.02 (s, 1 H), 8.36-8.38 (m, 1 H), 8.63 (br. s, 2 H), 9.38 (s, 1 H), OH missing; MS (ESI) m/z: 531.2 (M+H+).
Example 90: Using general method C, the TROC carbamate of Example B23 (150 mg, 0.421 mmol) and Example A12 (132 mg, 0.442 mmol) were combined to afford l-(3-tert-butyl-l-isopropyl-lH-pyrazol-5-yl)-3-(2-fluoro-5-(8-methyI-2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (13 mg, 6% yield). lH NMR (300 MHz, DMSO-4,): 8 1.18 (s, 9 H), 1.31 (d, J= 6.5, 6 H), 2.89 (s, 3 H), 3.50-3.61 (m, 3 H), 4.33 (hep,./ = 63, 1 H), 6.03 (s, 1 H), 7.24-7.26 (m, 2 H), 7.65-7.84 (m, 2 H), 8.37-8.39 (m, 1 H), 8.62-8.76 (m, 3 H); MS (ESI) m/z: 507.2 (M+tT).
Example 91: Using general method D, Example B16 (0.060 g, 0.31 mmol) and Example A4 (0.096 g, 0.31 mmol) were combined to afford l-(3-tert-butyl-l-ethyl-lH-pyrazol-5-yl)-3-(5-(8-emyl-2-(memylammo)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-2-fluorophenyI)urea (57 mg, 37% yield). !H NMR (400 MHz, DMSO-4, major rotomer): 5 8.82 (s, IH), 8.78 (m, IH), 8.64 (s, IH), 8.39 (dd, J= 2.0J and 8.4 Hz, IH), 7.85 (s, IH), 7.78 (m, IH), 7.27 (m, 2H), 6.08 (s,

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1H), 4.30 (m, 2H), 3.93 (q, ./= 7.2 Hz, 2H), 2.89 (brd, /= 4.0 Hz, 3H), 1.25 (m, 6H), 1.19 (s, 9H); MS (ESI) m/z: 507.2 (M+H+).
Example 92: Using general method F, Example A38 (88 mg, 0.29 mmol) and l-isocyanato-3-(trifluoromethyl)benzene (63 mg, 0.34 mmol) were combined to provide l-(2-fluoro-5-(l-methyl^methylaroinoJ^-oxo-l^-dihydro-l^-naphthyridinO-ylJpheny^-S^S-(trifluoromethyl)phenyl)urea (123 mg, 87 % yield). 'H NMR (400 MHz, DMSO-rf6): 5 9.40 (s, 1 H), 8.63 (s, I H), 8.44 (s, 1 H), 8.37 (dd, J = 8.2, 2.2 Hz, 1 H), 8.03 (s, 1 H), 7.87 (s, 1 H), 7.51 (m, 2 H), 7.32-7.22 (m, 3 H), 7.03 (q, J = 4.8 Hz, 1 H), 6.15 (s, 1 H), 3.52 (s, 3 H), 2.85 (d, J = 5.0 Hz, 3 H); MS (ESI) m/z: 486.2 (M+H*).
Example 93: Using general procedure B, Example Bll (0.125 g, 0.362 mmol) and Example A12 (0.104 g, 0.347 mmol) were combined to form crude l-(3-(l»(tert-butyldimethylsilyloxy)-2-methylpropan-2-yI)-l-phenyl-lH-pyrazol-5-yl)-3-(2-f]uoro-5-(8-methyl-2-(metliylamino)-7-oxo-7,8-dihydropyrido[2,3-d3pyrimidin-6-yl)phenyl)urea. TBAF (1.0 M in THF, 1.0 mL, 1.0 mmol) was added to the above filtrate, and die mixture was stirred at 30 DC for 2 d. Solvent was removed under reduced pressure. The residue was quenched with H2O (15 mL) and extracted with EtOAc (2x25 mL). The combined organic layers were washed with brine (15 mL), dried (MgS04), concentrated in vacuo and purified by chromatography to afford l-(2-fluoro-5-(8-methyI-2-(methylamino)-7~oxO"7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)-3-(3-(l-hydroxy-2-methylpropan-2~yl)-l-phenyl-lH-pyrazol-5-yl)urea (0.096 g, 52% yield) as a white solid. lH NMR (400 MHz, DMSO-d6), 8 8.98 (d, J= 1.2 Hz, 1H), 8.88 (s, 1H), 8.655 (s, JH),
8.40 (dd, .7= 8.0, 1.2 Hz, 1H), 7.86 (s, 1H), 7.82 (d, J = 4.4 Hz, 1H), 7.56-7.49 (m, 4H), 7.44-7.39 (m, 1H), 7.28-7.21 (m, 2H), 6.39 (s, 1H), 4.59 (t,7= 5.2 Hz, 1H), 3.61 (s, 2H), 3.54 (s, 1H),
3.40 (d, J= 5.2 Hz, 2H), 2.90 (d, J= 4.4 Hz, 3H), 1.19 (s, 6H); MS (ESI) m/z: 557.3 (M+H+).
Example 94: Using general method D, 3-tert-butyl-l-methyl-IH-pyrazole-5-carboxylic acid (0.041 g, 0.23 mmol) and Example A49 (0.081 g, 0.25 mmol) in presence of triethylamine (0.07 g, 0.68 mmol) and diphenylphospharyl azide (0.12 g, 0.45 mmol) were combined to afford l-(3-terl-buty]-]-methyJ-lH-pyrazo]-5-yJ)-3-(2-fluoro-5-(8-isopropyl-2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidm-6-yl)phenyl)urea as white solid (0.86 g, 75% yield). !H NMR

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(400 MHz, DMSCW6): 5 8.91 (s, IH), 8.83 (d, J= 2.4 Hz, IH), 8.62 (s, IH), 8.36-8.34 (m, IH), 7.79-7.76 (m, 2H), 7.26-7.23 (m, 2H), 6.08 (s, IH), 5.77-5.74 (ra, IH), 3.60 (s, 3H), 2.88 (d, .7 = 4.4 Hz, 3H), 1.58-1.51 (m, 6H), 1.18 (s, 9H); MS (ESI)m/z: 507.2 (M+H*).
Example 95: Using general method D, 4-methylpyrimidine-5-carboxylic acid (300 mg, 2.17 mmol) and Example A3 (687 mg, 2.17 mmol) were combined to afford l-(2-fluoro-5-(8-methyl-2-(methyltMo)-7-oxo-7,8-dihydropyrido[2,3-d]pyrmiidin-6-yl)phenyl)-3-(4-methylpyrimidin-5-yl)urea (305 mg, 31% yield). MS (ESI) m/z: 452.0 (M+H+).
Using a procedure analogous to Example Al, l-(2-fluoro-5-(8-methyl-2-(methylthio)-7-oxo-7)8-dihydropyrido[2,3-d]pyrimidin-6-yI)phenyl)-3-(4-methylpyrimidin-5-yl)urea (300 mg, 0.664 mmol) and 2.0 N methylamine in THF (2.3 mL, 4.53 mmol) were combined to afford l-(2-f!uoro-5-(8-methyI-2-(methylamino)-7-oxo-7,8-dihydropyrido[2J3-d]pyrimidin-6-yl)phenyl)-3-(4-methylpyrimidin-5-yl)urea (75 mg, 38% yield). 'H NMR (300 MHz, DMSO-rf6), 5 2.45 (s, 3 H), 2.88 (s, 3 H), 3.50-3.57 (m, 3 H), 7.23-7.29 (m, 2 H), 7.67-7.79 (m, 1 H), 7.S2 (s, 1 H), 8.39-8.42 (m, 1 H), 8.60 (s, 3 H), 8.68 (s, 2 H), 9.13 (m, 1 H); MS (ESI) m/z: 435.2 (M+H*).
Example 96: Using general method A, the TROC carbamate of Example B18 (0.5g, 1.58 mmol) and Example A10 (0.523g, 1.58 mmol) were combined to provide l-(3-tert-butylisoxazol-5-yl)-3'(2-iluoro-4-methyl-5-(8-methyl-2-(rnemylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-
yl)phenyl)urea (440mg, 56% yield). !H NMR (400 MHz, DMSO-d6): 5 10.3 (brs, IH), 8.9
(s,iH)), 8.70 (bis, IH), 7.94 (d, J = 9Hz, IH), 7.88 (s, IH), 7.20 (d, J = J2Hz, IH), 6.00 (s, IH), 3.64 (s, 3H), 2.61 (s, 3H),2.07 (s, 3H), 1.21 (s, 9H): MS(ESI) m/z : 497.2 (M+H*).
Using a procedure analogous to Example Al, l-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-4-methyI-5-(8-methyl-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]p}Timidin-6-yl)phenyl)urea (l.70g, 3.426 mmol) and methylamine (2ml, 4 mmol, 2.0M in THF) were combined to provide l-(3-tert-butylisoxazoI-5-yI)-3-(2-fIuoro-4-metliyl-5-(S-methyl-2-(methylamino)-7-oxo-7,8-
dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (92 mg, 42 % yield). H NMR (400 MHz, DMSO-d6): 8 10.28 (brs, IH), 8.67 (brs, IH), 8.61 (s, IH), 7.89 (d, J = 9Hz, IH), 7.82 (brs,
IH), 7.68 (s, IH), 7.17 (d, J = 12Hz, IH), 6.00 (s, IH), 3.58 (s, 3H), 2.90 (d, J = 5 Hz, 3H), 2.08 (s, 3H\ 1.21 (s, 9H): MS(ESI) m/z: 480.2(M+H+).

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Example 97: Using general method A, the TROC carbamate of Example B21 (0.2g. 0.5 mmol) and Example A39 (0.156g, 0.5 mmol) were combined to provide l"(2-fluoro-4-methyl-5-{8-memyl-2-(methylamino)-7-oxo-7,8H3mydropyrido[2,3-d]pyrimidin-6--yl)phenyl)-3-(l-phenyl-3-
(trifluoromemyl)-lH-pyrazol-5-yl)urea (210 mg, 75% yield). !H NMR (400 MHz, DMSO-d6):
$9.12 (s, IH), 9.02 (3, IH), 8.60 (s;lH), 7.90 (d, J = 9.5Hz, IH), 7.6 (m, 6H), 7.13 (d, J= 12Hz, IH), 6.83 (s, IH), 3.54 (s, 3H),.2.90 (d, J = 5Hz, 3H), 2.07 (s, 3H); MS (ESI, m/z: 567.3, M+H+).
Example 98: Using a modified general method B, the carbamate of Example B21 (0.071 g, 0.23 mmol), and Example A38 (0.068 g, 0.23) were heated at 130 °C for Ih under microwave irradiation to afford l-{l-tert-butyl-lH-pyrazol-4-yl)-3-{2-fluoro-5-(l-methyl-7-(methylamino)-2-oxo-f,2-dmydro-i,6-naphthyridm-3-yJ)phenyf)urea as the methane sulfonic acid salt (0.048 g, 45% yield). ]H NMR (400 MHz, DMSO-rf6): 6 8.72 (s, IH), 8.54 (brs, 2H), 8.41 (dd, J= 8.4 Hz, 2.4 Hz, IH), 7.95 (s, IH), 7.80 (s, IH), 7.40 (s, IH), 7.29-7.19 (m, 2H), 6.42 (brs, IH), 3.54 (s, 3H), 2.94 (s, 3H), 2.27 (s, 3H), 1.47 (s, 9H); (ESI) m/z: 464.2 (M+H*).
Example 99: Using general method A, the carbamate of Example Bl (0.45 g, 1.5 mmol) and Example A10 (0.4 g, 1.21 mmol) were combined to provide 1 -(3-tert-butyl-l -phenyl- 1H-pyrazol-5-yi)-3-(2-fluora-4-methyl-5-(8-memyl-2-(me&ylmio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea as white solid (0.25 gT 36% yield). lU NMR (400 MHz, DMSO-d6): 5 8.94 (d, J = 2.0 Hz, IH), 8.90 (s, IH), 8.83 (s, IH), 7.98 (d, J= 8.4 Hz, IH), 7.87 (s, IH), 7.54-7.47 (m, 4H), 7.43-7.39 (m, IH), 7.15 (d, J- 12.0 Hz, IH), 6.34 (s, IH), 3.64 (s, 3H), 2.61 (s, 3H), 2.06 (s, 3H), 1.22 (s, 9H); MS (ESI) m/z: 482.2 (M+H+).
Using a procedure analogous to Example Al, l-(3-tert-butyl-l-phenyl-lH-pyrazol-5-yl)-3-(2-fluoro-4-methyl-5-(8"memyl-2-(mediylthio)-7-oxO"7,8-dihydropyrido[23-d]pyrimidin-6-yl)phenyl)urea (0.25, 0.43 mmol), MCPBA (0.081 g, 0.47 mmol) and 2 M methylamine in THF (1 mL) were combined to provide l-(3-tert-butyl-l-phenyl-lH-pyrazoI-5-yl)-3-(2-fluoro-4-memyl-5-(8-methyl-2-(methyIamino)-7-oxo-7,8-dihydrop}'ridof2,3-d]pyrimidin-6-yl)phenyl)urea as white solid (0.17 g, 72% yield). !H NMR (400 MHz, DMSO-db): 5 8.90 (d,/=

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2.0 Hz, IH), 8.81 (s, 1H), 8.60 (s, 1H), 7.93 (d, J= 8.4 Hz, IH), 7.83-7.78 (m, 1H), 7.65 (s, 1H), 7.54-7.47 (m,4H), 7.43-7.38 (m, IH), 7.11 (d,J= 12.0 Hz, lH),6.34(s, IH), 3.59 (s, 3H), 2.90 (d,7 = 4.4 Hz, IH), 2.05 (s, 3H), 1.23 (s, 9H); MS (ESI) m/z: 555.2 (M+H4).
Example 100: Using general method B, Example B15 (0.15 g, 0.64 mrnol) and Example A39 (0.20 g, 0.64 mrnol) were combined to afford l-(2-fluoro-4-methyl-5-(8-memy]-2-(memylamino)"7-oxo-7,8-dihyaVopyrido[23-d]pyrimidin-6-yI)phenyl)-3-(3-(trifluoromethyI)isoxazoI-5-yl)urea (0.19 g, 60% yield). fH NMR (400 MHz, DMSO-rf6, major rotomer):5 11.0 (s, lH),8.82(s, lH),8.60(s, IH), 7.81 (d,7=8.0 Hz, lH),7.68(s, lH),7.20(s, IH), 6.46 (s, IH), 3.59 (brs, 3H), 2.90 (brd, J = 4.4 Hz, 3H), 2.09 (s, 3H); MS (ESI) m/z: 492.3 (M+H4).
Example 101: Using general method F? l-chloro-4-isocyanato-2-(trifluoromethyl)benzene {0.16
g, 0.55 mrnol )and Example A39 (0.113 g, 0.51 mmoll) were combined in ethyl acetate to
provide l-(4-chloro-3-(trifliioromethyl)phenyl)-3-(2-fluoro-4-methyl-5-(8-metliyl-2-
(methylamino)-7-oxo-7,8-dihydropyrido[23-d]pyrimidin-6-yI)phenyl)urea (150 mg, 55% yield)
*H NMR (400 MHz, DMSO-d6) 5 9.44 (s, IH), 8.6(s, IH), 8.1 (d, J= 2.5 Hz), 7.87 (d, J - 9Hz,
IH), 7.67 (s, IH), 7.59(d, J = 9.0 Hz, IH), 7.53 (dd, J = 9.0, 2.5Hz, IH), 7.15 (d, J = 12Hz, IH), 3.54 (s, 3H), 2.90 (d, J = 5Hz, 3H), 2.07 (s, 3H); MS (ESI, m/z: 535.0, M+H4).
Example 102: Using general procedure C, the TROC carbamate of Example B18 (0.212 g, 0.672 mrnol, 1.00 eq) and Example A26 (0.2100 g, 0.672 mrnol, 1.00 eq) were combined to provide crude desired product. The product was purified by reverse phase chromatography 5-42% MeCN (w/ 0.1% TFA)/ H20 (w/0.1% TFA) to obtain the TFA salt. The TFA salt thus obtained was treated with MP-Carbonate resin to obtain the free base and then 2 wt% MsOH/THF to afford l-(3-tert-butylisoxazol-5-yl)-3-(2"fluoro-4-methyl-5-(l-methyI-7-(methylammo)-2-oxo-l,2-dihydro-l,6-naphthyridin-3-yl)phenyl)urea (60 mg, 16% yield) as the MsOH salt. lH NMR (400MHz,DMSCMtf):5 10.32 (s, IH), 8.71 (d, J = 2.00 Hz, IH), 8.50 (s, IH), J = 8.8 Hz, IH), 7.81 (s, IH), 7.20 (d, J = 12.4 Hz, IH), 6.51 (s, IH), 6.00 (s, IH), 3.54 (s, 3H), 2.96 (brs, 3H), 2.31 (s, 3H), 2.09 (s, 3H), 1.21 (s, 9H); MS (ESI) m/z: 479.2 (M+H+).

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Example 103: Using general procedure D, 3-(t-buryl)l-methyl-lH-pyrazole-5-carboxylic acid (0.111 g, 0.611 mmol, 1.00 eq) and Example A26 (0.210 g, 0.72 mmol, 1.10 eq) were combined lo give desired product. The free base was slurried in THF" and treated with 2% MsOH/THF solution (1.44 g, 1.00 eq) and the thick suspension was stirred overnight at RT. The solids were collected by filtration, rinsed with THF and EtOAc and dried under high vacuum to afford l-(3-tert-buryI-l-methyMH-pyrazol-5-y^3-(2-fliro^
l^-dihydro-l,6-naphthyridin-3-yl)phenyl)urea (150 mg, 42% yield) as the MsOH salt. ]H NMR (400 MHz, DMSO-d6): 5 8.93 (s, 1H), 8.79 (bra, 1H), 8.50 (s, IH), 7.97 (d, J = 8.4 Hz), 7.80 (s: IH), 7.18 (d, J = 12.0 Hz, 1H), 6.50 (s, 1H), 6.05 (s, 1H), 3.59 (s, 3H), 3.53 (s, 3H), 2.96 (s, 3H), 2.30 (s, 3H), 2.07 (s, 3H), 1.17 (s, 9H); MS (ESI) m/z: 492.3 (M+H+).
Example 104: Using general method B, the carbamate of Example B2 (0.171 g, 0.720 mmol) and Example A39 (0.150 g, 0.48 mmol) were combined to afford l-(3-tert-butyl-l-metliyl-lH-pyrazol-5-yl)-3-(2-iluoro-4-memyl-5K8-methyl-2-(methylaiTiino)"7-oxo-7,8-dihydropyrido[2J3-d]pyrimidin~6-yl)phenyl)urea (0.105 g, 44% yield) as a white Solid. 'H NMR (400 MHz, DMSO-d6): 5 8.87 (s, 1H), 8.73 (d, J= 2.0 Hz, IH), 8.60 (s, 1H), 7.93 (d, J= 8.4 Hz, 1H), 7.80 (m, 1H), 7.66 (s, 1H); 7.14 (d, J= 12.4, IH), 6.04 (s, 1H), 3.59-3.57 (m, 6H), 2.90 (d, J = 4.4 Hz, 3H), 2.06 (s, 3H), 1.16 (s, 9H); MS (ESI) m/z: 493.2 (M+H4).
Example 105: Using a modified method B, the carbamate of Sample B19 (0.061 g, 0.27 mmol) and 6-(3-amino^-fluorophenyl)-8-isopropyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one from Example A59 (0.094 g, 0.27 mmol) in THF were stirred at 130 °C for lh under microwave irradiation. Solvents were removed and the crude residue was purified by silica gel chromatography to afford 1 -(1 -tert-butyl-1 H-pyrazo!^-yl)-3-(2-fluoro-5-(S-isopropyl-2-(methyImio)-7-oxo-7,8-dihydropyrido[2,3-dJpyrimidin-6-yI)phenyI)urea as off-white solid (68 mg, 49% yield). ]H NMR (400 MHz, Acetone-rfG): 5 8.89 (s, 1H), 8.58 (dd, J= 8.0 Hz, 2.4 Hz, 1H), 8.21 (brs, 1H), 7.99 (brs, IH), 7.96 (s, IH), 7.89 (s, IH), 7.39-7.35 (m, 2H), 7.J7 (dd, J = 11.2 Hz, 8.4 Hz, IH), 5.94-5.89 (m, IH), 2.65 (s, 3H), 1.66 (d, J = 6.8 Hz, 6H), 1.54 (m, 9H); MS (ESI) m/z: 507.2 (M+H4).
Using a procedure analogous to Example Al, l-(l-tert-butyl-lH-pyrazol-4-yl)-3-(2-fluoro-5-(8-isopropyl-2-(methylthio)-7-oxo-7J8-dihydropyrido[2)3-d]pyrimidin-6-yl)phenyl)urea

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(0.065 g, 0.13 mmol) and 2 M methylamine in THF (1 mL) were combined to afford 1 -(I-tert-butyl-lH-pyrazol-4-yl)-3-(2-fluoro-5-(S-isopropyi-2-(metliylamino)-7-oxo-7,S-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea as white solid (39 nig, 62%). lH NMR (400 MHz, DMSO-i6): 5 8.68 (s, 1H), 8.62 (s, IH), 8.48 (d, J= 2.0 Hz, IH), 8.34 (d, J= 7.6 Hz, 1H), 7.80 (s, IH), 7.79 (s, 1H), 7.78-7,74 (m, IH), 7.38 (s, 1H), 7.22-7.20 (m, 2H), 5.77-5.74 (m, IH), 2.89 (d, J=4.4 Hz, 3H), 1.59-1.55 (m, 6H), 1.46 (m, 9H); MS (ESI) m/z: 493.2 (M+H+).
Example 106: Using general method D, 6-phenylpyrimidine-4-carboxylic acid (250 mg, 1.25 mmol) and Example A3 were combined to afford l-(2-fluoro-5-(8-methyl-2-(methylthio)-7-oxo-7,8-dmydropyrido[2,3-d]pyrimidin-6-yl)phenyl>3-(6-phenylpyrimidin-4-yl)urea (265 mg, 41% yield) which was used without purification. 'H NMR (300 MHz, DMSO-tf6) 8 2.59 (a, 3 H), 3.66 (s, 3 H), 7.36-7.38 (m, 2 H), 7.53-7.55 (m, 3 H), 8.03-8.12 (m, 4 H), 8.50-8.52 (m, IH), 8.88 (s, 1 H), 8.95 (s, 1 H), 10.2 (br. s, 2 H); MS (ESI) m/z: 514.0 (M+H+).
Using a procedure analogous to Example Al, l-(2-fluoro-5-(8-methyl-2-(methykhio)-7-oxo-7s8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)-3-(6-phenylpyrimidin-4-yl)urea (265 mg, 0.516 mmol) and 2.00 N methylamine in THF (3.87 mL, 7.73 mmol) were combined to afford 1-(2-fluoro-5-(8-methyU2-(metliyIamino)-7-oxo-7)8-dmydropyrido[2,3^]pyiimidin-6-yl)phenyl)-3-(6-phenylpyrimidiiv4-yl)urea (139 mg, 54% yield). !H NMR (300 MHz, DMSO-^) 8 2.89 (m, 3 H), 3.54-3.62 (m, 3 H), 7.29-7.35 (m, 2 H), 7.53-7.55 (m, 3 H), 7.70-7.82 (m, 1 H), 7.91 (s, 1 H), 8.03-8.06 (m, 2 H), 8.13 (s, 1 H), 8.44-8.46 (S, 1 H), 8.60-8.75 (m, 1 H), 8.98 (s, 1 H), 10.1 (br. s, 1 H), 10.2 (s, 1 H); MS (ESI) m/z: 497.2 (M+H+).
Example 107: To a solution of l-(l-tert-butyl-lH-pyra2ol-4-yl)-3-{2-fluoro-5-(8-memyl-2-(memylsulfmyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea from Example 65 (0.1 g, 0.2 mmol) in DMF (1 mL) was added NLNl-dimethylethane-l,2-diamine (0.054g, 0.61 mmol) and the solution was stirred for 2h at RT. The reaction mixture was purified by reverse phase chromatography to furnish product as the TFA salt. The TFA salt (0.2 g) thus obtained was suspended in THF (5 ml). MP-carbonate resin (0.2 g) was added and the slurry was orbitally shaken for a few hours. The solution was separated and concentrated to provide l-(l-tert-butyl-lH-pyrazol-4-yI)-3-(5-(2-(2-(dimethylamino)ethylamino)-8-methyl-7-oxo-7?8-dihydropyrido[2,3-d]pyriniidin-6-yl)-2-iluorophenyl)urea as the hydrochloride salt (45 mg, 42%

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yield). ]H NMR (400 MHz, DMSO-d6): 5 8.70-8.69 (m, 2H), 8.49 (d, J= 2.0 Hz, IH), 8.38-8.36 (m, IH), 7.95-7.93 (brs, IH), 7.87 (s, IH), 7.75 (s, IH), 7.35 (s, IH), 7.21-7.18 (m, 2H), 3.67-3.52 (m, 7H), 2.79 (s, 3H), 2.78 (s, 3H), 1.42 (s, 9H); (ESI) m/z: 522.2 (M+H+).
Example 108: Using general method B, Example B35 (0.060 g, 0.25 mmol) and Example A30 (0.083 g, 0.25 mmol) were combined to afford l-(5-(l-ethyl-7-(methylamino)-2-oxo-l)2-dihydro-l,6-naphmyridin-3-yl)-2-fluoro-4-methylplienyl)-3-(3-(trifluoromethyl)isoxazol-5-yl)urea (0.060 g, 47% yield). 'H NMR (400 MHz, DMSO-d6): 5 11.0 (s, IH), 8.80 (s, IH), 8.39 (s, IH), 7.80 (d,/= 8.4 Hz, IH), 7.66 (s, IH), 7.18 (d,y = 12.0 Hz, IH), 6.99 (q,/= 5.2 Hz, 2H), 6.45 (s, IH), 6.23 (s, IH), 4.14 (q, J= 6.8 Hz, IH), 2.85 (d,/= 4.8 Hz, IH), 2.08 (s, 3H), 1.20 (t, J= 7.2 Hz, 3H); MS (ESI) m/z: 505.2 (M+H+).
Example 109: Using a modified general method B, the carbamate of Example BI9 (0.17 g. 0.76 mmol), Example A10 (0.25 g, 0.76 mmol) and N-methylpyrrolidine (catalytic amount) were stirred at 120 °C in THF for Ih under microwave irradiation. Solvents were removed and crude residue was purified by silica gel chromatography to afford I-(l-tert-butyl-lH-pyrazoI-4-yl)-3-(2-fluoro-4-memyl-5-(8"methyl-2-(methylmio)-7-oxo-7J8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea as an off-white solid (0.192 g, 51% yield). lH NMR (400 MHz, DMSO-4): 8 8.90(s, IH), 8.65 (s, IH), 8.44 (d, J= 1.6Hz, IH), 8.00 (d, J= 8.4Hz, IH), 7.87 (s, IH), 7.77 (s, IH), 7.36 (s, IH), 7.14 (d,y= 8.4 Hz, IH), 3.64 (s, 3H), 2.61 (s, 3H), 2.06 (s, 3H), 1.45 (s, 9H); (ESI) m/z: 496.3 (M+H+).
Using a procedure analogous to Example Al, l-(l-tert-butyl-lH-pyrazol-4-yl)-3-(2-fluoro-4-mediyl-5-(8-methyI-2-(methylthio)-7-oxo-7,8-dihydropvrido[2,3-d]pyrimidin-6-yl)phenyl)urea (0.192 g, 0.39 mmol) and 2M methylamine in THF (1 mL; 5eq) were combined to afford l-(l-tert-butyl-lH-pyrazol-4-yl)-3-(2-fluoro-4-metliyl-5-(8-methyl-2-(metliylamino)-7-oxo-7,8-dihydropyrido[2J3-d]p>Timidin-6-yl)phenyl)urea as an off-white solid (0.174 g, 94% yield). 'H NMR (400 MHz, DMSO-dG): 8 8.63 (s, IH), 8.60 (s, IH), 8.40 (d, J- 1.6 Hz, IH), 7.94 (d, J= 8.8 Hz, IH), 7.80-7.77 (m, 2H), 7.66 (s, IH), 7.36 (s, IH), 7.10 (d,./= 8.4 Hz, IH), 3.59-3.51 (m, 3H), 2.90 (d, J = 4.4 Hz, IH), 2.05 (s, 3H), 1.45 (s, 9H); (ESI) m/z: 479.2 (M+H+).

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Example 110: Using general method B, Example B15 and Example A30 (0.083 g, 0.25 mmol) were combined to afford l-(5-(l-ethyl-7-(metriylamino)-2-oxo-l,2-dihydro-l,6-naphthyridin-3-yl)-2-fluoro-4-methylphenyl)^3-(3-(trifiuorometbyl)isoxazo!-5-yI)urea (60 mg, 47% yield). 'H NMR (400 MHz, DMSO-d6): S 11.0 (s, IH), 8.80 (s, IH), 8.39 (s, IH), 7.80 (d, J = 8.4 Hz, IH), 7.66 (s, IH), 7.18 (d, J= 12. 0 Hz, IH), 6.99 (q, J = 5.2 Hz, IH), 6.45 (s, IH), 6.23 (s, IH), 4.13 (q,J~ 7.2 Hz, 2H), 2.85 (d, J = 4.8 Hz, 3H), 2.08 (s, 3H), 1.20 (t,J=7,2 Hz, 3H); MS (ESI) m/z: 505.2 (M+H4),
Example 111: Using a procedure analogous to Example 102, Example A34 (1.61 g, 4.85 mmol) was converted to 3-(5-amino-4-fluoro-2-methylphenyl)-l-ethyl-7-(methyIamino)-l,6-naphthyridii>2(IH)-one (1.16 g, 73% yield for two steps). 'H NMR (400 MHz, DMSO-c?6): 5 8.36 (s, IH), 7.58 (s, IH), 6.94-6.92 (brm, IH), 6.83 (d, J - 12.0 Hz, IH), 6.57 (d, J = 9.6 Hz, IH), 4.87 (brs, 2H), 4.12 (q, J = 6.8 Hz, 2H), 2.84 (d, J = 4.8 Hz, 3H), 1.94 (s, 3H), 1.185 (t, J = 7.2 Hz, 3H): MS (ESI) m/z: 327.2(M+H).
Using general procedure C, the TROC carbamate of B18 (0.212 g, 0.672 mmol, 1.00 eq) and 3-(5-amino-4-fluoro-2-methylphenyl)-l-etiiyl-7-(methylamino)-l,6-naphthyridin--2(lH)-one (0.210 g, 0.672 mmol, 1.00 eq) were combined to form desired product which was subsequently treated with MsOH to afford l-(3-tert-butylisoxazol-5-yl)-3~(5-(l-ethyl-7-(methylamino)-2-oxo-ls2-dihydro-l,6-naphthyridin-3-yl)-2-fluoro-4-methylphenyl)urea (96 mg, 24% yield) as the mesylate salt. lH NMR (400 MHz, DMSO-d6): 8 10.31 (s, IH), 8.70 (brs, IH), 8.50 (s, IH), 7.92 (d, J = 8.4 Hz, IH), 7.79 (s, IH), 7.20 (d, J = 11.6 Hz, IH), 6.526 (s, IH), 5.99 (s, IH), 4.16 (q, J = 7.6 Hz, 2H), 2.95 (s, 3H), 2.29 (s, 3H), 2.08 (s, 3H), 1,23-1.19 (m, 12H); MS (ESI) m/z: 493.2(M+H).
Example 112: Using general method D, Example B17 (0.061 g, 0.25 mmol) and Example A39 (0.088 g, 0.28 mmol) were combined in presence of triethy]amine (0.077 g, 0.76 mmol) and diphenylphospharyl azide (0.11 g, 0,38 mmol) to afford I -(3-tert-butyl-l -(2-(dimemylamino)emyl)-lH-pyrazol-5-yl)-3-(2-fluoro-4-metiiyl-5-(8-memyl-2-(memylaiTiino)-7-oxo-7,8-dihydropyrido[2.3-d3p)Timidin-6-yl)phenyl)urea as the hydrochloride salt (70 mg, 50% yield). ]H NMR (400 MHz, DMSO-^): 8 9.50 (s, IH), 9.26 (s, IH), 8.87 (s, IH), 8.59 (s, IH), 7.S8 (d, J= 8.4 Hz, IH), 7.82-7.80 (m, IH), 7.65 (s, IH), 7.15 {d,J-= 12.0 Hz, IH), 6.11 (s, IH),

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4.31 (t, J= 6.4 Hz, 2H), 3.59 (sf 3H), 3.51-3.46 (m, 2H), 2.89 (s, 3H), 2.79 (s, 3H), 2.78 (s, 3H), 2.06 (s, 3H), 1.19 (s, 9H); MS (ESI) m/z: 550.2 (M+H*).
Example 113: Using a modified general method G, the carbamate of 5-r-butyh'soxazol-3-amrne (60 mg, 0.27 mmol). Example A39 (84 mg, 0.27 mmol) and N-metliylpyrrolidine (2.3 mg, 0.027 mmol) were combined in THF (1 mL) and were heated to 60 °C overnight. The reaction mixture was diluted with acetonitrile and filtered. The filtered solid was washed with acetonitrile and dried in vacuo to provide l-(5-tert-butylisoxazol-3-yl)-3-(2-fluoro-4-methyl-5-(8-metIiyI"2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (53 mg, 41 % yield). 'H NMR (400 MHz, DMSO-cfc): 5 9.78 (s, 1 H), 8.74 (br s, 1 H), 8.60 (br s, 1 H), 7.92 (d, J = 8.4 Hz, 1 H), 7.81 (m, 1 H), 7.68 (s, 1 H), 7.16 (d, J = 12.3 Hz: 1 H), 6.43 (s, 1 H), 3.59-3.52 (m, 3 H), 2,90 (d, J = 4.5 Hz, 3 H), 2.07 (s, 3 H), 1.25 (s, 9 H); MS (ESI) m/z: 480.2 (M+H+).
Example 114: Using general method B, Example B15 (0.065 g, 0.28 mmol) and Example AtO (0.091 g, 0.28 mmol) were combined to afford I-(2"fluoro-4-metliyl-5-(8-methyl-2-(mediylthio)-7-oxo-7,8Kiihydropyrido[2,3-d]pyrinndin-6-yl)phenyl)-3-(3-(trifluorometliyl)isoxazol-5-yl)iirea (0.090 g, 64% yield). MS (ESI) m/z: 509.0 (M+H+).
Using a procedure analogous to Example Al, l-(2-fluoro-4-methyl-5-(8-methyl-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrirnidin~6-yl)phenyl)-3 -(3 -(trifluoromethyI)isoxazol-5-yl)urea (0.090 g, 0.18 mmol) was treated with mCPBA (70% wt, 0.052 g, 0.21 mmol) and then N,N-dimetiiylethylenediamine (0.039 g, 0.44 mmol) to afford l-(5-(2-(2-(dimemylamino)etliylamino)-8-memyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidiii-6-yl)-2-f]uoro--4-methylphenyl)-3-(3-(trifluoromethyl)isoxazol-5-yl)urea (0.071 g, 73% yield). 'H NMR (400 MHz, DMSO-^6, major rotomer): 5 8.69 (brs, IH), 8.60 (brs, IH), 7.83 (d, J= 8.4 Hz, IH), 7.76 (m, lH),7.67(s, IH), 7.17 (d, 7= 12.4 Hz, IH), 6.41 (s, lH),5.74(s, IH), 3.58 (brs, 3H), 3.48 (q, J = 6.4 Hz, 2H), 2.53 (m, 2H), 2.24 (s, 6H), 2.08 (s, 3H); MS (ESI) m/z: 523.2 (M+I-f).
Example 115: Using a procedure analogous to Example Al, l-(l-tert-butyl-lH-pyrazol~4-yl)-3-(2-tluoro-4-memyl-5-(8-memyl-2-(memylsulfinyl)-7-oxo-7,8"dilaydropyrido[2)3-d3pyrimidin-6-yl)phenyl)urea from Example 109 (0.081 g, 0.16 mmol) and (R)-l-phenylethanamine (0.058 g, 0.48 mmol) were combined in THF (1 mL) to provide (Rl-(l-tert-butyl-lH-pyrazol-4-yl)-3-(2-

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fluoro-4-methyl-5-(8-mcthyl-7-oxo-2-(l-phenylethylamino)-7.8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea as a wliite solid (0.048 g, 53% yield). 'H NMR (400 MHz, DMSO-d$): 5 8.62 (s, IH), 8.60 (s, IH), 8.48 (d, J = 7.2 Hz, IH), 8.39 (bra, IH), 7.90 (d, J = 8.0 Hz, IH), 7.76 (s, IH), 7.62 (s, IH), 7.43-7.35 (m, 3H), 7.31-7.27 (m, 2H), 7.18 (t, J= 7.2 Hz, IH), 7.08 (d, J-12.8 Hz, IH), 5.12 (t, J- 7.2 Hz, IH), 3.54-3.46 (m, 3H), 2.01 (s, 3H), 1.44 (s, 9H); (ESI) m/z: 569.3 (M+rT*).
Example 116: To a solution of J-(I-tert-butyI-lH-pyrazoI-4-yl)-3-(2-fluoro-4-methyl-5-(8-
metiiyl-2-(melhylsulfinyl)-7-oxO"7,8-dUiydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea from
Example 109 (0.075 g, 0.15 mmol) in THF (1 mL) was added, //;-dimethylemane-3,2-diamine (0,04 g, 0.44 mmol) and stirring continued for 4h at RT. Solvent was removed under vacuum and crude product was purified by silica gel chromatography to provide 1 -(1 -tert-buty]-lH-pyrazoI-4-yl)-3-(52-(2-(dimethylamino)emylainino)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-dJpyrimidin-6-yl)~2-fluoro-4-methylphenyl)urea as the hydrochloride salt (0.058, 74% yield). !H NMR (400 MHz, DMSO-d6): 8 9.61 (bis, IH), 8.67-8.64 (m, 2H), 8.42 (s, IH), 7.95-7.88 (m, 2H), 7.71 (s, IH), 7.68 (s, IH), 7.32 (s, IH), 7.07 {d,J= 12.4 Hz, IH), 3.68-3.65 (m, 2H), 3.57 (s, 3H), 3.28-3.26 (m, 2H), 2.79 (s, 3H), 2.78 (s, 3H), 2.00 (s, 3H), 1.40 (s, 9H); MS (ESI) m/z: 536.2 (M+H+).
Example 117: Using general method B, the carbamate of 5-?-butyIisoxazol-3-amine (0.10 g, 0.45 mmol) and Example A12 (0.13 g, 0.45 mmol) were combined to afford l-(5-tert-butylisoxazol-3-yl)-3-(2-fluoro-5-(8-memyl-2-(memylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyriim^in-6-yl)phenyl)urea (36 mg, 17% yield). ]H NMR (400 MHz, DMSO-(/6, major rotomer): 5 9.84 (s, IH), 8.81 (brs, IH), 8.65 (s, IH), 8.40 (d, J= 8.0 Hz, IH), 7.88 (s, IH), 7,2-7.4 (m, 2H), 6.49 (s, IH), 3.61 (brs, 3H), 2.90 (brd, J = 4.8 Hz, 3H); MS (ESI) m/z: 466.2 (M+H*).
Example 118: Using a procedure analogous to Example Al, l-(l-tert-butyl-lH-pyrazol-4-yl)-3-(2-fluoro-4-mefliyl-5-(8-memyl-2-(meUiylsultlnyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyi-irm"din-G-yl)phenyl)urea from Example 109 (0.075 g, 0.15 mmol) and (S)-l-phenylethanamine (0.053 g, 0.44 mmol) were combined in THF (1 mL) to afford (S)-l-(l-tert-butyl-lH-pyrazol-4-yl)-3-(2-fluoro-4-methyl-5-(8-methyl-7-oxo-2-(l-phenylemylamina)-7,8-dmydropyrido[2,3-d]pyrimidin-

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6-yl)phenyl)urea as a white solid (0.048 g, 58% yield). lH NMR (400 MHz, DMSO-rf6): 5 8.62 (s, IH), 8.60 (s, IH), 8.48 (d, J= 8.0 Hz, IH), 8.39 (bra, IH), 7.90 (d, J = 8.4 Hz, IH), 7.76 (s, IH), 7.62 (s, IH), 7.44-7.35 (m, 3H), 7.31-7.27 (m, 2H), 7.18 (t, J= 7.2 Hz, IH), 7.09 (d, J = 12.4 Hz, IH), 5.12 (t, J= 6.8 Hz, IH), 3.55-3.46 (m, 3H), 2.01 (ss 3H), 1.44 (s, 9H); (EST) m/z: 569.3 (M+HT*).
Example 119: Using general method C, 5-(trifluoromethyl)pyridin-3-amine (250 mg, 1.54 mmol) and Example A12 (295 mg, 0.984 mmol) were combined to afford l-(2-fluoro-5-(8-methyl-2-(methylamino)-7-oxo-7,8-diliydropyiido[2,3-d]pyrimidin-6-yl)phenyl)-3-(5-(trifIuoromethyI)pyridin-3-yI)urea (15 mg, 2.3% yield). 'H NMR (300 MHz, DMSO-rffl) 8 2.89 (s, 3 H), 3.54-3.61 (m, 3 H), 7.26-7.32 (m, 2 H), 7.70-7.85 (m, I H), 7.89 (s, 1 H), S.33-S.35 (m, 1 H), 8.46 (s, 1 H), 8.56 (s, 1 H), 8.65 (s, 1 H), 8.71 (s, 1 H), 8.91 (s, I H), 9.71 (s, 1 H); MS (ESI) m/z: 488.3 (M+H*).
Example 120: Using a procedure analogous to Example 57, l-(3-t~butylisoxazol-5-yl)-3-(2-tluoro-5-(8-methyl-2-(methylsultinyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea from Example 43 (0.150 g, 0.311 mmol, 1.00 eq) and L-(-)-alpha-methylbenzylamine (0.0846 ml. 0.656 mmol, 3.00 eq) were combined to afford (S)-l-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-5-(8-metliyl-7-oxO"2-(l-phenylediyIamino)-7,8-dihydropyrido[2,3-d]pyrimidin-6-yI)phenyI)urea (36 mg, 30% yield) as a white solid. 'H NMR (400 MHz, DMSO-rftf): 8 10.34 (s, IH), 8.73 (brs, IH), 8.65 (brs, IH), 8.51 (d, J = 7.6 Hz, IH), 8.37 (d, J = 7.6 Hz, IH), 7.85 (s, IH), 7.447.38 (m, 2H), 7.31-7.25 (m, 4H), 7.20-7.16 (m, IH), 6.06 (s, IH), 5.16-5.09 (m, IH), 3.48 (s, 3H), 1.48 (d, J = 7.2 Hz, 3H), 1.23 (s, 9H); MS (ESI) m/z: 556.3(M+H+).
Example 121: Using a procedure analogous to Example 57, l-(3-t-butylisoxazol-5-yl)-3-(2-fluoro-5-(8-methyl-2-(methylsulfinyl)-7-oxo-7I8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea from Example 43 (0.150 g, 0.311 mmol, 1.00 eq) and (R)-(+)-alpha-methylbenzylamine (0.0846 ml, 0.656 mmol, 3.00 eq) were combined to afford (R)-l-(3-tert-butyIisoxazol-5-yl)-3-(2-fluoro-5-(8-methyl-7-oxo-2-(l-phenyIethylamino)-7,8-dihydropyrido[2.3-d]pyrimidin-6-yl)phenyl)urea (51 mg, 42% yield) as a white solid. *H NMR

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(400 MHz, DMSO-40: 5 10.34 (s, IH), 8.73 (brs, IH), 8.65 (bra, IH), 8.51 (d, J = 7.6 Hz, IH), 8.37 (d, J - 7.6 Hz, IH), 7.85 (s, IH), 7.447.38 (m, 2H), 7.31-7.25 (m, 4H), 7.20-7.16 (m, IH), 6.06 (s, IH), 5.16-5.09 (m, IH), 3.48 (s, 3H), 1.48 (d, J = 7.2 Hz, 3H), 1.23 (s, 9H); MS (ESI) m/z: SSe^tM+H4).
Example 122: Using general procedure G, the carbamate of B31 (212 nig, 0.81 mmol) and Example A10 (260 mg, 0.79 mmol) were combined to provide l-(3-cyclopentyl-l-metliyl-lH-pyrazol-5-yl)-3-(2-fluoro-4-methyl-5-(8-methyl-2-(metliylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (285 mg, 68% yield). *H NMR (400 MHz, DMSO-rf6): 8 8.90 (s, 1 H), 8.89 (s, 1 H), 8.76 (d, J = 2.2 Hz, 1 H), 7.97 (d, J = 8.4 Hz, 1 H), 7.88 (s, 1 H), 7.18 (d, J = 12.4 Hz, 1 H), 5.98 (s, 1 H), 3.64 (s, 3 H), 3.57 (s, 3 H), 2.83 (in, 1 H), 2.61 (s, 3 H), 2.07 (s, 3 H), 1.90-1.80 (m, 2 H), 1.66-1.46 (m, 6 H): MS (EST) m/z: 522.2 (M+H+).
Using a procedure analogous to Example Al, l-(3"Cyclopentyl-l-methyl-lH-pyrazol-5-yl)-3-(2-fluoro-4-methyl-5-(8-metliyl-2-(methylthio)-7-oxo-7,8--dihydropyrido[2.3-d]pyrimidin-6-yl)phenyI)urea (283 mg, 0.54 mmo]) and metliylamine in THF (2.0 M, 1.0 mL, 2.0 mmol) were combined to provide l-(3-cyclopentyl-i-memyl-lH-pyrazol-5-yl)-3-(2-fluoro-4-methyl-5-(8-methyl-2-(memylainino)-7-oxo-7J8-dihydropyrido[2)3-d]pyrimidin-6-yI)phenyl)urea (34 mg, 46 %). 'H NMR (400 MHz, DMSO-d6): 5 8.87 (s, 1 H), 8.71 (d, J = 2.0 Hz, 1 H), 8.60 (br s, 1 H), 7.92 (d, } = 8,4 Hz, I H), 7.81 (m, 1 H), 7.66 (s, 1 H), 7.14 (d, J = 12.8 Hz, 1 H), 5,98 (s, 1 H), 3.59 (br a, 3 H), 3.57 (s, 3 H), 2.91-2.85 (m, 4 H), 2.06 (s, 3 H), 1.86 (m, 2 H), 1.64-1.50 (m, 6 H); MS (ESI) m/z: 505.2 (M+H*).
Example 123: Using general method B, the carbamate of 5-?-butylisoxazol-3-amine (0.15 g, 0.67 mmol) and Example A3 (0.21 g, 0.67 mmol) were combined to afford l-(5-tert-butylisoxazol-3-yI)-3-(2-fluoro-5-(8-methyI-2-(memyIthio)-7-oxo-7,8-dihydropyrida[2,3-d]pyrimidin-6-yl)phenyl)urea (0.15 g, 46% yield). MS (ESI) m/z: 483.2 (M+H*).
Using a procedure analogous to Example Al, l-(5-tert~butylisoxazol-3-yl)-3-(2-fluoro-5-(8-memyl-2-(methylthio)-7-oxo-7,8-dmyaYopyrido[2,3-d]pyrimidin»6-yl)phenyl)urea (0.15 g, 0.31 mmol) was treated with mCPBA (70% wt, 0.092 g, 0.37 mmol) and then N, N-dimethylethylenediamine (0.070 g, 0.78 mmol) to afford l-(54ert-butylisoxazol-3-yl)-3-(5-(2-(2-(dimethylamino)ethylamino)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-2-

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fluoropheny])urea (0,15 g, 92% yield). lH NMR (400 MHz, DMSO-cfe, major rotomer): 5 9.88 (brs, IH), 8.85 (bra, IH), 8.65 (s, IH), 8.40 (dd, J = 2.4, 8.0 Hz, IH), 7.88 (s, 1H), 7.76 (m, IH), 7.2-7.4 (m, 2H), 6.49 (s, 1H), 3.59 (brs, 3H), 3.46 (m, 4H), 2.19 (s, 6H), 1.27 (s, 9H); MS (ESI) m/z: 523.2 (M+H+).
Example 124: Using a procedure analogous to Example 136, l-(I-tert-butyMH-pyrazol-4-yl)-3-(2-fluoro-4-me±yl-5-(8-memyl-2-(memylsulfinyl)-7-oxo-7.8Hdmydropyrido[2,3-d]pyrirnidin-6-yl)phenyl)urea from Example 109 (0.071 g, 0.14 mmol) and (2,2-dimethyl-l,3-dioxolan-4-yl)methanamine (0.055 g, 0.42 mmol) were combined in THF (1 mL) to provide l-(l-tert-butyl-lH-pyrazoI-4-yl)-3-(5-(2-(2,3-dihydroxypropylamino)-8-methyI-7-oxo-7)8-diliydropyi'ido[2,3-d]pyrimidin-6-yI)-2-fluoro-4-methylphenyl)urea as a white solid (0.047 g, 63% yield; 2 steps). 'H NMR (400 MHz, DMSO-d6): 5 8.76 (s, IH), 8.63 (s, IH), SA8 (s, IH), 7.96 (d, J = 8A Hz, 1H), 7.79 (s, IH), 7.68 (s, IH), 7.54 (brs, IH), 7.33 (s, IH), 7.12 (d, J = 12.4 Hz, IH), 4.82 (brs, IH), 4.60 (t, J= 6.8 Hz, IH), 3.78-3.74 (m, IH), 3.59-3.52 (m, 5H), 2.01 (s, 3H), 1.44 (s, 9H); (ESI) m/z: 539.2 (M+H*).
Example 125: Using general metliod B, Example B15 (0.070 g, 0.30 mmol) and Example A26 (0.093 g, 0.30 mmol) were combined to afford l-(2-fluoro-4-methyl-5-(l-methyl-7-(memylmnino)-2-oxo-l,2"dihydro-l,6-naphthyridin-3-yl)phenyl)-3-(3-(trifluoromethyl)isoxazol-5-yi)urea (SO mg, 55% yield). *H NMR (400 MHz, DMSO- Example 126: Using general method B, Example B15 0.0378 g, 0.160 mmol) and Example A7 (0.0455 g, 0.123 mmol) were combined to afford l-(5-(7-(2-(dimethylamino)ethylamino)-l-methyl-2-oxo-l,2-dihydro-l,6-naphthyridin-3-yl)-2-fIuoro^l-methylphenyl)-3-(3-(trifluoromethyI)isoxazol-5-y])urea (0.018 g, 27% yield) as a white solid. U was converted to corresponding mesylate salt by reacting with MsOH (1.0 eq.). 'H NMR (400 MHz, DMSO-d6), 5 10.9 (s, IH), 9.31 (m, IH), 8.81 (s, IH), 8.41 (s, IH), 7.77 (d, J = 8.4 Hz, IH), 7.70 (s, IH), 7.29 (m, IH), 7.16 (d,y= 12.0 Hz, lH)36.39(s, IH), 6.31 (s, IH), 3.65 (q, J= 5.2 Hz, 2H), 3.47 (s,

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3H), 3.23 (m, 2H), 2.79 (d, J= 2.0 Hz, 6H), 2.24 (s, 3H), 2.04 (s, 3H); MS (ESI) m/z; 548.3 (M+H+).
Example 127: Using general method B, the carbamate of B2 (0.0463 g, 0.195 mmol) and Example A6 (0.0482 g, 0.130 mmol) were combined to afford 1-(3-tert-butyl-l-methyl-1H-pyrazoI-5-yl)-3-(5-(2-(2-(dimethylamino)ethylamino)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yI)-2-fluoro-4~methylphenyl)iirea (0.046 g, 64% yield) as a white solid. It was converted to the corresponding HC1 salt by reacting with HC1 (4.0 M HC1 in dioxane, 1.0 eq.). 'H NMR (400 MHz, DMSO-d6), 5 9.78 (s, 1H), 9.61 (s, 1H), 9.16 (s, 1H), 8.89 (s, 1H), 8.68 (s, 1H), 8.02 (s, 1H), 7.94 (d, J= 8.0 Hz, 1H), 7.73 (s, 1H), 7.16 (d,J= 12.4 Hz, 1H), 6.06 (m, 1H), 3.97 (m, 3H), 3.54 (m, 3 H), 3.32 (m, 2H), 2.82 (d, J= 4.4 Hz, 6H), 2.06 (s, 3H), 1.17 (s, 9H); MS (ESI) m/z: 550.2 (M+H+).
Example 128: Using general method A, the TROC carbamate of Example B18 (208 mg, 0.658 mmol) and Example A40 (120 mg, 0.470 mmol) were combined to afford 1 ~(3-tert-butylisoxazol-5-yl)-3-(2-Quoro-5-(2-oxo-l,2-dihydro-l>6-naphthyridin-3-yl)phenyl)urea (35 mg, 18% yield). *H NMR (300 MHz, DMSO-rf6): § 1.22 (s, 9 H), 6.07 (s, 1 H), 7.20-7.22 (m: 1 H), 7.31-7.35 (m, 1 H), 7.42-7.45 (m, 1 H), 8.15 (s; 1 H), 8.43-8.46 (m, 2 H), 8.80 (br. s, 1 H), 8.91 (br. s, 1 H), 10.3 (br. s, 1 H), 12.2 (br. s, 1 H); MS (ESI) m/z: 422.2 (M+H+).
Example 129: Using general method A. the TROC carbamate of Example B18 (0.256 g, 0.81 mmol) and Example A6 (0.300g, 0.81 mmol) were combined to provide l-(3-tert-butylisoxazol-5-yl)-3-(5-(2-(2-(dimetliylamino)ethy]amino)-8-methyl-7-oxo-7,8-dihydropyrido[2}3-d]pyriimdin-6-yl)-2-fluoro-4~methylphenyl)urea, which was converted to the mesylate salt (27
mg, 6% yield). ]H NMR (400 MHz, DMSO-d6): 5 10.36 (s, 1H), 9.62 (brs, 1H), 8.74 (s, 1H),
8.64 (s, 1H), 7.97 (brs, 1H), 7.85 (d, J= 9 Hz), 7.70 (s, 1H), 7.34 (d, J = 12Hz, 1H), 5.94 (s, 1H), 3.68 (brs, 2H), 3.28 (brs, 2H), 2.90 (brs, 6H), 2.23 (s, 3H), 2.03 (s, 3H), 1.16 (s, 9H); MS (ESI, m/z: 537.3, M+H+).
Example 130: Using general method B, the carbamate of 5-MutyIisoxazol-3-amine (0.029 g, 0.130 mmol) and Example A6 (0.032 g, 0.086 mmol) were combined to afford l-(5-tert-

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butylisoxazol-3-yl3-(5-(2-(2-(dimethylamino)ethylamino)-8-metliyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yI)-2-fluoro-4-metiiyIphenyl)urea (0.011 g, 24% yield) as a white solid. It was converted to the corresponding mesylate salt by reacting with MsOH (1.0 eq.). 'H NMR (400 MHz, DMSO-d6): 5 9.80 (s, IH), 9.34 (m, IH), 8.77 (s, 1H), 8.69 (s, IH), 7.99 (m, IH), 7.92 (d, J= 8.0 Hz, IH), 7.74 (s, IH), 7.18 (d, J*= 12.0 Hz, IH), 6.42 (s, IH), 3.70 (q, J = 6.0 Hz, 2H), 3.61 (m, 2H), 2.84 (s, 6 H), 2.31 (s, 3H), 2.07 (s, 3H), 1.33 (s, 3H)t 1.25 (s, 9H); MS (ESI) m/z: 537.3 (M+H4).
Example 131; A solution l-(3-cyclopentyl-l-methyl-lH-pyrazol-5-yl)-3-(2-fiuoro-4-methyl-5-(8-mediyl-2-(mefliylsultlnyl)-7-oxo-7,8-dihydropyrido[2.3-dJpyrirnidin-6-yl)phenyI)urea from Example 122 (80 mg, 0.15 mmol) in THF (1 mL) was treated with N,N-dimethylethylenediamine (0.080 mL. 0.74 mmol). The reaction was stirred 1 h at RT, diluted with EtOAc (15 mL) and washed with 2 M aq Na2C03 (2 x 10 mL), water (10 mL) and brine (10
mL). The organics were dried (Na7SO ), concentrated in vacuo and chromatographed on reverse
phase silica gel to provide l-(3-cyclopentyl-l-methyl-1 H"pyrazol-5-yl)-3-(5-(2-(2-(dimemylamino)emylamino)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-2-fluoro-4-methylphenyI)urea (33 mg, 39 % yield). lH NMR (400 MHz, DMSCW6): 5 8.87 (s, 1 H), 8.72 (d, J = 2.0 Hz, 1 H), 8.65 and 8.60 (brs, 1 H),7.91 (d, J = 8.6 Hz, 1 H), 7.75 and 7.59 (m, 1 H), 7.66 (s, 1 H), 7.14 (d, J= 8.4 Hz, 1 H), 5.98 (s, 1 H), 3.59-3.43 (m, 8 H), 2.86 (m, 1 H), 2,21 (br s, 6 H), 2.49 (m, 2 H obscured by solvent), 2.06 (s, 3 H), 1.87 (m, 2 H), 1.66-1.48 (m, 6 H); MS (ESI) m/z: 562.3 (M+H4).
Example 132: Using general method F, l-isocyanato-3-(trifluoromethyi)benzene (0.120 g, 0.648 mmol) and Example A6 (0.240 g, 0.648 mmol) were combined in ethyl acetate to provide l-(5-(2-(2-(dimediylamino)ethylamino)-8-Tnemyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-2-
fluoro-4-methylphenyI)-3-(3-(trifluoromethyl)phenyl)urea (106 mg, 28% yield) !H NMR (400 MHz, DMSO-d6): 59.34 (s, IH), 8.65 (m, IH), 8.65 (m, IH), 8.59 (m,lH)), 8.02 (s, IH), 7.91
(d, J = 9Hz; IH), 7.74 (m, IH), 7.67 (s, IH), 7.49 (m, 4H), 7.29 (d, J = 6.5Hz, IH), 7.15 (d, J -12Hz, IH); 3.45-3.6 (m, 4H), 2.18 (s, 6H), 2.07 (s, 3H), 1.97 (s, 3H); MS (ESI, m/z: 558.3, M+H+).

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Example 133: Using the general method E, l-(l-tert-butyl-lH-pyrazol-4-yl)-3-(2-fluoro-4-methyl-5-(S-methy2-(memyIsulfinyl)-7-oxo-7,8-dihydropyridc3[2,3-d3pyrimidin-6-yi)phenyl)urea from Example 109 (0.081 g, 0.16 mmol) and propan-2-amine (0.029 g, 0.49 mmol) were combined in THF (1 raL) to provide l-(l-tert-butyl-lH-pyrazol-4-yl)-3-(2-fluoro-5-(2-(isopropylamino)-8-metliyi-7-oxo-7,8-dihydropyrido[2,3-d3pyrimidin-6-yl)-4-methylphenyl)urea as a wliite solid (0.042 g, 50% yield). !H NMR (400 MHz, DMSO-d6): 5 8.63 (s, IE), 8.60 (s, IE), 8.40 (d, J=2.0 Hz, IH), 7.93 (d, J= 8.4 Hz, IE), 7.77 (s, IH), 7.64 (s, IH), 7.36 (s, IH), 7.10 (d, J~ 12.4 Hz, IH), 4.16-4.13 (m, IH), 3.56-3.54 (m, 3H), 2.05 (s, 3H), 1.45 (s, 9H), 1.20 (d, J = 6.0 Hz, 6H); (ESI) m/z: 507.2 (M+H4).
Example 134: Using general method B, the carbamate of 5-H>utylisoxazoI-3-amine (0.050 g, 0.22 mmol) and Example A26 (0.070 g, 0.22 mmol) were combined to afford 1 -(5-tert-butylisoxazol-3-yl3-(2-fluoro-methyl-5-(l-methyl"7-(methylamino)-2-oxo-l,2-dihydro-l,6-naphmyridin-3-yl)phenyl)urea {66 mg, 62% yield). 'H NMR (400 MHz, DMSO-d6): 5 9.78 (s, IH), 8.73 (s, IH), 8.38 (s, IH), 7.91 (d, J= 8.4 Hz: IH), 7.66 (S, IH), 7.14 (d, J= 12. 0 Hz, IH), 7.03 (q, .7=4.8 Hz, IH), 6.43 (s, IH), 6.17 (s, IH), 3.50 (s, 3H), 2.85 (d, J = 4.4 Hz, 3H), 2.07 (s, 3H), 1.28 (s, 9H); MS (ESI) m/z: 479.2 (M+H").
Example 135: Using a procedure analogous to Example 93, Example B12 (0.119 g) and Example A12 (0.086 g, 0.289 mmol) were combined to afford l-(2-fluoro-5-(8-methyl-2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)-3-(3-(l-hydroxy-2-methylpropan-2-yl)-I-metliyl-lH-pyrazol-5-yl)urea (0.043 g, 32% yield) as a light yellow solid. 'H NMR (400 MHz, DMSO-d6), 8 8.57 (s, IH), 8.29 (dd, J* 7.6, 2.0 Hz, IH), 7.85 (s, IH), 7.40-7.35 (m, IH), 7.18 (dd,/= 10.4, 8.4 Hz, IH), 6.17 (s, IH), 3.75-3.68 (m, 6H), 3.53 (s, 2H), 3.03 (s, 3H), 1.25 (s, 6H); MS (ESI) m/z: 495,2 (M+H+).
Example 136: To a solution of l-(l-tert-butyMH-pyrazoI-4-yl)-3-(2-fluoro-5-(8-methyl-2-(mediyIsulfinyl)-7-oxo-7,8-dihydropyrido[2,3-d3pyrimidin-6-yl)phenyl)urea from Example 65 (0.082 g, 0.16 mmol) in THF (I mL) was added 2,2-dimemyf-l,3-dioxoIan-4-yl)methanamine

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(0.065 g, 0.48 mmol). After stirring for 20h at RT, the solvent was removed and crude residue was purified by silica gel chromatography to afford l-(l-tert-butyl-lH-pyrazol-4-yl)-3-(5-(2-((2,2-dimethyl-l,3-dioxolan-4-yl)methylamino)-8-metliyl-7-oxo-7,S-dihydropyrido[2,3-d]pyrimidin-6-yi2-fluorophenyl)urea (64 mg) as a white solid.
This intermediate was stirred in THF and 2M HC1 (5 mL, 4:1) for 2h at RT. The reaction mixture was concentrated to 1 mL, and 2N NaOH was added until the pH of the solution was around 8. The resultant solid was filtered, washed with water and dried to provide l-(l-tert-butyl-lH'pyra2ol-4-yl)-3-(5-(2-(2,3-dihydroxypropyIamino)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-2-fluorophenyl)urea as a white solid (53 mg, 61% yield, 2 steps). 'H NMR (400 MHz, DMSCMs): 8 8.70 (brs: 2H), 8.65 (s, 1H), 8.49 (d, J= 2.0 Hz, 1H), 8.40 {d,J= 8.0 Hz, 1H), 7.85 (s, 1H), 7.81 (s, IH), 7.70-7.67 (m, IH), 7.38 (a, 1H), 7.24 (s, 1H): 7.22 (s, IH), 4.79 (d, J = 4.8 Hz, 1H), 4.58 (t, J= 5.6 Hz, 1H), 3.73-3.48 (m, 5H), 3.38-3.33 (m, 3H), 1.47 (s, 9H); (ESI) m/z: 525.3 (M+H+).
Example 137: Using general method G, 2-amino-5-t-butyl-l,3,4-thiadiazole (0.5000 g, 3.2 mmol) and Example A10 (0.342 g, 1.04 mmol) were combined to afford l-(5-t-butyM,3,4-thiadiazol-2-yl)-3-(241uoro-4-methyI-5-(8-methyl-2mediyltluo)-7-oxo-7,8-dihydropyrido[2!3-d]pyrimidin-6-yl)pheny0urea (0.345 g, 65% yield) as a white solid which was used as is in the next reaction. 'H NMR (400 MHz, CDC13): 5 8.67 (s, IH), 7.94 (d, J = 7.6 Hz), 7.67 (s, IH), 6.96 (d, J = 11.2 Hz), 3.91 (s, 3H), 2.69 (s, 3H), 2.15 (s, 3H), 1.45 (s, 9H); MS (ESI) m/z: 514.2 (M+H).
Using a procedure analogous to Example Al, l-(5-t-butyH,3,4-thiadiazoI-2-yl)-3-(2-fluoro-4-memyl-5-(8-methyl-2-(mediylthio)~7-oxo-7.8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (0.345 g, 0.672 mmol) and 2.00M MeNH2/THF (3.36 ml, 6.72 mmol) were combined to afford l-(54ert-butyl-l,3,4-thiadiazoI-2-yl)-3-(2-fluoro-4-methyl-5-(8-methyl-2-(methylamino)"7-oxo-7,8^ihya>opyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (0.311 g, 93% yield) as a white solid. lR NMR (400 MHz, DMSO-rf*): 5 7.822-7.75 (m, 3H), 7.69 (s, IH), 7.39-7.37 (m, IH), 7.34-7.30 (m, IH), 7.16 (d, J = 12.0 Hz, IH), 2.90 (brd, J = 4.8 Hz, 3H), 2.35 (s, 3H), 2.09 (s, 3H), 1.34 (s, 9H); MS (ESI) m/z: 497.0 (M+H).

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Example 138: Using general method B, the carbamate of Example B19 (0.080 g, 0.36 mmol) and Example A7 (0.088 g, 0.24 mmol) were combined to afford l-(1-tert-butyl-lH-pyrazol-4-yl)-3-(5-(7-(2-(dimetiiylainino)emylamino)-l-methyl-2-oxo-l,2~dihydro-l,6-naphthyridin-3-yl)-2-iluoro-4-methyIphenyI)urea (0.0469 g, 37% yield) as a white solid. ft was converted to corresponding mesyalte salt by reacting with MsOH (1.0 eq.). ]H NMR (400 MHz, DMSO-d^): 8 9.38 (s, 1H), 8.66 (s, 1H), 8.44-8.43 (m, 2H), 7.94 {±J= 8.4 Hz, 1H), 7.76 (s51H), 7.71 (s, 1H), 7.37 (s, 1H), 7.27 (t, /= 5,6 Hz, 1H), 7.11 (d, J= 12.0 Hz, 1H), 6.34 (s, 1H), 3.68 (q, J = 5.6 Hz, 2H), 3.50 (s, 3H), 3.27 (t, /= 5.6 Hz; 2H), 2.83 (s, 6H), 2.30 (s, 3H), 2.05 (s: 3H), 1.45 (s, 9H); MS (ESI) m/z: 535.2 (M+H*).
Example 139: Using General Method B, Example B15 (100 mg, 0.381 mmol) Example A16 (116 mg, 0.346 mmol) were combined to afford l-(2,4-difluoro-5-(8"methyl-2-(metliylthio)-7-oxo-7>8-dihydropyrido[2;3-d]pyrimidin-6-4)phenyl)0-(3-(trifluoromethyl)isoxazoI-5-yl)urea (65 mg, 37% yield) as an oil, which was used without purification in the next reaction.
Using a procedure analogous to Example Al, l-(2,4-difluoro-5-(8-metliy3-2-(memylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)-3"(3-
(trifluoromethyl)isoxaxo!-5-yl)urea (65 mg, 0.130 mmol) and 2.0N rnethylamine in THF (0.63 mL, 1.3 mmol) were combined to afford l-(2,4-difluoro-5-(8-methyl"2-(methylamino)-7-oxo-7,8Kiihydropyrido[23-d]pyiiinidm-6-yl)phenyl)-3-(3-(trifluoromethyl)isoxazol-5-yl)urea (8 mg, 13% yield). MS (ESI) m/z: 496.0 (M+H+).
Example 140: Using General Method B, Example B15 (120 mg, 0.457 ramol) and Example A17 (100 mg, 0.286 mmol) were combined to afford l-(4-chioro-2-fluoro-5-(8-methyl-2-(methyl thio)-7-oxo-7,8 -dihydropyrido [2,3 -d]pyrimidin-6 -yl)phenyl)-3-(3 -
(trifluoromethyl)isoxazol-5-yI)uTea (75 mg, 50% yield) wliich was used without further purification. MS (ESI) m/z: 529.0 (M+H+).
Using a procedure analogous to Example Al, l-(4-chloro-2-fluoro-5-(8-methyI-2-(memylthio)-7-oxo-7,8-dihydropyrido[2,3-d3pyrimidin'-6-yl)phenyl)-3--(3-(trifluoromethyi)isoxazol-5-yl)urea (75 mg, 0.140 mmol) and 2.0 N rnethylamine in THF (0.71 mL) were combined to afford l-(4-chloro-2-fluoro-5-(8-methyl-2-(metliylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyI)-3-(3-(trif!uorometliyI)isoxazol-5-yl)urea (15 mg,

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21% yield). (H NMR (300 MHz, DMSO-d6) 6 2.89 (s, 3 H), 3.51-3.58 (m, 3 H), 6.48 (s, 1H), 7.61 (d, J= 11 Hz, 1 H), 7.77 (s, 1 H), 7.88-7.90 (m, 1 H), 8.04 (d, J= 9.5 Hz, 1 H), 8.61-8.69 (m, 1 H), 9.01 (s, 1 H), 11.0 (s, 1 H); MS (ESI) m/z: 512.0 (M+H+),
Example 141: In a solution of ethanol:water:dioxane (1:1:1,9 rL) was placed ethyl 1 -tert-butyl-5-(trifluoromethyl)-lH-pyrazo!e-4-carboxylate (750 mg, 2.84 mmol) and lithium hydroxide hydrate (357 mg, 8.51 mmol). The mixture was stirred at *U) °C for 3 hrs and then at RT overnight. The mixture was diluted with water (25 mL) and IN HO (10 mL) and extracted with ethyl acetate (2 x 25 mL). The combined organic phases were washed with brine (20 mL), dried (Na2SC4) and evaporated at reduced pressure to afford l-tert-butyl-5-(trifluoromethyl)-lH-pyrazoIe~4-carboxylic acid (646 mg, 94% yield) as a solid. 'l{ NMR (300 MHz, DMSO-tfc) 8 1.63 (s, 9 H), 7.92 (s, 1 H); MS (ESI) m/z: 259.0 (M+Na*).
Using General Method D, l-tert-butyl-S-ftrifluoromethyO-lH^pyrazole-carboxylic acid (200 mg, 0.847 mmol) and Example A3 (268 mg, 0.847 rnmol) wc^-e combined to afford l-(l-tert-buryl-5-(trifluoromethyl)-lH-pyrazol-4-yl)-3-(2-fluoro-5-(8-methyl-2-(metliylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea(247 mg, 53% yield).
Using a procedure analogous to Example Al, l-(l-tert-butyl-5-(trifluoromethyl)-lH-pyrazoi-4-yl)-3-(2-fluoro-5-(8-memyl-2-(memyldiio)-7-oxo-7,8--dihydropyrido[23-d]pyrimidin-6-yl)phenyl)urea (247 mg, 0.449 mmol) and 2.0N methylaminfe in THF (2.25 mL, 4.49 mmol) were combined to afford l-(l-tert-butyl-5-(trifluoromethyl)-lU-pyrazol-4-yl)-3-(2-fluoro-5-(S-methyl-2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyiimi(Jin-6-yI)phenyl)urea (152 mg, 63% yield). lH NMR (300 MHz, acetone-) 8 1.64 (s, 9 H), 2.82 (s, 3 H), 3.06 (m, 3 H), 6.80-6.95 (in, 1 H), 7.14-7.19 (m, 1 H), 7.38-7.42 (m, 1 H), 7.85 (s, l H), 8.06 (s, 1 H), 8.11 (br. s, 1 H), 8.50 (br. s, 1 H), 8.57-8.59 (ra, 1 H), 8.60-8.63 (m, 1 H); M£ (ESI) m/z: 533.3 (M+H+).
Example 142: To a stirring solution of 4-crJoro-3-(rrifluoromethy])phenyl isocyanate (0.0750g, 0.401 mmol, 1.00 eq) in THF (5 ml) at 22 °C was added Example A25 (0.125 g, 0.401 mmol, 1.00 eq). The reaction became homogeneous and then solids precipitated. The suspension was stirred overnight at RT. The reaction was chilled thoroughly at 0-5 aC. The solids were collected by filtration, rinsed well with ice-cold THF and dried on the filter. The free base thus obtained was treated with MsOH in THF (2 wt%, 1.64 g, 0.342 mmol, 1.0 eq) to afford l-(2-

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fluoro-4-methyl-5-(l-methyl-7-(methylamino)-2-oxo-I,2-dihydro-lJ6-naphthyridin-3-yl)phenyl)-3-(3-(trifluorometliyl)phenyl)urea (182 mg, 76% yield) as the mesylate salt as a nearly white solid. ]H NMR (400 MHz, DMSO-d6): 5 9.34 (s, 1H), 8.65 (brs, 1H), 8.51 (s, 1H), 8.05 (s, 1H), 7.96 (d, J = 8.4 Hz, 1H), 7.82 (s, 1H), 7.51-7.44 (m, 2H), 7.30 (d, J = 7.6 Hz, 1H), 7.18 (d, J = 12.4 Hz, 1H), 6.51 (s, 1H), 3.54 (s, 3H), 2.96 (s, 3H), 2.30 (s, 3H), 2.08 (s, 3H); MS (ESI) m/z: 500.3 (M+H).
Example 143: Using a procedure analogous to Example 142, 4-chloro-3-(trifluoromethyl)phenyl isocyanate (0.1000 g, 0.451 mmol, 1.00 eq) and Example A26 (0.141 g, 0.451 mmol, 1.00 eq) were combined to afford l-(4-chloro-3-(trifiuoromethyl)phenyl)-3-(2-tluoro-4"methyl-5-(l-methyl-7-(methylamino)-2-oxo-l,2-dihydro-l)6-naphthyridm-3-yl)pheny])urea mesylate (168 mg, 59% yield) as a nearly white solid. !H NMR (400 MHz, DMSO-40 5 9.47 (s, 1H), 8.65 (brs, 1H), 8.48 (s, 1H), 8.12 (d, J = 2.4 Hz, 1H), 7.91 (d, J = 8.8 Hz, 1H), 7.78 (s, 1H), 7.59 (d, J = 8.8 Hz, 1H), 7.51 (dd, J = 2.4 and 8.8 Hz, 1H), 7.18 (d, J = 12.4 Hz, 1H), 6.43 (s, 1H), 3.53 (s, 3H), 2.94 (s, 3H), 2.28 (s, 3H), 2.08 (s, 3H); MS (ESI) m/z: 534.2 (M+H+).
Example 144: 3-(Trifluoromethyl)phenyl isocyanate (0.075 g, 0,40 mmol. 1.0 eq) and Example A10 (0.13 g, 0.40 mmol, 1.0 eq) were combined in THF (5 ml) and stirred at RT overnight. The resulting suspension was chilled at 0-5 °C and the solids collected by filtration. The solids were washed sparingly with ice-cold THF and dried on the filter to afford l-(2-fluoro-4-metliyl-5-(8-methyl-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6"yl)phenyl)-3-(3-(trifluoromethyl)phenyl)urea (92 mg, 44% yield) as a white solid which was used as is in the next reaction. 'H NMR (400 MHz, acetone-^) 5 8.89 (s, 1H), 8.78 (brs, 1H), 8.16-8.08 (m, 2H), 7.88 (s, 1H), 7.63 (brd, J = 8.0 Hz, 1H), 7.51 (dd, J = 8.0 and 16. 4 Hz, 1H), 7.33-7.31 (m, 1H), 7.09 (d, J = 12.4 Hz, 1H), 3.76 (s, 3H), 2.67 (s, 3H), 2.17 (s, 3H); MS (ESI) m/z: 518.0 (M+H+). Using a procedure analogous to Example Al, l-(2-fluoro-4-methyl-5-(8-methy]-2-(methyltliio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)-3-(3-
(trifluoromethyl)phenyl)urea (0.092 g, 0.18 mmol) and 2.00M MeNH2 /THF (0.89 ml, 1.8 mmol) were combined to afford 1 -(2-fluoro-4-metliyl-5-(8-methyl-2-(methylammo)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)-3"(3-(triiluoromethyl)phenyl)urea (28 mg, 31%

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yield) as a white solid. fH NMR (400 MHz, DMSO-40 5 8.78 (s, IH), 8.61 (s, IH), 8.12-8.09 (in, 2H), 8.04 (s, IH), 7.68 s, IH), 7.64 (brd, J = 10.0 Hz, IH), 7.50 (dd, J = 7.6 and 16.0 Hz, IH), 7.31 (brd, J = 7.6 Hz, IH), 7.06 (d, J= 12.4 Hz, IH), 6.82 (brs, IH), 3.59 (s, 3H), 3.08 (brd, J = 4.4 Hz, 3H), 2.16 (s, 3H); MS (ESI) m/z: 501.0 (M+H+).
Example 145: Using general method E, l-(l-tert"butyMH-pyrazol-4-yl)-3-(2-fluoro-4-niethyl-5-(8-methyl-2-(methylsulfinyI)-7-oxo-7,8-dihydropyrido[2,3-4]pyrimidin-6-yl)phenyl)urea from Example 109 (0.081 g, 0.16 mmol) and cyclopropanamine (0.027 g, 0.48 mmol) were combined in THF (I mL) to provide l-(l-tert-butyl-lH-pyrazol-4-yl)-3-(5-(2-(cyclopropylamino)-8-me(hyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-2-fluoro-4-methylphenyl)urea as a white solid (0.051 g, 64% yield). ]H NMR (400 MHz, DMSO-): 6 8.64 (s, IH), 8.60 (brs, IH), 8.40 (d, J= 1.6 Hz, IH), 8.06-8.04 (m, IH), 7,94 (d,J= 8.8 Hz, IH), 7.77 (s, IH), 7.66 (s, IH), 7.36 (s, IH), 7.10 (d, J= 12.4 Hz, IH), 3.61-3.54 (m, 3H), 2.78-2.83 (m, IH), 2.05 (s, 3H), 1.45 (s, 9H), 0.725 (brs, 2H), 0.55-0.53 (m, 2H): (ESI) m/z: 505.2 (M+H+).
Example 146: Using general method E, l-(l-tert-butyl-lH-pyrazol-4-yl)-3-(2-fluoro-4-methyI-5-(8-methyl-2-(methylsulfinyl)-7--oxo--7.8-dihydropyrido[2.3-d]pyrimidin-6-yl)phenyl)urea from Example 109 (0.081 g, 0.16 mmol) and (S)-2-aminopropan-l-ol (0.036 g, 0.48 mmol) were combined in THF (1 mL) to provide (S)-I-(l-tert-butyl-lH-pyrazoI-4-yl)-3-(2-fluoro-5-(2-(l-hydroxypropan-2-ylamino)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-4-methylphenyl)urea as a wliite solid (0.062 g, 75% yield). ]H NMR (400 MHz, DMSO-d6): S 8.64 (s, IH), 8.60 (s, IH), 8.40 {dtJ= 1.6 Hz, IH), 7.94 (d, J= 8.4 Hz, IH), 7.77 (s, IH), 7.64 (s, IH), 7.59 (d, J= S.O Hz, IH) 7.36 (s, IH), 7.10 (d,J= 12.4 Hz, IH), 4.72 (t, /= 5.6 Hz, IH), 4.10-4.06 (m, IH), 3.65-3.53 (m, 3H), 2.05 (s, 3H), 1.45 (s, 9H), 1.17 (d, J = 6.4 Hz, 3H); (ESI) m/z: 523.2 (M+H*).
Example147; Using genera! method E, l-(l-tert-butyl-lH-pyrazoI-4-yl)-3-(2-fluoro-4-methyl-5-(8-methyl-2-(memylsuIfinyl)-7-oxcH-7,8-dmydropyrido[2,3-d]pyrimidin-6-yI)phenyI)urea from Example 109 (0.085 g, 0.17 mmol) and (R)-2-aminoprapan-l-ol (0.037 g, 0.50 mmol) were combined in THF (1 mL) to provide (R)-l-(l-tert-butyl-lH-pyrazoI-4-yl)-3-(2-fluoro-5-(2-(l-hydroxypropan-2-ylamino)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-4-

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methylphenyl)urea as a white solid (0.055 g, 63% yield). *H NMR (400 MHz, DMSOc/6): 5 8,64 (s, IH), 8.60 (s, IH), 8.40 (d, J = 2.0 Hz, IH), 7.94 (d, J= 8.8 Hz, IH), 7.77 (s, IH), 7.64 (s: 1H), 7.59 (d,J = S.O Hz, IH) 7.36 (s, IH), 7.10 (d,J= 12.4 Hz, IH), 4.72 (t, J= 5.6 Hz, IH), 4.10-4.06 (m, IH), 3.56-3.53 (m, 3H), 2.05 (s, 3H), 1.45 (s, 9H), 1.17 (d, J= 6.4 Hz, 3H); (ESI) m/z: 523.2 (M+H+).
Example 148: Using general method B, the carbamate of 5-MmtylisoxazoI-3-amine (0.07 g, 0.31 mmol) and Example A17 (0.11 g, 0.31 mmol) were combined to afford l-(5-tert-butylisoxazoI-3-yl)-3"(4-cWoro-2"fluoro-5-(8-memyI-2-(memylmio)-7-oxo-7,8-dihydi'opyrido[2,3-d]pyriimdin-6-yl)phenyl)urea (48 mg, 30% yield). MS (ESI) m/z: 517.0 (M+fT).
Using a procedure analogous to Example Al, I-(5-tert-butyIisoxazoi-3-yI)-3-(4-chloro-2-fluoro-5-(8"mediyI-2-(memyltm^)-7K)xo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yI)phenyl)urea (0.048 g, 0.093mmol) was treated with mCPBA (70% wt, 0.027 g, 0.11 mmol) and then N-methylamine (2.0M in THF, 0.19 mL, 0.37 mmol) to afford l-(5-tert-butyIisoxazol-3-yl)~3-(4-chJoro-2-fluoro-5-(8-methyl -2- (methyl amino)- 7-oxo-7,8-dihydropyrido[2, 3-d] pyrimidin- 6-yl)phenyl)urea (30 mg, 65% yield). 'H NMR (400 MHz, DMSO-4, major rotomer): 5 9.86 (brs, IH), 8.92 (brs, IH), 8.62 (s, IH), 8.15 (d,y = 8.8 Hz, IH), 7.89 ( m, IH), 7.76 (s, IH), 7.58 (d, J - 10.8 Hz, IH), 6.44 (s, IH), 3.59 (brs, 3H), 2.90 (brd,y- 4.8 Hz, 3H), 1.25 (s, 9H); MS (ESI) m/z: 500.0 (M+rf).
Example 149: Using general method B, the carbamate of 5-f-butylisoxazol-3-amine (0.07 g, 0.31 mmol) and Example A41 0.11 g, 0.31 mmol) were combined to afford l-(5-tert-butyIisoxazoI-3-yl)-3-(5-(8-ethyI-2 Using a procedure analogous to Example AI, I-(5-tert-butylisoxazol-3-yI)-3-(5-(8-e£hyi-2-(mediylmio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yI)-2-fluoro-4-memylphenyl)urca (0.097 g, 0.19 mmol) was treated with mCPBA (70% wt, 0.056 g, 0.23 mmol) and then N-methylamine (2.0M in THF, 0.38 mL, 0.76 mmol) to afford l-(5-tert"butylisoxazol-3-yl)-3-(5-(S-ethyl-2-(memylainino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrhnidin-6-yl)--2-fluoro-4-methylphenyl)urea (59 mg, 63% yield). *H NMR (400 MHz, DMSO-6, major rotomer): 5 9.79 (s, 1H)5 8.74 (brs, IH), 8.60 (s, IH), 7.91 (d, J= 8.4 Hz, IH), 7.80 ( m, IH), 7.67 (s, IH), 7,16

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(d, J= 12.0 Hz, IH), 6.44 (s, IH), 4.35 (m, 2H), 2.89 (brd: J = 4.4 Hz, 3H), 2.06 (s, 3H), 1.25 (s, 9H), 1.19 (m, 3H); MS (ESI) m/z: 494.2 (M+H*).
Example 150: Using general method B, the carbamate of 3-isopropyl-l-phenyl-lH-pyrazol-5-amine (0.061 g, 0.21 mmol), and Example A50 (0.07 g, 0.21 mmol) were combined to afford 1-(5-(8-etliyl-2-(methylamino)-7»oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-2-fIuoro-4-methylphenyl)-3-(3-isopropyl-l-phenyl-lH-pyrazol-5-yl)urea as an off-white solid (53 mg, 45%, yield). 'H NMR (400 MHz, DMSCW6): 5 8.90 (s, IH), 8.82 (s, IH), 8.67-8.60 (m, IH), 7.91 (d, J = 8.4 Hz, IH), 7.81-7.79 (m, IH), 7.64 (s, IH), 7.54-7.47 (m, 4H), 7.43-7.38 (m, IH), 7.11 (d, J= 12.4 Hz, IH), 6.30 (s, IH), 4.36-4.32 (m, 2H), 2.89-2.80 (m, 4H), 2.04 (s, 3H), 1.23-1.17 (m, 9H); MS (ESI) m/z: 555.2 (M+H+).
Example 151: Using genera] method D, Example B30 (0.051 g, 0.3 mmol) and Example A50 (0.1 g, 0.3 mmol) were combined in presence of triethylamine (0.092 g, 0.91 mmol) and diphenylphospharyl azide (0.13 g, 0.45 mmol) to afford l-(l-tert-buty]-lH-pyrazol-4-yl)-3-(5-(8-emyl-2-(memylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)--2--fluoro-4-methylphenyl)urea (65 mg, 44% yield). !H NMR (400 MHz, DMSCW6); 5 S.63 (s, IH), 8.60 (s, IH), 8.40 (d, J = 2.0 Hz, IH), 7.94 (d, J= 8.8 Hz, IH), 7.80-7.77 (m, 2H), 7.65 (s, IH), 7.36 (s, 1H), 7.10 (d, J = 12.0 Hz, IH), 4.36-4.32 (m, 2H), 2.89 (d, J=4.4 Hz, 1H), 2.04 (s, 3H), 1.45 (s, 9H), 1.24-1.20 (m, 3H); MS (ESI) m/z: 493.2 (M+H+).
Example 152: Using general method A, the TROC carbamate of Example B18 (0.3 g, 0.95 mmol) and Example AI7 (0.3 g, 0.86 mmol) were combined to provide ]-(3-tert-butyIisoxazal-5-yl)-3-(4-chloro-2-fluoro-5-(8-metliyl-2-(methylthio)-7-oxo-7,8-diliydrop>Tido[2,3-
d]pyrimidin-6-yI)phenyI)urea (175 mg, 40 % yield) 3H NMR(400 MHz, DMSO-d6): 510.38
(brs, IH), S.92 (s,lH)), 8.90 (m, IH), 8.17 (d, J= 8.5Hz, IH), 8.00 (s, IH), 7.63 (d, J = 12 Hz, IH), 6.03 (s, IH), 3.54 (s, 3H), 2.50 (s, 3H), 2.61 (s, 3H), 1.21 (s, 9H); MS(ESI) m/z : 517.0 (M+H+).
Using a procedure analogous to Example Al, l-(3-tert-butylisoxazol-5-yI)-3-(4-chIoro-2-fluoro-5-(8-memyl-2-(methylmio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea and methylamine were combined to provide l-(3-tert-butylisoxazo!-5-yl)-3-(4-chk>ro-2-fluoro-

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5-(8-methyl-2-(metliylamino)-7-oxo-7,8-diliydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (88
mg, 50 % yield). *H NMR (400 MHz, DMSO-d6): 810.5 (brs, IH), 9.00 (brs, IH), 8.61 (s, IH),
8.11 (d, J = 9Hz, IH), 7.88 (brs, IH), 7.76 (s, IH), 7.57 (d, J = 12Hz, IH), 6.00 (s, IH), 3.58 (s, 3H), 2.89 (d, J = 5 Hz, 3H), 1.21 (s, 9H); MS(ESI) m/z : 500.3 (M+H*).
Example 153: Using general method A, the TROC carbamate of Example B18 (0.3 g, 0.95 mmol) and Example A41 (0.3g, 0.67 nimol) were combined in presence of N-methylpyrrolidine (0.080g, 0.95 mmol), to provide l-(3-tert-butylisoxazol-5-yl)-3-(5-(8-ethyl-2-(methyIthio)-7HDXo-7,8~dihydropyrido[2,3-d]pyrimidin-6-yl)-2-fluoro--4-methylphenyl)urea (320
mg, 72% yield) *H NMR (400 MHz, DMSO-d6) 510.3 (brs, IH), 8.91 (s,lH)), 8.71 (brs, IH),
7.94 (d, J = 9Hz, IH), 7.89 (s, IH), 7.20 (d, J = 12Hz, IH), 6.00 (s, IH), 3.64 (s, 3H), 4.38 (q, J = 6 Hz, 2H), 2.61 (s, 3H), 2.07 (s, 3H), 1.24 (t, J = 6Hz, , 3H), 1.21 (s, 9H); MS(ESI) m/z : 511.2 (M+H4).
Using a procedure analogous to Example Al, l-(3-tert-butylisoxazol-5-yl)-3-(5-(8-ethyl-2-(metliylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-2-fluoro-4-methylphenyl)urea (0.16g, 0.315 mmol ) and methylamine were combined to provide l-(3-tert-butylisoxazol-5-yl)-3-(5-(8-ethyl-2"(memylarm'no)-7-oxc-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)--2--fluoro-4-
methylphenyl)urea (62mg, 20 % yield). ]H NMR (400 MHz, DMSO-d6): 5 10.3 (brs, IH), 8.67
(brs, IH), 8.61 (brs, IH), 7.88 (d, J = 9Hz, IH), 7.80 (brs, IH), 7.66 (s, IH), 7.16 (d, J = 12Hz, IH), 6.00 (s, IH), 5.73 (s, IH), 4.34 (br, 2H), 2.89 (d, J = 6Hz, 3H), 2.07 (s, 3H), 1.21 (br, 12H); MS{ESI) m/z : 494.2 (M+H+).
Example 154: Using general procedure C, the TROC carbamate of Example B20 (0.150 g, 0.497 mmol, 1.00 eq) and Example A10 (0.164 g, 0.497 mmol, 1.00 eq) were combined to afford l-(2-tluoro-4-methyl-5-(8-methyl-2-(mcthylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)-3-(3-isopropylisoxazol-5-yl)urea (0.203 g, 85% yield) as a pale yellow solid. ]H NMR (400 MHz, DMSO-d6): 8 10.30 (s, IH), 8.90 (s, IH), 8.72 (brs, IH), 7.93 (d, J = 8.4 Hz, IH), 7.89 (s, IH), 7.21 (d, J = 12.4 Hz, IH), 5.96 (s, IH), 3.64 (s, 3H), 2.87 (septet, J = 7.2 Hz, IH), 2.61 (s, 3H), 2.09 (s, 3H), 1.16 (d, J = 6.8 Hz, 6H); MS (ESI) m/z: 483.0 (M+ff).

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Using a procedure analogous to Example Al, l-(2-fluoro-4-methyl-5-(8~methyI-2-(memyltliio)-7-oxo-7,8-dUiydropyrido[2,3-d]pyrimidin-6-yl)pheiiyl)-3-(3-isopropylisoxazol-5-yl)urea (0.203 g, 0.421 mmol, 1.00 eq) and 2.00M MeNH2/THF (2.10 ml, 4.21 mmol, 10.00 eq,) were combined o afford I -(2-fIuoro-4-methyl-5-(8-methyI-2-(methyIamino)-7-oxo-7J8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)-3-(3-isopropyHsoxazol-5-yl)urea (41 mg, 21 % yield) as a pale yellow powder. 'H NMR (400 MHz, DMSO-^) 6 10.28 (s, IH), 8.67 (brs, IH), 8.60 (s, IH), 7.88 (d, J = 8.0 Hz, IH), 7.81 (brq, J = 4.0 Hz, IH), 7.67 9s, IH), 7.17 (d, J - 12.8 Hz, IH), 5.96 (s, IH), 3.59 (s, 3H), 2.90 (d, J = 4.8 Hz, 3H), 2.89 (septet, J = 7.2 Hz: IH), 2.08 (s, 3H), 1.16 (d, J = 7.2 Hz, 6H); MS (ESI) m/z: 466.0 (M+H+).
Example 155: Using general method B, the carbamate of 5-f-butylisoxazol-3-amine (0.07 g, 0.31 mmol) and Example A16 (0.10 g, 0.31 mmol were combined to afford l-(5-tert-butylisoxazol-3-yl)02,4-difluoro-5-(8-methyl-2-(methyltiiio)-7-oxo-7,8-dihydropyrido[2,3-dJpyrimidin-6-yl)phenyl)urea (80 mg, 50% yield). MS (ESI) m/z: 501.0 (M+H^).
Using a procedure analogous to Example Al, l-(5-tert-butylisoxazol-3-yl)-3-(2,4-difluoro-5-(8-methyl-2-(methylthio) -7-oxo-7,8-dihydropyrido[2,3 -d]pyrimidin-6-yl)phenyl)urea (0.080 g, 0,16 mmol) was treated with mCPBA (70% wt, 0.047 g, 0.19 mmol) and then N-methylamine (2.0M in THE, 0.32 raL, 0.64 mmol) to afford l-(3-tert-butylisoxazol"3-yl)-3-(2,4-ditluoro-5-(8-methyl-2-(methylammo)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yi)phenyl)urea (58 mg, 75% yield). 'H NMR (400 MHz, DMSQ-rfe, major rotomer): 5 9.81 (s, IH), 8.78 (brs, IH), 8.63 (s, IH), 8.13 (t, J= 8.4 Hz, IH), 7.89 (m, IH), 7.84 (s, IH), 7.40 (dd, J = 10.0, and 11.2 Hz, IH), 6.45 (s, IH), 3.59 (s, 3H), 2.99 (brd, J=4.8 Hz, 3H), 1.28 (s, 9H); MS (ESI) m/z: 484.2 (M+H+).
Example 156: Using general method D, 3-tert-butyl-l-methyLiH-pyrazole-5-carboxyHc acid (0.061 g, 0.33 mmol) and Example A50 (0.1 g, 0.33 mmol) were combined in presence of triethylamlne (0.1 g, 1 mmol) and diphenylphospharyl azide (0.14 g, 0.5 mmol) to afford l-(3-tert-butyl-l-methyMH-pyrazol-5-yI)-3-(5-(8-ethyl-2-(metliylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-2-tluoro-4-methylphenyI)urea as a white solid (140 mg, 83% yield). !H NMR (400 MHz, DMSO-d6): 8 8.86 (s, IH), 8.73 (s, IH), 8.59 (s, IH), 7.93 (d, J = 8.4 Hz, IH), 7.81-7.79 (m, IH), 7.65 (s, IH), 7.14 {d, J= 12.4 Hz, IH), 6.04 (s, IH), 4.35-4.32

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(m, 2H), 3.58 (s, 3H), 2.89 (d,J = 4.4 Hz, 1H), 2.05 (s, 3H), 1.23-1.16 (m, 12H); MS (ESI) m/z: 507.2 (M+H+).
&cajap]e^l57: Using general method D, 3-tert-buryl-l-methyI-lH-pyrazole-5-carboxylic acid (0.21 g, 1.2 mmol), Example A17 (0.4 g, 1.2 mmol) were combined in presence of triethylamine (0.35 g, 3.5 mmol) and diphenylphospharyl azide (0.48 g, 1.7 mmol) to afford l-(3-tert-butyl-l-methyI-lH-pyrazol-5-yl)-3"(4-chloro-2-fluoro-5-(8-methyl-2-(methylthio)-7-oxo-7,8-dihydropyrido[2]3-d]pyrimidin"6-yl)phenyl)urea as a white solid (0.49 g, 80% yield). rH NMR (400 MHz, DMSO- Using a procedure analogous to example Al, l-(3-tert-butyl-I-memyl-lH-pyrazol-5-yl)-3-(4-chloro-2-fluoro-5-(8-memyl-2-(memylmio)-7-oxo-7,S-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (0.2, 0.38 mmol) and 2 M methylamine in THF (3 eq) were combined and purified via C-18 chromatography to provide l-(3-tert-butyl-l-methyl-lH-pyrazol-5-yl)-3--(4-chloro-2-fluoro-5-(8-methyl-2-(methylamino) -7-oxo-7,8-dihydropyri do [2,3-d]pyrimidin-6-yl)phenyl)urea as a wliite solid (0.045 g, 23% yield). 'H NMR (400 MHz, DMSO-rf6): 5 8.95 (brs, 2H), 8.61 (s, 1H), 8.17 (d, /= 8.8 Hz, IH), 7.87 (brs, IH), 7.75 (s, 1H), 7.55 (d, /== 10.8 Hz, IH), 6.04 (s, IH), 3,58-3.51 (m, 6H), 2.90 (s, 3H), 1.16 (s, 9H); MS (ESI) m/z: 513.3 (M+H+).
Example 158: Using general procedure B, the carbamate of 3-isopropyl-1-phenyl-lH-pyrazol-5-amine (0.075 g, 0.26 mmol, 1.0 eq) and Example A26 (0.082 g, 0.26 mmol, 1.0 eq) were combined to afford slightly impure desired product. This was slurried in MeCN/HjO, cooled thoroughly at 0-5 °C and the solids collected by filtration, rising with cold H2O. The solids were dried under high vacuum. The free base thus obtained was dissolved in a minimum volume of hot THF (70 °C) and treated with 2% MsOH/THF (0.82 g, 0.17 mmol, LOO eq) to afford l-(2-fluoro-4-methyl-5-( 1 -methyl-7-(methylarnino)-2-oxo-l ,2-dihydro-1,6-napbthyridin-3-yl)pbenyl)-3-(3-isopropyl-l-phenyl-lH-pyrazoI-5-yl)urea mesylate (92 mg; 56% yield) as an off-white solid. ]H NMR (400 MHz, BMSO~d6): 8 8.95 (brs, IH), 8.85 (s, IH), 8.49 (s, IH), 7.96 (d, J = 8.4 Hz, IH), 7.78 (s, IH), 7.56-7.48 (m, 4H), 7.44-7.40 (m, IH), 7.15 (d, J = 12.4 Hz, IH), 6.45

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(brs, IH), 6.31 (s, IH), 3.54 (s, 3H), 2.95 (s, 3H), 2,85 (septet, J = 6.8 Hz, IH
), 2.29 (s, 3H), 2.07 (s, 3H), 1.19 (d, J = 7.6 Hz, 6H); MS (ESI) ra/z: 540.3 (M+H*).
Example 159: Using general procedure D, 3-(t-butyI)l -methyl- lH-pyrazoie-5-carboxyIic acid (0.125 g, 0.686 mmol, 1.00 eq) and Example A30 (0.210 g, 0.672 mmol, 1.10 eq) were combined to afford desired product which was subsequently treated with 2% MsOHMHF (0.67 g, 0.14 mmol, 1.00 eq) to afford 1 -(3-tert-butyM -methyl- ] H-pyrazol-5-yl)-3-(5-( 1 -ethyl-7-(memylaiTiino)-2-oxo-l32-dihydrO"l,6"naphthyridin-3-yl)-2-fluoro-4-methylphenyl)urea mesylate (70 mg, 17% yield) as a white solid. 'H NMR (400 MHz, DMSO-^): 5 8.92 (s, 1H)5 8.79 (brs, IH), 8.50 (s, IH), 7.97 (d, J = 8.4 Hz, IH), 7.78 (s, IH), 7.18 (d, J = 12.0 Hz, IH), 6.53 (brs,lH), 6.05 (s, IH), 4.17 (q, J = 7.2 Hz, 2H), 3.59 (s, 3H), 2.95 (s, 3.H), 2.29 (s, 3H), 2.07 (s, 3H), 1.21 (t, J = 7.2 Hz, 3H), 1.16 (s, 9H); MS (ESI) m/z: 506.2 (M+H*). .
Example 160: Using general method A, the TROC carbamate of Example BIS (0.66 g, 1.9 mmol) and Example A42 (0.68 g, 2.09 mmol) were combined to provide l-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-5~(8-isopropyl-2-(metliyItl-iio)-7-oxo-7J8-dihydropyrido[2,3-d]pyrimidin-6-yl)-
4-melhy1phenyl)urea (440mg, 44%) !H NMR (400 MHz, DMSOdg) 5 10.3 (s, IH), 8.88
(s,lH)), 8.70 (brs, IH), 7.94 (d, J = 9Hz, IH), 7.85 (s, IH), 7.20 (d, J = 12Hz, IH), 6.00 (s, IH), 5.75 (in, IH), 2.61 (s, 3H), 2.07 (s, 3H), 1.55 (d, J = 6Hz, 6H)S 1.21 (s, 9H); MS(ESI) m/z : 525.3 (M+H+).
In a procedure analogous to Example AI, l-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-5-(8-isopropyl-2-(memylthio)-7-oxo-7,8-dihydropyrido[2,3-d3pyrimidin-6-yl)-4-metliylphenyl)urea (0,1 g, 0.2 mmol) and methylamine were combined to provide 1-(3-tert-butylisoxazol-5-yl)-3~ (2-fluoro-5-(8-isopropyI-2-(methyJamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-4-
methylphenyl)urea (45 mg, 50 % yield). ]H NMR (400 MHz, DMSO-d6): 5 8.78 (brs, IH), 8.57
(brs, IH), 7.85 (d, J = 9Hz, IH), 7.75 (brs, IH), 7.62 (s, IH), 7.15 (d, J = 12Hz, IH), 6.00 (s, IH), 5.74 (m, IH), 2.89 (d, J = 5 Hz, 3H), 2.07 (s, 3H), 1.56 (d, J=6Hz, 6H), 1.21 (s, 9H); MS(ESI) m/z : 508.3 (M+H4).

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Example 161: Using general method D, l-lert-butyl-lH-pyrazole-4-carboxy!ic acid (150 mg, 0.892 mmol) and Example A16 (298 mg, 0.892 mmol) were combined to afford I-(1 -tert-butyl-lH-pyrazol-4-yl)-3-(2)4-difli]oro-5-(8-methyl-2Kme%ltWo)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (80 mg, 95% yield).
Using a procedure analogous to Example Al, l-(l-tert-butyl-lH-pyrazol-4-yl)-3-(2,4-difluoro-5-(8-memyl-2-(methylthio)-7-oxo-778-dihydropyrido[2,3-d]pyrimidin-6--yl)phenyl)urea (80 mg, 0.160 mmol) and 2.00N methylamine in THF (0.9 mL, 1.80 mmol) were combined to afford l-(l-tert-butyI-lH-pyrazol^yl)-3-(2J4-difluoro-5-(8-memyl-2-(methylarriino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyI)urea (31 mg, 36% yield). 'H NMR (300 MHz, DMSO-6) 6 1.53 (s, 9 H), 2.90 (s, 3 H), 3.52-3.59 (m, 3 H), 7.31-7.38 (m, 2 H), 7.78-7.90 (m, 3 H), 8.12-8.16 (m, 1 H), 8.48 (s, I H), 8.63-8.70 (m; * H), 8.65 (s, 1 H); MS (ESI) m/z: 483.3 (M+H+).
Example 162: Using a procedure analogous to Example 141, ethyl l-tert-butyl-5-methyl-lH-pyrazole-4-carboxylate (500 mg. 2.38 mmol). Example A3 (260 mg, 0.823 mmol) and 2.0N methylamine in THF (2.0 mL, 3.96 mmol) were combined to afford l-(l-tert-butyl-5-methyl-lH-pyrazol-4-yl)-3-(2-fluoro-5-(8-methyl--2--(metliylamino)-7-oxo-7!8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (106 mg). *H NMR (300 MHz, DMS(W6) 8 1.50 (s, 9 H), 2.30 (s, 3 H), 2.90 (s, 3 H), 3.53-3.60 (m, 3 H), 7.20-7.24 (m, 2 H), 7.44 (s, I H), 7.60-7.81 (m, 1 H), 7.84 (s, 1 H), 8.16 (s, I H), 8.39-8.41 (m, 1 H), 8.54-8.72 (m, 1 H), 8.63 (s, 1 H); MS (ESI) m/z: 479.2 (M+H+).
Example 163: Using general method A, the the TROC carbamate of 3-isopropyl-1-phenyl-1H-
pyrazol-5-amine (0.25 g, 0.66 mmol) and Example AlO (0.22 g, 0.66 mmol) were combined to
afford l-(2-fluoro-4-metliyl-5-(8-methyl-2-(methyltliio)-7HDxo-7,8-dihydropyrido[2,3-
d]pyrimidin-6-yl)phenyI)-3-(3-isopropyI-I-phenyl-1H-pyrazoU5-yl)urea as an off-white solid (0.24 g, 65% yield). [H NMR (400 MHz, DMSCW6): S 8.96 (s, 1H), 8.90 (a, 1H), 8.87 (s, 1H), 7.97 (d, J = 8.4 Hz, 1H), 7.87 (s, 1H), 7.55-7.48 (m: 4H), 7.43-7.39 (m, 1H), 7.16 (d, J= 12.4 Hz, 1H), 6.30 (s, 1H), 3.65 (s, 3H), 2.S7-2.80 (m, 1H), 2.61 (s, 3H), 2.06 (s, 3H), 1.18 (d, J= 12 Hz, 6H); MS (ESI) m/z: 558.3 (M+H*).

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Using a procedure analogous to Example Al. l-(2-fluoro-4-methyl-5-(8-methyl-2-
(raediyltliio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)plienyl)-3-(3-isopropyl-l-phenyl-
lH-pyrazol-5-yl)urea (0.24, 0.43 mmol) and 2 M methylamine in THF (3 eq) were combined to
provide l-(2-fluoro^-metJiyl-5-{8-metiiyl-2-(methyIainino)-7-oxo-7,S-dihydropyrido[233-
d]pyrimidin-6-yl)phenyl)-3-(3-isopropyl-l-phenyl-lH-pyrazol-5~yl)urea as a white solid (0.12 g, 52% yield). 'H NMR (400 MHz, DMSO-d6): 5 8.90 (s, 1H), 8.82 (s, 1H), 8.68-8.60 (m, 1H), 7.92 (d, J = 8.8 Hz, 1H), 7.82-7.79 (m, 1H), 7.66 (s, 1H), 7.55-7.47 (m, 4H), 7.43-7.39 (m, 1H), 7.12 (d,./= 12.4 Hz, 1H), 6.30 (s, 1H), 3.59-3.52 (m, 3H), 2.91-2.80 (m, 4H% 2.05 (s, 3H), 1.18 (d, J= 7.2 Hz, 6H); MS (ESI) m/z: 541.3 (M+H+).
Example 164: Using general procedure D, 5-isopropylisoxazole-3-carboxylic acid (0,0750 g, 0.483 mmol, 1.00 eq) and Example A10 (0.192 g, 0.580 mmol, 1.20 eq) were combined to afford l-(2-fluoro-4-memyl-5-{8-methyl-2-{memylthio)-7H3xo-778-dihydropyridof273-dJp>rimidm-6" yl)phenyl)-3-(5-isopropylisoxazol-3-yl)urea (63.5 mg, 27% yield) as an off-white solid which was used as is in the next reaction. 'H NMR (400 MHz, DMSO-rffi): 5 9.79 (s, 1H), 8.91 (s, 1H), 8.79 (bra, 1H), 7.97 (d, J = 8.4 Hz, 1H), 7.90 (s, 1H), 7.20 (d, J- 12.4 Hz, 1H), 6.44 (s, 1H),3.65 (s, 3H), 2.99 (septet, J = 7.2 Hz, 1H), 2.62 (s, 3H), 2.08 (s, 3H), 1.20 (d, J = 6.8 Hz, 6H); MS (ESI) m/z: 483.3 (M+H*).
Following a procedure analogous to Example Al, l-(2-fluoro-4-methyl-5-(8-metliyl-2-
(metliylthio)-7-oxo-738-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)-3-(5-isopropylisoxazol-3-
yl)urea (0.0635 g, 0.13 mmol) and 2.0M MeNH2/THF (0.66 ml, 1.3 mmol) were combined to
afford l-(2-fluoro-4-methyl-5-(8-methyl-2-(metliylamino)-7-oxo-7,8-dihydTOpyrido[2,3-
d]pyrimidin-6-yl)phenyl)-3-(5-isopropyIisoxazol-3-yl)urea (38 mg, 62% yield) as a pale yellow solid. *H NMR (400 MHz, DMSO-^s): 8 9.77 (s, 1H), 8.75 (brs, 1H), 8.60 (s, 1H), 7.92 (d, J = 8.4 Hz, lH);7.80(brqrJ = 4.4Hz, lH):7.68(s, 1H), 7.16 (d, J = 12.4 Hz, IH), 6.45 (s, IH), 3.60 (s, 3H), 2.99 (septet, J = 6.8 Hz, 1H), 2.90 (bid, J = 4.4 Hz, 3H), 2.07 (s, 3H), 1.20 (d, J = 6.8 Hz, 6H); MS (ESI) m/z: 466.2 (M+H*).
Example 165: Using general procedure D, 5-isopropylisoxazole-3-carboxylic acid (0.0750 g, 0.483 mmol, 1.00 eq) and Example Al 7 (0.203 g, 0.580 mmol, 1.20 eq) were combined to afford l-(4-chloro-2-fluoro-5-(8-xnemyl-2-(methylmio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-

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yl)phenyl)-3-(5-isopropylisoxazol-3-yl)urea (0.113 g, 47% yield) as an off-white solid. 'H NMR (400 MHz, DMSO-4J): 5 9.87 (s, 1H), 8.97 (bra, 1H), 8.93 (s, 1H), 8.20 (d, J = 8.8 Hz, 1H), 8.00 (s, 1H), 7.63 (d, J = 10.8 Hz, 1H), 6.54 (s, 1H), 3.65 (s, 3H), 3.00 (septet, J = 6.8 Hz, 1H), 2.62 (s, 3H), 1.20 (d, J = 7.2 Hz, 6H); MS (ESI) m/z: 503.0 (M+H4), 505.0 (M+2+H*).
Using a procedure analogous to Example Al, l-(4-chloro-2-fluoro-5-(8-methyl-2-
{methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)-3-(5-isopropylisoxazol-3-
yl)urea (0.113 g, 0.225 mmol) and 2.0M MeNH2/THF (1.12 ml, 2.25 mmol) were combined to
afford l-(4-chloro-2-fluoro-5-(8-methyl-2-(methylairiino)-7-oxo--7,8-dihydropyrido[2,3-
d]pyrimidin-6-yl)phenyl)-3-(5-isopropylisoxazol-3-yl)urea (52 mg, 48% yield) as a faintly yellow solid. lH NMR (400 MHz, DMSOxfc): 6 9.85 (s, 1H), 8.94 (bra, 1H), 8.62 (s, 1H), 8.15 (d, J = 8.8 Hz, 1H), 7.88 (brq, J = 4.8 Hz, 1H), 7.77 (s, 1H), 7.58 (d, J = 10.8 Hz, 1H), 6.46 (s, 1H), 3.59 (s, 3H), 3.00 (septet, J = 6.8 Hz, 1H), 2.91 (d, J = 4.8 Hz, 3H), 1.20 (d, J = 6.8 Hz, 6H); MS (ESI) m/z: 486.2 (M+H4"), 488.3 (M+2+H*).
Example 166: Using general method A, the TROC carbamate of Example B18 (0,066 g, 0.21 mmol) and Example A43 (0.076 g, 0.20 mmol) were combined to afford l-(3-tert-butylisoxazol-5-yl)-3 Example 167: Example AH (0.125 g, 0.394 mmol, 1.00 eq) and aniline (0.108 ml, 1.18 mmol, 3.00 eq) were combined in NMP (4 ml) and heated in a microwave for 7 h at 220 °C. The roughly half-complete reaction was diluted with H20 (40 ml) and extracted with EtOAc (3 x 20 ml). The combined organics were washed with H2O (2x), brine (lx), dried (MgSC>4), concentrated in vacuo and purified by flash column chromatography (50:50 EtOAc/hexanes-100% EtOAc) to afford 3-(5-amino-4-fluoro-2-methylphenyl)-l-methyl-7-(phenylamino)"l,6-naphthyridin-2(lH)-one (51 mg, 17% yield) as an off-white solid. 'H NMR (400 MHz, DMSO-d6): 5 9.40 (s, 1H), 8.52, s, 1H), 7.70-7.64 (m, 3H), 7.31-7.27 (m, 2H), 6.95-6.93 (m, 1H), 6.86

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(ds J = 12.0 Hz, IH), 6.68 (s, 1H), 6.59 (d, J = 9.2 Hz, IH), 4.91 (brs, 2H), 3.52 (s, 3H), 1.96 (s, 3H); MS (ESI) m/z: 375.2 (M+H4).
Using general procedure A, the TROC carbamate of Example BIS (0,0431 g, 0.136 mmol) and 3-(5-ammo-4-fluoro-2-rnethyfphenyI)- \ -m ethyl-7-(phenylamino)-1,6-naphrhyridm-2(lH)-one (0.0511 g, 0.136 mmol) were combined to afford desired product. The free base thus obtained was converted to the meslyate salt, I-(3-tert-butylisoxazoI-5-yI)-3-(2-fluoro-4-methyI-5-(l-methyI-2-oxo-7-(phenylamino)-l,2--dihydro-l,6-naphthyridin-3-yl)phenyl)urea mesylate (19 mg, 21% yield) as an off-white solid. !H NMR (400 MHz, DMSO-&): 8 10.30 (s, 1H), 9.55 (s, IH), 8.69 (brs, 1H), 8.56 (s, 1H), 7.92 (d, J = 8.4 Hz, IH), 7.79 (s, 1H), 7.63 (dd, J = 1.2 and 8.4 Hz, 2H), 7.34-7.29 (m, 2H), 7.19 (d, J = 12.4 Hz, IH), 6.98 9dd, J = 7.2 and 13.6 Hz, IH), 6.71 (s, IH), 6.01 (s, IH), 3.54 (s, 3H), 2.30 (s, 3H), 2.10 (s, 3H), 1.21 (s, 9H); MS (ESI) m/z: 541.3 (M+H4).
Example 168: Example Al 1 (0.250 g, 0.787 mmol, 1.00 eq), phenylboronic acid (0.115 g, 0.944 mmol 1.20 eq) and 2M K2C03 (1.06 ml, 2.12 mmol, 2.70 eq) were combined in DME (0.90 ml) and degassed with Ar. Pd(PPh3)4 (0.0455 g, 0.0393 mmol, 0.05 eq) was then added and the mixture was stirred with heating at 90 °C. After 16 h, the completed reaction cooled to RT, diluted generously with EtOAc and filtered on Ceiite, rinsing forward with more EtOAc. The combined filtrates were washed with brine (2x), dried (MgS04), filtered and evaporated to a dark orange solid. This was triturated with cold EtOAc. The solid product was collected by filtration, rinsed sparingly with ice-cold EtOAc and dried on the filter to afford desired product (0.112 g, 40% yield) as a gold-colored solid which was used as is in the next reaction. !H NMR (400 MHz, DMSO-dfi): 5 8.96 (ss IH), 8.26-8.23 (m, 2H), 7.93-7.91 (m, 2H), 7.55-7.45 (m, 3H), 6.89 (d, J = 12.4 Hz, IH), 6.63 (d, J = 9.6 Hz, IH), 4.96 (brs, 2H)S 3.75 (s, 3H), 1.98 (s, 3H); MS (ESI) m/z: 360.0 (M+H").
Using general procedure A, the TROC carbamate of Example B18 (0.100 g. 0.317 mmol, 1.00 eq) and 3~(5-amino-4-fluoro-2-methylphenyl)-l-methyl-7-phenyl-lJ6-naphtliyridin-2(lH)-one (0.114 g, 0.317 mmol, 1.00 eq) were combined to afford desired product. The free base thus obtained was converted to the mesylate salt, 1 -(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-4-methyl-5-(l-methyl-2-oxo-7-phenyl-l,2-dihydro-l,6-naphthyridin-3-yi)phenyl)urea mesylate (53 mg, 27% yield) as a white solid. ]H NMR (400 MHz, DMSO-d6): 8 10.32 (s, IH), 9.04 (s, IH), 8.72

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(brs, 1H), 8.26-8.23 (m, 2H), 8.03-7.96 (m, 3H), 7.58-7.49 (m, 3H), 7.23 (d7 J = 12.0 Hz, IH), 6.01 (s, 1H), 3.78 (s, 3H), 2.29 (s, 3H), 2.12 (s, 3H), 1.21 (s, 9H); MS (ESI) m/z: 526.2 (M+H*).
Example 169: Using general method D, 3-tert-buryl-l-methyl-1 H-pyrazole-S-carboxylic acid (0.051 g, 0.28 mmol) and Example A51 (0.096 g, 0.28 mmol) were combined in presence of triethylamine (0.085 g, 0.84 mmol) and diphenylphospharyl azide (0.12 g, 0.42 mmol) to afford l-(3-tert-butyl-]-methyl-IH-pyrazol-5-yl)-3-(2-fluoro-5-(8-isopropyl-2-(methylamino)-7-oxo-7,8-dihydropyrido[2.3-d]pyrimidin-6-yl)-4-methylphenyl)urea as white solid (0.095 g, 65% yield). lH NMR (400 MHz, DMS(W6): 5 8.87 (s, 1H), 8.73 (s, IH), 8.57 (s, IH), 7.92 {d,J= 8.4 Hz, IH), 7.76-7.73 (m, IH), 7.60 (s, IH), 7.14 (d, J= 12.4 Hz, IH), 6.04 (s, IH), 5.74 (brs, IH), 3.58 (s, 3H), 2.88 (d, J = 4.4 Hz, 3H), 2.05 (s, 3H), 1.57-1.49 (m, 6H), 1.16 (s, 9H); MS (ESI) m/z: 521.3 (M+H+).
Example 170: Using general method D, Example B30 (0.041 g, 0.24 mmol) and Example A51 (0.083 g. 0.24 mmol) were combined in presence of triethylamine (0.074 g, 0.73 mmol) and diphenylphospharyl azide (0.1 g, 0.37 mmol) to afford l-(l-lert-butyl-lH-pyrazol-4-yl)-3-(2-fluoro-5-(8-isopropyl-2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-4-methylphenyl)urea as a white solid (0.055 g, 45% yield). ]H NMR (400 MHz, DMSO-rf6): 8 8.59 (s, IH), 8.52 (s, IH), 8.36 (s, IH), 7.88 (d, J= 8.0 Hz, IH), 7.73 (s, IH), 7.71-7.68 (m, IH), 7.55 (s, IH), 7.34 (s,lH), 7.05 Example 171: Using general procedure B, the carbamate of Example B21 (0.100 g, 0.321 mmol, 1.00 eq) and Example A44 (0.100 g, 0.321 mmol, 1.00 eq) were combined to afford 1 -(4-methyl-3-(8-methyl-2-(methyltJiio)-7-oxo-7,8-dihydropyrido[2,3-d]pyriim'din--6-yl)phenyl)-3-(l-phenyl-3-{trifluoromelhyl)-lH-pyrazol-5-yl)urea (0.1231 g, 68% yield) as a pale yellow solid which was used as is in the next reaction. 'H NMR (400 MHz, DMSO-de): 5 9.12 (s, IH), 8.91 (s, IH), 8.72 (s, IH), 7.89 (s, IH), 7.65—7.55 (m ,5H), 7,38 (brs, IH), 7.25 (brd, J = 8.8 Hz, IH), 7.18 (d, J = 8.4 Hz, IH), 6.86 (s, IH), 3.67 (s, 3H), 2.63 (s, 3H), 2.08 (s, 3H); MS (ESI) m/z: 566.2 (M+H*).
Using a procedure analogous to example Al, l-(4-methyl-3-(8-memyl-2-(metliylthio)-7-oxo-7,8-dihydropyridof2,3-d]pyrimidin-6--yl)phenyI)-3-(l-phenyI--3-(trifluoromethyl)-lH-

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pyrazol-5-yl)urea (0.1231 g, 0.218 mmol) and 2.0M MeNH2/THF (1.088 ml, 2.177 mmol) were combined to afford l-(4-methyl-3-(8-methyU2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyI)-3-(l-phenyl-3-(trifluoromethyl)-lH-pyrazol-5-yl)urea (93 mg, 78% yield) as a white solid. lH NMR (400 MHz, DMSQ-^): 6 9.08 (s, 1H), 8.69 (s, 1H), 8.59 (s, 1H), 7.81 (brq, J = 4.4 Hz, 1H), 7.66 (s, 1H), 7.63-7.52 (m, 5H), 7.30 (d, J = 2.0 Hz, 1H) 7.21 (dd, J = 2.0 and 8.4 Hz, 1H), 7.13 (d, J = 8.4 Hz, 1H), 6.85 (s, 1H), 3.59 (s, 3H), 2.90 (brd, J = 4.8 Hz, 3H), 2.05 (s, 3H); MS (ESI) m/z; 549.3 (M+H4).
Example 172: Using general method C, the TROC carbamate of Example Bl 8 (150 mg. 0.475 mmol) and Example A27 (142 mg. 0.475 mmol) were combined to provide l-(5-(7-amino-l-methyl-2"Oxo-l)2-dihydro-l,6-naphtliyridin-3-yl)-2-fluoro-4-metliylphenyl)-3-(3-tert-butylisoxazoI-5-yl)urea (105 mg, 48% yield). 'H NMR (400 MHz, DMSO-e): 6 10.31 (s, 1 H), 8.67 (s, I H), 8.33 (s, 1 H), 7.88 (d, J= 8.5 Hz, 1 H), 7.66 (s, 1 H), 7.16 (d, J = 12.3 Hz, I H), 6.54 (s, 2 H), 6.26 (s, 1 H), 6.01 (s, I H), 3.47 (s, 3 H), 2.08 (s, 3 H), 1.21 (s, 9 H); MS (ESI) m/z: 465.2 (M+H*).
Example 173: Using general method D, Example B30 (150 mg, 0.892 mmol), triethylamine (104 mg, 1.03 mmol) and Example A17 (313 mg, 0.892 mmol) were combined to afford 1-(1-tert-butyl-lH-pyrazol-4-yl)-3-(4-chloro-2-fluoro-5-(8-methyl-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)pheny3)urea (143 mg, 31% yield). Using a procedure analogous to Example AI. l-(l"tert-butyI-lH"pyrazol-4-yl)"3-(4-chloro-2-fluoro-5-(8-metliyl-2" (mediylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (143 mg, 0.277 mmol) and 2.ON were combined and purified by reverse phase chromatography (Biotage CI 8-25 column, 0-100% acetanitrile/water - 750 mL), treated with 10% potassium carbonate solution (2 mL) and set aside to precipitate. The solid was collected by filtration, washed with water (2x5 mL) and dried on high vacuum line to give l-(i-tert-butyl-lH-pyrazol-4-yl)-3-(4-chloro-2-fluoro-5-(8-methyl-2-(memylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (59 mg, 42% yield). 'H NMR (300 MHz, DMSO-d6): 5 1.45 (s, 9 H), 2.90 (s, 3 H), 3.51-3.59 (m, 3 H), 7.38 (s, 1 H), 7.52 (d, J = 10.9 Hz, 1 H), 7.75 (s, 1 H), 7.78 (s, 1 H), 7.86 (br s, 1 H), 8.20 (d, J = 8.9 Hz, 1 H), 8.62-8.69 (in, 2 H), 8.70-8.72 (m, 1 H); MS (ESI) m/z: 499.2 (M+H*).

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Example 174: Using general method D, Example B30 (0.041 g3 0.24 mmol) and Example A26 (0.076 g, 0.24 mmol) in presence of triethylamine (0.074 g, 0.75 mmol) and diphenylphospharyl azide (0.1 g, 0.37 mmol) were combined to afford l-(l-tert-butyl-iH-pyrazol-4-yi)-3-(2-fluoro-4-methyl-5-(l-memyl-7-(memyImTiino)-2-oxo-l,2-dihydro-l)6-naphthyridin-3-yl)phenyl)u]-ea as a white solid (0.055 g, 47% yield). !H NMR (400 MHz, DMS0^6): 5 8.63 (s, IH), 8.38 (s, 2H), 7.94 (d, /= S.8 Hz, IH), 7.78 (s, IH), 7.65 (s, IH), 7.36 (s, IH), 7.10 (d, J = 12.4 Hz, IH), 7.04-7.00 (m, IH), 6.17 (s, IH), 3.50 (s, 3H), 2.85 (d, /= 4.8 Hz, 3H), 2.05 (s, 3H), 1.45 (s, 9H); MS (ESI) m/z: 478.3 (M+H*).
Example 175: Using general method D, Example B30 (0.027 g, 0.161 mmol) and Example A53 (0.0925 g, 0.24 mmol) were combined to afford l-(l-tert-butyl-lH-pyrazol-4-yl)-3-(5-(7-(3-(dimetiiylamino)propylamino)-1 -methyl-2-oxo~ 1,2-dmydro-l ,6-iiaphmyridin-3-yl)-2-fluoro^-methylphenyljurea (0.029 g, 33% yield). It was converted to corresponding bis-mesylate salt by reacting with MsOH (2.0 eq.). [H NMR (400 MHz, DMSO-d6); 5 8.49 (s, IH), 8.00 (d, /= 8.4 Hz, IH), 7.76 (s, 2H), 7.38 (s, IH), 7.33 (t, J= 8.4 Hz, IH), 7.17-7.10 (m, IH), 6.46 (s, IH), 3.53 (s, 3H), 3.43 (m, 2H), 3.18-3.09 (m, 2H), 2.79 (s, 6H), 2.35 (s, 6H), 2.06 (s, 3H), 1.96-1.89 (m, 2H), 1.45 (s, 9H); MS (ESI) m/z: 549.3 (M+H*).
Example 176: Using general method C, the TROC carbamate of Example B18 (0.66g, 1.9 mmol) and Example A42 (0.68g, 2.09 mmol) were combined to provide l-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-5-(8-isopropyl-2-(mediylmio)-7-oxc-7,8-dihydr0pyrido[2,3Ki]pyriinidin-6-yl)-
4-methylphenyl)urea (0.44g, 44% yield). ]H NMR (400 MHz, bMSO-d6): 810.3 (s, IH), 8.88
(s,lH), 8.70 (brs, IH), 7.94 (d, J=9Hz, IH), 7.85 (s, IH), 7.20 (d, J = 12Hz, IH), 6.00 (s, IH), 5.75 (m,lH), 2.61 (s, 3H),2.07(s, 3H), 1.55 (d, J=6Hz, 6H), 1.21 (s, 9H);MS(ESI) m/z : 525.3 (M+H+).
Using a procedure analogous to Example Al, oxidation of the intermediate sulfide with MCPBA, followed by reaction with excess (S)-alaninol provided (S)-l-(3-tert-butylisoxazol-5-yl}-3-(2-fliioro-5-(2-(I-hydroxypropan-2-yiamino)-8-isopropyl-7-oxo-7,8-diliydropyrido[2,3-d]pyrimidin-6-yl)-4-methylphenyl)urea (33% yield). lH NMR (400 MHz, DMSO-d6): 88.75(s, IH), 8.58 (s:lH), 7.86 (d, J = 9Hz, IH), 7.61 (s, IH), 7.55 (m, IH), 7.15 (d, J = 12Hz, IH), 6.00

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(s, IH), 5.71 (brs, IH), 4.75 (bra, IH), 4.03 (m, IH), 3.50 (m, IH), 3.35 (m, IH), 2.07 (s, 3H), 1.55 (d, J = 6Hz, 6H), 1.21 (s, 9H), 1.16 (d, J = 6Hz, 3H); MS(ESI) m/z : 525.3 (M+H+).
Example Ml: Using general method B, the carbamate of Example B2 (120 rag, 0.506 mmol) and Example A28 (168 mg, 0.506 mmol) were combined to afford l-(3"tert-butyl-l-methyl-lH-pyrazol-5-yl)-3-(4-cmoTO-2-fluoro-5-(l-memyl-7-(methylamino)-2-oxo-l,2-dihydro-376-naphtliyridin-3-yl)phenyl)urea (128 mg, 49% yield). [H NMR (300 MHz, DMSO- Example 178: Using general method C, the TROC carbamate of Example B18 (0.080 g, 0.25 mmol) and Example A28 ( 85 mg, 0.25mmol) were combined to afford l-(3-tert-butylisoxazol-5-yl)-3-(4-chloro-2-rluoro-5-(l-methyl-7-(methylaiiiino)-2-oxci-l,2-dihydro-lJ6-naphtliyridin-3-yl)phenyl)urea (0.050 g,40% yield). lHNMR(400 MHz,DMSO-d6): 5 10.4 (s, IH), 8.86 (brs, IH), 8.40(8, IH), 8.12 (d,7=8.4 Hz, IH), 7.75 (s, IH), 7.58 (d,/= 10.4 Hz, IH), 7.11 (q,/= 4.8 Hz, IH), 6.17 (s, IH), 6.03 (s, IH), 3.50 (s, 3H), 2.86 (d, J = 4.8 Hz, 3H), 1.21 (s, 3H); MS (ESI) m/z: 499.2 (M+H+).
Example 179: Using general method B, the carbamate of 5-*-butylisoxazoI-3-amine (70 mg, 0.31 mmol) and Example A29 (99 mg, 0.31 mmol) were combined to afford l-(5-tert-butylisoxazol-3-yl)-3-(4-chloro-5-(l-ethyl-7-(methylamino)-2-oxo-i,2-dihydro-l,6-naphmyridin-3-yl)-2-fluorophenyl)urea (0.15& 100% yield). lH NMR (400 MHz, DMSO-rf6): 8 9.91 (brs, IH), 8.89 (brs, IH), 8.42 (s, IH), 8.11 (m, IH), 7.83 (s, IH), 7.38 (dds J= 9.6, and 10.8 Hz, IH), 7.13 (q,7 = 4.8 Hz, IH), 6.46 (s, 1H),6.17 (brs, IH), 3.50 (s, 3H), 2.85 (d,.7=4.8 Hz, 3H), 1.26 (s, 9H); MS (ESI) m/z: 483.3 (M+H*).
Example 180: Using general method D, l-methyl-lH-pyrazole-5-ciirboxylicacid (150 mg, 1.19 mmol) and Example A3 (376 mg, 1.19 mmol) were converted to the intermediate l-(2-fluoro-5-(8-mediy!-2-(methyltliio)-7-oxo-7,8-dihydropyTido[2,3-d]pyrimidin-6-yI)phenyl)-3-(l-mediyi-!H-pyrazol-5-yl)urea (487 mg, 93% yield). This was then further converted using a procedure

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analogous to Example Al with 2.0N memylamine in THF (5.5 mL, 11.1 mmol) to afford l-(2-
nioro-5-(8-methyl-2-(methylmm^o)-7-oxo-7,8-dihy
(l-methyl-lH-pyrazol-5-yl)urea (48 mg, 9% yield). 'H NMR (300 MHz, DMSO-4): 5 2.93 (s, 3
H), 3.59 (m, 3 H), 3.74 (s, 3 H), 6.27 (s, 1 H), 7.27-7.30 (m, 2 H), 7.41 (s, 1 H), 7.92 (s, 1 H),
8.20 (br s, 3 H), 8.36-8.38 (m, 1 H), 8.75 (s, 1 H), 9.20 (s, 1 H), 9.73 (s, 1 H); MS (ESI) m/z;
423.3 (M+H*).
Example 181: Using general method D, Example B32 (150 mg, 0.585 mmol) and Example A57 (165 mg, 0.585 mmol) were combined and purified by chromatography (Biotage Si-25 column, 50-100% ethyl acetate) to give l-(2"tert-butyl-4-phenylpyrimidin-5-yl)-3-(3-(8-methyl-2-(memylaniino)-7~oxo-7,8--dihydropyridot2,3-d]pyrimidin-6-y])phenyl)urea as an off white foam (81 mg, 25% yield). lH NMR (300 MHz, DMSO-4): 5 1.37 (s, 9 H), 2.90 (s, 3 H), 3.52-3.59 (m, 3 H), 7.21-7.31 (m, 2 H), 7.43-7.57 (m, 4 H), 7.70-7.88 (m, 5 H), 8.11 (s, 1 H), 8.62-8.70 (m, 1 H), 9.07 (s, 1 H), 9.19 (s, 1 H); MS (ESI) m/z: 535.2 (M+H*).
Example 182: Using general method G, Example B32 (150 mg, 0.585 mmol) and Example Al 0 (193 mg, 0.585 mmol) were combined to give the intermediate sulfide (224 mg, 65% yield). Using a procedure analogous to Example Al, The sulfide and 2.0N methylamine hi THF (1.917 ml, 3.83 mmol) were combined to afford l-(2-tert-buryl-4-phenylpyrimidin-5-yI)-3-(2-fluoro-4-methyl-5-(8-meUiyl-2-(methylthio)-7--oxo-7,8--dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (150 mg, 69% yield). 'H NMR (300 MHz, DMSO- Example 183: Using general method D, Example B32 (61 mg, 0.237 mmol) and Example A26 (74 mg, 0.237 mmol) were combined to afford l-(2-tert-butyl-4-phenylpyrimidin-5-yl)-3-(2-fluoro-4-methyl-5-(l-methyl-7-(methylajnino)-2-oxo-l,2-dihydro-],6-naphthyridin-3-yl)phenyl)urea (69 mg, 51% yield). lH NMR (300 MHz, DMSO-rf6): S 1.35 (s, 9 H), 2.05 (s, 3 H), 2.84 (s, 3 H), 3.49 (s, 3 H), 6.16 (s, 1 H), 7.03-7.04 (m, 1 H), 7.09-7.12 (m, 1 H), 7.51-7.57 (m, 3 H), 7.64 (s, 1 H), 7.71-7.74 (m, 2 H), 7.89 (d,J= 8.5 Hz, 1 H), 8.38 (s, 1 H), 8.53 (s, 1 H), 8.92 (s, 1 H), 9.02 (s, 1 H); MS (ESI) m/z: 566.2 (M+Na*).

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Example 184: Using general method F, Example A39 (0.100 g, 0.319 mmol) was reacted with 1-isocyanatonaphthalene(0.054 g, 0.319 mmol) in ethyl acelae at room temperature for 14 hours to provide l-(2-fluoro^-methyl-5^8-methyl-2-(methylamino)-7^xo-7J8Kiihydropyrido[23-d]pyriiriidin-6-
yl)phenyl)-3-(naphthalen-l-yl)urea (0.052 g, 33% yield). !H NMR (400 MHz, DMSO-d6): □ 9.12 (s,
IH), 9.00 (brs, IH), 8.60 (s, IH), 8.15 ( Example 185: Using a procedure analogous to Example 186, (R)-l -(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-5-(2-(l-hydroxy-3-metliylbutan-2-ylamino)-8-methyl"7-oxo-7J8-dihydropyrido[2,3-d]pyrimidin-6-yl)-4-methylphenyl)urea was prepared from the carbamate of B18, Example AlO
and R(-)2-amino-3-inetfayM-btrtanol. lH NMR (400 MHz, DMSO-d6): 88.67 (s, IH), 8,61 (m, IH),
7.88 (d, J = 9Hz, IH), 7.64 (m, IH), 7.57 (d, J = 9Hz, IH), 7.16 (d, J = 12Hz, IH), 6.10 (s, IH), 4.59 (m, IH), 3.97 (m, IH), 3.56 (s, 3H), 3.52 (m, 2H), 2.08 (s, 3H), 1.98 (m, IH), 1.22 (s, 9H), 0.9] (m. 6H); MS(ESI) m/z: 552.2 (M+H4).
Example 186: Using geneal method C, theTRQC carbamate of Example Bl 8 (0.5g, 1.58 mmol) and Example A10 (0.52g, 1.58 mmol) were combined to provide l-(3-tert-butylisoxazol-5-yl)-3-(2-flnoro-4-methyl-5-(8-meUiyl-2-(memylthio)-7-oxo-7,8-diliydropyrido[2,3-d]pyrimidin-6-
yl)phenyl)urea (0.44g, 56% yield). *H NMR (400 MHz, DMSO-d6): 5l0.3(brs, IH), 8.9 (s,lH),
8.70 (brs, IH), 7.94 (d, J = 9Hz, IH), 7.S8 (s, IH), 7.20 (d, J = 12Hz, IH), 6.00(s, IH), 3.64(s, 3H), 2.61(s, 3H), 2.07 (s, 3H), 1.21 (s, 9H); LC-MS(ES, m/z , M+H) 497.2.
Using a procedure analogius to Example Al, the sulfide was oxidatized with MCPBA and subjected to excess S(+)2-amino-3-methyl-l-butanol to provide (S)-l-(3-tert-butylisoxazol-5-yI)-3-(2-fluoro-5-(2-(l-hydroxy-3-methylbutan-2-ylamino)-8-methyl-7-oxo-7,8-
dihydropyrido[2)3-d]pyrimidin-6-yI)-4-methylphenyl}urca (47% yield). lH NMR (400 MHz, DMSO-d6): 8 8.67 (s, IH), 8.61 (m, IH), 7.88 (d, J = 9Hz, IH), 7.64 (m, IH), 7.57 (d, J = 9Hz,
IH), 7.16 (d, J = 12Hz, IH), 6.10 (s, IH), 4.59 (in, IH), 3.97 (m, 1H),3.56 (s, 3H), 3.52 (m, 2H), 2.08 (s, 3H), 1.98 (m, IH), 1.22 (s, 9H), 0.91(m. 6H); MS(ESI) m/z : 552.2 (M+H*).

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Example 187: Using general method C, the TROC carbamate of Example B18 (0.091 g, 0.29 mmol) and Example A33 (0.1 g, 0.29 mmol) were combined to afford l-(3-tert-buty]isoxazof-5-yl)-3-(4-diIoTo-5-(l-ethyl-7-(methylamino)-2-oxo-l^-dihydra-l,6-naphthyridin-3-yl)-2-fluorophenyl)urea as a white solid (0.051 g, 35% yield). 'H NMR (400 MHz, DMSCW6): 5 8.56 (s, IH), 8.41 (s, IH), S.ll (d,,/=8.8Hz, lH),7.74(s, IH), 7.57 (d,/= 10.8 Hz, IH), 7.07-7.04 (m, IH), 6.23 (s, IH), 6.02 (s, IH), 4.13 (q, J= 7.2 Hz, IH), 2.86 (d, J = 4.8 Hz, 3H), 1.21-1.17 (m, 12H); MS (ESI) m/z: 513.3 (M+H+).
Example 188: Using general method C, the TROC carbamate of Example B18 (0.091 g, 0.29 mmol) and Example A31 (0.09 g, 0.28 mmol) were combined to afford l-(5-(7-amino-l-ethyl-2-oxo-1,2-dihydro-1.6-naphthyridin-3-yl)-2-fluoro-4-memylphenyl)-3-(3-tert-butylisoxazol-5-yl)urea as a white solid (0.12 g, 87% yield). !H NMR (400 MHz, DMSO-db): 5 10.3 (s, IH), 8.66 (s, IH), 8.34 (s, IH), 7.87 (d, J = 8.4 Hz, IH), 7.65 (s, IH), 7.16 (d, J= 12.0 Hz, IH), 6.49 (s, lH),6.33(s, 1H),6.01 (s, IH), 4.09 (q, 7= 7.2 Hz, IH), 2.07 (s, 3H), 1.21-1.18 (m, 12H); MS (ESI) m/z: 479.2 (M+H+).
Example 189: Using general method B, the caramate of 5~/-butyiisoxazol-3-amine (70 mg, 0.31 mmol) and Example A47 (108 mg, 0.31 mmol) were combined to afford 1 -(5-tert-butylisoxazol-3-yl)-3-(4-emyI-2-fluoro-5-(8-me%l-2-(memylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (0.085 g, 53% yield). MS (ESI) m/z: 511.2 (M+H*).
Using a procedure analogous to Example Al, l-(5-tert-butylisoxazol-3-yl)-3-(4-ethyl-2-fluoro-5-(8-mem3^-2-(methyltm*o)-7H)xo-7,8"dihydropyrido[2,3HJ]pyrimidin-6-yl)pheiiyl)urea (0.085 g, 0.17 mmol) was treated with mCPBA (70% wt, 0.049 g, 0.20 mmol) and then N-methylamine (2.0M in THF, 0.34 mL, 0.67 mmol) to afford l-(5-tert-buty!isoxazol-3-yl)-3-(4-ethyl-2-fluoro-5-(8~metliyl-2-(mediylamino)-7-oxo-7J8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (72 mg, 88% yield). !H NMR (400 MHz, DMSO-&, major rotomer): 5 9.79 (s, lH),8.76(brs, lH),8.60(s, IH), 7.8S (d,y= 8.4 Hz, ]H),7.8J (q, J =4.4 Hz, lH),7.67(s, IH), 7.18 (d, J= 12.4 Hz, IH), 6.43 (s, IH), 3.59 (s, 3H), 2.91 (d, J = 4.4 Hz, 3H), 2.38 (q, J = 7.6 Hz, 2H), 1.25 (s, 9H), 1.02 (t, J= 7.6 Hz, 3H); MS (ESI) m/z: 494.0 (M+H+).

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Example 190: Using general method C, the TROC carbamate of Example B18 (212 mg, 0.672
mmol) and Example A44 (150 mg, 0.480 mmol) were combined and purified by reverse phase
cliromatography (Biotage Si-25 column, 25-85% ethyl acetate/Hex) to give tlie intermediate
sulfide l-(3-tert-butylisoxazol-5-yl)-3-(4~methyl-3-(8-methyl-2-(metiiylthio)-7-oxo-738-
dihydropyrido[2,3-d]pyrimidin-6-yl)phenyJ)urea (68 mg, 29% yield).
Using a procedure analogous to Example Al, l-(3-tert-butylisoxa2ol-5-yl)-3-(4-methyl-3-(8-memyl-2-(memylmio)-7-oxo-7,8-dihydropyrido[2)3-d]pyriniidin-6-yl)phenyl)urea (56 mg, 0.117 mmol) and 2.0N methylamine in THF (0.71 mL, 1.421 mmol) were combined to afford 1-(3-tert-butylisoxazol-5-yl)-3-(4-methyl-3-(8-methyl-2-(memylamino)-7-oxo-7?8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyI)urea ( 29 mg, 44% yield). (H NMR (300 MHz, DMSO-d6), 5 1.46 (s, 9 H), 2.04 (s, 3 H), 2.89 (s, 3 H), 3.52-3.60 (m, 3 H), 5.74 (s, 1 H), 7.08-7.10 (m, 1 H), 7.22-7.25 (m, 1 H), 7.33-7.36 (m, 2 H), 7.65 (s, 1 H), 7.78 (s, 1 H), 7.68-7.82 (m, J H), 8.25 (s, 1 H)t S.53 (s, 1 H), 8.6Q-8.65 (m, J H); MS (ESI)m/2; 462.3 (M+H+).
Example 191: Using general method D, Example B30 (150 mg, 0.585 mmol) and Example A44 (165 mg, 0.585 mmol) were combined to give the intermediate sulfide, l-(l-tert-butyl-lH-pyrazol-4-yl)-3-(4-mediyl-3-(8-methyl-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyI)urea (56 mg, 24% yield). Using a procedure analogous to Example AK tlie sulfide (56 mg, 0,117 mmol) was combined with 2.0N methylamine in THF (0.59 mL, 1.173 mmol) to afford the d esired product, 1 -(1 -tert-butyl-1 H-pyrazol-4-yl)-3-(4-methyl-3 -(8-methyl-2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyi-imidin-6-yl)phenyl)urea (43 mg, 80% yield). lH NMR (300 MHz, DMSQ-rf6), 8 1.22 (s, 9 H), 2.06 (s, 3 H), 2.90 (s, 3 H), 3.53-3.60 (m, 3 H), 6.01 (s, 1 H), 7.14-7.16 (d, 1 H), 7.27-7.29 (d, 1 H), 7.34 (s, I H), 7.67 (s, 1 H), 7.68-7.81 (m, 1 H), 8.60-8.65 (m, 1 H), 8.74 (s, 1 H), 10.06 (s, 1 H); MS (ESI) m/z: 461.2 (M+H+).
Example 192: Using general method F, l-isocyanato-3-methylbenzene (42 mg, 0.32 mmol) and Example A39 (100 mg. 0.32 mmol) in presence of pyridine (52 JXL, 0.64 mmol) were combined to afford l-(2-fiuoro-4-methyl-5-(8-methyl-2-(methylaniino)-7-oxo-7,8-dihydropyrido[2,3-d]pyriimdin-6-yl)phenyl)-3-m-lolylurea (91 mg, 64% yield). '-H NMR (400 MHz, DMSO-rf6, major rotomer): 8 8.94 (s, 1H), 8.61 (s, 1H), 8.47 (d, J*= 2.0 Hz, 1H), 7.96 (d, J = 8.8 Hz, 1H),

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7.81 (q,7 = 4.8 Hz, IH), 7.68 (s, IH), 7.28 (brs, IH), 7.14 (m, 2H), 6.77 (d,J= 7.2 Hz, IH), 3.60 (s, 3H), 2.91 (d, J = 4.8 Hz, 3H), 2.24 (s, 3H), 2.06 (s, 3H); MS (ESI) m/z: 447.0 (M+H+).
Example 193: Using general method F, l-chloro-3-isocyanatobenzene (49 mg, 0.32 mmol) and Example A39 (100 mg, 0.32 mmol) in presence of pyridine (52 \ih, 0.64 mmol) were combined to afford l-(3-chlorophcnyl)-3-(2-fluoro-4-methyl-5-(8-iTiethyl-2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (123 mg, 85% yield). ]H NMR (400 MHz, DMSO-ofc, major rotomer): 5 9.20 (s, IH), 8.61 5raanro\e \Wr. Vising general method P, romo-Visocyanrtcfctrafiite {$b -mg, 032 tttrtixX) ami Example A39 (100 mg, 0.32 mmol) in presence of pyridine (52 (J.L, 0.64 mmol) were combined to afford l-(3-bromoplienyl)-3-(2-fluoro-4-methyl-5-(8-niethyl-2»(niethyiamino)-7-oxo-738-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (115 mg, 71% yield). !H NMR (400 MHz, DMSO-4,, major rotomer): 5 9.19 (s, 1H),8.61 (s, IH), 8.55 (d, 7=2.0 Hz, IH), 7.91 (d,7=8.8 Hz, IH), 7.86 (m, IH), 7.81 (q,7=4.4 Hz, IH), 7.68 (s, IH), 7.1-7.3 (m, 4H), 3.60 (s, 3H), 2.91 (d,7 = 4.4 Hz, 3H), 2.07 (s, 3H); MS (ESI) m/z: 511.0 (M-t-H+)-
Example 195: Using general method F, l-fluoro-3-isocyanatobenzene (44 mg, 0.32 mmol) and Example A39 (100 mg, 0.32 mmol) in the presence of pyridine (52 \iL, 0.64 mmol) were combined to afford N(3-fIuorophenyI)-3-(2-iluoro-4-methyI-5-(8-methyI-2-(methyIamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (92 mg, 64% yield). 'H NMR (400 MHz, DMSO-43, major rotomer): 8 9.23 (s, IH), 8.61 (s, IH), 8.55 (d, 7= 2.0 Hz, IH), 7.91 (d,7 = 8.4 Hz, IH), 7.81 (q,7= 4.4 Hz, IH), 7.68 (s, IH), 7.46 (dt, ./ = 2.0, and 11.6 Hz, IH), 7.28 (m, IH), 7.15 (d, 7 = 12.4 Hz, IH), 7.04 (m, IH), 6.77 (dt,7 = 2.4, and 8.4 Hz, IH), 3.60 (s, 3H), 2.91 (d, 7 = 4.4 Hz, 3H), 2.07 (s, 3H); MS (ESI) m/z: 451.0 (M+H+).
Example 196: Using general method F, l-chloro-3-isocyanato-2-rnethylbenzene (43 mg, 0.26 mmol) and Example A39 (80 mg, 0.32 mmol) in the presence of pyridine (41 fiL- 0-51 mmol)

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were combined to afford 1 -(3-chloro-2-metiiylphenyl)-3-(2-fluoro-4-methyl-5-(8-metliyl-2-(methylamino)-7-0X0-7,8-dihydropyi'ido[2,3-d]pyiimidin-6-yl)phenyl)urea (98 mg, 80% yield). !H NMR (400 MHz, DMSO-d6, major rotomer): 5 8.95 (d, J= 1.6 Hz, IH), 8.60 (s, IH), 8.48 (s, IH), 7.96 (d, J= 8.8 Hz, IH), 7.81 (q,J= 4.4 Hz, IH), 7.74 (m, IH), 7.67 (s, IH), 7.12 (m, 3H), 3.59 (s, 3H), 2.90 (d, J= 4.4 Hz, 3H), 2.28 (s, 3H), 2.07 (s, 3H); MS (ESI) m/z: 481.0 (M+H*).
Example 197: Using general method F, l,2-dichloro-3-isocyanatobenzene (48 mg, 0.26 mmol) and Example A39 (80 mg, 0.32 mmol) in the presence of pyridine (41 pL, 0.51 mmol) were combined to afford l-(2,3-dichlorophenyI)-3-(2-fluoro-4-methyl-5-(8-methyf-2-(methylamino)-7-oxo-7;8-dihydropyrido[2,3-d]pyrimidin-6-yI)phenyl)urea (100 mg, 78% yield). ]H NMR (400 MHz, DMSCWfi, major rotomer): 6 9.39 (brs, IH), 8.89 (s, IH), 8.60 (s, IH), 8.10 (dd, J= 3.2, and 6.S Hz, IH), 7.94 (d, J= 8.4 Hz, IH), 7.81 (q, J= 4.4 Hz, IH), 7.68 (s, IH), 7.27 (m, 2H), 7.16 (d, J = 12.0 Hz, IH), 3.60 (s, 3H), 2.90 (d, J = 4.4 Hz, 3H), 2.07 (s, 3H); MS (ESI) m/z: 501.0 (M+H+).
Example 198: Using general method F, l-chloro-2-isocyanato-4-(trifluoromethyl)benzene (49 mg, 0.22 mmol) and Example A39 (70 mg, 0.22 mmol) in the presence of pyridine (36 \iL, 0.48 mmol) were combined to afford l-(2-chloro-5-(trifluoromethyl)phenyl)-3~(2»fluoro-4-methyl-5-(8-methyI-2-(methyIammo)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yI)pheny[)urea(100 mg, 84% yield). *H NMR (400 MHz, DMSO-4, major rotomer): 5 9.49 (brs, 1H), 9.04 (a, IH), 8.61 (brs, IH), 8.57 (d, J = 2.0 Hz, IH), 7.96 (d, J= 8.4 Hz, IH), 7.8l(q, J = 4.8 Hz, IH), 7.70 (m, 2H),7.35 (dd, /= 1.6, and 8.4 Hz, IH), 7.17 (d, 7= 12.4 Hz, IH), 3.60 (s, 3H), 2.90 (d, J= 4.8 Hz, 3H), 2.08 (s, 3H); MS (ESI) m/z: 535.0 (M+H*).
Example 199: Using general method B, the carbamate of 5-^-butylisoxazoI-3-amine (0.075 g, 0.334 mmol) and Example A2S (O.lllg, 0.334 mmol) were combined to afford I-(5-tert-butyIisoxazol-3-yI)-3-(4-chloro-2-fIuoro-5-(I-methyl-7-(methyIainino)-2-oxo-l,2-dihydro-l,6-naphthyridin-3-yl)phenyl)urea (0.042 g3 25%) as a white solid. *H NMR (400 MHz, DMSO-d6): 5 9.86 (s, IH), 8.91 (s, IH), 8.40 (s, IH), 8.15 (d, J= 8.4 Hz, IH), 7.75 (s, IH), 7.57 (d, J= 10.8 Hz, IH), 7.11 (m, IH), 6.45 (s, IH), 3.50 (s, 3H), 2.S6 (d,J= 5.2 Hz, 3H), 1.25 (s, 9H); MS (ESI) m/z: 499.0 (M+H*).

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Example 200: Using general method D, 2-methyl-5-(trifluoromentyl)benzoic acid (50 mg, 0.25 mmol) and Example A39 (92mg, 0.29 mmol) in presence of DPPA (58 yL, 0.27 mmol) and Et3N (38 \iL, 0.27 mmol) were combined to afford l-(2-fluoro-4-methy1-5-(8-methyl-2-(memylainmo)-7-oxo-7,8-dihydropyrido[2J3-d]pyrimidin-6-yl)phenyl)-3--(2-methyl-5" (trifluoromethy!)phenyl)iu-ea (83 mg, 66% yield), 'H NMR (400 MHz, DUSO~d6, major rotomer): 5 9.15 (d, J= 1.6 Hz, 1H), 8.61 (brs, IH), 8.54 (s, IH), 8.35 (d, J= 1.6 Hz, 1H), 7.99 (d, J= 8.4 Hz, IH), 7.8I(q, J= 4.4 Hz, 1H), 7.68 (s, IH), 7.38 (d, /= 8.4 Hz, 1H), 7.24 (m, 1H), 7.16 (d, J= 12.4 Hz, IH), 3.60 (s, 3H), 2.90 (d, J= 4.4 Hz, 3H), 2.32 (s, 3H), 2.07 (s, 3H); MS (ESI) m/z: 515.0 (M+H^.
Example 201: Using general method F, 3-(trifluoromethyl)phenylisocyanate. (45 mg, 0.24 mmol) and Example A28 (80 mg, 0.24 mmol)in the presence of pyridine (39 \iL, 0.48 mmol) were combined to afford l-(4-chloro-2-nuoro-5-(l-methyl-7-(methylammo)-2-oxo-l,2-dihydro-1,6-naphthyridin-3-yl)phenyl)-3-(3-(trifluoromethyl)phenyl)urea (55 mg. 44% yield). !H NMR (400 MHz, DMSO-^e): 5 9.53 (brs, IH), 8.85 (s, IH), 8.41 (s, IH), 8.14 (d, J= 8.8 Hz, 1H); 8.02 (brs, IH), 7.75 (s,lH), 7.55 (d,7=10.8 Hz, IH), 7.50 (m,2H)T 7.31 (m, IH), 7.11 (q, J = 4.4 Hz, IH), 6.17 (s, 1H),3.50 (s, 3H), 2.86 (d, /= 4.4 Hz, 3H); MS (ESI) m/z: 520.0 (M+Ff).
Example 202: Using general method D, 3-bromo-2-methylbenzoic acid (50 mg, 0.23 mmol) and Example A39 (87mg, 0.28 mmol) in presence of DPPA (55 \ih, 0.25 mmol) and Et3N (36 |iL, 0.25 mmol) were combined to afford l-(3-bromo-2-methylphenyI)-3-(2-fluoro-4-methyl-5-(8-memyI-2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yI)phenyl)urea (105 mgz 86% yield). 'H NMR (400 MHz, DMSO-6, major rotomer): 8 8.94 (d, J = 2.0 Hz, IH), 8.60 (brs, IH), 8.49 (s, IH), 7.95 (d, J = 8.8 Hz, IH), 7.81(q, J = 4.4 Hz, IH), 7.76 (brd, ./= 7.2 Hz, IH), 7.67 (s, IH), 7.29 (m, IH), 7.15 (d, J= 12.4 Hz, IH), 7.06 (t, 7= 8.4 Hz, IH), 3.59 (s, 3H), 2,90 (d, J- 4.4 Hz, 3H), 2.32 (s, 3H), 2.07 (s, 3H); MS (ESI) m/z: 525.0 (M+H+).
Example 203: Using general method F, 3-chloro-2-methylphenylisocyanate (39 mg, 0.23 mmol) and Example A12 (70 mg, 0.23 mmol) in the presence of pyridine (38 yiL, 0.47 mmol) were combined to afford l-(2-chloro-5-(trifiuoromethyl)phenyl)"3-(2-fluoro-4-memyl-5-(8-meliiyl-2-

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(methylammo)-7KJXO-7,S-dihydropyrido[23-d]pyrimidin-6-yl)phenyl)urea (75 mg, 69% yield). 'H NMR (400 MHz, DMS06, major rotomer): 5 9.03 (d, J= 2.0 Hz, IH), 8.65 (brs, 1H), 8.55 (s, 1H), 8.43 (m, IH), 7.86 (s, 1H),7.82 (m, 1H), 7.78 (dd, J = 2.8, and 6.8 Hz, 1H)5 7.27 (m, 2H), 7.15 (m, 2H), 3.61 (s, 3H), 2.90 (d, J = 4.4 Hz, 3H), 2.30 (s, 3H); MS (ESI) m/z: 467.0 (M+H+).
Example 204: Using general method B, the carbamate of 4-bromonaphthalen-l-amine (0.061 g, 0.2 mmol) and Example A14 (0.06 g, 0.2 mmol) were combined to afford 1-(5-(2-amino-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-2-fluoro-4-methylphenyl)-3-(4-bromonaphthalen-l-yl)urea as off-white solid (35 mg, 32%, yield). ]H NMR (400 MHz, DMSO-d6): 5 9.24 (s, 1H), 9.06 (s, 1H), 8.61 (s, 1H), 8.24-8.21 (m, IH), 8.15-8.13 (m, IH), 8.01 (d, J= 8.4 Hz, lH),7.98(d,J=8.4Hz, 1H),7.S1 (d,J=8.4Hz, IH), 7.74-7.68 (m, 3H), 7.31 (brs,2H), 7.18 {d,J= 12.4 Hz, IH), 3.54 (s, 3H), 2.08 (s, 3H); MS (ESI) m/z: 547.0 (M+H"*).
Example 205: To a degassed solution of 2-bromo-4-methyIbenzenamine (0.301 g, 1.618 mmol), phenyl boronic acid (Q.296 g, 2.427 mmol), and tetrakistriphenylphosphine palladium(O) (0.187 g, 0.162 mmol) in DME (8 mL) was added 2M sodium carbonate solution (3 ml, 6 mmol) and the mixture was stirred for 16h at 80 °C. Water (30 ml) was added and the product was extracted with EtOAc (2x30 mL). The combined organics were washed with brine, dried (NaaSO, concentrated and purified by silica gel chromatography to provide 2-phenyI-4-methylbenzenamine as a thick syrup (0.22 g, 75% yield). 'H NMR (400 MHz, CDC13): 5 7.47-7.41 (m, 4H), 7.36-7.32 (m, IH), 6.99-6.96 (m, 2H), 6.71 (d, J= 8.0 Hz, IH), 2.28 (s, 3H); MS (ESI) m/z: 184.2 (M+ff).
To a biphasic solution of 2-phenyl-4-methyIbenzenamine (0.29 g, 1.583 mmol) in EtOAc (10 mL) and NaHCO;, (10 ml) was added prop-l-en-2-yl carbonochloridate (0.259 ral, 2.374 mmol) and mixture w^s stirred for 16h at RT. The layers were separated and the aqueous layer was extracted with EtOAc (1x30 mL). The combined organics were washed with brine, dried (NaiS04) and concentrated to provide prop-l-en-2-yl 2-phenyl-4-methylphenylcarbamate as an off-white solid (0.33 g, 78% yield). 'H NMR (400 MHz, CDCI3): 6 8.00 (brs, IH), 7.50-7.46 (m, 2H), 7.42-7.35 (m, 3H), 7.18 (dd, J = 8.4 Hz, 1.6 Hz, IH), 7.05 (s, IH), 6.67 (brs, IH), 4.72 (s, IH), 4.68 (s, 1H), 2.34 (Sj 3H), 1.94 (s, 3H); MS (ESI) m/z: 290.0 (M+Na+).

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Using general method C, prop-l-en-2-yl 2-Phenyl-4-methylphenylcarbamate (0.061 g, 0.23 mmol) and Example A26 (0.071 g, 0.23 mmol) were combined to afford 1 -(2-phenyl-4-methylphenyl)-3-(2-iluoro-4-methyl-5-(l -methyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)phenyl)urea as a white solid (0.034 g, 28% yield). JH NMR (400 MHz, MeOH- Example 206: Using general method D, [l,l'-biplienyl]-2carboxylic acid, 2'-methyl (0.051 g, 0.24 mmol) and Example A26 (0.075 g, 0.24 mmol) in presence of triethylamine (0.073 g, 0.72 mmol) and dipbenylphospharyl azide (0.13 g, 0.48 mmol) were combined to afford l-[2-(2'-methylphenyl)]-3~(2-fluoro-4-niethyI-5-( 1 -methyl -7 -(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)phenyl)urea as a white solid (83 mg, 66%). ]H NMR (400 MHz, DMSO-rf6): 5 8.87 (s, 1H), 8.38 (s, IH), 7.91 (d, J= 8.4 Hz, 1H), 7.89 (d, J = 8.4 Hz, 1H), 7.76 (s, 1H), 7.65 (s, IH), 7.34-7.26 (m, 4H), 7.14-7.02 (m, 5H), 6.16 (s, IH), 3.50 (s, 3H), 2.84 (d, J = 4.8 Hz, 3H), 2.04 (s, 3H), 2.01 (s, 3H); MS (ESI) m/z: 522.2 (M+H+).
Example 207: Using general method B, the carbamate of 2-aminobiphenyl (0.071 g, 0.28 mmol) and Example A26 (0.088 g, 0.28 mmol) were combined to afford l-(2-phenylphenyl)-3-(2-fluoro-4-metliyl-5-(l-methyI-7-(metliylamino)-2-oxo-l,2-dihydro-l,6-naphthyridm-3-yi)phenyl)urea as a white solid (0.107 g, 75% yield). ]H NMR (400 MHz, DMSO-rf6): 5 8.82 (s, IH), 8.39 (s, IH), 8.11 (s, IH), 7.34 (d,J= 8.4 Hz, IH), 7.81 (d, 7=8.0 Hz, IH), 7.65 (s, IH), 7.51-7.47 (m, 2H), 7.42-7.37 (m, 3H), 7.30-7.26 (m, IH), 7.19 (dd, J = 8.0 Hz, 1.6 Hz; IH), 7.13-7.02 Example 208: A degassed mixture of ethyl 5-chloro-2-iodobenzoate (0.621 g, 2.00 mmol), Pd(PPh3)4 (0.116 mg, 0.1 mmol), dimethoxyethane (20 mL), phenylboronic acid (0.268 g, 2.2 mmol), K2C03 (0.829 g, 6.0 mmol), and water (5 mL) was heated under reflux for 6 h. Solvent was removed under reduced pressure. The residue was diluted with sat. NH4C1 (15 mL) and

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extracted with EtOAc (2x30 mL). The combined organic layers were dried (MgS04) and concentrated. The crude product was purified by chromatography to afford ethyl 5-chIoro-2-phenylbenzoate (0.473 g, 91%) as colorless oil. MS (ESI) ra/z: 261.0 (M+H4).
Ethyl 5-chloro-2-phenylbenzoate (0.473 g. 1.81 mmol) was hydrolyzed with lithium hydroxide monohydrate to provide 5-chloro-2-phenylhenzoic acid (0.336 g, 80 % yield). MS (ESI) m/z: 233.0 (M+H4)
Using general method D, 3-chloro-6~phenyl benzoic acid (0.084 g, 0.36 mmol) and Example A27 were combined to afford l-(3-chloro-6~phenylphenyl)-3-(2-fluoro-4-methyl-5-(l -methyl-7-(methyIamino)-2-oxo-l,2-dihydro-l}6-naphthyridin-3-yl)phenyl)urea (0.117 g, 60%) as a white solid. !HNMR(400MHz,DMSO-d6): 59.00(s, IH), 8.40 (s, lH),8.24(s, lH),8.03(s, IH), 7.94 (d,J- 8.4 Hz, IH), 7.66 (s, IH), 7.53-7.50 (m, 2H), 7.45-7.37 (m, 3H), 7.20-7.03 (m, 4H), 6.17 (s, IH), 3.51 (s, 3H), 2.86 (6,J= 4.8 Hz, 3H), 2.06 (s, 3H); MS (ESI) m/z: 542.0 (M+H"1).
Example 209: Using general method B, the carbamate of 4-chloronaphthalen-l-amine (0.061 g, 0.23 mmol) and Example A14 (0.07 g, 0.23 mmol) were combined to afford l-(5-(2-amino-8-methyl-7-oxo-7.S-dihydropyrido[2,3-d]pyiimidin-6-yl)-2-fluoro-4-methyIphenyl)-3-(4-cWoronaphthalen-l-yI)urea as off-white solid (25 mg, 21%, yield). [H NMR (400 MHz, DMSO-dG): 5 9.25 (s, IH), 9.17 (s, IH), 8.56 (s, IH), 8.27-8.24 (m, IH), 8.18-8.16 (m, IH), S.01 (d, J = 8.4 Hz, IH), 7.97 (d, J = 8.4 Hz, IH), 7.72-7.63 (m, 3H), 7.58 (d, J = 8.4 Hz, IH), 7.26 (brs, 2H): 7.13 (d, J= 12.4 Hz, IH), 3.49 (s, 3H), 2.03 (s, 3H); MS (ESI) m/z: 503.0 (M+H4).
Example 210: Using general method B, the carbamate of 5-r~butylisoxazol-3-amine {60 mg, 0.27 mmol) and Example A33 (93 mg, 0.27 mmol) were combined to afford l-(5-tert-butylisoxazol-3-yl)-3-(4-chloro-5-( 1 -ethyI-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)urea (0.045 g, 33% yield). ]H NMR (400 MHz, DMSO-d6): 5 9.86 (s, IH), 8.91 (brs, IH), 8.41 (s, IH), 8.15 (d, J= S.S Hz, IH), 7.74 (s, IH), 7.56 (d, J= 11.2 Hz, IH), 7.06 (q, J= 4.8 Hz, IH), 6.45 (s, IH), 6.24 (brs, IH), 4.14 (q, J = 6.8 Hz, 2H), 2.86 (d, J= 4.8 Hz, 3H), 1.26 (s, 9H), 1.20 (t, J= 6.8 Hz, 3H); MS (ESI) m/z: 513.3 (M+H+).

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Example 211: Using general metliod D, Example B33 (200 mg, 0.806 mmol) and Example A3 (255 mg, 0.806 mmol) were combined to give the intermediate sulfide (132 mg, 29% yield). Using a procedure analogous to Example Al, The sulfide and 2.0N methylamine in THF (1.2 mL, 2.35 mmol) were combined to give l-(2-tert-butyl-4-(trifluoromethyI)pyrimidiii-5-yl)-3-(2-fluoro-5-(8-memyl-2-(memylmio)-7-oxo-7,8-dihydropyrido[23-d]pyrimidin-6-yl)phenyl)urea (79 mg, 61% yield). lH NMR (300 MHz, DMSO-d6); 5 1.35 (s, 9 H), 2.90 {s, 3 H), 3.53-3.60 (m, 3 H), 7.29-7.33 (m, 2 H), 7.70-7.80 (br m, 1 H), 7,87 (s, 1 H), 8.37-8.39 (m, 1 H), 8.63-8.70 (m, 1 H), 8.89 (s, I H), 9.33 (s, 1 H), 9.38 (s, 1 H); MS (ESI) m/z: 545.3 (M+H*).
Example 212: Using general method F, Example A3 (0.173 g, 0.547 mmol) and 1-naphthy] isocyate (0.086 ml, 0.602 mmol) were combined to provide l-(2-fluoro-5-(8-methyl-2-(memyltMo)-7-oxo-7,8-dihydropyrido[2,3-d]pyrmiidin-6-yl)phenyl)»3-(naphthalene-l-yl)urea (246 mg, 94% yield). !H NMR (400 MHz, DMSO- Using a procedure analogous to Example Al, l-(2-fluoro-5-(8-methyl-2-(methyItl-iio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)-3-(Daphthalene-l-yl)urea (244 mg, 0.503 mmol), mCPBA (136 mg, 0.553 mmol) and N,N-dimethylethylenediamine (0.11 mL, 1.01 mmol) were combined to provide J-(5-(2-(2-(dimethylamino)ethy]amino)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-2-fluorophenyl)-3-(Daphthalene-l-yl)urea (110 mg, 100 % yield). 'H NMR (400 MHz, DMSO-4): 6 9.13 (s, 1 H), 9.05 (d, J = 1.9 Hz, 1 H), 8.67 and 8.61 (s, 1 H), S.45 (d, J = 8.5 Hz, 1 H), 8.12 (d, J= 8.0 Hz, 1 H), 8.00 (d, J = 8.2 Hz, 1 H), 7.88 (d, J= 7.7 Hz, 1 H), 7.83 (s, 1 H), 7.71 (t, J = 5.6 Hz, 1 H), 7.60-7.47 (m, 3 H), 7.41 (t, J = 7.9 Hz, 1 H), 7.25 (d, J= 8.2 Hz, 2 H), 3.55 and 3.50 (s, 3 H), 3.41 (q, J= 6.5 Hz, 2 H), 2.41 (m, 2 H), 2.14 and 2.11 (s, 6 H); MS (ESI) m/z: 526.2 (M+H+).
Example 213: Using general metiiod G, the carbamate of 5-/-butylisoxazol-3-amine (1.340 g, 5.97 mmol), and Example A30 (1.50 g, 4.60 mmol) were combined to furnish l-(5-tert-butylisoxazol-3-yl)-3-(5-(l-ethyl-7-(methylamino)-2-Qxo-l,2-dihydro-l,6-naphthyridin-3-yl)-2-
fluoro-4-methylphenyl)urea (1.99g, 88% yield). lH NMR (400 MHz, DMSO-d6): 5 9.79 (s, 1H),

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8.74 (s, IH)), 8.40 (s, IH), 7.91(d, J =8Hz, IH), 7.66 (s, IH), 7.15 (d, J= 13Hz, IH), 7.00 (m, IH), 6.44 (s, IH), 6.23 (s, IH), 4.15 (m, 2H), 2.86 (d, J = 5Hz, 3H), 2.07 (s, 3H), 1.26 (s, 9H), 1.20 (t, J = 6Hz, 3H): MS(ESI) m/z : 493.2 (M+H+).
Example 214: Using general method B, the carbamate of 2-phenylaniline (0.089 g, 0.353 mmol) and Example A54 (0.100 g, 0.353 mmol) were combined to afford l-(2-phenyiphenyl)-3-(2-fluoro-4~methyl-5-( 1 -methyl-2-oxo-l ,2-dihydro-1,6-naphthyridin-3-yl}phenyl)urea (0.128 g, 76% yield) as a white solid. 'H NMR (400 MHz, DMSO-d6): 8 8.92 (s, IH), 8.87 (s, IH), 8.60 (d,y= 5.6 Hz, IH), 8.14 (s, IH), 8.03-7.97 (m, 2H), 7.81 (d, J= 8.4 Hz, IH), 7.53-7.48 (m, 3H), 7.43-7.37 (m, 3H), 7.29 (t, J= 8.8 Hz, IH), 7.21-7.12 (m, 3H), 3.65 (s, 3H), 2.07 (s, 3H); MS (ESI) m/z: 479.2 (M+H+).
Example 215: Using general method B, the carbamate of 5-MrotyIisoxazol-3-amine (80 mg, 0.36 mmol) and Example A48 (122 mg, 0.36 mmol) were combined to afford 1 -(5-tert-butylisoxazoI-3-yl)-3-(4-cyano-2-fluoro-5-(8-methyl-2-(niethylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)pheny!)urea (0.046 g, 25% yield). MS (ESI) m/z: 508.2 (M+H+).
Using a procedure analogous to Example Al, l"(5-tert-butylisoxazol-3-yl)-3-(4-cyano-2-fluoro-5-(8-methyl-2-(methyltIiio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (0.046 g, 0.091 mmol) was treated with mCPBA (70% wt, 0.027 g, 0.11 mmol) and then N-methylamiae (2.0M in THF, 0.18 mL, 0.36 mmol) to afford l-(5-tert-butylisoxazol-3-yl)-3-(4-cyano-2-fluoro-5-(8-methyl-2-(methyIamino)-7-oxo-7,8-dihydropyrido[2,3-d3pyrimidin-6-yl)phenyl)urea (15 mg, 34% yield). 'H NMR (400 MHz, DMSO-6): 5 10.0 (s, IH), 9.24 (brs, IH), 8.67 (s, IH), 8.41 (d, J= 1.6 Hz, IH), 7.98 (d, J= 11.2Hz, IH), 7.94 (s, IH), 7.88 (m, IH), 6.49 (s, IH), 3.61 (s, 3H), 2.92 (d,7=4.8 Hz, 3H), 1.26 (s, 9H); MS (ESI) m/z: 491.2 (M+H+).
Example 216: Using general method D, Example B34 (200 mg, 0.646 mmol) and Example A3 (205 mg, 0.646 mmol) were combined to give the intermediate sulfide (215 mg, 53% yield). Using a procedure analogous to Example Al, the sulfide and 2.00N methylamine in THF (1.35 mL, 2.70 mmol) were combined to afford l-(2-tert-butyl-4-(l-methyl-lH-indoI-5-yl)pyrimidin-5-yl)-3-(2-fluoro-5-(8-memyl-2-(memyIainino)-7"Oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-

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yl)phenyl)urea (22 mg, 33% yield). lH NMR (300 MHz, DMSO-J6): 8 1.38 (s, 9 H), 2.90 (s, 3 H), 3.53-3.60 (m, 3 H), 3.83 (s, 3 H), 6.55 (s, 1 H), 7.23-7.29 (m, 3 H), 7.41 (m, 1 H), 7.56-7.61 (m, 2 H), 7.85 (s, 1 H), 7.98 (s, 1 H), 8.38-8.40 (m, 1 H), 8.63-8.70 (m, 2 H), 9.01-9.05 (br. s, 2 H); MS (ESI) m/z: 606.2 (M+H+).
Example 217: Using general method F, Example A30 (70 rag, 0.21 mmol) and 1-isocyanato-3-(trifluoromethyl)benzene (0.035 mL, 0.25 mmol) were combined to provide l-(5-(l-etliyI-7-(methylamino)-2-oxo-l,2-dihydro-l,6-naphthyTidin-3-yl)-2-fliiorO"4-methylphenyl)-3-(3-(£rifluoromethyl)phenyl)urea (43 mg, 39 % yield). ]H NMR (400 MHz: DMSO-4): 5 9.37 (s, 1 H), 8.58 (d, J = 1.5 Hz, 1 H), 8.41 (s, 1 H), 8.02 (s, 1 H), 7.90 (d, J = 8.4 Hz, 1 H), 7.67 (s, 1 H), 7.52-7.45 (m, 2 H), 7.30 ( br d, J = 6.2 Hz, 1 H), 7.14 (d, J = 12.2 Hz, 1 H), 7.00 (q, J = 4.8 Hz, 1 H), 6.24 (s, 1 H), 4.15 (q, J = 7.0 Hz, 2 H), 2.86 (d, J - 4.8 Hz, 3 H), 2.07 (s, 3 H), 1.21 (t, J = 7.0 Hz; 3 H); MS (ESI) m/z: 514.2 (M-f-H4).
Example 218: Using general metliod B, the carbamate of 2-phenylaniline (0.107 g, 0.422 mmol) and Example A56 (0.100 g, 0.281 mmol) were combined to afford 1 -(5-(7-(2-(dimethylamino)ethylamino)-l-methyl-2-oxo-l,2-dihydro-l,6-naphlhyridin-3-yl)-2-fluorophenyl>3-(2-phenylplienyl)urea (0.276g, 18%) as a white solid. It was converted to the corresponding bis-methylate salt by reacting with MsOH (2.0 eq.). !H NMR (400 MHz, DMSO-d6):5 8.54(s, m), 8.36 (dd, J = 7.6, 2.0 Hz, 1H), 7.94 (s, 1H), 7.82 (dd,,/ = 8.4, 0.8 Hz, ]H), 7.50-7.46 (m, 2H), 7.41-7.32 (m, 5H), 7.27 (dd, J = 7,6, 1.6 Hz, IH), 7.22-7.13 (m, 2H), 6.72 (s, IH), 3.90 (t, J= 6.0 Hz, 2H), 3.70 (s, 3H), 3.50 (t, J= 6.0 Hz3 2H), 3.01 (s, 6H), 2.72 (s, 6H); MS (ESI) m/z: 551.2 (M+H*).
Example 219: Using general metliod B, the carbamate of 3-isopropyI-I-phenyI-I H-pyrazoI-5-amine (0.100 g, 0.350 mmol) and Example A28 ( 0.111 g, 0.334 rnmol) were combined to afford l-(4-chloro-2-fluoro-5-(l -methyl-7-(methylamino)-2-oxo-l ,2-dihydro-l ,6-naphthyridin-3-yl)phenyl)-3-(3-isopropyl-l-phenyl-lH-pyra2ol-5-yl)urea (0.075 g, 40% yield) as a white solid. *H NMR (400 MHz, DMSO-d6): 6 8.36 (s, IH), 8.13 (d, J= 8.4 Hz, IH), 7.74 (s, 1H), 7.57-7.52 (m, 2H), 7.49-7.45 (m, 3H), 7.29 (d, J= 10.8 Hz, 1H), 6.39 (s, 1H), 6.29 (s, 1H), 3.62 (s, 3H), 2.97-2.91 (m, 4H), 1.27 (d, /= 6.8 Hz, 6H); MS (ESI) m/z: 560.2 (M+H+).

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Example 220: Using general method D, 2-fIuoro-5-(trifluoromethyl)benzoic acid (50 mg, 0.24 mmol) and Example A39 (75 mg, 0.24 mmol) in presence of DPPA (57 |iL, 0.26 mmol) and Et3N (37 jiL, 0.26 mmol) were combined to afford l-(2-fluoro^l-methyl-5"(8-methy]-2-(methyIamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)pbenyl)-3-(2-fluoro-5-(trifluoromethyl)phenyl)urea (90 mgs 76% yield). *H NMR (400 MHz, DMSO-4s, major rotomer): 5 9.33 (d, 7= 2.4 Hz, IH), 9.12 (brs, IH), 8.61 (s, IH), 8.59 (dd, J = 2.4, and 7.6 Hz, 1H), 7.97 (d,/= 8.4 Hz, IH), 7.81 (q, J = 4.4 Hz, IH), 7.69 (s, IH), 7.48 (m, 1H), 7.37 (in, IH), 7.16 (d, J= 12.4 Hz, IH), 3.60 (s, 3H), 3.54 (s, 3H), 2.91 (d,7- 4.4 Hz, 3H), 2.08 (s, 3H); MS (ESI) m/z: 519.0 (M+H+).
Example 221: In a manner analogous to that described for the preparation of Example 137, prop-l-en-2-yl 5-t-butyI-l,3,4-thiadiazol-2-ylcarbamate (100 mg, 0.414 mmol, LOO eq) and Example A17 (145 mg, 0.414 mmol, 1.00 eq) were reacted in the presence of N-methylpyrrolidine (0.043 ml, 0.041 mmol, 0.10 eq) in THF (4 ml). Subsequent oxidation with mCPBA (44.3 mg, 0.180 mmol, 1.20 eq) and displacement with 2.0M methylamine in THF (0.749 ml, 1.498 mmol, 10.00 eq) afforded l-(5-tert-butyl-l^,4-thiadiazol-2-yl)-3-(4-chloro-2-fiuoro-5-(S-memyl-2^memylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyI)urea (14 mg, 6.5% overall yield) as a white solid. lH NMR (400 MHz, DMSO-^): 5 8.98 (brs, IH), 8.66 (brs, IH), S.58 (brs, IH), 8.05 (d, IH, J = 8.0 Hz), 7.85 (brq, IH), 7.73 (s, IH), 7.56 (d, IH , J = 10.8 Hz), 3.55 (brs, 3H), 2.86 (brd, 3H), 1.30 (a, 9H); MS (ESI) m/z: 517.0 (M+H).
Example 222: Using general method B, the carbamate of Example B19 (3.00 g, 13.44 mmol) and Example A28 (3.00 g, 9.02 mmol) were combined to provide l-(l-tert-butyMH-pyrazoI-4-yl)-3-(4-chloro-2-fluoro-5-(l-mediyl-7-(methyIamino)-2-oxo-l,2-dihydro-l,6-naphthyridin-3-yl)phenyl)urea (1.85g, 41% yield). IH NMR (400 MHz, DMSO-d6): D 8.72 (s, IH), 8.63 (brs, IH), 8.40 (s, IH), 8.18 (d, J=9Hz , IH), 7.79 (s, IH), 7.73 (s, IH), 7.50 (d, J=llHz, IH), 7.39 (s, IH), 7.10 (m, lH),6.17(s, IH), 3.50 (s, 3H), 2.85 (d, J= 5Hz, 3H), 1.46 (s,9H);MS(ESI) m/z: 498.0 (M+H*).
Example 223: Using general method B, the carbamate of 5-f-butylisoxazol-3-amine (50 mg, 0.223 mmol) and Example A46 (72 mg, 0.223 mmol) were combined to afford l-(5-tert-

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butylisoxazoI-3-yi)-3-(4-ethyiiyl-2-fluoro-5--(8-methyl-2--(methylamino)-7-oxo-7,S-dihydropyrido[2,3-d]pyrirmdin-6-yl)phenyl)urea (0.058 g, 53% yield). 'H NMR (400 MHz, DMSO-4, major isomers): 5 9.90 (s, IH), 8.99 (s, IH), 8.62 (s, IH), 8.22 (d, J= 8.4 Hz, IH), 7.87 (q, J= 4.8 Hz, IH), 7.80 (s, IH), 7.48 {d, ,7=11.6 Hz, IH), 6.47 (s, IH), 4.08 (s, IH), 3.60 (s, 3H), 2.91 (d, ./= 4.8 Hz, 3H), 1.26 (s, 9H); MS (ESI) m/z: 490.2 (M+H+).
Example 224: To a stirring suspension of 3-t-butyl-l-(3-nitrophenyl)-lH-pyrazol-5-amine hydrochloride (0.500 g, 1.685 mmol, 1.00 eq) and pyridine (0.412 ml, 5.05 mmol, 3.00 eq) in CH2CI2 (17 ml) at 22 QC was added Troc-Cl (0.244 ml, 1.769 mmol, 1.05 eq). The reaction was stirred overnight at RT. The completed reaction was diluted with CH2CI2 and washed with 3M HC1 (2x). The combined aqueous were extracted with CH2CI2 (lx). The combined organics were washed with HiO (2x), brine (lx), dried (Na2SO4), filtered ad evaporated. The crude product was purified by flash column chromatography (100% hexanes to 30% EtOAc/hexanes) to afford 2,2,2-trichloroethyl 3-t-butyl-l-(3-nitrophenyl)-lH-pyrazol-5-ylcarbamate (0.67 g, 91% yield) as an oil.
2,2,2-TrichIoroethyl 3-t-butyl-l-(3-rutrophenyllH~pyrazol-5-ylcarbamate (0.67 g, 1.538 mmol, 1.00 eq) in EtOAc (30 ml) was shaken under H2 (3.5 arm) at 22 °C over 10% Pd/C (0.327 g, 0.154 mmol, 0.10 eq, 50% H2O) overnight. The completed hydrogenation was treated with AcsO (3 ml) and stirred at RT. After 45 min, the mixture was filtered through Celite, rinsing forward with EtOAc. The filtrate was treated with a roughly equal volume of satd. NaHCC>3 and stirred briskly at RT for 3h. The layers were separated and the organic layer washed with satd. NaHCOs (2x). The combined aqueous layers were extracted with EtOAc (lx). The combined organics were washed with brine (lx), dried (MgS04), filtered and evaporated to afford 2,2,2-trichloroethyl l-(3-acetamidophenyl)-3-t-buty]-lH-pyrazol-5-ylcarbamate (0.50 g, 73% yield) as a white solid which was used as is in the next reaction. 'H NMR (400 MHz, DMSO-^): 5 10.10 (s, IH), 9.95 (bis, IH), 7.74 (brs, IH), 7.54-7.51 (m, IH), 7.37-7.31 (m, IH), 7.08 (d, J = 7.6 Hz, IH), 6.26 (s, IH), 4.84 (s, 2H), 2.03 (s: 3H), 1.26 (s, 9H); MS (ESI) m/z: 447.0 (M+H), 449.0 ((M+2+H).
Using general method C, 2,2,2-trichloroethyl l-(3-acetamidophenyl)-3-t-buty!-lH-pyrazol-5-ylcarbamate (0.100 g, 0.223 mmol, 1.00 eq) and Example A39 (0.070 g, 0.223 mmol, 1.00 eq) were combined to afford l-(l-(3-acetamidophenyl)-3-tert-butyl-lH-pyrazol-5-yl)-3-(2-

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fluoro-4-methyl-5-(S-metliyl-2-(methylamino)-7-oxo-7,8"dihydix»pyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (20 mg, 15% yield) as an off-white solid. !H NMR (400 MHz, DMSO-40: 6 10.17 (s, 2H), 8.92 (s, 1H), 8.85 (s, 1H): 8.61 (brs, 1H), 7.95 (d, J = 8.4 Hz, 1H), 7.82 (brq, 1H), 7.68 (d, J = 8.0 Hz, 2H), 7,44 (dd, J = 7.6 and 16.4 Hz, IH), 7.16-7.11 (m, 2H), 6.35 (s, IH), 3.60 (s, 3H), 2.90 (bid, 3H), 2.05 (brs, 3H), 1.23 (s, 9H); MS (ESI) m/z: 612.3 (M+H).
Example 225: Using general method D, Example B30 (0.051 g, 0.3 mmol) and Example A30 (0.1 g, 0.3 mmol) in presence of triethylamine (0.12 g, 1.2 mmol) and diphenylphospharyl azide (0.25 g, 0.91 mmol) were combined to afford l-(l-tert-butyMH-pyrazol-4-yl)-3-(5-(l-ethyl-7-(methylamino)-2-oxo-l,2-dihydro-l,6-naplithyridin-3-yl)-2-fluoro-4-methylphenyl)urea as a white solid (41 mg. 27% yield). 'H NMR (400 MHz, DMSO-d6): 5 8.64 (s, 1H), 8.41 (s, 1H), 8.40 (s, 1H), 7.94 (d, J = 8.8 Hz, 1H), 7.78 (s, 1H), 7.64 (s, 1H), 7.36 (s, 1H), 7.10 (d, J= 12.0 Hz, 1H), 7.01-6.97 (m, 1H), 6.23 (s, 1H), 4.14 (q, , J= 6.8 Hz, 2H), 2.85 (d, J = 4.8 Hz, 3H), 2.05 (s, 3H), 1.45 (s, 9H), 1.20 (t, J= 6.8 Hz, 3H); MS (ESI) m/z: 492.3 (M+H+).
Example 226: Using general method F, Example A22 (0.060 g, 0.21 mmol) and 1-naphthyl isocyate (0.033mL, 0.23 mmol) were combined to provide l-(5-(l-ethyl-2-oxo-l,2-dihydro-l,6-naphthyridin-3-yl)-2-fliiorophenyl)-3-(naphrhalen-l-yl)urea (72 mg, 75 % yield). lH NMR (400 MHz, DMSO-40: 5 9,14 (s, 1 H), 9.08 (d, J = 2.0 Hz, 1 H), 8.92 (s, 1 H), 8.54-8.51 (m, 2 H), 8.13-8.11 (m, 2 H), 7.99 (d, J = 7.8 Hz, 1 H), 7.88 (d, J = 7.4 Hz, 1 H), 7.60-7.47 (m, 4 H), 7.42 (t, J = 7.8 Hz, 1 H), 7.31 (d, J = 9.0 Hz, 2 H), 4.26 (q, J - 7.0 Hz, 2 H), 1.19 (t, J = 7.0 Hz, 3 H); MS (ESI) m/z: 453.3 (M+H*).
Example 227: Using general method D, 2,3-difliiorobenzoic acid (40 mg, 0.25 mmol) and Example A39 (80 mg, 0.25 mmol) in presence of DPP A (60 jiL, 0.2S mmol) and Et3N (40 |^L, 0.28 mmol) were combined to afford l-(2,3-difluorophenyl)-3-(2-fluoro-4-methyl-5-(8-methyl-2-(methylaniino)-7-oxo-7I8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyt)urea (90 mg, 76% yield). 'H NMR (400 MHz, DMSO-rf6, major rotomer): 5 9.16 (brs, 1H), 9.02 (brs, 1H), 8.61 (brs, 1H), 7.9 -8.0 (m, 2H), 7.80 (m, IH), 7.69 (s, 1H), 7.16 (d, J = 12.4 Hz, JH), 7.10 (m, 1H), 7.00 (m, 1H), 3.60 (s, 3H), 2.91 (d, 7 = 4.4 Hz, 3H), 2.07 (s, 3H); MS (ESI) m/z: 469.0 (M+H+).

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Example 228: Using general method C, the TROC carbamate of 4-bromo-3-(trifluoromethyl)aniline (0.10 g, 0.24 mmol), and Example A12 (72 mg, 0.24mmol) (0.10 mL, 0.54 mmol) were combined to afford l-(4-bromo-3~(trifluoromethyl)phenyl)-3-(2-fluoro-5-(8-memyl-2-(methylainino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (0.027 g, 20% yield). lH NMR (400 MHz, DMSO-rf6, major rotomer): 59.52 (s, IH), 8.70(d,y=2.0 Hz, 1H), 8.66 (s, 1H), 8.35 (dd, J= 1.6, and 7.6 Hz, 1H), 8.11 (d, .7=2.4 Hz, IH), 7.90 (s, 1H), 7.73, m, IH), 7.76 (d, J= 92 Hz, 1H), 7.53 (dd, J= 2.8, and 8.8 Hz, 1H), 7.30 (m, 2H), 3.62 (s, 3H), 2,91 (d,J= 4.8 Hz, 3H); MS (ESI) m/z: 566.0 (M+H+).
Example 229: Using general method C, Example Al (127 mg, 0.444 mmol), and 2,2,2-trichloroethyl quinoIin-8-ylcarbamate (142 mg, 0.444 mmo!), at 120 °C, were combined to afford l-(5-(2-amiiio-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-2-fluorophenyI)-3-(quinolin-8-yl)urea (18 mg, 8% yield). lH NMR (300 MHz, DMSO-rf6): 8 3.55 (s, 3 H), 7.29-7.31 (m, 2 H), 7.51-7.64 (m, 3 H), 7.50-8.00 (br. s, 2 H), 7.94 (s, 1 H), 8.37-8.40 (m, 1 H), 8.45-8.48 (m, 1 H), 8.54-8.56 (m, 1 H), 8.75 (s, 1 H), 8.92-8.93 (m, 1 H), 9.82 (s, 1 H), 10.20 (s, t H); MS (ESI) m/z: 456.0 (M+H+).
Example 230: Using general method C, the TROC carbamate of Example B20 (0.10 g, 0.33 mmol) and Example A17 (116 mg, 0.33mmol) were combined to afford l-(4-cliloro-2-fluoro-5-(8-methyl-2-(methyltliio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)-3-(3-isopropylisoxazol-5-yl)urea (0.087 g, 52% yield). MS (ESI) m/z: 503.0 (M+H*).
Using a procedure analogous to Example Al, l-(4-chloro-2-lluoro-5-(8-methyl-2-(methylthio)-7-oxo-7,8-dihydropyiido[2,3-d]pyrimidin~6-yl)phenyi)-3-(3-isopropylisoxazol-5-yl)urea (0.087 g, 0.17 mmol) was treated with mCPBA (70% wt, 0.051 g, 0.21 mmol) and then N-methylamine (2.0M in THF, 0.35 mL, 0.69 mmol) to afford l-(4-chloro-2-fluoro-5-(8-methyl-2-(memylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)-3-(3-isopropylisoxazol-5-yl)urea (65 mg, 77% yield). ]H NMR (400 MHz, DMSO-6, major rotomer): 5 10.4 (brs, IH), 8.93 (bra, IH), 8.62 (s, IH), 8.11 (d, J = 8.8 Hz, IH), 7.88 (m, IH), 7.77 (s, IH), 7.59 (d, J = 10.8 Hz, IH), 5.99 (s, IH), 3.59 (s, 3H), 2.90 (m, 4H), 1.16 (dtJ= 7.2 Hz, 6H); MS (ESI) m/z: 486.0 (M-tTT).

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Example 231: Using general method F, Example Al (0.150 g, 0.526 mmol) and I-isocyanatonaphthalene (0.100 g, 0.591 mmol) were combined to provide l-(5-(2-amino-8-methy]-7-oxo-7,8-dihydropyrido[2)3-d]pyrimidin-6-yl)-2-fluorophenyl)-3-(naphthalen-l-
yl)urea(0.11g, 40% yield). ]H NMR (400 MHz, DMSO-d6): 8 9.16 (s, 1H), 9.10 (brs, 1H), 8.66
(s, 1H), 8.51 (m, 1H), 8.18 (d, J =9Hz, 1H), 8.05 (brd, J =8Hz, 1H), 7.93 (bid, J =8Hz, 1H), 7.89 (s, 1H), 7.65-7.45 (m, 4H), 7.31 (m, 4H), 3.56 (s, 3H); MS(ESI) m/z : 455.0 (M+H+).
Example 232: Using general method B, the carbamate of 3-isopropyl-I -phenyl- lH-pyrazol-5-amine (0.100 g, 0.350 mmol), and Example A30 (0.100 g, 0.306 mmol) were combined to provide 1 -(5-( 1 -ethyl-7-(rnethylamino)-2-oxo-l ,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoro-4-
methylphenyi)-3^3-isopropyI4-phenyl-lH-pyrazol-5-yl)urea (0.14g, 72% yield). h-I NMR (400 MHz, DMSO-d6): 8 8.89 (s, 1H), 8.82 (s, 1H), 8.40 (s, 1H), 7.91 (d, J =9Hz , 1H), 7.64 (s,
1H), 7.50 (m , 4H), 7.41 (ms 1H), 7.10 (d, J =32Hz, 1H), 7.00 (m, 1H),6.31 (s, 1H), 6.24 (s, 1H), 4.14 (q, J=6Hz, 2H), 2.85 (m 4H), 2.06 (s, 3H), 1.20 (t, J - 6Hz, 3H), 1.18 (d, J = 6Hz, 6H); MS(ESI) m/z : 554.2 (M+H+).
Example 233: To a sLirring solution of Example B28 (0.200 g, 1.314 mmol, 1.00 eq) and pyridine (0.213 ml, 2.63 mmol, 2.00 eq) in CH2C12 (13 ml) at 0 QC was added isopropenyl chloroformate (0.158 ml, 1.446 mmol, 1.10 eq). After 45 min at 0 °C, the completed reaction was diluted with CH2CI2 and washed with 3M HCl (2x). The combined aqueous layers were extracted with CH2CI2 (lx). Tlie combined organics were washed with H2O (lx), and brine (lx), dried {Na2S04), filtered and evaporated to afford crude prop-l-en-2-yl 3-cyclopentylisoxazol-5-ylcarbamate (0.41 g, 132% yield) as an oil which was used as is in the next reaction. MS (ESI) m/z: 237.0 (M+H).
Prop-l-en-2-yl 3-cyclopentylisoxazol-5-ylcarbamate (0,310 g, 1.312 mmol), Example A39 (0.411 g, 1.312 mmol) and 1-methylpyrrolidine (0.027 ml, 0.262 mmol) were combined in THF (13 ml) and stirred with heating at 60 °C overnight. The completed reaction was cooled to RT, applied to a samplet and allowed to dry. The crude product was purified by flash column chromatography (10-75% EtOAc/hexancs) and men by reverse phase chromatography (10-60% MeCN (w/ 0.1% TFA)/ H20 (w/0.1% TFA)) to afford l-(3-cyclopenlylisoxazol-5-yl)-3-(2-

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nuoro-4-meuiyl-5-(8-methyl-2-(memylamino)-7-oxo-7,S-dihydropyrido[2,3-d]pyrirnidin-6-yl)phenyl)urea (75 mg, 12% yield) as an off-white solid following lyophilization. 'H NMR (400 MHz, DMSO-4s): 5 10.30 (s, 1H), 8.68 (brs, IH), 8.61 (brs, 1H), 7.88 (d, J = 8.4 Hz, IH), 7.83 (brq, 1H), 7.68 (s, IH), 7.17 (d, J = 12.0 Hz, 1H), 5.93 (s, 1H), 3.60 (brs, 3H), 3.03-2.95 (m, IH), 2.90 (brs, 3H), 2.08 (s, 3H), 1.96-1.90 (m, 2H), 1.69-1.54 (m, 6H); MS (ESI) m/z: 492.3 (M+H).
Example 234: In a manner analogous to that described for the preparation of Example 233,
Example B29 (0.200 g, 1.203 mmol, 1.00 eq) and Example A39 (0.377 g, 1.203 mmol) were
reacted to afford 1 -(2-fluoro-4-methyl-5-(8-methyl-2-(rnethy]amiiio)-7-oxo-7,8-
dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)-3-(3-(l-methylcyclopentyl)isoxazol-5-yl)urea ( 107 mg, 18% yield) as an off-white solid. 'H NMR (400 MHz, DMSO-d6): 5 10.30 (s, IH), 8.68 (brs, 1H), 8.61 (s, 1H), 7.89 (d, J = 8.4 Hz, 1H), 7.85 (brq, 1H), 7.68 (s, 1H), 7.17 (d, J = 12.4 Hz, IH), 5.97 (s, 1H), 3.60 (brs, 3H), 2.95 (brs, 3H)2.08 (s, 3H), 1.95-1.91 (m, 2H), 1.70-1.52 (m, 6H), 1.23 (s, 3H): MS (ESI) m/z: 506.2 (M+H).
Example 235: The carbamate of 5-M>utylisoxazol-3-amine (100 mg, 0.446 mmol), Example A31 (139 mg, 0.446 mmol) and 1-methylpyrrolidine (9.27 pi, 0.089'mmol) were combined in THF (5 ml) and stirred with heating at 60 °C in a sealed screw-cap vial for 24 h. The completed reaction was cooled to RT and concentrated to diyness. The crude product was purified by reverse phase chromatography (5-45% MeCN (w/ 0.1% TFA)/ H20 (w/0.1% TFA)). Fractions containing pure product were pooled and neutralized with satd. NaHCOs. This was extracted with EtOAc (2x). The combined organics were washed with brine (2x), dried (MgS04), filtered and evaporated to a solid residue. This was dissolved/suspended in MeCN/H20, frozen and lyophilized to afford l-(5-(7-amino-]-ethyl-2-oxo-l,2-dihydro-l,6-naphthyridin-3-yl)-2-fluoro-4-mediylphenyl)-3-(5-tert-butylisoxazol-3-yI)urea (108 mg, 50.6 % yield) as a beige solid. *H NMR (400 MHz, DMSO-rffi): 5 9.79 (s, IH), 8.74 (s, 1H), 8.35 (s, 1H), 7.91 (d, I = 8.4 Hz, IH), 7.65 (s, IH), 7.15 (d, J = 12.0 Hz, IH), 6.49 (brs, 2H), 6.44 (s, IH), 6.34 (s, IH), 4.09 (q, J = 6.8 Hz, 2H), 2.07 (s, 3H), 1.25 (s, 9H), 1.20 (t, J- 6.8 Hz, 3H); MS (ESI) m/z: 479.2 (M+H).
Example 236: Using general method B, the carbamate of 5-f-butylisoxazol-3-amine (108 mg, 0.480 mmol) and Example A44 (150 mg, 0.480 mmol) were combined to give the intermediate

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sulfide, l-(5-tert-butylisoxazol-3-yl)-3-(4-methyl-3-(8-methyl-2-(mctliylthio)-7-oxo-7,8-
dihydropyrido[2,3-d]pyriniidin-6-yl)phenyl)urea (35 mg, 15% yield). Using a procedure analogous to Example Al, l-(5-tert-butylisoxazol-3-yl)-3-(4-methyl-3-(8-methyl-2-(methyltliio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin~6-yl)phenyl)urea (158 mg, 0.330 mmol) and 2.0N solution of methylamine in THF (1.7 mL) were combined and purified by chromatography (Biotage Si-25 column, 60-100% ethyl acetate/Hex) to afford l-(5-tert-buty!isoxazol-3-yl)-3-(4-metlryl-3-(8-methyI-2-(methylammo)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (49 mg, 32% yield). lH NMR (300 MHz, DMSO-d6): 5 1.26 (s, 9 H), 2.06 (s, 3 H), 2.90 (s, 3 H), 3.53-3.60 (m, 3 H), 6.46 (s, 1 H), 7.14-7.16 (m, 1 H), 7.26-7.28 (m, 1 H), 7.32 (s, 1 H), 7.67 (s? 1 H), 7.65-7.80 (br m, 1 H), 8.60-8.65 (m, 1 H), 8.72 (s, 1 H), 9.47 (s, 1 H); MS (ESI) m/z: 462.0 (M+H+).
Example 237: Using general method D, Example B40 (50 mg, 0.19 mmol) and Example AI2 (56 mg, 0.19 mmol) in presence of DPPA (46 uL, 0.21 mmol) and Et3N (30 uX, 0.21 mmol) were combined to afford l-(2-tert-butyl-4-morpholinopyrimidin-5-yl)-3-(2-fluoro-5-(8-methyl-2-(methylamino)-7-oxo-7.8-dihydropy]'ido[2,3-d]pyrimidin-6-yl)phenyl)urea. This was treated with aqueous HC1 (0.100 M) to afford l-(2-tert-butyl-4-morpholinopyrimidin-5-yl)-3-(2-fluoro-5-(8-methyl-2-(metliylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyI)urea HC1 salt (14 rag, 13% yield). 'H NMR (400 MHz, DMSO-df„ major isomers): 5 9.17 (s, IH), 8.90 (bis, IH), 8.65 (brs, IH), 8.32 (s, IH), 8.30 (dd, J- 2.0, and 8.0 Hz, IH), 7.88 (brs IH), 7.86 (s, IH), 7.27 (m, 2H), 4.00 (m, 4H), 3.73 (m, 4H), 3.60 (s, 3H); 2.90 (s, 3H), 1.36 (s, 9H); MS (ESI) m/z: 562.3 (M+H+).
Example 238: Using general method D, 3-tert-butyl-l-niethyl-lH-pyrazoIe-5-carboxylic acid (0.061 g, 0.33 mmol) and Example A63 (0.116 g, 0.33 mmol) in presence of triethyiamine (0.1 g, 0.97 mmol) and diphcnylphospharyl azide (0.14 g, 0.5 mmol) were combined to afford l-(3-tert-butyl-l-methyl-lH-pyrazol-5-yl)-3-(4-cliloro-5-(8-ethyl-2-(methylamino)-7-oxo-7}8-dihydropyrido[2,3-d]pyrimidin-6-yl)-2-fluorophenyl)urea as a white solid (0.045 g, 25% yield). ]H NMR (400 MHz, DMSCW6): 8 8.96-8.95 (m, 2H), 8.61 (s, IH), 8.17 (d, J= 8.8 Hz, IH), 7.88-7.86 (m, IH), 7.74 (s, IH), 7.56 (d,./= 7.2 Hz, IH), 6.05 (s, IH), 4.36-4.31 (m, 2H), 3.59 (s, 3H), 2.89 (d,./= 4.4 Hz, 3H), 1.24-1.17 (m, 12H); MS (ESI) m/z: 527.2 (M+H+).

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Example 239: Using general method D, 3-isopropyl-l-rnethyl-lH-pyrazole-5-carboxylic acid (0.055 g, 0.33 mmol) and Example A63 (0.114 g, 0.33 mmol) in presence of triethylamine (0.1 g, 0.97 mmol) and diphenylphospharyl azide (0.14 g, 0.5 mmol) were combined to afford l-(4-chloro-5-(8-ethyl-2-(methylamino)-7-oxo-7,8-dihydropyrido[23-d]pyriraidin-6-yl)-2-fluorophenyl)-3-(3-isopropyl-l-methyl~lH~pyrazol-5-yl)iirea as a white solid (0.037 g, 22% yield). ]H NMR (400 MHz, DMSO-d6): 5 8.98 (s, IH), 8.96 (s, IH), 8.61 (s, IH), 8,16 (d, J = 8.4 Hz, IH), 7.88-7.86 (m, IH), 7.74 (s, IH), 7.57 (d, J= 10.8 Hz, IH), 6.01 (s, IH), 4,36-4.31 (m, 2H), 3.58 (s, 3H), 2.90 (d,7=4.4 Hz, 3H), 2.77-2.70 (m, IH), 1.22 (t,V= 6.8 Hz, 3H), 1.12 (d,7 = 6.0 Hz, 6H); MS (ESI) m/z: 513.0 (M+H+).
Example 240: Using general method D, Example B45 (100 mg, 0.549 mmol), triethylamine (64 mg, 0.631 mmol), Example A38 (164 mg, 0.549 mmol) and diphenylphosphorylazide (174 mg, 0.631 mmol) were combined to afford l-(l-tert-butyl-5-metliyl-lH-pyrazol-4-yl)-3-(2-fluoro-5-(l-mediyl-7-(methylamino)-2-oxo-l,2-dihydro-l,6-naphthyridin-3-yl)phenyl)urea (81 mg, 30% yield). This was converted to the mono mesylate salt (91 mg). *H NMR (300 MHz, DMSO-tf6): 5 1.53 (s, 9 H), 2.31 (s, 3 H), 2.33 (s, 3 H), 2.97 (s, 3 H), 3.54 (s, 3 H), 6.53 (s, 1 H), 7.20-7.29 (m, 2 H), 7.45 (s, 1 H), 7.98 (s, 1 H), 8.18-8.35 (br. s, 1 H), 8.21 (s, 1 H), 8.42 (d, 1 H), 8.58 (s, 1 H), 8.63 (br. s, 1 H); MS (ESI) m/z: 478.3 (M+HH).
Example 241: Using general method D, Example B46 (124 mg, 0.525 mmol), triethylamine (61 mg, 0.604 mmol), Example A38 (157 mg. 0.525 mmol) and diphenylphosphorylazide (166 mg, 0,604 mmol) were combined to afford l-(l-tert-butyl-5-(trifluoromethyl)-lH-pyrazol-4-yl)-3-(2-fluoro-5-(l-mediyl-7-(methylamino)-2-oxo-1.2-dihydro-l,6-naphtiiyridm-3-yl)phenyl)urea (62 mg, 22% yield). This was converted lo the mono mesylate salt (55 mg). lH NMR (300 MHz, DMSO-4,): 6 1.57 (m, 9 H), 2.29 (s, 3 H), 2.95 (s, 3 H), 3.54 (s, 3 H), 6.46 (s, 1 H), 7.24-7.30 (m, 2 H), 7.94 (s, 1 H), 7.97 (s, 1 H), 8.05 (br. s, 1 H), 8.39-8.41 (m, 1 H), 8.56 (d, 2 H), 9.15 (s, 1 H); MS (ESI) m/z: 532.0 (M+H4).
Example 242: Using general method F, Example A39 (75 mg, 0.239 mmol) and cyciopentyl isocyanate (0.270 ml, 2.396 mmol) were combined to afford 1 -cyciopentyl-3-(2-fluoro-4-m ethyl-

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5-(8-methyl-2-(iriethylamino)-7-oxo-7,8-dihydropyrido[2.3-d]pyriniidin-6-yl)phenyl)urea (81 mg, 80% yield) as a white solid. ]H NMR (400 MHz, VUSO-d6): 5 8.59 (brs, IH), 8.05 (d, J = 2.4 Hz, IH), 7.94 (d, J = 8.81 Hz, IH), 7.80 (brq, IH), 7.64 (Sj IH), 7.05 (d, J = 12.8 Hz, IH), 6.60 (d, J = 7.21 Hz, IH), 3.87 (m, J = 6.8 Hz, IH), 3.59 (brs, 3H), 2.90 (brs, 3H), 2.03 (s, 3H), 1.84-1.75 (m, 2H), 1.64-1.46 (m, 4H), 1.36-1.28 (m, 2H); MS (ESI) m/z: 425.2 (M+H*).
Example 243: Using general method B, the carbamate of Example B2 (114 mg, 0.480 mmol) and Example A44 (150 mg, 0.480 mmol) were combined to afford l-(3-tert-butyl-l-methyl-3H-pyrazol-5-yl)-3-(4-metliyl-3-(8-methyl-2-(methyIthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyI)urea as a light yellow solid (217 mg, 92% yield). MS (ESI) m/z: 492.3 (M+H+).
Using a procedure analogous to Example Al, l-(3-tert-butyl-l-methyl-lH-pyrazol-5-yl)-3-(4-methyl-3-(8-inetliyl-2-(metliylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (217 mg, 0.441 mmol) and 2.0N methylamine in THF (2.2 mL, 4,41 mmol) were combined and purified by reverse phase chromatography (Biotage CI8-25 column, 10-100% acetonitrile/water)and neutralized with 10% sodium carbonate to give l-(3-tert-butyl-l-methyl-lH-pyrazol-5-yl)-3-(4-methyl-3-(8-methyl-2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidrn-6-yl)phenyl)urea (60 mg, 28% yield). 'H NMR (300 MHz, DMSO-d6): 5 1.15 (s, 9 H), 2.06 (s, 3 H), 2.90 (s, 3 H), 3.53-3.63 (m, 6 H), 6.02 (s, 1 H), 7.12-7.14 (m, 1 H), 7.23-7.26 (m, 1 H), 7.34 (s, 1 H), 7.66-7.80 (m, 2 H), 8.42 (s, 1 H), 8.58-8.68 (m, 1 H), 8.79 (s, 1 H); MS (ESI) m/z: 475.2 (M+H*).
Example 244: Using general method C, the TROC carbamate of Example B18 (0.150 g, 0.475 mmol) and Example A64 (0.1 OOg, 0.317 mmol) were combined to afford 1 -(3-tcrt-butylisoxazol-5-yl)-3-(4-chIoro-3-(8-methyl-2-(methylai,nino)-7-oxo-7;,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (0.055 g, 36%) as a white solid. 'H NMR (400 MHz, DMSO-d6): 6 10.20 (s, 1H), 8.99 (s, IH), 8.62 (s, IH), 7.88 (m, 1H), 7.77 (s, IH), 7.56 (t, J= 1.4 Hz, 1H), 7.44-7.42 (m, 2H), 6.04 (s, IH), 3.60 (s, 3H), 2.91 (m, 3H), 1.23 (s, 9H); MS (ESI) m/z: 482.0 (M+H+).
Example 245: Using general method D, Example B41 (60 mg, 0.22 mmol) and Example A12. (65 mg, 0.22 mmol) in presence of DPPA (52 [iL, 0.26 mmol) and Et3N (34 uX, 0.26 mmol) were combined to afford 1 -(2-tert-butyl-4-(3-fluorophenyl)pyrimidin-5-yl)-3-(2-tluoro-5-(8-

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methyl-2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (68 mg, 55% yield). *H NMR (400 MHz, DMSO-d6, major isomer): 5 9.08 (s, IH), 9.01 (brs, 1H), 8.64 (brs, IH), 8.62 (brs, 1H), 8.34 (dd, J = 2.0, and 8.0 Hz, IH), 7.85 (s, IH), 7.81 (m, IH), 7.59 (m, 3H), 7.38 (m, IH), 7.28 (m, 2H), 3.61 (s, 3H), 2.90 (d, J= 4.8 Hz, 3H), 1.37 (s, 9H); MS (ESI) m/z: 571.3 (M+H*).
Example 246: Using general method F, Example A12 (50 mg, 0.167 mmol) and 3,5-dimethylphenyl isocyanale (0.025 ml, 0.175 mmol) were combined and purified by reverse phase chromatography (MeCN (w/ 0.1% TFA)/ H20 (w/ 0.1% TFA)) to afford l-(3,5-dimemylphenyl)-3-(2-fluoro-5-(8-methyl-2-(methylamino)-7-oxo-7,S-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urca (34 mg, 46% yield) as a white solid. lH NMR (400 MHz, DMSO-d6): 6 8.95 (brs, IH), 8.69 (brs, IH), S.57 (brs, IH), 8.48-8.45 (m, IH), 7.90 (s, IH), 7.83 (brq, IH), 7.29-7.27 (m, 2H), 7.09-7.05 (m, 2H), 6.64-6.61 (m, IH), 3.60 (brs, 3H), 2.93 (brs, 3H), 2.24 (s, 3H), 2.22 (s, 3H); MS (ESI) m/z: 447.0
Example 247: Using general method F, Example A12 (50 mg, 0.167 mmol) and 3,5-dichlorophenyl isocyanate (0.024 ml, 0.175 mmol) were combined to afford 1 -(3,5-dichlorophenyl)-3-(2-fluoro-5 -(8 -methyl-2-(methyl amino) -7-oxo-7,8 -dihydropyrido[ 2,3-d]pyrimidin-6-yl)phenyl)urea (70 mg, 86% yield) as a solid. lH NMR (400 MHz, DMSO-4s): 5 9.42 (brs, IH), 8.75-8.68 (m, 2H), 8.39-8.37 (m, IH), 7.92 (s, IH), 7.84 (brq, IH), 7.54-7.53 (m, 2H), 7.35-7.27 (m, 2H), 7.21-7.19 (m, IH), 3.64 (brs, 3H), 2.93 (brs, 3H); MS (ESI) m/z: 487.0 (M+H+)> 489.0 (M+2+H+).
Example 248: Using general method D, Example B45 (69 mg, 0.378 mmol), triethylamine (44 mg, 0.435 mmol), Example AlO (125 mg, 0.378 mmol) and diphenylphosphorylazide (120 mg, 0.435 mmol) were combined and purified by chromatography (Biotage Si-25 column, 50-100% ethyl acetate/hexane - 1200 mL) to give l-(l-tert-butyl-5-methyl-lH-pyra2:ol-4-yl)-3-(2-fluoro-4-mediyl-5-(8-methyl-2-(memyUhio)-7-axo-7,8-dihydropyrido[2,3-d]pyrurjidin-6-yl)phenyl)urea as a tan solid (31 mg, 16% yield). MS (ESI) m/z: 510.0 (M+H*).
Using a procedure analogous to Example Al, l-(l-tert-butyl-5-methyl-lH-pyrazoI-4-yl)-3-(2-fluoro-4-methyl-5-(8-methyl-2-(metliyltiiio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-

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yl)phenyl)urea (31 mg, 0.061 mmol), MCPBA (19 mg, 0.079 mmol) and 2.0N methyiamine in THF (0.4 mL) were converted to l-(l-tert-butyl-5-methyl-lH-pyrazol-4-yl)-3-(2-fluoro-4-methyl-5-(8-memyl-2-(memylarm^o)-7-oxo-7,8-dihydropyrido[23-d]pyrimidin-6-yl)phenyl)urea (15 mg, 50% yield). 'H NMR (300 MHz, DMSO-d6), 6 1.60 (s, 9 H), 2.20 (s, 3 H), 2.35 (s, 3 H), 2.95 (s, 3 H), 3.60-3.70 (m, 3 H), 7.20-7.25 (m, 1 H), 7.50 (s, 1 H), 7.70 (s, 1 H), 7.70-7.90 (m, 1 H), 8.05 (m, 1 H), 8.20 (s, I H), 8.55 (m, 1 H), 8.70-8.80 (m, 1 H); MS (ESI) m/z: 493.0 (M+tT).
Example 249: Using general method D, quinoline-5-carboxylic acid (92 mg, 0.529 mmol), triethylamine (64 mg, 0.635 mmol), Example A22 (150 mg, 0.529 mmol) and diphenyiphosphorylazide (175 mg, 0.635 mmol) were combined to afford l-(5-(l-ethyl-2-oxo-1.2-dihydro-l ,6-naphthyridin-3-yl)-2-fluorophenyl)"3-(quinolin-5-yI)urea. This was converted to the dichloride salt using 4N HCl/dioxane, l-(5-(l -ethyI-2-oxo-l ,2-dihydro-l ,6-naphtliyridin-3-yl)-2-fluorophenyl)-3-(quinolin-5-yl)urea dihydrochloride (139 mg, 49% yield). lH NMR (300 MHz, DMSCWfi): 6 1.29 (t, 3 H), 4.37 (q, 2 H), 7.40-7.43 (m, 2 H), 7.86-8.00 (m, 4 H), 8.29-8.35 (m, 2 H), 8.57 (d, 1 H), 8.75-8.80 (m, 1 H), 9.14-9.19 (m, 2 H), 9.29 (s, 1 H), 9.53 (s, 1 H), 10.01 (s, 1 H); MS (EST) m/z: 454.0 (M+H4).
Example 250: Using general method D, Example B46 (101 mg, 0.428 mmol), triethylamine (52 mg, 0.513 mmol), Example A17 (150 mg, 0.428 mmol) and diphenyiphosphorylazide (141 mg, 0.513 mmol) were combined to afford l-(l-tert-butyl-5-(trifluorometliyl)-lH-pyrazol-4-yl)-3-(4-chloro-2-fluoro-5-(8-methyl"2-(metliylthio)-7-oxo»7,8-dihydropyrido[2,3-d]pyiimidin-6-yl)phenyl)urea (230 mg, 92% yield). MS (ESI) m/z: 584.0 (M+Na").
Using a procedure analogous to Example Al, I-(l-tert-butyl-5-(trifluoroniethyl)-lH~ pyrazol-4-yl)-3-(4-chloro-2-fluoro-5-(8-methyl-2-(metliylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (230 mg, 0.394 mmol), MCPBA (126 mg, 0.512 mmol) and 2.0N methyiamine in THF (1.97 mL, 3.94 mmol) were combined to afford l-(l-tert-butyl-5-(trifiuoromethyl)-lH-pyrazol"4-yl)-3-(4-chloro-2-fluoro-5-(8-methyl-2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)iirea (127 mg, 56% yield). 'H NMR (300 MHz, DMSO-rfg), 5 1.59 (s, 9 H), 2.92 (s, 3 H), 3.53-3.62 (m, 3 H), 7.55-7.65 (ms I H), 7.78 (s, 1 H),

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7.80-7.90 (m, I H), 7.93 (s, 1 H), 8.15-8.25 (m, 1 H), 8.45-8.70 (in, 2 H), 9.25 (s, I H); MS (ESI) m/z: 567.0 (M+rf).
Example 251: Using general method D, Example B42 (60 mg, 0.23 mmol) and Example A12 (70 mg, 0.23 mmol) in presence of DPPA (55 pL, 0.26 mmol) and Et3N (36 |iL, 0.26 mmol) were combined to afford l-(2-tei1-butyl-4-(pyridin-3-yl)pyrimidin-5-yl)-3-(2-fluoro-5-(8-methyl-2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (78 mg, 60% yield). 'H NMR (400 MHz, DMSO-rf6, major isomer): 6 9.10 (s, IH), 9.02 (brs, lH), 8.96 (m: IH), 8.75 (brs, IH), 8.72 (dd,/= 2.0, and 5.2 Hz, IH), 8.65 (brs, IH), 8.35 (dd, J= 2.0, and 7.6 Hz, IH), 8.19 (dt, J= 1.6, and 7.6 Hz, IH), 7.86 (s, IH), 7.83 (m, IH), 7.61 (ra, IH), 7.29 (m, 2H), 3.62 (s, 3H), 2.92 (d, J=4.0 Hz, 3H), 1.40 (s, 9H); MS (ESI) m/z: 554.2 (M+H+).
Example 252: Using general method D, B46 (89 rag, 0.378 mmol), diethyl amine (44 rag, 0.435 mmol), Example AlO (125 mg, 0.378 mmol) and diphenylphosphorytazide (120 mg, 0.435 mmol) were combined to afford l-(l-tert-butyl-5-(ti-ifluoromethyl)-lH-pyrazol-4-yl)-3-(2-fluoro-4-methyl-5 -(8 -methyl-2-(methylthio)- 7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (124 mg, 58% yield). MS (ESI) m/z: 564.0 (M+H+).
Using a procedure analogous to Example Al, l-(l-tert-butyl-5-(trifluoromethyl)-lH-pyrazol-4-yl)-3-(2-fluoro-4-memyl"5-(8-methyl-2-(memyItIno)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyI)urea (148 rag, 0.263 mmol), MCPBA (81 mg, 0.328 mmol) and 2.0N methylamine in THF (1.3 mL) were combined to afford l-(l-tert-butyl-5-(trifluoromethyl)-lH-pyrazol-4-yl)-3-(2-fluoro-4-methyl-5-(8-methyl-2-(raethylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (103 mg, 71% yield). 'H NMR (300 MHz, DMSO-rf0): 5 1.59 (s, 9 H), 2.08 (s, 3 H), 2.92 (s, 3 H), 3.55-3.62 (m, 3 H), 7.25-7.30 (m, 1 H), 7.69 (s, 1 H), 7.70-7.80 (m, 1 H), 7.93 (s, 1 H), 7.95-8.05 (m, 1 H), 8.51 (s, 1 H), 8.20-8.25 (in, 1 H), 9.04 (s, 1 H); MS (ESI) m/z: 547.2 (M+H+).
Example 253: Using general method D, Example B43 (50 mg, 0.18 mmol) and Example A12 (54 mg, 0.18 mmol) in presence of DPPA (43 |iL, 0.20 mmol) and Et3N (28 jiL, 0.20 mmol) were combined to afford l-(2-tert"butyl-4-(4-memylpiperazin-l-yl)pyrimidin-5-yl)-3-(2-fluoro-5-(8-methyl-2-(methylamino)-7-oxo-7,8-dihydropyrido[2J3-d]pyrimidin-6-yl)phenyl)urea (78

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mg, 60% yield). This was then treated with aqueous HCI (0.100 M) to afford l-(2-tert-butyl-4-(4-methylpiperazin-l-yl)pyrimidin-5-yl)-3-(2-fluoro-5-(8-methyl-2-(methylainino)-7-oxo-7,8-dmydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea HCI salt (27 mg, 37% yield). lH NMR (400 MHz, DMSO-rfe, major isomer): 8 9.92 (s, 1H), 8.64 (brs, 1H), 8.36 (dd, ./= 1.2, and 8.0 Hz, 1H), 8.33 (s, IH), 7.20 (s, 1H), 7.85 (s, 1H), 7.81 (in, 1H), 7.28 (m, 2H),
Example 254: Using general method F, Example A39 (50 mg, 0.160 mmol) and 1-isocyanato-1,2,3,4-tetrahydronaphthalene (0.0275 mL, 0.175 mmol) were combined to afford l-(2-fluoro-4-methyl-5-(8-memyl-2-(memylammo)-7-oxo-7J8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)-3-(l,2,3,4-tetrahydronaphthalen-l-yl)urea (73 mg, 94% yield) as a white solid. 5H NMR (400 MHz, DMSO-rftf): 5 8.69-8.61 (m, 1H), 8.15 (brs, 1H), 8.01 (d, J = 8.8 Hz, 1H), 7.82 (brq, 1H), 7.68 (s, 1H), 7.27-7.24 (m, 1H), 7.17-7.14 (m,2H), 7.13-7.06 (m,2H), 6.95 (d, J = 8.41 Hz, 1H), 4.81 (m, IH), 3.59 (brs, 3H), 2.92 (brs, 3H), 2.80-2.65 (m ,2H), 2.05 (s, 3H), 1.91-1.87 (m, 1H), 1.81-1.71 (m, 3H); MS (ESI) m/z: 487.3 (M+H4).
Example 255: Using general method D. Example B45 (78 mg, 0.428 mmol), triethylamine (52 mg, 0.513 mmol), Example A17 (150 mg, 0.428 mmol) and diphenylphosphorylazide (141 mg, 0.513 mmol) were combined to afford l-(l-tert-butyI-5-methyl-lH-pyrazol-4-yl)-3-(4-chloro-2-fluoro-5-(8-memyl-2-(methyltlaio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (80 mg, 35% yield). MS (ESI) m/z: 530.02 (M+).
Using a procedure analogous to Example Al, l-(l-tert-butyl-5-methyl-lH-pyrazol-4-yl)-3-(4-chloro-2-fluoro-5-(8-methyl-2-(methylthio)-7-oxo-7)8-dihydropyrido[2J3-d]pyrimidin-6-yl)phenyl)urea (80 mg, 0.151 mmol), MCPBA (47 mg, 0.189 mmol) and 2.0N methylamine in THF (0.8 mL) were combined to afford 1 -(l-tert-butyl-5-methyl-l H-pyrazol-4-yl)-3-(4-chloro-2-fluoro-5-(8-niethyl-2-(memylamino)-7-oxo-7,8-dihydropyrido[2>3-d]pyrimidin-6-yl)plieny])urea (48 mgT 62% yield). 'H NMR (300 MHz, DMSO-tf6): 5 1.49 (s, 9 H), 2.27 (s, 3 H), 2.89 (s, 3 H), 3.49-3.56 (m, 3 H), 7.39 (s, 1 H), 7.49 (d, 1 H), 7.74 (s, I H), 7.94 (br. s, 1 H), 8.17 (d, 1 H), 8.29 (s, 1 H), 8.62-8.74 (m, 2 H); MS (ESI) m/z: 513.0 (M+H+).
Example 256: Using general method D, Example B45 (84 mg, 0.460 mmol), triethylamine (56 mg, 0.552 mmol), Example A30 (150 mg, 0.460 mmol) and DPP A (152 mg, 0.552 mmol) were

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combined to afford l-(l-tert-butyl-5-metliyl-lH-pyrazol-4-yl)-3-(5-(l-ethyl-7-(methylai-nino)-2-oxo-l,2-dihydro-l,6-naphthyridin-3-yl)-2-fluoro-4-methylpheny])urea (52 mg, 22% yield). lH NMR (300 MHz, DMSO-rf6): 5 1.17 (t, 3 H), 1.49 (s, 9 H), 2.03 (s, 3 H), 2.26 (s, 3 H), 2.83 (s, 3 H), 4.11 (q, 2 H), 6.23 (s, 1 H), 7.05 (br. s, IH), 7.0S (d, 1 H), 7.38 (s, 1 H), 7.63 (s, 1 H), 7.92 (d, 1 H), 8.08 (s, 1 H), 8.38 (s, 1 H), 8.40 (br. s, 1 H); MS (ESI) m/z: 506.2 (M+H'1").
Example 257: ((R)-Aminoindan hydrochloride (81 mg, 0.475 mmol) and triphosgene (56.4 mg,
0.19 mmol) were combined in toluene (5 ml) and stirred with hearing at 110 °C. After 3h,
Example A39 (lOOmg, 0.319 rnmol) was added and the reaction was heated overnight at 110 °C.
The reaction was cooled to RT, diluted with H2O and extracted with EtOAc (2x). The combined
organics were washed with satd. NaHC03 (2x), H2O (lx), and brine (lx), dried (MgS04), filtered
and evaporated. The crude residue was triturated with CHiCh/hexanes. The solids were
collected by filtration, rinsed well with hexanes and dried on the filter to afford (R)-l-(2,3-
dihydro-lH-inden-l-yl)-3-(2-fluoro-4-methyl-5-(8-methyl-2-(methylamino)-7-oxo-7,8-
dihydropyrido[2,3-d]pyrimidin-6-yl)phenyI)urea (92 mg, 62% yield) as a pale tan solid. 'H
NMR (400 MHz, DMSCW„): 5 8.61 (s, IH), 8.19 (brs, IH), 7.99 (d, J = 8.4 Hz, IH), 7.80 (brq,
IH), 7.67 (s, IH), 7.29-7.16 (m, 4H), 7.07 (d, J = 12.4 Hz, IH), 6.93 (d, J = 8 Hz, IH), 5.17-5.07
(m, IH), 3.58 (brs, 3H), 2.90 (brs, 3H), 2.87-2.74 (m, IH), 2.48-2.39 (m, IH), 2.04 (s, 3H), 1.77-
1.67 (m, 2H); MS (ESI) m/z: 473.0 (M+H+).
Example 258: Using a procedure analogous to Example 257, (S)-aminoindan HCI (81 mg, 0.477 mmol), triphosgene (71.0 mg, 0.239 mmol) and Example A39 (100 mg, 0.319 mmo!) were combined and purified by flash column chromatography (EtOAc/hexanes) to afford (S)-l-(2,3-dihydro-1 H-inden-1 -yl)-3-(2-f3uoro-4-methyl-5-(8-methyl-2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidm-6-yl)phenyl)urea (41 mg, 27% yield) as an off-white solid. ]H NMR (400 MHz, DMSO-4,): 5 8.61 (s, IH), 8.19 (brs, IH), 7.99 (d, J = 8.4 Hz, IH), 7.80 (brq, IH), 7.67 (s, IH), 7.29-7.16 (m, 4H), 7.07 (d, J = 12.4 Hz, IH), 6.93 (d, J = 8 Hz, IH), 5.17-5.07 (m, IH), 3.58 (brs, 3H), 2.90 (brs, 3H), 2.87-2.74 (m, IH), 2.48-2.39 (m, IH), 2.04 (s, 3H), 1.77-1.67 (m, 2H); MS (ESI) m/z: 473.0 (M+H+).

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Example 259: Using general method C, the TROC carbamate of Example B18 (80 mg, 0.25 mmol) and Example A36 (91 mg, 0.25mmol) were combined to afford l-(3-tert-butyIisoxazol-5-yl)-3~(2-fluoro-5-(7-(methylamino)-2-oxo-l -phenyl-1,2-dihydro-l ,6-naphthyridin-3-yl)phenyl)urea (31 mg, 25% yield). !H NMR (400 MHz, DMSO-rf6): 6 10,4 (s, IH), 8.75 (brs, IH), 8.52 (s, IH), 8.45 (dd, J = 2.0, and 8.0 Hz, IH), 8.04 (s, IH), 7.2-7.7 (m, 7H), 7.01 (q, J= 4.4 Hz, IH), 6.08 (s, IH), 5.32 (s, IH), 2.69 (d, ./= 4.4 Hz, 2H), 1.25 (s, 9H); MS (ESI) m/z: 527.0 (M+H+).
Example 260: Using general method C, die TROC carbamate of Example B18 (100 mg: 0.32 mmol) and Example A21 (122 mg, 0.32 mmol) were combined to afford l-(3-tert-butylisoxazol-5-yl)-3-(5-(8-cyclopentyl-2-(memyImio)-7-oxo-7,8-dihydropyiHdo[2,3-d]pyrimidin-6-yl)-2-fluoro-4-methylphenyI)urea (115 mg, 66% yield). MS (ESI) m/z: 551.0 (M+H*).
Using a procedure analogous to Example Al, l-(3-tert-butylisoxazol-5-yl)-3-(5-(8-cyclopentyl-2-(metliylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-2-fluorO"4-methylphenyl)urea (115 mg, 0.21 mmol) was treated with mCPBA (70% wt, 62 mg, 0.25 mmol) and then 2 M methylaminc (0.42 mL, 0.84 mmol) to afford 1 -(3-tert-butyIisoxazol-5-yl)-3-(5-(8-cyclopentyl"2-(metliyIamino)-7-oxo-7.8-dihydropyrido[2,3-d]pyrimidin-6-yl)-2-fiuoro-4-methylphenyl)urea (91 mg, 82% yield). !H NMR (400 MHz, DMSO-^6; major isomer): 8 10.3 (s, IH), 8.69 (d, J = 2.0 Hz, IH), 8.61 (brs, IH), 7.89 (d, J= 8.4 Hz, IH), 7.79 (brs, IH), 7.65 (s, IH), 7.18 (d, J= 12.4 Hz; IH), 6.03 (s, IH), 5.94 (m, IH), 2.91 (d, J= 4.8 Hz, 3H), 2.33 (in, 2H), 2.09 (s, 3H), 1.98 (m, 2H), 1.81 (m, 2H), 1.63 (m, 2H), 1.24 (s, 9H); MS (ESI) m/z: 534.2 (M+H"1").
Example 261: Using general method C, the TROC carbamate of Example B18 (lOOmg, 0.32 mmol), and Example A19 (120 mg, 0.32mmol) were combined to afford l-(3-tert-buty!isoxazol-5-yI)-3-(5-(8-cyclopentyl-2-(metiiyltIuo)-7-oxo-7J8-dihydropyrido[2,3-d]pyrin2idin-6-yl)-2-fluorophenyl)urea (105 mg, 62% yield); MS (ESI) m/z: 537. (M+H+).
Using a procedure analogous to Example Al, l-(3-tert-butylisoxazol-5-yl)-3-(5-(8-cyclopentj4-2-(memylthio)-7-oxo-7,8^Uiydropyrido[2,3-d.]pyrimidin-6-yl)-2-f]uorophenyl)urea (105 mg, 0.20 mmol) was treated with mCPBA (70% wt, 58 mg, 0.24 mmol) and then 2 M methylamine (0.39 mL, 0.78 mmol) to afford l-(3-tert-butylisoxazol-5-yl)-3-(5-(8-cycIopentyl~

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2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-2-fluorophenyl)urea (61 mg. 60% yield). 1H NMR (400 MHz, DMSO-rf6, major isomer): 5 10.4 (s, IH), 8.80 (d, J = 2.0 Hz, IH), 8.68 (s, IH), 8.36 (m, IH), 7.88 (s, IH), 7.85 (m, IH), 7.35 (m, 2H), 6.11 (s, IH), 5.97 (m, IH), 2.93 (d, J= 4.8 Hz, 3H), 2.42 (m, 2H), 2.03 (s, 3H), 1.98 (m, 2H), 1.81 (m, 2H), 1.65 (m, 2H), 1.28 (s, 9H); MS (ESI) m/z: 520.2 (M+H+).
Example 262: Using general method D, Example B50 (0.061 g, 0.34 mmol) and Example A38 (0.1 g, 0.34 mmol) in presence of tri ethyl amine (0.1 g, 1 mmol) and DPPA (0.18 g, 0.67 mmol) were combined to afford l-(l-cycIopentyl-lH-pyrazol-4-yl)-3-(2-fluoro-5-(l-methyl-7-(methylamino)-2-oxo-l,2-dihydro-l,6-naphthyridin-3-yl)phenyl)urea as a white solid (0.061 g, 38% yield). 'H NMR (400 MHz, DMSO-4): 8 8.66 (s, IH), 8.42 (s, IH), 8.39 (s, IH), 8.35-8.33 (m, IH), 7.79 (s, IH), 7.73 (s, IH), 7.32 (s, IH), 7.18-7.16 (m, 2H), 7.03-7.00 (m, IH), 6.11 (s, IH), 4.58-4.51 (m, IH), 3.47 (s, 3H), 2.80 (d, J= 4.8 Hz, 3H), 2.00-1.93 (m, 2H), 1.85-1.64 (m, 4H), 1.59-1.50 (m, 2H); MS (ESI) m/z: 476.2 (M+H+).
Example 263: Using general method F, 1-isocyanatonaphthalene (0.051 g, 0.3 mmol) and Example A30 (0.1 g, 0.3 mmol) were combined to afford l-(5-(l-elhyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2"fluoro-4-metliylphenyl)-3-(naphthalen" 1 -yl)urea as a white solid (0.115 g, 77% yield). 'H NMR (400 MHz, DMSO-40: 5 9.16 (s, IH), 9.05 (s, IH), 8.45 (s, IH), 8.19 (d, J = 8.4 Hz, IH), 8.08-8.04 (m, 2H), 7.96 (d, J = 7.6 Hz, IH), 7.72 (s, IH), 7.67-7.58 (m, 3H), 7.47 (t, J= 8.0 Hz, IH), 7.21 (d,J= 12.4 Hz, IH), 7.05-7.02 (m, IH), 6.28 (s, IH), 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*).
Example 264: Using general method C, the TROC carbamate of Example B18 (100 mg, 0.32 mmol) and Example A59 (110 mg, 0.32 mmol) were combined to afford l-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-5-(8-isopropyI-2-(methylthio)-7-oxo-7,8-dihydropyrido[2J3-d]pyrimidin-6-yl)phenyl)urea (90 mg, 56% yield). MS (ESI) m/z: 511.0 (M+H*).
Using a procedure analogous to Example Al, l-(3-tert-butylisoxazol-5-yI)-3"(2-fiuoro-5-(8-isopropyl-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (87 mg, 0.17 mmol) was treated with mCPBA (70% wt, 50 mg, 0.20 mmol) and then 2 M methylamine

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(0.34 mL, 0.6S mmol) to afford l-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-5-(8-isopropyl-2-(methylainino)-7-oxo-718-dihydropyrido[233-d]pyrirnidin-6-yl)phenyl)urea (48 mg, 57% yield). 'H NMR (400 MHz, DMSO~d6, major isomer): 5 10.4 (s, 1H), 8.82 (d, J= 2.0 Hz, 1H), 8.69 (s, 1H), 8.42 {brd,J= 8.0 Hz, IH), 7.89 (s, \H), 7.85 (q, J =4.4 Hz J H),7.36 (m, 2H), 6.U (s, IH), 5.83 (brs, 1H), 2.97 (d, J = 4.4 Hz, 3H), 1.66 (d, J= 6.4 Hz, 6H), 1.30 (s, 9H); MS (ESI) m/z: 494.2 (M+H+).
Example 265: To a stirring solution of Example A39 (0.100 g, 0.319 mmol) in CH2C12 (5 ml) at 0 °C was rapidly added 20 wt% COC32 in PhMe (0.185 ml, 0.351 mmol). After 10 min at 0 °C, Et3N (0.200 ml, 1.436 mmol) was then added. The reaction was stirred at 0 °C for another 10 min and then treated with 8-methyl-8-azabicyclo[3.2.1]octan-3-amine dihydrochloride (0.068 g, 0.319 mmol). The reaction was stirred at RT overnight. The reaction was diluted generously with CH2CI2 and washed with brine (2x). The combined aqueous were back-extracted with CH2CI2 (2x). The combined organics were washed with brine (lx), dried (Na2S04), filtered, evaporated and purified by reverse phase chromatography (MeCN (w/ 0.1% TFA)/ H20 (w/0.1% TFA)). The TFA salt thus obtained was converted to the free base in the presence of MP-Carbonate resin to afford I-(2-fluoro-4-methyl-5-(8-memyl-2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)-3-(8-methyl-8-aza-bicyclo[3.2.1]octan-3-yl)urea (43 mg, 28% yield) as a white solid. 'H NMR (400 MHz, DMSO-d6): 8 9.37 (brs, 1H), 8.60 (brs, 1H), 8.40 (brs, 1H), 7.94 (d, J = 8.8 Hz, 1H), 7.78 (brq, 1H), 7.64 (s, 1H), 7.09 (d, J = 12.4 Hz, IH), 6.86-6.84 (m, 1H), 3.85-3.78 (m, 1H), 3.63-3.51 (brs, 3H), 2.91 (brs, 3H)S 2.69 (brs, 3H), 2.32-2.30 (in, 6H), 2.05 (s, 3H), 1.95-1.91 (m, 2H); MS (ESI) m/z: 480.2 (M+H+).
Example 266: Using general method F, l-isocyanato-3-(trifluoromethyl)benzene (0.055 ml, 0.401 mmol) and Example A58 (0.131 g, 0.401 mmol) were combined and purified by flash column chromatography (EtOAc/hexanes) and then by reverse phase chromatography (MeCN (w/ 0.1% TFA)/ H20 (w/ 0.1% TFA)). The TFA salt thus obtained was converted to the free base with MP-Carbonate resin to afford l-(2-fluoro-5-(l-isopropyl-7-(methylamino)-2-oxo-l,2-diliydro-l)6-naphthyridin-3-yl)phenyl)-3-(3-(trifluoromethyl)phenyI)urea (70 mg, 34% yield) as a pale yellow solid. 'H NMR (400 MHz, DMSO-^): 5 9.46 (s, IH), 8.71 (s, IH), 8.49 (s, IH), 8.32 (d, J = 8.4 Hz, IH), 8.05 (s, IH), 7.88 (s, IH), 7.53-7.49 (m, 3H), 7.33-7.27 (m, 3H), 6.80

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(s, IH), 6.58 (brs, IH), 2.91 (brs, 3H), 1.53 (d, J = 6.8 Hz, 6H); MS (ESI) m/z: 514.0 (M+H+).
Example 267: Using general method F. cyclohexyl isocyanate (0.051 ml, 0.399 mmol) and Example A58 (0.130 g, 0.399 mmol) were combined and purified directly by reverse phase chromatography (MeCN (w/ 0.1% TFA)/ H20 (w/ 0.1% TFA)) to give impure product after basification (2M Na2C03) and extraction into EtOAc. The impure product was re-purified by flash column chromatography (EtOAc/hexanes) to afford l-cyclohexyl-3-(2-fluoro-5-(l-isopropy]-7-(metliyIamino)-2-oxo-l,2-dihydro-l,6-naphtliyridin-3-yl)phenyl)urea (40 mg, 22% yield) as a fluffy white solid. lH NMR (400 MHz, DMSO-d6); 5 8.41 (s, IH), 8.34 (d, J = 8.4 Hz, IH), 8.18 (brs, IH), 7.74 (s, IH), 7.17-7.15 (m, 2H), 6.95 (m, IH), 6.86 (s, IH), 6.59 (d, J = 7.6 Hz, IH), 6.43 (brs, IH), 3.47-3.45 (m, IH), 2.85 (d, J = 4.80 Hz, 3H), 1.80-1.77 (m, 2H), 1.66-1.63 (m, 2H) Example 268: Using a procedure analogous to Example 265, Example A39 (0.100 g, 0.319 mmol), 20 wt% COCl2 in PliMe (0.185 ml, 0.351 mmol) and l-methyIpiperidin-4-arnine (0.036 g, 0.319 mmol) were combined to afford l"(2-fluoro-4-methyl-5-(8-methyl-2-(methylamino)-7-oxo-718-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)-3-(l-methyIpiperidin-4-yI)urea (63 mg, 44% yield) as a white solid. rH NMR (400 MHz, DMSO-^): 5 9.37 (brs, IH), 8.60 (brs, 1H); 8.40 (brs, IH), 7.94 (d, J = 8-8 Hz, IH), 7.78 (brq, IH), 7.64 (s, IH), 7.09 (d, J = 12.4 Hz, IH), 6.86-6.84 (m, IH), 3.69 (bis, 3H), 3.52-3.42 (m, IH), 3.22-3.08 (m, 4H), 2.91 (brs, 3H), 2.81 (brs, 3H), 2.040 (s, 3H), 2.02-1.79 (m, 4H); MS (ESI) m/z: 454.2 (M+H*).
Example 269: Using general method F, I-isocyanatonaphthalene (0.045 g, 0.26 mmol) and Example A24 (0.1 g, 0.3 mmol) were combined to afford l-(5-(l-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-l ,6-naplithyridin-3-yl)-2-fluorophenyl)-3-(naphthalen-l -yl)urea as a white solid (0.062 g, 48% yield). 'H NMR (400 MHz, DMSO-c/fi): 5 9.23 (s, IH), 9.14 (s, 1H), 8.56-8.54 (m, IH), 8.52 (s, IH), 8.23 (d, 7=8.4 Hz, IH), 8.11 (d, .7 = 7.6 Hz, IH), 8.09 (d,/= 7.6 Hz, IH), 7.93 (s, IH), 7.71-7.59 (m, 3H), 7.53 (t, J= 8.0 Hz, IH), 7.36-7.34 (m, 2H), 7.10-7.07 (m IH), 6.29 (s, IH), 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+).

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Example 270: Using general method D, Example B47 (0.071 g, 0.3 mmol) and Example A12 (0.1 g, 0.33 mmol; DP-2201) in presence of triethy!amine (0.09 g, 0.89 mmol) and DPPA (0.16 g, 0.59 mmol) were combined to afford l-(I-(2-(dimethylamino)-2-oxoediyl)-5-isopropyl-lH-pyrazol-3-yl)-3-(2-fluoro-5-(8-methyl-2-(mediylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyI)urea as a white solid (0.075 g, 47% yield). 'H NMR (400 MHz, DMSO-^j): 5 9.29 (s, IH), 8.73 (s, IH), 8.53 (d, J= 8.4 Hz, IH), 7.95 (s, IH), 7.90-7.87 (m, IH), 7.34-7.29 (m, 2H), 6.15-6.10 (m, IH), 4.98 (s, 2H), 3.69 (s, 3H), 3.10 (s, 3H), 2.97 (d, J = 4.8 Hz, 3H), 2.90-2.85 (m, 4H), 1.20 (d, 7= 6.4 Hz, 6H); MS (ESI) m/z: 536.2 (M+H*).
Example 271: Using general method D. Example B44 (70 mg, 0.19 mmol) and Example A4 (60 mg, 0.19 mmol) in presence of DPPA (55 JJ.L, 0.21 mmol) and Et3N (30 (iL, 0.21 mmol) were combined to afford tert-butyl 4-(2-tert-butyl-5-(3-(5-(8-ethyl-2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-2-fluorophenyl)ureido)pyrimidin-4-yl)piperazine-l-carboxylate (50 mg, 39% yield). This was then treated with HCI (4.0 M, in dioxane) to afford 1-(2-tert-butyl-4-(piperazin-l-yl)pyrimidin-5-yl)-3-(5-(8-etIiyl-2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrirmdin-6-yl)-2-fluorophenyl)urea HCI salt (40 mg, 94% yield). 'H NMR (400 MHz, DMSO- Example 272: Using general method B, the carbamate of Example B31 (0.123 g, 0.493 mmol)
and Example A3 (0.130 g, 0.411 mmol) were combined to afford l-(3-cyclopentyl-l-methyl-lH-
pyrazol-5-yl)-3-(2-fluoro-5-(8-methyl-2-(methylthio)-7-oxo-7,S-dihydropyrido[2,3-d]pyrimidin-
6-yl)phenyl)urea (0.068 g, 33%) as a white solid. MS (ESI) m/z: 508.0 (M+H*).
Using a procedure analogous to Example Al, l-(3-cyclopentyl-l-metliyl-IH-pyrazol-5-yl)-3-(2-
fluoro-5-(8-metliyl-2-(metliyltliio)-7-oxo-7,8-dihydropyrido[2,3'd]pyrimidin-6-yl)phenyl)urea
(0.068 g, 0.134 mmol) and MeNH2 (2.0 M in THF, 1.4 mL) were combined to afford l-(3-
cyclopentyl-l-'metliyl-lH-pyrazol-5-yl)-3-(2-fluoro-5-(8-methyI-2-(mediyIamino)-7-oxo-7,8-
dihydropyrido[2,3~d]pyrimidin-6-yl)phenyl)urea (0.013 g, 20%) as white solid. 'H NMR (400
MHz, DMSO-d6): 8 9.02 (s, IH), 8.89 (d, 7 = 2.0 Hz, IH), 8.73 (s, IH), 8.49 (d, 7 = 7.6 Hz, IH),

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7.95 (m, IH), 7.92 (m, 1H), 7.38-7.34 (m, 2H), 6.11 (s, IH), 3.70-3.68 (m, 6H), 2.99-2.94 (m, 4H), 1.99-1.94 (m, 2H), 1.73-1.68 (m, 2H), 1.67-1.60 (m, 4H); MS (ESI) m/z: 491.2 (M+tf*).
Example 273: Using general method D, 2-fluoro-5-(trifluoromethyl)benzoic acid (75 mg, 0.360 mmol), DPP A (0.116 ml, 0.541 mmol) and Example A58 (129 mg, 0,396 mmol) were combined and purified by flash column chromatography (10% EtOAc/hexanes to 100% EtOAc) to afford 1 -(2-fluoro-5-( 1 -isopropyl-7-(methyIamino)-2-oxo-1,2-dihydro-1 ,6~naphthyridin-3-yl)phenyl)-3 -(2-fluoro-5-(trifluoromethyl)phenyl)urea (111 mg, 58% yield) as a white solid. 'H NMR (400 MHz, DMSO-40: 8 9.37 (s, 1H), 9.17 (s, 1H), 8.63-8.61(m, 1H), 8.44 (s, 1H), 8.37-8.35 (m, 1H), 7.82 (s, IH), 7.53-7.48 (m, IH), 7.41-7.38 (, 1H), 7.29-7.24 (m, 2H), 6,96 (brm, 1H), 6.44 (bra, 1H), 2.86 (d, J = 4.4 Hz, 3H), 1.53 (d, J= 6.8 Hz, 6H); MS (ESI) m/z: 532.0 (M+H+).
Example 274: Using general method F, l-isocyanato-3-(trifluoromethyl)benzene (0.1 mg, 0.534 mmol) and Example A33 (0.093 mg, 0.267 mmol) were combined to provide l-(4-chloro-5-(l-ethyl-7-(metiiylainino)-2-oxo-l,2-dihydro-l,6-naphthyridin-3-yl)-2-fluorophenyl)-3-(3-
(trifTuoromethyl)phenyI)urea (0.115 mg, 81 % yield). ]H NMR (400 MHz, DMSO-d6): 5 8.45
(s, 1H), 8.17 (d, J =9Hz , IH), 8.05 (s, 1H), 7.78 (s, 1H), 7.58 (d, J=10.5Hz, IH), 7.52 (m, 2H), 7.35 (m, 1H), 7.08 (brs, IH),6.27(s, IH), 4.18 (q, J=6Hz, 2H), 2.89 (brs, 3H), 1.24(tJ=6Hz, 3H); MS(ESI) m/z : 534.0 (M+H*).
Example 275: Using general method F, l-chloro-4-isocyanato-2-(trifluorometliyl)benzene (0.100 g, 0.451 mmol) and Example A24 (0.141g, 0.451 mmol) were combined to provide l-(4-chloro-3-(trifluoix>rnelhyl)pheiiyl)-3-(5-(l -ethyl-7-(methylamino)-2-oxo-l ,2-dihydro-l ,6-
naphmyridin-3-yl)-2-fluorophenyl)urea (0.172g, 7 % yield). ]H NMR(400 MHz, DMSO-d6); 5
9.54 (s, 1H), 8.72 (brs, 1H), 8.49 (s, JH), 8.36 (m, IH), 8.14 (brs, 1H), 7.91 (s, IH), 7.64 (m, 2H), 7.38-7.26 (m, 2H), 7.05 (m, IH), 6.27 (s, IH), 4.18 (q, J =6Hz, 2H), 2.89 (d, J=5.5Hz, 3H), 1.25 (t, J=6Hz, 3H;. MS(ESI) m/z : 534.0 (M+H+).
Example 276: Using general method F, 1-isocyanatobenzene (0.05g, 0.420 mmol) and Example A33 (0.146 g, 0.420 mmol) were combined to provide l-(4-chloro-5-(l-ethyl-7-(methylamino)-

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2-oxo-l,2-dihydro-l,6-naphthyridin-3-yl)-2-f1uorophenyl)-3-phenylurea (0.180g, 92 % yield).
*H NMR (400 MHz, DMSO-d6): 8 9.16 (s, 1H), 8.75 (s, 1H), 8.45 (s, 1H), 8.22 (d, J =9Hz ,
1H), 7.78 (s, 1H), 7.58 (d, J=10.5Hz, 1H), 7.46 (s, 1H), 7.44 (s, 1H), 7.30 (m, 2H), 7.08 (m, 1H), 7.00 (ss 1H), 6.27 (s, 1H), 4.18 (q, J =5Hz, 2H), 2.89 (d, J= 5Hz, 3H), 1.24 (t, J=6Hz, 3H); MS(ESI) m/z : 466.0 (M+H+).
Example 277: Using general method D, 2,3-difluorobenzoic acid (0.100 g, 0.633 mmol) and Example A33 (0.219 g, 0.633 mmol) were combined to provide l-(4-cli!oro-5-(l-ethyl-7-(methylamino)-2-oxo-l,2-diliydro-l)6-naphthyridin-3-yl)-2-fluorophenyl)-3-(2,3-difluorophenyI)urea (0.172g, 54% yield). ]H NMR (400 MHz, DMSO-d6): 5 9.27 (s, 1H), 9.24
(s, 1H), 8.45 (s,lH)), 8.22 (d, J =10Hz , 1H), 7.96 (m, 1H), 7.77 (s,IH), 7.58 (d, J=12HzJH), 7.18-7.00 (m, 3H), 6.27 (s, 1H), 4.37 (q, J=6Hz, 2H), 2.90 (d, J=5.5Hz, 3H), 1.24 (t, J=6Hz, 3H;. MS(ESI) m/z : 502.0 (M+H+).
Example 278: Using a procedure analogous to Example 265, Example A39 (100 mg, 0.319 mmol), 20% COCl2 in PhMe (0.185 ml, 0.351 mmol) and 4-aminotetrahydropyran (32.3 mg, 0.319 mmol) were combined and purified directly by reverse phase cliromatography (MeCN(w/ 0.1% TFA)/H20(w/ 0.1% TFA)) to afford I"(2-fluoro-4-methyl-5-(8-methyl-2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin»6-yl)phenyl)-3-(tetraliydro-2H-pyran-4-yl)urea (46 mg. 33% yield) as a nearly white solid. lH NMR (400 MHz, DMSQ~d6): 6 8.60 (brs, 1H), 8.13 (brs, 1H), 7.92 (d, J = 8.4 Hz, 1H), 7.83 (brq, 1H), 7.65 (s, 1H), 7.06 (d, J = 12.4 Hz, 1H), 6.64 (d, J = 7.2 Hz, 1H), 3.81-3.76 (m, 2H), 3.68-3.57 (m, 1H), 3.59 (brs, 3H), 3.39-3.33 (m, 2H), 2.90 (brs, 3H), 2.04 (s, 3H), 1.79-1.76 (m, 2H), 1.38-1.30 (m, 2H); MS (ESI) m/z: 441.2 (M+H+).
Example 279: Using a procedure analogous to Example 265, Example A39 (0.100 g, 0.319
mmol), 20 wt% COCl2 in PhMe (0.185 ml, 0.351 mmol) and l-Cbz-4-aminopiperidine (0.075 g,
0.319 mmol) were combined and purified by flash column cliromatography (EtOAc/hexanes) to
afford benzyl 4-(3-(2-fluoro-4-metliyl-5-(8-methyl-2-(methylamino)-7-oxo-7,8-
dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)ureido) piperidine-1-carboxylate (80 mg, 44% yield) as a white solid. MS (ESI) m/z: 574.2 (M+H+).
Benzyl 4-(3-(2-fluoro-4-meUiyl-5-(8-metliyl-2"(methylamino)-7-oxo-7,8-dihydropyrido

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[2,3-d]pyrimidin-6~yl)phenyI)ureido)piperiduie-l-carboxylQte (80 mg, 0.139 mmol) was hydrogenated (1 arm) in MeOH (5 ml) over 10% Pd/C (50% H20) (98 mg, 0.046 mmol) After 3h, die reaction mixture was filtered through Celite, rinsing forward generously with MeOH. The combined ffitrates were concentrated to dryness. The crude product was purified by reverse phase chromatography (MeCN (w/ 0.1% TFA)/ H20 (w/ 0.1% TFA)) to afford 3-(2-fluoro-4-methyl-5-(8-memyl-2-(memylammo)-7HDxo-7,8-dihydVopyrido[2J3-d]pyrimidin-6-yl)phenyl)-3-(piperidin-4-yl)urea trifluoroacetic acid salt (12 mg 15% yield) as a white solid. !H NMR (400 MHz, DMSChde): 6 8.54 (brs, IH), 8.38 (brm, IH), 8.14 (brm, IH), 8.03 (brs, IH), 7.84-7.74 (m, 2H), 7.58 (s, IH), 7.02 (d, J =12.4 Hz, IH), 6.70 (d, J = 7.2 Hz, IH), 3.63 (m, IH), 3.59 (brs, 3H), 3.15-3.13 (m, 2H)3 2.97-2.92 (m, 2H), 2.90 (brs, 3H), 1-99 (s, 3H), 1.93-1.89 (m, 2H), 1.50-1.40 (m, 2H); MS (ESI) m/z: 440.2 (M+H+).
Example 280: Using general method C, the TROC carbamate of B18 (80 mg, 0.25 mmol) and Example A58 (83 mg, 0.254 mmol) were combined to afford l-(3-tert-butylisoxazol-5-yl)-3-{2-iluoro-5-(l-isopropyl-7-(methylaiTiino)-2-oxo-l,2-dihydro-l,6-naphthyridin-3-yI)phenyI)urea (43 mg, 34% yield), 'H NMR (400 MHz, DMSO-rf6): 5 10.4 (s, IH), 8.82 (d, J = 1.6 Hz, IH), 8.51 (brs, IH), 8.42 (dd, ./= 1.6, and 7.6 Hz, IH), 7.90 (s, IH), 7.38 (m, IH), 7.06 (q, 7 = 4.8 Hz, IH), 6.52 (brs, IH), 6.16 (s, IH), 2.94 (d, J= 4.8 Hz, 3H),1.62 (d, /= 7.2 Hz, 6H): 1.32 (s, 9H); MS (ESI) m/z: 493.2 (M+H*).
Example 281: Using general method F, Example A24 (100 mg, 0.320 mmol) and alpha,alpha,alpha-trifluoro-m-tolyI isocyanate (0.066 ml, 0.480 mmol) were combined and purified by flash column chromatography (5% EtOAc/hexanes to 100% EtOAc) to afford l-(5-(l-ethyI-7-(methylamino)-2-oxo-l,2-dihydro-l,6-naphdiyridin-3-yl)-2-fluorophenyl)-3-(3-(trifluoromethyl)phenyl)urea (8 mg, 5% yield) as a white solid. 'H NMR (400 MHz, DMSO-ofe): 5 9.47 (s, IH), 8.68 (brs, IH), 8.46 (s, IH), 8.40-8.37 (m, IH), 7.88 (s, IH), 7.67-7.62 (m, 3H), 7.34-7.24 (m, 2H), 7.01 (brq, IH), 6.23 (s, IH), 4.16 (q, J = 6.4 Hz, 2H), 2.86 (d, J = 4.4 Hz, 3H), 1.23 (t, J - 6.4 Hz, 3H); MS (ESI) m/z: 500.3 (M+H*).
Example 282: Using general method F, 1-isocyanatobenzene (0.036 g, 0.302 mmol) and Example A58 (0.1 g, 0.302 mmol) were combined to provide l-(2-fluoro-5-(l-isopropyl-7-

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(methylamino)-2-oxo-l,2-dihydro-1,6-naphthyridin-3-yl)phenyl)-3-phenylurea (0.94g, 70%
yield). 1H NMR (400 MHz, DMSO-d6): 5 9.03 (s, IH), 8.62 (s,lH)), 8.49 (s, IH), 8.42 (d, J
=8Hz , IH), 7.86 (s, IH), 7.52 (s,!H), 7.50 (s,lH), 7.32 (m, 4H)S 7.03 (m, 2H), 6.50 (brs, IH), 3.40 (s, IH), 2.91(d, J=6Hz, 3H), 1.60 (d, J=6Hz, 6H); MS(ESI) m/z : 446.3 (M+H4).
Example 283: Using general method B, me carbamate of Example B48 (0.084 g, 0.401 mmol) and Example A12 (0.060 g, 0.20 mmol) were combined to afford l-(2-fluoro-5-(8-methyl-2-(methylamino)-7-oxo-7J8-dihydropyrido[233-d]pyrimidin-6-yl)phenyl)-3-(I -isopropyl-1H-pyrazol-4-yl)urea (0.074 g, 82%) as white solid. 'H NMR (400 MHz, DMSO-d6): 8 8.82 (s, IH), 8.74 (s, IH), 8.58 (d,J = 1.6 Hz, IH), 8.50 (d, J= 8.0 Hz, IH), 7.96-7.79 (m, 3H), 7.46 (s, IH), 7.34-7.31 (m, 2H), 4.50 (m, IH), 3.71 (s, 3H), 2.99 (m, 3H), 1.45 (d, J= 6.8 Hz, IH); MS (ESI) m/z: 451.2 (M+H*).
Example 284: Using general method F, 1-isocyanatonaphthalene (0.05 g, 0.29 mmol) and Example A33 (0.1 g, 0.29 mmol) were combined to afford 1 -(4-chloro-5-( 1 -ethyl-7-(methylamino)-2-oxo-],2-dihydro-l,6-naphthyridin-3»yl)-2-fluorophenyl)-3-(naphthalen-l-yl)urea as a white solid (0.121 g, 79% yield). !H NMR (400 MHz, DMSO-4>): 8 9.26 (brs, 2H), 8.48 (s, IH), 8.32 (d, J= 8.8 Hz, IH), 8.21 (d, J= 8.8 Hz, IH), 8.05 (dd, 7= 7.6 Hz, 0.8 Hz, IH), 7.98(d,y=8.4Hz, IH), 7.81 (s, IH), 7.71-7.58 (m,4H), 7.51 (t, J =8.0 Hz, IH), 7.11 (q,7 = 4.8 Hz, lH),6.30(s, IH), 4.20 (q,J= 6.8 Hz, 2H), 2.92 (d, 7 = 4.8 Hz, 3H), 1.27 (t, 7 = 6.8 Hz, 3H); MS (ESI) m/z: 516.0 (M+H*).
Example 285: Using general method D, 2-fluoro-5-(trifluoromethyl)benzoic acid (75 mg, 0.360 mmol), DPPA (0.116 ml, 0.541 mmol) and Example A24 (124 mg, 0.396 mmoi) were combined and purified by flash column chromatography (5% EtOAc/hexanes to 100% EtOAc) to afford 1-(5-(l-edly7-(memylamino)-2-oxo-l,2-dihydro-l,6-naphthyridm-3-yl)-2-fluo^ophenyI)-3-(2-fluoro-5-(trifluoromethy3)phenyI)urea (66 mg, 35% yield) as a white solid. !H NMR (400 MHz, DMSO-dg): 5 9.38 (brs, IH), 9.18 (brs, IH), 8.64-8.62 (m, IH), 8.47 (s, IH), 8.44-8.41 (m, IH), 7.89 (s, IH), 7.53-7.48 (m, IH), 7.41-7.38 (m, IH), 7.33-7.26 (m, 2H), 7.01 (brq, IH), 6.23 (s, IH), 4.17 (q, J = 7.6 Hz, 2H), 2.86 (d, J = 4.4 Hz, 3H), 1.23 (t, J = 7.6 Hz, 3H); MS (ESI) m/z: 518.2 (M+H*).

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Example 286: Using general method B, prop-l-en-2-yl 5-tert-butyl-l,3,4-thiadiazol-2-ylcarbamate (0.06 g, 0.25 mmol) and Example A24 (0.08 g, 0.25 mmol) were combined to afford l-(5-tert-butyl-l ,3,4-tliiadiazoI-2-yl)-3-(5-(I-ethyi-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)urea as a white solid (0.08 g, 64% yield). :H NMR (400 MHz, DMSO-4): 6 11.16 (s, IH), 9.00 (s, IH), 8.54 (s, IH), 8.45 (d, J= 6.4 Hz, IH), 7.98 (s, IH), 7.47-7.36 (m,2H), 7.13-7.10 (m, 1H),6.31 (s, IH), 4.28A22 (m, 2H), 2.94 (d, 7=4.8 Hz, 3H), 1.46 (s,9H), 1.31 (t, .7 = 6.8 Hz, 3H); MS (ESI) m/z: 496.3 (M+H+).
Example 287: Using general method B, prop-1 -en-2-yl 5-tert-butyl-l ,3,4-thiadiazol-2-ylcarbamate (0.07 g, 0.3 mmol), and Example A30 (0.096 g, 0.29 mmol) were combined to afford 1 -(5-tert-butyl-1,3I4-tliiadiazol~2-yl)-3-(5-(I-etliyl-7-(metliylamino)-2-oxo-1,2-dihydro-l,6-naphthyridin-3-yl)-2-fluoro-4"methylphenyl)urea as a white solid (0.09 g, 60% yield). 'H NMR (400 MHz, DMSO-^): 5 11.12 (s, 1H)S 8.95 Example 288: Using general method D 3-tert-butyI-l-methyl-lH~pyrazole-5-carboxylic acid (0.051 g, 0.28 mmol) and Example A58 (0.09 g, 0.28 mmol) in presence of triethylamine (0.06 g, 0.56 mmol) and DPPA (0.15 g, 0.56 mmol) were combined to afford l-(3-tert-butyl-l-methyI-lH-pyrazol-5-yl)-3-(2-fluoro-5-(l-isopropyl-7-(methylaniino)-2-oxo-l,2-dihydro-l,6-naphthyridin-3-yl)phenyl}urea as a white solid (0.085 g? 60% yield). !H NMR (400 MHz, DMSO-rf6): 6 9.00 (s, IH), 8.89 (s, IH), 8.51 (s, IH), 8.44-8.42 (m, IH), 7.87 (s, IH), 7.35-7.33 (m, 2H), 7.07-7.04 (m IH), 6.52 (brs, IH), 6.17 (s, IH), 3.69 (s, 3H), 2.94 (d, J = 4.8 Hz, 3H), 1.61(d,y= 7.2 Hz, 3H), 1.28 (s, 9H); MS (ESI) m/z: 506.2 (M+H+).
Example 289: Using general method D, Example B50 (0.041 g, 0.23 mmol) and Example A12 (0.069 g, 0.23 mmol) were combined to afford l-(l-cycIopentyl-lH-pyrazol-4-yl)-3-(2-fluoro-5-(8-methyl-2-(metliylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yI)phenyl)urea (0.033 g, 30%) as abrown solid. !H NMR (400 MHz, DMSO-d6): 8 8.82 (s, IH), 8.75 (s, IH), 8.58 (d, J =

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1.6 Hz, IH), 8.50 (d, J= 8.0 Hz, IH), 7.96-7.79 (m, 3H), 7.47 (s, IH), 7.35-7.32 (m, 2H), 4.70 (m, IH), 3.71 (s, 3H), 2.99 (m, 3H), 2.14-2.09 (m, 2H), 1.98-1.92 (m, 2H), 1.86-1.82 (m, 2H), 1.71-1.97 (m, 2H); MS (ESI) m/z: 477.2 (M+H+).
Example 290: Using general method B, prop-l-en-2-yl 5-tert-butyl-l,3,4-thiadiazol-2-ylcarbamate (0.081 g, 0.33 mmol) and Example A49 (0.11 g, 0.33 mmol) were combined to afford l-(5-tert-butyI-l,3,4-thiadiazoI-2-yl)-3-(2-rluoro-5-(8-i5opropyl-2-(metliylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea as a white solid (0.09 g, 52% yield). "H NMR (400 MHz, DMSO-4): 8 11.17 (s, IH), 9.02 (s, IH), 8.73 (s, IH), 8.42 (brs, IH), 7.93 (s, IH), 7.90-7.87 (m, IH), 7.45-7.37 (m, 2H), 5.89 (brs, IH), 3.00 (d, 7=4.4 Hz, 3H), 1.69 (d, J = 6.4 Hz, 6H), 1.47 (ss 9H); MS (ESI) m/z: 511.2 (M+H*).
Example 291: Using general method B, the carbamate of Example B19 (70 mg, 0.31 mmol) and Example A36 (80 mg, 0.28 mmol) were combined to afford l-(l-tert-butyl-lH-pyrazol-4-yl)-3-(2-fIuoro-5-(7-(metb>damino)-2-oxo-l-phenyl-l,2-dihydro-l,6-naphthyridin-3-yl)phenyl)urea (55 mg, 33% yield). !H NMR (400 MHz, DMSO-4,): 5 8.80 (s, IH), 8.61 (s, IH), 8.58 (brs, IH), 8.53 (dd, J= 1.6, and 7.6 Hz, IH), 8.09 (s, IH), 7.91 (a, IH), 7.71 (m, 2H), 7.64 (m, IH), 7.49 (s,IH), 7.45 (m, 2H), 7.33 (m, 2H), 7.08 (q, J= 4.0 Hz, IH), 2.78 (d, J = 4.0 Hz, 3H), 1.57 (s, 9H); MS (ESI) m/z: 526.2 (M+H4).
Example 292: Using general method C, the TROC carbamate of Example B20 (80 mg, 0.27 mmol) and Example A36 (96 mg, 0.27 mmol) were combined to afford l-(2-fluoro-5-(7-(methylamino)-2-oxo-l-phenyl-l,2-dihydro-l,6-naphthyridin-3~yl)pheny])-3-(3-isopropylisoxazol-5-yl)urea (55 mg, 33% yield). 'l-I NMR (400 MHz, DMSO-rf6): 5 10.4 (s, IH), 8.84 (s, IH), 8.60 (s, IH), 8.52 (dd, J = 1.6, and 7.6 Hz, IH), 8.12 (s, IH), 7.67 (in, 3H), 7.41 (m, 4H), 7.09 (q, J = 4.0 Hz, IH), 6.12 (s, IH), 5.40 (s, Hi), 2.98 (m, IH), 2.77 (d, J = 4.0 Hz, IH), 1.28 (d, ./= 6.8 Hz, 3H): MS (ESI) m/z: 513.0 (M+H4).
Example 293: Using general method F, 3-(trifluoromethyl)phenylisocyanate (50 mg, 0.274 mmol) and Example A40 (70 mg, 0.274 mmol) were combined to afford I-(2-fluoro-5-(2-oxo-l,2-dihydro-l,6-napIithyridin-3-yl)phenyl)-3-(3-(trifluoromethy])phenyl) urea (69 mg, 57%

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yield'H NMR (400 MHz, DMSO-d6): 5 12.2 (s, IH), 9.44 (s, IH), 8.93 (s, IH), 8.72 (brs, IH), 8.44 (m, 2H), 8.16 (s, IH), 8.05 (brs, IH), 7.52 (m, 2H), 7.41 (m, IH), 7.32 (m, 2H), 7.22 (d, J = 5.6 Hz, IH); MS (ESI) m/z: 443.0 (M+H+).
Example 294: Using general metiiod C, the TROC carbamate of Example B20 (0.145 g, 0.482 mmol) and Example A26 (0.075 g, 0.0241 mmol) were combined to afford l-(2-fluoro-4-methyl-5-(l-methyl-7-(methylamino)-2-oxo-l,2-dihydro-l,6-naphthyridin-3-yl)phenyl)-3-(3-isopropylisoxazol-5-yl)urea (0.0612 g, 55%) as white solid. *H NMR (400 MHz, DMSO-d6): 8 10.44 (s, IH), 8.82 (s, IH), 8.53 (s, IH), 8.01 (d, J= 8.4 Hz, IH), 7.81 (s, 1H),7.31 (d,/=12.4 Hz, IH), 7.19 (ra, IH), 6.31 (s, IH), 6.11 (s, IH), 3.65 (s, 3H)> 3.04-2.99 (m, 4H), 2.23 (s, 3H), 1.30 (d, J= 7.2 Hz, 6H); MS (ESI) m/z: 465.2 (M+H*).
Example 295: Using general method C, the TROC carbamate of Example B20 (0.145 g, 0.482 mmol) and Example A30, 0.079 g, 0.0241 mmol) were combined to afford l-(5-(l-etliyl-7-(melhylammo)-2-oxo-l,2-dihydio-l,6-iiaphthyridin-3-yi)-2-fluoro-4-melliylphenyl)-3-(3-isopropylisoxazol-5-yl)urea (0.017 g, 15%) as white solid. 'H NMR (400 MHz, DMSO-d6): 5 10.31 (s, IH), 8.68 (s, IH), 8.41 (s, IH), 7.88 (d, 7 = 8.4 Hz, IH), 7.68 (s, IH), 7.17 (d, J= 12.4 Hz, IH), 7.01 (m, IH), 6.25 (s, IH), 5.98 (s, IH), 4.15 (m, IH), 2.91-2.86 (m, 4H), 2.09 (s, 3H), 1.24-1.16 (m, 9H); MS (ESI) m/z: 479.2 (M+H*).
Example 296: Using general method C, the TROC carbamate of Example Bl 8 (0.152 g, 0.483 mmol) and Example A62, 0.079 g, 0.241 mmol) were combined to afford l-(3~tert-butylisoxazol-5-yl)-3-(4-chloro-3-(l-ethyl-7-(methylamino)-2-oxo-l,2-diliydro-l,6-naphthyridin-3-yl)phenyl)urea (0.0423 g, 36%) as a white solid. lH NMR (400 MHz, DMSO-d6): 8 10.25 (s, IH), 9.02 (s, IH), 8.45 (s, IH), 7.78 (s, IH), 7.58 (d,J= 1.6 Hz, IH), 7.50-7.41 (m, 2H), 7.10 (m, IH), 6.28 (s, IH), 6.08 (s, IH), 4.18 (m, 2H), 2.90 (d, J = 4.8 Hz, 3H), 1.27-1.19 (m, 12H); MS (ESI) m/z: 495.2 (M+H+).
Example 297: A suspension of l-(3-tert-butyIisoxazoI-5-yl)-3-(2-fIuoro-4-methyI-5-(8-methyI-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)ureafrom Example 96 (15 mg, 0.030 mmol) in CH2C12 (1 mL) was treated with mCPBA (70 %, S.94 mg, 0.036 mmol).

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After 30 min, methanol (0.050 mL 1.2 mmol) and triethylamine (0.020 mL, 0.14 mmol) were added and the resultant mixture was heated to 40 DC overnight. The reaction was concentrated in vacuo and purified by chromatography to provide l-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-5-(2-methoxy-8-methyl-7-oxo-7,8~dihydropyrido[233-d3pyrimidin-6-yi)-4-metliylphenyl)urea. (8.6 mg, 59% yield). 'H NMR (400 MHz, DMSO-d6)\ 5 10.32 (s: 1 H), 8.93 (s, 1 H), 8.72 (s, 1 H), 7.93 (d, J = 8.3 Hz, 1 H), 7.90 (s, 1 H), 7.20 (d, J = 12.3 Hz, 1 H), 6.00 (s, 1 H), 4.02 (s, 3 H), 3.63 (s, 3 H), 2.09 (s, 3 H), 1.21 (s, 9 H); MS (ESI)m/z: 481.2 (M+H+).
Example 298: Using General Method F, Example A33 (100 rng, 0.288 mmol) and cyciohexyl isocyanate (0.074 ml, 0.577 mmol) were reacted to afford I-(4-chloro-5-(l-ethyi-7-(metliyla]Tiino)-2-oxo-l,2-dihydro-l,6-naphthyridin-3-yl)-2-fluorophenyl)-3-cyclohexylurea (37 mg, 27% yield) as a white solid. !H NMR (400 MHz, DMSO-^): 5 8.39 (s, 1H), 8.29 (d, J = 2.0 Hz, 1H), 8.14 (d, J = 8.8 Hz, 1H), 7.70 (s, 1H), 7.41 (D, J = 11.2 Hz, 1H), 7.30 (brs, IH), 6.80 (s, 1H), 6.61-6.58 (m, 2H), 6.28 (s, IH), 4.08 (q, J = 6.81 Hz, 2H), 3.40 (brm, IH), 2.83 (s, 3H), 1.75-1.68 (m, 2H), 1.61-1.55 (m, 2H), 1.46-1.40 (m, IH), 1.25-1.05 (m, 5H), 1.15 (I, J = 7.2 Hz, 3H); MS (ESI) m/z: 472.2 (M+H*), 474.2 (M+2+H+).
Example 299: By analogy to Example All, Example A41 125 mg, 0.363 mmol), mCPBA (107 mg, 0.436 mmol) and 2M MeNH2 in THF were reacted to afford 6-(5-aminp-4-fluoro-2-metliylphenyl)-8-ethyl-2-(methylamino)pyrido[2,3-d]pyrimidin-7(8H)-one (67 mg, 0.205 mmol) which, in turn, was reacled according to General Method F with cyciohexyl isocyanate (0.105 mL, 0.822 mmol) to afford l-cyclohexyl-3-(5-(8-ethyl-2-(methylamino)-7-oxo-7,8-dihydropvrido[2,3-d]pyrimidin-6-yI)-2-fluoro4-methylphenyl)urea (11 mg, 12% yield) as a white solid. 'H NMR (400 MHz, DMSO-rf Example 300: Using General Method F, Example A26 (0.100 g, 0.320 mmol) and cyciohexyl isocyanate (0.041 ml, 0.320 mmol) were reacted to afford l-cyclohexyl-3-(2-fluoro-4-methyl-5-(l-methyl-7-(memylamino)-2-oxo-l,2-dihydro-l,6-naphthyridm-3-yl)phenyl)urea (77 mg, 55%

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yield) as an off-white solid. lH NMR (400 MHz, DMSO-dtf): 5 8.38 (s, 1H), 8.10 (d, J = 2.0 Hz, IH), 7.93 (d, J = 8.4 Hz, IH), 7.63 (s, IH), 7.06-7.02 (m, 2H), 6.54 (d, J = 7.6 Hz, IH), 6.17 (s, 1H), 3.50 (s, 3H), 3.46-3.36 (m, 1H), 2.85 (d, J - 5.2 Hz, 3H), 2.03 (s, 3H), 1.81-1.75 (m, 2H), 1.73-1.56 (m, 2H), 1.48-1.45 (m, 1H), 1.38-1.09 (m, 5H); MS (ESI) m/z: 438.3 (M+H+).
Example 301: Using General Method B, Example B39 (125 mg, 0.66 mmol) and Example A26 (114 mg, 0.366 mmol) were reacted to afford l-(l-tert-butyl-lH-indazoI-3-yl)-3-(2-fluoro-4-methyl-5-(l-metliyl-7-(methylamino)-2-oxo-lT2-dihydro-K6-naphmyridin-3-yl)phenyl)urea (77 mg, 40% yield) as a white solid. 'H NMR (400 MHz, DMSO-^f): 8 10.04 (brs, 1H), 8.41 (s, IH), 8.09 (dd, J = 8.4 and 14.0 Hz, 1H), 7.77 (d, J = 8.4 Hz, 1H), 7.70 (s, 1H), 7.37 (dd, J= 7.6 and 15. 6 Hz, IH), 7.20 (d, J= 12.0 Hz, IH), 7.09-7.05 (m, 2H), 6.19 (s, IH), 3.52 (s, 3H), 2.86 (d, J = 5.2 Hz, 3H), 2.09 (s, 3H), 1.72 (s, 9H); MS (ESI) m/z: 528.3 (M+H*).
Example 302: Using General Method B, Example B39 (125 mg, 0.66 mmol) Example A28 (138 mg, 0.415 mmol) were reacted to afford l-(l-tert-butyI-lH-indazol-3-yl)-3-(4-chloro-2-fluoror5-(l-methyl-7-(methylamino)-2-oxo-Is2-dihydro-l,6-naphthyridin-3-yl)phenyl)urea (47 mg, 21% yield) as a white solid. 1H NMR (400 MHx, DMSO-^): 5 10.15 (brs, IH), 8.42 (s, IH), 8.33 {d, J - 8.8 Hz, IH), 8.06 (d, J - 7.6 Hz, JH), 7.78 (dd, J = 4.4 and 8.8 Hz, IH), 7.62 (d, J = JO. 4 vHz, IH), 7.40-7.36 (m, IH), 7.13-7.06 (m, 2H), 6.18 (s, IH), 3.51 (s, 3H), 2.86 (d, J = 4.8 Hz, 3H), 1.72 (s, 9H); MS (ESQ m/z: 548.3 (M+H*), 550.3 (M+2+H+).
Example 303: Using general method D, 3-tert-butyl-l-methyl-lH-pyrazole-5-carboxylic acid (50 mg, 0.27 mmol) and Example A19 (0.10 g, 0.27 mmol) in presence of DPP A {65 \iL, 0.30 mmol) and Et3N (42 (JL, 0.30 mmol) were combined to afford l-(3-terl-butyl-l-methyl-lH-pyrazol-5-yl)-3-(5-(8-cyclopentyl-2-(methyltliio)-7-oxo-7,8-dihydropyrido[2J3-d]pyiimidin-6-yl) -2 -fruorophenyl )urca.
Using a procedure analogous to Example Al, , l-(3-tert-butyl-l-methyMH-pyrazol-5-yl)-3-(5-(8-cyclopentyl-2-(methyIthio)-7-oxo-738-dihydropyrido[2,3-d]pyrimidiTi-6-yl)-2-fluorophenyl)urea (150 mg, 0.27 mmol) was treated with mCPBA (70% wt, 74 mg, 0.30 mmol) and then 2 M methylamine (1.4 mL) to afford l-(3-tert-butyl-l-methyl-lH-pyrazol-5-yl)-3-(5-(8-cyclopentyI-2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-dJpyrimidin-6-yl)-2-

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fluorophenyi)urea (67 mg, 46% yield). 'H NMR (400 MHz, DMSO-rf6, major isomer); 5 9.04 (s, IH), 8.94 (d, J= 2.4 Hz, IH), 8.76 (brs, IH), 8.46 (brd, J= 7.6 Hz, 1H), 7.93 (s, 1H), 7.74 (brq, J= 4.8 Hz, IH), 7.38 (m, 2H), 6.21 (s, IH), 6.04 (m, IH), 3.73 (s, 3H), 3.01 (d, J= 4.8 Hz, 3H), 2.49 (brs, IH), 2.33 (brs, IH), 2.11 (s, 3H), 2.11 (brs, 2H), 1.90 (brs, 2H), 1.74 (brs, 2H), 1.31 (s, 9H); MS (ESI) m/z: 533.3 (M+H4).
Example 304: Using general metliod D, Example B45 (100 mg, 0.549 mmol), triethylamine (64 mg, 0.631 mmol), Example A58 (179 mg, 0.549 mmol) and DPPA (174 mg, 0.631 mmol) were coambined to provide l-(l-tert-butyl-5-methyl-lH-pyrazol-4-yl)-3-(2-fluoro-5-(l~isopropyl-7-(methylamino)-2-oxo-l,2-dihydro-l,6-naphthyridin-3-yl)phenyl)urea (101 mg. 36% yield). 1H NMR (400 MHz, DMSO-rf6): 5 1.68 (d, 6 H), 1.69 (s, 9H), 2.46 (s, 3 H), 3.00 (d, 3 H), 4.16-4.18 (hep, 1 H), 6.58 (br. s, 1 H), 7.11 (br. s, 1 H), 7.35-7.38 (m, 2 H), 7.59 (s, 1 H), 7.92 (s, I H), 8.30 (s, 1 H), 8.49-8.51 (m, 1 H), 8.57 (s, 1 H), 8.69 (br. s, 1 H); MS (ESI) m/z: 506.2 (M+H4).
Example 305: Using general method D, Example B49 (134 mg, 0.501 mmol), triethylamine (58 mg, 0.577 mmol), Example A13 (135 mg, 0.501 mmol) and DPPA (159 mg, 0.577 mmol) were combined and purified by reverse phase chromatography (Biotage C18-25 column, 30-100% acetom'trile/water) to afford l-(2"fluoro-5-(8-methyl-7-oxo-7,S-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)-3-(2-metliyl-4-(l»metliyI-lH-indol-5-yl)pyrimidin-5-yl)urea (34 mg, 12% yield). 'H NMR (400 MHz, DMSO-4): 8 2.60 (s, 3 H), 3.69 (s, 3 H), 3.83 (s, 3 H), 6.55 (s, I H), 7.30-7.32 (m, 2 H), 7.41-7.42 (m, 1 H), 7.48 (d, 1 H), 7.60 (d, 1 H), 7.91 (s, 1 H), 8.13 (s, 1 H), 8.47-8.49 (m, 1 H), 8.58 (s, 1 H), 9.05 (br. s, 1 H), 9.10-9.25 (m, 2 H), 9.11 (s, 1 H); MS (ESI) m/z: 535.2 (M+H+).
Example 306: Using general metliod D, 2,3-difluorobenzoic acid (0.030 g, 0.190 mmol) was reacted with DPPA (0.0104 g, 0.380 mmol) in presence of tnetliylamine (0.058 g, 0.569 mmol) in Dioxane (2 ml) at room temp for 1 hour followed by treatment with Example A49 (0.062g, 0.190 mmol) at 80 °C for 2 hours to provide l-(2,3-difluorophenyl)-3-(2-fluoro-5-(8-isopropyl-2-(methylamino)-7-oxo-7,8~dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (0.065 g, 71 %
yield). 1HNMR(400 MHz, DMSO-d6):. 8 9.31 (brs, IH), 9.18 (s,lH)), 8.72 s, IH), 8.47 (d,
J=7Hz, IH), 8.07 (m, IH), 7.90 (s, IH), 7.86 (m,lH), 7.36 (d, J=8.5Hz, IH), 7.21 (m, IH), 7.12

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(m, IH), 5,85 (brs, IH), 2.90 (d, J=5Hz, 3H), 1.67 (d, J=6Hz, 6H); MS(ESI) m/z : 483.3 (M+H+).
Example SiTT: C/samj general method" G, 2,2,2-tn'chforoethyf pyridin-5-yfcarrjamate (0.060 g, 0.223 mmol) was reacted with Example A49 (0.073g, 0.223 mmol) in presence of N-methylpyrrolidine (O.Ql9g, 0.223mmol) in dioxane (3 ml) at 90 °C for 15 hours to provide l-(2-fluoro-5"(8"isopropyK2-(methylammo)-7-oxo-7,8-dihydropyridoE23-d]pyrimidin-6-yl)phenyl)-
3~(pyridin-3-yl)urea (0.025g, 25 % yield). lH NMR (400 MHz, DMSO-d6): 6 9.34 (s, IH),
8.79 (s, IH), 8.72 (s, iH), 8.68 (d, J=2.5Hz, IH), 8.43 (d, J=8Hz, IH), 8.27 (m, IH), 8.05 (m, IH), 7.92 (s,lH), 7.8^ (m, IH), 7.40 (dd, J=9, 5Hz, IH), 7.37 (ra, 2H), 5.85 (brs, IH), 2.90 (d, J=5Hz, 3H), 1.67 (d, J=6Hz, 6H): MS(ESI) m/z : 448.2 (U+it).
Example 308: Using general method F, 1 -isocyanato-3-(trifiuoromethyl)benzene (0.060 g, 0.321
mmol) was reacted Example A49 (0.060 g, 0.183 mmol) in methylene chloride (2 ml) for 6 hours
to provide l-(2-fluoro-5-(8-isopropyl-2-(metliylamino)-7-oxo-7,8-dihydropyrido[2,3-
d]pyrimidin-6-yI)pheQyi)»3-(3.(trifIuoromethyI)phei3yI)urea (0.090g, 95 % yield). ] H NMR (400 MHz, DMSO-d6:. 5 9.5? (s, IH), 8.79 (brs, IH), 8.75 (s, IH), 8.43 (d, J=8Hz, IH), 8.17 (s, IH),
7.92 (s,IH), 7.86 (m, JH), 7.62 (m, 2H), 7.37 (m, 2H), 5.85 (brs, IH), 2.90 (d, J=5Hz, 3H), 1.67 (d, J=6Hz, 6H); MS(Esi) m/z : 515.2 (M+H*).
Example 309: Using general method F, 1-isocyanatobenzene (0.050 g, 0.420 mmol) was reacted wi'tA £xampie A*&$S-Q6Q g, 0.183 mmofjm metnyfene cfifondc (2 mfl for 6 fours (o provufe f-(2-fluoro-5-(8-isopropyi.2.(metliylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-
yl)phenyl)-3-phenylurea (0.065g, 79 % yield). ]H NMR (400 MHz, DMSO-d6): 5 9.18 (s, IH),
8.75 (s, IH), 8.68 (brs,, JH), 8.48 (d, J=8Hz, IH), 7.93 (s, IH), 7.89 (m, IH), 7.56 (m,2H), 7.38 (m, 4H), 7.10 (m, IH). 5.85 (brs, IH), 2.90 (d, J=5Hz, 3H), 1.67 (d, J=6Hz, 6H); MS(ESI) m/z : 447.3 (M+H+).
Example 310: Using general mediod F, 1-isocyanatonaphthalene (0.060 g, 0.355 mmol) was reacted with Example A49 (0.060 g, 0.183 mmol) in methylene chloride (2 ml) for 6 hours to

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provide l-(2-fluoro-5-(8-isopropyl-2-(methyIamino)-7-oxo-7,8-dihydropyrido[2J3-d]pyrimidin-
6-yl)phenyl)-3-(naphthalen-l-yl)urea, (0.070g, 42 % yield). 1H NMR (400 MHz, DMSO-d6): 5
9.28 (s, 1H), 9.20 (s, 1H), 8.74 (S] 1H), 8.57 (d, J=8Hz, 1H), 8.27 (d, J=9Hz, 1H), 8.17 (m, 1H), 8.04 (ITLIH), 7.93 (s, 1H), 7.77-7.55 (m, 4H), 7.37 (m, 2H), 5.85 (brs, 1H), 2.90 (d, J=5Hz, 3H), 1.67 (d, J=6Hz, 6H); MS(ES1) m/z : 497.2.2 (M+H*).
Example 311: Using general method F, l-chloro-4-isocyanato-2-(trifluoromethyl)benzene (0.06 g, 0.271 mmol) was reacted with Example A49 (0.06 g, 0.183 mmol) in methylene chloride (2 ml) for 6 hours to provide l-(4-chloro-3-(trifluorometliyl)phenyl)-3-(2-fluoro-5-(8-isopropyl-2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (0.080g, 80 % yield)
!H NMR (400 MHz, DMSO-d6); 6 9.62 (s, 1H), 8.79 (s, 1H), 8.74 (s, 1H), 8.40 (d, J=8Hz, 1H),
8.21 (s, 1H): 7.93 (s, 1H), 7.89 (m,lH), 7.71 (s, 2H), 7.40 (m, 2H), 5.85 (brs, 1H), 2.90 (d, J=5Hz, 3H), 1.67 (d, J=6Hz, 6H): MS(ESI) m/z : 549.0 (M+H4).
Example 312: Using general method F, l-fluoro-2-isocyanato-4-(trifluorornetiiyI)benzene (0.060 g, 0.293 mmol) was reacted with Example A49 (0.06 g, 0.183 mmol) in methylene chloride (2 ml) for 6 hours to provide l-(2-fluoro-5-(8-isopropyl-2-(methylamiiio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyI)-3-(2-fluoro-5-(trifluoromethyl)phenyl)urea (0.075g,
48.2 % yield). *H NMR (400 MHz, DMSO-d6): 6 9.51 (s, 1H), 9.31 (s, 1H), 8.76 (m, 2H), 8.50
(d, J=8Hz, 1H), 7.95 (s, 1H), 7.90 (m, 1H), 7.63 (m,lH), 7.52 (m, 1H), 7.42 (s, 1H), 7.40 (s, 1H), 5.85 (brs, 1H), 2.90 (d, J=5Hz, 3H), 1.67 (d, J=6Hz, 6H;. MS(ESl) m/z : 533.0 (M+H*).
Example 313: Using general method F, 3-isocyanatobenzonitrile (0.06 g, 0.416 mmol) was
reacted with Example A49 (0.06 g, 0.183 mmol) in methylene chloride (2 ml) for 6 hours to
provide l-(3-cyanophenyl)-3-(2-fluoro-5-(8-isopropyI-2-(methylamino)-7-oxo-7,8-
dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (0.068g , 79 % yield). 1H NMR (400 MHz, DMSO-d6):5 9.51 (s, lH),8.83(s, IH),8.75(s, 1H), 8.43 (d, J*=8Hz, 1H),S.11 IH), 7.89 (m, 1H), 7.75 (m,lH), 7.60 (t, J=8Hz,lH), 7.54 (m: 1H), 7.37 (m, 2H), 5.85 (brs, 1H), 2.90 (d, J=5Hz, 3H), 1.67 (d, J=6Hz, 6H); MS(ESI) m/z : 472.2 (M+H+).

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Example 314: Using general metliode F, isocyanatocyclohexane (0.050 g, 0.399 mmol) was reacted with Example A49 (0.070 g, 0.214 mmol) in pyridine (2 ml) at 50 °C for 3 hours to provide l-cyclohexyI-3-(2-fluoro-5-(8-isopropyl-2-(metliylamino)-7-oxo-7,S-dihydropyrido[2,3-
d]pyrimidin-6-yl)phenyl)urea (0.03 g, 31% yield). lH NMR (400 MHz, DMSO-d6): 58.74 (s,
1H), 8.47 d, J=9Hz, 1H), 8.31 (brs, 1H), 7.88 (s, 2H), 7.27 (m, 2H), 6.72 (d, J=9Hz, IH), 5.87 (brs, IH), 3.58 (m, IH), 3.00 (d, J=5Hz, 3H), 1.95-1.20 (m, 10H), 1.70 (d, J=6Hz, 6H); MS(ESI) m/z : 453.3 (M+H4).
Example 315: Using general method F. isocyanatocyclohexane (0.050 g, 0.399 mmol) was reacted with Example Al 2 (0.070 g, 0.234 mmol) in pyridine (2 ml) at 50 °C for 3 hours provide l-cyclohexyl-3-(2-lluoro-5-(8-methyl-2-(methylamino)-7-oxo-718-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (0.045g, 45 % yield). 1H NMR (400 MHz, DMSO-d6;) 5 8.76 (s,
IH), 8.50 (d, J=9Hz, IH), 8.31 (brs, IH), 7.88 (s, 2H), 7.29 (m, 2H), 6.72 (d, J=9Hz, IH), 3.71 (s, 3H), 3.58 (m, IH), 3.00 (d, J=5Hz, 3H), 1.95-1.20 (m, 10H); MS(EST) m/z : 425.2 (M+rf).
Example 316: Using general Method F, isocyanatocyclohexane (0.100 g, 0.799 mmol) was reacted with Example A28 (0.100 g, 0.301 mmol) in pyridine (2 ml) at 50 °C for 2 hours to provide l-(4-chloro-2-fluoro-5-(l-methyl-7-(methylamino)-2-oxo-l,2-dihydro-l,6-naphthyridin-
3-yI)phenyl>3-cydohexylurea (0.082g, 60 % yield). ]H NMR (400 MHz, DMSO-d6): 6 8.39 (s,
IH), 8.32 (brs,lH)), 8.17 (d, J=9Hz, IH), 7.70 (s, IH), 7.43 (d, J=11.5Hz, IH), 7.08 (m, IH), 6.62 (d, J=8Hz, IH), 6.15 (s, IH), 3.49 (s, 3H), 3.41 (m, IH), 2.86 (d, J=5Hz, 3H), 1.85-1.45 (m,5H), 1.35-1.20 (m,5H); MS(ESI) m/z : 458.1 (M+H4).
Example 317: Using general method F, 1-isocyanatobenzene (0.050 g, 0.420 mmol) was reacted with Example A28 (0.070 g, 0.210 mmol) in ethylacetate (2 ml) for 13 hours to provide l-(4-chloro-2-fluoro-5-(l-methyl-7»(memyIainino)-2-oxo-l)2-dihydrc-l,6-naphtliyridin-3"yl)phenyl)-
3-phenylurea (0.080g, 84 % yield). lH NMR (400 MHz, DMSO-d6): 5 9.08 (s, IH), 8.68
(brs,lH)), 8.40 (s, IH), 8.17 (d, J=9Hz, IH), 7.74 (s, IH), 7.53 (d, J=l 1.5Hz, IH), 7.41 (m, IH),

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7.26 (m, IH), 7.10 (m, IH), 6.96 (m, IH), 6.15 (s, IH), 3.49 (s, 3H), 2.86 (d, J=5Hz, 3H); MS(ESI) m/z : 452.0 (M+H+).
Example 318: Using general method F, l-isocyanatonaphthalene (0.050 g, 0.296 mmol) was reacted with Example A28 (0.070 g, 0.210 mmol) in ethylacetate (2 ml) at RT for 13 hours to provide 1 -(4-cbloro-2-fluoro-5-(l -methyl-7-(methylamino)-2-oxo-l ,2-dihydro-1,6-naphthyridin-
3-yl)phenyl)-3-(naphthalen-l-yl)urea, (0.07g, 67 % yield). *H NMR (400 MHz, DMSO-d6): 5
9.18 (s, 2H), 8.40 (s, IH), 8.26 (d, J=9Hz, IH), 8.14 (d, J=9Hz, IH), 7.98 (d, J=7Hz, IH), 7.90 (d, J=8Hz, IH), 7.74 (s, IH), 7.60 (m, 3H), 7.43 (t, J=8Hz, IH), 7.11 (m, IH), 7.26 (m, IH), 6.16 (s, IH), 3.49 (s, 3H), 2.86 (d, J=5Hz, 3H); MS(ESI) m/z : 502.0 (M+H*).
Example 319: Using general method F, l-cldoro-4-isocyanato-2-(trifluoromethyl)benzene (0.070 g, 0.316 mmol) was reacted with Example A28 (0.070 g, 0.210 mmol) in ethyl acetate (2 m!) for 13 hours to provide 1 -(4-chloro-2-fluoro-5-( 1 -methyl-7-(methylamin6)-2-oxo-1,2-dihydro-l,6-naphthyridin-3-yl)phenyl)-3-(4-chloro-3-(trifluoromethyl)phenyl)urea (0.104g, 89 %
yield). *H NMR (400 MHz, DMSO-d6): 5 9.54 (s, IH), 8.83 (brs,lH)), 8.43 (s, IH), 8.12 (m,
2H), 7.77 (s, IH), 7.65-7.50 (m, 3H), 7.12 (m, IH), 6.15 (s, IH), 3.52 (s, 3H), 2.86 (d, J=5Hz, 3H): MS(ESl)m/z: 555.0(M+H4).
Example 320: Using general method F, l-fluoro-2-isocyanato-4-(trifluoromcthyl)benzene (0.070 g, 0.341 mmol) was reacted with Example A28 (0.070 g, 0.210 mmol) in ethyl acetae (2 ml) for 13 hours to provide I-(4-chioro-2-fluoro-5-(I-memyl-7-(methyiamino)-2-oxo-I)2-dihydro-lJ6-
iiaphthyridin-3-yl)phenyl)-3-(2-fIuoro-5-(trifluorometliyl)phenyl)urea (0.095g, 84 % yield). *H NMR (400 MHz, DMSO-d6); 5 9.41 (bra, IH), 9.31 (brs,lH)), 8.57 (dd, J=7, 2Hz, IH), 8.42 (s,
IH), 8.22 (d, J=9Hz, IH), 7.77 (s, IH), 7.58 (d, J=l 1.5Hz, IH), 7.51 (m, IH), 7.40 (m, IH), 7.10 (m, IH), 6.15 (s, IH), 3.51 (s, 3H), 2.86 (d, J=5Hz, 3H); MS(ESI) m/z :53S.0 (M+H+).
Example 321: Using general methode F, 3-isocyanatobenzonitrile (0.050 g, 0.347 mmol) was reacted with Example A28 (0.070 g, 0.210 mmol) in ethyl acetate (2 ml) for 13 hours to provide l-(4-cliloro-2-fluoro-5-(l-methyl-7-(methylamino)-2-oxo-lJ2-dihydro-l,6-naphthyridin-3-

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yl)phenyl)-3-(3-cyanophenyl)urea (0.090g, 90 % yield). 1H NMR (400 MHz, DMSO-d6):
5 9.42 (s, 1H), 8.86 (brs,lH), 8.44 (s, IH), 8.17 (d, J=9Hz, IH), 7.99 (m, 1H), 7.77 (s, 1H), 7.63 (m, IH), 7.58 (d, J=11.5Hz, IH), 7.51 (t, J=7Hz, 1H): 7.45 (m, IH), 7.14 (m, IH), 6.19 (s, IH), 3.52 (s, 3H), 2.86 (d, J=5Hz, 3H); MS(ESI) m/z : 477.0 (M+H+).
Example 322: Using general method D, 2,3-difluorobenzoic acid (0.071 g, 0.449 mmol), triethylamine (0.091 g, 0.898 mmol), DPPA (0.124 g, 0.449 mmol) and Example A28 (0.100 g, 0.299 mmol) were combined to provide l-(4-chloro-2-fluoro-5-(l-methy]~7-(methylamino)-2-oxO"l,2-dihydro-l,6-naphthyridin-3-yl)phenyl)-3-(2,3-difluorophenyl)urea (0.070g, 48 % yield).
lU NMR (400 MHz, DMSO-d6): 8 9.26 (bra, IH), 9.22 (brs,lH)), 8.42 (s, 1H), 8.20 (d,
J=10Hz, IH), 7.94 (m, IH), 7.77 (s, IH), 7.57 (d, J=12Hz,lH), 7.12 (mf 2H), 7.04 (m, IH), 6.18 (s, IH), 3.51 (s, 3H), 2.86 (d, J=5Hz, 3H); MS(ESI) m/z : 488.0 (M+H+).
Example 323: Using general method F, isocyanatocyclohexane (0.100 g, 0.799 mmol) was
reacted with Example A62 (0.100 g, 0.304 mmol) in pyridine (2 ml) for 3 hours at 50 °C to
provide l-(4-chloro-3-(l-ethyl-7-(methylamino)-2-oxC)-l,2-dihydro-l,6-naphthyridin-3-
yl)phenyl)-3-cyclohexylurea (Q.075g, 54 % yield). !H NMR (400 MHz, DMSO-d6): 5 8.46 (s,
IH), 8.40 (sTlH», 7.71 (s, IH), 7.45 (s, IH), 7.32 (bra, 2H), 7.04 (m, IH), 6.24 (s, IH), 6.11 (d, J=8Hz,lH), 6.25 (s, IH), 6.00 (s, IH), 4.15 (q, J=6Hz, 2H), 3.43 (m, IH), 2.86 (d, J=5HzT 3H), 1.85-1.50 (m, 5H), 1.35-1.20 (m, 5H), 1.20 (t, J=6Hz,3H); MS(ESI) m/z : 454.1 (M+H+).
Example 324: Using general method C, 2,2,2-trichloroethyl 3--isopropylisoxazol-5-ylcarbamate (0.077 g, 0.255 mmol) was reacted with Example A62 (0.070 g; 0.213 mmol) in dioxane (2 ml) in presence of N-methylpyrrolidine (0.018 g, 0.213 mmol) at 80 °C for 4 hours to provide l-(4-chloro-3-(l -ethyl-7-(rnethylamino)-2-oxo-l ,2-dihydro-l ,6-naphthyridin-3-yl)phenyl)-3-(3-
isopropyIisoxazol-5-yl)urea (0.080g, 78 % yield). *H NMR (400 MHz, DMSO-dg):, 6 10.2 (s,
IH), 9.00 (s,lH)), 8.43 (s, IH), 7.75 (s, IH), 7.54 (d, J=2.5Hz, JH), 7.44 (m, 2H), 7.06 (m,lH), 6.25 (s, IH), 6.00 (s, IH), 4.15 (q, J=6Hz, 2H), 2.90 (m, IH), 2.87 (d, J=6Hz, 3H), 1.20 (m, 9H); MS(ESI) m/z : 481.2 (M+H+).

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Example 325: Using general method D. 3-tert-butyl-l-methyl-lH-pyrazoIe-5-carboxylic acid (50 mg, 0.27 mmol) and Example A21 (0.102 g, 0.27 mmol) in presence of DPP A (65 iL, 0.30 mmol) and EtN (42 jlL, 0.30 mmol) were combined to afford 1-(3-tert-butyl-l-methyl-1H-pyrazol-5-yl)-3-(5-(S-cyclopentyU2-(memyltln^)-7-oxo-7)8-dihydropyrido[2J3-d]pyrimidin-6-yl)-2-fluoro-4-methylphenyI)urea.
Using a procedure analogous to Example Al, l-(3-tert-butyl"l-methyI-IH-pyrazol-5-yl)-3-(5-(8-cyclopentyl-2-(mediylmio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-2-fluoro-4-methylphenyl)urea (150 mg, 0.27 mmol) was treated with mCPBA (70% wt, 74 mg, 0.30 mmol) and then 2 M methylamine (1.4 mL) to afford l-(3-tert-butyI-l-methyl-lH-pyrazoI-5-yl)-3-(5-(8-cyclopentyl-2~(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-2-fluoro-4-methylphenyl)urea (85 mg, 58% yield). *H NMR (400 MHz, DMSO-6, major isomer): 5 9.00 (s, IH), 8.86 (d, 3= 2.0 Hz, IH), S.71 (brs, IH), 8.04 (d, J = 8.8 Hz, IH), 7.90 (q, J = 4.4 Hz, IH), 7.75 (s, IH), 7.26 (d, J= 12.4 Hz, IH), 6.17 (s, IH), 6.06 (brm, IH), 3.71 (s, 3H), 3.01 (d, J = 4.4 Hz, 3H), 2.42 (brs, 2H), 2.18 (s, 3H), 2.07 (brs, 2H), 1.90 (brs, 2H), 1.72 (brs, 2H)5 1.29 (s, 9H); MS (ESI) m/z: 547.2 (M+H+).
The following examples are prepared by the methods described in Schemes 1-12, General Methods A-G, the above Examples and the methods described in WO 2006/071940.
l-(3-tert-butyl-l-methyl-lH-pyrazol-5-yl)-3-(2-fluoro-5-(l-isopropyl-7-(methylamino)-2-oxo-
1,2-dihydro-l ^-naphthvridin-S-yl^-methylphenylJurea, 1 -(1 -(2-(dimethylamino)ethyI)-5-
isopropyl-lH-pyrazol-3-yI)-3-(2-fluoro-4-methyI-5"(8-methyl-2-(metliylamino)-7-oxo-7,8-
dihydropyrido[2,3-d]pvrimidin-6-yl)phenyl)urea, l-(2-tert-butyloxazol-5-yI)-3-(2-fluoro-4-
methyl-5-(8-metIiyl-2-(memylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea, l-(2-tert-butyloxa2oI-5-yl)-3-(4-chloro-2-fluoro-5~(8-methyl-2-(methyIamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea, l-(2-tert-butyloxazol-5-yl)-3-(5-(8-emyl-2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidiri-6'-yl)-2"fluorophenyl)urea, 1-(5-tert-butyl-4-memylisoxazol-3-yI)-3-(5-(8-ethyl-2-(metliylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyriinidin-6-yl)-2-fluoro-4-methylphenyl)urea, 1 -(bicyclo[2.2.1 ]hept-5-en-2-yl)-3-(2-fluoro-4-methyl-5-(8-methy[-2-(methylamino>7~oxo-.7,8-dihydropyrido[2,3-

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d]pyrimidin-6-yl)phenyl)urea, l-(bicyclo[2.2.i]heptan-2-yI)-3-(2-fluoro-4-methyl-5-(8-methyl-
2-(methylambo)-7-oxO"7,8-dUiydropyrido[2,3"d]pyrimidin--6'-yl)phenyl)urea, l-(2-fluoro-4-
metiiyl-5^8-met}iyl-2-(methy!amino)-7-oxo-7)8-dihydropyrido[2J3-d]pyrimidin-6-yl)phenyl)-3-
isopropylurea, (R)-l-(2-fluoro-4-metiiyl-5-(8-methyl-2-(metliylamino)-7-oxo-7,8-
dihydropyrido[2,3-d3pyrimidin-6-yl)phenyl)~3-(l-phenylethyI)urea. l-(2-fluoro-4-methyl-5-(8-
memyl-2-(merliylamino)-7"Oxo-7J8-dihydropyrido[23-d]pyrimidiii^-yl)phenyl)-3-(l-(pyridin-3-
yl)ethyl)urea. l-(2-fluoro-5-(l-(2-hydroxyethyl)-7-(methylamino)-2-oxo-l,2-dihydro-l,6-
naphthyridin-3-yl)-4-metliyIphenyl)-3-isopropylurea, I-(5-(8-ethyl-2-(methylamino)"7-oxo-7,8-dihydropyrido[23-d]pyrimidin-6-yl)-2-fiuorophenyl)0-(5-(trifluorome^yi)pyridin--3-yl)ureaI I-(2-fluoro-5^8-methyl-2-(methylmm^o)-7-oxo-7,8-dmydropyrido[2J3-d]pyrimidin-6-yI)phenyl)-3-(2-fluoro-5-(trifluoromethyl)phenyl)urea, l-(2-fluoro-5-(8-(2-hydroxyethyl)-2-(metliylamino)-7^xo-7J8-dihydropyrido[23-d]pyrirnidin-6-yl)phenyl)-3-(2-fluoro-5-
(trifluoromethyI)phenyl)urea, l-(4-chloro-2-fiuoro-5-(8-mediyl-2-(methylamino)-7-oxo-7,8-
dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)-3-cyclohexylurea, l-cyclohexyl-3-(2,4-difluoro-5-
(8-methyl-2-(methylamino)-7-oxo--7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea, l-(4-
cyano-2-fluoro-5-(8-methyI-2-(memylamino)-7-oxo-7,8-dihydropyrido[2)3-d]pyrimidin-6-
yl)phenyl)-3-cyclohexylurea, l-cyclohexyl-3-(5-(8-ethyl-2-(memyiamino)-7-oxo-7,8-
dihydropyrido[2,3-d]pyrimidin-6-yI)-2-fluorophenyl)urea, l-cyclohexyl-3-(2-fluoro-4-methyl-5~
(8 -methyl -2-(m ethyl amino) -7-ox o-7,8-dihydropyri do [2,3 -d]pyrimidin-6-yl)phenyl) urea, 1-
cyclohexyl-3-(2-fluoro-5-(8-(2-hydroxyethyl)-2-(methylamino)-7-oxO"7,8"dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea, l-(2-fluoro-4-metiiyl-5-(8-memyl-2^meUiylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)-3-(( 1 R,2R)-2-methylcyclohexyl)urea, 1 -(2-fluoro-4-methyI-5-(8-methyl-2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyI)-3-((lS,2S)-2-methyIcydohexyl)urea, and l-(2-fluoro-4-methyl-5-(8-methyl-2-(methylamino)-7-oxo-7,8-dihydropyrido[213-d]pyrimidin-6-yl)phenyl)-3-((Ir,4r)-4-methyIcyclohexyl)urea.
The following examples are prepared by the methods described in Schemes 1-12, General Methods A-G, the above Examples and the methods described in WO 2006/071940.
l-(4-tert-butyltliiophen-2-yl)-3-(2-fluoro-4-methyl-5-(l-methyl-7-(methylamino)-2-oxo-l,2-dihydro-l,6-naphthyridin-3-yl)phenyI)urea, l-(4-tert-butyl-3-methylthiophen-2-yl)-3-(2-fluoro-

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4-methyl-5"(l-methyl-7-(methyIamino)-2-oxo-l,2-dihydro-l,6-naphthyridin-3-yI)phenyl)urea, 1-
(4-tert-butyl-3-chIorothiophen-2-yl)-3-(2-f]uoro-4-methyl-5-(l-metliyl-7-(methylamino)-2-oxo-
l,2-dihydro-l,6-naphthyridin-3-yl)phenyI)urea, l-(4-tert-buryl-3-fluorothioplien-2-yl)-3-(2-
fluoro-4-methyi-5-( I -methyl-7-(methyIamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-
yl)phenyl)urea, l-(4-tert-butyl-3-methyUhiophen-2-yl)-3-(2-fiuoro-5-(l-(2-hydroxyethyl)-7-
(methylamino)-2-oxo-l,2-dihydro-l,6-naphthyridin-3-yl)-4-methylphenyI)urea} 1-(1-tert-butyl-
2-metliyI-lH-pyrrol-3-yl)-3-(2-fluoro-4-methyl-5-(l-methyl-7-(mediylamino)-2-oxo-l,2-
dihydro-l,6-naphthyridin-3-yl)pheivyl)urea, l-(l-tert-butyl-2-methyl-lH-pyrrol-3-yl)-3-(4-
chloro-2-fluoro-5-(l-methyl-7-(methylamino)-2-oxo-l,2-diliydro-l,6-iiaphthyridin-3-
yl)phenyl)urea, l-(l-tert-butyl-2-methyl-lH-pyrrol-3-yl)-3-(2,4-difluoro-5-(l-methyl-7-
(methylaminoj^-oxo-l^-dihydro-l^-naphthyridin^-yljphenyljurea, l-(l-tert-butyl~2-methyl-
lH-pyrrol-3-yl)-3-(5-(l -ethyl-7-(methylamino)-2-oxo-l ,2-dihydro-l ,6-naphthyridin-3-yl)-2-
fluoro-4-methylphenyl)urea, 1 -(1 -tert-butyl-2-methyl-l H-pyrrol-3-yl)-3-{5-( 1 -ethyl-7-
Craethylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyI)urea, 1 -(1 -tert-butyl-
1 H-pyrrol-3-yI)-3-(2-fluoro-4-methyI-5-( 1 -methyl-7-(rnethylamino)-2-oxo-1,2-dihydro-1,6-
naphUi>Tidin-3-yl)phenyl)urea, l-(l-tcrt-butyl-4-chloro-lH-pyrrol-3-yl)-3-(2-fluoro-4-methyl-5-
(l-methyl-7-(methylarnino)-2-oxo-l,2-dihydro-I,6-naphthyridin-3-yl)phenyl)urea) l-(4-tert-
butyf-l-rnethyI-lH-pyrro]-2-yI)-3-(2-fluoro-4-methyl-5-(l-methyJ-7-(methyJamino)-2-oxo-],2-
dihydro-1,6-naphthyridin-3-yl)phenyl)urea, 1 -(4-tert-buryl-I -methyl-lH-pyrroI-2-yl)-3-(5-{l -
etliyl-7-(methylamino)-2-oxo-l ,2-dihydro-l ,6-naphthyridin-3-yl)-2-fluoropbenyl)urea. 1 -(4-tert-
butyl-3-chloro-l-met!iyl-lH-pyiTol-2-yI)-3-(2-fluoro-4-rnetliyl-5-(l-aiethyl-7-(methylarnino)-2-
oxo-1,2-dihydro-1,6-naphthyridin-3-yI)phenyI)urea, 1 -(3-tert-butyl-l -methyl-1 H-pyrazol-5-yl)-
3-(2-fluoro-5-(l-isopropyl-7-(methylamino)-2-oxo-l,2-dihydro-lJ6-naphthyridin-3-yl)-4-
methylphenyl)urea, l-(2-tert-butyloxazol-5-yl)-3-(2-fluoro-4-methyl-5-(l-methyI-7-
(methylamino)-2-oxo-l,2-dihydro-l,6-naphthyridin-3-yl)phenyl)urea, l-(2-tert-butyloxazoI-5-
yl)-3-(4-chloro-2-fluoro-5-(l-methyl-7-(methylamino)-2-oxo-l,2-dihydro-l,6-naphthyridin-3-
yl)phenyl)urea, l-(2-tert-butyloxazol-5-yl)-3-(5-(l-ethyl-7-(metliylamino)-2-oxo-l,2-dihydro-
l,6-naphthyridin-3-yl)-2-fluorophenyl)urea, !-(2-tert-butyloxazol-5-yl)-3-(2-fiuoro-5-(l-(2-
hydroxyediyl)-7-(meUaylamino)-2-oxo-l,2-dihydro-l,6-naphthyridin-3-yl)-4-methylphenyl)urea) l-(2-tert-butyloxazol-5-y])-3-(4-chioro-2-fluoro-5-(l-{2-hydroxyethyl)-7-(merhy!amino)-2-oxo-1.2-dihydro-l,6-naphthyridin-3-yl)phenyl)urea, l-(5-tert-butylisoxazoI-3-yI)-3-(2-fluoro-5-(l-(2-

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hyfroxyethyl)-7-(methylammo)-2-oxo-1,2-dity
1 -(5-tert-butyl-4-methylisoxazol-3-yl)-3- naphthyridin-3-yl)-2-fluoro-4-methylphenyl)urea, l-(4-tert-butylfuran-2-y])--3-(2-fluoro-4-
methyI-5-(l -methyI-7-(methylamino)-2-oxo-1,2-dihydro-1 ^-naphthyridin-S-ylJphenylJurea, I -(4-tert-butyl-3 -chIororuran-2-yl)-3 -(2-fluoro~4~methyl-5 ~(1 -methyl-7-(methylamino)-2-oxo-1,2-dihydro-l,6-naphmyridin-3-yl)phenyl)urea, l-(4-tert-butyl-3-fluorofuran-2-yl)-3-(2-fluoro-4-methyl-5-(l-me±yl-7-(methyIaniino)-2-oxo-l,2-dihydro-l,6-iiaplithyridin-3-yI)phenyl)ure£i, 1-(4-tert-butyl-3-methylfuran-2-yl}-3^
dihydro-l,6-naplithyridiii-3-yl)-4-methylphenyl)urea, l-cyclopropyl-3-{2-fluoro-4-methyl-5-(l-
methyl-7-(methyIamino)-2--oxo-l,2-dihydro-l,6-naphthyridin-3-yl)pheDyl)urea, l-(2-fluoro-4-
methyl-5-(l-methyl-7-(methylamino)-2-oxo-l,2-dihydro-lt6-naphthyridin-3-yl)phenyl)--3~
isopropylurea, (R)-1 -(2-ff uoro-4-methyl-5-(l -methyl-7-(methyl amino)-2-oxo-1,2-dihydro-1,6-
naphmyridin-3-yI)phenyl)-3-(l-phenylethyl)urea, l-(2-fluoro-4-mcthyl-5-(l-methyI-7~
(methylamino)-2-oxo-l ,2-dihydro-l J6-naphthyridin~3-yl)phenyl)-3-(l -(pyridin-3-yl)ethyl)urea,
1 -(5-(l -cyclopentyl-7-(methylamirio)-2-oxo-] ,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoro-4-
methyiphenyl)-3-isopropylurea, 1 -(2-fluoro-5-(l -((3R)-3-hydroxycycIopentyI)-7-(methylammo)-
2-oxo-I,2-dihydro-l,6-naphthyridin-3-yl)-4-methylphenyl)-3-isopropylurea) l-(2-fluoro-4-
metliyI-5-(l-methyl-7-(methylamino)-2-oxo-l,2-dihydro-l,6-naphthyridm-3-yl)phenyl)-3-(5-
(trifmoromethyl)pyridin-3-yl)urea, l-(2-fluoro-4-methyl-5-(l-methyl-7-(methylamino)-2-oxo-
l,2-dihydro-l,6-naphthyridm-3-yl)phenyl)-3-(4-methyl-5-((TifluoromethyI)pyridin-3-yl)urea, J-
(2,4-difluoro-5-(l-methyl-7-(metliylamino)-2-oxo-l,2-dihydro-l,6-naphthyridin-3-yl)phenyl)-3-
(5-(trifluoromethyl)pyridin-3-yl)urea. l-(5-(l-ethyl-7~(methylamino)-2-oxo-l,2-dihydro-1.6-
naphthyridin-3-yl)-2-tluorophenyl)-3-(5-(trifluoromethyl)pyridin-3--yl)urea, 1-(2-fluoro-4-
methyl-5-(l-methyl-7"(methylamino)-2-oxo-l,2-dihydro-l,6-naphthyridin-3-yl)phenyl)-3-(4-
fluoro-5-(trifluoromethyl)pyridin-3-yl)urea, l-(4-chloro-2-fluoro-5-(l-methyl-7-(memy]amino)-
2-oxo-l, 2-dihydro-l,6-napht^yridin-3-yl)pheayl)-3-(5-(trifluoromethyl)pyridiii-3-yI)urea, l-(2-
fluoro-5-(l -(2-hydroxyethyl)-7-(memylamino)-2-oxo-l ,2-dihydro-l ,6-naphthyridin-3-
yl)phenyl)-3-(5-(trifluoromemyl)pyridin-3-yl)urea, l-(5-(7-amino-l-methyl-2-oxo-l,2-dihydro-
1,6-naphtl-iyridin-3-yl)-2-fluoro-4-methylphenyl)-3-(3-(trifluoromethyl)phenyl)urea, 1 -(2-fluoro-
5-(l-(2-hydroxyetliyl)-7-(methylamino)-2-oxo-l52-dihydro-lI6-naphthyridin-3-yl)-4-
methylphenyl)-3-(3-(triffuarornethyl)phenyI)urea, J-(2-fluoro-4-metliyl-5-(l-methyl-7-

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(methylamino)-2-oxo-l,2-dihydro-l,6-naphthyridin-3-yl)phenyl)"3-(2-fIuoro-5-
(trifluoromethyl)phenyl)urea, 1 -(2-fluoro-5-( 1 -(2-hydroxyethyI )-7-(methylamino)-2-oxo-1,2-
dihydro-1,6-naphthyridin-3-yI)-4-methylphenyl)-3-(2"fluoro-5-(trifluoromethyl)pheny])ureaT 1 -
(2-fluoro-5-(l-(2-hydroxyethyl)-7-(methylamino)-2-oxo-l,2-dihydro-l,6-naphthyridin-3-
yl)phenyl)-3-(2-fluoro-5-(trifluoromethyl)phenyl)ureaJ l-(l-tert-butyl-5-(hydroxymetliyI)-lH-
pyrazol-4-yl)-3-(4-chloro-2-fluoro-5-(I--methyI-7-(methylamino)-2-oxo-l,2-dihydro-l,6-
naphthyridin-3~yl)phenyl)i]rea, l-(l-tert-butyl-5-(hydroxyinethyl)-lH-pyrazoI-4-yl)-3-(2-fluoro-
4-methyl-5-( 1 -methyI-7-(methyIamino}-2-oxo-1 ,2-dihydro-1,6-naphthyridin-3-yl)pheny I)urea, I -
(l4ert-butyI-5-(hydroxymelhyl)-lH-pyrazol^yl)-3-(2,4-difluoro-5-(l-metliyl-7-(me(hylamiiio)-
2-oxo-1,2-dihydro-1,6-naphthyridin-3-yI)phenyl)urea, 1 -(1 -tert-butyl-5-( 1 -hydroxyethyl)-1H-
pyrazol-4-yl)-3-(4-chloro-2-fluoro-5-(l-methyl-7-(metliylamino}-2-oxo-],2-dihydro-1.6-
naphthyridin-3-yl)phenyl)urea, l-(l-tert-butyl-5-(l-hydroxyethyl)-lH-pyrazol-4-yl)-3-(2-fluoro-
4-metiiyl-5-(l-methyl-7-(methylainino)-2-oxo-I,2-dihydro-l,6-naphthyridin-3-yl)phenyl)iirea, 1-
(l-tert-butyl-5-(l-hydroxyethyl)-IH-pyrazol-4-yl)-3-(2J4-difluoro-5-(l-methyl-7-(Tnetliylamino)-
2-oxo-l,2-dihydro-l,6-naphtiiyridin-3-yl)phenyl)urea, l-(Mert-butyl-5-ethyi-lH-pyrazoI-4-yl)-
3-(4-chloro-2-fluoro-5-( 1 -methyl-7-(methylamino)-2-oxo-1,2-dihydro-l ,6-naphthyridiiv-3-
yl)phenyl)urea, I-(l-tert-butyl-5-ethyl-lH-pyrazol-4-yl)-3-(2-fluoro-4-methyI-5-(l-methyl-7-
(methylamino)-2-oxo-l,2-dihydro-lT6-naphthyridin~3-yl)phenyl)urea, l-(l-tert-butyl-5-etfryl-lH-
pyrazoI-4-yl)-3-(2,4-difluoro-5-( 1 -methyl-7-(methyIamino)-2-oxo-l ,2-dihydro-1,6-naphthyridin-
3-yl)phenyl)urea, 1 -(1 -tert-butyI-5-methyl-1 H-pyrazoI-4-yI)-3-(2-fluoro-4-methyl-5-( I -methyl-
7-(methylamino)-2-oxo-l,2-dihydro-lf6-naphthyridin-3-yl)phenyl)ureaT 1 -(1 -tert-butyl -5-
methyl-1 H-pyrazol-4-yl)-3-(4-chloro-2-fluoro-5-( 1 -methyl-7-(methylamino)-2-oxo-l ,2-dihydro-
l^-naphthyridin-S-yOpheny^urea, l-(l-tert-butyl-5-methyl-lH-pyrazol-4-yl)-3-(2,4-difluoro-5-
(1 -methyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)phenyl)urea, 1 -cyclohexyl-
3-(2-fluoro-4-methyl-5-(l-mediyl"7-(mediylaiiiiiio)-2-oxo-l)2-dihydro-l,6-naphthyridin-3-
yl)phenyl)urea, l-cyclohexyl-3-(5-(l-ethyl-7-(methylamino)-2-oxo-l,2-dihydro-l,6-
naphthyridin-3-yl)-2-fluoro-4-mediylphenyl)urea, l-cyclohexyl-3-(2-fiuoro-5-(l-isopropy3-7-
(methylamino)-2-oxo-],2-dihydro-l,6-naphthyridin-3-yl)-4-methylphenyl)ureaJ I-cyclohexyl-3-
(2-fluoro-5-(l-isopropyl-7-(methylamino)-2-oxo-l,2-dihydro-l,6-naphthyridin-3-yI)phenyl)urea,
1 -cyclohexyl-3-(5-(l-cyclopentyl-7-(methylamino)-2-oxo-1,2-dihydro-l ,6-naphthyridm-3-yl)-2-
fluorophenyl)urea. 1 -cyclohexyI-3 -(5-( 1 -ethyl-7-(methy] amino)-2-oxo-1,2-dihydro-1,6-

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naphthyridin-3-yl)-2-fluorophenyl)urea, l-cyclohexy]-3-(2-fluoro-5-(H(3R)-3-
hydroxycyclopcntyl)-7-(methylamino)-2-oxo-l ,2-dihydro-t ,6-naplithyridin-3-yl)phenyl)urea, 1 -
cyclohexyl-3-(2-fluoro-5-(l-((3R)-3-hydroxyi;yclopentyl)-7-(melhylamino)-2-oxo-l,2-dthydro-
l,6-naphthyridin-3-yl)-4-methylphenyl)urea, l-cyclohexyl-3-(2-fluoro-5-(l-(l-hydroxypropan-2-
yl)-7-(methylamino)-2-oxo-l,2-dihydro-l,6-naphtfajTidin-3-yl)phenyI)urea, l-(4-chloro-2-fluoro-
5-(l-metiiyl-7-(metliylamino)-2-oxo-l,2-dihydro-l,6-naphthyridin-3-yl)phenyl)-3-
cyclohexylurea, l-cyclohexyl-3-(214-dif]uoro-5-(l-methyl-7-(methylamino)-2-oxo-K2-dihydro-
I,6-naphthyridin-3-yI)phenyI)urea, I-(4-cyano-2-fluoro-5-(I-methyI-7-(memyIamino)-2-oxo-
1,2-dihydro-1,6-naphthyridin-3-yl)phenyl)-3-cyclohexylurea, I -(2-fluoro-4-methyl-5-( 1 -methyl-
7-(methylarnino)~2-oxo-l ,2-dihydro-l ,6-naphthyridin-3-yI)phenyl)-3-((l R,2R)-2-
methylcyelohexyl)urea, l-(2"fluoro-4-methyl-5-(l-metiiyl-7-(inetliylamino)-2-oxo-l,2-dihydro-
l)6-naphthyridin-3-yl}phenyl)-3-((lS12S)-2-methylcyclohexyl)urea, l-(2-fluoro-4-metliyI~5-(l-
raethyl-7-(metiiylamino)-2-oxo-l,2-dihydro-l>6-naphthyridin-3-yl)phenyl)-3-((lr;,4r)-4-
methyl cyc!ohexyl)urea, l-(3-tert-butylisoxazol-5-yl)-3-(5-(l-cyclopentyl-7-(methylamino)-2-
oxo-l,2-dihydro-l,6-naphthyridin-3-yl)~2-fluorophenyl)urea, l-(3-cyclopentylisoxazol-5-yI)-3-
(2-fluoro-4-methyl-5-(l-niethyl-7--(methylamino)-2-oxo-lT2-dihydro-l,6"naphthyridin-3-
yl)phenyl)urea, 1 -(5-{7-amino-l -ethyI-2-oxo~ 1,2-dihydro-156-naphthyridin-3-yl)-2-
fluorophenyl)~3~(3-tert-butylisoxazol-5-yl)urea, 1 -(5-(7-amino-l -ethyl-2-oxo-l ,2-dihydro-l ,6-
naphthyridin-3-yl)-2"fluoTO-4-methylphenyl)~3-(3-tert-butylisoxazol-5-yi)urea) I-(3-tert-
butylisoxazol-5-yl)-3-(4-chloro-2-fluoro-5"(l-(2-hydroxyethyl)~7"(methyIamino)-2-oxo-1.2-
dihydro-lJ6-naphthyridin-3-yl)phenyl)urea, l-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-5-(l-(2-
hydroxyethyl)-7-(methylamino)-2-oxo-l,2Uiydro-l)6-naphtiiyridin"3-yl)-4-inethylphenyl)urea,
1 -(2-f]uoro-4-methyI-5-(l -methyI-7-(methylamino)-2-oxo-l,2-dihydro-1,6-naphthyridin-3-
yl)phenyl)-3-(3-isopropylisoxazoI-5-y])urea, 1 -(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-5-( 1 -
isopropyl-7-(methylainino)-2-oxo-l ,2-dihydro-l,6-naphthyridin-3-yl)-4-metliylphenyl)urea, 1-
(3-tert-butyIisoxazol-5-yl)-3-(2-fluoro-5-(l-C2-hydroxyethyl)-7-(niethylamino)-2-oxo-l,2-
dihydro-1,6-naphthyridin-3-yl}phenyl)urea, 1 -(5-(7-amino-l -metiiyl-2-oxo-1,2-dihydro-1,6-
naphthyridin-3-yl)-2-fluoro-4-methylphenyl)-3-(3-tert-butylisoxazol-5-yI)urea, l-(3-
cyclopentyHsoxa2ol-5-yl)-3-(2-fluoro-5-(l-(2-hydroxyethyl)-7-(methyIamino)-2-oxo-l,2-dihydro-l^-naphthyridin^-yl^-methylphenyljurea, l-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-5-(I-(2-hydroxyethyl)-7"(methylamino)-2-oxo-l^-dihydro-l,6-naphthyridin-3-yl)-4-

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methylphenyl)urea, l-(3-tert-butylisoxazoi-5-yl)-3-(2-fluoro-5-(l-(2-hydroxyetliyl)-7-
(methylamino)-2-oxo-l,2-dihydro-l,6-naphthyridin-3-yl)phenyl)urea, l-(3-tert-butylisoxazol-5-
yl)-3-(2~fluorO"5-(l-((3R)-3-hydroxycydopentyl)-7-(niethyIaiTiino)-2-oxo-l)2-dihydro-l,6-
naphthTidin-3-yl)-4-metliyIphenyi)urea, l-(3-tert-butyIisoxazol-5-yl)-3-(2-flooro»5-(I-((3R)-3-
hydroxycyclopentyl)-7-(methylamino}-2 -oxo-1,2-dihydro-l,6-naphthyridin-3-yI)phenyl)urea, 1-
(3-tert-butyl^-raethyHsoxazol-5-yl)-3-(2-fluoro^-methyl-5-(l-methyl-7-(methylainino)-2-oxo--
l,2-dihydro-l,6-naphthyridin-3-yl)phenyl)urea, l-(3-tert-buty]-4-chloroisoxazol-5-yl)-3-(2-
fluoro-4-methyl-5-(l-methyI-7-(methylamino)-2-oxo-l,2-dihydro-lt6-naphthyridin-3-
yl)phenyl)urea, l-(3-lert-butyl»4-fluoroisoxazol-5-yl)-3-{2-fluoro-4-methyl-5-(l-metliyl-7-
(methylamino)-2-oxo-l,2-dihydro-l,6-naphthyridin-3-yl)phenyl)urea, l-(3-tert-butyI-4-
methylisoxazol-5-yl)-3-(2-fIuoro-5-(l-(2-hydroxyethyl)-7-(i-nethylamino)"2-oxo-i,2-dihydro-
l,6-naphthyridin-3-yl)-4-methylphenyl)urea, l-(3-tcrt-butyl-4-chloroisoxazol-5-yl)-3-(2-fluoro-
5-(l-(2-hydroxyethyl)-7-(methylamino)"2"OXO-l,2-diliydro~l,6-naphthyridin-3-yl)"4-
metliylphenyl)urea, 1 -(3-tert-butyl-4-fluoroisoxazol-5~yl)-3-(2-fluoro-5-( I -(2-hydroxyethyl)-7-
(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-4-methylphenyl)urea, 1 -(5-tert-butyl-
l,3T4-tliiadiazol-2-yI)-3-(4-chloro-2-flLioro-5-(l-methyl-7-(methyIamino)-2-oxo-1)2-dihydro-l,6-
naphtliyridin-3-yl)phenyl)urea, l-(5-tert-butyl-l,3,4-tliiadiazoI-2-y!)-3-(5-(l-ethyl-7-
(methylamino)-2-oxo-l ,2-dihydro-1,6-naphthyridin-3-yl)-2-fIuorophenyl)urea, 1 -(5-tert-butyI-
13,4-tliiadiazol-2-yl)-3-(2-fluoro-5-(1-(2-hydroxyetliyi)-7-(methylamino)-2-oxo-l)2-dihydro-
l,6-naphtiiyridin-3-yl)phenyl)urea, l-(5-tert-butyl-l,3,4-tliiadiazol-2-yl)-3-(2-fluoro-5-(l-(2-
hydroxyetliyl)-7-(methylamino)-2-oxo-l,2-dihydro-l,6-naphthyridin-3-yl)-4-methylphenyl)urea,
l-(5-tert-butyl-l,3;4-thiadiazol-2-yI)02,4-difiuoro-5-(l-(2-hydroxyetliyl)-7-(raetliylarnino)--2-
oxo-1,2-dihydro-l,6-naphthyridin-3-yl)phenyi)urea, l-(l-tert-butyl-5-methyl-lH-imidazol-4-yI)-
3-(2-fluoro-4-methyl-5-( I -metiiyl-7-(methylamino)-2-oxo-l ,2-dihydro-l ,6-naphthyridin-3-
yl)phenyl)urea, 1 -(1 -tert-butyl-5-chloro-l H-imidazol-4-yl)-3-(2-fluoro-4-methyl-5-( 1 -methyl-7-
(methylamfno)-2-oxo-i,2-drhydro-l,6-naphtliyridin-3-yJ)plienyI)urea, l-(I-tert-butyl-5-fiuoro-
IH-imidazol-4-yl)-3-(2-fluoro-4-methyl-5-(l-methyl-7-(methylamino)-2-oxo-l ,2-dihydro-l, 6-
naphthyridin-3-yI)phenyl)urea, l-(I-tert-butyI-5-metliyl-lH-imidazol-4-yl)-3-(5-(l-ethyl-7-
(methyIamino)-2-oxo-l ,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoro-4-methylphenyl)urea1 1 -(1 -tert-butyl-5-methyl-lH-imidazol-4-yl)-3"(5-(I-ethyl-7-(metliylamino)-2-oxo-l ,2-dihydro-l, 6-naphthyridin-3-yl)-2-fiuorophenyl)urea, and 1 -(1 -tert-butyl-5-methyl-l H-imidazol-4-yl)-3-(2-

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fluoro-5-(l -(2-hydroxyethyl)-7-(methylamino)-2-oxo-l ,2-dihydro-l ,6-naphthyridin-3-yl)phenyl)urea.
B-Raf(V600E) Kinase Assay: The activity of B-Raf(V600E) kinase was determined by following the formation of ADP from the reaction through coupling with the pyruvate kinase/lactate dehydrogenase system (e.g., Schindler, et al. Science (2000) 289, 1938-1942). In this assay, the oxidation of NADH (thus the decrease at Ajnm) was continuously monitored spectrophotometrically. The reaction mixture (100 ul) contained B-Raf(V600E) kinase (2.1 nM nominal concentration), unphosphoryteted, faV-}ength MEK1 (45 nM), MgC)2 (13 mM), pyruvate kinase (3.5 units), lactate dehydrogenase (5.5 units), phosphoenolpyruvate (1 mM), and NADH (0.28 mM), in 60 mM Tris buffer, containing 0.13% octyl-glucoside and 3.5 % DMSO concentration at pH 7.5. The test compounds were incubated with the reaction mixture at 30 °C for 2h or 4h. The reaction was initiated by adding ATP (0.2 mM, final concentration). The absorption at 340 nm was continuously monitored for 3h at 30 °C on a Polarstar Optima plate reader (BMG). The reaction rate was calculated using the 1.5h to 2.5h time frame. Percent inhibition was obtained by comparison of reaction rate with that of a control (i.e. with no test compound). IC5o values were calculated from a series of percent inhibition values determined at a range of inhibitor concentrations using software routines as implemented in the GraphPad Prism software package.
B-Raf(V600E) protein sequence used for screening:
EDRNRMKTLGRRDSSDr^tfEIPDGQITVGQM
GVLRKTRHVNILLFMG Y STKPQLAIVTQWCEG S SLYHHLHIIETKFEMIKLIDIARQTAQGMD YXHAKSI
!HRI)LKSI^IFLHEDLTVKIGrjFGLATEKSRWSGSHQFEQLSGSILWMAPEVIRMQDKNPYSFQSDVYAP
GlVLYELl^GQLPYSNINNRDQIIFMVGRGYLSPDL^
SIELLARSLPKIHR (SEQ. ID NO. 1}
MEK1 protein sequence used for screening:
IffiLKDDDFEKISELGAGNGGVVFKVSHKPSGLVMARKLIHLEIKPAIRNQIIRELQVLHECNSPYrVGFYG AFYSlX3EISICMEHMIXrcSU3QVXKKAGRIPEQ^
EIKLCDFGVSGQLIDSMANSFVGTRSYMSPERLOGTHYSVQSDIWSMGLSLVEMAVGRYPIPPPDAKELEL MFGCQVEGDAAETPPRPRT PGRPL S S YGMDSRPPMAI FEIJLDYIVNEPPPKLP SGVFSLEFQOFVNKC LIK 2&AERADLKQLMVHAFIKRSmEEVDFAGWLCSTIGLNQPSTPTHAAGV (SEQ. ID NO. 2)
C-Raf Kinase Assay: The activity of C-Raf kinase was determined by following the formation of ADP from the reaction through coupling with the pyruvate kinase/lactate dehydrogenase system (e.g., Schindler, et a!. Science (2000) 289, 1938-1942). hi this assay, the oxidation of

WO 2008/034008

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NADH (thus die decrease at Aonm) was continuously monitored spectrophotometrically. The reaction mixture (100 ul) contained C-Raf kinase (0.28 nM nominal concentration, available from Upstate, catalogue #14-352), unphosphorylated, full-length MEK1 (27 nM), MgCl2 (13 mM), pyruvate kinase (3,5 units), lactate dehydrogenase (5.5 units), phosphoenolpyruvate (1 mM), and NADH (0,28 mM), in 60 mM Tris buffer, containing 0.13% octyl-glucoside and 3.5 % DMSO concentration at pH 7.5. The test compounds were incubated with the reaction mixture at 30 DC for 2h or 4h. The reaction was initiated by adding ATP (0.2 mM, final concentration). The absorption at 340 nm was continuously monitored for 3h at 30 °C on a Polarstar Optima plate reader (BMG). The reaction rate was calculated using the l.Oh to 2.0h time frame. Percent inhibition was obtained by comparison of reaction rate with that of a control (i.e. with no test compound). ICso values were calculated from a series of percent inhibition values determined at a range of inhibitor concentrations using software routines as implemented in the GraphPad Prism software package.
In general, compounds 1-325 disclosed herein had > 50% inhibition activity at 0.2-2 uM concentration against V600E BRaf and CRaf kinases utilizing the above assay conditions.
Cell Culture: A-375 cells were obtained from American Type Culture Collection (Rockville, MD). Briefly, cells were grown in Dulbecco's Modified Eagle Medium with 4.5 g/L glucose, 6mM L-glutamine, and 10% certified fetal bovine serum (Invitrogen, Carlsbad, CA) at 37 degrees Celsius, 5% C02, 95% humidity. Cells were allowed to expand until reaching 80% confluency at which point they were subcultured or harvested for assay use.
Cell Proliferation Assav: A serial dilution of test compound was dispensed into a 96 well black clear bottom plate (Corning, Corning, NY). Five thousand cells (A375) were then added to each well in growth medium. Plates were incubated lor 72 hours at 37 degrees Celsius, 5% C02.95% humidity. At the end of the incubation period Cell Titer Blue (Promega, Madison, WI) was added to each well and an additional 4.5 hour incubation at 37 degrees Celsius, 5% C02, 95% humidity was performed. Plates were then read on a BMG Fluostar Optima (BMG, Durham. NC) using an excitation of 544 nM and an emission of 612 nM. Data was analyzed using Prism software (Graphpad, San Diego, CA) to calculate IC55 values.

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In general, compounds 1-325 disclosed herein had > 50% inhibition activity at 1-10 uM concentration against A375 cells utilizing the above assay conditions.
All references mentioned or referred to herein are incorporated by reference into this disclosure.

PCTUS2007078408-*eql-O00001-EN-20()70913 raw
SEQUENCE LISTING DECIPHERA PHARMACEUTICALS, LLC
Flynn, Daniel L Petillo, Peter A Kaufman, Michael D Patt, William C
NEW CYCLIC PYRIDONES FOR THE TREATMENT OF CANCERS AND PROLIFERATIVE DISEASES
38514-PCT
PCTUS0778408 2007-09-13
US 60/844,552 2006-09-14
2
Patentin version 3.3
1
294
PRT
Homo sapiens

MISC_FEATURE
B-Raf(v600E)
1
Glu Asp Arg Asn Arg Met Lys Thr Leu Gly Arg Arg Asp Ser ser ASD
1 5 10 15
Asp Trp Glu lie Pro Asp Gly Gin lie Thr val Gly Gin Arq j-|e Gly
20 25 3o
Ser Gly Ser Phe Gly Thr val Tyr Lys Gly Lys Trp His G,"iv ASD val
35 40 45
Ala val Lys Met Leu Asn val Thr Ala Pro Thr Pro Gin Gin Leu Gin
50 55 60
Ala Phe Lys Asn Glu val Gly val Leu Arg Lys Thr Arg H-js Val Asn
65 70 75 80
lie Leu Leu Phe Met Gly Tyr Ser Thr Lys Pro Gin Leu A,ia x~\e val
85 90 95
Thr Gin Trp Cys Glu Gly Ser Ser Leu Tyr His His Leu H-JS ne iie
100 105 lio
Glu Thr Lys Phe Glu Met lie Lys Leu lie Asp lie Ala Arq Gin Thr
115 120 125
Ala Gin Gly Met Asp Tyr Leu His Ala Lys Ser lie lie H-,-s Arg Asp
Page 1



PCTUS2007078408-seql-000001-EN-20070913.raw
50 55 60
Tyr lie Val Gly Phe Tyr Gly Ala Phe Tyr Ser Asp Gly Glu lie Ser
65 70 75 80
lie Cys Met Glu His Met Asp Gly Gly Ser Leu Asp Gin Val Leu Lys
85 90 95
Lys Ala Gly Arg lie Pro Glu Gin lie Leu Gly Lys val Ser lie Ala
100 105 110
val lie Lys Gly Leu Thr Tyr Leu Arg Glu Lys His Lys lie Met His
115 120 125
Arg Asp Val Lys Pro ser Asn lie Leu val Asn Ser Arg Gly Glu He
130 135 140
Lys Leu Cys Asp Phe Gly Val ser Gly Gin Leu lie Asp Ser Met Ala
145 150 155 160
Asn ser Phe Val Gly Thr Arg ser Tyr Met Ser Pro Glu Arg Leu Gin
165 170 175
Gly Thr His Tyr Ser Val Gin Ser Asp lie Trp Ser Met Gly Leu Ser
180 185 190
Leu val Glu Met Ala Val Gly Arg Tyr Pro lie Pro Pro Pro Asp Ala
195 200 205
Lys Glu Leu Glu Leu Met phe Gly Cys Gin val Glu Gly Asp Ala Ala
210 215 220
Glu Thr Pro Pro Arg Pro Arg Thr Pro Gly Arg Pro Leu Ser Ser Tyr
225 230 235 240
Gly Met Asp Ser Arg Pro Pro Met Ala lie Phe Glu Leu Leu Asp Tyr
245 250 255
lie Val Asn Glu Pro Pro Pro Lys Leu Pro Ser Gly Val Phe Ser Leu
260 265 270
Glu Phe Gin Asp Phe val Asn Lys Cys Leu lie LysAsn Pro Ala Glu
275 280 285
Arg Ala Asp Leu Lys Gin Leu Met val His Ala Phe lie Lys Arg Ser
290 295 300
Asp Ala Glu Glu val Asp Phe Ala Gly Trp Leu Cys Ser Thr lie Gly
305 310 315 320
Leu Asn Gin Pro Ser Thr Pro Thr His Ala Ala Gly val
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325 330


i. compounds or tne torrnuia la
9 (R16), Z6
R3 R3 1 II J
O^N^fT^ZG
wherein El is selected from the group consisting cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl piperidinyl, phenyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, pyrrolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, fiiryl, imidazolyl, pyridyl, pyrimidinyl and naphtliyl;
wherein A is selected from the group consisting of phenyl, naphthyl, C3-C8carbocyclyl, indanyl, tetralinyl, indenyl, Gl, G2, G3, G4 and -CHR4R8;
Gl is a heteroaryl taken from the group consisting of pyrrolyl, fiiryl, thienyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyrazinyl, pyridazinyl, triazinyl, pyridinyl, and pyrimidinyl;
G2 is a fused bicyclic heteroaryl taken from the group consisting of indolyl, indolinyl, isoindolyl,
isoindolinyl, indazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzothiazolonyl,
benzoxazolyl, benzoxazolonyl, benzis oxazolyl, bcnzisothiazolyl, benzimidazolyl,
benzimidazolonyl, benztriazolyl, imidazopyridinyl, pyrazolopyridinyl, imidazoJonopyridinyJ,
thiazolopyridinyl, thiazolonopyridinyl, oxazolopyridinyl, oxazolonopyridinyl,
isoxazolopyridinyl, isothiazolopyridinyl, triazolopyridinyl, imidazopyrimidinyl,
pyrazolopyrimidinyl, imidazolonopyrimidinylT thiazolopyridiminyl, thiazolonopyrimidinyl, oxazolopyridiminyl, oxazolonopyrimidinyl, isoxazolopyrimidinyl, isothiazolopyrimidinyl, triazolopyrimidinyl, dihydropurinonyl, pyrrol opyrimidinyl, purinyl, pyrazolopyrimidinyl, phthalimidyl, phthalimidinyl, pyrazinylpyridinyl, pyridinopyrimidinyl, pyrimidinopyrimidinyl, cinnolinyl, quinoxalinyl, quinazolinyl, quinolinyl, isoquinolinyl, phthalazinyl, benzodioxyl, benzisothiazoline-l,l,3-trionyl, dihydroquinolinyl, tetrahydroquinolinyl, dihydroisoquinolyl, tetrahydroisoquinolinyl, benzoazepinyl, benzodiazepinyl, benzoxapmyl, and benzoxazepinyl;

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G3 is a non-fused bicyclic heteroaryl taken from the group consisting of pyridyipyridiminyl
pyrimidinj'lpyrimidinyl, oxazolylpyrimidinyl, thiazolylpyrimidinyl, imidazolylpyrimidinyl,
isoxazolylpyrimidinyl, isothiazolylpyrimidinyl, pyrazolylpyrimidinyl, triazolylpyrimidinyl,
oxadiazoylpyrimidinyl, thiadiazoyipyrimidinyl, morpholinylpyrimidinyl,
dioxothiomorpholinylpyrimidinyl, and thiomorpholinylpyrimidinyl;
G4 is a heterocyclyl taken from the group consisting of oxetanyl, azetadinyl, tetrahydrofuranyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, imidazolonyl, pyranyl, thiopyranyl, tetrahydropyranyl, dioxalinyl, piperidinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S-dioxide, piperazinyl, azepinyl, oxepinyl, diazepinyl, tropanyl, and homorropanyl;
the A ring may be optionally substituted with one or more-XI-Al moieties;
XI is selected from the group consisting of -(CH2)n-(0)r-(CH2)n-, -(CH2)n-(NR3)r-(CH2)n-, -(CH2)I,-(S)r(CH2)n-, -(CH2MC=OMCH2)n-, -(CH2)n-(C(=0)-NR3)r(CH2)ll-s and -(CH2)n-(S02-NR3V(CH2)lr, wherein any of the alkylenes may be straight or branched chain;
X2 is selected from the group consisting of CI -C6alkyl, branched C2-C6alkyl, and a direct bond wherein El is directly linked to the NR3 group of formula la;
Al is selected from the group consisting of hydrogen, aryi, Gl, G2, G3, G4, CI-C6 alkyl, branched C3-C8alkyl, Rl 9 substituted C3-C8carbocyclyl, fluoroCl-C6alkyl wherein the alkyl is fully or partially fluorinated, halogen, cyano, hydroxyl, -N(R4)2; -R5, -C(0)N(R4)2, C(0)R5, Cl-C6alkoxy, and fluoroCI-C6alkoxy wherein the alkyl group is fully or partially fluorinated:
When A and Al have one or more substitutable sp2-hybridized carbon atom, each respective sp2 hybridized carbon atom may be optionally substituted with a Zl or 23 substituent;
when A and Al have one or more substitutable sp3-hybridized carbon atom, each respective sp3 hybridized carbon atom may be optionally substituted with a Z2 or R3 substituent;

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when A and Al have one or more substitutable nitrogen atom, each respective nitrogen atom may be optionally substituted with a Z4 substituent;
each Zl is independently and individually selected from the group consisting of hydrogen, hydroxyCl-C6alkyl, Cl-C6alkoxy, Cl~C6alkoxyCI-C6alkyI, (R4)2NC1-C6alkyl, (R4)2NC2-C6alkylN(R4)-(CH2)nj (R4)2NC2-C6alkylO-(CH2)n, (R3)2N-C(=0)-, (R4)2N-C(=0)-, (R4)2N-CO-C1 -CfialkyK CI -C6alkoxycarbonyl-, -carboxyCl -C6alkyl, C1 -C6alkoxycarbonylCl -CGalkyl, (R3)2NS02-, -SOR3, (R4)2NS02-, -S02R3, -SOR4, -C(=0)R6, -C(=NOH)R6, -C(=NOR3)R6, -(CH2)0N(R4)C(O)R8, -(CH2)n-Gl, -(CH2)„-G4, phenoxy, -(CH2)n-0-(CH2)n-G 1, -(CH2)n-0-(CH2)n-G4J - in the event that Zl contains an alkyl or alkylene moiety, such moieties may be further substituted with one or more Cl~C6alkyls;
each Z2 is independently and individually selected from the group consisting of hydrogen, aryl, Cl-C6alkyl, C3-C8carbocyclyl, hydroxyl, hydroxyCl-C6alkyl-, cyano, (R3)2N-, (R4)2N-, (R4)2NCi-C6alkyK (R4)2NC2"C6alky?N(R4)-(CH2)n-J (R4)2NC2-C6alkylO-(CH2)n-, (R3)2N-C(=0)-, (R4)2N-C(0)-, (R4)2N-CO-Cl-C6alkyl-, carboxyl, carboxyCl-CGalkyl, Cl-C6aIkoxycarbonyl, Cl-CealkoxycarbonylCl-Cealkyl, (R3)2NS02-, (R4)2NS02-, -S02R5; -S02R8, -(CH2)„N(R4)C(0)R8, -C(0)R8, =0, =NOH, =N(OR6), -(CH2}n-Gl, -(CH2)n-G4, -(CH2)n-0-(CH2)n-Gl, -(CH2)n-0-(CH2)n-G4, -(CH2)n-NR3-(CH2)n-arylT -(CH2)n-NR3-(CH2)n-G 1, -(CH2)n-NR3-(CH2)n-G4, -(CH2)nNHC(0)NHS(0)2R8, -(CH2)nNHS(0)2NHC(0)R8, C(0)NHS(0)2R8, -(CH2)NHC(0)(CH2)nR5, -(CH2)„NHS(0)2R5, -(CH2)nC(0)NH(CH2)qR5, -(CH2)nC(0)R5, -(CH2)nOC(0)R5, and -(CH2)nR5;

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in the event that Z2 contains an alkyi or alkylene moiety, such moiefies may be further substituted with one or more Cl-C6alkyls;
each Z3 is independently and individually selected from the group consisting of H, Cl-C6alkyl, branched C3-C7aJkyl, C3-C8carbocyclyl, haiogen, fluoroalkyl wherein the alkyl moiety can be partially or fully fluorinated, cyano, hydroxyl, methoxy, oxo, (R3)2N-C(=0)-, (R4)2N-C(=0)-, -N(R4)-0(=O)R8, (R3)2NS02-, (R4)2NS02-, -N(R4)S02R5; -N(R4)S02R8, -(CH2)„-N(R3)2j -(CH2)n-N(R4)2, -0- in the event that Z3 contains an alkyl or alkylene moiety, such moieties may be further substituted with one or more Cl-C6alkyls;
each Z4 is independently and individually selected from the group consisting of H, Cl-C6alkyl, hydroxyC2-C6a1kyl, Cl-C6alkoxyC2-C6alkyl, (R4)2N-C2-C6alkyI, (R4)2N-C2-C6alkylN(R4)-C2-C6alkyl, (R4)2N-C2-C6aIkyl-0-C2-C6alkyl, (R4)2N-CO-Cl-C6alkyl, carboxyCl-C6alkyl, Cl-C6alkoxycarbonylCl-C6alkyl, -C2-C6alkylN(R4)C(0)R8,R8-C(=NR3)-, -S02R8, -COR8, -(CH2)n-Gl, -(CH2)0-G4, -(CH2)q-0-(CH2)n-Gl, -(CH2)q-0-(CH2)n-G4, -(CH2)q-NR3-(CH2)n-Gl, -(CH2)q-NR3-(CH2)n-G4, -(CH2)qNHC(0)(CH2)nR51 -(CH2)qC(0)NH(CH2)qR5, -(CH2)qC(0)R5, -(CH2)qOC(0)R5, -(CH2)qR5, -(CH2)qNR4(CH2)qR5, and -(CH2)qO(CH2)qR5;
in the event that Z4 contains an alkyf or alkylene moiety, such moieties may be further substituted with one or more Cl-C6alkyls;
each Z6 is independently and individually selected from tile group consisting of H, Cl-C6alkyl, branched C3-C7alkyl? hydroxy], Cl-C6alkoxy, -OR4, Cl-C6alkyJthio, (R3)2N-, (R4)2N-t -R5, -N(R3)COR8, -N(R4)COR8, -N(R3)S02R6-, -CON(R3)2, -CON(R4)2, -COR5, -S02N(R4)2, halogen, fluoroCl-C6alkyl wherein the alkyl is fully or partially fluorinated, cyano, fluoroCl-C6alkoxy wherein tJie alkyl is fully or partially fluorinated, -0-
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in the event that Z6 contains an alkyl or alkylene moiety, such moieties may be further substituted with one or more Cl-C6alkyls;
wherein each R3 is independently and individually selected from the group consisting of H, Cl-C6alkyl, branched C3-C7alkyl, C3-C8carbocyclyl, and Z3-substituted phenyl;
each R4 is independently and individually selected from the group consisting of H, Cl-C6alky], hydroxyCl-C6alkyl, dihydroxyCl-Cfialkyl, Cl-C6alkoxyCl-C6alkyl, branched C3-C7alkyl, branched hydroxyCl-C6alkyl, branched CI-C6alkoxyCl-C6alkyl, branched dihydroxyCl-C6alkyl, -(CH2)P-N(R7)2, -(CH2)p-R5, -(CH2)p-C(0)N(R7)2l -(CH2)nC(0)R5, - each R5 is indenendentlv and individually selected from the sroun consisting of
and wherein the symbol {##) is the point of attachment of the R5 moiety;
each R6 is independently and individually selected from the group consisting of Cl-C6alkyl, branched C3-C7alkyl, C3-C8carbocyclyl, phenyl, Gl, and G4;
each R7 is independently and individually selected from the group consisting of H, Cl-C6alkyl, hydroxyC2-C6alkyl, dihydroxyC2-C6aIkyi, Cl-C6alkoxyC2-C6alkyl, branched C3-C7alkyl, branched hydroxyC2-C6 alkyl, branched Cl-C6alkoxyC2-C6alkyl, branched dihydroxyC2-C6alkyl, -(CH2)q-R5, -(CH2)H-C(0)R5, -(CH2)ir-C(0)OR3, C3-C8carbocyclyl, hydroxyl substituted C3-C8carbocycIyl, alkoxy substituted C3-C8carbocyclyl, dihydroxy substituted C3-CScarbocyclyl, and -(CH2)n-R17;

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each R8 is independently and individually selected from the group consisting of Cl-C6alkyl, branched C3-C7alkyl, fluoroalkyl wherein the alkyl moiety is partially or fully fluorinated, C3-C8carbocyclyl, Z3-substituted phenyl, Z3-substituted phenyl Cl-C6allcyl, Z3-substituted Gl, Z3-substituted Gl-Cl-C6alkyl, Z2-substituted G4, Z2-substituted G4-Cl-C6alkyl, OH, Cl-C6alkoxy, N(R3)2) N(R4)2, and R5;
each R10 is independently and individually selected from the group consisting of CO2H, CO2CI-C6alkyi, CO-N(R4)2, OH, Cl-C6alkoxy, and -N(R4)2;
R16 is independently and individually selected from the group consisting of hydrogen, Cl-C6alkyl, branched C3-C7alkyl, C3-C8carbocyclyl, halogen, fluoroalkyl wherein the alkyl moiety can be partially or fully fluorinated, cyano, hydroxy!, Cl-C6alkoxy, Cl-C6fluoroalkoxy wherein the alkyl moiety can be partially or fully fluorinated, -N(R3)2, -N(R4)2, C2-C3alkynyl, and nitro;
each R17 is taken from the group comprising phenyl, naphthyl, pyrrolyl. furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyrazinyl. pyridazinyl, triazinyl, oxetanyl, azetadinyl, tetrahydrofuranyl, oxazolinyl, oxazolidinyl, pvranyl, thiopyranyl, tetrahydropyranyl. dioxalinyl, azepinyl, oxepinyl, diazepinyl, pyrrolidinyl, and piperidinyl;
wherein R17 can be further substituted with one or more 22, Z3 or Z4 moieties;
R19isHorCl-C6alkyl;
wherein two R3 or R4 moieties are independently and individually taken from the group consisting of Cl-C6alkyl and branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen atom, said moieties may cyclize to form a C3-C7 heterocyclyl ring;
and k is 1 or2;n is 0-6; p is 1-4; qis 2-6; r is 0 or 1; tis 1-3.
2. Compounds of claim 1 having the formula lb.

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3.

Compounds of claim 2 having the formula Ic.






4. Compounds of claim 3 having the formula Id.
wherein Al is selected from the group consisting of branched C3-C8alkyl, R19 substituted C3-C8carbocyclyl, Cl-C6alkyi, fluoroCl-C6alkyl wherein the alkyl is fully or partially fluorinated, Z3-substituted phenyl, and Z3-substituted Gl;
and wherein R16 is C1 -C6alkyl, cyano, -CCH, or halogen.
5. Compounds of claim 4 having the formula le

6. ComDOunds of claim 4 having the formula If

wherein R16 is Cl-C6alkyl, cyano, -CCH, fluorine orchlonne.

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7. Compounds of claim 3 having the formula Ig
wherein Al is selected from the group consisting of branched C3-C8alkyl3 R19 substituted C3-C8carbocyclyl, Cl-C6alkyl, fluoroCl-C6alkyl wherein the alkyl is fully or partially fluoriiiated, Z3-substituted phenyl, and Z3-substituted Gl;
and wherein R16 is Cl-C6alkyl, cyano, -CCH, or halogen.
8. Compounds of claim 7 havine the formula Hi



9. Compounds of claim 7 having the formula Ii


wherein R16 is Cl-C6alkyl, cyano, -CCH, fluorine or chlorine. 10. Compounds of Claim 2 having formula Ij

wherein Al is selected from the group consisting of branched Z2-substitued C3-C8alkyl, R19 substituted C3-C8carbocyclyl, Z2-substituted Cl-C6alkyl, fluoroCl-C6alkyl wherein the alkyl is fully or partially fluorinated, Z3-substituted phenyl, and Z3-substituted G1;
and wherein R16 is Cl-C6alkyl, cyano, -CCH, or halogen.

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11. Compounds of Claim 10 having fonnula Ik



12. Compounds of Claim 10 having formula II



wherein R16 is Cl-C6alkyl, cyano, -CCH, fluorine or chlorine.
13. Compounds of Claim 2 having formula Im

wherein Al is selected from the group consisting of hydrogen, Z2-substituted branched C3-C8alkyl, R19 substituted C3-CScarbocyclyl, Z2-substituted CI-C6alkyl, fluoroCl-Cfialkyl wherein the alkyl is fully or partially fluorinated, Z3-substituted phenyl, and Z3-substituted Gl;
and wherein R16 is Cl-C6alkyl, cyano, -CCH, or halogen.
14. Compounds of Claim 13 having formula In

15. Compounds of Claim 13 having formula Io


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wherein R16 is Cl-C6alky1, cyano, -CCH, fluorine or chlorine.
16. Compounds of Claim 2 having formula Ip

wherein Al is selected from the group consisting of Z2-substituted branched C3-C8alkyl, RI9 substituted C3-C8carbocycIyl, Z2-substituted Cl-C6alkyl, f!uoroCl-C6alkyI wherein the alkyl is fully or partially fluorinated, Z3-substituted phenyl, and Z3-substituted Gl;
and wherein R16 is Cl-C6alkyl, cyano, -CCH. or halogen.
17. Compounds of Claim 16 having formula Iq



18. Compounds of Claim 16 having formula Ir


and wherein R16 is Cl-C6alkyl, cyano, -CCH, fluorine or chlorine. 19. Compounds of Claim 2 having formula Is

wherein the hashed bond is a saturated or unsaturated bond;

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and wherein Al is selected from the group consisting of hydrogen, Z2-substituted branched C3-C8alkyl, R19 substituted C3-C8carbocyclyl, 22-substituted Cl-C6alkyl, halogen, cyano, CI-C6alkoxy, fluoroCl-C6alkoxy, fluoroCl-C6alkyl wherein the alkyl is fully or partially fluorinated, Z3-substituted phenyl, and Z3-substituterf GI;
and wherein R16 is Cl-C6alkyl, cyano, -CCH, or halogen.
20. Compounds of Claim 19 having formula It



21. Compounds of Claim 19 having formula Iu


wherein Rl 6 is CI -C6alkyl, cyano, -CCH, fluorine or chlorine. 22. Compounds of Claim 2 having formula Iv


wherein the hashed bond is a saturated or unsaturated bond;
and wherein Al is selected from the group consisting of hydrogen, Z2-substituted branched C3-C8alkyl, R19 substituted C3-C8carbocyclyl, Z2-substituted Cl-C6alkyl, halogen, cyano, Cl-C6alkoxy, fluoroCl-C6alkoxy, fluoroCl-C6alky! wherein the alkyl is fully or partially fluorinated, Z3-substituted phenyl, and Z3-substituted G1;
and wherein R16 is Cl-C6alkyl, cyano, -CCH, or halogen.

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23. Compounds of Claim 22 having formula Iw

24. Compounds of Claim 22 having formula Ix

and wherein R16 is Cl-C6alkyl. cyano, -CCH, fluorine or chlorine.
25. Compounds of Claim 2 having formula Iy

wherein Al is selected from the group consisting of Z2-substituted branched C3-C8alkyl, R19 substituted C3-C8carbocyclyl, Z2-substituted Cl-C6alkyl, fluoroCl-C6alkyl wherein the alkyl is fully or partially fluorinated, Z3-substituted phenyl, and Z3-substituted Gl;
and wherein R16 is Cl-C6alkyl, cyano, -CCH, or halogen.
26. Compounds of Claim 25 having fonnula Iz

27. Compounds of Claim 25 having formula Iaa

wherein R16 is Cl-C6alkyl, cyano, -CCH, fluorine or chlorine.

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28. Compounds of Claim 2 having formula Ibb



wherein R16 is Cl-C6alkyl, cyano, -CCH, or halogen.
29. Compounds of Claim 28 having formula Ice



30. Compounds of Claim 28 having formula Idd

wherein R16 is Cl-C6alkyl, cyano, -LLH, fluorine or chlorine.
31. Compounds of Claim 2 having formula lee

wherein Ql and Q2 are individually and independently taken from the group consisting of N and CH;
and wherein R16 is Cl-C6alkyl, cyano, -CCH, or halogen.
32. Compounds of Claim 31 having formula Iff

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33. Compounds of Claim 31 having formula Igg



wherein R16 is Cl-C6alkyl, cyano, -CCH, fluorine or chlorine.
34. Compounds of Claim 2 having formula Ihh



and wherein R16 is Cl-C6alkyl, cyano, -CCH, or halogen.
35. Compounds of Claim 34 having formula Iii

36. Compounds of Claim 34 having formula IJJ

and wherein Rl 6 is methyl, cyano, -CCH, fluorine or chlorine.

37.

Compounds of Claim 2 having formula Ikk

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wherein Q6 is N or C-Al;
wherein Al is selected from the group consisting of hydrogen, Z2-substituted branched C3-C8alkyl, R19 substituted C3-C8carbocyclyl, Z2-substituted Cl-C6alkyl, fluoroCl-C6aikyI wherein the alkyl is fully or partially fluorinated. Z3-substituted phenyl, and Z3-substituted Gl;
and wherein R16 is Cl-C6alkyl, cyano, -CCH, or halogen.
38. Compounds of Claim 37 having formula 111



39. Compounds of Claim 37 having formula Imm



wherein R16 is Cl-C6alkyl, cyano, -CCH, fluorine or chlorine.
40. Compounds of Claim 2 having formula Inn

wherein Al is selected from the group consisting of hydrogen, Z2-substituted branched C3-C8alkyl, R19 substituted C3-C8carbocyclyl, Z2-substituted Cl-C6alkyl, fluoroCl-C6alkyl wherein the alkyl is fully or partially fluorinated, Z3-substituted phenyl, and Z3-substituted Gl;

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and wherein R16 is Cl-C6alkyl, cyano, -CCH, or halogen.
41. Compounds of Claim 40 having formula loo



42. Compounds of Claim 40 having formula Ipp


wherein R16 is Cl-C6alkyl, cyano, -CCH, fluorine or chlorine. 43. Compounds of Claim 2 having formula Iqq

wherein Q3, Q4 and Q5 are selected from the group consisting of N-Al and C-Al, and only one ufQ3,Q4,orQ5isN-Al;
and wherein Al is selected from the group consisting of hydrogen, Z2-substituted branched C3-CSalkyl, R19 substituted C3-C8caibocyclyl, Z2-substituted Cl-C6alkyl, fluoroCl-C6alkyl wherein the alkyl is fully or partially fluorinated, Z3-substituted phenyl, and Z3-substituted Gl;
and wherein R16 is Cl-C6alkyl, cyano, -CCH, or halogen.

44.

Compounds of Claim 43 having formula Irr

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45. Compounds of Claim 43 having formula Iss


wherein R16 is Cl-C6aI3cyl, cyano, -CCH, fluorine or chlorine. 46. Compounds of the formula Ila


wherein one of Ql and Q2 is N and the other is CR3;
wherein El is selected from the group consisting cyclopropyi, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl piperidinyl, phenyl, thienyl, oxazolyl, thiazolyl. isoxazolyl, isothiazolyl, pyrrolyl, pyrazolyl, oxadiazolyl, thiadiazoiyl, furyl, imidazoiyl, pyridyl, pyrimidinyi and naphthyl;
wherein A is selected from the group consisting of phenyl, naphtliyl, C3-C8carbocyclyl, indanyl, tetralinyl, indenyl, Gl, G2, G3, G4 and -CHR4R8;
Gl is a heteroaryl taken from the group consisting of pyrrolyl, furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, imidazoiyl, pyrazolyl, oxadiazolyl, thiadiazoiyl, triazolyl, tetrazolyl, pyrazinyl, pyridazinyl, rriazinyl, pyridinyl, and pyriimdiny];
G2 is a fused bicyclic heteroaryl taken from the group consisting of indolyl, indoliziyl, isoindolyl, isoindolinyl, indazolyl, benzofuranyl, benzothienyl, benzothiazoiyl, benzothiazolonyl, benzoxazolyl, benzoxazolonyl, benzisoxazoly], benzisolhiazolyl, benzimidazolyi,

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benzimidazolonyl, benztriazolyl, imidazopyridinyl, pyrazolopyridmyl, iraidazolonopyridinyl,
thiazolopyridinyl, thiazolonopyridinyl, oxazolopyridinyl, oxazolonopyridinyl,
isoxazolopyridinyl, isothiazolopyridinyl, triazolopyridinyl, imidazopyrimidinyl,
pyrazolopyrimidinyl, imidazolonopyrimidinyl, thiazolopyridiminyl, thiazolonopyrimidinyl, oxazolopyridiminyl, oxazolonopyrimidinyl, isoxazolopyrimidinyl, isothiazolopyrimidinyJ, triazolopyrimidinyl, dihydropurinonyl, pyrrolopyrimidinyl, purinyl, pyrazolopyrimidinyl, phthalimidyl, phthalimidinyl, pyrazinylpyridinyl, pyridinopyrimidinyl, pyrimidinopyrimidinyl, cinnolinyl, quinoxalinyl, quinazolinyl, quinolinyl, isoquinolinyl, phthalazinyl, benzodioxyl, benzisothiazoline-1,1,3-trionyl, dihydroquinolinyl, tetrahydroquinolinyl, dihydroisoquinolyl, tetrahydroisoquinolinyl, benzoazepinyl, benzodiazepinyl, benzoxapinyl, and benzoxazepinyl;
G3 is a non-iused bicyclic heteroary] taken from the group consisting of pyridylpyridirainyl
pyrimidinylpyrirnidinyl, oxazolylpyrimidinyl, thiazolylpyrimidinyl, imidazolylpyrimidinyl,
isoxazolylpyrimidinyl, isothiazolylpyrimidinyl, pyrazolylpyrimidinyl, triazolylpyrimidinyl,
oxadiazoylpyrimidinyl, tliiadiazoylpyrimidinyl, morphoHnylpyrimidinyl,
dioxothioraorpholinylpyrimidinyl, and thiomorpholinylpyrimidinyl;
G4 is a heterocyclyl taken from the group consisting of oxetanyl, azetadinyl, tetrahydrofiiranyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, imidazolonyl, pyranyl, thiopyranyl, tetrahydropyranyl, dioxalinyl, piperidinyl, morpholinyl, tluomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S-dioxide, piperazinyl, azepinyl, oxepinyl, diazepinyl, tropanyl, and homotropanyl;
the A ring may be optionally substituted with one or more -XI -Al moieties;
XI is selected from the group consisting of -{CH2)n-(0)r(CH2)n-I -(CH2)„-(NR3)r(CH2)I)-) -(CH2MS)r(CH2)n-, -(CH-CC-OVCCHsV, -(CH2)n-(C(=0)-NR3)r(CH2)I1-, and -(CH2)n-(S02-NR3)r(CH2)n-, wherein any of the alkylenes may be straight or branched chain;
X2 is selected from the group consisting of Cl-C6alkyl, branched C2-C6alkyl, and a direct bond wherein El is directly linked to the NR3 group of formula la;

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Al is selected from the group consisting of hydrogen, aryl, Gl, G2, G3, G4, C1-C6 alkyl, branched C3-C8alkyl, R19. substituted C3-C8carbocyclyl, fluoi"oCl-C6alkyl wherein the alkyl is fully or partially fluorinated halogen, cyano, hydroxyl, -N(R4)2, -R5, -C(0)N(R4)2, C(0)R5, Cl-C6alkoxy, and fluoroCl-C6alkoxy wherein the alkyl group is fully or partially fluorinated;
When A and Al have one or more substitutable sp2-hybridized carbon atom, each respective sp2 hybridized carbon atom may be optionally substituted with a Zl or Z3 substituent;
when A and A1 have one or more substitutable sp3-hybridized carbon atom, each respective sp3 hybridized carbon atom may be optionally substituted with a Z2 or R3 substituent;
when A and Al have one or more substitutable nitrogen atom, each respective nitrogen atom may be optionally substituted with a Z4 substituent;
each Zl is independently and individually selected from the group consisting of hydrogen, hydroxyCl-Cfialkyl, Cl-C6alkoxy, Cl-C6alkoxyCl-C6aIkyl, (R4)2NC1-C6alkyl, (R4)2NC2-C6alkylN(R4)-(CH2)n, (R4)2NC2-C6alkylO-(CH2)n, (R3)2N-C(=0)-: (R4)2N-C(=0)-, (R4)2N-COCl-C6aIkyl-, CI -C6alkoxycarbonyl-, -carboxyC 1 -C6alkyl, C1 -C6alkoxycarbonylC 1 -C6alkyl, (R3)2NS02-, -SOR3, (R4)2NS02-, -S02R3, -SOR4, -C(=0)R6, -C(=NOH)R6, -C(=NOR3)R6, -(CH2)«N(R4)C(0)R8, -(CH2)„-G1, -(CH2)n-G4, phenoxy, -(CH2)n-0-(CH2)n-Gl, -(CH2)n-0-(CH2)n-G4, -(CH2)n-NR3-(CH2)n-aryl, -(CH2)n-NR3^CH2)n-GlJ -(CH2VNR3-(CH2)n-G4T -S(0)2R5, -N=S(0)R6R8, -S(0)(=NR3)R6, -(CH2)nNHC(0)NHS(0)2R8, -(CH2)nNHS(0)2NHC(0)R8, -C(0)NHS(0)2R8, -S(0)2NHC(0)R8, -(CH2)nNHC(0)(CH2)nR5, -(CH2)nNHS(0)2(CH2)„R5, in the event that Zl contains an alkyl or aikylene moiety, such moieties may be further substituted witli one or more Cl-C6alkyls;

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each Z2 is independently and individually selected from the group consisting of hydrogen, aryl, Cl-C6alkyl, C3-C8carbocyclyl, hydroxyl, hydroxyCI-C6alkyl-, cyano, (R3)2N-, (R4)2N-, (R4)2NC1-C6alkyl-, (R4)2NC2-C6alkylN(R4)-(CH2)n-3 (R4)2NC2-C6alkylO-(CH2)n-, (R3)2N-C(=0>, (R4)2N-C(=0)-, (R4)2N-CO-Cl-C6alkyK carboxyl, carboxyCi-C6alkyI, CI-C6alkoxycarbonyl, Cl-C6alkoxycarbonylCl-C6alkyl, (R3)2NS02-, (R4)2NS02-, -S02R5, -S02R8, -{CH2)nN(R4)C(0)R8f -C(0)R8? =0, =NOH, =N(OR6), -(CH2)n-Gl, -{CH2)n-G4, -(CH2)n-0-(CH2)n-Gl, ^(CH2)n-0-(CH2)n^G4, -(CH2)irNR3-(CH2)n-aryl, -(CH2)n-NR3-(CH2)n-Gl, -(CH2)n-NR3-(CH2)n-G4, -(CH2)nNHC(0)NHS(0)2R8, -(CH2)nNHS(0)2NHC(0)R8, -C(0)NHS(0)2R8, -(CH2)NHC(0)(CH2)nR5, -(CH2)nNHS(0)2R5, -(CH2)„C(0)NH(CH2)qR5, -(CH2)nC(0)R5, -(CH2)nOC in the event that Z2 contains an alkyl or alkylene moiety, such moieties may be further substituted with one or more Cl-C6alkyls;
each Z3 is independently and individually selected from the group consisting of H, Cl-C6alkyl, branched C3-C7alkyl, C3-C8carbocyclyl, halogen, fluoraalkyl wherein the alkyl moiety can be partially or fully fluorinated, cyano, hydroxyl, methoxy, oxo, (R3)2N-C(=0)-, (R4)2N-C(=0)-, -N(R4)-C(0)R8, (R3)2NS02-, (R4)2NS02-, -N(R4)S02R5, -N(R4)S02R8, -(CH2)„-N(R3)2, -(CH2)n-N(R4)2) -0-(CH2)q-N(R4)2, -0-(CH2)q-0-alkyI, -N(R3)-(CH2)q-0-aIkyl, -N(R3)-(CH2)q -N(R4)2j -0-(CH2VR5, -N(R3)-(CH2VR5, -C(=0)R5, -C(=0)R8, and nitra;
in the event that 23 contains an alkyl or alkylene moiety, such moieties may be further substituted with one or more Cl-C6alkyls;
each Z4 is independently and individually selected from the group consisting of H, Cl-C6a!kyl, hydroxyC2-C6alkyl, Cl-C6alkoxyC2-C6alkyl, (R4)2N-C2-C6alkyl, (R4)2N-C2-C6alkylN(R4)-C2-C6alkyl, (R4)2N-C2-C6alkyl-0-C2-C6alkyl, (R4)2N-CO-Cl-C6aIkyl, carboxyCl-C6alkyl, Cl-C6alkoxycarbonylCI-C6alkyt, -C2-C6alkylN(R4)C(0)R8,R8-C(=NR3K -S02R8, -COR8, -(CH2)n-Gl, -(CH2)n-G4, -(CH2)q-0-(CH2)n-Gl, -(CH2)q-0-(CH2)n-G4, -(CH2)q-NR3-(CH2)n-Gl, -(CH2)q-NR3-(CH2)u-G43 -(CH2)qNHC(0)(CH2)nR5, -(CH2)qC(0)NH(CH2)qR5, -(CH2)qC(0)R5, -(CH2)qOC(0)R5, -(CH2)qR5, -(CH2)qNR4(CH2)qR5, and -(CH2)qO(CH2)qR5;

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in the event that Z4 contains an alkyl or alkylene moiety, such moieties may be further substituted with one or more Gl-C6alkyls;
each Z6 is independently and individually selected from the group consisting of H, Cl-Cdalkyi, branched C3-C7alkyl, hydroxy!, Cl-C6alkoxy, -OR4, Cl-C6alkylthio, (R3)2N-, (R4)2N-, -R5, -N(R3)COR8, -N(R4)COR8, -N(R3)S02R6-, -CON(R3)2, -CON(R4)2, -COR5, -S02N(R4)2, halogen, fluoroCl-C6alkyI wherein the alkyl is fully or partially fluorinated, cyano, fluoroCl-C6alkoxy wherein the alkyl is fully or partially fluorinated, -0-(CH2)q-N(R4)2, -N(R3)-(CH2)q-N(R4)2, -0-(CH2)c0^alkyl, -N(R3)-(CH2) in the event that Z6 contains an alkyl or alkylene moiety, such moieties may be further substituted with one or more CI -C6alkyls;
wherein each R3 is independently and individually selected from the group consisting of H, Cl-C6alkyl, branched C3-C7alkyl, C3-CScarbocyclyI, and Z3-substituted phenyl;
each R4 is independently and individually selected from the group consisting of H, Cl-C6alkyl. hydroxyCl-C6alky!, dihydroxyCl-C6aIkyl, Cl-C6alkoxyCl-C6alky1, branched C3-C7alkyl, branched hydroxyCl-C6alkyl, branched Cl-C6alkoxyCl-C6alkyl, branched dihydroxyCl-C6alkyl, - each R5 is independently and individually selected from the group consisting of and wherein the symbol (##) is the point of attachment of the R5 moiety;

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each R6 is independently and individually selected from the group consisting of Cl-C6alkyl, branched C3-C7alkyl, C3-CScarbocydyl, phenyl, Gl, and G4;
each R7 is independently and individually selected from the group consisting ofh, Cl-C6alkyl, hydroxyC2-C6alkyl, dihydroxyC2-C6alkyl, Cl-C6aIkoxyC2-C6alkyI, branched C3-C7alkyl, branched hydroxyC2-C6 alkyl, branched Cl-C6alkoxyC2~C6alkyl, branched dihydroxyC2-C6alkyl: -{CH2)q-R5, -(CH2)n-C(0)R5, -(CH2)n-C(0)OR3, C3-C8carbocycIyl, hydroxyl substituted C3-C8carbocyclyl, alkoxy substituted C3-C8carbocyclyl, dihydroxy substituted C3-C8carbocyclyl, and -(CH2)n-R17;
each R8 is independently and individually selected from the group consisting of Cl-C6alkyl, branched C3-C7alkyl, fluoroalkyl wherein the alkyl moiety is partially or fully fluorinated, C3-C8carbocyclyl, Z3-substituted phenyl, Z3-substituted phenyl Cl-C6alkyl, Z3-substituted Gl, Z3-substituted Gl-Cl-C6alkyl, Z2-substituted G4, Z2-substirated G4-Cl-C6alkyl, OH, Cl-C6alkoxy, N(R3)2, N(R4)2, and R5;
each R10 is independently and individually selected from the group consisting of C02H, C02C1-C6alkyl, CO-N(R4)2, OH, Cl-C6aIkoxy: and -N(R4)2;
R16 is independently and individually selected from the group consisting of hydrogen, CI-C6alkyl, branched C3-C7alkyl, C3-C8carbocyclyl, halogen, fluoroalkyl wherein the alkyl moiety can be partially or fully fluorinated, cyano, hydroxyl, Cl-C6alkoxy, Cl-C6fluoroalkoxy wherein the affcy? moiety can be partiafiy or flrtfy fluorinated, -N(R3)2, -N(R4)2, C2-C3alkynyl, and nitro;
each R17 is taken from the group comprising phenyl, naphthyl, pyrrolyl, furyl, thienyl, oxazolyl, thiazoly!, isoxazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyh thiadiazolyl, triazolyl, tetrazolyl, pyrazinyl, pyridazinyl, triazinyl, oxetanyl, azetadinyl, teo-ahydrofuranyl, oxazolinyl, oxazolidinyl, pyranyl, thiopyranyl, tetrahydropyranyl, dioxalinyl, azepinyl, oxepinyl, diazepinyi, pyrrolidinyl, and piperidinyl;
wherein R17 can be further suhstituted with one or more Z2, Z3 or Z4 moieties;

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R19isHorCl-C6alkyl:
wherein two R3 or R4 moieties are independently and individually taken from the group consisting of Cl-C6alkyl and branched C3-C6alkyl, hydroxyalkyl, and alkoxyalkyl and are attached to the same nitrogen atom, said moieties may cyclize to form a C3-C7 heterocyclyl ring;
andkis 1 or2; nis0-6;pis 1-4; qis2-6;ris0or 1; tis 1-3.
47. Compounds of claim 46 having the formula lib.



48. ComDOunds of claim 47 havins the formula He.



49. Compounds of claim 48 having the formula Hd.

wherein Al is selected from the group consisting of branched C3-C8alkyl, R19 substituted C3-C8carbocyclyl, Cl-C6alky3, fluoroCl-C6alkyl wherein the alkyl is fully or partially fhiorinated,
and wherein R16 is Cl-C6alkyl, -CCH, cyano, halogen.
50. Compounds of claim 49 having the formula He

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He

51, Compounds of claim 49 having the formula Ilf

wherein R16 is methyl, cyano, -CCH, fluorine or chlorine. 52. Compounds of claim 48 having the formula llg

wherein Al is selected from the group consisting of branched C3-C8alkyl, R19 substituted C3-C8carbocyclyl, Cl-C6alkyl, fluoroCl-C6alkyl wherein the alkyl is fully or partially fluorinated, Z3-substituted phenyl, and Z3-substituted Gl;
and wherein Rl 6 is CI -C6alky], cyano, -CCH, or halogen.
53. Compounds of claim 52 having the formula llh

54. Compounds of claim 52 having the formula Hi


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wherein R16 is methyl, cyano, -CCH, fluorine or chlorine.
55. Compounds of Claim 47 having formula IIj


X 26

wherein A1 is selected from the group consisting of branched Z2-substitued C3-C8alkyl, R19 substituted C3-C8carbocycly], Z2-substituted Cl-C6alkyl, fiuoroCl-C6alkyl wherein me alkyl is fully or partially fluorinated, Z3-substituted phenyl, and Z3-substituted Gl;
and wherein R16 is CI -C6alkyl, cyano, -CCH, or halogen.
56. Compounds of Claim 55 having formula Ilk

A1—N
N Uk


57. Compounds of Claim 55 having formula III wherein R16 is methyl, cyano, -CCH, fluorine or chlorine.
58. Compounds of Claim 47 having formula Ilm


wherein A! is selected from the group consisting of hydrogen, Z2-substituted branched C3-C8alkyl, R19 substituted C3-C8carbocyclyl, Z2-substituted Cl-C6alkyl, fluoroCl-C6alkyl wherein tlie alkyl is fully or partially fluorinated, Z3-substituted phenyl, and Z3-substituted Gl;

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and wherein R16 is C]~C6alkyl, cyano, -CCH, or halogen.
59. Compounds of Claim 58 having formula Hn



60. Compounds of Claim 58 having formula Ho


wherein R16 is Cl-C6alkyl. cyano, -CCH, fluorine or chlorine. 61. Compounds of Claim 47 having formula Hp

wherein Al is selected from the group consisting of Z2-substituted branched C3-C8alkyl, R19 substituted C3-C8carbocydyl, Z2-substituted Cl-C6alkyl, fluor0Cl-C6alkyl wherein the alkyl is fully or partially fiuorinated, Z3-substituted phenyl, and Z3-substituted Gl;
and whereinR)6is C\-C6a)ky\. cyano. -CCHr orbaJD,gen,
62. Compounds of Claim 61 having formula Ilq

63. Compounds of Claim 61 having formula Ilr

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and wherein Rl 6 is methyl, cyano, -CCH, fluorine or chlorine.
64. Compounds of Claim 47 having formula lis

wherein the hashed bond is a saturated or unsaturated bond;
and wherein Al is selected from the group consisting of hydrogen, Z2-substituted branched C3-C8alkyl, R19 substituted C3-C8carbocyclyI, Z2-substiruted Cl-C6alkyl, halogen, cyano, Cl-C6alkoxy, fluoroCl-C6aIkoxy. fluoroCl-C6alkyl wherein the alkyl is fully or partially fluorinated, 23-substituted phenyl, and Z3-substituted Gl;
and wherein Rl 6 is Cl-C6alky], cyano, -CCH. or halogen.

65.

Compounds of Claim 64 having formula lit


66. Compounds of Claim 64 having formula IIu

and wherein R16 is Cl-C6alkyl, cyano, -CCH, fluorine or chlorine.
67. Compounds of Claim 47 having formula Uv

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wherein the hashed bond is a saturated or unsaturated bond;
and wherein Al is selected from the group consisting of hydrogen, Z2-substituted branched C3-C8alkyl, R19 substituted C3-C8carbocyclyl, Z2-substituted Cl-C6alkyl, halogen, cyano, Cl-C6alkoxy, fluoroCl-C6aIkoxy, fluoroCl-CSalkyl wherein the alkyl is fully or partially fluorinated, Z3-substituted phenyl, and Z3-substituted Gl;
and wherein R16 is C1-C6alkyh cyano, -CCH, or halogen.
68. Compounds of Claim 67 having formula IIw

69. Compounds of Claim 67 having formula IIx

and wherein R16 is Cl-C6alkyl, cyano, -CCH, fluorine or chlorine.
70. Compounds of Claim 47 having formula Ily

wherein Al is selected from the group consisting of Z2-substituted branched C3~C8alkyl, R19 substituted C3-C8carbocyclyl, Z2-substituted Cl-C6alkyl, fluoroCl-C6alkyl wherein the alkyl is fully or partially fluorinated, Z3-substituted phenyl, and Z3-substituted Gl;

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and wherein R16 is Cl-C6alkyl, cyano, -CCH, or halogen. 71. Compounds of Claim 70 having formula Hz



72. Compounds of Claim 70 having formula Ilaa



wherein R16 is methyl, cyano, -CCH. fluorine or chlorine. 73. Compounds of Claim 47 having formula Ilbb

wherein R16 is Cl-C6alkyl, cyano, -CCH, or halogen. 74. Compounds of Claim 73 having formula lice
75, Compounds of Claim 73 having formula Hdd

wherein R16 is Cl-C6alkyl, cyano, -CCH, fluorine or chlorine.

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76. Compounds of Claim 47 having formula Ilee

wherein Ql and Q2 are individually and independently taken from the group consisting of N and CH;
and wherein R16 is Cl~C6alkyl, cyano, -CCH, or halogen.
77. Compounds of Claim 76 having formula Ilff


nrr

78. Compounds of Claim 76 having formula Ilgg

wherein R16 is Cl-C6alkyl, cyano, -CCH, fluorine or chlorine.
79. Compounds of Claim 47 having formula Ilhh

and wherein R16 is C1-C6alkyl, cyano, -CCH, or halogen.
80. Compounds of Claim 79 having formula Ilii


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81. Compounds of Claim 79 having formula IIjj


and wherein R16 is methyl, cyano, -CCH, fluorine or chlorine. 82. Compounds of Claim 47 having formula Ilkk

wherein Q6 is N or C-Al;

wherein Al is selected from the group consisting of hydrogen, Z2-substituted branched C3-C8alkyl, R19 substituted C3-C8carbocyclyl, Z2-substituted Cl-C6alkyl, fluoroCl-C6alkyl wherein the alkyl is fully or partially fluorinated, Z3-substituted phenyl, and Z3-substituted Gl;
and wherein R16 is Cl-C6alkyl. cyano, -CCH, or halogeu.
83. Compounds of Claim 82 having formula Till



84. Compounds of Claim 82 having formula Ilmm wherein R16 is Cl-C6alkyl, cyano, -CCH, fluorine or chlorine.

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85. Compounds of Claim 47 having formula linn

wherein Al is selected from the group consisting of hydrogtfn* Z2-substituted branched C3-C8alkyl, R19 substituted C3-C8carbocycIyl, Z2-substituted Cl-C6alkyl} fluoroCl-C6alkyI wherein the alkyl is fully or partially fluorinated, Z3-substituted phenyl, and Z3-substituted Gl;
and wherein R16 is Cl-C6alkyl, cyano, -CCH, or halogen.
86. Compounds of Claim 85 having formula Iloo



87. ComDOunds of Claim 85 havine formula Hon



wherein R16 is Cl-C6alkyl, cyano, -CCH, fluorine or chlorine.
88. Compounds of Claim 47 having formula Ilqq

wherein Q3, Q4 and Q5 are selected from the group consisting t>f N-AI and C-Al, and only one ofQ3,Q4, or Q5 is N-Al;

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and wherein Al is selected from the group consisting of hydrogen, Z2-substituted branched C3-C8alkyl, R19 substituted C3-C8carbocyclyl, Z2-substituted Cl-C6alkyl, fluoroCl-C6alkyl wherein the alkyl is fully or partially fluorinated, 23-substituted phenyl, and Z3-substituted Gl;
and wherein RI6 is CI 'C6alkyl, cyano, -CCH, or halogen.

89. Compounds of Claim 88 having formula Ilrr
90. Compounds of Claim 88 having formula IIss
wherein Rl 6 is Cl-C6alkyl, cyano, -CCH, fluorine or chlorine.
91. A compound selected from the group consisting of I-(5-(2-amino-8-methyl-7-oxo-7,8-
dihydropyrido[2,3-d]pyriniidin-6-yl)-2-fluorophenyl)-3-(3-tert-butyl-l-phenyl-lH-pyrazol-5-
yl)urea, j-(5-(2-amino-8-methyl-7-oxo-7I8-dihydropyrido[2,3-d]pyrimidin-6-yl)-2-
fluorophenyl)-3-(3-tert-butyl-l-methyl-lH-pyrazol-5-yl)urea, l-(l-(3-(2-amino-2-
oxoe%l)phenyl>34ert'butyl-lH-pyrazol-5-yl)-3-(5-(2-anuno-8-methyl-7-oxo-7,8-
dihydropyrido[2,3-d]pyriniidin-6-yl)-2-fliiorophenyI)urea, l-(5-(2-amino-8-methyI-7-oxo-7,8-
dihydropyrido[2,3-d]pyriniidin-6-yl)-2-fiuotx)pheiiyl)-3-(3"tert-butyl-l -(1 H-indazol-5-yiyi H-
pyrazoI-5-yl)urea, l-(5-(2-amino-8-nietliyl-7-oxo-7,8»dihydropyrido[2,3"d]p>Timidin"6-yl)-2-
fluorophenyl>3-(3-isopropyl-l-phenyl-lH-pyrazol-5-yl)urea, l-(5-{2-amino-8-methy!-7-oxo-
7)8-dihydropyrido[2,3-^]pyrimidin-6-yl)-2"fluorophenyl)-3-(3-tert-butyl-l-(2-(dimetliylammo)-
2-oxoethyI)-lH-pyrazol-5-yl)urea, l-(5-(2-amino-8-metliyI-7-oxo-7,8-dihydropyrido[2,3-
d]pyrimidin-6-yl)-2-flu0rophenyl)-3-(l-phenyl-3-(trifluorometliyl)-lH-pyrazol-5-yl)urea, l-(5-
(2-ainino-8-emyl-7-oxo-7,8-dihydropyrido[2)3-d]pyrimidin-6-yl)-2-fluorophenyI)-3-(3-tert-
butyl-1-methyl-lH-pyr^zol-5-yl)urea, l-(5-(2-amino-8-methyl-7-oxo-778- d]pyiimidin-6-yI)-2-fliiorophenyl)-3-(l-phenyl-3-(thiophen-2-yl)"lH-pyrazol-5-yl)urea, l-(5-(2-
*.

WO 2008/034008 PCTAJS 200 7/078408
ainino-8-ethyl-7"Oxo-73-dihydropyrido[2-d]pyrimidin-6-yl)-2-fIuorophenyl)-3-(3-tert-butyl-l-
phenyl-lH-pyrazol-5-yl)urea, l-(3-t-butyl-l-methyl-lH-pyrazol-5-yl)-3-(2-fluoro-5-(8-rnethyl-2-
(mediylaiiiino)-7-oxo-7,8-dihydropyrido[2)3-d]pyriiTudin-6-yl)phenyl)urea, l-(5-(2-amino-8-
methyl-7-oxo-7,8-dihydropyrido[2,3^]pyrimidin-6-yI)-2-fluorophenyl)-3-(3-tert-butyl-l-(3-
fluorophenyl)-lH-pyrazol-5-yl)urea, l-(5-(2-amino-8-methyl-7-oxO"7,8-dihydropyrido[2,3-
d]pyrimidin-6-yI)-2-fluorophenyI)-3-(3-tert-butyI-l-(quinoIin-6-yl)-lH-pyra2ol-5-yI)urea, l-(5-
(2-amino-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-2-fluorophenyl)-3"(3-(2-
fluorophenyl)-l-methyl-lH-pyrazol-5-yI)urea, l-(5-(2-amino-8-ethyl-7-oxo-7,8~
dihydropyrido[23-d]pyrimidin-6-yl)-2-fluorophenyl)-3-(3-tert-butyl-l-(6-methylpyridin-3-yl)-
1 H-pyrazol-5-yl)ure, 1 -(3-tert-butyl-1 -methyl-l H-pyrazol-5-yl)-3-(5-(8-ethyI-2-(methylamino)-
7-oxo-7,8-dihydropyrido [2,3-d]pyriniidin-6-yI)-2-fluorophenyI)urea, l-(3-tert-butyI-l-(6-
methylpyridin-3-yl)-lH-pyrazoI-5-yl)-3-{2-fluoro-5-(8-methyl-2-(methyiarnino)-7-oxo-7)8-
dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea, l-(5-(8-ethyl-2-(methylamino)-7-oxo-7,8~
dihydropyrido[2,3-d]pyrimidiri"6--yl)-2-fluorophenyl)-3-(3-isopropyl-l-methyl-lH-pyrazol-5-
yl)urea, l-(5-(2-amino-8-metliyl-7-oxo-7]8-dihydropyrido[2J3-d]pyrimidin-6-yl)-2-
(luorophenyI)-3-(3-tert-buty!-l-(2-morphoIinoemyI)-IH-pyrazoI-5-yI)ureaJ l-(5-(2-amino-8-
methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-2-fluorophenyl)-3-(3-tert-butyl-l-(2-
(piperazin-1 -yl)ethyl)-l H-pyrazol-5-yl)urea, 1 -(3-tert-butyI-1 -methyl-1 H-pyrazol-5-yl)-3-(5-(2-
(2-(dimetiiyIamino)ethylamino)-8-methyi-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-2-
fluorophenyl)urea, l-(5-(2-amino-8-metiiyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-2-
fluorophenyI)-3-(3-(trifluoromethyI)phenyi)urea, l-(5-(2-amino-8-methyI-7-oxo-7,8-
diliydropyrido[2,3-d]pyrimidin-6-yl)-2-fluorophenyl)-3-(3-tert-butyl-l-(2-
(dimethyIamino)ethyl)-lH-pyrazol-5-yl)urea, l-(5-(2-amino-8-cyclopropyU7-oxo-7,8-
dihydropyrido[2,3-d]pyiiniidin-6-yl)-2-fluorophenyl)-3-(3-tert-butyl-l-niethyl-lH-pyrazol~5-
yl)urea3 l-(5-(2-amino-8-methyl-7-oxo-7,8-dihydropyrido[2)3-d]pyrimidin-6-yl)-2-
fluorophenyl)-3-(2-fluoro-5-methylphenyl)urea, l-(5-(2-amino-8-ethyI-7-oxo-7,8-
dihydropyrido[2,3-d]pyrimidin-6-yl)-2-fluorophenyl)-3-(l-isopropyl-3-(thiophen-2-yl)-lH-pyrazol-5-yl)urea, l-(5-(2-amino-8-methyl-7-oxo-7J8-dihydropyrido[2,3-d]pyrirnidin-6-yl)-2-fluorophenyl)-3-(l-isopropyl-3-(thiophen-2-yl)-lH-pyrazol-5-yl)urea, l-(5-(2-amino-8-ethyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-2-fluoi-opbenyl)-3-(3-(2-fluorophenyl)-l -methyl-lH~pyrazol-5-yl)urea, l-(5-(2-ajiimo-8-ethyl-7-oxo-7,8-dihydropyrido[2,3-d]p)'rimidin-6-yl)-2-

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fluorophenyl)-3-(5-chloro-2-methyIphenyI)urea, l-(5-(2-amino-S-ethyl-7-oxo-7,8-
dihydropyrido[2,3-d]pyrimidin-6-yl)-2-fluorophenyl)-3-(4-chloro-2-methylphenyl)urea, I-(5-(2-
amino-S-ethyl-7"Oxo-7,8-dihydropyrido[2J3-d]pyrimidin-6-yl)-2-fluoropKenyl)-3-(iiaphthalen-l--
yl)urea, l-(5-(2-aniino-8-ethyl-7-oxO"7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-2-fIuorophenyl>
3-(3-chloro-2-methylphenyl)urea, !-(I-(4-(I)3,4-oxadia2ol-2-yl)phenyl)-3-tert-butyl-lH~pyra2ol-
5~yl)-3-(5^2-mTiino-8-methyl-7-oxo-7J8-dihydropyiido[23-d]pyrimidin-6-yl)-2-
fluorophenyl)urea, l-(5-(2-amino-8-ethyl-7-oxo-7J8-dihydropyrido[2,3-d]pyriniidin-6-yl)-2-
fluorophenyl)-3-(3-isopropyM-phenyMH-pyrazol-5-yI)urea, l-(5-{2-amino-8-methyl"7-oxo--
7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-2-fluorophenyl)-3-(3-tert-butyl-l-(2-methylquinolin-6-
yl)-1 H-pyrazoI-5-yl)urea, 1 -(2-fluoro-5-(8-methyl-2-(methyIamino)-7~oxo-738-
dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)-3-(3-isopropyl-l-phenyl-lH-pyra2ol-5-yl)uTea, 1-
(3-tert-butyl-l-phenyl-IR-pyrazol-5-yl)-3-(2-fIuoro-5-(8-methyU2-(methylaiBino)-7-oxo-7,8-
dihydropyridot2,3-d]pyrimidin-6-yl)phenyl)ureaJ l-(2-fluoro-5-(8-methyl-2-(methylamino)-7-
oxo-73-dihydrop)rido[2,3-d]pyrimidin-6-yl)pheiiyl)--3-(3-(2-fliioroplienyl)-l-methyl-lH-
pyrazol-5-yl)urea, l"(2-fluoro-5-{8-methyl-2-(inethy]amino)-7-oxo-7,8-dihydropyrido[2,3-
d]pyrimidin-6-yl)phenyl)-3-(4-biphenyl)urea, l-(3-{2-amino-8-methyl-7-oxo-7J8-
dihydropyrido[23^]pyrimidin^-yl)phenyI)-3-(3-tert-butyl-l-(2-(dimetIiylamino)ediy!)-lH-
pyrazol-5-yl)urea, l-(5-(2-amino-8-methyi-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-2-
fluorophenyl)-3-m-tolylurea, l-(3-tert-butylisoxazoI-5-yl)-3-(2-fluoro-5-(8-methyl"2-
(metliylainino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyI)urea. l-(5-(2-amino-8-
ethyl-7-oxo-7,8-dihydropyrido[2J3-d]pyrimidin-6-yl)-2-fluorophenyI)-3-(l-(3-cyanophenyl)-3-
isopropyl-1 H-pyrazol-5-yl)urea, 1 -(2-fluoro-5-(8-metiiyl-2-(inetliylamino)-7-oxo-7,8-
dihydropyrido[2,3-d]pyrimidin-6-yI)plienyl)-3-(3-biphenyl)urea, I-(5-(2-amino-8-metliyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yI)-2-fluorophenyl)-3-(4-chloro-3-
(trifluoromethyl)phenyl)urea, l-(5-tert-butyhhiophen-3-yl)-3-(2-fIuoro-5-(8-methyl~2-
(rnethylaTnino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)ureaI l-(2-fluoro-5-(8-
methyl-2-(methylmnino)-7-oxo-7J8-dihydropyrido[2,3-d3pyrimidin-6-yl)phenyl)-3-(l-phenyl-3-
(trifluoromethyl)-1 H-pyrazoI-5-yI)urea, I -(5-(2-ammo-8-isopropyI-7~oxo-7,8-dihydropyrido[2,3-
d]pyrimidm-6-yl)-2-fluorophenyl)-3-(3-tert-butyH-inetiiyI-1H-pyrazol-5-yl)iirea, l-(5-(2-
amino-8-ethyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6"yl)-2-fluorophenyl)-3-(l-(4-
fluorophenyl)-3-isopropyl-lH-pyrazol-5-yl)urea,. l-(5-(2-amino-8-methyl-7-oxo-7,8-

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dihydropyrido[2,3-d]pyrimidin-6-yl)-2-fluorophenyl)-3-(l-(3-cyanophenyl)-3-isopropyl-lH-
pyrazal-5-yI)urea, l-(5-(2-amino-8-ethyl-7-oxo-7,8-dihydropyrido[2,3-d3pyrimidin-6-yl}-2-
fluorophenyl)-3-(l -(3-fluoi"ophenyl)"3-isopropyl-1 H-pyrazol-5-yl)urea, 1 -(3-(2-amino-8-ethyI-7-
oxo-718-dihydropyrido[2)3--d]pyrimidin-6-yl)phenyl)-3-(3-isopropyl-l-(quinoliii-6-yl)-lH-
pyrazol-5-yl)urea, l-{5-(2-amino-8-isopropyl-7-oxo-7,8-^ihydropyrido[2,3-d3pyriraidin-6-yl)-2-
fluorophenyl)-3-(3-tert-butyl isoxazol-5-yl)urea, l-(3-tert-butylphenyl)-3-(2"fluoro-5-(8-methyI-
2^methylamino}-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6--yl)phenyl)urea, l-(3-tert-
butylisoxazol-5-yl)-3-(5-(2-(2-(diniethylamino)ethylainino)-8-methyl-7-oxo-7,8-dihydropyrido^^-djpyiimidiii-S-ylJ-S-fluorophenylJurea, l-(5-(2-amino-8-methyl-7-oxo-7,8-dihydropyrido[23-d]pyrimidin-6-yl)-2-fluoro-4-meto^
lK5-(2-araino-8-methyl-7-oxo-7,8-dihydropyrido[2T3-d]pyrimidin-6-yl)-2-fluorophenyl)'-3-(3-
tert-butylisoxazol-5-yl)urea, l-(5-(2-(2-(dimethyIamino)ethylaniino)-8-metliyl-7-oxo-7)8-
dihydropyrido[2,3-d]pyrimidin-6-yl)-2-fluorophenyl)-3-(3-(trifluoromethyl)phenyl)urea, 1 -(1 -(3-
(2-amino-2-oxoethyl)phenyI)-3-tert-butyI-lH-pyrazol-5-yl)-3-(5-(2-(2-
(dimetliyIamino)ethylamino)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]p>Timidin-6-yl)-2-
fluorophenyI)urea, l-(5-(2-amino-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-2-
fluorophenyI)-3-(l-(6-methylpyridin-3-yl)-3-(trifluoromethyl)-IH-pyrazol-5-yi)urea, 1-(5-(2-(2-
(dimethylamino)ethyIaimno)-8--methyl-7-oxo-7t8-dihydropyrido[2)3-d]pyrimidin-6-yl)-2-
fluorophenyi)~3-(3-isopropylisoxazol-5-yl)urea, 1 -(I -tert-butyl-1 H-pyrazol-4-yl)-3-(2-fluoro-5-
(8-iiiediyl-2-(methylamino)-7-oxo-7,8-dihydropyrido[213-d]pyrimidin-6-yl)phenyl)ureaJ l-(5-(2-
amino-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyriinidiii-6-yl)--2-fluoro-4-methyIphenyI)-3-(3-
tert-butyl-1 -methyl-1 H-pyrazol-5-yl)urea, 1 -(2-fluoro-5-(8-methyI-2-(methylamino)-7-oxo-7.8-
dihydropyrido[2,3-d3pyrimidin-6-yl)phenyl)"3-(3-(trifIuororaethyl)phenyl)urea) l-(2-fluoro-5-(8-
methyl-2-(methylamino)-7--oxo-7)8-dihydropyrido[2,3-d]pyrimidin-6--yI)phenyl)-3-(3-
isopropylisoxazol-5-yl)urea, l-(5-(8-etIiyl-2-(metbylamino)-7-oxo-7,8-dihydropyrido[2)3-
d]pyrimidm-6-yl)-2-fluorophenyl)-3-(3-isopropyl-l-phenyl-lH-pyrazol-5-yl)urea, l-(5-(2-
ammo-8-ethyl-7-oxo-7,8-dibydropyrido[2,3-d]pyrimidin-6-yl)-2-fluorophenyl)-3-(3-
(trifluoromethyl)phwiyl)urea, l-(3-teTt-bur}'lphenyl)-3-(5-(8-ethyl-2-(meth}'lamino)-7-oxo-7,8-
dihydropyrido[2,3-d]pyrimidin-6-yl)-2-fluorophenyl)urea) l-(5-(8-etliyI-2-(methylamino)-7-oxo-
7,8-dihydropyrido[23-d]pyrimidin-6-yl)-2-fluoro^
pyrazol-5-yl)urea, I-(3-tert-butyl-l-ethyl-lH-pyra2ol-5-yl)-3-(2-fluoro-5-(8-methyl-2-

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(methyl amino)-7-oxo-7.8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea, I-(4-chloro-3-
(trifluoromethyl)phenyI)-3-(2-fluoro-5-(8-methy 1-2-(methyl amino)-7-ox o-7?8-
dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea, (S)-l-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-5-
(2-(l-hydroxypropan-2-ylamino)-8-mediyl-7-oxo-73-dihydropyrido[23-d]pyriinidin-6-
yi)phenyl)urea, (S)-l-(2-tluoro-5-(2-(l-hydToxypropan-2-ylamino)-8-methyl-7-oxo-7,8-
dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)-3-(3-isopropylisoxazol-5-yl)urea, l-(2-tert-
butylthiazol-5-yl)-3-{2ifluoro-5-(8-methyl-2-(methylamino)-7-oxo-7,8Hdihydropyrido[2,3-
d]pyrimidin-6-yl)phenyl)urea, l-(5-(8-ethyl-2-(methylamino)-7-oxo-7,8-dihydTopyrido[2,3-
d]pyrimidin-6-yl)-2-fluorophenyl)"3-(l-methy3-3-(trifluoromethyl)-lH-pyrazol-5-yl)urea, l-(2-
fluoro-5-(8-methyl-2-(methylaniino)-7-oxo-7,8-dihydropyrido[2)3-^]pyrimidin-6-"yl)phenyl)-3-
(3-(trifluorometliyl)isoxazol-5-yl)ui'ea, I-(3-tert-butylphenyl)-3-(5-(2-(2-
(dimethyiamino)ethylamino)-8-methyI-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yI)-2-
fluorophenyl)urea, I-(2-fIuoro-5-(2-(l-hydroxypropan-2-ylamino)-8-methyl-7-oxo-7,8-
dihydropyrido[2,3-d]pyrimidm-6-yl)phenyl}-3-(3-(trifluoromethyl)phenyl)urea, l-(3-tert-butyl-
l-isopropyl-)H-pyrazol-5-yl)-3-(2-fJuoro-5-(8-methyl-2-(metliylammo)-7-oxo-7,S-
dihydropyrido[2,3-d]pyrimidin-6-yl)phenyt)urea, I-(3-tert-butyl-l-ethyl-lH-pyrazol-5-yl)-3-(5-
(8-ethyl-2-(methylaniino>7-oxo-7,8-dihydropyrido[2,3-d]pyrimidm-6-yl)-2-fluorophenyl)urea,
l-(2-fluoro-5-(8-methyl-2-(methylamino)-7-oxo-7J8-dihydropyrido[2,3-d]pyrimidin-6-
yl)phenyl)-3-(3-(l-hydroxy-2-metliyipropan-2-yl)-l-phenyl-lH-pyrazol-5-yl)urea, l-(3-tert-
butyl-l-methyl-lH-pyrdzol-5-yl)-3-(2-fluoro-5-(8-isopropyl-2-(methylaniino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yi)phenyI)urea, l-(2-fluoro-5-(8-metliyl-2-(methyiainino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)-3-(4-TneUiylpyrimidin-5-yl)urea3 l-(3-tert-
butylisoxazol-5-yl)-3-(2-fIuoro-4-metliyl-5-(8-methy]-2-(methylaTnino)-7-oxo-7,8-
dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea, l-(2-fluoro-4-methyl-5-(S-methyl-2-
(methylamino)-7-oxo-7;8-dihydropyrido[2J3Hd]pyriniidiii-6-yl)phenyl)--3-(l-phenyl-3-
(trifluoromethyl)-lH-pyrazol-5-yI)urea, l-(3-tert-butyl-l-phenyl-lH-pyrazol-5-yl)-3-(2-fluoro-4-
methyl-5-(8-methyl-2-(methylamino)- 7~oxo-7,8 -dihydropyrido[2,3-d]pyrimidin-6-
yl)phenyl)urea, l-(2-fluoro-4-methy!-5-(8-methyl-2-(methylamino)-7-oxo-7,8-
dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)-3-(3-(trifluoromethyl)isoxazol--5-yl)urea, l-(4-
chl oro-3 -(tri fluoromethyl )phenyl )-3 -(2-fl uoro-4-methy l-5-(8-methyl-2-(methy! amino)-7-oxo -7,8-dihydropyrido[2,3-d]pyrimidin-6-yI)phenyl)urea, l-(3-ter£-butyl-l-methyMH-pyrazoI~5-yI)-

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3-(2-fluoro^-methyl-5 yl)phenyl)urea, l-(l-tert-butyl-lH-pyrazol-4-yl)-3-(2-fluoro-5-(8-isopropyl-2-(methylamino)-7-
oxo-7,8-dihydropyrido[2,3-d3pyrimidin-6-yl}phenyl)urea, 1-(2-fluoro-5-(8-raetfayl-2-
(methylamino)-7-oxo-7,8-dihydropyrido [2,3-d]pyriniidin-6-yl)phenyI)-3-(6-phenylpyrimidin-4-
yl)urea, l-(l-tert-butyl4K-pyrazol-4-yl)-3"(5-(2K2-(dimethylamino)ethylamino)-8-methyl-7-
oxo-7]8-dihydropyridot2,3-d]pyrimidin-6-yl)-2-fluorophenyI)urea) 1-(5-(2-amino-8-metIiyl-7-
oxo-7,8-dihydropyrido[2^-d3pyrimidin-6-yl)-2-fluoro-4-methyIpheiiyl)-3-(I-phenyI-3-
(trifl'uoromethyl)-l H-pyrazol-5-yl)urea, 1 -(1 -tert-butyl-1 H-pyrazol-4-yl)-3 -(2-fluoro-4-methyl-5-
(8-mefliyl-2-(metiiylamino)-7-oxo-7)8-dihydropyridot2,3-d]pyrimidin-6-yl)phenyl)urea, !-(3-
tert-butyl-l-(2-(dimethyIamino)ethyl)-lH-pyrazol-5-yl)-3-(2-fluoro-4-methyl-5-{8-methyl-2-
(methyIamino)-7-oxo-7,8-dihydropyrfdo[2^-d]pyrinudin-6-yI)phenyl)urea, I-(5-lerL-
butyHsoxazol-3-yl)-3-(2-fluoro-4-methyl-5-(8-methyi-2-(methylamino)-7-oxo-7,8-
dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea, l-(5-(2-(2-(dimethy!amino)ethyIamino)-8-
methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-2-fluoro-4-methylphenyl)-3-(3-
(trifluoromethyl)isoxazol-5-yI)urea, (R)-1 -(1 -tert-butyl- lH-pyrazol-4-yl)-3-(2-fluoro-4-methyl-
5-(8-meUiyI-7-oxo-2-(l-phenyIethyIamino)-7.8-diIiydropyrido[2,3-d]pyrimidin-6-yI)phenyl)urea,
l-(I-tert-butyl-lH-pyrazol-4-yl)-3~(5-(2-(2-(dunethy1amino)ethylamino)-8-methy^
dihydropyrido[2,3-d]pyriTnidin-6-yl)-2-fluoro-4-methylphenyl)urea, l-(5-tert-butylisoxazol-3-
y])-3-(2-fluoro-5-(8-methyl-2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-
yl)phenyl)urea, (S)-l-(I-tert-butyMH-pyrazol-4-yl>3-(2-fluoro-4-methyl-5-(8-methyl"7-oxo-2-
(l-pheny!ethy!amino)-7,8-dihydropyrido[2,3-d]pyrimidin-6-yI)phenyI)urea, l-(2-fiuoro-5-(8-
methyI-2-(metliylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)-3-(5-
{trifIuoromethyl)pyridin-3-yI)urea, (S)-l-(3-tert-butylisoxazol-5-yl)-3-(2-f]uoro-5-(8-Tnethyl-7-
oxo-2-(l~phenylethylamino)-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea, (R)-l-(3-tert-
butylisoxazol-5-yl)-3-(2-fluoro-5-(8-methyl-7-oxo-2-(l-phen>detliyIamino)~7,8-
dihydropyrido[2,3-d]pyrimidin~6-yI)phenyl)urea, l-(3-cydopentyJ-l-methyl-IH-pyrazoI-5-yl)-3-
(2-fluoro-4-methyi-5-(8-metliyl-2-(raeUiylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-
yl)phenyl)urea, l-(5-tert-butylisoxazol-3-yl)-3-(5-(2-(2-(dimethylamino)ethylamino)-8-methyl-
7-oxo-7,8-dihydTOpyrido[2,3-d3pyrimidin-6-yl)-2-fluorophenyl)urea) I-(l-tert-butyl-lH-pyrazol-
4-yl)-3-(5-(2-(23-dihydroxypropylamino)-8-methyl"7-oxo-7J8-dihydropyrido[2,3-d]pyrimidin"
6~yl)-2-fluoro-4-methylphenyl)urea, l-(34ert-butyl-l-metliyl-lH-pyrazol-5-yl)-3-(5-(2-(2-

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(dimediyIamino)efeylainino)-8-methyU7-oxo-7,8-dihydropyrido[23-d]pyrimidin-6-yl)-2-f]uoro--
4-methylphenyl)urea, l-(3-tert-butylisoxazol-5-yl)-3-(5"(2-(2-(dimetliylamino)ethylamino)-8-
methyl-7-oxo-7,8^iydropyrido[2,3-d]pyrimidin-6-yl)-2-fluoro-4-methylphenyl)urea. l-(5-tert-
buty]isoxazol-3-yl)-3-(5-(2-(2-(dimethylamino)ethylamino)-8-methyl-7-oxo-7,8-
dihydTopyndo[2,3^]pynmldm-6-y])-2-fluoTO^-methylphenyl}urea, l-(3-cyclopentyl-l-methyl-
lH-pyrazoi-5-yl)-3-(5-(2-(2-(dimethylamino)ethylamino)-8-methyl-7-oxo-7,8-
dihydropyrido[2J3-d3pyrimidin-6-yl)-2-fluoro-4-methylphenyI)urea, l-(5-(2-(2-
(dimethylamino)ediylamino)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-2-fluoro
4-methylphenyl)-3-(3-(trifluoromethyl)plienyl)iirea) l-(l-tert-butyl-lH-pyrazol-4-yI)-3-(2-
fluoro-5--(2-(isopropylamino)-8-methyi-7-oxo-7,8-diliydropyrido[2,3~d]pyrimidin-6-yl)-4-
mediylphenyl)urea, l-(2-fluoro-5-(8-methyl-2-(methyIamino}-7-oxo-7,8-dihydropyiido[2,3-
d]pyrimidin-6-y])pheny3)-3-(3-(l-hydroxy-2-methylpropaji-2-y])-l-mediyI-]H-pyrazol-5-yl)urea, l-(l-tert-butyl-lH-pyrazol-4-yl)-3-(5-(2-{2,3-diliydroxypropylamino)-8-inethyl-7-oxo-738-dihydropyrido[2,3-d]pyrimidin-6-y1)"2-fluorophenyl)urea, I-(5-tert-butyI-l,3,4-thiadiazol-2-
yl)-3-(2-fluoro-4~methyl-5-(8-methyl-2-(methylaniino)-7-oxo-7)8-dihydropyrido[2,3-
d]pyrimidin-6-yl)phenyl)ureaJ ldifluoro-S-tS-methyl-CmethylaminoJ-oxo--
dihydropyrido[2)3-d]pyrimidin-6-}d)phenyl)-3-(3-(trif(uorometliyl)isoxazol-5-yl)urea, l-(4-
cWoro-2-fluoro-5-(8-methyl-2-(methylamino)-7-oxo-7,8-dihydropyridot2,3-d]pyrimidin-6-
y])pbeny3)-3-(3-(trifluoroinetliyl)isoxazol-5-yl)urea, 1 -(] -tert-butyl-5-(trifluorometi3yl)-l H-
pyrazol-4-yl)-3-(2-fluoro-5-(8-mediyl-2-(mediylani!no)-7-oxo-7,8"dihydropyrido[2,3-
d]pyrimidin-6-yI)phenyl)urea, l-(2-fluoro-4-methyl-5-(8-methyl-2-(methylamino)"7-oxo-7,8-
dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)-3-(3-(trifluorometiiyl)plienyI)urea, 1-(I-tert-butyl-
lH-pyrazol-4-yl)-3-(5-(2-(cycIopropylamino)-8-mediyl-7-oxo-7,8-dihydropyrido[2,3-
d]pyrimidin-6-yI)-2-fIuoro-4-methyIphenyI)urea, (S)-1 -(1 -tert-butyl-1 H-pyrazoi-4-yi)-3-(2-
f!uoro-5-(2-(l-hydroxypropan-2-ylaiTuno)-8-mediyI-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-
yl)-4-methylpheayl)urea, (R>1 -(1 -tert-butyl-1 H-pyra2ol-4-yl)-3^(2-fluoro-5-(2-(l -
hydrox>^ropan-2-yImnino)-8-methyl--7-oxo-7,8-dihydropyridot2,3-d]pyrimidin-6-yl)-4-
methylphenyl)urea, l-(5-tert-butylisoxazol-3-yI)-3-(4-cliloro-2-fluoro-5-(8-Tnethy]-2-
(methylamino)-7-oxo-7,8-dihydropyrido[23-d]pyrimidin-6-yl)phenyl)urea, I -(5-tert-
butylisoxazol-3-yl)-3-(5-(8-ethyl-2-(me1hylamino)-7-oxo-7,8-dihydropyrido[2J3-d3pyrirnidiii-6-yl}-2-fluoro-4-methylphenyl)urea, !-{5-(8^ethyl-2-(meihyIamino)-7-oxo-7)8~dihydropyrido[2,3-

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d]pyiimidiii-6-yl)-2-fluoro-4-methylpheiiyI)-3-(3-isopropyl-l-ph^nyl-lH-pyrazol-5-yl)urea, 1-
(Rert-butyl-lH-pyrazol-4-yl)-3-(5 d3pyrimidin-6-yl)-2-fluoro-4-methylphenyl)urea, I-(3-tert-bUtylisoxazol-5-yl)-3-(4-chloro-2-
fluoro-5-(8-methy2-(mel3iylamino)-7-oxo-
l-fS-tert-butylisoxazol-S-yO-S-CS^S-ethyl-CmethylaminoJ-T-oxO-V-dihydropyrido-
d]pyrimidin-6-yl)-2-fluoro-4-metiiylphenyl)urea, i_(2^fluoro-4-methyI-5-(8-methyI-2-
(methy]amino)-7-oxO"7-dihydropyrido[23]pyrinudin-6-yl)phenyl)-3-(3-isopropylisoxazo
yl)urea, H54ert-buty!isoxazol-3-yl)-3-(2Adifluoro-5-(8-mettiyl-2-(methylamiiio)-7-oxo-7,8-
dihydropyrido[23-d]pyrimidin-6-yl)phenyl)urea, l-(3-tert-butyI-l-methyI-lH-pyrazol-5-yI)-3-
(5H8-ethyl-2Kmethylamino)-7-oxo-7,8-dihydropyrido[23]pyri^din-6-yl)-2-fluoro-4-
methylphenyl)urea, l"(3"tert-butyI-l-methyl-lH-pyrazol-5-y])-3-(4-chloro-2-fluoro-5-(S-metliyl-
2-(methylamino)-7-oxo-7,8-dihydropyrido[2}3-d]pyrimidin-6-yl)phenyl)urea, l-(3-tert-
butyIisoxazol-5--yl)-3-(2-fiuoro-5-(8-isopropyl-2-(methylamiiio7-oxo-7,8-dihydropyrida[2,3-
d]pyrimidin-6-yI)-4-methylphenyl)urea) 1 -(14ert-butyl-l H-pyrazol-4-yl)-3-(2,4-difluoro-5-(8-
methyl-2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea, l-(l-tert-
butyl-5-methyi-lH-pyrazol-4-yl)-3-(2-fluoro-5-(8-methyl-2-(nietliylamino)-7-oxo-7)8-
dihydropyrido[2,3-d]pyrimidin-6-yI)phenyl)urea, i_(2-fluoro-4-methyi-5-(8~methyl"2-
(methylmnino)-7-oxo-7,8-dihydropyrido[23-d]pyrimidin-6-yl)pbenyI)-3-(3-isopropyl-l-phenyl-
lH-pyrazol-5-yl)urea, l-(2-fiuoro-4-methyl-5-(8-metyl-2-(methylamino)-7-oxo-7J8-
dihydropyridoU-dyrimidin-e-ylJphenyO-S-CS-isopropylisoxaol-S-yOurea, I-(4-chloro-2-
3uorO"5-(S-mediyl-2Kmethylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyI^
(5-isopropylisoxazoI-3-yl)urea, l-(3_tert-butylisoxazoI-5-yl)-3-(5-(2-{3-
(dimethylamino)propylamino)"8-methyl-7"Oxo-7,8^0iydropyridt?[23-d]pyrimidin-6-yl)-2-
fluoro-4-methylphenyl)urea, l-(3-tert-butyl-l-methyl-lH-pyrazol-5-yl)-3-(2-fiuoro-5-(8-
isopropyl-2-{methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyriii)idin-6-yl)-4-
methylphenyl)urea, l-(l-tert-buty!-lH-pyrazol-4-yl)-3-(2-fltioTO-5-(8-isopropyl-2-
(methylamino)-7"Oxo-7]8^ihydropyrido[2,3-d]pyrimidin-6-yl)-4'methylphenyl)urea, l-{4-
metiiylO-(8-metliyl-2-(methylamin
(l-phenyl-S-CtrifluoroniethylJ-lH-pyrazoUS-yurea, K(i-tert-butyl-lH-pyrazol-4-yI)-3-(4-
chloro-2-fluoro-5-(8-mhyI-2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin"6--
yl)phenyl)urea, (S)-l-(3-tert-butyIisoxazol-5-yl}-3(2-fluoro-5-(2-(hydroxypropan-2-ylaniino)-

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8-isopropyl-7-oxo-738-dihydropyrido[2,3-d]pyrimidin-6-yI)-4-rnethylphenyl)urea, l-(2-fluoro-5-(8-methyl-2-(methylmnino)-7-oxo-7,8-di
IH-pyrazol-5-yl)urea, l-(2"tert-butyl-4-phenylpyrimidin-5-yI)-3-(3-(8-methyl-2-(methylaniino)-
7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea, l-(2-tert-butyl-4-phenylpyrimidin-5-
yI)-3-(2-flmro-4-meti:yI-5-(8-methyl-2-(methylamino)-7-oxo-7}8-dihydropyrido[2!3-
d]pyrimidin-6-yl)phenyl)urea, I-(2-fIiioro-4-methyl-5-(8-methyl-2-(methylamino)-7-oxo-7,8-
dihydropyiido[2,3-d]pyrimidin-6-yI)phenyl)-3-(naphthalen-l-yl)urea, (R)-I-(3-tert-
butylisoxazol-5-yl)-3-(2-fluoro-5-(2-(l-hydroxy-3-methy]butan-2-ylamino)-8-methyl-7-oxo-7,8-
dihydropyrido[2,3-d]pyrimidin-6-yl)-4-methylpheny])urea, (S)-l-(3-tert-butylisoxazol-5-yl)-3-
(2-fluora-5-(2-(l-hydroxy-3-methy!butan-2-ylamino)-8-methyl-7-oxo-7J8-dihydropyrido[2,3-
dJpyrimidin-d-ylH-methylphenyiirea, l-(5-tert-butyIisoxazol-3-yI)-3-(4-ethyl-2-fluoro-5-(8-
methyl-2-(methylainino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea, l-(3-tert-
biityIisoxazol-5-yl)-3-(4-methyl-3-(8-methyl-2-(methylamino)-7-oxo-7,8-dihydropyrido[2)3-
d]pyriinidin-6-yl)phenyI)urea, l-(l-tert-butyl-lH-pyrazoI-4-yl)-3-(4-methyl-3-(8-methyl-2-
(methylamino)"7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea, 1-(2-fluoro-4-
methyI-5-(8-metliyI-2-(methylamino)-7-oxo-7,8-dihydropyrido[23-d]pyrimidin-6-yI)phenyl)-3-
m-tolylurea, l-(3-chlorophenyI)-3-(2-fluoro-4-methyI-5-(8-methyl-2-(metliylamino)-7-oxo-7,8-
dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)iiTea, l-(3-bromophenyl)-3-(2-f\uoTo-4-methyl-5-(8-
methyI-2-(methylamino)-7-oxo-7,8-dihydropyrido[233-d]pyrimidin-6-yl)phenyI)ureaf l-(2-
fluoro-4-metiiyl-5-(8-methyl-2-(methylamino)-7-oxo-7,8-dihydropTido[2,3-d3pyrimidin-6-
yl)phenyl)-3-(3-fluoropheny!)urea, l-(3-chloro-2-methylphenyl)~3-(2-fluoro-4-methyl-5-(8-
methyl-2-(metliyIamino)-7-oxo-7,8-dihydrapyrido[2,3-d]pyrimidin-6-yl)phenyl)urea5 l-(2,3-
dichlorophenyl)-3-(2-fluoro-4-methyl-5-(8-methyl-2-(methylamino)-7-oxo-7,8-
dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea} l-(2-chloro-5-(trifluoromethyl)phenyl)-3-(2-
fluoro-4-raethyl-5-(8-mediyl-2-(methylaniino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-
yl)phenyl)urea, l-(2-fluoro-4-methyl-5-(8-methyl-2-(metliyIaniino)-7-oxo-7>8-
dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)-3-(2-methyl-5-(trifluoromethyl)phenyl)ureaJ l-(3-bromo-2-raethylpheny])-3-(2-fluoro-4-methyl-5-(8-methyl-2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyI)urea, l-(3-chloTO-2-methylphenyl)-3-(2-fluoTO-5-(8-methyl-2-(methyl amino)-7-oxo-7,8-dihydropyrido [2,3-d]pyrimidin-6-yI)phenyl)urea, l-(5-(2-amino-8-methyl-7-oxo-7,8-dihydropyrido[2J3-d]pyrimidin-6-yl)-2-fluoro-4-methylphenyI)-3-(4-

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bromonaphtha1en-l-yl)urea, l-(5-(2-amino-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-
6-yl)-2-fluoro-4-methylphenyl)-3-(4-cliloronaphthalen-1-yl)urea. l-(2-tert-butyl-4-
(trifluoromethyl)pyrimidin-5-yl)-3-(2-fluoro-5-(8-Tnethyl-2-{methylaniino)-7-oxo-7,8-
dihydropyrido[2,3-d]pyrimidin-6-yI)pIieayI)urea. l-(5-(2-(2-(dimetihyIamino)ethyiamino)-8-
methyl-7-oxo-7s8-dUiydropyrido[2!3-d]pyriTnidin-6-yl)-2-f!uorophenyl)-3-(naphthalen-l-yl)urea,
l-(5-tert-butylisoxazo]-3-yl)-3-(4-cyano-2-fluoro-5-(8-methyl-2-(methylamino)-7-oxo-7,8-
dihydropyrido[2,3-d]pyrimidin-6-yl)pbenyl)urea, !-(2-tert-butyl-4-(l-methyl-lH-indol-5-
yl)pyrimidin-5-yl)-3-(2-fluoro-5-(8-methyl-2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-
d]pyrimidin-6-yl)phenyl)urea, l-(2-fluoro-4-methyl-5-(8-methyl-2-(methylamino)-7-oxo-7,8-
dihydropyrido[2,3-d]pyrimidin-6-yI)phenyl)-3-(2-fluoro-5-(trifluoromethyl)phenyl)urea; l-(5-
tert-butyl-l,3,4-tliiadiazol-2-yl)-3-(4-chloro-2"fluoro-5-(8-methyl-2-(metliylainiiio)"7-oxo-7,8-
dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea, l-(5-tert-butyiisoxazol-3-yl)-3-(4-ethynyl-2-
fluoro-5-{ 8 -jnethyl-2-(methyl amino)-7-oxo-7r8-dihydropyri do[2,3 -d]pyrimidin-6-yl)phenyl) urea,
l-(l-(3-acetamidophenyl>3-tert-butyl-lH-pyrazol-5-yl)-3-(2-fluoro-4-methyI-5-(8-methy]-2-
(methylamino)-7-oxo-7]8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea, l-(2,3-
difluorophenyl)-3-(2-fluoro-4-methyl-5-(8-methyl-2-(methyIamino)-7-oxo-7,8-
dihydropyrido[2,3-d]pyrimidin-6-yI)phenyl)urea, 3-(4-bromo-3-(trifluoromethyl)phenyI)-3-(2-
fluoro-5-(8-methyl-2-(m ethyl amino)- 7-oxo-7,8-dihydropyri do [2,3 -djpyrimidin-6-yl)phenyl)urea,
l-(5-(2-amino-8-methyl-7-oxo-7,8-dihydropyrido[2}3-d]pyrimidin-6-yl)-2-fluorophenyl)-3-
(quinolin-8-yl)urea, l-(4-chloro-2-fluoro-5-(8-metliyl-2-(methylamino)-7-oxo-7,8--
dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)-3-(3-isopropylisoxazol-5-yl)urea, l-(5-(2-ai-nino-8-
methyl-7-oxo-7,8-dihydropyrido[2J3--d]pyrimidin-6-yl)-2-fluorophenyl)-3-(naphthalen-l-yl)urea,
l-(3-cyclopentylisoxa2ol-5-y])-3-(2-fluoro-4-methyl-5-(8-methyl-2-(methylamino)-7-oxo-7,8-
dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea, l-(2-fluoro-4-methy1-5-(8-methyl-2-
{methylainino)-7-oxo-7,8-dihydTopyrido[2,3-d]pyriiTiidin-6-yl)phenyl)-3-(3-(l-
methylcydopentyI)isoxazol-5-yi)urea, l-(5-tert"butylisoxazol-3-yl)-3-(4-methyI-3-(8-metl-iyl-2-
(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyriinidin-6-yl)phenyl)urea, l-{2-tert-butyl-4-
morpholinopyrimidin-5-yl)-3-(2-fluoro-5-(8-methyl-2-(methy1ammo)-7-oxo-7,8-
dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea, 1 -(3-tert-butyl-1 -methyl-1 H-pyrazol-5-yl)-3-
(4-chloro-5-(8-ethyl-2-(methylamino)-7-oxo-7,8-dihydropyridot2,3-d]p)Tiniidin-6-yl)-2-
fluoropheny])urea, l-(4-chloro-5-(8-ethyl-2-(methylainmo)-7-oxo-7,8-dihydropyrido[2,3-

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d]pyrimidiii-6-y])-2-fluorophenyl)-3-(3-isopropyl-l--methyl-IH-pyrazol-5-yl)ureaJ 1-cyclopentyl-
3-(2-fluoro-4-mediyl-5-(8~methyl-2-(methylamino)-7-oxo-7,8-dihydropyrido[23-d]pyrimidin-6-
yl)phenyl)urea, 1 -(3-tert-butyl-I -metliyl-l H-pyrazol-5-yl)-3-(4-methyl-3-(8-methyI-2-
(raethylamino)-7-oxo-7-dihydropyrido[23-d]pyrimidin-6-yl)phenyl)uTea) ]-{3-tert-
butylisoxazol-5-yI)-3-(4-chloro-3-(8-methyl-2-(methylamino)-7~oxo-7.8-dihydropyrido[2,3-
d]pyrimidin-6-yl)phenyI)urea) l-(2-tert-butyl-4~(3-fluorophenyl)pyrimidin-5-yl)-3-(2"tluoro-5-
(8-methyl-2-(methylamino)-7~oxo~7,8-dihydropyrido[23-d]pyrii-nidin-6-yl)phenyl)uTea, l-(335-
dimethylphenyl)0-(2-fluoro-5-(8-methyl-2-(methylamino)-7-oxo-7J8-diliydropyrido[2,3-
6]pynmidin-6~yl)pheny\)uTQa, l-(3,5-dichlorophenyl)-3-(2-fluoro-5-(8-methyl-2-(methylamino)-
7-oxo-7,8-diliydropyrido[2,3-d]pyrimidin-6"yl)phenyl)urea. 1 -(1 -tert-butyl-5-methyl-1 H»
pyrazol-4-yI)-3-(2-fluoro-4-methyl-5-(8-methyl-2-(niediylaiTiino)-7-oxo-7,8-dihydropyrido[2)3-
d]pyrimidin-6-}i)phcnyl)iirea, l-(l-tert-butyl-5-(trifIuororaethyl)-lH-pyrazol-4-yI)-3-(4-chloro-
2-fluoro-5-(8-methyl-2-(methyIamino)-7-oxo-7,8--dihydropyrido[2,3-d]pyrimidin-6-
yl)phenyl)urea, l-(2-tert-butyl-4-(pyridin-3-yl)pyrimidin-5-yl)-3-(2-fluoro-5-(8-methyl»2-
(methyIamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea, I -(1 -tert-butyI-5-
(lrifluoromethyI)-lH-pyrazol-4-yl)-3-(2-fluoro-4-methyl-5-(8-methyl-2-(metliyIamino)-7-oxo-
7,8-dihydropyrido[2,3-d]pyrimidin-6-yI)plienyl)urea, l-(2-tert-butyI-4-(4-methylpiperazm-l-
yI)pyrimidin-5-yl)-3-(2-fluoro-5-(8-methyl-2-(methylamino)-7-oxo-7]8-dihydropyrido[2,3-
d]pyrimidin-6-yl)phenyl)urea? l-(2-fluoro-4-methy]-5-(8-methy]-2-(methyIamino)-7-oxo-7,8-
diliydropyrido[2,3-d]pyrimidin-6-yl)phenyl)-3-(l,2,3»4-tetrahydronaphthalen-1 -yl)urea, I -(1 -tert-
butyl-5-methyl-lH-pyrd2ol-4"yl)-3-(4-chloro-2-fluoro-5-(8-inethyl-2-(methyIamino)-7-oxo-7)8-
dihydropyrido[2^Hd]pyriraidin-6-yI)phenyl)urea, (R)-l-(2,3-dihydro-IH-inden-l-yl)-3-(2-fluoro-
4-methyl-5-(8-methyl-2-(metliylainino)-7-oxo-7,8"dihydropyrido[2,3-d]pyrimidin-6-
yl)phenyl)urea, (S)-l-(2s3-dihydro-IH-inden-l-yl)"3"(2-fluoro-4-methyl-5-(8-methyi-2-
(methyIamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea, I-(3-tert-
butylisoxazol-5-yl)-3-(5-(8-cydopentyl-2-(methylamino)-7-oxo-7,8-dibydTopyrido[2,3-
d]pyrimidm-6-yl)-2-fluoro-4-methylphenyl)urea, l-(3-tert-butylisoxa2ol-5-y!)-3-(5-(8-
cyc!opentyl-2-(m ethyl am ino)-7-oxo-7)8-dihydropyrido[2,3-d]pyrimidin-6-yl)-2-fIuorophenyl)urea, l-(3-tert-butylisoxazoI-5-yl}-3-(2-fluoro-5-(8-isapropyl-2-(methyIamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea, l-(2-fluoro-4-methyI-5-(8-methyI-2-(methylamino)-7-oxo-7)8-dihydropyrido[2h3-d]pyrimidin-6-y])phenyl)-3-(8-methyl-8-

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azabicycIo[3.2.1]octan-3-yl)urea, l~(2-fluoro-4-methyl-5-(8-methyl-2-(methylamino)-7-oxo-7,8-
dihydropyridop^-dJpynmidin-e-y^pheny-Sl-metiiylpiperidin^-ylJurea, 2-(3-(3-(2-fluoro-5-
(8 -metfiyl -2- (methyl amino)- 7-oxo-7,8-dihydropyrido [2,3-d]pyrimidin-6-yl)phenyl)ureido)-5-
isopropyl-1 H-pyrazol-1 -yI)-N,N-dimethyIacetamideT 1 -(2-tert-butyI-4-(piperazin-1 -yl)pyrimidia-
5-yl)-3-(5-(8-ethyl-2-(methyIamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-2-
fluorophenyl)urea, l-(3-cycIopentyl-l-methyl-lH-pyrazol-5-yl)-3-(2-tluoro-5-(8-methyl-2-
(methylammo)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea, l-(2-fluoro-4-
methyl-5-(8-memyl-2-(memylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)-3-
(tetrahydro-2H-pyran-4-yl)ureaJ l-(2-fluorG-4-metliyl-5-(8-methyl-2-(methylamino)-7-oxo-7)8-
dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)-3-(piperidin-4-yI)urea, l-(2-fluoro-5-(8-methyl-2-
(methylamino)-7-oxo-7,8-dihydropyrido[2J3-d]pyrimidin-6-yl)phenyI)-3-{ 1 -isopropyl-1H-
pyrazol-4-yl)urea, l-(l-cycIopentyl-lH-pyrazol-4-yl)-3-(2-fluoro-5-(8-metliyl-2-(mctliylamino)-
7-oxo-7,8-dihydropyrido[2)3-d]pyrimidin-6-y])phenyl)urea, 1 -(5-tert-butyI-1,3,4-thiadiazol-2-
yl)-3-(2-fluoro-5-(8-isopropyl-2-(memylamino)-7-oxo-7.8-dihydropyrido[2)3-d]pyrimidin-6-
yl)phenyl)urea, l-(3-tert-butyIisoxazol-5-yl)-3-(2-fluoro-5-(2-methoxy-8-methyl-7-oxo-7,8-
dihydropyrido[2,3"d]pyrimidin-6-yl)-4-methyiphenyl)urea, l-cyclohexyl-3-(5-(8-ethyl-2-
(methylarmo)-7-oxo-7,8-dihydropyridoE2,3-d3pyrimidin-6-yl)-2-f]uoro-4-methy]phenyl)urea) 1-
(3-tert-butyl-l-metliyl-lH-pyrazol-5-yl)-3-(5-(8-cyclopentyl-2-(methylamino)-7-oxO"7,8-
dihydropyrido[2,3-d]pyrimidin-6-yl)-2-fluorophenyl)urea, l-(l-tert-butyl-5-methyl-lH-pyrazol-
4-y])-3-(2-fluoro-4-methyI-5-(8-metliyl-2-(melJiylamino)-7-oxo-7,8-dihydropyrido[2,3-
d]pyrimidin-6~yl)phenyl)urea, l-(2,3-difluorophenyI)-3-(2-fluoro-5-(8-isopropyU2-
(methylamino)-7-oxo-7,8-dihydropyridot2J3-d]pyrimidin-6-yl)phenyl)urea, l-(2-tluoro-5-{8-isopropyI-2-(mediylamino)-7-oxo-7,8-dihydropyrido[2)3-d]pyriniidin-6-yl)phenyI)-3-(pyridin-3-yl)urea, l-(2-fluoro-5-(8-isopropyl-2-(mediylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyI)-3-{3-(trifluoromethyl)phenyl)urea, l-(2-fluoro-5-(8-isopropyl-2-(methyIamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yI)phenyl)-3-phenylurea, l-(2-fIuoro-5-(8-isopropyl-2-(methy]amino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrirnidin-6-yi)phenyl)-3-(naphthalen-l-yl)urea, !-(4-chIoro-3-(trifluoroTiiethyl)phenyl)-3-(2-fluoro-5-(8-isopropyl-2-(metliylainino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yI)phenyl)urea, l-(2-fluoro-5-(8-isopropyl-2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)-3-(2-fluoro-5-(trifluoromethyl)phenyl)urea3 l-(3-cyanophenyl)-3-(2-fluoro-5~(8-isopropyi-2-(methyIamino)-7-oxo-7,8-dihydropyrido[213-

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d]pyrimidin-6-yl)phenyl)urea, l-cyclohexyI-3-(2-fluoro-5-(S-isopropyl-2-(methyIarnino)-7-oxo-
7,8-dihydropyrido[2,3-d]pyrimidin-6-yI)phenyI)ureaL, l-cycIohexyI"3-(2-fluoro-5-(8-methyl-2-
(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyi)urea, l-(3-tert-butyl-l-
methyl-lH-pyrazol-5-yl)-3--(5"(8-cyclopentyI--2-(methylamino)-7-oxo-7,8-dihydropyrido[2)3"
djpyrimidin-G-ylJ^-fluoro^-methylpheny^urea, 1 -(3-tert-butyl-l -methyl-1 H-pyrazol-5-yl)-3-
(2-fluoro-5-(l-isopropyl-7-(methylamino)-2-oxo-l,2-dihydro-l>6-naphthyridin-3-yl)-4-
methylphenyl)urea. I -(1 -{2-(dimethyIamino)etliyl)-5-isopropyl-1 H-pyrazol-3-yl)-3-(2-fiuoro-4-
methyI-5-(8 -methyl -2-(methy]amino)-7-oxo-7,8 -dihydropyrido[2,3-d]pyrimidin-6-
yl)phenyl)urea, l-(2-tert-butyloxazol-5-yI)-3-(2-fluoro-4-methyl-5-(8-methyl-2-(inetiiylamino)-
7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yI)phenyl)urea, l-(2-tert-butyloxazo]-5-yl)-3-(4-
chloro-2-fluoro-5-(8-methyl-2-(methy!aiiiino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidiii-6-
yl)phenyl)urea, l-(2-tert-butyloxazol-5-yl)-3-(5-(8-ethyI-2-(metIiylamino)-7-oxo-7,8-
dihydropyrido[2!3-d]pyrimidin-6-yI)-2-fluorophenyl)urea, ]-(5-tert-butyI-4-methylisoxazol-3-
yl)-3-(5-(8-ethyl-2-(raethylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yi)-2-fluoro-4-
methylphenyl)urea, l-(bicyclo[2.2.1]hept-5-en-2-yl)-3-(2-fiuoro-4-methyl-5-(8-methyl-2-
(Tnethylamino)-7-oxo-7,8"dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea, 1-
(bicyclo[2.2.1]heptan-2-yl)-3-(2-fluoro-4-methyl-5"(8-methyl-2-(methylamino)-7"Oxo-7,8-
dihydropyrido[23-d3pyriirudin-6-yl)phenyl)urea, l-(2-fluoro-4-methyl-5-(8-methyl-2-
(methyl amino)-7-OXO-7.8-dihydropyrido[2,3-d]pyriniidin-6-yl)phenyl)-3-isopropyliiFeaJ (R)-l-(2-fluoro-4-methyl-5-{8-memyl-2-(methylamino)-7-oxo--7J8-dihydropyrido[2)3-d]pyriiTiidin-6-yl)phenyl)~3-(I-phenylethyl)urea, l-(2-fluoro-4-methyI-5-(8-methyl-2-(metliyIamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)-3-(l -(pyridin-3-yl)ethyl)urea, 1 -(2-fluon>5-( 1 -(2-hydroxyethyI)-7-(methyIamino)-2-oxo-l ,2-dihydro-1,6-naphthyridin-3-yl)-4-methylphenyl)-3-isopropylurea, l-(5-(8-ethyl-2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d3pyrimidin-6-yl)-2-fluorophenyl)-3-(5-(trifiuoromethyI)pyridin-3-yl)urea, 1-(2-fluoro-5-(8-methyl-2-(methyIaTnino)-7-oxO"7;8-dihydropyrido[2.3-d]pyrimidin-6-yl)phenyl)-3-(2-fluoro-5-
(trifluoromethyl)phenyl)urea5 l-(2-fluoro-5-(8-(2-hydroxyetiiyi)-2-(methylamino)-7-oxo-7,8-
dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)~3-(2--fiuoro-5-(trifluoromethyl)phenyl)urea) I-(4-
chIoro-2-fIuoro-5-(8-methyl-2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyriniidin-6-
yl)phenyl)-3-cyclohexyIurea, l-cyclohexyl-3-(2,4-difluon5-(8-methyI-2-(methyIamino)-7-oxo-
7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea, l-(4-cyano-2-fluoro-5-(8-methyl-2-

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(me%lamino)-7-oxo»7J8-dihydropyridot2^-d]pyrimidin-6-yl}phenyl)-3-cycIohexyIurea, 1-
cyclohexyl-3-(5-(8-ethyl-2-(methylamino)-7-oxo-7,8-dihydropyrida[2,3-d]pyrimidin-6--yl)-2-
fluorophenyl)urea, l-c;yclohexyI-3-(2-fluoro-4-methyI-.5-(8-methyl-2-(methyIamino)-7-oxo-7,8-
dftiy aropyri 6o\l ,3 -6]pyriTmdin-6-'y\)pVien'y\)YiTea, \ -cyc-\oViexy\-3 -\l-ftuoro-5 -{% -{1 -
hydroxyetiiyl)-2-(methylamino)-7-oxo-7J8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)ureaJ I-
(2-fluoro-4-methyi-5-(S-methyl-2-(methylamino)-7-oxo-7,8-d ihydropyri do[23-d]pyrimidin-6-
yl)phenyI)-3-({ 1 R32R)-2-methyIcyclohexyI)urea, I -(2-fluoro-4-methyl-5-(8-metiiyl-2-
(methyIamino)-7-oxo-738-dihya^opyrido[2,3-d]pyrimidin-6"yl)phenyI)-3-((lS,2S)-2-methylcyclohexyl)urea, and l-(2-fluoro-4-methyl-5-(8-methyl-2-(niethylamino)-7-oxo-7,8" dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)-3-((lr,4r)-4-methyIcyclohexyl)urea.
92. A compound selected from the group consisting of l-(3-tert-butylisoxazol-5-yI)-3-(5-(l-
ethyl-2-oxo-1,2-dihydr-1,6-naphthyridin-3-yl)-2-fluorophenyl)urea, 1 -(3-tert-butyIisoxazol-5-
yO-SS-fl-ethyl-fmethylam-oxo-l-diliydro-l-naphtliyridin-S-yl)-
fluorophenyI)urca, J-(3-tert-butyl-l-phenyl-lH-pyrazol-5-yl)-3-(2-fluoro-5-(l-i-nethyI-7-
(metliylamino)-2-oxo-l32-dihydro-l,6-naplithyridin-3-yl)phenyl)ureaJ l-(2-fluoro-5-(l-methyl-7-
(meUiylamino)-2-oxo-l)2-dihydro-lJ6-naphtliyridin-3-yI)phenyl)--3-(3-isopropyI-l-phenyl-lH-
pyrazol-5-yi)urea, 1 -(3-tert-butylphenyl)-3-(2-fluoro-5-(l -rnetliyI~7-(methylamino)-2-oxo-l ,2-
dihydro-l,6-naphthyridm-3-yI)phenyl)urea, l-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-5-(l-
methyl-7-(methylamino)"2-oxo-l,2-dihydro-lJ6-naphtliyridin-3-yl)phenyi)ureaJ l-(2-fluoro-5-(l-
methyl-7-(methylariTino)-2"Oxo-l,2-dibydro-l)6-napbthyridin-3-yl)phenyl)-3-(l-phenyl-3-
(trifIuoromethyl)-lH-pyi'azol-5-yl)urea, l-(3-tert-butyI-l-methyl-lH-pyrazoI-5-yl)-3-(2-fluoro-5-
(1 -methyl-7-(methylamJno)-2-oxo-l ,2-dihydro-l ,6-naphthyridin-3-yT)prienyT)iirea, 1 -(3-tert-
butyl-1 -methyl-1 H-pynizol-5-yl}-3-(5-( 1 -ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-
naphthyridin-3-yl)-2-rlttorophenyl)urea, l-(2-fluoro-5-(l-methyI-7-(methylamino)-2-oxo-l ,2-
dihydro- 1,6-naphthyridin-3-yl)phenyl)-3-(3-(trifluoromethyI)phenyI)urea; 1 -(1 -tert-butyl-1H-
pyrazol-4-y])-3-(2-fluoro-5-(l-meUiyl-7-(methylammo)-2-oxo-l,2-dihydro-l,6-naphthyridin-3-
yl)phenyl)urea, l-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-4-methyl-5-(I-methyl-7-(methylamino)-
2-oxo-1,2-dihydro-1,6-naphthyridin-3 -yl)phenyl)urea, 1 -(3 -tert-butyl-1 -methyl-1 H-pyrazol-5-
yl)-3-(2-fluoro-4-methyl-5-( I -methyl-7-(methyIamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-
yl)phenyl)urea, l-(5-(l-ethyl-7-(methylamino>-2-oxo-l,2-dihydro-I,6-naphthyridin-3-yl)-2-

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fliioro-4-methylphenyl)-3-(3-(trifluoromethyl)isoxazol-5'-yl)urea, l-(3-tert-butylisoxazol-5-yl)-3-
(5-(l -ethyl-7-(methylammo)-2-oxo-l ,2-dihydro-1,6-naphthyridin-3-yI)-2-fluoro-4-
methylphenyl)urea, l-(2-fluoro-4-methyl-5-(l-methyl-7-(methylamino)-2-oxo-l,2-dihydro-l,6-
naphthyridin-3-yl)phenyI)-3-(3-(trifluoromethyI)isoxazoI-5-yl)urea, I-(5-(7-(2-
(dimediyImnino)ethyImiiino)"l-methyl-2-oxo-l,2-dihydro-l,6-naphthyridin-3--yI)-2-fluoro-4-
methyIphenyI)-3-(3-(trifluoromethyI)iSOxazol-5-yI)urea, l-(3-tert-butyiisoxazoI-5-yI)-3-(2-
fluoro-5-(2-oxo-l,2-dmydro-l,6-naphthyridin-3-yl)phenyl)urea, l-(5-tert-butylisoxazol-3-yl)-3-
(2-fIuoro-4~methyl-5-( 1 -methyl-7-(methylamino)-2~oxo-l ,2-dihydro-1,6-naphthyridin-3-
yl)phenyl)urea, l-(l-tert-butyI-IH-pyrazol-4-yl)-3-(5-(7-(2-(dimethylainino)ethylamino)-l-
melhyl-2-oxo-l ,2-dihydro-1,6-naphmyridin-3-yl)-2-fluoro-4-methylphenyl)urea, 1 -(2-fluoro-4-
methyl-5-(l-methyl-7-(methylamino)-2-oxo-lI2-dihydro-l,6-naphthyridin-3-yl)phenyl)-3-(3-
(trifluoromethyl)phenyl)urea, l-(4-chIoro-3-(trifluoromethy])phenyl)-3-(2-fluoro-4-methyl-5-(l-
methyl-7 -(methyl amino)-2-oxo-1,2-dihydro-l ,6-naphtliyridin-3-yl)phenyl)urea, I -(2-fluoro-4-
methyl-5-(l-metliyl-7-(methylamino)-2-oxo-l,2-dihydro-l,6-naphthyridin-3"yl)phenyl)-3-(3-
isopropyl-I-pnenyl-lH-pyrazol-5-yl)urea, I-(3-tert-butyl-l-methyl-lH-pyrazol-5-yl)-3-(5-(l-
ediyl-7-(methylamino)-2-oxo-l,2-dihydro-l,6-naphtliyridin-3-yl)-2-fluoro-4-metiiyIphenyl)urea,
1 -(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-4-methyl-5-( 1 -memyl-2-oxo-7-(phenyl amino)-1,2-
dihydro-1,6-naphthyridin-3-yl)phenyI)urea, 1 -(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-4-methyl-5-
(1 -methyI-2-oxo-7-phenyl-l ,2-dihydra-l ,6-naphthyridin-3-yl)phenyl)urea, 1-(5-(7-amino-1 -
methyl-2-oxo-l,2-dihydro-l,6-naphthyridin-3-yl)-2-fluoro-4-methylpheny])-3-(3-tert-
butylisoxazoI-5-yl)urea, l-(l-tert-butyi-lH-pyrazoI-4-yI)-3-C2-fluoro-4-methyl-5-(l-me(hyl-7-
(methylammo)-2-oxo-l ,2-dihydro-1 ?6-naphthyridin-3-yI)phenyl)urea, 1 -(1 -tert-butyl-1H-
pyrazol-4-yl)-3-(5-(7-(3-(dimetliylamino)propylamino)-l-methy]-2-oxo-l,2-dihydro-l,6-
naphthyridin-3-yl)-2-fluoro-4-methylpheny!)urea, l-(3-tert-butyl-l-methyMH-pyrazol-5-yl)-3-
(4-chloro-2-fluoro-5-(l-metliyl-7-(methylamino)-2-oxo-lT2-dihydro-l,6-naphth3nidin-3-
yl)phenyl)urea, I-(3-tert-butyIisoxa2ol-5-yI)-3-(4-chloro-2-fluoro-5-(l-methy]-7-(methylamino)-
2-oxo-l,2-dihydro-l36-naphmyridin-3-yl)phenyl)urea, l-(5-tert-butylisoxazol-3-yl)-3-(2,4-
difluoro-5-( 1 -methyl -7 -(methyIamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)phenyl)urea, 1 -(2-tert-butyl-4-phenylpyrimidin-5-y!)-3-(2-fluoro-4-metliyI-5-(l-methyl-7-(methylainino)-2-oxo-l,2-dihydro-Is6-naphthyridin-3-yl)phenyl)urea, l-(3-tert-butylisoxazol-5-yl)-3-(4-chloro-5-(l-ethyl-7-(methyIamlno)-2-oxo-l,2-dihydro-l,6-naphthyridin-3-yl)-2-fiuorophenyl)urea, I-(5-(7-

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amino-l-ethyl-2-oxo-lJ2-dihydro-l,6-naphtiiyridin-3-yI)-2-fluoro-4-methyIphenyl)-3-(3-tert-
butylisoxazol-5-yl)urea, l-(5-tert-butylisoxazoI-3-yl)-3-(4-chloro-2-fluoro-5-(l-metliyl-7-
(methyIamino)-2-oxo-i)2-dihydro-l)6-naphdiyridin-3-yl)phenyI)urea, l-(4-chtoro-2-fluoro-5-(l-
m ethyl- 7-(methylamino)-2-oxo-1,2-dihydro-1 ,6-naphthyridin-3-yl)phenyl)-3-(3-
(trifluoromethyl)phenyl)urea, l-(5-tert-butylisoxazol-3-yl)-3-(4-chloro-5-(I-etiiyl-7-
(methylammo)-2-oxo-l,2-dihydro-l,6-naphthyridin-3-yl)-2-fluorophenyl)urea, l-(5-tert-
butylisoxazol-3-yl)-3-(5-(l-ethyl--7-(methyIamino)-2-oxo-l,2-dihydro-l,6-naphthyridin"3-yl)-2-
fluoro-4-methylphenyl)urea, 1 -(5-( 1 -ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphtlayridin-
3-yl)-2-fluoro-4-methylphenyl)-3-(3-(trifIuorometliyl)phenyl)urea, l-(5-(7-(2-
(dimethylamino)etiiylamino)--l-niethyl-2-oxo-lJ2-dihydro-i,6-naphthyridiii--3-yI)-2-
fluoropheivyl)-3-(2-phenylphenyl)urea, l-(4-chloro-2-fIuoro-5-(l-methyI-7-(methylamiiio)-2-
oxo-1,2-dihydro-l)6-naphthyridin"3-yl)phenyl)-3-(3-isopropyl-l-phenyl-lH-pyrazoI-5-yl)urea3
l-{l-tert-butyl-lH-pyrazol-4-yl)-3-(4-chloro-2-iluoro-5-(l-methyl-7-{methylaitiino)-2-oxo-I,2-
dihydro-l,6-naphthyridin-3-yl)pheiiyl)urea, l-(l-tert-butyl-lH-pyrazoI-4-yl)-3-(5-(l-ethy]-7-
(methylamino)-2-oxo-lI2-dihydro-lJ6-naphthyridinT3-yl)-2-fluoro-4-methylphenyl)urea, l-(5-(l-
ediy]-2-oxo-lT2-dihydro-1.6-naphthyridin-3-yl)-2-iluorophenyl)--3-(naphtl'ialen-l-yl)iirea, l-(5-
(1 -ethyl-7-(m ethyl amino)-2-oxo-l ,2-dihydro-1,6-naphtliyridin-3-yl)-2-fIuoro-4-methylphenyl)-
3-(3-isopropyl-l-phenyl-lH-pyrazol-5-yl)urea, l-(5-(7-amino-l-ethyl-2-oxo-l,2-dihydro-l,6-
naphtliyridiri-3-yl)-2-fluoro-4-methylphenyl)-3-{5-tert-butylisoxazol-3-yl)urea, 1 -(l-tert-butyl-5-
methyl- lH-pyrazol-4-yl)-3-(2-fluoro-5-{l -methyl"7-(methylammo)-2-oxp-] ,2-dihydro-l ,6-
naphthyridin-3-yl)phenyI)urea, l-(l-tert-bulyl-5-(trifluoromethyl)-lH-pyrazol-4-yl)-3-(2-fluoro-
5-(l-methyl-7-(methylamino)-2-oxo-l,2-dihydro-l,6-naphthyiidin-3-yl)phenyl)urea1 l-(5-(l-
ediyI-2-oxo-l,2-dihydro-l,6-naphthyridin-3-yl)-2-fiuorophenyl)-3-(quinolin-5-yl)urea, 1 -(1 -tert-
butyl-5-m ethyl-1 H-pyrazol-4-yI)-3-(5-( 1 -etiiyl-7-(methylamino)-2-oxo-l ,2-dihydro-1,6-
naphthyridin-3-yl)-2-fltioro-4-methylphenyI)urea, l-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-5-(7-
(methylaminoJ^-oxo-l-phenyl-l-dihydro-l^-naphthyridin^-ylJphenyOurea, 1-(1-
cyclopeutyl-lH-pyrazol-4-ylJ-3-2-fluoro-5-(l-methyl-7-(raethylarnino)-2-oxo-l,2-dihydro-l,6-
naphthyridin-3-yl)phenyl)urea, l-(5-(l-ethyl-7-(methylamino)-2-oxo-l ,2-dihydro-1,6-
naphthyridin-3-yl)-2-fluoro-4-meth.ylphenyl)-3-(naphthalcn-l-yl)urea, l-(2-fluoro-5-{l-
isopropyl-7-(methylamino)-2-oxo-l,2-dihydro-l,6-naphthyi"idin-3-yl)phenyl)-3-(3-(trifluoromethyljpheny^urea, l-cyclohexyl-3-(2-fluoro-5-(l-isopropyl-7-(methylamino)-2-oxo-

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l,2-dihydro-l,6-naphthyridin-3-yl)phenyl)urea, l-(5-(l-ethyl-7-(methylamino)-2-oxo-l,2-
dihydro-1 -naplithyridin-S-y-fiuoropheny-Cnaphthalen-l -yl)urea, 1 ~(2-fiuoro-5-(l -
isopropy]-7-(niethylamino>2-oxo-l,2-dihydro-lJ6-naphthyridin-3-yl)phenyl)-3-(2-fluoro-5-
(trirluorornethyl)phenyl)urea, 1 -(4-chloro-5-(l -ethyl-7-(methylamino)-2-oxo-1 ,2-dihydro-1,6-
naphthyridin-3-yl)-2-fluorophenyl)-3-(3-(trifluoromethyl)phenyl)urea, l-(4-ch!oro-3-
(trifluoromethyl)phenyl)-3-(5-(l-ethyl-7-(me%
yl)-2-tluorophenyl)urea, l-(4-chloro-5-(l -ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-
naphthyridin-3-yI)-2-fluorophenyI)-3-phenyIurea, l-(4-chloro-5-(l-ethyl-7-(metIiylamino)-2-
oxo-1,2-dihydro-l,6-naphthyridin-3-yl)-2-fluorophenyl)-3-(2,3-difiuorophenyI)urea, l-(3-tert-
butylisoxazol-5-yl)-3-(2-fluoro-5-(l-isopropyl-7-(methylamino)-2-oxo-l,2-dihydro-l,6-
naphthyridin-3-yl)phenyl)urea, l-(5-(I-ethyl-7-(methylainino)-2-oxo-l ,2-dihydro-l ,6-
naphthyridin-3-yI)-2-fluorophenyl)»3-(3-(trifluoromethyl)phenyl)urea, l-(2-fluoro-5-(l-
isopropyl-7-(methy]amino)-2-oxo-l ,2-dihydro-l,6-naphthyridin-3-yl)phenyl)-3-phenylurea, 1-
(4-crdoro-5-(I-ethyI-7-(methylamino)-2-oxo-lJ2-dihydro-l,6-naphthyridin-3-yl)-2-
fluorophenyl)-3-(naphthaien-l-yl)urea, l-(5-(l-ethyl-7-(methylamina)-2-oxo-l,2-dihydro-l,6-
naphti^yridin-3-yl)-2-fluorophenyl3-(2-fluoro-5"(trifluoromethyl)phenyI)ureaJ l-(5-tert-butyl-
13,4-tMadiazol-2-yl>3-(5-(l-ethyl-7-(methylamino)-2-oxo-l,2-dihydro-l,6-naphthyridin-3-yl)-
2-fiuorophenyl)urea, l-(5-tert-butyl-l,3,4-thiadia2ol-2-yl>3-(5-(l-etliyI-7-(methylamino)-2-oxo-
1,2-dihydro-1,6-naphf hyridin-3-yI)-2-fluoro-4-methy(phenyI)urea, 1 -(3-tert-butyl-1 -methyl-1H-
pyrazol-5-yl)-3-(2-fluoro-5-(l-isopropyl-7-(methyIamino)-2-oxo-l,2-dihydro-l,6-naphthyridin-
3-yl)phenyl)urea, l-(l-tert»buti-lH-pyra2ol-4-yl)-3-(2-fluoro-5-(7-(metliylamino)-2-oxo-l-
pbenyl-l^-diliydrolje-naphthyridin-j-yJJphenyl^rea, l-(2-fluoro-5-(7-(methyIamino)-2-oxo-l-
plienyl-I^-dihydro-l^-naphthyridin-S-ylJphenylJ-j-CS-fsopropylisoxazoI-S-yOurea, l-(2-fluoro-
S-oxo-l-dihydro-l-naphtiiyridin-S-ylJphenylVS-tS-CtrifluoromethyOphenylJurea l-(2-
fluoro-4-methyl-5-( 1 -methyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)phenyl)-
3-(3-isopropylisoxazol-5-yl)urea, l-(5-(l-ethyl-7-(i-nethylamino)"2-oxo-l,2-dihydro-l,6-
naphthyridin-3-yI)-2-fluoro-4-methyIphenyI)-3-(3-isopropyIisoxazoI-5-yI)urea) l-(3-tert-
butylisoxazol-5-yl)-3-(4-chloro-3-(l-ethyl-7-(methylamino)-2-oxo-l,2-dihydro-l,6-naphthyridin-3-yl)phenyl)urea, l-(4-chloro-5-(1-ethyl-7-(mediylamino)-2-oxo-l,2-dihydro-l,6-naphthyridin-3-yl)-2-fluorophenyI)-3-cyclohexyIurea, 1 -cyclohexyl~3-(2-fluoro-4-methyl-5~( ] -methyl-7-(methylamino)-2-oxo-I,2-dihydro-l,6-naphthyridin-3-yl)phenyl)urea, l-(l-tert-butyl-

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lH-indazol-3-yl)-3-(2-fluoro-mediyl-5-(l-methyl-7-(raethyIamino)-2-oxo-l,2-dihydro-I,6-
naphthyridin-3-yl)pheny])urea. l-(l-tert-butyl-lH-indazol-3-yl)-3-{4-chloro-2-fluoro-5-(l-
methyl-7-(methylamino)-2-oxo-])2-dihydro-l,6-naphthyridin-3"yl)phenyl)urea, l-(l-tert-butyl-
5-methyl-1 H-pyrazol-4-yl)-3-(2-fluoro-5-(l -isopropyl-7-(methyl amino)-2-oxo-1,2-dihydro-1,6-
naphthyridin-3-yI)phenyl)urea, l-(4-chloro-2-fluoro~5-(l-methyl-7-(methylammo)-2-oxo-l,2-
dihydro-l^-naphthyridin-S-yOphenyO-S-cyclohexylurea, l(4-ch]oro-2-fluoro-5-(l-methyI-7~
(methylamiao)-2-oxo-l,2-dihydro-l,6-naphtliyridin-3-yl)phenyl)-3-phenylurea, l-(4-chloro-2-
fluoro-5-(l-methyI-7"(mediylamino)-2-oxo-1.2-dihydro-l,6-naphthyridin-3-yI)phenyI)-3-
(naphlhalen-l-y])urea, l-(4-ch]oro-2-fluoro-5-{l-metliyl-7-(niethylaniino)-2-oxo-l)2-dihydro-
l,6-naphthyridin-3-yl)phenyl)-3-(4-chloro-3-(trifluoromethyl)pbenyl)urea5 l-(4-chloro-2-fluoro-
5-(l-metliyl-7-(methylaraino)-2-oxo-l,2Hdihydro-l,6-naphthyiidin-3-yl)pbenyl)-3-(2-fluoro-5-
(trifluoramethy[)phenyl)urea, l-(4-chloro-2-fluoro-5-(l-methyI-7-(methyIamino)-2-oxo-JJ2-
dihydro-l,6-naphthyridin-3-yI)phenyl)-3-(3-cyanophenyl)urea, l-(4-chloro-2-fluoro-5-(l-
methyl-7-(niethylamino)-2-oxo-l,2-dihydro-l)6-naplithyridin-3-yi)phenyl}-3-(2,3-
difluorophenyl)urea, l-(4-chloro-3-(l-ethyl-7-(methyIamino}"2-oxo-l,2-dihydro-lJ6-
naphtbyridin-3-y])pheny])-3-cycIohexylureaJ ]-{4-ch]oro-3-(l"ethy]-7-{metliylarnino)-2-oxo-l,2-
dihydro-l,6-naphthyridin-3-yi)phenyI>3-(3-isopropyIisoxazol-5-yl)urea, l-(4-tert-butylthiophen-
2-yl)-3-(2-f]uoro-4-methyl-5-(l -metliyI-7-(metliylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-
yl)phenyl)urea, I-(4-tert-butyl-3-methyIthiophen-2-yI)-3-(2-fIuoro-4-methyi-5-(l-methyl-7-
(methylamino)-2-oxo-1 ,2-dihydro-1,6-naphthyridin-3 -yl)phenyl)urea, 1 -(4-tert-butyl-3 -
chIorothiophen-2-yl)-3-(2-fluoro-4-methyl-5-(l-methyl-7-(mediylammo)-2-oxO"l)2-dihydro-l,6-
naphthyridiii-S-yOphenyiJurea, l-(4-tert-butyl-3-fluorothiophen-2-yl)-3-(2-fluorO"4-metliyl-5-(l-
metbyl-7-(metbyIamino)-2-oxo-lI2-dihydro-lJ6-naphthyridin-3-yi)phenyl)urea, l-(4-tert-butyI-
3-methylthiophen-2-yl)-3-(2-fluoro-5-(l-(2-hydroxyethyl)-7-(methylamino)~2-oxo-l ,2-dihydro-
l,6"naphthyridin-3-yl)-4-methylphenyl)urca, l-(l-tert-butyl-2-metliyl-lH-pyrrol-3-yi)-3-(2-
fluoro-4-methyl-5-( 1 -methyl-7-(methyl ami no)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-
yl)phenyl)urea, l-(l-tert-butyl-2-methyl-lH-pyrrol-3-yl)-3-(4-chloro-2-fluoro-5-(l-meUiyl-7-
(methylaminoj-2-oxo-1,2-dihydro-l ,6-naphthyridin-3-yl)phenyl)urea, 1 -(1 -tert-butyl-2-methyl-
m-pyrroI-3-y!)-3-{2,4-difIuoro-5-(l-TnethyI-7-(me(hyIamino)-2-oxo-l,2-dihydro-U6-
naphthyridin-3-yl)phenyl)urea, 1 -(I -tert-butyl-2-methyl-l H-pyrrol-3-yl)-3-{5-(l -emyI-7-
(methylainino)-2-oxo-l,2-dihydro-l,6-naphthyridin-3-yl)-2-fluoro-4-methylphenyl)urea> 1-(1-

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tert-butyl-2-methyl-lH-pyiTolO-yl)-3-(5-(l-ethyl-7mediylaiiiino)-2-oxo-lJ2-dihydro-l,6-
naphthyridin-3-yl)-2-fluorophenyl)urea, l-(l-tert"butyl-lH-pyrroi-3-yl)-3-(2-fluoro-4-methyl-5-
(1 -methyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)phenyI)urea, 1 -(1 -tert-
butyl-4-cMoro-IH-pyrrolO-yl)-3-(2-fluoro^-methyl-5-(I-meUiyl-7-(Tnethylainino)-2-oxo-lJ2-
dihydro-],6-naphthyridin-3-yl)phenyl)urea, l"(4-tert-butyl-l-methyl-lH-pyrrol-2-yl)-3-{2-
fluoro^-methyl-5-(l-mcthyl-7-(raethy]amino)-2-oxo-l,2-dihydro-l,6-naphthyridin-3-
yl)phenyl)urea, l-(4-tert-butyl-l-methyl-lH-pyrrol-2-yl)-3-(5-(l-ethyl-7--(metliyIamino)-2-oxo-
l^-dihydro-l^-naphthyridin^-yO^-fluorophenyOurea, l-(4-tert-butyl-3-chloro-l-methyl-lH-
pyrrol-2-yl)-3-(2-fluoro-4-methyI-5-( 1 -methyl-7-(methylamiBo)-2-oxo-l ,2-dihydro-l ,6-
naphthyridin-3-yl)phenyl)urea, l-(3-tert"butyl-l-metbyl-lH-pyrazol-5-yl)-3-(2-fluoro-5-(l-
isopropyl-7-(methylainino)-2-oxo-l,2-dihydro-I,6-naphthyridin-3-yl)-4-metliylphenyl)urea, 1-
(2-tert-butyloxazol-5-yl)-3-(2-fluoro-4-methyl-5-( 1 -methyl-7 -(methyl am ino)-2~oxo-1,2-dihydro-
1,6-naphthyridin-3-yl)phenyl)urea. 1 -(2-tert~butyloxazo]-5-yl)-3-(4-chloro-2-flxioro-5-(l -methyl-
7-(methylamino)-2-oxo-l,2-dihydro-l)6-naphthyridin-3-yl)phenyl)urea, 1-(2-tert-butyloxazol-5-
ylJ-CS-tl-etliylmethylaminoJ-a-oxo-l-dihydro-Ue-naphthyridin-S-ylJ-a-
fluorophenyl)urea, l-(2~tert-butyIoxazol-5-yl)-3-(2-fluoro-5-(l-(2-hydroxyethyl}-7-
(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-4-methyIphenyl)urea, 1 -(2-tert-
b^£yJoxazo5-y0-3-(4-chora-2-fluoro-5-((2-hydraxyefhy?)-7•(methylamino)-2-oxo-l,2"
dihydro-l,6-naphthyridin-3-yI)phenyl)urea, l-(5-tert-butyIisoxazol-3-yl)-3-(2-fluoro-5-(l-(2-
hydroxyethyl)-7-(methyiamino)-2-oxo-l,2-dihydro-l)6-naphthyridin-3-yl)-4-methylphenyl)urea,
I-(5-tert-butyl-4"methylisoxazol-3-yl)-3-(5-(l-ethyl-7-(methylamino)-2-oxo-I,2-dihydro-l,6-
naphthyridin-3-yl)-2-fluoro-4-methylphenyl)urea, l-(4-tert-butylfuran-2-yl}-3-(2-fiuoro-4-
methyl-5-(l-methyl-7-(methylamino)-2-oxo-l,2-diIiydro-l,6-naphthyridin-3-yl)phenyl)urea, 1-(4-tert-butylO-chlorofaran-2-yl)-3-(2-fluoro-4-^^
dihydro-l,6-napIithyridin-3-yl)phenyl)iirea, l-(4-tert-buty]-3-fluorofuran-2-yl)-3-(2-fluoro-4-methyl-5-(l-methyl-7-(methylamino)-2-oxo-l,2-dihydro-l,6-naphthyridm-3--y!)phenyl)urea. 1-(4-tert-butyl-3-methylfuran-2-yl)-3-(2-fluoro-5-(t-(2-hydroxyetliyl)-7-(methylamino)-2-oxo-l?2-dihydro-l,6-naphthyridin-3-yl)-4-inethyIphenyl)urea, l-cyclopropyl-3-(2-fluoro-4-methy1-5-(l-methyI-7-(methylainino)-2-oxo-l,2-dihydro-l,6-naphthyridin-3-yl)pheny])urea, 1 -(2-fIuoro-4-meUiyl-5-(l-methyl-7-(methylamino)-2-oxo-l)2-dihydro-l,6-naphthyridin-3-yl)phenyl)-3-isopropylurea, (R)-l-(2-fluoro-4-methyl-5-{l-methyl-7-(methylamino)-2-oxo-l,2-dihydro-l,6-

WO 2008/034008 PCT/US2007/078408
naphthyridin-3-yl)phenyl)-3-(l-phenylethyl)urea, l-(2-fluoro-4-m^hyl-5-(l-methyl-7-
(methylaiiiinoJ^-oxo-l^-dihydro-Ue-naphthyridin-S-y^phenyO-S-fl-Cpyridin-S-yOetliylVea,
1 -(5-(l -cydopentyl-7-(methylamino)-2-oxo-l ,2-dihydro-l ,6-naphthyridin-3-yl)-2-fluoro-4-
methylphenyl)-3-isopropylurea, l-(2-fluoro-5-(l-((3R)-3~hydroxycyclopentyl)-7-(raethylamino)-
2-oxo-l,2-d?hydro-l,6-naphthyridin-3"yl)-4-me(hylphenyI)-3-(SOpropylurea, l-(2-fluoro-4-
methyl-5-(l-mcthyl-7-(methylamino)-2-oxo-l,2-dihydro-l,6-naphthyridin-3-yl)phenyl)-3-(5-
(trifluoromethyl)pyridin-3-yl)urea, l-(2-fluoro-4-methyl-5-(l-Tnethyl-7-(methyIamino)-2-oxo-
1,2-dihydro-l ^-naphthyridin-S-y^phenylJ-S^-methyl-S-ttrifliioromethyOpyridm-S-ylJurea, 1 -
(2.4-difluoro-5-(l-methyl-7-(melhylamino)-2-oxo-lJ2-dihydro-lJ6-naphthyridin-3-yl)phcnyl)-3-
(5-(trifluoromethyl)pyridiri-3-yl)urea, l-(5-(l-ethyl-7-(methylamino)-2-oxo-l,2-dihydro-lJ6-
naphthyridin-3-yl)-2-fiuorophenyl)-3-(5-(trifluoromethyl)pyridin-3-yl)urea, 1-(2-fluoro-4-
methyl-5-(]-methy]-7-(methy]amino)-2-oxo-l,2-dihydro-l,6-naphthyridin-3-yJ)pheDy])-3-(4-
fluoro-5-(trifluoromethyl)pyridin-3-yl)urea, l-(4-chloro-2-fluoro-5-(l-methyl-7-(methylamino)-
2-oxo-1,2-dihydro-1,6-tiaphthyridin-3-yl)phenyl)-3-(5-(tri{luoromediyl)pyridin-3-yl)urea, 1 -(2-
fluoro-5-( l-(2-hydroxyethyl)-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-
yl)phenyl)-3-(5-(trifluoromethyl)pyridin-3-yl)urea, l-(5-(7-amino-l-methyl-2-oxo-l,2-dihydro-
1.6-naphthyridin~3-yI)-2-fluoro-4-methyIphenyI)-3-(3-(trifluoromethyl)phenyl)urea, 1 -(2-fIuoro-
5-( 1 -(2-hydroxyethyl)-7-(methy]amino)-2-oxo-1,2-dihydro-1,6-naphtIiyridin-3-yl)-4-
metliylphenyl)-3-(3-(trifluoromethyl)phenyl)urea, ] -(2-fluoro-4-methyl-5-( ] -methyl-7-
(rnethylarnino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)pheiryl)-3-(2-fluoro-5-(trifluorom ethyl Jphenyl) urea, l-(2-fluoro-5-(l-(2-hydroxyethyl)-7-(methylaniino)-2-oxo-l ,2-dihydro- 1,6-naphthyridin-3-yl)-4-rnethylphenyl)-3-(2-fluoro-5-(trifluoromethyl)phenyl)urea, 1 -(2-fluoro-5-(l-(2-hydroxyethyI)-7-(methylamino)-2-oxo-l,2-dihydro-l,6-naphthyridin-3-yJ)phenyi)-3-(2-fluoro-5-(rrifluoromethyf)phenyi)urea, i-(l-tert-butyl-5-(hydroxyiTiethyl)-IH-pyrazol-4-yl)-3-(4-chloro-2-fli]oro-5-(l-methyl-7-(methylamino)-2-axo-L2-dihydro-1.6-naphthyridin-3-yl)phenyl)urea, l-(l-tert-butyl-5-(hydroxymethyl)-lH-pyra2ol-4-yl)-3-(2-fluoro-4-methyl-5-(l-methyl-7-(methylamino)--2-oxo-l,2-di]iydro-1,6-naphthyridin-3-yl)phenyl)urea, 1-(l-tert-butyl-5-(hydroxyiTiethyJ)-lH-pyrazol-4-yl)-3-(2>4-difluoro-5-(l-i-riethyl-7-(rnethylamino)-2-oxo-l ,2-dihydro-l,6-naphthyridm-3-yl)phenyl)urea, l-(l-tert-butyl-5-(l-hydroxyethyl>lH-pyrazol-4-yl)-3-(4-chloro-2-fluoro-5-( 1 -methyl -7-(methyl am ino)-2-oxo-1,2-diliydro-1,6-naphthyridin-3-yI)pheiiyl)urea, l"(J-tert-butyl-5-(l-hydroxyethyl)-lH-pyrazol-4-yl)-3-(2-fluoro-

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4-methyI-5-(l -mediyl-7-(methy]aniino)-2-Qxo-] ,2-dihydro-1,6-«aplithyridirj-3-yl)pheriy])urea. 1 -
(l-tert-butyl-5-(l-hydroxyethyl)-lH-pyrazol-4-yl)-3-(2,4-difluoro-5-(l-mcthyl-7"{metliylamino)-
2-oxO" 1,2-dihydro-1,6-naphthyridin-3-yl)phenyl)urea, 1 -(1 -tert-butyl-5-ethyl-1 H-pyrdzoI-4~yl)-
3-(4-cIiloro-2-fluoro-5-(l-methyI-7-(methyIamino)-2-oxo-I,2-dihydro-l36-naphthyridin-3-
yl)phenyl)urea, l-(]-tert-butyl-5-ethyl-lH-pyrazol-4-yl)-3-(2-fluoro-4-methyl-5-(l-methyi-7-
(methyIamino)-2-oxo-l,2-dihydro-l,6-naphthyridin-3-yl)phenyl)urea, I-(l-tert-butyl-5-ethyI-lH-
pyrazoI-4-yl)-3-(2,4-difluoro-5-(l-methyl-7-(methylamijio)-2-oxo-l)2-dihydro-l,6-naphthyridin"
3-yI)pheny1)urea, l-(l-tert-butyl-5"methyl-lH-pyrazol-4-yl)-3-(2-fluoro-4"methyl-5-(l-met!iyl-
7-(metliylamino)-2-oxo-]I2-dihydro-lJ6-naphthyridin-3-yl)phenyl)urea, l-(]-tert-buty]-5-
methyt-lH-pyrazol-4-yI)-3-(4-chloro-2-fliioro-5"(l-inethyl-7-(methylamino)-2-oxo-l,2-dihydro-
l,6-naphthyridin-3-yl)phenyl)urea, l-(l-tert-butyl-5-methyl-lH-pyrazol-4-yl)-3-(2,4-difiuoro-5-
(I-methyI-7-(methylammo)-2-oxo-I,2-dihydro-I,6-naphthyridiii-3-yI)phenyI)urea, l-cyclohexyl-
3-(2-fluoro-4-methyI-5-(l-methyl-7-(methylamino)-2-oxo-lJ2Hlihydro-l,6-naphthyridin-3-
yl)phenyl)urea, l-cyclohexyl-3-(5-{l-ethyl-7-(metliylamino)-2-oxo-l,2-dihydro-l,6-
naphdiyridin-3-yl)-2-fluoro-4-methylphenyl)urea, l-cyclohexyl-3-(2-fluoro-5-(l-isopropyl-7-
(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-4-rnelhylphenyl)urea, 1 -cyclohexyl-3-
(2-fluoro-5-(l-isopropyI-7-(iri ethyl aiiiino)--2-oxo-lJ2-dihydro-l,6-naphthyridiri-3--yl)phenyl)urea,
l-cyclohexyI-3-(5-(l"Cyclopenty]-7-(methyIamino)-2-oxo-l)2-dihydro-l,6-napbthyridin~3-yl)-2-
fluorophenyl)urea, l-cyc!ohexyl-3-(5-(l-ethyl-7-(metiiylamino)~2-oxo-l,2-dihydro-l,6-
naph(hyridin-3-yl)-2-fluorophenyl)urea, l-cyctohexyl-3-(2-fluoro-5-(l-((3R)-3-
hydroxycyclopentyI)-7-(methylamino)-2-oxo-I,2-dihydro-l,6-naphtliyridin-3-yl)phenyl)urea, 1-
cyclohexyl-3-(2-fluoro-5-(l-((3R)"3-hydroxycyclopentyl)-7-(metiiylamino)-2-oxo-l ,2-dihydro-
1,6-naphthyridin-3-yl)-4-methylphenyl)urea, 1 -cyclohexyl-3-(2-fluoro-5-(I -(1 -hydroxypropan^-
yl^-Oiiethylamino^-oxo-l^-dihydro-l^-naphthyridin 1 -(4-crdoro-2-fluoro-
5-( 1 -methyl-7-(rnethylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)phenyl)-3-
cyclohexylurea. l-cycIohexyl-3-(2,4-difluoro-5-(l-methyl-7-(methylamino)-2-oxo-l,2-dihydro-
l,6-naphthyridin-3-yl)phenyl)urea, l-(4-cyaiio-2-fluoro-5-(l-methyl-7-(methylamino)-2-oxo-
1,2-dihydro-J ,6-napht]iyridin-3-yJ)pheny])-3-cyc]ohexyiurea, 1 -(2-fIuoro-4-methy]-5-(l -metJiyl-
7-(md:hy1ammo)-2-oxo-I,2-dihydro-l,6-naphdiyridin-3-yl)pheiiyl)-3-((lR,2R)-2-
methykyclohexyl)urea, l-(2-fluoro-4-methyl-5-(l-methyl-7-(methy]amino)-2-oxo-l,2-dihydro-
1,6-naphthyridin-3-yI)phenyI)-3-((I S,2S)-2-methyIcydohexyl)urea, I -(2-iluoro-4-methyI-5-(l -

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melhyl-7-(methylamino)"2-oxo-l,2-dihydro-l,6-naphthyiidin-3-yl)phenyl)-3-((lr,4r)-4-
methylcyclohexyl)urea, l-(3-tert-butylisoxazol-5-yl)-3-(5-(l-cyclopentyl-7-(methylamino)-2-
oxa-l,2-dihydro-l,6-naphthyridin-3-yl)-2-fluorophenyl)urea, l-(3-cyclopentylisoxazo!-5-yl)-3-
(2-fluoro-4-methyl-5-(l -methyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-
yl)phenyl)urea, 1 -{5-(7-amino-1 -ethyl-2-oxo-1,2-dihydro-l ,6-naphthyridin-3-yl)-2-
fluorophenyl)-3-(3~tert-butyIisoxazol-5-yl)urea, 1 -(5-(7-amino-1 -ethyl-2-oxo-1.2-dihydro-l ,6-
naphthyridin-3-yl)-2-fluoro-4-methylphenyl)-3-(3-tert-butylisoxazol-5-yl)«rea, 1 -(3-tert-
butylisoxazol-5-yl)-3-(4-chIoro-2-fluoro-5-(l-(2-hydroxyethyl)-7-(methylamino)-2-oxo-l,2-
dihydro-l,6-naphthyridin-3-yl)phenyl)urea, l-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-5-(l-(2-
Iiydroxyethyl)-7-(methyIamino)-2-oxo-I^Hiihydro-l,6-napIithyridin-3-yI)-4-iTiethy!phenyI)urea,
l-(2-fluoro-4-metbyl-5-(l-methyl-7-(methamitio)-2-oxo-lJ2-dihydro-l,6-naphthyridiri-3-
yI)phenyl)-3-(3-isopropylisoxazol-5-yl)urea, I -(3-tert-butyIisoxazoI-5-yl)-3-(2-fiuoro-5-( 1 -
isopropyI-7-(metiiylmnino)-2-oxo-l^-dihydro-l,6-naphthyridin-3-yl)-4-metliyIphenyl)urea, 1-
(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-5-(l-(2-hydroxyethyl)-7-(methylamino)-2-oxo-l^-
dihydro-l,6-naphthyridin-3-yl)phenyl)urea, l-(5-(7-amino-]-methyI-2-oxo-l,2-dihydro-l ,6-
naphthyridin-3-yl)-2-fluoro-4-methylphenyl)-3-(3-tert-butyIisoxazol-5-yl)urea1 l-(3-
cyclopentyHsoxazol-5-)-3-(2-fluoro-5-(l-(2-hydroxyethyl)-7-(methylamino)-2-oxo-l,2-
dihydro-l,6-naphthyridin-3-yl)-4-methylphenyI)urea, l-(3-tert-butylisoxazol-5-yI)-3-(2-fluoro~5-
(l-(2-hydroxyetliyl)-7-(methylamino)-2-oxo-1,2-dihydro-l, 6-naphthyridin-3-yl)-4-
methylphenyl)urea, l-(3-tert-butylisoxazo]-5-y3)-3-(2-fluoro-5-{l-(2-hydroxyethyl)-7-
(methy]amino)-2-oxo-l,2-dihydro-l,6-naphthyridin-3-yl)phenyl)urea, l-(3-tert-butylisoxazol-5-
yl)-3-(2-fluoro-5-( 1 -((3R)-3-hydroxycyclopentyl)-7-(metliylamino)-2-oxo-1,2-dihydro-1,6-
iiaplithyridin-3-yl)-4-methylphenyl)urea, 1 -(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-5-( 1 -((3R)-3-
hydroxycyclopentyl)-7-(methylamino)-2-oxo-l, 2-dihydro-l, 6-naphthyridin-3-yl)pheayl)urca, 1-
(3-tert-butyl-4-methylisoxazol-5-yl)-3-(2-fluoro-4-methyl-5-(l-methyl-7-(methylaraino)-2-oxo-
l,2-dihydro-I,6-naphthyridin-3-yl)phenyl)urea, l-{3-tert-butyl-4-chloroisoxazol-5-yl)-3-(2-
fluoro-4-methyl-5-( 1 -methyl -7-(methylamino)-2-oxo-1,2-dihydro-1 ^-naphthyridinO-
yl)phenyl)urea, I-(3-tert-butyI-4-fluoroisoxazol-5-yl)-3-(2-fluorO"4-methyI-5-(l-metliyl-7-
(methylamino)-2-oxo-1,2-dihydro-l ,6-naphthyridin-3-yl)pheny!)urea, 1 methylisoxazol-5-yl)-3-(2-fluoro-5-(l-(2-hydroxyethyl)-7-(inethylaniino)-2-oxo-l ,2-dihydro-l,6-naphthyridin-3-yl)-4-metliylphenyi)urea, l-(3-tert-butyl-4-cliloroisoxazol-5-yi)-3-(2-fluoro-

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5-(l-(2-hydroxyethyl)-7-(methylamino)-2-oxo-l,2-dihydro-l)6-naphthyridin-3-yl)-4-
methylphenyl)urea, l-(3-tert-butyl-4-fluoroisoxazol-5-yl)-3-(2-fluoro-5-(l-(2-hydroxyethyl)--7-
(methyIamino)-2-oxo-l,2-dihydra-l,6-naphthyridin-3-yl}-4-metliylphenyl)iirea, l-(5-tert-butyl-
13,4-diiadiazoI-2-yl)-3-(4-chloro-2-fIuoro-5-(l~methyl-7methylamino)-2-oxo-l,2-dihydro-l?6-
naphthyridin-3-yl)pheny])urea, l-(5-tert-hutyl-l,3,4-thiadiazoI-2-yl)-3-(5-(l-ethyl-7~
(methylamino)-2-oxo-l ,2-dihydro-l ,6-naphthyridin-3-yl)-2-fluorophenyl)urea, 1 -(5-tert-butyl-
l,314-thiadiazol-2-yi)-3-(2-fluoro*5-(l-(2-hydroxyethyI)-7-(methylamino)-2-oxo-l,2-dihydro-
1 ,6~naphthyridin-3-yl)phenyl)urea. 1 -(5-tert-butyl- l,3,4-tliiadiazol-2-yl)-3-(2-fluoro-5-( 1 -{2-
hydroxyethyl)-7-(methylamino)-2-oxo-lJ2-dihydro-l,6-naphthyridin-3-yl)-4-methylphenyl)urea,
l-(5-tert-butyI-lJ3s4-miadiazoI-2-yI}-3-(2J4-difluora-5-(1-(2-hydroxyethyI)-7-(methyIamino)-2-
oxo-l,2-dihydro-1.6-naphthyridin-3-yl)phenyl)urea, l-(l-tert-butyI-5-methyl-lH-imidazol-4-yl)-
3-(2-fluoro-4-methyl-5-(l"methyl-7-(methylamino)-2-oxo-l ,2-dihydro-l ,6-naphthyridu3-
yl)phenyl)urea, l-( 1 -tert-butyI-5-cliIoro-lH-imidazol-4-yl)-3-(2-fluoro-4-methyl-5-(l-methyl-7-
(methylamino)-2-oxo-l ,2-dihydro-l ,6-naphmyridin-3-yl)phenyl)urea, 1 -(1 -tert-butyl-5-fluoro-
lH-imidazol-4-yl)-3-(2-fluoro-4-metliyI-5-(l-methyl-7-Craethy1amino)-2-oxo-l,2-dihydro-l,6-
naphthyridin-3-yl)phenyl)urea, l-(l-tert-butyl-5-methyI-lH-imidazol-4-yl)-3-(5-(l-ethyI-7-
(methyIamino)-2-oxo-l,2-dihydro-l,6-naphthyridin-3-yl)-2-fluoro-4-methylphenyl)urea, I-(l-tert-butyl-5-methyl-lH-imidazol-4-yl)-3-(5-(l-ethyl-7-(methylainino)-2'-oxo-l,2-diliydro-l,6-naphmyridin-3-yl)-2-fluorophenyl)urea, and l-(l-tert-butyI-5-methyl-lH-imidazol-4-yI)-3-(2-f]uoro-5-(l-(2-ljydroxyethyl)-7-(rnethy]amino)-2-oxo-],2-dihydro-l)6-naphthyridin-3-yl)phenyl)urea.
93. A method of modulating a kinase activity of a wild-type kinase species, oncogenic forms thereof, aberrant fiasion proteins thereof and polymorphs of any of the foregoing, comprising the step of contacting said species with a compound of claims 1,46, 91 or 92.
94. The method of claim 93, said species being C-Raf kinase, B-Raf kinase and oncogenic forms thereof.

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PCT/US2007/078408

95. A pharmaceutical composition comprising a compound of claims 1,46,91 or 92 and salts thereof, together with a pharmaceutical!y acceptable carrier, said carrier including an additive selected from the group including adjuvants, excipients, diluents, and stablilizers.
96. A method of treating an individual suffering from a condition selected from the group consisting of cancer, hyperproliferative diseases, secondary cancer growth arising from metastasis, diseases characterized by hyper-vascularization, inflammation, osteoarthritis, respiratory diseases, stroke, systemic shock, immunological diseases, cardiovascular disease and diseases characterized by angiogenesis, comprising the step of administering to such individual a compound of claims 1,46,91 or 92.
97. The method treating an individual suffering from chronic myelogenous leukemia, acute lymphocytic leukemia, gastrointestinal stromal tumors, hypereosinophillie syndrome, glioblastomas, ovarian cancer, pancreatic cancer, prostate cancer, lung cancers, breast cancers, kidney cancers, cervical carcinomas, metastasis of primary solid tumor secondary sites, ocular diseases characterized by hyperproliferation leading to blindness including various retinopathies including diabetic retinopathy and age-related macular degeneration, rheumatoid arthritis, melanomas, colon cancer, thyroid cancer, a disease caused by a mutation in the RAS-RAF-MEK-ERK-MAP kinase pathway, human inflammation, rheumatoid spondylitis, ostero-arthritis, asthma, gouty arthritis, sepsis, septic shock, endotoxic shock, Gram-negative sepsis, toxic shock syndrome, adult respirator)' distress syndrome, stroke, reperfusion injury, neural trauma, neural ischemia, psoriasis, restenosis, chronic obstructive pulmonary disease, bone resoqjtive diseases, graft-versus-host reaction, Chron's disease, ulcerative colitis, inflammatory bowel disease, pyresis, and combinations thereof, comprising the step of administering to such individual a compound of claims 1,46, 91 or 92.
98. A method of administering to a mammal a compound of claims 1, 46, 91 or 92 said
method of administration selected from the group consisting of oral, parenteral, inhalation, and
substaneous.

Documents:

460-mum-2009-form 2(titel page).pdf

461-mumnp-2009-abstract.doc

461-mumnp-2009-abstract.pdf

461-mumnp-2009-amended specification.pdf

461-MUMNP-2009-ASSIGNMENT(13-4-2009).pdf

461-MUMNP-2009-ASSIGNMENT(7-12-2011).pdf

461-MUMNP-2009-CANCELLED PAGES(7-12-2011).pdf

461-MUMNP-2009-CLAIMS(AMENDED)-(26-7-2012).pdf

461-MUMNP-2009-CLAIMS(AMENDED)-(7-12-2011).pdf

461-MUMNP-2009-CLAIMS(MARKED COPY)-(26-7-2012).pdf

461-MUMNP-2009-CLAIMS(MARKED COPY)-(7-12-2011).pdf

461-mumnp-2009-claims.doc

461-mumnp-2009-claims.pdf

461-MUMNP-2009-CORRESPONDENCE(13-4-2009).pdf

461-MUMNP-2009-CORRESPONDENCE(24-10-2011).pdf

461-MUMNP-2009-CORRESPONDENCE(24-8-2009).pdf

461-MUMNP-2009-CORRESPONDENCE(25-5-2012).pdf

461-mumnp-2009-correspondence.pdf

461-mumnp-2009-description(complete).doc

461-mumnp-2009-description(complete).pdf

461-MUMNP-2009-ENGLISH TRANSLATION(24-8-2009).pdf

461-mumnp-2009-form 1.pdf

461-mumnp-2009-form 13(15-4-2009).pdf

461-MUMNP-2009-FORM 13(4-3-2009).pdf

461-mumnp-2009-form 13.pdf

461-mumnp-2009-form 18.pdf

461-mumnp-2009-form 2(title page)-(complete)-(4-3-2009).pdf

461-mumnp-2009-form 2.doc

461-mumnp-2009-form 2.pdf

461-MUMNP-2009-FORM 26(24-8-2009).pdf

461-MUMNP-2009-FORM 3(24-10-2011).pdf

461-MUMNP-2009-FORM 3(24-8-2009).pdf

461-MUMNP-2009-FORM 3(26-7-2012).pdf

461-mumnp-2009-form 3(4-3-2009).pdf

461-mumnp-2009-form 3.pdf

461-mumnp-2009-form 5(4-3-2009).pdf

461-mumnp-2009-form 5.pdf

461-mumnp-2009-general power of attorney(24-8-2009).pdf

461-mumnp-2009-pct-ib-304.pdf

461-mumnp-2009-pct-ib-306.pdf

461-mumnp-2009-pct-isa-210.pdf

461-mumnp-2009-pct-ro-101.pdf

461-MUMNP-2009-PETITION UNDER RULE 137(26-7-2012).pdf

461-MUMNP-2009-REPLY TO EXAMINATION REPORT(7-12-2011).pdf

461-MUMNP-2009-REPLY TO HEARING(26-7-2012).pdf

461-mumnp-2009-specification(amended)-(4-3-2009).pdf

461-MUMNP-2009-US DOCUMENT(26-7-2012).pdf

461-mumnp-2009-wo international publication report a3.pdf


Patent Number 253776
Indian Patent Application Number 461/MUMNP/2009
PG Journal Number 34/2012
Publication Date 24-Aug-2012
Grant Date 23-Aug-2012
Date of Filing 04-Mar-2009
Name of Patentee DECIPHERA PHARMACEUTICALS LLC
Applicant Address 643 MASSACHUSETTS. SUITE 200 LAWERENCE, KANSAS 66044, UNITED STATES OF AMERICA
Inventors:
# Inventor's Name Inventor's Address
1 DANIEL L FLYNN 4165 BLACKJACK OAK DRIVE, LAWRENCE, KANSAS 66047, U.S.A.
2 MICHAEL D KAUFMAN 4708 MUIRFIELD DRIVE, LAWRENCE, KANSAS 66047, U.S.A.
3 WILLIAM C PATT 801 WHEATON DRIVE, LAWRENCE, KANSAS 66049, U.S.A.
4 PETER A PETILLO 1424 NORTH 960 ROAD, LAWRENCE, KANSAS 66046, U.S.A.
PCT International Classification Number A61K31/54
PCT International Application Number PCT/US2007/078408
PCT International Filing date 2007-09-13
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 60/844,552 2006-09-14 U.S.A.
2 11/854,354 2007-09-12 U.S.A.