WO2012087938A1

WO2012087938A1 - Quinazolinone derivatives as antiviral agents

Info

Publication number: WO2012087938A1
Application number: PCT/US2011/065856
Authority: WO
Inventors: Anna Lindsey Banka; Janos Botyanszki; Maosheng Duan; Martin Robert Leivers; John Bradford Shotwell; Matthew David Tallant; Scott Howard Dickerson; Vincent W.-F. Tai; Robert Blount Mcfadyen; Aniko Maria Redman; Jianjun Yu; Xiofei LI; Dulce Maria Garrido; John George Catalano; George Adjabeng
Original assignee: Glaxosmithkline Llc
Priority date: 2010-12-20
Filing date: 2011-12-19
Publication date: 2012-06-28

Abstract

Provided are compounds and pharmaceutically acceptable salts thereof, their pharmaceutical compositions, their methods of preparation, and their use for treating viral infections mediated by a member of the Flaviviridae family of viruses such as hepatitis C virus (HCV).

Description

QUINAZOLINONE DERIVATIVES AS ANTIVIRAL AGENTS

FIELD OF THE INVENTION

[0001] Provided are compounds, pharmaceutical compositions, their methods of preparation, and their use for treating viral infections mediated by a member of the Flaviviridae family of viruses such as hepatitis C virus (HCV).

BACKGROUND OF THE INVENTION

[0002] Chronic infection with HCV is a major health problem associated with chronic liver disease, cirrhosis, hepatocellular carcinoma, and liver failure. HCV is a hepacivirus member of the Flaviviridae family of RNA viruses that affect animals and humans. The genome is a single ~9.6-kilobase strand of RNA, and consists of one open reading frame that encodes for a polyprotein of -3000 amino acids flanked by untranslated regions at both 5' and 3' ends (5'- and 3'-UTR). The polyprotein serves as the precursor to at least 10 separate viral proteins critical for replication and assembly of progeny viral particles. The organization of structural and non-structural proteins in the HCV polyprotein is as follows: C-E1-E2-p7-NS2-NS3-NS4a-NS4b- NS5a-NS5b. Because the replicative cycle of HCV does not involve any DNA intermediate and the virus is not integrated into the host genome, HCV infection can theoretically be cured. While the pathology of HCV infection affects mainly the liver, the virus is found in other cell types in the body including peripheral blood lymphocytes.

[0003] HCV is major causative agent for post-transfusion and for sporadic hepatitis.

Infection by HCV is insidious in a high proportion of chronically infected (and infectious) carriers who may not experience clinical symptoms for many years. An estimated 170 million chronic carriers worldwide are at risk of developing liver disease. See, for example, Szabo, et al., Pathol.Oncol.Res. 2003, 9:215-221 , and Hoofnagle JH, Hepatology 1997, 26:15S-20S. In the United States alone 2.7 million are chronically infected with HCV, and the number of HCV- related deaths in 2000 was estimated between 8,000 and 10,000, a number that is expected to increase significantly over the next years.

[0004] At present, the standard treatment for chronic HCV is interferon alpha (IFN- alpha) in combination with ribavirin and this requires at least six months of treatment. IFN-alpha belongs to a family of naturally occurring small proteins with characteristic biological effects such as antiviral, immunoregulatory, and antitumoral activities that are produced and secreted by most animal nucleated cells in response to several diseases, in particular viral infections. IFN-alpha is an important regulator of growth and differentiation affecting cellular communication and immunological control. Treatment of HCV with interferon has frequently been associated with adverse side effects such as fatigue, fever, chills, headache, myalgias, arthralgias, mild alopecia, psychiatric effects and associated disorders, autoimmune

phenomena and associated disorders and thyroid dysfunction. Ribavirin, an inhibitor of inosine 5'-monophosphate dehydrogenase (IMPDH), enhances the efficacy of IFN-alpha in the treatment of HCV. Despite the introduction of ribavirin, more than 50% of the patients do not eliminate the virus with the current standard therapy of interferon-alpha (IFN) and ribavirin. By now, standard therapy of chronic hepatitis C has been changed to the combination of pegylated IFN-alpha plus ribavirin. However, a number of patients still have significant side effects, primarily related to ribavirin. Ribavirin causes significant hemolysis in 10-20% of patients treated at currently recommended doses, and the drug is both teratogenic and embryotoxic. Even with recent improvements, a substantial fraction of patients do not respond with a sustained reduction in viral load and there is a clear need for more effective antiviral therapy of HCV infection.

[0005] A number of approaches are being pursued to combat the virus. These include, for example, application of antisense oligonucleotides or ribozymes for inhibiting HCV replication. Furthermore, low-molecular weight compounds that directly inhibit HCV proteins and interfere with viral replication are considered as attractive strategies to control HCV infection. Among the viral targets, the NS3/4a protease/helicase and the NS5b RNA-dependent RNA polymerase are considered the most promising viral targets for new drugs. Indeed, compounds said to be useful for treating HCV infections are disclosed, for example, in

WO2005/051318 (Chunduru, et al.) and WO2009/023179 (Schmitz, et al.). These references disclose methods for preparing the compounds, compositions comprising the compounds, compositions comprising the compounds and additional compounds, and methods of treating HCV.

[0006] Besides targeting viral genes and their transcription and translation products, antiviral activity can also be achieved by targeting host cell proteins that are necessary for viral replication. For example, antiviral activity can be achieved by inhibiting host cell cyclophilins. Alternatively, a potent TLR7 agonist has been shown to reduce HCV plasma levels in humans.

[0007] In view of the worldwide epidemic level of HCV and other members of the

Flaviviridae family of viruses, and further in view of the limited treatment options, there is a strong need for new effective drugs for treating infections cause by these viruses. SUMMARY OF THE INVENTION

[0008] In accordance with one embodiment of the present invention, there is provided a compound of any of Formulas I, II, III, IV, V, and VI described herein or a pharmaceutically acceptable salt thereof.

[0009] In yet other embodiments of the present invention, there is provided a compound of Formula (I):

(I)

or a pharmaceutically acceptable salt thereof, wherein:

Y and Z are independently selected from a bond or (d-C₆)alkylene;

X is selected from the group consisting of -NHS0₂R⁵, -NHSO₂R ⁰R⁵, -S0₂NHR⁵,

-SO₂NHR¹⁴, -SO₂NHR¹⁰R⁵, -SO₂R⁵, -S0₂R¹², -S0₂R¹⁴, -S0₂R ⁴R¹⁵, -C(0)R¹⁴, -C(0)NHR¹⁰, -C(0)NHR¹⁴, -R¹², -R ⁴,-R¹⁴R⁷, and -R¹⁴R¹⁰;

R¹ is selected from the group consisting of hydrogen, (CrC₆)alkyl, (C₄-Ci₄)aryl, nitrile, -R ⁴, and -S0₂R⁹;

R² is selected from the group consisting of hydrogen, (C -C₆)alkyl, (C₁-C₆)alkenyl, halo, -NHR ⁰, -R⁶, -R ⁰, -R¹³, -R ⁴, -R¹⁰R⁷, -R¹³R¹⁶, -R ⁰R¹⁴, -R ⁰R⁵, -R ⁴R⁷, -(CH₂)_WR¹⁴, -C(0)R⁸, and -R¹³OR⁸, wherein R¹ and R² may optionally join together along with any intervening N and C atoms to form a (d-C^ heterocyclic or a (C Cn)heteroaryl group fused to the adjacent pyridyl moiety and independently having one to three nitrogen heteroatoms;

R³ and R⁴ are independently selected from the group consisting of hydrogen, (Ci- C₆)alkyl, (C C₆)alkoxy, -R¹⁴, nitrile, -S0₂R⁸, oxo, -OR⁸, -R ², and halo;

R⁵ is selected from the group consisting of (Ci-C₆)alkyl, (CrC₆)alkoxy, nitrile, benzyl,

-R¹⁰R¹⁷, -R ⁰(R ⁷)_n, -OR⁹(R¹⁷)_m, -R⁹(R ⁷)_m, -R⁹R( ⁷)_n, -R⁹R¹², -R⁹R¹³, -R⁹OR⁸, -R ⁴, (C₄-Ci₄)aryl, and (C₃-Ci₂)cycloalkyl;

R⁶ is selected from the group consisting of -R¹⁰C(O)R¹⁴, -R¹⁰C(O)R¹⁴R¹⁶, -R¹⁰(CH₂)_WR¹², -R ⁰(CH₂)_WR¹⁴, and -R ⁰(CH₂)_WR¹⁴R¹⁶; R⁷ is independently selected from the group consisting of (Ci-C₅)alkyl, (CrC₆)alkoxy, oxo, halo, nitrile, -R⁹{R¹⁷)_m, -N0₂, -R⁹OR⁸, -C(0)R⁹, -(CH₂)_WCN, -S0₂R¹², -S0₂R⁹, -S0₂NH(CH₂)_wR¹⁴, -S0₂(CH₂)_wR¹⁴, -R ², -R ⁴, -(CH₂)_wOR⁸, -C(0)NHR¹³,

-C(0)NHR¹⁴, -C(0)NHR⁹, -R ⁰, -OR⁹(R ⁷)_m, -C(0)R¹², -NHC(O)NHR ⁰R¹¹, -C(0)NH(CH₂)_wR¹², -C(0)(CH₂)_wR¹², -C0₂R⁸,

-NHC(0)C(0)R¹⁴, -NHC0₂R⁸, -OR⁸, -C(0)NH(CH₂)_wR¹⁴, -C(0)(CH₂)_wR¹⁴, -(CH₂)_WR¹¹, -NH(CH₂)_WR¹⁴, -(CH₂)_WR¹⁴ , -(CH₂)_WR¹⁰, -(CH₂)_WNHR¹⁰, -(CH₂)_wC0₂R⁸, -C(O)NHR ⁰R¹¹, -C(0)NH(CH₂)_wOR^s, and -C(0)NH(CH₂)_wR¹¹;

R⁸ is independently selected from the group consisting of hydrogen, (CrC₆)alkyl, benzyl, -R ⁴, and {C₄-C ₄)aryl;

R⁹ is (CrC₆)alkyl;

R ⁰ is (C₄-C₁₄)aryl;

R is selected from the group consisting of nitrile, halo, (C C₆)alkyl, (C-i-C₆)alkoxy,

-NHS0₂R⁹, -C0₂R⁸, -OR⁸, -0(CH₂X_vR¹², -S0₂R¹², -S0₂R⁹, -NH(CH₂)_WR¹⁴ , -R ⁶, and -(CH₂)_WR¹⁴;

R ² is -NR⁸R⁸;

R ³ is (C₃-Ci₂)cycloalkyl;

R ⁴ is selected from the group consisting of (C₁-C₁ ^heterocyclic and (CrCn)heteroaryl, each independently having one to three heteroatoms selected from N and O; R ⁵ is independently selected from the group consisting of (CrC₆)alkyl, (Ci-C₆)alkoxy,

-OR⁸, halo, oxo, dioxo, nitrile, -N0₂, and -C0₂R⁸;

R¹⁶ is independently selected from the group consisting of (d-C₆)alkyl, (CrC₆)alkoxy,

-R ⁷, -(R¹⁷)₂, -R¹², nitrile, -NHS0₂R⁹, -C0₂R⁸, -OR⁸, -0(CH₂)_wR¹², -S0₂R¹²,

-S0₂R⁹, -NH(CH₂)_WR¹⁴, and -(CH₂)_WR¹⁴;

R ⁷ is halo;

each m is independently an integer from 1 to 3;

each n is independently an integer from 1 to 3; and

each w is independently an integer from 1 to 6.

[0010] Also provided is a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of any of Formulas I, l!, III, IV, V, and VI, or a pharmaceutically acceptable salt or solvate thereof.

[0011] Also provided are synthetic intermediates, methods for preparing the compounds of any of Formulas I, II, III, IV, V, and VI, or a pharmaceutically acceptable salt or solvate thereof, and compositions thereof and for their therapeutic uses. In some embodiments, provided is a method for treating a viral infection in a patient mediated at least in part by a virus in the Flaviviridae family of viruses, comprising administering to said patient a composition comprising a compound of any of Formulas I, II, III, IV, V, and VI, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the viral infection is mediated by hepatitis C virus. Those and other embodiments are further described in the text that follows.

DETAILED DESCRIPTION OF REPRESENTATIVE EMBODIMENTS

[0012] Throughout this application, references are made to various embodiments relating to compounds, compositions, and methods. The various embodiments described are meant to provide a variety of illustrative examples and should not be construed as descriptions of alternative species. Rather it should be noted that the descriptions of various embodiments provided herein may be of overlapping scope. The embodiments discussed herein are merely illustrative and are not meant to limit the scope of the present invention.

[0013] It is to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the scope of the present invention. In this specification and in the claims that follow, reference will be made to a number of terms that shall be defined to have the following meanings.

[0014] "Alkyl" refers to monovalent saturated aliphatic hydrocarbyl groups having from 1 to 14 carbon atoms and, in some embodiments, from 1 to 6 carbon atoms. "(C_x-C_y)alkyl" refers to alkyl groups having from x to y carbon atoms. This term includes, by way of example, linear and branched hydrocarbyl groups such as methyl (CH₃-), ethyl (CH₃CH₂-), n-propyl

(CH₃CH₂CH₂-), isopropyl ((CH₃)₂CH-), n-butyl (CH₃CH₂CH₂CH₂-), isobutyl ((CH₃)₂CHCH₂-), sec-butyl ((CH₃)(CH₃CH₂)CH-), f-butyl ((CH₃)₃C-), n-pentyl (CH₃CH₂CH₂CH₂CH₂-), and neopentyl ((CH₃)₃CCH₂-).

[0015] "Alkylidene" or "alkylene" refers to divalent saturated aliphatic hydrocarbyl groups having from 1 to 10 carbon atoms and, in some embodiments, from 1 to 6 carbon atoms.

"(C_u-_v)alkylene" refers to alkylene groups having from u to v carbon atoms. The alkylidene and alkylene groups include branched and straight chain hydrocarbyl groups. For example "(d. ₆)alkylene" is meant to include methylene, ethylene, propylene, 2-methypropylene, pentylene, and so forth.

[0016] "Alkenyl" refers to a linear or branched hydrocarbyl group having from 2 to 10 carbon atoms and in some embodiments from 2 to 6 carbon atoms or 2 to 4 carbon atoms and having at least 1 site of vinyl unsaturation (>C=C<). For example, (C_x-C_y)alkenyl refers to alkenyl groups having from x to y carbon atoms and is meant to include for example, ethenyl, propenyl, isopropylene, 1 ,3-butadienyl, and the like.

[0017] "Alkynyl" refers to a linear monovalent hydrocarbon radical or a branched monovalent hydrocarbon radical containing at least one triple bond. The term "alkynyl" is also meant to include those hydrocarbyl groups having one triple bond and one double bond. For example, (C₂-C₆)alkynyl is meant to include ethynyl, propynyl, and the like.

[0018] "Alkoxy" refers to the group -O-alkyl wherein alkyl is defined herein. Alkoxy includes, by way of example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, f-butoxy, sec-butoxy, and n-pentoxy.

[0019] "Acyl" refers to the groups H-C(O)-, alkyl-C(O)-, alkenyl-C(O)-, alkynyl-C(O)-, cycloalkyl-C(O)-, aryl-C(O)-, heteroaryl-C(O)-, and heterocyclic-C(O)-. Acyl includes the "acetyl" group CH₃C(0)-.

[0020] "Acylamino" refers to the groups -NR²⁰C(O)alkyl, -NR²⁰C(O)cycloalkyl,

-NR²⁰C{O)alkenyl, -NR²⁰C(O)alkynyl, -NR²⁰C{O)aryl, -NR²⁰C{O)heteroaryl, and

-NR²⁰C(O)heterocyclic, wherein R²⁰ is hydrogen or alkyl.

[0021] "Acyloxy" refers to the groups alkyl-C(0)0-, alkenyl-C(0)0-, alkynyl-C(0)0-, aryl-C(0)0-, cycloalkyl-C(0)0-, heteroaryl-C(0)0-, and heterocyclic-C(0)0-.

[0022] "Amino" refers to the group -NR² R²² where R² and R²² are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclic,

-S0₂-alkyl, -S0₂-alkenyl, -S0₂-cycloalkyl, -S0₂-aryl, -S0₂-heteroaryl, and -S0₂-heterocyclic, and wherein R²¹ and R²² are optionally joined together with the nitrogen bound thereto to form a heterocyclic group. When R²¹ is hydrogen and R²² is alkyl, the amino group is sometimes referred to herein as alkylamino. When R²¹ and R²² are alkyl, the amino group is sometimes referred to herein as dialkylamino. When referring to a monosubstituted amino, it is meant that either R² or R²² is hydrogen but not both. When referring to a disubstituted amino, it is meant that neither R²¹ nor R²² are hydrogen.

[0023] "Hydroxyamino" refers to the group -NHOH.

[0024] "Alkoxyamino" refers to the group -NHO-alkyl wherein alkyl is defined herein.

[0025] "Aminocarbonyl" refers to the group -C(0)NR²⁶R²⁷ where R²⁶ and R²⁷ are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclic, hydroxy, alkoxy, amino, and acylamino, and where R²⁶ and R²⁷ are optionally joined together with the nitrogen bound thereto to form a heterocyclic group.

[0026] "Aryl" refers to an aromatic group of from 6 to 14 carbon atoms and no ring heteroatoms and having a single ring (e.g., phenyl) or multiple condensed (fused) rings (e.g., naphthyl or anthryl). For multiple ring systems, including fused, bridged, and spiro ring systems having aromatic and non-aromatic rings that have no ring heteroatoms, the term "Aryl" or "Ar" applies when the point of attachment is at an aromatic carbon atom (e.g., 5,6,7,8

tetrahydronaphthalene-2-yl is an aryl group as its point of attachment is at the 2-position of the aromatic phenyl ring).

[0027] "Cyano" or "nitrile" refers to the group -CN.

[0028] "Cycloalkyl" refers to a saturated or partially saturated cyclic group of from 3 to

14 carbon atoms and no ring heteroatoms and having a single ring or multiple rings including fused, bridged, and spiro ring systems. For multiple ring systems having aromatic and non- aromatic rings that have no ring heteroatoms, the term "cycloalkyl" applies when the point of attachment is at a non-aromatic carbon atom (e.g. 5,6,7,8,-tetrahydronaphthalene-5-yl). The term "Cycloalkyl" includes cycloalkenyl groups, such as cyclohexenyl. Examples of cycloalkyl groups include, for instance, adamantyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclooctyl, cyclopentenyl, and cyclohexenyl. Examples of cycloalkyl groups that include multiple bicycloalkyl ring systems are bicyclohexyl, bicyclopentyl, bicyclooctyl, and the like. Two such bic cloalkyl multiple ring structures are exemplified and named below:

bicyclohexyl, and bicyclohexyl.

[0029] "(C_u-C_v)cycloalkyl" refers to cycloalkyl groups having u to v carbon atoms.

[0030] "Spiro cycloalkyl" refers to a 3 to 10 member cyclic substituent formed by replacement of two hydrogen atoms at a common carbon atom in a cyclic ring structure or in an alkylene group having 2 to 9 carbon atoms, as exemplified by the following structure wherein the group shown here attached to bonds marked with wavy lines is substituted with a spiro cycloalkyl group:

[0031] Fused cycloalkyl" refers to a 3 to 10 member cyclic substituent formed by the replacement of two hydrogen atoms at different carbon atoms in a cycloalkyl ring structure, as exemplified by the following structure wherein the cycloalkyl group shown here contains bonds marked with wavy lines which are bonded to carbon atoms that are substituted with a fused cycloalkyl group:

[0032] "Halo" or "halogen" refers to fluoro, chloro, bromo, and iodo.

[0033] "Haloalkoxy" refers to substitution of alkoxy groups with 1 to 5 (e.g. when the alkoxy group has at least 2 carbon atoms) or in some embodiments 1 to 3 halo groups (e.g. trifluoromethoxy).

[0034] "Hydroxy" or "hydroxyl" refers to the group -OH.

[0035] "Heteroaryl" refers to an aromatic group of from 1 to 14 carbon atoms and 1 to 6 heteroatoms selected from oxygen, nitrogen, and sulfur and includes single ring (e.g. imidazolyl) and multiple ring systems (e.g. benzimidazol-2-yl and benzimidazol-6-yl). For multiple ring systems, including fused, bridged, and spiro ring systems having aromatic and non-aromatic rings, the term "heteroaryl" applies if there is at least one ring heteroatom and the point of attachment is at an atom of an aromatic ring (e.g. 1 ,2,3,4-tetrahydroquinolin-6-yl and 5,6,7,8- tetrahydroquinolin-3-yl). In some embodiments, the nitrogen and/or the sulfur ring atom(s) of the heteroaryl group are optionally oxidized to provide for the N-oxide (N-→0), sulfinyl, or sulfonyl moieties. More specifically the term heteroaryl includes, but is not limited to, pyridyl, furanyl, thienyl, thiazolyl, isothiazolyl, triazolyl, imidazolyl, imidazolinyl, isoxazolyl, pyrrolyl, pyrazolyl, pyridazinyl, pyrimidinyl, purinyl, phthalazyl, naphthylpryidyl, benzofuranyl,

tetrahydrobenzofuranyl, isobenzofuranyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl, indolyl, isoindolyl, indolizinyl, dihydroindolyl, indazolyl, indolinyl, benzoxazolyl, quinolyl, isoquinolyl, quinolizyl, quianazolyl, quinoxalyl, tetrahydroquinolinyl, isoquinolyl, quinazolinonyl, benzimidazolyl, benzisoxazolyl, benzothienyl, benzopyridazinyl, pteridinyl, carbazolyl, carbolinyl, phenanthridinyl, acridinyl, phenanthrolinyl, phenazinyl, phenoxazinyl, phenothiazinyl, and phthalimidyl.

[0036] "Heterocyclic" or "heterocycle" or "heterocycloalkyl" or "heterocyclyl" refers to a saturated or partially saturated cyclic group having from 1 to 14 carbon atoms and from 1 to 6 heteroatoms selected from nitrogen, sulfur, phosphorus or oxygen and includes single ring and multiple ring systems including fused, bridged, and spiro ring systems. For multiple ring systems having aromatic and/or non-aromatic rings, the terms "heterocyclic", "heterocycle", "heterocycloalkyl", or "heterocyclyl" apply when there is at least one ring heteroatom and the point of attachment is at an atom of a non-aromatic ring (e.g. 1 ,2,3,4-tetrahydroquinoline-3-yl, 5,6,7,8-tetrahydroquinoline-6-yl, and decahydroquinolin-6-yl). In one embodiment, the nitrogen, phosphorus and/or sulfur atom(s) of the heterocyclic group are optionally oxidized to provide for the N-oxide, phosphinane oxide, sulfinyl, sulfonyl moieties. More specifically the heterocyclyl includes, but is not limited to, tetrahydropyranyl, piperidinyl, piperazinyl, 3-pyrrolidinyl, 2- pyrrolidon-1-yl, morpholinyl, and pyrrolidinyl. A prefix indicating the number of carbon atoms (e.g., C3-C10) refers to the total number of carbon atoms in the portion of the heterocyclyl group exclusive of the number of heteroatoms.

[0037] Examples of heterocycle and heteroaryl groups include, but are not limited to, azetidine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, pyridone, indolizine, isoindole, indole, dihydroindole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, phthalimide, 1 ,2,3,4-tetrahydroisoquinoline, 4,5,6,7-tetrahydrobenzo[b]thiophene, thiazole, thiazolidine, thiophene, benzo[b]thiophene, morpholine, thiomorpholine (also referred to as thiamorpholine), piperidine, pyrrolidine, and tetrahydrofuranyl.

[0038] "Fused heterocyclic" refers to a 3 to 10 member cyclic substituent formed by the replacement of two hydrogen atoms at different carbon atoms in a cycloalkyl ring structure, as exemplified by the following structure wherein the cycloalkyl group shown here contains bonds marked with wavy lines which are bonded to carbon atoms that are substituted with a fused heterocyclic group:

[0039] "Compound", "compounds", "chemical entity", and "chemical entities" as used herein refers to a compound encompassed by the generic formulae disclosed herein, any subgenus of those generic formulae, and any forms of the compounds within the generic and subgeneric formulae, including the racemates, stereoisomers, and tautomers of the compound or compounds.

[0040] "Oxazolidinone" refers to a 5-membered heterocyclic ring containing one nitrogen and one oxygen as heteroatoms and also contains two carbons and is substituted at one of the two carbons by a carbonyl group as exemplified by any of the following structures, wherein the oxazolidinone groups shown here are bonded to a parent molecule, which is indicated by a wavy line in the bond to the parent molecule:

[0041] "Racemates" refers to a mixture of enantiomers. In an embodiment of the invention, the compounds of Formula I, or pharmaceutically acceptable salts thereof, are enantiomerically enriched with one enantiomer wherein all of the chiral carbons referred to are in one configuration. In general, reference to an enantiomerically enriched compound or salt, is meant to indicate that the specified enantiomer will comprise more than 50% by weight of the total weight of all enantiomers of the compound or salt.

[0042] "Solvate" or "solvates" of a compound refer to those compounds, as defined above, which are bound to a stoichiometric or non-stoichiometric amount of a solvent. Solvates of a compound includes solvates of all forms of the compound. In certain embodiments, solvents are volatile, non-toxic, and/or acceptable for administration to humans in trace amounts. Suitable solvates include water.

[0043] "Stereoisomer" or "stereoisomers" refer to compounds that differ in the chirality of one or more stereocenters. Stereoisomers include enantiomers and diastereomers.

[0044] "Tautomer" refer to alternate forms of a compound that differ in the position of a proton, such as enol-keto and imine-enamine tautomers, or the tautomeric forms of heteroaryl groups containing a ring atom attached to both a ring -NH- moiety and a ring =N- moiety such as pyrazoles, imidazoles, benzimidazoles, triazoles, and tetrazoles.

[0045] "Pharmaceutically acceptable salt" refers to pharmaceutically acceptable salts derived from a variety of organic and inorganic counter ions well known in the art and include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, and

tetraalkylammonium, and when the molecule contains a basic functionality, salts of organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, and oxalate. Suitable salts include those described in P. Heinrich Stahl, Camille G. Wermuth (Eds.), Handbook of Pharmaceutical Salts Properties, Selection, and Use; 2002.

[0046] "Patient" refers to mammals and includes humans and non-human mammals.

[0047] "Treating" or "treatment" of a disease in a patient refers to 1 ) preventing the disease from occurring in a patient that is predisposed or does not yet display symptoms of the disease; 2) inhibiting the disease or arresting its development; or 3) ameliorating or causing regression of the disease. [0048] Unless indicated otherwise, the nomenclature of substituents that are not explicitly defined herein are arrived at by naming the terminal portion of the functionality followed by the adjacent functionality toward the point of attachment. For example, the substituent "arylalkyloxycarbonyl" refers to the group (aryl)-(alkyl)-0-C(0)-. In a term such as "C(R^X)₂", it should be understood that the two R^x groups can be the same, or they can be different if R^x is defined as having more than one possible identity. In addition, certain substituents are drawn as -R R^y, where the "-" indicates a bond adjacent to the parent molecule and R^y being the terminal portion of the functionality. Similarly, it is understood that the above definitions are not intended to include impermissible substitution patterns (e.g., methyl substituted with 5 fluoro groups). Such impermissible substitution patterns are well known to the skilled artisan.

[0049] In one embodiment of the present invention, there is provided a compound of

Formula (I):

(I)

or a pharmaceutically acceptable salt thereof, wherein:

Y and Z are independently selected from a bond or (C -C₆)alkylene;

-S0₂NHR¹⁴, -SO₂NHR ⁰R⁵, -S0₂R⁵, -S0₂R¹², -S0₂R¹⁴, -S0₂R ⁴R¹⁵, -C(0)R¹⁴, -C(0)NHR¹⁰, -C(0)NHR¹⁴, -R¹², -R ⁴,-R¹⁴R⁷, and -R¹⁴R¹⁰;

R is selected from the group consisting of hydrogen, (d-C₆)alkyl, (C₄-Ci₄)aryl, nitrile, -R¹⁴, and -S0₂R⁹;

R² is selected from the group consisting of hydrogen, (CrC₆)alkyl, (Ci-C₆)alkenyl, halo, -NHR ⁰, -R⁶, -R¹⁰, -R ³, -R ⁴, -R¹⁰R⁷, -R ³R¹⁶, -R ⁰R¹⁴, -R ⁰R⁵, -R ⁴R⁷, -(CH₂)_WR¹⁴, -C(0)R⁸, and -R¹³OR⁸, wherein R and R² may optionally join together along with any intervening N and C atoms to form a (Ci-Cn)heterocyclic or a (C C )heteroaryl group fused to the adjacent pyridyl moiety and independently having one to three nitrogen heteroatoms; R³ and R⁴ are independently selected from the group consisting of hydrogen, (d- C₆)alkyl, (C C₆)alkoxy, -R¹⁴, nitrile, -S0₂R⁸, oxo, -OR⁸, -R ², and halo;

-R¹⁰R¹⁷, -R ⁰(R ⁷)n, -OR⁹(R¹⁷)_m, -R⁹(R ⁷)_m, -R⁹R( ⁷)_n, -R⁹R¹², -R⁹R¹³, -R⁹OR⁸, -R ⁴, (C₄-Ci₄)aryl, and (C₃-Ci₂)cycloalkyl;

R⁶ is selected from the group consisting of -R¹⁰C(O)R¹⁴, -R¹⁰C(O)R¹⁴R¹⁶, -R¹⁰(CH₂)wR¹², - R ⁰(CH₂)_WR¹⁴, and -R ⁰(CH₂)_WR ⁴R¹⁶;

R⁷ is independently selected from the group consisting of (CrC₆)alkyl, (Ci-C₆)alkoxy, oxo, halo, nitrile, -R⁹(R¹⁷)_m, -N0₂, -R⁹OR⁸, -C(0)R⁹, -(CH₂)_WCN, -S0₂R¹², -S0₂R⁹, -S0₂NH(CH₂)_wR¹⁴, -S0₂(CH₂)_wR¹⁴, -R ², -R¹⁴, -{CH₂)_wOR⁸, -C(0)NHR¹³,

-C(0)NHR¹⁴, -C(0)NHR⁹, -R ⁰, -OR⁹(R¹⁷)_m, -C(0)R¹², -NHC(O)NHR ⁰R¹¹, -C(0)NH(CH₂)_wR¹², -C(0)(CH₂)_wR¹², -C0₂R⁸,

-NHC(0)C(0)R¹⁴, -NHC0₂R⁸, -OR⁸, -C(0)NH(CH₂)_wR¹⁴, -C(0)(CH₂)_wR¹⁴, -<CH₂)_WR¹¹, -NH(CH₂)_WR¹⁴, -(CH₂)_WR¹⁴ , -(CH₂)_WR¹⁰, -<CH₂)_WNHR¹⁰,

-(CH₂)_wC0₂R⁸, -C(O)NHR¹⁰R¹¹, -C(0)NH(CH₂)_wOR⁸, and -C(0)NH(CH₂)_wR¹¹;

R⁸ is independently selected from the group consisting of hydrogen, (d-CeJalkyl, benzyl, -R ⁴, and (C₄-C₁₄)aryl;

R⁹ is (C C₆)alkyl;

R¹⁰ is (C₄-C₁₄)aryl;

R is selected from the group consisting of nitrile, halo, (CrC₆)alkyl, (CrC₆)alkoxy, -NHS0₂R⁹, -C0₂R⁸, -OR⁸, -0(CH₂)_wR¹², -S0₂R¹², -S0₂R⁹, -NH(CH₂)_WR¹⁴ , -R¹⁶, and -(CH₂)_WR¹⁴;

R¹² is -NR⁸R⁸;

R ³ is (C₃-C₁₂)cycloalkyl;

R ⁴ is selected from the group consisting of (d-C heterocyclic and (CrCn)heteroaryl, each independently having one to three heteroatoms selected from N and O; R¹⁵ is independently selected from the group consisting of (CrC₆)alkyl, (Ci-C₆)alkoxy,

-OR⁸, halo, oxo, dioxo, nitrile, -N0₂, and -C0₂R⁸;

R ⁶ is independently selected from the group consisting of (CrC₆)alkyl, (CrC₆)alkoxy,

-R¹⁷, -(R¹⁷)₂, -R ², nitrile, -NHS0₂R⁹, -C0₂R⁸, -OR⁸, -0(CH₂)_wR¹², -S0₂R¹²,

-S0₂R⁹, -NH(CH₂)_WR¹⁴, and -(CH₂)_WR¹⁴;

R¹⁷ is halo;

each m is independently an integer from 1 to 3;

each n is independently an integer from 1 to 3; and each w is independently an integer from 1 to 6.

[0050] In another embodiment of the present invention, there is provided a compound of

Formula (I), wherein Y and Z are independently selected from the group consisting of a bond, methylene, and ethylene.

[0051] In another embodiment of the present invention, there is provided a compound of

Formula (I), wherein Y is selected from the group consisting of a bond, methylene, and ethylene.

[0052] In another embodiment of the present invention, there is provided a compound of

Formula (I), wherein Z is selected from the group consisting of a bond, methylene, and ethylene.

[0053] In another embodiment of the present invention, there is provided a compound of

Formula (I), wherein Z is a bond.

[0054] In another embodiment of the present invention, there is provided a compound of

Formula (I), wherein Z is methylene.

[0055] In another embodiment of the present invention, there is provided a compound of

Formula (I), wherein Y is a bond.

[0056] In another embodiment of the present invention, there is provided a compound of

Formula (I), wherein Y is methylene.

[0057] In another embodiment of the present invention, there is provided a compound of

Formula (I), wherein X is selected from the group consisting of -NHS0₂R⁵, -NHSO₂R¹⁰R⁵, - S0₂NHR⁵, -SO₂NHR ⁰R⁵, -SO2NHR¹⁴, -SO2R⁵, -SO2R¹², -SO2R¹⁴, and -S0₂R¹⁴R¹⁵.

[0058] In another embodiment of the present invention, there is provided a compound of

Formula (I), wherein R is selected from the group consisting of hydrogen, methyl, ethyl, phenyl, nitrite, -S0²R⁹, -(CH₂)_WR¹⁴, and -(CH₂)_wS0₂R⁹.

[0059] In another embodiment of the present invention, there is provided a compound of

Formula (I), wherein R² is selected from the group consisting of hydrogen, methyl, ethyl, isobutyl, ethylene, halo, -NHR ⁰SO₂R⁹, -R¹⁰R⁵, -R¹⁰R⁷, -R ⁰R¹⁴, -R¹³R¹⁶, -R¹⁴R⁷, -(CH₂)_WR¹⁴, - NHR¹⁰SO₂R¹², -NHR¹⁰R¹², -C(0)R⁸, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, hydroxycyclohexyl, phenyl, cyanophenyl, methylphenyl, tetrahydropyranyl, morpholinyl, methylbenzamide, pyridyl, pyrazolyl, pyrimidyl, benzoxazinyl, benzodioxolanyl, and

diazaspirodecanyl.

[0060] In another embodiment of the present invention, there is provided a compound of

Formula (I), wherein R and R² may optionally join together along with the intervening N and C atoms to form a ring structure, wherein said ring structure is fused to the adjacent pyridyl moiety and having the structure:

ring structure may be optionally substituted with one to three independent R⁸ groups.

[0061] In another embodiment of the present invention, there is provided a compound of

Formula (I), wherein R³ and R⁴ are independently selected from the group consisting of hydrogen, nitrile, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, oxo, hydroxyl, trifluoromethyl, methylamino, dimethylamino, amino, trifluoromethoxy, and halo.

[0062] In another embodiment of the present invention, there is provided a compound of

Formula (I), wherein R³ is selected from the group consisting of hydrogen and methyl.

[0063] In another embodiment of the present invention, there is provided a compound of

Formula (I), wherein R³ is hydrogen.

[0064] In another embodiment of the present invention, there is provided a compound of

Formula (I), wherein R⁴ is selected from the group consisting of nitrile, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, oxo, hydroxyl, trifluoromethyl, methylamino, dimethylamino, amino, trifluoromethoxy, and halo.

[0065] In another embodiment of the present invention, there is provided a compound of

Formula (I), wherein R⁴ is selected from the group consisting of nitrile, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, oxo, hydroxyl, trifluoromethyl, methylamino, dimethylamino, amino, and trifluoromethoxy.

[0066] In another embodiment of the present invention, there is provided a compound of

Formula (I), wherein R⁴ is selected from the group consisting of nitrile, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, and amino.

[0067] In another embodiment of the present invention, there is provided a compound of

Formula (I), wherein R⁴ is selected from the group consisting of methoxy and amino.

[0068] In another embodiment of the present invention, there is provided a compound of

Formula (I), wherein R⁴ is methoxy.

[0069] In another embodiment of the present invention, there is provided a compound of

Formula (I), wherein R⁴ is amino.

[0070] In another embodiment of the present invention, there is provided a compound of

Formula (I), wherein R⁵ is selected from the group consisting of methyl, ethyl, isopropyl, propyl, butyl, isobutyl, tert-butyl, methoxy, ethoxy, nitrile, phenyl, chlorophenyl, fluorophenyl, difluorophenyl, trifluorophenyl, benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, trifluoromethyl, trifluoroethyl, trifluoromethoxy, dimethylaminoethyl, pyridyl, quinolinyl, thiomorpholinyl, morpholinyl, hydroxyethyl, and furanyl.

[0071] In another embodiment of the present invention, there is provided a compound of

Formula (I), wherein R⁵ is selected from the group consisting of phenyl, chlorophenyl, fluorophenyl, difluorophenyl, and trifluorophenyl.

[0072] In another embodiment of the present invention, there is provided a compound of

Formula (I), wherein R⁵ is difluorophenyl.

[0073] In another embodiment of the present invention, there is provided a compound of

Formula (I), wherein R⁷ is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, methoxy, oxo, dioxo, chloro, flouro, bromo, trifluoromethyl,

trifluoroethyl, trifluoromethoxy, trifluoroethoxy, nitrile, phenyl, acetyl, carboxyl, acetoxy, -N0₂, -(CH₂)_WCN, -S0₂R¹², -S0₂R⁹, -OR⁸, -C0₂R⁸, -C(0)R⁹, -S0₂NH(CH₂)_wR¹⁴, -S0₂(CH₂)_wR¹⁴, -S0₂R¹⁴, -R¹² , -R¹⁴, -(CH₂)_wOR⁸, -C(0)R¹², -NHC(O)NHR ⁰R¹¹, -R⁹OR⁸, -C(0)NHR¹³,

-C(0)NHR¹⁴, -C(0)NH(CH₂)_wR¹², -C(0)(CH₂)_wR¹², -NHC(0)C(0)R¹⁴, -NHC0₂R⁸,

-C(0)NH(CH₂)_wR¹⁴, -C(0)(CH₂)_wR¹⁴, -(CH₂)_WR¹¹ , -NH(CH₂)_WR¹⁴, -(CH₂)_WR¹⁴,

-(CH₂)_WR¹⁰, -(CH₂)_WNHR¹⁰, -(CH₂)_wC0₂R⁸, -C(0)NHR⁹,

-C(O)NHR¹⁰R¹¹, -C(0)NH(CH₂)_wOR^s, and -C(0)NH(CH₂)_wR¹¹.

[0074] In another embodiment of the present invention, there is provided a compound of Formula (I), wherein R⁸ is independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, benzyl, phenyl and -R¹⁴.

[0075] In another embodiment of the present invention, there is provided a compound of

Formula (I), wherein R⁸ is selected from the group consisting of hydrogen, methyl, and ethyl.

[0076] In another embodiment of the present invention, there is provided a compound of

Formula (I), wherein R⁹ is independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, and tert-butyl.

[0077] In another embodiment of the present invention, there is provided a compound of

Formula (I), wherein R⁹ is independently selected from the group consisting of methyl, ethyl, and tert-butyl.

[0078] In another embodiment of the present invention, there is provided a compound of

Formula (I), wherein R ⁰ is phenyl.

[0079] In another em he present invention, there is provided a compound of

Formula (I), wherein R is:

[0080] In another embodiment of the present invention, there is provided a compound of

Formula (I), wherein R¹² is -NH₂.

[0081] In another embodiment of the present invention, there is provided a compound of

Formula (I), wherein R¹³ is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0082] In another embodiment of the present invention, there is provided a compound of

Formula (I), wherein R ⁴ is selected from the group consisting of morpholinyl, thiomorpholinyl, tetrahydropyranyl, dioxanyl, triazolyl, oxadiazolyl, pyrimidinyl, pyrazolyl, piperazinyl, pyrrolidinyl, piperidinyl, and pyridinyl.

[0083] In another embodiment of the present invention, there is provided a compound of

Formula (I), wherein R¹⁵ is independently selected from the group consisting of fluoro, oxo, dioxo, chloro, bromo, methoxy, ethoxy, methyl, ethyl, butyl, propyl, isopropyl, nitrile, -N0_2l trifluoromethoxy, and trifluoromethyl.

[0084] In another embodiment of the present invention, there is provided a compound of

Formula (I), wherein R ⁶ is independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, trifluoromethyl, trifluoromethoxy, methoxy, ethoxy, nitrile, -R ⁷, -(R ⁷)₂, -R¹², -NHSO₂R⁹, -C0₂R⁸, -OR⁸, -0(CH₂)_wR¹², -S0₂R¹², -S0₂R⁹, -NH(CH₂)_WR¹⁴, and - (CH₂)_WR¹⁴.

[0085] In another embodiment of the present invention, there is provided a compound of

Formula (I), wherein R¹⁷ is selected from the group consisting of chloro, fluoro, and bromo.

[0086] In another embodiment of the present invention, there is provided a compound of

Formula (I), wherein R ⁷ is fluoro.

[0087] In another embodiment of the present invention, there is provided a compound of

Formula (I), wherein m is 3.

[0088] In another embodiment of the present invention, there is provided a compound of

Formula (I), wherein n is 2.

[0089] In another embodiment of the present invention, there is provided a compound of

Formula (I), wherein w is 1.

[0090] In another embodiment of the present invention, there is provided a compound of

Formula (I):

(I)

or a pharmaceutically acceptable salt thereof, wherein:

Y and Z are independently selected from the group consisting of a bond, methylene, and ethylene;

X is selected from the group consisting of -NHS0₂R⁵, -NHSO₂R ⁰R⁵, -S0₂NHR⁵, - SO₂NHR¹⁰R⁵, -S0₂NHR¹⁴, -S0₂R⁵, -S0₂R¹², -S0₂R¹⁴, -S0₂R¹⁴R¹⁵, -C{0)R¹⁴, -C(0)NHR¹⁰, -C(0)NHR¹⁴, -R¹¹, -R¹², -R ⁴,-R¹⁴R⁷, and -R¹⁴R¹⁰;

R is selected from the group consisting of hydrogen, methyl, ethyl, phenyl, nitrile,

-S0²R⁹, -(CH₂)_WR¹⁴, and -(CH₂)_wS0₂R⁹;

R² is selected from the group consisting of hydrogen, methyl, ethyl, isobutyl, ethylene, halo, -NHR¹⁰SO₂R⁹, -R ⁰R⁵, -R ⁰R⁷, -R ⁰R¹⁴, -R ³R¹⁶, -R¹⁴R⁷, -(CH₂)_WR¹⁴, - NHR ⁰SO₂R¹², -NHR ⁰R¹², -C(0)R^s, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, hydroxycyclohexyl, phenyl, cyanophenyl, methylphenyl, tetrahydropyranyl, morpholinyl, methylbenzamide, pyridyl, pyrazolyl, pyrimidyl, benzoxazinyl, benzodioxolanyl, and diazaspirodecanyl, wherein R and R² may optionally join together along with the intervening N and C atoms to form a ring structure, wherein sai is fused to the adjacent pyridyl moiety and

having the structure:

and wherein said R and R -joined ring structure may be optionally substituted with one to three independent R⁸ groups;

R³ and R⁴ are independently selected from the group consisting of hydrogen, nitrile, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, oxo, hydroxyl, trifluoromethyl, methylamino, dimethylamino, amino, trifluoromethoxy, and halo;

R⁵ is selected from the group consisting of, methyl, ethyl, isopropyl, propyl, butyl,

isobutyl, tert-butyl, methoxy, ethoxy, nitrile, phenyl, chlorophenyl, fluorophenyl, difluorophenyl, trifluorophenyl, benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, trifluoromethyl, trifluoroethyl, trifluoromethoxy, dimethylaminoethyl, pyridyl, quinolinyl, thiomorpholinyl, morpholinyl,

hydroxyethyl, and furanyl;

R⁶ is selected from the group consisting of -R ⁰C(O)R¹⁴, -R¹⁰C(O)R ⁴R¹⁶, -R ⁰(CH₂)_WR¹², - R¹⁰(CH₂)_WR¹⁴, and -R ⁰(CH₂)_WR ⁴R¹⁶;

R⁷ is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl,

isobutyl, tert-butyl, methoxy, oxo, dioxo, chloro, flouro, bromo, trifluoromethyl, trifluoroethyl, trifluoromethoxy, trifluoroethoxy, nitrile, phenyl, acetyl, carboxyl, acetoxy, -N0₂, -(CH₂)_WCN, -S0₂R¹², -S0₂R⁹, -OR⁸, -C0₂R⁸, -C(0)R⁹, - S0₂NH(CH₂)_wR¹⁴, -S0₂(CH₂)_wR¹⁴, -S0₂R¹⁴, -R¹² , -R ⁴, -(CH₂)_wOR⁸, -C(0)R¹², -NHC(O)NHR ⁰R¹¹, -R⁹OR⁸, -C{0)NHR¹³, -C(0)NHR¹⁴,

-C(0)NH(CH₂)_wR¹², -C(0)(CH₂)_wR¹², -NHC(0)C(0)R¹⁴, -NHC0₂R⁸,

C(0)NH(CH₂)_wR¹⁴, -C(0)(CH₂)_wR¹⁴, -(CH₂)_WR¹¹, -NH(CH₂)_WR¹⁴, -(CH₂)_WR¹⁴, - (CH₂)_WR¹⁰, -(CH₂)_WNHR¹⁰, -(CH₂)_wC0₂R⁸, -C(0)NHR⁹,

C(O)NHR ⁰R¹¹, -C(0)NH{CH₂)_wOR⁸, and -C(0)NH(CH₂)_wR¹¹;

R⁸ is independently selected from the group consisting of hydrogen, methyl, ethyl,

propyl, isopropyl, butyl, isobutyl, tert-butyl, and phenyl;

R⁹ is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl,

isobutyl, and tert-butyl;

R¹⁰ is

R¹¹ is

R ² is -NR⁸R⁸,

R¹³ is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl;

R ⁴ is selected from the group consisting of morpholinyl, thiomorpholinyl,

tetrahydropyranyl, dioxanyl, triazolyl, oxadiazolyl, pyrimidinyl, pyrazolyl, piperazinyl, pyrrolidinyl, piperidinyl, and pyridinyl;

R¹⁵ is independently selected from the group consisting of fluoro, oxo, dioxo, chloro, bromo, methoxy, ethoxy, methyl, ethyl, butyl, propyl, isopropyl, nitrile, -N0₂, trifluoromethoxy, and trifluoromethyl;

R¹⁶ is independently selected from the group consisting of methyl, ethyl, propyl,

isopropyl, butyl, tert-butyl, trifluoromethyl, trifluoromethoxy, methoxy, ethoxy, nitrile, -R¹⁷, -(R ⁷)₂, -R¹², -NHS0₂R⁹, -C0₂R⁸, -OR⁸, -0(CH₂)_wR¹², S0₂R¹², -SO₂R⁹, -NH(CH₂)_WR¹⁴, and -(CH₂)_WR¹⁴;

R¹⁷ is selected from the group consisting of chloro, fluoro, and bromo;

each n is independently an integer from 1 to 3; and

each w is independently an integer from 1 to 6.

[0091] In another embodiment of the present invention, there is provided a compound of

Formul (I)

armaceutically acceptable salt thereof, wherein:

Y and Z are independently selected from a bond or (CrC₆)alkylene;

R is selected from the group consisting of hydrogen, (d-C₆)alkyl, (C₄-Ci₄)aryl, nitrile, -R ⁴, and -S0₂R⁹;

R² is selected from the group consisting of hydrogen, (CrC₆)alkyl, -R⁶, -R ⁰, -R ³, -R ⁴, -R ⁰R⁷, -R¹⁰R¹⁴, -R ⁰R⁵, -R ³R¹⁶, -R ⁴R⁷, -(CH₂)_WR¹⁴, -C(0)R^s, and -R¹³OR⁸, wherein R and R² may optionally join together along with any intervening N and C atoms to form a (d-Cn heterocyclic or a (d-C-i heteroaryl group fused to the adjacent pyridyl moiety and independently having one to three nitrogen heteroatoms;

R³ and R⁴ are independently selected from the group consisting of hydrogen, nitrile, (Ci-

C₆)alkyl, (C C₆)alkoxy, oxo, -OR⁸, -R ², and halo;

-R ⁰R¹⁷, -R ⁰(R ⁷)_n, -OR⁹(R¹⁷)_m, -R⁹(R ⁷)_m, -R⁹R( ⁷)_n, -R⁹R¹², -R⁹R¹³, -R⁹OR⁸, -R ⁴,

(C₄-Ci₄)aryl, and (C₃-Ci₂)cycloalkyl;

R⁶ is selected from the group consisting of -R¹⁰C(O)R¹⁴, -R¹⁰C(O)R¹⁴R¹⁶, -R ⁰(CH₂)_WR¹²,

-R ⁰(CH₂)_WR¹⁴, and -R ⁰(CH₂)_WR¹⁴R¹⁶;

R⁷ is independently selected from the group consisting of (CrC₆)alkyl, (Ci-C₆)alkoxy, halo, nitrile, -R⁹(R ⁷)_m, -C(0)R⁹, -S0₂R⁹, -C(0)NHR⁹, -R ⁰, -OR⁹(R¹⁷)_m, -C(0)R¹²,

R⁸ is independently selected from the group consisting of hydrogen, (d-C₆)alkyl, and

(C₄-C₁₄)aryl;

R⁹ is (CrC₅)alkyl;

R ² is -NR⁸R⁸;

R ³ is (C₃-Ci₂)cycloalkyl;

R ⁴ is selected from the group consisting of (C₁-C₁ ^heterocyclic and (CrCn)heteroaryl, each independently having one to three heteroatoms selected from N and O;

R ⁵ is selected from the group consisting of halo, oxo, and dioxo;

R ⁶ is selected from the group consisting of (Ci-C_e)alkyl, (Ci-C₆)alkoxy, -R¹⁷, -(R¹⁷)₂, -R¹², hydroxyl, and nitrile;

R¹⁷ is halo;

each m is independently an integer from 1 to 3;

each n is independently an integer from 1 to 3; and

each w is independently an integer from 1 to 6.

[0092] In another embodiment of the present invention, there is provided a compound of

Formula (I): (I)

or a pharmaceutically acceptable salt thereof, wherein:

X is selected from the group consisting of -NHS0₂R⁵, -NHSO₂R ⁰R⁵, -S0₂NHR⁵, - SO₂NHR¹⁰R⁵, -S0₂NHR¹⁴, -S0₂R⁵, -S0₂R¹², -S0₂R¹⁴, -S0₂R ⁴R¹⁵, -C(0)R¹⁴, -C(0)NHR¹⁰, -C(0)NHR¹⁴, -R¹¹, -R¹², -R¹⁴,-R ⁴R⁷, and -R ⁴R¹⁰;

R¹ is selected from the group consisting of hydrogen, methyl, nitrile, and -S0²R⁹;

R² is selected from the group consisting of hydrogen, methyl, ethyl, isobutyl, halo, -R¹⁰R⁵, -R¹⁰R⁷, -R ⁰R¹⁴, -R ³R¹⁶, -R¹⁴R⁷, -(CH₂)_WR¹⁴, -^■iC(0)R⁸, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, hydroxycyclohexyl, phenyl, cyanophenyl, methyl phenyl, tetrahydropyranyl, morpholinyl, methylbenzamide, pyridyl, pyrazolyl, pyrimidyl, wherein R and R² may optionally join together along with the intervening N and C atoms to form a ring structure, wherein said ring structure is

fused to the adjacent pyridyl moiety and having the structure:

, and wherein said R and R²-joined ring structure may be optionally substituted with one to three independent R⁸ groups;

R³ and R⁴ are independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, oxo, nitrile, hydroxyl, trifluoromethyl, methylamino, dimethylamino, amino, trifluoromethoxy, and halo;

isobutyl, tert-butyl, methoxy, ethoxy, nitrile, phenyl, chlorophenyl, fluorophenyl, difluorophenyl, trifluorophenyl, benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, trifluoromethyl, trifluoroethyl, trifluoromethoxy, dimethyl ami noethyl, pyridyl, quinolinyl, thiomorpholinyl, morpholinyl, and hydroxyethyl;

R⁶ is selected from the group consisting of -R¹⁰C(O)R¹⁴, -R¹⁰C(O)R¹⁴R¹⁶, -R¹⁰(CH₂)_WR¹²,

-R ⁰(CH₂)_WR¹⁴, and -R ⁰(CH₂)_WR¹⁴R¹⁶;

isobutyl, tert-butyl, methoxy, oxo, dioxo, chloro, flouro, bromo, trifluoromethyl, trifluoroethyl, trifluoromethoxy, trifluoroethoxy, nitrile, phenyl, acetyl, -S0₂R⁹,

-OR⁸, -C0₂R⁸, -C(0)R⁹, -C(0)R¹², and -C(0)NHR⁹;

propyl, isopropyl, butyl, isobutyl, tert-butyl, and phenyl;

isobutyl, and tert-butyl;

R ⁰ is phenyl;

.12 is -NR R , R ³ is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl;

R ⁴ is selected from the group consisting of morpholinyl, thiomorpholinyl,

tetrahydropyranyl, dioxanyl, oxadiazolyl, pyrimidinyl, pyrazolyl, piperazinyl, pyrrolidinyl, piperidinyl, and pyridinyl;

R¹⁵ is independently selected from the group consisting of fluoro, oxo, dioxo, chloro, and bromo;

R ⁶ is independently selected from the group consisting of methyl, ethyl, propyl,

isopropyl, butyl, tert-butyl, -R¹⁷, -(R ⁷)2, -R ², hydroxyl, methoxy, ethoxy, and nitrile;

R ⁷ is selected from the group consisting of chloro, fluoro, and bromo;

each n is independently an integer from 1 to 3; and

each w is independently an integer from 1 to 6.

[0093] In another embodiment of the present invention, there is provided a compound of

Formula (II):

or a pharmaceutically acceptable salt thereof, wherein:

Y and Z are independently selected from a bond or (d-C₆)alkylene;

R² is selected from the group consisting of (C C₆)alkyl, -(CH₂)_WR¹⁴, -R⁶, -R ⁰, -R¹³, -R ⁴, - R¹⁰R⁵, -R ⁰R⁷, -R¹⁰R¹⁴, -R ³R¹⁶, -R ⁴R⁷, -C(0)R^s, and -R ³OR⁸, wherein R¹ and R² may optionally join together along with any intervening N and C atoms to form a (C₁-C )heterocyclic or a (C-i-Cn)heteroaryl group fused to the adjacent pyridyl moiety and independently having one to three nitrogen heteroatoms, and wherein said R and R²-joined (CrCn)heterocyclic or (CrCn)heteroaryl group may be optionally substituted with one to three R ⁶ groups;

R³ and R⁴ are independently selected from the group consisting of hydrogen, (Ci-

C₆)alkyl, (C C₆)alkoxy, nitrile, -S0₂R⁸, oxo, -OR⁸, -R ², and halo;

R⁵ is selected from the group consisting of (CrC₆)alkyl, (CrC₆)alkoxy, -R ⁰R¹⁷,

-R ⁰(R ⁷)_n, benzyl, (C₄-C₁₄)aryl, (d-Cn heterocyclic, and (C Cn)heteroaryl; R⁶ is independently selected from the group consisting of -R¹⁰C(O)R¹⁴, -R ⁰C(O)R¹⁴R¹⁶,

-R ⁰(CH₂)_WR¹², -R ⁰(CH₂)_WR¹⁴, and -R¹⁰(CH₂)_WR ⁴R¹⁶;

R⁷ is independently selected from the group consisting of (Ci-C₅)alkyl, (d-C₆)alkoxy, halo, nitrile, -C(0)R⁹, -S0₂R⁹, -C(0)NHR⁹, -C(0)R¹², -C0₂R⁸, -R⁹(R¹⁷)_m,

-OR⁹(R ⁷)_m, and -OR⁸;

R⁸ is independently selected from the group consisting of hydrogen and (Ci-C₃)alkyl; R⁹ is (C C₆)alkyl;

R¹⁰ is (C₄-C₁₄)aryl;

R¹² is -NR⁸R⁸;

R ³ is (C₃-C₁₂)cycloalkyl;

R ⁴ is selected from the group consisting of (d-C heterocyclic and (d-Cn)heteroaryl, each independently having one to three heteroatoms selected from N and O;

R¹⁵ is independently selected from the group consisting of (d-C₆)alkyl, (Ci-C₆)alkoxy, -OR⁸, halo, nitrile, -N0₂, and -C0₂R⁸;

R ⁶ is independently selected from the group consisting of (CrC₆)alkyl, (CrC₆)alkoxy, -R¹⁷, -(R¹⁷)₂, -R ², hydroxyl, and nitrile;

R¹⁷ is halo;

each m is independently an integer from 1 to 3;

each n is independently an integer from 1 to 3; and

each w is independently an integer from 1 to 6.

[0094] In another embodiment of the present invention, there is provided a compound of

Formula (II):

(N)

or a pharmaceutically acceptable salt thereof, wherein:

R is selected from the group consisting of hydrogen, methyl, ethyl, phenyl, nitrile, and -S0²R⁹;

R² is selected from the group consisting of hydrogen, methyl, ethyl, isobutyl, halo, - (CH₂)_WR¹⁴, -R⁶, -R¹⁰R⁵, -R¹⁰R⁷, -R¹⁰R¹⁴, -R¹³R¹⁶, -R ⁴R⁷, -C(0)R⁸, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, hydroxycyclohexyl, phenyl, cyanophenyl, methylphenyl, tetrahydropyranyl, morpholinyl, acetylpiperidinyl, methylbenzamide, pyridyl, pyrazolyl, pyrimidyl, wherein R¹ and R² may optionally join together along with the intervening N and C atoms to form a ring structure, wherein s re is fused to the adjacent pyridyl moiety and having the

structure:

, and wherein said R and R -joined ring structure may be optionally substituted with one to three independent R⁸ groups; R³ and R⁴ are independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, oxo, hydroxyl, trifluoromethyl, amino,_, trifluoromethoxy, and halo;

R⁵ is selected from the group consisting of

, methyl, ethyl, isopropyl, propyl, butyl, isobutyl, tert-butyl, phenyl, chlorophenyl, fluorophenyl, difluorophenyl, benzyl, cyclopropyl, trifluoromethyl, trifluoroethyl, pyridyl, and quinolinyl; R⁶ is selected from the group consisting of -R ⁰C(O)R¹⁴, -R¹⁰C(O)R ⁴R¹⁶, -R¹⁰(CH₂)_WR¹², -

R ⁰(CH₂)_WR¹⁴, and -R ⁰(CH₂)_WR¹⁴R¹⁶;

R⁷ is independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, methoxy, oxo, chloro, flouro, bromo, trifluoromethyl, trifluoroethyl, trifluoromethoxy, trifluoroethoxy, nitrile, carboxyl, acetoxy, -S0₂R⁹,

-OR⁸, -C0₂R⁸, -C(0)R¹², and -C(0)NHR⁹;

propyl, isopropyl, butyl, isobutyl, and tert-butyl;

isobutyl, and tert-butyl;

R ⁰ is phenyl;

R is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, tert- butyl, halo, trifluoromethyl, trifluoromethoxy, methoxy, ethoxy, nitrile, -NHS0₂R⁹, -C0₂R⁸, -OR⁸, -0(CH₂)_wR¹², -S0₂R¹², -S0₂R⁹, and -R ⁶, -(CH₂)_WR¹⁴;

R¹² is -NR⁸R⁸,

R ³ is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl;

R ⁴ is selected from the group consisting of morpholinyl, tetrahydropyranyl, triazolyl, pyrimidinyl, pyrazolyl, piperazinyl, pyrrolidinyl, piperidinyl, pyridinyl, R ⁵ is independently selected from the group consisting of fluoro, chloro, bromo,

methoxy, ethoxy, methyl, ethyl, butyl, propyl, isopropyl, nitrile, -N0₂, trifluoromethoxy, and trifluoromethyl;

isopropyl, butyl, tert-butyl, hydroxyl, -R ⁷, -(R ⁷)₂, -R¹², methoxy, ethoxy, and nitrile;

R ⁷ is selected from the group consisting of chloro, fluoro, and bromo;

each n is independently an integer from 1 to 3; and

each w is independently an integer from 1 to 6.

[0095] In another embodiment of the present invention, there is provided a compound of

Formula (III):

(III)

armaceutically acceptable salt thereof, wherein:

Y and Z are independently selected from a bond or (d-C₆)alkylene;

R is selected from the group consisting of hydrogen, (CrC₆)alkyl, (C₄-Ci₄)aryl, nitrile, -R¹⁴, and -S0₂R⁹;

R² is selected from the group consisting of hydrogen, (CrC₆)alkyl, (C₁-C₆)alkenyl, halo, -NHR ⁰, -R⁶, -R¹⁰, -R ³, -R¹⁴, -R¹⁰R⁵, -R ⁰R⁷, -R ⁰R¹⁴, -R¹³R¹⁶, -R ⁴R⁷, -(CH₂)_WR¹⁴, -C(0)R⁸, and -R¹³OR⁸;

R³ and R⁴ are independently selected from the group consisting of hydrogen, (Ci- C₆)alkyl, (C₁-C₆)alkoxy, nitrile, -S0₂R⁸, oxo, -OR⁸, -R ², and halo;

R⁵ is selected from the group consisting of (Ci-C₆)alkyl, -R⁹OR⁸, (C C₆)alkoxy, -R¹⁰R¹⁷, -R ⁰(R ⁷)_n, benzyl, (C₄-C₁₄)aryl, (C₃-C₁₂)cycloalkyl, -R⁹R¹², -R⁹R¹³, -OR⁹(R ⁷)_m, trifluoromethyl, trifluoroethyl, (C -C )heterocyclic, and (C -C )heteroaryl;

R⁶ is selected from the group consisting of -R ⁰C(O)R¹⁴, -R ⁰C(O)R ⁴R¹⁶, -R ⁰(CH₂)_WR¹², -R¹⁰(CH₂)_WR¹⁴, and -R ⁰(CH₂)_WR¹⁴R¹⁶;

R⁷ is selected from the group consisting of (CrC₆)alkyl, (CrC₆)alkoxy, oxo, halo, nitrile, R⁹(R¹⁷)_m, -NO2, -R⁹OR⁸, -C0₂R⁸, -C(0)R⁹, -R⁹(R ⁷)_m, -OR⁹(R¹⁷)_m,

-(CH₂)_WCN, -S0₂R¹², -S0₂R⁹, -S0₂NH(CH₂)_wR¹⁴, -S0₂(CH₂)_wR¹⁴, -R¹², -R¹⁴, -(CH₂)_wOR⁸, -C(0)NHR¹³, -C(0)NHR¹⁴, -C(0)NHR⁹, -R ⁰, -OR⁹(R¹⁷)_m, -C(0)R¹², -NHC(O)NHR ⁰R¹¹, -C(0)NH(CH₂)_wR¹², -C(0)(CH₂)_wR¹², -NHC(0)C(0)R¹⁴, -NHC0₂R⁸, -OR⁸, -C(0)NH(CH₂)_wR¹⁴, -C(0)(CH₂)_wR¹⁴, -(CH₂)_WR¹¹, -NH(CH₂)_WR¹ -(CH₂)_WR¹⁴ , -(CH₂)_WR¹⁰, -(CH₂)_WNHR¹⁰, -(CH₂)_wC0₂R⁸, -C(O)NHR ⁰R¹¹, - C(0)NH(CH₂)_wOR⁸, and -C(0)NH(CH₂)_wR¹¹;

R⁸ is independently selected from the group consisting of hydrogen, (CrC₆)alkyl, and (C₄-C ₄)aryl;

R⁹ is (C C₆)alkyl;

R ⁰ is (C₄-C₁₄)aryl; R is selected from the group consisting of (C C₆)alkyl, -R ⁴, -R¹⁴R¹⁵, -R ³, -R¹²,

-NHR⁵, -NHR¹⁰R¹⁵, -NHR¹⁴, and -R¹⁶, -NHR¹⁰(R ⁷)_n;

R ² is -NR⁸R⁸;

R ³ is (C₃-C₁₂)cycloalkyl;

R¹⁴ is selected from the group consisting of (CrCn)heterocyclic and (CrC-n)heteroaryl, each independently having one to three heteroatoms selected from N and O; R ⁵ is selected from the group consisting of (d-C₆)alkyl, (Ci-C6)alkoxy, oxo, dioxo, -OR⁸, halo, nitrile, -N0₂, and -C0₂R⁸;

R ⁶ is selected from the group consisting of (C C₆)alkyl, (Ci-C₆)alkoxy, -R ⁷, -(R ⁷)₂, -R¹² nitrile, -NHS0₂R⁹, -C0₂R⁸, -OR⁸, -0(CH₂)_wR¹², -S0₂R¹², -S0₂R⁹,

-NH(CH₂)_WR¹⁴, and -(CH₂)_WR¹⁴;

R ⁷ is halo;

each m is independently an integer from 1 to 3;

each n is independently an integer from 1 to 3; and

each w is independently an integer from 1 to 6.

[0096] In another embodiment of the present invention, there is provided a compound of

Formula (III):

(III)

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is selected from the group consisting of hydrogen, methyl, ethyl, phenyl, nitrile,

-S0²R⁹, -(CH₂)_WR¹⁴, and -(CH₂)_wS0₂R⁹;

R² is selected from the group consisting of hydrogen, methyl, ethyl, isobutyl, halo, -

NHR ⁰SO₂R⁹, -R ⁰R⁵, -R¹⁰R⁷, -R ⁰R¹⁴, -R¹³R¹⁶, -R ⁴R⁷, -(CH₂)_WR¹⁴, -NHR ⁰SO₂R¹², -NHR ⁰R¹², -C(0)R⁸, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, hydroxycyclohexyl, phenyl, cyanophenyl, methylphenyl, acetylpiperidinyl, methylbenzamide, pyridyl, pyrazolyl, and pyrimidyl;

R³ and R⁴ are independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, oxo, hydroxy!, trifluoromethyl, methylamino, dimethylamino, amino, trifluoromethoxy, and halo;

R⁵ is selected from the group consisting of methyl, ethyl, isopropyl, propyl, butyl,

isobutyl, tert-butyl, methoxy, ethoxy, phenyl, chlorophenyl, fluorophenyl, difluorophenyl, benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, hydroxyethyl, dimethylaminoethyl, trifluoromethyl, trifluoroethyl, trifluoromethoxy, pyridyl, quinolinyl, and furanyl;

R⁶ is selected from the group consisting of -R ⁰C(O)R¹⁴, -R¹⁰C(O)R ⁴R¹⁶, -R ⁰(CH₂)_WR¹², -R¹⁰(CH₂)_WR¹⁴, and -R¹⁰(CH₂)_WR¹⁴R¹⁶;

isobutyl, tert-butyl, methoxy, ethoxy, oxo, chloro, flouro, bromo, trifluoromethyl, trifluoroethyl, trifluoromethoxy, trifluoroethoxy, nitrile, phenyl, carboxyl, acetoxy, -OR⁸, -C0₂R⁸, and -C(0)R⁹;

R⁸ is independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, and phenyl;

isobutyl, and tert-butyl;

R ⁰ is phenyl;

R¹¹ is selected from the group consisting of methyl, ethyl, -R ⁴, -R¹³, -R ², -NHR⁵,

-NHR¹⁴, -R ⁴R¹⁵, -NHR¹⁰R¹⁵, and -R¹⁶, -NHR¹⁰(R¹⁷)_n;

R ² is -NR⁸R⁸;

R¹⁴ is selected from the group consisting of morpholinyl, tetrahydropyranyl, dioxanyl, triazolyl, pyrimidinyl, pyrazolyl, piperazinyl, pyrrolidinyl, piperidinyl, and pyridinyl;

R ⁵ is selected from the group consisting of fluoro, chloro, bromo, oxo, dioxo, methoxy, ethoxy, methyl, ethyl, butyl, propyl, isopropyl, nitrile, -N0₂, trifluoromethoxy, and trifluoromethyl;

R¹⁶ is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, tert- butyl, -R¹⁷, -(R ⁷)₂, -R¹², methoxy, hydroxyl, ethoxy, and nitrile;

R ⁷ is selected from the group consisting of chloro, fluoro, and bromo; each n is independently an integer from 1 to 3; and

each w is independently an integer from 1 to 6.

[0097] In another embodiment of the present invention, there is provided a compound of

Formula (IV):

(IV)

armaceutically acceptable salt thereof, wherein:

Y and Z are independently selected from a bond or (C₁-C₆)alkylene;

R¹ is selected from the group consisting of hydrogen, (d-C₆)alkyl, (C₄-C₁₄)aryl, nitrile, -R ⁴, and -S0₂R⁹;

R² is selected from the group consisting of hydrogen, (C -C₆)alkyl, (C₁-C₆)alkenyl, halo, -NHR ⁰, -R⁶, -R¹⁰, -R ³, -R ⁴, -R¹⁰R⁷, -R ⁰R¹⁴, -R ³R¹⁶, -R ⁴R⁷, -(CH₂)_WR¹⁴, -C(0)R⁸, and -R ³OR⁸;

R³ and R⁴ are independently selected from the group consisting of hydrogen, (d- C₆)alkyl, (C C₆)alkoxy, nitrile, -S0₂R⁸, oxo, -OR⁸, -R¹², and halo;

-R¹⁰(R¹⁷)_n, benzyl, (C₄-Ci₄)aryl, (C₃-C ₂)cycloalkyl, trifluoromethyl, trifluoroethyl, (Ci-C )heterocyclic, and (Ci-Cn)heteroaryl;

R⁶ is selected from the group consisting of -R¹⁰C(O)R¹⁴, -R¹⁰C(O)R ⁴R¹⁶, -R ⁰(CH₂)_WR¹², -R¹⁰(CH₂)_WR¹⁴, and -R¹⁰(CH₂)_WR¹⁴R¹⁶;

R⁷ is selected from the group consisting of (C₁-C₆)alkyl, (CrC₆)alkoxy, oxo, halo, nitrile, -R⁹(R ⁷)_m, -N0₂, -R⁹OR⁸, -C0₂R⁸, -C(0)R⁹, -R⁹(R¹⁷)_m, -OR⁹(R¹⁷)_m, -(CH₂)_WCN, -S0₂R¹², -S0₂R⁹, -S0₂NH(CH₂)_wR¹⁴, -S0₂(CH₂)_wR¹⁴, -R¹², -R ⁴, -(CH₂)_wOR^s, -C(0)NHR¹³, -C(0)NHR¹⁴, -C(0)NHR⁹, -R ⁰, -OR⁹(R¹⁷)_m, -C(0)R¹², -NHC(O)NHR¹⁰R¹¹, -C(0)NH(CH₂)_wR¹², -C(0)(CH₂)_wR¹², -NHC(0)C(0)R¹⁴,

-NHC0₂R⁸, -OR⁸, -C{0)NH(CH₂)_wR¹⁴, -C(0){CH₂)_wR¹⁴, -{CH₂)_WR¹¹, -NH(CH₂)_WR¹⁴ -(CH₂)_WR¹⁴ , -(CH₂)_WR¹⁰, -(CH₂)_WNHR¹⁰, -(CH₂)_wC0₂R⁸, -C(O)NHR ⁰R¹¹, -C(0)NH(CH₂)_wOR⁸, and -C(0)NH(CH₂)_wR¹¹; and

R⁸ is independently selected from the group consisting of hydrogen, (CrC₆)alkyl, and

(C₄-C ₄)aryl;

R⁹ is (C C₆)alkyl;

R¹⁰ is (C₄-C₁₄)aryl;

R¹¹ is selected from the group consisting of (C C₆)alkyl, -R¹⁴, -R ⁴R¹⁵, -R ³, -R¹², -

NHR⁵, -NHR¹⁰, -NHR ⁴, -NHR ⁰R¹⁵, and -R ⁶, -NHR¹⁰(R ⁷)_n;

R ² is -NR⁸R⁸;

R ³ is (C₃-Ci₂)cycloalkyl;

R¹⁴ is selected from the group consisting of (d-Cn heterocyclic and (CrCn)heteroaryl, each independently having one to three heteroatoms selected from N and O; R ⁵ is selected from the group consisting of (d-C_e)alkyl, (Ci-C₆)alkoxy, oxo, dioxo,

-OR⁸, halo, nitrile, -N0₂, and -C0₂R^s;

R¹⁶ is selected from the group consisting of (CrC₆)alkyl, (C₁-C₆)alkoxy, -R¹⁷, -(R¹⁷)₂, -

R ², nitrile, -NHS0₂R⁹, -C0₂R⁸, -OR⁸, -0(CH₂)_wR¹², -S0₂R¹², -S0₂R⁹,

NH(CH₂)_WR¹⁴, and -(CH₂)_WR¹⁴;

R ⁷ is halo;

each m is independently an integer from 1 to 3;

each n is independently an integer from 1 to 3; and

each w is independently an integer from 1 to 6.

[0098] In another embodiment of the present invention, there is provided a compound of

Formula (IV):

or a pharmaceutically acceptable salt thereof, wherein:

Y and Z are independently selected from the group consisting of a bond, methylene, and ethylene; R is selected from the group consisting of hydrogen, methyl, ethyl, phenyl, nitrile, -S0²R⁹, -(CH₂)wR¹⁴, and -(CH₂)_wS0₂R⁹;

R² is selected from the group consisting of hydrogen, methyl, ethyl, isobutyl, ethylene, halo, -NHR¹⁰SO₂R⁹, -R ⁰R⁷, -R ⁰R¹⁴, -R¹³R¹⁶, -R¹⁴R⁷, -(CH₂)_WR¹⁴, -NHR¹⁰SO₂R¹², -NHR¹⁰R¹², -C(0)R⁸, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,

hydroxycyclohexyl, phenyl, cyanophenyl, methylphenyl, acetylpiperidinyl, methylbenzamide, pyridyl, pyrazolyl, pyrimidyl, wherein R¹ and R² may optionally join together along with the intervening N and C atoms to form a ring structure, wherein said ring structure is fused to the adjacent pyridyl moiety and having the

structure:

, and wherein said R¹ and R²-joined ring structure may be optionally substituted with one to three independent R groups;

R³ and R⁴ are independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, oxo, hydroxyl, trifluoromethyl, methylamino, dimethylamino, amino_, trifluoromethoxy, and halo;

isobutyl, tert-butyl, phenyl, chlorophenyl, fluorophenyl, difluorophenyl, benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, trifluoromethyl, trifluoroethyl, pyridyl, quinolinyl, and furanyl;

R⁶ is selected from the group consisting of -R¹⁰C(O)R¹⁴, -R¹⁰C(O)R ⁴R¹⁶, -R ⁰(CH₂)_WR¹², - R ⁰(CH₂)_WR¹⁴, and -R¹⁰(CH₂)_WR ⁴R¹⁶;

isobutyl, tert-butyl, methoxy, oxo, chloro, flouro, bromo, trifluoromethyl, trifluoroethyl, trifluoromethoxy, trifluoroethoxy, nitrile, phenyl, carboxyl, acetoxy, - , -OR⁸, -C0₂R⁸, and -C(0)R⁹;

propyl, isopropyl, butyl, isobutyl, tert-butyl, and phenyl;

isobutyl, and tert-butyl;

R ⁰ is phenyl;

R¹¹ is selected from the group consisting of methyl, ethyl, -R¹³, -R¹², -R ⁴, -NHR⁵,

-NHR ⁰, -NHR¹⁴, -R ⁴R¹⁵, -NHR ⁰R¹⁵, and -R ⁶, -NHR¹⁰(R ⁷)_n;

R ² is -NR^SR⁸; R ³ is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl;

R ⁴ is selected from the group consisting of morpholinyl, tetrahydropyranyl, dioxanyl, triazolyl, pyrimidinyl, pyrazolyl, piperazinyl, pyrrolidinyl, piperidinyl, and pyridinyl;

R¹⁵ is selected from the group consisting of fluoro, chloro, bromo, oxo, dioxo, methoxy, ethoxy, methyl, ethyl, butyl, propyl, isopropyl, nitrile, -N0₂, trifluoromethoxy, and trifluoromethyl;

R ⁶ is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, tert- butyl, -R¹⁷, -(R¹⁷)2, -R¹², hydroxy!, trifluoromethyl, trifluoromethoxy, methoxy, ethoxy, and nitrile;

R ⁷ is selected from the group consisting of chloro, fluoro, and bromo;

each n is independently an integer from 1 to 3; and

each w is independently an integer from 1 to 6.

[0099] In another embodiment of the present invention, there is provided a compound of

Formula (V),

(V)

or a pharmaceutically acceptable salt thereof, wherein:

Y and Z are independently selected from a bond or (d-C₆)alkylene;

A is selected from the group consisting of (C₄-Ci₄)aryl, (d-Cn heterocyclic, and (Ci-

Cii)heteroaryl, wherein said heterocyclic and heteroaryl of said A group has one to three heteroatoms independently selected from N, S and O, and wherein said A group may be optionally substituted with one to three R ⁵ groups;

R is selected from the group consisting of hydrogen, (Ci-C_e)alkyl, (C₄-Ci₄)aryl,

-R¹⁴, and -S0₂R⁹, wherein said (C₄-C₁₄)aryl of said R¹ group is optionally substituted with one to three R⁶ groups;

R² is selected from the group consisting of hydrogen, (C -C₆)alkenyl, halo, -NHR¹⁰, (C₄- C ₄)aryl, (d-d-i heterocyclic, and (d-Cuheteroaryl, wherein said (d- Cn heterocyclic and (d-d ^heteroaryl groups of said R² group each independently have one to three heteroatoms selected from N and O, and wherein said R² group may be optionally substituted with one to three R⁷ groups; R³ is selected from the group consisting of hydrogen, (CrC₆)alkyl, (d-C₆)alkoxy, nitrile, - S0₂R⁸, oxo, -OR⁸, -R¹², and halo, and wherein said (C C₆)alkyl and (C

C₆)alkoxy of said R³ and R⁴ groups may be optionally substituted with one to three R ⁷ groups;

R⁵ is selected from the group consisting of (CrC₆)alkyl, (CrC₆)alkoxy, (C₄-Ci₄)aryl, benzyl, (C₃-Ci₂)cycloalkyl, trifluoromethyl, trifluoroethyl, (C -Cn heterocyclic, and (Ci-Cn)heteroaryl, wherein said (CrCn)heterocyclic and (CrCn)heteroaryl of said R⁵ group each independently have one to three heteroatoms selected from N and O, and wherein R⁵ may be optionally substituted with one to three R ⁵ groups;

R⁶ is independently selected from the group consisting of (CrC₆)alkyl, (CrC₆)alkoxy, -OR⁸, -C(0)R¹⁴, and (C C,., heterocyclic, wherein said (d-Cn heterocyclic of said R⁶ group has one to three heteroatoms selected from N and O;

R⁷ is independently selected from the group consisting of (CrC₆)alkyl, (C₁-C₆)alkoxy, oxo, halo, nitrile, -N0_2> -R⁹OR⁸, -(CH₂)_WCN, -S0₂R¹², -S0₂R⁹, -S0₂NH(CH₂)_wR¹⁴, -S0₂(CH₂)_wR¹⁴, -R ², -R¹⁴, -(CH₂)_wOR⁸, -C(0)NHR¹³, -C(0)NHR¹⁴, -C(0)NHR⁹, -C(0)R¹², -NHC(O)NHR¹⁰R¹¹, -C(0)NH(CH₂)_wR¹², -C(0)(CH₂)_wR¹², -C0₂R⁸, -NHC(0)C(0)R¹⁴, -NHC0₂R⁸, -OR⁸, -C(0)NH(CH₂)_wR¹⁴, -C(0)(CH₂)_wR¹⁴, -C(0)R¹⁴, -(CH₂)_WR¹¹, -NH(CH₂)_WR¹⁴, -(CH₂)_WR¹⁴ , -(CH₂)_WR¹⁰, -(CH₂)_WNHR¹⁰, -(CH₂)_wC0₂R⁸, -C(O)NHR¹⁰R¹¹, -C(0)NH(CH₂)_wOR⁸, and -C(0)NH(CH₂)_wR¹¹; and wherein said (Ci-C₅)alkyl and (CrC₆)alkoxy of said R⁷ group may be optionally substituted with one to three R¹⁷ groups;

R⁸ is independently selected from the group consisting of hydrogen and (CrC₆)alkyl;

R⁹ is (C C₆)alkyl;

R ⁰ is (C₄-C₁₄)aryl;

R¹¹ is selected from the group consisting of nitrile, halo, (CrC₆)alkyl, (C -C₆)alkoxy,

-NHS0₂R⁹, -C0₂R⁸, -OR⁸, -0(CH₂)_wR¹², -S0₂R¹², -S0₂R⁹, -NH(CH₂)_WR¹⁴ , -R ⁶, and -(CH₂)_WR¹⁴; and wherein said (CrC₆)alkyl and (CrC₆)alkoxy of said R¹ group may be optionally substituted with one to three R¹⁷ groups;

R¹² is -NR⁸R⁸;

R¹³ is (C₃-C₁₂)cycloalkyl;

R ⁴ is selected from the group consisting of (C -C )heterocyclic and (d-Cuheteroaryl, each independently having one to three heteroatoms selected from N and O, wherein said (CrCn)heterocyclic and (Ci-Cn)heteroaryl may be optionally substituted by one to three independent R¹⁶ groups;

R ⁵ is selected from the group consisting of (d-C₆)alkyl, (Ci-C6)alkoxy, oxo, dioxo, -OR⁸, halo, nitrile, -N0₂, and -C0₂R⁸;

R¹⁶ is independently selected from the group consisting of (C -C₆)alkyl, (CrC₆)alkoxy, halo, nitrile, -NHS0₂R⁹, -C0₂R⁸, -OR⁸, -0(CH₂)_wR¹², -S0₂R¹², -S0₂R⁹,

-NH(CH₂)_WR¹⁴, and -(CH₂)_WR¹⁴; and wherein said (C C₆)alkyl and (C C₆)alkoxy of said R¹⁶ group may be optionally substituted with one to three R ⁷ groups;

R ⁷ is halo;

m is independently 0 or an integer from 1 to 4;

n is independently 0 or an integer from 1 to 3; and

w is independently 0 or an integer from 1 to 6.

[00100] In another embodiment of the present invention, there is provided a compound of Formula (V):

(V)

or a pharmaceutically acceptable salt thereof, wherein:

Y and Z are independently selected fro

A is selected from the group consisting

, phenyl, and dimethoxyphenyl, and wherein said A group may be optionally substituted with one to three R¹⁵ groups;

R is selected from the group consisting of hydrogen, (CrC₆)alkyl, (C₄-Ci₄)aryl,

-R¹⁴, and -S0₂R⁹, wherein said (C₄-Ci₄)aryl of said R¹ group is optionally substituted with one to three R⁶ groups;

R² is selected from the group consisting of hydrogen, (Ci-C_e)alkenyl, halo, -NHR¹⁰, (C₄- Ci₄)aryl, (Ci-Cn)heterocyclic, and (CrCn)heteroaryl, wherein said (d- Ci ^heterocyclic and (Ci-Cn)heteroaryl groups of said R² group each

independently have one to three heteroatoms selected from N and O, and wherein said R² group may be optionally substituted with one to three R⁷ groups;

C₆)alkyl, (C C₆)alkoxy, nitrile, -N₃, -SR⁸, -S0₂R⁸, oxo, -OR⁸, -R¹², and halo, and wherein said (CrC₆)alkyl and (CrC₆)alkoxy of said R³ and R⁴ groups may be optionally substituted with one to three R ⁷ groups;

R⁵ is selected from the group consisting of (CrC₆)alkyl, (CrC₆)alkoxy, (C₄-C₁₄)aryl, benzyl, (C₃-Ci₂)cycloalkyl, trifluoromethyl, trifluoroethyl, (C-i-Cn)heterocyclic, and (CrCi )heteroaryl, wherein said (C -Cn)heterocyclic and (CrCn)heteroaryl of said R⁵ group each independently have one to three heteroatoms selected from N and O, and wherein R⁵ may be optionally substituted with one to three R ⁵ groups;

R⁶ is independently selected from the group consisting of (Ci-C₆)alkyl, (C₁-C₆)alkoxy, -OR⁸, -C(0)R¹⁴, and (d-Cn heterocyclic, wherein said (CrC^heterocyclic of said R⁶ group has one to three heteroatoms selected from N and O;

R⁷ is independently selected from the group consisting of (Ci-C₅)alkyl, (CrC₆)alkoxy, oxo, halo, nitrile, -OR⁸, and wherein said (CrC₆)alkyl and (CrC₆)alkoxy of said R⁷ group may be optionally substituted with one to three R ⁷ groups;

R⁸ is independently selected from the group consisting of hydrogen and (Ci-C₃)alkyl;

R⁹ is (C C₅)alkyl;

R is selected from the group consisting of nitrile, halo, (CrC₆)alkyl, (CrC₆)alkoxy,

-NHSO₂R⁹, -CO₂R⁸, -OR⁸, -0(CH₂)_wR¹², -SO₂R¹², -SO₂R⁹, -NH(CH₂)_WR¹⁴ , -R ⁶, and -(CH₂)_WR¹⁴; and wherein said (CrC₆)alkyl and (CrC₆)alkoxy of said R¹¹ group may be optionally substituted with one to three R¹⁷ groups;

R ² is -NR⁸R⁸;

R ³ is (C₃-C₁₂)cycloalkyl;

R¹⁴ is selected from the group consisting of (CrCn)heterocyclic and (CrC-n)heteroaryl, each independently having one to three heteroatoms selected from N and O, wherein said (d-Cuheterocyclic and (d-Cuheteroaryl may be optionally substituted by one to three independent R ⁶ groups;

R ⁶ is independently selected from the group consisting of (CrC₆)alkyl, (Ci-C₆)alkoxy, halo, nitrile, -NHS0₂R⁹, -C0₂R⁸, -OR⁸, -0(CH₂)_wR¹², -S0₂R¹², -S0₂R⁹,

-NH(CH₂)wR¹⁴, and -(CH₂)_WR¹⁴; and wherein said (d-C₆)alkyl and (C C₆)alkoxy of said R ⁶ group may be optionally substituted with one to three R ⁷ groups;

R ⁷ is halo;

m is independently 0 or an integer from 1 to 4;

n is independently 0 or an integer from 1 to 3; and

w is independently 0 or an integer from 1 to 6.

[00101] In another embodiment of the present invention, there is provided a compound of Formula (VI):

or a pharmaceutically acceptable salt thereof.

[00102] In another embodiment of the invention, there is provided a compound of any of Formulas I, II, III, IV, V, and VI, wherein the compound or salt of the compound is used in the manufacture of a medicament for use in the treatment of a viral infection in a human.

[00 03] In another embodiment of the invention, there is provided a pharmaceutical composition comprising a pharmaceutically acceptable diluent and a therapeutically effective amount of a compound as defined in any of Formulas I, II, Ml, IV, V, and VI.

[00104] In another embodiment of the invention, there is provided a method for treating a viral infection in a mammal mediated at least in part by a virus in the Fiaviviridae family of viruses which method comprises administering to a mammal, that has been diagnosed with said viral infection or is at risk of developing said viral infection, a compound of any of Formulas I, II, III, IV, V, and VI.

[00105] In another embodiment of the invention, there is provided a method for treating a viral infection in a mammal mediated at least in part by a virus in the Fiaviviridae family of viruses which method comprises administering to a mammal, that has been diagnosed with said viral infection or is at risk of developing said viral infection, a compound of any of Formulas 1, 11, III, IV, V, and VI, wherein said virus is hepatitis C virus.

[00106] In another embodiment of the invention, there is provided a method for treating a viral infection in a mammal mediated at least in part by a virus in the Flaviviridae family of viruses which method comprises administering to a mammal, that has been diagnosed with said viral infection or is at risk of developing said viral infection, a compound of any of Formulas I, II, III, IV, V, and VI, further comprising administration of a therapeutically effective amount of one or more agents active against hepatitis C virus.

[00107] In another embodiment of the invention, there is provided a method for treating a viral infection in a mammal mediated at least in part by a virus in the Flaviviridae family of viruses which method comprises administering to a mammal, that has been diagnosed with said viral infection or is at risk of developing said viral infection, a compound of any of Formulas I, II, III, IV, V, and VI, further comprising administration of a therapeutically effective amount of one or more agents active against hepatitis C virus, wherein said agent active against hepatitis C virus is an inhibitor of HCV protease, HCV polymerase, HCV helicase, HCV entry, HCV assembly, HCV egress, HCV replicase, HCV NS5A protein, or inosine 5'-monophosphate dehydrogenase.

[00108] In another embodiment of the invention, there is provided a method for treating a viral infection in a mammal mediated at least in part by a virus in the Flaviviridae family of viruses which method comprises administering to a mammal, that has been diagnosed with said viral infection or is at risk of developing said viral infection, a compound of any of Formulas I, II, III, IV, V, and VI, further comprising administration of a therapeutically effective amount of one or more agents active against hepatitis C virus, wherein said agent active against hepatitis C virus is interferon.

[00109] In another embodiment of the invention, there is provided a method for treating a viral infection in a mammal mediated at least in part by a virus in the Flaviviridae family of viruses which method comprises administering to a mammal, that has been diagnosed with said viral infection or is at risk of developing said viral infection, a compound of any of Formulas I, II, III, IV, V, and VI, further comprising administration of a therapeutically effective amount of one or more agents active against hepatitis C virus, wherein said agent active against hepatitis C virus is ribavirin.

[00110] In another embodiment of the invention, there is provided a method for treating a viral infection in a mammal mediated at least in part by a virus in the Flaviviridae family of viruses which method comprises administering to a mammal, that has been diagnosed with said viral infection or is at risk of developing said viral infection, a compound of any of Formulas 1, 11, III, IV, V, and VI, further comprising administration of a therapeutically effective amount of one or more agents active against hepatitis C virus, wherein said agent active against hepatitis C virus is interferon in combination with ribavirin.

[00111] In yet further embodiments, the compound of the present invention, or a pharmaceutically acceptable salt thereof, is chosen from the compounds set forth in Table 1 .

Table 1

N-{5-[2-amino-4-oxo-3-(3- phenylphenyl)-3,4-

11 dihydroquinazolin-6-yl]-2- methoxypyridin-3-yl}-2,4- difluorobenzene-1 -sulfonamide

N-{5-[2-amino-3-(2-methylphenyl)- 4-oxo-3,4-dihydroquinazolin-6-yl]-2-

12

methoxypyridin-3-yl}-2,4- difluorobenzene-1 -sulfonamide

,s 2,4-difluoro-N-[2-(methyloxy)-5-(12- H^No oxo-5 , 12-di hydrobenzi midazo[2 , 1 -

13

b]quinazolin-2-yl)-3- pyridinyl]benzenesulfonamide

N-(5-{2-amino-3-[3-(morpholin-4- ylmethyl)phenyl]-4-oxo-3,4-

14 dihydroquinazolin-6-yl}-2- methoxypyridin-3-yl)-2,4- difluorobenzene-1 -sulfonamide

N-[5-(2-amino-3-{3- [(diethylamino)methyl]phenyl}-4-

15 oxo-3,4-dihydroquinazolin-6-yl)-2- methoxypyridin-3-yl]-2,4- difluorobenzene-1 -sulfonamide

N-(5-{2-amino-4-oxo-3-[3- (piperidin-1-ylmethyl)phenyl]-3,4-

16 dihydroquinazolin-6-yl}-2- methoxypyridin-3-yl)-2,4- I.- difluorobenzene-1 -sulfonamide

N-(5-{2-amino-4-oxo-3-[4- (piperidin-1-ylmethyl)phenyl]-3,4-

23 dihydroquinazolin-6-yl}-2- methoxypyridin-3-yl)-2,4- difluorobenzene-1 -sulfonamide

N-(5-{2-amino-3-[4-(morpholin-4- ylmethyl )phenyl]-4-oxo-3, 4-

24 dihydroquinazolin-6-yl}-2- methoxypyridin-3-yl)-2,4- difluorobenzene-1 -sulfonamide

N-{5-[2-amino-3-(4-cyanophenyl)-4- oxo-3,4-dihydroquinazolin-6-yl]-2-

25

methoxypyridin-3-yl}-2,4- difluorobenzene-1 -sulfonamide

N-[5-(2-amino-3-{4-[(4- methylpiperazin-1- yl)methyl]phenyl}-4-oxo-3,4-

26

dihydroquinazolin-6-yl)-2- methoxypyridin-3-yl]-2,4- difluorobenzene-1 -sulfonamide

N-(5-{2-amino-4-oxo-3-[4- (pyrrolidin-1-ylmethyl)phenyl]-3,4-

27 dihydroquinazolin-6-yl}-2- methoxypyridin-3-yl)-2,4- difluorobenzene-1 -sulfonamide

N-(5-{2-amino-4-oxo-3-[2- (trifluoromethyl)phenyl]-3,4-

28 dihydroquinazolin-6-yl}-2- methoxypyrid in-3-yl )-2 ,4- difluorobenzene-1 -sulfonamide N-(5-{2-amino-4-oxo-3-[2- (trifl uoromethoxy)phenyl j-3,4- dihydroquinazolin-6-yl}-2- methoxypyridin-3-yl)-2,4- difluorobenzene-1 -sulfonamide

0L N-{5-[2-amino-3-(3- methoxyphenyl)-4-oxo-3,4- dihydroquinazolin-6-yl]-2- methoxypyridin-3-yl}-2,4-

UM difluorobenzene-1 -sulfonamide

N-{5-[2-amino-3-(4-fluorophenyl)-4- oxo-3,4-dihydroquinazolin-6-yl]-2- methoxypyridin-3-yl}-2,4- difluorobenzene-1 -sulfonamide

⁽J . N-{5-[2-amino-3-(4- methoxyphenyl)-4-oxo-3,4- dihydroquinazolin-6-yl]-2- methoxypyridin-3-yl}-2,4- difluorobenzene-1 -sulfonamide

2,4-difluoro-N-[5-[2-(methylamino)- 4-oxo-3-phenyl-3,4-dihydro-6- quinazolinyl]-2-(methyloxy)-3- pyridinyl]benzenesulfonamide N-[5-(2-amino-4-oxo-3-phenyl-3,4-

dihydro-6-quinazolinyl)-2- (methyloxy)-3-pyridinyl]-8- quinolinesulfonamide

2-amino-3-phenyl-6-(1 H- pyrrolo[3,2-b]pyridin-6-yl)-4(3H)- quinazolinone

N-[2-amino-5-(2-amino-4-oxo-3- phenyl-3,4-dihydroquinazolin-6- yl)pyridin-3-yl]-2,4-difluorobenzene- 1 -sulfonamide

N-[5-[2-amino-3-(2-methylpropyl)-4- oxo-3,4-dihydro-6-quinazolinyl]-2- (methyloxy)-3-pyridinyl]-2,4- difluorobenzenesulfonamide

N-[5-[2-(cyanoamino)-4-oxo-3- phenyl-3,4-dihydro-6-quinazolinyl]- 2-(methyloxy)-3-pyridinyl]-2,4- difluorobenzenesulfonamide

N-[5-(2-amino-3-cyclobutyl-4-oxo- 3 ,4-d ihyd ro-6-qu inazol i nyl )-2- (methyloxy)-3-pyridinyl]-2,4- difluorobenzenesulfonamide

uoro enzenesu onam e

N-[5-(2-amino-4-oxo-3-phenyl-3,4- dihydro-6-quinazolinyl)-2- (methyloxy)-3-pyridi nyl]-4- (methyloxy)benzenesulfonamide

U S A₀ N-[5-(2-amino-4-oxo-3-phenyl-3,4- dihydro-6-quinazolinyl)-2- (methyloxy)-3-pyridi nyl]-3- chlorobenzenesulfonamide

N-[5-(2-amino-4-oxo-3-phenyl-3,4- dihydro-6-quinazolinyl)-2- (methyloxy)-3-pyridi nyl]-2- cyanobenzenesulfonamide

N-[5-(2-amino-4-oxo-3-phenyl-3,4- dihydro-6-quinazolinyl)-2- (methyloxy)-3-pyridi nyl]-3- cyanobenzenesulfonamide

N-[5-(2-amino-4-oxo-3-phenyl-3,4- 1 dihydro-6-quinazolinyl)-2- (methyloxy)-3-pyridinyl]-4- cyanobenzenesulfonamide N-[5-(2-amino-4-oxo-3-phenyl-3,4- dihydro-6-quinazolinyl)-2-

63

(methyloxy)-3-pyridi nyl]-3- methylbenzenesulfonamide

N-[5-(2-amino-4-oxo-3-phenyl-3,4- dihydro-6-quinazolinyl)-2-

64

(methyloxy)-3-pyridinyl]-4- ethylbenzenesulfonamide

U Τ ΧΛ_Ο N-[5-(2-amino-4-oxo-3-phenyl-3,4- dihydro-6-quinazolinyl)-2-

65

(methyloxy)-3-pyridinyl]-3,5- difluorobenzenesulfonamide

N-[5-(2-amino-4-oxo-3-phenyl-3,4- dihydro-6-quinazolinyl)-2-

66

(methyloxy)-3-pyridi nyl]-2- methylbenzenesulfonamide

N-[5-(2-amino-4-oxo-3-phenyl-3,4- dihydro-6-quinazolinyl)-2-

67

(methyloxy)-3-pyridi nyl]-2 ,5- difluorobenzenesulfonamide

N-[5-(2-amino-4-oxo-3-phenyl-3,4- dihydro-6-qutnazolinyl)-2-

68

(methyloxy)-3-pyridinyl]-2- fluorobenzenesulfonamide

(S methyl 4-[2-amino-6-[5-{[(2,4- difluorophenyl)sulfonyl]amino}-6-

82

(methyloxy)-3-pyridinyl]-4-oxo- 3(4H)-quinazolinyl]benzoate

4-[2-amino-6-[5-{[(2,4- difluorophenyl)sulfonyl]amino}-6-

83 (methyloxy)-3-pyridinyl]-4-oxo-

3(4H)-quinazolinyl]-N- methylbenzamide

methyl 4-[2-amino-6-(5-{[(2,4- difluorophenyl)sulfonyl]amino}-6-

84

oxo-1 ,6-dihydro-3-pyridinyl)-4-oxo- 3(4H)-quinazolinyl]benzoate

4-[2-amino-6-(5-{[(2,4- difluorophenyl)sulfonyl]amino}-6-

85

oxo-1 ,6-dihydro-3-pyridinyl)-4-oxo- 3(4H)-quinazolinyl]benzoic acid

4-[2-amino-6-[5-{[(2,4- difluorophenyl)sulfonyl]amino}-6-

86

(methyloxy)-3-pyridinyl]-4-oxo- 3(4H)-quinazolinyl]benzoic acid

4-[2-amino-6-[5-{[(2,4-

1 difluorophenyl)sulfonyl]amino}-6-

87 (methyloxy)-3-pyridinyl]-4-oxo-

3(4H)-quinazolinyl]-N,N- dimethylbenzamide N-[5-{2-amino-3-[4-(4- morpholinylcarbonyl)phenyl]-4-oxo-

88 3 ,4-d ihyd ro-6-qu inazol i nyl}-2- (methyloxy)-3-pyridinyl]-2,4- difluorobenzenesulfonamide

N-[5-(2-amino-3-{4-[(4-methyl-1- piperazinyl)carbonyl]phenyl}-4-oxo-

89 3,4-dihydro-6-quinazolinyl)-2- ( methyloxy)-3-pyridi nyl]-2 ,4- difluorobenzenesulfonamide

N-[5-{2-amino-4-oxo-3-[4-(1- piperidinylcarbonyl)phenyl]-3,4-

90 dihydro-6-quinazolinyl}-2- (methyloxy)-3-pyridi nyl]-2 ,4-

difluorobenzenesulfonamide

methyl 3-[2-amino-6-[5-{[(2,4- difluorophenyl)sulfonyljamino}-6-

91

°Y g f (methyloxy)-3-pyridinyl]-4-oxo- 3(4H)-quinazolinyl]benzoate

I 4-[2-amino-6-[5-{[(2,4- difluorophenyl)sulfonyl]amino}-6-

92

(methyloxy)-3-pyridinyl]-4-oxo- 3(4H)-quinazolinyl]benzamide

3-[2-amino-6-[5-{[(2,4- difluorophenyl)sulfonyljamino}-6-

93 (methyloxy)-3-pyridinyl]-4-oxo-

3(4H)-quinazolinyl]-N-

methylbenzamide 3-[2-amino-6-[5-{[(2,4- difluorophenyl)sulfonyl]amino}-6-

94 (methyloxy)-3-pyridinyl]-4-oxo-

3(4H)-quinazolinyl]-N,N- dimethylbenzamide

N-[5-{2-amino-4-oxo-3-[3-{ 1 - piperidinylcarbonyl)phenyl]-3,4-

95 dihydro-6-quinazolinyl}-2- (methyloxy)-3-pyridi nyl]-2 ,4-

difluorobenzenesulfonamide

3-[2-amino-6-[5-{[(2,4- difluorophenyl)sulfonyl]amino}-6-

96

(methyloxy)-3-pyridinyl]-4-oxo- 3(4H)-quinazolinyl]benzamide

N-[5-{2-amino-3-[3-(4- morpholinylcarbonyl)phenyl]-4-oxo-

97 3,4-dihydro-6-quinazolinyl}-2- (methyloxy)-3-pyridi nyl]-2 ,4- difluorobenzenesulfonamide

N-[5-(2-amino-3-{3-[(4-methyl- 1 - piperazinyl)carbonyl]phenyl}-4-oxo-

98 3 ,4-d ihyd ro-6-qu inazol i nyl )-2- (methyloxy)-3-pyridinyl]-2,4-

difluorobenzenesulfonamide

N-[5-(2-amino-4-oxo-1 ,4-dihydro-6- quinazolinyl)-2-(methyloxy)-3-

99

>* pyridinyl]-2,4- difluorobenzenesulfonamide

2-amino-6-(1 H-indazol-4-yl)-3-

117

phenyl-4(3H)-quinazolinone

2-amino-6-[3,4-

118 bis(methyloxy)phenyl]-3-phenyl- 4(3H)-quinazolinone

2-amino-6-[5-(4-

119 morpholinylcarbonyl)-3-pyridinyl]-3- phenyl-4(3H)-quinazolinone

5-(2-amino-4-oxo-3-phenyl-3,4-

120 dihydro-6-quinazolinyl)-3- pyridinecarboxamide

I

121 A i n 2-amino-6-[5,6-bis(methyloxy)-3- pyridinylj-3-phenyl-4(3H)- quinazolinone

9 2-amino-5-[2-amino-3-(2- fluorophenyl)-4-oxo-3,4-

122

dihydroquinazolin-6-yl]-N- phenylpyridine-3-sulfonamide

9 2-amino-5-[2-amino-3-(2- methoxyphenyl)-4-oxo-3,4-

123

dihydroquinazolin-6-yl]-N- phenylpyridine-3-sulfonamide 2-amino-5-[2-amino-3-(2- ch lorophenyl )-4-oxo-3 ,4- dihydroquinazolin-6-yl]-N- phenylpyridine-3-sulfonamide

<>- 2-amino-5-[2-amino-3-(2- methoxyphenyl)-4-oxo-3,4-

" dihydroquinazolin-6-yl]-N-(2,4- ι ί difluorophenyl)pyridine-3- sulfonamide

2-amino-5-[2-amino-3-(4- bromophenyl)-4-oxo-3,4- dihydroquinazolin-6-yl]-N- phenylpyridine-3-sulfonamide

2-amino-5-[2-amino-4-oxo-3-(4- phenylphenyl)-3,4- dihydroquinazolin-6-yl]-N- phenylpyridine-3-sulfonamide

2-amino-5-[2-amino-3-(2- ch lorophenyl )-4-oxo-3 ,4- dihydroquinazolin-6-yl]-N-(2,4- AX) difluorophenyl)pyridine-3- sulfonamide

5-{2-amino-4-oxo-3-[2-

(trifl uoromethoxy)phenyl j-3,4- dihydroquinazolin-6-yl}-N-(2,4- difluorophenyl)-2-methoxypyridine-

3-sulfonamide

5-(2-amino-4-oxo-3-(pyridin-3-yl)- 3,4-dihydroquinazolin-6-yl)-2- methoxy-N-phenylpyridine-3- sulfonamide

5-(2-amino-4-oxo-3-(pyridin-2-yl)- 3 ,4-d ihyd roqu inazol i n-6-yl )-2- methoxy-N-phenylpyridine-3- sulfonamide

2-amino-5-[2-amino-3-(1 ,4-dioxan- 2-ylmethyl)-4-oxo-3,4-dihydro-6- quinazolinyl]-N-phenyl-3- pyridinesulfonamide

2-amino-5-[2-amino-3-(2- methylpropyl)-4-oxo-3,4-dihydro-6- quinazolinyl]-N-phenyl-3- pyridinesulfonamide

2-amino-5-{2-amino-3-[(4-methyl-3- mo rp ho I i ny I ) meth yl ]-4-oxo-3 ,4- dihydro-6-quinazolinyl}-N-phenyl-3- pyridinesulfonamide

2-amino-5-(2-amino-4-oxo-3-

152 phenyl-3,4-dihydro-6-quinazolinyl)-

N-3-pyridinyl-3-pyridinesulfonamide

2-amino-6-[6-amino-5-(4-

153 morpholinylsulfonyl)-3-pyridinyl]-3- phenyl-4(3H)-quinazolinone

2-amino-6-[6-amino-5-(1-

154 piperidinylsulfonyl)-3-pyridinyl]-3- phenyl-4(3H)-quinazolinone

2-amino-5-(2-amino-4-oxo-3- phenyl-3,4-dihydro-6-quinazolinyl)-

155

N-(4-cyanophenyl)-3- pyridinesulfonamide

2- amino-6-{6-amino-5-[( 1 ,1- dioxido-4-thiomorpholinyl)sulfonyl]-

156 " x JD 3- pyridinyl}-3-phenyl-4(3H)- quinazolinone

2-amino-5-(2-amino-4-oxo-3- phenyl-3,4-dihydro-6-quinazolinyl)-

157

N-(tetrahydro-2H-pyran-4-yl)-3- pyridinesulfonamide

5-(2-amino-4-oxo-3-phenyl-3,4- dihydro-6-quinazolinyl)-N- cyclopentyl-2-(methyloxy)-3- pyridinesulfonamide

2-amino-6-{6-(methyloxy)-5-[(4- methy 1- 1 -piperazinyl )sulfonyl]-3- pyridinyl}-3-phenyl-4(3H)- quinazolinone

5-(2-amino-4-oxo-3-phenyl-3,4- dihydro-6-quinazolinyl)-N-(2- hydroxyethyl)-2-(methyloxy)-3-

pyridinesulfonamide

I

o=s=o 2-amino-6-[6-(methyloxy)-5-(1- pyrrolidinylsulfonyl)-3-pyridinyl]-3- phenyl-4(3H)-quinazolinone

5-(2-amino-4-oxo-3-phenyl-3,4- dihydro-6-quinazolinyl)-N- (cyclopropylmethyl)-2-(methyloxy)- 3-pyridinesulfonamide

5-(2-amino-4-oxo-3-phenyl-3,4- dihydro-6-quinazolinyl)-N-(1 ,1 - dimethylethyl)-2-(methyloxy)-3- pyridinesulfonamide

o ^F N-[5-[2-amino-4-oxo-3- (phenylcarbonyl)-3,4-dihydro-6- quinazolinyl]-2-(methyloxy)-3-

197 H i ° ° pyridinyl]-2,4- difluorobenzenesulfonamide

5-(2-amino-3-(4- morpholinophenyl)-4-oxo-3,4-

198 dihydroquinazolin-6-yl)-2-methoxy-

N-methyl-N-phenylpyridine-3- sulfonamide

I 5-(2-amino-4-oxo-3-phenyl-3,4- dihydroquinazolin-6-yl)-N-(2-fluoro-

199

3-methylphenyl)-2- methoxypyridine-3-sulfonamide

5-(2-amino-3-(4- morpholinophenyl)-4-oxo-3,4-

200 dihydroquinazolin-6-yl)-N-(3- fluorophenyl)-2-methoxypyridine-3- sulfonamide

5-(2-amino-3-(4- morpholinophenyl)-4-oxo-3,4-

201 dihydroquinazolin-6-yl)-N-(2- fluorophenyl)-2-methoxypyridine-3- sulfonamide

5-(2-amino-3-(4- morpholinophenyl)-4-oxo-3,4-

202 dihydroquinazolin-6-yl)-N-(4- fluorophenyl)-2-methoxypyridine-3- sulfonamide 5-(2-amino-4-oxo-3-phenyl-3,4-

203 dihydroquinazolin-6-yl)-2-chloro-N- phenylpyridine-3-sulfonamide

5-(2-amino-4-oxo-3-(2- (trifluoromethyl)phenyl)-3,4-

204

dihydroquinazolin-6-yl)-2-chloro-N- phenylpyridine-3-sulfonamide

5-(2-amino-4-oxo-3-phenyl-3,4-

205 dihydroquinazolin-6-yl)-2-methyl-N- phenylpyridine-3-sulfonamide

1 5-(2-amino-4-oxo-3-phenyl-3,4- dihydroquinazolin-6-yl)-2-chloro-N-

206

(3-fluorophenyl)pyridine-3- sulfonamide

5-(2-amino-4-oxo-3-phenyl-3,4- dihydroquinazolin-6-yl)-2-chloro-N-

207

(2-f 1 uorobe nzy 1 ) pyrid i n e-3- sulfonamide

•4- U 5-(2-amino-4-oxo-3-phenyl-3,4- dihydroquinazolin-6-yl)-2-chloro-N-

208

(3-fluorobenzyl)pyridine-3- sulfonamide 5-(2-amino-4-oxo-3-(2-

(trifluoromethyl)phenyl)-3,4-

209 dihydroquinazolin-6-yl)-2-chloro-N-

(3-fluorobenzyl)pyridine-3- sulfonamide

5-(2-amino-4-oxo-3-(2-

(trifluoromethyl)phenyl)-3,4-

210 dihydroquinazolin-6-yl)-2-chloro-N-

(2-fluorobenzyl)pyridine-3-

sulfonamide

2- amino-6-(6-methyl-5-nitropyridin-

211

3- yl)-3-phenylquinazolin-4(3H)-one

5-(2-amino-4-oxo-3-(2-

(trifluoromethyl)phenyl)-3,4-

212 dihydroquinazolin-6-yl)-N-(4- fluorobenzyl)-2-methoxypyridine-3- sulfonamide

5-(2-amino-4-oxo-3-phenyl-3,4- dihydroquinazolin-6-yl)-N-(4-

213

fluorobenzyl)-2-methoxypyridine-3- sulfonamide

5-(2-amino-4-oxo-3-phenyl-3,4- dihydroquinazolin-6-yl)-N-(2,5-

214

difluorophenyl)-2-methoxypyridine- 3-sulfonamide 5-(2-amino-4-oxo-3-phenyl-3,4- dihydroquinazolin-6-yl)-N-(3,4-

215

difluorophenyl)-2-methoxypyridine- 3-sulfonamide

8 ^ 5-(2-amino-4-oxo-3-phenyl-3,4- dihydroquinazolin-6-yl)-N-(tert-

216

butyl )-2-ch loropyridi ne-3- sulfonamide

« JL ^v»»*# . 2-amino-6-(5-(benzylsulfinyl)-6-

217 I t i L 1 methoxy pyrid in-3-yl )-3- phenylquinazolin-4(3H)-one

2-amino-6-(6-methoxy-5-

218 ((phenylsulfonyl)methyl)pyridin-3- yl)-3-phenylquinazolin-4(3H)-one

2-amino-6-(5-(benzylsulfonyl)-6-

219 methoxypyridin-3-yl)-3- phenylquinazolin-4(3H)-one

5-(2-amino-4-oxo-3-phenyl-3,4-

I t 1 I dihydroquinazolin-6-yl)-2-methoxy-

220

N-(pyridin-3-yl)pyridine-3- sulfonamide

5-(2-amino-3-(3-fluorophenyl)-4- oxo-3,4-dihydroquinazolin-6-yl)-N-

233

(2,4-difluorophenyl)-2- methoxypyridine-3-sulfonamide

5-(2-amino-3-(4-fluoro-2- methylphenyl)-4-oxo-3,4-

234 dihydroquinazolin-6-yl)-N-(2,4- difluorophenyl)-2-methoxypyridine-

3-sulfonamide

5-(2-amino-3-(2,4-difluorophenyl)- 4 -oxo-3 ,4 -d i hyd roq u i nazo 1 i n-6-y 1 )-

235

N-(2,4-difluorophenyl)-2- methoxypyridine-3-sulfonamide

5-(2-amino-3-(2,6-difluorophenyl)- 4-oxo-3,4-dihydroquinazolin-6-yl)-

236

N-(2,4-difluorophenyl)-2- methoxypyridine-3-sulfonamide

5-(2-amino-3-(2,4-dimethylphenyl)- 4-0X0-3 ,4-d i hyd roq u i nazo 1 i n -6-y 1 )-

237

N-(2,4-difluorophenyl)-2- methoxypyridine-3-sulfonamide

5-(2-amino-3-(2-fluoro-4- methylphenyl)-4-oxo-3,4-

238 dihydroquinazolin-6-yl)-N-(2,4- difluorophenyl)-2-methoxypyridine-

3-sulfonamide 5-(2-amino-3-(3,5-difluorophenyl)- 4-0X0-3 ,4-d i hyd roq u i nazo I i n-6-y I )-

239

N-(2,4-difluorophenyl)-2- methoxypyridine-3-sulfonamide

5-(2-amino-3-(3-methoxyphenyl)-4- oxo-3,4-dihydroquinazolin-6-yl)-N-

240

(2,4-difluorophenyl)-2- methoxypyridine-3-sulfonamide

5-(2-amino-3-(2-chloro-6- methylphenyl)-4-oxo-3,4-

241 dihydroquinazolin-6-yl)-N-(2,4- difluorophenyl)-2-methoxypyridine-

3-sulfonamide

5-(2-amino-3-(3,5-dimethylphenyl)- 4-oxo-3,4-dihydroquinazolin-6-yl)-

242

N-(2,4-difluorophenyl)-2- methoxypyridine-3-sulfonamide

5-(2-amino-3-(2,6-dimethylphenyl)- 4-0X0-3 ,4-d i hyd roq u i nazo I i n -6-y I )-

243

N-(2,4-difluorophenyl)-2- methoxypyridine-3-sulfonamide

5-(2-amino-4-oxo-3-(2-

(trifluoromethyl)phenyl)-3,4-

244 dihydroquinazolin-6-yl)-N-(2- fluorophenyl)-2-methoxypyridine-3- sulfonamide 5-(2-amino-4-oxo-3-(2-

(trifluoromethyl)phenyl)-3,4-

245 dihydroquinazolin-6-yl)-N-(4- fluorophenyl)-2-met oxypyridine-3- sulfonamide

5-(2-amino-4-oxo-3-(2-

4. (trifluoromethyl)phenyl)-3,4-

246 dihydroquinazolin-6-yl)-N-(3- fluorophenyl)-2-methoxypyridine-3- sulfonamide

5-(2-amino-4-oxo-3-(2-

(trifluoromethyl)phenyl)-3,4-

247 dihydroquinazolin-6-yl)-N-(3- chlorophenyl)-2-methoxypyridine-3- sulfonamide

5-(2-amino-4-oxo-3-(2-

(trifluoromethyl)phenyl)-3,4-

248 dihydroquinazolin-6-yl)-N-(2- chlorophenyl)-2-methoxypyridine-3- sulfonamide

5-(2-amino-4-oxo-3-(2-

(trifluoromethyl)phenyl)-3,4-

249 dihydroquinazolin-6-yl)-N-(4- chlorophenyl)-2-methoxypyridine-3-

sulfonamide

5-(2-amino-4-oxo-3-(2-

(trifluoromethyl)phenyl)-3,4-

250 dihydroquinazolin-6-yl)-N-(2,6- difluorophenyl)-2-methoxypyridine-

3-sulfonamide

(aS)-5-(2-amino-4-oxo-3-(2-

(trifluoromethyl)phenyl)-3,4-

257 dihydroquinazolin-6-yl)-N-(2,4- difluorophenyl)-2-methoxypyridine-

3-sulfonamide

(aR)-5-(2-amino-4-oxo-3-(2-

(trifluoromethyl)phenyl)-3,4-

258 dihydroquinazolin-6-yl)-N-(2,4- difluorophenyl)-2-methoxypyridine-

3-sulfonamide

5-(2-amino-4-oxo-3-(2- (trifluoromethyl)phenyl)-3,4-

259

dihydroquinazolin-6-yl)-2- methoxypyridine-3-sulfonamide

5-(2-amino-4-oxo-3-(pyridin-3-yl)-

260 3 ,4-d ihyd roqu inazol i n-6-yl )-2- methoxypyridine-3-sulfonamide

5-(2-am ino-4-oxo-3-( pyrid in-4-y 1 )- 3 ,4-d ihyd roqu inazol i n-6-yl )-N-(2 ,4-

261

difluorophenyl)-2-methoxypyridine- 3-sulfonamide

5-(2-amino-4-oxo-3-(2-

(trifluoromethyl)phenyl)-3,4-

262 dihydroquinazolin-6-yl)-2-methoxy-

N,N-dimethylpyridine-3-

sulfonamide 5-(2-amino-4-oxo-3-(2- (trifluoromethyl)phenyl)-3,4-

263

dihydroquinazolin-6-yl)-2-methoxy- N-methylpyridine-3-sulfonamide

5-(2-amino-4-oxo-3-(pyridin-3-yl)- 3 ,4-dihyd roqu inazol i n-6-yl )-N-(2 , 6-

264

difluorophenyl)-2-methoxypyridine- 3-sulfonamide

(S)-N-(5-(2-amino-4-oxo-3-(1- phenylethyl)-3,4-dihydroquinazolin-

265

6-yl)-2-methoxypyridin-3-yl)-2,4- difluorobenzenesulfonamide

(S)-5-(2-amino-4-oxo-3-(1- phenylethyl)-3,4-dihydroquinazolin-

266

6-yl)-N-(2,4-difluorophenyl)-2- methoxypyridine-3-sulfonamide

5-(2-amino-3-(naphthalen-1-yl)-4- oxo-3, 4-dihydroquinazolin-6-yl)-N-

267

(2,4-difluorophenyl)-2- methoxypyridine-3-sulfonamide

N-(5-(2-amino-3-(naphthalen-1-yl)- 4-0X0-3 ,4-d i hyd roq ui nazol in-6-yl )-

268

2-methoxypyridin-3-yl)-2,4- difluorobenzenesulfonamide

N-((5-(2-amino-4-oxo-3-phenyl-3,4- dihydroquinazolin-6-yl)-2-

275

methoxypyridin-3- yl)methyl)methanesulfonamide

2-amino-6-(5-(hydroxymethyl)-6-

276 methoxypyridin-3-yl)-3- phenylquinazolin-4(3H)-one

S-S 5-(2-amino-4-oxo-3-phenyl-3,4- dihydroquinazolin-6-yl)-N-(2,6-

277

difluorophenyl)-2-methoxypyridine- 3-sulfonamide

5-(2-amino-4-oxo-3-phenyl-3,4- dihydroquinazolin-6-yl)-N-(2,3-

278

difluorophenyl)-2-methoxypyridine- 3-sulfonamide

2-amino-6-(6-morpholinopyridin-3-

279

yl)-3-phenylquinazolin-4(3H)-one

2-amino-6-(5-(benzyloxy)-6-

280 methoxy pyrid in-3-yl )-3- phenylquinazolin-4(3H)-one )-

XX 5-(2-amino-3-((4-

(dimethylamino)tetrahydro-2H- pyran-4-yl)methyl)-4-oxo-3,4-

287

dihydroquinazolin-6-yl)-N-(2,4- difluorophenyl)-2-methoxypyridine-

3-sulfonamide

5-(2-amino-3-(2-(dimethylamino)-2- phenylethyl )-4-oxo-3 ,4-

288 dihydroquinazolin-6-yl)-N-(2,4- difluorophenyl)-2-methoxypyridine-

3-sulfonamide

methyl 5-(2-amino-4-oxo-3-phenyl-

289 3 ,4-d ihyd roqu inazol i n-6- yl)nicotinate

N-(6-(2-amino-4-oxo-3-phenyl-3,4-

290 dihydroquinazolin-6-yl)-1 H-indazol- 4-yl)benzenesulfonamide

2-amino-6-[2-(methyloxy)-5-

291 pyrimidinyl]-3-phenyl-4(3H)- quinazolinone

2-amino-6-[2-(dimethylamino)-5-

292 pyrimidinyl]-3-phenyl-4(3H)-

quinazolinone [5-(2-amino-4-oxo-3-phenyl-3,4-

293 dihydro-6-quinazolinyl)-3- pyridinyl]boronic acid

2-amino-3-phenyl-6-[6-(1 H-pyrazol-

294 4-yl)-3-pyridinyl]-4(3H)- quinazolinone

N-(6-(2-amino-4-oxo-3-phenyl-3,4- dihydroquinazolin-6-yl)-1 H-

295

benzo[d]imidazol-4-yl)-2,4- difluorobenzenesulfonamide

2-amino-6-(6-methoxy-5-(2-methyl-

296 2 H-tetrazol-5-yl )py rid i n-3-yl )-3- phenylquinazolin-4(3H)-one

2-amino-6-(6-methoxy-5-(1 -methyl-

297 1 H-tetrazol-5-yl)pyridin-3-yl)-3- phenylquinazolin-4(3H)-one

2-amino-6-(6-methoxy-5-(1 ,2,4- oxadiazol-3-yl)pyridin-3-yl)-3-

298

phenylquinazolin-4(3H)-one, Formic acid salt 2-amino-6-(6-methoxy-5-(1 H- tetrazol -5-yl )pyrid i n-3-y l)-3-

299

phenylquinazolin-4(3H)-one, 2 Hydrochloride

3-(5-(2-amino-4-oxo-3-phenyl-3,4- dihydroquinazolin-6-yl)-2-

300

methoxypyridin-3-yl)-1 ,2,4- oxadiazol-5(4H)-one

6-(5-(1 H-tetrazol-5-yl)pyridin-3-yl)-

301 2-amino-3-phenylquinazolin-4(3H)- one

6-(5-(1 ,2,4-oxadiazol-3-yl)pyridin-3-

302 yl)-2-amino-3-phenylquinazolin-

4{3H)-one

2-amino-3-phenyl-6-(5-(5-thioxo-

303 4,5-dihydro-1 ,2,4-oxadiazol-3- yl)pyridin-3-yl)quinazolin-4(3H)-one

N-(5-(2-amino-4-oxo-3-phenyl-3,4- dihydroquinazolin-6-yl)-2-

304

methoxypyridin-3-yl)-2,4-difluoro-N- methylbenzenesulfonamide

2-amino-6-[6-(methylsulfonyl)-3-

317 pyridinyl]-3-phenyl-4(3H)- quinazolinone

Sw ss* 5-(2-amino-4-oxo-3-phenyl-3,4- dihydroquinazolin-6-yl)-N-

318

cyclohexyl-2-methoxypyridine-3- sulfonamide

5-(2-amino-4-oxo-3-phenyl-3,4- dihydroquinazolin-6-yl)-N-(tert-

319

butyl)-2-methoxy-N-methylpyridine- 3-sulfonamide

5-(2-amino-4-oxo-3-phenyl-3,4-

320 dihydroquinazolin-6-yl)-N-benzyl-2- methoxypyridine-3-sulfonamide

0 5-(2-amino-4-oxo-3-phenyl-3,4- dihydroquinazolin-6-yl)-N-benzyl-2-

321

methoxy-N-methylpyridine-3- sulfonamide

5-(2-amino-4-oxo-3-phenyl-3,4-

322 dihydroquinazolin-6-yl)-2-methoxy-

N-neopentylpyridine-3-sulfonamide

5-(2-amino-4-oxo-3-phenyl-3,4- dihydroquinazolin-6-yl)-N-

329

cyclobutyl-2-methoxypyridine-3- sulfonamide

2-amino-6-(6-amino-5-

330 (trifluoromethyl)pyridin-3-yl)-3- phenylquinazolin-4(3H)-one

1-(5-(2-amino-4-oxo-3-phenyl-3,4-

331 dihydroquinazolin-6-yl)-2- methoxypyridin-3-yl)urea

1-(5-(2-amino-4-oxo-3-phenyl-3,4-

332 dihydroquinazolin-6-yl)pyridin-2-yl)-

3-(pyridin-3-yl)urea

5-(2-amino-4-oxo-3-phenyl-3,4- dihydroquinazolin-6-yl)-N-(3,5-

333

difluorophenyl)-2-methoxypyridine- 3-sulfonamide

1-(5-(2-amino-4-oxo-3-phenyl-3,4-

334 dihydroquinazolin-6-yl)pyridin-2-yl)-

3-phenylurea

assises* l 5-(2-amino-4-oxo-3-phenyl-3,4- dihydroquinazolin-6-yl)-N-(furan-2-

341

ylmethyl)-2-methoxypyridine-3- sulfonamide

5-(2-amino-4-oxo-3-phenyl-3,4- dihydroquinazolin-6-yl)-N-(2,3-

342

dihydro-1 H-inden-2-yl)-2- methoxypyridine-3-sulfonamide

5-(2-amino-4-oxo-3-phenyl-3,4- dihydroquinazolin-6-yl)-N-(2,3-

343

dihydro-1 H-inden-1-yl)-2- methoxypyridine-3-sulfonamide

344 A i fl 3-(5-(2-amino-4-oxo-3-phenyl-3,4- dihydroquinazolin-6-yl)pyridin-3- yl)oxazolidin-2-one

2-amino-6-(5-(indolin-1-ylsulfonyl)-

345 6-methoxy pyridi n-3-yl )-3- phenylquinazolin-4(3H)-one

sss sss 2- amino-6-(5-(isoindolin-2-

346 ylsulfonyl )-6-methoxypyridi n-3-yl)-

3- phenylquinazolin-4(3H)-one

5-(2-amino-4-oxo-3-phenyl-3,4- dihydroquinazolin-6-yl)-N-(3-(3-

353 aminopropoxy)phenyl)-2- methoxypyridine-3-sulfonamide, 0.47 Formic acid salt

tert-butyl (3-(3-(5-(2-amino-4-oxo-

3-phenyl-3,4-dihydroquinazolin-6-

354 yl)-2-methoxypyridine-3- sulfonamido)phenoxy)propyl)carba mate

N-(6-(2-amino-4-oxo-3-phenyl-3,4- dihydroquinazolin-6-

355

yl)benzo[d]oxazol-4-yl)-2,4- difluorobenzenesulfonamide

N-(6-(2-amino-4-oxo-3-phenyl-3,4- dihydroquinazolin-6-yl)-2-oxo-2,3-

356

dihydrobenzo[d]oxazol-4-yl)-2,4- difluorobenzenesulfonamide

2-amino-6-(2- aminobenzo[d]oxazol-5-yl)-3-

357

phenylquinazolin-4(3H)-one, Formic acid salt

N-(5-(2-amino-4-oxo-3-phenyl-3,4- dihydroquinazolin-6-yl)-2-

358

methoxypyridin-3-yl)-2- methoxybenzenesulfonamide 5- (2 -a m i no-4-oxo-3- (tetra hyd ro-2 H- pyran-4-yl)-3,4-dihydroquinazolin-

359

6- yl)-2-methoxy-N-phenylpyridine- 3-sulfonamide

5-(2-amino-3-cyclopropyl-4-oxo- 3,4-dihydroquinazolin-6-yl)-2-

360

methoxy-N-phenylpyridine-3- sulfonamide

5-(2-amino-4-oxo-3-((tetrahydro- 2 H-pyran-4-yl )methyl )-3 ,4-

361

ri ihydroq ui nazol in-6-y 1 )-2-methoxy- a N-phenylpyridine-3-sulfonamide

5-(2-amino-3-cyclobutyl-4-oxo-3,4-

362 d ihydroq ui nazol in-6-yl )-2-methoxy- N-phenylpyridine-3-sulfonamide

5- (3-(1-acetylpiperidin-4-yl)-2- amino-4-oxo-3,4-dihydroquinazolin-

363

6- yl)-2-methoxy-N-phenylpyridine-

1 3-sulfonamide

5- (2-amino-4-oxo-3-(tetrahydro-2H- pyran-4-yl)-3,4-dihydroquinazolin-

364

6- yl)-2-methoxy-N-(o-tolyl)pyridine-

3-sulfonamide

5- (2 -a m i no-4-oxo-3- (tetra hyd ro-2 H- pyran-4-yl)-3,4-dihydroquinazolin-

377

6- yl)-N-(2-fluorophenyl)-2- methoxypyridine-3-sulfonamide

N-(5-(2-amino-4-oxo-3-phenyl-3,4- dihydroquinazolin-6-yl)-2-

378 methoxypyridin-3-yl)-3-

(trifluoromethyl)benzenesulfonamid e

N-(5-(2-amino-4-oxo-3-phenyl-3,4- dihydroquinazolin-6-yl)-2-

379 methoxypyridin-3-yl)-3-(5-methyl- n 1 ,3,4-oxadiazol-2- yl)benzenesulfonamide

N-(5-(2-amino-4-oxo-3-phenyl-3,4- dihydroquinazolin-6-yl)-2-

380 methoxypyridin-3-yl)-3-(1-methyl- 1 H-pyrazol-5- yl)benzenesulfonamide

N-(5-(2-amino-4-oxo-3-phenyl-3,4- dihydroquinazolin-6-yl)-2-

381 t methoxypyridin-3-yl)-3-(2- methylthiazol-4- yl)benzenesulfonamide

N-(5-(2-amino-4-oxo-3-phenyl-3,4- dihydroquinazolin-6-yl)-2-

382 methoxypyridin-3-yl)-3-(5-methyl-

1 ,2,4-oxadiazol-3-

yl)benzenesulfonamide N-(5-(2-amino-4-oxo-3-phenyl-3,4- r dihydroquinazolin-6-yl)-2-

383

A methoxypyridin-3-yl)-4-(2- cyanoethoxy)benzenesulfonamide

N-(5-(2-amino-4-oxo-3-phenyl-3,4- dihydroquinazolin-6-yl)-2-

V methoxypyridin-3-yl)-1 ,3-dimethyl-

384

2,4-dioxo-1 ,2,3,4- tetrahydroquinazoline-6- sulfonamide

N-(5-(N-(5-(2-amino-4-oxo-3- ϊ phenyl-3,4-dihydroquinazolin-6-yl)-

385

2-methoxypyridin-3-yl)sulfamoyl)-2- ethoxyphenyl)acetamide

5-(2-amino-4-oxo-3-phenyl-3,4- dihydroquinazolin-6-yl)-N-(3-

386

V chlorophenyl)-2-methoxypyridine-3- sulfonamide

5-(2-amino-4-oxo-3-phenyl-3,4-

387 dihydroquinazolin-6-yl)-2-ethyl-N-

Ο^' phenylpyridine-3-sulfonamide

5-(2-amino-4-oxo-3-phenyl-3,4- dihydroquinazolin-6-yl)-N-(2,4-

388

difluorophenyl)-2-ethylpyridine-3- sulfonamide

5-(2-amino-4-oxo-3-phenyl-3,4-

413 A t Π dihydroquinazolin-6-yl)-N-

(methylsulfonyl)nicotinamide

5-(2-amino-4-oxo-3-phenyl-3,4-

414 dihydroquinazolin-6-yl)-N-

(cyclopropylsulfonyl)nicotinamide

2-amino-6-(3-methyl-1 , 1 -dioxido-

415 4 H-pyrido [2 , 3-e] [ 1 , 2 ,4]th iad i azi n-7- yl)-3-phenylquinazolin-4(3H)-one

2- amino-6-(1 , 1 -dioxido-4H-

416 py rido[2, 3-e] [ 1 ,2,4]th iad iazi n-7-yl )-

3- phenylquinazolin-4(3H)-one

[00112] The compounds of Table 1 can be synthesized according to the Synthetic Methods, General Schemes, and the Examples described below.

[00 13] In certain embodiments, the compound(s) of the present invention, or a pharmaceutically acceptable salt thereof, is chosen from the compounds set forth in Table 1.

Synthetic Methods

[00114] The methods of synthesis for the provided chemical entities employ readily available starting materials using the following general methods and procedures. It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given; other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures.

[00115] Additionally, the methods of this invention may employ protecting groups which prevent certain functional groups from undergoing undesired reactions. Suitable protecting groups for various functional groups as well as suitable conditions for protecting and

deprotecting particular functional groups are well known in the art. For example, numerous protecting groups are described in T. W. Greene and G. M. Wuts, Protecting Groups in Organic Synthesis, Third Edition, Wiley, New York, 1999, and references cited therein.

[00116] Furthermore, the provided chemical entities may contain one or more chiral centers and such compounds can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or diastereomers, or as stereoisomer-enriched mixtures. All such stereoisomers (and enriched mixtures) are included within the scope of this specification, unless otherwise indicated. Pure stereoisomers (or enriched mixtures) may be prepared using, for example, optically active starting materials or stereoselective reagents well-known in the art. Alternatively, racemic mixtures of such compounds can be separated using, for example, chiral column chromatography, chiral resolving agents and the like.

[00117] The starting materials for the following reactions are generally known compounds or can be prepared by known procedures or obvious modifications thereof. For example, many of the starting materials are available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA), Bachem (Torrance, California, USA), Ernka-Chemce or Sigma (St. Louis, Missouri, USA). Others may be prepared by procedures, or obvious modifications thereof, described in standard reference texts such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1 -15 (John Wiley and Sons, 1991 ), Rodd's Chemistry of Carbon

Compounds, Volumes 1-5 and Supplemental (Elsevier Science Publishers, 1989), Organic Reactions, Volumes 1 -40 (John Wiley and Sons, 1991 ), March's Advanced Organic Chemistry, (John Wiley and Sons, 4th Edition), and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989).

[00118] Unless specified to the contrary, the reactions described herein take place at atmospheric pressure, generally within a temperature range from -78 °C to 200 °C. Further, except as employed in the Examples or as otherwise specified, reaction times and conditions are intended to be approximate, e.g., taking place at about atmospheric pressure within a temperature range of about -78 °C to about 1 10 °C over a period of about 1 to about 24 hours; reactions left to run overnight average a period of about 16 hours. [00119] The terms "solvent," "organic solvent," and "inert solvent" each mean a solvent inert under the conditions of the reaction being described in conjunction therewith, including, for example, benzene, toluene, acetonitrile, tetrahydrofuranyl ("THF"), dimethylformamide ("DMF"), chloroform, methylene chloride (or dichloromethane), diethyl ether, methanol, N- methylpyrrolidone ("NMP"), pyridine and the like.

[00120] Isolation and purification of the chemical entities and intermediates described herein can be effected, if desired, by any suitable separation or purification procedure such as, for example, filtration, extraction, crystallization, column chromatography, thin-layer

chromatography or thick-layer chromatography, or a combination of these procedures. Specific illustrations of suitable separation and isolation procedures can be had by reference to the examples herein below. However, other equivalent separation or isolation procedures can also be used.

[00121] When desired, the (R)- and (S)-isomers may be resolved by methods known to those skilled in the art, for example by formation of diastereoisomeric salts or complexes which may be separated, for example, by crystallization; via formation of diastereoisomeric derivatives which may be separated, for example, by crystallization, gas-liquid or liquid chromatography; selective reaction of one enantiomer with an enantiomer-specific reagent, for example enzymatic oxidation or reduction, followed by separation of the modified and unmodified enantiomers; or gas-liquid or liquid chromatography in a chiral environment, for example on a chiral support, such as silica with a bound chiral ligand or in the presence of a chiral solvent. Alternatively, a specific enantiomer may be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer to the other by asymmetric transformation.

EXAMPLES

[00122] The following examples serve to more fully describe the manner of making and using the above-described invention. It is understood that these examples in no way serve to limit the true scope of the invention, but rather are presented for illustrative purposes. In the examples below and the synthetic schemes above, the following abbreviations have the following meanings. If an abbreviation is not defined, it has its generally accepted meaning. aq. = aqueous

ML = microliters

μΜ = micromolar nuclear magnetic resonance

tert-butoxycarbonyl

broad

benzyloxycarbonyl

doublet

chemical shift

degrees celcius

dichloromethane

doublet of doublets

Dulbeco's Modified Eagle's Medium

N,N-dimethylformamide

dimethylsulfoxide

ethyl acetate

gram

hours

hepatitus C virus

high performance liquid chromatography hertz

International Units

inhibitory concentration at 50% inhibition coupling constant (given in Hz unless otherwise indicated)

multiplet

molar

parent mass spectrum peak plus H⁺ milligram

milliliter

millimolar

millimole

mass spectrum

nanomolar

parts per million

sufficient amount

singlet saturated

triplet

trifluoroacetic acid

EXAMPLES

General Scheme 1

PdCI₂(dppf)-DCM

R = Me or CN or Ph

General Scheme 3

Example 1

N-(5-{3-benzyl-2-[(2-methanesulfonylethyl)amino]-4-oxo-3,4-dihydro methoxypyridin-3-yl)-2,4-difluorobenzene-1-sulfonamide

Step A

6-bromo-2,4( 1 H, 3H)-quinazolinedione

[00123] A mixture of methyl 2-amino-5-bromobenzoate (50 g, 217 mmol) and urea (65.3 g, 1087 mmol) were ground together and heated to 200 °C for 2 hours with stirring and while under nitrogen. The mixture went fully into solution after 10 minutes, and then solidified after 40 minutes. The reaction was cooled and the resulting solid was washed with water (1 L). The solid was then filtered and the remaining solids rinsed with more water and broken up into fine particles. The residue was triturated with EtOAc (ca 300 mL) and dried to yield 6-bromo- 2,4(1 H,3H)-quinazolinedione (42g, 80%). ES-LCMS: 241.0, 243.1 (M+1 ).

Step B

6-bromo-2,4-dichloroquinazoline

[00124] A mixture of 6-bromo-2,4(1 H,3H)-quinazolinedione (42.5 g, 176 mmol) and phosphorus oxychloride (164 mL, 1763 mmol) was treated with DIEA (46.2 mL, 264 mmol) and the mixture refluxed for 6 hours, then poured onto ice. This was then filtered, dissolved in DCM (500 mL) and washed with water and then brine, dried over Na₂S0₄, and concentrated to give a residue containing with partially hydrolyzed intermediate. The residue was resubjected to POCI₃ and worked up slower and with more ice to give 6-bromo-2,4-dichloroquinazoline (23 g, 43%). ES-LCMS: 278.9, 281.0 (M+1).

Step C

6-bromo-2-chloro-4(1H)-quinazolinone

[00125] A solution of 6-bromo-2,4-dichloroquinazoline (2.0 g, 7.20 mmol) in THF (17.99 mL) was treated with 1N NaOH (17.99 mL, 17.99 mmol) and stirred at room temperature for 2.5 hours. The solution was cooled to 0 °C and the pH was adjusted to 5 with AcOH. The resulting light yellow solid was filtered and rinsed with water. The solid was concentrated from toluene (3x) to remove any residual water, which yielded 6-bromo-2-chloro-4(1H)-quinazolinone (1.625 g, 87%). ES-LCMS: 259.0, 261.0 (M+1). Step D

6-bromo-2-chloro- -(phenylmethyl)-4(3H)-quinazolinone

[00126] A suspension of 6-bromo-2-chloro-4(1 H)-quinazolinone (0.420 g, 1.619 mmol) in DME (4.15 mL) and DMF (1.037 mL) at 0 °C was treated by addition of 60% NaH (0.071 g, 1.780 mmol). After stirring for 10 minutes, lithium bromide (0.281 g, 3.24 mmol) was added and the reaction was stirred at room temperature for 5 minutes. To the resulting suspension was added (bromomethyl)benzene (0.212 mL, 1.780 mmol), and the mixture was heated to 65 °C overnight. After cooling to room temperature, water (10 mL) was added. The mixture was then extracted with EtOAc. The combined organics were washed with 5% LiCI (3x), brine, dried over Na₂S0₄, filtered, and concentrated. The yellow solid was taken up in DCM and purified by silica gel chromatography (0-10% EtOAc/hexanes) to give 6-bromo-2-chloro-3-(phenylmethyl)-4(3H)- quinazolinone (0.410 g, 73%) as a white solid. ES-LCMS: 349.1 , 351.1 (M+1 ).

Step E

6-bromo-2-{[2-(methyls thyl)-4(3H)-qu^

[00127] A sealed tube containing 6-bromo-2-chloro-3-(phenylmethyl)-4(3H)- quinazolinone (0.110 g, 0.315 mmol), DIEA (0.082 mL, 0.472 mmol), and [2- (methylsulfonyl)ethyl]amine (0.058 g, 0.472 mmol) in NMP (1 .491 mL), under nitrogen was heated to 130 °C overnight. The reaction was cooled to room temperature and then diluted with water and EtOAc. The combined organics were washed with brine, dried over Na₂S0₄, filtered, and concentrated. The crude yellow oil was purified by silica gel chromatography (0-1 % MeOH/DCM) to give 6-bromo-2-{[2-(methylsulfonyl)ethyl]amino}-3-(phenylmethyl)-4(3H)- quinazolinone {0.096 g, 70%) as a white solid. ES-LCMS: 436.2, 438.2 (M+1 ).

Step F

2,4-difluoro-N-{2-(methyloxy)-5-[2-{[2-(methylsulfonyl)ethyl]amino

dihydro-6-quinazolinyl]-3-pyridinyl}benzenesutfonamide

[00128] A mixture of 6-bromo-2-{[2-(methylsulfonyl)ethyl]amino}-3-(phenylmethyl)-4(3H)- quinazolinone (0.084 g, 0.193 mmol), 2,4-difluoro-N-[2-(methyloxy)-5-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)-3-pyridinyl]benzenesulfonamide (0.090 g, 0.212 mmol), PdCI₂(dppf)-CH₂CI₂ adduct (0.016 g, 0.019 mmol), K₂C0₃ (0.080 g, 0.578 mmol) in 1 ,4-dioxane (4.01 mL) and water (4.01 mL), was heated to 80 °C overnight. After cooling to room temperature, the reaction was diluted with EtOAc and water. The combined organics were washed with brine, dried over Na₂S0₄, filtered, and concentrated. The crude residue was purified by reverse phase chromatography (10-90% ACN/ H₂0 + formic acid). Isolation and lyophilization of the fractions gave 2,4-difluoro-N-{2-(methyloxy)-5-[2-{[2-(methylsulfonyl)ethyl]amino}-4-oxo-3-(phenylmethyl)- 3,4-dihydro-6-quinazolinyl]-3-pyridinyl}benzenesulfonamide as a white solid (0.41 g, 32.5%). ¹H NMR (400 MHz, DMSO-af₆) δ ppm 10.30 (br. s., 1 H), 8.34 (br. s., 1 H), 8.08 - 8.11 (m, 1 H), 7.89 - 7.94 (m, 1 H), 7.85 - 7.89 (m, 1 H), 7.71 - 7.80 (m, 1 H), 7.52 - 7.61 (m, 1 H), 7.41 - 7.47 (m, 2 H), 7.29 - 7.36 (m, 2 H), 7.16 - 7.29 (m, 4 H), 5.31 (br. s., 2 H), 3.75 - 3.82 (m, 2 H), 3.65 (s, 3 H), 3.40 - 3.47 (m, 2 H), 2.89 (s, 3 H); ES-LCMS: 656.2 (M+1 ).

Example 2

2,4-difluoro-N-(5-{2-[(2-methanesulfonylethyl)amino]-4-oxo-3-phenyl-3,4- dihydroquinazolin-6-yl}-2-methoxypyridin-3-yl)benzene-1-sulfonamide

Step A

6-bromo-3-phenyi- -thioxo-2, 3-dihydro-4(1 H)-quinazolinone

[00129] A solution of 2-amino-5-bromobenzoic acid (10 g, 46.3 mmol) and

isothiocyanatobenzene (5.53 ml_, 46.3 mmol) were refluxed in EtOH (226 mL) overnight. The reaction was treated by additional isothiocyanatobenzene (2.5 mL) and continued to heat to reflux overnight. The reaction was then treated by additional isothiocyanatobenzene (3.0 mL) and heated to reflux overnight. After cooling to room temperature, the solid was filtered, rinsing with cold EtOH to give 6-bromo-3-phenyl-2-thioxo-2,3-dihydro-4(1H)-quinazolinone as a white solid (8.23 g, 53.4%). ES-LCMS: 333.2, 335.1 (M+1 ).

Step B

6-bromo-2- uinazolinone

[00130] A solution of 6-bromo-3-phenyl-2-thioxo-2,3-dihydro-4(1 H)-quinazolinone (1.5 g, 4.50 mmol) in POCI₃ (10.07 mL, 108 mmol) was treated with PCI₅ (1.556 g, 7.47 mmol). The mixture was heated to reflux for 3 hours. The solvents were removed under reduced pressure. The residue was taken up in EtOAc and washed with water, brine, dried over Na₂S0₄, filtered, and concentrated to give 6-bromo-2-chloro-3-phenyl-4(3H)-quinazolinone as a white solid (1.43 g, 95%). ES-LCMS: 335.1 , 337.0 (M+1 ).

Step C

6-jbromo-2-//^'2-^mei/7y/su/fony/ effty/7am noj-3-p/7eny/-4('3H -qu/^'nazo/ none

[00131] A sealed tube containing 6-bromo-2-chloro-3-phenyl-4(3H)-quinazolinone (0.100 g, 0.298 mmol), [2-(methylsulfonyl)ethyl]amine (0.055 g, 0.447 mmol), DIEA (0.078 ml_, 0.447 mmol), and NMP (1.412 ml_) was heated to 130 °C overnight. After cooling to room

temperature the reaction was diluted with EtOAc and water. The combined organics were washed with water (3x) and then brine. The washed organics were then dried over MgS0₄, filtered, and concentrated to give 6-bromo-2-{[2-(methylsulfonyl)ethyl]amino}-3-phenyl-4(3H)- quinazolinone (0.131 g, 100%). ES-LCMS: 422.1 , 424.1 (M+1 ).

Step D

2,4-difluoro-N-[2-(methyloxy)-5-(2-{[2-(methylsulfonyl)ethyl]am

6-q ide

[00132] A mixture of 6-bromo-2-{[2-(methylsulfonyl)ethyl]amino}-3-phenyl-4(3H)- quinazolinone (0.065 g, 0.154 mmol), 2,4-difluoro-N-[2-(methyloxy)-5-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)-3-pyridinyl]benzenesulfonamide (0.072 g, 0.169 mmol), PdCI₂(dppf)-CH₂CI₂ adduct (0.013 g, 0.015 mmol), K₂C0₃ (0.064 g, 0.462 mmol) in 1 ,4-dioxane (3.21 mL) and water (3.21 mL) was heated to 80 °C overnight. After cooling to room temperature, the reaction was diluted with EtOAc and water. The combined organics were washed with saturated NaHC0₃ followed by a wash with brine. The washed organics were then dried over Na₂S0₄, filtered, and concentrated. Nexxt, the residue was purified by reverse phase chromatography (10-90% ACN/ H₂0 + formic acid). Isolation and lyophilization of the resulting fractions gave 2,4-difluoro-N-[2- (methyloxy)-5-(2-{[2-(methylsulfonyl)ethyl]amino}-4-oxo-3-phenyl-3,4-dihydro-6-quinazolinyl)-3- pyridinyl]benzenesulfonamide as a white solid (0.076 g, 77%). H NMR (400 MHz, DMSO-d₆) δ ppm 10.32 (br. s., 1 H), 8.30 (br. s., 1 H), 8.03 - 8.06 (m, 1 H), 7.90 - 7.95 (m, 1 H), 7.82 - 7.86 (m, 1 H), 7.72 - 7.80 (m, 1 H), 7.51 - 7.64 (m, 4 H), 7.43 - 7.48 (m, 1 H), 7.38 (d, J=6.83 Hz, 2 H), 7.16 - 7.23 (m, 1 H), 6.10 - 6.15 (m, 1 H), 3.70 - 3.78 (m, 2 H), 3.66 (s, 3 H), 3.37 - 3.44 (m, 2 H), 3.00 (s, 3 H); ES-LCMS: 642.2 (M+1 ).

Example 3

N-[5-(2-amino-3-benzyl-4-oxo-3,4-dihydroquinazolin-6-yl)-2-metho

difluorobenzene- 1 -sulfonamide

Step A

2-({[3,4-bis(methyloxy)phenyi]methyl}amino)-6-bromo-3-(phenylmethyI)-4(3H)-qum^

[00133] A sealed tube containing 6-bromo-2-chloro-3-(phenylmethyl)-4(3H)- quinazolinone (0.150 g, 0.429 mmol), DIEA (0.097 mL, 0.558 mmol), and 1-[3,4- bis(methyloxy)phenyl]methanamine (0.083 mL, 0.558 mmol) in NMP (1.965 mL), under nitrogen was heated to 130 °C overnight. The reaction was complete by LCMS and cooled to room temperature. The reaction was diluted with water and EtOAc. The combined organics were washed with brine, dried over Na₂S0₄, filtered, and concentrated. The crude yellow oil was purified by silica gel chromatography (0-30% EtOAc/hexanes) to give 2-({[3,4- bis(methyloxy)phenyl]methyl}amino)-6-bromo-3-(phenylmethyl)-4(3H)-quinazolinone as a yellow solid (0.195 g, 95%). ES-LCMS: 480.2, 482.2 (M+1 ).

Step B

N-[5-[2-({[3 -bis(methyloxy)phenyl]methyl}amino)-4-oxo-3-(phen

quinazolinyl]-2-(methyloxy)-3 y dinyl]-2,4-difluorobenzenesulfonamide

[00134] A mixture of 2-({[3,4-bis(methyloxy)phenyl]methyl}amino)-6-bromo-3- (phenylmethyl)-4(3H)-quinazolinone (0.072 g, 0.150 mmol), 2,4-difluoro-N-[2-(methyloxy)-5- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-3-pyridinyl]benzenesulfonamide (0.077 g, 0.180 mmol), PdCI₂(dppf)-CH₂CI₂ adduct (0.012 g, 0.015 mmol), K₂C0₃ (0.062 g, 0.450 mmol) in 1 ,4- dioxane (3.12 mL) and water (3.12 mL) was heated to 80 °C overnight. After cooling to room temperature, the reaction was diluted with EtOAc and water. The combined organics were washed with saturated NaHC0₃ followed by a wash with brine. The washed organics were then dried over Na₂S0₄, filtered, and concentrated. The residue was purified by silica gel chromatography (0-4% MeOH/DCM) to give N-[5-[2-({[3,4-bis(methyloxy)phenyl]methyl}amino)- 4-oxo-3-(phenylmethyl)-3,4-dihydro-6-quinazolinyl]-2-(methyloxy)-3-pyridin

difluorobenzenesulfonamide as a pale yellow solid (0.102 g, 97%). ES-LCMS: 700.3 (M+1).

Step C

N-[5-(2-amino-3-benzyl-4-oxo-3,4-dihydroquinazolin-6-yl)-2-me

difluorobenzene- 1 -sulfonamide

[00135] A solution of N-[5-[2-({[3,4-bis(methyloxy)phenyl]methyl}amino)-4-oxo-3- (phenylmethyl)-3,4-dihydro-6-quinazolinyl]-2-(methyloxy)-3-pyridinyl]-2,4- difluorobenzenesulfonamide (0.096 g, 0.137 mmol) in DCM (0.686 mL) was treated by the addition of DDQ (0.034 g, 0.151 mmol) and the reaction was stirred at room temperature overnight. The solvents were removed under reduced pressure and the residue was purified by reverse phase chromatography (10-90% ACN/ H₂0 + formic acid). Isolation and lyophilization gave N-[5-(2-amino-3-benzyl-4-oxo-3,4-dihydroquinazolin-6-yl)-2-methoxypyridin-3-yl]-2,4- difluorobenzene-1-sulfonamideas a light yellow solid (0.031 g, 41 %). H NMR (400 MHz, DMSO-af₆) δ ppm 10.34 (br. s., 1 H), 8.32 (s, 1 H), 8.06 (d, J=1.76 Hz, 1 H), 7.81 - 7.89 (m, 2 H), 7.70 - 7.81 (m, 1 H), 7.52 - 7.63 (m, 1 H), 7.15 - 7.37 (m, 7 H), 7.1 1 (br. s., 2 H), 5.31 (s, 2 H), 3.65 (s, 3 H); ES-LCMS: 550.1 (M+1 ).

Example 4

N-[5-(2-amino-4-oxo-3-phenyl-3,4-dihydroquinazolin-6-yl)-2-metho

difluorobenzene- 1 -sulfonamide

Step A

2-({[3,4-bis(methyloxy)ph nyl-4(3H)-quinazo

[00136] A sealed tube containing 6-bromo-2-chloro-3-phenyl-4(3H)-quinazolinone (1.06 g, 3.16 mmol), {[3,4-bis(methyloxy)phenyl]methyl}amine (0.704 mL, 4.74 mmol), DIEA (0.828 mL, 4.74 mmol), and NMP (14.26 mL) was heated to 130 °C overnight. After cooling to room temperature, the reaction was diluted with EtOAc and water. The combined organics were washed with water (3x) followed by a wash with brine. The washed organics were then dried over MgS0₄, filtered, and concentrated to give 2-({[3,4-bis(methyloxy)phenylJmethyl}amino)-6- bromo-3-phenyl-4(3H)-quinazolinone (1.36 g, 92%). ES-LCMS: 466.1 , 468.1 (M+1 ).

Step B

N-[5-[2-({[3,4-bis(methyloxy)phenyl]methyl}amino)-4-oxo-3-phenyl-3,4-dihydro-6-quinazolinyl]-2- (methyloxy)-3-pyridinyl]-2,4-difluorobenzenesulfonamide

[00137] A solution of 2-({[3,4-bis(methyloxy)phenyl]methyl}amino)-6-bromo-3-phenyl- 4(3H)-quinazolinone (0.125 g, 0.268 mmol), 2,4-difluoro-N-[2-(methyloxy)-5-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)-3-pyridinyl]benzenesulfonamide (0.137 g, 0.322 mmol), PdCI₂(dppf)-CH₂CI₂ adduct (0.022 g, 0.027 mmol), and K₂C0₃ (0.1 1 1 g, 0.804 mmol) in 1 ,4- dioxane (5.58 mL) and water (5.58 ml.) was heated to 80 °C overnight. After cooling to room temperature, the reaction was diluted with EtOAc and the combined organics were washed with brine, dried over MgS0₄, filtered, and concentrated to give N-[5-[2-({[3,4- bis(methyloxy)phenyl]methyl}amino)-4-oxo-3-phenyl-3,4-dihydro-6-quinazolinyl]-2-(methyloxy)- 3-pyridinyl3-2,4-difluorobenzenesulfonamide (0.223 g, 100%). ES-LCMS: 686.3 (M+1 ).

Step C

N-[5-(2-amino-4-oxo-3-phenyl-3, 4-dihydro-6-quinazolinyl) -2-(methyloxy)-3-pyridinyl]-2, 4-

[00138] A solution of N-[5-[2-({[3,4-bis(methyloxy)phenyl]methyl}amino)-4-oxo-3-phenyl- 3,4-dihydro-6-quinazolinyl]-2-(methyloxy)-3-pyridinyl]-2,4-difluorobenzenesulfonamide (0.223 g, 0.325 mmol) in DCM (1.626 mL) was treated by the addition of DDQ (0.081 g, 0.358 mmol) and stirred at room temperature. The reaction mixture was concentrated and the crude residue was taken up in DMF and purified by reverse phase chromatography (10-90% ACN/ H₂0 + formic acid). Isolation and lyophilization gave product contaminated with DDQ. The product was repurified by reverse phase chromatography (10-90% ACN/ H₂0 + formic acid). Isolation and lyophilization gave N-[5-(2-amino-4-oxo-3-phenyl-3,4-dihydro-6-quinazolinyl)-2-(methyloxy)-3- pyridinyl]-2,4-difluorobenzenesulfonamide. ¹H NMR (400 MHz, CHLOROFORM-c/) δ ppm 8.21 (d, J=2.15 Hz, 1 H), 8.12 (d, J=2.34 Hz, 1 H), 7.97 (d, J=2.34 Hz, 1 H), 7.87 - 7.95 (m, 1 H), 7.74 - 7.79 (m, 1 H), 7.55 - 7.68 (m, 3 H), 7.46 (d, J=8.39 Hz, 1 H), 7.36 - 7.41 (m, 2 H), 6.89 - 7.02 (m, 2 H), 4.94 (br. s., 1 H), 3.96 (s, 3 H) (2 exchangeable protons not evident); ES-LCMS: 536.3 (M+1).

Example 5

N-{5-[2-amino-3-(2-bromophenyl)-4-oxo-3,4-dihydroquinazolin-6-yl]-2-methoxypyrid yl}-2,4-difluorobenzene- 1 -sulfonamide

Step A

3-(2-bromophenyl)-6-io -2-thioxo-2,3-dihydro-4(1H)-quinazolinone

[00139] A solution of 2-amino-5-iodobenzoic acid (3.1 g, 1 1.79 mmol) and 1-bromo-2- isothiocyanatobenzene (1.586 mL, 11.79 mmol) in EtOH (55.0 mL) and TEA (2.300 mL, 16.50 mmol) were refluxed overnight. After cooling to room temperature, the solid was filtered, rinsing with EtOH to give 3-(2-bromophenyl)-6-iodo-2-thioxo-2,3-dihydro-4(1 H)-quinazolinoneas a white solid (3.79 g, 70%). LCMS: 459.0, 461.0 ( +1 ).

Step B

3-(2-bromophen -2-chloro-6-iodo-4(3H)-quinazolinone

[00140] A solution of 3-(2-bromophenyl)-6-iodo-2-thioxo-2,3-dihydro-4(1 H)-quinazolinone (3.79 g, 8.26 mmol) in POCI₃ (18.47 mL, 198 mmol) was treated with PCI₅ (2.75 g, 13.21 mmol). The mixture was heated to reflux for 6 hours. The solvents were removed under reduced pressure to afford a yellow oil. The residue was taken up in EtOAc, at which point solid material was observed to precipitate. The solid organics were then washed with water followed by a wash with brine. Next, the solids were filtered and discarded, and the filtrate was dried over Na₂S0₄, filtered again, and then concentrated to give 3-(2-bromophenyl)-2-chloro-6-iodo-4(3H)- quinazolinone (2.77 g, 73%). LCMS: 461.0, 462.9 (M+1 ).

Step C

2-({[3,4-bis(methyloxy)phen -6-iod

[00141] A solution of 3-(2-bromophenyl)-2-chloro-6-iodo-4(3H)-quinazolinone (2.77 g, 6.00 mmol) in NMP (28.4 mL) was treated with {[3,4-bis(methyloxy)phenyl]methyl}amine (1 .505 g, 9.00 mmol) and DIEA (1.573 mL, 9.00 mmol) and heated to 90 °C for 2 hours. After cooling to room temperature, the reaction was diluted with EtOAc and water. The combined organics were washed with water (3x) followed by a wash with brine. The solids that were present were filtered (1.15 g) to give 2-({[3,4-bis(methyloxy)phenyl]methyl}amino)-3-(2-bromophenyl)-6-iodo- 4(3H)-quinazolinone (1.15 g, 32.4%). LCMS: 592.1 , 594.1 (M+1 ).

Step D N-[5-[2-({[3,4-bis(methyloxy)phenyl]methyl}amino)-3-(2-bromo

quinazolinyl]-2-(methyloxy)-3φyridinyl]-2,4-difluorobenzenesuifonamide

[00142] A solution of 2-({[3,4-bis(methyloxy)phenyl]methyl}amino)-3-(2-bromophenyl)-6- iodo-4(3H)-quinazolinone (0.200 g, 0.338 mmol), 2,4-difluoro-N-[2-(methyloxy)-5-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)-3-pyridinyl]benzenesulfonamide (0.151 g, 0.355 mmol), PdCI₂(dppf)-CH₂CI₂ adduct (0.028 g, 0.034 mmol), and K₂C0₃ (0.140 g, 1.013 mmol) in 1 ,4- dioxane (7.04 ml.) and water (7.04 ml_); was heated to 80 °C for overnight. After cooling to room temperature, the reaction was diluted with EtOAc and the combined organics were washed with brine, dried over MgS0₄, filtered, and concentrated. The dark brown/black reside (0.394 g) was purified by silica gel chromatography (1-4% MeOH/DCM) to give N-[5-[2-({[3,4- bis(methyloxy)phenyl]methyl}amino)-3-(2-bromophenyl)-4-oxo-3,4-dihydro-6-quinazolinyl]-2- (methyloxy)-3-pyridinyl]-2,4-difluorobenzenesulfonamide as a light yellow solid (0.208 g, 81 %). LCMS: 764.2, 766.2 (M+1).

Step E

N-{5-[2-amino-3-(2-bromophenyl)-4-oxo-3,4-dihydroquinazoli

difluorobenzene- 1 -sulfonamide

[00143] A solution of N-[5-[2-({[3,4-bis(methyloxy)phenyl]methyl}amino)-3-(2- bromophenyl)-4-oxo-3,4-dihydro-6-quinazolinyl]-2-(methyloxy)-3-pyriclinyl]-2,4- difluorobenzenesulfonamide (0.208 g, 0.272 mmol) in DCM (1.360 mL) was treated by the addition of DDQ (0.068 g, 0.299 mmol). The reaction was stirred at room temperature overnight and then directly purified by silica gel chromatography (0-4% MeOH/DCM). Fractions containing the product were repurified by silica gel chromatography (1-3.5% MeOH/DCM) to give N-{5-[2-amino-3-(2-bromophenyl)-4-oxo-3,4-dihydroquinazolin-6-yl]-2-methoxypyridin-3-yl}- 2,4-difluorobenzene-1 -sulfonamide. ¹H NMR (400 MHz, DMSO-cfe) δ ppm 10.29 (s, 1 H), 8.34 (d, J=2.34 Hz, 1 H), 8.02 (d, J=2.15 Hz, 1 H), 7.84 - 7.93 (m, 3 H), 7.70 - 7.80 (m, 1 H), 7.53 - 7.64 (m, 3 H), 7.45 - 7.52 (m, 1 H), 7.35 (d, J=8.58 Hz, 1 H), 7.15 - 7.23 (m, 1 H), 6.58 (br. s., 2 H), 3.65 (s, 3 H); ES-LCMS: 614.2, 616.1 (M+1 ).

Example 6

N-{5-[2-amino-3-(3-bromophenyl)-4-oxo-3,4-dihydroquinazolin-6-ylJ-2- ethoxypy

yl}-2,4-difluorobenzene-1-sulfonamide

Step A

3-(3-bromophenyl)-6-iodo-2-thioxo-2, 3-dihydro-4( 1 H)-quinazolinone

[00144] A solution of 2-amino-5-iodobenzoic acid (2.5 g, 9.50 mmol) and 1 -bromo-3- isothiocyanatobenzene (1.357 mL, 9.50 mmol) were refluxed in EtOH (46.2 mL) overnight. The reaction was treated by the addition of 2-amino-5-iodobenzoic acid (2.0 g) and heated for an additional 6 hours. The reaction was then treated by the addition of 2-amino-5-iodobenzoic acid (2.0 g) and heated overnight. After cooling to room temperature, the solids were filtered and then rinsed with cold EtOH to give 3-(3-bromophenyl)-6-iodo-2-thioxo-2,3-dihydro-4(1 H)- quinazolinone as a white solid (1.63 g, 37%). ES-LCMS: 459.0, 460.9 (M+1 ).

Step B

3-(3-bromophenyl)-2-chioro-6-iodo-4(3H)-quinazolinone

[00145] To a solution of 3-(3-bromophenyl)-6-iodo-2-thioxo-2,3-dihydro-4(1 H)- quinazolinone (1.63 g, 3.55 mmol) in POCI₃ (7.94 mL, 85 mmol) was added PCI₅ (1 .227 g, 5.89 mmol). The mixture was then heated to reflux for 6 hours. The solvents were removed under reduced pressure. The solid residue was taken up in EtOAc and washed with water and then brine. Next, the washed solids were then dried over Na₂S0₄, filtered, and concentrated to give 3-(3-bromophenyl)-2-chloro-6-iodo-4(3H)-quinazolinone (1.59 g, 97%). ES-LCMS: 461.0, 463.0 (M+1 ).

Step C

2-({[3,4-bis(methyloxy)phenyl]methyl}amino)-3-(3-bromophenyl)-6-iodo-4(3H^

[00146] A solution of 3-(3-bromophenyl)-2-chloro-6-iodo-4(3H)-quinazolinone (1.58 g, 3.42 mmol) in NMP (15.46 mL) was treated by the addition of {[3,4- bis(methyloxy)phenyl]methyl}amine (0.763 mL, 5.14 mmol) and D!EA (0.897 mL, 5.14 mmol) and heated to 90 °C. After cooling to room temperature, the reaction was diluted with EtOAc and water. The combined organics were washed with water (3x) followed by a wash with brine. Next the washed organics were dried over MgS0₄, filtered, and concentrated to give 2-({[3,4- bis(methyloxy)phenyl]methyl}amino)-3-(3-bromophenyl)-6-iodo-4(3H)-quinazolinone (2.10 g, 100%). ES-LCMS: 592.1 , 594.0 (M+1 ).

Step D

N-[5-[2-({[3 -bis(methyloxy)phenyl]methyl}amino)-3-(3-brom

quinazolinyl]-2-(met yloxy)-3^yridinyl]-2 -dffl

[00147] A solution of 2-({[3,4-bis(methyloxy)phenyl]methyl}amino)-3-(3-bromophenyl)-6- iodo-4(3H)-quinazolinone (0.200 g, 0.338 mmol), 2,4-difluoro-N-[2-(methyloxy)-5-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)-3-pyridinyl]benzenesulfonamide (0.151 g, 0.355 mmol), PdCI₂(dppf)-CH₂CI₂ adduct (0.028 g, 0.034 mmol), and K₂C0₃ (0.140 g, 1.013 mmol) in 1 ,4- dioxane (7.04 mL) and water (7.04 mL). The resulting solution was then heated to 80 °C overnight. After cooling to room temperature, the reaction was diluted with EtOAc and the combined organics were washed with brine, dried over MgS0₄, filtered, and concentrated. The residue was purified by silica gel chromatography (0-5% MeOH/DCM) to give N-[5-[2-({[3,4- bis(methyloxy)phenyl]methyl}amino)-3-(3-bromophenyl)-4-oxo-3,4-dihydro-6-quinazolinyl]-2- (methyloxy)-3-pyridinyl]-2,4-difluorobenzenesulfonamide (0.126 g, 49%). ES-LCMS: 764.3, 766.2 (M+1 ).

Step E

N-{5-[2-amino-3-(3-bromophenyl)-4-oxo-3,4-dihydroquinazofa

difluorobenzene- 1 -sulfonamide

[00148] A solution of N-[5-[2-({[3,4-bis(methyloxy)phenyl]methyl}amino)-3-(3- bromophenyl)-4-oxo-3,4-dihydro-6-quinazolinyl]-2-(methyloxy)-3-pyridinyl]-2,4- difluorobenzenesulfonamide (0.126 g, 0.165 mmol) in DCM (0.824 mL) was treated by the addition of DDQ (0.041 g, 0.181 mmol). The reaction was stirred at room temperature overnight. The reaction was not complete so an additional equivalent of DDQ was added and the reaction was stirred at room temperature overnight. The reaction was loaded directly onto a silica gel column and purified (1-4% MeOH/DCM). Fractions containing product were concentrated and repurified by silica gel chromatography (1 -4% MeOH/DCM) to give a solid. The solid was triturated with Et₂0 to give N-{5-[2-amino-3-(3-bromophenyl)-4-oxo-3,4- dihydroquinazolin-6-yl]-2-methoxypyridin-3-yl}-2,4-difluorobenzene-1 -sulfonamide (0.051 g, 50%). H NMR (400 MHz, DMSO-cf_e) δ ppm 10.31 (br. s., 1 H), 8.33 (d, J=2.34 Hz, 1 H), 8.01 (d, J=1.95 Hz, 1 H), 7.83 - 7.93 (m, 2 H), 7.68 - 7.80 (m, 3 H), 7.50 - 7.62 (m, 2 H), 7.42 (d, J=8.19 Hz, 1 H), 7.34 (d, J=8.39 Hz, 1 H), 7.21 (td, J=8.39, 1.76 Hz, 1 H), 6.62 (br. s., 2 H), 3.65 (s, 3 H); ES-LCMS: 614.2, 616.2 (M+1 ).

Example 7

N-{5-[2-amino-3-(4-bromophenyl)-4-oxo-3,4-dihydroquinazolin-6-yl]-2-meth

Step A

3-(4-bromophenyl)-6 4( 1 H)-quinazolinone

[00149] A solution of 2-amino-5-iodobenzoic acid (5.0 g, 19.01 mmol) and 4-bromophenyl isothiocyanate (4.88 g, 22.81 mmol) in EtOH (91 mL) and TEA (3.71 mL, 26.6 mmol) were refluxed overnight. After cooling to room temperature, the solid was filtered, rinsing with EtOH to give 3-(4-bromophenyl)-6-iodo-2-thioxo-2,3-dihydro-4(1 H)-quinazolinone as a white solid (7.79 g, 89%). LCMS: 458.9, 461.9 (M+1).

Step B

3-(4-bromophe -quinazotinone

[00150] A solution of 3-(4-bromophenyl)-6-iodo-2-thioxo-2,3-dihydro-4(1 H)-quinazolinone (5.0 g, 10.89 mmol) in POCI₃ (24.36 mL, 261 mmol) was treated with PCI₅ (3.63 g, 7.43 mmol). The mixture was heated to reflux for 6 hours. After cooling the solvents were removed under reduced pressure. The residue was taken up in EtOAc and washed with water and then washed with brine. The washed residue was then dried over Na₂S0₄, filtered, and concentrated to give 3-(4-bromophenyl)-2-chloro-6-iodo-4(3H)-quinazolinone. LC S: 461.0, 463.0 ( +1 ).

Step C

2-({[3 -bis(methyloxy)phenyl]methyl}amino)-3-(4-bromophenyl)-6-iodo-4(3H^

[00151] A solution of 3-(4-bromophenyl)-2-chloro-6-iodo-4(3H)-quinazolinone (4.49 g, 9.73 mmol) in N P (43.9 mL) was treated by the addition of {[3,4- bis(methyloxy)phenyl]methyl}amine (2.167 mL, 14.59 mmol) and DIEA (2.55 mL, 14.59 mmol)and heated to 90 °C for 2 hours. After cooling to room temperature, the reaction was diluted with EtOAc and water. The combined organics were washed with water (3x) and then brine. The washed organics were then dried over MgS0_4, filtered, and concentrated to give 2- ({[3,4-bis(methyloxy)phenyl]methyl}amino)-3-(4-bromophenyl)-6-iodo-4(3H)-quinazolinone (5.90 g, 100%). LCMS: 592.1 , 594.1 (M+1 ).

Step D

N-[5-[2-({[3 -bis(methyloxy)phenyl]methyl}amino)-3-(4-bromo

quinazo^inyl]-2-(methyloxy)-3 yridinyl]-2,4-difluorobenzenesulfonamide

[00152] A solution of 2-({[3,4-bis(methyloxy)phenyl]methyl}amino)-3-(4-bromophenyl)-6- iodo-4{3H)-quinazolinone {0.500 g, 0.844 mmol), 2,4-difluoro-N-[2-(methyloxy)-5-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)-3-pyridinyl]benzenesulfonamide (0.378 g, 0.886 mmol), PdCI₂(dppf)-CH₂CI₂ adduct (0.069 g, 0.084 mmol), and K₂C0₃ (0.350 g, 2.53 mmol) in 1 ,4- dioxane (17.59 mL) and water (17.59 mL) was heated to 80 °C for 1 hour. After cooling to room temperature, the reaction was diluted with EtOAc and the combined organics were washed with brine, dried over MgS0₄, filtered, and concentrated to give N-[5-[2-({[3,4- bis(methyloxy)phenyl]methyl}amino)-3-(4-bromophenyl)-4-oxo-3,4-dihydro-6-quinazolinyl]-2- (methyloxy)-3-pyridinyl]-2,4-difluorobenzenesulfonamide (0.807 g, 100%). ES-LCMS: 764.2, 766.2 (M+1 ).

Step E

N-[5-[2-amino-3-(4-bromophenyl)-4-oxo-3 -dihydro-6-quinazolinyl^

2, 4-difluorobenzenesulfonamide

[00153] A solution of N-[5-[2-({[3,4-bis(methyloxy)phenyl]methyl}amino)-3-(4- bromophenyl)-4-oxo-3,4-dihydro-6-quinazolinyl]-2-(methyloxy)-3-pyridinyl]-2,4- difluorobenzenesulfonamide (0.807 g, 1 .055 mmol) in DCM (5.28 mL) was treated by the addition of DDQ (0.264 g, 1.161 mmol). The reaction was filtered with filter paper and the filtrate was purified by silica gel chromatography (1-4% MeOH/DC ). The fractions containing the product were loaded onto Celite® and repurified by silica gel chromatography (0.5-3% MeOH/DCM) to elute DDQ impurities and then increased from (3-5% MeOH/DCM) to give the product as a brown solid (249 mg). The brown solid (85 mg) was then purified by reverse phase chromatography (10-90% ACN/ H₂0 + formic acid). Isolation and lyophilization gave N-[5-[2- amino-3-(4-bromophenyl)-4-oxo-3,4-dihydro-6-quinazolinyl]-2-(methyloxy)-3-pyridinyl]-2,4- difluorobenzenesulfonamide. H NMR (400 MHz, DMSO-cfe) δ ppm 8.27 (br. s., 1 H), 8.00 (s, 1 H), 7.71 - 7.91 (m, 5 H), 7.48 - 7.59 (m, 1 H), 7.28 - 7.41 (m, 3 H), 7.13 - 7.24 (m, 1 H), 6.53 (br. s., 2 H), 3.66 (s, 3 H); ES-LCMS: 614.2, 616.1 (M+1).

Example 8

N-(5-{2-amino-3-[4-(morpholin-4-yl)phenyl]-4-oxo-3,4-dihydroquin

methoxypyridin-3-yl)-2,4-difluorobenzene-1-sulfonamide

N-(5-{2-amino-3-[4-(morpholin-4-yl)phenyl]-4-oxo-3A-dihyd

3-yl)-2,4-difluorobenzene-1 -sulfonamide

[00154] A solution of 2-amino-6-iodo-3-[4-(4-morpholinyl)phenyl]-4(3H)-quinazolinone (0.050 g, 0.112 mmol), 2,4-difluoro-N-[2-(methyloxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan- 2-yl)-3-pyridinyljbenzenesulfonamide (0.052 g, 0.123 mmol), PdCI₂(dppf)-CH₂CI₂ adduct (9.1 1 mg, 0.011 mmol), and K₂C0₃ (0.046 g, 0.335 mmol) in 1 ,4-dioxane (2.324 mL) and water (2.324 mL) was heated to 80 °C for 2 hours. After cooling to room temperature, the reaction was diluted with EtOAc and the combined organics were washed with brine, dried over MgS0₄, filtered, and concentrated. The residue was purified by silica gel chromatography eluting with 5% MeOH/DCM to give N-(5-{2-amino-3-[4-(morpholin-4-yl)phenyl]-4-oxo-3,4-dihydroquinazolin- 6-yl}-2-methoxypyridin-3-yl)-2,4-difluorobenzene-1-sulfonamide. H NMR (400 MHz, DMSO-d₆) δ ppm 10.30 (br. s., 1 H), 8.32 (br. s., 1 H), 8.01 (br. s., 1 H), 7.85 (br. s., 2 H), 7.70 - 7.80 (m, 1 H), 7.57 (br. s., 1 H), 7.33 (br. s., 1 H), 7.04 - 7.25 (m, 5 H), 6.37 (br. s., 2 H), 3.77 (br. s., 4 H), 3.64 (br. s., 3 H), 3.21 (br. s., 4 H); ES-LCMS: 621.3 (M+1 ).

Example 9

N-{5-[2-amino-3-(3-cyanophenyl)-4-oxo-3,4-dihydroquinazolin-6-yl]-2-metho

yl}-2,4-difluorobenzene-1-sulfonamide

Step A

3-(3-bromophenyl)-6-iodo-2-({[4-(methyloxy)phenyl]methyl}am

[00155] A solution of 3-(3-bromophenyl)-2-chloro-6-iodo-4(3H)-quinazolinone (7.73 g, 16.75 mmol), {[4-(methyloxy)phenyl]methyl}amine (3.26 mL, 25.1 mmol), DIEA (4.39 mL, 25.1 mmol) in DMF (76 mL) was heated to 80 °C for 6 hours. After cooling to room temperature, the reaction was diluted with EtOAc and washed with 5% LiCI (3x) followed by a wash with brine. Next, the organic layer was dried over Na₂S0₄, filtered, and concentrated to give 3-(3- bromophenyl)-6-iodo-2-({[4-(methyloxy)phenyl]methyl}amino)-4(3H)-quinazolinone (9.89 g, 100%). ES-LCMS: 562.1 , 564.1 (M+1 ).

Step B

2-amino-3-(3-b -quinazolinone

[00156] A solution of 3-(3-bromophenyl)-6-iodo-2-({[4-(methyloxy)phenyl]methyl}amino)- 4(3H)-quinazolinone (5.0 g, 8.89 mmol) in TFA (0.685 mL, 8.89 mmol) was heated to 65 °C for 4 days. The reaction was concentrated and the residue was taken up in DCM and washed with saturated NaHC0₃ (2x) and then washed with brine. Next, the washed solids were filtered (2.641 g) from the organics, dried over Na₂S0₄, filtered, and concentrated. The residue was taken up in DCM and the solids were filtered (.379 g) and combined with the previously isolated solids to give 2-amino-3-(3-bromophenyl)-6-iodo-4(3H)-quinazolinone (3.024 g, 77%). ES- LCMS: 442.0, 444.0 ( +1).

Step C

N-[5-[2-amino-3-(3-bromophenyl)-4-oxo-3,4-dihydro-6-quinazolinyl]-2-(methylo^

2,4-difluorobenzenesuifonamide

[00157] A solution of 2-amino-3-(3-bromophenyl)-6-iodo-4(3H)-quinazolinone (0.500 g, 0.950 mmol), 2,4-difluoro-N-[2-(methyloxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-3- pyridinyl]benzenesulfonamide (0.405 g, 0.950 mmol), PdCI₂(dppf)-CH₂CI₂ adduct (0.078 g, 0.095 mmol), and K₂C0₃ (0.394 g, 2.85 mmol) in 1 ,4-dioxane (19.79 mL) and water (19.79 mL) was heated to 75 °C for 45 minutes. After the reaction was cooled to room temperature, the reaction was diluted with H₂0 and EtOAc. The combined organics were washed with brine, dried over Na₂S0₄, filtered, and concentrated. The crude residue (0.837 g) was triturated with Et₂0 and filtered to give N-[5-[2-amino-3-(3-bromophenyl)-4-oxo-3,4-dihydro-6-quinazolinyl]-2- (methyloxy)-3-pyridinyl]-2,4-difluorobenzenesulfonamide (0.466 g, 80%). ES-LCMS: 614.2, 616.2 (M+1 ).

Step D

N-[5-[2-amino-3-(3-cyanophenyl)-4-oxo-3 -dihydro-6-quinazolinyl]-2-(methylox

2,4-difluorobenzenesuifonamide

[00158] A solution of N-[5-[2-amino-3-(3-bromophenyl)-4-oxo-3,4-dihyclro-6-quinazolinyl]- 2-(methyloxy)-3-pyridinyl]-2,4-difluorobenzenesulfonamide (0.200 g, 0.326 mmol) in DMF (2.56 ml.) was treated by the addition of tetrakis triphenylphosphine palladium(O) (0.075 g, 0.065 mmol) and zinc cyanide (0.046 g, 0.391 mmol) and purged with nitrogen and heated to 90 °C for 1 hour. The reaction was cooled to room temperature and diluted with EtOAc and water. The combined organics were washed with 5% LiCI (3x), saturated NaHC0₃ and then brine. Next, the washed organics were dried over MgS0₄, filtered, and concentrated. The crude residue was purified by reverse phase chromatography (10-90% ACN/ H₂0 + formic acid). Isolation and lyophilization of the fractions gave N-[5-[2-amino-3-(3-cyanophenyl)-4-oxo-3,4-dihydro-6- quinazolinyl]-2-(methyloxy)-3-pyridinyl]-2,4-difluorobenzenesulfonamide as a white solid. H NMR (400 MHz, CHLOROFORM-cf) δ ppm 8.19 (s, 1 H), 8.13 (s, 1 H), 7.97 (s, 1 H), 7.87 - 7.94 (m, 2 H), 7.76 - 7.83 (m, 2 H), 7.74 (s, 1 H), 7.63 - 7.70 (m, 1 H), 7.48 (d, J=8.60 Hz, 1 H), 6.89 - 7.02 (m, 2 H), 3.96 (s, 3 H); ES-LCMS: 561.2 (M+1 ).

Example 10

N-{5-[2-amino-3-(3-methylphenyl)-4-oxo-3,4-dihydroquinazolin-6-yl]-2-m

yl}-2,4-difluorobenzene-1-sulfonamide

N-{5-[2-amino-3-(3-methylphenyl)-4-oxo-3,4-dihydroquinazolin-6-yl]-2-^

difluorobenzene- 1 -sulfonamide

[00159] A solution of N-[5-[2-amino-3-(3-bromophenyl)-4-oxo-3,4-dihydro-6-quinazolinyl]- 2-(methyloxy)-3-pyridinyl]-2,4-difluorobenzenesulfonamide (0.123 g, 0.200 mmol) in DMF (1.548 mL) was treated with tetrakis triphenylphosphine palladium(O) (0.023 g, 0.020 mmol) and K₂C0₃ (0.083 g, 0.601 mmol). The reaction was stirred for 5 minutes then treated with

trimethylboroxine (0.028 mL, 0.200 mmol) and then purged with nitrogen and then heated to 110 °C overnight. The reaction was cooled to room temperature and diluted with EtOAc and water. The combined organics were washed with 5% LiCI (3x), saturated NaHC0₃ followed by a wash with brine. Next, the washed organics were dried over MgS0₄, filtered, and

concentrated. The crude residue was purified by reverse phase chromatography (10-90% ACN/ H₂0 + formic acid) to give N-{5-[2-amino-3-(3-methylphenyl)-4-oxo-3,4-dihydroquinazolin-6-yl]- 2-methoxypyridin-3-yl}-2,4-difluorobenzene-1-sulfonamide (0.013 g, 12%). H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.20 (d, J=2.15 Hz, 1 H), 8.12 (d, J=2.15 Hz, 1 H), 7.96 (d, J=2.15 Hz, 1 H), 7.89 - 7.96 (m, 1 H), 7.77 (dd, J=8.59, 2.15 Hz, 1 H), 7.49 - 7.56 (m, 1 H), 7.46 (d, J=8.39 Hz, 1 H), 7.39 (d, J=7.80 Hz, 1 H), 7.14 - 7.21 (m, 2 H), 6.89 - 7.01 (m, 2 H), 3.96 (s, 3 H), 2.46 (s, 3 H); ES-LCMS: 550.2 (M+1 ).

Example 11

N-{5-[2-amino-4-oxo-3-(3-phenylphenyl)-3,4-dihydroquinazolin-6-yl]-2-me

yl}-2,4-difluorobenzene- 1 -sulfonamide

N-[5-[2-amino-3-(3-biphenylyl)-4-oxo-3 -dihydro-6-quinazolinyl]-2-(methy^

difluorobenzenesulfonamide [00160] A solution of N-[5-[2-amino-3-(3-bromophenyl)-4-oxo-3,4-dihydro-6-quinazolinyl3- 2-(methyloxy)-3-pyridinyl]-2_I4-difluorobenzenesulfonamide (0.125 g, 0.203 mmol),

phenylboronic acid (0.037 g, 0.305 mmol), K₂C0₃ (0.1 12 g, 0.814 mmol), PdCl₂(dppf)-CH₂CI₂ adduct (0.017 g, 0.020 mmol), and 1 ,4-dioxane (1.849 mL) under nitrogen was heated in the microwave at 160 °C for 10 minutes. The red reaction was diluted with EtOAc and water. The combined organics were washed with saturated NaHC0₃ followed by a wash with brine. Next, the washed organics were dried over Na₂S0₄, filtered, and concentrated. The crude residue was purified by reverse phase chromatography (10-90% ACN/ H₂0 + formic acid). Isolation and lyophilization gave a residue which was further purified with silica gel chromatography (1 -3% MeOH/DCM). The fractions were collected and concentrated to give N-[5-[2-amino-3-(3- biphenylyl)-4-oxo-3,4-dihydro-6-quinazolinyl]-2-(methyloxy)-3-pyridinyl]-2,4- difluorobenzenesulfonamide as a white solid (0.017 g, 14%). H NMR (400 MHz,

CHLOROFORM- /) δ ppm 8.08 - 8.29 (m, 2 H), 7.86 - 8.03 (m, 2 H), 7.54 - 7.85 (m, 6 H), 7.31 - 7.54 (m, 5 H), 6.86 - 7.04 (m, 2 H), 3.95 (s, 3 H); ES-LCMS: 612.5 (M+1 ).

Examples 12 and 13

N-{5-[2-amino-3-(2-methylphenyl)-4-oxo-3,4-dihydroquinazolin-6-yl]-2-m

yl}-2,4-difluorobenzene-1-sulfonamide and 2,4-difluoro-N-[2-(methyloxy)-5-(12-oxo-5,12- dihydrobenzimidazo[2,1-b]quinazolin-2-yl)-3^yridinyl]benzenesulfonamide

N-{5-[2-amino-3-(2-methylphenyl)-4-oxo-3,4-dihydroquinazolin^

difluorobenzene-1 -sulfonamide and 2,4-difluoro-N-[2-(methyloxy)-5-( 12-oxo-5, 12- dihydrobenzimidazo[2 -b]quinazolin-2-yl)-3φy dinyl]benzenesulfonamide [00161 ] A solution of N-[5-[2-amino-3-(2-bromophenyl)-4-oxo-3,4-dihydro-6-quinazolinyl]- 2-(methyloxy)-3-pyridinyl]-2,4-difluorobenzenesulfonamide (0.100 g, 0.163 mmol) in D F (1.259 mL) was treated with tetrakis triphenylphosphine palladium(O) (0.019 g, 0.016 mmol) and K₂C0₃ (0.067 g, 0.488 mmol). The reaction was stirred for 5 minutes then treated with

tri methyl boroxine (0.023 mL, 0.163 mmol) and followed by purging with nitrogen and then heating to 1 10 °C overnight. The reaction was treated by the addition of sodium bromide (0.017 g, 0.163 mmol) and then treated by the addition of additional tri methyl boroxine (0.023 mL, 0.163 mmol) and then purged with nitrogen and heated to 1 10 °C overnight. The reaction was treated with tetrakis triphenylphosphine palladium(O) (0.019 g, 0.016 mmol) and K₂C0₃ (0.067 g, 0.488 mmol) and stirred for 5 minutes then treated with trimethylboroxine (0.023 mL, 0.163 mmol). The reaction was purged with nitrogen and continued to heat to 1 10 °C for 48 hours. The reaction was diluted with water and EtOAc. The combined organics were washed with saturated NaHC0₃ followed by a wash with brine. Next, the washed organics were dried over Na₂S0₄, filtered, and concentrated. The crude residue was taken purified by reverse phase chromatography (10-90% ACN/ H₂0 + formic acid). Isolation and lyophilization gave N-{5-[2- amino-3-(2-methylphenyl)-4-oxo-3,4-dihydroquinazolin-6-yl]-2-methoxypyridin-3-yl}-2,4- difluorobenzene-1 -sulfonamide as a light beige solid (2 mg, 3%). H NMR (400 MHz,

CHLOROFORM-d) δ ppm 8.22 (s, 1 H), 8.13 (s, 1 H), 7.98 (s, 1 H), 7.88 - 7.95 (m, 1 H), 7.78 (dd, J=8.49, 2.24 Hz, 1 H), 7.42 - 7.51 (m, 4 H), 7.29 (s, 1 H), 6.89 - 7.01 (m, 2 H), 3.95 (s, 3 H), 2.23 (s, 3 H); ES-LCMS: 550.5 (M+1 ), and gave 2,4-difluoro-N-[2-(methyloxy)-5-(12-oxo-5,12- dihydrobenzimidazo[2,1 -b]quinazolin-2-yl)-3-pyridinyl]benzenesulfonamide as a light beige solid (0.017 g, 19%). ¹H NMR (400 MHz, DMSO-cf₆) δ ppm 10.33 (br. s., 1 H), 8.43 - 8.48 (m, 1 H), 8.30 - 8.36 (m, 1 H), 8.00 - 8.07 (m, 1 H), 7.87 - 7.93 (m, 1 H), 7.75 - 7.84 (m, 2 H), 7.13 - 7.68 (m, 6 H), 3.68 (s, 3 H); ES-LCMS: 534.5 (M+1 ).

Example 14

N-(5-{2-amino-3-[3-(morpholin-4-ylmethyl)phenyl]-4-oxo-3,4-dihydroquinazo

methoxypyridin-3-yl)-2,4-difluorobenzene-1-sulfonamide

N-(5-{2-amino-3-[3-(morpholin-4-ylmethyl)phenyl]-4-oxo-3,4-dihydroqu

methoxypyridin-3-yl)-2, 4-difluorobenzene- 1 -sulfonamide

[00162] A solution of N-[5-[2-amino-3-(3-bromophenyl)-4-oxo-3,4-dihydro-6-quinazolinyl]- 2-(methyloxy)-3-pyridinyl]-2,4-difluorobenzenesulfonamide (0.1 10 g, 0.179 mmol), potassium (morpholin-4yl)methyltrifluoroborate (0.041 g, 0.197 mmol), XPhos (5.12 mg, 10.74 mol), PdOAc₂ (1.206 mg, 5.37 Mmol), and Cs₂C0₃ (0.175 g, 0.537 mmol) was prepared in THF (0.651 mL) and water (0.065 ml_). Next, the solution was purged with nitrogen and then heated in a sealed tube at 85 °C under nitrogen overnight. After cooling to room temperature, the reaction was diluted with water and extracted into EtOAc. The combined organics were washed with brine, dried over Na₂S0₄, filtered, and concentrated. The crude residue was purified by reverse phase chromatography (10-90% ACN/ H₂0 + formic acid). Isolation and lyophilization of the fractions gave N-(5-{2-amino-3-[3-(morpholin-4-ylmethyl)phenyl]-4-oxo-3,4-dihydroquinazolin-6- yl}-2-methoxypyridin-3-yl)-2,4-difluorobenzene-1-sulfonamide as a white solid. H N R (400 MHz, CHLOROFORM-d) δ ppm 8.21 (s, 1 H), 8.12 (s, 1 H), 7.97 (s, 1 H), 7.87 - 7.95 (m, 1 H), 7.77 (dd, J=8.39, 1.95 Hz, 1 H), 7.53 - 7.62 (m, 2 H), 7.45 (d, J=8.59 Hz, 1 H), 7.38 (s, 1 H), 7.28 (br. s., 1 H), 6.90 - 7.01 (m, 2 H), 3.95 (s, 3 H), 3.73 (t, J=4.39 Hz, 4 H), 3.54 - 3.65 (m, 2 H), 2.51 (br. s., 4 H); ES-LCMS: 635.3 (M+ ).

Example 15

N-[5-(2-amino-3-{3-[(diethylamino)methyl]phenyl}-4-oxo-3,4-dihydroquinaz

me thoxypyridin-3-yl]-2, 4-difluorobenzene- 1 -sulfonamide

N-[5-(2-amino-3-{3-[(diethylamino)methyl]phenyl}-4-oxo-3,4-dih

methoxypyridin-3-yl]-2, 4-diftuorobenzene- 1 -sulfonamide

[00163] A solution of N-[5-[2-amino-3-(3-bromophenyl)-4-oxo-3,4-dihydro-6-quinazolinyl]- 2-(methyloxy)-3-pyridinyl]-2,4-difluorobenzenesulfonamide (0.115 g, 0.187 mmol), potassium diethylaminomethyltrifluoroborate (0.040 g, 0.206 mmol), XPhos (5.35 mg, 0.01 1 mmol), PdOAc₂ (1.261 mg, 5.62 Mmol), and Cs₂C0₃ (0.183 g, 0.562 mmol) was prepared in THF (0.681 mL) and water (0.068 ml_). Next, the solution was purged with nitrogen and then heated in a sealed tube at 85 °C under nitrogen overnight. After cooling to room temperature, the reaction was diluted with water and extracted into DCM. The combined organics were washed with brine, dried over Na₂S0₄, filtered, and concentrated. The crude residue was purified by reverse phase chromatography (10-90% ACN/ H₂0 + formic acid). Isolation and lyophilization of the fractions gave N-[5-(2-amino-3-{3-[(diethylamino)methyl]phenyl}-4-oxo-3,4-dihydroquinazolin-6- yl)-2-methoxypyridin-3-yl]-2,4-difluorobenzene-1-sulfonamide as a solid (0.013 g, 1 1%). ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.20 (d, J=2.15 Hz, 1 H), 8.12 (d, J=2.15 Hz, 1 H), 7.97 (d, J=2.15 Hz, 1 H), 7.88 - 7.95 (m, 1 H), 7.76 (dd, J=8.58, 2.34 Hz, 1 H), 7.53 - 7.62 (m, 2 H), 7.45 (d, J=8.39 Hz, 2 H), 7.29 - 7.32 (m, 1 H), 6.89 - 7.02 (m, 2 H), 3.95 (s, 3 H), 3.69 - 3.88 (m, 2 H), 2.66 - 2.79 (m, 4 H), 1.15 (t, J=7. 2 Hz, 6 H); ES-LCMS: 621.2 (M+1).

Example 16

N-(5-{2-amino-4-oxo-3-[3-(piperidin-1-ylmethyl)phenyl]-3,4-dihydroquin

me thoxypyridin-3-yl)-2, 4-difluorobenzene- 1 -sulfonamide

N-[5-{2-amino-4-oxo-3-[3-(1^iperidinylmethyl)phenyl]-3 -dihy

3-pyridinyl]-2,4-difluorobenzenesulfonamide

[00164] A solution of N-[5-[2-amino-3-(3-bromophenyl)-4-oxo-3,4-dihydro-6-quinazolinyl]- 2-(methyloxy)-3-pyridinyl]-2,4-difluorobenzenesulfonamide (0.115 g, 0.187 mmol), potassium (piperidin-l-yl)methyltriflouroborate (0.042 g, 0.206 mmol), XPhos (5.35 mg, 0.011 mmol), PdOAc₂ (1.261 mg, 5.62 Mmol), and Cs₂C0₃ (0.183 g, 0.562 mmol) was prepared in THF (0.681 mL) and water (0.068 ml_). Next, the solution was purged with nitrogen and then heated in a sealed tube at 85 °C under nitrogen overnight. After cooling to room temperature, the reaction was diluted with water and extracted into DCM. The combined organics were washed with brine, dried over Na₂S0₄, filtered, and concentrated. The crude residue was purified by reverse phase chromatography (10-90% ACN/ H₂0 + formic acid). Isolation and lyophilization gave N- [5-{2-amino-4-oxo-3-[3-(1-piperidinylmethyl)phenyl]-3,4-dihydro-6-quinazolinyl}-2-(methyloxy)-3- pyridinylJ-2,4-difluorobenzenesulfonamide (0.014 g, 12%). ¹H NMR (400 MHz, CHLOROFORM- c δ ppm 8.19 - 8.22 (m, 1 H), 8.11 - 8.14 (m, 1 H), 7.96 - 7.99 (m, 1 H), 7.88 - 7.96 (m, 1 H), 7.74 - 7.79 (m, 1 H), 7.52 - 7.63 (m, 2 H), 7.43 - 7.48 (m, 1 H), 7.41 (br. s., 1 H), 7.29 - 7.33 (m, 1 H), 6.90 - 7.01 (m, 2 H), 4.98 (br. s., 1 H), 3.95 (s, 3 H), 3.59 - 3.81 (m, 2 H), 2.50 - 2.67 (m, 4 H), 1.69 (br. s., 8 H); ES-LC S: 633.3 ( + ).

Example 17

N-(5-{2-amino-4-oxo-3-[3-(pyrrolidin-1-ylmethyl)phenyl]-3,4-dihydroquin

me thoxypyridin-3-yl)-2, 4-difluorobenzene- 1 -sulfonamide

N-(5-{2-amino-4-oxo-3-[3-(pyrrolidin-1-ylmethyl)phenyl]-3,4-dihydro

methoxypyridin-3-yl)-2, 4-difluorobenzene- 1 -sulfonamide

[00165] A solution of N-[5-[2-amino-3-(3-bromophenyl)-4-oxo-3,4-dihyclro-6-quinazolinyl]- 2-(methyloxy)-3-pyridinyl]-2,4-difluorobenzenesulfonamide (0.1 15 g, 0.187 mmol), potassium 1- trifluoroboratomethylpyrrolidine (0.039 g, 0.206 mmol), XPhos (5.35 mg, 0.011 mmol), PdOAc₂ (1 .261 mg, 5.62 mol), and Cs₂C0₃ (0.183 g, 0.562 mmol) was prepared in THF (0.681 mL) and water (0.068 mL). Next, the solution was purged with nitrogen and then heated in a sealed tube at 85 °C under nitrogen overnight. After cooling to room temperature, the reaction was diluted with water and extracted into DCM. The combined organics were washed with brine, dried over Na₂S0₄, filtered, and concentrated. The crude residue was purified by reverse phase chromatography 10-90% ACN/ H₂0. Isolation and lyophilization of the fractions gave N-(5-{2- amino-4-oxo-3-[3-(pyrrolidin-1-ylmethyl)phenyl]-3,4-dihydroquinazolin-6-yl}-2-methoxypyridin-3- yl)-2,4-difluorobenzene-1 -sulfonamide as a solid. (0.008 g, 7%). ¹H NMR (400 MHz,

CHLOROFORM- /) δ ppm 8.18 - 8.22 (m, 1 H), 8.1 1 - 8.14 (m, 1 H), 7.96 - 7.98 (m, 1 H), 7.88 - 7.96 (m, 1 H), 7.74 - 7.78 (m, 1 H), 7.55 - 7.63 (m, 2 H), 7.44 (s, 2 H), 7.29 - 7.34 (m, 1 H), 6.89 - 7.00 (m, 2 H), 4.98 (br. s., 1 H), 3.95 (s, 3 H), 3.77 - 3.94 (m, 2 H), 2.80 (br. s., 4 H), 1.92 (br. s., 6 H); ES-LC S: 619.3 ( + ).

Example 18

N-[5-(2-amino-3-{3-[(4-methylpiperazin-1-yl)methyl]phenyl}-4-oxo-3,4-dih

6-yl)-2-methoxypyridin-3-yl]-2,4-difluorobenzene-1-sulfonamide

N-[5-(2-amino-3-{3-[(4-methylpiperazin-1-yl)methyl]phenyl}-4-oxo-3

methoxypyridin-3-yl]-2, 4-difluorobenzene-1 -sulfonamide

[00166] A solution of N-[5-[2-amino-3-(3-bromophenyl)-4-oxo-3,4-dihyclro-6-quinazolinyl]- 2-(methyloxy)-3-pyridinyl]-2,4-difluorobenzenesulfonamide (0.1 15 g, 0.187 mmol), potassium 1 - methyl-4-trifluoroboratomethylpiperazine (0.046 g, 0.206 mmol), XPhos (5.35 mg, 0.01 1 mmol), PdOAc₂ (1.261 mg, 5.62 Mmol), and Cs₂C0₃ (0.183 g, 0.562 mmol) was prepared in THF (0.681 mL) and water (0.068 ml_). Next, the solution was purged with nitrogen and then heated in a sealed tube at 85 °C under nitrogen overnight. After cooling to room temperature, the reaction was diluted with water and extracted into DCM. The combined organics were washed with brine, dried over Na₂S0₄, filtered, and concentrated. The crude residue was purified by reverse phase chromatography (10-90% ACN/ H₂0 + formic acid). Isolation and lyophilization of the fractions gave N-[5-(2-amino-3-{3-[(4-methylpiperazin-1 -yl)methyl]phenyl}-4-oxo-3,4- dihydroquinazolin-6-yl)-2-methoxypyridin-3-yl]-2,4-difluorobenzene-1 -sulfonamide as a solid. (0.01 1 g, 9%). ¹H NMR (400 MHz, CHLOROFORM- /) δ ppm 8.21 (d, J=2.15 Hz, 1 H), 8.12 (d, J=2.15 Hz, 1 H), 7.97 (d, J=2.15 Hz, 1 H), 7.87 - 7.95 (m, 1 H), 7.76 (dd, J=8.59, 2.34 Hz, 1 H), 7.49 - 7.60 (m, 2 H), 7.45 (d, J=8.59 Hz, 1 H), 7.37 (s, 1 H), 7.28 (br. s., 1 H), 6.90 - 7.01 (m, 2 H), 4.86 (br. s., 1 H), 3.95 (s, 3 H), 3.64 (s, 2 H), 2.60 (br. s., 5 H), 2.38 (s, 3 H), 1.92 - 2.19 (m, 5 H); ES-LCMS: 648.3 (M+1 ).

Example 19

2,4-difluoro-N-(2-methoxy-5-{3-[3-(morpholin-4-yl)phenyl]-2,4-diox

tetrahydroquinazolin-6-yl}pyridin-3-yl)benzene-1-sulfonamide

Step A

{6-bromo-3-[3-(4-morpho 2-quin

[00167] A suspension of methyl 5-bromo-2-

{[(cyanoamino)(phenyloxy)methylidene]amino}benzoate (0.125 g, 0.334 mmol) in iPrOH (3.06 mL) was treated with [3-(4-morpholinyl)phenyl]amine (0.1 19 g, 0.668 mmol) and DMAP (0.016 g, 0. 34 mmol) and then was heated in a sealed tube to 85 °C overnight. After cooling to room temperature the solids were filtered. Thereafter, rinsing with Et₂0 yielded {6-bromo-3-[3-(4- morpholinyl)phenyl]-4-oxo-3,4-dihydro-2-quinazolinyl}cyanamide as a white solid. (0.073 g, 52%). ES-LCMS: 426.2, 428.2 (M+1 ).

Step B

6-bromo-3-[3-(4-morphoiinyl)phenyl]-2,4(1H,3H)-quinazolinedione

[00168] A suspension of {6-bromo-3-[3-(4-morpholinyl)phenyl]-4-oxo-3,4-dihydro-2- quinazonnyl}cyanamide (0.0734 g, 0.172 mmol) and 6 N HCI (1.349 mL, 8.09 mmol) in D SO (0.63 mL) was heated in a sealed tube at 100 °C for 2 hours. After cooling to room temperature, the solution was diluted with water (-10 mL) and treated with solid K₂C0₃ to bring the pH to basic. The suspension was diluted with EtOAc and the combined extracts were washed with water followed by a wash with brine. The extracts were then dried over Na₂S0₄, filtered, and concentrated to give 6-bromo-3-[3-(4-morpholinyl)phenyl]-2,4(1 H,3H)-quinazolinedione (0.053 g, 77%). ES-LCMS: 402.2, 404.2 (M+1 ).

Step C

2, 4-difluoro-N-(2-(methyloxy)-5-{3-[3-(4-morphotinyl)phenyl]-2, 4-dioxo-1, 2, 3, 4-tetrahydro-6- quinazolinyl}-3-pyridinyl)benzenesulfonamide

[00169] A solution of 6-bromo-3-[3-(4-morpholinyl)phenyl]-2,4(1 H,3H)-quinazolinedione (0.053 g, 0.132 mmol), 2,4-difluoro-N-[2-(methyloxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan- 2-yl)-3-pyridinyl]benzenesulfonamide (0.062 g, 0.145 mmol), K₂C0₃ (0.055 g, 0.396 mmol), and PdCI₂(dppf)-CH₂CI₂ adduct (10.79 mg, 0.013 mmol) in 1 ,4-dioxane (2.75 mL) and water (2.75 mL). Next, the solution was heated to 80 °C for 2 hours. The reaction was then cooled to room temperature and diluted with EtOAc. The combined organics were washed with brine, dried over Na₂S0₄, filtered, and concentrated. The crude residue was purified by reverse phase chromatography (10-90% ACN/ H₂0 + formic acid). Isolation and lyophilization of the fractions gave 2,4-difluoro-N-(2-(methyloxy)-5-{3-[3-(4-morpholinyl)phenyl]-2,4-dioxo-1 ,2,3,4-tetrahydro- 6-quinazolinyl}-3-pyridinyl)benzenesulfonamide as a white solid. H NMR (400 MHz,

CHLOROFORM-cf) δ ppm 9.39 (s, 1 H), 8.20 (d, J=1.37 Hz, 1 H), 8.09 (d, J=1.95 Hz, 1 H), 7.85 - 7.97 (m, 2 H), 7.70 (dd, J=8.29, 1.66 Hz, 1 H), 7.46 (t, J=8.29 Hz, 1 H), 7.29 (s, 1 H), 7.05 (d, J=8.39 Hz, 2 H), 6.90 - 7.02 (m, 2 H), 6.80 - 6.86 (m, 2 H), 3.96 (s, 3 H), 3.80 - 3.91 (m, 4 H), 3.18 - 3.27 (m, 4 H); ES-LCMS: 622.3 (M+1 ).

Example 20

N-{5-[2-amino-3-(2-chlorophenyl)-4-oxo-3,4-dihydroquinazolin-6-yl]-2-methoxyp

yl}-2,4-difluorobenzene-1-sulfonamide

Step A

3-(2-chlorophenyl)-6-io -2-thioxo-2,3-dihydro-4(1H)-quinazolinone

[00170] A solution of 2-amino-5-iodobenzoic acid (3.0 g, 1 1.41 mmol) and 1-chloro-2- isothiocyanatobenzene (1.787 ml_, 13.69 mmol) in EtOH (53.0 mL) and TEA (2.226 ml_, 15.97 mmol) was refluxed for 72 hours. After cooling to room temperature, the crude solid was filtered and then rinsed with EtOH to give 3-(2-chlorophenyl)-6-iodo-2-thioxo-2,3-dihydro-4(1 H)- quinazolinone as a white solid. (3.55 g, 75%). ES-LCMS: 415.0 (M+1 ). Step B

2-chloro-3-(2- -quinazolinone

[00171 ] A solution of 3-(2-chlorophenyl)-6-iodo-2-thioxo-2,3-dihydro-4(1 H)-quinazolinone (3.55 g, 8.56 mmol) in POCI₃ (19.15 mL, 205 mmol) and PCI₅ (2.85 g, 13.70 mmol) was heated to 1 15 °C and stirred for 4 hours. The reaction was then concentrated under reduced pressure and the residue was taken up in EtOAc, washed with water (2x) followed by a wash with brine. Next, the washed residue was dried over Na₂S0₄, filtered, and concentrated to give 2-chloro-3- (2-chlorophenyl)-6-iodo-4(3H)-quinazolinone (3.484 g, 98%). ES-LC S: 417.0 (M+1 ).

Step C

3-(2-chlorophenyl)-6-iodo- -({[4-(methyloxy)phenyl]methyl}am

[00172] A solution of 2-chloro-3-(2-chlorophenyl)-6-iodo-4(3H)-quinazolinone (3.484 g, 8.35 mmol), 4-methoxybenzylamine (1 .637 mL, 12.53 mmol), and DIEA (2.189 mL, 12.53 mmol) in DMF (37.9 mL) was heated to 80 °C for 3 hours. The reaction was diluted with EtOAc and washed with 5% LiCI (3x) followed by a wash with brine. The organic layer was then dried over MgS0₄, filtered, and concentrated to give 3-(2-chlorophenyl)-6-iodo-2-({[4- (methyloxy)phenyl]methyl}amino)-4(3H)-quinazolinone (4.31 g,100%). ES-LCMS: 518.2 (M+1 ).

Step D

2-amino-3-(2-chlorophenyi)-6-iodo-4(3H)-quinazolinone

[00173] A solution of 3-(2-chlorophenyl)-6-iodo-2-({[4-(methyloxy)phenyl]methyl}amino)- 4(3H)-quinazolinone (0.500 g, 0.966 mmol) in TFA (9.66 mL) was heated in a microwave at 140 °C for 15 minutes. The reaction was concentrated under reduced pressure and the residue was taken up in DCM and the pH was made basic by adding saturated NaHC0₃. The organics were washed with saturated NaHC0₃ (2x) followed by a wash with brine. The washed organics were then dried over Na₂S0₄, filtered, and concentrated. The crude residue was triturated with Et₂0 to give 2-amino-3-(2-chlorophenyl)-6-iodo-4(3H)-quinazolinone as a pale beige solid. (0.282 g, 73%), ES-LCMS: 398.1 (M+1 ).

Step E

N-[5-[2-amino-3-(2-chlorophenyl)-4-oxo-3,4-dihydro-6-quinazolinyl]-2-(m

2,4-difiuorobenzenesulfonamide

[00174] A solution of 2-amino-3-(2-chlorophenyl)-6-iodo-4(3H)-quinazolinone (0.080 g, 0.201 mmol), 2,4-difluoro-N-[2-(methyloxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-3- pyridinyl]benzenesulfonamide (0.094 g, 0.221 mmol), K₂C0₃ (0.083 g, 0.604 mmol), and PdCI₂(dppf)-CH₂CI₂ adduct (0.016 g, 0.020 mmol) was prepared in 1 ,4-dioxane (4.19 mL) and water (4.19 mL). The resulting solution was then was heated to 80 °C for 1 hour. Next, the reaction was cooled to room temperature and diluted with EtOAc. The combined organics were then washed with brine, dried over Na₂S0₄, filtered, and concentrated. The crude residue was purified by reverse phase chromatography (10-90% ACN/ H₂0 + formic acid). Isolation and lyophilization of the fractions gave N-[5-[2-amino-3-(2-chlorophenyl)-4-oxo-3,4-dihydro-6- quinazolinyl]-2-(methyloxy)-3-pyridinyl]-2,4-difluorobenzenesulfonamide as a white solid. H N R (400 MHz, DMSO-c/₆) δ ppm 10.30 (br. s., 1 H), 8.30 (s, 1 H), 8.01 (d, J=1.56 Hz, 1 H), 7.81 - 7.94 (m, 2 H), 7.69 - 7.81 (m, 2 H), 7.50 - 7.62 (m, 4 H), 7.34 (d, J=8.59 Hz, 1 H), 7.14 - 7.24 (m, 1 H), 6.62 (br. s., 2 H), 3.65 (s, 3 H); ES-LCMS: 570.3 (M+1 ).

Example 21

N-{5-[2-amino-3-(2-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-6-yl]-2-methoxy

3-yl}-2, 4-difluorobenzene- 1 -sulfonamide

Step A

6-iodo-3-[2-(methyloxy)phenyl]-2-thioxo-2,3-dihydro-4(1H)-quin

[00175] A solution of 2-amino-5-iodobenzoic acid (5.0 g, 19.01 mmol) and 1- isothiocyanato-2-(methyloxy)benzene (3.15 mL, 22.81 mmol) in EtOH (88 mL) and TEA (3.71 mL, 26.6 mmol) was refluxed for the weekend. After cooling to room temperature, the crude solid was filtered and then rinsed with EtOH to give 6-iodo-3-[2-(methyloxy)phenyl]-2-thioxo-2,3- dihydro-4(1 H)-quinazolinone as a white solid (7.26 g, 93%). ES-LCMS: 411.1 (M+1 ).

Step B

2-chloro-6-iodo-3 (3H)-quinazolinone

[00176] A solution of 6-iodo-3-[2-(methyloxy)phenyl]-2-thioxo-2,3-dihydro-4(1 H)- quinazolinone (7.26 g, 17.70 mmol) in POCI₃ (39.6 mL, 425 mmol) and PCI₅ (5.90 g, 28.3 mmol) was heated to 1 15 °C and stirred for 4 hours. The reaction was then concentrated under reduced pressure and the residue was taken up in EtOAc. The precipitate was washed with water (2x) followed by a wash with brine, and then filtered (2.62 g). The organics were dried over Na₂S0₄, filtered, and concentrated to give the crude product (3.28 g). The solids and the crude product were then combined to give 2-chloro-6-iodo-3-[2-(methyloxy)phenyl]-4(3H)- quinazolinone (5.9 g, 81 %). ES-LCMS: 413.1 (M+1 ).

Step C

6-iodo-3-[2-(methyloxy)pheny -2-({[4-(methyloxy)phenyl]methyl}am

[00177] A solution of 2-chloro-6-iodo-3-[2-(methyloxy)phenyl]-4(3H)-quinazolinone (5.9 g, 14.30 mmol), 4-methoxybenzylamine (2.80 mL, 21.45 mmol), and DIEA (3.75 mL, 21 .45 mmol) in DMF (64.9 mL) was heated to 80 °C for 3 hours. The reaction was diluted with EtOAc and washed with 5% LiCI (3x) followed by a wash with brine. The resulting solids were filtered (1 .507 g, desired product), and the organic layer were dried over MgS0₄, filtered, and concentrated. The crude residue and the solids were combined to give 6-iodo-3-[2- (methyloxy)phenyl]-2-({[4-(methyloxy)phenyl]methyl}amino)-4(3H)-quinazolinone. ES-LCMS: 515.0 (M+1).

Step D

2-amino-6-iodo-3-[2-(methyloxy)phenyl]-4(3H)-quinazoiinone

[00178] A solution of 6-iodo-3-[2-(methyloxy)phenyl]-2-({[4-

(methyloxy)phenyl]methyl}amino)-4(3H)-quinazolinone (0.500 g, 0.974 mmol) in TFA (9.74 mL) was heated in a microwave at 140 °C for 15 minutes. The reaction was concentrated under reduced pressure and the residue was taken up in DCM and the pH made basic by adding saturated NaHC0₃. The organics were then washed with saturated NaHC0₃ (2x) followed by a wash with brine. The washed organics were then dried over Na₂S0₄, filtered, and concentrated. The crude residue was triturated with Et₂0 to give 2-amino-6-iodo-3-[2-(methyloxy)phenylj- 4(3H)-quinazolinone as a pale beige solid. (0.344 g, 90%). ES-LCMS: 394.11 (M+1).

Step E

N-{5-[2-amino-3-(2-methoxyphenyi)-4-oxo-3,4-dihydroquinazoiin-6-yl]-2-m

2, 4-difluorobenzene- 1 -sulfonamide

[00179] A solution of 2-amino-6-iodo-3-[2-(methyloxy)phenyl]-4(3H)-quinazolinone (.080 g, 0.203 mmol), 2,4-difluoro-N-[2-(methyloxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-3- pyridinyl]benzenesulfonamide (0.095 g, 0.224 mmol), K₂C0₃ (0.084 g, 0.610 mmol), and PdCI₂(dppf)-CH₂CI₂ adduct (0.017 g, 0.020 mmol) wasa prepared in 1 ,4-dioxane (4.24 mL) and water (4.24 mL). Next, the prepared solution was heated to 80 °C for 1 hour. Thereafter, the reaction was cooled to room temperature and then diluted with EtOAc. The combined organics were then washed with brine, dried over Na₂S0₄, filtered, and concentrated. The crude residue was purified by reverse phase chromatography (10-90% ACN/ H₂0 + formic acid). Isolation and lyophilization of the fractions gave t N-{5-[2-amino-3-(2-methoxyphenyl)-4-oxo-3,4- dihydroquinazolin-6-yl]-2-methoxypyridin-3-yl}-2,4-difluorobenzene-1 -sulfonamide as a white solid (0.036 g, 31 %). H NMR (400 MHz, DMSO-d₆) δ ppm 10.17 - 10.51 (m, 1 H), 8.18 - 8.31 (m, 1 H), 7.98 (d, J=1.76 Hz, 1 H), 7.69 - 7.90 (m, 3 H), 7.45 - 7.60 (m, 2 H), 7.05 - 7.37 (m, 5 H), 6.38 (br. s., 2 H), 3.76 (s, 3 H), 3.66 (s, 3 H); ES-LCMS: 566.2 (M+1).

Example 22

N-{5-[2-amino-3-(2-fluorophenyl)-4-oxo-3,4-dihydroquinazolin-6-yl]-2-methoxypy

Step A

3-(2-fluorophenyl)-6-io -2-thioxo-2, 3-dihydro-4( 1 H)-quinazolinone

[00180] A solution of 2-amino-5-iodobenzoic acid (5.0 g, 19.01 mmol) and 1-fluoro-2- isothiocyanatobenzene (2.80 mL, 22.81 mmol) in EtOH (89 mL) and TEA (3.71 mL, 26.6 mmol) were refluxed for the weekend. After cooling to room temperature, the crude solid was filtered and then rinsed with EtOH to give 3-(2-fluorophenyl)-6-iodo-2-thioxo-2,3-dihydro-4(1 H)- quinazolinone as a white solid. (6.16 g, 81 %). ES-LCMS: 399.1 (M+1 ).

Step B

2-chioro-3-(2 -quinazolinone

[00181] A solution of 3-(2-fluorophenyl)-6-iodo-2-thioxo-2,3-dihydro-4(1 H)-quinazolinone (6.16 g, 15.47 mmol) in POCI₃ (34.6 mL, 371 mmol) and PCI₅ (5.15 g, 24.75 mmol) was heated to 1 15 °C and stirred for 4 hours. The reaction was then concentrated under reduced pressure and the residue was taken up in EtOAc, washed with water (2x) followed by a wash with brine. The washed residue was then dried over Na₂S0₄, filtered, and concentrated to give 2-chloro-3- (2-fluorophenyl)-6-iodo-4(3H)-quinazolinone (6.00 g, 97%). ES-LCMS: 401.1 (M+1 ). Step C

3-(2-fluorophenyl)-6-iodo-2-({[4-(methyloxy)phenyl]methyl}amino)-4(3H)

[00182] A solution of 2-chloro-3-(2-fluorophenyl)-6-iodo-4(3H)-quinazolinone (6.00 g, 14.98 mmol), 4-methoxybenzyl amine (2.94 mL, 22.47 mmol), and DIEA (3.92 mL, 22.47 mmol) in DMF (68.0 mL) was heated to 80 °C for 3 hours. The reaction was diluted with EtOAc and washed with 5% LiCI (3x), brine, dried over MgS0₄, filtered, and concentrated to give 3-(2- fluorophenyl)-6-iodo-2-({[4-(methyloxy)phenyl]methyl}amino)-4(3H)-quinazolinone

(7.38 g, 98%). ES-LCMS: 502.1 (M+1 ).

Step D

2-amino-3-(2- -quinazolinone

[00183] A solution of 3-(2-fluorophenyl)-6-iodo-2-({[4-(methyloxy)phenyl]methyl}amino)- 4(3H)-quinazolinone (0.500 g, 0.997 mmol) in TFA (9.97 mL) was heated in a microwave at 140 °C for 15 minutes. The reaction was concentrated under reduced pressure and the residue was taken up in DCM and the pH was made basic by addition of saturated NaHC0₃. The organics were washed with saturated NaHC0₃ (2x) followed by brine. The washed organics were then dried over Na₂S0₄, filtered, and concentrated. The crude residue was triturated with Et₂0 to give 2-amino-3-(2-fluorophenyl)-6-iodo-4(3H)-quinazolinone as a pale beige solid. (0.337 g, 89%). ES-LCMS: 382.1 (M+1).

Step E

N-{5-[2-amino-3-(2-fluorophenyl)-4-oxo-3 -dihydroquinazoli^

difluorobenzene-1 -sulfonamide

[00184] A solution of 2-amino-3-(2-fluorophenyl)-6-iodo-4(3H)-quinazolinone (0.080 g, 0.210 mmol), 2,4-difluoro-N-[2-(methyloxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-3- pyridinyl]benzenesulfonamide (0.098 g, 0.231 mmol), K₂C0₃ (0.087 g, 0.630 mmol), and PdCI₂(dppf)-CH₂CI₂ adduct (0.017 g, 0.021 mmol) was prepared in 1 ,4-dioxane (4.37 mL) and water (4.37 mL). The resulting solution was then heated to 80 °C for 1 hour. The reaction was cooled to room temperature and diluted with EtOAc. The combined organics were washed with brine, dried over Na₂S0₄, filtered, and concentrated. The crude residue was purified by reverse phase chromatography (10-90% ACN/ H₂0 + formic acid). Isolation and lyophilization of the fractions gave N-{5-[2-amino-3-(2-fluorophenyl)-4-oxo-3,4-dihydroquinazolin-6-yl]-2- methoxypyridin-3-yl}-2,4-difluorobenzene-1 -sulfonamide as a white solid. (0.065 g, 56%). ¹H NMR (400 MHz, DMSO-af₆) δ ppm 8.20 (br. s., 1 H), 8.00 (br. s., 1 H), 7.87 (d, J=8.21 Hz, 1 H), 7.72 - 7.82 (m, 2 H), 7.44 - 7.64 (m, 5 H), 7.37 - 7.44 (m, 1 H), 7.34 (d, J=8.60 Hz, 1 H), 7.13 - 7.22 (m, 1 H), 6.67 (br. s., 2 H), 3.67 (s, 3 H); ES-LCMS: 554.2 (M+1 ).

Example 23

N-(5-{2-amino-4-oxo-3-[4-(piperidin-1-ylmethyl)phenyl]-3,4-dihydroqu

methoxypyridin-3-yl)-2,4-difluorobenzene-1-sulfonamide

Step A

3-(4-bromophenyi)-6-iodo- -({[4-(methyloxy)phenyl]methyl}amino

[00185] A solution of 3-(4-bromophenyl)-2-chloro-6-iodo-4(3H)-quinazolinone (7.37 g, 15.97 mmol), 4-methoxybenzyl amine (3.1 1 mL, 23.96 mmol), and DIEA (4.18 mL, 23.96 mmol) in DMF (72.6 mL) was heated to 80 °C for 90 minutes. The reaction was diluted with EtOAc and washed with 5% LiCI (3x) followed by a wash with brine. Next, the washed reaction products were then dried over MgS0₄, filtered, and concentrated. The crude residue was purified by silica gel chromatography (10-30% EtOAc/hexanes) to give 3-(4-bromophenyl)-6-iodo-2-({[4- (methyloxy)phenyl]methyl}amino)-4(3H)-quinazolinone (6.87 g, 77%). ES-LCMS: 562.0, 564.1 (M+1 ).

Step B

2-amino-3- -quinazolinone

[00186] A solution of 3-(4-bromophenyl)-6-iodo-2-({[4-(methyloxy)phenyl]methyl}amino)- 4(3H)-quinazolinone (6.87 g, 12.22 mmol) in TFA (77 mL) was heated to reflux for 72 hours. The reaction was concentrated under reduced pressure and the residue was taken up in DCM and the pH was made basic by addition of saturated NaHC0₃. The organics were then washed with saturated NaHC0₃ (2x) followed by a wash with brine. Next, the white solids that were present in the organics were filtered (solids-4.45 g). Next, the organics were washed with brine, dried over Na₂S0₄, filtered, and concentrated. The crude residue was triturated with Et₂0 and filtered (1.3 g) and was combined with the solids to give 2-amino-3-(4-bromophenyl)-6-iodo- 4(3H)-quinazolinone as a pale grey solid (5.75 g, 100%). ES-LCMS: 442.0, 444.0 (M+1 ).

Step C

N-[5-[2-amino-3-(4-bromophenyl)-4-oxo-3,4-dihydro-6-quinazolin 2,4-difluorobenzenesulfonamide

[00187] A solution of 2-amino-3-(4-bromophenyl)-6-iodo-4(3H)-quinazolinone (1.0 g, 2.262 mmol), 2,4-difluoro-N-[2-(methyloxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-3- pyridinyl]benzenesulfonamide (0.964 g, 2.262 mmol), K₂C0₃ (0.938 g, 6.79 mmol), and

PdCI₂(dppf)-CH₂Cl₂ adduct (0.185 g, 0.226 mmol) was prepared in 1 ,4-dioxane (47.1 ml.) and water (47.1 ml_). The resulting solution was then stirred at room temperature overnight. The reaction was cooled to room temperature and diluted with EtOAc. The combined organics were washed with brine, dried over Na₂S0₄, filtered, and concentrated. The crude residue was taken up in DCM, the solids were filtered and the residue was purified by silica gel chromatography (1 % MeOH/DCM) to give N-[5-[2-amino-3-(4-bromophenyl)-4-oxo-3,4-dihydro-6-quinazolinyl]-2- (methyloxy)-3-pyridinyl]-2,4-difluorobenzenesulfonamide (0.972 g, 70%). ES-LCMS: 614.1 , 616.1 (M+1 ).

Step D

N-[5-{2-amino-4-oxo-3-[4-(1^iperidinylmethyl)phenyl]-3,4-dihydro-6-^

3-pyridinyl]-2,4-difluorobenzenesulfonamide

[00188] A solution of N-[5-[2-amino-3-(4-bromophenyl)-4-oxo-3,4-dihydro-6-quinazolinyl]- 2-(methyloxy)-3-pyridinyl]-2,4-difluorobenzenesulfonamide (0.243 g, 0.395 mmol), potassium (piperidin-l-yl)methyltriflouroborate (0.090 g, 0.435 mmol), XPhos (0.024 mmol), PdOAc₂ (2.66 mg, 0.012 mmol), and Cs₂C0₃ (0.387 g, 1 .186 mmol) in THF (1.438 ml_) and water (0.144 ml_) was purged with nitrogen and then heated in a sealed tube at 95 °C under nitrogen overnight. After cooling to room temperature, the reaction was diluted with water and extracted into EtOAc. The combined organics were washed with brine, dried over Na₂S0₄, filtered, and concentrated. The crude residue was purified by reverse phase chromatography (10-90% ACN/ H₂0 + formic acid). Isolation and lyophilization of the fractions gave N-[5-{2-amino-4-oxo-3-[4-(1- piperidinylmethyl)phenyl]-3,4-dihydro-6-quinazolinyl}-2-(methyloxy)-3-pyridinyl]-2,4- difluorobenzenesulfonamide as a solid. H NMR (400 MHz, DMSO-af₆) δ ppm 8.16 (br. s., 1 H), 7.94 - 8.00 (m, 1 H), 7.82 - 7.88 (m, 2 H), 7.71 - 7.82 (m, 2 H), 7.45 - 7.53 (m, 3 H), 7.28 - 7.35 (m, 3 H), 7.12 - 7.22 (m, 1 H), 6.40 (br. s., 2 H), 3.67 (s, 3 H), 3.57 (br. s., 2 H), 2.44 (br. s., 4 H), 1.50 - 1.59 (m, 4 H), 1.43 (br. s., 2 H); ES-LCMS: 633.6 (M+1 ).

Example 24

N-(5-{2-amino-3-[4-(morpholin-4-ylmethyl)phenyl]-4-oxo-3,4-dihydroqui

me thoxypyridin-3-yl)-2, 4-difluorobenzene- 1 -sulfonamide

N-(5-{2-amino-3-[4-(morpholin-4-ylmethyl)phenyl]-4-oxo-3,4-dihydroqu

methoxypyridin-3-yl)-2,4-difluorobenzene- 1 -sulfonamide

[00189] A solution of N-[5-[2-amino-3-(4-bromophenyl)-4-oxo-3,4-dihydro-6-quinazolinyl]- 2-(methyloxy)-3-pyridinyl]-2,4-difluorobenzenesulfonamide (0.243 g, 0.395 mmol), potassium (morpholin-4yl)methyltrifluoroborate (0.091 g, 0.435 mmol), XPhos (0.024 mmol), PdOAc₂ (2.66 mg, 0.012 mmol), and Cs₂C0₃ (0.387 g, 1 .186 mmol) was prepared in THF (1.438 mL) and water (0.144 mL). The resulting solution was then purged with nitrogen and heated in a sealed tube at 95 °C under nitrogen overnight. After cooling to room temperature, the reaction was diluted with water and extracted into EtOAc. The combined organics were washed with brine, dried over Na₂S0₄, filtered, and concentrated. The crude residue was purified by reverse phase chromatography (10-90% ACN/ H₂0 + formic acid). Isolation and lyophilization of the fractions gave a solid which was triturated to give N-(5-{2-amino-3-[4-(morpholin-4-ylmethyl)phenyl]-4- oxo-3,4-dihydroquinazolin-6-yl}-2-methoxypyridin-3-yl)-2,4-difluorobenzene-1-sulfonamide. ¹H NMR (400 MHz, DMSO-cf₆) δ ppm 8.16 (br. s., 1 H), 7.96 - 8.00 (m, 1 H), 7.82 - 7.87 (m, 1 H), 7.72 - 7.81 (m, 3 H), 7.49 (d, J=8.19 Hz, 3 H), 7.31 (dd, J=8.49, 2.44 Hz, 3 H), 7.13 - 7.21 (m, 1 H), 6.40 (br. s., 2 H), 3.67 (s, 3 H), 3.61 (t, J=4.29 Hz, 4 H), 3.55 (s, 2 H), 2.43 (br. s., 4 H); ES- LCMS: 635.4 (M+1 ).

Example 25

N-{5-[2-amino-3-(4-cyanophenyl)-4-oxo-3,4-dihydroquinazolin-6-yl]-2-metho

yl}-2,4-difluorobenzene-1-sulfonamide

N-[5-[2-amino-3-(4-cyanophenyl)-4-oxo-3 -dihydro-6-quinazolinyl]-2-(m

2,4-difiuorobenzenesuifonamide

[00190] A solution of N-[5-[2-amino-3-(4-bromophenyl)-4-oxo-3,4-dihydro-6-quinazolinyl]- 2-(methyloxy)-3-pyridinyl]-2,4-difluorobenzenesulfonamide (0.255 g, 0.415 mmol) in DMF (3.35 mL) was treated by the addition of tetrakis triphenylphospine palladium(O) (0.096 g, 0.083 mmol) and ZnCN₂ (0.058 g, 0.498 mmol) and purged with nitrogen and heated to 90 °C for 2 hours. The reaction was cooled to room temperature and diluted with EtOAc and water. The combined organics were washed with LiCI (3x) followed by saturated NaHC0₃ and then brine. Next, the washed organics were dried over MgS0₄, filtered, and concentrated. The crude residue was purified by reverse phase chromatography {10-90% ACN/ H₂0 + formic acid). Isolation and lyophilization of the fractions gave N-[5-[2-amino-3-(4-cyanophenyl)-4-oxo-3,4-dihydro-6- quinazolinyl]-2-(methyloxy)-3-pyridinyl]-2,4-difluorobenzenesulfonamide as a solid. NMR (400 MHz, DMSO-cf₆) δ ppm 10.31 (br. s., 1 H), 8.30 (br. s., 1 H), 8.07 (d, J=8.59 Hz, 2 H), 7.99 - 8.03 (m, 1 H), 7.87 - 7.93 (m, 1 H), 7.83 (br. s., 1 H), 7.71 - 7.79 (m, 1 H), 7.65 (d, J=8.39 Hz, 2 H), 7.51 - 7.60 (m, 1 H), 7.31 - 7.37 (m, 1 H), 7.16 - 7.23 (m, 1 H), 6.57 (br. s., 2 H), 3.65 (s, 3 H); ES-LCMS: 561.5 (M+1 ).

Example 26

N-[5-(2-amino-3-{4-[(4-methylpiperazin-1-yl)methyl]phenyl}-4-oxo-3,4-dih

6-yl)-2-methoxypyridin-3-yl]-2,4-difluorobenzene-1-sulfonamide

N-[5-(2-amino-3-{4-[(4-methyl-1-piperazinyl)methyl]phenyl}-4-oxo-3,4

(methyloxy)-3-pyridinyl]-2,4-difluorobenzenesulfonamide

[00191] A solution of N-[5-[2-amino-3-(4-bromophenyl)-4-oxo-3,4-dihydro-6-quinazolinyl]- 2-(methyloxy)-3-pyridinyl]-2,4-difluorobenzenesulfonamide (0.243 g, 0.395 mmol), potassium 1- methyl-4-trifluoroboratomethylpiperazine (0.096 g, 0.435 mmol), XPhos (0.011 g, 0.024 mmol), PdOAc₂ (2.66 mg, 0.012 mmol), and Cs₂C0₃ (0.387 g, 1.186 mmol) in THF (1.438 mL) and water (0.144 mL) was purged with nitrogen and then heated in a sealed tube at 95 °C under nitrogen overnight then stirred at room temperature for 72 hours. The reaction was diluted with water and extracted into DCM. The combined organics were washed with brine, dried over Na₂S0₄, filtered, and concentrated. The residue was purified by reverse phase chromatography (10-90% ACN/ H₂0 + formic acid). Isolation and lyophilization gave N-[5-(2-amino-3-{4-[(4- methyl-1-piperazinyl)methyl]phenyl}-4-oxo-3,4-dihydro-6-quinazolinyl)-2-(methyloxy)-3- pyridinyl]-2,4-difluorobenzenesulfonamide as a solid. (0.010 g, 4%). ¹H NMR (400 MHz, DMSO- cfe) δ ppm 8.19 (br. s., 1 H), 7.97 - 8.01 (m, 1 H), 7.82 - 7.88 (m, 1 H), 7.73 - 7.80 (m, 2 H), 7.45 - 7.55 (m, 3 H), 7.28 - 7.35 (m, 3 H), 7.14 - 7.21 (m, 1 H), 6.35 - 6.58 (m, 2 H), 3.67 (s, 3 H), 3.53 - 3.59 (m, 2 H), 2.66 - 2.68 (m, 1 H), 2.53 - 2.56 (m, 4 H), 2.43 - 2.47 (m, 2 H), 2.32 - 2.34 (m, 1 H), 2.26 (s, 3 H) (one exchangeable proton not evident); ES-LCMS: 648.1 (M+1 ).

Example 27

N-(5-{2-amino-4-oxo-3-[4-(pyrrolidin-1-ylmethyl)phenyl]-3,4-dihydroqui

me thoxypyridin-3-yl)-2, 4-difluorobenzene- 1 -sulfonamide

N-[5-{2-amino-4-oxo-3-[4-( 1 -pyrrolidinylmethyl)phenyl]-3, 4-dihydro-6-quinazolinyl}-2- (methyloxy)-3-pyridinyl]-2,4-diftuorobenzenesulfonamide

[00192] A solution of N-[5-[2-amino-3-(4-bromophenyl)-4-oxo-3,4-dihydro-6-quinazolinyl]- 2-(methyloxy)-3-pyridinyl]-2,4-difluorobenzenesulfonamide (0.243 g, 0.395 mmol), potassium 1- trifluoroboratomethylpyrrolidine (0.084 g, 0.435 mmol), XPhos (0.024 mmol), PdOAc₂ (2.66 mg, 0.012 mmol), and Cs₂C0₃ (0.387 g, 1.186 mmol) in THF (1.438 ml.) and water (0.144 mL) was purged with nitrogen and then heated in a sealed tube at 95 °C under nitrogen overnight. After cooling to room temperature, the reaction was diluted with water and extracted into DCM. The combined organics were washed with brine, dried over Na₂S0₄, filtered, and concentrated. The crude residue was purified by reverse phase chromatography (10-90% ACN/ H₂0 + formic acid). Isolation and lyophilization gave N-[5-{2-amino-4-oxo-3-[4-(1-pyrrolidinylmethyl)phenyl]- 3,4-dihydro-6-quinazolinyl}-2-(methyloxy)-3-pyridinyl]-2,4-difluorobenzenesulfonamide as a solid (0.007 g, 3%). H NMR (400 MHz, DMSO-cf₆) δ ppm 8.09 - 8.21 (m, 1 H), 7.96 - 8.00 (m, 1 H), 7.81 - 7.91 (m, 2 H), 7.71 - 7.81 (m, 2 H), 7.44 - 7.55 (m, 3 H), 7.27 - 7.36 (m, 3 H), 7.12 - 7.21 (m, 1 H), 6.55 (s, 1H), 6.33 - 6.46 (m, 1 H), 3.72 - 3.80 (m, 2 H), 3.64 - 3.69 (m, 3 H), 2.56 - 2.64 (m, 4 H), 1.71 - 1.80 (m, 4 H); ES-LC S: 619.0 (M+1).

Example 28

N-(5-{2-amino-4-oxo-3-[2-(trifluoromethyl)phenyl]-3,4-dihydroquina

methoxypyridin-3-yl)-2,4-difluorobenzene-1-sulfonamide

Step A

6-iodo-2-thioxo-3-[2-( triflu -4( 1H)-quinazolinone

[00193] A solution of 2-amino-5-iodobenzoic acid (3.0 g, 1 1.41 mmol) and 2- (trifluoromethyl)phenyl isothiocyanate (2.066 mL, 13.69 mmol) in EtOH (52.7 mL) and TEA (2.226 mL, 15.97 mmol) was refluxed overnight. After cooling to room temperature, the crude solid was filtered, rinsing with EtOH to give 6-iodo-2-thioxo-3-[2-(trifluoromethyl)phenyl]-2,3- dihydro-4(1 H)-quinazolinone as a white solid. (2.62 g, 51 %). ES-LCMS: 499.0 (M+1 ).

Step B

2-chloro-6-iodo-3-[2- (3H)-quinazolinone

[00194] A solution of 6-iodo-2-thioxo-3-[2-(trifluoromethyl)phenyl]-2,3-dihydro-4(1 H)- quinazolinone (2.62 g, 5.85 mmol) in POCI₃ (13.08 mL, 140 mmol) and PCI₅ (1.948 g, 9.35 mmol) was heated to 1 15 °C and stirred for 7 hours. The reaction was concentrated under reduced pressure and the residue was taken up in EtOAc, washed with water (2x), brine, dried over Na₂S0₄, filtered, and concentrated to give 2-chloro-6-iodo-3-[2-(trifluoromethyl)phenyl]- 4(3H)-quinazolinone (2.59 g, 98%). ES-LCMS: 450.8 (M+1 ).

Step C

6-iodo-2-({[4-(methyloxy)ph

[00195] A solution of 2-chloro-6-iodo-3-[2-(trifluoromethyl)phenyl]-4(3H)-quinazolinone (2.585 g, 5.74 mmol), 4-methoxybenzylamine (1.124 mL, 8.61 mmol), and DIEA (1 .503 mL, 8.61 mmol) in DMF (26.1 mL) was heated to 80 °C overnight. The reaction was diluted with EtOAc and washed with 5% LiCI (3x), brine, dried over MgS0₄, filtered, and concentrated to give 6- iodo-2-({[4-(methyloxy)phenyl]methyl}amino)-3-[2-(trifluoromethyl)phenyl3-4(3H)-quinazolinone (3.33 g, 100%). ES-LCMS: 552.1 (M+1 ).

Step D

2-amino-6-iodo-3-[2- 4(3H)-quinazolinone

[00196] A solution of 6-iodo-2-({[4-(methyloxy)phenyl]methyl}amino)-3-[2- (trifluoromethyl)phenyl]-4(3H)-quinazolinone (0.800 g, 1.451 mmol) in TFA (9.67 mL) was heated in a microwave at 140 °C for 15 minutes. The reaction was concentrated under reduced pressure and the residue was taken up in DCM and the pH was raised with saturated NaHC0₃. The organics were then washed with saturated NaHC0₃ (2x), brine, dried over Na₂S0₄, filtered, and concentrated to give 2-amino-6-iodo-3-[2-(trifluoromethyl)phenyl]-4(3H)-quinazolinone (0.646 g, 100%). ES-LCMS: 432.0 (M+1 ).

Step E N-[5-{2-amino-4-oxo-3-[2-(trifluoromethyl)phenyl]-3,4-dihydro-6-quinazoH

pyridinyi]-2,4-difluorobenzenesulfonamide

[00197] A solution of 2-amino-6-iodo-3-[2-(trifluoromethyl)phenyl]-4(3H)-quinazolinone (0.100 g, 0.232 mmol) and 2,4-difluoro-N-[2-(methyloxy)-5-(4_>4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)-3-pyridinyl]benzenesulfonamide (0.109 g, 0.255 mmol) was treated with K₂C0₃ (0.096 g, 0.696 mmol) and PdCI₂(dppf)-CH₂CI₂ adduct (0.019 g, 0.023 mmol) in 1 ,4- dioxane (4.83 mL) and water (4.83 mL) was heated to 80 °C for 4 hours. The reaction was treated by DMF (4 mL) and Cs₂C0₃ (0.227 g, 0.696 mmol) and PdCI₂(dppf)-CH₂CI₂ adduct (0.019 g, 0.023 mmol) and continued to heat overnight. The reaction was cooled to room temperature and diluted with EtOAc. The combined organics were washed with 5% LiCI (3x), brine, dried over Na₂S0₄, filtered, and concentrated. The crude residue was purified by reverse phase chromatography (10-90% ACN/ H₂0 + formic acid). Isolation and lyophilization of the fractions gave a solid which was triturated with Et₂0 to give N-[5-{2-amino-4-oxo-3-[2- (trifluoromethyl)phenyl]-3,4-dihydro-6-quinazolinyl}-2-(methyloxy)-3-pyridinyl]-2,4- difluorobenzenesulfonamide (0.037 g, 26%). H NMR (400 MHz, DMSO-d₆) δ ppm 10.30 (br. s., 1 H), 8.32 (br. s., 1 H), 8.00 (d, J=2.15 Hz, 1 H), 7.96 (d, J=7.80 Hz, 1 H), 7.83 - 7.93 (m, 3 H), 7.70 - 7.81 (m, 2 H), 7.63 (d, J=7.80 Hz, 1 H), 7.52 - 7.60 (m, 1 H), 7.34 (d, J=8.59 Hz, 1 H), 7. 5 - 7.23 (m, 1 H), 6.64 (br. s., 2 H), 3.64 (s, 3 H); ES-LCMS: 604.1 ( +1 ).

Example 29

N-(5-{2-amino-4-oxo-3-[2-(trifluoromethoxy)phenyl]-3,4-dihydroqum^

methoxypyridin-3-yl)-2,4-difluorobenzene-1-sulfonamide

Step A

6-iodo-2-thioxo-3-{2-[(trifluoro -dihydro-4(1H

[00198] A solution of 2-amino-5-iodobenzoic acid (3.0 g, 1 1.41 mmol) and 1- isothiocyanato-2-[(trifluoromethyl)oxy]benzene (2.216 mL, 13.69 mmol) in EtOH (52.6 mL) and TEA (2.226 mL, 15.97 mmol) was refluxed overnight. After cooling to room temperature, the crude solid was filtered, rinsing with EtOH to give 6-iodo-2-thioxo-3-{2- [(trifluoromethyl)oxy]phenyl}-2,3-dihydro-4(1 H)-quinazolinone as a white solid (3.14 g, 59%). ES-LCMS: 465.1 (M+1 ).

Step B

2-chloro-6-iodo-3-{2-[(trifluoromethyl)oxy]phenyl}-4(3H)-quinazolinone

[00199] A solution of 6-iodo-2-thioxo-3-{2-[(trifluoromethyl)oxy]phenyl}-2,3-dihydro-4(1H)- quinazolinone (3.14 g, 6.76 mmol) in POCI₃ (15.13 mL, 162 mmol) and PCI₅ (2.254 g, 10.82 mmol) was heated to 115 °C and stirred for 7 hours. The reaction was then concentrated under reduced pressure and the residue was taken up in EtOAc, washed with water (2x), brine, dried over Na₂S0₄, filtered, and concentrated to give 2-chloro-6-iodo-3-{2- [(trifluoromethyl)oxy]phenyl}-4(3H)-quinazolinone (2.69 g, 85%). ES-LCMS: 466.8 (M+1 ). Step C

6-iodo-2-({[4-(methyloxy)phenyl]methyi}amino)-3-{2-[(trifluorom

quinazolinone

[00200] A solution of 2-chloro-6-iodo-3-{2-[(trifluoromethyl)oxy]phenyl}-4(3H)- quinazolinone (2.689 g, 5.76 mmol), 4-methoxybenzylamine (1.129 mL, 8.64 mmol), and DIEA (1.510 mL, 8.64 mmol) in DMF (26.2 mL) was heated to 80 °C overnight. The reaction was diluted with EtOAc and washed with 5% LiCI (3x), brine, dried over MgS0₄, filtered, and concentrated to give 6-iodo-2-({[4-(methyloxy)phenyl]methyl}amino)-3-{2- [(trifluoromethyl)oxy]phenyl}-4(3H)-quinazolinone (3.55 g, 100%). ES-LCMS: 568.1 (M+1).

Step D

2-amino-6-iodo-3-{2-[(tri -4(3H)-quinazolinone

[00201 ] A solution of 6-iodo-2-({[4-(methyloxy)phenyl]methyl}amino)-3-{2- [(trifluoromethyl)oxy]phenyl}-4(3H)-quinazolinone (0.800 g, 1.410 mmol) in TFA (9.40 mL) was heated in a microwave at 140 °C for 15 minutes. The reaction was concentrated under reduced pressure and the residue was taken up in DCM and basified with saturated NaHC0₃. The organics were washed with saturated NaHC0₃ (2x), brine, dried over Na₂S0₄, filtered, and concentrated to give 2-amino-6-iodo-3-{2-[(trifluoromethyl)oxy]phenyl}-4(3H)-quinazolinone (0.562 g, 89%). ES-LCMS: 448.0 (M+1 ).

Step E

N-[5-(2-amino-4-oxo-3-{2-[(trifiuoromethyl)oxy]phenyl}-3,4-dihydro-6-qu

(methyloxy)-3-pyridinyl]-2,4-difluorobenzenesulfonamide

[00202] A solution of 2-amino-6-iodo-3-{2-[(trifluoromethyl)oxy]phenyl}-4(3H)- quinazolinone (0.100 g, 0.224 mmol) and 2,4-difluoro-N-[2-(methyloxy)-5-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)-3-pyridinyl]benzenesulfonamide (0.105 g, 0.246 mmol) was treated with K₂C0₃ (0.093 g, 0.671 mmol) and PdCI₂(dppf)-CH₂CI₂ adduct (0.018 g, 0.022 mmol) in 1 ,4- dioxane (4.66 mL) and water (4.66 mL) was heated to 80 °C for 90 minutes. The reaction was cooled to room temperature and diluted with EtOAc. The combined organics were washed with brine, dried over Na₂S0₄, filtered, and concentrated. The crude residue was purified by reverse phase chromatography (10-90% ACN/ H₂0 + formic acid). Isolation and lyophilization of the fractions gave a solid which was triturated with Et₂0 to give N-[5-(2-amino-4-oxo-3-{2- [(trifluoromethyl)oxy]phenyl}-3,4-dihydro-6-quinazolinyl)-2-(methyloxy)-3-pyridinyl]-2,4- difluorobenzenesulfonamide (0.064 g, 46%). H NMR (400 MHz, DMSO-af₆) δ ppm 10.35 (br. s., 1 H), 8.25 (br. s., 1 H), 8.00 (br. s., 1 H), 7.46 - 7.91 (m, 8 H), 7.30 - 7.38 (m, 1 H), 7.13 - 7.21 (m, 1 H), 6.69 (br. s., 2 H), 3.66 (s, 3 H); ES-LCMS: 620.1 (M+1 ).

Example 30

N-{5-[2-amino-3-(3-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-6-yl]-2-methoxypyri^

3-yl}-2,4-difluorobenzene- 1 -sulfopnamide

Step A

{6-bromo-3-[3-(methyloxy)phenyl]-4-oxo-3,4-dihydro-2-quinazolinyl}cyan

[00203] A suspension of methyl 5-bromo-2-

{[(cyanoamino)(phenyloxy)methylidene]amino}benzoate (0.200 g, 0.534 mmol) in iPrOH (2.502 mL) was treated with 3-(methyloxy)aniline(0.063 mL, 0.561 mmol) and DMAP (0.026 g, 0.214 mmol) and was heated in a sealed tube to 85 °C for 2 hours. The reaction was then treated with 3-(methyloxy)aniline (0.063 mL, 0.561 mmol) and was stirred at 85 °C overnight. The reaction was cooled to room temperature and then was diluted with 1 : 1 Et₂0 /hexanes and the solids were filtered, rinsing with Et₂0 to give {6-bromo-3-[3-(methyloxy)phenyl]-4-oxo-3,4-dihydro-2- quinazolinyljcyanamide (0.080 g, 40.3%). ES-LCMS: 371 .0, 372.9 (M+1 ).

Step B

2-amino-6-iodo-3-[ -(methyloxy)phenyl]-4(3H)-quinazolinone

[00204] A solution of {6-bromo-3-[3-(methyloxy)phenyl]-4-oxo-3 ,4-dihydro-2- quinazolinyljcyanamide (0.107 g, 0.288 mmol) was treated by the addition of 4N HCI in dioxanes (3.87 mL) and water (1 .179 mL) and concentrated HCI (100 \iL). The reaction was then heated to 90 °C with an open air reflux condenser overnight. The reaction was

concentrated under reduced pressure and the residue was triturated with Et₂0 to 2-amino-6- iodo-3-[3-(methyloxy)phenyl]-4(3H)-quinazolinone (0.063 g, 83%). ES-LCMS: 346.0, 384.1 (M+1 ). Step C

N-{5-[2-amino-3-(3-methoxyphenyl)-4-oxo-3,4-dihydroquinazo

2, 4-difiuorobenzene-1 -sulfonamide

[00205] A solution of 2-amino-6-iodo-3-[3-(methyloxy)phenyl]-4(3H)-quinazolinone (0.063 g, 0.160 mmol), 2,4-difluoro-N-[2-(methyloxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-3- pyridinyl]benzenesulfonamide (0.075 g, 0.176 mmol), K₂C0₃ (0.066 g, 0.481 mmol), and PdCI₂(dppf)-CH₂CI₂ adduct (0.013 g, 0.016 mmol) in 1 ,4-dioxane (3.34 mL) and water (3.34 mL) was heated to 80 °C for 1 hour. The reaction was cooled to room temperature and diluted with EtOAc. The combined organics were washed with brine, dried over Na₂S0₄, filtered, and concentrated. The crude residue was purified by reverse phase chromatography (10-90% ACN/ H₂0 + formic acid). The ACN was removed under reduced pressure and the residual aqueous was basified with saturated NaHC0₃ and extracted with DCM. The combined organics were washed with brine, dried over Na₂S0₄, filtered, and concentrated. The residue was purified by silica gel chromatography (1-3% MeOH/DCM) to give N-{5-[2-amino-3-(3-methoxyphenyl)-4- oxo-3,4-dihydroquinazolin-6-yl]-2-methoxypyridin-3-yl}-2,4-difluorobenzene-1 -sulfonamide. ES- LC S: 566.1 (M+1).

Example 31

N-{5-[2-amino-3-(4-fluorophenyl)-4-oxo-3,4-dihydroquinazolin-6-yl]-2-meth

yl}-2,4-difluorobenzene-1-sulfonamide

Step A

[6-bromo-3-(4-fiuoroph quinazolinyl]cyanamide

[00206] A suspension of methyl 5-bromo-2-

{[(cyanoamino)(phenyloxy)methylidene]amino}benzoate (0.200 g, 0.534 mmol) in iPrOH (2.502 mL) was treated with 4-fluoroaniline (0.054 mL, 0.561 mmol) and DMAP (0.026 g, 0.214 mmol) and was heated in a sealed tube to 85 °C for 2 hours. The reaction was treated by another equivalent of 4-fluoroaniline (0.054 mL, 0.561 mmol). The reaction was stirred at 85 °C overnight. The reaction was cooled to room temperature and was diluted with 1 :1 Et₂0 /hexanes, the solids were filtered, rinsing with Et₂0 to give [6-bromo-3-(4-fluorophenyl)-4-oxo- 3,4-dihydro-2-quinazolinyl]cyanamide (0.106 g, 55%). ES-LCMS: 358.9, 360.9 (M+1 ).

Step B

2-amino-3-(4- -quinazolinone

[00207] [6-bromo-3-(4-fluorophenyl)-4-oxo-3,4-dihydro-2-quinazolinyl]cyanamide (0.107 g, 0.298 mmol) in 4N HCI in dioxanes (5.28 mL) was treated with water (1.61 mL) and concentrated HCI (100 μΙ_) and heated to 90 °C with an open air reflux condenser overnight. The reaction was concentrated under reduced pressure and the residue was triturated with Et₂0 to give 2-amino-3-(4-fluorophenyl)-6-iodo-4(3H)-quinazolinone (0.099 g, 99%). ES-LCMS:

334.0, 336.0 (M+1 ).

Step C

N-[5-[2-amino-3-(4-fluorophenyl)-4-oxo-3,4-dihydro-6-quinazolinyl]-2-(m

2,4-difluorobenzenesuifonamide

[00208] A solution of 2-amino-3-(4-fluorophenyl)-6-iodo-4(3H)-quinazolinone (0.099 g, 0.260 mmol), 2,4-difluoro-N-[2-(methyloxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-3- pyridinyrjbenzenesulfonamide (0.122 g, 0.286 mmol), K₂C0₃ (0.108 g, 0.779 mmol), and PdCI₂(dppf)-CH₂CI₂ adduct (0.021 g, 0.026 mmol) in 1 ,4-dioxane (5.41 mL) and water (5.41 mL) was heated to 80 °C for 1 hour. The reaction was cooled to room temperature and diluted with EtOAc. The combined organics were washed with brine, dried over Na₂S0₄, filtered, and concentrated. The crude residue was purified by reverse phase chromatography (10-90% ACN/ H₂0 + formic acid). The ACN was removed under reduced pressure and the residual aqueous was basified with saturated NaHC₃0 and extracted with DCM. The combined organics were washed with brine, dried over Na₂S0₄, filtered, and concentrated. The residue was purified by silica gel chromatography (1 -3% MeOH/DCM) to give N-[5-[2-amino-3-(4-fluorophenyl)-4-oxo- 3,4-dihydro-6-quinazolinyl]-2-(methyloxy)-3-pyridinyl]-2,4-difluorobenzenesulfonamide (0.019 g, 13%). H NMR (400 MHz, DMSO-d₆) δ ppm 10.31 (br. s., 1 H), 8.33 (br. s., 1 H), 8.01 (br. s., 1 H), 7.81 - 7.95 (m, 2 H), 7.69 - 7.81 (m, 1 H), 7.54 - 7.64 (m, 1 H), 7.38 - 7.47 (m, 4 H), 7.32 - 7.34 (m, 1 H), 7.15 - 7.25 (m, 1 H), 6.54 (br. s., 2 H), 3.64 (br. s, 3 H); ES-LCMS: 554.1 (M+1 ).

Example 32 N-{5-[2-amino-3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-6-yl]-2-me

3-yl}-2, 4-difluorobenzene- 1 -sulfonamide

Step A

{6-bromo-3-[4-(me quinazolinyl}cyanam

[00209] A suspension of methyl 5-bromo-2-

{[(cyanoamino)(phenyloxy)methylidene]amino}benzoate (0.200 g, 0.534 mmol) in iPrOH (2.502 mL) was treated with 4-(methyloxy)aniline (0.069 g, 0.561 mmol), and DMAP (0.026 g, 0.214 mmol) and was heated in a sealed tube to 85 °C for 2 hours. The reaction was cooled to room temperature and was diluted with 1 :1 Et₂0 /hexanes and the solids were filtered, rinsing with Et₂0 to give {6-bromo-3-[4-(methyloxy)phenyl]-4-oxo-3,4-dihydro-2-quinazolinyl}cyanamide (0.1 17 g, 59%). ES-LCMS: 370.9, 373.0 (M+1 ).

Step B

2-amino-6-iodo- -[4-(methyloxy)phenyl]-4(3H)-quinazolinone

[00210] A solution of {6-bromo-3-[4-(methyloxy)phenyl]-4-oxo-3,4-dihydro-2- quinazolinyl}cyanamide (0.066 g, 0.178 mmol) in 4N HCI in dioxanes (3.15 mL) was treated with water (0.961 ml.) and concentrated HCI (100 μΙ_) and then heated to 90 °C with an open air reflux condenser overnight. After cooling to room temperature, the reaction was concentrated under reduced pressure to give 2-amino-6-bromo-3-[4-(methyloxy)phenyl]-4(3H)-quinazolinone (0.068 g, 100%). ES-LCMS: 346.1 , 348.0 ( +1).

Step C

N-{5-[2-amino-3-(4-methoxyphenyl)-4-oxo-3 - ihydroquinazolin-6-yl]-2-m

2, 4-difluorobenzene- 1 -sulfonamide

[00211 ] A solution of 2-amino-6-iodo-3-[4-(methyloxy)phenyl]-4(3H)-quinazolinone (0.068 g, 0.173 mmol), 2,4-difluoro-N-[2-(methyloxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-3- pyridinyrjbenzenesulfonamide (0.081 g, 0.190 mmol), K₂C0₃ (0.072 g, 0.519 mmol), and PdCI₂(dppf)-CH₂CI₂ adduct (0.014 g, 0.017 mmol) in 1 ,4-dioxane (3.60 mL) and water (3.60 ml.) was heated to 80 °C for 1 hour. The reaction was cooled to room temperature and diluted with EtOAc. The combined organics were washed with brine, dried over Na₂S0₄, filtered, and concentrated. The crude residue was purified by reverse phase chromatography (10-90% ACN/ H₂0 + formic acid). The ACN was removed under reduced pressure and the residual aqueous layer was basified with saturated NaHC₃0 and extracted with DCM. The combined organics were washed with brine, dried over Na₂S0₄, filtered, and concentrated. The residue was purified by silica gel chromatography (1-3% MeOH/DCM) to give N-{5-[2-amino-3-(4- methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-6-yl]-2-methoxypyridin-3-yl}-2,4-difluorobenzene- 1-sulfonamide (0.022 g, 23%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.31 (br. s., 1 H), 8.32 (br. s., 1 H), 8.01 (br. s., 1 H), 7.80 - 7.96 (m, 2 H), 7.75 (br. s., 1 H), 7.57 (br. s., 1 H), 7.05 - 7.42 (m, 6 H), 6.43 (br. s., 2 H), 3.83 (s, 3 H), 3.64 (s, 3 H); ES-LCMS: 566.2 (M+1).

Example 33 2,4-difluoro-N-[5-[2-(methylamino)-4-oxo-3-phenyl-3,4-dihydro-6-quinaz

(methyloxy)-3-pyridinyl]benzenesulfonamide

Step A

6-bromo-2-(meth lamino)-3-phenyl-4(3H)-quinazolinone

[00212] A solution of 6-bromo-2-chloro-3-phenyl-4(3H)-quinazolinone (225 mg, 0.670 mmol) and DIPEA (0.234 mL, 1 .341 mmol) in N,N-dimethylformamide (3 mL) was treated with DIPEA (0.234 mL, 1 .341 mmol) and maintained with stirring at 80 °C in a sealed pressure tube for 2 hours. The solution was cooled to room temperature, poured into ethyl acetate, and washed three times with 5% LiCI (aq). The organic layer was separated, dried over sodium sulfate, filtered, taken to a residue under reduced pressure, and purified by column chromatography to afford 6-bromo-2-(methylamino)-3-phenyl-4(3H)-quinazolinone (109 mg, 0.330 mmol, 49.2% yield) as a white solid. LCMS (m/z, ES+) = 332 (M+H).

Step B

2,4-difluoroΉ-[5-[2-(methylamino)-4-oxo-3 henyl-3,4-dihydro-6-quinazol^

pyridinyljbenzenesulfonamide

[00213] A solution of 6-bromo-2-(methylamino)-3-phenyl-4(3H)-quinazolinone (109 mg, 0.330 mmol), 2,4-difluoro-N-[2-(methyloxy)-5-(4,4,5-trimethyl-1 ,3,2-dioxaborolan-2-yl)-3- pyridinyl]benzenesulfonamide (170 mg, 0.413 mmol), potassium carbonate (91 mg, 0.660 mmol), and PdCI₂(dppf)-CH₂CI₂ adduct (27.0 mg, 0.033 mmol) in 1 ,4-dioxane (3 mL)/water (1 mL) was maintained with stirring at 80°C for 2 hours. The mixture was cooled to room temperature, poured into ethyl acetate, and washed with saturated sodium chloride (aq). The organic layer was separated, dried over sodium sulfate, filtered, taken to a residue under reduced pressure, and purified by column chromatography to afford 2,4-difluoro-N-[5-[2- (methylamino)-4-oxo-3-phenyl-3,4-dihydro-6-quinazolinyl]-2-(methyloxy)-3- pyridinyl]benzenesulfonamide (126 mg, 0.229 mmol, 69.5 % yield) as a white solid. LCMS (m/z, ES+) = 550 ( +H). H NMR (DMSO-cfe) δ: 10.30 (s, 1 H), 8.34 (d, J = 2.3 Hz, 1 H), 8.03 (d, J = 2.1 Hz, 1 H), 7.84 - 7.94 (m, 2H), 7.75 (td, J = 8.5, 6.4 Hz, 1 H), 7.51 - 7.64 (m, 4H), 7.30 - 7.48 (m, 3H), 7.10 - 7.26 (m, 1 H), 5.87 (q, J = 4.1 Hz, 1 H), 3.65 (s, 3H), 2.80 (d, J = 4.3 Hz, 3H).

Example 34

N-[5-(2-amino-4-oxo-3-phenyl-3,4-dihydro-6-quinazolinyl)-2-(methylo^

quinolinesulfonamide

Step A

N-[5-bromo-2-(meth loxy)-3 yπdinyl]-8-quinolinesulfonamide

[00214] A mixture of 5-bromo-2-(methyloxy)-3-pyridinamine (500 mg, 2.463 mmol), 8- quinolinesulfonyl chloride (1 121 mg, 4.93 mmol) and DMAP (30.1 mg, 0.246 mmol) in pyridine (10 mL) was maintained at room temperature. After 2 hours the resulting mixture was concentrated. The residue was taken up into CH₂CI₂ and filtered. The filtrate was purified by column chromatography (0-100% EtOAc/hexane) to obtain N-[5-bromo-2-(methyloxy)-3- pyridinyl]-8-quinolinesulfonamide (860 mg, 2.181 mmol, 89 % yield) as a white solid: H NMR (400 MHz, DMSO-cfe) δ: ppm 3.40 (s, 3 H) 7.69 - 7.79 (m, 2 H) 7.85 (d, J=2.24 Hz, 1 H) 7.95 (d, J=2.24 Hz, 1 H) 8.32 (dd, J=7.85, 2.10 Hz, 2 H) 8.58 (dd, J=8.29, 1.66 Hz, 1 H) 9.08 (dd, J=4.29, 1.66 Hz, 1 H) 9.43 (s, 1 H); ES LC-MS m/z =394.1 (Br⁷⁹, M+H)⁺, ES LC-MS m/z =396.1 (Br⁸¹, M+H)⁺.

Siep 6

N-[2-(methyloxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2^

uinoiinesuifonamide

[00215] A degassed mixture of N-[5-bromo-2-(methyloxy)-3-pyridinyl}-8- quinolinesulfonamide (858 mg, 2.176 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-1 ,3,2- dioxaborolane (608 mg, 2.394 mmol), Pd(dppf)₂CI₂ CH₂CI₂ adduct (1777 mg, 2.176 mmol) and potassium acetate (641 mg, 6.53 mmol) in 1 ,4-dioxane (30 mL) was heated at 80 °C. After 4 hours the reaction mixture was allowed to cool to room temperature and filtered through a pad of Celite® with the aid of EtOAc. The filtrate was concentrated and re-evaporated from

CH₂Cl₂/hexane. The residue was dissolved in CH₂CI₂ and purified by column chromatography (silica gel, 0-100% EtOAc/hexane) to obtain N-[2-(methyloxy)-5-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)-3-pyridinyl]-8-quinolinesulfonamide (901 mg, 2.042 mmol, 94% yield) as a grey solid: ¹H NMR (400 MHz, DMSO-cf₆) δ ppm 1 .28 (s, 12 H) 3.37 (s, 3 H) 7.67 - 7.73 (m, 1 H) 7.77 (dd, J=8.29, 4.29 Hz, 1 H) 7.86 (d, J=1.66 Hz, 1 H) 8.03 (d, J=1.66 Hz, 1 H) 8.25 (dd, J=7.32, 1.27 Hz, 1 H) 8.31 (dd, J=8.19, 1.27 Hz, 1 H) 8.58 (dd, J=8.39, 1.66 Hz, 1 H) 9.10 - 9.14 (m, 1 H) 9.23 (s, 1 H); ES LC-MS m/z = 442.4 (M+H)⁺.

Step C

6-bromo-2-({[4-(methylox henyί]methyl}amino)-3 henyί-4(3H)-quinazolinone

[00216] A solution of 6-bromo-2-chloro-3-phenyl-4(3H)-quinazolinone (2.44 g, 7.27 mmol), 4-methoxy-benzylamine (1 .425 mL, 10.91 mmol), and DIPEA (2.54 mL, 14.54 mmol) in Ν,Ν-dimethylformamide (40 ml.) was maintained with stirring at 80 °C for 3 hours. The solution was cooled, poured into ethyl acetate, and washed three times with 5% LiCI (aq) and once with saturated sodium chloride (aq). The organic layer was dried over sodium sulfate, filtered, taken to a residue under reduced pressure, and purified by column chromatography to afford 6-bromo- 2-({[4-(methyloxy)phenyl]methyl}amino)-3-phenyl-4(3H)-quinazolinone (2.9 g, 6.65 mmol, 91 % yield) as a white foam. LCMS (m/z, ES+) = 436 (M+H).

Step D

2-amino-6-bromo-3- henyl-4(3H)-quinazolinone

[00217] A solution of 6-bromo-2-({[4-(methyloxy)phenyl]methyl}amino)-3-phenyl-4(3H)- quinazolinone (2.75 g, 6.30 mmol) in trifluoroacetic acid (40 mL) was maintained with stirring at reflux for 48 hours. The solution was cooled, concentrated to a residue, dissolved in DCM, and washed three times with saturated sodium bicarbonate (aq). The organic layer was separated, dried over sodium sulfate, filtered, taken to a residue under reduced pressure, and purified by column chromatography to afford 2-amino-6-bromo-3-phenyl-4(3H)-quinazolinone (1.78 g, 5.63 mmol, 89 % yield) as a yellow-brown solid. LCMS (m/z, ES+) = 316 (M+H).

Step E

N-[5-(2-ami^'no-4-oxo-3-p eny\-3,4-0i ydro-6-quinazo\iny\)-2-(m

quinolinesulfonamide

[00218] A solution of 2-amino-6-bromo-3-phenyl-4(3H)-quinazolinone (70 mg, 0.221 mmol), N-[2-(methyloxy)-5-(4,4,5-trimethyl-1 ,3,2-dioxaborolan-2-yl)-3-pyridinyl]-8- quinolinesulfonamide ( 8 mg, 0.277 mmol), potassium carbonate (61.2 mg, 0.443 mmol), and PdCI₂(dppf)-CH₂CI₂ adduct (18.08 mg, 0.022 mmol) in 1 ,4-dioxane (3 ml_)/water (1 mL) was maintained with stirring at 80 °C for 3 hours. The mixture was cooled, diluted with ethyl acetate, and washed with water. The organic layer was separated, dried over sodium sulfate, filtered, taken to a residue under reduced pressure, and purified by reverse phase HPLC to afford after lyophlization: N-[5-(2-amino-4-oxo-3-phenyl-3,4-dihydro-6-quinazolinyl)-2-(methyloxy)-3- pyridinyl]-8-quinolinesulfonamide (62 mg, 0.104 mmol, 46.9% yield) as a white solid. LCMS (m/z, ES+) = 551 (M+H). H NMR (DMSO-c/₆) δ: 9.15 (dd, J = 4.3, 1 .6 Hz, 1 H), 8.57 (dd, J = 8.3, 1.5 Hz, 1 H), 8.31 (d, J = 7.4 Hz, 2H), 8.06 - 8.18 (m, 2H), 7.96 (s, 2H), 7.67 - 7.88 (m,

- 7.67 (m, 3H), 7.21 - 7.45 (m, 3H), 6.38 (br. s., 2H), 3.45 (s, 3H).

Example 35

2-amino-3-phenyl-6-(1H-pyrrolo[3,2-b]pyridin-6-yl)-4(3H)-quinazolinone

[00219] A solution of 2-amino-6-bromo-3-phenyl-4(3H)-quinazolinone (85 mg, 0.269 mmol), 6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrrolo[3,2-b]pyridine (92 mg, 0.376 mmol), potassium carbonate (74.3 mg, 0.538 mmol), and PdCI₂(dppf)-CH₂Cl₂ adduct (21.96 mg, 0.027 mmol) in 1 ,4-dioxane (3 ml_)/water (1 mL) was maintained at 80 °C for 3 hours. The mixture was cooled to room temperature, poured into ethyl acetate, and washed with water. The organic layer was dried over sodium sulfate, filtered, taken to a residue under reduced pressure, and purified by reverse phase HPLC to afford following lyophlization 2-amino-3- phenyl-6-(1 H-pyrrolo[3,2-b]pyridin-6-yl)-4(3H)-quinazolinone as the formate salt (60 mg, 0.170 mmol, 63.2 % yield) as a white solid. LCMS (m/z, ES+) = 354 (M+H). H NMR (DMSO-d₆) δ: 8.65 (d, J = 1.8 Hz, 1 H), 8.16 (d, J = 2.1 Hz, 1 H), 8.13 (s, 1 H), 7.97 - 8.06 (m, 2H), 7.68 (d, J = 3.1 Hz, 1 H), 7.49 - 7.64 (m, 3H), 7.38 (d, J = 8.0 Hz, 3H), 6.59 (d, J = 3.1 Hz, 1 H) .

EXAMPLE 36

N-[2-amino-5-(2-amino-4-oxo-3-phenyl-3,4-dihydroquinazolin-6-yl)pyrM

Step A

N-(2-amino-5-bromo-3-pyridinyl)-2,4-difluorobenzenesulfonamide

[00220] To a solution of 5-bromo-2,3-pyridinediamine (4.7 g, 25.00 mmol) in pyridine (50 mL) was treated with 2,4-difluorobenzenesulfonyl chloride (5.31 g, 25.00 mmol) and stirred at room temperature for 1 hour. The solvents were evaporated, the crude partitioned between DCM and water and the aqueous layer dried (brine, Na₂S0₄) and purified (silica gel) to give the product as a brown solid (4.5 g, 49%). ES-LCMS: m/z 364/366 (M+1 ).

Step B

N-[2-amino-5-( 2-amino-4-oxo-3-phenyl-3, 4-dihydroquinazolin-6-yi)pyridin-3-yl]-2, 4- difluorobenzene- 1 -sulfonamide

[00221] A degassed solution of N-(2-amino-5-bromo-3-pyridinyl)-2,4- difluorobenzenesulfonamide (80 mg, 0.220 mmol) and 2-amino-3-phenyl-6-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)quinazolin-4(3H)-one (80 mg, 0.220 mmol) with PdCI₂(dppf)-CH₂CI₂ adduct (17.99 mg, 0.022 mmol) in 1 ,4-dioxane (3 mL) and NaHC0₃ (sat aq, 1 mL) was degassed, then heated with microwave irridation to 120 °C for 20 minutes. The crude was purified by RP-HPLC to give N-[2-amino-5-(2-amino-4-oxo-3-phenyl-3,4-dihydroquinazolin-6- yl)pyridin-3-yl]-2,4-difluorobenzene- -sulfonamide (6.6 mg, 6%). ¹H NMR (400 MHz, DMSO d₆) δ = 7.91 (m,1 H), 7.82 (m, 2H), 7.65-7.40 (m, 9H), 7.2 (m, 1 H); ES-LCMS: m/z 521 (M+1 ).

EXAMPLE 37

N-[5-[2-amino-3-(2-methylpropyl)-4-oxo-3,4-dihydro-6-quinazolinyfr^

pyridiny -2,4-difluorobenzenesulfonamide

General Scheme 4

Step A

2-amino-6-bromo- -(2-methylpropyl)-4(3H)-quinazolinone

[00222] To a suspension of methyl 5-bromo-2-

{[(cyanoamino)(phenyloxy)methylidene]amino}benzoate (1 13 mg, 0.30 mmol) prepared as described in Arch. Pharm. (Weinheim) 328, (1995), 709-719, in isopropanol (1 .3 mL) was added isobutylamine (0.045 mL, 0.45 mmol) and the reaction heated to 85 °C in a sealed tube for 1 hour. The reaction was cooled to room temperature and the solids filtered and dried. The solids were suspended in DMSO (0.8 mL) and cone. HCI (1.6 mL) and heated to 100 °C for 4 hours in a sealed tube. The reaction was cooled to room temperature and treated with 8 M sodium hydroxide until the solution gave blue pH paper. Solids were filtered and dried to afford the title compound (67 mg, 73 %) as a white solid.

Step B

N-[5-[2-amino-3-(2-methylpropyl)-4-oxo-3,4-dihydro-6-quinazolinyl]-2-(methyloxy)-3-pyh^

2, 4-difluorobenzenesulfonamide [00223] A solution of 2-amino-6-bromo-3-(2-methylpropyl)-4(3H)-quinazolinone (40 mg,

0.14 mmol), 2,4-difluoro-A/-[2-(methyloxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-3- pyridinyl]benzenesulfonamide (63 mg, 0.15 mmol), potassium acetate (53 mg, 0.54 mmol) and PdCI₂(dppf)-CH₂Cl₂ (11 mg, 0.01 mmol) in dioxane (0.85 mL) and water (0.3 mL) was degassed with nitrogen and heated to 100 °C in a sealed tube for 1 hour. The reaction was concentrated in vacuo and the residue purified by HPLC eluting with 10-90% acetonitrile/water/0.1 % formic acid to afford the title compound (18 mg, 23% yield). H NMR (400 MHz, DMSO-c/₆) δ ppm 10.31 (br. s., 1 H), 8.30 (br. s., 1 H), 8.02 (d, J=2.1 Hz, 1 H), 7.79 - 7.87 (m, 2 H), 7.69 - 7.79 (m, 1 H), 7.50 - 7.64 (m, 1 H), 7.23 - 7.28 (m, 1 H), 7.15 - 7.23 (m, 1 H), 7.10 (br. s., 2 H), 3.89 (d, J=7.4 Hz, 2 H), 3.64 (s, 3 H), 2.07 - 2.20 (m, 1 H), 0.87 (d, J=6.6 Hz, 6 H). ES-LCMS: m/z = 516.32 (M+1 ).

Example 38

N-[5-[2-(cyanoamino)-4-oxo-3-phenyl-3,4-dihydro-6-quinazolinyl]-2-(m

pyridinyl]-2,4-difluorobenzenesulfonamide

Step A

6-bromo-4-oxo-3-phenyl-3,4-dihydro-2-quinazolinyl)cyanamide

[00224] To a suspension of methyl 5-bromo-2-

{[(cyanoamino)(phenyloxy)methylidene]amino}benzoate (65 mg, 0.17 mmol) in isopropanol (1.6 mL) was added aniline (0.03 mL, 0.34 mmol) and the reaction heated to 85 °C in a sealed tube for 1 hour. The reaction was cooled to room temperature and 4-dimethylaminopyridine (9 mg) was added and the reaction stirred at room temperature for 72 hours. The solids were filtered and dried (25 mg, 42%).

Step B

N-[5-[2-(cyanoamino)-4-oxo-3^henyl-3 -dihydro-6-qum^' ^

diftuorobenzenesulfonamide

[00225] The compound of the instant Example No. 38, Step B, was prepared in a similar manner to that described above in Example 37, Step B. ¹H NMR (400 MHz, DMSO-cfe) δ ppm 12.50 (br. s., 1 H), 10.35 (br. s., 1 H), 8.37 (br. s., 1 H), 8.00 - 8.20 (m, 2 H), 7.89 (br. s., 1 H), 7.69 - 7.85 (m, 2 H), 7.39 - 7.66 (m, 5 H), 7.34 (br. s., 1 H), 7.13 - 7.25 (m, 1 H), 3.65 (s, 3 H). LCMS: m/z = 561.04 (M+1 ).

Example 39

N-[5-(2-amino-3-cyclobutyl-4-oxo-3,4-dihydro-6-quinazolinyl)-2-(m

2,4-difluorobenzenesulfonamide

[00226] The compound of Example 39, Compound No. 39, was prepared in a manner similar to that described in Example 37 above. H NMR (400 MHz, DMSO- /₆) δ ppm 10.27 (br. s., 1 H), 8.30 (br. s., 1 H), 8.00 (d, J=2.3 Hz, 1 H), 7.66 - 7.88 (m, 3 H), 7.51 - 7.63 (m, 1 H), 7.13 - 7.28 (m, 2 H), 6.87 (br. s., 2 H), 4.36 - 4.72 (m, 1 H), 3.64 (s, 3 H), 2.56 - 2.75 (m, 3 H), 1.50 - 1.91 (m, 3 H). ES-LCMS: m/z = 514.25 (M+1 ).

Example 40

N-[5-(2-amino-3-cyclohexyl-4-oxo-3,4-dihydro-6-quinazolinyl)-2-(methyloxy)-3-pyridin

2,4-difluorobenzenesulfonamide

[00227] The compound of Example 40 was prepared as described in Example 37. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.30 (s, 1 H), 8.29 (br. s., 1 H), 7.93 - 8.04 (m, 1 H), 7.66 - 7.89 (m, 3 H), 7.48 - 7.65 (m, 1 H), 7.12 - 7.28 (m, 2 H), 7.05 (br. s., 2 H), 4.16 (br. s., 1 H), 3.64 (s, 3 H), 2.52 - 2.66 (m, 2 H), 1.72 - 1.89 (m, 2 H), 1.56 - 1.71 (m, 3 H), 1.31 - 1.52 (m, 2 H), 1.1 1 - 1.33 (m, 1 H). ES-LCMS: m/z = 542.30 (M+1 ).

Example 41

N-[5-[2-amino-4-oxo-3-(tetrahydro-2H-pyran-4-yl)-3,4-dihydro-6-quin

(methyloxy)- esulfonamide

Step A

2-amino-6-bromo-3-(tetrahydro-2H-pyran-4-yl)-4(3H)-quinazolinone

[00228] To a suspension of methyl 5-bromo-2-

{[(cyanoamino)(phenyloxy)methylidene]amino}benzoate (1.0 g, 2.7 mmol) in isopropanol (10 mL) was added tetrahydro-2H-pyran-4-amine (0.42 mL, 4.0 mmol) and the reaction heated to 85 °C in a sealed tube for 1 hour. The reaction was cooled to room temperature and the solids filtered and dried. The solids were suspended in DMSO (6 mL) and cone. HCI (12 mL) and heated to 100 °C for 3 hours in a sealed tube. The reaction was cooled to room temperature, poured into water {80 mL) and treated with potassium carbonate until the solution gave blue pH paper. The aqueous layer was extracted three times with dichloromethane and the organic layer was concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with a half-volume of water, brine, and the organic layer dried (MgS0₄) and concentrated in vacuo to afford the title compound as a white solid (610 mg, 70%).

Step B

N-[5-[2-amino-4-oxo-3-(tetrahydro-2H yran-4-yl)-3,4-dihydro-6-quinazolinyt]-2-(m

pyridinyl]-2,4-difluorobenzenesulfonamide

[00229] A solution of 2-amino-6-bromo-3-(tetrahydro-2H-pyran-4-yl)-4(3H)-quinazolinone (65 mg, 0.20 mmol), 2,4-difluoro-/V-[2-(methyloxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)-3-pyridinyl]benzenesulfonamide (94 mg, 0.22 mmol), potassium acetate (79 mg, 0.80 mmol) and PdCI₂(dppf)-CH₂CI₂ (16 mg, 0.02 mmol) in dioxane (1.0 mL) and water (0.33 mL) was degassed with nitrogen and heated to 100 °C in a sealed tube for 1 hour. The reaction was concentrated in vacuo and the residue purified by HPLC eluting with 10-90%

acetonitrile/water/0.1 % formic acid to afford the title compound (44 mg, 40% yield). H NMR (400 MHz, DMSO-de) δ ppm 10.25 (br. s., 1 H), 8.30 (br. s., 1 H), 8.00 (d, J=2.1 Hz, 1 H), 7.79 - 7.88 (m, 2 H), 7.75 (td, J=8.4, 6.5 Hz, 1 H), 7.47 - 7.66 (m, 1 H), 7.17 - 7.28 (m, 2 H), 7.15 (br. s., 2 H), 4.37 (br. s., 1 H), 3.94 (dd, J=10.9, 3.9 Hz, 2 H), 3.64 (s, 3 H), 3.43 (t, J=11.3 Hz, 2 H), 2.84 (dd, J=1 1.8, 4.2 Hz, 2 H), 1.46 - 1.68 (m, 2 H). ES-LCMS: m/z = 544.25 (M+1 ).

Example 42

N-[5-[2-amino-3-(trans-4-hydroxycyclohexyl)-4-oxo-3,4-dihydro-6-quinazolinyl]-2- (methyloxy)- -pyridinyl]-2,4-difluorobenzenesulfonamide

Step A 2-amino-6-bromo-3- -4(3H)-quinazolinone

[00230] To a solution of 0.3 M potassium hydroxide in ethanol (2 mL) was added trans-4- aminocyclohexanol hydrochloride (1 10 mg, 0.72 mmol) and the reaction stirred at room temperature for 30 minutes. To the reaction was added methyl 5-bromo-2- {[(cyanoamino)(phenyloxy)methylidene]amino}benzoate ( 50 mg, 0.40 mmol) and the reaction heated to 85 °C in a sealed tube for 1 hour. The reaction was cooled to room temperature and concentrated in vacuo and used without additional purification. The residue was suspended in DMSO (1.25 mL) and cone. HCI (2.5 mL) and heated to 100 °C for 1 hour in a sealed tube. The reaction was cooled to room temperature, poured into water (15 mL) and treated with potassium carbonate until the solution gave blue pH paper. The aqueous layer was extracted three times with dichloromethane and the organic layer was concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with a half-volume of water, brine, and the organic layer dried (MgS0₄) and concentrated in vacuo to afford the title compound as a white solid (46 mg, 34%).

Step B

'-amino-3-(trans-4-hydroxycyclohexyl)-4-oxo-3 -dihydro-6-quinazolinyl]-2-(methyloxy) pyridinyi]-2,4-difluorobenzenesulfonamide

[00231] The compound of Example 42 was prepared as described in Step B of Example

37 and then isolated as the formate salt. ¹H NMR (400 MHz, DMSO-cfe) δ ppm 9.73 - 10.91 (m, 1 H), 8.25 (s, 1 H), 8.13 (s, 1 H), 7.97 (s, 1 H), 7.67 - 7.86 (m, 3 H), 7.47 - 7.61 (m, 1 H), 7.14 - 7.28 (m, 2 H), 7.06 (br. s., 2 H), 4.62 (d, J=3.7 Hz, 1 H), 4.19 (br. s., 1 H), 3.65 (s, 3 H), 3.43 - 3.58 (m, 1 H), 2.58 - 2.74 (m, 2 H), 1.75 - 1.97 (m, 2 H), 1.52 - 1.70 (m, 2 H), 1.25 - 1.49 (m, 2 H). ES-LC S: m/z = 558.26 (M+1 ).

Example 43

N-[5-{2-amino-3-[2-(4-morpholinyl)ethyl]-4-oxo-3,4-dihydro-6-quinazo

3-pyridinyl]-2,4-difluorobenzenesulfonamide

Step A

2-amino-6-bromo- -[2-(4-morpholinyl)ethyl]-4(3H)-quinazolinone

[00232] To a suspension of methyl 5-bromo-2-

{[(cyanoamino)(phenyloxy)methylidene]amino}benzoate (125 mg, 0.33 mmol) in isopropanol (1 .5 mL) was added [2-(4-morpholinyl)ethyl]amine (0.06 mL, 0.5 mmol) and the reaction heated to 85 °C in a sealed tube for 1 hour. The reaction was cooled to room temperature and concentrated in vacuo. The solids were suspended in DMSO (1.25 mL) and cone. HCI (2.5 mL) and heated to 100 °C for 1 hour in a sealed tube. The reaction was cooled to room

temperature, poured into water (10 mL) and treated with potassium carbonate until the solution gave blue pH paper. The aqueous layer was extracted three times with dichloromethane and the organic layer was concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with a half-volume of water, brine, and the organic layer dried (MgS0₄) and

concentrated in vacuo to afford the title compound as a white solid (94 mg, 81 %), which was used without additional purification.

Step B

N-[5-{2-amino-3-[2-(4-morpholinyl)ethyl]-4-oxo-3,4-dihydro-6-quinazo

pyridinyl]-2,4-difluorobenzenesulfonamide

[00233] The compound of Example 43, Step B was prepared as described in Step B of Example 37. H NMR (400 MHz, DMSO-d₆) δ ppm 10.30 (br. s., 1 H), 8.29 (br. s., 1 H), 7.98 - 8.07 (m, 1 H), 7.81 - 7.87 (m, 2 H), 7.75 (dd, J=8.5, 2.1 Hz, 1 H), 7.49 - 7.63 (m, 1 H), 7.13 - 7.31 (m, 4 H), 4.17 (t, J=6.1 Hz, 2 H), 3.65 (s, 3 H), 3.55 (t, J=4.2 Hz, 4 H), 2.58 (t, J=6.2 Hz, 2 H). ES-LCMS: m/z = 573.28 (M+1 ). Example 44

1,1-dimethylethyl 4-[2-amino-6-[5-{[(2,4-difluorophenyl)sulfonyl]amino}-6-(methyloxy)-3- pyridinyl]-4-o -3(4H)-quinazolinyl]-1-piperidinecarboxylate

Step A

2-amino-6-brom -3-(4-piperidinyi)-4(3H)-quinazolinone

[00234] The compound of Example 44, Step A was prepared from 1 ,1-dimethylethyl 4- amino-1-piperidinecarboxylate in a similar manner as described in Step A of Example 43.

Step B

1, 1 -dimethylethyl 4-(2-amino- -bromo-4-oxo-3(4H)-quinazolinyl)-1-piperidinecarboxylate

[00235] To a solution of 2-amino-6-bromo-3-(4-piperidinyl)-4(3H)-quinazolinone (90 mg, 0.28 mmol) in anhydrous dichloromethane (2.5 mL) was added triethylamine (0.08 ml_, 0.56 mmol) followed by di-tert-butyl di-carbonate (79 mg, 0.36 mmol) and the reaction stirred at room temperature for 1 hour . The reaction was concentrated in vacuo and the residue purified by HPLC eluting with 10-90% acetonitrile/water/0.1 % formic acid to afford the title compound (41 mg, 35%). Step C

1, 1 -dimethylethyl 4-[2-amino-6-[5-{[(2, 4-difluorophenyl)sulfonyl]amino}-6-(methyloxy)-3- pyridinyl]-4-oxo-3(4H)-quinazolinyl]-1-pipehdinecarboxylate

[00236] The compound of Example 44, Step C was prepared in a similar fashion as described in Step B of Example 37. ¹H NMR (400 MHz, DMSO-af₆) δ ppm 10.29 (br. s., 1 H), 8.27 (br. s., 1 H), 7.98 (d, J=2.0 Hz, 2 H), 7.65 - 7.89 (m, 3 H), 7.43 - 7.66 (m, 1 H), 7.17 - 7.32 (m, 3 H), 7.14 (br. s., 2 H), 4.31 (br. s., 1 H), 4.04 (br. s., 2 H), 3.65 (s, 3 H), 2.83 (br. s., 2 H), 2.59 - 2.74 (m, 2 H), 1.53 - 1.71 (m, 2 H), 1.44 (s, 9 H). ES-LCMS: m/z = 643.24 (M+1 ).

Example 45

N-[5-{2-amino-3-[1-(methylsulfonyl)-4-piperidinyl]-4-oxo-3,4-dihydro-6-qui

(methyloxy)- -pyridinyl]-2,4-difluorobenzenesulfonamide

Step A

2-amino-6-bromo-3-[ 1 -(methylsulfonyl)-4-piperidinyl]-4(3H)-quinazolinone

[00237] To a solution of 2-amino-6-bromo-3-(4-piperidinyl)-4(3H)-quinazolinone (90 mg, 0.28 mmol), prepared as described in Step A of Example 44, in anhydrous dichloromethane (2.5 mL) was added triethylamine (0.08 mL, 0.56 mmol) and the reaction cooled to 0 °C. To the reaction was added methanesulfonyl chloride (0.024 mL, 0.31 mmol) and the reaction stirred at 0 °C for 30 minutes followed stirring at room temperature for another 30 minutes. The reaction was then concentrated in vacuo and the residue purified by HPLC eluting with 10-90% acetonitrile/water/0.1 % formic acid to afford the title compound (36 mg, 32%). Step B

N-[5-{2-amino-3-[1-(methy!sulfonyl)-4^iperidinyl]-4-o^

(methyloxy)-3-pyridinyl]-2,4-difluorobenzenesulfonamide

[00238] The compound of Example 45, Step B was prepared in a similar manner as previously described Step B of Example 37 and was isolated as the formate salt. ¹H NMR (400 MHz, DMSO-afs) δ ppm 10.36 (br. s., 1 H), 8.30 (s, 1 H), 8.14 (s, 1 H), 7.99 (d, J=2.1 Hz, 1 H), 7.79 - 7.86 (m, 2 H), 7.69 - 7.80 (m, 1 H), 7.48 - 7.64 (m, 1 H), 7.17 - 7.30 (m, 2 H), 7.14 (br. s., 2 H), 4.28 (br. s., 1 H), 3.71 (d, J=7.6 Hz, 2 H), 3.64 (s, 3 H), 2.94 (s, 3 H), 2.76 - 2.90 (m, 4 H), 1.64 - 1 .91 (m, 2 H). LCMS: m/z = 621 .1 1 (M+1 ).

Example 46

N-[5-[3-(1-acetyl-4-piperidinyl)-2-amino-4-oxo-3,4-dihydro-6-quinaz

p amide

Step A

^<tyl-4 -quinazolinone

[00239] To a solution of 2-amino-6-bromo-3-(4-piperidinyl)-4(3H)-quinazolinone (90 mg, 0.28 mmol), prepared as described in Step A of Example 44, in anhydrous dichloromethane (2.5 mL) was added triethylamine (0.08 mL, 0.56 mmol) and the reaction cooled to 0 °C. To the reaction was added acetic anhydride (0.03 mL, 0.31 mmol) and the reaction stirred at 0 °C for 30 minutes followed by a stirring at room temperature for 30 minutes. The reaction was concentrated in vacuo and the residue stirred in warm DMF and filtered, the solids dried to afford the title compound (37 mg, 36%) which was used without additional purification. Step B

N-[5-[3-(1-acetyl-4^iperidinyl)-2-amino-4-oxo-3,4-dihydro^

pyridinyl]-2,4-difiuorobenzenesulfonamide

[00240] The compound of Example 46, Step B was prepared in a similar manner as described in Step B of Example 37 and was isolated as the formate salt. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.31 (br. s., 1 H), 8.26 (br. s., 1 H), 8.13 (s, 1 H), 7.97 (d, J=2.0 Hz, 1 H), 7.78 - 7.87 (m, 2 H), 7.74 (td, J=8.5, 6.4 Hz, 1 H), 7.49 - 7.62 (m, 1 H), 7.19 - 7.29 (m, 1 H), 7.16 (br. s., 2 H), 4.47 - 4.57 (m, 1 H), 4.38 (br. s., 1 H), 3.85 - 3.98 (m, 1 H), 3.64 (s, 3 H), 3.03 - 3.21 (m, 1 H), 2.55 - 2.81 (m, 3 H), 2.04 (s, 3 H), 1.54 - 1.83 (m, 2 H). LCMS: m/z = 585.33 (M+1 ).

Example 47

N-[5-[2-amino-4-oxo-3-(tetrahydro-2H-pyran-4-ylmethyl)-3,4-dihydro-6-quinazoli

(methyloxy)- esulfonamide

[00241] The compound of Example 47 was prepared in a similar manner as described in Example 41 and was isolated as the formate salt. H NMR (400 MHz, DMSO-d₆) δ ppm 10.34 (br. s., 1 H), 8.29 (br. s., 1 H), 8.14 (s, 1 H), 8.02 (d, J=2.1 Hz, 1 H), 7.80 - 7.86 (m, 2 H), 7.71 - 7.80 (m, 1 H), 7.43 - 7.62 (m, 1 H), 7.25 (d, J=8.6 Hz, 1 H), 7.20 (td, J=8.5, 2.1 Hz, 1 H), 7.12 (s, 2 H), 3.93 - 4.02 (m, 2 H), 3.78 - 3.90 (m, 2 H), 3.65 (s, 3 H), 3.16 - 3.26 (m, 3 H), 1.98 - 2.12 (m, 1 H), 1.41 - 1.52 (m, 2 H), 1 .25 - 1.41 (m, 2 H). LCMS: m/z = 558.42 (M+1 ).

Example 48

1,1-dimethylethyl 2-{[2-amino-6-[5-{[(2,4-difluorophenyl)sulfonyl]amino}-6-(methyloxy)-3- pyridinyl]-4-oxo-3(4H)-quinazolinyl]methyl}-4-morpholinecarboxylate

Step A

2-amino-6-bro -3-(2-morpholinytmethyl)-4(3H)-quinazolinone

[00242] The compound of Example 48, Step A was prepared from 1 ,1-dimethylethyl 2- (aminomethyl)-4-morpholinecarboxylate in a similar manner to that previously described in Example 41 , Step A.

Step B

1, 1-dimethylethyl 2-[(2-amino-6-bromo-4-oxo-3(4H)-quinazolinyl)methyl]-4- mor holinecarboxylate

[00243] To a suspension of 2-amino-6-bromo-3-(2-morpholinylmethyl)-4(3H)- quinazolinone (75 mg, 0.22 mmol) in anhydrous dichloromethane (2.2 mL) was added triethylamine (0.06 mL, 0.44 mmol) followed by di-ferf-butyl di-carbonate (60 mg, 0.28 mmol) and the reaction stirred at room temperature for 1 hour. The reaction was next concentrated in vacuo and the residue purified by silica gel chromatography eluting with 75-100% hexanes/ethyl acetate to afford the title compound (78 mg, 80%).

Step C

1 , 1 -dimethylethyl 2-{[2-amino-6-[5-{[( 2, 4-difluorophenyl)sulfonyl]amino}-6-(methyloxy)-3- pyridinyl]-4-oxo-3(4H) -quinazolinyl]methyl}-4-morpholine carboxyla te

[00244] The title compound of Example 48 was prepared in a similar manner to that described in Example 37, Step B. H NMR (400 MHz, DMSO-cf₆) δ ppm 10.30 (s, 1 H), 8.32 (br. s., 1 H), 8.00 - 8.07 (m, 1 H), 7.81 - 7.89 (m, 2 H), 7.70 - 7.80 (m, 1 H), 7.50 - 7.64 (m, 1 H), 7.25 - 7.30 (m, 1 H), 7.17 - 7.24 (m, 1 H), 7.00 (br. s., 2 H), 4.23 - 4.38 (m, 1 H), 3.97 - 4.09 (m, 1 H), 3.75 - 3.96 (m, 2 H), 3.67 - 3.76 (m, 2 H), 3.65 (s, 3 H), 2.61 - 3.03 (m, 2 H), 1.40 (s, 9 H). LCMS: m/z = 659.52 (M+1 ).

Example 49

N-[5-{3-[(4-acetyl-2-morpholinyl)methyl]-2-amino-4-oxo-3,4-dihydro-6-^

(methyloxy)- -pyridinyl]-2,4-difluorobenzenesulfonamide

Step A

3-[(4-acetyl-2-morpholinyl)methyl]-2-amino-6-bromo-4(3H)-quina

[00245] To a suspension of 2-amino-6-bromo-3-(2-morpholinylmethyl)-4(3H)- quinazolinone (75 mg, 0.22 mmol), prepared as described Example 48, Step A, in anhydrous dichloromethane (2.2 mL), was added triethylamine (0.06 mL, 0.44 mmol) and next cooled to 0 °C. To the reaction was added acetic anhydride (0.02 mL, 0.24 mmol) and stirred at 0 °C for 30 min and room temperature for 30 minutes. The reaction was filtered and the solids dried and used in subsequent reactions without further purification (60 mg, 71 %).

Step B

N-[5-{3-[(4-acetyl-2-morpholinyl)methyl]-2-amino-4-oxo-3,4-dihydro-6-qui^

(methyloxy)-3-pyridinyl]-2,4-difluorobenzenesulfonamide [00246] This compound was prepared in a similar fashion to that escribed in Example 37, Step B and was isolated as the formate salt. H NMR (400 MHz, DMSO-cfe) δ ppm 9.95 - 10.63 (m, 1 H), 8.31 (s, 1 H), 8.12 (s, 1 H), 8.03 (s, 1 H), 7.81 - 7.88 (m, 2 H), 7.76 (td, J=8.5, 6.4 Hz, 1 H), 7.47 - 7.64 (m, 1 H), 7.27 (d, J=8.6 Hz, 1 H), 7.20 (td, J=8.5, 2.2 Hz, 1 H), 7.01 (br. s., 2 H), 4.20 - 4.50 (m, 2 H), 3.93 - 4.15 (m, 2 H), 3.73 - 3.92 (m, 2 H), 3.58 - 3.72 (m, 4 H), 1.97 - 2.09 (m, 3 H). LCMS: m/z = 601.49 (M+1 ).

Example 50

2-amino-6-[5-amino-6-(methyloxy)-3-pyridinyl]-3-phenyl-4(3H)-quinazo

Step A

2-(methyloxy)-5-(4, 4, 5, 5-tetrameth l-1 , 3, 2-dioxaborolan-2-yl)-3-pyridinamine

[00247] A solution of 5-bromo-2-(methyloxy)-3-pyridinamine (Small Molecules, Inc.,

Hoboken, NJ) (5.0 g, 24.6 mmol), 4,4,4',4',5,5,5^,,5'-octamethyl-2,2'-bi-1 ,3,2-dioxaborolane (7.5 g, 29.6 mmol), PdCI₂(dppf)-CH₂CI₂ (2.0 g, 2.46 mmol) and potassium acetate (7.25 g, 73.9 mmol) in anhydrous dioxane (120 mL) was degassed with nitrogen and heated to 100 °C for 18 hours under nitrogen. The reaction was concentrated in vacuo, the residue was diluted with ethyl acetate (500 mL) and filtered through Celite®. The filtrate was washed with cold water (250 mL), brine, dried (MgS0₄) and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 70-100% hexanes/ethyl acetate to afford the title compound (4.38 g, 71 %).

Step B

2-amino-6-[5-amino-6-(methyloxy)-3φyridinyl]-3 heny^-4(3H)-quinazolinone

[00248] A solution of the product from Step A in this Example 50, (4.38 g, 17.6 mmol), 2- amino-6-iodo-3-phenyl-4(3H)-quinazolinone (5.8 g, 16.0 mmol) cesium carbonate (15.6 g, 47.9 mmol) and PdCI₂(dppf)-CH₂CI₂ (1.30 g, 1.6 mmol) in THF (60 mL) and water (20 mL) was degassed with nitrogen and heated to 65 °C for 1 hour . The reaction was concentrated in vacuo and the residue diluted with ethyl acetate (500 mL) and filtered through Celite®. The filtrate was washed with water, brine, dried (MgS0₄) and concentrated in vacuo. The residue was triturated in hot acetonitrile (60 mL), cooled to room temperature and stirred for 30 minutes. Solids were filtered and dried (2.30 g, 40%). ¹H NMR (400 MHz, DMSO-cf₆) δ ppm 8.00 (d, J=2.3 Hz, 1 H), 7.85 (dd, J=8.6, 2.3 Hz, 1 H), 7.68 (d, J=2.1 Hz, 1 H), 7.46 - 7.64 (m, 3 H), 7.35 - 7.41 (m, 2 H), 7.31 (d, J=8.4 Hz, 1 H), 7.18 (d, J=2.1 Hz, 1 H), 6.31 (br. s., 2 H), 5.09 (s, 2 H), 3.89 (s, 3 H). LCMS: m/z = 360.08 (M+1 ).

Example 51

N-[5-(2-amino-4-oxo-3-phenyl-3,4-dihydro-6-quinazolinyl)-2-(methyioxy)-3- pyridinyl]-3-fluorobenzenesulfonamide

[00249] To a solution of the product from 2-amino-6-[5-amino-6-(methyloxy)-3-pyridinyl]- 3-phenyl-4(3H)-quinazolinone (Example 50, Step B) (50 mg, 0.14 mmol) in anhydrous pyridine (0.65 mL) was added 3-fluorobenzenesulfonyl chloride (0.02 mL, 0.14 mmol) and the reaction stirred at room temperature for 2 hours. The reaction was then poured into ethyl acetate (15 mL), washed with water (2 x 15 mL), brine, and then dried (MgS0₄). The organic layer was concentrated in vacuo to about 2 mL and stirred at room temperature until precipitation occurs. Solids were filtered and dried (43 mg, 62%). H NMR (400 MHz, DMSO-cf₆) δ ppm 10.18 (s, 1 H), 8.30 (d, J=2.0 Hz, 1 H), 7.99 (d, J=2.1 Hz, 1 H), 7.87 (dd, J=8.6, 2.3 Hz, 1 H), 7.81 (d, J=2.3 Hz, 1 H), 7.47 - 7.73 (m, 7 H), 7.36 (dd, J=18.4, 7.8 Hz, 3 H), 6.40 (br. s., 2 H), 3.66 (s, 3 H). LCMS: m/z = 518.41 (M+1 ).

Example 52

N-[5-(2-amino-4-oxo-3-phenyl-3,4-dihydro-6-quinazolinyl)-2-(methyloxy)-3-

[00250] The compound of Example 52 was prepared from 2-amino-6-[5-amino-6- (methyloxy)-3-pyridinyl]-3-phenyl-4(3H)-quinazolinone and 4-chlorobenzenesulfonyl chloride as previously described in Example 51 . ¹H NMR (400 MHz, DMSO-cf₆) δ ppm 10.12 (s, 1 H), 8.29 (d, J=2.1 Hz, 1 H), 8.02 (d, J=2.3 Hz, 1 H), 7.82 - 7.93 (m, 2 H), 7.69 - 7.78 (m, 2 H), 7.62 - 7.69 (m, 2 H), 7.49 - 7.62 (m, 3 H), 7.28 - 7.44 (m, 3 H), 6.39 (br. s., 2 H), 3.65 (s, 3 H). LCMS: m/z = 534.36 (M+1 ).

Example 53 N-[5-(2-amino-4-oxo-3-phenyl-3,4-dihydro-6-quinazolinyl)-2-(methyloxy)-3-

[00251] The compound of Example 53 was prepared from 2-amino-6-[5-amino-6- (methyloxy)-3-pyridinyl]-3-phenyl-4(3H)-quinazolinone and benzenesulfonyl chloride as previously described in Example 51 . ¹H NMR (400 MHz, DMSO-cf₆) δ ppm 8.25 (d, J=2.0 Hz, 1 H), 7.97 (d, J=2.3 Hz, 1 H), 7.85 (dd, J=8.6, 2.1 Hz, 1 H), 7.70 - 7.80 (m, 3 H), 7.49 - 7.68 (m, 7 H), 7.36 - 7.43 (m, 2 H), 7.33 (d, J=8.6 Hz, 1 H), 6.38 (br. s., 2 H), 3.67 (s, 3 H). LCMS: m/z = 500.44 (M+1 ).

Example 54

N-[5-(2-amino-4-oxo-3-phenyl-3,4-dihydro-6-quinazolinyl)-2-(methyloxy)-3- pyridinyl]-4-fluorobenzenesulfonamide

[00252] The compound of Example 54 was prepared from 2-amino-6-[5-amino-6- (methyloxy)-3-pyridinyl]-3-phenyl-4(3H)-quinazolinone and 4-fluorobenzenesulfonyl chloride as previously described in Example 51 . H NMR (400 MHz, DMSO-d₅) d ppm 10.05 (s, 1 H), 8.28 (d, J=2.0 Hz, 1 H), 8.00 (d, J=2.1 Hz, 1 H), 7.75 - 7.91 (m, 4 H), 7.49 - 7.64 (m, 3 H), 7.27 - 7.47 (m, 5 H), 6.38 (br. s., 2 H), 3.67 (s, 3 H). LCMS: m/z = 518.35 (M+1 ).

Example 55

N-[5-(2-amino-4-oxo-3-phenyl-3,4-dihydro-6-quinazolinyl)-2-(methyloxy)-3- pyridinyl]-4-methylbenzenesulfonamide

[00253] The compound of Example 55 was prepared from 2-amino-6-[5-amino-6- (methyloxy)-3-pyridinyl]-3-phenyl-4(3H)-quinazolinone and 4-toluenesulfonyl chloride as previously described in Example 51 . ¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.91 (s, 1 H), 8.23 (d, J=1.8 Hz, 1 H), 7.97 (d, J=2.3 Hz, 1 H), 7.84 (dd, J=8.5, 2.2 Hz, 1 H), 7.78 (d, J=2.3 Hz, 1 H), 7.65 (d, J=8.4 Hz, 2 H), 7.49 - 7.63 (m, 3 H), 7.29 - 7.44 (m, 5 H), 6.38 (br. s., 2 H), 3.69 (s, 3 H), 2.34 (s, 3 H). LCMS: m/z = 514.37 (M+1 ).

Example 56

N-[5-(2-amino-4-oxo-3-phenyl-3,4-dihydro-6-quinazolinyl)-2-(methyloxy)-3- pyridinyl]-3-(methyloxy)benzenesulfonamide

[00254] The compound of Example 56 was prepared from 2-amino-6-[5-amino-6- (methyloxy)-3-pyridinylj-3-phenyl-4(3H)-quinazolinone and 3-methoxybenzenesulfonyl chloride as previously described in Example 51. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.01 (s, 1 H), 8.26 (s, 1 H), 7.98 (s, 1 H), 7.85 (d, J=8.4 Hz, 1 H), 7.79 (s, 1 H), 7.43 - 7.67 (m, 4 H), 7.25 - 7.43 (m, 5 H), 7.20 (d, J=7.8 Hz, 1 H), 6.38 (br. s., 2 H), 3.76 (s, 3 H), 3.71 (s, 3 H). LCMS: m/z = 530.37 (M+1 ).

Example 57

N-[5-(2-amino-4-oxo-3-phenyl-3,4-dihydro-6-quinazolinyl)-2-(methyioxy)-3- pyridinyl]-3,5-dimethylbenzenesulfonamide

[00255] The compound of Example 57 was prepared from 2-amino-6-[5-amino-6- (methyloxy)-3-pyridinyl]-3-phenyl-4(3H)-quinazolinone and 3,5-dimethylbenzenesulfonyl chloride as previously described in Example 51. H NMR (400 MHz, DMSO-d₆) δ ppm 9.93 (s, 1 H), 8.25 (d, J=2.0 Hz, 1 H), 7.97 (d, J=2.3 Hz, 1 H), 7.84 (dd, J=8.6, 2.1 Hz, 1 H), 7.76 (d, J=2.3 Hz, 1 H), 7.48 - 7.66 (m, 3 H), 7.30 - 7.45 (m, 5 H), 7.26 (s, 1 H), 6.38 (br. s., 2 H), 3.73 (s, 3 H), 2.30 (s, 6 H). LCMS: m/z = 528.37 ( + ).

Example 58

N-[5-(2-amino-4-oxo-3-phenyl-3,4-dihydro-6-quinazolinyl)-2-(methyloxy)-3- pyridinyl]-4- ide

[00256] The compound of Example 58 was prepared from 2-amino-6-[5-amino-6- (methyloxy)-3-pyridinylj-3-phenyl-4(3H)-quinazolinone and 4-methoxybenzensulfonyl chloride as previously described in Example 51 . H NMR (400 MHz, DMSO-d₆) δ ppm 9.83 (s, 1 H), 8.23 (d, J=2.1 Hz, 1 H), 7.97 (d, J=2.3 Hz, 1 H), 7.85 (dd, J=8.6, 2.1 Hz, 1 H), 7.79 (d, J=2.1 Hz, 1 H), 7.70 (d, J=8.8 Hz, 2 H), 7.49 - 7.63 (m, 3 H), 7.38 (d, J=7.2 Hz, 2 H), 7.33 (d, J=8.6 Hz, 1 H), 7.07 (d, J=9.0 Hz, 2 H), 6.38 (br. s., 2 H), 3.78 (s, 3 H), 3.71 (s, 3 H). LCMS: m/z = 530.36 (M+1 ).

Example 59

N-[5-(2-amino-4-oxo-3-phenyl-3,4-dihydro-6-quinazolinyl)-2-(methyloxy)-3- pyridinyl]-3-chlorobenzenesulfonamide

[00257] The compound of Example 59 was prepared from 2-amino-6-[5-amino-6- (methyloxy)-3-pyridinyl]-3-phenyl-4(3H)-quinazolinone and 3-chlorobenzenesulfonyl chloride as previously described in Example 51. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.20 (s, 1 H), 8.31 (d, J=2.0 Hz, 1 H), 8.01 (d, J=2.1 Hz, 1 H), 7.88 (dd, J=8.6, 2.3 Hz, 1 H), 7.77 - 7.84 (m, 2 H), 7.73 (d, J=8.0 Hz, 1 H), 7.64 - 7.70 (m, 1 H), 7.49 - 7.64 (m, 4 H), 7.28 - 7.44 (m, 3 H), 6.38 (br. s., 2 H), 3.66 (s, 3 H). LCMS: m/z = 534.21 (M+1 ).

Example 60

N-[5-(2-amino-4-oxo-3-phenyl-3,4-dihydro-6-quinazolinyl)-2-(methyloxy)-3-

[00258] The compound of Example 60 was prepared from 2-amino-6-[5-amino-6- (methyloxy)-3-pyridinyl]-3-phenyl-4(3H)-quinazolinone and 2-cyanobenzenesulfonyl chloride as described in Example 51 , except that the reaction was performed at 0 °C and allowed to warm to room temperature. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.39 (s, 1 H), 8.33 (br. s., 1 H), 8.04 - 8.10 (m, 1 H), 8.01 (d, J=2.0 Hz, 1 H), 7.93 - 7.98 (m, 1 H), 7.75 - 7.93 (m, 4 H), 7.47 - 7.66 (m, 3 H), 7.24 - 7.44 (m, 3 H), 6.38 (br. s., 2 H), 3.54 (s, 3 H). LCMS: m/z = 525.29 (M+1 ).

Example 61

N-[5-(2-amino-4-oxo-3-phenyl-3,4-dihydro-6-quinazolinyl)-2-(methyloxy)-3- pyridinyl]-3-cyanobenzenesulfonamide

[00259] The compound of Example 61 was prepared from 2-amino-6-[5-amino-6- (methyloxy)-3-pyridinyl]-3-phenyl-4(3H)-quinazolinone and 3-cyanobenzenesulfonyl chloride as previously described in Example 51 , except that the reaction was performed at 0 °C and allowed to warm to room temperature. H NMR (400 MHz, DMSO-d₆) δ ppm 10.28 (s, 1 H), 8.32 (s, 1 H), 8.19 (s, 1 H), 8.13 (d, J=7.6 Hz, 1 H), 7.95 - 8.06 (m, 2 H), 7.89 (dd, J=8.6, 2.1 Hz, 1 H), 7.84 (d, J=2.1 Hz, 1 H), 7.71 - 7.81 (m, 1 H), 7.48 - 7.66 (m, 3 H), 7.26 - 7.44 (m, 3 H), 6.39 (br. s., 2 H), 3.61 (s, 3 H) LCMS: m/z = 525.28 (M+1).

Example 62

N-[5-(2-amino-4-oxo-3-phenyl-3,4-dihydro-6-quinazolinyl)-2-(methyloxy)-3-

[00260] The compound of Example 62 was prepared from 2-amino-6-[5-amino-6- (methyloxy)-3-pyridinyl]-3-phenyl-4(3H)-quinazolinone and 4-cyanobenzenesulfonyl chloride as previously described in Example 51 , except that the reaction was performed at 0 °C and allowed to warm to room temperature. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.34 (s, 1 H), 8.31 (br. s., 1 H), 7.99 - 8.11 (m, 3 H), 7.80 - 7.94 (m, 4 H), 7.46 - 7.66 (m, 3 H), 7.26 - 7.44 (m, 3 H), 6.38 (br. s., 2 H), 3.60 (s, 3 H). LCMS: m/z = 525.28 (M+1 ).

Example 63

N-[5-(2-amino-4-oxo-3-phenyl-3,4-dihydro-6-quinazolinyl)-2-(methyloxy)-3- pyridinyl]-3-methylbenzenesulfonamide

[00261] The compound of Example 63 was prepared from 2-amino-6-[5-amino-6- (methyloxy)-3-pyridinyl]-3-phenyl-4(3H)-quinazolinone and 3-methylbenzenesulfonyl chloride as previously described in Example 51 . H NMR (400 MHz, DMSO-d₆) δ ppm 9.97 (s, 1 H), 8.25 (d, J=1.8 Hz, 1 H), 7.97 (d, J=2.1 Hz, 1 H), 7.84 (dd, J=8.5, 2.2 Hz, 1 H), 7.77 (d, J=2.1 Hz, 1 H), 7.50 - 7.67 (m, 5 H), 7.44 (d, J=4.7 Hz, 2 H), 7.38 (d, J=7.0 Hz, 2 H), 7.33 (d, J=8.6 Hz, 1 H), 6.38 (br. s., 2 H), 3.70 (s, 3 H), 2.35 (s, 3 H). LCMS: m/z = 514.17 ( +1 ).

Example 64

N-[5-(2-amino-4-oxo-3-phenyl-3,4-dihydro-6-quinazolinyl)-2-(methyloxy)-3- pyridiny -4-ethylbenzenesulfonamide

[00262] The compound of Example 64 was prepared from 2-amino-6-[5-amino-6- (methyloxy)-3-pyridinylj-3-phenyl-4(3H)-quinazolinone and 4-ethylbenzenesulfonyl chloride as previously described in Example 51 . H NMR (400 MHz, DMSO-d₆) δ ppm 9.90 (s, 1 H), 8.24 (d, J=1.6 Hz, 1 H), 7.99 (d, J=2.3 Hz, 1 H), 7.81 - 7.87 (m, 1 H), 7.76 - 7.80 (m, 1 H), 7.63 - 7.70 (m, 2 H), 7.48 - 7.63 (m, 3 H), 7.35 - 7.43 (m, 4 H), 7.33 (d, J=8.6 Hz, 1 H), 6.39 (br. s., 2 H), 3.66 (s, 3 H), 2.64 (q, J=7.6 Hz, 2 H), 1.09 - 1 .19 (m, 3 H). LCMS: m/z = 528.17 (M+1 ).

Example 65

N-[5-(2-amino-4-oxo-3-phenyl-3,4-dihydro-6-quinazolinyl)-2-(methyloxy)-3- pyridinyl]-3,5-difluorobenzenesulfonamide

[00263] Prepared from 2-amino-6-[5-amino-6-(methyloxy)-3-pyridinyl]-3-phenyl-4(3H)- quinazolinone and 3,5-difluorobenzenesulfonyl chloride as described in Example 51. H NMR (400 MHz, DMSO-d₆) δ ppm 10.33 (s, 1 H), 8.34 (d, J=1.6 Hz, 1 H), 8.02 (d, J=2.1 Hz, 1 H), 7.89 (dd, J=8.6, 2.3 Hz, 1 H), 7.84 (d, J=2.1 Hz, 1 H), 7.50 - 7.72 (m, 4 H), 7.42 - 7.49 (m, 2 H), 7.30 - 7.41 (m, 3 H), 6.39 (br. s., 2 H), 3.68 (s, 3 H). LCMS: m/z = 536.12 (M+1 ).

Example 66

N-[5-(2-amino-4-oxo-3-phenyl-3,4-dihydro-6-quinazolinyl)-2-(methyloxy)-3- pyridinyl]- -methylbenzenesulfonamide

[00264] Prepared from 2-amino-6-[5-amino-6-(methyloxy)-3-pyridinyl]-3-phenyl-4(3H)- quinazolinone and 2-methylbenzenesulfonyl chloride as described in Example 51. H NMR (400 MHz, DMSO-d₆) δ ppm 10.04 (s, 1 H), 8.22 (d, J=1.4 Hz, 1 H), 7.94 (d, J=2.3 Hz, 1 H), 7.82 (dd, J=8.6, 2.3 Hz, 1 H), 7.68 - 7.77 (m, 2 H), 7.46 - 7.64 (m, 4 H), 7.36 - 7.44 (m, 3 H), 7.25 - 7.36 (m, 2 H), 6.38 (br. s., 2 H), 3.68 (s, 3 H), 2.64 (s, 3 H). LCMS: m/z = 514.12 (M+1).

Example 67

N-[5-(2-amino-4-oxo-3-phenyl-3,4-dihydro-6-quinazolinyl)-2-(methyloxy)-3- pyridinyl]-2,5-difluorobenzenesulfonamide

[00265] The compound of Example 67 was prepared from 2-amino-6-[5-amino-6- (methyloxy)-3-pyridinyl]-3-phenyl-4(3H)-quinazolinone and 2,5-difluorobenzenesulfonyl chloride as previously described in Example 51 except that the reaction was performed at 0 °C then allowed to warm to room temperature?. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.43 (s, 1 H), 8.34 (br. s., 1 H), 8.02 (d, J=2.3 Hz, 1 H), 7.79 - 7.96 (m, 2 H), 7.46 - 7.66 (m, 6 H), 7.36 (dd, 7.8 Hz, 3 H), 6.39 (br. s., 2 H), 3.65 (s, 3 H). LCMS: m/z = 536.09 (M+1 ).

EXAMPLE 68

N-[5-(2-amino-4-oxo-3^henyl-3,4-dihydro-6-quinazolinyl)-2-(methyloxy)-3-pyri^

fluorobenzenesulfonamide

[00266] To a solution of 2-amino-6-[5-amino-6-(methyloxy)-3-pyridinyl]-3-phenyl-4(3H)- quinazolinone (50 mg, 0.139 mmol) in pyridine (1.4 ml.) 2-fluorobenzenesulfonyl chloride (92.1 mg, 0.473 mmol) was added and the mixture was stirred at room temperature for 3 hours. 10 μΙ_ water was added, the mixture was evaporated and purified on RP-HPLC to give N-[5-(2-amino- 4-oxo-3-phenyl-3,4-dihydro-6-quinazolinyl)-2-(methyloxy)-3-pyridinyl]-2- fluorobenzenesulfonamide (10.5 mg, 0.020 mmol, 14.58 % yield) as a beige solid. LCMS: 518 (M+H); ¹H NMR (400 MHz, DMSO-cf₆) δ = 0.24 (br. s., 1 H), 8.31 (d, J = 2.2 Hz, 1 H), 8.01 (d, J = 2.1 Hz, 1 H), 7.90 (dd, J = 2.0, 8.6 Hz, 1 H), 7.83 (d, J = 2.2 Hz, 1 H), 7.76 - 7.64 (m, 2 H), 7.64 - 7.50 (m, 3 H), 7.50 - 7.28 (m, 5 H), 6.55 (br. s., 2 H), 3.64 (s, 3 H). EXAMPLE 69

N-[5-(2-amino-4-oxo-3-phenyf-3,4-dihydro-6-quinazofinyf)-2-(methyloxy

chloro-2-methylbenzenesulfonamide

[00267] The compound of Example 69 was synthesized similiar to that previously described for Example 69, except that 2-fluorobenzenesulfonyl chloride was replaced for 3- chloro-2-methylbenzenesulfonyl chloride. LCMS: 548 (M+H); H NMR (400 MHz ,DMSO-cf₆) δ = 10.28 (br. s., 1 H), 8.29 (d, J = 1.9 Hz, 1 H), 8.01 (d, J = 1 .6 Hz, 1 H), 7.92 (dd, 1 H), 7.83 (d, J = 1.9 Hz, 1 H), 7.77 - 7.66 (m, 2 H), 7.66 - 7.52 (m, 3 H), 7.49 - 7.35 (m, 3 H), 7.32 (t, J = 8.0 Hz, 1 H), 6.83 (br. s., 2 H), 3.66 (s, 3 H), 2.71 (s, 3 H).

EXAMPLE 70

N-[5-(2-amino-4-oxo-3^henyl-3,4-dihydro-6-quinazolinyl)-2-(methyloxy)-3-py dm

morpholinesulfonainide

[00268] A solution of 4-morpholinesulfonyl chloride (155 mg, 0.835 mmol) and 2-amino-6- [5-amino-6-(methyloxy)-3-pyridinyl]-3-phenyl-4(3H)-quinazolinone (50 mg, 0.139 mmol) in pyridine (1 mL) was maintained at room temperature for 18 hours. The resulting mixture was treated with MeOH (1 mL) and concentrated. The residue was dissolved in DMF and purified by HPLC (10-90% CH₃CN/H₂0, both containing 0.1 % formic acid) to obtain N-[5-(2-amino-4-oxo-3- phenyl-3,4-dihydro-6-quinazolinyl)-2-(methyloxy)-3-pyridinyl]-4-morpholinesulfonamide (7 mg, 0.014 mmol, 9.89% yield) as a white solid: H NMR (400 MHz, DMSO-d₆) δ ppm 3.02 - 3.1 1 (m, 4 H) 3.51 - 3.61 (m, 4 H) 3.97 (s, 3 H) 6.38 (br. s., 2 H) 7.31 - 7.43 (m, 3 H) 7.48 - 7.63 (m, 3 H) 7.90 (d, J=2.24 Hz, 1 H) 7.91 - 7.96 (m, 1 H) 8.05 (d, J=2.24 Hz, 1 H) 8.30 (d, J=2.15 Hz, 1 H) 9.20 - 10.05 (m, 1 H); ES LC-MS m/z =509.1 ( +H)⁺.

EXAMPLE 71

N-[5-(2-amino-4-oxo-3-phenyl-3,4-dihydro-6-quinazolinyl)-2-(methylo^

propanesulfonamide

[00269] A solution of 2-propanesulfonyl chloride (160 mg, 1.12 mmol) and 2-amino-6-[5- amino-6-(methyloxy)-3-pyridinyl]-3-phenyl-4(3H)-quinazolinone (50 mg, 0.139 mmol) in pyridine (1 ml.) was maintained at room temperature for 1 day. The resulting mixture was treated with MeOH (1 mL) and concentrated. The residue was dissolved in DMF and purified by HPLC (10- 90% CH₃CN/H₂0, both containing 0.1% formic acid) to obtain N-[5-(2-amino-4-oxo-3-phenyl- 3,4-dihydro-6-quinazolinyl)-2-(methyloxy)-3-pyhdinyl]-2-propanesulfonamide (8 mg, 0.015 mmol, 11.12 % yield) as a white solid: ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.24 - 1.31 (m, 6 H) 3.22 - 3.31 (m, 1 H) 3.96 (s, 3 H) 6.38 (br. s., 2 H) 7.36 (dd, J=12.49, 8.00 Hz, 3 H) 7.49 - 7.62 (m, 3 H) 7.88 - 7.94 (m, 2 H) 8.04 (d, J=2.15 Hz, 1 H) 8.31 (d, J=2.05 Hz, 1 H) 9.34 (br. s., 1 H); ES LC-MS m/z =466.3 (M+H)⁺.

EXAMPLE 72

N-[5-(2-amm^' o-4-oxo-3-phenyl-3,4-dihydro-6-quinazolinyl)-2-(methyloxy)-3- mide

[00270] A solution of 2-amino-6-[5-amino-6-(methyloxy)-3-pyridinyl]-3-phenyl-4(3H)- quinazolinone (50 mg, 0.139 mmol) and cyclopropanesulfonyl chloride (20 mg, 0.14 mmol) in pyridine (1 mL) was maintained at room temperature for 2 days. More cyclopropanesulfonyl chloride (40 mg, 0.28 mmol) was added. After 1 day at room temperature the resulting mixture was treated with a few drops of MeOH and concentrated. The residue was dissolved in DMF and purified by HPLC (10-90% CH₃CN/H₂0, both containing 0.1 % formic acid) to obtain N-[5- (2-amino-4-oxo-3-phenyl-3,4-dihydro-6-quinazolinyl)-2-(methyloxy)-3-pyridi

cyclopropanesulfonamide (22 mg, 0.047 mmol, 34.1 % yield) as a white solid: ¹H N R (400 MHz, DMSO-c/₆) δ ppm 0.80 - 1.04 (m, 4 H) 2.71 - 2.79 (m, 1 H) 3.96 (s, 3 H) 6.38 (br. s., 2 H) 7.36 (dd, J=12.10, 7.90 Hz, 3 H) 7.48 - 7.62 (m, 3 H) 7.87 - 7.95 (m, 2 H) 8.05 (d, J=2.15 Hz, 1 H) 8.32 (d, J=2.15 Hz, 1 H) 9.44 (br. s., 1 H); ES LC-MS m/z =464.3 (M+H)⁺.

EXAMPLE 73

N-[5-(2-amino-4-oxo-3-phenyl-3,4-dihydro-6-quinazolinyl)-2-(methyloxy)-3- pyridinyljmethanesulfonainide

[00271] A solution of methanesulfonyl chloride (128 mg, 1.12 mmol) and 2-amino-6-[5- amino-6-(methyloxy)-3-pyridinyl]-3-phenyl-4(3H)-quinazolinone (50 mg, 0.139 mmol) in pyridine (1 mL) was maintained at room temperature for 1 day. The resulting mixture was treated with MeOH (1 mL) and concentrated. The residue was dissolved in DMF and purified by HPLC (10- 90% CH₃CN/H₂0, both containing 0.1% formic acid) to obtain N-[5-(2-amino-4-oxo-3-phenyl- 3,4-dihydro-6-quinazolinyl)-2-(methyloxy)-3-pyridinyl]methanesulfonamide (17 mg, 0.038 mmol, 27.7 % yield) as a white solid: H NMR (400 MHz, DMSO-cfe) δ ppm 3.07 (s, 3 H) 3.95 (s, 3 H) 6.37 (br. s., 2 H) 7.29 - 7.42 (m, 3 H) 7.48 - 7.63 (m, 3 H) 7.87 (d, J=2.24 Hz, 1 H) 7.92 (dd, J=8.58, 2.34 Hz, 1 H) 8.05 (d, =2.24 Hz, 1 H) 8.29 (d, J=1.76 Hz, 1 H) 9.38 (br. s., 1 H); ES LC-MS m/z =438.4 (M+H)⁺.

Example 74

N-[5-(2-amino-4-oxo-3-phenyl-3,4-dihydro-6-quinazolinyl)-2-(m

[00272] 2-amino-6-[5-amino-6-(methyloxy)-3-pyridinyl3-3-phenyl-4(3H)-quinazolinone (35 mg, 0.097 mmol) was dissolved in pyridine (0.5 mL), 1.2 eq. 2-thiophenesulfonyl chloride (21.3 mg, 0.117 mmol) was added to the solution and stirred at room temperature for 3 hours. The mixture was poured into EtOAc (20 mL) and washed with water (3x15 mL). The organic layer was separated, dried over sodium sulfate, filtered, taken to a residue under reduced pressure, and purified by HPLC to give the product N-[5-(2-amino-4-oxo-3-phenyl-3,4-dihydro-6- quinazolinyl)-2-(methyloxy)-3-pyridinyl]-2-thiophenesulfonamide (29.3 mg, 0.058 mmol, 59.7% yield) as a white solid. H N MR (400 MHz, DMSO-d₆) δ ppm 10.15 (s, 1 H), 8.31 (d, J=2.15 Hz, 1 H), 8.00 (d, J=2.15 Hz, 1 H), 7.93 (dd, J=4.98, 1.07 Hz, 1 H), 7.88 (dd, J=8.59, 2.34 Hz, 1 H), 7.82 (d, J=2.34 Hz, 1 H), 7.56 - 7.62 (m, 2 H), 7.50 - 7.56 (m, 2 H), 7.38 (d, J=7.22 Hz, 2 H), 7.34 (d, J=8.58 Hz, 1 H), 7.14 (dd, J=4.88, 3.90 Hz, 1 H), 6.39 (br. s., 2 H), 3.73 (s, 3 H). LCMS: m/z = 506.24 (M+1 ).

Example 75

N-[5-(2-amino-4-oxo-3-phenyl-3,4-dihydro-6-quinazolinyl)-2-(methylo^

dimethyl-4-isoxazolesulfonamide

[00273] Prepared from 2-amino-6-[5-amino-6-(methyloxy)-3-pyridinyl]-3-phenyl-4(3H)- quinazolinone and 3,5-dimethyl-4-isoxazolesulfonyl chloride as described in Example 74. H NMR (400 MHz, DMSO-d₆) δ ppm 10.28 (s, 1 H), 8.21 - 8.44 (m, 1 H), 8.02 (s, 1 H), 7.90 (dd, J=8.59, 1.95 Hz, 1 H), 7.76 - 7.87 (m, 1 H), 7.50 - 7.62 (m, 3 H), 7.36 (dd, J=14.84, 7.81 Hz, 3 H), 6.40 (br. s., 2 H), 3.71 (s, 3 H), 2.31 (s, 3 H), 2.25 (s, 3 H). LCMS: m/z = 519.27 (M+1).

Example 76 N-[5-(2-amino-4-oxo-3-phenyl-3,4-dihydro-6-quinazolinyl)-2-(meth^

dimethyl-1H-pyrazole-4-suffonamide

[00274] Prepared from 2-amino-6-[5-amino-6-(methyloxy)-3-pyridinyl]-3-phenyl-4(3H)- quinazolinone and 3,5-dimethyl-1 H-pyrazole-4-sulfonyl chloride as described in Example 74. H NMR (400 MHz, DMSO-d₆) δ ppm 12.85 (s, 1 H), 9.60 (s, 1 H), 8.27 (d, J=2.15 Hz, 1 H), 7.99 (d, J=2.34 Hz, 1 H), 7.87 (dd, J=8.59, 2.34 Hz, 1 H), 7.80 (d, J=2.15 Hz, 1 H), 7.56 - 7.62 (m, 2 H), 7.54 (d, J=7.22 Hz, 1 H), 7.38 (d, J=7.02 Hz, 2 H), 7.34 (d, J=8.59 Hz, 1 H), 6.39 (br. s., 2 H), 3.72 (s, 3 H), 2.17 (s, 3 H), 2.13 (s, 3 H). LCMS: m/z = 518.31 (M+1 ).

Example 77

N-[5-(2-amino-4-oxo-3-phenyl-3,4-dihydro-6-quinazolinyl)-2-(m

methyl-1H-indole-7 -sulfonamide

[00275] Prepared from 2-amino-6-[5-amino-6-(methyloxy)-3-pyridinyl]-3-phenyl-4(3H)- quinazolinone and 1 -methyl- 1H-indole-7-sulfonyl chloride as described in Example 74.

1H NMR (400 MHz, DMSO-d₆) δ ppm 10.31 (br. s., 1 H), 8.19 (br. s., 1 H), 7.89 (d, J=2.15 Hz, 1 H), 7.83 (d, J=7.62 Hz, 1 H), 7.72 - 7.78 (m, 2 H), 7.69 (d, J=7.42 Hz, 1 H), 7.50 - 7.61 (m, 3 H), 7.47 (d, J=3.12 Hz, 1 H), 7.36 (d, J=7.23 Hz, 2 H), 7.29 (d, J=8.59 Hz, 1 H), 7.09 (t, J=7.71 Hz, 1 H), 6.62 (d, J=3.12 Hz, 1 H), 6.37 (br. s., 2 H), 4.24 (s, 3 H), 3.77 (s, 3 H). LCMS: m/z = 553.25 (M+1).

Example 78

N-[5-(2-amino-4-oxo-3^henyl-3,4-dihydro-6-quinazolm^' yl)-2-(meth^

(methyloxy)-3-pyridinesulfonamide

[00276] Prepared from 2-amino-6-[5-amino-6-(methyloxy)-3-pyridinyl]-3-phenyl-4(3H)- quinazolinone and 6-(methyloxy)-3-pyridinesulfonyl chloride as described in Example 74.

H NMR {400 MHz, DMSO-d₆) δ ppm 10.09 (s, 1 H), 8.46 {d, J=2.54 Hz, 1 H), 8.31 (d, J=2.34 Hz, 1 H), 7.97 - 8.04 (m, 2 H), 7.89 (dd, J=8.59, 2.34 Hz, 1 H), 7.86 (d, J=2.34 Hz, 1 H), 7.50 - 7.63 (m, 3 H), 7.36 (dd, J=15.62, 7.81 Hz, 3 H), 7.00 (d, J=8.98 Hz, 1 H), 6.41 (br. s., 2 H), 3.89 (s, 3 H), 3.66 (s, 3 H). LCMS: m/z = 531.25 (M+1 ).

Example 79

N-[5-(2-amino-4-oxo-3-phenyf-3,4-dihydro-6-quinazofinyf)-2-(methyloxy

[00277] Prepared from 2-amino-6-[5-amino-6-(methyloxy)-3-pyridinyl]-3-phenyl-4(3H)- quinazolinone and 3-pyridinesulfonyl chloride as described in Example 74. H NMR (400 MHz, DMSO-d₆) δ ppm 10.29 (br. s., 1 H), 8.87 (d, J=2.15 Hz, 1 H), 8.79 (d, J=4.10 Hz, 1 H), 8.30 (br. s., 1 H), 8.09 (dt, J=8.15, 1.88 Hz, 1 H), 8.01 (d, J=2.15 Hz, 1 H), 7.88 (dd, J=8.59, 1.95 Hz, 1 H), 7.84 (s, 1 H), 7.49 - 7.63 (m, 4 H), 7.38 (d, J=7.22 Hz, 2 H), 7.34 (d, J=8.59 Hz, 1 H), 6.39 (br. s., 2 H), 3.60 (s, 3 H). LCMS: m/z = 501.29 ( +1 ).

General Scheme 6

1 ,4-dioxane, H₂0

INTERMEDIATE 1

2-methyl-N-[2-(methyioxy)-5-(4,4, 5, 5-tetramethyl- 1, 3, 2-dioxaborolan-2-yi)-3-pyridinyi]- 1- propanesulfonamide

Step A

N-[5-bromo-2-(methyioxy)-3 yridinyl]-2-methyl-1-propanesulfonamide

[00278] A mixture of 5-bromo-2-(methyloxy)-3-pyridinamine (500 mg, 2.463 mmol), 2- methyl-1 -propanesulfonyl chloride (2314 mg, 14.78 mmol) and DMAP (30.1 mg, 0.246 mmol) in pyridine (10 ml.) was maintained at room temperature for 17 hours. The resulting mixture was concentrated. The residue was dissolved in CH₂CI₂ and purified by column chromatography (0- 100% EtOAc/hexane) to afford N-[5-bromo-2-(methyloxy)-3-pyridinyl]-2-methyl-1- propanesulfonamide (370 mg, 1.145 mmol, 46.5 % yield) as a yellow solid: ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.01 (d, 6 H) 2.17 (m, J=13.29, 6.64, 6.64, 6.64, 6.64 Hz, 1 H) 3.07 (d, J=6.35 Hz, 2 H) 3.90 (s, 3 H) 7.76 (d, J=2.25 Hz, 1 H) 8.08 (d, J=2.25 Hz, 1 H) 9.51 (s, 1 H) ES LC-MS m/z =323.1 (Br⁷⁹, M+H)⁺, ES LC-MS m/z =325.1 (Br⁸¹, M+H)⁺.

Step B

2-methyl-N-[2-(methyloxy)-5-(4 ,5,5-tetramethyl-1,3,2-dioxaborolan-2^

propanesulfonamide

[00279] A degassed mixture of N-[5-bromo-2-(methyloxy)-3-pyridinyl]-2-methyl-1- propanesulfonamide (366 mg, 1.132 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-1 ,3,2- dioxaborolane (316 mg, 1.246 mmol), Pd(dppf)₂CI₂ CH₂CI₂ adduct (92 mg, 0.1 13 mmol) and potassium acetate (333 mg, 3.40 mmol) in 1 ,4-dioxane (20 mL) was heated at 80 °C. After 2 hours the reaction mixture was allowed to cool to room temperature and filtered through a pad of Celite® with the aid of EtOAc. The filtrate was concentrated and reevaporated from

CH₂CI₂/hexane. The residue was dissolved in CH₂CI₂ and purified by column chromatography (silica gel, 0-100% EtOAc/hexane) to obtain 2-methyl-N-[2-(methyloxy)-5-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)-3-pyridinyl]-1-propanesulfonamide (346 mg, 0.934 mmol, 83 % yield) as a solid: H NMR (400 MHz, DMSO-d₆) δ ppm 1.00 (d, J=6.73 Hz, 6 H) 1.29 (s, 12 H) 2.17 (dt, J=13.22, 6.56 Hz, 1 H) 2.96 (d, J=6.34 Hz, 2 H) 3.93 (s, 3 H) 7.78 (s, 1 H) 8.20 (s, 1 H) 9.28 (s, 1 H); ES LC-MS m/z =371 .4 (M+H)⁺.

INTERMEDIATE 2

1, 1, 1-trifluoro-N-[2-(methyloxy)-5-(4, 4, 5, 5-tetramethyl-1 ,3, 2-dioxaborolan-2-yl)-3- pyridinyl]methanesulfonamide

Step A

N-[5-bromo-2-(methyloxy)-3-pyridinyl]-1, 1, 1-trifluoromethanesulfonamide

[00280] A 0 °C solution of 5-bromo-2-(methyloxy)-3-pyridinamine (500 mg, 2.463 mmol) in CH₂CI₂ (30 mL) was treated with trifluoromethanesulfonyl anhydride (2084 mg, 7.39 mmol). After 30 minutes the resulting mixture was diluted with water (50 mL) and extracted with CH₂CI₂ (100 mL). The organic layer was washed with a sat. NaHC0₃ solution. The aqueous layer was neutralized with a 1 N HCI solution and extracted with 4 x 75 mL CH₂CI₂. The organic layers were combined and concentrated to obtain N-[5-bromo-2-(methyloxy)-3-pyridinyl]-1 ,1 ,1- trifluoromethanesulfonamide (743 mg, 2.217 mmol, 90 % yield) as a white solid: ¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.90 (s, 3 H) 7.87 (dd, J=2.20, 1.12 Hz, 1 H) 8.21 (d, J=2.15 Hz, 1 H).

Step B

1, 1, 1-trifluoro-N-[2-(methyloxy)-5-(4,4, 5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-

[00281] A degassed mixture N-[5-bromo-2-(methyloxy)-3-pyridinyl]-1 ,1 ,1- trifluoromethanesulfonamide (741 mg, 2.21 1 mmol), 4,4,4',4',5,5,5',5^,-octamethyl-2,2'-bi-1 ,3,2- dioxaborolane (6 8 mg, 2.432 mmol), Pd(dppf)₂CI₂ CH₂CI₂ adduct ( 81 mg, 0.221 mmol) and potassium acetate (651 mg, 6.63 mmol) in 1 ,4-dioxane (20 mL) was heated at 80 °C for 2 hours. The resulting mixture was allowed to cool to room temperature and was filtered through a pad of Celite® with the aid of EtOAc. The filtrate was concentrated and reevaporated from

CH₂CI₂/hexane. The residue was dissolved in CH₂CI₂ and purified by column chromatography (silica gel, 0-100% EtOAc/hexane) to obtain 1 ,1 ,1 -trifluoro-N-[2-(methyloxy)-5-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)-3-pyridinyl]methanesulfonamide (502 mg, 1.314 mmol, 59.4 % yield) as a white solid: ¹H NMR (400 MHz, DMSO- ₆) δ ppm 1.30 (s, 12 H) 3.96 (s, 3 H) 7.75 (s, 1 H) 8.34 (s, 1 H); ES LC-MS m/z =383.3 (M+H)⁺.

EXAMPLE 80

N-[5-(2-amino-4-oxo-3-phenyl-3,4-dihydro-6-quinazolinyl)-2-(methyloxy)-3-py

trifluoromethanesulfonamide

[00282] A mixture of 1 ,1 ,1-trifluoro-N-[2-(methyloxy)-5-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)-3-pyridinyl]methanesulfonamide (70 mg, 0.183 mmol), 2-amino-6-iodo-3- phenyl-4(3H)-quinazolinone (66.5 mg, 0.183 mmol), potassium acetate (53.9 mg, 0.550 mmol), Pd(dppf)₂CI₂ CH₂CI₂ adduct (14.96 mg, 0.018 mmol) in dioxane (2 mL) and water (0.5 mL) was heated at 90 °C for 3 hours. The resulting mixture was allowed to cool to room temperature and diluted with EtOAc (50 mL) and water (50 mL). The aqueous layer was washed with CH₂CI₂ (50 mL). The organic layers were combined, dried (Na₂S0₄), filtered and concentrated. The residue was taken up into DMF and purified by HPLC (10-70% CH₃CN/H₂0, both containing 0.1% formic acid) to obtain N-[5-(2-amino-4-oxo-3-phenyl-3,4-dihydro-6-quinazolinyl)-2-(methyloxy)-3- pyridinyl]-1 ,1 ,1-trifluoromethanesulfonamide (25 mg, 0.048 mmol, 26.1 % yield) as a white solid: ¹H NMR (400 MHz, DMSO-cf₆) δ ppm 3.87 (s, 3 H) 7.44 (br. s., 3 H) 7.52 - 7.65 (m, 4 H) 7.83 (br. s., 1 H) 7.95 (d, J=8.88 Hz, 1 H) 8.06 (d, =1.95 Hz, 1 H) 8.10 - 8.19 (m, 1 H); ES LC-MS m/z =492.3 (M+H)⁺.

EXAMPLE 81

N-[5-(2-amino-4-oxo-3-phenyl-3,4-dihydro-6-quinazolinyl)-2-(methy

methyl- 1-propanesulfonamide

[00283] A mixture of 2-methyl-N-[2-(methyloxy)-5-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)-3-pyridinyl]-1-propanesulfonamide (68.3 mg, 0.184 mmol), 2-amino-6-iodo-3- phenyl-4(3H)-quinazolinone (67 mg, 0.184 mmol), potassium acetate (54.3 mg, 0.553 mmol), Pd(dppf)₂CI₂ CH₂CI₂ adduct (15.07 mg, 0.018 mmol) in dioxane (2 mL) and water (0.5 mL) was heated at 90 °C for 3 hours. The resulting mixture was allowed to cool to room temperature and diluted with EtOAc (50 mL) and water (50 mL). The aq. layer was washed with CH₂CI₂ (50 mL). The organic layers were combined, dried (Na₂S0₄), filtered and concentrated. The residue was taken up into DMF and purified by HPLC (10-60% CH₃CN/H₂0, both containing 0.1 % formic acid) to obtain N-[5-(2-amino-4-oxo-3-phenyl-3,4-dihydro-6-quinazolinyl)-2-(methyloxy)-3- pyridinyl]-2-methyl-1-propanesulfonamide (44 mg, 0.091 mmol, 49.2 % yield) as a white solid: ¹H NMR (400 MHz, DMSO-cf₆) δ ppm 1.02 (d, J=6.73 Hz, 6 H) 2.12 - 2.26 (m, 1 H) 3.05 (d, J=6.34 Hz, 2 H) 3.95 (s, 3 H) 6.38 (br. s., 2 H) 7.31 - 7.42 (m, 3 H) 7.49 - 7.64 (m, 3 H) 7.85 - 7.95 (m, 1 H) 8.05 (d, J=2.24 Hz, 1 H) 8.14 (s, 1 H) 8.31 (d, J=2.24 Hz, 1 H) 9.41 (br. s., 1 H); ES LC-MS m/z =480.4 (M+H)⁺. General Scheme 7

EXAMPLE 82

Methyl 4-[2-amino-6-[5-{[(2,4-difluorophenyl)sulfonyl]amino}-6-(methyloxy)-3-py oxo-3(4H)-quinazolinyl]benzoate

Step A

Methyl 4-( 6-iodo-4-oxo-2-thioxo- 1, 4-dihydro-3(2H)-quinazolinyl)benzoate

[00284] A solution of 2-amino-5-iodobenzoic acid (3 g, 1 1.41 mmol) methyl 4- isothiocyanatobenzoate (2.204 g, 1 1.41 mmol) and TEA (2.226 mL, 15.97 mmol) were refluxed in EtOH (54.8 mL). After 5 minutes, a heavy precipitate formed. After 1 hour the reaction mixture was cooled to 0 °C, the solid was filtered off, and then rinsed with cold EtOH (3x) to give methyl 4-(6-iodo-4-oxo-2-thioxo-1 ,4-dihydro-3(2H)-quinazolinyl)benzoate (3.072 g, 7.01 mmol, 61.5% yield) as an off-white solid. LCMS: 439 (M+H); 1 H NMR (400 MHz ,DMSO-cf₆) δ = 13.18 (br. s., 1 H), 8.18 (d, J = 2.0 Hz, 1 H), 8.09 (dd, J = 2.1 , 8.6 Hz, 1 H), 8.08 - 8.03 (m, 2 H), 7.50 - 7.42 (m, 2 H), 7.25 (d, J = 8.6 Hz, 1 H), 3.89 (s, 3 H).

Step B

Methyl 4-(2-chloro-6-iodo-4-oxo-3(4H)-quinazolinyl)benzoate

[00285] A solution of methyl 4-(6-iodo-4-oxo-2-thioxo-1 ,4-dihydro-3(2H)- quinazolinyl)benzoate (3.07 g, 7.01 mmol) in POCI₃ (15.67 mL, 168 mmol) was treated with PCI₅ (2.422 g, 1 1.63 mmol). The mixture was heated to reflux for 3 hours. The solvents were removed under reduced pressure. The residue was taken up in EtOAc and water when a solid formed which was filtered off, washed with water (3x) and EtOAc (3x), dried to give methyl 4-(2- chloro-6-iodo-4-oxo-3(4H)-quinazolinyl)benzoate (1.925 g, 4.37 mmol, 62.4 % yield) as a pale yellow powder. LCMS: 441 (M+H); ¹H NMR (400 MHz , DMSO-d₆) δ = 8.38 (d, J = 2.0 Hz, 1 H), 8.21 (dd, J = 2.0, 8.6 Hz, 1 H), 8.16 - 8.1 1 (m, 2 H), 7.73 - 7.66 (m, 2 H), 7.51 (d, J = 8.5 Hz, 1 H), 3.90 (s, 3 H). Step C

Methyl 4-(2-chloro-6-iodo-4-oxo-3(4H)-quinazolinyl)benzoate

[00286] Methyl 4-(2-chloro-6-iodo-4-oxo-3(4H)-quinazolinyl)benzoate (1 .66 g, 3.77 mmol) was suspended in 1 -butanol (30 mL), TEA (1 .050 mL, 7.53 mmol) and 4-methoxylbenzylamine (0.685 mL, 5.27 mmol) were added and the mixture was heated in a sealed tube at 140 °C in a microwave reactor for 25 minutes. It was cooled down, the crystallized product was filtered off, washed with EtOH (3x) and dried to give methyl 4-[6-iodo-2-({[4-

(methyloxy)phenyl]methyl}amino)-4-oxo-3(4H)-quinazolinyl]benzoate (1.71 g, 3.16 mmol, 84 % yield) as a white solid. LCMS: 542 (M+H); H NMR (400 MHz, DMSO-af₅) δ = 8.20 - 8.10 (m, 3 H), 7.86 (dd, J = 2.1 , 8.6 Hz, 1 H), 7.62 - 7.52 (m, 2 H), 7.27 - 7.17 (m, 2 H), 7.10 (d, J = 8.6 Hz, 1 H), 6.88 - 6.78 (m, 2 H), 6.62 (t, J = 5.9 Hz, 1 H), 4.41 (d, J = 5.9 Hz, 2 H), 3.91 (s, 3 H), 3.70 (s, 3 H).

Step D

Methyl 4-(2-amino-6-iodo-4-oxo-3(4H)-quinazolinyi)benzoate

[00287] A solution of methyl 4-[6-iodo-2-({[4-(methyloxy)phenyl]methyl}amino)-4-oxo- 3(4H)-quinazolinyl]benzoate (500 mg, 0.924 mmol) in Trifluoroacetic acid (TFA) (10 mL) was heated in a microwave reactor for 15 minutes at 140 °C then the TFA was distilled off, the residue was triturated with ether and dried to give methyl 4-(2-amino-6-iodo-4-oxo-3(4H)- quinazolinyl)benzoate (455 mg, 0.850 mmol, 92 % yield) TFA salt as a light green powder. LCMS: 422 (M+H); H NMR (400 MHz, DMSO-d₆) δ = 8.20 (d, J = 2.0 Hz, 1 H), 8.19 - 8.14 (m, 2 H), 8.03 (dd, J = 1.9, 8.6 Hz, 1 H), 7.61 (d, J = 8.5 Hz, 2 H), 7.21 (d, J = 8.6 Hz, 1 H), 3.92 (s, 3 H).

Step E

Methyl 4-[2-amino-6-[5-{[(2 -difluorophenyl)sulfonyl]amino}-6-(mefa^^

3(4H)-quinazolinyl]benzoate

[00288] A suspension of methyl 4-(2-amino-6-iodo-4-oxo-3(4H)-quinazolinyl)benzoate (450 mg, 1.068 mmol), 2,4-difluoro-N-[2-(methyloxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan- 2-yl)-3-pyridinyl]benzenesulfonamide (455 mg, 1.068 mmol), PdCI₂(dppf)-CH₂Cl₂ adduct (87 mg, 0.107 mmol) and cesium carbonate (348 mg, 1.068 mmol) in tetrahydrofuran (THF) (8547 μΙ_) and water (2137 μ!_) was heated at 60 C° for 1 hour. The solvent was evaporated and the residue was triturated with water to give methyl 4-[2-amino-6-[5-{[(2,4- difluorophenyl)sulfonyl]amino}-6-(methyloxy)-3-pyridinyl]-4-oxo-3(4H)-quinazolinyl]benzoate (528 mg, 0.890 mmol, 83 % yield). LCMS: 594 (M+H); ¹H NMR (400 MHz, DMSO-d₆) δ = 10.31 (br. s., 1 H), 8.30 (br. s., 1 H), 8.14 (d, J = 8.4 Hz, 2 H), 8.01 (d, J = 2.0 Hz, 1 H), 7.89 (dd, J = 2.0, 8.6 Hz, 1 H), 7.83 (d, J = 1.9 Hz, 1 H), 7.80 - 7.71 (m, 1 H), 7.60 - 7.51 (m, 3 H), 7.34 (d, J = 8.6 Hz, 1 H), 7.24 - 7.16 (m, 1 H), 6.55 (br. s., 2 H), 3.91 (s, 3 H), 3.65 (s, 3 H).

EXAMPLE 83

4-[2-amino-6-[5-{[(2,4-difluorophenyl)sulfonyl]amino}-6-(methyloxy)-^^

3(4H)-quinazolinyl]-N-methylbenzamide

Step A

4-[2-amino-6-[5-{[(2 -difiuorophenyl)sulfonyl]amino}-6-(^

quinazolinyljbenzoic acid

[00289] Methyl 4-[2-amino-6-[5-{[(2,4-difluorophenyl)sulfonyl]amino}-6-(methyloxy)-3- pyridinyl]-4-oxo-3(4H)-quinazolinyl]benzoate (528 mg, 0.890 mmol) and LiOH (187 mg, 4.45 mmol) was dissolved in a solvent mixture of tetrahydrofuran (THF) (2965 μΐ_), methanol (741 μΙ_) and water (741 μΙ_). The solution was stirred at room temperature for 1 hr then it was

evaporated, the residue diluted with water and neutralized with 1 M HCI (4448 μ!_, 4.45 mmol). The precipitate was spun down, washed with water (4x) by re-suspending and spinning down then lyophilized to give 4-[2-amino-6-[5-{[(2,4-difluorophenyl)sulfonyl]amino}-6-(methyloxy)-3- pyridinyl]-4-oxo-3(4H)-quinazolinyl]benzoic acid (in quantitative yield. LCMS: 580 (M+H); H NMR (400MHz, DMSO-d₆) δ = 13.20 (br. s., 1 H), 10.30 (br. s., 1 H), 8.30 (br. s., 1 H), 8.19 - 8.07 (m, 2 H), 8.02 (d, J = 2.1 Hz, 1 H), 7.89 (dd, J = 2.3, 8.6 Hz, 1 H), 7.83 (d, J = 2.1 Hz, 1 H), 7.76 (td, J = 6.4, 8.5 Hz, 1 H), 7.63 - 7.45 (m, 3 H), 7.34 (d, J = 8.5 Hz, 1 H), 7.20 (td, J = 2.1 , 8.5 Hz, 1 H), 6.51 (br. s., 2 H), 3.65 (s, 3 H). Step B

4-[2-amino-6-[5-{[(2,4-difluorophenyl)sulfonyl]amino}-6-(methyloxy)-^^

quinazolinyl]-N-methylbenzamide

[00290] To an ice cold solution of 4-[2-amino-6-[5-{[(2,4-difluorophenyl)sulfonyl]amino}-6- (methyloxy)-3-pyridinyl]-4-oxo-3(4H)-quinazolinyl]benzoic acid (50 mg, 0.086 mmol) and 2 M methylamine/THF (216 μΙ_, 0.431 mmol) in Ν,Ν-dimethylformamide (DMF) (570 μΙ_) T3P (77 μΙ_, 0.129 mmol) was added dropwise. The reaction stalled at about 65% conversion, therefore the same amount of methylamine and T3P was introduced again. After the reaction finished, the mixture was then evaporated, the residue triturated with water and then purified on a RP-HPLC to give 4-[2-amino-6-[5-{[(2,4-difluorophenyl)sulfonyl]amino}-6-(methyloxy)-3-pyhdinyl]-4-oxo- 3(4H)-quinazolinyl]-N-methylbenzamide (16.5 mg, 0.028 mmol, 32.3 % yield) as a white solid. LCMS: 593 (M+H). ¹H NMR (400 MHz, DMSO-cf₆) δ = 10.32 (br. s., 1 H), 8.73 - 8.52 (m, 1 H), 8.33 (d, J = 2.0 Hz, 1 H), 8.10 - 7.96 (m, 3 H), 7.95 - 7.82 (m, 2 H), 7.82 - 7.69 (m, 1 H), 7.65 - 7.52 (m, 1 H), 7.52 - 7.42 (m, 2 H), 7.34 (d, J = 8.6 Hz, 1 H), 7.27 - 7.12 (m, 1 H), 6.52 (br. s., 2 H), 3.64 (s, 3 H), 2.83 (d, J = 4.3 Hz, 3 H).

EXAMPLE 84

Methyl 4-[2-amino-6-(5-{[(2,4-difluorophenyl)sulfonyl]amino}-6-oxo- 1, 6-dihydro-3- pyridinyl)-4-oxo-3(4H)-quinazolinyl]benzoate

Step A

Methyl 4-[6-[5-{[(2,4-difluorophenyl)sulfonyl]amino}-6-(

(methyloxy)phenyl]methyl}amino)-4-oxo-3(4H)-quinazolinyl]benzoate

[00291] A suspension of methyl 4-[6-iodo-2-({[4-(methyloxy)phenyl]methyl}amino)-4-oxo- 3(4H)-quinazolinyl]benzoate (36 mg, 0.067 mmol), 2,4-difluoro-N-[2-(methyloxy)-5-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)-3-pyridinyl]benzenesulfonamide (28.3 mg, 0.067 mmol), PdCI₂(dppf)-CH₂C|₂ adduct (5.43 mg, 6.65 μιηοΙ) and cesium carbonate (21.67 mg, 0.067 mmol) in tetrahydrofuran (THF) (532 μΐ_) and water (133 μΙ_) was heated at 60 °C for 2 hours. The solvent was evaporated, the brown residue triturated with water and dried to give methyl 4-[6-[5- {[(2,4-difluorophenyl)sulfonyl]amino}-6-(methyloxy)-3-pyridinyl]-2-({[4- (methyloxy)phenyl]methyl}amino)-4-oxo-3(4H)-quinazolinyl]benzoate as a brown solid in quantitative yield. LCMS: 714 (M+H). It was used without further purification.

Step B Methyl 4-[2-amino-6-(5-{[(2, 4-difluorophenyl)sulfonyl]amino}-6-oxo- 1, 6-dihydro-3-pyridinyl)-4- oxo-3(4H)-quinazolinyi]benzoate

[00292] A solution of methyl 4-[6-[5-{[(2,4-difluorophenyl)sulfonyl]amino}-6-(methyloxy)-3- pyridinyl]-2-({[4-(methyloxy)phenyl]methyl}amino)-4-oxo-3(4H)-quinazolinyl]benzoate (54 mg, 0.076 mmol) in trifluoroacetic acid (TFA) (2 mL) was heated at 65 °C for 7 hour to reach about 20% conversion. The mixture was put then in a microwave reactor and heated at 140 °C for 40 minutes. The TFA was evaporated and the residue purified on a RP-HPLC to give methyl 4-[2- amino-6-(5-{[(2,4-difluorophenyl)sulfonyl]amino}-6-oxo-1 ,6-dihydro-3-pyridinyl)-4-oxo-3(4H)- quinazolinyl]benzoate (22 mg, 0.038 mmol, 50.2 % yield). LCMS: 580 (M+H); H NMR (400 MHz ,DMSO-Gf₆) δ = 12.16 (br. s., 1 H), 9.85 (br. s., 1 H), 8.22 - 8.05 (m, 2 H), 7.99 - 7.86 (m, 2 H), 7.79 (dd, J = 1.9, 8.6 Hz, 1 H), 7.72 (d, J = 2.1 Hz, 1 H), 7.64 - 7.48 (m, 4 H), 7.30 (d, J = 8.6 Hz, 1 H), 7.27 - 7.20 (m, 1 H), 6.52 (br. s., 2 H), 3.91 (s, 3 H).

EXAMPLE 85

4-[2-amino-6-(5-{[(2,4-difluorophenyl)sulfonyl]amino}-6-oxo-1,6-dihydro-3-pyridm

oxo-3(4H)-quinazolinyl]benzoic acid

Step A

4-[6-[5-{[(2 -difluorophenyl)sulfonyl]amino}-6-(methyloxy

(methyloxy)phenyl]methyl}amino)-4-oxo-3(4H)-quinazolinyl]benzoic acid

[00293] Methyl 4-[6-[5-{[(2,4-difluorophenyl)sulfonyl]amino}-6-(methyloxy)-3-pyridinyl]-2- ({[4-(methyloxy)phenyl]methyl}amino)-4-oxo-3(4H)-quinazolinyl]benzoate (100 mg, 0.140 mmol) and LiOHxH₂0 (29.4 mg, 0.701 mmol) were dissolved in a solvent mixture of tetrahydrofuran (THF) (467 μΙ_), methanol (1 17 μΙ_), water (1 17 μΙ_) and the solution was stirred at room temperature for 1 hour when the solvents were evaporated, the residue was dissolved in water and neutralized with 1 M HCI (701 μΙ_, 0.701 mmol), the precipitate was spun down, washed with water (4x) and lyophilized to give 4-[6-[5-{[(2,4-difluorophenyl)sulfonyl]amino}-6- (methyloxy)-3-pyridinyl]-2-({[4-(methyloxy)phenyl]methyl}amino)-4-oxo-3(4H)- quinazolinyl]benzoic acid (70 mg, 0.100 mmol, 71.4 % yield). LCMS: 700 (M+H); H NMR (400 MHz, DMSO- ₆) 6 = 13.23 (br. s., 1 H), 10.31 (br. s., 1 H), 8.32 (d, J = 1.2 Hz, 1 H), 8.19 - 8.08 (m, 2 H), 8.03 (d, J = 1.7 Hz, 1 H), 7.95 - 7.80 (m, 2 H), 7.79 - 7.72 (m, 1 H), 7.60 - 7.51 (m, J = 8.3 Hz, 4 H), 7.38 (d, J = 8.6 Hz, 1 H), 7.29 - 7.17 (m, J = 8.5 Hz, 2 H), 6.92 - 6.78 (m, 2 H), 6.60 (t, J = 5.9 Hz, 1 H), 4.45 (d, J = 5.4 Hz, 2 H), 3.70 (s, 3 H), 3.65 (s, 3 H).

Step B

4-[2-amino-6-(5-{[(2 -dif!uorophenyl)sulfonyl]amino}-6-oxo

3(4H)-quinazolinyl]benzoic acid

[00294] A solution of 4-[6-[5-{[(2,4-difluorophenyl)sulfonyl]amino}-6-(methyloxy)-3- pyridinyl]-2-({[4-(methyloxy)phenyl]methyl}amino)-4-oxo-3(4H)-quinazolinyl]ben acid (65 mg, 0.093 mmol)m in TFA (1 mL, 12.98 mmol) was heated at 70 °C for four days. The TFA was evaporated and the product was separated on RP-HPLC to give 4-[2-amino-6-(5-{[(2,4- difluorophenyl)sulfonyl]amino}-6-oxo-1 ,6-dihydro-3-pyridinyl)-4-oxo-3(4H)-quinazolinyl]benzoic acid (5.2 mg, 9.20 Mmol, 9.90 % yield). LCMS: 566 (M+H); ¹H NMR (400 MHz, DMSO-cf₆) δ = 12.17 (br. s., 1 H), 9.85 (br. s., 1 H), 8.12 (d, J = 8.4 Hz, 2 H), 7.97 - 7.87 (m, 2 H), 7.80 (dd, J = 2.1 , 8.6 Hz, 1 H), 7.72 (d, J = 2.4 Hz, 1 H), 7.60 - 7.46 (m, 5 H), 7.31 (d, J = 8.6 Hz, 1 H), 7.24 (td, J = 2.1 , 8.5 Hz, 1 H), 6.58 (br. s., 2 H).

[00295] The partially hydrolyzed product was also isolated: 4-[2-amino-6-[5-{[(2,4- difluorophenyl)sulfonyl]amino}-6-(methyloxy)-3-pyridinyl]-4-oxo-3(4H)-quinazolinyl]benzoic acid (Example 86) (8.2 mg, 0.014 mmol, 15.23 % yield). LCMS: 580 (M+H); ¹H NMR (400 MHz, DMSO-d₆) δ = 13.20 (br. s., 1 H), 10.30 (br. s., 1 H), 8.30 (br. s., 1 H), 8.19 - 8.07 (m, 2 H), 8.02 (d, J = 2.1 Hz, 1 H), 7.89 (dd, J = 2.3, 8.6 Hz, 1 H), 7.83 (d, J = 2.1 Hz, 1 H), 7.76 (td, J = 6.4, 8.5 Hz, 1 H), 7.63 - 7.45 (m, 3 H), 7.34 (d, J = 8.5 Hz, 1 H), 7.20 (td, J = 2.1 , 8.5 Hz, 1 H), 6.51 (br. s., 2 H), 3.65 (s, 3 H).

EXAMPLE 86

4-[2-amino-6-[5-{[(2,4-difluorophenyl)sulfonyl]amino}-6-(methyloxy)-3-pyrid

3(4H)-quinazolinyl]benzoic acid

[00296] 4-[2-amino-6-[5-{[(2,4-difluorophenyl)sulfonyl]amino}-6-(methyloxy)-3-pyridin oxo-3(4H)-quinazolinyl]benzoic acid has been synthesize in two ways as described in Example 85, Step B and Example 83, Step A. LCMS: 580 (M+H); H NMR (400 MHz, DMSO-d₆) δ = 13.20 (br. s., 1 H), 10.30 (br. s., 1 H), 8.30 (br. s., 1 H), 8.19 - 8.07 (m, 2 H), 8.02 (d, J = 2.1 Hz, 1 H), 7.89 (dd, J = 2.3, 8.6 Hz, 1 H), 7.83 (d, J = 2.1 Hz, 1 H), 7.76 (td, J = 6.4, 8.5 Hz, 1 H), 7.63 - 7.45 (m, 3 H), 7.34 (d, J = 8.5 Hz, 1 H), 7.20 (td, J = 2.1 , 8.5 Hz, 1 H), 6.51 (br. s., 2 H), 3.65 (s, 3 H).

EXAMPLE 87

4-[2-amino-6-[5-{[(2,4-difluorophenyl)sulfonyl]amino}-6-(methyloxy)-3-pyrid

3(4H)-quinazolinyl]-N, N-dime thylbenzamide

[00297] This compound was synthesized according to the procedure described in Example 83, Step B, except instead of methylamine, dimethylamine was used. LCMS: 607 (M+H); 1 H NMR (400 MHz, DMSO-d₆) δ = 10.31 (br. s., 1 H), 8.31 (d, J = 1.4 Hz, 1 H), 8.02 (d, J = 2.1 Hz, 1 H), 7.94 - 7.81 (m, 2 H), 7.76 (td, J = 6.4, 8.5 Hz, 1 H), 7.64 - 7.50 (m, 3 H), 7.43 (d, J = 8.3 Hz, 2 H), 7.34 (d, J = 8.6 Hz, 1 H), 7.20 (td, J = 2.1 , 8.4 Hz, 1 H), 6.55 (br. s., 2 H), 3.65 (s, 3 H), 3.01 (d, J = 3.3 Hz, 6 H). EXAMPLE 88

N-[5-{2-amino-3-[4-(4-morpholinylcarbonyl)phenyl]-4-oxo-3,4-dihyd^

(methyloxy)-3-pyridinyl]-2,4-difluorobenzenesulfonamide

[00298] This compound was synthesized according to the procedure described in Example 83, Step B, except instead of methylamine, morpholine was used. LCMS: 649 (M+H); H NMR (400 MHz ,DMSO-c/₆) δ = 10.31 (br. s., 1 H), 8.31 (d, J = 1.8 Hz, 1 H), 8.13 (s, 1 H), 8.02 (d, J = 2.2 Hz, 1 H), 7.89 (dd, J = 2.2, 8.5 Hz, 1 H), 7.84 (d, J = 2.2 Hz, 1 H), 7.76 (td, J = 6.5, 8.5 Hz, 1 H), 7.62 - 7.50 (m, 3 H), 7.45 (d, J = 8.3 Hz, 2 H), 7.34 (d, J = 8.6 Hz, 1 H), 7.20 (td, J = 2.0, 8.5 Hz, 1 H), 6.57 {br. s., 2 H), 3.65 (s, 3 H), 3.4-3.3 {m, 8H)

EXAMPLE 89

N-[5-(2-amino-3-{4-[(4-methyl-1-piperazinyl)carbonyl]phenyl}-4-oxo-3,4-dihydro-6- quinazolinyl)-2-(methyloxy)-3-pyridinyl]-2,4-difluorobenzenesulfonamide

[00299] This compound was synthesized according to the procedure described in Example 83, Step B, except instead of methylamine, 1 -methylpiperazine was used. LCMS: 662 (M+H); ¹H NMR (400 MHz, DMSO-d₆) δ = 8.30 (d, J = 2.2 Hz, 1 H), 8.13 (s, 1 H), 8.02 (d, J = 2.2 Hz, 1 H), 7.89 (dd, J = 2.2, 8.6 Hz, 1 H), 7.84 (d, J = 2.3 Hz, 1 H), 7.76 (td, J = 6.4, 8.5 Hz, 1 H), 7.60 - 7.50 (m, 3 H), 7.44 (d, J = 8.3 Hz, 2 H), 7.34 (d, J = 8.6 Hz, 1 H), 7.20 (td, J = 2.1 , 8.5 Hz, 1 H), 6.59 (br. s., 2 H), 3.65 (s, 3 H), 3.5-3.2 (4H obscured by water peak), 2.47 - 2.29 (m, 4 H), 2.25 (s, 3 H).

EXAMPLE 90

N-[5-{2-amino-4-oxo-3-[4-(1^iperidinylcarbonyl)phenyl]-3,4-dihydro-6-quinazoliny

(methyloxy)-3-pyridinyl]-2,4-difluorobenzenesulfonamide

[00300] This compound was synthesized according to the procedure described in Example 83, Step B, except instead of methylamine piperidine was used. LCMS: 647 M(+H); ¹H NMR (400MHz ,DMSO-d₆) δ = 10.30 (br. s., 1 H), 8.33 (d, J = 2.2 Hz, 1 H), 8.02 (d, J = 2.0 Hz, 1 H), 7.89 (dd, J = 2.0, 8.6 Hz, 1 H), 7.85 (d, J = 2.2 Hz, 1 H), 7.80 - 7.71 (m, 1 H), 7.61 - 7.48 (m, 3 H), 7.43 (d, J = 8.2 Hz, 2 H), 7.34 (d, J = 8.6 Hz, 1 H), 7.21 (td, J = 2.0, 8.4 Hz, 1 H), 6.59 (br. s., 2 H), 3.65 (s, 3 H), 3.25-3.4 (4H, obscured by water), 1.94 - 1.32 (m, 6 H).

EXAMPLE 91

Methyl 3-[2-amino-6-[5-{[(2,4-difluorophenyl)sulfonyl]amino}-6-(methyloxy)-3-pyri^^

oxo-3(4H)-quinazolinyl]benzoate

[00301] This compound was synthesized according to the procedure described in Example 82, Step A to Step E, except in Step A instead of methyl 4-isothiocyanatobenzoate methyl 3-isothiocyanatobenzoate was used. LCMS: 594 (M+H); LCMS: 594 (M+H); H NMR (400MHz ,DMSO-d₆) δ = 10.30 (br. s., 1 H), 8.33 (d, J = 2.2 Hz, 1 H), 8.15 - 8.06 (m, 1 H), 8.02 (d, J = 2.2 Hz, 1 H), 7.97 - 7.92 {m, 1 H), 7.90 (dd, J = 2.2, 8.6 Hz, 1 H), 7.85 (d, J = 2.2 Hz, 1 H), 7.81 - 7.64 (m, 3 H), 7.62 - 7.51 (m, 1 H), 7.34 (d, J = 8.6 Hz, 1 H), 7.21 (td, J = 2.3, 8.5 Hz, 1 H), 6.55 (br. s., 2 H), 3.89 (s, 3 H), 3.65 (s, 3 H).

EXAMPLE 92

4-[2-amino-6-[5-{[(2,4-difluorophenyl)sulfonyl]amino}-6-(methyloxy)-3-pyridiny

3(4H)-quinazolinyl]benzamide

[00302] This compound was synthesized according to the procedure described in Example 83, Step B, except instead of methylamine 0.5 M ammonia in dioxane was used. LCMS: 579 (M+H); ¹H NMR (400MHz ,DMSO-d₆) δ = 10.30 (br. s., 1 H), 8.33 (d, J = 2.1 Hz, 1 H), 8.15 (br. s., 1 H), 8.06 (d, J = 8.3 Hz, 2 H), 8.02 (d, J = 2.0 Hz, 1 H), 7.89 (dd, J = 2.1 , 8.6 Hz, 1 H), 7.85 (d, J = 2.1 Hz, 1 H), 7.80 - 7.71 (m, 1 H), 7.62 - 7.50 (m, 2 H), 7.47 (d, J = 8.3 Hz, 2 H), 7.34 (d, J = 8.5 Hz, 1 H), 7.20 {id, J = 2.1 , 8.5 Hz, 1 H), 6.50 (br. s., 2 H), 3.65 (s, 3 H).

EXAMPLE 93

3-[2-amino-6-[5-{[(2,4-difluorophenyl)sulfonyl]amino}-6-(methyloxy)-3-p^

3(4H)-quinazolinyl]-N-methylbenzamide

[00303] This compound was synthesized according to the procedure described in Example 83, Step B, except instead of 4-[2-amino-6-[5-{[(2,4-difluorophenyl)sulfonyl]amino}-6- (methyloxy)-3-pyridinyl]-4-oxo-3(4H)-quinazolinyl]benzoic acid the isomer 3-[2-amino-6-[5- {[(2,4-difluorophenyl)sulfonyl]amino}-6-(methyloxy)-3-pyridinyl]-4-oxo-3(4H)-quinazolinyl]benzoic acid was used. LCMS: 593 (M+H); H NMR (400MHz ,DMSO-d₆) δ = 10.30 (br. s., 1 H), 8.63 - 8.48 (m, J = 4.5 Hz, 1 H), 8.33 (d, J = 2.3 Hz, 1 H), 8.07 - 7.96 (m, 2 H), 7.90 (dd, J = 2.2, 8.6 Hz, 1 H), 7.85 (d, J = 2.2 Hz, 1 H), 7.84 - 7.80 (m, 1 H), 7.76 (td, J = 6.4, 8.5 Hz, 1 H), 7.67 (t, J = 7.8 Hz, 1 H), 7.62 - 7.50 (m, 2 H), 7.35 (d, J = 8.6 Hz, 1 H), 7.21 (td, J = 2.2, 8.5 Hz, 1 H), 6.52 (br. s., 2 H), 3.65 (s, 3 H), 2.81 (d, J = 4.4 Hz, 3 H).

EXAMPLE 94

3-[2-amino-6-[5-{[(2,4-difluorophenyl)sulfonyl]amino}-6-(methyloxy)-3-pyridinyl^^^

3(4H)-quinazolinyl]-N,N-dimethylbenzamide

[00304] This compound was synthesized according to the procedure described in EXAMPLE 83, Step B, except 3-[2-amino-6-[5-{[(2,4-difluorophenyl)sulfonyl]amino}-6- (methyloxy)-3-pyridinyl]-4-oxo-3(4H)-quinazolinyl]benzoic acid and 2 M dimethylamine in THF was used. LCMS: 607 (M+H); H NMR (400MHz ,DMSO-d₆) δ = 10.30 (br. s., 1 H), 8.32 (d, J = 2.1 Hz, 1 H), 8.02 (d, J = 2.2 Hz, 1 H), 7.89 (dd, J = 2.3, 8.6 Hz, 1 H), 7.84 (d, J = 2.3 Hz, 1 H), 7.76 (td, J = 6.4, 8.5 Hz, 1 H), 7.67 - 7.60 (m, 1 H), 7.60 - 7.51 (m, 2 H), 7.50 - 7.40 (m, 2 H), 7.34 (d, J = 8.5 Hz, 1 H), 7.20 (td, J = 2.1 , 8.5 Hz, 1 H), 6.56 (br. s., 2 H), 3.65 (s, 3 H), 3.00 (s, 6 H).

EXAMPLE 95

N-[5-{2-amino-4-oxo-3-[3-(1-piperidinylcarbonyl)phenyl]-3,4-dihydro-6-quinazolm

(methyloxy)-3-pyridinyl]-2,4-difluorobenzenesulfonamide

[00305] This compound was synthesized according to the procedure described in Example 83, Step B, except 3-[2-amino-6-[5-{[(2,4-difluorophenyl)sulfonyl]amino}-6-(methyloxy)- 3-pyridinylj-4-oxo-3(4H)-quinazolinyl]benzoic acid and piperidine was used. LCMS: 647 (M+H); ¹H NMR (400 MHz ,DMSO-cf₆) δ = 10.30 (br. s., 1 H), 8.32 (d, J = 2.2 Hz, 1 H), 8.01 (d, J = 2.1 Hz, 1 H), 7.89 (dd, J = 2.2, 8.6 Hz, 1 H), 7.84 (d, J = 2.2 Hz, 1 H), 7.76 (td, J = 6.4, 8.5 Hz, 1 H), 7.68 - 7.60 (m, 1 H), 7.60 - 7.53 (m, 1 H), 7.53 - 7.49 (m, 1 H), 7.48 - 7.43 (m, 1 H), 7.40 - 7.36 (m, 1 H), 7.33 (d, J = 8.5 Hz, 1 H), 7.20 (td, J = 2.1 , 8.5 Hz, 1 H), 6.56 (br. s., 2 H), 3.65 (s, 3 H), 3.63 - 3.43 (m, 4 H), 1.87 - .15 (m, 6 H).

EXAMPLE 96

3-[2-amino-6-[5-{[(2,4-difluorophenyl)sulfonyl]amino}-6-(methylo^

3(4H)-quinazolinyl]benzamide

[00306] This compound was synthesized according to the procedure described in Example 83, Step B, except 3-[2-amino-6-[5-{[(2,4-difluorophenyl)sulfonyl]amino}-6-(methyloxy)- 3-pyridinyl]-4-oxo-3(4H)-quinazolinyl]benzoic acid and ammonium chloride and TEA was used. LCMS: 579 (M+H); H NMR (400 MHz ,DMSO-d₆) δ = 10.31 (br. s., 1 H), 8.31 (br. s., 1 H), 8.11

- 7.99 (m, 3 H), 7.96 - 7.82 (m, 3 H), 7.76 (td, J = 6.5, 8.5 Hz, 1 H), 7.66 (t, J = 7.9 Hz, 1 H), 7.60

- 7.47 (m, 3 H), 7.35 (d, J = 8.6 Hz, 1 H), 7.20 (td, J = 2.0, 8.4 Hz, 1 H), 6.52 (br. s., 2 H), 3.65 (s, 3 H).

EXAMPLE 97

N-[5-{2-amino-3-[3-(4-morphoHnytcarbonyl)pheny/]-4-oxo-3,4-dihydro-6-quinazolin

(methyloxy)-3-pyridinyl]-2,4-difluorobenzenesulfonamide

[00307] This compound was synthesized according to the procedure described in Example 83, Step B, except 3-[2-amino-6-[5-{[(2,4-difluorophenyl)sulfonyl]amino}-6-(methyloxy)- 3-pyridinylj-4-oxo-3(4H)-quinazolinyl]benzoic acid and morpholine was used.

LCMS: 649 (M+H); H NMR (400 MHz ,DMSO-c/₆) δ = 10.31 (br. s., 1 H), 8.33 (d, J = 2.2 Hz, 1 H), 8.02 (d, J = 2.1 Hz, 1 H), 7.89 (dd, J = 2.1 , 8.6 Hz, 1 H), 7.85 (d, J = 2.2 Hz, 1 H), 7.81 - 7.71 (m, 1 H), 7.70 - 7.62 (m, 1 H), 7.61 - 7.52 (m, 2 H), 7.51 - 7.41 (m, 2 H), 7.34 (d, J = 8.6 Hz, 1 H), 7.21 (td, J = 1.9, 8.5 Hz, 1 H), 6.58 (br. s., 2 H), 3.65 (s, 3 H), 3.65-3.35 (m, 8H).

EXAMPLE 98

N-[5-(2-amino-3-{3-[(4-methyl-1-piperazinyl)carbonyl]phenyl}-4-oxo-3,4-dihydro-6- quinazolinyl)-2-(methyloxy)-3-pyridinyl]-2,4-difluorobenzenesulfonamide

[00308] This compound was synthesized according to the procedure described in Example 83, Step B, except 3-[2-amino-6-[5-{[(2,4-difluorophenyl)sulfonyl]amino}-6-(methyloxy)- 3-pyhdinyl]-4-oxo-3(4H)-quinazolinyl]benzoic acid and 1-methylpiperazine was used. LCMS: 662 (M+H); H NMR (400 MHz ,DMSO-d₆) δ = 8.31 (d, J = 2.2 Hz, 1 H), 8.01 (d, J = 2.1 Hz, 1 H), 7.89 (dd, J = 2.2, 8.6 Hz, 1 H), 7.84 (d, J = 2.3 Hz, 1 H), 7.76 (td, J = 6.4, 8.5 Hz, 1 H), 7.69 - 7.61 (m, 1 H), 7.60 - 7.51 (m, 2 H), 7.50 - 7.44 (m, 1 H), 7.44 - 7.38 (m, 1 H), 7.33 (d, J = 8.5 Hz, 1 H), 7.20 (td, J = 2.1 , 8.4 Hz, 1 H), 6.57 (br. s., 2 H), 3.65 (s, 3 H), 2.26 (br. s., 3 H), 3.6-3.3 (4H), 2.5-2.3 (4H).

Example 99

N-[5-(2-amino-4-oxo-1,4-dihydro-6-quinazolinyl)-2-(methyloxy

General Scheme 9

R= Me, H

Step A

2-amino-5-iodo-3-meth lbenzoic acid

[00309] Iodine monochloride (32.5 g, 200 mmol) was added to a solution of 2-amino-3- methyl benzoic acid (10.28 g, 68 mmol) in 60 mL of 6% HCI. The reaction mixture was stirred at 50-60 °C for 2 hrs before cooled down to rt. The mixture was poured into sodium metabisulfate (40 g, 0.2 mol) in crushed ice (400g) and was subsequently neutralized with KOH cautiously with ice bath cooling. The pale brown solid was collected by filtration and washed with ice-water and methanol, and dried in vacuo to give 2-amino-5-iodo-3-methylbenzoic acid (brown solid, 18.6 g, 99%). H NMR (DMSO-c/₆) δ ppm 7.86 (s, 1 H), 7.45 (br. s., 1 H), 5.20 - 7.07 (m, 2H), 1.80 - 2.14 (s, 3H).

Step B

6-iodo-2H-3, 1 -benzoxazine-2, 4(1 H) -dion e

[00310] To a stirred solution of 2-amino-5-iodobenzoic acid (8.29 g, 31 .5 mmol) and PBr₃ (8.58g, 31.5 mmol) in THF (50 mL) was added ethylchloroformate (10.58 g, 97.5 mmol) at rt. The mixture was stirred at reflux for 22 hrs under N₂ atmosphere. The solvent was removed in vacuo to give solid, which was redisolved in anhydrous ether (50 mL) and the resulting mixture was refluxed for 24 hrs before cooled down on ice and filtered off the solvent. The solid was washed with hexanes and then a mixture of DCM/MeOH (1/1 ). The resulting cake was dried to give 6-iodo-2H-3,1-benzoxazine-2,4(1 H)-dione as off-white solid (7.85g, Yield: 86%) ¹H NMR (DMSO-cf₆) 5 ppm: 1 1.82 (s, 1 H), 8.12 (d, J = 2.0 Hz, 1 H), 8.02 (dd, J = 8.5, 2.1 Hz, 1 H), 6.95 (d, 1 H).

6-iodo-8-methyl-2H-3, 1-benzoxazine-2,4( 1H)-dione

[00311] 6-lodo-8-methyl-2H-3,1-benzoxazine-2,4(1 H)-dione was prepared in the similar approach outlined as above (6 g, Yield: 61 %). H NMR (DMSO- /₆) δ ppm: 1 1.1 1 (br. s., 1 H), 8.00 (s, 1 H), 7.92 (s, 1 H), 2.24 (s, 3H).

Step C

2-amino-6-iodo-4(1H)-quinazolinone

[00312] 6-lodo-2H-3,1-benzoxazine-2,4(1 H)-dione (3.6g, 12.46 mmol), Na₂C0₃ (1.32 g, 12.46 mmol) and methyl imidothiocarbamate HI (3.26 g, 14.95 mmol) were mixed in a mixture of CH₃CN/H₂0 (20 mL/5 mL). The reaction mixture was heated to reflux for 3 hrs before cooled it down to rt. The solid was filtered off and washed with CH₃CN/H₂0 (5/1 ). After dried in vacuo, 2-amino-6-iodo-4(1 H)-quinazolinone was obtained as light yellow solid (2.1 g, Yield: 59%). H NMR (DMSO-cf₆) δ ppm: 8.09 (d, J = 2.1 Hz, 1 H), 7.71 (dd, J = 8.6, 2.1 Hz, 1 H), 6.95 (d, J = 8.6 Hz, 1 H), 6.68 - 6.90 (m, 2H).

2-amino-6-iodo-8-methyl-4(1H)-quinazolinone

[00313] 2-Amino-6-iodo-8-methyl-4(1 H)-quinazolinone was prepared in the similar approach outlined as above (1.95 g, Yield: 65%). H NMR (DMSO- /₆) δ ppm: 10.73 - 1 1.51 (m, 1 H), 7.97 (d, J = 1.8 Hz, 1 H), 7.71 (d, J = 1 .2 Hz, 1 H), 6.59 (br. s., 2H), 2.30 (s, 3H).

Step D

N-[5-(2-amino-4-oxo-1 ,4-dihydro-6-quinazolinyl)-2-(methyloxy)-3-pyridinyl]-2,4- difluorobenzenesulfonamide

[00314] 2,4-Difluoro-N-[2-(methyloxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-3- pyridinyl]benzenesulfonamide (426 mg, 1 .0 mmol), 2-amino-6-iodo-4(1 H)-quinazolinone (287 mg, 1.0 mmol), Na₂C0₃ (252 mg, 3.0 mmol) PdCI2 (dppf) (73 mg, 0.1 mmol) were mixed together in a schlenck flask charged with a mixed DME/water (4 mL /1 mL). The reaction mixture was purged with N₂ (3x) before heated to 80°C for 4hrs. Filtered through Celite® while the reaction mixture was hot and washed with MeOH. The filtrate was evaporated. The residual was triturated with DCM and the solid was re-suspended in water. The resulting mixture was centrifuged and the water was discarded. This washing process was repeated one more time. The precipitate was dried over pump to give N-[5-(2-amino-4-oxo-1 ,4-dihydro-6-quinazolinyl)-2- (methyloxy)-3-pyridinyl]-2,4-difluorobenzenesulfonamide as off white solid (240 mg, Yield: 50%). H NMR (DMSO-d₆) δ ppm: 7.85 (d, J = 2.1 Hz, 2H), 7.53 - 7.65 (m, 3H), 7.45 (d, J = 2.1 Hz, 1 H), 7.14 - 7.23 (m, 3H), 6.95 - 7.14 (m, 1 H), 6.33 - 6.65 (m, 2H), 3.76 (s, 3H). LC-MS: m/z 460.1 (M+1 ).

Example 100

N-[5-(2-amino-8-methyi-4-oxo-1,4-dihydro-6-quinazolinyl)-2-(methyloxy)-3^

difluorobenzenesulfonamide

[00315] N-[5-(2-Amino-8-methyl-4-oxo-1 ,4-dihydro-6-quinazolinyl)-2-(methyloxy)-3- pyridinyl]-2,4-difluorobenzenesulfonamide (200 g, yield 40%) was obtained from 2,4-difluoro-N- [2-(methyloxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-3-pyridinyl]benzenesulfonamide (425mg, 0.996 mmol) and 2-amino-6-iodo-8-methyl-4(1 H)-quinazolinone (300 mg, 0.996 mmol) by a similar approach outlined as in Example 99. ¹H NMR (DMSO-d₆) δ ppm: 10.82 - 1 1.25 (m, 1 H), 10.29 (br. s., 1 H), 8.32 (d, J = 2.1 Hz, 1 H), 7.89 (d, J = 1.8 Hz, 1 H), 7.84 (d, J = 2.1 Hz, 1 H), 7.70 - 7.80 (m, 2H), 7.58 (s, 1 H), 7.08 - 7.38 (m, 1 H), 6.53 (br. s., 2H), 3.65 (s, 3H), 2.43 (s, 3H). LC-MS: m/z 474.2 (M+1 ).

General Scheme 10

Intermediates 1

Assembly of Examples

oron c c

Example 101

2-amino-5-(2-amino-4-oxo-3-phenyl-3,4-dihydro-6-quinazolinyl)-N,N-dimethyl-3- ridinesulfonamide

Step A

2-amino-5-bromopyridine-3-sulfonyl chloride

[00316] 2-amino-5-bromo-pyridine (25 g, 144 mmol) was added into chlorosulfonic acid (50 mL) batchwise at 0 °C. The resulting mixture was heated to 145 °C, stirred for 3 hours, cooled to room temperature, and poured carefully into a mixture of ice/water. The precipitate was collected through filtration, and the filter cake was washed with water (50 mL), 5% THF in hexane (20 mL), and dried in vacuo overnight to provide 2-amino-5-bromopyridine-3-sulfonyl chloride (25 g, 64%) as a light yellow solid. ¹H-NMR (300 MHz, DMSO-d₆), δ ppm 8.43 (s, 1 H), 8.19 (s, 1 H), 6.00 (s, 2H). LCMS (m/z) ES+ 271 and 273 (m+1 ).

Step B

2-amino-5-bromo-N N-dimethylpyridine-3-suifonamide

[00317] To a solution of dimethylamine hydrochloride (4 g, 29.4 mmol) and Et₃N (4.45 g, 44.1 mmol) in DCM (60 mL) was added a solution of 2-amino-5-bromopyridine-3-sulfonyl chloride (8 g, 29.4 mmol) in DCM (10 mL) dropwise at 0 °C. The resulting mixture was stirred at room temperature overnight. The solution was washed with H₂0 (80 mL), and the aqueous phase was extracted with DCM (100 mL x 3). The combined organic layer was dried over Na₂S0₄, filtered, and concentrated in vacuo to give a crude product which was purified with silica gel chromatography (EtOAc/petroleum ether = 1 :10 to 1 :1 ) to provide 2-amino-5-bromo- N,N-dimethylpyridine-3-sulfonamide (3.0 g, 36.5%) as white solid. ¹H-NMR (300 MHz, CDCI₃), δ ppm 8.25 (s, 1 H), 7.97 (s, 1 H), 5.84 (s, 2H), 2.80 (s, 6H). LCMS (m/z) ES+ 280 and 282. (m+1 )

Step C

2-amino-N, N-dimethyl-5-(4, 4, 5, 5-tetrameth l-1 ,3, 2-dioxaborolan-2-yl)pyridine-3-sulfonamide

[00318] A mixture of -amino- 5-bromo-N,N-dimethylpyridine-3-sulfonamide (3.0 g, 10.7 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2^,-bi(1 ,3,2- dioxaborolane) (2.72 g, 10.7 mmol), KOAc (2.13 g, 10.7 mmol) and Pd(dppf)CI₂ (873 mg, 1.07 mmol) in dioxane (100 mL) was refluxed overnight. The mixture was cooled to room temperature and a filtration was conducted to remove solids. The filtrate was concentrated in vacuo and the residue was applied on silica gel column (EtOAc/petroleum ether = 1 :10 to 1 :1 ) to afford 2-amino-N,N-dimethyl-5-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridine-3-sulfonamide (2.5 g, 71 %) as white solid. ¹H-NMR (300 MHz, CDCI₃), δ ppm 8.48 (s, 1 H), 8.33 (s, 1 H), 6.90 (s, 2H), 2.84 (s, 6H), 1 .35 (s, 12H). LCMS (m/z) ES+ 328 (m+1 ), 246 (boronic acid +1 ).

Step D

2-amino-5-(2-amino-4-oxo-3^henyl-3,4-dihydro-6-quinazolinyl)-N,N-dimethyl-3- pyridinesulfonamide

[00319] A solution of 2-amino-6-bromo-3-phenyl-4(3H)-quinazolinone (100 mg, 0.316 mmol), 2-amino-N,N-dimethyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridine-3- sulfonamide (1 19 mg, 0.380 mmol), potassium carbonate (87 mg, 0.633 mmol), and

PdCI₂(dppf)-CH₂CI₂ adduct (258 mg, 0.316 mmol) in 1 ,4-dioxane (3 ml_)/water (1 mL) was maintained at 85 °C with stirring for 2 hours. The mixture was cooled, poured into ethyl acetate, and washed with saturated sodium chloride (aq). The organic layer was separated, dried over sodium sulfate, filtered, taken to a residue under reduced pressure, and purified by column chromatography. Fractions containing product were pooled, concentrated, and the resulting solids were triturated with DCM/diethyl ether to afford 2-amino-5-(2-amino-4-oxo-3-phenyl-3,4- dihydro-6-quinazolinyl)-N,N-dimethyl-3-pyridinesulfonamide (67 mg, 0.153 mmol, 48.5 % yield) as a white solid. LCMS (m/z, ES+) = 437 (M+H). H NMR (DMSO-cf₆) δ: 8.62 (d, J = 2.5 Hz, 1 H), 8.03 (d, J = 2.1 Hz, 1 H), 7.96 (d, J = 2.3 Hz, 1 H), 7.92 (dd, J = 8.7, 2.2 Hz, 1 H), 7.49 - 7.63 (m, 3H), 7.26 - 7.41 (m, 3H), 6.67 - 6.90 (m, 2H), 6.35 (br. s., 2H), 2.73 (s, 6H).

Example 102

2-amino-6-[5-(methylsulfonyl)-3-pyridinyl]-3-phenyl-4(3H)-quinazolinone

[00320] A solution of 2-amino-6-bromo-3-phenyl-4(3H)-quinazolinone (108 mg, 0.342 mmol), [5-(methylsulfonyl)-3-pyridinyl]boronic acid (93 mg, 0.461 mmol), potassium carbonate (94 mg, 0.683 mmol), and PdCI₂(dppf)-CH₂CI₂ adduct (27.9 mg, 0.034 mmol) in 1 ,4-dioxane (3 ml_)/water (1 ml.) was maintained with stirring at 80°C for 3 hours. The solution was cooled, poured into ethyl acetate, and washed with water. The aqueous layer was washed three times (DC X2; EtOAc X1 ) until all suspended solids had been dissolved. The combined organic layers were dried over sodium sulfate, filtered, concentrated, and suspended in 2 mL DMF. Solids were collected via vacuum filtration and washed with diethyl ether to afford 2-amino-6-[5- (methylsulfonyl)-3-pyridinyl]-3-phenyl-4(3H)-quinazolinone (77 mg, 0.196 mmol, 57.4 % yield) as a white solid. LCMS (m/z, ES+) = 393 (M+H). H NMR (DMSO-ci₆) δ: 9.26 (d, J = 2.1 Hz, 1 H), 9.01 (d, J = 2.0 Hz, 1 H), 8.57 (t, J = 2.1 Hz, 1 H), 8.31 (d, J = 2.1 Hz, 1 H), 8.13 (dd, J = 8.6, 2.3 Hz, 1 H), 7.47 - 7.64 (m, 3H), 7.31 - 7.44 (m, 3H), 6.51 (br. s., 2H), 3.42 (s, 3H).

Example 103

2-amino-5-(2-amino-4-oxo-3-phenyl-3,4-dihydro-6-quinazolinyl)-N-cyclopropyl-3- ridinesulfonamide

Step A

2-amino-5-bromo-N-cyclopropylpyridine-3-sulfonamide

[00321] To a solution of cyclopropanamine (1.68 g, 29.4 mmol) and Et₃N (4.45 g, 44.1 mmol) in DCM (60 mL) was added a solution of 2-amino-5-bromopyridine-3-sulfonyl chloride (8 g, 29.4 mmol) in DCM (10 mL) dropwise at 0 °C. The resulting mixture was stirred at room temperature overnight. Water (80 mL) was added and the aqueous phase was extracted with DCM (100 mL x 3). The combined organic layer was dried over Na₂S0₄, filtered, and concentrated in vacuo to produce a crude which was purified on silica gel column

(EtOAc/petroleum ether = 1 :10 to 1 :1 ) to afford 2-amino-5-bromo-N-cyclopropylpyridine-3- sulfonamide (2.4 g, 28%) as white solid. ¹H-NMR (300 MHz, CDCI₃), δ ppm 8.28 (s, 1 H), 8.11 (s, 1 H), 5.70 (s, 2H), 5.19 (s, 1 H), 2.28-2.25 (m, 1 H), 0.66-0.63 (m, 4H). LCMS (m/z) ES+ 292 and 294 (m+1 ).

Step B

2-amino-N-cyclopropyl-5-(4, 4, 5, 5-tetra meth l- 1, 3, 2-dioxaborolan-2-yl)pyridine-3-sulfonamide

[00322] A mixture of 2-amino-5-bromo-N-cyclopropylpyridine-3-sulfonamide (2.4 g, 8.2 mmol), 4,4,4^,,4',5,5,5^,,5^,-octamethyl-2,2'-bi(1 ,3,2- dioxaborolane) (2.09 g, 8.2 mmol), KOAc (1 .63 g, 8.2 mmol) and Pd(dppf)CI₂ (669 mg, 0.82 mmol) in dioxane (100 mL) was refluxed overnight. The mixture was cooled to room temperature and a filtration was conducted to remove the solid in the suspension. The filtrate was concentrated in vacuo and the residue was applied on silica gel column (EtOAc/petroleum ether = 1 :10 to 1 :1 ) to afford 2-amino-N- cyclopropyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridine-3-sulfonamide (2.32 g, 83%) as white solid. H-NMR (300 MHz, CDCI₃), δ ppm 8.59 (s, 1 H), 8.40 (s, 1 H), 6.06 (s, 1 H), 5.17 (s,1 H), 2.32-2.25 (m, 1 H), 1.35 (s, 12H), 0.64-0.62 (d, 4H). LCMS (m/z) ES+ 340 (m+1 ), 258 (boronic acid +1 ).

Step C

2-amino-5-(2-amino-4-oxo-3^henyl-3A-dihydro-6-quinazo

pyridinesulfonamide

[00323] A solution of 2-amino-6-bromo-3-phenyl-4(3H)-quinazolinone (80 mg, 0.253 mmol), 2-amino-N-cyclopropyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridine-3- sulfonamide (99 mg, 0.291 mmol), potassium carbonate (69.9 mg, 0.506 mmol), and

PdCI₂(dppf)-CH₂CI₂ adduct (31.0 mg, 0.038 mmol) in 1 ,4-dioxane (3 ml_)/water (1 ml.) was maintained at 90 °C for 2 hours. The solution was cooled, poured into ethyl acetate, and washed with water. The aqueous layer and insoluble solids were washed with DCM three times until all solids had been dissolved. The combined organic layers were dried over sodium sulfate, filtered, concentrated, and triturated three times (from DCM, DCM/MeOH, and DMF respectively). Collection of the white solids via vacuum filtration afforded 2-amino-5-(2-amino-4- oxo-3-phenyl-3,4-dihydro-6-quinazolinyl)-N-cyclopropyl-3-pyridinesulfonamide (10 mg, 0.022 mmol, 8.81 % yield) as a white solid. LCMS (m/z, ES+) = 449 (M+H). ¹H NMR (DMSO-d₆) δ: 8.60 (d, J = 2.3 Hz, 1 H), 8.18 (s, 1 H), 8.11 (d, J = 2.3 Hz, 1 H), 8.04 (d, J = 2.1 Hz, 1 H), 7.92 (dd, J = 8.6, 2.1 Hz, 1 H), 7.49 - 7.65 (m, 3H), 7.33 (d, J = 8.6 Hz, 1 H), 7.37 (d, J = 7.2 Hz, 2H), 6.72 (br. s., 2H), 6.35 (br. s., 2H), 2.07 - 2.22 (m, 1 H), 0.30 - 0.55 (m, 4H).

Example 104

2-amino-5-(2-amino-4-oxo-3-phenyl-3,4-dihydro-6-quinazolinyl)-N-phenyl-3- ridinesulfonamide

Step A

2-amino-5-bromo-N-phenyipyridine-3-sulfonamide

[00324] To a solution of aniline (2.73 g, 33.1 mmol) and Et₃N (5 g, 49.65 mmol) in DCM (60 mL) was added a solution of 2-amino-5-bromopyridine-3-sulfonyl chloride (9 g, 33.1 mmol) in DCM ( 0 mL) dropwise at 0 °C. The resulting mixture was stirred at room temperature overnight before water (80 mL) was added. The aqueous phase was extracted with DCM (100 mL x 3) and the combined organic layer was dried over Na₂S0₄, filtered and concentrated to give a residue which was purified by column (EtO Ac/petroleum ether = 1 :10 to 1 :1 ) to give 2- amino-5-bromo-N-phenylpyridine-3-sulfonamide (2.53 g, 23%) as white solid. LCMS (m/z) ES+ 328 and 332 (m+1 ).

Step B

2-amino-N-phenyl-5-(4, 4, 5, 5-tetrameth l- 1, 3, 2-dioxaborolan-2-yl) pyridine-3-sulfonamide

[00325] A mixture of 2-amino-5-bromo-N-phenylpyridine-3-sulfonamide (2.3 g, 7 mmol), 4,4,4\4\5,5,5\5'-octamethyl-2,2'-bi(1 ,3,2- di- oxaborolane) (1.78 g, 7 mmol), KOAc (4.18 g, 21 mmol) and Pd(dppf)CI₂ (571 mg, 2.7 mmol) in dioxane (50 mL) was stirred at reflux overnight. The mixture was cooled to room temperature and the solid in suspension was removed via filtration. The filtrate was concentrated in vacuo to give a residue which was applied on column (EtOAc/petroleum ether = 1 :10 to 1 :1 ) to provide 2-amino-N-phenyl-5-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl) pyridine-3-sulfonamide (1 .5 g, 58%) as a white solid. H-NMR (300 MHz, CDCI₃), δ ppm 8.46 (s, 1 H), 8.20 (s, 1 H), 7.16-7.05 (m, 5H), 6.13 (s, 2H), 5.86 (s, 1 H), 1 .29 (s, 12H). LCMS (m/z) ES+ 376 (m+1 ).

Step C 2- amino-5-(2-amino-4-oxo-3^henyl-3 -dihydro-6-quinazolinyl)-^^

[00326] A solution of 2-amino-6-bromo-3-phenyl-4(3H)-quinazolinone (90 mg, 0.285 mmol), 2-amino-N-phenyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl) pyridine-3-sulfonamide (123 mg, 0.327 mmol), potassium carbonate (79 mg, 0.569 mmol), and PdCI₂(dppf)-CH₂CI₂ adduct (23.25 mg, 0.028 mmol) in 1 ,4-dioxane (3 ml_)/water (1 ml.) was maintained with stirring at 90 °C for 1 hour. The mixture was cooled to room temperature, diluted with ethyl acetate, and washed with water. The organic layer and insoluble solids were washed with DCM and the combined organic layers were dried over sodium sulfate, filtered, taken to a residue under reduced pressure, and purified by column chromatography to afford 2-amino-5-(2-amino-4-oxo-

3- phenyl-3,4-dihydro-6-quinazolinyl)-N-phenyl-3-pyridinesulfonamide (79 mg, 0.163 mmol, 57.3 % yield) as a brown solid after trituration from DCM/MeOH. LCMS (m/z, ES+) = 485 (M+H). H NMR (DMSO-d₆) δ: 10.49 (s, 1 H), 8.51 (d, J = 2.3 Hz, 1 H), 8.05 (d, J = 2.3 Hz, 1 H), 7.94 (d, J = 2.1 Hz, 1 H), 7.82 (dd, J = 8.6, 2.3 Hz, 1 H), 7.45 - 7.65 (m, 3H), 7.37 (d, J = 7.2 Hz, 2H), 7.30 (d, J = 8.6 Hz, 1 H), 7.24 (t, J = 7.8 Hz, 2H), 7.1 1 (d, J = 7.6 Hz, 2H), 6.97 - 7.07 (m, 1 H), 6.81 (br. s., 2H), 6.35 (br. s., 2H)

Example 105

2-amino-5-{2-amino-3-[4-(4-morpholinyl)phenyl]-4-oxo-3,4-dihydro-6-quinaz

henyl-3-pyridinesulfonamide

4-(4-isothiocyanatophenyl)morpholine

[00327] A solution of 4-(4-morpholino)aniline (10.52 g, 59.0 mmol) and triethylamine (24.68 mL, 177 mmol) in tetrahydrofuran (300 mL) was cooled to 0 °C in an ice-water bath and thiophosgene (4.98 mL, 64.9 mmol) was added dropwise while an internal temperature < 15°C was maintained. Following the addition the reaction was warmed to room temperature, stirred for 45 minutes, and poured into water. The mixture was diluted with ethyl acetate and the organic layer was separated, dried over sodium sulfate, filtered, taken to a residue under reduced pressure, and the residue was purified by column chromatography to afford 4-(4- isothiocyanatophenyl)morpholine (10.67 g, 48.4 mmol, 82 % yield) as a yellow solid. LCMS (m/z, ES+) = 221 (M+H).

Step B

6-/odo-3- ^'4-(4-morpho//^'n /jprteny/J-2-fh/oxo-2,3-d hydro-4(iH -qu/nazo//none

[00328] A solution of 4-(4-isothiocyanatophenyl)morpholine (9.46 g, 36.5 mmol), 2-amino- 5-iodobenzoic acid (8 g, 30.4 mmol), and triethylamine (6.36 mL, 45.6 mmol) in 1 ,4-dioxane (150 mL) was kept at reflux with rapid stirring for 6 hours. The solution was cooled to room temperature and the precipitates were collected via vacuum filtration and washed with diethyl ether to afford 6-iodo-3-[4-(4-morpholinyl)phenyl]-2-thioxo-2,3-dihydro-4(1 H)-quinazolinone (1 1.5 g, 24.71 mmol, 81 % yield) as a yellow solid. LCMS (m/z, ES+) = 466 (M+H). Step C

2-chloro-6-iodo-3- 4-(4-morpholinyl)phenyl]-4(3H)-quinazolinone

[00329] A solution of 6-iodo-3-[4-(4-morpholinyl)phenyl]-2-thioxo-2,3-dihydro-4(1 H)- quinazolinone (3.21 g, 6.90 mmol) in POCI₃ (12.86 ml_, 138 mmol) was cooled to 0°C and treated with PCI₅ (2.51 g, 12.07 mmol) in one portion. The mixture was warmed to reflux, maintained for 5 hours, and additional PCI₅ (2.51 g, 12.07 mmol) and POCI₃ (12.86 ml_, 138 mmol) were added and the solution was maintained at reflux for an additional 3 hours. The solution was concentrated under reduced pressure, suspended in ethyl acetate, and poured into ice water. The mixture was stirred vigorously and passed through a plug of Celite® which was washed with additional ethyl acetate. The organic layer was separated, dried over sodium sulfate, filtered, concentrated, and afforded 2-chloro-6-iodo-3-[4-(4-morpholinyl)phenyl]-4(3H)- quinazolinone with sufficient purity (about 65-75% purity) for use directly in the next

transformation. LCMS (m/z, ES+) = 468 (M+H).

Step D

6-iodo-2-({[4-(methyloxy)phenyl methyl}amino)-3-[4-(4-morpholinyl)phen

[00330] A solution of 2-chloro-6-iodo-3-[4-(4-morpholinyl)phenyl]-4(3H)-quinazolinone (2.89 g, 6.18 mmol), 4-methoxy-benzylamine (1.211 ml_, 9.27 mmol), and DIPEA (2.158 ml_, 12.36 mmol) in N,N-dimethylformamide (40 mL) was maintained with stirring at 80°C for 3 hours. The solution was cooled, poured into ethyl acetate, and washed three times with 5% LiCI (aq). The organic layer was separated, dried over sodium sulfate, filtered, taken to a residue under reduced pressure, and purified by column chromatography to afford 6-iodo-2-({[4- (methyloxy)phenyl]methyl}amino)-3-[4-(4-morpholinyl)phenyl3-4{3H)-quinazolinone {1.77 g, 3.1 1 mmol, 50.4 % yield) as a yellow solid (roughly 65-70% purity). LCMS (m/z, ES+) = 569 (M+H).

Step E

2-amino-6-iodo-3- 4-(4-morpholinyl)phenyl]-4(3H)-quinazolinone

[00331 ] A solution of 6-iodo-2-({[4-(methyloxy)phenyl]methyl}amino)-3-[4-(4- morpholinyl)phenyl]-4(3H)-quinazolinone (1.75 g, 3.08 mmol) in trifluoroacetic acid (50 mL) was maintained at reflux for 48 hours. The reaction was concentrated under reduced pressure, dissolved in DCM, and washed twice with saturated sodium bicarbonate. The organic layer was dried over sodium sulfate, filtered, taken to a residue under reduced pressure, and purified by column chromatography. The fractions containing product were triturated from DCM/diethyl ether to afford 2-amino-6-iodo-3-[4-(4-morpholinyl)phenyl]-4(3H)-quinazolinone (308 mg, 0.687 mmol, 22.32 % yield) as a yellow solid. LCMS (m/z, ES+) = 449 (M+H).

Step F

2-amino-5-{2-amino-3-[4-(4-morpholinyl)phenyl]-4-oxo-3,4-dihydro-6-quin

py dinesulfonamide

[00332] A solution of 2-amino-6-iodo-3-[4-(4-morpholinyl)phenyl]-4(3H)-quinazolinone (100 mg, 0.223 mmol), 2-amino-N-phenyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-3- pyridinesulfonamide (92 mg, 0.245 mmol), PdCI₂(dppf)-CH₂CI₂ adduct (18.22 mg, 0.022 mmol), and potassium carbonate (61.7 mg, 0.446 mmol) in 1 ,4-dioxane (4 mL)/water (1 mL) was maintained at 80 °C for 2 hours. The mixture was cooled, poured into ethyl acetate, and washed with water. The organic layer was dried over sodium sulfate, filtered, and taken to a residue under reduced pressure. The aqueous layer was filtered and the solids were combined with the residue from the organic layer. All combined solids were triturated with

dichloromethane to afford 2-amino-5-{2-amino-3-[4-(4-morpholinyl)phenyl]-4-oxo-3,4-dihydro-6- quinazolinyl}-N-phenyl-3-pyridinesulfonamide (35 mg, 0.061 mmol, 27.5 % yield) as a brown solid. LCMS (m/z, ES+) = 570 (M+H). ¹H NMR (DMSO-af₆) δ: 10.49 (br. s., 1 H), 8.50 (br. s., 1H), 8.04 (br. s., 1 H), 7.93 (s, 1 H), 7.80 (d, J = 8.4 Hz, 1 H), 7.14 - 7.37 (m, 5H), 7.10 (d, J = 6.4 Hz, 4H), 6.91 - 7.06 (m, 1H), 6.81 (br. s., 2H), 6.32 (br. s., 2H), 3.76 (br. s., 4H), 3.21 (br. s., 4H).

Example 106

5-(2-amino-4-oxo-3^henyl-3,4-dihydro-6-quinazolinyl)-3^yridinesulfonamide

Step A

2-Amino-3-phenyl-6-(4, 4, 5, 5-tetrameth l- 1 , 3, 2-dioxaborolan-2-yl)quinazolin-4(3H)-one

[00333] A solution of 2-amino-6-bromo-3-phenylquinazolin-4(3H)-one (500 mg, 1.582 mmol),PdCI₂(dppf)-CH₂Cl₂ adduct (129 mg, 0.158 mmol), bis(pinacolato)diboron (803 mg, 3.16 mmol), and potassium acetate (466 mg, 4.74 mmol) in 1 ,4-dioxane (10 mL) was sparged with nitrogen, then heated with stirring in a sealed tube to 90 °C for 3 hours . The reaction was cooled, diluted with DCM (100 mL), washed with water, and the precipitates were filtered off. The resulting solution was dried (brine, Na₂S0₄), concentrated to an oil and purified on silica (eluting at 100% EtOAc) to give 2-amino-3-phenyl-6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)quinazolin-4(3H)-one as a white solid. ES-LCMS: m/z 364/366 (M+1 ), H NMR (400MHz, DMSO-de) δ = 8.25 (s,1H), 7.82 (m, 1 H), 7.60-7.50 (m, 3H), 7.35 (m, 2H), 7.2 (m, 1 H), 1.30 (s, 12 H); ES-LCMS: m/z 521 (M+1 ).

Step B

5-(2-amino-4-oxo-3 henyl-3,4-dihydro-6-quinazolinyl)-3 yridinesulfonamide [00334] A solution of 2-amino-3-phenyl-6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)- 4(3H)-quinazolinone (103 mg, 0.285 mmol), 5-bromopyridine-3-sulfonamide (45 mg, 0.190 mmol), potassium carbonate (79 mg, 0.569 mmol), and PdCI₂(dppf)-CH₂Cl2 adduct (23.25 mg, 0.028 mmol) in 1 ,4-dioxane (3 ml_)/water (1 ml_) was maintained at 80°C with stirring for 3 hours. The mixture was poured into ethyl acetate and washed with water. The organic layer was separated, dried over sodium sulfate, filtered, taken to a residue under reduced pressure, and purified by column chromatography (DCM/MeOH) to afford 5-(2-amino-4-oxo-3-phenyl-3,4- dihydro-6-quinazolinyl)-3-pyridinesulfonamide (53 mg, 0.135 mmol, 71.0 % yield) as a white foam. LCMS (m/z, ES+) = 394 (M+H). ¹H NMR (DMSO-cf₆) δ: 9.16 (d, J = 2.0 Hz, 1 H), 8.91 (d, J = 2.0 Hz, 1 H), 8.47 (t, J = 2.0 Hz, 1 H), 8.25 (d, J = 2.1 Hz, 1 H), 8.08 (dd, J = 8.6, 2.1 Hz, 1 H), 7.67 (s, 2H), 7.48 - 7.64 (m, 3H), 7.31 - 7.44 (m, 3H), 6.51 (br. s., 2H).

Example 107

5-(2-amino-4-oxo-3-phenyl-3,4-dihydro-6-quinazolinyl)-N-(2,4-difluo

Step A

5-bromo-N-(2,4- esulfonamide

[00335] A solution of 5-bromo-3-pyridinesulfonyl chloride (CombiBlocks, 860 mg, 3.35 mmol) in pyridine (8 mL) was cooled to 0 °C and treated with 2,4-difluoroaniline (1 .015 ml_, 10.06 mmol) in one portion. The mixture was warmed to room temperature and maintained with stirring for one hour. The solution was concentrated under reduced pressure, dissolved in ethyl acetate, and washed with saturated sodium bicarbonate (aq). The organic layer was separated, dried over sodium sulfate, filtered, concentrated, and triturated with DCM/diethyl ether. The solids were collected to afford 5-bromo-N-(2,4-difluorophenyl)-3-pyridinesulfonamide (498 mg, 1.426 mmol, 42.5 % yield) as a white solid. The filtrates were concentrated and purified by column chromatography to afford additional 5-bromo-N-(2,4-difluorophenyl)-3- pyridinesulfonamide (158 mg, 0.453 mmol, 13.50 % yield) as a yellow solid. LCMS (m/z, ES+) = 349 (M+H).

Step B

5-(2-amino-4-oxo-3^henyt-3,4-dihydro-6-quinazoiinyl)-N-(2,4-difluorophenyi)-3- pyridinesulfonamide

[00336] A solution of bis(pinacolato)diboron (172 mg, 0.679 mmol), 5-bromo-N-(2,4- difluorophenyl)-3-pyridinesulfonamide (158 mg, 0.453 mmol), PdCI₂(dppf)-CH₂CI₂ adduct (37.0 mg, 0.045 mmol), and potassium acetate (133 mg, 1.358 mmol) in 1 ,4-dioxane (3 mL) was maintained with stirring in a sealed pressure tube for 16 hours. The mixture was cooled, filtered through Celite®, and the Celite® was washed with ethyl acetate. The residue was concentrated under reduced pressure and used directly. A solution of the crude residue, 2-amino-6-iodo-3- phenyl-4(3H)-quinazolinone (98 mg, 0.270 mmol), PdCI₂(dppf)-CH₂CI₂ adduct (36.7 mg, 0.045 mmol), and potassium carbonate (187 mg, 1.350 mmol) in dioxane/water was maintained at 80 °C with stirring for 3 hours. The mixture was cooled to room temperature, poured into ethyl acetate, and washed with water. The organic layer was dried over sodium sulfate, filtered, taken to a residue under reduced pressure, and purified by reverse phase hplc to afford 5-(2- amino-4-oxo-3-phenyl-3,4-dihydro-6-quinazolinyl)-N-(2,4-difluorophenyl)-3-pyridinesulfonamide (35 mg, 0.069 mmol, 15.39 % yield) as a tan solid following lyophlization. LCMS (m/z, ES+) = 506 (M+H). ¹H NMR (DMSO-d₆) δ: 9.20 (d, J = 2.0 Hz, 1 H), 8.71 (d, J = 2.0 Hz, 1 H), 8.33 (t, J = 2.0 Hz, 1 H), 8.19 (d, J = 2.1 Hz, 1 H), 8.14 (s, 1 H), 8.03 (dd, J = 8.6, 2.3 Hz, 1 H), 7.46 - 7.66 (m, 3H), 7.35 - 7.46 (m, 3H), 7.19 - 7.34 (m, 2H), 6.97 - 7.12 (m, 1 H), 6.50 (br. s., 2H).

Example 108

5-(2-amino-4-oxo-3-phenyl-3,4-dihydro-6-quinazolinyl)-N,N-dimethyl-3- pyridinesulfonainide

Step A

6-iodo-3-phenyl-2-thioxo-2 3-dih dro-4( 1 H) -quinazoHnone

[00337] A solution of isothiocyanatobenzene (7.14 ml_, 59.7 mmol), 2-amino-5- iodobenzoic acid (15.7 g, 59.7 mmol), and triethylamine (12.48 ml_, 90 mmol) in 1 ,4-dioxane (250 mL) was maintained at reflux for 6 hours. The mixture was cooled to room temperature and solids collected via vacuum filtration. The solids were washed with diethyl ether and dried under vacuum to afford 6-iodo-3-phenyl-2-thioxo-2,3-dihydro-4(1 H)-quinazolinone (18 g, 47.3 mmol, 79 % yield) as a white solid. LCMS (m/z, ES+) = 381 (M+H).

Step B

2-chloro-6-iodo-3- henyl-4(3H)-quinazolinone

[00338] A suspension of 6-iodo-3-phenyl-2-thioxo-2,3-dihydro-4(1 H)-quinazolinone (18 g, 47.3 mmol) in POCI₃ (106 mL, 1 136 mmol) was treated with PCI₅ (17.25 g, 83 mmol) in one portion at room temperature, stirred for 30 minutes, then warmed to reflux and maintained with stirring for 4 hours. The solution was cooled to room temperature and concentrated under reduced pressure. The solids were suspended in ethyl acetate and added as a slurry portionwise to ice water. The mixture was maintained with rapid stirring for 45 minutes until all solids had dissolved. The organic layer was separated, dried over sodium sulfate, filtered, concentrated, and the solids were triturated with diethyl ether to afford 2-chloro-6-iodo-3-phenyl- 4(3H)-quinazolinone (18.8 g, 49.1 mmol, 104 % yield) as a white solid. LCMS (m/z, ES+) = 383 (M+H).

Step C

6-iodo-2-({[4-(methyloxy) henyl]methyl}amino)-3 henyl-4(3H)-quinazolinon

[00339] A solution of 2-chloro-6-iodo-3-phenyl-4(3H)-quinazolinone (7.8 g, 20.39 mmol), 4-methoxy-benzylamine (3.20 mL, 24.47 mmol), and DIPEA (7.12 mL, 40.8 mmol) in N,N- dimethylformamide (100 mL) was maintained at 80 °C for 3 hours. The mixture was diluted with ethyl acetate and washed three times with 5% LiCI (aq) and once with saturated sodium chloride (aq). The organic layer was separated, dried over sodium sulfate, filtered, taken to a residue under reduced pressure, and purified by column chromatography to afford 6-iodo-2-({[4- (methyloxy)phenyl]methyl}amino)-3-phenyl-4(3H)-quinazolinone (8.15 g, 16.86 mmol, 83 % yield) as a white foam. LCMS (m/z, ES+) = 484 (M+H).

Step D

2-amino-6-iodo-3- henyl-4(3H)-quinazolinone

[00340] A solution of 6-iodo-2-({[4-(methyloxy)phenyl]methyl}amino)-3-phenyl-4(3H)- quinazolinone (6.8 g, 14.07 mmol) in trifluoroacetic acid (75 mL) was maintained at reflux for 48 hours. The mixture was concentrated to a residue, dissolved in dichloromethane, and washed with saturated sodium bicarbonate. The organic layer was separated, dried over sodium sulfate, filtered, concentrated, and the residue purified by trituration from DCM/diethyl ether to afford 2-amino-6-iodo-3-phenyl-4(3H)-quinazolinone (3.87 g, 10.66 mmol, 76 % yield) as a yellow solid. LCMS (m/z, ES+) = 364 (M+H). Step E

5-bromo-N, esulfonamide

[00341] A solution of 5-bromo-3-pyridinesulfonyl chloride (2000 mg, 7.80 mmol) and DIPEA (2.043 mL, 1 1.70 mmol) in tetrahydrofuran (100 mL) was treated with 2.0M N,N- dimethylamine in THF (1 1 .70 mL, 23.39 mmol) and maintained with stirring at room temperature for 2 hours. The mixture was poured into ethyl acetate and washed with saturated sodium bicarbonate. The organic layer was separated, dried over sodium sulfate, filtered, taken to a residue under reduced pressure, and purified by trituration from diethyl ether to afford 5-bromo- N,N-dimethyl-3-pyridinesulfonamide (1.38 g, 5.21 mmol, 66.8 % yield) as a white solid. LCMS (m/z, ES+) = 265(M+H).

Step F

5-(2-amino-4-oxo-3 henyi-3 -dihydro-6-quinazoiiny^)-N,N-dimethyl-3 yrid

[00342] A solution of 5-bromo-N,N-dimethyl-3-pyridinesulfonamide (200 mg, 0.754 mmol), bis(pinacolato)diboron (220 mg, 0.868 mmol), PdCI₂(dppf)-CH₂CI₂ adduct (62 mg, 0.075 mmol), and potassium acetate (222 mg, 2.263 mmol), in 1 ,4-dioxane (3 mL) was maintained at 90°C in a sealed pressure tube for 16 hours. The mixture was cooled, filtered through Celite®, and the filtrates concentrated. A solution of the crude residue, 2-amino-6-iodo-3-phenyl-4(3H)- quinazolinone (120 mg, 0.330 mmol), potassium carbonate (137 mg, 0.991 mmol), and

PdCI₂(dppf)-CH₂CI₂ adduct (27.0 mg, 0.033 mmol) in 1 ,4-dioxane/water (3 mL) was maintained at 80°C for 2 hours. The mixture was cooled, poured into ethyl acetate, and washed with water. The aqueous layer and insoluble solids were washed with dichloromethane and the combined organic layers were dried over sodium sulfate, filtered, concentrated, and purified by reverse phase HPLC to afford following lyophlization 5-(2-amino-4-oxo-3-phenyl-3,4-dihydro-6- quinazolinyl)-N,N-dimethyl-3-pyridinesulfonamide as the formate salt (88 mg, 0.188 mmol, 57.0 % yield) as a white solid. LCMS (m/z, ES+) =422 (M+H). ¹H NMR (DMSO-c¾) δ: 9.24 (d, J = 2.1 Hz, 1 H), 8.88 (d, J = 2.1 Hz, 1 H), 8.31 (t, J = 2.1 Hz, 1 H), 8.25 (d, J = 2.1 Hz, 1 H), 8.06 - 8.18 (m, 1 H), 7.50 - 7.65 (m, 3H), 7.39 (d, J = 8.4 Hz, 3H), 6.50 (br. s., 2H), 2.72 (s, 6H). Example 109

5-(2-amino-4-oxo-3-phenyf-3,4-dihydro-6-quinazoUnyl)-N-cyclopropyl-3- ridinesulfonamide

Step A

5-bromo-N- esulfonamide

[00343] A solution of 5-bromo-3-pyridinesulfonyl chloride (2.85 g, 1 1.11 mmol) and DIPEA (5.82 mL, 33.3 mmol) in tetrahydrofuran (100 mL) was treated with cyclopropylamine (1 .537 mL, 22.22 mmol) and maintained with stirring for 45 minutes. The solution was poured into ethyl acetate and washed with saturated sodium bicarbonate. The organic layer was separated, dried over sodium sulfate, filtered, taken to a residue under reduced pressure, and purified by trituration from diethyl ether to afford 5-bromo-N-cyclopropyl-3-pyridinesulfonamide (1 .41 g, 5.09 mmol, 45.8 % yield) as a white solid. LCMS (m/z, ES+) = 277 (M+H).

Step B

5-(2-a ino-4-oxo-3^henyl-3,4-di ydro-6-quinazolinyl)-N-cyclopro

[00344] A solution of potassium acetate (212 mg, 2.165 mmol), bis(pinacolato)diboron (211 mg, 0.830 mmol), 5-bromo-N-cyclopropyl-3-pyridinesulfonamide (200 mg, 0.722 mmol), and PdCI₂(dppf)-CH₂CI₂ adduct (58.9 mg, 0.072 mmol) in 1 ,4-dioxane (3 mL) was maintained at 90°C in a sealed pressure tube for 16 hours. The reaction was cooled, filtered through Celite®, and the filtrates concentrated. A solution of the crude residue, 2-amino-6-iodo-3-phenyl-4(3H)- quinazolinone (120 mg, 0.330 mmol), potassium carbonate (137 mg, 0.991 mmol), and

PdCI₂(dppf)-CH₂CI₂ adduct (27.0 mg, 0.033 mmol) in 1 ,4-dioxane/water was maintained at 90 °C for 1 hour. The mixture was poured into ethyl acetate and washed with water. The aqueous layer and insoluble solids were washed with dichloromethane and the combined organic layer was dried over sodium sulfate, filtered, taken to a residue under reduced pressure, and purified by HPLC to afford the following lyophlization 5-(2-amino-4-oxo-3-phenyl-3,4-dihydro-6- quinazolinyl)-N-cyclopropyl-3-pyridinesulfonamide as the formate salt (44 mg, 0.092 mmol, 27.8 % yield) as a white solid. LCMS (m/z, ES+) = 434 (M+H). H NMR (DMSO-af₆) δ: 9.22 (d, J = 2.1 Hz, 1 H), 8.90 (d, J = 2.1 Hz, 1 H), 8.40 (t, J = 2.1 Hz, 1 H), 8.25 (d, J = 2.3 Hz, 1 H), 8.13 - 8.22 (m, 1 H), 8.09 (dd, J = 8.6, 2.3 Hz, 1 H), 7.48 - 7.65 (m, 3H), 7.35 - 7.43 (m, 3H), 6.50 (br. s., 2H), 2.23 (dd, J = 6.8, 3.5 Hz, 1 H), 0.48 - 0.57 (m, 2H), 0.34 - 0.44 (m, 2H).

Example 110

2-amino-5-(2-amino-4-oxo-3-phenyl-3,4-dihydro-6-quinazolinyl)-N,N-diethyl-3- ridinesulfonamide

Step A

2-amino-5-bromo- -diethyl-3-pyridinesulfonamide

[00345] A solution of 2-amino-5-bromo-3-pyridinesulfonyl chloride (3000 mg, 11 .05 mmol) and DIPEA (2.89 ml_, 16.57 mmol) in tetrahydrofuran (200 mL) was cooled to 0°C and treated with diethylamine (3.46 mL, 33.1 mmol). The mixture was warmed to room temperature and stirred for 45 minutes. The reaction was poured into ethyl acetate and washed with saturated sodium bicarbonate (aq). The organic layer was separated, dried over sodium sulfate, filtered, taken to a residue under reduced pressure, and purified by trituration with diethyl ether to afford 2-amino-5-bromo-N,N-diethyl-3-pyridinesulfonarnide (2.82 g, 9.15 mmol, 83 % yield) as a yellow solid. LCMS (m/z, ES+) = 308 (M+H).

Step B

2-amino-5-(2-amino-4-oxo-3 henyl-3 -dihydro-6-quinazolinyl)-N,^

pyridinesulfonamide

[00346] A solution of 2-amino-5-bromo-N,N-diethyl-3-pyridinesulfonamide (200 mg, 0.649 mmol), bis(pinacolato)diboron (198 mg, 0.779 mmol), potassium acetate (191 mg, 1.947 mmol) and PdCI₂(dppf)-CH₂Cl₂ adduct (53.0 mg, 0.065 mmol) in 1 ,4-dioxane (3 mL) was maintained in a sealed pressure tube for 16 hours at 90 °C. The solution was cooled, filtered through Celite®, rinsed with ethyl acetate, and the filtrates were concentrated. A solution of the crude residue, 2- amino-6-iodo-3-phenyl-4(3H)-quinazolinone (105 mg, 0.289 mmol), potassium carbonate (120 mg, 0.867 mmol), and PdCI₂(dppf)-CH₂CI₂ adduct (23.61 mg, 0.029 mmol) in 1 ,4-dioxane (5 mL)/ water (3 mL) was maintained at 90 °C for 20 minutes. The mixture was cooled, poured into ethyl acetate, and washed with water. The combined aqueous layer and insoluble solids were washed with dichloromethane and the combined organic layers were separated, dried over sodium sulfate, filtered, taken to a residue under reduced pressure, and purified by reverse phase HPLC to afford following lyophlization 2-amino-5-(2-amino-4-oxo-3-phenyl-3,4-dihydro-6- quinazolinyl)-N,N-diethyl-3-pyridinesulfonamide (39 mg, 0.076 mmol, 26.4 % yield) as a white foam. LCMS (m z, ES+) = 465 (M+H). H NMR (DMSO-af₆) δ: 8.59 (d, J = 2.5 Hz, 1 H), 8.03 (t, J = 2.1 Hz, 2H), 7.92 (dd, J = 8.6, 2.3 Hz, 1 H), 7.47 - 7.65 (m, 3H), 7.32 (d, J = 8.6 Hz, 1 H), 7.37 (d, J = 7.2 Hz, 2H), 6.72 (br. s., 2H), 6.35 (br. s., 2H), 3.22 - 3.32 (m, 4H), 1.06 (t, J = 7.0 Hz, 6H).

Example 111

2-amino-5-(2-amino-4-oxo-3-phenyl-3,4-dihydro-6-quinazolinyl)-N-methyl-N-phenyl-3- ridinesulfonamide

Step A

2-amino-5-bromo-N-methyl-N-phenyl-3-pyridinesulfonamide

[00347] A solution of 2-amino-5-bromo-3-pyridinesulfonyl chloride (3 g, 1 1.05 mmol) and N-methylaniline (2.413 mL, 22.10 mmol) in pyridine (60 mL) was maintained with stirring for three hours. The mixture was concentrated under reduced pressure, dissolved in

dichloromethane, and washed with saturated sodium bicarbonate. The organic layer was separated, dried over sodium sulfate, filtered, taken to a residue under reduced pressure, and purified by trituration from diethyl ether to afford 2-amino-5-bromo-N-methyl-N-phenyl-3- pyridinesulfonamide (980 mg, 2.86 mmol, 25.9 % yield) as an orange solid. LCMS (m/z, ES+) = 342 (M+H).

Step B

2-amino-5-(2-amino-4-oxo-3^henyl-3,4-dihydro-6-quinazoliny^

pyridinesulfonamide

[00348] A solution of bis(pinacolato)diboron (171 mg, 0.672 mmol), potassium acetate (172 mg, 1.753 mmol), 2-amino-5-bromo-N-methyl-N-phenyl-3-pyridinesulfonamide (200 mg, 0.584 mmol), and PdCI₂(dppf)-CH₂CI₂ adduct (47.7 mg, 0.058 mmol) in 1 ,4-dioxane (3 mL) was maintained at 90 °C with stirring for 16 hours. The solution was cooled, filtered through Celite®, and the Celite® rinsed with ethyl acetate. The filtrates were concentrated. A solution of this crude residue, 2-amino-6-iodo-3-phenyl-4(3H)-quinazolinone (135 mg, 0.372 mmol), potassium carbonate (154 mg, 1.115 mmol), and PdCI₂(dppf)-CH₂CI₂ adduct (30.4 mg, 0.037 mmol) in dioxane/water was maintained at 90°C for 2 hours. The mixture was cooled, poured into ethyl acetate, and washed with water. The organic layer was separated, dried over sodium sulfate, filtered, taken to a residue under reduced pressure, and purified by reverse phase HPLC.

Fractions containing product were concentrated and triturated with acetonitrile to afford 2- amino-5-(2-amino-4-oxo-3-phenyl-3,4-dihydro-6-quinazo inyl)-N-methyl-N-phenyl-3- pyridinesulfonamide (28 mg, 0.056 mmol, 15.11 % yield) as a white solid. LCMS (m/z, ES+) = 499 (M+H). ¹H NMR (DMSO-d₆) δ: 8.59 (s, 1 H), 8.14 (s, 1 H), 7.85 (s, 1 H), 7.74 (d, J = 8.4 Hz, 1H), 7.48 - 7.65 (m, 4H), 7.18 - 7.43 (m, 7H), 6.60 (br. s., 2H), 6.35 (br. s., 2H), 3.24 (s, 3H).

Example 112 and 113

2-amino-5-(2-amino-4-oxo-3^henyl-3,4-dihydro-6-quinazolinyl)-N-(phenylm

ridinesulfonamide

Step A

2-amino-5-bromo- -(phenylmethyl)-3-pyridinesulfonamide

[00349] A solution of 2-amino-5-bromo-3-pyridinesulfonyl chloride (2.5 g, 9.21 mmol), DIPEA (3.22 mL, 18.41 mmol), and benzylamine (3.01 mL, 27.6 mmol) in tetrahydrofuran (55 mL) was maintained with stirring at room temperature for 2 hours. The mixture was poured into ethyl acetate and washed with saturated sodium bicarbonate (aq). The organic layer was separated, dried over sodium sulfate, filtered, concentrated, and triturated with diethyl ether to afford 2-amino-5-bromo-N-(phenylmethyl)-3-pyridinesulfonamide (1.89 g, 5.52 mmol, 60.0 % yield) as a white solid. LCMS (m/z, ES+) = 342 (M+H).

Step B

2-amino-5-(2-amino-4-oxo-3^henyl-3 -dihydro-6-quinazolinyl)-N-(phenylm

pyridinesulfonamide [00350] A solution of potassium acetate (172 mg, 1.753 mmol), bis(pinacolato)diboron (171 mg, 0.672 mmol), 2-amino-5-bromo-N-(phenylmethyl)-3-pyridinesulfonamide (200 mg, 0.584 mmol), and PdCI₂(dppf)-CH₂CI₂ adduct (47.7 mg, 0.058 mmol) in 1 ,4-dioxane (3 mL) was maintained at 90°C in a sealed pressure tube for 16 hours. The mixture was cooled, filtered through Celite®, and the Celite® was washed with ethyl acetate. The filtrates were

concentrated and used crude. The crude residue, 2-amino-6-iodo-3-phenyl-4(3H)- quinazolinone (1 10 mg, 0.303 mmol), potassium carbonate (126 mg, 0.909 mmol), and

PdCI₂(dppf)-CH₂Cl₂ adduct (37.1 mg, 0.045 mmol) in dioxane/water was maintained at 90°C for 3 hours. The mixture was cooled, poured into DCM, and washed with saturated sodium chloride (aq). The organic layer was separated, dried over sodium sulfate, filtered, taken to a residue under reduced pressure, and suspended in DMF. The solids were removed by vacuum filtration to afford 2-amino-5-(2-amino-4-oxo-3-phenyl-3,4-dihydro-6-quinazolinyl)-N- (phenylmethyl)-3-pyridinesulfonamide (28 mg, 0.056 mmol, 18.54 % yield) as a grey solid (free base). The filtrates were purified by reverse phase HPLC, and fractions containing product were concentrated and triturated with DCM/MeOH to afford 2-amino-5-(2-amino-4-oxo-3-phenyl- 3,4-dihydro-6-quinazolinyl)-N-(phenylmethyl)-3-pyridinesulfonamide (40 mg, 0.073 mmol, 24.25 % yield) formate salt as a white solid. LCMS (m/z, ES+) = 499 (M+H). NMR for Free Base: H NMR (DMSO- 3f₅) δ: 8.50 (d, J = 2.3 Hz, 1 H), 8.43 (t, J = 6.1 Hz, 1 H), 8.00 (d, J = 2.1 Hz, 2H), 7.86 (dd, J = 8.7, 2.2 Hz, 1 H), 7.49 - 7.64 (m, 3H), 7.38 (d, J = 7.2 Hz, 2H), 7.32 (d, J = 8.6 Hz, 1 H), 7.09 - 7.26 (m, 5H), 6.69 (br. s., 2H), 6.34 (br. s., 2H), 4.07 (d, J = 6.0 Hz, 2H).

Example 114

2-amino-5-(2-amino-4-oxo-3-phenyl-3,4-dihydro-6-quinazolinyl)-N-m

ridinesulfonamide

Step A

2-amino-5-bromo-N-methyl-3-pyridinesulfonamide

[00351] A solution of 2-amino-5-bromo-3-pyridinesulfonyl chloride (2.5 g, 9.21 mmol), DIPEA (3.22 mL, 18.41 mmol), and 2.0M methylamine in THF (13.81 ml_, 27.6 mmol) in tetrahydrofuran (55 mL) was maintained with stirring at room temperature for 1 hour. The mixture was poured into ethyl acetate and washed with saturated sodium bicarbonate (aq). The organic layer was separated, dried over sodium sulfate, filtered, taken to a residue under reduced pressure, and triturated with diethyl ether to afford after vacuum filtration 2-amino-5- bromo-N-methyl-3-pyridinesulfonamide (2.10 g, 7.89 mmol, 86 % yield) as a white solid. LCMS (m/z, ES+) = 266 (M+H).

Step B

2-amino-5-(2-amino-4-oxo-3φhenyl-3 -dihydro-6-quinazol^

[00352] A solution of bis(pinacolato)diboron (192 mg, 0.756 mmol), potassium acetate (194 mg, 1.973 mmol), 2-amino-5-bromo-N-methyl-3-pyridinesulfonamide (175 mg, 0.658 mmol), and PdCI₂(dppf)-CH₂CI₂ adduct (53.7 mg, 0.066 mmol) in 1 ,4-dioxane (3 mL) was maintained in a sealed tube at 80 °C for 16 hours. The solution was cooled to room

temperature and filtered through Celite®. The Celite® was washed with ethyl acetate and the combined filtrates were concentrated under reduced pressure. A solution of the crude filtrates, 2-amino-6-iodo-3-phenyl-4(3H)-quinazolinone (135 mg, 0.372 mmol), potassium carbonate (154 mg, 1.1 15 mmol), and PdCI₂(dppf)-CH₂Cl₂ adduct (45.5 mg, 0.056 mmol) in dioxane/water was maintained at 90°C for 2 hours. The mixture was poured into DCM and washed with water. The organic layer was separated, dried over sodium sulfate, filtered, taken to a residue under reduced pressure, and purified by reverse phase HPLC to afford 2-amino-5-(2-amino-4-oxo-3- phenyl-3,4-dihydro-6-quinazolinyl)-N-methyl-3-pyridinesulfonamide as the formate salt (38 mg, 0.090 mmol, 24.20 % yield) as a white solid following lyophlization. LCMS (m/z, ES+) = 423 (M+H). ¹H NMR (DMSO-d₆) δ: 8.59 (d, J = 2.3 Hz, 1 H), 8.05 (d, J = 2.3 Hz, 1 H), 8.07 (d, J = 2.3 Hz, 1 H), 7.92 (dd, J = 8.7, 2.2 Hz, 1 H), 7.73 (q, J = 5.0 Hz, 1 H), 7.47 - 7.65 (m, 3H), 7.27 - 7.42 (m, 3H), 6.71 (br. s., 2H), 6.34 (br. s., 2H), 2.46 (d, J = 4.9 Hz, 3H).

Example 115

2-amino-6-(2-oxo-2,3-dihydro-1H-indol-5-yl)-3-phenyl-4(3H)-quinazolinone

[00353] A solution of 2-amino-6-bromo-3-phenyl-4(3H)-quinazolinone (100 mg, 0.316 mmol), 5-(4,4,5-trimethyl-1 ,3,2-dioxaborolan-2-yl)-1 ,3-dihydro-2H-indol-2-one (97 mg, 0.395 mmol), potassium carbonate (87 mg, 0.633 mmol), and PdCI₂(dppf)-CH₂Cl₂ adduct (25.8 mg, 0.032 mmol) in 1 ,4-dioxane (3 ml_)/water (1 mL) was maintained with stirring at room

temperature for 3 hours. The solution was cooled, poured into ethyl acetate, and washed with water. The organic layer was separated, dried over sodium sulfate, filtered, concentrated under reduced pressure, and purified by reverse phase HPLC to afford 2-amino-6-(2-oxo-2,3-dihydro- 1 H-indol-5-yl)-3-phenyl-4(3H)-quinazolinone as the formate salt (45 mg, 0.122 mmol, 38.6 % yield) as a white solid following lyophlization. LCMS (m/z, ES+) = 369 (M+H). H NMR (DMSO- d₆) 6: 12.75 (s, 1 H), 10.47 (s, 1 H), 8.07 (d, J = 2.1 Hz, 1 H), 7.93 (dd, J = 8.6, 2.0 Hz, 1 H), 7.47 - 7.70 (m, 5H), 7.29 - 7.47 (m, 3H), 6.91 (d, J = 8.0 Hz, 1 H), 6.69 (br. s., 1 H), 3.54 (s, 2H).

Example 116

2-amino-6-( 1 H-indazol-6-yl)-3-phenyl-4(3H)-quinazolinone

[00354] A solution of 2-amino-6-bromo-3-phenyl-4(3H)-quinazolinone (92 mg, 0.291 mmol), 5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-indazole (89 mg, 0.364 mmol), potassium carbonate (80 mg, 0.582 mmol), and PdCI₂(dppf)-CH₂CI₂ adduct (23.76 mg, 0.029 mmol) in 1 ,4-dioxane (3 ml_)/water (1 mL) was maintained at 80 °C for 2 hours. The mixture was cooled, poured into ethyl acetate, and washed with water. The organic layer was separated, dried over sodium sulfate, filtered, taken to a residue under reduced pressure, and purified by reverse phase hplc to afford 2-amino-6-(1 H-indazol-6-yl)-3-phenyl-4(3H)- quinazolinone (35 mg, 0.099 mmol, 34.0 % yield) as a white solid following lyophlization. LCMS (m/z, ES+) = 354 (M+H). ¹H N R (DMSO-d₆) δ: 13.1 1 (br. s., 1H), 8.09 - 8.18 (m, 2H), 8.04 (s, 1 H), 7.99 (dd, J = 8.6, 2.3 Hz, 1 H), 7.66 - 7.73 (m, 1 H), 7.47 - 7.66 (m, 4H), 7.17 - 7.46 (m, 3H), 6.31 (br. s., 2H).

Example 117

2-amino-6-( 1 -quinazolinone

[00355] A solution of 2-amino-6-bromo-3-phenyl-4(3H)-quinazolinone (85 mg, 0.269 mmol), 1 H-indazol-4-ylboronic acid (76 mg, 0.471 mmol), potassium carbonate (74.3 mg, 0.538 mmol), and PdCI₂(dppf)-CH₂CI₂ adduct (21 .96 mg, 0.027 mmol) in 1 ,4-dioxane (3 ml_)/water (1 mL) was maintained at 80°C for 3 hours. The solution was cooled to room temperature, poured into ethyl acetate, and washed with water. The organic layer was separated, dried over sodium sulfate, filtered, taken to a residue under reduced pressure, and purified by reverse phase hplc to afford 2-amino-6-(1 H-indazol-4-yl)-3-phenyl-4(3H)-quinazolinone (50 mg, 0.141 mmol, 52.6 % yield) as a white solid as the formate salt. LCMS (m/z, ES+) = 354 (M+H). H NMR (DMSO-cf₆) δ: 13.27 (br. s., 1 H), 8.20 (d, J = 2.1 Hz, 1 H), 8.15 (s, 1 H), 8.01 (dd, J = 8.6, 2.1 Hz, 1 H), 7.49 - 7.63 (m, 4H), 7.36 - 7.49 (m, 4H), 7.26 (d, J = 7.0 Hz, 1 H), 6.40 (br. s., 2H).

Example 118

2-amino-6-[3,4-bis(meth loxy)phenyl]-3-phenyl-4(3H)-quinazolinone

[00356] A solution of 2-amino-6-iodo-3-phenyl-4(3H)-quinazolinone (100 mg, 0.275 mmol), [3,4-bis(methyloxy)phenyl]boronic acid (57.6 mg, 0.317 mmol), PdCI₂(dppf)-CH₂CI₂ adduct (22.49 mg, 0.028 mmol), and potassium carbonate (114 mg, 0.826 mmol) in dioxane/water was maintained at 80 °C for 1 hour. The mixture was cooled to room

temperature, poured into ethyl acetae, and washed with water. The organic layer was separated, dried over sodium sulfate, filtered, taken to a residue under reduced pressure, and purified by column chromatography to afford 2-amino-6-[3,4-bis(methyloxy)phenyl]-3-phenyl- 4(3H)-quinazolinone (25 mg, 0.067 mmol, 24.31 % yield) as a yellow foam. LCMS (m/z, ES+) = 374 (M+H). H NMR (DMSO-d₆) δ: 8.08 (d, J = 2.3 Hz, 1 H), 7.93 (dd, J = 8.6, 2.1 Hz, 1 H), 7.47 - 7.63 (m, 3H), 7.34 - 7.41 (m, 2H), 7.31 (d, J = 8.6 Hz, 1 H), 7.16 - 7.24 (m, 2H), 7.04 (d, J = 8.2 Hz, 1 H), 6.30 (br. s., 2H), 3.85 (s, 3H), 3.79 (s, 3H).

Example 119

2-amino-6-[5-(4-morpholin lcarbonyl)-3-pyridinyl]-3-phenyl-4(3H)-quinazolin

[00357] A solution of 2-amino-6-bromo-3-phenyl-4(3H)-quinazolinone (90 mg, 0.285 mmol), [5-(4-morpholinylcarbonyl)-3-pyridinyl]boronic acid (101 mg, 0.427 mmol), potassium carbonate (79 mg, 0.569 mmol), and PdCI₂(dppf)-CH₂CI₂ adduct (23.25 mg, 0.028 mmol) in 1 ,4- dioxane (3 ml_)/water (1 mL) was maintained at 80°C with stirring for 3 hours. The mixture was cooled, poured into ethyl acetate, and washed with water. The organic layer was separated, dried over sodium sulfate, filtered, taken to a residue, and purified by reverse phase hplc to afford 2-amino-6-[5-(4-morpholinylcarbonyl)-3-pyridinyl]-3-phenyl-4(3H)-quinazolinone (70 mg, 0.164 mmol, 57.5 % yield) as a white solid following lyophilization. LCMS (m/z, ES+) = 428 (M+H). H NMR (DMSO-c ₆) δ: 8.88 - 9.07 (m, 1 H), 8.50 - 8.63 (m, 1 H), 8.18 - 8.27 (m, 1 H), 8.09 - 8.18 (m, 1 H), 7.99 - 8.09 (m, 1 H), 7.49 - 7.67 (m, 3H), 7.24 - 7.48 (m, 3H), 6.53 (br. s., 2H), 3.58 (br. s., 4H), 3.40 (br. s., 4H).

Example 120

5-(2-amino-4-oxo-3-phenyl-3,4-dihydro-6-quinazolinyl)-3-pyridinecarboxa

[00358] A solution of 2-amino-6-bromo-3-phenyl-4(3H)-quinazolinone (95 mg, 0.300 mmol), 5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-3-pyridinecarboxamide (89 mg, 0.361 mmol), potassium carbonate (83 mg, 0.601 mmol), and PdCl₂(dppf)-CH₂CI₂ adduct (24.54 mg, 0.030 mmol) in 1 ,4-dioxane (3 mL)/water (1 mL) was maintained at 80 °C for 2 hours. The mixture was cooled, poured into ethyl acetate, and washed with water. The aqueous layer and insoluble solids were washed with DCM and the combined organic layers were dried over sodium sulfate, filtered, taken to a residue under reduced pressure, and purified by column chromatography to afford 5-(2-amino-4-oxo-3-phenyl-3,4-dihydro-6-quinazolinyl)-3- pyridinecarboxamide (12 mg, 0.034 mmol, 11 .17 % yield) as a brown solid. LCMS (m/z, ES+) = 358 (M+H). No exchangeable protons evident. H NMR (METHANOLS) δ: 8.99 (d, J = 1.8 Hz, 1 H), 9.02 (d, J = 2.0 Hz, 1 H), 8.58 (t, J = 2.1 Hz, 1 H), 8.39 (d, J = 2.1 Hz, 1 H), 8.06 (dd, J = 8.6, 2.1 Hz, 1 H), 7.57 - 7.69 (m, 3H), 7.49 (d, J = 8.6 Hz, 1 H), 7.38 - 7.44 (m, 2H).

Example 121

2-amino-6-[5,6-bis(meth loxy)-3-pyridinylJ-3^henyl-4(3H)-quinazolinone

[00359] A solution of 2-amino-6-iodo-3-phenyl-4(3H)-quinazolinone (100 mg, 0.275 mmol), 2,3-bis(methyloxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridine (91 mg, 0.344 mmol), potassium carbonate (1 14 mg, 0.826 mmol), and PdCI₂(dppf)-CH₂CI₂ adduct (22.49 mg, 0.028 mmol) in dioxane/water was maintained with stirring at 80 °C for 3 hours. The mixture was cooled, poured into ethyl acetate, and washed with water. The organic layer was separated, dried over sodium sulfate, filtered, taken to a residue under reduced pressure, and purified by column chromatography. Fractions containing product were concentrated under reduced pressure and the residue was triturated with diethyl ether to afford 2-amino-6-[5,6- bis(methyloxy)-3-pyridinyl]-3-phenyl-4(3H)-quinazolinone (65 mg, 0.174 mmol, 63.0 % yield) as a grey solid. LCMS (m/z, ES+) = 375 (M+H). ¹H NMR (DMSO-d₅) δ: 8.1 1 (s, 1 H), 7.91 - 8.03 (m, 2H), 7.49 - 7.63 (m, 4H), 7.27 - 7.41 (m, 3H), 6.34 (br. s., 2H), 3.80 - 3.95 (m, 6H).

General Scheme 11

General Scheme 12

Example 122

2-amino-5-[2-amino-3-(2-ftuorophenyl)-4-oxo-3,4-dihydroquinazofin-6-yi]-N-

2-amino-5-[2-amino-3-(2-fluorophenyl)-4-oxo-3,4-dihydro-6-quinazolinyl]-N-phenyl-3- pyridinesulfonamide

[00360] A solution of 2-amino-3-(2-fluorophenyl)-6-iodo-4(3H)-quinazolinone (0.080 g, 0.210 mmol), 2-amino-N-phenyl-5-(4,4,5_>5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-3- pyridinesulfonamide (0.087 g, 0.231 mmol), K₂C0₃ (0.087 g, 0.630 mmol), and PdCI₂(dppf)- CH₂CI₂ adduct (0.017 g, 0.021 mmol) in 1 ,4-dioxane (4.37 ml.) and water (4.37 mL) was heated to 80 °C for 2 hours. The reaction was cooled to room temperature and diluted with EtOAc. The combined organics were washed with brine, dried over Na₂S0₄, filtered, and concentrated. The crude residue was triturated with Et₂0. The residue was taken up in MeOH and filtered, then rinsed with Et₂0 to give 2-amino-5-[2-amino-3-(2-fluorophenyl)-4-oxo-3,4-dihydro-6- quinazolinyl]-N-phenyl-3-pyridinesulfonamideas a beige solid. ¹H NMR (400 MHz, DMSO-de) δ ppm 10.48 (s, 1 H), 8.52 (d, .7=1.95 Hz, 1 H), 8.06 (d, J=1.76 Hz, 1 H), 7.95 (d, J=1.56 Hz, 1 H), 7.84 (dd, J=8.60, 1.76 Hz, 1 H), 7.56 - 7.64 (m, 1 H), 7.44 - 7.56 (m, 2 H), 7.37 - 7.43 (m, 1 H), 7.31 (d, J=8.60 Hz, 1 H), 7.21 - 7.29 (m, 2 H), 7.1 1 (d, J=7.82 Hz, 2 H), 6.98 - 7.05 (m, 1 H), 6.81 (br. s., 1 H), 6.66 (br. s., 2 H), 3.57 (br. s., 1 H); ES-LCMS: 503.1 (M+1 ).

Example 123

2-amino-5-[2-amino-3-(2-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-6-yl]-N- phenylpyridine-3-sulfonamide

2-amino-5-{2-amino-3-[2-(methyloxy)phenyl]-4-oxo-3,4-dihydro-6-quina

pyridinesulfonamide

[00361 ] A solution of 2-amino-6-iodo-3-[2-(methyloxy)phenyl]-4(3H)-quinazolinone (.080 g, 0.203 mmol), 2-amino-N-phenyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-3- pyridinesulfonamide (0.084 g, 0.224 mmol), K₂C0₃ (0.084 g, 0.610 mmol), and PdCI₂(dppf)- CH₂CI₂ adduct (0.017 g, 0.020 mmol) in 1 ,4-dioxane (4.24 mL) and water (4.24 mL) was heated to 80 °C for 2 hours. The reaction was cooled to room temperature and diluted with EtOAc. The combined organics were washed with brine, dried over Na₂S0₄, filtered, and concentrated. The residue crude was taken up in MeOH and filtered, then rinsed with Et₂0 to give 2-amino-5- {2-amino-3-[2-(methyloxy)phenyl]-4-oxo-3,4-dihydro-6-quinazolinyl}-N-phenyl-3- pyridinesulfonamide as a beige solid. H NMR (400 MHz, DMSO-d₆) δ ppm 10.48 (br. s., 1 H), 8.51 (br. s., 1 H), 8.06 (br. s., 1 H), 7.93 (br. s., 1 H), 7.81 (d, J=8.40 Hz, 1 H), 7.51 (t, J=7.72 Hz, 2 H), 7.20 - 7.33 (m, 5 H), 7.08 - 7.16 (m, 3 H), 6.98 - 7.06 (m, 1 H), 6.80 (br. s., 2 H), 6.36 (br. s., 1 H), 3.75 (s, 3 H); ES-LCMS: 515.2(M+1 ).

Example 124

2-amino-5-[2-amino-3-(2-chlorophenyl)-4-oxo-3,4-dihydroquinazolin-6-yl]-N-

2-amino-5-[2-amino-3-(2-chlorophenyl)-4-oxo-3 -dihydroquinazo

sulfonamide

[00362] A solution of 2-amino-3-(2-chlorophenyl)-6-iodo-4(3H)-quinazolinone (.080 g, 0.201 mmol), 2-amino-N-phenyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-3- pyridinesulfonamide (0.083 g, 0.221 mmol), K₂C0₃ (0.083 g, 0.604 mmol), and PdC (dppf)- CH₂CI₂ adduct (0.016 g, 0.020 mmol) in 1 ,4-dioxane (4.19 mL) and water (4.19 mL) was heated to 80 °C for 2 hours. The reaction was cooled to room temperature and diluted with EtOAc. The combined organics were washed with brine, dried over Na₂S0₄, filtered, and concentrated. The crude residue was taken up in MeOH and filtered, then rinsed with Et₂0 to give 2 -amino- 5- [2-amino-3-(2-chlorophenyl)-4-oxo-3,4-dihydroquinazolin-6-yl]-N-phenylpyridine-3-sulfonamide as a beige solid. H NMR (400 MHz, DMSO-af₆) δ ppm 10.47 (br. s., 1 H), 8.50 - 8.53 (m, 1 H), 8.03 - 8.08 (m, 1 H), 7.92 - 7.97 (m, 1 H), 7.80 - 7.89 (m, 1 H), 7.69 - 7.76 (m, 1 H), 7.56 (d, J=1.37 Hz, 4 H), 7.28 - 7.33 (m, 1 H), 7.21 - 7.28 (m, 2 H), 7.08 - 7.14 (m, 2 H), 6.99 - 7.06 (m, 1 H), 6.82 (br. s., 2 H), 6.58 (br. s., 1 H); ES-LCMS: 519.1 (M+1 ).

Example 125

2-amino-5-[2-amino-3-(2-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-6^

difluorophenyl)pyridine-3-sulfonamide

2-amino-5-{2-amino-3-[2-(methyloxy)phenyl]-4-oxo-3,4-dihydro-6-quinaz

difluorophenyl)-3-pyridinesulfonamide

[00363] A solution of 2-amino-6-iodo-3-[2-(methyloxy)phenyl]-4(3H)-quinazolinone (.080 g, 0.203 mmol), 2-amino-N-(2,4-difluorophenyl)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)- 3-pyridinesulfonamide (0.092 g, 0.224 mmol), K₂C0₃ (0.084 g, 0.610 mmol), and PdCI₂(dppf)- CH₂CI₂ adduct (0.017 g, 0.020 mmol) in 1 ,4-dioxane (4.24 mL) and water (4.24 mL) was heated to 80 °C for 1 hour. The reaction was cooled to room temperature and diluted with EtOAc. The combined organics were washed with brine, dried over Na₂S0₄, filtered, and concentrated. The crude residue was purified by reverse phase chromatography (10-90% ACN/ H₂0 + formic acid). Isolation and lyophilization of the fractions gave 2-amino-5-{2-amino-3-[2- (methyloxy)phenyl]-4-oxo-3,4-dihydro-6-quinazolinyl}-N-(2,4-difluorophenyl)-3- pyridinesulfonamide as a solid. H NMR (400 MHz, DMSO-d₆) δ ppm 8.52 (br. s., 1 H), 7.89 - 7.96 (m, 2 H), 7.76 - 7.83 (m, 1 H), 7.47 - 7.56 (m, 1 H), 7.22 - 7.33 (m, 4 H), 7.07 - 7.14 (m, 1 H), 6.97 (br. s., 1 H), 6.76 (br. s., 2 H), 6.34 (br. s., 2 H), 3.75 (s, 3 H) (2 exchangeable protons not evident); ES-LCMS: 551.2 (M+1 ).

Example 126

2-amino-5-[2-amino-3-(4-bromophenyl)-4-oxo-3,4-dihydroquinazolin-6-yl]-N- phenylpyridine-3-sulfonamide

2-amino-5-[2-amino-3-(4-bromophenyl)-4-oxo-3,4-dihydroquinazo

sulfonamide

[00364] A solution of 2-amino-3-(4-bromophenyl)-6-iodo-4(3H)-quinazolinone (0.1 g, 0.226 mmol), 2-amino-N-phenyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-3- pyridinesulfonamide (0.085 g, 0.226 mmol), sodium bicarbonate (0.057 g, 0.679 mmol), and tetrakis triphenylphosphine palladium(O) (0.026 g, 0.023 mmol) in 1 ,4-dioxane (4.71 mL) and water (4.71 mL) was heated to 65 °C overnight. The reaction was diluted with water and the solids were filtered, then rinsed with MeOH to 2-amino-5-[2-amino-3-(4-bromophenyl)-4-oxo- 3,4-dihydroquinazolin-6-yl]-N-phenylpyridine-3-sulfonamide as a light beige solid (0.086 g, 68%). H NMR (400 MHz, DMSO-c/₆) δ ppm 9.95 (br. s., 1 H), 8.49 (d, J=1.95 Hz, 1 H), 8.04 (d, J=2.15 Hz, 1 H), 7.94 (d, J=1.76 Hz, 1 H), 7.72 - 7.87 (m, 1 H), 7.35 - 7.43 (m, 1 H), 7.17 - 7.30 (m, 5 H), 7.05 - 7.13 (m, 2 H), 6.94 - 7.03 (m, 1 H), 6.66 - 6.88 (m, 3 H), 6.51 (br. s., 1 H), 4.41 (d, J=5.66 Hz, 1 H); ES-LCMS: 563.1 , 565.1 (M+1 ). Example 127

2-amino-5-[2-amino-4-oxo-3-(4-phenytphenyl)-3,4-dihydroquinazolin-6-yf]-N-

2-amino-5-[2-amino-3-(4-biphenylyl)-4-oxo-3,4-dihydro-6-quinazolin

pyridinesulfonamide

[00365] A solution of 2-amino-5-[2-amino-3-(4-bromophenyl)-4-oxo-3,4-dihydro-6- quinazolinyl]-N-phenyl-3-pyridinesulfonamide (0.088 g, 0.156 mmol), phenylboronic acid (0.029 g, 0.234 mmol), K₂C0₃ (0.086 g, 0.625 mmol), PdCI₂(dppf)-CH₂CI₂ adduct (0.013 g, 0.016 mmol), and 1 ,4-dioxane (1.420 mL) under nitrogen was heated in the microwave at 160 °C for 15 minutes. The reaction was diluted with EtOAc and water. The combined organics were washed with saturated NaHC0₃, brine, dried over Na₂S0₄, filtered, and concentrated. The crude residue was purified by reverse phase chromatography (10-90% ACN/ H₂0 + formic acid). Isolation and lyophilization gave a beige solid. The solid was triturated with Et₂0 to give 2-amino-5-[2-amino-3-(4-biphenylyl)-4-oxo-3,4-dihydro-6-quinazolinyl]-N-phenyl-3- pyridinesulfonamide as a beige solid (0.018 g, 21 %). ¹H NMR (400 MHz, DMSO-cf₆) δ ppm 8.48 - 8.53 (m, 1 H), 8.05 (d, J=2.34 Hz, 1 H), 7.95 (s, 1 H), 7.80 - 7.90 (m, 3 H), 7.77 (d, J=7.41 Hz, 2 H), 7.38 - 7.65 (m, 7 H), 7.27 - 7.35 (m, 1 H), 7.19 - 7.26 (m, 2 H), 7.07 - 7.13 (m, 2 H), 6.96 - 7.04 (m, 1 H), 6.75 - 6.84 (m, 1 .5 H), 6.43 - 6.53 (m, 1.5 H); ES-LCMS: 561 .5 (M+1 ).

Example 128

2-amino-5-[2-amino-3-(2-chlorophenyl)-4-oxo-3,4-dihydroquinazoHn-^^

difluorophenyl)pyridine-3-sulfonamide

2-amino-5-[2-amino-3-(2-chlorophenyl)-4-oxo-3,4-dihydro-6-quinaz

3-pyridinesulfonamide

[00366] A solution of 2-amino-3-(2-chlorophenyl)-6-iodo-4(3H)-quinazolinone (0.080 g, 0.201 mmol), 2-amino-N-(2,4-difluorophenyl)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-3- pyridinesulfonamide (0.091 g, 0.221 mmol), K₂C0₃ (0.083 g, 0.604 mmol), and PdCI₂(dppf)- CH₂CI₂ adduct (0.016 g, 0.020 mmol) in 1 ,4-dioxane (4.19 ml.) and water (4.19 mL) was heated to 80 °C for 1 hour. The reaction was cooled to room temperature and diluted with EtOAc. The combined organics were washed with brine, dried over Na₂S0₄, filtered, and concentrated. The crude residue was purified by reverse phase chromatography (10-90% ACN/ H₂0 + formic acid). Isolation and lyophilization of the fractions gave a solid. The solid was triturated with Et₂0 to give 2-amino-5-[2-amino-3-(2-chlorophenyl)-4-oxo-3,4-dihydro-6-quinazolinyl]-N-(2,4- difluorophenyl)-3-pyridinesulfonamide (0.053 g, 48%). H NMR (400 MHz, DMSO-d₆) δ ppm 10.33 (br. s., 1 H), 8.56 (d, J=1.95 Hz, 1 H), 7.93 (d, J=1.76 Hz, 2 H), 7.78 - 7.85 (m, 1 H), 7.68 - 7.75 (m, 1 H), 7.52 - 7.60 (m, 3 H), 7.20 - 7.37 (m, 3 H), 6.98 - 7.07 (m, 1 H), 6.78 (br. s., 2 H), 6.57 (br. s., 2 H); ES-LCMS: 555.3 (M+1 ).

Example 129

5-[2-amino-4-oxo-3-(pyridin-3-ylmethyl)-3,4-dihydroquinazolin^

difluorophenyl)-2-methoxypyridine-3-sulfonamide

Step A

[6-bromo-4-oxo-3- -2-quinazolinyt]cyanamide

[00367] A suspension of methyl 5-bromo-2-

{[(cyanoamino)(phenyloxy)methylidene]amino}benzoate (.100 g, 0.267 mmol) in iPrOH (1.306 mL) was treated with 1-(3-pyridinyl)methanamine (0.030 mL, 0.294 mmol) and DMAP (0.013 g, 0.107 mmol) and was heated in a sealed tube to 85 °C for 2 hours. The reaction was cooled overnight and then diluted with Et₂0. Additionally, the above reaction was done without DMAP. The two reactions were combined rinsing with Et₂0 to [6-bromo-4-oxo-3-(3-pyridinylmethyl)-3,4- dihydro-2-quinazolinyl]cyanamide (0.156 g, 82%) as a white solid. ES-LCMS: 355.9, 358.0 (M+1 ).

Step B

2-amino-6-bromo-3-(3^yridinylmet yl)-4(3H)-quinazolinone

[00368] A solution of [6-bromo-4-oxo-3-(3-pyridinylmethyl)-3,4-dihydro-2- quinazolinyl]cyanamide (0.156 g, 0.438 mmol) in DMSO (2.433 mL) and concentrated HCI (4.87 mL) was heated in a sealed tube at 100 °C for 1 hour. After cooling to room temperature, the solution was poured water (50 mL) and basified with solid K₂C0₃. The solids were filtered to give 2-amino-6-bromo-3-(3-pyridinylmethyl)-4(3H)-quinazolinone (0.121 g, 83%). ES-LCMS: 331.0, 333.0 (M+1 ).

Step C

5-[2-amino-4-oxo-3-(3^yridinylmethyl)-3 -dihydro-6-quinazolin

(methyloxy)-3-pyridinesuifonamide

[00369] A solution of 2-amino-6-bromo-3-(3-pyridinylmethyl)-4(3H)-quinazolinone (.061 g, 0.184 mmol), [5-{[(2,4-difluorophenyl)amino]sulfonyl}-6-(methyloxy)-3-pyridinyl]boronic acid (0.108 g, 0.313 mmol), K₂C0₃ (0.076 g, 0.553 mmol), and PdCI₂(dppf)-CH₂CI₂ adduct (0.015 g, 0.018 mmol) in 1 ,4-dioxane (3.84 mL) and water (3.84 mL) was heated to 80 °C for 1 hour. The reaction was cooled to room temperature and diluted with EtOAc. The combined organics were washed with brine, dried over Na₂S0₄, filtered, and concentrated. The crude residue was purified by reverse phase chromatography (10-90% ACN/ H₂0 + formic acid). Isolation and lyophilization of the fractions gave 5-[2-amino-4-oxo-3-(3-pyridinylmethyl)-3,4-dihydro-6- quinazolinyl]-N-(2,4-difluorophenyl)-2-(methyloxy)-3-pyridinesulfonamide as a white solid (0.023 g, 23%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.24 (br. s., 1 H), 8.69 - 8.78 (m, 1 H), 8.52 - 8.60 (m, 1 H), 8.43 - 8.51 (m, 1 H), 8.16 - 8.21 (m, 1 H), 8.04 - 8.09 (m, 1 H), 7.86 - 7.92 (m, 1 H), 7.56 - 7.63 (m, 1 H), 7.14 - 7.37 (m, 6 H), 6.94 - 7.05 (m, 1 H), 5.32 (s, 2 H), 3.96 (s, 3 H); ES-LCMS: 551.5 (M+1).

Example 130

5-[2-amino-4-oxo-3-(pyridin-2-ylmethyl)-3,4-dihydroquinazolin-6-yl]-N-(2,4- difluorophenyl)-2-methoxypyridine-3-sulfonamide

Step A

[6-bromo-4-oxo-3- -2-quinazolinyl]cyanamide

[00370] A suspension of methyl 5-bromo-2-

{[(cyanoamino)(phenyloxy)methylidene]amino}benzoate (0.200 g, 0.534 mmol) in Isopropanol (2.61 mL) was treated with 1-(2-pyridinyl)methanamine (0.058 mL, 0.561 mmol) and DMAP (0.026 g, 0.214 mmol) and was heated in a sealed tube to 85 °C for 2 hours. The reaction was cooled overnight and then diluted with Et₂0. The solid was filtered, rinsing with Et₂0 to give [6- bromo-4-oxo-3-(2-pyridinylmethyl)-3,4-dihydro-2-quinazolinyl]cyanamide as a solid (0. 5 g, 60%). ES-LCMS: 356.0, 358.0 (M+1 ).

Step B

2-amino-6-bromo (3H)-quinazolinone

[00371] A solution of [6-bromo-4-oxo-3-(2-pyridinylmethyl)-3,4-dihydro-2- quinazolinyl]cyanamide (.1 15 g, 0.323 mmol) in DMSO (1.794 mL) and concentrated HCI (3.59 mL) was heated in a sealed tube at 100 °C for 1 hour. After cooling to room temperature, the solution was poured into water (50 mL) and basified with solid K₂C0₃. The solids were filtered to give 2-amino-6-bromo-3-(2-pyridinylmethyl)-4(3H)-quinazolinone. (0.103 g, 96%). ES-LCMS: 331.9, 333.9 (M+1 ).

Step C

5-[2-amino-4-oxo-3-(2^yridinylmethyl)-3,4-dihydro-6-quina

(methyloxy)-3-pyridinesulfonamide

[00372] A solution of 2-amino-6-bromo-3-(2-pyridinylmethyl)-4(3H)-quinazolinone (.051 g, 0.154 mmol), [5-{[(2,4-difluorophenyl)amino]sulfonyl}-6-(methyloxy)-3-pyridinyl]boronic acid (0.090 g, 0.262 mmol), K₂C0₃ (0.064 g, 0.462 mmol), and PdCI₂(dppf)-CH₂CI₂ adduct (0.013 g, 0.015 mmol) in 1,4-dioxane (3.21 mL) and water (3.21 mL) was heated to 80 °C for 1 hour. The reaction was cooled to room temperature and diluted with EtOAc. The combined organics were washed with brine, dried over Na₂S0₄, filtered, and concentrated. The crude residue was purified by reverse phase chromatography (10-90% ACN/ H₂0 + formic acid). Isolation and lyophilization of the fractions gave 5-[2-amino-4-oxo-3-(2-pyridinylmethyl)-3,4-dihydro-6- quinazolinyl]-N-(2,4-difluorophenyl)-2-(methyloxy)-3-pyridinesulfonamide as a white solid (0.020 g, 24%). H NMR (400 MHz, DMSO-d₆) δ ppm 10.21 (br. s., 1 H), 8.73 (br. s., 1 H), 8.43 - 8.51 (m, 1 H), 8.16 - 8.19 (m, 1 H), 8.01 - 8.06 (m, 1 H), 7.85 - 7.91 (m, 1 H), 7.75 - 7.82 (m, 1 H), 7.26 - 7.37 (m, 4 H), 7.17 - 7.26 (m, 1 H), 7.08 - 7.17 (m, 2 H), 6.94 - 7.05 (m, 1 H), 5.37 (s, 2 H), 3.96 (s, 3 H); ES-LCMS: 551.5 (M+1 ).

Example 131

5-[2-amino-4-oxo-3-(pyridin-4-ylmethyl)-3,4-dihydroquinazolin-6-ytf^

difluorophenyl)-2-methoxypyridine-3-sulfonamide

Step A

[6-bromo-4-oxo-3-(4^yridinylmethyl)-3,4-dihydro-2-quin^

[00373] A suspension of methyl 5-bromo-2-

{[(cyanoamino)(phenyloxy)methylidene]amino}benzoate (0.200 g, 0.534 mmol) in Isopropanol (2.62 mL) was treated with 1-(4-pyridinyl)methanamine (0.057 mL, 0.561 mmol) and DMAP (0.026 g, 0.214 mmol) and was heated in a sealed tube to 85 °C for 2 hours. The reaction was cooled overnight and then diluted with Et₂0. The solid was filtered, rinsing with Et₂0 to give [6- bromo-4-oxo-3-(4-pyridinylmethyl)-3,4-dihydro-2-quinazolinyl]cyanamide (0.135 g, 71 %). ES- LCMS: 355.9, 357.9 ( +1).

Step B

2-amino-6-bromo-3-(4^yridinylmethyl)-4(3H)-quinazolinone

[00374] A solution of [6-bromo-4-oxo-3-(4-pyridinylmethyl)-3,4-dihydro-2- quinazolinyl]cyanamide (0.135 g, 0.379 mmol) in DMSO (2.106 mL) and concentrated HCI (4.21 mL) was heated in a sealed tube at 100 °C for 1 hour. After cooling to room temperature, the solution was poured into water (50 mL) and basified with solid K₂C0_3. The solids were filtered to give 2-amino-6-bromo-3-(4-pyridinylmethyl)-4(3H)-quinazolinone (0.068 g, 54%). ES-LCMS: 330.8, 332.9 (M+1 ).

Step C

5-[2-am no -oxo-3-{4-pyrid\ny\met y\)-3 -d\ y

(methyloxy)-3-pyridinesulfonamide

[00375] A solution of 2-amino-6-bromo-3-(4-pyridinylmethyl)-4(3H)-quinazolinone (0.068 g, 0.205 mmol), [5-{[(2,4-difluorophenyl)amino]sulfonyl}-6-(methyloxy)-3-pyridinyl]boronic acid (0.120 g, 0.349 mmol), K₂C0₃ (0.085 g, 0.616 mmol), and PdCI₂(dppf)-CH₂CI₂ adduct (0.017 g, 0.021 mmol) in 1 ,4-dioxane (4.28 mL) and water (4.28 mL) was heated to 80 °C for 1 hour. The reaction was cooled to room temperature and diluted with EtOAc. The combined organics were washed with brine, dried over Na₂S0₄, filtered, and concentrated. The crude residue was purified by reverse phase chromatography (10-90% ACN/ H₂0 + formic acid). Isolation and lyophilization of the fractions gave 5-[2-amino-4-oxo-3-(4-pyridinylmethyl)-3,4-dihydro-6- quinazolinyl]-N-(2,4-difluorophenyl)-2-(methyloxy)-3-pyridinesulfonamide as a white solid (0.024 g, 21 %). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.74 (d, J=2.34 Hz, 1 H), 8.50 (d, J=5.85 Hz, 2 H), 8.18 (d, J=2.54 Hz, 1 H), 8.06 (d, J=2.34 Hz, 1 H), 7.90 (dd, J=8.59, 2.34 Hz, 1 H), 7.26 - 7.36 (m, 2 H), 7.14 - 7.25 (m, 5 H), 6.95 - 7.05 (m, 1 H), 5.32 (s, 2 H), 3.96 (s, 3 H) (1 exchangeable proton not evident); ES-LCMS: 551.5 ( +1 ).

Example 132

5-[2-amino-3-(2-methylphenyl)-4-oxo-3,4-dihydroquinazolin-6-yl]-N-(2,4-difluorophe

methoxypyridine-3-sulfonamide

5-[2-amino-3-(2-methylphenyl)-4-oxo-3,4-dihydro-6-quinazolinyl]-N-(2,4-difluoroph

(methyloxy)-3-pyridinesulfonamide

[00376] A solution of 2-amino-6-iodo-3-(2-methylphenyl)-4(3H)-quinazolinone (0.100 g, 0.265 mmol) and [5-{[(2,4-difluorophenyl)amino]sulfonyl}-6-(methyloxy)-3-pyridinyl]boronic acid (0.137 g, 0.398 mmol) was treated with K₂C0₃ (0.1 10 g, 0.795 mmol) and PdCI₂(dppf)-CH₂CI₂ adduct (0.022 g, 0.027 mmol) in 1 ,4-dioxane (5.52 mL) and water (5.52 mL) and was heated to 80 °C for 90 minutes. The reaction was cooled to room temperature and diluted with EtOAc. The combined organics were washed with brine, dried over Na₂S0₄, filtered, and concentrated. The crude residue was purified by reverse phase chromatography (10-90% ACN/ H₂0 + formic acid). Isolation and lyophilization of the fractions gave a solid which was then triturated with Et₂0 to give 5-[2-amino-3-(2-methylphenyl)-4-oxo-3,4-dihydro-6-quinazolinyl]-N-(2,4- difluorophenyl)-2-(methyloxy)-3-pyridinesulfonamide (0.052 g, 36%). H NMR (400 MHz, DMSO-d₆) δ ppm 10.19 (br. s., 1 H), 8.76 (s, 1 H), 8.17 (s, 1 H), 8.03 (s, 1 H), 7.90 - 7.95 (m, 1 H), 7.21 - 7.49 (m, 7 H), 6.99 - 7.06 fm, 1 H), 6.46 (br. s., 2 H), 3.97 (s, 3 H), 2.05 (s, 3 H); ES- LCMS: 550.2 (M+1 ).

Example 133

5-{2-amino-4-oxo-3-[2-(trifluoromethyl)phenyl]-3,4-dihydroquinazolm

difluorophenyl)-2-methoxypyridine-3-sulfonamide

5-{2-amino-4-oxo-3-[2-(thfluoromethyl)phenyl]-3,4-dihydroquinazolin

difluorophenyl)-2-methoxypyridine-3-sulfonamide

[00377] A solution of 2-amino-6-iodo-3-[2-(trifluoromethyl)phenyl]-4(3H)-quinazolinone (0.100 g, 0.232 mmol) and [5-{[(2,4-difluorophenyl)amino]sulfonyl}-6-(methyloxy)-3- pyridinyl]boronic acid (0.120 g, 0.348 mmol) was treated with K₂C0₃ (0.096 g, 0.696 mmol) and PdCI₂(dppf)-CH₂CI₂ adduct (0.019 g, 0.023 mmol) in 1 ,4-dioxane (4.83 mL) and water (4.83 mL) was heated to 80 °C for 4 hours. After 4 hours, the reaction was treated by DMF (4 mL) and Cs₂C0₃ (0.227 g, 0.696 mmol) and PdCI₂(dppf)-CH₂CI₂ adduct (0.019 g, 0.023 mmol) and continued to heat overnight. The reaction was cooled to room temperature and diluted with EtOAc. The combined organics were washed with 5% LiCI (3x), brine, dried over Na₂S0₄, filtered, and concentrated. The crude residue was purified by reverse phase chromatography (10-90% ACN/ H₂0 + formic acid). Isolation and lyophilization of the fractions gave a solid which was then triturated with Et₂0 to give 5-{2-amino-4-oxo-3-[2-(trifluoromethyl)phenyl]-3,4- dihydroquinazolin-6-yl}-N-(2,4-difluorophenyl)-2-methoxypyridine-3-sulfonamide (0.029 g, 21 %). H NMR (400 MHz, DMSO-d₆) δ ppm 10.21 (br. s., 1 H), 8.74 (s, 1 H), 8.17 (d, J=2.54 Hz, 1 H), 8.01 (d, J=2.34 Hz, 1 H), 7.85 - 7.98 (m, 3 H), 7.73 - 7.79 (m, 1 H), 7.62 (d, J=7.80 Hz, 1 H), 7.26 - 7.36 (m, 2 H), 7.18 - 7.26 (m, 1 H), 6.97 - 7.05 (m, 1 H), 6.68 (br. s., 2 H), 3.96 (s, 3 H); ES-LC S: 604.4 ( +1 ).

Example 134

5-{2-amino-4-oxo-3-[2-(trifluoromethoxy)phenyl]-3,4-dihydroquinazo

difluorophenyl)-2-methoxypyridine-3-sulfonamide

5-(2-amino-4-oxo-3-{2-[(trifluoromethyl)oxy]phenyl}-3,4-dihydro-6-quin

difluorophenyl)-2-(methyloxy)-3-pyridinesutfonamide

[00378] A solution of 2-amino-6-iodo-3-{2-[(trifluoromethyl)oxy]phenyl}-4(3H)- quinazolinone (0.100 g, 0.224 mmol) and [5-{[(2,4-difluorophenyl)amino]sulfonyl}-6-(methyloxy)- 3-pyridinyl]boronic acid (0.1 15 g, 0.335 mmol) was treated with K₂C0₃ (0.093 g, 0.671 mmol) and PdCI₂(dppf)-CH₂CI₂ adduct (0.018 g, 0.022 mmol) in 1 ,4-dioxane (4.66 mL) and water (4.66 mL) was heated to 80 °C for 90 minutes. The reaction was cooled to room temperature and diluted with EtOAc. The combined organics were washed with brine, dried over Na₂S0₄, filtered, and concentrated. The crude residue was purified by reverse phase chromatography (10-90% ACN/ H₂0 + formic acid). Isolation and lyophilization of the fractions gave a solid which was then triturated with Et₂0 to give 5-(2-amino-4-oxo-3-{2-[(trifluoromethyl)oxy]phenyl}- 3,4-dihydro-6-quinazolinyl)-N-(2,4-difluorophenyl)-2-(methyloxy)-3-pyridinesulfonamide (0.064 g, 46%). H NMR (400 MHz, DMSO-c/₆) δ ppm 10.22 (br. s., 1 H), 8.74 (s, 1 H), 8.18 (d, J=2.34 Hz, 1 H), 8.02 (d, J=2.15 Hz, 1 H), 7.89 - 7.95 (m, 1 H), 7.54 - 7.72 (m, 4 H), 7.26 - 7.37 (m, 2 H), 7.16 - 7.26 (m, 1 H), 6.96 - 7.04 (m, 1 H), 6.72 (br. s., 2 H), 3.96 (s, 3 H); ES-LCMS: 620.4 (M+1 ).

Example 35

5-(2-amino-4-oxo-3-(pyridin-3-yi)-3,4-dihydroquinazoiin-6-yl)-2-m

phenylpyridine-3-sulfonamide

Step A

3-iso e

[00379] To a stirred solution of 3-aminopyridine (5 g, 53.2 mmol) and NaHC0₃ (13.4 g, 59.6 mmol) in CHCI₃/H₂0 (50 mL/10mL) was added thiophosgene (4.89 mL, 63.8 mmol) dropwise at 0 °C. After the addition was complete, the reaction mixture was stirred at room temperature for another 2 hours and then diluted with water (50 mL). Two phases were separated and the organic was dried over Na₂S0₄, filtered, and concentrated to give 3- isothiocyanatopyridine (5 g) as a dark oil.

Step B

6-bromo-3-(3 yridinyl)-2-thioxo-2,3-dihydro-4(1H)-quinazolinone

[00380] To a solution of 3-isothiocyanatopyridine (5 g) in dioxane (50 mL) was added 2- amino-5-bromobenzoic acid (11.5 g, 53.2 mmol) and DIPEA (20.6 g, 159.6 mmol). The resulting mixture was refluxed for 16 hours. The solid formed was collected by filtration and washed with MeOH (50 mL x 3), to give 6-bromo-3-(3-pyridinyl)-2-thioxo-2,3-dihydro-4(1 H)-quinazolinone (5.7 g, 32%) as an off white solid. ¹H-NMR (300 MHz, DMSO-af₆) δ ppm 13.24 (s, 1 H), 8.60 (d, 1 H), 8.49 (s, 1 H), 8.03 (s, 1 H), 7.98 (d, 1 H), 7.76 (d, 1 H), 7.53 (m, 1 H), 7.40 (d, 1 H); LCMS (m/z) ES+ 334 (m+1 ). Step C

6-bromo-2-(m azolin-4(3H)-one

[00381] A solution of 6-bromo-3-(3-pyridinyl)-2-thioxo-2,3-dihyclro-4(1 H)-quinazolinone (1.0 g, 2.99 mmol) in DMF (12.73 mL) was treated with K₂C0₃ (0.414 g, 2.99 mmol) and stirred at room temperature for 1 hour. The reaction was then treated by the addition of Mel (0.281 mL, 4.49 mmol) and stirred for an additional 90 minutes. The reaction was concentrated under reduced pressure and the crude residue was purified by silica gel chromatography (loaded with Celite®, 30-50% EtOAc/hexane) to give 6-bromo-2-(methylthio)-3-(pyridin-3-yl)quinazolin-4(3H)- one (0.820 g, 79%). ES-LCMS: 348.3, 350.3 (M+1 ).

Step D

6-bromo-2-((4-methoxybenzyl)amino)-3-(pyridin-3-yl)quinazolin-4(3H)-one

[00382] A solution of 6-bromo-2-(methylthio)-3-(pyridin-3-yl)quinazolin-4(3H)-one (0.509 g, 1.462 mmol) in 4-methoxybenzylamine (6.0 mL, 45.9 mmol) was heated to 160 °C overnight. After cooling to room temperature, the mixture was acidified with 1 N HCI and washed with EtOAc. The organic layer was discarded and the aqueous layer was basified with 1 NaOH and extracted with EtOAc. The combined organics were washed with brine, dried over Na₂S0₄, filtered, and concentrated to give 6-bromo-2-((4-methoxybenzyl)amino)-3-(pyridin-3- yl)quinazolin-4(3H)-one (.222 g, 34.7%). ES-LCMS: 437.1 , 439.1 (M+1).

Step E

2-amino-6-bro -3-(pyridin-3-yl)quinazolin-4(3H)-one

[00383] A solution of 6-bromo-2-((4-methoxybenzyl)amino)-3-(pyridin-3-yl)quinazolin- 4(3H)-one (.222 g, 0.508 mmol) in TFA (5.08 mL) was heated to 140 °C in the microwave for 15 minutes. The reaction was concentrated, taken up in DCM and washed with saturated NaHC0₃ (3x), brine, dried over Na₂S0 , filtered, and concentrated to give 2-amino-6-bromo-3-(pyridin-3- yl)quinazolin-4(3H)-one (0.215 g, 100%). ES-LCMS: 317.0, 319.0 (M+1 ).

Step F

5-(2-amino-4-oxo-3-(pyridin-3-yl)-3,4-dihydroquinazolin-6-yl)-2-meth^

sulfonamide

[00384] A solution of 2-amino-6-bromo-3-(pyridin-3-yl)quinazolin-4(3H)-one (0.215 g, 0.678 mmol), 2-methoxy-N-phenyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridine-3- sulfonamide (0.265 g, 0.678 mmol), K₂C0₃ (0.281 g, 2.034 mmol), and PdCI₂(dppf)-CH₂CI₂ adduct (0.055 g, 0.068 mmol) in DMF (14.12 mL) and water (14.12 mL) was heated to 80 °C overnight. After cooling to room temperature, the reaction was diluted with water and EtOAc. The combined organics were washed with saturated NaHC0₃, brine, dried over Na₂S0₄, filtered, and concentrated. The crude residue was purified by reverse phase chromatography (10-90% ACN/H20 + formic acid). Isolation and lyophilization gave 5-(2-amino-4-oxo-3-(pyridin-3-yl)-3,4- dihydroquinazolin-6-yl)-2-methoxy-N-phenylpyridine-3-sulfonamide (.018 g, 5.30%) as a solid. H NMR (400 MHz, DMSO-af₆) δ ppm 10.41 (s, 1 H), 8.71 - 8.78 (m, 2 H), 8.63 - 8.68 (m, 1 H), 8.31 - 8.35 (m, 1 H), 8.09 - 8.14 (m, 1 H), 8.00 - 8.08 (m, 1 H), 7.91 - 7.98 (m, 1 H), 7.63 - 7.70 (m, 1 H), 7.42 - 7.52 (m, 1 H), 7.17 - 7.25 (m, 2 H), 7.10 - 7.17 (m, 2 H), 6.95 - 7.02 (m, 1 H), 4.01 (s, 3 H). ES-LCMS: 501 .2 (M+1 ).

Example 136

5-(2-amino-4-oxo-3-(pyridin-2-yl)-3,4-dihydroquinazolin-6-yl)-2-methoxy-N-

Step A

methyl tobenzoate

[00385] A solution of methyl 2-amino-5-bromobenzoate (6.0 g, 26.1 mmol) and TEA (14.54 mL, 104 mmol) in THF (133 mL) was cooled to 0 °C and then treated by the dropwise addition of neat thiophosgene (2.399 mL, 31.3 mmol). The cooling bath was removed and the reaction was stirred at room temperature for 1 hour. The mixture was poured into ice/saturated NaHC0₃/EtOAc and the organic layer was separated, dried over Na₂S0₄, filtered, and concentrated to give methyl 5-bromo-2-isothiocyanatobenzoate (7.26 g, 100%) as a brown residue. ES-LCMS: 271.9, 274.0 (M+1).

Step B

6-bromo-3-(2-pyridinyt)-2-thioxo-2,3-dihydro-4(1H)-quinazolinone

[00386] A solution of methyl 5-bromo-2-isothiocyanatobenzoate (2.0 g, 7.35 mmol) and 2- pyridinamine (0.692 g, 7.35 mmol) in EtOH (34.8 mL) and TEA (1.537 mL, 11.02 mmol) were refluxed for the 72 hours. After cooling to room temperature, the crude solid was filtered, rinsing with EtOH to give 6-bromo-3-(2-pyridinyl)-2-thioxo-2,3-dihydro-4(1H)-quinazolinone (0.339 g, 13.80%) as a brown solid. ES-LCMS: 334.0, 336.0 (M+1).

Step C

6-bromo-2-(me azolin-4(3H)-one

[00387] A solution of 6-bromo-3-(2-pyridinyl)-2-thioxo-2,3-dihydro-4(1 H)-quinazolinone (.339 g, 1.014 mmol) in DMF (4.98 mL) was treated with K₂C0₃ (0.140 g, 1.014 mmol) and stirred at room temperature for 1 hour. The reaction was then treated by the addition of Mel (0.095 mL, 1.522 mmol) and stirred for an additional 90 minutes. The reaction was concentrated under reduced pressure and the crude residue was purified by silica gel chromatography (loaded with Celite®, 30-50% EtOAc/hexane) to give 6-bromo-2-(methylthio)-3- (2-pyridinyl)-4(3H)-quinazolinone (0.342 g, 97%). ES-LCMS: 348.0, 350.0 (M+1 ).

Step D

6-bromo-2-((4-meth uinazoiin-4(3H)-one

[00388] A solution of 6-bromo-2-(methylthio)-3-(pyridin-2-yl)quinazolin-4(3H)-one (.324 g, 0.930 mmol) in 4-methoxybenzylamine (6.0 m!_, 45.9 mmol) was heated to 160 °C overnight. After cooling to room temperature, the mixture was acidified with 1 N HCI and washed with EtOAc. The organic layer was discarded and the aqueous layer was basified with 1 N NaOH and extracted with EtOAc. The combined organics were washed with brine, dried over Na₂S0₄, filtered, and concentrated to give 6-bromo-2-((4-methoxybenzyl)amino)-3-(pyridin-2- yl)quinazolin-4(3H)-one (0.480 g, 118%). ES-LCMS: 437.1 , 439.1 (M+1 ).

Step E

2-amino-6-bro -3-(pyridin-2-yl)quinazolin-4(3H)-one

[00389] A solution of 6-bromo-2-((4-methoxybenzyl)amino)-3-(pyridin-2-yl)quinazolin- 4(3H)-one (.480 g, 1.098 mmol) in TFA (10.98 mL) was heated to 140 °C in the microwave for 15 minutes. The reaction was concentrated, taken up in DCM and washed with saturated NaHC0₃ (3x), brine, dried over Na₂S0₄, filtered, and concentrated to give 2-amino-6-bromo-3- (pyridin-2-yl)quinazolin-4(3H)-one (.207 g, 0.653 mmol, 59.5 % yield). ES-LCMS: 317.0, 319.0 (M+1 ).

Step F

5-(2-amino-4-oxo-3-(pyridin-2-yl)-3,4-dihydroquinazolin-6-yi)-2-methoxy-^

sulfonamide [00390] A solution of 2-amino-6-bromo-3-(pyridin-2-yl)quinazolin-4(3H)-one (0.207 g, 0.653 mmol), 2-methoxy-N-phenyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridine-3- sulfonamide (0.255 g, 0.653 mmol), K₂C0₃ (0.271 g, 1.958 mmol), and PdCI₂(dppf)-CH₂CI₂ adduct (0.053 g, 0.065 mmol) in DMF (13.60 mL) and water (13.60 ml_) was heated to 80 °C overnight. After cooling to room temperature, the reaction was diluted with water and EtOAc. The combined organics were washed with saturated NaHC0₃, brine, dried over Na₂S0₄, filtered, and concentrated. The crude residue was purified by reverse phase chromatography (10-90% ACN/H₂0 + formic acid). Isolation and lyophilization gave 5-(2-amino-4-oxo-3-(pyridin-2-yl)-3,4- dihydroquinazolin-6-yl)-2-methoxy-N-phenylpyridine-3-sulfonamide (9.4 mg, 2.88%). H NMR (400 MHz, DMSO-d₆) δ ppm 8.63 - 8.73 (m, 2 H), 8.24 - 8.32 (m, 1 H), 8.01 - 8.11 (m, 2 H), 7.90 - 7.97 (m, 1 H), 7.53 - 7.60 (m, 2 H), 7.31 - 7.37 (m, 1 H), 7.06 - 7.23 (m, 4 H), 6.91 - 6.99 (m, 1 H), 6.55 - 6.67 (m, 2 H), 3.94 - 4.02 (m, 3 H) (one exchangeable proton not evident); ES-LCMS: 501.2 (M+1).

General Scheme 13

Example 137

2-amino-5-[2-amino-3-(1,4-dioxan-2-ylmethyl)-4-oxo-3,4-dihydro-6-quinazofiny

3-pyridinesulfonamide

Step A

2-amino-6-bromo-3- -dioxan-2-ylmethyt)-4(3H)-quinazolinone

Prepared from (1 ,4-dioxan-2-ylmethyl)amine in a manner similar as described in steD A.

Step B

2-amino-5-[2-amino-3-(1,4-dioxan-2-ylmethyl)-4-oxo-3,4-dihydro^

pyridinesulfonamide

[00392] Prepared in a manner similar as described in Example 37, Step B. H NMR (400 MHz, DMSO-d₆) δ ppm 8.45 (d, J=2.1 Hz, 1 H), 8.31 (s, 1 H), 8.06 (d, J=2.3 Hz, 1 H), 7.96 (d, J=2.1 Hz, 1 H), 7.78 (dd, J=8.6, 2.1 Hz, 1 H), 7.23 (d, J=8.6 Hz, 1 H), 7.11 - 7.21 (m, 2 H), 7.04 (d, J=7.8 Hz, 2 H), 6.84 - 6.99 (m, 3 H), 6.78 (br. s., 2 H), 4.20 - 4.34 (m, 1 H), 3.83 - 4.01 (m, 2 H), 3.70 - 3.83 (m, 2 H), 3.58 - 3.67 (m, 1 H), 3.45 - 3.58 (m, 3 H). LCMS: m/z = 509.29 (M+1 ).

Example 138

2-amino-5-[2-amino-3-(2-methylpropyl)-4-oxo-3,4-dihydro-6-quinazolinyl]-N-phenyl-3-

[00393] Prepared from intermediate Example 37, Step A and 2-amino-N-phenyl-5- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl) pyridine-3-sulfonamide in a manner similar as described in Example 37, Step B. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.45 (br. s., 1 H), 8.06 (d, J=2.3 Hz, 1 H), 7.96 (d, J=2.3 Hz, 1 H), 7.76 (dd, J=8.6, 2.1 Hz, 1 H), 7.22 (d, J=8.6 Hz, 1 H), 7.12 - 7.20 (m, 2 H), 6.98 - 7.12 (m, 5 H), 6.92 (br. s., 1 H), 6.76 (br. s., 2 H), 3.89 (d, J=7.4 Hz, 2 H), 2.06 - 2.22 (m, 1 H), 0.87 (d, J=6.8 Hz, 6 H). LCMS: m/z = 465.33 (M+1 ).

Example 139

2-amino-5-{2-amino-3-[(4-methyl-3-morpholinyl)methyl]-4-oxo-3,4-di

quinaz amide

Step A

2-amino-6-bromo-3-[(4-methyl-3-morpholinyi)methyl]-4(3H)-qw

[00394] Prepared from [(4-methyl-3-morpholinyl)methyl]amine in a manner similar as described in Example 41 , Step A.

Step B

2-amino-5-{2-amino-3-[(4-methyl-3-morpholinyl)methyl]-4-oxo-3,4-dih

phenyl-3-pyridinesulfonamide

[00395] Prepared in a manner similar as described in Example 37, Step B. Isolated as the formate salt. H NMR (400 MHz, DMSO-d₆) δ ppm 8.51 (d, J=2.5 Hz, 1 H), 8.14 (s, 1 H), 8.07 (d, J=2.5 Hz, 1 H), 7.98 (d, J=2.1 Hz, 1 H), 7.79 (dd, J=8.6, 2.3 Hz, 1 H), 7.21 - 7.30 (m, 3 H), 7. 1 (d, J=7.6 Hz, 2 H), 6.98 - 7.06 (m, 3 H), 6.80 (br. s., 2 H), 4.44 (dd, J=14.5, 5.1 Hz, 1 H), 3.92 - 4.07 (m, 1 H), 3.61 - 3.70 (m, 1 H), 3.45 - 3.57 (m, 2 H), 2.75 - 2.85 (m, 1 H), 2.58 - 2.70 (m, 1 H), 2.37 (s, 3 H), 2.23 (ddd, J=12.1 , 8.8, 3.3 Hz, 1 H). LCMS: m/z = 522.50 (M+1 ). Example 140

2-amino-5-[2-amino-3-(1-methyl-4^iperidinyl)-4-oxo-3,4-dihydro-6-^

-pyridinesulfonamide

Step A

2-amino-6-bromo-3- -methy^-4 ipeήdinyl)-4(3H)-quinazolinone

[00396] Prepared from 4-amino,1-methylpiperidine in a manner similar as described in Example 41 , Step A.

Step B

2-amino-5-[2-amino-3-(1-methyl-4 ipe dinyl)-4-oxo-3,4-dihydro-6-qum^

pyridinesulfonamide

[00397] Prepared in a manner similar as described in Example 37, Step B. Isolated as the formate salt. H NMR (400 MHz, DMSO-cfe) δ ppm 8.50 (br. s., 1 H), 8.16 (s, 2 H), 8.05 (br. s., 1 H), 7.93 (br. s., 1 H), 7.71 - 7.81 (m, 1 H), 7.16 - 7.32 (m, 3 H), 6.97 - 7.15 (m, 5 H), 6.80 (br. s., 2 H), 4.14 (br. s., 1 H), 2.79 - 3.01 (m, 4 H), 2.27 (br. s., 3 H), 2.1 1 - 2.23 (m, 2 H), 1.49 - 1.69 (m, 2 H). LCMS: m/z = 506.52 (M+1 ).

Example 141

2-amino-5-[2-amino-4-oxo-3-(tetrahydro-2H-pyran-4-yl)-3,4-dihydro-6-quin

phenyl-3-pyridinesulfonamide

[00398] Prepared from intermediate Example 41 , Step A and 2-amino-N-phenyl-5- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl) pyridine-3-sulfonamide in a manner similar as described in Example 37, Step B. H NMR (400 MHz, DMSO-cie) δ ppm 10.48 (br. s., 1 H), 8.49 (d, J=1.6 Hz, 1 H), 8.05 (d, J=2.0 Hz, 1 H), 7.94 (d, J=1.6 Hz, 1 H), 7.75 (dd, J=8.5, 1.9 Hz, 1 H), 7.16 - 7.30 (m, 3 H), 7.07 - 7.15 (m, 4 H), 6.96 - 7.05 (m, 1 H), 6.80 (br. s., 2 H), 4.37 (br. s., 1 H), 3.87 - 4.03 (m, 2 H), 3.39 - 3.50 (m, 2 H), 2.76 - 2.96 (m, 2 H), 1.50 - 1.65 (m, 2 H).

LCMS: m/z = 493.46 (M+1).

Example 142

2-amino-5-[2-amino-3-(trans-4-hydroxycyclohexyl)-4-oxo-3,4-dihydro-6-quin

[00399] Prepared from intermediate Example 42, Step A and 2-amino-N-phenyl-5- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl) pyridine-3-sulfonamide in a manner similar as described in Example 37, Step B. H NMR (400 MHz, DMSO-d₆) δ ppm 8.49 (d, J=1.8 Hz, 1 H), 8.16 (br. s., 1 H), 8.05 (br. s., 1 H), 7.93 (s, 1 H), 7.74 (d, J=8.4 Hz, 1 H), 7.16 - 7.31 (m, 3 H), 7.11 (d, J=7.8 Hz, 2 H), 6.96 - 7.07 (m, 3 H), 6.79 (br. s., 2 H), 4.61 (br. s., 1 H), 4.20 (br. s., 1 H), 2.57 - 2.73 (m, 3 H), 1.81 - 1.96 (m, 2 H), 1.53 - 1.68 (m, 2 H), 1.26 - 1.48 (m, 2 H) LCMS: m/z = 507.47 (M+1 ).

Example 143

5-{3-[(4-acetyl-2-morpholinyl)methyl]-2-amino-4-oxo-3,4-dihydro-6-quina

N-phenyl-3-pyridinesulfonamide

[00400] Prepared from intermediate example 49, step A and 2-amino-N-phenyl-5- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl) pyridine-3-sulfonamide in a manner similar as described in Example 37, Step B. ¹H NMR (400 MHz, DMSO- /₆) δ ppm 10.57 (br. s., 1 H), 8.49 (d, J=2.1 Hz, 1 H), 8.06 (d, J=2.3 Hz, 1 H), 7.96 (s, 1 H), 7.78 (dd, J=8.6, 2.3 Hz, 1 H), 7.17 - 7.28 (m, 3 H), 7.09 (d, J=7.8 Hz, 2 H), 6.94 - 7.04 (m, 3 H), 6.80 (br. s., 2 H), 4.24 - 4.50 (m, 2 H), 3.88 - 4.14 (m, 2 H), 3.57 - 3.87 (m, 3 H), 2.99 - 3.28 (m, 2 H), 2.01 (d, J=13.9 Hz, 3 H). LCMS: m/z = 550.34 (M+1 ).

Example 144

1,1-dimethylethyl 2-{[2-amino-6-{6-amino-5-[(phenylamino)sulfonyl]-3-pyridinyl}-4- 3(4H)-quinazolin l]methyl}-4-morpholinecarboxylate

[00401] Prepared from intermediate Example 48, Step B and 2-amino-N-phenyl-5- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl) pyridine-3-sulfonamide in a manner similar as described in Example 37, Step B. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.51 (s, 1 H), 8.53 (d, J=2.3 Hz, 1 H), 8.08 (d, J=2.1 Hz, 1 H), 8.02 (s, 1 H), 7.89 (br. s., 1 H), 7.38 (br. s., 1 H), 7.21 - 7.29 (m, 2 H), 7.09 - 7.18 (m, 2 H), 6.97 - 7.06 (m, 1 H), 6.86 (br. s., 1 H), 4.25 - 4.43 (m, 1 H), 3.99 - 4.1 1 (m, 1 H), 3.85 - 3.99 (m, 1 H), 3.75 - 3.85 (m, 1 H), 3.59 - 3.75 (m, 2 H), 2.64 - 3.01 (m, 2 H), 1.40 (s, 9 H). LCMS: m/z = 608.35 (M+1 ). Example 145

2-amino-5-[2-amino-3-(1-methyf-3^yrrolidinyl)-4-oxo-3,4-dihydro-6-quinazoli

N-ph

Step A

2-amino-6-bromo-3-(1 -4(3H)-quinazoiinone

[00402] Prepared from 1-methyl-3-pyrrolidinamine in a manner similar as described in Example 41 , Step A.

Step B

2-amino-5-[2-amino-3-( 1 -methyl-3-pyrrolidinyl)-4-oxo-3, 4-dihydro-6-quinazolinyl]-N- phenyl-3-pyridinesuifonamide

[00403] Prepared in a similar manner as described in Example 37, Step B. H N R (400 MHz, DMSO-cfe) δ ppm 10.16 - 10.77 (m, 1 H), 8.49 (d, J=2.3 Hz, 1 H), 8.13 (s, 1 H), 8.03 (d, J=2.3 Hz, 1 H), 7.94 (d, J=2.1 Hz, 1 H), 7.75 (dd, J=8.6, 2.1 Hz, 1 H), 7.21 - 7.32 (m, 2 H), 7.17 (d, J=8.4 Hz, 1 H), 7.1 1 (d, J=7.6 Hz, 2 H), 6.97 - 7.06 (m, 1 H), 6.80 (br. s., 2 H), 6.08 {br. s., 1 H), 3.02 - 3.28 (m, 3 H), 2.36 (br. s., 3 H), 2.11 - 2.31 (m, 2 H), 1.94 - 2.12 (m, 1 H). LCMS: m/z = 492.41 ( +1).

Example 146

2-amino-5-[2-amino-4-oxo-3-(t trahydro-2H-pyran-4-yl)-3,4-di ydro-6-quina

N-cyclopropyl-3-pyridinesulfonamide

[00404] Prepared from intermediate Example 41 , Step A and 2-amino-N-cyclopropyl-5- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridine-3-sulfonamide in a manner similar as described in Example 37, Step B. ¹H N R (400 MHz, DMSO-d₆) δ ppm 8.59 (d, J=2.1 Hz, 1 H), 8.20 (s, 1 H), 8.10 (d, J=2.0 Hz, 1 H), 8.02 (d, J=1 .8 Hz, 1 H), 7.86 (d, J=2.3 Hz, 1 H), 7.22 (d, J=8.4 Hz, 1 H), 7.1 1 (s, 2 H), 6.71 (br. s., 2 H), 4.36 (br. s., 1 H), 3.78 - 4.02 (m, 2 H), 3.27 - 3.51 (m, 2 H), 2.75 - 2.95 (m, 2 H), 1.52 - 1.68 (m, 2 H), 0.42 (d, J=2.7 Hz, 4 H). LCMS: m/z = 457.41 (M+1 ).

Example 147

5-[2-amino-4-oxo-3-(tetrahydro-2H-pyran-4-yl)-3,4-dihydro-6-quinazolinyl]-N-(2,4- difluorophe sulfonamide

[00405] Prepared from intermediate Example 41 , Step A and 2,4-difluoro-A/-[2- (methyloxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-3-pyridinyl]benzenesulfonamide in a manner similar as described in Example 37, Step B. H NMR (400 MHz, DMSO-cfe) δ ppm 8.72 (d, J=2.0 Hz, 1 H), 8.1 1 - 8.21 (m, 1 H), 8.00 (d, J=2.3 Hz, 1 H), 7.84 (dd, J=8.5, 2.2 Hz, 1 H), 7.28 - 7.39 (m, 1 H), 7.12 - 7.26 (m, 4 H), 6.94 - 7.08 (m, 1 H), 4.29 - 4.45 (m, 1 H), 3.86 - 3.98 (m, 5 H), 3.39 - 3.50 (m, 3 H), 2.74 - 2.92 (m, 2 H), 1.51 - 1.66 (m, 2 H). LCMS: m/z = 544.36 (M+1 ).

Example 148

5-[2-amino-4-oxo-3-(tetrahydro-2H-pyran-4-yl)-3,4-dihydro-6-quinazolinyi]-N-cyclopro

2-(methyloxy)-3-pyridinesulfonamide.

[00406] Prepared from intermediate Example 41 , Step A and N-cyclopropyl-2- (methyloxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-3-pyridinesulfonamide in a manner similar as described in Example 37, Step B. H N R (400 MHz, DMSO-c/₆) δ ppm 8.77 (d, J=2.5 Hz, 1 H), 8.31 (d, J=2.3 Hz, 1 H), 8.09 (d, J=2.1 Hz, 1 H), 8.03 (d, J=2.7 Hz, 1 H), 7.92 (dd, J=8.5, 2.2 Hz, 1 H), 7.26 (d, J=8.6 Hz, 1 H), 7.19 (s, 2 H), 4.29 - 4.47 (m, 1 H), 4.04 (s, 3 H), 3.85 - 3.99 (m, 2 H), 3.43 (t, J=1 1.0 Hz, 2 H), 2.71 - 2.95 (m, 2 H), 2.15 - 2.27 (m, 1 H), 1.53 - 1.66 (m, 2 H), 0.36 - 0.54 (m, 4 H). LCMS: m/z = 472.37 (M+1).

Example 149

5-(2-amino-3-ethyl-4-oxo-3,4-dihydro-6-quinazolinyl)-N-(2,4-difluorophenyl)-2-

(me mide

Step A

2-amino-6-b uinazolinone

[00407] Prepared from ethylamine in a manner similar as described in Example 41 , Step A.

Step B

5-(2-amino-3-ethyl-4-oxo-3,4-dihydro-6-quinazolinyi)-N-(2,4-difluoroph

pyridinesulfonamide [00408] Prepared in a similar manner as described in Example 37, Step B. H NMR (400 MHz, DMSO-d₆) δ ppm 8.72 (d, J=2.1 Hz, 1 H), 8.10 - 8.23 (m, 2 H), 8.02 {d, J=2.3 Hz, 1 H), 7.85 (dd, J=8.7, 2.2 Hz, 1 H), 7.31 (td, J=9.0, 6.2 Hz, 1 H), 7.24 (d, J=8.6 Hz, 2 H), 7.17 (s, 2 H), 6.97 - 7.07 (m, 1 H), 3.99 - 4.09 (m, 2 H), 3.96 (s, 3 H), 1.17 (t, J=6.9 Hz, 3 H). LCMS: m/z = 488.33 (M+1 )

Example 150

5-(2-amino-3-ethyl-4-oxo-3,4-dihydro-6-quinazolinyl)-N-cyclopropy

[00409] Prepared from intermediate Example 149, Step A and N-cyclopropyl-2- (methyloxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-3-pyridinesulfonamide in a manner similar as described in Example 37, Step B. H NMR (400 MHz, DMSO-c ₆) δ ppm 8.77 (d, J=2.3 Hz, 1 H), 8.31 (d, J=2.3 Hz, 1 H), 8.15 (s, 1 H), 8.1 1 (d, J=2.1 Hz, 1 H), 8.03 (d, J=2.7 Hz, 1 H), 7.93 (dd, J=8.6, 2.1 Hz, 1 H), 7.27 (d, J=8.6 Hz, 1 H), 7.18 (br. s., 2 H), 3.94 - 4.14 (m, 5 H), 2.17 - 2.27 (m, 1 H), 1.19 (t, J=6.8 Hz, 3 H), 0.37 - 0.56 (m, 4 H) LCMS: m/z = 416.45 (M+1 ).

Example 151

2-amino-5-(2-amino-4-oxo-3-phenyl-3,4-dihydro-6-quinazolinyl)-N-(2,4-difluorophenyl)-3- pyridinesulfonamide

Step A

2-amino-5-bromo-3-pyridinesulfonyl chloride

[00410] To a cooled (0 °C) solution of chlorosulfonic acid (44.5 mL) under vigorous stirring was added 5-bromo-2-pyridinamine (1 1.5 g, 66.5 mmol) portionwise. The reaction mixture was then heated at reflux for 3 hrs. Upon cooling to room temperature, the reaction mixture was poured over ice (100 g) with vigorous stirring. The resulting yellow precipitate was collected by suction filtration, washing with cold water and petroleum ether to provide the title compound as an orange-yellow solid (13g, 72% yield).

Step B

2-amino-N-(2, 4-difluorophenyl)-5-(4, 4, 5, 5-tetramethyl-1 ,3, 2-dioxaborolan-2-yl)-3- pyridinesulfonamide

[00411] To a cold (0 °C) suspension of 2-amino-5-bromo-3-pyridinesulfonyl chloride ( 1.36g, 5 mmol) in dry 1 ,4-dioxane (15 mL) was added pyridine (0.48 mL, 6 mmol) followed by a 1 ,4-difluoro-aniline (0.547 mL, 6 mmol). The reaction mixture was allowed to warm to rt for 2 hrs, heated to 50 °C for 1 h, then cooled to rt. After standing for 2 h, the precipitate was collected by filtration and rinsed with a minimal amount of cold water. Drying the precipitate to constant weight under high vacuum provided red solid. ES-LCMS: m/z 364.21 , 366.19 (M+1 ). [00412] To a solution of 2- amino-5-bromo-N, N-dimethyl-3-pyridinesulfonamide in THF (20 mL) was added 4,4_I4^,,4',5,5,5',5'-octamethyl-2,2'-bi-1 ,3,2-dioxaborolane (1.27 g, 5 mmol), potassium acetate (1.47 g, 15 mmol) and Pd(PPh3)2CI2 (351 mg, 0.5 mmol). The reaction mixture was stirred at 100 °C for 18 hours. The reaction was concentrated in vacuo, purified on silica using 60% ethyl acetate/ hexane to yield the title compound as a grey solid (76%). ES- LCMS: m/z 330.31 (B(OH)₂) (M+1 ).

[00413] The intermediate boronesters listed in the Table 2 below were prepared according to the procedures described above by using the corresponding amines in Example 151 , Step B.

Table 2

-amino-5-(2-amino-4-oxo-3-phenyl-3, 4-dihydro-6-quinazolinyl)-N-(2, 4-difluorophenyl)-3- pyridinesulfonamide [00414] A mixture of 2-amino-N-(2,4-difluorophenyl)-5-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)-3-pyridinesulfonamide (85 mg, 0.21 mmol), 2-amino-6-iodo-3-phenyl-4(3H)- quinazolinone (50 mg, 0.14 mmol), PdCI₂(dppf)-CH₂Cl₂ adduct(1 1 mg, 0.01 mmol), and potassium acetate (40.5 mg, 0.41 mmol) in ,2-dimethoxyethane (DME) (2 ml_) was added water(0.5 ml_). Then the flask was sealed and purged with N₂ (3 times) before heated to 80 °C overnight. The mixture was cooled down to room temperature and it was filtered through Celite® and the Celite® was washed with EtOAc and MeOH. The filtrate was concentrated in vacuo and the residue was purified by flash chromatography on silica gel (10 % MeOH:EtOAc) to give the titile compound (10 mg, 13%) as a grey solid. ¹H NMR (400 MHz, METHANOL-d4) δ ppm 8.46 (d, J=2.15 Hz, 1 H) 7.98 - 8.08 (m, 2 H) 7.75 (dd, J=8.49, 2.24 Hz, 2 H) 7.55 - 7.66 (m, 5 H) 7.44 - 7.52 (m, 1 H) 7.39 (dd, J=7.80, 3.12 Hz, 4 H) 6.88 - 6.97 (m, 2 H);

ES-LCMS: m/z 521.31 (M+1 ).

[00415] Examples 152 through 157 were synthesized as described for Example 151 above.

Example 152

2-amino-5-(2-amino-4-oxo-3-phenyl-3, 4-dihydro-6-quinazolinyl)-N-3-pyridinyl-3- pyridinesulfonamide

[00416] ¹H NMR (400 MHz, DMSO-cf₆) δ ppm 10.76 (br. s., 1 H) 8.54 (d, J=2.54 Hz, 4 H) 8.30 (d, J=2.54 Hz, 1 H) 8.22 - 8.26 (m, 1 H) 8.07 (d, J=2.35 Hz, 1 H) 7.96 (d, J=2.35 Hz, 1 H) 7.84 (dd, J=8.60, 2.35 Hz, 1 H) 7.50 - 7.62 (m, 4 H) 7.37 (d, J=7.04 Hz, 2 H) 7.27 - 7.32 (m, 2 H) 6.82 (br. s, 2 H) 6.35 (br. s., 2 H); ES-LCMS: m/z 486.30 (M+1 ).

Example 153 2-amino-6-[6-amino-5-(4-morpholinylsulfonyl)-3^yridinyl]-3-phenyl-4(3H)-q

[00417] ¹H NMR (400 MHz, DMSO-d6) δ ppm 8.65 (d, J=2.35 Hz, 1 H) 8.04 (d, J=2.15 Hz, 1 H) 7.96 (d, J=2.35 Hz, 1 H) 7.93 (dd, J=8.60, 2.15 Hz, 1 H) 7.49 - 7.63 (m, 3 H) 7.35 (dd, J=16.71 , 7.91 Hz, 3 H) 6.83 (br. s., 2 H) 6.35 (br. s., 2 H) 3.58 - 3.67 (m, 4 H) 3.07 (m, 4 H); ES- LCMS: m/z 479.33 (M+1 ).

Example 154

2-amino-6-[6-amino-5-(1-piperidinylsulfonyl)-3-pyridinyl]-3-phenyl^

[00418] H NMR (400 MHz, DMSO-cf₆) δ ppm 8.61 (d, J=1.95 Hz, 1 H) 7.94 - 8.06 (m, 2 H) 7.92 (dd, J=8.59, 1 .95 Hz, 1 H) 7.49 - 7.64 (m, 3 H) 7.30 - 7.40 (m, 3 H) 6.79 (br. s., 2 H) 6.35 (br. s., 2 H) 3.08 (br. s., 4 H) 1.53 (br. s., 4 H) 1 .41 (d, 2 H); ES-LCMS: m/z 477.34 (M+1 ).

Example 155

2-a ino-5-(2-amino-4-oxo-3-phenyl-3,4-dihydro-6-quinazolinyl)-N-(4-cyanophenyl)-3- pyridinesulfonamide

[00419] H NMR (400 MHz, DMSO-c/₆) δ ppm 1 1 .20 (br. s., 1 H) 8.57 (br. s., 1 H) 8.19 (br. s., 1 H) 8.01 (br. s., 1 H) 7.89 (d, J=8.21 Hz, 1 H) 7.71 (d, J=8.01 Hz, 2 H) 7.49 - 7.63 (m, 4 H) 7.38 (d, J=7.23 Hz, 2 H) 7.32 (d, J=8.60 Hz, 1 H) 7.24 (d, J=8.21 Hz, 2 H) 6.85 (br. s., 2 H) 6.36 (br. s., 2 H); ES-LCMS: m/z 510.28 (M+1 ).

Example 156

2-amino-6-{6-amino-5-[(1 , 1-dioxido-4-thiomorpholinyl)sulfonyl]-3-pyridinyl}-3-phenyl-

4( 3H) -quinazolinone

[00420] ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.66 (d, J=2. 5 Hz, 1 H) 8.07 (dd, J=4.20, 2.25 Hz, 2 H) 7.95 (dd, J=8.60, 2.15 Hz, 1 H) 7.49 - 7.63 (m, 3 H) 7.30 - 7.40 (m, 3 H) 6.87 (br. s., 2 H) 6.35 (br. s., 2 H) 3.67 (br. s., 4 H) 3.23 (br. s., 4 H); ES-LCMS: m/z 527.34 (M+1 ).

Example 157

2-amino-5-(2-amino-4-oxo-3-phenyi-3,4-dihydro-6-quinazoiinyl)-N-(tetrahydro-2H-pyra yl)-3-pyridinesulfonamide

[00421] H NMR (400 MHz, DMSO-d₆) δ ppm 8.57 (br. s., 1 H) 8.13 (br. s., 1 H) 8.04 (br. s., 2 H) 7.91 (br. s., 1 H) 7.48 - 7.65 (m, 3 H) 7.29 - 7.41 (m, 3 H) 6.71 (br. s., 2 H) 6.34 (br. s., 2 H) 3.71 (d, J=1 1.12 Hz, 2 H) 3.19 - 3.29 (m, 2 H) 1.55 (br. s., 2 H) 1.38 (br. s., 2 H); ES-LCMS: m/z 493.36 (M+1 ).

General Scheme 14

General Scheme 15

EXAMPLE 158

5-(2-amino-4-oxo-3-phenyl-3,4-dihydro-6-quinazolinyl)-N,N-dimethyl-2-(methy

pyridinesulfonamide

Step A

5-bromo-2-chioro-3-pyridinesulfonyl chloride

[00422] Step (a) thionyl chloride (14 mL, 192 mmol) was added dropwise over 60 min to water (83 mL), cooled to 0 °C, maintaining the temperature of the mixture 0-7 °C. The solution was allowed to warm to room temperature overnight. Copper(l) chloride (0.131 g, 1.326 mmol) was added to the mixture, and the resultant yellow-green solution was cooled to -10 °C using an acetone/ice bath.

Step B

[00423] HCI (121 ml_, 3977 mmol) was added, with agitation, to 5-bromo-2-chloro-3- pyridinamine (25 g, 121 mmol), maintaining the temperature of the mixture below 30 °C with ice cooling. The reaction mixture was cooled to -10 °C using an ice/acetone bath and a solution of sodium nitrite (9.15 g, 133 mmol) in water (36 mL) was added dropwise over 15 minutes, maintaining the temperature of the reaction mixture between -15 to -10 °C, the resultant slurry was cooled to -5 °C and stirred for 30 minutes.

Step C

[00424] The slurry from step (b) was cooled to -10 °C and added to the solution obtained from step (a) over 30 min, maintaining the temperature of the reaction mixture between -10 to - 15 °C (the slurry from step (b) was maintained at -10 °C throughout the addition). As the reaction proceeded, a solid began to precipitate. When the addition was complete, the reaction mixture was agitated at 0 °C for 75 minutes. The suspended solid was collected by vacuum filtration, washed with water, and dried under vacuum to give 5-bromo-2-chloro-3- pyridinesulfonyl chloride (30 g, 86%). H NMR (CHLOROFORM-d) δ: 8.77 (d, 1 H), 8.56 (d, J = 2.3 Hz, 1 H). LCMS (m/z) ES+ 288 and 290 (M+)

Step D

5-bromo-N,N-dimethyl-2- methyloxy)-3-pyridinesulfonamide

[00425] To 5-bromo-2-chloro-3-pyridinesulfonyl chloride (1 g, 3.44 mmol) in

tetrahydrofuran (10 mL) was added dimethylamine (3.44 mL, 6.87 mmol) and after 15 mins of stirring at room temperature, the volatiles were removed under reduced pressure. The residue was taken up in methanol (10.00 mL) and treated with sodium methoxide (10 mL, 3.44 mmol). After stirring at room temperature for 30 minutes, the volatiles were removed under reduced pressure and 5-bromo-N,N-dimethyl-2-(methyloxy)-3-pyridinesulfonamide (860 mg, 85%) was obtained. ¹H NMR (DMSO-cf₆) δ: 8.58 (d, J = 2.3 Hz, 1 H), 8.19 (d, J = 2.5 Hz, 1 H), 3.98 (s, 2.79 (s, 6H). LCMS (m/z) ES+ 295 and 297 (M+1).

Step E

N, N-dimethyl-2-(methyloxy)-5-(4, 4, 5, 5-tetramethyl- 1, 3, 2-dioxaborolan-2-yl)-3- ridinesulfonamide

[00426] A solution of 5-bromo-N,N-dimethyl-2-(methyloxy)-3-pyridinesulfonamide (500 mg, 1.694 mmol), bis(pinacolato)diboron (516 mg, 2.033 mmol), and bis(pinacolato)diboron (516 mg, 2.033 mmol), and potassium acetate (499 mg, 5.08 mmol) in 1 ,4-dioxane (7 mL) was maintained at 90 °C in a sealed pressure tube for 16 hours. The mixture was cooled, filtered through Celite®, and the filtrates concentrated to give N,N-dimethyl-2-(methyloxy)-5-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)-3-pyridinesulfonamide (550 mg, 95%). LCMS (m/z) ES+ 343 (m+1 ).

Step F

6-iodo-3-phenyl-2-thioxo-2 3-dihydro-4(1H)-quinazolinone

[00427] A solution of isothiocyanatobenzene (20.47 mL, 171 mmol), 2-amino-5- iodobenzoic acid (45 g, 171 mmol), and triethylamine (35.8 mL, 257 mmol) in 1 ,4-dioxane (750 mL) was maintained at reflux for 6 hours. The mixture was cooled to room temperature and solids collected via vacuum filtration. The solids were washed with diethyl ether and dried under vacuum to afford 6-iodo-3-phenyl-2-thioxo-2,3-dihydro-4(1 H)-quinazolinone (48.86 g, 75%) as a white solid. ¹H NMR (DMSO-c/₆) δ: 13.1 1 (s, 1 H), 8.17 (d, J = 2.0 Hz, 1 H), 8.08 (dd, J = 8.6, 2.0 7.44 - 7.52 (m, 2H), 7.36 - 7.44 (m, 1 H), 7.19 - 7.32 (m, 3H). LCMS (m/z) ES+ 381

Step G

2-chloro-6-iodo-3- henyl-4(3H)-quinazolinone

[00428] A suspension of 6-iodo-3-phenyl-2-thioxo-2,3-dihydro-4(1 H)-quinazolinone (36 g, 95 mmol) in POCI₃ (212 ml_, 2272 mmol) was treated with PCI₅ (34.5 g, 166 mmol) in one portion at room temperature, stirred for 30 minutes, then warmed to reflux and maintained with stirring for 6 hours. POCI₃ was distilled off. The residue turned solid upon cooling. The solids were suspended in ethyl acetate and water. The mixture was maintained with stirring overnight. The solid was filtered and washed with water to afford 2-chloro-6-iodo-3-phenyl-4(3H)- quinazolinone. (34 g, 94%). LCMS (m/z) ES+ 383 (m+1 ).

Step H

6-iodo-2-({[4-(methylox henyl]methyl}amino)-3 henyl-4(3H)-quinazolinon

[00429] A solution of 2-chloro-6-iodo-3-phenyl-4(3H)-quinazolinone (33 g, 86 mmol), 4- methoxy-benzylamine (13.52 ml_, 104 mmol), and DIPEA (30.1 ml_, 173 mmol) in N,N- dimethylformamide (D F) (200 mL) was maintained at 80 °C for 3 hours. The mixture was cooled, poured into ethyl acetate, and washed twice with 5% LiCI (aqueous) and once with saturated NaCI (aqueous). The organic layer was separated, dried over sodium sulfate, filtered, concentrated, and purified by column chromatography to afford 6-iodo-2-({[4- (methyloxy)phenyl]methyl}amino)-3-phenyl-4(3H)-quinazolinone (35 g, 84%) as a yellow foam. LCMS (m/z) ES+ 484 (m+1 ). Step I

2-amino-6-iodo-3- henyl-4(3H)-quinazolinone

[00430] A solution of 6-iodo-2-({[4-(methyloxy)phenyl]methyl}amino)-3-phenyl-4(3H)- quinazolinone (33 g, 68.3 mmol) in trifluoroacetic acid (380 mL) was maintained at reflux for 24 hours. The mixture was cooled and concentrated under reduced pressure. The residue was dissolved in dichloromethane and added dropwise to ice-chilled sodium bicarbonate (aqueous, saturated). Following addition the organic layer was separated, dried over sodium sulfate, filtered, taken to a residue under reduced pressure, and purified by trituration from DCM/diethyl ether to afford 2-amino-6-iodo-3-phenyl-4(3H)-quinazolinone (20 g, 81%) as a white solid. LCMS (m/z) ES+ 364 (m+1 ).

Step J

5-(2-amino-4-oxo-3^henyl-3,4-dihydro-6-quinazolinyl)-N,N^

pyridinesulfonamide

[00431] N,N-dimethyl-2-(methyloxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-3- pyridinesulfonamide (143 mg, 0.551 mmol), 2-amino-6-iodo-3-phenyl-4(3H)-quinazolinone (100 mg, 0.275 mmol), PdCl₂(dppf)-CH₂Cl₂ adduct (22.49 mg, 0.028 mmol) were placed in a microwave vial, sealed and purged with nitrogen and 2 N sodium carbonate (0.50 mL) and 1 ,4- dioxane (2 mL) were added. The reaction mixture was maintained at 80 °C for 2 hours. The mixture was cooled, silica was added and the volatiles were removed under reduced pressure and the residue was purified by HPLC to afford 5-(2-amino-4-oxo-3-phenyl-3,4-dihydro-6- quinazolinyl)-N,N-dimethyl-2-(methyloxy)-3-pyridinesulfonamide (33 mg, 26.5%). ¹H NMR (DMSO-cf₆) δ: 8.77 (d, J = 2.5 Hz, 1 H), 8.29 (d, J = 2.5 Hz, 1 H), 8.12 (d, J = 2.3 Hz, 1 H), 7.99 (dd, J = 8.6, 2.3 Hz, 1 H), 7.48 - 7.70 (m, 3H), 7.25 - 7.47 (m, 3H), 6.43 (br. s., 2H), 4.04 (s, 3H), 2.81 (s, 6H). LCMS (m/z) ES+ 452 (m+1 ).

EXAMPLE 159

5-(2-amino-4-oxo-3-phenyl-3,4-dihydro-6-quinazolinyl)-N-(2,4-difl

(methyloxy)-3-pyridinesulfonamide

Step A

5-bromo-N-(2,4-difluorophenyi)-2-(methyloxy)-3-pyridinesulfonamide

[00432] To 5-bromo-2-chloro-3-pyridinesulfonyl chloride (1 g, 3.44 mmol) in

dichloromethane (10 mL) was added pyridine (0.306 mL, 3.78 mmol) followed by 2,4- difluoroaniline (0.488 g, 3.78 mmol) and after 1 hour of stirring at room temperature, the volatiles were removed under reduced pressure. The residue was taken up in methanol (10.00 mL) and treated with sodium methoxide (10 mL, 3.44 mmol). After stirring at room temperature for 1 hour the volatiles were removed under reduced pressure to give 5-bromo-N-(2,4- difluorophenyl)-2-(methyloxy)-3-pyridinesulfonamide (927 mg, 71 %). LCMS (m/z) ES+ 380 (m+1 ).

Step B

N-(2,4-difluorophenyl)-2-(methyloxy)-5-(4, 4, 5, 5-tetramethyl-1 ,3, 2-dioxaborolan-2-yl)-3- pyridinesuifonamide

[00433] N^^-difluorophenyl^-imethyloxyJ-S^^.S.S-tetramethyl-I .S^-dioxaborolan^- yl)-3-pyridinesulfonamide was obtained in a procedure analogous to Example 118, Step C from 5-bromo-N-(2,4-difluorophenyl)-2-(methyloxy)-3-pyridinesulfonamide (905 mg, 2.387 mmol), yield (1 g, 98%). LCMS (m/z) ES+ 427 (m+1 ), 325 (boronic acid + 1 ).

Step C

5-(2-amino-4-oxo-3^henyl-3,4-dihydro-6-quinazolinyl)-N-(2,4-difluo

pyridinesulfonamide

[00434] 5-(2-amino-4-oxo-3-phenyl-3,4-dihydro-6-quinazolinyl)-N-(2,4-difluorophenyl)-2- (methyloxy)-3-pyridinesulfonamide was obtained in a procedure analogous to Example 118, Step E from N-(2,4-difluorophenyl)-2-(methyloxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)-3-pyridinesulfonamide (1 17 mg, 0.275 mmol) and 2-amino-6-iodo-3-phenyl-4(3H)- quinazolinone (100 mg, 0.275 mmol), yield (0.1 1 g, 75%). H NMR (DMSO-d6) δ: 10.19 (s, 1 H), 8.76 (d, J = 2.3 Hz, 1 H), 8.17 (d, J = 2.5 Hz, 1 H), 8.02 (d, J = 2.3 Hz, 1 H), 7.91 (dd, J = 8.7, 2.2 Hz, 1 H), 7.47 - 7.69 (m, 4H), 7.29 - 7.41 (m, 4H), 6.97 - 7.1 1 (m, 1 H), 6.42 (br. s., 2H), 3.97 (s, 3H). LCMS (m/z) ES+ 536 (m+1 ).

EXAMPLE 160

5-(2-amino-4-oxo-3-phenyi-3,4-dihydro-6-qu^' azoUnyi)-N-cyciopropyi-2-(m

ridines ulfonamide

Step A

5-bromo-N-cycloprop l-2-(methyloxy)-3-pyhdinesulfonamide

[00435] 5-bromo-N-cyclopropyl-2-(methyloxy)-3-pyridinesulfonamicle was obtained in a procedure analogous to Example 120, Step A from 5-bromo-2-chloro-3-pyridinesulfonyl chloride (1 g, 3.44 mmol) and cyclopropylamine (0.339 mL, 4.81 mmol), yield (0.88 g, 83%). LCMS (m/z) ES+ 307 and 309 (m+1 ).

Step B

N-cyclopropyl-2-(methyloxy)-5-(4,4, 5, 5-tetramethyl-1 ,3, 2-dioxaborolan-2-yl)-3- ridinesulfonamide

[00436] N-cyclopropyl-2-(methyloxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-3- pyridinesulfonamide was obtained in a procedure analogous to Example 1 18, Step C from 5- bromo-N-cyclopropyl-2-(methyloxy)-3-pyridinesulfonamide (870 mg, 2.83 mmol), yield (0.95 g, 95%). LCMS (m/z) ES+ 355 (m+1 ).

Step C

5-(2-amino-4-oxo-3^henyl-3,4-di ydro-6-quinazolinyl)-N-cyclopropyl-2-(^

pyridinesulfonamide

[00437] 5-(2-amino-4-oxo-3-phenyl-3,4-dihydro-6-quinazolinyl)-N-cyclopropyl-2- (methyloxy)-3-pyridinesulfonamide was obtained in a procedure analogous to Example 118, Step E from N-cyclopropyl-2-(methyloxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-3- pyndinesulfonamide (219 mg, 0.620 mmol) and 2-amino-6-iodo-3-phenyl-4(3H)-quinazolinone (150 mg, 0.413 mmol), yield (65 mg, 34%). ¹H NMR (D SO-d₆) δ: 8.78 (d, J = 2.3 Hz, 1H), 8.32 (d, J = 2.3 Hz, 1 H), 8.11 (d, J = 2.1 Hz, 1 H), 7.99 (dd, J = 8.6, 2.1 Hz, 2H), 7.47 - 7.69 (m, 3H), 7.26 - 7.47 (m, 3H), 6.43 (br. s., 2H), 4.04 (s, 3H), 2.23 (dt, J = 6.7, 3.2 Hz, 1H), 0.20 - 0.65 (m, 4H). LCMS (m/z) ES+ 464 (m+1 ).

EXAMPLE 161

5-{2-amino-3-[4-(4-morpholinyl)phenyl]-4-oxo-3,4-dihydro-6-quin

[00438] 5-{2-amino-3-[4-(4-morpholinyl)phenyl]-4-oxo-3,4-dihydro-6-quinazolinyl}-N,N- dimethyl-2-(methyloxy)-3-pyridinesulfonamide was obtained in a procedure analogous to Example 1 18, step E from N,N-dimethyl-2-(methyloxy)-5-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)-3-pyridinesulfonamide (186 mg, 0.544 mmol) and 2-amino-6-iodo-3-[4-(4- morpholinyl)phenyl]-4(3H)-quinazolinone (122 mg, 0.272 mmol), yield (95 mg, 65%). H NMR (DMSO-de) δ: 8.77 (d, J = 2.3 Hz, 1 H), 8.29 (d, J = 2.3 Hz, 1 H), 8.11 (d, J = 2.1 Hz, 1 H), 7.97 (dd, J = 8.6, 2.1 Hz, 1 H), 7.34 (d, J = 8.6 Hz, 1 H), 7.15 - 7.26 (m, 2H), 7.05 - 7.14 (m, 2H), 6.38 (br. s., 2H), 4.03 (s, 3H), 3.71 - 3.82 (m, 4H), 3.16 - 3.28 (m, 4H), 2.81 (s, 6H). LCMS (m/z) ES+ 537 (m+1 ).

EXAMPLE 162

5-{2-amino-3-[4-(4-morpholinyl)phenyl]-4-oxo-3,4-dihydro-6-quinazolin^

2-(methyloxy)-3-pyridinesulfonamide

[00439] 5-{2-amino-3-[4-(4-morpholinyl)phenyl]-4-oxo-3,4-dihydro-6-quinazolinyl}-N cyclopropyl-2-(methyloxy)-3-pyridinesulfonamide was obtained in a procedure analogous to Example 1 18, Step E from N-cyclopropyl-2-(methyloxy)-5-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)-3-pyridinesulfonamide (193 mg, 0.544 mmol) and 2-amino-6-iodo-3-[4-(4- morpholinyl)phenylj-4(3H)-quinazolinone (122 mg, 0.272 mmol), yield (66 mg, 44%). H NMR (DMSO-c/₆) δ: 8.77 (d, J = 2.0 Hz, 1 H), 8.32 (d, J = 1.8 Hz, 1 H), 8.06 - 8.20 (m, 1H), 8.02 (br. s., 1H), 7.97 (d, J = 8.4 Hz, 1H), 7.34 (d, J = 8.6 Hz, 1H), 7.19 (d, J = 8.6 Hz, 2H), 7.03 - 7.15 (m, 2H), 6.39 (br. s., 2H), 4.04 (s, 3H), 3.77 (br. s., 4H), 3.21 (br. s., 4H), 2.23 (d, J = 2.7 Hz, 1 H), 0.31 - 0.57 (m, 4H). LCMS (m/z) ES+ 549 (m+1 ).

EXAMPLE 163

5-{2-amino-3-[4-(4-morpholinyi)phenyl]-4-oxo-3,4-dihydro-6-quinazolinyl}-N-(2,4- diflu amide

[00440] 5-{2-amino-3-[4-(4-morpholinyl)phenyl]-4-oxo-3,4-dihydro-6-quinazolinyl}-N-(2,4- difluorophenyl)-2-(methyloxy)-3-pyridinesulfonamide was obtained in a procedure analogous to Example 1 18, Step E from N-(2,4-difluorophenyl)-2-(methyloxy)-5-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)-3-pyridinesulfonamide (187 mg, 0.544 mmol) and 2-amino-6-iodo-3-[4-(4- morpholinyl)phenyl]-4(3H)-quinazolinone (122 mg, 0.272 mmol), yield (0.084 g, 50%). H NMR (DMSO-d₆) δ: 10.24 (br. s., 1 H), 8.74 (d, J = 2.3 Hz, 1H), 8.16 (d, J = 2.3 Hz, 1 H), 8.01 (d, J = 2.0 Hz, 1 H), 7.89 (dd, J = 8.6, 2.1 Hz, 1 H), 7.28 - 7.40 (m, 2H), 7.21 - 7.28 (m, 1 H), 7.14 - 7.20 (m, 2H), 7.07 - 7.14 (m, 2H), 6.98 - 7.07 (m, 1 H), 6.24 - 6.53 (m, 2H), 3.96 (s, 3H), 3.68 - 3.87 (m, 4H), 3.09 - 3.31 (m, 4H). LCMS (m/z) ES+ 621 (m+1).

EXAMPLE 164

5-{2-amino-3-[4-(4-morpholinyl)phenyl]-4-oxo-3,4-dihydro-6-quinazo

N- henyl-3-pyridinesulfonamide

Step A

5-bromo-2-(me esulfonamide

[00441] 5-bromo-2-(methyloxy)-N-phenyl-3-pyridinesulfonamicle was obtained in a procedure analogous to Example 120, Step A from 5-bromo-2-chloro-3-pyridinesulfonyl chloride (1.4 g, 4.81 mmol) and aniline (0.483 mL, 5.29 mmol), yield (1.8 g, 109%). LCMS (m/z) ES+ 344 (m+1 ).

Step B

2-(methyloxy)-N-phenyl-5-(4,4, 5, 5-tetramethyl- 1, 3,2-dioxaborolan-2-yl)-3-pyridinesuIfonamide

[00442] 2-(methyloxy)-N-phenyl-5-(4,4,5₎5-tetramethyl-1 ₎3,2-dioxaborolan-2-yl)-3- pyridinesulfonamide was obtained in a procedure analogous to Example 1 18, Step C from 5- bromo-2-(methyloxy)-N-phenyl-3-pyridinesulfonamide (1.4 g, 4.08 mmol), yield (1.5 g, 94%). LCMS (m/z) ES+ 391 (m+1 ).

Step C

5-{2-amino-3-[4-(4-morpholinyl)phenyl]-4-oxo-3 -dihydro-6-quin

phenyl-3-pyridinesuifonamide

[00443] 5-{2-amino-3-[4-(4-morpholinyl)phenyl]-4-oxo-3,4-dihydro-6-quinazolinyl}-2- (methyloxy)-N-phenyl-3-pyridinesulfonamide was obtained in a procedure analogous to

Example 1 18, Step E from 2-(methyloxy)-N-phenyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)-3-pyridinesulfonamide (87 mg, 0.223 mmol) and 2-amino-6-iodo-3-[4-(4-morpholinyl)phenyl]- 4(3H)-quinazolinone (100 mg, 0.223 mmol), yield (62 mg, 48%). ¹H NMR (DMSO-d₆) δ: 10.40 (br. s., 1 H), 8.69 (s, 1 H), 8.30 (s, 1 H), 8.03 (s, 1 H), 7.90 (d, J = 8.4 Hz, 1 H), 7.31 (d, J = 8.4 Hz, 1 H), 7.05 - 7.27 (m, 8H), 6.92 - 7.05 (m, 1 H), 6.39 (br. s., 2H), 4.00 (s, 3H), 3.77 (br. s., 4H), 3.22 (br. s., 4H), LCMS (m/z) ES+ 585 (m+1 ).

EXAMPLE 165

2-amino-6-[6-(methylox -5-(methylsulfonyl)-3-pyridinyl]-3-phenyl-4(3H^

Step A 5-bromo-2-chloro-3- methylsulfonyl)pyridine

[00444] HCI (45 ml_, 1481 mmol) was added, with agitation, to 5-bromo-2-chloro-3- pyridinamine (10 g, 48.2 mmol), maintaining the temperature of the mixture below 30 °C with ice cooling. The reaction mixture was cooled to -5 °C using an ice/acetone bath and a solution of sodium nitrite (3.33 g, 48.3 mmol) in water (13 ml.) was added dropwise over 15 minutes, maintaining the temperature of the reaction mixture between -5 to 0 °C, the resultant slurry was cooled to -2 °C and stirred for 10 minutes. Sodium thiomethoxide (3.38 g, 48.2 mmol) was added slowly and the reaction mixture stirred at 0 °C for 1 hour and then at room temperature overnight. Dichloromethane was added and the layers separated, the organic layer was washed with saturated bicarbonate and sodium chloride and dried over sodium sulfate and concentrated to afford the title compound (955 mg, 7.32%). ¹H NMR (CHLOROFORM-d) δ: 8.70 (d, J = 2.3 Hz, 1 H), 8.59 (d, J = 2.3 Hz, 1 H), 3.34 (s, 3H), LCMS (m/z) ES+ 271 (m+1 ).

Step B

5-bromo-2-(meth loxy)-3-(methylsulfonyl)pyridine

[00445] 5-bromo-2-chloro-3-(methylsulfonyl)pyridine (725 mg, 2.68 mmol) in methanol (20 mL) was treated with sodium methoxide (145 mg, 2.68 mmol) and after stirring at room temperature for 1 hour the reaction was concentrated and the residue taken up in DCM, washed with 1 N HCI and brine, dried over sodium sulfate and concentrated to afford 5-bromo-2- (methyloxy)-3-(methylsulfonyl)pyridine (700 mg, 98%). H NMR (CHLOROFORM-d) δ: 8.44 (d, 1 H), 8.35 (d, J = 2.5 Hz, 1 H), 4.12 (s, 3H), 3.24 (s, 3H), LCMS (m/z) ES+ 267 and 269 (m+1 ).

Step C

2-(methyloxy)-3-(methyisulfonyl)-5-(4,4, 5, 5-tetramethyi- 1, 3, 2-dioxaborolan-2-yl)pyridine

[00446] 2-(methyloxy)-3-(methylsulfonyl)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)pyridine was obtained in a procedure analogous to Example 118, Step C from 5-bromo-2- (methyloxy)-3-(methylsulfonyl)pyridine (683 mg, 2.57 mmol), yield (550 mg, 68%). LC S (m/z) ES+ 314 (m+1 ).

Step D

2-amino-6-[6-(methyloxy)-5-(methylsulfonyl)-3 yridinyl]-3 h

[00447] 2-amino-6-[6-(methyloxy)-5-(methylsulfonyl)-3-pyridinyl]-3-phenyl-4(3H)- quinazolinone was obtained in a procedure analogous to Example 1 18, Step E from 2- (methyloxy)-3-(methylsulfonyl)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridine (205 mg, 0.655 mmol) and 2-amino-6-iodo-3-phenyl-4(3H)-quinazolinone (120 mg, 0.330 mmol), yield (1 10 mg, 79%). H N R (DMSO-d₆) δ: 8.84 (d, J = 2.3 Hz, 1 H), 8.33 (d, J = 2.5 Hz, 1H), 8.08 - 8.23 (m, 2H), 7.99 (dd, J = 8.6, 2.1 Hz, 1 H), 7.47 - 7.70 (m, 3H), 7.27 - 7.46 (m, 2H), 6.43 (br. s., 2H), 4.09 (s, 3H), 3.35 (s, 3H). LCMS (m/z) ES+ 423 (m+1 ).

EXAMPLE 166

2-amino-6-[6-(methyloxy)-5-(methylsulfonyO-3-pyridinylJ-3-[4-(4-mo

-quinazolinone

[00448] 2-amino-6-[6-(methyloxy)-5-(methylsulfonyl)-3-pyridinyl]-3-[4-(4- morpholinyl)phenyl]-4(3H)-quinazolinone was obtained in a procedure analogous to Example 118, step E from 2-(methyloxy)-3-(methylsulfonyl)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)pyridine (204 mg, 0.651 mmol) and 2-amino-6-iodo-3-[4-(4-morpholinyl)phenyl]-4(3H)- quinazolinone (140 mg, 0.312 mmol), yield (97 mg, 61 %). ¹H NMR (DMSO-a⁽ ₆) δ: 8.84 (d, J = 2.1 Hz, 1 H), 8.33 (d, J = 2.1 Hz, 1 H), 8.05 - 8.23 (m, 1 H), 7.98 (dd, J = 8.6, 2.0 Hz, 1H), 7.34 (d, J = 8.4 Hz, 1H), 7.19 (d, J = 8.8 Hz, 2H), 7.04 - 7.15 (m, 2H), 6.39 (br. s., 2H), 4.09 (s, 3H), 3.77 (br. s., 4H), 3.35 (s, 3H), 3.22 (br. s., 4H). LCMS (m/z) ES+ 508 (m+1 ).

General Scheme 16

EXAMPLE 167

5-(2-amino-4-oxo-3-phenyl-3,4-dihydro-6-quinazolinyl)-2-(ethyloxy)-N,N-dim

pyridinesulfonainide

Step A

5-bromo-2-(ethyloxy)-N,N-dimethyl-3-pyridinesulfonamide

[00449] To a cooled solution of 5-bromo-2-chloro-3-pyridinesulfonyl chloride (0.5 g, 1.719 mmol) in tetrahydrofuran (THF) (5 ml.) 2 dimethylamine in THF (1.890 ml_, 3.78 mmol) was added dropwise. Immediate precipitation occurred. The stirring was continued at room temperature for 30 minutes. The mixture was evaporated, taken up in EtOAc/water, the organic phase washed with brine, dried over magnesium sulfate and was evaporated. The residue was dissolved in Ethanol (5 ml_), 21 wt% sodium ethoxide (0.674 ml_, 1.804 mmol) was added and the mixture was stirred 50 C° temperature for 30 minutes. The mixture was evaporated, taken up in ethyl acetate, washed with water and brine, dried with magnesium sulfate and evaporated to dryness to give 5-bromo-2-(ethyloxy)-N,N-dimethyl-3-pyridinesulfonamide (450 mg, 1.455 mmol, 85 % yield) as a reddish oil which crystallized upon standing. LCMS: 309, 31 1 (M+H); H NMR (400 MHz, DMSO-af₆) δ = 8.56 (d, J = 2.4 Hz, 1 H), 8.19 (d, J = 2.4 Hz, 1 H), 4.44 (q, J = 7.1 Hz, 2 H), 2.80 (s, 6 H), 1.35 (t, J = 7.1 Hz, 3 H).

Step B

2-(ethyloxy)-N,N-dimethyl-5-(4, 4, 5, 5-tetramethyl-1 ,3, 2-dioxaborolan-2-yl)-3-pyridinesulfonamide

[00450] The mixture of 5-bromo-2-(ethyloxy)-N,N-dimethyl-3-pyridinesulfonamide (450 mg, 1.455 mmol), bis(pinacolato)diboron (444 mg, 1 .747 mmol), potassium acetate (429 mg, 4.37 mmol) and PdCI₂(dppf)-CH₂CI₂ adduct (1 19 mg, 0.146 mmol) in 1 ,4-Dioxane (7277 μΙ_) was heated under nitrogen atmosphere at 100 °C overnight. The mixture was filtered through Celite® and was evaporated to dryness to give the crude 2-(ethyloxy)-N,N-dimethyl-5-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)-3-pyridinesulfonamide as a black solid in quantitative yield. It was used without further purification. LCMS: 357 (M+H). Step C

5-{2-aminoA-oxo-3^heny]-3 -dihydro-6-quinazo\iny\)-2-{^^

pyridinesulfonamide

[00451] A suspension of 2-amino-6-iodo-3-phenyl-4(3H)-quinazolinone (50 mg, 0.138 mmol), 2-(ethyloxy)-N,N-dimethyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-3- pyridinesulfonamide (98 mg, 0.275 mmol), PdCI₂(dppf)-CH₂CI₂ adduct (1 1.24 mg, 0.014 mmol) and cesium carbonate (44.9 mg, 0.138 mmol) in tetrahydrofuran (THF) (1 mL) and water (0.250 mL) was heated at 65 °C for 1 h. The solvent was evaporated and the residue was purified on a RP-HPLC to give 5-(2-amino-4-oxo-3-phenyl-3,4-dihydro-6-quinazolinyl)-2-(ethyloxy)-N,N- dimethyl-3-pyridinesulfonamide (34.5mg, 0.074 mmol, 53.8 % yield); as an off white solid. LCMS: 466 (M+H); ¹H NMR (400MHz, DMSO-d₆) δ = 8.82 - 8.71 (m, 1 H), 8.35 - 8.25 (m, 1 H), 8.16 - 8.07 (m, 1 H), 7.99 (dt, J = 1 .1 , 8.6 Hz, 1 H), 7.66 - 7.49 (m, 3 H), 7.43 - 7.29 (m, 3 H), 6.43 (br. s., 2 H), 4.50 (q, J = 7.0 Hz, 2 H), 2.82 (s, 6 H), 1.38 (t, J = 7.1 Hz, 3 H).

EXAMPLE 168

5-(2-amino-4-oxo-3-phenyl-3,4-dihydro-6-quinazolinyl)-N,N-dimethyl-2-(me

pyridinesulfonamide

[00452] This compound was synthesized as described for Example 167, except in Step A sodium ethoxide was replaced for methylamine. LCMS: 451 (M+H); H NMR (400MHz ,DMSO- cfe) δ = 8.71 (d, J = 2.3 Hz, 1 H), 8.06 (d, J = 2.0 Hz, 1 H), 8.02 - 7.93 (m, 2 H), 7.65 - 7.48 (m, 3 H), 7.48 - 7.34 (m, 3 H), 7.24 - 6.32 (m, 3 H), 2.96 (d, J = 4.7 Hz, 3 H), 2.73 (s, 6 H)

EXAMPLE 169

5-(2-amino-4-oxo-3-phenyl-3,4-dihydro-6-quinazolinyl)-2-(dimethylamino)-N,N-dimeth pyridinesulfonamide

[00453] This compound was synthesized as described for Example 167, except in Step A only dimethylamine was used in a 4-fold excess. LCMS: 465 (M+H); H NMR (400MHz ,DMSO- c/₆) 5 = 8.78 (d, J = 2.3 Hz, 1 H), 8.16 (d, J = 2.3 Hz, 1 H), 8.11 (d, J = 2.2 Hz, 1 H), 8.00 (dd, J = 2.2, 8.6 Hz, 1 H), 7.68 - 7.48 (m, 3 H), 7.44 - 7.33 (m, 3 H), 6.58 (br. s., 2 H), 2.97 (s, 6 H), 2.76 (s, 6 H).

EXAMPLE 170

5-(2-amino-4-oxo-3-phenyl-3,4-dihydro-6-quinazolinyl)-N-(2,4-difluorophenyl)-2-

(ethyloxy)-3-pyridinesulfonamide

Step A

5-bromo-N-(2,4-difluorophenyl)-2-(ethyloxy)-3-pyridinesulfonamide

[00454] To a solution of 5-bromo-2-chloro-3-pyridinesulfonyl chloride (0.5 g, 1.719 mmol) in Dichloromethane (DC ) (5.00 mL) pyridine (0.142 mL, 1.753 mmol) and 2,4-difluoroaniline (0.177 mL, 1.753 mmol) were added. The stirring was continued at room temperature overnight. The mixture was evaporated, taken up in EtOAc/water, the organic phase washed with brine, dried over magnesium sulfate and was evaporated. The residue was dissolved in Ethanol (5 mL), 21 wt% sodium ethoxide (1.41 1 mL, 3.78 mmol) was added and the mixture was stirred 50 C° temperature overnight then it was evaporated to dryness, taken up in ethyl acetate, washed with water and brine, dried over magnesium sulfate and evaporated to dryness to give 5- bromo-N-(2,4-difluorophenyl)-2-(ethyloxy)-3-pyridinesulfonamide (501 mg, 1.274 mmol, 74.1 % yield) as a brown solid. LCMS:393, 395 (M+H); H NMR (400MHz, DMSO-cf₆) δ = 10.15 (s, 1 H), 8.54 (d, J = 2.4 Hz, 1 H), 8.08 (d, J = 2.4 Hz, 1 H), 7.38 - 7.23 (m, 2 H), 7.13 - 6.99 (m, 1 H), 4.40 (q, J = 7.1 Hz, 2 H), 1.25 (t, J = 7.0 Hz, 3 H).

Step B

N-(2, 4-difluorophenyl)-2-(ethyloxy)-5-(4, 4, 5, 5-tetramethyl-1,3, 2-dioxaborolan-2-yl)-3- pyridinesulfonamide

[00455] The mixture of 5-bromo-N-(2,4-difluorophenyl)-2-(ethyloxy)-3- pyridinesulfonamide (501 mg, 1.274 mmol), bis(pinacolato)diboror) (388 mg, 1.529 mmol), potassium acetate (375 mg, 3.82 mmol) and PdCI₂(dppf)-CH₂CI₂ adduct (104 mg, 0.127 mmol) in 1 ,4-dioxane (6371 μΙ_) was heated under nitrogen atmosphere at 100 °C overnight. The mixture was filtered through Celite® and was evaporated to dryness to give the crude N-(2,4- difluorophenyl)-2-(ethyloxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-3- pyridinesulfonamide as a black solid in quantitative yield. It was used without further purification. LCMS: 441 (M+H).

Step C

5-(2-amino-4-oxo-3φhenyl-3,4-dihydro-6-quinazolinyl)-N-(2,4-diflu

pyridinesulfonamide

[00456] The mixture of 2-amino-6-iodo-3-phenyl-4(3H)-quinazolinone (50 mg, 0.138 mmol), N-(2,4-difluorophenyl)-2-(ethyloxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-3- pyridinesulfonamide (121 mg, 0.275 mmol), PdCI₂(dppf)-CH₂CI₂ adduct (11.24 mg, 0.014 mmol) and Cs₂C0₃ (44.9 mg, 0.138 mmol) in tetrahydrofuran (THF) (1 mL) and water (0.25 mL) was heated at 65 °C for 1.5 hrs then it was evaporated and purified on a RP-HPLC to give 5-(2- amino-4-oxo-3-phenyl-3,4-dihydro-6-quinazolinyl)-N-(2,4-difluorophenyl)-2-(ethyloxy)-3- pyridinesulfonamide (32 mg, 0.058 mmol, 42.3 % yield) as an off white solid. LCMS: 550 (M+H); H NMR (400MHz, DMSO-d₆) δ = 10.1 1 (br. s., 1 H), 8.72 (d, J = 2.2 Hz, 1 H), 8.20 (d, J = 2.3 Hz, 1 H), 8.03 (d, J = 2.1 Hz, 1 H), 7.91 (dd, J = 2.1 , 8.5 Hz, 1 H), 7.68 - 7.47 (m, 3 H), 7.44 - 7.29 (m, 4 H), 7.29 - 7.19 (m, 1 H), 7.03 (t, J = 8.5 Hz, 1 H), 6.41 (br. s., 2 H), 4.44 (q, J = 7.0 Hz, 2 H), 1.27 (t, J = 7.0 Hz, 3 H).

EXAMPLE 171

5-(2-amino-4-oxo-3-phenyl-3,4-dihydro-6-quinazolinyl)-N-(2,4-difluorophenyl)-2- (methylamino)-3-pyridinesulfonamide

[00457] This compound was synthesized as described for Example 170 except in Step A sodium ethoxide was replaced for methylamine. LCMS: 535 (M+H); H NMR (400MHz, DMSO- cf₆) δ = 10.34 (br. s., 1 H), 8.65 (d, J = 2.3 Hz, 1 H), 7.90 (dd, J = 2.3, 5.2 Hz, 2 H), 7.81 (dd, J = 2.3, 8.6 Hz, 1 H), 7.66 - 7.47 (m, 4 H), 7.43 - 7.20 (m, 5 H), 7.10 - 6.97 (m, 1 H), 6.63 (q, J = 4.4 Hz, 1 H), 6.37 (br. s., 1 H), 2.96 (d, J = 4.6 Hz, 3 H).

EXAMPLE 172

5-(2-amino-4-oxo-3-phenyl-3,4-dihydro-6-quinazolinyl)-N-(2,4-difluorophenyl)-2- (dimethylamino)-3-pyridinesulfonamide

[00458] This compound was synthesized as described for Example 170 except in Step A sodium ethoxide was replaced for dimethylamine. LCMS: 549 (M+H); H NMR (400MHz, DMSO-dg) δ = 10.47 (br. s., 1 H), 8.67 (d, J = 2.3 Hz, 1 H), 8.35 (d, J = 2.3 Hz, 1 H), 8.03 (d, J = 2.2 Hz, 1 H), 7.89 (dd, J = 2.3, 8.6 Hz, 1 H), 7.65 - 7.49 (m, 3 H), 7.42 - 7.35 (m, 2 H), 7.33 (d, J = 8.6 Hz, 1 H), 7.28 - 7.13 (m, 2 H), 7.04 - 6.89 (m, 1 H), 6.37 (br. s., 2 H), 3.02 {s, 6 H).

2-Methoxy-3-pyridylsulfonamide Intermediates intermediate 1

5-bromo-2-ch chloride

Step A

[00459] Thionyl chloride (60.1 ml_, 823 mmol) was added dropwise over 60 min to water (361 ml_), cooled to 0 °C, while maintaining the temperature of the mixture at 0-7 °C. The solution was allowed to warm to 18 °C over 17 hours. Copper(l) chloride (218 mg, 2.2 mmol) was added to the mixture, and the resultant yellow-green solution was cooled to -3 °C using an acetone/ice bath.

Step B

[00460] HCI (195 mL, 6.418mol)(37% w/w) was added, with agitation, to 5-bromo-2- chloro-3-pyridineamine (25g, 121 mmol), maintaining the temperature of the mixture below 30 °C with ice cooling. The reaction mixture was cooled to -5 °C using an ice/acetone bath and a solution of sodium nitrite (14.72g, 213 mmol) in water (58 mL) was added dropwise over 45 min, maitaining the temperature of the reaction mixture between -5 to 0 °C, the resultant slurry was cooled to -2 °C and stirred for 10 minutes.

Step C

[00461] The slurry from step (b) was cooled to -5 °C and added to the solution obtained from step a over 30 min, maintaining the temperature of the reaction mixture between -3 to 0 °C ( the slurry from step b was maintained at -5 °C throughout the addition). As the reaction proceeded, a solid began to precipitate. When the addition was complete, the reaction mixture was agitated at 0 °C for 75 minutes. The suspended solid was collected by vacuum filtration, washed with water, and dried under vacuum to give 5- bromo-2-chloro-3-pyridinesulfonyl chloride. ES-LCMS: m/z 271.94, 269.97 (M-1 ).

Intermediate 2

5-bromo-N-cyclopentyl-2-(methyloxy)-3-pyridinesulfonamide

Step A

[00462] To a cold (0 °C) suspension of 2-chloro-5-bromo-3-pyridinesulfonyl chloride (2.91 g, 10 mmol) in dry 1 ,4-dioxane (25mL) was added pyridine (3.26 mL, 40 mmol) followed by a cyclopentanamine (1 mL, 10 mmol). The reaction mixture was allowed to warm to rt for 2 hrs, heated to 50 °C for 1h, then cooled to rt. 1 ,4-dioxane was evaporated under vacuum condition. The residue was extracted by EtOAc (50 mL), the organic layer was washed by H₂O(50 mL), and brine (50 mL), dried by anhydrous Mg₂S0₄. The solvent was evaporated to afford brown oil.

Step B

[00463] The brown oil in the step (a) was dissolved in 10 mL anhydrous methanol and sodium methoxide (25 % in methanol)(6 mL) was added and the mixture was sealed and heated by microwave at 95 °C for 30 minutes. After cooled to rt, the mixture was dissolved in 60 mL EtOAc and washed with H₂0 (50 mL), brine {50 mL), dried by g₂S0₄. The solid was filtrated and the filtration was evaporated to afford the yellow solid 1.8 g, yield 54%. ES-LCMS: m/z 335, 337 (M+1 ).

[00464] The following intermediates in Table 3 were synthesized as described above.

Table 3

fro 5-bromo-2-(methyloxy)-3- pyridinesulfonamide 267, 269 Η₂

5-bromo-N-(cyclopropylmethyl)-2- (methyloxy)-3-pyridinesulfonamide 321 ,323 Η

5-bromo-N-(1 ,1-dimethylethyl)-2- (methyloxy)-3-pyridinesulfonamide 323, 325 Η

5-bromo-2-(methyloxy)-3-(1 - pyrrolidinylsulfonyl)pyridine 321 , 323

_ΒΓΛ |-,ο 5-bromo-N-(2-fluorophenyl)-2- (methyloxy)-3-pyridinesulfonamide 361 , 363

ΝΗ

5-bromo-N-(3-fluorophenyl)-2- H (methyloxy)-3-pyridinesulfonamide 361 , 363

5-bromo-N-(4-fluorophenyl)-2- (methyloxy)-3-pyridinesulfonamide 361 , 363

5-bromo-2-(methyloxy)-N-[2- (methyloxy)phenyl]-3-

1 373, 375 NH pyridinesulfonamide

5-bromo-2-(methyloxy)-N-[3- (methyloxy)phenyl]-3-

NH 373, 375 pyridinesulfonamide

5-bromo-2-(methyloxy)-N-[4-

NH (methyloxy)phenyl]-3-

373, 375 pyridinesulfonamide

5-bromo-2-(methyloxy)-N-(2- methylphenyl)-3-pyridinesulfonamide 357, 359

NH

5-bromo-2-(methyloxy)-N-(3- methylphenyl)-3-pyridinesulfonamide 357, 359

NH

5-bromo-2-(methyloxy)-N-(4-

NH methylphenyl)-3-pyridinesulfonamide 357, 359

Intermediate 3

N-cyclopentyl-2-(methyloxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-3- pyridinesulfonamide

[00465] To a solution of 5-bromo-A/-cyclopentyl-2-(methyloxy)-3-pyridinesulfonamide (2 .Og, 5.9 mmol) in 1 ,4-dioxane (30 mL) was added 4,4,4',4',5,5,5',5^,-octamethyl-2,2'-bi-1 ,3,2- dioxaborolane (2.3 g, 8.9 mmol), potassium acetate (1.8 g, 17.9 mmol) and Pd(PPh₃)₂CI₂ (487 mg, 0.6 mmol). The reaction mixture was stirred at 100 °C overnight. The reaction was concentrated in vacuo, purified on silica using 60% ethyl acetate/ hexane to yield the title compound as a white solid 1.2 g (52%). ES-LCMS: m/z 383 (M+1 ).

[00466] The following boronester-intermediates in Table 4 were synthesized as described above. Table 4

A/-(4-fluorophenyl)-2-(methyloxy)-5- (4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)-3- 409 pyridinesulfonamide

2-(methyloxy)-A/-[2- (methyloxy)phenyl]-5-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)- 421 3-pyridinesulfonamide

(T^NTo 2-(methyloxy)-/V-[3- (methyloxy)phenyl]-5-(4,4,5,5-

' V-O NH tetramethyl-1 ,3,2-dioxaborolan-2-yl)- 421

3-pyridinesulfonamide

1

2-(methyloxy)-A/-[4- (methyloxy)phenyl]-5-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)- 421 3-pyridinesulfonamide

2-(methyloxy)-/V-(2-methylphenyl)-5- (4,4,5,5-tetramethyl-1 ,3,2-

" ~0 dioxaborolan-2-yl)-3- 405

NH pyridinesulfonamide

2-(methyloxy )-/V-(3-methyl phe nyl )-5- (4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)-3- 405 pyridinesulfonamide

2-(methyloxy)-/V-(4-methylphenyl)-5- (4,4,5,5-tetramethyl-1 ,3,2-

" )H-0 NH dioxaborolan-2-yl)-3- 405 pyridinesulfonamide

A/-[2-fluoro-3-(methyloxy)phenyl]-2- (methyloxy)-5-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)-3- 439 pyridinesulfonamide

EXAMPLE 173 -(2-amino-4-oxo-3-phenyl-3,4-dihydro-6-quinazolinyl)-N-cyclopentyl-2-(meth pyridinesulfonamide

[00467] The mixture of 2-amino-6-iodo-3-phenyl-4(3H)-quinazolinone (50 mg, 0.138 mmol), N-cyclopentyl-2-(methyloxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-3- pyridinesulfonamide (63.2 mg, 0.165 mmol), PdCI₂(dppf)-CH₂CI₂ adduct (1 1.24 mg, 0.014 mmol) and Cs₂C0₃ (44.9 mg, 0.138 mmol) in Tetrahydrofuran (THF) (1 mL) and Water (0.25 mL) was heated at 65 C° for 1.5hrs then it was evaporated and purified on a RP-HPLC to give 5-(2- amino-4-oxo-3-phenyl-3,4-dihydro-6-quinazolinyl)-N-cyclopentyl-2-(methy!oxy)-3- pyridinesulfonamide (17.5 mg, 0.036 mmol, 25.9 % yield) as a off white solid. LCMS: 492 (M+H); ¹H NMR (400MHz, DMSO-cf₆) δ = 8.74 (d, J = 2.3 Hz, 1 H), 8.29 (d, J = 2.3 Hz, 1 H), 8.1 1 (d, J = 2.1 Hz, 1 H), 7.99 (dd, J = 2.1 , 8.6 Hz, 1 H), 7.72 (d, J = 7.7 Hz, 1 H), 7.64 - 7.50 (m, 3 H), 7.44 - 7.28 (m, 3 H), 6.44 (br. s., 2 H), 4.04 (s, 3 H), 3.60 - 3.48 (m, 1 H), 1 .71 - 1.47 (m, 4 H), 1.46 - 1.27 (m, 4 H).

EXAMPLE 174

2-amino-6-{6-(methyloxy)-5-[(4-methyl-1^iperazinyl)sulfonyl]-3-pyrid

quinazolinone

[00468] This compound was synthesized as described for Example 173, except N- cyclopentyl-2-(methyloxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-3-pyridinesulfonamide was replaced for 1-methyl-4-{[2-(methyloxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-3- pyridinyl]sulfonyl}piperazine. LCMS: 507 (M+H); ¹H NMR (400MHz, DMSO-af₆) δ = 8.84 (d, J = 2.4 Hz, 1 H), 8.34 (d, J = 2.4 Hz, 1 H), 8.17 (d, J = 2.2 Hz, 1 H), 8.05 {dd, J = 2.1 , 8.6 Hz, 1 H), 7.67 - 7.51 (m, 3 H), 7.44 - 7.36 (m, 3 H), 6.85 (br. s., 2 H), 4.06 (s, 3 H), 3.93 (br. s., 4 hours obscured by water), 3.10 (br. s., 4 hours obscured by water), 2.81 (s, 3 H).

EXAMPLE 175

5-(2-amino-4-oxo-3-phenyl-3,4-dihydro-6-quinazolinyl)-N-(2-hydroxyethyl)-2-(m

3-pyridinesulfonamide

[00469] This compound was synthesized as described for Example 173, except N- cyclopentyl-2-(methyloxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-3-pyridinesulfonamide was replaced for N-(2-hydroxyethyl)-2-(methyloxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)-3-pyridinesulfonamide. LCMS: 468 (M+H); ¹H NMR (400MHz ,DMSO-d₆) δ = 8.74 (d, J = 2.4 Hz, 1 H), 8.29 (d, J = 2.4 Hz, 1 H), 8.16 - 8.09 (m, 2 H), 7.99 (dd, J = 2.3, 8.6 Hz, 1 H), 7.68 - 7.48 (m, 4 H), 7.45 - 7.28 (m, 3 H), 6.45 (br. s., 2 H), 4.79 - 4.54 (m, 1 H), 4.04 (s, 3 H), 3.41 - 3.38 (m, 1 H), 2.94 (q, J = 6.2 Hz, 2 H).

EXAMPLE 176

2-amino-6-[6-(methyloxy)-5-(1-pyrrolidinylsulfonyl)-3-pyridinyl]-3-p^

quinazolinone

[00470] This compound was synthesized as described for Example 173, except N- cyclopentyl-2-(methyloxy)-5-{4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-3-pyridinesulfonamide was replaced for 2-(methyloxy)-3-(1 -pyrrolidinylsulfonyl)-5-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)pyridine. LCMS: 478 (M+H); ¹H N R (400MHz ,DMSO-Gf₆) δ = 8.76 (d, J = 2.4 Hz, 1 H), 8.30 (d, J = 2.4 Hz, 1 H), 8.1 1 (d, J = 2.2 Hz, 1 H), 7.99 (dd, J = 2.3, 8.6 Hz, 1 H), 7.67 - 7.48 (m, 3 H), 7.43 - 7.28 (m, 3 H), 6.42 (br. s., 2 H), 4.04 {s, 3 H), 3.32 - 3.30 (m, 4 hours obscured under water), 1.90 - 1.68 (m, 4 H).

EXAMPLE 177

5-(2-amino-4-oxo-3-phenyl-3,4-dihydro-6-quinazolinyl)-N-(cyclopropylmethyl)-2-

(methyloxy)-3-pyridinesulfonamide

[00471] This compound was synthesized as described for Example 173, except N- cyclopentyl-2-(methyloxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-3-pyridinesulfonamide was replaced for N-(cyclopropylmethyl)-2-(methyloxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan- 2-yl)-3-pyridinesulfonamide. LCMS: 478 (M+H); H NMR (400MH, DMSO-d₆) δ = 8.73 (d, J = 2.4 Hz, 1 H), 8.28 (d, J = 2.4 Hz, 1 H), 8.10 (d, J = 2.1 Hz, 1 H), 7.98 (dd, J = 2.1 , 8.6 Hz, 1 H), 7.78 (t, J = 5.9 Hz, 1 H), 7.64 - 7.48 (m, 3 H), 7.42 - 7.32 (m, 3 H), 6.42 (br. s., 2 H), 4.04 (s, 3 H), 2.81 (t, J = 6.4 Hz, 2 H), 0.83 - 0.65 (m, 1 H), 0.34 - 0.19 (m, 2 H), 0.15 - -0.02 (m, 2 H).

EXAMPLE 178

5-(2-amino-4-oxo-3-phenyl-3,4-dihydro-6-quinazolinyl)-N-(1, 1-dimethylethyl)-2-

(methyloxy)-3-pyridinesulfonamide

[00472] This compound was synthesized as described for Example 173, except N- cyclopentyl^-imethyloxy S^^^^-tetramethyl-l ^^-dioxaborolan^-y -S-pyridinesulfonamide was replaced for N-(1 , 1-dimethylethyl)-2-(methyloxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan- 2-yl)-3-pyridinesulfonamide. LCMS: 480 (M+H); ¹H NMR (400MHz, DMSO- /₆) δ = 8.74 (d, J = 2.2 Hz, 1 H), 8.30 (d, J = 2.2 Hz, 1 H), 8.09 (d, J = 1.9 Hz, 1 H), 7.98 (dd, J = 2.0, 8.6 Hz, 1 H), 7.70 - 7.46 (m, 4 H), 7.42 - 7.28 (m, 3 H), 6.42 (br. s., 2 H), 4.05 (s, 3 H), 1.1 1 (s, 9 H).

EXAMPLE 179

5-(2-amino-4-oxo-3^henyl-3,4-dihydro-6-quinazolinyl)-2-(methyloxy)-N-(2-methylphenyl)

3-pyridinesulfonamide

[00473] This compound was synthesized as described for Example 173, except N- cyclopentyl-2-(methyloxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-3-pyridinesulfonamide was replaced for 2-(methyloxy)-N-(2-methylphenyl)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)-3-pyridinesulfonamide. LCMS: 514 (M+H); ¹H NMR (400MHz, DMSO-d₆) δ = 9.77 (br. s., 1 H), 8.74 (d, J = 1.8 Hz, 1 H), 8.1 1 (d, J = 1.9 Hz, 1 H), 7.99 (dd, 1 H), 7.89 (dd, 1 H), 7.66 - 7.48 (m, 3 H), 7.44 - 7.25 (m, 3 H), 7.20 - 6.97 (m, 4 H), 6.43 (br. s., 2 H), 3.99 (s, 3 H), 2.14 (s, 3 H).

EXAMPLE 180

5-(2-amino-4-oxo-3-phenyl-3,4-dihydro-6-quinazolinyl)-2-(methyloxy)-N-(4-methylph

3-pyridinesulfonamide

[00474] This compound was synthesized as described for Example 173, except N- cyclopentyl-2-(methyloxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-3-pyridinesulfonamide was replaced for 2-(methyloxy)-N-(4-methylphenyl)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)-3-pyridinesulfonamide. LCMS: 514 (M+H); H NMR (400MHz, DMSO-d₆) δ = 10.24 (br. s., 1 H), 8.69 (d, J = 2.3 Hz, 1 H), 8.26 (d, J = 2.3 Hz, 1 H), 8.03 (d, J = 2.1 Hz, 1 H), 7.91 (dd, J = 2.2, 8.6 Hz, 1 H), 7.67 - 7.48 (m, 3 H), 7.42 - 7.28 (m, 3 H), 7.04 - 6.98 (m, 4 H), 6.44 (br. s., 2 H), 4.01 (s, 3 H), 2.14 (s, 3 H).

EXAMPLE 181

5-(2-amino-4-oxo-3^henyl-3,4-dihydro-6-quinazolinyl)-2-(methyloxy)-N-(3-methylph

3-pyridinesulfonamide

[00475] This compound was synthesized as described for Example 173, except N- cyclopentyl-2-(methyloxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-3-pyridinesulfonamide was replaced for 2-(methyloxy)-N-(3-methylphenyl)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)-3-pyridinesulfonamide. LCMS: 514 (M+H); ¹H NMR (400MHz, DMSO-d₆) δ = 10.32 (s, 1 H), 8.69 (d, J = 2.4 Hz, 1 H), 8.30 (d, J = 2.4 Hz, 1 H), 8.04 (d, J = 2.2 Hz, 1 H), 7.92 (dd, J = 2.3, 8.6 Hz, 1 H), 7.63 - 7.50 (m, 3 H), 7.41 - 7.31 (m, 3 H), 7.1 1 - 7.05 (m, 1 H), 6.99 - 6.89 (m, 2 H), 6.81 (d, J = 7.5 Hz, 1 H), 6.61 - 6.27 (m, 2 H), 4.00 (s, 3 H), 2.18 (s, 3 H). EXAMPLE 182

5-(2-amino-4-oxo-3-phenyl-3,4-dihydro-6-quinazolinyl)-N-(4-fluoroph n^

3-pyridinesulfonamide

[00476] This compound was synthesized as described for Example 173 except N- cyclopentyl-2-(methyloxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-3-pyridinesulfonamid^ was replaced for N-(4-fluorophenyl)-2-(methyloxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)-3-pyridinesulfonamide. LCMS: 518 M+H); ¹H NMR (400MHz, DMSO- /₆) δ = 10.40 (br. s., 1 H), 8.71 (d, J = 1.9 Hz, 1 H), 8.27 (d, J = 1.9 Hz, 1 H), 8.04 (d, J = 1.4 Hz, 1 H), 7.98 - 7.87 (m, J = 8.5 Hz, 1 H), 7.69 - 7.49 (m, 3 H), 7.35 (dd, 3 H), 7.22 - 7.01 (m, 4 H), 6.43 (br. s., 2 H), 4.00 (s, 3 H).

EXAMPLE 183

5-(2-amino-4-oxo-3-phenyl-3,4-dihydro-6-quinazolinyl)-2-(methyloxy)-N-[3- (methyloxy)phenyl]-3-pyridinesulfonamide

[00477] This compound was synthesized as described for Example 173, except N- cyclopentyl-2-(methyloxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-3-pyridinesulfonamide was replaced for 2-(methyloxy)-N-[3-(methyloxy)phenyl]-5-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)-3-pyridinesulfonamide. LCMS: 530 (M+H); ¹H NMR (400MHz, DMSO-d₆) δ = 10.41 (br. s., 1 H), 8.71 (d, J = 2.4 Hz, 1 H), 8.32 (d, J = 2.3 Hz, 1 H), 8.05 (d, J = 2.2 Hz, 1 H), 7.93 (dd, J = 2.3, 8.6 Hz, 1 H), 7.64 - 7.48 (m, 3 H), 7.41 - 7.30 (m, 3 H), 7.1 1 (t, J = 8.1 Hz, 1 H), 6.75 - 6.61 (m, 2 H), 6.57 (dd, J = 2.1 , 8.3 Hz, 1 H), 6.42 (br. s., 2 H), 4.01 (s, 3 H), 3.63 (s, 3 H).

EXAMPLE 184

5-(2-amino-4-oxo-3-phenyl-3,4-dihydro-6-quinazolinyl)-N-[2-(dimethylam

(methyloxy)-3-pyridinesulfonamide

[00478] This compound was synthesized as described for Example 173, except N- cyclopentyl-2-(methyloxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-3-pyridinesulfonamide was replaced for N-[2-(dimethylamino)ethyl]-2-(methyloxy)-5-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)-3-pyridinesulfonamide. LCMS: 495 (M+H); ¹H NMR (400MHz, DMSO-d₆) δ = 9.69 (br. s., 1 H), 8.82 (d, J = 2.1 Hz, 1 H), 8.34 (d, J = 2.1 Hz, 1 H), 8.20 (d, J = 1.5 Hz, 1 H), 8.13 (dd, 1 H), 8.03 (t, J = 5.4 Hz, 1 H), 7.69 - 7.53 (m, 4 H), 7.52 - 7.41 (m, 3 H), 4.07 (s, 3 H), 3.33 - 3.09 (m, 4 H), 2.80 (s, 6 H).

Example 185

5-(2-amino-4-oxo-3-phenyl-3, 4-dihydro-6-quinazolinyl)-2-(methyloxy)-N-phenyl-3- pyridinecarboxamide

Step A

methyl 2-(methyloxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3^yrid

[00479] To a solution of methyl 5-bromo-2-(methyloxy)-3-pyridinecarboxylate(0.5 g, 2.03 mmol) in THF (20 mL) was added 4,4,4\4\5,5,5\5'-octamethyl-2,2^,-bi-1 ,3,2-dioxaborolane (0.77 g, 3.05 mmol), potassium acetate (0.60 g, 6.10 mmol) and PdCI₂(dppf)-CH₂CI₂ adduct (166 mg, 0.2 mmol). The reaction mixture was stirred at 65 °C overnight. The reaction was concentrated in vacuo, purified on silica using 50 % ethyl acetate/ hexane to yield the title compound as a white solid (69%). ES-LCMS: m/z 294.41 (M+1 ).

[00480] The following boronesters in Table 5 were prepared using similar procedure as above.

Table 5

Step B

methyl 5-(2-amino-4-oxo-3 henyl-3 - ihydro-6-quinazolinyl)-2-(methyloxy)-3- pyridinecarboxylate

[00481] To a solution of 2-amino-6-iodo-3-phenyl-4(3H)-quinazolinone (0.49 g, 1.35 mmol) in 1 ,2-Dimethoxyethane (D E) (20 mL) and water (5 mL) was added methyl 2- (methyloxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-3-pyridinecarboxylate (0.59 g, 2.03 mmol), potassium acetate (0.40 g, 4.05 mmol) and PdCI₂(dppf)-CH₂CI₂ adduct (110 mg, 0.14 mmol). The reaction mixture was stirred at 80 °C overnight. The reaction was concentrated in vacuo, purified on silica using 80% ethyl acetate/ hexane to yield the title compound as a white solid (42%). ES-LCMS: m/z 403.45 ( +1).

[00482] The following quinazolinones Table 6 were prepared using similar procedure above.

Table 6

Step C

5-(2-amino-4-oxo-3^henyl-3 -dihydro-6-quinazolinyl)-2-(m acid

[00483] To a solution of methyl 5-(2-amino-4-oxo-3-phenyl-3,4-dihydro-6-quinazolinyl)-2- (methyloxy)-3-pyridinecarboxylate (230 mg, 0.572 mmol) in mixture solvent of Methanol (4 mL), THF (4 mL) and H₂0 (2 mL) was added lithium hydroxide (17.79 mg, 0.743 mmol). The reaction mixture was stirred at 25 °C overnight. The reaction was concentrated in vacuo to afford the crude product, which was used directly for the next step without purification. ES-LCMS: m/z 389.35 (M+1 ).

[00484] The following acids in Table 7 were prepared using similar procedure above.

Table 7

Step D

[00485] HATU (151 mg, 0.40 mmol) was added to a mixture of 5-(2-amino-4-oxo-3- phenyl-3, 4-dihydro-6-quinazolinyl)-2-(methyloxy)-3-pyridinecarboxylic acid (77 mg, 0.198 mmol), aniline(0.023 mL, 0.26 mmol) and DIPEA (0.10 mL, 0.60 mmol) in N,N- Dimethylformamide (DMF) (5 mL). The reaction mixture was stirred at 25 °C for 12 hours. After it was concentrated in vacuo, purified by HPLC using 10-90 % CH₃CN / H₂0 (0.1 % formic acid) to yield the title compound as a white solid (30%). H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.87 (s, 1 H) 8.87 (d, J=2.54 Hz, 1 H) 8.60 (d, J=2.34 Hz, 1 H) 8.39 (d, J=1.76 Hz, 1 H) 7.93 (dd, J=8.39, 1.76 Hz, 1 H) 7.71 (d, J=7.80 Hz, 2 H) 7.56 - 7.68 (m, 3 H) 7.49 (d, J=8.58 Hz, 1 H) 7.37 - 7.43 (m, 4 H) 7.14 - 7.20 (m, 1 H) 5.36 (br.s., 2 H) 4.26 (s, 3 H); ES-LCMS: m/z 464.36 (M+1 ).

[00486] Examples from Example 186 through 192 were synthesized as described for Example 185.

Example 186

5-(2-amino-4-oxo-3-phenyl-3,4-dihydro-6-quinazolinyl)-2-(methyloxy)-N-3-pyri^

pyridinecarboxamide

[00487] ¹H NMR (400 MHz, DMSO-cfe) δ ppm 10.50 (s, 1 H) 8.88 (d, J=2.34 Hz, 1 H) 8.69

(d, J=2.54 Hz, 1 H) 8.35 (d, J=2.34 Hz, 1 H) 8.33 (dd, J=4.68, 1.37 Hz, 1 H) 8.15 - 8.22 (m, 2 H) 8.01 (dd, J=8.59, 2.34 Hz, 1 H) 7.50 - 7.63 (m, 3 H) 7.34 - 7.44 (m, 4 H) 6.40 (br. s., 2 H) 4.03 (s, 3 H). ES-LCMS: m/z 465.36 (M+1 ).

Example 187

5-(2-amino-4-oxo-3-phenyl-3,4-dihydro-6-quinazolinyl)-2-(m

ridinecarboxamide

[00488] H NMR (400 MHz, DMSO-d₆) δ ppm 10.68 (s, 1 H) 9.15 (s, 2 H) 8.96 (s, 1 H)

8.71 (d, J=2.54 Hz, 1 H) 8.40 (d, J=2.54 Hz, 1 H) 8.17 (d, J=2.15 Hz, 1 H) 8.01 (dd, J=8.68, 2.24 Hz, 1 H) 7.50 - 7.63 (m, 3 H) 7.34 - 7.41 (m, 3 H) 6.40 (br. s., 2 H) 4.04 (s, 3 H)

ES-LCMS: m/z 466.36 (M+1).

Example 188

2-amino-5-(2-amino-4-oxo-3-phenyl-3,4-dihydro-6-quinazolinyl)-N-phenyl-3- pyridinecarboxamide

[00489] H NMR (400 MHz, DMSO-d₆) δ ppm 10.36 (s, 1 H) 8.50 (d, J=2.34 Hz, 1 H) 8.35

(d, J=2.34 Hz, 1 H) 8.18 (d, J=2.15 Hz, 1 H) 8.00 (dd, J=8.59, 2.34 Hz, 1 H) 7.70 (d, J=7.80 Hz, 2 H) 7.50 - 7.62 (m, 3 H) 7.32 - 7.40 (m, 5 H) 7.08 - 7.14 (m, 3 H) 6.31 (br. s., 2 H)

ES-LCMS: m/z 449.36 (M+1 ).

Example 89

2-amino-5-(2-amino-4-oxo-3-phenyl-3,4-dihydro-6-quinazolinyl)-N,N-dimethyl-3- ridinecarboxamide

[00490] ¹H NMR (400 MHz, DMSO-cfe) δ ppm 8.35 (d, J=2.34 Hz, 1 H) 8.02 (d, J=2.15 Hz, 1 H) 7.89 (dd, =8.59, 2.34 Hz, 1 H) 7.70 (d, J=2.54 Hz, 1 H) 7.50 - 7.62 (m, 3 H) 7.34 - 7.40 (m, 2 H) 7.29 (d, J=8.59 Hz, 1 H) 6.29 (br. s., 2 H) 6.1 1 (s, 2 H) 2.96 (s, 6 H)

ES-LCMS: m/z 401.35 (M+1 ).

Example 190

5-(2-amino-4-oxo-3-phenyl-3,4-dihydro-6-quinazolinyl)-2-methyl-N-phenyl-3- pyridinecarboxamide

[00491] ¹H NMR (400 MHz, DMSO-cf₆) δ ppm 10.54 (s, 1 H) 8.90 (d, J=2.15 Hz, 1 H) 8.26

(d, J=2.15 Hz, 1 H) 8.18 (d, J=2.15 Hz, 1 H) 8.07 (dd, J=8.58, 2.15 Hz, 1 H) 7.75 (d, J=7.61 Hz, 2 H) 7.50 - 7.63 (m, 3 H) 7.33 - 7.41 (m, 5 H) 7.09 - 7.15 (m, 1 H) 6.42 (br. s., 2 H) 2.61 (s, 3 H) ES-LCMS: m/z 448.32 (M+1 ).

Example 191

5-(2-amino-4-oxo-3-phenyl-3,4-dihydro-6-quinazolinyl)-2-methyl-N-(phenylm

ridinecarboxamide

[00492] H NMR (400 MHz, DMSO-d₆) δ ppm 9.13 (t, J=5.95 Hz, 1 H) 8.84 (d, J=2.34 Hz,

1 H) 8.22 (d, J=2.15 Hz, 1 H) 8.00 - 8.07 (m, 2 H) 7.50 - 7.62 (m, 3 H) 7.33 - 7.41 (m, 7 H) 7.23 - 7.29 (m, 1 H) 6.41 (br. s., 2 H) 4.46 - 4.54 (m, 2 H) 2.57 (s, 3 H) ES-LCMS: m/z 462.36 (M+1 ).

Example 192

5-(2-amino-4-oxo-3^henyl-3,4-dihydro-6-quinazolinyl)-2-methyl-3^yridin

[00493] ¹H NMR (400 MHz, DMSO-c/₆) δ ppm 8.82 (d, J=2.15 Hz, 1 H) 8.22 (d, J=2.15 Hz, 1 H) 7.99 - 8.10 (m, 3 H) 7.50 - 7.63 (m, 4 H) 7.34 - 7.41 (m, 3 H) 6.41 (br. s., 2 H) 2.59 (s, 3 H) ES-LCMS: m/z 372.28 (M+1 ).

General Scheme 16

Example 193

2-amino-6-[6-(methyloxy)-5-(1H-pyrazol-4-yl)-3-pyridinyl]-3-phenyl-4(3H)-^

Step A

3-chloro-2-(methyloxy)-5-(4, -tetramethyl- 1, 3, 2-dioxaborolan-2-yl)pyridine

[00494] 2-Methoxy-3-chloro-5-bromopyridine (500 mg, 2.25 mmol),

bis(pinacolate)diboron (856 mg, 3.37 mmol) KOAc (662 mg, 6.74 mmol) and Pd(Ph₃P)₄ (130 mg, 0.05 mmol) were mixed together in a schlenck flask charged with 18 mL of dioxane. The reaction mixture was purged with N₂ (3x) before heated to 60°C overnight. The solvents were evaporated and the residual was purified by column chromatography (silica gel, 0 to 30% ethyl acetate in hexanes) to give 3-chloro-2-(methyloxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)pyridine (150mg, Yield: 25%).

Step B

2-amino-6-[5-chloro-6-(methyloxy)-3 yridiny^]-3 henyl-4(3H)-qu

[00495] 2-Amino-6-iodo-3-phenyl-4(3H)-quinazolinone (177 mg, 0.486 mmol), 3-chloro-2- (methyloxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridine (131 mg, 0.486 mmol), KOAc(143mg, 1.458 mmol) and PdCI₂ (dppf)₂ were mixed together in a schlenck flask charged with a mixed DME/water (2mL/0.5 mL). The reaction mixture was purged with N₂ (3x) before heated to 80 °C for 4 hrs. The solvents were evaporated and the residual was purified by column chromatography (silica gel, 0 to 90 % ethyl acetate in hexanes) to give 2-amino-6-[5- chloro-6-(methyloxy)-3-pyridinyl]-3-phenyl-4(3H)-quinazolinone (66 mg, Yield: 36%). LC-MS: m/z 379.3, 381.3 (M+1 ).

Step C

2-amino-6-[6-(methyloxy)-5-(1Hφyrazol-4-yl)-3 yridinyl]-3φhenyl-4(3H

[00496] 2-Amino-6-[5-chloro-6-(methyloxy)-3-pyridinyl]-3-phenyl-4(3H)-quinazolinone (33mg, 0.087mmol), 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole (20.6 mg, 0.078mmol). Xphos (4.2 mg, 0.1 eq.), Pd₂(dba)₃ (4 mg, 0.05 eq.) and K₃P0₄ (56 mg, 0.26mmol) were mixed into a schlenck flask charged with a mixed n-butanol/water (2 mL/0.5 mL). The reaction mixture was purged with N₂ (3x) before heated to 100°C for18hrs. The solvents were evaporated and the residual was purified by column chromatography (silica gel, 0 to 10% MeOH.2M NH₃ in DCM) to give 2-amino-6-[6-(methyloxy)-5-(1tf-pyrazol-4-yl)-3-pyridinyl]-3- phenyl-4(3H)-quinazolinone (10.5mg, Yield: 25%). ¹H N R (CHLOROFOR -d) δ ppm: 8.23 (dd, J = 12.0, 2.2 Hz, 2H), 7.96 - 8.08 (m, 3H), 7.82 (dd, J = 8.5, 2.1 Hz, 1 H), 7.45 - 7.64 (m, 5H), 7.27 - 7.45 (m, 4H), 4.02 (s, 3H). LC-MS: m/z 41 1.3 (M+1 ). Example 194

2-amino-6-[6-(methyloxy)-5-(1^ropyl-1H^yrazol-4-yl)-3-pyridinyl]-3-phen

[00497] 2-Amino-6-[5-(1 -propyl-1 H-pyrazol-4-yl)-6-(methyloxy)-3-pyridinyl]-3-phenyl- 4(3/-/)-quinazolinone (10.5 mg, Yield: 25%) was obtained from 1 -propyl-4-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole and 2-amino-6-[5-chloro-6-(methyloxy)-3-pyridinylj-3- phenyl-4(3H)-quinazolinone by a similar procedure outlined in Step C of Example 193. H NMR (CHLOROFORM-d) δ ppm: 8.24 - 8.53 (m, 2H), 7.79 - 8.20 (m, 4H), 7.53 - 7.79 (m, 3H), 7.33 - 7.53 (m, 3H), 4.93 (br. s., 2H), 4.05 - 4.16 (m, 5H), 1 .96 (dt, J = 14.5, 7.2 Hz, 2H), 0.89 - 1.07 (m, 3H). LC-MS: z 453.3(M+1 ).

General Scheme 17

Example 195

2-amino-6-[6-(methyloxy)-5-(5-phenyl-1,3,4-oxadiazol-2-yl)-3-pyrW^

Step A

5-bromo-2-(methylox -3-pyridinecarboxylic acid lithium salt

[00498] To a stirred solution of methyl-5-bromo-2-methoxynicotinate (500 mg, 2.03 mmol) in a mixed THF/water (10 mL/2.5 mL) was added LiOH (64mg, 2.64 mmol). The resulting mixture was stirred for 4 hrs before removal of the solvents. The resultant lithium salt was used for the next step.

Step B

5-bromo-2-(me diazol-2-yl)pyridine

[00499] To a stirred solution of 5-bromo-2-(methyloxy)-3-pyridinecarboxylic acid lithium salt (200 mg, 0.84 mmol) and benzoic hydrazide (1 14 mg, 0.84 mmol) in DMF 10 mL) was added HATU (320mg, 0.84 mmol). The mixture was stirred for 2 hrs before introducing Burgess reagent (4eq). The reaction was continued over weekend before diluted with EtOAc and washed with NaHC0₃(ss) and brine. The organic phase was dried and concentrated. The crude residual was purified by column (silica gel, 10 to 50 % ethyl acetate in hexane) to give 5- bromo-2-(methyloxy)-3-(5-phenyl-1 ,3,4-oxadiazol-2-yl)pyridine (50 mg, Yield:18 %). ¹H NMR (CHLOROFORM-d) δ ppm: 8.46 (d, J = 2.5 Hz, 1H), 8.39 (d, J = 2.3 Hz, 1 H), 8.15 {dd, J = 7.8, 1.8 Hz, 2H), 7.42 - 7.68 (m, 3H), 4.13 (s, 3H). LC-MS: m/z 332.2 (M+1 ).

5-bromo-3-(5-methyl- 1, 3, 4 pyridine

[00500] 5-Bromo-3-(5-methyl-1 ,3,4-oxadiazol-2-yl)-2-(methyloxy)pyridine was prepared using a similar approach outlined as in Step B. LC-MS: m/z 270.2,272.2 (M+1 ).

Step C

2-ammo-6-[6-{methy\oxy)-5-{5-p eny\-1,3,4-oxad\azo\-2-y\)-3-^^

quinazolinone

[00501] 5-Bromo-2-(methyloxy)-3-(5-phenyl-1 ,3,4-oxadiazol-2-yl)pyridine (50mg, 0.151 mmol), bis(pinacolate)diboron (38.2 mg, 0.151 mmol), KOAc (59 mg, 0.602 mmol) and PdCI₂ (dppf) (11 mg, 0.15 mmol) were mixed in a schlenck flask charged with 2 mL of dioxane. The reaction mixture was purged with N₂ (3x) before heated to 65°C overnight. LC-MS indicated the completion of the reaction. To this reaction solution were introduced 0.5 mL of water, 2-amino-6- iodo-3-phenyl-4(3H)-quinazolinone (54.7 mmg, 0.151 mmol), the second portion of Pd catalysts and KOAc. The flask was sealed again and purged with N₂ (3X) before heated 80 °C overnight. The solvents were evaporated and the residual was purified by column chromatography (silica gel, 0 to 10% MeOH (2M NH₃) in DCM) to give 2-amino-6-[6-(methyloxy)-5-(5-phenyl-1 ,3,4- oxadiazol-2-yl)-3-pyridinyl]-3-phenyl-4(3H)-quinazolinone (18.5 mg, Yield 24%). H NMR (CHLOROFORM-d) δ ppm: 8.63 (dd, J = 11 .7, 2.5 Hz, 2H), 8.40 (d, J = 2.3 Hz, 1 H), 8.09 - 8.24 (m, 2H), 7.91 (dd, J = 8.5, 2.2 Hz, 1 H), 7.53 - 7.71 (m, 6H), 7.49 (d, J = 8.6 Hz, 1 H), 7.33 - 7.44 (m, 2H), 4.82 (br. s., 2H), 4.20 (s, 3H). LC-MS: m/z 489.4 (M+1 ).

Example 196

2-amino-6-[5-(5-methyl-1,3,4-oxadiazol-2-yl)-6-(methyloxy)-3-pyrM

quinazolinone

[00502] 2-Amino-6-[5-(5-methyl-1 ,3,4-oxadiazol-2-yl)-6-(m^

4(3H)-quinazolinone was prepared from 5-bromo-3-(5-methyl-1 ,3,4-oxadiazol-2-yl)-2- (methyloxy)pyridine, bis(pinacolate)diboron and 2-amino-6-iodo-3-phenyl-4(3H)-quinazolinone using a similar procedure outlined as in Example 195. ¹H NMR (CHLOROFORM-d) δ ppm: 8.62 (d, J = 2.5 Hz, 1 H), 8.50 (d, J = 2.3 Hz, 1 H), 8.37 (d, J = 2.1 Hz, 1 H), 7.89 (dd, J = 8.5, 2.2 Hz, 1 H), 7.54 - 7.74 (m, 3H), 7.48 (d, J = 8.6 Hz, 1 H), 7.39 (d, J = 7.2 Hz, 2H), 4.71 (br. s., 2H), 4.17 (s, 3H), 2.66 (s, 3H). LC-MS: m/z 427.3 (M+1).

Example 197

N-[5-[2-amino-4-oxo-3-(phenylcarbonyl)-3,4-dihydro-6-quinazolinyl]-2-(me pyridin l]-2,4-difluorobenzenesulfonamide

General Scheme 18

Step a

Step A

N-cyanobenzamide

[00503] To a stirred solution of benzoyl chloride (2.8 g, 20 mmol) in 40 mL of anhydrous

THF was aaded a stoichiometric amount of cyanamide dissolved in 12 mL of 2 M NaOH solution. The resulting reaction mixture was stirred at 25 °C for 6 h before acidified with 0.1 N HCI to pH ~3. The reaction mixture was extracted with EtOAc (100 mL X 2), and the organic phase was washed with brine (50 mL), dried over MgS0₄ and evaporated the solvent to afford the crude product, which was directly used for the next step without further purification.

ES-LCMS: m/z 147 ( +1 ).

Step B

2-amino-6-bromo-3-(phenylcarbonyl)-4(3H)-quinazolinone

[00504] Methyl 2-amino-5-bromobenzoate(2.99g,13mmol) was dissolved in 60 ml of DMF and benzoylcyanamide (1.9 g, 13 mmol) was introduced. The resulting mixture was heated to 90-95 °C for 5 hr. After the reaction solution was concentrated down in vacuo, the crude product was triturated with diethyl ether to provide the desired product as whit solid.

ES-LCMS: m/z 344, 346 (M+1 ).

Step C

N-[5-[2-amino-4-oxo-3-(phenylcarbonyl)-3, 4-dihydro-6-quinazotinyl]-2-(methytoxy)-3-pyridinyl]-

2, 4-difiuorobenzenesutfonamide

[00505] A mixture of 2-amino-3-benzoyl-6-bromoquinazolin-4(3H)-one (60 mg, 0.17 mmol), 2,4-difluoro-N-(2-methoxy-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyriclin-3- yl)benzenesulfonamide (89 mg, 0.21 mmol), PdCI₂(dppf)-CH₂CI₂ adduct(14 mg, 0.017 mmol), and potassium acetate(51 mg, 0.52 mmol) in 1 ,4-dioxane (2 ml.) was added water(0.5 mL). Then the flask was sealed and purged with N₂(3 x) before heated to 130 °C for 15 min. The mixture was cooled down to room temperature and it was filtered through Celite and the solid product was washed with water and MeOH to give the titled compound (55 mg, 53%) as a grey solid. H NMR (400 MHz, DMSO-d₆) δ ppm 1 1.95 (br. s., 1 H) 10.36 (s, 1 H) 8.42 (br. s., 1 H) 8.22 (br. s., 1 H) 8.04 - 8.15 (m, 3 H) 7.95 (br. s., 1 H) 7.73 - 7.81 (m, 1 H) 7.67 (br. s., 2 H) 7.57 (d, J=8.19 Hz, 3 H) 7.22 (t, J=8.29 Hz, 1 H) 3.67 (s, 3 H). ES-LCMS: m/z 564 (M+1 ).

EXAMPLE 198

5-{2-amino-3-[4-(4-morpholinyl)phenyl]-4-oxo-3,4-dihydm-6-quinazolin

(methyloxy)-N-phenyl-3-pyridinesulfonamide

STEP A

5-bromo-N-methyl-2-(methyloxy)-N-phenyt-3-pyridinesulfonamide

5-bromo-N-methyl-2-(methy]oxy)-A/-phenyl-3-pyridinesulfonamide was obtained in a procedure analogous to Example 159, Step A from 5-bromo-2-chloro-3-pyridinesulfonyl chloride (1 g, 3.44 mmol) and N-methylaniline (0.405 G, 3.78 mmol) and sodium methoxide, yield (0.65 g, 52%). LCMS (m/z) ES+ 358 and 360 (m+1 ).

STEP B

N-mefhy/-2-(mef/7y/oxyJ-N-pheny/-5-^

ridinesulfonamide

N-methy!-2-(methyloxy)-N-phenyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-3- pyridinesulfonamide was obtained in a procedure analogous to Example 158, Step E from 5- bromo-A/-methyl-2-(methyloxy)-/V-phenyl-3-pyridinesulfonamide (0.604 g, 1.69 mmol), yield (0.81 g, 100%). LCMS (m/z) ES+ 405 (m+1 ).

STEP C

5-{2-amino-3-[4-(4-morphoiinyl)phenyl]-4-oxo-3,4-dihydro^

(methyloxy)-N-phenyl-3-pyridinesulfonamide

5-{2-amino-3-[4-(4-morpholinyl)phenyl]-4-oxo-3,4-dihydro-6-quinazolinyl}-A/-methyl-2- (methyloxy)-/V-phenyl-3-pyridinesulfonamide was obtained in a procedure analogous to Example 158, Step J from /V-methyl-2-(methyloxy)-/V-phenyl-5-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)-3-pyridinesulfonamide and 2-amino-6-iodo-3-(4- morpholinophenyl)quinazolin-4(3H)-one (Example 105 Step E), (100 mg, 0.223 mmol), yield (0.040 g, 30%). H NMR (D SO-d₆) δ: 8.74 (d, J = 1.8 Hz, 1 H), 8.09 (d, J = 1.6 Hz, 1H), 7.98 (s, 1H), 7.90 - 7.92 (m, OH), 7.87 (d, J = 8.6 Hz, 1 H), 7.03 - 7.41 (m, 10H), 6.12 - 6.62 (m, 2H), 3.93 (s, 3H), 3.76 (br. s., 4H), 3.35 (br. s., 3H), 3.21 (br. s., 4H). LCMS (m/z) ES+ 599 (m+1 ).

EXAMPLE 199

5-(2-amino-4-oxo-3-phenyl-3,4-dihydro-6-quinazolinyl)-N-(2-fluoro-3-methylphen

(methyloxy)-3-pyridinesulfonamide

5-(2-amino-4-oxo-3-phenyl-3,4-dihydro-6-quinazolinyl)-N-(2-fluoro-3-methylphenyl)-2- (methyloxy)-3-pyridinesulfonamide was obtained in a procedure analogous to Example 158, Step J from N-(2-fluoro-3-methylphenyl)-2-(methyloxy)-5-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)-3-pyridinesulfonamide (0.174 g, 0.412 mmol) and 2-amino-6-iodo-3- phenyl-4(3H)-quinazolinone (0.165 g, 0.453 mmol). H NMR (DMSO-d₆) δ: 10.22 (br. s., 1H), 8.73 (d, J = 2.3 Hz, 1 H), 8.19 (d, J = 2.3 Hz, 1H), 8.02 (d, J = 2.1 Hz, 1 H), 7.91 (dd, J = 8.6, 2.3 Hz, 1H), 7.46 - 7.68 (m, 3H), 7.35 (dd, J = 16.1 , 7.9 Hz, 3H), 6.83 - 7.20 (m, 3H), 6.42 (br. s., 2H), 3.96 (s, 3H), 2.13 (d, J = 1.4 Hz, 3H). LCMS (m/z) ES+ 532 (m+1 ).

EXAMPLE 200

5-{2-amino-3-[4-(4-morpholinyl)phenyl]-4-oxo-3,4-dihydro-6-quinazolinyl}-N-(3- fluorophenyl)-2-(methyloxy)-3-pyridinesulfonamide

5-{2-amino-3-[4-(4-morpholinyl)phenyl]-4-oxo-3,4-dihydro-6-quinazoliny^

2-(methyloxy)-3-pyridinesulfonamide has been synthesized analogously as described for Example 198, Steps A to C, using 3-fluoro aniline in step A. ¹H NMR (DMSO-d₆) δ: 8.70 (d, J = 2.3 Hz, 1H), 8.35 (d, J = 2.1 Hz, 1 H), 8.06 (d, J = 2.0 Hz, 1 H), 7.92 (dd, J = 8.6, 2.1 Hz, 1 H), 7.32 (d, J = 8.4 Hz, 1 H), 7.14 - 7.28 (m, 3H), 7.06 - 7.14 (m, 2H), 6.88 - 7.01 (m, 2H), 6.79 (t, J = 9.4 Hz, 1 H), 6.38 (br. s., 2H), 3.98 (s, 3H), 3.68 - 3.89 (m, 4H), 3.12 - 3.28 (m, 4H). LCMS (m/z) ES+ 603 (m+1 ).

EXAMPLE 201

5-{2-amino-3-[4-(4-morpholinyl)phenyl]-4-oxo-3,4-dihydro-6-quinazoli

fluorophenyl)-2-(methyloxy)-3-pyridinesulfonamide

5-{2-amino-3-[4-(4-morpholinyl)phenyl]-4-oxo-3,4-dihydro-6-quinazolinyl}-/V-(2-fluorophenyl)- 2-(methyloxy)-3-pyridinesulfonamide has been synthesized as described for Example 198, Steps A to C, using 2-fluoro aniline in step A. ¹H NMR (DMSO-d₆) δ: 8.71 (d, J = 2.3 Hz, 1 H), 8.13 - 8.24 (m, 2H), 8.00 (d, J = 2.1 Hz, 1 H), 7.88 (dd, J = 8.6, 2.1 Hz, 1 H), 7.25 - 7.35 (m, 2H), 7.04 - 7.23 (m, 7H), 6.37 (br. s., 2H), 3.95 (s, 3H), 3.71 - 3.83 (m, 4H), 3.15 - 3.25 (m, 4H). LCMS (m/z) ES+ 603 (m+1 ). EXAMPLE 202

5-{2-amino-3-[4-(4-morpholinyl)phenyl]-4-oxo-3,4-dihydro-6-quinazolin

fluorophenyl)-2-(methyloxy)-3-pyridinesulfonamide

5-{2-amino-3-[4-(4-morpholinyl)phenyl]-4-oxo-3,4-dihydro^

2-(methyloxy)-3-pyridinesulfonamide has been synthesized as described for Example 198, Steps A to C, using 4-fluoro aniline in step A. ¹H NMR (DMSO-d₆) δ: 8.69 (br. s., 1 H), 8.32 (br. s., 1 H), 8.26 (br. s., 1 H), 8.03 (br. s., 1 H), 7.90 (d, J = 8.8 Hz, 1 H), 7.31 (d, J = 8.6 Hz, 1 H), 6.96 - 7.24 (m, 8H), 6.38 (br. s., 2H), 3.99 (s, 3H), 3.77 (br. s., 4H), 3.22 (br. s., 4H). LCMS (m/z) ES+ 603 (m+1 ).

EXAMPLE 203

5-(2-amino-4-oxo-3-phenyl-3,4-dihydro-6-quinazolinyl)-2-chloro-N-phenyl-3- pyridinesulfonamide

Step A

5-bromo-2-ch 3-suifonamide

To 5-bromo-2-chloro-3-pyridinesulfonyl chloride (2 g, 6.87 mmol) in Tetrahydrofuran (THF) (10 mL) was added aniline (0.690 mL, 7.56 mmol) and after 15 minutes of stirring at rt, the volatiles were removed under reduced pressure. The residue was used as is, without further purification. Step B

2-chloro-N-phenyl-5-(4, 4, 5, -2-yi)pyridine-3-sulfonamide

A solution of 5-bromo-2-chloro-N-phenylpyridine-3-sulfonamicle (3 g, 8.63 mmol), bis(pinacolato)diboron (2.411 g, 9.49 mmol), and potassium acetate (2.54 g, 25.9 mmol), and PdCI₂(dppf)-CH₂CI₂ adduct (0.705 g, 0.863 mmol) in 1 ,4-Dioxane (20 mL) was maintained at 100oC in a sealed pressure tube over the weekend. The mixture was cooled, filtered through celite, and the filtrates concentrated and column chromatographed with hexane and ethyl acetate to afford 1g (29%) boronester. MS (ES+) m/z 313 (corresponding boronic acid);

Step C

5-(2-amino-4-oxo-3^henyl-3,4-dihydro-6-quinazolinyl)-2-chloro-N-phenyl-3- pyridinesulfonamide

2-chloro-N-phenyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridine-3-sulfonamide (250 mg, 0.633 mmol), 2-amino-6-iodo-3-phenylquinazolin-4(3H)-one (Example 158 Step I) (253 mg, 0.697 mmol), PdCI₂(dppf)-CH₂CI₂ adduct (51.7 mg, 0.063 mmol), potassium carbonate (88 mg, 0.633 mmol) and 1 ,4-Dioxane (6 mL) stirred at 50 degC for 1 hr. Filtered through a pad of celite, concentrated and purified on HPLC to afford 5-(2-amino-4-oxo-3- phenyl-3,4-dihydroquinazolin-6-yl)-2-chloro-N-phenylpyridine-3-sulfonamide (107 mg, 0.212 mmol, 33.5 % yield). ¹H NMR (DMSO-d₆) δ: 10.95 (none, 1 H), 8.96 (br. s., 1 H), 8.54 (br. s., 1H), 8.16 (br. s., 1H), 8.00 (d, J = 7.6 Hz, 1 H), 7.47 - 7.69 (m, 3H), 7.30 - 7.46 (m, 3H), 7.08 - 7.30 (m, 4H), 7.01 (br. s., 1H), 6.51 (br. s., 2H). LCMS (m/z) ES+ 504 (m+1 ).

EXAMPLE 204

5-{2-amino-4-oxo-3-[2-(trifluoromethyl)phenylJ-3,4-dihydro-6-quinaz

phenyl-3-pyridinesulfonamide

5-{2-amino-4-oxo-3-[2-(trifluoromethyl)phenyl]-3,4-dihydro-6-quinazolinyl}-2-chloro-N- phenyl-3-pyridinesulfonamide was synthesized as described for Example 203 Steps A to C, using 3-fluorobenzylamine in Step A and 2-amino-6-iodo-3-(2-

(trifluoromethyl)phenyl)quinazolin-4(3H)-one (Example 28, Step D) in Step C to afford 12mg (8.3%) of the title compound. ¹H NMR (DMSO-d₆) δ: 8.96 (d, J = 2.3 Hz, 1H), 8.55 (d, J = 2.3 Hz, 1H), 8.12 - 8.19 (m, 2H), 8.02 (dd, J = 8.6, 2.3 Hz, 1 H), 7.96 (d, J = 7.8 Hz, 1H), 7.89 (d, J = 7.6 Hz, 1 H), 7.73 - 7.82 (m, 1H), 7.64 (d, J = 7.8 Hz, 1 H), 7.37 (d, J = 8.8 Hz, 1 H), 7.18 - 7.26 (m, 2H), 7.1 1 - 7.18 (m, 2H), 6.95 - 7.04 (m, 1 H), 6.76 (br. s., 2H). LCMS (m/z) ES+ 572 (m+1).

EXAMPLE 205

N-[5-(2-amino-4-oxo-3-phenyl-3,4-dihydro-6-quinazolinyl)-2-methyl-3- pyridinyljbenzenesulfonamide

Step A

N-(5-bromo-2-me enzenesulfonamide

To 5-bromo-2-methylpyridin-3-amine (509 mg, 2.72 mmol) in Dichloromethane (DCM) (10 mL) was added pyridine (0.220 mL, 2.72 mmol) followed by benzenesulfonyl chloride (0.697 mL, 2.72 mmol) and after 1 hr of stirring at rt, the volatiles were removed under reduced pressure. The volatiles were removed under reduced pressure to give N-(5-bromo-2- methylpyridin-3-yl)benzenesulfonamide (700 mg, 2.139 mmol, 79 % yield).

Step B

N-(2-methyl-5-(4,4,5,5-tetramethyl- -dioxaborolan-2-yl)pyridin-3-yl)benzenes

A solution of N-(5-bromo-2-methylpyridin-3-yl)benzenesulfonamide (690 mg, 2.109 mmol), bis(pinacolato)diboron (589 mg, 2.320 mmol), and potassium acetate (621 mg, 6.33 mmol), and PdCI2(dppf)-CH2CI2 adduct (172 mg, 0.211 mmol) in 1 ,4-Dioxane (20 mL) was maintained at 100oC in a sealed pressure tube over the weekend. The mixture was cooled, filtered through celite, and the filtrates concentrated and column chromatographed with hexane and ethyl acetate. MS (ES+) m/z 293 (corresponding boronic acid)

Step C

To N-(2-methyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridin-3- yl)benzenesulfonamide (227 mg, 0.606 mmol), 2-amino-6-iodo-3-phenylquinazolin-4(3H)- one (Example 158 Step I) (200 mg, 0.551 mmol), and PdCI2(dppf)-CH2CI2 adduct (45.0 mg, 0.055 mmol) was added potassium carbonate (0.826 mL, 1.652 mmol) and 1 ,4-Dioxane (6 mL) and reaction mixture stirred at 90 overnight. Filtered through a pad of celite,

concentrated and the residue was purified with HPLC to give the final compound (40mg, 15%). H NMR (DMSO-d₆) δ: 10.07 (br. s., 1 H), 8.59 (br. s., 1 H), 7.93 (br. s., 1 H), 7.83 (d, J = 8.4 Hz, 1 H), 7.45 - 7.76 (m, 9H), 7.28 - 7.45 (m, 3H), 6.42 (br. s., 2H), 2.21 (s, 3H). LCMS (m/z) ES+ 484 (m+1 ).

EXAMPLE 206

5-(2-amino-4-oxo-3-phenyl-3,4-dihydro-6-quinazolinyl)-2-chloro-N-(3-fto^

pyridinesulfonamide

5-(2-amino-4-oxo-3-pheny!-3,4-dihydro-6-quinazolinyl)-2-chloro-/\/-(3-fluorophenyl)-3- pyridinesulfonamide was synthesized similarly as described for Example 203 Steps A to C, using 3-fluoroaniline in the Step A. Yield 71 mg (25%). ¹H NMR (DMSO-d₆) δ: 11.28 (br. s., 1 H), 8.96 (s, 1 H), 8.60 (d, J = 1.8 Hz, 1H), 8.19 (d, J = 1.4 Hz, 1 H), 7.97 - 8.11 (m, 1H), 7.48 - 7.71 (m, 3H), 7.32 - 7.49 (m, 3H), 7.25 (q, J = 7.9 Hz, 1H), 6.88 - 7.09 (m, 2H), 6.74 - 6.88 (m, 1 H), 6.52 (br. s., 2H). LCMS (m/z) ES+ 522 (m+1 ).

EXAMPLE 207

5-(2-amino-4-oxo-3-phenyl-3,4-dihydro-6-quinazoiinyl)- V-[(2-fluorophenyl)methyl]-2-

(methyloxy)-3-pyridinesulfonamide

5-(2-amino-4-oxo-3-phenyl-3,4-dihydro-6-quinazolinyl)-/V-[(2-fluorophenyl)methyl]-2- (methyloxy)-3-pyridinesulfonamide was synthesized as described for Example 198 Steps A to C, using 2-fluorobenzylamine in Step A and 2-amino-6-iodo-3-phenylquinazolin-4(3H)-one (Example 58 Step I) in Step C affording 69g (23.5%) yield. H NMR (DMSO-d₆) δ: 8.55 (br. s., 1 H), 8.24 (br. s., 1 H), 7.96 - 8.17 (m, 2H), 7.89 (d, J = 7.4 Hz, 1 H), 7.59 (d, J = 6.2 Hz, 5H), 7.24 - 7.47 (m, 6H), 6.95 - 7.23 (m, 2H), 6.87 (br. s., 1H), 6.42 (br. s., 2H), 3.92 (br. s., 3H), 3.34 (br. s., 3H). LCMS (m/z) ES+ 532 (m+1 ). EXAMPLE 208

5-(2-amino-4-oxo-3-phenyl-3,4-dihydro-6-quinazolinyl)-N-[(3-fluorophenyl)m

(methyloxy)-3-pyridinesulfonamide

5-(2-amino-4-oxo-3-phenyl-3,4-dihydro-6-quinazolinyl)-A/-[(3-fluorophenyl)meihyl3-2- (methyloxy)-3-pyridinesulfonamide was synthesized as described for Example 198 Steps A to C, using 3-fluorobenzylamine in Step A and 2-amino-6-iodo-3-phenylquinazolin-4(3H)-one (Example 158 Step I) in Step C, affording 65g (22%) yield. ¹H NMR (DMSO-d₆) δ: 8.58 (d, J = 2.3 Hz, 1H), 8.31 (t, J = 6.3 Hz, 1H), 8.13 (d, J = 2.3 Hz, 1 H), 8.05 (d, J = 2.1 Hz, 1 H), 7.90 (dd, J = 8.6, 2.1 Hz, 1H), 7.47 - 7.70 (m, 3H), 7.37 (dd, J = 14.1 , 7.9 Hz, 3H), 7.12 - 7.23 (m, 1 H), 7.00 (d, J = 8.2 Hz, 2H), 6.85 - 6.95 (m, 1 H), 6.42 (br. s., 2H), 4.18 (d, J = 6.2 Hz, 2H), 3.96 (s, 3H). LCMS (m/z) ES+ 532 (m+1 ).

EXAMPLE 209

5-{2-amino-4-oxo-3-[2-(trifluoromethyl)phenyl]-3,4-dihydro-6-quinazoli

fluorophenyl)methyl]-2-(methyloxy)-3-pyridinesulfonamide

5-{2-amino-4-oxo-3-[2-(trifluoromethyl)phenyl]-3,4-dihydro-6-quinazolinyl}-A/-[(3- fluorophenyl)methyl]-2-(methyloxy)-3-pyridinesulfonamide was synthesized as described for Example 198 Steps A to C, using 3-fluorobenzylamine in Step A and 2-amino-6-iodo-3-(2- (trifluoromethyl)phenyl)quinazolin-4(3H)-one (Example 28, Step D) in Step C, affording 77g (27%) yield. ¹H N R (DMSO-d₆) δ: 8.59 (d, J = 1.6 Hz, 1H), 8.31 (br. s., 1H), 8.14 (d, J = 1.6 Hz, 1H), 8.04 (d, J = 1.2 Hz, 1 H), 7.85 - 8.00 (m, 3H), 7.73 - 7.83 (m, 1 H), 7.64 (d, J = 7.6 Hz, 1H), 7.36 (d, J = 8.4 Hz, 1H), 7.12 - 7.24 (m, 1 H), 7.00 (d, J = 8.2 Hz, 2H), 6.91 (t, J = 8.1 Hz, 1H), 6.67 (br. s., 2H), 4.17 (br. s., 2H), 3.95 (s, 3H). LCMS (m/z) ES+ 600 (m+1 ).

EXAMPLE 210

5-{2-amino-4-oxo-3-[2-(trifluoromethyi)phenyl]-3,4-dihydro-6-quinazolinyl}-N-[(2- fluorophenyi)methyl]-2-(methyloxy)-3-pyridinesuifonamide

5-{2-amino-4-oxo-3-[2-(trifluoromethyl)phenyl]-3,4-dihydro-6-quinazolinyl}-A/-[(2- fluorophenyl)methyl]-2-(methyloxy)-3-pyridinesulfonamide was synthesized as described for Example 198 Steps A to C, using 2-fluorobenzylamine in Step A and 2-amino-6-iodo-3-(2- (trifluoromethyl)phenyl)quinazolin-4(3H)-one (Example 28, Step D) in Step C, affording 112 mg (40%) yield.

¹H NMR (DMSO-d₆) δ: 8.56 (d, J = 1.8 Hz, 1 H), 8.24 (br. s., 1 H), 8.11 (d, J = 1.6 Hz, 1H), 8.03 (d, J = 1.2 Hz, 1 H), 7.96 (d, J = 7.6 Hz, 1 H), 7.85 - 7.94 (m, 2H), 7.73 - 7.83 (m, 1 H), 7.65 (d, J = 7.6 Hz, 1 H), 7.27 - 7.42 (m, 2H), 7.08 - 7.18 (m, 1 H), 6.97 - 7.06 (m, 1H), 6.87 (t, J = 9.2 Hz, 1H), 6.68 (br. s., 2H), 4.21 (br. s., 2H), 3.92 (s, 3H). LCMS (m/z) ES+ 600 (m+1 ).

EXAMPLE 211

2-amino-6-(6-methyl-5-nitro-3-pyridinyl)-3-phenyl-4(3H)-quinazolinone

2-amino-6-(6-methyl-5-nitro-3-pyridinyl)-3-phenyl-4(3H)-quinazolinone was synthesized similarly as described for Example 203 Steps B and C, using 5-bromo-2-methyl-3- nitropyridine in Step B. Yield 435 mg (85%). H NMR (DMSO-d₆) δ: 9.12 (d, J = 2.1 Hz, 1 H), 8.64 (d, J = 2.0 Hz, 1 H), 8.25 (d, J = 2.1 Hz, 1H), 8.08 (dd, J = 8.6, 2.3 Hz, 1 H), 7.48 - 7.70 (m, 4H), 7.38 (dd, J = 10.2, 7.9 Hz, 4H), 2.76 (s, 3H). LCMS (m/z) ES+ 374 (m+1 ).

EXAMPLE 212

5-{2-amino-4-oxo-3-[2-(trifluoromethyl)phenyl]-3,4-dihydro-6-qu

fluorophenyl)methyl]-2-(methyloxy)-3-pyridinesulfonamide

5- {2-amino-4-oxo-3-[2-(trifluoromethyl)phenyl3-3,4-dihydro-6-quinazolinyl}-A-[(4- fluorophenyl)methyl]-2-(methyloxy)-3-pyridinesulfonamide was synthesized similarly as described for Example 198 Steps A to C, using 4-fluorobenzylamine in Step A and 2-amino-

6- iodo-3-(2-(trifluoromethyl)phenyl)quinazolin-4(3H)-one (Example 28, Step D) in Step C, affording 77 mg (27%) yield. ¹H NMR (D SO-d₆) δ: 8.60 (d, J = 1.6 Hz, 1 H), 8.24 (br. s., 1H), 8.10 (br. s., 1H), 8.04 (s, 1H), 7.85 - 8.01 (m, 3H), 7.73 - 7.84 (m, 1H), 7.65 (d, J = 7.8 Hz, 1H), 7.36 (d, J = 8.6 Hz, 1 H), 7.13 - 7.30 (m, 2H), 6.95 (t, J = 8.7 Hz, 2H), 6.67 (br. s., 2H), 4.14 (br. s., 2H), 3.96 (s, 3H). LCMS (m/z) ES+ 600 (m+1 ).

EXAMPLE 213

5-(2-amino-4-oxo-3-phenyl-3,4-dihydro-6-quinazolinyl)-N-[(4-fluoropheny

(methyloxy)-3-pyridinesulfonamide

5-(2-amino-4-oxo-3-phenyl-3,4-dihydro-6-quinazolinyl)-A/-[(4-fluorophenyl)m

(methyloxy)-3-pyridinesulfonamide was synthesized similarly as described for Example 198 Steps A to C, using 4-fluorobenzylamine in Step A and 2-amino-6-iodo-3-phenylquinazolin- 4(3H)-one (Example 158 Step I) in Step C, affording 124 mg (42%) yield. ¹H NMR (DMSO- d₆) 5: 8.59 (d, J = 2.3 Hz, 1 H), 8.24 (br. s., 1 H), 8.09 (d, J = 2.5 Hz, 1 H), 8.05 (d, J = 2.1 Hz, 1H), 7.90 (dd, J = 8.7, 2.2 Hz, 1 H), 7.50 - 7.63 (m, 3H), 7.37 (dd, J = 13.0, 7.9 Hz, 3H), 7.19 (dd, J = 8.6, 5.7 Hz, 2H), 6.94 (t, J = 8.9 Hz, 2H), 6.41 (br. s., 2H), 4.14 (d, J = 3.7 Hz, 2H), 3.96 (s, 3H). LCMS (m/z) ES+ 532 (m+1 ).

EXAMPLE 214

5-(2-amino-4-oxo-3-phenyl-3,4-dihydro-6-quinazolinyl)-N-(2,5-difluoroph

(methyloxy)-3-pyridinesulfonamide

5-(2-amino-4-oxo-3-phenyl-3,4-dihydro-6-quinazolinyl)-A7-(2,5-difluorophenyl)-2-(methyloxy)- 3-pyridinesulfonamide was synthesized similarly as described for Example 198 Steps A to C, using 2,4-difluoroaniline in Step A and 2-amino-6-iodo-3-phenylquinazolin-4(3H)-one (Example 158 Step I) in Step C, affording 124 mg (42%) yield. H NMR (DMSO-d₆) δ: 10.52 (br. s., 1 H), 8.75 (br. s., 1 H), 8.26 (br. s., 1 H), 8.05 (br. s., 1 H), 7.93 (d, J = 8.6 Hz, 1 H), 7.47 - 7.67 (m, 3H), 7.31 - 7.44 (m, 3H), 7.12 - 7.30 (m, 2H), 7.05 (br. s., 1 H), 6.43 (br. s., 2H), 3.93 (s, 3H). LCMS (m/z) ES+ 536 (m+1 ).

EXAMPLE 215

5-(2-amino-4-oxo-3-phenyl-3,4-dihydro-6-quinazolinyl)-N-(3,4-difluorophenyl)-2-

(methyloxy)-3-pyridinesulfonamide

5-(2-amino-4-oxo-3-phenyl-3,4-dihydro-6-quinazolinyl)-A/-(3,4-difluorophenyl)-2-(m

3-pyridinesulfonamide was synthesized similarly as described for Example 198 Steps A to C, using 3,4-difluoroaniline in Step A and 2-amino-6-iodo-3-phenylquinazolin-4(3H)-one {Example 158 Step I) in Step C. ¹H NMR (DMSO-d₆) δ: 10.64 (br. s., 1H), 8.73 (d, J = 2.1 Hz, 1H), 8.35 (d, J = 2.1 Hz, 1 H), 8.07 (d, J = 1.8 Hz, 1 H), 7.94 (dd, J = 8.6, 2.0 Hz, 1H), 7.47 - 7.69 (m, 3H), 7.22 - 7.46 (m, 4H), 7.15 (ddd, J = 12.0, 7.2, 2.2 Hz, 1H), 6.96 (d, J = 8.8 Hz, 1H), 6.43 (br. s., 2H), 3.99 (s, 3H). LCMS (m/z) ES+ 536 (m+1 ).

EXAMPLE 216

5-(2-amino-4-oxo-3-phenyl-3, 4-dihydro-6-quinazolinyl)-2-chloro-N-(1, 1-dimethylethyl)-

3-pyridinesulfonamide

5-(2-amino-4-oxo-3-phenyl-3,4-dihydro-6-quinazolinyl)-2-chloro-A/-(1 ,1-dimethylethyl)-3- pyridinesulfonamide was synthesized similarly as described for Example 203 Steps A to C, using terf-butylamine in the Step A. Yield 201 mg (72%). H NMR (DMSO-d₆) δ: 8.99 (br. 1H), 8.55 (br. s., 1 H), 7.91 - 8.40 (m, 3H), 7.13 - 7.80 (m, 6H), 6.52 (br. s., 2H), 1.16 (br. 9H). LCMS (m/z) ES+ 484 (m+1 ).

General Scheme 19

EXAMPLE 217

2-amino-6-{6-(methyloxy)-5-[(phenylmethyl)sulfinyl]-3-pyridinyl}-3-pheny

Step A

3-(benzylthio)-5-bromo-2-chloropyridine

5-bromo-2-chloropyridin-3-amine (2 g, 9.64 mmol) and 1 ,2-dibenzyldisulfane (2.61 g, 10.60 mmol) in acetonitrile (10 mL) heated to 80 degC. isopentyl nitrite (3.27 mL, 19.28 mmol) was slowly added and after 30 minutes the reaction mixture was cooled to rt and concentrated to afford 3-(benzylthio)-5-bromo-2-chloropyridine in quantitative yield. Used without further purification. MS (ES+) m/z 315.

Step B

3-(benzylsulfi chloropyridine

3-(benzylthio)-5-bromo-2-chloropyridine (1 g, 3.18 mmol) in dichloromethane (DCM) (20 mL) was added m-CPBA (1.097 g, 6.36 mmol) in DCM. Stirred at rt overnight. Reaction mixture was diluted further with DCM and washed with sodium bicarbonate, dried over sodium sulfate and concentrated. The residue was purified on silicagel eluted with hexane and ethyl acetate to give 3-(benzylsulfinyl)-5-bromo-2-chloropyridine (332 mg, 1.004 mmol, 31.6 % yield). MS (ES+) m/z 332; *H NMR (400MHz ,CHLOROFORM-d) δ = 8.46 (d, J= 2.3 Hz, 1 H), 7.71 (d, J = 2.3 Hz, 1 H), 7.37 - 7.21 (m, 3 H), 7.05 - 6.96 (m, 2 H), 4.33 (d, J= 13.5 Hz, 1 H), 4.11 (d, J = 13.3 Hz, 1 H)

Step C

3-(benzylsulfinyl)-5-bromo-2-methoxypyridine

3-(benzylsulfinyl)-5-bromo-2-chloropyridine (320 mg, 0.968 mmol) in Methanol (5 mL) was added sodium methoxide (5 mL, 0.968 mmol) and the reaction mixture stirred at rt for 2 nr. Concentrated and ethyl acetate was added and washed with 1 N HCI and brine and dried over sodium sulfate. Concentrated to give 3-(benzylsulfinyl)-5-bromo-2-methoxypyridine (294 mg, 0.901 mmol, 93 % yield). MS (ES+) m/z 326,328; 'H NM (400MHz

,CHLOROFORM-d) δ = 8.22 (d, J= 2.5 Hz, 1 H), 7.73 (d, J= 2.3 Hz, 1 H), 7.35 - 7.21 (m, 3 H), 7.08 - 6.96 (m, 2 H), 4.27 (d, J= 13.1 Hz, 1 H), 4.07 - 3.95 (m, 4 H)

Step D

3-(benzylsulfinyl)-2-methoxy-5- -tetramethyl- 1,3, 2-dioxaborolan-2-yl)pyridine

A solution of 3-(benzylsulfinyl)-5-bromo-2-methoxypyridine (290 mg, 0.889 mmol), bis(pinacolato)diboron (248 mg, 0.978 mmol), potassium acetate (262 mg, 2.67 mmol), and PdCI₂(dppf)-CH₂CI₂ adduct (72.6 mg, 0.089 mmol) in 1 ,4-Dioxane (20 mL) was maintained at 100 degC in a sealed pressure tube over the weekend. The mixture was cooled, filtered through Celite, and the filtrates concentrated to give 3-(benzylsulfinyl)-2-methoxy-5-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridine. MS (ES+) m/z 374; Used in the next reaction without purification.

Step E

2-amino-6-{6-(methyloxy)-5-[( henylmethyl)sulfinyί]-3 yridinyl}-3

quinazolinone

3-(benzylsulfinyl)-2-methoxy-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridi (234 mg, 0.627 mmol), 2-amino-6-iodo-3-phenylquinazolin-4(3H)-one (Example 158 Step I) (150 mg, 0.413 mmol), PdCI₂(dppf)-CH₂CI₂ adduct (33.7 mg, 0.041 mmol), potassium carbonate (0.620 mL, 1.239 mmol) and 1 ,4-Dioxane (6 mL) stirred at 50 degC for 1 hr. Filtered through a pad of celite, concentrated and purified on HPLC to afford 2-amino-6-(5-(benzylsulfinyl)-6- methoxypyridin-3-yl)-3-phenylquinazolin-4(3H)-one (62 mg, 0.128 mmol, 31.1 % yield). ¹H NMR (DMSO-d₆) δ: 8.59 (d, J = 2.3 Hz, 1 H), 7.90 (d, J = 2.0 Hz, 1H), 7.83 (dd, J = 8.6, 2.0 Hz, 1H), 7.49 - 7.69 (m, 4H), 7.32 - 7.47 (m, 3H), 7.17 - 7.31 (m, 3H), 6.98 (dd, J = 6.0, 3.3 Hz, 2H), 6.43 - 6.92 (m, 2H), 4.43 (d, J = 13.1 Hz, 1H), 4.11 (d, J = 13.1 Hz, 1 H), 4.03 (s, 3H). LCMS (m/z) ES+ 483 (m+1 ).

EXAMPLE 218

2-amino-6-{6-(methyloxy)-5-[(phenylsulfonyl) thyl]-3^yridinyi}-3-ph

quinazolinone

2-amino-6-{6-(methyloxy)-5-[(phenylsulfonyl)methyl]-3-pyridinyl}-3-phenyl-4(3/-/)- quinazolinone was synthesized similarly as described for Example 203 step B and C, using 5-bromo-2-methoxy-3-((phenylsulfonyl)methyl)pyridine in Step B. Yield 104 mg (45%). H NMR (D SO-d₆) δ: 8.46 (d, J = 2.3 Hz, 1 H), 8.00 (d, J = 2.1 Hz, 1H), 7.82 - 7.91 (m, 2H), 7.71 - 7.79 (m, 1 H), 7.64 - 7.71 (m, 2H), 7.49 - 7.64 (m, 5H), 7.37 (dd, J = 19.0, 7.9 Hz, 3H), 6.38 (br. s., 2H), 4.68 (s, 2H), 3.53 (s, 3H). LCMS (m/z) ES+ 499 (m+1). EXAMPLE 219

2-amino-6-{6-(methyfoxy)-5-[(phenylmethyl)sulfonyl]-3-pyridinyl}-3-phenyi-4(3^ quinazolinone

Step A

3-(benzylsulfo chloropyridine

3-(benzylthio)-5-bromo-2-chloropyridine (3.5 g, 11.12 mmol) (Example 217, Step A) in Dichloromethane (DCM) (20 mL) was added m-CPBA (7.68 g, 44.5 mmol) in DCM. Stirred at rt overnight. LC S showed a mixture of the sulfone and sulfoxide. The reaction mixture was heated to 55oC for 4 hrs. No change observed in LCMS. The reaction mixture was cooled to rt and washed with sodium bicarbonate, brine and dried over sodium sulfate. The residue was purified on silicagel eluting with hexane and ethyl acetate to give 125mg (11 %) product. LCMS (m/z) ES+ 347 (m+1).

Step B

2-amino-6-{6-(methyloxy)-5-[( henylmethyl)sulfonyί]-3 yridinyl}-3

quinazolinone

2- amino-6-{6-(methyloxy)-5-[(phenylmethyl)sulfonyl]-3-pyridinyl}-3-phenyl-4(3/- )- quinazolinone was synthesized similarly as described for Example 217 Steps C to E, using

3- (benzylsulfonyl)-5-bromo-2-chloropyridine in Step C. Yield 103mg (53%). H NMR

(DMSO-d₆) δ: 8.81 (d, J = 2.3 Hz, 1 H), 8.03 (d, J = 2.3 Hz, 1 H), 7.97 (d, J = 2.3 Hz, 1 H), 7.87 (dd, J = 8.6, 2.3 Hz, 1 H), 7.49 - 7.64 (m, 3H), 7.18 - 7.43 (m, 8H), 6.42 (br. s., 2H), 4.82 (s, 2H), 4.14 (s, 3H). LCMS (m/z) ES+ 499 (m+1 ). EXAMPLE 220

5-(2-amino-4-oxo-3-phenyl-3,4-dihydro-6-quinazoHnyl)-2-(methyto^

pyridinesulfonamide

5-(2-amino-4-oxo-3-phenyl-3,4-dihydro-6-quinazolinyl)-2-(methyloxy)-A/-3-p

pyridinesulfonamide has been synthesized analogously as described for Example 198, Steps A to C, using 3-aminopyridine in step A. ¹H NMR (DMSO-d₆) δ: 10.67 (br. s., 1 H), 8.73 (d, J = 1.8 Hz, 1 H), 8.34 (br. s., 2H), 8.23 (d, J = 3.9 Hz, 1 H), 8.07 (s, 1 H), 7.94 (d, J = 8.4 Hz, 1 H), 7.48 - 7.71 (m, 4H), 7.15 - 7.47 (m, 4H), 6.42 (br. s., 2H), 3.97 (s, 3H). LCMS (m/z) ES+ 501 (m+1).

EXAMPLE 221

5-(2-amino-4-oxo-3-phenyl-3,4-dihydro-6-quinazolinyl)-2-chloro-N-(phenylmethyl)-3- pyridinesulfonamide

5-(2-amino-4-oxo-3-phenyl-3,4-dihydro-6-quinazolinyl)-2-chloro-A/-(phenylmethyl)-3- pyridinesulfonamide was synthesized similarly as described for Example 203 Steps A to C, using benzylamine in Step A. Yield 38mg (13%). H NMR (DMSO-d₆) δ: 8.83 (d, J = 2.3 Hz, 1 H), 8.79 (br. s., 1 H), 8.24 (d, J = 2.3 Hz, 1H), 8.13 (d, J = 2.1 Hz, 1H), 7.95 (dd, J = 8.7, 2.2 Hz, 1 H), 7.50 - 7.66 (m, 3H), 7.30 - 7.47 (m, 3H), 7.17 - 7.24 (m, 2H), 7.13 (t, J = 7.4 Hz, 2H), 7.01 - 7.10 (m, 1 H), 6.50 (br. s., 2H), 4.21 (s, 2H). LCMS (m/z) ES+ 518 (m+1 ). EXAMPLE 222

5-(2-amino-4-oxo-3-phenyl-3,4-dihydro-6-quinazolinyl)-2-(methyloxy)-

3-pyridinesulfonamide

5-(2-amino-4-oxo-3-phenyl-3,4-dihydro-6-quinazolinyl)-2-(m

pyridinesulfonamide has been synthesized analogously as described for Example 198, Steps A to C, using 5-aminopyrimidine in step A. Yield 69mg (25%); H NMR (D SO-d₆) δ: 10.95 (br. s., 1H), 8.87 (br. s., 1H), 8.68 - 8.79 (m, 1 H), 8.59 (br. s., 1H), 8.41 (br. s., 1 H), 8.10 (br. s., 1 H), 7.49 - 7.67 (m, 4H), 7.29 - 7.49 (m, 4H), 6.42 (br. s., 2H), 3.91 (br. s., 3H). LCMS (m/z) ES+ 502 (m+1 ).

EXAMPLE 223

5-(2-amino-4-oxo-3^henyl-3,4-dihydro-6-quinazolinyl)-N-(4-chloro-3-pyrffl

(methyloxy)-3-pyridinesulfonamide

5-(2-amino-4-oxo-3-phenyl-3,4-dihydro-6-quinazolinyl)-/\/-(4-chloro-3-pyridinyl)-2- (methyloxy)-3-pyridinesulfonamide has been synthesized analogously as described for Example 198, Steps A to C, using 3-amino-4-chloropyridine in step A. Yield 128mg (97%); *H NMR (DMSO-d₆) δ: 10.52 (br. s., IH), 8.75 (d, J = 2.1 Hz, 1H), 8.51 (s, 1H), 8.34 (d, J = 4.7 Hz, 1H), 8.21 (d, J = 2.3 Hz, IH), 8.03 (d, J = 2.1 Hz, 1H), 7.92 (dd, J = 8.6, 2.3 Hz, 1H), 7.43 - 7.68 (m, 4H), 7.35 (dd, J = 14.9, 7.9 Hz, 3H), 6.42 (br. s., 2H), 3.86 (s, 3H). LCMS (m/z) ES+ 535 (m+1 ).

EXAMPLE 224 2-amino-6-[6-(methyloxy)-5-(phenylsulfonyl)-3-pyridinyl]-3-phenyl-4(3H)-quin

2- amino-6-[6-(methyloxy)-5-(phenylsulfon was synthesized similarly as described for Example 219 Steps A and B, using 5-bromo-2-chloro-

3- (phenylthio)pyridine in Step A. Yield 35 mg (13%). ¾ NMR (DMSO-d₆) δ: 8.81 (d, J = 2.3 Hz, IH), 8.58 (d, J = 2.3 Hz, 1H), 8.12 - 8.27 (m, 2H), 8.03 (d, J = 7.8 Hz, 2H), 7.69 - 7.82 (m, 1H), 7.46 - 7.69 (m, 5H), 7.27 - 7.47 (m, 3H), 6.44 (br. s., 2H), 3.89 (s, 3H). LCMS (m/z) ES+ 485 (m+1).

EXAMPLE 225

5-(2-amino-4-oxo-3^henyl-3,4-dihydro-6-quinazolinyl)-N-(3-fluoro-4-pyrffl

(methyloxy)-3-pyridinesulfonamide

5-(2-amino-4-oxo-3-phenyl-3,4-dihydro-6-quinazolinyl)-/V-(3-fluoro-4-pyridinyl)-2- (methyloxy)-3-pyridinesulfonamide has been synthesized analogously as described for Example 198, Steps A to C, using 3-fluoro-4-aminopyridine in step A. Yield 9mg (9%); Ή NMR (DMSO-d₆) δ: 8.64 (d, J = 2.3 Hz, IH), 8.36 (d, J = 2.5 Hz, 1H), 8.32 (d, J = 4.9 Hz, 1H), 8.08 (d, J = 2.3 Hz, IH), 7.92 - 8.00 (m, 2H), 7.48 - 7.63 (m, 5H), 7.31 - 7.43 (m, 3H), 6.40 (br. s., 2H), 3.87 (s, 3H). LCMS (m/z) ES+ 519 (m+1).

EXAMPLE 226

5-(2-amino-4-oxo-3-phenyl-3,4-dihydro-6-quinazolinyl)-N-phenyl-2,3-dihydro-1- benzofuran-7-sulfonamide

5-(2-amino-4-oxo-3-phenyl-3,4-dihydro-6-quinazolinyl)-/V-phenyl-2,3-dihydro-1-benzofuran- 7-sulfonamide was synthesized similarly as described for Example 203 Steps A to C, using aniline in Step A. Yield 58 mg (33%). ¾ NMR (DMSO-d₆) δ: 10.34 (br. s., 1H), 8.00 (d, J = 1.6 Hz, 1H), 7.74 - 7.89 (m, 2H), 7.67 (s, 1H), 7.49 - 7.64 (m, 3H), 7.27 - 7.44 (m, 3H), 7.09 - 7.26 (m, 4H), 6.88 - 7.04 (m, 1H), 6.36 (br. s., 2H), 4.70 (t, J = 8.6 Hz, 2H), 3.27 (t, 2H). LC S (m/z) ES+ 511 (m+1 ).

Example 227

5-(2-amino-3-(3-((dimethylamino)methyl)phenyl)-4-oxo-3,4-dihydroquinazoli

meth ide

Step A

(6-bromo-3-{3-[(dimethylamino)methyl]phenyl}-4-oxo-3,4-di

A suspension of methyl 5-bromo-2-{[(cyanoamino)(phenyloxy)methylidene]amino}benzoate (.200 g, 0.534 mmol) in iPrOH (2.67 ml) was treated with 3-[(dimethylamino)methyl]aniline (0.084 g, 0.561 mmol) and DMAP (0.026 g, 0.214 mmol) and was heated in a sealed tube to 85 °C for 2 hours. Additional 3-[(dimethylamino)methyl]aniline (0.084 g, 0.561 mmol) was added and the reaction was heated overnight. After cooling to room temperature, the reaction was diluted with 1 :1 (Et₂0 /hexanes). The solids were filtered, rinsing with Et₂0 /hexanes to give the title product as a solid (.032 g). The reaction was redone due to low recovery.

A suspension of methyl 5-bromo-2-{[(cyanoamino)(phenyloxy)methylidene]amino}benzoate (.200 g, 0.534 mmol) in iPrOH (2.67 ml) was treated with 3-[(dimethylamino)methyl]aniline (0.168 g, 1.12 mmol) and DMAP (0.026 g, 0.214 mmol) was heated in a sealed tube to 85 °C. After cooling to room temperature, the reaction was diluted with 1 :1 (Et₂0 /hexanes). The solids were filtered, rinsing with Et₂0 /hexanes to give the title product as a solid (0.072 g) which was combined with the previously isolated batch to give (6-bromo-3-{3-

[(dimethylamino)methyl]phenyl}-4-oxo-3,4-dihydro-2-quinazolinyl)cyanamide (0.104 g, 49%). ES-LCMS: 397.99, 399.88 (M+1 )

Step B

2-amino-6-bromo-3-{3-[(dimethylamino)methyl]phenyt}-4(3H)-quinazolino

A solution (6-bromo-3-{3-[(dimethylamino)methyl]phenyl}-4-oxo-3,4-dihydro-2- quinazolinyl)cyanamide (0.091 g, .228 mmol) in 4N in dioxanes HCI (4.05 mL) was treated with water (1.23 mL) and then treated by the addition of concentrated HCI (100 uL) and heated to 90 °C with an open air reflux condenser. The reaction was concentrated and the solid was concentrated from toluene (3x) to give 2-amino-6-bromo-3-{3-[(dimethylamino)methyl]phenyl}- 4(3H)-quinazolinone (0.082 g, 96%). ES-LCMS: 374.05, 376.06 (M+1 )

Step C

5-(2-amino-3-(3-((dimethylamino)methyl)phenyi)-4-oxo-3,4-dihydroqu

N-phenylpyridine-3-sulfonamide

A solution of 2-amino-6-bromo-3-{3-[(dimethylamino)methyl]phenyl}-4(3H)-quinazolinone (.085 g, 0.228 mmol), 2-(methyloxy)-N-phenyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-3- pyridinesulfonamide (0.178 g, 0.455 mmol), K₂C0₃ (0.094 g, 0.683 mmol), and PdCI₂(dppf)- DCM adduct (0.019 g, 0.023 mmol) in 1 ,4-dioxane (4.74 ml) and water (4.74 ml) was heated to 80 °C overnight. The reaction was cooled to room temperature and diluted with EtOAc. The combined organics were washed with brine, dried over Na₂S0₄, filtered, and concentrated. The crude residue was purified by reverse phase chromatography (10-90% ACN/ H₂0 + formic acid) to give 5-(2-amino-3-(3-((dimethylamino)methyl)phenyl)-4-oxo-3,4-dihydroquinazolin-6-yl)-2- methoxy-N-phenylpyridine-3-sulfonamide (0.014 g, 11 %). H NMR (400 MHz, DMSO-d₆) δ ppm 8.70 (s, 1 H), 8.30 (s, 1 H), 8.04 (s, 1 H), 7.89 - 7.96 (m, 1 H), 7.50 - 7.56 (m, 1 H), 7.44 (d, J=7.51 Hz, 1 H), 7.33 (d, J=8.58 Hz, 1 H), 7.18 - 7.27 (m, 4 H), 7.1 1 - 7.15 (m, 2 H), 6.95 - 7.02 (m, 1 H), 6.45 (br. s., 2 H), 4.00 (s, 3 H), 3.46 (s, 3 H), 2.18 (s, 6 H); ES-LCMS: 557.15 (M+1)

Example 228

N-[5-{2-amino-3-[3-(4-morpholinyl)phenyl]-4-oxo-3,4-dihydro-6-quinazolinyl}-2- (methyloxy)-3-pyridinyl]-2,4-difluorobenzenesuIfonamide

Step A

{6-bromo-3-[3-(4-morpholinyl)phenyl]-4-oxo-3,4-dihydro-2-quinazolinyl}cyanam

A suspension of methyl 5-bromo-2-{[(cyanoamino)(phenyloxy)methylidene]amino}benzoate (.300 g, 0.802 mmol) in iPrOH (7.36 ml) was treated with [3-(4-morpholinyl)phenyl]amine (0.157 g, 0.882 mmol) and DMAP (0.039 g, 0.321 mmol) was heated in a sealed tube to 85 °C overnight. After cooling to room temperature, the solids were filtered, rinsing with Et₂0 to give {6-bromo-3-[3-(4-morpholinyl)phenyl]-4-oxo-3,4-dihydro-2-quinazolinyl}cyanamide (0.128 g, 37.5%) as a light yellow solid. ES-LC S: 426.10, 428.06 (M+1)

Step B

2-amino-6-bromo-3-[3- -morpholinyt)phenyl]-4(3H)-quinazoiinone

A solution of {6-bromo-3-[3-(4-morpholinyl)phenyl]-4-oxo-3,4-dihydro-2-quinazolinyl}cyanamide (.128 g, 0.300 mmol) in H₂0 (1.623 ml, 90 mmol) and 4N in dioxanes HCI (5.32 ml, 21.29 mmol) was heated to 90 °C with an open air reflux condenser for 1 hour. The reaction was

concentrated under reduced pressure to give 2-amino-6-bromo-3-[3-(4-morpholinyl)phenyl]- 4(3H)-quinazolinone (0.120 g, 100%, assumed quantitative). ES-LCMS: 402.04, 404.04 (M+1)

Step C

N-[5-{2-amino-3-[3-(4-morpholinyl)phenyl]-4-oxo-3,4-dihydro-6-qui

pyridinyl]-2,4-difluorobenzenesulfonamide

A solution of 2-amino-6-bromo-3-[3-(4-morpholinyl)phenyl]-4(3H)-quinazo inone (.120 g, 0.299 mmol), 2,4-difluoro-N-[2-(methyloxy)-5-(4_J4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-3- pyridinyl]benzenesulfonamide (0.140 g, 0.329 mmol), K₂C0₃ (0.124 g, 0.897 mmol), and PdCI₂(dppf)-DCM adduct (0.024 g, 0.030 mmol) in 1 ,4-dioxane (6.23 ml) and water (6.23 ml) was heated to 80 °C overnight. The reaction was cooled to room temperature and diluted with EtOAc. The combined organics were washed with brine, dried over Na₂S0₄, filtered, and concentrated. The crude residue was purified by reverse phase chromatography (10-90% ACN/ H₂0 + formic acid) to give N-[5-{2-amino-3-[3-(4-morpholinyl)phenyl]-4-oxo-3,4-dihydro-6- quinazolinyl}-2-(methyloxy)-3-pyridinyl]-2,4-difluorobenzenesulfonamide (0.022 g, 12%). ¹H N R (400 MHz, DMSO-af₆) δ ppm 8.29 (s, 1 H), 8.13 (s, 1 H), 8.01 (s, 1 H), 7.81 - 7.90 (m, 2 H), 7.71 - 7.80 (m, 1 H), 7.51 - 7.61 (m, 1 H), 7.38 - 7.44 (m, 1 H), 7.29 - 7.36 (m, 1 H), 7.16 - 7.23 (m, 1 H), 7.05 - 7.12 (m, 1 H), 6.94 (s, 1 H), 6.73 - 6.79 (m, 1 H), 6.35 (br. s., 2 H), 3.70 - 3.77 (m, 4 H), 3.65 (s, 3 H), 3.18 (br. s., 4 H); ES-LCMS: 621.19 (M+1 )

Example 229

5-[2-amino-3-(cyclopropylmethyl)-4-oxo-3,4-dihydro-6-quinazolinyl]-2-(methyloxy)-N- phenyl-3-pyridinesulfonamide

5-[2-amino-3-(cyclopropylmethyl)-4-oxo-3,4-dihydro-6-quinazolinyl]-2-(m

pyridinesulfonamide A solution of 2-amino-6-bromo-3-(cyclopropylmethyl)-4(3H)-quinazolinone (.090 g, 0.306 mmol),

2- (methyloxy)-N-phenyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-3-pyriclinesulfonamicle (0.179 g, 0.459 mmol), K₂C0₃ (0.127 g, 0.918 mmol), and PdCI₂(dppf)-DCM adduct (0.025 g, 0.031 mmol) in 1 ,4-dioxane (6.37 ml) and water (6.37 ml) was heated to 80 °C for 1 hour. The reaction was cooled to room temperature and diluted with EtOAc. The combined organics were washed with brine, dried over Na₂S0₄, filtered, and concentrated. The crude residue was purified by reverse phase chromatography (10-90% ACN/ H₂0 + formic acid) to give 5-[2-amino-

3- (cyclopropylmethyl)-4-oxo-3,4-dihydro-6-quinazolinyl]-2-(methyloxy)-N-phenyl-3- pyridinesulfonamide (0.077 g, 53%). ¹H NMR (400 MHz, DMSO- ₆) δ ppm 10.41 (br. s., 1 H), 8.70 (d, J=2.44 Hz, 1 H), 8.30 (d, J=2.54 Hz, 1 H), 8.05 (d, J=2.15 Hz, 1 H), 7.84 - 7.90 (m, 1 H), 7.11 - 7.29 (m, 7 H), 6.93 - 7.03 (m, 1 H), 4.00 (s, 3 H), 3.94 - 3.99 (m, 2 H), 1.21 - 1.31 (m, 1 H), 0.37 - 0.50 (m, 4 H); ES-LCMS: 478.19 (M+1 )

Example 230

5-(2-amino-3-(3-fluorophenyl)-4-oxo-3,4-dihydroquinazolin-6-yl)-2-methoxy-N-

Step A

3-(3-fIuorophenyl)-6-iodo-2-thioxo-2,3-dihydroquinazoiin-4(1H)-one

A solution of 2-amino-5-iodobenzoic acid (2.6 g, 9.88 mmol) and 1-fluoro-3- isothiocyanatobenzene (1.192 ml, 9.88 mmol) and TEA (2.067 ml, 14.83 mmol) in EtOH (46.2 ml) was heated to reflux overnight. After cooling to room temperature, the solids were filtered, rinsing with EtOH to yield 3-(3-fluorophenyl)-6-iodo-2-thioxo-2,3-dihydroquinazolin-4(1 H)-one (2.88 g, 7.23 mmol, 73.2 % yield). ES-LCMS: 398.95 (M+1)

Step B

2-chloro-3-(3-fluorophenyl)-6-iodoquinazolin-4(3H)-one

A solution of 3-(3-fluorophenyl)-6-iodo-2-thioxo-2,3-dihydroquinazolin-4(1 H)-one (2.88 g, 7.23 mmol) in POCI₃ (16.18 ml, 174 mmol) and PCI₅ (2.410 g, 1 1.57 mmol) was heated to 115 °C overnight. The reaction was then concentrated under reduced pressure and the residue was taken up in EtOAc, washed with water (2x), brine, dried over Na₂S0₄, filtered, and concentrated to give 2-chloro-3-(3-fluorophenyl)-6-iodoquinazolin-4(3H)-one (3.28 g, 8.19 mmol, 113 % yield). ES-LCMS: 400.86 (M+1 )

Step C

3-(3-f/uorop/7e/7y/)-6-/odo-2-((4-mei 7oxybenzy/)am/nojqu/nazo//n-4(3/-/j-one

A solution of 2-chloro-3-(3-fluorophenyl)-6-iodoquinazolin-4(3H)-one (3.28 g, 8.19 mmol) in DMF (37.6 ml) was treated by the addition of 4-methoxybenzylamine (1.177 ml, 9.01 mmol) and DIEA (2.145 ml, 12.28 mmol) was heated to 80 °C 48 hours. The reaction was cooled to room temperature and diluted with EtOAc and washed with 5% LiCI (3x), brine, dried over Na₂S0₄, filtered, and concentrated to give 3-(3-fluorophenyl)-6-iodo-2-((4- methoxybenzyl)amino)quinazolin-4(3H)-one (3.61 g, 7.20 mmol, 88 % yield) as a tan solid. LCMS: 502.06 (M+1)

Step D

2-amino-3-(3-fluorophenyl)-6-iodoquinazolin-4(3H)-one

A solution of 3-(3-fluorophenyl)-6-iodo-2-((4-methoxybenzyl)amino)quinazolin-4(3H)-one (1.19 g, 2.374 mmol) in TFA (11.87 ml) was heated to 140 °C in the microwave for 15 minutes. After cooling to room temperature, the solvents were removed under reduced pressure. The residue was taken up in DCM, washed with saturated NaHC0₃ (3x), brine, the solid was filtered; the organics were dried over Na₂S0₄, filtered, and concentrated. The crude residue was triturated with Et₂0 and combined with the solids to give 2-amino-3-(3-fluorophenyl)-6-iodoquinazolin- 4(3H)-one (.685 g, 1.797 mmol, 76 % yield). ES-LCMS: 381.98 (M+1)

Step E

5-[2-amino-3-(cyclopropylmethyl)-4-oxo-3 -dihydro-6-quinazo

A solution of 2-amino-3-(3-fluorophenyl)-6-iodoquinazolin-4(3H)-one (.100 g, 0.262 mmol), 2- methoxy-N-phenyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridine-3-sulfonamide (0.102 g, 0.262 mmol), PdCI₂(dppf)-DCM adduct (0.021 g, 0.026 mmol), K₂C0₃ (0.109 g, 0.787 mmol) in 1 ,4-dioxane (5.47 ml) and water (5.47 ml) was heated to 80 °C overnight. After cooling to room temperature, the reaction was diluted with EtOAc, washed with brine, dried over Na₂S0₄, filtered, and concentrated. The crude residue was purified by reverse phase chromatography (10-90% ACN/ H₂0 + formic acid) to give 5-(2-amino-3-(3-fluorophenyl)-4-oxo-3,4- dihydroquinazolin-6-yl)-2-methoxy-N-phenylpyridine-3-sulfonamide (.043 g, 0.083 mmol, 31.7 % yield) as a solid. ¹H N R (400 MHz, DMSO-d₆) δ ppm 10.43 (br. s., 1 H), 8.69 (d, J=2.24 Hz, 1 H), 8.29 (d, J=2.24 Hz, 1 H), 8.04 (d, J=1.95 Hz, 1 H), 7.92 (dd, J=8.59, 2.05 Hz, 1 H), 7.61 (d, J=6.73 Hz, 1 H), 7.35 - 7.42 (m, 2 H), 7.32 (d, J=8.58 Hz, 1 H), 7.17 - 7.26 (m, 3 H), 7.09 - 7.16 (m, 2 H), 6.95 - 7.02 (m, 1 H), 6.58 (br. s., 2 H), 4.00 (s, 3 H); ES-LCMS: 518.16 (M+1)

Example 231

N-(5-(2-amino-3-(2-isopropylphenyl)-4-oxo-3,4-dihydroquinazolin-6-yl)-2-m

3-yl)-2,4-difluorobenzenesulfonamide

Step A

6-bromo-3-(2-is quinazolin-4(1H)-one

A solution of methyl 5-bromo-2-isothiocyanatobenzoate (.378 g, 1.389 mmol) and methyl 5- bromo-2-isothiocyanatobenzoate (.378 g, 1.389 mmol) in EtOH (6.46 ml) and TEA (0.290 ml, 2.084 mmol) were refluxed overnight. After cooling to room temperature, the crude solid was filtered, rinsing with EtOH to give 6-bromo-3-(2-isopropylphenyl)-2-thioxo-2,3-dihydroquinazolin- 4(1H)-one (.417 g, 1.11 mmol, 80 % yield) as a brown solid. ES-LCMS: 377.0, 379.0 (M+1).

Step B

6-bromo-2-chloro-3-( 2-isopropylphenyl)quinazolin -4(3H) -one

A solution of 6-bromo-3-(2-isopropylphenyl)-2-thioxo-2,3-dihydroquinazolin-4(1 H)-one (.417 g, 1.1 11 mmol) in POCI₃ (2.486 ml, 26.7 mmol) was treated by the addition of PCI₅ (0.370 g, 1.778 mmol) and was heated to 115 °C for 4 hours. The reaction was then concentrated under reduced pressure and the residue was taken up in EtOAc, washed with water (2x), brine, dried over Na₂S0₄, filtered, and concentrated to give 6-bromo-2-chloro-3-(2- isopropylphenyl)quinazolin-4(3H)-one (.416 g, 1.102 mmol, 99 % yield). ES-LCMS: 377.0, 379.0 (M+1).

Step C

6-bromo-3-(2-isopropylphen -2-((4-methoxybenzyl)amino)quinazolin-4(3H)-one

A solution of 6-bromo-2-chloro-3-(2-isopropylphenyl)quinazolin-4(3H)-one (.416 g, 1.102 mmol) in 4-methoxybenzylamine (0.158 ml, 1.212 mmol) was treated by the addition of 4- methoxybenzylamine (0.158 ml, 1.212 mmol) was heated to 80 °C overnight. After cooling to room temperature, the reaction was diluted with EtOAc and washed with 5% LiCI (3x), brine, dried over Na₂S0₄, filtered and concentrated to give 6-bromo-3-(2-isopropylphenyl)-2-((4- methoxybenzyl)amino)quinazolin-4(3H)-one (.624 g, 1.304 mmol, 118 % yield) as a yellow oil. ES-LCMS: 478.1 , 480.1 (M+1).

Step D

2-amino-6-bromo-3-(2-isopropylphenyl)quinazoiin-4(3H)-one

A solution of 6-bromo-3-(2-isopropylphenyl)-2-((4-methoxybenzyl)amino)quinazolin-4(3H)-one (.527 g, 1.102 mmol) in TFA (5.51 ml) was heated to 140 °C in a microwave for 15 minutes. The solvents were removed under reduced pressure and the residue was taken up in EtOAc and was washed with saturated NaHC0₃ (3x), brine, dried over Na₂S0₄, filtered, and concentrated. The residue was triturated with Et₂0 to give 2-amino-6-bromo-3-(2- isopropylphenyl)quinazolin-4(3H)-one (.315 g, 0.879 mmol, 80 % yield) as a brown solid. ES- LCMS: 358.05, 360.06 (M+1 ).

Step E

N-(5-(2-amino-3-(2-isopropylphenyl)-4-oxo-3,4-dihydroquinazolin-6-yl)-2-m

2, 4-difluorobenzenesulfonamide

A solution of 2-amino-6-bromo-3-(2-isopropylphenyl)quinazolin-4(3H)-one (.105 g, 0.293 mmol) and 2,4-difluoro-N-(2-methoxy-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridin-3- yl)benzenesulfonamide (0.125 g, 0.293 mmol) in DMF (6.11 ml) and water (6.1 1 ml) was treated by the addition of K₂C0₃ (0.122 g, 0.879 mmol) and PdCI₂(dppf)-DCM adduct (0.024 g, 0.029 mmol) and heated to 80 °C overnight. The reaction was treated by the addition of dioxanes (6 mL) and Cs₂C0₃ (0.286 g, 0.879 mmol) and PdCI₂(dppf)-DCM adduct (0.024 g, 0.029 mmol) and continued to heat to 80 °C. The reaction was cooled to room temperature and diluted with EtOAc and water. The combined extracts were washed with brine, dried over Na₂S0₄, filtered, and concentrated. The residue was purified by reverse phase chromatography (10-90% ACN/ H₂0 + formic acid). Isolation of the fractions containing the product gave .046 g. The product was purified by silica gel chromatography (1 -3% MeOH/DC ). Isolation of the fractions containing the product were purified by silica gel chromatography (50-70% EtOAc/hexanes) to give N-(5-(2-amino-3-(2-isopropylphenyl)-4-oxo-3,4-dihydroquinazolin-6-yl)-2-methoxypyridin-3- yl)-2,4-difluorobenzenesulfonamide (.023 g, 0.040 mmol, 13.59 % yield). ¹H NMR (400 MHz, CHLOROFORM- /) δ ppm 8.22 (d, J=2.15 Hz, 1 H), 8.13 (d, J=2.25 Hz, 1 H), 7.96 (d, J=2.25 Hz, 1 H), 7.88 - 7.94 (m, 1 H), 7.83 (dd, J=8.55, 2.20 Hz, 1 H), 7.59 - 7.65 (m, 3 H), 7.43 - 7.50 (m, 1 H), 7.23 (d, J=7.82 Hz, 1 H), 6.91 - 7.03 (m, 2 H), 3.96 (s, 3 H), 2.69 - 2.80 (m, 1 H), 1.21 - 1.27 (m, 6 H) (no exchangeable protons evident); ES-LCMS: 578.22 (M+1 ).

Example 232

5-(2-amino-3-(2-isopropylphenyl)-4-oxo-3,4-dihydroquinazolin-6-yl)-2-methoxy

5-(2-amino-3-(2-isopropylphenyl)-4-oxo-3,4-dihydroquinazolin-6-yl)-2-methoxy

phenylpyridine-3-sulfonamide

A solution of 2-amino-6-bromo-3-(2-isopropylphenyl)quinazolin-4(3H)-one (.105 g, 0.293 mmol) and 2-methoxy-N-phenyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridine-3-sulfonamide (0.114 g, 0.293 mmol) in DMF (6.11 ml) and water (6.11 ml) was treated by the addition of K₂C0₃ (0.879 mg, 0.293 mmol) and PdCI₂(dppf)-DCM adduct (0.024 g, 0.029 mmol) and heated to 80 °C overnight. The reaction was treated by the addition of dioxane (5 mL) and Cs₂C0₃ (0.286 g, 0.879 mmol) and PdCI₂(dppf)-DCM adduct (0.024 g, 0.029 mmol). The reaction was cooled to room temperature and diluted with EtOAc and water. The combined extracts were washed with brine, dried over Na₂S0₄, filtered, and concentrated. The crude residue was purified by reverse phase chromatography (10-90% ACN/ H₂0 + formic acid). Isolation of the fractions that contained the product were purified by silica gel chromatography (50-70% EtOAc/hexanes) to give 5-(2-amino-3-(2-isopropylphenyl)-4-oxo-3,4-dihydroquinazolin-6-yl)-2- methoxy-N-phenylpyridine-3-sulfonamide (.007 g, 0.013 mmol, 4.41 % yield). H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.56 (br. s., 1 H), 8.23 - 8.38 (m, 2 H), 7.73 - 7.83 (m, 1 H), 7.58 (br. s., 2 H), 7.38 - 7.52 (m, 2 H), 7.08 - 7.31 (m, 6 H), 4.98 - 5.24 (m, 1 H), 4.22 (br. s., 3 H), 2.76 (br. s., 1 H), 1.24 (d, J=6.64 Hz, 6 H) (2 exchangeable protons not evident); ES-LCMS: 542.3 (M+1).

Example 233

5-(2-amino-3-(3-fluorophenyl)-4-oxo-3,4-dihydroquinazolin-6-yl)-N-(2,4-difluorophen

methoxypyridine-3-sulfonamide

5-(2-amino-3-(3-fluorophenyl)-4-oxo-3,4-dihydroquinazolin-6-yl)-N-(2,4-difluom

methoxypyridine-3-sulfonamide

A solution of 2-amino-3-(3-fluorophenyl)-6-iodoquinazolin-4(3H)-one (.100 g, 0.262 mmol), N- (2,4-difluorophenyl)-2-methoxy-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridine-3- sulfonamide (0.123 g, 0.289 mmol), PdCI₂(dppf)-DCM adduct (0.021 g, 0.026 mmol), K₂C0₃ (0.109 g, 0.787 mmol) in 1 ,4-dioxane (5.47 ml) and water (5.47 ml) was heated to 80 °C overnight. After cooling to room temperature, the reaction was diluted with EtOAc, washed with brine, dried over Na₂S0₄, filtered, and concentrated. The residue was purified by reverse phase chromatography (10-90% ACN/ H₂0 + formic acid) to give 5-(2-amino-3-(3-fluorophenyl)-4-oxo- 3,4-dihydroquinazolin-6-yl)-N-(2,4-difluorophenyl)-2-methoxypyridine-3-sulfonamide (.044 g, 0.079 mmol, 30.3 % yield). H NMR (400 MHz, CHLOROFORM-of) δ ppm 8.59 (d, J=2.35 Hz, 1 H), 8.27 (dd, J=14.17, 2.25 Hz, 2 H), 7.76 (dd, J=8.55, 2.20 Hz, 1 H), 7.60 (dd, J=15.19, 6.11 Hz, 2 H), 7.43 (d, J=8.60 Hz, 1 H), 7.28 - 7.34 (m, 1 H), 7.11 - 7.23 (m, 2 H), 6.69 - 6.87 (m, 2 H), 4.80 (br. s., 2 H), 4.19 (s, 3 H) (1 exchangeable protons not evident); ES-LCMS: 554.14 (M+1).

Example 234

5-(2-amino-3-(4-fluoro-2-methylphenyl)-4-oxo-3,4-dihydroquinazolin-6-yl)-N-(2,4- difluorophenyl)-2-methoxypyridine-3-sulfonamide

Step A

3-(4-fluoro-2-methylpheny -6-iodo-2-thioxo-2, 3-dihydroquinazolin-4( 1 H)-one

A solution of 2-amino-5-iodobenzoic acid (3.0 g, 1 1.41 mmol) and 4-fluoro-1-isothiocyanato-2- methylbenzene (1.907 g, 11.41 mmol) and TEA (2.385 ml, 17.11 mmol) in EtOH (54.6 ml) was heated to reflux overnight. After cooling to room temperature, the solids were filtered, rinsing with EtOH to yield 3-(4-fluoro-2-methylphenyl)-6-iodo-2-thioxo-2,3-dihydroquinazolin-4(1 H)-one (3.993 g, 9.69 mmol, 85 % yield) as a solid. ES-LCMS: 412.97 (M+1 ).

Step B

2-chloro-3-(4-fluoro- -methylphenyl)-6-iodoquinazolin-4(3H)-one

A solution of 3-(4-fluoro-2-methylphenyl)-6-iodo-2-thioxo-2,3-dihydroquinazolin-4(1 H)-one (3.73 g, 9.05 mmol) in POCI₃ (20.24 ml, 217 mmol) and PCI₅ (3.01 g, 14.48 mmol) was heated to 1 15 °C overnight. The reaction was then concentrated under reduced pressure and the residue was taken up in EtOAc, washed with water (2x), brine, dried over Na₂S0₄, filtered, and concentrated to give 2-chloro-3-{4-fluoro-2-methylphenyl)-6-iodoquinazolin-4(3H)-one (3 8.61 mmol, 95 % yield) as a solid. ES-LCMS: 414.95 (M+1 ).

Step C

3-(4-f/uoro-2-meffty/p/7eny/ -6-^'odo-2-ff4-mei 70xybenzy/ am/^'noJqu/^'nazo/n-4('3H -one

A solution of 2-chloro-3-(4-fluoro-2-methylphenyl)-6-iodoquinazolin-4(3H)-one (3.571 g, 8.61 mmol) in DMF (39.6 ml) was treated by the addition of 4-methoxybenzylamine (1.238 ml, 9.47 mmol) and DIEA (2.256 ml, 12.92 mmol) was heated to 80 °C overnight. The reaction was cooled to room temperature and diluted with EtOAc and washed with 5% LiCI (3x), brine, dried over Na₂S0₄, filtered, and concentrated to give 3-(4-fluoro-2-methylphenyl)-6-iodo-2-((4- methoxybenzyl)amino)quinazolin-4(3H)-one (4.69 g, 9.10 mmol, 106 % yield) as a tan solid. ES- LCMS: 516.1 (M+1 ).

Step D

2-amino-3-(4-fluoro- -methylphenyl)-6-iodoquinazolin-4(3H)-one

A solution of 3-(4-fluoro-2-methylphenyl)-6-iodo-2-((4-methoxybenzyl)amino)quinazolin-4(3H)- one (1.4 g, 2.72 mmol) in TFA (13.58 ml) was heated in the microwave at 140 °C for 15 minutes. After cooling to room temperature, the solvents were removed under reduced pressure. The residue was taken up in DCM and washed with saturated NaHC0₃ (3x), brine, dried over Na₂S0₄, filtered, and concentrated. The residue was triturated with Et₂0 to give 2- amino-3-(4-fluoro-2-methylphenyl)-6-iodoquinazolin-4(3H)-one (1.06 g, 2.68 mmol, 99 % yield) as a light beige solid. ES-LCMS: 396.1 (M+1 ).

Step E

5-(2-amino-3-(4-fluoro-2-methylphenyl)-4-oxo-3,4-dihydroquinazoH

2-methoxypyridine-3-sulfonamide

A solution of 2-amino-3-(4-fluoro-2-methylphenyl)-6-iodoquinazolin-4(3H)-one (.100 g, 0.253 mmol), N-(2,4-difluorophenyl)-2-methoxy-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)pyridine-3-sulfonamide (0.1 19 g, 0.278 mmol), PdCI₂(dppf)-DCM adduct (0.021 g, 0.025 mmol), K₂C0₃ (0.105 g, 0.759 mmol) in 1 ,4-dioxane (6.33 ml) and water (6.33 ml) was heated to 80 °C overnight. After cooling to room temperature, the reaction was diluted with EtOAc, washed with brine, dried over Na₂S0₄, filtered, and concentrated. The crude residue was purified by reverse phase chromatography (10-95% ACN/ H₂0 + formic) to give 5-(2-amino-3- (4-fluoro-2-methylphenyl)-4-oxo-3,4-dihydroquinazolin-6-yl)-N-(2,4-difluorophenyl)-2- methoxypyridine-3-sulfonamide (.051 g, 0.090 mmol, 35.5 % yield) as a solid. H NMR (400 MHz, CHLOROFOR -d) δ ppm 8.59 (d, J=1.66 Hz, 1 H), 8.21 - 8.31 (m, 2 H), 7.76 (d, J=7.72 Hz, 1 H), 7.52 - 7.63 (m, 1 H), 7.44 (d, J=8.11 Hz, 1 H), 7.23 - 7.26 (m, 1 H), 7.10 - 7.22 (m, 2 H), 6.70 - 6.86 (m, 2 H), 4.19 (s, 3 H), 2.20 (s, 3 H) (no exchangeable protons evident); ES- LCMS: 568.16 (M+1 ).

Example 235

5-(2-amino-3-(2,4-difluorophenyl)-4-oxo-3,4-dihydroquinazolin-6-yl)-N-(2,4- difluorophenyl)-2-methoxypyridine-3-sulfonamide

Step A

3-(2 -difluorophenyl)-6-iodo-2-thioxo-2,3-dihydroquinazolin-4(1H)-one

A solution of 2-amino-5-iodobenzoic acid (3.0 g, 1 1.41 mmol) and 2,4-difluoro-1- isothiocyanatobenzene (1.349 ml, 10.01 mmol) and TEA (2.385 ml, 17.11 mmol) in EtOH (53.3 ml) was heated to reflux overnight. After cooling to room temperature, the solids were filtered, rinsing with EtOH to yield 3-(2,4-difluorophenyl)-6-iodo-2-thioxo-2,3-dihydroquinazolin-4(1H)- one (3.021 g, 7.26 mmol, 63.6 % yield) as a solid. ES-LCMS: 416.9 (M+1 ).

Step B

2-chloro-3-(2,4-difluorophenyl)-6-iodoquinazolin-4(3H)-one

A solution of 3-(2,4-difluorophenyl)-6-iodo-2-thioxo-2,3-dihydroquinazolin-4(1 H)-one (3.021 g, 7.26 mmol) in POCI₃ (16.24 ml, 174 mmol) and PCI₅ (2.419 g, 11.61 mmol) was heated to 1 15 °C overnight. The reaction was then concentrated under reduced pressure and the residue was taken up in EtOAc, washed with water (2x), brine, dried over Na₂S0₄, filtered, and concentrated to give 2-chloro-3-(2,4-difluorophenyl)-6-iodoquinazolin-4(3H)-one (2.975 g, 7.11 mmol, 98 % yield) as a solid. ES-LCMS: 418.9 (M+1 ).

Step C

3-(2,4-difluorophenyl)-6-iodo-2-((4-methoxybenzyl)amino)quinazo

A solution of 2-chloro-3-(2,4-difluorophenyl)-6-iodoquinazolin-4(3H)-one (2.975 g, 7.11 mmol) in DMF (32.7 ml) was treated by the addition of 4-methoxybenzylamine (1.021 ml, 7.82 mmol) and DIEA (1.862 ml, 10.66 mmol) was heated to 80 °C for 2.5 hours. The reaction was cooled to room temperature and diluted with EtOAc and washed with 5% LiCI (3x), brine, dried over Na₂S0₄, filtered, and concentrated to give 3-(2,4-difluorophenyl)-6-iodo-2-((4- methoxybenzyl)amino)quinazolin-4(3H)-one (3.679 g, 7.08 mmol, 100 % yield) as a tan solid. ES-LCMS: 520.0 (M+1).

Step D

2-amino-3-(2, 4-difluorophenyl)-6-iodoquinazolin-4(3H)-one N 18740-49

A solution of 3-(2,4-difluorophenyl)-6-iodo-2-((4-methoxybenzyl)amino)quinazolin-4(3H)-one (1.4 g, 2.70 mmol) in TFA (13.48 ml) was heated in the microwave at 140 °C for 5 minutes. After cooling to room temperature, the solvents were removed under reduced pressure. The residue was taken up in DCM and washed with saturated NaHC0₃ (3x), brine, the solids were filtered; the organics were dried over Na₂S0₄, filtered, and concentrated. The crude residue and the solids were combined and triturated with Et₂0 to give 2-amino-3-(2,4-difluorophenyl)-6- iodoquinazolin-4(3H)-one (1.05 g, 2.63 mmol, 98 % yield) as a light beige solid. ES-LCMS: 400.0 (M+1).

Step E

5-(2-amino-3-(2,4-difluorophenyl)-4-oxo-3 -dihydroquinazolin^

methoxypyridine-3-sulfonamide

A solution of 2-amino-3-(2,4-difluorophenyl)-6-iodoquinazolin-4(3H)-one (.100 g, 0.251 mmol), N-(2,4-difluorophenyl)-2-methoxy-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridine-3- sulfonamide (0.117 g, 0.276 mmol), PdCI₂(dppf)-DCM adduct (0.020 g, 0.025 mmol), K₂C0₃ (0.104 g, 0.752 mmol) in 1 ,4-dioxane (6.26 ml) and water (6.26 ml) was heated to 80 °C overnight. After cooling to room temperature, the reaction was diluted with EtOAc, washed with brine, dried over Na₂S0₄, filtered, and concentrated. The residue was purified by reverse phase chromatography (10-95% ACN/ H₂0 + formic) to give 5-(2-amino-3-(2,4-difluorophenyl)-4-oxo- 3,4-dihydroquinazolin-6-yl)-N-(2,4-difluorophenyl)-2-methoxypyridine-3-sulfonamide (.071 g, 0.124 mmol, 49.6 % yield) as a solid. ¹H NMR (400 MHz, CHLOROFORM-of) δ ppm 8.59 (d, J=2.44 Hz, 1 H), 8.26 (dd, J=11.97, 2.20 Hz, 2 H), 7.76 (d, J=2.05 Hz, 1 H), 7.52 - 7.64 (m, 1 H), 7.38 - 7.50 (m, 2 H), 7.07 - 7.19 (m, 2 H), 6.72 - 6.88 (m, 2 H), 5.03 (br. s., 1 H), 4.19 (s, 3 H) (2 exchangeable protons not evident); ES-LCMS: 572.2 (M+1 ).

Example 236

5-(2-amino-3-(2,6-difluorophenyl)-4-oxo-3,4-dihydroquinazolin-6-yl)-N-(2,4- difluorophenyl)-2-methoxypyridine-3-sulfonamide

Step A

3-(2, 6-difluorophenyl)-6-iodo-2-thioxo-2, 3-dihydroquinazolin-4( 1H)-one

A solution of 2-amino-5-iodobenzoic acid (3.0 g, 1 1.41 mmol) and 1 ,3-difluoro-2- isothiocyanatobenzene (1.468 ml, 11.41 mmol) and TEA (2.385 ml, 17.11 mmol) in EtOH (53.2 ml) was heated to reflux overnight. After cooling to room temperature, the solids were filtered, rinsing with EtOH to yield 3-(2,6-difluorophenyl)-6-iodo-2-thioxo-2,3-dihydroquinazolin-4(1H)- one (3.307 g, 7.95 mmol, 69.7 % yield) as a solid. ES-LCMS: 416.9 (M+1 ).

Step B

2-chloro-3-(2,6- azolin-4(3H)-one

A solution of 3-(2,6-difluorophenyl)-6-iodo-2-thioxo-2,3-dihydroquinazolin-4(1 H)-one (3.307 g, 7.95 mmol) in POCI₃ (17.78 ml, 191 mmol) and PCI₅ (2.65 g, 12.71 mmol) was heated to 115 °C overnight. The reaction was then concentrated under reduced pressure and the residue was taken up in EtOAc, washed with water (2x), brine, dried over Na₂S0₄, filtered, and concentrated to give 2-chloro-3-(2,6-difluorophenyl)-6-iodoquinazolin-4(3H)-one (2.811 g, 6.72 mmol, 85 % yield) as a solid. ES-LCMS: 419.0 (M+1 ).

Step C

3-(2,6-difluorophenyl)-6-iodo- -((4-methoxybenzyl)amino)quinazolin-4(3H)-on

A solution of 2-chloro-3-(2,6-difluorophenyl)-6-iodoquinazolin-4(3H)-one (2.81 1 g, 6.72 mmol) in DMF (30.9 ml) was treated by the addition of 4-methoxybenzylamine (0.965 ml, 7.39 mmol) and DIEA (1.759 ml, 10.07 mmol) was heated to 80 °C for 2.5 hours. The reaction was cooled to room temperature and diluted with EtOAc, washed with 5% LiCI (3x), brine, dried over Na₂S0₄, filtered, and concentrated to give 3-(2,6-difluorophenyl)-6-iodo-2-((4- methoxybenzyl)amino)quinazolin-4(3H)-one (3.623 g, 6.98 mmol, 104 % yield) as a tan solid. ES-LCMS: 520.0 (M+1).

Step D

2-amino-3-(3-flu azolin-4(3H)-one

A solution of 3-(2,6-difluorophenyl)-6-iodo-2-((4-methoxybenzyl)amino)quinazolin-4(3H)-one (1.4 g, 2.70 mmol) in TFA (13.48 ml) was heated in the microwave at 140 °C for 15 minutes. After cooling to room temperature, the solvents were removed under reduced pressure. The residue was taken up in DCM and washed with saturated NaHC0₃ (3x), brine, the solids were filtered; the organic layer was dried over Na₂S0₄, filtered, and concentrated. The crude residue and the solids were combined and triturated with Et₂0 to give 2-amino-3-(2,6-difluorophenyl)-6- iodoquinazolin-4(3H)-one (1.17 g, 2.93 mmol, 109 % yield) as a beige solid. ES-LCMS: 400.0 (M+1 ).

Step E

5-(2-amino-3-(2,6-difluorophenyl)-4-oxo-3 -dihydroquinazolin-6-yl)-N^

methoxypyridine-3-sulfonamide

A solution of 2-amino-3-(3-fluorophenyl)-6-iodoquinazolin-4(3H)-one (.100 g, 0.262 mmol), N- (2,4-difluorophenyl)-2-methoxy-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)

sulfonamide (0.112 g, 0.262 mmol), PdCI₂(dppf)-DCM adduct (0.021 g, 0.026 mmol), K₂C0₃ (0.109 g, 0.787 mmol) in 1 ,4-dioxane (5.47 ml) and water (5.47 ml) was heated to 80 °C overnight. After cooling to room temperature, the reaction was diluted with EtOAc, washed with brine, dried over Na₂S0₄, filtered, and concentrated. The crude residue was purified by reverse phase chromatography (10-95% ACN/ H₂0 + formic) to give 5-(2-amino-3-(2,6-difluorophenyl)- 4-oxo-3,4-dihydroquinazolin-6-yl)-N-(2,4-difluorophenyl)-2-methoxypyridine-3-sulfonamide (.050 g, 0.087 mmol, 34.9 % yield) as a solid. ¹H NMR (400 MHz, CHLOROFORM-ci) δ ppm 8.59 (d, J=2.44 Hz, 1 H), 8.28 (dd, J=6.50, 2.30 Hz, 2 H), 7.75 - 7.84 (m, 1 H), 7.53 - 7.65 (m, 2 H), 7.47 (d, J=8.50 Hz, 1 H), 7.20 (d, J=1.07 Hz, 2 H), 6.70 - 6.87 (m, 2 H), 4.83 (br. s., 2 H), 4.20 (s, 3 H) (1 exchangeable proton not evident); ES-LCMS: 572.1 (M+1 ).

Example 237

5-( 2-amino-3-( 2, 4-dimethylphenyl)-4-oxo-3, 4-dihydroquinazolin- 6-yl) -N-( 2, 4- difluorophenyl)-2-methoxypyridine-3-sulfonamide

Step A

3-(2, 4-dimethylphenyl)- -iodo-2-thioxo-2, 3-dihydroquinazolin-4( 1 H)-one

A solution of 2-amino-5-iodobenzoic acid (3.0 g, 1 1.41 mmol) and 1-isothiocyanato-2,4- dimethylbenzene (1.862 g, 11.41 mmol) and TEA (2.385 ml, 17.1 1 mmol) in EtOH (54.6 ml) heated to reflux overnight. After cooling to room temperature, the solids were filtered, rinsing with EtOH to yield 3-(2,4-dimethylphenyl)-6-iodo-2-thioxo-2,3-dihydroquinazolin-4(1H)-one {3.23 g, 7.91 mmol, 69.4 % yield) as a solid. ES-LCMS: 409.0 (M+1).

Step B

2-chloro-3-(2,4 azolin-4(3H)-one

A solution of 3-(2,4-dimethylphenyl)-6-iodo-2-thioxo-2,3-dihydroquinazolin-4(1H)-one (3.23 g, 7.91 mmol) in POCI₃ (17.70 ml, 190 mmol) and PCI₅ (2.64 g, 12.66 mmol) was heated to 115 °C overnight. The reaction was concentrated under reduced pressure and the residue was taken up in EtOAc, washed with water (2x), brine, dried over Na₂S0₄, filtered, and concentrated to give 2-chloro-3-(2,4-dimethylphenyl)-6-iodoquinazolin-4(3H)-one (3.18 g, 7.74 mmol, 98 % yield) as a solid. ES-LCMS: 411.0 (M+1 ).

Step C

3-(2,4-dimethylphenyl)-6-io -2-((4-methoxybenzyl)amino)qui

A solution of 2-chloro-3-(2,4-dimethylphenyl)-6-iodoquinazolin-4(3H)-one (3.18 g, 7.74 mmol) in DMF (35.6 ml) was treated by the addition of 4-methoxybenzylamine (1.113 ml, 8.52 mmol) and DIEA (2.029 ml, 11.62 mmol) was heated at 80 °C for 48 hours. The reaction was cooled to room temperature and diluted with EtOAc and washed with 5% LiCI (3x), brine, dried over Na₂S0₄, filtered, and concentrated to give 3-(2,4-dimethylphenyl)-6-iodo-2-((4- methoxybenzyl)amino)quinazolin-4(3H)-one (4.18 g, 8.17 mmol, 106 % yield) as a light beige solid. ES-LCMS: 512.1 (M+1).

Step D

2-amino-3-(2,4-dimethylphenyl)-6-iodoquinazolin-4(3H)-one

A solution of 3-(2,4-dimethylphenyl)-6-iodo-2-((4-methoxybenzyl)amino)quinazolin-4(3H)-one (1.5 g, 2.93 mmol) in TFA (14.67 ml) was heated in the microwave at 140 °C for 15 minutes. After cooling to room temperature, the solvents were removed under reduced pressure and the residue was taken up in DCM, the organics were washed with saturated NaHC0₃ (3x), brine, dried over Na₂S0₄, filtered, and concentrated. The crude residue was triturated with Et₂0 to give 2-amino-3-(2,4-dimethylphenyl)-6-iodoquinazolin-4(3H)-one (1.23 g, 3.14 mmol, 107 % yield) as a beige solid. ES-LCMS: 392 (M+1 ).

Step E

3-(2,6-difluorophenyl)-6-iodo-2-thioxo-2,3-dihydroquinazolin-4(1H)-one

A solution of 2-amino-3-(2,4-dimethylphenyl)-6-iodoquinazolin-4(3H)-one (.100 g, 0.256 mmol), N-(2,4-difluorophenyl)-2-methoxy-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridine-3- sulfonamide (0.120 g, 0.281 mmol), PdCI₂(dppf)-DCM adduct (0.021 g, 0.026 mmol), K₂C0₃ (0.106 g, 0.767 mmol) in 1 ,4-dioxane (6.39 ml) and water (6.39 ml) was heated to 80 °C overnight. After cooling to room temperature, the reaction was diluted with EtOAc, washed with brine, dried over Na₂S0₄, filtered, and concentrated. The crude residue was purified by reverse phase chromatography (10-95% ACN/ H₂0 + formic) to give 5-(2-amino-3-(2,4-dimethylphenyl)- 4-oxo-3,4-dihydroquinazolin-6-yl)-N-(2,4-difluorophenyl)-2-methoxypyridine-3-sulfonamide (.088 g, 0.156 mmol, 61.1 % yield) as a solid. H NMR (400 MHz, DMSO-dg) δ ppm 8.72 - 8.76 (m, 1 H), 8.15 - 8.19 (m, 1 H), 8.01 - 8.04 (m, 1 H), 7.89 - 7.93 (m, 1 H), 7.16 - 7.36 (m, 6 H), 7.10 - 7.15 (m, 1 H), 6.96 - 7.06 (m, 1 H), 6.41 (br. s., 2 H), 3.97 (s, 3 H), 2.36 (s, 3 H), 2.00 (s, 3 H); ES-LCMS: 564.2 (M+1). Example 238

5-(2-amino-3-(2-fluoro-4-methylphenyt)-4-oxo-3,4-dihydroquinazoiin-6-yt)-N-(2,4- difluorophenyl)-2-methoxypyridine-3-sulfonamide

Step A

3-(2-fluoro-4-methylphenyl -6-iodo-2-thioxo-2,3-dihydroquinazolin-4(1H)-one

A solution of 2-amino-5-iodobenzoic acid (3.0 g, 1 1.41 mmol) and 2-fluoro-1-isothiocyanato-4- methylbenzene (1.907 g, 11.41 mmol) and TEA (2.385 ml, 17.11 mmol) in EtOH (54.6 ml) was heated to reflux overnight. After cooling to room temperature, the solids were filtered, rinsing with EtOH to yield 3-(2-fluoro-4-methylphenyl)-6-iodo-2-thioxo-2,3-dihydroquinazolin-4(1 H)-one {3.34 g, 8.10 mmol, 71.0 % yield) as a solid. ES-LCMS: 413.0 (M+1).

Step B

2-chloro-3-(2-fluoro- -methylphenyl)-6-iodoquinazolin-4(3H)-one

A solution of 3-(2-fluoro-4-methylphenyl)-6-iodo-2-thioxo-2,3-dihydroquinazolin-4(1 H)-one (3.34 g, 8.10 mmol) in POCI₃ (18.13 ml, 194 mmol) and PCI₅ (2.70 g, 12.96 mmol) was heated to 1 15 °C overnight. The reaction was then concentrated under reduced pressure and the residue was taken up in EtOAc, washed with water (2x), brine, dried over Na₂S0₄, filtered, and concentrated to give 2-chloro-3-(2-fluoro-4-methylphenyl)-6-iodoquinazolin-4(3H)-one (3.20 g, 7.72 mmol, 95 % yield) as a solid. ES-LCMS: 415.0 (M+1). Step C

3-(2-fluoro-4-methylphenyl)- amino)quinazolin-4(3H)-one

A solution of 2-chloro-3-(2-fluoro-4-methylphenyl)-6-iodoquinazolin-4(3H)-one (3.20 g, 7.72 mmol) in D F (35.5 ml) was treated by the addition of 4-methoxybenzylamine (1.109 ml, 8.49 mmol) and DIEA (2.022 ml, 11.58 mmol) was heated at 80 °C for 48 hours. The reaction was cooled to room temperature and diluted with EtOAc and washed with 5% LiCI (3x), brine, dried over Na₂S0₄, filtered, and concentrated to give 3-(2-fluoro-4-methylphenyl)-6-iodo-2-((4- methoxybenzyl)amino)quinazolin-4(3H)-one (3.65 g, 7.08 mmol, 92 % yield) as a brown solid. ES-LCMS: 516.1 (M+1).

Step D

2-amino-3-(2-fluoro-4-methylphenyl)-6-iodoquinazolin-4(3H)-one

A solution of 3-(2-fluoro-4-methylphenyl)-6-iodo-2-((4-methoxybenzyl)amino)quinazolin-4(3H)- one (1.5 g, 2.91 mmol) in TFA (14.55 ml) was heated in the microwave at 140 °C for 15 minutes. After cooling to room temperature, the solvents were removed under reduced pressure and the residue was taken up in DCM, washed with saturated NaHC0₃ (3x), brine, the solids were filtered, the organic layer was dried over Na₂S0₄, filtered, and concentrated. The crude residue and the solids were combined and triturated with Et₂0 to give 2-amino-3-(2-fluoro-

4- methylphenyl)-6-iodoquinazolin-4(3H)-one (.582 g, 1.473 mmol, 50.6 % yield) as a beige solid. ES-LCMS: 396.0 (M+1 ).

Step E

5- (2-amino-3-(2-fluoro-4-methylphenyi)-4-oxo-3,4-dihydroquinaz

2-methoxypyridine-3-sulfonamide

A solution of 2-amino-3-(2-fluoro-4-methylphenyl)-6-iodoquinazolin-4(3H)-one (.100 g, 0.253 mmol), N-(2,4-difluorophenyl)-2-methoxy-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)pyridine-3-sulfonamide (0.1 19 g, 0.278 mmol), PdCI₂(dppf)-DCM adduct (0.021 g, 0.025 mmol), K₂C0₃ (0.105 g, 0.759 mmol) in 1 ,4-dioxane (6.33 ml) and water (6.33 ml) was heated to 80 °C overnight. After cooling to room temperature, the reaction was diluted with EtOAc, washed with brine, dried over Na₂S0₄, filtered, and concentrated. The crude residue was purified by reverse phase chromatography (10-95% ACN/ H₂0 + formic) to give 5-(2-amino-3- (2-fluoro-4-methylphenyl)-4-oxo-3,4-dihydroquinazolin-6-yl)-N-(2,4-difluorophenyl)-2- methoxypyridine-3-sulfonamide (.051 g, 0.090 mmol, 35.5 % yield) as a solid. ¹H NMR (400 MHz, DMSO-afs) δ ppm 10.18 (br. s., 1 H), 8.76 (s, 1 H), 8.17 (s, 1 H), 8.02 (s, 1 H), 7.86 - 7.96 (m, 1 H), 7.14 - 7.43 (m, 6 H), 6.97 - 7.08 (m, 1 H), 6.69 (br. s., 2 H), 3.97 (s, 3 H), 2.42 (s, 3 H); ES-LCMS: 568.2 (M+1).

Example 239

5-(2-amino-3-(3,5-difiuorophenyl)-4-oxo-3,4-dihydroquinazolin-6-yl)-N-(2,4- difluorophenyl)-2-methoxypyridine-3-sulfonamide

Step A 3-(3, 5-difluorophenyl)-6-iodo-2-thioxo-2, 3-dihydroquinazolin-4( 1H)-one

A solution of 2-amino-5-iodobenzoic acid (3.0 g, 1 1.41 mmol) and 1 ,3-difluoro-5- isothiocyanatobenzene (1.952 g, 11.41 mmol) and TEA (2.385 ml, 17.11 mmol) in EtOH (54.6 ml) was heated to reflux overnight. After cooling to room temperature, the solids were filtered, rinsing with EtOH to yield 3-(3,5-difluorophenyl)-6-iodo-2-thioxo-2,3-dihydroquinazolin-4(1H)- one (2.50 g, 6.01 mmol, 52.7 % yield) as a solid. ES-LCMS: 417.0 (M+1 ).

Step B

2-chloro-3-(3,5-difluorophenyt)-6-iodoquinazotin-4(3H)-one

A solution of 3-(3,5-difluorophenyl)-6-iodo-2-thioxo-2,3-dihydroquinazolin-4(1 H)-one (2.50 g, 6.01 mmol) in POCI₃ (13.44 ml, 144 mmol) and PCI₅ (2.001 g, 9.61 mmol) was heated to 115 °C overnight. The reaction was then concentrated under reduced pressure and the residue was taken up in EtOAc, washed with water (2x), brine, dried over Na₂S0₄, filtered, and concentrated to give 2-chloro-3-(3,5-difluorophenyl)-6-iodoquinazolin-4(3H)-one (2.26 g, 5.40 mmol, 90 % yield) as a solid. ES-LCMS: 418.9 (M+1 ).

Step C

3-(3,5-difluorophenyl)-6-iodo-2-((4-methoxybenzyl)amino)quinazo

A solution of 2-chloro-3-(3,5-difluorophenyl)-6-iodoquinazolin-4(3H)-one (2.26 g, 5.40 mmol) in DMF (24.81 ml) was treated by the addition of 4-methoxybenzylamine (0.776 ml, 5.94 mmol) and DIEA (1.415 ml, 8.10 mmol) was heated at 80 °C for 48 hours. The reaction was cooled to room temperature, diluted with EtOAc, washed with 5% LiCI (3x), brine, dried over Na₂S0₄, filtered, and concentrated to give 3-(3,5-difluorophenyl)-6-iodo-2-({4- methoxybenzyl)amino)quinazolin-4(3H)-one (2.80 g, 5.39 mmol, 100 % yield) as a tan solid. ES- LCMS: 520.0 (M+1).

Step D

2-amino-3-(3,5-difluorophenyl)-6-iodoquinazolin-4(3H)-one

A solution of 3-(3,5-difluorophenyl)-6-iodo-2-((4-methoxybenzyl)amino)quinazolin-4(3H)-one (1.5 g, 2.89 mmol) in TFA (14.44 ml) was heated in the microwave at 140 °C for 15 minutes. After cooling to room temperature, the solvents were removed under reduced pressure. The residue was taken up in DCM and washed with saturated NaHC0₃ (3x), brine, the solids were filtered; the organic layer was dried over Na₂S0₄, filtered, and concentrated. The crude residue and the solids were combined and triturated with Et₂0 to give 2-amino-3-(3,5-difluorophenyl)-6- iodoquinazolin-4(3H)-one (1.03 g, 2.58 mmol, 89 % yield) as a beige solid. ES-LCMS: 400.0 (M+1 ).

Step E

5-(2-amino-3-(3,5-difluorophenyl)-4-oxo-3,4-dihydroquinazolifr

methoxypyridine-3-suIfonamide

A solution of 2-amino-3-(3,5-difluorophenyl)-6-iodoquinazolin-4(3H)-one (.100 g, 0.251 mmol), N-(2,4-difluorophenyl)-2-methoxy-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridine-3- sulfonamide (0.117 g, 0.276 mmol), PdCI₂(dppf)-DCM adduct (0.020 g, 0.025 mmol), K₂C0₃ (0.104 g, 0.752 mmol) in 1 ,4-dioxane (6.26 ml) and water (6.26 ml) was heated to 80 °C overnight. After cooling to room temperature, the reaction was diluted with EtOAc, washed with brine, dried over Na₂S0₄, filtered, and concentrated. The crude residue was purified by reverse phase chromatography (10-95% ACN/ H₂0 + formic). Isolation and lyophilization gave a solid which was triturated with Et₂0 to give 5-(2-amino-3-(3,5-difluorophenyl)-4-oxo-3,4- dihydroquinazolin-6-yl)-N-(2,4-difluorophenyl)-2-methoxypyridine-3-sulfonamide (0.018 g, 0.031 mmol, 12.57 % yield) as a solid. H NMR (400 MHz, DMSO-cf₆) δ ppm 10.21 (br. s., 1 H), 8.71 - 8.82 (m, 1 H), 8.13 - 8.20 (m, 1 H), 7.99 - 8.06 (m, 1 H), 7.88 - 7.95 (m, 1 H), 7.39 - 7.49 (m, 1 H), 7.18 - 7.39 (m, 5 H), 6.97 - 7.08 (m, 1 H), 6.70 (br. s., 2 H), 3.97 (s, 3 H); ES-LCMS: 572.2 (M+1 ).

Example 240

5-(2-amino-3-(3-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-6-yl)-N-(2,4-d

2-methoxypyridine-3-sulfonamide

Step A

6-iodo-3-(3-methoxyphenyl)-2-thioxo-2,3-dihydroquinazolin-4(1H)-one

A solution of 2-amino-5-iodobenzoic acid (3.0 g, 1 1.41 mmol) and 1-isothiocyanato-3- methoxybenzene (1.598 ml, 1 1.41 mmol) and TEA (2.385 ml, 17.11 mmol) in EtOH (53.0 ml) was heated to reflux overnight. After cooling to room temperature, the solids were filtered, rinsing with EtOH to yield 6-iodo-3-(3-methoxyphenyl)-2-thioxo-2,3-dihydroquinazolin-4(1H)-one (3.79 g, 9.24 mmol, 81 % yield) as a solid. ES-LC S: 411.0 (M+1).

Step B

2-chloro-6-iodo-3-(3-methoxyphenyl)quinazolin-4(3H)-one

A solution of 6-iodo-3-(3-methoxyphenyl)-2-thioxo-2,3-dihydroquinazolin-4(1 H)-one (3.79 g, 9.24 mmol) in POCI₃ (20.67 ml, 222 mmol) and PCI₅ (3.08 g, 14.78 mmol) was heated to 115 °C overnight. The reaction was then concentrated under reduced pressure and the residue was taken up in EtOAc, washed with water (2x), brine, the solids filtered and discarded, the organics were dried over Na₂S0₄, filtered, and concentrated to give 2-chloro-6-iodo-3-(3- methoxyphenyl)quinazolin-4(3H)-one (.542 g, 1.314 mmol, 14.22 % yield) as a oil. ES-LCMS: 413.0 (M+1).

Step C

6-iodo-2-((4-methoxybenzyl)amino)-3-(3-methoxyphenyl)quinazolin-4(3H)-one

A solution of 2-chloro-6-iodo-3-(3-methoxyphenyl)quinazolin-4(3H)-one (.542 g, 1.314 mmol) in DMF (6.04 ml) was treated by the addition of 4-methoxybenzylamine (0.189 ml, 1.445 mmol) and DIEA (0.344 ml_, 1.970 mmol) was heated at 80 °C for 48 hours. The reaction was cooled to room temperature and diluted with EtOAc and washed with 5% LiCI (3x), brine, dried over Na₂S0₄, filtered, and concentrated to give 3-(3,5-difluorophenyl)-6-iodo-2-((4- methoxybenzyl)amino)quinazolin-4(3H)-one as a tan solid. ES-LCMS: 514.1 (M+1 ).

Step D

2-amino-6-iodo-3-(3-methoxyphenyl)quinazolin-4(3H)-one

A solution of 6-iodo-2-((4-methoxybenzyl)amino)-3-(3-methoxyphenyl)quinazolin-4(3H)-one (.656 g, 1.278 mmol) in TFA (6.39 ml) was heated in the microwave at 140 °C for 15 minutes. After cooling to room temperature, the solvents were removed under reduced pressure. The residue was taken up in DCM and washed with saturated NaHC0₃ (3x), brine, dried over Na₂S0₄, filtered, and concentrated. The residue was triturated with Et₂0 to give 2-amino-6-iodo- 3-(3-methoxyphenyl)quinazolin-4(3H)-one (.396 g, 1.007 mmol, 79 % yield) as a beige solid. ES-LCMS: 394.0 (M+1 ).

Step E

5-(2-amino-3-(3-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-6-yl)^

methoxypyridine-3-sulfonamide

A solution of 2-amino-6-iodo-3-(3-methoxyphenyl)quinazolin-4(3H)-one (.100 g, 0.254 mmol), N- (2,4-difluorophenyl)-2-methoxy-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridine-3- sulfonamide (0.1 19 g, 0.280 mmol), PdCI₂(dppf)-DCM adduct (0.021 g, 0.025 mmol), K₂C0₃ (0.105 g, 0.763 mmol) in 1 ,4-dioxane (6.36 ml) and water (6.36 ml) was heated to 80 X overnight. After cooling to room temperature, the reaction was diluted with EtOAc, washed with brine, dried over Na₂S0₄, filtered, and concentrated. The crude residue was purified by reverse phase chromatography ( 0-95% ACN/ H₂0 + formic) to give 5-(2-amino-3-(3-methoxyphenyl)-4- oxo-3,4-dihydroquinazolin-6-yl)-N-(2,4-difluorophenyl)-2-methoxypyridine-3-sulfonamide (0.013 g, 0.023 mmol, 9.04 % yield) as a solid. ¹H NMR (400 MHz, DMSO-af₆) δ ppm 8.69 - 8.74 (m, 1 H), 8.16 - 8.19 (m, 1 H), 8.00 - 8.04 (m, 1 H), 7.87 - 7.94 (m, 1 H), 7.44 - 7.51 (m, 1 H), 7.15 - 7.37 (m, 4 H), 7.07 - 7.11 (m, 1 H), 6.95 - 7.04 (m, 2 H), 6.89 - 6.95 (m, 1 H), 6.43 (br. s., 2 H), 3.95 (s, 3 H), 3.79 (s, 3 H); ES-LCMS: 566.3 (M+1).

Example 241

5-(2-amino-3-(2-chloro-6-methylphenyl)-4-oxo-3,4-dihydroquinazolin-6-yl)-N-(2,4- difluorophenyl)-2-methoxypyridine-3-sulfonamide

Step A

3-(2-chloro-6-methylphenyl)-6-iodo-2-thioxo-2,3-dihydroquinazolin-4(1H)-on

A solution of 2-amino-5-iodobenzoic acid (3.0 g, 1 1.41 mmol) and 1-chloro-2-isothiocyanato-3- methylbenzene (1.689 ml, 11.41 mmol) and TEA (2.385 ml, 17.1 1 mmol) in EtOH (53.0 ml) was heated to reflux overnight. After cooling to room temperature, the solids were filtered, rinsing with EtOH to yield 3-(2-chloro-6-methylphenyl)-6-iodo-2-thioxo-2,3-dihydroquinazolin-4(1H)-one (3.859 g, 9.00 mmol, 79 % yield) as a solid. ES-LCMS: 429.0 (M+1).

Step B

2-chloro-3-(2-chloro-6-methylphenyl)-6-iodoquinazolin-4(3H)-one

A solution of 3-(2-chloro-6-methylphenyl)-6-iodo-2-thioxo-2,3-dihydroquinazolin-4(1H)-one (3.859 g, 9.00 mmol) in POCI₃ (20.14 ml, 216 mmol) and PCI₅ (3.00 g, 14.40 mmol) was heated to 1 15 °C overnight. The reaction was then concentrated under reduced pressure and the residue was taken up in EtOAc, washed with water (2x), brine, the solids were filtered and discarded, the organics were dried over Na₂S0₄, filtered, and concentrated to give 2-chloro-3- (2-chloro-6-methylphenyl)-6-iodoquinazolin-4(3H)-one (1.434 g, 3.33 mmol, 37.0 % yield) as a solid. ES-LCMS: 430.9 (M+1 ).

Step C

3-(2-chloro-6-methylphenyl)-6- amino)quinazoli

A solution of 2-chloro-3-(2-chloro-6-methylphenyl)-6-iodoquinazolin-4(3H)-one (1.434 g, 3.33 mmol) in DMF (15.28 ml) was treated by the addition of 4-methoxybenzylamine (0.478 ml, 3.66 mmol) and DIEA (0.872 ml, 4.99 mmol) was heated to 80 °C for 48 hours. The reaction was cooled to room temperature and diluted with EtOAc and washed with 5% LiCI (3x), brine, dried over Na₂S0₄, filtered, and concentrated to give an oily residue which was used without further purification 3-(2-chloro-6-methylphenyl)-6-iodo-2-((4-methoxybenzyl)amino)quinazolin-4(3H)- one (2.00 g, 3.76 mmol, 113 % yield). ES-LCMS: 532.0 (M+1 ).

Step D

2-amino-3-(2-chloro-6 quinazolin-4(3H)-one

A solution of 3-(2-chloro-6-methylphenyl)-6-iodo-2-((4-methoxybenzyl)amino)quinazolin-4(3H)- one (2.00 g, 3.76 mmol) in TFA (18.81 ml) was heated to 140 °C in the microwave for 15 minutes. After cooling to room temperature, the solvents were removed under reduced pressure. The residue was taken up in DCM, washed with saturated NaHC0₃ (3x), brine, dried over Na₂S0₄, filtered, and concentrated. The residue was triturated in Et₂0 to give 2-amino-3- (2-chloro-6-methylphenyl)-6-iodoquinazolin-4(3H)-one (1.031 g, 2.505 mmol, 66.6 % yield). ES- LCMS: 412.0 (M+1 ). Step E

5-(2-amino-3-(2-chloro-6-methylphenyl)-4-oxo-3 -dihydroquinazoH

difluorophenyl)-2-methoxypyridine-3-sulfonamide

A solution of 2-amino-3-(2-chloro-6-methylphenyl)-6-iodoquinazolin-4(3H)-one (.100 g, 0.243 mmol), N-(2,4-difluorophenyl)-2-methoxy-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)pyridine-3-sulfonamide (0.1 14 g, 0.267 mmol), PdCI₂(dppf)-DCM adduct (0.020 g, 0.024 mmol), K₂C0₃ (0.101 g, 0.729 mmol) in 1 ,4-dioxane (6.07 ml) and water (6.07 ml) was heated to 80 °C overnight. After cooling to room temperature, the reaction was diluted with EtOAc, washed with brine, dried over Na₂S0₄, filtered, and concentrated. The crude residue was purified by reverse phase chromatography (10-95% ACN/ H₂0 + formic) to give 5-(2-amino-3- (2-chloro-6-methylphenyl)-4-oxo-3,4-dihydroquinazolin-6-yl)-N-(2,4-difluorophenyl)-2- methoxypyridine-3-sulfonamide (0.031 g, 0.053 mmol, 21.85 % yield) as a solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.19 (s, 1 H), 8.77 (d, J=2.44 Hz, 1 H), 8.18 (d, J=2.44 Hz, 1 H), 8.05 <d, J=2.15 Hz, 1 H), 7.95 (dd, J=8.59, 2.24 Hz, 1 H), 7.52 - 7.57 (m, 1 H), 7.42 - 7.50 <m, 2 H), 7.20 - 7.39 (m, 3 H), 6.99 - 7.06 (m, 1 H), 6.83 (br. s., 2 H), 3.98 (s, 3 H), 2.11 (s, 3 H); ES- LCMS: 584.3 (M+1 ).

Example 242

5-(2-amino-3-(3,5-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-6-yl)-N-(2,4- difluorophenyl)-2-methoxypyridine-3-sulfonamide

Step A

3-(3, 5-dimethylphenyl)- -iodo-2-thioxo-2, 3-dihydroquinazolin-4( 1 H)-one

A solution of 2-amino-5-iodobenzoic acid (3.0 g, 1 1.41 mmol) and 1-isothiocyanato-3,5- dimethylbenzene (1.862 g, 11.41 mmol) and TEA (2.385 ml, 17.1 1 mmol) in EtOH (54.6 ml) was heated to reflux overnight. After cooling to room temperature, the solids were filtered, rinsing with EtOH to yield 3-(3,5-dimethylphenyl)-6-iodo-2-thioxo-2,3-dihydroquinazolin-4(1H)-one (3.99 g, 9.77 mmol, 86 % yield) as a solid. ES-LCMS: 409.0 (M+1 ).

Step B

2-chloro-3-(3,5- azolin-4(3H)-one

A solution of 3-(3,5-dimethylphenyl)-6-iodo-2-thioxo-2,3-dihydroquinazolin-4(1H)-one (3.99 g, 9.77 mmol) in POCI₃ (21.86 ml, 235 mmol) and PCI₅ (3.26 g, 15.64 mmol) was heated to 115 °C overnight. The reaction was then concentrated under reduced pressure and the residue was taken up in EtOAc, washed with water (2x), brine, the solids were filtered (3.51 g) and discarded, the organics were dried over Na₂S0₄, filtered, and concentrated to give 2-chloro-3- (3,5-dimethylphenyl)-6-iodoquinazolin-4(3H)-one (.604 g, 1.471 mmol, 15.05 % yield) as a solid.

A solution of 2-chloro-3-(3,5-dimethylphenyl)-6-iodoquinazolin-4(3H)-one (.604 g, 1.471 mmol) in DMF (6.76 ml) was treated by the addition of 4-methoxybenzylamine (0.211 ml, 1.618 mmol) and DIEA (0.385 ml, 2.206 mmol) was heated to 80 °C for 48 hours. The reaction was cooled to room temperature and diluted with EtOAc and washed with 5% LiCI (3x), brine, dried Na₂S0₄, filtered, and concentrated to give 3-(3,5-dimethylphenyl)-6-iodo-2-((4- methoxybenzyl)amino)quinazolin-4(3H)-one (1.08 g, 2.112 mmol, 144 % yield) as an oily residue which was used without further purification. ES-LCMS: 512.1 (M+1 ).

Step D

2-amino-3-(3,5- azolin-4(3H)-one

A solution of 3-(3,5-dimethylphenyl)-6-iodo-2-((4-methoxybenzyl)amino)quinazolin-4(3H)-one (1.08 g, 2.1 12 mmol) in TFA (10.56 ml) was heated to 140 °C in a microwave for 15 minutes. The reaction was cooled to room temperature, and the solvents were removed under reduced pressure. The residue was taken up in DCM and washed with saturated NaHC0₃ (3x), brine, dried over Na₂S0₄, filtered, and concentrated. The residue was triturated with Et₂0 to give 2- amino-3-(3,5-dimethylphenyl)-6-iodoquinazolin-4(3H)-one (.537 g, 1.373 mmol, 65.0 % yield) as a tan solid. ES-LCMS: 392.0 (M+1 ).

Step E

5-(2-amino-3-(3,5-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-6-yl)-N-(2,4-d^

methoxypyridine-3-sulfonamide

A solution of 2-amino-3-(3,5-dimethylphenyl)-6-iodoquinazolin-4(3H)-one (.100 g, 0.256 mmol), N-(2,4-difluorophenyl)-2-methoxy-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridine-3- sulfonamide (0.120 g, 0.281 mmol), PdCI₂(dppf)-DCM adduct (0.021 g, 0.026 mmol), K₂C0₃ (0.106 g, 0.767 mmol) in 1 ,4-dioxane (6.39 ml) and water (6.39 ml) was heated to 80 °C overnight. After cooling to room temperature, the reaction was diluted with EtOAc, washed with brine, dried over Na₂S0₄, filtered, and concentrated. The crude residue was purified by reverse phase chromatography (10-95% ACN/ H₂0 + formic) to give 5-(2-amino-3-(3,5-dimethylphenyl)- 4-oxo-3,4-dihydroquinazolin-6-yl)-N-(2,4-difluorophenyl)-2-methoxypyridine-3-sulfonamide (.022 g, 0.039 mmol, 15.27 % yield) as a solid. H NMR (400 MHz, DMSO- ₆) δ ppm 10.21 (br. s., 1 H), 8.71 - 8.77 (m, 1 H), 8.15 - 8.19 (m, 1 H), 7.98 - 8.04 (m, 1 H), 7.86 - 7.94 (m, 1 H), 7.27 - 7.36 (m, 2 H), 7.19 - 7.27 (m, 1 H), 7.13 - 7.18 (m, 1 H), 6.99 - 7.07 (m, 1 H), 6.95 (s, 2 H), 6.38 (br. s., 2 H), 3.96 (s, 3 H), 2.34 (s, 6 H); ES-LCMS: 564.4 (M+1 ).

Example 243

5-(2-amino-3-(2,6-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-6-yl)-N-(2,4- difluorophenyl)-2-methoxypyridine-3-sulfonamide

Step A 3-(2, 6-dimethylphenyl)- quinazolin-4( 1H)-one

A solution of 2-amino-5-iodobenzoic acid (3.0 g, 1 1.41 mmol) and 2-isothiocyanato-1 ,3- dimethylbenzene (1.716 ml, 11.41 mmol) and TEA (2.385 ml, 17.1 1 mmol) in EtOH (52.9 ml) was heated to reflux overnight. After cooling to room temperature, the solids were filtered, rinsing with EtOH to yield 3-(2,6-dimethylphenyl)-6-iodo-2-thioxo-2,3-dihydroquinazolin-4(1H)- one (3.122 g, 7.65 mmol, 67.0 % yield). ES-LCMS: 409.0 (M+1 ).

Step B

2-chloro-3-(2,6- azolin-4(3H)-one

A solution of 3-(2,6-dimethylphenyl)-6-iodo-2-thioxo-2,3-dihydroquinazolin-4(1H)-one (3.122 g, 7.65 mmol) in POCI₃ (17.11 ml, 184 mmol) and PCI₅ (2.55 g, 12.24 mmol) was heated to 115 °C overnight. The reaction was then concentrated under reduced pressure and the residue was taken up in EtOAc, washed with water (2x), brine, the solids filtered (1.82 g) and discarded, the organics were dried over Na₂S0₄, filtered, and concentrated to give 2-chloro-3-(2,6- dimethylphenyl)-6-iodoquinazolin-4(3H)-one (1.179 g, 2.87 mmol, 37.5 % yield). ES-LCMS: 411.0 (M+1).

Step C

3-(2^-dimethylphenyl)-6-iod -2-((4-methoxybenzyl)amino)quinazolin-4(3H)-one

A solution of 2-chloro-3-(2,6-dimethylphenyl)-6-iodoquinazolin-4(3H)-one (1.179 g, 2.87 mmol) in DMF (13.19 ml) was treated by the addition of 4-methoxybenzylamine (0.413 ml, 3.16 mmol) and DIEA (0.752 ml, 4.31 mmol) was heated to 80 °C overnight. The reaction was cooled to room temperature and diluted with EtOAc and washed with 5% LiCI (3x), brine, dried over Na₂S0₄, filtered, and concentrated to give an oily residue. The residue was purified by silica gel chromatography (10% EtOAc/hexane, then 50% EtOAc/hexane) to give 3-(2,6-dimethylphenyl)- 6-iodo-2-((4-methoxybenzyl)amino)quinazolin-4(3H)-one (.695 g, 1.359 mmol, 47.3 % yield). ES-LCMS: 512.1 ( +1).

Step D

2-amino-3-(2,6- azolin-4(3H)-one

A solution of 3-(2,6-dimethylphenyl)-6-iodo-2-((4-methoxybenzyl)amino)quinazolin-4(3H)-one (.695 g, 1.359 mmol) in TFA (6.80 ml) was heated to 140 °C in the microwave for 15 minutes. After cooling to room temperature, the solvents were removed under reduced pressure. The residue was taken up in DCM and washed with saturated NaHC0₃ (3x), brine, dried over Na₂S0₄, filtered, and concentrated. The residue was triturated in Et₂0 to give 2-amino-3-(2,6- dimethylphenyl)-6-iodoquinazolin-4(3H)-one (.231 g, 0.590 mmol, 43.4 % yield) as a beige solid. ES-LCMS: 392.1 (M+1).

Step E

5-(2-amino-3-(2,6-dimethylphenyl)-4-oxo-3,4-dihydroquin^

methoxypyridine-3-sulfonamide

A solution of 2-amino-3-(2,6-dimethylphenyl)-6-iodoquinazolin-4(3H)-one (.231 g, 0.590 mmol), N-(2,4-difluorophenyl)-2-methoxy-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridine-3- sulfonamide (0.277 g, 0.650 mmol), PdCI₂(dppf)-DCM adduct (0.048 g, 0.059 mmol), K₂C0₃ (0.245 g, 1.771 mmol) in 1 ,4-dioxane (14.76 ml) and water (14.76 ml) was heated to 80 °C overnight. After cooling to room temperature, the reaction was diluted with EtOAc, washed with brine, dried over Na₂S0₄, filtered, and concentrated. The crude residue was purified by reverse phase chromatography (10-95% ACN/ H₂0 + formic) to give 5-(2-amino-3-(2,6-dimethylphenyl)- 4-oxo-3,4-dihydroquinazolin-6-yl)-N-(2,4-difluorophenyl)-2-methoxypyridine-3-sulfonamide (0.039 g, 0.069 mmol, 1 1.72 % yield) as a solid. H NMR (400 MHz, DMSO-af₆) δ ppm 8.70 - 8.78 (m, 1 H), 8.18 (d, J=2.44 Hz, 1 H), 8.04 (d, J=2.15 Hz, 1 H), 7.89 - 7.95 (m, 1 H), 7.52 - 7.69 (m, 1 H), 7.25 - 7.39 (m, 5 H), 7.15 - 7.24 (m, 1 H), 6.94 - 7.04 (m, 1 H), 6.50 (br. s., 2 H), 3.96 (s, 3 H), 2.02 (s, 6 H); ES-LCMS: 564.5 (M+1 ).

Example 244

5-(2-amino-4-oxo-3-(2-(trifluoromet yl)ph&nyl)-3,4-dihydroqM

fluoroph namide

5-(2-amino-4-oxo-3-(2-(trifluoromethyl)phenyl)-3 -dihydroquin

methoxypyridine-3-sulfonamide

A solution of 2-amino-6-iodo-3-(2-(trifluoromethyl)phenyl)quinazolin-4(3H)-one (.096 g, 0.223 mmol), N-(2-fluorophenyl)-2-methoxy-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridine-3- sulfonamide (0.100 g, 0.245 mmol), PdCI₂(dppf)-DCM adduct (0.018 g, 0.022 mmol), Cs₂C0₃ (0.218 g, 0.668 mmol) in 1 ,4-dioxane (0.891 ml) and water (0.223 ml) was heated to 80 °C for 2 hours. After cooling to room temperature, the reaction was diluted with water and EtOAc, the combined organics washed with brine, dried over Na₂S0₄, filtered through a plug of silica, and concentrated to give a yellow solid. The solid was purified by silica gel chromatography (1-3% MeOH/DCM) to give 5-(2-amino-4-oxo-3-(2-(trifluoromethyl)phenyl)-3,4-dihydroquinazolin-6-yl)- N-(2-fluorophenyl)-2-methoxypyridine-3-sulfonamide (.111 g, 0.190 mmol, 85 % yield). H NMR (400 MHz, DMSO-af₆) δ ppm 10.20 (br. s., 1 H), 8.74 (br. s., 1 H), 8.18 (br. s., 1 H), 7.83 - 8.06 (m, 4 H), 7.56 - 7.83 (m, 2 H), 7.03 - 7.40 (m, 5 H), 6.67 (br. s., 2 H), 3.95 (br. s., 3 H); ES- LCMS: 586.2 (M+1 ). Example 245

5-(2-amino-4-oxo-3-(2-(triffuoromethyl)phenyl)-3,4-dihydroquin^

fluoroph namide

5-(2-amino-4-oxo-3-(2-(trifluoromethyl)phenyl)-3 -dihydroquin

methoxypyridine-3-sulfonamide

A solution of 2-amino-6-iodo-3-(2-(trifluoromethyl)phenyl)quinazolin-4(3H)-one (.155 g, 0.360 mmol), N-(4-fluorophenyl)-2-methoxy-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridine-3- sulfonamide (0.147 g, 0.360 mmol), PdCI₂(dppf)-DCM adduct (0.029 g, 0.036 mmol), K₂C0₃ (0.149 g, 1.079 mmol) in 1 ,4-dioxane (14.38 ml) and water (3.60 ml) was heated to 80 °C overnight. After cooling to room temperature, the reaction was diluted with EtOAc, washed with brine, dried over Na₂S0₄, filtered, and concentrated. The crude residue was purified by reverse phase chromatography (10-95% ACN/ H₂0 + formic) to give 5-(2-amino-4-oxo-3-(2- (trifluoromethyl)phenyl)-3,4-dihydroquinazolin-6-yl)-N-(4-fluorophenyl)-2-methoxypyridine-3- sulfonamide (0.029 g, 0.050 mmol, 13.78 % yield) as a solid. H NMR (400 MHz, DMSO-d₆) δ ppm 8.72 (d, J=2.24 Hz, 1 H), 8.28 (d, J=2.24 Hz, 1 H), 8.03 (d, J=2.05 Hz, 1 H), 7.92 - 7.98 (m, 2 H), 7.86 - 7.92 (m, 1 H), 7.74 - 7.80 (m, 1 H), 7.63 (d, J=7.90 Hz, 1 H), 7.33 (d, J=8.59 Hz, 1 H), 7. - 7.17 (m, 2 H), 7.03 - 7.10 (m, 3 H), 6.66 (br. s., 2 H), 4.00 (s, 3 H); ES-LCMS 586.2 (M+1).

Example 246

5-(2-amino-4-oxo-3-(2-(trifluoromethyl)phenyl)-3,4-dihydroquinazolm

fluorophenyl)-2-methoxypyridine-3-sulfonamide

5-(2-amino-4-oxo-3-(2-(trifluoromethyl)phenyl)-3,4-dihydroquinazoli

methoxypyridine-3-sulfonamide

A solution of 2-amino-6-iodo-3-(2-(trifluoromethyl)phenyl)quinazolin-4(3H)-one (.155 g, 0.360 mmol), N-(3-fluorophenyl)-2-methoxy-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridine-3- sulfonamide (0.147 g, 0.360 mmol), PdCI₂(dppf)-DCM adduct (0.029 g, 0.036 mmol), K₂C0₃ (0.149 g, 1.079 mmol) in 1 ,4-dioxane (14.38 ml) and water (3.60 ml) was heated to 80 °C overnight. The mixture was treated with Cs₂C0₃ (0.351 g, 1.079 mmol), additional PdCI₂(dppf)- DCM adduct (0.029 g, 0.036 mmol) and continued to heated to 80 °C overnight. After cooling to room temperature, the reaction was diluted with EtOAc, washed with brine, dried over Na₂S0₄, filtered, and concentrated. The crude residue was purified by reverse phase chromatography (10-95% ACN/ H₂0 + formic) to give 5-(2-amino-4-oxo-3-(2-(trifluoromethyl)phenyl)-3,4- dihydroquinazolin-6-yl)-N-(3-fluorophenyl)-2-methoxypyridine-3-sulfonamide (.041 g, 0.070 mmol, 19.48 % yield) as a solid. ¹H NMR (400 MHz, DMSO-af₆) δ ppm 8.72 (d, J=2.15 Hz, 1 H), 8.37 (d, J=2.34 Hz, 1 H), 8.06 (d, J=1.95 Hz, 1 H), 7.96 (d, J=8.00 Hz, 2 H), 7.85 - 7.92 (m, 1 H), 7.78 (d, J=7.71 Hz, 1 H), 7.63 (d, J=7.80 Hz, 1 H), 7.34 (d, J=8.58 Hz, 1 H), 7.20 - 7.28 (m, 1 H), 6.86 - 7.01 (m, 3 H), 6.77 - 6.85 (m, 1 H), 6.67 (br. s., 2 H), 3.99 (s, 3 H); ES-LCMS: 586.2 (M+1 ).

Example 247

5-(2-amino-4-oxo-3-(2-(trifluoromethyl)phenyl)-3,4-dihydroquinazolin^

chlorophenyl)-2-methoxypyridine-3-sulfonamide

5-(2-amino-4-oxo-3-(2-(trifluoromethyl)phenyl)-3,4-dihydroquinazo

methoxypyridine-3-sulfonamide

A solution of mixture 2-amino-6-iodo-3-(2-(trifluoromethyl)phenyl)quinazolin-4(3H)-one (.100 g, 0.232 mmol), N-(3-chlorophenyl)-2-methoxy-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)pyridine-3-sulfonamide (0.108 g, 0.255 mmol), PdCI₂(dppf)-DCM adduct (0.019 g, 0.023 mmol), Cs₂C0₃ (0.227 g, 0.696 mmol) was treated with 1 ,4-dioxane (0.928 ml) and water (0.232 ml) and heated to 80 °C for 3 hours. After cooling to room temperature the mixture was diluted with EtOAc and water. The combine organics were washed with brine, dried over Na₂S0₄, filtered and concentrated to give dark brownish residue. The residue was loaded onto celite and purified by silica gel chromatography (50-100% EtOAc/hexanes) to give 5-(2-amino-4-oxo-3-(2- (trifluoromethyl)phenyl)-3,4-dihydroquinazolin-6-yl)-N-(3-chlorophenyl)-2-methoxypyridine-3- sulfonamide (.101 g, 0.168 mmol, 72.3 % yield) as a yellow solid. ¹H NMR (400 MHz, DMSO- cf₆) δ ppm 10.69 (s, 1 H), 8.73 (d, J=2.44 Hz, 1 H), 8.37 (d, J=2.44 Hz, 1 H), 8.07 (d, J=2.24 Hz, 1 H), 7.96 (dd, J=8.59, 1.95 Hz, 2 H), 7.86 - 7.92 (m, 1 H), 7.74 - 7.82 (m, 1 H), 7.60 - 7.66 (m, 1 H), 7.35 (d, J=8.59 Hz, 1 H), 7.21 - 7.28 (m, 1 H), 7.15 - 7.18 (m, 1 H), 7.08 - 7.13 (m, 1 H), 7.03 - 7.08 (m, 1 H), 6.67 (br. s., 2 H), 3.99 (s, 3 H); ES-LCMS: 602.1 (M+1).

Example 248

5-(2-amino-4-oxo-3-(2-(trifluoromethyl)phenyl)-3,4-dihydroquinazolin^

chlorophenyl)-2-methoxypyridine-3-sulfonamide

5-(2-amino-4-oxo-3-(2-(trifluoromethyl)phenyl)-3,4-dihydroqui

methoxypyridine-3-sulfonamide

A solution of mixture 2-amino-6-iodo-3-(2-(trifluoromethyl)phenyl)quinazolin-4(3H)-one (.10 g, 0.232 mmol), N-(2-chlorophenyl)-2-methoxy-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)pyridine-3-sulfonamide (0.108 g, 0.255 mmol), PdCI₂(dppf)-DCM adduct (0.019 g, 0.023 mmol), Cs₂C0₃ (0.227 g, 0.696 mmol) was treated with 1 ,4-dioxane (0.928 ml) and water (0.232 ml) and heated to 80 °C for 3 hours. After cooling to room temperature the mixture was diluted with EtOAc and water. The combine organics were washed with brine, dried over Na₂S0₄, filtered, and concentrated to give dark brownish residue. The residue was loaded onto celite and purified with silica gel chromatography (50-100% EtOAc/hexanes) to give 5-(2-amino-4- oxo-3-(2-(trifluoromethyl)phenyl)-3,4-dihydroquinazolin-6-yl)-N-(2-chlorophenyl)-2- methoxypyridine-3-sulfonamide (.101 g, 0.168 mmol, 72.3 % yield) as a yellow solid. H NMR (400 MHz, DMSO-cf₆) δ ppm 10.05 (s, 1 H), 8.75 (d, J=2.25 Hz, 1 H), 8.17 (d, J=2.35 Hz, 1 H), 8.00 (d, J=2.05 Hz, 1 H), 7.84 - 7.97 (m, 3 H), 7.73 - 7.81 (m, 1 H), 7.62 (d, J=7.82 Hz, 1 H), 7.24 - 7.47 (m, 4 H), 7.14 - 7.24 (m, 1 H), 6.66 (br. s., 2 H), 3.92 (s, 3 H); ES-LCMS: 602.1 (M+1 ).

Example 249

5-(2-amino-4-oxo-3-(2-(trifluoromethyl)phenyl)-3,4-dihydroqum^

chlorophenyl)-2-methoxypyridine-3-sulfonamide

5-(2-amino-4-oxo-3-(2-(trifluoromethyl)phenyl)-3,4-dihydroquinazolin

methoxypyridine-3-sulfonamide

A solution of mixture 2-amino-6-iodo-3-(2-(trifluoromethyl)phenyl)quinazolin-4(3H)-one (.1 g, 0.232 mmol), N-(4-chlorophenyl)-2-methoxy-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)pyridine-3-sulfonamide (0.108 g, 0.255 mmol), PdCI₂(dppf)-DCM adduct (0.019 g, 0.023 mmol), Cs₂C0₃ (0.227 g, 0.696 mmol) was treated with 1 ,4-dioxane (0.928 ml) and heated to 80 °C for 3 hours. After cooling to room temperature, the mixture was diluted with EtOAc and water. The combined organics were washed with brine, dried over Na₂S0₄, and concentrated to give dark brownish residue. The residue was loaded onto celite and purified by silica gel chromatography (50-100% EtOAc/hexanes) to give 5-(2-amino-4-oxo-3-(2- (trifluoromethyl)phenyl)-3,4-dihydroquinazolin-6-yl)-N-(4-chlorophenyl)-2-methoxypyridine-3- sulfonamide (.088 g, 0.146 mmol, 63.0 % yield) as a yellow solid. H NMR (400 MHz, DMSO-cf₆) δ ppm 10.57 (s, 1 H), 8.73 (d, J=2.44 Hz, 1 H), 8.34 (d, J=2.44 Hz, 1 H), 8.06 (d, J=2.24 Hz, 1 H), 7.93 - 8.00 (m, 2 H), 7.87 - 7.94 (m, 1 H), 7.73 - 7.81 (m, 1 H), 7.60 - 7.69 (m, 1 H), 7.34 (d, J=8.58 Hz, 1 H), 7.28 (d, J=8.88 Hz, 2 H), 7.15 (d, J=8.88 Hz, 2 H), 6.68 (br. s., 2 H), 3.97 - 4.00 (m, 3 H); ES-LCMS: 602.1 (M+1).

Example 250

5-(2-amino-4-oxo-3-(2-(trifluoromethyl)phenyl)-3,4-dihydroquinazolm

difluorophenyl)-2-methoxypyridine-3-sulfonamide

5-(2-amino-4-oxo-3-(2-(trifluoromethyl)phenyl)-3,4-dihydroquinazo

difluorophenyl)-2-methoxypyridine-3-sulfonamide

A solution of mixture 2-amino-6-iodo-3-(2-(trifluoromethyl)phenyl)quinazolin-4(3H)-one (.10 g, 0.232 mmol), N-(2,6-difluorophenyl)-2-methoxy-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)pyridine-3-sulfonamide (0.109 g, 0.255 mmol), PdCI₂(dppf)-DCM adduct (0.019 g, 0.023 mmol), Cs₂C0₃ (0.227 g, 0.696 mmol) was treated with 1 ,4-dioxane (0.928 ml) and water (0.232 ml) and heated to 80 °C overnight. After cooling to room temperature, the mixture was diluted with EtOAc and water. The combine organics were washed with brine, dried over Na₂S0₄, and loaded onto celite. The residue was purified by silica gel chromatography (50-100%

EtOAc/hexanes) to give 5-(2-amino-4-oxo-3-(2-(trifluoromethyl)phenyl)-3,4-dihydroquinazolin-6- yl)-N-(2,6-difluorophenyl)-2-methoxypyridine-3-sulfonamide (.078 g, 0.129 mmol, 55.7 % yield) as a solid. H NMR (400 MHz, DMSO-d₆) δ ppm 10.05 (br. s., 1 H), 8.78 (br. s., 1 H), 8.18 (br. s., 1 H), 7.84 - 8.07 (m, 4 H), 7.71 - 7.82 (m, 1 H), 7.62 (d, J=7.61 Hz, 1 H), 7.27 - 7.42 (m, 2 H), 7.03 - 7.17 (m, 2 H), 6.66 (br. s., 2 H), 3.97 (s, 3 H); ES-LCMS: 604.1 ( +1).

Example 251

5-(2-amino-4-oxo-3-(2-(trifluoromethyl)phenyl)-3,4-dihydroquinazoli

difluorophenyl)-2-methoxypyridine-3-sulfonamide

5-(2-amino-4-oxo-3-(2-(trifluoromethyl)phenyl)-3,4-dihydroquinazolin-6-yl)-N-(2,5^

difluorophenyl)-2-methoxypyridine-3-sulfonamide

A solution of mixture 2-amino-6-iodo-3-(2-(trifluoromethyl)phenyl)quinazolin-4(3H)-one (.10 g, 0.232 mmol), N-(2,5-difluorophenyl)-2-methoxy-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)pyridine-3-sulfonamide (0.109 g, 0.255 mmol), PdCI₂(dppf)-DCM adduct (0.019 g, 0.023 mmol), Cs₂C0₃ (0.227 g, 0.696 mmol) was treated with 1 ,4-dioxane (0.928 ml) and water (0.232 ml) and heated to 80 °C overnight. After cooling to room temperature, the mixture was diluted with EtOAc and water. The combined organics were washed with brine, dried over Na₂S0₄, and loaded onto celite. The residue was purified by silica gel chromatography (50-100%

EtOAc/hexanes) to give 5-(2-amino-4-oxo-3-(2-(trifluoromethyl)phenyl)-3,4-dihydroquinazolin-6- yl)-N-(2,5-difluorophenyl)-2-methoxypyridine-3-sulfonamide (.085 g, 0.141 mmol, 60.7 % yield) as a solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.50 (s, 1 H), 8.76 (s, 1 H), 8.26 (s, 1 H), 7.56 - 8.10 (m, 6 H), 6.94 - 7.41 (m, 4 H), 6.67 (br. s., 2 H), 3.93 (s, 3 H); ES-LCMS: 604.1 (M+1 ).

Example 252

5-(2-amino-4-oxo-3-(2-(trifluoromethyl)phenyl)-3,4-dihydroquinazoli^

difluoroph namide

5-(2-amino-4-oxo-3-(2-(trifluoromethyl)phenyl)-3,4-dihydroquinazo

difluorophenyl)-2-methoxypyridine-3-sulfonamide

A solution of mixture 2-amino-6-iodo-3-(2-(trifluoromethyl)phenyl)quinazolin-4(3H)-one (.10 g, 0.232 mmol), N-(2,3-difluorophenyl)-2-methoxy-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)pyridine-3-sulfonamide (0.109 g, 0.255 mmol), PdCI₂(dppf)-DCM adduct (0.019 g, 0.023 mmol), Cs₂C0₃ (0.227 g, 0.696 mmol) was treated with 1 ,4-dioxane (0.928 ml) and water (0.232 ml) and heated to 80 °C overnight. After cooling to room temperature, the mixture was diluted with EtOAc and water. The combine organics were washed with brine, dried over Na₂S0₄, and loaded onto celite. The residue was purified by silica gel chromatography (50-100%

EtOAc/hexanes) to give 5-(2-amino-4-oxo-3-(2-(trifluoromethyl)phenyl)-3,4-dihydroquinazolin-6- yl)-N-(2,3-difluorophenyl)-2-methoxypyridine-3-sulfonamide (.077 g, 0.128 mmol, 55.0 % yield) as a solid. H NMR (400 MHz, DMSO-c/₆) δ ppm 10.52 (s, 1 H), 8.77 (d, J=2.15 Hz, 1 H), 8.24 (d, J=2.24 Hz, 1 H), 8.03 (d, J=1.95 Hz, 1 H), 7.85 - 7.99 (m, 3 H), 7.73 - 7.81 (m, 1 H), 7.58 - 7.66 (m, 1 H), 7.34 (d, J=8.58 Hz, 1 H), 7.18 - 7.27 (m, 1 H), 7.09 - 7.17 (m, 2 H), 6.69 (br. s., 2 H), 3.96 (s, 3 H); ES-LCMS: 604.2 (M+1 ).

Example 253

5-(2-amino-4-oxo-3-(2-(trifluoromethyl)phenyl)-3,4-dihydroquinazoli

difluorophenyl)-2-methoxypyridine-3-sulfonamide

5-(2-amino-4-oxo-3-(2-(trifluoromethyl)phenyl)-3,4-dihydroquinazo

difluorophenyl)-2-methoxypyridine-3-sulfonamide

A solution of mixture 2-amino-6-iodo-3-(2-(trifluoromethyl)phenyl)quinazolin-4(3H)-one (.10 g, 0.232 mmol), N-(3,5-difluorophenyl)-2-methoxy-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)pyridine-3-sulfonamide (0.109 g, 0.255 mmol), PdCI₂(dppf)-DCM adduct (0.019 g, 0.023 mmol), Cs₂C0₃ (0.227 g, 0.696 mmol) was treated with 1 ,4-dioxane (0.928 ml) and water (0.232 ml) and heated to 80 °C overnight. After cooling to room temperature the mixture was diluted with EtOAc and water. The combined organics were washed with brine, dried over Na₂S04, and loaded onto celite. The residue was purified by silica gel chromatography (50-100%

EtOAc/hexanes) to give 5-(2-amino-4-oxo-3-(2-(trifluoromethyl)phenyl)-3,4-dihydroquinazolin-6- yl)-N-(3,5-difluorophenyl)-2-methoxypyridine-3-sulfonamide (.112 g, 0.186 mmol, 80 % yield) as a solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.98 (s, 1 H), 8.75 (s, 1 H), 8.44 (s, 1 H), 8.09 (s, 1 H), 7.92 - 8.03 (m, 2 H), 7.86 - 7.92 (m, 1 H), 7.73 - 7.82 (m, 1 H), 7.63 (d, J=7.71 Hz, 1 H), 7.35 (d, J=8.58 Hz, 1 H), 6.77 - 6.91 (m, 3 H), 6.67 (br. s., 2 H), 3.99 (s, 3 H); ES-LCMS: 604.2 (M+1 ).

Example 254

5-(2-amino-4-oxo-3-(2-(trifluoromethyl)phenyl)-3,4-dihydroquinazo

difluorophenyl)-2-methoxypyridine-3-sulfonamide

5-(2-amino-4-oxo-3-(2-(trifluoromethyl)phenyl)-3,4-dihydroquinazo

difluorophenyl)-2-methoxypyridine-3-sulfonamide

A solution of mixture 2-amino-6-iodo-3-(2-(trifluoromethyl)phenyl)quinazolin-4(3H)-one (. 0 g, 0.232 mmol), N-(3,4-difluorophenyl)-2-methoxy-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)pyridine-3-sulfonamide (0.109 g, 0.255 mmol), PdCI₂(dppf)-DCM adduct (0.019 g, 0.023 mmol), Cs₂C0₃ (0.227 g, 0.696 mmol) was treated with 1 ,4-dioxane (0.928 ml) and water (0.232 ml) and heated to 80 °C overnight. After cooling to room temperature the mixture was diluted with EtOAc and water. The combined organics were washed with brine, dried over Na₂S0₄, and loaded onto celite. The residue was purified by silica gel chromatography (50-100%

EtOAc/hexanes) to give 5-(2-amino-4-oxo-3-(2-(trifluoromethyl)phenyl)-3,4-dihydroquinazolin-6- yl)-N-(3,4-difluorophenyl)-2-methoxypyridine-3-sulfonamide (.076 g, 0.126 mmol, 54.3 % yield) as a solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.63 (s, 1 H), 8.74 (s, 1 H), 8.36 (s, 1 H), 8.07 (s, 1 H), 7.84 - 8.01 (m, 3 H), 7.71 - 7.84 (m, 1 H), 7.57 - 7.69 (m, 1 H), 7.24 - 7.40 (m, 2 H), 7.08 - 7.20 (m, 1 H), 6.90 - 7.00 (m, 1 H), 6.67 (br. s., 2 H), 3.93 - 4.07 (m, 3 H); ES-LCMS: 604.1 (M+1).

Example 255

5-(2-amino-3-(2-isopropylphenyl)-4-oxo-3,4-dihydroquinazolin-6-yl)-N-(2,4- difluorophenyl)-2-methoxypyridine-3-sulfonamide

5-(2-amino-3-(2-isopropylphenyl)-4-oxo-3,4-dihydroquinazolin-6-yl)-N-(2

methoxypyridine-3-sulfonamide

A solution of mixture 2-amino-6-iodo-3-(2-isopropylphenyl)quinazolin-4(3H)-one (.10 g, 0.247 mmol), N-(2,4-difluorophenyl)-2-methoxy-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)pyridine-3-sulfonamide (0.1 16 g, 0.271 mmol), PdCI₂(dppf)-DCM adduct (0.020 g, 0.025 mmol), Cs₂C0₃ (0.241 g, 0.740 mmol) was treated with 1 ,4-dioxane (0.987 ml) and water (0.247 ml) and heated to 80 °C overnight. After cooling to room temperature the mixture was diluted with EtOAc and water. The combine organics were washed with brine, dried over Na₂S0₄, and loaded onto celite. The residue was purified by silica gel chromatography (50-100%

EtOAc/hexanes) to give 5-(2-amino-3-(2-isopropylphenyl)-4-oxo-3,4-dihydroquinazolin-6-yl)-N- (2,4-difluorophenyl)-2-methoxypyridine-3-sulfonamide (.069 g, 0.1 19 mmol, 48.4 % yield) as a solid. H NMR (400 MHz, DMSO-c/₆) δ ppm 10.18 (s, 1 H), 8.76 (s, 1 H), 7.84 - 8.26 (m, 3 H), 7.15 - 7.65 (m, 7 H), 7.03 (s, 1 H), 6.43 (br. s., 2 H), 3.97 (br. s., 3 H), 2.55 - 2.68 (m, 1 H), 0.93 - 1.28 (m, 6 H); ES-LCMS: 578.3 (M+1 ).

Example 256 5-(2-amino-3-(3-cyanophenyl)-4-oxo-3,4-dihydroquinazolin-6-yl)-N-(2,4-difluoroph

methoxypyridine-3-suffonamide

Step A

3-(6-iodo-4-oxo-2-th -3(4H)-yl)benzonitrile

A solution of 2-amino-5-iodobenzoic acid (5.5 g, 20.91 mmol),3-isothiocyanatobenzonitrile (3.19 ml, 20.91 mmol), and TEA (4.08 ml, 29.3 mmol) in 1 ,4-dioxane (97 ml) was heated at reflux overnight. After cooling to room temperature, the solids was filtered rinsing with Et₂0 to give 3- (6-iodo-4-oxo-2-thioxo-1 ,2-dihydroquinazolin-3(4H)-yl)benzonitrile (5.72 g, 14.12 mmol, 67.5 % yield) as an off white solid. ES-LCMS: 406.0 (M+1).

Step B

3-(2-chloro-6-io -4-oxoquinazolin-3(4H)-yl)benzonitrHe

A solution of 3-(6-iodo-4-oxo-2-thioxo-1 ,2-dihydroquinazolin-3(4H)-yl)benzonitrile (3.0 g, 7.40 mmol) in POCI₃ (16.56 ml, 178 mmol) was treated with PCI₅ (2.467 g, 11.85 mmol) and heated to 1 10 °C overnight. The reaction was concentrated under reduced pressure and the residue was taken up in EtOAc, washed with water (3x), brine, dried over MgS0₄, filtered and concentrated to give 3-(2-chloro-6-iodo-4-oxoquinazolin-3(4H)-yl)benzonitrile (2.953 g, 7.24 mmol, 98 % yield) as a yellow solid. ES-LCMS: 407.9 (M+1).

Step C

3-(6-iodo-2-((4-metho lin-3(4H)-yi)ben

A solution of 3-(2-chloro-6-iodo-4-oxoquinazolin-3(4H)-yl)benzonitrile (2.95 g, 7.24 mmol) in DMF (33.3 ml) was treated by the addition of DIEA (1.896 ml, 10.86 mmol) and 4- methoxybenzylamine (1.040 ml, 7.96 mmol). The reaction was heated to 80 °C overnight. After cooling to room temperature, the reaction was diluted with EtOAc and washed with 5% LiCI (3x), brine, dried over Na₂S0₄, filtered, and concentrated to give 3-(6-iodo-2-((4- methoxybenzyl)amino)-4-oxoquinazolin-3(4H)-yl)benzonitrile (3.52 g, 6.92 mmol, 96 % yield) as a yellow solid. ES-LCMS: 509.1 (M+1 ).

Step D

3-(2-amino-6-iodo-4-oxoquinazolin-3(4H)-yl)benzonitrile

A solution of 3-(6-iodo-2-((4-methoxybenzyl)amino)-4-oxoquinazolin-3(4H)-yl)benzonitrile (1.55 g, 3.05 mmol) in TFA (15.25 ml) was heated in the microwave for 20 minutes at 140 °C. After concentrating under reduced pressure, the residue was taken up in DCM and washed with saturated NaHC0₃ (3x), the solid formed in the aqueous layer was filtered to give 3-(2-amino-6- iodo-4-oxoquinazolin-3(4H)-yl)benzonitrile (1.14 g, 2.94 mmol, 96 % yield). ES-LCMS: 389.0 (M+1).

Step E

5-(2-amino-3-(3-cyanophenyl)-4-oxo-3 -dihydroquinazolin-6-yl)-N-(2,4-difl

methoxypyridine-3-sulfonamide

A solution of mixture 3-(2-amino-6-iodo-4-oxoquinazolin-3(4H)-yl)benzonitrile (.250 g, 0.644 mmol), N-(2,4-difluorophenyl)-2-methoxy-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)pyridine-3-sulfonamide (0.302 g, 0.708 mmol), PdCI₂(dppf)-DCM adduct (0.053 g, 0.064 mmol), Cs₂C0₃ (0.630 g, 1.932 mmol) was treated with 1 ,4-dioxane (2.58 ml) and water (0.644 ml) and heated to 80 °C overnight. After cooling to room temperature the mixture was diluted with EtOAc and water. The combined organics were washed with brine, dried over Na₂S0₄, and loaded onto celite. The residue was purified by silica gel chromatography (50-100%

EtOAc/hexanes) to give a residue which was triturated with Et₂0 to give 5-(2-amino-3-(3- cyanophenyl)-4-oxo-3,4-dihydroquinazolin-6-yl)-N-(2,4-difluorophenyl)-2-methoxypyridine-3- sulfonamide (.099 g, 0.177 mmol, 27.4 % yield) as a solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.19 (br. s., 1 H), 8.75 (s, 1 H), 8.16 (s, 1 H), 7.87 - 8.07 (m, 4 H), 7.76 (br. s., 2 H), 7.17 - 7.41 (m, 3 H), 6.99 - 7.10 (m, 1 H), 6.64 (br. s., 2 H), 3.97 (s, 3 H); ES-LCMS: 561.2 (M+1).

Example 257/Exampie 258

(aS)-5-(2-amino-4-oxo-3-(2-(trifluoromethyl)phenyl)-3,4-dihydroquinazo

dif!uorophenyl)-2-methoxypyridine-3-sulfonamide and (aR)- 5-(2-amino-4-oxo-3-(2- (trifluoromethyl)phenyl)-3,4-dihydroquinazolin-6-yl)-N-(2,4-difluom

methoxypyridine-3-sulfonamide

(aS)-5-(2-amino-4-oxo-3-(2-(trifluoromethyl)phenyl)-3 -dihydroquinazo

difluorophenyl)-2-methoxypyridine-3-sulfonamide and (aR)-5-(2-amino-4-oxo-3-(2- (trifluoromethyl)phenyl)-3^-dihydroquinazolin-6-yl)^-(2,4-difl

sulfonamide

Separation of 5-(2-amino-4-oxo-3-(2-(trifluoromethyl)phenyl)-3,4-dihydroquinazolin-6-yl)-N-(2,4- difluorophenyl)-2-methoxypyridine-3-sulfonamide was preformed by dissolving 5 g of material in 100 ml_ of CHCI₃:MeOH (3:1 ) with some formic acid, then separated by a prep SFC method 40% MeOH/C0₂, 100 bar, 40 °C, 90 g/min, 220 nm, AD 25cm x 3cm, 83 mg/inj., to afford first eluting isomer, (aS)-5-(2-amino-4-oxo-3-(2-(trifluoromethyl)phenyl)-3,4-dihydroquinazolin-6-yl)- N-(2,4-difluorophenyl)-2-methoxypyridine-3-sulfonamide ( 2.1 g >99 %ee, H NMR (400 MHz, DMSO-c/₆) δ ppm 10.19 (br. s., 1 H), 8.76 (d, J=2.44 Hz, 1 H), 8.18 (d, J=2.44 Hz, 1 H), 8.02 (d, J=2.15 Hz, 1 H), 7.86 - 7.98 (m, 3 H), 7.73 - 7.81 (m, 1 H), 7.63 (d, J=7.82 Hz, 1 H), 7.29 - 7.36 (m, 2 H), 7.20 - 7.28 (m, 1 H), 6.98 - 7.07 (m, 1 H), 6.67 (br. s., 2 H), 3.98 (s, 3 H); ES-LCMS: 604.2 (M+1).) and a second eluting isomer, (aR)-5-(2-amino-4-oxo-3-(2-(trifluoromethyl)phenyl)- 3,4-dihydroquinazolin-6-yl)-N-(2,4-difluorophenyl)-2-methoxypyridine-3-sulfonamide (2.22 g, >99 %ee, H NMR (400 MHz, DMSO-d₆) δ ppm 10.18 (br. s., 1 H), 8.75 (d, J=2.34 Hz, 1 H), 8. 7 (d, J=2.44 Hz, 1 H), 8.01 (d, J=2. 5 Hz, 1 H), 7.86 - 7.98 (m, 3 H), 7.72 - 7.80 (m, 1 H), 7.59 - 7.66 (m, 1 H), 7.27 - 7.36 (m, 2 H), 7.18 - 7.27 (m, 1 H), 6.97 - 7.05 (m, 1 H), 6.67 (br. s., 2 H), 3.97 (s, 3 H); ES-LCMS: 604.2 (M+1 )). Absolute stereochemical assignments were made by VCD Analysis. Appl. Spectrosc. 65 (7), 699 (2011 ).

Example 259

5-(2-amino-4-oxo-3-(2-(trifluoromethyl)phenyl)-3,4-dihydroquinazo

methoxypyridine-3-sulfonamide

5-(2-amino-4-oxo-3-(2-(trifluoromethyl)phenyl)-3,4-dihydro

sulfonamide

A solution of mixture 2-amino-6-iodo-3-(2-(trifluoromethyl)phenyl)quinazolin-4(3H)-one (.125 g, 0.290 mmol), 2-methoxy-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridine-3-sulfonamide (0.100 g, 0.319 mmol), PdCI₂(dppf)-DCM adduct (0.024 g, 0.029 mmol), Cs₂C0₃ (0.283 g, 0.870 mmol) was treated with 1 ,4-dioxane (1.160 ml) and water (0.290 ml) and heated to 80 °C overnight. After cooling to room temperature the mixture was diluted with EtOAc and water. The combine organics were washed with brine, dried over Na₂S0₄, and loaded onto celite. The residue was purified by silica gel chromatography (50-100% EtOAc/hexanes) to give 5-(2- amino-4-oxo-3-(2-(trifluoromethyl)phenyl)-3,4-dihydroquinazolin-6-yl)-2-methoxypyridine-3- sulfonamide (.075 g, 0.153 mmol, 52.6 % yield) as a solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.72 (d, J=2.24 Hz, 1 H), 8.30 (d, J=2.15 Hz, 1 H), 8.09 (d, J=1.95 Hz, 1 H), 7.93 - 8.01 (m, 2 H), 7.85 - 7.93 (m, 1 H), 7.73 - 7.80 (m, 1 H), 7.64 (d, J=7.71 Hz, 1 H), 7.45 (s, 2 H), 7.37 (d, J=8.49 Hz, 1 H), 6.67 (br. s., 2 H), 4.04 (s, 3 H); ES-LCMS: 492.1 (M+1 ).

Example 260

5-(2-amino-4-oxo-3-(pyridin-3-yl)-3,4-dihydroquinazolin-6-yl)-2-methoxypy

sulfonamide

5-(2-amino-4-oxo-3-(pyridin-3-yl)-3,4-dihydroquinazolin-6-yl)-2-methoxypyridi A solution of mixture 2-amino-6-bromo-3-(pyridin-3-yl)quinazolin-4(3H)-one (.150 g, 0.473 mmol), 2-methoxy-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridine-3-sulfonamide (0.163 g, 0.520 mmol), PdCI₂(dppf)-DCM adduct (0.039 g, 0.047 mmol), Cs₂C0₃ (0.462 g, 1.419 mmol) was treated with 1 ,4-dioxane (1.892 ml) and water (0.473 ml) and heated to 80 °C overnight. After cooling to room temperature the mixture was diluted with EtOAc and water. The combined organics were washed with brine, dried over Na₂S0₄, and loaded onto celite. The residue was purified by silica gel chromatography (50-100% EtOAc/hexanes) to give 5-(2-amino-4-oxo-3- (pyridin-3-yl)-3,4-dihydroquinazolin-6-yl)-2-methoxypyridine-3-sulfonamide (77.7 mg, 0.183 mmol, 38.7 % yield) as a solid. ¹H NMR (400 MHz, DMSO- ₆) δ ppm 8.67 - 8.76 (m, 2 H), 8.60 (d, J=2.24 Hz, 1 H), 8.29 (d, J=2.44 Hz, 1 H), 8.10 (d, J=2.24 Hz, 1 H), 7.98 (dd, J=8.58, 2.34 Hz, 1 H), 7.86 - 7.93 (m, 1 H), 7.62 (dd, J=8.00, 4.78 Hz, 1 H), 7.45 (s, 2 H), 7.37 (d, J=8.58 Hz, 1 H), 6.67 (br. s., 2 H), 4.04 (s, 3 H); ES-LCMS: 425.2 (M+1 ).

Example 261

5-(2-amino-4-oxo-3-(pyridin-4-yl)-3,4-dihydroquinazolin-6-yl)-N-(2,4-difluo

methoxypyridine-3-sulfonamide

Step A

amino-5-bromo-N-(pyridin-4-yl)benzamide

A solution of 6-bromo-1 H-benzo[d][1 ,3]oxazine-2,4-dione (5.0 g, 20.66 mmol) and pyridine- amine (2.139 g, 22.72 mmol) and DMAP (0.252 g, 2.066 mmol) in DMF (77 ml) was stirred at room temperature overnight. The reaction was then heated to 60 °C overnight. The reaction was diluted with water and the solid was filtered. To remove residual water, the solid was taken up in EtOAc and dried over Na₂S0₄, filtered, and concentrated to give 2-amino-5-bromo-N- (pyridin-4-yl)benzamide (3.406 g, 11.66 mmol, 56.4 % yield) as a solid. ES-LCMS: 292.0, 294.0 (M+1 ).

Step B

5-bromo-N-(pyridin-4-yl)- -((triphenylphosphoranylidene)amino)b

A mixture of 2-amino-5-bromo-N-(pyridin-4-yl)benzamide (1.4 g, 4.79 mmol), triphenylphosphine (1.885 g, 7.19 mmol), and 1 ,2-dibromotetrachloroethane (2.341 g, 7.19 mmol) in dry DCM (41.6 ml) was treated by the drop wise addition of TEA (2.004 ml, 14.38 mmol) at room temperature. After being stirred overnight, the reaction was concentrated onto celite and purified by silica gel chromatography (70-100% EtOAc/hexanes) to give 5-bromo-N-(pyridin-4-yl)-2- ((triphenylphosphoranylidene)amino)benzamide (.485 g, 0.878 mmol, 18.32 % yield) as a yellow solid. ES-LCMS: 552.1 , 554.1 (M+1 ).

Step C

6-bromo-2-((4-methoxybenzyl)amino)-3-(pyridin-4-yl)quinazolin

A solution of 5-bromo-N-(pyridin-4-yl)-2-((triphenylphosphoranylidene)amino)benzamide (0.490 g, .860 mmol) and 1-(isocyanatomethyl)-4-methoxybenzene (0.150 ml, 1.503 mmol) in anhydrous o-xylene (6.0 ml) was placed in a microwave tube under nitrogen. The reaction was heated in the microwave for 20 minute at 160 °C. The reaction was concentrated under reduced pressure. The was purified by silica gel chromatography (70-100% EtOAc/hexane) to give 6-bromo-2-((4-methoxybenzyl)amino)-3-(pyridin-4-yl)quinazolin-4(3H)-one (.571 g, 1.306 mmol, 100 % yield) as a yellow solid. ES-LCMS: 437.1 , 439.1 (M+1 ). Step D

2-amino-6-bro -3-(pyridin-4-yl)quinazolin-4(3H)-one

A solution of 6-bromo-2-((4-methoxybenzyl)amino)-3-(pyridin-4-yl)quinazolin-4(3H)-one (.345 g, 0.789 mmol) in TFA (8.77 ml) was heated in a microwave at 140 °C for 15 minutes. The reaction was concentrated under reduced pressure. The residue was taken up in DCM and washed with saturated NaHC0₃ (3x), the solid were filtered, the organics were washed with brine, dried over Na₂S0₄, filtered, and concentrated. The residue was purified by silica gel chromatography (3-10% eOH/DCM, then 10% 2N NH₄OH in MeOH/DCM). The isolated product was combined with solids to give 2-amino-6-bromo-3-(pyridin-4-yl)quinazolin-4(3H)-one (0.080 g, 32%). ES-LCMS: 317.0, 319.1 (M+1).

Step E

5-(2-amino-4-oxo-3-(pyridin-4-yl)-3,4-dihydroquinazolin-6-yt)-N-(2,4-diftuoroph

methoxypyridine-3-sulfonamide

A solution of mixture 2-amino-6-bromo-3-(pyridin-4-yl)quinazolin-4(3H)-one (.080 g, 0.252 mmol), N-(2,4-difluorophenyl)-2-methoxy-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)pyridine-3-sulfonamide (0.1 18 g, 0.277 mmol), PdCI₂(dppf)-DCM adduct (0.021 g, 0.025 mmol), Cs₂C0₃ (0.247 g, 0.757 mmol) was treated with 1 ,4-dioxane (1.009 ml) and water (0.252 ml) and heated to 80 °C overnight. After cooling to room temperature the mixture was diluted with EtOAc and water. The combined organics were washed with brine, dried over Na₂S0₄, and loaded onto celite. The residue was purified by silica gel chromatography (100% EtOAc, then 5- 10% MeOH/DCM). The fractions containing the product were combined and were purified by reverse phase chromatography (ACN/H₂0 + formic acid) to give 5-(2-amino-4-oxo-3-(pyridin-4- yl)-3,4-dihydroquinazolin-6-yl)-N-(2,4-difluorophenyl)-2-methoxypyridin (.044 g,

0.082 mmol, 32.5 % yield). H NMR (400 MHz, DMSO-cfe) δ ppm 10.22 (br. s., 1 H), 8.77 - 8.83 (m, 2 H), 8.71 - 8.77 (m, 1 H), 8.14 - 8.19 (m, 1 H), 8.00 - 8.05 (m, 1 H), 7.89 - 7.96 (m, 1 H), 7.46 - 7.52 (m, 2 H), 7.27 - 7.37 (m, 2 H), 7.18 - 7.27 (m, 1 H), 6.96 - 7.08 (m, 1 H), 6.65 (br. s., 2 H), 3.97 (s, 3 H); ES-LCMS: 537.2 (M+1 ).

Example 262

5-(2-amino-4-oxo-3-(2-(trifluoromethyl)phenyl)-3,4-dihydroquinazoli

N,N-dimethylpyridine-3-sulfonamide

5-(2-amino-4-oxo-3-(2-(trifluoromethyl)phenyl)-3,4-dihydroquinazoli

dimethylpyridine-3-sulfonamide

A solution of mixture 2-amino-6-iodo-3-(2-(trifluoromethyl)phenyl)quinazolin-4(3H)-one (.125 g, 0.290 mmol), 2-methoxy-N,N-dimethyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridine-3- sulfonamide (0.149 g, 0.435 mmol), PdCI₂(dppf)-DCM adduct (0.024 g, 0.029 mmol), Cs₂C0₃ (0.283 g, 0.870 mmol) was treated with 1 ,4-dioxane (1.160 ml) and heated to 80 °C overnight. After cooling to room temperature the mixture was diluted with EtOAc and water. The combined organics were washed with brine, dried over Na₂S0₄, and loaded onto celite. The residue was purified by silica gel chromatography (50-100% EtOAc/hexanes) to give 5-(2-amino-4-oxo-3-(2- (trifluoromethyl)phenyl)-3,4-dihydroquinazolin-6-yl)-2-methoxy-N,N-dimethylpyridine-3- sulfonamide (.104 g, 0.200 mmol, 69.1 % yield) as a solid. H NMR (400 MHz, DMSO-d₆) δ ppm 8.77 (br. s., 1 H), 8.29 (br. s., 1 H), 7.49 - 8.22 (m, 6 H), 7.37 (br. s., 1 H), 6.68 (br. s., 2 H), 4.03 (br. s., 3 H), 2.80 (br. s., 6 H); ES-LCMS: 520.2 (M+1 ).

Example 263

5-(2-amino-4-oxo-3-(2-(trifluoromethyl)phenyl)-3,4-dihydroquinazolm

methylpyridine-3-sulfonamide

5-(2-amino-4-oxo-3-(2-(trifluoromethyl)phenyl)-3,4-dihydroquinazo

methylpyridine-3-sulfonamide

A solution of mixture 2-amino-6-iodo-3-(2-(trifluoromethyl)phenyl)quinazolin-4(3H)-one (.125 g, 0.290 mmol), 2-methoxy-N-methyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridine-3- sulfonamide (0.105 g, 0.319 mmol), PdCI₂(dppf)-DC adduct (0.024 g, 0.029 mmol), Cs₂C0₃ (0.283 g, 0.870 mmol) was treated with 1 ,4-dioxane (1.160 ml) and water (0.290 ml) and heated to 80 °C overnight. After cooling to room temperature the mixture was diluted with EtOAc and water. The combined organics were washed with brine, dried over Na₂S0₄, and loaded onto celite. The residue was purified by silica gel chromatography (50-100% EtOAc/hexanes) to give 5-(2-amino-4-oxo-3-(2-(trifluoromethyl)phenyl)-3,4-dihydroquinazolin-6-yl)-2-methoxy-N- methylpyridine-3-sulfonamide (.083 g, 0.164 mmol, 56.6 % yield) as a solid. H NMR (400 MHz, DMSO-cf₆) δ ppm 8.76 (s, 1 H), 8.27 (s, 1 H), 8.10 (s, 1 H), 7.84 - 8.04 (m, 3 H), 7.71 - 7.82 (m, 1 H), 7.58 - 7.67 (m, 1 H), 7.43 - 7.50 (m, 1 H), 7.36 (d, J=8.49 Hz, 1 H), 6.68 (br. s., 2 H), 4.03 (s, 3 H), 2.50 (br. s., 3 H); ES-LCMS: 506.2 (M+1 ).

Example 264

5-(2-amino-4-oxo-3-(pyridin-3-yl)-3,4-dihydroquinazolin-6-yl)-N-(2,6-diff

5-(2-amino-4-oxo-3-(pyridin-3-yl)-3,4-dihydroquinazolin-6-yl)-N-(2^-difl methoxypyridine-3-sulfonamide

A solution of mixture 2-amino-6-bromo-3-(pyridin-3-yl)quinazolin-4(3H)-one (.150 g, 0.473 mmol), N-(2,6-difluorophenyl)-2-methoxy-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)pyridine-3-sulfonamide (0.222 g, 0.520 mmol), PdCI₂(dppf)-DCM adduct (0.039 g, 0.047 mmol), Cs₂C0₃ (0.462 g, 1.419 mmol) was treated with 1 ,4-dioxane (1.892 ml) and water (0.473 ml) and heated to 80 °C overnight. After cooling to room temperature the mixture was diluted with EtOAc and water. The combined organics were washed with brine, dried over Na₂S0₄, and loaded onto celite. The residue was purified by silica gel chromatography (50-100%

EtOAc/hexanes) to give 5-(2-amino-4-oxo-3-(pyridin-3-yl)-3,4-dihydroquinazolin-6-yl)-N-(2,6- difluorophenyl)-2-methoxypyridine-3-sulfonamide (.071 g, 0.132 mmol, 28.0 % yield) as a solid. H NMR (400 MHz, DMSO-d₆) δ ppm 8.76 (s, 1 H), 8.70 (s, 1 H), 8.58 (s, 1 H), 8.18 (s, 1 H), 8.03 (s, 1 H), 7.85 - 7.97 (m, 2 H), 7.51 - 7.65 (m, 2 H), 7.29 - 7.38 (m, 2 H), 7.10 (t, J=8.00 Hz, 2 H), 6.67 (br. s., 2 H), 3.96 (s, 3 H); ES-LCMS: 537.1 (M+1 ).

Example 265

(S)-N-(5-(2-amino-4-oxo-3-(1^henylethyl)-3,4-dihydroquinazolin-6-yl)-2-me

3-yl)-2,4-difluorobenzenesulfonamide

Step A

(S)-2-amino-5-bromo-N-( 1 -phenylethyl)benzamide

A solution of 6-bromo-1 H-benzo[d][1 ,3]oxazine-2,4-dione (5.0 g, 20.66 mmol) and (S)-1- phenylethanamine (2.89 ml, 22.72 mmol) and DMAP (0.252 g, 2.066 mmol) in DMF (73.6 ml) was stirred at room temperature overnight. The reaction was diluted with water and the solid was filtered. To remove residual water, the solid was taken up in EtOAc and dried with Na₂S0₄, filtered, and concentrated to give (S)-2-amino-5-bromo-N-(1-phenylethyl)benzamide (4.901 g, 15.35 mmol, 74.3 % yield) as a solid. ES-LCMS: 319.0, 321.0 (M+1 ).

Step B

(S)-5-bromo-N-(1^henyiethyl)-2-((triphenylphosphoranylidene)amino)benzamide

A mixture of (S)-2-amino-5-bromo-N-(1-phenylethyl)benzamide (1.0 g, 3.13 mmol),

triphenylphosphine (1.233 g, 4.70 mmol), and 1 ,2-dibromotetrachloroethane (1.530 g, 4.70 mmol) in dry DCM (27.2 ml) was treated by the drop wise addition of TEA (1.310 ml, 9.40 mmol) at room temperature overnight. The reaction was concentrated onto celite and purified by silica gel chromatography (20-50% EtOAc/hexanes) to give (S)-5-bromo-N-(1-phenylethyl)-2- ((triphenylphosphoranylidene)amino)benzamide (.617 g, 1.065 mmol, 34.0 % yield) as a light beige solid. ES-LCMS: 579.1 , 581.2 (M+1 ).

Step C

(S)-6-bromo-2-((4-meth thyl)quinazolin

A solution of (S)-5-bromo-N-(1-phenylethyl)-2-((triphenylphosphoranylidene)amino)benzamide (.617 g, 1.065 mmol) and 1-(isocyanatomethyl)-4-methoxybenzene (0.182 ml, 1.278 mmol) in anhydrous o-xylene (11.65 ml) was placed in a microwave tube under nitrogen. The reaction was heated in the microwave for 5 hours at 160 °C. The reaction was concentrated onto celite and purified with silica gel chromatography (0-50% EtOAc/hexanes) to give (S)-6-bromo-2-((4- methoxybenzyl)amino)-3-(1-phenylethyl)quinazolin-4(3H)-one as a yellow solid. ES-LCMS: 464.1 , 466.2 (M+1 ).

Step D

(S)-2-amino- azolin-4(3H)-one

A solution of (S)-6-bromo-2-((4-rnethoxybenzyl)amino)-3-(1-phenylethyl)quinazolin-4(3H)-one (.295 g, 0.635 mmol) in DCM (1.626 ml) was treated by the addition of DDQ (0.159 g, 0.699 mmol) and stirred at room temperature for 48 hours. The reaction was then treated with DDQ (0.159 g, 0.699 mmol) and stirred overnight. The reaction was then treated with DDQ (0.159 g, 0.699 mmol) and stirred overnight. The reaction was treated with celite and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-50%

EtOAc/hexane) to give mostly pure product (.549 g). The brown oil was re-purified by silica gel chromatography (0-50% EtOAc/hexane) to give (S)-2-amino-6-bromo-3-(1- phenylethyl)quinazolin-4(3H)-one (.194 g, 0.564 mmol, 89 % yield) as a reddish/brown solid. ES-LCMS: 344.0, 346.0 (M+1).

Step E

(S)-N-(5-(2-amino-4-oxo-3-(1^henylethyl)-3,4-dihydroquinazolin-6-yl)-2-m

2, 4-difluorobenzenesulfonamide

A solution of mixture (S)-2-amino-6-bromo-3-(1-phenylethyl)quinazolin-4(3H)-one (.097 g, 0.282 mmol), 2,4-difluoro-N-(2-methoxy-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridin-3- yl)benzenesulfonamide (0.132 g, 0.310 mmol), PdCI₂(dppf)-DCM adduct (0.023 g, 0.028 mmol), Cs₂C0₃ (0.275 g, 0.845 mmol) was treated with 1 ,4-dioxane (1.127 ml) and water (0.282 ml) and heated to 80 °C overnight. After cooling to room temperature the mixture was diluted with EtOAc and water. The combined organics were washed with brine, dried over Na₂S0₄, and loaded onto celite. The residue was purified by silica gel chromatography {50-100%

EtOAc/hexanes) to give (S)-N-(5-(2-amino-4-oxo-3-(1-phenylethyl)-3,4-dihydroquinazolin-6-yl)- 2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide (.019 g, 0.034 mmol, 11.96 % yield) as a solid. H NMR (400 MHz, DMSO-d₆) δ ppm 10.20 - 10.33 (m, 1 H), 8.25 - 8.38 (m, 1 H), 7.93 - 8.00 (m, 1 H), 7.80 - 7.88 (m, 2 H), 7.67 - 7.79 (m, 1 H), 7.50 - 7.60 (m, 1 H), 7.14 - 7.42 (m, 7 H), 6.79 (br. s., 2 H), 5.91 - 6.23 (m, 1 H), 3.59 - 3.67 (m, 3 H), 1.75 - 1.95 (m, 3 H); ES-LCMS: 564.2 (M+1).

Example 266

(S)-5-(2-amino-4-oxo-3-(1-phenylethyl)-3,4-dihydroquinazolin-6-yl)-N^

2-methoxypyridine-3-sulfonamide

(S)-5-(2-amino-4-oxo-3-(1^henylethyl)-3,4-dihydroquinazolin-6-yl)-N-(2,4-diflu

methoxypyridine-3-sulfonamide

A solution of mixture (S)-2-amino-6-bromo-3-(1-phenylethyl)quinazolin-4(3H)-one (.097 g, 0.282 mmol), N-(2,4-difluorophenyl)-2-methoxy-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)pyridine-3-sulfonamide (0.132 g, 0.310 mmol), PdCI₂(dppf)-DCM adduct (0.023 g, 0.028 mmol), Cs₂C0₃ (0.275 g, 0.845 mmol) was treated with 1,4-dioxane (1.127 ml) and water (0.282 ml) and heated to 80 °C overnight. After cooling to room temperature the mixture was diluted with EtOAc and water. The combined organics were washed with brine, dried over Na₂S0₄, and loaded onto celite. The residue was purified by silica gel chromatography (50-100%

EtOAc/hexanes) to give (S)-5-(2-amino-4-oxo-3-(1-phenylethyl)-3,4-dihydroquinazolin-6-yl)-N- (2,4-difluorophenyl)-2-methoxypyridine-3-sulfonamide (.025 g, 0.044 mmol, 15.74 % yield) as a solid. ¹H NMR (400 MHz, DMSO-af₆) δ ppm 10.17 (s, 1 H), 8.71 (s, 1 H), 8.14 (s, 1 H), 7.98 (s, 1 H), 7.79 - 7.89 (m, 1 H), 7.16 - 7.45 (m, 8 H), 7.01 - 7.11 (m, 1 H), 6.84 (br. s., 2 H), 6.07 (br. s., 1 H), 3.98 (s, 3 H), 1.79 - 1.93 (m, 3 H); ES-LCMS: 564.2 (M+1).

Example 267

5-(2-amino-3-(naphthalen-1-yl)-4-oxo-3,4-dihydroquinazolin-6-yl)-N-(2,4-d^

methoxypyridine-3-sulfonamide

Step A

6-iodo-3-(naphthalen- 1 -yl)-2-thioxo-2, 3-dihydroquinazolin-4( 1 H)-one

A solution of 2-amino-5-iodobenzoic acid (5.0 g, 19.01 mmol), 1 -isothiocyanatonaphthalene (3.87 g, 20.91 mmol), and TEA (3.71 ml, 26.6 mmol) in 1 ,4-dioxane (91 ml) was heated at reflux overnight. The reaction was then cooled to room temperature and the solids were filtered rinsing with Et₂0 to give 6-iodo-3-(naphthalen-1-yl)-2-thioxo-2,3-dihydroquinazolin-4(1H)-one (7.3 g, 16.97 mmol, 89 % yield) as an white solid. ES-LCMS: 431.0 (M+1).

Step B

2-chloro-6-iodo azolin-4(3H)-one

A flask containing 6-iodo-3-(naphthalen-1-yl)-2-thioxo-2,3-dihydroquinazolin-4(1 H)-one (3.11 g, 7.23 mmol) was treated with POCI₃ (16.17 ml, 173 mmol) and then PCI₅ (2.408 g, 11.57 mmol) and heated to 110 °C overnight. After cooling, the solvents were removed under reduced pressure and the residue was taken up in EtOAc, washed with water (3x), brine, dried over MgS0₄, filtered, and concentrated to give 2-chloro-6-iodo-3-(naphthalen-1-yl)quinazolin-4(3H)- one (2.485 g, 5.74 mmol, 79 % yield) as a yellowish brown solid. ES-LCMS: 433.0 (M+1 ).

Step C

6-iodo-2-((4-methoxybe -1-yl)quinazolin-4(3H)-on

A flask containing 2-chloro-6-iodo-3-(naphthalen-1-yl)quinazolin-4(3H)-one (2.49 g, 5.76 mmol) in DMF (26.4 ml) was treated with DIEA (1.508 ml, 8.63 mmol) and4-methoxybenzylamine (0.827 ml, 6.33 mmol) and heated to 80 °C for 90 minutes. After cooling to room temperature, the reaction was diluted with EtOAc and then washed with 5% LiCI (3x), brine, the solids were filtered and discarded, the organics were dried over Na₂S0₄, filtered, and concentrated to give 6-iodo-2-((4-methoxybenzyl)amino)-3-(naphthalen-1-yl)quinazolin-4(3H)-one (2.786 g, 5.22 mmol, 91 % yield) as a yellow solid. ES-LCMS: 534.1 (M+1 ).

Step D

2-amino-6-iodo-3- azolin-4(3H)-one

A solution of 6-iodo-2-((4-methoxybenzyl)amino)-3-(naphthalen-1-yl)quinazolin-4(3H)-one (2.0 g, 3.75 mmol) in TFA (18.75 ml) was heated in the microwave at 140 °C for 20 minutes. After concentrating under reduced pressure, the residue was taken up in DCM and washed with saturated NaHC0₃ (3x), brine, dried Na₂S0₄, filtered, and concentrated to give 2-amino-6-iodo- 3-(naphthalen-1-yl)quinazolin-4(3H)-one (1.80 g, 4.36 mmol, 116 % yield) as a brown solid. ES-LCMS: 514.0 (M+1). Step E

5-(2-amino-3-(naphthalen-1-yl)-4-oxo-3,4-dihydroquinazolin-6-yi)-N^

methoxypyridine-3-sulfonamide

A solution of mixture 2-amino-6-iodo-3-(naphthalen-1-yl)quinazolin-4(3H)-one (.300 g, 0.726 mmol), N-(2,4-difluorophenyl)-2-methoxy-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)pyridine-3-sulfonamide (0.340 g, 0.799 mmol), PdCI₂(dppf)-DCM adduct (0.059 g, 0.073 mmol), Cs₂C0₃ (0.710 g, 2.178 mmol) was treated with 1 ,4-dioxane (2.90 ml) and water (0.726 ml) and heated to 80 °C overnight. After cooling to room temperature the mixture was diluted with EtOAc and water. The combined organics were washed with brine, dried over Na₂S0₄, and loaded onto celite. The residue was purified by silica gel chromatography (50- 00%

EtOAc/hexanes) to give 5-(2-amino-3-(naphthalen-1-yl)-4-oxo-3,4-dihydroquinazolin-6-yl)-N- (2,4-difluorophenyl)-2-methoxypyridine-3-sulfonamide (.118 g, 0.202 mmol, 27.8 % yield) as a solid. H NMR (400 MHz, DMSO-c/₆) δ ppm 10.19 (s, 1 H), 8.77 (s, 1 H), 8.00 - 8.23 (m, 4 H), 7.88 - 8.00 (m, 1 H), 7.17 - 7.78 (m, 8 H), 6.96 - 7.09 (m, 1 H), 6.52 (br. s., 2 H), 3.97 (s, 3 H); ES-LCMS: 582.2 (M+1).

Example 268

N-(5-(2-amino-3-(naphthaien-1-yl)-4-oxo-3,4-dihydroquinazolin-6-yl)-2-meth^

yl)-2,4-difluorobenzenesulfonamide

6-iodo-3-(naphthalen- 1 -yl) -2-thioxo-2, 3-dihydroquinazolin-4(1 H)-one

A solution of mixture 2-amino-6-iodo-3-(naphthalen-1-yl)quinazolin-4(3H)-one (.300 g, 0.726 mmol), 2,4-difluoro-N-(2-methoxy-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridin-3- yl)benzenesulfonamide (0.340 g, 0.799 mmol), PdCI₂(dppf)-DCM adduct (0.059 g, 0.073 mmol), Cs₂C0₃ (0.710 g, 2.178 mmol) was treated with 1 ,4-dioxane (2.90 ml) and water (0.726 ml) and heated to 80 °C overnight. After cooling to room temperature the mixture was diluted with EtOAc and water. The combined organics were washed with brine, dried over Na₂S0₄, and loaded onto celite. The residue was purified by silica gel chromatography (50-100%

EtOAc/hexanes) to give N-(5-(2-amino-3-(naphthalen-1-yl)-4-oxo-3,4-dihydroquinazolin-6-yl)-2- methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide (.120 g, 0.205 mmol, 28.2 % yield) as a solid. H NMR (400 MHz, DMSO-d₆) δ ppm 10.29 (s, 1 H), 8.34 (s, 1 H), 8.07 - 8.17 (m, 2 H), 8.01 - 8.07 (m, 1 H), 7.91 - 7.96 (m, 1 H), 7.84 - 7.89 (m, 1 H), 7.65 - 7.79 (m, 2 H), 7.44 - 7.66 (m, 5 H), 7.39 - 7.43 (m, 1 H), 7.15 - 7.24 (m, 1 H), 6.51 (br. s., 2 H), 3.65 (s, 3 H); ES-LCMS: 586.2 (M+1).

Example 269

(R)-N-(5-(2-amino-4-oxo-3-(1-phenylethyl)-3,4-dihydroquinazolin-6-yl)-2-m

3-yl)-2,4-difluorobenzenesulfonamide

Step A

(R)-2-amino-5-bromo-N-( 1 -phenylethyl)benzamide

A solution of 6-bromo-1 H-benzo[d][1 ,3]oxazine-2,4-dione (5.0 g, 20.66 mmol) and (R)-1- phenylethanamine (2.89 ml, 22.72 mmol) and DMAP (0.252 g, 2.066 mmol) in DMF (73.6 ml) was stirred at room temperature overnight. The reaction was diluted with water and the solid was filtered. To remove residual water, the solid was taken up in EtOAc and dried with Na₂S0₄, filtered, and concentrated to give (R)-2-amino-5-bromo-N-(1-phenylethyl)benzamide (4.412 g, 13.82 mmol, 66.9 % yield) as a solid. ES-LCMS: 319.0, 321.0 (M+1).

Step B

(R)-5-bromo-N-(1^henylethyl)-2-((triphenylphosphoranylidene)amino)b

A mixture of (R)-2-amino-5-bromo-N-(1-phenylethyl)benzamide (3.0 g, 9.40 mmol),

triphenylphosphine (3.70 g, 14.10 mmol), and 1 ,2-dibromotetrachloroethane (4.59 g, 14.10 mmol) in dry DCM (82 ml) was treated by the drop wise addition of TEA (3.93 ml, 28.2 mmol) at room temperature. After stirring overnight, the reaction was loaded onto celite concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-50%

EtOAc/hexanes) to give (R)-5-bromo-N-(1 -phenylethyl)-2-

((triphenylphosphoranylidene)amino)benzamide (4.65 g, 8.02 mmol, 85 % yield). ES-LCMS: 579.1 , 581.1 (M+1 ).

Step C

(R)-6-bromo-2-((4-methoxybenzyl)amino)-3-(1^henylethyl)quinazolin-4(3H)-

A solution of (R)-5-bromo-N-(1-phenylethyl)-2-((triphenylphosphoranylidene)amino)benzamide (2.5 g, 4.31 mmol) and 1-(isocyanatomethyl)-4-methoxybenzene (0.739 ml, 5.18 mmol) in anhydrous o-xylene (24.64 ml) was placed in a microwave tube under nitrogen. The reaction was placed in an oil bath 160 °C and stirred overnight. The reaction was concentrated onto celite and purified with silica gel chromatography (0-50% EtOAc/hexanes) to give pure (R)-6- bromo-2-((4-methoxybenzyl)amino)-3-(1-phenylethyl)quinazolin-4(3H)-one (1.19 g, 2.56 mmol, 59.4 % yield) as a yellow solid. ES-LCMS: 464.1 , 466.1 (M+1 ).

Step D

'-amino-6-bromo-3-( 1 -phenylethyl)quinazolin-4(3H)-

A solution of (R)-6-bromo-2-((4-methoxybenzyl)amino)-3-(1-phenylethyl)quinazolin-4(3H)-one (1.19 g, 2.56 mmol) in DCM (1.626 ml) was treated by the addition of DDQ (0.873 g, 3.84 mmol) and stirred at room temperature for 48 hours. The reaction was then treated with additional DDQ (0.873 g, 3.84 mmol) and stirred overnight. The reaction was then treated with additional DDQ (0.873 g, 3.84 mmol) and stirred overnight. The reaction was treated with celite and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-50% EtOAc/hexanes) to give product mixed with DDQ. The residue was loaded onto silica gel and purified by silica gel chromatography (1-5% MeOH/DCM) to give(R)-2-amino-6-bromo- 3-(1-phenylethyl)quinazolin-4(3H)-one (.636 g, 1.848 mmol, 72.1 % yield) as a 50-50 mixture with DDQ impurity. ES-LCMS: 344.1 , 346.2 (M+1 ).

Step E

6-iodo-3-(naphthalen-1-yl)-2-thioxo-2,3-dihydroquinazolin-4(1H)-one

A solution of mixture (R)-2-amino-6-bromo-3-(1-phenylethyl)quinazolin-4(3H)-one (.160 g, 0.465 mmol), 2,4-difluoro-N-(2-methoxy-5-(4,4,5,5-tetramethyl-1 _J3,2-dioxaborolan-2-yl)pyridin-3- yl)benzenesulfonamide (0.139 g, 0.325 mmol), PdCI₂(dppf)-DCM adduct (0.038 g, 0.046 mmol), Cs₂C0₃ (0.454 g, 1.395 mmol) was treated with 1 ,4-dioxane (1.859 ml) and water (0.465 ml) and heated to 80 °C overnight. After cooling to room temperature the mixture was diluted with EtOAc and water. The combine organics were washed with brine, dried over Na₂S0₄, and loaded onto celite. The residue was purified by silica gel chromatography (50-100%

EtOAc/hexanes) to give (R)-N-(5-(2-amino-4-oxo-3-(1-phenylethyl)-3,4-dihydroquinazolin-6-yl)- 2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide (.041 g, 0.073 mmol, 15.65 % yield) as a solid. ¹H NMR (400 MHz, DMSO-af₆) δ ppm 10.28 (br. s., 1 H), 8.30 (br. s., 1 H), 7.97 (br. s., 1 H), 7.85 (br. s., 2 H), 7.68 - 7.80 (m, 1 H), 7.56 (br. s., 1 H), 7.10 - 7.44 (m, 8 H), 6.81 (br. s., 1 H), 6.08 (br. s., 1 H), 3.63 (s, 3 H), 1.89 (d, 3 H); ES-LCMS: 564.2 (M+1 ).

Example 270

(R)-5-(2-amino-4-oxo-3-(1-phenylethyl)-3,4-dihydroquinazolin-6-yl)-N^

2-methoxypyridine-3-sulfonamide

(R)-5-(2-amino-4-oxo-3-(1^henylethyl)-3,4-dihydroquinazoiin-6-y^ methoxypyridine-3-sulfonamide

A solution of mixture (R)-2-amino-6-bromo-3-(1-phenylethyl)quinazolin-4(3H)-one (.160 g, 0.465 mmol), N-(2,4-difluorophenyl)-2-methoxy-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)pyridine-3-sulfonamide (0.139 g, 0.325 mmol), PdCI₂(dppf)-DCM adduct (0.038 g, 0.046 mmol), Cs₂C0₃ (0.454 g, 1.395 mmol) was treated with 1 ,4-dioxane (1 .859 ml) and water (0.465 ml) and heated to 80 °C overnight. After cooling to room temperature the mixture was diluted with EtOAc and water. The combined organics were washed with brine, dried over Na₂S0₄, and loaded onto celite. The residue was purified by silica gel chromatography (50-100%

EtOAc/hexanes) to give (R)-5-(2-amino-4-oxo-3-(1-phenylethyl)-3,4-dihydroquinazolin-6-yl)-N- (2,4-difluorophenyl)-2-methoxypyridine-3-sulfonamide (.033 g, 0.059 mmol, 12.60 % yield) as a solid. H NMR (400 MHz, DMSO-cf₆) δ ppm 10.17 (br. s., 1 H), 8.73 (br. s., 1 H), 8.15 (br. s., 1 H), 7.78 - 8.07 (m, 2 H), 7.27 (br. s., 9 H), 7.02 (br. s., 1 H), 6.86 (br. s., 1 H), 6.14 (br. s., 1 H), 3.96 (br. s., 3 H), 1.88 (br. s., 3 H); ES-LCMS: 564.2 (M+1 ).

Example 271

5-(2-amino-4-oxo-3-(3-(trifluoromethyl)phenyl)-3,4-dihydroquinazolin^

difluorophenyl)-2-methoxypyridine-3-sulfonamide

6-iodo-2-thioxo-3-(3- uinazolin-4( 1 H)-one

A solution of 2-amino-5-iodobenzoic acid (5.0 g, 19.01 mmol) and 1-isothiocyanato-3- (trifluoromethyl)benzene (3.19 ml, 20.91 mmol) in 1 ,4-dioxane (88 ml) was treated with TEA (3.71 ml, 26.6 mmol) and heated to reflux overnight. After cooling to room temperature, the solvents were removed under reduced pressure and the brown residue was sonicated with Et₂0 for 5 minutes. The solids were filtered to give 6-iodo-2-thioxo-3-(3-(trifluoromethyl)phenyl)-2,3- dihydroquinazolin-4(1H)-one (5.2 g, 11.60 mmol, 61.0 % yield) as a white solid. ES-LCMS: 449.0 (M+1).

Step B

2-chloro-6-iodo-3-( -(trifluoromethyl)phenyl)quinazolin-4(3H)-one

A solution of 6-iodo-2-thioxo-3-(3-(trifluoromethyl)phenyl)-2,3-dihydroquinazolin-4(1 H)-one (3.0 g, 6.69 mmol) was treated with POCI₃ (14.97 ml, 161 mmol) and PCI₅ (2.230 g, 10.71 mmol) and heated to reflux overnight. The reaction was concentrated under reduced pressure and the residue was taken up in EtOAc. The organic layer was washed with water (3x), water, dried over Na₂S0₄, filtered, and concentrated to give 2-chloro-6-iodo-3-(3-

(trifluoromethyl)phenyl)quinazolin-4(3H)-one (2.68 g, 5.95 mmol, 89 % yield) as a yellow solid. ES-LCMS: 451.0 (M+1).

Step C

6-iodo-2-((4-methoxybenzyl)amino)-3-(3-(trifluoromethyl)phen

A solution of 2-chloro-6-iodo-3-(3-(trifluoromethyl)phenyl)quinazolin-4(3H)-one (2.68 g, 5.95 mmol) in DMF (27.3 ml) was treated with 4-methoxybenzylamine (0.855 ml, 6.54 mmol) and D!EA (1.558 ml, 8.92 mmol). The reaction was heated to 80 °C overnight. The reaction was treated by the addition of 4-methoxybenzylamine (0.855 ml, 6.54 mmol) and DIEA (1.558 ml, 8.92 mmol) and continued to heat for 3 hours. After cooling to room temperature, the reaction was diluted with EtOAc and washed with 5% LiCI (3x), brine, dried over Na₂S0₄, filtered, and concentrated to give the crude residue as a dark brown semi-solid. The residue was loaded onto celite and purified by silica gel chromatography (0-50% EtOAc/hexanes) to give 6-iodo-2- ((4-methoxybenzyl)amino)-3-(3-(trifluoromethyl)phenyl)quinazolin-4(3H)-one (2.42 g, 4.39 mmol, 73.8 % yield) as a yellow solid. ES-LCMS: 552.1 (M+1 ).

Step D 2-amino-6-iodo-3-(3- quinazolin-4(3H)-one

A solution of 6-iodo-2-((4-methoxybenzyl)amino)-3-(3-(trifluoromethyl)phenyl)quinazolin-4(3H)- one (2.42 g, 4.39 mmol) in TFA (21.95 ml) was heated to 140 °C using the microwave for 25 minutes. The reactions were combined and concentrated under reduced pressure. The residue was taken up in DCM and washed with saturated NaHC0₃ (3x), brine, the solids were filtered to give 2-amino-6-iodo-3-(3-(trifluoromethyl)phenyl)quinazolin-4(3H)-one (1.522 g, 3.53 mmol, 80 % yield) as a white solid. ES-LCMS: 432.0 (M+1).

Step E

5-(2-amino-4-oxo-3-(3-(trifluoromethyl)phenyl)-3,4-dihydroquinazotin^

difluorophenyl)-2-methoxypyridine-3-sulfonamide

A solution of 2-amino-6-iodo-3-(3-(trifluoromethyl)phenyl)quinazolin-4(3H)-one (.113 g, 0.262 mmol), N-(2,4-difluorophenyl)-2-methoxy-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)pyridine-3-sulfonamide (0.123 g, 0.288 mmol), Cs₂C0₃ (0.256 g, 0.786 mmol), and

PdCI₂(dppf)-DCM adduct (0.021 g, 0.026 mmol) in 1 ,4-dioxane (1.048 ml) and water (0.262 ml) was heated to 80 °C for 1 hour. After cooling to room temperature, the solution was diluted with EtOAc and washed with water, brine, dried over Na₂S0₄, and concentrated. The residue was loaded onto celite and purified by silica gel chromatography eluting with (50-100%

EtOAc/hexane) to give product. The product was triturated with Et₂0 to give 5-(2-amino-4-oxo- 3-(3-(trifluoromethyl)phenyl)-3,4-dihydroquinazolin-6-yl)-N-(2,4-difluorophenyl)-2- methoxypyridine-3-sulfonamide (.041 g, 0.068 mmol, 25.9 % yield) as a light beige solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.19 (s, 1 H), 8.75 (d, J=2.44 Hz, 1 H), 8.16 (d, J=2.44 Hz, 1 H), 8.02 (d, J=2.24 Hz, 1 H), 7.83 - 7.97 (m, 3 H), 7.77 - 7.83 (m, 1 H), 7.67 - 7.74 (m, 1 H), 7.19 - 7.38 (m, 3 H), 6.99 - 7.07 (m, 1 H), 6.62 (br. s., 2 H), 3.97 (s, 3 H); ES-LC S: 604.1 ( +1 ).

Example 272

5-(2-amino-4-oxo-3-(4-(trifluoromethyl)phenyl)-3,4-dihydroquinazolm

difluorophenyl)-2-methoxypyridine-3-sulfonamide

6-iodo-2-thioxo-3-(4 uina

A solution of 2-amino-5-iodobenzoic acid (5.0 g, 19.01 mmol), 1-isothiocyanato-4- (trifluoromethyl)benzene (4.25 g, 20.91 mmol), TEA (3.71 ml, 26.6 mmol) and 1 ,4-dioxane (91 ml) was heated to reflux overnight. The reaction was cooled to room temperature and concentrated under reduced pressure. The residue was sonicated in Et₂0 and filtered to give 6- iodo-2-thioxo-3-(4-(trifluoromethyl)phenyl)-2,3-dihydroquinazolin-4(1 H)-one (8.076 g, 18.02 mmol, 95 % yield) as an off-white solid. ES-LCMS: 449.0 (M+1).

Step B

2-chioro-6-iodo-3-(4 inazoiin-4(3H)-one

A solution of 6-iodo-2-thioxo-3-(4-(trifluoromethyl)phenyl)-2,3-dihydroquinazolin-4(1 H)-one (2.96 g, 6.60 mmol) was treated with POCI₃ (14.77 ml, 159 mmol) and PCI₅ (2.200 g, 10.57 mmol) and heated to reflux overnight. The reaction was concentrated under reduced pressure and the solid residue was taken up in EtOAc. The organic layer was washed with water (3x), water, dried over Na₂S0₄, filtered, and concentrated to give 2-chloro-6-iodo-3-(4- (trifluoromethyl)phenyl)quinazolin-4(3H)-one (2.52 g, 5.59 mmol, 85 % yield) as a yellow solid. ES-LCMS: 451.0 ( +1).

Step C

6-iodo-2-((4-methoxybenzyl) enyl)quin

A solution of 2-chloro-6-iodo-3-(4-(trifluoromethyl)phenyl)quinazolin-4(3H)-one (2.52 g, 5.59 mmol) was treated with DIEA (1.465 ml, 8.39 mmol) and 4-methoxybenzylamine (0.877 ml, 6.71 mmol) and heated to 80 °C for 48 hours. The reaction was cooled to room temperature and then diluted with EtOAc and washed with 5% LiCI (3x), brine, dried over Na₂S0₄, filtered, and concentrated to give 6-iodo-2-((4-methoxybenzyl)amino)-3-(4-(trifluoromethyl)phenyl)quinazolin- 4(3H)-one (3.414 g, 6.19 mmol, 111 % yield) as a light brown solid. ES-LCMS: 552.0 (M+1 ).

Step D

2-amino-6-iodo-3-( -(trifluoromethyl)phenyl)quinazolin-4(3H)-one

A solution of 6-iodo-2-((4-methoxybenzyl)amino)-3-(4-(trifluoromethyl)phenyl)quinazolin-4(3H)- one (3.414 g, 6.19 mmol) was treated with TFA (31.0 ml) and heated to 140 °C in the microwave for 20 minutes. The reactions was concentrated and the residue was taken up in DCM and washed with saturated NaHC0₃ (3x), brine, the solids were filtered to give 2-amino-6- iodo-3-(4-(trifluoromethyl)phenyl)quinazolin-4(3H)-one (1.101 g, 41.2%) as a pale yellow solid. ES-LCMS: 432.0 (M+1).

Step E

5-(2-amino-4-oxo-3-(4-(trifluoromethyl)phenyl)-3,4-dihydroqu

difluorophenyl)-2-methoxypyridine-3-sulfonamide

A solution of 2-amino-6-iodo-3-(4-(trifluoromethyl)phenyl)quinazolin-4(3H)-one (.100 g, 0.232 mmol), N-(2,4-difluorophenyl)-2-methoxy-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)pyridine-3-sulfonamide (0.109 g, 0.255 mmol), Cs₂C0₃ (0.227 g, 0.696 mmol), and

PdCI₂(dppf)-DCM adduct (0.019 g, 0.023 mmol) in 1 ,4-dioxane (0.928 ml) and water (0.232 ml) was heated to 80 °C for 1 hour. After cooling to room temperature, the solution was diluted with EtOAc and washed with water, brine, dried over Na₂S0₄, and concentrated onto celite. The residue was purified with silica gel chromatography (50-100% EtOAc/hexanes) to give a residue which was triturated with Et₂0 to give 5-(2-amino-4-oxo-3-(4-(trifluoromethyl)phenyl)-3,4- dihydroquinazolin-6-yl)-N-(2,4-difluorophenyl)-2-methoxypyridine-3-sulfonamide (.083 g, 0.138 mmol, 59.3 % yield) as a light beige solid. H N R (400 MHz, DMSO-of₆) δ ppm 10.19 (s, 1 H), 8.76 (d, J=2.54 Hz, 1 H), 8.16 (d, J=2.44 Hz, 1 H), 8.02 (d, J=2.34 Hz, 1 H), 7.87 - 7.99 (m, 3 H), 7.64 (d, J=8.19 Hz, 2 H), 7.20 - 7.36 (m, 3 H), 6.96 - 7.08 (m, 1 H), 6.60 (br. s., 2 H), 3.97 (s, 3 H); ES-LCMS: 604.1 (M+1).

Example 273 and Example 274

(aS)- N-(5-(2-amino-3-(naphthalen-1-yl)-4-oxo-3,4-dihydroquinazolin-6-yl)-2- methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide and (aR)- N-(5-(2-amino-3- (naphthalen-1-yl)-4-oxo-3,4-dihydroquinazolin-6-yl)-2-methoxypyridm^

difluorobenzenesulfonamide

(aS)- N-(5-(2-amino-3-(naphthalen-1-yl)-4-oxo-3 -dihydroquinazolin-6-yl)^

yl)-2,4-difluorobenzenesulfonamide and (aR)- N-(5-(2-amino-3-(naphthalen-1-yl)-4-oxo-3,4- dihydroquinazolin-6-yl)-2-methoxypyridin-3-yl)-2,4-difluo

Separation of N-(5-(2-amino-3-(naphthalen-1-yl)-4-oxo-3,4-dihydroquinazolin-6-yl)-2- methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide was preformed by dissolving 102 mg of material in 1.5 mL MeOH and 1 mL CHCI₃ with some formic acid, then separated by a prep SFC method 30% MeOH/C0₂, 100 bar, 40 °C, 85 g/min, 220 nm, ASH 25cm x 3cm, 12 mg/inj., to afford first eluting isomer ( 40 mg >99 %ee, ¹H NMR (400 MHz, DMSO- ₆) δ ppm 10.31 (br. s., 1 H), 8.32 (br. s., 1 H), 8.05 - 8.19 (m, 2 H), 8.02 (br. s., 1 H), 7.87 - 7.96 (m, 1 H), 7.84 (br. s., 1 H), 7.34 - 7.79 (m, 8 H), 7.12 - 7.28 (m, 1 H), 6.48 (br. s., 2 H), 3.65 (br. s., 3 H); ES-LCMS: 449.0 (M+1).) and a second eluting isomer (47 mg, >99 %ee, ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.37 (br. s., 1 H), 8.25 (br. s., 1 H), 8.11 (br. s., 2 H), 8.01 (br. s., 1 H), 7.85 - 7.94 (m, 1 H), 7.34 - 7.85 (m, 9 H), 7.17 (br. s., 1 H), 6.48 (br. s., 2 H), 3.66 (br. s., 3 H); ES-LCMS: 449.0 (M+1 )). Absolute stereochemical assignments were not made.

Example 275

N-{[5-(2-amm^' o-4-oxo-3-phenyl-3,4-dihydro-6-quinazolinyl)-2-(methyloxy)-3- ide

Step A

(5-bromo-2-methoxypyridin-3-yl)methanol

5-bromo-2-methoxynicotinaldehyde (1.36 g, 6.30 mmol) was dissolved in methanol (20 mL) and tetrahydrofuran (THF) (20 mL) before sodium borohydride (0.238 g, 6.30 mmol) was added. The mixture was stirred for 3 hours and concentrated. Saturated sodium bicarbonate and ethyl acetate were added to the mixture, which was extracted 3 times with ethyl acetate. The combined organic layers were concentrated and the residue purified by silica chromatography eluting with a gradient of 0% to 10% ethyl acetate in dichloromethane. Fractions were concentrated to give the title compound (1.13 g, 82%). ES LC- S m/z =218, 220 (M+H)⁺.

Step B

5-bromo-3-(chloromethyl)-2-methoxypyridine

(5-bromo-2-methoxypyridin-3-yl)methanol (1.1 g, 5.0 mmol) was dissolved in dichloromethane (DCM) (35 mL) and thionyl chloride (3.68 mL, 50.4 mmol) added drop-wise. The mixture was stirred for 1 hour and concentrated. Saturated sodium bicarbonate was added and the mixture extracted 3 times with dichloromethane. The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated to give the title compound (1.2 g, 99%). ES LC-MS m/z =236, 238 (M+H)⁺.

Step C bis( 1, 1-dimethylethyl) {[5-bromo-2-(methyloxy)-3 yridinyl]methyl}imidodicarbonate Sodium hydride (60% in mineral oil) (56.8 mg, 1.42 mmol) was added to a solution of bis(1 , 1- dimethylethyl) imidodicarbonate (0.33 mL, 1.4 mmol) in Ν,Ν-dimethylformamide (DMF) (10 mL). 5-bromo-3-(chloromethyl)-2-methoxypyridine (336 mg, 1.42 mmol) was added and the mixture stirred at room temperature for 4 hours. Additional portions of bis(1 , 1-dimethylethyl) imidodicarbonate (0.328 mL, 1.42 mmol) and sodium hydride (60% in mineral oil) (56.8 mg, 1.42 mmol) were added and the mixture stirred at room temperature overnight. The mixture was quenched with water and extracted 3 times with ethyl acetate. The combined organic layers were washed with 5% lithium chloride, washed with brine, dried over sodium sulfate, and concentrated to give the title compound (593 mg, >99%). ES LC-MS m/z =417, 419 (M+H)⁺.

Step D

N-((5-bromo-2-methoxypyridin-3-yl)methyl)methanesulfonamide bis(1 , 1-dimethylethyl) {[5-bromo-2-(methyloxy)-3-pyridinyl]methyl}imidodicarbonate (0.631 mL, 1.42 mmol) was dissolved in 5 mL of 4M hydrogen chloride in 1 ,4-dioxane and the mixture stirred at room temperature for 4 hours. The mixture was concentrated to give the deprotected amine. The product and triethylamine (0.305 mL, 2.19 mmol) were slurried in dichloromethane (DCM) (3 mL). Methanesulfonyl chloride (0.041 mL, 0.53 mmol) was added and the mixture stirred at room temperature overnight. Additional methanesulfonyl chloride (0.024 mL, 0.30 mmol) was added and the mixture continued to stir for 3 hours. The mixture was quenched with water and extracted 3 times with ethyl acetate. The combined organic layers were washed with brine and concentrated. The residue was purified by silica chromatography eluting with a gradient of 0% to 25% ethyl acetate in dichloromethane. Fractions were concentrated to give the title compound (180 mg, 72% purity, >99%) as a white solid. LC-MS and NMR were consistent with desired product and clean. Greater than theoretical mass suggests some inorganic impurity was present. ES LC-MS m/z = 295, 297 (M+H)⁺. HN

N NH₂

Step E

N-{[5-(2-amino-4-oxo-3^henyl-3 -dihydro-6-quinazoiinyl)-2-(methyloxy

pyridinyl]methyl}methanesulfonamide

N-((5-bromo-2-methoxypyridin-3-yl)methyl)methanesulfonamide (180 mg, 0.488 mmol), potassium acetate (144 mg, 1.46 mmol), bis(pinacolato)diboron (186 mg, 0.732 mmol), and PdCI₂(dppf)-CH₂CI₂ adduct (39.8 mg, 0.0490 mmol) in 1 ,4-dioxane (4 mL) were heated to 95 °C overnight. The reaction mixture was allowed to cool to room temperature and concentrated to 2 mL of 1 ,4-dioxane. Water (0.5 mL), 2-amino-6-iodo-3-phenylquinazolin-4(3H)-one (134 mg, 0.368 mmol), cesium carbonate (300 mg, 0.920 mmol), and PdCI2(dppf) (22.45 mg, 0.031 mmol) were added and the mixture was heated to 95 °C and stirred for 4 hours. The mixture was allowed to cool to room temperature and stirred over the weekend. The mixture was filtered through celite and the celite pad washed with dichloromethane. The filtrate was concentrated and the residue purified by silica chromatography eluting with a gradient of 0% to 100% ethyl acetate. Fractions were concentrated and the product dried under vacuum to give the title compound (45 mg, 32%) as a solid. ES LC-MS m/z = 452 (M+H)⁺. ¹H NMR (400 MHz, D SO-d₆) δ ppm 8.42 (d, 1 H), 8. (d, 1 H), 8.03 (d, 1 H), 7.93 (dd, 1 H), 7.47 - 7.68 (m, 4 H), 7.27 - 7.45 (m, 3 H), 6.35 (br. s., 2 H), 4.19 (d, 2 H), 3.95 (s, 3 H), 2.95 (s, 3 H).

Example 276

2-amino-6-(5-(hydroxymethyl)-6-methoxypyridin-3-yl)-3-phenylquinazolin^

(5-bromo-2-methoxypyridin-3-yl)methanol (222 mg, 1.02 mmol), potassium acetate (300 mg, 3.05 mmol), bis(pinacolato)diboron (388 mg, 1.53 mmol), and PdCI₂(dppf)-CH₂CI₂ adduct (83 mg, 0.102 mmol) in 1 ,4-dioxane (2 mL) were heated to 95 °C overnight. The reaction mixture was allowed to cool to room temperature. Water (0.5 mL), 2-amino-6-iodo-3-phenylquinazolin- 4(3H)-one (222 mg, 0.61 1 mmol), cesium carbonate (498 mg, 1.53 mmol), and PdCI₂(dppf) (37 mg, 0.051 mmol) were added and the mixture heated to 95 °C for 4 hours. The mixture was allowed to cool to room temperature and stirred over the weekend. The mixture was filtered through celite and the celite pad washed with dichloromethane. The filtrate was concentrated and the residue purified by silica chromatography eluting with a gradient of 0% to 10% of methanol in ethyl acetate. Fractions were concentrated and the residue dried under vacuum to give the title compound (7 mg, 4%) as a solid. ES LC-MS m/z = 375 (M+H)⁺. ¹H NMR (400 MHz, DMSO- 3f₆) δ ppm 8.37 (s, 1 H), 8.09 (d, 1 H), 8.01 (s, 1 H), 7.94 (dd, 1 H), 7.46 - 7.68 (m, 4 H), 7.30 - 7.42 (m, 2 H), 6.35 (br. s., 2 H), 5.32 (t, 1 H), 4.52 (d, 2 H), 3.84 - 3.98 (m, 3 H).

Example 277

5-(2-amino-4-oxo-3-phenyl-3,4-dihydroquinazolin-6-yl)-N-(2,6-difluo

2-amino-6-iodo-3-phenylquinazolin-4(3H)-one (152 mg, 0.419 mmol), cesium carbonate (241 mg, 0.739 mmol), N-(2,6-difiuorophenyl)-2-methoxy-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)pyridine-3-sulfonamide (126 mg, 0.296 mmol), and PdCI₂(dppf) (18 mg, 0.025 mmol) in 1 ,4- dioxane (2 mL) and water (0.5 mL) were heated at 95 °C for 2 hours. The reaction mixture was allowed to cool to room temperature and filtered through celite. The celite pad was washed with dichloromethane. The filtrate was concentrated and the residue slurried in dichloromethane. Solids were collected by filtration. The product was purified by reverse phase HPLC. Fractions were concentrated to give the title compound (26 mg; 92% pure, 18%). ES LC-MS m/z = 536 (M+H)⁺. ¹H NMR (400 MHz, DMSO-af₆) δ ppm 10.07 (br. s., 1 H), 8.75 (br. s., 1 H), 8.19 (d, 1 H), 8.03 (d, 1 H), 7.93 (dd, 1 H), 7.47 - 7.67 (m, 3 H), 7.25 - 7.43 (m, 4 H), 7.09 (br. s., 2 H), 6.41 (br. s., 2 H), 3.96 (s, 3 H).

Example 278

5-(2-amino-4-oxo-3-phenyl-3,4-dihydroquinazolin-6-yl)-N-(2,3-difluorophenyl)-2- methoxypyridine-3-sulfonamide

2-amino-6-iodo-3-phenylquinazolin-4(3H)-one (152 mg, 0.419 mmol), cesium carbonate (241 mg, 0.739 mmol), N-(2,3-difluorophenyl)-2-methoxy-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)pyridine-3-sulfonamide (126 mg, 0.296 mmol), and PdCI₂(dppf) (18 mg, 0.025 mmol) in 1 ,4- dioxane (2 mL) and water (0.5 mL) were heated at 95 °C for 2 hours. The mixture was allowed to cool to room temperature and was filtered through a pad of celite. The celite pad was washed with methanol and the filtrate concentrated. The residue was slurried in water. The mixture was briefly sonicated and then stirred for 1 hour. Solids were collected by filtration and dried under vacuum to give the title compound (83 mg; 63%) as a tan solid. ES LC-MS m/z = 536 (M+H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.46 (br. s., 1 H), 8.25 (br. s., 1 H), 8.01 (br. s., 1 H), 7.86 (d, 1 H), 7.58 (br. s., 4 H), 7.25 - 7.47 (m, 3 H), 6.94 (br. s., 1 H), 6.65 (br. s., 1 H), 6.36 (br. s., 3 H), 3.85 (br. s., 3 H).

Example 279

2-amino-6-(6-m azolin-4(3H)-one

2-amino-6-iodo-3-phenylquinazolin-4(3H)-one (104 mg, 0.286 mmol), cesium carbonate (280 mg, 0.859 mmol), 4-(5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridin-2-yl)morpholine (91 mg, 0.32 mmol), and PdCI₂(dppf) (21 mg, 0.029 mmol) in 1 ,4-dioxane (2 mL) and water (0.5 mL) were heated at 95 °C for 2 hours. The mixture was allowed to cool to room temperature and stirred overnight. The mixture was filtered through a celite pad and the celite pad washed with both dichloromethane and methanol. The filtrate was concentrated and the residue purified by silica chromatography eluting with a gradient of 0% to 100% ethyl acetate in dichloromethane. Fractions were concentrated to give the title compound (50 mg; 44%) a white powder. ES LC- MS m/z = 400 (M+H)⁺. H NMR (400 MHz, DMSO-d₆) δ ppm 8.47 (d, 1 H), 8.10 - 8.29 (m, 3 H), 7.47 - 7.73 (m, 6 H), 7. 1 - 7.26 (m, 1 H), 4.80 - 5.85 (m, 2 H), 3.67 - 3.80 (m, 4 H), 3.62 (d, 4 H).

Example 280

2-amino-6-(5-(benzyloxy)- enylquinazolin-4(3H)-on

Step A

3-(benzyloxy)-5-bromopyridin-2-ol

Potassium hydroxide (0.797 g, 14.2 mmol) was dissolved in methanol (20 mL) before 5- bromopyridine-2,3-diol (2.7 g, 14 mmol) was added portion-wise. The mixture was stirred for 10 minutes before benzyl bromide (1 .69 mL, 14.2 mmol) was added drop-wise. The mixture was stirred for 4 hours. 400 mg of additional potassium hydroxide was added followed by 0.84 mL of benzyl bromide. The mixture was stirred at room temperature overnight. The mixture was concentrated and the residue slurried in saturated sodium bicarbonate. The mixture was extracted 3 times with ethyl acetate. The combined organic layers were washed with brine and concentrated. The residue was slurried in dichloromethane/hexanes (1 :1 ). Solids were collected by filtration and air dried to give the title compound (1.48 g, 80% pure, 30%). ES LC- MS m/z = 280, 282 (M+H)⁺.

Ste B

3-( benzyloxy) -5-bromo-2-methoxypyridine

3-(benzyloxy)-5-bromopyridin-2-ol (1.4 g, 5.0 mmol) was slurried in chloroform (40 ml_) before silver carbonate (3.45 g, 12.5 mmol) and methyl iodide (3.13 ml_, 50.0 mmol) were added. The mixture was allowed to stir at room temperature for 3 days. Solids were filtered off and washed with dichloromethane. Water was added to the filtrate and the mixture extracted 2 times with dichloromethane. The combined organic layers were washed with brine and concentrated. The residue was purified by silica chromatography eluting with dichloromethane. Fractions were concentrated. The resulting oil solidified upon standing to give the title compound (910 mg, 62%) as a white solid. ES LC-MS m/z = 294, 296 (M+H)⁺. Regiochemistry was confirmed by VCD-IR.

Step C

2-amino-6-(5-(benzyloxy)-6-methoxypyridin-3-yl)-3^henylqum^' ^

3-(benzyloxy)-5-bromo-2-methoxypyridine (310 mg, 1.05 mmol), potassium acetate (310 mg, 3.16 mmol), bis(pinacolato)diboron (401 mg, 1 .58 mmol), and PdCI₂(dppf)-CH₂CI₂ adduct (86 mg, 0.1 1 mmol) in 1 ,4-dioxane (4 mL) were heated to 90 °C overnight. The reaction mixture was allowed to cool to room temperature and concentrated to 2 mL. Water (0.25 mL), 2-amino- 6-iodo-3-phenylquinazolin-4(3H)-one (105 mg, 0.290 mmol), cesium carbonate (258 mg, 0.791 mmol), and PdCI₂(dppf) ( 9.30 mg, 0.026 mmol) were added and the mixture heated at 90 °C for 2 hours. The mixture was allowed to cool to room temperature, filtered through celite, and the celite plug washed with dichloromethane and tetrahydrofuran. The filtrate was concentrated and the residue purified by silica chromatography eluting with a gradient of 0% to 100% ethyl acetate in dichloromethane. Fractions were concentrated. The material was purified by reverse phase HPLC. Fractions were concentrated to give the title compound (60 mg, 50%). ES LC-MS m/z = 451 (M+H)⁺. H NMR (400 MHz, DMSO-d₆) δ ppm 8.15 (br. s., 1 H), 8.04 (br. s., 2 H), 7.69 (s, 1 H), 7.60 (dt, 3 H), 7.29 - 7.53 (m, 8 H), 5.26 (s, 2 H), 3.91 (s, 3 H), 3.27 - 3.56 (m, 2 H).

Example 281

N-((5-(2-amino-4-oxo-3-phenyl-3,4-dihydroquinazolin-6-yl)-2-metho

Step A

N-((5-bromo-2-methoxypyridin-3-yl)methyi)-N-(phenylsuifon

Sodium hydride (64.0 mg, 1.60 mmol) was added to a solution of N- (phenylsulfonyl)benzenesulfonamide (476 mg, 1.60 mmol) in tetrahydrofuran (THF) (4 mL). The mixture was stirred for 5 minutes before 5-bromo-3-(chloromethyl)-2-methoxypyridine (344 mg, 1.46 mmol) and tetrabutylammonium iodide (537 mg, 1.46 mmol) were added. The mixture was heated at 65 °C for 4 hours. Ν,Ν-Dimethylformamide (DMF) (4 mL) was added to the mixture and all solids dissolved. The mixture was heated to 90 °C and the tetrahydrofuran allowed to distill off. The reaction vessel was capped. The mixture continued to heat for 3 days, allowed to cool to room temperature, and was concentrated. The residue was purified by silica chromatography eluting with dichloromethane. Fractions were concentrated to give the title compound (456 mg, 63%). ES LC-MS m/z = 497, 498 (M+H)⁺.

Step B

N-((2-methoxy-5-(4, 4, 5, 5-tetramethyl- 1, 3, 2-dioxaborolan-2-yl)pyridin-3-yl)methyl)-N-

(phenylsuifonyi)benzenesulfonamide

N-((5-bromo-2-methoxypyridin-3-yl)methyl)-N-(phenylsulfonyl)benzenesulfon (450 mg,

0.905 mmol), potassium acetate (266 mg, 2.71 mmol), 4,4,4',4', 5,5,5', 5'-octamethyl-2,2'-bi(1 , 3,2- dioxaborolane) (345 mg, 1.36 mmol), and PdCI₂(dppf) (66 mg, 0.090 mmol) in 1 ,4-dioxane (4 mL) were heated at 90 °C overnight. The mixture was allowed to cool to room temperature and filtered through a silica plug. The filtrate was concentrated and the residue purified by silica chromatography eluting with ethyl acetate. Fractions were concentrated to give the title compound (490 mg, 62% purity, 62%) as a greenish solid. ES LC- S m/z = 545 ( +H)⁺.

Ste C

N-((5-(2-amino-4-oxo-3^henyl-3,4-dihydroquinazolin-6-yl)-2-metho

(phenylsulfonyl)benzenesulfonamide

2-amino-6-iodo-3-phenylquinazolin-4(3H)-one (233 mg, 0.643 mmol), potassium phosphate tribasic (3M in water) (0.643 mL, 1.93 mmol), N-((2-methoxy-5-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)pyridin-3-yl)methyl)-N-(phenylsulfonyl)benzenesulfonamide (350 mg, 0.643 mmol) and PdCI2(dppf) (23.52 mg, 0.032 mmol) in acetonitrile (4 mL) were heated to 80 °C for 3 hours. The mixture was allowed to cool, diluted with water, and extracted 3 times with ethyl acetate. The combined organic layers were washed with brine and concentrated. The residue was purified by silica chromatography eluting with a gradient of 0% to 100% ethyl acetate in dichloromethane. Fractions were concentrated to give the title compound (170 mg, 77% purity, 31%). ES LC- S m/z = 654 (M+H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.28 - 8.35 (m, 1 H), 8.05 - 8.12 (m, 1 H), 7.80 - 7.92 (m, 4 H), 7.65 - 7.75 (m, 2 H), 7.50 - 7.66 (m, 8 H), 7.28 - 7.47 (m, 4 H), 6.37 (br. s., 2 H), 5.1 1 (s, 2 H), 3.82 - 3.93 (m, 3 H).

Example 282

5-(2-amino-4-oxo-3-pheny -3,4-dihydroquinazolin-6-yl)-N-isopropylnicotinamide

Step A

methyl 5-bromonicotinate

Thionyl chloride (4.91 ml_, 67.3 mmol) was added carefully drop-wise to 5-bromonicotinic acid (3.4 g, 17 mmol) in methanol (50 mL) and the mixture stirred overnight at room temperature. The mixture was heated to 60 °C for 5 hours. The mixture was concentrated and ethyl acetate added to the white solids. Saturated sodium bicarbonate was added and the mixture extracted 2 times with ethyl acetate. The combined organic layers were washed with saturated sodium bicarbonate, washed with brine, dried over sodium sulfate, and concentrated to give the title compound (3.38 g, 95%) as a white solid. ES LC-MS m/z = 216, 218 (M+H)⁺.

Step B methyl 5-(4, 4, 5, 5-tetramethyl- 1, 3, 2-dioxaborolan-2-yl)nicotinate

Methyl 5-bromonicotinate (900 mg, 4.17 mmol), potassium acetate (1227 mg, 12.50 mmol), bis(pinacolato)diboron (1590 mg, 6.25 mmol), and PdCI₂(dppf)-CH₂CI₂ adduct (340 mg, 0.417 mmol) in 1 ,4-dioxane (20 mL) were heated at 90 °C overnight. The mixture was allowed to cool to room temperature and was filtered through a celite plug. The filtrate was concentrated and the residue purified by silica chromatography eluting with ethyl acetate. Fractions were concentrated to give the title compound (890 mg, 81 %) as a tan solid. ¹H NMR (400 MHz, CHLOROFORM-cf) δ ppm 9.23 - 9.35 (m, 1 H), 9.09 (s, 1 H), 8.59 - 8.73 (m, 1 H), 3.96 (s, 3 H), 1.37 (s, 12 H).

Step C

methyl 5-(2-amino-4-oxo-3-phenyl-3,4-dihydroquinazolin-6-yl)nicotinate

2-amino-6-iodo-3-phenylquinazolin-4(3H)-one (200 mg, 0.551 mmol), potassium phosphate tribasic (3M in water) (0.551 mL, 1.65 mmol), methyl 5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan- 2-yl)nicotinate (159 mg, 0.606 mmol) and PdCI₂(dppf) (20 mg, 0.028 mmol) in acetonitrile (4 mL) were heated to 80 °C for 3 hours. The mixture was allowed to cool to room temperature, quenched with water, and extracted 2 times with ethyl acetate. The combined organic layers were washed with brine and concentrated. The residue was purified by silica chromatography eluting with a gradient of 0% to 5% methanol in dichloromethane. Fractions were concentrated to give the title compound (120 mg, 72% purity, 42%). ES LC-MS m/z = 373 (M+H)⁺.

Step D

5-(2-amino-4-oxo-3^henyl-3,4-dihydroquinazolin-6-yl)-N-isopropylnicotinamide Methyl 5-(2-amino-4-oxo-3-phenyl-3,4-dihydroquinazolin-6-yl)nicotinate (60 mg, 0.16 mmol) was dissolved in tetrahydrofuran (THF) (3 mL) before sodium hydroxide (1M) (0.177 mL, 0.177 mmol) was added. The mixture was stirred for 2 hours and concentrated. The residue was co- evaporated 1 time with toluene then dissolved in Ν,Ν-dimethylformamide (DMF) (2.5 mL).

Propan-2-amine (14.3 μΙ, 0.193 mmol), N,N-diisopropylethylamine (0.084 mL, 0.48 mmol), and HATU (73.5 mg, 0.193 mmol) were added sequentially. The mixture was stirred for 2 hours, diluted with water, and extracted 3 times with ethyl acetate. The combined organic layers were washed with brine and concentrated. The residue was purified by reverse phase HPLC.

Fractions were concentrated to give the title compound (22 mg, 87% purity, 30%). ES LC-MS m/z = 400 (M+H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.03 (d, 1 H), 8.95 (d, 1 H), 8.58 (d, 1 H), 8.45 (t, 1 H), 8.26 (d, 1 H), 8.15 (s, 1 H), 8.07 (dd, 1 H), 7.50 - 7.63 (m, 3 H), 7.34 - 7.43 (m, 3 H), 6.32 - 6.56 (m, 1 H), 4.14 (d, 1 H), 1.20 (d, 6 H).

Example 283

5-(2-amino-4-oxo-3-pheny -3,4-dihydroquinazolin-6-yl)-N-isobutylnicotinam

Methyl 5-(2-amino-4-oxo-3-phenyl-3,4-dihydroquinazolin-6-yl)nicotinate (60 mg, 0.16 mmol) was dissolved in tetrahydrofuran (THF) (3 mL) before sodium hydroxide (1 M) (0.177 mL, 0.177 mmol) was added. The mixture was stirred for 2 hours and concentrated. The residue was co- evaporated 1 time with toluene then dissolved in Ν,Ν-dimethylformamide (DMF) (2.5 mL). 2- methylpropan-1 -amine (0.018 mL, 0.19 mmol), N,N-diisopropylethylamine (0.084 mL, 0.48 mmol), and HATU (73.5 mg, 0.19 mmol) were added sequentially. The mixture stirred for 2 hours, diluted with water, and extracted 3 times with ethyl acetate. The combined organic layers were washed with brine and concentrated. The residue was purified by reverse phase HPLC. Fractions were concentrated to give the title compound (20 mg, 82% purity, 25%). ES LC-MS m/z = 414 (M+H)⁺. ¹H NMR (400 MHz, DMSO-af₆) δ ppm 9.04 (d, 1 H), 8.95 (d, 1 H), 8.77 - 8.87 (m, 1 H), 8.47 (t, 1 H), 8.27 (d, 1 H), 8.15 (s, 1 H), 8.07 (dd, 1 H), 7.51 - 7.65 (m, 3 H), 7.39 (dd, 2 H), 6.28 - 6.60 (m, 2 H), 3.09 - 3.20 (m, 2 H), 1.75 - 1.99 (m, 1 H), 0.91 (d, 6 H). Example 284

5-(2-amino-3-(2-methoxyethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)-N-(2,4-difluorophe

methoxypyridine-3-sulfonamide

Step A

N-(6-bromo-3-(2-methoxyethyl)-4-oxo-3,4-dihydroquinazolin-2-yl)cyanamide 2-methoxyethanamine (0.035 mL, 0.40 mmol) was added to a slurry of (Z)-methyl 5-bromo-2- (((cyanoimino)(phenoxy)methyl)amino)benzoate (100 mg, 0.267 mmol) in isopropanol (2 mL). The mixture was heated at 80 °C for 2 hours and allowed to cool to room temperature. Solids were collected by filtration and air dried to give the title compound (49 mg, 56%). ES LC-MS m/z = 323, 325 (M+H)⁺.

Step B

2-amino-6-bromo-3-(2-methoxyethyl)quinazolin-4(3H)-one N-(6-bromo-3-(2-methoxyethyl)-4-oxo-3,4-dihydroquinazolin-2-yl)cyanamide (49 mg, 0.15 mmol) was dissolved in dimethyl sulfoxide (DMSO) (1 mL) and concentrated hydrochloric acid (2 mL) added. The mixture was heated to reflux until starting material had been consumed. The mixture was allowed to cool to room temperature and was carefully poured into an iced saturated sodium bicarbonate solution. The mixture was extracted 2 times with ethyl acetate. The combined organic layers were washed with brine and concentrated to give the title compound (45 mg, 46% purity, 46%). ES LC-MS m/z = 298, 300 (M+H)⁺.

Step C

5-(2-amino-3-(2-methoxyethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)-N-(^

methoxypyridine-3-sulfonamide

2-amino-6-bromo-3-(2-methoxyethyl)quinazolin-4(3H)-one (45 mg, 0.15 mmol), potassium phosphate tribasic (3M in water) (0.151 mL, 0.453 mmol), N-(2,4-difluorophenyl)-2-methoxy-5- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridine-3-sulfonamide (77 mg, 0.18 mmol) and PdCI₂(dppf) (1 1 mg, 0.015 mmol) in acetonitrile (3 mL) were heated to 80 °C for 5 hours. The mixture was allowed to cool to room temperature and filtered through a plug of celite. The filtrate was concentrated and the residue purified by reverse phase HPLC. Fractions were concentrated to give the title compound (6 mg, 7%). ES LC-MS m/z = 518 (M+H)⁺.

Example 285

N-((5-(2-amino-4-oxo-3-phenyl-3,4-dihydroquinazolin-6-yl)-2-methoxy

N-((5-(2-amino-4-oxo-3-phenyl-3,4-dihydroquinazolin-6-yl)-2-methoxypyridin-3-yl)methyl)-N- (phenylsulfonyl)benzenesulfonamide (167 mg, 0.255 mmol) and sodium hydroxide (1 M) (1 mL, 1 mmol) were added to methanol and heated to reflux for 4 hours. The mixture was allowed to cool and was concentrated to dryness. The residue was slurried in tetrahydrofuran (THF) (2 mL) before lithium hydroxide monohydrate (130 mg, 3.10 mmol) in 1 mL of water was added. The mixture was heated at reflux for 2 days. The mixture was quenched with saturated ammonium chloride and extracted 2 times with ethyl acetate. The combined organic layers were washed with brine and concentrated. The residue was purified by reverse phase HPLC. Appropriate fractions were combined and lyophilized to give the title compound (20 mg, 15%). ES LC-MS m/z = 514 (M+H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.32 (d, 1 H), 8.24 (d, 1 H), 8.04 (d, 1 H), 7.80 - 7.87 (m, 2 H), 7.74 - 7.80 (m, 2 H), 7.48 - 7.65 (m, 6 H), 7.30 - 7.43 (m, 3 H), 6.19 - 6.54 (m, 2 H), 3.98 - 4.15 (m, 2 H), 3.84 (s, 3 H).

Example 286

5-(2-a ino-3-(3-morpholinopropyl)-4-oxo-3,4-dihydroquinazolin-6-yl)-N-(2,4- amide

N-(6-bromo-3-(3-morpholinopropyl)-4-oxo-3,4-dihydroquinazolin-2-yl)cyanamide 3-morpholinopropan-1 -amine (0.182 mL, 1 .24 mmol) was added to a slurry of (Z)-methyl 5- bromo-2-(((cyanoimino)(phenoxy)methyl)amino)benzoate (310 mg, 0.828 mmol) in isopropanol (2 mL). The mixture was heated at 80 °C for 2 hours and allowed to cool to room temperature. The mixture was concentrated and the residue purified by silica chromatography to give the title compound (180 mg, 55%). ES LC-MS m/z = 392, 394 (M+H)⁺.

2-amino-6-bromo-3-(3-morphoiinopropyl)quinazolin-4(3H)-one

N-(6-bromo-3-(3-morpholinopropyl)-4-oxo-3,4-dihydroqum^ (180 mg, 0.459 mmol) was dissolved in dimethyl sulfoxide (DMSO) (1 mL) and concentrated hydrochloric acid (2 mL) added. The mixture was heated to reflux until starting material had been consumed. The mixture was allowed to cool to room temperature and was carefully poured into an iced saturated sodium bicarbonate solution. The mixture was extracted 2 times with ethyl acetate. The combined organic layers were washed with brine and concentrated. The residue was purified by silica chromatography eluting with a gradient of 0% to 5% 2M ammonia/methanol in dichloromethane. Fractions were concentrated to give the title compound (80 mg, 47%). ES LC-MS m/z = 367, 369 (M+H)⁺.

5-(2-amino-3-(3-morpholinopropyl)-4-oxo-3,4-dihydroquinazolin-6-yl)-N-(2,4

methoxypyridine-3-sulfonamide

2-amino-6-bromo-3-(3-morpholinopropyl)quinazolin-4(3H)-one (80 mg, 0.22 mmol), cesium carbonate (213 mg, 0.654 mmol), N-(2,4-difluorophenyl)-2-methoxy-5-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)pyridine-3-sulfonamide (11 1 mg, 0.261 mmol), and PdC (dppf) (16 mg, 0.022 mmol) in 1 ,4-dioxane (4 mL) and water (1 mL) were heated at 90 °C for 2 hours. The mixture was allowed to cool to room temperature and filtered through a plug of celite. The filtrate was concentrated and the residue purified by silica chromatography eluting with a gradient of 0% to 5% 2M ammonia/methanol in dichloromethane. Fractions were concentrated to give the title compound (48 mg, 90% purity, 34%). ES LC-MS m/z = 587 (M+H)⁺. ¹H NMR (400 MHz, DMSO- cfe) δ ppm 10.09 - 10.26 (m, 1 H), 8.71 - 8.78 (m, 1 H), 8.17 (s, 1 H), 8.00 - 8.08 (m, 1 H), 7.82 - 7.91 (m, 1 H), 7.46 - 7.61 (m, 2 H), 7.35 (s, 1 H), 7.26 (d, 1 H), 6.99 - 7.08 (m, 1 H), 4.19 - 4.53 (m, 1 H), 3.99 - 4.05 (m, 2 H), 3.97 (s, 3 H), 3.94 (s, 1 H), 3.55 (br. s., 4 H), 2.35 (d, 5 H), 1.76 - 1.91 (m, 2 H).

Example 287

5-(2-amino-3-((4-(dimethylamino)tetrahydro-2H^yran-4-yl)methyl)-4-oxo-3,4- dihydroquinazolin-6-yl)-N- -difluorophenyl)-2-methoxypyridin

Step A

N-(6-bromo-3-((4-(dimethylamino)tetrahydro-2H^yran-4-yl)m

2-yl)cyanamide

4-(aminomethyl)-N,N-dimethyltetrahydro-2H-pyran-4-amine (197 mg, 1.243 mmol) was added to a slurry of (Z)-methyl 5-bromo-2-(((cyanoimino)(phenoxy)methyl)amino)benzoate (310 mg, 0.828 mmol) in Isopropanol (2 mL). The mixture was heated at 80 °C for 2 hours and allowed to cool to room temperature. The mixture was concentrated and the residue purified by silica chromatography to give the title compound (330 mg, 50% purity, 49%). ES LC-MS m/z = 406, 408 (M+H)⁺.

Step B

2-amino-6-bromo-3-((4-(dimethylamino)tetrahydro-2H^yran-4-yl)methyl)qui

N-(6-bromo-3-((4-(dimethylamino)tetrahydro-2H-pyran-4-yl)methyl)-4-oxo-3,4-dihydroquinazolin- 2-yl)cyanamide (330 mg, 0.406 mmol) was dissolved in dimethyl sulfoxide (DMSO) (1 mL) and concentrated hydrochloric acid (2 mL) added. The mixture was heated to reflux until starting material had been consumed. The mixture was allowed to cool to room temperature and was carefully poured into an iced saturated sodium bicarbonate solution. The mixture was extracted 2 times with ethyl acetate. The combined organic layers were washed with brine and concentrated. The residue was purified by silica chromatography eluting with a gradient of 0% to 5% 2M ammonia/methanol in dichloromethane. Fractions were concentrated to give the title compound (140 mg, 90%). ES LC-MS m/z = 381 , 383 (M+H)⁺.

Step C

5-(2-amino-3-((4-(dimethylamino)tetra ydro-2H^yran-4-yl)me

6-yl)-N-(2,4-difluorophenyl)-2-methoxypyridine-3-sulfonamide 2-amino-6-bromo-3-((4-(dimethylamino)tetrahydro-2H-pyran-4-yl)methyl)quinazolin-4(3H)-one (140 mg, 0.367 mmol), cesium carbonate (359 mg, 1.10 mmol), N-(2,4-difluorophenyl)-2- methoxy-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridine-3-sulfonamide (188 mg, 0.441 mmol), and PdCI₂(dppf) (27 mg, 0.037 mmol) in 1 ,4-dioxane (4 mL) and water (1 mL) were heated at 90 °C for 2 hours. The mixture was allowed to cool to room temperature and filtered through a plug of celite. The filtrate was concentrated and the residue purified by silica chromatography eluting with a gradient of 0% to 5% 2M ammonia/methanol in dichloromethane. Fractions were concentrated to give the title compound (30 mg, 1 1 %). ES LC-MS m/z = 601 (M+H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.14 - 10.24 (m, 1 H), 8.68 - 8.85 (m, 1 H), 8.15 - 8.21 (m, 1 H), 8.02 - 8.09 (m, 1 H), 7.85 - 7.90 (m, 1 H), 7.70 - 7.78 (m, 1 H), 7.48 - 7.69 (m, 2 H), 7.28 - 7.37 (m, 1 H), 7.23 - 7.28 (m, 1 H), 6.99 - 7.10 (m, 1 H), 3.98 (s, 3 H), 3.54 - 3.68 (m, 2 H), 3.42 - 3.54 (m, 2 H), 2.35 (s, 6 H), 1.74 - 1 .91 (m, 2 H), 1.24 (br. s., 4 H).

Example 288

5-(2-amino-3-(2-(dimethylamino)-2^henylethyl)-4-oxo-3,4-dihydro

difluorophenyl)-2-methoxypyridine-3-sulfonamide

Step A

N-(6-bromo-3-(2-(dimethylamino)-2^henylethyl)-4-oxo-3,4-dihydro^

N1 ,N1-dimethyl-1 -phenylethane-1 ,2-cliamine (204 mg, 1 .24 mmol) was added to a slurry of (Z)- methyl 5-bromo-2-(((cyanoimino)(phenoxy)methyl)amino)benzoate (310 mg, 0.828 mmol) in isopropanol (2 ml_). The mixture was heated at 80 °C for 2 hours and allowed to cool to room temperature. The mixture was concentrated and the residue purified by silica chromatography to give the title compound (190 mg, 55%). ES LC-MS m/z = 412, 414 (M+H)⁺.

Step B

2-am no-6-bromo-3-(2-(dimei/iy/am noj-2-p/ieny/ef/7y/Jqu/nazo/in-4(3/-/j-one N-(6-bromo-3-(2-(dimethylamino)-2-phenylethyl)-4-oxo-3,4-dihydroquinazolin-2-yl)cyanamide (190 mg, 0.230 mmol) was dissolved in dimethyl sulfoxide (DMSO) (1 mL) and concentrated hydrochloric acid (2 mL) added. The mixture was heated to reflux until starting material had been consumed. The mixture was allowed to cool to room temperature and was carefully poured into an iced saturated sodium bicarbonate solution. The mixture was extracted 2 times with ethyl acetate. The combined organic layers were washed with brine and concentrated. The residue was purified by silica chromatography eluting with a gradient of 0% to 5% 2M ammonia/methanol in dichloromethane. Fractions were concentrated to give the title compound (60 mg, 67%). ES LC-MS m/z = 387, 389 ( +H)⁺.

Step C

5-(2-amino-3-(2-(dimethylamino)-2^henylethyl)-4-oxo-3 -di ydro

difluorophenyI)-2-methoxypyridine-3-suIfonamide

2-amino-6-bromo-3-(2-(dimethylamino)-2-phenylethyl)quinazolin-4(3H)-one (60 mg, 0.16 mmol), cesium carbonate (151 mg, 0.465 mmol), N-(2,4-difluorophenyl)-2-methoxy-5-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridine-3-sulfonamide (79 mg, 0.19 mmol), and PdCI₂(dppf) (1 1 mg, 0.015 mmol) in 1 ,4-dioxane (4 ml.) and water (1 mL) were heated at 90 °C for 2 hours. The mixture was allowed to cool to room temperature and filtered through a plug of celite. The filtrate was concentrated and the residue purified by silica chromatography eluting with a gradient of 0% to 5% 2M ammonia/methanol in dichloromethane. Fractions were concentrated to give the title compound (30 mg, 32%). ES LC-MS m/z = 607 (M+H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.18 (s, 1 H), 8.74 (d, 1 H), 8.16 (d, 1 H), 8.00 (d, 1 H), 7.82 - 7.89 (m, 1 H), 7.19 - 7.39 (m, 10 H), 6.98 - 7.10 (m, 1 H), 4.58 - 4.80 (m, 1 H), 4.22 - 4.40 (m, 1 H), 3.98 (s, 4 H), 2.08 (s, 6 H).

Example 289

methyl 5-(2-amino-4-o -3-phenyl-3,4-dihydroquinazolin-6-yl)nicotinate

2-amino-6-iodo-3-phenylquinazolin-4(3H)-one (1.7 g, 4.68 mmol), potassium phosphate tribasic (3M in water) (2.98 g, 14.0 mmol), methyl 5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)nicotinate (1.69 g, 5.15 mmol) and PdCI₂(dppf) (0.171 g, 0.234 mmol) in 1,4-dioxane (20 mL) were heated to 80 °C for 3 hours. The mixture was allowed to cool to room temperature, filtered through celite, and concentrated. The residue was purified by silica chromatography eluting with a gradient of 0% to 5% 2M ammonia/methanol in dichloromethane. Fractions were concentrated to give a tan solid. Dichloromethane was added to the product and the mixture stirred vigorously for 30 minutes. Solids were collected by filtration and air dried to give the title compound (530 mg, 30%). ES LC-MS m/z = 373. H NMR (400 MHz, DMSO-af₆) δ ppm 9.17 (d, 1 H), 9.05 (d, 1 H), 8.47 (t, 1 H), 8.21 (d, 1 H), 8.07 (dd, 1 H), 7.48 - 7.67 (m, 3 H), 7.29 - 7.48 (m, 3 H), 6.34 - 6.66 (m, 2 H), 3.93 (s, 3 H).

Example 290

N-(6-(2-amino-4-oxo-3-phenyl-3,4-dihydroquinazolin-6-yl)-1H-indazol-4-

2-amino-6-iodo-3-phenylquinazolin-4(3H)-one (130 mg, 0.358 mmol), N-(6-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-1 H-indazol-4-yl)benzenesulfonamide (152 mg, 0.381 mmol), potassium phosphate tribasic (228 mg, 1.07 mmol), palladium(ll) acetate (7.2 mg, 0.032 mmol), and cataXCium A (23 mg, 0.064 mmol) were added to a stirring mixture of 1 ,4-dioxane (3 mL) and water (0.75 mL). The reaction vessel was placed into an oil bath that was preheated to 95 °C. The mixture was stirred for 2 hours and allowed to cool to room temperature. The mixture was quenched with water and extracted 3 times with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated. The residue was taken up in dichloromethane. Solids precipitated and were collected by filtration. The product was purified by reverse phase HPLC. Fractions were concentrated. The residue was dissolved in methanol and the solution transferred to a registration vial. The methanol was evaporated under a stream of nitrogen and the white solids dried under vacuum to give the title compound (36 mg, 20%). ES LC-MS m/z = 509. H NMR (400 MHz, DMSO-d₆) δ ppm 13.10 (s, 1 H), 10.58 - 10.97 (m, 1 H), 8.20 (s, 1 H), 8.02 (d, 1 H), 7.78 - 7.91 (m, 3 H), 7.47 - 7.68 (m, 6 H), 7.38 - 7.44 (m, 3 H), 7.35 (d, 1 H), 7.18 (d, 1 H), 6.38 (br. s., 2 H).

General Scheme 20

Hereocycle

Example 291

2-amino-6-(2-methoxypyrimidin-5-yl)-3-phenylquinazolin-4(3H)-one

To a schlenck flask were added 2-amino-6-iodo-3-phenyl-4(3H)-quinazolinone (40mg, 0.11 mmol), 2-methoxy-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyrimidine (26.0 mg, 0.11 mmol), KOAc (32.5 mg, 0.33 mmol) and Pd(Ph₃P)₄ (12.7 mg, 0.01 mmol). A mixed solvent of DME/water (2mL/0.5mi_) was introduced. After purged with N₂ (3x), the reaction mixture was heated to 80°C overnight. The product was purified by HPLC (C18, 5 to 65% CH₃CN/H₂0 (0.1 % formic acid)) to give the title compound (15mg, yield: 38%). LCMS (m/z) ES+ 346(M+H) H NMR (CHLOROFORM-d) δ: 8.78 (s, 3H), 8.30 (d, J = 2.1 Hz, 1H), 8.26 (s, 1H), 7.82 (dd, J = 8.5, 2.2 Hz, 2H), 7.55 - 7.70 (m, 6H), 7.51 (d, J = 8.4 Hz, 2H), 7.38 (d, J = 7.0 Hz, 2H), 4.01 - 4.16 (m, 3H).

Example 292

2-amino-6-[2-(dimethylamino)pyrimidin-5-yl]-3-phenylquinazolin-4(3H^

2-Amino-6-[2-(dimethylamino)pyrimidin-5-yl]-3-phenylquinazolin-4(3H)-one was obtained from 2-amino-6-iodo-3-phenyl-4(3H)-quinazolinone and /V,/V-dimethyl-5-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)pyrimidin-2-amine as solid using a similar procedure outlined in Example 291. LCMS (m/z) ES+ 405(M+H), ¹H NMR (CHLOROFORM-d) δ: 8.62 (s, 2H), 8.17 - 8.34 (m, 2H), 7.76 - 7.87 (m, 1 H), 7.57 - 7.74 (m, 3H), 7.52 (d, J = 8.4 Hz, 1 H), 7.38 (d, J = 6.8 Hz, 2H), 3.26 (s, 6H).

Example 293

2-amino-3-phenyl-6- -(1H-pyrazol-4-yl)pyridin-3-yl]quinazolin-4(3H)-one

2-Amino-3-phenyl-6-[6-(1 H-pyrazol-4-yl)pyridin-3-yl]quinazolin-4(3H)-one was obtained from 2- amino-6-iodo-3-phenyl-4(3H)-quinazolinone and 2-(1 /-/-pyrazol-4-yl)-5-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)pyridine as solid using a similar procedure outlined in Example 291. LC S (m/z) ES+ 381 (M+H), H N R (CHLOROFOR -d) δ: 8.88 (d, J = 2.1 Hz, 1H), 8.39 (d, J = 2.1 Hz, 1 H), 8.12 - 8.24 (m, 3H), 7.95 (br. s., 3H), 7.57 - 7.71 (m, 4H), 7.51 (d, J = 8.6 Hz, 1 H), 7.36 - 7.45 (m, 2H).

Example 294

[5-(2-amino-4-oxo-3^henyl-3,4-dihydroquinazolin-6-yl)pyridin-3-yl]boronic acid

2-Amino-6-(5-bromopyridin-3-yl)-3-phenylquinazolin-4(3H)-one was obtained from 2-amino-6- iodo-3-phenyl-4(3H)-quinazolinone and (5-bromo-3-pyridinyl)boronic acid as solid using a similar procedure outlined in Example 291. LCMS (m/z) ES+ 393,395 (M+H).

[5-(2-amino-4-oxo-3 henyl-3,4-dihydroquinazolin-6-yl) yήdin-3-yl]boronic acid

To a schlenck flask were added 2-amino-6-(5-bromo-3-pyridinyl)-3-phenyl-4(3H)-quinazolinone (33mg, 0.084mmol), bispinacol diboron (32mg, 0.126 mmol), KOAc(24.7 mg, 0.252mmol) and PdCI2(dppf) (6.1 mg, 0.008 mmol), followed by introduction of 2mL of 1 ,4-dioxane. The mixture was purged with N₂ (3X) before heated to 60 °C over weekend. The resulting boronic acid pinacol ester was purified with HPLC (C18, 5 to 70%, CH₃CN/ water (0.1 % formic acid)) (22.0 mg). To this ester 2 N HCI (2 mL) was added and stirred at 45°C overnight. Evaporated solvents and purified by HPLC (C18, 5 to 50% CH₃CN/water (0.1 % formic acid)) to give the title compound (7.4mg, yield: 23% over two steps). LC S (m/z) ES+ 359(M+H), H NMR (DMSO-d₆) δ: 9.25 (br. s., 1 H), 8.84 - 9.01 (m, 3H), 8.38 - 8.48 (m, 1 H), 8.43 (d, J = 1.6 Hz, 1 H), 7.57 - 7.72 (m, 5H), 7.56 - 7.72 (m, 2H).

Example 295

N-(6-(2-amino-4-oxo-3-phenyl-3,4-dihydroquinazolin-6-yl)-1H-benzo[d]im^

difluorobenzenesulfonamide dihydrochloride

Step A

4-bro -2, 6-dinitroaniline

A solution of bromine (3.09 ml_, 60.1 mmol) in acetic acid (2 mL) was added dropwise to a solution of 2,6-dinitroaniline (10.00 g, 54.6 mmol) in acetic acid (100 mL). The mixture was heated at 120°C for 2 hrs. The reaction mixture was cooled to room temperature and poured into water (1000 mL). The precipitated solid was collected by filtration, washed with water, and dried under vacuum overnight to give 13.55 g (95%) of 4-bromo-2,6-dinitroaniline as a yellow solid. ES-LCMS: 260, 262 (M-1 , M+1 ).

Step B

5-bromo-3 , 2-diamine

Iron powder (5.33 g, 95 mmol) was added to a suspension of 4-bromo-2,6-dinitroaniline (5.00 g, 19.08 mmol) in acetic acid (10 mL). The mixture was heated at 40°C for 6 hrs. The reaction mixture was filtered through Celite, washing the filter with methanol. The filtrate was

evaporated. The residue was treated with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated to give 5-bromo3-nitrobenzene-1 ,2-diamine as a dark red solid (2.52 g, 57%). ES- LCMS: 232 (M+1 ). This material was taken to the next step without further purification.

Step C

5-bromo- zole

A mixture of 5-bromo-3-nitrobenzene-1 ,2-diamine (1.79 g, 7.71 mmol), trtethyl orthoformate (20 mL, 120 mmol) and one drop of cone hydrochloric acid was heated at 100°C for 2 hrs. The mixture was diluted with ethyl acetate and 1 N aqueous sodium hydroxide. The aqueous layer was back-extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated. Chromatography on silica gel with

dichloromethane:methanol gave 817 mg (44%) of 5-bromo-7-nitro-1H-benzo[djimidazole as a yellow solid. LCMS: 242, 244 (M+1 , M+2). Step D

6-bromo-4-nitro-1-((2-(trimethylsiiyl)ethoxy)methyl)-1H-ben

Sodium hydride (60% oil dispersion) (183 mg, 4.57 mmol) was added to a solution of 5-bromo- 7-nitro-1H-benzo[c ]imidazole (885 mg, 3.66 mmol) in DMF (10 mL) while cooling in an ice bath. The mixture was then stirred at room temperature for 1.5 hrs and 2-(trimethylsilyl)ethoxymethyl chloride (0.649 mL, 3.66 mmol) was added. The reaction mixture was stirred at room temperature overnight. Saturated aqueous sodium bicarbonate was added and the mixture was extracted three times with ethyl acetate. The combined organic layers were washed twice with water and brine, dried over sodium sulfate and concentrated to give 6-bromo-4-nitro-1((2- (trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole as a dark yellow oil (1.29 g, 95%). This crude material was carried to the next step without further purification. LCMS: 372, 374 ( +1 , M+2).

Step E

6-bromo-1-((2-(t methylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-4^

Iron powder (0.960 g, 17.19 mmol) was added to a solution of 6-bromo-4-nitro-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole (1.28 g, 3.44 mmol) in acetic acid (50 mL). The mixture was heated at 40°C for 30 min. The reaction mixture was filtered through Celite, washing the filter with methanol. The filtrate was evaporated and the residue was treated with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over sodium sulfate and concentrated to give 6- bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1 H-benzo[d]imidazol-4-am as an amber oil. This material was carried on to next step without further purification. LCMS: 342, 344 {M+1 , M+2).

Step F

N-(6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo

mide

-—

2,4-Difluorobenzene-1-sulfonyl chloride (0.415 ml_, 3.09 mmol) was added dropwise to a solution of 6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1 H-benzo[d]imidazol-4-amine (961 mg, 2.81 mmol) in pyridine (20 mL) at room temperature. The mixture was stirred at room temperature for 30 min. The solvent was evaporated and the residue was taken up in ethyl acetate, washed with saturated aqueous sodium bicarbonate and brine, dried over sodium sulfate and concentrated. Silica gel chromatography gave 963 mg (66%) of N-(6-bromo-1-((2- (trimethylsilyl)ethoxy)methyl)-1/-/-benzo[ /3imidazol-4-yl)-2,4-difluorobenzenesulfonamide. LCMS: 517, 519 (M+, M+2).

Step G

2, 4-difluoro-N-(6-(4, 4, 5, 5-tetramethyl- 1, 3, 2-dioxaborolan-2-yl)- 1 -((2- (trimethylsilyl)ethoxy)methyi)-1H-benzo[d]imidazoi-4-yl)benze

A mixture of N-(6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1 /-/-benzo[d]imidazol-4-yl)-2,4- difluorobenzenesulfonamide (959 mg, 1.850 mmol), 4,4,4\4\5,5,5\5'-octamethyl-2,2'-bi(1 ,3,2- dioxaborolane) (564 mg, 2.22 mmol), potassium acetate (545 mg, 5.55 mmol) and PdCI₂(dppf)- CH₂CI₂ adduct (151 mg, 0.185 mmol) in 1 ,4-Dioxane (10 mL) was heated at

100°C under nitrogen for 16 hrs. Additional 4,4,4',4^,,5,5,5',5'-octamethyl-2,2^,-bi{1 ,3,2- dioxaborolane) (564 mg, 1.2 eq) and PdCI₂(dppf)-CH₂CI₂ adduct (151 mg) were added and heating at 100°C was continued for 20 hrs. The cooled reaction mixture was filtered through Celite, washing the filter with ethyl acetate. The combined filtrates were evaporated and the residue subjected to silica gel chromatography with hexane:ethyl acetate to give 835 mg of a mixture 2,4-difluoro-N-(6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-4-yl)benzenesulfonamide (60%) and the des- bromo product . This material was taken to the next step without further purification. ES-LCMS: 566 (M+1 ).

Step H

N-(6-(2-amino-4-oxo-3^henyl-3,4-dihydroquinazolin-6-yl)-1-((2-(trim

1 H-benzo[d]imidazol-4-yl)-2, 4-difluorobenzenesulfonamide

A mixture of 2,4-difluoro-N-(6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-benzo[d3imidazol-4-yl)benzenesulfonamide (173 mg, 0.184 mmol), 2-amino-6-iodo-3-phenylquinazolin-4(3H)-one (66.7 mg, 0.184 mmol), PdCI2(dppf)- CH₂CI₂ adduct (42.6 mg, 0.052 mmol) and cesium carbonate (179 mg, 0.551 mmol) in 1,4- dioxane (6 mL) and water (1.5 mL) was heated at 70°C. The reaction mixture was filtered through Celite. The filter was washed with ethyl acetate. The combined filtrates were washed with saturated aqueous sodium bicarbonate and brine, dried over sodium sulfate and concentrated. Purification by reverse phase HPLC (C18, acetonitrile:water with 0.1% formic acid) gave 58 mg (47%) of N-(6-(2-amino-4-oxo-3-phenyl-3,4-dihydroquinazolin-6-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-benzo[ /3imidazol-4-yl)-2,4-difluorobenzenesulfonamide. ES- LCMS: 575 (M+1 ).

Step I

N-(6-(2-amino-4-oxo-3-phenyl-3A-dihydroquinazolin-6-yl)-1H-benzo[d]^

difluo loride

To a solution of N-(6-(2-amino-4-oxo-3-phenyl-3,4-dihydroquinazolin-6-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1/-/-benzo[ /3imidazol-4-yl)-2,4-difluorobenzenesulfonamide (58 mg, 0.086 mmol) in methanol (3 mL) was added 3M aqueous HCI (1.4 mL, 4.30 mmol). The mixture was heated at 55°C for 36 hrs. Additional 3M HCI (1 mL) was added and heating was continued for 20 hrs. The reaction mixture was cooled to room temperature and filtered. The collected white solid was washed with diethyl ether and dried under vacuum to give 35 mg (65%) of N-(6-(2-amino-4-oxo-3-phenyl-3,4-dihydroquinazolin-6-yl)-1 H-benzo[d]imidazol-4-yl)- 2,4-difluorobenzenesulfonamide dihydrochloride. ¹H NMR (400 MHz, DMSO-cf₆) δ ppm 9.03 (br. s., 1 H) 8.04 - 8.12 (m, 1 H) 7.99 - 8.04 (m, 1 H) 7.85 - 7.93 (m, 1 H) 7.80 - 7.85 (m, 1 H) 7.58 - 7.72 (m, 4 H) 7.47 - 7.58 (m, 4 H) 7.28 (s, 1 H) 7.22 (m, 1 H). EXAMPLE 296

2-amino-6-(6-methoxy-5-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)-3-phenylqui^

one

Step A

5-bromo-2-methoxy-3-(1H-tetrazol-5-yl)pyridine

A mixture of 5-bromo-2-methoxynicotinonitrile (1.00 g, 4.69 mmol), sodium azide (0.915 g, 14.08 mmol) and tributyltin chloride (3.8 mL, 14.08 mmol) tetrabutylammonium bromide (0.197 g, 0.610 mmol) in toluene (15.4 mL) was heated in a 15°C sand bath overnight. The mixture was cooled then placed in an ice bath before being diluted with MeOH (19 mL) water (13.5 mL) and acetic acid (5.5 mL). A white solid precipitated. The mixture was stirred for one hour then the solid was filtered and washed with toluene to yield 5-bromo-2-methoxy-3-(1 H-tetrazol-5- yl)pyridine as a white solid (1.09 g, 91%), LCMS: 256 (M+H) H NMR (400 MHz, DMSO-d₆) δ 8.58 - 8.50 (m, 2 H), 4.03 (s, 3 H).

Step B

5-bromo-2-methoxy-3-(2-methyl-2H-tetrazol-5-yl)pyridine

A mixture of 5-bromo-2-methoxy-3-(1 H-tetrazol-5-yl)pyridine (100 mg, 0.39 mmol) and potassium carbonate (219 mg, 1.58 mmol) in DMF ( 1.6 mL) was stirred as methyl iodide ( 0.29 mL, 0.469 mmol ) was added. The mixture was allowed to stir at room temperature for three hours. LCMS showed a roughly 1 :1 mix of alkylation products. The mixture was then poured onto ice and allowed to stir for ~ 1 hour. The mixture was then filtered to yield a white solid. The residue was purified by silica gel chromatography (0-30% acetone in hexanes) Top spot fractions were combined and concentrated to yield 5-bromo-2-methoxy-3-(2-methyl-2H-tetrazol- 5-yl)pyridine (0.30 g, 36%). LCMS: 270 (M+H) ¹H NMR (400 MHz, DMSO-cf₆) δ 8.50 (d, J=2.5 Hz, 1 H) 8.41 (d, J=2.5 Hz, 1 H) 4.45 (s, 3 H) 3.96 (s, 3 H).

Step C

2-methoxy-3-(2-methyl-2H-tetrazol-5-yl)-5-(4, 4, 5, 5-tetramethyl-1 ,3, 2-dioxaborolan-2-yl)pyridine

The mixture of 5-bromo-2-methoxy-3-(2-methyl-2H-tetrazol-5-yl)pyridine (0.30 g, 1.111 mmol), bis(pinacolato)diboron (0.338 g, 1.333 mmol), potassium acetate (0.327 g, 3.33 mmol) and PdCI₂(dppf)-CH₂CI₂ adduct (0.091 g, 0. 1 mmol) in dioxane (6.5 mL) was heated under nitrogen atmosphere at 100 C° for 2 hours. The mixture was filtered through celite and was evaporated to dryness to give a black solid. The crude sample was purified by silica gel chromatography (12 g column eluted with 0-30% EtOAc in hexanes. Fractions containing the product were combined and concentrated to yield 2-methoxy-3-(2-methyl-2H-tetrazol-5-yl)-5- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridine (471 mg, 1.040 mmol, 94 % yield) as an off-white solid. LCMS: 318 (M+H).

Step D N-[5-(2-amino-4-oxo-3^henyl-3,4-dihydro-6-quinazolinyl)-2-(methyloxy)-3^yridin

fluorobenzenesuifonamide

A solution of 2-methoxy-3-(2-methyl-2H-tetrazol-5-yl)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan- 2-yl)pyridine (150 mg, 0.378 mmol), 2-amino-6-iodo-3-phenylquinazolin-4(3H)-one (137 mg, 0.378 mmol), PdCI₂(dppf)-CH₂CI₂ adduct (30.9 mg, 0.038 mmol), and cesium carbonate (370 mg, 2.19 mmol) in 1 ,4-dioxane (6.2 ml_)/water (6.20 mL) was maintained at 80°C for 1 hour. The solution was cooled, poured into DCM, and washed with water. The organic layer was separated, dried over sodium sulfate, filtered, taken to a residue under reduced pressure, and purified by silica gel chromatography (isocratic run with 50% DCM, 45 % EtOAc 5% MeOH, 12 gram column. Fractions containing the product were combined and concentrated. The residue was slurried in DCM / ether and the solution decanted to yield to yield a solid. The sample was dried under reduced pressure to yield 2-amino-6-(6-methoxy-5-(2-methyl-2H-tetrazol-5- yl)pyridin-3-yl)-3-phenylquinazolin-4(3H)-one (62 mg, 38 yield %), LCMS: 427 (M+H); H NMR (400 MHz, DMSO-c ₆) δ 8.70 (d, J=2.5 Hz, 1 H) 8.51 (d, J=2.5 Hz, 1 H) 8.15 (d, J=2.3 Hz, 1 H) 8.02 (dd, J=8.6, 2.3 Hz, 1 H) 7.49 - 7.64 (m, 3 H) 7.33 - 7.41 (m, 3 H) 6.39 (br. s., 2 H) 4.46 (s, 3 H) 4.01 (s, 3 H).

EXAMPLE 297

2-amino-6-(6-methoxy-5-(1-methyl-1H-tetrazol-5-yl)pyridin-3-yl)-3-phen

one

Step A

5-bromo-2-methox -3-( 1 -methyl- 1 H-tetrazol-5-yl)pyridine

A mixture of 5-bromo-2-methoxy-3-(1H-tetrazol-5-yl)pyridine (100 mg, 0.39 mmol) and potassium carbonate (219 mg, 1.58 mmol) in DMF ( 1.6 mL) was stirred as methyl iodide ( 0.29 mL, 0.469 mmol ) was added. The mixture was allowed to stir at room temperature for three hours. LCMS showed a roughly 1 :1 mix of alkylation products. The mixture was then poured onto ice and allowed to stir for ~ 1 hour. The mixture was then filtered to yield a white solid. The residue was purified by silica gel chromatography (0-30% acetone in hexanes) bottom spot fractions were combined and concentrated to yield 5-bromo-2-methoxy-3-(1-methyl-2H-tetrazol- 5-yl)pyridine (0.19 g, 23%). LCMS: 270 (M+H) ¹H NMR (400 MHz, DMSO-cfe) δ 8.61 (d, J=2.5 Hz, 1 H) 8.25 (d, J=2.5 Hz, 1 H) 3.99 (s, 3 H) 3.93 (s, 3 H).

Step B

2-methoxy-3-( 1 -methyl- 1 H-tetrazol-5-yl)-5-(4, 4, 5, 5-tetramethyl-1 ,3, 2-dioxaborolan-2-yl)pyridine

The mixture of 5-bromo-2-methoxy-3-(1-methyl-1 H-tetrazol-5-yl)pyridine (0.19 g, 0.703 mmol), bis(pinacolato)diboron (0.214 g, 0.844 mmol), potassium acetate (0.207 g, 2.110 mmol) and PdCI₂(dppf)-CH₂CI₂ adduct (0.057 g, 0.070 mmol) in dioxane (4.1 mL) was heated under nitrogen atmosphere at 100 C° for 2 hours. The mixture was filtered through celite and was evaporated to dryness to give a black solid. The crude sample was purified by silica gel chromatography (4g column eluted with 0-30% EtOAc in hexanes). Fractions containing the product were combined and concentrated to yield 2-methoxy-3-(1 -methyl-1 H-tetrazol-5-yl)-5- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridine (203 mg, 0.448 mmol, 63.7 % yield) as an off-white solid. LCMS: 318 (M+H).

Step C

2-amino-6-(6-methoxy-5-( 1 -methyl-1 H-tetrazol-5-yl)pyridin-3-yl)-3-phenylquinazolin-4(3H)-one

A solution of 2-methoxy-3-(1 -methyl-1 H-tetrazol-5-yl)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan- 2-yl)pyridine (0.133 mL, 0.300 mmol), 2-amino-6-iodo-3-phenylquinazolin-4(3H)-one (109 mg, 0.300 mmol), PdCI₂(dppf)-CH₂CI₂ adduct (24.51 mg, 0.030 mmol), and cesium carbonate (293 mg, 0.9 mmol) in 1 ,4-dioxane (4.9 mL)/water (4.90 mL) was maintained at 80°C for 1 hour. The solution was cooled, poured into DCM, and washed with water. The organic layer was separated, dried over sodium sulfate, filtered, taken to a residue under reduced pressure, and purified by reverse phase hplc (10-70% MeCN water with 0.1 % formic acid). The sample was purified further by silica gel chromatography (isocratic run with 50% DCM, 45 % EtOAc 5% MeOH, 4 gram column). Fractions containing the product were combined and concentrated to yield 2-amino-6-(6-methoxy-5-(1-methyl-1H-tetrazol-5-yl)pyridin-3-yl)-3-phenylquinazolin-4(3H)- one as a white solid (30 mg, 23%). LCMS: 427 (M+H); H NMR (400 MHz, DMSO-c/₆) δ ppm 8.80 (d, J=2.3 Hz, 1 H) 8.32 (d, J=2.5 Hz, 1 H) 8.17 (d, J=2.3 Hz, 1 H) 8.01 (dd, J=8.6, 2.3 Hz, 1 H) 7.48 - 7.65 (m, 3 H) 7.31 - 7.42 (m, 3 H) 6.40 (br. s., 2 H) 4.01 (s, 3 H) 3.99 (s, 3 H).

EXAMPLE 298

2-amino-6-(6-methoxy-5-( 1, -oxadiazol-3-yl)pyridin-3-yl)-3-phenylquinazolm^' -4(3H)-one

Step A

5-bromo-N'-hydroxy-2-methoxynicotinimidamide

A mixture of 5-bromo-2-methoxynicotinonitrile (1.00 g, 4.69 mmol), sodium bicarbonate (0.592 g, 7.04 mmol) and hydroxylamine hydrochloride (0.424 g, 1.3 mmol) in methanol (20 mL) was heated to reflux. After four hours the mixture was allowed to cool then was partitioned between EtOAc and water. The organic layer was washed with brine, dried with Na₂S0₄, filtered and concentrated to yield 5-bromo-N'-hydroxy-2-methoxynicotinimidamide (1.146 g, 99% yield) as a white solid. LCMS: 246 (M+H); ¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.70 (s, 1 H) 8.33 (d, J=2.5 Hz, 1 H) 7.91 (d, J=2.5 Hz, 1 H) 5.83 (br. s., 2 H) 3.88 (s, 3 H).

Step B

3-(5-bromo-2-methoxypyridin-3-yl)-1, 2, 4-oxadiazole

A mixture of 5-bromo-N'-hydroxy-2-methoxynicotinimidamide (400 mg, 1.626 mmol) in trimethylorthoformate (5.1 mL, 46.1 mmol) was heated to 80°C. One drop of concentrated HCI was added to the resulting solution. The resulting mixture was allowed to stir at 80°C for ~ 0.5 hours. The reaction was allowed to cool to room temperature before the addition of hexanes (50 mL). The resulting mixture was filtered to yield 3-(5-bromo-2-methoxypyridin-3-yl)-1 ,2,4- oxadiazole (238 mg, 57%) as a white solid. LCMS: 256 (M+H); H NMR (400 MHz, DMSO-c/₆) δ ppm 9.77 (s, 1 H) 8.54 (d, J=2.5 Hz, 1 H) 8.43 (d, J=2.5 Hz, 1 H) 3.99 (s, 3H).

Step C

3-(2-methoxy-5-(4, 4, 5, 5-tetramethyl-1 ,3, 2-dioxaborolan-2-yl)pyridin-3-yl)-1, 2,4-oxadiazole

The mixture of 3-(5-bromo-2-methoxypyridin-3-yl)-1 ,2,4-oxadiazole (234 mg, 0.914 mmol), bis(pinacolato)diboron (278 mg, 1.097 mmol), potassium acetate (359 mg, 3.66 mmol) and PdCI₂(dppf)-CH₂Cl2 adduct (74.6 mg, 0.091 mmol) in dioxane (5.3 mL) was heated under nitrogen atmosphere at 100 C° for two hours. The mixture was filtered through celite and was evaporated to dryness. The residue was purified by silica gel chromatography (5-35% EtOAc in hexanes) to yield 3-(2-methoxy-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridin-3-yl)- 1 ,2,4-oxadiazole (266 mg, 67% yield). LCMS: 304 (M+H).

Step D

2-amino-6-(6-methoxy-5-(1,2,4-oxadiazol-3-yl)pyridin-3-yl)-3^henylquinazolin^

A solution of 3-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)-1 ,2,4- oxadiazole (0.095 mL, 0.224 mmol), 2-amino-6-iodo-3-phenylquinazolin-4(3H)-one (81 mg, 0.224 mmol), PdCI₂(dppf)-CH₂CI₂ adduct (18.29 mg, 0.022 mmol), and Cesium carbonate (714 mg, 2.19 mmol) in 1 ,4-dioxane (5.3 mL) was maintained at room temperature overnight.

Additional PdCI₂(dppf)-CH₂Cl₂ adduct (18.29 mg, 0.022 mmol), was added and the reaction was heated in a 40°C sand bath for 3 hours, no change. Water (1 mL) was added and the mixture allowed to stir at RT for ~ 2 hours. The mixture was then partitioned between DCM and water. The organic layer was separated and concentrated. The residue was purified by reverse phase HPLC (MeCN/ water with 0.1 % Formic acid). Fractions containing the product were combined and concentrated. The residue was slurried in DCM/ether and filtered to yield 2-amino-6-(6- methoxy-5-(1 ,2,4-oxadiazol-3-yl)pyridin-3-yl)-3-phenylquinazolin-4(3H)-one, Formic acid salt (24 mg, 22% yield) as an off white solid. LCMS: 413 (M+H). H NMR (400 MHz, DMSO-d₆) δ ppm 9.77 (s, 1 H) 8.74 (d, J=2.5 Hz, 1 H) 8.55 (d, J=2.5 Hz, 1 H) 8.14 (d, J=2.1 Hz, 1 H) 8.01 (dd, J=8.6, 2.1 Hz, 1 H) 7.47 - 7.70 {m, 4 H) 7.29 - 7.48 (m, 3 H) 6.40 (br. s., 2 H) 4.04 (s, 3 H).

EXAMPLE 299

2-amino-6-(6-methoxy-5-(1H-tetrazol-5-yl)pyridin-3-yl)-3-phenylquinazolin-4(3

Step A

5-bromo-2-methoxy-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-M and 5- bromo-2-(meth loxy)-3-[2-({[2-(trimethy!silyl)ethyl]oxy}m

A mixture of 5-bromo-2-methoxy-3-(1 H-tetrazol-5-yl)pyridine (500 mg, 1.953 mmol) in DMF (9.8 mL) was stirred in an ice bath as sodium hydride (94 mg, 2.34 mmol) was added. After a minute the bath was removed and the resulting clear solution was allowed to stir for 5 minutes before the addition of SEMCI (0.42 mL, 2.34 mmol). The solution was allowed to stir at room temperature for one our then was partitioned between EtOAc and 5% LiCI solution. The organic layer was washed twice with LiCI solution then dried with Na2S0 , filtered and concentrated to yield a mixture of 5-bromo-2-methoxy-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1 H-tetrazol-5- yl)pyridine and 5-bromo-2-(methyloxy)-3-[2-({[2-(trimethylsilyl)ethyl]oxy}methyl)-2H-tetrazol-5- yljpyridine (827 mg, assume theoretical yield) LCMS: 386 (M+H). Sample was used without purification assuming theoretical yield.

Step B

2-methoxy-5-(4, 4, 5, 5-tetramethyl- 1 , 3, 2-dioxaborolan-2-yl)-3-(1-((3- (trimethylsilyl)propoxy)methyl)- 1 H-tetrazol-5-yl) pyridine and 2-(methyioxy)-5-(4, 4, 5, 5- tetramethyl-1,3,2-dioxaborolan-2-yl)-3-[2-({[2-(trimethylsi^

yljpyridine A mixture of 5-bromo-2-methoxy-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1 H-tetrazol-5-yl)pyridine and 2-(methyloxy)-5-{4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-3-[2-({[2- (trimethylsilyl)ethyl]oxy}methyl)-2H-tetrazol-5-yl]pyridine (825 mg, 1.922 mmol),

bis(pinacolato)diboron (586 mg, 2.306 mmol), potassium acetate (755 mg, 7.69 mmol) and PdCI₂(dppf)-CH₂CI₂ adduct (157 mg, 0.192 mmol) in dioxane (11.2 mL) was heated under nitrogen atmosphere at 100 C° for two hours. The mixture was filtered through celite and was evaporated to dryness. The residue was purified by silica gel chromatography (40g column eluted with 10-40% EtOAc hexanes). Fractions containing the product were combined and concentrated to yield 2-methoxy-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-3-(1-((3- (trimethylsilyl)propoxy)methyl)-1 H-tetrazol-5-yl)pyridine and 2-(methyloxy)-5-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)-3-[2-({[2-(trimethylsilyl)ethyl]oxy}methyl)-2H-tetrazol-5- yl]pyridine (534 m 56%) as a light yellow oil. LCMS: 434 (M+H).

Step C

2-amino-6-(6-methoxy-5-(1-((2-(trimethylsilyl)ethoxy)methyl)-M

phenylquinazolin-4(3H)-one and 2-amino-6-{6-(methyloxy)-5-[2-({[2- (trimethylsilyl)ethyl]oxy}methyl)-2H-tetrazol-5-yl]-3-pyr^^'

A solution of 2-methoxy-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-3-(1-((3- (trtmethylsilyl)propoxy)methyl)-1H-tetrazol-5-yl)pyridine (0.429 mL, 0.900 mmol), 2-amino-6- iodo-3-phenylquinazolin-4(3H)-one (327 mg, 0.9 mmol), PdCI₂(dppf)-CH₂CI₂ adduct (73.5 mg, 0.090 mmol), and Cesium carbonate (714 mg, 2.19 mmol) in 1 ,4-dioxane (14.8 mL)/water

(14.80 mL) was maintained at 80°C for 1 hour. The solution was cooled, poured into DCM, and washed with water. The organic layer was separated, dried over sodium sulfate, filtered, and concentrated. The crude material was purified by silica gel chromatography (5% MeOH 45% EtOAc 50% DCM). Fractions containing product were concentrated to afford a mixture of 2- amino-6-(6-methoxy-5-(1-((2-(trimethylsilyl)ethoxy)methyl)-1 H-tetrazol-5-yl)pyridin-3-yl)-3- phenylquinazolin-4(3H)-one and 2-amino-6-{6-(methyloxy)-5-[2-({[2-

(trimethylsilyl)ethyl]oxy}methyl)-2H-tetrazoί-5-yl]-3φyrid^ (229 mg, 47%) as a tan solid. LCMS: 543 (M+H).

Step D

2-amino-6-(6-methoxy-5-(1H-tetrazol-5-yl)pyridin-3-yl)-3 henylqu

A solution of in 2-amino-6-(6-methoxy-5-(1 -((2-(trimethylsilyl)ethoxy)methyl)-1 H-tetrazol-5- yl)pyridin-3-yl)-3-phenylquinazolin-4(3H)-one and 2-amino-6-{6-(methyloxy)-5-[2-({[2- (trimethylsilyl)ethyl]oxy}methyl)-2H-tetrazol-5-yl]-3^yrid^

(117 mg, 0.216 mmol) MeOH (3.9 mL) was stirred as was 3N HCI (3.9 ml.) added. The solution was heated in a 55°C sand bath for two hours. The sample was allowed to cool then was filtered. The white solid was slurried in ether and filtered to yield 2-amino-6-(6-methoxy-5- (1 H-tetrazol-5-yl)pyridin-3-yl)-3-phenylquinazolin-4(3H)-one, dihydrochloride (80 mg,76%). LCMS: 413 (M+H). ¹H NMR (400 MHz, DMSO-cf₆) δ ppm 8.81 (s, 1 H) 8.74 (s, 1 H) 8.30 (s, 1 H) 8.20 - 8.28 (m, 1 H) 7.57 - 7.70 (m, 4 H) 7.52 (d, J=7.2 Hz, 2 H) 4.1 1 (s, 3 H).

EXAMPLE 300

3-(5-(2-amino-4-oxo-3-phenyl-3,4-dihydroquinazolin-6-yl)-2-methoxypyrM

oxadiazol-5(4H)-one

Step A

3-(5-bromo-2-methoxypyridin-3-yl)-1, 2, 4-oxadiazol-5(4H)-one

A mixture of 5-bromo-N'-hydroxy-2-methoxynicotinimidamicle (1.60 g, 6.5 mmol) in THF (120 mL) and ethyl acetate (120 ml.) was stirred as CDI (3.16 g, 19.51 mmol) was added. The mixture was heated to reflux start 12:47 sand bath temp 85°C for ~ 2 hours. The reaction was allowed to cool to room temperature before the being partitioned between EtOAc and 10% citric acid solution. The organic layer was washed with 10% citric acid then brine before being dried with Na2SC> filtered and concentrated. The residue was slurried in hot EtOAc then hexanes were added. The mixture was allowed to cool then was filtered to yield 3-(5-bromo-2- methoxypyridin-3-yl)-1 ,2,4-oxadiazol-5(4H)-one (1.29 g , 73 %) as a white solid. H NMR (400 MHz, DMSO-cf₆) δ ppm 12.63 (br. s., 1 H) 8.56 (d, J=2.5 Hz, 1 H) 8.27 (d, J=2.3 Hz, 1 H) 3.95 (s, 3 H)

Step B

3-(5-bromo-2-methoxypyridin-3-yl)-4-((2-(trimethylsilyl)ethoxy)me

one

A mixture of 3-(5-bromo-2-methoxypyridin-3-yl)-1 ,2,4-oxadiazol-5(4H)-one (600 mg, 2.205 mmol) in DMF (9.4 mL) was stirred in an ice bath as sodium hydride (106 mg, 2.65 mmol) was added. After a minute the bath was removed and the resulting clear solution was allowed to stir for 5 minutes before the addition of SEMCI (0.47 mL, 2.65 mmol). The solution was allowed to stir at room temperature for one hour then was partitioned between EtOAc and 5% LiCI solution. The organic layer was washed twice with LiCI solution then dried with IS^SC^, filtered and concentrated. The residue was purified by silica gel chromatography (0-100% EtOAc in hexanes) to yield 3-(5-bromo-2-methoxypyridin-3-yl)-4-((2-(trimethylsilyl)ethoxy)methyl)- ,2,4- oxadiazol-5(4H)-one (0.51g, 58% yield). H NMR (400 MHz, DMSO-d₆) δ ppm 8.63 (d, J=2.3 Hz, 1 H) 8.31 (d, J=2.3 Hz, 1 H) 4.92 (s, 2 H) 3.93 (s, 3 H) 3.43 (t, J=8.2 Hz, 2 H) 0.74 (t, J=8.2 Hz, 2 H) -0.07 (s, 9 H).

Step C

3-(2-methoxy-5-(4, 4, 5, 5-tetramethyl- 1, 3, 2-dioxaborolan-2-yl)pyridin-3-y!)-4-((2- (trimethylsilyl)ethoxy)methyl)-1,2,4-oxadiazol-5(4H)-one

A mixture of 3-(5-bromo-2-methoxypyridin-3-yl)-4-((2-(trimethylsilyl)ethoxy)methyl)-1 ,2,4- oxadiazol-5(4H)-one (505 mg, 1.255 mmol), bis(pinacolato)diboron (383 mg, 1.506 mmol), potassium acetate (370 mg, 3.77 mmol) and PdCI₂(dppf)-CH₂CI₂ adduct (103 mg, 0.126 mmol) in dioxane (13.7 mL) was heated under nitrogen atmosphere at 100 C° for 2 hours. The mixture was filtered through celite and was evaporated to dryness to give a black solid. The crude sample was purified by silica gel chromatography (24g column eluted with 0-70% EtOAc in hexanes. Fractions containing the product were combined and concentrated to yield 3-(2- methoxy-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridin-3-yl)-4-((2- (trimethylsilyl)ethoxy)methyl)-1 ,2,4-oxadiazol-5(4H)-one (140 mg, 0.312 mmol, 24.82 % yield) as an off-white solid. LCMS: 450 (M+H).

Step D

3-(5-(2-amino-4-oxo-3^henyl-3,4-dihydroquinazolin-6-yl)-2-methoxypyridm^

(trimethylsilyl)ethoxy)methyl)-1,2,4-oxadiazol-5(4H)-one

A solution of 3-(2-methoxy-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridin-3-yl)-4-((2- (trimethylsilyl)ethoxy)methyl)-1 ,2,4-oxadiazol-5(4H)-one (137 mg, 0.305 mmol), 2-amino-6-iodo- 3-phenylquinazolin-4(3H)-one (109 mg, 0.3 mmol), PdCI₂(dppf)-CH₂CI₂ adduct (24.50 mg, 0.030 mmol), and Cesium carbonate (293 mg, 0.9 mmol) in 1 ,4-Dioxane (5 ml_)/Water (5.00 mL) was maintained at 80°C for 1 hour. The solution was cooled, poured into DCM, and washed with water. The organic layer was separated, dried over sodium sulfate, filtered, and concentrated. The crude material was purified by HPLC (10-70% MeCN in water with 0.1 % formic acid).

Fractions containing product were concentrated to afford 3-(5-(2-amino-4-oxo-3-phenyl-3,4- dihydroquinazolin-6-yl)-2-methoxypyridin-3-yl)-4-((2-(trimethylsilyl)ethoxy)methyl)-1 ,2,4- oxadiazol-5(4H)-one (38 mg, 23%) as a tan solid. H NMR (400 MHz, DMSO-d₆) δ ppm 8.83 (dd, J=3.5, 2.1 Hz, 1 H) 8.42 (dd, J=3.4, 2.1 Hz, 1 H) 8.11 - 8.22 (m, 1 H) 7.92 - 8.06 (m, 1 H) 7.47 - 7.71 (m, 3 H) 7.27 - 7.46 (m, 3 H) 6.41 (br. s., 2 H) 4.94 (d, J=3.7 Hz, 2 H) 3.92 - 4.06 (m, 3 H) 3.39 - 3.55 (m, 2 H) 0.60 - 0.86 (m, 2 H) -0.37 - 0.00 (m, 9 H).

Step E

3-(5-(2-amino-4-oxo-3^henyl-3A-dihydroquinazolin-6-yl)-2-met oxypyn

oxadiazol-5(4H)-one

A solution of in 3-(5-(2-amino-4-oxo-3-phenyl-3,4-dihydroquinazolin-6-yl)-2-methoxypyridin-3- yl)-4-((2-(trimethylsilyl)ethoxy)methyl)-1 ,2,4-oxadiazol-5(4H)-one (37 mg, 0.066 mmol) MeOH (3.9 mL) was stirred as was 3N HCI (3.9 mL) added. The solution was heated in a 55°C sand bath for two hours. The sample was heated in a 75°C sand bath for 3 hours. The sample was allowed to cool then was filtered. The filtrate was brought to pH 7 and concentrated to dryness. The residue was slurried in hot ethanol and filtered to remove salt. The filtrate was

concentrated and combined with the original solid and purified by HPLC (0-70% eCN water with 0.1% formic acid. Fractions containing the product were combined and concentrated to yield 3-(5-(2-amino-4-oxo-3-phenyl-3,4-dihydroquinazolin-6-yl)-2-methoxypyridin-3-yl)-1 ,2,4- oxadiazol-5(4H)-one (3 mg, 10 %) as a white solid. LCMS: 429 (M+H). ¹H NMR (400 MHz, DMSO-af₆) δ ppm 12.70 (br. s., 1 H) 8.79 (br. s., 1 H) 8.43 (br. s., 1 H) 8.24 (br. s., 1 H)

8.13 (br. s., 1 H) 7.39 - 7.69 (m, 6 H) 4.02 (s, 3 H) 3.56 (d, J=1.4 Hz, 2 H)

EXAMPLE 301

6-(5-(1H-tetrazol-5-yl)pyridin-3-yl)-2-amino-3-phenylquinazolin-4(3H)-one

Step A

5-(4, 4, 5, 5-tetramethyi- 1, 3, 2-dioxaboroian-2-yl)nicotinonitrile

A mixture of 5-bromonicotinonitrile (500 mg, 2.73 mmol), bis(pinacolato)diboron (833 mg, 3.28 mmol), potassium acetate (804 mg, 8.20 mmol) and PdCI₂(dppf)-CH₂CI₂ adduct (223 mg, 0.273 mmol) in dioxane (16 ml.) was heated under nitrogen atmosphere at 100 C° for 2 hours. The mixture was filtered through celite and was evaporated to dryness to give a black solid. The crude sample was purified by silica gel chromatography (4g column eluted with 0-30% EtOAc in hexanes). Fractions containing the product were combined and concentrated to yield a sample containing 5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)nicotinonitrile (0.727 g, 1.896 mmol, 69.4 % yield assuming 60% purity) as an off-white solid. LCMS: 149 (boronic acid M+H).

Step B

5- 2-am/^'no-4-oxo-3-p 7eny/-3,4- /77ydroqu nazo/ n-6-y/ n cof/non/Me

A solution of 5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)nicotinonitrile (0.72 g, 1.878 mmol), 2-amino-6-iodo-3-phenylquinazolin-4(3H)-one (0.682 g, 1.878 mmol), PdCI₂(dppf)-CH₂CI₂ adduct (0.153 g, 0.188 mmol), and cesium carbonate (714 mg, 2.19 mmol) in 1 ,4-dioxane (31 ml_)/Water (31.0 mL) was maintained at 80°C for 1 hour. The solution was cooled, and partitioned between DC and water. The organic layer was separated, dried over sodium sulfate, filtered, and concentrated. The residue was slurried in EtOAc and filtered. The solid was slurried in DCM/EtOAc and filtered to yield 5-(2-amino-4-oxo-3-phenyl-3,4- dihydroquinazolin-6-yl)nicotinonitrile (349 mg, 55%) as a tan solid. LCMS: 340 (M+H). H NMR (400 MHz, DMSO-c/₆) δ ppm 9.21 (d, J=2.3 Hz, 1 H) 8.98 (d, J=1.8 Hz, 1 H) 8.70 (t, J=2.1 Hz, 1 H) 8.27 (d, J=2.1 Hz, 1 H) 8.08 (dd, J=8.6, 2.3 Hz, 1 H) 7.47 - 7.65 (m, 3 H) 7.32 - 7.44 (m, 3 H) 6.48 (br. s., 2 H). Step C

6-(5-(1 H-tetrazol-5-yl)pyridin-3-yl)-2-amino-3-phenylquinazolin-4(3H)-one

A mixture of 5-(2-amino-4-oxo-3-phenyl-3,4-dihydroquinazolin-6-yl)nicotinonitrile (200 mg, 0.59 mmol) and TMS-azide (352 μΙ_, 2.65 mmol) and tetraethylammoniumfluoride hydrate (148 mg, 0.88 mmol) in DMF (2 mL) and water (0.2 mL) was heated in a 1 10°C sand bath for 28 hours, then allowed to cool to room temperature. The sample was partitioned between DCM and 5% LiCI solution. Large amounts of a brown emulsion formed. The mixture was filtered. The solid was slurried in DCM/MeOH and filtered. The filtrate was concentrated and the residue was purified by HPLC (10-60% MeCN in water with 0.1% formic acid). Fractions containing the product were combined and concentrated to yield 6-(5-(1 H-tetrazol-5-yl)pyridin-3-yl)-2-amino-3- phenylquinazolin-4(3H)-one (25 mg, 11 %). LCMS: 383 (M+H). H NMR (400 MHz, DMSO-d₆) δ ppm 9.14 (s, 1 H) 8.97 (s, 1 H) 8.59 (s, 1 H) 8.26 (d, J=2.1 Hz, 1 H) 8.02 - 8.20 (m, 1 H) 7.48 - 7.72 (m, 3 H) 7.40 (d, J=8.4 Hz, 3 H) 6.89 - 7.27 (m, 1 H) 6.46 (br. s., 2 H).

EXAMPLE 302

6-(5-('i,2,4-oxad azo/-3-y/ pyri /n-3-y/ -2-am/no-3-pheny/q« nazo/ n-4f3H -one

Step A

5-bromo-N'-hydroxynicotinimidamide

A mixture of 5-bromonicotinonitrile (4.00 g, 21.86 mmol), sodium bicarbonate (2.75 g, 32.8 mmol) and hydroxylamine hydrochloride (1.975 g, 28.4 mmol) in methanol (93 mL) was heated to reflux. After four hours the mixture was allowed to cool then was concentrated. The residue was partitioned between EtOAc and water. A white solid precipitated. The solid was collected by filtration. The layers of the filtrate were separated. The organic layer was washed with brine, dried with Na2SC>4, filtered and concentrated. The residue was combined with the solid from the initial filtration to yield 5-bromo-N'-hydroxynicotinimidamide (3.115 g, 66%) as a white solid. The crude material was used without purification. LC S: 218 (M+H). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.02 (s, 1 H) 8.85 (d, J=1.8 Hz, 1 H) 8.70 (d, J=2.1 Hz, 1 H) 8.23 (t,

J=2.0 Hz, 1 H) 6.07 (s, 2 H)

Step B

3-(5-bromopyridin-3-yl)- 1, 2, 4-oxadiazole

A mixture of 5-bromo-N'-hydroxynicotinimidamide (2.176 g, 10.07 mmol) in

trimethylorthoformate (5.1 mL, 46.1 mmol) was heated to 80°C. Three drops of concentrated HCI was added to the mixture. The resulting mixture was allowed to stir at 80°C for ~ 30 minutes. The reaction was allowed to cool to room temperature before the addition of hexanes (50 mL). The resulting mixture was filtered to yield 3-(5-bromopyridin-3-yl)-1 ,2,4-oxadiazole (2.092 g, 92%) as a light pink solid. LCMS: 226 (M+H). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.86 (s, 1 H) 9.18 (d, J=1.8 Hz, 1 H) 8.96 (d, J=2.1 Hz, 1 H) 8.57 (t, J=2.0 Hz, 1 H)

Step C

3-(5-(4 ,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)-1,2,4-oxadiazole

The mixture of 3-(5-bromopyridin-3-yl)-1 ,2,4-oxadiazole (0.712 g, 3.15 mmol),

bis(pinacolato)diboron (0.960 g, 3.78 mmol), potassium acetate (1.237 g, 12.60 mmol) and PdCI₂(dppf)-CH₂Cl2 adduct (0.257 g, 0.315 mmol) in dioxane (5.3 mL) was heated under nitrogen atmosphere at 100 C° for two hours. The mixture was filtered through celite and was evaporated to dryness to yield a mixture containing 3-(5-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)pyridin-3-yl)-1 ,2,4-oxadiazole (3.2 g) as a black solid . The sample contains several impurities but was used without purification. LCMS: 192 (boronic acid M+H).

Step D

6-(5-(1,2 -oxadiazol-3-yl)pyridin-3-yl)-2-amino-3^henylquinazolin-4(3H^

A solution of 3-(5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridin-3-yl)-1 ,2,4-oxadiazole (246 mg, 0.450 mmol), 2-amino-6-iodo-3-phenylquinazolin-4(3H)-one (163 mg, 0.45 mmol), PdCI₂(dppf)-CH₂CI₂ adduct (36.7 mg, 0.045 mmol), and cesium carbonate (714 mg, 2.19 mmol) in 1 ,4-dioxane (7.4 ml_)/water (1.5 mL) was maintained at room temperature for 8 hours. An additional portion of 3-(5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridin-3-yl)-1,2,4- oxadiazole (246 mg, 0.45 mmol) was added followed by another 37 mg of catalyst. The solution was then allowed to stir at room temperature overnight. The solution partitioned between DCM and water. The organic layer was separated, dried over sodium sulfate, filtered, and

concentrated. The residue was purified by silica gel chromatography (DCM to 50% DCM 45% EtOAc 5 % MeOH 12 gram column). Fractions containing mostly product were combined and concentrated. The residue was slurried in EtOAc and filtered to yield 6-(5-(1 ,2,4-oxadiazol-3- yl)pyridin-3-yl)-2-amino-3-phenylquinazolin-4(3H)-one (89 mg, 52%) as a tan solid. LCMS: 383 (M+H). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.86 (s, 1 H) 9.09 - 9.22 (m, 2 H) 8.58 (s, 1 H) 8.25 (s, 1 H) 8.06 - 8.16 (m, 1 H) 7.47 - 7.65 (m, 3 H) 7.40 (d, J=8.0 Hz, 3 H) 6.48 (br. s., 2 H).

EXAMPLE 303

2-amino-3-phenyl-6-(5-(5-thioxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)pyridin-3-yl)qum

4(3H)-one

Step A

bis( 1, 1-dimethylethyl) [6-(5-cyano-3-pyridinyl)-4-oxo-3-phenyl-3, 4-dihydro-2- quinazolinyljimidodicarbonate

A solution of 5-(2-amino-4-oxo-3-phenyl-3,4-dihydroquinazolin-6-yl)nicotinonitrile (679 mg, 2.07 mmol combination of N9809-72-2 ,75-1 , 75-2 samples) DMAP (24 mg, 0.20 mmol)and BOC₂0

(1.22 g, 5.59 mmol) in MeCN (20 mL) was heated to reflux for 1.5 hours. The mixture was allowed to cool then was concentrated. The residue was partitioned between EtOAc and saturated NaHSC^ solution. The organic layer was washed with NaHSC^ then brine before being dried with a2SC>4. The mixture was filtered and concentrated. The residue was purified by silica gel chromatography (0-50% EtOAc in hexanes, 80 g column) to yield bis(1 ,1- dimethylethyl) [6-(5-cyano-3-pyridinyl)-4-oxo-3-phenyl-3,4-dihydro-2- quinazolinyl]imidodicarbonate (0.86 g, 80%) as a light yellow foam. LCMS: 540 (M+H).

Step B bis(1 ,1 -dimethylethyl) (6-{5-[(hydroxyamino)(imino)methyl]-3-pyridinyl}-4-oxo-3-phenyl-3,4- dihydro-2-quinazolinyl)imidodicarbonate

A mixture of bis(1 ,1-dimethylethyl) [6-(5-cyano-3-pyridinyl)-4-oxo-3-phenyl-3,4-dihydro-2- quinazolinyl]imidodicarbonate (0.43 g, 0.79 mmol), sodium bicarbonate (0.100 g, 1 .12 mmol) and hydroxylamine hydrochloride (0.072 g, 1.04 mmol) in methanol (3.4 mL) was heated to reflux. After 3.5 hours the mixture was allowed to cool then was partitioned between EtOAc and water. The organic layer was washed with brine, dried with is^SC^, filtered and concentrated. The residue was purified by silica gel chromatography (0-10 % MeOH in DCM, 40 g column) to yield bis(1 ,1-dimethylethyl) (6-{5-[(hydroxyamino)(imino)methyl]-3-pyridinyl}-4- oxo-3-phenyl-3,4-dihydro-2-quinazolinyl)imidodicarbonate as a white solid (282 mg, 62%).

LCMS: 573 (M+H).

Step C

bis(1 ,1-dimethylethyl) {4-oxo-3-phenyl-6-[5-(5-thioxo-2,5-dihydro-1 ,2,4-oxadiazol-3-yl)-3- pyridinyl]-3,4-dihydro-2-quinazolinyl}imidodicarbonate

A mixture of bis(1 ,1-dimethylethyl) (6-{5-[-(hydroxyamino)(imino)methyl]-3-pyridinyl}-4-oxo-3- phenyl-3,4-dihydro-2-quinazolinyl)imidodicarbonate (279 mg, 0.487 mmol) in MeCN (4.8 mL) was stirred as di(1 H-imidazol-1-yl)methanethione (104 mg, 0.585 mmol) was added followed by DBU (0.88 mL, 0.585 mmol). The mixture was allowed to stir at room temperature for 1.5 hours. The reaction was concentrated and the residue was partitioned between DCM and saturated aqueous NH4CI solution. The organic layer was washed with NH4CI again, dried with Na2SC> , filtered and concentrated. The residue was purified by silica gel chromatography (0-10% MeOH in DCM, 80 g column). Fractions containing the product were combined and concentrated. The residue was slurried in dcm/hexanes and filtered to yield a sample containing bis(1 ,1- dimethylethyl) {4-oxo-3-phenyl-6-[5-(5-thioxo-2,5-dihydro-1 ,2,4-oxadiazol-3-yl)-3-pyridinyl]-3,4- dihydro-2-quinazolinyl}imidodicarbonate, 1 ,8-Diazabicyclo[5.4.0]undec-7-ene salt (DBU) (186 mg, 39 % as 80% pure) as a white solid. LCMS: 615 (M+H).

Step D

2-amino-3^henyl-6-(5-(5-thioxo-4,5-dihydro-1,2 -oxadiazol-3-yl)pyn

one

A solution of bis(1 ,1-dimethylethyl) {4-oxo-3-phenyl-6-[5-(5-thioxo-2,5-dihydro-1 ,2,4-oxadiazol-3- yl)-3-pyridinyl]-3,4-dihydro-2-quinazolinyl}imidodicarbonate (160 mg, 0.209 mmol) was stirred as 4 N HCI in dioxane (6.6 mL) was added. The resulting solution was allowed to stir at room temperature for 1.5 hours. A white solid had precipitated. The residual solid was dissolved in D F and purified by HPLC (10-70% MeCN/water with 0.1% formic acid). Samples containing product was combined and concentrated. The residue was slurried in DCM/hexanes and concentrated to yield 2-amino-3-phenyl-6-(5-(5-thioxo-4,5-dihydro-1 ,2,4-oxadiazol-3-yl)pyridin-3- yl)quinazolin-4(3H)-one (2 mg, 2% yield). LCMS: 415 (M+H). H NMR (400 MHz, DMSO-d₆) δ ppm 8.98 (br. s., 2 H) 8.39 (br. s., 1 H) 8.21 (br. s., 2 H) 8.08 (br. s., 1 H) 7.47 - 7.66 (m, 3 H) 7.29 - 7.47 (m, 3 H) 6.43 (br. s., 2 H).

EXAMPLE 304

N-(5-(2-amino-4-oxo-3-phenyl-3,4-dihydroquinazolin-6-yl)-2-methoxypyrM

difluoro-N-methylbenzenesulfonamide

A solution of 2,4-difluoro-N-(2-methoxy-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-y^rl)pyridin-3- yl)-N-methylbenzenesulfonamide (0.073 ml_, 0.168 mmol), 2-amino-6-iodo-3-phenylquinazolin- 4(3H)-one (61.0 mg, 0.168 mmol), PdCI₂(dppf)-CH₂Cl₂ adduct (13.73 mg, 0.017 mmol), and cesium carbonate (164 mg, 0.504 mmol) in 1 ,4-dioxane (2.76 ml_)/water (2.76 mL) was maintained at room temperature for 17 hours. The solution was diluted with DCM and washed with water. The organic layer was separated, and concentrated. The residue was purified by HPLC (10-80% MeCN water with 0.1 % formic acid). Fractions containing pure product were concentrated to afford N-(5-(2-amino-4-oxo-3-phenyl-3,4-dihydroquinazolin-6-yl)-2- methoxypyridin-3-yl)-2,4-difluoro-N-methylbenzenesulfonamide (50 mg, 54%) as a tan solid. LCMS: 550 (M+H). H NMR (400 MHz, DMSO-cfe) δ ppm 8.51 (d, J=2.3 Hz, 1 H) 8.10 (d, J=2.1 Hz, 1 H) 8.01 (d, J=2.3 Hz, 1 H) 7.95 (dd, J=8.6, 2.1 Hz, 1 H) 7.75 (td, J=8.5, 6.4 Hz, 1 H) 7.51 - 7.69 (m, 4 H) 7.38 (dd, J=16.5, 7.9 Hz, 3 H) 7.26 (td, J=8.4, 2.2 Hz, 1 H) 6.41 (br. s., 2 H) 3.63 (s, 3 H) 3.28 (d, J=1.2 Hz, 3 H).

EXAMPLE 305

5-(2-amino-4-oxo-3-phenyl-3,4-dihydroquinazolin-6-yl)-N-(2-chlorophenyl)-2- methoxypyridine-3-sulfonamide formic acid salt

Step A

N-( 2-chlorophenyl)-2-methoxy-5-(4, 4, 5, 5-tetramethyl-1 ,3, 2-dioxaborolan-2-yl)pyridine-3- suifonamide

N-(2-chlorophenyl)-2-methoxy-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridine-3- sulfonamide has been synthesized as described for Example 198 Steps A and B, using 2- chloroaniline in Step A. yield 1.1g (57.5%). ES LC-MS m/z 425;

Step B

A degassed mixture of N-(2-chlorophenyl)-2-methoxy-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan- 2-yl)pyridine-3-sulfonamide (80 mg, 0.188 mmol), 2-amino-6-iodo-3-phenylquinazolin-4(3H)-one (68.4 mg, 0.188 mmol), Pd(dppf)₂CI₂ CH₂CI₂ adduct (15.38 mg, 0.019 mmol) and potassium acetate (55.5 mg, 0.565 mmol) in 1 ,4-dioxane (4 mL) and water (1 mL) was heated in a microwave apparatus at 130 °C for 15 min. The resulting mixture was diluted with H₂0 (50 mL) and extracted with EtOAc (50 mL), followed by CH₂CI₂ (50 mL). The organic layers were filtered through paper. The filtrate was concentrated. The residue was dissolved in DMF and purified by HPLC (10-60% CH₃CN in H₂0, both containing 0.1 % formic acid). White precipitate formed in the fractions, which were filtered. The pure fractions were combined and concentrated. The residue was mixed with the filtered solid to obtain 5-(2-amino-4-oxo-3-phenyl-3,4- dihydroquinazolin-6-yl)-N-(2-chlorophenyl)-2-methoxypyridine-3-sulfonamide formic acid salt (40 mg, 0.069 mmol, 37 % yield) as a white solid: H N R (400 MHz, DMSO-afe) δ ppm 3.91 (s, 3 H) 6.41 (br. s., 2 H) 7.13 - 7.25 (m, 1 H) 7.25 - 7.48 (m, 6 H) 7.47 - 7.67 (m, 3 H) 7.90 (d, J=8.58 Hz, 1 H) 8.01 (s, 1 H) 8.16 (s, 1 H) 8.74 (s, 1 H) 10.07 (br. s., 1 H) signal for sulfonamide NH is not observed; ES LC-MS m/z =534.3 (CI³⁵, M+H)⁺ ES LC-MS m/z =536.2 (CI³⁷, M+H)⁺.

EXAMPLE 306

5-(2-amino-4-oxo-3-phenyl-3,4-dihydroquinazolin-6-yl)-N-(4-chlorophenyl)-2- methoxypyridine-3-sulfonamide formic acid salt

Step A

N-(4-chlorophenyl)-2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin

sulfonamide

N-(4-chlorophenyl)-2-meihoxy-5-(4,4,5,5-ietramethyl-1 ,3,2-dioxaborolan-2-yl)pyridine-3- sulfonamide has been synthesized as described for Example 198 Steps A and B, using 2- chloroaniline in Step A. yield 1.2g (62%). ES LC-MS m/z 425;

A degassed mixture of N-{4-chlorophenyl)-2-methoxy-5-{4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan- 2-yl)pyridine-3-sulfonamide (80 mg, 0.188 mmol), 2-amino-6-iodo-3-phenylquinazolin-4(3H)-one (68.4 mg, 0.188 mmol), Pd(dppf)₂CI₂ CH₂CI₂ adduct (15.38 mg, 0.019 mmol) and potassium acetate (55.5 mg, 0.565 mmol) in 1 ,4-dioxane (4 mL) and water (1 mL) was heated in a microwave apparatus at 130 °C for 15 min. The resulting mixture was diluted with H₂0 (50 mL) and extracted with EtOAc (50 mL) and CH₂CI₂ (50 mL). The organic layers were filtered through paper. The filtrate was concentrated, the residue was dissolved in DMF and purified by HPLC (10-60% CH₃CN in H₂0, both containing 0.1 % formic acid) to obtain 5-(2-amino-4-oxo-3-phenyl- 3,4-dihydroquinazolin-6-yl)-N-(4-chlorophenyl)-2-methoxypyridine-3-sulfonamide (18 mg, 0.034 mmol, 18 % yield) as a white solid: H NMR (400 MHz, DMSO-d₅) δ ppm 3.98 (s, 3 H) 6.42 (br. s., 2 H) 7.12 (d, J=8.78 Hz, 2 H) 7.25 (d, J=8.78 Hz, 2 H) 7.34 (d, J=8.58 Hz, 1 H) 7.37 (d, J=7.32 Hz, 2 H) 7.49 - 7.67 (m, 3 H) 7.94 (dd, J=8.58, 2.24 Hz, 1 H) 8.06 (d, =2.15 Hz, 1 H) 8.32 (d, J=2.44 Hz, 1 H) 8.70 (d, J=2.34 Hz, 1 H) 10.29 - 11.61 (m, 1 H); ES LC-MS m/z =534.3 (CI³⁵, M+H)⁺ ES LC-MS m/z =536.2 (CI³⁷, M+H)⁺.

EXAMPLE 307 methyl 5-(2-amino-4-oxo-3-phenyl-3,4-dih droquinazolin-6-yl)-2-methoxynicotinate

A degassed mixture of methyl 2-methoxy-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)nicotinate (0.807 g, 2.75 mmol), 2-amino-6-iodo-3-phenylquinazolin-4(3H)-one (1 g, 2.75 mmol), Pd(dppf)₂CI₂ CH₂CI₂ adduct (0.225 g, 0.275 mmol) and K₂C0₃ (1.142 g, 8.26 mmol) in 1 ,4-dioxane (40 mL) and water (10 mL) was stirred at room temperature for 2 h. The resulting mixture was diluted with water (100 mL) and extracted with CH₂CI₂. The organic layer was concentrated onto Celite, reevaporated from CH₂CI₂/hexane and purified by column

chromatography (0-100% CH₂CI₂/hexane, then 0-100% EtOAc in CH₂CI₂) to obtain methyl 5-(2- amino-4-oxo-3-phenyl-3,4-dihydroquinazolin-6-yl)-2-methoxynicotinate (840 mg, 2.087 mmol, 76 % yield) as a beige solid: ¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.81 - 3.88 (m, 3 H) 3.97 (s, 3 H) 6.40 (br. s., 2 H) 7.30 - 7.41 (m, 3 H) 7.49 - 7.64 (m, 3 H) 7.97 (dd, J=8.58, 2.24 Hz, 1 H) 8.10 (d, J=2.24 Hz, 1 H) 8.37 (d, J=2.63 Hz, 1 H) 8.71 (d, J=2.63 Hz, 1 H); ES LC-MS m/z =403.4 (M+H)⁺.

EXAMPLE 308

5-(2-amino-4-oxo-3-phenyl-3,4-dihydroquinazolin-6-yl)-2-methoxynicotinic acid lithium

A slurry of methyl 5-(2-amino-4-oxo-3-phenyl-3,4-dihydroquinazolin-6-yl)-2-methoxynicotinate (820 mg, 2.038 mmol) in THF (20 mL) was treated with a solution of LiOH H₂0 (94 mg, 2.242 mmol) in water (5 mL). The reaction mixture was maintained at room temperature for 3 days. The resulting mixture was concentrated to obtain 5-(2-amino-4-oxo-3-phenyl-3,4- dihydroquinazolin-6-yl)-2-methoxynicotinic acid lithium salt (800 mg, 2.024 mmol, 99 % yield) as a white solid: ¹H NMR (400 MHz, DMSO- /₆) δ ppm 3.84 (s, 3 H) 6.33 (br. s., 2 H) 7.33 (d, J=8.59 Hz, 1 H) 7.36 - 7.41 (m, 2 H) 7.46 - 7.66 (m, 3 H) 7.87 - 7.96 (m, 2 H) 8.04 (d, J=2.24 Hz, 1 H) 8.30 (d, J=2.63 Hz, 1 H); ES LC-MS m/z =389.3 (M+H)⁺ EXAMPLE 309

5-(2-amino-4-oxo-3-phenyl-3,4-dihydroquinazolin-6-yl)-2-methoxy-N,N- dimethylnicotinamide formic acid salt

To a mixture of 5-(2-amino-4-oxo-3-phenyl-3,4-dihydroquinazolin-6-yl)-2-methoxynicotinic acid lithium salt (60 mg, 0.152 mmol), dimethylamine (18.82 mg, 0.167 mmol) and HATU (63.5 mg, 0.167 mmol) in DMF (1 mL) was added DIPEA (0.056 ml_, 0.319 mmol). After 15 min the reaction mixture was purified by HPLC (10-90% CH₃CN in H₂0, both containing 0.1 % formic acid) to obtain 5-(2-amino-4-oxo-3-phenyl-3,4-dihydroquinazolin-6-yl)-2-methoxy-N,N- dimethylnicotinamide formic acid salt (43 mg, 0.093 mmol, 61 % yield) as a white solid: ¹H NMR (400 MHz, DMSO-de) δ ppm 2.82 (s, 3 H) 3.00 (s, 3 H) 3.94 (s, 3 H) 6.37 (br. s., 2 H) 7.33 (d, J=8.49 Hz, 1 H) 7.35 - 7.41 (m, 2 H) 7.49 - 7.62 (m, 3 H) 7.94 - 8.00 (m, 2 H) 8.11 (d, J=2.24 Hz, 1 H) 8.14 (s, 1 H) 8.56 (d, J=2.44 Hz, 1 H); ES LC-MS m/z =416.2 (M+H)⁺

EXAMPLE 310

5-(2-amino-4-oxo-3-phenyl-3,4-dihydroquinazolin-6-yl)-N-(2-(dimethy

meth salt

To a mixture of 5-(2-amino-4-oxo-3-phenyl-3,4-dihydroquinazolin-6-yl)-2-methoxynicotinic acid lithium salt (60 mg, 0.152 mmol), N1 ,N1-dimethylethane-1 ,2-diamine (14.72 mg, 0.167 mmol) and HATU (63.5 mg, 0.167 mmol) in DMF (1 mL) was added DIPEA (0.056 mL, 0.319 mmol). After 15 min the reaction mixture was purified by HPLC (10-90% CH₃CN in H₂0, then 5-50% CH₃CN in H₂0, both containing 0.1 % formic acid) to obtain 5-(2-amino-4-oxo-3-phenyl-3,4- dihydroquinazolin-6-yl)-N-(2-(dimethylamino)ethyl)-2-methoxynicotinamide formic acid salt (22 mg, 0.040 mmol, 26 % yield) as a white solid: H NMR (400 MHz, DMSO-c/₆) δ ppm 2.25 (s, 6 H) 3.42 (q, J=6.37 Hz, 4 H) 4.03 (s, 3 H) 6.38 (br. s., 2 H) 7.32 - 7.41 (m, 3 H) 7.49 - 7.62 (m, 3 H) 7.98 (dd, J=8.63, 2.29 Hz, 1 H) 8.1 1 (d, J=2.34 Hz, 1 H) 8.16 (s, 2 H) 8.41 (d, =2.63 Hz, 1 H) 8.44 (t, J=5.41 Hz, 1 H) 8.65 (d, J=2.63 Hz, 1 H); LC-MS m/z =459.2 (M+H)⁺

EXAMPLE 311

5-(2-amino-4-oxo-3-phenyl-3,4-dihydroquinazolin-6-yl)-N-(tert-butyl)-2- meth acid salt

A thick slurry of 5-(2-amino-4-oxo-3-phenyl-3,4-dihydroquinazolin-6-yl)-2-methoxynicotinic acid lithium salt (80 mg, 0.202 mmol), 2-methylpropan-2-amine (16.28 mg, 0.223 mmol), DIPEA (0.074 ml_, 0.425 mmol) and HATU (85 mg, 0.223 mmol) in DMF (1 mL) was stirred at room temperature. After 15 min the resulting solution was purified by HPLC (10-90% CH₃CN in H₂0, both containing 0.1 % formic acid) to obtain 5-(2-amino-4-oxo-3-phenyl-3,4-dihydroquinazolin-6- yl)-N-(tert-butyl)-2-methoxynicotinamide formic acid salt (71 mg, 0.145 mmol, 72 % yield) as a white solid: H NMR (400 MHz, DMSO-d₆) δ ppm 1.39 (s, 9 H) 4.02 (s, 3 H) 6.39 (br. s., 2 H) 7.30 - 7.42 (m, 3 H) 7.48 - 7.63 (m, 3 H) 7.92 - 8.02 (m, 2 H) 8.11 (d, J=2.15 Hz, 1 H) 8.14 (s, 1 H) 8.30 (d, J=2.54 Hz, 1 H) 8.61 (d, J=2.44 Hz, 1 H); ES LC-MS m/z =444.4 (M+H)⁺

EXAMPLE 312

5-(2-amino-4-oxo-3^henyl-3,4-dihydroquinazolin-6-yl)-N-isobutyl-2-m

formic acid salt

To a mixture of 5-(2-amino-4-oxo-3-phenyl-3,4-dihydroquinazolin-6-yl)-2-methoxynicotinic acid lithium salt (60 mg, 0.152 mmol), 2-methylpropan- -amine (12.21 mg, 0.167 mmol) and HATU (63.5 mg, 0.167 mmol) in DMF (1 mL) was added DIPEA (0.056 mL, 0.319 mmol). After 40 minutes the resulting mixture was purified by HPLC (10-90% CH₃CN in H₂0, both containing 0.1 % formic acid) to obtain 5-(2-amino-4-oxo-3-phenyl-3,4-dihydroquinazolin-6-yl)-N-isobutyl-2- methoxynicotinamide formic acid salt (40 mg, 0.082 mmol, 53.8 % yield) as a white solid: H N R (400 MHz, D SO-cfe) δ ppm 1.77 - 1.91 (m, 1 H) 3.13 (t, J=6.39 Hz, 2 H) 4.01 (s, 3 H) 6.38 (br. s., 2 H) 7.36 (dd, J=12.54, 7.95 Hz, 3 H) 7.47 - 7.64 (m, 3 H) 7.97 (dd, J=8.59, 2.24 Hz, 1 H) 8.07 - 8.19 (m, 2 H) 8.25 - 8.37 (m, 2 H) 8.62 (d, J=2.54 Hz, 1 H); ES LC-MS m/z =444.1 (M+H)⁺

EXAMPLE 313

5-(2-amino-4-oxo-3-phenyl-3,4-dihydroquinazolin-6-yl)-N-isopropyl-2- meth acid salt

To a mixture of 5-(2-amino-4-oxo-3-phenyl-3,4-dihydroquinazolin-6-yl)-2-methoxynicotinic acid lithium salt (60 mg, 0.152 mmol), propan-2-amine (9.87 mg, 0.167 mmol) and HATU (63.5 mg, 0.167 mmol) in DMF (1 mL) was added DIPEA (0.056 mL, 0.319 mmol). After 15 min the resulting mixture was purified by HPLC (10-90% CH₃CN in H₂0, both containing 0.1 % formic acid) to obtain 5-(2-amino-4-oxo-3-phenyl-3,4-dihydroquinazolin-6-yl)-N-isopropyl-2- methoxynicotinamide formic acid salt (60 mg, 0.140 mmol, 92 % yield) as a white solid: 'H NMR (400 MHz, DMSO-de) δ ppm 1.13 - 1.22 (m, 6 H) 4.00 (s, 3 H) 4.03 - 4.16 (m, 1 H) 6.38 (br. s., 2 H) 7.32 - 7.41 (m, 3 H) 7.48 - 7.62 (m, 3 H) 7.97 (dd, J=8.58, 2.34 Hz, 1 H) 8.06 - 8.13 (m, 2 H) 8.13 (s, 1 H) 8.27 (d, J=2.54 Hz, 1 H) 8.61 (d, J=2.63 Hz, 1 H); ES LC-MS m/z =430.9 (M+H)⁺

EXAMPLE 314

5-(2-amino-4-oxo-3-phenyl-3,4-dihydroquinazolin-6-yl)-2-methoxy-N-(2,2,2- trifluoroethyl)pyridine-3-sulfonamide

Step A

5-bromo-2-chloro-N-(2,2,2-trifluoroethyl)pyridine-3-suifonamide

A mixture of 5-bromo-2-chloropyridine-3-sulfonyl chloride (1 g, 3.44 mmol), 2,2,2- trifluoroethanamine (0.374 g, 3.78 mmol) and pyridine (0.834 mL, 10.31 mmol) in 1 ,4-dioxane (5 mL) was heated at 50 °C for 90 min. The resulting mixture was diluted with EtOAc (50 mL) and water (50 mL). The organic layer was concentrated, the residue was dissolved in CH₂CI₂and purified by column chromatography (silica gel, 0-50% EtOAc in hexane) to obtain 5-bromo-2- chloro-N-(2,2,2-trifluoroethyl)pyridine-3-sulfonamide (0.85 g, 2.404 mmol, 70 % yield) as a white solid: H NMR (400 MHz, DMSO-d₆) δ ppm 3.93 (q, 2 H) 8.48 (d, J=2.44 Hz, 1 H) 8.85 (d, J=2.44 Hz, 1 H) 9.40 (s, 1 H); ES LC-MS m/z =352.8 (Br⁷⁹, M+H)⁺ ES LC-MS m/z =354.9 (Br⁸¹ , M+H)⁺

Step B

5-bromo-2-methoxy-N-(2 -trifiuoroethyl)pyridine-3-sulfonamide

A solution of 5-bromo-2-chloro-N-(2,2,2-trifluoroethyl)pyridine-3-sulfonamide (848 mg, 2.399 mmol) in MeOH (5 mL) and a 25% NaOMe solution in MeOH (1 mL, 2.399 mmol) was heated in a microwave apparatus at 95 °C for 30 min. More MeOH (2 mL) and a 25% NaOMe solution in MeOH (1 mL, 2.399 mmol) were added and the reaction mixture was heated in a microwave apparatus at 95 °C for 30 min. The resulting mixture was diluted with water (100 mL), then 10% citric acid was added to adjust the pH to 8. The mixture was extracted with EtOAc (1000 mL) and concentrated to obtain 5-bromo-2-methoxy-N-(2,2,2-trifluoroethyl)pyridine-3-sulfonamide (860 mg, 2.316 mmol, 97 % yield) as a white solid: H NMR (400 MHz, DMSO-afe) δ ppm 3.84 (q, J=9.40 Hz, 2 H) 4.00 (s, 3 H) 8.14 - 8.25 (m, 1 H) 8.54 - 8.62 (m, 1 H) 8.82 (br. s., 1 H); ES LC-MS m/z =348.8 (Br⁷⁹, M+H)⁺ ES LC-MS m/z =350.7 (Br⁸¹ , M+H)⁺

Step C

2-methoxy-5-(4, 4, 5, 5-tetramethyl-1 , 3, 2-dioxaborolan-2-yl)-N-(2, 2, 2-trifluoroethyl)pyridine-3- sulfonamide

A degassed mixture of 5-bromo-2-methoxy-N-(2,2,2-trifluoroethyl)pyridine-3-sulfonamide (858 mg, 2.458 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2^,-bi-1 ,3,2-dioxaborolane (686 mg, 2.70 mmol), Pd(dppf)₂Cl₂ CH₂CI₂ adduct (201 mg, 0.246 mmol) and potassium acetate (724 mg, 7.37 mmol) in 1 ,4-dioxane (20 mL) was heated at 80 °C for 2 h. The resulting mixture was allowed to cool to room temperature and filtered through a pad of Celite with the aid of EtOAc. The filtrate was concentrated onto Celite and purified by column chromatography (silica gel, 0-100% EtOAc in hexane) to obtain 2-methoxy-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-N-(2,2,2- trifluoroethyl)pyridine-3-sulfonamide (766 mg, 1.933 mmol, 79 % yield) as a white solid: ¹H NMR (400 MHz, DMSO-cfg) δ ppm 1.31 (s, 12 H) 3.74 - 3.88 (m, 2 H) 4.04 (s, 3 H) 8.25 (d, J=1.46 Hz, 1 H) 8.57 (d, J=1.37 Hz, 1 H) 8.65 (br. s., 1 H); ES LC-MS m/z =397.0 (M+H)⁺

Step D

5-(2-amino-4-oxo-3^henyl-3^-dihydroquinazolin-6-yl)-2-methoxy-N-(2,2,2- trifluoroethyl)pyridine-3-sulfonamide

A degassed mixture of 2-methoxy-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-N-(2,2,2- trifluoroethyl)pyridine-3-sulfonamide (580 mg, 1.464 mmol), 2-amino-6-iodo-3-phenylquinazolin- 4(3H)-one (532 mg, 1.464 mmol), Pd(dppf)2CI₂ CH₂Cl2 adduct (120 mg, 0.146 mmol) and K₂C0₃ (607 mg, 4.39 mmol) in 1 ,4-dioxane (30 mL) and water (7.5 mL) was stirred at room

temperature for 18 h. The resulting mixture was diluted with H₂0 (50 mL) and extracted with EtOAc (50 mL) and CH₂CI₂ (50 mL). The organic layers combined, concentrated onto Celite and purified by silica gel chromatography (5-100% EtOAc in hexane), then reevaporated from a mixture of CH₂CI₂ and pentane to obtain 5-(2-amino-4-oxo-3-phenyl-3,4-dihydroquinazolin-6-yl)- 2-methoxy-N-(2,2,2-trifluoroethyl)pyridine-3-sulfonamide (420 mg, 0.831 mmol, 57 % yield) as a white solid: ¹H NMR (400 MHz, DMSO- ₆) δ ppm 3.80 - 3.96 (m, 2 H) 4.06 (s, 3 H) 6.43 (br. s., 2 H) 7.32 - 7.43 (m, 3 H) 7.51 - 7.63 (m, 3 H) 8.00 (dd, J=8.63, 2.29 Hz, 1 H) 8.13 (d, J=2.24 Hz, 1 H) 8.31 (d, J=2.44 Hz, 1 H) 8.72 (br. s., 1 H) 8.77 (d, J=2.44 Hz, 1 H); ES LC-MS m/z =506.3

(M+H)⁺

EXAMPLE 315

methyl 2-am/no-5-f2-am no-4-oxo-3-pheny/-3,4-d/hydroqu nazo//n-6-y/jn/cof nate

Step 1

methyl 2-amino-5-(4, 4, 5, 5-tetra methyl- 1, 3, 2-dioxaborolan-2-yl)nicotinate

A degassed mixture of methyl 2-amino-5-bromonicotinate (939 mg, 4.06 mmol),

4,4,4^,,4',5,5,5^,,5'-octamethyl-2,2'-bi-1 ,3,2-dioxaborolane (1187 mg, 4.67 mmol),

Pd(dppf)₂CI₂ CH₂CI₂ adduct (332 mg, 0.406 mmol) and potassium acetate (1 197 mg, 12.19 mmol) in 1 ,4-dioxane (40 ml.) was heated at 80 °C for 3 h. The resulting mixture was filtered through a pad of Celite with the aid of EtOAc. The filtrate was concentrated onto Celite and purified by column chromatography (silica gel, 0-100% EtOAc in hexane), followed by trituration using Et₂0 to obtain methyl 2-amino-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)nicotinate (697 mg, 2.506 mmol, 62 % yield) as a white solid: ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.27 (s, 12 H) 3.82 (s, 3 H) 7.52 (s, 2 H) 8.28 (s, 1 H) 8.38 (s, 1 H).

Step 2

methyl 2-amino-5-(2-amino- uinazolin-6-yl)nicotinate

A degassed mixture of methyl 2-amino-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)nicotinate (345 mg, 1.239 mmol), 2-amino-6-iodo-3-phenylquinazolin-4(3H)-one (450 mg, 1 .239 mmol), Pd(dppf)₂CI₂ CH₂CI₂ adduct (101 mg, 0.124 mmol) and K₂C0₃ (514 mg, 3.72 mmol) in 1 ,4- dioxane (20 mL) and water (5 mL) was heated at 90 °C for 3 h. The resulting thick slurry was filtered, solid washed with water and hexane to obtain methyl 2-amino-5-(2-amino-4-oxo-3- phenyl-3,4-dihydroquinazolin-6-yl)nicotinate (460 mg, 1.128 mmol, 91 % yield) as a lime colored solid: H NMR (400 MHz, DMSO-d₆) δ ppm 3.86 (s, 3 H) 6.33 (br. s., 2 H) 7.24 - 7.35 (m, 3 H) 7.35 - 7.41 (m, 2 H) 7.48 - 7.63 (m, 3 H) 7.91 (dd, J=8.58, 2.34 Hz, 1 H) 8.02 (d, J=2.24 Hz, 1 H) 8.29 (d, J=2.63 Hz, 1 H) 8.59 (d, J=2.54 Hz, 1 H); ES LC-MS m/z =388.1 (M+H)⁺ EXAMPLE 316

2-amino-5-(2-amino-4-oxo-3-phen -3,4-dihydroquinazolin-6-yl)-N-(tert-butyl)

Step 1

2-amino-5-(2-amino-4-oxo-3-ph -6-yl)nicotinic acid lithium salt

A slurry of methyl 2-amino-5-(2-amino-4-oxo-3-phenyl-3,4-dihydroquinazolin-6-yl)nicotinate (460 mg, 1.187 mmol) in THF (50 mL) and MeOH (50 mL) was treated with a solution of LiOH H₂0 (74.8 mg, 1 .781 mmol) in water (10 mL). After ten days the resulting mixture was concentrated to obtain 2-amino-5-(2-amino-4-oxo-3-phenyl-3,4-dihydroquinazolin-6-yl)nicotinic acid lithium salt (0.49 g, 1.288 mmol, quant, yield) as a white solid: ES LC-MS m/z =374.5 (M+H)⁺

Step 2

2-amino-5-(2-amino-4-oxo-3 henyl-3,4-dihydroquinazolin-6-y ^

To a mixture of 2-amino-5-(2-amino-4-oxo-3-phenyl-3,4-dihydroquinazolin-6-yl)nicotinic acid lithium salt (60 mg, 0.158 mmol), 2-methylpropan-2-amine (12.69 mg, 0.174 mmol) and HATU (66.0 mg, 0.174 mmol) in DMF (1 mL) was added DIPEA (0.058 mL, 0.331 mmol). The resulting slurry was filtered and the filtrate was purified by HPLC (10-70% CH₃CN in H₂0, both containing 0.1 % formic acid) to obtain 2-amino-5-(2-amino-4-oxo-3-phenyl-3,4-dihydroquinazolin-6-yl)-N- (tert-butyl)nicotinamide (1 1 mg, 0.026 mmol, 16 % yield) as a white solid: ¹H NMR (400 MHz, DMSO-c/₆) δ ppm 1.39 (s, 9 H) 6.29 (br. s, 2 H) 6.95 (s, 1 H) 7.32 (d, J=8.58 Hz, 1 H) 7.35 - 7.41 (m, 2 H) 7.49 - 7.56 (m, 1 H) 7.56 - 7.63 (m, 2 H) 7.94 (dd, J=8.59, 2.24 Hz, 1 H) 8.03 (s, 1 H) 8.06 (d, J=2.34 Hz, 1 H) 8.11 (d, J=2.24 Hz, 1 H) 8.18 (s, 1 H) 8.38 (d, J=2.34 Hz, 1 H); ES LC-MS m/z =429.3 (M+H)⁺

General Scheme 21 : Synthesis of Functionalized Pyridyls

X = N, C

General Scheme 22: Synthesis of Examples

Example #s: 326-353

Example 317

2-amino-6-[6-(methylsulfonyl)-3-pyridinyl]-3-phenyl-4(3H)-quinazoiinone

A solution of [6-(methylsulfonyl)-3-pyridinyl]boronic acid (86 mg, 0.426 mmol, CombiBlocks), 2- amino-6-iodo-3-phenyl-4(3H)-quinazolinone (119 mg, 0.328 mmol), potassium carbonate (136 mg, 0.983 mmol), and PdCI₂(dppf)-CH₂CI₂ adduct (26.8 mg, 0.033 mmol) in 1 ,4-dioxane (5 ml_)/water (3 mL) was maintained at 90°C for 1 hour. The mixture was cooled, poured into ethyl acetate, and washed with water. The aqueous layer and insoluble solids were washed with dichloromethane and the combined organic layers were dried over sodium sulfate, filtered, concentrated, and purified by reverse phase HPLC. Fractions containing product were pooled, concentrated, triturated with dichloromethane, and the white solid collected via vacuum filtration to afford 2-amino-6-[6-(methylsulfonyl)-3-pyridinyl]-3-phenyl-4(3H)-quinazolinone (72 mg, 0.164 mmol, 50.1 % yield) as a white solid as the formate salt. LCMS (m/z, ES+) = 439 (M+H). H NMR (400 MHz, DMSO-cie) δ ppm 3.31 (s, 3 H) 6.52 (br. s., 2 H) 7.28 - 7.45 (m, 3 H) 7.48 - 7.65 (m, 3 H) 8.03 - 8.19 (m, 3 H) 8.28 (d, J=2.34 Hz, 1 H) 8.46 (dd, J=8.39, 2.34 Hz, 1 H) 9.14 (d, J=2.15 Hz, 1 H).

Example 318

5-(2-amino-4-oxo-3-phenyl-3,4-dihydroquinazolin-6-yl)-N-cyclohexyl-2-m

sulfonamide

Step A:

5-bromo-N-cyclohexyl-2-methoxypyridine-3-sulfonamide Pyridine (1.1 mL, 13.7 mmol) was added to 5-bromo-2-chloropyridine-3-sulfonyl chloride (1 g, 3.4 mmol) in 1 ,4-dioxane (15 mL), cyclohexanamine (0.34 g, 3.4 mmol) was added to the mixture above, and the mixture was stirred at room temperature for 1 hour, then the mixture was warmed at 50 °C for 2 hours. The solvent was removed under reduced pressure and then extracted with water and EtOAc (100mU 100ml_). The organic layer was dried over anhydrous MgS0 , filtered, and concentrated. The residue was dissolved in methanol (15 mL), then sodium methoxide (2.5mL (25%) in methanol) was added and the flask was sealed and maintained at 95°C under microwave irradiation for 45 minutes. The crude product was added to a silica gel column and was eluted with Hex/EtOAc to afford 5-bromo-N-cyclohexyl-2- methoxypyridine-3-sulfonamide (0.78g, 2.23 mmol).

Step B:

N-cyciohexyl-2-methoxy-5-( 4, 4, 5, 5-tetramethyl- 1 , 3, 2-dioxaborolan-2-yl)pyridine-3-sulfonamide

A solution of 5-bromo-N-cyclohexyl-2-methoxypyridine-3-sulfonamide (1.1 g, 2.97 mmol), 4,4,4^,,4^,,5,5,5^,,5'-octamethyl-2,2^,-bi(1 ,3,2-dioxaborolane) (1.1g, 4.45 mmol), PdCI₂(dppf)-CH₂CI₂ (0.24g, 0.297 mmol), and potassium acetate (0.87g, 8.9 mmol) in 1 ,4-dioxane (5 mL) was maintained at 95°C for 16 hours. The mixture was filtered through celite and the filtrates concentrated and purified by column chromatography to afford N-cyclohexyl-2-methoxy-5- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridine-3-sulfonamide (0.9g, 2.1 mmol).

Step C:

5-(2-amino-4-oxo-3^henyl-3,4-dihydroquinazolin-6-yl)-N-cyclo exyl-2^

sulfonamide

A solution of 2-amino-6-iodo-3-phenylquinazolin-4(3H)-one (75 mg, 0.207 mmol), N-cyclohexyl- 2-methoxy-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridine-3-sulfonamide (127 mg, 0.320 mmol), PdCI₂(dppf)-CH₂CI₂ adduct (16.87 mg, 0.021 mmol), and potassium carbonate (86 mg, 0.620 mmol) in 1 ,4-dioxane (3 mL)/water (3.00 mL) was maintained at 80°C for 1 hour. The mixture was cooled briefly, poured into ethyl acetate, and washed with saturated sodium chloride (aq). The organic layer was separated, dried over sodium sulfate, filtered, taken to a residue under reduced pressure, and the residue was purified by reverse phase HPLC to afford 5-(2-amino-4-oxo-3-phenyl-3,4-dihydroquinazolin-6-yl)-N-cyclohexyl-2-methoxypyridine-3- sulfonamide (14 mg, 0.028 mmol, 13.41 % yield) as a white foam following lyophilization. LCMS (m/z, ES+) = 506 (M+H). H NMR (400 MHz, DMSO-d₆) δ ppm 1.09 - 1.31 (m, 6 H) 1.43 (br. s., 1 H) 1.58 (br. s., 3 H) 3.11 (br. s., 1 H) 4.04 (s, 3 H) 6.40 (br. s., 2 H) 7.30 - 7.43 (m, 3 H) 7.49 - 7.64 (m, 3 H) 7.67 (d, J=8.00 Hz, 1 H) 7.99 {dd, J=8.68, 2.24 Hz, 1 H) 8.10 (d, J=2.34 Hz, 1 H) 8.30 (d, J=2.54 Hz, 1 H) 8.73 (d, J=2.34 Hz, 1 H).

Example 319

5-(2-amino-4-oxo-3-phenyl-3,4-dihydroquinazolin-6-yl)-N-(tert-butyl)-2-m

Step A:

5-bromo-N-(tert-butyl)-2-methoxy-N-methylpyridine-3-sulfonamide

A solution of 5-bromo-N-(tert-butyl)-2-methoxypyridine-3-sulfonamide (460 mg, 1.423 mmol), potassium carbonate (983 mg, 7.12 mmol), and methyl iodide (0.267 ml_, 4.27 mmol) in N,N- dimethylformamide (8 ml.) was maintained at 80°C for 45 minutes. The solution was cooled to room temperature, poured into ethyl acetate, and washed three times with 5% LiCI (aq). The organic layer was separated, dried over sodium sulfate, filtered, taken to a residue under reduced pressure, and purified by column chromatography (20% EtOAc in hexanes) to afford 5- bromo-N-(tert-butyl)-2-methoxy-N-methylpyridine-3-sulfonamide (400 mg, 1.186 mmol, 83 % yield) as a yellow solid. H NMR (DMSO-d₆) δ: 8.56 (d, J = 2.5 Hz, 1 H), 8.20 (d, J = 2.5 Hz, 1H), 4.01 (s, 3H), 3.01 (s, 3H), 1.21 (s, 9H).

Step B:

N-(tert-butyl)-2-methoxy-N-methyl-5-(4, 4, 5, 5-tetramethyl-1 , 3, 2-dioxaborolan-2-yl)pyridine-3- suifonamide

A degassed mixture of 5-bromo-N-(tert-butyl)-2-methoxy-N-methylpyridine-3-sulfonamide (334 mg, 0.990 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2^,-bi-1 ,3,2-dioxaborolane (277 mg, 1.089 mmol), Pd(dppf)₂CI₂ CH₂CI₂ adduct (81 mg, 0.099 mmol) and potassium acetate (292 mg, 2.97 mmol) in 1 ,4-dioxane (10 mL) was heated at 95 °C for 10 h, allowed to cool to room temperature, and stirred over the weekend. The solution was filtered through a pad of Celite. The filtrate was concentrated, dissolved in CH₂CI₂, concentrated onto Celite, and purified by column chromatography (silica gel, 0-30% EtOAc/hexane) to obtain N-(tert-butyl)-2-methoxy-N- methyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridine-3-sulfonamide (356 mg, 0.741 mmol, 74.8 % yield) as a pale yellow oil. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.27 - 1 .35 (m, 12 H) 3.01 (s, 3 H) 4.04 (s, 3 H) 8.24 (d, J=1.86 Hz, 1 H) 8.56 (d, J=1.76 Hz, 1 H); ES LC-MS m/z =385.2 (M+H)⁺

Step C:

5-(2-amino-4-oxo-3^henyl-3,4-dihydroquinazolin-6-yl)-N-(tert-butyl)-2-metho

methylpyridine-3-sulfonamide

A solution of 2-amino-6-iodo-3-phenylquinazolin-4(3H)-one (75 mg, 0.207 mmol), N-(tert-butyl)- 2-methoxy-N-methyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridine-3-sulfonamide (95 mg, 0.248 mmol), PdCI₂(dppf)-CH₂CI₂ adduct (16.87 mg, 0.021 mmol), and potassium carbonate (86 mg, 0.620 mmol) in 1 ,4-dioxane (3 ml_)/water (3.00 mL) was maintained at 80°C for 1 hour. The mixture was cooled briefly, poured into ethyl acetate, and washed with saturated sodium chloride (aq). The organic layer was separated, dried over sodium sulfate, filtered, taken to a residue under reduced pressure, and the residue was purified by reverse phase HPLC to afford 5-(2-amino-4-oxo-3-phenyl-3,4-dihydroquinazolin-6-yl)-N-(tert-butyl)-2- methoxy-N-methylpyridine-3-sulfonamide (82 mg, 0.166 mmol, 80 % yield) as a white foam following lyophilization. LCMS (m/z, ES+) = 494 (M+H). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.23 (s, 9 H) 3.05 (s, 3 H) 4.06 (s, 3 H) 6.41 (br. s., 2 H) 7.28 - 7.42 (m, 3 H) 7.50 - 7.64 (m, 3 H) 7.97 (dd, J=8.59, 2.34 Hz, 1 H) 8.09 (d, J=2.15 Hz, 1 H) 8.16 (s, 1 H) 8.29 (d, J=2.54 Hz, 1 H) 8.74 (d, J=2.34 Hz, 1 H).

Example 320

5-(2-amino-4-oxo-3-phenyl-3,4-dihydroquinazolin-6-yl)-N-benzyl-2-m

sulfonamide

Step A :

N-benzyl-5-bromo-2-methoxypyridine-3-sulfonamide

Pyridine (1.1 mL, 13.7 mmol) was added to 5-bromo-2-chloropyridine-3-sulfonyl chloride (1g, 3.4 mmol) in 1 ,4-dioxane (15 mL), phenyimethanamine (0.44 g, 4.12 mmol) was added to the mixture above, and the mixture was stirred at room temperature for 1 hour, then the mixture was warmed at 50 °C for 2 hours. The solvent was removed under reduced pressure and then extracted with water and EtOAc (100mL/ 100mL). The organic layer was dried over anhydrous MgSC>4, filtered, and concentrated. The residue was dissolved in methanol (15 mL), then sodium methoxide (2.5mL (25%) in methanol) was added and the flask was sealed and maintained at 95°C under microwave irradiation for 45 minutes. The crude product was added to a silica gel column and was eluted with Hex/EtOAc to afford N-benzyl-5-bromo-2- methoxypyridine-3-sulfonamide (0.82g, 2.3 mmol).

Step B:

N-benzyl-2-methoxy-5-(4,4, 5, 5-tetramethyl-1 , 3, 2-dioxaborolan-2-yl)pyridine-3-sulfonamide

A solution of N-benzyl-5-bromo-2-methoxypyridine-3-sulfonamide (1.1g, 3.08 mmol), 4,4,4^,,4^,,5,5,5^,,5'-octamethyl-2,2^,-bi(1 ,3,2-cl^'ioxaborolane) (1.17 g, 4.62 mmol), PdCI₂(DPPF)- CH₂CI₂ (0.25g, 0.308 mmol), and potassium acetate (0.9 g, 9.24 mmol) in 1,4-dioxane (5 mL) was maintained at 98°C overnight. The mixture was filtered through celite and the residue concentrated and purified by column chromatography to afford N-benzyl-2-methoxy-5-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridine-3-sulfonamide (0.87g, 2.15 mmol).

Step C:

5-(2-amino-4-oxo-3^henyi-3,4-dihydroquinazolin-6-yl)-N-benzyl-2-m sulfonamide

A solution of 2-amino-6-iodo-3-phenylquinazolin-4(3H)-one (75 mg, 0.207 mmol), , PdCI₂(dppf)- CH₂CI₂ adduct (16.87 mg, 0.021 mmol), and potassium carbonate (86 mg, 0.620 mmol) in 1 ,4- dioxane (3 ml_)/water (3.00 mL) was maintained at 80°C for 1 hour. The mixture was cooled briefly, poured into ethyl acetate, and washed with saturated sodium chloride (aq). The organic layer was separated, dried over sodium sulfate, filtered, taken to a residue under reduced pressure, and the residue was purified by reverse phase HPLC to afford 5-(2-amino-4-oxo-3- phenyl-3,4-dihydroquinazolin-6-yl)-N-benzyl-2-methoxypyridine-3-sulfonamide (24 mg, 0.047 mmol, 22.63 % yield) as a white foam following lyophilization. LCMS (m/z, ES+) = 514 (M+H). H NMR (400 MHz, DMSO-cf₆) δ ppm 3.95 (s, 3 H) 4.15 (d, J=6.24 Hz, 2 H) 6.40 (br. s., 2 H) 7.04 - 7.21 (m, 5 H) 7.39 (d, J=7.22 Hz, 2 H) 7.35 (d, J=8.59 Hz, 1 H) 7.50 - 7.64 (m, 3 H) 7.90 (dd, J=8.59, 2.15 Hz, 1 H) 8.04 (d, J=2.15 Hz, 1 H) 8.10 (d, J=2.54 Hz, 1 H) 8.23 (t, J=6.34 Hz, 1 H) 8.57 (d, J=2.54 Hz, 1 H).

Example 321

5-(2-amino-4-oxo-3-phenyi-3,4-dihydroquinazolin-6-yl)-N-benzyl-2-methoxy-N- methylpyridine-3-sulfonamide

Step A:

N-benzyl-5-bromo-2-methoxy-N-methylpyridine-3-sulfonamide

Pyridine (1.1 mL, 13.7 mmol) was added to 5-bromo-2-chloropyridine-3-sulfonyl chloride (1 g, 3.4 mmol) in 1 ,4-dioxane (15 mL), N-methyl-1-phenylmethanamine (0.42 g, 3.44 mmol) was added to the mixture above, and the mixture was stirred at room temperature for 1 hour, then the mixture was warmed at 50 °C for 2 hours. The solvent was removed under reduced pressure and then extracted with water and EtOAc (100mL/ 100ml_). The organic layer was dried over anhydrous MgSC^, filtered, and concentrated. The residue was dissolved in methanol (15 mL), then sodium methoxide (2.5ml_ (25%) in methanol) was added and the flask was sealed and maintained at 95°C under microwave irradiation for 45 minutes. The crude product was added to a silica gel column and was eluted with Hex/EtOAc to afford N-benzyl-5- bromo-2-methoxy-N-methylpyridine-3-sulfonamide (0.85g, 2.29 mmol).

Step B:

N-benzyl-2-methoxy-N-methyl-5-(4, 4, 5, 5-tetramethyl-1 ,3, 2-dioxaborolan-2-yl)pyridine-3- suifonamide

A solution of N-benzyl-5-bromo-2-methoxy-N-methylpyridine-3-sulfonamide (1.1g, 2.97 mmol), 4,4,4',4',5,5,5^,,5^,-octamethyl-2,2'-bi(1 ,3,2-dioxaborolane) (1.1g, 4.45 mmol), PdCI₂(dppf)-CH₂CI₂ (0.24g, 0.29 mmol), and potassium acetate (0.87g, 8.9 mmol) in 1 ,4-dioxane (15 mL) was maintained at 95°C for 16 hours. The mixture was filtered through celite, and the filtrate was concentrated and purified by column chromatography to afford N-benzyl-2-methoxy-N-methyl-5- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridine-3-sulfonamide (0.860g, 1.9 mmol).

Step C:

5-(2-amino-4-oxo-3^henyl-3,4-dihydroquinazoiin-6-yl)-N-benzyi-2-meth^

3-sulfonamide

A solution of 2-amino-6-iodo-3-pheny!quinazolin-4(3H)-one (75 mg, 0.207 mmol), N-benzyl-2- methoxy-N-methyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridine-3-sulfonamide (104 mg, 0.248 mmol), PdCI₂(dppf)-CH₂CI₂ adduct (16.87 mg, 0.021 mmol), and potassium carbonate (86 mg, 0.620 mmol) in 1 ,4-dioxane (3 mL)/water (3.00 mL) was maintained with stirring at 80°C for 20 minutes. The solution was cooled to room temperature, diluted with ethyl acetate, and washed with water. The organic layer was separated, dried over sodium sulfate, filtered, taken to a residue under reduced pressure, and purified by reverse phase HPLC to afford 5-(2-amino-4-oxo-3-phenyl-3,4-dihydroquinazolin-6-yl)-N-benzyl-2-methoxy-N- methylpyridine-3-sulfonamide formate salt (68 mg, 0.129 mmol, 62.4 % yield) as a white solid. LCMS (m/z, ES+) = 528 (M+H). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.75 (s, 3 H) 4.05 (s, 3 H) 4.39 (s, 2 H) 6.42 (br. s., 2 H) 7.20 - 7.43 (m, 8 H) 7.47 - 7.66 (m, 4 H) 8.01 (d, J=8.59 Hz, 1 H) 8.14 (s, 1 H) 8.30 - 8.40 (m, 1 H) 8.71 - 8.83 (m, 1 H). Example 322

5-(2-amm^' o-4-oxo-3-phenyl-3,4-dihydroquinazolin-6-yl)-2-methoxy-N-neo

sulfonamide

Step A:

5-bromo-2-methoxy-N-neopentylpyridine-3-sulfonamide

A solution of 5-bromo-2-chloropyridine-3-sulfonyl chloride (6.87 mmol) in 1 ,4 dioxane (20 mL) was treated with pyridine (2.2 mL, 27.5 mmol) and 2,2-dimethylpropan-1 -amine (0.60 g, 6.87 mmol) and the mixture was maintained with stirring at 50°C for 2 hours. The solvent was removed under reduced pressure and the residue was partitioned between water and ethyl acetate. The organic layer was separated, dried over magnesium sulfate, filtered, and concentrated. The residue was dissolved in methanol (20 mL), then sodium methoxide (4.5mL (25%) in methanol) was added and the flask was sealed and maintained at 95°C under microwave irradiation for 30 minutes. The crude product was added to a silica gel column and was eluted with Hex/EtOAc to afford 5-bromo-2-methoxy-N-neopentylpyridine-3-sulfonamide (1.2g, 3.56 mmol).

Step B:

2-methoxy-N-neopentyl-5-(4,4, 5, 5-tetramethyl- 1, 3, 2-dioxaborolan-2-yl)pyridine-3-sulfonamide

A solution of 5-bromo-2-methoxy-N-neopentylpyridine-3-sulfonamide (1.15g, 3.41 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2^,-bi(1 ,3,2-dioxaborolane), (1.299g, 5.12 mmol), PdCI₂(dppf)₂- CH₂CI₂ (0.28g, 0.341 mmol), and potassium acetate (1.0g, 10.23 mmol) in 1 ,4-dioxane was combined in a flask, purged with nitrogen, and maintained at 95°C overnight. The mixture was cooled and purified by column chromatography to afford 2-methoxy-N-neopentyl-5-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridine-3-sulfonamide (970 mg, 2.52 mmol). Step C:

5-(2-amino-4-oxo-3^henyi-3 -dihydroquinazolin-6-yl)-2-methoxy

sulfonamide

A solution of 2-amino-6-iodo-3-phenylquinazolin-4(3H)-one (75 mg, 0.207 mmol), 2-methoxy-N- neopentyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridine-3-sulfonamide (95 mg, 0.248 mmol), PdCI₂(dppf)-CH₂Cl₂ adduct (16.87 mg, 0.021 mmol), and potassium carbonate (86 mg, 0.620 mmol) in 1 ,4-dioxane (3 ml_)/water (3.00 mL) was maintained at 80°C for 25 minutes. The solution was cooled, poured into ethyl acetate, and washed with water. The organic layer was separated, dried over sodium sulfate, filtered, taken to a residue under reduced pressure, and purified by reverse phase HPLC to afford 5-(2-amino-4-oxo-3-phenyl-3,4-dihydroquinazolin-6- yl)-2-methoxy-N-neopentylpyridine-3-sulfonamide (35 mg, 0.071 mmol, 34.3 % yield) as a white foam following lyophilization. LCMS (m/z, ES+) = 494 (M+H). H NMR (400 MHz, DMSO-c/₆) δ ppm 0.83 (s, 9 H) 2.67 (d, J=6.44 Hz, 2 H) 4.04 (s, 3 H) 6.42 (br. s., 2 H) 7.29 - 7.43 (m, 3 H) 7.48 - 7.65 (m, 4 H) 7.99 (dd, J=8.59, 1.76 Hz, 1 H) 8.07 - 8.15 (m, 1 H) 8.28 (d, J=1.95 Hz, 1 H) 8.74 (d, J=1.95 Hz, 1 H).

Example 323

5-(2-amino-4-oxo-3-phenyI-3,4-dihydroquinazoIin-6-yl)-2-methoxy-N-(1 ph ide

Step A:

5-bromo-2-methoxy-N-( 1 -phenylethyl)pyridine-3-suifonamide

NaHC0₃ (1.7g, 20 mmol) was dissolved in 50 mL water and 1-phenylethanamine (0.750 g , 6.2 mmol) in 50 mL EtOAc was added. 5-bromo-2-chloropyridine-3-sulfonyl chloride(1.5g, 5.2 mmol) was added dropwise to the mixture, and the mixture was stirred at room temperature for 3 hours. The organic layer was dried over anhydrous MgSC>4 and concentrated under reduced pressure. The crude sulfonamide was dissolved in methanol (15 mL), then sodium methoxide (3.6 mL, 25% in methanol) was added and the flask was sealed and maintained at 95°C under microwave irradiation for 30 minutes. The crude product was added to a silica gel column and was eluted with Hex/EtOAc to afford 5-bromo-2-methoxy-N-(1-phenylethyl)pyridine-3- sulfonamide (1.0g, 2.69 mmol).

Step B:

2-methoxy-N-(1-phenylethyi)-5-(4, 4, 5, 5-tetramethyl- 1, 3, 2-dioxaborolan-2-yi)pyridine-3- sulfonamide

A solution of 4,4,4',4^,,5,5,5',5'-octamethyl-2,2'-bi(1 ,3,2-dioxaborolane) (1.74g, 6.83 mmol), 5- bromo-2-methoxy-N-(1-phenylethyl)pyridine-3-sulfonamide (1.69g, 4.56 mmol), PdCI₂(dppf)- CH₂CI₂ (0.37 g, 0.456 mmol), and potassium acetate (1.34g, 13.67 mmol) in 1 ,4-dioxane (15 mL) was combined in a flask, purged with nitrogen, and maintained with heating at 95°C overnight. The mixture was cooled and purified by column chromatography to afford 2- methoxy-N-(1-phenylethyl)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridine-3- sulfonamide (1.3g, 3.11 mmol).

Step C:

5-(2-amino-4-oxo-3^heny\-3 -dibydroquinazo\in-6-y\ ^

sulfonamide

A solution of 2-amino-6-iodo-3-phenylquinazolin-4(3H)-one (75 mg, 0.207 mmol), 2-methoxy-N- (1 -phenylethyl)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridine-3-sulfonamide (104 mg, 0.248 mmol), PdCI₂(dppf)-CH₂CI₂ adduct (16.87 mg, 0.021 mmol), and potassium carbonate (86 mg, 0.620 mmol) in 1 ,4-dioxane (3 mL)/water (3.00 mL) was maintained at 80°C for 25 minutes. The mixture was cooled to room temperature, diluted with ethyl acetate, and washed with water. The organic layer was dried over sodium sulfate, filtered, taken to a residue under reduced pressure, and purified by reverse phase HPLC to afford 5-(2-amino-4-oxo-3-phenyl-3,4- dihydroquinazolin-6-yl)-2-methoxy-N-(1-phenylethyl)pyridine-3-sulfonamide (63 mg, 0.119 mmol, 57.8 % yield) as a white solid. LCMS (m/z, ES+) = 528 (M+H). ¹H NMR (400 MHz, DMSO-cfe) δ ppm 1.35 (d, J=6.84 Hz, 3 H) 3.90 (s, 3 H) 4.42 (t, J=7.52 Hz, 1 H) 6.41 (br. s., 2 H) 6.96 - 7.22 (m, 5 H) 7.26 - 7.44 (m, 3 H) 7.47 - 7.65 (m, 3 H) 7.84 (d, J=8.59 Hz, 1 H) 7.99 (br. s., 2 H) 8.47 (s, 1 H).

Example 324

5-(2-amino-4-oxo-3-phenyl-3,4-dihydroquinazolin-6-yl)-N-(cyclopentylmethyl)-2- methoxypyridine-3-sulfonamide

Step A:

N-(cyclopentylmethyl)-2-methoxy-5-( 4, 4, 5, 5-tetramethyl-1 ,3, 2-dioxaborolan-2-yl)pyridine-3- sulfonamide

To a stirred flask precharged with 5-bromo-2-chloropyridine-3-sulfonyl chloride (1 .5g, 5.16 mmol) and cyclopentylmethanamine hydrochloride (0.7g, 5.16 mmol) in 1 ,4-dioxane was added pyridine (1.6g, 20.6 mmol). The reaction mixture was stirred at 50 °C for 3 hours. The mixture was diluted with EtOAc and washed with NaHC0₃ and brine (aq). The organic layer was dried over sodium sulfate, filtered, concentrated, and treated with NaOMe in 20 ml of anhydrous eOH (25% by weight) at 68°C for 4 hours. Solvents were removed under reduced pressure and to the residue was added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1 ,3,2-dioxaborolane) (0.94g, 0.72 mmol), KOAc (0.726g, 9.4 mmol), PdCI₂(dppf) (200mg) and 1 ,4-dioxane (10 ml_). The mixture was purged with N₂ before heating to 80°C overnight. The reaction mixture was purified by column chromatography to afford N-(cyclopentylmethyl)-2-methoxy-5-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)pyridine-3-sulfonamide (0.650 g, 1.64 mmol).

Step B:

5-(2-amino-4-oxo-3-phenyl-3, 4-dihydroquinazolin-6-yl) -N-(cyclopentylmethyl)-2- methoxypyridine-3-sulfonamide

A solution of N-(cyclopentylmethyl)-2-methoxy-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)pyridine-3-sulfonamide (98 mg, 0.248 mmol), 2-amino-6-iodo-3-phenylquinazolin-4(3H)-one (75 mg, 0.207 mmol), PdCI₂(dppf)-CH₂CI₂ adduct (16.87 mg, 0.021 mmol), and potassium carbonate (86 mg, 0.620 mmol) in 1 ,4-dioxane (3 ml_)/water (3.00 mL) was maintained with stirring at 80°C for 25 minutes. The solution was cooled, poured into ethyl acetate, and washed with water. The organic layer was separated, dried over sodium sulfate, filtered, and concentrated. The resulting residue was purified by reverse phase column chromatography to afford 5-(2-amino-4-oxo-3-phenyl-3,4-dihydroquinazolin-6-yl)-N- (cyclopentylmethyl)-2-methoxypyridine-3-sulfonamide (38 mg, 0.075 mmol, 36.4 % yield) as a white foam following lyophilization. LCMS (m/z, ES+) = 506 (M+H). H NMR (400 MHz, DMSO- Gfe) 6 ppm 1.13 (dd, J=12.19, 6.73 Hz, 2 H) 1.33 - 1 .54 (m, 4 H) 1.59 (dd, J=12.00, 5.56 Hz, 2 H) 1.92 (dt, J=14.88, 7.49 Hz, 1 H) 2.78 (t, J=6.63 Hz, 2 H) 4.04 (s, 3 H) 6.42 (br. s., 2 H) 7.29 - 7.42 (m, 3 H) 7.47 - 7.65 (m, 3 H) 7.69 (t, J=5.85 Hz, 1 H) 7.98 (dd, J=8.59, 2.34 Hz, 1 H) 8.1 1 (d, J=2.34 Hz, 1 H) 8.27 (d, J=2.34 Hz, 1 H) 8.74 (d, J=2.34 Hz, 1 H).

Example 325

5-(2-amino-4-oxo-3-phenyl-3,4-dihydroquinazolin-6-yl)-N-iso

Step A:

5-bromo-N-isopropyl-2-methoxypyridine-3-sulfonamide

Pyridine (2.2 mL, 27.5 mmol) was added to 5-bromo-2-chloropyridine-3-sulfonyl chloride (2g, 6.9 mmol) in 1 ,4-dioxane (20 mL). Propan-2-amine (0.406 g, 6.9 mmol) was added to the mixture, and the mixture was stirred at room temperature for 1 hour, then the mixture was warmed at 50 °C for 2 hours. The solvent was removed under reduced pressure and the residue was extracted with water and EtOAc (100mL/ 100mL). The organic layer was dried over anhydrous MgSC^, filtered, and concentrated under reduced pressure. The resulting residue was dissolved in methanol (20 mL), then sodium methoxide (4.5mL, 25% in methanol) was added and the flask was sealed and warmed at 95°C for 30 min using microwave irradiation. The residue was concentrated and purified by column chromatography to afford 5-bromo-N- isopropyl-2-methoxypyridine-3-sulfonamide (1.3g, 4.20 mmol). Step B:

N-isopropyl-2-methoxy-5-(4, 4, 5, 5-tetramethyl- 1, 3, 2-dioxaborolan-2-yl)pyridine-3-sulfonamide

A solution of 5-bromo-N-isopropyl-2-methoxypyridine-3-sulfonamide (1.7g, 5.5 mmol), 4,4,4^,,4',5,5,5^,,5'-octamethyl-2,2'-bi(1 ,3,2-dioxaborolane) (2.09g, 8.25 mmol), PdCI₂(dppf)- CH₂CI₂ adduct (4.49g, 5.50 mmol), and potassium acetate (1.62g, 16.50 mmol) in 1 ,4-dioxane (20 mL) was maintained at 100°C overnight. The mixture was cooled and purified directly by column chromatography to afford N-isopropyl-2-methoxy-5-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)pyridine-3-sulfonamide (1 .2g, 3.37 mmol).

Step C:

5-(2-amino-4-oxo-3-phenyl-3,4-dihydroquinazolin-6-yl)-N-isoprop

sulfonamide

A solution of 2-amino-6-iodo-3-phenylquinazolin-4(3H)-one (75 mg, 0.207 mmol), N-isopropyl-2- methoxy-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridine-3-sulfonamide (81 mg, 0.227 mmol), potassium carbonate (86 mg, 0.620 mmol), and PdCI₂(dppf)-CH₂CI₂ adduct (16.87 mg, 0.021 mmol) in 1 ,4-dioxane (3 ml_)/water (3.00 mL) was maintained with stirring at 80°C for 30 minutes. The solution was cooled to room temperature, poured into ethyl acetate, and washed with water. The organic layer was separated, dried over sodium sulfate, filtered, taken to a residue under reduced pressure, and purified by reverse phase HPLC to afford 5-(2-amino-4- oxo-3-phenyl-3,4-dihydroquinazolin-6-yl)-N-isopropyl-2-methoxypyridine-3-sulfonamide, formic acid salt (38 mg, 0.074 mmol, 36.0 % yield) as a white foam. LCMS (m/z, ES+) = 512 (M+H). ¹H NMR (400 MHz, DMSO-ci₆) d ppm 0.99 (d, J=6.44 Hz, 6 H) 3.37 - 3.45 (m, 1 H) 4.05 (s, 3 H) 6.41 (br. s., 2 H) 7.29 - 7.43 (m, 3 H) 7.48 - 7.68 (m, 5 H) 7.98 (dd, J=8.59, 2.15 Hz, 1 H) 8.1 1 (d, J=2.15 Hz, 1 H) 8.29 (d, J=2.54 Hz, 1 H) 8.74 (d, J=2.34 Hz, 1 H).

Example 326

5-(2-amino-4-oxo-3-phenyl-3,4-dihydroquinazolin-6-yl)-2-methoxy-N-methylpyridine-3- sulfonamide

Step A:

5-bromo-2-methoxy-N-methylpyridine-3-sulfonamide

Pyridine (1.7 mL, 20.6 mmol) was added to 5-bromo-2-chloropyridine-3-sulfonyl chloride (1.5g, 5.2 mmol) in 1 ,4-dioxane (15 mL). Methylamine (5.2 mmol as a 2.0M solution in THF) was added to the mixture above, and the mixture was stirred at room temperature for 1 h, then the mixture was warmed at 50 °C for 2 hours. The solvent was removed under reduced pressure and the residue was extracted with water and EtOAc (100ml_/ 100ml_). The organic layer was dried over anhydrous MgSC^, filtered and concentrated. The residue was dissolved in methanol (15 mL), then sodium methoxide (3.6 mL, 25% in methanol) was added and the flask was sealed and maintained at 95°C for 30 minutes under microwave irradiation. The residue was purified by column chromatography to afford 5-bromo-2-methoxy-N-methylpyridine-3- sulfonamide (0.920g, 3.27 mmol).

Step B:

2-methoxy-N-methyl-5-(4, 4, 5, 5-tetramethyl- 1, 3, 2-dioxaborolan-2-yl)pyridine-3-sulfonamide

A solution of 5-bromo-2-methoxy-N-methylpyridine-3-sulfonamide (0.834 g, 2.97 mmol), 4,4,4^,,4^,,5,5,5',5'-octamethyl-2,2'-bi(1 ,3,2-dioxaborolane) (1.13 g, 4.45 mmol), PdC (dppf)- CH₂CI₂ (0.24g, 0.30 mmol), and potassium acetate (0.87g, 8.90 mmol) in 1 ,4-dioxane (15 mL) was maintained at 100°C overnight. The mixture was cooled and purified by column chromatography to afford 2-methoxy-N-methyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)pyridine-3-sulfonamide (0.72 g, 2.194 mmol).

Step C:

5- ( 2-amino-4-oxo-3-phenyl-3, 4-dihydroquinazolin- 6-yl)-2-methoxy-N-me thylpyridine -3- sulfonamide A solution of 2-amino-6-iodo-3-phenylquinazolin-4(3H)-one (75 mg, 0.207 mmol), 2-methoxy-N- methyl-5-{4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-3-sulfonamide (74.6 mg, 0.227 mmol), PdCI₂(dppf)-CH₂Cl2 adduct (16.87 mg, 0.021 mmol), and potassium carbonate (86 mg, 0.620 mmol) in 1 ,4-dioxane (3 ml_)/water (3.00 ml_) was maintained at 80°C for 30 minutes. The solution was cooled, poured into ethyl acetate, and washed with water. The organic layer was dried over sodium sulfate, filtered, concentrated, and the resulting residue was purified by reverse phase HPLC to afford 5-(2-amino-4-oxo-3-phenyl-3,4-dihydroquinazolin-6-yl)-2- methoxy-N-methylpyridine-3-sulfonamide (28 mg, 0.064 mmol, 31.0 % yield) as a white foam following lyophlization. LCMS (m/z, ES+) = 438 (M+H). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.51 (br. s., 3 H) 4.04 (s, 3 H) 6.42 (br. s., 2 H) 7.31 - 7.42 (m, 3 H) 7.44 - 7.65 (m, 4 H) 7.98 (dd, J=8.59, 2.34 Hz, 1 H) 8.11 (d, J=2.15 Hz, 1 H) 8.27 (d, J=2.54 Hz, 1 H) 8.75 (d, J=2.34 Hz, 1 H).

Example 327

2-amino-6-(6-methoxy-5-(mo -phenylquinazolin-4(3H)-one

Step A:

5-bromo-2-methoxy-N-methylpyridine-3-sulfonamide

Pyridine (1.1 ml_, 13.7 mmol) was added to 5-bromo-2-chloropyridine-3-sulfonyl chloride (1.0g, 3.44 mmol) in 1 ,4-dioxane (15 ml_). orpholine (0.30g, 3.44 mmol) was added to the mixture above, and the mixture was stirred at room temperature for 1 hour, then the mixture was warmed at 50 °C for 2 hours. The solvent was removed under reduced pressure and the residue was extracted with water and EtOAc (100mL/ 100ml_). The organic layer was dried over anhydrous MgSC^, filtered and concentrated. The residue was dissolved in methanol (15 ml_), then sodium methoxide (2.5 ml_, 25% in methanol) was added and the flask was sealed and maintained at 95°C for 30 minutes under microwave irradiation. The residue was purified by column chromatography to afford 5-bromo-2-methoxy-N-methylpyridine-3-sulfonamide (0.920g, 3.27 mmol).

Step B:

4-((2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)sulfony

A solution of potassium acetate (0.873g, 8.9 mmol), PdCI₂(dppf)-CH₂Cl₂ (0.24 g, 0.297 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2^,-bi(1 ,3,2-dioxaborolane) (1.130 g, 4.45 mmol), and 4-((5-bromo- 2-methoxypyridin-3-yl)sulfonyl)morpholine (1.0g, 2.97 mmol), in 1 ,4-dioxane was maintained at 100°C for 16 hours. The mixture was cooled and purified directly by column chromatography to afford 4-((2-methoxy-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridin-3- yl)sulfonyl)morpholine (0.870g, 2.22 mmol).

Step C:

2-amino-6-(6-methoxy-5-(morpho^inosu^fonyl)pyridin-3-y^)-3 heny^

A solution of 2-amino-6-iodo-3-phenylquinazolin-4(3H)-one (75 mg, 0.207 mmol), 4-((2- methoxy-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridin-3-yl)sulfonyl)morpholine (87 mg, 0.227 mmol), PdCI₂(dppf)-CH₂CI₂ adduct (16.87 mg, 0.021 mmol), and potassium carbonate (86 mg, 0.620 mmol) in 1 ,4-dioxane (3 ml_)/water (3.00 mL) was maintained at 80°C for 45 minutes. The solution was cooled to room temperature, poured into ethyl acetate, and washed with saturated aqueous NaCI solution. The organic layer was separated, dried over sodium sulfate, filtered, concentrated, and the resulting residue was purified by reverse phase HPLC to afford 2- amino-6-(6-methoxy-5-(morpholinosulfonyl)pyridin-3-yl)-3-phenylquinazolin-4(3H)-one (40 mg, 0.081 mmol, 39.2 % yield) as a white foam following lyophilization. LCMS (m/z, ES+) = 494 ( +H). H N R (400 MHz, DMSO-d₆) δ ppm 3.12 - 3.26 (m, 4 H) 3.53 - 3.68 (m, 4 H) 4.04 (s, 3 H) 6.42 (br. s., 2 H) 7.32 - 7.44 (m, 3 H) 7.48 - 7.67 (m, 3 H) 7.99 (dd, J=8.59, 2.34 Hz, 1 H) 8.12 (d, J=2.15 Hz, 1 H) 8.29 (d, J=2.34 Hz, 1 H) 8.80 (d, J=2.54 Hz, 1 H).

Example 328

5-(2-amino-4-oxo-3-phenyl-3,4-dihydroquinazolin-6-yl)-2-methoxy-N-(tetrahydro-2H- pyran-4-yI)pyridine-3-sulfonamide

Step A:

5-bromo-2-methoxy-N-methylpyridine-3-sulfonamide

Pyridine (1.7 mL, 20.6 mmol) was added to 5-bromo-2-chloropyridine-3-sulfonyl chloride (1.5g, 5.2 mmol) in 1 ,4-dioxane (15 mL). Tetrahydro-2H-pyran-4-amine (0.52 g, 5.16 mmol) was added to the mixture above, and the mixture was stirred at room temperature for 1 hour, then the mixture was warmed at 50 °C for 2 hours. The solvent was removed under reduced pressure and the residue was extracted with water and EtOAc (100mL/ 100mL). The organic layer was dried over anhydrous MgSC> , filtered and concentrated. The residue was dissolved in methanol (15 mL), then sodium methoxide (3.6 mL, 25% in methanol) was added and the flask was sealed and maintained at 95°C for 30 minutes under microwave irradiation. The residue was purified by column chromatography to afford 5-bromo-2-methoxy-N-methylpyridine- 3-sulfonamide (0.920g, 3.27 mmol).

Step B:

2-methoxy-N-(tetrahydro-2H-pyran-4-yl)-5-(4, 4, 5, 5-tetramethyl-1 ,3, 2-dioxaborolan-2-yl)pyridine-

3-sulfonamide

A solution of potassium acetate (0.873g, 8.9 mmol), PdCI₂(dppf)-CH₂CI₂ (0.24 g, 0.297 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1 ,3,2-dioxaborolane) (1.130 g, 4.45 mmol), and 5-bromo-2- methoxy-N-(tetrahydro-2H-pyran-4-yl)pyridine-3-sulfonamide (1.04g, 2.97 mmol), in 1 ,4-dioxane was maintained at 100°C for 16 hours. The mixture was cooled and purified directly by column chromatography to afford 2-methoxy-N-(tetrahydro-2H-pyran-4-yl)-5-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)pyridine-3-sulfonamide (0.0.440g, 1.105 mmol). Step C:

5-(2-amino-4-oxo-3^henyl-3 -dihydroquinazolin-6-yl)

yl)pyridine-3-sulfonamide

A solution of 2-amino-6-iodo-3-phenylquinazolin-4(3H)-one (75 mg, 0.207 mmol), 2-methoxy-N- (tetrahydro-2H-pyran-4-yl)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridine-3-sulfonamide (90 mg, 0.227 mmol), PdCI₂(dppf)-CH₂CI₂ adduct (16.87 mg, 0.021 mmol), and potassium carbonate (86 mg, 0.620 mmol) in 1 ,4-dioxane (3 ml_)/water (3.00 mL) was maintained at 80°C with stirring for 30 minutes. The solution was cooled to room temperature, diluted with ethyl acetate, and poured into saturated water. The organic layer was separated, dried over sodium sulfate, filtered, taken to a residue under reduced pressure, and the residue was purified by reverse phase HPLC to afford 5-(2-amino-4-oxo-3-phenyl-3,4-dihydroquinazolin-6-yl)-2- methoxy-N-(tetrahydro-2H-pyran-4-yl)pyridine-3-sulfonamide (53 mg, 0.104 mmol, 50.6 % yield) as a formate salt following lyophilization. LCMS (m/z, ES+) = 508 (M+H). ¹H NMR (400 MHz, DMSO-c/₆) δ ppm 1 .34 - 1.63 (m, 4 H) 3.23 (td, J=1 1 .37, 2.05 Hz, 2 H) 3.29 - 3.42 (m, 1 H) 3.66 - 3.80 (m, 2 H) 4.05 (s, 3 H) 6.50 (br. s., 2 H) 7.33 - 7.43 (m, 3 H) 7.49 - 7.66 (m, 4 H) 7.85 (d, J=7.80 Hz, 1 H) 8.00 (dd, J=8.59, 2.15 Hz, 1 H) 8.12 (d, J=2.15 Hz, 1 H) 8.31 (d, J=2.34 Hz, 1 H) 8.74 (d, J=2.54 Hz, 1 H).

Example 329

5-(2-amino-4-oxo-3-phenyl-3,4-dihydroquinazolin-6-yl)-N-cyclobutyl-2-methoxypyridine-3- sulfonamide

Step A:

N-cyclobutyl-2-methoxy-5-(4, 4, 5, 5-tetramethyl-1 ,3, 2-dioxaborolan-2-yl)benzenesulfonamide To cooled water (15 mL, 0°C) was added 5-bromo-2-chloropyridine-3-sulfonyl chloride (1.5g, 5.16 mmol) followed by addition of cyclobutylarnine (0.37 g, 5.16 mmol). The suspension was stirred for 2 hours at 0°C. The precipitate was collected by filtration and was treated with an excess of MeONa in MeOH (25% by weight, 10mL) at 50°C for 1hour. The reaction was quenched with NaHC0₃ (aq) and extracted with EtOAc. The organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was combined with 4,4,4',4',5,5,5',5'- octamethyl-2,2'-bi(1 ,3,2-dioxaborolane) (760mg, 3.0mmol), KOAc (600mg, 6 mml), PdCI₂(dppf)- CH₂CI₂ adduct (150mg) in dioxane (10 mL), purged with N₂ (3x), and maintained with heating at 80°C overnight. The reaction mixture was loaded to a silica column directly and purified by column chromatography to afford N-cyclobutyl-2-methoxy-5-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)benzenesulfonamide (0.42g, 1.14 mmol).

Step B:

5-(2-amino-4-oxo-3^ enyl-3,4-dihydroquinazolin-6-yi)-N-cyclobutyi-2-m

sulfonamide

A solution of 2-amino-6-iodo-3-phenylquinazolin-4(3H)-one (80 mg, 0.220 mmol), N-cyclobutyl- 2-methoxy-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridine-3-sulfonamide (89 mg, 0.242 mmol), PdCI₂(dppf)-CH₂CI₂ adduct (17.99 mg, 0.022 mmol), and potassium carbonate (91 mg, 0.661 mmol) in 1 ,4-dioxane (3 mL)/water (3.00 mL) was maintained at 80°C for 30 minutes. The solution was cooled to room temperature, poured into ethyl acetate, and diluted with water. The organic layer was separated, dried over sodium sulfate, filtered, taken to a residue under reduced pressure, and the residue was purified by reverse phase HPLC to afford 5-(2-amino-4- oxo-3-phenyl-3,4-dihydroquinazolin-6-yl)-N-cyclobutyl-2-methoxypyridine-3-sulfonamide (43 mg, 0.090 mmol, 40.9 % yield) as a white foam following lyophilization. LCMS (m/z, ES+) = 478 (M+H). ¹H NMR (400 MHz, DMSO-af₅) d ppm 1.33 - 1.58 (m, 2 H) 1.75 - 2.00 (m, 4 H) 3.71 (sxt, J=8.47 Hz, 1 H) 4.05 (s, 3 H) 6.49 (br. s., 2 H) 7.28 - 7.45 (m, 3 H) 7.48 - 7.66 (m, 3 H) 7.93 - 8.16 (m, 3 H) 8.27 (d, J=2.34 Hz, 1 H) 8.74 (d, J=2.34 Hz, 1 H).

Example 330

2-amino-6-(6-amino-5-(trifluoromethyI)pyridin-3-yl)-3-phenylquinazolin-4(3H)-one

A solution of 5-bromo-3-(trifluoromethyl)pyridin-2-amine (0.230 mL, 0.975 mmol), potassium acetate (287 mg, 2.93 mmol), PdCI₂(dppf)-CH₂CI₂ adduct (80 mg, 0.098 mmol), and bis(pinacolato)diboron (272 mg, 1.073 mmol) in 1 ,4-dioxane (7 mL) was maintained at 80°C in a sealed pressure tube for 14 hours. The mixture was cooled, filtered through celite, concentrated, combined with 2-amino-6-iodo-3-phenylquinazolin-4(3H)-one (280 mg, 0.771 mmol), PdCI₂(dppf)-CH₂Cl₂ adduct (31.5 mg, 0.039 mmol), and potassium carbonate (320 mg, 2.313 mmol) in 1 ,4-dioxane (10 mL)/water (7 mL) and was maintained at 80°C for 20 minutes. The solution was cooled to room temperature, diluted with ethyl acetate, and poured into water. The organic layer was separated, dried over sodium sulfate, filtered, taken to a residue under reduced pressure, and purified by reverse phase HPLC. Fractions containing products were concentrated and the solids triturated with diethyl ether and collected via vacuum filtration to afford 2-amino-6-(6-amino-5-(trifluoromethyl)pyridin-3-yl)-3-phenylquinazolin-4(3H)-one (58 mg, 0.146 mmol, 18.93 % yield) as a white solid. LCMS (m/z, ES+) = 398 (M+H). H NMR (400 MHz, DMSO-ds) δ ppm 6.33 (br. s., 2 H) 6.59 (s, 2 H) 7.31 (d, J=8.59 Hz, 1 H) 7.37 (d, J=8.01 Hz, 2 H) 7.47 - 7.63 (m, 3 H) 7.93 (dd, J=8.59, 2.15 Hz, 1 H) 7.97 (s, 1 H) 8.00 - 8.06 (m, 1 H) 8.55 (s, 1 H).

Example 331

1-(5-(2-amino-4-oxo-3-phenyi-3,4-dihydroquinazoiin-6-yl)-2-methoxypyridin-3-yl)urea

Step A: 1-( 5-bromo-2-methoxypyridin-3-yl) urea

A solution of 5-bromo-2-methoxypyridin-3-amine (1 .529 mL, 7.68 mmol) in acetic acid (10 ml_)/water (10.00 mL) was maintained at 75°C and treated with potassium cyanate (3.12 g, 38.4 mmol) portion-wise over 30 minutes. The solution was maintained with stirring for 45 minutes, cooled, poured into DCM, and neutralized via slow addition of saturated sodium bicarbonate (aq). The organic layer was separated, dried over sodium sulfate, filtered, concentrated, and triturated with DCM. Isolation of the solids by vacuum filtration afforded 1-(5-bromo-2- methoxypyridin-3-yl)urea (435 mg, 1.768 mmol, 23.01 % yield) as a white solid with roughly 80% purity by LCMS.

Step B:

1-(5-(2-amino-4-oxo-3^henyl-3 -dihydroquinazol^

A solution of 1 -(5-bromo-2-methoxypyridin-3-yl)urea (150 mg, 0.610 mmol), potassium acetate (239 mg, 2.438 mmol), PdCI₂(dppf)-CH₂CI₂ adduct (49.8 mg, 0.061 mmol), and bis(pinacolato)diboron (194 mg, 0.762 mmol) in 1 ,4-dioxane (8 mL) was maintained at 80°C overnight. The mixture was cooled, filtered through celite, the celite rinsed with DCM, and the filtrates concentrated. A solution of the resulting residue, 2-amino-6-iodo-3-phenylquinazolin- 4(3H)-one (175 mg, 0.482 mmol), PdCI₂(dppf)-CH₂CI₂ adduct (39.4 mg, 0.048 mmol), and potassium carbonate (200 mg, 1.446 mmol) in 1 ,4-dioxane (5 mL)/water (5.00 mL) was maintained with stirring at 80°C for 45 minutes. The solution was cooled to room temperature and poured into ethyl acetate. The organic layer was washed with water, separated, dried over sodium sulfate, filtered, concentrated, and purified by reverse phase HPLC to afford 1 -(5-(2- amino-4-oxo-3-phenyl-3,4-dihydroquinazolin-6-yl)-2-methoxypyridin-3-yl)urea (47 mg, 0.1 17 mmol, 24.24 % yield) as a white foam. LCMS (m/z, ES+) = 403 (M+H). H NMR (400 MHz, DMSO-d₆) δ ppm 3.98 (s, 3 H) 6.34 (br. s., 2 H) 6.40 (br. s., 2 H) 7.27 - 7.45 (m, 3 H) 7.45 - 7.63 (m, 3 H) 7.87 (dd, J=8.60, 2.35 Hz, 1 H) 8.01 (t, J=2.25 Hz, 2 H) 8.20 (s, 1 H) 8.73 (d, J=2.35 Hz, 1 H).

Example 332

1-(5-(2-amino-4-oxo-3-phenyl-3,4-dihydroquinazo

Step A:

1-(5-bromopyridin-2-yl)-3-(pyridin-3-yl)urea

A solution of 3-isocyanatopyridine (0.936 mL, 7.95 mmol), 5-bromopyridin-2-amine (1 100 mg, 6.36 mmol), and triethylamine (1.772 mL, 12.72 mmol) was maintained with stirring in dichloromethane (20 mL) for 1 hour. The solids were collected by vacuum filtration to afford 1- (5-bromopyridin-2-yl)-3-(pyridin-3-yl)urea (1200 mg, 4.09 mmol, 64.4 % yield) as a white solid.

Step B:

1-(5-(2-amino-4-oxo-3^henyl-3,4-dihydroquinazolin-6-yl)pyridm^

A solution of 1-(5-bromopyridin-2-yl)-3-(pyridin-3-yl)urea (0.147 mL, 0.512 mmol), potassium acetate (151 mg, 1 .535 mmol), bis(pinacolato)diboron (162 mg, 0.640 mmol), and PdCI₂(dppf)- CH₂CI₂ adduct (41.8 mg, 0.051 mmol) in 1 ,4-dioxane (5 mL) was maintained at 90°C for 3 hours. The mixture was cooled, filtered through celite, and the celite was rinsed with DCM. A solution of the resulting residue, 2-amino-6-iodo-3-phenylquinazolin-4(3H)-one (150 mg, 0.413 mmol), PdCI₂(dppf)-CH₂CI₂ adduct (33.7 mg, 0.041 mmol), and potassium carbonate (171 mg, 1 .239 mmol) in 1 ,4-dioxane (7 mL)/water (7.00 mL) was maintained at 80°C for 2 hours. The mixture was cooled, poured into ethyl acetate, and washed with water. The organic layer was washed with DCM and the combined organic layers were dried over sodium sulfate and filtered. The solution was left at room temperature without stirring for 3 hours. A fine white precipitate was collected via vacuum filtration and subsequently purified by reverse phase hplc to afford 1-(5-(2-amino-4-oxo-3-phenyl-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)-3-(pyridin-3- yl)urea (57 mg, 0.127 mmol, 30.7 % yield) as a yellow foam following lyophilization. LCMS (m/z, ES+) = 450 (M+H). ¹H NMR (400 MHz, DMSO-cf₆) d ppm 6.73 (br. s., 2 H) 7.30 - 7.47 (m, 4 H) 7.51 - 7.71 (m, 4 H) 7.97 - 8.1 1 (m, 2 H) 8.11 - 8.21 (m, 2 H) 8.26 (dd, J=4.68, 1.17 Hz, 1 H) 8.59 - 8.80 (m, 2 H) 9.71 (s, 1 H) 10.66 (br. s., 1 H).

Example 333 5-(2-amino-4-oxo-3-phenyI-3,4-dihydroquinazoIin-6-yl)-N-(3,5-difluorophenyl)-2- methoxypyridine-3-sulfonamide

Step A:

5-bromo-N-(3,5-difluorophenyl)-2-methoxypyridine-3-sulfonamide

Pyridine (12 mL) was added to a solution of 5-bromo-2-chloropyridine-3-sulfonyl chloride (1.5g, 5.16 mmol) in 1 ,4-dioxane (15 mL), 3,5-difluoroaniline (0.666 g, 5.16 mmol) was added to the mixture above, and the mixture was stirred at room temperature for 1 hour, then the mixture was warmed at 50 °C for 2 hours. The solvent was removed under reduced pressure and then the residue was partitioned between ethyl acetate and water. The organic layer was separated, dried over sodium sulfate, filtered, and concentrated. The residue was dissolved in methanol (15 mL), then sodium methoxide (4.8 mL, 25% in methanol) was added and the flask was sealed and maintained at 100°C for 15 minutes under microwave irradiation. The crude product was added to a silica gel column and was eluted with Hex/EtOAc to afford 5-bromo-N-(3,5- difluorophenyl)-2-methoxypyridine-3-sulfonamide (1.6g, 4.22 mmol).

Step B:

N-(3, 5-difluorophenyl)-2-methoxy-5-(4, 4, 5, 5-tetramethyl-1 , 3, 2-dioxaborolan-2-yl)pyridine-3- sulfonamide

A solution of 5-bromo-N-(3,5-difluorophenyl)-2-methoxypyridine-3-sulfonamide (1.5g, 3.96 mmol), 4,4,4',4',5,5,5',5^,-octamethyl-2,2'-bi(1 ,3,2-dioxaborolane) (1.51 g, 5.93 mmol), PdCI₂(dppf)-CH₂CI₂ adduct (0.32 g, 0.396 mmol), and potassium acetate (1.16g, 11.87 mmol) in 1 ,4-dioxane (20 mL) was maintained at 95°C overnight. The mixture was cooled and purified by column chromatography to afford N-(3,5-difluorophenyl)-2-methoxy-5-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)pyridine-3-sulfonamide (1 .1g, 2.58 mmol).

Step C:

5-(2-amino-4-oxo-3^ enyl-3,4-dihydroquinazolin-6-yl)^^

methoxypyridine-3-sulfonamide

A solution of N-(3,5-difluorophenyl)-2-methoxy-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)pyridine-3-sulfonamide (0.194 mL, 0.463 mmol), 2-amino-6-iodo-3-phenylquinazolin-4(3H)- one (153 mg, 0.421 mmol), PdCI₂(dppf)-CH₂CI₂ adduct (34.4 mg, 0.042 mmol), and potassium carbonate (175 mg, 1.264 mmol) in 1 ,4-dioxane (7 mL)/water (7.00 mL) was maintained at 80°C for 1 hour. The solution was cooled, poured into ethyl acetate, and washed with water. The organic layer was separated, dried over sodium sulfate, filtered, taken to a residue under reduced pressure, and purified by reverse phase HPLC. Fractions containing product were concentrated and the resulting solids were triturated with DCM/diethyl ether to afford 5-(2- amino-4-oxo-3-phenyl-3,4-dihydroquinazolin-6-yl)-N-(3,5-difluorophenyl)-2-methoxypyridine-3- sulfonamide (82 mg, 0.153 mmol, 36.3 % yield) as a white solid. LCMS (m/z, ES+) = 536 (M+H). H NMR (400 MHz, DMSO-d₆) δ ppm 3.99 (s, 3 H) 6.43 (br. s., 2 H) 6.71 - 6.93 (m, 3 H) 7.38 (d, J=7.22 Hz, 2 H) 7.35 (d, J=8.58 Hz, 1 H) 7.47 - 7.68 (m, 3 H) 7.97 (dd, J=8.59, 2.34 Hz, 1 H) 8.10 (d, J=2.34 Hz, 1 H) 8.43 (d, J=2.34 Hz, 1 H) 8.75 (d, J=2.34 Hz, 1 H) 10.99 (br. s., 1 H).

Example 334

1-(5-(2-amino-4-oxo-3 in-2-yl)-3-phenylurea

Step A:

1-( 5-bromopyridin-2-yl)-3-phenylurea

A solution of isocyanatobenzene (0.810 mL, 6.94 mmol), 5-bromopyridin-2-amine (960 mg, 5.55 mmol), and triethylamine (1.547 mL, 1 1.10 mmol) in dichloromethane (20 mL) was maintained with stirring at room temperature for 3 hours. Stirring was stopped and the solution was allowed to sit for 4 hours. The white solids were collected by vacuum filtration to afford 1-(5- bromopyridin-2-yl)-3-phenylurea (1.100 g, 3.77 mmol, 67.9 % yield) as a white solid.

Step B:

1-phenyl-3-(5-(4,4, 5, 5-tetra methyl- 1, 3, 2-dioxaborolan-2-yl)pyridin-2-yl)urea

A solution of 1-(5-bromopyridin-2-yl)-3-phenylurea (0.147 mL, 0.513 mmol), potassium acetate (151 mg, 1.540 mmol), bis(pinacolato)diboron (163 mg, 0.642 mmol), and PdCI₂(dppf)-CH₂CI₂ adduct (41.9 mg, 0.051 mmol) in 1 ,4-dioxane (5 mL) was maintained at 80°C in a sealed pressure tube for 16 hours. The solution was cooled, filtered through celite, and the celite was washed with DCM. The filtrates were concentrated and the solids triturated with diethyl ether to afford 1-phenyl-3-(5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridin-2-yl)urea (58 mg, 0.171 mmol, 33.3 % yield) as a dark brown solid.

Step C:

1-(5-(2-amino-4-oxo-3-phenyl-3,4-dihydroquinazoiin-6-yfy^

A solution of 1-phenyl-3-(5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridin-2-yl)urea (0.172 mL, 0.516 mmol), 2-amino-6-iodo-3-phenylquinazolin-4(3H)-one (150 mg, 0.413 mmol), PdCI₂(dppf)-CH₂CI₂ adduct (33.7 mg, 0.041 mmol), and potassium carbonate (171 mg, 1.239 mmol) in 1 ,4-dioxane (7 mL)/water (7.00 mL) was maintained at 80°C for 2 hours. The solution was cooled, poured into ethyl acetate, and washed with water. The organic layer was separated, dried over sodium sulfate, filtered, and concentrated. The solids were triturated with DCM/MeOH to afford 1-(5-(2-amino-4-oxo-3-phenyl-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)-3- phenylurea (90 mg, 0.201 mmol, 48.6 % yield) as a grey solid. LCMS (m/z, ES+) = 449 (M+H). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 6.36 (br. s., 2 H) 7.02 (t, J=7.43 Hz, 1 H) 7.24 - 7.42 (m, 5 H) 7.47 - 7.67 (m, 6 H) 7.97 (d, J=8.79 Hz, 1 H) 8.06 - 8.19 (m, 2 H) 8.64 (s, 1 H) 9.54 (s, 1 H) 10.45 (br. s., 1 H).

Example 335

1-(5-(2-amino-4-oxo-3-phenyl-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)-3-(pyridin-4-^

Step A:

1-(5-bromopyridin-2-yl) -3-(pyridin-4-yl)urea

A solution of 5-bromopyridin-2-amine (950 mg, 5.49 mmol), triethylamine (1.531 mL, 10.98 mmol), and 4-isocyanatopyridine (824 mg, 6.86 mmol) in 1 ,2-dichloroethane (20 mL) was maintained at reflux for 2 hours. The solution was cooled to room temperature, mixed with celite, and concentrated. The residue was purified by column chromatography to afford 1-(5- bromopyridin-2-yl)-3-(pyridin-4-yl)urea (170 mg, 0.580 mmol, 10.56 % yield) as a white solid.

Step B:

1-(5-(2-amino-4-oxo-3^henyl-3,4-dihydroquinazolin-6-yl)pyridin-2-yl)-3-(pyridin-4^

A solution of 1-(5-bromopyridin-2-yl)-3-(pyridin-4-yl)urea (0.167 mL, 0.580 mmol), potassium acetate (171 mg, 1.740 mmol), bis(pinacolato)diboron (169 mg, 0.667 mmol), and PdCI₂(dppf)- CH₂CI₂ adduct (47.4 mg, 0.058 mmol) in 1 ,4-dioxane (5 mL) was maintained at 80°C for 16 hours. The solution was cooled, filtered through celite, and the celite was rinsed with DCM. The filtrates were concentrated. A solution of the crude residue, 2-amino-6-iodo-3- phenylquinazolin-4(3H)-one (170 mg, 0.468 mmol), PdCI₂(dppf)-CH₂CI₂ adduct (38.2 mg, 0.047 mmol), and potassium carbonate (194 mg, 1.404 mmol) in 1 ,4-dioxane (7 mL)/water (7.00 mL) was maintained with stirring at 80°C for 1 hour. The solution was cooled to room temperature and a fine white precipitate collected via vacuum filtration. The precipitates were further triturated with diethyl ether to afford 1-(5-(2-amino-4-oxo-3-phenyl-3,4-dihydroquinazolin-6- yl)pyridin-2-yl)-3-(pyridin-4-yl)urea (105 mg, 0.234 mmol, 49.9 % yield) as a white solid. LCMS (m/z, ES+) = 450 (M+H). ¹H NMR (400 MHz, DMSO-af₆) δ ppm 7.38 (d, J=7.02 Hz, 2 H) 7.35 (d, J=8.58 Hz, 1 H) 7.48 - 7.63 (m, 5 H) 7.71 (d, J=8.78 Hz, 1 H) 7.97 (dd, J=8.59, 2.34 Hz, 1 H) 8.07 - 8.19 (m, 2 H) 8.39 (d, J=6.24 Hz, 2 H) 8.65 (d, J=2.34 Hz, 1 H); no exchangeable protons present.

Example 336 5-(2-amino-4-oxo-3-phenyl- -dihydroquinazolin-6-yl)-N-(tert-butyl)nicotinamide

A solution of (5-(tert-butylcarbamoyl)pyridin-3-yl)boronic acid (0.1 12 ml_, 0.516 mmol, CombiBlocks), 2-amino-6-iodo-3-phenylquinazolin-4(3H)-one (150 mg, 0.413 mmol), PdCI₂(dppf)-CH₂CI₂ adduct (33.7 mg, 0.041 mmol), and potassium carbonate (171 mg, 1.239 mmol) in 1 ,4-dioxane (7 ml_)/water (7.00 mL) was maintained at 80°C for 2 hours. The mixture was cooled, poured into ethyl acetate, and washed with water. The organic layer was dried over sodium sulfate, filtered, and purified by column chromatography. The fractions containing product were pooled, concentrated, and re-purified by reverse phase hplc to afford 5-(2-amino- 4-oxo-3-phenyl-3,4-dihydroquinazolin-6-yl)-N-(tert-butyl)nicotinamide, formic acid salt (56 mg, 0.122 mmol, 29.5 % yield) as a white solid. LCMS (m/z, ES+) = 460 (M+H). ¹H NMR (400 MHz, DMSO- /₆) δ ppm 1 .41 (s, 9 H) 6.72 (br. s., 1 H) 7.36 - 7.48 (m, 3 H) 7.49 - 7.66 (m, 3 H) 8.02 - 8.20 (m, 3 H) 8.27 (d, J=2.15 Hz, 1 H) 8.40 (s, 1 H) 8.91 (d, J=1 .56 Hz, 1 H) 9.01 (d, J=1.76 Hz, 1 H).

Example 337

6-(5-((1H-pyrazol-1-yl)methyl)-6-methoxypyridin-3-yl)-2-amino-3-phenylquinazol

one

Step A:

3-((1H-pyrazol-1-yl)methyl)-5-bromo-2-methoxypyhdine

A solution of 5-bromo-3-(chloromethyl)-2-methoxypyridine (650 mg, 2.75 mmol, see WO 2001053288 ), 1 H-pyrazole (0.275 mL, 4.12 mmol), and potassium carbonate (1140 mg, 8.25 mmol) in acetonitrile (15 mL) was maintained at 80°C overnight. The mixture was cooled to room temperature and diluted with ethyl acetate and water. The organic layer was separated, dried over sodium sulfate, filtered, concentrated, and purified by column chromatography to afford 3-((1 H-pyrazol-1-yl)methyl)-5-bromo-2-methoxypyridine (558 mg, 2.081 mmol, 76 % yield) as a white solid.

Step B:

6-(5-((1H^yrazol-1-yl)methyl)-6-methoxypyridin-3-yl)-2-amm^' ^

A solution of 3-((1 H-pyrazol-1-yl)methyl)-5-bromo-2-methoxypyridine (0.123 mL, 0.466 mmol), potassium acetate (137 mg, 1.399 mmol), bis(pinacolato)diboron (148 mg, 0.583 mmol), and PdCI₂(dppf)-CH₂Cl₂ adduct (38.1 mg, 0.047 mmol) in 1 ,4-dioxane (5 mL) was maintained at 90°C overnight. The mixture was cooled, filtered through celite, and concentrated. A solution of the crude residue, 2-amino-6-iodo-3-phenylquinazolin-4(3H)-one (130 mg, 0.358 mmol), PdCI₂(dppf)-CH₂CI₂ adduct (29.2 mg, 0.036 mmol), and potassium carbonate (148 mg, 1.074 mmol) in 1 ,4-dioxane (7 mL)/water (7.00 mL) was maintained at 80°C for 2 hours. The mixture was cooled to room temperature and diluted with ethyl acetate and water. The organic layer was separated, dried over sodium sulfate, filtered, concentrated, and purified by column chromatography to afford 6-(5-((1H-pyrazol-1-yl)methyl)-6-methoxypyridin-3-yl)-2-amino-3- phenylquinazolin-4(3H)-one (86 mg, 0.203 mmol, 56.6 % yield) as a white solid. LCMS (m/z, ES+) = 425 (M+H). H NMR (400 MHz, DMSO- ₆) δ ppm 3.95 (s, 3 H) 5.36 (s, 2 H) 6.29 (t, J=1.95 Hz, 1 H) 7.37 (d, J=7.22 Hz, 2 H) 7.32 (d, J=8.39 Hz, 1 H) 7.44 - 7.63 (m, 5 H) 7.79 - 7.89 (m, 2 H) 7.97 (d, J=2.34 Hz, 1 H) 8.44 (d, J=2.54 Hz, 1 H).

Example 338

6-(5-((1H-imidazol-1-yl)methyl)-6-methoxypyridin-3-yl)-2-amino-3-phenylquinazoH

one

Step A:

3-(( 1 H-imidazol- 1 -yl)methyl)-5-bromo-2-methoxypyridine

A solution of 5-bromo-3-(chloromethyl)-2-methoxypyridine (526 mg, 2.224 mmol), 1 H-imidazole (454 mg, 6.67 mmol), and potassium carbonate (1537 mg, 11.12 mmol) in acetonitrile (20 mL) was maintained at 80°C for 6 hours. The mixture was cooled to room temperature and diluted with ethyl acetate and water. The organic layer was separated, dried over sodium sulfate, filtered, concentrated, and purified by column chromatography to afford 3-((1 H-imidazol-1 - yl)methyl)-5-bromo-2-methoxypyridine (596 mg, 2.223 mmol, 100 % yield) as a white solid.

Step B:

6-(5-((1 H-imidazol-1 -yl)methyl)-6-methoxypyridin-3-yl)-2-am

A solution of 3-((1 H-pyrazol-1 -yl)methyl)-5-bromo-2-methoxypyridine (0.123 mL, 0.466 mmol), potassium acetate (137 mg, 1.399 mmol), bis(pinacolato)diboron (148 mg, 0.583 mmol), and PdCI₂(dppf)-CH₂CI₂ adduct (38.1 mg, 0.047 mmol) in 1 ,4-dioxane (5 mL) was maintained at 90°C overnight. The mixture was cooled, filtered through celite, and concentrated. A solution of the residue, 2-amino-6-iodo-3-phenylquinazolin-4(3H)-one (130 mg, 0.358 mmol), PdCI₂(dppf)- CH₂CI₂ adduct (29.2 mg, 0.036 mmol), and potassium carbonate (148 mg, 1.074 mmol) in 1 ,4- dioxane (7 mL)/water (7.00 mL) was maintained at 80°C for 2 hours. The mixture was cooled, poured into ethyl acetate, and washed with water. The organic layer was separated, dried over sodium sulfate, filtered, concentrated, and purified by column chromatography. Fractions containing product were further purified by reverse phase HPLC to afford 6-(5-((1 H-imidazol-1 - yl)methyl)-6-methoxypyridin-3-yl)-2-amino-3-phenylquinazolin-4(3H)-one, formic acid salt (18 mg, 0.038 mmol, 10.69 % yield) as a yellow solid. LCMS (m/z, ES+) = 471 (M+H). ¹H NMR (400 MHz, DMSO-de) δ ppm 3.96 (s, 3 H) 5.29 (s, 2 H) 6.38 (br. s., 2 H) 7.18 (s, 1 H) 7.38 (d, J=7.23 Hz, 2 H) 7.34 (d, J=8.60 Hz, 1 H) 7.46 (s, 1 H) 7.50 - 7.66 (m, 3 H) 7.85 - 7.98 (m, 2 H) 8.08 (d, J=2.15 Hz, 1 H) 8.14 (s, 1 H) 8.29 (br. s., 1 H) 8.50 (d, J=2.35 Hz, 1 H). Example 339

3-((5-(2-amino-4-oxo-3-phenyl-3,4-dihydroquinazolin-6-yl)-2-methoxypyridin-3- yl)methyl)oxazolidin-2-one

Step A:

2-((( 5-bromo-2-methoxypyridin-3-yl)methyl)amino)ethanol

A solution of 5-bromo-2-methoxynicotinaldehyde (917 mg, 4.24 mmol, CombiBlocks), ethanolamine (0.513 mL, 8.49 mmol), acetic acid (0.607 mL, 10.61 mmol), and sodium triacetoxyborohydride (1799 mg, 8.49 mmol) in 1,2-dichloroethane (20 mL) was maintained with stirring at room temperature for 2 hours. The solution was poured into saturated sodium bicarbonate and the organic layer was separated, dried over sodium sulfate, filtered, concentrated, and purified by column chromatography to afford 2-(((5-bromo-2-methoxypyridin- 3-yl)methyl)amino)ethanol (225 mg, 0.862 mmol, 20.30 % yield) as a white solid.

Step B:

3-((5-bromo-2-methoxypyridin-3-yl)methyl)oxazolidin-2-one

A solution of 2-(((5-bromo-2-methoxypyridin-3-yl)methyl)amino)ethanol (215 mg, 0.823 mmol) and CDI (267 mg, 1.647 mmol) in toluene (15 mL) was maintained at 100°C for 1 hours. The solution was cooled to room temperature, diluted with ethyl acetate, and washed with saturated sodium bicarbonate. The organic layer was separated, dried over sodium sulfate, filtered, concentrated, and purified by column chromatography to afford 3-((5-bromo-2-methoxypyridin- 3-yl)methyl)oxazolidin-2-one (196 mg, 0.683 mmol, 83 % yield) as a white solid. Step C:

3-((5-(2-amino-4-oxo-3^henyl-3,4-dihydroquinazolin-6-yl)-2-methoxypyrid

yl)methyl)oxazoiidin-2-one

A solution of 3-((5-bromo-2-methoxypyridin-3-yl)methyl)oxazolidin-2-one (100 mg, 0.348 mmol), potassium acetate (103 mg, 1 .045 mmol), bis(pinacolato)diboron (1 1 1 mg, 0.435 mmol), and PdCI₂(dppf)-CH₂CI₂ adduct (28.4 mg, 0.035 mmol) in 1 ,4-dioxane (5 mL) was maintained at 80°C for 16 hours. The solution was cooled, filtered through celite, and the filtrates were concentrated. A solution of the crude residue, 2-amino-6-iodo-3-phenylquinazolin-4(3H)-one (100 mg, 0.275 mmol), PdCI₂(dppf)-CH₂CI₂ adduct (22.49 mg, 0.028 mmol), and potassium carbonate (1 14 mg, 0.826 mmol) in 1 ,4-dioxane (7 ml_)/water (7.00 mL) was maintained at 80°C for 1 hour. The mixture was cooled, poured into ethyl acetate, and washed with water. The organic layer was separated, dried over sodium sulfate, filtered, concentrated, and purified by colum chromatography to afford 3-((5-(2-amino-4-oxo-3-phenyl-3,4-dihydroquinazolin-6-yl)-2- methoxypyridin-3-yl)methyl)oxazolidin-2-one (86 mg, 0.194 mmol, 70.4 % yield) as a white solid. LCMS (m/z, ES+) = 444 (M+H). H NMR (400 MHz, DMSO-cfe) δ ppm 3.47 - 3.61 (m, 2 H) 3.94 (s, 3 H) 4.20 - 4.34 (m, 2 H) 4.38 (s, 2 H) 6.36 (br. s., 2 H) 7.37 (d, J=7.02 Hz, 2 H) 7.34 (d, J=8.39 Hz, 1 H) 7.49 - 7.65 (m, 3 H) 7.84 - 7.99 (m, 2 H) 8.08 (d, J=2.15 Hz, 1 H) 8.44 (d, J=2.34 Hz, 1 H).

Example 340

1-(5-(2-amino-4-oxo-3-phenyi-3,4-dihydroquinazoiin-6-yl)pyridin-3-yl)pyrrolidine-2,5-di^

Step A:

4-((5-bromopyridin-3-yi)amino)-4-oxobutanoic acid A solution of 5-bromopyridin-3-amine (4600 mg, 26.6 mmol) and succinic anhydride (3.99g, 39.9 mmol) in 1 ,4-dioxane (5 mL) was maintained at reflux for 16 hours. The solution was cooled in an ice bath, diluted with DC , and left to crystalize for 2 hours. Crystals were collected by vacuum filtration to afford 4-((5-bromopyridin-3-yl)amino)-4-oxobutanoic acid (6280 mg, 23.00 mmol, 86 % yield) as a white solid.

Step B:

1 -(5-bromopyridin-3-yl)pyrrolidine-2, 5-dione

A suspension of 4-((5-bromopyridin-3-yl)amino)-4-oxobutanoic acid (3 g, 10.99 mmol), sodium acetate (2.70 g, 33.0 mmol), and acetic anhydride (31.1 ml, 330 mmol) was maintained at 90°C for 3 hours. The solution was diluted with toluene and concentrated to a residue. The residue was suspended in DCM and saturated sodium bicarbonate was added so as to adjust the pH to 9. The organic layer was separated, dried over sodium sulfate, filtered, and concentrated. The solids were triturated with DCM/diethyl ether to afford 1-(5-bromopyridin-3-yl)pyrrolidine-2,5- dione (1.87 g, 7.33 mmol, 66.7 % yield) as a white solid.

Step C:

1-(5-(2-amino-4-oxo-3^henyl-3 -di ydroquinazolin-6^

A solution of 1-(5-bromopyridin-3-yl)pyrrolidine-2, 5-dione (125 mg, 0.490 mmol), potassium acetate (144 mg, 1.470 mmol), bis(pinacolato)diboron (156 mg, 0.613 mmol), and PdCI₂(dppf)- CH₂CI₂ adduct (40.0 mg, 0.049 mmol) in 1,4-dioxane (5 mL) was maintained at 80°C for 16 hours in a sealed pressure tube. The tube was cooled to room temperature, filtered through celite, and the filtrates were concentrated. A solution of the crude residue, 2-amino-6-iodo-3- phenylquinazolin-4(3H)-one (135 mg, 0.372 mmol), PdCI₂(dppf)-CH₂CI₂ adduct (30.4 mg, 0.037 mmol), and potassium carbonate (154 mg, 1.1 15 mmol) in anhydrous N,N-dimethylformamide (5 mL) was maintained at 65°C for 3 hours. The solution was cooled, poured into ethyl acetate, and washed with water. The organic layer was separated, dried over sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by reverse phase HPLC to afford 1-(5-(2-amino-4-oxo-3-phenyl-3,4-dihydroquinazolin-6-yl)pyridin-3-yl)pyrrolidine-2, 5-dione formic acid salt (45 mg, 0.109 mmol, 29.4 % yield) as a white solid following lyophilization. LCMS (m/z, ES+) = 412 (M+H). H NMR (400 MHz, DMSO-cf₆) δ ppm 2.83 (s, 4 H) 6.45 (br. s., 2 H) 7.32 - 7.43 (m, 3 H) 7.50 - 7.64 (m, 3 H) 8.03 (dd, J=8.68, 2.24 Hz, 1 H) 8.08 (t, J=2.15 Hz, 8.13 (s, 1 H) 8.17 (d, J=2.34 Hz, 1 H) 8.46 (d, J=2.15 Hz, 1 H) 8.97 (d, J=2.15 Hz, 1 H).

Example 341

5-(2-amino-4-oxo-3-phenyI-3,4-dihydroquinazolin-6-yl)-N-(furan-2-ylmethyl)-2- methoxypyridine-3-sulfonamide

Step A: 5-bromo-N-(furan-2-ylmethyl)-2-methoxypyridine-3-sulfonamide A solution of 5-bromo-2-chloropyridine-3-sulfonyl chloride (750 mg, 2.58 mmol), furan-2- ylmethanamine (0.298 mL, 3.22 mmol), and pyridine (0.625 mL, 7.73 mmol) in dichloromethane (15 mL) was maintained at room temperature for 2 hours. The mixture was concentrated under reduced pressure, dissolved in methanol, treated with sodium methoxide (25% by wt in MeOH) (2.90 mL, 12.89 mmol) and maintained at reflux for 16 hours. The mixture was cooled to room temperature, concentrated, suspended in ethyl acetate, and washed with water. The organic layer was separated, dried over sodium sulfate, filtered, concentrated, and purified by column chromatography to afford 5-bromo-N-(furan-2-ylmethyl)-2-methoxypyridine-3-sulfonamide (823 mg, 2.370 mmol, 92 % yield) as a yellow glass.

Step B:

5-(2-amino-4-oxo-3^henyl-3,4-dihydroquinazolin-6-yi)-N-(furan-2-ylm

3-sulfonamide

A solution of 5-bromo-N-(furan-2-ylmethyl)-2-methoxypyridine-3-sulfonamide (100 mg, 0.288 mmol), potassium acetate (85 mg, 0.864 mmol), bis(pinacolato)diboron (91 mg, 0.360 mmol), and PdCI₂(dppf)-CH₂CI₂ adduct (23.52 mg, 0.029 mmol) in 1 ,4-dioxane (5 mL) was maintained at 80°C in a sealed pressure tube for 16 hours. The mixture was cooled to room temperature, filtered through celite, and concentrated to a black residue. A solution of the crude residue, 2- amino-6-iodo-3-phenylquinazolin-4(3H)-one (80 mg, 0.220 mmol), PdCI₂(dppf)-CH₂CI₂ adduct (17.99 mg, 0.022 mmol), and potassium carbonate (91 mg, 0.661 mmol) in water (5 ml_)/1 ,4- dioxane (10 mL) was maintained at 80°C for 1 hour. The mixture was cooled, poured into ethyl acetate, and washed with water. The organic layer was separated, dried over sodium sulfate, filtered, concentrated, and purified by reverse phase hplc. HPLC fractions were chilled to 0°C, maintained for 2 hours, and the solids were collected via vacuum filtration to afford analytically pure 5-(2-amino-4-oxo-3-phenyl-3,4-dihydroquinazolin-6-yl)-N-(furan-2-ylmethyl)-2- methoxypyridine-3-sulfonamide (8 mg, 0.016 mmol, 7.21 % yield) as a white solid. LCMS (m/z, ES+) = 504 (M+H). H NMR (400 MHz, DMSO-af₆) δ ppm 3.98 (s, 3 H) 4.16 (d, J=6.05 Hz, 2 H) 6.08 (d, J=2.93 Hz, 1 H) 6.16 (dd, J=3.12, 1.95 Hz, 1 H) 6.41 (br. s., 2 H) 7.24 - 7.42 (m, 4 H) 7.47 - 7.67 (m, 3 H) 7.94 (dd, J=8.59, 2.34 Hz, 1 H) 8.08 (d, J=2.15 Hz, 1 H) 8.15 (d, J=2.54 Hz, 1 H) 8.20 (t, J=6.05 Hz, 1 H) 8.64 (d, J=2.54 Hz, 1 H).

Example 342

5-(2-amino-4-oxo-3-phenyl-3,4-dihydroquinazolin-6-yl)-N-(2,3-dihydro-1H-inden-2-yI)-2- e

Step A:

5-bromo-N-(2,3-dihydro-1H-inden-2-yl)-2-methoxypyridine-3-su

A solution of 5-bromo-2-chloro-N-(2,3-dihydro-1 H-inden-2-yl)pyridine-3-sulfonamide (750 mg, 1.935 mmol) and sodium methoxide (25% by wt in MeOH, 2.200 mL, 9.67 mmol) in methanol (10 mL) was maintained at reflux for 12 hours. The solution was cooled, concentrated, suspended in ethyl acetate, and washed with water. The organic layer was separated, dried over sodium sulfate, filtered, concentrated, and the resulting residue was triturated with diethyl ether and the solids collected by vacuum filtration to afford 5-bromo-N-(2,3-dihydro-1H-inden-2- yl)-2-methoxypyridine-3-sulfonamide (300 mg, 0.783 mmol, 40.5 % yield) as a white solid. Step B:

5-(2-amino-4-oxo-3-phenyl-3, 4-dihydroquinazolin-6-yl)-N-(2, 3-dihydro- 1 H-inden-2-yl)-2- methoxypyridine-3-sulfonamide

A solution of 5-bromo-N-(2,3-dihydro-1 H-inden-2-yl)-2-methoxypyridine-3-sulfonamide (100 mg, 0.261 mmol), potassium acetate (77 mg, 0.783 mmol), bis(pinacolato)diboron (83 mg, 0.326 mmol), and PdCI₂(dppf)-CH₂CI₂ adduct (21.31 mg, 0.026 mmol) in 1 ,4-dioxane (5 mL) was maintained at 80°C in a sealed pressure tube for 16 hours. The mixture was cooled to room temperature, filtered through celite, and concentrated to a dark residue. A solution of the residue, PdCI₂(dppf)-CH₂CI₂ adduct (17.99 mg, 0.022 mmol), and potassium carbonate (91 mg, 0.661 mmol) in water (5 ml_)/1 ,4-dioxane (10 mL) was maintained at 80°C for 1 hour. The mixture was cooled to room temperature, poured into ethyl acetate, and washed with water. The organic layer was separated, dried over sodium sulfate, concentrated, and suspended in 3 mL DMF. A turbid, insoluble solid formed. The solid was collected by vacuum filtration to afford 5-(2-amino-4-oxo-3-phenyl-3,4-dihydroquinazolin-6-yl)-N-(2,3-dihydro-1 H-inden-2-yl)-2- methoxypyridine-3-sulfonamide (64 mg, 0.1 19 mmol, 53.8 % yield) with 93% purity. The solids were dissolved in DCM (freely soluble) and purified by normal phase column chromatography (0-10% MeOH/DCM) to afford 5-(2-amino-4-oxo-3-phenyl-3,4-dihydroquinazolin-6-yl)-N-(2,3- dihydro-1 H-inden-2-yl)-2-methoxypyridine-3-sulfonamide (17 mg, 0.032 mmol, 14.30 % yield) as a yellow solid. LCMS (m/z, ES+) = 540 (M+H). H NMR (400 MHz, DMSO-cfe) δ ppm 2.69 - 2.86 (m, 2 H) 2.86 - 3.03 (m, 2 H) 3.93 - 4.18 (m, 4 H) 6.41 (br. s., 2 H) 6.99 - 7.21 (m, 4 H) 7.27 - 7.44 (m, 3 H) 7.48 - 7.66 (m, 3 H) 8.00 (dd, J=8.59, 2.34 Hz, 1 H) 8.06 - 8.18 (m, 2 H) 8.33 (d, J=2.54 Hz, 1 H) 8.78 (d, J=2.54 Hz, 1 H).

Example 343

5-(2-amino-4-oxo-3-phenyl-3,4-dihydroquinazolin^

methoxypyridine-3-sulfonamide

Step A:

5-bromo-N-(2, 3-dihydro- 1 H-inden- 1 -yl)-2-methoxypyridine-3-sulfonamide

A solution of 5-bromo-2-chloropyridine-3-sulfonyl chloride (750 mg, 2.58 mmol), pyridine (0.250 ml_, 3.09 mmol), and (+/-)-2,3-dihydro-1 H-inden-1 -amine (378 mg, 2.84 mmol) in dichloromethane (20 mL) was maintained with stirring for 2 hours. The mixture was concentrated, dissolved in methanol (20.00 mL), treated with 25% by wt. sodium methoxide solution (2.93 mL, 12.89 mmol), and maintained at reflux overnight. The mixture was concentrated, suspended in ethyl acetate, and washed with water. The organic layer was separated, dried over sodium sulfate, filtered, concentrated, and purified by column chromatography to afford 5-bromo-N-(2,3-dihydro-1 H-inden-1 -yl)-2-methoxypyridine-3- sulfonamide (340 mg, 0.887 mmol, 34.4 % yield) as a white solid.

Step B:

5-bromo-N-(2,3-dihydro-1H-inden-1-yl)-2-methoxypyridine-3-sulfonamide

A solution of 5-bromo-N-(2,3-dihydro-1 H-inden-1-yl)-2-methoxypyridine-3-sulfonamide (175 mg, 0.457 mmol), potassium acetate (134 mg, 1.370 mmol), bis(pinacolato)diboron (145 mg, 0.571 mmol), and PdCI₂(dppf)-CH₂CI₂ adduct (37.3 mg, 0.046 mmol) in 1 ,4-dioxane (5 mL) was maintained at 80°C in a sealed pressure tube for 16 hours. The mixture was cooled to room temperature, filtered through celite, and concentrated to give a black residue. A solution of the residue, 2-amino-6-iodo-3-phenylquinazolin-4(3H)-one (130 mg, 0.358 mmol), PdCI₂(dppf)- CH₂CI₂ adduct (29.2 mg, 0.036 mmol), and potassium carbonate (148 mg, 1.074 mmol) in water (5 mL)/1 ,4-dioxane (10 mL) was maintained at 80°C for 2 hours. The mixture was cooled to room temperature, poured into ethyl acetate, and washed with water. The organic layer was separated, dried over sodium sulfate, filtered, concentrated, and purified by column chromatography. The fractions containing product were collected and triturated with DCM/diethyl ether to afford 5-(2-amino-4-oxo-3-phenyl-3,4-dihydroquinazolin-6-yl)-N-(2,3- dihydro-1 H-inden-1 -yl)-2-methoxypyridine-3-sulfonamide (78 mg, 0.145 mmol, 40.4 % yield) as a tan solid. LCMS (m/z, ES+) = 540 (M+H). ¹H NMR (400 MHz, DMSO- /₆) δ ppm 1.68 - 1.85 (m, 1 H) 2.06 - 2.21 (m, 1 H) 2.67 (dt, J=16.00, 8.19 Hz, 1 H) 2.80 - 2.94 (m, 1 H) 3.90 - 4.10 (m, 3 H) 4.83 (q, J=8.00 Hz, 1 H) 6.42 (br. s., 2 H) 7.07 - 7.23 (m, 4 H) 7.30 - 7.43 (m, 3 H) 7.49 - 7.65 (m, 3 H) 8.00 (dd, J=8.59, 2.34 Hz, 1 H) 8.13 (d, J=2.34 Hz, 1 H) 8.24 (d, J=8.59 Hz, 1 H) 8.34 (d, J=2.34 Hz, 1 H) 8.77 (d, J=2.54 Hz, 1 H).

Example 344

3-(5-(2-amino-4-oxo-3-phenyl-3,4-dihydroquinazolin-6-yl)pyridin-3-yl)oxazolidin-2-one

Step A:

3-(5-bromopyridin-3-yl)oxazolidin-2-one

A solution of 5-bromopyridin-3-amine (3 g, 17.34 mmol), 2-chloroethyl carbonochloridate (2.68 ml_, 26.0 mmol), and potassium carbonate (4.79 g, 34.7 mmol) in acetonitrile (50 mL) was maintained at 80°C in a sealed pressure tube for 72 hours. The mixture was cooled, concentrated, diluted with ethyl acetate, and washed twice with water. The organic layer was separated, dried over sodium sulfate, filtered, concentrated, and the solids were triturated with diethyl ether and collected via vacuum filtration to afford 3-(5-bromopyridin-3-yl)oxazolidin-2-one (2.56 g, 10.53 mmol, 60.7 % yield) as a brown solid.

Step B:

3-(5-(2-amino-4-oxo-3-phenyl-3,4-dihydroquinazolin-6-yl)pyridin^

A solution of 3-(5-bromopyridin-3-yl)oxazolidin-2-one (150 mg, 0.617 mmol), potassium acetate (182 mg, 1.851 mmol), bis(pinacolato)diboron (196 mg, 0.771 mmol), and PdCI₂(dppf)-CH₂CI₂ adduct (50.4 mg, 0.062 mmol) in 1 ,4-dioxane (5 mL) was maintained with stirring at 80°C in a sealed pressure tube for 16 hours. The mixture was cooled to room temperature and filtered through celite. The filtrates were concentrated to give a black residue. A solution of the crude residue, PdCI₂(dppf)-CH₂CI₂ adduct (38.2 mg, 0.047 mmol), and potassium carbonate (194 mg, 1.404 mmol) in N,N-dimethylformamide (5 mL) was maintained at 90°C for 5 hours. The solution was cooled, poured into water, and the solids were collected via vacuum filtration. The solid residue was purified by flash column chromatography and fractions containing product were pooled, concentrated, and suspended in DMF. Collection of the solids afforded 3-(5-(2- amino-4-oxo-3-phenyl-3,4-dihydroquinazolin-6-yl)pyridin-3-yl)oxazolidin-2-one formate salt (15 mg, 0.038 mmol, 8.02 % yield) as a white solid. LCMS (m/z, ES+) = 400 (M+H). ¹H NMR (400 MHz, DMSO-c/₆) δ ppm 4.20 (t, J=8.00 Hz, 2 H) 4.51 (t, J=7.90 Hz, 2 H) 6.43 (br. s., 2 H) 7.38 (dd, J=7.80, 3.12 Hz, 3 H) 7.46 - 7.72 (m, 3 H) 7.95 (s, 1 H) 8.00 (dd, J=8.59, 2.15 Hz, 1 H) 8.17 (d, J=2.15 Hz, 1 H) 8.28 (t, J=2.05 Hz, 1 H) 8.67 (d, J=1.76 Hz, 1 H) 8.75 (d, J=2.34 Hz, 1 H).

Example 345

2-amino-6-(5-(indolin-1-ylsulfonyl)-6-methoxypyridin-3-yl)-3-phenylquinaz

Step A:

1-((5-bromo-2-methoxypyridin-3-yl)sulfonyl)indoline

A solution of 5-bromo-2-chloropyridine-3-sulfonyl chloride (750 mg, 2.58 mmol), indoline (384 mg, 3.22 mmol), and pyridine (0.271 ml_, 3.35 mmol) in dichloromethane (15 mL) was maintained with stirring at room temperature for 45 minutes. The solution was concentrated under reduced pressure, redissolved in methanol, and treated with 25% by wt. sodium methoxide in methanol (2.90 mL, 12.89 mmol) in one portion. The mixture was stirred at room temperature for 2 hours and then warmed to 70°C for 2 hours. The mixture was cooled, concentrated under reduced pressure, suspended in ethyl acetate, and washed with water. The organic layer was separated, dried over sodium sulfate, filtered, concentrated, and purified by column chromatography to afford 1-((5-bromo-2-methoxypyridin-3-yl)sulfonyl)indoline (810 mg, 2.194 mmol, 85 % yield) as a yellow solid.

Step B:

2-amino-6-(5-(indolin-1-ylsulfonyl)-6-methoxypyridin-3-yl)-3^hen A solution of 1 -((5-bromo-2-methoxypyridin-3-yl)sulfonyl)indoline (150 mg, 0.406 mmol), potassium acetate (120 mg, 1.219 mmol), bis(pinacolato)diboron (129 mg, 0.508 mmol), and PdCI₂(dppf)-CH₂CI₂ adduct (33.2 mg, 0.041 mmol) in 1 ,4-dioxane (5 mL) was maintained at 80°C in a sealed pressure tube for 16 hours. The mixture was cooled to room temperature, filtered through celite and the filtrates concentrated. A solution of the crude residue, 2-amino-6- iodo-3-phenylquinazolin-4(3H)-one (1 15 mg, 0.317 mmol), PdCI₂(dppf)-CH₂CI₂ adduct (25.9 mg, 0.032 mmol), and potassium carbonate (131 mg, 0.950 mmol) in water (5 ml_)/1 ,4-dioxane (10 mL) was maintained with stirring at 80°C for 2 hours. The mixture was cooled, poured into ethyl acetate, and washed with water. The organic layer was separated, dried over sodium sulfate, filtered, concentrated, and purified by column chromagraphy to afford 2-amino-6-(5-(indolin-1- ylsulfonyl)-6-methoxypyridin-3-yl)-3-phenylquinazolin-4(3H)-one (95 mg, 0.181 mmol, 57.1 % yield) as a yellow solid. LCMS (m/z, ES+) = 526 (M+H). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.07 (t, J=8.49 Hz, 2 H) 3.87 (s, 3 H) 4.20 (t, J=8.49 Hz, 2 H) 6.43 (br. s., 2 H) 6.89 - 7.03 (m, 1 H) 7.09 (t, J=7.61 Hz, 1 H) 7.15 - 7.30 (m, 2 H) 7.38 (d, J=7.22 Hz, 2 H) 7.35 (d, J=8.58 Hz, 1 H) 7.47 - 7.67 (m, 3 H) 7.97 (dd, J=8.58, 2.15 Hz, 1 H) 8.10 (d, J=2.34 Hz, 1 H) 8.44 (d, J=2.54 Hz, 1 H) 8.73 (d, J=2.34 Hz, 1 H).

Example 346

2-amino-6-(5-(isoindolin-2-yIsulfonyI)-6-metho

one

Step A:

2-((5-bromo-2-methoxypyridin-3-yl)sulfonyl)isoindoline

A solution of 5-bromo-2-chloropyridine-3-sulfonyl chloride (750 mg, 2.58 mmol), isoindoline (384 mg, 3.22 mmol), and pyridine (0.417 mL, 5.16 mmol) in dichloromethane (15 mL) was maintained with stirring at room temperature for 45 minutes. The solution was concentrated under reduced pressure, redissolved in methanol (15.00 mL), treated in one portion with 25% by weight, sodium methoxide in methanol (2.87 mL, 12.89 mmol), and maintained at 60°C for 3 hours. The solution was cooled to room temperature, concentrated, suspended in ethyl acetate, and washed with water. The organic layer was separated, dried over sodium sulfate, filtered, taken to a residue under reduced pressure, and purified by column chromatography to afford 2- ((5-bromo-2-methoxypyridin-3-yl)sulfonyl)isoindoline (850 mg, 2.302 mmol, 89 % yield) as a yellow solid.

Step B:

2-amino-6-(5-(isoindolin-2-ylsulfonyl)-6-methoxypyridin-3-yl)-3-^

A solution of potassium acetate (120 mg, 1 .219 mmol), 2-((5-bromo-2-methoxypyridin-3- yl)sulfonyl)isoindoline (150 mg, 0.406 mmol), bis(pinacolato)diboron (129 mg, 0.508 mmol), and PdCI₂(dppf)-CH₂CI₂ adduct (33.2 mg, 0.041 mmol) in 1 ,4-dioxane (5 mL) was maintained at 80°C in a sealed pressure tube for 16 hours. The mixture was filtered through celite and the filtrates concentrated. A solution of the crude residue, 2-amino-6-iodo-3-phenylquinazolin- 4(3H)-one (1 15 mg, 0.317 mmol), PdCI₂(dppf)-CH₂CI₂ adduct (25.9 mg, 0.032 mmol), and potassium carbonate (131 mg, 0.950 mmol) in water (5 mL)/1 ,4-dioxane (10 mL) was maintained at 80°C with stirring for one hour. The mixture was poured into ethyl acetate and washed with water. The organic layer was separated, dried over sodium sulfate, filtered, concentrated, and purified by column chromatography to afford 2-amino-6-(5-(isoindolin-2- ylsulfonyl)-6-methoxypyridin-3-yl)-3-phenylquinazolin-4(3H)-one (76 mg, 0.145 mmol, 45.7 % yield) as a yellow solid. LCMS (m/z, ES+) = 526 (M+H). H NMR (400 MHz, DMSO-d₆) δ ppm 3.87 (s, 3 H) 4.75 (s, 4 H) 6.43 (br. s., 2 H) 7.20 - 7.33 (m, 4 H) 7.38 (d, J=7.42 Hz, 2 H) 7.35 (d, J=8.79 Hz, 1 H) 7.47 - 7.64 (m, 3 H) 7.96 (dd, J=8.59, 2.15 Hz, 1 H) 8.09 - 8.15 (m, 1 H) 8.36 (d, J=2.34 Hz, 1 H) 8.73 (d, J=2.15 Hz, 1 H).

Example 347

5-(2-amino-4-oxo-3-phenyl-3,4-dihydroquinazolin-6-yi)-2-methoxy-N-(oxazol-2- ylmethyl)pyridine-3-sulfonamide

Step A:

5-bromo-2-methoxy-N-(oxazol-2-ylmethyl)pyridine-3-sulfonamide

A solution of 5-bromo-2-chloropyridine-3-sulfonyl chloride (800 mg, 2.75 mmol), oxazol-2- ylmethanamine hydrochloride (462 mg, 3.44 mmol), DIPEA (0.720 mL, 4.12 mmol), and pyridine (1.1 12 mL, 13.75 mmol) in dichloromethane (15 mL) was maintained with stirring at room temperature for 2 hours. The mixture was concentrated, redissolved in methanol (15.00 mL), treated with sodium methoxide (25% by wt in MeOH) (3.09 mL, 13.75 mmol), and maintained with stirring at reflux for 16 hours. The mixture was cooled, poured into ethyl acetate, and washed with water. The organic layer was separated, dried over sodium sulfate, filtered, concentrated, and purified by column chromatography to afford 5-bromo-2-methoxy-N-(oxazol- 2-ylmethyl)pyridine-3-sulfonamide (310 mg, 0.890 mmol, 32.4 % yield) as a yellow solid.

Step B:

5-(2-amino-4-oxo-3 henyl-3,4-dihydroquinazolin-6-yl)-2-methoxy-N-(oxazol-2- ylmethyl)pyridine-3-sulfonamide

A solution of 5-bromo-2-methoxy-N-(oxazol-2-ylmethyl)pyridine-3-sulfonamide (150 mg, 0.431 mmol), potassium acetate (127 mg, 1.292 mmol), bis(pinacolato)diboron (137 mg, 0.539 mmol), and PdCI₂(dppf)-CH₂Cl₂ adduct (35.2 mg, 0.043 mmol) in 1 ,4-dioxane (5 mL) was maintained at 80°C in a sealed pressure tube for 16 hours. The mixture was cooled to room temperature, filtered through celite, and washed with DCM. The filtrates were concentrated. A solution of the residue, 2-amino-6-iodo-3-phenylquinazolin-4(3H)-one (120 mg, 0.330 mmol), PdCI₂(dppf)- CH₂CI₂ adduct (27.0 mg, 0.033 mmol), and potassium carbonate (137 mg, 0.991 mmol) in water (5 mL)/1 ,4-dioxane (10 mL) was maintained with stirring at 80°C for 2 hours. The mixture was cooled to room temperature, poured into ethyl acetate, and washed with water. The organic layer was separated, dried over sodium sulfate, filtered, concentrated, and purified by column chromatography to afford 5-(2-amino-4-oxo-3-phenyl-3,4-dihydroquinazolin-6-yl)-2-methoxy-N- (oxazol-2-ylmethyl)pyridine-3-sulfonamide (70mg, 0.139 mmol, 42.0 % yield) as a yellow solid. LCMS (m/z, ES+) = 505 (M+H). ¹H N R (400 MHz, D SO-cfe) δ ppm 3.99 (s, 3 H) 4.32 (d, J=5.86 Hz, 2 H) 6.42 (br. s., 2 H) 6.96 (s, 1 H) 7.28 - 7.43 (m, 3 H) 7.46 - 7.65 (m, 3 H) 7.88 (s, 1 H) 7.94 (dd, J=8.59, 2.34 Hz, 1 H) 8.09 (d, J=2.15 Hz, 1 H) 8.18 (d, J=2.34 Hz, 1 H) 8.50 (t, J=5.96 Hz, 1 H) 8.67 (d, J=2.54 Hz, 1 H).

Example 348

5-(2-amino-4-oxo-3-phenyl-3,4-dihydroquinazolin-6-yl)-2-methoxy-N-(oxazol-5-

Step A:

5-bromo-2-methoxy-N-(oxazol-5-ylmethyl)pyridine-3-sulfonamide

A solution of 5-bromo-2-chloropyridine-3-sulfonyl chloride (625 mg, 2.148 mmol), oxazol-5- ylmethanamine hydrochloride (0.344 mL, 2.69 mmol), DIPEA (0.563 mL, 3.22 mmol), and pyridine (0.869 mL, 10.74 mmol) in dichloromethane (15 mL) was maintained with stirring at room temperature for 3 hours. The solution was concentrated under reduced pressure, dissolved in methanol, and treated with sodium methoxide (25% by wt in MeOH) (2.418 mL, 10.74 mmol). The mixture was maintained at reflux for 16 hours, cooled to room temperature, and concentrated. The solids were suspended in ethyl acetate and washed with water. The organic layer was separated, dried over sodium sulfate, filtered, concentrated, and purified by column chromatography to afford 5-bromo-2-methoxy-N-(oxazol-5-ylmethyl)pyridine-3- sulfonamide (435 mg, 1.249 mmol, 58.2 % yield) as a yellow solid.

Step B:

5-(2-amino-4-oxo-3^henyl-3,4-dihydroquinazotin-6-yl)-2-methoxy-N-(oxazol-5- ylmethyl)pyridine-3-sulfonamide

A solution of 5-bromo-2-methoxy-N-(oxazol-5-ylmethyl)pyridine-3-sulfonamide (150 mg, 0.431 mmol), potassium acetate (127 mg, 1.292 mmol), bis(pinacolato)diboron (137 mg, 0.539 mmol), and PdCI₂(dppf)-CH₂Cl₂ adduct (35.2 mg, 0.043 mmol) in 1 ,4-dioxane (5 mL) was maintained at 80°C in a sealed tube for 16 hours. The mixture was cooled, filtered throuch celite, and concentrated. A solution of the residue, 2-amino-6-iodo-3-phenylquinazolin-4(3H)-one (120 mg, 0.330 mmol), PdCI₂(dppf)-CH₂CI₂ adduct (27.0 mg, 0.033 mmol), and potassium carbonate (137 mg, 0.991 mmol) in water (5 ml_)/1 ,4-dioxane (10 mL) was maintained at 80°C for 2 hours. The mixture was cooled to room temperature and poured into ethyl acetate and washed with water. The organic layer was separated, dried over sodium sulfate, filtered, concentrated, and the resulting residue purified by column chromatography to afford 5-(2-amino-4-oxo-3-phenyl- 3,4-dihydroquinazolin-6-yl)-2-methoxy-N-(oxazol-5-ylmethyl)pyridine-3-sulfonamide (70 mg, 0.139 mmol, 42.0 % yield) as a yellow solid. LCMS (m/z, ES+) = 505 (M+H). H NMR (400 MHz, DMSO-d₆) δ ppm 3.99 (s, 3 H) 4.26 (d, J=5.47 Hz, 2 H) 6.42 (br. s., 2 H) 6.83 (s, 1 H) 7.30 - 7.43 (m, 3 H) 7.47 - 7.64 (m, 3 H) 7.90 - 8.01 (m, 1 H) 8.06 - 8.13 (m, 2 H) 8.15 - 8.20 (m, 1 H) 8.32 (t, J=5.76 Hz, 1 H) 8.59 - 8.70 (m, 1 H).

Example 349

N-(2,4-difluorophenyl)-2-methoxy-5-(2-(methylamino)-4-oxo-3

dihydro namide

Sfep A:

6-iodo-2-(methylamino)-3-phenylquinazolin-4(3H)-one

A solution of 2-chloro-6-iodo-3-phenylquinazolin-4(3H)-one (5.8 g, 15.16 mmol), DIPEA (13.24 mL, 76 mmol), and methylamine hydrochloride (3.07 g, 45.5 mmol) in N,N-dimethylformamide (25 mL) was maintained at 80°C in a sealed pressure tube for 2 hours. The mixture was cooled to room temperature, poured into water, and the white solid collected by vacuum filtration to afford 90% pure 6-iodo-2-(methylamino)-3-phenylquinazolin-4(3H)-one (5.25 g, 13.92 mmol, 92 % yield).

Step B:

N-(2 -difluorophenyl)-2-methoxy-5-(2-(methylamino)-4-oxo-3^heny

yl)pyridine-3-sulfonamide

A solution of 6-iodo-2-(methylamino)-3-phenylquinazolin-4(3H)-one (1 g, 2.65 mmol), PdCI₂(dppf)-CH₂CI₂ adduct (0.325 g, 0.398 mmol), potassium carbonate (0.733 g, 5.30 mmol), and N-(2,4-difluorophenyl)-2-methoxy-5-(2-(methylamino)-4-oxo-3-phenyl-3,4- dihydroquinazolin-6-yl)pyridine-3-sulfonamide (800 mg, 1.456 mmol, 54.9 % yield) in 1 ,4- dioxane (30 ml_)/water (20 mL) was maintained for 80°C for 2 hours. The mixture was cooled to room temperature, poured into ethyl acetate, and washed with water. The organic layer was separated, dried over sodium sulfate, filtered, concentrated, and purified by column chromatography to afford N-(2,4-difluorophenyl)-2-methoxy-5-(2-(methylamino)-4-oxo-3-phenyl- 3,4-dihydroquinazolin-6-yl)pyridine-3-sulfonamide (800 mg, 1.456 mmol, 54.9 % yield) as a tan solid. LCMS (m/z, ES+) = 550 (M+H). H NMR (400 MHz, DMSO-d₆) δ ppm 2.79 (d, J=4.30 Hz, 3 H) 3.97 (s, 3 H) 5.90 (d, J=4.30 Hz, 1 H) 6.96 - 7.08 (m, 1 H) 7.18 - 7.28 (m, 1 H) 7.28 - 7.46 (m, 4 H) 7.50 - 7.64 (m, 3 H) 7.92 (d, J=8.59 Hz, 1 H) 8.03 (s, 1 H) 8.13 - 8.22 (m, 1 H) 8.66 - 8.86 (m, 1 H) 10.19 (s, 1 H).

Example 350

2-Amino-6-(6-methoxy- uinazolm

Step A

5-Bromo- -methoxynicotinamide

To a solution of 5-bromo-2-methoxynicotinic acid (3 g, 12.93 mmol) in DMF (53.4 mL) was added N,N-diisopropylethylamine (11.29 mL, 64.6 mmol), ammonium chloride (1.037 g, 19.39 mmol) and HATU (5.41 g, 14.22 mmol) at room temperature. After 2 hours 20 minutes, ammonium chloride (540 mg) was added to the dark solution and the mixture was stirred for 3 hours. The solvent was evaporated under reduced pressure. The residue was diluted with EtOAc (150 mL) and washed with saturated aqueous NaHC0₃ (2 x 50 mL), brine (50 mL), dried (Na₂S0₄), filtered and concentrated. The crude solid was triturated with DCM (15 mL) and EtOAc (2 mL). The white solid was filtered, rinsed with DCM, and dried under high vacuum to give 5-bromo-2-methoxynicotinamide (2.0987 g, 9.08 mmol, 70 % yield). The filtrate was absorbed on silica gel and purified by column chromatography [10-60% EtOAc in hexanes] to give a second batch of 5-bromo-2-methoxynicotinamide (0.6445 g, 2.51 mmol, 19 % yield) as light yellow solid. H NMR (400 MHz, DMSO-d₆) δ ppm 3.95 (s, 3 H), 7.77 (br.s., 1 H), 7.82 (br.s., 1 H), 8.21 (d, J=2.5 Hz, 1 H), 8.43 (d, J=2.5 Hz, 1 H); LCMS (m/z) ES+ 230.9, 232.9 (M+1 ).

Step B

5-Bromo-2-methoxypyridine-3-carbothioamide

A suspension of 5-bromo-2-methoxynicotinamide (2.5145 g, 10.88 mmol), Lawesson's reagent (3.08 g, 7.62 mmol) was heated in THF (27.2 mL) at 85 °C. After 1 hour, the mixture was cooled to room temperature. The crude was absorbed on silica gel and purified by column

chromatography [0-15% EtOAc in hexane] to give 5-bromo-2-methoxypyridine-3-carbothioamide (1.9012 g, 71 % yield) as yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.90 (s, 3 H), 8.11 - 8.16 (m, 1 H), 8.32 - 8.37 (m, 1 H), 9.56 (br. s., 1 H), 10.24 (br. s., 1 H); LCMS (m/z) ES+ 246.9, 248.9 (M+1).

Step C

2-(5-Bromo- -3-yi)thiazole

A suspension of 5-bromo-2-methoxypyridine-3-carbothioamide (1.422 g, 5.75 mmol), 2-bromo- 1 ,1-diethoxyethane (1.039 mL, 6.91 mmol) and 1 N HCI (0.058 mL, 0.058 mmol) was heated in ethanol (27.7 mL) at 90 °C. After 1 day, reaction was incomplete, 2-bromo- 1 ,1-diethoxyethane (0.1 mL) was added. After 6 hours, the reaction was allowed to stir at room temperature for 2 days. The suspension was transferred to a sealed tube, and 2-bromo-1 ,1-diethoxyethane (0.5 mL) and 1N HCI (58 uL) were added. The mixture was heated at 90 °C for 7 hours and allowed to stir at room temperature overnight. 2-Bromo-1 ,1-diethoxyethane (0.2 mL) was added to the mixture and the mixture was heated at 90 °C for 4 hours. The mixture was cooled to room temperature. Saturated aqueous NaHC0₃ (10 mL) was added to the mixture and the organic solvent was removed under reduced pressure. EtOAc (150 mL) and water (20 mL) were added to digest the solid. The aqueous phase (pH 8) was separated and extracted with EtOAc (150 mL). The combined organic phase was washed with brine (50 mL), dried (Na₂S0₄), filtered and concentrated. The crude solid was triturated with ACN/EtOAc and the solid filtered. The filtrate was absorbed on silica gel and purified by column chromatography [0-10% EtOAc in hexanes] to give 2-(5-bromo-2-methoxypyridin-3-yl)thiazole (459 mg, 1.693 mmol, 29 % yield) as light yellow solid. ¹H NMR (400 MHz, DMSO-cf₆) δ ppm 4.09 (br. s., 3 H), 7.95 (d, J=3.2 Hz, 1 H), 8.04 (d, J=3.1 Hz, 1 H), 8.44 (d, J=2.4 Hz, 1 H), 8.67 (d, J=2.4 Hz, 1 H); LCMS (m/z) ES+ 270.9, 272.9 (M+1).

Ste D

2-(2-Methoxy-5-(4,4, 5, 5-tetram orolan-2-yl)pyridin-3-yl)thiazole

A suspension of 2-(5-bromo-2-methoxypyridin-3-yl)thiazole (454 mg, 1.674 mmol),

bis(pinacolato)diboron (553 mg, 2.177 mmol), potassium acetate (493 mg, 5.02 mmol) and PdCI₂(dppf)-DCM adduct (68.4 mg, 0.084 mmol) was heated at 100 °C in 1 ,4-dioxane (5.6 mL). After 2.5 hours, the mixture was cooled, filtered through a pad of Celite and washed with EtOAc (30 mL). The solvent was concentrated with silica gel. The crude was purified by column chromatography [0-100% EtOAc in hexanes] to give 2-(2-methoxy-5-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)pyridin-3-yl)thiazole (467.8 mg, 1.470 mmol, 88 % yield) as light brown solid. H NMR (400 MHz, DMSO-c/₆) δ ppm 1.33 (s, 12 H), 4.14 (s, 3 H), 7.89 (d, J=3.3 Hz, 1 H), 8.01 (d, J=3.2 Hz, 1 H), 8.48 (d, J=1.9 Hz, 1 H), 8.84 (d, J=2.0 Hz, 1 H); LCMS (m/z) ES+ 319.1 (M+1 ).

Ste E

2-Amino-6-(6-methoxy-5-(thiazol-2-yl)pyridin-3-yl)-3^henyiquin

A suspension of 2-(2-methoxy-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridin-3- yl)thiazole (91 mg, 0.286 mmol), 2-amino-6-iodo-3-phenylquinazolin-4(3H)-one (80 mg, 0.220 mmol), palladium(ll) acetate (4.95 mg, 0.022 mmol), cataCXium® A (7.90 mg, 0.022 mmol) and 2M aqueous sodium carbonate (330 μΙ, 0.661 mmol) was degassed and stirred at room temperature for 30 minutes. The suspension was then heated at 100 °C for 30 minutes. Upon cooling, the solvent was concentrated under reduced pressure and triturated with saturated aqueous NaHC0₃ (8 mL). The aqueous layer was decanted and the residue was digested with DMSO and purified by reverse phase preparative HPLC [5-70% ACN gradient w/ 0.1 % formic acid] to give 2-amino-6-(6-methoxy-5-(thiazol-2-yl)pyridin-3-yl)-3-phenylquinazolin-4(3H)-one (30.6 mg, 0.071 mmol, 32.2 % yield) as white solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 4.17 (s, 3 H), 7.42 - 7.48 (m, 2 H), 7.50 (d, J=8.6 Hz, 1 H), 7.54 - 7.69 (m, 3 H), 7.92 (d, J=3.2 Hz, 1 H), 8.04 (d, J=3.2 Hz, 1 H), 8.12 - 8.18 (m, 1 H), 8.22 (d, J=2.0 Hz, 1 H), 8.68 (d, J=2.5 Hz, 1 H), 8.86 (d, J=2.4 Hz, 1 H); LCMS (m/z) ES+ 428.1 (M+1 ).

Example 351

2-Amino-6-(6-methoxy-5-(1H-1,2,3-triazol-5-yl)pyridin-3-yl)-3-phenyl^

Step A 5-Bromo-3 e

To a suspension of 5-bromo-2-methoxynicotinaldehyde (3 g, 13.89 mmol) in methanol (90 mL) was added potassium carbonate (3.84 g, 27.8 mmol) and dimethyl (1-diazo-2- oxopropyl)phosphonate (2.501 mL, 16.66 mmol). The mixture was allowed to stir at room temperature for 7 hours. Saturated aqueous ammonium chloride solution (20 mL) was added to the suspension and the organic solvent was removed under reduced pressure. The residual aqueous layer was extracted with EtOAc (200 mL, 50 mL). The combined organic phase was washed with brine (50 mL), dried (Na₂S0₄), filtered and concentrated. The crude was absorbed on silica gel and purified by column chromatography [0-10% EtOAc in hexanes] to give 5- bromo-3-ethynyl-2-methoxypyridine (1.711 1 g, 7.26 mmol, 52 % yield, 90% pure) as white solid H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.39 (s, 1 H), 4.00 (s, 3 H), 7.81 (d, J=2.4 Hz, 1 H), 8.17 (d, J=2.3 Hz, 1 H).

Step B

5-Bromo-2-methoxy-3-(2H- 1, 2, 3-triazol-4-yl) yridine

A solution of 5-bromo-3-ethynyl-2-methoxypyridine (1.1 g, 5.19 mmol), trimethylsilyl azide (1.033 mL, 7.78 mmol) and copper(l) iodide (0.049 g, 0.259 mmol) was heated in DMF (22.4 mL) and methanol (2.5 mL) at 100 °C. After 6 hours, the mixture was cooled to room

temperature. The solvent was removed under reduced pressure to give a solid which was triturated with Et₂0 (10 mL). The solid was filtered to give 5-bromo-2-methoxy-3-(2H-1 ,2,3- triazol-4-yl)pyridine (484.5 mg, 1.899 mmol, 37 % yield) as light green solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 4.01 (s, 3 H), 8.13 - 8.67 (m, 3 H); LCMS (m/z) ES+ 254.9, 256.9 (M+1).

Step C

5-Bromo-2-methoxy-3-(2-((2-(trimethylsilyl)ethoxy)methyl)-2H-^

and 5-bromo-2-methoxy-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-^

To a solution of 5-bromo-2-methoxy-3-(2H-1 ,2,3-triazol-4-yl)pyridine (480 mg, 1.882 mmol) in DMF (9.009 mL) at 0 °C (ice-water bath) was added 2-(trimethylsilyl)ethoxymethyl chloride (0.40 mL, 2.258 mmol) followed by sodium hydride (60%wt, 90 mg, 2.258 mmol). After 1 hour, water (2 mL) was added slowly. The mixture was diluted with EtOAc (100 mL) and washed with saturated aqueous NaHC0₃ (25 mL), then brine (25 mL), dried (Na₂S0₄), filtered and concentrated. The crude was absorbed on silica gel and purified by column chromatography [0- 30% EtOAc in hexanes] to give a mixture of 5-bromo-2-methoxy-3-(2-((2- (trimethylsilyl)ethoxy)methyl)-2H-1 ,2,3-triazol-4-yl)pyridine and 5-bromo-2-methoxy-3-(1-((2- (trimethylsilyl)ethoxy)methyl)-1H-1 ,2,3-triazol-5-yl)pyridine (405.3 mg, 1.052 mmol, 55.9 % yield). LCMS (m/z) ES+ 385.0, 387.0 (M+1 ). The mixture was used for the next step.

Ste D

2-Methoxy-5-(4 ,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(2-((2-(th

2H- 1, 2, 3-triazol-4-yl)pyridine

and

2-methoxy-5-(4^5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(1-((2-(M

1H-1 ,2,3-triazol-5-yl)pyridine

"

A suspension of 5-bromo-2-methoxy-3-(2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1 ,2,3-triazol-4- yl)pyridine and 5-bromo-2-methoxy-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1 H-1 ,2,3-triazol-5- yl)pyridine (475 mg, 1.233 mmol), potassium acetate (363 mg, 3.70 mmol) and PdCI₂(dppf)- DCM adduct (50.3 mg, 0.062 mmol) was heated at 100 °C in 1 ,4-dioxane (6.2 mL). After 2 hours, LCMS showed little reaction. KOAc (180 mg), and bis(pinacolato)diboron (200 mg) were added and the mixture was heated overnight. The mixture was cooled, filtered through a pad of Celite and washed with EtOAc (80 ml_). The organic solvent was concentrated with silica gel. The crude was purified by column chromatography [0-100% EtOAc in hexanes] to give a mixture of 2-methoxy-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-3-(2-((2- (trimethylsilyl)ethoxy)methyl)-2H-1 ,2,3-triazol-4-yl)pyridine and 2-methoxy-5-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)-3-(1 -((2-(trimethylsilyl)ethoxy)methyl)-1 H-1 ,2,3-triazol-5- yl)pyridine (570.7 mg, 1.320 mmol, quantitative) as brown oil. LCMS (m/z) ES+ 433.2 (M+1). The mixture was used for the next step.

Step E

2-Amino-6-(6-methoxy-5-(2-((2-(trimethylsilyl)ethoxy)methyl)-2H^

phenyiquinazolin-4(3H)-one

and

2-amino-6-(6-methoxy-5-(1 -((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2, 3-triazol-5-yl)pyridin-3-yl)-3-

A suspension of 2-amino-6-iodo-3-phenylquinazolin-4(3H)-one (100 mg, 0.275 mmol), 2- methoxy-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-3-(2-((2-(trimethylsilyl)ethoxy)methyl)- 2H-1 ,2,3-triazol-4-yl)pyridine and 2-methoxy-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-3- (1-((2-(trimethylsilyl)ethoxy)methyl)-1 H-1 ,2,3-triazol-5-yl)pyridine (155 mg, 0.358 mmol), palladium(ll) acetate (6.18 mg, 0.028 mmol), CataCXium® A (9.87 mg, 0.028 mmol) and 2 M aqueous sodium carbonate (0.413 ml_, 0.826 mmol) in 1 ,4-dioxane (1.2 mL) was heated to 70 °C. After 2.5 hours, the mixture was cooled, diluted with ACN (10 mL), filtered through 45 urn disc, and absorbed on silica gel. This was purified on silica gel [30-100% EtOAc in hexanes] to give a mixture of 2-amino-6-(6-methoxy-5-(2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1 ,2,3-triazol-4- yl)pyridin-3-yl)-3-phenylquinazolin-4(3H)-one and 2-amino-6-(6-methoxy-5-(1-((2- (trimethylsilyl)ethoxy)methyl)-1H-1 ,2,3-triazol-5-yl)pyridin-3-yl)-3-phenylquinazolin-4(3H)-one (73.8 mg, 0.136 mmol, 49.5 % yield) as white solid. LCMS (m/z) ES+ 542.2 (M+1 ). The mixture was used for the next step.

Step F

2-Amino-6-(6-methoxy-5-(1 H- -triazol-5-yl)pyridin-3-yl)-3-phenylquinazolin-4(3H)-

A mixture of 2-amino-6-(6-methoxy-5-(2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1 ,2,3-triazol-4- yl)pyridin-3-yl)-3-phenylquinazolin-4(3H)-one and 2-amino-6-(6-methoxy-5-(1 -((2- (trimethylsilyl)ethoxy)methyl)-1H-1 ,2,3-triazol-5-yl)pyridin-3-yl)-3-phenylquinazolin-4(3H)-one (71 mg, 0.131 mmol), and 3N HCI (1 mL, 3.00 mmol) was heated at 55 °C in methanol (1.5 mL). White precipitate formed. After 5 hours, 20 minutes, 3N aqueous HCI (0.25 mL) was added. After 2 hours 15 minutes, the solvent was removed under reduced pressure and the crude was purified by preparative RP-HPLC [0-90%ACN gradient, 0.1% formic acid] to give 2-amino-6-(6- methoxy-5-(1 H-1 ,2,3-triazol-5-yl)pyridin-3-yl)-3-phenylquinazolin-4(3H)-one (18 mg, 0.043 mmol, 33.0 % yield) as white solid. H NMR (400 MHz, DMSO-c/₆) δ ppm 4.07 (s, 3 H), 6.52 (br. s., 2 H), 7.36 - 7.45 (m, 3 H), 7.50 - 7.66 (m, 3 H), 8.03 (dd, J=8.5, 1.8 Hz, 1 H), 8.12 - 8.33 (m, 1.5 H), 8.41 - 8.84 (m, 2.5 H); LCMS (m/z) ES+ 412.2 (M+1).

Example 352

2-Amino-6-(1-methyl-2,2-dioxido-1,3-dihydroisothiazol^^

Step A

N-(5-Bromo-2-chloropyridin-3-yl)-N-(methylsulfonyl)methanesulfonamide

To a solution of 5-bromo-2-chloropyridin-3-amine (5.34 g, 25.7 mmol) in pyridine (40 mL) at 0 °C was added DMAP and methanesulfonyl chloride (10.03 mL, 129 mmol). After 30 minutes, the ice-water bath was removed. After 5 hours 40 minutes, the mixture was cooled with ice-water bath and water was added (10 mL) followed by saturated aqueous NaHC0₃ (100 mL). The suspension was extracted with EtOAc (400 mL). The organic extract was separated and washed with brine (100 mL), dried (Na₂S0₄), filtered and concentrated to give N-(5-bromo-2- chloropyridin-3-yl)-N-(methylsulfonyl)methanesulfonamide (9.14 g, 25.1 mmol, 98 % yield) as light brown solid. H NMR (400 MHz, DMSO-d₆) δ ppm 3.65 (s, 6 H), 8.69 (d, J=2.3 Hz, 1 H), 8.76 (d, J=2.3 Hz, 1 H ); LCMS (m/z) ES+ 362.8, 364.8 (M+1 ).

Step B

N-(5-Bromo-2-chlo thanesulfonamide

To a solution of N-(5-bromo-2-chloropyridin-3-yl)-N-(methylsulfonyl)methanesulfonamide (9.14 g, 25.1 mmol) in THF (72.9 mL) was added 1 sodium hydroxide solution(52.8 mL, 52.8 mmol). After 1 .5 hours, the organic solvent was removed under reduced pressure. The aqueous phase was washed with Et₂0 (2 x 50 mL). 1 N aq. HCI (55 mL) was added to give a precipitate. After stirring for 15 minutes, the solid was filtered and dried to give N-(5-bromo-2-chloropyridin-3- yl)methanesulfonamide (6.8817 g, 24.10 mmol, 96 % yield) as beige solid. ¹H NMR (400 MHz, DMSO-cfg) δ ppm 3.18 (s, 3 H), 8.08 (d, J=2.2 Hz, 1 H), 8.42 (d, J=2.2 Hz, 1 H), 9.96 (br. s., 1 H); LCMS (m/z) ES+ 284.8, 286.9 (M+1 ).

Step C

N-(5-Bromo-2-chloropyridin-3-yl)-N-methylmethanesulfonamide

To a stirred solution of N-(5-bromo-2-chloropyridin-3-yl)methanesulfonamide (500 mg, 1.751 mmol) in DMF (8 mL) was added potassium carbonate (484 mg, 3.50 mmol), Mel (0.131 mL, 2.101 mmol) and tetrabutylammonium bromide (5 mg, 0.016 mmol) at room temperature. After 15.5 hours, reaction was incomplete as shown by LCMS, Mel (55 uL,0.5 eq) was added. After 10 minutes, the mixture was filtered through 45 urn disc, diluted with EtOAc (80 mL), washed with saturated aqueous NaHC0₃ (40 mL), then brine (40 mL). The organic extracts were dried (Na₂S0₄), filtered and concentrated to give N-(5-bromo-2-chloropyridin-3-yl)-N- methylmethanesulfonamide (478.5 mg, 1.597 mmol, 91 % yield) as beige solid. ¹H NMR (400 MHz, DMSO-cf₆) δ ppm 3.20 (s, 3 H), 3.21 (s, 3 H), 8.44 (d, J=2.3 Hz, 1 H), 8.60 (d, J=2.3 Hz, 1 H); LCMS (m/z) ES+ 298.9, 300.9 (M+1 ).

Step D

6-Bromo- 1 -methyl- 1 , 3-dihydroisothiazolo[4, 3-b]pyridine 2, 2-dioxide

To a solution of N-(5-bromo-2-chloropyridin-3-yl)-N-methylmethanesulfonamide (475 mg, 1.586 mmol) in DMSO (5 mL) at room temperature was added potassium tert-butoxide (712 mg, 6.34 mmol) in one portion. After 40 minutes, the mixture was poured into saturated aq. NH₄CI (50 mL) with solid Na₂S0₄. The mixture was extracted with EtOAc (2 x 100 mL). The combined organic extracts were washed with brine (50 mL), dried (Na₂S0₄), filtered and concentrated. The crude was absorbed on silica gel and purified by column chromatography [0-30% EtOAc in hexanes] to give 6-bromo-1-methyl-1 ,3-dihydroisothiazolo[4,3-b]pyridine 2,2-dioxide (259.8 mg, 0.987 mmol, 62.3 % yield) as white solid. H NMR (400 MHz, DMSO-d₆) δ ppm 3.10 (s, 3 H), 4.87 (s, 2 H), 7.72 (d, J=2.0 Hz, 1 H), 8.27(d, J=2.0 Hz, 1 H); LCMS (m/z) ES+ 262.9, 264.9 (M+1 ).

Step E

1-Methyl-6-(4, 4, 5, 5-tetramethyl- 1,3, 2-dioxaborolan-2-yl)-1 , 3-dihydroisothiazolo[4, 3-b]pyridine 2,2-dioxide

A suspension of 6-bromo-1-methyl-1 ,3-dihydroisothiazolo[4,3-b]pyricline 2,2-dioxide (241.5 mg, 0.918 mmol), bis(pinacolato)diboron (303 mg, 1.193 mmol), potassium acetate (270 mg, 2.75 mmol) and PdCI₂(dppf)-DC adduct (37.5 mg, 0.046 mmol) was heated at 00 °C in ,4- dioxane (4.6 mL). After 1.5 hours, the mixture was cooled, filtered through Celite, washed with EtOAc (30 mL). The solvent was concentrated with silica gel. The crude was purified by column chromatography [0-100% EtOAc in hexanes] to give 1-methyl-6-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)-1 ,3-dihydroisothiazolo[4,3-b]pyridine 2,2-dioxide (94.1 mg, 0.303 mmol, 33.1 % yield) as a yellow solid. H NMR (400 MHz, DMSO-d₆) δ ppm 1.32 (s, 12 H), 3.1 1 (s, 3 H), 4.89 (s, 2 H), 7.42 (d, J=1.0 Hz, 1 H), 8.35 (d, J=1.1 Hz, 1 H); LCMS (m/z) ES+ 229.3 (M+1 of boronic acid).

Step F

2-Amino-6-(1-methyl-2,2-dioxido-1,3-dihydroisothiazolo[4,3-b]pyridi^

-one

A suspension of 2-amino-6-iodo-3-phenylquinazolin-4(3H)-one (90 mg, 0.248 mmol), 1-methyl- 6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 ,3-dihydroisothiazolo[4,3-b]pyridine 2,2-dioxide (92 mg, 0.297 mmol), palladium(ll) acetate (5.56 mg, 0.025 mmol), CataCXium® A (8.89 mg, 0.025 mmol) and sodium carbonate (0.372 mL, 0.743 mmol) in 1 ,4-dioxane (1.2 mL) was heated to 70 °C. After 3 hours, the solvent was removed under reduced pressure. The residue was triturated with saturated aqueous NaHC0₃ (20 mL) and centrifuged. The supernantant was descanted and the residue was purified by preparative HPLC [5-70% ACN gradient, 0.1% formic acid) to give 2-amino-6-(1-methyl-2,2-dioxido-1 ,3-dihydroisothiazolo[4,3-b]pyridin-6-yl)-3- phenylquinazolin-4(3H)-one (76.5 mg, 73% yield) as white powder. ¹H NMR (400 MHz, DMSO- cfe) δ ppm 3.18 (s, 3 H), 4.84 - 4.94 (m, 2 H), 7.40 (d, J=8.0 Hz, 3 H), 7.51 - 7.66 (m, 3 H), 7.69 (d, J=1.8 Hz, 1 H), 8.06 (dd, J=8.6, 2.2 Hz, 1 H), 8.25 (d, J=2.2 Hz, 1 H), 8.48 (d, J=1.9 Hz, 1 H); LCMS (m/z) ES+ 420.1 (M+1 ).

Example 353

tert-Butyl (3-(3-(5-(2-amino-4-oxo-3-phenyl-3,4-dihydroquinazolin-6-yl)-2- methoxypyridin opyl)carbamate

3-((tert-Butoxyca enzenesulfonate

To a solution of tert-butyl (3-hydroxypropyl)carbamate (3.9 g, 22.26 mmol) and triethylamine (3.72 ml_, 26.7 mmol) in DCM (200 mL) at room temperature was added p-toluenesulfonyl chloride (5.09 g, 26.7 mmol) and DMAP (0.272 g, 2.226 mmol). After 29 hours, the mixture was concentrated with silica gel and purified by silica gel chromatography [0-30% EtOAc in hexanes] to give 3-((tert-butoxycarbonyl)amino)propyl 4-methylbenzenesulfonate (5.21 g, 15.82 mmol, 71.1 % yield) as colorless oil. ¹H N (400 MHz, DMSO-cf₆) δ ppm .37 (br. s., 9 H), .68 (quin, J=6.6 Hz, 2 H), 2.39 - 2.45 (m, 3 H), 2.90 (q, J=6.6 Hz, 2 H), 3.95 - 4.03 (m, 2 H), 6.82 (br. s., 1 H), 7.44 - 7.51 (m, 2 H), 7.77 (d, J=8.3 Hz, 2 H); LCMS (m/z) ES+ 274.0 (M+1 - 56).

Step B

tert-Butyl (3-(3-aminophenoxy)propyl)carbamate

A suspension of 3-aminophenol (1.45 g, 13.29 mmol), 3-((tert-butoxycarbonyl)amino)propyl 4- methylbenzenesulfonate (5.21 g, 15.82 mmol) and cesium carbonate (5.20 g, 15.94 mmol) was stirred at room temperature in DMF (44.3 mL). After 1 day, the mixture was diluted with EtOAc (400 mL) and washed with saturated aqueous NH₄CI (125 mL), then brine (125 mL), dried (Na₂S0₄), filtered and concentrated. The crude was absorbed on silica gel and purified by column chromatography [0-35% EtOAc in hexanes] to give tert-butyl (3-(3- aminophenoxy)propyl)carbamate (3.3082 g, 12.42 mmol, 93 % yield) as white solid. H NMR (400 MHz, DMSO-cf₆) δ ppm 1.37 (s, 9 H), 1.77 (quin, J=6.6 Hz, 2 H), 3.04 (q, J=6.8 Hz, 2 H), 3.84 (t, =6.3 Hz, 2 H), 5.01 (s, 2 H), 6.01 - 6.07 (m, 1 H), 6.08 - 6.15 (m, 2 H), 6.81 - 6.92 (m, 2 H); LCMS (m/z) ES+ 267.1 (M+1 ), 21 1.0 (M+1 - 56).

Step C

tert-Butyl (3-(3-(5-bromo- -methoxypyridine-3-sulfonamido)phenoxy)propyl)carbamate

A mixture of tert-butyl (3-(3-aminophenoxy)propyl)carbamate (1.007 g, 3.78 mmol), 5-bromo-2- chloropyridine-3-sulfonyl chloride (1 g, 3.44 mmol) and pyridine (0.306 mL, 3.78 mmol) in DCM (10 mL) was stirred at room temperature. After 2 hours, the solvent was removed under reduced pressure to give crude tert-butyl (3-(3-(5-bromo-2-chloropyridine-3- sulfonamido)phenoxy)propyl)carbamate (2.2732 g) as red foam. LCMS (m/z) ES+ 542.0, 544.0 (M+Na).

Crude tert-butyl (3-(3-(5-bromo-2-chloropyridine-3-sulfonamido)phenoxy)propyl)carbamate was dissolved in MeOH (8 mL) and sodium methanolate solution (9.97 mL, 44.7 mmol) (25 wt% in MeOH) was added. The mixture was heated at 50 °C for 3 hours. The mixture was cooled and the solvent was removed under reduced pressure. The crude oil was diluted with EtOAc (60 mL) and water (30 mL). The aqueous phase was separated and extracted with EtOAc (60 mL). The combined organic phase was washed with brine (30 mL), dried (Na₂S0₄), filtered and concentrated. The crude foam was absorbed on silica gel and purified by silica gel

chromatography [0-30% EtOAc in hexanes] to give tert-butyl (3-(3-(5-bromo-2-methoxypyridine- 3-sulfonamido)phenoxy)propyl)carbamate (1.2263 g, 2.375 mmol, 69.1 % yield) as light yellow foam. H NMR (400 MHz, DMSO-d₆) δ ppm 1.36 (s, 9 H), 1.70 - 1.82 (m, 2 H), 3.03 (q, J=6.6 Hz, 2 H), 3.85 (t, J=6.2 Hz, 2 H), 3.96 (s, 3 H), 6.59 (dd, J=8.2, 1.9 Hz, 1 H), 6.62 - 6.68 (m, 2 H), 6.88 (br. s., 1 H), 7.12 (t, J=8.1 Hz, 1 H), 8.24 (d, J=2.3 Hz, 1 H), 8.52 (d, J=2.4 Hz, 1 H), 10.45 (s, 1 H); LCMS (m/z) ES+ 460.0, 462.0 (M+1 - 56).

Step D tert-Butyl (3-(3-(2-methoxy-5-(4, 4, 5, 5-tetramethyl- 1, 3, 2-dioxaborolan-2-yl)pyridine-3- sulfon amate

A suspension of tert-butyl (3-(3-(5-bromo-2-methoxypyridine-3- sulfonamido)phenoxy)propyl)carbamate (1.2226 g, 2.368 mmol), bis(pinacolato)diboron (0.782 g, 3.08 mmol), potassium acetate (0.697 g, 7.10 mmol) and PdCI2(dppf)-DC adduct (0.097 g, 0.1 18 mmol) was heated at 100 °C in 1 ,4-dioxane (12 ml_). After 2 hours, the mixture was cooled, filtered through a pad of Celite and washed with EtOAc (100 ml_). The solvent was concentrated with silica gel. The crude was purified by column chromatography [0-100% EtOAc in hexanes] to give tert-butyl (3-(3-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)pyridine-3-sulfonamido)phenoxy)propyl)carbamate (876.8 mg, 1.556 mmol, 65.7 % yield) as light yellow foam. LCMS (m/z) ES- 562.3 (M-1 ); 480.2 (M-1 ) for boronic acid observed.

Step E

tert-Butyl (3-(3-(5-(2-amino-4-oxo-3-phenyl-3 -dihydroquinazo^

sulfon mate

A suspension of 2-amino-6-iodo-3-phenylquinazolin-4(3H)-one (320 mg, 0.881 mmol), tert-butyl (3-(3-(2-methoxy-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridine-3- sulfonamido)phenoxy)propyl)carbamate (555 mg, 0.985 mmol), palladium(ll) acetate (18.4 mg, 0.082 mmol), cataCXium® A (29.4 mg, 0.082 mmol) and 2 M aq. sodium carbonate solution (1.23 ml_, 2.460 mmol) in 1 ,4-dioxane (4 mL) was heated at 60 °C. After 2 hours, the mixture was cooled, filtered through a pad of Celite, washed with EtOAc (120 mL). The filtrate was washed with saturated aqueous NaHC0₃ (40 mL), then brine (40 mL), dried (Na₂S0₄), filtered and concentrated. The crude was absorbed on silica gel and purified by silica gel

chromatography [0-8%MeOH in (DCM/EtOAc 1 :1 v/v)] to give tert-butyl (3-(3-(5-(2-amino-4-oxo- 3-phenyl-3,4-dihydroquinazolin-6-yl)-2-methoxypyridine-3- sulfonamido)phenoxy)propyl)carbamate (387.5 mg, 0.570 mmol, 64.7 % yield) as beige solid. H N R (400 MHz, DMSO-c/₆) δ ppm 1.35 (s, 9 H), 1.73 (t, J=6.4 Hz, 2 H), 2.99 (q, J=6.3 Hz, 2 H), 3.82 (t, J=6.1 Hz, 2 H), 4.01 (s, 3 H), 6.42 (br. s., 2 H), 6.55 (s, 1 H), 6.65 - 6.75 (m, 2 H), 6.83 (br. s., 1 H), 7.09 (t, J=8.1 Hz, 1 H), 7.30 - 7.42 (m, 3 H), 7.49 - 7.67 (m, 3 H), 7.92 (dd, J=8.6, 1.7 Hz, 1 H), 8.05 (s, 1 H), 8.31 (d, J=1.8 Hz, 1 H), 8.70 (d, J=2.0 Hz, 1 H), 10.39 (s, 1 H);

LCMS (m/z) ES+ 673.3 (M+1 ).

Example 354

5-(2-Amino-4-oxo-3-phenyl-3,4-dihydroquinazolin-6-yl)-N-(3-(3-amm^' op

tert-Butyl (3-(3-(5-(2-amino-4-oxo-3-phenyl-3,4-dihydroquinazolin-6-yl)-2-methoxypyridine-3- sulfonamido)phenoxy)propyl)carbamate (88.5 mg, 0.132 mmol) was stirred in trifluoroacetic acid (4 ml_, 51.9 mmol) at room temperature. After 30 minutes, the solvent was removed under reduced pressure and purified by preparative RP-HPLC [5-90% ACN gradient, 0.1 % formic acid] to give 5-(2-amino-4-oxo-3-phenyl-3,4-dihydroquinazolin-6-yl)-N-(3-(3-aminopropoxy)phenyl)-2- methoxypyridine-3-sulfonamide, 0.47 formic acid salt (79 mg, 0.132 mmol, 100 % yield) as white powder. H NMR (400 MHz, DMSO-c/₆) δ ppm 1.92 (quin, 2 H), 2.89 (t, J=7.3 Hz, 2 H), 3.92 (t, J=6.0 Hz, 2 H), 4.01 (s, 3 H), 6.44 (br. s., 2 H), 6.57 (dd, J=8.3, 1.7 Hz, 1 H), 6.69 - 6.75 (m, 2 H), 7.08 - 7.16 (m, 1 H), 7.32 - 7.41 (m, 3 H), 7.49 - 7.64 (m, 3 H), 7.93 (dd, J=8.6, 2.3 Hz, 1 H), 8.05 (d, J=2.2 Hz, 1 H), 8.20 (s, 0.47 H, formic acid), 8.32 (d, J=2.5 Hz, 1 H), 8.71 (d, J=2.4 Hz, 1 H); LCMS (m/z) ES- 571.3 (M-1 ).

Example 355

N-(6-(2-Amino-4-oxo-3-phenyl-3,4-dihydroquinazolin-6-yl)benzo[d]oxazol-4-yl)-2,4- difluorobenzenesulfonamide

Step A

6-Bromo- -nitrobenzo[d]oxazole

A suspension of 2-amino-5-bromo-3-nitrophenol (prepared following literature procedure: Paul S. Charifson, et al, J. Med. Chem., 2008, 51, 5243-5263), (1 g, 4.29 mmol) and p- toluenesulfonic acid monohydrate (0.041 g, 0.215 mmol) in trimethyl orthoformate (1.33 mL, 12.02 mmol) was heated to 105 °C in a sealed tube. After 3 hours, trimethyl orthoformate (0.7 mL) was added and mixture was continued to heat at 105 °C for 21 hours. The mixture was diluted with EtOAc (100 mL) and washed with saturated aqueous NaHC0₃ (20 mL), then brine (20 mL), dried (Na₂S0₄), filtered and concentrated. The crude was absorbed on silica gel and purified by column chromatography [0-5% EtOAc in DCM] to give 6-bromo-4- nitrobenzo[d]oxazole (759.4 mg, 3.12 mmol, 72.8 % yield) as yellow solid. H NMR (400 MHz, DMSO-af₆) δ ppm 8.38 (d, J=1.7 Hz, 1 H), 8.69 (d, J=1.7 Hz, 1 H), 9.10 - 9.13 (m, 1 H); (m/z) ES+ 242.8, 244.8 (M+1 ).

Step B

6-Bromobenzo[d]oxazol-4-am

To a suspension of 6-bromo-4-nitrobenzo[d]oxazole (554.5 mg, 2.282 mmol), ammonium chloride (244 mg, 4.56 mmol) in ethanol (20 mL) and water (20.00 mL) at 90 °C was added iron (637 mg, 1 1 .41 mmol) in one portion. After 3.5 hours, ammonium chloride (122 mg) was added. After 50 minutes, the reaction was cooled to room temperature. The suspension was filtered through Celite and washed with EtOAc (50 mL). The filtrate was concentrated under reduced pressure to give brown solid. The solid was dissolved in EtOAc (75 mL) and brine (25 mL). The aqueous phase was separated and extracted with EtOAc (50 mL). The combined organic phase was dried (Na₂S0₄), filtered and concentrated. The crude was absorbed on silica gel and purified by silica gel chromatography [0-6% MeOH in DCM] to give 6-bromobenzo[d]oxazol-4- amine (153.2 mg, 0.719 mmol, 31.5 % yield) as red solid. H NMR (400 MHz, DMSO-cf₆) δ ppm 6.01 (s, 2 H), 6.68 (d, J=1.7 Hz, 1 H), 7.07 (d, J=1.7 Hz, 1 H), 8.48 - 8.54 (s, 1 H); LCMS (m/z) ES+ 212.9, 214.9 (M+1).

Step C

N-(6-Bromobenzo[d]oxazol-4-yl)-2,4-difluorobenzenesulfonamide

To a solution of 6-bromobenzo[d]oxazol-4-amine (150 mg, 0.704 mmol) in pyridine (5 mL) at room temperature was added 2,4-difluorobenzene-1-sulfonyl chloride (0.1 14 mL, 0.845 mmol) dropwise. After 1 hour, 2,4-difluorobenzene sulfonyl chloride (48 uL, 0.5 eq) was added and the mixture was allowed to stir overnight. Water (15 mL) was added to the mixture followed by extraction with EtOAc (100 mL). The organic phase was separated and washed with brine (15 mL), dried (Na₂S0₄), filtered and concentrated. The crude was absorbed on silica gel and purified by column chromatography [0-35% EtOAc in hexanesj to give N-(6- bromobenzo[d]oxazol-4-yl)-2,4-difluorobenzenesulfonamide (200.8 mg, 0.516 mmol, 73.3 % yield) as white solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.20 - 7.27 (m, 1 H), 7.38 (d, J=1.7 Hz, 1 H), 7.48 - 7.56 (m, 1 H), 7.87 (td, J=8.6, 6.2 Hz, 1 H), 7.92 (d, J=1.5 Hz, 1 H), 8.67 - 8.72 (m, 1 H), 1 1.31 (s, 1 H); LCMS (m/z) ES+ 388.9, 390.9 (M+1 ).

Step D

2, 4-Difluoro-N-(6-(4, 4, 5, 5-tetramethyl-1 , 3, 2-dioxaborolan-2-yl)benzo[d]oxazol-4- yl)benzenesulfonamide

A suspension of A/-(6-bromobenzo[d]oxazol-4-yl)-2,4-difluorobenzenesulfonamide (198 mg, 0.509 mmol), bis(pinacolato)diboron (214 mg, 0.843 mmol), potassium acetate (165 mg, 1.681 mmol) and PdCI2(dppf)-DCM adduct (46 mg, 0.056 mmol) was heated at 100 °C in 1 ,4-dioxane (3 mL) in a sealed tube. After 75 minutes the mixture was cooled, filtered through a pad of Celite and washed with EtOAc. The solvent was evaporated under reduced pressure. The crude was absorbed on silica gel and purified by column chromatography [0-30% EtOAc in hexanes] to give 2,4-difluoro-N-(6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzo[d]oxazol-4- yl)benzenesulfonamide (140.5 mg, 0.322 mmol, 63.3 % yield) as white solid. H NMR (400 MHz, DMSO-c/₆) δ ppm 1.25 - 1.37 (m, 12 H), 7.18 (td, J=8.6, 2.1 Hz, 1 H), 7.45 - 7.55 (m, 2 H), 7.69 - 7.80 (m, 2 H), 8.72 (s, 1 H), 10.90 (s, 1 H); LCMS (m/z) ES+ 437.1 (M+ 1).

Ste E

A suspension of 2-amino-6-iodo-3-phenylquinazolin-4(3H)-one (40 mg, 0.110 mmol), 2,4- difluoro-N-(6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzo[d]oxazol-4- yl)benzenesulfonamide (67.3 mg, 0.154 mmol), palladium(M) acetate (2.473 mg, 0.011 mmol), cataCXium® A (3.95 mg, 0.011 mmol) and 2 M aq. sodium carbonate (0.165 mL, 0.330 mmol) was heated at 100 °C. After 4 hours, the mixture was cooled, diluted with EtOAc (100 mL) and washed with saturated aqueous NaHC0₃ (15 mL). The solid formed was filtered. The organic phase was dried (Na₂S0₄), filtered and concentrated. The crude was absorbed on silica gel and purified by column chromatogrphy [0-7%MeOH in DCM] to give impure product. The material was further purified using preparative RP- HPLC [5-70% ACN gradient, 0.1 % formic acid] to give impure product (30.6 mg). The material was purified using silica gel chromatography [0-6% eOH in DC /EtOAc (1 :1 v/v)] to give N-(6-(2-amino-4-oxo-3-phenyl-3,4-dihydroquinazolin-6- yl)benzo[d]oxazol-4-yl)-2,4-difluorobenzenesulfonamide (13.4 mg, 0.024 mmol, 22.08 % yield) as white solid. ¹H NMR (400 MHz, DMSO-cf₆) δ ppm 6.41 (br. s., 2 H), 7.20 (td, J=8.5, 2.2 Hz, 1 H), 7.35 (d, J=8.6 Hz, 1 H), 7.37 - 7.43 (m, 2 H), 7.47 - 7.64 (m, 5 H), 7.82 - 7.94 (m, 3 H), 8.08 (d, J=2.3 Hz, 1 H), 8.68 (s, 1 H), 11.1 1 (s, 1 H); LCMS (m/z) ES+ 546.1 (M+1 ).

Example 356

N-(6-(2-Amino-4-oxo-3-phenyl-3,4-dihydroquinazolin-6-yl)-2-oxo-2,3- dihydrobenzo[d]oxazol-4-yl)-2,4-difluorobenzenesulfonamide

Step A

6-Bromo-4 2(3H)-one

To a suspension of 2-amino-5-bromo-3-nitrophenol (815 mg, 3.50 mmol) in THF (35 mL) at room temperature was added CDI (624 mg, 3.85 mmol) in one portion. After 3.25 hours, CDI (170 mg, 0.3 eq ) was added. After 2 hours, the solvent was evaporated under reduced pressure. The yellow solid was diluted with EtOAc (100 mL) and 1 N HCI (25 mL). The organic phase was separated and washed with 1 N HCI (25 mL), brine (25 mL), dried (Na₂S0₄), filtered and concentrated to give 6-bromo-4-nitrobenzo[d]oxazol-2(3H)-one (876.1 mg, 3.38 mmol, 97 % yield) as orange solid. H NMR (400 MHz, DMSO- /₆) δ ppm 8.07 (m, 2 H), 12.85 (br. s., 1 H); LCMS (m/z) ES- 256.9, 258.9 (M-1). Step B

4-Amino-6-bromobenzo[d]oxazol-2(3H)-one

A suspension of 6-bromo-4-nitrobenzo[djoxazol-2(3H)-one (816.4 mg, 3.15 mmol) and iron (880 mg, 15.76 mmol) was heated in acetic acid (15.8 mL) at 100 °C. After 100 minutes, the mixture was cooled and the solvent evaporated under reduced pressure. The solid was digested with EtOAc (100 mL) and saturated aqueous NaHC0₃ (25 mL). The suspension was filtered through a pad of Celite. The aqueous phase was separated and extracted with EtOAc (50 mL). The combined organic phase was dried (Na₂S0₄), filtered and concentrated to give 4-amino-6- bromobenzo[d3oxazol-2(3H)-one (670.6 mg, 2.93 mmol, 93 % yield) as a light pink solid. ¹H NMR (400 MHz, DMSO-c₆) δ ppm 6.56 (d, J=1.6 Hz, 1 H), 6.60 (d, J=1.7 Hz, 1 H), 10.01 (br. s., 1 H), 10.60 (d, 2 H); LCMS (m/z) ES+ 228.9, 230.9 (M+1 ).

Step C

N-( 6-Bromo-2-oxo-2, 3-dihydrobenzo[d]oxazol-4-yl) -2, 4-difluorobenzenesulfonamide

To a solution of 4-amino-6-bromobenzo[djoxazol-2(3H)-one (666.7 mg, 2.91 mmol) in pyridine (15 mL) at room temperature was added 2,4-difluorobenzene-1-sulfonyl chloride (0.587 mL, 4.37 mmol) dropwise. After 20 hours, water (25 mL) was added to the mixture which was extracted with EtOAc (150 mL, 50 mL). The combined organic phase was washed with brine (25 mL), dried (Na₂S0₄), filtered and concentrated to give syrup. The crude was triturated with DCM (6 mL) to give a precipitate which was centrifuged. The supernatant was decanted and the solid dried under high vacuum to give N-(6-bromo-2-oxo-2,3-dihydrobenzo[djoxazol-4-yl)-2,4- difluorobenzenesulfonamide (882.8 mg, 2.179 mmol, 74.8 % yield) as off-white solid. ¹H NMR (400 MHz, DMSO-af₆) δ ppm 6.66 (d, J=1.5 Hz, 1 H), 7.04 (s, 1 H), 7.33 - 7.45 (m, 1 H), 7.69 - 7.81 (m, 1 H), 7.90 - 8.01 (m, 1 H), 11.11 (s, 1 H), 1 1.39 (s, 1 H); LCMS (m/z) ES+ 404.9, 406.9 (M+1 ).

Step D

2 -Difluoro-N-(2-oxo-6-(4 A5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3- dihydroben nesulfonamide

A suspension of N-(6-bromo-2-oxo-2,3-dihydrobenzo[d]oxazol-4-yl)-2,4- difluorobenzenesulfonamide (850 mg, 2.098 mmol), bis(pinacolato)diboron (799 mg, 3.15 mmol), potassium acetate (618 mg, 6.29 mmol) and PdCI₂(dppf)-DCM adduct (171 mg, 0.210 mol) was heated at 100 °C in 1 ,4-dioxane (10.5 mL) in a sealed tube. After 4.5 hours, the mixture was cooled, filtered through a pad of Celite and washed with EtOAc (75 mL). The solvent was concentrated under reduced pressure. The crude was purified by silica gel chormatography [0-100% EtOAc in hexanes] to give 2,4-difluoro-N-(2-oxo-6-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)-2,3-dihydrobenzo[d]oxazol-4-yl)benzenesulfonamide (567.7 mg, 1.255 mmol, 59.8 % yield) as light brown solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.24 (br. s., 12 H), 6.64 (s, 1 H), 7.07 (s, 1 H), 7.35 (td, J=8.5, 2.0 Hz, 1 H), 7.74 - 7.84 (m, 1 H), 7.89 (td, J=8.5, 6.1 Hz, 1 H), 11.01 (d, J=0.9 Hz, 1 H), 11.42 (s, 1 H); LCMS (m/z) ES+ 453.0 (M+1 ).

Step E

N- (6- ( 2-Amino-4-oxo-3-phenyl-3, 4-dihydroquinazolin- 6-yl) -2-oxo-2, 3-dihydrobenzo[d]oxazol-4- yl)-2,4-difluorobenzenesulfonamide

A suspension of 2-amino-6-iodo-3-phenylquinazolin-4(3H)-one (75 mg, 0.207 mmol), 2,4- difluoro-N-(2-oxo-6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan^

yl)benzenesulfonamide (140 mg, 0.310 mmol), palladium(ll) acetate (4.64 mg, 0.021 mmol), cataCXium® A (7.40 mg, 0.021 mmol) and 2M aq. sodium carbonate (310 μΙ, 0.620 mmol) was heated at 120 °C for 5 minutes under microwave conditions. The mixture was concentrated under reduced pressure. The residue was triturated with saturated aqueous NaHC0₃ (6 mL). The supernatant was discarded. The residue was digested with DMSO and acidified with TFA. This was purified by preparative RP- HPLC [5-60% ACN gradient, 0.1% formic acid] to give Λ/- (6-(2-amino-4-oxo-3-phenyl-3,4-dihydroquinazolin-6-yl)-2-oxo-2,3-dihydrobenzo[d]oxazol-4-yl)- 2,4-difluorobenzenesulfonamide (36.1 mg, 0.064 mmol, 30.8 % yield) as white solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 6.35 (br. s., 2 H), 6.69 (d, J=1.2 Hz, 1 H), 7.13 (d, J=1.3 Hz, 1 H), 7.27 (d, 1 H), 7.32 - 7.41 (m, 3 H), 7.48 - 7.64 (m, 3 H), 7.68 (dd, J=8.6, 2.3 Hz, 1 H), 7.72 - 7.81 (m, 1 H), 7.83 (d, J=2.1 Hz, 1 H), 7.96 (td, J=8.5, 6.2 Hz, 1 H), 11.03 (br. s., 1 H), 11.29 (br. s., 1 H); LCMS (m/z) ES+ 562.0 (M+1 ).

Example 357

2-Amino-6-(2-a olin-4(3H)-one

A suspension of 2-amino-6-iodo-3-phenylquinazolin-4(3H)-one (80 mg, 0.220 mmol), 5-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzo[d]oxazol-2-amine (available from Milestone, 74.5 mg, 0.286 mmol), palladium(ll) acetate (4.95 mg, 0.022 mmol), cataCXium® A (7.90 mg, 0.022 mmol) and 2M aq. sodium carbonate (0.330 mL, 0.661 mmol) in 1 ,4-dioxane (1 mL) was heated to 70 °C. After 7 hours, the mixture was cooled and the solvent removed under reduced pressure. The crude solid was triturated with saturated aqueous NaHC0₃ (6 mL) and the supernatant decanted. The solid was purified by preparative RP-HPLC [5-70% ACN gradient, 0.1 % formic acid] to give 2-amino-6-(2-aminobenzo[d]oxazol-5-yl)-3-phenylquinazolin-4(3H)- one, Formic acid salt (62 mg, 0.145 mmol, 65.7 % yield) as white powder. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 6.47 (br. s., 2 H), 7.26 (dd, J=8.3, 1.9 Hz, 1 H), 7.31 - 7.37 (m, 1 H), 7.39 (d, J=8.2 Hz, 3 H), 7.44 - 7.50 (m, 3 H), 7.50 - 7.63 (m, 3 H), 7.95 (dd, J=8.6, 2.1 Hz, 1 H), 8.09 (d, J=2.2 Hz, 1 H), 8.13 (s, 1 H, formic acid); LCMS (m/z) ES+ 370.1 (M+1 ).

Example 358

N-[5-(2-amino-4-oxo-3-phenyl-3,4-dihydro-6-quinazolinyl)-2-(meth^

Prepared from 2-amino-6-[5-amino-6-(methyloxy)-3-pyridinyl]-3-phenyl-4(3/-/)- quinazolinone and 2-methoxybenzenesulfonyl chloride as described in example 51.. ¹H NMR (400 MHz, DMSO-af₆) δ ppm 9.26 (s, 1 H), 8.20 (d, J=1.8 Hz, 1 H), 7.95 (d, J=2.3 Hz, 1 H), 7.78 - 7.91 (m, 2 H), 7.70 (dd, J=7.8, 1.8 Hz, 1 H), 7.47 - 7.65 (m, 4 H), 7.27 - 7.44 (m, 3 H), 7.20 (d, J=8.4 Hz, 1 H), 7.01 (t, J=7.4 Hz, 1 H), 6.38 (br. s., 2 H), 3.84 (s, 3 H), 3.78 (s, 3 H). ES-LCMS: m/z = 530.1 1 (M+1 ).

Example 359

5-[2-amino-4-oxo-3-(tetrahydro-2H-pyran-4-yl)-3,4-dihydro-6-quinazolinyl]-2-(methy

-phenyl-3-pyridinesulfonamide

Prepared as described in example 37. ¹H NMR (400 MHz, DMSO- ₆) δ ppm 10.36 (br. s., 1 H), 8.69 (s, 1 H), 8.30 (s, 1 H), 8.16 (br. s., 1 H), 8.03 (br. s., 1 H), 7.82 - 7.90 (m, 1 H), 6.93 - 7.30 (m, 8 H), 4.30 - 4.45 (m, 1 H), 3.88 - 4.08 (m, 5 H), 2.75 - 2.94 (m, 2 H), 1.50 - 1.69 (m, 2 H). ES-LCMS: m/z = 508.14 (M+1)

Example 360

5-(2-amino-3-cyclopropyl-4-oxo-3,4-dihydro-6-quinazolinyl)-2-(methyloxy)^^

pyridinesulfonamide

Prepared as described in example 37. ¹H NMR (400 MHz, DMSO-c/₆) δ ppm 10.20 - 10.63 (m, 1 H), 8.68 (d, J=2.3 Hz, 1 H), 8.28 (d, J=2.3 Hz, 1 H), 8.16 (s, 1 H), 8.01 (d, J=2.0 Hz, 1 H), 7.79 - 7.87 (m, 1 H), 7.21 (dd, J=8.0, 4.9 Hz, 4 H), 6.93 - 7.17 (m, 5 H), 4.00 (s, 3 H), 1.17 - 1.29 (m, 2 H), 0.78 (br. s., 2 H). ES-LCMS: m/z = 464.15 (M+1 )

Example 361

5-[2-amino-4-oxo-3-(tetrahydro-2H^yran-4-ylmethyl)-3,4-dihydm

(methylo -N-phenyl-3-pyridinesulfonamide

Prepared as described in example 37. ¹H NMR (400 MHz, DMSO-af₆) δ ppm 10.38 (br. s., 1 H), 8.69 (d, J=2.3 Hz, 1 H), 8.29 (d, J=2.5 Hz, 1 H), 8.05 (d, J=2.1 Hz, 1 H), 7.86 (dd, J=8.6, 2.3 Hz, 1 H), 7.10 - 7.30 (m, 7 H), 6.91 - 7.06 (m, 1 H), 4.00 (s, 3 H), 3.91 - 3.98 (m, 2 H), 3.75 - 3.87 (m, 2 H), 3.12 - 3.25 (m, 2 H), 2.07 (br. s., 1 H), 1.40 - 1.54 (m, 2 H), 1.20 - 1.38 (m, 2 H). ES-LCMS: m/z = 522.16 (M+1 )

Example 362

5-(2-amino-3-cyclobutyl-4-oxo-3,4-dihydro-6-quinazolinyl)-2-(methyloxy)-N-phen

pyridinesulfonamide

Prepared as described in example 37. ¹H NMR (400 MHz, DMSO- ₆) δ ppm 10.12 - 10.59 (m, 1 H), 8.68 (d, J=2.3 Hz, 1 H), 8.29 (d, J=2.3 Hz, 1 H), 8.02 (d, J=2.1 Hz, 1 H), 7.84 (dd, J=8.6, 2.3 Hz, 1 H), 7.17 - 7.26 (m, 3 H), 7.08 - 7.16 (m, 2 H), 6.95 - 7.03 (m, 1 H), 6.89 {s, 2 H), 4.52 - 4.68 (m, 1 H), 4.00 (s, 3 H), 2.56 - 2.71 (m, 3 H), 1.56 - 1.83 (m, 3 H). ES-LCMS: m/z = 478.15 (M+1 )

Example 363

5-[3-(1-acetyl-4-piperidinyl)-2-amino-4-oxo-3,4-dihydro-6-quinazo

Prepared as described in example 37. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.35 (br s, 1 H), 8.67 (d, J=2.3 Hz, 1 H), 8.28 (d, J=2.3 Hz, 1 H), 8.17 (s, 1 H), 8.00 (d, J=2.1 Hz, 1 H), 7.85 (dd, J=8.6, 2.1 Hz, 1 H), 7.08 - 7.29 (m, 7 H), 6.92 - 7.04 (m, 1 H), 4.28 - 4.60 (m, 2 H), 4.00 (s, 3 H), 3.87 - 3.97 (m, 1 H), 3.05 - 3.18 (m, 1 H), 2.54 - 2.78 (m, 3 H), 2.04 (s, 3 H), 1.56 - 1.78 (m, 2 H). ES-LCMS: m/z = 549.26 (M+1

Example 364

5-[2-amino-4-oxo-3-(t trahydro-2H-pyran-4-yl)-3,4-dihydro-6-quinazoliny

N-(2-methylphenyl)-3-pyridinesulfonamide

Prepared as described in example 37. ¹H NMR (400 MHz, DMSO- ₆) δ ppm 9.28 - 10.12 (m, 1 H), 8.73 (d, J=2.3 Hz, 1 H), 8.15 (s, 1 H), 8.11 (d, J=2.5 Hz, 1 H), 7.98 (d, J=2.1 Hz, 1 H), 7.81 (dd, J=8.6, 2.3 Hz, 1 H), 6.92 - 7.26 (m, 6 H), 4.36 {br. s., 1 H), 4.00 (s, 3 H), 3.87 - 3.97 (m, 2 H), 3.37 - 3.50 (m, 2 H), 2.74 - 2.92 (m, 2 H), 2.15 (s, 3 H), 1.57 (d, J=12.3 Hz, 2 H). ES- LCMS: m/z = 522.26 (M+1 ).

Example 365

5-[2-amino-4-oxo-3-(tetrahydro-2H-pyran-4-yl)-3,4-dihydro-6-quin

fluoroph mide

Prepared as described in example 37. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.02 - 10.79 (m, 1 H), 8.70 (d, J=2.3 Hz, 1 H), 8.26 (d, J=2.5 Hz, 1 H), 8.14 (br. s., 1 H), 8.03 (d, J=2.3 Hz, 1 H), 7.85 (dd, J=8.6, 2.3 Hz, 1 H), 6.95 - 7.31 (m, 7 H), 4.37 (br. s., 1 H), 4.00 (s, 3 H), 3.94 (d, J=10.9 Hz, 2 H), 3.39 - 3.50 (m, 2 H), 2.72 - 2.97 (m, 1 H), 1.51 - 1.65 (m, 2 H). ES-LCMS: m/z = 526.26 (M+1 ).

Example 366

5-[2-amino-4-oxo-3-(tetrahydro-2H-pyran-4-yl)-3,4-dihydro-6-quinazolinyl]-2-(meth^

N-[3-(methyloxy)phenyl]-3-pyridinesulfonamide

Prepared as described in example 37.¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.20 - 10.56 (m, 1 H), 8.70 (d, J=2.3 Hz, 1 H), 8.31 (d, J=2.1 Hz, 1 H), 8.04 (d, J=2.1 Hz, 1 H), 7.85 (dd, J=8.7, 2.1 Hz, 1 H), 6.93 - 7.31 (m, 5 H), 6.65 - 6.82 (m, 2 H), 6.52 - 6.60 (m, 1 H), 4.37 (br. s., 1 H), 4.01 (s, 3 H), 3.87 - 3.98 (m, 2 H), 3.63 (s, 3 H), 3.39 - 3.51 (m, 2 H), 2.75 - 2.99 (m, 1 H), 1.47 - 1.66 (m, 2 H). ES-LCMS: m/z = 538.28 (M+1 ).

Example 367

5-[2-a ino-4-oxo-3-(tetrahydro-2H-pyran-4-yl)-3,4-dihydro-6-quinazoliny

N- amide

Prepared as described in example 37. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.12 - 10.71 (m, 1 H), 8.68 (d, J=2.5 Hz, 1 H), 8.29 (d, J=2.5 Hz, 1 H), 8.15 (s, 1 H), 8.03 (d, J=2.3 Hz,

1 H), 7.85 (dd, J=8.6, 2.3 Hz, 1 H), 7.23 (d, J=8.6 Hz, 1 H), 7.17 (br. s., 2 H), 7.04 - 7.13 (m, 1 H), 6.90 - 6.99 (m, 2 H), 6.81 (d, J=7.6 Hz, 1 H), 4.37 (br. s., 1 H), 4.01 (s, 3 H), 3.88 - 3.98 (m,

2 H), 3.39 - 3.48 (m, 2 H), 2.75 - 2.95 (m, 2 H), 2.18 (s, 3 H), 1.46 - 1.68 (m, 2 H). ES-LCMS: m/z = 522.30 (M+1 ).

Example 368

5-[2-amino-4-oxo-3-(tetrahydro-2H-pyran-4-yl)-3,4-dihydro-6-quinazoHnyl^

N-(4-methylphenyl)-3-pyridinesulfonamide

Prepared as described in example 37. ¹H NMR (400 MHz, DMSO- ₆) δ ppm 10.22 (br. s., 1 H), 8.68 (d, J=2.3 Hz, 1 H), 8.25 (d, J=2.3 Hz, 1 H), 8.16 (br. s., 1 H), 8.01 (d, J=2.0 Hz, 1 H), 7.84 (dd, J=8.5, 2.2 Hz, 1 H), 7.22 (d, J=8.6 Hz, 1 H), 7.17 (br. s., 2 H), 7.02 (s, 4 H), 4.36 (br. s., 1 H), 4.02 (s, 3 H), 3.89 - 3.98 (m, 2 H), 3.39 - 3.50 (m, 1 H), 2.76 - 2.95 (m, 2 H), 2.14 (s, 3 H), 1.49 - 1.66 (m, 2 H). ES-LCMS: m/z = 522.26 (M+1 ).

Example 369

N-[5-(2-amino-4-oxo-3-phenyl-3,4-dihydro-6-quinazolinyl)-2-(methylo^

oxo-2,3- namide

Prepared from 2-amino-6-[5-amino-6-(methyloxy)-3-pyridinyl]-3-phenyl-4(3H)- quinazolinone and 2-oxo-2,3-dihydro-1 ,3-benzoxazole-6-sulfonyl chloride as described in example 51. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 11.84 - 12.42 (m, 1 H), 10.01 (br. s., 1 H), 8.25 (s, 1 H), 8.00 (s, 1 H), 7.79 - 7.93 (m, 2 H), 7.67 (s, 1 H), 7.49 - 7.64 (m, 4 H), 7.30 - 7.44 (m, 3 H), 7.21 (d, J=8.2 Hz, 1 H), 6.39 (br. s., 2 H), 3.69 (s, 3 H). ES-LCMS: m/z = 557.11 (M+1 ).

Example 370

N-[5-(2-amino-4-oxo-3-phenyl-3,4-dihydro-6-quinazolinyl)-2-(methylo^

chloro-6-methylbenzenesulfonamide

Prepared from 2-amino-6-[5-amino-6-(methyloxy)-3-pyridinyl]-3-phenyl-4(3H)- quinazolinone and 2-chloro-6-methylbenzenesulfonyl chloride as described in example 51. ¹H NMR (400 MHz, DMSO-c₆) δ ppm 10.00 (s, 1 H), 8.27 (d, J=1.4 Hz, 1 H), 7.97 (d, J=2.3 Hz, 1 H), 7.85 (dd, J=8.6, 2.3 Hz, 1 H), 7.78 (d, J=2.3 Hz, 1 H), 7.41 - 7.63 (m, 5 H), 7.38 (d, J=7.0 Hz, 2 H), 7.33 (d, J=8.4 Hz, 2 H), 6.33 (br. s., 2 H), 3.63 (s, 3 H), 2.53 (s, 3 H). ES-LCMS: m/z = 548.32 (M+1).

Example 371

N-[5-(2-amino-4-oxo-3^henyl-3,4-dihydro-6-quinazolinyl)-2-(methyloxy)-3-pyridin

Prepared from 2-amino-6-[5-amino-6-(methyloxy)-3-pyridinyl]-3-phenyl-4(3/-/)- quinazolinone and 2,6-difluorobenzenesulfonyl chloride as described in example 51. H NMR (400 MHz, DMSO-af₆) δ ppm 10.55 (br. s., 1 H), 8.32 (br. s., 1 H), 8.00 (d, J=1.8 Hz, 1 H), 7.79 - 7.93 (m, 2 H), 7.71 (br. s., 1 H), 7.48 - 7.63 (m, 3 H), 7.30 - 7.42 (m, 3 H), 7.19 - 7.30 (m, 2 H), 6.38 (br. s., 2 H), 3.63 (s, 3 H). ES-LCMS: m/z = 536.09 (M+1).

Example 372

N-[5-(2-amino-4-oxo-3-phenyl-3,4-dihydro-6-quinazolinyl)-2-(methylo^

chlorobenzenesulfonamide

Prepared from 2-amino-6-[5-amino-6-(methyloxy)-3-pyridinyl]-3-phenyl-4(3W)- quinazolinone and 2-chlorobenzenesulfonyl chloride as described in example 51. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.13 {s, 1 H), 8.27 (s, 1 H), 7.96 (s, 1 H), 7.90 (d, J=7.8 Hz, 1 H), 7.85 (d, J=8.6 Hz, 1 H), 7.77 (s, 1 H), 7.44 - 7.72 (m, 6 H), 7.38 (d, J=8.2 Hz, 2 H), 7.32 (d, J=8.6 Hz, 1 H), 6.38 (br. s., 2 H), 3.67 (s, 3 H). ES-LCMS: m/z = 534.32 (M+1 ).

Example 373

N-[5-(2-amino-4-oxo-3-phenyl-3,4-dihydro-6-qum^' azo myl)-2-(me

[(diflu amide

Prepared from 2-amino-6-[5-amino-6-(methyloxy)-3-pyridinyl]-3-phenyl-4(3H)- quinazolinone and 3-[(difluoromethyl)oxy]benzenesulfonyl chloride as described in example 51. H NMR (400 MHz, DMSO-af₆) δ ppm 10.17 (s, 1 H), 8.29 (d, J=1.4 Hz, 1 H), 8.00 (d, J=2.1 Hz, 1 H), 7.86 (dd, J=8.6, 2.3 Hz, 1 H), 7.82 (d, J=2.1 Hz, 1 H), 7.50 - 7.68 (m, 6 H), 7.43 - 7.49 (m, 1 H), 7.26 - 7.41 (m, 4 H), 6.39 (br. s., 2 H), 3.65 (s, 3 H). ES-LCMS: m/z = 566.12 (M+1).

Example 374

N-[5-(2-amino-4-oxo-3-phenyl-3,4-dihydro-6-quinazolinyl)-2-(methyloxy

[(trifluoromethyl)oxyjbenzenesulfonamide

Prepared from 2-amino-6-[5-amino-6-(methyloxy)-3-pyridinyl]-3-phenyl-4(3/-/)- quinazolinone and 3-[(trifluoromethyl)oxy]benzenesulfonyl chloride as described in example 51. H NMR (400 MHz, DMSO-c/₆) δ ppm 10.24 (s, 1 H), 8.30 (br. s., 1 H), 8.01 (d, J=2.0 Hz, 1 H), 7.80 - 7.92 (m, 2 H), 7.64 - 7.78 (m, 4 H), 7.49 - 7.64 (m, 3 H), 7.38 (d, J=7.0 Hz, 2 H), 7.33 (d, J=8.6 Hz, 1 H), 6.38 (br. s., 2 H), 3.60 (s, 3 H). ES-LCMS: m/z = 584.31 (M+1).

Example 375

N-[5-(2-amino-4-oxo-3-phenyl-3,4-dihydro-6-quinazolinyl)-2-(methyloxy)-3-^^

( 1, 1- ide

Prepared from 2-amino-6-[5-amino-6-(methyloxy)-3-pyridinyl]-3-phenyl-4(3/-/)- quinazolinone and 3-(1 ,1 -dimethylethyl)benzenesulfonyl chloride as described in example 51. H NMR (400 MHz, DMSO-cf₆) δ ppm 9.92 (s, 1 H), 8.25 (s, 1 H), 7.99 (d, J=2.1 Hz, 1 H), 7.75 - 7.92 (m, 2 H), 7.63 - 7.71 (m, 2 H), 7.44 - 7.63 (m, 5 H), 7.29 - 7.42 (m, 3 H), 6.38 (br. s., 2 H), 3.64 (s, 3 H), 1.20 (s, 9 H). ES-LCMS: m/z = 556.39 (M+1).

Example 376

5-[2-amino-4-oxo-3-(tetrahydro-2H-pyran-4-yl)-3,4-dihydro-6-quinazolinyl]-N-(3- fluorophenyl)-2-(methyloxy)-3-pyridinesulfonamide

Prepared as described in example 37. ¹H NMR (400 MHz, DMSO-cfe) δ ppm 12.73 (br. s., 1 H), 10.69 (s, 1 H), 8.72 (s, 1 H), 8.37 (s, 1 H), 8.01 - 8.22 (m, 2 H), 7.88 (br. s., 1 H), 7.25 (br. s., 4 H), 6.90 - 7.06 (m, 2 H), 6.75 - 6.89 (m, 1 H), 4.38 (br. s., 1 H), 3.81 - 4.15 (m, 5 H), 3.39 - 3.52 (m, 1 H), 2.83 (br. s., 2 H), 1.58 (br. s., 2 H). ES-LCMS: rn/z = 526.39 (M+1 ).

Example 377

5-[2-amino-4-oxo-3-(tetrahydro-2H-pyran-4-yl)-3,4-dihydro-6-quinazolinyl]-N-(2- fluoroph amide

Prepared as described in example 37. ¹H NMR (400 MHz, DMSO- /₆) δ ppm 8.71 (s, 1 H), 8.19 (br. s., 2 H), 8.01 (s, 1 H), 7.73 - 7.88 (m, 1 H), 7.27 - 7.36 (m, 1 H), 7.23 (d, J=8.6 Hz, 1 H), 7.01 - 7.19 (m, 5 H), 4.39 (br. s., 1 H), 3.87 - 3.99 (m, 5 H), 3.39 - 3.53 (m, 2 H), 2.85 (br. s., 2 H), 1.48 - 1.68 (m, 2 H). ES-LCMS: m/z = 526.38 (M+1 ).

Example 378

N-[5-(2-amino-4-oxo-3^henyl-3,4-dihydro-6-quinazolinyl)-2-(methyloxy

(trifluoromethyl)benzenesulfonamide

Prepared from 2-amino-6-[5-amino-6-(methyloxy)-3-pyridinyl]-3-phenyl-4(3H)- quinazolinone and 3-(trifluoromethyl)benzenesulfonyl chloride as described in example 51. ¹H NMR (400 MHz, DMSO-cfe) δ ppm 10.29 (s, 1 H), 8.31 (br. s., 1 H), 7.95 - 8.12 (m, 4 H), 7.84 - 7.93 (m, 2 H), 7.77 - 7.83 (m, 1 H), 7.49 - 7.65 (m, 3 H), 7.28 - 7.43 (m, 3 H), 6.38 (br. s., 2 H), 3.57 (s, 3 H). ES-LCMS: m/z = 568.37 (M+1)

Example 379

N-[5-(2-amino-4-oxo-3-phenyl-3,4-dihydro-6-quinazolinyl)-2-(methylo^

methyl-1, -oxadiazol-2-yl)benzenesulfonamide

Prepared from 2-amino-6-[5-amino-6-(methyloxy)-3-pyridinyl]-3-phenyl-4(3H)- quinazolinone and 3-(5-methyl-1 ,3,4-oxadiazol-2-yl)benzenesulfonyl chloride as described in example 51. ¹H NMR (400 MHz, DMSO-d_e) δ ppm 12.70 (br. s., 1 H), 10.23 (br. s., 1 H), 8.36 (s, 1 H), 8.29 (s, 1 H), 8.18 - 8.25 (m, 1 H), 7.97 (s, 1 H), 7.93 (d, J=8.0 Hz, 1 H), 7.87 (dd, J=8.5, 1.9 Hz, 1 H), 7.74 - 7.85 (m, 2 H), 7.46 - 7.66 (m, 3 H), 7.29 - 7.43 (m, 3 H), 6.38 (br. s., 2 H), 3.62 (s, 3 H), 2.55 (s, 3 H). ES-LCMS: m/z = 582.38 (M+1 )

Example 380

N-[5-(2-amino-4-oxo-3-phenyl-3,4-dihydro-6-quinazolinyl)-2-(methyloxy)-3-pyrid

methyl-1H-pyrazol-5-yl)benzenesulfonamide

Prepared from 2-amino-6-[5-amino-6-(methyloxy)-3-pyridinyl]-3-phenyl-4(3H)- quinazolinone and 3-(1-methyl-1H-pyrazol-5-yl)benzenesulfonyl chloride as described in example 51. ¹H NMR (400 MHz, DMSO-cf₆) δ ppm 8.27 (d, J=2.0 Hz, 1 H), 8.14 (s, 1 H), 8.00 (d, J=2.3 Hz, 1 H), 7.75 - 7.90 (m, 5 H), 7.65 - 7.73 (m, 1 H), 7.57 - 7.63 (m, 2 H), 7.50 - 7.56 (m, 1 H), 7.49 (d, J=1.8 Hz, 1 H), 7.36 - 7.42 (m, 2 H), 7.32 (d, J=8.6 Hz, 1 H), 6.30 - 6.48 (m, 3 H), 3.76 (s, 3 H), 3.63 (s, 3 H). ES-LCMS: m/z = 580.30 (M+1)

Example 381

N-[5-(2-amino-4-oxo-3-phenyl-3,4-dihydro-6-quinazolinyl)-2-(methylox

methyl- -thiazol-4-yl)benzenesulfonamide

Prepared from 2-amino-6-[5-amino-6-(methyloxy)-3-pyridinyl]-3-phenyl-4(3/-/)- quinazolinone and 3-(2-methyl-1 ,3-thiazol-4-yl)benzenesulfonyl chloride as described in example 51. H NMR (400 MHz, DMSO-c/₆) δ ppm 9.85 - 10.37 (m, 1 H), 8.40 (s, 1 H), 8.10 - 8.27 (m, 2 H), 8.05 (s, 1 H), 7.99 (s, 1 H), 7.81 (br. s., 2 H), 7.65 - 7.73 (m, 1 H), 7.48 - 7.64 (m, 4 H), 7.38 (d, J=7.2 Hz, 2 H), 7.25 - 7.34 (m, 1 H), 6.38 (br. s., 2 H), 3.65 (s, 3 H), 2.70 (s, 3 H). ES-LCMS: m/z = 597.36 (M+1 )

Example 382

N-[5-(2-amino-4-oxo-3-phenyl-3,4-dihydro-6-quinazolinyl)-2-(methyloxy) methyl-1, -oxadiazol-3-yl)benzenesulfonamide

Prepared from 2-amino-6-[5-amino-6-(methyloxy)-3-pyridinyl]-3-phenyl-4(3/-/)- quinazolinone and 3-(5-methyl-1 ,2,4-oxadiazol-3-yl)benzenesulfonyl chloride as described in example 51. H NMR (400 MHz, DMSO-d₆) δ ppm 10.25 (br. s., 1 H), 8.41 (s, 1 H), 8.09 - 8.34 (m, 2 H), 7.98 (s, 1 H), 7.79 - 7.95 (m, 3 H), 7.70 - 7.79 (m, 1 H), 7.43 - 7.65 (m, 3 H), 7.38 (d, J=7.2 Hz, 2 H), 7.32 (d, J=8.6 Hz, 1 H), 6.38 (br. s., 2 H), 3.61 (s, 3 H), 2.66 (s, 3 H). ES-LCMS: m/z = 582.38 (M+1 ).

Example 383

N-[5-(2-amino-4-oxo-3-phenyl-3,4-dihydro-6-quinazolinyl)-2-(methyloxy)-3-pyridm

ide

Prepared from 2-amino-6-[5-amino-6-(methyloxy)-3-pyridinyl]-3-phenyl-4(3/-/)- quinazolinone and 4-[(2-cyanoethyl)oxy]benzenesulfonyl chloride as described in example 51. H NMR (400 MHz, DMSO-af₆) δ ppm 9.87 (br. s., 1 H), 8.57 (s, 1 H), 8.25 (s, 1 H), 7.95 (s, 1 H), 7.82 - 7.89 (m, 1 H), 7.66 - 7.80 (m, 3 H), 7.48 - 7.64 (m, 3 H), 7.28 - 7.46 (m, 3 H), 7.05 - 7.20 (m, 2 H), 6.40 (br. s., 2 H), 4.15 - 4.33 (m, 2 H), 3.73 (s, 3 H), 2.93 - 3.05 (m, 2 H). ES-LCMS: m/z = 569.23 (M+1 )

Example 384

N-[5-(2-amino-4-oxo-3-phenyl-3,4-dihydro-6-quinazolinyl)-2-(methyloxy)-3-^^

dimethyl-2, 4-dio -1, 2, 3, 4-tetrahydro-6-quinazolinesulfonamide

Prepared from 2-amino-6-[5-amino-6-(methyloxy)-3-pyridinyl]-3-phenyl-4(3/-/)- quinazolinone and 1 ,3-dimethyl-2,4-dioxo-1 ,2,3,4-tetrahydro-6-quinazolinesulfonyl chloride as described in example 51. H NMR (400 MHz, DMSO-d₆) δ ppm 10.19 (br. s., 1 H), 8.42 (s, 1 H), 8.26 (br. s., 1 H), 7.99 - 8.09 (m, 1 H), 7.93 (s, 1 H), 7.82 - 7.89 (m, 1 H), 7.78 (br. s., 1 H), 7.50 - 7.67 (m, 4 H), 7.28 - 7.43 (m, 3 H), 6.39 (br. s., 2 H), 3.69 (s, 3 H), 3.50 (s, 3 H), 3.26 (s, 3 H). ES-LCMS: m/z = 612.38 (M + 1 ).

Example 385

N-[5-({[5-(2-amino-4-oxo-3-phenyl-3,4-dihydro-6-quinazolinyl)-2-(methyloxy)-3- pyridinyl]a cetamide

Prepared from 2-amino-6-[5-amino-6-(methyloxy)-3-pyridinyl]-3-phenyl-4(3/-/)- quinazolinone and 3-(acetylamino)-4-(ethyloxy)benzenesulfonyl chloride as described in example 51. ¹H NMR (400 MHz, DMSO-c/₆) δ ppm 9.84 (s, 1 H), 9.17 (s, 1 H), 8.54 (s, 1 H), 8.22 (br. s., 1 H), 7.95 (s, 1 H), 7.83 (dd, J=8.4, 2.0 Hz, 1 H), 7.72 (s, 1 H), 7.49 - 7.65 (m, 3 H), 7.27 - 7.48 (m, 4 H), 7.15 (d, J=8.8 Hz, 1 H), 6.38 (br. s., 2 H), 4.09 - 4.24 (m, 2 H), 3.73 (s, 3 H), 2.09 (s, 3 H), 1.34 (t, J=6.9 Hz, 3 H). ES-LCMS: m/z = 601.29 (M + 1 ).

Example 386

N-[5-(2-amino-4-oxo-3-phenyl-3,4-dihydro-6-quinazolinyl)-2-(methy

Prepared from 2-amino-6-[5-amino-6-(methyloxy)-3-pyridinyl]-3-phenyl-4(3H)- quinazolinone and 3-chlorobenzenesulfonyl chloride as described in example 51. ¹H NMR (400 MHz, DMSO-afs) δ ppm 10.59 - 10.90 (m, 1 H), 8.71 (s, 1 H), 8.35 (d, J=2.0 Hz, 1 H), 8.07 (s, 1 H), 7.88 - 8.01 (m, 1 H), 7.47 - 7.71 (m, 3 H), 7.30 - 7.47 (m, 3 H), 6.96 - 7.29 (m, 4 H), 6.42 (br. s., 2 H), 3.98 (s, 3 H). ES-LCMS: m/z = 534.10 (M + 1 ).

Example 387

5-(2-amino-4-oxo-3-phenyl-3,4-dihydro-6-quinazolinyl)-2-ethyl-N-phenyl-3-

Step A

2-bromo-5-chloro-N-phenyl-3-pyridinesulfonamide

To a solution of 2-bromo-5-chloro-3-pyridinesulfonyl chloride (100 mg, 0.34 mmol), prepared in a manner similar as described in example 158 in dichloromethane (2.5 mL) was added aniline (0.04 mL, 0.4 mmol) and pyridine (0.03 mL, 0.4 mmol) and the reaction stirred at room temperature for 1 h. The solution was diluted with ethyl acetate and washed with 0.1 N HCI. The aqueous layer was treated with potassium carbonate and extracted with

dichloromethane. The combined organic layers were dried over MgS0₄ and evaporated. The residue was purified by reverse phase HPLC eluting with 10-90% acetonitrile/water/0.1 % formic acid to afford the title compound (81 mg, 68% yield). ES-LCMS: m/z = 346.90 (M + 1).

Step B

5-chloro-2-ethyl- -phenyl-3-pyridinesulfonamide

In a sealed tube was placed a solution of 2-bromo-5-chloro-N-phenyl-3- pyridinesulfonamide (80 mg, 0.23 mmol) in anhydrous dioxane (1.8 mL) to which was added PdCI₂dppf-CH₂CI₂ (19 mg, 0.020 mmol) and the solution degassed with nitrogen. A solution of diethylzinc (0.5 mL, 1M in hexanes) was added and the reaction heated to 75 °C for 1 h. The reaction was cooled to room temperature and quenched with water. The solution was partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with brine, dried over MgS0₄ and evaporated. The residue was purified by silica gel chromatography eluting with 10-50% hexanes/ethyl acetate to afford the title compound (53 mg, 78% yield). ES-LCMS: m/z = 297.03 (M + 1 ).

Step C

2-ethyl-N-phenyl-5-(4, 4, 5, 5-tetramethyl-1 , 3, 2-dioxaborolan-2-yl)-3-pyridinesulfonamide

A solution of 5-chloro-2-ethyl-N-phenyl-3-pyridinesulfonamide (49 mg, 0.17 mmol), dicyclohexyl[2,4,6-tris(1-methylethyl)phenyl]phosphane (16 mg, 0.03 mmol), Pd₂dba₃ (7 mg, 0.008 mmol), potassium acetate (48 mg, 0.5 mmol) and 4,4,4',4\ 5,5,5', 5'-octamethyl-2,2'-bi- 1 ,3,2-dioxaborolane (50 mg, 0.2 mmol) in dioxane was degassed with nitrogen and heated to 110 °C for 1.5 h. The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, brine and dried over MgS0₄ and evaporated to yield the title compound which was used without additional purification. ES-LCMS: m/z = 307.03 (M + 1 , boronic acid)

Step D

5-(2-amino-4-oxo-3^henyl-3,4-dihydro-6-quinazolinyi)-2-ethyi-N^heny

A solution of 2-amino-6-iodo-3-phenyl-4(3H)-quinazolinone (55 mg, 0.15 mmol), 2-ethyl- N-phenyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-3-pyridinesulfonamide (65 mg, 0.17 mmol), potassium acetate (45 mg, 0.45 mmol) and PdCI₂dppf-CH₂CI₂ (12 mg, 0.020 mmol) in dioxane (1.1 ml.) and water (0.4 mmol) was degassed with nitrogen and heated to 100 °C for 1h. The reaction is cooled to room temperature, evaporated and the residue purified by HPLC eluting with 10-90% acetonitrile/water/0.1 % formic acid to afford the title compound (31 mg, 41 % yield). ¹H NMR (400 MHz, DMSO-ci₆) δ ppm 10.81 (br. s., 1 H), 9.03 (d, J=1.2 Hz, 1 H), 8.36 (d, J=1.8 Hz, 1 H), 8.11 (d, J=1.8 Hz, 1 H), 7.97 (dd, J=8.6, 2.0 Hz, 1 H), 7.47 - 7.65 (m, 3 H), 7.32 - 7.45 (m, 3 H), 7.19 - 7.29 (m, 2 H), 7.1 1 (d, J=7.8 Hz, 2 H), 6.95 - 7.07 (m, 1 H), 6.47 (br. s., 2 H), 3.04 - 3.19 (m, 2 H), 1.23 (t, J=7.4 Hz, 3 H). ES-LCMS: m/z = 498.20 (M + 1 ).

Example 388 5-(2-amino-4-oxo-3-phenyl-3,4-dihydro-6-quinazolinyl)-N-(2,4-difluorophenyl)-2-

Prepared in a manner similar as described in example 387. H NMR (400 MHz, DMSO- Gfe) δ ppm 10.55 (s, 1 H), 9.08 (s, 1 H), 8.21 (d, J=2.0 Hz, 1 H), 8.08 (d, J=2.0 Hz, 1 H), 7.95 (dd, J=8.6, 2.1 Hz, 1 H), 7.46 - 7.69 (m, 3 H), 7.18 - 7.44 (m, 5 H), 6.98 - 7.1 1 (m, 1 H), 6.46 (br. s., 2 H), 3.11 (q, J=7.2 Hz, 2 H), 1.24 (t, J=7.4 Hz, 3 H). ES-LCMS: m/z = 534.12 (M + 1 )

Example 389

5-(2-amino-4-oxo-3-phenyl-3,4-dihydro-6-quinazolinyl)-N-(2,4-difluorophe

Prepared in a manner similar as described in example 387. H NMR (400 MHz, DMSO- /₆) δ ppm 10.53 (br. s., 1 H), 9.01 (s, 1 H), 8.17 (d, J=2.0 Hz, 1 H), 8.06 (d, J=2.1 Hz, 1 H), 7.93 (dd, J=8.6, 2.1 Hz, 1 H), 7.48 - 7.68 (m, 3 H), 7.18 - 7.44 (m, 5 H), 7.03 (br. s., 1 H), 6.46 (br. s., 2 H), 2.76 (s, 3 H). ES-LCMS: m/z = 520.09 (M + 1 )

Example 390

5-(2-amino-4-oxo-3^henyl-3,4-dihydro-6-quinazolinyl)-N-methyl-6'-(methyloxy)-2,^ bipyridine-3-sulfonamide

Step A

2-bromo-5-chloro-N-methyl-3-pyridinesulfonamide

To a solution of 2-bromo-5-chloro-3-pyridinesulfonyl chloride (275 mg, 0.95 mmol) prepared as described in example 158 in anhydrous THF (6 mL) cooled to 0 °C was added methylamine (1 mL, 2M in THF) and the reaction stirred for 5 minutes. The reaction was poured into ethyl acetate and washed with water, brine and dried over anhydrous MgS0₄ and evaporated to give the title compound which was used without additional purification (263 mg, 97%). ES-LCMS: m/z = 284.77 (M + 1 )

Step B

5-chloro-N-methyl- '-(methyloxy)-2,3'-bipyridine-3-sulfonamide

To a solution of 2-bromo-5-chloro-N-methyl-3-pyridinesulfonamide (130 mg, 0.46 mmol) in dioxane (2.5 mL) and water (0.83 mL) was added [6-(methyloxy)-3-pyridinyl]boronic acid (73 mg, 0.48 mmol), potassium acetate (134 mg, 1.40 mmol) and PdCI₂dppf-CH₂CI₂ (37 mg, 0.050 mmol) and the reaction degassed with nitrogen and heated to 75 °C for 1 h. Additional PdCI₂dppf-CH₂CI₂ (37 mg, 0.050 mmol) was added and the reaction heated to 100 °C for an additional hour. The reaction was cooled to room temperature, poured into ethyl acetate and washed with water, brine and dried over anhydrous MgS0₄ and evaporated. The residue was purified by silica gel chromatography eluting with 20-75% hexanes/ethyl acetate to afford the title compound (87 mg, 61 % yield). ES-LCMS: m/z = 314.00 (M +1 ) Step C

N-methyl-6'-(methyIoxy)-5-(4,4, 5, 5-tetramethyl- 1, 3,2-dioxaborolan-2-yI)-2,3'-bipyridine-3- sulfonamide

To a solution of 5-chloro-N-methyl-6'-(methyloxy)-2,3'-bipyridine-3-sulfonamide (67 mg, 0.22 mmol) in anhydrous dioxane (2 mL) was added 4,4,4^,,4^,,5,5,5',5'-octamethyl-2,2'-bi-1 ,3_I2- dioxaborolane (66 mg, 0.26 mmol) potassium acetate (63 mg, 0.65 mmol), Pd₂dba₃ (10 mg, 0.011 mmol) and dicyclohexyl[2,4,6-tris(1-methylethyl)phenyl]phosphane (20 mg, 0.040 mmol) and the solution degassed with nitrogen and heated to 75 °C for 1 h. The reaction is cooled to room temperature and poured into ethyl acetate, washed with water, brine, dried over anhydrous MgS0₄ and evaporated and used in subsequent reactions without additional purification. ES-LCMS: m/z = 323.95 (M + 1 , boronic acid)

Step D

5-(2-amino-4-oxo-3φhenyl-3,4-dihydro-6-quinazolinyl)-N-methyl-6'-(m

-sulfonamide.

To a solution of N-methyl-6'-(methyloxy)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-2,3'- bipyridine-3-sulfonamide (86 mg, 0.21 mmol) was added 2-amino-6-iodo-3-phenyl-4(3H)- quinazolinone (70 mg, 0.19 mmol), potassium acetate (57 mg, 0.58 mmol) and PdCI₂dppf- CH₂CI₂ (16 mg, 0.02 mmol) in dioxane (1.5 mL) and water (0.5 mmol) was degassed with nitrogen and heated to 100 °C for 1h. The reaction was cooled to room temperature, evaporated and the residue purified by reverse phase HPLC eluting with 10-90%

acetonitrile/water/0.1 % formic acid to afford the title compound (47 mg, 46% yield). H NMR (400 MHz, DMSO-d₆) δ ppm 9.22 (s, 1 H), 8.53 (s, 1 H), 8.42 (d, J=2.0 Hz, 1 H), 8.31 (s, 1 H), 8.05 - 8.24 (m, 2 H), 7.96 (dd, J=8.6, 2.3 Hz, 1 H), 7.88 (d, J=4.9 Hz, 1 H), 7.48 - 7.69 (m, 3 H), 7.34 - 7.47 (m, 3 H), 6.92 (d, J=8.6 Hz, 1 H), 6.50 (br. s., 2 H), 3.93 (s, 3 H), 2.45 (d, J=4.7 Hz, 3 H). ES-LCMS: m/z = 515.1 1 (M + 1 ).

Example 391

5-(2-amino-4-oxo-3-phenyl-3,4-dihydro-6-quinazolinyl)-N-methyl-2,3'-bipyri^

sulfonamide

Prepared in a manner similar as described in example 390. H N R (400 MHz, DMSO- cf₆) δ ppm 9.26 (d, J=2.0 Hz, 1 H), 8.77 (s, 1 H), 8.65 (d, J=3.9 Hz, 1 H), 8.57 (d, J=2.0 Hz, 1 H), 8.33 (d, J=2.1 Hz, 1 H), 8.14 (dd, J=8.8, 2.1 Hz, 1 H), 8.01 (dd, J=7.8, 1.8 Hz, 1 H), 7.88 - 7.96 (m, 1 H), 7.47 - 7.66 (m, 4 H), 7.33 - 7.47 (m, 3 H), 6.43 (br. s., 2 H), 2.46 (d, J=4.7 Hz, 3 H). ES-LCMS: m/z = 485.24 (M + 1 ).

Example 392

5-( 2-amino-4-oxo-3-phenyl-3,4-dihydro-6-quinazolinyl)-N-methyl-2, 2 '-bipyridine-3- sulfonamide

Step A

5-chloro-N-methyl-2, 2 '-bipyridine-3-sulfonamide

io a solution of 2-bromo-5-chloro-N-methyl-3-pyridinesulfonamide (140 mg, 0.49 mmol) (prepared as described in step A example 394) in anhydrous DMF (3 ml.) was added 2- pyridinylboronic acid (121 mg, 0.980 mmol), copper (I) chloride (48 mg, 0.49 mmol), cesium carbonate (319 mg, 0.980 mmol), palladium acetate (11 mg, 0.050 mmol) and DPPF (54 mg, 0.10 mmol) and the reaction degassed with nitrogen and heated to 100 °C for 3 h. The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, brine and dried over MgS0₄ and evaporated. The residue was purified by silica gel chromatography eluting with 15-75% hexanes/ethyl acetate to afford the title compound (55 mg, 40% yield). ES-LCMS: m/z = 283.97 (M + 1).

Step B

N-methyl-5-(4, 4, 5, 5-tetramethyl- 1, 3, 2-dioxaborolan-2- l)-2, 2'-bipyridine-3-sulfonamide

Prepared in a manner similar as described in Step C, example 390, except that the reaction was performed at 60 °C. ES-LCMS: m/z = 293.97 (M + 1 , boronic acid).

Step C

5-(2-amino-4-oxo-3^henyl-3, -dihydro-6-quinazolinyl)-N-methyl-2,2

Prepared in a manner similar as described in step D example 390 to afford the title compound (45 mg, 46% yield). ¹H NMR (400 MHz, DMSO-ck) δ ppm 9.29 (d, J=2.0 Hz, 1 H), 8.72 (s, 1 H), 8.56 (d, J=2.0 Hz, 1 H), 8.31 (s, 1 H), 8.11 - 8.27 (m, 2 H), 8.01 - 8.10 (m, 1 H), 7.90 - 8.01 (m, 1 H), 7.68 - 7.86 (m, 2 H), 7.50 - 7.68 (m, 4 H), 7.32 - 7.46 (m, 3 H), 6.55 (br. s., 2 H), 2.66 (d, J=4.9 Hz, 3 H). ES-LCMS: m/z = 485.22 (M + 1 ).

Example 393

5-(2-amino-4-oxo-3-phenyl-3,4-dihydro-6-quinazolinyl)-N,4'-dime

sulfonamide

Prepared in a manner similar as described in example 392. ¹H NMR (400 MHz, DMSO- cf₆) δ ppm 9.25 (d, J=2.1 Hz, 1 H), 8.57 (d, J=2.1 Hz, 1 H), 8.48 (br. s., 1 H), 8.24 - 8.42 (m, 2 H), 7.99 - 8.20 (m, 1 H), 7.65 - 7.83 (m, 1 H), 7.47 - 7.64 (m, 3 H), 7.28 - 7.47 (m, 4 H), 6.51 (br. s„ 2 H), 2.08 (s, 3 H), 2.01 (d, J=14.6 Hz, 3 H). ES-LCMS: m/z = 499.23 (M + 1

Example 394

N-{[5-(2-amino-4-oxo-3-phenyl-3,4-di ydro-6-quinazoHnyl)-2-(methyloxy)-3- namide

Step A

N-{[5-bromo-2-(methyloxy)-3 -2,2-dimethylpro ana

To a suspension of sodium hydride (25 mg, 0.62 mmol, 60% dispersion in mineral oil) in anhydrous DMF (0.5 mL) was added 5-bromo-2-(methyloxy)-3-pyridinesulfonamide (75 mg, 0.28 mmol) (see table 3) as a solution in DMF (1.5 mL) and the reaction stirred at room temperature for 15 minutes under nitrogen. To the solution was added 2,2-dimethylpropanoyl chloride (0.04 mL, 0.34 mmol) and the reaction stirred an additional hour at room temperature. The reaction was quenched with 1 N HCI and purified by reverse phase HPLC without workup, eluting with 10-90% acetonitrile/water/0.1% formic acid to afford the title compound (57 mg, 58% yield). ES-LC S: m/z = 350.95 ( + 1 )

Step B

2,2-dimethyl-N-{[2-(methyloxy)-5-(4 A5-tetramethyl-1,3,2-dioxab

pyridin l]sulfonyl}propanamide

To a solution of N-{[5-bromo-2-(methyloxy)-3-pyridinyl]sulfonyl}-2,2- di methyl propanamide (56 mg, 0.16 mmol) in anhydrous dioxane (1.6 mL) was added potassium acetate (47 mg, 0.48 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-1 ,3,2-dioxaborolane (49 mg, 0.19 mmol) and PdCI₂dppf-CH₂Cl2 (13 mg, 0.016 mmol) and the solution degassed with nitrogen and heated to 100 °C for 1 h. The reaction was poured into ethyl acetate and washed with an aqueous HCI solution (pH = 3), washed with brine, dried over anhydrous MgS0₄ and

evaporated to afford the title compound which was used without additional purification. ES- LCMS: m/z = 317.06 (M + 1 , boronic acid).

Step C

N-{[5-(2-amino-4-oxo-3 henyl-3 -dihydro-6-quinazoiinyl)-2-(methyίoxy)-3 y

-dimethylpropanamide

Prepared in a manner similar as described in step D, example 390 to afford the title compound (13 mg, 15% yield). H NMR (400 MHz, DMSO-cf₆) δ ppm 12.00 (br. s., 1 H), 8.81 (br. s., 1 H), 8.36 (br. s., 1 H), 8.11 (s, 1 H), 7.99 (d, J=10.2 Hz, 1 H), 7.50 - 7.69 (m, 4 H), 7.29 - 7.42 (m, 3 H), 6.43 (br. s., 2 H), 4.02 (s, 3 H), 1.09 (s, 9 H). ES-LCMS: m/z = 508.15 (M + 1) Example 395

N-{[5-(2-amino-4-oxo-3-phBnyl-3,4-dihydro-6-quinazolinyl)-2-(methyloxy)-3-

Prepared in a manner similar as described in example 394. H NMR (400 MHz, DMSO- d₆) δ ppm 12.65 (br. s., 1 H), 8.80 (s, 1 H), 8.48 (d, J=2.1 Hz, 1 H), 8.15 (d, J=2.0 Hz, 1 H), 8.02 (dd, J=8.5, 1.9 Hz, 1 H), 7.90 (d, J=7.6 Hz, 2 H), 7.51 - 7.67 (m, 4 H), 7.45 - 7.51 (m, 2 H), 7.41 (d, J=7.8 Hz, 3 H), 6.54 (br. s., 2 H), 3.99 (s, 3 H). ES-LCMS: m/z = 528.02 (M + 1 )

Example 396

5-(2-amino-4-oxo-3-phenyl-3,4-dihydro-6-quinazolinyl)-N-(cyclobutylmethyl)-N-hydroxy

To a solution of 5-(2-amino-4-oxo-3-phenyl-3,4-dihydro-6-quinazolinyl)-N- (cyclobutylmethyl)-2-(methyloxy)-N-[(phenylmethyl)oxy]-3-pyridinecarboxamide (90 mg, 0.16 mmol) prepared as described in example 401 , in ethanol (5 mL), was added 20% Pd(OH)₂ on carbon (10 mg) and the reaction mixture stirred under an atmosphere of hydrogen (50 psi) at room temperature for 1 h and then at 50 °C for 1 h. The reaction was filtered through celite and evaporated. The residue was purified by reverse phase HPLC eluting with 10-90%

acetonitrile/water/0.1% formic acid to afford the title compound (28 mg, 37% yield). H NMR (400 MHz, DMSO-d₆) δ ppm 9.69 (br. s., 1 H), 8.50 (br. s., 1 H), 8.16 (s, 1 H), 8.10 (d, J=2.0 Hz, 1 H), 7.96 (dd, J=8.6, 2.1 Hz, 1 H), 7.83 - 7.91 (m, 1 H), 7.44 - 7.66 (m, 3 H), 7.28 - 7.45 (m, 3 H), 6.37 (br. s., 2 H), 3.91 (br. s., 3 H), 3.70 (br. s., 2 H), 2.67 (br. s., 1 H), 2.05 (br. s., 2 H), 1.84 (br. s., 4 H). ES-LCMS: m/z = 472.17 (M + 1 ).

Example 397

5-(2-amino-4-oxo-3-phenyl-3,4-dihydro-6-quinazolinyl)-N-(cyclobutylmethyl)-2- (methyloxy)-N-[(phenylmethyl)oxy]-3-pyridinecarboxamide

Step A

N-(cyclobutylmethyl)-0-(phenylmethyl)hydroxylamine hydrochloride

To a suspension of sodium hydride (98 mg, 2.5 mmol, 60% dispersion in mineral oil) in anhydrous DMF (4 mL) was added 1 ,1-dimethylethyl [(phenylmethyl)oxy]carbamate (500 mg, 2.2 mmol) as a solution in DMF (7 mL) and the reaction was stirred at room temperature for 5 minutes under nitrogen. To the reaction was added (bromomethyl)cyclobutane (501 mg, 3.4 mmol) and the reaction stirred at room temperature for 2 h. The reaction was poured into ethyl acetate, washed with water, brine, dried over anhydrous MgS0₄ and evaporated. The residue was dissolved in anhydrous dichloromethane (22 mL) and 4N HCI in dioxane (5.6 mL) was added. The reaction was stirred at room temperature for 1 h. The reaction was evaporated and the residue triturated in ethyl acetate. Solids were filtered and dried to afford the title compound (424 mg, 83% yield). Step B

5-bromo-N-(cyclobutylmethyl)-2-(m ethy^

To a solution of N-(cyclobutylmethyl)-0-(phenylmethyl)hydroxylamine hydrochloride (206 mg, 0.9 mmol) in anhydrous dichloromethane (3.5 mL) was added 5-bromo-2-(methyloxy)-3- pyridinecarboxylic acid (175 mg, 0.750 mmol), triethylamine (0.4 mL, 3 mmol) and HATU (315 mg, 0.830 mmol) and the reaction stirred at room temperature for 2 h. The reaction was evaporated and the residue purified by silica gel chromatography eluting with 5-50%

hexanes/ethyl acetate to afford the title compound (163 mg, 53% yield). ES-LCMS: m/z = 405.08 (M + 1 ).

Step C

N-(cyclobutyimethyl)-2-(methyloxy)-N-[(phenylmethyl)oxy]-5-(4,4,5,5-tetramet^^

dioxaborolan-2- l)-3-pyridinecarboxamide

Prepared as described in step B of example 398. ES-LCMS: m/z = 453.21 (M + 1).

Step D

5-(2-amino-4-oxo-3 henyl-3 -dihydro-6-quinazolinyl)-N-(cyclobutyl^

[(phenylmethyl)oxy]-3-pyridinecarboxamide

Prepared as described in step D of example 390. H NMR (400 MHz, DMSO-af₆) δ ppm 12.74 (s, 1 H), 8.47 - 8.74 (m, 1 H), 8.05 - 8.20 (m, 1 H), 7.79 - 7.98 (m, 2 H), 7.46 - 7.68 (m, 2 H), 7.31 - 7.43 (m, 2 H), 7.21 (br. s., 4 H), 6.83 (br. s., 2 H), 6.39 (br. s., 1 H), 4.47 - 4.82 (m, 2 H), 3.86 (d, J=10.7 Hz, 5 H), 2.72 (br. s., 1 H), 2.03 (br. s., 2 H), 1.84 (br. s., 4 H). ES-LCMS: m/z = 562.20 ( + 1).

Example 398

5-{2-amino-4-oxo-3-[2-(trifluoromethyl)phenyl]-3,4-dihydro-6-quinazoli

N-( 1 -methyl- 1 H-pyrazol-5-yl)-3-pyridinesulfonamide

Step A

5-bromo-2-(methyloxy)-N-(1- 5-yl)-3φyridinesulfon

To a solution of 5-bromo-2-chloro-3-pyridinesulfonyl chloride (250 mg, 0.86 mmol), prepared as described in example 158 in dichloromethane (3 mL), was added pyridine (0.08 mL, 1.0 mmol) and 1-methyl-1/-/-pyrazol-5-amine (100 mg, 1.0 mmol) and the reaction stirred at room temperature for 3 h. The reaction was poured into ethyl acetate and washed with water, brine and dried over anhydrous MgS0₄ and evaporated. The residue was transferred to a sealed tube and dissolved in methanol (2 mL). Sodium methoxide (6.2 mL, 0.5 M in methanol) was added and the reaction heated to 90 °C for 18 h. The reaction was evaporated, diluted with ethyl acetate, washed with saturated NaHC0₃ solution, and the aqueous layer extracted with 15% isopropanol/dichloromethane. The combined organic extracts were dried over anhydrous MgS0₄ and evaporated to give the title compound (108 mg, 40% yield). ES-LCMS: m/z = 346.94 (M + 1 ).

Step B

2-(methyloxy)-N-(1-methyl-1H-pyrazol-5-yl)-5-(4, 4, 5, 5-tetramethyl-1 ,3, 2-dioxaborolan-2-yl)-3- ridinesulfonamide

Prepared in a manner similar as described in step B of example 394.

Step C

5-{2-amino-4-oxo-3-[2-(trifluoromethyl)phenyi]-3,4-dihydro-6-qui

methyl- 1 H-pyrazol-5-yl)-3-pyridinesulfonamide

To a solution of 2-(methyloxy)-N-(1-methyl-1 H-pyrazol-5-yl)-5-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)-3-pyridinesulfonamide (72 mg, 0.18 mmol) in dioxane (0.9 mL) and water (0.3 mL) was added 2-amino-6-iodo-3-[2-(trifluoromethyl)phenyl]-4(3/-/)-quinazolinone (68 mg, 0.16 mmol), prepared as described in step D, example 28, potassium acetate (46 mg, 0.47 mmol) and PdCI₂dppf-CH₂CI₂ (13 mg, 0.016 mmol). The reaction was degassed with nitrogen and heated to 100 °C for 1 h. The reaction was evaporated and the residue was purified by HPLC eluting with 10-90% acetonitrile/water/0.1% formic acid. Appropriate fractions were concentrated and the residue triturated in ethyl acetate. Solids were filtered and discarded. The filtrate was evaporated to give the title compound (19 mg, 18% yield). H NMR (400 MHz, DMSO-af₆) δ ppm 10.55 (br. s., 1 H), 8.79 (s, 1 H), 8.18 (d, J=2.5 Hz, 1 H), 8.03 (d, J=2.3 Hz, 1 H), 7.86 - 8.00 (m, 3 H), 7.70 - 7.83 (m, 1 H), 7.58 - 7.69 (m, 2 H), 7.34 (d, J=8.6 Hz, 1 H), 7.21 (s, 1 H), 6.66 (br. s., 2 H), 4.06 (s, 3 H), 3.55 - 3.74 (m, 3 H). ES-LCMS: m/z = 572.21 (M + 1 ).

Example 399

5-{2-amino-4-oxo-3-[2-(trifluoromethyl)phenyl]-3,4-dihydro-6-quin

N-(2- amide

Step A

5-bromo-2-(methyloxy) -( -thienylmethyl)-3-pyridinesulfonamide

To a solution of 5-bromo-2-chloro-3-pyridinesulfonyl chloride (250 mg, 0.86 mmol), prepared as described in example 158, in dichloromethane (3 ml_), cooled to 0 °C was added (2-thienylmethyl)amine (204 mg, 1.80 mmol) and the reaction stirred at 0 °C for 30 minutes. The reaction was poured into ethyl acetate, washed with water, brine, dried over anhydrous MgS0₄ and evaporated. The residue was transferred to a sealed tube, dissolved in methanol (2 ml_), sodium methoxide (7.3 ml_, 0.5 M in methanol) added, and the reaction heated to 90 °C overnight. The reaction was cooled to room temperature, evaporated, diluted with ethyl acetate, washed with aqueous NaHC0₃ solution, washed with brine, dried over anhydrous MgS0₄ and evaporated to afford the title compound (290 mg, 93% yield).

Step B 2-(methyloxy)-5-(4, 4, 5, 5-tetramethyl- 1, 3, 2-dioxaborolan-2-yl)-N-(2-thienylmethyl)-3- ridinesulfonamide

Prepared in a manner similar as described in step B of example 394. ES-LCMS: m/z = 410.99 (M + 1 ).

Step C

5-{2-amino-4-oxo-3-[2-(trifluoromethyl)phenyl]-3 -dihy

Prepared in a manner similar as described in step C of example 398. ¹H NMR (400 MHz, DMSO-cfe) δ ppm 8.64 (d, J=2.1 Hz, 1 H), 8.26 - 8.36 (m, 1 H), 8.15 (d, J=2.1 Hz, 1 H), 8.05 (s, 1 H), 7.85 - 8.00 (m, 3 H), 7.71 - 7.83 (m, 1 H), 7.64 (d, J=7.8 Hz, 1 H), 7.36 (d, J=8.6 Hz, 1 H), 7.26 (d, J=5.1 Hz, 1 H), 6.74 - 6.88 (m, 2 H), 6.66 (br. s., 2 H), 4.35 (d, J=6.1 Hz, 2 H), 3.98 (s, 3 H). ES-LCMS: m/z = 587.97 (M + 1).

Example 400

5-{2-amino-4-oxo-3-[2-(trifluoromethyl)phenyl]-3,4-dihydro-6-quinazolin

N-( 1-methyl-1H-pyrazol-4-yl)-3-pyridinesulfonamide

Prepared in a manner similar as described in example 398. H NMR (400 MHz, DMSO- d₆) δ ppm 9.79 (br. s., 1 H), 8.73 (d, J=2.3 Hz, 1 H), 8.19 (d, J=2.3 Hz, 1 H), 8.03 (d, J=2.1 Hz, 1 H), 7.93 - 8.00 (m, 2 H), 7.85 - 7.93 (m, 1 H), 7.73 - 7.82 (m, 1 H), 7.63 (d, J=7.8 Hz, 1 H), 7.49 (s, 1 H), 7.34 (d, J=8.6 Hz, 1 H), 7.09 (s, 1 H), 6.66 (br. s., 2 H), 4.06 (s, 3 H), 3.67 (s, 3 H). ES- LCMS: m/z = 571.92 (M + 1).

Example 401

5-{2-amino-4-oxo-3-[2-(trifluoromethyl)phenyl]-3,4-dihydro-6-qui

pyrazol-3- -2-(methyloxy)-3-pyridinesulfonamide

Prepared in a manner similar as described in example 398. H NMR (400 MHz, DMSO- c/₆) δ ppm 10.51 (br. s., 1 H), 8.72 (d, J=2.3 Hz, 1 H), 8.35 (d, J=2.3 Hz, 1 H), 8.07 (d, J=2.3 Hz, 1 H), 7.93 - 8.01 (m, 2 H), 7.84 - 7.93 (m, 1 H), 7.72 - 7.82 (m, 1 H), 7.63 (d, J=7.8 Hz, 1 H), 7.50 (d, J=2.3 Hz, 1 H), 7.35 (d, J=8.6 Hz, 1 H), 6.66 (br. s., 2 H), 5.89 (d, J=2.3 Hz, 1 H), 4.00 (s, 3 H), 3.85 - 3.97 (m, 2 H), 1.13 - 1.23 (m, 3 H). ES-LCMS: m/z = 586.29 (M + 1 ).

Example 402

2-amino-3-phenyl-6-{5-[(1-phenyl-1H-tetrazol-5-yl)amino]-3^yridinyl}-4(3H)- quinazolinone N

Step A

5-bromo-N-( 1 -phenyl- 1 H-tetrazol-5-yl)-3-pyridinam

To a solution of sodium amide (95 mg, 2.4 mmol) in anhydrous DMSO (3 mL) was added 5-bromo-3-pyridinamine (422 mg, 2.4 mmol) as a solution in DMSO (4 mL) and the reaction stirred at room temperature for 15 minutes under nitrogen. A solution of 5-chloro-1- phenyl-1 H-tetrazole (200 mg, 1.1 mmol) in DMSO (3 mL) and the reaction was stirred at room temperature for 1 h. The reaction was quenched with water, diluted with ethyl acetate, washed with dilute HCI, washed with water, washed with brine, dried over anhydrous MgS0₄ and evaporated. The residue was purified by silica gel chromatography eluting with 30-100% hexanes/ethyl acetate to afford the title compound (195 mg, 56% yield).

Step B

N-( 1 -phenyl- 1 H-tetrazol-5-yl)-5-(4, 4 5, 5-tetramethyl-1 ,3, 2-dioxaborolan-2-yl)-3-pyridinam

Prepared in a manner similar as described in step B of example 394. Step C

2-amino-3-phenyl-6-{5-[( 1 -phenyl- 1 H-tetrazol-5-yl)amino]-3-pyhdinyl}-4(3H)-

Prepared in a manner similar as described in step D of example 390. H NMR (400 MHz, DMSO-afs) δ ppm 9.69 (br. s., 1 H), 8.84 (br. s., 1 H), 8.60 (br. s., 1 H), 8.42 (s, 1 H), 8.17 (s, 2 H), 8.01 (d, J=8.6 Hz, 1 H), 7.48 - 7.81 (m, 7 H), 7.39 (d, J=7.0 Hz, 3 H), 6.43 (br. s., 2 H). ES- LCMS: m/z = 474.30 (M + 1 )

Example 403

2-amino-6-{6-(methyloxy)-5-[(1-phenyl-1H-tetrazol-5-yl)amino]-3^yrffl

p

Prepared in a manner similar as described in example 402. ¹H NMR (400 MHz, DMSO- cf₆) δ ppm 8.67 (s, 1 H), 8.39 (d, J=2.1 Hz, 1 H), 8.19 (d, J=2.1 Hz, 1 H), 8.09 (d, J=2.1 Hz, 1 H), 7.93 (dd, J=8.6, 2.3 Hz, 1 H), 7.48 - 7.74 (m, 8 H), 7.30 - 7.44 (m, 3 H), 6.37 (br. s., 2 H), 3.91 (s, 3 H). ES-LCMS: m/z = 504.33 (M + 1 ).

Example 404

5-(2-amino-4-oxo-3-phenyl-3,4-dihydro-6-quinazolinyl)-2-(methyloxy)-N^

pyrazol-4-yl)-3-pyridinesulfonamide

Prepared in a manner similar as described in example 398. H NMR (400 MHz, DMSO- d₆) δ ppm 9.80 (br. s., 1 H), 8.73 (d, J=2.5 Hz, 1 H), 8.16 - 8.24 (m, 1 H), 8.05 (d, J=2.3 Hz, 1 H), 7.93 (dd, J=8.6, 2.3 Hz, 1 H), 7.51 - 7.65 (m, 3 H), 7.49 (s, 1 H), 7.29 - 7.41 (m, 3 H), 7.09 (s, 1 H), 6.41 (br. s., 2 H), 4.06 (s, 3 H), 3.67 (s, 3 H). ES-LCMS: m/z = 504.14 (M + 1 ).

Example 405

5-(2-amino-4-oxo-3^henyl-3,4-dihydro-6-quinazolinyl)-2-(methyloxy)-N-(2-th

-pyridinesulfonamide

Prepared in a manner similar as described in example 399. H NMR (400 MHz, DMSO- cf₆) δ ppm 8.63 (d, J=2.3 Hz, 1 H), 8.24 - 8.39 (m, 1 H), 8.14 (d, J=2.3 Hz, 1 H), 8.07 (d, J=2.0 Hz, 1 H), 7.93 (dd, J=8.6, 2.3 Hz, 1 H), 7.49 - 7.70 (m, 3 H), 7.32 - 7.47 (m, 3 H), 7.22 - 7.30 (m,

1 H), 6.84 (d, J=2.5 Hz, 1 H), 6.77 (dd, J=5.0, 3.4 Hz, 1 H), 6.41 (br. s., 2 H), 4.36 (d, J=5.3 Hz,

2 H), 3.99 (s, 3 H). ES-LCMS: m/z = 520.26 (M + 1 ).

Example 406

5-(2-amino-4-oxo-3-phenyl-3,4-dihydroquinazolin-6-yl)-N-(2-fluorophenyl)-2- methoxypyridine-3-sulfonamide

A mixture of N-(2-fluorophenyl)-2-methoxy-5-(4,4,5,5-tetramethyl-1 ,3,2-clioxaborolan-2- yl)pyridine-3-sulfonamide (94 mg, 0.23 mmol), 2-amino-6-iodo-3-phenyl-4(3H)-quinazolinone (70 mg, 0.19 mmol), PdCI₂(dppf)-CH₂CI₂ adduct(15mg, 0.019 mmol), and potassium

acetate(56.8 mg, 0.578 mmol) in 1 ,2-Dimethoxyethane (DME) (2 ml_) was added water(0.5 mL). Then the flask was sealed and purged with N2 (3 times) before heated to 80 °C overnight. The mixture was cooled down to room temperature and it was filtered through celite and the celite was washed with EtOAc and MeOH. The filtrate was concentrated in vacuum and the residue was purified by flash chromatography on silica gel (10 % MeOH/EtOAc) to give the titile compound (51 mg, 49%) as a grey solid. MS (m/z) ES+ 518 (M+H). ¹H NMR (400 MHz, DMSO- cfe) δ ppm 10.22 (s, 1 H) 8.17 (d, J=2.34 Hz, 1 H) 8.01 (d, J=2.34 Hz, 1 H) 7.92 (d, J=2.34 Hz, 0 H) 7.89 (d, J=2.34 Hz, 1 H) 7.48 - 7.66 (m, 3 H) 7.28 - 7.40 (m, 4 H) 7.08 - 7.20 (m, 3 H) 6.28 - 6.53 (m, 2 H) 3.96 (s, 3 H)

Examples 407 to 410 were prepared using similar procedure as Example 406 by varying the choice of boronic esters.

Example 407

5-(2-amino-4-oxo-3^henyl-3,4-dihydroquinazolin-6-yl)-2-methoxypyridine-3-

Grey solid, 16 mg, 19%. MS (m/z) ES+ 424 (M+H); H NMR (400 MHz, DMSO-c/₆) δ ppm 8.72 (d, J=2.54 Hz, 1 H) 8.29 (d, J=2.34 Hz, 1 H) 8.10 (d, J=2.34 Hz, 1 H) 7.97 (dd, J=8.59, 2.34 Hz, 1 H) 7.50 - 7.62 (m, 3 H) 7.46 (s, 2 H) 7.34 - 7.41 (m, 3 H) 6.26 - 6.54 (m, 2 H) 4.04 (s, 3 H).

Example 408

5-(2-amino-4-oxo-3-phenyl-3,4-dihydroquinazolin-6-yl)-2-methoxy-N-(2- meth ulfonamide

Grey solid, 64 mg, 54%; MS (m/z) ES+ 530 (M+H); H NMR (400 MHz, DMSO-d₆) δ ppm 9.36 (s, 1 H) 8.70 (d, J=2.34 Hz, 1 H) 8.12 (d, J=2.34 Hz, 1 H) 7.98 (d, J=2.34 Hz, 1 H) 7.88 (dd, J=8.59, 2.34 Hz, 1 H) 7.50 - 7.61 (m, 3 H) 7.23 - 7.40 (m, 4 H) 7.06 - 7.14 (m, 1 H) 6.82 - 6.95 (m, 2 H) 6.24 - 6.56 (m, 2 H) 4.01 (s, 3 H) 3.54 (s, 3 H).

Example 409

5-(2-amino-4-oxo-3-phenyl-3,4-dihydroquinazolin-6-yl)-N-(3-fluorophenyl)-2- meth namide

Grey solid, 3.6 mg, 4%; MS (m/z) ES+ 518 (M+H); H NMR (400 MHz, DMSO-af₆) δ ppm 10.71 (s, 1 H) 8.73 (d, J=1.95 Hz, 1 H) 8.36 (d, J=2.34 Hz, 1 H) 8.07 (d, J=2.15 Hz, 1 H) 7.95 (dd, J=8.68, 2.24 Hz, 1 H) 7.51 - 7.64 (m, 3 H) 7.32 - 7.41 (m, 3 H) 7.21 - 7.29 (m, 1 H) 6.96 (br. s., 2 H) 6.83 (br. s., 1 H) 6.43 (br. s., 2 H) 3.99 (s, 3 H).

Example 410 5-(2-amino-4-oxo-3-phenyl-3,4-dihydroquinazolin-6-yl)-2-methoxy-N-(4- methoxyph uffonamide

Grey solid, 50 mg, 46%; MS (m/z) ES+ 530 (M+H); ¹H NMR (400 MHz, DMSO-cf₆) δ ppm 10.04 (s, 1 H) 8.70 (d, =2.34 Hz, 1 H) 8.20 (d, J=2.54 Hz, 1 H) 8.02 (d, J=2.34 Hz, 1 H) 7.90 (dd, J=8.68, 2.24 Hz, 1 H) 7.50 - 7.62 (m, 3 H) 7.34 (dd, 7=18.63, 7.90 Hz, 3 H) 7.03 (d, 7=8.98 Hz, 2 H) 6.78 (d, J=8.98 Hz, 2 H) 6.39 (none, 2 H) 4.03 (s, 3 H) 3.33 (s, 3 H).

General Scheme 23

Example 411

N-(6-(5-(2,4-difluorophenylsulfonamido)-6-methoxypyridin-3-yl)-4-oxo-3,4- dihydroquinazolin-2-yl)benzamide

Step A

N-(6-bromo-4-oxo-3,4-dihydroquinazolin-2-yl)benzamide

Methyl 2-amino-5-bromobenzoate(2.99g,13mmol) was dissolved in 60 ml of DMF and benzoylcyanamide (1.9 g, 13 mmol) was added. The solution was stirred and heated at 90-95 °C for 5 hr. The solution was then concentrated (in vacuo) to afford the crude product which was then washed with diethyl ether and afford the white product.

ES-LCMS: m/z 344, 346 (M+1 ).

Step B

N-(6-(5-(2 -difluorophenylsuifonamido)-6- ethoxypyridin-3-yi)-4-ox

A mixture of N-(6-bromo-4-oxo-3,4-dihydroquinazolin-2-yl)benzamide (60 mg, 0.174 mmol), 2 2,4-difluoro-N-(2-methoxy-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridin-3- yl)benzenesulfonamide (89 mg, 0.209 mmol), PdCI₂(dppf)-CH₂CI₂ adduct(14mg, 0.017 mmol), and potassium acetate(51.3 mg, 0.523 mmol) in 1 ,2-Dimethoxyethane (DME) (2 mL) was added water(0.5 mL). Then the flask was sealed and purged with N₂ (3 times) before heated to 80 °C overnight. The mixture was cooled down to room temperature and it was filtered through celite and the celite was washed with EtOAc and MeOH. The filtrate was concentrated in vacuum and the residue was purified by flash chromatography on silica gel (10 % MeOH/EtOAc) to give the titile compound (54 mg, 55%) as a grey solid.

MS (m/z) ES+ 564 (M+H); ¹H NMR (400 MHz, DMSO- /₆) δ ppm 12.36 (br. s., 1 H) 11.95 (br. s., 1 H) 10.36 (s, 1 H) 8.42 (br. s., 1 H) 8.03 - 8.26 (m, 4 H) 7.77 (td, J=8.49, 6.44 Hz, 1 H) 7.17 - 7.25 (m, 1 H) 3.67 (s, 3 H)

General Scheme 24

Example 412

5-(2-amino-4-oxo-3-phenyl-3,4-dihydroquinazolin-6-yl)-2-methoxy-N-

Step A

5-bromo- tinic acid

To a solution of methyl methyl 5-bromo-2-methoxynicotinate (2 g, 8.13 mmol) in mixture solvent of Methanol (8 ml_), THF (4 ml.) and H₂0 (2 mL) was added lithium hydroxide (234 mg, 9.75 mmol). The reaction mixture was stirred at 25 °C overnight. The reaction was concentrated in vacuo to afford the crude product, which was used directly for the next step without purification. ES-LCMS: m/z 232, 234 (M+H).

Step B

5-bromo-2-methoxy-N-(methylsulfonyl)nicotinamide

HATU (3.28 g, 8.62 mmol) was added to a mixture of 5-bromo-2-methoxynicotinic acid (1 g, 4.31 mmol), methanesulfonamide (533mg, 5.6 mmol) and DIPEA (2.25 mL, 12.93 mmol) in N,N- Dimethylformamide (DMF) (10 mL). The reaction mixture was stirred at 25 °C for 12 h. After it was concentrated in vacuum, the crude product was loaded on to column and eluted with EtOAc/hexane from 0-100% to afford the desired product. ES-LCMS: m/z 309, 31 1 (M+H).

Step C

2-methoxy-N-(methyisulfonyl)-5-(4, 4, 5, 5-tetramethyt-1 ,3, 2-dioxaborotan-2-yl)nicotinamide

To a solution of 5-bromo-2-methoxy-N-(methylsulfonyl)nicotinamide (1.4 g, 4.53 mmol) in 1 ,4- dioxane (12 mL) was added 4,4,4',4^,,5,5,5',5'-octamethyl-2,2'-bi-1 ,3,2-dioxaborolane (1.725 g, 6.79 mmol), potassium acetate (1.333 g, 13.59 mmol) and PdCI2(dppf)-CH2CI2 adduct (370 mg, 0.453 mmol). The reaction mixture was stirred at 100 °C overnight. The reaction was concentrated in vacuo, purified on silica using 50% ethyl acetate/ hexane to yield the title compound as a white solid. ES-LCMS: m/z 357 (M+H).

Step D

5-(2-amino-4-oxo-3-phenyl-3,4-dihydroquinazolin-6-yl)-2-methoxy-N-

To a solution of 2-amino-6-iodo-3-phenyl-4(3H)-quinazolinone (50 mg, 0.138 mmol) in 1 ,4- dioxane (2 mL) and water (0.5 mL) was added 2-methoxy-N-(methylsulfonyl)-5-(4 ,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)nicotinamide (58.9 mg, 0.165 mmol), potassium acetate (40.5 mg, 0.413 mmol) and PdCI₂(dppf)-CH₂CI₂ adduct (1 1.24 mg, 0.014 mmol). The reaction mixture was stirred at 85 °C overnight. The reaction was concentrated in vacuum, purified on silica column by using 10% methanol in EtOAc to yield the title compound as a white solid (15 mg, 22 %). ES-LCMS: m/z 466 (M+1 ); ¹H NMR (400 MHz, DMSO-af₆) δ ppm 1 1.99 (br. s., 1 H) 8.68 (d, 1 H) 8.27 (d, J=2.54 Hz, 1 H) 8.18 (d, J=2.15 Hz, 1 H) 8.00 (dd, J=8.59, 2.34 Hz, 1 H) 7.50 - 7.63 (m, 4 H) 7.37 (dd, J=1 1 .12, 7.80 Hz, 3 H) 6.40 (d, J=1 .95 Hz, 2 H) 3.98 (s, 3 H) 3.37 (s, 3 H).

Example 413 and 414 were synthesized using similar steps as described for Example 412

Example 413

5-(2-amino-4-oxo-3-phenyl-3,4-dihydroquinazolin-6-yl)-N-(methylsulfony

ES-LCMS: m/z 436 (M+1 ); ¾ NMR (400 MHz, CHLOROFORM-i ) δ ppm 9.17 (d, J=l .37 Hz, 1 H) 9.02 (s, 1 H) 8.30 (s, 1 H) 8.12 (s, 1 H) 7.54-7.66 (m, 3 H) 7.42 (d, 2 H) 7.22 (br. s., 1 H) 5.45(br s., 2 H) 3.51 (s, 3 H)

Example 414

5-(2-amino-4-oxo-3-phenyl-3,4-dihydroquinazolin

(cyclopropylsulfonyl)nicotinamide

GSK2824823A

N 18786-92-1

ES-LCMS: m/z 462 (M+1 ); H NMR (400MHz ,METHANOL-d₄) d = 9.94 (d, J = 2.0 Hz, 1 H), 9.79 (d, J = 1 .9 Hz, 1 H), 9.39 (t, J = 2.0 Hz, 1 H), 9.12 (d, J = 2.2 Hz, 1 H), 8.91 (dd, J = 2.2, 8.6 Hz, 1 H), 8.46 - 8.27 (m, 3 H), 8.24 - 8.11 (m, 3 H), 7.37 (br. s., 2 H), 4.01 - 3.88 (m, 1 H), 2.07 1.80 (m, 4 H)

General Scheme 25

Example 415

2-amino-6-(3-methyl-1,1-dioxido-4H-pyrido[2,3-effl

e

Step A

2-amino-5-bromopyridine-3-sulfonamide (1g, 3.97 mmol) was dissolved in 1 ,1 ,1-triethoxyethane (12.87 g, 79 mmol). The reaction mixture was stirred at 150 °C overnight. After cooled to room temperature, the precipitate was filtrated and washed with ether to afford the desired compound as white solid (800mg, 95%) which was used without further purification in the next step. MS (ES+) m/z 276, 268

Step B

To a solution of 7-bromo-3-methyl-4H-pyrido[2,3-e][1 ,2,4]thiadiazine 1 ,1 -dioxide (88 mg, 0.319 mmol), 4,4,4',4', 5,5,5', 5'-octamethyl-2,2'-bi(1 ,3,2-dioxaborolane) (89 mg, 0.351 mmol) and potassium acetate (94 mg, 0.956 mmol) in 1 ,4-Dioxane (2 ml.) stirred under nitrogen at room temp was added PdCI2(dppf)-CH2CI2 adduct (26.0 mg, 0.032 mmol). The reaction mixture was stirred at 100 °C overnight. The mixture was cooled to rt and loaded onto the silical column and eluted with EtOAc/hexane from 0-100% to afford the title compound (66.7mg, 65%). MS (ES+) m/z 242 (corresponding boronic acid) ;

Step C

3-methyl-7-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-4H-pyrido[2,3-e][1 ,2,4]thiadiazine 1 ,1- dioxide (66.7mg), 3-methyl-7-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-4H-pyrido[2,3- e][1 ,2,4]thiadiazine 1 ,1-dioxide (50mg), PdCI2(dppf)-CH2CI2 (11.2mg) and potassium acetate were suspended in dioxane (2ml_) and water (0.5mL). The mixture was heated under nitrogen at 100 degC in a microvawe reactor. The reaction mixture was filtered and evaporated followed by purification with RP-HPLC to afford 2-amino-6-(3-methyl-1 ,1 -dioxido-4H-pyrido[2,3- e][1 ,2,4]thiadiazin-7-yl)-3-phenylquinazolin-4(3H)-one {8mg (12.7%) as a white solid. MS (ES+) m/z 433 ; ¾ NMR (400MHz ,DMSO-d₆) δ = 12.81 (br. s., 1 H), 9.06 (d, J= 2.1 Hz, 1 H), 8.50 (s, 1 H), 8.23 (d, J= 2.2 Hz, 1 H), 8.09 (dd, J= 2.3, 8.7 Hz, 1 H), 7.66 - 7.47 (m, 3 H), 7.46 - 7.25 (m, 3 H), 6.66 - 6.29 (m, 2 H), 2.34 (s, 3 H)

Example 416

2-amino-6-( 1, 1-dioxido-4H-pyrido[2,3-e][ 1,2,4]thiadiazin-7-yl)-3-phenylquinazolin-

4(3H)-one

The title molecule has been synthesized as described for Example 415.

MS (ES+) m/z 419 ; *H NMR (400MHz ,DMSO-d₆) δ = 12.96 (br. s., 1 H), 9.10 (d, J= 2.2 Hz, 1 H), 8.58 (d, J= 2.2 Hz, 1 H), 8.26 (d, J= 2.2 Hz, 1 H), 8.17 - 8.06 (m, 2 H), 7.68 - 7.50 (m, 3 H), 7.46 - 7.32 (m, 3 H), 6.49 (br. s., 2 H).

Administration and Formulation

[00506] The chemical entities provided herein may inhibit viral replication by inhibiting the enzymes involved in replication, such as the non-structural proteins including RNA dependent RNA polymerase. They may also inhibit other enzymes utilized in the activity or proliferation of viruses in the Flaviviridae family, such as HCV. The chemical entities are administered at a therapeutically effective dosage, e.g., a dosage sufficient to provide treatment for the disease.

[00507] In another embodiment, there is provided a pharmaceutical composition comprising a pharmaceutically acceptable diluent and a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[00508] The compounds of the present invention can also be supplied in the form of a pharmaceutically acceptable salt. The terms "pharmaceutically acceptable salt" refer to salts prepared from pharmaceutically acceptable inorganic and organic acids and bases.

[00509] Pharmaceutically acceptable inorganic bases include metallic ions. More preferred metallic ions include, but are not limited to, appropriate alkali metal salts, alkaline earth metal salts and other physiological acceptable metal ions. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like and in their usual valences. Exemplary salts include aluminum, calcium, lithium, magnesium, potassium, sodium and zinc. Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts.

[00510] Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, including in part, trimethylamine, diethylamine, N, N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine; substituted amines including naturally occurring substituted amines; cyclic amines; quaternary ammonium cations; and basic ion exchange resins, such as arginine, betaine, caffeine, choline, Ν,Ν-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N- ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like.

[00511] Illustrative pharmaceutically acceptable acid addition salts of the compounds of the present invention can be prepared from the following acids, including, without limitation formic, acetic, propionic, benzoic, succinic, glycolic, gluconic, lactic, maleic, malic, tartaric, citric, nitic, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, hydrochloric, hydrobromic, hydroiodic, isocitric, trifluoroacetic, pamoic, propionic, anthranilic, mesylic, oxalacetic, oleic, stearic, salicylic, p-hydroxybenzoic, nicotinic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, phosphoric, phosphonic, ethanesulfonic, benzenesulfonic, pantothenic, toluenesulfonic, 2-hydroxyethanesulfonic, sulfanilic, sulfuric, salicylic,

cyclohexylaminosulfonic, algenic, β-hydroxybutyric, galactaric and galacturonic acids. Preferred pharmaceutically acceptable salts include the salts of hydrochloric acid and trifluoroacetic acid. All of the above salts can be prepared by those skilled in the art by conventional means from the corresponding compound of the present invention. For example, the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. The salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent. The degree of ionisation in the salt may vary from completely ionised to almost non-ionised. Lists of suitable salts are found in Remington's Pharmaceutical Sciences. 17th ed., Mack Publishing Company, Easton, Pa., 1985, p.1418, the disclosure of which is hereby incorporated by reference only with regards to the lists of suitable salts.

[00512] The compounds of the invention may exist in both unsolvated and solvated forms. The term 'solvate' is used herein to describe a molecular complex comprising the compound of the invention and one or more pharmaceutically acceptable solvent molecules, for example, ethanol. The term 'hydrate' is employed when said solvent is water. Pharmaceutically acceptable solvates include hydrates and other solvates wherein the solvent of crystallization may be isotopically substituted, e.g. D₂0, d₆-acetone, d₆-DMSO.

[00513] Compounds of formula (I) containing one or more asymmetric carbon atoms can exist as two or more stereoisomers. Where a compound of formula (I) contains an alkenyl or alkenylene group or a cycloalkyl group, geometric cis/trans (or Z/E) isomers are possible.

Where the compound contains, for example, a keto or oxime group or an aromatic moiety, tautomeric isomerism ('tautomerism') can occur. It follows that a single compound may exhibit more than one type of isomerism.

[00514] Included within the scope of the claimed compounds present invention are all stereoisomers, geometric isomers and tautomeric forms of the compounds of formula (I), including compounds exhibiting more than one type of isomerism, and mixtures of one or more thereof. Also included are acid addition or base salts wherein the counterion is optically active, for example, D-lactate or L-lysine, or racemic, for example, DL-tartrate or DL-arginine.

[00515] Cis/trans isomers may be separated by conventional techniques well known to those skilled in the art, for example, chromatography and fractional crystallisation.

[00516] Conventional techniques for the preparation/isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid

chromatography (HPLC).

[00517] Alternatively, the racemate (or a racemic precursor) may be reacted with a suitable optically active compound, for example, an alcohol, or, in the case where the compound of formula (I) contains an acidic or basic moiety, an acid or base such as tartaric acid or 1 - phenylethylamine. The resulting diastereomeric mixture may be separated by chromatography and/or fractional crystallization and one or both of the diastereoisomers converted to the corresponding pure enantiomer(s) by means well known to a skilled person. [00518] Chiral compounds of the invention (and chiral precursors thereof) may be obtained in enantiomerically-enriched form using chromatography, typically HPLC, on a resin with an asymmetric stationary phase and with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from 0 to 50% isopropanol, typically from 2 to 20%, and from 0 to 5% of an alkylamine, typically 0.1 % diethylamine. Concentration of the eluate affords the enriched mixture.

[00519] Mixtures of stereoisomers may be separated by conventional techniques known to those skilled in the art. [see, for example, "Stereochemistry of Organic Compounds" by E L Eliel (Wiley, New York, 1994).]

[00520] The present invention includes all pharmaceutically acceptable isotopically- labelled compounds of formula (I) wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature.

[00521] Examples of isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, such as ²H and ³H, carbon, such as ¹C, ³C and ⁴C, chlorine, such as ³⁶CI, fluorine, such as ¹⁸F, iodine, such as ²³l and ¹²⁵l, nitrogen, such as ³N and ¹⁵N, oxygen, such as ^1sO, ¹⁷0 and ⁸0, phosphorus, such as ³²P, and sulphur, such as ³⁵S.

[00522] Certain isotopically-labelled compounds of formula (I), for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies. The radioactive isotopes tritium, i.e. ³H, and carbon-14, i.e. ⁴C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.

[00523] Substitution with heavier isotopes such as deuterium, i.e. ²H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.

[00524] Isotopically-labelled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using an appropriate isotopically- labelled reagents in place of the non-labelled reagent previously employed.

[00525] The compounds of the present invention may be administered as prodrugs. Thus, certain derivatives of compounds of formula (I) which may have little or no

pharmacological activity themselves can, when administered into or onto the body, be converted into compounds of formula (I) having the desired activity, for example, by hydrolytic cleavage. Such derivatives are referred to as 'prodrugs'. [00526] Administration of the chemical entities described herein can be via any of the accepted modes of administration for agents that serve similar utilities including, but not limited to, orally, sublingually, subcutaneously, intravenously, intranasally, topically, transdermally, intraperitoneally, intramuscularly, intrapulmonarilly, vaginally, rectally, or intraocularly. In some embodiments, oral or parenteral administration is used.

[00527] Pharmaceutical compositions or formulations include solid, semi-solid, liquid and aerosol dosage forms, such as, e.g., tablets, capsules, powders, liquids, suspensions, suppositories, aerosols or the like. The chemical entities can also be administered in sustained or controlled release dosage forms, including depot injections, osmotic pumps, pills, transdermal (including electrotransport) patches, and the like, for prolonged and/or timed, pulsed

administration at a predetermined rate. In certain embodiments, the compositions are provided in unit dosage forms suitable for single administration of a precise dose.

[00528] The chemical entities described herein can be administered either alone or more typically in combination with a conventional pharmaceutical carrier, excipient or the like (e.g., mannitol, lactose, starch, magnesium stearate, sodium saccharine, talcum, cellulose, sodium crosscarmellose, glucose, gelatin, sucrose, magnesium carbonate, and the like). If desired, the pharmaceutical composition can also contain minor amounts of nontoxic auxiliary substances such as wetting agents, emulsifying agents, solubilizing agents, pH buffering agents and the like (e.g., sodium acetate, sodium citrate, cyclodextrine derivatives, sorbitan monolaurate, triethanolamine acetate, triethanolamine oleate, and the like). Generally, depending on the intended mode of administration, the pharmaceutical composition will contain about 0.005% to 95%; in certain embodiments, about 0.5% to 50% by weight of a chemical entity. Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pennsylvania.

[00529] In certain embodiments, the compositions will take the form of a pill or tablet and thus the composition will contain, along with the active ingredient, a diluent such as lactose, sucrose, dicalcium phosphate, or the like; a lubricant such as magnesium stearate or the like; and a binder such as starch, gum acacia, polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives or the like. In another solid dosage form, a powder, marume, solution or suspension (e.g., in propylene carbonate, vegetable oils or triglycerides) is encapsulated in a gelatin capsule.

[00530] Liquid pharmaceutically administrable compositions can, for example, be prepared by dissolving, dispersing, etc. at least one chemical entity and optional pharmaceutical adjuvants in a carrier (e.g., water, saline, aqueous dextrose, glycerol, glycols, ethanol or the like) to form a solution or suspension. Injectables can be prepared in conventional forms, either as liquid solutions or suspensions, as emulsions, or in solid forms suitable for dissolution or suspension in liquid prior to injection. The percentage of chemical entities contained in such parenteral compositions is highly dependent on the specific nature thereof, as well as the activity of the chemical entities and the needs of the subject. However, percentages of active ingredient of 0.01 % to 10% in solution are employable, and will be higher if the composition is a solid which will be subsequently diluted to the above percentages. In certain embodiments, the composition will comprise from about 0.2 to 2% of the active agent in solution.

[00531] Pharmaceutical compositions of the chemical entities described herein may also be administered to the respiratory tract as an aerosol or solution for a nebulizer, or as a microfine powder for insufflation, alone or in combination with an inert carrier such as lactose. In such a case, the particles of the pharmaceutical composition have diameters of less than 50 microns, in certain embodiments, less than 10 microns.

[00532] In general, the chemical entities provided will be administered in a therapeutically effective amount by any of the accepted modes of administration for agents that serve similar utilities. The actual amount of the chemical entity, i.e., the active ingredient, will depend upon numerous factors such as the severity of the disease to be treated, the age and relative health of the subject, the potency of the chemical entity used, the route and form of administration, and other factors. The drug can be administered more than once a day, such as once or twice a day.

[00533] Therapeutically effective amounts of the chemical entities described herein may range from approximately 0.01 to 200 mg per kilogram body weight of the recipient per day; such as about 0.01-100 mg/kg/day, for example, from about 0.1 to 50 mg/kg/day. Thus, for administration to a 70 kg person, the dosage range may be about 7-3500 mg per day.

[00534] In general, the chemical entities will be administered as pharmaceutical compositions by any one of the following routes: oral, systemic (e.g., transdermal, intranasal or by suppository), or parenteral (e.g., intramuscular, intravenous or subcutaneous) administration. In certain embodiments, oral administration with a convenient daily dosage regimen that can be adjusted according to the degree of affliction may be used. Compositions can take the form of tablets, pills, capsules, semisolids, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols, or any other appropriate compositions. Another manner for administering the provided chemical entities is inhalation.

[00535] The choice of formulation depends on various factors such as the mode of drug administration and bioavailability of the drug substance. For delivery via inhalation the chemical entity can be formulated as liquid solution, suspensions, aerosol propellants or dry powder and loaded into a suitable dispenser for administration. There are several types of pharmaceutical inhalation devices-nebulizer inhalers, metered dose inhalers (MDI) and dry powder inhalers (DPI). Nebulizer devices produce a stream of high velocity air that causes the therapeutic agents (which are formulated in a liquid form) to spray as a mist that is carried into the patient's respiratory tract. MDIs typically are formulation packaged with a compressed gas. Upon actuation, the device discharges a measured amount of therapeutic agent by compressed gas, thus affording a reliable method of administering a set amount of agent. DPI dispenses therapeutic agents in the form of a free flowing powder that can be dispersed in the patient's inspiratory air-stream during breathing by the device. In order to achieve a free flowing powder, the therapeutic agent is formulated with an excipient such as lactose. A measured amount of the therapeutic agent is stored in a capsule form and is dispensed with each actuation.

[00536] Recently, pharmaceutical compositions have been developed for drugs that show poor bioavailability based upon the principle that bioavailability can be increased by increasing the surface area i.e., decreasing particle size. For example, U.S. Patent No. 4,107,288 describes a pharmaceutical formulation having particles in the size range from 10 to 1 ,000 nm in which the active material is supported on a cross-linked matrix of macromolecules. U.S. Patent No. 5,145,684 describes the production of a pharmaceutical formulation in which the drug substance is pulverized to nanoparticles (average particle size of 400 nm) in the presence of a surface modifier and then dispersed in a liquid medium to give a pharmaceutical formulation that exhibits remarkably high bioavailability.

[00537] The compositions are comprised of, in general, at least one chemical entity described herein in combination with at least one pharmaceutically acceptable excipient.

Acceptable excipients are non-toxic, aid administration, and do not adversely affect the therapeutic benefit of the at least one chemical entity described herein. Such excipient may be any solid, liquid, semi-solid or, in the case of an aerosol composition, gaseous excipient that is generally available to one of skill in the art.

[00538] Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk and the like. Liquid and semisolid excipients may be selected from glycerol, propylene glycol, water, ethanol and various oils, including those of petroleum, animal, vegetable or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil, etc. Liquid carriers, for injectable solutions, include water, saline, aqueous dextrose, and glycols. [00539] Compressed gases may be used to disperse a chemical entity described herein in aerosol form. Inert gases suitable for this purpose are nitrogen, carbon dioxide, etc. Other suitable pharmaceutical excipients and their formulations are described in Remington's

Pharmaceutical Sciences, edited by E. W. Martin (Mack Publishing Company, 18th ed., 1990).

[00540] The amount of the chemical entity in a composition can vary within the full range employed by those skilled in the art. Typically, the composition will contain, on a weight percent (wt%) basis, from about 0.01 -99.99 wt% of at least one chemical entity described herein based on the total composition, with the balance being one or more suitable pharmaceutical excipients. In certain embodiments, the at least one chemical entity described herein is present at a level of about 1 -80 wt%. Representative pharmaceutical compositions containing at least one chemical entity described herein are described below.

[00541] In another embodiment, there is provided a method for treating a viral infection in a mammal mediated at least in part by a virus in the Flaviviridae family of viruses, which method comprises administering to a mammal that has been diagnosed with said viral infection or is at risk of developing said viral infection a compound described herein. In another embodiment, the virus is hepatitis C virus.

[00542] In another embodiment, the method for treating a viral infection in a mammal mediated at least in part by a virus in the Flaviviridae family of viruses further comprises administration of a therapeutically effective amount of one or more agents active against hepatitis C virus. In another embodiment, the agent is an inhibitor of HCV protease, HCV polymerase, HCV helicase, HCV NS4B protein, HCV entry, HCV assembly, HCV egress, HCV replicase, HCV NS5A protein, or inosine 5'-monophosphate dehydrogenase. In another embodiment, the agent is interferon. In another embodiment, the agent is ribavirin. In yet another embodiment, the agent(s) is a combination of interferon and ribavirin that is

administered either simultaneously or sequentially.

[00543] In addition, the chemical entities described herein can be co-administered with, and the pharmaceutical compositions can include, other medicinal agents, pharmaceutical agents, adjuvants, and the like. Suitable medicinal and pharmaceutical agents include therapeutically effective amounts of one or more agents active against HCV. In some embodiments, the agent active against HCV is an inhibitor of HCV protease, HCV polymerase, HCV helicase, HCV NS4B protein, HCV entry, HCV assembly, HCV egress, HCV replicase, HCV NS5A protein, or inosine 5'-monophosphate dehydrogenase.

[00544] Active agents against HCV include ribavirin, levovirin, viramidine, thymosin alpha-1 , an inhibitor of NS3 serine protease, and inhibitor of inosine monophosphate dehydrogenase, interferon-alpha, either alone or in combination with ribavirin or levovirin. In some embodiments, the additional agent active against HCV is interferon-alpha or pegylated interferon-alpha alone or in combination with ribavirin or levovirin. In some embodiments, the agent active against hepatitis C virus is interferon.

[00545] The above other therapeutic agents, when employed in combination with the chemical entities described herein, may be used, for example, in those amounts indicated in the Physicians' Desk Reference (PDR) or as otherwise determined by one of ordinary skill in the art.

[00546] Additionally, the present specification is directed to a pharmaceutical composition comprising a therapeutically effective amount of at least one chemical entity described herein in combination with a therapeutically effective amount of another active agent against RNA- dependent RNA virus and, in particular, against HCV. Agents active against HCV include, but are not limited to, ribavirin, levovirin, viramidine, thymosin alpha-1 , an inhibitor of HCV NS3 serine protease, or an inhibitor of inosine monophosphate dehydrogenase, interferon-alpha pegylated interferon-alpha (peginterferon-alpha), a combination of interferon-alpha and ribavirin, a combination of peginterferon-alpha and ribavirin, a combination of interferon-alpha and levovirin, and a combination of peginterferon-alpha and levovirin. Interferon-alpha includes, but is not limited to, recombinant interferon-alpha2a (such as ROFERON interferon available from Hoffman-LaRoche, Nutley, NJ), interferon-alpha2b (such as Intron-A interferon available from Schering Corp., Kenilworth, New Jersey, USA), a consensus interferon, and a purified interferon-alpha product. For a discussion of ribavirin and its activity against HCV, see J.O. Saunders and S.A. Raybuck, "Inosine Monophosphate Dehydrogenase: Consideration of Structure, Kinetics and Therapeutic Potential," Ann. Rep. Med. Chem., 2:201 -210 (2000).

[00547] The following examples serve to more fully describe the manner of making and using the above-described invention. It is understood that these examples in no way serve to limit the true scope of the invention, but rather are presented for illustrative purposes.

BIOLOGICAL EXAMPLES

EXAMPLE 417

ANTI-HEPATITIS C ACTIVITY

[00548] In certain embodiments, the presently described formulas and compounds can exhibit anti-hepatitis C activity by fully or partially inhibiting the host cell's PI4Ka enzyme, which has been recently described as an important host factor for HCV replication. The presently described formulas and compounds show various potencies against PI4Ka, which correlates well with the corresponding antiviral (e.g., replicon) activities. A number of assays have been published to assess these activities. A general method that assesses the gross increase of HCV virus in culture was disclosed in U.S. Patent No. 5,738,985 to Miles et al. In vitro assays have been reported in Ferrari et al. Jnl. of Vir., 73:1649-1654, (1999); Ishii et al., Hepatology, 29:1227-1235, (1999); Lohmann et al., J. Biol. Chem., 274:10807-10815, (1999); and

Yamashita et al., J. Biol. Chem., 273:15479-15486, (1998).

EXAMPLE 418

REPLICON ASSAY

[00549] Compounds were assayed for activity against HCV using the genotype 1 a and 1 b subgenomic replicon model systems. Stable cell lines bearing the genotype 1 a and 1 b replicons were used for screening of compounds. Both replicons are bicistonic and contain the firefly luciferase gene. The ET cell line is stably transfected with RNA transcripts harboring a l₃₈₉luc- ubi-neo/NS3-3'/ET replicon with firefly luciferase-ubiquitin-neomycin phosphotransferase fusion protein and EMCV-IRES driven NS3-5B polyprotein containing the cell culture adaptive mutations (E1202G; T1280I; K1846T) (Krieger at al, 2001 and unpublished). The genotype 1 a replicon is a stable cell line licensed from Apath LLC, modified to contain the firefly luciferase gene. The cells were grown in DMEM, supplemented with 10% fetal calf serum, 2 mM

Glutamine, Penicillin (100 IU/mL)/Streptomycin (100 g mL), 1x nonessential amino acids, and 250-500 g/mL G418 ("Geneticin"). They were all available through Life Technologies

(Bethesda, Md.). The cells were plated at 0.5 x 10⁴ cells/well in 384 well plates containing compounds. The final concentration of compounds ranged between 0.03 pM to 50 μιη and the final DMSO concentration of 0.5-1%.

[00550] Luciferase activity was measured 48 hours later by adding a Steady glo

(Promega, Madison, Wis.). Percent inhibition of replication data was plotted relative to no compound control. Under the same condition, cytotoxicity of the compounds was determined using cell titer glo (Promega, Madison, Wis). IC₅₀s were determined from a 10 point dose response curve using 3-4-fold serial dilution for each compound, which spans a concentration range > 1000 fold. BioAssay determines the level of inhibition for each compound by normalizing cross-talk corrected plate values against the negative (low or background, cells with no compound present) and positive (high DMSO, no cells) controls to determine Percent Inhibition:

100 * (1 -(Cross-talk corrected value - Compound Positive Control Mean)) DMSO Negative Control Mean - Compound Positive Control Mean

[00551] These normalized values are exported to IC₅₀ where they are plotted against the molar compound concentrations using the standard four parameter logistic equation:

Where:

A = minimum y D= slope factor

B = maximum y x = log₁₀ compound concentration [M]

C = log₁₀EC₅o

[00552] As shown below, the tested compounds were found to inhibit the activity of the replicon with plC₅₀ values of about 9 or less. Preferably, the compounds will exhibit plC₅₀ values of about 8 or less, in some embodiments, about 7 or less, and in some embodiments, about 6 or less. Further, compounds of the present disclosure, which were tested against more than one genotype of HCV replicon, were found to have similar inhibitory properties.

EXAMPLE 419

PI4KAipha IC₅₀ determination

[00553] To determine the potency of compounds as inhibitors of PI4Kalpha protein, a microfluidics-based kinase detection platform was utilized confidentialy through a contract research organization (Nanosyn, Inc, Research Triangle Park, North Carolina). Compounds were sent at top concentration of 10 μΜ and subsequently serially diluted to 10 pM. This enzymatic assay detection technology is based upon the difference between net charge of substrates and products, allowing electrophoretic separation of product from substrate. The product of PI4KAIpha kinase reactions are then quantitated using Caliper LabChip microfluidic instrumentation. IC₅₀s are calculated as the concentration corresponding to 50% inhibition of PI4Kalpha product production.

[00554] When tested in biological in vitro models, certain compounds of Table 1 were found to have plC₅₀ values listed in Table 8. Table 8

29 8 8.7 8.2

30 - - -

31 8.6 8.7 9

32 8.7 9.5 8.8

33 5.3 5.8 5.3

34 7.7 8.5 8.8

35 5.8 6.7 6.6

36 6.7 7.8 8.9

37 8 8.8 9

38 5.3 6.2 6.1

39 7.9 8.9 9.1

40 8.1 9 9

41 8.4 9.3 9.2

42 8.2 9.2 9.8

43 7.9 8.7 8.9

44 8.2 9.2 8.9

45 8.2 9.1 9.4

46 8.2 9 8.9

47 8.2 8.8 8.9

48 8.6 9.5 9.5

49 8.7 9.5 9.4

50 6.1 6.5 6.5

51 8.4 9.8 8.8

52 8.1 9 8.1

53 8.5 9.3 8.6

54 8.2 9.1 8.3

55 7.7 8.5 7.8

56 7.8 8.6 8.1

57 7.4 8.3 7.7

58 7.5 8.4 7.5

59 8.5 9.4 8.8

60 9 9.7 9.8

61 8.4 9.2 9.2 62 8.3 9.2 9

63 8.2 8.9 8.6

64 7.5 8.3 7.4

65 8.1 9 8.8

66 - - 8.8

67 - - 9.2

68 8.5 9.1 9

69 9.2 9.9 9.4

70 7.7 8.4 8.6

71 6.6 7.5 6.9

72 6.9 7.7 7.8

73 6.6 7.7 7.7

74 8.7 9.3 9.3

75 8.8 9.5 9.4

76 8.6 9.5 9

77 9.1 9.7 9.1

78 7.6 8.3 8.2

79 8.2 9.1 9.5

80 6.5 7.4 8.7

81 7 7.8 7.3

82 7.8 8.7 9

83 8.1 8.8 9.4

84 6.2 6.6 8.1

85 5.7 6.3 8.5

86 5.8 7.2 9.6

87 8.2 9.3 8.9

88 8.1 8.9 9.1

89 7.9 8.8 8.9

90 8.3 9.6 9.2

91 8.2 9.2 9.1

92 7.1 8 9.2

93 7.7 8.5 9.3

94 8.5 9.3 9.6 95 8.6 9.3 -

96 6.9 7.9 9

97 8.2 9.3 -

98 7.6 8.7 9.6

99 6.5 7.1 -

100 5.8 6.6 -

101 7.2 7.8 8.4

102 5.8 6.8 7

103 7.6 8 8.5

104 8.3 9.2 9.1

105 8 8.8 9.2

106 6.3 7.3 7.7

107 6.4 7.1 7.4

108 6.6 7.2 7.1

109 6.6 7.6 7.6

110 7.2 8 7

11 1 7.7 8.5 7.6

112 7.6 8.3 7.3

113 7.5 8.2 7.5

114 7.3 8 8.1

115 5.3 5.3 5.8

116 5.6 6.2 6

117 5.3 5.6 5.7

118 6.4 7.3 6.8

119 5.3 5.4 5.5

120 5.3 6 6.6

121 6.3 7 7.2

122 8.1 9.1 8.1

123 7.5 8.4 7.3

124 8 8.8 7.5

125 7 7.8 7.4

126 8 8.8 7.7

127 7.5 8.3 6.7 128 7.5 8.5 7.9

129 7.2 7.9 7.5

130 7 7.7 7.4

131 7.2 7.8 7.6

132 7.8 8.6 8

133 7.7 8.5 7.8

134 6.9 7 6.7

135 - - -

136 - - -

137 8.1 8.9 8.1

138 7.8 8.5 8.5

139 7.7 8.5 8.7

140 7.8 8.7 8.3

141 8.4 9.2 8.3

142 7.9 9 8.5

143 7.7 8.8 8.8

144 7.9 8.8 8

145 7.4 8.4 7.5

146 7.4 8.3 8.2

147 7.5 8.4 8.2

148 7.2 8 8

149 6.9 7.7 7.7

150 6.8 7.7 7.6

151 7.5 8.3 8

152 6.5 7.5 8.8

153 6.6 7.5 6.8

154 7.1 7.9 7.1

155 6.6 7.7 7.9

156 6.7 7.6 7.1

157 7.6 8.4 8.2

158 6.9 7.4 7.6

159 7.4 8.3 7.8

160 7.4 8.1 8.1 161 7 7.6 7.7

162 7.2 7.8 7.8

163 7 7.7 8.1

164 8 8.8 8.1

165 6.4 7.2 7.4

166 6.4 7.1 7.2

167 6.6 7.5 7.1

168 7 7.6 7.3

169 6.4 7.4 7

170 7.3 8.1 7.5

171 6.9 7.8 7.5

172 7 7.6 7.2

173 7.6 8.4 7.6

174 6.9 7.7 7.5

175 6.9 7.8 8

176 6.8 7.7 7.2

177 7.5 8.2 7.6

178 7.6 8.4 8.1

179 7.7 8.5 7.7

180 8 8.7 7.5

181 8 9.1 7.9

182 7.7 8.8 7.7

183 7.7 8.8 5.5

184 6.7 7.9 7.6

185 5.5 6.2 5.6

186 5.8 6.4 6.2

187 5.6 6.3 6.1

188 6.7 6.9 6.7

189 6.2 7.2 7

190 6.2 7.1 6.3

191 5.8 6.8 6.4

192 5.8 5.8 6.9

193 5.7 6.2 5.4 194 5.4 6.1 5.2

195 5.6 6 5

196 6.1 6.4 6.1

197 - - -

198 7.5 8.3 7.9

199 7.7 8.5 7.6

200 7.2 8.1 7.8

201 7.3 8.1 8.3

202 7.3 8.2 7.4

203 7.6 8.4 8.2

204 7.8 8.8 7.6

205 8.3 8.8 9

206 7.5 8 8.2

207 7.4 8.1 7.8

208 7.2 7.9 7.5

209 7.5 8.3 7.4

210 7.7 8.5 7.8

21 1 6.3 6.3 6.1

212 7.1 8.1 7.2

213 7.1 8 7.4

214 7.3 7.7 8.2

215 7.3 8.1 7.3

216 7.4 8.2 7.7

217 6.1 6.8 6.8

218 6.7 6.7 6.1

219 7.7 8.6 7.7

220 7.3 8 8.5

221 7.1 8 7.3

222 5.2 6.4 6.6

223 6.5 7.5 8.4

224 6.8 7 6.4

225 6.1 6.8 8.2

226 6.8 7.6 6.5 227 7.4 8.3 7.9

228 8.4 9.1 9.1

229 7.9 8.6 7.5

230 8.4 8.8 7.8

231 8.7 9.4 9.1

232 7.7 8.6 6.9

233 7.3 8.2 7.8

234 7.7 8.4 8

235 7.5 8.3 7.7

236 7.6 8.4 7.4

237 7.5 8.2 7.5

238 7.4 8 7.6

239 7.4 8.2 6.9

240 7.2 8 7.7

241 7.4 8.3 7

242 6.8 7.5 6.8

243 7.1 8 7.7

244 7.9 8.8 8.1

245 7.7 8.6 7.3

246 7.6 8.6 7.3

247 7.7 8.6 7.3

248 7.6 8.4 7.7

249 7.6 8.1 6.7

250 8 8.7 8.7

251 7.4 8.1 7.9

252 7.5 8 7.6

253 7.2 8 7

254 7.3 8.2 7

255 7.4 8.2 7.5

256 7.5 8.3 8

257 7.8 8.6 8

258 6.9 7.8 6.9

259 7.2 7.9 7.9 260 6.4 7.5 7.9

261 7.5 8.3 8.2

262 7 7.9 7.5

263 7.2 8.1 7.7

264 7.4 8.2 8.9

265 7.5 8.5 7.8

266 6.5 7.5 6.9

267 6.9 7.4 6.7

268 7.4 8.2 7.9

269 7.9 8.7 8.4

270 6.7 7.5 7.1

271 7.1 7.1 7.3

272 7.1 8 7.3

273 7.5 8.4 8.4

274 7.4 8.1 7.4

275 6.3 6.8 6.4

276 6.3 6.7 6.7

277 7.9 8.7 9

278 7.2 7.7 7.8

279 6.3 6.3 5.9

280 6.5 7.1 6.4

281 5.3 6.1 5.7

282 5.7 6.8 6.8

283 5.7 6.1 6.7

284 6.9 7.8 7.7

285 6.1 6.6 6.1

286 7.3 8.3 8.2

287 6.9 7.7 7.4

288 6.4 7.4 6.7

289 4.8 5.6 6

290 6.3 6.5 6.2

291 5.3 6.2 6.2

292 5.4 6.1 6 293 5.3 5.3 6.9

294 5.4 6.1 6

295 6.3 7 7.4

296 6.3 6.3 6.3

297 6.3 6.3 6.4

298 5.7 6.6 6.5

299 4.7 5.4 8.2

300 4.9 5.1 7.4

301 4.3 4.3 7.4

302 5.2 5.4 6

303 6.3 6.3 7.5

304 5.3 5.7 5.4

305 7.6 8.4 8.2

306 7.3 8.2 7.1

307 5.5 6.7 6.8

308 5.2 5.4 6.9

309 5.3 6.3 6.2

310 5.4 6.5 6.2

31 1 5.8 6.7 6.5

312 5.3 5.9 6

313 5.2 6 6.4

314 7.4 8.3 8

315 6.3 6.9 6.8

316 7.2 8.1 7.8

317 5.3 5.3 5.1

318 7.8 8.4 7.4

319 7.3 8.1 7.3

320 7.6 8.3 8.1

321 6.7 7.3 6.5

322 7.1 8 7.1

323 7.2 8 7.2

324 7.6 8.2 7.3

325 7.2 8 7.9 326 7.1 7.9 7.9

327 6.6 7.5 7.6

328 7.2 8 7.9

329 7.3 8.1 7.6

330 7 7.4 7.3

331 6.3 6.3 5.9

332 6.3 6.3 5

333 7.7 7.9 7.4

334 6.3 6.3 5

335 6.3 6.3 5.4

336 6.2 6.9 7.1

337 5.3 6.2 5.9

338 5.1 5.9 5.5

339 5.6 5.8 6.3

340 6.3 6.3 5.5

341 7.4 8.1 8

342 6.8 7.4 6.6

343 6.8 7.9 7

344 5.5 5.6 6.1

345 7.2 8 6.8

346 6.5 7.4 6.4

347 6.8 7.8 7.8

348 6.8 7.2 7.6

349 6.8 6.5 5

350 5.4 6 5.4

351 5.7 6.5 6.3

352 5.3 5.6 6

353 8.5 9.3 9

354 7.5 8.5 7.6

355 6.3 7.2 7

356 6.3 6.3 5.6

357 5.5 6 5.5

358 8.1 9.1 8.1 359 8 8.8 8.5

360 7.8 8.7 7.9

361 7.6 8.5 7.9

362 7.6 8.3 7.6

363 7.6 8.7 8.4

364 8 8.9 8.1

365 8 8.9 8.1

366 7.8 8.6 7.7

367 7.9 8.9 7.7

368 7.8 8.7 7.5

369 7.6 8.7 9.5

370 9.4 9.9 9.6

371 8.4 9.4

372 8.8 9.7 9.5

373 7.7 8.6 8.7

374 7.4 8.3 8.4

375 7 8.1 6.5

376 7.8 8.9 8

377 8.1 8.9 8.5

378 8 8.7 8.4

379 7.9 8.1 9.1

380 8 8.9 8.3

381 7.2 8 7.3

382 7.2 8.3 7.9

383 7.5 8.4 7.9

384 7.5 8.3 8.1

385 7.5 8.7 8

386 7.6 8.7 7.7

387 8.2 9 8

388 7 8.1 7.7

389 7.1 8 8

390 5.3 5.6 5.1

391 5.1 5.3 6.3 392 5.8 6.8 6.6

393 4.4 4.5 5.7

394 4.4 5.3 6.4

395 4.7 5.6 7.3

396 5.9 6.5 6.5

397 5.2 5.4 5

398 6.3 7.1 7.6

399 7.7 8.5 8.1

400 7.7 8.7 8.1

401 7.1 8.1 7.9

402 6 6.4 5.9

403 6.1 6.6 5.9

404 7.6 8.5 8.3

405 7.9 8.7 8.1

406 7.9 8.8 8.5

407 7.3 8 8.2

408 7.1 8 7

409 8 8.8 8

410 7.6 8.4 7.5

41 1 6.4 6.7 6.1

412 6.3 6.3 6.9

413 4.9 5.3 7

414 4.3 4.4 6.9

415 4.3 5 6.1

416 5.3 6.4 6.6

Formulation Examples

The following are representative pharmaceutical formulations containingormula (I) or a pharmaceutically acceptable salt thereof.

Formulation Example 1

Tablet formulation [00556] The following ingredients are mixed intimately and pressed into single scored tablets.

Ingredient Quantity per tablet (mg)

compound 400

cornstarch 50

croscarmellose sodium 25

lactose 120

magnesium stearate 5

Formulation Example 2

Capsule formulation.

[00557] The following ingredients are mixed intimately and loaded into a hard-shell gelatin capsule.

Ingredient Quantity per capsule (mg)

compound 200

Lactose, spray-dried 148

magnesium stearate 2

Formulation Example 3

Suspension formulation

[00558] The following ingredients are mixed to form a suspension for oral administration.

Ingredient Amount

compound 1.0 g

fumaric acid 0.5 g

sodium chloride 2.0 g

methyl para ben 0.15 g

propyl paraben 0.05 g

granulated sugar 25.0 g

sorbitol (70% solution) 13.00 g

Veegum K (Vanderbilt Co.) 1.0 g

flavoring 0.035 ml_

colorings 0.5 mg

distilled water q.s. (quantity sufficient) to I00 ml_ Formulation Example 4

Injectable formulation

[00559] The following ingredients are mixed to form an injectable formulation.

Ingredient Amount

compound 0.2 mg-20 mg sodium acetate buffer solution, 0.4 M 2.0 ml_

HCI (1 N) or NaOH (1 N) q.s. to suitable pH

water (distilled, sterile) q.s. to 20 ml_

Formulation Example 5

Suppository Formulation

[00560] A suppository of total weight 2.5 g is prepared by mixing the compound with Witepsol® H-15 (triglycerides of saturated vegetable fatty acid; Riches-Nelson, Inc., New York), and has the following composition:

Ingredient Amount

compound 500 mg

Witepsol® H-15 balance

[00561] Although the invention has been shown and described above with reference to some embodiments, those skilled in the art will readily appreciate that the specific experiments detailed are only illustrative of the invention, it should be understood that various modifications can be made without departing from the spirit of the invention.

[00562] For example, for claim construction purposes, it is not intended that the claims set forth hereinafter be construed in any way narrower than the literal language thereof, and it is thus not intended that exemplary embodiments from the specification be read into the claims. Accordingly, it is to be understood that the present invention has been described by way of illustration and not limitations on the scope of the claims. Accordingly, the invention is limited only by the following claims. All publications, issued patents, patent applications, books and journal articles, cited in this application are each herein incorporated by reference in their entirety.

Claims

WHAT IS CLAIMED IS:

1.

armaceutically acceptable salt thereof, wherein:

Y and Z are independently selected from a bond or (d-C₆)alkylene;

X is selected from the group consisting of -NHS0₂R⁵, -NHSO₂R¹⁰R⁵, -S0₂NHR⁵,

R is selected from the group consisting of hydrogen, (C C₆)alkyl, (C₄-C ₄)aryl, nitrile, -R ⁴, and -S0₂R⁹;

R² is selected from the group consisting of hydrogen, (C -C₆)alkyl, (C₁-C₆)alkenyl, halo, -NHR¹⁰, -R⁶, -R¹⁰, -R ³, -R ⁴, -R¹⁰R⁷, -R ³R¹⁶, -R ⁰R¹⁴, -R ⁰R⁵, -R ⁴R⁷, -(CH₂)_WR¹⁴, -C(0)R^s, and -R ³OR⁸, wherein R¹ and R² may optionally join together along with any intervening N and C atoms to form a (d-Cn heterocyclic or a (Ci- Cii)heteroaryl group fused to the adjacent pyridyl moiety and independently having one to three nitrogen heteroatoms;

R³ and R⁴ are independently selected from the group consisting of hydrogen, (Ci- C₆)alkyl, (C C₅)alkoxy, -R¹⁴, nitrile, -S0₂R⁸, oxo, -OR⁸, -R¹², and halo;

R⁵ is selected from the group consisting of {CrC₆)alkyl, (CrC₆)alkoxy, nitrile, benzyl,

-R ⁰R¹⁷, -R ⁰(R ⁷)_n, -OR⁹(R¹⁷)_m, -R⁹(R ⁷)_m, -R⁹R(¹⁷)_n, -R⁹R¹², -R⁹R¹³, -R⁹OR⁸, -R ⁴, (C₄-C₁₄)aryl, and (C₃-Ci₂)cycloalkyl;

R⁶ is selected from the group consisting of -R ⁰C(O)R¹⁴, -R¹⁰C(O)R ⁴R¹⁶, -R¹⁰(CH₂)_WR¹², - R ⁰(CH₂)_WR¹⁴, and -R ⁰(CH₂)_WR¹⁴R¹⁶;

R⁷ is independently selected from the group consisting of (CrC₆)alkyl, (Ci-C₆)alkoxy, oxo, halo, nitrile, -R⁹(R¹⁷)_m, -N0₂, -R⁹OR⁸, -C(0)R⁹, -(CH₂)_WCN, -S0₂R¹², -S0₂R⁹, -S0₂NH(CH₂)_wR¹⁴, -S0₂(CH₂)_wR¹⁴, -R ², -R ⁴, -(CH₂)_wOR⁸, -C(0)NHR¹³, -C(0)NHR¹⁴, -C(0)NHR⁹, -R ⁰, -OR⁹(R¹⁷)_m, -C(0)R¹², -NHC(O)NHR ⁰R¹¹, -C(0)NH(CH₂)_wR¹², -C(0)(CH₂)_¾vR¹², -C0₂R⁸,

-NHC(0)C(0)R¹⁴, -NHC0₂R⁸, -OR⁸, -C(0)NH(CH₂)_wR¹⁴, -C(0)(CH₂)_wR¹⁴, -(CH₂)_WR¹¹, -NH(CH₂)_WR¹⁴, -(CH₂)_WR¹⁴ , -(CH₂)_WR¹⁰, -(CH₂)_WNHR¹⁰,

R⁸ is independently selected from the group consisting of hydrogen, (Ci-C₆)alkyl, benzyl, -R ⁴, and (C₄-C ₄)aryl;

R⁹ is (C C₆)alkyl;

R ⁰ is (C₄-C₁₄)aryl;

R¹¹ is selected from the group consisting of nitrile, halo, (CrC₆)alkyl, (d-C₆)alkoxy,

-NHS0₂R⁹, -C0₂R⁸, -OR⁸, -0(CH₂)_wR¹², -S0₂R¹², -S0₂R⁹, -NH(CH₂)_WR¹⁴ , -R ⁶, and -(CH₂)_WR¹⁴;

R ² is -NR⁸R⁸;

R¹³ is (C₃-C₁₂)cycloalkyl;

R¹⁴ is selected from the group consisting of (C -C )heterocyclic and (d-C-i heteroaryl, each independently having one to three heteroatoms selected from N and O; R ⁵ is independently selected from the group consisting of (CrC₆)alkyl, (Ci-C₆)alkoxy,

-OR⁸, halo, oxo, dioxo, nitrile, -N0₂, and -C0₂R⁸;

R¹⁶ is independently selected from the group consisting of (CrC₆)alkyl, (Ci-C₆)alkoxy,

-S0₂R⁹, -NH(CH₂)_WR¹⁴, and -(CH₂)_WR¹⁴;

R¹⁷ is halo;

each m is independently an integer from 1 to 3;

each n is independently an integer from 1 to 3; and

each w is independently an integer from 1 to 6.

2. The compound according to claim 1 , wherein Y and Z are independently selected from the group consisting of a bond, methylene, and ethylene.

3. The compound according to claim 2, wherein Y is selected from the group consisting of a bond, methylene, and ethylene.

4. The compound according to claim 2, wherein Z is selected from the group consisting of a bond, methylene, and ethylene.

5. The compound according to claim 2, wherein Z is a bond.

6. The compound according to claim 2, wherein Z is methylene.

7. The compound according to claim 2, wherein Y is a bond.

8. The compound according to claim 2, wherein Y is methylene.

9. The compound according to claim 2, wherein X is selected from the group consisting of

-NHS0₂R⁵, -NHSO₂R ⁰R⁵, -S0₂NHR⁵, -SO₂NHR¹⁰R⁵, -S0₂NHR¹⁴, -S0₂R⁵, - S0₂R¹², -S0₂R¹⁴, and -S0₂R ⁴R¹⁵.

10. The compound according to claim 1 , wherein R is selected from the group consisting of hydrogen, methyl, ethyl, phenyl, nitrile, -S0²R⁹, -(CH₂)_WR¹⁴, and -(CH₂)_wS0₂R⁹.

11. The compound according to claim 1 , wherein R² is selected from the group consisting of hydrogen, methyl, ethyl, isobutyl, ethylene, halo, -NHR¹⁰SO₂R⁹, -R ⁰R⁵, -R ⁰R⁷, - R ⁰R¹⁴, -R¹³R¹⁶, -R¹⁴R⁷, -(CH₂)_WR¹⁴, -NHR ⁰SO₂R¹², -NHR ⁰R¹², -C(0)R⁸, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, hydroxycyclohexyl, phenyl, cyanophenyl, methylphenyl, tetrahydropyranyl, morpholinyl, methylbenzamide, pyridyl, pyrazolyl, pyrimidyl, benzoxazinyl, benzodioxolanyl, and diazaspirodecanyl.

12. The compound according to claim 1 , wherein R¹ and R² may optionally join together along with the intervening N and C atoms to form a ring structure, wherein said ring structure is fused to the adjacent pyridyl moiety and having the structure:

, and wherein said R¹ and R²-joined ring structure may be optionally substituted with one to three independent R groups.

13. The compound according to claim 1 , wherein R³ and R⁴ are independently selected from the group consisting of hydrogen, nitrile, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, oxo, hydroxyl, trifluoromethyl, methylamino, dimethylamino, amino, trifluoromethoxy, and halo.

14. The compound according to claim 1 , wherein R³ is selected from the group consisting of hydrogen and methyl.

15. The compound according to claim 1 , wherein R³ is hydrogen.

16. The compound according to claim 1 , wherein R⁴ is selected from the group consisting of nitrile, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, oxo, hydroxyl,

trifluoromethyl, methylamino, dimethylamino, amino, trifluoromethoxy, and halo.

17. The compound according to claim 1 , wherein R⁴ is selected from the group consisting of nitrile, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, oxo, hydroxyl,

trifluoromethyl, methylamino, dimethylamino, amino, and trifluoromethoxy.

18. The compound according to claim 1 , wherein R⁴ is selected from the group consisting of nitrile, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, and amino.

19. The compound according to claim 1 , wherein R⁴ is selected from the group consisting of methoxy and amino.

20. The compound according to claim 1 , wherein R⁴ is selected from the group consisting of methoxy.

21. The compound according to claim 1 , wherein R⁴ is selected from the group consisting of amino.

22. The compound according to claim 1 , wherein R⁵ is selected from the group consisting of methyl, ethyl, isopropyl, propyl, butyl, isobutyl, tert-butyl, methoxy, ethoxy, nitrile, phenyl, chlorophenyl, fluorophenyl, difluorophenyl, trifluorophenyl, benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyl methyl, trifluoromethyl, trifluoroethyl, trifluoromethoxy, dimethylaminoethyl, pyridyl, quinolinyl,

thiomorpholinyl, morpholinyl, hydroxyethyl, and furanyl.

23. The compound according to claim 1 , wherein R⁵ is selected from the group consisting of phenyl, chlorophenyl, fluorophenyl, difluorophenyl, and trifluorophenyl.

24. The compound according to claim 1 , wherein R⁵ is difluorophenyl.

25. The compound according to claim 1 , wherein R⁷ is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, methoxy, oxo, dioxo, chloro, flouro, bromo, trifluoromethyl, trifluoroethyl, trifluoromethoxy, trifluoroethoxy, nitrile, phenyl, acetyl, carboxyl, acetoxy, -N0₂, -(CH₂)_WCN, -S0₂R¹², -S0₂R⁹, -OR⁸, -C0₂R⁸, -C(0)R⁹, -S0₂NH(CH₂)_wR¹⁴, -S0₂(CH₂)_wR¹⁴, -S0₂R¹⁴, -R¹² , -R¹⁴, -{CH₂)_wOR⁸, -C(0)R¹², -NHC(O)NHR ⁰R¹¹, -R⁹OR⁸, -C(0)NHR¹³, -C(0)NHR¹⁴,

-C(0)NH(CH₂)_wR¹², -C(0)(CH₂)_wR¹², -NHC(0)C(0)R¹⁴, -NHC0₂R⁸,

-C(0)NH(CH₂)_wR¹⁴, -C(0)(CH₂)_wR¹⁴, -(CH^R , -NH(CH₂)_WR¹⁴, -(CH₂)_WR¹⁴,

-(CH₂)_WR¹⁰, -(CH₂)_WNHR¹⁰, -(CH₂)_wC0₂R⁸, -C(0)NHR⁹,

-C(O)NHR¹⁰R¹¹, -C(0)NH(CH₂)_wOR⁸, and -C(0)NH(CH₂)_wR¹¹.

26. The compound according to claim 1 , wherein R⁸ is independently selected from the

group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert- butyl, benzyl, phenyl and -R¹⁴.

27. The compound according to claim 1 , wherein R⁸ is selected from the group consisting of hydrogen, methyl, and ethyl.

28. The compound according to claim 1 , wherein R⁹ is independently selected from the

group consisting of methyl, ethyl, propyl, isopropyl, butyl, and tert-butyl.

29. The compound according to claim 1 , wherein R⁹ is independently selected from the

group consisting of methyl, ethyl, and tert-butyl.

30. The compound according to claim 1 , wherein R¹⁰ is phenyl.

31. The compound according to claim 1 , wherein R is:

32. The compound according to claim 1 , wherein R¹² is -NH₂.

33. The compound according to claim 1 , wherein R ³ is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

34. The compound according to claim 1 , wherein R ⁴ is selected from the group consisting of morpholinyl, thiomorpholinyl, tetrahydropyranyl, dioxanyl, triazolyl, oxadiazolyl, pyrimidinyl, pyrazolyl, piperazinyl, pyrrolidinyl, piperidinyl, and pyridinyl.

35. The compound according to claim 1 , wherein R¹⁵ is independently selected from the group consisting of fluoro, oxo, dioxo, chloro, bromo, methoxy, ethoxy, methyl, ethyl, butyl, propyl, isopropyl, nitrile, -N0₂, trifluoromethoxy, and trifluoromethyl.

36. The compound according to claim 1 , wherein R¹⁶ is independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, trifluoromethyl, trifluoromethoxy, methoxy, ethoxy, nitrile, -R ⁷, -(R¹⁷)₂, -R ², -NHS0₂R⁹, -C0₂R⁸, -OR⁸, -0(CH₂)_wR¹², -S0₂R¹², -S0₂R⁹, -NH(CH₂)_WR¹⁴, and -(CH₂)_WR¹⁴.

37. The compound according to claim 1 , wherein R¹⁷ is selected from the group consisting of chloro, fluoro, and bromo.

38. The compound according to claim 1 , wherein R ⁷ is fluoro.

39. The compound according to claim 1 , wherein m is 3.

40. The compound according to claim 1 , wherein n is 2.

41. The compound according to claim 1 , wherein w is 1.

42. A compound of Formula (I):

(I)

or a pharmaceutically acceptable salt thereof, wherein:

X is selected from the group consisting of -NHS0₂R⁵, -NHSO₂R¹⁰R⁵, -S0₂NHR⁵, - SO₂NHR¹⁰R⁵, -S0₂NHR¹⁴, -S0₂R⁵, -S0₂R¹², -S0₂R¹⁴, -S0₂R ⁴R¹⁵, -C(0)R¹⁴, -C(0)NHR¹⁰, -C(0)NHR¹⁴, -R , -R ², -R ⁴ ,-R ⁴R⁷, and -R ⁴R¹⁰;

-S0²R⁹, -(CH₂)_WR¹⁴, and -(CH₂)_wS0₂R⁹;

R² is selected from the group consisting of hydrogen, methyl, ethyl, isobutyl, ethylene, halo, -NHR ⁰SO₂R⁹, -R ⁰R⁵, -R¹⁰R⁷, -R ⁰R¹⁴, -R ³R¹⁶, -R¹⁴R⁷, -(CH₂)_WR¹⁴, - NHR ⁰SO₂R¹², -NHR¹⁰R¹², -C(0)R⁸, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, hydroxycyclohexyl, phenyl, cyanophenyl, methylphenyl,

tetrahydropyranyl, morpholinyl, methylbenzamide, pyridyl, pyrazolyl, pyrimidyl, benzoxazinyl, benzodioxolanyl, and diazaspirodecanyl, wherein R and R² may optionally join together along with the intervening N and C atoms to form a ring structure, wherein said ring structure is fused to the adjacent pyridyl moiety and

having the structure:

, and wherein said R and R²-joined ring structure may be optionally substituted with one to three independent R groups;

isobutyl, tert-butyl, methoxy, ethoxy, nitrile, phenyl, chlorophenyl, fluorophenyl, difluorophenyl, trifluorophenyl, benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, trifluoromethyl, trifluoroethyl, trifluoromethoxy, dimethyl ami noethyl, pyridyl, quinolinyl, thiomorpholinyl, morpholinyl,

hydroxyethyl, and furanyl;

R⁶ is selected from the group consisting of -R ⁰C(O)R¹⁴, -R ⁰C(O)R¹⁴R¹⁶, -R¹⁰(CH₂)_WR¹², - R ⁰(CH₂)_WR¹⁴, and -R¹⁰(CH₂)_WR ⁴R¹⁶;

isobutyl, tert-butyl, methoxy, oxo, dioxo, chloro, flouro, bromo, trifluoromethyl, trifluoroethyl, trifluoromethoxy, trifluoroethoxy, nitrile, phenyl, acetyl, carboxyl, acetoxy, -N0₂, -(CH₂)_WCN, -S0₂R¹², -S0₂R⁹, -OR⁸, -C0₂R⁸, -C(0)R⁹, - S0₂NH(CH₂)_wR¹⁴, -S0₂(CH₂)_wR¹⁴, -S0₂R¹⁴, -R ² , -R ⁴, -(CH₂)_wOR⁸, -C(0)R¹², -NHC(O)NHR¹⁰R¹¹, -R⁹OR⁸, -C(0)NHR¹³, -C(0)NHR¹⁴,

-C(0)NH(CH₂)_wR¹², -C(0)(CH₂)_wR¹², -NHC{0)C(0)R¹⁴, -NHC0₂R⁸, C(0)NH(CH₂)_wR¹⁴, -C(0)(CH₂)_wR¹⁴, -(CH₂)_WR¹¹, -NH(CH₂)_WR¹⁴, -(CH₂)_WR¹⁴, - (CH₂)_WR¹⁰, -(CH₂)_WNHR¹⁰, -(CH₂)_wC0₂R⁸, -C(0)NHR⁹,

C(O)NHR ⁰R¹¹, -C(0)NH(CH₂)_wOR⁸, and -C(0)NH(CH₂)_wR¹¹;

R⁹ is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl;

R¹⁰ is phenyl;

R ² is -NR⁸R⁸,

R ⁴ is selected from the group consisting of morpholinyl, thiomorpholinyl,

R ⁶ is independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, trifluoromethyl, trifluoromethoxy, methoxy, ethoxy, nitrile, -R ⁷, -(R ⁷)₂, -R¹², -NHS0₂R⁹, -C0₂R^s, -OR⁸, -0(CH₂)_wR¹²,

S0₂R¹², -S0₂R⁹, -NH(CH₂)_WR¹⁴, and -(CH₂)_WR¹⁴;

R¹⁷ is selected from the group consisting of chloro, fluoro, and bromo;

each n is independently an integer from 1 to 3; and

each w is independently an integer from 1 to 6.

43. A compound of Formula (I):

(I)

armaceutically acceptable salt thereof, wherein:

Y and Z are independently selected from a bond or (d-C₆)alkylene;

-S0₂NHR¹⁴, -SO₂NHR ⁰R⁵, -S0₂R⁵, -S0₂R¹², -S0₂R¹⁴, -S0₂R ⁴R¹⁵, -C(0)R¹⁴, -C(0)NHR¹⁰, -C(0)NHR¹⁴, -R¹², -R ⁴,-R ⁴R⁷, and -R¹⁴R¹⁰;

R is selected from the group consisting of hydrogen, (CrC₆)alkyl, (C₄-Ci₄)aryl, nitrile, -R ⁴, and -S0₂R⁹;

R² is selected from the group consisting of hydrogen, (C -C₆)alkyl, -R⁶, -R ⁰, -R¹³, -R ⁴, - R ⁰R⁷, -R ⁰R¹⁴, -R ⁰R⁵, -R ³R¹⁶, -R ⁴R⁷, -(CH₂)_WR¹⁴, -C(0)R⁸, and -R ³OR⁸, wherein R and R² may optionally join together along with any intervening N and C atoms to form a (d-Cn heterocyclic or a (d-C-i heteroaryl group fused to the adjacent pyridyl moiety and independently having one to three nitrogen heteroatoms;

C₆)alkyl, (C C₆)alkoxy, oxo, -OR⁸, -R ², and halo;

(C₄-Ci₄)aryl, and (C₃-Ci₂)cycloalkyl;

-R¹⁰(CH₂)_WR¹⁴, and -R ⁰(CH₂)_WR¹⁴R¹⁶;

R⁷ is independently selected from the group consisting of (CrC₆)alkyl, (CrC₆)alkoxy, halo, nitrile, -R⁹(R¹⁷)_m, -C(0)R⁹, -S0₂R⁹, -C(0)NHR⁹, -R ⁰, -OR⁹(R¹⁷)_m, -C(0)R¹², and -C0₂R⁸;

(C₄-C ₄)aryl;

R⁹ is (C C₆)alkyl;

R ⁰ is (C₄-C₁₄)aryl; R ² is -NR⁸R⁸;

R¹³ is (C₃-C ₂)cycloalkyl;

R ⁴ is selected from the group consisting of (d-Cn heterocyclic and (CrCn)heteroaryl, each independently having one to three heteroatoms selected from N and O;

R¹⁵ is selected from the group consisting of halo, oxo, and dioxo;

R¹⁶ is selected from the group consisting of (CrC₆)alkyl, (Ci-C6)alkoxy, -R ⁷, -(R¹⁷)2, -R ², hydroxyl, and nitrile;

R ⁷ is halo;

each m is independently an integer from 1 to 3;

each n is independently an integer from 1 to 3; and

each w is independently an integer from 1 to 6.

44.

or a pharmaceutically acceptable salt thereof, wherein:

X is selected from the group consisting of -NHS0₂R⁵, -NHSO₂R ⁰R⁵, -S0₂NHR⁵, - SO₂NHR¹⁰R⁵, -SO2NHR¹⁴, -S0₂R⁵, -S0₂R¹², -S0₂R¹⁴, -S0₂R ⁴R¹⁵, -C(0)R¹⁴, -C(0)NHR¹⁰, -C(0)NHR¹⁴, -R¹¹, -R¹², -R¹⁴,-R¹⁴R⁷, and -R¹⁴R¹⁰;

R is selected from the group consisting of hydrogen, methyl, nitrile, and -S0²R⁹;

R² is selected from the group consisting of hydrogen, methyl, ethyl, isobutyl, halo, - R ⁰R⁵, -R ⁰R⁷, -R¹⁰R¹⁴, -R¹³R¹⁶, -R ⁴R⁷, -(CH^R ⁴, -C(0)R⁸, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, hydroxycyclohexyl, phenyl, cyanophenyl, methylphenyl, tetrahydropyranyl, morpholinyl, methylbenzamide, pyridyl, pyrazolyl, pyrimidyl, wherein R and R² may optionally join together along with the intervening N and C atoms to form a ring structure, wherein said ring structure is fused to the adjacent pyridyl moiety and having the structure:

, and wherein said R¹ and R²-joined ring structure may be optionally substituted with one to three independent R⁸ groups;

R⁶ is selected from the group consisting of -R ⁰C(O)R¹⁴, -R¹⁰C(O)R¹⁴R¹⁶, -R¹⁰(CH₂)_WR¹², -

R ⁰(CH₂)_WR¹⁴, and -R ⁰(CH₂)_WR ⁴R¹⁶;

isobutyl, tert-butyl, methoxy, oxo, dioxo, chloro, flouro, bromo, trifluoromethyl, trifluoroethyl, trifluoromethoxy, trifluoroethoxy, nitrile, phenyl, acetyl, -S0₂R⁹, -

OR⁸, -C0₂R⁸, -C(0)R⁹, -C(0)R¹², and -C(0)NHR⁹;

propyl, isopropyl, butyl, isobutyl, tert-butyl, and phenyl;

isobutyl, and tert-butyl;

R ⁰ is phenyl;

R ² is -NR⁸R⁸,

R¹⁴ is selected from the group consisting of morpholinyl, thiomorpholinyl,

tetrahydropyranyl, dioxanyl, oxadiazolyl, pyrimidinyl, pyrazolyl, piperazinyl, pyrrolidinyl, piperidinyl, and pyridinyl; R ⁵ is independently selected from the group consisting of fluoro, oxo, dioxo, chloro, and bromo;

isopropyl, butyl, tert-butyl, -R ⁷, -(R ⁷)2, -R¹², hydroxyl, methoxy, ethoxy, and nitrile;

R¹⁷ is selected from the group consisting of chloro, fluoro, and bromo;

each n is independently an integer from 1 to 3; and

each w is independently an integer from 1 to 6.

45. A compound of Formula (II):

or a pharmaceutically acceptable salt thereof, wherein:

Y and Z are independently selected from a bond or (d-C₆)alkylene;

R² is selected from the group consisting of (C C₆)alkyl, -(CH₂)_WR¹⁴, -R⁶, -R¹⁰, -R¹³, -R ⁴, - R¹⁰R⁵, -R ⁰R⁷, -R¹⁰R¹⁴, -R¹³R¹⁶, -R¹⁴R⁷, -C(0)R⁸, and -R¹³OR⁸, wherein R¹ and R² may optionally join together along with any intervening N and C atoms to form a (C -C )heterocyclic or a (C₁-C )heteroaryl group fused to the adjacent pyridyl moiety and independently having one to three nitrogen heteroatoms, and wherein said R and R²-joined (CrCn)heterocyclic or (CrCn)heteroaryl group may be optionally substituted with one to three R ⁶ groups;

R³ and R⁴ are independently selected from the group consisting of hydrogen, (Ci- C₆)alkyl, (C C₆)alkoxy, nitrile, -S0₂R⁸, oxo, -OR⁸, -R ², and halo; R⁵ is selected from the group consisting of (Ci-C₆)alkyl, (CrC₆)alkoxy, -R ⁰R¹⁷, -

R¹⁰(R¹⁷)_n, benzyl, (C₄-C₁₄)aryl, (CrCn)heterocyclic, and (Ci-Cn)heteroaryl; R⁶ is independently selected from the group consisting of -R ⁰C(O)R¹⁴, -R ⁰C(O)R¹⁴R¹⁶, -

R¹⁰(CH₂)_WR¹², -R¹⁰(CH₂)_WR¹⁴, and -R ⁰(CH₂)_WR ⁴R¹⁶;

R⁷ is independently selected from the group consisting of (d-C₆)alkyl, (CrC₆)alkoxy, halo, nitrile, -C{0)R⁹, -S0₂R⁹, -C(0)NHR⁹, -C(0)R¹², -C0₂R⁸, -R⁹(R¹⁷)_m, -

OR⁹(R ⁷)_m, and -OR⁸;

R⁸ is independently selected from the group consisting of hydrogen and (CrC₆)alkyl; R⁹ is (Ci-Ce)alkyl;

R¹⁰ is (C₄-C₁₄)aryl;

R ² is -NR⁸R⁸;

R ³ is (C₃-C₁₂)cycloalkyl;

R ⁴ is selected from the group consisting of (d-C^heterocyclic _anc| (d-d^heteroaryl, each independently having one to three heteroatoms selected from N and O;

R¹⁵ is independently selected from the group consisting of (C C₆)alkyl, (C₁-C₆)alkoxy, -OR⁸, halo, nitrile, -N0₂, and -C0₂R⁸;

R ⁶ is independently selected from the group consisting of (CrC₆)alkyl, (Ci-C₆)alkoxy, - R¹⁷, -(R ⁷)₂, -R ², hydroxyl, and nitrile;

R¹⁷ is halo;

each m is independently an integer from 1 to 3;

each n is independently an integer from 1 to 3; and

each w is independently an integer from 1 to 6.

46. A compound of Formula (II):

(ll)

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is selected from the group consisting of hydrogen, methyl, ethyl, phenyl, nitrile, and -S0²R⁹;

structure:

R⁵ is selected from the group consisting of

R ⁰(CH₂)_WR¹⁴, and -R ⁰(CH₂)_WR¹⁴R¹⁶;

R⁷ is independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, methoxy, oxo, chloro, flouro, bromo, trifluoromethyl, trifluoroethyl, trifluoromethoxy, trifluoroethoxy, nitrile, carboxyl, acetoxy, -S0₂R⁹, -

OR⁸, -C0₂R⁸, -C(0)R¹², and -C(0)NHR⁹;

propyl, isopropyl, butyl, isobutyl, and tert-butyl;

isobutyl, and tert-butyl;

R ⁰ is phenyl;

R¹² is -NR⁸R⁸,

R ⁴ is selected from the group consisting of morpholinyl, tetrahydropyranyl, triazolyl, pyrimidinyl, pyrazolyl, piperazinyl, pyrrolidinyl, piperidinyl, pyridinyl,

R ⁵ is independently selected from the group consisting of fluoro, chloro, bromo,

R ⁷ is selected from the group consisting of chloro, fluoro, and bromo;

each n is independently an integer from 1 to 3; and

each w is independently an integer from 1 to 6.

47. A compound of Formula (III):

(III)

or a pharmaceutically acceptable salt thereof, wherein:

Y and Z are independently selected from a bond or (d-C₆)alkylene;

R² is selected from the group consisting of hydrogen, (CrC_e)alkyl, (CrC₆)alkenyl, halo, -NHR¹⁰, -R⁶, -R¹⁰, -R¹³, -R¹⁴, -R¹⁰R⁵, -R¹⁰R⁷, -R ⁰R¹⁴, -R ³R¹⁶, -R¹⁴R⁷, -(CH₂)_WR¹⁴, -C(0)R⁸, and -R¹³OR⁸;

R³ and R⁴ are independently selected from the group consisting of hydrogen, (Ci- C₆)alkyl, (C C₆)alkoxy, nitrile, -S0₂R⁸, oxo, -OR⁸, -R ², and halo;

R⁵ is selected from the group consisting of (Ci-C₆)alkyl, -R⁹OR⁸, (C C₆)alkoxy, -R¹⁰R¹⁷, -R ⁰(R ⁷)_n, benzyl, (C₄-C₁₄)aryl, (C₃-C₁₂)cycloalkyl, -R⁹R¹², -R⁹R¹³, -OR⁹(R ⁷)_m, trifluoromethyl, trifluoroethyl, (C -C )heterocyclic, and (d-C^heteroaryl;

R⁷ is selected from the group consisting of (C -C₆)alkyl, (CrC₆)alkoxy, oxo, halo, nitrile, - R⁹(R¹⁷)_m, -N0₂, -R⁹OR⁸, -C0₂R⁸, -C{0)R⁹, -R⁹(R ⁷)_m, -OR⁹(R¹⁷)_m, -(CH₂)_WCN, -S0₂R¹², -S0₂R⁹, -S0₂NH(CH₂)_wR¹⁴, -S0₂(CH₂)_wR¹⁴, -R¹², -R ⁴, - (CH₂)_wOR⁸, -C(0)NHR¹³, -C(0)NHR¹⁴, -C(0)NHR⁹, -R ⁰, -OR⁹(R ⁷)_m, -C(0)R¹², - NHC(O)NHR ⁰R¹¹, -C(0)NH(CH₂)_wR¹², -C(0)(CH₂)_wR¹², -NHC(0)C(0)R¹⁴, - NHC0₂R⁸, -OR⁸, -C(0)NH(CH₂)_wR¹⁴, -C(0)(CH₂)_wR¹⁴, -(CH₂)_WR¹¹, -NH(CH₂)_WR¹⁴, -(CH₂)_WR¹⁴ , -(CH₂)_WR¹⁰, -(CH₂)_WNHR¹⁰, -(CH₂)_wC0₂R⁸, -C(O)NHR ⁰R¹¹, - C(0)NH(CH₂)_wOR⁸, and -C(0)NH(CH₂)_wR¹¹;

R⁸ is independently selected from the group consisting of hydrogen, (Ci-C₆)alkyl, and

R⁹ is (C C₆)alkyl;

-NHR⁵, -NHR¹⁰R¹⁵, -NHR¹⁴, -R¹⁶, and -NHR¹⁰(R ⁷)_n;

R ² is -NR⁸R⁸;

R ³ is (C₃-C₁₂)cycloalkyl;

-NH(CH₂)_WR¹⁴, and -(CH₂)_WR¹⁴;

R ⁷ is halo;

each m is independently an integer from 1 to 3;

each n is independently an integer from 1 to 3; and

each w is independently an integer from 1 to 6.

48. A compound of Formula (III):

(111)

or a pharmaceutically acceptable salt thereof, wherein:

-S0²R⁹, -(CH₂)_WR¹⁴, and -(CH₂)_wS0₂R⁹;

NHR¹⁰SO₂R⁹, -R¹⁰R⁵, -R ⁰R⁷, -R ⁰R¹⁴, -R¹³R¹⁶, -R ⁴R⁷, -(CH₂)_WR¹⁴, -NHR ⁰SO₂R¹², -NHR ⁰R¹², -C(0)R⁸, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, hydroxycyclohexyl, phenyl, cyanophenyl, methylphenyl, acetylpiperidinyl, methylbenzamide, pyridyl, pyrazolyl, and pyrimidyl;

isobutyl, tert-butyl, methoxy, ethoxy, phenyl, chlorophenyl, fluorophenyl, difluorophenyl, benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, hydroxyethyl, dimethylaminoethyl, trifluoromethyl,

trifluoroethyl, trifluoromethoxy, pyridyl, quinolinyl, and furanyl;

isobutyl, tert-butyl, methoxy, ethoxy, oxo, chloro, flouro, bromo, trifluoromethyl, trifluoroethyl, trifluoromethoxy, trifluoroethoxy, nitrile, phenyl, carboxyl, acetoxy, - OR⁸, -C0₂R⁸, and -C(0)R⁹;

propyl, isopropyl, butyl, isobutyl, tert-butyl, and phenyl;

isobutyl, and tert-butyl;

R ⁰ is phenyl;

R¹¹ is selected from the group consisting of methyl, ethyl, -R ⁴, -R¹³, -R ², -NHR⁵, -

NHR¹⁴, -R¹⁴R ^S, -NHR¹⁰R^1S, -R¹⁶, and -NHR¹⁰(R¹⁷)_n;

R ² is -NR⁸R⁸;

each w is independently an integer from 1 to 6.

49. A compound of Formula (IV):

(IV)

or a pharmaceutically acceptable salt thereof, wherein:

Y and Z are independently selected from a bond or (d-C₆)alkylene;

R² is selected from the group consisting of hydrogen, (CrC₆)alkyl, (Ci-C₆)alkenyl, halo, -NHR ⁰, -R⁶, -R¹⁰, -R ³, -R¹⁴, -R¹⁰R⁷, -R ⁰R¹⁴, -R ³R¹⁶, -R¹⁴R⁷, -(CH₂)_WR¹⁴, - C(0)R^s, and -R¹³OR⁸;

R³ and R⁴ are independently selected from the group consisting of hydrogen, (Ci- C₆)alkyl, (C C₆)alkoxy, nitrile, -S0₂R⁸, oxo, -OR⁸, -R¹², and halo;

R⁵ is selected from the group consisting of (Gj-C6)alkyl, (CrC₆)alkoxy, -R ⁰R¹⁷, -

R ⁰(R¹⁷)_n, benzyl, (C₄-C₁₄)aryl, (C₃-C₁₂)cycloalkyl, trifluoromethyl, trifluoroethyl, (d-C^heterocyclic, and (d-C^Jheteroaryl;

R⁶ is selected from the group consisting of -R ⁰C(O)R¹⁴, -R ⁰C(O)R ⁴R¹⁶, -R ⁰(CH₂)_WR¹², R¹⁰(CH₂)_WR¹⁴, and -R¹⁰(CH₂)_WR¹⁴R¹⁶;

R⁷ is selected from the group consisting of (C₁-C₆)alkyl, (C -C₆)alkoxy, oxo, halo, nitrile,^■ R⁹(R¹⁷)_m, -N0_2l -R⁹OR⁸, -C0₂R⁸, -C(0)R⁹, -R⁹(R ⁷)_m, -OR⁹(R¹⁷)_m, -(CH₂)_WCN, -S0₂R¹², -S0₂R⁹, -S0₂NH(CH₂)_wR¹⁴, -S0₂(CH₂)_wR¹⁴, -R¹², -R¹⁴, - (CH₂)_wOR⁸, -C(0)NHR¹³, -C(0)NHR¹⁴, -C(0)NHR⁹, -R¹⁰, -OR⁹(R ⁷)_m, -C(0)R¹², - NHC{O)NHR ⁰R¹¹, -C(0)NH(CH₂)_wR¹², -C(0)(CH₂)_wR¹², -NHC(0)C{0)R¹⁴, - NHC0₂R⁸, -OR⁸, -C(0)NH(CH₂)_wR¹⁴, -C(0)(CH₂)_wR¹⁴, -(CH₂)_WR¹¹, -NH(CH₂)_WR¹⁴, -(CH₂)_WR¹⁴ , -(CH₂)_WR¹⁰, -(CH₂)_WNHR¹⁰, -(CH₂)_wC0₂R⁸, -C(O)NHR¹⁰R¹ , - C(0)NH(CH₂)_wOR⁸, and -C(0)NH(CH₂)_wR¹¹; and

(C₄-C ₄)aryl;

R⁹ is (C C₆)alkyl;

R¹⁰ is (C₄-C₁₄)aryl;

NHR⁵, -NHR¹⁰, -NHR ⁴, -NHR ⁰R¹⁵, -R ⁶, and -NHR¹⁰(R ⁷)_n;

R ² is -NR⁸R⁸;

R ³ is (C₃-Ci₂)cycloalkyl;

R¹⁴ is selected from the group consisting of (d-Cn heterocyclic and (d-Cn)heteroaryl, each independently having one to three heteroatoms selected from N and O; R ⁵ is selected from the group consisting of (Ci-C_e)alkyl, (Ci-C₆)alkoxy, oxo, dioxo, -

OR⁸, halo, nitrile, -N0₂, and -C0₂R^s;

NH(CH₂)_WR¹⁴, and -(CH₂)_WR¹⁴;

R ⁷ is halo;

each m is independently an integer from 1 to 3;

each n is independently an integer from 1 to 3; and

each w is independently an integer from 1 to 6.

50. A compound of Formula (IV):

or a pharmaceutically acceptable salt thereof, wherein:

R² is selected from the group consisting of hydrogen, methyl, ethyl, isobutyl, ethylene, halo, -NHR¹⁰SO₂R⁹, -R ⁰R⁷, -R ⁰R¹⁴, -R¹³R¹⁶, -R¹⁴R⁷, -(CH₂)_WR¹⁴, -NHR¹⁰SO₂R¹², - NHR¹⁰R¹², -C(0)R⁸, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,

structure:

propyl, isopropyl, butyl, isobutyl, tert-butyl, and phenyl;

isobutyl, and tert-butyl;

R ⁰ is phenyl;

R¹¹ is selected from the group consisting of methyl, ethyl, -R¹³, -R¹², -R ⁴, -NHR⁵, -

NHR ⁰, -NHR¹⁴, -R¹⁴R¹⁵, -NHR¹⁰R¹⁵, -R¹⁶, and -NHR ⁰(R ⁷)_n;

R ⁶ is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, tert- butyl, -R¹⁷, -(R¹⁷)₂, -R¹², hydroxy!, trifluoromethyl, trifluoromethoxy, methoxy, ethoxy, and nitrile;

R ⁷ is selected from the group consisting of chloro, fluoro, and bromo;

each n is independently an integer from 1 to 3; and

each w is independently an integer from 1 to 6.

51. A compound of Formula (V):

(V)

or a pharmaceutically acceptable salt thereof, wherein:

Y and Z are independently selected from a bond or (C₁-C₆)alkylene;

A is selected from the group consisting of (C₄-C₁₄)aryl, (CrC, ^heterocyclic, and (C

-R ⁴, and -S0₂R⁹, wherein said (C₄-Ci₄)aryl of said R group is optionally substituted with one to three R⁶ groups;

R² is selected from the group consisting of hydrogen, (Ci-C_e)alkenyl, halo, -NHR¹⁰, (C₄- Ci₄)aryl, (C₁-C₁ ^heterocyclic, and (CrCn)heteroaryl, wherein said (d- C heterocyclic and (C -C-n)heteroaryl groups of said R² group each independently have one to three heteroatoms selected from N and O, and wherein said R² group may be optionally substituted with one to three R⁷ groups; R³ is selected from the group consisting of hydrogen, (CrC₆)alkyl, (d-C₆)alkoxy, nitrile, - S0₂R⁸, oxo, -OR⁸, -R¹², and halo, and wherein said (C C₆)alkyl and (C

R⁵ is selected from the group consisting of (CrC₆)alkyl, (CrC₆)alkoxy, (C₄-Ci₄)aryl, benzyl, (C₃-Ci₂)cycloalkyl, trifluoromethyl, trifluoroethyl, (C-Cn heterocyclic, and (Ci-Cn)heteroaryl, wherein said (CrCn)heterocyclic and (CrCn)heteroaryl of said R⁵ group each independently have one to three heteroatoms selected from N and O, and wherein R⁵ may be optionally substituted with one to three R ⁵ groups;

R⁹ is (C C₆)alkyl;

R ⁰ is (C₄-C₁₄)aryl;

R¹¹ is selected from the group consisting of nitrile, halo, (CrC₆)alkyl, (C-C₆)alkoxy,

R¹² is -NR⁸R⁸;

R¹³ is (C₃-C₁₂)cycloalkyl;

R ⁷ is halo;

m is independently 0 or an integer from 1 to 4;

n is independently 0 or an integer from 1 to 3; and

w is independently 0 or an integer from 1 to 6.

52. A compound of Formula (V):

(V)

or a pharmaceutically acceptable salt thereof, wherein:

Y and Z are independently selected fro

A is selected from the group consisting

, phenyl, and dimethoxyphenyl, and wherein said A group may be optionally substituted with one to three R¹⁵ groups; selected from the group consisting of hydrogen, (CrC₆)alkyl, (C₄-Ci₄)aryl,

-R ⁴, and -S0₂R⁹, wherein said (C₄-Ci₄)aryl of said R¹ group is optionally substituted with one to three R⁶ groups; R² is selected from the group consisting of hydrogen, (CrC₆)alkenyl, halo, -NHR¹⁰, (C₄- C_M)aryl, (d-Cn heterocyclic, and (CrCn)heteroaryl, wherein said (d- C )heterocyclic and (d-Cn)heteroaryl groups of said R² group each

C₆)alkyl, (C C₆)alkoxy, nitrile, -N₃, -SR⁸, -S0₂R⁸, oxo, -OR⁸, -R ², and halo, and wherein said (CrC₆)alkyl and (CrC₆)alkoxy of said R³ and R⁴ groups may be optionally substituted with one to three R ⁷ groups;

R⁵ is selected from the group consisting of (Ci-C₆)alkyl, (CrC₆)alkoxy, (C₄-Ci₄)aryl, benzyl, (C₃-Ci₂)cycloalkyl, trifluoromethyl, trifluoroethyl, (d-d ₁ heterocyclic, and (CrCii)heteroaryl, wherein said (d-di)heterocyclic and (CrCn)heteroaryl of said R⁵ group each independently have one to three heteroatoms selected from N and O, and wherein R⁵ may be optionally substituted with one to three R ⁵ groups;

R⁶ is independently selected from the group consisting of (d-C₆)alkyl, (C -C₆)alkoxy, -OR⁸, -C(0)R¹⁴, and (d-Cn)heterocyclic, wherein said (CrCn)heterocyclic of said R⁶ group has one to three heteroatoms selected from N and O;

R⁷ is independently selected from the group consisting of (d-C₆)alkyl, (Ci-C₆)alkoxy, oxo, halo, nitrile, -OR⁸, and wherein said (CrC₆)alkyl and (CrC₆)alkoxy of said R⁷ group may be optionally substituted with one to three R ⁷ groups;

R⁹ is (C C₆)alkyl;

R ⁰ is (C₄-C₁₄)aryl;

-NHSO₂R⁹, -C0₂R⁸, -OR⁸, -0(CH₂)_wR¹², -S0₂R¹², -S0₂R⁹, -NH(CH₂)_WR¹⁴ , -R ⁶, and -(CH₂)_WR¹⁴; and wherein said (CrC₆)alkyl and (CrC₆)alkoxy of said R¹¹ group may be optionally substituted with one to three R¹⁷ groups;

R ² is -NR⁸R⁸;

R¹³ is (C₃-C₁₂)cycloalkyl;

R¹⁴ is selected from the group consisting of (C₁-C₁₁)heterocyclic and (d-C-i heteroaryl, each independently having one to three heteroatoms selected from N and O, wherein said (C -C )heterocyclic and (d-Cuheteroaryl may be optionally substituted by one to three independent R ⁶ groups; R ⁵ is selected from the group consisting of fluoro, chloro, bromo, oxo, dioxo, methoxy, ethoxy, methyl, ethyl, butyl, propyl, isopropyl, nitrile, -N0₂, trifluoromethoxy, and trifluoromethyl;

R ⁶ is independently selected from the group consisting of (C C₆)alkyl, (CrC₆)alkoxy, halo, nitrile, -NHS0₂R⁹, -C0₂R⁸, -OR⁸, -0(CH₂)_wR¹², -S0₂R¹², -S0₂R⁹, -NH(CH₂)_WR¹⁴, and -(CH₂)_WR¹⁴; and wherein said (C C₆)alkyl and (C C₆)alkoxy of said R ⁶ group may be optionally substituted with one to three R ⁷ groups;

R ⁷ is halo;

m is independently 0 or an integer from 1 to 4;

n is independently 0 or an integer from 1 to 3; and

w is independently 0 or an integer from 1 to 6.

53. A compound having the structure of Formula (VI):

or a pharmaceutically acceptable salt thereof.

54. A compound selected from the group consisting of those compounds in Table 1.

55. A pharmaceutical composition comprising a pharmaceutically acceptable diluent and a therapeutically effective amount of a compound as according to claim 1.

56. A method for treating a viral infection in a mammal mediated at least in part by a virus in the Flaviviridae family of viruses which method comprises administering to a mammal, that has been diagnosed with said viral infection or is at risk of developing said viral infection, a compound according to claim 1.

57. The method of claim 56, wherein said virus is hepatitis C virus.

58. The method of claim 56, further comprising administration of a therapeutically effective amount of one or more agents active against hepatitis C virus.

59. The method of claim 58, wherein said agent active against hepatitis C virus is an inhibitor of HCV protease, HCV polymerase, HCV helicase, HCV entry, HCV assembly, HCV egress, HCV replicase, HCV NS5A protein, or inosine 5'-monophosphate dehydrogenase.

60. The method of claim 59, wherein said agent active against hepatitis C virus is interferon.

61. The method of claim 59, wherein said agent active against hepatitis C virus is ribavirin.

62. The method of claim 59, wherein said agent active against hepatitis C virus is interferon in combination with ribavirin.