WO2006012577A2 - Quinazolinone derivatives useful for the regulation of glucose homeostasis and food intake - Google Patents

Abstract

This invention relates to substituted quinazolinone derivatives, compositions, and methods for treating diabetes, obesity and related disorders, and regulation of food intake (e.g., stimulation and suppression).

Description

QUINAZOLINONE DERIVATIVES USEFUL FOR THE REGULATION OF GLUCOSE HOMEOSTASIS AND FOOD INTAKE

[001] This application claims benefit of U.S. Provisional Application Serial No.60/590,804; filed on July 22, 2004, the contents of which are incorporated herein by reference in their entirety.

FIELD OF THE INVENTION

[002] This invention relates to compounds that may be useful for the treatment of diabetes, obesity and related disorders and regulation of food intake (e.g., stimulation and suppression). For example, it relates to certain quinazolinone derivatives which are useful in the treatment of said conditions. It also relates to certain quinazolinone derivatives which are useful for the treatment of wasting (e.g., cachexia) associated with various diseases or conditions, for example, wasting associated with cancer, AIDS, chronic liver disease, chronic obstructive pulmonary disease (COPD) or respiratory insufficiency, as well as wasting associated with bone fractures or with aging.

BACKGROUND OF THE INVENTION

[003] Diabetes is characterized by impaired glucose metabolism manifesting itself among other things by an elevated blood glucose level in the diabetic patient. Underlying defects lead to a classification of diabetes into two major groups. Type 1 diabetes, or insulin dependent diabetes mellitus (IDDM), arises when patients lack insulin-producing beta-cells in their pancreatic glands. Type 2 diabetes, or non-insulin dependent diabetes mellitus (NIDDM), occurs in patients with impaired beta-cell function and alterations in insulin action.

[004] The current treatment for type 1 diabetic patients is injection of insulin, while the majority of type 2 diabetic patients are treated with agents that stimulate beta-cell function or with agents that enhance the tissue sensitivity of the patients towards insulin. The drugs presently used to treat type 2 diabetes include alpha-glucosidase inhibitors, insulin sensitizers, insulin secretagogues, and metformin.

[005] Over time, almost one-half of type 2 diabetic subjects lose their response to these agents. Insulin treatment is instituted after diet, exercise, and oral medications have failed to adequately control blood glucose. The drawbacks of insulin treatment are the need for drug injection, the potential for hypoglycemia, and weight gain.

[006] Because of the problems with current treatments, new therapies to treat type 2 diabetes are needed. In particular, new treatments to retain normal (glucose-dependent) insulin secretion are needed. Such new drugs should have the following characteristics: dependency on glucose for promoting insulin secretion {i.e., compounds that stimulate insulin secretion only in the presence of elevated blood glucose); low primary and secondary failure rates; and preservation of islet cell function. [007] Obesity, which is an excess of body fat relative to lean body mass, is a chronic disease that is highly prevalent in modern society. This disorder is a significant risk factor for type 2 diabetes and is also associated with decreased life span and numerous other medical problems, including adverse psychological development, coronary artery disease, hypertension, stroke, hyperlipidaemia, and some cancers, (see, e.g., Nishina, et al., Metab. 43:554-558, 1994; Grundy and Barnett, Dis. Mon. 36:641-731 , 1990; Rissanen, et al., British Medical Journal, 301:835-837, 1990).

[008] Wasting, (e.g., cachexia) is a condition associated with various diseases or other conditions, for example, wasting associated with cancer, AIDS, chronic liver disease, chronic obstructive pulmonary disease (COPD) or respiratory insufficiency, as well as wasting associated with bone fractures or with aging.

[009] Diabetes, obesity, and wasting remain serious health problems. As a result of the limitations in current treatments, there is a significant need to develop pharmaceuticals and treatment regimes effective in the alleviation of these disorders.

DETAILED DESCRIPTION OF THE INVENTION

[010] The invention relates to substituted quinazolinone derivatives that have utility for the regulation of glucose homeostasis and food intake, said derivatives of Formula (I)

(i) wherein

R¹ is selected from

R² is selected from

• H,

• (CrCβJalkyl optionally substituted with (C_rC₄)alkoxy or benzyloxy,

• (C₁-C₂)alkyl substituted with phenyl that is optionally substituted with up to two R⁵ groups,

• (d-C^haloalkyl, • (C₃-C₆)cycloalkyl optionally substituted with up to two substituents selected from (C₁-C₃JaIkVl and halo,

• a five-membered heterocyclic aromatic ring containing up to two heteroatoms selected from the group of N and O, and said ring being optionally substituted with (C₁-C₃)alkyl or (C₁- C₃)alkoxy,

• pyridyl optionally substituted with up to two R⁵ groups,

• phenyl optionally substituted with up to three R⁵ groups, and

R³ is selected from

• H,

• halo,

• (C_rC₆)alkyl optionally substituted with OH, (C₁-C₂)BIkOXy, or (C₃-C₆)cycloalkyl,

• (C₃-C₆)cycloalkyl,

• (CrC₄)haloalkyl,

• a five-membered heterocyclic aromatic ring containing up to two heteroatoms selected from N, O, and S, and said ring being optionally substituted with up to two R⁷ groups,

• a five-membered heterocyclic aromatic ring containing one heteroatom selected from N, O, and S, and said ring being fused to a phenyl ring optionally substituted at any position with halo or (d-C₃)alkyl,

• pyridyl optionally substituted with up to two R⁸ groups,

• phenyl optionally substituted with up to three R⁸ groups,

• phenyl that is fused to a five-membered or six-membered aromatic ring optionally containing one heteroatom selected from N, O, and S, and said ring system being optionally substituted at any position with halo or (C₁-C^aIkVl, and

• phenyl that is fused to a five-membered or six-membered non-aromatic ring optionally containing up to two oxygen atoms;

R⁴ is selected from

• H,

• (C₃-C₆)cycloalkyl,

• (C_rC₆)alkyl optionally substituted with (C₃-C₆)cycloalkyl, one to two (C_rC₆)alkoxy groups, one to three halo, one to two OH, phenyl, pyrrolyl, or (CrC^alkenyl, and • phenyl;

R⁵ is selected from

• (C₁-C₆)BIkOXy optionally substituted with OH or alkoxy,

• phenoxy optionally substituted with halo,

• (CrC^alkyl optionally substituted with (C₁-C₃JaIkOXy,

• (C₃-C₆)cycloalkyl,

• (CrC_∑Jhaloalkyl,

• (C₁-C₂)haloalkoxy,

• halo,

• CN,

• NO₂

• SO₂CH₃,

• morpholine, and

• pyrrolidine;

R⁶ is selected from

• H,

• C(O)R⁹,

• (CrC^alkyl optionally substituted with phenyl, and

• phenyl optionally substituted with halo;

R⁷ is selected from

• (C-COalkyl,

• halo

• C(O)CH₃

• C(O)OCH₃,

• C(O)OC₂H₅,

• phenyl optionally substituted with up to two R⁵ groups,

• pyridyl optionally substituted with halo or (CrC₃)alkyl,

• furanyl optionally substituted with halo or (CrC^alkyl,

• thiophenyl optionally substituted with halo or (C₁-C₃)alkyl,

• thiazolyl optionally substituted with halo or (d-C₃)alkyl, and

R⁸ is selected from

• halo,

• (C_rC₆)alkyl,

• (C₁-C₂)haloalkyl,

• (C_rC₆)alkoxy optionally substituted with a cyclopropyl ring or OH,

• (C_rC₂)haloalkoxy,

• (C_rC₃)alkylthio,

• phenyl optionally substituted with halo,

• (C,-C₄)alkenyl,

• C(O)CH₃,

• CN,

• CH₂CN,

• NO₂,

• NH₂,

• N(R⁹)₂,

• OH, and

• SO₂CH₃;

R⁹ is (CrCeJalkyl or phenyl;

L is selected from

• a bond,

• O,

• C(O),

• S,

• SO₂,

• NR⁶,

• NHSO₂

• methylene,

• ethylene,

• ethenyl, and

• ethynyl;

m is O, 1 , or 2;

n is 1 or 2;

p is O, 1 , or 2;

or pharmaceutically acceptable salts thereof;

^ ,R⁴ provided that when R¹ = ' \--^ , n = 1 , p = 1 , L = bond, and R²-(CH₂)_m- = H, methyl, or ethyl, then R³ is not H or halo,

and further provided that when R¹ =

p = 1 , L = bond, and R²-(CH₂)_m- is H or methyl, then R³ is not H or methyl.

[011] The terms identified above have the following meaning throughout:

The terms "(C₁-C₂)alkyl," "(C₁-C₃)BlKyI," and "(CrC^alkyl" mean a linear or branched saturated hydrocarbon groups having from about 1 to about 2 carbon atoms, from about 1 to about 3 carbon atoms, and from about 1 to about 6 carbon atoms, respectively. Such groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, and the like.

[012] The terms "(C₁-C₂)alkoxy", "(C₁-C₃JaIkOXy", "(C₁-C₄JaIkOXy", and "(C_rC₆)alkoxy" mean a linear or branched saturated hydrocarbon group having from about 1 to about 2 carbon atoms, from about 1 to about 3 carbon atoms, from about 1 to about 4 carbon atoms, and from about 1 to about 6 carbon atoms, respectively, said group being attached to an oxygen atom. The oxygen atom is the atom through which the alkoxy substituent is attached to the rest of the molecule. Such groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, n- hexyloxy, 3,3-dimethylpropoxy, and the like.

[013] The term "(C₁-C₂)haloalkoxy" means a (C₁-C₂JaIkOXy group substituted on C with one or more halogen atom. Such groups include, but are not limited to, trifluoromethoxy, difluoromethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, 2-chloroethoxy, 1-fluoro-2,2,-dichloroethoxy, and the like.

[014] The term "(C₂-C₄)alkenyl" means a linear or branched unsaturated hydrocarbon radical containing a double bond and from about 2 to about 4 carbon atoms. The double bond may be between any two available carbon atoms in the chain. Such groups include, but are not limited to, vinyl, allyl, isopropenyl, 2-butenyl, 2-ethyl-2-butenyl, 1-hexenyl, and the like. [015] The term "(CrC^alkylthio" means a linear or branched saturated hydrocarbon radical having from about 1 to about 3 C atoms, said radical being attached to an S atom. The S atom is the atom through which the alkylthio substituent is attached to the rest of the molecule. Such groups include, but are not limited to, methylthio, ethylthio, n-propylthio, and isopropylthio.

[016] The term "halo" means F, Br, Cl, and I.

[017] The terms "(CrCaJhaloalkyl" and "(CrC₄)haloalkyl" mean a (C_rC₂)alkyl group or (C₁- C₄)alkyl group, respectively, substituted on C with a halogen atom. Such groups include, but are not limited to, trifluoromethyl, difluoroethyl, 1-fluoro-2,2-dichloroethyl, 3-chloropropyl, 4- bromohexyl, and the like.

[018] The term "(C₃-C₆)cycloalkyl" means a saturated monocyclic alkyl group of from 3 to about 6 carbon atoms and includes such groups as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[019] The term "five-membered heterocyclic aromatic ring containing up to two heteroatoms selected from the group of N and O, and said ring being optionally substituted with (CrC₃)alkyl or (C₁-C₃JaIkOXy" is intended to mean a stable 5-membered monocyclic heterocyclic unsaturated ring which consists of carbon atoms and from one to two heteroatoms independently selected from the group consisting of N and O. The heterocyclic group may be attached to its pendant group at any heteroatom or carbon atom which results in a chemically stable structure. The heterocyclic ring may optionally be substituted with a (d-C₃)alkyl group or an (C₁-C₃JaIkOXy group either on a carbon or on a nitrogen atom if the resulting compound is stable. The total number of O atoms does not exceed one. Examples of said ring systems include, but are not limited to, furanyl, pyrrolyl, oxazolyl, imidazolyl, isoxazolyl, and pyrazolyl.

[020] The term "five-membered heterocyclic aromatic ring containing up to two heteroatoms selected from N, O, and S, and said ring being optionally substituted with up to two R⁷ groups" is intended to mean a stable 5-membered monocyclic heterocyclic unsaturated ring which consists of carbon atoms and from one to two heteroatoms independently selected from the group consisting of N, O, and S. The heterocyclic group may be attached to its pendant group at any heteroatom or carbon atom which results in a chemically stable structure. The heterocyclic ring may optionally be substituted with from one to two independently selected R⁷ groups either on a carbon or on a nitrogen atom if the resulting compound is stable. The total number of S and O atoms does not exceed one. Examples of said ring systems include, but are not limited to, thiophenyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, isothiazolyl, isoxazolyl, and pyrazolyl.

[021] The term "five-membered heterocyclic aromatic ring containing one heteroatom selected from N, O, and S, and said ring being fused to a phenyl ring optionally substituted at any position with halo and (CrC^alkyl" is intended to mean a stable 9-membered bicyclic heterocyclic ring which consists of a five-membered and a phenyl ring that are fused and form an unsaturated ring system. The five-membered ring consists of carbon atoms and one heteroatom independently selected from the group consisting of N, O, and S. This ring system may be attached to its pendant group at any heteroatom or carbon atom of the five-membered ring which results in a chemically stable structure. This 9-membered bicyclic heterocyclic ring may optionally be substituted with a halo atom or a (C_rC₃)alkyl group either on a carbon or on a nitrogen atom if the resulting compound is stable. Examples of said ring systems include, but are not limited to, benzothiophenyl, benzofuranyl, and indolyl.

[022] The term "phenyl that is fused to a five-membered or six-membered aromatic ring optionally containing one heteroatom selected from N, O, or S, and said ring system being optionally substituted at any position with halo and (CVCaJalkyl" is intended to mean a stable nine- to ten-membered bicyclic heterocyclic ring which consists of a five- to six-membered and a phenyl ring that are fused and form an unsaturated ring system. The five- to six-membered ring consists of carbon atoms and one heteroatom independently selected from the group consisting of N, O, and S. This ring system may be attached to its pendant group at any carbon atom of the phenyl ring which results in a chemically stable structure. This nine- to ten-membered bicyclic heterocyclic ring may optionally be substituted with a halo atom or a (CrCsJalkyl group either on a carbon or on a nitrogen atom if the resulting compound is stable. Examples of said ring systems include, but are not limited to, benzothiophenyl, benzofuranyl, indolyl, quinolinyl, and isoquinolinyl.

[023] The term "phenyl that is fused to a five-membered or six-membered non-aromatic ring optionally containing up to two oxygen atoms" is intended to mean a stable nine- to ten-membered bicyclic heterocyclic ring which consists of a five- to six-membered saturated ring and a phenyl ring that are fused. The five- to six-membered saturated ring consists of carbon atoms and from zero to two oxygen atoms which are located at positions of the ring that result in a chemically stable structure. This ring system may be attached to its pendant group at any carbon atom of the phenyl ring which results in a chemically stable structure. Examples of said ring systems include, but are not limited to, tetrahydronaphthyl, dihydroindenyl, chromanyl, isochromanyl, dihydrobenzofuranyl, dihydroisobenzofuranyl, 1 ,2-ethylenedioxybenzenyl, and 1 ,2-methylenedioxybenzenyl.

[024] The formula C(O) means a radical in which the C atom bears a doubly bonded oxygen atoms, (an oxo substituent) and in which there remain two additional binding sites, that is, represents a radical of the formula:

O

[025] The formula SO₂ means a radical in which the S atom bears two doubly bonded oxygen atoms, (oxo substituents) and in which there remain two additional binding sites, that is, represents a radical of the formula:

⁰V⁰

[026] The term "optionally substituted" means that the moiety so modified may have from none to up to at least the highest number of substituents indicated. Each substituent may replace any H atom on the moiety so modified as long as the replacement is chemically possible and chemically stable. When there are two or more substituents on any moiety, each substituent is chosen independently of any other substituent and can, accordingly, be the same or different.

[027] In Formula (I), up to two (L-R³) substituent(s) may attached to the quinazolinone ring core at any available 5, 6, 7, or 8 position of the quinazolinone ring core, the positions 5-8 being numbered as illustrated below:

[028] Representative salts of the compound of Formula (I) include the conventional non-toxic salts and the quaternary ammonium salts which are formed, for example, from inorganic or organic acids or bases by means well known in the art. For example, such acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cinnamate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, itaconate, lactate, maleate, mandelate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, sulfonate, tartrate, thiocyanate, tosylate, and undecanoate.

[029] Base salts include alkali metal salts such as potassium and sodium salts, alkaline earth metal salts such as calcium and magnesium salts, and ammonium salts with organic bases such as dicyclohexylamine salts and Λ/-methyl-D-glucamine. Additionally, basic nitrogen containing groups may be quaternized with such agents as lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, and dibutyl sulfate; and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and strearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides and others.

[030] The esters in the present invention are non-toxic, pharmaceutically acceptable ester derivatives of the compound of Formula (I). This includes, for example, ester derivatives of hydroxy-containing a compound of Formula (I) prepared with acetic, benzoic, mandelic, stearic, lactic, salicylic, hydroxynaphthoic, glucoheptonic, and gluconic acid. The compound of Formula (I) may be esterified by a variety of conventional procedures well known by those skilled in the art. One skilled in the art would readily know how to successfully carry out these as well as other methods of esterification.

[031] Sensitive or reactive groups on the compound of Formula (I), may need to be protected during any of the above methods for forming esters, and protecting groups may be added and removed by conventional methods well known in the art. [032] The compounds of this invention may, either by nature of asymmetric centers or by restricted rotation, be present in the form of isomers. Any isomer may be present in which the asymmetric center is in the (R)-, (S)-, or (R₁S) configuration.

[033] It will also be appreciated that when two or more asymmetric centers are present in the compounds of the invention, that several diastereomers and enantiomers of the exemplified structures will often be possible, and that pure diastereomers and pure enantiomers represent preferred embodiments. It is intended that pure stereoisomers, pure diastereomers, pure enantiomers, and mixtures thereof, are within the scope of the invention.

[034] All isomers, whether separated, pure, partially pure, or in racemic mixture, of the compounds of this invention are encompassed within the scope of this invention. The purification of said isomers and the separation of said isomeric mixtures may be accomplished by standard techniques known in the art.

[035] Geometric isomers by nature of substituents about a double bond or a ring may be present in cis (= Z-) or trans (= E-) form, and both isomeric forms are encompassed within the scope of this invention.

[036] The particular process to be utilized in the preparation of the compounds of this invention depends upon the specific compound desired. Such factors as the selection of the specific moieties and the specific substituents on the various moieties, all play a role in the path to be followed in the preparation of the specific compounds of this invention. These factors are readily recognized by one of ordinary skill in the art.

[037] For synthesis of any particular compound, one skilled in the art will recognize that the use of protecting groups may be required for the synthesis of compounds containing certain substituents. A description of suitable protecting groups and appropriate methods of adding and removing such groups may be found, for example, in Protective Groups in Organic Synthesis, Second Edition, T. W. Greene, John Wiley and Sons, New York, 1991.

[038] In the reaction schemes below, one skilled in the art will recognize that reagents and solvents actually used may be selected from several reagents and solvents well known in the art to be effective equivalents. When specific reagents or solvents are shown in a reaction scheme, therefore, they are meant to be illustrative examples of conditions desirable for the execution of that particular reaction scheme. Abbreviations not identified in accompanying text are listed later in this disclosure under "Abbreviations and Acronyms."

[039] Another object of this invention is to provide methods of making the compounds of the invention. The compounds may be prepared from readily available materials by the methods outlined in the reaction scheme and Examples below, and by obvious modifications thereto. General Methods of Preparation of Compounds of the Invention

[040] Compounds of the invention may be prepared from readily available starting materials using the general methods illustrated in Reaction Schemes 1-18 below.

[041] Reaction Scheme 1

(H) (III)

1) RM

2) Ac₂O

(Ia) deprotection, neutralization, and further transformations, as necessary

(I) [042] For example, compounds of the Formula (I) can be synthesized as shown in Reaction Scheme 1 starting from an anthranilic acid (2-aminobenzoic acid) derivative of Formula (III). Formula (III) compounds are either commercially available, or readily synthesized by standard methods (e.g., reduction of the readily available nitrobenzoic acids of Formula (II) using hydrogen and a Pd catalyst or Zn/HOAc). Treatment of 2-amino-5-bromobenzoic acid (III) with an acid chloride of Formula (IVa) and base or an acid of Formula (IVb) and amide coupling reagents known in the art, followed by heating with acetic anhydride and a catalytic amount of acid, yields the lactone derivative of Formula (V). Alternatively, the lactone derivative of Formula (V) can be obtained in one step by treatment of 2-amino-5-bromobenzoic acid (III) with an ortho ester of Formula (IVc). Heating of the lactone of Formula (V) with a substituted amine of Formula (Vl) yields the amino amide intermediate of Formula (VII). Cyclization to the quinazolinone ring structure under basic conditions (e.g., NaOH or LiOH) or acidic conditions (e.g., TFA or BF₃ Et₂O) and subsequent purification, in most cases by HPLC, yields the product (Ia) as a salt. The Formula (Ia) compound can be converted to the compound of Formula (I) by neutralizing the salt, and if necessary, deprotection of groups attached at R¹-R³ positions or conducting other transformations, using procedures well-known in the art and described in the following reaction schemes.

[043] A specific example of this method is illustrated further in Reaction Scheme 2.

[044] Reaction Scheme 2

[045] Reaction Scheme 2 illustrates the addition of a protected amine of Formula (Via) with the lactone of Formula (V) to form the intermediate of Formula (Vila) and subsequent treatment with an inorganic base, such as aqueous NaOH, to produce the protected intermediate of Formula (VIII). Deprotection of this compound with an acid, such as TFA, gives the salt of Formula (Ib). As an alternative to the base-mediated cyclization, the intermediate of Formula (Vila) may be cyclized and deprotected through treatment with acid to form the product of Formula (Ib) in one step. The salt of Formula (Ib) may be converted, either by a reductive amination procedure using an aldehyde of Formula (IX) and a reducing agent, or an alkylating agent such as an alkyl halide, mesylate or tosylate of Formula (X) and a base to give the product of Formula (Ic). Suitable reducing agents include sodium triacetoxyborohydride, or in the case where R⁴ = H, formic acid may be used. The salt of Formula (Ic) may be further converted to the free base (Id) through a neutralization reaction. Depending on the workup or purification method, free base (Id) may also be directly produced from the reductive amination or alkylation reaction introducing R⁴.

[046] Another specific example of the general method described in Scheme 1 is described in Reaction Scheme 3.

[047] Reaction Scheme 3

(Xl) (XII)

base

(Ie)

Y = halo, MsO, or TsO R^4'-CH₂— = R⁴

[048] Reaction Scheme 3 illustrates the addition of the benzyl-protected aminomethyl- substituted morpholine derivative of Formula (VIb) with the lactone of Formula (V) to form the intermediate of Formula (VIIb) and subsequent treatment with an inorganic base, such as aqueous NaOH, to produce the ring-closed benzyl-protected intermediate of Formula (Xl). Removal of the benzyl group, for example with hydrogen/catalytic palladium on carbon or chloromethylchloroformate, gives the unprotected morpholine derivative (XII). Compound (XII) may be converted, either by a reductive amination or alkylation reduction, as described in Reaction Scheme 2, to the alkylated product (Ie).

[049] A third specific example of the general method described in Scheme 1 is outlined in Reaction Scheme 4.

Reducing agent

(if)

[051] Reaction Scheme 4 illustrates the addition of the aminoalkyl-substituted pyridine of Formula (VIc) with the lactone of Formula (V) to form the intermediate of Formula (VIIc) and subsequent treatment with an inorganic base, such as aqueous NaOH, to produce the ring-closed pyridine intermediate of Formula (XIII). Alkylation of this compound with an alkylating reagent R⁴- Y of Formula (X) gives the pyridinium salt intermediate (XIV) which is further converted to the 1 ,2,3,6-tetrahydropyridine product of Formula (If) using a reducing agent (e.g., NaBH₄).

[052] Preparation of compounds of Formula (I) containing (L-R³) groups which are optionally substituted aryl, alkyl, cycloalkyl, aromatic or non-aromatic heterocyclyl, or alkenyl is illustrated below in Reaction Scheme 5. [053] Reaction Scheme 5

R³-B(OR')₂

hal = Cl, Br, I (Ih) [Formula I where (Ig) [Formula I where L = bond and p = 1 ] L = bond, p = 1 , and R³ = hal]

(Ii) [Formula I where (Ij) [Formula I where L = ethenyl and p = 1 ] L = ethylene and p - 1]

[054] In Reaction Scheme 5, a compound of Formula (Ig) [Formula (I) where (L-R³) is halo and p = 1] can be converted to Formula (I) compounds containing R³ groups that are directly attached to the core rendering compounds of Formula (Ih) [Formula (I) where L = bond and p = 1] or compounds containing an R³ groups that is linked to the core via an ethenyl group rendering compounds of Formula (Ii) [Formula (I) where L = ethenyl and p = 1]. This transformation can be done using Suzuki coupling conditions, that is, a boronic acid of Formula (XV) or (XVa), a palladium catalyst, and a base such as potassium carbonate. Alkenes of Formula (Ii) can be reduced, for example, by using hydrogen and palladium on carbon, to compounds of Formula (Ij).

[055] Preparation of compounds of Formula (I) containing (L-R³) groups which are acetyl or optionally substituted alkinyl is illustrated below in Reaction Scheme 6.

[056] Reaction Scheme 6

Pd catalyst hal = Cl, Br, I (Ik) [Formula I where L = C(O),

(ig) R³ = CH₃ and p = 1]

(I I) [Formula I where (Ij) [Formula I where L = ethinyl and p = 1] L - ethylene and p = 1]

[057] In Reaction Scheme 6, a compound of Formula (Ig) [Formula (I) where (L-R³) is halo and p = 1] can be converted to other Formula (I) compounds containing an acetyl group rendering compounds of Formula (Ik) [Formula I where L = C(O), R³ = CH_3, and p = 1]. This transformation can be done in a single step using Stille coupling conditions, for example, tributyl(1-ethoxyvinyl)tin of Formula (XVI) and a palladium catalyst. Alternatively, a compound of Formula (Ig) can be converted to an alkyne derivative of Formula (I I) [Formula (I) where L = ethynyl and p =1] by using Sonogashira coupling conditions, that is, a terminal alkyne of Formula (XVII), a palladium catalyst, and a base. The alkyne derivatives of Formula (I I) may be further transformed to the corresponding alkyl derivatives of Formula (Ij) [Formula (I) where L = ethylene and p = 1] through hydrogenation reaction, using, for example, hydrogen and palladium on carbon.

[058] The methodology described in Reaction Scheme 5 may also be used at an earlier stage of the synthetic sequence outlined in Reaction Scheme 1 , as illustrated below in Reaction Scheme 7.

[059] Reaction Scheme 7

hal = Cl, Br, I base

(Vb) [Formula V where (Va) L = bond and p = 1]

[060] In Reaction Scheme 7, a lactone of Formula (Va) [Formula (V) where R is halo] can be used as the starting material for Suzuki coupling reactions that can be conducted under similar conditions as described in Reaction Scheme 6.

[061] Apart from the use in carbon-carbon bond formation reactions, intermediate (Ig) may also be used for heteroatom bond formation reactions as outlined in Reaction Scheme 8 below.

[062] Reaction Scheme 8

R³-NH₂ R³-SH

R³-SO₂NH₂ (XIX) (XXI) (XX) Pd catalyst Pd catalyst Cu catalyst base base base

(In) [Formula I where (Ip) [Formula I where (Iq) [Formula I where L = NH and p = 1 ] L = NHSO₂ and p = 1] L = S and p = 1]

(lo) [Formula I where (Ir) [Formula I where L = NR⁶ and p = 1] L = SO₂ and p = 1]

[063] As illustrated in Reaction Scheme 8, an intermediate of Formula (Ig) can be transformed to an ether derivative of Formula (Im) by using Ullmann type coupling conditions, that is, reaction of an alcohol of Formula (XVIII) in the presence of a base, such as potassium carbonate, and a copper catalyst. Furthermore, the intermediate of Formula (Ig) can be transformed to an amino derivative of Formula (In) or a sulfonamido derivative of Formula (Ip) by applying Buchwald- Hartwig type coupling conditions, that is, reaction of an amine R³-NH₂ [Formula (XIX)] or a sulfonamide R³-SO₂NH₂ [Formula (XX)] in the presence of a base, such as cesium carbonate, and a palladium catalyst. The reaction product (In) may be further alkylated using an alkylating reagent R⁶-Y and a base, to form a product of formula (lo) [Formula (I) where L = NR⁶ and p = 1]. In addition, the intermediate of Formula (Ig) can be transformed to a thioether derivative of Formula (Iq) by using Ullmann type coupling conditions as described above, using a thiol R³-SH [Formula (XXI)] as starting material. The thioether product of Formula (Iq) may be further converted to a sulfone derivative of Formula (Ir) through oxidation reactions known in the art, for example, using oxone^®.

[064] Carbon-linked and oxygen-linked compounds as described in Reaction Schemes 5 and 8, respectively, may also be synthesized in a reverted manner, as outlined in Reaction Scheme 9.

[065] Reaction Scheme 9

Pd catalyst

hal ]

(It) [Formula I where (Ih) [Formula I where L = O, p = 1 , and R³ = H] L = bond and p = 1 ]

(Im) [Formula I where L = O and p = 1]

[066] In Reaction Scheme 9, a halogen intermediate of Formula (Ig) can, through reaction with bis-pinacolatodiboron, a palladium catalyst, and a base, be transformed into the boronate of Formula (Is). This compound can be further converted to a product of Formula (Ih) by using Suzuki coupling conditions, that is, reaction with a compound R³-hal, a palladium catalyst, and a base. Furthermore, the compound of Formula (Is) can be converted to the corresponding hydroxy derivative of Formula (It) through reaction with hydrogen peroxide and base. The hydroxy compound of Formula (It) may be further alkylated using an alkylating reagent R³-hal and a base to form a product of Formula (Im). [067] An alternative approach of accessing compounds with R³ groups linked through an ether bond is highlighted in Reaction Scheme 10.

[068] Reaction Scheme 10

(Ilia) [Formula III where L = O, p = 1 , and R³ = H]

[069] Reaction Scheme 10 illustrates the reaction of a hydroxy-substituted 2-aminobenzoic acid derivative (Ilia) [Formula III where L = O, p = 1 , and R³ = H] with an acid chloride of Formula (IVa) or an acid of Formula (IVb) in the presence of amide coupling reagents known in the art and subsequent cyclization using acetic acid anhydride to form the acetate (Vc) [Formula (V) where L = O, p = 1 , and R³ = C(O)CH₃]. Heating the acetate (Vc) with a substituted amine of Formula (Vl) and subsequent cyclization using an inorganic base, such as NaOH, yields the hydroxy derivative (It) which can be further alkylated to product (Im) by using an alkylating reagent R³-hal and a base.

[070] The halogen intermediate (Ig) may also be converted to a thioamide derivative of Formula (Iv) that can be further transformed into a thiazole derivative of Formula (Iw) shown below. [071] Reaction Scheme 11

hal = Cl, Br, I (I_U) [Formula I where

(Ig) L = bond, p = 1 , and R³ = CN]

(Iw) [Formula I where _R7

L = bond, p = 1 , and R³ = C(S)NH₂] _{L = bond] p} = 1 , and R³ = →fϊ ]

N _R7

[072] Reaction Scheme 11 illustrates the reaction of intermediate (Ig) with Zn(CN)₂ and a Pd catalyst to yield the cyano derivative (Iu) (Formula (I) where L = bond, p = 1 , and R³ = CN]. Using hydrogen sulfide and a base, such as diethylamine, the compound of Formula (Iu) can be further transformed to the thioamide derivative (Iv) (Formula (I) where L = bond, p = 1 , and R³ = C(S)NH₂] which can then be converted to a thiazole derivative of Formula (Iw), for example, by using an α- haloketone of Formula (XXII) and applying the Hantzsch thiazole formation reaction. The two R⁷ groups attached to the α-haloketone and the thiazole ring, respectively, are selected independently from the other so that they may be the same or they may be different.

[073] R¹ may be introduced prior to R². The halogenated aminoamide intermediate of Formula (XXIIIa), obtained after incorporating R¹, can be transformed to a product of Formula (Ih) through a variety of different reaction sequences as outlined in Reaction Scheme 12 below.

[074] Reaction Scheme 12

(Ih) [Formula I where L = bond and p =1]

[075] In Reaction Scheme 12, the anthranilic acid derivative of Formula (lllb) or isatoic acid anhydride derivative of Formula (MIc) can be first converted to the aminoamide of Formula (XXIIIa). In the case of an anthranilic acid derivative, the use of a coupling reagent and base is required. In the case of an isatoic acid derivative as the starting material, the presence of a base is sufficient. The aminoamide derivative of Formula (XXIIIa) can be transformed to the product of Formula (Ih) through a variety of different sequences. For example, it can be subjected to Suzuki coupling conditions, that is, a boronic acid of Formula (XV), a palladium catalyst, and a base, to give an aminoamide derivative that is substituted with an R³ group [Formula (XXIIIb)], This intermediate can then be treated with an acid chloride of Formula (IVa) or can also be treated with an acid of Formula (IVb) in the presence of coupling agents known in the art and base, to give the diamide of Formula (VIIe) which can then be cyclized as previously described. Alternatively, the order of introducing R³ and R² may be reverted, using similar reaction conditions in a different order. Reaction of the intermediate of Formula (XXIIIa) with an acid chloride of Formula (IVa), an acid of Formula (IVb) in the presence of coupling agents, or anhydride of Formula (IVd) in the presence of base yields the diamide derivative (VIId) which can then be coupled with an R³ group and cyclized as previously described. A third variation is the cyclization of the intermediate of Formula (VIId) to form an intermediate of Formula (Ig) and subsequent Suzuki-type coupling to form the product of Formula (Ih).

[076] Reaction Scheme 13, shown below, illustrates a variation of Reaction Scheme 12 that allows access of the intermediate of Formula (Ig) from the aminoamide of Formula (XXIIIa) in one step.

[077] Reaction Scheme 13

[078] In Reaction Scheme 13, the aminoamide derivative of Formula (XXMIa) can be heated in the presence of an ortho ester of Formula (IVc) to directly yield the intermediate of Formula (Ig).

[079] A special variation of the base-mediated cyclization to the quinazolinone scaffold as illustrated in Reaction Schemes 1-3 and 10 is the cyclization of intermediate (VIIf) [Formula VII where m = 0 and R² = 2,4-difluorophenyl] which proceeds under substitution of either the 4-fluoro group or both the 2- and 4-fluoro substituents by ethanediol used as the solvent to give compounds of the Formula (Ix) and (Iy). The alcohol function of the compound of Formula (Ix) can be further methylated to give a compound of Formula (Iz) (Reaction Scheme 14). [080] Reaction Scheme 14

[081] Another, closely related, variation of the reaction sequence shown in Reaction Scheme 14 is depicted in Reaction Scheme 15. Instead of substituting a fluorine atom during the cyclization reaction, ethylene glycol substitutes a thfluoroethoxy group to yield a product of Formula (laa).

[082] Reaction Scheme 15

[083] Starting materials used in the preparations of the Formula (I) compounds described above are either readily available or prepared by means well-known in the art. For example, nitrobenzoic acid derivatives of Formula (II) in which R³ is a substituted amino group (Formula (lib)), may be prepared from the corresponding fluoro-nitrobenzoic acid (Formula (Ha)) as shown in Reaction Scheme 16, using an amine of Formula (XXIV) and a base. [084] Reaction Scheme 16

base (Ma) (Mb)

[085] Boronates of the Formula (XV) can be prepared if needed, from compounds of the Formula (XXV) using a borylating agent, such as tetraalkoxydiboron, a palladium catalyst, such as PdCI₂(dppf), and a base, such as potassium acetate (Reaction Scheme 17).

[086] Reaction Scheme 17

Borylating agent, Pd cat, base

R³— Y - R³— B(OR¹J₂

Y = hal, OTf

(XXV) (^XV)

[087] Amines of Formula (Vl) used as starting materials can be prepared if needed, by the method shown in Reaction Scheme 18. This route employs the N-alkylation conditions described above for the preparation of the compound of Formula (Ic), namely, reductive amination of the protected cyclic amine of Formula (XXVI) using an aldehyde and reducing agent, or an alkyl halide, etc., and a base to give the protected intermediate of Formula (XXVII). Removal of the protecting group provides the intermediates of Formula (VId) [Formula (Vl) in which R¹ is a cyclic amino group substituted with R⁴].

[088] Reaction Scheme 18

base

Y = halo, MsO, or TsO

At= acid anion, e.g., Cl^", CF₃CO₂ ^', etc.

[089] Examples of compounds of the invention may be found in the Examples described below and in Table 1. The compounds described in the Examples are intended to be representative of the invention, and it will be understood that the scope of the invention is not limited by the scope of the examples. Those skilled in the art will recognize that the invention may be practiced with variations on the disclosed structures, materials, compositions and methods, and such variations are regarded as within the ambit of the invention.

General Experimental Methods

[090] Air and moisture sensitive liquids and solutions were transferred via syringe or cannula, and introduced into reaction vessels through rubber septa. Commercial grade reagents and solvents were used without further purification. The term "concentration under reduced pressure" refers to use of a Buchi rotary evaporator at approximately 15 mm of Hg. All temperatures are reported uncorrected in degrees Celsius (⁰C). Column chromatography (flash chromatography) was performed on a Biotage system using 32-63 micron, 60 A, silica gel pre-packed cartridges. Purification using preparative reversed-phase HPLC chromatography were accomplished using a Gilson 215 system, typically using a YMC Pro-C18 AS-342 (150 x 20 mm I. D.) column. Typically, the mobile phase used was a mixture of H₂O (A) and MeCN (B). The water could be mixed or not with 0.1% TFA.

[091] As indicated in the experimental section, certain reactions were performed using a reflux reaction block by J-Kem (J-Kem Scientific, Inc., St. Louis, MO). The specifications are as follows: customized reaction block to fit 40 mL EPA vials; 9 x 7 array, 34.2 cm x 30.5 cm x 8 cm; 28.2 mm id hole size to accommodate EPA vials. The reaction block shakes on a typical orbital shaker such as Model BTS 3000 (J-Kem Scientific, Inc.).

[092] As indicated in the experimental section, certain reactions were performed using a microwave reactor (e.g., Emrys™ Optimizer from Biotage, Charlottesville, VA).

Analytical methods

Thin layer chromatography (TLC)

[093] TLC was performed on EM Science pre-coated glass-backed silica gel 60 A F-254 250 μm plates.

HPLC - Electrospray Mass Spectra (ES-MS)

[094] Method A: Spectra were obtained using a Hewlett Packard 1100 HPLC system equipped with a quaternary pump, a variable wavelength detector, a YMC Pro 18 2.0 mm x 23 mm column, and a Finnigan LCQ ion trap mass spectrometer with electrospray ionization. Gradient elution from 90% A to 95% B over 5 minutes was used on the HPLC. Buffer A was 98% water, 2% acetonitrile, and 0.02% TFA, and Buffer B was 98% acetonitrile, 2% water, and 0.018% TFA. Spectra were scanned from 140-1200 amu using a variable ion time according to the number of ions in the source. If not otherwise stated in the experimental section, method A was used as the standard HPLC-MS method for characterizing compounds described herein.

[095] Method B: Spectra were obtained using a Gilson HPLC system equipped with two Gilson 306 pumps, a Gilson 215 Autosampler, a Gilson diode array detector, a Waters Symmetry column (4.6 x 50mm, 5um), and a Micromass LCZ single quadrupole mass spectrometer with z-spray electrospray ionization. Spectra were scanned from 120-1000 amu over 2 seconds. Gradient elution was used with Buffer A as 2% acetonitrile in water with 0.02% TFA and Buffer B as 2% water in acetonitrile with 0.02% TFA at 4.0 mL/min. Samples were eluted as follows: 90% A for 1.0 minutes ramped to 95% B over 3.0 minutes and held at 95% B for 0.8 minutes and then the column is brought back to initial conditions over 0.1 minutes.

NMR spectroscopy

[096] Proton (¹H) nuclear magnetic resonance (NMR) spectra were measured using the following spectrometers: (a) General Electric GΛ/-Omega 300 (300 MHz) spectrometer using either Me₄Si (δ 0.00) or residual protonated solvent (CHCI₃ δ 7.26; MeOH δ 3.30; DMSO δ 2.49) as standard, (b) Varian Mercury Plus 400 (400 MHz) spectrometer using the compounds mentioned above as standard.

[097] Carbon (¹³C) NMR spectra were measured using the following spectrometers: (a) General Electric GΛ/-Omega 300 (75 MHz) spectrometer using solvent (CDCI₃ δ 77.0, MeOD-c/₃; δ 49.0; DMSO-d₆δ 39.5) as standard, (b) Varian Mercury Plus 400 (100 MHz) spectrometer using the solvents mentioned above as standards. Abbreviations and Acronyms

[098] When the following abbreviations are used throughout the disclosure, they have the following meaning:

Ac₂O acetic anhydride

AcO (or OAc) acetate anhyd anhydrous aq aqueous

Ar aryl atm atmosphere b.i.d. twice a day

BINAP 2,2'-bis(diphenylphosphino)-1 ,1 '-binaphthyl

Biotage silica gel chromatographic system, Biotage Inc.

Bn benzyl bp boiling point

Bz benzoyl

BOC tert-butoxycarbonyl n-BuOH n-butanol t-BuOH tert-butanol t-BuOK potassium tert-butoxide calcd calculated

Cbz carbobenzyloxy

CDI carbonyl diimidazole

CD₃OD methanol-d,

Celite^® diatomaceous earth filter agent, Celite Corp.

CI-MS chemical ionization mass spectroscopy

¹³C NMR carbon-13 nuclear magnetic resonance cone concentrated

CTC-Q-PHOS 1 ,2,3,4,5-pentaphenyl-1 '-(di-t-butylphosphino)ferrocene

DCC dicyclohexylcarbodiimide

DCM dichloromethane

DEAD diethyl azodicarboxylate dec decomposition

DIA diisopropyl amine

DIBAL diisobutylaluminum hydroxide

DMAP 4-(N,N-dimethylamino)pyidine

DME 1 ,2-dimethoxyethane

DMF N,N-dimethylformamide

DMSO dimethylsulfoxide

E entgegen (configuration) EDCI 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride e.g. for example

El electron impact

ELSD evaporative light scattering detector

EPA vial Environmental Protection Agency Vial, 40 mL size with teflon septum cap equiv equivalent

ES-MS electrospray mass spectroscopy et al. and others

EtOAc ethyl acetate

EtOH ethanol (100%)

EtSH ethanethiol

Et₂O diethyl ether

Et₃N thethylamine

GC gas chromatography

GC-MS gas chromatography-mass spectroscopy h hour, hours

¹H NMR proton nuclear magnetic resonance

HMPA hexamethylphosphoramide

HMPT hexamethylphosphoric triamide

HPLC high performance liquid chromatography i.e. that is insol insoluble

IPA isopropylamine

IR infrared

J coupling constant (NMR spectroscopy)

L liter

LAH lithium aluminum hydride

LC liquid chromatography

LC-MS liquid chromatography-mass spectrometry

LDA lithium diisopropylamide

MeCN acetonitrile

MeOH methanol

MHz megahertz min minute, minutes μL microliter mL milliliter μM micromolar mp melting point

MS mass spectrum, mass spectrometry Ms methanesulfonyl m/z mass-to-charge ratio

NBS N- bromosuccinimide

NEt₃ triethylamine nM nanomolar

NMM 4-methylmorpholine

NMP N-methylpyrrolidone obsd observed oxone^® 2KHSO₅ KHSO₄ K₂SO₄ (KHSO₅ = potassium peroxomonosulfate)

P page

PP pages

Pd₂dba₃ tris(dibenzylideneacetone)dipalladium(0)

PdCI₂(dppf) [1 ,1 '-bis(diphenylphosphino)ferrocene]dichloropalladium(ll)

Pd(OAc)₂ palladium acetate

Pd[P(Ph)₃]₄ tetrakis(thphenylphosphine)palladium(0)

PH negative logarithm of hydrogen ion concentration pK negative logarithm of equilibrium constant pK_a negative logarithm of equilibrium constant for association

PS-DIEA polystyrene-bound diisopropylethylamine p-tol-BINAP 2,2'-bis(di-p-tolyl-phosphino)-1 ,1 '-binaphthyl

Q-PHOS 1 ,2,3,4,5-pentaphenyl-1 '-(di-t-butylphosphino)ferrocene

Rf retention factor (TLC)

RT retention time (HPLC) rt room temperature sat saturated

TEA triethylamine

THF tetrahydrofuran

TFA trifluoroacetic acid

TFFH fluoro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate

TLC thin layer chromatography

TMAD N,N,N',N'-tetramethylethylenediamine

TMHD 2,2,6,6-tetramethylheptane-3,5-dione

TMSCI thmethylsilyl chloride

Ts p-toluenesulfonyl v/v volume per volume w/v weight per volume w/w weight per weight

XANTPHOS 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene

Z zusammen (configuration) PREPARATIVE EXAMPLES OF THE INVENTION

[099] EXAMPLE 1

6-rButyl(methyl)amino1-2-(2-methoxyphenyl)-3-(piperidin-3-ylmethyl)quinazolin-4(3H)-one trifluoroacetate

[100] Step 1. Preparation of 5-fbutyl(methyl)aminol-2-nitrobenzoic acid

[101] To a solution of 5-fluoro-2-nitrobenzoic acid (25.0 g, 135.1 mmol) and N-methylbutylamine (27.9 g, 310.6 mmol) in DMF (150 ml.) was added cesium carbonate (92.41 g, 283.6 mmol), and the reaction mixture was stirred at 50°C for 15 h. Water (500 mL) was added, and the mixture was extracted with ethyl acetate (3 x 300 mL). The combined extracts were washed with water, dried over MgSO₄, and concentrated under reduced pressure to give the product as a light yellow solid (33.1 g, 97%). ¹H NMR (300 MHz, CD₃OD) δ 8.01 (d, 1 H), 6.77 (dd, 1 H), 6.69 (dd, 1 H), 3.28 (t, 2H), 3.09 (s, 3H), 1.57-1.67 (m, 2H)₁ 1.31-1.48 (m, 2H), 0.98 (t, 3H); ES-MS m/z 252.9 (MH⁺); HPLC RT (min) 2.77.

[102] Step 2. Preparation of 2-amino-5-[butyl(methyl)aminolbenzoic acid

[103] A mixture of 2-nitro-5-[butyl(methyl)amino]benzoic acid (33.0 g, 130.8 mmol), 10% palladium on carbon (696.1 mg, 0.654 mmol), and ethanol (330 mL) was hydrogenated using a Parr apparatus at 60 PSI for 4 h. The mixture was filtered through a pad of Celite® and concentrated under reduced pressure to afford 25.1 g (86%) of the product as a yellow solid. ¹H NMR (300 MHz, CD₃OD) δ 7.97 (dd, 1 H), 7.45 (dd, 1 H), 6.93 (d 1 H), 3.49 (t, 2H), 3.22 (s, 3H), 1.28-1.58 (m, 4H), 0.92 (t, 3H); ES-MS m/z 223.1 (MH⁺); HPLC RT (min) 0.29. [104] Step 3. Preparation of 6-fbutyl(rnethyl)aminol-2-(2-methoxyphenyl)-4H-3,1-benzoxazin-4- one

[105] A solution of 2-amino-5-[butyl(methyl)amino]benzoic acid (1.88 g, 8.46 mmol) and Et₃N (2.57 g, 25.37 mmol) in DCM (20 mL) was cooled in an ice bath, and o-anisoyl chloride (1.73 g, 10.15 mmol) was added. The reaction mixture was stirred at 40⁰C for 17 h. DCM (20 mL) was added, and the solution was washed with ice-cold water, saturated aq Na₂CO₃ (3 x 10 mL), 1 N NaOH (3 x 10 mL), and brine (10 mL). The organic layer was concentrated under reduced pressure to give a dark green oily solid. This material was purified by silica gel flash chromatography (Biotage), eluting with a 20% EtOAc/hexane solvent system. Concentration of the product fractions under reduced pressure gave 0.9 g (31%) of the product as a yellow solid. ¹H NMR (300 MHz, CD₂CI₂) 57.79 (d, 1 H), 7.47-7.55 (m, 2H), 7.33 (d 1 H), 7.22 (dd, 1 H), 7.04-7.10 (m, 2H), 3.94 (s, 3H), 3.25 (t, 2H), 3.08 (s, 3H), 1.55-1.69 (m, 2H), 1.33-1.47 (m, 2H), 0.99 (t, 3H); ES-MS m/z 339.2 (MH⁺); HPLC RT (min) 4.07.

[106] Step 4. Preparation of 6-fbutyl(methyl)aminol-2-(2-methoxyphenyl)-3-(piperidin-3-ylmethyl)- quinazolin-4(3H)-one trifluoroacetate

[107] A solution of 6-[butyl(methyl)amino]-2-(2-methoxyphenyl)-4H-3,1-benzoxazin-4-one (200 mg, 0.59 mmol) (step 3) and tert-butyl 3-(aminomethyl)piperidine-1-carboxylate (152.0 mg, 0.71 mmol) in CHCI₃ (70 mL) was stirred at reflux for 2.5 days. tert-Butyl 3-(aminomethyl) piperidine-1-carboxylate (50 mg, 0.51 mmol) was added, and the mixture was heated under reflux for 10 h to form the uncyclized intermediate. 1 ,2-Ethanediol (2 mL) and NaOH (5.5 mg, 0.14 mmol) were added, chloroform was removed in vacuo, and the resulting mixture was stirred at 130⁰C for 3 h. More NaOH (15 mg, 0.38 mmol) was added, and the resulting mixture was stirred at 130⁰C for 15 h. To remove the BOC protecting group from the cyclized material, DCM (2 mL) was added, followed by TFA (1.35 g, 11.82 mmol). The mixture was stirred at rt for 3 h. The volatile solvents were removed, MeOH (2 mL) was added, and the mixture was purified on a Gilson HPLC reversed-phase system eluting with the gradient 2-60% MeCN/water (containing 0.1% TFA) to afford 78 mg (23%) of the product as a clear, colorless oil. ¹H NMR (300 MHz, CD₃OD) δ 7.71 (d, 1H), 8.18 (dd, 1 H), 7.86-7.87 (m, 1H), 7.67 (dd, 1H), 7.53-7.61 (m, 1 H), 7.20 (d, 1 H), 7.05-7.12 (m, 1 H), 4.11 (s, 3H), 3.56-3.64 (m, 2H), 3.33-3.51 (m, 4H), 3.28 (s, 3H), 2.85-2.97 (m, 1 H), 2.73-2.84 (m, 1 H), 2.06-2.22 (br m, 1 H), 1.87-2.04 (m, 2H), 1.65-1.83 (m, 1 H), 1.46-1.60 (m, 2H), 1.29-1.45 (m, 3H), 0.93 (t, 3H); ES-MS m/z 435.3 (MH⁺); HPLC RT (min) 2.76.

[108] EXAMPLE 2

6-rButyl(methyl)aminol-3-r(1-ethylpiperidin-3-yl)methvπ-2-(2-methoxyphenvπquinazolin-

4(3H)-one trifluoroacetate

[109] A mixture of 6-[butyl(methyl)amino]-2-(2-methoxyphenyl)-3-(piperidin-3-ylmethyl)quinazolin- 4(3H)-one (23.0 mg, 0.05 mmol) (Example 1), acetaldehyde (4.7 mg, 0.11 mmol), acetic acid (11.4 mg, 0.19 mmol), and methanol (0.7 ml_) was stirred at 60⁰C for 2 h. The reaction mixture was cooled to rt, and acetaldehyde (4.7 mg, 0.11 mmol) was added, followed by NaBH₃CN (4.0 mg, 0.06 mmol), and the mixture was stirred at rt for 15 h. The solvent was removed, and the crude mixture was purified on a Gilson reversed-phase HPLC system eluting with the gradient 2-60% MeCN/water (containing 0.1 % TFA) to afford 3 mg (11%) of the product as a clear, light yellow oil. ¹H NMR (400 MHz, CD₃OD) δ 7.62-7.71 (m, 1H), 7.53-7.61 (m, 2H), 7.40-7.45 (m, 2H), 7.18-7.32 (m, 2H), 4.32 (dd, 0.6 H), 4.15 (dd, 0.4H), 3.91 (s, 3H), 3.85 (dd, 0.4H), 3.53 (dd, 0.6H), 3.52 (t, 2H), 3.41-3.50 (m, 2H), 3.05-3.17 (m, 5H), 2.65-2.69 (m, 1.6 H), 2.50 (t, 0.4H), 2.06-2.26 (br m, 1 H), 1.84-1.96 (m, 1 H), 1.52-1.75 (m, 4H), 1.25-1.51 (m, 5H), 1.05-1.20 (m, 1 H)₁ 1.01 (t, 3H); ES-MS m/z 463.4 (MH⁺); HPLC RT (min) 2.30.

[110] EXAMPLE 3

6-rButyl(methvhaminol-2-(2-methoxyphenyl)-3-rπ-methylpiperidin-3-yl)methyllαuinazolin-

4(3K0-one trifluoroacetate

[111] A mixture of 6-tbutyl(methyl)amino]-2-(2-methoxyphenyl)-3-(piperidin-3-ylmethyl)quinazolin- 4(3H)-one (33 mg, 0.08 mmol) (Example 1), formic acid (24.9 mg, 0.52 mmole), and 37% aq formaldehyde solution (0.04 mL, 0.51 mmol) was stirred at 50⁰C for 1 h and then at 80⁰C for 15 h. MeOH (2 mL) was added, and the mixture was purified on Gilson reversed-phase HPLC system using a gradient of 1-50% MeCN/water (containing 0.1 % TFA) to afford 12 mg (28%) of the product as a clear, colorless oil. ¹H NMR (400 MHz, CD₃OD) δ 7.66-7.73 (m, 1 H), 7.54-7.62 (m, 2H), 7.41-7.47 (m, 2H), 7.18-7.32 (m, 2H), 4.32 (dd, 0.6 H), 4.18 (dd, 0.4H), 3.92 (s, 3H), 3.81 (dd, 0.4H), 3.62 (dd, 0.6H), 3.53 (t, 2H)₁ 3.36-3.51 (m, 2H), 3.13 (s, 3H), 2.60-2.87 (m, 4.6 H), 2.54 (t, 0.4H), 2.06-2.27 (br m, 1 H), 1.84-1.97 (m, 1 H), 1.52-1.69 (m, 4H), 1.38-1.46 (m, 2H), 1.05-1.21 (m, 1 H), 1.01 (t, 3H); ES-MS m/z 449.3 (MH⁺); HPLC RT (min) 2.41.

[112] EXAMPLE 4

6-fButyl(ιnethyl)amino1-3-(ri-(cvclopropylmethyl)piperidin-3-vnmethyl>-2-(2- methoxyphenyl)quinazolin-4(3H)-one

[113] Step 1. Preparation of tert-butyllH-fcvclopropylmethvDpiperidin-S-vπmethvDcarbamate

[114] To a dry 10 mL round-bottom flask was added 3-Λ/-(tert-butoxycarbonylaminomethyl piperidine (500 mg, 2.33 mmol) followed by anhydrous dichloroethane (5.0 mL). The mixture was stirred at rt under an atmosphere of N₂ for 5 min, and then cyclopropanecarboxaldehyde (0.17 mL, 2.33 mmol) and glacial acetic acid (0.80 mL, 14.0 mmol) were added. After stirring for 10 min, NaB(OAc)₃H (1.98 g, 9.33 mmol) was added, and the milky white reaction mixture was stirred for 15 h. The mixture was quenched with saturated aq Na₂CO₃ (10 mL) and was extracted with CH₂CI₂ (3 x 20 mL). The combined organic layers were washed with water (2 x 20 mL), dried over MgSO₄, filtered, and concentrated under reduced pressure. Purification by flash silica gel chromatography (95% CH₂CI₂: 5% 2M NH₃ in MeOH) gave the product as a yellow oil (388 mg, 62%). R,= 0.23 (97% CH₂CI₂: 3% 2M NH₃ in MeOH); ¹H NMR (300 MHz, CDCI₃) δ 4.60 (br s, 1 H), 3.05-2.96 (m, 4H), 2.27 (d, 2H), 1.96 (dd, 1 H), 1.76-1.61 (m, 5H), 1.44 (s, 9H), 0.98-0.85 (m, 2H), 0.55-0.49 (m, 2H), 0.13-0.09 (dd, 2H); ES-MS m/z 269 (MH⁺).

[115] Step 2. Preparation of i-fi-fcvclopropylmethyDpiperidin-S-yllmethanamine dihydrochloride

[116] To a solution of tert-butylfti^cyclopropylmethylJpiperidin-S-yllmethylJcarbamate (137 mg, 0.510 mmol) (step 1 ) in methanol (0.50 mL) was added 1 M aq HCI (2.55 ml_, 2.55 mmol), and the mixture was stirred at rt for 3 h. Additional 1 M HCI (1.50 mL, 1.50 mmol) was added, and the mixture was stirred for 15 h. The mixture was concentrated under reduced pressure. The product gave a characteristic bright red spot when stained on a TLC plate using the ninhydrin stain. R_f = 0.0 (90% CH₂CI₂, 10% MeOH); ¹H NMR (300 MHz, CD₃OD) δ 10.54 (br s, 1H), 7.96 (br s, 3H), 3.28 (d, 1 H), 3.06 (d, 1 H), 2.93-2.21 (m, 6H), 1.96 (br s, 1 H), 1.55-1.42 (m, 2H), 0.82-0.71 (m, 2H), 0.27-0.20 (m, 2H), 0.08-0.00 (m, 2H).

[117] Step 3. Preparation of 6-rbutyl(methyl)aminol-3-!H-(cvclopropylmethyl)piperidin-3-yll methyl)-2-(2-methoxyphenyl)quinazolin-4(3H)-one

[118] To a solution of 1-[1-(cyclopropylmethyl)piperidin-3-yl]methanamine dihydrochloride (106.9 mg, 0.44 mmol) (step 2) in toluene (2.0 mL) was added triethylamine (120 mg, 1.18 mmol, 0.17 mL). The mixture was stirred at rt under a nitrogen atmosphere, and then 6-[butyl(methyl)- amino]-2-(2-methoxyphenyl)-4H-3,1-benzoxazin-4-one (100 mg, 0.296 mmol) (Example 1 , step 3) was added. The reaction mixture was stirred at 85⁰C for 18 h. More triethylamine was added (-0.12 mL), and the mixture was stirred at 85⁰C for another 15 h. The reaction mixture was concentrated under reduced pressure and purified by silica gel flash chromatography using 97% CH₂CI₂ and 3% 2M NH₃ in MeOH to furnish 5-[butyl(methyl)amino]-N-{[1-cyclopropylmethyl)- piperidin-3-yl]methyl}-2-[(2-methoxybenzoyl)amino]benzamide (148.9 mg, 99%). R^= 0.15 (95% CH₂CI₂: 5% MeOH).

[119] 5-[Butyl(methyl)amino]-N-{[1-cyclopropylmethyl)piperidin-3-yl]methyl}-2-[(2-methoxy- benzoyl)amino]benzamide (113 mg, 0.222 mmol) was mixed with ethylene glycol (2.0 mL) and NaOH (118.2 mg, 2.96 mmol), and the mixture was stirred under a nitrogen atmosphere for 15 h at 12O⁰C. The mixture was brought to pH 10 by addition of 1 M aq NaOH and extracted with EtOAc (3 x 30 ml_). The combined organic layers were dried over MgSO₄, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel flash chromatography using 97% CH₂CI₂ and 3% 2M NH₃ in MeOH to give 32.7 (30.1%) mg of the product as a yellow oil. R_f = 0.19 (95% CH₂CI₂: 5% MeOH); ¹H NMR (300 MHz, CDCI₃) δ 7.60 (d, 1 H), 7.46-7.39 (m, 3H), 7.25- 6.93 (m, 3H), 4.32-4.25 (m, 1 H), 3.77 (s, 3H), 3.47-3.27 (m, 4H), 3.03 (s, 3H), 2.94-2.80 (br s, 2H), 2.13-2.09 (m, 2H), 1.86-1.19 (m, 9H), 0.94 (t, 3H), 0.75 (br s, 2H), 0.42 (br s, 2H), 0.00 (br s, 2H); ES-MS m/z 489.3 (MH⁺); HPLC RT (min) 2.56.

[120] EXAMPLE 5

6-rButyl(methyl)amino1-2-(2-methoxyphenyl)-3-(ri-(4,4.4-trifluorobutyl)piperidin-3- vllmethyl}quinazolin-4(3H)-one

[121] Step 1. Preparation of tert-butyl fH-(4,4.4-trifluorobutyl)piperidin-3-vπmethyl)carbamate

[122] To a mixture of tert-butyl (piperidin-3-ylmethyl)carbamate (0.30 g, 1.40 mmol) in anhydrous CH₃CN (10 ml_) was added CsF-celite (0.53 g) followed by 1-iodo-4,4,4-trifluorobutane (0.40 g, 1.68 mmol). The mixture was heated to reflux and stirred for 16 h. The mixture was diluted with EtOAc, filtered through a pad of Celite® and then concentrated to dryness under reduced pressure. Water (40 ml_) was added, and the mixture was extracted with CH₂CI₂ (2 x 40 mL) and EtOAc (1 x 40 mL). The combined organic layers were dried over MgSO₄, filtered, and concentrated in vacuo. The white residue was taken up in CH₂CI₂ (with a minimal amount of MeOH) and loaded onto a silica gel column. The mixture was then purified by silica gel flash chromatography (97% CH₂CI₂: 3% 2M NH₃ in MeOH). This gave the product as a light yellow oil (0.31 mg, 68%). ¹H NMR (300 MHz, CD₃CN) δ 5.30 (br s, 1 H), 2.86-2.90 (m, 2H), 2.66-2.73 (m, 2H), 2.29-2.34 (m, 2H), 2.09-2.23 (m, 2H), 1.95-1.99 (m, 2H), 1.57-1.71 (m, 6H), 1.37 (s, 9H), 0.83-0.99 (m, 1 H); ES-MS m/z 325.1 (MH⁺); HPLC RT (min) 1.76. [123] Step 2. Preparation of 1-f1 -(4.4.4-trifluorobutvhpiperidin-3-vπmethanannine hydrochloride

[124] tert-Butyl {[1-(4,4,4-trifluorobutyl)piperidin-3-yl]methyl}carbamate (0.31 g, 0.95 mmol) (step 1) was dissolved in MeOH (0.5 mL), and then 2 M aq HCI (5.0 ml_, 10 mmol) was added. The mixture was stirred at rt for 15 h. The mixture was concentrated in vacuo and dried for 5 h in the vacuum oven at 50⁰C. The product was obtained as a light yellow oil (308 mg). ¹H NMR (300 MHz, CD₃OD) δ 3.31-3.71 (m, 2H), 3.20-3.29 (m, 2H), 2.90-3.02 (m, 3H), 2.78-2.86 (m, 1 H), 2.26-2.42 (m, 3H), 1.68-2.15 (m, 5H), 1.29-1.42 (m, 1 H).

[125] Step 3. Preparation of 6-rbutyl(methv0aminol-2-(2-methoxyphenyl)-3-!H -(4,4.4- trifluorobutvπpiperidin-3-vnmethyllαuinazolin-4(3H)-one

[126] The product was obtained by reaction of 1 -[1 -(4,4,4-trifluorobutyl)piperidin-3-yl] methanamine hydrochloride (step 2) and 6-[butyl(methyl)amino]-2-(2-methoxyphenyl)-4H-3,1- benzoxazin-4-one (Example 1 , step 3) in a similar manner as described in Example 4, step 3. ¹H NMR (300 MHz, CD₃CN) δ 7.67-7.60 (m, 2H), 7.56-7.51 (m, 1 H), 7.45-7.41 (m, 2H), 7.20-7.11 (m, 2H), 4.22-4.01 (m, 1H), 3.83 (s, 3H), 3.81 (s, 1H), 3.67-3.53 (m, 1 H), 3.49 (d, 2H), 3.43-3.10 (m, 2H), 3.08 (s, 3H), 3.04-2.78 (m, 2H), 2.78-2.46 (m, 1 H), 2.36-2.10 (m, 3H), 1.95 (s, 1 H), 1.92-1.66 (m, 3H), 1.63-1.53 (m, 3H), 1.43-1.30 (m, 3H), 0.94 (t, 3H); ES-MS m/z 545.4 (MH⁺); HPLC RT (min) 3.05.

[127] EXAMPLE 6

2-(2-Methylphenyl)-3-(piperidin-3-ylmethyl)-6-(tetrahvdro-2H-pyran-4-yloxy)quinazolin-4(3H)-

[128] Step 1. Preparation of 6-bromo-2-(2-methylphenyl)-4H-3,1-benzoxazin-4-one

[129] o-Toluoyl chloride (10.0 g, 64.7 mmol) was added slowly into a mixture_. of 2-amino-5- bromobenzoic acid (12.7 g, 58.8 mmol) and triethylamine (24.6 mL, 176.4 mmol) in DCM (120 ml.) at O⁰C. The reaction mixture was stirred at rt for 14 h. Half of the DCM was removed under reduced pressure, acetic anhydride (50 mL) was added, and the mixture was heated at 5O⁰C for 2 h. The reaction mixture was cooled to rt, quenched by slow addition of ice water, and diluted with DCM. The layers were separated, and the DCM layer was washed with NaHCO₃, brine, and dried over Na₂SO₄. After concentrating under reduced pressure, the crude product was treated with ethanol and stirred for 10 min. The solid was filtered and washed with additional ethanol. It was then dried in a vacuum oven at 5O⁰C for 3 h to give 11.5 g (62%) of the product. ES-MS mlz 316.3 (MH⁺); HPLC RT (min) 3.71.

[130] Step 2. Preparation of tert-butyl 3-ff6-bromo-2-(2-methylphenyl)-4-oxoquinazolin-3(4H)- ylimethyllpiperidine-i-carboxylate

[131] tert-Butyl 3-(aminomethyl)piperidine-1-carboxylate (3.00 g, 14.0 mmol) in toluene (20 mL) was added to 6-bromo-2-(2-methylphenyl)-4H-3,1-benzoxazin-4-one (3.69 g, 11.7 mmol) (step 1), and the solution was stirred at reflux for 16 h under a nitrogen atmosphere. The mixture was concentrated under reduced pressure and passed through a silica gel plug using EtOAc as eluent. Removal of the solvent under reduced pressure gave the intermediate as a yellow oil which was used in the next step without further purification.

[132] The intermediate described above (3.00 g, 5.66 mmol) was added to a dry round-bottom flask followed by ethylene glycol (20 mL) and LiOH (0.48 g, 11.3 mmol). The resulting mixture was stirred at 135⁰C for 16 h, cooled to rt, and diluted with DCM and water. The mixture was extracted with DCM (50 mL x 2), and the combined organic layers were concentrated under reduced pressure. Purification via silica gel column chromatography using a gradient elution from 10 to 50% ethyl acetate in hexanes yielded the product (1.4 g, 48%). ES-MS m/z512.5 (MH⁺); HPLC RT (min) 4.01. [133] Step 3. Preparation of tert-butyl 3-([2-(2-methylphenyl)-4-oxo-6-(tetrahvdro-2H- Pyran-4-yloxy)quinazolin-3(4H)-yllmethyl)piperidine-1-carboxylate

[134] To a solution of tert-butyl 3-{[6-bromo-2-(2-methylphenyl)-4-oxoquinazolin-3(4H)- yl]methyl}piperidine-1-carboxylate (0.50 g, 0.98 mmol) in toluene (10 mL) was added tetrahydro- 2H-pyran-4-ol (0.14 mL, 1.46 mmol), Pd₂(dba)₃ (0.05 g, 0.05 mmol), p-tol-BINAP (0.08 g, 0.12 mmol), and NaH (60% in mineral oil) (0.08 g, 1.95 mmol). The mixture was then stirred at 100⁰C for 14 h. The mixture was cooled to rt and diluted with EtOAc (100 mL), filtered, and concentrated under reduced pressure. Purification by silica gel column chromatography (elution with 50% EtOAc/hexane) gave the product as light yellow oil (269 mg, 52%). ES-MS mlz 434.4 ([MH₂- BOC]⁺); HPLC RT (min) 3.87.

[135] Step 4. Preparation of 2-(2-methylphenyl)-3-(piperidin-3-ylmethyl)-6-(tetrahvdro-2H-pyran- 4-yloxy)quinazolin-4(3H)-one

[136] To a solution of tert-butyl 3-{[2-(2-methylphenyl)-4-oxo-6-(tetrahydro-2H-pyran-4-yloxy)- quinazolin-3(4H)-yl]methyl}piperidine-1-carboxylate (268 mg, 0.50 mmol) (step 3) in DCM (5 mL) was added TFA (2.5 mL), and the reaction mixture was stirred at rt for 3 h. The solvents were removed and the crude mixture was redissolved in EtOAc. The organic solution was washed with sat NaHCO₃ and brine, and dried over Na₂SO₄. Filtration and concentration under reduced pressure gave the product (53 mg, 24%). ¹H NMR (400 MHz, CD₃OD) δ 7.70 (d, 1 H), 7.60-7.62 (d, 1 H), 7.45-7.49 (m, 3 H), 7.38-7.40 (m, 2 H), 4.73-4.77 (m, 1 H), 4.18-4.19 (m, 1 H), 3.96-4.02 (m, 2 H), 3.62-3.68 (m, 2 H), 3.40-3.49 (m, 1 H), 2.68-2.89 (m, 2 H), 2.41-2.50 (m, 1 H), 2.26-2.31 (m, 1 H), 2.22-2.24 (d, 3 H), 2.10-2.17 (m, 2 H)₁ 1.76-1.84 (m, 3 H), 1.30-1.63 (m, 3 H), 0.99-1.05 (m, 1 H); ES-MS m/z (MH⁺) 434.3; HPLC RT (min) 2.42. [137] EXAMPLE 7

3-r(1-lsopropylpiperidin-3-yl)methvπ-2-(2-methylphenyl-6-(tetrahvdro-2H-pyran-4- vloxy)quinazolin-4(3H)-one

[138] To a mixture of 2-(2-methylphenyl)-3-(piperidin-3-ylmethyl)-6-(tetrahydro-2H-pyran-4- yloxy)quinazolin-4(3H)-one (45.0 mg, 0.10 mmol) (Example 6) and K₂CO₃ (57.3 mg, 0.42 mmol) in MeCN (6 mL) was added 2-iodopropane (0.01 ml_, 0.12 mmol). The reaction mixture was stirred at 70⁰C for 14 h. The mixture was cooled to rt and concentrated under reduced pressure. The residue was diluted with water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined extracts were concentrated under reduced pressure, and purification of the crude product using a Gilson reversed-phase HPLC system with 10% to 80% acetonitrile in water (0.1% TFA) gave the product (19 mg, 38 %) as light yellow oil. ¹H NMR (400 MHz, CD₃OD) δ 7.71 (m, 1 H), 7.62 (dd, 1 H), 7.45-7.49 (m, 3 H), 7.39-7.41 (m, 2H), 4.76 (m, 1 H), 4.15-4.20 (m, 1 H), 3.96-4.01 (m, 2 H), 3.62-3.68 (m 1 H), 3.51 (m, 1 H), 2.48-2.79 (m, 3 H), 2.24 (d 3H), 1.27-2.15 (m, 10 H), 0.95-1.02 (m, 6 H), 0.81-0.93 (m, 1 H); ES-MS m/z 476.4 (MH⁺); HPLC RT (min) 2.64.

[139] EXAMPLE 8

6-lsobutoxy-2-(2-methylphenyl)-3-r(3S)-piperidin-3-ylmethyl1quinazolin-4(3H)-one

[140] Step 1. Preparation of 2-(2-methylphenyl)-4-oxo-4H-3,1-benzoxazin-6-yl acetate

[141] o-Toluoyl chloride (23.30 g, 150.8 mmol) was added slowly into a mixture of 2-amino-5- hydroxybenzoic acid (23.09 g, 150.8 mmol) and triethylamine (63.05 mL, 452.3 mmol) in DCM (250 mL) at O⁰C. After addition, the flask was stirred at rt for 14 h. Half of the DCM was removed under reduced pressure, and acetic anhydride (125 mL) was added to the mixture, followed by heating to 5O⁰C for 2 h. The reaction mixture was cooled to rt, slowly quenched with ice water, and diluted with DCM. The layers were separated, and the DCM layer was washed with NaHCO₃, brine, and dried over Na₂SO₄. After concentrating under reduced pressure, the crude product was treated with DCM/hexane (5:95; v/v) and stirred for 5 min. The precipitate was collected by filtration and washed with additional hexane. It was then dried in a vacuum oven at 50⁰C for 13 h to give 8.99 g (27%) of the product. ES-MS m/z 296.05 (MH⁺); HPLC RT (min) 3.42.

[142] Step 2. Preparation of tert-butyl (3R)-3-(r6-hvdroxy-2-(2-methylphenyl)-4-oxoquinazolin- 3(4H)-yl1methyl)piperidine-1-carboxylate

[143] tert-Butyl (3R)-3-(aminomethyl)piperidine-1-carboxylate (11.61 g, 54.18 mmol) in toluene (50 mL) was added to 2-(2-methylphenyl)-4-oxo-4H-3,1 -benzoxazin-6-yl acetate (8.00 g, 27.09 mmol) (step 1), and the mixture was stirred at reflux for 16 h under a nitrogen atmosphere. The mixture was concentrated under reduced pressure. The resulting intermediate (8.50 g , 18.2 mmol) (yellow oil) was added to a dry round-bottom flask followed by ethylene glycol (50 mL) and LiOH (1.53 g, 36.4 mmol). This mixture was stirred at 135⁰C for 16 h and subsequently diluted with DCM and water. The mixture was extracted with DCM (100 mL x 2), and the combined organic layers were concentrated under reduced pressure. The crude product was then purified via silica gel column chromatography using ethyl acetate/hexanes (70:30; v/v). ES-MS m/z 450.1 (MH⁺); HPLC RT (min) 3.15.

[144] Step 3. Preparation of tert-butyl (3R)-3-(|^'6-isobutoxy-2-(2-methylphenyl)-4-oxoquinazolin- 3(4H)-yllmethyl)piperidine-1-carboxylate

[145] To a solution of tert-butyl (3R)-3-{[6-hydroxy-2-(2-methylphenyl)-4-oxoquinazolin- 3(4H)-yl]methyl}piperidine-1 -carboxylate (1.30 g, 2.89 mmol) (step 2) and Cs₂CO ₃ (2.83 g, 8.68 mmol) in acetonitrile (15 mL) was added 1-iodo-2-methylpropane (0.40 ml_, 3.47 mmol). The resulting mixture was stirred at 7O⁰C for 14 h. The mixture was cooled to rt and concentrated under reduced pressure. The residue was diluted with water (20 mL) and extracted with EtOAc (2 x 20 mL). The solvent was removed under reduced pressure, and the crude product purified via silica gel column chromatography with a gradient elution of 30% to 60% EtOAc in hexane to give the product (996 mg, 68%). ES-MS m/z 406.4 ([MH₂ - BOC]⁺); HPLC RT (min) 4.24.

[146] Step 4. Preparation of 6-isobutoxy-2-(2-methylphenyl)-3-r(3S)-piperidin-3-ylmethyll- quinazolin-4(3H)-one

[147] To a solution of tert-butyl (3R)-3-{[6-isobutoxy-2-(2-methylphenyl)-4-oxoquinazolin-3(4H)- yl]methyl}piperidine-1-carboxylate (0.59 g, 1.17 mmol) (step 3) in DCM (10 mL) was added TFA (5 mL), and the reaction mixture was stirred at rt for 3 h. The solvents were removed and the crude was redissolved in EtOAc. The organic solution was washed with sat aq NaHCO₃ and brine, and dried over Na₂SO₄. After filtration and concentration under reduced pressure, the crude product was purified using a Gilson reversed-phase HPLC system with 10% to 80% acetonitrile in water (0.1% TFA) to give the product (206 mg, 31%) as light yellow oil. ES-MS m/z 406.3 (MH⁺); HPLC RT (min) 2.69.

[148] EXAMPLE 9

6-lsobutoxy-3-fr(3S)-1-isopropylpiperidin-3-vnmethyl)-2-(2-methylphenyl)quinazolin-4(3H)- one

[149] To a mixture of 6-isobutoxy-2-(2-methylphenyl)-3-[(3S)-piperidin-3-ylmethyl]quinazolin- 4(3H)-one (0.60 g, 1.48 mmol) (Example 8) and Cs₂CO₃ (1.45 g, 4.44 mmol) in CH₃CN (10 mL) was added 2-bromopropane (0.21 mL, 2.22 mmol). The resulting mixture was stirred at 7O⁰C for 14 h. The mixture was cooled to rt and concentrated under reduced pressure. The residue was diluted with water (20 mL) and extracted with EtOAc (2 x 20 mL). The solvent was removed under reduced pressure and the crude product purified using a Gilson reversed-phase HPLC system with 10% to 80% acetonitrile in water (0.1% TFA) to give the product (206 mg, 31%) as a light yellow oil. ¹H NMR (400 MHz, CD₃OD) δ 7.6-7.65 (m, 2 H), 7.37-7.50 (m, 5 H), 4.14-4.23 (m, 1 H), 3.89- 3.91 (d, 2 H), 3.44-3.68 (m, 1 H), 2.94-3.03 (m, 3 H), 2.37-2.38 (m, 1 H), 2.23-2.25 (d, 3 H), 2.03- 2.12 (m, 3 H), 1.31-1.77 (m, 3 H), 1.07-1.16 (m, 12 H), 0.85-1.04 (m, 1 H); ES-MS m/z 448.4 (MH⁺); HPLC RT (min) 2.69.

[150] EXAMPLE 10

6-(Cvclobutyloxy)-3-U(3S)-1-isopropylpiperidin-3-vnmethyl>-2-(2-methylphenyl)quinazolin-

4(3H)-one

[151] The title compound was prepared from the product obtained in step 2 of Example 8, using the BOC-deprotection procedure described in Example 6, step 4, subsequent reductive amination similar to Example 12, followed by O-alkylation similar to the procedure of step 3 of Example 8. ES-MS m/z 446.4 (MH⁺); HPLC RT (min) 2.85.

[152] EXAMPLE 11

6-r(3-Chloropyridin-2-yl)oxy1-2-(2-methylphenyl)-3-r(3S)-piperidin-3-ylmethyllquinazolin-

[153] Step 1. Preparation of tert-butyl (3R)-3-fr6-[(3-chloropyridin-2-yl)oxyl-2-(2-methylphenyl)-4- oxoquinazolin-3(4H)-yllmethyl)piperidine-1-carboxylate

[154] To a solution of tert-butyl (3R)-3-{[6-hydroxy-2-(2-methylphenyl)-4-oxoquinazolin-3(4H)- yl]methyl}piperidine-1-carboxylate (Example 8, step 2) (0.60 g, 1.34 mmol) and Cs₂CO ₃ (1.31 g, 4.01 mmol) in DMF (10 ml.) was added 2,3-dichloropyridine (0.24 g, 1.60 mmol) and 5 drops of water. The reaction mixture was stirred at 90⁰C for 14 h. The mixture was cooled to rt and concentrated under reduced pressure. The residue was diluted with water (20 ml_) and extracted with EtOAc (2 x 20 ml_). The solvent was removed under reduced pressure and the crude product purified by silica gel column chromatography with 30% to 80% EtOAc in hexane to afford 660 mg (88%) of the product. ES-MS m/z 461.3 ([MH₂ - BOC]⁺); HPLC RT (min) 4.00.

[155] Step 2. Preparation of 6-f(3-chloropyridin-2-yl)oxyl-2-(2-methylphenyl)-3-r(3SV piperidin-3-ylmethvπquinazolin-4(3H)-one

[156] To a solution of tert-butyl (3R)-3-{[6-[(3-chloropyridin-2-yl)oxy]-2-(2-methylphenyl)-4- oxoquinazolin-3(4H)-yI]methyl}piperidine-1-carboxylate (0.66 g, 1.17 mmol) (step 1 ) in DCM (10 ml_) was added TFA (5 mL), and the reaction mixture was stirred at rt for 3 h. The solvents were removed and the crude was redissolved in EtOAc. The organic layer was washed with sat aq NaHCO₃ and brine, and dried over Na₂SO₄. After filtration and concentration under reduced pressure, the crude product (265 mg, 49%) was used in the next step without further purification. ES-MS m/z 461.2 (MH⁺); HPLC RT (min) 2.42. [157] EXAMPLE 12

6-H3-Chloropyridin-2-yl)oxy1-3-m3SH-ethylpiperidin-3-yllmethyl)-2-(2- methylphenyl)quinazolin-4(3H)-one

[158] To a solution of 6-[(3-chloropyridin-2-yl)oxy]-2-(2-methylphenyl)-3-[(3S)-piperidin-3- ylmethyl]quinazolin-4(3H)-one (0.56 g, 1.21 mmol) (Example 11 ) in THF (15 mL) was added acetaldehyde (0.4 mL, 7.28 mmol) at O⁰C in a sealed round bottom flask, followed by rapid addition of AcOH (0.14 mL, 2.43 mmol) and sodium triacetoxyborohydride (1.03 g, 4.85 mmol). The reaction mixture was stirred under a nitrogen atmosphere at rt for 4 h. Sat aq NaHCO₃ solution was added, and stirring at rt was continued for 15 min. The mixture was diluted with DCM (50 mL) and extracted. The organic layer was washed with brine, dried over Na₂SO₄, filtered, and concentrated to dryness. The crude product was purified using a Gilson reversed-phase HPLC system with 10% to 80% acetonitrile in water (0.1% TFA) to give the product (116 mg, 20%) as a light yellow oil. ¹H NMR (400 MHz, CD₃OD) δ 8.03-8.04 (dd, 1 H), 7.96-7.98 (dd, 1 H), 7.92-7.93 (m, 1 H), 7.73-7.75 (d, 1 H), 7.63-7.66 (m, 1 H), 7.47-7.52 (m, 2 H), 7.38-7.42 (m, 2 H), 7.15-7.18 (q, 1 H), 4.11-4.18 (m, 1 H), 3.49- 3.64 (m, 1 H), 2.35-2.90 (m, 4 H), 2.26-2.27 (d, 3 H), 1.31-2.00 (m, 6 H), 1.00- 1.06 (m, 3 H), 0.80-0.99 (m, 1 H); ES-MS m/z 489.2 (MH⁺); HPLC RT (min) 2.44.

[159] EXAMPLE 13

3-(f1-r2-Hvdroxy-1-(hvdroxymethyl)ethvnpiperidin-3-yl>methyl)-2-(2-methylphenyl)-6- (trifluoromethoxy)quinazolin-4(3H)-one

[160] Step 1. Preparation of 2-(2-methylphenyl)-6-(trifluoromethoxy)-4H-3.1-benzoxazin-4-one

[161] The compound was prepared using the method of step 1 of Example 6 and 2-amino-5- (trifluoromethoxy) benzoic acid as starting material.

[162] Step 2. Preparation of 2-(2-methylphenyl)-3-(piperidin-3-ylmethyl)-6-(trifluoromethoxyV quinazolin-4(3H)-one

[163] The compound was prepared using the sequence of steps 2 and 4 of Example 6, and 2-(2- methylphenyl)-6-(trifluoromethoxy)-4H-3,1-benzoxazin-4-one (step 1 ) as starting material. ES-MS m/z 418.2 (MH⁺); HPLC RT (min) 2.48.

[164] Step 3. Preparation of 3-(fH2-hvdroxy-1-(hvdroxymethyl)ethvπpiperidin-3-yl)methyl)-2-(2- methylphenyl)-6-(trifluoromethoxy)quinazolin-4(3H)-one

[165] To a mixture of 2-(2-methylphenyl)-3-(piperidin-3-ylmethyl)-6-(trifluoromethoxy)quinazolin- 4(3H)-one (200 mg, 0.48 mmol) (step 2) and Cs₂CO₃ (624 mg, 1.92 mmol) in DMF (8 mL) was added oxetan-3-yl-4-methylbenzenesulfonate (164 mg, 0.72 mmol). The reaction mixture was stirred at 125⁰C for 14 h, then cooled to rt, and concentrated under reduced pressure. The residue was diluted with water and extracted with EtOAc (2 x 20 mL). The solvent was removed under reduced pressure and the crude mixture purified by HPLC with 5% to 80% acetonitrile in water (0.1% TFA) to give the product (14 mg, 6 %) as light yellow solid. ¹H NMR (400 MHz, CD₃OD) δ 8.10-8.11 (m, 1 H), 7.75-7.76 (m, 2 H), 7.47-7.51 (m, 2 H), 7.39-7.42 (m, 2 H), 4.06-4.25 (m, 1 H), 3.42-3.73 (m, 4 H), 2.77-2.85 (m, 2 H), 2.38-2.46 (m, 2 H), 2.25-2.26 (d, 3 H), 1.94-1.99 (m, 2 H), 1.29-1.64 (m, 4 H), 0.87-0.92 (m, 1 H); ES-MS m/z 492.4 (MH⁺); HPLC RT (min) 2.80.

[166] EXAMPLE 14

3-r(1-Ethylpiperidin-3-yl)methyll-2-(2-methylphenyl)-6-(trifluoromethoxy)quinazolin-4(3H)-

[167] The compound was prepared from the product of step 2 of Example 13, using the reductive amination procedure described in Example 12. ES-MS m/z 446.3 (MH⁺); HPLC RT (min) 2.54.

[168] EXAMPLE 15

3-rπ-Ethylpiperidin-3-yl)methvn-β-methoxy-2-(2-methoxyphenyl)quinazolin-4(3H)-one

[169] 2-(2-Methoxyphenyl)-6-methoxy-4H-3,1-benzoxazin-4-one, prepared similar to 6-bromo-2- (2-methoxyphenyl)-4H-3,1-benzoxazin-4-one (Example 39, step 1 ; using 2-amino-5-methoxy- benzoic acid as starting material), was reacted with 1-(1-ethylpiperidin-3-yl)methanamine trifluoroacetate as described in Example 49, step 1 , to form the title compound. ES-MS m/z 408.3 (MH⁺); HPLC RT (min) 2.39.

[170] EXAMPLE 16

6-(4-Fluorophenoxy)-2-(2-methoxyphenyl)-3-(piperidin-3-ylmethyl)quinazolin-4(3H)-one

[171] Step 1. Preparation of tert-butyl 3-{f6-(4-fluorophenoxy)-2-(2-methoxyphenyl)-4- oxoquinazolin-3(4HWI1methyl)piperidine-1 -carboxylate

[172] To a flask (25 ml_) was added tert-butyl 3-{[6-bromo-2-(2-methoxyphenyl)-4-oxoquinazolin- 3(4H)-yl]methyl}piperidine-1-carboxylate (100 mg, 0.189 mmol) (Example 43, step 2), 4- fluorophenot (25 mg, 0.227 mmol), cesium carbonate (123 mg, 0.378 mmol), copper(l) chloride (9.4 mg, 0.095 mmol), TMHD (14 mg, 0.047 mmol), and NMP (1 mL). The mixture was degassed and heated to 12O⁰C for 16 h, then diluted with EtOAc, and filtered through celite. The filtrate was separated using a Gilson reversed-phase HPLC system with a gradient elution from 5% to 90% acetonitrile in water containing 1% TFA to afford 78 mg (74%) of the product.

[173] Step 2: Preparation of 6-(4-fluorophenoxy)-2-(2-methoxyphenyl)-3-(piperidin-3- ylmethyl)quinazolin-4(3H)-one

[174] The preparation of this compound was carried out using the BOC-deprotection procedure described in step 4 of Example 6 using the product of step 1 above as starting material. ¹H NMR (300 MHz, CD3OD-d₄) δ 7.68 (d, 1 H), 7.60-7.42 (m, 4H), 7.16 (m, 6H), 4.25-4.04 (m, 1 H), 3.84 (s, 3H), 3.58-3.40 (m, 1 H), 2.90-0.82 (m, 9H); ES-MS m/z 460.3 (MH⁺), HPLC RT (min) 2.87.

[175] EXAMPLE 17

6-(4-Fluorophenoxy)-3-r(1-isobutylpiperidin-3-yl)methvn-2-(2-methoxyphenyl)quinazolin-

4(3H)-one

[176] To a mixture of 6-(4-fluorophenoxy)-2-(2-methoxyphenyl)-3-(piperidin-3-ylmethyl)- quinazolin-4(3H)-one (Example 16) (31 mg, 0.068 mmol) and K₂CO₃ (28 mg, 0.204 mmol) in CH₃CN (14 mL) was added 1-bromo-2-methylpropane (9.8 mg, 0.071 mmol). This mixture was stirred at 55⁰C for 14 h, then cooled to rt, and concentrated under reduced pressure. The residue was diluted with water (20 mL) extracted with EtOAc (2 x 20 mL). The solvent was removed under reduced pressure and the crude product purified using a Gilson reversed-phase HPLC system with 10% to 80% acetonitrile in water (0.1 % TFA) to give the product (11.7 mg, 33.4 %). ¹H NMR (300 MHz, CD₃OD) δ 7.69 (d, 1 H), 7.62-7.42 (m, 4H), 7.17 (m, 6H), 4.24-4.10 (m, 1 H), 3.88 (s, 3H), 3.62-3.44 (m, 1 H), 2.85-2.32 (bm, 2H), 2.00-1.10 (bm, 9H), 0.9 (m, 7H); ES-MS m/z 516.3 (MH⁺), HPLC RT (min) 2.65.

[177] EXAMPLE 18

6-(4-Fluorophenoxy)-3-{r(3S)-1-isopropylpiperidin-3-vnmethyl)-2-methylquinazolin-4(3H)- one

[178] Step 1. Preparation of tert-butyl (3R)-3-{F(2-amino-5-bromobenzoyl)amino1methyl)- piperidine-1 -carboxylate

[179] A mixture of 5-bromoisatoic anhydride (20.3 g, 84 mmol), tert-butyl (3R)-3-(aminomethyl)- piperidine-1 -carboxylate (15.0 g, 70.0 mmol), potassium carbonate (19.3 g, 140 mmol), and THF (100 mL) was heated to 7O⁰C for 20 h, followed by cooling to rt. Water was added to give a clear biphasic solution, and the mixture was stirred for 4 h while passing nitrogen through the reaction vessel to remove most of the organic solvent. The solid was collected by filtration, washed with copious water, and air dried to give 24.9 g (86%) product. ES-MS m/z 312.3 ([MH₂- BOC]⁺); HPLC RT (min) 3.26. [180] Step 2. Preparation of tert-butyl (3R)-3-r(6-bromo-2-methyl-4-oxoquinazolin-3(4H)- yl)methyllpiperidine-1-carboxylate

[181] A mixture of tert-butyl (3R)-3-{[(2-amino-5-bromobenzoyl)amino] methyl} piperidine-1- carboxylate (1 O g, 24.3 mmol) (step 1) and triethyl orthoacetate (30 mL) was heated to 140⁰C for 10 h while stirring. The excess triethyl orthoacetate was then removed under reduced pressure to give the product which was used in the next step without further purification. ES-MS m/z 338.4 ([MH₂- BOC]⁺); HPLC RT (min) 3.47.

[182] Step 3. Preparation of 6-bromo-3-(f(3S)-1-isopropylpiperidin-3-yllmethyl)-2-methyl- quinazolin-4(3H)-one

[183] tert-Butyl (3R)-3-[(6-bromo-2-methyl-4-oxoquinazolin-3(4H)-yl)methyl]pipehdine-1- carboxylate (step 2) was treated with 20% TFA in DCM (30 mL) at rt for 15 h. The solvent and excess TFA were removed under reduced pressure. The residue was then treated with potassium carbonate (16.8g, 121 mmol) and 2-isopropanyl iodide (6.2 g, 36 mmol) in acetonitrile (50 mL) at 70⁰C for 15 h. The mixture was then cooled to rt and diluted with water (200 mL) and EtOAc (400 mL) to give a clear biphasic solution. The organic layer was separated and washed with water and brine, dried over magnesium sulfate, and evaporated to give 7.36 g product (80% from 2 steps). ES-MS m/z 378.3 (MH⁺); HPLC RT (min) 1.95.

[184] Step 4. Preparation of 6-(4-fluorophenoxy)-3-fr(3SH -isopropylpiperidin-3-yllmethyl)- 2-methylquinazolin-4(3H)-one

[185] To a microwave reactor tube was added 6-bromo-3-{[(3S)-1 -isopropylpiperidin-3- yl]methyl}-2-methylquinazolin-4(3H)-one (620 mg, 1.64 mmol) (step 3), 4-fluorophenol (220 mg, 1.97 mmol), cesium carbonate (1.6 g, 4.92 mmol), copper(l) chloride (64.9 mg, 0.66 mmol), TMHD (97.7 mg, 0.33 mmol), and NMP (8 ml_). The tube was then sealed, degassed, flashed with nitrogen, and heated to 205⁰C for 20 min. The reaction mixture was then filtered and the filtrate was purified using a Gilson reversed-phase HPLC system with a gradient elution from 5% to 60% acetonitrile in water containing 1% TFA. The desired fractions were combined, treated with 10% Na₂CO₃, and extracted with EtOAc (3x). The extract was then washed with water and brine, dried over MgSO₄, and evaporated to afford 255 mg (38%) of the title product. ¹H NMR (400 MHz, CD₂CI₂) δ 7.55-7.60 (m, 2H), 7.39 (dd, 1 H), 7.15-7.00 (m, 4H), 3.96 (d, 2H), 2.75-2.61 (m, 3H), 2.60 (s, 3H), 2.22 (t, 1 H), 2.11-2.02 (m, 2 H), 1.78-1.54 (m, 2H), 1.49-1.40 (m, 1 H), 1.21-1.09 (m, 1 H), 0.95 (d, 6H): ES-MS m/z410.3 (MH⁺); HPLC RT (min) 2.26.

[186] EXAMPLE 19

3-f[(3S)-1-Ethylpiperidin-3-vnmethyl)-6-(4-fluorophenoxy)-2-methylquinazolin-4(3H)-one

[187] terf-Butyl-(3R)-3-[(6-bromo-2-methyl-4-oxoquinazolin-3(4H)-yl)methyl]piperidine-1- carboxylate (Example 18, step 2) was deprotected using a similar procedure as described in Example 6, step 4, followed by a reductive amination reaction with acetaldehyde similar to Example 12, and subsequently reacted with 4-fluorophenol under Ullmann coupling conditions as described in Example 18, step 4. ES-MS m/z 396.2 (MH⁺); HPLC RT (min) 2.26. [188] EXAMPLE 20

2-Ethyl-6-(4-fluorophenoxy)-3-ff(3S)-1-isopropylpiperidin-3-vnmethyl)quinazolin-4(3H)-one

[189] Step 1. Preparation of 6-bromo-2-ethyl-3-(r(3S)-1-isopropylpiperidin-3-yllmethyl)- quinazolin-4(3H)-one

[190] tert-Butyl (3R)-3-({[5-bromo-2-(propionylamino)benzoyl]amino}methyl)piperidine-1- carboxylate, synthesized in a similar way as the compound produced in Example 70, step 2, was further transformed into the title compound by using the sequence of Example 71 , step 3 and 4. ES-MS m/z 392.3 (MH⁺); HPLC RT 2.14 (min).

[191] Step 2. Preparation of 2-ethyl-6-(4-fluorophenoxy)-3-(r(3SH -isopropylpiperidin-3- vπmethyl)quinazolin-4(3H)-one

[192] The product was obtained from 6-bromo-2-ethyl-3-{[(3S)-1-isopropylpiperidin-3-yl]methyl}- quinazolin-4(3H)-one (step 1) and 4-fluorophenol using the Ullmann coupling conditions as described in Example 18, step 4. ¹H NMR (400 MHz, CD₂CI₂) δ 7.62-7.60 (m, 2 H), 7.41 (dd, 1 H), 7.12-7.04 (m, 4 H), 4.03 (s, 2 H), 2.94-2.88 (q, 2 H), 2.71-2.66 (m, 3 H), 2.21 (t, 1 H), 2.15-2.01 (m, 2 H), 1.75-1.59 (m, 2 H), 1.55-1.40 (m, 1 H), 1.35 (t, 3 H), 1.24-1.10 (m, 1 H), 0.96 (d, 6 H); ES-MS m/z 424.2.4 (MH+); HPLC RT (min) 2.50; ES-MS m/z 424.2 (MH⁺); HPLC RT (min) 2.50. [193] EXAMPLE 21

6-(2-Chlorophenoxy)-3-(f(3S)-1-ethylpiperidin-3-vnmethyl>-2-isopropylquinazolin-4(3H)-one

[194] The product was obtained from 6-bromo-3-{[(3S)-1-ethylpiperidin-3-yl]methyl}-2-isopropyl- quinazolin-4(3H)-one (Example 57, step 1) and 2-chlorophenol using the Ullmann coupling conditions as described in Example 18, step 4. ES-MS m/z 400.3 (MH⁺); HPLC RT (min) 2.62.

[195] EXAMPLE 22

2-(Cvclopropylmethyl)-6-(4-fluorophenoxy)-3-{r(3S)-1-isopropylpiperidin-3- yllmethyl|quinazolin-4(3H)-one

[196] 6-Bromo-2-(cyclopropylmethyl)-3-{[(3S)-1-isopropylpiperidin-3-yl]methyl}quinazolin-4(3H)- one, synthesized similarly to the product of step 4 of Example 71 , was reacted with 4-fluorophenol using the Ullmann coupling conditions as described in Example 18, step 4. ES-MS m/z 450.4 (MH⁺); HPLC RT (min) 3.00.

[197] EXAMPLE 23

2-Cvclopropyl-6-(4-fluorophenoxy)-3-r(1-isopropylpiperidin-3-yl)methyllquinazolin-4(3H)- one

[198] 6-Bromo-2-cyclopropyl-3-[(1 -isopropylpiperidin-3-yl)methyl]quinazolin-4(3H)-one (Example 55, step 1 ) was reacted with 4-fluorophenol using Ullmann coupling conditions as described in Example 18, step 4. ES-MS m/z 436.4 (MH⁺); HPLC RT (min) 3.02.

[199] EXAMPLE 24

6-(4-Chlorophenoxy)-2-methyl-3-r(3S)-piperidin-3-ylmethyllquinazolin-4(3H)-one

[200] The product was prepared starting from the product of Example 18, step 2, and using a sequence of Ullmann reaction with 4-chlorophenol and subsequent deprotection of the BOC group as described in Example 6, step 4. ES-MS m/z 384.3 (MH⁺); HPLC RT (min) 2.36.

[201] EXAMPLE 25 6-(4-Fluorophenoxy)-3-(piperidin-3-ylmethyl)quinazolin-4(3H)-one

[202] tert-Butyl (3R)-3-[(6-bromo-4-oxoquinazolin-3(4H)-yl)methyl]piperidine-1 -carboxylate (Example 58, step 2) was reacted with 4-fluorophenol using Ullmann coupling conditions similar to Example 18, step 4, followed by removal of the BOC protecting group using the procedure of Example 6, step 4. ES-MS m/z 354.4 (MH⁺); HPLC RT (min) 2.22.

[203] EXAMPLE 26

6-r(4-Fluorophenyl)aminol-3-r(1-isopropylpiperidin-3-yl)methyl1-2-(2- methylphenyl)quinazolin-4(3H)-one

[204] To a dry 25 mL round bottom flask were added 6-bromo-3-[(1-isopropylpiperidin-3- yl)methyl]-2-(2-methylphenyl)quinazolin-4(3H)-one (300 mg, 0.66 mmol) (Example 53, step 1 ), 4- fluoroaniline (88 mg, 0.79 mmol), Pd₂(dba)₃ (60.5 mg, 0.066 mmol), BINAP (65.8 mg, 0.106 mmol), and Cs₂CO₃ (430.2 mg, 1.32 mmo!) sequentially. Toluene (8 mL) was added and the reaction mixture was degassed for 2 min. The reaction mixture was then heated to 100°C for 20 h. The mixture was cooled to rt, filtered through a silica gel plug using ethyl acetate as eluent, concentrated to dryness, and purified using a Gilson reversed-phase HPLC system with a gradient elution from 10% to 90% acetonitrile in water to afford 19 mg (6%) of the product. ¹H NMR (300 MHz, CD₂CI₂) δ 7.71 (s, 1 H), 7.65 (d, 1 H), 7.32-7.51 (m, 5 H), 7.19-7.25 (m, 2 H), 7.10 (t, 2 H), 4.15-4.31 (m, 1 H), 3.30-3.43 (m, 4 H), 2.45-2.61 (m, 2 H), 2.21-2.39 (m, 4 H), 1.80-1.92 (m, 2 H), 1.21-1.39 (m, 7 H), 1.01-1.17 (m, 1 H); ES-MS m/z 485.4 (MH⁺); HPLC RT (min) 2.48.

[205] EXAMPLE 27

6-rEthyl(4-fluorophenyl)aminol-3-r(1-isopropylpiperidin-3-yl)methyll-2-(2- methylphenyl)quinazolin-4(3H)-one

[206] To a solution of 6-[(4-fluorophenyl)amino]-3-[(1 -isopropylpiperidin-3-yl)methyl]-2-(2-methyl- phenyl)quinazolin-4(3H)-one (25 mg, 0.052 mmol) (Example 26) in THF (1 mL) was added 2 M lithium diisopropylamide in heptane/THF/ethylbenzene (26 μL, 0.052 mmol) at 0⁰C. The reaction mixture was stirred 10 min and iodoethane (5 μL, 0.057 mmol) was added via syringe. The reaction was stirred for 15 h at rt, quenched with 1 N aq ammonium chloride solution, and extracted with ethyl acetate. Removal of the solvent under reduced pressure and purification using a Gilson reversed-phase HPLC system afforded 7 mg (26%) of the product. ¹H NMR (300 MHz, CD₂CI₂) δ 7.26 (d, 1 H), 7.32-7.55 (m, 5 H), 7.13-7.22 (m, 5 H), 4.18-4.35 (m, 1 H), 3.85 (q, 2 H), 3.31-3.48 (m, 4 H), 2.46-2.61 (m, 2 H), 2.20- 2.40 (m, 4 H), 1.81 -1.95 (m, 2 H), 1.21-1.40 (m, 10 H), 1.02- 1.18 (m, 1 H); ES-MS m/z 513.5 (MH⁺); HPLC RT (min) 2.82.

[207] EXAMPLE 28

6-r(4-Fluorophenyl)amino1-3-r(1-isopropylpiperidin-3-yl)methvHquinazolin-4(3H)-one

[208] tert-Butyl (3R)-3-[(6-bromo-4-oxoquinazolin-3(4H)-yl)methyl]piperidine-1 -carboxylate (Example 58, step 2) was reacted with 4-fluoroaniline under Buchwald coupling conditions as described in Example 26, followed by removal of the BOC group similar to the procedure described in Example 6, step 4, and N-alkylation as described in Example 7. ES-MS m/z 395.4 (MH⁺); HPLC RT (min) 2.21.

[209] EXAMPLE 29

N-f3-r(1-Ethylpiperidin-3-yl)methvn-2-(2-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-6- yllbenzenesulfonamide

[210] To a sealed tube was added 6-bromo-3-[(1-ethylpiperidin-3-yl)methyl]-2-(2-methoxy- phenyl) quinazolin-4(3H)-one (Example 49, step 1 ) (66 mg, 0.145 mmol), benzenesulfonamide (34 mg, 0.217 mmol), Pd₂dba₃ (6.62 mg, 0.007 mmol), XANTPHOS (8 mg, 0.014 mmol), cesium carbonate (94 mg, 0.289 mmol), along with dioxane (1 ml_). The mixture was heated at 100⁰C for 16 h. The crude material was passed through Celite® to remove the solids, and methanol was used to elute the product. The methanolic solution was purified by HPLC using a gradient from 5- 55% acetonitrile in water to afford the title product (33 mg, 35%) after evaporation. ¹H NMR (CD₃OD) 58.10-8.00 (m, 1 H), 7.90-7.80 (m, 2H), 7.65-7.40 (m, 7H), 7.30-7.10 (m, 2H), 4.30-4.10 (m, 1 H), 3.85 (s, 3H), 3.70-3.35 (m, 2H), 3.30-2.30 (m, 5H), 2.20-0.90 (m, 8H); ES-MS m/z 533.2 (MH⁺); HPLC RT (min) 1.92.

[211] EXAMPLE 30

6-(4-Fluorophenoxy)-2-isopropyl-3-(piperidin-3-ylmethyl)quinazolin-4(3H)-one

[212] Step 1. Preparation of 6-bromo-2-isopropyl-4H-3,1 -benzoxazin-4-one

[213] To a mixture of 2-amino-5-bromobenzoic acid (25 g, 116 mmol) in DCM was added triethylamine (31.7 g, 312 mmol). The mixture was cooled to 0°C and 2-methylpropanoyl chloride (30.8 g, 289 mmol) was added dropwise. The solution was allowed to warm to rt over 2 h. The reaction mixture was quenched with water and extracted with DCM (2x). The combined organic fractions were washed with brine, dried over MgSO₄, filtered and concentrated in vacuo to afford 31 g (99%) of the product. ES-MS m/z 268.1 (MH⁺); HPLC RT (min) 3.29.

[214] Step 2. Preparation of tert-butyl 3-f(6-bromo-2-isopropyl-4-oxoαuinazolin-3(4H)- yl)methyl1piperidine-1-carboxylate

[215] A mixture of 6-bromo-2-isopropyl-4H-3,1-benzoxazin-4-one (18.8 g, 70 mmol) (step 1 ) and tert-butyl 3-(aminomethyl)pipehdine-1-carboxylate (18 g, 84 mmol) in toluene was heated at reflux for 4 h. After removal of the organic solvent under reduced pressure, ethylene glycol (25 ml_) and LiOH (3.35 g, 140 mmol) were added, and the mixture was heated at 130⁰C for 5 h. After cooling to rt, water was added, and the mixture was extracted with DCM (3x). The combined organic layers were washed with brine, dried over MgSO₄, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (20% ethyl acetate in hexane) to afford 15.5 g (48%) of the product. ES-MS m/z 464.1 (MH⁺); HPLC RT (min) 4.01.

[216] Step 3. Preparation of tert-butyl 3-f[6-(4-fluorophenoxy)-2-isopropyl-4-oxoQuinazolin- 3(4H)-yl1methyl)piperidine-1-carboxylate

[217] A mixture of tert-butyl 3-[(6-bromo-2-isopropyl-4-oxoquinazolin-3(4H)-yl)methyl]piperidine- 1 -carboxylate (3.0 g, 6.46 mmol) (step 2), 4-fluorophenol (1.45 g, 12.9 mmol), CuCI (0.32 g, 3.23 mmol), Cs₂CO₃ (4.2 g, 12.9 mmol), and TMHD (0.58 g, 1.94 mmol) in NMP (50 mL) was degassed and then heated at 125°C for 15 h. After cooling to rt, the reaction mixture was poured into 100 mL water and extracted with ethyl acetate (2x). The combined organic fractions were washed with brine, dried over MgSO₄, filtered, concentrated and purified by silica gel chromatography (40% ethyl acetate in hexane) to afford 2.5 g (77%) of the product. ES-MS m/z 496.1 (MH⁺); HPLC RT (min) 4.40.

[218] Step 4. Preparation of 6-(4-fluorophenoxy)-2-isopropyl-3-(piperidin-3-ylmethvhαuinazolin- 4(3H)-one

[219] To a solution of tert-butyl 3-{[6-(4-fluorophenoxy)-2-isopropyl-4-oxoquinazolin-3(4H)- yl]methyl}piperidine-1-carboxylate (2.5 g, 5.04 mmol) (step 3) in DCM (40 ml.) was added TFA (3.9 ml_, 50.4 mmol) at rt. The reaction mixture was stirred for 15 h, concentrated under reduced pressure, dissolved in DCM (40 mL), and washed with sat aq NaHCO₃ and brine. The organic layer was dried over MgSO₄ and concentrated under reduced pressure to afford 1.4 g (70%) product. ES-MS m/z 396.2 (MH⁺); HPLC RT (min) 2.72.

[220] EXAMPLE 31

6-(4-Fluorophenoxy)-2-isopropyl-3-fri-(2-methylprop-2-en-1-yl)piperidin-3- vπmethyl)quinazolin-4(3H)-one

[221] To a solution of 6-(4-fluorophenoxy)-2-isopropyl-3-(piperidin-3-ylmethyl)quinazolin-4(3H)- one (100 mg, 0.253 mmol) (Example 30) and K₂CO₃ (105 mg, 0.759 mmol) in MeCN (1 mL) was added 1-bromo-2-fluoro-2-methylpropane (391 mg, 2.53 mmol), and the mixture was then heated to 80⁰C for 2 h. The reaction mixture was cooled to rt, filtered, and concentrated. The crude product was redissolved in methanol and purified using a Gilson reversed-phase HPLC system with a gradient elution from 10% to 90% acetonitrile in water to afford 58 mg (51%) of the product. ¹H NMR (300 MHz, CD₂CI₂) 5 7.75 (d, 1 H), 7.58 (d, 1 H), 7.47 (dd, 1 H), 7.03-7.14 (m, 4 H), 5.26 (t, 1 H), 5.16 (S, 1 H), 4.23-4.28 (m, 1 H), 4.04-4.09 (m, 1 H), 3.46-3.64 (m, 4 H), 3.12-3.18 (m, 1 H), 2.51-2.70 (m, 3 H), 1.91-2.05 (m, 4 H), 1.82 (s, 3 H), 1.42 (t, 6 H); ES-MS m/z 450.5 (MH⁺); HPLC RT (min) 2.78. [222] EXAMPLE 32

3-(ri-(2.2-Difluoropropyl)piperidin-3-vnmethyl>-6-(4-fluorophenoxy)-2-isopropylquinazolin-

4(3H)-one

[223] To a solution of 6-(4-fluorophenoxy)-2-isopropyl-3-(piperidin-3-ylmethyl)quinazolin-4(3H)- one (100 mg, 0.253 mmol) (Example 30) and K₂CO₃ (105 mg, 0.759 mmol) in MeCN (1 mL) was added 1-chloro-2,2-difluoropropane (289 mg, 2.53 mmol), and the mixture was heated to 80⁰C for 2 h. The reaction mixture was cooled to rt, filtered, and concentrated. The crude product was redissolved in methanol and purified using a Gilson reversed-phase HPLC system with a gradient elution from 10% to 90% acetonitrile in water to afford 28 mg (23%) of the product. ¹H NMR (300 MHz, CD₂CI₂).δ 7.85 (t, 1 H), 7.55-7.62 (m, 2 H), 7.05-7.16 (m, 4 H), 4.32-4.39 (br, 1 H), 4.03-4.15 (br, 1 H), 4.00 (s, 2 H), 3.52-3.58 (br, 3 H), 3.05-3.35 (m, 2 H), 2.43-2.57 (br, 1 H), 1.85 -2.12 (m, 3 H), 1.48 (dd, 6 H), 1.26-1.33 (m, 2 H), 1.11-1.19 (m, 2 H); ES-MS m/z 474.0 (MH⁺); HPLC RT (min) 2.59.

[224] EXAMPLE 33

3-r(1-Ethylpiperidin-3-yl)methyll-6-(4-fluorophenoxy)-2-isopropylquinazolin-4(3H)-one

[225] The compound was prepared starting from the product of Example 30 using the reductive amination procedure described in Example 12. ES-MS m/z 424.4 (MH⁺); HPLC RT (min) 2.63.

[226] EXAMPLE 34

6-(3-Chlorophenoxy)-3-r(1-isopropylpiperidin-3-yl)methvn-2-(2-methoxyphenyl)quina2θlin-

4(3H)-one

[227] The compound was prepared similar to Example 30 combined with Example 31 , with the difference that N-deprotection and N-alkylation were performed prior to introducing the phenol via Ullmann coupling reaction. ES-MS m/z 518.6 (MH⁺); HPLC RT (min) 2.76.

[228] EXAMPLE 35

6-lsobutoxy-2-isopropyl-3-fr(3S)-1-isopropylpiperidin-3-yllmethyl>quinazolin-4(3H)-one

[229] Step 1. Preparation of tert-butyl (3R)-3-r(6-bromo-2-isopropyl-4-oxoquinazolin-3(4H)- vDmethylipiperidine-1-carboxylate

[230] A mixture of 6-bromo-2-isopropyl-4H-3,1-benzoxazin-4-one (18.8 g, 70 mmol) (Example 46, step 1) and tert-butyl (3R)-3-(aminomethyl)piperidine-1 -carboxylate (18 g, 84 mmol) in toluene was heated at 120⁰C for 4 h. After removal of toluene under reduced pressure, ethyleneglycol (25 mL) and LiOH (3.35 g, 140 mmol) were added, and the mixture was heated at 130⁰C for 5 h. The reaction mixture was cooled to rt, diluted with water, and extracted with DCM (3x). The combined organic extracts were washed with brine, dried over MgSO₄, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (20% ethyl acetate in hexane) to afford 15.5 g (48%) of the product. ES-MS m/z 464.4 (MH⁺); HPLC RT (min) 4.01.

[231] Step 2. Preparation of tert-butyl (3R)-3-{r2-isopropyl-4-oxo-6-(4.4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2yl)quinazolin-3(4H)-yllmethyl)piperidine-1-carboxylate

[232] To a solution of tert-butyl (3R)-3-[(6-bromo-2-isopropyl-4-oxoquinazolin-3(4H)-yl)methyl]- piperidine-1 -carboxylate (1.0 g, 2.15 mmol) (step 1 ), and 4,4,4',4',5,5,5',5',-octamethyl-2,2'-bi- 1 ,3,2-dioxaborolane (0.68 g, 2.69 mmol) in anhydrous DMF was added KOAc (0.88 g, 8.96 mmol) and PdCI₂(dppf) (0.095 g, 0.129 mmol). The reaction mixture was degassed for 2 min and then heated to 60⁰C for 15 h. After cooling to rt and filtering through a pad of Celite®, the solvent was removed under reduced pressure and the residue diluted with water and DCM. The aq phase was extracted with DCM (3x), and the combined organic layers dried with MgSO₄ and concentrated to afford 0.88 g (82%) of the product. ES-MS m/z 512.2 (MH⁺); HPLC RT (min) 4.20.

[233] Step 3. Preparation of tert-butyl (3R)-3-[(6-hvdroxy-2-isopropyl-4-oxoquinazolin-3(4H)- yl)methvπpiperidine-1-carboxylate

[234] To a solution of tert-butyl (3R)-3-{[2-isopropyl-4-oxo-6-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2yl)quinazolin-3(4H)-yl]methyl}piperidine-1 -carboxylate (5.07 g, 9.91 mmol) (step 2) and NaOH (0.79 g, 19.8 mmol) in THF (100 mL) was added 30% H₂O₂ (6 ml_, 59.4 mmol). The reaction mixture was stirred 1 h. The pH of the mixture was adjusted to 7 using aq NH₄CI solution. The mixture was extracted with ethyl acetate (2x) and dried over MgSO₄. The organic layer was then concentrated and the crude product purified by silica gel chromatography (30% ethyl acetate in hexane) to afford 3.5 g (88%) of the product. ES-MS m/z 402.0 (MH⁺); HPLC RT (min) 3.07. [235] Step 4. Preparation of tert-butyl (3R)-3-f(6-isobutoxy-2-isopropyl-4-oxoquinazolin-3(4H)- yl)metriyllpiperidine-1-carboxylate

[236] To a solution of tert-butyl (3R)-3-[(6-hydroxy-2-isopropyl-4-oxoquinazolin-3(4H)-yl)methyl]- piperidine-1-carboxylate (400 mg, 0.996 mmol) (step 3) and Cs₂CO₃ (649 mg, 1.993 mmol) in DMF (10 ml.) was added 1-iodo-2-methylpropane (0.573 mL, 4.981 mmol). The reaction mixture was heated at 90⁰C for 15 h. After removal of the solvent under reduced pressure, the crude product was purified by silica gel chromatography to afford 340 mg (74%) of the product. ES-MS m/z 458.1 (MH⁺); HPLC RT (min) 4.21.

[237] Step 5. Preparation of 6-isobutoxy-2-isopropyl-3-r(3S)-piperidin-3-ylmethyllquinazolin- 4(3H)-one

[238] To a solution of tert-butyl (3R)-3-[(6-isobutoxy-2-isopropyl-4-oxoquinazolin-3(4H)-yl)- methyl]piperidine-1-carboxylate (936 mg, 1.397 mmol) (step 4) in DCM (15 mL) was added TFA (1.1 mL, 13.97 mmol) at rt. The reaction mixture was stirred for 15 h, concentrated, dissolved in DCM (40 mL), and washed with sat aq NaHCO₃ solution and brine. The organic layer was dried over MgSO₄ and concentrated to afford 395 mg (79%) of the product.

[239] Step 6. Preparation of 6-isobutoxy-2-isopropyl-3-fr(3S)-1 -isopropylpiperidin-3-vπmethyl)- quinazolin-4(3H)-one

[240] To a solution of 6-isobutoxy-2-isopropyl-3-[(3S)-piperidin-3-ylmethyl]quinazolin-4(3H)-one (400 mg, 1.12 mmol) (step 5) and Cs₂CO₃ (729 mg, 2.24 mmol) in MeCN (5 mL) was added 2- iodopropane (1.9 g, 11.1 mmol), and the mixture was heated to 90⁰C for 15 h. The reaction mixture was cooled to rt, filtered, and concentrated. The crude product was redissolved in methanol and purified using a Gilson reversed-phase HPLC system with a gradient elution from 10% to 90% acetonitrile in water to afford 132 mg (30%) of the product. ¹H NMR (300 MHz, CD₂CI₂) δ 7.58 (s, 1 H)₁ 7.53 (d, 1 H), 7.32 (d, 1 H), 4.05-4.15 (br, 2 H), 3.85 (d, 2 H), 3.20-3.30 (m, 1 H), 2.72-2.85 (br, 3 H), 2.06-2.36 (m, 4 H), 1.62-1.80 (m, 2 H), 1.51-1.62 (m, 1 H), 1.38 (t, 6 H), 1.25-1.30 (m, 1 H), 1.02-1.10 (m, 12 H); ES-MS m/z 400.4 (MH⁺); HPLC RT (min) 2.64.

[241] EXAMPLE 36

6-(Cvclopropyloxy)-3-fr(3S)-1-ethylpiperidin-3-vnmethyl)-2-isopropylquinazolin-4(3H)-one

[242] The product was obtained using the sequence described in Example 35, step 1-5, and appropriate starting materials, followed by a reductive amination reaction as described in Example 12. ES-MS m/z 370.3 (MH⁺); HPLC RT (min) 2.27.

[243] EXAMPLE 37

6-r(4-Fluorophenyl)thiol-3-{f(3S)-1-isopropylpiperidin-3-yllmethyl)quinazolin-4(3H)-one

[244] Step 1. Preparation of 6-iodo-4H-3.1-benzoxazin-4-one

[245] The compound was prepared using the method of step 1 of Example 58 and 2-amino-5- iodobenzoic acid as starting material. [246] Step 2. Preparation of tert-butyl (3R)-3-r(6-iodo-4-oxoquinazolin-3(4H)-yl)methyl1- piperidine-1 -carboxylate

[247] The compound was prepared using the method of step 2 of Example 58 and 6-iodo-4H- 3,1-benzoxazin-4-one as starting material. ES-MS m/z 370.15 ([MH₂- BOC]⁺); HPLC RT (min) 3.42.

[248] Step 3. Preparation of 6-iodo-3-(r(3S)-1-isopropylpiperidin-3-vπmethyl)quinazolin-4(3H)- one

[249] The compound was prepared using the method of Example 58, step 3, and tert-butyl (3R)- 3-[(6-iodo-4-oxoquinazolin-3(4H)-yl)methyl]piperidine-1-carboxylate as starting material.

[250] Step 4. Preparation of 6-r(4-fluorophenyl)thio1-3-(r(3S)-1-isopropylpiperidin-3-yl1methyl)- quinazolin-4(3H)-one

[251] To a solution of 4-fluorobenzenethiol (299 mg, 2.33 mmol), KOH (327 mg, 5.84 mmol), CuI (18.5 mg, 0.10 mmol), and N-methyl glycine (43.3 mg, 0.49 mmol) in toluene (10 mL) was added 6-iodo-3-{[(3S)-1-isopropylpiperidin-3-yl]methyl}quinazolin-4(3H)-one (800 mg, 1.95 mmol) (step 3) under a nitrogen atmosphere. The reaction mixture was stirred under reflux for 24 h. The resulting suspension was cooled to rt and filtered through a silica gel pad. The filtrate was concentrated and the resulting residue purified using a Gilson reversed-phase HPLC system to afford the product (236 mg, 29%) as light yellow oil. ¹H NMR (400 MHz, CD₃OD) δ 8.23 (s, 1 H), 7.94-7.95 (d, 1 H), 7.58-7.63 (m, 2 H), 7.50-7.53 (m, 2 H), 7.15-7.19 (m, 2 H), 3.87-3.98 (m, 2 H), 2.76-2.84 (m, 2 H), 2.70-2.75 (m, 1 H),2.04-2.24 (m, 3 H), 1.69-1.79 (m, 2 H), 1.52-1.59 (m, 1 H), 1.09-1.15 (m, 1 H), 1.04-1.06 (m, 6 H); ES-MS m/z412.2 (MH⁺); HPLC RT (min) 2.45.

[252] EXAMPLE 38 β-r(4-Fluorophenyl)sulfonyll-3-{r(3S)-1-isopropylpiperidin-3-vnmethyl>quinazolin-4(3H)-one

[253] 6-[(4-Fluorophenyl)thio]-3-{[(3S)-1-isopropylpiperidin-3-yl]methyl}quinazolin-4(3H)-one (130 mg, 0.32 mmol) (Example 37) was added to a vigorously stirred suspension of wet alumina (AI₂O₃) (161 mg, 1.58 mmol) and oxone^® (583 mg, 0.96 mmol) in DCM (10 ml). The mixture was heated at reflux for 5 h. The mixture was then cooled to rt, filtered, and the solid was washed with additional DCM. Concentration under reduced pressure and purification by HPLC with 5% to 60% acetonitrile in water (0.1% TFA) gave the product (36 mg, 26%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ 8.76-8.77 (d, 1 H), 8.38 (s, 1 H), 8.25-8.28 (dd, 1 H), 8.05-8.09 (m, 2 H), 7.81-7.83 (d, 1 H), 7.30-7.35 (m, 2 H), 3.90-4.02 (m, 2 H), 2.77-2.84 (m 2H), 2.70-2.75 (m, 1 H), 2.14-2.25 (m, 2 H), 2.06-2.13 (m, 1 H), 1.71-1.79 (m, 2 H), 1.52-1.57 (m, 1 H), 1.10-1.14 (m, 1 H), 1.04-1.08 (m, 6 H); ES-MS m/z 444.3 (MH⁺); HPLC RT (min) 2.04.

[254] EXAMPLE 39

6-(4-Chlorophenv0-2-(2-methoxyphenvh-3-r(3ffl-piperidin-3-ylmethyl1 quinazolin-4(3H)-one trifluoroacetate

[255] Step 1. Preparation of 6-bromo-2-(2-methoxyphenyl)-4H-3.1-benzoxazin-4-one

[256] 2-Methoxybenzoyl chloride (9.5 g, 55.5 mmol) was added slowly into a mixture of 2-amino-

5-bromobenzoic acid (10 g, 46.3 mmol) and triethylamine (19.5 mL, 138.9 mmol) in DCM (100 mL) at 1O⁰C. The reaction mixture was stirred at rt for 3 h followed by addition of oxalyl chloride (8 ml_). After 2 h, acetic anhydride (50 ml.) was added into the mixture and it was heated to 5O⁰C for 1 h. The reaction mixture was cooled to rt, slowly quenched with water, and diluted with DCM. The layers were separated and the DCM layer was washed with aq NaHCO₃ solution, brine, and dried over Na₂SO₄. After concentrating under reduced pressure, the crude was treated with methanol and stirred for 10 min. The solid was filtered off and washed with a small amount of methanol until it turned white. The residue was then dried in a vacuum oven at 5O⁰C for 3 h to give 9.8 g (69%) of the product. ¹H NMR (300 MHz, CD₂CI₂) δ 8.34 (d, 1 H), 7.93 (dd, 1 H), 7.85 (dd, 1 H), 7.52-7.58 (m, 2 H), 7.05-7.11 (m, 2 H), 3.93 (s, 3 H).

[257] Step 2. Preparation of 6-(4-chlorophenyl)-2-(2-methoxyphenyl)-4H-3.1-benzoxazin-4-one

[258] 6-Bromo-2-(2-methoxyphenyl)-4H-3,1-benzoxazin-4-one (2.5 g, 7.53 mmol) (step 1 ), 4- chlorophenylboronic acid (1.77, 11.3 mmol), and PdCI₂(dppf) CH₂CI₂ (275 mg, 3.6 mmol) were dissolved in a toluene/dioxane mixture (25 ml_, 4/1) followed by addition of 2 N aq Na₂CO₃ (10 ml.) and K₂CO₃ (3.1 g, 22.6 mmol). The mixture was degassed and heated to 9O⁰C for 1 h. After cooling to rt, the mixture was diluted with ethyl acetate and the water layer was removed. The organic layer was washed with Na₂CO₃ (50 ml_, 2 N) and brine, dried over Na₂SO₄, and concentrated under reduced pressure. To the crude was added methanol (50 mL) and it was stirred for 10 min. The solid was filtered off and washed with a small amount of methanol until it turned white. The product was dried in a vacuum oven at 50 ⁰C to give 2.64 g (96%) of the product. ¹H NMR (300 MHz, CD₂CI₂) δ 8.96 (d, 1 H), 8.36 (d, 1 H), 8.08 (dd, 1 H), 7.90 (dd, 1 H), 7.68 (d, 2 H), 7.58 (td, 1 H), 7.49 (d, 2 H), 7.22 (d, 1 H), 7.13 (t, 1 H), 4.09(s, 3 H).

[259] Step 3. Preparation of tert-butyl (3SV3-(r6-(4-chlorophenvπ-2-(2-methoxyphenyl)-4- oxoquinazolin-3(4H)-yllmethyl)piperidine-1-carboxylate

[260] tert-Butyl (3S)-3-(aminomethyl)piperidine-1-carboxylate (1.00 g, 4.67 mmol) in toluene (20 mL) was added to 6-(4-chlorophenyl)-2-(2-methoxyphenyl)-4H-3,1 -benzoxazin-4-one (1.31 g, 3.59 mmol) (step 2) and the mixture was stirred at reflux for 15 h. Ethanediol (20 mL) and NaOH (288 mg, 7.2 mmol) were added, and the resulting mixture was stirred at 150⁰C for for 15 h. The crude was diluted with DCM and water. The aq mixture was extracted with DCM (50 mL x 2) and the organic solvent was removed under reduced pressure. The crude was then purified by silica gel flash chromatography with 10 to 50% ethyl acetate in hexanes. ¹H NMR (300 MHz, DMSO-d6) δ 8.41 (d, 1 H), 8.18 (dd, 1 H), 7.85 (d, 2 H), 7.76 (d, 1 H), 7.54-7.61 (m, 3 H), 7.47-7.51 (m, 1 H), 7.21 (dd, 1 H), 7.14 (t, 1 H), 4.00-4.20 (br, 1 H), 3.80 (s, 3 H), 3.56-3.70 (br, 1 H), 2.52-2.68 (br, 2 H), 2.21-2.38 (br, 1 H), 1.11 -1.72 (br, 15 H); ES-MS m/z 560.1 (MH⁺); HPLC RT (min) 4.50.

[261] Step 4. Preparation of 6-(4-chlorophenvπ-2-(2-methoxyphenyl)-3-[(3/^:?)-piperidin-3-yl methyllquinazolin-4(3H)-one trifluoroacetate

[262] To a solution of tert-butyl (3S)-3-{[6-(4-chlorophenyl)-2-(2-methoxyphenyl)-4-oxo- quinazolin-3(4H)-yl]methyl}piperidine-1-carboxylate (1.38 g, 3.18 mmol) (step 3) in DCM (20 mL) was added TFA (2.5 mL, 31.8 mmol), and the reaction mixture was stirred at rt for 3 h. The solvents were removed and the crude was redissolved in EtOAc. The organic layer was washed with sat aq NaHCO₃ and brine, and dried over Na₂SO₄. After filtration and concentration under reduced pressure, 1.8 g (99.6%) of the product was obtained. ¹H NMR (300 MHz, CD₃OD) δ 8.50 (d, 1 H), 8.15 (dd, 1 H), 7.42-7.79 (m, 3 H), 7.65 (t, 1 H), 7.50-7.57 (m, 3 H), 7.18-7.29 (m, 2 H), 4.38 (0.6 H), 4.19 (dd, 0.4 H), 3.91 (s, 3 H), 3.76 (0.6 H), 3.56 (dd, 0.4 H), 3.10-3.31 (m, 2 H), 2.5- 2.91 (m, 2 H), 2.0-2.25 (br, 1 H), 1.75-1.59 (m, 1 H), 1.35-1.74 (m, 2 H), 1.12-1.32 (m, 1 H); ES- MS m/z 460.4 (MH⁺); HPLC RT (min) 2.48.

[263] EXAMPLE 40

6-(4-Chlorophenyl)-3-(r(3ff)-1-ethylpiperidin-3-yllmethyl)-2-(2-methoxyphenyl)quinazolin-

[264] To a mixture of 6-(4-chlorophenyl)-2-(2-methoxyphenyl)-3-[(3f?)-piperidin-3-ylmethyl] quinazolin-4(3H)-one (1.38 g, 3.0 mmol) (Example 39) and K₂CO₃ (1.24 g, 9.0 mmol) in CH₃CN (200 mL) was added ethyl bromide (0.24 mL, 3.24 mmol). The mixture was stirred at 8O⁰C for 4 h, then cooled to rt and diluted with ether (200 mL). After removal of the solid by filtration, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel flash chromatography using 97% CH₂CI₂: 3% 2M NH₃ in MeOH to give the crude product which was then purified using a Gilson reversed-phase HPLC system with 5 to 50% acetonitrile in water (0.1% TFA). The product fractions were concentrated, dissolved in EtOAc, and solid NaCI was added. The organic layer was washed with sat aq NaHCO₃, Na₂CO₃, and brine to give 765 mg (52%) of product. ¹H NMR (300 MHz, CD₃OD) δ 8.44 (d, 1 H)₁ 8.07 (dd, 1 H), 7.70 (dd, 3 H), 7.59 (t, 1 H), 7.45-7.54 (m, 3 H), 7.14-7.25 (m, 2 H), 4.18-4.29 (m, 1 H), 3.87 (s, 3 H), 3.48-3.51 (m, 1 H), 2.5-2.82 (br, 2 H), 2.22-2.39 (m, 2 H), 1.21 -1.91 (m, 6 H), 0.69-1.05 (m, 4 H); ES-MS m/z 488.4 (MH⁺); HPLC RT (min) 3.06.

[265] EXAMPLE 41

6-(4-Chlorophenyl)-3-{r(3R)-1-ethylpiperidin-3-vnmethyl)-2-(2-methylphenyl)quinazolin-

[266] 6-(4-chlorophenyl)-2-(2-methylphenyl)-3-[(3/^:?)-piperidin-3-yl methyl]quinazolin-4(3W)-one, prepared similar to the product described in Example 39, was further transformed into the title product by using the reductive amination procedure described in Example 12. ES-MS m/z 472.4 (MH⁺); HPLC RT (min) 3.24.

[267] EXAMPLE 42

6-(4-Chlorophenyl)-3-ff1-(2-hydroxyethyl)piperidin-3-vnmethyl>-2-(2- methylphenyl)quinazolin-4(3H)-one

[268] Step 1. Preparation of 3-(ri-(2-{rtert-butyl(dimethyl)silvnoxy)ethyl)piperidin-3-yl1methyl)-6- (4-chlorophenyl)-2-(2-methylphenyl)quinazolin-4(3H)-one

[269] To a solution of 6-(4-chlorophenyl)-2-(2-methylphenyl)-3-(piperidin-3-ylmethyl)quinazolin- 4(3H)-one (250 mg, 0.56 mmol), prepared similarly to Example 39, in THF (5 mL) was added {[tert- butyl(dimethyl)silyl]oxy}acetaldehyde (147 mg, 0.85 mmol), followed by AcOH (1 drop), and NaBH(OAc)₃ (358 mg, 1.69 mmol) in rapid succession. The reaction mixture was stirred for 3 days. Saturated aq NaHCO₃ was added, and the reaction mixture was stirred for 15 min. The mixture was diluted with DCM and extracted into the organic layer. The organic layer was washed with brine, dried over Na₂SO₄, filtered and concentrated under reduced pressure. Chromatography using a Biotage cartridge (25S) and eluting with EtOAc/hexane (30% - 60%) gave the product (150 mg, 44%). ES-MS m/z 602.7 (MH⁺); HPLC RT (min) 3.40.

[270] Step 2. Preparation of 6-(4-chlorophenyl)-3-(^r1-(2-hvdroxyethv0piperidin-3-vπmethyl|-2-(2- methylphenyl)quinazolin-4(3H)-one

[271] To a solution of 3-{[1-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)piperidin-3-yl]methyl}-6-(4- chlorophenyl)-2-(2-methylphenyl)quinazolin-4(3H)-one (150 mg, 0.25 mmol) (step 1) in THF (3 mL) was added TBAF (1.0 M in THF, 1.2 mL, 1.2 mmol). The reaction mixture was stirred at rt for 3 h. Saturated aq NaHCO₃ was added, and the mixture was diluted with DCM and extracted into the organic layer. The organic layer was washed with brine, dried over Na₂SO₄, filtered and concentrated to dryness. The residue was purified using a Gilson reversed-phase HPLC system to give the title product (100 mg, 82%). ¹H NMR (400 MHz, CD₃OD) δ 1.25-1.38 (m, 3H), 1.39- 1.71 (m, 3H)₁ 1.85-2.00 (m, 2H), 2.22 (d, 3H), 2.42 (dd, 2H); 2.58-2.83 (m, 2H); 3.50-3.62 (m, 3H); 4.05-4.20 (ddd, 1 H); 7.38-7.52 (m, 6H); 7.61-7.71 (m, 3H); 8.02 (dd, 1 H); 8.41 (d, 1 H). ES-MS m/z 488.6 (MH⁺); HPLC RT (min) 2.59. [272] EXAMPLE 43

6-(4-Chlorophenyl)-2-(2-methoxyphenvh-3-(piperidin-3-ylmethyl)quinazolin-4(3H)-one hydrochloride

[273] Step 1. Preparation of 6-bromo-2-(2-methoxyphenyl)-4H-3.1-benzoxazin-4-one

[274] To a dry 250 mL round-bottom flask was added 2-amino-5-bromobenzoic acid (5.00 g, 23.1 mmol) followed by anhydrous dichloroethane (100 mL), Et₃N (9.68 mL, 69.4 mmol), and 2- anisoyl chloride (3.90 mL, 27.8 mmol). The resulting brown solution was stirred at rt under an atmosphere of N₂. After 16 h, acetic anhydride (5.00 mL, 53.0 mmol) was added to the mixture along with cone H₂SO₄ (1.00 mL). The resulting mixture was heated to 55⁰C for 5 h. The mixture was then diluted with CH₂CI₂ (100 mL) and sat aq NaHCO₃ (100 mL). The layers were separated and the organic layer was dried over MgSO₄, filtered, and concentrated under reduced pressure. The product was taken up in EtOAc (100 mL) and was washed with sat aq NaHCO₃ (4 x 100 mL). The organic layer was then dried with MgSO₄, filtered, and concentrated under reduced pressure to give the product as a white solid (7.60 g, 98 %). ¹H NMR (300 MHz, CDCI₃) δ 8.35 (d, 1 H), 7.91-7.85 (m, 2H), 7.57 (d, 1 H), 7.52-7.49 (m, 1 H), 7.09-7.02 (m, 2H), 3.93 (s, 3H). ES-MS m/z 332 (MH⁺).

[275] Step 2. Preparation of tert-butyl 3-{r6-bromo-2-(2-methoxyphenyl)-4-oxoquinazolin- 3(4HWI1methyl)piperidine-1-carboxylate

[276] To a dry 5O mL round-bottom flask was added 6-bromo-2-(2-methoxyphenyl)-4H-3,1 - benzoxazin-4-one (1.50 g, 4.51 mmol) (step 1), followed by anhydrous toluene (10 ml_), and 3- aminomethyl-1-N-BOC-piperidine (1.16 g, 5.42 mmol). The mixture was heated to 80⁰C and was stirred for 16 h under an atmosphere of N₂. The mixture was concentrated under reduced pressure and purified by silica gel flash chromatography (100% CH₂CI₂ ramping to 97% CH₂CI₂: 3% MeOH with 1% Et₃N). This gave the intermediate as a viscous light yellow oil. R_f = 0.18 (95% CH₂CI₂: 5% MeOH); ES-MS m/z 547 (MH⁺, 75), 430 (46), 332 (39).

[277] The intermediate described above (1.55 g, 2.83 mmol) was added to a dry 50 ml. round- bottom flask followed by ethylene glycol (8.00 mL) and NaOH (1.80 g, 45.2 mmol). The mixture was heated to 120⁰C and after 16 h, diluted with water (10 mL), and subsequently extracted with CH₂CI₂ (5 x 40 mL). Purification by flash silica gel chromatography (80% hexanes: 20% EtOAc containing 1 % Et₃N) gave the product as a white solid (1.58 g, 66% (for 2 steps)). ES-MS m/z 528 (MH⁺, 100), 472 (20), 430 (41), 333 (10); ¹H NMR (300 MHz, CDCI₃) δ 8.51-8.45 (m, 1 H), 7.85- 7.80 (m, 1 H), 7.65-7.59 (m, 1 H), 7.59-7.43 (m, 1 H), 7.29-7.26 (m, 1 H), 7.15-7.08 (m, 1 H), 6.95 (m, 1 H), 4.27-4.20 (m, 1 H), 3.81-3.70 (m, 1 H), 3.72 (s, 3H), 3.70-3.57 (m, 1 H), 3.48-3.38 (m, 1 H), 2.65-2.45 (m, 1 H), 1.77-1.56 (m, 3H), 1.46-1.29 (m, 2H), 1.38 (br s, 9H), 1.09-0.87 (m, 1 H).

[278] Step 3. Preparation of tert-butyl 3-(f6-(4-chlorophenyl)-2-(2-methoxyphenyl)-4- oxoquinazolin-3(4H)-yllmethyl|piperidine-1-carboxylate

[279] To a dry 100 mL round-bottom flask was added tert-butyl 3-{[6-bromo-2-(2-methoxy- phenyl)-4-oxoquinazolin-3(4H)-yl]methyl}piperidine-1-carboxylate (1.23 g, 2.33 mmol) (step 2), followed by anhydrous toluene (20.0 mL) and dioxane (5.00 mL). The mixture was stirred under an atmosphere of N₂ followed by the addition of 4-chlorophenyl boronic acid (473 mg, 3.03 mmol), Na₂CO₃ (2.0 M solution, 3.50 mL, 6.98 mmol), K₂CO₃ (965 mg, 6.98 mmol), and PdCI₂(dppf) (85.1 mg, 0.116 mmol). The solution was heated to 90⁰C and after 1 h, cooled, filtered through a plug of silica gel with EtOAc as the eluent (40 mL), and then concentrated under reduced pressure. Purification by flash silica gel chromatography (80% hexanes: 20% EtOAc) gave the product as a white solid (1.14 g, 88%). R_f = 0.25 (80% hexanes: 20% EtOAc); ES-MS m/z 560 (MH⁺, 100), 462 (21), 460 (81 ), 363 (36); ¹H NMR (300 MHz, CDCI₃) 88.51 (d, 1 H), 7.95 (dd, 1 H), 7.79 (d, 1 H), 7.70-7.61 (m, 2H), 7.53-7.44 (m, 4H), 7.16-7.09 (m, 1 H), 7.01 (d, 1 H), 4.32-4.24 (m, 1 H), 3.85-3.81 (m, 1 H), 3.81 (s, 3H), 3.49-3.41 (m, 1 H), 2.66-2.57 (m, 1H), 1.81-1.69 (m, 1H)₁ 1.63 (br s, 4H), 1.46-1.41 (m, 1 H), 1.37 (br s, 9H), 1.08-0.89 (m, 1 H). [280] Step 4, Preparation of 6-(4-chlorophenyl)-2-(2-methoxyphenvO-3-(piperidin-3-ylmethvn- quinazolin-4(3H)-one hydrochloride

[281] To a 100 mL round-bottom flask was added tert-butyl 3-{[6-(4-chlorophenyl)-2-(2-methoxy- phenyl)-4-oxoquinazolin-3(4H)-yl]methyl}piperidine-1-carboxylate (1.31 g, 2.34 mmol) (step 3) and a minimum amount of CH₂CI₂ (~ 1 mL). The mixture was then stirred at rt for 2 h with 1 M HCI in ether (23.4 mL, 23.4 mmol). Another 5 equiv of HCI were added, and the light orange mixture was stirred for another 1 h. The mixture was then concentrated under reduced pressure yielding the product as a white powder (1.14 g, 98%). ¹H NMR (300 MHz, CD₃CN) δ 8.46 (dd, 1 H), 8.09 (dd, 1H), 7.78-7.73 (m, 3H), 7.61-7.43 (m, 4H), 7.17-7.11 (m, 2H), 4.26 (dd, 1H), 4.02 (dd, 1H), 3.82 (s, 3H), 3.47 (br s, 2H), 3.20-3.13 (m, 2H), 2.84-2.65 (m, 1 H), 1.83-1.35 (m, 3H), 1.19-1.01 (m, 1 H). ES-MS m/z 460.2 (MH⁺); HPLC RT (min) 2.58.

[282] EXAMPLE 44

6-(4-Chlorophenvπ-3-r(1-cvclopentylpiperidin-3-yl)methvn-2-(2-methoxyphenyl) quinazolin-4(3H)-one trifluoroacetate

[283] In a 5 mL amber, screw-capped vial was added K₂CO₃ (104 mg, 0.755 mmol) followed by a solution of 6-(4-chlorophenyl)-2-(2-methoxyphenyl)-3-(piperidin-3-ylmethyl)quinazolin-4(3H)-one hydrochloride (75.0 mg, 0.151 mmol) (Example 43) in anhydrous CH₃CN (1.0 mL). Bromo- cyclopentane (24.8 mg, 0.166 mmol) was then added and the vial was capped, placed on a shaker apparatus, and heated to 70⁰C. After 16 h, additional bromocyclopentane was added (24.8 mg, 0.166 mmol) and the mixture was heated on the shaker apparatus for another 16 h. Purification using a Gilson reversed-phase HPLC system gave the product as the TFA salt (52.3 mg, 54%). ¹H NMR (300 MHz, CD₃CN) δ 8.49-8.46 (m, 1 H), 8.17-8.08 (m, 1 H), 7.83-7.75 (m, 3H), 7.62-7.43 (m, 4H), 7.19-7.11 (m, 2H), 5.19 (br s, 4H, TFA protons), 4.26-4.10 (m, 1 H), 3.83 (d, 3H), 3.58- 3.29 (m, 3H), 3.27 (s, 3H), 2.66-2.56 (m, 1 H), 2.30-1.98 (m, 2H), 1.87-1.52 (m, 9H), 1.33-0.98 (m, 1 H). ES-MS m/z 528.4 (MH⁺); HPLC RT (min) 3.12.

[284] EXAMPLE 45 e^'-Chlorobiphenyl^-vn-a-irORμi-ethylpiperidin-a-yllmethvD-Σ-fa- methoχyphenyl)quinazolin-4(3H)-one trifluoroacetate

[285] tert-Butyl (3S)-3-{[6-(4'-ch!orobiphenyl-4-yl)-2-(2-methoxyphenyl)-4-oxoquinazolin-3(4H)- yl]methyl}piperidine-1-carboxylate, obtained as a side product from a reaction carried out analogously to Example 43, step 3, was further transformed to the product using the procedures described in Example 43, step 4, and Example 44, and appropriate starting materials. ES-MS m/z 564.3 (MH⁺); HPLC RT (min) 3.42.

[286] EXAMPLE 46

6-(4-Fluorophenyl)-2-isopropyl-3-r(3S)-piperidin-3-ylmethyllquinazolin-4(3h0-one

[287] Step 1. Preparation of 6-bromo-2-isopropyl-4H-3.1-benzoxazin-4-one

[288] To a solution of 2-amino-5-bromobenzoic acid (94 g, 435 mmol) and triethylamine (182 mL, 1.3 mol) in DCM (1.1 L) was added isobutyryl chloride (55 mL, 522 mmol) dropwise at O⁰C, and the solution was stirred at rt for 15 h. The solvent was removed under reduced pressure, and the residue was heated in acetic anhydride (300 mL) at 55⁰C for 3 h. After concentration under reduced pressure, the residue was dissolved in DCM and washed with aq NaHCO₃ solution, dried over Na₂SO₄, concentrated and dried under reduced pressure for 15 h to give 115 g (99%) of the product a yellow solid. ¹H NMR (400 MHz, CD₂CI₂) δ 8.28 (s, 1 H)₁ 7.90 (d, 1 H), 7.45 (d, 1 H),

2.94 (m, 1 H), 1.38 (d, 6H). ES-MS m/z 268.3 (MH⁺); HPLC RT (min) 3.19. [289] Step 2. Preparation of tert-butyl (3R)-3-(([5-bromo-2-(isobutyrylamino)benzoyl1amino)- methvDpiperidine-1-carboxylate

[290] A solution of 6-bromo-2-isopropyl-4H-3,1-benzoxazin-4-one (20 g, 74.6 mmol) (step 1 ) and tert-butyl (3R)-3-(aminomethyl)piperidine-1-carboxylate (7 g, 33 mmol) in toluene (500 ml_) was heated to reflux (13O⁰C, oil bath) for 4 h. Then, an additional 7 g of tert-butyl (3R)-3-(amino- methyl)piperidine-1-carboxylate was added. After 4 h of heating under reflux, 7 g of tert-butyl (3R)- 3-(aminomethyl)piperidine-1-carboxylate was added, and the solution were heated under reflux for another 15 h. The solvent was concentrated under reduced pressure, and the residue was purified by column chromatography (200 g of silica gel) using a gradient from 5% to 20% EtOAc in hexanes to afford 35 g (97% yield) of the product as a foam.

[291] Step 3. Preparation of tert-butyl (3R)-3-r(6-bromo-2-isopropyl-4-oxoquinazolin-3(4H)- yl)methyl1piperidine-1-carboxylate

[292] A mixture of tert-butyl (3R)-3-({[5-bromo-2-(isobutyrylamino)benzoyl]amino}methyl)- piperidine-1-carboxylate (33.9 g, 72 mmol) (step 2) and LiOH (3.4 g, 140 mmol) in ethylene glycol (150 ml.) was heated at 130⁰C for 15 h. LC/MS analysis showed 5 peaks including the product as the major component. Water and DCM were added, and the organic layer was separated, washed with water (2 x), and dried over MgSO₄ to give a brown oil. The crude product was purified by silica gel column chromatography using a gradient elution from 0% to 6% MeOH in DCM to afford 12.6 g (38% yield) of the product as a foam. ES-MS m/z 464.0 (MH⁺), HPLC RT (min) 4.04. [293] Step 4. Preparation of tert-butyl (3R)-3-ff6-(4-fluorophenyl)-2-isopropyl-4-oxoquinazolin- 3(4H)-yllmethyl)piperidine-1-carboxylate

[294] A mixture of tert-butyl (3R)-3-[(6-bromo-2-isopropyl-4-oxoquinazolin-3(4H)-yl)methyl]- piperidine-1-carboxylate (3.8 g, 8.2 mmol) (step 3), and 4-fluorophenylboronic acid (1.72 g, 12.3 mmol) in a solvent mixture consisting of toluene (60 mL), dioxane (15 mL), and aq K₂CO₃ (2 M, 15 mL) was brought under a nitrogen atmosphere. To the mixture was added PdCI₂(dppf) (0.43 g, 0.53 mmol), and the mixture was heated at 8O⁰C for 15 h. The solvent was concentrated under reduced pressure and the residue passed through a short silica gel column using a gradient elution from 0% to 5% MeOH in DCM. The resulting crude product was purified by silica gel column chromatography (110 g silica gel) using a gradient elution from 5% to 40% EtOAc in hexanes give the product as a white foam (3.7 g, 94%). ES-MS m/z 480.1 (MH⁺), HPLC RT (min) 4.18.

[295] Step 5. Preparation of 6-(4-fluorophenvD-2-isopropyl-3-r(3S)-piperidin-3-ylmethvπ- quinazolin-4(3H)-one

[296] A solution of tert-butyl (3R)-3-{[6-(4-fluorophenyl)-2-isopropyl-4-oxoquinazolin-3(4H)- yl]methyl}piperidine-1-carboxylate (3.2 g, 6.7 mmol) (step 4) and TFA (6 mL) in DCM (30 mL) was stirred at rt for 15 h. The solvent was concentrated and the residue dissolved in DCM, washed with aq NaHCO₃ solution, and dried over MgSO₄. After the MgSO₄ was filtered off and the solvent was removed under reduced pressure, the product (2.43 g, 96%) was obtained as a white foam. ¹H NMR (400 MHz, CD₂CI₂) δ 8.38 (d, 1H), 7.92 (dd, 1H), 7.67 (m, 3H), 7.17 (m, 2H), 4.10 (m, 4H), 3.21 (m, 1 H)₁ 3.03 (d, 2H), 2.69 (m, 1 H), 2.59 (q, 1 H), 2.03 (m, 1 H), 1.78 (m, 2H), 1.56 (m, 1 H), 1.38 (d, 6H); ES-MS: m/z 380.3 (MH⁺), HPLC RT (min) 2.54. [297] EXAMPLE 47

6-(4-Fluorophenyl)-2-isopropyl-3-(rf3S)-1-isopropylpiperidin-3-yllmethyl>αuinazolin-4(3H)- one

[298] A solution of 6-(4-fluorophenyl)-2-isopropyl-3-[(3S)-piperidin-3-ylmethyl]quinazolin-4(3H)- one (2.2 g, 5.8 mmol) (Example 46), 2-bromopropane (1.7 mL, 17 mmol), and K₂CO₃ (1.6 g, 11.6 mmol) in 100 mL of acetonitrile was heated at 7O⁰C for 4 h. The precipitate was filtered off and the solvent removed under reduced pressure. The residue was purified by column chromatography (40 g of silica gel) using a gradient elution with 0% to 6% MeOH in DCM to give the product as an oil. The product was dried under high vacuum at 5O⁰C to afford 1.9 g (77% yield) of a white sticky solid. ¹H NMR (400 MHz, CD₂CI₂) δ 8.40 (s, 1 H), 7.95 (d, 1 H), 7.70 (m, 3H), 7.20 (t, 2H), 4.15 (s, 2H), 3.30 (m, 1 H), 2.9 (m, 3H), 2.3 (m, 3H), 1.8 (m, 3H) 1.38 (d, 6H), 1.3 (m, 1 H), 1.1 (d, 6H); ES-MS m/z 422.3 (MH⁺), HPLC RT (min) 2.66.

[299] EXAMPLE 48

6-π,3-Benzodioxol-5-yl)-2-r2-(difluoromethoxy)phenyll-3-(piperidin-3-ylmethyl)quinazolin-

[300] tert-Butyl (3R)-3-{[(2-amino-5-bromobenzoyl)amino]methyl}piperidine-1 -carboxylate (Example 18, step 1 ) was coupled with 2-(difluoromethoxy)benzoic acid and cyclized using similar procedures as described in Example 77, steps 1 and 2. The resulting intermediate, tert-butyl 3-{[6- bromo-2-[2-(difluoromethoxy)phenyl]-4-oxoquinazolin-3(4H)-yl]methyl}piperidine-1 -carboxylate, was reacted with 1 ,3-benzodioxol-5-ylboronic acid using the Suzuki coupling procedure described in Example 46, step 4, followed by removal of the BOC group as described in Example 46, step 5. ES-MS m/z 506.4 (MH⁺), HPLC RT (min) 2.89. [301] EXAMPLE 49

6-(3-Chlorophenyl)-3-rπ-ethylpiperidin-3-yl)methvn-2-(2-methoxyρhenvn quinazolin-4(3H)-one trifluoroacetate

[302] Step 1. Preparation of 6-bromo-3-f(1-ethylpiperidin-3-yl)methvn-2-(2-methoxyphenyl) quinazolin-4(3H)-one

[303] A mixture of 1-(1-ethylpiperidin-3-yl)methanamine trifluoroacetate (1.39 g, 5.4 mmol, synthesized by a similar procedure as Example 4, steps 1 and 2, using bromoethane as the alkylating agent) and TEA (1.5 ml_, 10.8 mmol) in toluene (1.2 ml_) was added to 6-bromo-2-(2- methoxyphenyl)-4H-3,1-benzoxazin-4-one (1.20 g, 3.61 mmol) (Example 39, step 1), and the mixture was stirred at reflux for 15 h. Ethanediol (20 mL) and NaOH (289 mg, 7.2 mmol) were added, and the resulting mixture was stirred at 18O⁰C for 3 h. The crude was diluted with DCM and water, followed by extraction with DCM (50 mL x 2) and concentration of the combined organic layers under reduced pressure. The crude was then purified by silica gel flash chromatography using 3% 2M methanolic NH₃ in DCM to give 1.4 g (85%) of the product. ¹H NMR (300 MHz, CD₃OD) δ 8.37 (d, 1 H), 7.94 (dd, 1 H), 7.48-7.64 (m, 3 H), 7.14-7.23 (m, 2 H), 4.15-4.25 (m, 1 H), 3.88 (s, 3 H), 3.47-3.57 (m, 1 H), 2.52-2.83 (br, 2 H), 2.26-2.39 (m, 2 H), 1.24-1.95 (m, 6 H), 0.71 - 1.06 (m, 4 H); ES-MS m/z 349.9 (MH⁺); HPLC RT (min) 3.03.

[304] Step 2. Preparation of 6-(3-chlorophenyl)-3-f(1-ethylpiperidin-3-yl)methvH-2-(2- methoxyphenyl)quinazolin-4(3H)-one trifluoroacetate

[305] 6-Bromo-3-[(1-ethylpiperidin-3-yl)methyl]-2-(2-methoxyphenyl)quinazolin-4(3H)-one (70 mg, 0.15 mmol) (step 1 ), 3-chlorophenylboronic acid (36 mg, 0.23 mmol), and PdCI₂(dppf)^'CH₂CI₂ (9 mg, 0.008 mmol) were dissolved in a toluene/dioxane mixture (1.6 ml_, 4/1 ), followed by addition of 2N aq Na₂CO₃ (0.4 ml_). The mixture was heated to 100⁰C for -2.5 days under a nitrogen atmosphere. After cooling to rt, the mixture was passed through a silica gel plug using EtOAc as eluent, and the filtrate was concentrated under reduced pressure. The crude product was purified using a Gilson reversed-phase HPLC system with a gradient elution from 5% to 55% acetonitrile in water to afford 43 mg (47%) of the product. ¹H NMR (300 MHz, CD₃OD) δ 8.50 (d, 1 H), 8.16 (dd, 1 H), 7.41 -7.81 (m, 7 H), 7.16-7.25 (m, 2 H), 4.34 (dd, 0.6 H), 4.22 (dd, 0.4 H), 3.89 (s, 3 H), 3.72 (0.6 H), 3.54 (dd, 0.4 H), 3.38-3.50 (br, 2 H), 3.09 (qr, 2 H), 2.42-2.80 (m, 2 H), 2.08-2.28 (br, 1 H), 1.47-2.0 (m, 2 H), 0.98-1.45 (m, 5 H); ES-MS m/z 488.2 (MH⁺); HPLC RT (min) 2.10.

[306] EXAMPLE 50

6-(3-Chlorophenyl)-3-(ri-(cvclopropylmethyl)piperidin-3-vnmethyl>-2-(2- methoxyphenyl)quinazolin-4(3H)-one trifluoroacetate

[307] Step 1. Preparation of 6-bromo-3-([1-(cvclopropylmethyl)piperidin-3-yllmethyl)-2-(2- methoxyphenyl)quinazolin-4(3H)-one trifluoroacetate

[308] The compound was prepared using 6-bromo-2-(2-methoxyphenyl)-4H-3,1-benzoxazin-4- one (Example 39, step 1) and reacting it with 1-[1-(cyclopropylmethyl)pipehdin-3-yl]methanamine (Example 4, step 2), applying the method described in Example 39, step 3. [309] Step 2. Preparation of e-O-chlorophenvh-S-iri-fcvclopropylmethyDpiperidin-S-yllmethyll- 2-(2-methoxyphenyl)αuinazolin-4(3H)-one trifluoroacetate

[310] The compound was prepared using 6-bromo-3-{[1-(cyclopropylmethyl)piperidin-3- yl]methyl}-2-(2-methoxyphenyl)quinazolin-4(3H)-one trifluoroacetate (step 1) and reacting it with 3- chlorophenylboronic, applying the method described in Example 49, step 2. ES-MS m/z 514.4; HPLC RT (min) 3.10.

[311] EXAMPLE 51 e-(4-Chlorophenyl)-3-r(1-ethylpiperidin-3-yl)methvn-2-(4-methylphenvnauinazolin-4(3H)-one

[312] Step 1. Preparation of 2-amino-5-bromo-N-r(1-ethylpiperidin-3-yl)methyllbenzamide

[313] A mixture of 3-aminomethyl-1 -N-ethylpiperidine trifluoroacetate (7.64 g, 20.6 mmol) (synthesized in a similar way as Example 5, step 2), 5-bromoisatoic anhydride (4.28 mg, 15.9 mmol), K₂CO₃ (8.77 g, 63.5 mmol), and acetonitrile (200 mL) was stirred at 70°C for 15 h. After cooling, the solids were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (Biotage) using a solvent system consisting of 6% of 2 M methanolic NH₃ in DCM to afford 4.18 g (58%) of the product. ¹H NMR (300 MHz, CD₃OD) δ 7.54 (s, 1 H)₁ 7.23 (d, 1 H), 6.71 (d 1 H), 3.14-3.25 (m, 2H), 2.88-3.06 (m, 2H), 2.43 (q, 2H), 1.51-1.95 (m, 6H), 1.09 (t, 3H), 0.92-1.05 (m, 1 H); ES-MS m/z 340.4 (MH⁺); HPLC RT (min) 1.31. [314] Step 2. Preparation of S-ffft^amino-^-chlorobiphenyl-S-vDcarbonyllaminolmethvD-i- ethylpiperidine

[315] A mixture of 2-amino-5-bromo-N-[(1-ethylpiperidin-3-yl)methyl]benzamide (4.12 g, 12.1 mmol) (step 1), 4-chlorophenyl boronic acid (2.84 g, 18.2 mmol), Pd[P(Ph)₃J₄ (699.6 mg, 0.61 mmol), 2 M aq Na₂CO₃ solution (30.1 mL, 60.5 mmol), and DMF (40 mL) was degassed and stirred at 100⁰C for 15 h. Water (120 mL) and EtOAc (120 mL) were added. The layers were separated, and the organic layer was washed with water (3 x 80 mL), and brine (80 mL), and concentrated under reduced pressure. The crude product was purified by silica gel flash chromatography (Biotage) eluting with a solvent system consisting of 4% of 2 M methanolic NH₃ in DCM to afford 1.9 g (32%) of the product. ¹H NMR (300 MHz, CD₃OD) δ 7.91 (s, 1 H), 7.59-7.71 (m, 3H), 7.42 (d, 2H), 7.13 (d 1 H), 3.50-3.64 (m, 2H), 3.31-3.45 (m, 2H), 3.14 (q, 2H), 2.76-2.82 (m, 1 H), 2.69 (t, 1 H), 2.11-2.35 (m, 1 H), 1.64-2.09 (m, 3H), 1.23-1.42 (m, 4H); ES-MS m/z 372.3 (MH⁺); HPLC RT (min) 2.08.

[316] Step 3. Preparation of 4'-chloro-N-[(1-ethylpiperidin-3-yl)methyll-4-[(4-methylbenzoyl) aminoibiphenyl-3-carboxamide trifluoroacetate

[317] A mixture of 3-({[(4-amino-4'-chlorobiphenyl-3-yl)carbonyl]amino}methyl)-1-ethylpiperidine (102 mg, 0.27 mmol) (step 2), 4-methylbenzoyl chloride (62.4 mg, 0.40 mmol), triethylamine (0.11 mL, 0.81 mmol), and dichloroethane (1.0 mL) was stirred at 120⁰C for 15 h. The crude reaction mixture was diluted with MeOH (1.0 mL) and purified on a Gilson reversed-phase HPLC system eluting with 20-80% of a MeCN/water solvent system (containing 0.1% TFA) to afford 40 mg (31%) of the product. ¹H NMR (300 MHz, CD₃OD) δ 8.96 (br t, NH), 8.59 (d, 1 H), 7.99-8.00 (m, 1 H), 7.85 (d, 2H), 7.77-7.82 (m, 1 H), 7.66 (d 2H), 7.43 (d, 2H), 7.34 (d, 2H), 3.54-3.60 (m, 2H), 3.37-3.49 (m, 2H), 3.10 (q, 2H), 2.66-2.86 (m, 2H), 2.43 (s, 3H), 2.15-2.23 (m, 1 H), 1.93-2.05 (m, 2H), 1.65-1.86 (m, 1 H), 1.21-1.43 (m, 4H); ES-MS m/z 490.4 (MH+); HPLC RT (min) 2.80. [318] Step 4, Preparation of 6-(4-chlorophenylV3-r(1-ethylpiperidin-3-yl)methyll-2-(4- methylphenyl)quinazolin-4(3H)-one trifluoroacetate

[319] A mixture of 4'-chloro-N-[(1 -ethylpiperidin-3-yl)methyl]-4-[(4-methylbenzoyl)amino]- biphenyl-3-carboxamide trifluoroacetate (108 mg, 0.22 mmol) (step 3), NaOH (26.7 mg, 0.67 mmol), and ethylene glycol (1.5 mL) was stirred at rt for 15 h. The solvent was removed, and the crude product was purified on a Gilson reversed-phase HPLC system eluting with 20-80% of a MeCN/water solvent system (containing 0.1% TFA) to afford 121 mg (74%) of the title product. ¹H NMR (300 MHz, CD₃OD) δ 8.48-8.50 (m, 1H), 8.14 (m, 1H), 7.71-7.76 (m, 3H), 7.48-7.56 (m, 4H), 7.42 (d 2H), 4.46-4.55 (m, 0.2H), 4.18-4.26 (m, 0.8H), 3.94-4.01 (m, 1 H), 3.31-3.47 (m, 2H), 2.97-3.28 (m, 2H), 2.56-2.77 (m, 2H), 2.40 (s, 3H), 2.05-2.21 (m, 1H), 1.73-1.95 (m, 1H), 1.45-1.68 (m, 2H), 1.31 (t, 0.6H), 1.25 (t, 2.4H), 1.01-1.20 (m, 1 H); ES-MS m/z 472.5 (MH⁺); HPLC RT (min) 2.71.

[320] EXAMPLE 52

6-(3-Fluorophenvn-2-(2-methoxyphenyl)-3-(π-(3.3.3-trifluoropropyl)piperidin-3- vπmethyl)quinazolin-4(3H)-one trifluoroacetate

[321] Step 1. Preparation of 6-bromo-2-(2-methoxyphenvπ-3-(piperidin-3-ylmethyl)αuinazolin- 4(3H)-one

[322] The compound was prepared using the BOC-deprotection procedure described in step 4 of Example 6 using the product of step 2 of Example 43 as starting material. [323] Step 2. Preparation of 6-bromo-2-(2-methoxyphenyl)-3-fri-(3.3,3-trifluoropropy0piperidin- 3-yllmethyl)αuinazolin-4(3H)-one

[324] The compound was prepared by using a similar procedure as described in Example 9 using the product of step 1 above as starting material and 3-bromo-1 ,1 ,1 -trifluoropropane as the alkylating agent.

[325] Step 3. Preparation of 6-(3-fluorophenyl)-2-(2-methoxyphenyl)-3-(ri-(3.3,3-trifluoro- propyl)piperidin-3-vHmethyl)quinazolin-4(3H)-one trifluoroacetate

[326] The preparation of this compound was the same as that of Example 104 using the product of step 2 above as starting material and (3-fluorophenyl)boronic acid instead of (3-chlorophenyl)- boronic acid. In addition, the reaction was run at 100 ⁰C instead of 80⁰C.

¹H NMR (300 MHz, CD₃OD) δ 8.50 (s, 1 H), 8.14 (d, 1H), 7.78 (d, 1H), 7.67-7.38 (m, 5H), 7.36-7.09 (m, 3H), 4.46-4.05 (bm, 1 H), 3.90 (s, 3H), 3.85-3.24 (m, 6H)₁ 2.98-2.40 (bm, 3H), 2.30-2.02 (bm, 1 H), 2.01-1.80 (bm, 1 H), 1.78-1.00 (bm, 3H); ES-MS m/z 540.3 (MH)⁺, HPLC RT (min) 2.64.

[327] EXAMPLE 53

3-r(1-lsopropylpiperidin-3-yl)methvπ-2-(2-methylphenyl)-6-(3-methylphenvhquinazolin-4(3H)- one trif luoroacetate

[328] Step 1. Preparation of 6-bromo-3-r(1-isopropylpiperidin-3-yl)methyl1-2-(2-methylphenyl)- quinazolin-4(3HVone

[329] The title compound was prepared using a similar sequence as used for the synthesis of Example 6 with the difference that step 3 was omitted. ES-MS m/z 454.2 (MH⁺); HPLC RT (min) 2.35.

[330] Step 2. Preparation of 3-f(1-isopropylpiperidin-3-yl)methvn-2-(2-methylphenyl)-6-(3- methylphenyl)quinazolin-4(3H)-one trifluoroacetate

[331] 6-Bromo-3-[(1-isopropylpiperidin-3-yl)methyl]-2-(2-methylphenyl)quinazolin-4(3H)-one (44.4 mg, 0.10 mmol) (step 1), 3-methylphenyl boronic acid (27.2 mg, 0.20 mmol), and anhydrous DMA (2 mL) were combined in a microwave vial along with 2 N aq potassium carbonate (0.31 mmol), followed by PdCI₂(dppf) (2.2 mg, 0.003 mmol). DMA (0.5 mL) was added to wash the solids off the sides of the vial, and the mixture was degassed for 10 min. The vial cap was crimped, and the mixture was irradiated in a microwave reactor at 140⁰C for 10 min. The mixture was passed through a filter and purified by preparative HPLC (Waters Symmetry column; gradient elution with 90% A [CH₃CN/water (2:98; v/v)] for 1.0 min ramped to 95% B [CH₃CN/water (98:2; v/v)] over 3.0 min and held at 95% B for 0.8 min) to afford 29.2 mg (62.7 %) of product. ¹H NMR (400 MHz, DMSO-cfe) δ ppm 8.77 (s, 1 H), 8.40 (s, 1 H), 8.19 (d, 1 H)₁ 7.78 (d, 1 H), 7.58 (m, 2H), 7.50 (t, 1 H), 7.42 (d, 3H), 7.26 (d, 1 H), 4.10 (s, 1 H), 3.49 (S, 1 H), 3.20 (s, 1 H), 2.99(s, 1 H), 2.73 (s, 1 H), 2.20 (d, 4H), 1.76 (s, 1 H), 1.50 (s, 1 H), 1.31 (s, 1 H), 1.18 (d, 3H), 1.15 (m, 9H); ES-MS m/z 466.3; HPLC RT (min) 3.13 (Method B). [332] EXAMPLE 54

6-(1.3-Benzodioxol-5-yl)-2-isopropyl-3-{r(3S)-1-isopropylpiperidin-3-yllmethyl)quinazolin-

4(3H)-one

[333] Step 1 : Preparation of 6-bromo-2-isopropyl-3-(r(3S)-1-isopropylpiperidin-3-vπmethyl)- quinazolin-4(3H)-one

[334] The product was synthesized starting from the product of step 1 of Example 35, subsequent deprotection as described in Example 39, step 4, followed by N-alkylation as described in Example 9. ¹H NMR (300 MHz, CD₂CI₂) δ 8.34 (s, 1 H), 7.78 (d, 1 H), 7.50 (d, 1 H), 4.09 (s, 2 H), 3.25-3.33 (m, 1 H), 2.61-2.85 (m, 3 H), 2.25 (t, 1 H), 2.15 (t, 1 H), 2.01 -2.09 (m, 1 H), 1.61-1.78 (m, 2 H), 1.42-1.58 (m, 1 H), 1.38 (t, 6 H), 1.21-1.30 (m, 1 H), 0.99 (t, 6 H); ES-MS m/z 406.5 (MH⁺); HPLC RT (min) 2.28.

[335] Step 2. Preparation of 6-(1.3-benzodioxol-5-yl)-2-isopropyl-3-(f(3S)-1-isopropylpiperidin-3- yllmethyl)quinazolin-4(3H)-one

[336] To a 5 mL microwave reaction vial equipped with a stir bar was added 1 ,3-benzodioxol-5- ylboronic acid (38 mg, 0.227 mmol), 6-bromo-2-isopropyl-3-{[(3S)-1-isopropylpiperidin-3-yl]methyl}- quinazolin-4(3H)-one (46 mg, 0.113 mmol) (step 1) in DMA (2 mL), PdCI₂(dppf) (5 mg, 0.007 mmol), and 2 M aq potassium carbonate solution (0.46 mL, 0.92 mmol). The reaction mixture was sealed with a cap and then heated in a microwave reactor at 13O⁰C for 15 min. After cooling to rt, the mixture was filtered through a silica gel plug, and the precipitate was washed with DMSO (1.5 mL). The filtrate was then purified on a Gilson HPLC system equipped with an Xterra reversed-phase column using a gradient elution from 30% acetonitrile to 90% acetonitrile in water under basic conditions with 0.1% NH₃ as modifier. The title product was obtained in a yield of 28.3 mg (56%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.23 (s, 1 H), 8.04 (d, 1 H), 7.65 (d, 1 H), 7.34 (s, 1 H), 7.23 (d, 1 H), 7.03 (d, 1 H), 6.08 (s, 2 H), 4.09 (s, 1 H), 2.61 (s, 3 H), 2.17 (s, 1 H), 2.06 (s, 1 H), 1.95 (m, 1 H), 1.62 (s, 1 H), 1.53 (s, 1 H), 1.30 (dd, 7 H), 1.23 (s, 2 H), 1.14 (s, 1 H), 0.92 (s, 6 H); ES-MS m/z 448.3 (MH⁺); HPLC RT (min) 2.89 (Method B).

[337] EXAMPLE 55

6-(4-Chlorophenyl)-2-cvclopropyl-3-r(1-isopropylpiperidin-3-yl)methvnquinazolin-4(3H)-one

[338] Step 1. Preparation of e-bromo^-cvclopropyl-S-rd-isopropylpiperidin-S-vDmethvπ- αuinazolin-4(3HVone

[339] To a solution of 2-amino-5-bromo-N-[(1-isopropylpiperidin-3-yl)methyl]benzamide (500 mg, 1.41 mmol) (Example 61 , step 1) in DCM (5 mL) and triethylamine (0.59 mL, 4.23 mmol) was added cyclopropanecarbonyl chloride (221 mg, 2.12 mmol) at rt, followed by stirring for 2 h. The solution was then washed with water and brine, dried over MgSO₄ and evaporated to afford an intermediate that was further treated with LiOH monohydrate (178 mg, 4.23 mmol), ethylene glycol (2 mL), and ethanol (2 mL). The mixture was heated to 18O⁰C for 25 min via microwave. The reaction mixture was then filtered, and the filtrate separated using a Gilson reversed-phase HPLC system with a gradient elution of 5% to 60% acetonitrile in water (containing 1% TFA). The product fractions were combined, treated with 10% aq Na₂CO₃, and extracted with EtOAc (x3). The combined organic fractions were washed with water and brine, dried over MgSO₄, and concentrated under reduced pressure to afford 330 mg (58%) of the product. ES-MS m/z 404.6 (MH⁺); HPLC RT (min) 2.76. [340] Step 2, Preparation of S-fΦchlorophenvD^-cvclopropyl-S-rπ-isopropylpiperidin-S- yl)methyllquinazolin-4(3H)-one

[341] To a microwave reactor tube was added 6-bromo-2-cyclopropyl-3-[(1-isopropylpiperidin-3- yl)methyl]quinazolin-4(3H)-one (150 mg, 0.37 mmol) (step 1 ), 4-chlorophenylboronic acid (87 mg, 0.56 mmol), potassium carbonate (128 mg, 0.93 mmol), PdCI₂dppf CH₂CI₂ complex (24 mg, 0.03 mmol), dimethoxyethane (3 mL), and water (2 ml_). The tube was then sealed with a rubber septum, degassed, flashed with nitrogen, and heated in the microwave reactor at 15O⁰C for 20 min. The reaction mixture was then filtered, and the filtrate was separated by preparative HPLC using a gradient elution from 5% to 60% acetonitrile in water containing 1 % TFA. The product fractions were combined, treated with 10% Na₂CO₃, and extracted with EtOAc (x3). The combined organic layers was washed with water and brine, dried over MgSO₄, and concentrated under reduced pressure to afford 57 mg (35%) of the title product. ¹H NMR (400 MHz, DMSO-d₆) 58.26 (d, 1 H), 8.03 (dd, 1 H), 7.76 (tt, 2 H), 7.56 (d, 1 H), 7.51 (π, 2 H), 4.23 (d, 2 H), 2.67-2.58 (m, 3 H), 2.38 - 2.34 (m, 1 H), 2.17 - 2.06 (m, 3 H), 1.67 - 1.58 (m, 2 H), 1.23 - 1.07 (m, 6 H), 0.90 (t, 6H); ES-MS m/z 436.4 (MH⁺); HPLC RT (min) 2.64.

[342] EXAMPLE 56 β^-ChlorophenvD-Σ-cvclopropyl-S-fpiperidin-S-ylmethvDquinazolin^OHVone

[343] Using the procedure described in Example 63, step 2, tert-butyl (3R)-3-{[(2-amino-5- bromobenzoyl)amino]methyl}piperidine-1-carboxylate (Example 18, step 1) was converted to tert- butyl 3-[(6-bromo-2-cyclopropyl-4-oxoquinazolin-3(4H)-yl)methyl]piperidine-1-carboxylate which was further transformed to the final product by using the Suzuki coupling procedure and subsequent BOC-deprotection procedure described in Example 43, steps 3 and 4. ES-MS m/z 394.4 (MH⁺); HPLC RT (min) 2.69. [344] EXAMPLE 57 β-O-Chloro^-fluorophenvπ-a-irOSM-ethylpiperidin-S-yllmethvD-Σ-isopropylquinazolin-

[345] Step 1. Preparation of 6-bromo-3-(r(3S)-1-ethylpiperidin-3-yllmethyl)-2-isopropyl- quinazolin-4(3H)-one

[346] tert-Butyl 3-[(6-bromo-2-isopropyl-4-oxoquinazolin-3(4H)-yl)methyl]piperidine-1 - carboxylate (Example 30, step 2) was deprotected as described in Example 30, step 4, and then converted to the desired product by applying the reductive amination procedure described in Example 12. ES-MS m/z 392.4 (MH⁺); HPLC RT (min) 2.28.

[347] Step 2. Preparation of 6-(3-chloro-4-fluorophenyl)-3-U(3S)-1-ethylpiperidin-3-yllmethyl)-2- isopropylαuinazolin-4(3H)-one

[348] The compound was prepared using the method of Example 58, step 4, and 6-bromo-3- {[(3S)-1-ethylpiperidin-3-yl]methyl}-2-isopropylquinazolin-4(3H)-one (step 1) as starting material. ¹H NMR (400 MHz, CD₃OD) δ 8.33-8.34 (d, 1 H), 8.00-8.02 (dd, 1 H), 7.79-7.81 (dd, 1 H), 7.71- 7.73 (d, 1 H), 7.63-7.67 (m, 1 H), 7.31-7.36 (t, 1 H), 4.08-4.13 (m, 1 H), 4.20-4.25 (m, 1 H), 3.32- 3.36 (m, 1 H), 2.87-2.96 (m, 2 H)₁ 2.46-2.51 (q, 2 H), 1.99-2.14 (m, 3 H), 1.75-1.82 (m, 2 H), 1.53- 1.64 (m, 1 H), 1.39-1.42 (t, 6 H), 1.19-1.30 (m, 1 H), 1.06-1.10 (t, 3 H); ES-MS m/z 442.3 (MH⁺); HPLC RT (min) 2.70. [349] EXAMPLE 58 β-rs-Chloro-^trifluoromethvDphenvn-S-^rOSM-isopropylpiperidin-S-vnmethyllquinazolin-

4(3H)-one

[350] Step 1. Preparation of 6-bromo-4H-3,1-benzoxazin-4-one

[351] A mixture of 2-amino-5-bromobenzoic acid (25.0 g, 115.7 mmol) in thethylorthoformate (100 mL) was heated to 140⁰C for 4 h. The volatiles were evaporated under reduced pressure and the residue was dried under high vacuum to give the product (18.7 g, 71%) as a light yellow solid, which was used in the next step without any further purification.

[352] Step 2. Preparation of tert-butyl (3R)-3-r(6-bromo-4-oxoquinazolin-3(4H)-yl)methyll- piperidine-1 -carboxylate

[353] A mixture of 6-bromo-4H-3,1-benzoxazin-4-one (14.0 g, 61.94 mmol) (step 1) and tert- butyl (3R)-3-(aminomethyl)piperidine-1 -carboxylate (15.9 g, 74.33 mmol) was heated under reflux in xylene for 5 h. After cooling to rt, the organic solvent was removed under reduced pressure, and the crude material purified by silica gel column chromatography (elution with 40% EtOAc in hexane) to afford 18.2 g (69%) of the product as a yellow-brown oil. ES-MS m/z 322.2 ([MH₂- BOC]⁺); HPLC RT (min) 3.34. [354] Step 3. Preparation of 6-bromo-3-f[(3SV1-isopropylpiperidin-3-yllmethyl)quinazolin-4(3H)- one

[355] tert-Butyl (3R)-3-[(6-bromo-4-oxoquinazolin-3(4H)-yl)methyl]piperidine-1 -carboxylate (step 2) was deprotected using the method of step 4 of Example 6 and subsequently N-alkylated using the method of Example 7. ES-MS m/z 364.3 (MH⁺); HPLC RT (min) 1.92.

[356] Step 4. Preparation of 6-r3-chloro-4-(trifluoromethyl)phenyl1-3-fr(3S)-1-isopropyl piperidin-3-vπmethyl)quinazolin-4(3H)-one

[357] To a solution of 6-bromo-3-{[(3S)-1-isopropylpiperidin-3-yl]methyl}quinazolin-4(3H)-one (200 mg, 0.55 mmol), 3-chloro-4-(trifluoromethyl)benzeneboronic acid (185 mg, 0.82 mmol), cesium fluoride (250 mg, 1.65 mmol), and CTC-Q-PHOS (39.0 mg, 0.06 mmol) in THF was added Pd₂(dba)₃ (28 mg, 0.03 mmol) under a nitrogen atmosphere. The mixture was stirred at rt for 18 h. After filtering and concentrating the reaction mixture, purification using a Gilson reversed-phase HPLC system with 10% to 80% acetonitrile in water (0.1% TFA) gave the product (164 mg, 64%) as a light yellow solid. ¹H NMR (400 MHz, CD₃OD) 58.45-8.46 (m, 1 H), 8.32 (s, 1 H), 8.11-8.13 (dd, 1 H), 8.06 (s, 1 H), 7.93-7.96 (dd, 1 H), 7.77-7.79 (d, 1 H), 7.70-7.72 (d, 1 H), 3.93-4.03 (m, 2 H), 2.83-2.85 (m, 2 H)₁ 2.71-2.78 (m, 1 H), 2.17-2.26 (m, 2 H), 2.08-2.13 (m, 1 H), 1.74-1.81 (m, 2 H), 1.55-1.60 (m, 1 H), 1.13-1.18 (m 1 H)₁ 1.05-1.08 (m, 6 H); ES-MS m/z 464.4 (MH⁺); HPLC RT (min) 2.93.

[358] EXAMPLE 59

6-(4-Chlorophenvπ-3-r(1-isopropylpiperidin-3-yl)methvnquinazolin-4(3H)-one

[359] tert-Butyl 3-[(6-Bromo-4-oxoquinazolin-3(4H)-yl)methyl]piperidine-1-carboxylate (made similar to the product of Example 58, step 2) was coupled with 4-chlorophenyl boronic acid using Suzuki coupling conditions similar to Example 58, step 4, and subsequently deprotected and N- alkylated as described in Example 58, step 3. ES-MS m/z 396.2 (MH⁺); HPLC RT (min) 2.31.

[360] EXAMPLE 60 6-(4-Chlorophenyl)-2-r4-(difluoromethoxy)phenvn-3-r(1-ethylpiperidin-3-

[361] 6-Bromo-2-[4-(difluoromethoxy)phenyl]-3-(piperidin-3-ylmethyl)quinazolin-4(3H)-one (Example 77) was transformed into the corresponding N-ethyl derivative using the reductive amination procedure described in Example 12. In the last step, the p-CI-phenyl group was introduced via Suzuki reaction as described in Example 58, step 4. ES-MS m/z 524.3 (MH⁺); HPLC RT (min) 2.93.

[362] EXAMPLE 61

6-(4-Chlorophenyl)-3-r(1-isopropylpiperidin-3-yl)methvn-2-(trifluoromethyl)quinazolin-4(3H)- one

[363] Step 1. Preparation of 2-amino-5-bromo-N-r(1-isopropylpiperidin-3-yl)methyl1benzamide

[364] A mixture of 5-bromoisatoic anhydride (3.1 g, 12.8 mmol), 3-[(1-isopropylpiperidin-3- yl)]methylamine dihydrochloride (2.93 g, 12.8 mmol) (synthesized in a similar way as Example 4, step 2), potassium carbonate (5.3 g, 38.4 mmol), acetonitrile (25 mL), and DMF (5 mL) was heated to 7O⁰C for 2 days, followed by cooling to rt, and treatment with 10% aq Na₂CO₃ (50 mL) and EtOAc (200 mL) to form a biphasic solution. The organic layer was separated, washed with water and brine, dried over MgSO₄, and concentrated under reduced pressure to give 2.5 g (55%) product. ES-MS m/z 354.5 (MH⁺); HPLC RT (min) 2.56.

[365] Step 2. Preparation of 5-bromo-N-r(1-isopropylpiperidin-3-yl)methyll-2-r(trifluoroacetvn- aminolbenzamide

[366] To a solution of 2-amino-5-bromo-N-[(1-isopropylpiperidin-3-yl)methyl]benzamide (500 mg, 1.41 mmol) (step 1) and triethylamine (0.59 mL, 4.23 mmol) in DCM (5 mL) was added dropwise a solution of thfluoacetic anhydride (445 mg, 2.12 mmol) in DCM (1 mL), followed by stirring at rt for 2 h. The solution was then washed with water and brine, dried over MgSO₄ and evaporated to give 560 mg (88%) product. ES-MS m/z 450.4 (MH⁺); HPLC RT (min) 2.74.

[367] Step 3. Preparation of 6-bromo-3-r(1-isopropylpiperidin-3-yl)methvH-2-(trifluoromethyl) quinazolin-4(3H)-one

[368] A sealed vial containing 5-bromo-N-[(1-isopropylpiperidin-3-yl)methyl]-2-[(trifluoroacetyl)- amino]benzamide (330 mg, 0.73 mmol) (step 2) was heated at 200⁰C for 1 h under nitrogen to give 300 mg (95%) crude product which was used in the next step without further purification. ES-MS m/z 432.4 (MH⁺); HPLC RT (min) 2.70. [369] Step 4. Preparation of B-f^chlorophenvD-S-rd-isopropylpiperidin-S-vnmethyli^-drifluoro- methvQquinazolin-4(3hO-one

[370] To a microwave reactor tube was added 6-bromo-3-[(1 -isopropylpiperidin-3-yl)methyl]-2- (trifluoromethyl)quinazolin-4(3H)-one (300 mg, 0.69 mmol) (step 3), 4-chlorophenylboronic acid (163 mg, 1.04 mmol), potassium carbonate (240 mg, 1.73 mmol), PdCI₂(dppf) CH₂CI₂ (45.3 mg, 0.06 mmol), and THF (5 ml_). The tube was sealed with a rubber septum, degassed, flashed with nitrogen, and heated to 150⁰C for 20 min. The reaction mixture was then filtered and the filtrate purified using a Gilson reversed-phase HPLC system with a gradient elution from 5% to 60% acetonitrile in water containing 1% TFA. The product fractions were combined, treated with 10% aq Na₂CO₃, and extracted with EtOAc (3x). The combined organic fractions were then washed with water and brine, dried over MgSO₄, and evaporated to afford 45 mg (14%) of the title product. ¹H NMR (400 MHz, DMSO-d₆) δ 8.41 (s, 1 H), 8.22 (dd, 1 H), 7.90 (dd, 1 H), 7.82 (d, 2 H), 7.56 (d, 2H), 4.11-3.90 (m, 2H), 2.72-2.51 (m, 3H), 2.19-1.90 (m, 2 H), 1.69-1.46 (m, 2 H), 1.40-1.22 (m, 1 H), 1.14-0.97 (m, 1 H)₁ 0.95-0.78 (m, 7H): ES-MS m/z 464.3 (MH⁺); HPLC RT (min) 2.85.

[371] EXAMPLE 62

6-(4-Chlorophenyl)-3-(r(3S)-1-isopropylpiperidin-3-yllmethyl)-2-(trifluoromethyl)quinazolin-

[372] Step 1. Preparation of tert-butyl (3R)-3-r(f5-bromo-2-r(trifluoroacetyl)amino1benzoyl)- amino)methyllpiperidine-1-carboxylate

[373] To a solution of tert-butyl (3R)-3-{[(2-amino-5-bromobenzoyl)amino]methyl}piperidine-1- carboxylate (5.0 g, 12.1 mmol) (Example 18, step 1) and triethylamine (5.1 mL, 36.4 mmol) in DCM (30 mL) was added at rt trifluoroacetic anhydride (3.8 g, 18.2 mmol) dropwise, followed by stirring at rt for 15 h. The solution was washed with water and brine, dried over MgSO₄, and evaporated. The residue was separated by silica gel column chromatography (0-30 % EtOAc in hexane) to afford 4.5 g (73%) of product. ES-MS m/z 408.5 (MH⁺); HPLC RT (min) 4.41.

[374] Step 2. Preparation of 6-bromo-3-[(3S)-piperidin-3-ylmethyll-2-(trifluoromethv0quinazolin- 4(3H)-one

[375] A solution of tert-butyl(3R)-3-[({5-bromo-2-[(trifluoroacetyl)amino]benzoyl}-amino)methyl]- piperidine-1-carboxylate (3.5 g, 6.9 mmol) (step 1) and TFA (10 mL) was heated at 15O⁰C for 1 h via microwave followed by evaporation to afford the TFA salt of the title compound in a yield of 3.6 g (100%). ES-MS m/z 390.2 (MH⁺); HPLC RT (min) 2.14.

[376] Step 3. Preparation of 6-bromo-3-(f(3S)-1-isopropylpiperidin-3-yl1methyl)-2-(trifluoro- methyl)αuinazolin-4(3H)-one

[377] To a solution of 6-bromo-3-[(3S)-piperidin-3-ylmethyl]-2-(trifluoromethyl)quinazolin-4(3H)- one (3.1 g, 6.15 mmol) (step 2) and isopropyl iodide (1.57 g, 9.23 mmol) in acetonitrile (40 mL) was added potassium carbonate (4.25 g, 30.75 mmol) in small portions at rt while stirring. The mixture was then heated to 70⁰C for 15 h, followed by cooling to rt, addition of water and EtOAc to give a clear biphasic solution. The organic layer was separated, washed with water and brine, dried over MgSO₄, and evaporated to give an oil that was treated with TFA (14 mL) at 15O⁰C for 30 min via microwave to achieve cyclization. TFA was then removed in vacuo to give the TFA salt of title compound. ES-MS m/z 432.5 (MH⁺); HPLC RT (min) 2.84.

[378] Step 4. Preparation of 6-(4-chlorophenyl)-3-(r(3SH-isopropylpiperidin-3-yl1methyl)-2- (trifluoromethyl)quinazolin-4(3H)-one

[379] A mixture of 6-bromo-3-{[(3S)-1-isopropylpiperidin-3-yl]methyl}-2-(trifluoromethyl)- quinazolin-4(3H)-one (2.5 g, 4.58 mmol) (step 3), 4-chlorophenylboronic acid (1.07 g, 6.86 mmol), Q-PHOS (325 mg, 0.46 mmol), Pd₂(dba)₃ CHCI₃ complex (189 mg, 0.18 mmol), and CsF (7 g, 45.76 mmol) in THF (20 mL) was stirred at rt for 12 h. The reaction mixture was filtered and the filtrate was purified by preparative HPLC using a gradient elution from 5% to 60% acetonitrile in water containing 1% TFA. The product fractions were combined, treated with 10% Na₂CO₃, and extracted with EtOAc (x3). The extract was then washed with water and brine, dried over MgSO₄, and evaporated to afford 1.82 g (86%) of the title product. ¹H NMR (400 MHz, CDCI₃) δ 8.47 (d, 1 H), 8.02 (dd, 1 H), 7.88 (d, 1 H), 7.63 (tt, 2 H), 7.46 (tt, 2H), 4.21-4.06 (m, 2H), 2.78-2.67 (m, 2H), 2.19-2.06 (m, 2 H), 1.77 -1.70 (m, 2 H), 1.67 -1.49 (m, 1 H), 1.26 -1.11 (m, 1 H), 1.10-0.89 (m, 6H); ES-MS m/z 464.3 (MH⁺); HPLC RT (min) 2.86.

[380] EXAMPLE 63 e^-ChlorophenvD-Σ-cvclobutyl-S-fpiperidin-S-ylmethvDquinazolin^OhD-one

[381] Step 1. Preparation of tert-butyl 3-(f[(4-amino-4'-chlorobiphenyl-3-yl)carbonyllamino)- methyl)piperidine-1 -carboxylate

[382] To a microwave tube was added tert-butyl 3-{[(2-amino-5-bromobenzoyl)amino]methyl}- piperidine-1-carboxylate (3.24 g, 7.86 mmol) (Example 18, step 1), 4-chlorophenylboronic acid (1.47 g, 9.34 mmol), potassium carbonate (2.7 g, 19.6 mmol), PdCI₂(dppf) CH₂CI₂ (534 mg, 6.3 mmol), THF (12 mL), and water (4 ml_). The tube was then sealed with a rubber septum, degassed, flashed with nitrogen, and heated to 150⁰C for 20 min via microwave. The reaction mixture was then filtered, and the filtrate purified by silica gel column chromatography (40% EtOAc in hexane) to afford 1.7 g (49%) of the product. ES-MS m/z 344.5 ([MH₂ - BOC]⁺); HPLC RT (min) 3.96.

[383] Step 2. Preparation of 6-(4-chlorophenyl)-2-cvclobutyl-3-(piperidin-3-ylmethyl)αuinazolin- 4(3H)-one

[384] To a solution of tert-butyl 3-({[(4-amino-4'-chlorobiphenyl-3-yl)carbonyl]amino}methyl)- piperidine-1 -carboxylate (700 mg, 1.58 mmol) (step 1) in chloroform (4 mL) and triethylamine (0.88 mL, 6.31 mmol) was added cyclobutylcarbonyl chloride (374 mg, 3.15 mmol) at rt. The solution was kept at rt for 15 h, followed by washing with water and brine, drying over MgSO₄, and removal of the solvent under reduced pressure.

[385] The residue was treated with LiOH monohydrate (132 mg, 3.15 mmol) and ethylene glycol (4 mL), followed by heating to 18O⁰C for 20 min via microwave. The mixture was diluted with water and extracted with EtOAc (3x). The combined organic fractions were concentrated under reduced pressure and treated with 50% TFA in DCM. Excess TFA was then removed in vacuo, and the residue was separated using a Gilson reversed-phase HPLC system with a gradient elution from 5% to 60% acetonitrile in water containing 1% TFA. The product fractions were combined, treated with 10% Na₂CO₃, and extracted with EtOAc (3x). The extracts was then washed with water and brine, dried over MgSO₄, and dried under high vacuum to afford 190 mg (30%) of the title product.

¹H NMR (400 MHz, CD₃OD) δ 8.36 (s, 1 H), 8.02 (d, 1 H), 7.90 (d, 1 H), 7.62 (d, 2 H), 7.46 (d, 2H), 4.11-4.02 (m, 2H), 3.92-3.79 (m, 2H), 2.99-2.82 (m, 2 H), 2.70-2.35 (m, 6 H), 2.20-2.10 (m, 1 H), 2.05-1.90 (m, 1 H)₁ 1.81 -1.65 (m, 2H), 1.43-1.55 (m, 1 H), 1.39-1.25 (m, 1 H): ES-MS m/z 408.2 (MH⁺); HPLC RT (min) 2.66.

[386] EXAMPLE 64 β^-ChlorophenvD-Σ-cvclobutyl-S-rd-isopropylpiperidin-S-vπmethyllαuinazolin^OhO-one

[387] A mixture of 6-(4-chlorophenyl)-2-cyclobutyl-3-(piperidin-3-ylmethyl)quinazolin-4(3H)-one (100 mg, 0.25 mmol) (Example 63), isopropyl iodide (46 mg, 0.27 mmol), and potassium carbonate (136 mg, 0.98 mmol) in acetonitrile (5 ml.) was heated at 80⁰C for 15 h. The mixture was then cooled to rt and filtered. The filtrate was loaded onto a column and separated by silica gel column chromatography (10% MeOH in DCM) to give 21 mg (19%) of the title product. ¹H NMR (400 MHz, DMSOd₆) δ 8.35 (s, 1 H), 8.19 (dd, 1 H), 7.88 (d, 2 H), 7.80 (d, 1 H), 7.59 (d, 2H)₁ 4.01- 3.90 (m, 3H), 2.82-2.51 (m, 4H), 2.41-2.36 (m, 3 H), 2.20-2.00 (m, 3 H), 1.98-1.80 (m, 1 H), 1.79- 1.64 (m, 1 H), 1.62-1.50 (m, 2 H), 1.44-1.38 (m, 1 H), 1.32-1.16 (m, 1 H), 0.96 (s, 6 H); ES-MS m/z 450.5 (MH⁺); HPLC RT (min) 2.83.

[388] EXAMPLE 65

6-(4-Chlorophenyl)-3-fr(3S)-1-isopropylpiperidin-3-vnmethyl>-2-methylquinazolin-4(3H)-one

[389] To a microwave reactor tube was added 6-bromo-3-{[(3S)-1 -isopropylpiperidin-3-yl]- methyl}-2-methylquinazolin-4(3H)-one (223 mg, 0.59 mmol) (Example 18, step 3), 4-chlorophenyl- boronic acid (138 mg, 0.88 mmol), potassium carbonate (244 mg, 1.77 mmol), PdCI₂(dppf) CH₂CI₂ (38.5 mg, 0.05 mmol), DMF (4 mL), and water (0.5 mL). The tube was then sealed with a rubber septum, degassed, flashed with nitrogen, and heated to 15O⁰C for 20 min. The reaction mixture was then filtered, and the filtrate was, after concentration, purified using a Gilson reversed-phase HPLC system with a gradient elution from 5% to 60% acetonitrile in water containing 1% TFA. The product fractions were combined, treated with 10% Na₂CO₃, and extracted with EtOAc (3x). The combined organic fractions were then washed with water and brine, dried over MgSO₄, and dried under high vacuum to afford 82 mg (31%) of the title product. ¹H NMR (400 MHz, CD₂CI₂) δ 8.41 (d, 1 H), 7.94 (dd, 1 H), 7.68-7.63 (m, 3 H), 7.46 (dd, 2 H), 4.12-3.99 (m, 2 H), 2.70-2.68 (m, 6H)₁ 2.28-2.21 (m, 1 H), 2.20-2.08 (m, 2 H), 1.78-1.61 (m, 2 H), 1.59-1.45 (m, 1 H), 1.30-1.16 (m, 1 H), 0.99 (d, 6H); ES-MS m/z410.3 (MH⁺); HPLC RT (min) 2.47.

[390] EXAMPLE 66

6-(3-Chloro-4-fluorophenyl)-2-ethyl-3-(r(3S)-1-ethylpiperidin-3-yllmethyl)quinazolin-4(3H)-

[391] tert-Butyl (3R)-3-[(6-bromo-2-ethyl-4-oxoquinazolin-3(4H)-yl)methyl]piperidine-1- carboxylate, obtained in a similar way as the product of step 2 of Example 18, was deprotected using the procedure described in step 4 of Example 6, N-alkylated using the reductive amination procedure described in Example 12, and reacted with (3-chloro-4-fluorophenyl)boronic acid using Suzuki coupling conditions as described in Example 53 to give the title product. ES-MS m/z 428.3 (MH⁺); HPLC RT (min) 2.54.

[392] EXAMPLE 67

6-(4-Chlorophenyl)-2-(3-methyl-2-furyl)-3-(piperidin-3-ylmethyl)quinazolin-4(3H)-one

[393] tert-Butyl 3-{[6-bromo-2-(3-methyl-2-furyl)-4-oxoquinazolin-3(4H)-yl]methyl}piperidine-1- carboxylate, synthesized in a similar way as the product of Example 77, step 2, was deprotected by using the same procedure as described in Example 6, step 4, and subsequently reacted with 4- chlorophenylboronic acid using Suzuki coupling reactions as described in step 4 of Example 46. ES-MS m/z 434.4 (MH⁺); HPLC RT (min) 2.73. [394] EXAMPLE 68

6-(4-Chlorophenyl)-3-r(1-ethylpiperidin-3-vnmethyll-2-(3-methyl-2-furyl)quinazolin-4(3H)-one

[395] 6-(4-Chlorophenyl)-2-(3-methyl-2-furyl)-3-(piperidin-3-ylmethyl)quinazolin-4(3H)-one (Example 67) was alkylated in a similar way as described in Example 40. ES-MS m/z 462.3 (MH⁺); HPLC RT (min) 3.10.

[396] EXAMPLE 69

6-(4-Chlorophenyl)-2-(2-methylphenyl)-3-(piperidin-3-ylmethyl)quinazolin-4(3H)-one

[397] To a solution of 6-bromo-2-(2-methylphenyl)-3-(pipehdin-3-ylmethyl)quinazolin-4(3H)-one (480 mg, 1.164 mmol), [obtained by deprotection of tert-butyl 3-{[6-bromo-2-(2-methylphenyl)-4- oxoquinazolin-3(4H)-yl]methyl}piperidine-1-carboxylate (Example 6, step 2) using a similar procedure as described in Example 6, step 4], K₂CO₃ (483 mg, 3.492 mmol), and PdCI₂(dppf) (110 mg, 0.116 mmol) in toluene/dioxane/water (10:1 :1 , 12 mL) was added (4-chlorophenyl)- boronic acid (182 mg, 1.164 mmol). The reaction mixture was degassed for 1 min, followed by heating at 100⁰C for 15 h. After the reaction was cooled to rt, the mixture was filtered through a pad of Celite®, concentrated, and purified by silica gel chromatography (5% methanol in DCM) to afford 400 mg (77%) of the product. ES-MS m/z 444.3 (MH⁺); HPLC RT (min) 3.10.

[398] EXAMPLE 70 e^-ChlorophenvD-Σ-ffluoromethvD-S-irOSVI-isopropylpiperidin-S-yllmethvDquinazolin-

4(3H)-one

[399] Step 1. Preparation of tert-butyl (3R)-3-({f(4-amino-4'-chlorobiphenyl-3-yl)carbonvn- amino]methyl)piperidine-1 -carboxylate

[400] To a solution of tert-butyl (3R)-3-{[(2-amino-5-bromobenzoyl)amino]methyl}piperidine-1 - carboxylate (1 .0 g, 2.43 mmol) (Example 18, step 1 ), K₂CO₃ (1.0 g, 7.276 mmol), and PdCI₂(dppf) (100 mg, 0.121 mmol) in DME/water (10:1 , 50 mL) was added (4-chlorophenyl)boronic acid (0.46 g, 2.91 mmol). The reaction mixture was degassed for 1 min and heated at 60⁰C for 15 h. After cooling to rt, the reaction mixture was filtered through a pad of Celite®, concentrated, and purified by silica gel chromatography (40% ethyl acetate in hexane) to afford 0.89 g (83%) of the product.

[401] Step 2. Preparation of tert-butyl (3R)-3-(r((4'-chloro-4-r(fluoroacetyl)amino1biphenyl-3- yl)carbonyl)aminolmethyl)piperidine-1 -carboxylate

[402] To a solution of tert-butyl (3R)-3-({[(4-amino-4'-chlorobiphenyl-3-yl)carbonyl]amino}- methyl)piperidine-1 -carboxylate (0.80 g, 1.802 mmol) (step 1 ) and TEA (0.38 mL, 2.703 mmol) in DCM (18 mL) at O⁰C was slowly added fluoroacetyl chloride. The reaction was allowed to warm to rt for 15 h. After washing with water and brine, the organic layer was concentrated and purified by silica gel chromatography (40% ethyl acetate in hexane) to afford 0.81 g (89%) of the product. ES- MS m/z 504.1 (MH⁺); HPLC RT (min) 3.92.

[403] Step 3. Preparation of 6-(4-chlorophenyl)-2-(fluoromethyl)-3-r(3S)-pipehdin-3-ylmethyl1- quinazolin-4(3H)-one

[404] A solution of tert-butyl (3R)-3-{[({4'-chloro-4-[(fluoroacetyl)amino]biphenyl-3-yl}carbonyl)- amino]methyl}piperidine-1-carboxylate (300 mg, 0.595 mmol) (step 2) and BF₃ etherate (75μL, 0.595 mmol) in AcOH (11 mL) was heated 130⁰C for 25 min in a microwave reactor. AcOH was then removed under reduced pressure and the residue was dissolved in DCM and washed with sat aq NaHCO₃, brine, dried and concentrated to afford 200 mg (87%) of the product. ES-MS m/z 386.2 (MH⁺); HPLC RT (min) 2.45.

[405] Step 4. Preparation of 6-(4-chlorophenyl)-2-(fluoromethyl)-3-ff(3S)-1-isopropylpiperidin-3- yllmethyl)quinazolin-4(3H)-one

[406] To a solution of 6-(4-chlorophenyl)-2-(fluoromethyl)-3-[(3S)-piperidin-3-ylmethyl]quinazolin- 4(3H)-one (200 mg, 0.518 mmol) (step 3) and Cs₂CO₃ (506 mg, 1.56 mmol) in MeCN (5 mL) was added 2-iodopropane (881 mg, 5.183 mmol), and the mixture was heated to 70°C for 15 h. The reaction mixture was cooled to rt, filtered, and concentrated. The crude product was redissolved in methanol and purified using a Gilson reversed-phase HPLC system with a gradient elution from 10% to 90% acetonitrile in water to afford 59 mg (27%) of the product. ¹H NMR (300 MHz, CD₂CI₂) δ 8.45 (s, 1 H), 8.00 (d, 1 H), 7.78 (d, 1 H), 7.68 (d, 2 H), 7.47 (d, 2 H), 5.48-5.75 (m, 2 H), 4.12-4.21 (m, 2 H), 2.64-2.82 (m, 3 H), 2.20-2.48 (m, 3 H), 1.60-1.80 (m, 3 H), 1.30-1.38 (m, 1 H), 1.05 (t, 6 H); ES-MS m/z 428.3 (MH⁺); HPLC RT (min) 2.54.

[407] EXAMPLE 71

2-(Difluoromethyl)-6-(4-fluoroprienyl)-3-{r(3S)-1-isopropyl-piperidin-3-yl1methyl)quinazolin-

4(3H)-one

[408] Step 1. Preparation of tert-butyl (3R)-3-(f(2-amino-5-bromobenzoyl)amino1 methyl) piperidine-1 -carboxylate

[409] A solution of 5-bromoisatoic anhydride (30 g, 111 mmol), (R)-N-BOC-piperidine-3-methyl- amine (25 g, 111 mmol), and K₂CO₃ (31 g, 223 mmol) in acetonitrile (750 mL) was heated at 7O⁰C for 15 h to form a white precipitate. The solvent was concentrated to -300 mL of volume, and water (600 mL) was added. After the mixture was stirred for 30 min, the precipitate was collected by filtration to afford 37 g (80%) of the product as a white solid. ES-MS m/z 312.2 ([MH₂ - BOC]⁺), HPLC RT (min) 3.58.

[410] Step 2. Preparation of tert-butyl (3RV3-r((5-bromo-2-[(difluoroacetyl)aminolbenzovU- amino)methyllpiperidine-1 -carboxylate

[411] A solution of tert-butyl (3R)-3-{[(2-amino-5-bromobenzoyl)amino]methyl} piperidine-1- carboxylate (5.0 g, 12 mmol) (step 1), difluoroacetic acid (1.7 g, 18 mmol), and triphenyl phosphine (4.8 g, 18 mmol) in carbon tetrachloride (200 mL) in a sealed vial was heated at 100⁰C for 2 h. The solution was purified via silica gel column chromatography using a gradient elution of 5% to 25% EtOAc in hexanes to afford 4.2 g (70%) of the product as a yellow solid. ¹H NMR (400 MHz, CD₂CI₂) δ 8.52 (d, 1 H), 7.85 (s, 1 H), 7.60 (d, 1H), 6.02 (t, 1 H), 3.60 (m, 3H), 3.3 (bs, 1 H), 3.10 (bs, 2H), 1.9 (m, 2H), 1.7 (m, 2H), 1.5 (s, 9H), 1.4 (m, 1H); ES-MS m/z 512.1 [(M₊Na)⁺], HPLC RT (min) 3.64. [412] Step 3. Preparation of 6-bromo-2-(difluoromethyl)-3-r(3S)-piperidin-3-ylmethvπquinazolin- 4(3H)-one

[413] A solution of tert-butyl (3R)-3-[({5-bromo-2-[(difluoroacetyl)amino]benzoyl}amino)methyl]- piperidine-1-carboxylate (200 mg, 0.41 mmol) (step 2) in acetic acid (5 mL) in a sealed vial was heated at 100⁰C for 2 h. The solvent was concentrated and co-evaporated with toluene (3x) to give the crude product as an oil which was used in the next step without further purification. ES- MS m/z 372.1 (MH⁺), HPLC RT (min) 2.06.

[414] Step 4. Preparation of 6-bromo-2-(difluoromethyl)-3-(r(3S)-1-isopropylpiperidin-3- yllmethyl)quinazolin-4(3H)-one

[415] A solution of 6-bromo-2-(difluoromethyl)-3-[(3S)-piperidin-3-ylmethyl]quinazolin-4(3H)-one (3.3 g, 8.9 mmol) (step 3), 2-iodopropane (2.7 mL, 27 mmol), and K₂CO₃ (3.7 g, 27 mmol) in 100 mL acetonitrile was stirred at 70⁰C for 4 h. The precipitate was filtered off, and the solvent was concentrated. The residue was then treated with CH₂CI₂, the insoluble material was filtered off, and the solvent was concentrated under reduced pressure to afford 3.0 g (81 %) of the crude product which was used in the next step without further purification. ES-MS m/z 414.3 (MH⁺), HPLC RT (min) 2.18.

[416] Step 5. Preparation of 2-(difluoromethyl)-6-(4-fluorophenvO-3-(r(3S)-1-isopropylpiperidin- 3-yll methyl)quinazolin-4(3H)-one

[417] A solution of 6-bromo-2-(difluoromethyl)-3-{[(3S)-1-isopropylpiperidin-3-yl]methyl}- quinazolin-4(3H)-one (1.25 g, 3.0 mmol) (step 4), 4-fluorophenylboronic acid (844 mg, 6 mmol), and cesium fluoride (2.3 g, 15 mmol) in THF (20 mL) was degassed with N₂ for 20 min. To the mixture was added Pd₂dba₃CHCI₃ (156 mg, 0.15 mmol) and CTC-Q-PHOS (214 mg, 0.30 mmol), and the dark colored mixture was stirred at rt for 10 h. The solution was passed through a Celite® bed and the solvent removed under reduced pressure. The residue was purified through silica gel column chromatography using a gradient elution from 0% to 6% MeOH in CH₂CI₂ to afford a dark oil. The product was combined with 2.55 g of Si-Thiol (Silicycle product), and stirred in THF for 2 h. The precipitate was filtered off and the solvent was removed under reduced pressure. The residue was repurified via silica gel column chromatography to afford 500 mg (42%) of the title product. ¹H NMR (400 MHz, CD₂CI₂) 58.45 (d, 1 H), 8.02 (d, 1 H), 7.82 (d, 1 H), 7.70 (m, 2H), 7.20 (t, 2H), 6.90 (t, 1 H), 4.20 (d, 2H), 2.7 (m, 3H), 2.3 (m, 2H), 2.20 (m, 1 H)₁ 1.7 (M, 2H), 1.55 (m, 1 H), 1.30 (m, 1H), 1.00 (t, 6H); ES-MS m/z 430.3 (MH⁺), HPLC RT (min) 2.51.

[418] EXAMPLE 72

3-r(1-Ethylpiperidin-3-yl)methyll-2-(2-methoxyphenyl)quinazolin-4(3H)-one trifluoroacetate

[419] The product was obtained as a side product of a Buchwald reaction performed similar to Example 29. The product may also be obtained by using a similar sequence as described in Example 13 and 2-aminobenzoic acid as starting material in the first step. ES-MS m/z 378.2 (MH⁺); HPLC RT (min) 1.95.

[420] EXAMPLE 73

6-Butyl-3-r(1-ethylpiperidin-3-yl)methvn-2-(2-methoxyphenyl)quinazolin-4(3H)-one

[421 ] 6-Bromo-3-[(1 -ethylpiperidin-3-yl)methyl]-2-(2-methoxyphenyl)quinazolin-4(3H)-one

(65 mg, 0.14 mmol) (Example 49, step 1), n-butylboronic acid (22 mg, 0.21 mmol), and Pd[P(Ph₃J₄] (8 mg, 0.07 mmol) were dissolved in DMF (2 ml_) followed by addition of Na₂CO₃ (0.4 mL, 2 N). The mixture was degassed and subjected to microwave radiation at 155⁰C for 5 min. The mixture was filtered through a silica gel plug using EtOAc as eluent. The filtrate was concentrated under reduced pressure. The crude was purified using a Gilson reversed-phase HPLC system with a gradient elution from 5% to 55% acetonitrile in water to afford 18.8 mg (24%) of the title product. ¹H NMR (300 MHz, CD₃OD) δ 8.09 (d, 1 H), 7.75 (dd, 1 H), 7.59-7.66 (m, 2 ), 7.51 -7.56 (m, 1 H), 7.14-7.26 (m, 2 H), 4.31 (dd, 0.6 H), 4.18 (dd, 0.4 H), 3.88 (s, 3 H), 3.70 (dd, 0.6 H), 3.54 (dd, 0.4 H)₁ 3.38-3.49 (br, 2 H), 3.09 (m, 2 H), 2.41 -2.84 (m, 4 H), 2.04-2.28 (br, 1 H)₁ 1.81 -1.95 (m, 1 H), 1.01-1.78 (m, 10 H), 0.98 (t, 3 H); ES-MS m/z 434.3 (MH⁺); HPLC RT (min) 1.03.

[422] EXAMPLE 74 6-Butyl-2-(2-methoxyphenyl)-3-(piperidin-3-ylmethyl)quinazolin-4(3H)-one

[423] The product was obtained by using the product of step 1 of Example 52 as starting material and using the Suzuki coupling procedure described in Example 73. ES-MS m/z 406.4 (MH⁺); HPLC RT (min) 2.90.

[424] EXAMPLE 75

3-r(1-Ethylpiperidin-3-yl)methyll-6-hexyl-2-(2-methoxyphenyl)quinazolin-4(3H)-one trifluoroacetate

[425] 6-Hexyl-2-(2-methoxyphenyl)-3-(piperidin-3-ylmethyl)quinazolin-4(3H)-one, synthesized as the compound of Example 74, was N-alkylated using the procedure described in Example 40. ES- MS m/z 462.4 (MH⁺); HPLC RT (min) 3.26. [426] EXAMPLE 76

6-r4-(3-Chloro-2-thienyl)-1.3-thiazol-2-vn-3-f(1-isopropylpiperidin-3-yl)methvn-2-(2- methylphenyl)quinazolin-4(3H)-one trifluoroacetate

[427] Step 1. Preparation of 3-r(1-isopropylpiperidin-3-yl)methyll-2-(2-methylphenyl)-4-oxo-3.4- dihvdroαuinazoline-6-carbonitrile

[428] To a mixture of 6-bromo-3-[(1 -isopropylpiperidin-3-yl)methyl]-2-(2-methylphenyl)- quinazolin-4(3H)-one (250 mg, 0.55 mmol) (Example 53, step 1 ) and zinc cyanide (200 mg, 1.7 mmol) in DMF (2 ml.) was added Pd[P(Ph₃)₄] (50 mg) under a nitrogen atmosphere. The mixture was heated at 12O⁰C for 15 h. The white precipitate was filtered off, washed with ether and discarded. The filtrate was diluted with ether and washed with water (2x). The solvent was removed under reduced pressure, and the residue purified by column chromatography (12 g of silica gel) using a gradient elution of 0% to 6% MeOH in DCM to afford 95 mg (43%) of the product as a sticky oil. ¹H NMR (400 MHz, CD₂CI₂) δ 8.64 (s, 1 H), 7.94 (d, 1 H), 7.75 (d, 1 H), 7.45 (m, 1 H), 7.34 (m, 3H), 4.15 (m, 1 H) 3.55 (m, 1 H), 2.50 (m, 3H), 2.24 (s, 3H), 2.00 (m, 1 H), 1.8 (m, 1 H), 1.60 (m, 3H), 1.30 (m, 2H), 0.9 (m, 6H); ES-MS m/z 401.3 (MH⁺), HPLC RT (min) 2.33.

[429] Step 2. Preparation of 3-[(1-isopropylpiperidin-3-yl)methyl1-2-(2-methylphenyl)- 4-oxo-3,4-dihvdroαuinazoline-6-carbothioamide

[430] 3-[(1-lsopropylpiperidin-3-yl)methyl]-2-(2-methylphenyl)-4-oxo-3,4-dihydroquinazoline-6- carbonitrile (5.5 g, 14 mmol) (step 1) was dissolved in DMF (75 ml_), and H₂S gas was then passed through the solution for several minutes. The reaction mixture was heated to 60⁰C and diethylamine (1.5 g, 21 mmol), dissolved in a small amount of DMF, was added. After 3.5 h stirring at 60⁰C, the orange solution was allowed to cool to rt over 10 h. The reaction mixture was purged with nitrogen for 1 h, and then the solvent was removed under reduced pressure. The crude product was dissolved in DCM and purified via silica gel chromatography using a Biotage Flash 40 cartridge with DCM/methanol (95:5; v/v) to afford the product as an amber solid (2.88 g, 48%). ES-MS m/z 435.2 (MH)⁺, HPLC RT (min) 2.08.

[431] Step 3. Preparation of 6-r4-(3-chloro-2-thienyl)-1 ,3-thiazol-2-yll-3-[(1 -isopropylpiperidin-3- yl)methvπ-2-(2-rnethylphenvDquinazolin-4(3H)-one trifluoroacetate

[432] To an EPA vial was added 2-bromo-1-(3-chloro-thiophen-2-yl)ethanone (47.9 mg, 0.20 mmol) and 3-(1 -isopropylpiperin-S-yl-methylH-oxo^-o-tolyl-S^-dihydroquinazoline-e-carbo- thioamide (56.5 mg, 0.13 mmol, 0.65 equiv) with 8 ml. of anhydrous ethanol. The reaction mixture was heated to 74°C for 10 h in a J-Kem shaker, then cooled to rt and concentrated to dryness under reduced pressure. The residue was dissolved in 3 ml. DMSO and purified using a Gilson reversed-phase HPLC system to afford 64.4 mg (56 %) of the title product. ¹H NMR (400 MHz, DMSO-Cf₆) δ ppm 8.74 (s, 1 H), 8.45 (d, 1 H), 8.33 (s, 1 H), 7.85 (d, 1 H), 7.76 (d, 1 H), 7.52 (m, 2H), 7.42 (m, 2H), 7.22 (d, 1 H), 4.09 (s, 1 H), 3.19 (s, 1H), 2.99 (s, 1H), 2.74 (s, 1H), 2.22 (d, 3H), 2.17 (s, 1 H), 1.51 (d, 2H), 1.34 (s, 1 H), 1.16 (m, 9H), 0.99 (s, 1 H); ES-MS m/z 575.2; HPLC RT (min) 3.34 (Method B). [433] EXAMPLE 77

6-Bromo-2-r4-(difluoromethoxy)phenvn-3-(piperidin-3-ylmethvhquinazolin-4(3H)-one

[434] Step 1. Preparation of tert-butyl 3-(r(5-bromo-2-(r4-(difluoromethoxy)benzoyl1amino)- benzoyl)aminolmethyl)piperidine-1-carboxylate

[435] A mixture of tert-butyl 3-{[(2-amino-5-bromobenzoyl)amino]methyl}piperidine-1-carboxylate (2.00 g, 4.85 mmol) (Example 18, step 1 ), 4-difluoromethoxy benzoic acid (1.01 g, 5.82 mmol), DMAP (59.2 mg, 0.49 mmol), TEA (0.68 mL, 4.85 mmol), and EDCI (1.86 g, 9.70 mmol) in DCM (20 mL) was stirred at rt for 16 h. Water was added, and the reaction mixture was extracted with DCM (2 x 40 mL). The combined organic layers were washed with brine, dried over Na₂SO₄, filtered and concentrated to dryness. Purification via column chromatography (elution with 60% EtOAc in hexane) afforded 1.66 g (59%) of the product as a yellow brown oil. ES-MS m/z 482.3 ([MH₂- BOC]⁺); HPLC RT (min) 4.03.

[436] Step 2. Preparation of tert-butyl 3-([6-bromo-2-f4-(difluoromethoxy)phenyl1-4-oxo- quinazolin-3(4H)-yl1methyl)piperidine-1-carboxylate

[437] The compound was prepared using the method of step 2 of Example 6, and tert-butyl 3- {[(5-bromo-2{[4-(difluoromethoxy)benzoyl]amino}benzoyl)amino]methyl}piperidine-1-carboxylate (step 1) as starting material. ES-MS m/z 464.7 ([MH₂ - BOC]⁺); HPLC RT (min) 2.18.

[438] Step 3. Preparation of 6-bromo-2-[4-(difluoromethoxy)phenyl1-3-(piperidin-3-ylmethvh- quinazolin-4(3H)-one

[439] The compound was prepared from the product of step 2 using the BOC-deprotection procedure described in Example 6, step 4. ES-MS m/z 464.1 (MH⁺); HPLC RT (min) 2.46.

[440] EXAMPLE 78

6-Cvclopentyl-2-f4-(difluoromethoxy)phenvn-3-r(1-isopropylpiperidin-3- Vl)methyllquinazolin-4(3H)-one

[441] Step 1. Preparation of 6-bromo-2-[4-(difluoromethoxy)phenvn-3-[(1-isopropylpipehdin-3- vπmethyllquinazolin-4(3H)-one

[442] 6-Bromo-2-[4-(difIuoromethoxy)phenyl]-3-(piperidin-3-ylmethyl)quinazolin-4(3H)-one (Example 77) was deprotected using the method of step 4 of Example 6 and subsequently N- alkylated using the method of Example 7. ES-MS m/z 506.2 (MH⁺); HPLC RT (min) 2.57. [443] Step 2. Preparation of 6-cvclopentyl-2-r4-(difluoromethoxy)phenvn-3-r(1-isopropyl piperidin-3-yl)methyl1quinazolin-4(3H)-one

[444] The compound was prepared using a similar procedure as described in Example 73, step 1 , and 6-bromo-2-[4-(difluoromethoxy)phenyl]-3-[(1-isopropylpiperidin-3-yl)methyϊ]quinazolin- 4(3H)-one (step 1) and cyclopentylboronic acid as starting materials. ¹H NMR (400 MHz, CD₃OD) δ 8.50 (d, 1 H), 8.10 (s, 1 H), 7.77(dd, 1 H), 7.66-7.69 (dd, 2 H), 7.59 (d, 1 H), 6.81-7.17 (t, 1 H), 4.04 (m, 2 H), 3.20 (m, 1 H), 2.64-2.80 (m, 3 H), 2.02-2.17 (m, 3 H), 1.58-1.91 (m, 9 H), 1.29-1.50 (m, 2 H), 0.96-0.99 (m, 6 H); 0.81-0.89 (m, 1 H); ES-MS m/z 496.4 (MH⁺); HPLC RT (min) 3.13.

[445] EXAMPLE 79 β-fCvclopropylethvnvD-a-rd-isopropylpiperidin-S-vDmethvn-Σ-fΣ-methylphenvDquinazolin-

4(3H)-one

[446] To a solution of 6-bromo-3-[(1 -isopropylpiperidin-3-yl)methyl]-2-(2-methylphenyl)- quinazolin-4(3H)-one (500 mg, 1.1 mmol) (Example 53, step 1 ) in DMF (6 mL) was added ethynyl- cyclopropane (109.1 mg, 1.65 mmol), triethylamine (0.46 mL, 3.3 mmol), copper(l) iodide (10.5 mg, 0.06 mmol), and dichlorobis(thphenylphosphine)palladium(ll) (38.6 mg, 0.06 mmol) in a sealed vial. The mixture was then degassed, flashed with nitrogen, and heated to 80⁰C for 10 h, followed by cooling to rt and filtration. The filtrate was concentrated and purified using a Gilson reversed-phase HPLC system with a gradient elution from 5% to 60% acetonitrile in water containing 1% TFA. The desired fractions were combined, treated with 10% Na₂CO₃, and extracted with EtOAc (3x). The combined organic fractions were washed with water and brine, dried over MgSO₄, and evaporated to afford 220 mg (45%) of the title product. ¹H NMR (400 MHz, CD₂CI₂) 68.26 (s, 1 H), 7.75 (dd, 1 H), 7.60 (dd, 1 H), 7.45-7.26 (m, 4 H), 4.19-4.03 (m, 1 H), 3.59- 3.41 (m, 1 H), 2.72-2.51 (m, 2H), 2.21 (s, 3 H), 2.05-1.96 (m, 1 H), 1.90-1.75 (m, 1 H), 1.64-1.43 (m, 4H), 1.41-1.20 (m, 2H), 1.03-0.87 (m, 11 H); ES-MS m/z 440.4 (MH⁺); HPLC RT (min) 2.92.

[447] EXAMPLE 80 β-fΣ-CvclopropylethvD-S-rd-isopropylpiperidin-S-vDmethvn-Σ-fZ-methylphenvDαuinazolin-

4(3H)-one

[448] A mixture of 6-(cyclopropylethynyl)-3-[(1-isopropylpiperidin-3-yl)methyl]-2-(2-methyl- phenyl)quinazolin-4(3H)-one (180 mg, 0.41 mmol) (Example 79), 10% Pd/C (20 mg), and EtOAc (5 mL) in a sealed vial connected to a hydrogen balloon was stirred at rt for 24 h, followed by filtration. The filtrate was concentrated and purified using a Gilson reversed-phase HPLC system with a gradient elution from 5% to 60% acetonitrile in water containing 1% TFA. The product fraction was treated with 10% aq Na₂CO₃, and extracted with EtOAc (3x). The extract was then washed with water and brine, dried over MgSO₄, and dried under high vacuum to give 95.6 mg (53%) of the product. ES-MS m/z 444.4 (MH⁺); HPLC RT (min) 2.61.

[449] EXAMPLE 81

3-r(1-lsopropylpiperidin-3-yl)methvn-2-(2-methylphenvh-6-pentylquinazolin-4(3H)-one

[450] The title compound was isolated from the crude reaction mixture that was obtained at the synthesis of 6-(2-cyclopropylethyl)-3-[(1 -isopropylpiperidin-3-yl)methyl]-2-(2-methylphenyl)- quinazolin-4(3H)-one described in Example 80. The second preparative HPLC fraction obtained from the purification of said mixture was treated with 10% Na₂CO₃, and extracted with EtOAc (3x). The combined organic fractions were washed with water and brine, dried over MgSO₄, and dried under high vacuum to give 88.1 mg (48%) of the title product. ES-MS m/z 446.2 (MH⁺); HPLC RT (min) 2.69. [451] EXAMPLE 82

6-r(4-Fluorophenyl)ethvnyll-3-[(1-isopropylpiperidin-3-yl)methvn-2-methylquinazolin-4(3H)- one

[452] 6-Bromo-3-{[(3S)-1-isopropylpiperidin-3-yl]methyl}-2-methylquinazolin-4(3H)-one (Example 18, step 3), was transformed into the product by reacting with 1-ethynyl-4-fluorobenzene using the coupling procedure described in Example 79. ES-MS m/z 418.3 (MH⁺); HPLC RT (min) 2.51.

[453] EXAMPLE 83

2-lsopropyl-3-(r(3S)-1-isopropylpiperidin-3-vnmethyl)-6-r(E)-2-phenylvinyllquinazolin-4(3H)- one

[454] 6-Bromo-2-isopropyl-3-{[(3S)-1-isopropylpiperidin-3-yl]methyl}quinazolin-4(3H)-one (Example 54, step 1) was reacted with styrylboronic acid using the Suzuki coupling conditions described in Example 54, step 2. ES-MS m/z 430.3 (MH⁺); HPLC RT (min) 3.13.

[455] EXAMPLE 84

2-lsopropyl-3-fr(3S)-1-isopropylpiperidin-3-yllmethyl)-6-(2-phenylethv0quinazolin-4(3H)-one

[456] A suspension of 2-isopropyl-3-{[(3S)-1-isopropylpiperidin-3-yl]methyl}-6-[(E)-2-phenyl- vinyl]quinazolin-4(3H)-one (14 mg, 0.031 mmol) (Example 83) and 10% Pd/C (5 mg) in MeOH (3 mL) was stirred under 1 atm of hydrogen for 3 h. The suspension was filtered over a Celite® pad, and the solution was concentrated to dryness to afford 13 mg (90%) of the title product. ¹H NMR (300 MHz₁ CD₂CI₂) δ 7.90 (s, 1 H), 7.41 (s, 2 H), 7.15-7.20 (m, 2 H), 7.05-7.09 (m, 3 H), 3.99 (d, 2 H), 3.15-3.23 (m, 1 H), 2.91-2.97 (m, 2 H), 2.85-2.91 (m, 2 H), 2.50-2.69 (br, 3 H), 2.18 (t, 1 H), 1.86-2.11 (m, 2 H), 1.50-1.61 (m, 2 H), 1.35-1.46 (m, 1 H), 1.23 (t, 6 H), 1.10-1.20 (m, 1 H), 0.90 (t, 6 H); ES-MS m/z 432.4 (MH⁺); HPLC RT (min) 2.80.

[457] EXAMPLE 85

6-Acetyl-3-r(1-isopropylpiperidin-3-yl)methvn-2-(2-methylphenyl)quinazolin-4(3H)-one

[458] To a sealed vial was added 6-bromo-3-[(1 -isopropylpiperidin-3-yl)methyl]-2-(2-methyl- phenyl)quinazolin-4(3H)-one (1000 mg, 2.2 mmol) (Example 53, step 1), tributyl(i -ethoxyvinyl)- stannane (993 mg, 2.75 mmol), PdCI₂(dppf) CH₂CI₂ (144 mg, 0.18 mmol), potassium carbonate (912 mg, 6.6 mmol), and toluene (4 mL). The mixture was heated to 105⁰C for 10 h while stirring, followed by cooling to rt and filtration. The filtrate was separated by silica gel column chromatography (30% EtOAc in hexane). The combined product fractions were concentrated under reduced pressure and treated with 1 N aq HCI (5 mL) in THF (10 mL) at rt for 15 h. The solution was concentrated to dryness and separated using a Gilson re versed-phase HPLC system with a gradient elution of 5% to 60% acetonitrile in water containing 1% TFA. The combined product fractions were treated with 10% Na₂CO₃, and extracted with EtOAc (3x). The combined organic fractions were washed with water and brine, dried over MgSO₄, concentrated under reduced pressure, and dried under high vacuum to give 850 mg (93%) of the product. ES-MS m/z 418.3 (MH⁺); HPLC RT (min) 2.09.

[459] EXAMPLE 86 β-(2-Fluorobenzyl)-2-isopropyl-3-fr(3S)-1-isopropylpiperidin-3-vnmethyl>quinazolin-4(3H)- one

[460] Step 1. Preparation of tert-butyl (3R)-3-(r6-(2-fluorobenzyl)-2-isopropyl-4-oxoquinazolin- 3(4H)-yllmethyl)piperidine-1-carboxylate

[461] To a solution of tert-butyl (3R)-3-{[2-isopropyl-4-oxo-6-(4,4,5,5-tetramethyl-1 ,3,2-dioxa- borolan-2yl)quinazolin-3(4H)-yl]methyl}piperidine-1-carboxylate (400 mg, 0.782 mmol) (Example 35, step 2), K₂CO₃ (216 mg, 1.564 mmol), and PdCI₂(dppf) (29 mg, 0.039 mmol) in toluene/dioxane (10:1 , 11 mL) was added 1-(bromomethyl)-2-fluorobenzene (147 mg, 0.782 mmol). The reaction mixture was degassed for 1 min and heated at 90⁰C for 15 h. After the reaction was cooled to rt, the mixture was filtered through a pad of Celite®, concentrated, and purified by silica gel chromatography (40% ethyl acetate in hexane) to afford 275 mg (71%) of the product. ES-MS m/z 494.1 (MH⁺); HPLC RT (min) 4.16.

[462] Step 2. Preparation of 6-(2-fluorobenzyl)-2-isopropyl-3-[(3S)-piperidin-3-ylmethyll- quinazolin-4(3H)-one

[463] To a solution of tert-butyl (3R)-3-{[6-(2-fluorobenzyl)-2-isopropyl-4-oxoquinazolin-3(4H)- yl]methyl}piperidine-1-carboxylate (200 mg, 0.405 mmol) (step 1) in DCM (10 mL) was added TFA (0.5 mL, 6.35 mmol) at rt. The reaction mixture was stirred for 15 h, concentrated, dissolved in DCM (30 mL), and washed with sat aq NaHCO₃ solution and brine. The organic layer was dried over MgSO₄ and concentrated to dryness to afford 140 mg (87%) of the product. ES-MS m/z 394.2 (MH⁺); HPLC RT (min) 2.53. [464] Step 3. Preparation of 6-(2-fluorobenzyl)-2-isopropyl-3-{f(3S)-1-isopropylpiperidin-3- yllmethyl)quinazo!in-4(3H)-one

[465] To a solution of 6-(2-fluorobenzyl)-2-isopropyl-3-[(3S)-piperidin-3-ylmethyl]quinazolin- 4(3H)-one (440 mg, 1.12 mmol) (step 2) and Cs₂CO₃ (729 mg, 2.24 mmol) in MeCN (5 ml.) was added 2-iodopropane (1.9 g, 11.1 mmol), and the mixture was then heated to 90⁰C for 15 h. The reaction mixture was cooled to rt, filtered, and concentrated. The crude product was redissolved in methanol and purified using a Gilson reversed-phase HPLC system with a gradient elution from 10% to 90% MeCN in water to afford 56 mg (11%) of the product. ¹H NMR (300 MHz, CD₂CI₂) δ 7.90 (s, 1 H), 7.41-7.49 (m, 2 H), 7.10-7.15 (m, 2 H), 6.93-7.03 (m, 2 H), 4.03 (s, 2 H), 3.91-3.99 (br, 2 H), 3.15-3.21 (m, 1 H), 2.48-2.62 (m, 3 H), 2.17 (t, 1 H), 2.02 (t, 1 H), 1.85-1.95 (br, 1 H), 1.50-1.63 (m, 2 H), 1.31-1.45 (m, 1 H), 1.23 (t, 6 H), 1.11-1.20 (m, 1 H), 0.89 (t, 6 H); ES-MS m/z 436.3 (MH⁺); HPLC RT (min) 2.65.

[466] EXAMPLE 87

6-Benzyl-2-isopropyl-3-ff(3S)-1-isopropylpiperidin-3-yl1methyl>quinazolin-4(3H)-one

[467] Step 1. Preparation of 2-benzyl-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane

[468] To a solution of benzyl bromide (50 g, 292 mmol) and 4,4,4',4', 5,5,5', 5',-octamethyl-2,2'-bi- 1 ,3,2-dioxaborolane (111 g, 438 mmol) in anhydrous 1 ,4-dioxane (500 mL) were added KOAc (43 g, 438 mmol) and PdCI₂(dppf) (14.3 g, 17.5 mmol). The reaction mixture was degassed for 30 min and heated under N₂ at 100⁰C for 6 h, and at 65°C for 15 h. The mixture was then cooled to rt, and filtered through a pad of Celite®. The filtrate was washed with water (2 x 1 L) and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (5% ethyl acetate in hexane) to afford 45 g (71%) of the product.

[469] Step 2. Preparation of tert-butyl (3R)-3-f(6-benzyl-2-isopropyl-4-oxoquinazolin-3(4H)- yPmethylipiperidine-i-carboxylate

[470] To a solution of tert-butyl (3R)-3-[(6-bromo-2-isopropyl-4-oxoquinazolin-3(4H)-yl)methyl]- pipehdine-1-carboxylate (370 mg, 0.797 mmol) (Example 30, step 2), K₂CO₃ (330 mg, 2.39 mmol), and PdCI₂(dppf) (75 mg, 0.08 mmol) in toluene/dioxane/water (10/1/1) (12 mL) was added 2- benzyl-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (348 mg, 1.59 mmol) (step 1). The reaction mixture was degassed for 1 min and heated at 90⁰C for 15 h. After cooling to rt, the reaction mixture was filtered through a pad of Celite®, concentrated, and purified by silica gel chromatography (40% ethyl acetate in hexane) to afford 285 mg (75%) of the product.

[471] Step 3. Preparation of 6-benzyl-2-isopropyl-3-r(3S)-piperidin-3-ylmethyllquinazolin-4(3H)- one

[472] To a solution of tert-butyl (3R)-3-[(6-benzyl-2-isopropyl-4-oxoquinazolin-3(4H)-yl)methyl]- piperidine-1 -carboxylate (200 mg, 0.420 mmol) (step 2) in DCM (10 mL) was added TFA (0.5 mL, 6.35 mmol) at rt. The reaction mixture was stirred for 15 h and concentrated. The residue was dissolved in DCM (30 mL) and washed with sat aq NaHCO₃ solution and brine. The organic layer was dried over MgSO₄ and concentrated under reduced pressure to afford 114 mg (72%) of the product. [473] Step 4. Preparation of 6-benzyl-2-isopropyl-3-{r(3S)-1-isopropylpiperidin-3-yllmethyl)- quinazolin-4(3H)-one

[474] To a solution of 6-benzyl-2-isopropyl-3-[(3S)-piperidin-3-ylmethyl]quinazolin-4(3H)-one (420 mg, 1.12 mmol) (step 3) and Cs₂CO₃ (729 mg, 2.24 mmol) in MeCN (5 mL) was added 2- iodopropane (1.9 g, 11.1 mmol), and the mixture was heated to 90⁰C for 15 h. The reaction mixture was cooled to rt, and filtered and concentrated. The crude product was redissolved in methanol and purified using a Gilson reversed-phase HPLC system with a gradient elution from 10% to 90% acetonitrile in water to afford 104 mg (22%) of the product. ¹H NMR (300 MHz, CD₂CI₂) δ 8.03 (s, 1 H), 7.58 (d, 2 H), 7.30-7.35 (m, 2 H), 7.20-7.25 (m, 3 H), 4.03-4.15 (br, 4 H), 3.25-3.35 (m, 1 H), 2.63-2.72 (m, 3 H), 2.25 (t, 1 H), 2.15 (t, 1 H), 2.00-2.11 (br, 1 H), 1.62-1.78 (m, 2 H), 1.48-1.58 (m, 1 H), 1.38 (t, 6 H), 1.20-1.31 (m, 1 H), 1.01 (t, 6 H); ES-MS m/z 418.3 (MH⁺); HPLC RT (min) 2.65.

[475] EXAMPLE 88

6-rButyl(methyl)amino1-2-(2-methoxyphenyl)-3-(pyrrolidin-3-ylmethyl)quinazolin-4(3H)-one hydrochloride

[476] Step 1 : Preparation of tert-butyl 3-fr6-rbutyl(methyl)aminol-2-(2-methoxyphenyl)- 4-oxoαuinazolin-3(4H)-yl1methyl)pyrrolidine-1-carboxylate

[477] To a dry 25 ml_ round-bottom flask was added 6-[butyl(methyl)amino]-2-(2-methoxy- phenyl)-4H-3,1 -benzoxazin-4-one (500 mg, 1.48 mmol) (Example 1 , step 3), followed by anhydrous toluene (1.50 mL) and 3-aminomethyl-1-N-BOC-pyrrolidine (444 mg, 2.22 mmol). The mixture was heated to 80⁰C and stirred for 16 h under an atmosphere of N₂. The mixture was concentrated under reduced pressure and purified by silica gel flash chromatography (100% CH₂CI₂ ramping to 95% CH₂CI₂: 5% MeOH). This gave a viscous light yellow oil. ES-MS m/z 539 (MH⁺, 100), 439 (56), 339 (45).

[478] The intermediate obtained above was added to a dry 25 mL round-bottom flask followed by ethylene glycol (5.00 mL) and NaOH (295 mg, 7.39 mmol). The mixture was heated to 120⁰C and, after 16 h, diluted with water (20 mL) and extracted with CH₂CI₂ (5 x 40 mL). Purification of the combined and concentrated organic extracts by silica gel flash chromatography (97% CH₂CI₂: 3% MeOH) gave the product as a light yellow oil (430 mg, 56% (for 2 steps)). ¹H NMR (300 MHz, CD₃CN) δ 7.57-7.37 (m, 3H), 7.30-7.26 (m, 2H), 7.11-7.06 (m, 2H), 4.26-4.19 (m, 1H), 4.08-4.04 (m, 3H), 3.79 (d, 2H), 3.66-3.61 (m, 3H), 3.58-3.39 (m, 3H), 3.03 (s, 3H), 2.91 -2.88 (m, 1 H), 2.01 (S, 3H), 1.63-1.51 (m, 2H), 1.37 (d, 9H), 0.94 (t, 3H); ES-MS m/z 521 (MH⁺, 100), 465 (59), 421 (25), 338 (28).

[479] Step 2: Preparation of 6-rbutyl(methvπaminol-2-(2-methoxyphenyl)-3-(pyrrolidin-3- ylmethyl)quinazolin-4(3H)-one hydrochloride

[480] To a 10 mL round-bottom flask was added tert-butyl 3-{[6-[butyl(methyl)amino]-2-(2- methoxyphenyl)-4-oxoquinazolin-3(4H)-yl]methyl}pyrrolidine-1-carboxylate (401 mg, 0.770 mmol) (step 1 ) and MeOH (1 mL). The mixture was then stirred at rt for 2 h with 1 M HCI in ether (3.85 mL, 3.85 mmol). An additional 5 equiv of HCI were added, and the light orange mixture was stirred for another 1 h. The mixture was then concentrated under reduced pressure yielding the title product as a viscous dark orange oil (373 mg, 98%). ¹H NMR (300 MHz, CD₃OD) δ 7.85-7.65 (m, 5H), 7.40-7.29 (m, 2H), 3.96 (br s, 3H), 3.59 (br m, 8H), 3.19 (br s, 4H), 3.25-2.55 (m, 2H), 1.63-1.36 (m, 4H), 0.98 (t, 3H). ES-MS m/z 421.3 (MH⁺); HPLC RT (min) 2.68. [481] EXAMPLE 89

6-rButyl(methyl)aminol-2-(2-methoxyphenyl)-3-(π-(3-methylbutyl)pyrrolidin-3-vn methyl)quinazolin-4(3H)-one trifluoroacetate

[482] In a 5 mL amber, screw-capped vial was added K₂CO₃ (88.2 mg, 0.64 mmol) followed by a solution of the 6-[butyl(methyl)amino]-2-(2-methoxyphenyl)-3-(pyrrolidin-3-ylmethyl)quinazolin- 4(3H)-one hydrochloride (63.0 mg, 0.13 mmol) (Example 88) in anhydrous CH₃CN (2.0 mL). 1- Bromo-3-methylbutane (21.2 mg, 0.14 mmol) was then added and the vial was capped, placed on a shaker apparatus, and heated to 70⁰C. After 16 h, additional 1-bromo-3-methylbutane (24.8 mg, 0.17 mmol) was added along with K₂CO₃ (1 equiv), and the mixture was heated on the shaker apparatus for 16 h. Purification using a Gilson reversed-phase HPLC system gave the product as a viscous yellow oil (16.5 mg, 21%). ¹H NMR (300 MHz, CD₃OD) δ 7.69-7.63 (m, 1 H), 7.58-7.54 (m, 2H), 7.44-7.40 (m, 2H), 7.29-7.18 (m, 2H), 4.51-4.44 (m, 1 H), 4.29-4.26 (m, 1 H), 3.90 (s, 3H), 3.81-3.56 (m, 1 H), 3.52 (m, 3H), 3.19-3.12 (m, 3H), 3.11 (m, 3H), 3.04-2.95 (m, 1 H), 2.80-2.42 (m, 1 H), 2.03-1.81 (m, 1 H), 1.71-1.47 (m, 6H), 1.42-1.35 (m, 2H), 1.06-0.86 (m, 9H). ES-MS m/z 491.4 (MH⁺); HPLC RT (min) 2.52.

[483] EXAMPLE 90

6-(4-Fluorophenoxy)-2-(2-methylphenyl)-3-(morpholin-2-ylmethyl)quinazolin-4(3H)-one

[484] Step 1. Preparation of 3-[(4-benzylmorpholin-2-yl)methyll-6-bromo-2-(2-methylphenyl)- guinazolin-4(3H)-one

[485] 1-(4-Benzylmorpholin-2-yl)methanamine (2.00 g, 9.70 mmol) in toluene (15 ml_) was added to 6-bromo-2-(2-methylphenyl)-4H-3,1-benzoxazin-4-one (Example 6, Step 1 ) (2.55 g, 8.08 mmol), and the solution was stirred at reflux for 16 h under a nitrogen atmosphere. The mixture was concentrated under reduced pressure and passed through a silica gel plug (100% EtOAc). The resulting intermediate (yellow oil) (2.50 g, 4.79 mmol) was added to a dry round- bottom flask followed by ethylene glycol (20 mL) and LiOH (0.40 g, 9.57 mmol). The resulting mixture was stirred at 135⁰C for 16 h. This mixture was cooled to rt, diluted with DCM and water, and extracted with DCM (50 mL x 2). The combined organic fractions were concentrated under reduced pressure and the residue purified by silica gel column chromatography with 10 to 50% ethyl acetate in hexanes to afford 1.62 g (67%) of the product. ES-MS m/z 504.3 (MH⁺); HPLC RT (min) 2.83.

[486] Step 2. Preparation of 3-r(4-benzylmorpholin-2-v0methyll-6-(4-fluorophenoxy)-2- (2-methylphenyl)quinazolin-4(3H)-one

[487] To a solution of 3-[(4-benzylmorpholin-2-yl)methyl]-6-bromo-2-(2-methylphenyl)quinazolin- 4(3H)-one (0.80 g, 1.59 mmol) and 4-fluorophenol (0.21 g, 1.90 mmol) in 1-methyl-2-pyrrolidinone (20 mL) was added CuCI (0.078 g, 0.79 mmol), TMHD (0.17 mL, 0.79 mmol), and Cs₂CO₃ (1.03 g, 3.17 mmol). The mixture was then stirred under a nitrogen atmosphere for 14 h at 120⁰C. The reaction mixture was cooled to rt, diluted with EtOAc, and passed through a silica gel plug with EtOAc. Removal of the solvent under reduced pressure and subsequent purification using a Gilson reversed-phase HPLC system with 10% to 90% acetonithle in water (0.1% TFA) gave the product (503 mg, 59%) as a light yellow oil. ES-MS m/z 536.2 (MH⁺); HPLC RT (min) 3.21. [488] Step 3. Preparation of 6-(4-fluorophenoxy)-2-(2-methylphenyl)-3-(morpholin-2- ylmethyl)quinazolin-4(3H)-one

[489] A solution of 3-[(4-benzylmorpholin-2-yl)methyl]-6-(4-fluorophenoxy)-2-(2-methylphenyl)- quinazolin-4(3H)-one (503 mg, 0.94 mmol) in EtOAc (10 ml_) and AcOH (1 mL) was treated with Pd/C (20 mg). The reaction mixture was stirred at rt for 24 h under a hydrogen atmosphere. The solids were removed by filtration and the filtrate concentrated to dryness to afford the product (246 mg, 58%) as off-white solid. [490] ES-MS m/z 446.2 (MH⁺); HPLC RT (min) 2.48.

[491] EXAMPLE 91

6-(4-Fluorophenoxy)-3-r(4-isopropylmorpholin-2-yl)methyll-2-(2-methylphenyl)quinazolin-

4(3H)-one

[492] To a mixture of 6-(4-fluorophenoxy)-2-(2-methylphenyl)-3-(morpholin-2-ylmethyl)- quinazolin-4(3H)-one (200 mg, 0.45 mmol) (Example 90) and K₂CO₃ (248 mg, 1.80 mmol) in acetonitrile (8 mL) was added 2-bromopropane (0.08 mL, 0.90 mmol). This mixture was stirred at 70⁰C for 14 h. The mixture was cooled to rt, concentrated under reduced pressure, and water (10 mL) was added. After extraction with EtOAc (2 x 10 mL), the combined organic fractions were concentrated under reduced pressure. The crude product was purified using a Gilson reversed- phase HPLC system with 10% to 80% acetonitrile in water (0.1% TFA) to give the product (106 mg, 48%) as a light yellow oil. ¹H NMR (400 MHz, CD₃OD) δ 7.65-7.68 (dd, 1 H), 7.60-7.61 (d, 1 H), 7.31-7.54 (m, 5 H), 7.13-7.17 (m, 4 H), 4.16-4.21 (dd, 1 H), 3.92-4.06 (m, 1 H), 3.66-3.79 (m, 2 H), 3.35-3.42 (m, 1 H), 2.52- 2.73 (m, 3 H), 2.30 (s, 1 H), 2.11-2.18 (m, 3 H), 1.72-1.77 (t, 1 H), 0.99-1.01 (m, 6 H); ES-MS m/z 488.3 (MH⁺); HPLC RT (min) 2.54. [493] EXAMPLE 92

3-f(4-Benzylmorpholin-2-vhmethvn-6-(4-chlorophenyl)-2-(2-methylphenyl)quinazolin-4(3H)- one

[494] To a dry 100 mL round-bottom flask was added 3-[(4-benzylmorpholin-2-yl)methyl]-6- bromo-2-(2-methylphenyl)quinazolin-4(3H)-one (2.44 g, 4.84 mmol) (Example 90, step 1 ) followed by anhydrous toluene (20.0 mL), dioxane (5.00 mL), and water (2.5 mL). The mixture was stirred under a nitrogen atmosphere and 4-chlorophenyl boronic acid (756 mg, 4.84 mmol), K₂CO₃ (4.01 g, 29.0 mmol), and PdCI₂(dppf) (395 mg, 0.48 mmol) were added. The reaxtion mixture was heated to 90°C for 12 h and then filtered through a silica gel plug with EtOAc as the eluent (60 mL). Removal of the solvent under reduced pressure and purification of the residue by silica gel flash chromatography (80% hexanes: 20% EtOAc) gave the product as a light yellow solid (1.99 g, 76%). ¹H NMR (400 MHz, CD₃OD) δ 8.46-8.48 (m, 1 H), 8.10-8.12 (dd, 1 H), 7.72-7.75 (m, 3 H), 7.49-7.51 (d, 3 H), 7.35-7.36 (m, 3 H), 7.25-7.28 (m, 5 H), 4.18-4.22 (m, 1 H), 3.65-4.08 (m, 3 H), 3.30-3.48 (m, 3 H), 2.55-2.71 (m, 2 H), 2.20-2.31 (d, 3 H), 2.00-2.08 (m, 1 H), 1.63-1.69 (m, 1 H); ES-MS m/z 536.2 (MH⁺); HPLC RT (min) 2.89.

[495] EXAMPLE 93

6-(4-Chlorophenvh-3-r(4-isopropylmorpholin-2-yl)methyll-2-(2-methylphenyl)αuinazolin-

4(3Hi-one

[496] Step 1. Preparation of 6-(4-chlorophenyl)-2-(2-methylphenvh-3-(morpholin-2-ylmethyl)- αuinazolin-4(3H)-one

[497] A solution of 3-[(4-benzylmorpholin-2-yl)methyl]-6-(4-chlorophenyl)-2-(2-methylphenyl)- quinazolin-4(3H)-one (2.59 g, 4.84 mmol) (Example 92) in 1 ,2-dichloroethane (25 mL) was treated with 1-chloromethyl chloroformate (1.32 mL, 12.09 mmol) at rt for 30 min. The reaction mixture was then heated under reflux for 2 h. The solvent was evaporated under reduced pressure and the residue heated in MeOH (20 mL) under reflux for another 2 h. The solvent was removed under reduced pressure, and the residue was triturated with hexane. The residue was washed with diethylether to provide the product (1.96 g, 91%) as a white solid. ES-MS mlz 446.14 (MH⁺); HPLC RT (min) 2.63.

[498] Step 2. Preparation of 6-(4-chlorophenyl)-3-r(4-isopropylmorpholin-2-yl)methyll-2-(2- methylphenyl)quinazolin-4(3H)-one

[499] The compound was prepared using the method of Example 91 and 6-(4-chlorophenyl)-2- (2-methylphenyl)-3-(morpholin-2-ylmethyl)quinazolin-4(3H)-one (step 1) as starting material. ¹H NMR (400 MHz, CD₃OD) δ 8.48-8.49 (s, 1 H), 8.10-8.13 (m, 1 H), 7.72-7.76 (d, 3 H), 7.34-7.52 (m, 6 H), 4.23-4.27 (m, 1 H), 3.99-4.10 (m, 1 H), 3.69-3.85 (m, 2 H) 3.38-3.45 (m, 1 H), 2.72-2.79 (t, 1 H), 2.53-2.66 (m, 2 H), 2.33 (s, 1 H), 2.12-2.22 (m 3 H), 1.76-1.82 (m, 1 H), 1.01-1.03 (m, 6 H); ES-MS m/z 488.2 (MH⁺); HPLC RT (min) 2.71. [500] EXAMPLE 94

6-(4-Chlorophenvπ-3-r(4-ethylmorpholin-2-vπmethyll-2-(2-methylphenvhαuinazolin-4(3H)- one

[501] The compound was made from the product of Example 93, step 1 , and acetaldehyde using the reductive amination procedure described in Example 12. ES-MS m/z 474.2 (MH⁺); HPLC RT (min) 2.66.

[502] EXAMPLE 95

3-r(1-Ethyl-1.2.5.6-tetrahvdropyridin-3-yl)methvn-6-(4-fluorophenoxy)-2-(2- methylphenyl)quinazolin-4(3H)-one

[503] Step 1. Preparation of 6-bromo-2-(2-methylphenvO-3-(pyridin-3-ylmethyl)quinazolin-4(3H)- one

[504] The compound was prepared using the method of step 2 of Example 6, and 1-pyridin-3-yl- methanamine as starting material. ES-MS m/z 406.3 (MH⁺); HPLC RT (min) 2.78. [505] Step 2. Preparation of 6-(4-fluorophenoxy)-2-(2-methylphenyl)-3-(pyridin-3-ylmethvO- quinazolin-4(3H)-one

[506] The compound was prepared using the method of Example 90, step 2, and 6-bromo-2-(2- methylphenyl)-3-(pyridin-3-ylmethyl)quinazolin-4(3H)-one (step 1) as starting material. ES-MS m/z 438.2 (MH⁺); HPLC RT (min) 2.68.

[507] Step 3. Preparation of 1-ethyl-3-(f6-(4-fluorophenoxy)-2-(2-methylphenyl)-4oxoquinazolin- 3(4H)-vnmethyl)pyridinium iodide

[508] To a solution of 6-(4-fluorophenoxy)-2-(2-methylphenyl)-3-(pyridin-3-ylmethyl)quinazolin- 4(3H)-one (400 mg, 0.91 mmol) (step 2) in acetone (20 mL) was added iodoethane (3.66 mL, 45.72 mmol), and the solution was stirred under nitrogen at 5O⁰C for 36 h in a sealed reaction tube. The mixture was cooled to rt, and concentrated under reduced pressure. The residue was washed with ether and dried in a high vacuum oven for 12 h. The product (420 mg, 77%) was used in the next step without further purification. ES-MS m/z 466.4 (MH⁺); HPLC RT (min) 2.68.

[509] Step 4. Preparation of 3-T(1 -ethyl-1.2.5.6-tetrahydropyridin-3-yl)methvπ-6-(4- fluorophenoxy)-2-(2-methylphenyl)quinazolin-4(3H)-one

[510] 1 -Ethyl-3-{[6-(4-fluorophenoxy)-2-(2-methylphenyl)-4-oxoquinazolin-3(4H)-yl]methyl}- pyridinium iodide (420 mg, 0.71 mmol) (step 3) was dissolved in a mixture of MeOH/DCM (1 :1 ). The mixture was cooled to O⁰C, NaBH₄ (214 mg, 5.66 mmol) was added, and stirring was continued for 3 h at 0-5⁰C. Ice water was added to the reaction mixture followed by extraction with DCM (2 x 50 ml_). The combined organic layers were washed with brine and dried over Na₂SO₄. After removal of the solvent under reduced pressure, the residue was purified using a Gilson reversed-phase HPLC system with 10% to 80% acetonitrile in water (0.1% TFA) to give the product (56 mg, 17%) as a yellow oil. ¹H NMR (400 MHz, CD₃OD) δ 7.68-7.70 (d, 1 H), 7.61-7.62 (d, 1 H), 7.53-7.56 (dd, 1 H), 7.43-7.47 (m, 1 H)₁ 7.31-7.40 (m, 3 H), 7.12-7.20 (m, 4 H), 4.98-5.00 (m, 1 H), 4.64-4.68 (d, 1 H), 4.18-4.22 (d, 1 H), 2.69-2.73 (d, 1 H), 2.56-2.61 (d, 1 H), 2.38-2.50 (m, 4 H), 2.22 (s, 3 H), 2.07 (s 2 H), 1.03-1.06 (t, 3 H); ES-MS m/z 470.2 (MH⁺); HPLC RT (min) 2.85.

[511] EXAMPLE 96 β-(4-Chlorophenvn-3-r(1-ethyl-1.2.5.6-tetrahvdropyridin-3-vnmethvn-2-(2- methylphenyl)quinazolin-4(3H)-one

[512] Step 1. Preparation of 6-(4-chlorophenvπ-2-(2-methylphenyl)-3-(pyridin-3-ylmethyl)-4(3H)- one

[513] The compound was prepared using the method of Example 92 and 6-bromo-2-(2- methylphenyl)-3-(pyridin-3-ylmethyl)quinazolin-4(3H)-one (Example 95, step 1) and 4-chloro- phenylboronic acid as starting materials. ES-MS m/z 438.26 (MH⁺); HPLC RT (min) 3.15.

[514] Step 2. Preparation of 6-(4-chlorophenyl)-3-r(1-ethyl-1 ,2,5,6-tetrahvdropyridin-3- yl)methyll-2-(2-methylphenyl)αuinazolin-4(3H)-one

[515] Starting from 6-(4-chlorophenyl)-2-(2-methylphenyl)-3-(pyridin-3-ylmethyl)quinazolin- 4(3H)-one (step 1), the title compound was prepared using the method of Example 95 (sequence of step 3 and 4). ¹H NMR (400 MHz, CD₃OD) δ 8.49 (d, 1 H), 8.11-8.14 (dd, 1 H), 7.72-7.76 (m, 3 H), 7.48-7.52 (m, 3 H), 7.2,2-7 Al (m, 3 H), 5.02-5.04 (m, 1 H), 4.70-4.74 (d, 1 H), 4.24-4.28 (d, 1 H), 2.74-2.78 (d, 1 H), 2.61-2.65 (d, 1 H), 2.47-2.52 (m, 2 H), 2.40-2.45 (m, 2 H), 2.26 (s, 3 H), 2.08 (m, 2H), 1.04-1.08 (t, 3 H); ES-MS m/z 470.3 (MH⁺); HPLC RT (min) 2.74.

[516] EXAMPLE 97

3-f(3R)-1-Azabicvclor2.2.2loct-3-ylmethvn-6-(4-chlorophenvh-2-(2-methoxyphenvl)-

[517] The product was obtained by using the synthetic sequence described in Example 43, steps 1-3, using the appropriate staring materials. ES-MS m/z 486.4 (MH⁺); HPLC RT (min) 3.03.

[518] EXAMPLE 98

2-r2-Fluoro-4-(2-hvdroxyethoxy)phenvn-6-(4-fluorophenoxy)- 3-f(3S)-piperidin-3-ylmethvπquinazolin-4(3H)-one

[519] Step 1. Preparation of 6-bromo-2-(2.4-difluorophenyl)-4H-3,1-benzoxazin-4-one

[520] To a solution of 2-amino-5-bromobenzoic acid (10 g, 46 mmol) and triethylamine (19 mL, 139 mmol) in chloroform (100 mL) was added 2,4-difluorobenzoylchloride (6.8 mL, 55 mmol) dropwise at rt to form a precipitate. After the solution was stirred for 2 h, the solvent was removed under reduced pressure, and the residue was heated in acetic acid anhydride (90 mL) at 5O⁰C for 2 h. The resulting precipitate was collected by filtration, washed with MeOH, and dried under vacuum for 15 h to afford 15 g (97% yield) of the product as a light yellow solid. ES-MS analysis showed the presence of a single peak with m/z = 339 (MH⁺). [521] Step 2. Preparation of tert-butyl (3R)-3-r({5-bromo-2-f(2,4-difluorobenzoyl)-amino1- benzovPamino) methyllpiperidine-1 -carboxylate

[522] A solution of 6-bromo-2-(2,4-difluorophenyl)-4H-3,1-benzoxazin-4-one (7.00 g, 20.7 mmol) (step 1) and tert-butyl (3R)-3-(aminomethyl)piperidine-1-carboxylate (6.21 g, 29 mmol) in toluene (250 ml_) was heated to reflux for 4 h. The solvent was removed under reduced pressure to afford the crude product which was used in the next step without further purification. ES-MS m/z 452.0 ([MH₂- BOC]⁺); HPLC RT (min) 4.74.

[523] Step 3. Preparation of tert-butyl (3R)-3-(f6-bromo-2-f2-fluoro-4-(2-hvdroxyethoxy) phenyll- 4-oxoguinazolin-3(4H)-yllmethyl)piperidine-1 -carboxylate

[524] A solution of tert-butyl (3R)-3-[({5-bromo-2-[(2,4-difluorobenzoyl)-amino]benzoyl} amino) methyl]piperidine-1-carboxylate (7.30 g, 13.2 mmol) (step 2) and K₂CO₃ in ethylene glycol (100 mL) was heated at 14O⁰C for 10 h. TLC analysis (EtOAc/hexanes 1 :1) indicated an R_f value of the product of 0.15. The solution was partitioned between EtOAc and water. The organic phase was separated, concentrated, and the crude product purified via silica gel column chromatography using a gradient elution from 10% to 90% EtOAc in hexanes to afford 1.4 g (18%) of the product as a white solid. ES-MS m/z 576.5 (MH⁺); HPLC RT (min) 3.54. [525] Step 4. Preparation of tert-butyl (3R)-3-fr2-f2-fluoro-4-(2-hvdroxyethoxy)phenvπ-6-(4- fluorophenoxy)-4-oxoαuinazolin-3(4H)-yllmethyl)piperidine-1-carboxylate

[526] A solution of tert-butyl (3R)-3-{t6-bromo-2-[2-fluoro-4-(2-hydroxyethoxy) phenyl]-4- oxoquinazolin-3(4H)-yl]methyl}piperidine-1-carboxylate (1.8 g, 3.1 mmol) (step 3), 4-fluorophenol (525 mg, 4.68 mmol), cesium carbonate (2.0 g, 6.25 mmol), copper(l) chloride (156 mg, 1.56 mmol), and TMHD (260 mg, 0.87 mmol) in 1-methyl-2-pyrrolidinone (30 mL) was degassed and then heated at 115⁰C for 10 h. The mixture was diluted with ether and passed through a Celite® bed. The organic solution was washed with water (2x). After removal of the solvent under reduced pressure, the residue was purified using a Gilson reversed-phase HPLC system with a gradient elution from 10 % to 90% acetonitrile in water to give 900 mg (47%) of the product. ES- MS m/z 630.3 [(M+Na)⁺]; HPLC RT (min) 3.91.

[527] Step 5. Preparation of 2-r2-fluoro-4-(2-hvdroxyethoxy)phenvπ-6-(4-fluorophenoxy)-3-r(3S)- piperidin-3-ylmethyllαuinazolin-4(3H)-one

[528] A solution of tert-butyl (3R)-3-{[2-[2-fluoro-4-(2-hydroxyethoxy)phenyl] -6-(4-fluoro- phenoxy)-4-oxoquinazolin-3(4H)-yl]methyl}piperidine-1-carboxylate (0.9 g, 1.48 mmol) (step 4) and TFA (1 mL) in DCM (15 mL) was stirred at rt for 2 h. The solvent was removed under reduced pressure, and the residue was purified via silica gel column chromatography using a gradient elution from 0% to 6% NH₃ (2N in MeOH) in DCM to afford 165 mg (22%) of a white solid. ¹H NMR (400 MHz, CD₂CI₂) δ 7.67 (m, 2H), 7.44 (m, 2H), 7.09 (m, 4H), 6.91 (d, 1 H), 6.76 (d, 1 H), 4.20-3.57 (m, 4H), 3.00-2.19 (m, 4H), 1.89-0.87 (m, 7H); ES-MS m/z 508.4 (MH⁺); HPLC RT (min) 2.53. [529] EXAMPLE 99

2-r2-Fluoro-4-(2-hvdroxyethoxy)phenvn-6-(4-fluorophenoxy)-3-(r(3S)-1-isopropylpiperidin-3- yllmethyl>quinazolin-4(3H)-one

[530] A solution of 2-[2-fluoro-4-(2-hydroxyethoxy)phenyl]-6-(4-fluorophenoxy)-3-[(3S)-piperidin- 3-ylmethyl]quinazolin-4(3H)-one (Example 98) (180 mg, 0.355 mmol), 2-iodopropane (0.042 mL, 0.426 mmol), and K₂CO₃ (147 mg, 1.1 mmol) in acetonitrile (30 mL) with few drops water was stirred at 80⁰C for 10 h. The precipitate was filtered off and the solvent was removed under reduced pressure. The residue was purified via silica gel column chromatography using a gradient elution from 0% to 7% MeOH in DCM to afford 56 mg (25%) of the product as white foam. ¹H NMR (400 MHz, CD₂CI₂) δ 7.68 (m, 2H), 7.44 (m, 2H), 7.08 (m, 4H), 6.89 (d, 1 H), 6.79 (d, 1 H), 4.20-3.59 (m, 4H), 2.61-1.24 (m, 8H), 0.91 (m, 6H); ES-MS m/z 550.5 (MH⁺); HPLC RT (min) 2.60.

[531] EXAMPLE 100

2-r2-Fluoro-4-(2-methoxyethoxy)phenyll-6-(4-fluorophenoxy)-3-fr(3S)-1-isopropylpiperidin-3- vπmethyl)quinazolin-4(3H)-one

[532] To a solution of sodium hydride (17 mg, 0.43 mmol, 60%) in THF (2 mL) was added 2-[2- fluoro-4-(2-hydroxyethoxy)phenyl]-6-(4-fluorophenoxy)-3-{1-isopropylpiperidin-3-yl]methyl}- quinazolin-4(3H)-one (194 mg, 0.355 mmol) (Example 857; prepared similarly to Example 99) at O⁰C. Then, iodomethane (60 mg, 0.43 mmol) was added at rt. The mixture was stirred at rt for 10 h. The crude product was purified via to silica gel column chromatography using a gradient elution from 0% to 7 % MeOH in DCM to afford 5 mg (2.5%) of the product as a light yellow solid. ¹H NMR (CD₂CI₂) δ 9.96 (s, 1 H), 7.78 (t, 1 H), 7.70 (d, 1 H), 7.58 (s, 1 H), 7.40 (d, 1 H), 7.00 (m, 4H), 6.90 (d, 1 H), 6.70 (d, 1 H), 4.22 (t, 1 H), 4.10 (s, 2H), 3.67 (d, 2H), 3.4-3.2 (m, 6H), 2.90-2.20 (m, 4H), 1.70 (d, 1 H), 1.4-1.2 (m, 9H); ES-MS m/z 564.5 (MH⁺); HPLC RT (min) 2.71. [533] EXAMPLE 101

6-Bromo-3-(ri-(cvclobutylmethyl)piperidin-3-vnmethyl)-2-r2-fluoro-4-(2- hvdroxyethoxy)phenyllquinazolin-4(3H)-one

[534] Step 1. Preparation of 6-bromo-2-[2-fluoro-4-(2-hvdroxyethoxy)phenyll-3-(piperidin-3- ylmethvQquinazolin-4(3H)-one

[535] tert-Butyl 3-{[6-bromo-2-[2-fluoro-4-(2-hydroxyethoxy)phenyl]-4-oxoquinazolin-3(4H)- yl]methyl}piperidine-1-carboxylate (prepared analogously to the product of step 3 of Example 98) was BOC-deprotected using a similar procedure as described in step 5 of Example 98.

[536] Step 2. Preparation of β-bromo-S-iπ-fcvclobutylmethvOpiperidin-S-yllmethyll^-re-fluoro- 4-(2-hvdroxyethoxy)phenvnquinazolin-4(3H)-one

[537] The compound was synthesized in a similar way as Example 9 except that (bromomethyl)- cyclobutane instead of 2-bromopropane was used as the alkylating agent and 6-bromo-2-[2-fluoro- 4-(2-hydroxyethoxy)phenyl]-3-(piperidin-3-ylmethyl)quinazolin-4(3H)-one was used as the starting material (product of step 1 above) instead of of 6-isobutoxy-2-(2-methylphenyl)-3-[(3S)-piperidin-3- ylmethyl]quinazolin-4(3H)-one. ¹H NMR (300 MHz, CD₃OD) δ 8.34 (s, 1 H), 7.92 (d, 1 H), 7.57 (m, 2H), 7.00 (m, 2H), 4.15 (m, 3H), 3.90 (m, 2H), 3.80-3.62 (bm, 1 H), 2.88-2.24 (bm, 6H), 2.10-1.24 (bm, 11 H), 0.84 (bm, 1 H); ES-MS m/z 544.4 (MH⁺), HPLC RT (min) 2.94. [538] EXAMPLE 102

3-fri-(Cvclobutylmethyl)piperidin-3-yllmethyl)-2-r2-fluoro-4-(2-hvdroxyethoxy)phenvn-6- phenoxyquinazolin-4(3H)-one

[539] 6-Bromo-3-{[1-(cyclobutylmethyl)piperidin-3-yl]methyl}-2-[2-fluoro-4-(2-hydroxyethoxy)- phenyl]quinazolin-4(3H)-one (Example 101 ) and phenol were reacted by using the Ullmann coupling procedure as described in Example 98, step 4. ES-MS m/z 558.3 (MH⁺); HPLC RT (min) 2.65.

[540] EXAMPLE 103

6-Anilino-3-ff1-(cvclobutylmethyl)piperidin-3-yl1methyl)-2-r2-fluoro-4-(2-hvdroxyethoxy)- phenyllquinazolin-4(3H)-one

[541] 6-Bromo-3-{[1-(cyclobutylmethyl)piperidin-3-yl]methyl}-2-[2-fluoro-4-(2-hydroxyethoxy)- phenyl]quinazolin-4(3H)-one (Example 101) and aniline were reacted using a similar procedure as described in Example 26. ¹H NMR (300 MHz, CD₃OD) δ 7.84 (s, 1 H), 7.53 (m, 3H), 7.28 (m, 2H), 7.20 (m, 2H), 6.95 (m, 3H), 4.12 (m, 3H), 3.90 (m, 2H), 3.72-3.57 (m,1 H), 2.72-2.53 (bm, 2H), 2.52-2.32 (bm, 1 H), 2.28 (bs, 2H), 2.02-1.23 (bm, 12H), 0.80 (bm, 1 H); ES-MS m/z 557.3 (MH)⁺, HPLC RT (min) 2.52.

[542] EXAMPLE 104

6-(3-Chlorophenyl)-2-r2-fluoro-4-(2-hvdroxyethoxy)phenvn-3-(piperidin-3- ylmethyl)quinazolin-4(3H)-one

[543] To a solution of 6-bromo-2-[2-fluoro-4-(2-hydroxyethoxy)phenyl]-3-(piperidin-3-ylmethyl)- quinazolin-4(3H)-one (product of step 1 of Example 101 ) (100 mg, 0.210 mmol), Na₂CO₃ (111 mg, 1.05 mmol), and PdCI₂(dppf) (7.68 mg, 0.010 mmol) in toluene/dioxane (1.2 ml_, 0.3 mL) was added (3-chlorophenyl)boronic acid (49.24 mg, 0.315 mmol). The reaction mixture was degassed for 1 min, followed by heating at 8O⁰C for 15 h. After the reaction was cooled to rt, the mixture was filtered through a pad of Celite®, concentrated, and purified using a Gilson reversed-phase HPLC system with a gradient elution from 10% to 90% acetonitrile in water to afford 22.6 mg (21%) of the product. ¹H NMR (300 MHz, CD₃OD) δ 8.44 (s, 1H), 8.08 (d, 1H), 7.75 (m, 2H), 7.65 (m, 1 H), 7.56 (m, 1H), 7.45 (m, 1H), 7.41 (m, 1H), 7.00 (m, 2H), 4.30-4.10 (m, 3H), 3.92 (m, 2H), 3.85-3.55 (bm, 1 H), 3.04-2.28 (bm, 3H), 1.93-0.89 (bm, 6H); ES-MS m/z 508.3 (MH)⁺, LCMS RT (min) 2.98.

[544] EXAMPLE 105

6-(3-Chlorophenyl)-3-fri-(cvclobutylmethyl)piperidin-3-vnmethyl)-2-r2-fluoro-4-(2- hydroxyethoxy)phenvnquinazolin-4(3H)-one

[545] The procedure for the preparation of this compound was the same as that for Example 104 except that the product of Example 101 (6-bromo-3-{[1-(cyclobutylmethyl)piperidin-3- yl]methyl}-2-[2-fluoro-4-(2-hydroxyethoxy)phenyl]quinazolin-4(3H)-one) was used as the starting material. ¹H NMR (300 MHz, CD₃OD) δ 8.42 (s, 1 H), 8.05 (m, 1H), 7.80-7.37 (m, 6H), 6.98(m, 2H), 4.20 (bm, 3H), 3.9 (m, 2H)₁ 3.70 (bm, 1 H), 2.80-2.20 (bm, 5H), 2.00-1.24 (bm, 12H), 0.98- 0.70 (m, 1 H); ES-MS m/z 576.3 (MH⁺), HPLC RT (min) 2.75.

[546] EXAMPLE 106

6-Anilino-2-r2,4-bis(2-hvdroxyethoxy)phenvπ-3-(piperidin-3-ylmethyl)quinazolin-4(3H)-one

[547] Step 1. Preparation of 2-r2.4-bis(2-hvdroxyethoxy)phenyl1-6-bromo-3-(piperidin-3- ylmethvDquinazolin-4(3H)-one

[548] tert-Butyl 3-{[2-[2,4-bis(2-hydroxyethoxy)phenyl]-6-bromo-4-oxoquinazolin-3(4H)- yl]methyl}piperidine-1-carboxylate, obtained as a side product from a reaction carried out analogously to step 3 of Example 98 was BOC-deprotected using the procedure described in step 5 of Example 98.

[549] Step 2. Preparation of 6-anilino-2-f2.4-bis(2-hvdroxyethoxy)phenvπ-3-(piperidin-3- ylmethyl)αuinazolin-4(3H)-one

[550] 2-[2,4-Bis(2-hydroxyethoxy)phenyl]-6-bromo-3-(piperidin-3-ylmethyl)quinazolin-4(3H)-one (step 1) was reacted with aniline using the Buchwald coupling conditions as described in Example 26. ES-MS m/z 531.2 (MH⁺); HPLC RT (min) 2.18.

[551] EXAMPLE 107

2-r2.4-Bis(2-hvdroxyethoxy)phenvn-6-(4-fluorophenoxy)-3-(piperidin-3-ylmethyl)quinazolin-

[552] 2-[2,4-Bis(2-hydroxyethoxy)phenyl]-6-bromo-3-(piperidin-3-ylmethyl)quinazolin-4(3H)-one (Example 106, step 1) was reacted with 4-fluorophenol using Ullmann coupling conditions as described in Example 98, step 4. ES-MS m/z 550.3 (MH⁺); HPLC RT (min) 2.80. [553] EXAMPLE 108

2-r2.4-Bis(2-hvdroxyethoxy)phenyll-6-(3-chlorophenyl)-3-(piperidin-3-ylmethyl)quinazolin-

4(3H)-one

[554] The procedure for the preparation of this compound was the same as the preparation of Example 104 except the product of step 1 of Example 106 was used as starting material. ¹H NMR (300 MHz, CD₃OD) δ 8.45 (s, 1 H), 8.10 (m, 1 H), 7.96 (m, 2H), 7.69 (m,1 H), 7.54-7.39 (m, 3H), 6.78 (m, 2H), 4.37-4.09 (bm, 5H), 3.9 (m, 2H), 3.76 (bs, 2H), 3.70-3.57 (bm, 1 H), 3.06-0.86 (bm, 9H); ES-MS m/z 550.3 (MH⁺), HPLC RT (min) 2.88.

[555] EXAMPLE 109

6-(4-Chlorophenyl)-3-r(1-ethylpiperidin-3-yl)methvn-2-f6-(2-hvdroxyethoxy)pyridin-3- yllquinazolin-4(3H)-one

[556] N-[4'-Chloro-3-({[(1 -ethylpiperidin-3-yl)methyl]amino}carbonyl)biphenyl-4-yl]-6-(2,2,2- trifluoroethoxy)nicotinamide, obtained by using the procedure described in Example 51 , steps 1 -3, and appropriate starting materials, was further cyclized using the procedure of step 3 of Example 98 which proceeded under exchange of the trifluoroethoxy group by a 2-hydroxyethoxy group from ethylene glycol used as the solvent. ES-MS m/z 519.7 (MH⁺); HPLC RT 2.49 min.

[557] EXAMPLE 110

6-(4-Chlorophenyl)-2-[β-(2-hvdroxyethoxy)pyridin-3-vn-3-r(3R)-piperidin-3- ylmethyllquinazolin-4(3H)-one

[558] N-[4'-chloro-3-({[(3R)-piperidin-3-ylmethyl]amino}carbonyl)biphenyl-4-yl]-6-(2,2,2-trifluoro- ethoxy)nicotinamide, obtained by using the procedure described in the first part of Example 63 (step 1 and the amide coupling part of step 2) was cyclized as described in the second part of Example 63, which proceeded under exchange of the trifluoroethoxy group by a 2-hydroxyethoxy group from ethylene glycol used as the solvent. ES-MS m/z 491.3 (MH⁺); HPLC RT 2.81 min.

[559] EXAMPLE 111

6-(4-Fluorophenoxy)-2-(4-hvdroxyphenyl)-3-(piperidin-3-ylmethyl)quinazolin-4(3H)-one

[560] A mixture of 2-[4-(benzyloxy)phenyl]-6-(4-fluorophenoxy)-3-(piperidin-3-ylmethyl)- quinazolin-4(3H)-one (200 mg, 0.37 mmol) (Example 177; synthesized in a similar manner as Example 30) and palladium on carbon (10%, 20 mg) in methanol (15 ml_) was degassed and then brought under a hydrogen atmosphere for 15 h. The catalyst was filtered off and the solvent concentrated under reduced pressure to give a white residue. The residue was treated with ether and the solid collected by filtration to afford 100 mg (61%) of product. ES-MS m/z 446.3 (MH⁺), HPLC RT (min) 2.43.

[561] EXAMPLE 112

6-(4-Fluorophenoxy)-2-(4-hvdroxyphenyl)-3-r(1-isopropylpiperidin-3-yl)methvnquinazolin-

4(3H)-one

[562] The product was obtained by debenzylation of 2-[4-(benzyloxy)phenyl]-6-(4-f!uoro- phenoxy)-3-[(1-isopropylpipehdin-3-yl)methyl]quinazolin-4(3H)-one (Example 184) using the procedure described in Example 111. ES-MS m/z 488.3 (MH⁺); HPLC RT 2.47 min.

[563] Using appropriate starting materials and the experimental procedures described above, compounds listed in Table 1 were prepared. It will be understood by those skilled in the art that some minor modifications to the described procedures may have been made, but such modifications do not significantly affect the results of the preparation.

Prep. Method

Example HPLC RT LC-MS LC-MS

Structure Chemical name of Example Number (min) [M₊H]⁺ Method

No.

ClH

3-{[6-[butyl(methyl)amino]-2-(2-

123 methoxyphenyl)-4-oxoquinazolin-3(4H)- 2.37 463.3 yl]methyl}-1 -ethylpiperidinium chloride

6-[butyl(methyl)amino]-3-[(1 -

124 isobutylpiperidin-3-yl)methyl]-2-(2- 2.71 491.3 methoxyphenyl)quinazolin-4(3H)-one

Prep. Method

Example HPLC RT LC-MS LC-MS

Structure Chemical name of Example Number (min) [M+H]⁺ Method

No.

3-{[{3S)- 1 -cyclobutylpiperidin-3-yl]

129 methyl}-6-isobutoxy-2-(2- 2.66 460.3 8, 9 methylphenyl)quinazolin-4(3H)-one

3-{[(3S)- 1 -cyclobutylpiperidin-3-

130 yl]methyl}-6-(2,2-difluoroethoxy)-2-(2- 2.38 468.3 8, 9 methylphenyl)quinazolin-4(3H)-oπe

Prep. Method

Example HPLC RT LC-MS LC-MS

Structure Chemical name of Example Number (min) [M₊H]⁺ Method

No.

3-{[(3S)-1 -isopropylpiperidin-3-yl]methyl}

131 2-(2-methylphenyl)-6-(2,2,3,3- 2.64 506.3 8, 9 tetrafluoropropoxy)quinazolin-4(3H)-one

6-(cyclopropylmethoxy)-3-{[(3S)-1 -

132 isopropylpiperidin-3-yl]methyl}-2-(2- 2.63 446.4 8, 9 methylphenyl)quinazolin-4(3H)-one

Prep. Method

Example HPLC RT LC-MS LC-MS

Structure Chemical name of Example Number (min) [M+H]⁺ Method

No.

6-(2,2-difluoroethoxy)-3-{[(3S)-1-

137 ethylpiperidin-3-yl]methyl}-2-(2- 2.26 442.2 8, 12 methylphenyl)quinazolin-4(3H)-one

3-{[{3S)-1-ethylpiperidin-3-yl]methyl}-2-

138 (2-methylphenyl)-6-(2,2,2- 2.48 460.3 8, 12 trifluoroethoxy)quinazolin-4(3H)-one

Prep. Method

Example HPLC RT LC-MS LC-MS

Structure Chemical name of Example Number (min) [M+H]⁺ Method

No.

6-[(5-chloropyridin-2-yl)oxy]-3-{[(3S)-1 -

139 ethylpiperidin-3-yl]methyl}-2-(2- 2.53 489.3 11 , 12 methylphenyl)quinazolin-4(3H)-one

3-{[(3S)-1 -ethylpiperidin-3-yl]methyl}-2-

140 (2-methylphenyl)-6-{[4-(trifluoromethyl) 2.67 523.2 11 , 12 pyridin-2-yl]oxy}quinazolin-4(3H)-one

Prep. Method

Example HPLC RT LC-MS LC-MS

Structure Chemical name of Example Number (min) [M+H]⁺ Method

No.

6-(difluoromethoxy)-3-{[(3S)-1 -

141 ethylpiperidin-3-yl]methyl}-2-(2- 2.32 428.3 8, 12 methylphenyl)quinazolin-4(3H)-one

3-{[(3S)-1 -ethylpiperidin-3-yl]methyl}-2-

142 (2-methylphenyl)-6-(2,2,3,3- 2.52 492.3 8, 12 tetrafluoropropoxy)quinazolin-4(3H)-one

Prep. Method

Example HPLC RT LC-MS LC-MS

Structure Chemical name of Example Number (min) [M₊H]⁺ Method

No.

3-{[1 -(cyclopropylmethyl)piperidin-3-

145 yl]methyl}-2-(2-methylphenyl)-6- 2.64 472.3 13 (trifluoromethoxy)quinazolin-4(3H)-one

3-{[1 -(cyclobutylmethyl)piperidin-3-

146 yl]methyl}-2-(2-methylphenyl)-6- 2.73 486.3 13 (trifluoromethoxy)quina2olin-4(3H)-one

Prep. Method

Example HPLC RT LC-MS LC-MS

Structure Chemical name of Example Number (min) [M+H]⁺ Method

No.

3-[(1 -cyclopropylpiperidin-3-yl)methyl]-2-

147 (2-methylphenyl)-6- 2.54 458.4 13 (trifluoromethoxy)quinazolin-4(3H)-one

3-[(1 -isopropylpiperidin-3-yl)methyl]-2-(2

148 methylphenyl)-6- 2.49 460.3 13 (trifluoromethoxy)quιnazolin-4(3H)-one

Prep. Method

Example HPLC RT LC-MS LC-MS

Structure Chemical name of Example Number (min) [M+H]⁺ Method

No.

3-[(1 -cyclobutylpiperidin-3-yl)methyl]-2-

149 (2-methylphenyl)-6-(trifluoromethoxy) 2.68 472.2 13 quinazolin-4(3H)-one

3-{[1-(cyclobutylmethyl)piperidin-3-

150 yl]methyl}-6-(4-fluorophenoxy)-2-(2- 2.69 528.3 17 methoxyphenyl)quinazolin-4(3H)-one

Prep. Method

Example HPLC RT LC-MS LC-MS

Structure Chemical name of Example Number (min) [M+H]⁺ Method

No.

6-(4-fluorophenoxy)-3-{[(3S)-1 -

155 isopropylpiperidin-3-yl]methyl}-2- 2.53 438.3 18 propylquinazolin-4(3H)-one

6-(4-chlorophenoxy)-3-{[(3S)-1 -

156 isopropylpiperidin-3-yl]methyl}-2- 2.66 454.3 18 propylquinazolin-4(3H)-one

Prep. Method

Example HPLC RT LC-MS LC-MS

Structure Chemical name of Example Number (min) [M+H]⁺ Method

No.

6-(4-chlorophenoxy)-3-{[(3S)-1 -

157 ethylpιperιdιn-3-yl]methyl}-2- 2.88 412.4 19 methylquιnazolιn-4(3H)-one

2-[2-(dιfluoromethoxy)phenyl]-3-[(1 -

158 ιsopropylpιpeπdιn-3-yl)methyl]-6-(2- 2.69 5503 20 methoxyphenoxy)quιnazolιn-4(3H)-one

Prep. Method

Example HPLC RT LC-MS LC-MS

Structure Chemical name of Example Number (min) [M+H]⁺ Method

No.

6-(4-fluorophenoxy)-3-{[(3R)-1 -

159 isopropylpiperidin-3-yl]methyl}-2-(2- 2.81 486.3 20 methylphenyl)quinazolin-4(3H)-one

6-(4-fluorophenoxy)-3-{[(3S)-1 -

160 isopropylpiperidin-3-yl]methyl}-2-(2- 2.60 486.4 20 methylphenyl)quinazolin-4(3H)-one

Prep. Method

Example HPLC RT LC-MS LC-MS

Structure Chemical name of Example Number (min) [M+H]⁺ Method

No.

6-[(4-fluorophenyl)(propyl)amιno]-3-[(1-

173 ιsopropylpιperιdιn-3-yl)methyl]-2-(2- 2 91 527.5 27 methylphenyl)quιnazolιn-4(3H)-one

6-[(4-fluorophenyl)(pentyl)amιno]-3-[(1 -

174 ιsopropylpιperιdιn-3-yl)methyl]-2-(2- 2 93 555.3 27 methylphenyl)quιnazolιn-4(3H)-one

Prep. Method

Example HPLC RT LC-MS LC-MS

Structure Chemical name of Example Number (min) [WkH]⁺ Method

No.

2-[4-(benzyloxy)phenyl]-6-(4-

177 fluorophenoxy)-3-(piperidin-3- 2.98 536.2 30 ylmethyl)quinazolin-4(3H)-one

6-(4-fluoro-2-methylphenoxy)-2-(2-

178 methoxyphenyl)-3-(piperidin-3- 2.71 474.3 30 ylmethyl)quinazolin-4(3H)-one

Prep. Method

Example HPLC RT LC-MS LC-MS

Structure Chemical name of Example Number (min) [M+H]⁺ Method

No.

3-{[1 -(2-fluoroethyl)piperidin-3-yl]methyl}

181 6-(4-fluorophenoxy)-2- 2.73 442.4 30, 7

isopropylquinazolin-4(3H)-one

2-[2-(difluoromethoxy)phenyl]-6-(4-

182 fluorophenoxy)-3-[(1-isopropylpiperidin-3 2.65 538.5 30, 7 yl)methyl]quina2olin-4(3H)-one

Prep. Method

Example HPLC RT LC-MS LC-WIS

Structure Chemical name of Example Number (min) [M+H]⁺ Method

No.

6-{4-f luorophenoxy)-3-[(1 -

183 isopropylpiperidin-3-yl)methyl]-2-(2- 2.92 486.4 30, 7 methylphenyl)quinazolin-4(3H)-one

2-[4-(benzyloxy)phenyl]-6-(4-

184 fluorophenoxy)-3-[(1 -isopropylpiperidin-3 3.06 578.5 31 yl)methyl]quiπazolin-4(3H)-one

Prep. Method

Example HPLC RT LC-MS LC-MS

Structure Chemical name of Example Number (min) [M+H]⁺ Method

No.

6-(2-ethylphenoxy)-3-[(1 -

191 isopropylpiperidin-3-yl)methyl]-2-(2- 2.76 512.3 34 methoxyphenyl)quinazolin-4(3H)-one

6-(5-chloro-2-methylphenoxy)-3-[(1 -

192 isopropylpiperidin-3-yl)methyl]-2-(2- 2.81 532.3 34 methoxyphenyl)quinazolin-4(3H)-one

Prep. Method

Example HPLC RT LC-MS LC-MS

Structure Chemical name of Example Number (min) [M+H]⁺ Method

No.

6-(cyclopropylmethoxy)-2-isopropyl-3-

203 {[(3S)-1 -isopropylpiperidin-3- 2.25 398.4 35 yl]methyl}quinazolin-4(3H)-one

6-(2,2-difluoroethoxy)-2-isopropyl-3-

204 {[(3S)-1 -isopropylpiperidin-3- 2.56 408.4 35 yl]methyl}quinazolin-4(3H)-one

Prep. Method

Example HPLC RT LC-MS LC-MS

Structure Chemical name of Example Number (min) [M₊H]⁺ Method

No.

3-{[(3S)-1-cyclobutylpiperidin-3-

221 yl]methyl}-6-(4-fluorophenyl)-2- 2.23 434.4 39, 44 isopropylquinazolin-4(3H)-one

6-(2-chlorophenyl)-3-[(1 -

222 cyclobutylpiperidin-3-yl)methyl]-2- 3.00 450.4 39, 44 isopropylquinazolin-4(3H)-one

Prep. Method

Example HPLC RT LC-MS LC-MS

Structure Chemical name of Example Number (min) [M+H]⁺ Method

No.

6-(4-chlorophenyl)-3-{[(3S)-1 -

223 ethylpiperidin-3-yl]methyl}-2-(2- 3.25 472.4 39, 41 methylphenyl)quinazolin-4(3H)-one

6-(4-chlorophenyl)-3-{[1 -

224 (cyclopropylmethylJpiperidin-S-ylJmethyl} 3.12 498.4 39, 41 2-(2-methylphenyl)quinazolin-4(3H)-one

Prep. Method

Example HPLC RT LC-MS LC-MS

Structure Chemical name of Example Number (min) [M+H]* Method

No.

6-(2,4-difluorophenyl)-2-(2-

227 methoxyphenyl)-3-[(3S)-piperidin-3- 2.62 462.2 43 ylmelhyl]quinazolin-4(3H)-one

6-(4-fluorophenyl)-2-(2-methoxyphenyl)-

228 3-(piperidin-3-ylmethyl)quinazolin-4(3H)- 2.48 444.1 43 one trifluoroacelate

Prep. Method

Example HPLC RT LC-MS LC-MS

Structure Chemical name of Example Number (min) [M+H]⁺ Method

No.

3-{[(3R)-1 -cyclobutylpιpeπdιn-3-

303 yl]methyl}-2-(2-methoxyphenyl)-6- 2 56 480 3 43, 44 phenylquιnazolιn-4(3H)-one

3-{[(3R)-1-cyclopentylpιperιdιn-3-

304 yl]methyl}-2-(2-methoxyphenyl)-6- 2 62 494 3 43, 44 phenylquιnazolιn-4(3H)-one

Example HPLC RT LC-MS Prep. Method

LC-MS

Structure Chemical name of Example Number (min) [M+H]⁺ Method

No.

2-isopropyl-3-{[(3S)-1-isopropylpiperidin-

335 3-yl]methyl}-6-(3- 2.70 418.3 46, 47 methylphenyl)quinazolin-4(3H)-one

3-{[(3S)-1-(2-fluoroethyl)piperidin-3-

336 yl]methyl}-6-(4-fluorophenyl)-2- 2.57 426.3 46, 47 isopropylquinazolin-4(3H)-one

Prep. Method

Example HPLC RT LC-MS LC-MS

Structure Chemical name of Example Number (min) [M+H]⁺ Method

No.

3-[(1-cyclobutylpiperidin-3-yl)methyl]-2-

415 (2-methoxyphenyl)-6-(3- 2.99 510.4 52 methoxyphenyl)quinazolin-4(3H)-one

3-[(1-cyclobutylpiperidin-3-yl)methyl]-2-

416 (2-methoxyphenyl)-6-(4- 2.97 510.4 52 methoxyphenyl)quinazolin-4(3H)-one

Prep. Method

Example HPLC RT LC-MS LC-MS

Structure Chemical name of Example Number (min) [M+H]⁺ Method

No.

3-[(1 -cyclobutylpiperidin-3-yl)methyl]-6-

417 (3,4-difluorophenyl)-2-(2- 3.05 516.4 52 methoxyphenyl)quinazolin-4(3H)-one

3-[(1 -cyclobutylpiperidin-3-yl)methyl]-6-

418 (3,5-difluorophenyl)-2-(2- 3.06 516.4 52 methoxyphenyl)quinazolin-4(3H)-one

Prep. Method

Example HPLC RT LC-MS LC-MS

Structure Chemical name of Example Number (min) [M+H]⁺ Method

No.

6-(3-chloro-4-fluorophenyl)-3-[(1 -

419 cyclobutylpiperidin-3-yl)methyl]-2-(2- 3.16 532.4 52 methoxyphenyl)quinazolin-4(3H)-one

3-[(1 -cyclobutylpiperidin-3-yl)methyl]-6-

420 (3-fluoro-4-methoxyphenyl)-2-(2- 2.98 528.4 52 methoxyphenyl)quinazolin-4(3H)-one

Prep. Method

Example HPLC RT LC-MS LC-MS

Structure Chemical name of Example Number (min) [M+H]⁺ Method

No.

3-{[1-(2-methoxyethyl)piperidin-3-

425 yl]methyl}-2-(2-methoxyphenyl)-6-(3- 2.50 514.3 52 methoxyphenyl)quinazolin-4(3H)-one

3-{[1-(2-methoxyethyl)piperidin-3-

426 yl]methyl}-2-(2-methoxyphenyl)-6-(4- 2.50 514.2 52 methoxyphenyl)quinazolin-4(3H)-one

Prep. Method

Example HPLC RT LC-MS LC-MS

Structure Chemical name of Example Number (min) [M₊H]⁺ Method

No.

6-(3-chloro-4-fluorophenyl)-3-{[1 -(1 -

441 ethylpropyl)piperidin-3-yl]methyl}-2-(2- 3.20 548.4 52 methoxyphenyl)quinazolin-4(3H)-one

6-(4-ethoxyphenyl)-3-{[1 -(1 -

442 elhylpropyl)piperidin-3-yl]methyl}-2-(2- 3.15 540.4 52 methoxyphenyl)quinazolin-4(3H)-one

Prep. Method

Example HPLC RT LC-MS LC-MS

Structure Chemical name of Example Number (min) [M₊H]⁺ Method

No.

3-[(1-cyclopentylpiperidin-3-yl)methyl]-2-

443 (2-methoxyphenyl)-6-(3- 3.02 524.4 52 methoxyphenyl)quinazolin-4(3H)-one

3-[(1-cyclopentylpiperidin-3-yl)methyl]-2-

444 (2-methoxyphenyl)-6-(4- 2.99 524.4 52 methoxyphenyl)quinazolin-4(3H)-one

Prep. Method

Example HPLC RT LC-MS LC-MS

Structure Chemical name of Example Number (min) [M+H]⁺ Method

No.

3-[( 1 -cyclopentylpipeιϊdin-3-yl)methyl]-6-

445 (3,4-difluorophenyl)-2-(2- 3.11 530.4 52 methoxyphenyl)quinazolin-4(3H)-one

3-[(1 -isopropylpiperidin-3-yl)methyl]-2-(2

446 methoxyphenyl)-6-(3- 2.94 498.4 52 methoxyphenyl)quinazolin-4(3H)-one

Prep. Method

Example HPLC RT LC-MS LC-MS

Structure Chemical name of Example Number (min) [M+H]⁺ Method

No.

6-(3-chloro-4-fluorophenyl)-3-[(1 -

457 cyclopentylpiperidin-3-yl)methyl]-2-(2- 3.20 546.4 52 methoxyphenyl)quinazolin-4(3H)-one

6-(3,4-difluorophenyl)-3-[(1 -

458 isopropylpiperidin-3-yl)methyl]-2-(2- 3.01 504.4 52 methoxyphenyl)quinazolin-4(3H)-one

Prep. Method

Example HPLC RT LC-MS LC-MS

Structure Chemical name of Example Number (min) [M₊H]⁺ Method

No.

6-(2,3-dihydro-1 -benzofuran-5-yl)-2-

539 isopropyl-3-{[(3S)-1-isopropylpiperidin-3- 2.98 446.3 54 yl]methyl}quinazolin-4(3H)-one

2-isopropyl-3-{[(3S)-1 -isopropylpiperidin-

540 3-yl]methyl}-6-(4- 3.08 418.3 54 methylphenyl)quinazolin-4(3H)-one

Prep. Method

Example HPLC RT LC-MS LC-MS

Structure Chemical name of Example Number (min) [M+H]⁺ Method

No.

3-{[(3S)-1-cyclobutylpiperidin-3-

547 yl]methyl}-6-(4-fluorophenyl)-2- 2.33 406.3 54 methylquinazolin-4(3H)-one

3-{[(3S)-1 -cyclobulylpiperidin-3-

548 yl]methyl}-6-(2,5-dichlorophenyl)-2- 2.57 456.2 54 methylquinazolin-4(3H)-one

Prep. Method

Example HPLC RT LC-MS LC-MS

Structure Chemical name of Example Number (min) [M₊H]⁺ Method

No.

6-(2,3-dichlorophenyl)-3-{[(3S)-1-

607 ethylpiperidin-3-yl]methyl}-2- 2.47 430.2 57 methylquinazolin-4(3H)-one

6-(2,4-dichlorophenyl)-3-{[(3S)-1-

608 ethylpiperidin-3-yl]methyl}-2- 2.51 430.2 57 methylquinazolin-4(3H)-one

Prep. Method

Example HPLC RT LC-MS LC-MS

Structure Chemical name of Example Number (min) [M+H]⁺ Method

No.

6-(3-chloro-2-fluorophenyl)-3-{[(3S)-1-

609 ethylpiperidin-3-yl]methyl}-2- 2.39 414.2 57 methylquinazolin-4(3H)-one

6-(5-chloro-2-fluorophenyl)-3-{[(3S)-1 -

610 ethylpipeιϊdin-3-yl]methyl}-2- 2.38 414.2 57 methylquinazolin-4(3H)-one

Prep. Method

Example HPLC RT LC-MS LC-MS

Structure Chemical name of Example Number (min) [M+H]⁺ Method

No.

3-{[(3S)-1-ethylpiperidin-3-yl]methyl}-6-

613 (4-fluoro-3-methylphenyl)-2- 2.66 422.3 57 isopropylquinazolin-4(3H)-one

6-(3,4-dichlorophenyl)-3-{[(3S)-1-

614 ethylpiperidin-3-yl]methyl}-2- 2.83 458.3 57 isopropylquinazolin-4(3H)-one

Prep. Method

Example HPLC RT LC-MS LC-MS

Structure Chemical name of Example Number (min) [M₊H]⁺ Method

No.

6-(3,5-dichlorophenyl)-3-{[(3S)-1-

615 ethylpiperidin-3-yl]methyl}-2- 2.57 430.2 57 methylquinazolin-4(3H)-one

6-(3-chloro-4-fluorophenyl)-3-{[(3S)-1 -

616 ethylpiperidin-3-yl]methyl}-2- 2.42 414.2 57 methylquinazolin-4(3H)-one

Prep. Method

Example HPLC RT LC-MS LC-MS

Structure Chemical name of Example Number (min) [M₊H]⁺ Method

No.

6-(3-chlorophenyl)-3-{[(3S)-1 -

617 ethylpiperidin-3-yl]methyl}-2- 2.38 396.3 57 methylquinazolin-4(3H)-one

6-(4-chloro-3-methylphenyl)-3-{[(3S)-1-

618 ethylpiperidin-3-yl]methyl}-2- 2.83 438.4 57 isopropylquinazolin-4(3H)-one

Prep. Method

Example HPLC RT LC-MS LC-MS

Structure Chemical name of Example Number (min) [M+H]⁺ Method

No.

6-(4-chloro-3-methylphenyl)-3-{[(3S)-1 -

619 ethylpiperidin-3-yl]methyl}-2- 2.97 410.4 57

methylquinazolin-4(3H)-one

6-(3,4-dichlorophenyl)-3-{[(3S)-1 -

620 ethylpiperidin-3-yl]methyl}-2- 2.95 430.5 57

methylquinazolin-4(3H)-one

Prep. Method

Example HPLC RT LC-MS LC-MS

Structure Chemical name of Example Number (min) [M+H]⁺ Method

No.

2-[4-(difluoromethoxy)phenyl]-3-[(1-

653 ethylpiperidin-3-yl)methyl]-6-(4- 2.79 508.2 60 fluorophenyl)quinazolin-4(3H)-one

2-[4-(difluoromethoxy)phenyl]-3-[(1 -

654 ethylpiperidin-3-yl)methyl]-6-(3- 2.81 508.2 60 fluorophenyl)quinazolin-4(3H)-one

Prep. Method

Example HPLC RT LC-MS LC-MS

Structure Chemical name of Example Number (min) [M+H]⁺ Method

No.

6-(4-fluorophenyl)-3-{[(3S)-1 -

655 isopropylpiperidin-3-yl]methyl}-2- 2.68 448.2 62

(trifluoromethyl)quinazolin-4(3H)-one

6-(2-fluorophenyl)-3-{[(3S)-1 -

656 isopropylpiperidin-3-yl]methyl}-2- 2.65 448.2 62

(trifluoromethyl)quinazolin-4(3H)-one

Prep. Method

Example HPLC RT LC-MS LC-MS

Structure Chemical name of Example Number (min) [M₊H]⁺ Method

No.

6-[3-chloro-4-(trifluoromethyl)phenyl]-3-

691 {[(3S)-1-isopropylpiperidin-3-yl]methyl}-2 2.69 478.2 65 methylquinazolin-4(3H)-one

6-[3-chloro-4-(trifluoromethyl)phenyl]-2-

692 ethyl-3-{[(3S)-1-isopropylpiperidin-3- 2.85 492.3 65 yl]methyl}quinazolin-4(3H)-one

Prep. Method

Example HPLC RT LC-MS LC-WIS

Structure Chemical name of Example Number (min) [M+H]⁺ Method

No.

6-[4-chloro-3-(trifluoromethyl)phenyl]-3-

705 {[(3S)-1-isopropylpiperidin-3-yl]methyl}-2 2.64 478.3 65 methylquinazolin-4(3H)-one

6-(2,3-dichlorophenyl)-3-{[(3S)-1-

706 isopropylpiperidin-3-yl]methyl}-2- 2.48 444.2 65 methylquinazolin-4(3H)-one

Prep. Method

Example HPLC RT LC-MS LC-MS

Structure Chemical name of Example Number (min) [M+H]⁺ Method

No.

6-(3-chloro-2-fluorophenyl)-3-{[(3S)-1 -

711 isopropylpiperidiπ-3-yl]methyl}-2- 2.46 428.3 65 methylquinazoliπ-4(3H)-one

6-(5-chloro-2-fluorophenyl)-3-{[(3S)-1 -

712 isopropylpiperidin-3-yl]methyl}-2- 2.50 428.3 65 methylquinazolin-4(3H)-one

Prep. Method

Example HPLC RT LC-MS LC-MS

Structure Chemical name of Example Number (min) [M+H]⁺ Method

No.

6-(4-chloro-3-methylphenyl)-3-{[(3S)-1 -

719 isopropylpiperidin-3-yl]methyl}-2- 2.65 424.3 65 methylquinazolin-4(3H)-one

6-(3,5-dimethylphenyl)-3-{[(3S)-1 -

720 isopropylpiperidin-3-yl]methyl}-2- 2.56 404.3 65 methylquinazolin-4(3H)-one

Prep. Method

Example HPLC RT LC-MS LC-MS

Structure Chemical name of Example Number (min) [M+H]⁺ Method

No.

6-(3-chloro-4-fluorophenyl)-2-ethyl-3-

729 {[(3S)-1-isopropylpiperidin-3- 2.60 442.3 65 yl]methyl}quinazolin-4(3H)-one

3-{[(3S)-1-isopropylpiperidin-3-yl]methyl}

730 2-methyl-6-(2,4,5- 2.42 430.2 65 trifluorophenyl)quinazolin-4(3H)-one

Prep. Method

Example HPLC RT LC-MS LC-MS

Structure Chemical name of Example Number (min) [M+H]⁺ Method

No.

3-{[(3S)-1 -ιsopropylpιperιdιn-3-yl]methyl}

731 2-methyl-6-(2,3,4- 2 44 430 2 65 tπfluorophenyl)quιnazolιn-4(3H)-one

6-(2,3-dιfluorophenyl)-3-{[(3S)-1 -

732 ιsopropylpιperιdιn-3-yl]methyl}-2- 2 37 412 2 65 methylquιnazolιn-4(3H)-one

Prep. Method

Example HPLC RT LC-MS LC-MS

Structure Chemical name of Example Number (min) [M+H]⁺ Method

No.

3-{[(3S)-1 -isopropylpiperidin-3-yl]methyl}

733 2-methyl-6-(2,4,6- 2.38 430.2 65 trifluorophenyl)quinazolin-4(3H)-one

6-(2,6-difluorophenyl)-3-{[(3S)-1-

734 isopropylpiperidin-3-yl]methyl}-2- 2.32 412.2 65 methylquinazolin-4(3H)-one

Prep. Method

Example HPLC RT LC-MS LC-MS

Structure Chemical name of Example Number (min) [M₊H]⁺ Method

No.

6-(3-chloro-4-methylphenyl)-3-{[(3S)-1-

739 isopropylpiperidin-3-yl]methyl}-2- 2.57 424.3 65 methylquinazolin-4(3H)-one

2-ethyl-6-(4-fluoro-3-methylphenyl)-3-

740 {[(3S)-1 -isopropylpiperidin-3- 2.45 422.3 65 yl]methyl}quinazolin-4(3H)-one

Prep. Method

Example HPLC RT LC-MS LC-MS

Structure Chemical name of Example Number (min) [M+H]⁺ Method

No.

6-(4-chloro-3-fluorophenyl)-2-ethyl-3-

749 {[(3S)-1 -isopropylpiperidin-3- 2.62 442.3 65 yl]melhyl}quinazolin-4(3H)-one

6-(4-chlorophenyl)-3-{[(3S)-1 -

750 isopropylpiperidin-3-yl]methyl}-2- 2.66 438.3 65 propylquinazolin-4(3H)-one

Prep. Method

Example HPLC RT LC-MS LC-MS

Structure Chemical name of Example Number (min) [M₊H]⁺ Method

No.

6-(3,4-dichlorophenyl)-2-(2-

763 methoxyphenyl)-3-(piperidin-3- 3.13 494.3 69 ylmethyl)quinazolin-4(3H)-one

6-(3-fluoro-4-methylphenyl)-2-(2-

764 methoxyphenyl)-3-(piperidin-3- 3.00 458.4 69 ylmethyl)quinazolin-4(3H)-one

Prep. Method

Example HPLC RT LC-MS LC-MS

Structure Chemical name of Example Number (min) [M+H]⁺ Method

No.

2-(2-methoxyphenyl)-6-(3-

767 methoxyphenyl)-3-(piperidin-3- 2.86 456.3 69 ylmethyl)quinazolin-4(3H)-one

6-(3-chloro-4-fluorophenyl)-2-(2-

768 methoxyphenyl)-3-(piperidin-3- 3.03 478.3 69 ylmethyl)quinazolin-4(3H)-one

Prep. Method

Example HPLC RT LC-MS LC-MS

Structure Chemical name of Example Number (min) [M+H]⁺ Method

No.

6-(4-chlorophenyl)-2-(cyclopropylmethyl)

783 3-{[(3S)-1 -isopropylpiperidin-3- 3.09 450.5 71 yl]methyl}quinazolin-4(3H)-one

6-ethyl-3-[(1 -ethylpiperidin-3-yl)methyl]-2

784 (2-methoxyphenyl)quinazolin-4(3H)-one 2.13 406.3 73 trifluoroacetate

^OH

Prep. Method

Example HPLC RT LC-MS LC-MS

Structure Chemical name of Example Number (min) [M₊H]⁺ Method

No.

2-[4-(difluoromethoxy)phenyl]-6-(4-

829 fluorophenyl)-3-[(1 -isopropylpiperidin-3- 2.78 522.5 78 yl)methyl]quinazolin-4(3H)-one

2-[4-(difluorome(hoxy)phenyl]-6-(3-

830 fluorophenyl)-3-[(1-isopropylpiperidin-3- 2.79 522.5 78 yl)methyl]quinazolin-4(3H)-one

Prep. Method

Example HPLC RT LC-MS LC-MS

Structure Chemical name of Example Number (min) [M₊H]⁺ Method

No.

2-[4-(difluoromethoxy)phenyl]-6-(1 H-

833 indol-5-yl)-3-[(1 -isopropylpiperidin-3- 2.72 543.5 78 yl)methyl]quinazolin-4(3H)-one

2-[4-(difluoromethoxy)phenyl]-6-(3,4-

834 difluorophenyl)-3-[(1 -isopropylpiperidin-3 2.Θ2 540.5 78 yl)methyl]quinazolin-4(3H)-one

Prep. Method

Example HPLC RT LC-MS LC-MS

Structure Chemical name of Example Number (min) [M₊H]⁺ Method

No.

6-[(E)-2-(4-fluorophenyl)vinyl]-2-

841 isopropyl-3-{[(3S)-1 -isopropylpiperidin-3- 3.15 448.3 83 yl]methyl}quinazolin-4(3H)-one

6-[(E)-2-(4-chlorophenyl)vinyl]-2-

842 isopropyl-3-{[(3S)-1-isopropylpiperidin-3- 3.28 464.2 83 yl]methyl}quinazolin-4(3H)-one

Prep. Method

Example HPLC RT LC-MS LC-MS

Structure Chemical name of Example Number (min) [M+H]⁺ Method

No.

2-[2-fluoro-4-(2-hydroxyethoxy)phenyl]-6

865 (3-methoxyphenyl)-3-(pipeιϊdin-3- 2.84 504.3 104 ylmethyl)quinazolin-4(3H)-one

2-[2-fluoro-4-(2-hydroxyethoxy)phenyl]-6

866 (3-fluorophenyl)-3-(piperidin-3- 2.93 492.4 104 ylmethyl)quinazolin-4(3H)-one

Methods Of Use

[564] As used herein, various terms are defined below.

[565] When introducing elements of the present invention or the preferred embodiment(s) thereof, the articles "a," "an," "the," and "said" are intended to mean that there are one or more of the elements. The terms "comprising," "including," and "having" are intended to be inclusive and mean that there may be additional elements other than the listed elements.

[566] The term "subject" as used herein includes mammals (e.g., humans and animals).

[567] The term "treatment" includes any process, action, application, therapy, or the like, wherein a subject, including a human being, is provided medical aid with the object of improving the subject's condition, directly or indirectly, or slowing the progression of a condition or disorder in the subject.

[568] The term "combination therapy" or "co-therapy" means the administration of two or more therapeutic agents to treat a disease and/or disorder. Such administration encompasses co¬ administration of two or more therapeutic agents in a substantially simultaneous manner, such as in a single capsule having a fixed ratio of active ingredients or in multiple, separate capsules for each inhibitor agent. In addition, such administration encompasses use of each type of therapeutic agent in a sequential manner.

[569] The phrase "therapeutically effective" means the amount of each agent administered that will achieve the goal of improvement in an obese condition or disorder severity, while avoiding or minimizing adverse side effects associated with the given therapeutic treatment.

[570] The term "pharmaceutically acceptable" means that the subject item is appropriate for use in a pharmaceutical product.

[571] The compounds of Formula (I) are expected to be valuable as therapeutic agents. Accordingly, an embodiment of this invention includes a method of treating the various conditions in a patient (including mammals) which comprises administering to said patient a composition containing an amount of the compound of Formula (I) that is effective in treating the target condition.

[572] The compounds of the present invention may be employed in the treatment of diabetes, including both type 1 and type 2 diabetes (non-insulin dependent diabetes mellitus). Such treatment may also delay the onset of diabetes and diabetic complications. The compounds may be used to prevent subjects with impaired glucose tolerance from proceeding to develop type 2 diabetes. Other diseases and conditions that may be treated or prevented using compounds of the invention in methods of the invention include: Maturity-Onset Diabetes of the Young (MODY) (Herman, et al., Diabetes 43:40, 1994); Latent Autoimmune Diabetes Adult (LADA) (Zimmet, et al., Diabetes Med. 11 :299, 1994); impaired glucose tolerance (IGT) (Expert Committee on Classification of Diabetes Mellitus, Diabetes Care 22 (Supp. 1):S5, 1999); impaired fasting glucose (IFG) (Charles, et al., Diabetes 40:796, 1991); gestational diabetes (Metzger, Diabetes, 40:197, 1991 ); and metabolic syndrome X.

[573] This invention also relates to compounds that may be useful for the regulation of food intake (e.g., stimulation and suppression). For example, an object of this invention is to provide methods for treating obesity and inducing weight loss in an individual by administration of a compound of the invention. The method of the invention comprises administering to an individual a therapeutically effective amount of at least one compound of the invention, or a prodrug thereof, which is sufficient to improve glucose homeostasis and/or induce weight loss. The invention further comprises a method of preventing weight gain in an individual by administering an amount of at least one compound of the invention, or a prodrug thereof, which is sufficient to prevent weight gain.

[574] The present invention also relates to the use of the compounds of this invention for the treatment of diabetes, obesity and related diseases including associated dyslipidemia and other diabetes and/or obesity- and overweight-related complications such as, for example, cholesterol gallstones, gallbladder disease, gout, cancer (e.g., colon, rectum, prostate, breast, ovary, endometrium, cervix, gallbladder, and bile duct), menstrual abnormalities, infertility, polycystic ovaries, osteoarthritis, and sleep apnea, as well as for a number of other pharmaceutical uses associated therewith, such as the regulation of appetite and food intake, dyslipidemia, hypertriglyceridemia, Syndrome X, , atherosclerotic diseases such as heart failure, hyperlipidemia, hypercholesteremia, low HDL levels, hypertension, cardiovascular disease (including atherosclerosis, coronary heart disease, coronary artery disease, and hypertension), cerebrovascular disease such as stroke, and peripheral vessel disease. The compounds of this invention may also be useful for treating physiological disorders related to, for example, regulation of insulin sensitivity, inflammatory response, plasma triglycerides, HDL, LDL and cholesterol levels and the like.

[575] Another embodiment of the present invention is to provide compounds which are useful for the treatment of wasting (e.g., cachexia) associated with various diseases or conditions, for example, wasting associated with cancer, AIDS, chronic liver disease, chronic obstructive pulmonary disease (COPD) or respiratory insufficiency, as well as wasting associated with bone fractures or with aging.

[576] Compounds of Formula (I) may be administered alone or in combination with one or more additional therapeutic agents. Combination therapy includes administration of a single pharmaceutical dosage formulation which contains a compound of Formula (I) and one or more additional therapeutic agents, as well as administration of the compound of Formula (I) and each additional therapeutic agents in its own separate pharmaceutical dosage formulation. For example, a compound of Formula (I) and a therapeutic agent may be administered to the patient together in a single oral dosage composition such as a tablet or capsule, or each agent may be administered in separate oral dosage formulations. [577] Where separate dosage formulations are used, the compound of Formula (I) and one or more additional therapeutic agents may be administered at essentially the same time (e.g., concurrently) or at separately staggered times (e.g., sequentially).

[578] For example, the compound of Formula (I) may be used in combination with other therapies and drugs useful for the treatment of obesity and diabetes. For example, anti-obesity drugs include β-3 agonists such as CL 316,243; cannabinoid (e.g., CB-1) antagonists, such as, for example, rimonabant (Acomplia); neuropeptide Y5 inhibitors; appetite suppressants, such as, for example, sibutramine (Meridia); and lipase inhibitors, such as, for example, orlistat (Xenical). The compounds of the present invention may also be administered in combination with a drug compound that modulates digestion and/or metabolism such as drugs that modulate thermogenesis, lipolysis, gut motility, fat absorption, and satiety.

[579] In addition, the compound of Formula (I) may be administered in combination with one or more of the following agents for the treatment of diabetes or diabetes-related disorders including PPAR ligands (agonists, antagonists), insulin secretagogues, for example, sulfonylurea drugs and non-sulfonylurea secretagogues, α-glucosidase inhibitors, insulin sensitizers, hepatic glucose output lowering compounds, and insulin and insulin derivatives. Such therapies may be administered prior to, concurrently with, or following administration of the compounds of the invention. Insulin and insulin derivatives include both long and short acting forms and formulations of insulin. PPAR ligands may include agonists and/or antagonists of any of the PPAR receptors or combinations thereof. For example, PPAR ligands may include ligands of PPAR-α, PPAR-γ, PPAR-δ or any combination of two or three of the receptors of PPAR. PPAR ligands include, for example, rosiglitazone, troglitazone, and pioglitazone. Sulfonylurea drugs include, for example, glyburide, glimepihde, chlorpropamide, tolbutamide, and glipizide. α-Glucosidase inhibitors that may be useful in treating diabetes when administered with a compound of the invention include acarbose, miglitol, and voglibose. Insulin sensitizers that may be useful in treating diabetes include PPAR-γ agonists such as the glitazones (e.g., troglitazone, pioglitazone, englitazone, MCC-555, rosiglitazone, and the like) and other thiazolidinedione and non-thiazolidinedione compounds; biguanides such as metformin and phenformin; protein tyrosine phosphatase-1 B (PTP-1 B) inhibitors; dipeptidyl peptidase IV (DPP-IV) inhibitors, and 11 beta-HSD inhibitors. Hepatic glucose output lowering compounds that may be useful in treating diabetes when administered with a compound of the invention include glucagon anatgonists and metformin, such as Glucophage and Glucophage XR. Insulin secretagogues that may be useful in treating diabetes when administered with a compound of the invention include sulfonylurea and non- sulfonylurea drugs: GLP-1 , GIP, PACAP, secretin, and derivatives thereof; nateglinide, meglitinide, repaglinide, glibenclamide, glimepiride, chlorpropamide, glipizide. GLP-1 includes derivatives of GLP-1 with longer half-lives than native GLP-1 , such as, for example, fatty-acid derivatized GLP-1 and exendin.

[580] Compounds of the invention may also be used in methods of the invention in combination with drugs commonly used to treat lipid disorders in patients. Such drugs include, but are not limited to, HMG-CoA reductase inhibitors, nicotinic acid, fatty acid lowering compounds (e.g., acipimox); lipid lowering drugs (e.g., stanol esters, sterol glycosides such as tiqueside, and azetidinones such as ezetimibe), ACAT inhibitors (such as avasimibe), bile acid sequestrants, bile acid reuptake inhibitors, microsomal triglyceride transport inhibitors, and fibric acid derivatives. HMG-CoA reductase inhibitors include, for example, lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rivastatin, itavastatin, cerivastatin, and ZD-4522. Fibric acid derivatives include, for example, clofibrate, fenofibrate, bezafibrate, ciprofibrate, beclofibrate, etofibrate, and gemfibrozil. Sequestrants include, for example, cholestyramine, colestipol, and dialkylaminoalkyl derivatives of a cross-linked dextran.

[581] Compounds of the invention may also be used in combination with anti-hypertensive drugs, such as, for example, β-blockers and ACE inhibitors. Examples of additional anti¬ hypertensive agents for use in combination with the compounds of the present invention include calcium channel blockers (L-type and T-type; e.g., diltiazem, verapamil, nifedipine, amlodipine and mybefradil), diuretics (e.g., chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide, bendroflumethiazide, methylchlorothiazide, trichloromethiazide, polythiazide, benzthiazide, ethacrynic acid tricrynafen, chlorthalidone, furosemide, musolimine, bumetanide, thamtrenene, amiloride, spironolactone), renin inhibitors, ACE inhibitors (e.g., captopril, zofenopril, fosinopril, enalapril, ceranopril, cilazopril, delapril, pentopril, quinapril, ramipril, lisinopril), AT-1 receptor antagonists (e.g., losartan, irbesartan, valsartan), ET receptor antagonists (e.g., sitaxsentan, atrsentan, neutral endopeptidase (NEP) inhibitors, vasopepsidase inhibitors (dual NEP-ACE inhibitors) (e.g., omapathlat and gemopatrilat), and nitrates.

[582] The compound of Formula (I) may also be utilized, in free base form or in compositions, as well as in research and diagnostics or as analytical reference standards, and the like, which are well known in the art. Therefore, the present invention includes compositions which are comprised of an inert carrier and an effective amount of a compound of Formula (I), or a salt, or ester thereof. An inert carrier is any material which does not interact with the compound to be carried and which lends support, means of conveyance, bulk, traceable material, and the like to the compound to be carried. An effective amount of the compound is that amount which produces a result or exerts an influence on the particular procedure being performed.

[583] It is anticipated that prodrug forms of the compounds of this invention will prove useful in certain circumstances, and such compounds are also intended to fall within the scope of the invention. Prodrug forms may have advantages over the parent compounds exemplified herein, in that they are better absorbed, better distributed, more readily penetrate the central nervous system, are more slowly metabolized or cleared, etc. Prodrug forms may also have formulation advantages in terms of crystallinity or water solubility. For example, compounds of the invention having one or more hydroxyl groups may be converted to esters or carbonates bearing one or more carboxyl, hydroxyl or amino groups, which are hydrolyzed at physiological pH values or are cleaved by endogenous esterases or lipases in vivo (see, e.g., U.S. Patent Nos. 4,942,184; 4,960,790; 5,817,840; and 5,824,701 , all of which are incorporated herein by reference in their entirety, and references therein).

Pharmaceutical Compositions

[584] Based on the above tests, or other well known assays used to determine the efficacy for treatment of conditions identified above in mammals, and by comparison of these results with the results of known medicaments that are used to treat these conditions, the effective dosage of the compounds of this invention can readily be determined for treatment of each desired indication. The amount of the active ingredient to be administered in the treatment of one of these conditions can vary widely according to such considerations as the particular compound and dosage unit employed, the mode of administration, the period of treatment, the age and sex of the patient treated, and the nature and extent of the condition treated.

[585] The total amount of the active ingredient to be administered may generally range from about 0.001 mg/kg to about 200 mg/kg, and preferably from about 0.01 mg/kg to about 200 mg/kg body weight per day. A unit dosage may contain from about 0.05 mg to about 1500 mg of active ingredient, and may be administered one or more times per day. The daily dosage for administration by injection, including intravenous, intramuscular, subcutaneous, and parenteral injections, and use of infusion techniques may be from about 0.01 to about 200 mg/kg. The daily rectal dosage regimen may be from 0.01 to 200 mg/kg of total body weight. The transdermal concentration may be that required to maintain a daily dose of from 0.01 to 200 mg/kg. Of course, the specific initial and continuing dosage regimen for each patient will vary according to the nature and severity of the condition as determined by the attending diagnostician, the activity of the specific compound employed, the age of the patient, the diet of the patient, time of administration, route of administration, rate of excretion of the drug, drug combinations, and the like. The desired mode of treatment and number of doses of a compound of the present invention or a pharmaceutically acceptable salt thereof may be ascertained by those skilled in the art using conventional treatment tests.

[586] The compounds of this invention may be utilized to achieve the desired pharmacological effect by administration to a subject in need thereof in an appropriately formulated pharmaceutical composition. A subject, for example, may be a mammal, including a human, in need of treatment for a particular condition or disease. Therefore, the present invention includes pharmaceutical compositions which are comprised of a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound identified by the methods described herein, or a pharmaceutically acceptable salt or ester thereof. A pharmaceutically acceptable carrier is any carrier which is relatively non-toxic and innocuous to a patient at concentrations consistent with effective activity of the active ingredient so that any side effects ascribable to the carrier do not vitiate the beneficial effects of the active ingredient. A pharmaceutically effective amount of a compound is that amount which produces a result or exerts an influence on the particular condition being treated. The compounds identified by the methods described herein may be administered with a pharmaceutically-acceptable carrier using any effective conventional dosage unit forms, including, for example, immediate and timed release preparations, orally, parenterally, topically, or the like.

[587] For oral administration, the compounds may be formulated into solid or liquid preparations such as, for example, capsules, pills, tablets, troches, lozenges, melts, powders, solutions, suspensions, or emulsions, and may be prepared according to methods known to the art for the manufacture of pharmaceutical compositions. The solid unit dosage forms may be a capsule which can be of the ordinary hard- or soft-shelled gelatin type containing, for example, surfactants, lubricants, and inert fillers such as lactose, sucrose, calcium phosphate, and corn starch.

[588] In another embodiment, the compounds of this invention may be tableted with conventional tablet bases such as lactose, sucrose, and cornstarch in combination with binders such as acacia, cornstarch, or gelatin; disintegrating agents intended to assist the break-up and dissolution of the tablet following administration such as potato starch, alginic acid, corn starch, and guar gum; lubricants intended to improve the flow of tablet granulation and to prevent the adhesion of tablet material to the surfaces of the tablet dies and punches, for example, talc, stearic acid, or magnesium, calcium or zinc stearate; dyes; coloring agents; and flavoring agents intended to enhance the aesthetic qualities of the tablets and make them more acceptable to the patient. Suitable excipients for use in oral liquid dosage forms include diluents such as water and alcohols, for example, ethanol, benzyl alcohol, and polyethylene alcohols, either with or without the addition of a pharmaceutically acceptable surfactant, suspending agent, or emulsifying agent. Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit. For instance tablets, pills or capsules may be coated with shellac, sugar or both.

[589] Dispersible powders and granules are suitable for the preparation of an aqueous suspension. They provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent, and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example, those sweetening, flavoring and coloring agents described above, may also be present.

[590] The pharmaceutical compositions of this invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil such as liquid paraffin or a mixture of vegetable oils. Suitable emulsifying agents may be (1) naturally occurring gums such as gum acacia and gum tragacanth, (2) naturally occurring phosphatides such as soy bean and lecithin, (3) esters or partial esters derived from fatty acids and hexitol anhydrides, for example, sorbitan monooleate, and (4) condensation products of said partial esters with ethylene oxide, for example, polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents.

[591] Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil such as, for example, arachis oil, olive oil, sesame oil, or coconut oil; or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent such as, for example, beeswax, hard paraffin, or cetyl alcohol. The suspensions may also contain one or more preservatives, for example, ethyl or n-propyl p-hydroxybenzoate; one or more coloring agents; one or more flavoring agents; and one or more sweetening agents such as sucrose or saccharin.

[592] Syrups and elixirs may be formulated with sweetening agents such as, for example, glycerol, propylene glycol, sorbitol, or sucrose. Such formulations may also contain a demulcent, and preservative, flavoring and coloring agents.

[593] The compounds of this invention may also be administered parenterally, that is, subcutaneously, intravenously, intramuscularly, or interperitoneally, as injectable dosages of the compound in a physiologically acceptable diluent with a pharmaceutical carrier which may be a sterile liquid or mixture of liquids such as water, saline, aqueous dextrose and related sugar solutions; an alcohol such as ethanol, isopropanol, or hexadecyl alcohol; glycols such as propylene glycol or polyethylene glycol; glycerol ketals such as 2,2-dimethyl-1 ,1-dioxolane-4- methanol, ethers such as poly(ethyleneglycol) 400; an oil; a fatty acid; a fatty acid ester or glyceride; or an acetylated fatty acid glyceride with or without the addition of a pharmaceutically acceptable surfactant such as a soap or a detergent, suspending agent such as pectin, carbomers, methycellulose, hydroxypropylmethylcellulose, or carboxymethylcellulose, or emulsifying agent and other pharmaceutical adjuvants.

[594] Illustrative of oils which can be used in the parenteral formulations of this invention are those of petroleum, animal, vegetable, or synthetic origin, for example, peanut oil, soybean oil, sesame oil, cottonseed oil, corn oil, olive oil, petrolatum, and mineral oil. Suitable fatty acids include oleic acid, stearic acid, and isostearic acid. Suitable fatty acid esters are, for example, ethyl oleate and isopropyl myristate. Suitable soaps include fatty alkali metal, ammonium, and triethanolamine salts and suitable detergents include cationic detergents, for example, dimethyl dialkyl ammonium halides, alkyl pyridinium halides, and alkylamine acetates; anionic detergents, for example, alkyl, aryl, and olefin sulfonates, alkyl, olefin, ether, and monoglyceride sulfates, and sulfosuccinates; nonionic detergents, for example, fatty amine oxides, fatty acid alkanolamides, and polyoxyethylenepolypropylene copolymers; and amphoteric detergents, for example, alkyl- beta-aminopropionates, and 2-alkylimidazoline quarternary ammonium salts, as well as mixtures.

[595] The parenteral compositions of this invention may typically contain from about 0.5% to about 25% by weight of the active ingredient in solution. Preservatives and buffers may also be used advantageously. In order to minimize or eliminate irritation at the site of injection, such compositions may contain a non-ionic surfactant having a hydrophile-lipophile balance (HLB) of from about 12 to about 17. The quantity of surfactant in such formulation ranges from about 5% to about 15% by weight. The surfactant can be a single component having the above HLB or can be a mixture of two or more components having the desired HLB.

[596] Illustrative of surfactants used in parenteral formulations are the class of polyethylene sorbitan fatty acid esters, for example, sorbitan monooleate and the high molecular weight adducts of ethylene oxide with a hydrophobic base, formed by the condensation of propylene oxide with propylene glycol.

[597] The pharmaceutical compositions may be in the form of sterile injectable aqueous suspensions. Such suspensions may be formulated according to known methods using suitable dispersing or wetting agents and suspending agents such as, for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethyl-cellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents which may be a naturally occurring phosphatide such as lecithin, a condensation product of an alkylene oxide with a fatty acid, for example, polyoxyethylene stearate, a condensation product of ethylene oxide with a long chain aliphatic alcohol, for example, heptadecaethyleneoxycetanol, a condensation product of ethylene oxide with a partial ester derived form a fatty acid and a hexitol such as polyoxyethylene sorbitol monooleate, or a condensation product of an ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride, for example polyoxyethylene sorbitan monooleate.

[598] The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent. Diluents and solvents that may be employed are, for example, water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally employed as solvents or suspending media. For this purpose, any bland, fixed oil may be employed including synthetic mono or diglycerides. In addition, fatty acids such as oleic acid may be used in the preparation of injectables.

[599] A composition of the invention may also be administered in the form of suppositories for rectal administration of the drug. These compositions may be prepared by mixing the drug with a suitable non-irritation excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such material are, for example, cocoa butter and polyethylene glycol.

[600] Another formulation employed in the methods of the present invention employs transdermal delivery devices ("patches"). Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds of the present invention in controlled amounts. The construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art (see, e.g., U.S. Patent No. 5,023,252, incorporated herein by reference). Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.

[601] Another formulation employs the use of biodegradable microspheres that allow controlled, sustained release of the compounds of this invention. Such formulations can be comprised of synthetic polymers or copolymers. Such formulations allow for injection, inhalation, nasal, or oral administration. The construction and use of biodegradable microspheres for the delivery of pharmaceutical agents is well known in the art (e.g., US Patent No. 6, 706,289, incorporated herein by reference). [602] It may be desirable or necessary to introduce the pharmaceutical composition to the patient via a mechanical delivery device. The construction and use of mechanical delivery devices for the delivery of pharmaceutical agents is well known in the art. For example, direct techniques for administering a drug directly to the brain usually involve placement of a drug delivery catheter into the patient's ventricular system to bypass the blood-brain barrier. One such implantable delivery system, used for the transport of agents to specific anatomical regions of the body, is described in U.S. Patent No. 5,011 ,472, incorporated herein by reference.

[603] The compositions of the invention may also contain other conventional pharmaceutically acceptable compounding ingredients, generally referred to as carriers or diluents, as necessary or desired. Any of the compositions of this invention may be preserved by the addition of an antioxidant such as ascorbic acid or by other suitable preservatives. Conventional procedures for preparing such compositions in appropriate dosage forms can be utilized.

[604] Commonly used pharmaceutical ingredients which may be used as appropriate to formulate the composition for its intended route of administration include: acidifying agents, for example, but are not limited to, acetic acid, citric acid, fumaric acid, hydrochloric acid, nitric acid; and alkalinizing agents such as, but are not limited to, ammonia solution, ammonium carbonate, diethanolamine, monoethanolamine, potassium hydroxide, sodium borate, sodium carbonate, sodium hydroxide, thethanolamine, troiamine.

[605] Other pharmaceutical ingredients include, for example, but are not limited to, adsorbents (e.g., powdered cellulose and activated charcoal); aerosol propellants (e.g., carbon dioxide, CCI₂F₂, F₂CIC-CCIF₂ and CCIF₃); air displacement agents (e.g., nitrogen and argon); antifungal preservatives (e.g., benzoic acid, butylparaben, ethylparaben, methylparaben, propylparaben, sodium benzoate); antimicrobial preservatives (e.g., benzalkonium chloride, benzethonium chloride, benzyl alcohol, cetylpyridinium chloride, chlorobutanol, phenol, phenylethyl alcohol, phenylmercuric nitrate and thimerosal); antioxidants (e.g., ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, hypophosphorus acid, monothioglycerol, propyl gallate, sodium ascorbate, sodium bisulfite, sodium formaldehyde sulfoxylate, sodium metabisulfite); binding materials (e.g., block polymers, natural and synthetic rubber, polyacrylates, polyurethanes, silicones and styrene-butadiene copolymers); buffering agents (e.g., potassium metaphosphate, potassium phosphate monobasic, sodium acetate, sodium citrate anhydrous and sodium citrate dihydrate); carrying agents (e.g., acacia syrup, aromatic syrup, aromatic elixir, cherry syrup, cocoa syrup, orange syrup, syrup, corn oil, mineral oil, peanut oil, sesame oil, bacteriostatic sodium chloride injection and bacteriostatic water for injection); chelating agents (e.g., edetate disodium and edetic acid); colorants (e.g., FD&C Red No. 3, FD&C Red No. 20, FD&C Yellow No. 6, FD&C Blue No. 2, D&C Green No. 5, D&C Orange No. 5, D&C Red No. 8, caramel and ferric oxide red); clarifying agents (e.g., bentonite); emulsifying agents (but are not limited to, acacia, cetomacrogol, cetyl alcohol, glyceryl monostearate, lecithin, sorbitan monooleate, polyethylene 50 stearate); encapsulating agents (e.g., gelatin and cellulose acetate phthalate); flavorants (e.g., anise oil, cinnamon oil, cocoa, menthol, orange oil, peppermint oil and vanillin); humectants (e.g., glycerin, propylene glycol and sorbitol); levigating agents (e.g., mineral oil and glycerin); oils (e.g., arachis oil, mineral oil, olive oil, peanut oil, sesame oil and vegetable oil); ointment bases (e.g., lanolin, hydrophilic ointment, polyethylene glycol ointment, petrolatum, hydrophilic petrolatum, white ointment, yellow ointment, and rose water ointment); penetration enhancers (transdermal delivery) (e.g., monohydroxy or polyhydroxy alcohols, saturated or unsaturated fatty alcohols, saturated or unsaturated fatty esters, saturated or unsaturated dicarboxylic acids, essential oils, phosphatidyl derivatives, cephalin, terpenes, amides, ethers, ketones and ureas); plasticizers (e.g., diethyl phthalate and glycerin); solvents (e.g., alcohol, corn oil, cottonseed oil, glycerin, isopropyl alcohol, mineral oil, oleic acid, peanut oil, purified water, water for injection, sterile water for injection and sterile water for irrigation); stiffening agents (e.g., cetyl alcohol, cetyl esters wax, microcrystalline wax, paraffin, stearyl alcohol, white wax and yellow wax); suppository bases (e.g., cocoa butter and polyethylene glycols (mixtures)); surfactants (e.g., benzalkonium chloride, nonoxynol 10, oxtoxynol 9, polysorbate 80, sodium lauryl sulfate and sorbitan monopalmitate); suspending agents (e.g., agar, bentonite, carbomers, carboxymethylcellulose sodium, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, kaolin, methylcellulose, tragacanth and veegum); sweetening e.g., aspartame, dextrose, glycerin, mannitol, propylene glycol, saccharin sodium, sorbitol and sucrose); tablet anti- adherents (e.g., magnesium stearate and talc); tablet binders (e.g., acacia, alginic acid, carboxymethylcellulose sodium, compressible sugar, ethylcellulose, gelatin, liquid glucose, methylcellulose, povidone and pregelatinized starch); tablet and capsule diluents (e.g., dibasic calcium phosphate, kaolin, lactose, mannitol, microcrystalline cellulose, powdered cellulose, precipitated calcium carbonate, sodium carbonate, sodium phosphate, sorbitol and starch); tablet coating agents (e.g., liquid glucose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, ethylcellulose, cellulose acetate phthalate and shellac); tablet direct compression excipients (e.g., dibasic calcium phosphate); tablet disintegrants (e.g., alginic acid, carboxymethylcellulose calcium, microcrystalline cellulose, polacrillin potassium, sodium alginate, sodium starch glycollate and starch); tablet glidants (e.g., colloidal silica, corn starch and talc); tablet lubricants (e.g., calcium stearate, magnesium stearate, mineral oil, stearic acid and zinc stearate); tablet/capsule opaquants (e.g., titanium dioxide); tablet polishing agents (e.g., carnuba wax and white wax); thickening agents (e.g., beeswax, cetyl alcohol and paraffin); tonicity agents (e.g., dextrose and sodium chloride);viscosity increasing agents (e.g., alginic acid, bentonite, carbomers, carboxymethylcellulose sodium, methylcellulose, povidone, sodium alginate and tragacanth); and wetting agents (e.g., heptadecaethylene oxycetanol, lecithins, polyethylene sorbitol monooleate, polyoxyethylene sorbitol monooleate, and polyoxyethylene stearate).

[606] The compounds identified by the methods described herein may be administered as the sole pharmaceutical agent or in combination with one or more other pharmaceutical agents where the combination causes no unacceptable adverse effects. For example, the compounds of this invention can be combined with known anti-obesity, or with known antidiabetic or other indication agents, and the like, as well as with admixtures and combinations thereof.

[607] The compounds identified by the methods described herein may also be utilized, in free base form or in compositions, in research and diagnostics, or as analytical reference standards, and the like. Therefore, the present invention includes compositions which are comprised of an inert carrier and an effective amount of a compound identified by the methods described herein, or a salt or ester thereof. An inert carrier is any material which does not interact with the compound to be carried and which lends support, means of conveyance, bulk, traceable material, and the like to the compound to be carried. An effective amount of compound is that amount which produces a result or exerts an influence on the particular procedure being performed.

[608] Formulations suitable for subcutaneous, intravenous, intramuscular, and the like; suitable pharmaceutical carriers; and techniques for formulation and administration may be prepared by any of the methods well known in the art (see, e.g., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa., 20^th edition, 2000).

EVALUATION OF BIOLOGICAL ACTIVITY

[609] In order that this invention may be better understood, the following examples are set forth. These examples are for the purpose of illustration only, and are not to be construed as limiting the scope of the invention in any manner. All publications mentioned herein are incorporated by reference in their entirety.

[610] Demonstration of the activity of the compounds of the present invention may be accomplished through in vitro, ex vivo, and in vivo assays that are well known in the art. For example, to demonstrate the efficacy of a pharmaceutical agent for the treatment of diabetes, obesity and related disorders such as Syndrome X, impaired glucose tolerance, impaired fasting glucose, and hyperinsulinemia, the following assays may be used.

Effects of Compounds on Insulin Secretion from Dispersed Rat Islet Cells

[611] Insulin secretion of dispersed rat islets mediated by compounds of the present invention is measured as follows. Islets of Langerhans, isolated from male Sprague-Dawley rats (200-250 g), are digested using collagenase. The dispersed islet cells are treated with trypsin, seeded into 96 well V-bottom plates, and pelleted. The cells are then cultured overnight in media with or without compounds of this invention. The media is aspirated, and the cells are pre-incubated with Krebs-Ringer-HEPES buffer containing 3 mM glucose for 30 minutes at 37°C. The pre-incubation buffer is removed, and the cells are incubated at 37°C with Krebs-Ringer-HEPES buffer containing the appropriate glucose concentration (e.g., 8 mM) with or without compounds for an appropriate time. In some studies, an appropriate concentration of GLP-1 or forskolin is also included. A portion of the supernatant is removed and its insulin content is measured. To determine the amount of insulin secreted, the supernatants are mixed with anti-insulin antibody and a tracer amount of ¹²⁵l-insulin in phosphate buffered saline containing 0.5% bovine serum albumin. Protein A coated SPA (scintillation proximity assay) beads are added. The plates are incubated for 5-20 h and counted on a scintillation counter to measure insulin levels. Activity for compounds at a given concentration is expressed as a fold-stimulation of insulin secretion relative to controls.

Effect of Compounds on Intraperitoneal Glucose Tolerance in Rats

[612] The in vivo activities of the compounds of this invention when administered via oral gavage are examined in rats utilizing the IPGTT (Intraperitoneal Glucose Tolerance Test). Rats fasted overnight are given an oral dose of vehicle control or compound. Three hours later, basal blood glucose is measured, and the rats are given 2 g/kg of glucose intraperitoneal^. Blood glucose is measured again after 15, 30, and 60 min.

Effect of Compounds in the Chronic Diet-induced Obese Mouse Model

[613] The in vivo efficacy of test compounds is determined by using the diet-induced obese (DIO) mouse model, which is an industry standard for the identification and development of therapeutic agents for the treatment of obesity (Trillou, et al., Am. J. Physiol. 284(2, Pt. 2):R345- R353, 2003). Male C57BI/6 mice are fed a high fat diet (containing 45% calories from fat) for a minimum of 10 weeks before the start of the studies. The animals included in the studies have an average body weight greater than 4 standard deviations of the mean body weight of mice that are fed a standard chow low fat diet (5% calories from fat). The DIO mouse model uses "growing" adult DIO mice, typically 16-20 weeks in age, that continued to gain weight on the high fat diet during the compound study period. Depending on the goal and design of the study, DIO mice are treated with vehicle or test compound, qd or bid, for a minimum of 7 days and a maximum of 28 days. Test compound or vehicle is administered orally approximately 0.5 to 1.0 h before the feeding phase (dark cycle). Food/water intake and body weights are measured daily for the duration of the study. At the end of the studies, additional measurements are included based on the study goals (i.e., NMR to measure body fat composition, indirect calorimetry, necropsy, blood chemistry).

Evaluation of Compounds' Efficacy in Fasted-Refed Acute Feeding Assay

[614] The anorexigenic properties of test compounds are determined using a fasted-refed mouse model in lean male C57/B mice. Mice housed two per cage are weighed and adapted to handling, food, and housing conditions (e.g., grid floors) at least 24 h before the start of the study. Mice are fasted overnight (18 h), and dosed p.o. the following day with vehicle or test compounds one hour before re-feeding with pre-weight standard mouse chow. Cumulative food intake corrected by spillage is determined at 1 , 2, 4, 24, and 48 h after food return.

Evaluation of Compounds' Efficacy in the Sated Rodent Model

[615] The orexigenic properties of test compounds are determined using a sated rodent model. Studies are carried out in ad-libitum fed rodents (rats and mice) during the early light phase (at least 1 h after lights on). Increases in food intake by orexigenic agents are apparent during this portion of the light-dark cycle because ad-libitum-ied rodents normally consume little food during this period. Rodents are weighed and are adapted to handling, food, and housing conditions (e.g., grid floors) at least 24 h before the start of the study. Rodents are administered either vehicle or the test compound at appropriate pretreatment times, doses, and routes of administration (e.g., Lp., s.c, p.o., i.v., and i.c.v.). Following dosing, rodents are returned to cages containing a known quantity of fresh food, and food consumption is measured at specified time intervals (e.g., 0.5, 1.0, 1.5, 3.0, 4.0, 24, 48, or 72 h). Body weights are taken at 24 h intervals.

[616] The structures, materials, compositions, and methods described herein are intended to be representative examples of the invention, and it will be understood that the scope of the invention is not limited by the scope of the examples. Those skilled in the art will recognize that the invention may be practiced with variations on the disclosed structures, materials, compositions and methods, and such variations are regarded as within the ambit of the invention. All publications and patents mentioned in the above specification are incorporated herein by reference. Various modifications and variations of the described compositions and methods of the invention will be apparent to those skilled in the art without departing from the scope and spirit of the invention. Although the invention has been described in connection with specific preferred embodiments, it should be understood that the invention as claimed should not be unduly limited to such specific embodiments. Indeed, various modifications of the above-described modes for carrying out the invention which are obvious to those skilled in the field of molecular biology or related fields are intended to be within the scope of the following claims. Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein.

Claims

Claims We claim:

1. A compound of Formula (I)

wherein

R¹ is selected from ⁴

R² is selected from

• H,

• (C_rC₆)alkyl optionally substituted with (C₁-C₄JaIkOXy or benzyloxy,

• (C₁-C₂)alkyl substituted with phenyl that is optionally substituted with up to two R⁵ groups,

• (CrC^haloalkyl,

• (C₃-C₆)cycloalkyl optionally substituted with up to two substituents selected from (C₁- C₃)alkyl and halo,

• a five-membered heterocyclic aromatic ring containing up to two heteroatoms selected from the group of N and O, and said ring being optionally substituted with (CrC^alkyl or (C₁-C₃) kOXy,

• pyridyl optionally substituted with up to two R⁵ groups,

• phenyl optionally substituted with up to three R⁵ groups, and

R³ is selected from

• H,

• halo, • (d-CeJalkyl optionally substituted with OH, (C₁-C₂JaIkOXy, or (C₃-C₆)cycloalkyl,

• (C₃-C₆)cycloalkyl,

• (C_rC₄)haloalkyl,

• a five-membered heterocyclic aromatic ring containing up to two heteroatoms selected from N, O, and S, and said ring being optionally substituted with up to two R⁷ groups,

• a five-membered heterocyclic aromatic ring containing one heteroatom selected from N, O, and S, and said ring being fused to a phenyl ring optionally substituted at any position with halo or (C₁-C₃JaIkVl,

• pyridyl optionally substituted with up to two R⁸ groups,

• phenyl optionally substituted with up to three R⁸ groups,

• phenyl that is fused to a five-membered or six-membered aromatic ring optionally containing one heteroatom selected from N, O, and S, and said ring system being optionally substituted at any position with halo or (d-C₃)alkyl, and

• phenyl that is fused to a five-membered or six-membered non-aromatic ring optionally containing up to two oxygen atoms;

R⁴ is selected from

• H,

• (C₃-C₆)cycloalkyl,

• (d-C₆)alkyl optionally substituted with (C₃-C₆)cycloalkyl, one to two (C_rC₆)alkoxy groups, one to three halo, one to two OH, phenyl, pyrrolyl, or (C_rC₄)alkenyl, and

• phenyl;

R⁵ is selected from

• (C₁-C₆JaIkOXy optionally substituted with OH or alkoxy,

• phenoxy optionally substituted with halo,

• (CrC₆)alkyl optionally substituted with (C_rC₃)alkoxy,

• (C₃-C₆)cycloalkyl,

• (C_rC₂)haloalkyl,

• (d-C₂)haloalkoxy,

• halo,

• CN,

• NO₂

• SO₂CH₃,

• morpholine, and

• pyrrolidine;

R⁶ is selected from

• H,

• C(O)R⁹,

• (C_rC₆)alkyl optionally substituted with phenyl, and

• phenyl optionally substituted with halo;

R⁷ is selected from

• (C_rC₆)alkyl,

• halo

• C(O)CH₃

• C(O)OCH₃,

• C(O)OC₂H₅,

• phenyl optionally substituted with up to two R⁵ groups,

• pyridyl optionally substituted with halo or (C₁-C₃)alkyl,

• furanyl optionally substituted with halo or (C_rC₃)alkyl,

• thiophenyl optionally substituted with halo or (C^C^alkyl,

• thiazolyl optionally substituted with halo or (C₁-C₃JaIRyI, and

R⁸ is selected from

• halo,

• (C_rCβ)alkyl,

• (CrC₂)haloalkyl,

• (C₁-C₆JaIkOXy optionally substituted with a cyclopropyl ring or OH,

• (CrC₂)haloalkoxy,

• (C_rC₃)alkylthio,

• phenyl optionally substituted with halo,

• (CrC₄)alkenyl,

• C(O)CH₃, • CN,

• CH₂CN,

• NO₂,

• NH₂,

• N(R⁹)_2l

• OH, and

• SO₂CH₃;

R⁹ is (d-C₆)alkyl or phenyl;

L is selected from

• a bond,

• O,

• C(O),

• s,

• SO₂,

• NR⁶,

• NHSO₂

• methylene,

• ethylene,

• ethenyl, and

• ethynyl;

m is O, 1 , or 2;

n is 1 or 2;

p is O, 1 , or 2;

or pharmaceutically acceptable salts thereof;

.R⁴

N^' provided that when R¹ = ' ^^ , n = 1 , p = 1 , L = bond, and R²-(CH₂)_m- = H, methyl, or ethyl, then R³ is not H or halo, and further provided that when R¹ =

, p = 1 , L = bond, and R²-(CH₂)_m- is H or methyl, then R D3 ; is not H or methyl.

The compound of claim 1 , wherein

R¹ is selected from

L is selected from

• a bond,

• O,

• C(O),

• S,

• SO₂,

• NR⁶, and

NHSO₂

3. The compound of claim 1 , wherein

R is selected from

R is selected from • H, • (C_rC₆)alkyl optionally substituted with (C₁-C₄)SIkOXy or benzyloxy,

• (Ci-C₂)alkyl substituted with phenyl that is optionally substituted with up to two R⁵ groups,

• (CrC₄)haloalkyl,

• (C₃-C₆)cycloalkyl optionally substituted with up to two substituents selected from (CrC₃)alkyl and halo, and

• phenyl optionally substituted with up to three R⁵ groups;

R³ is selected from

• H,

• halo,

• (C_rC₆)alkyl optionally substituted with OH, (C₁-C₂)BIkOXy, or (C₃-C₆)cycloalkyl,

• (C₃-C₆)cycloalkyl,

• (C_rC₄)haloalkyl,

• a five-membered heterocyclic aromatic ring containing up to two heteroatoms selected from N, O, and S, and said ring being optionally substituted with up to two R⁷ groups,

• pyridyl optionally substituted with up to two R⁸ groups,

• phenyl optionally substituted with up to three R⁸ groups, and

• phenyl that is fused to a five-membered or six-membered non-aromatic ring optionally containing up to two oxygen atoms;

R⁴ is selected from

• H,

• (C₃-C₆)cycloalkyl, and

• (d-CβJalkyl optionally substituted with (C₃-C₆)cycloalkyl, one to two (C₁-C₆JaIkOXy groups, one to three halo, one to two OH, phenyl, pyrrolyl, or (C_rC₄)alkenyl;

R⁵ is selected from

• (C_t-CβJalkoxy optionally substituted with OH or alkoxy,

• phenoxy optionally substituted with halo,

• (d-CβJalkyl optionally substituted with (C₁-C₃JaIkOXy,

• (C₃-C₆)cycloalkyl,

• (C_rC₂)haloalkyl, • (C₁-C₂)IIaIOaIkOXy,

• halo,

• CN, and

• NO₂;

R⁶ is selected from

• H, and

• (C₁-C₆JaIkYl optionally substituted with phenyl;

R⁷ is selected from

• (C₁-Ce)₃IkYl,

• halo

• C(O)CH₃

• phenyl optionally substituted with up to two R⁵ groups,

• pyridyl optionally substituted with halo or (CrC₃)alkyl, and

• thiazolyl optionally substituted with halo or (Ci-C₃)alkyl;

L is selected from

• a bond,

• O,

• C(O),

• S,

• SO₂,

• NR⁶, and

• NHSO₂.

4. The compound of claim 1 ,

R¹ is selected from ⁴

R² is selected from

• H,

• (CrCβJalkyl optionally substituted with (C₁-C₄)BIkOXy or benzyloxy,

• (CrCzJalkyl substituted with phenyl that is optionally substituted with up to two R⁵ groups,

• (d-C^haloalkyl,

• (C₃-C₆)cycloalkyl optionally substituted with up to two substituents selected from (CrCsJalkyl and halo, and

• phenyl optionally substituted with up to three R⁵ groups;

R³ is selected from

• H,

• halo,

• (CrC^alkyl optionally substituted with OH, (C₁-C₂JaIkOXy, or (C₃-C₆)cycloalkyl,

• (C₃-C₆)cycloalkyl,

• (CrC^haloalkyl,

• a five-membered heterocyclic aromatic ring containing up to two heteroatoms selected from N, O₁ and S, and said ring being optionally substituted with up to two R⁷ groups,

• phenyl optionally substituted with up to three R⁸ groups, and

• phenyl that is fused to a five-membered or six-membered non-aromatic ring optionally containing up to two oxygen atoms;

R⁴ is selected from

• H,

• (CrC₆)alkyl optionally substituted with (C₃-C₆)cycloalkyl, one to two (C₁-C₆JaIkOXy groups, one to three halo, one to two OH, phenyl, pyrrolyl, or (C₁-C₄)alkenyl;

R⁵ is selected from

• (CrC₆)alkoxy optionally substituted with OH or alkoxy,

• phenoxy optionally substituted with halo, • (CVC^alkyl optionally substituted with (C₁-C₃JaIkOXy,

• (C₁-C₂)haloalkyl,

• (C₁-C₂)IIaIOaIkOXy,

• halo, and

• CN;

R⁶ is selected from

• H, and

• (C_rC₆)alkyl optionally substituted with phenyl;

L is selected from

• a bond,

• O₁

• C(O),

• S, and

• NR⁶;

m is O or 1 ; and n is 1.

5. The compound of claim 1 ,

R¹ is selected from

R² is selected from

• H,

• (C_rC₆)alkyl optionally substituted with (C₁-C₄JaIkOXy or benzyloxy,

• (d-C^haloalkyl,

• (C₃-C₆)cycloalkyl optionally substituted with up to two substituents selected from (C_rC₃)alkyl and halo, • pyridyl optionally substituted with up to two R⁵ groups,

• phenyl optionally substituted with up to three R⁵ groups,

R³ is selected from

• H,

• halo,

• (CrC₆)alkyl optionally substituted with OH, (CrC₂)alkoxy, or (C₃-C₆)cycloalkyl,

• (C₃-C₆)cycloalkyl,

• (CrC^haloalkyl,

• a five-membered heterocyclic aromatic ring containing up to two heteroatoms selected from N and S, and said ring being optionally substituted with up to two R⁷ groups,

• phenyl optionally substituted with up to three R⁸ groups, and

• phenyl that is fused to a five-membered or six-membered non-aromatic ring optionally containing up to two oxygen atoms;

R⁴ is selected from

• H,

• (C₃-C₆)cycloalkyl,

• (CrC^alkyl optionally substituted with one to two (C₁-C₆JaIkOXy groups, one to three halo, or one to two OH;

R⁵ is selected from

• (C₁-C₆JaIkOXy optionally substituted with OH or alkoxy,

• phenoxy optionally substituted with halo,

• (CrCβJalkyl optionally substituted with (C₁-C₃JaIkOXy,

• (C₁-C₂)haloalkyl,

• (CrC_∑Jhaloalkoxy,

• halo, and

• CN;

R⁶ is selected from

• H, and

• (CrCβJalkyl optionally substituted with phenyl; R⁷ is selected from

• (C_rC₆)alkyl,

• halo

. C(O)CH₃

• phenyl optionally substituted with up to two R⁵ groups,

• pyridyl optionally substituted with halo or (C₁-C₃JaIRyI, and

• thiazolyl optionally substituted with halo or (C_rC₃)alkyl,

R⁸ is selected from

• halo,

• (Ci-C₆)alkyl,

• (C₁-C₂)haloalkyl,

• (Ci-C₆)alkoxy optionally substituted with a cyclopropyl ring or OH,

• (CrC₂)haloalkoxy, and

• (Ci-C₃)alkylthio;

R⁹ is (C_rC₆)alkyl;

L is selected from

• a bond,

• O,

• C(O),

• S,

• SO₂,

• NR⁶,

m is O or 1 ;

n is 1 ;

p is 1. The compound of claim 1 , wherein

R¹ is selected from

R² is selected from

• H₁

• (C₁-C₆)SlRyI optionally substituted with (C₁-C₄JaIRoXy or benzyloxy,

• (C_rC₄)haloalRyl,

• (C₃-C₆)cycloalRyl optionally substituted with up to two substituents selected from (C₁-C₃JaIRyI and halo, and

• phenyl optionally substituted with up to three R⁵ groups;

R³ is selected from

• H,

• halo,

• (C₁-C₆JaIRyI optionally substituted with OH, (C₁-C₂JaIRoXy, or (C₃-C₆)cycloalRyl,

• (C₃-C₆)cycloalRyl,

• (C_rC₄)haloalRyl,

• a five-membered heterocyclic aromatic ring containing up to two heteroatoms selected from N and S, and said ring being optionally substituted with up to two R⁷ groups,

• pyridyl optionally substituted with up to two R⁸ groups,

• phenyl optionally substituted with up to three R⁸ groups, and

• phenyl that is fused to a five-membered or six-membered non-aromatic ring optionally containing up to two oxygen atoms;

R⁴ is selected from

• H,

• (C₃-C₆)cycloalRyl, and

• (C₁-C₆JaIRyI optionally substituted with one to two (C₁-C₆JaIRoXy groups, one to three halo, or one to two OH; R⁵ is selected from

• (Ci-CβJalkoxy optionally substituted with OH or alkoxy,

• phenoxy optionally substituted with halo,

• (Ci-C₆)alkyl optionally substituted with (C₁-C₃JaIkOXy,

• (CrC₂)haloalkyl,

• (CrC₂)haloalkoxy, and

• halo;

R⁶ is selected from

• H;

R⁷ is selected from

• (C-CβJalkyl,

• phenyl optionally substituted with up to two R⁵ groups, and

• pyridyl optionally substituted with halo or (Ci-C₃)alkyl,

R⁸ is selected from

• halo,

• (CrC₆)alkyl,

• (Ci-C₂)haloalkyl,

• (CrC₆)alkoxy optionally substituted with a cyclopropyl ring or OH,

• (CrC₂)haloalkoxy,

• (d-CsJalkylthio,

• phenyl optionally substituted with halo, and

• N(R⁹)₂;

R⁹ is (C,-C₆)alkyl;

L is selected from

• a bond,

• O,

• C(O),

• S, and NR⁶

m is 0 or 1 ;

n is 1 ;

and

p is 1 or 2.

7. The compound of claim 1 selected from the group consisting of :

2-(cyclopropylmethyl)-6-(4-fluorophenoxy)-3-{[(3S)-1-isopropylpiperidin-3-yl]methyl}quinazolin-

4(3H)-one, 2-(cyclopropylmethyl)-6-(4-fluorophenyl)-3-{[(3S)-1-isopropylpiperidin-3-yl]methyl}quinazolin-4(3H)- one,

2-(difluoromethyl)-6-(4-fluorophenyl)-3-[(1-isopropylpiperidin-3-yl)methyl]quinazolin-4(3H)-one, 2-(fluoromethyl)-6-(4-fluoro-3-methylphenyl)-3-{[(3S)-1-isopropylpiperidin-3-yl]methyl}quinazolin-

4(3H)-one, 2-[2-fluoro-4-(2-hydroxyethoxy)phenyl]-6-(4-fluorophenoxy)-3-[(1-isopropylpiperidin-3- yl)methyl]quinazolin-4(3H)-one,

2-cyclopropyl-6-(4-fluorophenoxy)-3-[(1-isopropylpiperidin-3-yl)methyl]quinazolin-4(3H)-one, 2-ethyl-6-(4-fluorophenoxy)-3-{[(3S)-1-isopropylpiperidin-3-yl]methyl}quinazolin-4(3H)-one, 2-isopropyl-3-[(1-isopropylpiperidin-3-yl)methyl]-6-(2-methylphenoxy)quinazolin-4(3H)-one, 2-isopropyl-3-[(1-isopropylpiperidin-3-yl)methyl]-6-(3-methylphenoxy)quinazolin-4(3H)-one, 2-isopropyl-3-{[(3S)-1-isopropylpiperidin-3-yl]methyl}-6-(2-phenylethyl)quinazolin-4(3H)-one, 2-isopropyl-3-{[(3S)-1-isopropylpiperidin-3-yl]methyl}-6-(3-methoxyphenyl)quinazolin-4(3H)-one, 3-[(1-ethylpiperidin-3-yl)methyl]-2-(2-methylphenyl)-6-(trifluoromethoxy)quinazolin-4(3H)-one, 3-{[(3S)-1-ethylpiperidin-3-yl]methyl}-6-(2-fluorophenyl)-2-(2-methylphenyl)quinazolin-4(3H)-one, 3-{[(3S)-1-ethylpiperidin-3-yl]methyl}-6-(4-fluoro-3-methylphenyl)-2-methylquinazolin-4(3H)-one, 3-{[(3S)-1-ethylpipehdin-3-yl]methyl}-6-(4-fluorophenoxy)-2-methylquinazolin-4(3H)-one, 3-{[1-(1-ethylpropyl)piperidin-3-yl]methyl}-6-(4-fluorophenyl)-2-isopropylquinazolin-4(3H)-one, 3-{[1-(2-fluoroethyl)piperidin-3-yl]methyl}-6-(4-fluorophenoxy)-2-isopropylquinazolin-4(3H)-one, 3-{[1-(cyclopropylmethyl)piperidin-3-yl]methyl}-2-(2-methylphenyl)-6-(trifluoromethoxy)quinazolin-

4(3H)-one,

6-(2,4-dichlorophenyl)-2-isopropyl-3-{[(3S)-1-isopropylpiperidin-3-yl]methyl}quinazolin-4(3H)-one, 6-(2,4-dichlorophenyl)-3-{[(3S)-1 -ethylpiperidin-3-yl]methyl}-2-methylquinazolin-4(3H)-one, 6-(2,4-dichlorophenyl)-3-{[(3S)-1-isopropylpiperidin-3-yl]methyl}-2-methylquinazolin-4(3H)-one, 6-(2,4-dichlorophenyl)-3-{[(3S)-1-isopropylpiperidin-3-yl]methyl}quinazolin-4(3H)-one, -(2,4-difluorophenyl)-2-isopropyl-3-{[(3S)-1-isopropylpiperidin-3-yl]methyl}quinazolin-4(3H)-one, -(2-chloro-4-fiuorophenoxy)-3-{[(3S)-1-ethylpiperidin-3-yl]methyi}-2-isopropylquinazolin-4(3H)- one, -(2-chloro-4-fluorophenyl)-2-isopropyl-3-{[(3S)-1-isopropylpiperidin-3-yl]methyl}quiπazolin-4(3H)- one, -(2-chlorophenyl)-2-isopropyl-3-{[(3S)-1-isopropylpiperidin-3-yl]methyl}quinazolin-4(3H)-one, -(2-fluorobenzyl)-2-isopropyl-3-{[(3S)-1-isopropylpiperidin-3-yl]methyl}quinazolin-4(3H)-one, -(2-fluorophenyl)-3-{[(3S)-1-isopropylpiperidin-3-yl]methyl}-2-(2-methylphenyl)quinazolin-4(3H)- one, -(3,4-dichlorophenyl)-3-{[(3S)-1-isopropylpiperidin-3-yl]methyl}-2-methylquinazolin-4(3H)-one, -(3,4-dichlorophenyl)-3-{[(3S)-1-isopropylpiperidin-3-yl)methyl}quinazolin-4(3H)-one, -(3,4-dimethylphenyl)-2-ethyl-3-{[(3S)-1-isopropylpiperidin-3-yl]methyl}quinazolin-4(3H)-one, -(3-chloro-4-fluorophenyl)-2-(difluoromethyl)-3-[(1-isopropylpiperidin-3-yl)methyl]quinazolin-4(3H)- one, -(3-chloro-4-fluorophenyl)-2-ethyl-3-{[(3S)-1-ethylpiperidin-3-yl]methyl}quinazolin-4(3H)-one, -(3-chloro-4-fluorophenyl)-2-ethyl-3-{[(3S)-1-isopropylpiperidin-3-yl]methyl}quinazolin-4(3H)-one, -(3-chloro-4-fluorophenyl)-3-{[(3S)-1-isopropylpiperidin-3-yl]methyl}quinazolin-4(3H)-one, -(3-ethoxyphenyl)-3-{[(3S)-1-isopropylpiperidin-3-yl]methyl}-2-methylquinazolin-4(3H)-one, -(4,5-dimethyl-1 ,3-thiazol-2-yl)-3-[(1-isopropylpiperidin-3-yl)methyl]-2-(2-methylphenyl) quinazolin-

4(3H)-one trifluoroacetate, -(4-chloro-3-fluorophenyl)-3-{[(3S)-1-isopropylpiperidin-3-yl]methyl}-2-methylquinazolin-4(3H)- one, -(4-chlorophenoxy)-2-(cyclopropylmethyl)-3-{[(3S)-1 -isopropylpiperidin-3-yl]methyl}quinazolin-

4(3H)-one, -(4-chlorophenoxy)-3-{[(3S)-1-ethylpiperidin-3-yl]methyl}-2-methylquinazolin-4(3H)-one, -(4-chlorophenoxy)-3-{[(3S)-1-isopropylpiperidin-3-yl]methyl}-2-methylquinazolin-4(3H)-one, -(4-chlorophenoxy)-3-{[(3S)-1-isopropylpiperidin-3-yl]methyl}-2-propylquinazolin-4(3H)-one, -(4-chlorophenoxy)-3-{[(3S)-1-isopropylpiperidin-3-yl]methyl}quinazolin-4(3H)-one, -(4-chlorophenyl)-2-(cyclopropylmethyl)-3-{[(3S)-1-isopropylpiperidin-3-yl]methyl}quinazolin-

4(3H)-one, -(4-chlorophenyl)-2-(difluoromethyl)-3-[(1-isopropylpiperidin-3-yl)methyl]quinazolin-4(3H)-one, -(4-chlorophenyl)-2-(fluoromethyl)-3-{[(3S)-1-isopropylpiperidin-3-yl]methyl}quinazolin-4(3H)-one, -(4-chlorophenyl)-2-ethyl-3-{[(3S)-1-isopropylpiperidin-3-yl]methyl}quinazolin-4(3H)-one, -(4-chlorophenyl)-2-isopropyl-3-{[(3S)-1-isopropylpipehdin-3-yl]methyl}quinazo!in-4(3H)-one, -(4-chlorophenyl)-3-[(1-ethyl-1 ,2,5,6-tetrahydropyridin-3-yl)methyl]-2-(2-methylphenyl)quinazolin-

4(3H)-one, -(4-chlorophenyl)-3-[(1-isopropylpiperidin-3-yl)methyl]-2-(3-methylpyridin-2-yl)quinazolin-4(3H)- one, -(4-chlorophenyl)-3-{[(3R)-1-ethylpiperidin-3-yl]methyl}-2-(2-methoxyphenyl)quinazolin-4(3H)-one, -(4-chlorophenyl)-3-{[(3R)-1-ethylpiperidin-3-yl]methyl}-2-(2-methylphenyl)quinazolin-4(3H)-one, -(4-chlorophenyl)-3-{[(3S)-1-ethylpiperidin-3-yl]methyl}-2-(2-methylphenyl)quinazolin-4(3H)-one, -(4-chlorophenyl)-3-{[(3S)-1-ethylpiperidin-3-yl]methyl}-2-[4-(trifluoromethyl)phenyl]quinazolin-

4(3H)-one, -(4-chlorophenyl)-3-{[(3S)-1-isopropylpiperidin-3-yl]methyl}-2-(trifluoromethyl)quinazolin-4(3H)- one, -(4-chlorophenyl)-3-{[(3S)-1-isopropylpiperidin-3-yl]methyl}-2-methylquinazolin-4(3H)-one, -(4-chlorophenyl)-3-{[(3S)-1-isopropylpiperidin-3-yl]methyl}-2-propylquinazolin-4(3H)-one, -(4-chlorophenyl)-3-{[1-(2-hydroxyethyl)piperidin-3-yl]methyl}-2-(2-methylphenyl)quinazolin-4(3l-l)- one, -(4-chlorophenyl)-3-{[1-(cyclopropylmethyl)piperidin-3-yl]methyl}-2-(2-methylphenyl)quinazolin-

4(3H)-one, -(4-fluoro-2-methylphenoxy)-2-isopropyl-3-[(1-isopropylpiperidin-3-yl)methyl]quinazolin-4(3H)- one, -(4-fluorophenoxy)-2-isopropyl-3-[(1 -isopropylpiperidin-3-yl)methyl]quinazolin-4(3H)-one, -(4-fluorophenoxy)-3-{[(3S)-1-isopropylpiperidin-3-yl]methyl}-2-(2-methylphenyl)quinazolin-4(3H)- one, -(4-fluorophenoxy)-3-{[(3S)-1 -isopropylpiperidin-3-yl]methyl}-2-methylquinazolin-4(3H)-one, -(4-fluorophenoxy)-3-{[(3S)-1 -isopropylpiperidin-3-yl]methyl}-2-propylquinazolin-4(3H)-one, -(4-fluorophenoxy)-3-{[(3S)-1-isopropylpiperidin-3-yl]methyl}quinazolin-4(3H)-one, -(4-fluorophenyl)-2-isopropyl-3-[(1-isopropylpiperidin-3-yl)methyl]quinazolin-4(3H)-one, -(4-fluorophenyl)-3-[(1-isopropylpiperidin-3-yl)methyl]-2-(2-methylphenyl)quinazolin-4(3H)-one trifluoroacetate, -(4-fluorophenyl)-3-{[(3S)-1-isopropylpiperidin-3-yl]methyl}-2-propylquinazolin-4(3H)-one, -(5-chloro-2-methylphenoxy)-2-isopropyl-3-[(1-isopropylpiperidin-3-yl)methyl]quinazolin-4(3H)- one, -[(4-chlorophenyl)thio]-3-{[(3S)-1-isopropylpiperidin-3-yl]methyl}quinazolin-4(3H)-one, -[(4-fluorophenyl)thio]-3-{[(3S)-1-isopropylpiperidin-3-yl]methyl}quinazolin-4(3H)-one, -[3-chloro-4-(trifluoromethyl)phenyl]-2-cyclopropyl-3-{[(3S)-1-isopropylpiperidin-3- yl]methyl}quinazolin-4(3H)-one, -[3-chloro-4-(trifluoromethyl)phenyl]-3-{[(3S)-1-isopropylpiperidin-3-yl]methyl}-2-methylquinazolin-

4(3H)-one, -[4-chloro-3-(trifluoromethyl)phenyl]-3-{[(3S)-1-isopropylpiperidin-3-yl]methyl}-2-methylquinazolin-

4(3H)-one, -[4-chloro-3-(thfluoromethyl)phenyl]-3-{[(3S)-1-isopropylpiperidin-3-yl]methyl}quinazolin-4(3H)- one, -benzyl-2-isopropyl-3-{[(3S)-1-isopropylpiperidin-3-yl]methyl}quinazolin-4(3H)-one, -isobutoxy-2-isopropyl-3-{[(3S)-1-isopropylpiperidin-3-yl]methyl}quinazolin-4(3H)-one, and -isopropoxy-3-{[(3S)-1-isopropylpiperidin-3-yl]methyl}-2-(2-methylphenyl)quinazolin-4(3H)-one. 8. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt, in combination with a pharmaceutically acceptable carrier.

9. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier and one or more pharmaceutical agents.

10. The pharmaceutical composition of claim 9, wherein said pharmaceutical agent is selected from the group consisting of β-3 agonists, cannabinoid antagonists or agonists, neuropeptide Y5 inhibitors, appetite suppressants, and lipase inhibitors.

11. The pharmaceutical composition of claim 9, wherein said pharmaceutical agent is an agent for the treatment of diabetes selected from the group consisting of insulin, insulin derivatives, PPAR ligands, sulfonylurea drugs, α-glucosidase inhibitors, biguanides, PTP-1 B inhibitors, DPP-IV inhibitors, 11-beta-HSD inhibitors, GLP-1 and GLP-1 derivatives, GIP and GIP derivatives, PACAP and PACAP derivatives, and secretin and secretin derivatives.

12. The pharmaceutical composition of claim 9, wherein said pharmaceutical agent is an agent for the treatment of lipid disorders selected from the group consisting of HMG-CoA inhibitors, nicotinic acid, fatty acid lowering compounds, lipid lowering drugs, ACAT inhibitors, bile sequestrants, bile acid reuptake inhibitors, microsomal triglyceride transport inhibitors, and fibric acid derivatives.

13. The pharmaceutical composition of claim 9, wherein said pharmaceutical agent is an anti¬ hypertensive agent selected from the group consisting of β-blockers, calcium channel blockers, diuretics, renin inhibitors, ACE inhibitors, AT-1 receptor antagonists, ET receptor antagonists, and nitrates.

14 A method of regulating glucose homeostasis, body weight, energy expenditure, or food intake comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound of claim 1 or a composition of claim 8.

15. A method of treating diabetes comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound of claim 1 or a pharmaceutical composition of claim 8.

16. The method of claim 15, wherein said diabetes is selected from the group consisting of type 1 diabetes, type 2 diabetes, maturity-onset diabetes of the young, latent autoimmune diabetes adult, and gestational diabetes.

17. A method of treating Syndrome X comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound of claim 1 or a pharmaceutical composition of claim 8.

18. A method of treating hyperglycemia, hyperinsulinemia, impaired glucose tolerance, impaired fasting glucose, dyslipidemia, hypertriglyceridemia, and insulin resistance comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound of claim 1 or a pharmaceutical composition of claim 8.

19. A method of treating diabetes comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound of claim 1 in combination with one or more pharmaceutical agents.

20. The method of claim 19, wherein said pharmaceutical agent is selected from the group consisting of PPAR agonists, sulfonylurea drugs, non-sulfonylurea secretagogues, α- glucosidase inhibitors, insulin sensitizers, insulin secretagogues, hepatic glucose output lowering compounds, insulin, and anti-obesity agents.

21. The method of claim 20, wherein said diabetes is selected from the group consisting of type 1 diabetes, type 2 diabetes, maturity-onset diabetes of the young, latent autoimmune diabetes adult, and gestational diabetes.

22. A method of treating Syndrome X comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound of claim 1 in combination with one or more pharmaceutical agents.

23. The method of claim 22, wherein said pharmaceutical agent is selected from the group consisting of PPAR agonists, sulfonylurea drugs, non-sulfonylurea secretagogues, α- glucosidase inhibitors, insulin sensitizers, insulin secretagogues, hepatic glucose output lowering compounds, insulin, and anti-obesity agents.

24. A method of treating hyperglycemia, hyperinsulinemia, impaired glucose tolerance, impaired fasting glucose, dyslipidemia, hypertriglyceridemia, and insulin resistance comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound of claim 1 in combination with one or more pharmaceutical agents.

25. The method of claim 24, wherein said pharmaceutical agent is selected from the group consisting of PPAR agonists, sulfonylurea drugs, non-sulfonylurea secretagogues, α- glucosidase inhibitors, insulin sensitizers, insulin secretagogues, hepatic glucose output lowering compounds, insulin, and anti-obesity agents.

26. A method of treating diabetes, Syndrome X, hyperglycemia, hyperinsulinemia, impaired glucose tolerance, impaired fasting glucose, dyslipidemia, hypertriglyceridemia, and insulin resistance comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound of claim 1 in combination with one or more agents selected from the group consisting of HMG-CoA reductase inhibitors, nicotinic acid, lipid lowering drugs, ACAT inhibitors, bile acid sequestrants, bile acid reuptake inhibitors, microsomal triglyceride transport inhibitors, fibric acid derivatives, β-blockers, ACE inhibitors, calcium channel blockers, diuretics, renin inhibitors, AT-1 receptor antagonists, ET receptor antagonists, neutral endopeptidase inhibitors, vasopepsidase inhibitors, and nitrates.

27. A method of treating obesity comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound of claim 1 or a composition of claim 8.

28. A method of inducing weight loss comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound of claim 1 or a composition of claim 8.

29. A method of preventing weight gain comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound of claim 1 or a composition of claim 8.

30. A method of treating obesity comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound of claim 1 in combination with one or more pharmaceutical agents.

31. The method of claim 30, wherein said pharmaceutical agent is selected from the group consisting of PPAR agonists, sulfonylurea drugs, non-sulfonylurea secretagogues, α- glucosidase inhibitors, insulin sensitizers, insulin secretagogues, hepatic glucose output lowering compounds, insulin, anti-obesity agents, HMG-CoA reductase inhibitors, nicotinic acid, lipid lowering drugs, ACAT inhibitors, bile acid sequestrants, bile acid reuptake inhibitors, microsomal triglyceride transport inhibitors, fibric acid derivatives, β-blockers, ACE inhibitors, calcium channel blockers, diuretics, renin inhibitors, AT-1 receptor antagonists, ET receptor antagonists, neutral endopeptidase inhibitors, vasopepsidase inhibitors, and nitrates.

32. A method of treating wasting disorders comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound of claim 1 or a composition of claim 8.

33. The method of claim 19, 22, 24, or 30, wherein the compound of claim 1 and one or more pharmaceutical agents are administered as a single pharmaceutical dosage formulation. 34. Compounds according to claim 1 for the treatment and/or prophylaxis of diabetes, obesity, and related disorders.

35. Medicament containing at least one compound according to claim 1 in combination with at least one pharmaceutically acceptable, pharmaceutically safe carrier or excipient.

36. Use of compounds according to claim 1 for manufacturing a medicament for the treatment and/or prophylaxis of diabetes, obesity, and related disorders.

37. Medicaments according to claim 35 for the treatment and/or prophylaxis of diabetes, obesity, and related disorders.