WO2005113554A2

WO2005113554A2 - Method of preparing 3-phenyl-2-[9h-purin-6-ylamino)-methyl]-3h-quinazolin-4-one and substituted and related compounds

Info

Publication number: WO2005113554A2
Application number: PCT/US2005/016661
Authority: WO
Inventors: Edward A. Kesicki; Paul Zhichkin
Original assignee: Icos Corporation
Priority date: 2004-05-13
Filing date: 2005-05-12
Publication date: 2005-12-01
Also published as: US8980901B2; SI3153514T1; US10336756B2; HRP20161657T1; AU2005245875C1; SI2612862T1; CY1118516T1; CA2566609C; LUC00005I2; US20100256168A1; EP1761540B1; NL300867I2; CN101031569A; US20210332047A1; US20140121224A1; AU2009230739A1; US20130116266A1; CN102229609A; LUC00005I1; LTPA2017004I1

Abstract

A method of synthesizing compounds of structural formulae (II), (IIa), and (III), in high yield and high stereospecific selectivity is disclosed. (IIa, R5≠H, S-enantiomer)

Description

METHOD OF PREPARING 3-PHENYL-2- [ (9H-PURIN-6- Y AMINO) -METHYL] -3H-QUINAZOLIN-4-ONE AND SUBSTITUTED AND RELATED COMPOUNDS

CROSS REFERENCE TO RELATED APPLICATIONS This application claims the benefit of

U.S. provisional application Serial No. 60/570,784, filed May 13, 2004.

FIELD OF THE INVENTION

The present invention is directed to a method of preparing compounds such as 3-phenyl-2- [ (9H-purin-6-ylamino) -methyl] -3H-quinazolin-4-one (i.e., the compound of structural formula (I)), and compounds structurally related to (I) .

BACKGROUND OF THE INVENTION

Significant advances have been made in the design and synthesis of inhibitors of phosphatidyl- inositol 3 -kinase (PI3 ) enzymes, and more particularly to inhibitors, including selective inhibitors, of PI3Kδ activity. In particular, 4-quinazolin-4- one compounds that are inhibitors of PI3K5 activity, also termed pllOδ inhibitors, are disclosed in U.S. Patent Nos . 6,518,277 and 6,667,300, each of which is incorporated herein by reference . Compounds disclosed in these patents have been shown to inhibit the PI3Kδ isoform, and many selectively inhibit the Pl3Kδ isoform over the α, β, and Y isoforms of PI3K. Selective inhibitors of PI3Kδ possess the advantage of enabling the skilled artisan to inhibit the δ isoform in an in vi tro or in vivo system, while leaving the other PI3K isoforms substantially unaffected. Such utility can have important, consequences in treating diseases or conditions that are mediated by PI3Kδ, inasmuch as at therapeutic concentrations a selective PI3Kδ inhibitor can avoid undesirable side effects or tox- icities that would be associated with inhibition of the α, β, and γ isoforms of PI3K. While effective inhibitors of pllOδ have been found, e.g., compound 3-phenyl-2- [ (9H-purin-6- ylamino) -methyl] -3H-quinazolin-4-one of structural formula (I) and substituted and related compounds, a need exists in the art to provide an improved method of synthesizing compound (I) and compounds structurally related to compound (I) . In particular, a need exists for a short synthetic route to such compounds wherein the yield of the desired compound is increased, in the desired stereochemistry, and at decreased cost . SUMMARY OF THE INVENTION

The present invention relates to a method of preparing a compound such as 3-phenyl-2- [ (9H- purin-6-ylamino) -methyl] -3H-quinazolin-4-one and compound structurally related thereto. In particular, the present invention relates to a method preparing a compound of structural formula (I) , and substituted and related compounds, for example, compounds of structural formulae (II) and (III) . More particularly, the present invention is directed to a new and facile synthesis of compounds (I) , (II) , and (III) , which are inhibitors of pllOδ. The method disclosed herein is a new arid economical synthesis of these and other compounds and is particularly valuable in that it allows the. synthesis of Pl3Kδ-inhibiting compounds that have optimized PI3Kδ inhibition properties, including in vi tro potency, in vivo potency, and selectivity for Pl3Kδ over other PI3K isoforms. Therefore, one aspect of the present invention is to provide a method of synthesizing compounds capable of inhibiting the biological activity of human PI3Kδ, in particular compounds that inhibit Pl3Kδ selectively compared to the other PI3K iso- forms. Another aspect of the present invention is to provide a method of synthesizing a compound of structural formula (I) :

Still another aspect of the present invention is to provide a method of synthesizing com- pounds structurally related to compound (I) , for example, compounds having a structural formula (II) :

wherein X and Y, independently, are N or CR^C; Z is selected from the group consisting of NR⁷, 0, and CR^R¹¹, wherein R¹⁰ and R¹¹, independently, are hydrogen or Cι_₃alkyl; R¹, independently, are hydrogen, halo, or Cι-₃alkyl ; R² and R³, independently, are hydrogen, halo, or Cι_₃alkyl; R⁴ is hydrogen, halo, OR^a, CN, C₂-6alkynyl, C(=0)R^a, C(=0)NR^aR^b, C₃-₆heterocycloalkyl, Cι_₃alkyl- eneC₃_₆heterocycloalkyl, OCι_₃alkyleneOR^a, OCι-₃alkyl- eneNR^aR^b, OCι_₃alkyleneC₃-₆cycloalkyl, OC_3-6heterocyclo- alkyl, OCι_₃alkyleneC≡CH, or OC^alkyleneC (=0)NR^aR^b; R⁵ is hydrogen Cι_₃alkyl, CH₂CF₃, phenyl, CH₂C≡CH, Cx.salkyleneOR⁶, C_1-.₄alkyleneNRR^b, or C^alk- yleneNHC(=0)OR^a, R⁶ is hydrogen, halo, or NR^aR^b; R⁷ is hydrogen or R⁵ and R⁷ are taken together with the atoms to which they are attached to form a five- or six-membered saturated ring; R⁸ is C_1-3alkyl, halo, CF₃, or CH₂C₃-₆hetero- cycloalkyl; n is 0, 1, or 2; R^a is hydrogen, Cι-₄alkyl, or CH₂C₆H₅; R^b is hydrogen or Cι_₃alkyl; and R^c is hydrogen, Cι_₃alkyl, or halo. Another aspect of the present invention is to provide a method of synthesizing the S- or the R- enantiomer of a compound of structural formula (II) when R⁵ is different from hydrogen. The method provides an increased stereochemical yield of the desired S- or R-enantiomer, e.g., the S-enantiomer having a structural formula (Ila) :

Yet another aspect of the present invention is to provide a method of preparing compounds structurally related to compound (I) , for example, a compound having a structural formula (III) :

wherein B is an optionally substituted monocyclic or bicyclic ring system containing at least two nitrogen atoms, and at least one ring of the system is aromatic; C is selected from the group consisting of C(R^d)₂, CH₂CHR^d, and CH=C(R^d); D is selected from the group consisting of null, S, SO, S0₂, NH, 0, C(=0), OC(=0), C(=0)0, and NHC(=0)CH₂S; R⁸ is selected from the group consisting of Cι_₃alkyl, halo, CF₃, aryl, heteroaryl, halo, OCF₃, CN, OR^d, N(R^d)₂, C(=0)R^d, OC(=0)R^d, C(=0)OR^d, C_1-3alk- ylenearyl, C₃-₆cycloalkyl, C₃_₈heterocycloalkyl, S0₂N(R^d)₂, OS0₂CF₃, or Cι-₃alkyleneC₃-₈heterocycloalkyl; R⁹ is selected from the group consisting of hydrogen, Cι-₆alkyl, C₃_₆cycloalkyl, C₃-₆cycloalkenyl, C₃_₈heterocycloalkyl, aryl, heteroaryl, Cι_₃alkylene- aryl, Cχ.₃alkyleneheteroaryl , and C₂_₆alkenyl; R^d is selected from the group consisting of hydrogen, Cι-₆alkyl, heteroCι_₃alkyl, Cι_₃alkylenehet- eroCι-₃alkyl , arylheteroCι_₃alkyl , aryl, heteroaryl, arylC_!-₃alkyl, heteroarylCx-salkyl, C;ι_.-₃alkylenearyl, and Cι_₃alkyleneheteroaryl ; and n is 0, 1, or 2. Still another aspect of the present invention is to provide a method of cyclizing and preserving the chirality of a compound having a structure

wherein R , R , R , and n are as defined above; * indicates a chiral center; and PG is hydrogen or a protecting group, comprising a step of subjecting the compound to reducing conditions to form a compound having a structure

Yet another aspect of the present invention is to provide a method of cyclizing and preserving the chirality of a compound having a structure

wherein R⁵, R⁸, R⁹, *, PG, and n are as defined above; A is NH₂, protected NH₂, or N₃, comprising a step of deprotecting the protected NH₂ group to provide an NH₂ group or converting the N₃ group to provide an NH₂ group, followed by cyclizing the resulting intermediate compound under acidic or basic conditions to form a compound having a structure

One method of synthesizing the compound of structural formula (I) is illustrated as follows:

1) oxalyl chloride 2) aniline

(1)

(2)

(3)

(4) 6 -bromopurine

( 5 ]

As disclosed hereafter, compounds of structural formulae (II) and (III) also can be made by the above and modified procedures. In addition, compounds disclosed in U.S. Patent No. 6,667,300, incorporated herein by reference, also can be prepared by the methods set forth herein. Importantly, chiral compounds of structural formulae (II) and (III), and chiral compounds disclosed in U.S. Patent No. 6,667,300, can be prepared in high stereochem- ical purity. Another aspect of the present invention is to provide a method of preparing compounds related to the compound of structural formula (I) , such as, for example, compounds of structural formulae (II) and (III), and, related compounds, such as the compounds disclosed in U.S. Patent Nos . 6,518,277 and 6,667,300, each of which is incorporated herein by reference . These compounds are prepared according to the synthetic schemes provided herein by selecting a properly substituted starting materials and reagents, for example. These and other aspects and advantages of the present invention will become apparent from the following detailed description of the preferred embodiments, which are provided to enhance the understanding of the invention without limiting the scope of the invention.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present invention is directed to an efficient synthesis of 3-phenyl-2- [ (9H-purin-6-yl- amino) -methyl] -3H-quinazolin-4-one (i.e., compound (I) ) . The present invention also is directed to methods of synthesizing compounds related in structure to compound (I) , including substituted compounds of structural formula (I) , for example, compounds having a structural formula (II) or (III) , and particularly a desired S- or R-enantiomer of chiral compounds of structural formulae (II) and (III) (e.g., compounds of structural formula (II) wherein R⁵ is different from hydrogen) in a high stereochemical yield:

wherein X and Y, independently, are N or CR^C; Z is selected from the group consisting of NR⁷, O, and CR^R¹¹, wherein R¹⁰ and R¹¹, independently, are hydrogen or C_₃alkyl; R¹, independently, are hydrogen, halo, or d-salkyl; R² and R³, independently, are hydrogen, halo, or C_!-₃alkyl; R⁴ is hydrogen, halo, OR^a, CN, C₂__salkynyl, C(=0)R^a, C(=0)NR^aR^b, C₃.₆heterocycloalkyl, Cι_₃alkyl- eneC₃-₆heterocycloalkyl, OCx-salkyleneOR³, OC;,_₃alkyl- eneNR^aR^b, OCι_₃alkyleneC₃_₆cycloalkyl, OC₃.₆heterocyclo- alkyl, OC₁_₃alkyleneC≡CH, or OCι_₃alkyleneC (=0)NRR^b; R⁵ is Cι_₃alkyl, CH₂CF₃, phenyl, CH₂C≡CH, C_!-₃alkyleneOR^e, Cι_₄alkyleneNR^aR^b, or Cx^alkyleneNHC- (=0)OR^a, R⁶ is hydrogen, halo, or NR^aR^b; R⁷ is hydrogen or R⁵ and R⁷ are taken together with the atoms to which they are attached to form a five- or six-membered saturated ring; R⁸ is Cι-₃alkyl , halo , CF₃ , or CH₂C₃-₆hetero- cyclo lkyl ; n is 0 , 1 , or 2 ; R^a is hydrogen, C₁_ alkyl, or CH₂C₆H₅; R^b is hydrogen or Cι-₃alkyl; and R^c is hydrogen, Cι_₃alkyl, or halo. The present disclosure first illustrates a synthetic route to provide simple, unsubstituted compound (I) . However, as disclosed hereafter, using properly substituted starting materials and reagents of desired stereochemistry yields compounds of structural formulae (II) and (III) , stereoselec- tively and in good yield, using an identical or similar synthetic route. For example, to prepare compounds of structural formula (II) , the following benzoic acid (a) , aniline (b) , purine compound (c) , and carboxyl- ic acid (d) can be utilized in the present methods.

(c) (d) More generally, the present method can be utilized to prepare compounds of structural formula (III) =

(III)

including a desired S- or R-enantiomer in high stereospecific yield. The present invention provides a more efficient route to chiral compounds having a structural formula (II) or (III) , and improves the yield of the desired enantiomer of compounds having a structural formula (II) or (III) . As used herein, the term "alkyl" is defined as straight chained and branched hydrocarbon groups containing the indicated number of carbon atoms, e.g., methyl, ethyl, and straight chain and branched propyl and butyl groups . The terms "Cι-₃alkylene" and "C₁_₄alkylene" are defined as hydrocarbon groups containing the indicated number of carbon atoms and one less hydrogen than the corresponding alkyl group. The terms "C₂-_Salkenyl" and "C₂_₆alkynyl" are defined as a hydrocarbon group containing the indicated number of carbon atoms and a carbon-carbon double bond or a carbon-carbon triple bond, respec- tively. The terms "C_3-6cycloalkyl" and "C₃_₆cyclo- alkenyl" are defined as a cyclic hydrocarbon group containing the indicated number of carbon atoms . The C₃_₆cycloalkenyl group contains a carbon-carbon double bond in the ring. The term "C₃_₆heterocycloalkyl" is defined similarly as cycloalkyl except the ring contains one or two heteroatoms selected from the group consisting of O, NR^d, and S. The term "aryl, " alone or in combination, is defined herein as a monocyclic or polycyclic aromatic group, preferably a monocyclic or bicyclic aromatic group, e.g., phenyl or naphthyl . Unless otherwise indicated, an "aryl" group can be unsub- stituted or substituted, for example, with one or more, and in particular one to three, halo, alkyl, phenyl, hydroxyalkyl, alkoxy, alkoxyalkyl, halo- alkyl, nitro, amino, alkylamino, acylamino, alkyl- thio, alkylsulfinyl, and alkylsulfonyl . Exemplary aryl groups include phenyl, naphthyl, biphenyl, tetrahydronaphthyl , chlorophenyl, fluorophenyl, aminophenyl, methylphenyl, methoxyphenyl, trifluoro- methylphenyl, nitrophenyl, carboxyphenyl , and the like. The term "heteroaryl" is defined herein as a monocyclic or bicyclic ring system containing one or two aromatic rings and containing at least one nitrogen, oxygen, or sulfur atom in an aromatic ring, and which can be unsubstituted or substituted, . for example, with one or more, and in particular one to three, substituents, like halo, alkyl, hydroxyl, hydroxyalkyl, alkoxy, alkoxyalkyl, haloalkyl, nitro, amino, alkylamino, acylamino, alkythio, alkylsul- finyl, and alkylsulfonyl . Examples of heteroaryl groups include thienyl, furyl, pyridyl, oxazolyl, quinolyl, isoquinolyl, indolyl, triazolyl, iso- thiazolyl, isoxazolyl, imidizolyl, benzothiazolyl, pyrazinyl, pyrimidinyl, thiazolyl, and thiadiazolyl . The term "halo" is defined as fluoro, bromo, chloro, and iodo. The term "hydroxy" 3 is defined as -OH. The term "alkoxy" is defined as -OR, wherein R is alkyl. The term "alkoxyalkyl" is defined as an alkyl group wherein a hydrogen has been replaced by an alkoxy group. The term " (alkylthio) alkyl" is defined similarly as alkoxyalkyl, except a sulfur atom, rather than an oxygen atoms, is present. The term "hydroxyalkyl" is defined as a hydroxyl group appended to an alkyl group. The term "amino" is defined as -NH₂, and the term "alkylamino" is defined as -NR₂, wherein at least one R is alkyl and the second R is alkyl or hydrogen. The term "acylamino" is defined as RC(=0)N, wherein R is alkyl or aryl. The term "alkylthio" is defined as -SR, wherein R is alkyl. The term "alkylsulfinyl" is defined as R-S0₂, wherein R is alkyl. The term "alkylsulfonyl" is defined as

R-S0₃, wherein R is alkyl. The term "nitro" is defined as -N₂. The term "trifluoromethyl" is defined as -CF, The term "trifluoromethoxy" is defined as -OCF₃ The term "cyano" is defined as -CN. In some embodiments of structural formulae (II) and (Ila) , the bicyclic ring system containing X and Y is

In other embodiments of structural formulae (II) and (Ila) , R¹ is hydrogen, fluoro, chloro, methyl, or

R² is hydrogen, methyl, chloro, or fluoro; R³ is hydrogen or fluoro; R⁶ is NH₂, hydrogen, or fluoro; R⁷ is hydrogen or R⁵ and R⁷ are taken together to form

R⁸ is methyl, trifluoromethyl, chloro, or fluoro; R⁴ is hydrogen, fluoro, chloro, OH, OCH₃, OCH₂C≡CH, 0(CH₂)₂N(CH₃)₂, C(=0)CH₃, C≡CH, CN, C(=0)NH₂, OCH₂C- (=0)NH₂, 0(CH₂)₂0CH₃, 0(CH₂)₂N(CH₃)₂,

-OCH₂

-CH₂-N 0 \_V

/ \ -N 0 \ /

and R⁵ is methyl, ethyl, propyl, phenyl, CH₂OH, CH₂OCH₂C₆H₅, CH₂CF₃, CH₂0C(CH₃)₃, CH₂C≡CH, (CH₂)₃N- (C₂H₅)₂, (CH₂)₃NH₂, (CH₂)₄NH₂, (CH₂) ₃NHC (=0) OCH₂C_sH₅, or (CH₂)₄NHC(=0)0CH₂C₆H₅; R^c is hydrogen, methyl, fluoro, or bromo; and n is 0 or 1. . In some embodiments of compounds of structural formula (III) , X is selected from the group consisting of CH₂, CH₂CH₂, CH=CH, CH(CH₃), CH(CH₂CH₃), CH₂CH(CH₃), and C(CH₃)₂. In further preferred embodiments, Y is selected from the group consisting of null, S, O, and NH. The B ring can be monocyclic or bicyclic. Monocyclic B ring systems are aromatic. Bicyclic B ring systems contain at least one aromatic ring, but both rings can be aromatic. Examples of A ring systems include, but are not limited to, imidazolyl, pyrazolyl, 1, 2, 3-triazolyl, pyridizinyl, pyrimidin- yl, pyrazinyl, 1, 3 , 5-triazinyl, purinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1,8- naphthyridinyl , pteridinyl, lH-indazolyl, and benzimidazolyl . The following abbreviations are used in this specification: aq (aqueous) , h (hour) , min (minutes) , mol (mole) , eq (equivalent) , mL (milli- liter) , L (liter), sat ' d (saturated), THF (tetra- hydrofuran) , RT (room temperature) , Et₃N (triethyl- amine) , Zn (zinc dust metal) , Sn (tin) , Fe (iron) , n-BuOH ^λ (n-butyl alcohol), t-BuOH (tertiary butyl alcohol) , NaCI (sodium chloride) , MgS0₄ (magnesium sulfate) , NH₄C1 (ammonium chloride), BOC (C(=0)0tBu), CDC1₃ (deuterated chloroform) , H₂0 (water) , CHC1₃ (chloroform) , HCI (hydrochloric acid) , MeOH (methanol) , NaOH (sodium hydroxide) , NaOMe (sodium meth- oxide) , TFA (trifluoroacetic acid) , K₂C0₃ (potassium carbonate) , S0C1₂ (thionyl chloride) , CH₂Cl₂ (methyl- ene chloride) , EtOAC (ethyl acetate) , DMF (dimethyl- formamide) , EtOH (ethanol) , DMSO (dimethyl sulfox- ide) , NaHC0₃ (sodium bicarbonate) , CO (carbon monoxide) , (C0C1)₂ (oxalyl chloride), POCl₃ (phosphorus oxychloride) , CC1₄ (carbon tetrachloride) , PPh₃ (tri- phenylphosphine) , Cl₂ (chlorine) , PC1₅ (phosphorus pentachloride), Pd (palladium), Pt (platinum)', TLC (thin layer chromatography) , HPLC (high performance liquid chromatography) , HOBT (hydroxybenzotriazole) , EDC (ethyldiethylaminopropylcarbodiimide) , DIEA (di- isopropylethylamine) , KHDMS (potassium hexamethyl disilazane) , and HOAc (acetic acid) . For illustrative purposes, one synthesis of compound (I) is summarized below: 1) oxalyl chloride 2) aniline

(1)

(2)

(3)

(4) 6 -bromopurine

( 5 )

One starting material for the present synthetic route to compound (I) is an o-nitro-substi- tuted benzoic acid (1) . In the first step of the synthesis, the benzoic acid (1) optionally is converted to the corresponding acid chloride using a reagent well known in the art, e.g., oxalyl chloride or thionyl chloride in the presence of a catalytic amount of DMF in an organic solvent, such as CH₂C1₂ or THF. The acid chloride then is reacted with an aniline, in the presence of a base, to form an N- phenyl-benzamide (2) . The N-phenyl-benzamide (2) is reacted with thionyl chloride or a similar reagent known to persons skilled in the art, either neat or in a solvent and in the presence of optional catalytic amount of DMF, to provide the corresponding N-chloro compound, followed by the addition of an N-protected 2-amino substituted carboxylic acid, e.g., N-BOC-2-amino- acetic acid and a base in an organic or aqueous solvent, to yield a carbamic acid ester derivative (3). The protecting group for the amino substituent of the carboxylic acid can be any protecting group typically used by persons skilled in the art, such as BOC, i.e., C (=0) C (CH₃) ₃. By using an S-2-amino substituted carboxylic acid, a desired S-enantiomer of compound (II), i.e., a compound (Ila), is pro- vided in high stereochemical yield. The carbamic acid ester derivative (3) then is subjected to reducing conditions, such as zinc metal dust and acetic acid, tin (II) chloride, iron, or catalytic hydrogenation in the presence of a palladium, platinum, rhodium, or nickel catalyst, to form the cyclized carbamic acid ester (4) . The cyclized carbamic acid ester (4) then is treated under conditions that remove the BOC protecting group from the amino group, e.g., trifluroacetic acid or hydrogen chloride, to provide a 2- (1-amino- methyl) -3-phenyl-3H-quinazolin-4-one (5). The quinozolin-4-one (5) then is reacted with 6-bromo- purine in the presence of a base in a solvent, e.g., ethanol, n-butanol, t-butanol, or THF, at 60°C to 120°C for 8 to 36 hours, to provide the 3-phenyl-2- [ (9H-purin-6-ylamino) -methyl] -3H-quinazolin-4-one

(I) . As disclosed below, compounds related in structure to compound (I) can be prepared by the above and related synthetic routes by a proper choice of starting materials and reagents. The above general method is more fully illustrated below for the following compound (7) , wherein the desired S-enantiomer is provided stereoselectively. Compound (7) is a compound falling within the scope of structural formula (II) . Other compounds of structural formulae (II) and (III) can be synthesized using the methods disclosed below.

In accordance with the present invention, the method provides a desired S- or R-enantiomer of a compound (II) when R⁵ is different from hydrogen. The desired enantiomer of a chiral compound (III) also can be provided in high stereochemical yield. Using a present method, a chiral compound (II) or (III) can be prepared in at least 95% stereochemical purity, typically at least 97% stereochemical purity, and more typically at least 98% stereochemical purity. In preferred embodiments, the stereochemical purity of the desired S- or R-enantiomer is at least 99%, and often greater than 99%. In the synthetic sequence described below, unless otherwise noted, all starting materials and reagents were obtained from commercial suppliers and used without further purification. All reactions and chromatography fractions were analyzed by thin- layer chromatography (TLC) on 250 mm silica gel plates, visualized with ultraviolet (UV) light or iodine (I₂) stain. Products and intermediates were purified by flash chromatography or reverse-phase high performance liquid chromatography (HPLC) .

1) oxalyl chloride, THF,

10 min. (la)

10°C-RT (2a)

(3a)

(4a)

( 5a)

Preparation of 2-fluoro-6-nitro-N-phenyl- benzamide (2a) . A solution of 2-fluoro-6-nitro- ' benzoic acid 1 (100 g, 0.54 mol) and DMF (5 mL) in CHC1₂ (600 mL) was treated dropwise with oxalyl chloride (2 M in CH₂C1₂, 410 mL, 0.8 mol, 1.5 eq) over 30 min. After stirring 2 h at room temperature, the reaction was concentrated to an orange syrup with some solids present. The syrup was dissolved in dry dioxane (80 mL) and slowly added to a suspension of aniline (49 mL, 0.54 mol, 1 eq) and NaHC0₃ (90 g, 1.08 mol, 2 eq) in a mixture of dioxane (250 mL) and H₂0 (250 mL) at 6°C. The temperature reached 27°C at the end of the addition. After 30 min, the reaction mixture was treated with H₂0 (1.2 L) . The precipitate was collected by vacuum filtration, washed with H₂0 (300 mL) , air dried in the funnel, and dried in vacua at 50°C for 24 h to afford an off-white solid product (139 g, 99%) . ^XH NMR (300 MHz, DMS0-d₆) δ: 10.82 (s, 1H) , 8.12 (d, J = 7.7 Hz, 1H) , 7.91-7.77 (m, 2H) , 7.64 (d, J = 7.7 . Hz, 2H) , 7.38 (t, J = 7.9 Hz, 2H) , 7.15 (t, J = 7.4 Hz, 1H) , ESI-MS m/z 261 (MH+) . Preparation of (S) - [1- (2-fluoro-6-nitro- benzoyl) -phenyl-aminocarbonyl] -propyl) -carbamic acid tert-butyl ester (3a) . A suspension of 2-fluoro-6- nitro-N-phenyl-benzamide 2 (130 g, 0.5 mol) and DMF . (5 mL) in S0C1₂ (256 mL, 2.5 mol, 5 eq) was stirred at 85°C for 5 hours. The reaction mixture was concentrated in vacuo to a brown syrup . The syrup was dissolved in CH₂Cl₂ (200 mL) and was slowly added to a solution of N-BOC-L-2-aminobutyric acid (112 g, 0.55 mol, 1.1 eq) and Et₃N (77 mL, 0.55 mol, 1.1 eq) in CH₂Cl₂ (600 mL) at 10°C. After stirring at room temperature for 3 h, salts were removed by filtra- tion, and the solution was washed with 100 mL of H₂0, sat'd. NaHC0₃, H₂0, 5% citric acid, and saturated NaCI . The organic phase was dried with MgS0 and concentrated to a red syrup. The syrup was dissolved in CH₂C1₂ (450 mL) and purified by flash chromatography on a silica gel plug (15 x 22 cm, 4 L dry silica) eluted with hexanes/EtOAc (10%, 8 L; 15%, 8 L; 20%, 8 L; 25%, 4 L) to yield the product as an off-white solid (147 g, 66k) . ^H NMR (300 MHz, DMSO-de) δ: 8.13 (d, J = 8.0 Hz, 1H) , 7.84 (t, J = 8.6 Hz, 1H) , 7.78-7.67 (m, 1H) , 7.65-7.49 (m, 3H) , 7.40-7.28 ( m, 2H) , 7.19 (d, J = 7.5 Hz, 1H) , 4.05 (broad s, 1H) , 1.75-1.30 (m, 2H) , 1.34 (s, 9H) , 0.93 (broad s, 3H) . ESI-MS m/z 446.3 (MH⁺) . Preparation of (S) - [1- (5-fluoro-4-oxo-3- phenyl-3_/4-dihydro-quinazolin-2-yl) -propyl] -carbamic acid tert-butyl ester (4a) . A solution of [1- (2- fluoro-6-nitro-benzoyl) -phenyl-aminocarbonyl] - propyl) -carbamic acid tert-butyl ester 3 (56 g, 125 mmol, 1 eq) in HOAc (500 mL) was treated with Zn (48.4 g, 740 mmol, 6 eq) added in 3 portions, allow- ing the reaction mixture to cool to below 35 °C between additions. After stirring for 2 h at ambient temperature, solids were filtered by vacuum filtration and washed with HOAc (50 mL) . The filtrate was concentrated in vacuo, dissolved in EtOAc (400 mL) , washed with H₂0 (300 mL) , and the water layer was extracted with EtOAc (300 mL) . The combined organic layers were washed with H₂0 (200 mL) , satd. NaHC0₃ (2 x 200 mL) , satd. NaCI (100 mL) , dried with MgS0₄, and concentrated to a syrup. The syrup was dissolved in toluene (200 mL) and purified by flash chromatography on a silica gel plug (13 x 15 cm, 2 L dry silica) eluted with hexanes/EtOAc (10%, 4 L; 15%, 4 L; 17.5%, 8 L; 25%, 4 L) to yield the product as an off-white foamy solid (33.6 g, 69%). ^XH NMR (300 MHz, DMS0-d₆) δ: 7.83 (td, J = 8.2, 5.7 Hz, 1H) , 7.64-7.48 (m, 5H) , 7.39 (broad d, J = 7.6 Hz, 1H) , 7.30 (dd, J = 8.3 Hz, 1H) , 7.23 (d, J = 7.6 Hz, 1H) , 4.02-3.90 (m, 1H) , 1.76-1.66 (m, 1H) , 1.62-1.46 (m, 1H) , 1.33 (s, 9H) , 0.63 (t, J = 7.3 Hz, 3H) . ESI-MS m/z 398.3 (MH⁺) . Preparation of (S) -2- (1-amino- ropyl) -5- fluoro-3-phenyl-3H-quinazolin-4-one (5a) . A solution of [1- (5-fluoro-4-oxo-3 -phenyl-3,4-dihydro- quinazolin-2-yl) -propyl] -carbamic acid tert-butyl ester 4 (33.6 g, 85 mmol) in CH₂C1₂ (60 mL) was treated with TFA (60 mL) . The reaction mixture was stirred for 1 h, concentrated in vacuo, and partitioned between CH₂C1₂ (150 mL) and 10% K₂C0₃ (sufficient amount to keep the pH greated than 10) . The aqueous layer was extracted with additional CH₂C1₂ (100 mL) , and the combined organic layers were washed with H₂0 (50 mL) and brine (50 mL) . After drying with MgS0 , the solution was concentrated to an off-white solid (22 g, 88%) . R NMR (300 MHz, CDC1₃) δ: 7.73-7.65 (m, 1H) , 7.62-7.49 (m, 4H) , 7.32-7.22 (m, 2H) , 7.13-7.06 (m, 1H) , 3.42 (dd, J = 7.5, 5.2 Hz, 1H) , 1.87-1.70 (m, 1H) , 1.58-1.43 (m, 1H) , 0.80 (t, J = 7.4 Hz, 3H) . ESI-MS m/z 298.2 (MH⁺) . Preparation of (S) -5-fluoro-3-phenyl-2- [1- (9H-purin-6-ylamino) -propyl] -3H-quinazolin-4-one

(7). A suspension of 2- (1-amino-propyl) -5-fluoro-3- phenyl-3H-quinazolin-4-one 5 (19.5 g, 65.6 mmol, 1 eq) , 6-bromopurine (14.6 g, 73.4 mmol, 1.1 eq) , and DIEA (24.3 mL, 140 mmol, 2 eq) in t-BuOH (40 mL) was stirred for 24 h at 80°C. The reaction mixture was concentrated in vacuo and triturated with H₂0 to yield a solid crude product that was collected by vacuum filtration, washed with water, and air dried. Half of the yield was dissolved in MeOH (600 mL) , concentrated onto silica gel (300 mL dry) , and pur- ified by flash chromatography (7.5 x 36 cm, eluted with 10 L of 4% Me0H/CH₂Cl₂) to yield a solid product that was dissolved in EtOH (250 mL) and concentrated in vacuo to a light yellow solid (7.2 g, 50%) . K NMR (300 MHz, 80°C, DMS0-d₆) δ: 12.66 (broad s, 1H) , 8.11 (s, 1H) , 8.02 (broad s, 1H) , 7.81-7.73 (m, 1H) , 7.60-7.42 (m, 6H) , 7.25-7.15 (m, 2H) , 4.97 (broad s, 1H) , 2.02-1.73 (m, 2H) , 0.79 (t, J = 7.3 Hz, 3H) . ESI-MS m/z 416.2 (MH⁺) . Anal. (C₂₂Hι₈N₇OF_*EtOH«0.4 H₂0) C, H, N. Chiral purity 99.8:0.2 (S:R) using chiral HPLC (4.6 x 250 mm Chiralpak ODH column,

20°C, 85:15 hexanes :EtOH, 1 mL/min, sample loaded at a concentration of 1 mg/mL in EtOH) .

Additional compounds related to compound (7) can be prepared using the present general synthetic method by a proper selection of appropriate starting materials and reagents, and by scaling all reagent amounts proportionately based on the amount of starting material used. Specific nonlimiting examples of compounds prepared by the method of the invention are provided below. It is understood in the art that protecting groups can be employed where necessary in accordance with general principles of synthetic chemistry. These protecting groups are removed in the final steps of the synthesis under basic, acidic, or hydrogenolytic conditions well known to persons skilled in the art. By employing appropriate manipulation and protection of chemical functionalities, synthesis of compounds related to compounds of structural formulae (II) and (III) , not specifically set forth herein can be accomplished using the synthetic scheme set forth herein.

(S) -3-Phenyl-2- [1- (9H-purin-6-ylamino) -ethyl] -3H- quinazolin-4-one Prepared following the procedure for Compound (7) substituting 2-nitrobenzoic acid for 2- fluoro-6-nitrobenzoic acid, and substituting N-BOC- L-alanine for N-BOC-L-2-aminobutyric acid. ESI-MS m/z 384.3 (MH⁺) . Chiral purity 99.5:0.5 (S:R)

(S) -6-Fluoro-3-phenyl-2- [1- (9H-purin-6-ylamino) - ethyl] -3H-quinazolin-4-one.

Prepared following the procedure for Compound (7) substituting 2-nitro-5-fluorobenzoic acid for 2-fluoro-6-nitrobenzoic acid, and substituting N-BOC-L-alanine for N-BOC-L-2-aminobutyric acid. ESI-MS m/z 402.3 (MH⁺) . Chiral purity 99.9:0.1 (S:R)

(S) -3- (3,5-Difluoro-phenyl) -5-methyl-2- [1- (9H-purin- 6-ylamino) -ethyl] -3H-quinazolin-4-one

Prepared following the procedure for Compound (7) substituting 2-nitro-5-methylbenzoic acid for 2-fluoro-6-nitrobenzoic acid and 3 , 5-difluoro- aniline for aniline, substituting N-BOC-L-alanine for N-BOC-L-2-aminobutyric acid. ESI-MS m/z 434.3 (MH⁺) .

(£) -5-Fluoro-2- [1- (2-fluoro-9H-purin-6-ylamino) - ethyl] -3 -phenyl-3H-quinazolin-4 -one .

Prepared following the procedure from Compound (7) substituting 2-nitro-6-fluorobenzoic acid for 2-fluoro-6-nitrobenzoic acid, N-BOC-L-alanine for N-BOC-L-2-aminobutyric acid, and 6-chloro-2- fluoropurine for 6-bromopurine. ESI-MS m/z 420.3 (MH⁺) . Chiral purity 100:0 (S:R)

(S) -3 - (3 -Fluoro-phenyl) -2 - [1- ( 9H-purin-6-ylamino) - ethyl] -3H-quinazolin-4 -one .

Prepared following the procedure for Compound (7) substituting 2-nitrobenzoic acid for 2- fluoro-6-nitrobenzoic acid and 3-fluoroaniline for aniline, and N-BOC-L-alanine for N-BOC-L-2-amino- butyric acid. ESI-MS m/z 402.3 (MH⁺) . Chiral purity 96:4 (S:R)

(S) -5-Chloro-3- (3 , 5-difluoro-phenyl) -2- [1- (9H-purin- 6-ylamino) -propyl] -3H-quinazolin-4-one .

Prepared following the procedure for Compound (7) substituting 2-nitro-5-chlorobenzoic acid for 2-fluoro-6-nitrobenzoic acid, and 3 , 5-difluoroaniline for aniline. ESI-MS m/z 468.3 (MH⁺) . Chiral purity 100:0 (S:R)

(S) -3- (2, 6-Difluoro-phenyl) -5-methyl-2- [1- (9H-purin- 6-ylamino) -ethyl] -3H-quinazolin-4-one .

Prepared using the following steps: Step A. N- (2, 6-difluoro-phenyl) -2-methyl-

6-nitro-benzamide . Following the procedure for Compound (7) substituting 2-nitro-5-methylbenzoic acid for 2- fluoro-6-nitrobenzoic acid and 2 , 6-difluoroaniline for aniline. Step B. L-{2- [ (2, 6-Difluoro-phenyl) - (2- methyl-6-nitro-benzoyl) -amino] -1-methyl-2-oxo- ethyl} -carbamic acid tert-butyl ester. A solution of N- (2, 6-difluoro-phenyl) -2- methyl-6-nitro-benzamide (13.8 g, 47 mmol) in THF (200 mL) at 0°C was treated dropwise with a solution of KHMDS (0.5 M in toluene, 95 mL, 47 mmol, 1 eq) and stirred for 30 min at 0°C. The reaction mixture was treated with L-2-tert-butoxycarbonylamino- propionic acid 2 , 5-dioxo-pyrrolidin-l-yl ester (13.5 g, 47 mmol, 1 eq) and stirred at 0°C for 30 min. The reaction mixture then was quenched with water (50 mL) and concentrated in vacuo. The residue was dissolved in EtOAc (300 mL) , washed with 100 mL of the following: H₂0, sat ' d NaHC0₃, H₂0, 5% citric acid, H₂0, and brine. The organic layer was dried over MgS0, then concentrated to a syrup. The crude material was dissolved in CH₂C1₂ (75 mL) and purified by flash chromatography on silica gel (7.5 x 40 cm), eluted with 20% EtOAc in hexanes (10 L of 20%, then 6 L of 33%) . Step C. Used the procedure for compound (7) . Step D. Used the procedure for compound (7) . ESI- MS m/z 434.3 (MH+) . Chiral purity 100:0 (S:R)

(S) -3- (2, 6-Difluoro-phenyl) -2- [1- (9H-purin-6- ylamino) -ethyl] -3H-quinazolin-4-one .

Prepared following the procedure for the previous compound substituing 2-nitrobenzoic acid for 2-amino-6-nitrobenzoic acid in Step A. ESI-MS m/z 420.3 (MH+) . Chiral purity 100:0 (S:R) More generally, the present method is utilized to prepare compounds of structural formula (III):

wherein B is an optionally substituted monocyclic or bicyclic ring system containing at least two nitrogen atoms, and at least one ring of the system is aromatic; C is selected from the group consisting of

C(R^d)₂, CH₂CHR^d, and CH=C(R); D is selected from the group consisting of null, S, SO, S0₂, NH, O, C(=0), OC(=0), C(=0)0, and NHC(=0)CH₂S; R⁸ is selected from the group consisting of

C_halky!, halo, CF₃, aryl, heteroaryl, halo, 0CF₃, CN, 0R^d, N(R^d)₂, C(=0)R^d, OC(=0)R^d, C(=0)0R^d, Cι_₃alk- ylenearyl, C₃_₆cycloalkyl, C₃.₈heterocycloalkyl, S0₂N(R^d)₂, OS0₂CF₃, or Cι-₃alkyleneC₃_₈heterocycloalkyl; R⁹ is selected from the group consisting of hydrogen, C_!-₆alkyl, C₃_₆cycloalkyl, C₃__scycloalkenyl, C₃_₈heterocycloalkyl, aryl, heteroaryl, Cχ-₃alkylene- aryl, C_!-₃alkyleneheteroaryl, and C₂-₆alkenyl; R^d is selected from the group consisting of hydrogen, Cι_₆alkyl, heteroCι_₃alkyl, Cι_₃alkylenehet- eroCι-₃alkyl, arylheteroC_!_₃alkyl, aryl, heteroaryl, arylCι_₃alkyl, heteroarylCι-₃alkyl, Cι_-3alkylenearyl, and Ci-salkyleneheteroaryl; and n is 0, 1, or 2. Compounds of structural formula (III) are prepared using the same general procedures and reagents set forth above for compounds of structural formulae (I) , (II) , and (Ila) . However, synthetic modifications are available which likewise provide chiral compounds of structural formula (III) having the desired stereochemistry in a high stereochemical purity. For example, in methods of preparing compounds of structural formulae (II) , (Ila) , and (III) , the following starting material also can be used:

wherein A is N0₂, a protected NH₂ group, N₃, or NH₂. When A is N0₂, the group is a "protected" amino group, i.e., a surrogate amino group. This is demonstrated in the above synthetic sequences wherein the N0₂ group is converted to an amino group via a reduction step. If A is a protected NH₂ group or N₃, an NH₂ group can be provided by deprotecting a pro- tected NH₂ group or by converting an N₃ group to an NH₂ group by conversion procedures well known in the art. In some instances, an unprotected NH₂ group also can be the A group, as long as the NH₂ group is available for cyclization in a subsequent step. See, for example, J^". Chem. Soc. (1956), page 985. Accordingly, a starting material for the synthesis of a compound (II) or (III) can be the substituted benzoic acid (lb)

(lb)

which optionally can be converted to an acid chloride, prior to reaction with an amine, R⁹NH₂, to provide an amide compound (2b) .

^(2b) Amide compound (2b) then is converted to an intermediate imidoyl halide. The halide can be a chloride, bromide, or iodide. Amide compound (2b) can be converted to an intermediate imidoyl halide, preferably an imidoyl chloride, by procedures known in the art. For example, amide compound (2b) can be converted to an intermediate imidoyl halide by reaction of amide (2b) with a chlorinating, brominat- ing, or iodinating agent, e.g., S0C1₂, PPh₃Cl₂, a complex of PPh₃ and Cl₂ obtained in si tu, a mixture of PPh₃ and CC1₄, PC1₅, P0C1₃, (C0C1)₂, phosgene, diphosgene, triphosgene, or a corresponding and stable bromo or iodo compound, in the absence or presence of base, such as triethylamine, and either neat, such as with S0C1₂ or POCl₃, or in a solvent. The intermediate imidoyl halogenide also can be formed in a one-pot reaction from a compound (lb) and amine R⁹NH₂ by using an excess amount of chlorinating agent, such as a mixture of PPh₃ and CC1₄. In another embodiment , the imidoyl halogenide intermediate also can be formed by halogenation of an imine, such as a Schiff base

with Cl₂, S0₂C1₂, or similar halogenating agent known to persons skilled in the art. In still another embodiment, intermediate compounds having a facile leaving group other than halogen also can be used in place of an imidoyl halogenide. For example, an imidoyl triflate formed in si tu from triflie anhydride and an amide (2b) can be used. After generation of the intermediate imidoyl halogenide or triflate, the intermediate is reacted with a carboxylic acid (PG-DH-C-C0₂H) and base, or a salt of a carboxylic acid, in an organic solvent, water, or mixture thereof to form a com- pound (3b) .

wherein PG is hydrogen or a protecting group. In accordance with an important feature of the present invention, the stereochemistry of the carboxylic acid is retained. Therefore, the desired stereo- isomer is provided, as set forth in the previous examples . In the next step, compound (3b) is cyclized (i) by reduction of group A, if A is N0₂, or (ii) by deprotecting or converting group A to NH₂, if A is protected amino or N₃, respectively, to provide the following compound

followed by a cyclization reaction to provide compound (4b) .

(4b)

The reduction reaction can be performed, for example, by reduction with tin (II) chloride in aq. HCI or organic solvent such as DMF, reduction with Fe or Zn with HOAc, HCI, NH₄C1, reduction with hydrogen over a metal catalyst such as palladium, platinum, rhodium, or nickel, reduction with hydrogen in si tu, for example, Pd with formic acid or its salt in an alcohol solution, reduction of an o- nitrobenzoylimide with CO, base, and selenium (Tetr. Lett, 43 , (2002) , 1855-1858) and with CO and a metal complex, such as Pt(PPh₃)₄ or Fe(CO)₅ (JOC, 58, (1993), 310-312), or catalyzed by a transition metal by other inorganic or organic reducing agents (e.g., sodium dithionite or thiourea dioxide) known in the art. To obtain the highest degree of stereoselec- tivity, an excess of reducing agent and low temperatures are preferred in order to reduce racemization of intermediates.

Claims

WHAT IS CLAIMED IS:

1. A method of preparing a compound having a structure

wherein X and Y, independently, are N or CR^C; Z is selected from the group consisting of NR⁷, O, and CR¹⁰R^1:L, wherein R¹⁰ and R¹¹, independently, are hydrogen or Cχ_₃alkyl; R¹ are the same and are hydrogen, halo, or C_x-₃alkyl ; R² and R³, independently, are hydrogen, halo, or Cι-₃alkyl; R⁴ is hydrogen, halo, OR^a, CN, C₂-₆alkynyl, C(=0)R^a, C(=0)NR^aR^b, C_3-6heterocycloalkyl, Cι-₃alkyl- eneC_3-6heterocycloalkyl, OCι-₃alkyleneOR^a, 0Cι_₃alkyl- eneNR^aR^b, OC_1-3alkyleneC₃-₆cycloalkyl, 0C₃_₆heterocyclo- alkyl, OCι-₃alkyleneC≡CH, or OCι_₃alkyleneC (=0)NR^aR^b; R is hydrogen, C_x-₃alkyl , CH₂CF₃ , phenyl ,

CH₂C≡CH, Cι-₃alkyleneOR^e, Cι_₄alkyleneNR ,a^aτR,b, or C_1-4alk- yleneNHC(=0)OR^a, R is hydrogen, halo, or NRaRτ-,b; R⁷ is hydrogen or R⁵ and R⁷ are taken together with the atoms to which they are attached to form a five- or six-membered saturated ring; R⁸ is C_!_₃alkyl, halo, CF₃, or CH₂C₃._shetero- cycloalkyl; n is 0, 1, or 2; R^a is hydrogen, C^alkyl, or CH₂C₆H₅; R^b is hydrogen or C_!_₃alkyl; and R^c is hydrogen, C_x-₃alkyl, or halo, comprising the steps of : (a) optionally converting a 2-nitrobenzoic acid having a structure

to a corresponding acid chloride; (b) reacting the 2-nitro-benzoic acid or the corresponding. acid chloride of step (a) with an aniline having a structure

to form an N-phenyl-benzamide having a structure

(c) optionally converting the N-phenyl- benzamide of step (b) to a corresponding N-chloro compound; (d) reacting the N-phenylbenzamide of step (b) or the corresponding N-chloro compound of step (c) with an N-protected 2-amino-substituted carboxylic acid having a structure

R= -CH- "C0₂H I z PG

wherein PG is hydrogen or a protecting group, to provide a compound having a structure

(e) subjecting the compound of step (d) to reducing conditions to form a cyclized compound, then removing the protecting group to provide a compound having a structure

(f) reacting the compound of step (e) with a compound having a structural formula

to form the compound of structural formula

2. The method of claim 1 wherein R⁵ is different from hydrogen.

3. The method of claim 2 wherein the S- enantiomer of the compound is prepared. 4. The method of claim 3 wherein the desired S- or R-enantiomer of the compound is prepared in at least 95% stereochemical purity.

5. The method of claim 1 wherein the N- protected 2-amino-substituted carboxylic acid of step (d) is the S-stereoisomer .

6. The method of claim 1 wherein the compound having a structure

7. The method of claim 6 wherein R^c is hydrogen or Cι_₃alkyl .

8. The method of claim 1 wherein the compound of step (d) is reduced using zinc metal dust or iron and an acid or ammonium chloride, tin (II) chloride in hydrochloric acid or an organic solvent, catalytic hydrogenation in the presence of palladium, platinum, rhodium, or nickel catalyst, sodium dithionite, thiourea dioxide, carbon monoxide and catalytic selenium, or carbon monoxide and a metal complex. 9. The method of claim 4 wherein the protecting group of step (d) is C(=0)C(CH₃)₃ or C(=0)0CH₂C_sH₅.

10. A method of preparing a compound having a structure

wherein B is an optionally substituted monocyclic or bicyclic ring system containing at least two nitrogen atoms, and at least one ring of the system is aromatic; C is selected from the group consisting of C(R^d)₂, CH₂CHR^d, and CH=C (R^d) ; D is selected from the group consisting of null, S, SO, S0₂, NH, O, C(=0), OC(=0), C(=0)0, and NHC(=0)CH₂S; R⁸ is selected from the group consisting of Cι-₃alkyl, halo, CF₃, aryl, heteroaryl, halo, 0CF₃,

CN, 0R^d, N(R^d)₂, C(=0)R^d, 0C(=0)R^d, C(=0)OR^d, Cι-₃alk- ylenearyl, C₃-₆cycloalkyl, C₃_₈heterocycloalkyl, S0₂N- (R^d)₂, OS0₂CF₃, or Ci-salkyleneCs-sheterocycloalkyl ; R⁹ is selected from the group consisting of hydrogen, C_halky!, C₃-_ecycloalkyl, C₃_₆cycloalkenyl, C₃.₈heterocycloalkyl, aryl, heteroaryl, Cι_₃alklene- aryl, Cι-₃alkyleneheteroaryl, and C₂„_salkenyl; R^d is selected from the group consisting of hydrogen, C_halky!, heteroCι-₃alkyl, Cι_₃alkylenehet- eroC_1-3alkyl , arylheteroCι_₃alkyl, aryl, heteroaryl, arylCι-₃alkyl , heteroarylC_!-₃alkyl , Cι-₃alkylenearyl , and Cι_₃alkyleneheteroaryl ; and n is 0 , 1 , or 2 , comprising the steps of (a) optionally converting a benzoic acid having a structure

wherein A is N0₂, NH₂, a protected NH₂, or N₃, to a corresponding acid chloride; (b) reacting the benzoic acid or the corresponding acid chloride of step (a) with an amine having a formula R⁹NH₂ to form a benzamide having a structure

(c) optionally converting the amide of step (b) to a corresponding imidoyl halogenide or triflate; (d) reacting the benzamide of step (b) or the corresponding imidoyl halogenide or triflate of step (c) with a carboxylic acid having a structure

PG-DH-C-C0₂H, wherein PG is a protecting group or hydrogen, to provide a compound having a structure

(e) subjecting the compound of step (d) to conditions to convert group A to an amino group amine form a cyclized compound, then removing the protecting group to provide a compound having a structure

to form the compound of structural formula

- so il. The method of claim 10 wherein the C moiety is chiral, and an S-enantiomer of the compound is prepared.

12. The method of claim 10 wherein the C moiety is chiral, and a desired S- or R-enantiomer of the compound is prepared in at least 95% stereochemical purity.

13. The method of claim 10 wherein the carboxylic acid of step (d) is an S-stereoisomer. 14. The method of claim 10 wherein the compound of step (d) is reduced using zinc metal dust or iron and an acid or ammonium chloride, tin(II) chloride in hydrochloric acid or an organic solvent, catalytic hydrogenation in the presence of palladium, platinum, rhodium, or nickel catalyst, sodium dithionite, thiourea dioxide, carbon monoxide and catalytic selenium, or carbon monoxide and a metal complex.

15. The method of claim 10 wherein the protecting group of step (d) is C(=0)C(CH₃)₃ or C(=0)0CH₂C₆H₅.

16. A method of cyclizing and preserving the chirality of a compound having a structure

wherein Z is selected from the group consisting of

NR⁷, O, and CR¹⁰R^1:L, wherein R¹⁰ and R¹¹, independently, are hydrogen or Cι_₃alkyl; PG is hydrogen or a protecting group, R⁵ is Cι_₃alkyl, CH₂CF₃, phenyl, CH₂C≡CH, C_!-₃alkyleneOR^e, C₁_alkyleneNR^aR^b, or C₁.₄alkylene- NHC(=0)0R^a, R⁸ is Cι_₃alkyl, halo, CF₃, or CH₂C_3-6hetero- cycloalkyl ; R⁹ is selected from the group consisting of hydrogen, Cx-galkyl, C₃_₆cycloalkyl, C₃-_Scycloalkenyl, C₃_₈heterocycloalkyl, aryl, heteroaryl, Cι-₃alklene- aryl, Cι-₃alkyleneheteroaryl, and C₂-₆alkenyl; n is 0, 1, or 2; comprising a step of subjecting the com- pound to reducing conditions to form a compound having a structure

17. The method of claim 16 wherein the reducing conditions comprise zinc metal dust or iron and an acid or ammonium chloride, tin (II) chloride in hydrochloric acid or an organic solvent, catalytic hydrogenation in the presence of palladium, platinum, rhodium, or nickel catalyst, sodium dithionite, thiourea dioxide, carbon monoxide and catalytic selenium, or carbon monoxide and a metal complex. 18. A method of cyclizing and preserving the chirality of a compound having a structure

wherein A is NH₂, protected NH₂, or N₃; Z is selected from the group consisting of

NR⁷, O, and CR¹⁰R¹¹, wherein R¹⁰ and R¹¹, independently, are hydrogen or Cι_₃alkyl; PG is hydrogen or a protecting group, R⁵ is d-galkyl , CH₂CF₃ , phenyl , CH₂C≡CH, ^alkyleneOR⁶, C_1-4alkyleneNRR^b, or Cι-₄alkylene-

NHC (=0) OR^a , R⁸ is C_halky!, halo, CF₃, or CH₂C₃.₆hetero- cycloalkyl; R⁹ is selected from the group consisting of hydrogen, C_halky!, C₃_₆cycloalkyl, C₃_₆cycloalkenyl, C₃-₈heterocycloalkyl, aryl, heteroaryl, Cι_₃alklene- aryl, Cχ_₃alkyleneheteroaryl, and C₂.₆alkenyl; n is 0, 1, or 2; comprising a step of deprotecting the protected NH₂ group to an NH group or converting the N₃ group to an NH₂ group, followed by cyclizing the resulting inter- mediate compound under acidic or basic conditions to form a compound having a structure