Gonadotropin-releasing hormone receptor antagonists and methods relating thereto

Abstract

GnRH receptor antagonists are disclosed which have utility in the treatment of a variety of sex-hormone related conditions in both men and women. The compounds of this invention have the structure: 1

Description

TECHNICAL FIELD

[0003] This invention relates generally to gonadotropin-releasing hormone (GnRH) receptor antagonists, and to methods of treating disorders by administration of such antagonists to a warm-blooded animal in need thereof.

BACKGROUND OF THE INVENTION

[0004] Gonadotropin-releasing hormone (GnRH), also known as luteinizing hormone-releasing hormone (LHRH), is a decapeptide (pGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2) that plays an important role in human reproduction. GnRH is released from the hypothalamus and acts on the pituitary gland to stimulate the biosynthesis and release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH). LH released from the pituitary gland is responsible for the regulation of gonadal steroid production in both males and females, while FSH regulates spermatogenesis in males and follicular development in females.

[0005] Due to its biological importance, synthetic antagonists and agonists to GnRH have been the focus of considerable attention, particularly in the context of prostate cancer, breast cancer, endometriosis, uterine leiomyoma, and precocious puberty. For example, peptidic GNRH agonists, such as leuprorelin (pGlu-His-Trp-Ser-Tyr-D-Leu-Leu-Arg-Pro-NHEt), have been used to treat such conditions. Such agonists appear to function by binding to the GnRH receptor in the pituitary gonadotropins, thereby inducing the synthesis and release of gonadotropins. Chronic administration of GNRH agonists depletes gonadotropins and subsequently down-regulates the receptor, resulting in suppression of steroidal hormones after some period of time (e.g., on the order of 2-3 weeks following initiation of chronic administration).

[0006] In contrast, GNRH antagonists are believed to suppress gonadotropins from the onset, and thus have received the most attention over the past two decades. To date, some of the primary obstacles to the clinical use of such antagonists have been their relatively low bioavailability and adverse side effects caused by histamine release. However, several peptidic antagonists with low histamine release properties have been reported, although they still must be delivered via sustained delivery routes (such as subcutaneous injection or intranasal spray) due to limited bioavailability.

[0007] In view of the limitations associated with peptidic GnRH antagonists, a number of nonpeptidic compounds have been proposed. For example, Cho et al. (J. Med Chem. 41:4190-4195, 1998) discloses thieno[2,3-b]pyridin-4-ones for use as GnRH receptor antagonists; U.S. Pat. Nos. 5,780,437 and 5,849,764 teach substituted indoles as GnRH receptor antagonists (as do published PCTs WO 97/21704, 98/55479, 98/55470, 98/55116, 98/55119, 97/21707, 97/21703 and 97/21435); published PCT WO 96/38438 discloses tricyclic diazepines as GnRH receptor antagonists; published PCTs WO97/14682, 97/14697 and 99/09033 disclose quinoline and thienopyridine derivatives as GnRH antagonists; published PCTs WO 97/44037, 97/44041, 97/44321 and 97/44339 teach substituted quinolin-2-ones as GnRH receptor antagonists; and published PCT WO 99/33831 discloses certain phenyl-substituted fused nitrogen-containing bicyclic compounds as GNRH receptor antagonists.

[0008] While significant strides have been made in this field, there remains a need in the art for effective small molecule GNRH receptor antagonists. There is also a need for pharmaceutical compositions containing such GnRH receptor antagonists, as well as methods relating to the use thereof to treat, for example, sex-hormone related conditions. The present invention fulfills these needs, and provides other related advantages.

SUMMARY OF THE INVENTION

[0009] In brief, this invention is generally directed to gonadotropin-releasing hormone (GNRH) receptor antagonists, as well as to methods for their preparation and use, and to pharmaceutical compositions containing the same. More specifically, the GnRH receptor antagonists of this invention are compounds having the following general structure (I): 2

[0010] including stereoisomers, prodrugs and pharmaceutically acceptable salts thereof, wherein A, Q, R1, R2, R3a, R3b, R4, R5, R6, and n are as defined below.

[0011] The GnRH receptor antagonists of this invention have utility over a wide range of therapeutic applications, and may be used to treat a variety of sex-hormone related conditions in both men and women, as well as a mammal in general (also referred to herein as a “subject”). For example, such conditions include endometriosis, uterine fibroids, polycystic ovarian disease, hirsutism, precocious puberty, gonadal steroid-dependent neoplasia such as cancers of the prostate, breast and ovary, gonadotrophe pituitary adenomas, sleep apnea, irritable bowel syndrome, premenstrual syndrome, benign prostatic hypertrophy, contraception and infertility (e.g., assisted reproductive therapy such as in vitro fertilization). The compounds of this invention are also useful as an adjunct to treatment of growth hormone deficiency and short stature, and for the treatment of systemic lupus erythematosis. The compounds are also useful in combination with androgens, estrogens, progesterones, and antiestrogens and antiprogestogens for the treatment of endometriosis, fibroids, and in contraception, as well as in combination with an angiotensin-converting enzyme inhibitor, an angiotensin II-receptor antagonist, or a renin inhibitor for the treatment of uterine fibroids. In addition, the compounds may be used in combination with bisphosphonates and other agents for the treatment and/or prevention of disturbances of calcium, phosphate and bone metabolism, and in combination with estrogens, progesterones and/or androgens for the prevention or treatment of bone loss or hypogonadal symptoms such as hot flashes during therapy with a GnRH antagonist.

[0012] The methods of this invention include administering an effective amount of a GNRH receptor antagonist, preferably in the form of a pharmaceutical composition, to a mammal in need thereof. Thus, in still a further embodiment, pharmaceutical compositions are disclosed containing one or more GNRH receptor antagonists of this invention in combination with a pharmaceutically acceptable carrier and/or diluent.

[0013] These and other aspects of the invention will be apparent upon reference to the following detailed description. To this end, various references are set forth herein which describe in more detail certain background information, procedures, compounds and/or compositions, and are each hereby incorporated by reference in their entirety.

DETAILED DESCRIPTION OF THE INVENTION

[0014] As mentioned above, the present invention is directed generally to compounds useful as gonadotropin-releasing hormone (GnRH) receptor antagonists. The compounds of this invention have the following structure (I): 3

[0015] including stercoisomers, prodrugs and pharmaceutically acceptable salts thereof,

[0016] wherein:

[0017] Q is a direct bond or —(CR8aR8b)r-Z-(CR10aR10b)s—;

[0018] A is O, S, or NR7;

[0019] r and s are the same or different and independently 0, 1, 2, 3, 4, 5 or 6;

[0020] n is 2, 3 or 4;

[0021] Z is a direct bond or —O—, —S—, —NR9—, —SO—, —SO2—, —OSO2—, —SO2O—, —SO2NR9—, —NR9SO2—, —CO—, —COO—, —OCO—, —CONR9—, —NR9CO—, —NR9CONR9a, —OCONR9— or —NR9COO—;

[0022] R1 and R2 are the same or different and independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocycle, substituted heterocycle, heterocyclealkyl, substituted heterocyclealkyl, —C(R1a)(═NR1b) or —C(NR1aR1c)(═NR1b);

[0023] or R1 and R2 taken together with the nitrogen atom to which they are attached form a heterocycle ring or a substituted heterocycle ring;

[0024] R3a and R3b are the same or different and, at each occurrence, independently hydrogen, alkyl, substituted alkyl, alkoxy, alkylthio, alkylamino, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocycle, substituted heterocycle, heterocyclealkyl, substituted heterocyclealkyl, —COOR14 or —CONR14R15;

[0025] or R3a and R3b taken together with the carbon atom to which they are attached form a homocyclic ring, substituted homocyclic ring, heterocyclic ring or substituted heterocyclic ring;

[0026] or R3a and R3b taken together form ═NR3c;

[0027] or R3a and the carbon to which it is attached taken together with R1 and the nitrogen to which it is attached form a heterocyclic ring or substituted heterocyclic ring;

[0028] R4 is higher alkyl, substituted alkyl, aryl, substituted aryl, heterocycle, substituted heterocycle, —COR11, —COOR11, —CONR12R13, —OR11, —OCOR11, —OSO2R11, —SR11, —SO2R11, —NR12R13, —NR11COR12, —NR11CONR12R13, —NR11SO2R12 or —NR11SO2NR12R13;

[0029] R5 is hydrogen, halogen, lower alkyl, substituted lower alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, alkoxy, alkylthio, alkylamino, cyano or nitro;

[0030] R6 is higher alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl;

[0031] R7 is hydrogen, —SO2R11, cyano, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl; and

[0032] R1a, R1b, R1c, R3c, R8a, R8b, R9, R9a, R10a, R10b, R11, R12, R13, R14 and R15 are the same or different and, at each occurrence, independently hydrogen, acyl, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocycle, substituted heterocycle, heterocyclealkyl or substituted heterocyclealkyl;

[0033] or R1a and R1b, R8a and R8b, R10a and R10b, R12 and R13, or R14 and R15 taken together with the atom or atoms to which they are attached form a homocyclic ring, substituted homocyclic ring, heterocyclic ring or substituted heterocyclic ring.

[0034] As used herein, the above terms have the following meaning:

[0035] “Alkyl” means a straight chain or branched, noncyclic or cyclic, unsaturated or saturated aliphatic hydrocarbon containing from 1 to 10 carbon atoms, while the term “lower alkyl” has the same meaning as alkyl but contains from 1 to 6 carbon atoms. The term “higher alkyl” has the same meaning as alkyl but contains from 2 to 10 carbon atoms. Representative saturated straight chain alkyls include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, and the like; while saturated branched alkyls include isopropyl, sec-butyl, isobutyl, tert-butyl, isopentyl, and the like. Representative saturated cyclic alkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like; while unsaturated cyclic alkyls include cyclopentenyl and cyclohexenyl, and the like. Cyclic alkyls are also referred to herein as a “homocycles” or “homocyclic rings.” Unsaturated alkyls contain at least one double or triple bond between adjacent carbon atoms (referred to as an “alkenyl” or “alkynyl”, respectively). Representative straight chain and branched alkenyls include ethylenyl, propylenyl, 1-butenyl, 2-butenyl, isobutylenyl, 1-pentenyl, 2-pentenyl, 3-methyl-1-butenyl, 2-methyl-2-butenyl, 2,3-dimethyl-2-butenyl, and the like; while representative straight chain and branched alkynyls include acetylenyl, propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 3-methyl-1-butynyl, and the like.

[0036] “Aryl” means an aromatic carbocyclic moiety such as phenyl or naphthyl.

[0037] “Arylalkyl” means an alkyl having at least one alkyl hydrogen atoms replaced with an aryl moiety, such as benzyl, —(CH2)2 phenyl, —(CH2)3 phenyl, —CH(phenyl)2, and the like.

[0038] “Heteroaryl” means an aromatic heterocycle ring of 5- to 10 members and having at least one heteroatom selected from nitrogen, oxygen and sulfur, and containing at least 1 carbon atom, including both mono- and bicyclic ring systems. Representative heteroaryls are furyl, benzofuranyl, thiophenyl, benzothiophenyl, pyrrolyl, indolyl, isoindolyl, azaindolyl, pyridyl, quinolinyl, isoquinolinyl, oxazolyl, isooxazolyl, benzoxazolyl, pyrazolyl, imidazolyl, benzimidazolyl, thiazolyl, benzothiazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, cinnolinyl, phthalazinyl, and quinazolinyl.

[0039] “Heteroarylalkyl” means an alkyl having at least one alkyl hydrogen atom replaced with a heteroaryl moiety, such as —CH2 pyridinyl, —CH2 pyrimidinyl, and the like.

[0040] “Heterocycle” (also referred to herein as a “heterocyclic ring”) means a 4- to 7-membered monocyclic, or 7- to 10-membered bicyclic, heterocyclic ring which is either saturated, unsaturated, or aromatic, and which contains from 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and wherein the nitrogen and sulfur heteroatoms may be optionally oxidized, and the nitrogen heteroatom may be optionally quaternized, including bicyclic rings in which any of the above heterocycles are fused to a benzene ring. The heterocycle may be attached via any heteroatom or carbon atom. Heterocycles include heteroaryls as defined above. Thus, in addition to the heteroaryls listed above, heterocycles also include morpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydroprimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, and the like.

[0041] “Heterocyclealkyl” means an alkyl having at least one alkyl hydrogen atom replaced with a heterocycle, such as —CH2 morpholinyl, and the like.

[0042] “Homocycle” (also referred to herein as “homocyclic ring”) means a saturated or unsaturated (but not aromatic) carbocyclic ring containing from 3-7 carbon atoms, such as cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclohexene, and the like.

[0043] The term “substituted” as used herein means any of the above groups (i.e., alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, homocycle, heterocycle and/or heterocyclealkyl) wherein at least one hydrogen atom is replaced with a substituent. In the case of a keto substituent (“—C(═O)—”) two hydrogen atoms are replaced. When substituted one or more of the above groups are substituted, “substituents” within the context of this invention include halogen, hydroxy, cyano, nitro, amino, alkylamino, dialkylamino, alkyl, alkoxy, alkylthio, haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycle and heterocyclealkyl, as well as —NRaRb, —NRaC(═O)Rb, —NRaC(═O)NRaNRb, —NRaC(═O)ORb —NRaSO2Rb, C(═O)Ra, C(═O)ORa, —C(═O)NRaRb, —OC(═O)NRaRb, —ORa, —SRa, —SORa, —S(═O)2Ra, —OS(═O)2Ra and —S(═O)2ORa. In addition, the above substituents may be further substituted with one or more of the above substituents, such that the substituent substituted alky, substituted aryl, substituted arylalkyl, substituted heterocycle or substituted heterocyclealkyl. Ra and Rb in this context may be the same or different and independently hydrogen, alkyl, haloalkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocycle, substituted heterocycle, heterocyclealkyl or substituted heterocyclealkyl.

[0044] “Halogen” means fluoro, chloro, bromo and iodo.

[0045] “Haloalkyl” means an alkyl having at least one hydrogen atom replaced with halogen, such as trifluoromethyl and the like.

[0046] “Alkoxy” means an alkyl moiety attached through an oxygen bridge (i.e., —O-alkyl) such as methoxy, ethoxy, and the like.

[0047] “Alkylthio” means an alkyl moiety attached through a sulfur bridge (i.e., —S-alkyl) such as methylthio, ethylthio, and the like.

[0048] “Alkylsulfonyl” means an alkyl moiety attached through a sulfonyl bridge (i.e., —SO2-alkyl) such as methylsulfonyl, ethylsulfonyl, and the like.

[0049] “Alkylamino” and “dialkylamino” mean one or two alkyl moiety attached through a nitrogen bridge (i.e., —N-alkyl) such as methylamino, ethylamino, dimethylamino, diethylamino, and the like.

[0050] In one embodiment of this invention, A is O and representative GnRH receptor antagonists of this invention include compounds having the following structure (II): 4

[0051] In another embodiment, Q is —(CR8aR8b)r-Z-(CR10aR10b)s—, r and s are both zero, and representative GnRH receptor antagonists of this invention include compounds having the following structure (III): 5

[0052] In another embodiment, A is S, as represented by the following structure (IV): 6

[0053] Similarly, in another embodiment, A is NR7, as represented by the following structure (V): 7

[0054] In further embodiments of this invention, R6 is substituted or unsubstituted benzyl as represented by the following structure (VI) (wherein Y represents one or more optional substituents as defined above): 8

[0055] In a more specific embodiment of structure (VI), A is O, n is 2, and each occurrence of R3a and R3b is H, as represented by the following structure (VII): 9

[0056] With regard to the “R1R2N(CR3aR3b)n—” moiety of structure (I), n may be 2, 3 or 4. Accordingly, this moiety may be represented by the following structure (i) when n is 2, structure (ii) when n is 3, and structure (iii) when n is 3: 10

[0057] wherein each occurrence of R3a and R3b above may be the same or different, and are as defined above. For example, when each occurrence of R3a and R3b in structures (i), (ii) and (iii) is hydrogen, the “R1R2N(CR3aR3b)n—” moiety has the structure R1R2N(CH2)2—, R1R2N(CH2)3— and R1R2N(CH2)4—, respectively.

[0058] The compounds of the present invention may be prepared by known organic synthesis techniques, including the methods described in more detail in the Examples. However in general, the compounds of structure (T) above may be made by the following Reaction Schemes. Specifically, compounds of structure (I) wherein A is oxygen may be made by Reaction Schemes A to E. Reaction Schemes F to K are appropriate for compounds of structure (I) wherein A is sulfur or NR7, as well as where A is oxygen. Reaction Scheme L shows conditions for the conversion of thiouracils (where A is sulfur) to embodiments wherein A is NR7. All substituents in the following Reaction Schemes are as defined above unless indicated otherwise. 1112

[0059] Allylurea (i) and substituted acetoacetate (ii) are condensed under acidic conditions in a solvent such as ethanol or DMF at 25 to 100° C. and then cyclized under strongly basic conditions to give the substituted 3-allyl-2,4-pyrimidinedione (iii). Compound (iii) can then be modified by alkylation with an appropriate alkyl halide (where X is halogen) in a solvent such as DMF or ethanol for 1 hour to 2 days in the presence of a base such as sodium hydride or tetrabutylammonium fluoride to yield (iv). Oxidation of the allyl functionality, using osmium tetroxide and/or sodium periodate in solvent such as THF and/or water for 1-24 hours, gives aldehyde (v). Bromination of (v) using bromine or n-bromosuccinimide in a solvent such as acetic acid or chloroform for 1-24 hours resulted in brominated compound (vi). Reductive amination of (vi) with an appropriate amine using a reducing agent such as sodium triacetoxyborohydride in a solvent such as dichloroethane at 0 to 100° C. for 1-24 hours gives (vii) which when coupled with an appropriate boronic acid in a solvent such as ethanol or toluene at 25 to 150° C. for 1-24 hours in the presence of a Pd(0) catalyst gives (viii).

[0060] The final two steps of the above synthesis may also be reversed, the Suzuki coupling in that instance being the penultimate step and the reductive amination the final step. Alternatively, compound (iii) may be synthesized by the procedure in Example 2. 13

[0061] Compound (iii) from Reaction Scheme Al may also be synthesized by condensing and cyclizing allyl isocyanate (viii) and appropriate aminoalkene ester (ix) such as ethyl 3-aminocrotonate in a solvent such as toluene or DMF at 25 to 100° C. for 1-24 hours. 14

[0062] Cyclization of (xi) and (xii) in a solvent such as ethanol or DMF at 25 to 150° C. for 1 to 24 hours gives oxazime (xiii). Amination of (xiii) in a solvent such as DMF or ethanol at 25 to 150° C. for 1-24 hours yielded uracil derivative (xiv). Alkylation of (xiv) by an appropriate alkyl bromide in the presence of a base such as sodium hydride or sodium hydroxide in a solvent such as THF or DMF at 0 to 100° C. for 1-24 hours gives substituted uracil (xvi). The order of the reaction scheme may be changed allowing oxazine (xiii) to first be alkylated under conditions above to (xv) followed by amination to the product (xvi). 15

[0063] Compound (xvii) or (xviii) react with an appropriately substituted isocyanate in a solvent such as toluene or chloroform at room temperature to 100° C. for 1-24 hours as an alternative synthesis to intermediate oxazine (xv). Amination with a substituted amine in a solvent such as DMF or ethanol at a temperature of 25 to 100° C. for a period of 1-24 hours results in product uracil (xvi). 16

[0064] Intermediate (xvi) may be brominated using a brominating agent such as N-bromosuccinimide or bromine in a solvent such as acetic acid or chloroform at 0 to 100° C. for a period of 1-24 hours to yield bromo compound (ixx). The bromo compound can undergo various palladium catalyzed cross coupling reactions. Compound (ixx) taken in solvent such as ethanol or THF under nitrogen atmosphere using an appropriate Pd(0) catalyst such as tetrakis(triphenylphosphine)Pd(0), may be reacted for 1-24 hours at 25 to 150° C. with either an aryl boronic acid (ArB(OH)2 where Ar is substituted aryl or heteroaryl) to yield product (xx) or with a substituted vinyl boronic acid to give compound (xxi). Compound (ixx) taken in solvent such as ethanol or THF using an appropriate Pd(0) catalyst in the presence of carbon monoxide and boronic acid yields (xxiv) after 1-24 hours at 0 to 150° C. Again using Pd(0) chemistry, compound (xxiii) is synthesized in a solvent such as THF or dioxane from the alkylation of (ixx) with an appropriate metal halide reagent for 1-24 hours at 0 to 150° C. Compound (ixx) in the presence of a substituted acetylene, Pd(0) catalyst, metal halide such as CuI, and base such as triethylamine in an appropriate solvent such as acetonitrile or DMF at 25 to 150° C. for 1-24 hours gives alkyne (xxii). Alkynyl uracil (xxii) may be selectively reduced to the alkene using a catalyst such as palladium/BaSO4 under hydrogen atmosphere in solvent such as ethyl acetate or methanol to give (xxi). 17

[0065] Vinyl ester (xxvi) and (xxv) can be cyclized in a solvent such as DMF or EtOH at 25 to 150° C. for 1-24 hours to give (xxvii). Alkylation of (xxvii) with an appropriate alkyl or aryl halide in a solvent such as DMF or THF in the presence of a base such as sodium hydride or sodium hydroxide for 1-24 hours at 0 to 150° C. gives (xxviii). 18

[0066] Vinyl ester (xxvi) can be condensed with a substituted amine in a solvent such as DMF or ethanol at 25 to 150° C. for 1-24 hours to give (xxix). Cyclization of (xxix) with an isocyanate, isothiocyanate, or other appropriate compound in a solvent such as DMF, THF or dioxane, with or without a base such as sodium ethoxide or sodium hydride at 0 to 100° C. for 1-24 hours gives product (xxviii). 19

[0067] Compound (xxx) may be alkylated by an appropriate alkyl halide in the presence of abase such as sodium hydride or sodium hydroxide in a solvent such as THF or DMF at 0 to 50° C. for 1-24 hours to give (xxxi), which under further alkylation by a second alkyl halide gives product (xxviii). 20

[0068] Compound (xxxi) may be alkylated by an appropriate alkyl halide in the presence of a base such as sodium hydride or sodium hydroxide in a solvent such as THF or DMF at 0 to 100° C. for 1-24 hours to give (xxxii). The terminal double bond is oxidized using an appropriate oxidizing reagent such as osmium tetroxide or sodium periodate in solvent such as THF and/or water for 1-24 hours at 0 to 100° C. to give aldehyde (xxxiii). Reductive amination of (xxxiii) with an appropriate amine using a reducing agent such as sodium cyanoborohydride in a solvent such as dichloroethane or acetonitrile at 0 to 100° C. for 1-24 hours gives (xxviii). 21

[0069] Compound (xxxii) can be oxidized to the alcohol (xxxiv) first by hydroboration with a borane complex in a solvent such as THF followed by oxidation with ozone or hydrogen peroxide in a solvent such as methanol, ethanol and/or water at −25 to 100° C. for a period of 0.5-24 hours. Treatment of (xxxiv) with mesyl or tosyl chloride in methylene chloride with a base such as triethylamine or pyridine at 0 to 100° C. for 1-24 hours followed by reaction with an amine in a solvent such as DMF or toluene for 0.5-12 hours at 25 to 100° C. gives (xxviii). 22

[0070] Compound (xxxi) can be alkylated with an appropriate ester in a solvent such as DMF or ethanol in the presence of a base such as sodium hydride or sodium ethoxide at a temperature of 25 to 150° C. for a period of 1-24 hours to give (xxxv). Ester (xxxv) in a solvent such as chloroform or benzene with substituted amine and Lewis acid such as triethylaluminum gives amide (xxxvi) after 1-24 hours at 0 to 100° C. Reduction of (xxxvi) with lithium aluminum hydride or borane complex in a solvent such as THF or ether at 0 to 100° C. for 1-12 hours gives product (xxviii). 23

[0071] Thiouracil compound (xxxvii) in the presence of a substituted sulfonylisocyanate in a solvent such as benzene or toluene for 1-48 hours at 25 to 125° C. gives sulfonamide (xxxviii). Thiouracil (xxxvii) chlorinated by thionyl chloride or phosphorous oxychloride at −25 to 100° C. for 1-24 hours followed by amination with an appropriate amine in a solvent such as benzene or toluene at 25 to 150° C. for 1-24 hours gives compound (xxxix). 24

[0072] Substituted amine in the presence of urea or thiourea is heated at a temperature of 50-125° C. for 0.5 to 12 hours to give (xl). Cyclization of (xl) with diketene at 50-150° C. in acidic media such as acetic or formic acid for 5 minutes to 4 hours gives a mixture of isomers (xli) and (xlii). Halogenation of (xlii) using a halogenating reagent such as N-halosuccinimide in chloroform or bromine in acetic acid for 5 minutes to 24 hours gives halogenated product (xliii). 25

[0073] Uracil compound (xliii) and an appropriately substituted alcohol are condensed under Mitsonobu conditions such as diethyl or dibutyl axodicarboxylate and triphenylphosphine in a solvent such as THF at 0-100° C. for 0.5 to 10 hours to give compound (xliv). A Suzuki coupling of (xliv) and a boronic acid or boronic acid ester in a solvent such as ethanol or toluene at 25 to 150° C. for 1-24 hours in the presence of a Pd(0) catalyst gives (xlv). Deprotection of the protected amine gives (xlvi). Reductive amination of (xlvi) with an appropriate aldehyde in a solvent such as methylene chloride or acetonitrile using a reducing agent such as sodium triacetoxyborohydride or sodium borohydride at 0 to 100° C. for 1-24 hours gives (xlvii). 26

[0074] Keto or aldehyde xlviii in the presence of chlorosulfonylisocyanate or chlorocarbonylisocyanate yields oxaz-2,4-dione xlix after stirring for 1-24 hours at 0° C. to 75° C. in a solvent such as THF or ether. Mitsonobu condensation with an appropriate alcohol gives l which when in the presence of amine R6NH2 at room temperature to 125° C., with or without solvent such as DMF or catalyst such as acetic or hydrochloric acid, for ½ to 24 hours gives xlvii.

[0075] The compounds of the present invention may generally be utilized as the free acid or free base. Alternatively, the compounds of this invention may be used in the form of acid or base addition salts. Acid addition salts of the free amino compounds of the present invention may be prepared by methods well known in the art, and may be formed from organic and inorganic acids. Suitable organic acids include maleic, fumaric, benzoic, ascorbic, succinic, methanesulfonic, acetic, trifluoroacetic, oxalic, propionic, tartaric, salicylic, citric, gluconic, lactic, mandelic, cinnamic, aspartic, stearic, palmitic, glycolic, glutamic, and benzenesulfonic acids. Suitable inorganic acids include hydrochloric, hydrobromic, sulfuric, phosphoric, and nitric acids. Base addition salts included those salts that form with the carboxylate anion and include salts formed with organic and inorganic cations such as those chosen from the alkali and alkaline earth metals (for example, lithium, sodium, potassium, magnesium, barium and calcium), as well as the ammonium ion and substituted derivatives thereof (for example, dibenzylammonium, benzylammonium, 2-hydroxyethylammonium, and the like). Thus, the term “pharmaceutically acceptable salt” of structure (I) is intended to encompass any and all acceptable salt forms.

[0076] In addition, prodrugs are also included within the context of this invention. Prodrugs are any covalently bonded carriers that release a compound of structure (I) in vivo when such prodrug is administered to a patient. Prodrugs are generally prepared by modifying functional groups in a way such that the modification is cleaved, either by routine manipulation or in vivo, yielding the parent compound. Prodrugs include, for example, compounds of this invention wherein hydroxy, amine or sulfhydryl groups are bonded to any group that, when administered to a patient, cleaves to form the hydroxy, amine or sulfhydryl groups. Thus, representative examples of prodrugs include (but are not limited to) acetate, formate and benzoate derivatives of alcohol and amine functional groups of the compounds of structure (I). Further, in the case of a carboxylic acid (—COOH), esters may be employed, such as methyl esters, ethyl esters, and the like.

[0077] With regard to stereoisomers, the compounds of structure (I) may have chiral centers and may occur as racemates, racemic mixtures and as individual enantiomers or diastereomers. All such isomeric forms are included within the present invention, including mixtures thereof. Compounds of structure (I) may also possess axial chirality which may result in atropisomers. Furthermore, some of the crystalline forms of the compounds of structure (I) may exist as polymorphs, which are included in the present invention. In addition, some of the compounds of structure (I) may also form solvates with water or other organic solvents. Such solvates are similarly included within the scope of this invention.

[0078] The effectiveness of a compound as a GnRH receptor antagonist may be determined by various assay methods. Suitable GnRH antagonists of this invention are capable of inhibiting the specific binding of GnRH to its receptor and antagonizing activities associated with GnRH. For example, inhibition of GnRH stimulated LH release in immature rats may be measured according to the method of Vilchez-Martinez (Endocrinology 96:1130-1134, 1975). Briefly, twenty-five day old male Spraque-Dawley rats are administered an GnRH antagonist in saline or other suitable formulation by oral gavage, sub-cutaneous injection, or intravenous injection. This is followed by sub-cutaneous injection of 200 ng GnRH in 0.2 ml saline. Thirty minutes after the last injection, the animals are decapitated and trunk blood collected. After centrifigation, the separated plasma is stored at −20° C. until determination of the LH and FSH by radioimmunoassay. Other techniques for determining the activity of GNRH receptor antagonists are well known in the field, such as the use of cultured pituitary cells for measuring GnRH activity (Vale et al., Endocrinology 91:562-572, 1972), and a technique for measuring radioligand binding to rat pituitary membranes (Perrin et al., Mol. Pharmacol. 23:44-51, 1983).

[0079] For example, effectiveness of a compound as a GnRH receptor antagonist may be determined by one or more of the following assays.

[0080] Rat Anterior Pituitary Cell Culture Assay of GNRH Antagonists

[0081] Anterior pituitary glands are collected from 7-week-old female Sprague-Dawley rats and the harvested glands digested with collagenase in a dispersion flask for 1.5 hr at 37° C. After collagenase digestion, the glands are further digested with neuramimidase for 9 min at 37° C. The digested tissue is then washed with 0.1% BSA/McCoy's 5A medium, and the washed cells suspended in 3% FBS/0.1 BSA/McCoy's SA medium and plated into 96-well tissue culture plates at a cell density of 40,000 cells per well in 200 μl medium. The cells are then incubated at 37° C. for 3 days. One pituitary gland normally yields one 96-well plate of cells, which can be used for assaying three compounds. For assay of a GnRH antagonist, the incubated cells are first washed with 0.1% BSA/McCoy's 5A medium once, followed by addition of the test sample plus 1 nM GnRH in 200 μl 0.1% BSA/McCoy's 5A medium in triplicate wells. Each sample is assayed at 5-dose levels to generate a dose-response curve for determination of its potency on the inhibition of GnRH stimulated LH and/or FSH release. After 4-hr incubation at 37° C., the medium is harvested and the level of LH and/or FSH secreted into the medium determined by RIA.

[0082] RIA of LH and FSH

[0083] For determination of the LH levels, each sample medium is assayed in duplicates and all dilutions are done with RIA buffer (0.01M sodium phosphate buffer/0.15M NaCl/1% BSA/0.01% NaN3, pH 7.5) and the assay kit is obtained from the Nation Hormone and Pituitary Program supported by NIDDK. To a 12×75 mm polyethylene test tube is added 100 μl of sample medium diluted 1:5 or rLH standard in RIA buffer and 100 μl of [125I]-labeled rLH (−30,000 cpm) plus 100 μl of rabbit anti-rLH antibody diluted 1:187,500 and 100 μl RIA buffer. The mixture is incubated at room temperature over-night. In the next day, 100 μl of goat anti-rabbit IgG diluted 1:20 and 100 μl of normal rabbit serum diluted 1:1000 are added and the mixture incubated for another 3 hr at room temperature. The incubated tubes are then centrifuged at 3,000 rpm for 30 min and the supernatant removed by suction. The remaining pellet in the tubes is counted in a gamma-counter. RIA of FSH is done in a similar fashion as the assay for LH with substitution of the LH antibody by the FSH antibody diluted 1:30,000 and the labeled rLH by the labeled rFSH.

[0084] Radio-Iodination of GnRH Peptide

[0085] The GnRH analog is labeled by the chloramine-T method. To 10 μg of peptide in 20 μl of 0.5M sodium phosphate buffer, pH 7.6, is added 1 mCi of Nal251, followed by 22.5 μg chloramine-T and the mixture vortexed for 20 sec. The reaction is stopped by the addition of 60 μg sodium metabisulfite and the free iodine is removed by passing the iodinated mixture through a C-8 Sep-Pak cartridge (Millipore Corp., Milford, Mass.). The peptide is eluted with a small volume of 80% acetonitrile/water. The recovered labeled peptide is further purified by reverse phase HPLC on a Vydac C-18 analytical column (The Separations Group, Hesperia, Calif.) on a Beckman 334 gradient HPLC system using a gradient of acetonitrile in 0.1% TFA. The purified radioactive peptide is stored in 0.1% BSA/20% acetonitrile/0.1% TFA at −80° C. and can be used for up to 4 weeks.

[0086] GnRH Receptor Membrane Binding Assay

[0087] Cells stably, or transiently, transfected with GnRH receptor expression vectors are harvested, resuspended in 5% sucrose and homogenized using a polytron homogenizer (2×15 sec). Nucleii are removed by centrifugation (3000×g for 5 min.), and the supernatant centrifuged (20,000×g for 30 min, 4° C.) to collect the membrane fraction. The final membrane preparation is resuspended in binding buffer (10 mM Hepes (pH 7.5), 150 mM NaCl, and 0.1% BSA) and stored at −70° C. Binding reactions are performed in a Millipore MultiScreen 96-well filtration plate assembly with polyethylenimine coated GF/C membranes. The reaction is initiated by adding membranes (40 ug protein in 130 ul binding buffer) to 50 ul of [125I]-labeled GnRH peptide (−100,000 cpm), and 20 ul of competitor at varying concentrations. The reaction is terminated after 90 minutes by application of vacuum and washing (2×) with phosphate buffered saline. Bound radioactivity is measured using 96-well scintillation counting (Packard Topcount) or by removing the filters from the plate and direct gamma counting. Ki values are calculated from competition binding data using non-linear least squares regression using the Prism software package (GraphPad Software).

[0088] Activity of GnRH receptor antagonists are typically calculated from the IC50 as the concentration of a compound necessary to displace 50% of the radiolabeled ligand from the GnRH receptor, and is reported as a “Ki” value calculated by the following equation: 1$K_i=\frac{{\mathrm{IC}}_{50}}{1+L/K_D}$

[0089] where L=radioligand and KD=affinity of radioligand for receptor (Cheng and Prusoff, Biochem. Pharmacol. 22:3099, 1973). GnRH receptor antagonists of this invention have a Ki of 100 μM or less. In a preferred embodiment of this invention, the GnRH receptor antagonists have a Ki of less than 10 μM, and more preferably less than 1 μM, and even more preferably less than 0.1 μM (i.e., 100 nM). To this end, representative GnRH receptor antagonists of this invention which have a Ki of less than 100 nM when using the GnRH receptor membrane binding assay as described above include the following Compound Nos.

Table
No. Compound No.
1   3, 10, 11, 12, 13
3   1, 4
6   1, 2, 3, 8
7   2, 3, 4, 7, 9, 10, 11
8   2, 3, 4, 7, 12, 13, 14, 15, 16, 17, 19-21, 23, 25, 27-29,
    31-36, 38-39, 42, 44, 51, 58, 59, 61, 63-66, 68, 70, 75,
    77-97, 100, 106, 107, 109-113, 115-117, 124-135, 137-140
9   3, 4, 6, 7, 10, 14-16, 19, 24, 26, 32, 35, 37, 39, 40, 42,
    46-49, 51-53, 55, 56, 58, 61, 63, 64, 66-68, 70, 72-78,
    80-82, 85, 86, 89-93, 95, 96, 98-102, 107, 109, 110, 112,
    138, 140, 142, 143, 145, 146, 149, 151-155, 157-162, 164,
    166-168, 170-176, 178-188, 191, 194-197, 199, 200,
    202-207, 210-212, 214, 215, 219, 224, 225, 227, 229,
    232-234, 237, 240, 242, 244, 245, 247, 249, 251-256,
    258-261, 263, 265-267, 270, 275, 277-279, 281, 286,
    287, 295-301, 304, 305, 307-309, 312, 318, 320, 321, 325-329,
    331-336, 338-346, 348-355, 357-359, 361, 362, 364-385,
    387-397, 399, 402, 406, 409, 410, 413, 415, 417, 419-424,
    427-434, 437-439, 441, 443, 446, 448, 454, 455, 470, 473, 477,
    480-487, 490-493, 495, 502, 503, 509, 512, 514, 517, 519-524,
    547-552, 554-560, 565-568, 570, 581-584, 589, 595, 596, 602,
    606-609, 612, 613, 618, 621, 622, 624-627, 634, 636, 642-648,
    652, 653, 655-658, 660-662, 664, 665, 668-672, 677, 678, 680,
    681, 688, 694, 696, 698-702, 704, 706-708, 711, 712, 714,
    718-726, 729-741, 745, 747-750, 755-756, 759-763,
    774
10  1, 10, 14, 21-23, 25, 52, 54-56, 60, 61, 64, 65
12  1, 4, 5, 10, 20-22, 24, 27, 32
13  2, 4
15  1, 2

[0090] As mentioned above, the GnRH receptor antagonists of this invention have utility over a wide range of therapeutic applications, and may be used to treat a variety of sex-hormone related conditions in both men and women, as well as mammals in general. For example, such conditions include endometriosis, uterine fibroids, polycystic ovarian disease, hirsutism, precocious puberty, gonadal steroid-dependent neoplasia such as cancers of the prostate, breast and ovary, gonadotrophe pituitary adenomas, sleep apnea, irritable bowel syndrome, premenstrual syndrome, benign prostatic hypertrophy, contraception and infertility (e.g., assisted reproductive therapy such as in vitro fertilization).

[0091] The compounds of this invention are also useful as an adjunct to treatment of growth hormone deficiency and short stature, and for the treatment of systemic lupus erythematosis.

[0092] In addition, the compounds are useful in combination with androgens, estrogens, progesterones, and antiestrogens and antiprogestogens for the treatment of endometriosis, fibroids, and in contraception, as well as in combination with an angiotensin-converting enzyme inhibitor, an angiotensin II-receptor antagonist, or a renin inhibitor for the treatment of uterine fibroids. The compounds may also be used in combination with bisphosphonates and other agents for the treatment and/or prevention of disturbances of calcium, phosphate and bone metabolism, and in combination with estrogens, progesterones and/or androgens for the prevention or treatment of bone loss or hypogonadal symptoms such as hot flashes during therapy with a GNRH antagonist.

[0093] In another embodiment of the invention, pharmaceutical compositions containing one or more GnRH receptor antagonists are disclosed. For the purposes of administration, the compounds of the present invention may be formulated as pharmaceutical compositions. Pharmaceutical compositions of the present invention comprise a GnRH receptor antagonist of the present invention and a pharmaceutically acceptable carrier and/or diluent. The GnRH receptor antagonist is present in the composition in an amount which is effective to treat a particular disorder—that is, in an amount sufficient to achieve GnRH receptor antagonist activity, and preferably with acceptable toxicity to the patient. Typically, the pharmaceutical compositions of the present invention may include a GnRH receptor antagonist in an amount from 0.1 mg to 250 mg per dosage depending upon the route of administration, and more typically from 1 mg to 60 mg. Appropriate concentrations and dosages can be readily determined by one skilled in the art.

[0094] Pharmaceutically acceptable carrier and/or diluents are familiar to those skilled in the art. For compositions formulated as liquid solutions, acceptable carriers and/or diluents include saline and sterile water, and may optionally include antioxidants, buffers, bacteriostats and other common additives. The compositions can also be formulated as pills, capsules, granules, or tablets which contain, in addition to a GNRH receptor antagonist, diluents, dispersing and surface active agents, binders, and lubricants. One skilled in this art may further formulate the GNRH receptor antagonist in an appropriate manner, and in accordance with accepted practices, such as those disclosed in Remington's Pharmaceutical Sciences, Gennaro, Ed., Mack Publishing Co., Easton, Pa. 1990.

[0095] In another embodiment, the present invention provides a method for treating sex-hormone related conditions as discussed above. Such methods include administering of a compound of the present invention to a warm-blooded animal in an amount sufficient to treat the condition. In this context, “treat” includes prophylactic administration. Such methods include systemic administration of a GnRH receptor antagonist of this invention, preferably in the form of a pharmaceutical composition as discussed above. As used herein, systemic administration includes oral and parenteral methods of administration. For oral administration, suitable pharmaceutical compositions of GnRH receptor antagonists include powders, granules, pills, tablets, and capsules as well as liquids, syrups, suspensions, and emulsions. These compositions may also include flavorants, preservatives, suspending, thickening and emulsifying agents, and other pharmaceutically acceptable additives. For parental administration, the compounds of the present invention can be prepared in aqueous injection solutions which may contain, in addition to the GNRH receptor antagonist, buffers, antioxidants, bacteriostats, and other additives commonly employed in such solutions.

[0096] The following example is provided for purposes of illustration, not limitation. In summary, the GnRH receptor antagonists of this invention may be assayed by the general methods disclosed above, while the following Examples disclose the synthesis of representative compounds of this invention.

EXAMPLE 1

Synthesis of 1-(2,6-difluorobenzyl)-5-(3-methoxyphenyl)-6-methyl-3-[N-methyl-N-(2-pyridylethyl)aminoethyl]uracil

[0097] 27 28

[0098] Step 1A 3-Allyl-6-methyluracil

[0099] To allylurea (25 g, 0.25 mol) in ethanol (10 mL) was added ethyl acetoacetate (31.86 mL, 0.25 mol) and 10 drops conc. HCl. After 12 days at room temperature, concentration gave an oil which was dissolved in MeOH. KOH (22.5 g, 0.34 mol) was added and the solution refluxed for 1 hour. After neutralization, the resulting solid 1 was collected. Yield 2.7 g (7%). NMR (CDCl3) δ: 2.16 (3H, s), 4.52 (2H, d), 5.18 (1H, d), 5.23 (1H, d), 5.60 (1H, s), 5.82-5.93 (1H, m), 10.3 (1H, s).

[0100] Step 1 B 3-Allyl-1-(2,6-difluorobenzyl)-6-methyluracil

[0101] To 1 (2.6 g, 15.7 mmol) in DMF (20 mL) was added tetrabutylammoniumfluoride (25 mmol) and 2,6-difluorobenzyl bromide (4.14 g, 20 mmol). After 2 days stirring at room temperature, column chromatography using ethyl acetate/hexane gave 2.7 g (59% yield) of 2. MS 293 (MH)+.

[0102] Step 1 C3-Acetaldehyde-1-(2,6-difluorobenzyl)-6-methyluracil

[0103] To a solution of 2 (1.46 g, 5 mmol) in THF (20 mL) and H2O (10 mL) was added osmium tetroxide (200 mg) and NalO4 (3.2 g, 15 mmol). After 2 hr. another 1 g of NalO4 was added. Ethyl acetate and H2O were added and the layers separated. Evaporation of the organic layer gave 3 as a crude solid (1.0 g, 68%). MS 295 (MH)+.

[0104] Step 1 D 3-Acetaldehyde-5-bromo-1-(2,6-difluorobenzyl)-6-methyluracil

[0105] 3 (294 mg, 1 mmol) was dissolved in acetic acid and bromine (1.2 eq) was added. The reaction mixture was stirred at room temperature for 1 hr, evaporated and the residue was dissolved in EtOAc, washed with 1N KOH solution and concentrated to give 4 as a crude oil (295 mg, 79%). MS 373/375 (MH)+. NMR (CDCl3) δ: 2.55 (3H, s), 4.87 (2H, d), 5.33 (2H, s), 7.26-7.33 (3H, 2m), 9.59 (1h, d).

[0106] Step 1E 5-Bromo-1-(2,6-difluorobenzyl)-6-methyl-3-[N-methyl-N-(2-pyridylethyl)aminoethyl]uracil

[0107] To 4 (295 mg, 0.8 mmol) in dichloroethane was added 2-(methylaminoethyl)pyridine (200 mg, 1.5 mmol) and NaBH(OAc)3 (636 mg, 3 mmol). After overnight stirring, the reaction mixture was concentrated, dissolved in EtOAc, washed with H2O, and purified by prep TLC to give 190 mg of 5 (48%).

[0108] Step 1F 1-(2,6-Difluorobenzyl)-5-(3-methoxyphenyl)-6-methyl-3-[N-methyl-N-(2-pyridylethyl)aminoethyl]uracil (“Cpd. No. 1”)

[0109] 5 (150 mg, 0.3 mmol), 3-methoxyphenylboronic acid (92 mg, 0.6 mmol), K2CO3 (100 mg, 0.72 mmol), and Pd(PPh3)4 (20 mg) in H2O (5 mL) and toluene (10 mL) was heated in a sealed tube at 100 IC for 12 hr. Purification by HPLC gave 40 mg of 6 (“Cpd. No. 1”) as the TFA salt (21% yield). MS 521 (MH)+ NMR (CDCl3) δ: 2.14 (3H, s), 3.02 (3H, s), 3.50 (2H, m), 3.63 (2H, m), 3.71 (2H, m), 3.81 (3H, s), 4.37 (2H, m), 5.25 (2H, s), 6.81-6.83 (2H, m), 6.88-6.95 (3H, m), 7.28-7.34 (2H, m), 7.63 (1H, m), 7.89 (1H, d), 8.13 (1H, t), 8.62 (1H, br s).

EXAMPLE 2

Representative Compounds

[0110] Following the procedures as set forth in Example 1 above, the compounds of the following Table 1 were prepared.

TABLE 1
29
Cpd.
No.	R1	R2	MS (MH)+
1-1	2-PyCH2CH2	H	507
1-2	2-PyCH2	H	493
1-3	2-PyCH2	Me	507
1-4	Bz	Me	506
1-5	PhCH2CH2	Me	520
1-6	2-PyCH2CH2	Pr	549
1-7	PhCHCH3	Me	520
1-8	PhCHCH3	Me	520
1-9	Bz	(CH3)2N(CH2)2	563
1-10	2-PyCH2CH2	Et	535
1-11	2-(6-Cl—Py)CH2CH2	Me	416, 555
1-12	2-PyCH2CH2	CyclopropylCH2	561
1-13	1-Et-3-pyrrolidinyl	Et	527
1-14	30	H	557
1-15	31	H	541
1-16	(CH3)2CHOCH2CH2CH2	H	502
1-17	Et2NCH2CH2	Me	515
1-18	32	H	513
1-19	CH3OCH2CH2CH2	H	474
1-20	(EtO)2CHCH2CH2	H	532
1-21	CH3OCH2CH2	Me	474
1-22	33	Me	575
1-23	34	Me	575
1-24	35	H	550
1-25	CH3OCH2CH2CH2	Me	488
1-26	(EtO)2CHCH2CH2	Me	546
1-27	36	Me	564
1-28	37	Me	571
1-29	38	Me	555
1-30	(CH3)2CHOCH2CH2CH2	Me	516
1-31	39	Me	527
1-32	40	Me	513
1-33	41	Me	502
1-34	Et2NCH2CH2	Me	487
1-35	Me2NCH2CH2CH2	Me	501
1-36	Et2NCH2CH2CH2	Me	529
1-37	42	Me	499
1-38	EtOCH2	Me	474
1-39	43	Me	516
1-40	44	Me	550
1-41	45	H	513
1-42	46	H	496
1-43	47	H	529
1-44	Me2NCH2CH2CH2	H	487
1-45	Et2NCH2CH2CH2	H	515
1-46	48	H	510
1-47	49	H	541
1-48	Me2CHCH2OCH2CH2CH2	H	516
1-49	50	H	502
1-50	51	H	471
1-51	52	H	471
1-52	53	H	536
1-53	54	H	516
1-54	PyCH2CH2	HOCH2CH2	551
1-55	55	Me	527
1-56	56	Me	510
1-57	57	Me	543
1-58	Me2CHN(Me)CH2CH2CH2	Me	529
1-59	58	Me	524
1-60	59	Me	555
1-61	Me2CHCH2OCH2CH2CH2	Me	530
1-62	BuOCH2CH2CH2	Me	530
1-63	60	Me	499
1-64	61	Me	499
1-65	62	Me	550
1-66	63	Me	530
1-67	PhCH2CH2CH2	H	506
1-68	64	Me	535

EXAMPLES 3

Further Representative Compounds

[0111] By reversing Step 1E and Step 1F in Example 1, where the boronic acid coupling is performed followed by the reductive amination, the compounds of the following Tables 2-7 were also prepared.

TABLE 2
65
	Cpd. No.	R1	R2	MS (MH)+
	2-1	2-PyCH2CH2	Me	519
	2-2	Bz	Me	504
	2-3	2-PyCH2	H	491
	2-4	2-PyCH2CH2	H	505
	2-5	PhCH2CH2	Me	518

[0112]

TABLE 3
66
	Cpd. No.	R1	R2	MS (MH)+
	3-1	2-PyCH2CH2	Me	535
	3-2	PhCH2CH2	Me	534
	3-3	4-PyCH2CH2	Me	535
	3-4	2-PyCH2CH2	Et	549

[0113]

TABLE 4
67
Cpd. No.	R1	R2	MS (MH)+
4-1	PhCH2	Me	474
4-2	2-PyCH2CH2	Me	489
4-3	68	69	518
4-4	70	71	520
4-5	72	73	491
4-6	74	75	547

[0114]

TABLE 5
76
Cpd. No.	R1	R2	MS (MH)+
5-1	PhCH2CH2	Me	488
5-2	2-PyCH2CH2	Me	503
5-3	77		545
5-4	78		559

[0115]

TABLE 6
79
Cpd. No.	R4	MS (MH)+
6-1	80	509
6-2	81	583
6-3	82	549
6-4	83	481
6-5	84	551
6-6	85	495
6-7	86	519
6-8	87	606
6-9	88	497
6-10	89	525
6-11	90	559/561
6-12	91	525
6-13	92	519
6-14	93	505
6-15	94	551
6-16	95	548
6-17	96	490
6-18	97	504
6-19	98	516
6-20	99	575
6-21	100	543
6-22	101	535
6-23	102	581
6-24	103	541
6-25	104	575
6-26	105	521
6-27	106	519
6-28	107	531
6-29	108	533
6-30	109	567
6-31	110	519
6-32	111	537
6-33	112	521
6-34	113	581
6-35	114	509
6-36	115	509
6-37	116	536
6-38	117	497
6-39	118	535
6-40	119	519
6-41	120	567
6-42	121	481
6-43	122	497
6-44	123	507
6-45	124	548
6-46	125	573
6-47	126	584
6-48	127	645
6-49	128	534
6-50	129	535
6-51	130	506
6-52	131	562
6-53	132	533
6-54	133	516
6-55	134	505

[0116]

TABLE 7
135
	Cpd. No.	NR1R2	MS (MH)+
	7-1	136	486
	7-2	137	539
	7-3	138	567
	7-4	139	571
	7-5	140	590
	7-6	141	527
	7-7	142	486
	7-8	143	514
	7-9	144	530
	7-10	145	484
	7-11	146	513
	7-12	147	546
	7-13	148	553
	7-14	149	485
	7-15	150	485
	7-16	151	499
	7-17	152	499
	7-18	153	513
	7-19	154	472
	7-20	155	546

EXAMPLE 4

Synthesis OF 5-bromo-1-(2,6-difluorobenzyl)-6-methyl-uracil

[0117] 156

[0118] Step A 2,6-Difluorobenzyl Urea

[0119] 2,6-Difluorobenzylamine (25.0 g, 0.175 mol) was added dropwise to a stirring solution of urea (41.92 g, 0.699 mol) in water (70 mL) and concentrated HCl (20.3 mL). The resulting mixture was refluxed for 2.5 hours, after which time it was cooled to room temperature. The solids that formed were filtered under vacuum, and were washed thoroughly with water. After drying under vacuum, the solids were recrystallized from EtOAc to yield the product 1 as light white needles (24.0 g, 0.129 mol, 74%).

[0120] Step B 1-(2,6-Difluorobenzyl)-6-methyl-uracil

[0121] Diketene (9.33 mL, 0.121 mol) was added in one portion to a refluxing solution of 2,6-difluorobenzyl urea 1 (20.46 g, 0.110 mol) and glacial acetic acid (110 mL). After 40 minutes at reflux, the mixture was cooled to room temperature and poured onto water (600 mL). The precipitate was collected by filtration, washed with water and dried under vacuum to yield a 1:3 mixture of isomers 2 and 3, respectively (19.07 g, 0.076 mol, 69%). The mixture was recrystallized from acetonitrile (600 mL) to give the pure title compound 3 as white prisms (1St crop −7.85 g, 0.031 mol, 28%).

[0122] Step C5—Bromo-1-(2,6-difluorobenzyl)-6-methyl-uracil

[0123] 1-(2,6-Difluorobenzyl)-6-methyl-uracil 3 (7.56 g, 30 mmol) was suspended in glacial acetic acid (100 mL) and to that mixture, bromine (1.93 mL, 37.5 mmol) was added dropwise. The resulting orange solution turned into a suspension in about 5 minutes. After stirring for 1 hour at room temperature, the precipitate was filtered under vacuum and washed with water. The solids were triturated with diethyl ether and dried under vacuum to give 4 (8.6 g, 0.026 mmol, 87%).

EXAMPLE 5

Further Representative Compounds

[0124] 157

[0125] Step A-1 3-(1-[2-BOC-(S)-amino-3-phenylpropyl)-5-bromo-1-(2,6-difluorobenzyl)-6-methyl-uracil

[0126] 2-BOC-(S)-amino-3-phenyl-1-propanol (2.51 g, 10 mmol) and triphenylphosphine (3.14 g, 12 mmol) were added to a solution of 5-bromo-1-(2,6-difluorobenzyl)-6-methyl-uracil 1 (3.31 g, 10 mmol) in THF (50 mL). Di-tert-butyl azodicarboxylate (2.76 g, 12 mmol) was added in several portions over 5 minutes. After 5 minutes the reaction mixture was clear. After 1 hour the reaction mixture was concentrated and the residue was purified by silica cartridge column (hexane/EtOAc as elutant). Concentration of like fractions gave 6.8 g of an oily material which was precipitated from hexane to yield product 2 (4.95 g, 88%).

[0127] Step B-1 3-(1-[2-BOC-(S)-amino-3-phenylpropyl)-1-(2,6-difluorobenzyl)-5-(2-fluoro-3-methoxyphenyl)-6-methyl-uracil

[0128] Compound 2 (4.95 g, 8.78 mmol) and sodium carbonate (2.12 g, 20 mmol) were suspended in toluene (50 mL) and dimethoxyethane (10 mL). Water (20 mL) was added and N2 was bubbled through the reaction mixture. After 5 minutes, both layers were clear and Pd(OAc)2 (394 mg, 0.2 eq) and triphenylphosphine ((921 mg, 0.4 eq) were added. The boronic acid (1.7 g, 10 mmol) was added and the reaction vessel was sealed and heated overnight at 100° C. The organic layer was separated, evaporated and purified by silica chromatography. Product containing fractions were combined and evaporated to give 3 as a brown oil (1.5 g, 28% yield).

[0129] Step C-1 3-(1-[2-(S)-Amino-3-phenylpropyl)-1-(2,6-difluorobenzyl)-5-(2-fluoro-3-methoxyphenil)-6-methyl-uracil

[0130] Compound 3 (1.5 g, 2.5 mmol) in trifluoroacetic acid/dichloromethane (1:1, 50 mL) was heated for 4 hours. Evaporation gave a red oil which was purified by reverse phase prep HPLC using water/CH3CN with 0.05% trifluoroacetic acid as elutant. The product containing fractions were concentrated and lyophilized to give product 4 (0.56 g, 44%, MH+=510). 158

[0131] Step A-2 1-(2,6-Difluorobenzyl-3-[(2R)-tert-butoxycarbonylamino-2-phenyl]ethyl-6-methyl-5-(4-[tetrahydropyran-2-yloxy]phenyl)uracil

[0132] 1-(2,6-Difluorobenzyl-3-[(2R)-tertbutylcarbonylamino-2-phenyl]ethyl-6-methyl-5-bromouracil 1 (2.58 g, 4.7 mmol), tetrakis(triphenylphosphine) palladium (0) (550 mg, 0.47 mmol), 4-hydroxyphenyl boronic acid tetrahydropyran ether (1.25 g, 5.7 mmol) and barium hydroxide (38 mL of 0.14M solution, 5.2 mmol) in a benzene/ethanol/dimethoxyethane solution (10/1/11, 90 mL) was heated at 90° C. in a pressure vessel under N2 atmosphere overnight. The organic layer was concentrated in vacuo and the residue was purified by silica gel chromatography (hexanes/ethyl acetate as elutant) to give 3.0 g of 2 as an off white foam.

[0133] Step B-2 1-(2,6-Difluorobenzyl-3-[(2R)-tert-butoxycarbonylamino-2-phenyl]ethyl-6-methyl-5-(4-hydroxyphenyl)uracil

[0134] A mixture of 2 (3.0 g, 4.6 mmol) and pyridinium-p-toluenesulfonate (231 mg, 0.92 mmol) in ethanol (92 mL) was stirred at 45° C. for 5 hours. The reaction mixture was concentrated in vacuo and the residue was dissolved in methylene chloride and H2O. The organic layer was concentrated and the residue purified by silica gel chromatography using hexanes/ethyl acetate as elutant to give 2.1 g of compound 3 as a yellow foam.

[0135] Step C-2 1-(2,6-Difluorobenzyl-3-[(2R)-amino-2-phenyl]ethyl-5-(4-[4-tolyloxy]phenyl)uracil

[0136] Substituted uracil 3 (50 mg, 0.089 mmol), p-tolylboronic acid (18 mg, 0.133 mmol), copper (II) acetate (16 mg, 0.089 mmol) and triethylamine (0.06 mL, 0.445 mmol) in CH2Cl2 (1 mL) were stirred for 3 days at room temperature. The reaction mixture was purified by silica gel chromatography using 1% McOH in CH2Cl2 to give 30 mg of protected product. This material was dissolved in CH2Cl2 (1 mL) with 5 drops of trifluoroacetic acid. Purification by reverse phase HPLC/MS gave 5.0 mg of product 4 m/z (CI) 554 (MH+). 159

[0137] Step A-3 (S)-3-(1-N-tert-Butoxycarbonylamino-1-carboxylic Acid ethyl)-1-(2,6-difluorobenzyl)-5-(3-methoxyphenyl)-6-methyluracil

[0138] To a stirred solution of 1 (306 mg, 0.55 mmol) in tetrahydrofuran (15 mL) at room temperature, was added aqueous lithium hydroxide solution (15 mL of a 1 M solution, 15 mmol). After 2 h, most of the tetrahydrofuran was removed in vacuo and the resulting solution was acidified to pH 4 (with 10% aqueous citric acid solution). The resultant precipitate was extracted into ethyl acetate (2×15 mL) and the combined organic layer was washed with water, brine and dried (MgSO4). The solvent was removed in vacuo to give 2 (283 mg, 94%) as a yellow oil which was not purified further, δH (300 MHz; CDCl3) 7.26-7.34 (2H, m, Ar), 6.73-6.95 (5H, m, Ar), 5.74 (1H, brd, J 6, NH), 5.37 (1H, d, J 16, CHHAr), 5.22 (1H, d, J 16, CHHAr), 4.62 (1H, brs, CHN), 4.32-4.49 (2H, m, CH2N), 3.80 (3H, s, OCH3), 2.17 (3H, s, CH3) and 1.42 (9H, s, 3×CH3), m/z (CI) 446 (MH+-Boc, 100%). Step B-3 (S)-3-(1-Amino-1-NH-benzylcarboxamide ethyl)-1-(2,6-difluorobenzyl)-5-(3-methoxyphenyl)-6-methyluracil trifluoroacetic acid salt

[0139] To a stirred solution of 2 (20 mg, 0.037 mmol), benzylamine (15 μL, 0.14 mmol), 1-(hydroxy)benzotriazole hydrate (9 mg, 0.066 mmol) and triethylamine (10 μL, 0.074 mmol) in anhydrous N,N-dimethylformamide (1 mL) at room temperature, was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (11 mg, 0.056 mmol). After 10 h, the reaction mixture was poured into water (ca. 5 mL) and the resulting precipitate was extracted into ethyl acetate (ca. 5 mL). The organic layer was washed with brine and dried (MgSO4). The solvent was removed in vacuo to give a yellow oil, which was redissolved in a mixture of dichloromethane (1 mL) and trifluoroacetic acid (0.5 mL, 6.5 mmol) and stirred at room temperature. After 1 h, the solvent was removed in vacuo to give a yellow oil, which was purified by reverse phase HPLC/MS to give 3 (6 mg, 30%) as a colorless solid, m/z (CI) 535.2 (MH+, 100%).

[0140] By the above procedure, the compounds of the following Table 8 were also prepared.

TABLE 8
160
			MS	MS
Cpd. No.	R1R2N(CR3aR3b)n-	-Q-R4	(calc)	Ion
8-1	161	162	491.5	492
8-2	163	164	509.5	510
8-3	165	166	509.5	510
8-4	167	H	385.4	386
8-5	168	169	415.4	416
8-6	170	171	433.4	434
8-7	172	H	385.4	386
8-8	173	174	415.4	416
8-9	175	176	415.4	416
8-10	177	178	433.4	434
8-11	179	180	515.6	516
8-12	181	H	391.5	392
8-13	182	183	495.5	496
8-14	184	185	495.5	496
8-15	186	187	539.6	540
8-16	188	189	477.5	478
8-17	190	191	479.5	480
8-18	192	193	539.6	540
8-19	194	195	505.5	506
8-20	196	197	501.5	502.2
8-21	198	199	501.5	502.2
8-22	200	201	465.5	450
8-23	202	203	475.5	476.2
8-24	204	205	461.5	462.2
8-25	206	207	461.5	462.2
8-26	208	209	487.5	488.2
8-27	210	211	487.5	488.2
8-28	212	213	527.5	528
8-29	214	215	523.6	524
8-30	216	217	523.6	524
8-31	218	219	495.5	496
8-32	220	221	475.5	476.2
8-33	222	223	491.5	492
8-34	224	225	539.6	540
8-35	226	227	481.9	482
8-36	228	229	493.6	494
8-37	230	231	525.6	526
8-38	232	233	489.5	490.2
8-39	234	235	475.5	476.2
8-40	236	237	449.4	450
8-41	238	239	445.4	446
8-42	240	241	467.5	469
8-43	242	243	449.5	450
8-44	244	245	479.5	480
8-45	246	247	459.4	460.2
8-46	248	249	445.4	446.1
8-47	250	251	534.6	535.2
8-48	252	253	514.5	515.2
8-49	254	255	521.5	522.2
8-50	256	257	548.6	549.2
8-51	258	259	520.3	521.2
8-52	260	261	512.6	513.2
8-53	262	263	527.6	528.2
8-54	264	265	502.5	503.2
8-55	266	267	528.6	529.3
8-56	268	H	371.4	372.1
8-57	269	270	490.6	491.2
8-58	271	272	478.5	479.1
8-59	273	274	491.5	492.2
8-60	275	276	515.5	516.2
8-61	277	278	493.6	494.1
8-62	279	280	553.6	554.2
8-63	281	282	553.6	554.2
8-64	283	284	553.6	554.2
8-65	285	286	557.6	558.2
8-66	287	288	557.6	558.2
8-67	289	290	569.6	570.2
8-68	291	292	569.6	570.2
8-69	293	294	574.0	574.2
8-70	295	296	574	574.2
8-71	297	298	581.7	582.3
8-72	299	300	595.7	596.3
8-73	301	302	607.6	608.2
8-74	303	304	608.5	608.1
8-75	305	306	488	488.1
8-76	307	308	489.5	490.2
8-77	309	310	447.5	488.2
8-78	311	312	465.5	466.1
8-79	313	314	513.5	514.1
8-80	315	316	495.5	496.2
8-81	317	318	509.5	510.1
8-82	319	320	465.5	466.2
8-83	321	322	495.5	496.2
8-84	323	324	513.5	514.2
8-85	325	326	509.5	510.2
8-86	327	328	461.5	462
8-87	329	330	477.5	478
8-88	331	332	481.9	482
8-89	333	334	461.5	462
8-90	335	336	515.5	516
8-91	337	338	489.6	490
8-92	339	340	531.5	532
8-93	341	342	523.6	524
8-94	343	344	465.5	466
8-95	345	346	481.9	482
8-96	347	348	461.5	462
8-97	349	350	475.5	476
8-98	351	352	503.6	504
8-99	353	354	523.6	524
8-100	355	356	477.5	478
8-101	357	358	531.5	532
8-102	359	360	491.5	482
8-103	361	362	497.5	498
8-104	363	364	516.4	516
8-105	365	366	475.5	476
8-106	367	368	467.5	468
8-107	369	370	453.5	454
8-108	371	372	476.5	474
8-109	373	374	489.6	490
8-110	375	376	465.5	466.1
8-111	377	378	495.5	496.2
8-112	379	380	513.5	514.2
8-113	381	382	509.5	510.1
8-114	383	384	498.6	498
8-115	385	386	545.5	546.2
8-116	387	388	563.5	564.2
8-117	389	390	559.5	560.2
8-118	391	392	561.5	562.2
8-119	393	394	579.5	580.2
8-120	395	396	575.5	576.2
8-121	397	398	481.9	482.1
8-122	399	400	525.9	526.1
8-123	401	402	512	512.1
8-124	403	404	529.9	530.1
8-125	405	406	483.5	484.1
8-126	407	408	513.5	496.2
8-127	409	410	531.5	532.1
8-128	411	412	491.5	492.2
8-129	413	414	513.5	514.2
8-130	415	416	527.5	528.1
8-131	417	418	531.5	532.2
8-132	419	420	483.5	484.1
8-133	421	422	513.5	514.2
8-134	423	424	527.5	528.2
8-135	425	426	531.5	532.2
8-136	427	428	483.5	484.1
8-137	429	430	513.5	514.1
8-138	431	432	527.5	528.2
8-139	433	434	531.5	532.2
8-140	435	436	483.5	484.1

EXAMPLE 6

Synthesis of Boronic Acids

[0141] Step A 2-Fluoro-3-methoxyphenylboronic Acid

[0142] n-Butyl lithium (20 mL, 2.5M) was added to a solution of tetramethylpiperidine (8.44 mL, 50 mmol) in THF (125 mL) at −78° C. The reaction mixture was stirred at −78° C. for 1.5 hours. 2-Fluoroanisole (6.31 g, 50 mmol) was added and the mixture was stirred for 8 hours at −78° C. Trimethyl borate (6.17 mL, 55 mmol) was added and the reaction mixture was allowed to warm slowly to room temperature overnight. The mixture was poured into 1N HCl (250 mL). Extraction with EtOAc followed by evaporation gave a sticky solid which was triturated with hexanes to give product (2.19 g, 26% yield).

EXAMPLE 7

Synthesis of Representative Compounds

[0143] 437

[0144] Step A BOC-(S)-1-amino-2-propanol

[0145] Di-t-butyl dicarbonate (6.76 g, 31 mmol) was added portionwise to a stirred solution of (S)-1-amino-2-propanol and triethylamine (4.4 mL, 31.5 mmol) in CH2Cl2 (75 mL) at 0° C. The reaction mixture was stirred for 1 hour at 0° C. and for 30 minutes at room temperature. Evaporation gave product 1 which was used without further purification.

[0146] Step B 3-(2-BOC-(R)-1-aminopropyl)-5-bromo-1-(2,6-difluorobenzyl)-6-methyl-uracil

[0147] 5-Bromo-1-(2,6-difluorobenzyl)-6-methyluracil (3.31 g, 10 mmol) was suspended in THF (200 mL). Compound 1 (1.84 g, 10.5 mmol) and triphenylphosphine (3.93 g, 15 mmol) were added and the mixture was stirred. DEAD (2.36 mL, 15 mmol) was added and the reaction mixture became a solution. After stirring overnight, the volatiles were removed and the residue was chromatographed on silica using EtOAc/hexanes as elutant to give white solid 2 (4.57 g, 94% yield).

EXAMPLE 8

Synthesis of Representative Compounds

[0148] 438 439

[0149] Step A

[0150] A solution of N-(t-butyloxycarbonyl)-D-α-alaminol (1.75 g, 10 mmol) in anhydrous THF (15 mL) was treated with 5-bromo-1-(2,6-difluorobenzyl)-6-methyluracil (3.31 g, 10 mmol) and triphenylphosphine (3.15 g, 12 mmol) at ambient temperature, then di-tert-butylazodicarboxylate (2.76 g, 12 mmol) was introduced. The reaction mixture was stirred at ambient temperature for 16 hours and volatiles were evaporated. The residue was partitioned between saturated NaHCO3/H2O and EtOAc. The organic layer was dried (sodium sulfate), evaporated, and purified by flash chromatography (silica, 1:2 EtOAc/hexanes) to give compound 1 (4.69 g, 96.1%), MS (CI) m/z 388.0, 390.0 (MH+-Boc).

[0151] Step B

[0152] To compound 1 (1.0 g, 2.05 mmol) in benzene/EtOH/ethylene glycol dimethyl ether (20/2/22 mL) was added 2-fluoro-3-methoxyphenylboronic acid (435 mg, 2.56 mmol) and saturated Ba(OH)2/water (−0.5 M, 15 mL). The reaction mixture was deoxygenated with N2 for 10 min, tetrakis(triphenylphosphine) palladium (0) (242 mg, 0.21 mmol) was added and the reaction mixture was heated at 80° C. overnight under the protection of N2. The reaction mixture was partitioned between brine and EtOAc. The organic layer was dried (sodium sulfate), evaporated, purified by flash chromatography (silica, 40% EtOAc/hexanes) to give compound 2 (450 mg, 41.2%), MS (CI) m/z 434.2 (MH+-Boc).

[0153] Step C

[0154] TFA (2 mL) was added to a solution of 2 (267 mg, 0.5 mmol) in dichloromethane (2 mL) and the reaction mixture was stirred at ambient temperature for 1 hour. Volatiles were evaporated and the residue was partitioned between saturated NaHCO3/water and EtOAc. The organic layer was dried (sodium sulfate), evaporated, and purified by reverse phase HPLC (C-18 column, 15-75% acetonitrile/water) to give compound 3, MS (CI) m/z 434.2 (MH+).

[0155] Step D

[0156] 2-Pyridinecarboxyaldehyde (80 mg, 0.75 mmol) was added to a solution of 3 (267 mg, 0.5 mmol) in MeOH (5 mL) and the reaction mixture was stirred at ambient temperature for 10 hours. NaBH4 (56 mg, 1.5 mmol) was added and the reaction mixture was kept at ambient temperature for 10 minutes. Volatiles were evaporated and the residue was partitioned between saturated NaHCO3/water and dichloromethane. The organic layer was dried (sodium sulfate), evaporated, and purified by reverse phase HPLC (C-18 column, 15-75% acetonitrile/water) to give compound 4, MS (CI) m/z 525.20 (MH+).

[0157] Step E

[0158] To a solution of 4 (20 mg, 0.04 mmol) in dichloroethane (2 mL) was added 1 drop of formaldehyde (37% solution in water) and NaBH(OAc)3 (16 mg, 0.08 mmol). The reaction mixture was stirred at ambient temperature for 2 hours, volatiles were evaporated and the residue was partitioned between water and dichloromethane. The organic layer was dried (sodium sulfate), evaporated, and purified by reverse phase HPLC (C-18 column, 15-75% acetonitrile/water) to give compound 5, MS (CI) m/z 539.20 (MH+).

EXAMPLE 9

Synthesis of Representative Compounds

[0159] 440

[0160] Step A

[0161] A solution of N′-(t-butyloxycarbonyl)-L-α-cyclohexylglycine (2.0 g, 7.77 mmol) in anhydrous THF (10 mL) was cooled down to 0° C. Borane solution (1 M in THF, 15.5 mL, 15.5 mmol) was added slowly and then warmed to ambient temperature, and the reaction mixture was stirred at ambient temperature for 2 h. The reaction was quenched with MeOH (5 mL), volatiles were evaporated and the residue was partitioned between water and EtOAc. The organic layer was washed with saturated NaHCO3/water and brine, and then was dried (sodium sulfate) and evaporated to give compound 1 (1.26 g, 66.7%), MS (CI) m/z 144.20 (MH+-Boc).

[0162] Step B

[0163] A solution of 1 (638 mg, 2.62 mmol) in THF (10 mL) was treated with 5-bromo-1-(2,6-difluorobenzyl)-6-methyluracil (869 mg, 2.62 mmol) and triphenylphosphine (1.03 g, 3.93 mmol) at ambient temperature, then di-tert-butylazodicarboxylate (906 mg, 3.93 mmol) was introduced. The reaction mixture was stirred at ambient temperature for 16 h and volatiles were evaporated. The residue was partitioned between saturated NaHCO3/H2O and EtOAc. The organic layer was dried (sodium sulfate), evaporated, and purified by flash chromatography (silica, 25% EtOAc/hexanes) to give compound 2 (1.39 g, 95.4%), MS (CI) m/z 456.10, 458.10 (MH+-Boc).

[0164] Step C

[0165] Compound 2 (1.0 g, 1.79 mmol) in benzene/EtOH/ethylene glycol dimethyl ether (20/2/22 mL) was added 2-fluoro-3-methoxyphenylboronic acid (382 mg, 2.24 mmol) and saturated Ba(OH)2/water (−0.5 M, 15 mL). The reaction mixture was deoxygenated with N2 for 10 min, tetrakis(triphenylphosine) palladium (0) (208 mg, 0.18 mmol) was added and the reaction mixture was heated at 80° C. overnight under the protection of N2. The reaction mixture was partitioned between brine and EtOAc. The organic layer was dried (sodium sulfate), evaporated, and purified by flash chromatography (silica, 30% EtOAc/hexanes) to give compound 3 (348 mg, 32.3%), MS (CI) m/z 502.20 (MH+-Boc).

[0166] Step D

[0167] A solution of 3 (300 mg, 0.5 mmol) in dichloromethane (2 mL) was added TFA (2 mL) and the reaction mixture was stirred at ambient temperature for 1 h. Volatiles were evaporated and the residue was partitioned between saturated NaHCO3/water and EtOAc. The organic layer was dried (sodium sulfate), evaporated, and purified by reverse phase HPLC (C-18 column, 15-75% ACN/water) to give compound 4, MS (CI) m/z 502.20 (MH+).

[0168] By the above procedure, the compounds of the following Table 9 were also prepared.

TABLE 9
441
Cpd.			NR1R2—		MW
No.	R5	R6	(CR3aCR3b)n—	—Q—R4	(calc.)	(obs.)
9-1	Me	442	443	444	485.5	486
9-2	Me	445	446	447	589.6	590
9-3	Me	448	449	450	526.6	527
9-4	Me	451	452	453	485.5	486
9-5	Me	454	455	456	513.5	514
9-6	Me	457	458	459	529.5	530
9-7	Me	460	461	462	512.5	513
9-8	Me	463	464	465	518.6	519
9-9	Me	466	467	468	532.6	533
9-10	Me	469	470	471	427	428
9-11	Me	472	473	474	505.6	506
9-12	Me	475	476	477	519.6	520
9-13	Me	478	479	480	520.6	521
9-14	Me	481	482	483	534.6	535
9-15	Me	484	485	486	532.6	533
9-16	Me	487	488	489	560.6	561
9-17	Me	490	491	492	534.6	535
9-18	Me	493	494	495	534.6	535
9-19	Me	496	497	498	529.6	530
9-20	Me	499	500	501	549.6	550
9-21	Me	502	503	504	554.6	555
9-22	Me	505	506	507	554.6	555
9-23	Me	508	509	510	575.6	576
9-24	Me	511	512	513	538.6	539
9-25	Me	514	515	516	537.6	538
9-26	Me	517	518	519	441.5	442
9-27	Me	520	521	522	546.6	547
9-28	Me	523	524	525	538.6	539
9-29	Me	526	527	528	579.6	447
9-30	Me	529	530	531	567.6	447
9-31	Me	532	533	534	533.6	534
9-32	Me	535	536	537	689.6	690
9-33	Me	538	539	540	590.7	591
9-34	Me	541	542	543	517.6	518
9-35	Me	544	545	546	666.7	667
9-36	Me	547	548	549	561.6	562
9-37	Me	550	551	552	574.6	575
9-38	Me	553	554	555	559.6	560
9-39	Me	556	557	558	643.7	644
9-40	Me	559	560	561	643.1	643
9-41	Me	562	563	564	561.7	562
9-42	Me	565	566	567	628.6	629
9-43	Me	568	569	570	666.7	667
9-44	Me	571	572	573	469.5	373
9-45	Me	574	575	576	505.5	373
9-46	Me	577	578	579	493.5	373
9-47	Me	580	581	582	459.5	373
9-48	Me	583	584	585	615.5	616
9-49	Me	586	587	588	516.6	517
9-50	Me	589	590	591	443.5	373
9-51	Me	592	593	594	592.6	593
9-52	Me	595	596	597	487.5	373
9-53	Me	598	599	600	500.5	501
9-54	Me	601	602	603	485.5	373
9-55	Me	604	605	606	569.6	372
9-56	Me	607	608	609	569.0	569
9-57	Me	610	611	612	487.6	373
9-58	Me	613	614	615	592.6	593
9-59	Me	616	617	618	495.5	399
9-60	Me	619	620	621	531.6	532
9-61	Me	622	623	624	519.5	399
9-62	Me	625	626	627	485.5	399
9-63	Me	628	629	630	641.5	642
9-64	Me	631	632	633	542.6	543
9-65	Me	634	635	636	469.5	470
9-66	Me	637	638	639	618.6	619
9-67	Me	640	641	642	513.5	514
9-68	Me	643	644	645	526.5	527
9-69	Me	646	647	648	511.6	512
9-70	Me	649	650	651	595.0	595
9-71	Me	652	653	654	513.6	399
9-72	Me	655	656	657	618.6	619
9-73	Me	658	659	660	493.6	397
9-74	Me	661	662	663	529.6	397
9-75	Me	664	665	666	517.6	397
9-76	Me	667	668	669	483.6	397
9-77	Me	670	671	672	639.6	640
9-78	Me	673	674	675	540.7	541
9-79	Me	676	677	678	467.6	468
9-80	Me	679	680	681	616.7	617
9-81	Me	682	683	684	511.6	512
9-82	Me	685	686	687	524.6	525
9-83	Me	688	689	690	509.6	510
9-84	Me	691	692	693	593.7	594
9-85	Me	694	695	696	593.1	593
9-86	Me	697	698	699	511.7	512
9-87	Me	700	701	702	578.6	579
9-88	Me	703	704	705	616.7	617
9-89	Me	706	707	708	509.5	413
9-90	Me	709	710	711	545.6	413
9-91	Me	712	713	714	533.6	413
9-92	Me	715	716	717	499.6	500
9-93	Me	718	719	720	556.6	557
9-94	Me	721	722	723	483.5	484
9-95	Me	724	725	726	632.7	633
9-96	Me	727	728	729	527.6	528
9-97	Me	730	731	732	540.6	541
9-98	Me	733	734	735	525.6	526
9-99	Me	736	737	738	527.6	528
9-100	Me	739	740	741	632.7	633
9-101	Me	742	743	744	554.5	555
9-102	Me	745	746	747	455.45	456
9-103	Me	748	749	750	581.66
9-104	Me	751	752	753
9-105	Me	754	755	756	588.65
9-106	Me	757	758	759	568.66
9-107	Me	760	761	762	572.62
9-108	Me	763	764	765	543.65	544.3
9-109	Me	766	767	768	506.55	507.2
9-110	Me	769	770	771	520.57	521.2
9-111	Me	772	773	774	552.61	553.3
9-112	Me	775	776	777	554.63	555.3
9-113	Me	778	779	780	570.63	571.3
9-114	Me	781	782	783	581.66	582.2
9-115	Me	784	785	786	525.98	526.2
9-116	Me	787	788	789	540.00	540.2
9-117	Me	790	791	792	525.98	526.2
9-118	Me	793	794	795	543.97	544.2
9-119	Me	796	797	798	560.42	561.1
9-120	Me	799	800	801	540.00	540.2
9-121	Me	802	803	804	574.45	574.0
9-122	Me	805	806	807	563.64	564.2
9-123	Me	808	809	810	497.58	498.2
9-124	Me	811	812	813	483.55	484.2
9-125	Me	814	815	816	469.52	470
9-126	Me	817	818	819	519.58	520.2
9-127	Me	820	821	822	520.57	521.2
9-128	Me	823	824	825	583.63	584.2
9-129	Me	826	827	828	535.58	536.2
9-130	Me	829	830	831	583.63	584.2
9-131	Me	832	833	834	501.57	502.2
9-132	Me	835	836	837	529.62	528
9-133	Me	838	839	840	556.60	557
9-134	Me	841	842	843	578.61	578
9-135	Me	844	845	846	540.60	541
9-136	Me	847	848	849	559.65	560.4
9-137	Me	850	851	852	547.64	548.5
9-138	Me	853	854	855	545.50	546.4
9-139	Me	856	857	858	585.62	586.4
9-140	Me	859	860	861	657.75	658.4
9-141	Me	862	863	864	561.66	562.6
9-142	Me	865	866	867	598.60	599.3
9-143	Me	868	869	870	598.60	599.3
9-144	Me	871	872	873	549.57	550.4
9-145	Me	874	875	876	639.59	640.4
9-146	Me	877	878	879	608.68	609.4
9-147	Me	880	881	882	607.65	608.2
9-148	Me	883	884	885	549.61	550.4
9-149	Me	886	887	888	485.54	486.4
9-150	Me	889	890	891	473.53	474
9-151	Me	892	893	894	471.39	472.2
9-152	Me	895	896	897	511.51	512.4
9-153	Me	898	899	900	583.65	584.2
9-154	Me	901	902	903	487.56	488.2
9-155	Me	904	905	906	524.49	525.4
9-156	Me	907	908	909	524.49	525.4
9-157	Me	910	911	912	527.62	528.4
9-158	Me	913	914	915	475.46	476.3
9-159	Me	916	917	918	565.48	566.4
9-160	Me	919	920	921	534.57	535.4
9-161	Me	922	923	924	533.55	534.5
9-162	Me	925	926	927	475.50	476.3
9-163	Me	928	929	930	499.55	500.4
9-164	Me	931	932	933	497.41	498.3
9-165	Me	934	935	936	537.53	538.4
9-166	Me	937	938	939	609.67	610.3
9-167	Me	940	941	942	513.58	514.6
9-168	Me	943	944	945	550.51	551.3
9-169	Me	946	947	948	550.51	551.2
9-170	Me	949	950	951	553.64	554.3
9-171	Me	952	953	954	501.48	502.3
9-172	Me	955	956	957	591.50	592.4
9-173	Me	958	959	960	560.59	561.3
9-174	Me	961	962	963	559.57	560.4
9-175	Me	964	965	966	501.52	502.3
9-176	Me	967	968	969	509.63	510.6
9-177	Me	970	971	972	497.62	498.5
9-178	Me	973	974	975	495.48	496.5
9-179	Me	976	977	978	535.60	536.6
9-180	Me	979	980	981	607.74	608.4
9-181	Me	982	983	984	511.65	512.5
9-182	Me	985	986	987	548.58	549.4
9-183	Me	988	989	990	551.71	552.4
9-184	Me	991	992	993	499.55	500.4
9-185	Me	994	995	996	589.57	590.5
9-186	Me	997	998	999	558.66	559.3
9-187	Me	1000	1001	1002	557.64	558.3
9-188	Me	1003	1004	1005	499.59	500.4
9-189	Me	1006	1007	1008	525.59	526.4
9-190	Me	1009	1010	1011	513.58	514.2
9-191	Me	1012	1013	1014	511.44	512.5
9-192	Me	1015	1016	1017	551.56	552.3
9-193	Me	1018	1019	1020	623.69	624.4
9-194	Me	1021	1022	1023	564.54	565.4
9-195	Me	1024	1025	1026	564.54	565.4
9-196	Me	1027	1028	1029	567.67	568.5
9-197	Me	1030	1031	1032	515.51	516.3
9-198	Me	1033	1034	1035	605.53	606.4
9-199	Me	1036	1037	1038	574.6	575.4

[0169]

Cpd.			NR1R2—		MW
No.	R5	R6	(CR3aCR3b)n—	—Q—R4	(calc.)	(obs.)
9-200	Me	1039	1040	1041	573.6	574.3
9-201	Me	1042	1043	1044	515.6	516.3
9-202	Me	1045	1046	1047	543.56	544.2
9-203	Me	1048	1049	1050	609.07	609.2
9-204	Me	1051	1052	1053	593.54	595.2
9-205	Me	1054	1055	1056	498.62	499.3
9-206	Me	1057	1058	1059	484.59	485.2
9-207	Me	1060	1061	1062	595.64	596.4
9-208	Me	1063	1064	1065	532.58	533.2
9-209	Me	1066	1067	1068	532.58	533.2
9-210	Me	1069	1070	1071	574.62	575
9-211	Me	1072	1073	Br	564.42	466/ 464
9-212	Me	1074	1075	Br	564.42	464/ 466
9-213	Me	1076	1077	1078	575.69	576.3
9-214	Me	1079	1080	1081	597.65	535.3
9-215	Me	1082	1083	1084	597.65	598.2
9-216	Me	1085	1086	1087	627.68	628.3
9-217	Me	1088	1089	1090	517.57	518.2
9-218	Me	1091	1092	1093	585.62	586.2
9-219	Me	1094	1095	1096	617.69	618.2
9-220	Me	1097	1098	1099	545.62	546.2
9-221	Me	1100	1101	1102	576.68	577.3
9-222	Me	1103	1104	1105	533.61	534.2
9-223	Me	1106	1107	1108	491.53	492.2
9-224	Me	1109	1110	1111	519.58	520.2
9-225	Me	1112	1113	1114	622.71	623.3
9-226	Me	1115	1116	1117	501.59	502.3
9-227	Me	1118	1119	1120	460.49	461.2
9-228	Me	1121	1122	1123	523.55	524.2
9-229	Me	1124	1125	1126	553.57	554.2
9-230	Me	1127	1128	1129	443.46	444.2
9-231	Me	1130	1131	1132	511.51	512.2
9-232	Me	1133	1134	1135	543.58	544.2
9-233	Me	1136	1137	1138	429.44	430.1
9-234	Me	1139	1140	1141	471.52	472.2
9-235	Me	1142	1143	1144	502.57	503.3
9-236	Me	1145	1146	1147	459.50	460.2
9-237	Me	1148	1149	1150	417.42	418.1
9-238	Me	1151	1152	1153	445.48	446.1
9-239	Me	1154	1155	1156	548.60	549.2
9-240	Me	1157	1158	1159	500.56	501.2
9-241	Me	1160	1161	1162	527.60	528.3
9-242	Me	1163	1164	1165	486.51	487.2
9-243	Me	1166	1167	1168	549.57	550.2
9-244	Me	1169	1170	1171	579.59	580.2
9-245	Me	1172	1173	1174	469.48	470.2
9-246	Me	1175	1176	1177	537.53	538.2
9-247	Me	1178	1179	1180	569.60	570.2
9-248	Me	1181	1182	1183	497.53	498.2
9-249	Me	1184	1185	1186	528.59	529.2
9-250	Me	1187	1188	1189	485.52	486.2
9-251	Me	1190	1191	1192	443.44	444.1
9-252	Me	1193	1194	1195	471.50	472.2
9-253	Me	1196	1197	1198	574.62	575.2
9-254	Me	1199	1200	1201	526.58	527.2
9-255	Me	1202	1203	1204	525.68	526.3
9-256	Me	1205	1206	1207	484.58	485.2
9-257	Me	1208	1209	1210	547.64	548.3
9-258	Me	1211	1212	1213	577.66	578.3
9-259	Me	1214	1215	1216	467.55	468.2
9-260	Me	1217	1218	1219	535.60	536.2
9-261	Me	1220	1221	1222	567.67	568.3
9-262	Me	1223	1224	1225	495.61	496.2
9-263	Me	1226	1227	1228	526.66	527.3
9-264	Me	1229	1230	1231	483.59	484.25
9-265	Me	1232	1233	1234	441.51	442.2
9-266	Me	1235	1236	1237	469.57	470.3
9-267	Me	1238	1239	1240	572.69	573.3
9-268	Me	1241	1242	1243	524.65	525.3
9-269	Me	1244	1245	1246	541.63	542.3
9-270	Me	1247	1248	1249	500.54	501.2
9-271	Me	1250	1251	1252	563.59	564.2
9-272	Me	1253	1254	1255	593.62	594.2
9-273	Me	1256	1257	1258	483.51	484.2
9-274	Me	1259	1260	1261	551.56	552.2
9-275	Me	1262	1263	1264	583.63	584.2
9-276	Me	1265	1266	1267	511.56	512.2
9-277	Me	1268	1269	1270	542.62	543.3
9-278	Me	1271	1272	1273	499.55	500.3
9-279	Me	1274	1275	1276	457.47	458.2
9-280	Me	1277	1278	1279	485.52	486.2
9-281	Me	1280	1281	1282	588.65	589.3
9-282	Me	1283	1284	1285	560.42	560
9-283	Me	1286	1287	1288	539.66	540
9-284	Me	1289	1290	1291	509.59	510
9-285	Me	1292	1293	1294	510.60	511.5
9-286	Me	1295	1296	1297	538.56	539.5
9-287	Me	1298	1299	1300	516.58	517.4
9-288	Me	1301	1302	1303	547.64	547
9-289	Me	1304	1305	1306	519.56	534
9-290	Me	1307	1308	1309	523.55	524.2
9-291	Me	1310	1311	1312	615.65	616.3
9-292	Me	1313	1314	1315	507.55	508.2
9-293	Me	1316	1317	1318	522.56	523.6
9-294	Me	1319	1320	1321	508.54	509.5
9-295	Me	1322	1323	1324	537.57	538.7
9-296	Me	1325	1326	1327	552.59	553.2
9-297	Me	1328	1329	1330	538.56	539.5
9-298	Me	1331	1332	1333	469.58	470.3
9-299	Me	1334	1335	1336	484.59	485.3
9-300	Me	1337	1338	1339	470.57	471.3
9-301	Me	1340	1341	1342	546.65	547
9-302	Me	1343	1344	1345	513.53	514
9-303	Me	1346	1347	1348	495.56	496
9-304	Me	1349	1350	1351	523.55	524
9-305	Me	1352	1353	1354	537.57	538
9-306	Me	1355	1356	1357	572.62	573
9-307	Me	1358	1359	1360	537.57	538.3
9-308	Me	1361	1362	Br	505.36	505/ 507
9-309	Me	1363	1364	1365	522.56	523
9-310	Me	1366	1367	1368	505.56	506
9-311	Me	1369	1370	1371	469.52	470
9-312	Me	1372	1373	1374	505.56	506
9-313	Me	1375	1376	1377	469.52	470
9-314	Me	1378	1379	1380	519.58	520
9-315	Me	1381	1382	1383	483.55	484
9-316	Me	1384	1385	1386	519.58	520
9-317	Me	1387	1388	1389	483.55	484
9-318	Me	1390	1391	1392	534.60	535.3
9-319	Me	1393	1394	1395	534.60	535.3
9-320	Me	1396	1397	1398	511.56	512.5
9-321	Me	1399	1400	1401	578.63	598
9-322	Me	1402	1403	1404	427.44	428.1
9-323	Me	1405	1406	1407	517.57	518.2
9-324	Me	1408	1409	1410	518.56	519.2
9-325	Me	1411	1412	1413	648.70	649.5
9-326	Me	1414	1415	1416	561.66	562.5
9-327	Me	1417	1418	1419	602.07	447.3
9-328	Me	1420	1421	1422	491.53	447.4
9-329	Me	1423	1424	1425	503.54	447.3
9-330	Me	1426	1427	1428	519.58	447.2
9-331	Me	1429	1430	1431	676.68	677.5
9-332	Me	1432	1433	1434	604.65	605.3
9-333	Me	1435	1436	1437	595.68	596.4
9-334	Me	1438	1439	1440	632.70	633.4
9-335	Me	1441	1442	1443	698.81	699.5
9-336	Me	1444	1445	1446	574.62	575.4
9-337	Me	1447	1448	1449	636.73	637.5
9-338	Me	1450	1451	1452	574.59	575.4
9-339	Me	1453	1454	1455	558.60	559.3
9-340	Me	1456	1457	1458	487.56	488.3
9-341	Me	1459	1460	1461	527.97	373.3
9-342	Me	1462	1463	1464	417.42	373.1
9-343	Me	1465	1466	1467	429.44	373.3
9-344	Me	1468	1469	1470	445.48	373.2
9-345	Me	1471	1472	1473	602.57	603.5
9-346	Me	1474	1475	1476	530.54	531.3
9-347	Me	1477	1478	1479	521.58	373.1
9-348	Me	1480	1481	1482	558.60	559.3
9-349	Me	1483	1484	1485	624.70	625.3
9-350	Me	1486	1487	1488	442.43	373.3
9-351	Me	1489	1490	1491	500.51	501.4
9-352	Me	1492	1493	1494	562.63	563.4
9-353	Me	1495	1496	1497	600.61	601.3
9-354	Me	1498	1499	1500	584.62	585.2
9-355	Me	1501	1502	1503	616.06	201.3
9-356	Me	1504	1505	1506	513.58	399.2
9-357	Me	1507	1508	1509	553.99	399.2
9-358	Me	1510	1511	1512	443.44	399.3
9-359	Me	1513	1514	1515	455.45	399.2
9-360	Me	1516	1517	1518	471.50	399.3
9-361	Me	1519	1520	1521	628.59	629.6
9-362	Me	1522	1523	1524	556.56	557.3
9-363	Me	1525	1526	1527	547.59	548.5
9-364	Me	1528	1529	1530	584.62	585.2
9-365	Me	1531	1532	1533	650.72	651.2
9-366	Me	1534	1535	1536	468.45	399.1
9-367	Me	1537	1538	1539	526.53	527.3
9-368	Me	1540	1541	1542	588.65	589.5
9-369	Me	1543	1544	1545	598.68	599.4
9-370	Me	1546	1547	1548	582.69	583.4
9-371	Me	1549	1550	1551	511.65	512.5
9-372	Me	1552	1553	1554	552.06	397
9-373	Me	1555	1556	1557	441.51	397.1
9-374	Me	1558	1559	1560	453.53	397
9-375	Me	1561	1562	1563	469.57	397.1
9-376	Me	1564	1565	1566	626.66	627.6
9-377	Me	1567	1568	1569	554.63	555.5
9-378	Me	1570	1571	1572	545.67	546.4
9-379	Me	1573	1574	1575	582.69	583.3
9-380	Me	1576	1577	1578	648.79	649.6
9-381	Me	1579	1580	1581	524.60	525.5
9-382	Me	1582	1583	1584	586.72	587.5
9-383	Me	1585	1586	1587	614.64	615.5
9-384	Me	1588	1589	1590	598.64	599.4
9-385	Me	1591	1592	1593	527.60	528.2
9-386	Me	1594	1595	1596	568.01	568.5
9-387	Me	1597	1598	1599	457.47	458
9-388	Me	1600	1601	1602	485.52	486.3
9-389	Me	1603	1604	1605	642.62	643.7
9-390	Me	1606	1607	1608	570.59	571
9-391	Me	1609	1610	1611	561.62	562.5
9-392	Me	1612	1613	1614	598.64	599.4
9-393	Me	1615	1616	1617	664.74	665.5
9-394	Me	1618	1619	1620	540.56	541.6
9-395	Me	1621	1622	1623	602.67	603.6
9-396	Me	1624	1625	1626	442.43	373.3
9-397	Me	1627	1628	1629	520.57	521.3
9-398	Me	1630	1631	1632	520.57	521.2
9-399	Me	1633	1634	1635	503.56	504.2
9-400	Me	1636	1637	1638	532.58	533.2
9-401	Me	1639	1640	1641	506.55	507
9-402	Me	1642	1643	1644	506.55	507
9-403	Me	1645	1646	1647	515.55	416
9-404	Me	1648	1649	1650	531.6	532
9-405	Me	1651	1652	1653	549.5	550
9-406	Me	1654	1655	1656	550.57	550
9-407	Me	1657	1658	1659	534.60	535
9-408	Me	1660	1661	1662	534.60	535
9-409	Me	1663	1664	1665	538.56	539
9-410	Me	1666	1667	1668	524.54	525
9-411	Me	1669	1670	1671	554.63	555
9-412	Me	1672	1673	H	335.35	336
9-413	Me	1674	1675	Br	533.41	533/ 535
9-414	Me	1676	1677	1678	459.46	460
9-415	Me	1679	1680	H	454.51	455
9-416	Me	1681	1682	1683	534.60	535.5
9-417	Me	1684	1685	1686	520.57	521.5
9-418	Me	1687	1688	1689	557.99	558
9-419	Me	1690	1691	1692	539.55	540
9-420	Me	1693	1694	1695	553.57	554
9-421	Me	1696	1697	1698	537.57	538
9-422	Me	1699	1700	1701	539.55	540
9-423	Me	1702	1703	1704	553.57	554
9-424	Me	1705	1706	1707	541.54	542
9-425	Me	1708	1709	1710	541.54	542
9-426	Me	1711	1712	1713	568.66	569
9-427	Me	1714	1715	1716	664.14	664.2
9-428	Me	1717	1718	1719	614.13	614.2
9-429	Me	1720	1721	1722	590.04	590.2
9-430	Me	1723	1724	1725	630.08	630.2
9-431	Me	1726	1727	1728	469.48	470.2
9-432	Me	1729	1730	1731	482.48	483.1
9-433	Me	1732	1733	1734	466.52	467.2
9-434	Me	1735	1736	1737	516.54	517.2
9-435	Me	1738	1739	1740	595.68	596.3
9-436	Me	1741	1742	1743	595.68	596.3
9-437	Me	1744	1745	1746	538.56	539.2
9-438	Me	1747	1748	1749	552.59	553.3
9-439	Me	1750	1751	1752	506.55	507.2
9-440	Me	1753	1754	1755	506.55	507.2
9-441	Me	1756	1757	1758	520.57	521.2
9-442	Me	1759	1760	1761	520.57	521.2
9-443	Me	1762	1763	1764	537.57	538
9-444	Me	1765	1766	1767	521.56	522.2
9-445	Me	1768	1769	1770	521.56	522.2
9-446	Me	1771	1772	1773	523.55	524.2
9-447	Me	1774	1775	1776	523.55	524.2
9-448	Me	1777	1778	1779	523.55	524.2
9-449	Me	1780	1781	1782	530.57	531.2
9-450	Me	1783	1784	1785	530.57	531.2
9-451	Me	1786	1787	1788	530.57	531.2
9-452	Me	1789	1790	1791	533.61	534.3
9-453	Me	1792	1793	1794	533.61	534.3
9-454	Me	1795	1796	1797	533.61	534.2
9-455	Me	1798	1799	1800	535.58	536.2
9-456	Me	1801	1802	1803	547.64	548.3
9-457	Me	1804	1805	1806	548.63	549.3
9-458	Me	1807	1808	1809	549.57	550.2
9-459	Me	1810	1811	1812	535.58	536.2
9-460	Me	1813	1814	1815	547.59	548.3
9-461	Me	1816	1817	1818	556.00	556.2
9-462	Me	1819	1820	1821	556.00	556.2
9-463	Me	1822	1823	1824	556.00	556.2
9-464	Me	1825	1826	1827	557.99	558.2
9-465	Me	1828	1829	1830	557.99	558.2
9-466	Me	1831	1832	1833	573.55	574.2
9-467	Me	1834	1835	1836	544.59	545.2
9-468	Me	1837	1838	1839	558.62	559.2
9-469	Me	1840	1841	1842	495.52	496.2
9-470	Me	1843	1844	1845	538.56	539
9-471	Me	1846	1847	1848	495.52	496.2
9-472	Me	1849	1850	1851	519.58	520.2
9-473	Me	1852	1853	1854	519.58	520.2
9-474	Me	1855	1856	1857	519.58	520.2
9-475	Me	1858	1859	1860	521.56	535.2
9-476	Me	1861	1862	1863	533.61	534.2
9-477	Me	1864	1865	1866	535.58	536.2
9-478	Me	1867	1868	1869	549.61	550.2
9-479	Me	1870	1871	1872	551.65	552.2
9-480	Me	1873	1874	1875	555.62	556.3
9-481	Me	1876	1877	1878	552.59	553
9-482	Me	1879	1880	1881	537.57	538.2
9-483	Me	1882	1883	1884	539.55	540.2
9-484	Me	1885	1886	1887	539.55	540.2
9-485	Me	1888	1889	1890	541.54	542.2
9-486	Me	1891	1892	1893	541.54	542.2
9-487	Me	1894	1895	1896	541.54	542.2
9-488	Me	1897	1898	1899	548.56	549.2
9-489	Me	1900	1901	1902	548.56	549.3
9-490	Me	1903	1904	1905	551.60	552.3
9-491	Me	1906	1907	1908	551.60	552.2
9-492	Me	1909	1910	1911	553.57	554.2
9-493	Me	1912	1913	1914	553.57	554.2
9-494	Me	1915	1916	1917	553.57	554.2
9-495	Me	1918	1919	1920	565.58	566.2
9-496	Me	1921	1922	1923	565.63	566.3
9-497	Me	1924	1925	1926	565.63	566.3
9-498	Me	1927	1928	1929	566.62	566.2
9-499	Me	1930	1931	1932	567.56	567.3
9-500	Me	1933	1934	1935	567.60	568.2
9-501	Me	1936	1937	1938	569.64	568.2
9-502	Me	1939	1940	1941	573.61	570.2
9-503	Me	1942	1943	1944	573.99	574.2
9-504	Me	1945	1946	1947	573.99	574.2
9-505	Me	1948	1949	1950	573.99	574.2
9-506	Me	1951	1952	1953	575.98	574.2
9-507	Me	1954	1955	1956	575.98	576.2
9-508	Me	1957	1958	1959	591.54	592.2
9-509	Me	1960	1961	1962	562.58	563.2
9-510	Me	1963	1964	1965	513.51	514.2
9-511	Me	1966	1967	1968	513.51	514.2
9-512	Me	1969	1970	1971	524.54	525.2
9-513	Me	1972	1973	1974	547.64	548.3
9-514	Me	1975	1976	1977	557.99	558.2
9-515	Me	1978	1979	1980	525.63	526.3
9-516	Me	1981	1982	1983	511.60	512.3
9-517	Me	1984	1985	1986	523.55	524
9-518	Me	1987	1988	1989	521.53	522
9-519	Me	1990	1991	1992	555.63	556
9-520	Me	1993	1994	H	499.55	400 (MH −BOC)+
9-521	Me	1995	1996	H	399.43	400
9-522	Me	1997	1998	H	397.42	398
9-523	Me	1999	2000	Br	478.33	478/ 480
9-524	Me	2001	2002	Br	476.31	476/ 478
9-525	Me	2003	2004	2005	505.56	506.3
9-526	Me	2006	2007	2008	519.58	520.3
9-527	Me	2009	2010	2011	505.56	506.2
9-528	Me	2012	2013	2014	519.58	520.2
9-529	Me	2015	2016	2017	471.54	472.2
9-530	Me	2018	2019	2020	485.57	486.3
9-531	Me	2021	2022	2023	499.59	500.3
9-532	Me	2024	2025	2026	521.60	522.2
9-533	Me	2027	2028	2029	527.65	528.3
9-534	Me	2030	2031	2032	539.66	540.3
9-535	Me	2033	2034	2035	583.75	584.4
9-536	Me	2036	2037	2038	523.62	524.3
9-537	Me	2039	2040	2041	555.70	556.3
9-538	Me	2042	2043	2044	483.55	484.2
9-539	Me	2045	2046	2047	483.55	484.2
9-540	Me	2048	2049	2050	497.58	498.3
9-541	Me	2051	2052	2053	485.57	486.3
9-542	Me	2054	2055	2056	499.59	500.3
9-543	Me	2057	2058	2059	510.58	511.2
9-544	Me	2060	2061	2062	513.62	514.3
9-545	Me	2063	2064	2065	525.63	526.3
9-546	Me	2066	2067	2068	501.54	502.2
9-547	Me	2069	2070	2071	559.58	560.2
9-548	Me	2072	2073	2074	515.57	516.2
9-549	Me	2075	2076	2077	519.56	520.2
9-550	Me	2078	2079	2080	557.99	558.2
9-551	Me	2081	2082	2083	548.56	549.2
9-552	Me	2084	2085	2086	541.54	542.2
9-553	Me	2087	2088	2089	513.51	514.2
9-554	Me	2090	2091	2092	543.60	544.2
9-555	Me	2093	2094	2095	543.60	544.2
9-556	Me	2096	2097	2098	529.58	530.1
9-557	Me	2099	2100	2101	489.53	490.2
9-558	Me	2102	2103	2104	557.65	558.2
9-559	Me	2105	2106	2107	503.56	504.2
9-560	Me	2108	2109	2110	545.64	546.2
9-561	Me	2111	2112	2113	521.60	522.2
9-562	Me	2114	2115	2116	537.57	538.2
9-563	Me	2117	2118	2119	517.58	518.2
9-564	Me	2120	2121	2122	559.66	560.2
9-565	Me	2123	2124	2125	548.56	549.2
9-566	Me	2126	2127	2128	515.57	516.2
9-567	Me	2129	2130	2131	501.54	502.2
9-568	Me	2132	2133	2134	515.57	516.2
9-569	Me	2135	2136	2137	513.51	514.2
9-570	Me	2138	2139	2140	529.58	530.2
9-571	Me	2141	2142	2143	539.55	540.2
9-572	Me	2144	2145	2146	557.65	558.3
9-573	Me	2147	2148	2149	545.64	546.3
9-574	Me	2150	2151	2152	503.56	504.3
9-575	Me	2153	2154	2155	546.65	547.3
9-576	Me	2156	2157	2158	559.66	560.3
9-577	Me	2159	2160	2161	565.63	566.3
9-578	Me	2162	2163	2164	548.56	549.2
9-579	Me	2165	2166	2167	607.71	608.4
9-580	Me	2168	2169	2170	505.53	506.2
9-581	Me	2171	2172	2173	524.54	525.2
9-582	Me	2174	2175	2176	538.56	539.2
9-583	Me	2177	2178	2179	523.55	524.2
9-584	Me	2180	2181	2182	523.55	524.2
9-585	Me	2183	2184	2185	519.58	520.2
9-586	Me	2186	2187	2188	535.58	536.2
9-587	Me	2189	2190	2191	523.55	536.2
9-588	Me	2192	2193	2194	521.56	522.2
9-589	Me	2195	2196	2197	529.6	530.2
9-590	Me	2198	2199	2200	531.61	532.3
9-591	Me	2201	2202	2203	541.56	542.3
9-592	Me	2204	2205	2206	513.51	514.2
9-593	Me	2207	2208	2209	527.54	528.2
9-594	Me	2210	2211	2212	601.74	602.4
9-595	Me	2213	2214	2215	541.56	542.2
9-596	Me	2216	2217	2218	543.62	542.2
9-597	Me	2219	2220	2221	483.55	484.2
9-598	Me	2222	2223	2224	471.54	472.1
9-599	Me	2225	2226	2227	485.57	486.3
9-600	Me	2228	2229	2230	499.59	500.3
9-601	Me	2231	2232	2233	601.74	602.4
9-602	Me	2234	2235	2236	527.54	528.2
9-603	Me	2237	2238	2239	513.51	514.2
9-604	Me	2240	2241	2242	546.63	547
9-605	Me	2243	2244	2245	524.99	525
9-606	Me	2246	2247	2248	501.54	502.2
9-607	Me	2249	2250	2251	557.99	558.2
9-608	Me	2252	2253	2254	541.54	542.2
9-609	Me	2255	2256	2257	539.55	540.3
9-610	Me	2258	2259	2260	601.74	602.4
9-611	Me	2261	2262	2263	573.69	574.3
9-612	Me	2264	2265	2266	545.64	546.3
9-613	Me	2267	2268	2269	503.56	504.2
9-614	Me	2270	2271	2272	541.61	542.3
9-615	Me	2273	2274	2275	475.50	476.2
9-616	Me	2276	2277	2278	489.53	490.3
9-617	Me	2279	2280	2281	505.53	506.30
9-618	Me	2282	2283	2284	526.55	527.2
9-619	Me	2285	2286	2287	539.55	540.2
9-620	Me	2288	2289	2290	539.55	540.2
9-621	Me	2291	2292	2293	529.58	530.2
9-622	Me	2294	2295	2296	608.47	608.1
9-623	Me	2297	2298	2299	524.54	525.2
9-624	Me	2300	2301	2302	559.53	560.2
9-625	Me	2303	2304	2305	513.51	514.2

[0170]

Cpd.			NR1R2—		MW
No.	R5	R6	(CR3aCR3b)n—	—Q—R4	(calc.)	(obs.)
9-626	Me	2306	2307	2308	530.56	531.2
9-627	Me	2309	2310	2311	530.56	531.2
9-628	Me	2312	2313	2314	592.40	594.1
9-629	Me	2315	2316	2317	519.58	520.2
9-630	Me	2318	2319	2320	521.58	522.2
9-631	Me	2321	2322	2323	507.55	508.3
9-632	Me	2324	2325	2326	525.54	526.2
9-633	Me	2327	2328	2329	541.99	542.2
9-634	Me	2330	2331	2332	537.57	538.3
9-635	Me	2333	2334	2335	581.58	582.2
9-636	Me	2336	2337	2338	551.60	552.3
9-637	Me	2339	2340	2341	523.55	524.2
9-638	Me	2342	2343	2344	575.55	576.2
9-639	Me	2345	2346	2347	521.58	522.2
9-640	Me	2348	2349	2350	573.55	574.2
9-641	Me	2351	2352	2353	591.54	592.2
9-642	Me	2354	2355	2356	629.67	630
9-643	Me	2357	2358	2359	607.66	608
9-644	Me	2360	2361	2362	643.70	644
9-645	Me	2363	2364	2365	649.73	650
9-646	Me	2366	2367	2368	647.66	648
9-647	Me	2369	2370	2371	664.12	664
9-648	Me	2372	2373	2374	671.71	672
9-649	Me	2375	2376	2377	543.53	544.2
9-650	Me	2378	2379	2380	524.54	525.2
9-651	Me	2381	2382	2383	505.53	506.2
9-652	Me	2384	2385	2386	513.51	514.2
9-653	Me	2387	2388	2389	537.57	538.3
9-654	Me	2390	2391	2392	513.51	514.2
9-655	Me	2393	2394	2395	475.50	476.2
9-656	Me	2396	2397	2398	503.56	504.3
9-657	Me	2399	2400	2401	487.51	488.3
9-658	Me	2402	2403	2404	501.54	502.2
9-659	Me	2405	2406	2407	524.54	525.2
9-660	Me	2408	2409	2410	543.53	544.2
9-661	Me	2411	2412	2413	489.53	490.3
9-662	Me	2414	2415	2416	541.56	542.3
9-663	Me	2417	2418	2419	557.99	558.2
9-664	Me	2420	2421	2422	526.55	527.2
9-665	Me	2423	2424	2425	541.56	542.3
9-666	Me	2426	2427	2428	559.53	560.2
9-667	Me	2429	2430	2431	524.54	525.2
9-668	Me	2432	2433	2434	513.51	514.2
9-669	Me	2435	2436	2437	517.58	518.2
9-670	Me	2438	2439	2440	524.54	525.2
9-671	Me	2441	2442	2443	501.54	502
9-672	Me	2444	2445	2446	639.66	540
9-673	Me	2447	2448	2449	679.73	680
9-674	Me	2450	2451	2452	659.70	660
9-675	Me	2453	2454	2455	543.62	544.3
9-676	Me	2456	2457	2458	543.62	544.3
9-677	Me	2459	2460	2461	564.02	564.2
9-678	Me	2462	2463	2464	531.61	532.3
9-679	Me	2465	2466	2467	529.6	530.2
9-680	Me	2468	2469	2470	539.55	540.2
9-681	Me	2471	2472	2473	517.58	518.3
9-682	Me	2474	2475	2476	537.57	538.2
9-683	Me	2477	2478	2479	545.64	544.3
9-684	Me	2480	2481	2482	539.55	540.2
9-685	Me	2483	2484	2485	487.51	488.2
9-686	Me	2486	2487	2488	609.77	610.3
9-687	Me	2489	2490	2491	569.64	570.2
9-688	Me	2492	2493	2494	531.61	532.3
9-689	Me	2495	2496	2497	601.74	602.4
9-690	Me	2498	2499	2500	557.99	558.2
9-691	Me	2501	2502	2503	549.59	550.2
9-692	Me	2504	2505	2506	517.58	518.2
9-693	Me	2507	2508	2509	503.56	504.3
9-694	Me	2510	2511	2512	503.56	504.3
9-695	Me	2513	2514	2515	503.51	504
9-696	Me	2516	2517	2518	537.53	538.2
9-697	Me	2519	2520	2521	551.60	552.3
9-698	Me	2522	2523	2524	529.6	530.2
9-699	Me	2525	2526	2527	543.62	544.3
9-700	Me	2528	2529	2530	529.6	530.2
9-701	Me	2531	2532	2533	543.62	544.3
9-702	Me	2534	2535	2536	523.55	524.2
9-703	Me	2537	2538	2539	549.54	450
9-704	Me	2540	2541	2542	503.56	504.3
9-705	Me	2543	2544	2545	608.47	610.1
9-706	Me	2546	2547	2548	529.58	530.2
9-707	Me	2549	2550	2551	517.58	518.2
9-708	Me	2552	2553	2554	503.56	504.3
9-709	Me	2555	2556	2557	535.56	536.2
9-710	Me	2558	2559	2560	489.53	490.2
9-711	Me	2561	2562	2563	489.53	490.2
9-712	Me	2564	2565	2566	503.56	504.2
9-713	Me	2567	2568	2569	503.56	504.2
9-714	Me	2570	2571	2572	489.53	490.2
9-715	Me	2573	2574	2575	489.53	490.2
9-716	Me	2576	2577	2578	523.55	524.2
9-717	Me	2579	2580	2581	517.54	518.2
9-718	Me	2582	2583	2584	523.55	524
9-719	Me	2585	2586	2587	517.58	518.3
9-720	Me	2588	2589	2590	535.57	536.3
9-721	Me	2591	2592	2593	531.61	532.3
9-722	Me	2594	2595	2596	503.56	504.3
9-723	Me	2597	2598	2599	517.54	518
9-724	Me	2600	2601	2602	543.60	544
9-725	Me	2603	2604	2605	530.56	531
9-726	Me	2606	2607	2608	553.57	554
9-727	Me	2609	2610	2611	523.55	524.2
9-728	Me	2612	2613	2614	509.52	510.2
9-729	Me	2615	2616	2617	515.57	516.3
9-730	Me	2618	2619	2620	529.6	530.3
9-731	Me	2621	2622	2623	519.56	520.2
9-732	Me	2624	2625	2626	487.519	488
9-733	Me	2627	2628	2629	503.562	504
9-734	Me	2630	2631	2632	517.6	518.2
9-735	Me	2633	2634	2635	485.6	486.2
9-736	Me	2636	2637	2638	541.6	542
9-737	Me	2639	2640	2641	509.5	510.2
9-738	Me	2642	2643	2644	491.5	492.2
9-739	Me	2645	2646	2647	543.6	544.3
9-740	Me	2648	2649	2650	515.6	516.3
9-741	Me	2651	2652	2653	513.5	514
9-742	Me	2654	2655	2656	637.8	638
9-743	Me	2657	2658	2659	637.7	638
9-744	Me	2660	2661	2662	625.7	626
9-745	Me	2663	2664	2665	553.6	554
9-746	Me	2666	2667	2668	661.6	662
9-747	Me	2669	2670	2671	505.5	506.2
9-748	Me	2672	2673	2674	519.5	520.2
9-749	Me	2675	2676	2677	517.5	518
9-750	Me	2678	2679	2680	489.5	490.2
9-751	Me	2681	2682	2683	541.6	542
9-752	Me	2684	2685	2686	536.5	537
9-753	Me	2687	2688	2689	529.5	530
9-754	Me	2690	2691	2692	542.6	543
9-755	Me	2693	2694	2695	471.5	472.2
9-756	Me	2696	2697	2698	485.5	486.2
9-757	Me	2699	2700	2701	559.6	460.2
9-758	Me	2702	2703	2704	527.6	428.2
9-759	Me	2705	2706	2707	483.6	484.2
9-760	Me	2708	2709	2710	511.6	512.2
9-761	Me	2711	2712	2713	49.6	500.2
9-762	Me	2714	2715	2716	497.6	498.2
9-763	Me	2717	2718	2719	525.6	526.2
9-764	Me	2720	2721	2722	533.5	534.2
9-765	Me	2723	2724	2725	455.5	456.2
9-766	Me	2726	2727	2728	455.5	456.2
9-767	Me	2729	2730	2731	459.5	460.1
9-768	Me	2732	2733	2734	459.5	459
9-769	Me	2735	2736	2737	489.5	489
9-770	Me	2738	2739	2740	487.5	488
9-771	Me	2741	2742	Br	442.3	442
9-772	Me	2743	2744	H	363.4	364
9-773	Me	2745	2746	2747	587.6	588
9-774	Me	2748	2749	2750	491.5	491

EXAMPLE 10

Synthesis of Representative Compounds

[0171] 2751

[0172] Step A 6-Methyl-5-(2-fluorophenyl)-oxaz-2,4-dione

[0173] To a stirred solution of 2′-fluorophenylacetone 1 (7.6 g, 50 mmol) in ether (50 mL) was added dropwise chlorosulfonylisocyanate (CSI, 16.2 g, 115 mmol) at room temperature. The yellow solution was stirred overnight, poured into ice (100 g) and basified with sodium carbonate. The product was extracted with ethyl acetate (2×200 mL) and the extract was washed with water and brine, dried over magnesium sulfate and concentrated in vacuo to give a yellow residue (9.5 g, proton NMR, about 70% product). The crude product was crystallized from ether-hexanes to give compound 2 as a yellow solid (3.6 g, 33% yield); 1H NMR (CDCl3): 2.14 (s, 3H), 7.16 (t, J=9.0 Hz, 1H), 7.24 (m, 2H), 7.41 (m, 1H), 9.20 (brs, 1H).

[0174] Step B 6-Methyl-5-(2-fluorophenyl)-3-[2(R)-tert-butoxycarbonylamino-2-phenylethyl]oxaz-2,4-dione

[0175] DEAD (348 mg, 1.2 mmol) was added into a solution of oxazine 2 (221 mg, 1.0 mmol), triphenylphosphine (314 mg, 1.2 mmol) and N-Boc-(R)-phenylglysinol (249 mg, 1.05 mmol) in dry THF (5 mL). The mixture was stirred at room temperature for 2 hours, concentrated, and purified by chromatography on silica gel with 1:3 ethyl acetate/hexanes to give the product 3 (380 mg, 87%) as a white solid; 1H NMR (CDCl3): 1.39 (s, 9H), 2.14 (s, 3H), 4.02 (m, 1H), 4.28 (m, 1H), 5.21 (brs, 1H), 5.30 (m, 1H), 7.38 (m, 9H); MS (341, MH+-BuOCO).

[0176] Step C6-Methyl-5-(2-fluorophenyl)-3-[2(R)-amino-2-phenylethyl]oxaz-2,4-dione Trifluoroacetic Acid Salt

[0177] 6-Methyl-5-(2-fluorophenyl)-3-[2(R)-tert-butoxycarbonylamino-2-phenylethyl]oxaz-2,4-dione 3 (30 mg) was treated with trifluoroacetic acid (1 mL) at room temperature for 30 minutes. Concentration in vacuo gave the title compound 4 as a colorless oil in quantitative yield; 1H NMR (CDCl3): 2.05 & 2.08 (s, 3H), 4.10 (m, 1H), 4.45 (m, 1H), 4.62 (m, 1H), 7.15 (m, 3H), 7.40 (m, 6H), 8.20 (brs, 3H); MS: 341 (MH+).

[0178] Step D 6-Methyl-5-(2-fluorophenyl)-3-[2(R)-tert-butoxycarbonylamino-2-phenylethyl]-1-(2-methoxybenzyl)uracil

[0179] A mixture of 6-methyl-5-(2-fluorophenyl)-3-[2(R)-tert-butoxycarbonylamino-2-phenylethyl]oxaz-2,4-dione 3 (29 mg) and 2-methoxybenzylamine (0.15 mL) was heated in a sealed reacti-vial at 100° C. for 1 hour. Chromatography on silica gel with 1:2 ethyl acetate-hexanes gave compound 5 as a colorless oil; 1H NMR, (CDCl3): 1.40 (s, 9H), 2.04 (s, 3H), 3.87 (sj 3H), 4.18 (m, 1H), 4.44 (m, 1H), 5.22 (m, 2H), 5.65 (brs, 1H), 5.78 (m, 1H), 6.85-7.42 (m, 13H); MS: 460 (MH+-BuOCO).

[0180] The following protected intermediates were made using the same procedure but substituting different amines for 2-methoxybenzylamine. Acetic acid may be used to catalyze the reaction.

[0181] 6-Methyl-5-(2-fluorophenyl)-3-[2(R)-tert-butoxycarbonylamino-2-phenylethyl]-1-(2,6-difluorobenzyl)uracil

[0182] 1 H NMR (CDCl3): 1.39 (s, 9H), 2.18 (s, 3H), 4.10 (m, 1H), 4.38 (m, 1H), 4.90-5.80 (m, 4H), 6.92 (m, 2H), 7.10-7.42 (m, 10H); MS: 466 (MH+-BuOCO).

[0183] 6-Methyl-5-(2-fluorophenyl)-3-[2(R)-tert-butoxycarbonylamino-2-phenylethyl]-1-(2-chlorobenzyl)uracil

[0184] 1 H NMR (CDCl3): 1.40 (s, 9H), 2.02 (s, 3H), 4.15 (m, 1H), 4.50 (m, 1H), 5.35 (m, 3H), 5.62 (m, 1H), 6.95 (m, 13H); MS: 464 (MH+-BuOCO).

[0185] 6-Methyl-5-(2-fluorophenyl)-3-[2(R)-tert-butoxycarbonylamino-2-phenylethyl]-1-(2-methylbenzyl)uracil

[0186] 1 H NMR (CDCl3): 1.40 (s, 9H), 2.02 (s, 3H), 2.37 (s, 3H), 4.15 (m, 1H), 4.42 (m, 1H), 5.72 (m, 1H), 6.80-7.42 (m, 13H); MS: 444 (MH+-BuOCO).

[0187] Step E 6-Methyl-5-(2-fluorophenyl)-3-[2(R)-amino-2-phenylethyl]-1-(2-methoxybenzyl)uracil Trifluoroacetic Acid Salt

[0188] 6-Methyl-5-(2-fluorophenyl)-3-[2(R)-tert-butoxycarbonylamino-2-phenylethyl]-1-(2-methoxybenzyl)uracil 5 (20 mg) was treated with trifluoroacetic acid (1 mL) at room temperature for 30 minutes. Concentration in vacuo gave the product 6 as a colorless oil in quantitative yield; 1H NMR (CDCl3): 2.04 (s, 3H), 3.82 & 3.85 (s, 3H), 4.20 (m, 1H), 4.62 (m, 2H), 5.10 (m, 2H), 6.82-7.40 (m, 13H), 8.05 (brs, 3H); MS: 460 (MH+).

[0189] The following products were also prepared using the same procedure.

[0190] 6-Methyl-5-(2-fluorophenyl)-3-[2(R)-amino-2-phenylethyl]-1-(2-chlorobenzyl)uracil trifluoroacetic acid salt

[0191] 1 H NMR (CDCl3): 2.01 (s, 3H), 4.20 (m, 1H), 4.70 (m, 2H), 5.25 (m, 2H), 6.90-7.45 (m, 13H), 8.20 (brs, 3H); MS: 464 (MH+).

[0192] 6-Methyl-5-(2-fluorophenyl)-3-[2(R)-amino-2-phenylethyl]-1-(2-methylbenzyl)uracil trifluoroacetic acid salt

[0193] 1 H NMR (CDCl3):2.00 (s, 3H), 2.27 & 2.34 (s, 3H), 4.15 (m, 4H), 4.62 (m, 2H), 5.15 (m, 2H), 6.80-7.40 (m, 13H); MS: 444 (MH+).

[0194] 6-Methyl-5-(2-fluorophenyl)-3-[2(R)-amino-2-phenylethyl]-1-(2,6-difluorobenzyl)uracil trifluoroacetic acid salt

[0195] 1 H NMR (CDCl3): 2.14 (s, 3H), 4.18 (m, 1H), 4.62 (m, 2H), 5.20 (m, 2H), 5.62 (brs, 3H), 6.85-7.40 (m, 13H); MS: 466 (MH+).

[0196] By the above procedure, the compounds of the following Table 10 were also prepared.

TABLE 10
2752
Cpd.			MW
No.	R6	—Q—R4	(calc.)	(obs.)
10-1	2753	2754	465.5	466
10-2	2755	2756	393.5	394.2
10-3	2757	2758	379.4	363
10-4	2759	2760	407.5	323.3
10-5	2761	2762	421.5	405.4
10-6	2763	2764	435.5	436.2
10-7	2765	2766	450.6	451.3
10-8	2767	2768	433.5	417.3
10-9	2769	2770	423.5	407.2
10-10	2771	2772	435.5	419.2
10-11	2773	2774	451.5	452.3
10-12	2775	2776	436.5	323.3
10-13	2777	2778	466.6	450.3
10-14	2779	2780	430.5	414.4
10-15	2781	2782	444.5	428.4
10-16	2783	2784	430.5	414.4
10-17	2785	2786	430.5	414.4
10-18	2787	2788	512.6	513.3
10-19	2789	2790	410.5	323.3
10-20	2791	2792	381.4	382.2
10-21	2793	2794	429.5	413.2
10-22	2795	2796	447.5	431.4
10-23	2797	2798	447.5	431.3
10-24	2799	2800	498.4	481.4
10-25	2801	2802	459.5	443.3
10-26	2803	2804	443.5	427.2
10-27	2805	2806	463.9	447.1
10-28	2807	2808	443.5	427.2
10-29	2809	2810	397.4	398.2
10-30	2811	2812	395.5	379.2
10-31	2813	2814	409.5	393.3
10-32	2815	2816	396.5	380.3
10-33	2817	2818	410.5	394.1
10-34	2819	2820	397.4	381.2
10-35	2821	2822	383.4	367.1
10-36	2823	2824	443.5	427.2
10-37	2825	2826	379.4	363.3
10-38	2827	2828	409.5	393.3
10-39	2829	2830	382.4	366.2
10-40	2831	2832	381.4	365.2
10-41	2833	2834	424.5	408.5
10-42	2835	2836	397.4	381.2
10-43	2837	2838	396.5	380.3
10-44	2839	2840	409.5	393.3
10-45	2841	2842	465.5	449.4
10-46	2843	2844	497.5	481.4
10-47	2845	2846	395.5	379.3
10-48	2847	2848	450.6	451.3
10-49	2849	2850	411.5	395.2
10-50	2851	2852	393.5	377.3
10-51	2853	2854	444.5	428.4
10-52	2855	2856	463.9	447.1
10-53	2857	2858	457.5	441.3
10-54	2859	2860	481.9	465.4
10-55	2861	2862	498.4	481.2
10-56	2863	2864	413.4	397.1
10-57	2865	2866	498.4	481.2
10-58	2867	2868	408.5	409.2
10-59	2869	2870	425.5	409.2
10-60	2871	2872	444.5	428.4
10-61	2873	2874	422.5	323.4
10-62	2875	2876	487.5	471.3
10-63	2877	2878	473.5	474.2
10-64	2879	2880	498.4	498.1
10-65	2881	2882	447.5	448.2
10-66	2883	2884	459.5	460.2
10-67	2885	2886	443.5	434.2
10-68	2887	2888	443.5	444.2
10-69	2889	2890	451.6	452.3
10-70	2891	2892	409.5	410.2
10-71	2893	2894	409.5	410.2
10-72	2895	2896	427.5	428.2

EXAMPLE 11

Synthesis of Representative Compounds

[0197] 2897

[0198] Step A 1-(2,6-difluorobenzyl-3-[(2R)-tertbutylcarbonylamino-2-phenyl]ethyl-5-(1-ethoxyvinyl)-6-methyluracil

[0199] A solution of 1-(2,6-difluorobenzyl-3-[(2R)-tert-butylcarbonylamino-2-phenyl]ethyl-5-bromo-6-methyluracil 1 (500 mg, 0.91 mmol), tributyl(ethoxyvinyl)tin (0.39 mL) and (Ph3P)4Pd(0) (105 mg) in dioxane (5 mL) was heated at 100° C. under nitrogen for 2 hours. The reaction mixture was concentrated in vacuo and the crude product 2 was used for next step. MS: 442 (MH+-Boc).

[0200] Step B 1-(2,6-Difluorobenzyl-3-[(2R)-tertbutyloxycarbonylamino-2-phenyl]ethyl-5-acetyl-6-methyluracil

[0201] A solution of 1-(2,6-difluorobenzyl-3-[(2R)-tertbutylcarbonylamino-2-phenyl]ethyl-5-(1-ethoxyvinyl)-6-methyluracil 2 (490 mg) in THF (10 mL) was treated with 2.5M aqueous HCl (3 mL) and stirred at r.t. for one hour. The reaction mixture was neutralized with NaHCO3 and concentrated in vacuo to remove THF. The product was extracted with ethyl acetate. The extract was washed with water and brine, dried over MgSO4 and concentrated in vacuo to give a brown solid. Chromatography on silica gel with 1:2 to 1:1 ethyl acetate/hexanes gave compound 3 as a white solid (227 mg, 50% yield); 1H NMR:1.37 (s, 9H), 2.38 (s, 3H), 2.58 (s, 3H), 4.12 (dd, J=4.2, 10.0 Hz, 1H), 4.65 (dd, J=6.5, 10.0 Hz, 1H), 5.20 (m, 1H), 5.40 (d, J=12.0 Hz, 1H), 5.49 (d, J=12.0 Hz, 1H), 5.58 (d, J=6.0 Hz, 1H), 6.92 (t, J=8.0 Hz, 2H), 7.38 (m, 6H); MS: 414 (MH+-Boc).

[0202] Step C 1-(2,6-Difluorobenzyl-3-[(2R)-tertbutoxycarbonylamino-2-phenyl]ethyl-5-(3-dimethylamino-1-oxopropenyl)-6-methyluracil

[0203] 1-(2,6-Difluorobenzyl-3-[(2R)-tertbutylcarbonylamino-2-phenyl]ethyl-5-acetyl-6-methyluracil 3 (44 mg) was suspended in DMFDMA (1.0 mL) and heated at 50° C. for 1 hour. The product was purified on silica gel with 1:1 ethyl acetate/hexanes to give compound 4 as a yellow oil; 1H NMR: 1.39 (s, 9H), 2.36 (s, 3H), 2.84 (s, 6H), 4.05 (m, 1H), 4.30 (m, 1H), 4.66 (d, J=12.0 Hz, 1H), 5.03 (m, 1H), 5.20 (d, J=12 Hz, 1H), 5.46 (d, J=12 Hz, 1H), 5.84 (d, J=7 Hz, 1H), 6.64 (d, J=12.0 Hz, 1H), 6.87 (t, J=8.0 Hz, 2H), 7.20-7.40 (m, 6H); MS: 596 (MH+).

[0204] Step D 1-(2,6-Difluorobenzyl-3-[(2R)-amino-2-phenyl]ethyl-5-(isoxazol-5-yl)-6-methyluracil

[0205] A mixture of 1-(2,6-difluorobenzyl-3-[(2R)-tertbutoxycarbonylamino-2-phenyl]ethyl-5-(3-dimethylamino-1-oxopropenyl)-6-methyluracil 4 (95 mg), hydroxylamine hydrochloride (150 mg), sodium carbonate (18 mg) in methanol (5 mL) was acidifiedwith acetic acid to pH-4. The mixture was then heated at 120° C. for 1.5 hours, cooled down to r.t., filtered, and concentrated in vacuo to give the protected product. MS: 539 (MH+). The protected product was dissolved in dichloromethane (2 mL), treated with TFA (1 mL), and stirred at r.t. for 1 hour. Concentration in vacuo followed by purification on silica gel eluting with 1% aq. NH4OH in ethyl acetate gave product 5; MS: 439 (MH+); 1H NMR (CD3OD): 3.05 (s, 3H), 4.70 (m, 1H), 4.55 (m, 2H), 5.48 (d, J=12.0 Hz, 1H), 5.60 (d, J=12.0 Hz, 1H), 7.00 (t, J=8.0 Hz, 2H), 7.30-7.65 (m, 7H), 8.50 (d, J=6.0 Hz, 1H).

EXAMPLE 12

Synthesis of Representative Compounds

[0206] 2898

[0207] Step A 1-(2,6-Difluorobenzyl-3-[(2R)-tertbutylcarbonylamino-2-phenyl]ethyl-5-bromoacetyl-6-methyluracil

[0208] A solution of 1-(2,6-difluorobenzyl-3-[(2R)-tertbutylcarbonylamino-2-phenyl]ethyl-5-(1-ethoxyvinyl)-6-methyluracil 1 (3.68 g, 6.8 mmol) in THF (120 mL) and water (120 mL) was treated with N-bromosuccinimide (2.3 g) at r.t. and the mixture was stirred for 4 hours. THF was removed in vacuo and the product which precipitated on standing was collected by filtration and was washed with ether to give white solid 2 (1.6 g, 40%); 1H NMR: 1.39 (s, 9H), 2.40 (s, 3H), 4.04 (dd, J=2.0, 7.0 Hz, 1H), 4.36 (d, J=7.0 Hz, 1H), 4.10 (d, J=5.5 Hz, 1H), 4.56 (d, J=5.5 Hz, 1H), 55.50 (m, 1H), 5.24 (d, J=12.0 Hz, 1H), 5.40 (brs, 1H), 5.50 (d, J=12.0 Hz, 1H), 6.94 (t, J=8.0 Hz, 1H), 7.36 (m, 6H); MS: 492 (MH+).

[0209] Step B 1-(2,6-Difluorobenzyl-3-[(2R)-amino-2-phenyl]ethyl-5-(5-methylthiazol-4-yl)-6-methyluracil

[0210] A solution of 1-(2,6-difluorobenzyl-3-[(2R)-tertbutylcarbonylamino-2-phenyl]ethyl-5-bromoacetyl-6-methyluracil (100 mg, 0.17 mmol) and thioacetamide (30 mg, 0.4 mmol) in ethanol (2 mL) was heated at 80° C. in a sealed reaction vessel for 3 hours. The reaction mixture was then concentrated in vacuo to give an oil and LCMS indicated protected product; MS: 569 (MH+). The protected product was dissolved in dichloromethane (2 mL) and treated with TFA (1 mL) at r.t. for 1 hour, and concentrated in vacuo. The product was purified on silica gel eluting with 5% aq. NH4OH in ethyl acetate to give yellow solid 3; 1H NMR: 2.12 (s, 3H), 2.71 (s, 3H), 4.15-4.70 (m, 3H), 5.66 (s, 2H), 7.00 (t, J=8.0 Hz, 2H), 7.30 (m, 7H); MS: 469 (MH+).

[0211] Step C 1-(2,6-Difluorobenzyl-3-[(2R)-amino-2-phenyl]ethyl-5-(5-benzylaminolthiazol-4-yl)-6-methyluracil

[0212] A solution of 1-(2,6-difluorobenzyl-3-[(2R)-tertbutylcarbonylamino-2-phenyl]ethyl-5-bromoacetyl-6-methyluracil 2 (35 mg) and ammonium thioisocyanate (10 mg) in ethanol (1 mL) was heated at 80° C. in a sealed reaction vessel for 1 hour. Benzylamine (0.2 mL) was added and the mixture was heated at 80° C. overnight. The reaction mixture was then concentrated in vacuo, and the protected product was dissolved in dichloromethane (1 mL) and treated with TFA (1 mL) at r.t. for 1 hour. The mixture was concentrated in vacuo and the residue was purified on silica gel with 5% aq. NH4OH in ethyl acetate to give product 4 as a yellow solid; 1H NMR: 2.25 (s, 3H), 4.05 (dd, J=3.0, 7.5 Hz, 1H), 4.28 (dd, J=6.5, 7.5 Hz, 1H), 4.42 (m, 1H), 4.44 (s, 2H), 5.32 (d, J=12.0 Hz, 1H), 5.36 (d, J=12.0 Hz, 1H), 6.54 (s, 1H), 6.92 (t, J=8.0 Hz, 2H), 7.20-7.50 (m, 11H); MS: 560 (MH+).

[0213] Step D 1-(2,6-Difluorobenzyl-3-[(2R)-amino-2-phenyl]ethyl-5-(imidazolo [1,2-a]pyrid-2-yl)-6-methyluracil

[0214] A mixture of 1-(2,6-difluorobenzyl-3-[(2R)-tertbutylcarbonylamino-2-phenyl]ethyl-5-bromoacetyl-6-methyluracil 2 (35 mg) and 2-aminopyridine (7 mg) in ethanol was heated at 80° C. overnight. The reaction mixture was then concentrated in vacuo, and the protected product was dissolved in dichloromethane (1 mL) and treated with TFA (1 mL) at r.t. for 1 hour. After concentration in vacuo, the product 5 was purified on preparative HPLC; 1H NMR: 2.32 (s, 3H), 4.04 (m, 1H), 4.67 (m, 2H), 5.17 (d, J=16.2 Hz, 1H), 5.41 (d, J=16.2 Hz, 1H), 6.92 (t, J=8.1 Hz, 2H), 7.24-7.40 (m, 7H), 7.73 (m, 1H), 7.80 (m, 1H), 8.03 (s, 1H), 8.30 (brs, 3H), 8.44 (d, J=5.5 Hz, 1H); MS: 488 (MH+).

TABLE 12
2899
Cpd.	MW
No.	—Q—R4	(calc.)	(obs.)
12-1	2900	468.5	469.1
12-2	2901	469.5	470.1
12-3	2902	497.6	498.2
12-4	2903	530.6	531.1
12-5	2904	544.6	545.2
12-6	2905	526.6	527.2
12-7	2906	488.5	489.2
12-8	2907	507.6	508.2
12-9	2908	508.6	509.1
12-10	2909	575.6	576.2
12-11	2910	545.6	546.2
12-12	2911	563.6	564.2
12-13	2912	590.6	591.1
12-14	2913	559.6	560.2
12-15	2914	487.5	488.2
12-16	2915	539.6	540.2
12-17	2916	559.6	560.2
12-18	2917	573.7	574.2
12-19	2918	509.5	510
12-20	2919	598.6	599.2
12-21	2920	565.0	565.2
12-22	2921	565.0	565.1
12-23	2922	583.0	583.1
12-24	2923	548.6	549.2
12-25	2924	559.6	560.2
12-26	2925	575.6	576.2
12-27	2926	605.7	606.3
12-28	2927	573.7	574.2
12-29	2928	573.7	574.2
12-30	2929	573.7	574.2
12-31	2930	573.7	574.2
12-32	2931	559.6	560.2

EXAMPLE 13

Synthesis of Representative Compounds

[0215] 2932

[0216] Step A. 5-Bromo-1-(2,6-difluorobenzylhuracil

[0217] A suspension of 5-bromouracil (18.45 g, 96.6 mmol) in 300 mL of dichloroethane was treated with N,O-bis(trimethylsilyl)acetamide (48 mL, 39.5 g, 194 mmol). The reaction mixture was heated at 80° C. for 3 hr under the nitrogen. The solution was cooled down to ambient temperature, 2,6-difluorobenzyl bromide (25 g, 120 mmol) was added and the reaction mixture was heated at 80° C. overnight under the protection of nitrogen. The reaction was cooled down, quenched with MeOH (15 mL), and partitioned between dichloromethane (500 mL) and water (250 mL). The organic layer was washed with brine, dried (sodium sulfate), and evaporated to give a solid. The crude product was triturated with ether, filtered, and washed with ether three times to give compound 1 (15.2 g, 50%) as a white solid; MS (CI) m/z 316.90, 318.90 (MH+).

[0218] Step B 1-(2,6-Difluorobenzyl-3-[(2R)-tertbutylcarbonylamino-2-phenyl]ethyl-5-bromouracil

[0219] A solution of (R)-N-(tert-butoxycarbonyl)-2-phenylglycinol (14.97 g, 63.1 mmol) in anhydrous THF (300 mL) was treated with 5-bromo-1-(2,6-difluorobenzyl)uracil 1 (20 g, 63.1 mmol) and triphenylphosphine (20.68 g, 78.8 mmol) at ambient temperature, then diisopropylazodicarboxylate (15.52 mL, 15.94 g, 78.8 mmol) in THF (30 mL) was introduced via a dropping funnel. The reaction mixture was stirred at ambient temperature for 16 h and volatiles were evaporated. The residue was purified by flash chromatography (silica, 25% EtOAc/hexanes) to give compound 2 (31.15 g, 92.1%) as a white solid, MS (CI) m/z 436.0, 438.0 (MH+-Boc).

[0220] Step C1-(2,6-Difluorobenzyl-3-[(2R)-tert-butoxycarbonylamino-2-phenyl]ethyl-S-(2,4,6-trimethylphenyl)uracil

[0221] To compound 2 (134 mg, 0.25 mmol) in toluene/H2O/EtOH (6/3.75/0.75 mL) was added 2,4,6-trimethylphenyl boronic acid ester (87 mg, 1.5 eq), K2CO3 (86 mg, 2.5 eq), and saturated Ba(OH)2/water (0.1 mL). The reaction mixture was deoxygenated with N2 for 10 min, tetrakis(triphenylphosphine) palladium (0) (29 mg, 0.1 eq) was added and the reaction mixture was heated at 100° C. overnight under the protection of N2. The reaction mixture was partitioned between brine and EtOAc. The organic layer was dried (sodium sulfate), evaporated, purified by flash chromatography (silica, 25% EtOAc/hexanes) to give compound 3 (130 mg) as a pale yellow oil.

[0222] Step D 1-(2,6-Difluorobenzyl-3-[(2R)-amino-2-phenyl]ethyl-5-(2,4,6-trimethylphenyl)uracil

[0223] TFA (3 mL) was added to a solution of 3 (130 mg, 0.22 mmol) in dichloromethane (3 mL) and the reaction mixture was stirred at ambient temperature for 2 hours. Volatiles were evaporated and the residue was partitioned between saturated NaHCO3/water and EtOAc. The organic layer was dried (sodium sulfate), evaporated, and purified by prep TLC eluting with 5% MeOH in CH2Cl2 to give compound 4, MS (CI) m/z 476.2 (MH+).

TABLE 13
2933
Cpd.			MW
No.	NR1R2—(CR3aCR3b)n—	—Q—R4	(calc.)	(obs.)
13-1	2934	2935	475.5	476.2
13-2	2936	2937	481.5	482
13-3	2938	2939	528.6	529
13-4	2940	2941	475.5	476.2

EXAMPLE 14

Synthesis of Representative Compounds

[0224] 2942

[0225] Step A 1-(2,6-Difluorobenzyl)-5-carbethoxyuracil

[0226] 5-Carbethoxyuracil (5 g, 27.15 mmol) and N,O-bis(trimethylsilyl)acetamide (13.4 mL, 2 eq) in dichloroethane (35 mL) were heated at 80° C. for 2 hours. Difluorobenzyl bromide (8.4 g, 1.5 eq) was added and the reaction mixture was heated at 80° C. for 16 hours. The reaction was quenched with methanol and partitioned between methylene chloride and sodium bicarbonate solution. The organic layer was washed with brine, dried and concentrated in vacuo and the residue was triturated with ether to give compound 1 as a white solid (3.26 g).

[0227] Step B 1-(2,6-Difluorobenzyl-3-[(2R)-tert-butoxycarbonylamino-2-phenyl]ethyl-5-carbethoxyuracil

[0228] A solution of (R)-N-(tert-butoxycarbonyl)-2-phenylglycinol (316 mg, 1.33 mmol) in anhydrous THF (30 mL) was treated with 1-(2,6-difluorobenzyl)-5-carbethoxyuracil 1 (413 mg, 1.33 mmol) and triphenylphosphine (525 mg, 2 mmol) at ambient temperature, then diisopropylazodicarboxylate (460 mg, 2 mmol) in THF (5 mL) was introduced via a dropping funnel. The reaction mixture was stirred at ambient temperature for 5 h and volatiles were evaporated. The residue was purified by flash chromatography (silica, 35% EtOAc/hexanes) to give compound 2 (427 mg) as a white foam.

[0229] Step C 1-(2,6-Difluorobenzyl-3-[(2R)-tertbutylcarbonylamino-2-phenyl]ethyl-5-n-butylamidouracil

[0230] A solution of triethylaluminum (1.9 M in toluene, 0.26 mL, 0.5 mmol) was added to n-butylamine (0.1 mL, 1 mmol) in dichloroethane and the reaction mixture was sealed under nitrogen and stirred for 12 hour. 1-(2,6-Difluorobenzyl-3-[(2R)-tertbutylcarbonylamino-2-phenyl]ethyl-5-carbethoxyuracil 2 was added and the mixture was stirred at 70-80° C. for 12 hours to give 3. Trifluoroacetic acid (1 mL) was added and the reaction mixture was stirred for 1 hour. The mixture was concentrated in vacuo and the residue was partitioned between methylene chloride and sodium carbonate solution. The organic layer was washed with brine, dried and concentrated to give a residue which was purified by prep HPLC to give compound 4 (56 mg, MH+457).

TABLE 14
2943
Cpd.			MW
No.	NR1R2—(CR3aCR3b)n—	—Q—R4	(calc.)	(obs.)
14-1	2944	2945	456.5	457.2
14-2	2946	2947	456.5	457.2
14-3	2948	2949	456.5	457.2
14-4	2950	2951	413.4	414.1
14-5	2952	2953	523.6	424.2
14-6	2954	2955	423.5	424.2

EXAMPLE 15

Synthesis of Representative Compounds

[0231] 2956

[0232] Step A 1-(2,6-Difluorobenzyl-3-[(2R)-tert-butoxycarbonylamino-2-phenyl]ethyl-5-bromo-6-ethyluracil

[0233] 1-(2,6-Difluorobenzyl-3-[(2R)-tert-butoxycarbonylamino-2-phenyl]ethyl-5-bromo-6-methyluracil 1 (550 mg, 1 mmol) was dissolved in THF (10 mL) and the solution was cooled to 0° C. Lithium bis(trimethylsilyl)amide (1.0 M in THF, 1.3 mL, 1.3 mmol) was added dropwise and the reaction was stirred for 40 minutes at 0° C. Iodomethane (0.093 mL, 1.5 mmol) was added dropwise and after 30 minutes, water was added and the mixture extracted with ethyl acetate. Concentration in vacuo gave compound 2 as a yellow foam.

TABLE 15
2957
Cpd.			MW
No.	NR1R2—(CR3aCR3b)n—	—Q—R4	(calc.)	(obs.)
15-1	2958	2959	509.5	510.2
15-2	2960	2961	491.5	492
15-3	2962	2963	534.6	535
15-4	2964	H	428.5	429
15-5	2965	2966	504.6	505
15-6	2967	2968	546.65
15-7	2969	2970	548.58	549.2
15-8	2971	2972	503.6	504.3
15-9	2973	2974	523.6	524

EXAMPLE 16

Synthesis of Representative Compounds

[0234] 2975

[0235] Step A 1-(2,6-Difluorobenzyl)-3-(4-methyl-2R-guanidopentyl)-5-(2-fluoro-3-methoxyphenyl)-6-methyluracil

[0236] A solution of 1-(2,6-difluorobenzyl)-3-(4-methyl-2R-aminopentyl)-5-(2-fluoro-3-methoxyphenyl)-6-methyluracil 1 (75 mg), (1H)-pyrazole-1-carboxamidine hydrochloride (23 mg) diisopropylethylamine (21 mg) in anhydrous DMF was heated at 40-50° C. overnight (0.5 mL). The reaction mixture was treated with water and the product was extracted with ethyl acetate. The extract was dried over MgSO4, filtered and concentrated in vacuo and the residue was purified on silica gel (Et3N/MeOH/CHCl3 (2:5:93) as elutant) to give white solid 2. MS: 518 (MH+).

[0237] It will be appreciated that, although specific embodiments of the invention have been described herein for purposes of illustration, various modifications may be made without departing from the spirit and scope of the invention. Accordingly, the invention is not limited except as by the appended claims.

Claims

1. A compound having the following structure:

2. The compound of claim 1 wherein A is 0.

3. The compound of claim 1 wherein A is S.

4. The compound of claim 1 wherein A is NR7.

5. The compound of claim 1 wherein R1 is aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocycle, substituted heterocycle, heterocyclealkyl or substituted heterocyclealkyl.

6. The compound of claim 5 wherein heterocycle is heteroaryl, substituted heterocycle is substituted heteroaryl, heterocyclealkyl is heteroarylalkyl, and substituted heterocyclealkyl is substituted heteroarylalkyl.

7. The compound of claim 7 wherein R1 is heteroarylalkyl or substituted heteroarylalkyl.

8. The compound of claim 1 wherein R1 is phenylalkyl or substituted phenylalkyl.

9. The compound of claim 1 wherein R1 is benzyl.

10. The compound of claim 1 wherein R1 is hydrogen or lower alkyl.

11. The compound of claim 1 wherein R2 is hydrogen, alkyl or substituted alkyl.

12. The compound of claim 1 wherein R2 is hydrogen or methyl.

13. The compound of claim 1 wherein Q is a direct bond.

14. The compound of claim 1 wherein Q is —(CR9aR8b)r-Z-(CR10aR10b)s—.

15. The compound of claim 1 wherein R3a and R3b are, at each occurrence, hydrogen.

16. The compound of claim 1 wherein R3a is hydrogen, alkyl, aryl or arylalkyl.

17. The compound of claim 1 wherein R3a is hydrogen, methyl, isobutyl, cyclohexyl, phenyl or benzyl.

18. The compound of claim 1 wherein R3b is, at each occurrence, hydrogen.

19. The compound of claim 1 wherein n is 1.

20. The compound of claim 1 wherein n is 2.

21. The compound of claim 20 wherein —(R3aR3bC)n— has the structure —C(R3a)(R3b)CH2—.

22. The compound of claim 21 wherein R3a is benzyl.

23. The compound of claim 21 wherein R3a is alkyl.

24. The compound of claim 23 wherein R3a is isobutyl or cyclohexyl.

25. The compound of claim 21 wherein R3b is hydrogen or methyl.

26. The compound of claim 1 wherein R4 is substituted aryl or substituted heterocycle.

27. The compound of claim 1 wherein R4 is substituted phenyl.

28. The compound of claim 27 wherein R4 is phenyl substituted with halogen, alkoxy, or both halogen and alkoxy.

29. The compound of claim 1 wherein R5 is H, lower alkyl or substituted lower alkyl.

30. The compound of claim 1 wherein R5 is hydrogen or methyl.

31. The compound of claim 1 wherein R6 is aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl.

32. The compound of claim 1 wherein R6 is arylalkyl, substituted arylalkyl, heteroarylalkyl or substituted heteroarylalkyl.

33. The compounds of claim 1 wherein R6 is benzyl or substituted benzyl.

34. The compound of claim 1 wherein R6 is benzyl substituted with two halogens.

35. The compound of claim 1 wherein Q is a bond and R4 is substituted aryl or heterocycle.

36. The compound of claim 1 wherein R1 is —CH2(heteroaryl) or —CH2CH2(heteroaryl).

37. The compound of claim 1 wherein R1 and R2 taken together with the nitrogen atom to which they are attached form a heterocyclic ring or substituted heterocyclic ring.

38. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier or diluent.

39. A method for antagonizing gonadotropin-releasing hormone in a subject in need thereof, comprising administering to the subject an effective amount of a compound of claim 1 or a pharmaceutical composition of claim 38.

40. A method for treating an sex-hormone related condition of a subject in need thereof, comprising administering to the subject an effective amount of a compound of claim 1 or a pharmaceutical composition of claim 38.

41. The method of claim 40 wherein the sex-hormone related condition is cancer, benign prostatic hypertrophy or myoma of the uterus.

42. The method of claim 41 wherein the cancer is prostatic cancer, uterine cancer, breast cancer or pituitary gonadotroph adenomas.

43. The method of claim 41 wherein the sex-hormone related condition is endometriosis, polycystic ovarian disease, uterine fibroids or precocious puberty.

44. A method for preventing pregnancy of a subject in need thereof, comprising administering an effective amount of a compound of claim 1 or a pharmaceutical composition of claim 38.

45. A method for treating lupus erythematosis, irritable bowel syndrome, premenstrual syndrome, hirsutism, short stature or sleep disorders of a subject in need thereof, comprising administering to the subject an effective amount of a compound of claim 1 or a pharmaceutical composition of claim 38.