AU2004200664B2 - Gonadotropin-releasing hormone receptor antagonists and methods relating thereto - Google Patents

Description

AUSTRALIA

PATENTS ACT 1990 DIVISIONAL APPLICATION NAME OF APPLICANT: Neurocrine Biosciences, Inc.

ADDRESS FOR SERVICE: DAVIES COLLISON CAVE Patent Attorneys 1 Nicholson Street Melbourne, 3000.

INVENTION TITLE: "Gonadotropin-releasing hormone receptor antagonists and methods relating thereto" The following statement is a full description of this invention, including the best method of performing it known to us: 1 GONADOTROPIN-RELEASING HORMONE RECEPTOR ANTAGONISTS AND METHODS RELATING THERETO STATEMENT OF GOVERNMENT INTEREST Partial funding of the work described herein was provided by the U.S.

Government under Grant No. R43-HD38625 provided by the National Institutes of Health. The U.S. Government may have certain rights in this invention.

TECHNICAL FIELD 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 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-NH 2 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.

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 on the order of 2-3 weeks following initiation of chronic administration).

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.

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. Patent 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 W097/14682, 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 nitrogencontaining bicyclic compounds as GnRH receptor antagonists.

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 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 R R 2

R

N

N

A N R

RI

R6

(I)

including stereoisomers, prodrugs and pharmaceutically acceptable salts thereof, wherein A, Q, RI, R 2 R3a, R3b, R 4 Rs, R6, and n are as defined below.

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 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 P \OPF.RIK2:TI;i r(C X4 rcsl doc-2(01dN(17 4 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.

The methods of this invention include administering an effective amount of a GnRI- 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.

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.

Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.

The reference in this specification to any prior publication (or information derived from it), or to any matter which is known, is not, and should not be taken as an acknowledgment or admission or any form of suggestion that that prior publication (or information derived from it) or known matter forms part of the common general knowledge in the field of endeavour to which this specification relates.

DETAILED DESCRIPTION OF THE INVENTION 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 P \OPERKbni ua(2(x WiX resl doc.20t) w21(7

N

N

N R4 S(R3aR3bC, Q A N R N I R6

(I)

including stereoisomers and pharmaceutically acceptable salts thereof, wherein: Q is a direct bond; A is O, S, or NR7; r and s are the same or different and independently 0, 1, 2, 3, 4, 5 or 6; n is 2; Z is a direct bond or -NRg-, -SOz-, -OSO2-,

-SO

2 NRg-, -NR 9

SO

2 -COO-, -OCO-, -CONR 9 -NRqCO-, -NRoCONR 9

-OCONR

9 or -NR 9

COO-;

RI and R 2 are the same or different and independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocycle, substituted heterocycle, heterocyclealkyl, substituted heterocyclealkyl, -C(Rla)(=NRib) or -C(NRiaRic)(=NRib); or Ri, and R 2 taken together with the nitrogen atom to which they are attached form a heterocycle ring or a substituted heterocycle ring; 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, -COORI4 or-CONRi 4 Ri 5 or R3a and R3h taken together with the carbon atom to which they are attached form a homocyclic ring, substituted homocyclic ring, heterocyclic ring or OP PHIR\KtII)Mn 12(9"- rcsl doc-20AJ2I)7 6 substituted heterocyclic ring; or R3a and R3b taken together form =NR 3 c; or R3a and the carbon to which it is attached taken together with RI and the nitrogen to which it is attached form a heterocyclic ring or substituted heterocyclic ring;

R

4 is aryl or substituted aryl;

R

5 is hydrogen, halogen, lower alkyl, substituted lower alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, alkoxy, alkylthio, alkylamino, cyano or nitro;

R

6 is higher alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl;

R

7 is hydrogen, -SO 2

R

11 cyano, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl; and Ria, Rib, Ric, R3c, R 9 Rga, R I, R 1 4 and R 1 5 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; or Ria and Rib, or R 1 4 and R|s 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.

As used herein, the above terms have the following meaning: "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, npentyl, 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 6A 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, 3methyl-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, I-pentynyl, 2-pentynyl, 3methyl-I -butynyl, and the like.

"Aryl" means an aromatic carbocyclic moiety such as phenyl or naphthyl.

"Arylalkyl" means an alkyl having at least one alkyl hydrogen atoms replaced with an aryl moiety, such as benzyl, -(CH 2 2 phenyl, -(CH 2 3 phenyl, -CH(phenyl) 2 and the like.

"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.

"Heteroarylalkyl" means an alkyl having. at least one alkyl hydrogen atom replaced with a heteroaryl moiety, such as -CH 2 pyridinyl, -CH 2 pyrimidinyl, and the like.

"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 I 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.

"Heterocyclealkyl" means an alkyl having at least one alkyl hydrogen atom replaced with a heterocycle, such as -CH 2 morpholinyl, and the like.

"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.

The term "substituted" as used herein means any of the above groups 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 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 -NRRb, -NRaC(=O)Rb, NRaC(=O)NRaNRb, -NRaC(=O)ORb -NRaSO 2 Rb, -C(=O)ORa, -C(=O)NR,Rb, -OC(=O)NRaRb, -ORa, -SORa, 2 -OS(=0) 2 R, and S(=0)20Ra. 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. R, 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.

"Halogen" means fluoro, chloro, bromo and iodo.

"Haloalkyl" means an alkyl having at least one hydrogen atom replaced with halogen, such as trifluoromethyl and the like.

"Alkoxy" means an alkyl moiety attached through an oxygen bridge -O-alkyl) such as methoxy, ethoxy, and the like.

"Alkylthio" means an alkyl moiety attached through a sulfur bridge -S-alkyl) such as methylthio, ethylthio, and the like.

"Alkylsulfonyl" means an alkyl moiety attached through a sulfonyl bridge -SO 2 -alkyl) such as methylsulfonyl, ethylsulfonyl, and the like.

"Alkylamino" and "dialkylamino" mean one or two alkyl moiety attached through a nitrogen bridge -N-alkyl) such as methylamino, ethylamino, dimethylamino, diethylamino, and the like.

In one embodiment of this invention, A is O and representative GnRH receptor antagonists of this invention include compounds having the following structure

(II):

Ri

N

R4

(R

3 aR 3 C) Q

N

0 N

R

I

R6 6

(II)

In another embodiment, Q is -(CRsaR8b),-Z-(CRioaROb)s-, r and s are both zero, and representative GnRH receptor antagonists of this invention include compounds having the following structure (III):

N

R

4 ,z (1Il) In another embodiment, A is S, as represented by the following structure

(IV):

R

R

"R

2

N

R4

(R

3 aR 3 bC) n Q

Q

N

S N

R

R 6

(IV)

Similarly, in another embodiment, A is NR 7 as represented by the following structure Ri R

N

(R

3 aR 3 bNC)N

N

Ri-N N Rs

R

6

(V)

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):

RR

R, R2

N

(VI)

In a more specific embodiment of structure A is O, n is 2, and each occurrence of R3a and R3b is H, as represented by the following structure (VII): R2 NR -N R4 R O\

N

0 N

Y-

(VII)

With regard to the "RIR 2

N(CR

3 aR3b)n-" moiety of structure 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: RI\ ,R 2 RI

R

2

N

R ,R 2 N R3a R3a N R3a

R

3 a R3b R3b R3a R3a R3b R3b R3a R3a SR3 R3b R3b (ii) (iii) 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 (ii) and (iii) is hydrogen, the "RIR 2

N(CR

3 aR 3 moiety has the structure RIR 2

N(CH

2 2

RIR

2

N(CH

2 3 and RIR 2

N(CH

2 4 respectively.

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 above may be made by the following Reaction Schemes. Specifically, compounds of structure wherein A is oxygen may be made by Reaction Schemes A to E. Reaction Schemes F to K are appropriate for compounds of structure wherein A is sulfur or NR 7 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 NR 7 All substituents in the following Reaction Schemes are as detined above unless indicated otherwise.

Reaction Scheme A 0 0 0 0i J I.)HCI,EtOH

X-R,

N NH, R O KOH, MeOH H N R i ii H 0 0 0 0 Z NB 0 Br [01 R, B r O N I I

SR

6

R

6 iv v vi

/R

2 O

/R

2

O

RN N Br RN N R R RNH N R 4

B(OH)

2 0 J N RS b N R, R6 R 6 vii viii Allylurea and substituted acetoacetate (ii) are condensed under acidic conditions in a solvent such as ethanol or DMF at 25 to 100 0 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 Bromination of using bromine or n-bromosuccinimide in a solvent such as acetic acid or chloroform for 1-24 hours resulted in brominated compound 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 0 C for 1-24 hours in the presence of a Pd(0) catalyst gives (viii).

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.

14 Reaction Scheme B

NH

2 0 ±R 5 0

NR

0 N R

H

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 0 C for 1-24 hours.

Reaction Scheme C o o o 0 NH, R 5 QR o o0 X 4 R,R2N(R.,R, Br R

R

N

0 0

RR

4 R 4

R

6 NH 0 <N Q R4

RIR

2

N(R

3

R

3 bC)BrjI

R

6

NH

2 R' R

N

r 0' 'O R 5 O0 'N R,

I

v R 6 xvi Cyclization of(xi) and (xii) in a solvent such as ethanol or DMF at 25 to 150 0 C for I to 24 hours gives oxazime (xiii). Amination of (xiii) in a solvent such as DMF or ethanol at 25 to 150 0 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).

Reaction Scheme D 0 O 0, R O R, xvii or R

R

N

r

R

,R,

N

R, RN(CR,,R,,),NCO R NH 0 o xvii 'Rs xvi Compound (xvii) or (xviii) react with an appropriately substituted isocyanate in a solvent such as toluene or chloroform at room temperature to 100 0 C for 1-24 hours as an alternative synthesis to intermediate oxazine 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).

Reaction Scheme E

,R

2 R xvi is H)

P

0 (R3aR 3 bC

N

0 N R5

R,

7ixx R, R 2

N

o ArB(OH) 2 Pd(O) ArB(OH),

CO/P

ArCH,ZnBr R R2

N

XX

d(0) R

N

0 0

(R,,R

3 b C) ON Ar

R

6 xxiv

R

N Ar N R

I/

(R II

R,

6 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 0 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 0 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 0 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 0

C.

Compound (ixx) in the presence of a substituted acetylene, Pd(0) catalyst, metal halide such as Cul, and base such as triethylamine in an appropriate solvent such as acetonitrile or DMF at 25 to 150 0 C for 1-24 hours gives alkyne (xxii). Alkynyl uracil (xxii) may be selectively reduced to the alkene using a catalyst such as palladium/BaSO 4 under hydrogen atmosphere in solvent such as ethyl acetate or methanol to give (xxi).

Reaction Scheme F A R4 0

N

Ri RN(CR ,R 3 b)N NH+ 0 (R 3a

R

3 bC) R I 2 Q'R 4

HR

5 A N R xxvi H xxvii T OH, OMe, CI, dialkylamine /RBr

N

0 (R3a,R, ,C

(R

3 lR QbC) R 4 N R

I

R

6 XXVIII xxviii Vinyl ester (xxvi) and (xxv) can be cyclized in a solvent such as DMF or EtOH at 25 to 150 0 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 0 C gives (xxviii).

Reaction Scheme G R I 0 R 6

NH

2 4 RNH, NH

R

6 6 R

/,R

2

N

C

(R ,,R 3 b c), R, RN(CR3.R3b),,NCA

N

T OH, OMe, CI, dialkylamine xxviii Vinyl ester (xxvi) can be condensed with a substituted amine in a solvent such as DMF or ethanol at 25 to 150 0 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).

Reaction Scheme H RBr

M

I

,R

2 N(CRl,R,,),,Br

R

R

2

N

/0 (R3 ,R3bC), AN R,

R

6 XXVIii Compound (xxx) 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 50°C for 1 -24 hours to give (xxxi), which under further alkylation by a second alkyl halide gives product (xxviii).

Reaction Scheme 1 O o

S(RR

3

(R

3 aR 3 b A N RsB AN R [R O I

I

R6

R

6 xxxi xxxii

R

2 00

N

(R

3 aR3bC)n II (R3aR 3 bC NQ N QR4 RR2NH N Q R4 N

R

A N R5 A N R R6

R

xxxiii xxvi 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 0 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 0 C for 1-24 hours gives (xxviii).

Reaction Scheme J

RI

OH N-R2 R 3 R3 R 3 bC) (R 3

R

3 bC), (RR3a N .3a N b N N QR 4

RR

2 N N 4 A N IN R N R AN R R, R, R, RR6 R 6 xxxii xxxiv xxviii 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 to 100 0 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 0 C gives (xxviii).

Reaction Scheme K 'R4

(R

3 aR 3 b)n Br ON Yf

RR

2 NH/Et 3

AI

xxir R2

RIII

A j-

XXXV

R

4

[H]

xxxvi xxviii 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 0

C.

Reduction of (xxxvi) with lithium aluminum hydride or borane complex in a solvent such as THF or ether at 0 to 100 0 C for 1-12 hours gives product (xxviii).

Reaction Scheme L RI

R

2

NN

I RR4 (R~(R3AC) 0OR N H /R2 R ONON

IIR

(RRA a RI 1 Q S.N N NR5 1I 1 Th ioail compound Qxxi)i h rsneo usiue givesai compound (xxxix).hepesnc f ubttue Reaction Scheme M R NH 2 Urea, HO0 HCI, reflux 0 RIN H NH 2

H

)-01 HOAc, reflux, 40 min.

-NIA

0; NO xli 0

OHN

I

0 hal

OIN

Xliii 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 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). H-alogenation of (xlii) using a halogenating reagent such as N-halosuccinimide in chloroformn or bromine in acetic acid for 5 minutes to 24 hours gives halogenated product (xliii).

Reaction Scheme N NR Prot 0 (R~h~Cf Hhalogen

O

01O NlIiRi

D

/NR Prot (R'aR~bC)l 0 \N Br

R

X i S /NR Pro:

(R

3 aR~bC)fl 0 R6

/NHRI

(R

3 aR 3 1iC)n 0

R

N 4

R

xlvi

/NRIR

(R.',R'bC)II 0

R

ONR

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 0 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).

Reaction Scheme O

NRR

2

R

5

CISO

2 NCO R4 RO o N OH o Et20/r.t., o/n 0- 0 R5 PPh,/DEAD/THF xlviii xlix NRR, NR R, R4 R RNR4H I xlvii 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 I which when in the presence of amine R 6

NH

2 at room temperature to 125 with or without solvent such as DMF or catalyst such as acetic or hydrochloric acid, for /2 to 24 hours gives xlvii.

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 saltsformed 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 is intended to encompass any and all acceptable salt forms.

In addition, prodrugs are also included within the context of this invention. Prodrugs are any covalently bonded carriers that release a compound of structure 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 Further, in the case of a carboxylic acid (-COOH), esters may be employed, such as methyl esters, ethyl esters, and the like.

With regard to stereoisomers, the compounds of structure 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 may also possess axial chirality which may result in atropisomers. Furthermore, some of the crystalline forms of the compounds of structure may exist as polymorphs, which are included in the present invention. In addition, some of the compounds of structure may also form solvates with water or other organic solvents. Such solvates are similarly included within the scope of this invention.

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 centrifugation, the separated plasma is stored at -20 °C until determination of the LH and FSH by radioimmunoassay. Other techniques for determining the activity of GnRHreceptor 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).

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

Rat Anterior Pituitary Cell Culture Assay of GnRH Antagonists 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 hr at 37 0 C. After collagenase digestion, the glands are further digested with neuraminidase for 9 min at 37 0 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 5A medium and plated into 96-well tissue culture plates at a cell density of 40,000 cells per well in 200 .tl medium. The cells are then incubated at 37 0 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 an 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 InM GnRH in 200 pl 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 GnRI- 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.

RIA of LH and FSH 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 NaCI/I% 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 12x75 mm polyethylene test tube is added 100 itl of sample medium diluted 1:5 or rLH standard in RIA buffer and 100 .tl of [1251]-labeled rLH (-30,000 cpm) plus 100 p.l of rabbit antirLH antibody diluted 1:187,500 and 100 tpl RIA buffer. The mixture is incubated at room temperature over-night. In the next day, 100 pl of goat anti-rabbit IgG diluted 1:20 and 100 ptl 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 supematant 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.

Radio-iodination of GnRH peptide The GnRH analog is labeled by the chloramine-T method. To 10 pg of peptide in 20 pl of 0.5M sodium phosphate buffer, pH 7.6, is added 1 mCi of followed by 22.5 pg chloramine-T and the mixture vortexed for 20 sec. The reaction is stopped by the addition of 60 pg sodium metabisulfite and the free iodine is removed by passing the iodinated mixture through a C-8 Sep-Pak cartridge (Millipore Corp., Milford, MA). 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, CA) 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 0 C and can be used for up to 4 weeks.

GnRH receptor membrane binding assay Cells stably, or transiently, transfected with GnRI- receptor expression vectors are harvested, resuspended in 5% sucrose and homogenized using a polytron homogenizer (2x15 sec). Nucleii are removed by centrifugation (3000 x g for 5 min.), and the supernatant centrifuged (20,000 x g for 30 min, 4 to collect the membrane fraction. The final membrane preparation is resuspended in binding buffer Hepes (pH 150 mM NaCI, and 0.1% BSA) and stored at -70 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 50ul of 2 5 1]-labeled GnRH peptide (-100,000 cpm), and 20ul of competitor at varying concentrations. The reaction is terminated after 90 minutes by application of vacuum and washing (2X) 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 nonlinear least squares regression using the Prism software package (GraphPad Software).

Activity of GnRH receptor antagonists are typically calculated from the

IC

50 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: Ki= IC 50

K

1

+L/KD

where L radioligand and KD affinity of radioligand for receptor (Cheng and Prusofl Biochem. Pharmnacol. 22:3099, 1973). GnR- receptor antagonists of this invention have a Ki of 100 jiM or less. In a preferred embodiment of this invention, the GnR-1 receptor antagonists have'a Ki of less than 10 pM, and more preferably less than 1 pM, and even more preferably less than 0.1 pM 100 nM). To this end, representative GnR~i- receptor antagonists of this invention which have a Ki of less than 100 nMwhen 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, 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 1, 10, 14, 21-23, 25, 52, 54-56, 60,61, 64, 12 1, 4, 5, 10, 20-22, 24, 27, 32 13 2,4 1,2 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 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.

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 11-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.

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 GnRI-I 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.

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.

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 GnR-I 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 32 injection solutions which may contain, in addition to the GnRH receptor antagonist, buffers, antioxidants, bacteriostats, and other additives commonly employed in such solutions.

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.

33 EXAMPLE I SYNTHESIS OF I -(2,6-DIFLUOROBENZYL)-5-(3-METHOXYPHENYL)-6-METHYL-3-[N- METHYL-N-(2-PYRIDYLETHYL)AMINOETHYLIURACIL 0 0 0

H

0 HCI, EtOHN KOH, MeOH O

H

0 0 0 Br Br 2 HOAc

O:<N

F F p Fb 3 4 0S0 4 NalO 4 NaBI(ROAc),

H

Pd(Ph 3 4 110-B Step IlA 3-Al lyl -6-inethyluraci I To allylurea (25 g, .25 mol) in ethanol (10 mL) was added ethyl acetoacetate (31.86 mL, .25 mol) and 10 drops conc. HCI. 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 I hour. After neutralization, the resulting solid I was collected. Yield 2.7 g NMR (CDCI 3 8: 2.16 (3H, 4.52 (2H, 5.18 (IH, 5.23 (lH, 5.60 (IH, 5.82-5.93 (IH, in), 10.3 (1H, s).

Step I B 3-Allyl-lI-(2,6-difluorobenzyl)-6-methyluracil To 1 (2.6 g, 15.7 mnmol) in DMF (20 mL) was added.

tetrabutyl am mon ium fluoride (25 mmol) and 2,6-difluorobenzyl bromide (4.14 g, mmol). After 2 days stirring at room temperature, column chromatography using ethyl acetate! hexane gave 2.7 g (59% yield) of 2. MS 293 Step I C 3-Acetaldehyde-l1-(2,6-di tluorobenzyl)-6-methyluraci I To a solution of 2 (1.46 g, 5 minol) in THF (20 mL) and H 2 0 (10 mL) was added osmium tetroxide (200 mg) and NaIO 4 (3.2 g, 15 inmol). After 2 hr, another I g of NaIO 4 was added. Ethyl acetate and H 2 0 were added and the layers separated.

Evaporation of the organic layer gave 3 as a crude solid (1.0 g, MS 295 Step I D 3-Acetaidehyde-5-bromo- 1 -(2,6-difluorobenzyl)-6-methyluraciI 3 (294 mg, I rmol) was dissolved in acetic acid and bromine (1.2 eq) 1 5 was added. The reaction mixture was stirred at room temperature for I hr, evaporated and the residue was dissolved in EtOAc, washed with IN KOH solution and concentrated to give 4 as a crude oil (295 mg, MS 373/375 NMR

(CDCI

3 6: 2.5 5 (3H, 4.87 (214, 5.33 (2H, 7.26-7.33 (3H, 2m), 9.59 (1lh, d).

Step 1 E 5-Bromo-l1-(2,6-difluorobenzyl)-6-methyl-3-rN-methyl-N-(2pyridylethyl)aminoethylluracil To 4 (295 mng, 0.8 inmol) in dichloroethane was added 2- (methylaminoethyl)pyridine (200 mng, 1.5 mmol) and NaBH(OAc) 3 (636 mg, 3mmol).

After overnight stirring, the reaction mixture was concentrated, dissolved in EtOAc, washed with H 2 0, and purified by prep TLC to give 190 mg of 5 Step I F I -(2,6-Difluorobenzyl)-5-(3-methoxyphenyl)-6-methvl-3 N-methyl-N- (2-pyridylethyl)aminoethylluraciI ("Cpd. No. V") (150 mg, 0.3 mmol), 3-methoxyphenylboronic acid (92 mg, 0.6 mmol),

K

2 C0 3 (100 mg, 0.72 mmol), and Pd(PPh 3 4 (20 mg) in H 2 0 (5 mL and toluene mL) was heated in a sealed tube at 100 'C for 12 hr. Purification by HPLC gave 40 mg of 6 ("Cpd. No. I1") as the TFA salt (2 1% yield). MS 521 NMR (CDCI 3 8: 2.14 (3H, 3.02 (3H, 3.50 in), 3.63 in), 3.71 (2H, in), 3.81 (3H, 4.37 (2H, in), 5.25 (2H, 6.81-6.83 (2H, in), 6.88-6.95 (3H, in), 7.28-7.34 (2H, in), 7.63 (IH, in), 7.89 (1IH, 8.13 (1 H, 8.62 (1IH, br s).

EXAMPLE 2 REPRESENTATIVE COMPOUNDS Following the procedures as set forth in Example 1 above, the compounds of the following Table 1 were prepared.

Table I Cpd. No. RR 2 MIS (MH)' 1-1 2-PyCH 2

CH

2 H 507 1-2 2-PyCH 2 H 493 1-3 2-PyCH 2 Me 507 1-4 Bz Me 506 PhCH 2

CH

2 Me 520 1-6 2-PyCH 2

CH

2 Pr 549 1-7 PhCHCH 3 Me 520 1-8 PhCHCH 3 Me 520 1-9 Bz (CH 3 2

N(CH

2 2 563 1-10 2-PyCH 2

CH

2 Et 535 1-1 1 2-(6-CI-Py)CH 2

CH

2 Me 416, 555 1-12 2-PyCH 2

CH

2 CyclopropylCH 2 561 1-13 1-Et-3-pyrrolidinyl Et 527 1-14 H 557 1-15 H 541 1-16 (CH 3 2

CHOCH

2

CH

2

CH

2 H 502 1-17 Et 2

NCH

2

CH

2 Me 515 1-18 C-"yH 513 1-19 CH 3

OCH

2

CH

2

CH

2 H 474 1-20 (EtO) 2

CHCH

2

CH

2 H 532 1-21 CH 3

OCH

2

CH

2 Me 474 1-22 MeN 575M 1-23 Me 575 1-24 H 550 1-25 CH 3

OCH

2

CH

2

CH

2 Me 488 1-26 (EtO) 2

CHCH

2

CH

2 Me 546 1-27 Me 564 1-28 -lMe 571 1-29 Me 555 1-30 (CH 3 2

CHOCH

2

CH

2

CFI

2 Me 516 1-31 Me 527 1-32 NKMe 513 1-3 Me 502 1-34 Et 2

NCH

2

CH

2 Me 487 1-35 Me 2

NCH

2

CH

2

CH

2 Me 501 1-36 Et 2

NCH

2

CH

2

CH

2 Me 529 1-37 Me 499 1-38 EtOCH 2 Me 474 1-39 Me 516 1-40 Me 550 1-41 H 513 1-42 H 496 1-43 H 529 1-44 Me 2

NCH

2

CH

2

CH

2 H 487 1-45 Et 2

NCH

2

CH

2

CH

2 H 515 1-46 H 510 1-47 H 541 1-48 Me 2

CHCH

2 0CH 2

CH

2

CH

2 H 516 1-49 H 502 1-50 H 471 1-51 H 471 1-52 H 536 1-53 H 516 1-54 PyCH 2

CH

2

HOCH

2

CH

2 551 1-55 Me 527 1-56 Me 510 1-57 r Me 543 1-58 Me 2 CHN(Me)CH 2

CH

2

CH

2 Me 529 1-59 Me 524 1-60 Me 555 1-61 Me 2

CHCH

2 0CH 2

CH

2

CH

2 Me 530 1-62 BuOCH 2

CH

2

CH

2 Me 530 1-63 Me 499 1-64 Me 499 1-65 Me 550 1-66 o'fY Me 530 1-67 PhCH 2

CH

2

CH

2 H 506 1-68 Me 535 EXAMPLES 3 FURTHER REPRESENTATIVE COMPOUNDS By reversing Step I E and Step IF 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 Cpd. No. MR VS (MH)- 2-1 2-PyCH 2

CH

2 Me 519 2-2 Bz Me 504 2-3 2-PyCH 2 H 491 2-4 2-PyCH 2

CH

2 H 505 PhCH 2

C-

2 Me 518 Table 3 Cpd. No. R 1 R2 MS (MH)+ 3-1 2-PyCH 2

CH

2 Me 535 3-2 PhCH 2

CH

2 Me 534 3-3 4-PyCH 2

CH

2 Me 535 3-4 2-PyCH 2

CH

2 Et 549 Table 4 R2 0 0 0

F

Cpd. No. RR 2 MS (MH)' 4-1 PhCH 2 Me 474 4-2 .2-PYCF1 2

CH

2 Me 489 4-3 518 4 H F 4-~4 N 520

H

T- iN 491 4-6 NF 547 Table /R 2

R-N

Cpd. No. RR 2 MS (MH)' 5-1 PhCH 2

CH

2 Me 488 5-2 2-PyCH 2

CH

2 Me 503 N H 5-3 545 5-4 N559 Table 6 Cpd. No. R4MS (MH)- 6-1 509

F

6-2 583 6-3 0 549 6-4 481 r 551 o 6-6 N 495 o 6-7 519 6-8 606 yNAo 6-9 497 6-10 525 6-11 CI 559/561 6-12 Cl) 525 6-13 519 6-14 505 6-15 -0 551 6-16 548 6-18 *Jf 504 6-219 543 6-22 53 6-23 581 0 6-25 575 0 -a -CF 3 6-26 N.521 6-27 519 6-28 -531 0 6-29 N.533 6-30 567 6-31 'N519 6-32 SCH 3 537 6-33 Oe521 6-34 OMe 581 ~OMe 6-35 Oe509 6-36 F509 6-37 536

""NO

2 6-38 497 6-39 <'h~Ot535 6-40 519 6-41 'N567 6-42 481 6-43 497 6-44 <IOH507 6-45 j~Nc548 6-46 0 573 6-47 0 584 6-48 0 645

N-S

6-49 <1 ~534 6-50 535 -OMe 6-51 N506 6-52 NN(562 6-53 533 6-54 <~~~N516 6-55 505 Table 7 Cpd. No. NR 1

R

2 MS (MH)' 7-1 486

CNOH

7-2 KN53 7-3 567 7-4 0571 0A N

N

590 7-6 527 N-0 7-7 OH486 7-8 514 CN0- 7-9 530 7-10 484 7-11 513

N'

7-13 N 553 7-14 N 485 7-15 'N 485 7-16 /499 7-17. /499 7-18 -N 051 7-19 HO 472 7-20 546 EXAMPLE 4 SYNTHESIS OF 5-BROMO- I-(2,6-DIFLUOROBENZYL)-6-METHYL-URACIL 0 F F 0 C N1NH 2 Urea, H20 N .N NH 2 SHCI, reflux H HOAc, refux, 40 min.

F F (69%) 0 0 NH HNHN Br O F O N F Br,, HOAc,rt O N F S+ l60 min.

1 (87%) 2 3 4 I: 3 Step A 2,6-Difluorobenzyl urea 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 HCI (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%).

Step B 1-(2,6-Difluorobenzyl)-6-methyl-uracil 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 (1 st crop 7.85 g, 0.031 mol, 28 Step C 5-Bromo-l-(2,6-difluorobenzvl)-6-methyl-uracil 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 FURTHER REPRESENTATIVE COMPOUNDS O Ph O HN Br OH N Br 0 I N o O.II 0F (Oi) DBAD, PPh, 0 Na 2

CO,

Pd(OAc),, PPh, F

F

1 2 0 1 O NI TFA 1^ 1 I I

°^I

Step A-I 3-(1-[2-BOC-(S)-amino-3-phenylpropyl)-5-bromo- 1-(2,6difluorobenzyl)-6-methyl-uracil 2-BOC-(S)-amino-3-phenyl-l-propanol (2.51 g, 10 mmol) and triphenylphosphine (3.14 g, 12 mmol) were added to a solution of 5-bromo-l-(2,6difluorobenzyl)-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%).

Step B-I 3-(1-r2-BOC-(S)-amino-3-phenylpropyl)- -(2,6-difluorobenzvl)-5-(2fluoro-3-methoxyphenyl)-6-methyl-uracil Compound 2 (4.95 g, 8.78 mmol) and sodium carbonate (2.12g, mmol) were suspended in toluene (50 mL) and dimethoxyethane (10 mL). Water mL) was added and N 2 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).

Step C-I 3-(1-[2-(S)-Amino-3-phenylpropvl)-1-(2,6-difluorobenzvl)-5-(2-fluoro- 3-methoxyphenyl)-6-methyl-uracil Compound 3 (1.5 g, 2.5 mmol) in trifluoroacetic acid/dichloromethane 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).

0 0- 0) 0 boc~ 0 N aboc~ 0H O~N- 12

F

001 1 -0

O.-

boc O Cu(OAc), H 0N Fo/ 0XNY TFA 0' F Step A-2 1 ,6-Di tluorobenzyl R)-tert-butoxycarbonvlam ino-2phenyllethyl-6-methyl-5-(4-rtetrahydropyran-2-yloxylphenyl)uracil 1 -(2,6-Difluorobenzyl-3-[(2R)-tertbutylcarbonylamino-2-phenyl]ethyl-6- 1 (2.58 g, 4.7 mmol), tetrakis(triphenylphosphine) palladium (0) (550 mg, 0.47 mmmol), 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 (10/111 1, 90 mL) was heated at 90?C in a 1 0 pressure vessel under N 2 atmosphere overnight. The organic layer was concentrated in vacuc 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.

Step B-2 I -(2,6-Diluorobenzyl-3-f(2R)-tert-butoxycarbonylamino-2phenyl Iethyl -6-methyl-5-(4-hydroxyphenyl )urac i 1 I S 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 H 2 0. 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.

Step C-2 1 Difluorobenz 1-3 f(2 R)-am ino-2-phenyl Iethyl -5 44- [4tol vioxyl phenyl)uraci I Substituted uracil 3 (50 mg, 0.089 mmol), p-tolylboronic acid (18 mg, 0.133 mmol), copper (11) acetate (16 mg, 0.089 mmol) and triethylamine (0.06 mL, 0.445 mmol) in CH 2

CI

2 (0 mL) were stirred for 3 days at room temperature. The reaction mixture was purified by silica gel chromatography using I% MeOH in CH 2

CI

2 to give 30 mg of protected product. This material was dissolved in CH 2

CI

2 (0 mL) with 5 drops of trifluoroacetic acid. Purification by reverse phase HPLC/MS gave 5.0 mg of product 4 m/z (CI) 554 0 0~ O 0 0 0 j N LiOH, H,O, THF, rt HO0 NH" L.N kOyNH~ F 1~0 FNkY F -6 F (2) 0~~ 0 HN N EDC, HOBI, H ,N TEA. DMF, rt I N F ii) TFA,DCM, rt I Step A-3 (S)-3-(1-N-tert-Butoxycarbonylamino- -carboxylic acid ethyl)- 1 difluorobenzvl)-5-(3-methoxyphenyl)-6-methyluracil To a stirred solution of 1 (306 mg, 0.55 mmol) in tetrahydrofuran 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 x 15 mL) and the combined organic layer was washed with water, brine and dried (MgSO 4 The solvent was removed in vacuo to give 2 (283 mg, 94%) as a yellow oil which was not purified further, dH (300 MHz; CDC13) 7.26-7.34 (2 H, m, Ar), 6.73-6.95 (5 H, m, Ar), 5.74 (1 H, brd, J 6, NH), 5.37 (1 H, d, J 16, CHI-Ar), 5.22 (1 H, d, J 16, CI-HAr), 4.62 (1 H, brs, CHN), 4.32-4.49 (2 H, m, CH 2 3.80 (3 H, s, OCH 3 2.17 (3 H, s, CH 3 and 1.42 (9 H, s, 3 x CH 3 m/z (CI) 446 (MH+-Boc, 100%).

Step B-3 (S)-3-(1-Amino- -NH-benzvlcarboxamide ethyl)- -(2,6-difluorobenzyl)- 5-(3-methoxyphenyl)-6-methyluracil trifluoroacetic acid salt To a stirred solution of 2 (20 mg, 0.037 mmol), benzylamine (15 pL, 0.14 mmol), I-(hydroxy)benzotriazole hydrate (9 mg, 0.066 mmol) and triethylamine pL, 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. mL). The organic layer was washed with brine and dried (MgSO 4 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%).

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

Table 8

"R

2

N

Cpd. No. RIR2N(CR 3

.R

3 -Q-R4 MS MsNS Ion 8-1 H j1~~ 491.5 492 8- 509.5 510

SNH

2

F

8-3 510

F

8-4 H 385.4 386 N- H 2 415.4 416 2 N 434 44 0

F

8-7 -H 385.4 386 8-8 HN415.4 416 56 8-9 H 415.4 416 0

F

8-11 515.6 .516 NH," S.Q o

F

8-12 H 391.5 392 NH 2 8-13 495.5 496

NH

2

F.

8-14 495.5 496

NH

2

F

8-15 539.6 540

F

8-16 I477.5 478 8-17 479.5 480 N H, F

F

8-19 505.5 506 N H, 8-20 IIN~ 501.5 502.2 ,,q0

F

8-21 H 2 N j501.5 502.2 S F NH2 0

F

8-22 HOY 465.5 450.

N H 2 S o,

F

8-24 142N 475.5 46.2 4H S

F

8-24 H,N 461.5 462.2

F

8-27 1-,N j 555 461.5 462.2

F

8-26 F2 52..47.5 48.

N H,

F

8-27 487.5 488.

F

58 8-33 0 491.5 492

NH

2 8-34 I i:539.6 540

NH

2 8-35 481.9 482

NH

2

CI

8-36 493.6 494

NH,

8-37 -o 525.6 526

NH

2 8-38 489.5 490.2

F

8-39 O 475.5 476.2 nH* 0

F

8-40 449.4 450

NH

2 %,Sq 0

F

8-41 H0 445.4 446 NH, ao 8-42 467.5 469

NH

2 8-43 449.5 450

NHN

8-44 479.5 480

NH.)

8-45 0 459.4 460.2 NH 2 8-46 0 445.4 446.1 HOA<K>

NH,

8-47 0 534.6 535.2 H NH, 8-48 0 514.5 515.2 N 0 8-49 o0 521.5 522.2 N 0 H NH, 8-50 o 548.6 549.2 8-51 0 520.3 521.2 H

NH

2 8-52 0N O 512.6 513.2 H NHH 0 8-53 0 527.6 528.2 N 0 SN.) 0" 50.00.

H NH2 8-55 0528.6 529.3 8-56 H 371.4 372.1 N H, 8-57 2N 490.6 491.2

NH

2 8-58 478.5 479.1 8-59 I 491.5 492.2

NH,

8-60 515.5 516.2

NH/,

NH

2 8-62 °,553.6 554.2 NH 2 8-63 Y 553.6 554.2 8-65 0 557.6 558.2

NH,

8-66 O F 557.6 558.2

I

NH;'

8-67 569.6 570.2

NH,

8-68 569.6 570.2

NH

2 8-69 574.0 574.2

NH

2 8-70 574 574.2

NH,

8-71 581.7 582.3 8-72 595.7 596.3

NH

2 8-73 607.6 608.2

NH,

8-74 CI 608.5 608.1 NH, CI 8-75 s 488 488.1

NH

2 8-76 0 489.5 490.2

NH

2 8-77 447.5 488.2

NH,

8-78 F 465.5 466.1 N H, 8-79 F 513.5 514.1 NH 2

F

8-80 F 495.5 496.2 NH 2 8-81 F, 509.5 510.1 NH 2 8-82 F 465.5 466.2 NH 2 8-83 F495.5 496.2 NH 2 0

NH,F

8-85 F >kr 509.5 510.2.

N H, 8-86 461.5 462 N H, 8-87 477.5 478 N H, 0 8-88 481.9 482 N H 2 8-89 461.5 462 N H, 8-90 'N515.5 516 8-91 489.6 490

NH

2 8-92 I531.5 532

CF

NH 2 8-93 523.6 524 NH 2 8-94 F 465.5 466

NH

2 8-95 c 1 .CI 481.9 482

NH.

2 8-96 461.5 462

NH,

8-97 'NC C 475.5 476 NH 2 8-98 503.6 504 NH 2 8-99 523.6 524

NH.)'

8-100 H 2 '.jiIir 0 1~ 477.5 478 8-101 0I ,JjyOCF 3 531.5 532 NH 2 8-102 491.5 482 NH 2 8-103 H' 497.5 498 8-104 CI 516.4 516 NH 2 8-105 N475.5 476 NH 2 46. 46

NH

2 8-1067 467.5 468 N H NH2 8-1079 453.5 490

NH,

8-110NN 465.5 474.

N H, 8-1101 465.5 466.1 0 N H, 8-112 513.5 514.2 F 0

NH

2

F

8-113 509.5 510.1 NH 2 8-114 498.6 498 8-115 545.5 546.2 NH 2

F

3 C 0 N H, F 8-117 cj 559.5 560.2 N H, 8-118 FC~ 561.5 562.2 N H, 8-119 F 3 C 579.5 580.2 0 NH, I- 8-120 F c~ 0 0 575.5 576.2 N H, 8-121 CI481.9 482.1

NH,

8-122 cl 0 525.9 526.1 N H, 8-123 cl- 512 51 2.1 NH0 66 8-124 cl,. 529.9 530.1 0

NH

2

F

8-125 483.5 484.1 F NH 2 8-126 513.5 496.2 F0 F NH 2 8-127 531.5 532.1 F 0 F NH, F 8-128 0, 0^ 491.5 492.2

NH

2 8-129 F ,513.5 514.2

NH

2 8-130 F O> 527.5 528.1

F

NH,

8-131 F 531.5 532.2 0 F F

NH,

8-132 F 483.5 484.1

NH,

8-133 F 513.5 514.2 F 0"

NH,

8-134 F r 527.5 528.2

NH,

8-135 F 531.5 532.2 F 0

NH

2

F

8-136 F 483.5 484.1 F

NH

2 8-137 F F 513.5 514.1

NH

2 8-138 F F 0o, 527.5 528.2

NH

2 8-139 VF F ,531.5 532.2 NHI F 8-140 F F 483.5 484.1

NH

2 EXAMPLE 6 SYNTHESIS OF BORONIC ACIDS Steo A 2-Fluoro-3-methoxyphenylboronic acid 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 0 C. The reaction mixture was stirred at -78 0 C for 1.5 hours. 2-Fluoroanisole (6.31 g, 50 mmol) was added and the mixture was stirred for 8 hours at -78 0 C. Trimethyl borate (6.17 mL, mmol) was added and the reaction mixture was allowed to warm slowly to room temperature overnight. The mixture was poured into IN HCI (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 0 HN N r HN Tr OH OH DEAD, PPh I 2 Step A BOC-(S)-1-amino-2-propanol Di-t-butyl dicarbonate (6.76 g, 31 mmol) was added portionwise to a stirred solution of (S)-l-amino-2-propanol and triethylamine (4.4 mL, 31.5 mmol) in

CH

2

C

2 (75 mL) at 0°C. The reaction mixture was stirred for 1 hour at 0°C and for minutes at room temperature. Evaporation gave product I which was used without further purification.

Step B -aminopropyl)-5-bromo- -(2,6-dif uorobenzyl)-6methyl-uracil 5-Bromo-l-(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 0 Br 0O N

F

BocHN

OH

B(OH)

2 Pd(Ph 3P) 4 Ba(OH) 2 N '74 CHO0 NaB H 4

TFA/DCM

0 N

F

4

CH

2 O N aB H(OA C) 3 Step A A solution of N-(t-butyloxycarbonyl)-D-cx-alaninoI (1 .75g, 1 0 mmol) in anhydrous THF (15 mL) was treated with 5-bromo-1-(2,6-ditluorobenzyl)-6methyluracil (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/H 2 0 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 (Cl) m/z 388.0, 390.0 (MH+-Boc).

Step B 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 N 2 for 10 min, tetrakis(triphenylphosphine) palladium (242 mg, 0.21 mmol) was added and the reaction mixture was heated at 80 0 C overnight under the protection of N 2 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).

Step C 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 NaHCO 3 /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 Step D 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. NaBH 4 (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 NaHCO 3 /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 Step E 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 EXAMPLE 9 SYNTHESIS OF REPRESENTATIVE COMPOUNDS o Br 01N

F

7 Borane BocHN OH THF

H

OH OH BocHN

O

N Br 2 F O 1B(OII), Pd(Ph 3

P)

4 Ba(OH) 2 BocHN 0 N 0 F F

F

TFA

Step A A solution of N 0 -(t-butyloxycarbonyl)-L-a-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 NaHCO 3 /water and brine, and then was dried (sodium sulfate) and evaporated to give compound 1 (1.

2 6g, MS (CI) m/z 144.20 (MH+-Boc).

Step B 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 (1.03g, 3.93 mmol) at ambient temperature, then di-tertbutylazodicarboxylate (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 NaHC03/H 2 0 and EtOAc. The organic layer was dried (sodium sulfate), evaporated, and purified by flash chromatography (silica, EtOAc/hexanes) to give compound 2 (1.39 g, MS (Cl) m/z 456.10, 458.10 (MH+-Boc).

Step C 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 N 2 for 10 min, tetrakis(triphenylphosine) palladium (208 mg, 0.18 mmol) was added and the reaction mixture was heated at 80 0 C overnight under the protection of N 2 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).

Step D 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 NaHCO 3 /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 0 By the above procedure, the compounds of the following Table 9 were also prepared.

Table 9 R\ /R2

N

'O R

(R

3 aR 3 bC)n 14 N

Q

O N O-N SR 5 R6 Cpd. Rs R6 NRiR 2

-Q-R

4

MW

No.

(CR

3 aCR3b)n- (calc.) (obs.) 9-1 Me OH 485.5 486 9-2 Me oF 1 589.6 590 9-3 Me F 526.6 527 H N

M

0 74 9-4 Me -Q i M 9-4 Me 485.5 486 Me F 513.5 514

NN

9-6 Me F 529.5 530 N HO' 9-7 Me F -N 512.5 513

N'I

9-8 Me F 518.6 519 N"Il 9-9 Me IOMC 532.6 533

F

9-10 Me FoM. 427 428 9-11 Me oF 505.6 506 N 9-12 Me F ZOM. 519.6 520 9-13 Me oM, 520.6 521 9-14 Me on 534.6 535 9-15 Me Fo 532.6 533

F

9-16 Me oN 560.6 561 9-17 Me 534.6 535 9-18 Me N534.6 535 NN N

FN

9-18 Me F534.6 53

N

N

WO 01/55119 PCTUS01IO2740 9-35 Me F 666.7 667 9-36 Me 561.6 562 9-37 Me 0 F OY°Y 574.6 575 9-38 Me F 559.6 560 9-39 Me -F 643.7 644 9-40 Me 7°O 643.1 643 9-41 Me 561.7 562 9-42 Me F F .C 6o 628.6 629

F

9- 4 3 Me o o 6 6 67 667 9-44 Me 469.5 373 9-45 Me 505.5 373 9-46 Me 493.5 373 9-47 Me F 459.5 373

F

9-48 Me CF, 615.5 616 9-49 Me N i 516.6 517 N N F F 9-50 Me O 443.5 373 77 9-51 Me F 592.6 593

F

9-52 Me F 487.5 373

NN

FF

9-54 Me F AN 0 9-55 Me 569.6 372 9-56 Me ,F -569.0 569

NN

9-57 Me 487.6 373

FF

9-58 Me F 592.6 593 Ij Qr F F 9-59 Me F 495.5 399 9-60 Me F 0 531.6 532

FN

9-61 Me o. o 519.5 399 N 0

F

9-62 Me r) 485.5 399 9-63 Me F CF, o) 641.5 642

N

FcF, N 9-64 Me F 542.6 543 9-65 Me F riN> 469.5 470 -0

F

9-66 Me F 618.6 619 N0 78 9-67 Me 0>513.5 514 N0 9-68 Me HN0526.5 527 9-69 Me F511.6 512 9-70 Me F595.0 595 N l-a

F

9-71 Me F513.6 399 9-72 Me 0618.6 619 F V1 9-73 Me 493.6 397 9-74 Me F529.6 397 9-75 Me F 517.6 397 9-76 Me F483.6 397 9-77 Me F,639.6 640 F F,C N 9-78 Me F 540.7 541 9-79 Me F467.6 468 9-80 Me F N616.7 617 9-81 Me F 511.6 5 12 9-82 Me IN0.524.6 525 79 9-83 Me F 509.6 510 9-84 Me F 593.7 594

F

9-87 Me F FC N 578.6 579 9-86 Me 6 511.7 512 9-89 Me ,509.5 413 9-9087 Me F 57845.6 41579 9-91 Me F 533.6 413 9-92 Me 545.6 50413 F IIN 9-91 Me F 0 53356.6 55413 9-94 Me 483.5 484 9-95 Me F 632.7 633 9-96 Me F 527.6 528 9-97 Me Z.i) 540.6 541 9-98 Me 525.6 526 F N, 9-99 Me F 527.6 528 N 0 9-100 Me F .zi: 632.7 633 N0 9-101 Me F F,C 0 554.5 555 N0

F

9-102 Me F Y 455.45 456

FN

9-103 Me 581.66 9-104 Me 0 545.58 546 9-105 Me F 588.65 9-106 Me F 568.66 9-107 Me o, 572.62 N N OMe

F

9-108 Me F 0 543.65 544.3 9-109 Me 506.55 507.2 9-110 Me F 520.57 521.2 9-111 Me F I> 552.61 553.3 6 N O&

N

9-112 Me F 554.63 555.3 I U

O,

9-113 Me F, 0 0 570.63 571.3 N NX

OMC

81 9-114 Me HNh 581.66 582.2

F

9-115 Me o e 525.98 526.2 9-116 Me CKo 540.00 540.2 9-117 Me F

HNI

9-117 Me N e 525.98 526.2 9-118 Me Nj 543.97 544.2 9-119 Me F e 560.42 561.1 N NN 9-120 Me F c o 540.00 540.2 9-121 Me Fcl H 574.45 574.0 N CI 9-122 Me )oMV 563.64 564.2 9-123 Me Ff d 497.58 498.2 9-124 Me F it 483.55 484.2 9-125 Me HF 469.52 470 9-126 Me oF 519.58 520.2 9-127 Me F 520.57 521.2 N

NI

9-128 Me F o 583.63 584.2 9-129 Me o 535.58 536.2 9-129 Me F i 535.58 536.2 N N 9-130 Me oF 583.63 584.2

NN\.

1

N

9-131 Me F o0) 501.57 502.2

NN

9-132 Me F 529.62 528 9-133 Me F- oe 556.60 557

NI

9-134 Me or/ 578.61 578

F

9-135 Me oF 540.60 541 rN 9-136 Me O 559.65 560.4 9-137 Me F 547.64 548.5 N N F H\N- 9-138 Me F FCo 545.50 546.4 N a 9-139 Me r 585.62 586.4 9-140 Me H <r 657.75 658.4 9-141 Me F 561.66 562.6 Fb 9-142 Me F 598.60 599.3 N 0 9-143 Me F 0 598.60 599.3

NN

9-144 Me No H 549.57 550.4 9-145 Me F (C 639.59 640.4

NIN

9-146 Me 608.68 609.4 9-147 Me 607.65 608.2 9-148 Me F 549.61 550.4 9-149 Me F 485.54 486.4 9-150 Me F 473.53 474 9-151 Me F 471.39 472.2 9-152 Me F,511.51 512.4 9-153 Me 583.65 584.2 9-154 Me F 488.2 9-155 Me F 524.49 525.4 9-156 Me F o524.49 525.4 9-157 Me F y~527.62 528.4 Fb 9-158 Me F F 475.46 476.3 9-159 Me F 565.48 566.4

N

9-160 Me O-N..534.57 535.4 9-161 Me. 533.55 534.5 84 9-162 Me F 475.50 476.3 9-163 Me 499.55 500.4

N'N

9-164 Me 497.41 498.3

NN

9-165 Me F Io> 537.53 538.4

F

9-166 Me F 0 609.67 610.3 N0 9-167 Me 513.58 514.6 9-169 Me F 9 550.51 551.2 I 0i A 'c 9-170 Me F 0" 553.64 554.3 9-171 Me F 501.48 502.3 NI 0 9-172 Me 0 591.50 592.4 515 9.

9-173 Me F "2jIfZy> 560.59 561.3 9-174 Me F 559.57 560.4 9-175 Me 01 >501.52 502.3

F-

9-176 Me F Hi. 509.63 510.6 NA^ N' 9-177 Me F. 497.62 498.5 F, 9-178 Me F F,C- A 495.48 496.5 9-179 Me F 535.60 536.6 9-180 M e F -607.74 608.4 9-181 Me .F 512.5 9-182 Me F548.58 549.4 9-183 Me f 0' 551.71 552.4 9-184 Me F 499.55 500.4 S 0 N Fb 9-185 Me F H589.57 590.5 9-186 Me F558.66 559.3 9-187 Me F -557.64 558.3 9-188 Me F >499.59 500.4 Fb 9-191 Me F FC H514 1.

9-190 Me 5 N.1513.58 514.2 Aao 9-193 Me F 623.69 624.4 9-194 Me 564.54 565.4 9-195 Me F .o 564.54 565.4 9-196 Me 567.67 568.5 9-197 Me 515.51 516.3 9-198 Me F F oY 0 605.53 606.4 9-199 Me a 574.6 575.4 9-200 Me 0 1 .7 0 573.6 574.3 9-201 Me F 515.6 516.3 9-202 Me i y 543.56 544.2 9-203 Me F 609.07 609.2 9-204 Me F F, C Yo 593.54 595.2 9-205 Me o 498.62 499.3 9-206 Me 484.59 485.2 9-207 Me 0 595.64 596.4 9-208 Me N 532.58 533.2 ^T r' *Ab~ 87 9-209 Me F 532.58 533.2 N NI 9-210 Me F N 574.62 575 9-211 Me F .J Br 564.42 466/4 ,O-ffN 64 F 0 9-212 Me Br 564.42 464/4 SONTr 66

F

9-213 Me F 575.69 576.3

NH

9-214 Me O 597.65 535.3 9-215 Me N 597.65 598.2 1-)b ,0 H 9-216 Me F 1 Y 627.68 628.3 F 0) 1'^j -o 1 9-217 Me F c- Oo 517.57 518.2

F

9-218 Me F N1. 585.62 586.2 F H

F

9-219 Me F y 617.69 618.2

F

9-221 Me F 576.68 577.3 9-220 Me 53345.62 546.2

F

9-221 MeF 5976.68 5277.3 9-222 Me F 533.61 534.2 9-223 Me Fi\3 YY 491.53 492.2 N-2 e ^r V 519.58 520.2

F^^

9-225 Me F -a622.71 623.3 9-226 Ne F 501.59 502.3

F

9-227 Me F-I460.49 461.2

F

9-228 Me F I523.55 524.2

AF

9-230 Me

F

9-23 Me 443.46 444.2

N%

9-231 Me F 511.51 512.2 4' F 9-232 Me F 543.58 544.2 NF F 9-233 Me F 429.44 430.1 9-234 Me F 471.52 472.2

F

9-235 Me F .i 502.57 503.3 9-236 Me F'459.50 460.2 9-23 Me -417.42 418.1 9-23 Me ~445.48 446.1 F F 9-239 Me i F 548.60 549.2 F F 9-240 Me F N3 500.56 501.2 F F 9-24 1 Me F Kr 0 527.60 528.3 H 0>

F

9-242 Me F 486.51 487.27 4

H

9-243 Me F 549.57 550.2 00 9-4 M e F 1 A~NN L 0 579.59 580.2 9-4F 469.48 470.2 9-246 M e F 3.5 3.

9-4 53 47.53 538.2 F F 9-247 Me F 569.60 570.2

F

F

9-248 Me >47.53 498.2 N 0 9-249 Me F 0 2.5 2.

F 485.52 486.2 9-250 Me N0N ill> 565 2.

F

9-252 Me F N Jc 0 474.50 472.2 9-257 Me r547.64 548.3 'o H 9-258 Me 577.66 578.3 9-259 Me 467.55 468.2 9-260 Me -I535.60 536.2 9-261 Me -567.67 568.3 9-262 Me 495.61 496.2 9-263 Me F-526.66 527.3 9-264 Me 483.59 484.2 9-265 Me F441.51 442.2 F 9-266 Me F-469.57 470.3 9-267 Me 572.69 573.3 9-268 Me 524.65 525.3 9-269 Me F c J541.63 542.3 9-270 M e F N500.54 501.2

F

9-271 M e F -rY' 563.59 564.2 N 0 H 9-272 Me F c 0593.62 594.2 N a 9-273 Me0>NN O 483.51 484.2 9-27 Me55156 52.

F

F

9-275 Me IF583.63 584.2 9-276 Me F 511.56 512.2 9-277 Me F %y 542.62 543.3

F

922 MIF 5604256 9-28 Me 499.556540.

9-279 Me N J579.47 58.2 9-280 Me F '45.6052148.2

NN

9-286 Me F588.56 589.3

NNI

9-282 e565 560.

9-283 Me .I~aOiNIM, 539.66 540 92 9-289 Me o 519.56 534 l OM¢

F

9-290 Me 523.55 524.2

F

9-291 Me 615.65 616.3 9-292 Me F 507.55 508.2 F F 9-293 Me 522.56 523.6 9-294 Me .F 508.54 509.5

F

9-295 Me o i 'N 537.57 538.7 9-296 Me r' 552.59 553.2 N ONIC 9-297 Me F 538.56 539.5 CN ONIC 9-298 Me o 469.58 470.3 9-299 Me 484.59 485.3 9-300 Me N 470.57 471.3 9-301 Me .546.65 547 9-302 Me F 513.53 514 9-303 Me F 495.56 496 9-304 Me F 523.55 524 i) j. 9-305 Me o. 537.57 538 9-306 Me o 572.62 573 N OMe

F

9-307 Me o-N 537.57 538.3 9-308 Me Br 505.36 505/5 F CY-1,07

F~V

9-309 Me 522.56 523 F

F

9-310 Me Fo 505.56 506 9-311 Me F e 469.52 470 9-312 Me F. 505.56 506 F N HNJ, 9-313 Me on. 469.52 470 9-314 Me /7J IOhic 9-314 Me oi 519.58 520

F

9-315 Me F 483.55 484 9-316 Meo 519.58 520 9-317 Me oF 483.55 484

F

9-318 Me F. 534.60 535.3

F

9-319 Me o-4 534.60 535.3 9-320 Me F511.56 512.5 N0 94 9-321 Me N- i 578.63 598 Ohic

F

9-322 Me ca I o 427.44 428.1 9-323 Me J",3 oo 517.57 518.2 9-324 Me 518.56 519.2 F 0 9-325 Me F 0 .r.r0 648.70 649.5 9-326 Me F 561.66 562.5 9-327 Me F o 602.07 447.3 F^ 'NC 9-328 Me F o. 491.53 447.4 F 0 9-329 Me F r 503.54 447.3 9-330 Me F 519.58 447.2

F

9-331 Me F F0C *N0'N' 676.68 677.5 0'NN 9-332 Me F 604.65 605.3 9-333 Me F )VY 0 I 595.68 596.4 F Y A 1 1 9-334 Me F N 0 632.70 633.4

F

9-335 Me F j, T 698.81 699.5

'NN

F 9-336i Me 9-336 Me F N 574.62 575.4 0 Fb' 9-337 Me 636.73 637.5 9-338 Me 574.59 575.4 F F 9-339 Me F 558.60559.3

F

9-340 Me F 487.56 488.3 N

F

9-341 Me F 527.97 373.3 F F 9-342 Me F1 417.42 373.1 F F 9-343 Me 429.44 373.3 Fb F 9-4-eF1 445.48 373.2 N

F

9-345 Me F- 602.57 603.5 F,C

F

9-346 Me F 530.54 531.3 N F 9-347 Me F 521.58 373.1 b F_ 9-348 Me F N 558.60 559.3 F F 9-349 Me F 624.70 625.3 9-350 Me F 442.43 373.3 F F 9-351 Me F yN 500.51 501.4

F

9-352 Me F 562.63 563.4 4 F 9-353 Me F -o 600.61 601.3 9-354 Me I 584.62 585.2

F

9-35 Me 616.06 201.3 F0 9-356 Me 0 ,[,.513.58 399.2 N1

IN

FN

9-358 Me F 1 :211:0°\443.44 399.3 N0

F

9-359 Me F .j 455.45 399.2 9-360 Me F J2 471.50 399.3

N>

9-361 Me F 628.59 629.6 9-362 Me F ,1 556.56 557.3 Fb 9-363 Me F .1 N. 547.59 548.5 9-364 Me F N 584.62 585.2 NC 0 Fb 9-365 Me F )Y 650.72 651.2 N0 9-366 Me F 468.45 399.1 9-367 Me F N 526.53 527.3 9-.368 Me F 9-368 e 588.65 589.5 4 ."Cc 97 9-369 Me F Oy. 598.68 599.4 9-370 Me F H- 582.69 583.4

F

9-380 Me L: r "N879 4.

9-371 Me o 511.65 512.5 NXJ I4N^N. N*J 9-372 Me J\ 552.06 397 IINN N m 9-373 Me J 441.51 397.1 9-374 Me F iK- 453.53 397 9-375 Me F 469.57 397.1 F NN 9-376 Me F- 0 626.66 627.6 F I^ 1 r'c 9-377 Me F "o,1 554.63 555.5 9-378 Me F y 545.67 546.4 K 9-379 Me 11 F N 582.69 583.3 9-380 Me F 'N 648.79 649.6 9-381 Me F y 524.60 525.5

F

9-382 Me 586.72 587.5 N ~N 9-383 Me F 10 614.64 615.5 9-384 Me F HI 0N)[ 598.64 599.4 98 9-385 Me KY 0 527.60 528.2 9-386 Me F c 568.01 568.5

F)

9-387 Me F 457.47 458

F

9-388 Me H 485.52 486.3

F

9-389 Me F 642.62 643.7 F,c

F

9-390 Me o 570.59 571 N0

F

9-391 Me 561.62 562.5 N0

F

9-392 Me FN &598.64 599.4

F

9-393 Me F 0 664.74 665.5 F N 9-394 Me F 540.56 541.6

F

9-395 Me F 0 602.67 603.6

F

F

9-396 Me442.43 373.3 4 9-397 Me F 520.57 521.3 9-398 Me F Ku520.57 521.2 9-399 e F I503.56 504.2

H

1 Ohic 9-400 Me F 532.58 533.2

NI

99 9-401 Me 506.55 507 9-402 Me FK 506.55 507

NH

9-403 Me F 515.55 416 9-404 Me F 531.6 532 9-405 Me F 549.5 550 9-406 Me-7 550.57 550 9-407 Me Fo 534.60 535 9-408 Me F 534.60 535

F

9-408 Me F \NNyciOC534.6 535 Ni 9-410 Me F- 524.54 525 ONN. OMe

F

9-411 Me F 554.63 555 9-412 Me H 335.35 336 F r, N Br 533.41 533/5

F

9-414 Me F0 459.46 460 9-415 Me F H 454.51 455 9-416 Me F Br 534.60 535.5

F

F

101 9-433 Me F N--v 466.52 467.2

FN

9-434 Me F .f °,516.54 517.2 9-435 Me F 595.68 596.3

FF

9-436 Me F 595.68 596.3 F N 9-437 Me 538.56 539.2

NI

F F 9-438 Me 552.59 553.3 OMe F F 9-439 Me F i 506.55 507.2 Fb 9-440 Me F 506.55 507.2 Fb 9-441 Me F 520.57 521.2 9-442 Me F 520.57 521.2

N*A~

I C. OM F F 9-444 Me F io <,iN 521.56 522.2

NNI

9- 4 4 Me Fj XI0 5 2156 5 2 2.2 Fb 9-445 Me F Ho 521.56 522.2 9-446 Me F 523.55 524.2 N F 9-447 Me F F j- %)I1 523.55 524.2 9-448 Me -523.55 524.2 F N 9-449 Me F CNe 530.57 531.2 9-450 Me F nc> N 530.57 531.2 9-451 Me 530.57 531.2 9-452 Me F.O 533.61 534.3 9-455 Me F 535.58 536.2 9-456 Me 53347.64 548.3 9-457 M one, 548.63 549.3

NNNI

9-458 Me or 549.57 550.2 9-459 Me 0Fo- 535.58 536.2 9-460 Me Foe 547.59 548.3 F N 9-45761 Me \N556.00 556.2 NI ~548.6 549.

9-45862 Me o 54956.0057 556.2 9-45963 Me F o 556.0058 556.2 9-464 Me F <a onI 557.99 558.2

F

9-461 Me F V-NOil 556.00 556.2

NN

ci H.

9-462 Me r O/ 556.00 556.2 9-463 Me F io7-, i 556.00 556.2

FN

9-464 Me F ~557.99 558.2 N I cl

HCOI

9-465 Me F onI 557.99 558.2 9-466 Me F 573.55 574.2 9-467 Me F 544.59 545.2

F

9-468 Me o 558.62 559.2 9-470 Me 538.56 539 F F 9-471 Me F N 495.52 496.2 9-472 Me F i 519.58 520.2 9-474 Me F. 519.58 520.2 9-475 Me o 521.56 535.2 F

H

9-476 Me F 533.61 534.2 9-477 Me F 535.58 536.2 I] o oMC 9-478 Me F 549.61 550.2 9-479 Me F 551.65 552.2 9-480 Me o. 555.62 556.3 I X) 1 y *'a'oNI 104 9-481 Me 552.59 553 N' OMe

F

9-482 Me 537.57 538.2 F- F 9-483 Me o F 539.55 540.2 F' F 9-484 Me F HO-- vMe 539.55 540.2 9-485 Me F 5 541.54 542.2 9-486 Me F 541.54 542.2

F

9-487 Me i,,o)541.54 542.2 N 0Ml 9-489 Me F NC on, 548.56 549.3 9-490 Me 541.560 5452.3 H OMe 9-491 Me 551.60 552.2 9-492 Me 553.57 554.2 F F 9-49 Me F o 553.57 554.2 9-495 Me F o0' 565.58 566.2 9-496 Me 565.63 566.3 NH F 9-497 Me oF O. 565.63 566.3 9-498 Me F- 566.62 566.2 F 0 9-499 Me F o 567.56 567.3 9-501 Me F 569.64 568.2 9-502 Me 573.61 570.2

NN

OMc

F

9-503 Me F 1OH 573.99 574.2 N -NN OMe CI H F 9-504 Me F H 573.99 574.2 9-505 Me F 573.99 574.2 4 N 9-506 Me o F575.98 574.2 9-507 Me F 575.98 576.2

NN

9-508 Me FoFn. 591.54 592.2 9-509 Me F j,?562.58 563.2 9-510 Me F e 513.51 514.2 F OH 9-511 Me F o 513.51 514.2 9-512 Me OMe 524.54 525.2 Fb 9-505 Me F /A573.99 574.2

F

106 9-513 Me o 547.64 548.3

F

9-514 Me F /F 557.99 558.2 9-515 Me F 525.63 526.3 9-516 Me F 511.60 512.3

F

9-517 Me Fo 523.55 524 9-518 Me FI 521.53 522 9-519 Me F 555.63 556 Om, 9-520 Me H 499.55 400

N(MH-

BOC)

9-521 Me F H 399.43 400 4HNN 9-522 Me H 397.42 398

F

9-523 Me Br F Br478.33 478/4 HN 9-524 Me Br 476.31 476/4 i-)b 78 9-525 Me F 505.56 506.3 H 400~hi 9-526 Me o, ~519.58 520.3 9-521 Me FH40 9-527 Me 505.56 506.2 9-528 Me F 519.58 520.2 9-529 Me I F uo 471.54 472.2 9-530 Me 485.57 486.3 9-531 Me o 499.59 500.3 9-532 Me oF 521.60 522.2 9-534 Me 539.66 540.3 9-535 Me F 583.75 584.4 9-536 Me 523.62 524.3 9-537 Me ,555.70 556.3 9-538 Me H 483.55 484.2 9-539 Me F 483.55 484.2 9-540 Me H 497.58 498.3 9-541 Me F' 485.57 486.3 9-542 Me 499.59 500.3

F

9-543 Me F 510.58 511.2 9-544 Me F H. 513.62 514.3 108 9-545 Me T 525.63 526.3

FH

9-546 Me F i Q 501.54 502.2 9-547 Me F 0 559.58 560.2 9-549 Me O 0 o 519.56 520.2 9-550 Me oF Of 557.99 558.2 N HN OM.

F

9-553 Me F iN 513.51 514.2 9-554 Me oF 543.60 544.2 9-555 Me F om, 543.60 544.2 9-556 Me F 529.58 530.1

S

H N OMe

F

9-557 Me F 1 489.53 49.2 N OMe 9-558 Me F os 557.65 558.2 9-560 Me F o\ i 545.64 546.2 F F 9-561 Me F 521.60 522.2 9-562 Me F ri( f[ 537.57 538.2 I) OMe "N F 9-563 Me F 51758 518.2

FF

9-564 Me 559.66 560.2 OMe

F

9-565 Me 548.56 549.2 9-567 Me o 5 N F H F OMe N F 9-567 Me F 501.54 502.2

F

9-568 Me F -i 515.57 516.2

-F

9-569 Me F H 513.51 514.2 9-570 Me F .H 529.5 530.2 9-576 Me .fN. 529.58 530.2 N'y 1 OMe

F

9-57 1 Me F HO 539.55 540.2 Fb

F

9-572 Me F 557.65 558.3 N F 9-573 Me H 545.64 546.3

IOMC

9-574 Me 1 503.56 504.3 ^6N ^VOMe N F 9-575 Me F 546.65 547.3 9-576 Me F 1 559.66 560.3 OMe N F 9-577 Me 565.63 566.3 9-578 Me N N 548.56 549.2 F F 9-579 Me F 607.71 608.4 9-580 Me F 505.53 506.2

F

9-581 Me .N 524.54 525.2 9-582 Me F o 538.56 539.2 9-583 Me F 523.55 524.2 OMc 9-584 Me o 523.55 524.2 9-588 Me Fo 521.56 522.2 9-589 Me 529.6 530.2

F

SY

N OMe Me 541.56 542.3 F. F 9-5892 Me F i o 513.51 514.2 N NF 9-593 Me 527.54 528.2 9-594 Me H 601.74 602.4

F

F^

1 9-595 Me 541.56 542.2 N F 9-596 Me 543.62 542.2

~NI

9-597 Me 0o.483.55 484.2 N H 9-598 Me 471.54 472.1 o, 9-599 Me 485.57 486.3 9-600 Me 499.59 500.3 H Y a> OMe

NN

F, F 9-601 Me 601.74 602.4 NY} 9-602 Me 527.54 528.2 9-0 e F K' F.

F

N

F

9-604 Me N~~'546.63 547 9-605 Me F C o, 524.99 55.2 9-606 Me F I 501.54 5402.2 I 1^ I N. Os e

F

9-607 Me 557.99 558.2 N q

F

9-608 Me F 541.54 542.2 NN. Ohl I F 112 9-609 Me o 539.55 540.3 9-610 Me 601.74 602.4 9-611 Me F old 573.69 574.3 9 I. 9-612 Me F I 545.64 546.3 F F 9-613 Me F 503.56 504.2 9-614 Me o 541.61 542.3 N 9-615 Me F 475.50 476.2

S

H N OMe 9-616 Me F 489.53 490.3 -b F 9-617 Me F 505.53 506.3 9-619 Me F 539.55 540.2 OMe 0

FF

9-62018 Me N 53926.55 54027.2 9-619 Me 5239.58 540.2 9F 9-620 Me F F 539.55 540.2 -X N\ 113 9-625 Me o o, 513.51 514.2 9-626 Me OMe 9-626 Me F f, 530.56 531.2 F F 9-627 Me F I 530.56 531.2 9-628 Me F, 592.40 594.1 N9-62 M

OM.

9-629 Me F 1 N 519.58 520.2 N, .NH 9-630 Me 521.58 522.2 7 1NH F 9-631 Me 4 507.55 508.3 9-632 Me F 525.54 526.2 9-633 Me 541.99 542.2 N. HNAN/ F 9-634 Me F 0 537.57 538.3 N. HN F 9-635 Me O o 581.58 582.2 HN 9-636 Me F o- 551.60 552.3 N. HN

*F

9-637 Me F OH 523.55 524.2 f

HN

J,

9-638 Me C F 575.55 576.2 FI F 9-639 Me F 521.58 522.2 9-640 Me c 573.55 574.2 Fy UI1**.

9-641 Me F O F, 591.54 592.2 I HNJ,.

F

9-642 Me 0 o" 629.67 630 OMe Nj F e 9-643 Me F o 607.66 608 'N 9 N H N ,I N Ft N

OM.

9-644 Me F f 643.70 644 4. N 9-645 Me F 649.73 650 966 Me N F s F 9-646 Me 647.66 648 FN F" F 9-647 Me i -f 664.12 664

U

N H OM. F O 0yH. F.

9-648 Me f 671.71 672 OMe N6 H o- e

F

9-649 Me r l 543.53 544.2 6 Me- Ho K- N oM.

F^ F 9-650 Me F Q 524.54 525.2 I l)

OM.

F F 9-651 Me F o 505.53 506.2

NNI

F F 9-652 Me r 0 N 513.51 514.2 J g) V F F 9-653 Me F 537.57 538.3

OM.

F

F0 9-654 Me 513.51 514.2 9-655 Me F 1 475.50 476.2 9-656 Me F o 503.56 504.3 NN _C ONIc F F 115 9-657 Me F ,,487.51 488.3 9-658 Me 501.54 502.2

FF

9-659 Me o 524.54 525.2 F F

F

9-660 Me HO o( 543.53 544.2 9-661 Me F 489.53 490.3

NNW

F

9-662 Me F N. 541.56 542.3 9-6 M L. Nl N F F 9-663 Me F 557.99 558.2 N OM

F

9-664 Me F 526.55 527.2 9-665 Me F i° N 541.56 542.3 F

F

9-666 Me F r. 559.53 560.2 F F r

.F

9-667 Me 524.54 525.2 F

F

9-668 Me F f 513.51 514.2

OM

N F 9-669 Me F 517.58 518.2 N N D I 9-670 Me 524.54 525.2 F

F

9-671 Me H A 9-671 Me n. 501.54 502 ONte N

F

9-672 Me o0639.66 540 n .o^O hl, ^j0 F^^ 116 9-673 Me ,F 679.73 680

F

F

9-674 Me F 659.70 660

OON

0- 9-675 Me F 0 A 543.62 544.3 9-676 Me n rNI 543.62 544.3

F

9-679 Me F 529.6 530.2 9-680 Me oF .I .539.5561 540.2.3 b, OMe

F

9-681 Me F 1 52917.5 530.2 OMe F 9-682 Me-o, 537.57 538.2 9-683 Me F A Af 545.64 544.3 F 9-684 Me H 539.5 54038.2 9-688 Me 545.64 544.3 OMe F 5

F

9-686 Me F 609.77 610.3 9-687 Me F 569.64 570.2 F F 9-688 Me 9531.61 532.3 F N

O

117

F

9-689 Me M- 601.74 602.4 9-690 Me c-o 557.99 558.2

F

9-691 Me Fv n 549.59 550.2

F

9-692 Me F- 517.58 518.2 9-693 Me oe 503.56 504.3 9-694 Me oI 503.56 504.3

NNI

F

F

9-695 Me oF o, 503.51 504.3

N

9-696 Me 537.53 538.2 9-697 Me I 551.60 552.3O F

F

9-698 Me F H- 5329.6 530.2

FF

9-699 Me 543.62 544.3

N

9-69700 MeN 529.6 530.2 9-701 MeN 543.62 544.3 F

F

9-702 Me oF/ 523.55 53024.2 F, 9-703 Me Fo 549.54 450 9-699 Me F- 543.62 544.3 9-700 Me F ON 52.65 530.2 F

F

9-703 Me F 549.5 Nl N N F 9-704 Me o 503.56 504.3 9-705 Me F U 608.47 610.1 rH ON F F 9-706 Me F 529.58 530.2 9-707 Me 517.58 518.2 Fl OMe F F 9-710 Me 489.53 490.2 ole

F

9-711 Me 489.53 490.2 F F 9-712 Me F i 503.56 504.2 9-713 Me r y "503.56 504.2 N OhMc Fb F 9-714 Me IF 489.53 490.2 9-715 Me F 489.53 490.2 9-716 Me 523.55 524.2 9-717 Me F Y ,F 517.54 518.2 9-718 Me 523.55 524 IN NH,

F

9-719 Me 517.58 518.3 NH OMe F

F

9-720 Me 535.57 536.3 I I F OMe 9-721 Me F 531.61 532.3 F

F

9-722 Me F- 503.56 504.3 F F 9-723 Me H 517.54 518

F

9-724 Me o(4 543.60 544 9-725 Me F N 530.56 531 ome Fb F 9-726 Me F 553.57 554 (YHI NOMe F) F

FH

9-727 Me o-523.55 524.2

FF

9-728 Me Fn 509.52 510.2 N F

F

9-729 Me 515.57 516.3 9-730 Me F 529.6 530.3 OMe F F 9-731 Me 519.56 520.2 7 N O M e F F 9-732 Me 487.519 488 9-733 Me FY t 503.562 504 9-734 Me o 517.6 518.2 N ,NH OW~

F

9-735 Me F 485.6 486.2 ,,NH N OMe N F

FF

9-736 Me FH 541.6 542

F

9-737 Me N 509.5 510.2 9-738 Me Fo 491.5 492.2 9-739 Me F 543.6 544.3 F F 9-740 Me F N 515.6 516.3 F4 F 9-741 Me F I 513.5 514 F F 9-742 Me F 637.8 638 9-743 Me F- 637.7 638 9-744 Me 625.7 626 9-745 Me o- Y553.6 554 9-746 Me F) 661.6 662 9-747 Me 505.5 506.2 F N11 9-748 Me F 519.5 520.2 t NH 9-749 Me F 517.5 518 9-750 Me F 489.5 490.2 9-751 Me 541.6 542 9-752 Me F 536.5 537 IIAN, 9-753 Me 529.5 530 9-754 Me F 542.6 543 -0 9-755 Me i- 471.5 472.2 4 9-756 Me i 0 485.5 486.2 9-757 Me F 559.6 460.2 NJ~ -Y 52.6 28.

F

9-758 Me. F

H

9-759 Me F% C )NZ 483.6 484.2 F NH M51 5 2 2 9-760 Me 511.6 512.2

NN

Fb 9-761 Me F H oa i 49.6 500.2 F N Me N

F

9-763 Me 3, 497.6 498.2 9-763 Me F 525.6 526.2 9-764 Me ,1i 533.5 534.2

'NH

F

o 9-765 Me F 1 ?II f^ 455.5 456.2 9-766 Me Q -,455.5 456.2

F

9-767 Me 459.5 460.1 9-768 Me F 459.5 459 F O1.k FY J o, 122 9-769 Me )cO .489.5 489 Fm 9-770 Me INI 487.5 488 9-771 e Br 42.3 44

F

9-772 Me FH 363.4 364

F

9-773 Me LNr..*N 587.6 588 9-774 Me 49.-9 EXAMPLE SYNTHESIS OF REPRESENTATIVE COMPOUNDS N o

CISO

2 NCO N Et 2 on F PPh 3 /DEAD/THF/r.t., 2h a F

I^

TFA

SR

6

NH

2 R4 I j R 6 N IH2

TFA

Step A 6-Methvl-5-(2-fluorophenyl)-oxaz-2,4-dione 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 (2x200 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 product). The crude product was crystallized from ether-hexanes to give compound 2 as a yellow solid (3.6 g, 33% yield); 'H NMR (CDCI3): 2.14 3H), 7.16 J 9.0Hz, 1 7.24 2H), 7.41 1 9.20 (brs, I H).

Step B 6-Methyl-5-(2-fluorophenvl)-3 -[2(R)-tert-butoxycarbonylamino-2phenylethylloxaz-2,4-dione 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 mmnol) in dry THIF (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; 'H NMR (CDCI1 3 1.3 9 9H), 2.14 3H), 4.02 (in, I 4.2 8 (mn, IRH), 5.21 (brs, I 5.3 0 (in, I 7.3 8 (mn, 9H); M S (34 1, MH+-BuOCO).

Step C 6-Methyl-5-(2-fluorophenyl)-3-r2(R)-ainino-2-phenylethylloxaz-2,4dione trifluoroacetic acid salt 6-Methyl-5-(2-fl uorophenyl)-3- (2(R)-tert-butoxycarbonylamino-2phenylethyl]oxaz-2,4-dione 3 (30 mg) was treated with tritluoroacetic acid (I ml-) at room temperature for 30 minutes. Concentration in vacuo gave the title compound 4 as a colorless oil in quantitative yield; 'H NMVR (CDCI 3 2.05 2.08 3H), 4.10 (in, 1H), 4.45 (in, IH), 4.62 (in, IH), 7.15 (mn, 3H), 7.40 (mn, 6H), 8.20 (brs, 3H); MS. 341 Step D 6-Methvl-5 42-fl uorophenyl)-3 -r2(R)-tert -butox ycarbony lai no-2phenylethyll- I -(2-methoxybenzyl)uracil A mixture of 6-methyl-5-(2-fluorophenyl)-3-[2(R)-tertbutoxycarbonylamino-2-phenylethyl]oxaz-2,4-dione 3 (29 mg) and 2methoxybenzylainine 15 mL) was heated in a sealed reacti-vial at I100 0 C for 1 hour.

Chromatography on silica gel with 1:2 ethyl acetate-hexanes gave compound 5 as a colorless oil; 'H NMR (CDC13): 1.40 9H), 2.04 3H), 3.87 3H), 4.18 (mn, 11-), 4.44 (in, IH), 5.22 (in, 2H), 5.65 (brs, IH), 5.78 (mn, 1H), 6.85-7.42 (mn, 13H); MS: 460 (MH+-BuOCO).

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.

6-Methyl -5-(2-fl uorophenyl)-3 -[2(R)-tert-butoxycarbonylamino-2phenylethyl-I -(2,6-difluorobenzyl)uracil H NMR (CDC13): 1.39 9H), 2.18 3H), 4. 10 (in, I 4.38 (in, I H), 4.90-5.80 (in, 4H), 6.92 (in, 2H), 7.10-7.42 (in, IOH); MS: 466 (MH+-BuOCO).

6-Methyl-5-(2-fl uorophenyl)-3 -[2(R)-tert-butoxycarbonylamino-2phenylethyl]- i-(2-chlorobenzyl)uraci I IH NMR (CDCI 3 1.40 9H), 2.02 3H), 4.15 (in, 4.50 (mn, I H), 5.35 (in, 3H), 5.62 (in, 1H), 6.95 (in, 13H); MS: 464 (MH+-BuOCO).

6-Methyl-5-(2-tl uorophenyl)-3-[2(R)-tert-butoxycarbonylainino-2phenylethyl]- I -(2-methylbenzyl)uracil 'H NMR (CDCI 3 1 .40 9H), 2.02 3H), 2.37 3H), 4. 15 (mn, I H), 4.42 (in, 5.72(in, 1H), 6.80-7.42 (in,13H); MS: 444 (MH+-BuOCO).

Step E 6-Methvl-5-(2-fluorophenyl)-3-[2(R)-ainino-2-phenvlethyll- 1 methoxybenzyl )uraci I tri luoroacetic acid salt 6-Methyl-5-(2-fl uorophenyl)-3 -[2(R)-tert-butoxycarbonylainino-2phenyl ethyl] -I-(2-inethoxybenzyl)urac i 15 (20 mg) was treated with trifluoroacetic acid (1 inL) at room temperature for 30 minutes. Concentration in vacuo gave the product 6 as a colorless oil in quantitative yield; 'H NMR (CDCI 3 2.04 3H), 3.82 3.85 (s, 4.20 (in, 4.62 (in, 2H), 5.10 (mn, 2H), 6.82-.7.40 (in, 13H), 8.05 (brs, 3H); MS: 460 The following products were also prepared using the same procedure.

6-Methyl -5-(2-fl uorophenyl)-3 -[2(R)-aini no-2-pheny let hyl] 1 chlorobenzyl)uracil trifluoroacetic acid salt 'H NMR (CDCI 3 2.01 3H), 4.20 (in, 11-1), 4.70 (in, 2H), 5.25 (in, 2H), 6.90-7.45 (in, 1 3H), 8.20 (brs, 3H); MS: 464 6-Methyl-5-(2-fluorophenyl)-3 -[2(R)-amino-2-phenylethyl]- 1 methylbenzyl)uraci I tri fluoroacetic acid salt 'H NMR (CDCI 3 ):2.00 3H), 2.27 2.34 3H), 4.15 (in, 4H), 4.62 (mn, 2H), 5.15 (mn, 2H), 6.80-7.40 (mn, 13H); MS: 444 6-Methyl-5-(2-fluorophenyl)-3 -[2(R)-ainino-2-phenylethyl] difluorobenzyl)uracil trifluoroacetic acid salt 'H NMR (CDCI 3 2.14 3H), 4.18 (in, 4.62 (mn, 2H), 5.20 (mn, 2H), 5.62 (brs, 3H), 6.85-7.40 (in, 13H); MS: 466 By the above procedure, the compounds of the following Table 10 were 1 0 also prepared.

Table Cpd. R16 -Q-R 4

MW

No. caic.) (obs.) 10-1 465.5 466 10-2 393.5 394.2 10-3 -1379.4 363 10-4 407.5 323.3 10-5 L-0G 421.5 405.4 10-6 ~435.5 436.2 10-7 )450.6 451.3 10-8 JIi'433.5 417.3 127 10-9 H.

0 423.5 407.2 10-10 +.>435.5 419.2 10-12 436.5 323.3 10-13 466.6 450.3 10-15 444.5 428.4 10-16 430.5 414.4 10-17 430.5 414.4 10-18 31111512.6 513.3 10-19 410.5 323.3 10-20 .<381.4 382.2 10-221 447.5 413.4 10-22 447.5 431.3 10-.24 :ici 498.4 481.4 10-25 jI21459.5 443.3 10-26 443.5 427.2 10-27 463.9 447.1 10-28 ~-~443.5 427.2 10-29 -y397.4 398..2 10-30 395.5 379.2 128 10-31 409.5 393.3 10-32 H..-K396.5 380.3 10-33 IJ410.5 394.1 10-34 397.4 381.2 10-35 "383.4 367.1 10-36 .3443.5 427.2 10-37 379.4 363.3 10-38 409.5 393.3 10-39 H~-'382.4 366.2 10-40 381.4 365.2 10-41 j~i~ 465.5 449.4 10-46 497.5 481.4 10-48 495 451.3 10-44 40~ 9.5 377.3 10-4I5~ 444.5 428.4 10-42 463.9 447.1 129 10-54 7F481.9 465.4 10-55 498.4 481.2 10-56 ~(~413.4 397.1 10-57 498.4 481.2 10-58 LO"408.5 409.2 10-59 425.5 409.2 10-60 444.5 428.4 10-61 422.5 323.4 10-62 487.5 471.3 10-63 473.5 474.2 10-64 498.4 498.1 10-65 447.5 448.2 10-66 459.5 460.2 10-67 1443.5 434.2 10-68 L4O443.5 444.2 10-69 451.6 452.3 10-70 409.5 410.2 10-71 409.5 410.2 10-72 )cIomc 427.5 428.2 EXAMPLE I11 SYNTHESIS OF REPRESENTATIVE COMPOUNDS 0 0 0 0 Br

O

boc' bN A bocN H 0 N &CON THF H 6 F (Ph 2 P),Pd(O) Fic 6F I-0 N

F

1Y 2 3 b I- H 0 ON DMFDMA ~H 0 N N2N,1

FF

4 Step A I -(2,6-difluorobenzyl-3-[(2R)-tertbutylcarbonylamino-2-phenyllethyl-5- (1 -ethoxy i ny D-6-m ethyl uraci I A solution of I -(2,6-difluorobenzyl-3-[(2R)-tert-butylcarbonylamino-2phenyl~ethyl-5-bromo-6-methyluracil 1 (500 mg, 0.91 mmol), tributyl(ethoxyvinyl)tin (0.39 mL) and (Ph 3

P)

4 Pd(0) (105 mg) in dioxane (5 mL) was heated at I 00*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).

Step B I -(2,6-Difluorobenzyl-3-[(2R)-tertbutyloxycarbonvlamino-2phenyllethyl-5-acety1-6-methyluraciI A solution of I -(2,6-difluorobenzyl-3-[(2R)-tertbutylcarbonylamino-2- -ethoxyvinyl)-6-methyluracil 2 (490 mg) in THF (10 mL) was treated with 2.5M aqueous HCI (3 mL) and stirred at r.t. for one hour. The reaction mixture was neutralized with NaH-C0 3 and concentrated in vacuo to remove TI-F. The product was extracted with ethyl acetate. The extract was washed with water and brine, dried over MgSO 4 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); IH NMR:I.37 9H), 2.38 3H), 2.58 3H), 4.12 (dd, J 4.2, 10O.0Hz, 11-1), 4.65 (dd, J 6.5, 10O.0Hz, I 5.20 (in, I 5.40 J 12.0Hz, I H), 5.49 J 12.0Hz, I 5.58 J 6.0Hz, I 6.92 J =8.0Hz, 2H), 7.38 (in, 6H); MS: 414 Boc).

Step C I -(2,6-Difluorobenzyl-3.k(2R)-tertbutoxycarbonylamino-2-phenvflethyl- 5-(3-dimethylamino-I -oxopropenyl)-6-methyluracil I -(2,6-Di fl uorobenzyl -3 -[(2R)-tertbutyl carbonylamni no-2-phenyl ]ethyl -5 acetyl-6-methyluracil 3 (44 mng) was suspended in DMFDMA (1.0 mL) and heated at 0 C for I hour. The product was purified on silica gel with 1:1 ethyl acetate/hexanes to give compound 4 as a yellow oil; I H NMR: 1.39 9H), 2.36 3H), 2.84 6H), 4.05 (mn, I 4.30 (in, I 4.66 J 12.0Hz, I 5.03 (in, I 5.20 J =12Hz, I 5.46 J 12Hz, I 5.84 J 7Hz, I 6.64 J 12.0Hz, I1-H), 6.87 J= 2H), 7.20-7.40 (mn, 6H); MS: 596 Step D I ifluorobenzy 1-3 -[f(2R)-amino-2-pheny 11 ethy 5-(i sox azo-5-Y I)- 6-methyluracil A mixture of I -(2,6-difluorobenzyl-3-[(2R)-tertbutoxycarbonylamino-2phenyl]ethyl-5-(3-dimethylamino- I -oxopropenyl)-6-methyluracil 4 (95 ing), hydroxylamine hydrochloride (150 mg), sodium carbonate (18 mg) in methanol (5 inL) was acidified with acetic acid to pH-4. The mixture was then heated at 120*C for hours, cooled down to filtered, and concentrated in vacuc to give the protected product. MS: 539 The protected product was dissolved in dichloroinethane (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. NH 4 0H in ethyl acetate gave product 5; MS: 439 I H NMR (CD 3 OD): 3.05 3H), 4.70 (in, I 4.55 (in, 2H), 5.48 J 12.0Hz, I 5.60 J 12.0Hz, 114), 7.00 J 8.0Hz, 2H), 7.30- 7.65 (mn, 7H), 8.50 J 6.0Hz, I H).

EXAMPLE 12 SYNTHESIS OF REPRESENTATIVE COMPOUNDS 0 0~ 0 NI, CH BrN' OlEt

NC-

2 r

N.

bocijboN O- H H 2

J~

bc00F N THF, HO H0 F N CHCSNFI.: FN N NBS N FOH, FF F 2 H~~3 0 H 9 NI N NN H I NN 0 2 ON HN N N F

F

4 Step A I -(2,6-Difluorobenzyl-3-f(2R)-tertbutylcarbonylamino-2-phenyllethyl-5bromoacetyl-6-methyluracil A solution of I ifl uorobenzyl -3 R)-tertbutylIcarbony lam ino-2phenylI]ethyl -ethoxyvi nyl)-6-m ethylIuracil 1 (3.68g, 6.8 mmol) in THF (120 rnL) 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 %vacuc and the product which precipitated on standing was collected by filtration and was washed with ether to give white solid 2 (1.6g, 40%);I1H NMR: 1.39 9H), 2.40 3H), 4.04 (dd, J 2.0, 7.0Hz, I1-H), 4.36 (d, J =7.0Hz, IH), 4. 10 J 5.5Hz, I 4.56 J =5.5Hz, IH), 55.50 (in, I 5.24 (d, J 12.0Hz, I1H), 5.40 (brs, I 5.50 J 12.0Hz, I1-H), 6.94 J 8.0Hz, I 7.36 (in, MS: 492 Step B I -(2,6-Difluorobenzyl-3-f(2R)-amino-2-phenyllethyl-5-(5..methylthiazol- 4-yi)-6-methyluracil A solution of I ifl uorobenzyl -3 -[(2R)-tertbuty Icarbony lam ino-2phenyl]ethyl-5-bromoacetyl-6-methyluracil (100 mg, 0. 17 mmrol) and thioacetamide mg, 0.4 mmol) in ethanol (2 mL) was heated at 80 0 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 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.

NH

4 0H in ethyl acetate to give yellow solid 3; 1H NMR: 2.12 3H), 2.71 3H), 4.15-4.70 3H), 5.66 2H), 7.00 J 8.0Hz, 2H), 7.30 7H); MS: 469 Step C 1-(2,6-Difluorobenzvl-3-[(2R)-amino-2-phenyl]ethyl-5-(5benzvlaminolthiazol-4-yl)-6-methyluracil A solution of I-(2,6-difluorobenzyl-3-[(2R)-tertbutylcarbonylamino-2phenyl]ethyl-5-bromoacetyl-6-methyluracil 2 (35 mg) and ammonium thioisocyanate mg) in ethanol (1 mL) was heated at 80 0 C in a sealed reaction vessel for 1 hour.

Benzylamine (0.2 mL) was added and the mixture was heated at 80 0 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 aq. NH 4 0H in ethyl acetate to give product 4 as a yellow solid; 'H NMR: 2.25 3H), 4.05 (dd, J 3.0, 7.5Hz, 1H), 4.28 (dd, J 6.5, 7.5Hz, 1H), 4.42 1H), 4.44 2H), 5.32 J 12.0Hz, 1H), 5.36 J 12.0Hz, 1H), 6.54 1H), 6.92 J 8.0Hz, 2H), 7.20-7.50 11 MS: 560 (MH Step D 1-(2,6-Difluorobenzvl-3-[(2R)-amino-2-phenyl]ethyl-5-(imidazolor 1,2alpvrid-2-yl)-6-methyluracil A mixture of 1-(2,6-difluorobenzyl-3-[(2R)-tertbutylcarbonylamino-2phenyl]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; IH NMR: 2.32 3H), 4.04 IH), 4.67 2H), 5.17 J 16.2Hz, I1H), 5.41 J 16.2Hz, I1H), 6.92 J 8. 1Hz, 2H), 7.24-7.40 (in, 7H), 7.73 (in, I 7.80 (in, I1H), 8.03 I 8.30 (brs, 3H), 8.44 J =5.5Hz, I H); MS: 488 Table 12 Cpd. -R4MW No. (caic.) (obs.) 12-1 468.5 469.1 12-2 469.5 470.1 12-3 497.6 498.2 12-4 530.6 531.1 12-5 544.6 545.2 12-6 526.6 527.2 12-7 488.5 489.2 12-8 y. 507.6 508.2 12-9 508.6 509.1 12-10 575.6 576.2 12-11 545.6 546.2 12-12 563.6 564.2 12-13 590.6 591.1 12-14 559.6 560.2 12-15 487.5 488.2 12-16 539.6 540.2 12-17 559.6 560.2 12-18 573.7 574.2 12-19 509.5 510 12-20 598.6 599.2 12-21 565.0 565.2 12-22 565.0 565.1 12-23 583.0 583.1 12-24 548.6 549.2 12-25 N 559.6 560.2 12-26 575.6 576.2 12-27 605.7 606.3 12-28 573.7 574.2 12-29 573.7 574.2 12-30 573.7 574.2 12-31 N 573.7 574.2 12-32 559.6 560.2 EXAMPLE 13 SYNTHESIS OF REPRESENTATIVE COMPOUNDS 0 Br 0

N

HN

F Br bocs

M

NH

boc

TFA

3 4 Step A. 5-Bromo- -(2,6-difluorobenzyl)uracil 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 0 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 0 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 Step B I -(2,6-Difluorobenzyl-3-[(2R)-tertbutylcarbonylamino-2-phenvllethyl-5bromouracil 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-(2,6difluorobenzyl)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 (Cl) m/z 436.0, 438.0 (MH'-Boc).

Step C 1-(2,6-Difluorobenzvl-3-[(2R)-tert-butoxycarbonylamino-2phenyl]ethyl-5-(2,4,6-trimethylphenyl)uracil To compound 2 (134 mg, 0.25 mmol) in toluene/H 2 0/EtOH (6/3.75/0.75 mL) was added 2,4,6-trimethylphenyl boronic acid ester (87 mg, 1.5 eq), K 2

CO

3 (86 mg, 2.5 eq), and saturated Ba(OH) 2 /water (0.1 mL). The reaction mixture was deoxygenated with N 2 for 10 min, tetrakis(triphenylphosphine) palladium (29 mg, 0.1 eq) was added and the reaction mixture was heated at 100 0 C overnight under the protection of N 2 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.

Step D 1-(2,6-Difluorobenzyl-3-[(2R)-amino-2-phenyl]ethyI-5-(2,4,6trimethylphenyl)uracil 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 NaHCO 3 /water and EtOAc. The organic layer was dried (sodium sulfate), evaporated, and purified by prep TLC eluting with 5% MeOH in CH 2

CI

2 to give compound 4, MS (CI) m/z 476.2 (MlHl).

Table 13 Ril N/R 2

N

Cpd. NR 1

R

2 -R4MW No. (CR 3

.CR

3 (caic.) (obs.) 13-1 -I475.5 476.2

N

13-2 Il 481.5 482

HN

13-3 -IckOMe 528.6 529 13-4 -475.5 476.2 e OMe EXAMPLE 14 SYNTHESIS OF REPRESENTATIVE COMPOUNDS 0 0 0 0 0 0 lyH N OEEN

O

HN OEIN NH 0 N F N bock 0F N*OH

'NO

B 6 F b NHF boc 2 0 0 0 0 NN

N'N

F F 3 4 Step A I -(2,6-Difluorobenzyl)-5-carbethoxyuracil 5-Carbethoxy-uracil (5 g, 27.15 mmol) and N,Obis(trimethylsilyl)acetamide (13.4 mL, 2 eq) in dichloroethane(35 mL) were heated at 801C 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 vacuc and the residue was triturated with ether to give compound 1 as a white solid (3.26 g).

Step B 1 2 ,6-Difluorobenzyl-3-[(2R)-tert-butoxycarbonylamino-2phenvilethyl -5-carbethoxyuraci I 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)-5carbethoxyuracil 1 (413 mg, 1.33 mmol) and triphenylphosphine (525 mg, 2 mmol) at ambient temperature, then d iisopropylazodicarboxyl ate (460 mg, 2 mmol) in THF 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.

Step C I -(2,6-Di fl uorobenzyl -3 [(2R)-tertbutylcarbonyl am ino-2-phenyl ]ethyl -5 n-butvlamidouracil A solution of triethylaluminum (1.9 M in toluene, 0.26 mL, 0.5 mmol) was added to n-butylamine 1 mL, 1 mmol) in dichloroethane and the reaction mixture was sealed under nitrogen and stirred for 1/2 hour. l-(2,6-Difluorobenzyl-3-[(2R)tertbutylcarbonylamino-2-phenyl]ethyl-S-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 vacuc and the residue was partitioned between methylene chloride and sodium carbonate s olution. 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 R" /R 2

N

1 0

R

(R

3 ARPb'f I \N Q 01)N IF F6 Cpd. NR 1

R

2

MW

No. (CR 3 aCR 3 b)n- (caIc.) (obs.) 14-1 456.5 457.2 14-2 456.5 457.2

_NH,

14-3 456.5 457.2

NHH

14-4 0413.4 414.1 14-5 523.6 424.2 14-6 423.5 424.2 EXAMPLE SYNTHESIS OF REPRESENTATIVE COMPOUNDS Br Br

~N

N H LiN(SiNMe) NH boc 0 FN THF boc 0FN Mel F F Step A 1 -(2,6-Di fiuorobenzyl-3 -[(2R)-tert-butoxycarbonvlamino-2phenyllethyl-5-bromo-6-ethyluraciI 1 ,6-Di fluorobenzyl-3 -[(2R)-tert-butoxycarbonyl amino-2phenylI]ethyl -5 -bromo-6-methylIurac i 1I (550 mg, I mmol) was dissolved in THF mL) and the solution was cooled to 0 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 minutes at 0 0 C. lodomethane (0.093 mL, 1.5 mmol) was added dropwise and after minutes, water was added and the mixture extracted with ethyl acetate. Concentration in vacuo gave compound 2 as a yellow foam.

Table RIN ,R 2

N

(R 3 aRJbC) 0 N

Q

N

F

Cpd. NR 1

R

2 -Q-R4 MW No. (CR 38

.CR

3 (ca Ic.) (obs.) 15-1 -j509.5 510.2

DNI

NH,

15-2 491.5 492

NH,

15-3 534.6 535 15-4 1 H 428.5 429 15-5 504.6 505 15-6 N546.65

N

15-7EI 548.58 549.2 15-8 NHN503.6 504.3 oble 15-9 -I523.6 524 ~JI, OMe Nil EXAMPLE 16 SYNTHESIS OF REPRESENTATIVE COMPOUNDS 0 0 HN F H, F 0 N N F NH F F F I 2 Step A I-(2,6-Difluorobenzyl)-3-(4-methyl-2R-guanidopentyl)-5-(2-fluoro-3methoxyphenyl)-6-methyluracil A solution of l-(2,6-difluorobenzyl)-3-(4-methyl-2R-aminopentyl)-5-(2fluoro-3-methoxyphenyl)-6-methyluracil 1 (75 mg), (IH)-pyrazole-l-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 MgSO 4 filtered and concentrated in vacuo and the residue was purified on silica gel (Et 3 N/MeOH/CHCI 3 (2:5:93) as elutant) to give white solid 2. MS: 518 (MH 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 (36)

1. A compound having the following structure: R\ R 2 N 0 R4 (R 3 ,abC Q A N R6 or a stercoisomer or pharmaceutically acceptable salt thereof, wherein: Q is a direct bond; A is O, S, or NR 7 r and s are the same or different and independently 0, 1, 2, 3, 4, 5 or 6; nis 2; Z is a direct bond or -NRq-, -SO 2 -OSO2-, -SO 2 0-, -SO2NR9-, -NR 9 SO2-, -COO-, -OCO-, -CONR9-, -NR 9 CO-, -NR 9 CONR9,, -OCONR 9 or -NRqCOO-; R, and R 2 are the same or different and independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocycle, substituted heterocycle, heterocyclealkyl, substituted heterocyclealkyl, -C(Rla)(=NRIb), or -C(NRiaRic)(=NRih); or RI and R 2 taken together with the nitrogen atom to which they are attached form a heterocyclic ring or a substituted heterocyclic ring; 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, -COORi4 or -CONRi 4 Ris; P \OPER\KbNTIx)42XW rCi doc.2()A/2-()7 146 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; or R3a and R3b taken together form =NR 3 c; or R3a and the carbon to which it is attached taken together with RI and the nitrogen to which it is attached form a heterocyclic ring or substituted heterocyclic ring; R 4 is aryl or substituted aryl; R 5 is hydrogen, halogen, lower alkyl, substituted lower alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, alkoxy, alkylthio, alkylamino, cyano or nitro; R 6 is higher alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl; R 7 is hydrogen, -SO 2 Rli, cyano, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl; and Ri 1 Rib, Ric, R3c, R 9 R 1 1 R 1 4 and R 15 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; or Ria and Rib or R 14 and Rl 5 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.

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

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

4. The compound of claim 1 wherein A is NR7. The compound of claim 1 wherein Ri is aryl, substituted aryl, arylalkyl, substituted P \OPER\KLt ,i(iKM2I(XM4 rcs I docx.2(AK 2i7 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 subsituted heterocyclealkyl is substituted heteroarylalkyl.

7. The compound of claim 6 wherein RI is heteroarylalkyl or substituted heteroarylalkyl.

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

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

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

11. The compound of claim 1 wherein R 2 is hydrogen, alkyl or substituted alkyl.

12. The compound of claim 1 wherein R 2 is hydrogen or methyl.

13. The compound of claim 1 wherein R 3 h and R3h are, at each occurrence, hydrogen.

14. The compound of claim 1 wherein R 3 a is hydrogen, alkyl, aryl or arylalkyl.

15. The compound of claim 1 wherein R 3 a is hydrogen, methyl, isobutyl, cyclohexyl, phenyl or benzyl.

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

17. The compound of claim 1 wherein -(R 3 aR 3 bC)n- has the structure -C(R 3 a)(R 3 b)CH 2 P 'OPER\Khi,\:(iU rclI do 2)/lKNld.? S148 ;1

18. The compound of claim 17 wherein R3a is benzyl.

19. The compound of claim 17 wherein R 3 a is alkyl. D 5 20. The compound of claim 19 wherein R 3 a is isobutyl or cyclohexyl.

21. The compound of claim 17 wherein R3b is hydrogen or methyl.

22. The compound of claim I wherein R 4 is substituted aryl.

23. The compound of claim 1 wherein R 4 is substituted phenyl.

24. The compound of claim 23 wherein R 4 is phenyl substituted with halogen, alkoxy, or both halogen and alkoxy. The compound of claim 1 wherein R 5 is lower alkyl or substituted lower alkyl.

26. The compound of claim 1 wherein Rs is hydrogen or methyl.

27. The compound of claim 1 wherein R( is aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl.

28. The compound of claim 1 wherein R 6 is arylalkyl, substituted arylalkyl, heteroarylalkyl or substituted heteroarylalkyl.

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

31. The compound of claim 1 wherein Ri is -CH 2 (heteroaryl) or -CH 2 CI-1 2 (heteroaryl). P \OPER\KhW-bl2)42(XW.,64 rcsl 149

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

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

34. A method for antagonising 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 33. A method for treating a 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 33.

36. The method of claim 35 wherein the sex-hormone related condition is cancer, benign prostatic hypertrophy or myoma of the uterus.

37. The method of claim 36 wherein the cancer is prostatic cancer, uterine cancer, breast cancer or pituitary gonadotroph adenomas.

38. The method of claim 36 wherein the sex-hormone related condition is endometriosis, polycystic ovarian disease, uterine fibroids or precocious puberty.

39. 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 33. 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 33. P \OPF-R\Kl ,il Ka2 i IcIl 150

41. Use of a compound of claim 1 in the manufacture of a medicament for antagonising gonadotropin-releasing hormone, treating a sex-hormone related condition, preventing pregnancy or lupus erythematosis, irritable bowel syndrome, premenstrual syndrome, hirsutism, short stature or sleep disorders.

42. A compound according to claim 1, a pharmaceutical composition of claim 33, a method of any one of claims 34, 35, 39 and 40 or a use according to claim 41, substantially as hereinbefore described and/or exemplified.