ZA200309041B - HIV protease inhibitors, compositions containing the same, their pharmaceutical uses and materials for their synthesis. - Google Patents

Description

02521.000212.PC y -1- :

TITLE

HIV PROTEASE INHIBITORS, COMPOSITIONS CONTAINING

THE SAME, THEIR PHARMACEUTICAL USES AND

MATERIALS FOR THEIR SYNTHESIS

BACKGROUND OF THE INVENTION Field of the Invention

This invention relates to novel compounds useful as HIV protease inhibitors and to the use of such compounds as antiviral agents for treatment of HIV infected individuals.

This invention also relates to methods of preparation of these compounds and to intermediates that are useful in the preparation thereof.

Related Background Art

Acquired Immune Deficiency Syndrome (AIDS) causes a gradual breakdown of the body's immune system as well as progressive deterioration of the central and ) 20 peripheral nervous systems. Since its initial recognition in the early 1980's, AIDS has spread rapidly and has now reached epidemic proportions within a relatively limited segment of the population. Intensive research has led to the discovery of the responsible agent, human T-lymphotropic retrovirus III (HTLV-II), now more commonly referred to as the human immunodeficiency virus or HIV.

HIV is a member of the class of viruses known as retroviruses. The retroviral genome is composed of RNA which is converted to DNA by reverse transcription. This retroviral DNA is then stably integrated into a host cell's chromosome and, employing the oo replicative processes of the host cells, produces new retroviral particles and advances the . 5 infection to other cells. HIV appears to have a particular affinity for the human T-4 lymphocyte cell which plays a vital role in the body's immune system. HIV infection of these white blood cells depletes this white cell population. Eventually, the immune system 1s rendered inoperative and ineffective against various opportunistic diseases such as, among others, pneumocystic carini pneumonia, Kaposi's sarcoma, and cancer of the lymph system.

Although the exact mechanism of the formation and working of the HIV virus is not understood, identification of the virus has led to some progress in controlling the disease. For example, the drug azidothymidine (AZT) has been found effective for inhibiting the reverse transcription of the retroviral genome of the HIV virus, thus giving a measure of control, though not a cure, for patients afflicted with AIDS. The search continues for drugs that can cure or at least provide an improved measure of control of the deadly HIV virus.

Retroviral replication routinely features post-translational processing of polyproteins. This processing is accomplished by virally encoded HIV protease enzyme.

This yields mature polypeptides that will subsequently aid in the formation and function of infectious virus. If this molecular processing is stifled, then the normal production of HIV 1s terminated. Therefore, inhibitors of HIV protease may function as anti-HIV viral agents.

HIV protease is one of the translated products from the HIV structural protein pol gene. This retroviral protease specifically cleaves other structural polypeptides at discrete sites to release these newly activated structural proteins and enzymes, thereby rendering the virion replication-competent. As such, inhibition of the HIV protease by potent compounds may prevent proviral integration of infected T-lymphocytes during the early phase of the HIV-1 life cycle. as well as inhibit viral proteolytic processing during its late \ 30 stage. Additionally, the protease inhibitors may have the advantages of being more readily available. longer lived in virus, and less toxic than currently available drugs, possibly due to their specificity for the retroviral protease.

Related inhibitors of HIV proteases have been described in, e.g., U.S. Patent No. 5.962.640. U.S. Patent No. 5.932.550. Australian Patent No. 705193, Canadian Patent

Application No. 2,179,935, Europan Patent Application No. 0 751 145, and Japanese

Patent Application No.100867489. Other related HIV protease inhibitors have been described in K. Yoshimura, et al., Proct. Natl. Acad. Sci. USA, 96, 8675-8680 (1999) and ’ T. Mimoto, et al., J. Med. Chem., 42, 1789-1802 (1999). ‘ 5 On-going treatment of HIV-infected individuals with compounds that inhibit HIV protease has led to the development of mutant viruses that possess protesases that are resistant to the inhibitory effect of these compounds. Thus, to be effective, new HIV protease inhibitors must be effective not only against wild-type strains of HIV, but must also demonstrate efficacy against the newly emerging mutant strains that are resistant to the commercially available protease inhibitors. Accordingly, there continues to be a need for new inhibitors targeting the HIV protease in both wild type and mutant strains of HIV.

SUMMARY OF THE INVENTION

This invention relates to compounds useful for inhibiting the activity of

HIV-protease of Formula I:

RE R?

NENG

7 rR! A N A 3 fon z

I wherein:

R'is an aliphatic, carbocyclic or heterocyclic group, or a group having the formula: OR", SR", NHR", N(R")R!" or C(O)R", wherein Ris an aliphatic, carbocyclic or heterocyclic group, and R'is H or a C,-Cg aliphatic group or Rand R" together with ’ the atom to which they are attached form a substituted or unsubstituted heterocyclic ring;

Vis C=0, C=S or SO»; ) R? is an aliphatic group, a carbocyclic group, a carbocyclic-aliphatic group, a heterocyclic group, a heterocyclic-aliphatic group or N(R*)R?®, wherein R*is an aliphatic, carbocyclic or heterocyclic group, and R?®isHor a C,-Cg aliphatic group;

Wis N, O, Cor CH;

when Wis N, C or CH, R? is H or a C,-Cg aliphatic group or R? and R? taken together with the atom W to which they are attached form an unsubstituted or substituted carbocyclic or heterocyclic ring; } when W is O, R? is absent; i "\¢ Me Ro A a, TL, TT

Xis gu x | = IN Sor x | crv where Y' and Y" are independently selected from H, halo, or a C,-Cs aliphatic group; nis 0,1 or2;

RY is H or one or more substituents independently selected from C,-Cg alkyl, nitro, amino, cyano, halogen, C,-C¢ haloalkyl, hydroxyl, C,-Cs alkoxy, alkylenedioxy, C;-Cs alkylcarbonyl, C,-Cs alkyloxycarbonyl, C,-Cg alkylcarbonyloxy, carboxyl, carbamoyl, formyl, C;-Cs alkylamino, dialkylamino, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminothiocarbonyl, di-C;-Cs- alkylaminothiocarbonyl, C,-Cs alkylsulfonyl, C;-Cs alkylsulfenyl, C-Cg¢ alkylcarbonylamino, C;-C¢ alkylthiocarbonylamino, C;-Cg alkylsulfonyloxy, C,-C¢ alkylsulfonylamino, mercapto, and C,-C, alkylthio;

R® and R® are each independently H, halo or a C,-C; aliphatic group;

A is CH,, CH(R®) or is absent;

ZisS, 0. SO, SO,, CH, CHF, CF,, CH(OH), CH(O-R?%), CH(N-R? R%),

CH(S-R%), C(=0), or CH(R?), where R? is a C;-Cg aliphatic group or a carbocyclic or heterocyclic group and R” is H or a C,-Cj aliphatic group; : or R* and R” , taken together with A and Z form an unsubstituted or substituted 5 or 6 membered carbocyclic or heterocyclic ring;

Ris Hora C;-Cs aliphatic group;

R” and R’ are independently selected from H, halo, a C,-Cg aliphatic group or a group having the formula C(O)R*, wherein R* is an aliphatic, carbocyclic or heterocyclic . group; or R* and R®, taken together with the atom to which they are bound, form an “ unsubstituted or substituted carbocyclic ring; or R* and R® or R’, together with the atoms to which they are bound, form an unsubstituted or substituted carbocyclic ring;

R® and R’ are independently selected from H, halo or a C,-Cs aliphatic group;

or R® and R’, taken together with the atom to which they are bound, form an unsubstituted or substituted carbocyclic or heterocyclic group; wherein any of said aliphatic groups are saturated, partially unsaturated or fully unsaturated and unsubstituted or substituted by one or more suitable substituents; and , 5 wherein any of said carbocyclic or heterocyclic groups are unsubstituted or substituted by one or more suitable substituents; saturated, partially unsaturated or fully unsaturated; or mono-, bi- or tri-cyclic; provided that R? is not an aliphatic group, a phenyl group or a phenyl-substituted aliphatic group when A is absent; Z is S, SO, SO,, CHF, O or CH,; V is C=0;W is N; R%,

R, R®and R® are H; RY, R’, Rand R” are Hor a C-Cs alkyl groups. “\¢

X is , wherein R” is H; and R’ is a substituted or unsubstituted 5 or 6- membered mono-cyclic carbocyclic or heterocyclic group; or provided that R? is not t-butyl when R' is substituted or unsubstituted phenyloxymethylene, or quinolylmethyenecarbonylaminomethylene; A is absent; Z is S;

VisC=0:WisN;R?* R’, R* R’,R® and R¥ are H; R®and R are H, methyl, ethyl or 1

NN NE propyl; and X is , wherein R" 1s H or methoxy.

The present invention relates to compounds of Formula | below, and prodrugs, pharmaceutically active metabolites, and pharmaceutically acceptable salts and solvates thereof that inhibit the protease encoded by human immunodeficiency virus (HIV) type (HIV-1)ortype 2 (HIV-2), as well as mutant strains thereof. These compounds are useful in the treatment of infection by HIV and the treatment of the acquired immune deficiency syndrome (AIDS). The compounds, their pharmaceutically acceptable salts, and the pharmaceutical compositions of the present invention can be used alone or in combination . with other antivirals, immunomodulators, antibiotics or vaccines. Compounds of the present invention can also be converted to prodrugs, by derivatization, according to : conventional techniques. Methods of treating AIDS, methods of treating HIV infection and methods of inhibiting HIV protease are disclosed.

DETAILED DESCRIPTION OF INVENTION

AND PREFERRED EMBODIMENTS

In the compounds of this invention, the aliphatic groups are optionally substituted by one or more suitable substituents selected from aryl, cycloalkyl, heterocycloalkyl, heteroaryl, nitro, amino, cyano, halogen, hydroxyl, alkoxy, alkylenedioxy, aryloxy, cycloalkoxy, heterocycloalkoxy, heteroaryloxy, alkylcarbonyl, alkyloxycarbonyl, alkylcarbonyloxy, arylcarbonyl, arylcarbonyloxy, aryloxycarbonyl, cycloalkylcarbonyl, cycloalkylcarbonyloxy, cycloalkyoxycarbonyl, heteroarylcarbonyl, heteroarylcarbonyloxy, heteroaryloxycarbonyl, heterocycloalkylcarbonyl, heterocycloalkyicarbonyloxy, heterocycloalkyoxycarbonyl, carboxyl, carbamoyl, formyl, keto (0x0), thioketo, sulfo, alkylamino, cycloalkylamino, arylamino, heterocycloalkylamino, heteroarylamino, dialkylamino, alkylaminocarbonyl, cycloalkylaminocarbonyl, arylaminocarbonyl, heterocycloalkylaminocarbonyl, heteroarylaminocarbonyl, dialkylaminocarbonyl, alkylaminothiocarbonyl, cycloalkylaminothiocarbonyl, arylaminothiocarbonyl, heterocycloalkylaminothiocarbonyl, heteroarylaminothiocarbonyl, dialkylaminothiocarbonyl, alkylsulfonyl, arylsulfonyl, alkylsulfenyl, arylsulfenyl, alkylcarbonylamino, cycloalkylcarbonylamino, arylcarbonylamino, heterocycloalkylcarbonylamino, heteroarylcarbonylamino, alkylthiocarbonylamino, cycloalkylthiocarbonylamino, arylthiocarbonylamino, heterocycloalkylthiocarbonylamino, heteroarylthiocarbonylamino, alkylsulfonyloxy, arylsulfonyloxy, alkylsulfonylamino, arylsulfonylamino, mercapto, alkylthio, haloalkylthio, arylthio, heteroarylthio, wherein any of the alkyl, alkylene, aryl, cycloalkyl, heterocycloalkyl, heteroaryl moieties present in the above substituents may be further substituted. The alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl moieties of any of the above substituents may be optionally substituted by one or more of alkyl (except for alkyl), haloalkyl, aryl, nitro, amino, alkylamino, dialkylamino, halogen, hydroxyl, alkoxy, haloalkoxy, aryloxy, mercapto, alkylthio or arylthio groups.

In the compounds of this invention the substituted carbocyclic or heterocyclic groups may be optionally substituted by one or more of the following: alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, heteroaryl, . 30 nitro, amino. cyano. halogen, hydroxyl, alkoxy, alkenyloxy, alkynyloxy, alkylenedioxy, aryloxy. cycloalkoxy, cycloalkenyloxy, heterocycloalkoxy, heterocycloalkenyloxy, heteroaryloxy, alkylcarbonyl, alkyloxycarbonyl, alkylcarbonyloxy, arylcarbonyl, arylcarbonyloxy, aryloxycarbonyl, cycloalkylcarbonyl, cycloalkylcarbonyloxy, cycloalkyoxycarbonyl, heteroarylcarbonyl, heteroarylcarbonyloxy, heteroaryloxycarbonyl,

heterocycloalkylcarbonyl, heterocycloalkylcarbonyloxy, heterocycloalkyoxycarbonyl, carboxyl, carbamoyl, formyl, keto (oxo), thioketo, sulfo, alkylamino, cycloalkylamino, arylamino, heterocycloalkylamino, heteroarylamino, dialkylamino, alkylaminocarbonyl, cycloalkylaminocarbonyl, arylaminocarbonyl, heterocycloalkylaminocarbonyl, heteroarylaminocarbonyl, dialkylaminocarbonyl, alkylaminothiocarbonyl, cycloalkylaminothiocarbonyl, arylaminothiocarbonyl, heterocycloalkylaminothiocarbonyl, heteroarylaminothiocarbonyl, dialkylaminothiocarbonyl, alkylsulfonyl, arylsulfonyl, alkylsulfenyl, arylsulfenyl, alkylcarbonylamino, cycloalkylcarbonylamino, arylcarbonylamino, heterocycloalkylcarbonylamino, heteroarylcarbonylamino, alkylthiocarbonylamino, cycloalkylthiocarbonylamino, arylthiocarbonylamino, heterocycloalkylthiocarbonylamino, heteroarylthiocarbonylamino, alkylsulfonyloxy, arylsulfonyloxy, alkylsulfonylamino, arylsulfonylamino, mercapto, alkylthio, haloalkylthio, arylthio, heteroarylthio, wherein any of the alkyl, alkylene, aryl, cycloalkyl, heterocycloalkyl, heteroaryl moieties present in the above substituents may be further substituted. Preferred "suitable substituents” include alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, halogen, hydroxyl, alkoxy, alkylenedioxy, aryloxy, cycloalkoxy, heteroaryloxy, alkylthio, haloalkylthio and carboxyl. The alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl moieties of any of the above substituents may be optionally substituted by one or more of: alkyl, haloalkyl, nitro, amino, alkylamino. dialkylamino, halogen, hydroxyl, alkoxy, haloalkoxy, mercapto, alkylthio. /

In accordance with a convention used in the art, a 1s used in structural formulas herein to depict the bond that is the point of attachment of the moiety or substituent to the core or backbone structure.

As used herein, the term "aliphatic" represents a saturated or unsaturated, straight- or branched-chain hydrocarbon, containing 1 to 10 carbon atoms which may be unsubstituted or substituted by one or more of the substituents described below. The term “aliphatic” is intended to encompass alkyl, alkenyl and alkynyl groups. . As used herein, the term "alkyl" represents a straight- or branched-chain saturated or unsaturated hydrocarbon, containing 1 to 10 carbon atoms which may be unsubstituted or substituted by one or more of the substituents described below. Exemplary alkyl substituents include, but are not limited to methyl (Me), ethyl (Et), propyl, isopropyl,

butyl, isobutyl, t-butyl, and the like. The term “lower alkyl” refers to an alkyl group containing from 1 to 6 carbon atoms

The term "alkenyl" represents a straight- or branched-chain hydrocarbon, containing one or more carbon-carbon double bonds and having 2 to 10 carbon atoms . 5 which may be unsubstituted or substituted by one or more of the substituents described below. Exemplary alkenyl substituents include, but are not limited to ethenyl, propenyl, butenyl, allyl, pentenyl and the like.

The term "alkynyl" represents a straight- or branched-chain hydrocarbon, containing one or more carbon-carbon triple bonds and having 2 to 10 carbon atoms which may be unsubstituted or substituted by one or more of the substituents described below.

An alkynyl moiety may also contain one or more carbon-carbon double bonds. Exemplary alkynyl substituents include, but are not limited to ethynyl, butynyl, propynyl (propargyl) 1sopropynyl, pentynyl, hexynyl and the like.

The term “carbocyclic” represents a saturated, partially saturated, or fully unsaturated (aromatic) cyclic hydrocarbon group containing from 3 to 14 carbon atoms which may be unsubstituted or substituted by one or more of the substituents described herein below. The term “carbocyclic” is intended to encompass mono-, bi- and tri-cyclic saturated, partially saturated, or fully unsaturated hydrocarbon groups; for example, cycloalkyl, cycloalkenyl and aryl groups. The term “carbocyclic” is also intended to encompass bi- and tri-cyclic hydrocarbon groups which contain any combination of ring moieties that are saturated, partially saturated, or fully unsaturated (aromatic). Partially saturated carbocycles include, for example, dihydroarenes (e.g., indanyl) or tetra-hydro- arenes (e.g. tetrahydronaphthalene), wherein any one or more points of saturation may occur in any ring moiety of the carbocycle. In addition, it is understood that bonding between any bi- or tri-cyclic carbocyclic group and any other substituent or variable group may be made at any suitable position of the carbocycle. The term “carbocyclic-aliphatic” group is intended to encompass aliphatic groups having a carbocyclic substituent (e.g., phenylmethyl- (benzyl), phenylethyl-, cyclopropylmethyl-, etc.), wherein the carbocyclic moiety and the aliphatic moiety thereof may be independently substituted by one or more . 30 suitable substituents.

"Cycloalkyl” represents a group comprising a non-aromatic monocyclic, bicyclic, or tricyclic hydrocarbon containing from 3 to 14 carbon atoms which may be unsubstituted or substituted by one or more of the substituents described below.

Exemplary cycloalkyls include monocyclic rings having from 3-8 carbon atoms, such as cyclopropyl, cyclobutyl, . 5 cyclopentyl, cyclohexyl, cycloheptyl and the like.

Illustrative examples of cycloalkyl groups include the following: «oC O00 CD and L . "Cycloalkenyl” represents a group comprising a non-aromatic monocyclic,

bicyclic, or tricyclic hydrocarbon containing from 4 to 14 carbon atoms which may be unsubstituted or substituted by one or more of the substituents described below and contains at least one carbon-carbon double bond.

Exemplary monocyclic cycloalkenyls include groups having from 4-8, preferably 5-6, carbon atoms, such as cyclopentenyl, cyclopentadienyi, cyclohexenyl, cycloheptenyl and the like.

Illustrative examples of cycloalkenyl groups include the following:

0 000 Ay by "Aryl" represents a group comprising an aromatic, monovalent monocyclic, bicyclic, or tricyclic radical containing from 6 to 18 carbon ring atoms, which may be unsubstituted or substituted by one or more of the substituents described below.

Illustrative examples of aryl groups include the following: . $ and

The term “carbocyclic” also to encompasses mixed bi- and tri-cyclic cycloalkyl/cycloalkenyl/aryl groups, which may be unsubstituted or substituted by one or more of the substituents described below. Illustrative examples of such mixed bi-and tri- cyclic groups include the following:

It is understood that bonding or substitution of any bi-cyclic or tri-cyclic carbocyclic or heterocyclic group described herein may be at any suitable position on any ring. Illustrative examples of such bonding in mixed bi-and tri-cyclic carbocyclic groups include the following:

SS

NR | ES Xn ( x

N A

/ ~~ . \ A = R' y 3 x a X : SIR Rt x \ 2 ¢ XX \ Vi _I-R . . Na PF 2

SN R'

ZF . vs . . and , wherein R' is any suitable substituent.

The term “heterocyclic” represents a saturated, partially saturated, or fully unsaturated (aromatic) cyclic group containing from 3 to 18 ring atoms, which includes 1 to 5 heteroatoms selected from nitrogen, oxygen and sulfur, and which may be . 5 unsubstituted or substituted by one or more of the substituents described herein below.

The term “heterocyclic” is intended to encompass mono-, bi- and tri-cyclic saturated, partially saturated, or fully unsaturated heteroatom-containing cyclic groups; for example, heterocycloalkyl, heterocycloalkenyl and heteroaryl groups. The term “heterocyclic” is also intended to encompass bi- and tri-cyclic groups which contain any combination of ring moieties that are saturated, partially saturated, or fully unsaturated (aromatic).

Partially saturated heterocycles include, for example, dihydroheteroarenes (e.g., dihydroindole) or tetrahydro-heteroarenes (e.g. tetrahydroquinoline), wherein any one or more points of saturation may occur in any ring moiety of the heterocycle. In addition, it 1s understood that bonding between any bi- or tri-cyclic heterocyclic group and any other substituent or variable group may be made at any suitable position of the heterocycle (i.e., there is no restriction that a substituent or variable group must be bonded to the heteroatom-containing moiety of a bi- or tri-cyclic heterocyclic group). The term “heterocyclic-aliphatic” group is intended to encompass aliphatic groups having a heterocyclic substituent (e.g., pyridylmethyl-, thiazolylmethyl-, tetrahydrofuranylmethyl-, etc.) wherein the heterocyclic moiety and the aliphatic moiety thereof may be independently substituted by one or more suitable substituents. "Heterocycloalkyl" represents a group comprising a saturated monovalent monocyclic, bicyclic, or tricyclic radical, containing 3 to 18 ring atoms, which includes 1 to 5 heteroatoms selected from nitrogen, oxygen and sulfur, and which may be unsubstituted or substituted by one or more of the substituents described below.

Iustrative examples of heterocycloalky! groups include, but are not limited to, azetidinyl, pyrrolidyl, piperidyl, piperazinyl, morpholinyl, tetrahydro-2H-1,4-thiazinyl, tetrahydrofuryl, tetrahydropyranyl, 1,3-dioxolanyl, 1,3-dioxanyl, 1,4-dioxanyl, 1.3-oxathiolanyl, 1,3-oxathianyl, 1,3-dithianyl, azabicylo[3.2.1]octyl, ; 30 azabicylo[3.3.1]nonyl, azabicylo[4.3.0]nonyl, oxabicylo[2.2.1}heptyl, 1,5.9-triazacyclododecyl, and the like. Illustrative examples of heterocycloalkyl groups include the following:

R 0] - oe

LL

I A w 0

Ong J 2 NR NR “SNR (J he, 3

In) NTN $

LCD) OL Co

R . - 5 :

Pe, JS CL)

NR

Ng and i: wherein R is H, alkyl, hydroxyl or represents a compound according to Formula I, and the bond depicted as Mn ”, represents bonding to either face of the bi-cyclic moiety (i.e., endo or exo).

The term “heterocycloalkeny!” is used herein to represent a non-aromatic, monovalent monocyclic, bicyclic, or tricyclic radical, containing 4 to 18 ring atoms, which may include from 1 to 5 heteroatoms selected from nitrogen, oxygen and sulfur, and which may be unsubstituted or substituted by one or more of the substituents described below and which contains at least one carbon-carbon or carbon-heteroatom double bond.

Exemplary monocyclic heterocycloalkenyls include groups having from 4-8, preferably 5-6, ring atoms. Illustrative examples of heterocycloalkenyl groups include, but are not limited to, dihydrofuryl, dihydropyranyl, isoxazolinyl, dihydropyridyl, tetrahydropyridyl, and the like. Illustrative examples of heterocycloalkenyl groups include the following: 00) CL : NON. Pw, N o 000 Q (J Ss 0 | X Ss 0

HN HN % 00 D0

AN oN No. No 0 0) and » , wherein R is H, alkyl, hydroxyl or represents a compound according to

Formula I. "Heteroaryl” represents a group comprising an aromatic monovalent monocyclic, bicyclic, or tricyclic radical, containing 5 to 18 ring atoms, including 1 to 5 heteroatoms selected from nitrogen, oxygen and sulfur, which may be unsubstituted or substituted by one or more of the substituents described below. As used herein, the term "heteroaryl" is also intended to encompass the N-oxide derivative (or N-oxide derivatives, if the heteroaryl group contains more than one nitrogen such that more than one N-oxide : derivative may be formed) of the nitrogen-containing heteroaryl groups described herein. [Hustrative examples of heteroaryl groups include, but are not limited to, thienyl, pyrrolyl, ) imidazolyl, pyrazolyl, furyl, isothiazolyl, furazanyl, isoxazolyl, thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, benzo[b]thienyl, naphtho[2,3-b]thianthreny!, : isobenzofuranyl, chromenyl, xanthenyl, phenoxathienyl, indolizinyl, isoindolyl, indolyl, : indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxyalinyl, quinzolinyl. benzothiazolyl, benzimidazolyl, tetrahydroquinolinyl, cinnolinyl, pteridinyl, carbazolyl. beta-carbolinyl, phenanthridinyl. acridinyl, perimidinyl, phenanthrolinyl, phenazinyl. isothiazolyl, phenothiazinyl. and phenoxazinyl. Illustrative examples of N-

oxide derivatives of heteroaryl groups include, but are not limited to, pyridyl N-oxide, pyrazinyl N-oxide, pyrimidinyl N-oxide, pyridazinyl N-oxide, triazinyl N-oxide, isoquinolyl N-oxide, and quinolyl N-oxide. Further examples of heteroaryl groups include the following moieties: . 5

N

— N / \ N ooo Yon

R ss. NW. To R ss

N

/ \ / \ Cl CJ C] Cl 7 LN

Ve / ) J Pp ~

N N

R (o) . y . Ny : = . Se : Sy : R ,

N

ND SN NP ON | \ \ | »

Ry

N00 NN R s R : N

CD CI b ) ) o W a YN P :

R N N wy OD fn

CI (10) CD

N

AN a R . Ss s

Cl AN A C1 7 RE

ALT LE es

N : N ' N : N ‘ N : N h 0 lo] 0 o 0 ©

SONS SOT nee

EN ZN<g x Pe . gO8 xX NZ 1 i ' . 0 0

NZ | x AY Nd | x XN lo}

SN FN LN FN NT Xr TINT 7 0) and N 7 , : wherein R is H, alkyl, hydroxyl or represents a compound according to Formula I.

The term "heterocyclic” also to encompasses mixed bi-"and tri-cyclic heterocycloalkyl/heterocycloalkenyl/heteroaryl groups. which may be unsubstituted or substituted by one or more of the substituents described below. Illustrative examples of such mixed bi-and tri-cyclic heterocyclic groups include the following:

CTL CLC 9

NR NR N NR

Co R

[0] 0 [eo] .

IA

Tn OD CL

N NR

S . N - N " R . )

Zz | N

GN 9

R : R . R + and NT lustrative examples of such bonding in mixed bi-and tri-cyclic heterocyclic groups include the following:

N SU

AH Vn 2 Xe

CI) Res sg “ . N \ .

R R

~ . \ ~~ SS

TD to OO \ / i. FEN . N :

R

Sag

FNC CD

NA »7 NTT

N and ~Y , wherein R’ is any suitable substituent.

Unless otherwise stated, exemplary “suitable substituents” that may be present on any of the above aliphatic, carbocyclic, heterocyclic, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl or heteroaryl groups, described herein, include alkyl (except for alkyl), aryl, cycloalkyl, heterocycloalkyl, heteroaryl, nitro, amino, cyano, halogen. hydroxyl, alkoxy, alkylenedioxy, aryloxy, cycloalkoxy, heterocycloalkoxy, heteroaryloxy, alkylcarbonyl, alkyloxycarbonyl, alkylcarbonyloxy, arylcarbonyl, arylcarbonyloxy, aryloxycarbonyl, cycloalkylcarbonyl,

cycloalkylcarbonyloxy, cycloalkyoxycarbonyl, heteroarylcarbonyl, heteroarylcarbonyloxy, heteroaryloxycarbonyl, heterocycloalkylcarbonyl, heterocycloalkylcarbonyloxy, heterocycloalkyoxycarbonyl, carboxyl, carbamoyl, formyl, keto (oxo), thioketo, sulfo, alkylamino, cycloalkylamino, arylamino, heterocycloalkylamino, heteroarylamino, dialkylamino, alkylaminocarbonyl, cycloalkylaminocarbonyl, arylaminocarbonyl, heterocycloalkylaminocarbonyl, heteroarylaminocarbonyl, dialkylaminocarbonyl, alkylaminothiocarbonyl, cycloalkylaminothiocarbonyl, arylaminothiocarbonyl, heterocycloalkylaminothiocarbonyl, heteroarylaminothiocarbonyl, dialkylaminothiocarbonyl, alkylsulfonyl, arylsulfonyl, alkylsulfenyl, arylsulfenyl, alkylcarbonylamino, cycloalkylcarbonylamino, arylcarbonylamino, heterocycloalkylcarbonylamino, heteroarylcarbonylamino, alkylthiocarbonylamino, cycloalkylthiocarbonylamino, arylthiocarbonylamino, heterocycloalkylthiocarbonylamino, heteroarylthiocarbonylamino, alkylsulfonyloxy, arylsulfonyloxy, alkylsulfonylamino, arylsulfonylamino, mercapto, alkylthio, arylthio, heteroarylthio, wherein any of the alkyl, alkylene, aryl, cycloalkyl, heterocycloalkyl, heteroaryl moieties present in the above substituents may be further substituted. The alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl moieties of any of the above substituents may be optionally substituted by one or more of alkyl (except for alkyl), haloalkyl, aryl, nitro, amino, alkylamino, dialkylamino, halogen, hydroxyl, alkoxy, haloalkoxy, aryloxy, mercapto, alkylthio or arylthio groups.

If the substituents themselves are not compatible with the synthetic methods of this invention, the substituent may be protected with a suitable protecting group that is stable to the reaction conditions used in these methods. The protecting group may be removed at a suitable point in the reaction sequence of the method to provide a desired intermediate or target compound. Suitable protecting groups and the methods for protecting and de-protecting different substituents using such suitable protecting groups are well known i to those skilled in the art; examples of which may be found in T. Greene and P. Wuts,

Protecting Groups in Chemical Synthesis (3" ed.), John Wiley & Sons, NY (1999), which is incorporated herein by reference in its entirety. In some instances, a substituent may be specifically selected to be reactive under the reaction conditions used in the methods of this invention. Under these circumstances, the reaction conditions convert the selected substituent into another substituent that is either useful in an intermediate compound in the methods of this invention or is a desired substituent in a target compound.

In the compounds of this invention, R? and R?, independently or taken together, may be a suitable nitrogen protecting group. As indicated above, nitrogen protecting groups are well known in the art and any nitrogen protecting group that is useful in the methods of preparing the compounds of this invention or may be useful in the HIV . 5 protease inhibitory compounds of this invention may be used. Exemplary nitrogen protecting groups include alkyl, substituted alkyl, carbamate, urea, amide, imide, enamine, sulfenyl, sulfonyl, nitro, nitroso, oxide, phosphinyl, phosphoryl, silyl, organometallic, borinic acid and boronic acid groups. Examples of each of these groups, methods for protecting nitrogen moieties using these groups and methods for removing these groups from nitrogen moieties are disclosed in T. Greene and P. Wuts, supra. Preferably, when

R? and/or R? are independently suitable nitrogen protecting groups, suitable R? and R* substituents include, but are not limited to, carbamate protecting groups such as alkyloxycarbonyl (e.g., Boc: t-butyloxycarbonyl) and aryloxycarbonyl (e.g., Cbz: benzyloxycarbonyl. or FMOC: fluorene-9-methyloxycarbonyl), alkyloxycarbonyls (e.g., methyloxycarbonyl), alkyl or arylcarbonyl, substituted alkyl, especially arylalkyl (e.g., trityl (triphenylmethyl), benzyl and substituted benzyl), and the like. When R? and R? taken together are a suitable nitrogen protecting group, suitable R?/R* substituents include phthalimido and a stabase (1,2-bis (dialkylsilyl))ethylene).

The terms "halogen" and "halo" represent chloro, fluoro, bromo or iodo substituents. “Heterocycle” is intended to mean a heteroaryl or heterocycloalkyl group. "Acyl" is intended to mean a -C(O)-R radical, where R is a substituted or unsubstituted alkyl, cycloalkyl, aryl, heterocycloalkyl or heteroaryl group. "Acyloxy” is intended to mean an -OC(O)-R radical, where R is a substituted or unsubstituted alkyl, cycloalkyl, aryl, heterocycloalky! or heteroaryl group. “Thioacyl” is intended to mean a -C(S)-R radical, where R is a substituted or unsubstituted aikyl, cycioalkyl, aryl, heterocycloalkyl or heteroaryl group. “Sulfonyl” is intended to mean an -SO»- biradical. “Sulfenyl” is intended to mean an -SO- biradical. “Sulfo” is intended to mean an -SO,H radical. “Hydroxy” is intended to mean the radical -OH. “Amine” or “amino” is intended to mean the radical -NH,. “Alkylamino” is intended to mean the radical -NHR,, where R, is an . 30 alkyl group. “Dialkylamino” is intended to mean the radical -NR,Rs, where R, and Ry, are each independently an alkyl group, and is intended to include heterocycloalkyl groups, wherein R, and Ry, taken together, form a heterocyclic ring that includes the amine nitrogen. “Alkoxy” is intended to mean the radical -OR,, where R, is an alkyl group.

Exemplary alkoxy groups include methoxy, ethoxy, propoxy. and the like. “Lower alkoxy” groups have alkyl moieties having from 1 to 4 carbons. “Alkoxycarbonyl” is intended to mean the radical -C(O)OR,, where R, is an alkyl group. “Alkylsulfonyl” is intended to mean the radical -SO,R,, where R, is an alkyl group. “Alkylenedioxy” is intended to mean the divalent radical -OR,0- which is bonded to adjacent atoms (e.g., ] 5 adjacent atoms on a phenyl or naphthyl ring) , wherein R, is a lower alkyl group. "Alkylaminocarbonyl” is intended to mean the radical -C(O)NHR,, where R, is an alkyl group. “Dialkylaminocarbonyl” is intended to mean the radical -C(O)NR,R,, where R, and Ry, are each independently an alkyl group. "Mercapto” is intended to mean the radical -SH. "Alkylthio" is intended to mean the radical -SR,, where R, is an alkyl group. "Carboxy" is intended to mean the radical -C(O)OH. “Keto” or “oxo” is intended to mean the diradical =O. “Thioketo” is intended to mean the diradical =S. "Carbamoyl" is intended to mean the radical -C(O)NH,. “Cycloalkylalkyl” is intended to mean the radical -alkyl-cycloalkyl, wherein alkyl and cycloalkyl are defined as above, and is represented by the bonding arrangement present in the groups -CHs-cyclohexane or -CHa-cyclohexene. “Arylalkyl” is intended to mean the radical -alkylaryl, wherein alkyl and aryl are defined as above, and is represented by the bonding arrangement present in a benzyl group. “Aminocarbonylalkyl” is intended to mean the radical ~alkylC(O) NH; and is represented by the bonding arrangement present in the group -CH,CH,C(O)NH,. *Alkylaminocarbonylalkyl” is intended to mean the radical -alkylC(O)NHR,, where R, is an alkyl group and is represented by the bonding arrangement present in the group -CH,CH,C(O)NHCH3;. “Alkylcarbonylaminoalky! is intended to mean the radical -alkyINHC(O)-alkyl and is represented by the bonding arrangement present in the group -CH>NHC(O)CHj;. “Dialkylaminocarbonylalkyl” is intended to mean the radical -alkylC(O)NR.R;, where R, and R;, are each independently an alkyl group. "Aryloxy" is intended to mean the radical -OR,, where R. is an aryl group. "Heteroaryloxy" is intended to mean the radical -ORy4, where Ry is a heteroaryl group. "Arylthio" is intended to mean the radical -SR., where R. is an aryl group. "Heteroarylthio” is intended to mean the radical -SRy, where Ry is a heteroaryl group.

One embodiment of this invention comprises the compounds depicted by . 30 Formula I-A:

RY rR?

IBEW

, rR! N N RS oR \ A

R® - I-A wherein:

R' is an aliphatic group, a bi- or tri- cyclic carbocyclic or heterocyclic group or a group having the formula: OR", SR", NHR", N(R")R'" or C(O)R", wherein R'is an aliphatic, carbocyclic or heterocyclic group, and R'" is H or a C;-Cy aliphatic group or R" and R" together with the atom to which they are attached form a substituted or unsubstituted heterocyclic ring;

R? is an aliphatic group, a carbocyclic group, a carbocyclic-aliphatic group, a heterocyclic group, or a heterocyclic-aliphatic group; :

R¥isHora C,-Cs alkyl group; or R? and R? taken together with the nitrogen atom to which they are attached form an unsubstituted or substituted carbocyclic or heterocyclic ring; ey S¢ es

Ly Oh, CL

Xis CL, , | os , | % or | erry” , wherein Y' and Y" are independently selected from H, halo, or a C,-Cs aliphatic group, wherein RY is H or one or more substituents independently selected from alkyl, nitro, amino, cyano, halogen, haloalkyl, hydroxyl, alkoxy, alkylenedioxy, alkylcarbonyl, : alkyloxycarbonyl, alkylcarbonyloxy, carboxyl, carbamoyl, formyl, alkylamino, dialkylamino, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminothiocarbonyl, dialkylaminothiocarbonyl, alkylsulfonyl, alkylsulfenyl, alkylcarbonylamino, alkylthiocarbonylamino, alkylsulfonyloxy, alkylsulfonylamino, mercapto, and alkyithio; nis lor?2;

R® and R® are each independently H, halo or a C,-C, aliphatic group; . Zis S, 0, SO, SO, CH,, CHF, CF,, CH(OH), CH(O-R?), CH(N-R? R%),

CH(S-R9), C(=0). or CH(R?), where R? is a C,-Cg aliphatic group or a carbocyclic or heterocyclic group and R% is Hora C,-Cg aliphatic group;

R’isHoraC,-Cs aliphatic group;

R* and R’ are independently selected from H, halo, a C,-Cs aliphatic group or a group having the formula C(O)R*, wherein R* is an aliphatic, carbocyclic or heterocyclic group;

R® and R’ are independently selected from H, halo or a C;-Cg aliphatic group; } 5 wherein any of said aliphatic groups are unsubstituted or substituted by one or more suitable substituents and saturated, partially unsaturated or fully unsaturated; and wherein any of said carbocyclic or heterocyclic groups are mono-, bi- or tri-cyclic; saturated, partially unsaturated or fully unsaturated; or unsubstituted or substituted by one or more suitable substituents. provided that R? is not an aliphatic group, a phenyl group or a phenyl-substituted aliphatic group, when A is absent; Z is S, SO, SO,, CHF, O,or CHa; V is C=O; W is N; RZ, rR’, R¥and R¥ are Hor a C-C4 alkyl group; RY, Rr’, Rand R’ are Hora C,-Cq alkyl 1 oN group; X is R' is a substituted or unsubstituted 5 or 6-membered mono-cyclic carbocyclic or heterocyclic group;

Another embodiment of this invention comprises the compounds depicted by

Formula I-A, wherein:

R'is a 3-, 4-, or 7-membered mono-cyclic carbocyclic or heterocyclic group.

In another embodiment, the compounds of this invention are depicted by

Formula I-A, wherein:

R'is a 5- or 6-membered monocyclic carbocyclic or heterocyclic group; and

Ris cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, a bi- or tri- cyclic carbocyclic group, a bi- or tri-cyclic carbocyclic-alkyl group, a bi- or tri-cyclic carbocyclic-alkenyl group, a bi- or tri-cyclic carbocyclic-alkynyl group, a heterocyclic group, a heterocyclic-alkyl group, a heterocyclic-alkenyl group or a heterocyclic-alkynyl group; ] Another embodiment of this invention relates to compounds useful for inhibiting the activity of HIV-protease having Formula I-A, wherein: . R' is an aliphatic, carbocyclic or heterocyclic group, or a group having the formula: OR", SRY, NHR', NRMRY or C(O)R', wherein R' is an aliphatic, carbocyclic or heterocyclic group, and R'" is H or a C,-Cs aliphatic group or Rand R" together with the atom to which they are attached form a substituted or unsubstituted heterocyclic ring;

"\¢ Me \e "\¢

L Us Ol, CL

X is LL, AY | 4 AY | <4 or x cv” where Y' and Y" are independently selected from H, halo, or a C,-Cg aliphatic . group, nis 0, 1 or 2 and R" is H or one or more suitable substituents independently selected from C,-Cg alkyl, nitro, amino, cyano, halogen, C,-Cs haloalkyl, hydroxyl, C,-Cs alkoxy, alkylenedioxy, C;-Cs alkylcarbonyl, C;-Cs alkyloxycarbonyl, C,-Cg alkylcarbonyloxy, carboxyl, carbamoyl, formyl, C,-C alkylamino, di-C-Cs alkylamino,

C1-Cs alkylaminocarbonyl, di - C,-C4 alkylaminocarbonyl, C;-Cs alkylaminothiocarbonyl, di-C,-C¢- alkylaminothiocarbonyl, C;-Cs alkylsulfonyl, C;-Cs alkylsulfenyl, C;-Cs alkylcarbonylamino, C,-C; alkylthiocarbonylamino, C,-Cq alkylsulfonyloxy, C,-Cs alkylsulfonylamino, mercapto, C;-Cs alkylthio and halo-C,-Cs alkylthio; and

R® and R® are each independently H, halo or a C,-C; aliphatic group "\¢ a a, provided that R” and R” are not both H when X is .

Another embodiment of this invention relates to compounds depicted by Formula

I-A, wherein:

R'is a bi- or tri-cyclic carbocyclic or heterocyclic group, wherein said carbocyclic or heterocyclic group is saturated, partially unsaturated or fully unsaturated; and unsubstituted or substituted by one or more suitable substitutents.

A specific embodiment of a compound of Formula I-A of this invention, wherein Z is S and R*, R® and R? are each H, may be represented as follows: rR?

EN

BN 7

OR? \ Js oR wherein the formula variables are as defined in Formula I-A, above.

Another embodiment of this invention comprises the compounds depicted by

Formula I-B:

R® R?

R® X 0} 0 0 R?

PN 7 oR A

R® I-B wherein

R'is an aliphatic, carbocyclic or heterocyclic group, or a group having the formula: OR", SR", NHR", N(R")R"" or C(O)R", wherein R'is an aliphatic, carbocyclic or heterocyclic group, and R'is H or a C,-Cg aliphatic group or R" and R"" together with the atom to which they are attached form a substituted or unsubstituted heterocyclic ring;

R%is an aliphatic group, a carbocyclic group, a carbocyclic-aliphatic group, a heterocyclic group, or a heterocyclic-aliphatic group;

R* is H or a C,—C aliphatic group; ey pt pS

LL Uly Dy CL

X is gv x | 5% } x | 5 or x err wherein Y' and Y" are independently selected from H, halo, or a C;-Cs aliphatic group; n is 1 or 2; and R* is H or one or more suitable substituents independently selected from alkyl. nitro, amino, cyano, halogen, haloalkyl, hydroxyl, alkoxy, alkylenedioxy, alkylcarbonyl, alkyloxycarbonyl, alkylcarbonyloxy, carboxyl, carbamoyl, formyl, alkylamino, dialkylamino, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminothiocarbonyl, dialkylaminothiocarbonyl, alkylsulfonyl, alkylsulfenyl, alkylcarbonylamino, alkylthiocarbonylamino, alkylsulfonyloxy, alkylsulfonylamino, mercapto, and alkylthio;

R® and R¥ are each independently H, halo or a C,-C; aliphatic group;

Zis S, 0, SO, SO, CHa, CHF, CF,, CH(OH), CH(O-R?), CH(N-R? R%),

CH(S-R%), C(=0), or CH(R?), where RZ is a C,-Cg aliphatic group or a carbocyclic or : heterocyclic group and R” is H or a C,-Cs aliphatic group;

R’ is H or a C,-Cg aliphatic group;

R* and R’ are independently selected from H, halo, a C;-Cs aliphatic group or a group having the formula C(O)RY, wherein R* is an aliphatic, carbocyclic or heterocyclic group;

R® and R are independently selected from H, halo or a C;-C aliphatic group; where any of said aliphatic groups are saturated, partially unsaturated or fully unsaturated and unsubstituted or substituted by one or more suitable substituents; and where any of said carbocyclic or heterocyclic groups are optionally unsubstituted, . 5 substituted by one or more suitable substituents; saturated, partially unsaturated or fully unsaturated; or mono-, bi- or tri-cyclic.

A specific embodiment of a compound of Formula I-B of this invention, wherein Z is S and R*, R* and R¥ are each H, may be represented as follows:

Rr?

X 0}

Oo 0

A

R! ISB

OR? . pu

RY Ls wherein the formula variables are as defined in Formula I-B, above.

In yet another embodiment, the compounds of this invention useful for inhibiting the activity of HIV-protease have the Formula [-C:

RY R? 0] BE boy

A

R! N N RS

OR A

R® I-C wherein

R' is an aliphatic, carbocyclic or heterocyclic group, or a group having the formula: OR", SR", NHR", NR"R" or C(O)R", wherein R" is an aliphatic, carbocyclic or heterocyclic group, and R" is H or a C,-Cg aliphatic group or Rand R" together with ] the atom to which they are attached form a substituted or unsubstituted heterocyclic ring;

R? is an aliphatic group, a carbocyclic group, a carbocyclic-aliphatic group, a . heterocyclic group, or a heterocyclic-aliphatic group;

WisN,OorC; when Wis N or C, R? is H or a C,-Cq alkyl group or R* and R” taken together with the atom W to which they are attached form an unsubstituted or substituted carbocyclic or heterocyclic ring;

when W is O, R? is absent; "\¢ Me Ae "\¢

LC Ol, CL

X is Jy | oN | = or | erry” ) wherein Y' and Y" are independently selected from H, halo, or a C,-Cs aliphatic group; n is 1 or 2; and R" is H or one or more substituents independently selected from alkyl, nitro, amino, cyano, halogen, haloalkyl, hydroxyl, alkoxy, alkylenedioxy, alkylcarbonyl, alkyloxycarbonyl, alkylcarbonyloxy, carboxyl, carbamoyl, formyl, alkylamino, dialkylamino, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminothiocarbonyl, dialkylaminothiocarbonyl, alkylsulfonyl, alkylsulfenyl, alkylcarbonylamino, alkylthiocarbonylamino, alkylsulfonyloxy, alkylsulfonylamino, mercapto, and alkylthio;

R® and R® are each independently H, halo or a C,-C, aliphatic group;

Z is CF, CH(OH), CH(O-R?%) or CH(R?), where R% is a C,-Cg aliphatic group or a carbocyclic or heterocyclic group;

R'isHora C,-C, aliphatic group;

R* and R® are independently selected from H, halo, a C,-C aliphatic group or a group having the formula C(O)R*, wherein R* is an aliphatic, carbocyclic or heterocyclic group;

R® and R’ are independently selected from H, halo or a C,-Cg aliphatic group; where any of said aliphatic groups are saturated, partially unsaturated or fully unsaturated and unsubstituted or substituted by one or more suitable substituents; and where any of said carbocyclic or heterocyclic groups are unsubstituted or substituted by one or more suitable substituents; saturated, partially unsaturated or fully unsaturated; or mono-, bi- or tri-cyclic.

A specific embodiment of a compound of Formula I-C of this invention, wherein Z is CF, and R® and R® are each H, may be represented as follows: . R? 0 x 0] ° Weg . PY R7

R' A i OR?

R? F

R® OF wherein the formula variables are as defined in Formula I-C, above.

Another embodiment of this invention comprises the compounds depicted by the

Formula I-D, as follows:

R¥ R?

R® X o! / lo o) W—g?

PY RY

R! Bes

OR? A

RY Is

R I-D wherein

R'is an aliphatic, carbocyclic or heterocyclic group, or a group having the formula: OR", SR! NHR', N(RHRY or C(O)R', wherein R'is an aliphatic, carbocyclic or heterocyclic group, and R'" is H or a C,-Cg aliphatic group or Rand R"” together with the atom to which they are attached form a substituted or unsubstituted heterocyclic ring;

R? is an aliphatic group, a carbocyclic group, a carbocyclic-aliphatic group, a heterocyclic group, or a heterocyclic-aliphatic group;

Wis N, OorC; when Wis Nor C,R*isHora C1-Cs alkyl group or R* and R? taken together with the atom W to which they are attached form an unsubstituted or substituted carbocyclic or heterocyclic ring; when Wis O, R? is absent; 0, TT,

Xis h rd , A , LL ,or SS _— , wherein Y' and Y" are independently selected from H, halo, or a C,-Cg aliphatic group; n 1s 1 or 2; and R” is H or one or more suitable substituents independently selected from alkyl. nitro, amino, cyano, halogen, haloalkyl, hydroxyl, alkoxy, alkylenedioxy, . alkylcarbonyl, alkyloxycarbonyl, alkylcarbonyloxy, carboxyl, carbamoyl, formyl, alkylamino, dialkylamino, alkylaminocarbonyl, dialkylaminocarbonyl, ‘ alkylaminothiocarbonyl, dialkylaminothiocarbonyl, alkylsulfonyl, alkylsulfenyl, alkylcarbonylamino, alkylthiocarbonylamino, alkylsulfonyloxy, alkylsulfonylamino, mercapto, and alkylthio;

R® and R® are each independently H, halo or a C;-C, aliphatic group;

Zis S, 0, SO, SO,, CHF, CH,, CF,, CH(OH), CH(O-R%), CH(N-R? R%),

CH(S-R%), C(=0), or CH(R?), where R% is a C,-Cg aliphatic group or a carbocyclic or heterocyclic group and R” is H or a C;-Cg aliphatic group;

R’ is Hora C,-Cg aliphatic group; ] 5 R’? and R® are independently selected from H, halo, a C-Cj aliphatic group or a group having the formula C(O)R*, wherein R* is an aliphatic, carbocyclic or heterocyclic group;

R® and R are independently selected from H, halo or a C,-Cg aliphatic group; where any of said aliphatic groups are saturated, partially unsaturated or fully unsaturated and unsubstituted or substituted by one or more suitable substituents; and where any of said carbocyclic or heterocyclic groups are unsubstituted or substituted by one or more suitable substituents; saturated, partially unsaturated or fully unsaturated; or mono-, bi- or tri-cyclic. :

Another embodiment of this invention comprises the compounds depicted by the

Formula I-E, as follows: . RE R?

A

R’ N A

OR3 es

RE NeHan 1p wherein

R'is an aliphatic, carbocyclic or heterocyclic group, or a group having the formula: OR", SR", NHR, N(RMRY or C(O)R", wherein R" is an aliphatic, carbocyclic or heterocyclic group, and R' is H or a C,-C; aliphatic group or Rand R" together with the atom to which they are attached form a substituted or unsubstituted heterocyclic ring; : R? is an aliphatic group, a carbocyclic group, a carbocyclic-aliphatic group, a heterocyclic group, or a heterocyclic-aliphatic group; ) Wis N,OorC; . 25 when W is N or C, R? is H or a C,-C; alkyl group or R? and R? taken together with the atom W to which they are attached form an unsubstituted or substituted carbocyclic or heterocyclic ring; when W is O, R? is absent:

SS Ne Ro *\

Ll Ol CL

X is LL, : | 0’ , SN | = or | CO wherein Y' and Y" are independently selected from H, halo, or a C,-Cs aliphatic group, . wherein R* is H or one or more suitable substituents independently selected from alkyl, nitro, amino, cyano, halogen, haloalkyl, hydroxyl, alkoxy, alkylenedioxy, alkylcarbonyl, alkyloxycarbonyl, alkylcarbonyloxy, carboxyl, carbamoyl, formyl, alkylamino, dialkylamino, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminothiocarbonyl, dialkylaminothiocarbonyl, alkylsulfonyl, alkylsulfenyl, alkylcarbonylamino, alkylthiocarbonylamino, alkylsulfonyloxy, alkylsulfonylamino, mercapto, alkylthio;

R® and R® are each independently H, halo or a C,-C; aliphatic group;

ZisS, 0, SO, SO,, CHa, CHF, CF,, CH(OH), CH(O-R?), CH(N-R? R?),

CH(S-R?), C(=0), or CH(R?), where R% is a C,-Cs aliphatic group or a carbocyclic or heterocyclic group and R” is H or a C,-Cs aliphatic group; nis! or2;

R’isH ora C,-Cg aliphatic group;

R'is selected from H, halo, a C,-Cs aliphatic group or a group having the formula

C(O)RY, wherein R* is an aliphatic, carbocyclic or heterocyclic group;

R’ is H, halo or a C,-Cs aliphatic group; where any of said aliphatic groups are saturated, partially unsaturated or fully unsaturated and unsubstituted or substituted by one or more suitable substituents; and where any of said carbocyclic or heterocyclic groups are unsubstituted, substituted by one or more suitable substituents; saturated, partially unsaturated or fully unsaturated; or mono-, bi- or tri-cyclic.

A specific embodiment of s compound of Formula I-E, wherein n is 2 and R® and

R? are each H,. may be represented as follows: rR? ) 0] x 0 ° Nr

OR? wherein the formula variables are as defined above.

Another embodiment of this invention comprises the compounds of Formula I, wherein A is CH(R?®), Z is CH(R?) and R” and RZ taken together form a S or 6-membered carbocyclic ring, depicted by the Formula I-F, as follows: . . i” o Et ON Wer?

PN wv

R' N N RE

OR? "IF wherein

R'is an aliphatic, carbocyclic or heterocyclic group, or a group having the formula: OR", SR", NHR", N(R"R" or C(O)R", wherein R" is an aliphatic, carbocyclic or heterocyclic group, and R' is H or a C,-Cg aliphatic group or R" and R'" together with the atom to which they are attached form a substituted or unsubstituted heterocyclic ring;

R? is an aliphatic group, a carbocyclic group, a carbocyclic-aliphatic group, a heterocyclic group, or a heterocyclic-aliphatic group; - WisN,OorC; when Wis N or C, R¥isHoraC 1-Ce alkyl group or R? and R? taken together with the atom W to which they are attached form an unsubstituted or substituted carbocyclic or heterocyclic ring; when W is O, R? is absent; ey Te pS p=

Ly Dh, CL

Xis LL, , o , ~ | <% or ~ | crv i wherein Y' and Y" are independently selected from H, halo, or a C,-Cs aliphatic group, wherein R* is H or one or more substituents independently selected from alkyl, nitro, amino, cyano, halogen, haloalkyl, hydroxyl, alkoxy, alkylenedioxy, alkylcarbonyl, alkyloxycarbonyl, alkylcarbonyloxy, carboxyl, carbamoyl, formyl, alkylamino, . dialkylamino, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminothiocarbonyl, dialkylaminothiocarbonyl, alkylsulfonyl, alkylsulfenyl, alkylcarbonylamino, alkylthiocarbonylamino, alkylsulfonyloxy, alkylsulfonylamino, mercapto, and alkylthio; nis!or2;

R? is H or a C;-Cs aliphatic group;

R* and R® are independently selected from H, halo, a C;-Cg aliphatic group or a group having the formula C(O)RY, wherein R* is an aliphatic, carbocyclic or heterocyclic group;

R® and R’ are independently selected from H, halo or a C,-Cg aliphatic group;

R® and R® are each independently H, halo or a C-C, aliphatic group; where any of said aliphatic groups ar saturated, partially unsaturated or fully unsaturated and unsubstituted or substituted by one or more suitable substituents; and where any of said carbocyclic or heterocyclic groups are unsubstituted or substituted by one or more suitable substituents; saturated, partially unsaturated or fully unsaturated; or mono-, bi- or tri-cyclic.

A specific embodiment of a compound of Formula I-F, wherein n is 2 and R® and

R® are each H, may be represented as follows:

R2 0 : 0 ° deg

JL 1

R! N N RS

OR®

R* hs wherein the formula variables are as defined above.

In one embodiment, the compounds of Formula I-A of this invention, wherein R® and R’, taken together with the atom to which they are bound, form a carbocyclic group, comprise spiro-fused bi-cyclic compounds having the Formula I-G:

R® Re

R® X lo)

I

ON YY

OR! \ A "

R® I-G wherein . 20 R'isan aliphatic, carbocyclic or heterocyclic group, or a group having the formula: OR", SR, NHR', N(RMR" or C(O)R', wherein R'is an aliphatic, carbocyclic or heterocyclic group, and R'is H or a C;-Cs aliphatic group or R"and RY together with the atom to which they are attached form a substituted or unsubstituted heterocyclic ring;

R?isan aliphatic group, a carbocyclic group, a carbocyclic-aliphatic group, a heterocyclic group, or a heterocyclic-aliphatic group;

WisN,OorC; when WisNorC,R¥isHora C1-Cs alkyl group or R? and R? taken together with } 5 the atom W to which they are attached form an unsubstituted or substituted carbocyclic or heterocyclic ring. when Wis O, RY is absent;

PN oy RM

Le ly Oly CL

Xis ge , | or , | 5% ,or ~ | crvr” ’ wherein Y' and Y" are independently selected from H, halo, or a C,-Cg aliphatic group, wherein R" is H or one or more substituents independently selected from alkyl, nitro, amino, cyano, halogen, haloalkyl, hydroxyl, alkoxy, alkylenedioxy, alkylcarbonyl, alkyloxycarbonyl, alkylcarbonyloxy, carboxyl, carbamoyl, formyl, alkylamino, dialkylamino, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminothiocarbonyl, dialkylaminothiocarbonyl, alkylsulfonyl, alkylsulfenyl, alkylcarbonylamino, alkylthiocarbonylamino, alkylsulfonyloxy, alkylsulfonylamino, mercapto, alkylthio;

R® and R¥ are each independently H, halo or a C,-C, aliphatic group;

ZisS, 0, SO, SO, CHF, CH,, CF,, CH(OH), CH(O-R?), CH(N-R? R%),

CH(S-R?). C(=0), or CH(RY), where RZ is a C}-C aliphatic group or a carbocyclic or heterocyclic group and R? is H or a C;-Cg aliphatic group; nisl.2. 3o0r4;

R’isHora C,-C aliphatic group;

R* and R® are independently selected from H, halo, a C,-Cg aliphatic group or a group having the formula C(O)R*, wherein R* is an aliphatic, carbocyclic or heterocyclic group; where any of said aliphatic groups are saturated, partially unsaturated or fully unsaturated and unsubstituted or substituted by one or more suitable substituents; and where any of said carbocyclic or heterocyclic groups are unsubstituted, substituted : by one or more suitable substituents; saturated, partially unsaturated or fully unsaturated, or mono-, bi- or tri-cyclic.

In the compounds of this inventions, R? may consist of a substituted aliphatic group; wherein R’ may be represented as -CH»-B, -CH,CH,-B, -CH(CH;)B, and the like,

wherein B is a carbocyclic or heterocyclic group as described herein, and wherein the B group may be unsubstituted or substituted with one or more substituents selected from

C,-C, alkyl, halo, haloalkyl, hydroxy, alkoxy, halo alkoxy, alkylthio, haloalkylthio, amino, : dialkylamino, alkyl-SO,, cyano, alkylcarbonylamino and cycloalkylalkyloxy.

Specific embodiments of the compounds of this invention comprise the compounds ) depicted by Formula I-A";

R2 0] x 0] © Mere

A @

R’ AA oR, A

R® I-A’ wherein:

R'is an alkyl, alkenyl, or alkynyl group, a bi- or tri-cyclic cycloalkyl, cycloalkenyl, aryl, heterocycloalkyl, heterocycloalkenyl or heteroaryl group or a group having the formula: OR", SR", NHR", N(R")R"" or C(O)R"", wherein R" is an alkyl, alkenyl, or alkynyl group, a bi- or tri-cyclic cycloalkyl, cycloalkenyl, aryl, heterocycloalkyl, heterocycloalkenyl or heteroaryl group, or a cycloalkylalkyl, cycloalkenylalkyl, arylalkyl, heterocycloalkylalkyl, heterocycloalkenylalkyl, heteroarylalkyl, cycloalkylalkenyl, cycloalkenylalkenyl, arylalkenyl, heterocycloalkylalkenyl, heterocycloalkenylalkenyl, heteroarylalkenyl, cycloalkylalkynyl, cycloalkenylalkynyl, arylalkynyl, heterocycloalkylalkynyl, heterocycloalkenylalkynyl, or heteroarylalkynyl group; and R"" is H or a C,-Cs alkyl, alkenyl or alkynyl group or R" and

R' together with the atom to which they are attached form a substituted or unsubstituted heterocyclic ring;

R? is a cycloalkyl, cycloalkylalkyl, cycloalkenyl, or cycloalkenylalkyl group, a bi- or tri-cyclic aryl group, a bi- or tri-cyclic arylalkyl group, a bi- or tri-cyclic arylalkenyl group, a bi- or tri-cyclic arylalkynyl group, or a heterocycloalkyl, heterocycloalkylalkyl, : heterocycloalkenyl, heterocycloalkenylalkyl, heteroaryl or heteroarylalkyl group;

R? is H ora C;-Cs alkyl group; or R? and R” taken together with the nitrogen atom to which they are attached form a heterocycloalkyl or heterocycloalkenyl ring;

ey Te bs pt

Heels!

X is ge , | os } ~ % or | cri” wherein Y' and Y" are independently selected from H, halo, or a C,-Cs aliphatic group, } wherein R is H or one or more substituents independently selected from alkyl, nitro, amino, cyano, halogen, haloalkyl, hydroxyl, alkoxy, alkylenedioxy, alkylcarbonyl, alkyloxycarbonyl, alkylcarbonyloxy, carboxyl, carbamoyl, formyl, alkylamino, dialkylamino, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminothiocarbonyl, dialkylaminothiocarbonyl, alkylsulfonyl, alkylsulfenyl, alkylcarbonylamino, alkylthiocarbonylamino, alkylsulfonyloxy, alkylsulfonylamino, mercapto, and alkylthio;

Zis S, 0, SO, SO,, CH,, CHF, CF,, CH(OH), CH(0-R?), CH(N-R? R?),

CH(S-R"), C(=0), or CH(R?), where RZ is a C,-Cj aliphatic group or a carbocyclic or heterocyclic group and R% is H or a C,-Cg aliphatic group;

R’is Hora C,-Cq aliphatic group;

R* and R® are independently selected from H, halo, and a C,-Cj aliphatic group;

R®and R are independently selected from H, halo and a C,-Cg aliphatic group; where any of the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocycloalkyl, heterocycloalkenyl or heteroaryl groups or the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocycloalkyl, heterocycloalkenyl or heteroaryl moieties of the cycloalkylalkyl, cycloalkenylalkyl, arylalkyl, heterocycloalkylalkyl, heterocycloalkenylalkyl, heteroarylalkyl, cycloalkylalkenyl, cycloalkenylalkenyl, arylalkenyl, heterocycloalkylalkenyl, heterocycloalkenylalkenyl, heteroarylalkenyl, cycloalkylalkynyl, cycloalkenylalkynyl, arylalkynyl, heterocycloalkylalkynyl, and heterocycloalkenylalkynyl, heteroarylalkynyl groups are unsubstituted or substituted by one or more suitable substituents; and where any of said carbocyclic or heterocyclic groups are optionally mono-, bi- or trni-cyclic; saturated, partially unsaturated or fully unsaturated; and unsubstituted or substituted by one or more suitable substituents. provided that Ris not an aliphatic group, a phenyl group or a phenyl-substituted aliphatic group, when Z is S, SO, SO,, CHF, O,or CH,; R*, R?, R® and R® are H or a C,-C, 1 4 pS pb 7 oN 5 1. alkyl group; R", R”, R” and R" are H or a C;-C, alkyl group; X is Risa substituted or unsubstituted 5 or 6-membered mono-cyclic carbocyclic or heterocyclic group; or provided that R? is not t-butyl when R' is substituted or unsubstituted - phenyloxymethylene, or quinolylmethylenecarbonylaminomethylene; A is absent; Z is S;

RY

. xX 2 p3 pd 5 6 7 . gy

R%,R°,R% and R’, are H; R” and R’ are H, methyl, ethyl or propyl; and X is , wherein R* is H or methoxy,

In another embodiment, the compounds of this invention are depicted by Formula

I-A; wherein:

Z is CF,, CH(OH), CH (O-R%), CH(NR"R?), CH(S-R?), C=O or CH(R?), where R® isa C,-Cq aliphatic group or a carbocyclic or heterocyclic group and R? is H or a C;-Cs aliphatic group.

Specific examples of the compounds of Formula [-B comprise compounds having the formula I-B’

Rr? 0 X 0] © R?

A @ oR A

R® I-B' wherein

R' is an aliphatic, carbocyclic or heterocyclic group,

R? is an aliphatic group, a carbocyclic-aliphatic group, or a heterocyclic-aliphatic group;

R? is H or a C-Cq alkyl group; or R? and R? taken together with the carbon atom to which they are both attached form an unsubstituted or substituted carbocyclic ring; . o on

Xis h ed or 4 ,wherein R" is H or one or more substituents independently selected from alkyl, nitro, amino, cyano, halogen, haloalkyl, hydroxyl, alkoxy, alkylenedioxy, alkylcarbonyl, alkyloxycarbonyl, alkylcarbonyloxy, carboxyl,

carbamoyl, formyl, alkylamino, dialkylamino, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminothiocarbonyl, dialkylaminothiocarbonyl, alkylsulfonyl, alkylsulfenyl, alkylcarbonylamino, alkylthiocarbonylamino, alkyisulfonyloxy, alkylsulfonylamino, - mercapto, and alkylthio;

ZisS, 0, SO, SO,, CHF, CH,, CF,, C(=0), or CH(R?), where R% is a C,-Cs aliphatic group or a carbocyclic or heterocyclic group;

Ris Hora C,-Cg aliphatic group;

R* and R® are independently selected from H, halo, or a C;-Cs aliphatic group;

R® and R’ are independently selected from H, halo or a C,-Cg aliphatic group; wherein any of said aliphatic groups are saturated, partially saturated or fully unsaturated and unsubstituted or substituted by one or more suitable substituents; and wherein any of said carbocyclic or heterocyclic groups are unsubstituted or substituted by one or more suitable substituents; saturated, partially unsaturated or fully unsaturated; or mono-, bi- or tri-cyclic.

More specific examples of the compounds of Formula I-B' comprise compounds wherein

R' is a carbocyclic group,

R? is a C,-C; aliphatic group or a carbocyclic- C,-Cs -aliphatic group;

ZisS, O, CH, CFy;

R? R* and R® are each H; and

R® and R’ are each a C,-Cs aliphatic group; where any of said aliphatic groups are saturated, partially unsaturated or fully unsaturated and unsubstituted or substituted by one or more suitable substituents; and where any of said carbocyclic or heterocyclic groups are unsubstituted or substituted by one or more suitable substituents; saturated, partially unsaturated or fully unsaturated; or mono-, bi- or tri-cyclic.

Specific examples of the compounds of Formula I-B’ comprise compounds wherein ‘ R' is a phenyl group, unsubstituted or substituted with one or more substituents selected from alkyl, hydroxyl, halo, halo alkyl, haloalkoxy, methylene dioxy, and di- fluoromethylene dioxy;

R? is an alkenyl group, an aralkyl group or a straight or branched chain saturated alkyl;

lL

NY ‘

Xis where R" is H; ’ ZisS;

R’, R* and R? are each H; and

R® and R’ are each methyl; wherein any of said alkenyl, aralkyl, or alkyl groups are unsubstituted or substituted with one or more substituents, independently selected from methyl, halo, trifluoromethyl or methoxy.

Another specific emobdiment of the compounds of Formula I-B' comprise compounds wherein

R'isa phenyl group, unsubstituted or substituted with one or more substituents selected from alkyl, hydroxyl, halo, halo alkyl, haloalkoxy, methylene dioxy, and di- fluoromethylene dioxy; ’

Ris an alkenyl group, an aralkyl group or a straight or branched chain saturated alkyl; "\¢

ROT.

X is where R” 1s H;

Z is CF;

R? s R* and R? are each H; and

R® and R are each methyl;

Wherein any of said alkenyl, aralkyl, or alkyl groups are unsbstituted or substituted with one or more substitutents, independently selected from methyl, halo, trifluoromethyl or methoxy.

Other specific examples of this invention, comprise the compounds having the

Formula I-C:

R? 0 x 0 ° dg

A wv ’ R' AAA oR’, A

R® I-C' wherein

R'is an aliphatic, carbocyclic or heterocyclic group, or a group having the formula: OR", wherein R" is a carbocyclic or heterocyclic group;

R? is an aliphatic group, a carbocyclic group, a carbocyclic-aliphatic group, a - heterocyclic group, or a heterocyclic-aliphatic group;

Wis N;

R” is H or a C,-C alkyl group; )

NN Ce

X is , wherein R” is H; dialkylaminocarbonyl, alkylaminothiocarbonyl, dialkylaminothiocarbonyl, alkylsulfonyl, alkylsulfenyl, alkylcarbonylamino, alkylthiocarbonylamino, alkylsulfonyloxy, alkylsulfonylamino, mercapto, or alkylthio;

Z is CF,, CH(OH) or C(=0);

R} , R* and R’ are each H; and

R® and R’ are each methyl.

More specific examples of this invention, comprise the compounds having the

Formula I-C', wherein:

R'is an aryl group, an aryloxyalkyl group, an alkynyloxy group, a heterocycloalkyloxy group or heteroaryl group;

R? is an alkyl, alkenyl, or alkynyl group, an arylalkyl group; a heteroarylalky! group, an indany! group, a chromanyl group, a tetrahydronaphthalene group, an aliphatic group, a carbocyclic group, a carbocyclic-aliphatic group, a heterocyclic group, or a heterocyclic-aliphatic group; and

R” is H; wherein the alkyl, alkenyl, alkynyl, arylalkyl; heteroarylalkyl, indanyl, chromanyl or tetrahydronaphthalene group is optionaaly unsubstituted or substitutee with one or more substituents independently selected from alkyl, hydroxy, halo, haloalkyl, cyano, alkoxy or methylenedioxy.

Specific examples of this invention, comprise the compounds having the Formula

I-C', wherein:

R'is a phenyl group, a phenyoxymethyl group, a tetrahydrofuranyloxy group, a

C,-Cq4 alkynyloxy group, or a isoxazolyl group, where the phenyl group, phenyoxymethyl group or isoxazolyl group is unsubstituted or substituted by hydroxyl or methyl;

R? is an C;-Cs alkyl, C;-Cs alkenyl, or C,-C4 alkynyl group, a benzyl group; a furanylmethyl group, a thienylmehtyl group, an indanyl group, a chromanyl group, a : tetrahydronaphthalene group, or a cyclohexenyl group, where the alkyl groups 1s v unsubstituted or substituted with one or more halogen; and the phenyl group is unsubstituted or substituted with halogen, hydroxyl, methoxy, methylenedioxy or methyl;

R” is H; "¢

X is , wherein R* is H; and

Z 1s CF; :

Other specific embodiments of this invention comprise the compounds depicted by the Formula I-D' or I-E/, as follows:

R2

X 0) [ fo) 'e) W— 2

A

1

R N N RS

OR? At

RY Ig

R I-D’

R2

X 0 / 0 o W—R?

PN 7

R! N N oo

H

OR? Pt 4

R (CHa), I-E' wherein

R'is a carbocyclic or heterocyclic group,

R? is an aliphatic group, a carbocyclic group, a carbocyclic-aliphatic group, a ’ heterocyclic group, or a heterocyclic-aliphatic group;

Wis N;

R? is H or a C,-Cs alkyl group;

“\¢

Xis , wherein R” 1s H or one or more substituents independently ) selected from alkyl, nitro, amino, cyano, halogen, haloalkyl, hydroxyl, alkoxy, alkylenedioxy, alkylcarbonyl, alkyloxycarbonyl, alkylcarbonyloxy, carboxyl, carbamoyl, formyl, alkylamino, dialkylamino, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminothiocarbonyl, dialkylaminothiocarbonyl, alkylsulfonyl, alkylsulfenyl, alkylcarbonylamino, alkylthiocarbonylamino, alkylsulfonyloxy, alkylsulfonylamino, mercapto, and alkylthio;

Z is O, CHa, CHF, CF, or CH(R?), where R” is a C,-Cy aliphatic group;

R’, R*, R’, R® and R’ are each H; and wherein any of said aliphatic groups are saturated, partially unsaturated or fully unsaturated and unsubstituted or substituted by one or more suitable substituents; and wherein any of said carbocyclic or heterocyclic groups are unsubstituted or substituted by one or more suitable substituents; saturated, partially unsaturated or fully unsaturated; or mono-, bi- or tri-cyclic.

More specifically, embodiments of this invention, comprise compounds according to Formula I-D’ or I-E' wherein

R'is a carbocyclic group;

R’ is an arylalkyl group;

RY is H; "\¢

ROS

Xis , wherein R™ is H; and

Zis CH, wherein said carbocyclic group and arylalkyl group are unsubstituted or substituted with one or more substituents selected from methyl, halo, or hydroxy. . Another specific embodiment of this invention comprises compounds of Formula

I-F, as follows:

R2

X 0 / 0 o) Wg? . R’ AA RE

OR’

R? RS "LF wherein

Rlisa carbocyclic or heterocyclic group,

R? is an aliphatic group, a carbocyclic group, a carbocyclic-aliphatic group, a heterocyclic group, or a heterocyclic-aliphatic group;

Wis N;

R? is Hora C;-Cs alkyl group;

Me

Xis , wherein R” is H or one or more substituents independently selected from alkyl, nitro, amino, cyano, halogen, haloalkyl, hydroxyl, alkoxy, alkylenedioxy, alkylcarbonyl, alkyloxycarbonyl, alkylcarbonyloxy, carboxyl, carbamoyl, formyl, alkylamino, dialkylamino, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminothiocarbonyl, dialkylaminothiocarbonyl, alkylsulfonyl, alkylsulfenyl, alkylcarbonylamino, alkylthiocarbonylamino, alkylsulfonyloxy, alkylsulfonylamino, mercapto, and alkylthio; nisl or2;

R’, R* and R’ are each H; and

Ris H; wherein any of said aliphatic groups are saturated, partially unsaturated or fully unsaturated and unsubstituted or substituted by one or more suitable substituents; and wherein any of said carbocyclic or heterocyclic groups are unsubstituted or 2 substituted by one or more suitable substituents; saturated, partially unsaturated or fully unsaturated; or mono-, bi- or tri-cyclic. ’ More specifically, embodiments of this invention, comprise compounds according to Formula I-F', wherein

R'is a carbocyclic group;

R? is an arylalkyl group;

R% is H;

Me

Xis , Wherein R* is H; wherein said carbocyclic group, and arylalkyl group unsubstituted or substituted with one or more substituents selected from methyl, halo, or hydroxy.

In one embodiment, the compounds of Formula I-A of this invention, wherein R® and R’, taken together with the atom to which they are bound, form a carbocyclic group, comprise spiro-fused bi-cyclic compounds having the Formula I-G';

R2 0 x 0} ° Weg

OR \ Je ’

R® I-G' wherein

R'is a carbocyclic or heterocyclic group;

R’isan aliphatic group, a carbocyclic group, a carbocyclic-aliphatic group, a heterocyclic group, or a heterocyclic-aliphatic group;

Wis N, C or CH;

R”isH "\¢

Xis >» wherein R” is H or one or more suitable substituents independently selected from alkyl, nitro, amino, cyano, halogen, haloalkyl, hydroxyl, alkoxy, alkylenedioxy, alkylcarbonyl, alkyloxycarbonyl, alkylcarbonyloxy, carboxyl, carbamoyl, formyl, alkylamino, dialkylamino, alkylaminocarbonyl, dialkylaminocarbonyl, i alkylaminothiocarbonyl, dialkylaminothiocarbonyl, alkylsulfonyl, alkylsulfenyl, alkylcarbonylamino, alkylthiocarbonylamino, alkylsulfonyloxy, alkylsulfonylamino, : mercapto, and alkylthio;

Zis S, O, CH, CHF, CF, or CH(RY), where R% is a C,-Cs aliphatic group; © mnis2,3o0r4,;

R?, R* and R’ are each H;

wherein any of said aliphatic groups are saturated, partially unsaturated or fully unsaturated and unsubstituted or substituted by one or more suitable substituents; and wherein any of said carbocyclic or heterocyclic groups are unsubstituted or : substituted by one or more suitable substituents; saturated, partially unsaturated or fully unsaturated; or mono-, bi- or tri-cyclic.

More specific embodiments comprise the compounds of Formula I-G' wherein:

R'isa carbocyclic group;

R? is an arylalkyl group;

Wis N;

R% is H; "\¢ )

ROVE

X is , wherein R” 1s H; and

Z is CH,

R®, R*, R® and R’ are each H; wherein said carbocyclic group and arylalkyl group unsubstituted or substituted with one or more substituents selected from methyl, halo, or hydroxy.

More specific embodiments comprise the compounds of Formula I-G' wherein:

R' is a carbocyclic group;

R? is an arylalkyl group;

Wis N;

R” is H; 1 ) 9 | ol . .

Xis , wherein R” 1s H; and

Zis CF»,

R®, R* R’ and R’ are each H; wherein said carbocyclic group and arylalkyl group unsubstituted or substituted with one or more substituents selected from methyl, halo, or hydroxy. : More specific embodiments comprise the compounds of Formula I-G' wherein:

R' is a carbocyclic group;

R? is an arylalkyl group;

Wis N;

R” is H; "\¢

ROVE

Xis , wherein R* is H; and . ZisS;

R’, R*, R® and R are each H; wherein said carbocyclic group and arylalkyl group unsubstituted or substituted with one or more substituents selected from methyl, halo, or hydroxy.

If an inventive compound is a base, a desired salt may be prepared by any suitable method known in the art, including treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, or with an organic acid, such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, pyranosidyl acid, such as glucuronic acid or galacturonic acid, alpha-hydroxy acid, such as citric acid or tartaric acid, amino acid, such as aspartic acid or glutamic acid, aromatic acid, such as benzoic acid or cinnamic acid, sulfonic acid, such as p-toluenesulfonic acid or ethanesulfonic acid, or the like.

If an inventive compound is an acid, a desired salt may be prepared by any suitable method known to the art, including treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary, or tertiary); an alkali metal or alkaline earth metal hydroxide; or the like. Illustrative examples of suitable salts include organic salts derived from amino acids such as glycine and arginine; ammonia; primary, secondary, and tertiary amines; and cyclic amines, such as piperidine, morpholine, and piperazine; as well as inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, and lithium.

All compounds of this invention contain at least one chiral center and may exist as single stereoisomers (e.g., single enantiomers or single diastereomers), any mixture of stereosisomers (e.g., any mixture of enantiomers or diastereomers) or racemic mixtures thereof. All such single stereoisomers, mixtures and racemates are intended to be i encompassed within the broad scope of the present invention. Compounds identified herein as single stereoisomers are meant to describe compounds that are present in a form that contains at least 90% of a single stereoisomer of each chiral center present in the compounds. Where the stereochemistry of the chiral carbons present in the chemical structures illustrated herein is not specified, the chemical structure is intended to encompass compounds containing either stereoisomer of each chiral center present in the compound. Preferably, however, the inventive compounds are used in optically pure, that ’ is, stereoisomerically pure, form or substantially optically pure (substantially stereoisomerically pure) form. As used herein, the term "stereoisomeric” purity (or "optical" purity) refers to the "enantiomeric" purity and/or "diastereomeric" purity of a compound. Compounds that are substantially enantiomerically pure contain at least 90% of a single isomer and preferably contain at least 95% of a single isomer of each chiral center present in the enantiomer. Compounds that are substantially diastereomerically pure contain at least 90% of a single isomer of each chiral center present in the diastereomer, and preferably contain at least 95% of a single isomer of each chiral center.

More preferably, the substantially enantiomerically and diasteriomerically pure compounds in this invention contain at least 97.5% of a single isomer and most preferably contain at least 99% of a single isomer of each chiral center in the compound. The term “racemic” or “racemic mixture” refers to a mixture of equal amounts of enantiomeric compounds, which encompasses mixtures of enantiomers and mixtures of enantiomeric diastereomers. The compounds of this invention may be obtained in stereoisomerically pure (i.e., enantiomerically and/or diastereomerically pure) or substantially stereoisomerically pure (i.e., substantially enantiomerically and/or diastereomerically pure) form. Such compounds may be obtained synthetically, according to the procedures described herein using optically pure or substantially optically pure materials.

Alternatively, these compounds may be obtained by resolution/separation of a mixture of stereoisomers, including racemic mixtures, using conventional procedures. Exemplary methods that may be useful for the resolution/separation of stereoisomeric mixtures include chromatography and crystallization/re-crystallization. Other useful methods may be found in "Enantiomers, Racemates, and Resolutions," J. Jacques et al., 1981, John

Wiley and Sons, New York, NY, the disclosure of which is incorporated herein by reference. Preferred stereoisomers of the compounds of this invention are described herein.

Especially preferred embodiments of this invention comprise compounds, wherein the stereogenic centers (chiral carbons) have the following designated stereochemistry:

+44

R¥ R? 8 0 /

R X (8) W—p2

R7 : Ry N

H R® oR’ A z _ . R* A

RS }

More preferably, at least two of the stereogenic centers have the following designated stereochemistry:

RY Re 8 0]

R7

RV Sy N

H R®

OR’ A Z

RY Is A

R®

Even more preferably, at least three of the stereogenic centers have the following designated stereochemistry:

R® CR

R® X 0 / lo) Dats

Rr’

RY Sy NT

H T—R®

Or? A 74

RY | A

R® .

Exemplary compounds of this invention may be represented as follows:

R? R?

X O / i X 0] / 0 o N—g? o) 0 R?

ML R’ J RY 1 1

R N L RS R N L RS

. 3

OR’ g OR g . 2 _?

X 0 / X 0 . 0 0 NH 0 0 x B x . 1 “, 1 N “,)

OH S OH S

R? R?

X Q lI X 0 / 0 0 N——pg2 oO 0 Da - H H 4

OR’ OH —L

F F

. F 3

R2 x 0 /

R?

X 0 / PS x L. rR N N

H

OR? and wherein each of the formula variables are as defined above.

Exemplary compounds of this invention include the following. The abbreviation "Bn" in some of the following structures indicates a "benzyl" substituent. 0) 0] 0) (0) 0] 0

N

- - =

OH NeXT OH SX 0] 0] 0] ( ] 0] 0) 0]

NF HoH (XT H Xe NE Hon (eX A 0) 0 0) Io) 0 0

H Z-H H ZH o on LX on {AM 0 : o 0 oO 0

H =—H N H Z -H

OH (eK z oH LX 0 fo) 0 0 “OY ETO . Hon (A H ZN : 0 0 0 $ 0 0 0 “Or \ Ay ® HO \ N— ow

H OH (KX H H OH (A H 0 0 0 fo) fo) 0 o

Beas vss SOS ER RAGE RY,

H oH (KN H oH (AK 0 oOo © 0

H OH (XK H 0 0 0 Oo 0 0 0 S

H Zz -H H = ~H

OH (AK OH (KX lo) fo) fo) IO 0) lo) lo)

HO L SE a PN HO. J ga oJ H on { XH J J H (xt VY

SN = OH s\ 2 fo) fo) 0 0)

HO N NN

Hon (AN fo oOo oO 0 0 0 . : Hoon (XT NG Hoon (XH o o fo) 0 0

Ld Lf et a

H oy (KH 5: H on (KN 0 0 0 lo} lo} lo} oO

NEY ay NEY i 1

OH (AK OH (KX of o ©

H On (KH

Io) 0 fo) fo oO 0

Cr ron Or NN

S OH N OH (AK L_o 0 oO oO 0 oO © J @! no LL, i SAO no A q N=

J H oH (KH J H OH (AK 78 0) 0 0 0 0 0 ] oH LX Ls oH LAX

0 oO 0 0 0 0 (ry

Or NN “ry Nn : OH (AK OH (KX 0) 0 fo) 5

H on (KX H 0 oO ©O @ 0 0 o or NS ROR hd

H =z -H H =z -H oH LX OH LA 0 0 0) 0 lo) 0

OH (KX OH (KX 0 0 0)

LC

OH (A x 9 o 9 [@

HO NY ON ON ZN

H Z ~H 1

OH (A xX 0 0 0 fo) fo) Io} \ oR Bee RoR SR = N-N =

OH (AT OH (KX 0

0 oO 0 0 oc oo . H ZH 0 H =z -H — 0 o © 0 o © 9) o oO 0 o 0 y

OH NeXT on LX o) o oO y

Rea Ere a

OH Sg AT a, go”

ON ry YY re AAT 2 OH N\A § ba Lg 0 3 © 0 . HO N Ne F 0 o) 0 0)

H ZH

F on LX

3 we

N fo) le) Dok

HO

. N N “, or OH CA

Po a ¥

N fo) 0 ON O o ON

OH LK oH L.¢ yay yay . : . ; o 5 ON o 5 ON

HO N we HO N ve on Ld OH LK 0 0 Bi

HO N—" “NN 0 o © (o

EPs EW

HN St _H

S OH (KX 0 0 o 0 yy © Oo 0

SE Rtec Arla se saee Rr

Hon NE H On (A 0 o 0 0 o ©

JEENSECE PRS

H oH Ne \=p H on Ne s1 0 o © o o ©

S on SER HN N Ne

HOH (KM Ho 3, CAH 0 0 Oo = 0 Oo Oo

NERS BRN Uo

H OH (AK H OH (KH

N= 0 / 0 0 o ©

N N—" "N or OH SAT 0 Zo OH Cx 0 1 Q o o 0

Soon = N ry

H OH (AH H OH Ne 0 (®) 0 fe) 0 le)

SN - EI ad hd

H : OH (AK H OH (KH

N | Hon NO Hon ZO 0 0 0 0 oO ©

Fe AL A ry Po SORE

HOH (AH Ho CH

0 0 fo 0 fo 0 “Ort NP SPN o MAM "oon (XH "oon LH a 0 0] 0 's} Oo e)

Or Ne NF a SERS

H { = H H z H on (x bn (x 2 fo) Pi 0 0 Bi

ON N—" "N AN

Cr H oH ENV : OH EHV 0 oO 0 o) 0 fo fo) 0

WIELD, ambit oH (A oH (A 0 oO © 0 0 oOo 0

Nes Ay N—" Nn o Ay LA

AN H OH NE H oH (KH

CL lo} 0) 0 0 lo} 0 oy § J, “Ory (ELI

OH (AT OH (AK

N= © 0 0 0 0 o)

OH sN OH sN

N= 0 o} 0 0 0 0

HN o

CO En . "oon (XH o Hoon {XM 0) lo) 0) 0) lo) lo) ey P10 ey fn

OH (A OH (AK lo) 0 lo) 0 0 0) “ N—"N “rh No)

H : _H H tH

S OH (AK OH (A o BH lo) 0 0) 0 0 XN

HN 3 or NN ow : ry oH LX Hoon Lg cl

F F

H

F 2 0 YD) 0 0 0 AD

NTN N K Soy N 4

HH on Lg F HoH on LN OF o H R rR _F oOo H ) 1 o HO) F Jig 0) or = 0" ™N NY 5 “NTN NTF . ZO NT C / H H 8x LK FN

H

Jil o ©@ N lo} eo} SN

N { . 5 xX"No N E oN 4

OH ~¢'N FA Hoon Lg CFs 0] 0) O (o] Bn ©O 0]

AER 0 oR NN

H H H =

OH (JX yp OH (A

Br 0 Bh O lo} Bn O 0] 1 I o I nH . H 11 ol OH CX | 8 OH LX H

S

O Bn O fo} © Bn O o

EN EN J IL

NTN N N N"ON N—

Org Soaastaray

S (0) S

O Bn O g "0 Bn oO 0

Ao A RAS NE

H H on (KX H H H on (KX H © Bh O © ig IR iy

A AA ENP NPN >No ON NT ONT

N N N N AN - | ~ .

WEA "oo we le "oon (eX " Cl, 0) Bn O 0

SNS ers oR

N N N xX N Pn TN X

H on (XH J Ho on (JH ln

S Ss lo) Bh O 0 \ Oo Bn O it

H on (JH | _n \ H on (XH ln

Jil Bn 0 i ~o J Bn O i font aneaslioan acs: acl

S

F it Bh O ig Br Jit Bn © i

CERRO ORE LTO

S s

O Bn O 0 O Bn O 0

A XK _o iy n

N° °N . oO 8 0 o O Bn O [0]

FC A A 0 J iI 7 2 wg 9 Oo BO © oA N Sey ot IL

CURLY JOR

0 oO 0 0 o 0

OH (KX OH s 2 Le 20 C1? 2D

NY N= ON Z AOR RAGE

Z H -_—H

Cr OH (AK OH lO 0 0 OH o ’ A

HO HO !

0 lo} 0 0} 0 0 I®

HO \ Ly HO \ N—N

Tonle TonSe

FF FOF fo oO 0 o) oO 0

HO N N—""N Foro N N= "on (on | Tonle

OH

FF FF : 0 oO 0 o) oO ©

HO N NON HO N NN

Tonle onion

FOF FOF

0 oO 0 cl 0 oO 0

AE NEVE) onion OH 5

FF FF

0 oO 0 o oO ©

Or SLAvs “rs SEROR on {2 J on {_*

F F FF ’ 4 N 1) 9) oO © 0 oO 0 F “Or SER! *r SRDS on 5 © on 5 cl

FF FOF

. fo) oO 0 fo 9) 0)

FOF FOF

O 0 0 lo) lo) lo) cl

HO

N’ - NNN Ho N° - » "oon SA oon SK

F

FF FOF

0) 0) 0) 0 0 0

OH SA on { %—H

FF ay

O O O oO Io) 0

HO N NN HO N ~~ )

Toon SK "oon SK

F'F FF 0) 0) 0) 0 fo) 0) lo)

RR N— Ne, Or N=

OH SAX H oon (XH 0 lo) o) 0 0 o) ry SER Or rs

OH SAX 0 OH SA g

FOF FOF

0 0 fo) 0 lo) 0 J @ “rh Ely “rh hy

OH LAT on {A ’ o} o} 0) oO O o

HO RS HO N N SL

N N N N I

0 o 0 Q Q i

H H on Se on {XS lo) lo) fo) 0) 0) ¢ I@ “ry z Hees ROR N—Y N

OH be: OH os (5 3% 0 (Too

ROR NW Ho N Noy on Ory LOH

F

0 0 0 0 lo} I®

OH Be OH Co 0 0) 0 0 a 0 0 fo) oN, y SL oN y NY

HL, $ H Ho Ly (J H

FOF FOF

0 0 7 fo) fo) 3

HO N N— ON 2 N NN

H On CJ H Hoo, (J H ) FFF FF 0 0 0 0 0 fo

JL JL oN JU SN

Zo N N KS N N N . N 7 H on LL H H oH (J H £F FOF lo) 0) 0 2 7 ?

HO oN RLS N NN

N N N H on 2 _H

Toon CN Ne

F F o) 0 Jo} fo}

J Q e

HO { 3 SL Ho Ho

H OH H N N ug

H H OH N

0 0 0 0 lo} lo) rr NP ry NE

S OH (AK OH (AC F lo) lo) PUN lo) 0 0)

OH eg oH LX

O OES o 0 ro) (@] | |&

HO Ma no N nn

LS a CoH

H > © sN "°F

H K \

OH Lu OH CX 0 0) 0 CL lo) 0 0)

Ao SEND oy N— NF

OH (KX oH { A

CL bt 0 0 0) 0) 0

Ay Cr rd) oH LX oH { A 0 0) lo) o NE

HN 0)

OH s\ HoH Lg Cl 9) ( oO 0 pe fo oO ©

FF OH (eA \=N Hon (A H and the prodrugs, pharmaceutically active metabolites, and pharmaceutically acceptable salts and solvates thereof.

The invention 1s also directed to the intermediates of Formula II, which are useful in the synthesis of certain compounds of Formula I:

oO O 0 0) 0 Oo 0 Oo od Ao, SoA Ao SLA A, oly Hon

ETT TE

20a 20b 20¢ 20d 0 lo) 0 0 o 0 0 0

SAA, SLA A, SAA OH SAA OH (J LF CoS (XK 20e 20f 20g 20h

O 0 Oo 0 Oo 0

SoA, SoA, Hon po 0? n— on

SAD) EEN eS n=0-6 o 20i 20j 20k

The HIV protease inhibitor compounds of this invention include prodrugs, the pharmaceutically active metabolites, and the pharmaceutically acceptable salts and solvates thereof. . In preferred embodiments, the compounds of Formula I, prodrugs, pharmaceutically acceptable salts, and pharmaceutically active metabolites and solvates thereof demonstrate an HIV-protease inhibitory activity, corresponding to K; of at least 100 nM, an ECs of at least 10 mM or an ICs; of at least 10 mM. Preferably, the compounds of this invention demonstrate an HIV-protease inhibitory activity, corresponding to a Kj of at least 10 nM, an ECs, of at least 1 mM or an ICs; of at least 1 mM. More preferably, the compounds of this invention demonstrate an HIV-protease inhibitory activity against mutant strains of HIV, corresponding to a K; of at least 100 nM, an ECs of at least 10 mM or an ICs of at least 10 mM. Even more preferably, the compounds of this invention demonstrate protease inhibitory activity against mutant strains corresponding to a K; of at least 10 nM, an ECs of at least | mM or an ICs of at least 1 mM. ) A "prodrug" is intended to mean a compound that is converted under physiological conditions or by solvolysis or metabolically to a specified compound that is ~ pharmaceutically active. A prodrug may be a derivative of one of the compounds of this invention that contains a moiety, such as for example -CO;R, -PO(OR), or -C=NR, that may be cleaved under physiological conditions or by solvolysis. Any suitable R substituent may be used that provides a pharmaceutically acceptable solvolysis or cleavage product. A prodrug containing such a moiety may be prepared according to conventional procedures by treatment of a compound of this invention containing, for example, an amido, carboxylic acid, or hydroxyl moiety with a suitable reagent. A "pharmaceutically ) active metabolite" is intended to mean a pharmacologically active compound produced through metabolism in the body of a specified compound. Prodrugs and active metabolites of compounds of this invention of the above-described Formulas may be determined using techniques known in the art, for example, through metabolic studies.

See, e.g., "Design of Prodrugs, " (Bundgaard, ed.), 1985, Elsevier Publishers B.V.,

Amsterdam, The Netherlands. The following are examples of prodrugs that can be converted to the compounds of this invention under physiological conditions, by solvolysis or metabolically: ) oO 0 0 & oN

Cedtidede edd 0 Hoon {7H 0 HOH F and F .

A "pharmaceutically acceptable salt" is intended to mean a salt that retains the biological effectiveness of the free acids and bases of a specified compound and that is not biologically or otherwise undesirable. Examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, : succinates, suberates, sebacates, fumarates, maleates, butyne-1,4-dioates, hexyne-1,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, y-hydroxybutyrates, glycollates, tartrates, methane-sulfonates (mesylates), propanesulfonates, i naphthalene-1-sulfonates, naphthalene-2-sulfonates, and mandelates. A "solvate" is } intended to mean a pharmaceutically acceptable solvate form of a specified compound that retains the biological effectiveness of such compound. Examples of solvates include compounds of the invention in combination with water, isopropanol, ethanol, methanol,

DMSO, ethyl acetate, acetic acid, or ethanolamine. In the case of compounds, salts, or solvates that are solids, it is understood by those skilled in the art that the inventive compounds, salts, and solvates may exist in different crystal forms, all of which are intended to be within the scope of the present invention and specified formulas.

The present invention is also directed to a method of inhibiting HIV protease ) activity, comprising contacting the protease with an effective amount of a compound of ) 5 Formula l, or a pharmaceutically acceptable salt, prodrug, pharmaceutically active metabolite, or solvate thereof. For example, HIV protease activity may be inhibited in mammalian tissue by administering a compound of Formula I or a pharmaceutically acceptable salt, prodrug, pharmaceutically active metabolite, or solvate thereof. More preferably, the present method is directed at inhibiting HIV -protease activity. "Treating" or "treatment" is intended to mean at least the mitigation of a disease condition in a mammal, such as a human, that is alleviated by the inhibition of the activity of HIV proteases. The methods of treatment for mitigation of a disease condition include the use of the compounds in this invention in any conventionally acceptable manner, for example, as a prophylactic. The activity of the inventive compounds as inhibitors of HIV protease activity may be measured by any of the suitable methods known to those skilled in the art, including in vivo and in vitro assays. Examples of suitable assays for activity measurements are escribed herein. Administration of the compounds of the Formula I and their pharmaceutically acceptable prodrugs, salts, active metabolites, and solvates may be performed according to any of the generally accepted modes of administration available to those skilled in the art. Illustrative examples of suitable modes of administration include oral, nasal, parenteral, topical, transdermal, and rectal.

An inventive compound of Formula I or a pharmaceutically acceptable salt, prodrug, active metabolite, or solvate thereof may be administered as a pharmaceutical composition in any pharmaceutical form recognizable to the skilled artisan as being suitable. Suitable pharmaceutical forms include solid, semisolid, liquid, or lyophilized formulations, such as tablets, powders, capsules, suppositories, suspensions, liposomes, and aerosols. Pharmaceutical compositions of the invention may also include suitable excipients, diluents, vehicles, and carriers, as well as other pharmaceutically active agents, ; depending upon the intended use or mode of administration. Acceptable methods of

B 30 preparing suitable pharmaceutical forms of the pharmaceutical compositions may be routinely determined by those skilled in the art. For example, pharmaceutical preparations may be prepared following conventional techniques of the pharmaceutical chemist involving steps such as mixing, granulating, and compressing when necessary for tablet forms, or mixing, filling, and dissolving the ingredients as appropriate, to give the desired products for oral, parenteral, topical, intravaginal, intranasal, intrabronchial, intraocular, intraaural, and/or rectal administration.

The present invention includes pharmaceutical compositions useful for inhibiting > HIV protease, comprising an effective amount of a compound of this invention, and a pharmaceutically acceptable carrier. Pharmaceutical compositions useful for treating infection by HIV, or for treating AIDS or ARC, are also encompassed by the present invention, as well as a method of inhibiting HIV protease, and a method of treating infection by HIV, or of treating AIDS or ARC. Additionally, the present invention is directed to a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present invention in combination with a therapeutically effective amount of an HIV infection/AIDS treatment agent selected from: 1) an HIV/AIDS antiviral agent, 2) an anti-infective agent, and 3) an immunomodulator.

The present invention also includes the use of a compound of the present invention as described above in the preparation of a medicament for (a) inhibiting HIV protease, (b) preventing or treating infection by HIV, or (c) treating AIDS or ARC.

The present invention further includes the use of any of the HIV protease inhibiting compounds of the present invention as described above in combination with one or more

HIV infection/AIDS treatment agents selected from an HIV/AIDS antiviral agent, an anti- infective agent, and an immunomodulator for the manufacture of a medicament for (a) inhibiting HIV protease, (b) preventing or treating infection by HIV, or (c) treating AIDS or ARC, said medicament comprising an effective amount of the HIV protease inhibitor compound and an effective amount of the one or more treatment agents.

Solid or liquid pharmaceutically acceptable carriers, diluents, vehicles, or excipients may be employed in the pharmaceutical compositions. Illustrative solid carriers include starch, lactose, calcium sulfate dihydrate, terra alba, sucrose, talc, gelatin, pectin, acacia, magnesium stearate, and stearic acid. Illustrative liquid carriers include syrup, pa peanut oil, olive oil, saline solution, and water. The carrier . diluent may include a suitable prolonged-release material, such as glyceryl monostearate or glyceryl distearate, ’ alone or with a wax. When a liquid carrier is used, the preparation may be in the form of a syrup, elixir, emulsion, soft gelatin capsule, sterile injectable liquid (e.g., solution), or a nonaqueous or aqueous liquid suspension. A dose of the pharmaceutical composition contains at least a therapeutically effective amount of the active compound (i.e., a compound of Formula I or a pharmaceutically acceptable salt, prodrug, active metabolite, or solvate thereof), and preferably is made up of one or more pharmaceutical dosage units.

The selected dose may be administered to a mammal, for example, a human patient, in » need of treatment mediated by inhibition of HIV protease activity, by any known or suitable method of administering the dose, including: topically, for example, as an ointment or cream; orally; rectally, for example, as a suppository; parenterally by injection; or continuously by intravaginal, intranasal, intrabronchial, intraaural, or intraocular infusion. A "therapeutically effective amount" is intended to mean the amount of an inventive agent that, when administered to a mammal in need thereof, is sufficient to effect treatment for disease conditions alleviated by the inhibition of the activity of one or more variant of the HIV protease. The amount of a given compound of the invention that will be therapeutically effective will vary depending upon factors such as the particular compound, the disease condition and the severity thereof, the identity of the mammal in need thereof, which amount may be routinely determined by artisans. [

The compounds of this invention are also useful in the preparation and execution of screening assays for antiviral compounds.

For example, the compounds of this invention are useful for isolating enzyme mutants that are excellent screening tools for so more powerful antiviral compounds.

Furthermore, the compounds of this invention are useful in establishing or determining the binding site of other antivirals to HIV protease, e.g., by competitive inhibition.

Thus the compounds of this invention are commercial products to be sold for these purposes. .

GENERAL SYNTHETIC METHODS

Preferably, the inventive compounds are prepared by the methods of the present > invention, including the General Methods shown below. When stereochemistry is not specified in chemical structures, either stereocenter may be utilized. The following abbreviations also apply: Boc (tert-butoxycarbonyl), Ac (acetyl), Cbz (benzyloxycarbonyl), DMB (2,4-dimethoxybenzyl), TBS (fert-butyldimethylsilyl),

TBDPS (tert-butyldiphenylsilyl), Ms (methanesulfonate), Ts (toluenesulfonate), Bn (benzyl), and Tr (triphenylmethyl)

All reactions were performed in septum-sealed flasks under a slight positive pressure of argon unless otherwise noted. All commercial reagents and solvents were used as received from their respective suppliers with the following exceptions: Tetrahydrofuran (THF) was distilled from sodium benzophenone ketyl prior to use. Dichloromethane (CHCl) was distilled from calcium hydride prior to use. Flash chromatography was performed using silica gel 60 (Merck art. 9385). 'H NMR spectra were recorded at 300

MHz utilizing a Varian UNITY plus 300 spectrometer. Chemical shifts are reported in ppm (8) downfield relative to internal tetramethylsilane, and coupling constants are given in Hertz. Infrared absorption spectra were recorded using a Perkin-Elmer 1600 series

FTIR spectrometer. Elemental analyses were performed by Atlantic Microlab, Inc.,

Norcross, GA. Melting points are uncorrected.

All P2’ amine variants mentioned in General Methods A-E described hereinbelow were either purchased and used directly or synthesized as follows.

METHOD A: REPRESENTATIVE PROCEDURE FOR REDUCTION OF

KETONES TO ALCOHOLS,

A TT oN 1 2 ‘ 6,7-Dihydro-4-(5H)-benzofuranone (1) (1.00 g 7.34 mmol) was dissolved in methanol (55 mL). The mixture was cooled to 0 °C and NaBH, (0.31 g, 8.08 mmol) was added in portions. The reaction was stirred for 2 h at 0 °C at which time the methanol was evaporated. The residue was dissolved in EtOAc and poured into NaHCO; (saturated aqueous) and extracted with EtOAc (3 x 10 mL). The combined organic extracts were washed with brine (10 mL), passed over a short plug of Na,SO,, and concentrated in y vacuo to give 2 (1.01 g, 99%, as a mixture of isomers) as a pale yellow, thick oil, which _ was of sufficient quality to be advanced to the next step without further purification. Rf . 5 (50% EtOAc/hexanes): 0.53. '

METHOD B: REPRESENTATIVE PROCEDURE FOR REDUCTION OF ACIDS

TO ALCOHOLS.

Oo

Ho” NN — i 1 2

Tiglic acid (1) (20.0 g, 0.200 mol) was dissolved in ether (80m!) and added dropwise over 30 min to a suspension of LiAlH, (15.0 g, 0.417 mol) in ether (80 ml) at 0 °C and the reaction mixture was allowed to warm to room temperature. After 3 h the - mixture was re-cooled to 0 °C and quenched slowly by the addition of H,O (15 ml), 15%

NaOH (15 ml) and HO (15 ml). The reaction mixture was filtered to remove the granular precipitate and washed thoroughly with ether. The filtrate was washed successively with

IN HCl, NaHCO; (saturated aqueous), and brine. The combined organic layers were dried over MgSO, and concentrated in vacuo to give (E)-2-methyl-but-2-en-1-ol (2)asa clear oil (12.8g, 74%).

METHOD C: REPRESENTATIVE PROCEDURE FOR ALKYLATION OF :

PHENOLS ALCOHOLS.

HO [ ] ort — a» HO 1 yd 1 2 / .

Sl 25 3-Hydroxybenzylalcohol (1) (0.500 g 4.03 mmol) was dissolved in DMF (2 mL) at ambient temperature. Ethyl bromide (0.900 mL, 12.1 mmol) and finely crushed K,CO, ' (2.78 g, 20.1 mmol) were added and the reaction mixture was stirred for 5 h. The DMF was then removed in vacuo and the residue was partitioned between EtOAc and H,0, and extracted with EtOAc (3 x 10 mL). The organic layers were washed with brine (10 mL) and passed over a short plug of Na,SO,. The solvents were removed in vacuo to give alcohol 2 (0.55 g, 90%) as a pale yellow, thick oil, which was of sufficient quality to be advanced to the next step without further purification. Rf (40% EtOAC/hexanes): 0.69. ’ METHOD D: REPRESENTATIVE PROCEDURE FOR CONVERSION OF ] 5 ALCOHOLS TO AMINES.

LO Did WT — YO 1 2 3 3-Ethoxy-phenyl-methanol (1) (1.23 g 8.08 mmol) was dissolved in CH,Cl, (10 mL) at ambient temperature and diphenylphosphoryl azide (2.67 g, 9.70 mmol) and 1,8- diazabicyclo [5.4.0] undec-7-ene (1.45 mL, 9.70 mmol) were added. The mixture was stirred for 5 h at which time the CH,Cl; was removed in vacuo and the crude residue was partitioned between EtOAc and H,O and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (10 mL), passed over a short plug of

Na;SOy,, and concentrated in vacuo to give a yellow oil that was loaded directly onto a flash silica gel column and was quickly eluted with 10% EtOAc/hexanes. The solvents were removed in vacuo to give azide 2 (1.43 g, 84%) as a colorless oil. Rf (30%

EtOAc/hexanes): 0.79. 1-Azidomethyl-3-ethoxy-benzene (2) (1.19 g 6.71 mmol) was dissolved in MeOH (15 mL) and palladium 10% on activated carbon, wet (20% in weight) was added. The reaction was hydrogenated for 30 min at 40 PSI in a Parr Hydrogenator. The black suspension was then filtered through compacted celite and the methanol was removed in vacuo to give amine 3 (0.88 g, 88%) as a pale yellow, thick oil, which was of sufficient quality to be advanced to the coupling reactions without further purification.

METHOD E: REPRESENTATIVE PROCEDURE FOR CONVERSION OF 3 ALCOHOLS TO BROMIDES.

H J — pul

V . 5

Cis-2-penten-1-o0l (1) (1.00 g, 11.6 mmol) and carbon tetrabromide (3.85 g, 13.9 mmol) were dissolved in CHCl; (75 mL). The mixture was cooled to 0 °C and triphenylphosphine (3.65 mL, 13.9 mmol) dissolved in CH>Cl; (50 mL) was added dropwise. The mixture was allowed to warm to room temperature and was stirred overnight. The CH,Cl, was removed in vacuo and the crude residue was loaded directly ) onto a flash silica gel column and eluted quickly with 20% EtOAc/hexanes. The solvents } 5 were removed in vacuo to give bromide 2 (1.53 g, 88%) as a colorless volatile oil. Rf (30% EtOAC/hexanes): 0.89.

METHOD F: REPRESENTATIVE PROCEDURE FOR CONVERSION OF :

BROMIDES TO AMINES.

Br —= @oopN YP = TRARNTP 1 2 3

A mixture of bromide 1 (3.00 g, 20.1 mmol), di-tert-butyl-iminodicarboxylate (4.8 g, 22 mmol), and K,COj3 (3.10 g, 80.4 mmol) in DMF (30ml) was stirred at ambient temperature overnight. The mixture was partitioned between IN HCI and EtOAc. The organic layer was washed with H,O and brine, then dried over NaSO,. Concentration in vacuo affored a yellow oil which upon purification by flash column chromatography (hexanes to 5% EtOAc/Hexane gradient) yielded protected amine 2 as a clear oil (2.0g, 35%).

A mixture of the diBOC amine 2 (2.0 g, 7.0 mmol), trifluoroacetic acid (2.7 ml, 35 mmol) and CH,Cl, (40 ml) was stirred at ambient temperature overnight. The reaction mixture was concentrated in vacuo to give the TFA salt of (E)-2-methyl-but-2-enylamine (3). :

METHOD G: REPRESENTATIVE PROCEDURE FOR REDUCTION OF

AROMATIC NITRO GROUPS BY HYDROGENATION. eon Yt woo (OY ; ] 5 ] 4

Compound 1 (2.04, 5.79 mmol) was dissolved in EtOAc (20 mL) and palladium 10% on activated carbon, wet (20% in weight) was added. The reaction was hydrogenated for 4h at 45 PSI in a Parr Hydrogenator. The black suspension was then filtered through compacted celite and the methanol was removed in vacuo to give aniline 2 (1.65 g, 88%)

as a pale yellow, thick oil, which was of sufficient quality to be advanced to the acetylation reaction without further purification. ’ METHOD H: REPRESENTATIVE PROCEDURE FOR ACETYLATION OF

ANILINES.

NH NHAc oN CT : soo J 1 2

Aniline 1 (1.65 g, 5.12 mmol) was dissolved in CH,Cl, (25 mL) at ambient temperature. Acetyl chloride (0.48 g, 6.14 mmol) and N,N-Diisopropylethylamine (0.79 g, 6.14 mmol) were added, and the reaction was stirred overnight. The CH,Cl; was removed in vacuo and the crude residue was partitioned between EtOAc and 5% KHSO, and extracted with EtOAc (3 x 10 mL). The combined organic extracts were washed with

NaHCO; ( saturated aqueous, 10 mL), brine (10 mL), and dried over Na>SO,. The solvents were removed in vacuo to give an orange oil which was of sufficient quality to be advanced to the next step without further purification. Rf (50% EtOAC/hexanes): 0.42.

METHOD I: REPRESENTATIVE PROCEDURE FOR REDUCTION OF

ALDEHYDES TO AMINES. o "On 2

SOT AT CIT

1 2 3

Hydroxyl amine hydrochloride (758 mg, 10.7 mmol) and pyridine (2.16 mL) was added to a solution of 2,2-difluoro-5-formyl benzodioxole (1) (2.00 g, 10.7 mmol) in

MeOH (10 mL). After 18 hours the MeOH was removed in vacuo. The reaction mixture ! was diluted with EtOAc and was washed sequentially with H,O, 10% w/v CuSQ4, and brine and then dried over MgSQO,. The solution was concentrated in vacuo. The hydroxy imine was purified by column chromatography using 20% EtOAc/Hexanes to give 1.37 g (64% yield) of a white solid. Imine was then subjected to LAH reduction as described above to provide amine 3.

Method J: REPRESENTATIVE PROCEDURE FOR THE HYDROXYLATION OF

A SUBSTITUTED BENZOIC ACID

’ 0] 0)

Sa ie : —_— 1 2 2,5-dimethyl-benzoic acid (1) (20 g, 133 mmol) was dissolved in concentrated

H>S0,4 (30 mL) and fuming H,SO,4 (20% SO;, 70 mL). The reaction mixture was heated to 110 °C for 2 hours. After cooling, the solution was poured carefully into a beaker of ice

HO (400 mL) and was then neutralized with 20% aqueous NaOH (400 mL). The H,O was partially removed in vacuo until a white salt mixture started to form. The solid was collected on a sintered-glass funnel and was then dried in a vacuum oven. The dried salt mixture was placed in a ceramic crucible with KOH (160 g) and was melted together using a butane torch for 0.5 h. After cooling, the fused solid was dissolved in H,O (300 mL) and acidified with concentrated HCI (300 mL). The product was extracted from the aqueous solution with EtOAc (3 x 200 mL). The combined organic layers were washed with brine (100 mL) and dried over MgSO,. The solvents were removed in vacuo and the solid residue was recrystallized with 20% EtOAc/CHCI; four times to afford 3-hydroxy-2, 5- dimethyl-benzoic acid (2) as a light brown solid (9.8 g, 44%) 'H NMR (Acetone-dg) 6 10.93 (brs, 1H), 8.34 (brs, 1H), 7.20 (s, 1H), 6.86 (s, 1H), 2.37 (s, 3H), 2.24 (s, 3H).

References- Fujiwara, A. N.; Acton, E. M. Can. J. Chem. 1970, 48, 1346 - 1349.

Charlesworth, E. H.; Levene, L. Can. J. Chem. 1963, 41, 1071 - 1077.

The following amines were synthesized for the corresponding example numbers:

Example A35 and Example A36 0) Oo

HN H,N

Amines were generated from reducing the corresponding ketone as described in method A above followed by conversion to the azide and reduction as described in method

D above. The mixture of isomers was coupled to the chiral thiazolidine core and separated.

Example A37 and Example A38

S S

H,N HN

Amines were generated as described for Examples A35 and A36, separating the diastereomers at the thiazolidine stage.

Example A84 and Example A85 oN HN b fe

Amines were generated as described for Examples A35 and A36, separating the diastereomers at the thiazolidine stage.

I)

Example A86 and Example A87 y HN . s HN" » s ) Amines were generated as described for Example A35 and A36, separating the diastereomers at the thiazolidine stage.

Example A43 0)

WOT ~

Amine was generated by alkylation of 3-hydroxybenzyl alcohol with ethyl bromide as describe in method C above followed by conversion of the alcohol to the amine as described in method D above provided desired amine.

Example A44 0) acne

Amine was generated as described above for Example AA43 using the cyclopropyl alkylating agent.

Example A93 ©)

SO ~~

Amine was generated as described above for Example A43 using propylbromide as the alkylating agent.

Example A67

N

HN YY

& 0)

Amine was generated from displacement of bromide in 3-nitrobenzylbromide with di BOC ‘ amine as described in method F above. Reduction of the nitro moiety to the aniline (method G above) followed by acetylation (method H above) and BOC removal (method F above) provided desired amine.

Example A72, Example A73 and Example A80

HN CE, Ea ed

Amines were generated from conversion of the corresponding primary alcohols as

RX described in method E above. Displacement of the bromide with di BOC amine and deprotection with TFA (method F above) provided the desired amines.

Example A77 !

WY ~

Amine was generated from 3-dimethylaminobenzyl alcohol as described in method

D above.

Example A48

Cl

S

Amine was generated by bromination of the corresponding methyl compound (Nussbaumer, P., et. al. J. Med Chem., 1991, 34, 65-73.). Conversion of the bromide to the amine was accomplished by azide displacement of the bromide followed by reduction as described in method D above.

Example A69

HY

Amine was generated by reduction of the corresponding methyl ester to the primary alcohol (Wipf, J. Org. Chem. 1994, 59, 4875-86.). Conversion to the bromide ’ (method E above) followed by displacement with diBOC amine and deprotection (method : F above) provided desired amine.

Example A70 and Example A71

Amines were generated from the corresponding carboxylic acids. Reduction of the : acid as described in method B above followed by bromide displacement as described in method E above gave the primary bromide. Conversion of the bromide to the primary amine followed the procedure described in method F above.

Example A74 :

Ww Y 2 \ d

Amine was generated from the primary alcohol as described in method D above.

Example A76

N

H NT

2 CJ

Amine was generated by first reduction of the corresponding aldehyde with sodium borohydride to the primary alcohol (Dondoni, J. Org. Chem. 1995, 60, 4749-54.). The alcohol was then converted to the amine as described in method D above.

Example A82 and Example A83

Oo 0)

Amines were generated by conversion of the primary alcohol as described in method D above. Tetrahydrofuran amine (Example A83) was the byproduct of over- reduction of A82.

Example A91 ) XN

H,N pS

Amine was generated from the corresponding carboxylic acid. Reduction of the acid as described in method B above gave the primary alcohol. The alcohol was then converted to the amine using the procedure described in method D above.

Example A92

Claims (43)

WE CLAIM:

1. A compound having the Formula I: . R® R? Rx , © Weg

V. R7 OR Aer z wherein: R'is an aliphatic, carbocyclic or heterocyclic group, or a group having the formula: OR" SR", NHR", NRHR" or C(O)R", wherein R" is an aliphatic, carbocyclic or heterocyclic group, and R' is H or a C,-Cy aliphatic group or R"and R" together with the atom to which they are attached form a substituted or unsubstituted heterocyclic ring; V is C=0, C=S or SO;; R?is an aliphatic group, a carbocyclic group, a carbocyclic-aliphatic group, a heterocyclic group, a heterocyclic-aliphatic group or N(R**)R?®, wherein R*is an aliphatic, carbocyclic or heterocyclic group, and R? is H or a C;-Cg aliphatic group; Wis N, O, C or CH; } when Wis N, C or CH, R” is H or a C;-Cg aliphatic group or R? and R? taken together with the atom W to which they are attached form an unsubstituted or substituted carbocyclic or heterocyclic ring; when Wis O, R? is absent; X is ~ rd } ls i ls or NN crv” , : where Y' and Y" are independently selected from H, halo, or a C;-Cg aliphatic group; nis 1or?2; R* is H or one or substituents independently selected from C,-Cs alkyl, nitro, amino, cyano, halogen, C,-Cs haloalkyl, hydroxyl, C,-Cs alkoxy, alkylenedioxy, C,-Cs alkylcarbonyl, C,-Cs alkyloxycarbonyl, C;-Cs alkylcarbonyloxy, carboxyl, carbamoyl, formyl, C,-Cs alkylamino, dialkylamino, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminothiocarbonyl, di-C;-Cs- alkylaminothiocarbonyl, C-Cs alkylsulfonyl, C;-Cq ) alkylsulfenyl, C,-Cq alkylcarbonylamino, C,-Cg alkylthiocarbonylamino, C;-C; ] alkylsulfonyloxy, C,-Cs alkylsulfonylamino, mercapto, and C;-Cs alkylthio; R® and R?® are each independently H, halo or a C,-C; aliphatic group; A is CH, CHR?) or is absent; Zis 8S, 0, SO, SO;, CH, CHF, CF,, CH(OH), CH(O-R?), CH(N-RZ R%), CH(S-R?), C(=0), or CH(R?), where R? is a C,-Cg aliphatic group or a carbocyclic or heterocyclic group and RZ is H or a C;-C aliphatic group; or R* and R?, taken together with A and Z form an unsubstituted or substituted 5 or 6 membered carbocyclic or heterocyclic ring; RlisHoraC 1-Ce aliphatic group; R? and R’ are independently selected from H, halo, a C,-Cs aliphatic group or a group having the formula C(O)R*, wherein R* is an aliphatic, carbocyclic or heterocyclic group; or R* and R’, taken together with the atom to which they are bound, form an unsubstituted or substituted carbocyclic ring; orR* and R®or R’, together with the atoms to which they are bound, form an unsubstituted or substituted carbocyclic ring; R®and R’ are independently selected from H, halo or a C,-Cg aliphatic group; or R® and R, taken together with the atom to which they are bound, form an unsubstituted or substituted carbocyclic or heterocyclic group; wherein any of said aliphatic groups are saturated, partially saturated or fully unsaturated and unsubstituted or substituted by one or more suitable substituents; and wherein any of said carbocyclic or heterocyclic groups are unsubstituted or substituted by one or more suitable substituents; saturated, partially unsaturated or fully unsaturated; or mono-, bi- or tri-cyclic; . provided that R? is not an aliphatic group, a phenyl group or a phenyl-substituted aliphatic group, when A is absent; Z is S, SO, SO,, CHF, O,or CH,; V is C=0;W is N; R?, R3 R®and R¥ are Hora C,-C, alkyl group; R*, R’>, R® and R” are Hor a Ci-Cs alkyl group; X oN : 1s R'is a substituted or unsubstituted 5 or 6-membered mono-cyclic carbocyclic . or heterocyclic group; or provided that R? is not t-butyl when R' is substituted or unsubstituted phenyloxymethylene, or quinolylmethylenecarbonylaminomethylene; A is absent; ZisS; Vis : C=0;W is N; R?, R®, RY R®, R® and R® are H; R®and R’ are H, methyl, ethyl or propyl; and Me Xis , wherein R” is H or methoxy, or a prodrug, pharmaceutically acceptable salt, pharmaceutically active metabolite, or pharmaceutically acceptable solvate thereof,

2. A compound having the Formula I-A: RE R? R® X o) / o) o) N—g2 PY R7 R! LL oR \ Pe R® I-A wherein: R'isan aliphatic group, a mono-, bi- or tri- cyclic carbocyclic or heterocyclic group or a group having the formula: OR", SR", NHR", N(R"R"" or C(O)R", wherein R" is an aliphatic, carbocyclic or heterocyclic group, and R'is H or a C;-Cs aliphatic group or R" and RY together with the atom to which they are attached form a substituted or unsubstituted heterocyclic ring; . R? is an aliphatic group, a carbocyclic — a carbocyclic-aliphatic group, a heterocyclic group, or a heterocyclic-aliphatic group; ’ R? is H or a C,-C; alkyl group; or R? and R? taken together with the nitrogen atom to which they are attached form an unsubstituted or substituted carbocyclic or heterocyclic ring;

Xis NN , gE , J ,or errr” , Wherein . Y' and Y" are independently selected from H, halo, or a C;-Cg aliphatic group, wherein R" is H or one or more substituents independently selected from alkyl, nitro, amino, cyano, halogen, haloalkyl, hydroxyl, alkoxy, alkylenedioxy, alkylcarbonyl, alkyloxycarbonyl, alkylcarbonyloxy, carboxyl, carbamoyl, formyl, alkylamino, dialkylamino, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminothiocarbonyl, dialkylaminothiocarbonyl, alkylsulfonyl, alkylsulfenyl, alkylcarbonylamino, alkylthiocarbonylamino, alkylsulfonyloxy, alkylsulfonylamino, mercapto, and alkylthio; nis lor2; R® and R® are each independently H, halo or a C,-Cj aliphatic group; Zis S, 0, SO, SO, CHa, CHF, CF,, CH(OH), CH(O-R?), CH(N-R? R%), CH(S-RH), C(=0), or CH(R?), where RZ is 2 C,-Cg aliphatic group or a carbocyclic or heterocyclic group and RZ is H or a C;-Cs aliphatic group; R’ is H or a C-Cg aliphatic group; R* and R® are independently selected from H, halo, a C,-Cq aliphatic group or a group having the formula C(O)R*, wherein R is an aliphatic, carbocyclic or heterocyclic group; R® and R’ are independently selected from H, halo or a C,-Cs aliphatic group; wherein any of said aliphatic groups are unsubstituted or substituted by one or more suitable substituents and saturated, partially unsaturated or fully unsaturated; and wherein any of said carbocyclic or heterocyclic groups are mono-, bi- or tri-cyclic saturated, partially unsaturated or fully unsaturated or unsubstituted or substituted by one or more suitable substituents; provided that R? is not an aliphatic group, a phenyl group or a phenyl-substituted aliphatic group, when Z is S, SO, SO,, O, CHF or CH,; R*, R>, R® and R¥ are Hor a Ci-Cqy . ® 4 nS pb 7 : gy 1. alkyl group; R", R°, R” and R’ are H or a C,-Cs alkyl group; X is andR' isa substituted or unsubstituted 5- or 6-membered mono-cyclic carbocyclic or heterocyclic group; or provided that R? is not t-butyl when R' is substituted or unsubstituted phenyloxymethylene, or quinolyimethylenecarbonylaminomethylene; Z is S; RY, R*, RY, R, "\¢ 8 8 6 7 . LL, RX § R” and R” are H; R” and R’ are H, methyl, ethyl or propyl; and X is , wherein R 1s H or methoxy, or a prodrug, pharmaceutically acceptable salt, pharmaceutically active metabolite, or : pharmaceutically acceptable solvate thereof.

3. The compound, prodrug, salt, metabolite, or solvate according to claim 2, wherein: R'is a 3-, 4-, or 7-membered mono-cyclic carbocyclic or heterocyclic group.

4. The compound, prodrug, salt, metabolite, or solvate according to claim 2, wherein: R'is a 5- or 6-membered monocyclic carbocyclic or heterocyclic group; and R? is cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, a bi- or tri-cyclic carbocyclic group, a bi- or tri-cyclic carbocyclic-alkyl group, a bi- or tri-cyclic carbocyclic- alkenyl group, a bi- or tri-cyclic carbocyclic-alkynyl group, a heterocyclic group, a heterocyclic-alkyl group, a heterocyclic-alkenyl group or a heterocyclic-alkynyl group.

5. The compound, prodrug, metabolite, salt, or solvate according to claim 2, wherein: R'is an aliphatic group, or a group having the formula: OR', SR", NHR", NRMR" or C(O)R", wherein R" is an aliphatic group, and R"" is Hor a C-C; aliphatic group or R" and R" together with the atom to which they are attached form a substituted or unsubstituted heterocyclic ring; . 8} ® _ Me [3 xis > F : ls gE or NY err” where Y' and Y" are independently selected from H, halo, or a C;-Cg aliphatic group; nis 1 or 2; and R” is H or one or more suitable substituents independently selected from

C,-Cs alkyl, nitro, amino, cyano, halogen, C;-Cg haloalkyl, hydroxyl, C,-Cg alkoxy, alkylenedioxy, C,-Cs alkylcarbonyl, C;-Cg alkyloxycarbonyl, C-Cs alkylcarbonyloxy, ‘ carboxyl, carbamoyl, formyl, C,-Cs alkylamino, di-C,-C¢ alkylamino, C,-Cg } alkylaminocarbonyl, di - C;-C;4 alkylaminocarbonyl, C;-Cs alkylaminothiocarbonyl, di-C;-Cs- alkylaminothiocarbonyl, C,-Cg alkylsulfonyl, C,-Cs alkylsulfenyl, C,-Cg¢ alkylcarbonylamino, Ci-Ce alkylthiocarbonylamino, C,-Cq alkylsulfonyloxy, C,-Cs alkylsulfonylamino, mercapto, C-Cs alkylthio and halo-C;-Cg alkylthio; and R® and R¥ are each independently H, halo or a C,-C, aliphatic group “\¢ provided that R” and R" are not both H when X is . :

6. The compound, prodrug, salt, metabolite, or solvate according to claim 2, wherein: R'is a bi- or tri-cyclic carbocyclic or heterocyclic group, wherein said carbocyclic or heterocyclic group is saturated, partially unsaturated or fully unsaturated; and unsaturated or substituted by one or more suitable substituents.

7. A compound having the Formula I-A": R? 0 * 9 AN Ng? R’ N N RS oR Ae R® I-A wherein:

. R' is an alkyl, alkenyl, or alkynyl group, a bi- or tri-cyclic cycloalkyl, cycloalkenyl, aryl, heterocycloalkyl, heterocycloalkenyl or heteroaryl group or a group having the formula:

. OR", SR", NHR", N(R")R" or C(O)R", wherein R" is an alkyl, alkenyl, or alkynyl group, a bi- or tri-cyclic cycloalkyl, cycloalkenyl, aryl, heterocycloalkyl, heterocycloalkenyl or heteroaryl group, or a cycloalkylalkyl, cycloalkenylalkyl, arylalkyl, heterocycloalkylalkyl, heterocycloalkenylalkyl, heteroarylalkyl, cycloalkylalkenyl, cycloalkenylalkenyl, arylalkenyl,

heterocycloalkylalkenyl, heterocycloalkenylalkenyl, heteroarylalkenyl, cycloalkylalkynyl, cycloalkenylalkynyl, arylalkynyl, heterocycloalkylalkynyl, heterocycloalkenylalkynyl, or heteroarylalkynyl group; and R"" is H or a C,-Cj alkyl, alkenyl or alkynyl group or R" and R" } together with the atom to which they are attached form a substituted or unsubstituted heterocyclic ring; R’isa cycloalkyl, cycloalkylalkyl, cycloalkenyl, or cycloalkenylalkyl group, a bi- or tri-cyclic aryl group, a bi- or tri-cyclic arylalkyl group, a bi- or tri-cyclic arylalkenyl group, a bi- or tri-cyclic arylalkynyl group, or a heterocycloalkyl, heterocycloalkylalkyl, heterocycloalkenyl, heterocycloalkenylalkyl, heteroaryl or heteroarylalkyl group; R? is H ora C;-Cg alkyl group; or R? and R? taken together with the nitrogen atom to which they are attached form a heterocycloalkyl or heterocycloalkenyl ring; ey Se PS pts OL QL, Qu Qo X is NY , os , = or evr” , wherein Y' and Y" are independently selected from H, halo, or a C;-Cg aliphatic group, wherein R* is H or one or more substituents independently selected from alkyl, nitro, amino, cyano, halogen, haloalkyl, hydroxyl, alkoxy, alkylenedioxy, alkylcarbonyl, alkyloxycarbonyl, alkylcarbonyloxy, carboxyl, carbamoyl, formyl, alkylamino, dialkylamino, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminothiocarbonyl, dialkylaminothiocarbonyl, alkylsulfonyl, alkylsulfenyl, alkylcarbonylamino, alkylthiocarbonylamino, alkylsulfonyloxy, alkylsulfonylamino, mercapto, and alkylthio; ZisS, 0, SO, SO, CH,, CHF, CF,, CH(OH), CH(O-R?), CH(N-R” R%), CH(S-R?), C(=0), or CH(RY), where RZ is a C,-Cs aliphatic group or a carbocyclic or heterocyclic group and R” isH ora C,-Ce aliphatic group; R? is H or a C,-Cj aliphatic group; R* and R’ are independently selected from H, halo, and a C,-Cg aliphatic group; . Ré and R are independently selected from H, halo and a C,-Cs aliphatic group; where any of the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocycloalkyl, heterocycloalkenyl or heteroaryl groups or the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocycloalkyl, heterocycloalkenyl or heteroaryl moieties of the cycloalkylalkyl, cycloalkenylalkyl, arylalkyl, heterocycloalkylalkyl, heterocycloalkenylalkyl, heteroarylalkyl, cycloalkylalkenyl, cycloalkenylalkenyl, arylalkenyl, ’ heterocycloalkylalkenyl, heterocycloalkenylalkenyl, heteroarylalkenyl, cycloalkylalkynyl, cycloalkenylalkynyl, arylalkynyl, heterocycloalkylalkynyl, heterocycloalkenylatkynyl, and heteroarylalkynyl groups are unsubstituted or substituted by one or more suitable substituents; and : where any of said carbocyclic or heterocyclic groups are mono-, bi- or tri-cyclic; saturated, partially unsaturated or fully unsaturated, and unsubstituted or substituted by one or more suitable substituents; provided that R? is not an aliphatic group, a phenyl group or a phenyl-substituted aliphatic group, when Z is S, SO, SO,, O, CHF or CH; R” and Rare Hora C,-Cq4 alkyl "\¢ 4 pS pb 7 . LL, Is group; R*, R°, R” and Rare H or a C,-C; alkyl group; X is andR isa substituted or unsubstituted 5 or 6-membered mono-cyclic carbocyclic or heterocyclic group; or provided that R? is not t-butyl when R' is substituted or unsubstituted phenyloxymethylene, or quinolylmethylenecarbonylaminomethylene; ZisS; RZ, R3, R® and "\¢ Rare H; R” and R" are H, methyl, ethyl or propyl; and X is , wherein Ris H or methoxy, : or a prodrug, pharmaceutically acceptable salt, pharmaceutically active metabolite, or pharmaceutically acceptable solvate thereof.

8. The compound, prodrug, salt, metabolite, or solvate according to claim 7, wherein: Z is CF,, CH(OH), CH(O-R?), CH(N-R?R?), CH(S-R?), C=0 or CH(R?), where RZ is a C-Ce aliphatic group or a carbocyclic or heterocyclic group and RZ is H a C,;-Cq aliphatic group.

:

9. A compound having the Formula I-B:

R® R? RE X 0) 0 0 R? . PY R7 ’ oR A R® I-B wherein: R'isan aliphatic, carbocyclic or heterocyclic group, or a group having the formula: OR", SR", NHR", N(R")R" or C(O)R", wherein R" is an aliphatic, carbocyclic or heterocyclic group, and R"" is H or a C,-Cy aliphatic group or R" and R"" together with the atom to which they are attached form a substituted or unsubstituted heterocyclic ring; Ris an aliphatic group, a carbocyclic group, a carbocyclic-aliphatic group, a heterocyclic group, or a heterocyclic-aliphatic group; RZisHora C,-Cs aliphatic group; or R? and R? taken together with the carbon atom to which they are attached form an unsubstituted or substituted carbocyclic ring; Bey Tey Te ps SHeN eel X is NT , | ot , ~~ 4 ,or ~~ evr” , wherein Y' and Y" are independently selected from H, halo, or a C,-Cq aliphatic group; nis 1 or 2; and R* is H or one or more substituents independently selected from alkyl, nitro, amino, cyano, halogen, haloalkyl, hydroxyl, alkoxy, alkylenedioxy, alkylcarbonyl, alkyloxycarbonyl, alkylcarbonyloxy, carboxyl, carbamoyl, formyl, alkylamino, dialkylamino, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminothiocarbonyl, dialkylaminothiocarbonyl, alkylsulfonyl, alkylsulfenyl, alkylcarbonylamino, alkylthiocarbonylamino, alkylsulfonyloxy, alkylsulfonylamino, mercapto, and alkylthio; R® and RY are each independently H, halo or a C,-Cj aliphatic group; Zis 8, 0, SO, SO, CHF, CH,, CF,, CH(OH), CH(O-R?), CH(N-RZ R%), ’ CH(S-R?), C(=0), or CH(R?), where Ris a Cy-Cq aliphatic group or a carbocyclic or heterocyclic group and RZ is H or a C;-Cy aliphatic group; R? is H or a C,-Cg aliphatic group;

R* and R® are independently selected from H, halo, a C;-Cs aliphatic group or a group having the formula C(O)R*, wherein R* is an aliphatic, carbocyclic or heterocyclic group; R® and R’ are independently selected from H, halo or a C,-Cs aliphatic group; } where any of said aliphatic groups are saturated, partially saturated or fully unsaturated and unsubstituted or substituted by one or more suitable substituents; and where any of said carbocyclic or heterocyclic groups are unsubstituted, or substituted by one or more suitable substituents; saturated, partially unsaturated or fully unsaturated; or mono-, bi- or tri-cyclic; : or a prodrug, pharmaceutically active metabolite or pharmaceutically active salt or solvate thereof.

10. A compound having the Formula I-C: R® x X 0 ; 0 o) W—g?

x . R! JL oR A R? I-C wherein: R'is an aliphatic, carbocyclic or heterocyclic group, or a group having the formula: OR", SR", NHR", N(R")R"" or C(O)R", wherein R" is an aliphatic, carbocyclic or heterocyclic group, and R" is H or a C;-Cg aliphatic group or R" and R" together with the atom to which they are attached form a substituted or unsubstituted heterocyclic ring; R? is an aliphatic group, a carbocyclic group, a carbocyclic-aliphatic group, a heterocyclic group, or a heterocyclic-aliphatic group; WisN,OorC; when W is N or C, R? is H or a C;-Cj alkyl group or R? and R? taken together with the atom W to which they are attached form an unsubstituted or substituted carbocyclic or . heterocyclic ring; when W is O, R? is absent;

"\¢ RX RY RY X is id , ot , N ss ,or errr” , wherein , Y' and Y" are independently selected from H, halo, or a C,-Cq aliphatic group; nis 1 or 2; and R* is H or one or more substituents independently selected from alkyl, nitro, amino, cyano, halogen, haloalkyl, hydroxyl, alkoxy, alkylenedioxy, alkylcarbonyl, alkyloxycarbonyl, : alkylcarbonyloxy, carboxyl, carbamoyl, formyl, alkylamino, dialkylamino, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminothiocarbonyl, dialkylaminothiocarbonyl, alkylsulfonyl, alkylsulfenyl, alkylcarbonylamino, alkylthiocarbonylamino, alkylsulfonyloxy, alkylsulfonylamino, mercapto, and alkylthio; R® and R® are each independently H, halo or a C,-C, aliphatic group; Z is CF,, CH(OH), CH(O-R%) or CH(R?), where R% is a C-Cg aliphatic group or a carbocyclic or heterocyclic group; R* is Hor a C)-Ce aliphatic group; R* and R’ are independently selected from H, halo, a C;-Cs aliphatic group or a group having the formula C(O)R?, wherein R? is an aliphatic, carbocyclic or heterocyclic group; R® and R’ are independently selected from H, halo or a C;-Cj aliphatic group; where any of said aliphatic groups are saturated, partially saturated or fully unsaturated and unsubstituted or substituted by one or more suitable substituents; and where any of said carbocyclic or heterocyclic groups are unsubstituted or substituted by one or more suitable substituents; saturated, partially unsaturated or fully unsaturated; mono-, bi- or tri-cyclic; or a prodrug, pharmaceutically active metabolite or pharmaceutically active salt or solvate thereof.

11. A compound having the Formula I-D:

rR il X 0 ; 0 0 W—g? EN SNE R® 1-D wherein: R'is an aliphatic, carbocyclic or heterocyclic group, or a group having the formula: OR", SR", NHR", N(R"R" or C(O)R", wherein R" is an aliphatic, carbocyclic or heterocyclic group, and R" is H or a C,-Cj aliphatic group or R"and R"" together with the atom to which they are attached form a substituted or unsubstituted heterocyclic ring; R? is an aliphatic group, a carbocyclic group, a carbocyclic-aliphatic group, a heterocyclic group, or a heterocyclic-aliphatic group; Wis N, O or C; when W is N or C, R* is H or a C,-Cg alkyl group or R? and R? taken together with the atom W to which they are attached form an unsubstituted or substituted carbocyclic or heterocyclic ring; : when Wis O, R? is absent; Tey Ben Se pt Og Oe QL X is ~ , ~ os , | oh ,or N cry” , wherein Y' and Y" are independently selected from H, halo, or a C;-Cg aliphatic group; nis 1 or 2; and R* is H or one or more substituents independently selected from alkyl, nitro, amino, cyano, halogen, haloalkyl, hydroxyl, alkoxy, alkylenedioxy, alkylcarbonyl, alkyloxycarbonyl, alkylcarbonyloxy, carboxyl, carbamoyl, formyl, alkylamino, dialkylamino, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminothiocarbonyl, : dialkylaminothiocarbonyl, alkylsulfonyl, alkylsulfenyl, alkylcarbonylamino, alkylthiocarbonylamino, alkylsulfonyloxy, alkylsulfonylamino, mercapto, and alkylthio; ’ | R® and R¥ are each independently H, halo or a C,-C, aliphatic group; ZisS, 0, SO, SO, CH,, CF,, CHF, CH(OH), CH(O-R?%), CH(N-R? R?%), CH(S-RY), C(=0), or CH(R?Y), where RZ is a C;-Cs aliphatic group or a carbocyclic or heterocyclic group and RZ is Hor a C,-Cq aliphatic group; R’isHora C,-Cs aliphatic group; R* and R® are independently selected from H, halo, a C,-Cs aliphatic group or a group having the formula C(O)R?, wherein R* is an aliphatic, carbocyclic or heterocyclic group; R® and R7 are independently selected from H, halo or a C,-Cg aliphatic group; where any of said aliphatic groups are saturated, partially saturated or fully unsaturated and unsubstituted or substituted by one or more suitable substituents; and where any of said carbocyclic or heterocyclic groups are unsubstituted or substituted by one or more suitable substituents; saturated, partially unsaturated or fully unsaturated; or mono-, bi- or tri-cyclic; or a prodrug, pharmaceutically active metabolite or pharmaceutically active salt or solvate thereof.

12. A compound having the Formula I-E: RE R2 : o R® x 0 “ re PN R' N ny OR? ee RY NeHan 1p wherein: R! is an aliphatic, carbocyclic or heterocyclic group, or a group having the formula: OR", SR", NHR", N(R"R"" or C(O)R", wherein R" is an aliphatic, carbocyclic or heterocyclic group, and R"" is H or a C;-Cg aliphatic group or R" and R" together with the atom to which they are attached form a substituted or unsubstituted heterocyclic ring; R? is an aliphatic group, a carbocyclic group, a carbocyclic-aliphatic group, a ] heterocyclic group, or a heterocyclic-aliphatic group; WisN,OorC; : when W is N or C, R? is H or a C;-Cs alkyl group or R? and R? taken together with the atom W to which they are attached form an unsubstituted or substituted carbocyclic or heterocyclic ring; when W is O, R%is absent;

X is ¥ , ~~ os , ,or crv” , wherein } Y' and Y" are independently selected from H, halo, or a C,-C aliphatic group, wherein R* is H or one or more substituents independently selected from alkyl, nitro, amino, cyano, halogen, haloalkyl, hydroxyl, alkoxy, alkylenedioxy, alkylcarbonyl, alkyloxycarbonyl, alkylcarbonyloxy, carboxyl, carbamoyl, formyl, alkylamino, dialkylamino, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminothiocarbonyl, dialkylaminothiocarbonyl, alkylsulfonyl, alkylsulfenyl, alkylcarbonylamino, alkylthiocarbonylamino, alkylsulfonyloxy, alkylsulfonylamino, mercapto, and alkylthio; R® and R® are each independently H, halo or a C,-C,4 aliphatic group; Zis §, 0, SO, SO,, CH,, CHF, CF,, CH(OH), CH(O-R?), CH(N-R? R%), CH(S-R?), C(=0), or CH(R?), where RZ is a C,-Cs aliphatic group or a carbocyclic or heterocyclic group and RZ is H or a C,-Cq aliphatic group; nis 1or2; R*is Hora C,-C aliphatic ’group; R‘ is selected from H, halo, a C,-Cq aliphatic group or a group having the formula C(O)R*, wherein R* is an aliphatic, carbocyclic or heterocyclic group; R’ is H, halo or a C,-C aliphatic group; where any of said aliphatic groups are saturated, partially unsaturated or fully unsaturated and unsubstituted or substituted by one or more suitable substituents; and where any of said carbocyclic or heterocyclic groups are unsubstituted or substituted by one or more suitable substituents, saturated, partially unsaturated or fully unsaturated or mono-, bi- or tri-cyclic; or a prodrug, pharmaceutically active metabolite or pharmaceutically active salt or solvate thereof.

13. A compound having the Formula I-F:

RE R? : PR 7 R' N N RS OR? \ R RS "IF wherein: R'isan aliphatic, carbocyclic or heterocyclic group, or a group having the formula: OR", SR", NHR", N(R")R" or C(O)R", wherein R" is an aliphatic, carbocyclic or heterocyclic group, and R" is H or a C,-C; aliphatic group or R"and R" together with the atom to which they are attached form a substituted or unsubstituted heterocyclic ring; R? is an aliphatic group, a carbocyclic group, a carbocyclic-aliphatic group, a heterocyclic group, or a heterocyclic-aliphatic group; WisN,OorC; when W is N or C, R% is H or a C,-Cy alkyl group or R? and R? taken together with the atom W to which they are attached form an unsubstituted or substituted carbocyclic or heterocyclic ring; : when W is O, R? is absent; Xis h ¥ , ot , 5% ,or N ery” , wherein Y' and Y" are independently selected from H, halo, or a C,-Cs aliphatic group, wherein R* is H or one or more substituents independently selected from alkyl, nitro, amino, cyano, halogen, haloalkyl, hydroxyl, alkoxy, alkylenedioxy, alkylcarbonyl, alkyloxycarbonyl, alkylcarbonyloxy, carboxyl, carbamoyl, formyl, alkylamino, dialkylamino, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminothiocarbonyl, dialkylaminothiocarbonyl, alkylsulfonyl, alkylsulfenyl, alkylcarbonylamino, . alkylthiocarbonylamino, alkylsulfonyloxy, alkylsulfonylamino, mercapto, and alkylthio; nisl or2; nis or2; R? is H or a C,-Cj aliphatic group;

R* and R® are independently selected from H, halo, a C;-Cg aliphatic group or a group having the formula C(O)R*, wherein R* is an aliphatic, carbocyclic or heterocyclic group; R® and R are independently selected from H, halo or a C,-Cs aliphatic group; R® and R¥ are each independently H, halo or a C,-C; aliphatic group; where any of said aliphatic groups are saturated, partially unsaturated or fully unsaturated and unsubstituted or substituted by one or more suitable substituents; and where any of said carbocyclic or heterocyclic groups are unsubstituted or substituted by one or more suitable substituents; saturated, partially unsaturated or fully unsaturated; or mono-, bi- or tri-cyclic; or a prodrug, pharmaceutically active metabolite or pharmaceutically active salt or solvate thereof.

14. A compound having the Formula I-G: R® rR? R® X 0 / Q o W—g? oR Je ’ R® I-G wherein: R' is an aliphatic, carbocyclic or heterocyclic group, or a group having the formula: OR", SR', NHR', NRHRY or C(O)R', wherein R" is an aliphatic, carbocyclic or heterocyclic group, and R'" is H or a C,-Cg aliphatic group or R"and R" together with the atom to which they are attached form a substituted or unsubstituted heterocyclic ring; R%is an aliphatic group, a carbocyclic group, a carbocyclic-aliphatic group, a heterocyclic group, or a heterocyclic-aliphatic group; . WisN,OorC; when Wis Nor C, R¥ is H or a C;-Cs alkyl group or R? and R? taken together with ’ the atom W to which they are attached form an unsubstituted or substituted carbocyclic or heterocyclic ring; when Wis O, R¥ is absent;

Xis h i , os , J ,or crv” , wherein ] Y'and Y" are independently selected from H, halo, or a C,-Cg aliphatic group, wherein R* is H or one or more substituents independently selected from alkyl, nitro, amino, cyano, halogen, haloalkyl, hydroxyl, alkoxy, alkylenedioxy, alkylcarbonyl, alkyloxycarbonyl, alkylcarbonyloxy, carboxyl, carbamoyl, formyl, alkylamino, dialkylamino, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminothiocarbonyl, dialkylaminothiocarbonyl, alkylsulfonyl, alkylsulfenyl, alkylcarbonylamino, alkylthiocarbonylamino, alkylsulfonyloxy, alkylsulfonylamino, mercapto, and alkylthio; R® and R* are each independently H, halo or a C,-C, aliphatic group; Zis S, 0, SO, SO,, CH,, CHF, CF,, CH(OH), CH(O-R?), CH(N-R? R?), CH(S-R?), C(=0), or CH(R?), where R% is a C;-Cg aliphatic group or a carbocyclic or heterocyclic group and R” is H or a C;-C aliphatic group; nisl, 2,3 ord; n'islor2; Ris H ora C;-C aliphatic group; R* and R* are independently selected from H, halo, a C,-Ce aliphatic group or a group having the formula C(O)R, wherein R* is an aliphatic, carbocyclic or heterocyclic group; where any of said aliphatic groups are saturated, partially unsaturated or fully unsaturated and unsubstituted or substituted by one or more suitable substituents; and where any of said carbocyclic or heterocyclic groups are unsubstituted or substituted by one or more suitable substituents; saturated, partially unsaturated or fully unsaturated; or mono-, bi- or tri-cyclic; or a prodrug, pharmaceutically active metabolite or pharmaceutically active salt or solvate thereof.

15. A compound having the Formula I-B":

R? 0 4: 0) er . PY R7 : oR ) A R® I-B' wherein: R'is an aliphatic, carbocyclic or heterocyclic group, R’is an aliphatic group, a carbocyclic-aliphatic group, or a heterocyclic-aliphatic group; R¥isHora C,-Cs alkyl group; or R?and R? taken together with the carbon atom to which they are both attached form an unsubstituted or substituted carbocyclic ring; lL 1 : Xis ~ ed or s” % wherein R* is H or one or more substituents independently selected from alkyl, nitro, amino, cyano, halogen, haloalkyl, hydroxyl, alkoxy, alkylenedioxy, alkylcarbonyl, alkyloxycarbonyl, alkylcarbonyloxy, carboxyl, carbamoyl, formyl, alkylamino, dialkylamino, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminothiocarbonyl, dialkylaminothiocarbonyl, alkylsulfonyl, alkylsulfenyl, alkylcarbonylamino, alkylthiocarbonylamino, alkylsulfonyloxy, alkylsulfonylamino, mercapto, and alkylthio; Zis§, 0, SO, SO,, CHF, CH,, CF,, C(=0), or CH(RY), where R%isa C 1-Cs aliphatic group or a carbocyclic or heterocyclic group; R? is H or a C;-Cg aliphatic group; . R* and R® are independently selected from H, halo, or a C;-Cg aliphatic group; R®and R are independently selected from H, halo or a C,-Cq aliphatic group; ) wherein any of said aliphatic groups are saturated, partially unsaturated or fully unsaturated and unsubstituted or substituted by one or more suitable substituents; and wherein any of said carbocyclic or heterocyclic groups are unsubstituted or substituted by one or more suitable substituents; saturated, partially unsaturated or fully unsaturated; or mono-, bi- or tri-cyclic; ; or a prodrug, pharmaceutically acceptable salt, pharmaceutically active metabolite, or pharmaceutically acceptable solvate thereof.

16. The compound, prodrug, salt, metabolite or solvate according to claim 15, wherein: R'is a carbocyclic group, R?is a C}-C aliphatic group or a carbocyclic- C;-Cg -aliphatic group; ZisS, Q, CH,, CF»; R? R* and R® are each H; R®and R’ are each a C,-C aliphatic group; wherein any of said aliphatic groups are saturated, partially unsaturated or fully unsaturated and unsubstituted or substituted by one or more suitable substituents; and wherein any of said carbocyclic or heterocyclic groups are unsubstituted or substituted by one or more suitable substituents; saturated, partially unsaturated or fully unsaturated; or mono-, bi- or tri-cyclic.

17. The compound, prodrug, salt, metabolite, or solvate according to claim 15, wherein: R'is a phenyl group, unsubstituted or substituted with one or more substituents selected from alkyl, hydroxyl, halo, halo alkyl, haloalkoxy, methylene dioxy, and di- fluoromethylene dioxy; R? is an alkenyl group, an aralkyl group or a straight or branched chain saturated alkyl; "\¢

ROT. : Xis where R” is H; ZisS; rR, R* and R® are each H; and R® and R7 are each methyl; wherein any of said alkenyl, aralkyl, or alkyl groups are unsubstituted or substituted with one or more substituents, independently selected from methyl, halo, trifluoromethyl or methoxy.

18. The compound, prodrug, salt, metabolite, or solvate according to claim 15, wherein: R' is a phenyl group, unsubstituted or substituted with one or more substituents selected from alkyl, hydroxyl, halo, halo alkyl, haloalkoxy, methylene dioxy, and di- fluoromethylene dioxy; R? is an alkenyl group, an aralkyl group or straight or branched chain saturated alkyl; "\¢ NOV Xis where R* is H; Z is CFy; rR} , R* and R® are each H; and : R® and R’ are each methyl; wherein any of said alkenyl, aralkyl, or alkyl groups are unsubstituted or substituted with one or more substituents, independently selected from methyl, halo, trifluoromethyl or methoxy.

19. A compound having the Formula I-C*: R2 0 x 0 > Wg LLL Te RON aA OR A R® 1-C' wherein: R'is an aliphatic, carbocyclic or heterocyclic group, or a group having the formula: . OR", wherein R'is a carbocyclic or heterocyclic group; R? is an aliphatic group, a carbocyclic group, a carbocyclic-aliphatic group, a heterocyclic group, or a heterocyclic-aliphatic group; Wis N;

R¥is Hora C;-Cg alkyl group; NY xi a Xs , wherein R” is H; dialkylaminocarbonyl, alkylaminothiocarbonyl, dialkylaminothiocarbonyl, alkylsulfonyl, alkylsulfenyl, alkylcarbonylamino, alkylthiocarbonylamino, alkylsulfonyloxy, alkylsulfonylamino, mercapto, or alkylthio; Z is CF,, CH(OH) or C(=0); R? , R? and R® are each H; and R® and R are each methyl; or a prodrug, pharmaceutically acceptable salt, pharmaceutically active metabolite, or pharmaceutically acceptable solvate thereof.

20. The compound, prodrug, salt, metabolite, or solvate according to claim 19, wherein: R'is an aryl group, an aryloxyalkyl group, an alkynyloxy group, a heterocycloalkyloxy group or heteroaryl group; R? is an alkyl, alkenyl, or alkynyl group, an arylalkyl group; a heteroarylalkyl group, an indanyl group, a chromanyl group, a tetrahydronaphthalene group, an aliphatic group, a carbocyclic group, a carbocyclic-aliphatic group, a heterocyclic group, or a heterocyclic- aliphatic group; R?% is H; wherein the alkyl, alkenyl, alkynyl, arylalkyl; heteroarylalkyl, indanyl, chromany! or tetrahydronaphthalene group is unsubstituted or substitutes with one or more substituents independently selected from alkyl, hydroxy, halo, haloalkyl, cyano, alkoxy or methylenedioxy. ’ 21. The compound, prodrug, salt, metabolite, or solvate according to claim 19, wherein: R'isa phenyl group, a phenyoxymethyl group, a tetrahydrofuranyloxy group, a C,-C, alkynyloxy group, or a isoxazolyl group, where the phenyl group, phenyoxymethyl group or isoxazoly!l group is unsubstituted or substituted by hydroxyl or methyl;

Ris an C)-Cs alkyl, C,-Cs alkenyl, or C,-C, alkynyl group, a benzyl group; a furanylmethyl group, a thienylmehtyl group, an indanyl group, a chromanyl group, a tetrahydronaphthalene group, or a cyclohexenyl group, where the alkyl groups is unsubstituted or substituted with one or more halogen; and the phenyl group is unsubstituted or substituted with halogen, hydroxyl, methoxy, methylenedioxy or methyl; R? is H; "\¢ NOV Xis . wherein R" is H; and Z is CF.

22. A compound having the Formula I-D’: Rr? 0 “0 ° Weg x : OR® A 7 R* 5 R I-D’ wherein: R! is a carbocyclic or heterocyclic group, R? is an aliphatic group, a carbocyclic group, a carbocyclic-aliphatic group, a heterocyclic group, or a heterocyclic-aliphatic group; WisN,R”isHora C,-Cs alkyl! group; \¢ X is , wherein R™ is H or one or more substituents independently selected : from alkyl, nitro, amino, cyano, halogen, haloalkyl, hydroxyl, alkoxy, alkylenedioxy, alkylcarbonyl, alkyloxycarbonyl, alkylcarbonyloxy, carboxyl, carbamoyl, formyl, alkylamino, dialkylamino, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminothiocarbonyl, dialkylaminothiocarbonyl, alkylsulfonyl, alkylsulfenyl, alkylcarbonylamino, alkylthiocarbonylamino, alkylsulfonyloxy, alkylsulfonylamino, mercapto, alkylthio;

Z is 0, CH,, CHF, CF,, or CH(R?), where R% is a C1-Cs aliphatic group; nis 1 or2; R®, R* and R® are each H; Ris H; wherein any of said aliphatic groups are saturated, partially unsaturated or fully unsaturated and unsubstituted or substituted by one or more suitable substituents; and wherein any of said carbocyclic or heterocyclic groups are unsubstituted or substituted by one or more suitable substituents; saturated, partially unsaturated or fully unsaturated; or mono-, bi- or tri-cyclic; or a prodrug, pharmaceutically acceptable salt, pharmaceutically active metabolite, or pharmaceutically acceptable solvate thereof.

23. A compound having the Formula I-E’: R2 Ne x 0 ° dep

A . OR? ez R* CHn Lp wherein R' is a carbocyclic or heterocyclic group, Ris an aliphatic group, a carbocyclic group, a carbocyclic-aliphatic group, a heterocyclic group, or a heterocyclic-aliphatic group; Wis N; R% is H or a C;-Cg alkyl group; "\ J X is , Wherein R” is H or one or more substituents independently selected ' from alkyl, nitro, amino, cyano, halogen, haloalkyl, hydroxyl, alkoxy, alkylenedioxy, alkylcarbonyl, alkyloxycarbonyl, alkylcarbonyloxy, carboxyl, carbamoyl, formyl, alkylamino, dialkylamino, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminothiocarbonyl,

dialkylaminothiocarbonyl, alkylsulfonyl, alkylsulfenyl, alkylcarbonylamino, alkylthiocarbonylamino, alkylsulfonyloxy, alkylsulfonylamino, mercapto, and alkylthio; ’ Z is O, CH,, CHF, CF», or CH(R?), where R% is a C;-Cg aliphatic group; nis lor2; R’, R* and R® are each H; and Ris H; wherein any of said aliphatic groups are saturated, partially unsaturated or fully unsaturated and unsubstituted or substituted by one or more suitable substituents; and wherein any of said carbocyclic or heterocyclic groups are unsubstituted or substituted by one or more suitable substituents; saturated, partially unsaturated or fully unsaturated; or mono-, bi- or tri-cyclic; : or a prodrug, pharmaceutically acceptable salt, pharmaceutically active metabolite, or pharmaceutically acceptable solvate thereof.

24. The compound, prodrug, salt, metabolite, or solvate according to claims 22 or 23, wherein: R'is a carbocyclic group; R?is an arylalkyl group; R” is H; "\¢ ’ 3g! X is NT ¥ , wherein R* is H; and Z 1s CH,. wherein said carbocyclic group and arylalkyl group are unsubstituted or substituted with one or more substituents selected from methyl, halo, or hydroxy.

25. A compound having the Formula I-F:

R? 0 x 0 : Weg A wv R' 278% OR? R* iE

"LF wherein:

R'is a carbocyclic or heterocyclic group,

R’isan aliphatic group, a carbocyclic group, a carbocyclic-aliphatic group, a heterocyclic group, or a heterocyclic-aliphatic group;

Wis N;

R¥is Hora C,-C alkyl group;

"\¢ )

X is , wherein R™ is H or one or more substituents independently selected from alkyl, nitro, amino, cyano, halogen, haloalkyl, hydroxyl, alkoxy, alkylenedioxy, alkylcarbonyl, alkyloxycarbonyl, alkylcarbonyloxy, carboxyl, carbamoyl, formyl, alkylamino, dialkylamino, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminothiocarbonyl, dialkylaminothiocarbonyl, alkylsulfonyl, alkylsulfenyl, alkylcarbonylamino, alkylthiocarbonylamino, alkylsulfonyloxy, alkylsulfonylamino, mercapto, and alkylthio;

nislor2; .

rR? , R* and R® are each H; and

Ris H;

wherein any of said aliphatic groups are saturated, partially unsaturated or fully unsaturated and unsubstituted or substituted by one or more suitable substituents; and wherein any of said carbocyclic or heterocyclic groups are unsubstituted or substituted , by one or more suitable substituents; saturated, partially unsaturated or fully unsaturated; or mono-, bi- or tri-cyclic; or a prodrug, pharmaceutically acceptable salt, pharmaceutically active metabolite, or pharmaceutically acceptable solvate thereof.

26. The compound, prodrug, salt, or metabolite according to claim 25, wherein: R'is a carbocyclic group; R? is an arylalkyl group; R* is H; and "\v¢ RSV X is , Wherein R* is H; wherein said carbocyclic group and arylalkyl group are unsubstituted or substituted with one or more substituents selected from methyl, halo, or hydroxy.

27. A compound having the Formula I-G": R? 0 x 0] ° na OR Pe ’ R® I-G' wherein: Risa carbocyclic or heterocyclic group, R? is an aliphatic group, a carbocyclic group, a carbocyclic-aliphatic group, a heterocyclic group, or a heterocyclic-aliphatic group; WisN or C; R%isH or C,-Cs alkyl group; “\¢ : Xis , wherein R* is H or one or more substituents independently selected from alkyl, nitro, amino, cyano, halogen, haloalkyl, hydroxyl, alkoxy, alkylenedioxy, alkylcarbonyl, alkyloxycarbonyl, alkylcarbonyloxy, carboxyl, carbamoyl, formyl, alkylamino, dialkylamino, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminothiocarbonyl, dialkylaminothiocarbonyl, alkylsulfonyl, alkylsulfenyl, alkylcarbonylamino,

alkylthiocarbonylamino, alkylsulfonyloxy, alkylsulfonylamino, mercapto, and alkylthio; Zis S, 0, CH», CHF, CF», or CH(R?), where R? is a C,-Cs aliphatic group; nis 2,3 or4; R3 ,R* and R® are each H; wherein any of said aliphatic groups are saturated, partially unsaturated or fully unsaturated and unsubstituted or substituted by one or more suitable substituents; and wherein any of said carbocyclic or heterocyclic groups are unsubstituted or substituted by one or more suitable substituents; saturated, partially unsaturated or fully unsaturated; or mono-, bi- or tri-cyclic; ora prodrug, pharmaceutically acceptable salt, pharmaceutically active metabolite, or pharmaceutically acceptable solvate thereof.

28. The compound, prodrug, salt, metabolite, or salt according to claim 27, wherein: R'isa carbocyclic group; R%is an arylalkyl group; Wis N; R¥ is H; Me RO Xis , wherein R* is H; and Z is CH;; wherein said carbocyclic group and arylalkyl group are unsubstituted or substituted with one or more substituents selected from methyl, halo, or hydroxy.

29. The compound, prodrug, salt, metabolite, or solvate according to claim 27, wherein: R' is a carbocyclic group; R?is an arylalkyl group; Wis N; R? is H;

RX ING Xis , wherein R* is H; and Z 1s CF; wherein said carbocyclic group and arylalkyl group are unsubstituted or substituted with one or more substituents selected from methyl, halo, or hydroxy. :

30. The compound, prodrug, salt, metabolite, or solvate according to claim 27, wherein: Risa carbocyclic group; R’ is an arylalkyl group; Wis N; R? is H; “\¢ X is , wherein R* is H; and ZisS; wherein said carbocyclic group and arylalkyl group are unsubstituted or substituted with one or more substituents selected from methyl, halo, or hydroxy.

31. The compound, prodrug, pharmaceutically acceptable salt, pharmaceutically active metabolite, or pharmaceutically acceptable solvate according to claim 1, having the formula: Rr? Re R® X 0 0 W— Rr?

7

V. ! R

1.77 . R N N RE . rR? as A

32. The compound, prodrug, pharmaceutically acceptable salt, pharmaceutically active metabolite, or pharmaceutically acceptable solvate according to claim 1, having the ’ formula: RE Re 8 o R X fa) W—_ rR?

7

V. R ON rR! N N A " OR? Zz 4 ~~ R RS A

33. The compound, prodrug, pharmaceutically acceptable salt, pharmaceutically active metabolite, or pharmaceutically acceptable solvate according to claim 1, having the formula: RY R? R® X 0 /

7

V. / R ZN “, R N N fort OR’ A z

R .

34. A pharmaceutical composition comprising: a therapeutically effective amount of at least one HIV agent selected from compounds, prodrugs, pharmaceutically acceptable salts, pharmaceutically active metabolites, and pharmaceutically acceptable solvates defined in any one of claims 1,2,9,10,11, 12,13, 14, 15, 19,22,23, 25 or 27; and a pharmaceutically acceptable carrier, diluent, vehicle, or excipient. ’

35. The pharmaceutical composition according to claim 34, wherein the composition further comprises a therapeutically effective amount of at least one HIV infection/AIDS treatment agent selected from the group consisting of HIV/AIDS antiviral agents, immunomodulators, and anti-infective agents.

36. The pharmaceutical composition according to claim 35, wherein the composition further comprises a therapeutically effective amount of at least one antiviral agent selected from the group consisting of non-nucleoside HIV reverse transcriptase inhibitors and nucleoside HIV reverse transcriptase inhibitors.

37. The pharmaceutical composition according to claim 36, further comprising a therapeutically effective amount of at least one HIV protease inhibitor.

38. Use of at least one compound, prodrug, pharmaceutically acceptable salt, pharmaceutically active metabolite, or pharmaceutically acceptable solvate defined in any one of claims 1, 2, 9, 10, 11, 12, 13, 14, 15, 19, 22, 23, 25 or 27 in the manufacture ofa medicament for treating a mammalian disease condition mediated by HIV protease activity.

39. Use of at least one compound, prodrug, pharmaceutically acceptable salt, pharmaceutically active metabolite, or pharmaceutically acceptable solvate defined in any one of claims 1, 2,9, 10, 11, 12, 13, 14, 15, 19, 22, 23, 25 or 27 in the manufacture ofa ; medicament for inhibiting the activity of HIV protease, wherein the HIV protease is contacted with the compound prodrug, pharmaceutically acceptable sal, pharmaceutically active : metabolite or pharmaceutically acceptable solvate.

40. Use of a compound according to any one of claims 1, 2, 9, 10, 11, 12, 13, 14, 15, 19, 22, 23, 25 or 27 in the manufacture of a medicament for preventing or treating infection by HIV.

41. Use according to claim 40, wherein the compound is administered in combination with a therapeutically effective amount of at least one HIV infection/AIDS treatment agent selected from the group consisting of HIV/AIDS antiviral agents, -immunomodulators, and anti-infective agents. NY_MAIN 263533_1

42. A compound selected from: SL 1 O Sl. oO 0] SL 0) 0] SL 0) 0) F* °F F 2 FF 0) 0 0 0 SL 0 0 0 0 J SL SoA Aon SoA Ao, o 0 OH oP nom 7 , Fm oN" (XK Oo 0] Oo 0 S| Oo 0 SA, Hobs 0 n—Hon LAD), N : . and I ’ wherein n is an integer from 0 to 6.

43. A compound selected from: 0 0] 0) 0 0] 10) HO Av" NN HO N NN _ H oH (AH H oH (KH J oO 0] 0 0] 0 0] . HO p 4G, HO p rs Ho on {XH H OH og H (&~

0 oO 0 - 0 oO oOo He N ny HO N N= oN Hoon {XH s Hon LH [ fo) oO © 0 0 © Ho N ZY HO N eu H OH (KH ZN H OH NC 0 fo) 0 or TEAS H ZH OH (AK 2zN 0 o o ¢ 0 o 0 H OH (KH H OH (AH 9) Oo 0 0 0 0 0 HO N 0) HO N NN) Hoon {XH H OH (eA H 7 \ 0) o © 0 HO N N Jel H OH (A H fo) o © 0 fo oO © s . HO p Ys] HO p 5 Hoon (x Hon (KH

0 oO 0 S 0) 0) 0 “rs N—ON “rs N— ON AV Hoon (XH | H On { AH 0 oO © 0 HO y N Aw H OH (A H fo o © fo) : ) fo) H OH (AH NZ H oH (KH 0 oO O° cl 0 0) 0 ro Go Is Hoon (XH (J H OH (KH 0) 0 0 0) 0} 0 DO NEY } in ey JA Hoon Lx | Hoon (XH 7 N\ 0 o © Or NO Hoon (x H S fo) lo) 0 lo) 0 lo) : HO | F 50n HO p fa LT + ZH | 5 OH (KX | H OH (AK L_o

{55,0 00 3.0 “rs N A “Or NN Hoon (x H on {KH 0 : oO 0 0 : 0) o) “or NNN “rs Ne Hoon (x Ls Hoon LX ) 0 o © 0) 0 0 Lr “ry \ AN HO N NAS Hoon (XH H OH (XK H 0 oO © o “rs N NG H OH (AT H o) o © O 0 o © or \ A HO N N NN H OH (AK H H OH (KX H bs: VA 0 o oO 9) o © HO _N N HO (3 NA N N N—" "NN" N N— NY oh OH GR oh OH (AH CJ ’ fo) o 0 y HO N NON ZN H OH (AT Ho A

0 o © . “Or NAS = N H ZH OH (AK x 0 ; o 0 0 oO © “rt ee “ry NY OH (KX | Hoon (xn 0 0 o 0 fo fo fo = H = — OH KAT OH (AK o) o 0 lo) 0 0 H = — H = — on LA | oH LA 0 (@) 0 0] 0] 0 Jon rou AAA ANA “yy : N= - H =H = H ZH = A on LX 2 on LX } 0 fo) o) \ “Or N= OR 74 \ H 2-H = ] oH LX

. Oo 0 0] fo) fo) o N © “Oy N 1 Y 0 \ A H | OH (AH 0] 0 Lg 0) 0 © 0 HO N \ A, F 0 3d © Hoon (XH " n rN F Hoon (XH " AS lo) 0} bd HO N N Pa H OH Lg 18) 3 N N o! 0 Ox N 0 0 Os N Ho T Ho hi N N ~ N NT", o) LX 0 LK H H J a, oO a _ 0 _ N HO ] HO AA J N N “, N N =, R) LK fo LK H H 0 ; Oo © } HO N NON HOH XH Lo o) oO © o NET ENS H OH (KH fe) Oo 0) 0) Oo 0] 0) vA 3 ted QL Hoon (XH | Hoon (XH 0 o 0 0 o ©

NY . 20 if 1 20) Hoon {AH \=n H On (AH 0 oO 0 0 o 0 LE ed "AKT "oon (XH 0 o © = © 0 © o Ay N 0 HN \ N Ay Hoon (XH Hoon (XH 7 \ N= ©O o © o o © AN N 0 oN N—"ON Hoon (XH Z Hoon {XH o) 0. 0 9) : oO oO SN SERS 0 : SEAS Hoon (JX | Hoon (AH

0} 0 0 fo) 0 0) SN SERS AA NS 2s fo) 0 0) fo) 0 fo) PS SERS SA 0 H H OH (A H | Hoon Lx H 0) lo) 9) 0 0 lo) Fe A 50 AA SERS H OH (AK H OH (AH 0 lo) 0 fo) fo) 0 HN N NN oA Ne NF Res Rs N= © 0) 0 0) fo) 0 LC I.

WD SPP J 7 on (x LIRR CL 0 oO oO 0 0 fo) o Ay NNN "iN N NNN H OH (XK H H OH (AH o) ; fo) 0 o 0 9) 0 0 ) HN N N= ON o Ay N= Ho on (XH H OH (KH 0 oO 0 o 0 o 0 SSN NON oA N—" ON TeX "oon CO 0 : 0) 0 0) : 0 fo) oN N—N AN N NN H OH { <H H OH IQ EA H AS S , sN , Wh 0 0 0 0) lo) 0] STEN CORTES on Le XH "oon (XH Wi fo) 0 o) 0 0 fo) 2 0 NS - EIN Yn NNN & H OH SH —0 HOH (AH \ / 0 o) o) 0 0 0) 0 “or — “Or N LL Hoon (XH Hoon (XH fo 0 fo 0 0 o) H HN SOR: No N NON Hoon (XH H oH (A H 0 0 fo) oH N N—7 NTN oN N = Hom (XH Zz H Bn LX cl o nF 3 ALTA gg NON NT, IY NT, C0 Hon LK F Ho Gn LX F o H F FF Oo.

H i 9) 0) i. be 0 bas ne =~ TO" ON NT N” ON NTL E = H OH LX F HoH On LX FN OE aw ISLAY AAT NN SN N . = ZO ON N : Ho Ow LL . F \ Zz H OH LX CF; 2) O Bn O O O O F oN A Ns N NAF HH on {XH JH on {AH Bh O 0) Br 0 IL 0 Bh O ig S—HN N—/ ON ASTER “SN 6 an 57 an (JH

QO Bn O o © Bn O © HAA “0 Jig ig NN N—" °N “NTN N— ON oth or ited O Bn O 0 0 Br O 0 Orr Soy SRERR, Tn : H OH (KX OH (JX o Bo © O Bn O © J I Sot RS N N N N O Bn O 2 o Bo 0

~y . 2S SORES Le H OH JX | OH (JX oN O Bn O 0 \ 0] Bn O 0 I I Ee HoH (JH Lov NN Hon (XH _N bh] N b Oo Bn O 0) ) O Bn O 0) on NY SRER. A F 0 Bn O 0 Br O Bn O eo] } RR Ay ORERS. Ay mS . H H on {XH H H on (JH D his LX i LAR,_R o N™ ON N— ON xy 7 x N™ ON N— °N BS LIER FiC . 0 ) N N N N N N N N Ts H LEO |SRN: Len O

Cl O Bn O 0} OO Bn O 0) ‘ 0} 4 SOEs asia re ae 0 oO ©O 0 o) lo H ZH OH (XT OH No XT 0 0 0 IQ 0] 0 0) 2 on { X~ OH SAT 0 0] OH 0 0 O\NH HO : { H on Lg H on Lg 0 0 0 0 0 0 I® HO y \ Ady HO \ N= "one ELV FF FF 7 \ 0) oO © ) oO © RoR <M “Or 0 H OH Zz H H OH Z H >< , FF F . 0 0 0} | 0 0 lo} HO N N= ON HO N NPS HooHG oH ono FF FOF o o ° 0) 0} Pi Cl ) HO EN A N N—""N H OH NF H OH \% FOF FF : 0 oO 0 0) 0 © H on S H on { ° 0 fo oO 0 o) o o F OE CL OE es 0 H ZH H : H or 5 o OH Nd ci FF FOF fo 0 o) lo) 0) 0) HO N N—ON HO N Holy "oH SAT "on STH FOF FF 0 0 0 lo} 0 0 cl HO N” - A HO N° - 3, FF FOF i 0 O 0 fo) fo} 0 ) ; lo ’ H OH SAH H OH SAT" \ J FoF , “FF

© WO 02/100844 PCT/US02/18717

: HO N NN HO N on) FOF FOE 0] Oo 0 0 0 0 : 0 HO N N— SNCF HO N N= HOH SA H OH CAM FF FOF 0 o © 0 oO 0 oO = H H 3 H Jes he Jes hes FOF , FF i fo) fo) 0 fo) 0 fo) J® rh ad) ROR Ay H ZH H ZH OH LAT | OH LC 0 0 0 0 0 2 H H OH ne: OH “UY o o o 0 fo) 0 HO y \ SL HO N Ne ton (? ONT

0 fo) 0 lo) 0) lo) I® Ren N N es “or N RS N H OH H We OH we fo) fo) fo) o 5 o HO N N EN HO RS H OH { N N N Ss H oH { Ss Fo, 0 lo) lo) 0 0 0 I® Or N ENN “rs N Sy H OH H H H fo) Ce OH Cer] 0 oO 0 CL 0} 0) 0} oN N N RS N oN N N RS N A9e% 230% F7OF FF lo) lo) lo) lo) 0) lo) ou AA In aA A EC JT F&O FU FL FU FF } FF } fo) 0) 0) 0) fo} lo) , } 0 R evs Hy IVs Ay on GO Ton ’ FF , : FFF ,

° 5 o 0 lo) 0) ’ HO o £ NNN N N—" ~N H OH ZH "on LH F' F , lo) 0) 0 0 0 RS Oo 0 N N—" °N 0 Ho H OH H N N ug H H 3 \ lo) lo} 0 0 0 lo) on LX” OH (LK F 0) 0 0) 0 0) 0 ROR A ROR NAO H z H ES on { A | OH (AK 0 lo} 0 9 0 0 HO MN J HO Ma N N N H on {A $C sN , FF ,

0 oO 0 J@ SN o oO 0 HO A \ FEY! he hd OH (n" H on (SH 0] 0 0] CL bt 0) 0 oo oH KAT OH (A CL 0 0 0) 0) 0} 0 oN NNN oA N— oN © . H OH { z= _-H H oH { Zz —-H \ J sN s 0 0 0 oH (0) o] N HN Oo or Gi COD OH (KX Ho Ay AN Cl 7 \ 0] 0 (0) ] 0 0 fo) j b > a NNN Hoon Lx" \=N "oon (XN EZ and S , or the prodrugs, pharmaceutically active metabolites, and pharmaceutically acceptable salts and solvates thereof.