TETRACYCLIC HETEROCYCLE COMPOUNDS USEFUL AS HIV INTEGRASE

INHIBITORS

FIELD OF THE INVENTION

The present invention relates to Tetracyclic Heterocycle Compounds, compositions comprising at least one Tetracyclic Heterocycle Compound, and methods of using the Tetracyclic Heterocycle Compounds for treating or preventing HIV infection in a subject.

BACKGROUND OF THE INVENTION

A retrovirus designated human immunodeficiency virus (HIV), particularly the strains known as HIV type-1 (HIV-1) virus and type-2 (HIV-2) virus, is the etiological agent of the complex disease that includes progressive destruction of the immune system (acquired immune deficiency syndrome; AIDS) and degeneration of the central and peripheral nervous system. A common feature of retrovirus replication is the insertion by virally-encoded integrase of +proviral DNA into the host cell genome, a required step in HIV replication in human T- lymphoid and monocytoid cells. Integration is believed to be mediated by integrase in three steps: assembly of a stable nucleoprotein complex with viral DNA sequences; cleavage of two nucleotides from the 3' termini of the linear proviral DNA; covalent joining of the recessed 3' OH termini of the proviral DNA at a staggered cut made at the host target site. The fourth step in the process, repair synthesis of the resultant gap, may be accomplished by cellular enzymes.

Nucleotide sequencing of HIV shows the presence of a pol gene in one open reading frame [Ratner, L. et al, Nature, 313, 277(1985)]. Amino acid sequence homology provides evidence that the pol sequence encodes reverse transcriptase, integrase and an HIV protease [Toh, H. et al, EMBO J. 4, 1267 (1985); Power, M.D. et al, Science, 231, 1567 (1986); Pearl, L.H. et al, Nature, 329, 351 (1987)]. All three enzymes have been shown to be essential for the replication of HIV.

It is known that some antiviral compounds which act as inhibitors of HIV replication are effective agents in the treatment of AIDS and similar diseases, including reverse transcriptase inhibitors such as azidothymidine (AZT) and efavirenz and protease inhibitors such as indinavir and nelfmavir. The compounds of this invention are inhibitors of HIV integrase and inhibitors of HIV replication.

The following references are of interest as background:

International Publication Nos. WO 11/045330 and WO 11/121105 disclose macrocyclic compounds having HIV integrase inhibitory activity.

Kinzel et al, Tet. Letters 2007, 48(37): pp. 6552-6555 discloses the synthesis of tetrahydropyridopyrimidones as a scaffold for HIV-1 integrase inhibitors. Ferrara et al, Tet. Letters 2007, 48(37), pp. 8379-8382 discloses the synthesis of a hexahydropyrimido[l,2-a]azepine-2-carboxamide derivative useful as an HIV integrase inhibitor.

Muraglia et al, J. Med. Chem. 2008, 5J_: 861-874 discloses the design and synthesis of bicyclic pyrimidinones as potent and orally bioavailable HIV-1 integrase inhibitors.

US2004/229909 discloses certain compounds having integrase inhibitory activity.

US 7232819 and US 2007/0083045 disclose certain 5,6-dihydroxypyrimidine-4- carboxamides as HIV integrase inhibitors.

US 7169780, US 7217713, and US 2007/0123524 disclose certain N-substituted 5-hydroxy-6-oxo-l,6-dihydropyrimidine-4-carboxamides as HIV integrase inhibitors.

US 7279487 discloses certain hydroxynaphthyridinone carboxamides that are useful as HIV integrase inhibitors.

US 7135467 and US 7037908 disclose certain pyrimidine carboxamides that are useful as HIV integrase inhibitors.

US 7211572 discloses certain nitrogenous condensed ring compounds that are HIV integrase inhibitors.

US 7414045 discloses certain tetrahydro-4H-pyrido[l,2-a]pyrimidine carboxamides, hexahydropyrimido[l,2-o]azepine carboxamides, and related compounds that are useful as HIV integrase inhibitors.

WO 2006/103399 discloses certain tetrahydro-4H-pyrimidooxazepine carboaxmides, tetrahydropyrazinopyrimidine carboxamides, hexahydropyrimidodiazepine carboxamides, and related compounds that are useful as HIV integrase inhibitors.

US 2007/0142635 discloses processes for preparing hexahydropyrimido[l,2- a]azepine-2-carboxylates and related compounds.

US 2007/0149556 discloses certain hydroxypyrimidinone derivatives having HIV integrase inhibitory activity.

Various pyrimidinone compounds useful as HIV integrase inhibitors are also disclosed in US 7115601, US 7157447, US 7173022, US 7176196, US 7192948, US 7273859, and US 7419969.

US 2007/0111984 discloses a series of bicyclic pyrimidinone compounds useful as HIV integrase inhibitors.

US 2006/0276466, US 2007/0049606, US 2007/0111985, US 2007/0112190, US 2007/0281917, US 2008/0004265 each disclose a series of bicyclic pyrimidinone compounds useful as HIV integrase inhibitors.

SUMMARY OF THE INVENTION

aspect, the present invention provides Compounds of Formula (I)

OH O

(I)

or a pharmaceutically acceptable salt or prodrug thereof,

wherein:

X is O, -CH(R ⁴ )- or -N(R ⁵ )-;

Y is O, -N(R ⁶ )- or C C ₃ alkylene;

Z is a single bond or -C(R ⁷ )-;

R ¹ represents up to 5 optional phenyl group substituents, each independently selected from Ci-C ₆ alkyl, -0-(Ci-C ₆ alkyl) and halo;

R ² is H;

R ³ is selected from H, Ci-C ₆ alkyl, Ci-C ₆ haloalkyl, -OR ⁶ and -N(R ⁶ ) ₂ ;

each occurrence of R ^3a is independently selected from H, Ci-C ₆ alkyl, Ci-C ₆ haloalkyl, -OR ⁶ and -N(R ⁶ ) ₂ ;

R ⁴ is H or Ci-C ₆ alkyl or -0-(Ci-C ₆ alkyl);

R ⁵ is selected from H, C C ₆ alkyl and -C(0)R ⁸ and -S0 ₂ R ⁸ ;

each occurrence of R ⁶ is independently H or Ci-C ₆ alkyl;

R ⁷ is selected from H, Ci-C ₆ alkyl and -0-(Ci-C ₆ alkyl);

each occurrence of R ⁸ is Ci-C ₆ alkyl or NR ⁶ ;

m is 0, 1 or 2; and

n is 1, 2 or 3, such that the sum of m+ n is 2 or 3.

The Compounds of Formula (I) (also referred to herein as the "Tetracyclic Heterocycle Compounds") and pharmaceutically acceptable salts or prodrugs thereof can be useful, for example, for inhibiting HIV viral replication or replicon activity, and for treating or preventing HIV infection in a subject. Without being bound by any specific theory, it is believed that the Tetracyclic Heterocycle Compounds inhibit HIV viral replication by inhibiting HIV Integrase. Accordingly, the present invention provides methods for treating or preventing HIV infection in a subject, comprising administering to the subject an effective amount of at least one Tetracyclic Heterocycle Compound.

The details of the invention are set forth in the accompanying detailed description below.

Although any methods and materials similar to those described herein can be used in the practice or testing of the present invention, illustrative methods and materials are now described. Other embodiments, aspects and features of the present invention are either further described in or will be apparent from the ensuing description, examples and appended claims.

DETAILED DESCRIPTION OF THE INVENTION

The present invention includes Tetracyclic Heterocycle Compounds, compositions comprising at least one Tetracyclic Heterocycle Compound, and methods of using the Tetracyclic Heterocycle Compounds for treating or preventing HIV infection in a subject.

Definitions and Abbreviations

The terms used herein have their ordinary meaning and the meaning of such terms is independent at each occurrence thereof. That notwithstanding and except where stated otherwise, the following definitions apply throughout the specification and claims. Chemical names, common names, and chemical structures may be used interchangeably to describe the same structure. These definitions apply regardless of whether a term is used by itself or in combination with other terms, unless otherwise indicated. Hence, the definition of "alkyl" applies to "alkyl" as well as the "alkyl" portions of "hydroxyalkyl," "haloalkyl," "-O-alkyl," etc...

As used herein, and throughout this disclosure, the following terms, unless otherwise indicated, shall be understood to have the following meanings:

A "subject" is a human or non-human mammal. In one embodiment, a subject is a human. In another embodiment, a subject is a primate. In another embodiment, a subject is a monkey. In another embodiment, a subject is a chimpanzee. In still another embodiment, a subject is a rhesus monkey.

The term "effective amount" as used herein, refers to an amount of Tetracyclic Heterocycle Compound and/or an additional therapeutic agent, or a composition thereof that is effective in producing the desired therapeutic, ameliorative, inhibitory or preventative effect when administered to a subject suffering from HIV infection or AIDS. In the combination therapies of the present invention, an effective amount can refer to each individual agent or to the combination as a whole, wherein the amounts of all agents administered are together effective, but wherein the component agent of the combination may not be present individually in an effective amount.

The term "preventing," as used herein with respect to an HIV viral infection or

AIDS, refers to reducing the likelihood or severity of HIV infection or AIDS.

The term "alkyl," as used herein, refers to an aliphatic hydrocarbon group having one of its hydrogen atoms replaced with a bond. An alkyl group may be straight or branched and contain from about 1 to about 20 carbon atoms. In one embodiment, an alkyl group contains from about 1 to about 12 carbon atoms. In different embodiments, an alkyl group contains from 1 to 6 carbon atoms (Ci-C ₆ alkyl) or from about 1 to about 4 carbon atoms (C ₁ -C4 alkyl). Non- limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, neopentyl, isopentyl, n-hexyl, isohexyl and neohexyl. An alkyl group may be unsubstituted or substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of halo, alkenyl, alkynyl, aryl, cycloalkyl, cyano, hydroxy, -O-alkyl, -O-aryl, -alkylene-O-alkyl, alkylthio, -NH ₂ , -NH(alkyl), -N(alkyl) ₂ , -NH(cycloalkyl), -0-C(0)-alkyl, -0-C(0)-aryl, -O-C(O)- cycloalkyl, -C(0)OH and -C(0)0-alkyl. In one embodiment, an alkyl group is linear. In another embodiment, an alkyl group is branched. Unless otherwise indicated, an alkyl group is unsubstituted.

The term "alkenyl," as used herein, refers to an aliphatic hydrocarbon group containing at least one carbon-carbon double bond and having one of its hydrogen atoms replaced with a bond. An alkenyl group may be straight or branched and contain from about 2 to about 15 carbon atoms. In one embodiment, an alkenyl group contains from about 2 to about 12 carbon atoms. In another embodiment, an alkenyl group contains from about 2 to about 6 carbon atoms. Non-limiting examples of alkenyl groups include ethenyl, propenyl, n-butenyl, 3- methylbut-2-enyl, n-pentenyl, octenyl and decenyl. An alkenyl group may be unsubstituted or substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of halo, alkenyl, alkynyl, aryl, cycloalkyl, cyano, hydroxy, -O-alkyl, -O-aryl, -alkylene-O-alkyl, alkylthio, -NH ₂ , -NH(alkyl), -N(alkyl) ₂ , - NH(cycloalkyl), -0-C(0)-alkyl, -0-C(0)-aryl, -0-C(0)-cycloalkyl, -C(0)OH and -C(0)0-alkyl. The term "C ₂ -C ₆ alkenyl" refers to an alkenyl group having from 2 to 6 carbon atoms. Unless otherwise indicated, an alkenyl group is unsubstituted. The term "alkynyl," as used herein, refers to an aliphatic hydrocarbon group containing at least one carbon-carbon triple bond and having one of its hydrogen atoms replaced with a bond. An alkynyl group may be straight or branched and contain from about 2 to about 15 carbon atoms. In one embodiment, an alkynyl group contains from about 2 to about 12 carbon atoms. In another embodiment, an alkynyl group contains from about 2 to about 6 carbon atoms. Non-limiting examples of alkynyl groups include ethynyl, propynyl, 2-butynyl and 3- methylbutynyl. An alkynyl group may be unsubstituted or substituted by one or more

substituents which may be the same or different, each substituent being independently selected from the group consisting of halo, alkenyl, alkynyl, aryl, cycloalkyl, cyano, hydroxy, -O-alkyl, - O-aryl, -alkylene-O-alkyl, alkylthio, -NH ₂ , -NH(alkyl), -N(alkyl) ₂ , -NH(cycloalkyl), -O-C(O)- alkyl, -0-C(0)-aryl, -0-C(0)-cycloalkyl, -C(0)OH and -C(0)0-alkyl. The term "C ₂ -C ₆ alkynyl" refers to an alkynyl group having from 2 to 6 carbon atoms. Unless otherwise indicated, an alkynyl group is unsubstituted.

The term "alkylene," as used herein, refers to an alkyl group, as defined above, wherein one of the alkyl group's hydrogen atoms has been replaced with a bond. Non- limiting examples of alkylene groups include -CH ₂ -, -CH ₂ CH ₂ -, -CH ₂ CH ₂ CH ₂ -, -CH ₂ CH ₂ CH ₂ CH ₂ -, - CH(CH ₃ )CH ₂ CH ₂ -, -CH(CH ₃ )- and -CH ₂ CH(CH ₃ )CH ₂ -. In one embodiment, an alkylene group has from 1 to about 6 carbon atoms. In another embodiment, an alkylene group has from about 3 to about 5 carbon atoms. In another embodiment, an alkylene group is branched. In another embodiment, an alkylene group is linear. In one embodiment, an alkylene group is -CH ₂ -. The term "C 1-C4 alkylene" refers to an alkylene group having from 1 to 4 carbon atoms. The term "C ₂ -C ₄ alkylene" refers to an alkylene group having from 2 to 4 carbon atoms.

The term "alkenylene," as used herein, refers to an alkenyl group, as defined above, wherein one of the alkenyl group's hydrogen atoms has been replaced with a bond. Non- limiting examples of alkenylene groups include -CH=CH-, -CH=CHCH ₂ -, -CH ₂ CH=CH-, - CH ₂ CH=CHCH ₂ -, -CH=CHCH ₂ CH ₂ -, -CH ₂ CH ₂ CH=CH- and -CH(CH ₃ )CH=CH-. In one embodiment, an alkenylene group has from 2 to about 6 carbon atoms. In another embodiment, an alkenylene group has from about 3 to about 5 carbon atoms. In another embodiment, an alkenylene group is branched. In another embodiment, an alkenylene group is linear. The term "C ₂ -C ₆ alkylene" refers to an alkenylene group having from 2 to 6 carbon atoms. The term "C ₃ - C5 alkenylene" refers to an alkenylene group having from 3 to 5 carbon atoms.

The term "aryl," as used herein, refers to an aromatic monocyclic or multicyclic ring system comprising from about 6 to about 14 carbon atoms. In one embodiment, an aryl group contains from about 6 to about 10 carbon atoms. An aryl group can be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined herein below. In one embodiment, an aryl group can be optionally fused to a cycloalkyl or cycloalkanoyl group. Non-limiting examples of aryl groups include phenyl and naphthyl. In one embodiment, an aryl group is phenyl. Unless otherwise indicated, an aryl group is unsubstituted.

The term "arylene," as used herein, refers to a bivalent group derived from an aryl group, as defined above, by removal of a hydrogen atom from a ring carbon of an aryl group. An arylene group can be derived from a monocyclic or multicyclic ring system comprising from about 6 to about 14 carbon atoms. In one embodiment, an arylene group contains from about 6 to about 10 carbon atoms. In another embodiment, an arylene group is a naphthylene group. In another embodiment, an arylene group is a phenylene group. An arylene group can be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined herein below. An arylene group is divalent and either available bond on an arylene group can connect to either group flanking the arylene group. For example, the group "A-arylene-B," wherein the arylene group is:

is understood to represent both:

In one embodiment, an arylene group can be optionally fused to a cycloalkyl or cycloalkanoyl group. Non-limiting examples of arylene groups include phenylene and naphthalene. In one embodiment, an arylene group is unsubstituted. In another embodiment, an arylene group is:

Unless otherwise indicated, an arylene group is unsubstituted. The term "cycloalkyl," as used herein, refers to a non-aromatic mono- or multicyclic ring system comprising from about 3 to about 10 ring carbon atoms. In one embodiment, a cycloalkyl contains from about 5 to about 10 ring carbon atoms. In another embodiment, a cycloalkyl contains from about 3 to about 7 ring atoms. In another embodiment, a cycloalkyl contains from about 5 to about 6 ring atoms. The term "cycloalkyl" also

encompasses a cycloalkyl group, as defined above, which is fused to an aryl (e.g., benzene) or heteroaryl ring. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. Non-limiting examples of multicyclic cycloalkyls include 1-decalinyl, norbornyl and adamantyl. A cycloalkyl group can be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined herein below. In one embodiment, a cycloalkyl group is

unsubstituted. The term "3 to 7-membered cycloalkyl" refers to a cycloalkyl group having from 3 to 7 ring carbon atoms. Unless otherwise indicated, a cycloalkyl group is unsubstituted. A ring carbon atom of a cycloalkyl group may be functionalized as a carbonyl group. An illustrative example of such a cycloalkyl group (also referred to herein as a "cycloalkanoyl" group) includes, but is not limited to, cyclobutanoyl:

The term "halo," as used herein, means -F, -CI, -Br or -I.

The term "haloalkyl," as used herein, refers to an alkyl group as defined above, wherein one or more of the alkyl group's hydrogen atoms has been replaced with a halogen. In one embodiment, a haloalkyl group has from 1 to 6 carbon atoms. In another embodiment, a haloalkyl group is substituted with from 1 to 3 F atoms. Non-limiting examples of haloalkyl groups include -CH ₂ F, -CHF ₂ , -CF ₃ , -CH ₂ C1 and -CC1 ₃ . The term "Ci-C ₆ haloalkyl" refers to a haloalkyl group having from 1 to 6 carbon atoms.

The term "hydroxyalkyl," as used herein, refers to an alkyl group as defined above, wherein one or more of the alkyl group's hydrogen atoms have been replaced with an - OH group. In one embodiment, a hydroxyalkyl group has from 1 to 6 carbon atoms. Non- limiting examples of hydroxyalkyl groups include -CH ₂ OH, -CH ₂ CH ₂ OH, -CH ₂ CH ₂ CH ₂ OH and -CH ₂ CH(OH)CH ₃ . The term "Ci-C ₆ hydroxyalkyl" refers to a hydroxyalkyl group having from 1 to 6 carbon atoms. The term "heteroaryl," as used herein, refers to an aromatic monocyclic or multicyclic ring system comprising about 5 to about 14 ring atoms, wherein from 1 to 4 of the ring atoms is independently O, N or S and the remaining ring atoms are carbon atoms. In one embodiment, a heteroaryl group has 5 to 10 ring atoms. In another embodiment, a heteroaryl group is monocyclic and has 5 or 6 ring atoms. In another embodiment, a heteroaryl group is bicyclic. A heteroaryl group can be optionally substituted by one or more "ring system substituents" which may be the same or different, and are as defined herein below. A heteroaryl group is joined via a ring carbon atom, and any nitrogen atom of a heteroaryl can be optionally oxidized to the corresponding N-oxide. The term "heteroaryl" also encompasses a heteroaryl group, as defined above, which is fused to a benzene ring. Non- limiting examples of heteroaryls include pyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, pyridone (including N-substituted pyridones), isoxazolyl, isothiazolyl, oxazolyl, oxadiazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, triazolyl, 1,2,4-thiadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl, oxindolyl, imidazo[l,2-a]pyridinyl, imidazo[2,l-b]thiazolyl, benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl, imidazolyl, benzimidazolyl, thienopyridyl, quinazolinyl, thienopyrimidyl, pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindolyl, 1,2,4-triazinyl, benzothiazolyl and the like, and all isomeric forms thereof. The term

"heteroaryl" also refers to partially saturated heteroaryl moieties such as, for example, tetrahydroisoquinolyl, tetrahydroquinolyl and the like. In one embodiment, a heteroaryl group is a 5-membered heteroaryl. In another embodiment, a heteroaryl group is a 6-membered monocyclic heteroaryl. In another embodiment, a heteroaryl group comprises a 5- to 6- membered monocyclic heteroaryl group fused to a benzene ring. Unless otherwise indicated, a heteroaryl group is unsubstituted.

The term "heterocycloalkyl," as used herein, refers to a non-aromatic saturated monocyclic or multicyclic ring system comprising 3 to about 11 ring atoms, wherein from 1 to 4 of the ring atoms are independently O, S, N or Si, and the remainder of the ring atoms are carbon atoms. A heterocycloalkyl group can be joined via a ring carbon, ring silicon atom or ring nitrogen atom. In one embodiment, a heterocycloalkyl group is monocyclic and has from about 3 to about 7 ring atoms. In another embodiment, a heterocycloalkyl group is monocyclic has from about 4 to about 7 ring atoms. In another embodiment, a heterocycloalkyl group is bicyclic and has from about 7 to about 11 ring atoms. In still another embodiment, a heterocycloalkyl group is monocyclic and has 5 or 6 ring atoms. In one embodiment, a heterocycloalkyl group is monocyclic. In another embodiment, a heterocycloalkyl group is bicyclic. There are no adjacent oxygen and/or sulfur atoms present in the ring system. Any -NH group in a heterocycloalkyl ring may exist protected such as, for example, as an -N(BOC), -N(Cbz), -N(Tos) group and the like; such protected heterocycloalkyl groups are considered part of this invention. The term "heterocycloalkyl" also encompasses a heterocycloalkyl group, as defined above, which is fused to an aryl (e.g. , benzene) or heteroaryl ring. A heterocycloalkyl group can be optionally substituted by one or more "ring system substituents" which may be the same or different, and are as defined herein below. The nitrogen or sulfur atom of the heterocycloalkyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. Non-limiting examples of monocyclic heterocycloalkyl rings include oxetanyl, piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1 ,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, delta-lactam, delta-lactone and the like, and all isomers thereof.

A ring carbon atom of a heterocycloalkyl group may be functionalized as a carbonyl group. An illustrative example of such a heterocycloalkyl group is:

In one embodiment, a heterocycloalkyl group is a 5-membered monocyclic heterocycloalkyl. In another embodiment, a heterocycloalkyl group is a 6-membered

monocyclic heterocycloalkyl. The term "3 to 6-membered monocyclic heterocycloalkyl" refers to a monocyclic heterocycloalkyl group having from 3 to 6 ring atoms. The term "4 to 7- membered monocyclic heterocycloalkyl" refers to a monocyclic heterocycloalkyl group having from 4 to 7 ring atoms. The term "7 to 1 1-membered bicyclic heterocycloalkyl" refers to a bicyclic heterocycloalkyl group having from 7 to 1 1 ring atoms. Unless otherwise indicated, a heterocycloalkyl group is unsubstituted.

The term "ring system substituent," as used herein, refers to a substituent group attached to an aromatic or non-aromatic ring system which, for example, replaces an available hydrogen on the ring system. Ring system substituents may be the same or different, each being independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, - alkylene-aryl, -arylene-alkyl, -alkylene-heteroaryl, -alkenylene-heteroaryl, -alkynylene- heteroaryl, -OH, hydroxyalkyl, haloalkyl, -O-alkyl, -O-haloalkyl, -alkylene-O-alkyl, -O-aryl, -O- alkylene-aryl, acyl, -C(0)-aryl, halo, -N0 ₂ , -CN, -SF ₅ , -C(0)OH, -C(0)0-alkyl, -C(0)0-aryl, - C(0)0-alkylene-aryl, -S(0)-alkyl, -S(0) ₂ -alkyl, -S(0)-aryl, -S(0) ₂ -aryl, -S(0)-heteroaryl, - S(0) ₂ -heteroaryl, -S-alkyl, -S-aryl, -S-heteroaryl, -S-alkylene-aryl, -S-alkylene-heteroaryl, - S(0) ₂ -alkylene-aryl, -S(0) ₂ -alkylene-heteroaryl, -Si(alkyl) ₂ , -Si(aryl) ₂ , -Si(heteroaryl) ₂ , - Si(alkyl)(aryl), -Si(alkyl)(cycloalkyl), - Si(alkyl)(heteroaryl), cycloalkyl, heterocycloalkyl, -O- C(0)-alkyl, -0-C(0)-aryl, -0-C(0)-cycloalkyl, -C(=N-CN)-NH ₂ , -C(=NH)-NH ₂ , -C(=NH)- NH(alkyl), -N(Yi)(Y ₂ ), -alkylene-N(Yi)(Y ₂ ), -C(0)N(Yi)(Y ₂ ) and -S(0) ₂ N(Yi)(Y ₂ ), wherein Yj and Y ₂ can be the same or different and are independently selected from the group consisting of hydrogen, alkyl, aryl, cycloalkyl, and -alkylene-aryl. "Ring system substituent" may also mean a single moiety which simultaneously replaces two available hydrogens on two adjacent carbon atoms (one H on each carbon) on a ring system. Examples of such moiety are methylenedioxy, ethylenedioxy, -C(CH ₃ ) ₂ - and the like which form moieties such as, for example:

The term "substituted" means that one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency under the existing circumstances is not exceeded, and that the substitution results in a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds. By "stable compound' or "stable structure" is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.

The term "in substantially purified form," as used herein, refers to the physical state of a compound after the compound is isolated from a synthetic process (e.g., from a reaction mixture), a natural source, or a combination thereof. The term "in substantially purified form," also refers to the physical state of a compound after the compound is obtained from a purification process or processes described herein or well-known to the skilled artisan (e.g., chromatography, recrystallization and the like), in sufficient purity to be characterizable by standard analytical techniques described herein or well-known to the skilled artisan.

It should also be noted that any carbon as well as heteroatom with unsatisfied valences in the text, schemes, examples and tables herein is assumed to have the sufficient number of hydrogen atom(s) to satisfy the valences.

When a functional group in a compound is termed "protected", this means that the group is in modified form to preclude undesired side reactions at the protected site when the compound is subjected to a reaction. Suitable protecting groups will be recognized by those with ordinary skill in the art as well as by reference to standard textbooks such as, for example, T. W. Greene et al, Protective Groups in Organic Synthesis (1991), Wiley, New York. When any substituent or variable (e.g., alkyl, R ¹ , R ⁷ , etc.) occurs more than one time in any constituent or in Formula (I), its definition on each occurrence is independent of its definition at every other occurrence, unless otherwise indicated.

As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results from combination of the specified ingredients in the specified amounts.

Prodrugs and solvates of the compounds of the invention are also contemplated herein. A discussion of prodrugs is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems (1987) 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, (1987) Edward B. Roche, ed., American Pharmaceutical Association and

Pergamon Press. The term "prodrug" means a compound (e.g., a drug precursor) that is transformed in vivo to provide a Tetracyclic Heterocycle Compound or a pharmaceutically acceptable salt of the compound. The transformation may occur by various mechanisms (e.g., by metabolic or chemical processes), such as, for example, through hydrolysis in blood. For example, if a Tetracyclic Heterocycle Compound or a pharmaceutically acceptable salt, hydrate or solvate of the compound contains a carboxylic acid functional group, a prodrug can comprise an ester formed by the replacement of the hydrogen atom of the acid group with a group such as, for example, (Ci-Cg)alkyl, (C ₂ -Ci ₂ )alkanoyloxymethyl, l-(alkanoyloxy)ethyl having from 4 to 9 carbon atoms, 1 -methyl- l-(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms,

alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, l-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms, 1 -methyl- l-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms, N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms, 1-(N- (alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms, 3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl, di-N,N-(Ci-C ₂ )alkylamino(C ₂ -C ₃ )alkyl (such as β- dimethylaminoethyl), carbamoyl-(Ci-C ₂ )alkyl, N,N-di (Ci-C ₂ )alkylcarbamoyl-(Ci-C ₂ )alkyl and piperidino-, pyrrolidino- or morpholino(C ₂ -C ₃ )alkyl, and the like.

Similarly, if a Tetracyclic Heterocycle Compound contains an alcohol functional group, a prodrug can be formed by the replacement of one or more of the hydrogen atoms of the alcohol groups with a group such as, for example, (Ci-C ₆ )alkanoyloxymethyl, l-((Ci- C ₆ )alkanoyloxy)ethyl, 1 -methyl- l-((Ci-C ₆ )alkanoyloxy)ethyl, (Ci-C ₆ )alkoxycarbonyloxymethyl, N-(Ci-C ₆ )alkoxycarbonylaminomethyl, succinoyl, (Ci-C ₆ )alkanoyl, a-amino(Ci-C ₄ )alkyl, a- amino(Ci-C ₄ )alkylene-aryl, arylacyl and a-aminoacyl, or α-aminoacyl-a-aminoacyl, where each a-aminoacyl group is independently selected from the naturally occurring L-amino acids, or glycosyl (the radical resulting from the removal of a hydroxyl group of the hemiacetal form of a carbohydrate).

If a Tetracyclic Heterocycle Compound incorporates an amine functional group, a prodrug can be formed by the replacement of a hydrogen atom in the amine group with a group such as, for example, R-carbonyl-, RO-carbonyl-, NRR'-carbonyl- wherein R and R' are each independently (Ci-Cio)alkyl, (C3-C7) cycloalkyl, benzyl, a natural a-aminoacyl, - C(OH)C(0)OY ¹ wherein Y ¹ is H, (Ci-C ₆ )alkyl or benzyl, -C(OY ² )Y ³ wherein Y ² is (C C ₄ ) alkyl and Y ³ is (Ci-C ₆ )alkyl; carboxy (Ci-C ₆ )alkyl; amino(Ci-C ₄ )alkyl or mono-N- or di-N,N-(Ci- C ₆ )alkylaminoalkyl; -C(Y ⁴ )Y ⁵ wherein Y ⁴ is H or methyl and Y ⁵ is mono-N- or di-N,N-(Ci- C6)alkylamino morpholino; piperidin-l-yl or pyrrolidin-l-yl, and the like.

Pharmaceutically acceptable esters of the present compounds include the following groups: (1) carboxylic acid esters obtained by esterification of the hydroxy group of a hydroxyl compound, in which the non-carbonyl moiety of the carboxylic acid portion of the ester grouping is selected from straight or branched chain alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, t-butyl, sec-butyl or n-butyl), alkoxyalkyl (e.g., methoxymethyl), aralkyl (e.g., benzyl), aryloxyalkyl (for example, phenoxymethyl), aryl (e.g., phenyl optionally substituted with, for example, halogen, Ci_ ₄ alkyl, -0-(Ci_ ₄ alkyl) or amino); (2) sulfonate esters, such as alkyl- or aralkylsulfonyl (for example, methanesulfonyl); (3) amino acid esters, including those

corresponding to both natural and non-natural amino acids (e.g., L-valyl or L-isoleucyl); (4) phosphonate esters and (5) mono-, di- or triphosphate esters. The phosphate esters may be further esterified by, for example, a Ci_ ₂ o alcohol or reactive derivative thereof, or by a 2,3-di (C ₆ _ ₂₄ )acyl glycerol.

One or more compounds of the invention may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the invention embrace both solvated and unsolvated forms. "Solvate" means a physical association of a compound of this invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. "Solvate" encompasses both solution-phase and isolatable solvates. Non- limiting examples of solvates include ethanolates, methanolates, and the like. A "hydrate" is a solvate wherein the solvent molecule is water.

One or more compounds of the invention may optionally be converted to a solvate. Preparation of solvates is generally known. Thus, for example, M. Caira et al, J. Pharmaceutical Sci., 93(3), 601-611 (2004) describe the preparation of the solvates of the antifungal fluconazole in ethyl acetate as well as from water. Similar preparations of solvates, hemisolvates, hydrates and the like are described by E. C. van Tonder et al, AAPS PharmSciTechours. , 5(1), article 12 (2004); and A. L. Bingham et al, Chem. Commun., 603-604 (2001). A typical, non-limiting, process involves dissolving the inventive compound in desired amounts of the desired solvent (organic or water or mixtures thereof) at a higher than room temperature, and cooling the solution at a rate sufficient to form crystals which are then isolated by standard methods.

Analytical techniques such as, for example IR spectroscopy, show the presence of the solvent (or water) in the crystals as a solvate (or hydrate).

The Tetracyclic Heterocycle Compounds can form salts which are also within the scope of this invention. Reference to a Tetracyclic Heterocycle Compound herein is understood to include reference to salts thereof, unless otherwise indicated. The term "salt(s)", as employed herein, denotes acidic salts formed with inorganic and/or organic acids, as well as basic salts formed with inorganic and/or organic bases. In addition, when a Tetracyclic Heterocycle Compound contains both a basic moiety, such as, but not limited to a pyridine or imidazole, and an acidic moiety, such as, but not limited to a carboxylic acid, zwitterions ("inner salts") may be formed and are included within the term "salt(s)" as used herein. In one embodiment, the salt is a pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salt. In another embodiment, the salt is other than a pharmaceutically acceptable salt. Salts of the Compounds of Formula (I) may be formed, for example, by reacting a Tetracyclic Heterocycle Compound with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.

Exemplary acid addition salts include acetates, ascorbates, benzoates,

benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, fumarates, hydrochlorides, hydrobromides, hydroiodides, lactates, maleates, methanesulfonates, naphthalenesulfonates, nitrates, oxalates, phosphates, propionates, salicylates, succinates, sulfates, tartarates, thiocyanates, toluenesulfonates (also known as tosylates) and the like.

Additionally, acids which are generally considered suitable for the formation of pharmaceutically useful salts from basic pharmaceutical compounds are discussed, for example, by P. Stahl et al, Camille G. (eds.) Handbook of Pharmaceutical Salts. Properties, Selection and Use. (2002) Zurich: Wiley- VCH; S. Berge et al, Journal of Pharmaceutical Sciences (1977) 66(1) 1-19; P. Gould, International J. of Pharmaceutics (1986) 33 201-217; Anderson et al, The Practice of Medicinal Chemistry (1996), Academic Press, New York; and in The Orange Book (Food & Drug Administration, Washington, D.C. on their website). These disclosures are incorporated herein by reference thereto.

Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (for example, organic amines) such as dicyclohexylamine, t-butyl amine, choline, and salts with amino acids such as arginine, lysine and the like. Basic nitrogen- containing groups may be quarternized with agents such as lower alkyl halides (e.g., methyl, ethyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, and dibutyl sulfates), long chain halides (e.g., decyl, lauryl, and stearyl chlorides, bromides and iodides), arylalkyl halides (e.g., benzyl and phenethyl bromides), and others.

All such acid salts and base salts are intended to be pharmaceutically acceptable salts within the scope of the invention and all acid and base salts are considered equivalent to the free forms of the corresponding compounds for purposes of the invention.

Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well-known to those skilled in the art, such as, for example, by chromatography and/or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. Sterochemically pure compounds may also be prepared by using chiral starting materials or by employing salt resolution techniques. Also, some of the Tetracyclic Heterocycle Compounds may be

atropisomers (e.g., substituted biaryls) and are considered as part of this invention. Enantiomers can also be directly separated using chiral chromatographic techniques.

It is also possible that the Tetracyclic Heterocycle Compounds may exist in different tautomeric forms, and all such forms are embraced within the scope of the invention. For example, all keto-enol and imine-enamine forms of the compounds are included in the invention.

All stereoisomers (for example, geometric isomers, optical isomers and the like) of the present compounds (including those of the salts, solvates, hydrates, esters and prodrugs of the compounds as well as the salts, solvates and esters of the prodrugs), such as those which may exist due to asymmetric carbons on various substituents, including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers, and diastereomeric forms, are contemplated within the scope of this invention. If a Tetracyclic Heterocycle Compound incorporates a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures, are embraced within the scope of the invention.

Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers, or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers. The chiral centers of the present invention can have the S or R configuration as defined by the IUPAC 1974 Recommendations. The use of the terms "salt", "solvate", "ester", "prodrug" and the like, is intended to apply equally to the salt, solvate, ester and prodrug of enantiomers, stereoisomers, rotamers, tautomers, racemates or prodrugs of the inventive compounds.

In the Compounds of Formula (I), the atoms may exhibit their natural isotopic abundances, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature. The present invention is meant to include all suitable isotopic variations of the compounds of generic Formula I. For example, different isotopic forms of hydrogen (H) include protium (1H) and deuterium ( ² H). Protium is the predominant hydrogen isotope found in nature. Enriching for deuterium may afford certain therapeutic advantages, such as increasing in vivo half-life or reducing dosage requirements, or may provide a compound useful as a standard for characterization of biological samples.

Isotopically-enriched Compounds of Formula (I) can be prepared without undue experimentation by conventional techniques well known to those skilled in the art or by processes analogous to those described in the Schemes and Examples herein using appropriate isotopically-enriched reagents and/or intermediates. In one embodiment, a Compound of Formula (I) has one or more of its hydrogen atoms replaced with deuterium.

The Tetracyclic Heterocycle Compounds are useful in human and veterinary medicine for treating or preventing HIV infection in a subject. In one embodiment, the

Tetracyclic Heterocycle Compounds can be inhibitors of HIV viral replication. In a specific embodiment, the Tetracyclic Heterocycle Compounds are inhibitors of HIV- 1. Accordingly, the Tetracyclic Heterocycle Compounds are useful for treating HIV infections and AIDS. In accordance with the invention, the Tetracyclic Heterocycle Compounds can be administered to a subject in need of treatment or prevention of HIV infection.

Accordingly, in one embodiment, the invention provides methods for treating HIV infection in a subject comprising administering to the subject an effective amount of at least one Tetracyclic Heterocycle Compound or a pharmaceutically acceptable salt thereof. In a specific embodiment, the present invention provides methods for treating AIDS in a subject comprising administering to the subject an effective amount of at least one Tetracyclic Heterocycle Compound or a pharmaceutically acceptable salt thereof.

List of Abbreviations

Anal. analytical

ACN acetonitrile

AcOH acetic acid

w-BuLi w-butyl lithium

BnBr benzyl bromide

br broad

calc. calculated

m-CPBA 3-chloroperoxybenzoic acid

d doublet

DBU 1 ,8-diazabicycloundec-7-ene

DCM dichloromethane

DEA diethylamine

DIPEA or DIEA N,N-diisopropylethylamine

DMF dimethylformamide

DMSO dimethyl sulfoxide

ESI electrospray ionization

Et ₂ 0 diethylether

Et ₃ N triethylamine

EtOAc ethyl acetate

EtOH ethanol

HC1 hydrochloric acid

HPLC high-pressure liquid chromatography

IPA sopropyl alcohol

IPAc sopropyl acetate

KF Karl-Fischer titration (to determine water content)

KOr-Bu potassium tert-butoxide

LCMS liquid chromatography-mass spectrometry

LiHMDS lithum hexamethyl silazane

m multiplet MeCN = acetonitrile

MeOH = methyl alcohol

MPa = millipascal

MS = mass spectroscopy

MTBE = methyl tert-butyl ether

NaHCC"3 = sodium bicarbonate

NBS = N-bromosuccinimide

NHS = normal human serum

NMP = N-methylpyrrolidine

NMR = nuclear magnetic resonance spectroscopy

Piv = pivalate, 2,2-dimethylpropanoyl

Pd/C = palladium on carbon

rt = room temperature

s = singlet

SFC = supercritical fluid chromatography

SiC"2 = silical gel

t = triplet

TFA = trifluoroacetic acid

THF = tetrahydrofuran

TLC = thin-layer chromatography

TMSN ₃ = trimethylsilyl azide

p-TsOH = para-toluene sulfonic acid

wt% = percentage by weight

The Compounds of Formula (I)

The present invention provides Tetracyclic Heterocycle Compounds of Formula

(I)

and pharmaceutically acceptable salts thereof, wherein m, n, X, Y, Z, R ² and R ³ are defined above for the Compounds of Formula (I). In one embodiment, X is O.

In another embodiment, X is -CH ₂ -.

In another embodiment, X is -N(-C(0)CH ₃ )-.

In one embodiment, Y is O.

In another embodiment, Y is -N(R ⁶ )-.

In another embodiment, Y is Ci-C ₃ alkylene.

In still another embodiment, Y is -CH ₂ -.

In one embodiment, Z is a single bond.

In another embodiment, Z is -C(R ⁷ )-.

In one embodiment, R ¹ represents 1 or 2 optional phenyl group substituents, each independently selected from Ci-C ₆ alkyl, -0-(Ci-C ₆ alkyl), halo.

In another embodiment, R ¹ represents 1 or 2 optional phenyl group substituents, each independently selected from halo.

In another embodiment, R ¹ represents an ortho F group and a para F group.

In one embodiment, R ³ is H.

In another embodiment, R ³ is Ci-C ₆ alkyl.

In another embodiment, R ³ is methyl.

In one embodiment, each occurrence of R ^3a is H.

In another embodiment, at least one occurrence of R ^3a is Ci-C ₆ alkyl.

In one embodiment, R ⁴ is H.

In another embodiment, R ⁴ is Ci-C ₆ alkyl.

In one embodiment, R ⁵ is H.

In another embodiment, R ⁵ is Ci-C ₆ alkyl.

In another embodiment, R ⁵ is -C(0)R ⁸ .

In still another embodiment, R ⁵ is -S0 ₂ R ⁸ .

In one embodiment, each occurrence of R ⁶ is H or Ci-C ₆ alkyl.

In another embodiment, at least one occurrence of R ⁶ is Ci-C ₆ alkyl.

In one embodiment, R ⁷ is H.

In another embodiment, R ⁷ is Ci-C ₆ alkyl.

In another embodiment, R ⁷ is -0-(Ci-C ₆ alkyl). In one embodiment, the com ounds of formula (I) have the formula (la):

(la)

or a pharmaceutically acceptable salt or prodrug thereof,

wherein:

X is O or -N(-C(0)CH ₃ )-)-;

R ¹ represents up to 2 optional phenyl group substituents, each independently selected from halo;

m is 0 or 1 ; and

n is 1, 2 or 3, such that the sum of m+n is 2 or 3.

In one embodiment, for the compounds of formulas (I) and (la), m is 0.

In another embodiment, for the compounds of formulas (I) and (la), m is 1.

In another embodiment, for the compounds of formulas (I) and (la), m is 2.

In one embodiment, for the compounds of formulas (I) and (la), n is 1.

In another embodiment, for the compounds of formulas (I) and (la), n is 2.

In another embodiment, for the compounds of formulas (I) and (la), n is 3.

In one embodiment, for the compounds of formulas (I) and (la), m is 0 and n is 2.

In another embodiment, for the compounds of formulas (I) and (la), m is 0 and n is 3.

In another embodiment, for the compounds of formulas (I) and (la), m is 1 and n is 1.

In one embodiment, variables m, n, X, Y, Z, R ¹ , R ² and R ³ for the Compounds of Formula (I) are selected independently of each other.

In another embodiment, the Compounds of Formula (I) are in substantially purified form.

Other embodiments of the present invention include the following: (a) A pharmaceutical composition comprising an effective amount of a Compound of Formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

(b) The pharmaceutical composition of (a), further comprising a second therapeutic agent selected from the group consisting of HIV antiviral agents, immunomodulators, and anti-infective agents.

(c) The pharmaceutical composition of (b), wherein the HIV antiviral agent is an antiviral selected from the group consisting of HIV protease inhibitors, HIV integrase inhibitors, nucleoside reverse transcriptase inhibitors, CCR5 co-receptor antagonists and non- nucleoside reverse-transcriptase inhibitors.

(d) A pharmaceutical combination that is (i) a Compound of Formula (I) and (ii) a second therapeutic agent selected from the group consisting of HIV antiviral agents, immunomodulators, and anti-infective agents; wherein the Compound of Formula (I) and the second therapeutic agent are each employed in an amount that renders the combination effective for inhibiting HIV replication, or for treating HIV infection and/or reducing the likelihood or severity of symptoms of HIV infection.

(e) The combination of (d), wherein the HIV antiviral agent is an antiviral selected from the group consisting of HIV protease inhibitors, HIV integrase inhibitors, nucleoside reverse transcriptase inhibitors, CCR5 co-receptor antagonists and non-nucleoside reverse-transcriptase inhibitors.

(f) A method of inhibiting HIV replication in a subject in need thereof which comprises administering to the subject an effective amount of a Compound of Formula (I).

(g) A method of treating HIV infection and/or reducing the likelihood or severity of symptoms of HIV infection in a subject in need thereof which comprises

administering to the subject an effective amount of a Compound of Formula (I).

(h) The method of (g), wherein the Compound of Formula (I) is administered in combination with an effective amount of at least one second therapeutic agent selected from the group consisting of HIV antiviral agents, immunomodulators, and anti-infective agents.

(i) The method of (h), wherein the HIV antiviral agent is an antiviral selected from the group consisting of HIV protease inhibitors, HIV integrase inhibitors, nucleoside reverse transcriptase inhibitors, CCR5 co-receptor antagonists and non-nucleoside reverse- transcriptase inhibitors. (j) A method of inhibiting HIV replication in a subject in need thereof which comprises administering to the subject the pharmaceutical composition of (a), (b) or (c) or the combination of (d) or (e).

(k) A method of treating HIV infection and/or reducing the likelihood or severity of symptoms of HIV infection in a subject in need thereof which comprises

administering to the subject the pharmaceutical composition of (a), (b) or (c) or the combination of (d) or (e).

The present invention also includes a compound of the present invention for use (i) in, (ii) as a medicament for, or (iii) in the preparation of a medicament for: (a) medicine, (b) inhibiting HIV replication or (c) treating HIV infection and/or reducing the likelihood or severity of symptoms of HIV infection. In these uses, the compounds of the present invention can optionally be employed in combination with one or more second therapeutic agents selected from HIV antiviral agents, anti-infective agents, and immunomodulators.

Additional embodiments of the invention include the pharmaceutical compositions, combinations and methods set forth in (a)-(k) above and the uses set forth in the preceding paragraph, wherein the compound of the present invention employed therein is a compound of one of the embodiments, aspects, classes, sub-classes, or features of the

compounds described above. In all of these embodiments, the compound may optionally be used in the form of a pharmaceutically acceptable salt or hydrate as appropriate. It is understood that references to compounds would include the compound in its present form as well as in different forms, such as polymorphs, solvates and hydrates, as applicable.

It is further to be understood that the embodiments of compositions and methods provided as (a) through (k) above are understood to include all embodiments of the compounds, including such embodiments as result from combinations of embodiments.

The Compounds of Formula (I) may be referred to herein by chemical structure and/or by chemical name. In the instance that both the structure and the name of a Compound of Formula (I) are provided and a discrepancy is found to exist between the chemical structure and the corresponding chemical name, it is understood that the chemical structure will predominate.

Non- limiting examples of the Compounds of Formula (I) include compounds 1- 10 as set forth below, and pharmaceutically acceptable salts thereof.

Methods For Making the Compounds of Formula (I)

The Compounds of Formula (I) may be prepared from known or readily prepared starting materials, following methods known to one skilled in the art of organic synthesis. Methods useful for making the Compounds of Formula (I) are set forth in the Examples below and generalized in Scheme 1 below. Alternative synthetic pathways and analogous structures will be apparent to those skilled in the art of organic synthesis. Scheme 1 describes a method for making the compounds of formula (I), which corresponds to the bridged tetracyclic 4-pyridinone compounds of Formula (I).

Scheme 1

steps 4&5 G A compound of formula A is oxidized to a dihydropyridinone of formula B then condensed with amines of type C to provide bridged dihydropyridinone compounds of formula D. Bromination followed by carbonylation with amines of formula F and deprotection of the benzyl protecting group provides the product G. EXAMPLES

General Methods

The compounds described herein can be prepared according to the procedures of the following schemes and examples, using appropriate materials and are further exemplified by the following specific examples. The compounds illustrated in the examples are not, however, to be construed as forming the only genus that is considered as the invention. The examples further illustrate details for the preparation of the compounds of the present invention. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds. All temperatures are degrees Celsius unless otherwise noted. Mass spectra (MS) were measured by electrospray ion- mass spectroscopy (ESI). 1H NMR spectra were recorded at 400-500 MHz. Compounds described herein were synthesized as a racemic mixture unless otherwise stated in the experimental procedures.

Example 1

Preparation of Intermediate Compound A

1 f A

Step A - Synthesis of Intermediate Compound lb

To a 20L 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 3-hydroxy-2-methyl-4H-pyran-4-one la (2 kg, 15.87 mol, 1.00 equiv), MeCN (10 L), potassium carbonate (2.63 kg, 19.01 mol, 1.20 equiv), BnBr (2.85 kg, 16.67 mol, 1.05 equiv). The resulting solution was heated to reflux overnight. The solid was filtered. The filtrate was concentrated in vacuo. This resulted in 3.5 kg (crude) of 3-(benzyloxy)- 2-methyl-4H-pyran-4-one lb as brown oil which was used directly.

Step B - Synthesis of Intermediate Compound lc

Into a 20-L 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 3-(benzyloxy)-2-methyl-4H-pyran-4-one lb (930 g, 4.30 mol, 1.00 equiv), THF (4.75 L). This was followed by the addition of LiHMDS (5 L, 1 N in THF, 1.20 equiv) dropwise with stirring at -60°C. The resulting solution was stirred for 3 h at -60°C. To this was added benzaldehyde (450 g, 4.25mol, 1.20 equiv) dropwise with stirring at -60°C. The resulting solution was allowed to react, with stirring, for an additional 2 h at -60°C. The reaction was then quenched by the addition of 1.2 L of cone, hydrogen chloride dropwise at - 20°C. The resulting solution was diluted with 10 L/5 L of EtOAc/H ₂ 0. The aqueous phase was extracted with 2x5 L of EtOAc and the organic layers combined, dried and concentrated in vacuo. The solid was washed with Et ₂ 0 (3x2 L). This resulted in 3-(benzyloxy)-2-(2-hydroxy-2- phenylethyl)-4H-pyran-4-one (907 g, 65% yield) lc, as yellow crystals. Step C - Synthesis of Intermediate Compound Id

Into a 20-L 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 3-(benzyloxy)-2-(2-hydroxy-2-phenylethyl)-4H-pyran-4-one lc (900 g, 2.79 mol, 1.00 equiv), dichloromethane (4.5 L), TEA (423.8 g, 4.19 mol, 1.50 equiv). This was followed by the addition of MsCl (419.0 g, 3.66mol, 1.31 equiv) dropwise with stirring at -30°C. The resulting solution was stirred for 2 h at -30°C. To this was added DBU (1.698 kg, 11.15mol, 4.00 equiv) dropwise with stirring at 0°C. The resulting solution was stirred for an additional 20 min at 0°C. The pH of the solution was adjusted to 5 with hydrogen chloride (cone). The combined organic layer was washed with 3x3 L of Na ₂ S0 ₃ , dried over anhydrous sodium sulfate and concentrated in vacuo. This resulted in 3-(benzyloxy)-2-[(E)-2- phenylethenyl]-4H-pyran-4-one (740 g, 87% yield) Id as a yellow solid.

Step D - Synthesis of Intermediate Compound le

Into a 20-L 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 3-(benzyloxy)-2-[(E)-2-phenylethenyl]-4H-pyran-4-one Id (950 g, 3.12 mol, 1.00 equiv), MeCN (3 L), EtOAc (3 L), water (3 L). To this was added RuCl ₃ (13 g, 62.67 mmol, 0.02 equiv) at 15°C. This was followed by the addition of NaI0 ₄ (2.673 kg, 12.50 mol, 4.00 equiv) in portions at 15°C in 2 hrs. To this was added sodium chlorite (847.87 g, 9.37 mol, 3.00 equiv) in portions at 20°C. The resulting solution was stirred for 2 h at 20°C. The solid was filtered out and washed with 3x2 L of THF. The combined filtrate was diluted with 5 L of Na ₂ S0 ₃ (0.7 N). The pH of the solution was adjusted to 11 with sodium hydroxide (1 mol/L). The resulting solution was extracted with 2x5 L of EtOAc. The pH of the combined aqueous layer was adjusted to 3 with hydrogen chloride (12mol/L). The resulting solution was extracted with 2x5 L of EtOAc. The combined organic layer was dried then concentrated in vacuo. The resulting solid was washed with 4x1 L of ether. This resulted in 3-(benzyloxy)-4-oxo-4H-pyran- 2-carboxylic acid (397 g ,52% yield) le as a white solid.

Step E - Synthesis of Intermediate Compound If

Into a 2-L 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 3-(benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid le (200 g, 812.30 mmol, 1.00 equiv), ethanol (800 mL), 3-aminopropane-l,2-diol (222 g, 2.44 mol, 3.00 equiv). The resulting solution was heated to reflux overnight. The resulting solution was diluted with 200 mL of water. The resulting mixture was concentrated in vacuo to remove EtOH. The resulting solution was extracted with 2x200 mL of EtOAc and the aqueous layers combined. The pH value of the solution was adjusted to 3 with hydrogen chloride (cone). The solids were collected by filtration and washed with water (2x100 mL), dried in an oven in vacuo. This resulted in 3-(benzyloxy)-l-(2,3-dihydroxypropyl)-4-oxo-l,4-dihydropyrid ine-2-carboxylic acid (200 g,77% yield) If as a white solid.

Step E - Synthesis of Intermediate Compound A

Into a 2-L 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen. This was followed by the addition of 3-(benzyloxy)-l-(2,3- dihydroxypropyl)-4-oxo-l,4-dihydropyridine-2-carboxylic acid If (200 g, 626.35 mmol, 1.00 equiv), NMP (1000 mL), sodium bicarbonate (158 g, 1.88 mol, 3.00 equiv), CH ₃ I (133.5 g, 940.54 mmol, 1.50 equiv). The resulting solution was stirred overnight at room temperature. The reaction mixture was cooled to 0 °C with a water/ice bath. The resulting solution was diluted with a solution of NaCl (73 g) in 500 mL of H ₂ 0. Then the pH value of the solution was adjusted to 4 with hydrogen chloride (cone). The reaction mixture was then stirred for another 2 hours. The solids were collected by filtration, washed with water (2x100 mL) and then dried in an oven in vacuo. This resulted in methyl 3-(benzyloxy)-l-(2,3-dihydroxypropyl)-4-oxo-l,4- dihydropyridine-2-carboxylate (117.6 g, 55% yield) A as a white solid.

Example 2

Preparation of Intermediate Compound 2e

2d 2e

- Synthesis of Intermediate Compound 2b To a stirred solution of TMSN ₃ (167.0 g, 1.41 mol) in DCM (3.0 L) was added AcOH (84 g, 1.41 mol) and the resulting solution was stirred at room temperature for 30 min. A solution of cyclopent-2-enone 2a (100 g, 1.21 mol) in DCM (200 mL) was added and then cooled to 0 °C. Et ₃ N (370 mL, 2.78 mol) was added for 30 min at the same temperature. The resulting reaction mixture was warmed to room temperature and stirred overnight. The reaction progress was monitored by TLC [40 % EtOAc in petroleum ether, using KMN0 ₄ solution to visualize the spot]. R _f values of starting material and product are 0.1 and 0.4 respectively. After completion of the reaction (TLC), the reaction mixture was diluted with water and extracted into DCM (2 x 500 mL) and washed with NaHC0 ₃ solution. The organic layer was concentrated in vacuo to provide the crude compound 2b (220 g). This was used as such in the next step without further purification.

Step B - Synthesis of Intermediate Compound 2c

To a slurry of Pd/C (10 g) in ethanol (450 mL) was added solution of compound 2b (220 g, 1.76 mol) and Boc anhydride (200 mL, 0.88 mol). The resulting reaction mixture was hydrogenated in a Parr shaker at room temperature for 5 h at 30 psi. The reaction progress was monitored by TLC [60 % EtOAc in petroleum ether, using KMn0 ₄ to visualize the spot]. R _f values of the starting material and product are 0.4 and 0.6 respectively. After completion of reaction (TLC), the reaction mixture was filtered through a Celite bed and the filtrate was concentrated in vacuo to get the crude compound 2c (180.0 g). The crude compound 2c was adsorbed on 400 g of 100-200 silica gel, which was loaded over a pre-packed column with silica gel [120 mm x 75 cm width and height of column, loaded with 2.4 kg of 100-200 silica gel]. Elution started with 10 % EtOAc/ petroleum ether and finished with 30 % EtOAc/ petroleum ether. All the pure fractions were collected, concentrated in vacuo to provide compound 2c (110 g, 31% yield) as a liquid.

Step C - Synthesis of Intermediate Compound 2d

To a stirred solution of compound 2c (110 g, 0.55 mol) in methanol (700 mL) was added NaBH ₄ (20.79 g, 0.55 mol) portion wise at 0 °C and stirred for 5 h. The reaction progress was monitored by TLC [60 % EtOAc in petroleum ether, using KMn0 ₄ to visualize the spot]. R _f values of starting material and product are 0.6 and 0.3 respectively. After completion of reaction (TLC), methanol was concentrated in vacuo and diluted with water, then extracted with EtOAc (2 x 1.0 L). The combined organic layers were dried over sodium sulfate and concentrated in vacuo to get a crude mixture of cis & trans isomers (65 g). The crude mixture was adsorbed on 200 g of 100-200 silica gel, which was loaded over a pre-packed column with silica gel [100 mm x 60 cm width and height of column, loaded with 1.2 kg of 100-200 silica gel]. Elution started with 30 % EtOAc/ petroleum ether and finished with 40 % EtOAc/ petroleum ether. All the pure fractions were collected, concentrated in vacuo to provide the compound 2d (47 g, 45% yield) as a colorless gum liquid.

Step D - Synthesis of Intermediate Compound 2e

To a stirred solution of compound 2e (47 g, 0.23 mol) in Dioxane (400 mL) was added 2M Dioxane in HC1 (150 mL) at 0 °C and stirred for 5 h. The reaction progress was monitored by TLC [100 % EtOAc, using KMn0 ₄ to visualize the spot]. R _f values of the starting material and product are 0.6 and 0.1 respectively. After completion of reaction (TLC), dioxane was concentrated in vacuo to get the crude compound 2e (36 g). The crude mixture was washed with acetonitrile to provide the title compound 2e (31 g, 96 % yield) as an off white solid. IR (KBr, cm ^"1 ): 3431, 2969, 1626 and 1024. 1H NMR (400 MHz, DMSO-d ₆ ) δ: 8.0 (s, 3 H), 4.97 (d,

1 H, / = 3.6 Hz), 4.12 (t, 1 H, / = 4.4 Hz), 3.43 (t, 1 H, / = 6 Hz), 2.12-2.0 (m, 1 H), 1.98-1.85 (m, 1 H), 1.80-1.60 (m, 3 H), 1.60-1.50 (m, 1 H). ¹³ C NMR (100.57 MHz, DMSO-d ₆ ) δ: 70.5, 49.7, 33.2, 28.3. M+l = 102.2

Example 3

Preparation of Compounds 1 and 2

A B 3b

3c 1 and 2 Step A - Synthesis of Intermediate B

To a solution of compound A (0.4 g, 1.2 mmol) in acetonitrile/water (1 : 1 - 4 mL/4 mL) was added acetic acid (7.21 mg, 0.12 mmol) and sodium periodate (0.308 g, 1.44 mmol) at room temperature. The mixture was then stirred for 2 h at the same temperature, LCMS showed the reaction was complete. Aqueous sodium thiosulfate (10%, 1.2 mL) was added and the mixture was cooled to 5-10 C, concentrated and filtered by washing with water to provide compound B (0.23 g, 61% yield) as a white solid. 1H-NMR: (400 MHz, DMSO-d ₆ ) δ 7.61 (d, / = 7.6Hz, 1H), 7.39-7.34 (m, 5H), 6.37-6.28 (m, 3H), 5.09 (s, 2H), 4.94-4.89 (m, 1H), 3.80 (s, 3H), 3.74 (d, / = 5.6 Hz, 2H). M+l: 319.9.

Step B - Synthesis of Compound 3b

To a solution of compound 3a (HC1 salt) in MeOH was added saturated NaHC0 ₃ (1 equiv) solution and the resuoting reaction was stirred for 10 minutes, then concentrated in vacuo. To the residue was added MeOH, then filtered (repeated twice to remove salts), the filtrate was concentrated in vacuo for cyclization.

Compound B (800 mg, 2.51 mmol) was taken up in MeOH (20 mL) and heated until complete dissolution. The solution was then concentrated in vacuo, and toluene (20 mL) was added stirred for 5 minutes and concentrated in vacuo. To the mixture, toluene (35 mL), acetic acid (0.8 mL, 2.51 mmol), and amino alcohol 3a (free base, 537 mg, 4.51 mmol) were added and the mixture was heated and stirred at 90 C for 2 h. The mixture was concentrated in vacuo washed with saturated aqueous NaHC0 ₃ (20 mL) and extracted with DCM (15 mL x 3). The organic layers were concentrated in vacuo and the residue was purified using column chromatography (Si0 ₂ , DCM: MeOH = 50: 1 to 30: 1) to provide compound 3b (300 mg, 34% yield) as a light yellow solid. 1H-NMR: (400 MHz, CDC1 ₃ ) δ 7.64 (d, / = 7.2Hz, 2H), 7.35-7.27 (m, 3H), 7.13 (d, / = 7.2 Hz, 1H), 6.46 (d, / = 7.2 Hz, 1H), 5.41 (d, / = 10.0 Hz, 1H), 5.35-5.34 (m, 1H), 5.25-5.19 (m, 2H), 4.59 (s, 1H), 3.90-3.84 (m, 2H), 2.04-1.97 (m, 4H), 1.77-1.75 (m, 1H), 1.56-1.51 (m, 1H). M+l: 352.9.

Step C - Synthesis of Compound 3c

To a solution of compound 3b (37 mg, 0.11 mmol) in NMP (2 mL) was added

NBS (20.6 mg, 0.12 mmol) at room temperature. The reaction mixture was stirred for 2 h, then H ₂ 0 (3 mL) was added, and then extracted with DCM (6 mL). The organic layers were washed with H ₂ 0 (2 mL) concentrated in vacuo and purified using prep-TLC (DCM: MeOH = 15: 1) to provide compound 3c (45 mg, quantitative) as a white solid. 1H-NMR: (400 MHz, CDC1 ₃ ) δ 7.66 (d, / = 6.8 Hz, 2H), 7.60 (s,lH), 7.36-7.28 (m, 3H), 5.40 (d, / = 10.0 Hz, 1H), 5.33-5.26 (m, 1H), 5.24-5.23 (m, 1H), 5.18 (d, / = 10.0 Hz, 1H), 4.60 (s, 1H), 4.01-3.89 (m, 2H),

2.05-2.01 (m, 4H), 1.77-1.72 (m, 1H), 1.56-1.52 (m, 1H). M+l: 430.8. Steps D&E - Synthesis of Compound 1&2

To a solution of compound 3c (300 mg, 0.7 mmol) in DMSO (2 mL) was added benzyl amine 3d (1 g, 7.0 mmol), Et ₃ N (0.61 mL, 3.5 mmol) and Pd(PPh ₃ ) ₄ (80.6 mg, 0.07 mmol) at room temperature under CO atmosphere. The mixture was then heated to 90°C and stirred for 15 h. Reaction progresss was followed by LC-MS. Then H ₂ 0 (20 mL) was added, extracted with EtOAc (15 mL x 4), and the organic layers were washed with H ₂ 0 (10 x 2 mL). The mixture was concentrated in vacuo and purified using column chromatography (Si0 ₂ , DCM: MeOH = 100: 1 to 20: 1) to provide the racemic mixture (130 mg, 34% yield) as a white solid, which was resolved and deprotected using the procedures below. 1H-NMR: (400 MHz, CDC1 ₃ ) δ 8.33 (s, 1H), 7.61 (d, / = 7.2 Hz, 2H), 7.35-7.30 (m, 3H), 6.79-6.74 (m, 3H), 5.35-5.33 (m, 2H), 5.26-5.23 (m, 1H), 5.20-5.17 (m, 1H), 4.81 (s, 2H), 4.62 (s, 2H), 4.13-4.11 (m, 1H), 4.00-3.97 (m, 1H), 2.06-1.99 (m, 4H), 1.79-1.76 (m, 1H), 1.55-1.54 (m, 1H). M+l: 522.0.

Separated by chiral SFC (SFC condition: Column: Chiralpak AD 250 x 30mm I.D., 20μιη, Mobile phase: Supercritical C0 ₂ /A (0.1%) NH ₃ ^■ H ₂ 0 = 45/55 at 80 mL/min, A= EtOH+ACN (2: 1), Column Temp: 38 ^° C, Nozzle Pressure: 100 Bar, Nozzle Temp: 60 ^° C,

Evaporator Temp: 20 C, Trimmer Temp: 25 C, Wavelength: 220 nm) to provide Peak 1 (50 mg) & Peak 2 (50 mg).

To a solution of compound from peak 1 (50 mg, 0.096 mmol) in DMF (2 mL) was added LiCl (120.9 mg, 2.88 mmol) at room temperature under N ₂ atmosphere, then the mixture was stirred at 95 C for 2 h, LCMS showed the reaction was completed. The mixture was purified using prep-HPLC to provide compound 1 (30 mg, 73% yield) as a white solid. ^-NMR: (400 MHz, DMSO-d ₆ ) δ 12.47 (s, 1H), 10.37 (t, / = 6.0Hz, 1H), 8.46 (s, 1H), 7.39-7.37 (m, 1H), 7.27-7.22 (m, 1H), 7.09-7.06 (m, 1H), 5.46-5.43 (m, 1H), 5.09 (s, 1H), 4.69 (d, / = 8.8Hz, 1H), 4.60 (s, 1H), 4.53 (t, / = 6.0Hz, 2H), 4.06-4.02 (m, 1H), 1.94 (s, 4H), 1.83 (d, / = 12.0Hz, 1H), 1.59-1.56 (m, 1H). M+l= 431.9. To a solution of compound from peak 2 (50 mg, 0.096 mmol) in DMF (2 mL) was added LiCl (120.9 mg, 2.88 mmol) at room temperature under N ₂ atmosphere, then the mixture was stirred at 95 C for 2 h, LCMS showed the reaction was completed. The mixture was purified using prep-HPLC to provide compound 2 (31 mg, 75% yield) as a white solid. ^-NMR: (400 MHz, DMSO-d ₆ ) δ 12.47 (s, 1H), 10.37 (t, / = 6.0Hz, 1H), 8.46 (s, 1H), 7.39-7.37 (m, 1H), 7.27-7.22 (m, 1H), 7.09-7.06 (m, 1H), 5.46-5.43 (m, 1H), 5.09 (s, 1H), 4.69 (d, / = 8.8Hz, 1H), 4.60 (s, 1H), 4.53 (t, / = 6.0Hz, 2H), 4.06-4.02 (m, 1H), 1.94 (s, 4H), 1.83 (d, / = 12.0Hz, 1H), 1.59-1.56 (m, 1H). M+l= 431.9.

Example 4

Preparation of Intermediate Compound 4e

4a 4b 4c

LiAIH

4d 4e

Step A - Synthesis of Intermediate Compound 4b

To a solution of compound 4a (4.0 g, 35.1 mmol) in DCM (50 ml) and MeOH (5 mL) was added TMSCH ₂ N ₂ (30 mL, 60.0 mmol) at 0 °C. The solution was allowed to stir at 0°C for 1.5 h. The solvent was evaporated in vacuo to provide the compound 4b (4.4 g, 98% yield) as an oil.

Step B - Synthesis of Intermediate Compound 4c

To a solution of compound 4b (4.4 g, 34.3 mmol) and dibenzylamine (8.13 g, 41.2 mmol) in AcOH (5 mL)/THF (50 mL) at room temperature was added NaBH(OAc) ₃ (17.5 g, 82 mmol) and allowed to stir at room temperature overnight. The mixture was concentrated in vacuo and diluted with H ₂ 0 (100 mL), the pH was adjusted to 8 with aqueous NaHC0 ₃ , and then extracted with EtOAc (80 mL x 3). The combined organic layers were concentrated in vacuo and the residue was purified using column chromatography (petroleum ether: EtOAc 100: 1 to 30: 1) to provide compound 4c (7.35 g, 69%> yield) as a colorless oil. Step C - Synthesis of Intermediate Compound 4d To a solution of compound 4c (7.35 g, 24.88 mmol) in THF (40 mL) at 0°C was added to a solution of L1AIH ₄ (1.03 g, 27.4 mmol) in THF (40 mL) dropwise. The mixture solution was allowed to stir at 0°C for 2.5 h then mixture was quenched with H ₂ 0 (1 mL), 15%NaOH (1 mL) and H ₂ 0 (3 mL), then dried over MgS0 ₄ . The solution was filtered and concentrated in vacuo to provide compound 4d (6.0 g, 86% yield) as an oil.

Step D - Synthesis of Intermediate Compound 4e

A mixture of compound 4d (4.69 g, 16.67 mmol) and 10% Pd/C (1.77 g , 1.67 mmol) in AcOH (2.0 mL)/EtOH (40 mL) was allowed to stir at room temperature under H ₂ (50 psi) for 16 h. The mixture was filtered through Celite eluting with excess 1 : 1 MeOH/DCM, and the filtrate was concentrated in vacuo. The resulting residue was dissolved in 45 mL MeOH. 1 mL AcOH was added to the solution, and it was loaded onto a pre-packed cation exchane column.

The column was washed with 250 mL MeOH. Product was eluted off the column with 250 mL

2 N NH ₃ in MeOH. The filtrate was concentrated in vacuo to provide compound 4e (1.39 g, 82% yield) as a clear oil, and a ~5: 1 mixture of cis/trans isomers. Data reported are for the major cis isomer. 1H NMR: (500 MHz, CD ₃ OD) δ 3.45-3.40 (m, 2H), 3.28-3.20(m, 1H), 2.38-2.24 (m,

2H), 2.18-2.00 (m, 1H), 1.57-1.41 (m, 2H).

Example 5

Preparation of Compound 3

Step A - Synthesis of Compound 5a Compound B (1000 mg, 3.13 mmol) was suspended in MeOH (5 mL) and heated at 65 °C for 15 mins, to complete dissolution. The solution was then concentrated in vacuo and THF (31 mL) was added. With stirring, acetic acid (1.03 mL mL, 17.2 mmol), and aminoalcohol 4e (950 mg, 9.40 mmol) were added, and the reaction mixture was heated and stirred at 70 C for 5 h, until LCMS analysis indicated complete consumption of starting material. LCMS showed a ratio 5a: 5b ~1 : 1. The mixture was concentrated in vacuo and the residue was purified directly by gradient elution on Si0 ₂ (2% to 8% MeOH/DCM over 35 mins) to provide 5a (370 mg, 34% yield) as a tan gum. 1H-NMR: (400 MHz, CD ₃ OD) δ 7.77 (d, / = 7.2 Hz, 1H), 7.51-7.49 (m, 2H), 7.34-7.29 (m, 3H), 6.58 (d, / = 7.2 Hz, 1H), 5.56-5.55 (m, 1H), 5.16 (s, 2H), 4.48-4.45 (m, 1H), 4.35-4.26 (m, 1H), 3.94 (s, 2H), 3.68-3.66 (m, 1H), 2.82-2.78 (m, 1H), 2.67- 2.52 (m, 2H), 2.09-2.02 (m, 1H), 1.86-1.81 (m, 1H). M+l: 352.9.

Step B - Synthesis of Compound 5c

To a solution of compound 5a (50 mg, 0.142 mmol) in DCM (1.5 mL) was added NBS (30.3 mg, 0.170 mmol) at room temperature. The mixture was stirred for 45 mins, concentrated in vacuo, and purified directly by reverse phase chromatogrpahy (SunFire™ Prep C18 OBD™ 5um 30 x 150 mm column; 5 to 95% CH ₃ CN/water with 0.1% TFA modifier over 18 minutes). Product was extracted out of the combined aquoues fraction with 2x 25 mL DCM. The combined organics were dried over Na ₂ S0 ₄ , filtered, and concentrated in vacuo to afford compound 5c (56 mg, 92% yield) as a white solid. 1H-NMR: (400 MHz, CD ₃ OD) δ 8.29 (s, 1H), 7.53-7.51 (m, 2H), 7.34-7.30 (m, 3H), 5.59-5.56 (m, 1H), 5.18 (s, 2H), 4.93-4.92 (m, 1H), 4.48- 4.47 (m, 1H), 4.34-4.33 (m, 1H), 3.94 (s, 2H), 2.84-2.78 (m, 1H), 2.70-2.66 (m, 2H), 2.07-2.04 (m, 1H), 1.87-1.84 (m, 1H). M+l: 430.8. Steps C&D - Synthesis of Compound 3

To a solution of compound 5c (56 mg, 0.130 mmol) in DMSO (4.3 mL) was added benzyl amine 3d (74.3 mg, 0.519 mmol), DIEA (0.113 mL, 0.649 mmol) and Pd(PPh ₃ ) ₄ (60 mg, 0.052 mmol) at room temperature. The resulting suspension was degassed under N ₂ for 5 mins, evacuated, and back-filled with CO _(g) three times. The mixture was then heated to 105 °C and stirred under a balloon of CO _(g) for 1 h. The reaction mixture was cooled to room temperature, filtered, and purified directly by reverse phase chromatogrpahy (SunFire™ Prep C18 OBD™ 5um 30 x 150 mm column; 5 to 95% CH ₃ CN/water with 0.1% TFA modifier over 18 minutes). Product was extracted out of the combined aquoues fraction with 2x 25 mL DCM. The combined organics were dried over Na ₂ S0 ₄ , filtered, and concentrated in vacuo to afford the penultimate intermediate (38 mg, 56% yield) as a tan solid.

A solution of the intermediate product above (15 mg, 0.029 mmol) in MeOH (1 mL) was degassed with N ₂ for 2 min, and then charged with 10% Pd/C (6.12 mg, 0.0058 mmol). The resulting suspension was evacuated, and back-filled with H ₂ (gas) three times. The mixture was then stirred at room temperature for 2 h. The reaction mixture was filtered, and then purified directly by reverse phase chromatogrpahy (SunFire™ Prep C18 OBD™ 5um 30 x 150 mm column; 5 to 95% CHsCN/water with 0.1% TFA modifier over 18 minutes). Product was isolated by lyophilization to afford compound 3 (7.5 mg, 60%> yield) as an off-white solid. ¹ HNMR: (400 MHz, DMSO-d ₆ ) δ 12.49 (s, 1H), 10.37 (s, 1H), 8.55 (s, 1H), 7.40-7.39 (m, 1H), 7.27-7.22 (m, 1H), 7.07-7.05 (m, 1H), 5.78 (s, 1H), 4.82-4.81 (m,lH), 4.58-4.55 (m, 4H), 3.90- 3.87 (m, 2H), 2.59-2.52 (m, 3H), 2.10-2.06 (m, 1H), 1.72-1.67 (m, 1H), M+l = 432.0

Example 6

Preparation of Intermediate Compound 6e

XX ^■ selectride f^^

NHBoc HCr ^-^NHBoc DEAD, PPh ₃

6b

HCI

6c 6d 6e

Step A - Synthesis of Intermediate Compound 6b

To a solution of compound 6a (5.0 g, 23.44 mmol) in THF (50 ml) was added L- Selectride (35.2 mL, 35.2 mmol) at -78°C. The mixture was stirred at -78°C for 2 h. TLC showed the reaction was complete and the reaction was quenched with 10% aqueous NaOH (20 mL). After concentration, the residue was diluted with EtOAc (200 mL), washed with brine (200 mL), dried over Na ₂ S0 ₄ , and concentrated in vacuo. The residue was purified using column

chromatography (Si0 ₂ , Petroleum ether: EtOAc = 10: 1 to 1 : 1) to provide compound 6b (4.1 g, 81 % yield) as a white solid.

Step B - Synthesis of Intermediate Compound 6c To a solution of compound 6b (4.1 mg, 19.04 mmol), 4-nitrobenzoic acid (3.82 g, 22.85 mmol), and PPh ₃ (9.9g, 38.1 mmol) in THF (60 ml) was added DEAD (6.03 mL, 38.1 mmol) at 0°C. The reaction mixture was then stirred at 25°C for 16 h, quenched with water (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic phase was washed with water (100 mL x 2), dried over Na ₂ S0 ₄ , and concentrated in vacuo. The residue was purified using column chromatography (Si02, Petroleum ether: EtOAc = 10: 1 to 5: 1) to provide compound 6c (1.3 g, 81% yield) as a white solid.

Step C - Synthesis of Intermediate Compound 6d

To a solution of compound 6c (1.3 g, 3.57 mmol) in MeOH (40 mL) was added

K ₂ C0 ₃ (1.97 g, 14.27 mmol). The mixture was stirred at room temperature for 16 h. After concentration, the residue was diluted with EtOAc (50 mL), washed with water (50 mL) and brine (50 mL), dried over Na ₂ S0 ₄ , and concentrated in vacuo to provide compound 6d (700 mg, 91 ) yield) as a white solid.

Step D - Synthesis of Intermediate Compound 6e

A mixture of compound 6d (700 mg, 3.25 mmol) and 4M HCl/MeOH (10 mL) was stirred at room temperature for 1 h and concentrated in vacuo to provide compound 6e (350 mg, 93% yield) as a brown oil. ¹ HNMR: (400 MHz, DMSO-d ₆ ) δ 3.57-3.51 (m, 1H), 3.06-2.99 (m, lH), 2.12 (d, / = 15.6 Hz, 1H), 1.85-1.75 (m, 3H), 1.30-1.14 (m, 4H). M+l=l 16.

Example 7

Preparation of Compound 4

4 Step A - Synthesis of Compound 7a

Compound B (200 mg, 0.626 mmol) was taken up in MeOH (5 mL) and heated until complete dissolution. The solution was then concentrated in vacuo, toluene (20 mL) was then added and the solution was stirred for 5 minutes and concentrated in vacuo. To the mixture, toluene (20 mL), acetic acid (263 mg, 4.38 mmol), and amino alcohol 6e (free base, 537 mg,

4.51 mmol) were added, and the mixture was heated and stirred at 90 C for 1.5 h. The mixture was concentrated in vacuo and the residue was purified using prep-TLC separation to provide compound 7a (50 mg, 22% yield) as a solid. Step B - Synthesis of Compound 7b

To a solution of compound 7a (50 mg, 0.136 mmol) in DCM (3 mL) was added NBS (48.6 mg, 0.273 mmol) at room temperature. The mixture was stirred for 2 h, then concentrated in vacuo and purified using prep-TLC (DCM: MeOH = 15: 1) to provide compound 7b (20 mg, 74% yield) as a yellow oil.

Steps C&D - Synthesis of Compound 4

To a solution of compound 7b (30 mg, 0.067 mmol) in DMSO (3 mL) was added benzyl amine 3d (33.2 mg, 0.232 mmol), DIEA (0.04 mL, 0.232 mmol) and Pd(PPh ₃ ) ₄ (11 mg, 9.30 mmol) at room temperature under CO atmosphere. The mixture was then heated to 90°C and stirred for 15h. Reaction progresss was followed by LC-MS. Then H ₂ 0 (20 mL) was added, the mixture was extracted with EtOAc (15 mL x 4), and the organic layers were washed with H ₂ 0 (10 x 2 mL). The mixture was concentrated in vacuo and the residue was purified using prep-TLC separation to provide the intermediate (10 mg, 28% yield) as a solid, which was deprotected using the procedure below.

To a solution of the intermediate (10 mg, 0.019 mmol) in DMF (0.5 mL) was added LiCl (24 mg, 0.56 mmol) at room temperature under N ₂ atmosphere, then the mixture was stirred at 90 C for 2 h, LCMS showed the reaction was completed, the mixture was purified using prep-HPLC to provide compound 4 (5 mg, 60% yield) as a pink solid. ¹ HNMR: (400 MHz, DMSO-de) δ 10.38 (s, 1H), 8.31 (s, 1H), 7.39-7.33 (m, 1H), 6.83-6.78 (m, 2H), 5.52 (s, 1H), 4.64-4.50 (m, 4H), 4.25-4.12 (m, 1H), 4.05-3.95 (m, 1H), 2.46 (d, / = 14 Hz, 1H), 2.15 (d, / = 14.8Hz, 1H), 1.89-1.81 (m, 3H), 1.55-1.43 (m, 3H). M+l=446.

Example 8

Preparation of Intermediate Compound 8e ^HO< ^ CbzCI ^H0 «,^ MsCI ^Ms0 '^

I NH ₂ ► I — NHCbz _» I VlMHCbz

Na2C03

8a 8b 8c

8d ^8e

Step A - Synthesis of Intermediate Compound 8b

To a solution of compound 8a (140 mg, 1.39 mmol) in DCM (2 mL) : H ₂ 0 (2 mL) was added Na ₂ C0 ₃ (294 mg, 2.77 mmol). The mixture was stirred at room temperature for 5 min then added CbzCI (237 mg, 1.39 mmol). The reaction mixture was stirred at room temperature for 1.5 h. After concentration, the residue was diluted with H ₂ 0 (20 mL), extracted with DCM (20 mL x 3), dried over Na ₂ S0 ₄ , and concentrated in vacuo to provide compound 8b (260 mg, 77% yield) as a brown solid.

Step B - Synthesis of Intermediate Compound 8c

To a solution of compound 8b (260 mg, 1.07 mmol) in DCM (4 mL) was added Et ₃ N (0.3 mL, 2.14 mmol). The mixture was stirred at 0°C for 5 min then added MsCI (0.17 mL, 2.14 mmol). The mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with H ₂ 0 (20 mL), extracted with DCM (20 mL x 3), dried over Na ₂ S0 ₄ , and

concentrated in vacuo to provide a crude mixture of compound 8c (400 mg) as a brown solid.

Step C - Synthesis of Intermediate Compound 8d

To a solution of compound 8c (400 mg, 1.28 mmol) in DMF (5 mL) was added

NaN ₃ (166 mg, 2.56 mmol). The mixture was stirred at 60°C for 2 h. The reaction mixture was quenched with water (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic phase was washed with water (30 mL x 2), dried over Na ₂ S0 ₄ and concentrated in vacuo to provide compound 8d (300 mg, 90% yield) as a brown oil.

Step D - Synthesis of Intermediate Compound 8e

A mixture of compound 8d (300 mg, 1.15 mmol) and 10%> Pd/C (30 mg) in MeOH (15 mL) was stirred at 30°C under H ₂ balloon for 16 h. The reaction mixture was filtered and filtrate was concentrated in vacuo to provide compound 8e (140 mg, 93% yield) as a colorless oil. 1H-NMR: (400 MHz, MeOH-d ₄ ) 3.33-3.28 (m, 2H), 2.27-2.23 (m, 1H), 1.94-1.89 (m, 2H), 1.56-1.53 (m, 2H), 1.20-1.17 (m, 1H). M+l: 101.

Example 9

Preparation of Compounds 5 and 6

Step A - Synthesis of Compound 9a

Compound B (80 mg, 0.25 mmol) was taken up in MeOH (2 mL) and heated until complete dissolution. The solution was then concentrated in vacuo, toluene (2 mL) was added and the mixture was stirred for 5 minutes and concentrated in vacuo. To the mixture, toluene (2 mL), acetic acid (0.08 mL), and diamine 8e (30 mg, 0.3 mmol) were added and the mixture was heated and stirred at 90 C for 1.5 h. The mixture was concentrated in vacuo and the residue was purified using prep-TLC separation to provide compound 9a (50 mg, 57% yield) as a brown solid.

Step B - Synthesis of Compound 9b

To a solution of compound 9a (35 mg, 0.100 mmol) in DCM (1 mL) was added Et ₃ N (0.028 mL, 0.199 mmol). The mixture was stirred at room temperature for 5 min, then added acetyl chloride (10.16 mg, 0.129 mmol). The mixture was stirred at room temperature for 2 h. The reaction was quenched with H ₂ 0 (1 mL), the residue was diluted with DCM (20 mL), washed with saturated aqueous NaHC0 ₃ (20 mL) and brine (20 mL), dried over Na ₂ S0 ₄ and concentrated in vacuo to provide compound 9b (50 mg, 77% yield) as yellow oil. Step C - Synthesis of Compound 9c

To a solution of compound 9b (30 mg, 0.076 mmol) in DCM (1 mL) was added NBS (20.36 mg, 0.114 mmol). The mixture was stirred at room temperature for 2 h. The residue was purified using prep-TLC (DCM: MeOH = 10: 1) to provide compound 9c (25 mg, 69% yield) as yellow oil.

Steps D&E - Synthesis of Compounds 5 and 6

To a solution of compound 9c (20 mg, 0.042 mmol) in DMSO (3 mL) was added DIEA (0.037mL, 0.212 mmol), (2, 4-difluorophenyl) methanamine (60.6 mg, 0.423 mmol) and

Pd(Ph ₃ P) ₄ (9.79 mg, 8.47 μιηοΐ) at room temperature under CO atmosphere, then the mixture was stirred at 90 °C for 15 h. The reaction was quenched with H ₂ 0 (10 mL), extracted with EtOAc (10 mL x4) and the organic layers were concentrated in vacuo. The residue was purified using prep-TLC (DCM:MeOH = 10: 1) to provide the intermediate (6 mg, 25% yield) as a colorless oil, which was resolved and then deprotected using the procedures below.

Separated by chiral SFC (SFC condition: Column: Chiralpak OJ 250 x 30mm I.D., 20μιη,

Mobile phase: Supercritical C0 ₂ /A (0.1%) at 80 mL/min, A= EtOH+ NH ₃ H ₂ 0 (1 : 1), Column

Temp: 38 C, Nozzle Pressure: 100 Bar, Nozzle Temp: 60 C, Evaporator Temp: 20 C, Trimmer

Temp: 25 C, Wavelength: 220 nm) to provide Peak 1 (18 mg) & Peak 2 (15 mg).

To a solution of the intermediate from peak 1 (6 mg, 0.010 mmol) in DMF (0.5 mL) was added LiCl (14 mg, 0.32 mmol) at room temperature under N ₂ atmosphere. The mixture was stirred at 90 C for 2 h, LCMS showed the reaction was completed, the mixture was purified using prep-HPLC to provide compound 5 as a pink solid. ¹ H-NMR: (400 MHz, MeOH-d4) δ 8.44 (s, 1H), 7.45 (s, 1H), 7.00-6.82 (m, 2H), 5.60 (m, 1H), 5.33 (m, 1H), 5.06-5.00 (m, 1H), 4.73-4.66 (m, 2H), 4.11-4.00 (m, 1H), 2.30 (s, 3H), 2.17-2.09 (m, 2H), 2.00-1.97 (m, 1H), 1.87-1.63 (m, 4H). M+1: 473. A similar deprotection procedure was used starting with peak 2 to provide compound 6 1H-NMR: (400 MHz, MeOH-d ₄ ) δ 8.44 (s, 1H), 7.45 (s, 1H), 7.00-6.82 (m, 2H), 5.60 (m, 1H), 5.33 (m, 1H), 5.06-5.00 (m, 1H), 4.73-4.66 (m, 2H), 4.11-4.00 (m, 1H), 2.30 (s, 3H), 2.17-2.09 (m, 2H), 2.00-1.97 (m, 1H), 1.87-1.63 (m, 4H). M+1: 473.

Example 10

Assay for inhibition of HIV replication

This assay is a kinetic assay that employs a reporter cell line (MT4-gag-GFP) to quantify the number of new cells infected in each round of replication. MT4-GFP cells (250,000 cells/ml) were bulk-infected with HIV-1 (NL4-3 strain) at low multiplicity of infection (MOI) in RPMI + 10% FBS for 24 hours. Cells were then washed once in RPMI + 10% FBS and resuspended in RPMI + 0% or 10% or 100% normal human serum (NHS). Test compounds were serial-diluted in DMSO on ECHO. The infected MT4-GFP cells were added to a 384-well poly-D-lysine coated black plate with clear bottom in which the diluted test compounds were placed. The cells were seeded at 8,000 cells per well and the final DMSO concentration was 0.4%. The infected cells (Green GFP cells) were quantified at both 24 and 48 hours post incubation using Acumen eX3. Viral reproductive ratio (Ro) was determined using the number of infected cells at 48 hours divided by the number of infected cells at 24 hours. Percent viral growth inhibition was calculated by [l-(R-Rtri _P iedmg)/(RDMSO-Rtripiedrug)] * 100. Compound potency IP or IC ₅₀ was determined by a 4-parameter dose response curve analysis.

Illustrative compounds of the present invention were tested using this assay protocol and results are presented in the Table below.

WILD WILD TYPE TYPE CELL CELL

No. Structure

ASSAY ASSAY IP (0% IP (100%

NHS) NHS)

1 2 nM 209 nM

OH O

single enantiomer A

2 2 nM 466 nM

OH O

single enantiomer B

3 2 nM 86 nM

OH O

racemic

4 4 nM 88 nM

OH O

racemic 5 2 nM 43 nM

OH 0

single enantiomer A

6 2 nM 37 nM

OH 0

single enantiomer B

Treatment or Prevention of HIV Infection

The Tetracyclic Heterocycle Compounds are useful in the inhibition of HIV, the inhibition of HIV integrase, the treatment of HIV infection and/or reduction of the likelihood or severity of symptoms of HIV infection and the inhibition of HIV viral replication and/or HIV viral production in a cell-based system. For example, the Tetracyclic Heterocycle Compounds are useful in treating infection by HIV after suspected past exposure to HIV by such means as blood transfusion, exchange of body fluids, bites, accidental needle stick, or exposure to subject blood during surgery or other medical procedures.

Accordingly, in one embodiment, the invention provides methods for treating

HIV infection in a subject, the methods comprising administering to the subject an effective amount of at least one Tetracyclic Heterocycle Compound or a pharmaceutically acceptable salt or prodrug thereof. In a specific embodiment, the amount administered is effective to treat or prevent infection by HIV in the subject. In another specific embodiment, the amount administered is effective to inhibit HIV viral replication and/or viral production in the subject. In one embodiment, the HIV infection has progressed to AIDS.

The Tetracyclic Heterocycle Compounds are also useful in the preparation and execution of screening assays for antiviral compounds. For example the Tetracyclic Heterocycle Compounds are useful for identifying resistant HIV cell lines harboring mutations, which are excellent screening tools for more powerful antiviral compounds. Furthermore, the Tetracyclic Heterocycle Compounds are useful in establishing or determining the binding site of other antivirals to the HIV Integrase.

The compositions and combinations of the present invention can be useful for treating a subject suffering from infection related to any HIV genotype.

Combination Therapy In another embodiment, the present methods for treating or preventing HIV infection can further comprise the administration of one or more additional therapeutic agents which are not Tetracyclic Heterocycle Compounds.

In one embodiment, the additional therapeutic agent is an antiviral agent.

In another embodiment, the additional therapeutic agent is an immunomodulatory agent, such as an immunosuppressive agent.

Accordingly, in one embodiment, the present invention provides methods for treating a viral infection in a subject, the method comprising administering to the subject: (i) at least one Tetracyclic Heterocycle Compound (which may include two or more different Tetracyclic Heterocycle Compounds), or a pharmaceutically acceptable salt or prodrug thereof, and (ii) at least one additional therapeutic agent that is other than a Tetracyclic Heterocycle Compound, wherein the amounts administered are together effective to treat or prevent a viral infection.

When administering a combination therapy of the invention to a subject, therapeutic agents in the combination, or a pharmaceutical composition or compositions comprising therapeutic agents, may be administered in any order such as, for example, sequentially, concurrently, together, simultaneously and the like. The amounts of the various actives in such combination therapy may be different amounts (different dosage amounts) or same amounts (same dosage amounts). Thus, for non-limiting illustration purposes, a

Tetracyclic Heterocycle Compound and an additional therapeutic agent may be present in fixed amounts (dosage amounts) in a single dosage unit (e.g., a capsule, a tablet and the like).

In one embodiment, at least one Tetracyclic Heterocycle Compound is administered during a time when the additional therapeutic agent(s) exert their prophylactic or therapeutic effect, or vice versa.

In another embodiment, at least one Tetracyclic Heterocycle Compound and the additional therapeutic agent(s) are administered in doses commonly employed when such agents are used as monotherapy for treating a viral infection.

In another embodiment, at least one Tetracyclic Heterocycle Compound and the additional therapeutic agent(s) are administered in doses lower than the doses commonly employed when such agents are used as monotherapy for treating a viral infection.

In still another embodiment, at least one Tetracyclic Heterocycle Compound and the additional therapeutic agent(s) act synergistically and are administered in doses lower than the doses commonly employed when such agents are used as monotherapy for treating a viral infection. In one embodiment, at least one Tetracyclic Heterocycle Compound and the additional therapeutic agent(s) are present in the same composition. In one embodiment, this composition is suitable for oral administration. In another embodiment, this composition is suitable for intravenous administration. In another embodiment, this composition is suitable for subcutaneous administration. In still another embodiment, this composition is suitable for parenteral administration.

Viral infections and virus-related disorders that can be treated or prevented using the combination therapy methods of the present invention include, but are not limited to, those listed above.

In one embodiment, the viral infection is HIV infection.

In another embodiment, the viral infection is AIDS.

The at least one Tetracyclic Heterocycle Compound and the additional therapeutic agent(s) can act additively or synergistically. A synergistic combination may allow the use of lower dosages of one or more agents and/or less frequent administration of one or more agents of a combination therapy. A lower dosage or less frequent administration of one or more agents may lower toxicity of therapy without reducing the efficacy of therapy.

In one embodiment, the administration of at least one Tetracyclic Heterocycle Compound and the additional therapeutic agent(s) may inhibit the resistance of a viral infection to these agents.

As noted above, the present invention is also directed to use of a compound of

Formula I with one or more anti-HIV agents. An "anti-HIV agent" is any agent which is directly or indirectly effective in the inhibition of HIV reverse transcriptase or another enzyme required for HIV replication or infection, the treatment or prophylaxis of HIV infection, and/or the treatment, prophylaxis or delay in the onset or progression of AIDS. It is understood that an anti-HIV agent is effective in treating, preventing, or delaying the onset or progression of HIV infection or AIDS and/or diseases or conditions arising therefrom or associated therewith. For example, the compounds of this invention may be effectively administered, whether at periods of pre-exposure and/or post-exposure, in combination with effective amounts of one or more anti- HIV agents selected from HIV antiviral agents, immunomodulators, antiinfectives, or vaccines useful for treating HIV infection or AIDS. Suitable HIV antivirals for use in combination with the compounds of the present invention include, for example, those listed in Table A as follows: Table A

Name Type abacavir, ABC, Ziagen® nRTI abacavir +lamivudine, Epzicom® nRTI abacavir + lamivudine + zidovudine, Trizivir® nRTI amprenavir, Agenerase® PI atazanavir, Reyataz® PI

AZT, zidovudine, azidothymidine, Retrovir® nRTI darunavir, Prezista® PI ddC, zalcitabine, dideoxycytidine, Hivid® nRTI ddl, didanosine, dideoxyinosine, Videx® nRTI ddl (enteric coated), Videx EC® nRTI delavirdine, DLV, Rescriptor® nnRTI efavirenz, EFV, Sustiva®, Stocrin® nnRTI efavirenz + emtricitabine + tenofovir DF, Atripla® nnRTI + nRTI emtricitabine, FTC, Emtriva® nRTI emtricitabine + tenofovir DF, Truvada® nRTI emvirine, Coactinon® nnRTI enfuvirtide, Fuzeon® FI enteric coated didanosine, Videx EC® nRTI etravirine, TMC-125 nnRTI fosamprenavir calcium, Lexiva® PI indinavir, Crixivan® PI lamivudine, 3TC, Epivir® nRTI lamivudine + zidovudine, Combivir® nRTI lopinavir PI lopinavir + ritonavir, Kaletra® PI maraviroc, Selzentry® EI nelfmavir, Viracept® PI nevirapine, NVP, Viramune® nnRTI rilpivirine, TMC-278 nnRTI

ritonavir, Norvir® PI saquinavir, Invirase®, Fortovase® PI stavudine, d4T,didehydrodeoxythymidine, Zerit® nPvTI tenofovir DF (DF = disoproxil fumarate), TDF, nRTI Viread®

tipranavir, Aptivus® PI

EI = entry inhibitor; FI = fusion inhibitor; PI = protease inhibitor; nRTI = nucleoside reverse transcriptase inhibitor; nnRTI = non-nucleoside

reverse transcriptase inhibitor. Some of the drugs listed in the table are used in a salt form; e.g., abacavir sulfate, indinavir sulfate, atazanavir sulfate, nelfinavir mesylate.

In one embodiment, one or more anti-HIV drugs are selected from, lamivudine, abacavir, ritonavir, darunavir, atazanavir, emtricitabine, tenofovir, rilpivirine and lopinavir.

In another embodiment, the compound of formula (I) is used in combination with lamivudine.

In still another embodiment, the compound of formula (I) is used in combination atazanavir.

In another embodiment, the compound of formula (I) is used in combination with darunavir.

In another embodiment, the compound of formula (I) is used in combination with rilpivirine.

In one embodiment, the compound of formula (I) is used in combination with lamivudine and abacavir.

In another embodiment, the compound of formula (I) is used in combination with darunavir.

In another embodiment, the compound of formula (I) is used in combination with emtricitabine and tenofovir.

In still another embodiment, the compound of formula (I) is used in combination atazanavir.

In another embodiment, the compound of formula (I) is used in combination with ritonavir and lopinavir. In another embodiment, the compound of formula (I) is used in combination with lamivudine.

In one embodiment, the compound of formula (I) is used in combination with abacavir and lamivudine.

In another embodiment, the compound of formula (I) is used in combination with lopinavir and ritonavir.

In one embodiment, the present invention provides pharmaceutical compositions comprising (i) a compound of formula (I) or a pharmaceutically acceptable salt or prodrug thereof; (ii) a pharmaceutically acceptable carrier; and (iii) one or more additional anti-HIV agents selected from lamivudine, abacavir, ritonavir and lopinavir, or a pharmaceutically acceptable salt or prodrug thereof, wherein the amounts present of components (i) and (iii) are together effective for the treatment or prophylaxis of infection by HIV or for the treatment, prophylaxis, or delay in the onset or progression of AIDS in the subject in need thereof.

In another embodiment, the present invention provides a method for the treatment or prophylaxis of infection by HIV or for the treatment, prophylaxis, or delay in the onset or progression of AIDS in a subject in need thereof, which comprises administering to the subject (i) a compound of formula (I) or a pharmaceutically acceptable salt or prodrug thereof and (ii) one or more additional anti-HIV agents selected from lamivudine, abacavir, ritonavir and lopinavir, or a pharmaceutically acceptable salt or prodrug thereof, wherein the amounts administered of components (i) and (ii) are together effective for the treatment or prophylaxis of infection by HIV or for the treatment, prophylaxis, or delay in the onset or progression of AIDS in the subject in need thereof.

It is understood that the scope of combinations of the compounds of this invention with anti-HIV agents is not limited to the HIV antivirals listed in Table A, but includes in principle any combination with any pharmaceutical composition useful for the treatment or prophylaxis of AIDS. The HIV antiviral agents and other agents will typically be employed in these combinations in their conventional dosage ranges and regimens as reported in the art, including, for example, the dosages described in the Physicians' Desk Reference, Thomson PDR, Thomson PDR, 57 ^th edition (2003), the 58 ^th edition (2004), the 59 ^th edition (2005), and the like. The dosage ranges for a compound of the invention in these combinations are the same as those set forth above.

The doses and dosage regimen of the other agents used in the combination therapies of the present invention for the treatment or prevention of HIV infection can be determined by the attending clinician, taking into consideration the approved doses and dosage regimen in the package insert; the age, sex and general health of the subject; and the type and severity of the viral infection or related disease or disorder. When administered in combination, the Tetracyclic Heterocycle Compound(s) and the other agent(s) can be administered

simultaneously (i.e., in the same composition or in separate compositions one right after the other) or sequentially. This is particularly useful when the components of the combination are given on different dosing schedules, e.g., one component is administered once daily and another component is administered every six hours, or when the preferred pharmaceutical compositions are different, e.g., one is a tablet and one is a capsule. A kit comprising the separate dosage forms is therefore advantageous.

Compositions and Administration

When administered to a subject, the Tetracyclic Heterocycle Compounds can be administered as a component of a composition that comprises a pharmaceutically acceptable carrier or vehicle. The present invention provides pharmaceutical compositions comprising an effective amount of at least one Tetracyclic Heterocycle Compound and a pharmaceutically acceptable carrier. In the pharmaceutical compositions and methods of the present invention, the active ingredients will typically be administered in admixture with suitable carrier materials suitably selected with respect to the intended form of administration, i.e., oral tablets, capsules (either solid-filled, semi-solid filled or liquid filled), powders for constitution, oral gels, elixirs, dispersible granules, syrups, suspensions, and the like, and consistent with conventional pharmaceutical practices. For example, for oral administration in the form of tablets or capsules, the active drug component may be combined with any oral non-toxic pharmaceutically acceptable inert carrier, such as lactose, starch, sucrose, cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, talc, mannitol, ethyl alcohol (liquid forms) and the like. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories. Powders and tablets may be comprised of from about 0.5 to about 95 percent inventive composition. Tablets, powders, cachets and capsules can be used as solid dosage forms suitable for oral administration.

Moreover, when desired or needed, suitable binders, lubricants, disintegrating agents and coloring agents may also be incorporated in the mixture. Suitable binders include starch, gelatin, natural sugars, corn sweeteners, natural and synthetic gums such as acacia, sodium alginate, carboxymethylcellulose, polyethylene glycol and waxes. Among the lubricants there may be mentioned for use in these dosage forms, boric acid, sodium benzoate, sodium acetate, sodium chloride, and the like. Disintegrants include starch, methylcellulose, guar gum, and the like. Sweetening and flavoring agents and preservatives may also be included where appropriate.

Liquid form preparations include solutions, suspensions and emulsions and may include water or water-propylene glycol solutions for parenteral injection.

Liquid form preparations may also include solutions for intranasal administration.

Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration. Such liquid forms include solutions, suspensions and emulsions.

For preparing suppositories, a low melting wax such as a mixture of fatty acid glycerides or cocoa butter is first melted, and the active ingredient is dispersed homogeneously therein as by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool and thereby solidify.

Additionally, the compositions of the present invention may be formulated in sustained release form to provide the rate controlled release of any one or more of the components or active ingredients to optimize therapeutic effects, i.e., antiviral activity and the like. Suitable dosage forms for sustained release include layered tablets containing layers of varying disintegration rates or controlled release polymeric matrices impregnated with the active components and shaped in tablet form or capsules containing such impregnated or encapsulated porous polymeric matrices.

In one embodiment, the one or more Tetracyclic Heterocycle Compounds are administered orally.

In another embodiment, the one or more Tetracyclic Heterocycle Compounds are administered intravenously.

In one embodiment, a pharmaceutical preparation comprising at least one

Tetracyclic Heterocycle Compound is in unit dosage form. In such form, the preparation is subdivided into unit doses containing effective amounts of the active components.

Compositions can be prepared according to conventional mixing, granulating or coating methods, respectively, and the present compositions can contain, in one embodiment, from about 0.1% to about 99% of the Tetracyclic Heterocycle Compound(s) by weight or volume. In various embodiments, the present compositions can contain, in one embodiment, from about 1% to about 70% or from about 5% to about 60% of the Tetracyclic Heterocycle Compound(s) by weight or volume. The compounds of Formula I can be administered orally in a dosage range of 0.001 to 1000 mg/kg of mammal (e.g., human) body weight per day in a single dose or in divided doses. One preferred dosage range is 0.01 to 500 mg/kg body weight per day orally in a single dose or in divided doses. Another preferred dosage range is 0.1 to 100 mg/kg body weight per day orally in single or divided doses. For oral administration, the compositions can be provided in the form of tablets or capsules containing 1.0 to 500 milligrams of the active ingredient, particularly 1, 5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, and 500 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the subject to be treated. The specific dose level and frequency of dosage for any particular subject may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy.

For convenience, the total daily dosage may be divided and administered in portions during the day if desired. In one embodiment, the daily dosage is administered in one portion. In another embodiment, the total daily dosage is administered in two divided doses over a 24 hour period. In another embodiment, the total daily dosage is administered in three divided doses over a 24 hour period. In still another embodiment, the total daily dosage is administered in four divided doses over a 24 hour period.

The amount and frequency of administration of the Tetracyclic Heterocycle

Compounds will be regulated according to the judgment of the attending clinician considering such factors as age, condition and size of the subject as well as severity of the symptoms being treated. The compositions of the invention can further comprise one or more additional therapeutic agents, selected from those listed above herein.

Kits

In one aspect, the present invention provides a kit comprising a therapeutically effective amount of at least one Tetracyclic Heterocycle Compound, or a pharmaceutically acceptable salt or prodrug of said compound and a pharmaceutically acceptable carrier, vehicle or diluent.

In another aspect the present invention provides a kit comprising an amount of at least one Tetracyclic Heterocycle Compound, or a pharmaceutically acceptable salt or prodrug of said compound and an amount of at least one additional therapeutic agent listed above, wherein the amounts of the two or more active ingredients result in a desired therapeutic effect. In one embodiment, the one or more Tetracyclic Heterocycle Compounds and the one or more additional therapeutic agents are provided in the same container. In one embodiment, the one or more Tetracyclic Heterocycle Compounds and the one or more additional therapeutic agents are provided in separate containers.

The present invention is not to be limited by the specific embodiments disclosed in the examples that are intended as illustrations of a few aspects of the invention and any embodiments that are functionally equivalent are within the scope of this invention. Indeed, various modifications of the invention in addition to those shown and described herein will become apparent to those skilled in the art and are intended to fall within the scope of the appended claims.

A number of references have been cited herein, the entire disclosures of which are incorporated herein by reference.