WO2015179448A1 - Therapeutic compounds - Google Patents

Therapeutic compounds Download PDF

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Publication number
WO2015179448A1
WO2015179448A1 PCT/US2015/031640 US2015031640W WO2015179448A1 WO 2015179448 A1 WO2015179448 A1 WO 2015179448A1 US 2015031640 W US2015031640 W US 2015031640W WO 2015179448 A1 WO2015179448 A1 WO 2015179448A1
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Prior art keywords
alkyl
aryl
heterocycle
heteroaryl
carbocycle
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PCT/US2015/031640
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French (fr)
Inventor
Kerim Babaoglu
Ryan Mcfadden
Michael L. Mitchell
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Gilead Sciences, Inc.
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Publication of WO2015179448A1 publication Critical patent/WO2015179448A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D215/14—Radicals substituted by oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/473—Quinolines; Isoquinolines ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/04—Ortho- or peri-condensed ring systems
    • C07D221/18—Ring systems of four or more rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • HIV infection immunodeficiency virus (HIV) infection are disclosed.
  • novel compounds and methods for their preparation and use as therapeutic or prophylactic agents are disclosed.
  • HIV-1 Human immunodeficiency virus infection and related diseases are a major public health problem worldwide.
  • Human immunodeficiency virus type 1 (HIV-1) encodes three enzymes which are required for viral replication: reverse transcriptase, protease, and integrase.
  • drugs targeting reverse transcriptase and protease are in wide use and have shown effectiveness, particularly when employed in combination, toxicity and development of resistant strains have limited their usefulness (Palella, et al. N. Engl. J Med. (1998) 338:853-860; Richman, D. D. Nature (2001) 410:995-1001). Accordingly, there is a need for new agents that inhibit the replication of HIV. There is also a need for agents that are directed against alternate sites in the viral life cycle including agents that target the interaction of Lens Epithelial Derived Growth Factor (LEDGF/p75) and HIV-1 integrase.
  • LEDGF/p75 Lens Epithelial Derived Growth Factor
  • the present disclosure is directed to novel compounds, having antiviral activity, including stereoisomers and pharmaceutically acceptable salts thereof, and the use of such compounds in the treatment of HIV infections.
  • compounds having antiviral activity are provided, the compounds having the following Formula (I):
  • compounds having antiviral activity are provided, the compounds having the following
  • a pharmaceutical composition comprising a compound of formula I or formula la, or apharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier is disclosed.
  • a pharmaceutical composition comprising a compound of formula I or formula la, or a pharmaceutically acceptable salt thereof, and an additional therapeutic agent.
  • the additional therapeutic agent is an HIV protease inhibiting compound, an HIV non-nucleoside inhibitor of reverse
  • transcriptase an HIV nucleoside inhibitor of reverse transcriptase, an HIV nucleotide inhibitor of reverse transcriptase, an HIV integrase inhibitor, a gp41 inhibitor, a CXCR4 inhibitor, agpl20 inhibitor, a CCR5 inhibitor, a capsid polymerization inhibitor, or a non-catalytic site HIV integrase inhibitor and combinations thereof.
  • a pharmaceutical composition of formula I or formula la, for use in treating an HIV infection in a patient in need thereof is disclosed.
  • a method for treating a HIV infection in a patient in need thereof comprising administering a therapeutically effective amount of a compound of formula I or formula la, or a pharmaceutically acceptable salt thereof, to the patient, is disclosed.
  • a method for treating an HIV infection in a patient in need thereof comprising administering to the patient a therapeutically effective amount of a compound of any one of formula I or formula la, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of an additional therapeutic agent is disclosed.
  • the additional therapeutic agent is an HIV protease inhibiting compound, an HIV non-nucleoside inhibitor of reverse transcriptase, an HIV nucleoside inhibitor of reverse transcriptase, an HIV nucleotide inhibitor of reverse transcriptase, an HIV integrase inhibitor, a gp41 inhibitor, a CXCR4 inhibitor, a gpl20 inhibitor, a CCR5 inhibitor, a capsid polymerization inhibitor, or a non-catalytic site HIV integrase site inhibitor and combinations thereof.
  • a compound of formula I or formula la, or a pharmaceutically acceptable salt thereof, for use in medical therapy is disclosed.
  • a compound of formula I or formula la or a
  • a compound of formula I or formula la, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating an HIV virus infection in a mammal is disclosed.
  • a wavy line drawn through a line in a structure indicates a point of attachment of a group. Unless chemically or structurally required, no directionality is indicated or implied by the order in which a chemical group is written or the point at which it is attached to the remainder of the molecule. For instance, the group “-SO 2 CH 2 -" is equivalent to "-CH 2 SO 2 -" and both may be connected in either direction. Similarly, an "arylalkyl” group, for example, may be attached to the remainder of the molecule at either an aryl or an alkyl portion of the group. A prefix such as “C u - V " or (C u -C v ) indicates that the following group has from u to v carbon atoms. For example, "Ci_ 6 alkyl” indicates that the alkyl group has from 1 to 6 carbon atoms.
  • Alkyl refers to any group derived from a linear or branched saturated hydrocarbon.
  • Alkyl groups include, but are not limited to, methyl, ethyl, propyls such as propan-l-yl, propan-2-yl (iso-propyl), butyls such as butan-l-yl, butan-2-yl (sec- butyl), 2-methyl-propan-l-yl (iso-butyl), 2-methyl-propan-2-yl (t-butyl), pentyls, hexyls, octyls, decyls, and the like.
  • an alkyl group has from 1 to about 10 carbon atoms, for example from 1 to 10 carbon atoms, for example from 1 to 6 carbon atoms, for example from 1 to 4 carbon atoms.
  • Alkenyl refers to any group derived from a straight or branched hydrocarbon with at least one carbon-carbon double bond.
  • Alkenyl groups include, but are not limited to, ethenyl (vinyl), propenyl (allyl), 1-butenyl, 1,3-butadienyl, and the like. Unless otherwise specified, an alkenyl group has from 2 to about 10 carbon atoms, for example from 2 to 10 carbon atoms, for example from 2 to 6 carbon atoms, for example from 2 to 4 carbon atoms.
  • Alkynyl refers to any group derived from a straight or branched hydrocarbon with at least one carbon-carbon triple bond and includes those groups having one triple bond and one double bond.
  • alkynyl groups include, but are not limited to, ethynyl (-C ⁇ CH), propargyl (-CH 2 C ⁇ CH), (£)-pent-3-en-l-ynyl, and the like.
  • an alkynyl group has from 2 to about 10 carbon atoms, for example from 2 to 10 carbon atoms, for example from 2 to 6 carbon atoms, for example from 2 to 4 carbon atoms.
  • Aryl refers to any group derived from one or more all carbon aromatic rings, that is, a single aromatic ring, a bicyclic or a multicyclic ring system.
  • Aryl groups include, but are not limited to, those groups derived from acenaphthylene, anthracene, azulene, benzene, chrysene, a cyclopentadienyl anion, naphthalene, fluoranthene, fluorene, indane, perylene, phenalene, phenanthrene, pyrene and the like.
  • an aryl group has from 6 to about 20 carbon atoms, for example from 6 to 20 carbon atoms, for example from 6 to 14 carbon atoms, for example from 6 to 10 carbon atoms.
  • Cycloalkyl refers to a cyclic alkyl group.
  • a cycloalkyl group can have one or more cyclic rings and includes fused and bridged groups. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, and the like.
  • Carbocycle refers to a cyclic, non-aromatic group derived from a linear or branched hydrocarbon, including alkyls, alkenyls, and alkynyls.
  • An alicyclic group can comprise one or more rings, includes fused and bridged groups, and can be saturated or have any degree of unsaturation. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, adamantyl, and the like.
  • a carcocyclic group has from 1 to about 10 carbon atoms, for example from 1 to 10 carbon atoms, for example from 1 to 6 carbon atoms or for example from 1 to 4 carbon atoms or for example from 1 to 3 carbon atoms.
  • Halo and halogen refer to fluoro, chloro, bromo and iodo.
  • Haloalkyl refers to an alkyl wherein one or more hydrogen atoms are each replaced by a halogen. Examples include, but are not limited to, -CH 2 C1, -CH 2 F, - CH 2 Br, -CFClBr, -CH 2 CH 2 C1, -CH 2 CH 2 F, -CF 3 , -CH 2 CF 3 , -CH 2 CC1 3 , and the like, as well as alkyl groups such as perfluoroalkyl in which all hydrogen atoms are replaced by fluorine atoms.
  • Heteroalkyl refers to an alkyl in which one or more of the carbon atoms are each independently replaced with a heteroatom selected from the group consisting of O, N, S, and Si.
  • a heteroatom may optionally be oxidized or alkylated.
  • a heteroatom may be placed at any interior position of the heteroalkyl group or at a position at which the group is attached to the remainder of the molecule.
  • Examples include, but are not limited to, -CH 2 OCH 3 , -CH 2 CH 2 NHCH 3 , -CH 2 CH 2 N(CH 3 ) -CH 3 , -CH 2 SCH 2 CH 3 , - S(0)CH 3 , -CH 2 CH 2 S(0) 2 CH 3 , -CHCHOCH 3 , -Si(CH 3 ) 3 , -CH 2 CHNOCH 3 , - CHCHN(CH 3 )CH 3, -CH 2 NHOCH 3 and -CH 2 OS(CH 3 ) 3 .
  • Heteroaryl refers to an aryl group in which one or more of the carbon atoms (and any associated hydrogen atoms) are each independently replaced with the same or different heteroatom selected from the group consisting of O, N, S, and Si.
  • a heteroatom may be placed at any interior position of the heteroaryl group or at a position at which the group is attached to the remainder of the molecule.
  • Heteroaryl groups include, but are not limited to, groups derived from acridine, benzoimidazole, benzothiophene, benzofuran, benzoxazole, benzothiazole, carbazole, carboline, cinnoline, furan, imidazole, imidazopyridine, indazole, indole, indoline, indolizine, isobenzofuran, isochromene, isoindole, isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, perimidine, phenanthridine, phenanthroline, phenazine, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolizine, quinazoline
  • an heteroaryl group has from 3 to about 20 carbon atoms and from 1 to about 3 heteroatoms, for example from 5 to 20 carbon atoms and from 1 to 3 heteroatoms, for example from 5 to 14 carbon atoms and from 1 to 3 heteroatoms, for example from 5 to 10 carbon atoms and from 1 to 3 heteroatoms.
  • Heterocycle refers to a single saturated or partially unsaturated non-aromatic ring or a non-aromatic multiple-ring system with at least one heteroatom, as defined above.
  • Heterocycles include, but are not limited to, groups derived from azetidine, aziridine, imidazolidine, morpholine, oxirane (epoxide), oxetane, piperazine, piperidine, pyrazolidine, piperidine, pyrrolidine, pyrrolidinone, tetrahydrofuran, tetrahydrothiophene, dihydropyridine, tetrahydropyridine,
  • pharmaceutically acceptable refers to that substance which is generally regarded as safe and suitable for use without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio.
  • “Pharmaceutically acceptable salt” refers to a salt of a compound that is pharmaceutically acceptable and that possesses (or can be converted to a form that possesses) the desired pharmacological activity of the parent compound.
  • Such salts include acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, benzenesulfonic acid, benzoic acid,
  • camphorsulfonic acid citric acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, lactic acid, maleic acid, malonic acid, mandelic acid, methanesulfonic acid, 2-napththalenesulfonic acid, oleic acid, palmitic acid, propionic acid, stearic acid, succinic acid, tartaric acid, p-toluenesulfonic acid, trimethylacetic acid, and the like, and salts formed when an acidic proton present in the parent compound is replaced by either a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as diethanolamine, triethanolamine, N- methylglucamine and the like.
  • a metal ion e.g., an alkali metal ion, an alkaline earth ion, or an
  • ammonium and substituted or quaternized ammonium salts are also included in this definition.
  • Representative non-limiting lists of pharmaceutically acceptable salts can be found in S.M. Berge et al., J. Pharma Sci., 66(1), 1-19 (1977), and Remington: The Science and Practice of Pharmacy, R.
  • Treating” and “treatment” of a disease include the following:
  • magnesium sulfate MgCC : magnesium carbonate; mg: millilgram; MsCl: mesyl chloride; mmol: millimoles mL: milliliter; sodium hydrogen sulfite; mCPBA: meta- chloroperoxybenzoic acid; N: normality; N 2 : nitrogen; Na 2 CC> 3 : sodium carbonate; NaHCC : sodium bicarbonate; NaN0 2 : sodium nitrite; NaOH: sodium hydroxide; Na 2 S 2 C> 3 : sodium bisulfate; Na 2 S0 4 : sodium sulfate; NBS: N-bromosuccinimide; NH4CI: ammonium chloride; NH 4 OAc: ammonium acetate; NMR: nuclear magnetic resonance; Pd/C: palladium on carbon; ⁇ 13 ⁇ 4: triphenyl phosphine; iPrOH: isopropyl alcohol; RT: room temperature; SOCl 2 : thion
  • Antiviral agent refers to any agent that inhibits the formation or replication of a virus in a mammal, including but not limited to agents that interfere with either host or viral mechanisms necessary for the formation or replication of a virus in a mammal.
  • Effective amount refers to an amount that may be effective to elicit the desired biological or medical response, including the amount of a compound that, when administered to a subject for treating a disease, is sufficient to effect such treatment for the disease.
  • the effective amount will vary depending on the compound, the disease and its severity and the age, weight, etc., of the subject to be treated.
  • the effective amount can include a range of amounts.
  • the invention disclosed herein is also meant to encompass all pharmaceutically acceptable compounds of Formula (I) being isotopically-labeled by having one or more atoms replaced by an atom having a different atomic mass or mass number.
  • isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, and iodine, such as 2 H, 3 H, n C, 13 C, 14 C, 13 N, 15 N, 15 0, 17 0, 18 0, 31 P, 32 P, 35 S, 18 F, 36 C1, 123 I, and 125 I, respectively.
  • These radiolabeled compounds could be useful to help determine or measure the effectiveness of the compounds, by characterizing, for example, the site or mode of action, or binding affinity to pharmacologically important site of action.
  • radioactive isotopes are useful in drug and/or substrate tissue distribution studies.
  • Substitution with heavier isotopes such as deuterium, i.e. 2 H, may afford certain therapeutic advantages resulting from greater metabolic stability. For example, in vivo half-life may increase or dosage requirements may be reduced. Thus, heavier isotopes may be preferred in some circumstances.
  • Isotopically-labeled compounds of Formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the Examples as set out below using an appropriate isotopically-labeled reagent in place of the non-labeled reagent previously employed.
  • the invention disclosed herein is also meant to encompass the in vivo metabolic products of the disclosed compounds. Such products may result from, for example, the oxidation, reduction, hydrolysis, amidation, esterification, and the like of the administered compound, primarily due to enzymatic processes. Accordingly, the invention includes compounds produced by a process comprising administering a compound of this invention to a mammal for a period of time sufficient to yield a metabolic product thereof. Such products are typically identified by administering a radiolabeled compound of the invention in a detectable dose to an animal, such as rat, mouse, guinea pig, monkey, or to human, allowing sufficient time for metabolism to occur, and isolating its conversion products from the urine, blood or other biological samples.
  • an animal such as rat, mouse, guinea pig, monkey, or to human
  • Racemates refers to a mixture of enantiomers.
  • the mixture can comprise equal or unequal amounts of each enantiomer.
  • Stereoisomer and “stereoisomers” refer to compounds that differ in the chirality of one or more stereocenters. Stereoisomers include enantiomers and diastereomers. The compounds may exist in stereoisomeric form if they possess one or more asymmetric centers or a double bond with asymmetric substitution and, therefore, can be produced as individual stereoisomers or as mixtures. Unless otherwise indicated, the description is intended to include individual stereoisomers as well as mixtures. The methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art (see, e.g., Chapter 4 of Advanced Organic Chemistry, 4th ed., J. March, John Wiley and Sons, New York, 1992).
  • the compounds disclosed herein display
  • the resultant conformational isomers are observed as distinct entities by characterization techniques such as NMR and HPLC.
  • the compounds disclosed herein exist as a mixture of atropisomers.
  • the synthetic examples provided herein note where such mixtures of atropisomers have been observed.
  • the detection of atropisomers is dependent on factors such as temperature, solvent, conditions of purification, and timescale of spectroscopic technique. Characterization data presented herein may not represent the equilibrium state depending on the conditions of purification, isolation, handling, solvents used, and temperature.
  • Protecting group refers to a moiety of a compound that masks or alters the properties of a functional group or the properties of the compound as a whole.
  • Chemical protecting groups and strategies for protection/deprotection are well known in the art. See e.g., Protective Groups in Organic Chemistry, Theodora W. Greene, John Wiley & Sons, Inc., New York, 1991. Protecting groups are often utilized to mask the reactivity of certain functional groups, to assist in the efficiency of desired chemical reactions, e.g., making and breaking chemical bonds in an ordered and planned fashion.
  • Protection of functional groups of a compound alters other physical properties besides the reactivity of the protected functional group, such as the polarity, lipophilicity (hydrophobicity), and other properties which can be measured by common analytical tools.
  • Chemically protected intermediates may themselves be biologically active or inactive.
  • the compounds described herein, or their pharmaceutically acceptable salts may contain one or more asymm Protecting Groups etric centers and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)-.
  • This disclosure includes all such possible isomers, as well as their racemic and optically pure forms.
  • Optically active (+) and (-), or (R)- and (S)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, for example, chromatography and fractional crystallization.
  • V is N or CH
  • R 3 is (Ci-C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 3 -C 6 )cycloalkyl, (Ci-C6)-alkyl-(C 3 -C 6 )cycloalkyl or -0(Ci-C 6 )alkyl, -0-(C 3 -C 6 )cycloalkyl wherein any (C C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 3 -C 6 )cycloalkyl, (Ci-C6)-alkyl-(C 3 -C 6 )cycloalkyl or -0(C C 6 )alkyl, -0-(C 3 -
  • C 6 )cycloalkyl of R 3 is optionally substituted with one to three groups selected from the group consisting of -0(Ci-C6)alkyl, halo, oxo and -CN;
  • D is (C6-C12) aryl, (C5-Cio)carbocycle, 5-10-membered heterocycle, or 5-10-membered heteroaryl, wherein any (C6-Ci 2 ) aryl, (C5-Cio)carbocycle, 5-10-membered heterocycle, or 5-10- membered heteroaryl of D is substituted by R 2 ; wherein any (C 6 -Ci 2 ) aryl, (C5-Cio)carbocycle, 5-10-membered heterocycle, or 5-10- membered heteroaryl of D is optionally substituted by R 5 , R 6 , R 7 , R 8 and R 12 ;
  • R 2 is H, oxo, halo ,(C C 6 )alkyl or -0(C C 6 )alkyl;
  • each R 11 is independently H, (Ci-C6)alkyl, (C 2 -C6)alkenyl, (C 2 -
  • N(R 9 )R 10 or -(C C 6 )alkyl-S0 2 -N(R 9 )R 10 , wherein each R 9 is independently H, (Ci-C6)alkyl or (C3-C7)cycloalkyl; and wherein each R 10 is independently H, (Ci-C6)alkyl, (C 2 -C6)alkenyl, (C 2 -
  • heteroaryl of R e are each independently substituted with one to three Z5 groups; and each R f is independently H, -R g, -OR a, -(C C 6 )alkyl-Z 6 , -S0 2 R g , -C(0)R g , C(0)OR g or -C(0)NR e R g ; and each R g is independently H, (C]-C6)alkyl, (C3-C7)carbocycle (Ci-C6)haloalkyl, (C 2 -C6)alkenyl, (C 2 -C6)alkynyl, (C6-Ci 2 )aryl, 5-12 membered heterocycle or 5- 12 membered heteroaryl, wherein any (Ci-C6)alkyl, (C3-C7)carbocycle -(Ci-C6)haloalkyl, (C 2 -C6)alkenyl, (C 2 -C6)alkynyl, (C6
  • any heteroaryl or heterocycle of Z 5 is a 5-12 membered heteroaryl or a 5-12 membered heterocycle; and each Z 6 is independently -N0 2 , -CN, -NR a R a , NR a C(0)R b ,-C(0)NR c R d , (C 3 - C7)halocarbocycle, (C6-Ci 2 )aryl, heteroaryl, heterocycle, -0-(C6-Ci 2 )aryl, -Oheteroaryl, -Oheterocycle, -0(C3-C7)halocarbocycle, -0(Ci-C6)alkyl, -0(C 3 - C7)carbocycle, -0(Ci-C6)haloalkyl, -S-(C6-Ci
  • any heteroaryl or heterocycle of Z 6 is a 5-12 membered heteroaryl or a 5-12 membered heterocycle.
  • D is monocyclic, bicyclic or tricyclic (C6-Ci 2 ) aryl ; monocyclic, bicyclic or tricyclic (C5-Cio)carbocycle; 5-10-membered monocyclic, bicyclic or tricyclic heterocycle; or 5-10-membered monocyclic, bicyclic or tricyclic heteroaryl.
  • D is monocyclic, bicyclic or tricyclic (C6-Ci 2 ) aryl. In certain embodiments, D is monocyclic, bicyclic or tricyclic (C6-C1 0 ) aryl. In certain embodiments, D is monocyclic or bicyclic (C6-C1 0 ) aryl. In certain embodiments, D is monocyclic (C6-C1 0 ) aryl. In certain embodiments, D is bicyclic (C6-C1 0 ) aryl. In certain embodiments, D is monocyclic, bicyclic or tricyclic (C6-C 12 ) carbocycle.
  • D is monocyclic, bicyclic or tricyclic (C 5 - Cio)carbocycle. In certain embodiments, D is monocyclic or bicyclic (C 5 - Cio)carbocycle. In certain embodiments, D is monocyclic (C5-Cio)carbocycle. In certain embodiments, D is bicyclic (C5-Cio)carbocycle.
  • D is 5-10-membered monocyclic, bicyclic or tricyclic heterocycle. In certain embodiments, D is 5-10-membered monocyclic or bicyclic heterocycle. In certain embodiments, D is 5-10-membered monocyclic heterocycle. In certain embodiments, D is 5-10-membered bicyclic heterocycle.
  • D is 5-10-membered monocyclic, bicyclic or tricyclic heteroaryl. In certain embodiments, D is 5-10-membered monocyclic or bicyclic heteroaryl. In certain embodiments, D is 5-10-membered monocyclic heteroaryl. In certain embodiments, D is 5-10-membered bicyclic heteroaryl.
  • D is phenyl, pyridyl, pyrimidinyl, naphthyl, quinolinyl, benzthiazolyl, indazolyl, thienopyridinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, pyranothienopyridinyl, pyrimidoindazolyl, cyclopentaquinolinyl, 6,7,8,9- tetrahydrobenzoquinolinyl, 7,8,9, 10-tetrahydrobenzoquinolinyl,
  • D is phenyl, pyridyl, pyrimidinyl, naphthyl, quinolinyl, or benzthiazolyl.
  • naphthyl or quinolinyl are in still more embodiments.
  • R 3 is -0(Ci-C6)alkyl optionally substituted with one to three groups selected from the group consisting of halo and -CN.
  • R 3 is -OC(CH 3 ) 3 .
  • D is substituted with R 2 and R 5 , R 6 , R 7 , R 8 and R 12 are hydrogen.
  • R 2 is halo, H or -CH 3 .
  • R 2 is -CH 3 .
  • R 5 , R 6 , R 7 , R 8 and R 12 are each independently:
  • R 5 , R 6 , R 7 , R 8 and R 12 are each independently:
  • each R 9 is independently H, (Ci-C6)alkyl or (C3-C7)cycloalkyl
  • R 5 , R 6 , R 7 , R 8 and R 12 are each independently H, (d-
  • each R 11 is independently H, (Ci-C6)alkyl, (C 2 -C6)alkenyl, (C 2 -C6)alkynyl, (Ci-C6)haloalkyl, (C3-C7)carbocycle, (C6-Ci 2 )aryl, heterocycle or heteroaryl, wherein (C6-Ci 2 )aryl, 5-10-membered heterocycle and 5-10-membered heteroaryl are each optionally substituted with one to three Z 11 groups.
  • R 5 , R 6 , R 7 , R 8 and R 12 are each independently H, (Cr C 6 )alkyl, (Ci-C6)haloalkyl, (C3-C7)carbocycle, 5-10-membered heterocycle, wherein 5- 10-membered heterocycle is optionally substituted with one to three Z 11 groups.
  • R 5 , R 6 , R 7 , R 8 and R 12 are each independently H, (Cr
  • R 5 , R 6 , R 7 , R 8 and R 12 are each independently H or (Cr C 6 )alkyl.
  • R 5 , R 6 , R 7 , R 8 and R 12 are each independently
  • R 5 , R 6 , R 7 , R 8 and R 12 are each independently -NR e R f or-C(0)NR e R f .
  • R 5 , R 6 , R 7 , R 8 and R 12 are each independently hydrogen.
  • any heteroaryl or heterocycle of Z is a 5-12 membered heteroaryl or a
  • each Z 1 is independently :
  • C 7 cycloalkyl, (C3-C 7 )cycloalkyl-(Ci-C 6 )alkyl-, -OH, -0(C C 6 )alkyl, -0(C C 6 )haloalkyl, -SH, -S(C C 6 )alkyl, -SO(C C 6 )alkyl, -S0 2 (C C 6 )alkyl, -NH 2 , -NH(C C 6 )alkyl or
  • any heterocycle or heteroaryl of Z 1 is a 5-12 membered heterocycle or 5-12 membered heteroaryl.
  • each Z 1 is independentlyhalo, oxo, thioxo, (C 2 - C 6 )alkenyl, (C C 6 )haloalkyl, (C 3 -C 7 )cycloalkyl, (C3-C 7 )cycloalkyl-(Ci-C 6 )alkyl-, -OH, -0(Ci-C 6 )alkyl, -0(C C 6 )haloalkyl, -SH, -S(C C 6 )alkyl, -SO(C C 6 )alkyl, -S0 2 (C C 6 )alkyl, -NH 2 , -NH(C C 6 )alkyl or -N((C C 6 )alkyl) 2 .
  • each Z 1 is independently (Ci-C6)alkyl optionally substituted with -OH, -0-(Ci-C 6 )haloalkyl, or -0-(Ci-C 6 )alkyl.
  • each Z 1 is independently (C6-Ci 2 )aryl, heterocycle or heteroaryl, which (C6-Ci 2 )aryl, heterocycle and 5- heteroaryl is optionally substituted with halo, (Ci-C6)alkyl or COOH, wherein any heterocycle or heteroaryl of Z 1 is a 5-12 membered heterocycle or 5-12 membered heteroaryl.
  • each Z 1 is independentlyhalo or (Ci-C6)haloalkyl -NH 2 , or (Ci-C 6 )alkyl optionally substituted with -OH, -0-(Ci-C 6 )haloalkyl, or -0-(C
  • each Z 1 is independentlyhalo or (Ci-C6)alkyl optionally substituted with -OH, -0-(Ci-C 6 )haloalkyl, or -0-(Ci-C 6 )alkyl.
  • each Z 1 is independentlyhalo or (Ci-C6)alkyl.
  • compounds having antiviral activity are provided, the compounds having the following Formula (la):
  • R 2 is H, oxo, halo, (C C 6 )alkyl or -0(C C 6 )alkyl;
  • R 3 is (Ci-C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 3 -C 6 )cycloalkyl, (Ci-C 6 )-alkyl-(C 3 -
  • W is N or CR 1 when the dashed bond is a double bond, or W is O, NR 1 or CR la R lb when the dashed bond is a single bond;
  • E is selected from the group consisting of:
  • X is N when Y is N-R 7 and X is N-R 6 when Y is N;
  • G 1 is N
  • G 2 is CR 8
  • the dashed bond is a double bond
  • G 1 is CR 5 , G 2 is N, and the dashed bond is a double bond; or
  • G 1 is CR 5
  • G 2 is NR 13
  • the dashed bond is a single bond
  • G 1 is CR 5
  • G 2 is NR 13
  • the dashed bond is a single bond
  • R 7 and R 13 together with the atoms to which they are attached form a 5-10- membered heteroaryl, wherein the 5-10-membered heteroaryl is optionally substituted with one to three Z 1 groups;
  • G 1 is S
  • G 2 is N
  • the dashed bond connected to G 1 is a single bond
  • the dashed bond connected to G 2 is a double bond
  • the wavy bond connected to R 12 is a single bond
  • G 1 is N
  • G 2 is S
  • the dashed bond connected to G 1 is a double bond
  • the dashed bond connected to G 2 is a single bond
  • the wavy bond connected to R 12 is a single bond
  • G 1 is S
  • G 2 is NR 6
  • the dashed bond connected to G 1 is a single bond
  • the dashed bond connected to G 2 is a single bond
  • R la and R lb are each independently R ;
  • (C 2 -C6)alkenyl, (C2-C6)alkynyl, (C6-Ci2)aryl or heteroaryl, either alone or as a group is optionally substituted with one to three Z 1 groups; and wherein any heteroaryl or heterocycle is a 5-12 membered heteroaryl or a 5-12 membered heterocycle; or d) -NR e Rf, -C(0)NR e Rf, -OC(0)NR e R f , -S0 2 NR e R f , -(C C 6 )alkyl- NR e Rf, -(Ci-C 6 )alkylC(0)-NReRf, -(Ci-C 6 )alkyl-0-C(0)-NReR f or -(Ci-C6)alkyl-S0 2 NReRf; wherein each (Ci-C6)alkyl is independently substituted with one to three Z 6 groups and optionally substituted with one to three
  • each R a , R b , R c and R d is independently H or (Ci-C6)alkyl, (C 2 - C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C3-C7)carbocycle, heterocycle, (C 6 - Ci2)aryl, (C6-C 12 ) aryl(Ci-C6)alkyl-, heteroaryl or heteroaryl(d- C 6 )alkyl-, wherein any (Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl,
  • any (C2-C6)haloalkyl, (C2-C6)alkenyl or (C2-C6)alkynyl of R e is optionally substituted with one to three Zi groups; wherein any (C6-Ci2)aryl, 5-12 membered heterocycle or 5-12
  • R e are each independently substituted with one to three Z5 groups; and each R f is independently H, -R g, -OR a, -(C C 6 )alkyl-Z 6 , -S0 2 R g , -C(0)R g , C(0)OR g or -C(0)NR e R g ; and each R g is independently H, (Ci-C6)alkyl, (C3-C7)carbocycle
  • (Ci-C 6 )haloalkyl (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 6 -Ci 2 )aryl, 5-12 membered heterocycle or 5-12 membered heteroaryl, wherein any (Ci-C6)alkyl, (C3-C7)carbocycle -(Ci-C6)haloalkyl,
  • each Z 5 is independently -N0 2 , -CN, -NR a S0 2 NR c R d , -NR a S0 2 0(C 3 - C 7 )carbocycle, -NR a S0 2 0-(C 6 -Ci2)aryl, -NR a S0 2 (Ci-C 6 )alkyl, - NR a S0 2 (C2-C 6 )alkenyl, -NR a S0 2 (C2-C 6 )alkynyl, -NR a S0 2 (C 3 - C 7 )carbocycle, -NR a S0 2 (C 3 -C 7 )halocarbocycle,
  • each Z 6 is independently -N0 2 , -CN, -NR a R a , NR a C(0)R b ,-C(0)NR c R d (C 3 -C 7 )halocarbocycle, (C6-Ci2)aryl, heteroaryl, heterocycle, -0-(C 6 - Ci2)aryl, -Oheteroaryl, -Oheterocycle, -0(C 3 -C 7 )halocarbocycle, -0(Ci C 6 )alkyl, -0(C 3 -C 7 )carbocycle, -0(C C 6 )haloalkyl, -S-(C 6 -C 12 )aryl, -Sheteroaryl, -Sheterocycle, -S(C 3 -C 7 )halocarbocycle, -S(Ci-C6)alkyl, -S(Ci-C6)alkyl, -S(
  • any (C6-Ci2)aryl of Z 6 is optionally substituted with one to three halogen, -OH, -0(Cr C 6 )alkyl, -CN, NH 2 , or -(C C 6 )alkyl, and wherein any heteroaryl or heterocycle of Z 6 is a 5-12 membered
  • heteroaryl or a 5-12 membered heterocycle.
  • W is N, NH or CR 1 .
  • R 2 is oxo, halo, H or -CH 3 .
  • R 2 is -CH 3 .
  • R 3 is -0(Ci-C6)alkyl optionally substituted with three groups selected from the group consisting of halo and -CN.
  • R 3 is -
  • E is and R 5 is H.
  • R 6 is
  • (C6-Ci 2 )aryl is optionally substituted with one to three Z 10 groups;
  • each R 11 is independently selected from H, (Ci-C6)alkyl, (C 2 -C6)alkenyl, (C 2 -C 6 )alkynyl, (C C 6 )haloalkyl, (C 3 -C 7 )cycloalkyl, (C 6 -
  • Ci 2 aryl, 5-10-membered heterocycle and 5-10-membered heteroaryl, wherein any (C6-Ci 2 )aryl, 5-10-membered heterocycle or 5-10-membered heteroaryl of R 6 is optionally substituted with one to three Z 10 groups;
  • Ci 2 aryl, -(C 2 -C6)alkynyl-heteroaryl -(C 2 -C6)alkynyl- heterocycle, -(C 2 -C8)alkynyl-OR a and -(C2-C6)alkyl-(C3-C7)carbocycle-OR a , wherein
  • any heteroaryl or heterocycle of Z 6 is a 5-12 membered
  • heteroaryl or a 5-12 membered heterocycle.
  • R 7 and R 8 are H.
  • R 7 is:
  • R 6 and R 8 are H.
  • R 8 is:
  • each R 11 is independently H, (Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (Ci-C 6 )haloalkyl, (C 3 -C 7 )cycloalkyl, (C 6 -Ci 2 )aryl, 5-12 membered heterocycle or 5-12 membered heteroaryl, wherein (C6-Ci2)aryl, 5-12 membered heterocycle and 5-12 membered heteroary
  • each R 11 is independently H, (C C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C C 6 )haloalkyl, (C 3 - C7)cycloalkyl, (C6-Ci2) ryl, 5-12 membered heterocycle or 5-12 membered heteroaryl;
  • heterocycle -X-(C6-Ci2)aryl, -Xheteroaryl or -Xheterocycle, wherein any (C6-Ci2)aryl, heteroaryl and heterocycle, either alone or as part of a group, is substituted with one to three Z 5 groups and optionally substituted with one to three Z ⁇ oups, and wherein any -Xheteroaryl or -Xheterocycle is a 5-12 membered -Xheteroaryl or a 5-12 membered -Xheterocycle;
  • (C 2 -C6)alkynyl wherein (Ci-C6)haloalkyl, (C3-C7)carbocycle, (C2-C6)alkenyl or (C2-C6)alkynyl are each independently substituted with one to three Z 6 groups and optionally substituted with one to three Z ⁇ oups; or
  • R 5 , R 6 , R 7 , and R 8 are each hydrogen.
  • E is C-R 3
  • G L is N
  • the dotted bond is a double bond.
  • R 6 is H and R 5 is H or (Ci-C6)alkyl.
  • R 7 is:
  • R 7 is:
  • G 1 is S
  • G 2 is N
  • the dashed bond connected to G 1 is a single bond
  • the dashed bond connected to G 2 is a double bond
  • the wavy bond connected to R 12 is a single bond
  • G 1 is S
  • G 2 is NR 6
  • the dashed bond connected to G 1 is a single bond
  • the dashed bond connected to G 2 is a single bond
  • the wavy bond connected to R 12 is a double bond
  • R 5 is oxygen.
  • R 12 is
  • R is oxo and R 6 is R 11 or -(Ci-C 6 )alkyl-R n , wherein each R 11 is independently H, (Ci-C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C C6)haloalkyl, (C3-C7)cycloalkyl, (C6-Ci 2 )aryl, 5-12 membered heterocycle or 5-12 membered heteroaryl, wherein (C6-Ci 2 )aryl, 5-12 membered heterocycle or 5-12 membered heteroaryl are each optionally substituted with one to three Z 11 groups.
  • R 12 is:
  • each Z 10 is independently:
  • halo oxo, thioxo, (C 2 -C6)alkenyl, (Ci-C6)haloalkyl, (C3- C 7 )cycloalkyl, (C 3 -C7)cycloalkyl-(Ci-C 6 )alkyl-, -OH, -0(C C 6 )alkyl, -0(C C 6 )haloalkyl, -SH, -S(C C 6 )alkyl, -SO(C C 6 )alkyl, -S0 2 (C C 6 )alkyl, -NH 2 , -NH(C C 6 )alkyl or
  • R 8 is:
  • Z 1 is independently :
  • a pharmaceutical composition comprising a compound of any one of Formula I and Formula la or a stereoisomer or
  • Another embodiment comprising a method of treating or preventing an HIV infection in a human having or at risk of having the infection by administering to the human a therapeutically effective amount of a compound of any one of Formula I and Formula la, or a pharmaceutical composition thereof.
  • the compounds described herein are administered as a raw chemical or are formulated as
  • compositions of the present invention comprise a compound of Formula (I) and a pharmaceutically acceptable carrier, diluent or excipient.
  • the compound of Formula (I) is present in the composition in an amount which is effective to treat a particular disease or condition of interest.
  • the activity of compounds of Formula (I) can be determined by one skilled in the art, for example, as described in the Examples below. Appropriate concentrations and dosages can be readily determined by one skilled in the art.
  • compositions of the invention can be prepared by combining a compound of the invention with an appropriate pharmaceutically acceptable carrier, diluent or excipient, and may be formulated into preparations in solid, semi-solid, liquid or gaseous forms, such as tablets, capsules, powders, granules, ointments, solutions, suppositories, injections, inhalants, gels, microspheres, and aerosols.
  • compositions of the invention are formulated so as to allow the active ingredients contained therein to be bioavailable upon administration of the composition to a patient.
  • Compositions that will be administered to a subject or patient take the form of one or more dosage units, where for example, a tablet may be a single dosage unit, and a container of a compound of the invention in aerosol form may hold a plurality of dosage units.
  • composition to be administered will, in any event, contain a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, for treatment of a disease or condition of interest in accordance with the teachings of this invention.
  • compositions of the invention may be prepared by methodology well known in the pharmaceutical art.
  • a pharmaceutical composition intended to be administered by injection can be prepared by combining a compound of the invention with sterile, distilled water so as to form a solution.
  • a surfactant may be added to facilitate the formation of a homogeneous solution or suspension.
  • Surfactants are compounds that non-covalently interact with the compound of the invention so as to facilitate dissolution or homogeneous suspension of the compound in the aqueous delivery system.
  • the compounds of the invention are administered in a therapeutically effective amount, which will vary depending upon a variety of factors including the activity of the specific compound employed; the metabolic stability and length of action of the compound; the age, body weight, general health, sex, and diet of the patient; the mode and time of administration; the rate of excretion; the drug combination; the severity of the particular disorder or condition; and the subject undergoing therapy.
  • method for treating an HIV infection comprising administering to a patient in need thereof a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, thereof, in combination with a therapeutically effective amount of one or more additional therapeutic agents which are suitable for treating an HIV infection.
  • a compound as disclosed herein may be combined with one or more additional therapeutic agents in any dosage amount of the compound (e.g., from 50 mg to 300 mg of compound).
  • a method for treating or preventing an HIV infection in a human having or at risk of having the infection comprising administering to the human a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more additional therapeutic agents.
  • the invention provides pharmaceutical compositions comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with at least one additional therapeutic agent, and a pharmaceutically acceptable carrier.
  • the therapeutic agent used in combination with the compound disclosed herein can be any anti-HIV agent.
  • combination pharmaceutical agents comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with one or more additional therapeutic agents are provided.
  • the additional therapeutic agent may be an anti- HIV agent.
  • the additional therapeutic agent is selected from the group consisting of HIV protease inhibiting compounds (HIV protease inhibitors), HIV non-nucleoside inhibitors of reverse transcriptase, HIV nucleoside inhibitors of reverse transcriptase, HIV nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, entry inhibitors (e.g., CCR5 inhibitors, gp41 inhibitors (i.e., fusion inhibitors) and CD4 attachment inhibitors), CXCR4 inhibitors, gpl20 inhibitors, G6PD and NADH-oxidase inhibitors, capsid polymerization inhibitors or capsid disrupting
  • HIV protease inhibiting compounds HIV non-nucleoside inhibitors of reverse transcriptase
  • HIV nucleoside inhibitors of reverse transcriptase HIV nucleotide inhibitors of reverse
  • the additional therapeutic agent is selected from one or more of:
  • HIV protease inhibitors selected from the group consisting of amprenavir, atazanavir, fosamprenavir, indinavir, lopinavir, ritonavir, nelfinavir, saquinavir, tipranavir, brecanavir, darunavir, TMC-126, TMC-114, mozenavir (DMP-450), JE-
  • HIV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase selected from the group consisting of capravirine, emivirine, delaviridine, efavirenz, nevirapine, (+) calanolide A, etravirine, GW5634, DPC-083, DPC-961 , DPC-963, MIV-150, TMC-120, rilpivirene, BILR 355 BS, VRX 840773, lersivirine (UK- 453061), RDEA806, KM023 and MK-1439;
  • HIV nucleoside inhibitors of reverse transcriptase selected from the group consisting of zidovudine, emtricitabine, didanosine, stavudine, zalcitabine, lamivudine, abacavir, amdoxovir, elvucitabine, alovudine, MIV-210, ⁇ -FTC, D-d4FC,
  • HIV nucleotide inhibitors of reverse transcriptase selected from the group consisting of tenofovir, tenofovir disoproxil fumarate, tenofovir disoproxil
  • tenofovir disoproxil tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, tenofovir alafenamide, GS-7340 (Gilead Sciences), GS- 9148 (Gilead Sciences), adefovir, adefovir dipivoxil, CMX-001 (Chimerix) or CMX- 157 (Chimerix);
  • HIV integrase inhibitors selected from the group consisting of curcumin, derivatives of curcumin, chicoric acid, derivatives of chicoric acid, 3,5-dicaffeoylquinic acid, derivatives of 3,5-dicaffeoylquinic acid, aurintricarboxylic acid, derivatives of aurintricarboxylic acid, caffeic acid phenethyl ester, derivatives of caffeic acid phenethyl ester, tyrphostin, derivatives of tyrphostin, quercetin, derivatives of quercetin, S-1360, AR-177, L-870812, and L-870810, raltegravir, BMS-538158, GSK364735C, BMS-707035, MK-2048, BA Oi l, elvitegravir, dolutegravir and GSK- 744;
  • NICKI allosteric, integrase inhibitors
  • NCINI allosteric, integrase inhibitors
  • BI-224436 CX0516, CX05045, CX14442
  • compounds disclosed in WO 2009/062285 Boehringer Ingelheim
  • WO 2010/130034 Boehringer Ingelheim
  • WO 2013/159064 Gilead Sciences
  • WO 2012/145728 Gilead Sciences
  • gp41 inhibitors selected from the group consisting of enfuvirtide, sifuvirtide, albuvirtide, FB006M, and TRI-1144;
  • CCR5 inhibitors selected from the group consisting of aplaviroc, vicriviroc, maraviroc, cenicriviroc, PRO- 140, INCB 15050, PF-232798 (Pfizer), and CCR5mAb004;
  • CD4 attachment inhibitors selected from the group consisting of ibalizumab (TMB-355) and BMS-068 (BMS-663068);
  • pharmacokinetic enhancers selected from the group consisting of cobicistat, ritonavir, and SPI-452;
  • the additional therapeutic agent is selected from one or more of:
  • HIV protease inhibitors selected from the group consisting of amprenavir, atazanavir, fosamprenavir, indinavir, lopinavir, ritonavir, nelfinavir, saquinavir, tipranavir, brecanavir, darunavir, TMC-126, TMC-114, mozenavir (DMP-450), JE- 2147 (AG1776), L-756423, RO0334649, KNI-272, DPC-681, DPC-684, GW640385X, DG17, PPL-100 (TMB-657), DG35, AG 1859, fosamprenavir calcium, indinavir sulfate, nelfinavir mesylate, saquinavir mesylate, and TMC-310911 ;
  • HIV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase selected from the group consisting of capravirine, emivirine, delaviridine, efavirenz, nevirapine, (+) calanolide A, etravirine, GW5634, DPC-083, DPC-961 , DPC-963, MIV-150, TMC-120, rilpivirene, BILR 355 BS, VRX 840773, lersivirine (UK- 453061), RDEA806, KM023, MK-1439, delavirdine mesylate, dapivirine, doravirine, VM-1500, lentinan, and AIC-292.;
  • HIV nucleoside or nucleotide inhibitors of reverse transcriptase selected from the group consisting of zidovudine, emtricitabine, didanosine, stavudine, zalcitabine, lamivudine, abacavir, abacavir sulfate, amdoxovir, elvucitabine, alovudine, MIV-210, +-FTC, D-d4FC, emtricitabine, phosphazide, fozivudine tidoxil, apricitibine (AVX754), KP-1461 , GS-9131 (Gilead Sciences), fosalvudine tidoxil (formerly HDP 99.0003), tenofovir, tenofovir disoproxil fumarate, tenofovir alafenamide, tenofovir alafenamide hemifumarate, tenofovir alafenamide fumarate
  • HIV integrase inhibitors selected from the group consisting of curcumin, derivatives of curcumin, chicoric acid, derivatives of chicoric acid, 3,5-dicaffeoylquinic acid, derivatives of 3,5-dicaffeoylquinic acid, aurintricarboxylic acid, derivatives of aurintricarboxylic acid, caffeic acid phenethyl ester, derivatives of caffeic acid phenethyl ester, tyrphostin, derivatives of tyrphostin, quercetin, derivatives of quercetin, S-1360, AR-177, L-870812, and L-870810, raltegravir, BMS-538158, GSK364735C, BMS-707035, MK-2048, BA Oi l, elvitegravir, dolutegravir, dolutegravir sodium, GSK-744, and cabotegravir;
  • HIV non-catalytic site or allosteric, integrase inhibitors (NCINI) including, but not limited to, BI-224436, CX0516, CX05045, CX14442, CX-05168, compounds disclosed in WO 2009/062285 (Boehringer Ingelheim), WO 2010/130034 (Boehringer Ingelheim), WO 2013/159064 (Gilead Sciences), WO 2012/145728 (Gilead Sciences), WO 2012/003497 (Gilead Sciences), WO 2012/003498 (Gilead Sciences) each of which is incorporated by references in its entirety herein;
  • NCINI allosteric, integrase inhibitors
  • gp41 inhibitors selected from the group consisting of enfuvirtide, sifuvirtide, albuvirtide, FB006M, and TRI-1144;
  • CXCR4 inhibitors selected from the group consisting of plerixafor, ALT- 1188, vMIP, Haimipu, and AMD-070;
  • gpl20 inhibitors selected from the group consisting of Radha-108 (Receptol), BMS-663068, and BMS-488043;
  • CCR5 inhibitors selected from the group consisting of aplaviroc, vicriviroc, maraviroc, cenicriviroc, PRO- 140, INCB 15050, PF-232798 (Pfizer),
  • CD4 attachment inhibitors selected from the group consisting of ibalizumab (TMB-355) and BMS-068 (BMS-663068);
  • pharmacokinetic enhancers selected from the group consisting of cobicistat, SPI-452, and ritonavir;
  • other drugs for treating HIV selected from the group consisting of BAS- 100, SPI-452, REP 9, SP-01A, TNX-355, DES6, ODN-93, ODN-112, VGV-1, PA-457 (bevirimat), HRG214, VGX-410, KD-247, AMZ 0026, CYT 99007 A-221 HIV, DEBIO-025, BAY 50-4798, MDX010 (ipilimumab), PBS 119, ALG 889, and PA- 1050040 (PA-040), BanLec, MK-8507, AG-1105, TR-452, MK-8591, CYT-107, alisporivir, NOV-205, IND-02, metenkefalin, PGN-007, Acemannan, Gamimune, Prolastin, 1,5-dicaffeoylquinic acid, BIT-225, RPI-MN, VSSP, Hlviral, IMO-3100, SB- 728-T,
  • Immune-based therapies selected from the group consisting of dermaVir, interleukin-7, plaquenil (hydroxychloroquine), proleukin (aldesleukin, IL-2), interferon alfa, interferon alfa-2b, interferon alfa-n3, pegylated interferon alfa, interferon gamma, hydroxyurea, mycophenolate mofetil (MPA) and its ester derivative mycophenolate mofetil (MMF), WF-10, ribavirin, IL-2, IL-12, polymer polyethyleneimine (PEI), Gepon, VGV-1, MOR-22, BMS-936559, toll-like receptors modulators (tlrl, tlr2, tlr3, tlr4, tlr5, tlr6, tlr7, tlr8, tlr9, tlrlO, tlrl l, tlrl 2 and tlrl
  • HIV antibodies bispecific antibodies and "antibody-like" therapeutic proteins (such as DARTs®, Duobodies®, Bites®, XmAbs®, TandAbs ®, Fab derivatives) including BMS-936559, TMB-360 and those targeting HIV gpl20 or gp41 selected from the group consisting of bavituximab, UB-421, C2F5, C2G12, C4E10, C2F5+C2G12+C4E10, 3-BNC-117 , PGT145, PGT121, MDX010 (ipilimumab), VRCOl, A32, 7B2, 10E8, VRC-07-523 and VRC07;
  • latency reversing agents selected from the group consisting of Histone deacetylase inhibitors such as Romidepsin, vorinostat, panobinostat; Proteasome inhibitors such as Velcade; protein kinase C (PKC) activators such as Indolactam, Prostratin, Ingenol B and DAG-lactones, Ionomycin, GSK-343, PMA, SAHA, BRD4 inhibitors, IL-15, JQ1, disulfram, and amphotericin B;
  • Np7 HIV nucleocapsid p7 (NCp7) inhibitors selected from the group consisting of azodicarbonamide
  • Np7 HIV nucleocapsid p7
  • BMS- 955176 and GSK-2838232 HIV maturation inhibitors selected from the group consisting of BMS- 955176 and GSK-2838232
  • (23) PI3K inhibitors selected from the group consisting of idelalisib, AZD- 8186, buparlisib, CLR-457, pictilisib, neratinib, rigosertib, rigosertib sodium, EN-3342, TGR-1202, alpelisib, duvelisib, UCB-5857, taselisib, XL-765, gedatolisib, VS-5584, copanlisib, CAI orotate, perifosine, RG-7666, GSK-2636771, DS-7423, panulisib, GSK-2269557, GSK-2126458, CUDC-907, PQR-309, INCB-040093, pilaralisib, BAY-1082439, puquitinib mesylate, SAR-245409, AMG-319, RP-6530, ZSTK-474
  • a compound disclosed herein, or a pharmaceutically acceptable salt thereof is combined with two, three, four or more additional therapeutic agents. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with two additional therapeutic agents. In other embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with three additional therapeutic agents. In further embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with four additional therapeutic agents.
  • the two, three four or more additional therapeutic agents can be different therapeutic agents selected from the same class of therapeutic agents, or they can be selected from different classes of therapeutic agents.
  • a compound disclosed herein, or a pharmaceutically acceptable salt thereof is combined with an HIV nucleotide inhibitor of reverse transcriptase and an HIV non-nucleoside inhibitor of reverse transcriptase.
  • a compound disclosed herein, or a pharmaceutically acceptable salt thereof is combined with an HIV nucleotide inhibitor of reverse transcriptase, and an HIV protease inhibiting compound.
  • a compound disclosed herein, or a pharmaceutically acceptable salt thereof is combined with an HIV nucleotide inhibitor of reverse transcriptase, an HIV non-nucleoside inhibitor of reverse transcriptase, and an HIV protease inhibiting compound.
  • a compound disclosed herein, or a pharmaceutically acceptable salt thereof is combined with an HIV nucleotide inhibitor of reverse transcriptase, an HIV non- nucleoside inhibitor of reverse transcriptase, and a pharmacokinetic enhancer.
  • a compound disclosed herein, or a pharmaceutically acceptable salt thereof is combined with tenofovir, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, tenofovir disoproxil, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide.
  • a compound disclosed herein, or a pharmaceutically acceptable salt thereof is combined with tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir alafenamide.
  • a compound disclosed herein, or a pharmaceutically acceptable salt thereof is combined with emtricitibine, abacavir or lamivudine.
  • a compound disclosed herein, or a pharmaceutically acceptable salt thereof is combined with one of: tenofovir, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, tenofovir disoproxil, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide and one of: emtricitibine, abacavir or lamivudine.
  • a compound disclosed herein, or a pharmaceutically acceptable salt thereof is combined with one of: tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, tenofovir alafenamide fumarate, or tenofovir alafenamide and one of: emtricitibine or abacavir.
  • a compound disclosed herein, or a pharmaceutically acceptable salt thereof is combined with 5-30 mg tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide and 200 mg
  • a compound disclosed herein, or a pharmaceutically acceptable salt thereof is combined with 5-10; 5-15; 5-20; 5-25; 25- 30; 20-30; 15-30; or 10-30 mg tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide and 200 mg emtricitabine.
  • a compound disclosed herein, or a pharmaceutically acceptable salt thereof is combined with 10 mg tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide and 200 mg emtricitabine.
  • a compound disclosed herein, or a pharmaceutically acceptable salt thereof is combined with 25 mg tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide and 200 mg emtricitabine.
  • a compound as disclosed herein e.g., a compound of any of formulas I and III or a pharmaceutically acceptable salt thereof
  • may be combined with the agents provided herein in any dosage amount of the compound e.g., from 50 mg to 300 mg of compound the same as if each combination of dosages were specifically and individually listed.
  • a compound disclosed herein, or a pharmaceutically acceptable salt thereof is combined with 200-400 mg tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil and 200 mg emtricitabine. In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 200-250; 200-300; 200-350; 250-350; 250-400; 350-400; 300-400; or 250-400 mg tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil and 200 mg emtricitabine. In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 200-250; 200-300; 200-350; 250-350; 250-400; 350-400; 300-400; or 250-400 mg tenofovir disoproxil fumarate, tenofovir
  • a compound disclosed herein, or a pharmaceutically acceptable salt thereof is combined with 300 mg tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil and 200 mg emtricitabine.
  • a compound as disclosed herein e.g., a compound of any of formulas I and III or a pharmaceutically acceptable salt thereof
  • may be combined with the agents provided herein in any dosage amount of the compound e.g., from 50 mg to 300 mg of compound the same as if each combination of dosages were specifically and individually listed.
  • one or more of the compounds disclosed herein are combined with one or more other active therapeutic agents in a unitary dosage form for simultaneous or sequential administration to a patient.
  • a pharmaceutical composition including one or more of the compounds disclosed herein combined with one or more other active therapeutic agents is provided.
  • the compounds disclosed herein are combined with one or more other active therapeutic agents in a solid dosage form. The combination therapy may be administered as a simultaneous or sequential regimen.
  • the combination may be administered in two or more administrations.
  • one or more of the compounds disclosed herein are coadministered with one or more other active therapeutic agents.
  • Co-administration of a compound disclosed herein with one or more other active therapeutic agents generally refers to simultaneous or sequential administration of a compound disclosed herein and one or more other active therapeutic agents, such that therapeutically effective amounts of disclosed herein and one or more other active therapeutic agents are both present in the body of the patient.
  • the present application provides a method for treating an HIV infection comprising administering to a patient in need thereof a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more additional therapeutic agents such as those disclosed above.
  • D, V, and R 3 are as defined above. It is understood that one skilled in the art may be able to make these compounds by similar methods or by combining other methods known to one skilled in the art. It is also understood that one skilled in the art would be able to make, in a similar manner as described below, other compounds of Formula (I) not specifically illustrated below by using the appropriate starting components and modifying the parameters of the synthesis as needed.
  • starting components may be obtained from sources such as Sigma Aldrich, Lancaster Synthesis, Inc., Maybridge, Matrix Scientific, TCI, and Fluorochem USA, etc. or synthesized according to sources known to those skilled in the art (see, for example, Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th edition (Wiley, December 2000)) or prepared as described herein.
  • the aniline 1A is condensed with methyl vinyl ketone under aerobic conditions in the presence of acid, generating a salt of compound IB, which is neutralized with base to provide the parent form of quinoline IB.
  • Double benzylic bromination is conducted to prepare 1C which is treated with sodium sulfide hydrate to prepare ID.
  • the tricyclic ID is carried through a sequence of oxidation and cheletropic ring contraction under modified Ramberg-Backlund conditions to prepare IE.
  • compound IF may be prepared according to Scheme 2.
  • Monobrominatin of IB withN-bromosuccinimide gives 2 A.
  • the benzylic bromide 2A is oxidized with selenium dioxide, giving 2B, which can be treated with triphenylphosphine to make a quaternary phosphonium salt 2C.
  • Intramolecular Wittig annulation generates 2D, which can be cyclopropanated using a modification of the cyclopropanation described in Scheme 1 to yield IF.
  • Compound 3A is heated in the presence of copper powder and methylene diiodide to give rise to compound 3B.
  • 3B is treated with a brominating reagent such as N-bromosuccinimide, for example, 3C bromide 3C can be obtained.
  • Compound IF or Compound 3C may be borylated under palladium catalysis, and the product boronate ester or boronic acid maybe be either isolated or carried into a Suzuki-Miyaura cross-coupling with 13AA where X is a halide selected from CI, Br, I, or a pseudohalogen (such as OTf).
  • X is a halide selected from CI, Br, I, or a pseudohalogen (such as OTf).
  • the products of the Suzuki-Miyaura coupling, namely 4 A and 4B, which may optionally comprise an atropdiastereomeric set (having axial chirality at the bond connecting D to the tetracycle) can optionally be purified as individual diastereomers or carried on to the next reaction as a(n) (atrop)diastereomeric mixture.
  • 4A and 4B are then saponified as a(n) (atrop)diastereomeric mixture or individually to give 5A and/or 5B, which can be used as a(n) (atrop)diastereomeric mixture or separated into individual diastereomers via methods known to those skilled in the art.
  • Compound IF or Compound 3C may be borylated under palladium catalysis, and the product boronate ester or boronic acid maybe be either directly isolated or carried into a Suzuki-Miyaura cross-coupling with 16AA where X is a halide selected from CI, Br, I, or a pseudohalogen (such as OTf).
  • X is a halide selected from CI, Br, I, or a pseudohalogen (such as OTf).
  • the products of the Suzuki-Miyaura coupling, namely 5A and 5B, which may optionally comprise an atropdiastereomeric set (having axial chirality at the bond connecting system E with group W to the tetracycle) can optionally be purified as individual diastereomers or carried on to the next reaction as a(n) (atrop)diastereomeric mixture.
  • 5A and 5B are then saponified as a(n) (atrop)diastereomeric mixture or individually to give 5C and/or 5D, which can be used as a(n) (atrop)diastereomeric mixture or separated into individual diastereomers via methods known to those skilled in the art.
  • Compounds of Formula where D is a substituted pyridine may be prepared according to Scheme 6.
  • Compound 6A is cyclocondensed with 6B to provide 6C.
  • Bromination leads to 6D, which may be chlorinated with POCI 3 or other suitable chlorination reagents, giving 6E.
  • Metallation of the bromo group and trapping with an electrophile generates 6F.
  • Enantioselective reduction of the ketone provides 6G, which may undergo etherification to provide 6H.
  • Compound 6H may be chemoselectively functionalized with an R 7 containing coupling agent, wherein 61 is an example of 13AA.
  • R 3 -0(C r C 6 )alkyl, -0(C 2 -C 6 )alkenyl
  • a suitably protected alkyne (7B) such as ethynyl(trimethyl)silane
  • copper halide salt such as, for example, copper(I) iodide, N,N-diisopropylethylamine, tetrakis(triphenylphos
  • Deprotection of cross-coupled alkyne (7C) yields the corresponding terminal alkyne (7D) such as, for example, deprotection of a trimethylsilyl-protected alkyne with a fluoride source such as, for example, tetrabutylammonium fluoride.
  • Metalation of a terminal alkyl (7D) such as, for example, deprotonation with n-butyllithium, yields the corresponding metal acetylide such as, for example lithium acetylide, that undergoes nucleophilic addition to an appropriate electrophile (7E) to give the corresponding hydroxy alkyne addition product 7F.
  • a suitably substituted phenyl electrophile such as phenyl-2-propanone can be purchased or prepared by those skilled in the art through, for example, Friedel- Crafts alkylation of benzene with chloroacetone.
  • the hydroxyl alkyne 7F can undergo 6-endo-dig electrophilic cyclization under suitable reaction conditions such as, for example iodine and sodium bicarbonate to give the corresponding substituted naphthalene such as, for example the iodonaphthalene 7G.
  • the substituted naphthalene 7G can undergo a cross-coupling reaction such as, for example Stille cross-coupling using a tin reagent such as tributyl(vinyl)tin and a palladium catalyst such as bis(triphenylphosphine) palladium(II) dichloride to give the corresponding cross-coupled naphthalene such as, for example, vinylnaphthalene 7H.
  • the vinylnaphthalene 7H can be dihydroxylated by methods known to those skilled in the art such as, for example Sharpless asymmetric dihydroxylation using, for example, commercially available AD-mix-a.
  • the resulting diol 71 can be protected at the primary hydroxyl by suitable protecting groups such as, for example, pivalate ester using pivaloyl chloride and pyridine to provide 7J.
  • the secondary hydroxyl can be converted to the corresponding ether 7K such as tert-butyl ether using methods known to those skilled in the art such as, for example, tert-butyl acetate and perchloric acid.
  • the protected primary hydroxyl can be deprotected by methods known to those skilled in the art such as, for example the deprotection of a pivalate protecting group under basic conditions, such as, for example sodium hydroxide, to give the corresponding primary hydroxyl compound 7L.
  • the primary hydroxyl can be oxidized to the corresponding carboxylic acid 7M by methods known to those skilled in the art such as, for example, periodic acid and chromium trioxide.
  • Metalation of a suitably functionalized and protected terminal alkyne such as, for example, deprotonation with n-butyllithium, can yield the corresponding metal acetylide such as, for example lithium acetylide, that undergoes nucleophilic addition to an appropriate electrophile, such as, for example 7E, to give the corresponding hydroxy alkyne addition product 8A.
  • the hydroxyl alkyne 8A can undergo 6-endo-dig electrophilic cyclization under suitable reaction conditions such as, for example iodine and sodium bicarbonate to give the corresponding substituted naphthalene such as, for example iodonaphthalene 8B.
  • the substituted naphthalene 8B can undergo a cross- coupling reaction such as, for example Stille cross-coupling using a tin reagent such as, for example, tributyl(vinyl)tin and a palladium catalyst such as, for example, bis(triphenylphosphine)palladium(II) dichloride to give the corresponding cross- coupled naphthalene such as, for example, vinylnaphthalene 8C.
  • a cross- coupling reaction such as, for example Stille cross-coupling using a tin reagent such as, for example, tributyl(vinyl)tin and a palladium catalyst such as, for example, bis(triphenylphosphine)palladium(II) dichloride to give the corresponding cross- coupled naphthalene such as, for example, vinylnaphthalene 8C.
  • a tin reagent such as, for example, tributyl(vin
  • alkenylnaphthalene 8C can be dihydroxylated using methods known to those skilled in the art such as, for example Sharpless asymmetric dihydroxylation using, for example, commercially available AD-mix-a.
  • the resulting diol 8D can be protected at the primary hydroxyl by an orthogonal protecting groups, such as, for example, pivalate ester using pivaloyl chloride and pyridine.
  • the secondary hydroxyl of 8E can be converted to the corresponding ether 8F, such as a tert-butyl ether using methods known to those skilled in the art for example, using tert-butyl acetate and perchloric acid.
  • the naphthol protecting group can be differentially deprotected by methods known to those skilled in the art and converted to a leaving group (e.g. triflate) known to undergo cross-coupling reactions.
  • Compounds IF or 3C can be converted to the corresponding metalated species, such as the boronic acid using tetrakis(triphenylphosphine)palladium(0) bis(pinacolato)diboron and potassium acetate, and undergo Suzuki cross-coupling with the activated naphthalene 8G using palladium catalyst such as chloro(2-dicyclohexylphosphino-2',6'- dimethoxy-l,l'-biphenyl)[2-(2-aminoethylphenyl)]palladium(II) and a base such as cesium fluoride to complete the installation of R 4 moiety of naphthalene 8H.
  • palladium catalyst such as chloro(2-dicyclohexylphosphino-2',6'- dimethoxy-l,l'-biphenyl)[2-(2-aminoethylphenyl)]palladium(II) and a base such as
  • the protected primary hydroxyl can be deprotected by methods known to those skilled in the art such as, for example the deprotection of a pivalate protecting group under basic conditions, such as, for example sodium hydroxide, to give the corresponding primary hydroxyl.
  • the primary hydroxyl can be oxidized to the corresponding carboxylic acid analog 81 by methods known to those skilled in the art such as, for example, periodic acid and chromium trioxide.
  • Electrophilic aromatic substitution with a suitably functionalized and protected naphthol such as, for example 9A, with an electrophile such as, for example, ethyl glyoxylate under appropriate conditions such as, for example, titanium tetrachloride, can provide 9B.
  • the secondary alcohol can be protected with a protecting group and the naphthol converted to a leaving group (e.g. triflate) known to undergo cross- coupling reactions to provide 9C.
  • the alcohol protecting group can be removed and the resulting alcohol oxidized to the ketone using an oxidant such as Dess-Martin Periodinane, for example, to provide 9E.
  • the ketone can be reduced stereoselectively using an asymmetric reduction method such as, for example Corey-Bakshi-Shibata Reduction to provide 9F.
  • the secondary hydroxyl can be converted to the corresponding ether such as tert-butyl ether using methods known to those skilled in the art such as, tert-butyl acetate and perchloric acid to provide 9G.
  • Compounds IF or 3C can be converted to the corresponding boronic acid or ester using tetrakis(triphenylphosphine)palladium(0) bis(pinacolato)diboron and potassium acetate, and undergo Suzuki cross-coupling with the functionalized naphthalene 9G using a palladium catalyst such as chloro(2- dicyclohexylphosphino-2',6'-dimethoxy- 1 , 1 '-biphenyl)(2'-amino- 1 , 1 '-biphenyl-2-yl) palladium(II) to give the corresponding cross-coupled naphthalene 9H (wherein R 4 is the tetracyclic group of IF or
  • the protected ester can be deprotected by methods known to those skilled in the art such as, for example the deprotection of a ethyl ester protecting group under basic conditions, such as, for example sodium hydroxide, to give the corresponding carboxylic acid 91.
  • the functionalized naphthalenes e.g. 9E, 9G, or 9H
  • a halogen or pseudohalogen e.g. triflate
  • cross-coupling reactions such as but not limited to Suzuki reactions with boronic acids or esters, Stille reactions with trialkyltin reagents, Sonogashira reactions with alkynes, and Buchwald-Hartwig reactions with amines and carried forward in a similar manner to provide 91.
  • Compounds IF or 3C can be converted to the corresponding boronic acid or ester using tetrakis(triphenylphosphine)palladium(0) bis(pinacolato)diboron and potassium acetate, and Suzuki cross-coupled with naphthalene 9C to give the corresponding cross-coupled naphthalene 10A.
  • the alcohol protecting group can be removed and the resulting alcohol oxidized to the ketone using an oxidant such as Dess-Martin periodinane, for example, to provide 10B.
  • the ketone can be reduced stereoselectively using an asymmetric reduction method such as, for example Corey- Bakshi-Shibata Reduction to provide IOC.
  • the secondary hydroxyl can be converted to the corresponding ether such as tert-butyl ether using methods known to those skilled in the art such as, tert-butyl acetate and perchloric acid to provide 10D.
  • the protected ester can be deprotected by methods known to those skilled in the art such as, for example the deprotection of a ethyl ester protecting group under basic conditions, such as, for example sodium hydroxide, to give the corresponding carboxylic acid 10E.
  • the functionalized naphthalenes e.g. 10A or 10D
  • a halogen or pseudohalogen e.g. triflate
  • cross- coupling reactions such as but not limited to Suzuki reactions with boronic acids or esters, Stille reactions with trialkyltin reagents, Sonogashira reactions with alkynes, and Buchwald-Hartwig reactions with amines and carried forward in a similar manner to provide 10E.
  • 11L It is known to those skilled in the art that 11A can undergo the Horner- Wadsworth-Emmons reaction with stabilized phosphonate carbanions such as, for example (diethoxyphosphoryl)acetic acid ethyl ester and sodium hydride to provide 11B.
  • the olefin can be reduced by hydrogenation with palladium on carbon, for example, to provide 11C.
  • the protected ester can be deprotected by methods known to those skilled in the art such as, for example the deprotection of a ethyl ester protecting group under basic conditions, such as, for example lithium hydroxide, to give the corresponding carboxylic acid that can be converted to the corresponding acid chloride using oxalyl chloride to give 11D.
  • Friedel Crafts reaction catalyzed by a Lewis acid such as, for example, aluminum trichloride provides tetralone HE.
  • Condensation of HE with, for example, ethyl glyoxylate under acid catalysis provides 11F which can be brominated under radical conditions such as, for example, N-bromosuccinimide and ⁇ , and converted to 11H using an alkoxide such as that derived from reaction of 4-methoxybenzyl alcohol and LHMDS, for example.
  • the naphthol 11H can be converted to a leaving group (e.g. triflate) known to undergo cross-coupling reactions by methods known to those skilled in the art.
  • a leaving group e.g. triflate
  • Compounds IF or 3C can be converted to the corresponding boronic acid or ester using tetrakis(triphenylphosphine)palladium(0) bis(pinacolato)diboron and potassium acetate, and Suzuki cross-coupled with compound HI to give the corresponding cross-coupled naphthalene 11J wherein R 4 is the tetracyclic group of IF or 3C.
  • the alcohol protecting group can be removed by methods known to those skilled in the art and the resulting hydroxyl can be converted to the corresponding ether such as tert-butyl ether using methods known to those skilled in the art such as, tert- butyl acetate and perchloric acid to provide 11K.
  • the protected ester can be deprotected by methods known to those skilled in the art such as, for example the deprotection of a ethyl ester protecting group under basic conditions, such as, for example sodium hydroxide, to give the corresponding carboxylic acid 11L.
  • Bromination can be achieved using electrophilic sources of bromine such as N-bromosuccinimide to give 12D.
  • the phenol of 12D can be activated by transforming to the leaving group in 12E such as trifluoromethanesulfonate by treatment with trifluoromethanesulfonic anhydride and an appropriate base such as 2,6-lutidine.
  • Regioselective palladium catalysed cross- coupling reactions e.g.
  • Suzuki or Stille can be used to functionalize the quinoline with a vinyl group giving 12F, which can then be asymmetrically di-hydroxylated using reagent mixtures such as AD-mix-ot, giving diol 12G.
  • Selective protection of the primary hydroxyl can be achieved with bulky protecting groups, such as pivaloyl chloride, gives 12H.
  • Formation of the R group can be achieved by alkylation of the secondary alcohol by various methods, such as treatment with perchloric acid in tert-butyl acetate to give a tert-butyl ether.
  • Compounds IF or 3C can be converted to the corresponding boronic acid or ester using tetrakis(triphenylphosphine)palladium(0)
  • a quinolinone intermediate is achieved by N-oxidation of the quinoline 12J with a reagent such as mCPBA, followed by acylation, thermal rearrangement, and selective removal of the acetate.
  • a reagent such as mCPBA
  • Deprotonation of the quinolinone followed by methods to favor O-alkylation when treated with an appropriate electrophile allow for substituents at R 7 to be produced wherein the R 7 group of 13B is an ether.
  • Subsequent hydrolysis and oxidation can provide compounds of formula 1 with R 7 ether groups.
  • the quinolinyl triflate 15A can be made from the quinolinone 13A. Cross coupling reactions with the triflate (e.g. Suzuki and Sonagashira reaction) can introduce different R 7 moieties. Alternatively, the quinolinyl triflate 15A can react with Grignard or alkyl-lithium reagents in the presence of a catalyst such as Fe(AcAc)3 to give the corresponding quinoline. Hydrolysis and oxidation can yield the desired compounds.
  • the quinolinone 13A can be converted to 2-chloroquinoline 16A by treatment with reagents such as phosphorous oxychloride. Nucleophilic aromatic substitution can introduce different R 7 groups wherein the R 7 is linked through a heteroatom.
  • the methylquinoline 18A can be oxidized with mCPBA to give the N-oxide, which can react with acetic anhydride and rearrange to yield the
  • Oxidation of the alcohol can provide the carboxylic acid. Coupling with different amines can provide R 7 amide moieties. Subsequent hydrolysis can generate compounds of formula I with R 7 amides.
  • the quinoline carboxylic acid 18C can be converted to a primary amine via a Curtius rearrangement which can be converted to additional R 7 groups wherein the R 7 group is an amine. Subsequent hydrolysis can provide compounds of formula 1 with R 7 amine groups.
  • the hydroxymethylquinoline 18B can be converted to mesylate, which can be reacted with different nucleophiles to provide R 7 groups wherein the R 7 group is represented by the general formula "-CH 2 XR" wherein X is O, S or NR' . Subsequent hydrolysis can generate compounds of formula I.
  • the benzothiazole intermediate 21B can be converted to the final compound 22C by the methods used to convert 21C to 21M as outlined in Scheme 21 using the corresponding boronic acid or ester of compounds IF or 3C.
  • the benzothiazole intermediate 23E can be converted to the final compound 22C by the methods used to convert 21C to 21D and 21F to 21M as outlined in Scheme 21 using the corresponding boronic acid or ester of compounds IF or 3C.
  • the benzothiazole intermediate 24A can be converted to the final compound 24B by the methods used to convert 21C to 21D and 21F to 21M as outlined in Scheme 21 using the corresponding boronic acid or ester of compounds IF or 3C, wherein HNRR represents an HNR 9 R 10 , HNR e R f or a heterocycle (when R and R taken together with the nitrogen to which they are attached form a ring).
  • the benzothiazoline intermediate 25S can be converted to the final compound 25T by the methods used to convert 21C to 21M as outlined in Scheme 21 using the corresponding boronic acid or ester of compounds IF or 3C.
  • the benzothiazoline intermediate 26V can be converted to the final compound 26W by the methods used to convert 21C to 21M as outlined in Scheme 21 using the corresponding boronic acid or ester of compounds IF or 3C.
  • an appropriately substituted phenol 27 A is halogenated by the treatment of dihalide, for example bromine, in a suitable solvent such as, for example acetic acid.
  • the phenol 27B is converted to a leaving group (e.g., triflate) known to undergo cross-coupling reactions.
  • the corresponding activated phenol 27C undergoes a selective cross-coupling reaction such as, for example Stille cross-coupling using a tin reagent such as tributyl(vinyl)tin and a palladium catalyst such as bis(triphenylphosphine) palladium(II) dichloride to give the corresponding cross- coupled naphthalene such as styrene 27D.
  • the styrene is dihydroxylated to provide 27E by methods known to those skilled in the art such as, Sharpless asymmetric dihydroxylation using, for example, commercially available AD mix-a.
  • the resulting diol 27E is protected at the primary hydroxyl by suitable protecting groups such as pivalate ester using pivaloyl chloride and pyridine to provide 27F.
  • the secondary hydroxyl is converted to the corresponding ether such as tert-butyl ether using methods known to those skilled in the art such as, tert-butyl acetate and perchloric acid to provide 27G.
  • Benzothiazole 271 is formed by methods known to those skilled in the art such as potassium thiocyanate and pyridinium perbromide, for example.
  • the resulting benzothiazole undergoes Suzuki cross-coupling reaction with the corresponding boronic esters of IF or 3C, for example, using a palladium catalyst such as tetrakis(triphenylphosphine)palladium(0) to give the corresponding cross-coupled benzothiazole 27J wherein R 4 is the tetracylic group of IF or 3C.
  • the corresponding halobenzothiazole 27K is formed by methods known to those skilled in the art such as
  • the protected primary hydroxyl 27J (wherein R 4 is installed as described in Scheme 27) is deprotected by methods known to those skilled in the art such as the deprotection of a pivalate protecting group under basic conditions for example, using sodium hydroxide, to give the corresponding primary hydroxyl compound 28A.
  • the primary hydroxyl is oxidized to the corresponding carboxylic acid by methods known to those skilled in the art such as, for example, periodic acid and chromium trioxide.
  • the resulting carboxylic acid is protected by formation of corresponding carboxylic ester 28B with treatment of, for example,
  • the protected primary hydroxyl 27J is deprotected by methods known to those skilled in the art such as the deprotection of a pivalate protecting group under basic conditions for example, using sodium hydroxide, to give the corresponding primary hydroxyl compound 29A.
  • the primary hydroxyl is oxidized to the corresponding carboxylic acid 29B by periodic acid and chromium trioxide, for example.
  • the carboxylic acid is protected as, for example, a methyl ester by treatment with sulfuric acid in methanol.
  • the tert-butyl ether is re-installed by treating 29C with tert-butyl acetate and perchloric acid, for example, to provide 29D.
  • the corresponding halobenzothiazole 29E is formed by methods known to those skilled in the art such as ferf-butyl nitrite and a copper(II)halide such as copper(II)bromide, for example.
  • chlorobenzothiazole 30A is formed from 271 by methods known to those skilled in the art such as ferf-butyl nitrite and a
  • copper(II)halide such as copper(II)bromide
  • PG 2 selective palladium- catalyzed cross-coupling such as Suzuki or Stille with protected phenol boronic acid/ester or stannane, respectively, provides 30B.
  • Selective deprotection of PG 2 such as catalytic hydrogenation of a benzyl ether gives phenol 30C, which is converted to a leaving group (e.g., triflate) known to undergo cross-coupling reactions.
  • the corresponding activated phenol 30D undergoes a selective cross-coupling reaction such as, for example Suzuki cross-coupling using a boronic acid or ester and a palladium catalyst such as tetrakis(triphenylphosphine)palladium(0) to give the corresponding cross-coupled benzothiazole 30E.
  • a selective cross-coupling reaction such as, for example Suzuki cross-coupling using a boronic acid or ester and a palladium catalyst such as tetrakis(triphenylphosphine)palladium(0) to give the corresponding cross-coupled benzothiazole 30E.
  • the R 4 moiety is introduced by cross-coupling reaction such as a Suzuki cross-coupling reaction with the corresponding boronic acid or ester of compound IF or 3C, for example, using a palladium catalyst such as
  • halobenzothiazole 27K with the desired R 4 moiety already installed,undergoes selective palladium-catalyzed cross-coupling such as Suzuki or Stille with a boronic acid/ester or stannane that also contains a leaving group such as for example, a chloropyridylboronic acid, known to undergo cross-coupling reactions to give 31A.
  • the activated moiety 31A undergoes a cross-coupling reaction such as, for example Suzuki or Stille cross-coupling using a boronic acid/ester or stannane, respectively and a palladium catalyst such as
  • the protected primary hydroxyl 31B is deprotected by methods known to those skilled in the art such as the deprotection of a pivalate protecting group under basic conditions for example, using sodium hydroxide, to give the corresponding primary hydroxyl compound 31C.
  • the primary hydroxyl is oxidized to the corresponding carboxylic acid 31D by periodic acid and chromium trioxide, for example.
  • halobenzothiazole 27K with the desired R 4 moiety already installed, undergoes palladium-catalyzed cross-coupling such as Suzuki with a boronic acid or ester; Stille with a stannane; palladium-catalyzed carbonylation using carbon monoxide, for example in the presence of an amine; copper(I)halide catalyzed or Buchwald-Hartwig amination; palladium-catalyzed amidation; S AT with an amine; to introduce the R 5 moiety in 32A.
  • palladium-catalyzed cross-coupling such as Suzuki with a boronic acid or ester; Stille with a stannane; palladium-catalyzed carbonylation using carbon monoxide, for example in the presence of an amine; copper(I)halide catalyzed or Buchwald-Hartwig amination; palladium-catalyzed amidation; S AT with an amine; to introduce the R
  • the protected primary hydroxyl of 32A is deprotected by methods known to those skilled in the art such as the deprotection of a pivalate protecting group under basic conditions for example, using sodium hydroxide, to give the corresponding primary hydroxyl compound 32B.
  • the primary hydroxyl is oxidized to the corresponding carboxylic acid 32C by periodic acid and chromium trioxide, for example.
  • chlorobenzothiazole 30A undergoes selective palladium-catalyzed cross-coupling such as Suzuki or Stille with protected phenol boronic acid/ester or stannane, respectively, to provide 33A.
  • the R 4 moiety is introduced by cross-coupling reaction with corresponding boronate acid or esters of compound IF or 3C for example, in a Suzuki cross-coupling using a palladium catalyst such as tetrakis(triphenylphosphine)palladium(0) to give the corresponding cross-coupled benzothiazole 33B wherein R 4 is the tetracyclic group of IF or 3C.
  • the protected primary hydroxyl in 33B is deprotected by methods known to those skilled in the art such as the deprotection of a pivalate protecting group under basic conditions for example, using sodium hydroxide, to give the corresponding primary hydroxyl compound 33C.
  • the primary hydroxyl is oxidized to the corresponding carboxylic acid 33D by periodic acid and chromium trioxide, for example.
  • halobenzothiazole 29E with the desired R 4 moiety already installed, undergoes selective palladium-catalyzed cross-coupling such as Suzuki or Stille with a boronic acid/ester or stannane that also contains a leaving group such as for example, a chloropyridylboronic acid, known to undergo cross-coupling reactions to give 34A.
  • the activated moiety 34A undergoes an S Ar reaction with for example a secondary amine, or a cross-coupling reaction such as, for example Suzuki or Stille cross-coupling using a boronic acid/ester or stannane, respectively and a palladium catalyst such as tetrakis(triphenylphosphine)palladium(0) to give the corresponding cross-coupled benzothiazole 34B.
  • the protected carboxylic acid 34B is deprotected by methods known to those skilled in the art such as the deprotection of a carboxylic ester under basic conditions for example, using sodium hydroxide, or treatment with lithium iodide in pyridine, to give the corresponding carboxylic acid 34C.
  • halobenzothiazole 29E with the desired R 4 moiety already installed, undergoes palladium-catalyzed cross-coupling such as Suzuki with a boronic acid or ester; Stille with a stannane; palladium-catalyzed carbonylation using carbon monoxide, for example in the presence of an amine; copper(I)halide catalyzed or Buchwald-Hartwig amination; palladium-catalyzed amidation; S AT with an amine or alcohol; to introduce the R 5 moiety in 35A.
  • palladium-catalyzed cross-coupling such as Suzuki with a boronic acid or ester; Stille with a stannane; palladium-catalyzed carbonylation using carbon monoxide, for example in the presence of an amine; copper(I)halide catalyzed or Buchwald-Hartwig amination; palladium-catalyzed amidation; S AT with an amine or alcohol;
  • the protected carboxylic acid 35A is deprotected by methods known to those skilled in the art such as the deprotection of a carboxylic ester under basic conditions for example, using sodium hydroxide, or treatment with lithium iodide in pyridine to give the corresponding carboxylic acid 35B.
  • aminobenzothiazole 29D with the desired R 4 moiety already installed, undergoes reactions known to those skilled in the art such as amide formation using carboxylic acid EDCI, for example; sulfonamide formation using a sulfonyl chloride; urea formation using CDI in the presence of an amine; to introduce the R 5 moiety in 36A.
  • the protected carboxylic acid 36A is deprotected by methods known to those skilled in the art such as the deprotection of a carboxylic ester under basic conditions for example, using sodium hydroxide, to give the corresponding carboxylic acid 36B.
  • ketone 37A undergoes reactions known to those skilled in the art such as aldol condensation to give enone 37B.
  • Compounds IF and 3C can be metallated by treatment of n-butyllithium, for example, and added to enone 37B to undergo 1,2 organometallic to give tertiary alcohol 37C.
  • 37C Under the action of an acid such as polyphosphoric acid, 37C is converted to benzthiazole 37D.
  • Reaction of 37D under basic conditions such as lithium hexamethyldisilazane in the presence of oxaziridine such as Davis reagent, followed oxidation with an oxidant such as Dess- Martin periodinane can give ketoester 37E.
  • Chiral reductions of 37E such as CBS or Noyori can give chiral alcohol 37F.
  • the secondary hydroxyl is converted to the corresponding ether such as tert-butyl ether using methods known to those skilled in the art such as, tert-butyl acetate and perchloric acid to provide 37G.
  • the activated benzthiazole 37G undergoes a cross-coupling reaction such as, for example Buchwald, Heck, Negishi, Suzuki or Stille cross-coupling using a palladium catalyst such as tetrakis(triphenylphosphine)palladium(0); S AT reactions with for example, a secondary amine; to give the corresponding benzothiazole 37H.
  • the protected carboxylic acid 37H is deprotected by methods known to those skilled in the art such as the deprotection of a carboxylic ester under basic conditions for example, using sodium hydroxide, or treatment with lithium iodide in pyridine to give the corresponding carboxylic acid 371.
  • halobenzthiazole 29E undergoes palladium-catalyzed cross-coupling such as Suzuki with a boronic acid or ester, for example 2-(4-fluoro-3-nitrophenyl)-4,4,5,5-tetramethyl-l,3,2- dioxaborolane to give 38A, known to those skilled in the art to undergo SnAr reaction with nucleophiles, such as, for example methylamine, to give 38B.
  • Hydrogenation under platinium on carbon for example provides the bis-aniline 38C.
  • Cyclization with an orthoformate, such as triethylorthoformate in acetic acid for example gives benzimidazole 38D.
  • the protected carboxylic acid 38D is deprotected by methods known to those skilled in the art such as the deprotection of a carboxylic ester under basic conditions for example, using sodium hydroxide, or treatment with lithium iodide in pyridine to give the corresponding carboxylic acid 38E.
  • reaction was a suspension with particulate white solid in yellow liquid.
  • a pressure-equalizing addition funnel was attached to the flask and charged with Methyl Vinyl Ketone (26.8 mL, 0.322 mol).
  • the reaction was heated to 120 °C under N 2 .
  • a circulating chiller was applied to through the reflux condenser.
  • the bubbler was then removed and a stream of air was passed steadily over the reaction while the Methyl Vinyl Ketone was added drop wise over 10 min. Heating was continued for another 30 min, then the air stream was cut.
  • the reaction was refitted with the bubbler and an N 2 stream was applied as the reaction was cooled to 23 °C.
  • 8-bromo-4,5-dimethylquinoline A suspension of 8-bromo-4,5- dimethylquinoline, monohydrochloride (all of the material from the reaction above) was placed in a flask. The flask was charged with DCM (200 mL) and 50% w/v aq. KOH (200 mL). Et 3 N (100 ⁇ ) was added at 0 °C and the reaction was stirred vigorously and allowed to warm to 23 °C. All solids dissolved, giving a very yellow organic phase, which was collected, dried (Na 2 S0 4 ), filtered, and concentrated.
  • 8-bromo-4,5-bis(bromomethyl)quinoline A suspension of 8-bromo-4,5- dimethylquinoline (7.70 g, 32.6 mmol) in CC1 4 (150 mL) was treated with AIBN (536 mg, 3.26 mmol) and N-bromosuccinimide (12.2 g, 68.5 mmol). The slurry was sparged with argon for 5 min and later fitted with a reflux condenser under N 2 . The reaction was heated to 90 °C for 2 h. Complete consumption of starting material was seen using LCMS analysis, however there was a mixture of mono-, di-, and tri-brominated products.
  • the two organic layers were combined, dried (MgS0 4 ), and filtered.
  • the resulting solution was treated with more 10% w/v aq NaHS0 3 (100 mL) and warmed to 40 °C.
  • the organic phase was collected after 1 h.
  • the remaining aq. phase was extracted with DCM (100 mL).
  • the combined organic layers were dried (MgS0 4 ), filtered and transferred to a 250 mL pressure-equalizing addition funnel.
  • Diazomethane was prepared using 100 mL of a -0.13 M aqueous solution of Sodium 3-(N-Nitroso-N-Methyl-aminosulfonyl)-benzoate [see: Science 335, 1471 (2012), references therein, and supporting information], which was treated with Et 2 0 (100 mL) followed by 50% w/v aq. KOH (100 mL) at 0 °C. After 10 min, the organic layer was decanted onto solid KOH pellets, and swirled gently for 5 min, then decanted.
  • the compound is an -1:1 mixture of two cyclopropane epimers.
  • LCMS ESI + Calc'd for C 3 oH 3 oN 2 0 3 (M+H) + : 467.2; Found 467.3 (M+H) + .
  • a microwave tube was charged with (2S,4':8"aR)-ethyl 2-tert-butoxy-2-[4'-(quinolino[4",4a",5":bc]-bicyclo[3.1.0]hex-2"'- ene-8"-yl)-2'-methylquinolin-3'-yl]acetate (all of the material from the reaction above, mixture of two cyclopropane epimers), LiOH monohydrate (62 mg, 1.5 mmol), THF (1.2 mL), EtOH (absolute, 500 ⁇ ), and H 2 0 (500 ⁇ ).
  • 8-bromo-5-(bromomethyl)quinoline-4-carbaldehyde To a solution of 8- bromo-5-(bromomethyl)-4-methylquinoline (5.3 g, 16.82 mmol) in anhydrous dioxane (100 mL) was added selenium dioxide (4.67 g, 42.06 mmol) in one portion and the reaction mixture was stirred at 90 °C. The reaction was monitored by LC/MS. After 2.0-3.0 hours, no 8-bromo-5-(bromomethyl)-4-methylquinoline was observed by LC/MS. The brown reaction mixture was cooled to room temperature and filtered through a pad of Celite, rinsing with ethyl acetate.
  • (2S,4':8"aS)-2 ert-butoxy-2 4'-(quinolino[4",4a",5":bc]-bicyclo[3.1.0]hex-2'"- ene-8"-yl)-2'-methylnapthalen-3'-yl]acetic acid was prepared in a manner similar to (2S,4':8"aR)-2-tert-butoxy-2-[4'-(qm ⁇
  • the mixture was refluxed under N 2 for 48 h. Additional methylene iodide (65.4 g, 244 mmol, 3.1 eq) and copper powder (11.2 g, 175 mmol, 2.2 eq) were added, the reaction mixture were heated overnight. More methylene iodide (65.4 g, 244 mmol, 3.1 eq) was added, the reaction mixture was stirred under refluxed for 4 days. The reaction mixture was filtered through a pad of Celite, washed with hexane, and the filtrate was evaporated in vacuo to dryness, which was purified by silica gel chromatography column (hexane), and further recrystallized with EtOAc/hexane to give the title compound.
  • the vessel was sealed and heated to 60 °C for 60 h.
  • the reaction was incomplete.
  • the system was heated to 100 °C for 2 h and reached completion (HPLC analysis).
  • the reaction was cooled to 23 °C and filtered through a 0.45 micron Teflon® plug filter.
  • the filtrate was purified directly on a C- 18 Gemini column using a Gilson liquid handler (Eluent H 2 0 / C3 ⁇ 4CN gradient with both mobile phase components spiked 0.1% v/v with TFA).
  • the title compound was obtained as a mono-trifluoroacetic acid salt.
  • Assay plates were then incubated in a 37 °C incubator. After 5 days of incubation, 25 ⁇ of 2X concentrated CellTiter-GloTM Reagent (catalog # G7573, Promega Biosciences, Inc., Madison, WI) was added to each well of the assay plate. Cell lysis was carried out by incubating at room temperature for 2-3 minutes, and then chemiluminescence was read using the Envision reader (PerkinElmer).
  • the compounds of the present invention demonstrate antiviral activity in this assay as depicted in Table 1 below. Accordingly, the compounds of the invention may be useful for treating the proliferation of the HIV virus, treating AIDS, or delaying the onset of AIDS or ARC symptoms.

Abstract

Compounds for use in the treatment of human immunodeficiency virus (HIV) infection are disclosed. The compounds have the following Formula (I): including stereoisomers and pharmaceutically acceptable salts thereof, wherein D, V, and R3 are as defined herein. Methods associated with preparation and use of such compounds, as well as pharmaceutical compositions comprising such compounds, are also disclosed.

Description

THERAPEUTIC COMPOUNDS CROSS REFERENCE TO RELATED APPLICATIONS
This application claims priority to and the benefit under 35 U.S.C. 119(e) of U.S. Provisional Patent Application No. 62/001,573, filed May 21, 2014, the disclosure of which is hereby incorporated by reference in its entirety.
BACKGROUND
Field
Compounds, compositions, and methods for the treatment of human
immunodeficiency virus (HIV) infection are disclosed. In particular, novel compounds and methods for their preparation and use as therapeutic or prophylactic agents are disclosed.
Description of the Related Art
Human immunodeficiency virus infection and related diseases are a major public health problem worldwide. Human immunodeficiency virus type 1 (HIV-1) encodes three enzymes which are required for viral replication: reverse transcriptase, protease, and integrase. Although drugs targeting reverse transcriptase and protease are in wide use and have shown effectiveness, particularly when employed in combination, toxicity and development of resistant strains have limited their usefulness (Palella, et al. N. Engl. J Med. (1998) 338:853-860; Richman, D. D. Nature (2001) 410:995-1001). Accordingly, there is a need for new agents that inhibit the replication of HIV. There is also a need for agents that are directed against alternate sites in the viral life cycle including agents that target the interaction of Lens Epithelial Derived Growth Factor (LEDGF/p75) and HIV-1 integrase. SUMMARY
The present disclosure is directed to novel compounds, having antiviral activity, including stereoisomers and pharmaceutically acceptable salts thereof, and the use of such compounds in the treatment of HIV infections.
In one embodiment, compounds having antiviral activity are provided, the compounds having the following Formula (I):
Figure imgf000003_0001
I wherein V, D, and R3 are as defined herein.
In one embodiment, compounds having antiviral activity are provided, the compounds having the following
Figure imgf000003_0002
la wherein V, W, E, R2 and R3 are as defined herein. In one embodiment, a pharmaceutical composition comprising a compound of formula I or formula la, or apharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier is disclosed.
In another embodiment, a pharmaceutical composition comprising a compound of formula I or formula la, or a pharmaceutically acceptable salt thereof, and an additional therapeutic agent is disclosed. The additional therapeutic agent is an HIV protease inhibiting compound, an HIV non-nucleoside inhibitor of reverse
transcriptase, an HIV nucleoside inhibitor of reverse transcriptase, an HIV nucleotide inhibitor of reverse transcriptase, an HIV integrase inhibitor, a gp41 inhibitor, a CXCR4 inhibitor, agpl20 inhibitor, a CCR5 inhibitor, a capsid polymerization inhibitor, or a non-catalytic site HIV integrase inhibitor and combinations thereof.
In a futher embodiment, a pharmaceutical composition of formula I or formula la, for use in treating an HIV infection in a patient in need thereof is disclosed.
In one embodiment, a method for treating a HIV infection in a patient in need thereof comprising administering a therapeutically effective amount of a compound of formula I or formula la, or a pharmaceutically acceptable salt thereof, to the patient, is disclosed.
In anther embodiment, a method for treating an HIV infection in a patient in need thereof comprising administering to the patient a therapeutically effective amount of a compound of any one of formula I or formula la, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of an additional therapeutic agent is disclosed. The additional therapeutic agent is an HIV protease inhibiting compound, an HIV non-nucleoside inhibitor of reverse transcriptase, an HIV nucleoside inhibitor of reverse transcriptase, an HIV nucleotide inhibitor of reverse transcriptase, an HIV integrase inhibitor, a gp41 inhibitor, a CXCR4 inhibitor, a gpl20 inhibitor, a CCR5 inhibitor, a capsid polymerization inhibitor, or a non-catalytic site HIV integrase site inhibitor and combinations thereof.
In a further embodiment, a compound of formula I or formula la, or a pharmaceutically acceptable salt thereof, for use in medical therapy is disclosed.
In one embodiment, a compound of formula I or formula la, or a
pharmaceutically acceptable salt thereof, for the prophylactic or therapeutic treatment of an HIV virus infection is disclosed.
In one embodiment, use of a compound of formula I or formula la, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating an HIV virus infection in a mammal is disclosed.
Other embodiments, objects, features and advantages will be set forth in the detailed description of the embodiments that follows, and in part will be apparent from the description, or may be learned by practice, of the claimed invention. These objects and advantages will be realized and attained by the processes and compositions particularly pointed out in the written description and claims hereof. The foregoing Summary has been made with the understanding that it is to be considered as a brief and general synopsis of some of the embodiments disclosed herein, is provided solely for the benefit and convenience of the reader, and is not intended to limit in any manner the scope, or range of equivalents, to which the appended claims are lawfully entitled.
DETAILED DESCRIPTION
In the following description, certain specific details are set forth in order to provide a thorough understanding of various embodiments disclosed herein. However, one skilled in the art will understand that the embodiments may be practiced without these details. The description below of several embodiments is made with the understanding that the present disclosure is to be considered as an exemplification of the claimed subject matter, and is not intended to limit the appended claims to the specific embodiments illustrated. The headings used throughout this disclosure are provided for convenience only and are not to be construed to limit the claims in any way. Embodiments illustrated under any heading may be combined with embodiments illustrated under any other heading.
Definitions
Unless the context requires otherwise, throughout the present specification and claims, the word "comprise" and variations thereof, such as, "comprises" and
"comprising" are to be construed in an open, inclusive sense, that is as "including, but not limited to".
Reference throughout this specification to "one embodiment" or "an embodiment" means that a particular feature, structure or characteristic described in connection with the embodiment is included in at least one embodiment of the present invention. Thus, the appearances of the phrases "in one embodiment" or "in an embodiment" in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. A dash at the front or end of a chemical group is a matter of convenience; chemical groups may be depicted with or without one or more dashes without losing their ordinary meaning. A wavy line drawn through a line in a structure indicates a point of attachment of a group. Unless chemically or structurally required, no directionality is indicated or implied by the order in which a chemical group is written or the point at which it is attached to the remainder of the molecule. For instance, the group "-SO2CH2-" is equivalent to "-CH2SO2-" and both may be connected in either direction. Similarly, an "arylalkyl" group, for example, may be attached to the remainder of the molecule at either an aryl or an alkyl portion of the group. A prefix such as "Cu-V" or (Cu-Cv) indicates that the following group has from u to v carbon atoms. For example, "Ci_ 6alkyl" indicates that the alkyl group has from 1 to 6 carbon atoms.
Unless stated otherwise, the following terms and phrases as used herein are intended to have the following meanings:
When trade names are used herein, applicants intend to independently include the tradename product and the active pharmaceutical ingredient(s) of the tradename product.
"Alkyl" refers to any group derived from a linear or branched saturated hydrocarbon. Alkyl groups include, but are not limited to, methyl, ethyl, propyls such as propan-l-yl, propan-2-yl (iso-propyl), butyls such as butan-l-yl, butan-2-yl (sec- butyl), 2-methyl-propan-l-yl (iso-butyl), 2-methyl-propan-2-yl (t-butyl), pentyls, hexyls, octyls, decyls, and the like. Unless otherwise specified, an alkyl group has from 1 to about 10 carbon atoms, for example from 1 to 10 carbon atoms, for example from 1 to 6 carbon atoms, for example from 1 to 4 carbon atoms.
"Alkenyl" refers to any group derived from a straight or branched hydrocarbon with at least one carbon-carbon double bond. Alkenyl groups include, but are not limited to, ethenyl (vinyl), propenyl (allyl), 1-butenyl, 1,3-butadienyl, and the like. Unless otherwise specified, an alkenyl group has from 2 to about 10 carbon atoms, for example from 2 to 10 carbon atoms, for example from 2 to 6 carbon atoms, for example from 2 to 4 carbon atoms. "Alkynyl" refers to any group derived from a straight or branched hydrocarbon with at least one carbon-carbon triple bond and includes those groups having one triple bond and one double bond. Examples of alkynyl groups include, but are not limited to, ethynyl (-C≡CH), propargyl (-CH2C≡CH), (£)-pent-3-en-l-ynyl, and the like. Unless otherwise specified, an alkynyl group has from 2 to about 10 carbon atoms, for example from 2 to 10 carbon atoms, for example from 2 to 6 carbon atoms, for example from 2 to 4 carbon atoms.
"Aryl" refers to any group derived from one or more all carbon aromatic rings, that is, a single aromatic ring, a bicyclic or a multicyclic ring system. Aryl groups include, but are not limited to, those groups derived from acenaphthylene, anthracene, azulene, benzene, chrysene, a cyclopentadienyl anion, naphthalene, fluoranthene, fluorene, indane, perylene, phenalene, phenanthrene, pyrene and the like. Unless otherwise specified, an aryl group has from 6 to about 20 carbon atoms, for example from 6 to 20 carbon atoms, for example from 6 to 14 carbon atoms, for example from 6 to 10 carbon atoms.
"Cycloalkyl" refers to a cyclic alkyl group. A cycloalkyl group can have one or more cyclic rings and includes fused and bridged groups. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, and the like.
"Carbocycle" refers to a cyclic, non-aromatic group derived from a linear or branched hydrocarbon, including alkyls, alkenyls, and alkynyls. An alicyclic group can comprise one or more rings, includes fused and bridged groups, and can be saturated or have any degree of unsaturation. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, adamantyl, and the like. Unless otherwise specified, a carcocyclic group has from 1 to about 10 carbon atoms, for example from 1 to 10 carbon atoms, for example from 1 to 6 carbon atoms or for example from 1 to 4 carbon atoms or for example from 1 to 3 carbon atoms.
"Halo" and "halogen" refer to fluoro, chloro, bromo and iodo.
"Haloalkyl" refers to an alkyl wherein one or more hydrogen atoms are each replaced by a halogen. Examples include, but are not limited to, -CH2C1, -CH2F, - CH2Br, -CFClBr, -CH2CH2C1, -CH2CH2F, -CF3, -CH2CF3, -CH2CC13, and the like, as well as alkyl groups such as perfluoroalkyl in which all hydrogen atoms are replaced by fluorine atoms.
"Heteroalkyl" refers to an alkyl in which one or more of the carbon atoms are each independently replaced with a heteroatom selected from the group consisting of O, N, S, and Si. A heteroatom may optionally be oxidized or alkylated. A heteroatom may be placed at any interior position of the heteroalkyl group or at a position at which the group is attached to the remainder of the molecule. Examples include, but are not limited to, -CH2OCH3, -CH2CH2NHCH3, -CH2CH2N(CH3) -CH3, -CH2SCH2CH3, - S(0)CH3, -CH2CH2S(0)2CH3, -CHCHOCH3, -Si(CH3)3, -CH2CHNOCH3, - CHCHN(CH3)CH3, -CH2NHOCH3 and -CH2OS(CH3)3.
"Heteroaryl" refers to an aryl group in which one or more of the carbon atoms (and any associated hydrogen atoms) are each independently replaced with the same or different heteroatom selected from the group consisting of O, N, S, and Si. A heteroatom may be placed at any interior position of the heteroaryl group or at a position at which the group is attached to the remainder of the molecule. Heteroaryl groups include, but are not limited to, groups derived from acridine, benzoimidazole, benzothiophene, benzofuran, benzoxazole, benzothiazole, carbazole, carboline, cinnoline, furan, imidazole, imidazopyridine, indazole, indole, indoline, indolizine, isobenzofuran, isochromene, isoindole, isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, perimidine, phenanthridine, phenanthroline, phenazine, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolizine, quinazoline, quinoline, quinolizine, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene, triazole, xanthene, and the like. Unless otherwise specified, an heteroaryl group has from 3 to about 20 carbon atoms and from 1 to about 3 heteroatoms, for example from 5 to 20 carbon atoms and from 1 to 3 heteroatoms, for example from 5 to 14 carbon atoms and from 1 to 3 heteroatoms, for example from 5 to 10 carbon atoms and from 1 to 3 heteroatoms.
"Heterocycle," "heterocyclic," and "heterocyclyl" refer to a single saturated or partially unsaturated non-aromatic ring or a non-aromatic multiple-ring system with at least one heteroatom, as defined above. Heterocycles include, but are not limited to, groups derived from azetidine, aziridine, imidazolidine, morpholine, oxirane (epoxide), oxetane, piperazine, piperidine, pyrazolidine, piperidine, pyrrolidine, pyrrolidinone, tetrahydrofuran, tetrahydrothiophene, dihydropyridine, tetrahydropyridine,
quinuclidine, N-bromopyrrolidine, N-chloropiperidine, and the like.
The term "pharmaceutically acceptable" with respect to a substance refers to that substance which is generally regarded as safe and suitable for use without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio.
"Pharmaceutically acceptable salt" refers to a salt of a compound that is pharmaceutically acceptable and that possesses (or can be converted to a form that possesses) the desired pharmacological activity of the parent compound. Such salts include acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, benzenesulfonic acid, benzoic acid,
camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, lactic acid, maleic acid, malonic acid, mandelic acid, methanesulfonic acid, 2-napththalenesulfonic acid, oleic acid, palmitic acid, propionic acid, stearic acid, succinic acid, tartaric acid, p-toluenesulfonic acid, trimethylacetic acid, and the like, and salts formed when an acidic proton present in the parent compound is replaced by either a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as diethanolamine, triethanolamine, N- methylglucamine and the like. Also included in this definition are ammonium and substituted or quaternized ammonium salts. Representative non-limiting lists of pharmaceutically acceptable salts can be found in S.M. Berge et al., J. Pharma Sci., 66(1), 1-19 (1977), and Remington: The Science and Practice of Pharmacy, R.
Hendrickson, ed., 21st edition, Lippincott, Williams & Wilkins, Philadelphia, PA, (2005), at p. 732, Table 38-5, both of which are hereby incorporated by reference herein.
"Treating" and "treatment" of a disease include the following:
(1) preventing or reducing the risk of developing the disease, i.e., causing the clinical symptoms of the disease not to develop in a subject that may be exposed to or predisposed to the disease but does not yet experience or display symptoms of the disease, (2) inhibiting the disease, i.e., arresting or reducing the development of the disease or its clinical symptoms, or
(3) relieving the disease, i.e., causing regression of the disease or its clinical symptom,s ameliorating the disease state, delaying the progression of the disease, increasing the quality of life, and/or prolonging survival.
The following abbreviations may also be used: AcOH: acetic acid; nBuLi: n- butyllithium; CC: column chromatography; CS2CO3: cesium carbonate; CH2CI2 or DCM: dichloromethane; CHsMgl: methyl magnesium iodide; CuCl2: copper chloride; DAST: (diethylamino) sulfur trifluoride; DEAD: diethyl azodicarboxylate; DIBAL: diisobutylaluminum hydride; DIPEA: diisopropylethylamine; DMF:
dimethylformamide; DMSO: dimethyl sulfoxide; Et3N: triethylamine; EtOAc: ethyl acetate; EtOH: ethanol; g: gram(s); h: hour; H2: hydrogen; HBr: hydrogen bromide; HC1: hydrogen chloride; H20: water; H202: hydrogen peroxide; HPLC: high performance liquid chromatography; KCN: potassium cyanide; LHMDS: lithium hexamethyldisilazide; LiAlH4: lithium aluminum hydride; LiOH: lithium hydroxide; M: molar; MeCN: acetonitrile; Mel: methyl iodide; MeOH: methanol; MgS04:
magnesium sulfate; MgCC : magnesium carbonate; mg: millilgram; MsCl: mesyl chloride; mmol: millimoles mL: milliliter; sodium hydrogen sulfite; mCPBA: meta- chloroperoxybenzoic acid; N: normality; N2: nitrogen; Na2CC>3: sodium carbonate; NaHCC : sodium bicarbonate; NaN02: sodium nitrite; NaOH: sodium hydroxide; Na2S2C>3: sodium bisulfate; Na2S04: sodium sulfate; NBS: N-bromosuccinimide; NH4CI: ammonium chloride; NH4OAc: ammonium acetate; NMR: nuclear magnetic resonance; Pd/C: palladium on carbon; ΡΡ1¾: triphenyl phosphine; iPrOH: isopropyl alcohol; RT: room temperature; SOCl2: thionyl chloride; THF: tetrahydrofuran; TLC: thin layer chromatography; μΕ: microliter.
"Antiviral agent" refers to any agent that inhibits the formation or replication of a virus in a mammal, including but not limited to agents that interfere with either host or viral mechanisms necessary for the formation or replication of a virus in a mammal.
"Effective amount" refers to an amount that may be effective to elicit the desired biological or medical response, including the amount of a compound that, when administered to a subject for treating a disease, is sufficient to effect such treatment for the disease. The effective amount will vary depending on the compound, the disease and its severity and the age, weight, etc., of the subject to be treated. The effective amount can include a range of amounts.
Isotopes
The invention disclosed herein is also meant to encompass all pharmaceutically acceptable compounds of Formula (I) being isotopically-labeled by having one or more atoms replaced by an atom having a different atomic mass or mass number. Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, and iodine, such as 2H, 3H, nC, 13C, 14C, 13N, 15N, 150, 170, 180, 31P, 32P, 35S, 18F, 36C1, 123I, and 125I, respectively. These radiolabeled compounds could be useful to help determine or measure the effectiveness of the compounds, by characterizing, for example, the site or mode of action, or binding affinity to pharmacologically important site of action.
Certain isotopically-labeled compounds of Formula (I), for example, those
incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies. The radioactive isotopes tritium, i.e. 3H, and carbon-14, i.e. 14C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.
Substitution with heavier isotopes such as deuterium, i.e. 2H, may afford certain therapeutic advantages resulting from greater metabolic stability. For example, in vivo half-life may increase or dosage requirements may be reduced. Thus, heavier isotopes may be preferred in some circumstances.
Substitution with positron emitting isotopes, such as nC, 18F, 150 and 13N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy. Isotopically-labeled compounds of Formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the Examples as set out below using an appropriate isotopically-labeled reagent in place of the non-labeled reagent previously employed.
The invention disclosed herein is also meant to encompass the in vivo metabolic products of the disclosed compounds. Such products may result from, for example, the oxidation, reduction, hydrolysis, amidation, esterification, and the like of the administered compound, primarily due to enzymatic processes. Accordingly, the invention includes compounds produced by a process comprising administering a compound of this invention to a mammal for a period of time sufficient to yield a metabolic product thereof. Such products are typically identified by administering a radiolabeled compound of the invention in a detectable dose to an animal, such as rat, mouse, guinea pig, monkey, or to human, allowing sufficient time for metabolism to occur, and isolating its conversion products from the urine, blood or other biological samples.
"Racemates" refers to a mixture of enantiomers. The mixture can comprise equal or unequal amounts of each enantiomer.
"Stereoisomer" and "stereoisomers" refer to compounds that differ in the chirality of one or more stereocenters. Stereoisomers include enantiomers and diastereomers. The compounds may exist in stereoisomeric form if they possess one or more asymmetric centers or a double bond with asymmetric substitution and, therefore, can be produced as individual stereoisomers or as mixtures. Unless otherwise indicated, the description is intended to include individual stereoisomers as well as mixtures. The methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art (see, e.g., Chapter 4 of Advanced Organic Chemistry, 4th ed., J. March, John Wiley and Sons, New York, 1992).
In certain embodiments, the compounds disclosed herein display
atropisomerism resulting from steric hindrance affecting the axial rotation rate around a single bond. In certain circumstances, the resultant conformational isomers are observed as distinct entities by characterization techniques such as NMR and HPLC. In certain embodiments, the compounds disclosed herein exist as a mixture of atropisomers. The synthetic examples provided herein note where such mixtures of atropisomers have been observed. However, the detection of atropisomers is dependent on factors such as temperature, solvent, conditions of purification, and timescale of spectroscopic technique. Characterization data presented herein may not represent the equilibrium state depending on the conditions of purification, isolation, handling, solvents used, and temperature.
"Tautomer" refers to alternate forms of a compound that differ in the position of a proton, such as enol-keto and imine-enamine tautomers, or the tautomeric forms of heteroaryl groups containing a ring atom attached to both a ring -NH- and a ring =N- such as pyrazoles, imidazoles, benzimidazoles, triazoles, and tetrazoles.
Protecting Groups
"Protecting group" refers to a moiety of a compound that masks or alters the properties of a functional group or the properties of the compound as a whole. Chemical protecting groups and strategies for protection/deprotection are well known in the art. See e.g., Protective Groups in Organic Chemistry, Theodora W. Greene, John Wiley & Sons, Inc., New York, 1991. Protecting groups are often utilized to mask the reactivity of certain functional groups, to assist in the efficiency of desired chemical reactions, e.g., making and breaking chemical bonds in an ordered and planned fashion.
Protection of functional groups of a compound alters other physical properties besides the reactivity of the protected functional group, such as the polarity, lipophilicity (hydrophobicity), and other properties which can be measured by common analytical tools. Chemically protected intermediates may themselves be biologically active or inactive.
The compounds described herein, or their pharmaceutically acceptable salts may contain one or more asymm Protecting Groups etric centers and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)-. This disclosure includes all such possible isomers, as well as their racemic and optically pure forms. Optically active (+) and (-), or (R)- and (S)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, for example, chromatography and fractional crystallization. Conventional techniques for the preparation/isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC). When the compounds described herein contain olefinic double bonds or other centres of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers. Likewise, all tautomeric forms are also intended to be included. Compounds
As noted above, in one embodiment, compounds having antiviral activity are provided, the compounds having the following Formula (I):
Figure imgf000014_0001
I wherein:
V is N or CH;
R3 is (Ci-C6)alkyl, (C2-C6)alkenyl, (C3-C6)cycloalkyl, (Ci-C6)-alkyl-(C3-C6)cycloalkyl or -0(Ci-C6)alkyl, -0-(C3-C6)cycloalkyl wherein any (C C6)alkyl, (C2-C6)alkenyl, (C3-C6)cycloalkyl, (Ci-C6)-alkyl-(C3-C6)cycloalkyl or -0(C C6)alkyl, -0-(C3-
C6)cycloalkyl of R3 is optionally substituted with one to three groups selected from the group consisting of -0(Ci-C6)alkyl, halo, oxo and -CN;
D is (C6-C12) aryl, (C5-Cio)carbocycle, 5-10-membered heterocycle, or 5-10-membered heteroaryl, wherein any (C6-Ci2) aryl, (C5-Cio)carbocycle, 5-10-membered heterocycle, or 5-10- membered heteroaryl of D is substituted by R2; wherein any (C6-Ci2) aryl, (C5-Cio)carbocycle, 5-10-membered heterocycle, or 5-10- membered heteroaryl of D is optionally substituted by R5, R6, R7, R8 and R12;
R2 is H, oxo, halo ,(C C6)alkyl or -0(C C6)alkyl; R5, R6, R7, R8 and R12 are each independently: a) R11, -C(=0)-Rn, -C(=0)-0-Rn, -O-R11, -S-R11, -S(0)-Rn, -S02-Rn, -(Ci-C6)alkyl-Rn,
Figure imgf000014_0002
-(Ci-C6)alkyl-0-Rn, -(Ci-C6)alkyl-S-Rn, -(Ci-C6)alkyl-S(0)-Rn or
-(C C6)alkyl-S02-Rn, wherein each R11 is independently H, (Ci-C6)alkyl, (C2-C6)alkenyl, (C2-
C6)alkynyl, (C C6)haloalkyl, (C3-C7)carbocycle, (C6-Ci2)aryl, 5-12- membered heterocycle or 5-12-membered heteroaryl, wherein any (C6- Ci2)aryl, 5-12-membered heterocycle and 5-12-membered heteroaryl of R11 are each optionally substituted with one to three Z1 groups; or b) -N(R9)R10, -C(=0)-N(R9)R10, -0-C(=0)-N(R9)R10, -S02-N(R9)R10, -(C C6)alkyl-N(R9)R10,
Figure imgf000015_0001
N(R9)R10, or -(C C6)alkyl-S02-N(R9)R10, wherein each R9 is independently H, (Ci-C6)alkyl or (C3-C7)cycloalkyl; and wherein each R10 is independently H, (Ci-C6)alkyl, (C2-C6)alkenyl, (C2-
C6)alkynyl, (C C6)haloalkyl, (C3-C7)carbocycle, (C6-Ci2)aryl, 5-12- membered heterocycle or 5-12-membered heteroaryl, wherein any (C6- Ci2)aryl, 5-12-membered heterocycle and 5-12-membered heteroaryl of R10 are each optionally substituted with one to three Z1 groups; or c) -(Ci-C6)alkyl-0-(Ci-C6)alkyl-(C3-C7)carbocycle,
-(Ci-C6)alkyl-S-(Ci-C6)alkyl-(C3-C7)carbocycle,
-(CrC6)alkylS(0)-(CrC6)alkyl-(C3-C6)carbocycle,
-(Ci-C6)alkylS02(Ci-C6)alkyl-(C3-C7)carbocycle,
-(C2-C6)alkenyl-(Ci-C6)haloalkyl, -(C2-C6)alkynyl-(Ci-C6)haloalkyl, -(C3- C7)halocarbocycle, -NRaS02NRcRd, -NRaS020(C3-C7)carbocycle,
-NRaS020(C6-Ci2)aryl, -(C2-C6)alkenyl-(C3-C7)carbocycle, -(C2-C6)alkenyl- (C6-Ci2)aryl, -(C2-C6)alkenyl-heteroaryl, -(C2-C6)alkenyl-heterocycle,
-(C2-C6)alkynyl-(C3-C7)carbocycle, -(C2-C6)alkynyl-(C6-Ci2)aryl,
-(C2-C6)alkynyl-heteroaryl, -(C2-C6)alkynyl-heterocycle, -(C3-C7)carbocycle-Z1 or -(Ci-C6)haloalkyl-Z3, wherein any (Ci-C6)alkyl, (Ci-C6)haloalkyl, (C3-C7)carbocycle, (C2-C6)alkenyl, (C2-C6)alkynyl, (C6-Ci2)aryl or heteroaryl, either alone or as a group is optionally substituted with one to three Z1 groups; and wherein any heteroaryl or heterocycle is a 5-12 membered heteroaryl or a 5-12 membered heterocycle; or d) -NReRf, -C(0)NReRf, -OC(0)NReRf, -S02NReRf, -(Ci-C6)alkyl-NReRf, -(Ci-C6)alkylC(0)-NReRf, -(Ci-C6)alkyl-0-C(0)-NReRf or -(C C6)alkyl- S02NReRf; wherein each (Ci-C6)alkyl is independently substituted with one to three Z6 groups and optionally substituted with one to three Z1 groups; or e) oxo; and each Z1 is independently halo, -N02, -OH, =NORa, -SH, -CN, (C C6)alkyl, (C2 C6)alkenyl, (C2-C6)alkynyl, (C C6)haloalkyl, (C3-C7)carbocycle, (C3- C7)halocarbocycle, (C6-Ci2)aryl, heteroaryl, heterocycle, -0(Ci-C6)alkyl, -0(C2 C6)alkenyl, -0(C2-C6)alkynyl, -0(C C6)haloalkyl, -0(C3-C7)carbocycle, - 0(C3-C7)halocarbocycle, -0-(C6-Ci2)aryl, -Oheteroaryl, -Oheterocycle, -S(Cr C6)alkyl, -S(C2-C6)alkenyl, -S(C2-C6)alkynyl, -S(C C6)haloalkyl, -S(C3- C7)carbocycle, -S(C3-C7)halocarbocycle, -S-(C6-Ci2)aryl, -Sheteroaryl, - Sheterocycle, -S(0)(C C6)alkyl, -S(0)(C2-C6)alkenyl, -S(0)(C2-C6)alkynyl, -S(0)(Ci-C6)haloalkyl, -S(O) (C3-C7)carbocycle, -S(0)(C3-C7)halocarbocycle, -S02(Ci-C6)alkyl, -S(O)- (C6-Ci2)aryl, -S(0)carbocycle, -S(0)heteroaryl, - S(0)heterocycle, -S02(C2-C6)alkenyl, -S02(C2-C6)alkynyl, -S02(C
C6)haloalkyl, -S02(C3-C7)carbocycle, -S02(C3-C7)halocarbocycle, -S02-(C6- Ci2)aryl, -S02heteroaryl, -S02heterocycle, -S02NRcRd, -NRcRd, -NRaC(0)Ra, - NRaC(0)ORb, -NRaC(0)NRcRd -NRaS02Rb, -NRaS02NRcRd, -NRaS020(C3- C7)carbocycle, -NRaS020-(C6-Ci2)aryl, -OS(0)2Ra, -C(0)Ra, -C(0)ORb, -C(0)NRcRd, or -OC(0)NRcRd, wherein any (Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, -(C3-
C7)halocarbocycle, (C3-C7)carbocycle, (C3-C7)halocarbocycle, (C6- Ci2)aryl, heteroaryl or heterocycle of Z1, either alone or as part of a group, is optionally substituted with one to three halogen, -OH, -ORb, -CN, -RH2, -NRcRd -NRaC(0)2Rb, -heteroaryl, -heterocycle,
-Oheteroaryl, -Oheterocycle, -NHheteroaryl, -NHheterocycle or -S(0)2NRcRd; and wherein any heteroaryl or heterocycle of Z1 is a 5-12 membered heteroaryl or a 5-12 membered heterocycle; and each Z3 is independently -N02, -CN, -OH, oxo, =NORa, thioxo, (C6-C12)aryl, 5- 12 membered heterocycle, 5-12 membered heteroaryl, (C3-C7)halocarbocycle, -0(C C6)alkyl, -0(C3-C7)carbocycle, -0(C3-C7)halocarbocycle, -0-(C6- Ci2)aryl, -Oheterocycle, -Oheteroaryl, -S(Ci-C6)alkyl, -S(C3-C7)carbocycle, -S(C3-C7)halocarbocycle, -S-(C6-Ci2)aryl, -Sheterocycle, -Sheteroaryl, -S(0)(C C6)alkyl, -S(0)(C3-C7)carbocycle, -S(O) (C3-C7)halocarbocycle, -S(O)- (C6-Ci2)aryl, -S(0)heterocycle, -S(0)heteroaryl, -S02(C C6)alkyl, -S02(C3-C7)carbocycle, -S02(C3-C7)halocarbocycle, S02-(C6-Ci2)aryl, -S02heterocycle, -S02heteroaryl, -NRaRb, -NRaC(0)Rb, -C(0)NRcRd, - S02NRcRd, -NRaS02NRcRd, -NRaS020(C3-C7)carbocycle or -NRaS020-(C6- Ci2)aryl, wherein any heteroaryl or heterocycle of Z3 is a 5-12 membered heteroaryl or a 5-12 membered heterocycle; and each Ra, Rb, Rc and Rd is independently H or (Ci-C6)alkyl, (C2-C6)alkenyl, (C2- C6)alkynyl, (C3-C7)carbocycle, heterocycle, (C6-Ci2)aryl, (C6-Ci2) aryl(d- C6)alkyl-, heteroaryl or heteroaryl(Ci-C6)alkyl-, wherein any (Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C7)carbocycle, heterocycle, (C6-Ci2)aryl, or heteroaryl of Ra, Rb, Rc and Rd, either alone or as part of a group, is optionally substituted with one to three halogen, OH or cyano; or Rc and Rd together with the nitrogen to which they are attached form a 5-12 membered heterocycle, wherein any heterocycle of Rc and Rd together with the nitrogen to which they are attached is optionally substituted with one to three halogen, OH, cyano, or -RH2; wherein any heteroaryl or heterocycle of Ra, R , Rc and R<j is a 5-12 membered heteroaryl or a 5-12 membered heterocycle; and each Re is independently H, -ORa, (Ci-C6)alkyl or (C3-C7)carbocycle,
(C2-C6)haloalkyl, (C2-C6)alkenyl and (C2-C6)alkynyl, (C6-Ci2)aryl, 5-12 membered heterocycle or 5-12 membered heteroaryl; wherein (Ci-C6)alkyl and (C3-C7)carbocycle of Re are each independently
substituted with one to three Z6 groups and optionally substituted with one o three Z1 groups; wherein any (C2-C6)haloalkyl, (C2-C6)alkenyl or (C2-C6)alkynyl of Re is
optionally substituted with one to three Zi groups; wherein any (C6-Ci2)aryl, 5-12 membered heterocycle or 5-12 membered
heteroaryl of Re are each independently substituted with one to three Z5 groups; and each Rf is independently H, -Rg, -ORa, -(C C6)alkyl-Z6, -S02Rg, -C(0)Rg, C(0)ORg or -C(0)NReRg; and each Rg is independently H, (C]-C6)alkyl, (C3-C7)carbocycle (Ci-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C6-Ci2)aryl, 5-12 membered heterocycle or 5- 12 membered heteroaryl, wherein any (Ci-C6)alkyl, (C3-C7)carbocycle -(Ci-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C6-Ci2)aryl, 5-12 membered heterocycle or 5-12 membered heteroaryl of Rg is optionally substituted with one to three Zi groups; and each Z5 is independently -N02, -CN, -NRaS02NRcRd, -NRaS020(C3- C7)carbocycle, -NRaS020-(C6-Ci2)aryl, -NRaS02(C C6)alkyl, -NRaS02(C2- C6)alkenyl, -NRaS02(C2-C6)alkynyl, -NRaS02(C3-C7)carbocycle, -NRaS02(C3- C7)halocarbocycle, -NRaS02-(C6-Ci2)aryl, -NRaS02heteraryl, - NRaS02heteroaryl, -NRaS02heterocycle, -NRaC(0)alkyl, -NRaC(0)alkenyl, -NRaC(0)alkynyl, -NRaC(0) (C3-C7)carbocycle, -NRaC(0)(C3- C7)halocarbocycle, -NRaC(0)- (C6-Ci2)aryl, -NRaC(0)heteroaryl,
-NRaC(0)heterocycle, -NRaC(0)NRcRd or -NRaC(0)ORb, wherein any heteroaryl or heterocycle of Z5 is a 5-12 membered heteroaryl or a 5-12 membered heterocycle; and each Z6 is independently -N02, -CN, -NRaRa, NRaC(0)Rb,-C(0)NRcRd, (C3- C7)halocarbocycle, (C6-Ci2)aryl, heteroaryl, heterocycle, -0-(C6-Ci2)aryl, -Oheteroaryl, -Oheterocycle, -0(C3-C7)halocarbocycle, -0(Ci-C6)alkyl, -0(C3- C7)carbocycle, -0(Ci-C6)haloalkyl, -S-(C6-Ci2)aryl, -Sheteroaryl, - Sheterocycle, -S(C3-C7)halocarbocycle, -S(Ci-C6)alkyl, -S(C3-C7)carbocycle, -S(C C6)haloalkyl, -S(O)- (C6-C12)aryl, -S(0)heteroaryl, -S(0)heterocycle, - S(0)(C3-C7)halocarbocycle, -S(0)(C C6)alkyl, -S(0)(C3-C7)carbocycle, - S(0)(Ci-C6)haloalkyl, -S02-(C6-Ci2)aryl, -S02heteroaryl, -S02heterocycle, - S02(C C6)alkyl, -S02(C C6)haloalkyl, -S02(C3-C7)carbocycle, -S02(C3- C7)halocarbocycle, -S02NRcRd, -NRaS02(C3-C7)halocarbocycle, -NRaS02(C6- Ci2)aryl, -NRaS02heteraryl, -NRaS02heteroaryl, -NRaS02NRcRd,
-NRaS020(C3-C7)carbocycle or -NRaS020-(C6-Ci2)aryl, wherein any aryl of Z6, either alone or as part of a group, is optionally
substituted with one to three halogen, -OH, -0(C]-C6)alkyl, -CN, NH2, or -(C]-C6)alkyl, and wherein any heteroaryl or heterocycle of Z6 is a 5-12 membered heteroaryl or a 5-12 membered heterocycle.
In certain embodiments, D is monocyclic, bicyclic or tricyclic (C6-Ci2) aryl ; monocyclic, bicyclic or tricyclic (C5-Cio)carbocycle; 5-10-membered monocyclic, bicyclic or tricyclic heterocycle; or 5-10-membered monocyclic, bicyclic or tricyclic heteroaryl.
In certain embodiments, D is monocyclic, bicyclic or tricyclic (C6-Ci2) aryl. In certain embodiments, D is monocyclic, bicyclic or tricyclic (C6-C10) aryl. In certain embodiments, D is monocyclic or bicyclic (C6-C10) aryl. In certain embodiments, D is monocyclic (C6-C10) aryl. In certain embodiments, D is bicyclic (C6-C10) aryl. In certain embodiments, D is monocyclic, bicyclic or tricyclic (C6-C12) carbocycle. In certain embodiments, D is monocyclic, bicyclic or tricyclic (C5- Cio)carbocycle. In certain embodiments, D is monocyclic or bicyclic (C5- Cio)carbocycle. In certain embodiments, D is monocyclic (C5-Cio)carbocycle. In certain embodiments, D is bicyclic (C5-Cio)carbocycle.
In certain embodiments, D is 5-10-membered monocyclic, bicyclic or tricyclic heterocycle. In certain embodiments, D is 5-10-membered monocyclic or bicyclic heterocycle. In certain embodiments, D is 5-10-membered monocyclic heterocycle. In certain embodiments, D is 5-10-membered bicyclic heterocycle.
In certain embodiments, D is 5-10-membered monocyclic, bicyclic or tricyclic heteroaryl. In certain embodiments, D is 5-10-membered monocyclic or bicyclic heteroaryl. In certain embodiments, D is 5-10-membered monocyclic heteroaryl. In certain embodiments, D is 5-10-membered bicyclic heteroaryl.
In other embodiments, D is phenyl, pyridyl, pyrimidinyl, naphthyl, quinolinyl, benzthiazolyl, indazolyl, thienopyridinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, pyranothienopyridinyl, pyrimidoindazolyl, cyclopentaquinolinyl, 6,7,8,9- tetrahydrobenzoquinolinyl, 7,8,9, 10-tetrahydrobenzoquinolinyl,
pyrroloimidazopyridinyl, 6,7,8,9-tetrahydroimidazodipyridinyl, or
benzothieno[3,2:b]pyridinyl.
In further embodiments, D is phenyl, pyridyl, pyrimidinyl, naphthyl, quinolinyl, or benzthiazolyl.
In still more embodiments, naphthyl or quinolinyl.
In certain embodiments, R3 is -0(Ci-C6)alkyl optionally substituted with one to three groups selected from the group consisting of halo and -CN.
In other embodiments, R3 is -OC(CH3)3.
In certain embodiments, D is substituted with R2 and R5, R6, R7, R8 and R12 are hydrogen.
In certain embodiments, R2 is halo, H or -CH3.
In certain embodiments, R2 is -CH3.
In certain embodiments, R5, R6, R7, R8 and R12 are each independently:
a) R11, -C(=0)-Rn, -C(=0)-0-Rn or -O-R11, wherein each R11 is independently H, (C C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C C6)haloalkyl, (C3-C7)carbocycle, (C6-Ci2)aryl, 5-10-membered heterocycle or 5-10-membered heteroaryl, wherein (C6-Ci2)aryl, 5-10- membered heterocycle and 5-10-membered heteroaryl are each optionally substituted with one to three Z11 groups;
b) -N(R9)R10 and -C(=0)-N(R9)R10, wherein each R9 is
independently H, (Ci-C6)alkyl or (C3-C7)cycloalkyl, and each R10 is independently R11, -(Ci-C6)alkyl-Rn, -S02-Rn, -C(=0)-Rn, - C(=0)ORn or -C(=0)N(R9)Rn, wherein each R11 is independently H, (Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C C6)haloalkyl, (C3- C7)cycloalkyl, (C6-Ci2)aryl, 5-10-membered heterocycle or 5-10- membered heteroaryl;
c) -(C2-C6)alkynyl-(C3-C7)carbocycle, wherein
-(C2-C6)alkynyl-(C3-C7)carbocycle is optionally substituted with one to three Z1 groups; or
d) -NReRf and-C(0)NReRf.
in embodiments R5, R6, R7, R8 and R12 are each independently:
a) H, (C C6)alkyl, (C C6)haloalkyl, (C3-C7)carbocycle, heterocycle, -C(=0)-Rn, -C(=0)-0-Rn or -O-R11, wherein heterocycle is optionally substituted with one to three Z11 groups and wherein each R11 is independently H, (C C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (Ci-C6)haloalkyl, (C3-C7)carbocycle, (C6-Ci2)aryl, heterocycle or heteroaryl, wherein (C6-Ci2)aryl, 5-10-membered heterocycle and 5-10- membered heteroaryl are each optionally substituted with one to three Z groups;
b) -N(R9)R10 or -C(=0)-N(R9)R10, wherein each R9 is independently H, (Ci-C6)alkyl or (C3-C7)cycloalkyl, and each R10 is independently R11, -(Ci-C6)alkyl-Rn, -S02-Rn, -C(=0)-Rn, -C(=0)ORn or - C(=0)N(R9)Rn ; wherein each R11 is independently H, (C C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C C6)haloalkyl, (C3-C7)cycloalkyl, (C6-Ci2)aryl, 5-10-membered heterocycle or 5-10-membered heteroaryl; c) -(C2-C6)alkynyl-(C3-C7)carbocycle; wherein
-(C2-C6)alkynyl-(C3-C7)carbocycle is optionally substituted with one to three Z1 groups; or
d) -NReRf or-C(0)NReRf.
In certain embodiments R5, R6, R7, R8 and R12 are each independently H, (d-
C6)alkyl, (C C6)haloalkyl, (C3-C7)carbocycle, heterocycle, -C(=0)-Rn, -C(=0)-0-Rn or -O-R11, wherein heterocycle is optionally substituted with one to three Z11 groups and wherein each R11 is independently H, (Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (Ci-C6)haloalkyl, (C3-C7)carbocycle, (C6-Ci2)aryl, heterocycle or heteroaryl, wherein (C6-Ci2)aryl, 5-10-membered heterocycle and 5-10-membered heteroaryl are each optionally substituted with one to three Z11 groups.
In certain embodiments R5, R6, R7, R8 and R12 are each independently H, (Cr C6)alkyl, (Ci-C6)haloalkyl, (C3-C7)carbocycle, 5-10-membered heterocycle, wherein 5- 10-membered heterocycle is optionally substituted with one to three Z11 groups.
In certain embodiments R5, R6, R7, R8 and R12 are each independently H, (Cr
C6)alkyl, or (C C6)haloalkyl.
In certain embodiments R5, R6, R7, R8 and R12 are each independently H or (Cr C6)alkyl.
In certain embodiments R5, R6, R7, R8 and R12 are each independently - N(R9)R10 or -C(=0)-N(R9)R10, wherein each R9 is independently H, (C C6)alkyl or (C3-C7)cycloalkyl, and each R10 is independently R11, -(Ci-C6)alkyl-Rn, -S02-Rn, - C(=0)-Rn, -C(=0)ORn or -C(=0)N(R9)Rn; wherein each R11 is independently H, (C C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C C6)haloalkyl, (C3-C7)cycloalkyl, (C6- Ci2)aryl, 5-10-membered heterocycle or 5-10-membered heteroaryl.
In certain embodiments R5, R6, R7, R8 and R12 are each independently
-(C2-C6)alkynyl-(C3-C7)carbocycle; wherein -(C2-C6)alkynyl-(C3-C7)carbocycle is optionally substituted with one to three Z1 groups.
In certain embodiments R5, R6, R7, R8 and R12 are each independently -NReRf or-C(0)NReRf.
In certain embodiments, R5, R6, R7, R8 and R12 are each independently hydrogen. In certain embodiments, Z is independently halo, -N02, -OH, =NOR.
-CN, (Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C C6)haloalkyl, (C3- C7)carbocycle, (C3-C7)halocarbocycle, (C6-Ci2)aryl, heteroaryl, heterocycle, -0(Cr C6)alkyl, -0(C2-C6)alkenyl, -0(C2-C6)alkynyl, -0(C C6)haloalkyl, -0(C3- C7)carbocycle, -0(C3-C7)halocarbocycle, -0-(C6-Ci2)aryl, -Oheteroaryl, -
Oheterocycle, -S(C C6)alkyl, -S(C2-C6)alkenyl, -S(C2-C6)alkynyl, -S(C C6)haloalkyl, -S(C3-C7)carbocycle, -S(C3-C7)halocarbocycle, -S-(C6-Ci2)aryl, -Sheteroaryl, - Sheterocycle, -S(0)(C C6)alkyl, -S(0)(C2-C6)alkenyl, -S(0)(C2-C6)alkynyl, -S(0)(C C6)haloalkyl, -S(O) (C3-C7)carbocycle, -S(0)(C3-C7)halocarbocycle, -S02(C C6)alkyl, -S(O)- (C6-Ci2)aryl, -S(0)carbocycle, -S(0)heteroaryl, -S(0)heterocycle, -S02(C2- C6)alkenyl, -S02(C2-C6)alkynyl, -S02(C C6)haloalkyl, -S02(C3-C7)carbocycle, - S02(C3-C7)halocarbocycle, -S02-(C6-Ci2)aryl, -S02heteroaryl, -S02heterocycle, - S02NRcRd, -NRcRd, -NRaC(0)Ra, -NRaC(0)ORb, -NRaC(0)NRcRd -NRaS02Rb, -NRaS02NRcRd, -NRaS020(C3-C7)carbocycle, -NRaS020-(C6-Ci2)aryl, -OS(0)2Ra, -C(0)Ra, -C(0)ORb, -C(0)NRcRd, or -OC(0)NRcRd,
wherein any (Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, -(C3- C7)halocarbocycle, (C3-C7)carbocycle, (C3-C7)halocarbocycle, (C6-Ci2)aryl, heteroaryl or heterocycle of Z1, either alone or as part of a group, is optionally substituted with one to three halogen, -OH, -ORb, -CN, -NRaC(0)2Rb, - heteroaryl, -heterocycle, -Oheteroaryl, -Oheterocycle, -NHheteroaryl, - NHheterocycle or -S(0)2NRcRd; and
wherein any heteroaryl or heterocycle of Z is a 5-12 membered heteroaryl or a
5-12 membered heterocycle; and
In certain embodiments, each Z1 is independently :
i) -C(=0)-NH2, -C(=0)-NH(Ci-C4)alkyl, -C(=0)-N((C C4)alkyl)2, -C(=0)- (C6-Ci2)aryl, -C(=0)-heterocycle or -C(=0)-heteroaryl; ii) halo, oxo, thioxo, (C2-C6)alkenyl, (Ci-C6)haloalkyl, (C3-
C7)cycloalkyl, (C3-C7)cycloalkyl-(Ci-C6)alkyl-, -OH, -0(C C6)alkyl, -0(C C6)haloalkyl, -SH, -S(C C6)alkyl, -SO(C C6)alkyl, -S02(C C6)alkyl, -NH2, -NH(C C6)alkyl or
-N((CrC6)alkyl)2; or iii) (Ci-C6)alkyl optionally substituted with -OH, -0-(Cr
C6)haloalkyl, or -0-(C C6)alkyl; or
iii) (C6-Ci2)aryl, heterocycle or heteroaryl, which (C6-Ci2)aryl, heterocycle and 5- heteroaryl is optionally substituted with halo, (Ci-C6)alkyl or COOH,
wherein any heterocycle or heteroaryl of Z1 is a 5-12 membered heterocycle or 5-12 membered heteroaryl.
In certain embodiments, each Z1 is independently -C(=0)-NH2, -C(=0)-NH(d- C4)alkyl, -C(=0)-N((C C4)alkyl)2, -C(=0)- (C6-Ci2)aryl, -C(=0)-heterocycle or -C(=0)-heteroaryl, wherein any heterocycle or heteroaryl of Z1 is a 5-12 membered heterocycle or 5-12 membered heteroaryl.
In certain embodiments, each Z1 is independentlyhalo, oxo, thioxo, (C2- C6)alkenyl, (C C6)haloalkyl, (C3-C7)cycloalkyl, (C3-C7)cycloalkyl-(Ci-C6)alkyl-, -OH, -0(Ci-C6)alkyl, -0(C C6)haloalkyl, -SH, -S(C C6)alkyl, -SO(C C6)alkyl, -S02(C C6)alkyl, -NH2, -NH(C C6)alkyl or -N((C C6)alkyl)2.
In certain embodiments, each Z1 is independently (Ci-C6)alkyl optionally substituted with -OH, -0-(Ci-C6)haloalkyl, or -0-(Ci-C6)alkyl.
In certain embodiments, each Z1 is independently (C6-Ci2)aryl, heterocycle or heteroaryl, which (C6-Ci2)aryl, heterocycle and 5- heteroaryl is optionally substituted with halo, (Ci-C6)alkyl or COOH, wherein any heterocycle or heteroaryl of Z1 is a 5-12 membered heterocycle or 5-12 membered heteroaryl.
In certain embodiments, each Z1 is independentlyhalo or (Ci-C6)haloalkyl -NH2, or (Ci-C6)alkyl optionally substituted with -OH, -0-(Ci-C6)haloalkyl, or -0-(C
C6)alkyl.
In certain embodiments, each Z1 is independentlyhalo or (Ci-C6)alkyl optionally substituted with -OH, -0-(Ci-C6)haloalkyl, or -0-(Ci-C6)alkyl.
In certain embodiments, each Z1 is independentlyhalo or (Ci-C6)alkyl.
In one embodiment, compounds having antiviral activity are provided, the compounds having the following Formula (la):
Figure imgf000025_0001
la wherein:
R2 is H, oxo, halo, (C C6)alkyl or -0(C C6)alkyl;
R3 is (Ci-C6)alkyl, (C2-C6)alkenyl, (C3-C6)cycloalkyl, (Ci-C6)-alkyl-(C3-
C6)cycloalkyl or -0(Ci-C6)alkyl, -0-(C3-C6)cycloalkyl 1, wherein any (Ci-C6)alkyl, (C2-C6)alkenyl, (C3-C6)cycloalkyl, (Ci-C6)-alkyl-(C3- C6)cycloalkyl or -0(C C6)alkyl, -0-(C3-C6)cycloalkyl of R3 is optionally substituted with one to three groups selected from the group consisting of -0(Ci-C6)alkyl, halo, oxo and -CN;
W is N or CR1 when the dashed bond is a double bond, or W is O, NR1 or CRlaRlb when the dashed bond is a single bond;
E is selected from the group consisting of:
Figure imgf000025_0002
wherein
X is N when Y is N-R7 and X is N-R6 when Y is N;
Figure imgf000026_0001
hen E is
G1 is N, G2 is CR8, and the dashed bond is a double bond; or
G1 is CR5, G2 is N, and the dashed bond is a double bond; or
G1 is CR5, G2 is NR13, the dashed bond is a single bond, and R7 is an oxo (=0) group; or
G1 is CR5, G2 is NR13, the dashed bond is a single bond, and R7 and R13 together with the atoms to which they are attached form a 5-10- membered heteroaryl, wherein the 5-10-membered heteroaryl is optionally substituted with one to three Z1 groups;
Figure imgf000026_0002
when E is
G1 is S, G2 is N, the dashed bond connected to G1 is a single bond, the dashed bond connected to G2 is a double bond, and the wavy bond connected to R12 is a single bond; or
G1 is N, G2 is S, the dashed bond connected to G1 is a double bond, the dashed bond connected to G2 is a single bond, and the wavy bond connected to R12 is a single bond; or
G1 is S, G2 is NR6, the dashed bond connected to G1 is a single bond, the dashed bond connected to G2 is a single bond, the wavy bond connected to R12 is a double bond and R12 is oxygen (e.g."(wavy bond)-R12 is "=0");
Rla and Rlb are each independently R ;
R5, R6, R7, R8, R12, and R13 are each independently: a) R11, -C(=0)-Rn, -C(=0)-0-Rn, -O-R11, -S-R11, -S(0)-Rn, -S02- R11, -(C C6)alkyl-Rn, -(C C6)alkyl-C(=0)-Rn, -(C C6)alkyl-C(=0)- O-R11, -(Ci-C6)alkyl-0-Rn, -(Ci-C6)alkyl-S-Rn, -(Ci-C6)alkyl-S(0)-Rn or -(Ci-C6)alkyl-S02-Rn, wherein each R11 is independently H, (Ci-C6)alkyl, (C2-C6)alkenyl, (C2- C6)alkynyl, (Ci-C6)haloalkyl, (C3-C7)carbocycle, (C6-Ci2)aryl, 5- 12-membered heterocycle or 5-12-membered heteroaryl, wherein any (C6-Ci2)aryl, 5-12-membered heterocycle and 5-12- membered heteroaryl of R11 are each optionally substituted with one to three Z1 groups; or b) -N(R9)R10, -C(=0)-N(R9)R10, -0-C(=0)-N(R9)R10, -S02- N(R9)R10, -(Ci-C6)alkyl-N(R9)R10,
Figure imgf000027_0001
-(C C6)alkyl-0-C(=0)-N(R9)R10, or -(C C6)alkyl-S02-N(R9)R10, wherein each R9 is independently H, (Ci-C6)alkyl or (C3-C7)cycloalkyl; and wherein each R10 is independently H, (C]-C6)alkyl, (C2-C6)alkenyl, (C2- C6)alkynyl, (Ci-C6)haloalkyl, (C3-C7)carbocycle, (C6-Ci2)aryl, 5- 12-membered heterocycle or 5-12-membered heteroaryl, wherein any (C6-Ci2)aryl, 5-12-membered heterocycle and 5-12- membered heteroaryl of R10 are each optionally substituted with one to three Z1 groups; or c) -(Ci-C6)alkyl-0-(Ci-C6)alkyl-(C3-C7)carbocycle,
-(Ci-C6)alkyl-S-(Ci-C6)alkyl-(C3-C7)carbocycle,
-(Ci-C6)alkylS(0)-(Ci-C6)alkyl-(C3-C6)carbocycle,
-(Ci-C6)alkylS02(Ci-C6)alkyl-(C3-C7)carbocycle,
-(C2-C6)alkenyl-(Ci-C6)haloalkyl, -(C2-C6)alkynyl-(Ci-C6)haloalkyl, -(C3-C7)halocarbocycle, -NRaS02NRcRd, -NRaS020(C3-C7)carbocycle, -NRaS020(C6-Ci2)aryl, -(C2-C6)alkenyl-(C3-C7)carbocycle,
-(C2-C6)alkenyl-(C6-C12)aryl, -(C2-C6)alkenyl-heteroaryl,
-(C2-C6)alkenyl-heterocycle, -(C2-C6)alkynyl-(C3-C7)carbocycle, -(C2-C6)alkynyl-(C6-C12)aryl, -(C2-C6)alkynyl-heteroaryl,
-(C2-C6)alkynyl-heterocycle, -(C3-C7)carbocycle-Z1 or -(C)- C6)haloalkyl-Z3, wherein any (Ci-C6)alkyl, (Ci-C6)haloalkyl, (C3-C7)carbocycle,
(C2-C6)alkenyl, (C2-C6)alkynyl, (C6-Ci2)aryl or heteroaryl, either alone or as a group is optionally substituted with one to three Z1 groups; and wherein any heteroaryl or heterocycle is a 5-12 membered heteroaryl or a 5-12 membered heterocycle; or d) -NReRf, -C(0)NReRf, -OC(0)NReRf, -S02NReRf, -(C C6)alkyl- NReRf, -(Ci-C6)alkylC(0)-NReRf, -(Ci-C6)alkyl-0-C(0)-NReRf or -(Ci-C6)alkyl-S02NReRf; wherein each (Ci-C6)alkyl is independently substituted with one to three Z6 groups and optionally substituted with one to three Z1 groups; or e) oxo; and each Z1 is independently halo, -N02, -OH, =NORa, -SH, -CN, (C C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C C6)haloalkyl, (C3- C7)carbocycle, (C3-C7)halocarbocycle, (C6-Ci2)aryl, heteroaryl, heterocycle, -0(C C6)alkyl, -0(C2-C6)alkenyl, -0(C2-C6)alkynyl, -0(Ci-C6)haloalkyl, -0(C3-C7)carbocycle, -0(C3-C7)halocarbocycle, - 0-(C6-Ci2)aryl, -Oheteroaryl, -Oheterocycle, -S(C C6)alkyl, -S(C2- C6)alkenyl, -S(C2-C6)alkynyl, -S(C C6)haloalkyl, -S(C3-C7)carbocycle, -S(C3-C7)halocarbocycle, -S-(C6-Ci2)aryl, -Sheteroaryl, -Sheterocycle, -S(0)(C C6)alkyl, -S(0)(C2-C6)alkenyl, -S(0)(C2-C6)alkynyl,
-S(0)(Ci-C6)haloalkyl, -S(O) (C3-C7)carbocycle, -S(0)(C3- C7)halocarbocycle, -S02(Ci-C6)alkyl, -S(O)- (C6-Ci2)aryl,
-S(0)carbocycle, -S(0)heteroaryl, -S(0)heterocycle, -S02(C2- C6)alkenyl, -S02(C2-C6)alkynyl, -S02(Ci-C6)haloalkyl, -S02(C3- C7)carbocycle, -SC>2(C3-C7)halocarbocycle, -S02-(C6-Ci2)aryl, - S02heteroaryl, -S02heterocycle, -S02NRcRd, -NRcRd, -NRaC(0)Ra, - NRaC(0)ORb, -NRaC(0)NRcRd -NRaS02Rb, -NRaS02NRcRd,
-NRaS020(C3-C7)carbocycle, -NRaS020-(C6-Ci2)aryl, -OS(0)2Ra, -C(0)Ra, -C(0)ORb, -C(0)NRcRd, or -OC(0)NRcRd, wherein any (Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, -(C3-
C7)halocarbocycle, (C3-C7)carbocycle, (C3-C7)halocarbocycle, (C6-Ci2)aryl, heteroaryl or heterocycle of Z1, either alone or as part of a group, is optionally substituted with one to three halogen, -OH, -ORb, -CN, -RH2, -NRcRd -NRaC(0)2Rb, - heteroaryl, -heterocycle, -Oheteroaryl, -Oheterocycle,
-NHheteroaryl, -NHheterocycle or -S(0)2NRcRd; and wherein any heteroaryl or heterocycle of Z1 is a 5-12 membered
heteroaryl or a 5-12 membered heterocycle; and each Z3 is independently -NO2, -CN, -OH, oxo, =NORa, thioxo, (C6- Ci2)aryl, 5-12 membered heterocycle, 5-12 membered heteroaryl, (C3- C7)halocarbocycle, -0(C C6)alkyl, -0(C3-C7)carbocycle, -0(C3- C7)halocarbocycle, -0-(C6-Ci2)aryl, -Oheterocycle, -Oheteroaryl, -S(Cr C6)alkyl, -S(C3-C7)carbocycle, -S(C3-C7)halocarbocycle, -S-(C6- Ci2)aryl, -Sheterocycle, -Sheteroaryl, -S(0)(Ci-C6)alkyl,
-S(0)(C3-C7)carbocycle, -S(O) (C3-C7)halocarbocycle, -S(O)- (C6- C12)aryl, -S(0)heterocycle, -S(0)heteroaryl, -S02(C C6)alkyl, -S02(C3-C7)carbocycle, -S02(C3-C7)halocarbocycle, S02-(C6-Ci2)aryl, -S02heterocycle, -S02heteroaryl, -NRaRb, -NRaC(0)Rb, -C(0)NRcRd, - S02NRcRd, -NRaS02NRcRd, -NRaS020(C3-C7)carbocycle or - NRaS020-(C6-C12)aryl, wherein any heteroaryl or heterocycle of Z3 is a 5-12 membered
heteroaryl or a 5-12 membered heterocycle; and each Ra, Rb, Rc and Rd is independently H or (Ci-C6)alkyl, (C2- C6)alkenyl, (C2-C6)alkynyl, (C3-C7)carbocycle, heterocycle, (C6- Ci2)aryl, (C6-C12) aryl(Ci-C6)alkyl-, heteroaryl or heteroaryl(d- C6)alkyl-, wherein any (Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl,
(C3-C7)carbocycle, heterocycle, (C6-Ci2)aryl, or heteroaryl of Ra, Rb, Rc and R<j, either alone or as part of a group, is optionally substituted with one to three halogen, OH or cyano; or Rc and R<j together with the nitrogen to which they are attached form a 5-12 membered heterocycle, wherein any heterocycle of Rc and R<j together with the nitrogen to which they are attached is optionally substituted with one to three halogen, OH, cyano, or -RH2; wherein any heteroaryl or heterocycle of Ra, R , Rc and R<j is a 5-12 membered heteroaryl or a 5-12 membered heterocycle; and each Re is independently H, -ORa, (Ci-C6)alkyl or (C3-C7)carbocycle, (C2-C6)haloalkyl, (C2-C6)alkenyl and (C2-C6)alkynyl, (C6-Ci2)aryl, 5-12 membered heterocycle or 5-12 membered heteroaryl; wherein (Ci-C6)alkyl and (C3-C7)carbocycle of Re are each
independently substituted with one to three Z6 groups and optionally substituted with one to three Z1 groups; wherein any (C2-C6)haloalkyl, (C2-C6)alkenyl or (C2-C6)alkynyl of Re is optionally substituted with one to three Zi groups; wherein any (C6-Ci2)aryl, 5-12 membered heterocycle or 5-12
membered heteroaryl of Re are each independently substituted with one to three Z5 groups; and each Rf is independently H, -Rg, -ORa, -(C C6)alkyl-Z6, -S02Rg, -C(0)Rg, C(0)ORg or -C(0)NReRg; and each Rg is independently H, (Ci-C6)alkyl, (C3-C7)carbocycle
(Ci-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C6-Ci2)aryl, 5-12 membered heterocycle or 5-12 membered heteroaryl, wherein any (Ci-C6)alkyl, (C3-C7)carbocycle -(Ci-C6)haloalkyl,
(C2-C6)alkenyl, (C2-C6)alkynyl, (C6-Ci2)aryl, 5-12 membered heterocycle or 5-12 membered heteroaryl of Rg is optionally substituted with one to three Zi groups; and each Z5 is independently -N02, -CN, -NRaS02NRcRd, -NRaS020(C3- C7)carbocycle, -NRaS020-(C6-Ci2)aryl, -NRaS02(Ci-C6)alkyl, - NRaS02(C2-C6)alkenyl, -NRaS02(C2-C6)alkynyl, -NRaS02(C3- C7)carbocycle, -NRaS02(C3-C7)halocarbocycle, -NRaS02-(C6-Ci2)aryl, -NRaS02heteraryl, -NRaS02heteroaryl, -NRaS02heterocycle,
-NRaC(0)alkyl, -NRaC(0)alkenyl, -NRaC(0)alkynyl, -NRaC(0) (C3- C7)carbocycle, -NRaC(0)(C3-C7)halocarbocycle, -NRaC(0)- (C6- Ci2)aryl, -NRaC(0)heteroaryl, -NRaC(0)heterocycle, -NRaC(0)NRcRd or -NRaC(0)ORb, wherein any heteroaryl or heterocycle of Z5 is a 5-12 membered
heteroaryl or a 5-12 membered heterocycle; and each Z6 is independently -N02, -CN, -NRaRa, NRaC(0)Rb,-C(0)NRcRd (C3-C7)halocarbocycle, (C6-Ci2)aryl, heteroaryl, heterocycle, -0-(C6- Ci2)aryl, -Oheteroaryl, -Oheterocycle, -0(C3-C7)halocarbocycle, -0(Ci C6)alkyl, -0(C3-C7)carbocycle, -0(C C6)haloalkyl, -S-(C6-C12)aryl, -Sheteroaryl, -Sheterocycle, -S(C3-C7)halocarbocycle, -S(Ci-C6)alkyl, -S(C3-C7)carbocycle, -S(C C6)haloalkyl, -S(O)- (C6-Ci2)aryl, -S(0)heteroaryl, -S(0)heterocycle, -S(0)(C3-C7)halocarbocycle, -S(0)(Ci-C6)alkyl, -S(0)(C3-C7)carbocycle, -S(0)(C C6)haloalkyl, - S02-(C6-Ci2)aryl, -S02heteroaryl, -S02heterocycle, -S02(Ci-C6)alkyl, S02(Ci-C6)haloalkyl, -S02(C3-C7)carbocycle, -S02(C3- C7)halocarbocycle, -S02NRcRd, -NRaS02(C3-C7)halocarbocycle, -NRaS02(C6-Ci2)aryl, -NRaS02heteraryl, -NRaS02heteroaryl,
-NRaS02NRcRd, -NRaS020(C3-C7)carbocycle or -NRaS020-(C6- Ci2)aryl, wherein any (C6-Ci2)aryl of Z6, either alone or as part of a group, is optionally substituted with one to three halogen, -OH, -0(Cr C6)alkyl, -CN, NH2, or -(C C6)alkyl, and wherein any heteroaryl or heterocycle of Z6 is a 5-12 membered
heteroaryl or a 5-12 membered heterocycle.
In certain embodiments, W is N, NH or CR1.
In certain embodiments, R2 is oxo, halo, H or -CH3.
In other embodiments, R2 is -CH3.
In certain embodiments, R3 is -0(Ci-C6)alkyl optionally substituted with three groups selected from the group consisting of halo and -CN.
In other embodiments, R3 is -
In certain embodiments, E is
Figure imgf000032_0001
and R5 is H.
In certain embodiments, R6 is
a) H, halo and (C C6)alkyl;
b) (C2-C6)alkenyl, (C2-C6)alkynyl and (C6-Ci2)aryl, wherein any
(C6-Ci2)aryl is optionally substituted with one to three Z10 groups;
c) -(Ci-C6)alkyl-Rn and -(Ci-C6)alkyl-0-Rn, wherein each R11 is independently selected from H, (Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C C6)haloalkyl, (C3-C7)cycloalkyl, (C6-
Ci2)aryl, 5-10-membered heterocycle and 5-10-membered heteroaryl, wherein any (C6-Ci2)aryl, 5-10-membered heterocycle or 5-10-membered heteroaryl of R6 is optionally substituted with one to three Z10 groups;
d) -(C2-C6)alkynyl-(C3-C7)carbocycle, -(C2-C6)alkynyl-(C6-
Ci2)aryl, -(C2-C6)alkynyl-heteroaryl -(C2-C6)alkynyl- heterocycle, -(C2-C8)alkynyl-ORa and -(C2-C6)alkyl-(C3-C7)carbocycle-ORa, wherein
-(C2-C6)alkynyl-(C3-C7)carbocycle, -(C2-C6)alkynyl-(C6- Ci2)aryl, -(C2-C6)alkynyl-heteroaryl and -(C2-C6)alkynyl- heterocycle, are optionally substituted with one to three Z1 groups;
e) (Ci-C6)alkyl, wherein (Ci-C6)alkyl is substituted with one to three Z2 groups and optionally substituted with one to three Z1 groups;
1) (C6-Ci2)aryl, wherein (C6-Ci2)aryl is substituted with one to three Z5 groups and optionally substituted with one to three Z1 groups; and
g) (C2-C6)alkenyl and (C2-C6)alkynyl, wherein (C2-C6)alkenyl and (C2-C6)alkynyl are each independently substituted with one to threeZ6 groups and optionally substituted with one to three Z1 groups,
wherein any heteroaryl or heterocycle of Z6 is a 5-12 membered
heteroaryl or a 5-12 membered heterocycle.
In certain embodiments, one or both of R7 and R8 are H.
In certain embodiments, R7 is:
a) H, halo, (C C6)alkyl or (C C6)haloalkyl;
b) (C3-C7)cycloalkyl, cyano, (C6-Ci2)aryl or 5-12 membered
heteroaryl, wherein any (C6-Ci2)aryl or 5-12 membered heteroaryl is optionally substituted with one to three Z10 groups; c) -C(=0)-N(R9)R10, wherein each R9 is independently H, (C
C6)alkyl or (C3-C7)cycloalkyl, and each R10 is independently R11, -(Ci-C6)alkyl-Rn, -S02-Rn, -C(=0)-Rn, -C(=0)ORn or - C(=0)N(R9)Rn, wherein each R11 is independently H, (C C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C C6)haloalkyl, (C3- C7)cycloalkyl, (C6-Ci2)aryl, 5-12 membered heterocycle or 5-12 membered heteroaryl, wherein any (C6-Ci2)aryl, 5-12 membered 5-12 membered heterocycle or 5-12 membered heteroaryl is optionally substituted with one to threeZ10 groups; d) (Ci-C6)alkyl, wherein (Ci-C6)alkyl is substituted with one to threeZ2 groups and optionally substituted with one to three Z1 groups;
e) (C6-Ci2)aryl or 5-12 membered heteroaryl, wherein (C6-Ci2)aryl and 5-12 membered heteroaryl are each substituted with one to three Z5 groups and optionally substituted with one to three Z1 groups;
f) (Ci-C6)haloalkyl or (C3-C7)carbocycle, wherein (Ci-C6)haloalkyl or (C3-C7)carbocycle are each substituted with one to three Z6 groups and optionally substituted with one to three Z^oups; or g) -C(0)NReRf.
In certain embodiments, one or both of R6 and R8 are H.
In certain embodiments, R8 is:
a) halo, nitro and cyano;
b) R11, -C(=0)-Rn, -C(=0)-0-Rn, -O-R11, -S-R11, -S(0)-Rn, -S02-
R11, -(Ci-C6)alkyl-Rn,
Figure imgf000034_0001
-(C C6)alkyl- C(=0)-0-Rn, -(Ci-C6)alkyl-0-Rn, -(Ci-C6)alkyl-S-Rn, -(C C6)alkyl-S(0)-Rn or -(Ci-C6)alkyl-S02-Rn,wherein each R11 is independently H, (Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (Ci-C6)haloalkyl, (C3-C7)cycloalkyl, (C6-Ci2)aryl, 5-12 membered heterocycle or 5-12 membered heteroaryl, wherein (C6-Ci2)aryl, 5-12 membered heterocycle and 5-12 membered heteroaryl are each optionally substituted with one to three Z11 groups;
c) -N(R9)R10, -C(=0)-N(R9)R10, -0-C(=0)-N(R9)R10, -S02-
N(R9)R10, -(Ci-C6)alkyl-N(R9)R10, -(C C6)alkyl-C(=0)- N(R9)R10, -(Ci-C6)alkyl-0-C(=0)-N(R9)R10 or -(C C6)alkyl- S02-N(R9)R10, wherein each R9 is independently H, (C C6)alkyl or (C3-C7)cycloalkyl, and each R10 is independently R11, -(Cr C6)alkyl-Rn, -S02-Rn, -C(=0)-Rn, -C(=0)ORn or -
C(=0)N(R9)Rn, wherein each R11 is independently H, (C C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C C6)haloalkyl, (C3- C7)cycloalkyl, (C6-Ci2) ryl, 5-12 membered heterocycle or 5-12 membered heteroaryl;
d) (Ci-C6)alkyl, wherein (Ci-C6)alkyl is substituted with one to three Z2 groups and optionally substituted with one to three Z1 groups;
e) (C6-Ci2)aryl, 5-12 membered heteroaryl, 5-12 membered
heterocycle, -X-(C6-Ci2)aryl, -Xheteroaryl or -Xheterocycle, wherein any (C6-Ci2)aryl, heteroaryl and heterocycle, either alone or as part of a group, is substituted with one to three Z5 groups and optionally substituted with one to three Z^oups, and wherein any -Xheteroaryl or -Xheterocycle is a 5-12 membered -Xheteroaryl or a 5-12 membered -Xheterocycle;
f) (Ci-C6)haloalkyl, (C3-C7)carbocycle, (C2-C6)alkenyl or
(C2-C6)alkynyl, wherein (Ci-C6)haloalkyl, (C3-C7)carbocycle, (C2-C6)alkenyl or (C2-C6)alkynyl are each independently substituted with one to three Z6 groups and optionally substituted with one to three Z^oups; or
g) -NReRf, -C(0)NReRf, -OC(0)NReRf, -S02NReRf, -(C C6)alkyl- NReRf, -(Ci-C6)alkylC(0)-NReRf, -(Ci-C6)alkyl-0-C(0)-NReRf or -(Ci-C6)alkyl-S02NReRf, wherein any (Ci-C6)alky, as part of a group, is substituted with one to three Z6 groups and optionally substituted with one to three Z^roups.
In certain embodiments, R5, R6, R7, and R8 are each hydrogen.
In certain embodiments, on H.
In certain embodiments, E
Figure imgf000035_0001
is C-R3, GL is N and the dotted bond is a double bond.
In certain embodiments, R6 is H and R5 is H or (Ci-C6)alkyl.
In certain embodiments R7 is:
a) H, (Ci-C6)alkyl or (C C6)haloalkyl; b) (C2-C6)alkynyl or (C6-Ci2)aryl, wherein (C6-Ci2)aryl is optionally substituted with one to three Z10 groups; c) (Ci-C6)alkyl, wherein (Ci-C6)alkyl is substituted with one to three Z2 groups and optionally substituted with one to three Z1 groups;
d) (C6-Ci2)aryl, wherein (C6-Ci2)aryl is substituted with one to three Z5 groups and optionally substituted with one to three Z1 groups; or
e) (Ci-C6)haloalkyl, wherein (Ci-C6)haloalkyl is substituted with one to three Z6 groups and optionally substituted with one to three Z1 groups.
In certain embodiments, R7 is:
a) (Ci-C6)haloalkyl; or
b) (Ci-C6)haloalkyl, wherein (Ci-C6)haloalkyl is substituted with one to three Z6 groups and optionally substituted with one to
In certain
Figure imgf000036_0001
G1 is S, G2 is N, the dashed bond connected to G1 is a single bond, the dashed bond connected to G2 is a double bond, and the wavy bond connected to R12 is a single bond; or
G1 is S, G2 is NR6, the dashed bond connected to G1 is a single bond, the dashed bond connected to G2 is a single bond, the wavy bond connected to R12 is a double bond and R5 is oxygen. In certain embodiments, R12 is
a) H, (Ci-C6)alkyl, (C C6)haloalkyl, (C3-C7)carbocycle,
heterocycle, -C(=0)-Rn, -C(=0)-0-Rn or -O-R11, wherein heterocycle is optionally substituted with one to three Z11 groups and wherein each R11 is independently H, (Ci-C6)alkyl, (C2- C6)alkenyl, (C2-C6)alkynyl, (Ci-C6)haloalkyl, (C3-C7)carbocycle, (C6-C12)aryl, heterocycle or 5-12 membered heteroaryl, wherein (C6-C12)aryl, 5-12 membered heterocycle and 5-12 membered heteroaryl are each optionally substituted with one to three Z11 groups;
b) -N(R9)R10 or -C(=0)-N(R9)R10, wherein each R9 is independently
H, (C C6)alkyl and (C3-C7)cycloalkyl, and each R10 is independently R11, -(Ci-C6)alkyl-Rn, -S02-Rn, -C(=0)-Rn, - C(=0)ORn or -C(=0)N(R9)Rn ; wherein each R11 is independently H, (Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (Ci-C6)haloalkyl, (C3-C7)cycloalkyl, (C6-Ci2)aryl, 5-12 membered heterocycle or 5-12 membered heteroaryl;
c) -(C2-C6)alkynyl-(C3-C7)carbocycle; wherein
-(C2-C6)alkynyl-(C3-C7)carbocycle is optionally substituted with one to three Z1 groups; or
d) -NReRf or -C(0)NReRf.
In certain embodiments, R is oxo and R6 is R11 or -(Ci-C6)alkyl-Rn, wherein each R11 is independently H, (Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C C6)haloalkyl, (C3-C7)cycloalkyl, (C6-Ci2)aryl, 5-12 membered heterocycle or 5-12 membered heteroaryl, wherein (C6-Ci2)aryl, 5-12 membered heterocycle or 5-12 membered heteroaryl are each optionally substituted with one to three Z11 groups.
In certain embodiments, R12 is:
a) (C6-Ci2)aryl, 5-12 membered heterocycle or 5-12 membered heteroaryl, wherein (C6-Ci2)aryl, 5-12 membered heterocycle and 5-12 membered heteroaryl are each optionally substituted with one to three Z11 groups; or
b) (C6-Ci2)aryl, 5-12 membered heteroaryl or 5-12 membered heterocycle, wherein (C6-Ci2)aryl, 5-12 membered heteroaryl are 5-12 membered heterocycle, are each independently substituted with one to five Z5 groups and optionally substituted with one or to five Z^oups; or
c) (C6-Ci2)aryl, 5-12 membered heteroaryl, or 5-12 membered heterocycle, wherein (C6-Ci2)aryl, 5-12 membered heteroaryl and 5-12 membered heterocycle, are each independently substituted with one to five Z15 groups and optionally substituted with one to five Z^oups; or
each Z11 is independently selected from Z10, -C(=0)-NH2, -C(=0)-
NH(C C4)alkyl, -C(=0)-N((C C4)alkyl)2, -C(=0)- (C6-C12)aryl, -C(=0)-heterocycle or -C(=0)-heteroaryl, and wherein any heterocycle or heteroaryl of Z11 is 5-12 membered heterocycle or a 5-12 membered heteroaryl.
wherein each Z10 is independently:
i) halo, oxo, thioxo, (C2-C6)alkenyl, (Ci-C6)haloalkyl, (C3- C7)cycloalkyl, (C3-C7)cycloalkyl-(Ci-C6)alkyl-, -OH, -0(C C6)alkyl, -0(C C6)haloalkyl, -SH, -S(C C6)alkyl, -SO(C C6)alkyl, -S02(C C6)alkyl, -NH2, -NH(C C6)alkyl or
-N((CrC6)alkyl)2; or
ii) (Ci-C6)alkyl substituted with -OH, -0-(Ci-C6)haloalkyl, or -O- (Ci-C6)alkyl; or
iii) (C6-Ci2)aryl, which (C6-Ci2)aryl is optionally substituted with halo, (C C6)alkyl or COOH; and
each Z11 is independently Z10, -C(=0)-NH2, -C(=0)-NH(C C4)alkyl, -C(=0)-N((C C4)alkyl)2, -C(=0)- (C6-C12)aryl, -C(=0)- heterocycle or -C(=0)-heteroaryl, and wherein any heterocycle or heteroaryl of Z11 is 5-12 membered heterocycle or a 5-12 membered heteroaryl.
in embodiments, R8 is:
a) halo and cyano;
b) R11, -O-R11 or -(Ci-C6)alkyl-Rn, wherein each R11 is
independently H, (Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (Ci-C6)haloalkyl, (C3-C7)cycloalkyl, (C6-Ci2)aryl, 5-12 membered heterocycle or 5-12 membered heteroaryl, wherein (C6-Ci2)aryl, 5-12 membered heterocycle or 5-12 membered heteroaryl are each optionally substituted with one to three Z11 groups; c) -C(=0)-N(R9)R10, wherein each R9 is independently H, (C C6)alkyl and (C3-C7)cycloalkyl, and each R10 is independently R11, -(Ci-C6)alkyl-Rn, -S02-Rn, -C(=0)-Rn, -C(=0)ORn or - C(=0)N(R9)Rn, wherein each R11 is independently H, (C C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C C6)haloalkyl, (C3- C7)cycloalkyl, (C6-Ci2)aryl, 5-12 membered heterocycle or 5-12 membered heteroaryl;
d) (Ci-C6)alkyl, wherein (Ci-C6)alkyl is substituted with one to three Z2 groups and optionally substituted with one to threeZ^oups;
e) (C6-Ci2)aryl or 5-12 membered heteroaryl, wherein (C6-Ci2)aryl and 5-12 membered heteroaryl are each independently substituted with one to threeZ5 groups and optionally substituted with one to threeZ^oups;
1) (C2-C6)alkynyl, wherein (C2-C6)alkynyl is substituted with one to threeZ6 groups and optionally substituted with one to threeZ^oups; or
g) -C(0)NReRf..
in embodiments, Z1 is independently :
i) -C(=0)-NH2, -C(=0)-NH(Ci-C4)alkyl, -C(=0)-N((C C4)alkyl)2, -C(=0)- (C6-Ci2)aryl, -C(=0)-heterocycle or -C(=0)-heteroaryl; ii) halo, oxo, thioxo, (C2-C6)alkenyl, (Ci-C6)haloalkyl, (C3- C7)cycloalkyl, (C3-C7)cycloalkyl-(Ci-C6)alkyl-, -OH, -0(C C6)alkyl, -0(C C6)haloalkyl, -SH, -S(C C6)alkyl, -SO(C C6)alkyl, -S02(C C6)alkyl, -NH2, -NH(C C6)alkyl or
-N((CrC6)alkyl)2; or
iii) (Ci-C6)alkyl optionally substituted with -OH, -0-(Cr
C6)haloalkyl, or -0-(C C6)alkyl; or
iii) (C6-Ci2)aryl, heterocycle or heteroaryl, which (C6-Ci2)aryl, heterocycle and 5- heteroaryl is optionally substituted with halo, (Ci-C6)alkyl or COOH, wherein any heterocycle or heteroaryl of Z1 is a 5-12 membered heterocycle or 5-12 membered heteroaryl. ain embodiments, the compounds of Formula I or Formula la are:
Figure imgf000040_0001
1-4 1-5 1-6
Figure imgf000040_0002
-10 1-1 1 1 -12 As one of skill in the art will appreciate, compounds of Formulas I and la, including the compounds shown on the preceding page, may be shown in several
Figure imgf000041_0001
1-1 1-2 1-3
Figure imgf000041_0002
1-7 1-9
Figure imgf000041_0003
1-10 1-1 1 nr 1-12 In certain a la are:
Figure imgf000042_0001
In one embodiment, a pharmaceutical composition is provided comprising a compound of any one of Formula I and Formula la or a stereoisomer or
pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient.
Another embodiment is provided comprising a method of treating or preventing an HIV infection in a human having or at risk of having the infection by administering to the human a therapeutically effective amount of a compound of any one of Formula I and Formula la, or a pharmaceutical composition thereof.
In another embodiment, the use of a compound of any one of Formula I and Formula la, or a pharmaceutical composition thereof for the treatment or prevention of an HIV infection in a human having or at risk of having the infection.
Pharmaceutical Compositions
For the purposes of administration, in certain embodiments, the compounds described herein are administered as a raw chemical or are formulated as
pharmaceutical compositions. Pharmaceutical compositions of the present invention comprise a compound of Formula (I) and a pharmaceutically acceptable carrier, diluent or excipient. The compound of Formula (I) is present in the composition in an amount which is effective to treat a particular disease or condition of interest. The activity of compounds of Formula (I) can be determined by one skilled in the art, for example, as described in the Examples below. Appropriate concentrations and dosages can be readily determined by one skilled in the art.
Administration of the compounds of the invention, or their pharmaceutically acceptable salts, in pure form or in an appropriate pharmaceutical composition, can be carried out via any of the accepted modes of administration of agents for serving similar utilities. The pharmaceutical compositions of the invention can be prepared by combining a compound of the invention with an appropriate pharmaceutically acceptable carrier, diluent or excipient, and may be formulated into preparations in solid, semi-solid, liquid or gaseous forms, such as tablets, capsules, powders, granules, ointments, solutions, suppositories, injections, inhalants, gels, microspheres, and aerosols. Typical routes of administering such pharmaceutical compositions include, without limitation, oral, topical, transdermal, inhalation, parenteral, sublingual, buccal, rectal, vaginal, and intranasal. Pharmaceutical compositions of the invention are formulated so as to allow the active ingredients contained therein to be bioavailable upon administration of the composition to a patient. Compositions that will be administered to a subject or patient take the form of one or more dosage units, where for example, a tablet may be a single dosage unit, and a container of a compound of the invention in aerosol form may hold a plurality of dosage units. Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington: The Science and Practice of Pharmacy, 20th Edition (Philadelphia College of Pharmacy and Science, 2000). The composition to be administered will, in any event, contain a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, for treatment of a disease or condition of interest in accordance with the teachings of this invention.
The pharmaceutical compositions of the invention may be prepared by methodology well known in the pharmaceutical art. For example, a pharmaceutical composition intended to be administered by injection can be prepared by combining a compound of the invention with sterile, distilled water so as to form a solution. A surfactant may be added to facilitate the formation of a homogeneous solution or suspension. Surfactants are compounds that non-covalently interact with the compound of the invention so as to facilitate dissolution or homogeneous suspension of the compound in the aqueous delivery system.
The compounds of the invention, or their pharmaceutically acceptable salts, are administered in a therapeutically effective amount, which will vary depending upon a variety of factors including the activity of the specific compound employed; the metabolic stability and length of action of the compound; the age, body weight, general health, sex, and diet of the patient; the mode and time of administration; the rate of excretion; the drug combination; the severity of the particular disorder or condition; and the subject undergoing therapy.
Combination Therapy
In one embodiment, method for treating an HIV infection is disclosed, comprising administering to a patient in need thereof a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, thereof, in combination with a therapeutically effective amount of one or more additional therapeutic agents which are suitable for treating an HIV infection.
A compound as disclosed herein (e.g., a compound of any of formuls I or formula la or a pharmaceutically acceptable salt thereof) may be combined with one or more additional therapeutic agents in any dosage amount of the compound (e.g., from 50 mg to 300 mg of compound).
In one embodiment, a method for treating or preventing an HIV infection in a human having or at risk of having the infection is provided, comprising administering to the human a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more additional therapeutic agents.
In one embodiment, the invention provides pharmaceutical compositions comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with at least one additional therapeutic agent, and a pharmaceutically acceptable carrier. For example, the therapeutic agent used in combination with the compound disclosed herein can be any anti-HIV agent.
In one embodiment, combination pharmaceutical agents comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with one or more additional therapeutic agents are provided.
One embodiment provides pharmaceutical compositions comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with at least one additional therapeutic agent, and a pharmaceutically acceptable carrier. In one embodiment, the additional therapeutic agent may be an anti- HIV agent. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of HIV protease inhibiting compounds (HIV protease inhibitors), HIV non-nucleoside inhibitors of reverse transcriptase, HIV nucleoside inhibitors of reverse transcriptase, HIV nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, entry inhibitors (e.g., CCR5 inhibitors, gp41 inhibitors (i.e., fusion inhibitors) and CD4 attachment inhibitors), CXCR4 inhibitors, gpl20 inhibitors, G6PD and NADH-oxidase inhibitors, capsid polymerization inhibitors or capsid disrupting compounds such as those disclosed in US 2013/0165489 (University of Pennsylvania), and WO 2013/006792 (Pharma Resources), pharmacokinetic enhancers, and other drug for treating HIV, and combinations thereof.
In further embodiments, the additional therapeutic agent is selected from one or more of:
(1) HIV protease inhibitors selected from the group consisting of amprenavir, atazanavir, fosamprenavir, indinavir, lopinavir, ritonavir, nelfinavir, saquinavir, tipranavir, brecanavir, darunavir, TMC-126, TMC-114, mozenavir (DMP-450), JE-
2147 (AG1776), L-756423, RO0334649, KNI-272, DPC-681, DPC-684, GW640385X, DG17, PPL-100, DG35, and AG 1859;
(2) HIV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase selected from the group consisting of capravirine, emivirine, delaviridine, efavirenz, nevirapine, (+) calanolide A, etravirine, GW5634, DPC-083, DPC-961 , DPC-963, MIV-150, TMC-120, rilpivirene, BILR 355 BS, VRX 840773, lersivirine (UK- 453061), RDEA806, KM023 and MK-1439;
(3) HIV nucleoside inhibitors of reverse transcriptase selected from the group consisting of zidovudine, emtricitabine, didanosine, stavudine, zalcitabine, lamivudine, abacavir, amdoxovir, elvucitabine, alovudine, MIV-210, ±-FTC, D-d4FC,
emtricitabine, phosphazide, fozivudine tidoxil, apricitibine (AVX754), amdoxovir, KP- 1461, GS-9131 (Gilead Sciences) and fosalvudine tidoxil (formerly HDP 99.0003);
(4) HIV nucleotide inhibitors of reverse transcriptase selected from the group consisting of tenofovir, tenofovir disoproxil fumarate, tenofovir disoproxil
hemifumarate, tenofovir disoproxil, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, tenofovir alafenamide, GS-7340 (Gilead Sciences), GS- 9148 (Gilead Sciences), adefovir, adefovir dipivoxil, CMX-001 (Chimerix) or CMX- 157 (Chimerix);
(5) HIV integrase inhibitors selected from the group consisting of curcumin, derivatives of curcumin, chicoric acid, derivatives of chicoric acid, 3,5-dicaffeoylquinic acid, derivatives of 3,5-dicaffeoylquinic acid, aurintricarboxylic acid, derivatives of aurintricarboxylic acid, caffeic acid phenethyl ester, derivatives of caffeic acid phenethyl ester, tyrphostin, derivatives of tyrphostin, quercetin, derivatives of quercetin, S-1360, AR-177, L-870812, and L-870810, raltegravir, BMS-538158, GSK364735C, BMS-707035, MK-2048, BA Oi l, elvitegravir, dolutegravir and GSK- 744;
(6) HIV non-catalytic site, or allosteric, integrase inhibitors (NCINI) including, but not limited to, BI-224436, CX0516, CX05045, CX14442, compounds disclosed in WO 2009/062285 (Boehringer Ingelheim), WO 2010/130034 (Boehringer Ingelheim), WO 2013/159064 (Gilead Sciences), WO 2012/145728 (Gilead Sciences), WO
2012/003497 (Gilead Sciences), WO 2012/003498 (Gilead Sciences) each of which is incorporated by reference in its entirety herein;
(7) gp41 inhibitors selected from the group consisting of enfuvirtide, sifuvirtide, albuvirtide, FB006M, and TRI-1144;
(8) the CXCR4 inhibitor AMD-070;
(9) the entry inhibitor SP01 A;
(10) the gpl20 inhibitor BMS-488043;
(11) the G6PD and NADH-oxidase inhibitor immunitin;
(12) CCR5 inhibitors selected from the group consisting of aplaviroc, vicriviroc, maraviroc, cenicriviroc, PRO- 140, INCB 15050, PF-232798 (Pfizer), and CCR5mAb004;
(13) CD4 attachment inhibitors selected from the group consisting of ibalizumab (TMB-355) and BMS-068 (BMS-663068);
(14) pharmacokinetic enhancers selected from the group consisting of cobicistat, ritonavir, and SPI-452; and
(15) other drugs for treating HIV selected from the group consisting of BAS-
100, SPI-452, REP 9, SP-01A, TNX-355, DES6, ODN-93, ODN-112, VGV-1, PA-457 (bevirimat), HRG214, VGX-410, KD-247, AMZ 0026, CYT 99007 A-221 HIV, DEBIO-025, BAY 50-4798, MDX010 (ipilimumab), PBS 119, ALG 889, and PA- 1050040 (PA-040).
In further embodiments, the additional therapeutic agent is selected from one or more of:
(1) HIV protease inhibitors selected from the group consisting of amprenavir, atazanavir, fosamprenavir, indinavir, lopinavir, ritonavir, nelfinavir, saquinavir, tipranavir, brecanavir, darunavir, TMC-126, TMC-114, mozenavir (DMP-450), JE- 2147 (AG1776), L-756423, RO0334649, KNI-272, DPC-681, DPC-684, GW640385X, DG17, PPL-100 (TMB-657), DG35, AG 1859, fosamprenavir calcium, indinavir sulfate, nelfinavir mesylate, saquinavir mesylate, and TMC-310911 ;
(2) HIV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase selected from the group consisting of capravirine, emivirine, delaviridine, efavirenz, nevirapine, (+) calanolide A, etravirine, GW5634, DPC-083, DPC-961 , DPC-963, MIV-150, TMC-120, rilpivirene, BILR 355 BS, VRX 840773, lersivirine (UK- 453061), RDEA806, KM023, MK-1439, delavirdine mesylate, dapivirine, doravirine, VM-1500, lentinan, and AIC-292.;
(3) HIV nucleoside or nucleotide inhibitors of reverse transcriptase selected from the group consisting of zidovudine, emtricitabine, didanosine, stavudine, zalcitabine, lamivudine, abacavir, abacavir sulfate, amdoxovir, elvucitabine, alovudine, MIV-210, +-FTC, D-d4FC, emtricitabine, phosphazide, fozivudine tidoxil, apricitibine (AVX754), KP-1461 , GS-9131 (Gilead Sciences), fosalvudine tidoxil (formerly HDP 99.0003), tenofovir, tenofovir disoproxil fumarate, tenofovir alafenamide, tenofovir alafenamide hemifumarate, tenofovir alafenamide fumarate (Gilead Sciences), GS- 7340 (Gilead Sciences), GS-9148 (Gilead Sciences), adefovir, adefovir dipivoxil, CMX-001 (Chimerix) CMX-157 (Chimerix), VIDEX® and VIDEX® EC (didanosine, ddl), censavudine, phosphazid , apricitabine, amdoxovir , tenofovir disoproxil, tenofovir disproxil hemifumarate, and festinavir;
(4) HIV integrase inhibitors selected from the group consisting of curcumin, derivatives of curcumin, chicoric acid, derivatives of chicoric acid, 3,5-dicaffeoylquinic acid, derivatives of 3,5-dicaffeoylquinic acid, aurintricarboxylic acid, derivatives of aurintricarboxylic acid, caffeic acid phenethyl ester, derivatives of caffeic acid phenethyl ester, tyrphostin, derivatives of tyrphostin, quercetin, derivatives of quercetin, S-1360, AR-177, L-870812, and L-870810, raltegravir, BMS-538158, GSK364735C, BMS-707035, MK-2048, BA Oi l, elvitegravir, dolutegravir, dolutegravir sodium, GSK-744, and cabotegravir;
(6) HIV non-catalytic site, or allosteric, integrase inhibitors (NCINI) including, but not limited to, BI-224436, CX0516, CX05045, CX14442, CX-05168, compounds disclosed in WO 2009/062285 (Boehringer Ingelheim), WO 2010/130034 (Boehringer Ingelheim), WO 2013/159064 (Gilead Sciences), WO 2012/145728 (Gilead Sciences), WO 2012/003497 (Gilead Sciences), WO 2012/003498 (Gilead Sciences) each of which is incorporated by references in its entirety herein;
(7) gp41 inhibitors selected from the group consisting of enfuvirtide, sifuvirtide, albuvirtide, FB006M, and TRI-1144;
(8) CXCR4 inhibitors selected from the group consisting of plerixafor, ALT- 1188, vMIP, Haimipu, and AMD-070;
(9) the entry inhibitors selected from the group consisting of cenicriviroc and SP01A;
(10) the gpl20 inhibitors selected from the group consisting of Radha-108 (Receptol), BMS-663068, and BMS-488043;
(11) the G6PD and NADH-oxidase inhibitor immunitin;
(12) CCR5 inhibitors selected from the group consisting of aplaviroc, vicriviroc, maraviroc, cenicriviroc, PRO- 140, INCB 15050, PF-232798 (Pfizer),
CCR5mAb004, Adaptavir (RAP-101), nifeviroc (TD-0232), TD-0680, and vMIP (Haimipu);
(13) CD4 attachment inhibitors selected from the group consisting of ibalizumab (TMB-355) and BMS-068 (BMS-663068);
(14) pharmacokinetic enhancers selected from the group consisting of cobicistat, SPI-452, and ritonavir;
(15) other drugs for treating HIV selected from the group consisting of BAS- 100, SPI-452, REP 9, SP-01A, TNX-355, DES6, ODN-93, ODN-112, VGV-1, PA-457 (bevirimat), HRG214, VGX-410, KD-247, AMZ 0026, CYT 99007 A-221 HIV, DEBIO-025, BAY 50-4798, MDX010 (ipilimumab), PBS 119, ALG 889, and PA- 1050040 (PA-040), BanLec, MK-8507, AG-1105, TR-452, MK-8591, CYT-107, alisporivir, NOV-205, IND-02, metenkefalin, PGN-007, Acemannan, Gamimune, Prolastin, 1,5-dicaffeoylquinic acid, BIT-225, RPI-MN, VSSP, Hlviral, IMO-3100, SB- 728-T, RPI-MN, VIR-576, HGTV-43, MK-1376, rHIV7-shl-TAR-CCR5RZ, MazF gene therapy, BlockAide, ABX-464, SCY-635, naltrexone, and AAV-eCD4-Ig gene therapy.
(16) Combination drugs selected from the group consisting of ATRIPLA®
(efavirenz+tenofovir disoproxil fumarate +emtricitabine), COMPLERA®
(EVIPLERA®, rilpivirine+tenofovir disoproxil fumarate +emtricitabine), STRIBILD® (elvitegravir+cobicistat+tenofovir disoproxil fumarate +emtricitabine), dolutegravir + abacavir sulfate +lamivudine, TRIUMEQ® (dolutegravir + abacavir + lamivudine) , lamivudine + nevirapine + zidovudine, dolutegravir+rilpivirine, dolutegravir+rilpivirine hydrochloride, atazanavir sulfate + cobicistat, , atazanavir + cobicistat, darunavir + cobicistat, efavirenz + lamivudine + tenofovir disoproxil fumarate, tenofovir alafenamide hemifumarate + emtricitabine + cobicistat + elvitegravir, tenofovir alafenamide hemifumarate + emtricitabine, tenofovir alafenamide + emtricitabine, tenofovir alafenamide hemifumarate + emtricitabine + rilpivirine, tenofovir alafenamide + emtricitabine + rilpivirine , Vacc-4x + romidepsin, darunavir + tenofovir alafenamide hemifumarate+ emtricitabine + cobicistat, APH-0812, raltegravir + lamivudine, KALETRA® (ALUVIA®, lopinavir+ritonavir), atazanavir sulfate + ritonavir, COMBIVIR® (zidovudine+lamivudine, AZT+3TC), EPZICOM® (Livexa®, abacavir sulfate +lamivudine, ABC+3TC), TRIZIVIR® (abacavir
sulfate+zidovudine+lamivudine, ABC+AZT+3TC), TRUVADA® (tenofovir disoproxil fumarate +emtricitabine, TDF+FTC), doravirine + lamivudine + tenofovir disoproxil fumarate, doravirine + lamivudine + tenofovir disoproxil, tenofovir + lamivudine and lamivudine + tenofovir disoproxil fumarate;
(17) Immune-based therapies selected from the group consisting of dermaVir, interleukin-7, plaquenil (hydroxychloroquine), proleukin (aldesleukin, IL-2), interferon alfa, interferon alfa-2b, interferon alfa-n3, pegylated interferon alfa, interferon gamma, hydroxyurea, mycophenolate mofetil (MPA) and its ester derivative mycophenolate mofetil (MMF), WF-10, ribavirin, IL-2, IL-12, polymer polyethyleneimine (PEI), Gepon, VGV-1, MOR-22, BMS-936559, toll-like receptors modulators (tlrl, tlr2, tlr3, tlr4, tlr5, tlr6, tlr7, tlr8, tlr9, tlrlO, tlrl l, tlrl 2 and tlrl 3), rintatolimod and IR-103; (18) HIV vaccines selected from the group consisting of peptide vaccines, recombinant subunit protein vaccines, live vector vaccines, DNA vaccines, virus-like particle vaccines (pseudovirion vaccine), CD4-derived peptide vaccines, vaccine combinations, rgpl20 (AIDSVAX), ALVAC HIV (vCP1521)/ AIDSVAX B/E (gpl20) (RV144), monomeric gpl20 HIV-1 subtype C vaccine (Novartis), Remune, ITV-1, Contre Vir, Ad5-ENVA-48, DCVax-001 (CDX-2401), PEP-6409,Vacc-4x, Vacc-C5, VAC-3S, multiclade DNA recombinant adenovirus-5 (rAd5), Pennvax-G, VRC-HIV MAB060-00-AB, AVX-101, Tat Oyi vaccine, AVX-201, HIV-LAMP-vax, Ad35, Ad35-GRIN, NAcGM3/VSSP ISA-51, poly-ICLC adjuvanted vaccines, Tatlmmune, GTU-multiHIV (FIT-06), AGS-004, gpl40[delta]V2.TVl+ MF-59, rVSVIN HIV-1 gag vaccine, SeV-Gag vaccine, AT-20, DNK-4, Ad35-GRIN/ENV, TBC-M4, HIV AX , HIVAX-2, NYVAC-HIV-PT1, NYVAC-HIV-PT4, DNA-HIV-PT123, rAAVl- PG9DP, GOVX-B11, GOVX-B21, ThV-01, TUTI-16, VGX-3300, TVI-HIV-1, Ad-4 (Ad4-env Clade C + Ad4-mGag), EN41-UGR7C, EN41-FPA2, PreVaxTat, TL-01, SAV-001, AE-H, MYM-V101, CombiHIVvac, ADVAX, MYM-V201, MVA-CMDR, ETV-01, CDX-1401, rcAd26.MOSl.HIV-Env and DNA-Ad5 gag/pol/nef/nev
(HVTN505);
(19) HIV antibodies, bispecific antibodies and "antibody-like" therapeutic proteins (such as DARTs®, Duobodies®, Bites®, XmAbs®, TandAbs ®, Fab derivatives) including BMS-936559, TMB-360 and those targeting HIV gpl20 or gp41 selected from the group consisting of bavituximab, UB-421, C2F5, C2G12, C4E10, C2F5+C2G12+C4E10, 3-BNC-117 , PGT145, PGT121, MDX010 (ipilimumab), VRCOl, A32, 7B2, 10E8, VRC-07-523 and VRC07;
(20) latency reversing agents selected from the group consisting of Histone deacetylase inhibitors such as Romidepsin, vorinostat, panobinostat; Proteasome inhibitors such as Velcade; protein kinase C (PKC) activators such as Indolactam, Prostratin, Ingenol B and DAG-lactones, Ionomycin, GSK-343, PMA, SAHA, BRD4 inhibitors, IL-15, JQ1, disulfram, and amphotericin B;
(21) HIV nucleocapsid p7 (NCp7) inhibitors selected from the group consisting of azodicarbonamide; (22) HIV maturation inhibitors selected from the group consisting of BMS- 955176 and GSK-2838232;
(23) PI3K inhibitors selected from the group consisting of idelalisib, AZD- 8186, buparlisib, CLR-457, pictilisib, neratinib, rigosertib, rigosertib sodium, EN-3342, TGR-1202, alpelisib, duvelisib, UCB-5857, taselisib, XL-765, gedatolisib, VS-5584, copanlisib, CAI orotate, perifosine, RG-7666, GSK-2636771, DS-7423, panulisib, GSK-2269557, GSK-2126458, CUDC-907, PQR-309, INCB-040093, pilaralisib, BAY-1082439, puquitinib mesylate, SAR-245409, AMG-319, RP-6530, ZSTK-474, MLN-1117, SF-1126, RV-1729, sonolisib, LY-3023414, SAR-260301 and CLR-1401;
(24) the compounds disclosed in WO 2004/096286 (Gilead Sciences), WO
2006/110157 (Gilead Sciences), WO 2006/015261 (Gilead Sciences), WO
2013/006738 (Gilead Sciences), US 2013/0165489 (University of Pennsylvania), US20140221380 (Japan Tobacco), US20140221378 (Japan Tobacco), WO
2013/006792 (Pharma Resources), WO 2009/062285 (Boehringer Ingelheim), WO 2010/130034 (Boehringer Ingelheim), WO 2013/091096A1 (Boehringer Ingelheim), WO 2013/159064 (Gilead Sciences), WO 2012/145728 (Gilead Sciences),
WO2012/003497 (Gilead Sciences), WO2014/100323 (Gilead Sciences),
WO2012/145728 (Gilead Sciences), WO2013/159064 (Gilead Sciences) and WO 2012/003498 (Gilead Sciences);
and combinations thereof.
In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with two, three, four or more additional therapeutic agents. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with two additional therapeutic agents. In other embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with three additional therapeutic agents. In further embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with four additional therapeutic agents. The two, three four or more additional therapeutic agents can be different therapeutic agents selected from the same class of therapeutic agents, or they can be selected from different classes of therapeutic agents. In a specific embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with an HIV nucleotide inhibitor of reverse transcriptase and an HIV non-nucleoside inhibitor of reverse transcriptase. In another specific embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with an HIV nucleotide inhibitor of reverse transcriptase, and an HIV protease inhibiting compound. In a further embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with an HIV nucleotide inhibitor of reverse transcriptase, an HIV non-nucleoside inhibitor of reverse transcriptase, and an HIV protease inhibiting compound. In an additional embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with an HIV nucleotide inhibitor of reverse transcriptase, an HIV non- nucleoside inhibitor of reverse transcriptase, and a pharmacokinetic enhancer.
In a specific embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with tenofovir, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, tenofovir disoproxil, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide. In another specific embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir alafenamide. In a specific embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with emtricitibine, abacavir or lamivudine.
In a specific embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with one of: tenofovir, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, tenofovir disoproxil, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide and one of: emtricitibine, abacavir or lamivudine. In a specific embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with one of: tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, tenofovir alafenamide fumarate, or tenofovir alafenamide and one of: emtricitibine or abacavir.
In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 5-30 mg tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide and 200 mg
emtricitabine. In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 5-10; 5-15; 5-20; 5-25; 25- 30; 20-30; 15-30; or 10-30 mg tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide and 200 mg emtricitabine. In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 10 mg tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide and 200 mg emtricitabine. In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 25 mg tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide and 200 mg emtricitabine. A compound as disclosed herein (e.g., a compound of any of formulas I and III or a pharmaceutically acceptable salt thereof) may be combined with the agents provided herein in any dosage amount of the compound (e.g., from 50 mg to 300 mg of compound) the same as if each combination of dosages were specifically and individually listed.
In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 200-400 mg tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil and 200 mg emtricitabine. In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 200-250; 200-300; 200-350; 250-350; 250-400; 350-400; 300-400; or 250-400 mg tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil and 200 mg emtricitabine. In some
embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 300 mg tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil and 200 mg emtricitabine. A compound as disclosed herein (e.g., a compound of any of formulas I and III or a pharmaceutically acceptable salt thereof) may be combined with the agents provided herein in any dosage amount of the compound (e.g., from 50 mg to 300 mg of compound) the same as if each combination of dosages were specifically and individually listed.
In some embodiments, one or more of the compounds disclosed herein are combined with one or more other active therapeutic agents in a unitary dosage form for simultaneous or sequential administration to a patient. In certain embodiments, a pharmaceutical composition including one or more of the compounds disclosed herein combined with one or more other active therapeutic agents is provided. In certain embodiments, the compounds disclosed herein are combined with one or more other active therapeutic agents in a solid dosage form. The combination therapy may be administered as a simultaneous or sequential regimen. When administered
sequentially, the combination may be administered in two or more administrations.
In some embodiments, one or more of the compounds disclosed herein are coadministered with one or more other active therapeutic agents. Co-administration of a compound disclosed herein with one or more other active therapeutic agents generally refers to simultaneous or sequential administration of a compound disclosed herein and one or more other active therapeutic agents, such that therapeutically effective amounts of disclosed herein and one or more other active therapeutic agents are both present in the body of the patient.
In yet another embodiment, the present application provides a method for treating an HIV infection comprising administering to a patient in need thereof a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more additional therapeutic agents such as those disclosed above.
The following Examples illustrate various methods of making compounds of this invention, i.e., compound of Formula (I):
Figure imgf000054_0001
wherein D, V, and R3 are as defined above. It is understood that one skilled in the art may be able to make these compounds by similar methods or by combining other methods known to one skilled in the art. It is also understood that one skilled in the art would be able to make, in a similar manner as described below, other compounds of Formula (I) not specifically illustrated below by using the appropriate starting components and modifying the parameters of the synthesis as needed. In general, starting components may be obtained from sources such as Sigma Aldrich, Lancaster Synthesis, Inc., Maybridge, Matrix Scientific, TCI, and Fluorochem USA, etc. or synthesized according to sources known to those skilled in the art (see, for example, Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th edition (Wiley, December 2000)) or prepared as described herein.
The following examples are provided for purposes of illustration, not limitation.
EXAMPLES
GENERAL SYNTHETIC SCHEMES
Schemes 1-5 are provided as further embodiments of the invention and illustrate general methods which were used to prepare compounds having Formula (I) or
Formula (la) and which can be used to prepare additional compound having Formula (I) or Formula (la). Schemes 6-38 are also provided as further embodiments of the invention and illustrate processes that can be used to prepare compounds of Formula I or Formula la. Schemes 6-38 incorporate embodiments which rely upon Compound 16AA as a synthetic intermediate towards la. Unless otherwise specified, moiety R4 in the schemes below refers to the tetracyclic moiety of the compounds of Formula I or Formula la.
Scheme 1
Figure imgf000055_0001
The aniline 1A is condensed with methyl vinyl ketone under aerobic conditions in the presence of acid, generating a salt of compound IB, which is neutralized with base to provide the parent form of quinoline IB. Double benzylic bromination is conducted to prepare 1C which is treated with sodium sulfide hydrate to prepare ID. The tricyclic ID is carried through a sequence of oxidation and cheletropic ring contraction under modified Ramberg-Backlund conditions to prepare IE.
Cyclopropanation promoted by Palladium leads to IF.
Scheme 2
Figure imgf000056_0001
2C 2D 1 F
Alternatively, compound IF may be prepared according to Scheme 2.
Monobrominatin of IB withN-bromosuccinimide, for example, gives 2 A. The benzylic bromide 2A is oxidized with selenium dioxide, giving 2B, which can be treated with triphenylphosphine to make a quaternary phosphonium salt 2C. Intramolecular Wittig annulation generates 2D, which can be cyclopropanated using a modification of the cyclopropanation described in Scheme 1 to yield IF.
Figure imgf000057_0001
3A 3B
3C
Compound 3A is heated in the presence of copper powder and methylene diiodide to give rise to compound 3B. When 3B is treated with a brominating reagent such as N-bromosuccinimide, for example, 3C bromide 3C can be obtained.
Compounds of the type I (below, also shown as diastereomers 5A and 5B), wherein tetracycles containing group V are attached to system D, can be synthesized according to the method in Scheme 4.
Figure imgf000057_0002
I
Systems containing D with group are described below, especially embodiments which rely upon Compound 13AA as a synthetic intermediate towards I.
Scheme 4
Figure imgf000058_0001
Compound IF or Compound 3C may be borylated under palladium catalysis, and the product boronate ester or boronic acid maybe be either isolated or carried into a Suzuki-Miyaura cross-coupling with 13AA where X is a halide selected from CI, Br, I, or a pseudohalogen (such as OTf). The products of the Suzuki-Miyaura coupling, namely 4 A and 4B, which may optionally comprise an atropdiastereomeric set (having axial chirality at the bond connecting D to the tetracycle) can optionally be purified as individual diastereomers or carried on to the next reaction as a(n) (atrop)diastereomeric mixture. 4A and 4B are then saponified as a(n) (atrop)diastereomeric mixture or individually to give 5A and/or 5B, which can be used as a(n) (atrop)diastereomeric mixture or separated into individual diastereomers via methods known to those skilled in the art.
Compounds of the type la (below, also shown as diastereomers 5C and 5B), wherein tetracycles containing group V are attached to systems containing groups E with substituents W, are commonly synthesized according to the method in Scheme 5. Scheme 5
Figure imgf000059_0001
Compound IF or Compound 3C may be borylated under palladium catalysis, and the product boronate ester or boronic acid maybe be either directly isolated or carried into a Suzuki-Miyaura cross-coupling with 16AA where X is a halide selected from CI, Br, I, or a pseudohalogen (such as OTf). The products of the Suzuki-Miyaura coupling, namely 5A and 5B, which may optionally comprise an atropdiastereomeric set (having axial chirality at the bond connecting system E with group W to the tetracycle) can optionally be purified as individual diastereomers or carried on to the next reaction as a(n) (atrop)diastereomeric mixture. 5A and 5B are then saponified as a(n) (atrop)diastereomeric mixture or individually to give 5C and/or 5D, which can be used as a(n) (atrop)diastereomeric mixture or separated into individual diastereomers via methods known to those skilled in the art.
Scheme 6
Figure imgf000060_0001
Compounds of Formula where D is a substituted pyridine may be prepared according to Scheme 6. Compound 6A is cyclocondensed with 6B to provide 6C. Bromination leads to 6D, which may be chlorinated with POCI3 or other suitable chlorination reagents, giving 6E. Metallation of the bromo group and trapping with an electrophile generates 6F. Enantioselective reduction of the ketone provides 6G, which may undergo etherification to provide 6H. Compound 6H may be chemoselectively functionalized with an R7 containing coupling agent, wherein 61 is an example of 13AA.
Scheme 7
Figure imgf000061_0001
R3= -0(CrC6)alkyl, -0(C2-C6)alkenyl,
-0(C2-C6)alkynyl or -0(C3-C6)cycloalkyl,
Figure imgf000061_0002
7M
An aromatic or heteroaromatic halide or triflate (7A) such as IF or 3C, for example, can be crossed-coupled to a suitably protected alkyne (7B) such as ethynyl(trimethyl)silane using a palladium catalyst and copper halide salt such as, for example, copper(I) iodide, N,N-diisopropylethylamine, tetrakis(triphenylphosphine)palladium(0) and dimethylformamide or copper(I) iodide, diethylamine, and bis(triphenylphosphine) palladium(II) dichloride. Deprotection of cross-coupled alkyne (7C) yields the corresponding terminal alkyne (7D) such as, for example, deprotection of a trimethylsilyl-protected alkyne with a fluoride source such as, for example, tetrabutylammonium fluoride. Metalation of a terminal alkyl (7D) such as, for example, deprotonation with n-butyllithium, yields the corresponding metal acetylide such as, for example lithium acetylide, that undergoes nucleophilic addition to an appropriate electrophile (7E) to give the corresponding hydroxy alkyne addition product 7F. A suitably substituted phenyl electrophile such as phenyl-2-propanone can be purchased or prepared by those skilled in the art through, for example, Friedel- Crafts alkylation of benzene with chloroacetone.
The hydroxyl alkyne 7F can undergo 6-endo-dig electrophilic cyclization under suitable reaction conditions such as, for example iodine and sodium bicarbonate to give the corresponding substituted naphthalene such as, for example the iodonaphthalene 7G. The substituted naphthalene 7G can undergo a cross-coupling reaction such as, for example Stille cross-coupling using a tin reagent such as tributyl(vinyl)tin and a palladium catalyst such as bis(triphenylphosphine) palladium(II) dichloride to give the corresponding cross-coupled naphthalene such as, for example, vinylnaphthalene 7H. The vinylnaphthalene 7H can be dihydroxylated by methods known to those skilled in the art such as, for example Sharpless asymmetric dihydroxylation using, for example, commercially available AD-mix-a.
The resulting diol 71 can be protected at the primary hydroxyl by suitable protecting groups such as, for example, pivalate ester using pivaloyl chloride and pyridine to provide 7J. The secondary hydroxyl can be converted to the corresponding ether 7K such as tert-butyl ether using methods known to those skilled in the art such as, for example, tert-butyl acetate and perchloric acid. The protected primary hydroxyl can be deprotected by methods known to those skilled in the art such as, for example the deprotection of a pivalate protecting group under basic conditions, such as, for example sodium hydroxide, to give the corresponding primary hydroxyl compound 7L. The primary hydroxyl can be oxidized to the corresponding carboxylic acid 7M by methods known to those skilled in the art such as, for example, periodic acid and chromium trioxide.
Figure imgf000063_0001
Figure imgf000063_0002
R3 = -0(CrC6)alkyl, -0(C2-C6)alkenyl, LG = leavin9 9rouP
-0(C2-C6)alkynyl or -0(C3-C6)cycloalkyl,
Figure imgf000063_0003
Metalation of a suitably functionalized and protected terminal alkyne such as, for example, deprotonation with n-butyllithium, can yield the corresponding metal acetylide such as, for example lithium acetylide, that undergoes nucleophilic addition to an appropriate electrophile, such as, for example 7E, to give the corresponding hydroxy alkyne addition product 8A. The hydroxyl alkyne 8A can undergo 6-endo-dig electrophilic cyclization under suitable reaction conditions such as, for example iodine and sodium bicarbonate to give the corresponding substituted naphthalene such as, for example iodonaphthalene 8B. The substituted naphthalene 8B, can undergo a cross- coupling reaction such as, for example Stille cross-coupling using a tin reagent such as, for example, tributyl(vinyl)tin and a palladium catalyst such as, for example, bis(triphenylphosphine)palladium(II) dichloride to give the corresponding cross- coupled naphthalene such as, for example, vinylnaphthalene 8C. The
alkenylnaphthalene 8C can be dihydroxylated using methods known to those skilled in the art such as, for example Sharpless asymmetric dihydroxylation using, for example, commercially available AD-mix-a.
The resulting diol 8D can be protected at the primary hydroxyl by an orthogonal protecting groups, such as, for example, pivalate ester using pivaloyl chloride and pyridine. The secondary hydroxyl of 8E can be converted to the corresponding ether 8F, such as a tert-butyl ether using methods known to those skilled in the art for example, using tert-butyl acetate and perchloric acid. The naphthol protecting group can be differentially deprotected by methods known to those skilled in the art and converted to a leaving group (e.g. triflate) known to undergo cross-coupling reactions. Compounds IF or 3C can be converted to the corresponding metalated species, such as the boronic acid using tetrakis(triphenylphosphine)palladium(0) bis(pinacolato)diboron and potassium acetate, and undergo Suzuki cross-coupling with the activated naphthalene 8G using palladium catalyst such as chloro(2-dicyclohexylphosphino-2',6'- dimethoxy-l,l'-biphenyl)[2-(2-aminoethylphenyl)]palladium(II) and a base such as cesium fluoride to complete the installation of R4 moiety of naphthalene 8H. The protected primary hydroxyl can be deprotected by methods known to those skilled in the art such as, for example the deprotection of a pivalate protecting group under basic conditions, such as, for example sodium hydroxide, to give the corresponding primary hydroxyl. The primary hydroxyl can be oxidized to the corresponding carboxylic acid analog 81 by methods known to those skilled in the art such as, for example, periodic acid and chromium trioxide.
Scheme 9
Figure imgf000065_0001
Figure imgf000065_0002
Figure imgf000065_0003
Figure imgf000065_0004
Electrophilic aromatic substitution with a suitably functionalized and protected naphthol such as, for example 9A, with an electrophile such as, for example, ethyl glyoxylate under appropriate conditions such as, for example, titanium tetrachloride, can provide 9B. The secondary alcohol can be protected with a protecting group and the naphthol converted to a leaving group (e.g. triflate) known to undergo cross- coupling reactions to provide 9C. The alcohol protecting group can be removed and the resulting alcohol oxidized to the ketone using an oxidant such as Dess-Martin Periodinane, for example, to provide 9E. The ketone can be reduced stereoselectively using an asymmetric reduction method such as, for example Corey-Bakshi-Shibata Reduction to provide 9F.
The secondary hydroxyl can be converted to the corresponding ether such as tert-butyl ether using methods known to those skilled in the art such as, tert-butyl acetate and perchloric acid to provide 9G. Compounds IF or 3C can be converted to the corresponding boronic acid or ester using tetrakis(triphenylphosphine)palladium(0) bis(pinacolato)diboron and potassium acetate, and undergo Suzuki cross-coupling with the functionalized naphthalene 9G using a palladium catalyst such as chloro(2- dicyclohexylphosphino-2',6'-dimethoxy- 1 , 1 '-biphenyl)(2'-amino- 1 , 1 '-biphenyl-2-yl) palladium(II) to give the corresponding cross-coupled naphthalene 9H (wherein R4 is the tetracyclic group of IF or 3C). The protected ester can be deprotected by methods known to those skilled in the art such as, for example the deprotection of a ethyl ester protecting group under basic conditions, such as, for example sodium hydroxide, to give the corresponding carboxylic acid 91.
It is known to those skilled in the art that the functionalized naphthalenes (e.g. 9E, 9G, or 9H) that contain a halogen or pseudohalogen (e.g. triflate), can undergo cross-coupling reactions such as but not limited to Suzuki reactions with boronic acids or esters, Stille reactions with trialkyltin reagents, Sonogashira reactions with alkynes, and Buchwald-Hartwig reactions with amines and carried forward in a similar manner to provide 91.
Figure imgf000067_0001
Figure imgf000067_0002
Figure imgf000067_0003
Compounds IF or 3C can be converted to the corresponding boronic acid or ester using tetrakis(triphenylphosphine)palladium(0) bis(pinacolato)diboron and potassium acetate, and Suzuki cross-coupled with naphthalene 9C to give the corresponding cross-coupled naphthalene 10A. The alcohol protecting group can be removed and the resulting alcohol oxidized to the ketone using an oxidant such as Dess-Martin periodinane, for example, to provide 10B. The ketone can be reduced stereoselectively using an asymmetric reduction method such as, for example Corey- Bakshi-Shibata Reduction to provide IOC. The secondary hydroxyl can be converted to the corresponding ether such as tert-butyl ether using methods known to those skilled in the art such as, tert-butyl acetate and perchloric acid to provide 10D. The protected ester can be deprotected by methods known to those skilled in the art such as, for example the deprotection of a ethyl ester protecting group under basic conditions, such as, for example sodium hydroxide, to give the corresponding carboxylic acid 10E.
It is known to those skilled in the art that the functionalized naphthalenes (e.g. 10A or 10D) that contain a halogen or pseudohalogen (e.g. triflate), can undergo cross- coupling reactions such as but not limited to Suzuki reactions with boronic acids or esters, Stille reactions with trialkyltin reagents, Sonogashira reactions with alkynes, and Buchwald-Hartwig reactions with amines and carried forward in a similar manner to provide 10E.
Figure imgf000068_0001
111 LG = leaving group
Figure imgf000068_0002
11 L It is known to those skilled in the art that 11A can undergo the Horner- Wadsworth-Emmons reaction with stabilized phosphonate carbanions such as, for example (diethoxyphosphoryl)acetic acid ethyl ester and sodium hydride to provide 11B. The olefin can be reduced by hydrogenation with palladium on carbon, for example, to provide 11C. The protected ester can be deprotected by methods known to those skilled in the art such as, for example the deprotection of a ethyl ester protecting group under basic conditions, such as, for example lithium hydroxide, to give the corresponding carboxylic acid that can be converted to the corresponding acid chloride using oxalyl chloride to give 11D. Friedel Crafts reaction catalyzed by a Lewis acid such as, for example, aluminum trichloride provides tetralone HE.
Condensation of HE with, for example, ethyl glyoxylate under acid catalysis provides 11F which can be brominated under radical conditions such as, for example, N-bromosuccinimide and ΑΙΒΝ, and converted to 11H using an alkoxide such as that derived from reaction of 4-methoxybenzyl alcohol and LHMDS, for example.
The naphthol 11H can be converted to a leaving group (e.g. triflate) known to undergo cross-coupling reactions by methods known to those skilled in the art.
Compounds IF or 3C can be converted to the corresponding boronic acid or ester using tetrakis(triphenylphosphine)palladium(0) bis(pinacolato)diboron and potassium acetate, and Suzuki cross-coupled with compound HI to give the corresponding cross-coupled naphthalene 11J wherein R4 is the tetracyclic group of IF or 3C.
The alcohol protecting group can be removed by methods known to those skilled in the art and the resulting hydroxyl can be converted to the corresponding ether such as tert-butyl ether using methods known to those skilled in the art such as, tert- butyl acetate and perchloric acid to provide 11K. The protected ester can be deprotected by methods known to those skilled in the art such as, for example the deprotection of a ethyl ester protecting group under basic conditions, such as, for example sodium hydroxide, to give the corresponding carboxylic acid 11L. Scheme 12
Figure imgf000070_0001
Cyclocondensation of a substituted hydroxyaniline 12A with a substituted, unsaturated aldehyde 12B leads to quinolinols 12C. Bromination can be achieved using electrophilic sources of bromine such as N-bromosuccinimide to give 12D. The phenol of 12D can be activated by transforming to the leaving group in 12E such as trifluoromethanesulfonate by treatment with trifluoromethanesulfonic anhydride and an appropriate base such as 2,6-lutidine. Regioselective palladium catalysed cross- coupling reactions (e.g. Suzuki or Stille) can be used to functionalize the quinoline with a vinyl group giving 12F, which can then be asymmetrically di-hydroxylated using reagent mixtures such as AD-mix-ot, giving diol 12G. Selective protection of the primary hydroxyl can be achieved with bulky protecting groups, such as pivaloyl chloride, gives 12H. Formation of the R group can be achieved by alkylation of the secondary alcohol by various methods, such as treatment with perchloric acid in tert-butyl acetate to give a tert-butyl ether. Compounds IF or 3C can be converted to the corresponding boronic acid or ester using tetrakis(triphenylphosphine)palladium(0)
bis(pinacolato)diboron and potassium acetate, and Suzuki cross-coupled with 121 to install the tetracyclic R4 group of 12J. Following hydrolysis of the protecting group to give 12K, the primary alcohol may then be oxidized to produce desired compounds
12L.
Further functionalization of the quinoline core when R4 is already installed be achieved as outlined in Schemes 13-20.
Scheme 13
Figure imgf000071_0001
Generation of a quinolinone intermediate is achieved by N-oxidation of the quinoline 12J with a reagent such as mCPBA, followed by acylation, thermal rearrangement, and selective removal of the acetate. Deprotonation of the quinolinone followed by methods to favor O-alkylation when treated with an appropriate electrophile allow for substituents at R7 to be produced wherein the R7 group of 13B is an ether. Subsequent hydrolysis and oxidation can provide compounds of formula 1 with R7 ether groups.
Scheme 14
Figure imgf000072_0001
14B 14C
Deprotonation of the quinolinone 13A followed by methods to favor N- alkylation when treated with an appropriate electrophile can yield desired alkylated quinolinone analogues with R13 modifications. Subsequent hydrolysis and oxidation produces desired compounds.
Scheme 15
Figure imgf000072_0002
15C
The quinolinyl triflate 15A can be made from the quinolinone 13A. Cross coupling reactions with the triflate (e.g. Suzuki and Sonagashira reaction) can introduce different R7 moieties. Alternatively, the quinolinyl triflate 15A can react with Grignard or alkyl-lithium reagents in the presence of a catalyst such as Fe(AcAc)3 to give the corresponding quinoline. Hydrolysis and oxidation can yield the desired compounds. Scheme 16
Figure imgf000073_0001
The quinolinone 13A can be converted to 2-chloroquinoline 16A by treatment with reagents such as phosphorous oxychloride. Nucleophilic aromatic substitution can introduce different R7 groups wherein the R7 is linked through a heteroatom.
Hydrolysis and oxidation can produce the desired analogs 16C.
Scheme 17
Figure imgf000073_0002
Deprotonation of 2-chloroquinoline 17A, followed by reaction with trimethyl borate can generate the boronic acid. Zinc and acetic acid can be used to reduce the substituted chloroquinoline to the quinoline. Cross coupling and subsequent hydrolysis and oxidation can provide analogs with different R6 moieties.
Scheme 18
Figure imgf000074_0001
The methylquinoline 18A can be oxidized with mCPBA to give the N-oxide, which can react with acetic anhydride and rearrange to yield the
hydroxymethylquinoline. Oxidation of the alcohol can provide the carboxylic acid. Coupling with different amines can provide R7 amide moieties. Subsequent hydrolysis can generate compounds of formula I with R7 amides.
Figure imgf000075_0001
Figure imgf000075_0002
The quinoline carboxylic acid 18C can be converted to a primary amine via a Curtius rearrangement which can be converted to additional R7 groups wherein the R7 group is an amine. Subsequent hydrolysis can provide compounds of formula 1 with R7 amine groups.
Figure imgf000075_0003
Figure imgf000075_0004
The hydroxymethylquinoline 18B can be converted to mesylate, which can be reacted with different nucleophiles to provide R7 groups wherein the R7 group is represented by the general formula "-CH2XR" wherein X is O, S or NR' . Subsequent hydrolysis can generate compounds of formula I.
Scheme 21
Figure imgf000076_0001
21 K Scheme 22 f
Figure imgf000077_0001
boronic acid, halogen)
21 B 22A
Figure imgf000077_0002
The benzothiazole intermediate 21B can be converted to the final compound 22C by the methods used to convert 21C to 21M as outlined in Scheme 21 using the corresponding boronic acid or ester of compounds IF or 3C.
Scheme 23
Figure imgf000078_0001
Figure imgf000078_0002
The benzothiazole intermediate 23E can be converted to the final compound 22C by the methods used to convert 21C to 21D and 21F to 21M as outlined in Scheme 21 using the corresponding boronic acid or ester of compounds IF or 3C.
Figure imgf000078_0003
The benzothiazole intermediate 24A can be converted to the final compound 24B by the methods used to convert 21C to 21D and 21F to 21M as outlined in Scheme 21 using the corresponding boronic acid or ester of compounds IF or 3C, wherein HNRR represents an HNR9R10, HNReRf or a heterocycle (when R and R taken together with the nitrogen to which they are attached form a ring).
Figure imgf000079_0001
25T The benzothiazoline intermediate 25S can be converted to the final compound 25T by the methods used to convert 21C to 21M as outlined in Scheme 21 using the corresponding boronic acid or ester of compounds IF or 3C.
Scheme 26
Figure imgf000080_0001
26V 26W
The benzothiazoline intermediate 26V can be converted to the final compound 26W by the methods used to convert 21C to 21M as outlined in Scheme 21 using the corresponding boronic acid or ester of compounds IF or 3C.
Figure imgf000081_0001
Figure imgf000081_0002
Figure imgf000081_0003
In certain embodiments, an appropriately substituted phenol 27 A is halogenated by the treatment of dihalide, for example bromine, in a suitable solvent such as, for example acetic acid. The phenol 27B is converted to a leaving group (e.g., triflate) known to undergo cross-coupling reactions. The corresponding activated phenol 27C undergoes a selective cross-coupling reaction such as, for example Stille cross-coupling using a tin reagent such as tributyl(vinyl)tin and a palladium catalyst such as bis(triphenylphosphine) palladium(II) dichloride to give the corresponding cross- coupled naphthalene such as styrene 27D. The styrene is dihydroxylated to provide 27E by methods known to those skilled in the art such as, Sharpless asymmetric dihydroxylation using, for example, commercially available AD mix-a. The resulting diol 27E is protected at the primary hydroxyl by suitable protecting groups such as pivalate ester using pivaloyl chloride and pyridine to provide 27F. The secondary hydroxyl is converted to the corresponding ether such as tert-butyl ether using methods known to those skilled in the art such as, tert-butyl acetate and perchloric acid to provide 27G.
The nitro group of 27G is reduced to the corresponding aniline 27H by catalytic hydrogenation using platinum on carbon, for example, under a hydrogen atmosphere. Benzothiazole 271 is formed by methods known to those skilled in the art such as potassium thiocyanate and pyridinium perbromide, for example. The resulting benzothiazole undergoes Suzuki cross-coupling reaction with the corresponding boronic esters of IF or 3C, for example, using a palladium catalyst such as tetrakis(triphenylphosphine)palladium(0) to give the corresponding cross-coupled benzothiazole 27J wherein R4 is the tetracylic group of IF or 3C. The corresponding halobenzothiazole 27K is formed by methods known to those skilled in the art such as
Figure imgf000082_0001
28A 28B
In certain embodiments the protected primary hydroxyl 27J (wherein R4 is installed as described in Scheme 27) is deprotected by methods known to those skilled in the art such as the deprotection of a pivalate protecting group under basic conditions for example, using sodium hydroxide, to give the corresponding primary hydroxyl compound 28A. The primary hydroxyl is oxidized to the corresponding carboxylic acid by methods known to those skilled in the art such as, for example, periodic acid and chromium trioxide. The resulting carboxylic acid is protected by formation of corresponding carboxylic ester 28B with treatment of, for example,
trimethylsilyldiazomethane, to form the corresponding methyl ester.
Figure imgf000083_0001
Figure imgf000083_0002
Figure imgf000083_0003
In certain embodiments the protected primary hydroxyl 27J is deprotected by methods known to those skilled in the art such as the deprotection of a pivalate protecting group under basic conditions for example, using sodium hydroxide, to give the corresponding primary hydroxyl compound 29A. The primary hydroxyl is oxidized to the corresponding carboxylic acid 29B by periodic acid and chromium trioxide, for example. The carboxylic acid is protected as, for example, a methyl ester by treatment with sulfuric acid in methanol. The tert-butyl ether is re-installed by treating 29C with tert-butyl acetate and perchloric acid, for example, to provide 29D. The corresponding halobenzothiazole 29E is formed by methods known to those skilled in the art such as ferf-butyl nitrite and a copper(II)halide such as copper(II)bromide, for example. Scheme 30
Figure imgf000084_0001
30G 30H
30F
In certain embodiments chlorobenzothiazole 30A is formed from 271 by methods known to those skilled in the art such as ferf-butyl nitrite and a
copper(II)halide such as copper(II)bromide, for example. Selective palladium- catalyzed cross-coupling such as Suzuki or Stille with protected phenol boronic acid/ester or stannane, respectively, provides 30B. Selective deprotection of PG2 such as catalytic hydrogenation of a benzyl ether gives phenol 30C, which is converted to a leaving group (e.g., triflate) known to undergo cross-coupling reactions. The corresponding activated phenol 30D undergoes a selective cross-coupling reaction such as, for example Suzuki cross-coupling using a boronic acid or ester and a palladium catalyst such as tetrakis(triphenylphosphine)palladium(0) to give the corresponding cross-coupled benzothiazole 30E.
In certain embodiments the R4 moiety is introduced by cross-coupling reaction such as a Suzuki cross-coupling reaction with the corresponding boronic acid or ester of compound IF or 3C, for example, using a palladium catalyst such as
tetrakis(triphenylphosphine)palladium(0) to give the corresponding cross-coupled benzothiazole 30F wherein R4 is the tetracyclic group of IF or 3C. The protected primary hydroxyl 30F is deprotected by methods known to those skilled in the art such as the deprotection of a pivalate protecting group under basic conditions for example, using sodium hydroxide, to give the corresponding primary hydroxyl compound 30G. The primary hydroxyl is oxidized to the corresponding carboxylic acid 30H by periodic acid and chromium trioxide, for example.
Scheme 31
Figure imgf000085_0001
31 B 31 C 31 D
In certain embodiments halobenzothiazole 27K, with the desired R4 moiety already installed,undergoes selective palladium-catalyzed cross-coupling such as Suzuki or Stille with a boronic acid/ester or stannane that also contains a leaving group such as for example, a chloropyridylboronic acid, known to undergo cross-coupling reactions to give 31A. The activated moiety 31A undergoes a cross-coupling reaction such as, for example Suzuki or Stille cross-coupling using a boronic acid/ester or stannane, respectively and a palladium catalyst such as
tetrakis(triphenylphosphine)palladium(0) to give the corresponding cross-coupled benzothiazole 31B. The protected primary hydroxyl 31B is deprotected by methods known to those skilled in the art such as the deprotection of a pivalate protecting group under basic conditions for example, using sodium hydroxide, to give the corresponding primary hydroxyl compound 31C. The primary hydroxyl is oxidized to the corresponding carboxylic acid 31D by periodic acid and chromium trioxide, for example.
Figure imgf000086_0001
In certain embodiments halobenzothiazole 27K, with the desired R4 moiety already installed, undergoes palladium-catalyzed cross-coupling such as Suzuki with a boronic acid or ester; Stille with a stannane; palladium-catalyzed carbonylation using carbon monoxide, for example in the presence of an amine; copper(I)halide catalyzed or Buchwald-Hartwig amination; palladium-catalyzed amidation; S AT with an amine; to introduce the R5 moiety in 32A. The protected primary hydroxyl of 32A is deprotected by methods known to those skilled in the art such as the deprotection of a pivalate protecting group under basic conditions for example, using sodium hydroxide, to give the corresponding primary hydroxyl compound 32B. The primary hydroxyl is oxidized to the corresponding carboxylic acid 32C by periodic acid and chromium trioxide, for example.
Figure imgf000087_0001
In certain embodiments chlorobenzothiazole 30A undergoes selective palladium-catalyzed cross-coupling such as Suzuki or Stille with protected phenol boronic acid/ester or stannane, respectively, to provide 33A. The R4 moiety is introduced by cross-coupling reaction with corresponding boronate acid or esters of compound IF or 3C for example, in a Suzuki cross-coupling using a palladium catalyst such as tetrakis(triphenylphosphine)palladium(0) to give the corresponding cross-coupled benzothiazole 33B wherein R4 is the tetracyclic group of IF or 3C. The protected primary hydroxyl in 33B is deprotected by methods known to those skilled in the art such as the deprotection of a pivalate protecting group under basic conditions for example, using sodium hydroxide, to give the corresponding primary hydroxyl compound 33C. The primary hydroxyl is oxidized to the corresponding carboxylic acid 33D by periodic acid and chromium trioxide, for example.
Figure imgf000088_0001
In certain embodiments halobenzothiazole 29E, with the desired R4 moiety already installed, undergoes selective palladium-catalyzed cross-coupling such as Suzuki or Stille with a boronic acid/ester or stannane that also contains a leaving group such as for example, a chloropyridylboronic acid, known to undergo cross-coupling reactions to give 34A. The activated moiety 34A undergoes an S Ar reaction with for example a secondary amine, or a cross-coupling reaction such as, for example Suzuki or Stille cross-coupling using a boronic acid/ester or stannane, respectively and a palladium catalyst such as tetrakis(triphenylphosphine)palladium(0) to give the corresponding cross-coupled benzothiazole 34B. The protected carboxylic acid 34B is deprotected by methods known to those skilled in the art such as the deprotection of a carboxylic ester under basic conditions for example, using sodium hydroxide, or treatment with lithium iodide in pyridine, to give the corresponding carboxylic acid 34C.
Scheme 35
Figure imgf000089_0001
35B
In certain embodiments halobenzothiazole 29E, with the desired R4 moiety already installed, undergoes palladium-catalyzed cross-coupling such as Suzuki with a boronic acid or ester; Stille with a stannane; palladium-catalyzed carbonylation using carbon monoxide, for example in the presence of an amine; copper(I)halide catalyzed or Buchwald-Hartwig amination; palladium-catalyzed amidation; S AT with an amine or alcohol; to introduce the R5 moiety in 35A. The protected carboxylic acid 35A is deprotected by methods known to those skilled in the art such as the deprotection of a carboxylic ester under basic conditions for example, using sodium hydroxide, or treatment with lithium iodide in pyridine to give the corresponding carboxylic acid 35B.
Scheme 36
Figure imgf000090_0001
In certain embodiments aminobenzothiazole 29D, with the desired R4 moiety already installed, undergoes reactions known to those skilled in the art such as amide formation using carboxylic acid EDCI, for example; sulfonamide formation using a sulfonyl chloride; urea formation using CDI in the presence of an amine; to introduce the R5 moiety in 36A. The protected carboxylic acid 36A is deprotected by methods known to those skilled in the art such as the deprotection of a carboxylic ester under basic conditions for example, using sodium hydroxide, to give the corresponding carboxylic acid 36B.
Scheme 37
Figure imgf000091_0001
In certain embodiments, ketone 37A undergoes reactions known to those skilled in the art such as aldol condensation to give enone 37B. Compounds IF and 3C can be metallated by treatment of n-butyllithium, for example, and added to enone 37B to undergo 1,2 organometallic to give tertiary alcohol 37C. Under the action of an acid such as polyphosphoric acid, 37C is converted to benzthiazole 37D. Reaction of 37D under basic conditions such as lithium hexamethyldisilazane in the presence of oxaziridine such as Davis reagent, followed oxidation with an oxidant such as Dess- Martin periodinane can give ketoester 37E. Chiral reductions of 37E such as CBS or Noyori can give chiral alcohol 37F. The secondary hydroxyl is converted to the corresponding ether such as tert-butyl ether using methods known to those skilled in the art such as, tert-butyl acetate and perchloric acid to provide 37G. The activated benzthiazole 37G undergoes a cross-coupling reaction such as, for example Buchwald, Heck, Negishi, Suzuki or Stille cross-coupling using a palladium catalyst such as tetrakis(triphenylphosphine)palladium(0); S AT reactions with for example, a secondary amine; to give the corresponding benzothiazole 37H. The protected carboxylic acid 37H is deprotected by methods known to those skilled in the art such as the deprotection of a carboxylic ester under basic conditions for example, using sodium hydroxide, or treatment with lithium iodide in pyridine to give the corresponding carboxylic acid 371.
Scheme 38
Figure imgf000092_0001
38D
In certain embodiments, halobenzthiazole 29E, with the desired R4 moiety already installed, undergoes palladium-catalyzed cross-coupling such as Suzuki with a boronic acid or ester, for example 2-(4-fluoro-3-nitrophenyl)-4,4,5,5-tetramethyl-l,3,2- dioxaborolane to give 38A, known to those skilled in the art to undergo SnAr reaction with nucleophiles, such as, for example methylamine, to give 38B. Hydrogenation under platinium on carbon, for example provides the bis-aniline 38C. Cyclization with an orthoformate, such as triethylorthoformate in acetic acid, for example gives benzimidazole 38D. The protected carboxylic acid 38D is deprotected by methods known to those skilled in the art such as the deprotection of a carboxylic ester under basic conditions for example, using sodium hydroxide, or treatment with lithium iodide in pyridine to give the corresponding carboxylic acid 38E.
REPRESENTATIVE COMPOUNDS
Example 1
Preparation of Compound A
Figure imgf000094_0001
2-bromo-5-methyl 8-bromo-4,5-dimetriyl 8-bromo-4,5-dimetriyl benzenamine quinoline, monohydrochloride quinoline
Figure imgf000094_0002
8-bromocyclopentadieno[1 ',2',3':cie]quinoline A
8'-bromo-quinolino[4',4a',5':bc]- bicyclo[3.1.0]hex-2-ene
8-bromo-4,5-dimethylquinoline, monohydrochloride (A): At 23 °C, a 2-neck 500 mL round-bottom flask equipped with magnetic stirring bar, reflux condenser, and bubbler was flushed with N2 for several minutes. The flask was placed in a bath of aluminum beads and charged with 12 N aq. HCl (180 mL). Molten 2-bromo-5-methyl benzenamine (50.0 g, 0.270 mol) was added steadily to the flask while the aluminum bead bath was at 23 °C. Once addition ensued, an off-white chunky precipitate formed. A glass stirring rod was periodically used to pulverize the chunks. Once addition was complete, the reaction was a suspension with particulate white solid in yellow liquid. At this point, a pressure-equalizing addition funnel was attached to the flask and charged with Methyl Vinyl Ketone (26.8 mL, 0.322 mol). The reaction was heated to 120 °C under N2. A circulating chiller was applied to through the reflux condenser. The bubbler was then removed and a stream of air was passed steadily over the reaction while the Methyl Vinyl Ketone was added drop wise over 10 min. Heating was continued for another 30 min, then the air stream was cut. The reaction was refitted with the bubbler and an N2 stream was applied as the reaction was cooled to 23 °C. The reaction was poured into THF (1.0 L) and the slurry was cooled to - 20 °C overnight. The precipitate was collected in a Buchner funnel on filter paper and washed with 2 x 100 mL of ice-cold THF. This afforded 8-bromo-4,5-dimethylquinoline,
monohydrochloride. The material was immediately used in the reaction below. LCMS ESI+ Calc'd for CnH10BrN (M+H)+: 236.0 / 238.0. Found 236.1 / 238.1 (M+H)+
8-bromo-4,5-dimethylquinoline: A suspension of 8-bromo-4,5- dimethylquinoline, monohydrochloride (all of the material from the reaction above) was placed in a flask. The flask was charged with DCM (200 mL) and 50% w/v aq. KOH (200 mL). Et3N (100 μί) was added at 0 °C and the reaction was stirred vigorously and allowed to warm to 23 °C. All solids dissolved, giving a very yellow organic phase, which was collected, dried (Na2S04), filtered, and concentrated.
Chromatography on silica gel (330 g "gold" ISCO column; Hexane/EtOAc gradient eluent) afforded 8-bromo-4,5-dimethylquinoline. ]H NMR (400 MHz, CDC13) δ 8.81 (d, J = 5 Hz, 1H), 7.89 (d, J = 8 Hz, 1H), 7.23 (d, J = 5 Hz, 1H), 7.17 (d, J = 8 Hz, 1H), 2.96 (s, 3H), 2.87 (s, 3H).
8-bromo-4,5-bis(bromomethyl)quinoline: A suspension of 8-bromo-4,5- dimethylquinoline (7.70 g, 32.6 mmol) in CC14 (150 mL) was treated with AIBN (536 mg, 3.26 mmol) and N-bromosuccinimide (12.2 g, 68.5 mmol). The slurry was sparged with argon for 5 min and later fitted with a reflux condenser under N2. The reaction was heated to 90 °C for 2 h. Complete consumption of starting material was seen using LCMS analysis, however there was a mixture of mono-, di-, and tri-brominated products. In order to further convert the monobrominated products, additional N- bromosuccinimide (1.22 g, 6.85 mmol) was introduced. After a short time, the reaction was cooled to 23 °C and allowed to stand in the dark overnight at 23 °C. The next day, precipitate was removed by filtration. The filtrate was directly purified via
chromatography on silica gel (330 g "gold" ISCO column; Hexane/EtOAc gradient. Several sets of fraction were collected. The major set contained both the desired di- brominated product and a side product with tri-bromination. The mixture was concentrated and purified by chromatography on silica gel (120 g "gold" ISCO column, Hex/Et20 gradient) giving 8-bromo-4,5-bis(bromomethyl)quinoline. ]H NMR (400 MHz, CDC13) δ 9.02 (d, J = 5 Hz, 1H), 8.07 (d, J = 8 Hz, 1H), 7.53 (d, J = 5 Hz, 1H), 7.51 (d, J = 8 Hz, 1H), 5.166 (s, 2H), 5.166 (s, 2H).
9-bromo-4,6-dihydrothiopyrano[3,4,5-de]quinoline, monohydrate: A solution of 8-bromo-4,5-bis(bromomethyl)quinoline (5.30 g, 13.5 mmol) in DMF (28 mL) was cooled to 0 °C in an ice bath. A fresh solution of Na2S nonahydrate (3.72 g, 15.5 mmol) in DI H20 (28 mL) was added dropwise at 0 °C over 5 min. The reaction was kept at this temperature for another 15 min, then warmed to 23 °C. The reaction was stirred for 18 h. A significant precipitate had developed. At this point, the slurry was filtered. The solid was collected and washed with ice-cold DI water 2 x 30 mL, giving 9-bromo-4,6-dihydrothiopyrano[3,4,5-de]quinoline monohydrate. It was noted that vacuum drying did help remove some of the water of hydration, but in this case, the monohydrate was obtained. ]H NMR (400 MHz, CDC13) δ 8.95 (d, J = 5 Hz, 1H), 7.96 (d, J = 8 Hz, 1H), 7.27 (d, J = 5 Hz, 1H), 7.23 (d, J = 8 Hz, 1H), 4.140 (s, 2H), 4.140 (s, 2H), 1.61 (s, broad, 2H). LCMS ESI+ Calc'd for CnHBrNS (M+H)+: 266.0 / 268.0. Found 266.1 / 268.1 (M+H)+.
8-bromocyclopentadieno[l',2',3':de]quinoline: A 100 mL flask was charged with 9-bromo-4,6-dihydrothiopyrano[3,4,5-de]quinoline, monohydrate (2.04 g, 7.67 mmol) and glacial AcOH (15 mL). The solution was cooled to 0 °C and AcOOH (32% in dilute aq. AcOH, 1.82 mL) was added dropwise over 5 min. After 10 min, solid NaOAc (3.30 g, 38.4 mmol) was introduced. A solution of bromine (2.45 g, 15.3 mmol) in glacial AcOH (5.0 mL) was added to the reaction at 0 °C dropwise over 5 min. The reaction was warmed to 23 °C and stirred for 1.5 h. The reaction was then added over 5 min to a mixture of 10% w/v aq. NaHS03 (100 mL) and DCM (100 mL). After 2 h, solid KHCO3 (50 g) was portionwise (bubbling). The resulting slurry was filtered. The filtrate was transferred to a separatory funnel, and the organic phase was collected. The aqueous layer was extracted with 30 mL of DCM. The two organic layers were combined, dried (MgS04), and filtered. The resulting solution was treated with more 10% w/v aq NaHS03 (100 mL) and warmed to 40 °C. The organic phase was collected after 1 h. The remaining aq. phase was extracted with DCM (100 mL). The combined organic layers were dried (MgS04), filtered and transferred to a 250 mL pressure-equalizing addition funnel.
Separately, 20 grams of solid KOH pellets were treated with anhydrous MeOH (200 mL). To this solution was added pulverized activated neutral alumina (60 g). The methanol was removed at 50-100 mmHg with heating via rotary evaporation. The resulting damp powder was then quickly pulverized using a mortar and pestle and dried in a vacuum oven.
The pressure-equalizing funnel from earlier was attached to a flask containing DCM (90 mL) and t-BuOH (10 mL). To the pot was added 40 grams of the
aforementioned oven-dry KOH/ Alumina (1:3 w/w). The DCM solution in the addition funnel was added at -100 mL / h to the pot under N2. A series of color changes were observed, and after two hours the brown reaction was filtered. The filtrate was concentrated to -10 mL total volume and spiked with 10 mL of benzene. This solution was directly purified via chromatography on silica gel (80 g "gold" ISCO column; Hexane/EtOAc gradient) giving semipure product, which was again purified via chromatography on silica gel (40 g "gold" ISCO column; Hex→ 30% EtOAc / 70% hexane) giving 8-bromocyclopentadieno[l',2',3':de]quinoline. LCMS ESI+ Calc'd for CnH7BrN (M+H)+: 232.0, 234.0; Found 232.1, 234.1 (M+H)+; ]H NMR (400 MHz, CD3CN) δ 9.02 (d, J = 4.1 Hz, 1H), 7.94 (d, J = 7.6 Hz, 1H), 7.67 (d, J = 4.1 Hz, 1H), 7.55 (d, J = 7.6 Hz, 1H), 7.18 (d, J = 5.3 Hz, 1H), 7.04 (d, J = 5.3 Hz, 1H).
8,-bromo-quinolino[4',4a',5,:bc]-bicyclo[3.1.0]hex-2-ene: A beaker, visibly free of scratches, was charged with a smooth stirbar and 8- bromocyclopentadieno[l',2',3':de]quinoline (603 mg, 2.60 mmol). The setup was placed behind a blast shield. Diazomethane was prepared using 100 mL of a -0.13 M aqueous solution of Sodium 3-(N-Nitroso-N-Methyl-aminosulfonyl)-benzoate [see: Science 335, 1471 (2012), references therein, and supporting information], which was treated with Et20 (100 mL) followed by 50% w/v aq. KOH (100 mL) at 0 °C. After 10 min, the organic layer was decanted onto solid KOH pellets, and swirled gently for 5 min, then decanted. This solution of freshly prepared Diazomethane, (-0.13 M in Et20, 100 mL) was carefully added in one portion to the 8- bromocyclopentadieno[l',2',3':de]quinoline. Stirring was conducted until all solids dissolved. At this point, a freshly prepared solution of Palladium(II) Pivaloate (80 mg, 0.260 mmol) in Et20 (10 mL) was added to the reaction over a 2 min period. The reaction was gently stirred for 15 min, during which there was bubbling. Reaction was transferred to round-bottom flask (visibly free of scratches) and very carefully concentrated in vacuo. The crude residue was immediately dissolved in benzene and purified via chromatography on silica gel (40 g "gold" ISCO column; Hex→ 30% EtOAc / 70% hexane) giving 8,-bromo-quinolino[4',4a',5,:bc]-bicyclo[3.1.0]hex-2- ene in semipure form along with recovered 8- bromocyclopentadieno[l',2',3':de]quinoline. The semipure 8'-bromo- quinolino[4',4a',5':bc]-bicyclo[3.1.0]hex-2-ene was again treated with benzene and purified via chromatography on silica gel (40 g "gold" ISCO column; Hex→ 10% EtOAc / 90% hexane→ 30% EtOAc / 70% hexane) giving pure 8'-bromo- quinolino[4',4a',5':bc]-bicyclo[3.1.0]hex-2-ene. LCMS ESI+ Calc'd for Ci2H9BrN (M+H)+: 246.0, 248.0; Found 246.1, 248.1 (M+H)+; ]H NMR (400 MHz, CD3CN) δ
8.81 (d, J = 4.3 Hz, 1H), 7.86 (d, (J = 7.4 Hz, 1H), 7.44 (d, J = 4.3 Hz, 1H0, 7.34 (d, J = 7.4 Hz, 1H), 3.15 (ddd, J = 8.2, 8.2, 3.9 Hz, 1H), 3.13 (ddd, J = 8.2, 8.2, 3.9 Hz, 1H), 1.70 (ddd, J = 8.2, 8.2, 3.9 Hz, 1H), 0.91 (ddd, J = 3.9, 3.9, 3.9 Hz, 1H).
Example 2
Preparation of Compounds 1 and 2
Figure imgf000099_0001
2
(2S,4':8"aR)-ethyl 2-ieri-butoxy-2- (2S,4':8"aS)-ethyl 2-ieri-butoxy-2-
[4'-(quinolino[4",4a",5":bc]- [4'-(quinolino[4",4a",5":bc]- bicyclo[3.1.0]hex-2"'-ene-8"-yl)- bicyclo[3.1.0]hex-2"'-ene-8"-yl)- 2'-methylquinolin-3'-yl]acetate 2'-methylquinolin-3'-yl]acetate
(2S,4':8"aR)-ethyl 2-tert-butoxy-2-[4'-(quinolino[4",4a",5":bc]- bicyclo[3.1.0]hex-2"'-ene-8"-yl)-2'-methylquinolin-3'-yl]acetate and (2S,4':8"aS)-ethyl 2-tert-butoxy-2 4'<quinolino[4",4a",5":bc]-bicyclo[3.1.0]hex-2'"-ene-8"-yl)-2'- methylquinolin- 3 '-yl] acetate: A microwave tube was charged with 4,4,5, 5-tetramethyl- 2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (160 mg, 0.621 mmol), PdCl2(dppf) (7.5 mg, 10.4 μιηοΐ), and KOAc (204 mg, 2.07 mmol). The vessel was placed under vacuum, then backfilled with argon. A solution of 8'-bromo- quinolino[4',4a',5':bc]-bicyclo[3.1.0]hex-2-ene (A, 51 mg, 0.207 mmol) in dioxane (3.0 mL) was added, followed by a solution of glacial AcOH (13 μL·, 0.207 mmol) in dioxane (150 μί). The reaction was stirred at 23 °C for 2 min, then heated to 100 °C for 8 h. The reaction was stored in the dark at -20 °C overnight. The next day, the reaction was thawed and charged with (S)-ethyl 2-tert-butoxy-2-(4-iodo-2- methylquinolin-3-yl)acetate (132 mg, 0.311 mmol), K2CO3 (143 mg, 1.04 mmol), Pd(PPh3)4 (24 mg, 20.7 μιηοΐ), and H20 (750 μί). The reaction was resealed and heated to 100 °C for 40 min. After cooling to 23 °C, the reaction was treated with H20 (60 mL) and extracted with EtOAc (3 x 30 mL). Combined organic layers were dried (Na2S04), filtered, and concentrated to -500 μL· total volume. Benzene (500 μί) was added and the solution was purified via chromatography on silica gel (4 g "gold" ISCO column; EtOAc/hexane gradient) giving (2S,4':8"aR)-ethyl 2-tert-butoxy-2-[4'- (quinolino[4",4a",5":bc]-bicyclo[3.1.0]hex-2'"-ene-8"-yl)-2'-methylquinolin-3'- yljacetate. The compound is an -1:1 mixture of two cyclopropane epimers. LCMS ESI" Calc'd for C3oH3oN203 (M+H)+: 467.2; Found 467.3 (M+H)+, and (2S,4':8"aS)-ethyl 2- tert-butoxy-2 4'<quinolino[4",4a",5":bc]-bicyclo[3.1.0]hex-2'"-ene-8"-yl)-2'- methylquinolin-3'-yl]acetate. The compound is an -1:1 mixture of two cyclopropane epimers.LCMS ESI+ Calc'd for C3oH3oN203 (M+H)+: 467.2; Found 467.3 (M+H)+.
Example 3
Preparation of Compound 3
Figure imgf000100_0001
1
(2S,4' : 8"aR)-ethyl 2-t erf-butoxy-2- (2S,4':8"aR)-2-ferf-butoxy-2- [4'-(quinolino[4",4a",5":bc]- [4'-(quinolino[4",4a",5":bc]- bicyclo[3.1.0]hex-2"'-ene-8"-yl)- bicyclo[3.1.0]hex-2"'-ene-8"-yl)- 2'-methylquinolin-3'-yl]acetate 2'-methylquinolin-3'-yl]acetic acid
(2S,4':8"aR)-2-tert-butoxy-2-[4'-(quinolino[4",4a",5":bc]-bicyclo[3.1.0]hex-2"'- ene-8"-yl)-2'-methylquinolin-3'-yl]acetic acid: A microwave tube was charged with (2S,4':8"aR)-ethyl 2-tert-butoxy-2-[4'-(quinolino[4",4a",5":bc]-bicyclo[3.1.0]hex-2"'- ene-8"-yl)-2'-methylquinolin-3'-yl]acetate (all of the material from the reaction above, mixture of two cyclopropane epimers), LiOH monohydrate (62 mg, 1.5 mmol), THF (1.2 mL), EtOH (absolute, 500 μί), and H20 (500 μί). The vessel was sealed and heated to 100 °C for 2 h. The reaction was cooled to 23 °C and filtered (0.45 micron teflon filter). The filtrate was purified directly on a C- 18 Gemini column using a Gilson liquid handler (Eluent H20 / CH3CN gradient with both mobile phase components spiked 0.1% v/v with TFA). The title compound was obtained as a mono-trifluoroacetic acid salt. LCMS-ESI+: calc'd for C28H26N203: 439.2 (M+H+); Found: 439.3 (M+H+). ]H NMR (400 MHz, CD3OD) δ 8.59 (d, J = 5 Hz, 1H), 8.20 (d, J = 8 Hz, 1H), 8.01- 7.95 (m, 1H), 7.85-7.80 (m, 1H), 7.76-7.69 (m, 2H), 7.65-7.57 (m, 1H), 7.40 (d, J = 8 Hz, 0.5H), 7.22 (d, J = 8 Hz, 0.5H), 5.29 (s, 0.5H), 5.13 (s, 0.5H), 3.17 (s, 3H), 2.10-0.10 (m, 4H, multiple broad signals), 0.97 (s, 4.5H), 0.95 (s, 4.5H). 19F NMR (377 MHz, CD3OD) δ -53.2.
Example 4
Preparation of Compounds 4
Figure imgf000101_0001
(2 S,4': 8"aS)-ethyl 2-f eri-butoxy-2- (2S,4':8"aS)-2-ferf-butoxy-2- [4'-(quinolino[4",4a",5":bc]- [4'-(quinolino[4",4a",5":bc]- bicyclo[3.1.0]hex-2'"-ene-8"-yl)- bicyclo[3.1.0]hex-2'"-ene-8"-yl)- 2'-methylquinolin-3'-yl]acetate 2'-methylquinolin-3'-yl]acetic acid (2S,4':8"aS)-2-tert-butoxy-2-[4'-(quinolino[4",4a",5":bc]-bicyclo[3.1.0]hex-2"'- ene-8"-yl)-2'-methylquinolin-3'-yl]acetic acid: Prepared in a manner similar to
(2S,4':8"aR)-2-tert-butoxy-2-[4'-(quinolino[4",4a",5":bc]-bicyclo[3.1.0]hex-2'"-ene-8"- yl)-2'-methylquinolin-3'-yl]acetic acid except using (2S,4':8"aS)-ethyl 2-tert-butoxy-2- [4'<quinolino[4^4a^5":bc]-bicyclo[3.1 ]hex-2'"-ene-8"-yl)-2'-methylquinolin-3'- yljacetate as the starting material. LCMS-ESI+: calc'd for C28H26N2O3: 439.2 (M+H+); Found: 439.3 (M+H+). ]H NMR (400 MHz, CD3OD) δ 8.45 (d, J = 5 Hz, 1H), 8.04 (d, J = 8 Hz, 1H), 7.91-7.68 (m, 3H), 7.47 (d, J = 8 Hz, 1H), 7.36-7.28 (m, 1H), 7.13 (d, J = 8 Hz, -0.5 H). 6.98 (d, J = 8 Hz, 0.5H), 5.25 (s, 0.5H), 5.16 (s, 0.5H), 3.60-3.10 (m, 2H), 2.92 (s, 3H), 2.70-0.10 (m, 4H, many broad signals), 0.72 (s, 4.5H), 0.70 (s, 4.5H). 19F NMR (377 MHz, CD3OD) δ -52.9.
Example 5
Preparation of Compounds 5 and 6
Figure imgf000102_0001
(2S,4':l"aR,4"'S,5"'R)-2-tert-butoxy-2-[4'-(quinolino[4",4a",5":bc]- bicyclo[3.1.0]hex-2"'-ene-8"-yl)-2'-methylquinolin-3'-yl]acetic acid and
(2S,4':l"aR,4"¾,5'"S)-2-tert-butoxy-2-[4'-(quinolino[4^4a^5":bc]-bicyclo[3.1.0]hex- 2"'-ene-8"-yl)-2'-methylquinolin-3'-yl]acetic acid: (5 mg, mixture of 2 diastereomers above) in MeOH (1.0 rriL) was purified by a series of 100 μL· injections onto a ChiralPak AZ-H column (i.d. 10 mm, length 250 mm, 5 micron packing) (Eluent: Isocratic 20% EtOH / 80% supercritical C02, 10 min). 3 individual peaks were seen. Automated collection allowed for isolation of each of the 2 diasteromers above. Each diastereomer was isolated in the parent form. First peak to elute: (2S,4': l"aR,4"'R,5"'S)-2-tert-butoxy-2-[4'- (quinolino[4^4a^5":bc]-bicyclo[3.1 ]hex-2'"-ene-8"-yl)-2'-methylquinolin-3'-yl]acetic acid: LCMS-ESI+: calc'd for C28H26N2O3: 439.2 (M+H+); Found: 439.3 (M+H+). ]H NMR (400 MHz, CD3OD) δ 8.54-8.50 (m, 1H), 8.03 (d, J = 8 Hz, 1H), 7.77-7.50 (m, 4H), 7.36-7.29 (m, 1H), 7.16 (d, J = 8 Hz, 1H), 5.30-5.00 (s, broad, 1H), 2.97 (s, broad, 3H), 2.20-0.10 (m, 4H, multiple broad signals), 0.86 (s, 9H).
Last peak to elute: (2S,4':l"aR,4"'S,5"'R)-2-tert-butoxy-2-[4'- (quinolino[4",4a",5":bc]-bicyclo[3.1.0]hex-2'"-ene-8"-yl)-2'-methylquinolin-3'-yl]acetic acid: LCMS-ESI+: calc'd for C28H26N2O3: 439.2 (M+H+); Found: 439.3 (M+H+). ]H NMR (400 MHz, CD3OD) δ 8.54-8.46 (m, 1H), 8.02 (d, J = 8 Hz, 1H), 7.76-7.44 (m, 4H), 7.31-7.26 (m, 1H), 7.00 (d, J = 8 Hz, 1H), 5.30-5.00 (s, broad, 1H), 2.98 (s, broad, 3H), 2.20-0.10 (m, 4H, multiple broad signals), 0.83 (s, 9H).
Example 6
Preparation of Compound B
Figure imgf000103_0001
8-bromo-4,5-
8-bromo-5- 8-bromo-5- dimethylquinoline
(bromomethyl)-4- (bromomethyl)quinoline- methylquinoline 4-carbaldehyde
Figure imgf000103_0002
((8-bromo-4-
8-bromocyclopentadieno
formylquinolin-5- [1',2',3':cfe]quinoline 8'-bromo-quinolino[4',4a',5':bc]- yl)methyl)triphenylphos bicyclo[3.1.0]hex-2-ene phonium bromide
8-bromo-5-(bromomethyl)-4-methylquinoline: To a suspension of 8-bromo- 4,5-dimethylquinoline (9.00 g, 38.12 mmol) and N-bromosuccinimide (6.78 g, 38.12 mmol) in CC14 (300 mL) at reflux was added azoisobutyronitrile (0.313 g, 1.91 mmol). After refluxing for 3 hours, additional N-bromosuccinimide (0.678 g, 3.8 mmol) was added and the reaction was continued for one hour. The reaction was cooled to 23 °C, filtered, and concentrated. The residue was dissolved in CH2CI2 and adsorbed onto silica gel to produce a free-flowing solid that was loaded into an ISCO solid-load cartridge and purified by CombiFlash (120 g, 0 to 20% EtO Ac/Hex) to give a yellow- orange solid; (5.3 g, 44%). The filter cake was dissolved in CH2CI2 and purified as above to provide additional product (3.44 g, 29%). LCMS ESI+ Calc'd for CiiH10Br2N (M+H)+: 313.9, 315.9, 317.9; Found 314.0, 316.0, 318.0 (M+H)+; ]H NMR (400 MHz, CDCI3) δ 8.91 (d, J = 4.4 Hz, 1H), 8.01 (d, J = 7.6 Hz, 1H), 7.43 (d, J = 7.6 Hz, 1H), 7.35 (d, J = 4.4 Hz, 1H), 5.04 (s, 2H), 3.14 (s, 3H).
8-bromo-5-(bromomethyl)quinoline-4-carbaldehyde: To a solution of 8- bromo-5-(bromomethyl)-4-methylquinoline (5.3 g, 16.82 mmol) in anhydrous dioxane (100 mL) was added selenium dioxide (4.67 g, 42.06 mmol) in one portion and the reaction mixture was stirred at 90 °C. The reaction was monitored by LC/MS. After 2.0-3.0 hours, no 8-bromo-5-(bromomethyl)-4-methylquinoline was observed by LC/MS. The brown reaction mixture was cooled to room temperature and filtered through a pad of Celite, rinsing with ethyl acetate. The filtrate was concentrated and suspended in CH2CI2 containing MeOH, loaded onto an ISCO 120 g Gold column and purified (0 to 30% ethyl acetate/hex) to give the desired compound. LCMS ESI+ Calc'd for CnH8Br2NO (M+H)+: 327.9, 329.9, 331.9; Found 328.0, 330.0, 332.0 (M+H)+; ]H NMR (400 MHz, CDC13) δ 10.82 (s, 1H), 9.24 (d, J = 4.0 Hz, 1H), 8.10 (d, J = 8.0 Hz, 1H), 7.76 (d, J = 4.0 Hz, 1H), 7.571 (d, J = 8.0 Hz, 1H), 4.85 (s, 2H).
((8-bromo-4-formylquinolin-5-yl)methyl)triphenylphosphonium bromide: To a solution of 8-bromo-5-(bromomethyl)quinoline-4-carbaldehyde (1.50 g, 4.56 mmol) in anhydrous toluene (50 mL) was added triphenylphosphine (1.32 g, 5.01 mmol) in one portion. The reaction mixture was heated at 50 °C overnight to give a green mixture. LC/MS shows no 8-bromo-5-(bromomethyl)quinoline-4- carbaldehyde. The solid was collected by filtration, washed with toluene (10 mL) and dried under vacuum. LCMS ESI+ Calc'd for C29H22BrNOP (M)+: 510.1, 512.1. Found 510.2, 512.1 (M)+; ]H NMR (400 MHz, DMSO-d6) δ 10.06 (s, 1H), 9.17 (d, / = 4.1 Hz, 1H), 8.19 (d, 7 = 7.9 Hz, 1H), 7.84 (t, 7 = 7.4 Hz, 3H), 7.74 (d, 7 = 4.1 Hz, 1H), 7.70 - 7.47 (m, 9H), 7.19 (tt, / = 15.2, 7.4 Hz, 4H), 5.65 (d, / = 15.1 Hz, 2H). 8-bromocyclopentadiena[l',2',3':de]quinoline: To a green suspension of ((8- bromo-4-formylquinolin-5-yl)methyl)triphenylphosphonium bromide (2.25 g, 3.81 mmol) in anhydrous THF (20 mL) at 0 °C was carefully added 60% sodium hydride (0.183 g, 4.58 mmol). The reaction mixture was stirred for 5 minutes at 0°C, then the ice-bath was removed. After 45 minutes, the reaction turned into a yellow-brown solution. LC/MS showed only trace ((8-bromo-4-formylquinolin-5- yl)methyl)triphenylphosphonium bromide. The reaction mixture was diluted with ethyl acetate and washed with brine. The organic layer was dried (MgS04), filtered, concentrated and purified (ISCO 80 g Gold, 0 to 20% ethyl acetate/hex) to give the desired compound.
LCMS ES Calc'd for CnH7BrN (M+H)+: 232.0, 234.0; Found 232.1, 234.1 (M+H)+;
]H NMR (400 MHz, CDC13) δ 9.09 (d, J = 4.4 Hz, 1H), 7.88 (d, J = 7.2 Hz, 1H), 7.57 (d, J = 4.4 Hz, 1H), 7.44 (d, 7 = 7.2 Hz, 1H), 7.11 (d, 7 = 5.3 Hz, 1H), 6.95 (d, 7 = 5.3 Hz, 1H).
8,-bromo-quinolino[4',4a',5,:bc]-bicyclo[3.1.0]hex-2-ene: First, a solution of diazomethane was prepared: to a flask containing 50% w/v aq. potassium hydroxide (7.40 mL), dichloromethane (1.2 mL) and benzene (24 mL) at 0 °C was added 1- nitroso-l-methylurea portionwise over 5 minutes to give a bright yellow solution. The reaction mixture was stirred for 10 minutes, the organic layer was removed and dried over potassium hydroxide pellets for 2 hours.
To a nitrogen-sparged solution of 8- bromocyclopentadieno[l',2',3':de]quinoline (0.944 g, 4.07 mmol) was added palladium(II) pivalate (0.126 g, 0.407 mmol), followed by the dropwise addition of the diazomethane solution over 20 minutes. The dark brown reaction mixture was stirred for 40 minutes, stored in the freezer for 2 hours, warmed to room temperature, and concentrated. The residue was purified by CombiFlash (120 g, 0 to 20% EtO Ac/Hex) to give 8,-bromo-quinolino[4',4a',5,:bc]-bicyclo[3.1.0]hex-2-ene (0.536 g) and 8- bromocyclopentadieno[l',2',3':de]quinoline. LCMS ESI+ Calc'd for Ci2H9BrN (M+H)+: 246.0, 248.0; Found 246.1, 248.1 (M+H)+; 1H NMR (400 MHz, CDC13) δ 8.90 (d, J = 4.5 Hz, 1H), 7.84 (d, J = 7.4 Hz, 1H), 7.36 (d, J = 4.5 Hz, 1H), 7.28 (d, J = 7.3 Hz, 1H), 3.08 (dd, J = 8.1, 3.9 Hz, 2H), 1.69 (td, J = 8.1, 4.6 Hz, 1H), 0.97 (q, J = 4.1 Hz, 1H).
Example 7
Preparation of Compound C
Figure imgf000106_0001
8'-bromo-quinolino[4',4a',5':bc]- bicyclo[3.1 0]hex-2-ene quinolino[4',4a',5':bc]- bicyclo[3.1 0]hex-2-ene-8'-ylboronic acid, monotrifluoroacetic acid salt
Quinolino[4',4a',5':bc]-bicyclo[3.1.0]hex-2-ene-8'-ylboronic acid,
monotrifluoroacetic acid salt: A round-bottom flask was charged with 8'-bromo- quinolino[4',4a',5':bc]-bicyclo[3.1.0]hex-2-ene (0.2081 g, 0.846 mmol), potassium acetate (0.830 g, 8.46 mmol) and PdCl2(dppf) (0.031 g, 0.0423 mmol). The flask was flushed with nitrogen and anhydrous dioxane (12 mL) was added. After stirring the mixture for 5 minutes, acetic acid (0.053 mL, 0.931 mmol) was added. Reaction mixture was heated at 100°C for five hours, cooled to room temperature and concentrated. The residue was diluted with DMF, acidified with 3N HC1 to pH 5, filtered and the filtrate concentrated to ~8 mL. Purification by reverse phase HPLC (Gemini, 5 to 100% ACN/H20 + 0.1% TFA) and lyophilization provided impure product as a TFA salt (0.031 g). LCMS ESI+ Calc'd for Ci2HnBN02 (M+H)+: 212.0; Found 212.1 (M+H)+; ]H NMR (400 MHz, D20) δ 8.68 (d, / = 5.8 Hz, 1H), 8.16 (d, J = 7.1 Hz, 1H), 7.74 (d, 7 = 5.7 Hz, 1H), 7.61 (d, 7 = 7.1 Hz, 1H), 3.52 - 3.17 (m, 2H), 1.86 (dd, / = 13.3, 8.8 Hz, 1H), 1.22 (dd, / = 7.8, 3.9 Hz, 1H). The material was used in the next reaction without further purification. Example 8
Preparation of Compounds 7 and 8
Figure imgf000107_0001
quinolino[4',4a',5':bc]- (S)-ethy I 2
bicyclo[3.1.0]hex-2-ene-8'-ylboronic acid, (trifluorom
monotrifluoroaceti
Figure imgf000107_0002
8
(2S,4':8"aR)-ethyl 2-ieri-butoxy-2- (2S,4':8"aS)-ethyl 2-feri-butoxy-2- [4'-(quinolino[4",4a",5":bc]- [4'-(quinolino[4",4a",5":bc]- bicyclo[3.1.0]hex-2"'-ene-8"-yl)- bicyclo[3.1.0]hex-2"'-ene-8"-yl)- 2'-methylnapthalen-3'-yl]acetate 2'-methylnapthalen-3'-yl]acetate (2S,4':8"aS)-ethyl 2-tert-butoxy-2-[4'-(quinolino[4",4a",5":bc]- bicyclo[3.1.0]hex-2"'-ene-8"-yl)-2'-methylnapthalen-3'-yl]acetate and (2S,4':8"aR)-ethyl 2-tert-butoxy-2 4'<quinolino[4^4a^5":bc]-bicyclo[3.1.0]hex-2'"-ene-8"-yl)-2'- methylnapthalen-3'-yl]acetate: A mixture of quinolino[4',4a',5':bc]-bicyclo[3.1.0]hex-2- ene-8'-ylboronic acid, monotrifluoroacetic acid salt (15 mg, 0.046 mmol), (S)-ethyl 2- tert-butoxy-2-(3-methyl-l-(trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate (41 mg, 0.0923 mmol), chloro(2-dicyclohexylphosphino-2',6'-dimethoxy- 1 , 1 '-biphenyl)[2-(2- aminoethylphenyl)]palladium(II) (4.6 mg, 0.007 mmol) and cesium fluoride (33 mg, 0.184 mmol) in distilled DME (1.0 rriL) was sparged with nitrogen for five minutes. The mixture was heated in microwave at 110 °C for 30 minutes and stored in the freezer overnight.
A separate mixture of quinolino[4',4a',5':bc]-bicyclo[3.1.0]hex-2-ene-8'- ylboronic acid, monotrifluoroacetic acid salt (28.3 mg, 0.087 mmol), (S)-ethyl 2-tert- butoxy-2-(3-methyl-l-(trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate (98 mg, 0.218 mmol), chloro(2-dicyclohexylphosphino-2',6'-dimethoxy- 1 , 1 '-biphenyl) [2-(
2-aminoethylphenyl)]palladium(II) (8.8 mg, 0.13 mmol) and cesium fluoride (53 mg, 0.348 mmol) in distilled DME (1.0 mL) was sparged with nitrogen for five minutes. The mixture was heated in microwave at 110 °C for 30 minutes and stored at room temperature overnight.
The two reaction mixtures were combined, diluted with ethyl acetate and washed with brine. The aqueous layer was back-extracted with ethyl acetate. The combined organic layer was dried (MgS04), filtered, concentrated and purified by reverse phase HPLC (Gemini, 5 to 100% ACN/H20 + 0.1% TFA) and lyophilization provided a mixture of both atropisomers, each a 1 :1 mixture of cyclopropyl diastereomers. The mixture was diluted with ethyl acetate, washed with saturated sodium bicarbonate solution/brine and dried (MgS04) and filtered. Concentration and purification by CombiFlash (12 g, 0 to 30% EtOAc/Hex) gave each atropisomer as a 1:1 mixture of cyclopropyl diastereomers.
(2S,4':8"aR)-ethyl 2-tert-butoxy-2-[4'-(quinolino[4",4a",5":bc]- bicyclo[3.1.0]hex-2"'-ene-8"-yl)-2'-methylnapthalen-3'-yl]acetate: LCMS ESI+ Calc'd for C31H31NO3 (M+H)+: 466.6; Found 466.2 (M+H)+; ]H NMR (400 MHz, CD3OD) δ 8.42 (t, 7 = 5.0 Hz, 1H), 7.80 (d, 7 = 8.1 Hz, 1H), 7.76 (s, 1H), 7.58 (t, 7 = 7.3 Hz, 1H), 7.49 - 7.33 (m, 3H), 7.20 - 7.07 (m, 1H), 7.01 (d, / = 8.4 Hz, 0.5H), 6.89 (d, / = 8.5
Hz, 0.5H), 5.22 (s, 0.5H), 5.09 (s, 0.5H), 4.05 - 3.89 (m, 1H), 3.83 - 3.67 (m, 1H), 3.28 - 3.19 (m, 2H), 2.74 (s, 3H), 1.93 - 0.96 (m, 4H), 0.95 - 0.84 (m, 12H).
(2S,4':8"aS)-ethyl 2-tert-butoxy-2-[4'-(quinolino[4",4a",5":bc]- bicyclo[3.1.0]hex-2"'-ene-8"-yl)-2'-methylnapthalen-3'-yl]acetate:; LCMS ESI+ Calc'd for C31H31NO3 (M+H)+: 466.6; Found 466.2 (M+H)+.
Example 9
Preparation of Compounds 9 and 10
Figure imgf000109_0001
(2S,4':8"aS)-ethyl 2-ieri-butoxy-2- (2 S,4' :8"aS)-2-ieri-butoxy-2- [4'-(quinolino[4",4a",5":bc]- [4'-(quinolino[4",4a",5":bc]- bicyclo[3.1 .0]hex-2"'-ene-8"-yl)- bicyclo[3.1 .0]hex-2"'-ene-8"-yl)- 2'-methylnapthalen-3'-yl]acetate 2'-methylnapthalen-3'-yl]acetic acid
(2S,4':8"aR)-2-tert-butoxy-2-[4'-(quinoUno[4",4a",5":bc]-bicyclo[3.1.0]hex-2'"- ene-8"-yl)-2'-methylnapthalen-3'-yl]acetic acid: A solution of ethyl ester ( 4.5 mg, 0.0097 mmol) and 5M sodium hydroxide (39 μί) in methanol (0.1 mL) and THF (1.5 mL) was heated at 55 °C overnight. Reaction was cooled to room temperature, diluted with DMF (0.3 mL) and acetic acid (14 μί) was added. The mixture was concentrated to -0.3 mL, diluted with DMF/MeOH, filtered and purified by reverse phase HPLC (Gemini, 5 to 100% ACN/H20 + 0.1 % TFA). The product-containing fractions were pooled and lyophilized to give the desired compound. LCMS ESI+ Calc'd for
C29H28NO3 (M+H)+: 438.5; Found 438.2 (M+H)+; ]H NMR (400 MHz, CD3OD) ]H NMR (400 MHz, CD3OD) 8.61 (d, J = 5.6 Hz, 1H), 8.01 - 7.86 (m, 4H), 7.79 (d, J = 6.9 Hz, 0.5H), 7.74 (d, / = 6.5 Hz, 0.5H), 7.48 (dd, / = 13.3, 7.0 Hz, 1H), 7.26 (dt, / = 11.2, 7.8 Hz, 1H), 6.99 (d, / = 8.5 Hz, 0.5H), 6.82 (d, / = 8.6 Hz, 0.5H), 5.31 (s, 0.5H), 5.19 (s, 0.5H), 3.73 (dd, / = 5.1, 3.1 Hz, 1H), 3.66 - 3.57 (m, 1H), 2.78 (s, 1.5H), 2.77 (s, 1.5H), 2.14 (dd, / = 12.4, 8.1 Hz, 1H), 1.57 (dq, / = 20.5, 4.0 Hz, 1H), 0.90 (s, 4.5H), 0.88 (s, 4.5H).
(2S,4':8"aS)-2 ert-butoxy-2 4'-(quinolino[4",4a",5":bc]-bicyclo[3.1.0]hex-2'"- ene-8"-yl)-2'-methylnapthalen-3'-yl]acetic acid was prepared in a manner similar to (2S,4':8"aR)-2-tert-butoxy-2-[4'-(qm^^
yl)-2'-methylnapthalen-3'-yl]acetic acid except using (2S,4':8"aS)-ethyl 2-tert-butoxy-2- [4'-(quinolino[4",4a",5":bc]-bicyclo[3.1.0]hex-2'"-ene-8"-yl)-2'-methylnapthalen-3'- yljacetate as the starting material: LCMS ESI+ Calc'd for C291H28NO3 (M+H)+: 438.5; Found 438.2 (M+H)+.
Example 10
Figure imgf000111_0001
naptho[1',8a',8':bc]- acenaphthylene
bicyclo[3.1.0]hex-2-ene 1'-bromo-naptho[4',4a',5' bc]- -2-ene
Figure imgf000111_0002
15 12 14 13
(2S,4':1"a ,4"' ,5'"S)- (2S,4,:1"aR,4",Sl5",R)- (2S,4':1"aS,4l"R,5,"S)- (2S,4l:1"aS,4'"S,5'"R)- 2-ferf-butoxy-2-[4'-(naptho 2-ferf-butoxy-2-[4'-(naptho 2-ferf-butoxy-2-[4'-(naptho 2-ferf-butoxy-2-[4'-(naptho [4",4a",5":bc]-bicyclo[3.1.0] [4",4a",5":bc]-bicyclo[3.1.0] [4",4a",5":bc]-bicyclo[3.1.0] [4",4a",5":bc]-bicyclo[3.1.0] hex-2"'-ene-1 "-yl)-2'-methyl hex-2"'-ene-1"-yl)-2'-methyl hex-2"'-ene-1 "-yl)-2'-methyl hex-2'"-ene-1 "-yl)-2'-methyl quinolin-3'-yl]acetic acid quinolin-3'-yl]acetic acid quinolin-3'-yl]acetic acid quinolin-3'-yl]acetic acid
Figure imgf000112_0001
naptho[1 ',8a',8':bc]- acenaphthylene bicyclo[3.1.0]hex-2-ene naptho[l',8a',8':bc]-bicyclo[3.1.0]hex-2-ene: To a solution of acenaphthylene (12.0 g, 79 mmol, 1.0 eq) in benzene (750 mL) were added methylene iodide (19.7 mL, 65.4 g, 244 mmol, 3.1 eq), copper powder (22.4 g, 350 mmol, 4.4 eq) and I2 (1.0 g, 3.94 mmol, 0.05 eq). The mixture was refluxed under N2 for 48 h. Additional methylene iodide (65.4 g, 244 mmol, 3.1 eq) and copper powder (11.2 g, 175 mmol, 2.2 eq) were added, the reaction mixture were heated overnight. More methylene iodide (65.4 g, 244 mmol, 3.1 eq) was added, the reaction mixture was stirred under refluxed for 4 days. The reaction mixture was filtered through a pad of Celite, washed with hexane, and the filtrate was evaporated in vacuo to dryness, which was purified by silica gel chromatography column (hexane), and further recrystallized with EtOAc/hexane to give the title compound. ]H NMR (300 MHz, DMSO- ) δ 7.57-7.54 (m, 2H), 7.39-7.37 (m, 4H), 3.01 (dd, J = 3.9 and 7.8 Hz, 2 H), 1.52 (m, 1H), 0.78 (dd, J = 4.2 Hz, 1H).
Figure imgf000112_0002
naptho[1 ',8a',8':bc]- bicyclo[3.1.0]hex-2-ene 1 '-bromo-naptho[4',4a',5':bc]- bicyclo[3.1 .0]hex-2-ene
l'-bromo-naptho[4',4a,,5,:bc]-bicyclo[3.1.0]hex-2-ene: To a solution of naptho[l',8a',8':bc]-bicyclo[3.1.0]hex-2-ene (5.1 g, 30.7 mmol, 1.0 eq) in DMF (50 mL) at 0 oC was added NBS (5.56 g, 32.2 mmol, 1.05 eq) in five portions. The reaction mixture was warmed to room temperature slowly, stirred at rt overnight, poured into water. The reaction mixture was filtered, purified by silica gel chromatography column (hexane) to give the title compound. LC-MS: no observed. ]H NMR (400 MHz, CDC13) δ 7.72 (d, J = 4.4 Hz, 1H), 7.59 (d, J = 7.2 Hz, 1H), 7.47 (t, J= 7.2 Hz, 1H), 7.39 (d, J = 6.8 Hz, 1H), 7.20 (d, J = 7.6 Hz, 1H), 3.02 (m, 1H), 2.97 (m,lH), 1.53 (m, 1H), 0.80 (dd, J = 3.6 and 7.6 Hz, 1H).
Figure imgf000113_0001
(2S)-Ethyl 2-tert-butox -2-[4,-(naptho[4",4a",5":bc]-bic clo[3.1.0]hex-2,"- ene-l"-yl)-2'-methylquinolin-3'-yl]acetate: A microwave vessel was charged with - bromo-naptho[4',4a',5':bc]-bicyclo[3.1.0]hex-2-ene (100 mg, 0.408 mmol), bis- (pinacolato)diboron (114 mg, 0.449 mmol), Pd(PPh3)4 (47 mg, 41 μιηοΐ), and potassium acetate (132 mg, 1.35 mmol). The system was placed under a vacuum and backfilled with argon. Anhydrous dioxane (1.0 mL) was added. Reaction was heated in an oil bath to 110 °C (bath temperature). Reaction progress was very slow, so after 30 min the reaction was cooled to 23 °C. Under a stream of argon, PdCl2(dppf) (5.0 mg, 7.4 μιηοΐ) was added. The vessel was resealed and reheated to 110 °C (bath
temperature). After 16 h, the reaction was complete (HPLC analysis). The reaction was cooled to 23 °C. (S)-ethyl 2-tert-butoxy-2-(4-iodo-2-methylquinolin-3-yl)acetate (174 mg, 0.408 mmol), K2C03 (187 mg, 1.35 mmol), and H20 (500 μΓ) were introduced. The vessel was resealed and heated to 110 °C (oil bath temperature) for 2 h. Reaction was cooled to 23 °C and diluted with H20. The slurry was extracted with EtOAc (2x). Combined organic phases were dried (Na2S04), filtered, and concentrated. The residue was dissolved in benzene and purified on an ISCO 12 gram "gold" column (silica gel) via column chromatography (Eluent: Hexane/EtOAc gradient giving the title compound as a mixture of 4 diastereomers. One -half of the product mixture was carried onward. LCMS-ESI+: calc'd for C3iH3iN03: 466.2 (M+H+); Found: 466.2 (M+H+). ]H NMR (400 MHz, CDC13) δ 8.11-6.72 (m, 9H), 5.18-4.99 (4 lines, net 1H), 4.20-3.95 (m, 2H), 3.14-3.09 (m, 2H), 2.94-2.84 (4 lines, net 3H), 1.66-0.74 (m, 5H), 1.04-0.70 (4 lines, net 9H).
Figure imgf000114_0001
(2S)-ethyl 2-ierf-butoxy-2- 11
[4'-(naptho[4",4a",5":bc]-
(2S)-2-ferf-butoxy-2- bicyclo[3.1.0]hex-2"'-ene-1 "-yl
[4'-(naptho[4",4a",5":bc]- 2'-methylquinolin-3'-yl]acetate
bicyclo[3.1.0]hex-2"'-ene-1 "-yl)- 2'-methylquinolin-3'-yl]acetic acid
Compound 11: (2S)-2-tert-butoxy-2-[4'-(naptho[4",4a",5":bc]- bicyclo[3.1.0]hex-2'"-ene-l"-yl)-2,-methylquinolin-3,-yl]acetic acid: A microwave vessel was charged with one-half of the material from the previous reaction above ((2S)-Ethyl 2-tert-butoxy-2-[4,-(naptho[4",4a",5":bc]-bicyclo[3.1.0]hex-2,"-ene- l"-yl)-2'-methylquinolin-3'-yl]acetate, mixture of 4 diastereomers), LiOH monohydrate (150 mg), THF (2 mL), EtOH (absolute, 1 mL), and H20 (1 mL). The vessel was sealed and heated to 60 °C for 60 h. The reaction was incomplete. The system was heated to 100 °C for 2 h and reached completion (HPLC analysis). The reaction was cooled to 23 °C and filtered through a 0.45 micron Teflon® plug filter. The filtrate was purified directly on a C- 18 Gemini column using a Gilson liquid handler (Eluent H20 / C¾CN gradient with both mobile phase components spiked 0.1% v/v with TFA). The title compound was obtained as a mono-trifluoroacetic acid salt. LCMS-ESI+: calc'd for C29H27N03: 438.2 (M+H+); Found: 438.3 (M+H+). ]H NMR (400 MHz, CD3OD) δ 8.21-6.66 (m, 9H), 5.36-5.09 (4 lines, net 1H), 3.22-3.17 (m, 2H), 3.15-3.09 (3 lines, net 3H). 1.73-1.64 (m, 1H), 1.01-0.71 (4 lines, net 9H), 0.91-0.67 (m, 1H). 19F NMR (377 MHz, CDC13) δ -45.0.
Figure imgf000115_0001
(2S,4':1"a ,4"' ,5"'S)- (2S,4':1"aR,4"'S,5"'R)- (2S,4':1"aS,4"'R,5"'S)- (2S,4':1"aS,4"'S,5"'R)-
2-ferf-butoxy-2-[4'-(naptho 2-ferf-butoxy-2-[4'-(naptho 2-ferf-butoxy-2-[4'-(naptho 2-fert-butoxy-2-[4'-(naptho
[4",4a",5":bc]-bicyclo[3.1.0] [4",4a",5":bc]-bicyclo[3.1.0] [4",4a",5":bc]-bicyclo[3.1.0] [4",4a",5":bc]-bicyclo[3.1.0] ex-2"'-ene-1"-yl)-2'-methyl hex-2"'-ene-1"-yl)-2'-methyl hex-2"'-ene-1"-yl)-2'-methyl hex-2"'-ene-1"-yl)-2'-methyl quinolin-3'-yl]acetic acid quinolin-3'-yl]acetic acid quinolin-3'-yl]acetic acid quinolin-3'-yl]acetic acid
Isolation of Compound 15: (2S,4,:Γ,aR,4,"R,5,"S)-2-tert-butoxy-2-[4,- (naptho[4",4a",5":bc]-bicyclo[3.1.0]hex-2'"-ene-l"-yl)-2,-methyl quinolin-3'- yl]acetic acid,
Compound 12: ^S^r'aR^'S^'R^-tert-butoxy^-^'- (naptho[4",4a",5":bc]-bicyclo[3.1.0] hex-2'"-ene-l"-yl)-2'-methyl quinolin-3'- yl]acetic acid, Compound 14: ^S^r'aS^'R^'S^-tert-butoxy^-^'-
(naptho[4",4a",5":bc]-bicyclo[3.1.0]hex-2'"-ene-l"-yl)-2'-methyl quinolin-3'- yl]acetic acid, and
Compound 13: (2S,4,:l"aS,4,"S,5,"R)-2-tert-butoxy-2-[4,-(naptho
[4",4a",5":bc]-bicyclo[3.1.0]hex-2'"-ene-l"-yl)-2'-methyl quinolin-3'-yl]acetic acid via supercritical C02 Chromatography: A solution of (2S)-2-tert-butoxy-2-[4'- (naptho[4",4a",5":bc]-bicyclo[3.1.0]hex-2'"-ene-l"-yl)-2,-methylquinolin-3'- yl]acetic acid (10 mg, mixture of 4 diastereomers above) in MeOH (10 mL) was purified by a series of 100 μL· injections onto a ChiralPak IC column (i.d. 10 mm, length 250 mm, 5 micron packing) (Eluent: Isocratic 12.5% MeOH / 87.5%
supercritical C02, 10 min). 4 individual peaks were seen. Automated collection allowed for isolation of each of the 4 diasteromers above. Each diastereomer was isolated in the parent form.
lst peak to elute: Compound 12: (2S,4':l"aR,4"'S,5"'R)-2-tert-butoxy-2-[4'- (naptho[4",4a",5":bc]-bicyclo[3.1.0]hex-2"'-ene-l"-yl)-2'-methyl quinolin-3'-yl]acetic acid: LCMS-ESI+: calc'd for C29H27NO3: 438.2 (M+H+); Found: 438.3 (M+H+). ]H NMR (400 MHz, CD3CN) δ 7.99 (d, J = 8.2 Hz, IH), 7.68-7.64 (m, IH), 7.51 (d, J = 7.0 Hz, IH), 7.39 (d, J = 7.0 Hz, IH), 7.30-7.17 (m, 3H), 7.14 (d, J = 8.6 Hz, IH), 6.90 (d, J = 8.2 Hz, IH), 5.16 (s, IH), 3.15 (dd, J = 8.0, 3.9 Hz, IH), 3.15 (dd, J = 8.0, 3.9 Hz, IH), 2.86 (s, 3H), 1.63 (ddd, J = 8.0, 8.0, 3.9 Hz, IH), 0.94 (s, 9H), 0.82 (ddd, J = 3.9, 3.9, 3.9 Hz, IH).
2st peak to elute: Compound 13: (2S,4':l"aS,4"'S,5"'R)-2-tert-butoxy-2-[4'- (naptho[4",4a",5":bc]-bicyclo[3.1.0]hex-2"'-ene-l"-yl)-2'-methyl quinolin-3'-yl] acetic acid: LCMS-ESI+: calc'd for C29H27NO3: 438.2 (M+H+); Found: 438.3 (M+H+). ]H NMR (400 MHz, CD3CN) δ 7.97 (d, J = 8.2 Hz, IH), 7.68-7.60 (m, 2H), 7.37 (d, J = 7.0 Hz, IH), 7.28-7.11 (m, 3H), 6.98-6.94 (m, IH), 6.68 (d, J = 8.2 Hz, IH), 5.21 (s, IH), 3.16-3.13 (m, 2H), 2.78 (s, 3H), 1.64 (ddd, J = 8.0, 8.0, 4.0 Hz, IH), 0.90-0.88 (m, IH), 0.68 (s, 9H).
3st peak to elute: Compound 14: (2S,4':l"aS,4"'R,5"'S)-2-tert-butoxy-2-[4'- (naptho[4",4a",5":bc]-bicyclo[3.1.0]hex-2"'-ene-l"-yl)-2'-methyl quinolin-3'-yl] acetic acid: LCMS-ESI+: calc'd for C29H27NO3: 438.2 (M+H+); Found: 438.3 (M+H+). ]H NMR (400 MHz, CD3CN) δ 7.99 (d, J = 8.6 Hz, IH), 7.68-7.61 (m, 2H), 7.57-7.07 (m, 4H), 7.38 (d, 7.6 Hz, IH), 6.69 (d, J = 8.6 Hz, IH), 5.37 (s, IH), 3.16-3.13 (m, 2H), 2.78 (s, 3H), 1.65 (ddd, J = 8.0, 8.0, 3.9 Hz, IH), 0.88-0.84 (m, IH), 0.72 (s, 9H).
4st peak to elute: Compound 15: (2S,4':l"aR,4"'R,5"'S)-2-tert-butoxy-2-[4'- (naptho[4",4a",5":bc]-bicyclo[3.1.0]hex-2"'-ene-l"-yl)-2'-methyl quinolin-3'-yl] acetic acid: LCMS-ESI+: calc'd for C29H27NO3: 438.2 (M+H+); Found: 438.3 (M+H+). ]H NMR (300 MHz, CD3CN) δ 7.97 (d, J = 8.2 Hz, IH), 7.67-7.62 (m, IH), 7.49 (d, J = 7.0 Hz, IH), 7.38-7.33 (m, IH), 7.29-7.13 (m, 3H), 6.96-6.85 (m, 2H), 5.21 (s, IH), 3.14 (dd, J = 8.2, 3.5 Hz, IH), 3.14 (dd, J = 8.2, 3.5 Hz, IH), 2.85 (s, 3H), 1.63 (ddd, J = 8.2, 8.2, 3.5 Hz, IH), 0.89 (s, 9H), 0.78 (ddd, J = 3.5, 3.5, 3.5 Hz, IH). ANTIVIRAL ASSAY
Example 10
Antiviral Assays in MT4 Cells
For the antiviral assay utilizing MT4 cells, 0.4 μL· of 189X test concentration of
3-fold serially diluted compound in DMSO was added to 40 μL· of cell growth medium (RPMI 1640, 10% FBS, 1% penicilline/Streptomycine, 1% L-Glutamine, 1% HEPES) in each well of 384- well assay plates (10 concentrations) in quidruplicate.
1 mL aliquots of 2 x 106 MT4 cells are pre-infected for 1 and 3 hours respectively at 37 °C with 25 μΕ (MT4) or of either cell growth medium (mock- infected) or a fresh 1 :250 dilution of an HIV-IIIb concentrated ABI stock (0.004 m.o.i. for MT4 cells). Infected and uninfected cells are diluted in cell growth medium and 35 μΕ of 2000 (for MT4) cells is added to each well of the assay plates.
Assay plates were then incubated in a 37 °C incubator. After 5 days of incubation, 25 μΕ of 2X concentrated CellTiter-Glo™ Reagent (catalog # G7573, Promega Biosciences, Inc., Madison, WI) was added to each well of the assay plate. Cell lysis was carried out by incubating at room temperature for 2-3 minutes, and then chemiluminescence was read using the Envision reader (PerkinElmer).
Compounds of the present invention demonstrate antiviral activity in this assay as depicted in Table 1 below. Accordingly, the compounds of the invention may be useful for treating the proliferation of the HIV virus, treating AIDS, or delaying the onset of AIDS or ARC symptoms.
Table 1
Figure imgf000118_0001
All of the U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications and non-patent publications referred to in this specification are incorporated herein by reference, in their entirety to the extent not inconsistent with the present description.
From the foregoing it will be appreciated that, although specific embodiments of the invention have been described herein for purposes of illustration, various modifications may be made without deviating from the spirit and scope of the invention. Accordingly, the invention is not limited except as by the appended claims.

Claims

We claim:
1. A compound of formula I:
Figure imgf000119_0001
I or a pharmaceutically acceptable salt thereof, wherein: V is N or CH;
R3 is (Ci-C6)alkyl, (C2-C6)alkenyl, (C3-C6)cycloalkyl, (Ci-C6)-alkyl-(C3-C6)cycloalkyl or -0(Ci-C6)alkyl, -0-(C3-C6)cycloalkyl wherein any (C C6)alkyl, (C2-C6)alkenyl, (C3- C6)cycloalkyl, (Ci-C6)-alkyl-(C3-C6)cycloalkyl or -0(C C6)alkyl, -0-(C3-C6)cycloalkyl of R3 is optionally substituted with one to three groups selected from the group consisting of -0(Ci-C6)alkyl, halo, oxo and -CN;
D is (C6-C12) aryl, (C5-Cio)carbocycle, 5-10-membered heterocycle, or 5-10-membered heteroaryl, wherein any (C6-Ci2) aryl, (C5-Cio)carbocycle, 5-10-membered heterocycle, or 5-10- membered heteroaryl of D is substituted by R2; wherein any (C6-Ci2) aryl, (C5-Cio)carbocycle, 5-10-membered heterocycle, or 5-10- membered heteroaryl of D is optionally substituted by R5, R6, R7, R8 and R12;
R2 is H, oxo, halo ,(C C6)alkyl or -0(C C6)alkyl;
R5, R6, R7, R8 and R12 are each independently: a) R11, -C(=0)-Rn, -C(=0)-0-Rn, -O-R11, -S-R11, -S(0)-Rn, -S02-Rn, -(Ci-C6)alkyl-Rn,
Figure imgf000119_0002
-(Ci-C6)alkyl-C(=0)-0-Rn, -(Ci-C6)alkyl-0-Rn, -(Ci-C6)alkyl-S-Rn, -(Ci-C6)alkyl-S(0)-Rn or
-(CrC6)alkyl-S02-Rn, wherein each R11 is independently H, (Ci-C6)alkyl, (C2-C6)alkenyl, (C2-
C6)alkynyl, (C C6)haloalkyl, (C3-C7)carbocycle, (C6-Ci2)aryl, 5-12- membered heterocycle or 5-12-membered heteroaryl, wherein any (C6- C]2)aryl, 5-12-membered heterocycle and 5-12-membered heteroaryl of R11 are each optionally substituted with one to three Z1 groups; or b) -N(R9)R10, -C(=0)-N(R9)R10, -0-C(=0)-N(R9)R10, -S02-N(R9)R10, -(C C6)alkyl-N(R9)R10,
Figure imgf000120_0001
N(R9)R10, or -(Ci-C6)alkyl-S02-N(R9)R10, wherein each R9 is independently H, (Ci-C6)alkyl or (C3-C7)cycloalkyl; and wherein each R10 is independently H, (Ci-C6)alkyl, (C2-C6)alkenyl, (C2-
C6)alkynyl, (C C6)haloalkyl, (C3-C7)carbocycle, (C6-Ci2)aryl, 5-12- membered heterocycle or 5-12-membered heteroaryl, wherein any (C6- C]2)aryl, 5-12-membered heterocycle and 5-12-membered heteroaryl of R10 are each optionally substituted with one to three Z1 groups; or c) -(Ci-C6)alkyl-0-(Ci-C6)alkyl-(C3-C7)carbocycle,
-(Ci-C6)alkyl-S-(Ci-C6)alkyl-(C3-C7)carbocycle,
-(Ci-C6)alkylS(0)-(Ci-C6)alkyl-(C3-C6)carbocycle,
-(CrC6)alkylS02(CrC6)alkyl-(C3-C7)carbocycle,
-(C2-C6)alkenyl-(C C6)haloalkyl, -(C2-C6)alkynyl-(C C6)haloalkyl, -(C3- C7)halocarbocycle, -NRaS02NRcRd, -NRaS020(C3-C7)carbocycle,
-NRaS020(C6-Ci2)aryl, -(C2-C6)alkenyl-(C3-C7)carbocycle, -(C2-C6)alkenyl- (C6-Ci2)aryl, -(C2-C6)alkenyl-heteroaryl, -(C2-C6)alkenyl-heterocycle,
-(C2-C6)alkynyl-(C3-C7)carbocycle, -(C2-C6)alkynyl-(C6-Ci2)aryl,
-(C2-C6)alkynyl-heteroaryl, -(C2-C6)alkynyl-heterocycle, -(C3-C7)carbocycle-Z1 or -(Ci-C6)haloalkyl-Z3, wherein any (Ci-C6)alkyl, (Ci-C6)haloalkyl, (C3-C7)carbocycle, (C2-C6)alkenyl, (C2-C6)alkynyl, (C6-Ci2)aryl or heteroaryl, either alone or as a group is optionally substituted with one to three Z1 groups; and wherein any heteroaryl or heterocycle is a 5-12 membered heteroaryl or a 5-12 membered heterocycle; or d) -NReRf, -C(0)NReRf, -OC(0)NReRf, -S02NReRf, -(Ci-C6)alkyl-NReRf, -(Ci-C6)alkylC(0)-NReRf, -(Ci-C6)alkyl-0-C(0)-NReRf or -(C C6)alkyl- S02NReRf; wherein each (Ci-C6)alkyl is independently substituted with one to three Z6 groups and optionally substituted with one to three Z1 groups; or e) oxo; and each Z1 is independently halo, -N02, -OH, =NORa, -SH, -CN, (C C6)alkyl, (C2- C6)alkenyl, (C2-C6)alkynyl, (C C6)haloalkyl, (C3-C7)carbocycle, (C3- C7)halocarbocycle, (C6-Ci2)aryl, heteroaryl, heterocycle, -0(Ci-C6)alkyl, -0(C2- C6)alkenyl, -0(C2-C6)alkynyl, -0(C C6)haloalkyl, -0(C3-C7)carbocycle, -0(C3- C7)halocarbocycle, -0-(C6-Ci2)aryl, -Oheteroaryl, -Oheterocycle, -S(Cr C6)alkyl, -S(C2-C6)alkenyl, -S(C2-C6)alkynyl, -S(C C6)haloalkyl, -S(C3- C7)carbocycle, -S(C3-C7)halocarbocycle, -S-(C6-Ci2)aryl, -Sheteroaryl, - Sheterocycle, -S(0)(C C6)alkyl, -S(0)(C2-C6)alkenyl, -S(0)(C2-C6)alkynyl, -S(0)(C C6)haloalkyl, -S(O) (C3-C7)carbocycle, -S(0)(C3-C7)halocarbocycle, -S02(CrC6)alkyl, -S(O)- (C6-C12)aryl, -S(0)carbocycle, -S(0)heteroaryl, - S(0)heterocycle, -S02(C2-C6)alkenyl, -S02(C2-C6)alkynyl, -S02(C
C6)haloalkyl, -S02(C3-C7)carbocycle, -S02(C3-C7)halocarbocycle, -S02-(C6- Ci2)aryl, -S02heteroaryl, -S02heterocycle, -S02NRcRd, -NRcRd, -NRaC(0)Ra, - NRaC(0)ORb, -NRaC(0)NRcRd -NRaS02Rb, -NRaS02NRcRd, -NRaS020(C3- C7)carbocycle, -NRaS020-(C6-Ci2)aryl, -OS(0)2Ra, -C(0)Ra, -C(0)ORb, -C(0)NRcRd, or -OC(0)NRcRd, wherein any (Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, -(C3-
C7)halocarbocycle, (C3-C7)carbocycle, (C3-C7)halocarbocycle, (C6- Ci2)aryl, heteroaryl or heterocycle of Z1, either alone or as part of a group, is optionally substituted with one to three halogen, -OH, -ORb, -CN, -RH2, -NRcRd -NRaC(0)2Rb, -heteroaryl, -heterocycle,
-Oheteroaryl, -Oheterocycle, -NHheteroaryl, -NHheterocycle or -S(0)2NRcRd; and wherein any heteroaryl or heterocycle of Z1 is a 5-12 membered heteroaryl or a 5-12 membered heterocycle; and each Z3 is independently -N02, -CN, -OH, oxo, =NORa, thioxo, (C6-Ci2)aryl, 5- 12 membered heterocycle, 5-12 membered heteroaryl, (C3-C7)halocarbocycle, -0(C C6)alkyl, -0(C3-C7)carbocycle, -0(C3-C7)halocarbocycle, -0-(C6- Ci2)aryl, -Oheterocycle, -Oheteroaryl, -S(Ci-C6)alkyl, -S(C3-C7)carbocycle, -S(C3-C7)halocarbocycle, -S-(C6-Ci2)aryl, -Sheterocycle, -Sheteroaryl, -S(0)(Ci-C6)alkyl, -S(0)(C3-C7)carbocycle, -S(O) (C3-C7)halocarbocycle, -S(O)- (C6-Ci2)aryl, -S(0)heterocycle, -S(0)heteroaryl, -S02(C C6)alkyl, -S02(C3-C7)carbocycle, -S02(C3-C7)halocarbocycle, S02-(C6-Ci2)aryl, -S02heterocycle, -S02heteroaryl, -NRaRb, -NRaC(0)Rb, -C(0)NRcRd, - S02NRcRd, -NRaS02NRcRd, -NRaS020(C3-C7)carbocycle or -NRaS020-(C6- Ci2)aryl, wherein any heteroaryl or heterocycle of Z3 is a 5-12 membered heteroaryl or a 5-12 membered heterocycle; and each Ra, Rb, Rc and Rd is independently H or (Ci-C6)alkyl, (C2-C6)alkenyl, (C2- C6)alkynyl, (C3-C7)carbocycle, heterocycle, (C6-Ci2)aryl, (C6-Ci2) aryl(d- C6)alkyl-, heteroaryl or heteroaryl(Ci-C6)alkyl-, wherein any (Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C7)carbocycle, heterocycle, (C6-Ci2)aryl, or heteroaryl of Ra, Rb, Rc and Rd, either alone or as part of a group, is optionally substituted with one to three halogen, OH or cyano; or Rc and Rd together with the nitrogen to which they are attached form a 5-12 membered heterocycle, wherein any heterocycle of Rc and Rd together with the nitrogen to which they are attached is optionally substituted with one to three halogen, OH, cyano, or -RH2; wherein any heteroaryl or heterocycle of Ra, R , Rc and R<j is a 5-12 membered heteroaryl or a 5-12 membered heterocycle; and each Re is independently H, -ORa, (Ci-C6)alkyl or (C3-C7)carbocycle,
(C2-C6)haloalkyl, (C2-C6)alkenyl and (C2-C6)alkynyl, (C6-Ci2)aryl, 5-12 membered heterocycle or 5-12 membered heteroaryl; wherein (Ci-C6)alkyl and (C3-C7)carbocycle of Re are each independently
substituted with one to three Z6 groups and optionally substituted with one o three Z1 groups; wherein any (C2-C6)haloalkyl, (C2-C6)alkenyl or (C2-C6)alkynyl of Re is
optionally substituted with one to three Zi groups; wherein any (C6-Ci2)aryl, 5-12 membered heterocycle or 5-12 membered
heteroaryl of Re are each independently substituted with one to three Z5 groups; and each Rf is independently H, -Rg, -ORa, -(C C6)alkyl-Z6, -S02Rg, -C(0)Rg, C(0)ORg or -C(0)NReRg; and each Rg is independently H, (Ci-C6)alkyl, (C3-C7)carbocycle (Ci-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C6-Ci2)aryl, 5-12 membered heterocycle or 5- 12 membered heteroaryl, wherein any (Ci-C6)alkyl, (C3-C7)carbocycle -(Ci-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C6-Ci2)aryl, 5-12 membered heterocycle or 5-12 membered heteroaryl of Rg is optionally substituted with one to three Zi groups; and each Z5 is independently -N02, -CN, -NRaS02NRcRd, -NRaS020(C3- C7)carbocycle, -NRaS020-(C6-Ci2)aryl, -NRaS02(C C6)alkyl, -NRaS02(C2- C6)alkenyl, -NRaS02(C2-C6)alkynyl, -NRaS02(C3-C7)carbocycle, -NRaS02(C3- C7)halocarbocycle, -NRaS02-(C6-Ci2)aryl, -NRaS02heteraryl, - NRaS02heteroaryl, -NRaS02heterocycle, -NRaC(0)alkyl, -NRaC(0)alkenyl, -NRaC(0)alkynyl, -NRaC(0) (C3-C7)carbocycle, -NRaC(0)(C3- C7)halocarbocycle, -NRaC(0)- (C6-Ci2)aryl, -NRaC(0)heteroaryl,
-NRaC(0)heterocycle, -NRaC(0)NRcRd or -NRaC(0)ORb, wherein any heteroaryl or heterocycle of Z5 is a 5-12 membered heteroaryl or a 5-12 membered heterocycle; and each Z6 is independently -N02, -CN, -NRaRa, NRaC(0)Rb,-C(0)NRcRd, (C3- C7)halocarbocycle, (C6-Ci2)aryl, heteroaryl, heterocycle, -0-(C6-Ci2)aryl, -Oheteroaryl, -Oheterocycle, -0(C3-C7)halocarbocycle, -0(Ci-C6)alkyl, -0(C3- C7)carbocycle, -0(Ci-C6)haloalkyl, -S-(C6-Ci2)aryl, -Sheteroaryl, -Sheterocycle, -S(C3-C7)halocarbocycle, -S(C C6)alkyl, -S(C3-C7)carbocycle, -S(C
C6)haloalkyl, -S(O)- (C6-Ci2)aryl, -S(0)heteroaryl, -S(0)heterocycle, -S(0)(C3- C7)halocarbocycle, -S(0)(C C6)alkyl, -S(0)(C3-C7)carbocycle, -S(0)(C C6)haloalkyl, -S02-(C6-Ci2)aryl, -S02heteroaryl, -S02heterocycle, -S02(C C6)alkyl, -S02(C C6)haloalkyl, -S02(C3-C7)carbocycle, -S02(C3- C7)halocarbocycle, -S02NRcRd, -NRaS02(C3-C7)halocarbocycle, -NRaS02(C6- Ci2)aryl, -NRaS02heteraryl, -NRaS02heteroaryl, -NRaS02NRcRd,
-NRaS020(C3-C7)carbocycle or -NRaS020-(C6-Ci2)aryl, wherein any aryl of Z6, either alone or as part of a group, is optionally
substituted with one to three halogen, -OH, -0(Ci-C6)alkyl, -CN, NH2, or -(Ci-C6)alkyl, and wherein any heteroaryl or heterocycle of Z6 is a 5-12 membered heteroaryl or a 5-12 membered heterocycle.
2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein D is monocyclic, bicyclic or tricyclic (C6-Ci2) aryl' monocyclic, bicyclic or tricyclic (C5-Cio)carbocycle; 5-10-membered monocyclic, bicyclic or tricyclic heterocycle; or 5-10-membered monocyclic, bicyclic or tricyclic heteroaryl.
3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein D is phenyl, pyridyl, pyrimidinyl, naphthyl, quinolinyl, benzthiazolyl, indazolyl, thienopyridinyl, pyrazolopyridinyl, pyrazolopyrimidinyl,
pyranothienopyridinyl, pyrimidoindazolyl, cyclopentaquinolinyl, 6,7,8,9- tetrahydrobenzoquinolinyl, 7,8,9, 10-tetrahydrobenzoquinolinyl, pyrroloimidazopyridinyl, 6,7,8,9-tetrahydroimidazodipyridinyl, or
benzothieno[3,2:b]pyridinyl.
4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein D is phenyl, pyridyl, pyrimidinyl, naphthyl, quinolinyl, or benzthiazolyl.
5. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein D is naphthyl or quinolinyl.
6. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein R3 is -0(Ci-C6)alkyl optionally substituted with one to three groups selected from the group consisting of halo and -CN.
7. The compound of any one of claims 1-5 wherein R3 is -OC(CH3)3.
8. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein D is substituted with R2 and R5, R6, R7, R8 and R12 are hydrogen.
9. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt thereof, wherein R2 is halo, H or -CH3.
10. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt thereof, wherein R2 is -CH3.
11. The compound of any one of claims 1-10 wherein R5, R6, R7, R8 and R12 are each independently: a) R11, -C(=0)-Rn, -C(=0)-0-Rn or -O-R11, wherein each R11 is independently H, (C C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C C6)haloalkyl, (C3- C7)carbocycle, (C6-Ci2)aryl, 5-10-membered heterocycle or 5-10-membered heteroaryl, wherein (C6-Ci2)aryl, 5-10-membered heterocycle and 5-10-membered heteroaryl are each optionally substituted with one to three Z11 groups; b) -N(R9)R10 and -C(=0)-N(R9)R10, wherein each R9 is independently H, (C C6)alkyl or (C3-C7)cycloalkyl, and each R10 is independently R11, -(Ci-C6)alkyl-Rn, -S02-Rn, -C(=0)-Rn, -C(=0)ORn or -C(=0)N(R9)Rn, wherein each R11 is independently H, (C C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C C6)haloalkyl, (C3- C7)cycloalkyl, (C6-Ci2)aryl, 5-10-membered heterocycle or 5-10-membered heteroaryl; c) -(C2-C6)alkynyl-(C3-C7)carbocycle, wherein
-(C2-C6)alkynyl-(C3-C7)carbocycle is optionally substituted with one to three Z1 groups; or d) -NReRf and-C(0)NReRf.
12. The compound of any one of claims 1-10 wherein R5, R6, R7, R8 and R12 are each independently: a) H, (Ci-C6)alkyl, (Ci-C6)haloalkyl, (C3-C7)carbocycle, heterocycle, -C(=0)-Rn, -C(=0)-0-Rn or -O-R11, wherein heterocycle is optionally substituted with one to three Z11 groups and wherein each R11 is independently H, (Ci-C6)alkyl, (C2- C6)alkenyl, (C2-Ce)alkynyl, (Ci-C6)haloalkyl, (C3-C7)carbocycle, (C6-Ci2)aryl, heterocycle or heteroaryl, wherein (C6-Ci2)aryl, 5-10-membered heterocycle and 5-10- membered heteroaryl are each optionally substituted with one to three Z11 groups; b) -N(R9)R10 or -C(=0)-N(R9)R10, wherein each R9 is independently H, (C C6)alkyl or (C3-C7)cycloalkyl, and each R10 is independently R11, -(Ci-C6)alkyl-Rn, - S02-Rn, -C(=0)-Rn, -C(=0)ORn or -C(=0)N(R9)Rn; wherein each R11 is
independently H, (C C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C C6)haloalkyl, (C3- C7)cycloalkyl, (C6-Ci2)aryl, 5-10-membered heterocycle or 5-10-membered heteroaryl; c) -(C2-C6)alkynyl-(C3-C7)carbocycle; wherein
-(C2-C6)alkynyl-(C3-C7)carbocycle is optionally substituted with one to three Z1 groups; or d) -NReRf or-C(0)NReRf.
13. The compound of any one of claims 1-11 wherein R5, R6, R7, R8 and R12 are each independently hydrogen.
14. The compound of any one of claims 1-11 wherein each Z1 is independently halo, -N02, -OH, =NORa, -SH, -CN, (C C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C C6)haloalkyl, (C3-C7)carbocycle, (C3-C7)halocarbocycle, (C6-Ci2)aryl, heteroaryl, heterocycle, -0(C C6)alkyl, -0(C2-C6)alkenyl, -0(C2-C6)alkynyl, -0(C C6)haloalkyl, - 0(C3-C7)carbocycle, -0(C3-C7)halocarbocycle, -0-(C6-Ci2)aryl, -Oheteroaryl, - Oheterocycle, -S(C C6)alkyl, -S(C2-C6)alkenyl, -S(C2-C6)alkynyl, -S(C C6)haloalkyl, -S(C3-C7)carbocycle, -S(C3-C7)halocarbocycle, -S-(C6-Ci2)aryl, -Sheteroaryl, - Sheterocycle, -S(0)(C C6)alkyl, -S(0)(C2-C6)alkenyl, -S(0)(C2-C6)alkynyl, -S(0)(C C6)haloalkyl, -S(O) (C3-C7)carbocycle, -S(0)(C3-C7)halocarbocycle, -S02(C C6)alkyl, -S(O)- (C6-C12)aryl, -S(0)carbocycle, -S(0)heteroaryl, -S(0)heterocycle, -S02(C2- C6)alkenyl, -S02(C2-C6)alkynyl, -S02(C C6)haloalkyl, -S02(C3-C7)carbocycle, - S02(C3-C7)halocarbocycle, -S02-(C6-Ci2)aryl, -S02heteroaryl, -S02heterocycle, - S02NRcRd, -NRcRd, -NRaC(0)Ra, -NRaC(0)ORb, -NRaC(0)NRcRd -NRaS02Rb, -NRaS02NRcRd, -NRaS020(C3-C7)carbocycle, -NRaS020-(C6-Ci2)aryl, -OS(0)2Ra, -C(0)Ra, -C(0)ORb, -C(0)NRcRd, or -OC(0)NRcRd, wherein any (Ci-C6)alkyl, (C2-C6)alkenyl, (C2-Ce)alkynyl, -(C3-
C7)halocarbocycle, (C3-C7)carbocycle, (C3-C7)halocarbocycle, (C6- C]2)aryl, heteroaryl or heterocycle of Z1, either alone or as part of a group, is optionally substituted with one to three halogen, -OH, -ORb, -CN, -NRaC(0)2Rb, -heteroaryl, -heterocycle, -Oheteroaryl, - Oheterocycle, -NHheteroaryl, -NHheterocycle or -S(0)2NRcRd; and wherein any heteroaryl or heterocycle of Z1 is a 5-12 membered heteroaryl or a 5-12 membered heterocycle; and
15. The compound any of claims 1-14, or a pharmaceutically acceptable salt thereof, wherein each Z1 is independently : i) -C(=0)-NH2, -C(=0)-NH(Ci-C4)alkyl, -C(=0)-N((C C4)alkyl)2, - C(=0)- (C6-Ci2)aryl, -C(=0)-heterocycle and -C(=0)-heteroaryl; ii) halo, oxo, thioxo, (C2-C6)alkenyl, (Ci-C6)haloalkyl, (C3-C7)cycloalkyl, (C3-C7)cycloalkyl-(Ci-C6)alkyl-, -OH, -0(C C6)alkyl, -0(C C6)haloalkyl, -SH, -S(Ci-C6)alkyl, -SO(C C6)alkyl, -S02(C C6)alkyl, -NH2, -NH(C C6)alkyl or
-N((CrC6)alkyl)2; or iii) (Ci-C6)alkyl optionally substituted with -OH, -0-(Ci-C6)haloalkyl, or - 0-(Ci-C6)alkyl; or iii) (C6-Ci2)aryl, heterocycle and heteroaryl, which (C6-Ci2)aryl, heterocycle and 5- heteroaryl is optionally substituted with halo, (Ci-C6)alkyl or COOH, wherein any heterocycle or heteroaryl of Z1 is a 5-12 membered heterocycle or 5-12 membered heteroaryl.
16. A compound of formula la:
Figure imgf000128_0001
la wherein:
R2 is H, oxo, halo, (C C6)alkyl or -0(C C6)alkyl;
R3 is (Ci-C6)alkyl, (C2-C6)alkenyl, (C3-C6)cycloalkyl, (C C6)-alkyl-(C3-
C6)cycloalkyl or -0(Ci-C6)alkyl, -0-(C3-C6)cycloalkyl 1, wherein any (Ci-C6)alkyl, (C2-C6)alkenyl, (C3-C6)cycloalkyl, (Ci-C6)-alkyl-(C3- C6)cycloalkyl or -0(C C6)alkyl, -0-(C3-C6)cycloalkyl of R3 is optionally substituted with one to three groups selected from the group consisting of -0(Ci-C6)alkyl, halo, oxo and -CN;
W is N or CR1 when the dashed bond is a double bond, or W is O, NR1 or CRlaRlb when the dashed bond is a single bond;
E is selected from the group consisting of:
Figure imgf000129_0001
wherein
X is N when Y is N-R7 and X is N-R6 when Y is N;
Figure imgf000129_0002
when E is
G1 is N, G2 is CR8, and the dashed bond is a double bond; or
G1 is CR5, G2 is N, and the dashed bond is a double bond; or
G1 is CR5, G2 is NR13, the dashed bond is a single bond, and R7 is an oxo (=0) group; or
G1 is CR5, G2 is NR13, the dashed bond is a single bond, and R7 and R13 together with the atoms to which they are attached form a 5-10- membered heteroaryl, wherein the 5-10-membered heteroaryl is optionally substituted with one to three Z1 groups;
Figure imgf000129_0003
when E is
G1 is S, G2 is N, the dashed bond connected to G1 is a single bond, the dashed bond connected to G2 is a double bond, and the wavy bond connected to R12 is a single bond; or G1 is N, G2 is S, the dashed bond connected to G1 is a double bond, the dashed bond connected to G2 is a single bond, and the wavy bond connected to R12 is a single bond; or
G1 is S, G2 is NR6, the dashed bond connected to G1 is a single bond, the dashed bond connected to G2 is a single bond, the wavy bond connected to R12 is a double bond and R12 is oxygen (e.g."(wavy bond)-R12 is "=0");
Rla and Rlb are each independently R ;
R5, R6, R7, R8, R12, and R13 are each independently: a) R11, -C(=0)-Rn, -C(=0)-0-Rn, -O-R11, -S-R11, -S(0)-Rn, -S02- R11, -(Ci-C6)alkyl-Rn,
Figure imgf000130_0001
O-R11, -(Ci-C6)alkyl-0-Rn, -(Ci-C6)alkyl-S-Rn, -(Ci-C6)alkyl-S(0)-Rn or -(Ci-C6)alkyl-S02-Rn, wherein each R11 is independently H, (Ci-C6)alkyl, (C2-C6)alkenyl, (C2- C6)alkynyl, (Ci-C6)haloalkyl, (C3-C7)carbocycle, (C6-Ci2)aryl, 5- 12-membered heterocycle or 5-12-membered heteroaryl, wherein any (C6-Ci2)aryl, 5-12-membered heterocycle and 5-12- membered heteroaryl of R11 are each optionally substituted with one to three Z1 groups; or b) -N(R9)R10, -C(=0)-N(R9)R10, -0-C(=0)-N(R9)R10, -S02- N(R9)R10, -(Ci-C6)alkyl-N(R9)R10,
Figure imgf000130_0002
-(C C6)alkyl-0-C(=0)-N(R9)R10, or -(Ci-C6)alkyl-S02-N(R9)R10, wherein each R9 is independently H, (C]-C6)alkyl or (C3-C7)cycloalkyl; and wherein each R10 is independently H, (Ci-C6)alkyl, (C2-C6)alkenyl, (C2- C6)alkynyl, (C C6)haloalkyl, (C3-C7)carbocycle, (C6-C]2)aryl, 5- 12-membered heterocycle or 5-12-membered heteroaryl, wherein any (C6-Ci2)aryl, 5-12-membered heterocycle and 5-12- membered heteroaryl of R are each optionally substituted with one to three Z1 groups; or c) -(Ci-C6)alkyl-0-(Ci-C6)alkyl-(C3-C7)carbocycle,
-(Ci-C6)alkyl-S-(Ci-C6)alkyl-(C3-C7)carbocycle,
-(Ci-C6)alkylS(0)-(Ci-C6)alkyl-(C3-C6)carbocycle,
-(Ci-C6)alkylS02(Ci-C6)alkyl-(C3-C7)carbocycle,
-(C2-C6)alkenyl-(Ci-C6)haloalkyl, -(C2-C6)alkynyl-(Ci-C6)haloalkyl, -(C3-C7)halocarbocycle, -NRaS02NRcRd, -NRaS020(C3-C7)carbocycle, -NRaS020(C6-Ci2)aryl, -(C2-C6)alkenyl-(C3-C7)carbocycle,
-(C2-C6)alkenyl-(C6-C]2)aryl, -(C2-C6)alkenyl-heteroaryl,
-(C2-C6)alkenyl-heterocycle, -(C2-C6)alkynyl-(C3-C7)carbocycle, -(C2-C6)alkynyl-(C6-Ci2)aryl, -(C2-C6)alkynyl-heteroaryl,
-(C2-C6)alkynyl-heterocycle, -(C3-C7)carbocycle-Z1 or -(Cr
C6)haloalkyl-Z3, wherein any (Ci-C6)alkyl, (Ci-C6)haloalkyl, (C3-C7)carbocycle,
(C2-C6)alkenyl, (C2-C6)alkynyl, (C6-Ci2)aryl or heteroaryl, either alone or as a group is optionally substituted with one to three Z1 groups; and wherein any heteroaryl or heterocycle is a 5-12 membered heteroaryl or a 5-12 membered heterocycle; or d) -NReRf, -C(0)NReRf, -OC(0)NReRf, -S02NReRf, -(C C6)alkyl- NReRf, -(Ci-C6)alkylC(0)-NReRf, -(Ci-C6)alkyl-0-C(0)-NReRf or -(Ci-C6)alkyl-S02NReRf; wherein each (Ci-C6)alkyl is independently substituted with one to three Z6 groups and optionally substituted with one to three Z1 groups; or e) oxo; and each Z1 is independently halo, -N02, -OH, =NORa, -SH, -CN, (C C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C C6)haloalkyl, (C3- C7)carbocycle, (C3-C7)halocarbocycle, (C6-Ci2)aryl, heteroaryl, heterocycle, -0(C C6)alkyl, -0(C2-C6)alkenyl, -0(C2-C6)alkynyl, -0(C C6)haloalkyl, -0(C3-C7)carbocycle, -0(C3-C7)halocarbocycle, -O- (C6-Ci2)aryl, -Oheteroaryl, -Oheterocycle, -S(C C6)alkyl, -S(C2- C6)alkenyl, -S(C2-C6)alkynyl, -S(C C6)haloalkyl, -S(C3-C7)carbocycle, - S(C3-C7)halocarbocycle, -S-(C6-Ci2)aryl, -Sheteroaryl, -Sheterocycle, -S(0)(C C6)alkyl, -S(0)(C2-C6)alkenyl, -S(0)(C2-C6)alkynyl, -S(0)(C C6)haloalkyl, -S(O) (C3-C7)carbocycle, -S(0)(C3-C7)halocarbocycle, -S02(Ci-C6)alkyl, -S(O)- (C6-Ci2)aryl, -S(0)carbocycle, - S(0)heteroaryl, -S(0)heterocycle, -S02(C2-C6)alkenyl, -S02(C2- C6)alkynyl, -S02(C C6)haloalkyl, -S02(C3-C7)carbocycle, -S02(C3- C7)halocarbocycle, -S02-(C6-Ci2)aryl, -S02heteroaryl, -S02heterocycle, -S02NRcRd, -NRcRd, -NRaC(0)Ra, -NRaC(0)ORb, -NRaC(0)NRcRd - NRaS02Rb, -NRaS02NRcRd, -NRaS020(C3-C7)carbocycle, -NRaS020- (C6-C12)aryl, -OS(0)2Ra, -C(0)Ra, -C(0)ORb, -C(0)NRcRd, or - OC(0)NRcRd, wherein any (Ci-C6)alkyl, (C2-C6)alkenyl, (C2-Ce)alkynyl, -(C3-
C7)halocarbocycle, (C3-C7)carbocycle, (C3-C7)halocarbocycle, (C6-C]2)aryl, heteroaryl or heterocycle of Z1, either alone or as part of a group, is optionally substituted with one to three halogen, -OH, -ORb, -CN, -RH2, -NRcRd -NRaC(0)2Rb, - heteroaryl, -heterocycle, -Oheteroaryl, -Oheterocycle,
-NHheteroaryl, -NHheterocycle or -S(0)2NRcRd; and wherein any heteroaryl or heterocycle of Z1 is a 5-12 membered
heteroaryl or a 5-12 membered heterocycle; and each Z3 is independently -N02, -CN, -OH, oxo, =NORa, thioxo, (C6- C]2)aryl, 5-12 membered heterocycle, 5-12 membered heteroaryl, (C3- C7)halocarbocycle, -0(C C6)alkyl, -0(C3-C7)carbocycle, -0(C3- C7)halocarbocycle, -0-(C6-Ci2)aryl, -Oheterocycle, -Oheteroaryl, -S(Cr C6)alkyl, -S(C3-C7)carbocycle, -S(C3-C7)halocarbocycle, -S-(C6- C]2)aryl, -Sheterocycle, -Sheteroaryl, -S(0)(C]-C6)alkyl, -S(0)(C3-C7)carbocycle, -S(O) (C3-C7)halocarbocycle, -S(O)- (C6- Ci2)aryl, -S(0)heterocycle, -S(0)heteroaryl, -S02(Ci-C6)alkyl,
-S02(C3-C7)carbocycle, -S02(C3-C7)halocarbocycle, S02-(C6-Ci2)aryl, -S02heterocycle, -S02heteroaryl, -NRaRb, -NRaC(0)Rb, -C(0)NRcRd, - S02NRcRd, -NRaS02NRcRd, -NRaS020(C3-C7)carbocycle or -NRaS020- (C6-C12)aryl, wherein any heteroaryl or heterocycle of Z3 is a 5-12 membered
heteroaryl or a 5-12 membered heterocycle; and each Ra, Rb, Rc and Rd is independently H or (Ci-C6)alkyl, (C2- C6)alkenyl, (C2-C6)alkynyl, (C3-C7)carbocycle, heterocycle, (C6- C]2)aryl, (C6-Ci2) aryl(Ci-C6)alkyl-, heteroaryl or heteroaryl(Cr
C6)alkyl-, wherein any (C C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl,
(C3-C7)carbocycle, heterocycle, (C6-Ci2)aryl, or heteroaryl of Ra, Rb, Rc and Rd, either alone or as part of a group, is optionally substituted with one to three halogen, OH or cyano; or Rc and Rd together with the nitrogen to which they are attached form a 5-12 membered heterocycle, wherein any heterocycle of Rc and Rd together with the nitrogen to which they are attached is optionally substituted with one to three halogen, OH, cyano, or -RH2; wherein any heteroaryl or heterocycle of Ra, Rb, Rc and Rd is a 5-12 membered heteroaryl or a 5-12 membered heterocycle; and each Re is independently H, -ORa> (Ci-C6)alkyl or (C3-C7)carbocycle, (C2-C6)haloalkyl, (C2-C6)alkenyl and (C2-C6)alkynyl, (C6-Ci2)aryl, 5-12 membered heterocycle or 5-12 membered heteroaryl; wherein (Ci-C6)alkyl and (C3-C7)carbocycle of Re are each
independently substituted with one to three Z6 groups and optionally substituted with one to three Z1 groups; wherein any (C2-C6)haloalkyl, (C2-C6)alkenyl or (C2-C6)alkynyl of Re is optionally substituted with one to three Zi groups; wherein any (C6-Ci2)aryl, 5-12 membered heterocycle or 5-12
membered heteroaryl of Re are each independently substituted with one to three Z5 groups; and each Rf is independently H, -Rg, -ORa, -(C C6)alkyl-Z6, -S02Rg, -C(0)Rg, C(0)ORg or -C(0)NReRg; and each Rg is independently H, (Ci-C6)alkyl, (C3-C7)carbocycle
(Ci-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C6-Ci2)aryl, 5-12 membered heterocycle or 5-12 membered heteroaryl, wherein any (Ci-C6)alkyl, (C3-C7)carbocycle -(Ci-C6)haloalkyl,
(C2-C6)alkenyl, (C2-C6)alkynyl, (C6-Ci2)aryl, 5-12 membered heterocycle or 5-12 membered heteroaryl of Rg is optionally substituted with one to three Zi groups; and each Z5 is independently -N02, -CN, -NRaSC^NRcRc, -NRaS020(C3- C7)carbocycle, -NRaS020-(C6-Ci2)aryl, -NRaS02(Ci-C6)alkyl, - NRaS02(C2-C6)alkenyl, -NRaS02(C2-C6)alkynyl, -NRaS02(C3- C7)carbocycle, -NRaS02(C3-C7)halocarbocycle, -NRaS02-(C6-Ci2)aryl, -NRaS02heteraryl, -NRaS02heteroaryl, -NRaS02heterocycle,
-NRaC(0)alkyl, -NRaC(0)alkenyl, -NRaC(0)alkynyl, -NRaC(0) (C3- C7)carbocycle, -NRaC(0)(C3-C7)halocarbocycle, -NRaC(0)- (C6- Ci2)aryl, -NRaC(0)heteroaryl, -NRaC(0)heterocycle, -NRaC(0)NRcRd or -NRaC(0)ORb, wherein any heteroaryl or heterocycle of Z5 is a 5-12 membered
heteroaryl or a 5-12 membered heterocycle; and each Z6 is independently -N02, -CN, -NRaRa, NRaC(0)Rb,-C(0)NRcRd, (C3-C7)halocarbocycle, (C6-Ci2)aryl, heteroaryl, heterocycle, -0-(C6- Ci2)aryl, -Oheteroaryl, -Oheterocycle, -0(C3-C7)halocarbocycle, -0(Cr C6)alkyl, -0(C3-C7)carbocycle, -0(C C6)haloalkyl, -S-(C6-Ci2)aryl, -Sheteroaryl, -Sheterocycle, -S(C3-C7)halocarbocycle, -S(Ci-C6)alkyl, -S(C3-C7)carbocycle, -S(C C6)haloalkyl, -S(O)- (C6-Ci2)aryl,
-S(0)heteroaryl, -S(0)heterocycle, -S(0)(C3-C7)halocarbocycle, -S(0)(Ci-C6)alkyl, -S(0)(C3-C7)carbocycle, -S(0)(C C6)haloalkyl, - S02-(C6-Ci2)aryl, -S02heteroaryl, -S02heterocycle, -S02(C C6)alkyl, - S02(Ci-C6)haloalkyl, -S02(C3-C7)carbocycle, -S02(C3- C7)halocarbocycle, -S02NRcRd, -NRaS02(C3-C7)halocarbocycle,
-NRaS02(C6-C12)aryl, -NRaS02heteraryl, -NRaS02heteroaryl,
-NRaS02NRcRd, -NRaS020(C3-C7)carbocycle or -NRaS020-(C6- Ci2)aryl, wherein any (C6-Ci2)aryl of Z6, either alone or as part of a group, is optionally substituted with one to three halogen, -OH, -0(Cr C6)alkyl, -CN, NH2, or -(C C6)alkyl, and wherein any heteroaryl or heterocycle of Z6 is a 5-12 membered
heteroaryl or a 5-12 membered heterocycle.
17. The compound of claim 16, or a pharmaceutically acceptable salt thereof, wherein W is N, NH or CR1.
18. The compound of claim 16 or claim 17, or a pharmaceutically acceptable salt thereof, wherein R2 is oxo, halo, H or -CH3.
19. The compound of claim 16 or claim 17, or a pharmaceutically acceptable salt thereof, wherein R2 is -CH .
20. The compound of any one of claims 16-19, or a pharmaceutically acceptable salt thereof, wherein R3 is -0(Ci-C6)alkyl optionally substituted with one to three groups selected from the group consisting of halo and -CN.
21. The compound of any one of claims 16-19 wherein R3 is -OC(CH3)3. The 16-21, or a pharmaceutically acceptable salt
thereof, wh
Figure imgf000136_0001
and R5 is H.
23. The compound of claim 22, or a pharmaceutically acceptable salt thereof, wherein R6 is a) H, halo and (C C6)alkyl; b) (C2-C6)alkenyl, (C2-C6)alkynyl and (C6-C]2)aryl, wherein any (C6-Ci2)aryl is optionally substituted with one to three Z10 groups; c) -(Ci-C6)alkyl-Rn and -(Ci-C6)alkyl-0-Rn, wherein each R11 is independently selected from H, (C]-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C]-C6)haloalkyl, (C3-C7)cycloalkyl, (C6-C]2)aryl, 5-10-membered heterocycle and 5-10-membered heteroaryl, wherein any (C6-Ci2)aryl, 5-10-membered heterocycle or 5-10-membered heteroaryl of R6 is optionally substituted with one to three Z10 groups; d) -(C2-C6)alkynyl-(C3-C7)carbocycle, -(C2-C6)alkynyl-(C6-Ci2)aryl, -(C2-C6)alkynyl-heteroaryl -(C2-C6)alkynyl-heterocycle, -(C2-Cs)alkynyl-ORa and -(C2-C6)alkyl-(C3-C7)carbocycle-ORa, wherein
-(C2-C6)alkynyl-(C3-C7)carbocycle, -(C2-C6)alkynyl-(C6-Ci2)aryl,
-(C2-C6)alkynyl-heteroaryl and -(C2-C6)alkynyl-heterocycle, are optionally substituted with one to three Z^roups; e) (Ci-C6)alkyl, wherein (Ci-C6)alkyl is substituted with one to three Z2 groups and optionally substituted with one to three Z^roups; f) (C6-C]2)aryl, wherein (C6-Ci2)aryl is substituted with one to three Z5 groups and optionally substituted with one to three Z^roups; and g) (C2-C6)alkenyl and (C2-C6)alkynyl, wherein (C2-C6)alkenyl and (C2-C6)alkynyl are each independently substituted with one to threeZ6 groups and optionally substituted with one to three Z^roups, wherein any heteroaryl or heterocycle of Z6 is a 5-12 membered heteroaryl or a 5-12 membered heterocycle.
The compound of claim 23, wherein one or both of R7 and R8 are H. The compound of claim 22, wherein R7, is: a) H, halo, (C C6)alkyl and (C C6)haloalkyl; b) (C3-C7)cycloalkyl, cyano, (C6-Ci2)aryl and 5-12 membered heteroaryl, wherein any (C6-Ci2)aryl and 5-12 membered heteroaryl is optionally substituted with one to three Z10 groups; c) -C(=0)-N(R9)R10, wherein each R9 is independently selected from H, (Ci-C6)alkyl and (C3-C7)cycloalkyl, and each R10 is independently selected from R11, -(Ci-C6)alkyl-Rn, -S02-Rn, -C(=0)-Rn, -C(=0)ORn and - C(=0)N(R9)Rn, wherein each R11 is independently selected from H, (d- C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C C6)haloalkyl, (C3-C7)cycloalkyl, (C6-Ci2)aryl, 5-12 membered heterocycle and 5-12 membered heteroaryl, wherein any (C6-Ci2)aryl, 5-12 membered 5-12 membered heterocycle or 5-12 membered heteroaryl is optionally substituted with one to threeZ10 groups; d) (Ci-C6)alkyl, wherein (Ci-C6)alkyl is substituted with one to threeZ2 groups and optionally substituted with one to three Z^roups; e) (C6-Ci2)aryl and 5-12 membered heteroaryl, wherein (C6-Ci2)aryl and 5- 12 membered heteroaryl are each substituted with one to threeZ5 groups and optionally substituted with one to three Z^roups; f) (Ci-C6)haloalkyl and (C3-C7)carbocycle, wherein (Ci-C6)haloalkyl and (C3-C7)carbocycle are each substituted with one to three Z6 groups and optionally substituted with one to three Z^roups; and g) -C(0)NReRf.
26. The compound of claim 25, wherein one or both of R6 and R8 are H.
27. The compound of claim 22, wherein R is: a) halo, nitro and cyano; b) R11, -C(=0)-Rn, -C(=0)-0-Rn, -O-R11, -S-R11, -S(0)-Rn, -S02-Rn, - (Ci-C6)alkyl-Rn,
Figure imgf000138_0001
-(C C6)alkyl-0-Rn, -(Ci-C6)alkyl-S-Rn, -(Ci-C6)alkyl-S(0)-Rn and -(C C6)alkyl- S02-Rn,wherein each R11 is independently selected from H, (Ci-C6)alkyl, (C2- C6)alkenyl, (C2-C6)alkynyl, (C C6)haloalkyl, (C3-C7)cycloalkyl, (C6-Ci2)aryl, 5-12 membered heterocycle and 5-12 membered heteroaryl, wherein (C6- Ci2)aryl, 5-12 membered heterocycle and 5-12 membered heteroaryl are each optionally substituted with one to three Z11 groups; c) -N(R9)R10, -C(=0)-N(R9)R10, -0-C(=0)-N(R9)R10, -S02-N(R9)R10, -(C C6)alkyl-N(R9)R10,
Figure imgf000138_0002
N(R9)R10 and -(Ci-C6)alkyl-S02-N(R9)R10, wherein each R9 is independently selected from H, (Ci-C6)alkyl and (C3-C7)cycloalkyl, and each R10 is independently selected from R11, -(CrC6)alkyl-Rn, -S02-Rn, -C(=0)-Rn, - C(=0)ORn and -C(=0)N(R9)Rn, wherein each R11 is independently selected from H, (Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C C6)haloalkyl, (C3- C7)cycloalkyl, (C6-Ci2)aryl, 5-12 membered heterocycle and 5-12 membered heteroaryl; d) (C]-C6)alkyl, wherein (C]-C6)alkyl is substituted with one to threeZ2 groups and optionally substituted with one to three Z^roups; e) (C6-Ci2)aryl, 5-12 membered heteroaryl, 5-12 membered heterocycle, -X-(C6-C]2)aryl, -Xheteroaryl and -Xheterocycle, wherein any (C6-Ci2)aryl, heteroaryl and heterocycle, either alone or as part of a group, is substituted with one to three Z5 groups and optionally substituted with one to three Z^roups, and wherein any -Xheteroaryl or -Xheterocycle is a 5-12 membered -Xheteroaryl or a 5-12 membered -Xheterocycle; f) (Ci-C6)haloalkyl, (C3-C7)carbocycle, (C2-C6)alkenyl and (C2-C6)alkynyl, wherein (Ci-C6)haloalkyl, (C3-C7)carbocycle, (C2-C6)alkenyl and
(C2-C6)alkynyl are each independently substituted with one to three Z6 groups and optionally substituted with one to three Z^roups; and g) -NReRf, -C(0)NReRf, -OC(0)NReRf, -S02NReRf, -(Ci-C6)alkyl-NReRf, -(Ci-C6)alkylC(0)-NReRf, -(Ci-C6)alkyl-0-C(0)-NReRf and -(C C6)alkyl- S02NReRf, wherein any (Ci-C6)alky, as part of a group, is substituted with one to three Z6 groups and optionally substituted with one to three Z^roups.
28. The compound of any one of claims 22, or a pharmaceutically acceptable salt thereof, wherein R5, R6, R7, and R8 are each hydrogen.
29. The compound of claim 22, or a pharmaceutically acceptable salt thereof, wherein one or both of R6 and R7 are H.
30. The 1, or a pharmaceutically acceptable salt
thereof, wh
Figure imgf000139_0001
is C-R , G is N and the dotted bond is a double bond.
31. The compound of claim 30, or a pharmaceutically acceptable salt thereof, wherein R6 is H and R5 is H or (C C6)alkyl.
32. The compound of claim 30 or claim 31, or a pharmaceutically acceptable salt thereof, wherein R7 is selected from: a) H, (Ci-C6)alkyl and (C C6)haloalkyl; b) (C2-C6)alkynyl and (C6-Ci2)aryl, wherein (C6-Ci2)aryl is optionally substituted with one to three Z10 groups; c) (Ci-C6)alkyl, wherein (Ci-C6)alkyl is substituted with one to three Z2 groups and optionally substituted with one to three Z1 groups; d) (C6-Ci2) ryl, wherein (C6-Ci2) ryl is substituted with one to three Z5 groups and optionally substituted with one to three Z1 groups; and e) (Ci-C6)haloalkyl, wherein (Ci-C6)haloalkyl is substituted with one to three Z6 groups and optionally substituted with one to three Z1 groups.
33. The compound of any one of claims 30-32, or a pharmaceutically acceptable salt thereof, wherein R7 is selected from: a) (Ci-C6)haloalkyl; and b) (Ci-C6)haloalkyl, wherein (Ci-C6)haloalkyl is substituted with one to three Z6 groups and optionally substituted with one to three Z1 groups.
The comp 1, or a pharmaceutically acceptable salt
thereof, wherein
Figure imgf000140_0001
G1 is S, G2 is N, the dashed bond connected to G1 is a single bond, the dashed bond connected to G2 is a double bond, and the wavy bond connected to R12 is a single bond; or
G1 is S, G2 is NR6, the dashed bond connected to G1 is a single bond, the dashed bond connected to G2 is a single bond, the wavy bond connected to R12 is a double bond and R5 is oxygen.
The compound of claim 34, wherein R is a) H, (Ci-C6)alkyl, (Ci-C6)haloalkyl, (C3-C7)carbocycle, heterocycle, -C(=0)-Rn, -C(=0)-0-Rn and -O-R11, wherein heterocycle is optionally substituted with one to three Z11 groups and wherein each R11 is independently selected from H, (C C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C C6)haloalkyl, (C3-C7)carbocycle, (C6-Ci2)aryl, heterocycle and 5-12 membered heteroaryl, wherein (C6-Ci2)aryl, 5-12 membered heterocycle and 5-12 membered heteroaryl are each optionally substituted with one to three Z11 groups; b) -N(R9)R10 and -C(=0)-N(R9)R10, wherein each R9 is independently selected from H, (Ci-C6)alkyl and (C3-C7)cycloalkyl, and each R10 is independently selected from R11, -(Ci-C6)alkyl-Rn, -S02-Rn, -C(=0)-Rn, - C(=0)ORn and -C(=0)N(R9)Rn; wherein each R11 is independently selected from H, (Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C C6)haloalkyl, (C3- C7)cycloalkyl, (C6-Ci2)aryl, 5-12 membered heterocycle and 5-12 membered heteroaryl; c) -(C2-C6)alkynyl-(C3-C7)carbocycle; wherein
-(C2-C6)alkynyl-(C3-C7)carbocycle is optionally substituted with one to three Z1 groups; and d) -NReRf and-C(0)NReRf.
36. The compound of claim 34, wherein R12 is oxo and R6 is selected from R11 and - (Ci-C6)alkyl-Rn, wherein each R11 is independently selected from H, (C]-C6)alkyl, (C2- C6)alkenyl, (C2-C6)alkynyl, (C C6)haloalkyl, (C3-C7)cycloalkyl, (C6-C12)aryl, 5-12 membered heterocycle and 5-12 membered heteroaryl, wherein (C6-Ci2)aryl, 5-12 membered heterocycle and 5-12 membered heteroaryl are each optionally substituted with one to three Z11 groups.
37. The compound of claim 34, wherein R12 is: a) (C6-Ci2)aryl, 5-12 membered heterocycle or 5-12 membered heteroaryl, wherein (C6-Ci2)aryl, 5-12 membered heterocycle and 5-12 membered heteroaryl are each optionally substituted with one to three Z11 groups; or b) (C6-Ci2)aryl, 5-12 membered heteroaryl or 5-12 membered heterocycle, wherein (C6-Ci2)aryl, 5-12 membered heteroaryl are 5-12 membered heterocycle, are each independently substituted with one to five Z5 groups and optionally substituted with one or to five Z^roups; or c) (C6-C]2)aryl, 5-12 membered heteroaryl, or 5-12 membered heterocycle, wherein (C6-Ci2)aryl, 5-12 membered heteroaryl and 5-12 membered heterocycle, are each independently substituted with one to five Z15 groups and optionally substituted with one to five Z^roups; or each Z11 is independently selected from Z10, -C(=0)-NH2, -C(=0)-NH(C C4)alkyl, -C(=0)-N((C C4)alkyl)2, -C(=0)- (C6-Ci2)aryl, -C(=0)-heterocycle or -C(=0)-heteroaryl, and wherein any heterocycle or heteroaryl of Z11 is 5-12 membered heterocycle or a 5-12 membered heteroaryl. wherein each Z10 is independently: i) halo, oxo, thioxo, (C2-C6)alkenyl, (Ci-C6)haloalkyl, (C3- C7)cycloalkyl, (C3-C7)cycloalkyl-(Ci-C6)alkyl-, -OH, -0(C C6)alkyl, -0(C C6)haloalkyl, -SH, -S(C C6)alkyl, -SO(C C6)alkyl, -S02(C C6)alkyl, -NH2, - NH(Ci-C6)alkyl or -N((C C6)alkyl)2; or ii) (C C6)alkyl substituted with -OH, -0-(C C6)haloalkyl, or -O- (Ci-C6)alkyl; or iii) (C6-C]2)aryl, which (C6-Ci2)aryl is optionally substituted with halo, (C C6)alkyl or COOH; and each Z11 is independently Z10, -C(=0)-NH2, -C(=0)-NH(C C4)alkyl, -C(=0)-N((Ci-C4)alkyl)2, -C(=0)- (C6-Ci2)aryl, -C(=0)-heterocycle or
-C(=0)-heteroaryl, and wherein any heterocycle or heteroaryl of Z11 is 5-12 membered heterocycle or a 5-12 membered heteroaryl.
38. The compound of any one of claims 1-37 wherein R8 is selected from: a) halo and cyano; b) R11, -O-R11 and -(Ci-C6)alkyl-Rn, wherein each R11 is independently selected from H, (C C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C C6)haloalkyl, (C3- C7)cycloalkyl, (C6-Ci2)aryl, 5-12 membered heterocycle and 5-12 membered heteroaryl, wherein (C6-Ci2)aryl, 5-12 membered heterocycle and 5-12 membered heteroaryl are each optionally substituted with one to three Z11 groups; c) -C(=0)-N(R9)R10, wherein each R9 is independently selected from H, (C]-C6)alkyl and (C3-C7)cycloalkyl, and each R10is independently selected from R11, - (Ci-C6)alkyl-Rn, -S02-Rn, -C(=0)-Rn, -C(=0)ORn and -C(=0)N(R9)Rn, wherein each R11 is independently selected from H, (Ci-C6)alkyl, (C2-C6)alkenyl, (C2- C6)alkynyl, (Ci-C6)haloalkyl, (C3-C7)cycloalkyl, (C6-Ci2)aryl, 5-12 membered heterocycle and 5-12 membered heteroaryl; d) (Ci-C6)alkyl, wherein (Ci-C6)alkyl is substituted with one to three Z2 groups and optionally substituted with one to threeZ^roups; e) (C6-Ci2)aryl and 5-12 membered heteroaryl, wherein (C6-Ci2)aryl and 5- 12 membered heteroaryl are each independently substituted with one to threeZ5 groups and optionally substituted with one to threeZ^roups; f) (C2-C6)alkynyl, wherein (C2-C6)alkynyl is substituted with one to threeZ6 groups and optionally substituted with one to threeZ^roups; and g) -C(0)NReRf..
39. The compound any of claims 1-38, or a pharmaceutically acceptable salt thereof, wherein each Z1 is independently : i) -C(=0)-NH2, -C(=0)-NH(Ci-C4)alkyl, -C(=0)-N((C C4)alkyl)2, - C(=0)- (C6-Ci2)aryl, -C(=0)-heterocycle and -C(=0)-heteroaryl; ii) halo, oxo, thioxo, (C2-C6)alkenyl, (Ci-C6)haloalkyl, (C3-C7)cycloalkyl, (C3-C7)cycloalkyl-(Ci-C6)alkyl-, -OH, -0(C C6)alkyl, -0(C C6)haloalkyl, -SH, -S(Ci-C6)alkyl, -SO(C C6)alkyl, -S02(Ci-C6)alkyl, -NH2, -NH(C C6)alkyl or -N((Ci-C6)alkyl)2; or iii) (Ci-C6)alkyl optionally substituted with -OH, -0-(Ci-C6)haloalkyl, or - 0-(Ci-C6)alkyl; or iii) (C6-Ci2)aryl, heterocycle and heteroaryl, which (C6-Ci2)aryl, heterocycle and 5- heteroaryl is optionally substituted with halo, (Ci-C6)alkyl or COOH, wherein any heterocycle or heteroaryl of Z1 is a 5-12 membered heterocycle or 5-12 membered heteroaryl.
Figure imgf000144_0001
143
41. The compound of any one of claims 1-39, or a pharmaceutically acceptable salt thereof which is:
Figure imgf000145_0001
42. A pharmaceutical composition comprising a compound of any one of claims 1- 41, or apharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
43. A pharmaceutical composition comprising a compound of any one of claims 1- 41, or a pharmaceutically acceptable salt thereof, and an additional therapeutic agent, wherein the additional therapeutic agent is an HIV protease inhibiting compound, an HIV non-nucleoside inhibitor of reverse transcriptase, an HIV nucleoside inhibitor of reverse transcriptase, an HIV nucleotide inhibitor of reverse transcriptase, an HIV integrase inhibitor, a gp41 inhibitor, a CXCR4 inhibitor, agpl20 inhibitor, a CCR5 inhibitor, a capsid polymerization inhibitor, or a non-catalytic site HIV integrase inhibitor and combinations thereof.
44. A pharmaceutical composition of any one of claim 1-41, for use in treating an HIV infection in a patient in need thereof.
45. A method for treating a HIV infection in a patient in need thereof comprising administering a therapeutically effective amount of a compound of any one of claims 1- 41, or a pharmaceutically acceptable salt thereof, to the patient.
46. A method for treating an HIV infection in a patient in need thereof comprising administering to the patient a therapeutically effective amount of a compound of any one of claims 1-41, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of an additional therapeutic agent, wherein the additional therapeutic agent is an HIV protease inhibiting compound, an HIV non- nucleoside inhibitor of reverse transcriptase, an HIV nucleoside inhibitor of reverse transcriptase, an HIV nucleotide inhibitor of reverse transcriptase, an HIV integrase inhibitor, a gp41 inhibitor, a CXCR4 inhibitor, a gpl20 inhibitor, a CCR5 inhibitor, a capsid polymerization inhibitor, or a non-catalytic site HIV integrase site inhibitor and combinations thereof.
47. A compound of any of claims 1-41, or a pharmaceutically acceptable salt thereof, for use in medical therapy.
48. A compound of any one of claims 1-41, or a pharmaceutically acceptable salt thereof, for the prophylactic or therapeutic treatment of an HIV virus infection.
49. The use of a compound of any one of claims 1-41, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating an HIV virus infection in a mammal.
50. A compound or method as described herein.
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