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  • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
  • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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  • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
  • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D207/36—Oxygen or sulfur atoms
  • C07D207/40—2,5-Pyrrolidine-diones
  • C07D207/416—2,5-Pyrrolidine-diones with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to other ring carbon atoms
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  • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
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  • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
  • A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
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  • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
  • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
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  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/4192—1,2,3-Triazoles
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  • 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
  • A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
  • A61K31/437—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/445—Non condensed piperidines, e.g. piperocaine
  • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
  • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
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  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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  • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
  • A61K31/5375—1,4-Oxazines, e.g. morpholine
  • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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  • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
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  • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
  • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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  • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
  • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
  • C07D295/125—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
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Definitions

• the present invention is directed to compounds, methods and compositions for preventing, treating and/or curing hepatitis B virus (HBV) infections. More specifically, the invention describes specifically substituted aromatic/heteroaromatic compounds, pharmaceutically acceptable salts, or other derivatives thereof, and the use thereof in the treatment or curing of HBV infections as monomer or as linked multimeric agents.
• HBV hepatitis B virus
• Hepatitis B virus causes a serious human health problem and is second only to tobacco as a cause of human cancer.
• the mechanism by which HBV induces cancer is unknown. It is postulated that it may directly trigger tumor development, or indirectly trigger tumor development through chronic inflammation, cirrhosis, and cell regeneration associated with the infection.
• HBV infection can lead to acute hepatitis and liver damage, resulting in abdominal pain, jaundice and elevated blood levels of certain enzymes. HBV can cause fulminant hepatitis, a rapidly progressive, often fatal form of the disease in which large sections of the liver are destroyed.
• Subjects typically recover from the acute phase of HBV infection. In some persons, however, the virus continues replication for an extended or indefinite period, causing a chronic infection. Chronic infections can lead to chronic persistent hepatitis. Subjects infected with chronic persistent HBV are most common in developing countries. By mid-l99l, there were approximately 225 million chronic carriers of HBV in Asia alone and worldwide almost 300 million carriers. Chronic persistent hepatitis can cause fatigue, cirrhosis of the liver, and hepatocellular carcinoma, a primary liver cancer.
• HBV high-risk group for HBV infection includes those in contact with HBV carriers or their blood samples.
• the epidemiology of HBV is very similar to that of HIV/AIDS, which is a reason why HBV infection is common among persons infected with HIV or suffering from AIDS.
• HBV is much more contagious than HIV.
• 3TC lamvudine
• interferon alpha-2b interferon alpha-2b
• peginterferon alpha-2a hepsera
• baraclude entecavir
• Tyzeka Telbivudine
• Viread Tinofovir disoproxil fumarate
• tenofovir alafenamide fumarate (formerly GS- 7340) was also recently approved. All these drugs are highly effective in reducing viral load, but none of them can provide a high remission rate. In addition, their impact can be limited by drug resistance, low efficacy and tolerability issues. The low cure rates of HBV are attributed primarily to the presence and persistence of covalently closed circular DNA (cccDNA) in the nucleus of infected hepatocytes.
• cccDNA covalently closed circular DNA
• the present invention provides compounds, methods and compositions for preventing, treating and/or curing HBV infection in a host, or reducing the activity of HBV in the host.
• the methods involve administering a therapeutically or prophylactically-effective amount of at least one compound as described herein to treat, cure or prevent an infection by, or an amount sufficient to reduce the biological activity of, an HBV infection.
• the pharmaceutical compositions include one or more of the compounds described herein, in combination with a pharmaceutically acceptable carrier or excipient, for treating a host infected with HBV. These compounds can be used in combination with nucleoside and non-nucleoside inhibitors of HBV.
• the formulations can further include at least one other therapeutic agent.
• the present invention includes processes for preparing such compounds.
• pharmaceutical compositions that include one or more of the compounds of Formulas 1-10, and a pharmaceutically-acceptable carrier.
• the carrier can be, for example, an oral composition, an injectable composition, a transdermal composition, or a nanoparticulate composition.
• the compositions can further include a second antiviral agent, particularly where the agent is active against HBV infection, and more particularly where the second antiviral agent is active against HBV infection via a different mechanism than the instantly-described compounds.
• second antiviral agents include polymerase inhibitors, viral entry inhibitors, viral maturation inhibitors, capsid assembly modulators, IMPDH inhibitors, protease inhibitors, immune-based therapeutic agents, reverse transcriptase inhibitors, TLR-agonists, and agents of distinct or unknown mechanism. Combinations of these agents can be used.
• the compounds described herein can be used to prepare medicaments for treating HBV infection, preventing an HBV infection, or reducing the biological activity of an infection with HBV.
• the medicaments can further include another anti- HBV agent.
• the compounds and compositions can be used in methods for treating a host infected with HBV, preventing an infection from a HBV, and reducing the biological activity of an infection with HBV in a host.
• the methods can also involve the co administration of another anti-HBV agent, which co-administration can be simultaneous or sequential.
• Compounds and compositions useful in treating, preventing, or curing HBV infection are disclosed. Methods for treating, preventing, or curing HBV infection are also disclosed.
• the compounds described herein show inhibitory activity against HBV in cell- based assays. Therefore, the compounds can be used to treat or prevent HBV in a host, or reduce the biological activity of the virus.
• the host can be a mammal, and in particular, a human, infected with HBV.
• the methods involve administering an effective amount of one or more of the compounds described herein.
• compositions including one or more compounds described herein, in combination with a pharmaceutically acceptable carrier or excipient, are also disclosed.
• the formulations include at least one compound described herein and at least one further therapeutic agent.
• HBV capsid assembly is a critical step in virus production.
• a“HBV capsid assembly effector” is a compound which inhibits assembly of the HBV capsid. In some embodiments, these compounds target and misdirect capsid assembly, and/or disrupt pre-formed capsids, resulting in the suppression of HBV replication and virion production.
• the phrase“inhibition of assembly” of an HBV capsid assembly effector includes, but is not limited to, modulation of the rate of capsid assembly, stabilizing or destabilizing assembly, and disrupting pre-formed capsids.
• Small-molecule compounds targeting HBV core, or capsid assembly effectors can be grouped into two main classes according to their effect on assembly: the phenylpropenamide and sulfamoylbenzamide chemical series accelerate formation of capsid-like particles (Campagna et al,“Sulfamoylbenzamide derivatives inhibit the assembly of hepatitis B virus nucleocapsids,” J Virol 87:6931-6942 (2013); Katen et al., “Trapping of hepatitis B virus capsid assembly intermediates by phenylpropenamide assembly accelerators.
• HAP heteroaryldihydropyrimidine
• AB-506 Albutus Biopharma
• JNJ-379 also known as JNJ-56136379, a compound which binds to the HBV core protein, disrupts early and late-stage processes in the virus life cycle, prevents the encapsidation of RNA, and blocks hepatitis B virus replication
• AT-61 AT-130, Bay 41-4109
• NVR 3-778 GLS4, HAP-12, bis-ANS, and RO7049389 (a core allosteric modulator (Roche)).
• HBV capsid assembly inhibitors 3-[(8aS)-7-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-l,4- dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro-lH-imidazo[l,5-a]pyrazin- 2-yl] -2,2-dimethyl-propanoic acid; 3-[(8aS)-7-[[(4S)-5-ethoxycarbonyl-4-(3-fluoro-2- methyl-phenyl)-2-thiazol-2-yl-l,4-dihyd- ropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a- tetrahydro-l
• R 9 is Ci-6alkyl
• R 10 is phenyl, which is once or twice or three times substituted by halogen or Ci-6alkyl
• R 11 is hydrogen or Ci-6alkyl
• R 12 is monocyclic, bicyclic fused or bicyclic bridged heterocyclyl; or pharmaceutically acceptable salt, enantiomer or diastereomer thereof.
• Another representive HBV capsid inhibitor disclosed in Wang et al, Antimicrob. Agents Chemother. November 2015 vol. 59, no. 11, 7061-7072 has the following structure:
• the term“enantiomerically pure” refers to a compound composition that comprises at least approximately 95%, and, preferably, approximately 97%, 98%, 99% or 100% of a single enantiomer of that compound.
• the term“substantially free of’ or“substantially in the absence of’ refers to a compound composition that includes at least 85 to 90% by weight, preferably 95% to 98 % by weight, and, even more preferably, 99% to 100% by weight, of the designated enantiomer of that compound.
• the compounds described herein are substantially free of enantiomers.
• the term“isolated” refers to a compound composition that includes at least 85 to 90% by weight, preferably 95% to 98% by weight, and, even more preferably, 99% to 100% by weight, of the compound, the remainder comprising other chemical species or enantiomers.
• alkyl refers to a saturated straight, branched, or cyclic, primary, secondary, or tertiary hydrocarbons, including both substituted and unsubstituted alkyl groups.
• the alkyl group can be optionally substituted with any moiety that does not otherwise interfere with the reaction or that provides an improvement in the process, including but not limited to but limited to halo, haloalkyl, hydroxyl, carboxyl, acyl, aryl, acyloxy, amino, amido, carboxyl derivatives, alkylamino, dialkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, thiol, imine, sulfonyl, sulfanyl, sulfmyl, sulfamonyl, ester, carboxylic acid, amide, phosphonyl, phosphinyl, phosphoryl, phosphine, thioester, thioether, oxime, hydrazine, carbamate, phosphonic acid, phosphonate, either unprotected, or protected as necessary, as known to those skilled in the art, for example,
• C(alkyl range) the term independently includes each member of that class as if specifically and separately set out.
• the term“alkyl” includes C l-22 alkyl moieties, and the term“lower alkyl” includes C l-6 alkyl moieties. It is understood to those of ordinary skill in the art that the relevant alkyl radical is named by replacing the suffix“-ane” with the suffix“-yl”.
• a“bridged alkyl” refers to a bicyclo- or tricyclo alkane, for example, a 2: 1 : 1 bicyclohexane.
• a“spiro alkyl” refers to two rings that are attached at a single (quaternary) carbon atom.
• alkenyl refers to an unsaturated, hydrocarbon radical, linear or branched, in so much as it contains one or more double bonds.
• the alkenyl group disclosed herein can be optionally substituted with any moiety that does not adversely affect the reaction process, including but not limited to but not limited to those described for substituents on alkyl moieties.
• Non-limiting examples of alkenyl groups include ethylene, methylethylene, isopropylidene, l,2-ethane-diyl, l,l-ethane- diyl, 1, 3-propane- diyl, 1 ,2-propane-diyl, l,3-butane-diyl, and l,4-butane-diyl.
• alkynyl refers to an unsaturated, acyclic hydrocarbon radical, linear or branched, in so much as it contains one or more triple bonds.
• the alkynyl group can be optionally substituted with any moiety that does not adversely affect the reaction process, including but not limited to those described above for alkyl moieties.
• Non- limiting examples of suitable alkynyl groups include ethynyl, propynyl, hydroxypropynyl, butyn-l-yl, butyn-2-yl, pentyn-l-yl, pentyn-2-yl, 4-methoxypentyn- 2-yl, 3-methylbutyn-l-yl, hexyn-l-yl, hexyn-2-yl, and hexyn-3-yl, 3,3-dimethylbutyn- l-yl radicals.
• alkylamino or“arylamino” refers to an amino group that has one or two alkyl or aryl substituents, respectively.
• protected refers to a group that is added to an oxygen, nitrogen, or phosphorus atom to prevent its further reaction or for other purposes.
• oxygen and nitrogen protecting groups are known to those skilled in the art of organic synthesis, and are described, for example, in Greene et al., Protective Groups in Organic Synthesis, supra.
• aryl alone or in combination, means a carbocyclic aromatic system containing one, two or three rings wherein such rings can be attached together in a pendent manner or can be fused.
• Non-limiting examples of aryl include phenyl, biphenyl, or naphthyl, or other aromatic groups that remain after the removal of a hydrogen from an aromatic ring.
• aryl includes both substituted and unsubstituted moieties.
• the aryl group can be optionally substituted with any moiety that does not adversely affect the process, including but not limited to but not limited to those described above for alkyl moieties.
• Non-limiting examples of substituted aryl include heteroarylamino, N-aryl-N- alkylamino, N-heteroarylamino- N-alkylamino, heteroaralkoxy, arylamino, aralkylamino, arylthio, monoarylamidosulfonyl, arylsulfonamido, diarylamidosulfonyl, monoaryl amidosulfonyl, arylsulfmyl, arylsulfonyl, heteroarylthio, heteroarylsulfmyl, heteroarylsulfonyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl, hydroxyaralkyl, hydoxyheteroaralkyl, haloalkoxyalkyl, aryl, aralkyl, aryloxy, aralkoxy, aryloxyalkyl, saturated heterocyclyl, partially saturated hetero
• alkaryl or “alkylaryl” refer to an alkyl group with an aryl substituent.
• alkyl or “alkylaryl” refer to an alkyl group with an aryl substituent.
• aralkyl or“arylalkyl” refer to an aryl group with an alkyl substituent.
• halo includes chloro, bromo, iodo and fluoro.
• acyl refers to a carboxylic acid ester in which the non-carbonyl moiety of the ester group is selected from the group consisting of straight, branched, or cyclic alkyl or lower alkyl, alkoxyalkyl, including, but not limited to methoxymethyl, aralkyl, including, but not limited to, benzyl, aryloxyalkyl, such as phenoxymethyl, aryl, including, but not limited to, phenyl, optionally substituted with halogen (F, Cl, Br, or I), alkyl (including but not limited to C l C 2 , C 3 , and C 4 ) or alkoxy (including but not limited to C l C 2 , C 3 , and C 4 ), sulfonate esters such as alkyl or aralkyl sulphonyl including but not limited to me
• aliphatic refers to hydrocarbons which are not aromatic, including those having an open chain structure, such as alkanes, alkenes, and alkynes, ideally those with from 1-10 carbons, and cyclic hydrocarbons, ideally those with from 3-10 carbons.
• alkoxy and “alkoxyalkyl” embrace linear or branched oxy- containing radicals having alkyl moieties, such as methoxy radical.
• alkoxyalkyl also embraces alkyl radicals having one or more alkoxy radicals attached to the alkyl radical, that is, to form monoalkoxyalkyl and dialkoxyalkyl radicals.
• The“alkoxy” radicals can be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide“haloalkoxy” radicals.
• radicals include fluoromethoxy, chloromethoxy, trifluoromethoxy, difluoromethoxy, trifluoroethoxy, fluoroethoxy, tetrafluoroethoxy, pentafluoroethoxy, and fluoropropoxy.
• alkylamino denotes “monoalkyl amino” and “dialkylamino” containing one or two alkyl radicals, respectively, attached to an amino radical.
• arylamino denotes“monoarylamino” and“diarylamino” containing one or two aryl radicals, respectively, attached to an amino radical.
• aralkylamino embraces aralkyl radicals attached to an amino radical.
• aralkylamino denotes “monoaralkylamino” and“diaralkylamino” containing one or two aralkyl radicals, respectively, attached to an amino radical.
• aralkylamino further denotes “monoaralkyl monoalkylamino” containing one aralkyl radical and one alkyl radical attached to an amino radical.
• heteroatom refers to oxygen, sulfur, nitrogen and phosphorus.
• heteroaryl or “heteroaromatic,” as used herein, refer to an aromatic that includes at least one sulfur, oxygen, nitrogen or phosphorus in the aromatic ring.
• heterocyclic refers to a nonaromatic cyclic group wherein there is at least one heteroatom, such as oxygen, sulfur, nitrogen, or phosphorus in the ring.
• heteroaryl and heterocyclic groups include furyl, furanyl, pyridyl, pyrimidyl, thienyl, isothiazolyl, imidazolyl, tetrazolyl, pyrazinyl, benzofuranyl, benzothiophenyl, quinolyl, isoquinolyl, benzothienyl, isobenzofuryl, pyrazolyl, indolyl, isoindolyl, benzimidazolyl, purinyl, carbazolyl, oxazolyl, thiazolyl, isothiazolyl, 1,2,4- thiadiazolyl, isooxazolyl, pyrrolyl, quinazolinyl, cinnolinyl, phthalazinyl, xanthinyl, hypoxanthinyl, thiophene, furan, pyrrole, isopyrrole, pyrazole, imidazo
• the heteroaromatic group can be optionally substituted as described above for aryl.
• the heterocyclic or heteroaromatic group can be optionally substituted with one or more substituents selected from the group consisting of halogen, haloalkyl, alkyl, alkoxy, hydroxy, carboxyl derivatives, ami do, amino, alkylamino, and dialkylamino.
• the heteroaromatic can be partially or totally hydrogenated as desired.
• dihydropyridine can be used in place of pyridine.
• Suitable protecting groups are well known to those skilled in the art, and include trimethylsilyl, dimethylhexylsilyl, t-butyldimethylsilyl, and t-butyldiphenylsilyl, trityl or substituted trityl, alkyl groups, acyl groups such as acetyl and propionyl, methanesulfonyl, and p- toluenelsulfonyl.
• the heterocyclic or heteroaromatic group can be substituted with any moiety that does not adversely affect the reaction, including but not limited to but not limited to those described above for aryl.
• the term“host,” as used herein, refers to a unicellular or multicellular organism in which the virus can replicate, including but not limited to cell lines and animals, and, preferably, humans. Alternatively, the host can be carrying a part of the viral genome, whose replication or function can be altered by the compounds of the present invention.
• the term host specifically refers to infected cells, cells transfected with all or part of the viral genome and animals, in particular, primates (including but not limited to chimpanzees) and humans. In most animal applications of the present invention, the host is a human being.
• Veterinary applications in certain indications, however, are clearly contemplated by the present invention (such as for use in treating chimpanzees).
• peptide refers to a natural or synthetic compound containing two to one hundred amino acids linked by the carboxyl group of one amino acid to the amino group of another.
• pharmaceutically acceptable salt or prodrug is used throughout the specification to describe any pharmaceutically acceptable form (such as an ester) compound which, upon administration to a patient, provides the compound.
• Pharmaceutically-acceptable salts include those derived from pharmaceutically acceptable inorganic or organic bases and acids. Suitable salts include those derived from alkali metals such as potassium and sodium, alkaline earth metals such as calcium and magnesium, among numerous other acids well known in the pharmaceutical art.
• pharmaceutically acceptable salt or prodrug is used throughout the specification to describe any pharmaceutically acceptable form (such as an ester) compound which, upon administration to a patient, provides the compound.
• Pharmaceutically acceptable salts include those derived from pharmaceutically acceptable inorganic or organic bases and acids.
• Suitable salts include those derived from alkali metals such as potassium and sodium, alkaline earth metals such as calcium and magnesium, among numerous other acids well known in the pharmaceutical art.
• Pharmaceutically acceptable prodrugs refer to a compound that is metabolized, for example hydrolyzed or oxidized, in the host to form the compound of the present invention. Typical examples of prodrugs include compounds that have biologically labile protecting groups on functional moieties of the active compound.
• Prodrugs include compounds that can be oxidized, reduced, aminated, deaminated, hydroxylated, dehydroxylated, hydrolyzed, dehydrolyzed, alkylated, dealkylated, acylated, deacylated, sulfated, desulfated, phosphorylated, or dephosphorylated to produce the active compound.
• the prodrug forms of the compounds of this invention can possess antiviral activity, can be metabolized to form a compound that exhibits such activity, or both.
• HBV is an enveloped, partially double-stranded DNA (dsDNA) virus of the Hepadnavirus family (Hepadnaviridae). Its genome contains 4 overlapping reading frames: the precore/core gene; the polymerase gene; the L, M, and S genes, which encode for the 3 envelope proteins; and the X gene.
• dsDNA partially double-stranded DNA
• the partially double-stranded DNA genome (the relaxed circular DNA; rcDNA) is converted to a covalently closed circular DNA (cccDNA) in the nucleus of the host cell, and the viral mRNAs are transcribed.
• the pregenomic RNA (pgRNA), which also codes for core protein and Pol, serves as the template for reverse transcription, which regenerates the partially dsDNA genome (rcDNA) in the nucleocapsid.
• cccDNA can remain following clinical treatment in liver cells, and can reactivate.
• the relative quantity of cccDNA present is an indicator for HBV treatment (Bourne, et al, (January 2007). "Quantitative analysis of HBV cccDNA from clinical specimens: correlation with clinical and virological response during antiviral therapy". Journal of Viral Hepatitis 14 (1): 56-63).
• a capsid is the protein shell of a virus, and includes oligomeric structural subunits made of proteins called protomers.
• the capsid encloses the genetic material of the virus.
• HBV capsids assemble around an RNA-reverse transcriptase complex.
• capsid Assembly of the capsid is required for reverse transcription of the RNA pregenome to the mature DNA form.
• the dominant form of capsid is composed of 120 copies of the capsid protein dimer. Even modest mutations of the capsid protein can have dramatic effects on the viability of progeny virus.
• Inhibiting capsid assembly for example, by disrupting or adversely affecting capsid assembly, can reduce cccDNA, the main reservoir for HBV, and can also decrease the levels of HBV DNA, HBeAg and HBsAg.
• Compounds which do not necessarily inhibit formation of the capsid, but rather, modulate or affect the formation of capsids are also known as capsid assembly modulators or capsid assembly effectors, and their use in forming the dimers and trimers described herei is intended to be within the scope of the invention.
• the compounds are dimers or trimers of the formulas:
• Formula 1 Formula la or an enantiomer, a diasteroisomer, a tautomer, a pharmaceutically acceptable salt or prodrug thereof, wherein: A 1 , B 1 and C 1 are, independently, an HBV capsid assembly effector, each A 1 , and B 1 , and C 1 may be the same or different;
• L 1 is a chemical linker selected from the group consisting of -W 1 -(C3-6alkyl-0) s -Ci- ealkyl-W 1 -; -W 1 -(CH 2 -CH 2 -0)t-Ci-6alkyl-W 1 -; -W 1 -((CH 2 -CH 2 -0) s ) m -; W ⁇ Ci-so alkyl-W 1 -;
• R’ is H, Ci-6 alkyl, optionally unsaturated C3-8 cycloalkyl, C1-6 haloalkyl, C2-8 alkoxyalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, heteroaryl, alkylaryl, or arylalkyl,
• R 7 and R 8 are, independently, -OH, optionally unsaturated -O-C1-6 alkyl, C1-6 alkyl, C2-
• the compound has the following formula:
• R 1 is C2-6 alkenyl optionally substituted with one or more R a or C2-6 alkynyl optionally substituted with one or more R a
• R a is Ci-6 alkyl optionally substituted with one or more R
• C 2 -6 alkenyl optionally substituted with one or more R’ C 2 -6 alkynyl optionally substituted with one or more R’
• C3-6 cycloalkyl optionally substituted with one or more R b N3, -OR’, -C(0)0R’, oxo, -SF5,
• R b is independently Ci-6alkyl optionally substituted with cyano Ni. -O-R’, -C(0)0-R’,
• R d is, independently, cyclopropanyl, alkylamino carbonyl, amino carbonyl, alkyl carbonyl, cyclopropanyloxy, halocyclopropanyl, or halocyclopropanyloxy;
• A is a pyrrolidine or a 5-7 membered bicyclic heterocycle having one nitrogen, optionally substituted with one or more R 2 ;
• R 2 is, independently, hydrogen, halogen, OH, C1-6 alkyl, C 2 -6 alkene, C 2 -6 alkyne, haloalkyl, cycloalkyl, CN, amino, alkoxy, alkylsulfonylamino, azido or cycloalkyloxyl;
• R 3 is hydrogen, halogen, C1-6 alkyl, haloalkyl, alkyloxyl, haloalkyloxyl or cycloalkyl,
• R 4 is an C6-10 aryl optionally substituted with 1 to 5 R 4a or a 5-12 membered heteroaryl having one or more heteroatoms selected from the group consisting of N, O, and S, optionally substituted with one or more R 4b ;
• R 4a and R 4b are, independently, H, CN, halogen, -O-Ci-6 alkyl, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, alkylamino carbonyl, amino carbonyl, alkyl carbonyl, cyclopropanyloxy, halocyclopropanyl, or halocyclopropanyloxy;
• R’ is H, Ci-6 alkyl, C1-6 haloalkyl, C2-8 alkoxyalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, heteroaryl, alkylaryl, arylalkyl, a six-membered ring or a six-membered bridged or spiro-fused ring containing zero, one, or two heteroatoms which are, independently, N, O, or S, a seven- membered bridged or spiro-fused ring containing zero, one, or two heteroatoms which are, independently, N, O, or S, a five-membered ring containing zero, one, or two heteroatoms which are, independently, N, O, or S; a four-membered ring containing zero, one, or two heteroatoms which are, independently, N, O, or S; or a three membered ring containing zero or one heteroatom which are, independently, N, O, or S;
• R 10 and R n are, independently, H, Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, heteroaryl, alkylaryl, arylalkyl, a six-membered ring or a six-membered bridged or spiro- fused ring containing zero, one, or two heteroatoms which are, independently, N, O, or S, a seven-membered bridged or spiro-fused ring containing zero, one, or two heteroatoms which are, independently, N, O, or S, a five-membered ring containing zero, one, or two heteroatoms which are, independently, N, O, or S; a four-membered ring containing zero, one, or two heteroatoms which are, independently, N, O, or S; or a three membered ring containing zero or one heteroatom which are, independently, N, O, or S, alternatively, R
• R 10 and R 11 groups can optionally be substituted with one or more substituents, which substituents are, independently, halo, Ci-6 haloalkyl, C 1-6 hydroxy alkyl, hydroxyl, carboxyl, acyl, aryl, acyloxy, amino, amido, carboxyl derivatives, alkylamino, dialkylamino, arylamino, alkoxy, alkoxyalkyl, aryloxy, nitro, cyano, sulfonic acid, thiol, imine, sulfonyl, sulfanyl, sulfinyl, sulfamonyl, ester, carboxylic acid, amide, phosphonyl, phosphinyl, phosphoryl, phosphine, thioester, thioether, oxime, hydrazine, carbamate, phosphonic acid, or phosphonate.
• substituents are, independently, halo, Ci-6
• the compound has the same general formula as Formula 2 shown above, or is an enantiomer, a diasteroisomer, a tautomer, a pharmaceutically acceptable salt or prodrug thereof, but the variables are defined as follows:
• R 1 is Ci-6 alkyl substituted with one or more R a , C3-6 cycloalkyl substituted with one or more R b , or monocyclic or bicyclic heterocyclyl containing one or more heteroatoms selected from the group consisting of N, O, and S, optionally substituted with one or more R c ;
• R a is Ci-6 alkyl optionally substituted with one or more R , C 2 -6 alkenyl optionally substituted with one or more R’, C 2 -6 alkynyl optionally substituted with one or more R’, C3-6 cycloalkyl optionally substituted with one or more R b , N3, -OR’, -C(0)0-R’, oxo, -SF5,
• R b is independently Ci-6 alkyl optionally substituted with cyano, N3, -O-R’, -C(0)0-
• heteroaryl containing one or more heteroatoms selected from the group consisting ofN, O, and S, optionally substituted with one or more R d , cycloalkylalkynyl, cycloalkyloxyl, or halocycloalkylalkyl;
• R c is, independently, C 2 -6 alkenyl optionally substituted with one or more R a , C 2 -6 alkynyl optionally substituted with one or more R a , C3-6 cycloalkyl optionally substituted with
• R d is, independently, cyclopropanyl, alkylamino carbonyl, amino carbonyl, alkyl carbonyl, cyclopropanyloxy, halocyclopropanyl, or halocyclopropanyloxy;
• A is a pyrrolidine or a 5-7 membered bicyclic heterocycle having one nitrogen, optionally substituted with one or more R 2 ;
• R 2 is, independently, hydrogen, halogen, OH, Ci-6 alkyl, C 2 -6 alkene, C 2 -6 alkyne, haloalkyl, cycloalkyl, CN, amino, alkoxy, alkylsulfonylamino, azido or cycloalkyloxyl;
• R 3 is hydrogen, halogen, Ci-6 alkyl, haloalkyl, alkyloxyl, haloalkyloxyl or cycloalkyl,
• R 4 is an Ce-io aryl optionally substituted with 1 to 5 R 4a or a 5-12 membered heteroaryl having one or more heteroatoms selected from the group consisting of N, O, and S, optionally substituted with one or more R 4b ;
• R 4a and R 4b are, independently, H, CN, halogen, -O-Ci-6 alkyl, Ci-6 alkyl, C2-6 alkenyl, C 2 -6 alkynyl, C3-6 cycloalkyl, alkylamino carbonyl, amino carbonyl, alkyl carbonyl, cyclopropanyloxy, halocyclopropanyl, or halocyclopropanyloxy;
• R’ is H, Ci-6 alkyl, Ci-6 haloalkyl, C 2 -8 alkoxyalkyl, C 2 -6 alkenyl, C 2 -6 alkynyl, aryl, heteroaryl, alkylaryl, arylalkyl, a six-membered ring or a six-membered bridged or spiro-fused ring containing zero, one, or two heteroatoms which are, independently, N, O, or S, a seven- membered bridged or spiro-fused ring containing zero, one, or two heteroatoms which are, independently, N, O, or S, a five-membered ring containing zero, one, or two heteroatoms which are, independently, N, O, or S; a four-membered ring containing zero, one, or two heteroatoms which are, independently, N, O, or S; or a three membered ring containing zero or one heteroatom which are, independently, N, O, or
• R 10 and R n are, independently, H, Ci-6 alkyl, Ci-6 haloalkyl, C 2 -6 alkenyl, C 2 -6 alkynyl, aryl, heteroaryl, alkylaryl, arylalkyl, a six-membered ring or a six-membered bridged or spiro- fused ring containing zero, one, or two heteroatoms which are, independently, N, O, or S, a seven-membered bridged or spiro-fused ring containing zero, one, or two heteroatoms which are, independently, N, O, or S, a five-membered ring containing zero, one, or two heteroatoms which are, independently, N, O, or S; a four-membered ring containing zero, one, or two heteroatoms which are, independently, N, O, or S; or a three membered ring containing zero or one heteroatom which are, independently, N, O, or S, alternatively
• R 10 and R 11 groups can optionally be substituted with one or more substituents, which substituents are, independently, halo, Ci-6 haloalkyl, Ci-6 hydroxy alkyl, hydroxyl, carboxyl, acyl, aryl, acyloxy, amino, amido, carboxyl derivatives, alkylamino, dialkylamino, arylamino, alkoxy, alkoxyalkyl, aryloxy, nitro, cyano, sulfonic acid, thiol, imine, sulfonyl, sulfanyl, sulfmyl, sulfamonyl, ester, carboxylic acid, amide, phosphonyl, phosphinyl, phosphoryl, phosphine, thioester, thioether, oxime, hydrazine, carbamate, phosphonic acid, or phosphonate, wherein at least one of R 2 , R’, R a
• R 3 is haloalkyl, alkyloxyl, haloalkyloxyl, or cycloalkyl.
• R 1 is Ci-6 alkyl substituted with one or more R a , C3-6 cycloalkyl substituted with one or more R b , or monocyclic or bicyclic heterocyclyl containing one or more heteroatoms selected from the group consisting of N, O, and S, optionally substituted with one or more R c ;
• R a is Ci-6 alkyl optionally substituted with one or more R , C2-6 alkenyl optionally substituted with one or more R’, C2-6 alkynyl optionally substituted with one or more R’, C3-6 cycloalkyl optionally substituted with one or more R b , N3, -OR’, -C(0)0-R’, oxo, -SF5,
• R b is independently C1-6 alkyl optionally substituted with cyano, N3, -O-R’, -C(0)0- , or C5-8 heteroaryl containing one or more heteroatoms selected from the group consisting ofN, O, and S, optionally substituted with one or more R d , cycloalkylalkynyl, cycloalkyloxyl, or halocycloalkylalkyl;
• R c is, independently, C 2 -6 alkenyl optionally substituted with one or more R a , C 2 -6 alkynyl optionally substituted with one or more R a , C3-6 cycloalkyl optionally substituted with
• R d is, independently, cyclopropanyl, alkylamino carbonyl, amino carbonyl, alkyl carbonyl, cyclopropanyloxy, halocyclopropanyl, or halocyclopropanyloxy;
• A is a pyrrolidine or a 5-7 membered bicyclic heterocycle having one nitrogen, optionally substituted with one or more R 2 ;
• R 2 is, independently, hydrogen, halogen, OH, C1-6 alkyl, C 2 -6 alkene, C 2 -6 alkyne, haloalkyl, cycloalkyl, CN, amino, alkoxy, alkylsulfonylamino, azido or cycloalkyloxyl;
• R 3 is hydrogen, halogen, C1-6 alkyl, haloalkyl, alkyloxyl, haloalkyloxyl or cycloalkyl
• R 4 is an Ce-io aryl optionally substituted with 1 to 5 R 4a or a 5-12 membered heteroaryl having one or more heteroatoms selected from the group consisting of N, O, and S, optionally substituted with one or more R 4b ;
• R 4a and R 4b are, independently, H, CN, halogen, -O-Ci-6 alkyl, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, alkylamino carbonyl, amino carbonyl, alkyl carbonyl, cyclopropanyloxy, halocyclopropanyl, or halocyclopropanyloxy;
• R’ is H, Ci-6 alkyl, C1-6 haloalkyl, C2-8 alkoxyalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, heteroaryl, alkylaryl, arylalkyl, a six-membered ring or a six-membered bridged or spiro-fused ring containing zero, one, or two heteroatoms which are, independently, N, O, or S, a seven- membered bridged or spiro-fused ring containing zero, one, or two heteroatoms which are, independently, N, O, or S, a five-membered ring containing zero, one, or two heteroatoms which are, independently, N, O, or S; a four-membered ring containing zero, one, or two heteroatoms which are, independently, N, O, or S; or a three membered ring containing zero or one heteroatom which are, independently, N, O, or S;
• R 10 and R n are, independently, H, Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, heteroaryl, alkylaryl, arylalkyl, a six-membered ring or a six-membered bridged or spiro- fused ring containing zero, one, or two heteroatoms which are, independently, N, O, or S, a seven-membered bridged or spiro-fused ring containing zero, one, or two heteroatoms which are, independently, N, O, or S, a five-membered ring containing zero, one, or two heteroatoms which are, independently, N, O, or S; a four-membered ring containing zero, one, or two heteroatoms which are, independently, N, O, or S; or a three membered ring containing zero or one heteroatom which are, independently, N, O, or S, alternatively, R
• R 10 and R 11 groups can optionally be substituted with one or more substituents, which substituents are, independently, halo, Ci-6 haloalkyl, C 1-6 hydroxy alkyl, hydroxyl, carboxyl, acyl, aryl, acyloxy, amino, amido, carboxyl derivatives, alkylamino, dialkylamino, arylamino, alkoxy, alkoxyalkyl, aryloxy, nitro, cyano, sulfonic acid, thiol, imine, sulfonyl, sulfanyl, sulfmyl, sulfamonyl, ester, carboxylic acid, amide, phosphonyl, phosphinyl, phosphoryl, phosphine, thioester, thioether, oxime, hydrazine, carbamate, phosphonic acid, or phosphonate, wherein at least one of R 2 , R’, R a
• R 3 is haloalkyl, alkyloxyl, haloalkyloxyl, or cycloalkyl.
• R 1 is Ci-6 alkyl
• R a is Ci-6 alkyl optionally substituted with one or more R
• C2-6 alkenyl optionally substituted with one or more R’ C2-6 alkynyl optionally substituted with one or more R’
• C3-6 cycloalkyl optionally substituted with
• R b is independently Ci-6 alkyl optionally substituted with cyano, N3, -O-R’, -C(0)0- 0 O
• R 1 is cycloalkyl
• R b is Ci-6 alkyl substituted with cyano, N3, -O-R’, -C(0)0-R’, oxo, -SF5, ,
• OR 11 or C5-8 heteroaryl containing one or more heteroatoms selected from the group consisting of N, O, and S, substituted with one or more R d , cycloalkylalkynyl, cycloalkyloxyl, or halocycloalkylalkyl.
• At least one of R 2 , R’, R a , or R c is C 2 -6 alkenyl or C 2 -6 alkynyl.
• the compound has the formula:
• W 1 and W are each independently selected from the group consisting of N, NR m , CR m , O and S, with the proviso that when one of W and W 1 is O or S, the other is CR m ; and wherein when one of W 1 or W is N, the other is NR m ,
• X is N or CR n
• Y is a bond,-C(0)- or -S0 2 -;
• Z is NH or -(CR 6 R 7 ) m -NH-; n is 0, 1, 2 or 3, m is 0, 1, 2, 3 or 4,
• R m and R n are, independently, H, Ci-6 alkyl, C2-6 alkynyl, or C2-6 alkenyl;
• R 1 is C2-6 alkynyl, optionally substituted with one or more R z ,
• R z is Ci-6 alkyl, Ci-6 haloalkyl, C1-6 alkyl-OH, aryl, heteroaryl, C3-6 cycloalkyl, C3-6
• halocycloalkyl Cs-e heterocydyl, CN, -C(0)R ⁇ -C(0)0-R , OR 1 1 , N(R’)S(0) 2 R’, -S-R’;
• R 2 , R 3 and R 4 are independently selected from the group consisting ofH, OH, halo, Ci- 6 alkyl, C 1-6 haloalkyl, O-C1-6 alkyl, -O-C 1-6 haloalkyl, C2-6 alkynyl, C2-6 alkenyl, C3-6 cycloalkyl, C3-6 halocycloalkyl, C3-6heterocyclyl, -CN, O-C3-6 cycloalkyl, and O-C3-6 halocycloalkyl; alternatively, R 2 and R 3 can come together to form a 5-7 heterocyclic ring containing 1 to 3 heteroatoms selected from the group consisting of N, O and S, alternatively, R 2 and R 4 can come together to form a C3-6 cycloalkyl ring or a 3-7 heterocyclic ring containing 1 to 3 heteroatoms selected from the group consisting of N, O and S,
• R 5 is Ci-6 alkyl, optionally substituted with one or more R a , C2-6 alkenyl, optionally substituted with one or more R a , C2-6 alkynyl, optionally substituted with one or more R a , C3-6 cycloalkyl optionally substituted with one or more R b , or monocyclic or bicyclic heterocyclyl containing one or more heteroatoms selected from the group consisting of N, O, and S, optionally substituted with one or more R c ;
• R 6 is, at each occurrence, independently selected from the group consisting ofH,—OH, halo, Ci-C6-alkyl, Ci-C6-haloalkyl,— O— Ci-C6-alkyl, and Ci-C6-alkyl-OH;
• R 7 is selected from the group consisting ofH, Ci-C6-alkyl, and Ci-C6-alkyl-OH;
• R a is Ci-6 alkyl optionally substituted with one or more R’, C2-6 alkenyl optionally substituted with one or more R’, C2-6 alkynyl optionally substituted with one or more R’, C3-6 cycloalkyl optionally substituted with one or more R b , N3, -O-R’, -C(0)0-R’, oxo, -SF5,
• R b is independently Ci-6 alkyl optionally substituted with cyano N3, -O-R’, -C(0)0-R’,
• R 1U R C5-8 heteroaryl containing one or more heteroatoms selected from the group consisting of N, O, and S, optionally substituted with one or more R d , cycloalkylalkynyl, cycloalkyloxyl, or halocycloalkylalkyl;
• R c is, independently, C 2 -6 alkenyl optionally substituted with one or more R a , C 2 -6 alkynyl optionally substituted with one or more R a , C3-6 cycloalkyl optionally substituted with
• R d is independently cyclopropanyl, alkylamino carbonyl, amino carbonyl, alkyl carbonyl, cyclopropanyloxy, halocyclopropanyl, halocyclopropanyloxy;
• R’ is H, Ci-6 alkyl, C1-6 haloalkyl, C 2 -8 alkoxyalkyl, C 2 -6 alkenyl, C 2 -6 alkynyl, aryl, heteroaryl, alkylaryl, arylalkyl, a six-membered ring or a six-membered bridged or spiro-fused ring containing zero, one, or two heteroatoms which are, independently, N, O, or S, a seven- membered bridged or spiro-fused ring containing zero, one, or two heteroatoms which are, independently, N, O, or S, a five-membered ring containing zero, one, or two heteroatoms which are, independently, N, O, or S; a four-membered ring containing zero, one, or two heteroatoms which are, independently, N, O, or S; or a three membered ring containing zero or one heteroatom which are, independently, N, O, or
• R 10 and R 11 groups can optionally be substituted with one or more substituents, which substituents are, independently, halo, Ci-6 haloalkyl, C 1-6 hydroxy alkyl, hydroxyl, carboxyl, acyl, aryl, acyloxy, amino, amido, carboxyl derivatives, alkylamino, dialkylamino, arylamino, alkoxy, alkoxyalkyl, aryloxy, nitro, cyano, sulfonic acid, thiol, imine, sulfonyl, sulfanyl, sulfmyl, sulfamonyl, ester, carboxylic acid, amide, phosphonyl, phosphinyl, phosphoryl, phosphine, thioester, thioether, oxime, hydrazine, carbamate, phosphonic acid, or phosphonate.
• substituents are, independently, halo, Ci-6
• the compound has the same Formula 3 as shown above, or is an enantiomer, a diasteroisomer, a tautomer, a pharmaceutically acceptable salt or prodrug thereof, but the variables are defined as follows:
• W 1 and W are each independently selected from the group consisting of N, NR m , CR m , O and S, with the proviso that when one of W and W 1 is O or S, the other is CR m ; and wherein when one of W 1 or W is N, the other is NR m ,
• X is N or CR n
• Y is a bond, -C(O)- or -SO2-;
• Z is NH or -(CR 6 R 7 ) m -NH-; n is 0, 1, 2 or 3, m is 0, 1, 2, 3 or 4,
• R m and R n are, independently, H, C 1-6 alkyl, C2-6 alkynyl, or C2-6 alkenyl;
• R 1 is C2-6 alkenyl substituted with one or more R y , C3-8-cycloalkyl substituted with one or more R y , C3-6 heterocyclyl substituted with one or more R y , or C 1-6 alkyl substituted with one or more R y ,
• R y is C2-6 alkynyl, C2-6 alkenyl, aryl, heteroaryl, C3-6 cycloalkyl, C3-6halocycloalkyl, C3-
• R 2 , R 3 and R 4 are independently selected from the group consisting ofH, OH, halo, Ci- 6 alkyl, Ci-6haloalkyl, O-C1-6 alkyl, -0-Ci-6haloalkyl, C2-6 alkynyl, C2-6 alkenyl, C3-6 cycloalkyl, C3-6 halocycloalkyl, C3-6 heterocyclyl, -CN, O-C3-6 cycloalkyl, and 0-C3-6halocycloalkyl; alternatively, R 2 and R 3 can come together to form a 5-7 heterocyclic ring containing 1 to 3 heteroatoms selected from the group consisting of N, O and S, alternatively, R 2 and R 4 can come together to form a C3-6 cycloalkyl ring or a 3-7 heterocyclic ring containing 1 to 3 heteroatoms selected from the group consisting of N, O and S,
• R 5 is Ci-6 alkyl, optionally substituted with one or more R a , C2-6 alkenyl, optionally substituted with one or more R a , C2-6 alkynyl, optionally substituted with one or more R a , C3-6 cycloalkyl optionally substituted with one or more R b , or monocyclic or bicyclic heterocyclyl containing one or more heteroatoms selected from the group consisting of N, O, and S, optionally substituted with one or more R c ;
• R 6 is, at each occurrence, independently selected from the group consisting ofH,—OH, halo, Ci-C6-alkyl, Ci-C6-haloalkyl,— O— Ci-C6-alkyl, and Ci-C6-alkyl-OH;
• R 7 is selected from the group consisting ofH, Ci-C6-alkyl, and Ci-C6-alkyl-OH;
• R a is Ci-6 alkyl optionally substituted with one or more R’, C 2 -6 alkenyl optionally substituted with one or more R’, C 2 -6 alkynyl optionally substituted with one or more R’, C3-6 cycloalkyl optionally substituted with one or more R b , N3, -O-R’, -C(0)0-R’, oxo, -SF5,
• R b is independently Ci-6 alkyl optionally substituted with cyano Ni. -O-R’, -C(0)0-R’,
• R c is, independently, C 2 -6 alkenyl optionally substituted with one or more R a , C 2 -6 alkynyl optionally substituted with one or more R a , C3-6 cycloalkyl optionally substituted with
• R d is independently cyclopropanyl, alkylamino carbonyl, amino carbonyl, alkyl carbonyl, cyclopropanyloxy, halocyclopropanyl, halocyclopropanyloxy;
• R’ is H, Ci-6 alkyl, Ci-6 haloalkyl, C 2 -8 alkoxyalkyl, C 2 -6 alkenyl, C 2 -6 alkynyl, aryl, heteroaryl, alkylaryl, arylalkyl, a six-membered ring or a six-membered bridged or spiro-fused ring containing zero, one, or two heteroatoms which are, independently, N, O, or S, a seven- membered bridged or spiro-fused ring containing zero, one, or two heteroatoms which are, independently, N, O, or S, a five-membered ring containing zero, one, or two heteroatoms which are, independently, N, O, or S; a four-membered ring containing zero, one, or two heteroatoms which are, independently, N, O, or S; or a three membered ring containing zero or one heteroatom which are, independently, N, O, or
• R 10 and R n are, independently, H, Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, heteroaryl, alkylaryl, arylalkyl, a six-membered ring or a six-membered bridged or spiro- fused ring containing zero, one, or two heteroatoms which are, independently, N, O, or S, a seven-membered bridged or spiro-fused ring containing zero, one, or two heteroatoms which are, independently, N, O, or S, a five-membered ring containing zero, one, or two heteroatoms which are, independently, N, O, or S; a four-membered ring containing zero, one, or two heteroatoms which are, independently, N, O, or S; or a three membered ring containing zero or one heteroatom which are, independently, N, O, or S; alternatively, R
• R 10 and R 11 groups can optionally be substituted with one or more substituents, which substituents are, independently, halo, Ci-6 haloalkyl, C 1-6 hydroxy alkyl, hydroxyl, carboxyl, acyl, aryl, acyloxy, amino, amido, carboxyl derivatives, alkylamino, dialkylamino, arylamino, alkoxy, alkoxyalkyl, aryloxy, nitro, cyano, sulfonic acid, thiol, imine, sulfonyl, sulfanyl, sulfmyl, sulfamonyl, ester, carboxylic acid, amide, phosphonyl, phosphinyl, phosphoryl, phosphine, thioester, thioether, oxime, hydrazine, carbamate, phosphonic acid, or phosphonate.
• substituents are, independently, halo, Ci-6
• the compound has the formula:
• Formula 4 or is an enantiomer, a diasteroisomer, a tautomer, a pharmaceutically acceptable salt or prodrug thereof, wherein:
• W 1 and W are each, independently, N, NR m , CR m , O or S; with the proviso that when one of W and W 1 is O or S, the other is CR m , and wherein when one of W 1 or W is N, the other is NR m ,
• X is NR m or CR n ,
• Y is a bond, -C(O)- or -SO2-;
• Z is NH or -(CR 6 R 7 ) m -NH-; n is 0, 1, 2 or 3, m is 0, 1, 2, 3 or 4,
• R m and R n are, independently, H, Ci-6 alkyl, C2-6 alkynyl, or C2-6 alkenyl;
• R 2 , R 3 and R 4 are, independently, -O-C1-6 haloalkyl, C2-6 alkynyl, C2-6 alkenyl, C3-6 cycloalkyl, C3-6 halocycloalkyl, C3-6 heterocyclyl, -CN, -O-C3-6 cycloalkyl, or -O-C3-6 halocycloalkyl; alternatively, R 2 and R 3 can come together to form a 5-7 heterocyclic ring containing 1 to 3 heteroatoms selected from the group consisting of N, O and S; alternatively, R 2 and R 4 can come together to form a C3-6 cycloalkyl ring or a 3-7 heterocyclic ring containing 1 to 3 heteroatoms selected from the group consisting of N, O and S;
• R 1 is C3-6 cycloalkyl, C3-6 heterocyclyl, Ci-6 alkyl, halo, C2-6 alkynyl optionally substituted with one or more R z , C2-6 alkenyl optionally substituted with one or more R y , C3-8- cycloalkyl optionally substituted with one or more R y , or C3-6 heterocyclyl, optionally substituted with one or more R y , or Ci-6 alkyl optionally substituted with one or more R y ,
• R z is Ci-6 alkyl, Ci-6haloalkyl, Ci-6 alkyl-OH, C2-6 alkynyl, C2-6 alkenyl, aryl, heteroaryl,
• R y is Ci-6 alkyl, Ci-6haloalkyl, C1-6 alkyl-OH, C 2 -6 alkynyl, C 2 -6 alkenyl, aryl, heteroaryl,
• R 5 is Ci-6 alkyl, optionally substituted with one or more R a , C 2 -6 alkenyl, optionally substituted with one or more R a , C 2 -6 alkynyl, optionally substituted with one or more R a , C3-6 cycloalkyl, optionally substituted with one or more R b , or a monocyclic or bicyclic heterocyclyl containing one or more heteroatoms selected from the group consisting of N, O, and S, optionally substituted with one or more R c ;
• R 6 is, at each occurrence, independently selected from the group consisting ofH,—OH, halo, Ci-C6-alkyl, Ci-C6-haloalkyl, -0-Ci-C6-alkyl, and Ci-C6-alkyl-OH;
• R 7 is selected from the group consisting ofH, Ci-C6-alkyl, and Ci-C6-alkyl-OH;
• R a is Ci-6 alkyl, optionally substituted with one or more R’, C 2 -6 alkenyl, optionally substituted with one or more R’, C 2 -6 alkynyl, optionally substituted with one or more R’, or C3-6 cycloalkyl, optionally substituted with one or more R b , -N3, -OR’, -C(0)0-R’, oxo, -SF5,
• R b is independently C 1-6 alkyl, optionally substituted with cyano, -N3, -OR’, -C(0)0-
• OR 1 1 or C5-8 heteroaryl containing one or more heteroatoms selected from the group consisting ofN, O, and S, optionally substituted with one or more R d , cycloalkylalkynyl, cycloalkyloxyl, halocycloalkylalkyl;
• R c is, independently, C 2 -6 alkenyl, optionally substituted with one or more R a , C 2 -6 alkynyl, optionally substituted with one or more R a , C3-6 cycloalkyl, optionally substituted with
• R d is, independently, cyclopropanyl, alkylamino carbonyl, amino carbonyl, alkyl carbonyl, cyclopropanyloxy, halocyclopropanyl, or halocyclopropanyloxy;
• R’ is H, Ci-6 alkyl, C1-6 haloalkyl, C 2 -8 alkoxyalkyl, C 2 -6 alkenyl, C 2 -6 alkynyl, aryl, heteroaryl, alkylaryl, arylalkyl, a six-membered ring or a six-membered bridged or spiro-fused ring containing zero, one, or two heteroatoms which are, independently, N, O, or S, a seven- membered bridged or spiro-fused ring containing zero, one, or two heteroatoms which are, independently, N, O, or S, a five-membered ring containing zero, one, or two heteroatoms which are, independently, N, O, or S; a four-membered ring containing zero, one, or two heteroatoms which are, independently, N, O, or S; or a three membered ring containing zero or one heteroatom which are, independently, N, O, or
• R 10 and R n are, independently, H, C1-6 alkyl, C1-6 haloalkyl, C 2 -6 alkenyl, C 2 -6 alkynyl, aryl, heteroaryl, alkylaryl, arylalkyl, a six-membered ring or a six-membered bridged or spiro- fused ring containing zero, one, or two heteroatoms which are, independently, N, O, or S, a seven-membered bridged or spiro-fused ring containing zero, one, or two heteroatoms which are, independently, N, O, or S, a five-membered ring containing zero, one, or two heteroatoms which are, independently, N, O, or S; a four-membered ring containing zero, one, or two heteroatoms which are, independently, N, O, or S; or a three membered ring containing zero or one heteroatom which are, independently, N, O, or S, alternatively
• R 10 and R 11 groups can optionally be substituted with one or more substituents, which substituents are, independently, halo, Ci-6 haloalkyl, Ci-6 hydroxy alkyl, hydroxyl, carboxyl, acyl, aryl, acyloxy, amino, amido, carboxyl derivatives, alkylamino, dialkylamino, arylamino, alkoxy, alkoxyalkyl, aryloxy, nitro, cyano, sulfonic acid, thiol, imine, sulfonyl, sulfanyl, sulfmyl, sulfamonyl, ester, carboxylic acid, amide, phosphonyl, phosphinyl, phosphoryl, phosphine, thioester, thioether, oxime, hydrazine, carbamate, phosphonic acid, or phosphonate.
• substituents are, independently, halo, Ci-6 hal
• At least one of R’, R a , R c , R m , R n , R y , R z , R 1 , R 2 , R3, R 4 , or R 5 is C2-6 alkynyl.
• the compound has the formula:
• Formula 5 is an enantiomer, a diasteroisomer, a tautomer, a pharmaceutically acceptable salt or prodrug thereof, wherein:
• W 1 and W are each independently N, NR m , CR m , O or S, with the proviso that when one of W and W 1 is O or S, the other is CR m , and with the proviso that when one of W and W 1 is O or S, the other is CR m , and wherein when one of W 1 or W is N, the other is NR m , X is N or CR 1
• Y is a bond, -C(O)-, or -S0 2 -;
• Z is NH or -(CR 6 R 7 ) m -NH-; n is 0, 1, 2 or 3, m is 0, 1, 2, 3 or 4
• R m and R n are, independently, H, Ci-6 alkyl, C 2 -6 alkynyl, or C 2 -6 alkenyl;
• R 5 is Ci-4 alkyl, optionally substituted with one or more R b , C 2 -6 alkenyl, optionally substituted with one or more R a , C 2 -6 alkynyl, optionally substituted with one or more R a , C3-6 cycloalkyl, optionally substituted with one or more R a , or monocyclic or bicyclic heterocyclyl containing one or more heteroatoms selected from the group consisting of N, O, and S, optionally substituted with one or more R c ;
• R 6 is, at each occurrence, independently selected from the group consisting ofH,—OH, halo, Ci-C6-alkyl, Ci-C6-haloalkyl, -0-Ci-C6-alkyl, and Ci-C6-alkyl-OH;
• R 7 is selected from the group consisting ofH, Ci-C6-alkyl, and Ci-C6-alkyl-OH;
• R a is Ci-6 alkyl, optionally substituted with one or more R’, C 2 -6 alkenyl, optionally substituted with one or more R’, C 2 -6 alkynyl, optionally substituted with one or more R’, C3-6 cycloalkyl, optionally substituted with one or more R , N3, -O-R’, -C(0)0-R’, oxo, -SF5,
• R b is, independently, Ci-6 alkyl, optionally substituted with one or more R a , -N3, -OR’,
• R c is, independently, C 2 -6 alkenyl, optionally substituted with one or more R a , C 2 -6 alkynyl, optionally substituted with one or more R a , C3-6 cycloalkyl, optionally substituted with
• R d is, independently, cyclopropanyl, alkylamino carbonyl, amino carbonyl, alkyl carbonyl, cyclopropanyloxy, halocyclopropanyl, or halocyclopropanyloxy;
• R’ is H, Ci-6 alkyl, C 1-6 haloalkyl, C 2 -8 alkoxy alkyl, C 2 -6 alkenyl, C 2 -6 alkynyl, aryl, heteroaryl, alkylaryl, arylalkyl, a six-membered ring or a six-membered bridged or spiro-fused ring containing zero, one, or two heteroatoms which are, independently, N, O, or S, a seven- membered bridged or spiro-fused ring containing zero, one, or two heteroatoms which are, independently, N, O, or S, a five-membered ring containing zero, one, or two heteroatoms which are, independently, N, O, or S; a four-membered ring containing zero, one, or two heteroatoms which are, independently, N, O, or S; or a three membered ring containing zero or one heteroatom which are, independently, N, O,
• R 10 and R n are, independently, H, Ci-6 alkyl, Ci-6 haloalkyl, C 2 -6 alkenyl, C 2 -6 alkynyl, aryl, heteroaryl, alkylaryl, arylalkyl, a six-membered ring or a six-membered bridged or spiro- fused ring containing zero, one, or two heteroatoms which are, independently, N, O, or S, a seven-membered bridged or spiro-fused ring containing zero, one, or two heteroatoms which are, independently, N, O, or S, a five-membered ring containing zero, one, or two heteroatoms which are, independently, N, O, or S; a four-membered ring containing zero, one, or two heteroatoms which are, independently, N, O, or S; or a three membered ring containing zero or one heteroatoms which are, independently N, O, or S; alternatively
• R 10 and R 11 groups can optionally be substituted with one or more substituents, which substituents are, independently, halo, Ci-6 haloalkyl, C 1-6 hydroxyalkyl, hydroxyl, carboxyl, acyl, aryl, acyloxy, amino, amido, carboxyl derivatives, alkylamino, dialkylamino, arylamino, alkoxy, alkoxyalkyl, aryloxy, nitro, cyano, sulfonic acid, thiol, imine, sulfonyl, sulfanyl, sulfmyl, sulfamonyl, ester, carboxylic acid, amide, phosphonyl, phosphinyl, phosphoryl, phosphine, thioester, thioether, oxime, hydrazine, carbamate, phosphonic acid, or phosphonate;
• R 1 is Ci-6 alkyl, halo, C2-6 alkynyl optionally substituted with one or more R z , C2-6 alkenyl, optionally substituted with one or more R y , C3-8 cycloalkyl, optionally substituted with one or more R y , C3-6 heterocyclyl, optionally substituted with one or more R y , Ci-6 alkyl optionally substituted with one or more R y ,
• R z is Ci-6 alkyl, Ci-6 haloalkyl, Ci-6 hydroxyalkyl, C2-6 alkynyl, C2-6 alkenyl, aryl, heteroaryl, C3-6 cycloalkyl, C3-6 halocycloalkyl, C3-6 heterocyclyl, -CN, -C(0)R’, -C(0)0-R’,
• R y is Ci-6 alkyl, Ci-6 haloalkyl, Ci-6 hydroxyalkyl, C2-6 alkynyl, C2-6 alkenyl, aryl, heteroaryl, C3-6 cycloalkyl, C3-6 halocycloalkyl, C3-6 heterocyclyl, CN, -C(0)R’, -C(0)0-R’, R 1( t
• R 2 , R 3 and R 4 are, independently, H, OH, halo, Ci-6 alkyl, Ci-6 haloalkyl, -O-Ci-6 alkyl, Ci-6 alkyl-OH, -0-Ci-6 haloalkyl, C 2 -6 alkynyl, C 2 -6 alkenyl, C3-6 cycloalkyl, C3-6halocycloalkyl, C3-6 heterocyclyl, -CN, -O-C3-6 cycloalkyl, or -0-C3-6 halocycloalkyl; alternatively, R 2 and R 3 can come together to form a 5-7 heterocyclic ring containing 1 to 3 heteroatoms selected from the group consisting of N, O and S; and alternatively, R 2 and R 4 can come together to form a C3-6 cycloalkyl ring or a 3-7 heterocyclic ring containing 1 to 3 heteroatoms selected from the group consisting ofN, O and S, wherein at least one of R’
• the compound has the formula:
• Formula 6 is an enantiomer, diasteroisomer, tautomer, pharmaceutically acceptable salt or prodrug thereof, wherein:
• A is H, CN, OH, Ci-3 alkyl, C1-3 haloalkyl, Cm hydroxyalkyl, Cm thioalkyl or halogen;
• R 1 is , or an optionally substituted C 1-6 alkyl
• R 2 is hydrogen, deuterium or C1-3 alkyl optionally substituted with one or more fluoro atoms; or R 2 and A, together with the carbons to which they are attached, form a 4-7 membered ring, optionally containing one or more heteroatoms, where each is, independently, O, S or N, wherein the 4-7 membered ring is optionally substituted with one or more substituents selected from the group consisting of C1-C3 alkyl, halogen, oxo and OH; each R 3 is, independently, H, -CN, -OH, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 hydroxy alkyl, Ci-3 thioalkyl or halogen;
• R 6 is H, Ci-3 alkyl, or C1-3 haloalkyl
• B is -(CR 7 R 7a ) n - or -C(O)-, where n is 0, 1, 2 or 3, each a is independently 0, 1, 2, 3 or 4; each R 7 andR 7a is independently H, C1-6 alkyl or C1-6 haloalkyl; alternatively, R 7 and R 7a can come together with the carbon to which they are attached to form a 6-10 membered bi cyclic or bridged ring, a 3 to 8 saturated ring, or a 5 membered unsaturated ring; such bicyclic, bridged, saturated and unsaturated rings optionally containing one or more additional heteroatoms, where each is, independently, O, S or N, and optionally being substituted with one or more substituents, wherein each, independently, is halogen (including F, Cl, Br, I), -CF3, hydroxy, -N(R’)S(0)2R’, -S(0)2R’, -S(0)2N(R’)2, C 1-6 alkoxy, cyano
• R’ is H, Ci-6 alkyl, C1-6 haloalkyl, C2-8 alkoxyalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, heteroaryl, alkylaryl, arylalkyl, a six-membered ring or a six-membered bridged or spiro-fused ring containing zero, one, or two heteroatoms which are, independently, N, O, or S, a seven- membered bridged or spiro-fused ring containing zero, one, or two heteroatoms which are, independently, N, O, or S, a five-membered ring containing zero, one, or two heteroatoms which are, independently, N, O, or S; a four-membered ring containing zero, one, or two heteroatoms which are, independently, N, O, or S; or a three membered ring containing zero or one heteroatom which are, independently, N, O, or S, R
• R 10 and R 11 are, independently, H, Ci-6 alkyl, Ci-6 haloalkyl, C2-8 alkoxyalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, heteroaryl, alkylaryl, arylalkyl, a six-membered ring or a six- membered bridged or spiro-fused ring containing zero, one, or two heteroatoms which are, independently, N, O, or S, a seven-membered bridged or spiro-fused ring containing zero, one, or two heteroatoms which are, independently, N, O, or S, a five-membered ring containing zero, one, or two heteroatoms which are, independently, N, O, or S; a four-membered ring containing zero, one, or two heteroatoms which are, independently, N, O, or S; a three membered ring containing zero or one heteroatoms which are, independently, N,
• R 10 and R 11 can come together to form a six-membered ring or a six-membered bridged or spiro-fused ring containing zero, one, or two heteroatoms which are, independently, N, O, or S, a seven-membered bridged or spiro-fused ring containing zero, one, or two heteroatoms which are, independently, N, O, or S, a five-membered ring containing zero, one, or two heteroatoms which are, independently, N, O, or S; a four-membered ring containing zero, one, or two heteroatoms which are, independently, N, O, or S; or a three membered ring containing zero heteroatoms;
• R 10 and R 11 groups can optionally be substituted with one or more substituents, which substituents are, independently, halo, Ci-6 haloalkyl, Ci-6 hydroxy alkyl, hydroxyl, carboxyl, acyl, aryl, acyloxy, amino, amido, carboxyl derivatives, alkylamino, dialkylamino, arylamino, alkoxy, alkoxyalkyl, aryloxy, nitro, cyano, sulfonic acid, thiol, imine, sulfonyl, sulfanyl, sulfmyl, sulfamonyl, ester, carboxylic acid, amide, phosphonyl, phosphinyl, phosphoryl, phosphine, thioester, thioether, oxime, hydrazine, carbamate, phosphonic acid, or phosphonate,
• R 12 and R 12a are, independently, H, F, Ci-6 alkyl, Ci-6 haloalkyl, C2-8 alkoxyalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, heteroaryl, alkylaryl, arylalkyl, a six-membered ring or a six- membered bridged or spiro-fused ring containing zero, one, or two heteroatoms which are, independently, N, O, or S, a seven-membered bridged or spiro-fused ring containing zero, one, or two heteroatoms which are, independently, N, O, or S, a five-membered ring containing zero, one, or two heteroatoms which are, independently, N, O, or S; a four-membered ring containing zero, one, or two heteroatoms which are, independently, N, O, or S; a three membered ring containing zero or one heteroatom which are, independently,
• R 12 and R 12a groups can optionally be substituted with one or more substituents, which substituents are, independently, halogen, Ci-6 haloalkyl, C 1-6 hydroxy alkyl, hydroxyl, carboxyl, acyl, aryl, acyloxy, amino, amido, azido, carboxyl derivatives, alkylamino, dialkylamino, arylamino, alkoxy, alkoxyalkyl, aryloxy, nitro, cyano, sulfonic acid, thiol, imine, sulfonyl, sulfanyl, sulfmyl, sulfamonyl, ester, carboxylic acid, amide, phosphonyl, phosphinyl, phosphoryl, phosphine, thioester, thioether, oxime, hydrazine, carbamate, phosphonic acid, or phosphonate, b is 0, 1, 2 or 3, c is
• C is O, S, NR 10 , -C(O), or -C(R 12 R 12a )-, d is 0, 1, 2 or 3,
• F is sulfonyl or -C(R 12 R 12a )-
• D is -C(R 12 R 12a )- or -O- ,
• R 14 , R 15 and R 16 are, independently, H, optionally substituted Ci-6 alkyl, Ci-6 haloalkyl, C2-8 alkoxyalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, heteroaryl, alkylaryl, arylalkyl, a six- membered ring or a six-membered bridged or spiro-fused ring containing zero, one, or two heteroatoms which are, independently, N, O, or S, a seven-membered bridged or spiro-fused ring containing zero, one, or two heteroatoms which are, independently, N, O, or S, a five- membered ring containing zero, one, or two heteroatoms which are, independently, N, O, or S; a four-membered ring containing zero, one, or two heteroatoms which are, independently, N, O, or S; a three membered ring containing zero or one heteroatom
• R 4 is C1-6 alkyl, C1-6 haloalkyl, C2-8 alkoxyalkyl, C2- 6 alkenyl, or C2-6 alkynyl, and in another aspect, R 4 is C2-6 alkynyl.
• R 3 is C1-3 alkyl, C1-3 haloalkyl, C 1-3 hydroxy alkyl, or Cm thioalkyl.
• the compound has the formula:
• Formula 7 is an enantiomer, diasteroisomer, tautomer, pharmaceutically acceptable salt or prodrug thereof, wherein:
• A is H, CN, OH, Ci-3 alkyl, C1-3 haloalkyl, Ci-3 hydroxyalkyl, Ci-3 thioalkyl or halogen;
• R 1 is or an optionally substituted C1-6 alkyl
• R 2 is hydrogen, deuterium or C1-3 alkyl optionally substituted with one or more fluoro atoms; or R 2 and A, together with the carbons to which they are attached, form a 4-7 membered ring, optionally containing one or more heteroatoms, where each is, independently, O, S or N, wherein the 4-7 membered ring is optionally substituted with one or more substituents selected from the group consisting of C1-C3 alkyl, halogen, oxo and OH; each R 3 is, independently, H, -CN, -OH, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 hydroxy alkyl, C1-3 thioalkyl or halogen;
• R 6 is H, Ci-3 alkyl, or C1-3 haloalkyl
• B is -(CR 7 R 7a ) n - or -C(O)-, where n is 0, 1, 2 or 3, each a is independently 0, 1, 2, 3 or 4; each R 7 andR 7a is independently H, C1-6 alkyl or C1-6 haloalkyl; alternatively, R 7 and R 7a can come together with the carbon to which they are attached to form a 6-10 membered bi cyclic or bridged ring, a 3 to 8 saturated ring, or a 5 membered unsaturated ring; such bicyclic, bridged, saturated and unsaturated rings optionally containing one or more additional heteroatoms, where each is, independently, O, S or N, and optionally being substituted with one or more substituents, wherein each, independently, is halogen (including F, Cl, Br, I), -CF3, hydroxy, -N(R’)S(0)2R’, -S(0)2R’, -S(0)2N(R’)2, Ci-6 alkoxy, cyano,
• R’ is H, Ci-6 alkyl, C1-6 haloalkyl, C2-8 alkoxyalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, heteroaryl, alkylaryl, arylalkyl, a six-membered ring or a six-membered bridged or spiro-fused ring containing zero, one, or two heteroatoms which are, independently, N, O, or S, a seven- membered bridged or spiro-fused ring containing zero, one, or two heteroatoms which are, independently, N, O, or S, a five-membered ring containing zero, one, or two heteroatoms which are, independently, N, O, or S; a four-membered ring containing zero, one, or two heteroatoms which are, independently, N, O, or S; or a three membered ring containing zero or one heteroatom which are, independently, N, O, or S,
• R 4 is an optionally substituted Ci-6 alkyl, Ci-6 haloalkyl, C2-8 alkoxy alkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, heteroaryl, alkylaryl, arylalkyl, a six-membered ring or a six-membered bridged or spiro-fused ring containing zero, one, or two heteroatoms which are, independently, N, O, or S, a seven-membered bridged or spiro-fused ring containing zero, one, or two heteroatoms which are, independently, N, O, or S, a five-membered ring containing zero, one, or two heteroatoms which are, independently, N, O, or S; a four-membered ring containing zero, one, or two heteroatoms which are, independently, N, O, or S; or a three membered ring containing zero or one heteroatom which are, independently, N, O, or
• R 10 and R 11 are, independently, H, Ci-6 alkyl, Ci-6 haloalkyl, C2-8 alkoxyalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, heteroaryl, alkylaryl, arylalkyl, a six-membered ring or a six- membered bridged or spiro-fused ring containing zero, one, or two heteroatoms which are, independently, N, O, or S, a seven-membered bridged or spiro-fused ring containing zero, one, or two heteroatoms which are, independently, N, O, or S, a five-membered ring containing zero, one, or two heteroatoms which are, independently, N, O, or S; a four-membered ring containing zero, one, or two heteroatoms which are, independently, N, O, or S; a three membered ring containing zero or one heteroatoms which are, independently, N,
• R 10 and R 11 groups can optionally be substituted with one or more substituents, which substituents are, independently, halo, Ci-6 haloalkyl, Ci-6 hydroxy alkyl, hydroxyl, carboxyl, acyl, aryl, acyloxy, amino, amido, carboxyl derivatives, alkylamino, dialkylamino, arylamino, alkoxy, alkoxyalkyl, aryloxy, nitro, cyano, sulfonic acid, thiol, imine, sulfonyl, sulfanyl, sulfmyl, sulfamonyl, ester, carboxylic acid, amide, phosphonyl, phosphinyl, phosphoryl, phosphine, thioester, thioether, oxime, hydrazine, carbamate, phosphonic acid, or phosphonate,
• R 12 and R 12a are, independently, H, F, Ci-6 alkyl, Ci-6 haloalkyl, C2-8 alkoxyalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, heteroaryl, alkylaryl, arylalkyl, a six-membered ring or a six- membered bridged or spiro-fused ring containing zero, one, or two heteroatoms which are, independently, N, O, or S, a seven-membered bridged or spiro-fused ring containing zero, one, or two heteroatoms which are, independently, N, O, or S, a five-membered ring containing zero, one, or two heteroatoms which are, independently, N, O, or S; a four-membered ring containing zero, one, or two heteroatoms which are, independently, N, O, or S; a three membered ring containing zero or one heteroatom which are, independently,
• R 12 and R 12a groups can optionally be substituted with one or more substituents, which substituents are, independently, halogen, Ci-6 haloalkyl, C 1-6 hydroxy alkyl, hydroxyl, carboxyl, acyl, aryl, acyloxy, amino, amido, azido, carboxyl derivatives, alkylamino, dialkylamino, arylamino, alkoxy, alkoxyalkyl, aryloxy, nitro, cyano, sulfonic acid, thiol, imine, sulfonyl, sulfanyl, sulfmyl, sulfamonyl, ester, carboxylic acid, amide, phosphonyl, phosphinyl, phosphoryl, phosphine, thioester, thioether, oxime, hydrazine, carbamate, phosphonic acid, or phosphonate, b is 0, 1, 2 or 3, c is
• C is O, S, NR 10 , -C(O), or -C(R 12 R 12a )-, d is 0, 1, 2 or 3,
• F is sulfonyl or -C(R 12 R 12a )-
• D is -C(R 12 R 12a )- or -O- ,
• R 14 , R 15 and R 16 are, independently, H, optionally substituted Ci-6 alkyl, Ci-6 haloalkyl, C2-8 alkoxyalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, heteroaryl, alkylaryl, arylalkyl, a six- membered ring or a six-membered bridged or spiro-fused ring containing zero, one, or two heteroatoms which are, independently, N, O, or S, a seven-membered bridged or spiro-fused ring containing zero, one, or two heteroatoms which are, independently, N, O, or S, a five- membered ring containing zero, one, or two heteroatoms which are, independently, N, O, or S; a four-membered ring containing zero, one, or two heteroatoms which are, independently, N, O, or S; a three membered ring containing zero or one heteroatom
• R 14 , R 15 and R 16 can optionally, and independently, be substituted with one or more substituents selected from the group consisting of halogen, Ci-6 haloalkyl, Ci-6 hydroxyalkyl, hydroxyl, carboxyl, acyl, aryl, acyloxy, amino, amido, carboxyl derivatives, alkylamino, dialkylamino, arylamino, alkoxy, alkoxyalkyl, aryloxy, nitro, cyano, sulfonic acid, thiol, imine, sulfonyl, sulfanyl, sulfmyl, sulfamonyl, ester, carboxylic acid, amide, phosphonyl, phosphinyl, phosphoryl, phosphine, thioester, thioether, oxime, hydrazine, carbamate, phosphonic acid, and phosphonate, alternatively, R 14 and R 16 can come together to
• the compound has the formula:
• Formula 8 or is an enantiomer, a diasteroisomer, a tautomer, a pharmaceutically acceptable salt or prodrug thereof, wherein:
• A is H, CN, OH, C1-3 alkyl, C1-3 haloalkyl, C1-3 hydroxyalkyl, C 1-3 thioalkyl or halogen;
• R 1 is or an optionally substituted Ci-6 alkyl wherein the substituents on the optionally substituted Ci-6 alkyl are selected from the group consisting of halogen, Ci-6 haloalkyl, Ci-6 hydroxy alkyl, hydroxyl, carboxyl, acyl, aryl, acyloxy, amino, amido, carboxyl derivatives, alkylamino, dialkylamino, arylamino, alkoxy, alkoxyalkyl, aryloxy, nitro, cyano, sulfonic acid, thiol, imine, sulfonyl, sulfanyl, sulfmyl, sulfamonyl, ester, carboxylic acid, amide, phosphonyl, phosphinyl, phosphoryl, phosphine, thioester, thioether, oxime, hydrazine, carbamate, phosphonic acid, and phosphonate,
• R 2 is hydrogen, deuterium or C1-3 alkyl optionally substituted with one or more fluoro atoms; or R 2 and A, together with the carbons to which they are attached, form a 4-7 membered ring, optionally containing one or more heteroatoms, where each is, independently, O, S or N, wherein the 4-7 membered ring is optionally substituted with one or more substituent selected from the group consisting of C1-C3 alkyl, halogen, oxo and OH; each R 3 is, independently, H, CN, OH, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, Ci- 3 thioalkyl or halogen; each a is independently 0, 1, 2, 3 or 4;
• R 4 is an optionally substituted Ci-6 alkyl, Ci-6 haloalkyl, C2-8 alkoxyalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, heteroaryl, alkylaryl, arylalkyl, a six-membered ring or a six-membered bridged or spiro-fused ring containing zero, one, or two heteroatoms which are, independently, N, O, or S, a seven-membered bridged or spiro-fused ring containing zero, one, or two heteroatoms which are, independently, N, O, or S, a five-membered ring containing zero, one, or two heteroatoms which are, independently, N, O, or S; a four-membered ring containing zero, one, or two heteroatoms which are, independently, N, O, or S; or a three membered ring containing zero or one heteroatom which are, independently, N, O, or
• R 12 and R 12a are, independently, H, F, Ci-6 alkyl, Ci-6 haloalkyl, C2-8 alkoxyalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, heteroaryl, alkylaryl, arylalkyl, a six-membered ring or a six- membered bridged or spiro-fused ring containing zero, one, or two heteroatoms which are, independently, N, O, or S, a seven-membered bridged or spiro-fused ring containing zero, one, or two heteroatoms which are, independently, N, O, or S, a five-membered ring containing zero, one, or two heteroatoms which are, independently, N, O, or S; a four-membered ring containing zero, one, or two heteroatoms which are, independently, N, O, or S; a three membered ring containing zero or one heteroatom which are, independently,
• R 10 and R 11 are, independently, H, Ci-6 alkyl, Ci-6 haloalkyl, C2-8 alkoxyalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, heteroaryl, alkylaryl, arylalkyl, a six-membered ring or a six- membered bridged or spiro-fused ring containing zero, one, or two heteroatoms which are, independently, N, O, or S, a seven-membered bridged or spiro-fused ring containing zero, one, or two heteroatoms which are, independently, N, O, or S, a five-membered ring containing zero, one, or two heteroatoms which are, independently, N, O, or S; a four-membered ring containing zero, one, or two heteroatoms which are, independently, N, O, or S; a three membered ring containing zero or one heteroatoms which are, independently, N,
• R 10 and R 11 can come together to form a six-membered ring or a six-membered bridged or spiro-fused ring containing zero, one, or two heteroatoms which are, independently, N, O, or S, a seven-membered bridged or spiro-fused ring containing zero, one, or two heteroatoms which are, independently, N, O, or S, a five-membered ring containing zero, one, or two heteroatoms which are, independently, N, O, or S; a four-membered ring containing zero, one, or two heteroatoms which are, independently, N, O, or S; or a three membered ring containing zero heteroatoms;
• R 10 and R 11 groups can optionally be substituted with one or more substituents, which substituents are, independently, halo, Ci-6 haloalkyl, C 1-6 hydroxy alkyl, hydroxyl, carboxyl, acyl, aryl, acyloxy, amino, amido, carboxyl derivatives, alkylamino, dialkylamino, arylamino, alkoxy, alkoxyalkyl, aryloxy, nitro, cyano, sulfonic acid, thiol, imine, sulfonyl, sulfanyl, sulfmyl, sulfamonyl, ester, carboxylic acid, amide, phosphonyl, phosphinyl, phosphoryl, phosphine, thioester, thioether, oxime, hydrazine, carbamate, phosphonic acid, or phosphonate, alternatively, R 12 and R 12a can come together to form a
• R 12 and R 12a groups can optionally be substituted with one or more substituents, which substituents are, independently, halogen, Ci-6 haloalkyl, Ci-6 hydroxy alkyl, hydroxyl, carboxyl, acyl, aryl, acyloxy, amino, amido, azido, carboxyl derivatives, alkylamino, dialkylamino, arylamino, alkoxy, alkoxyalkyl, aryloxy, nitro, cyano, sulfonic acid, thiol, imine, sulfonyl, sulfanyl, sulfmyl, sulfamonyl, ester, carboxylic acid, amide, phosphonyl, phosphinyl, phosphoryl, phosphine, thioester, thioether, oxime, hydrazine, carbamate, phosphonic acid, or phosphonate,
• R’ is H, Ci-6 alkyl, Ci-6 haloalkyl, C2-8 alkoxyalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, heteroaryl, alkylaryl, arylalkyl, a six-membered ring or a six-membered bridged or spiro-fused ring containing zero, one, or two heteroatoms which are, independently, N, O, or S, a seven- membered bridged or spiro-fused ring containing zero, one, or two heteroatoms which are, independently, N, O, or S, a five-membered ring containing zero, one, or two heteroatoms which are, independently, N, O, or S; a four-membered ring containing zero, one, or two heteroatoms which are, independently, N, O, or S; or a three membered ring containing zero or one heteroatoms which are, independently, N, O, or S,
• R 1 is
• the compounds have the formula:
• Formula 9 or a pharmaceutically acceptable salt or prodrug thereof wherein when R 1 and R 1 are attached to a carbon they are, independently, hydrogen, halogen, CF3, hydroxy, SF5, N(R’)S(0)2R’, S(0) 2 R’, S(0) 2 N(R’) 2 , C1-6 alkoxy, cyano, C 2 -6 alkynyl, C3- 6 alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, C1-6 alkyl, arylalkoxycarbonyl, carboxy, Ci-6 haloalkyl, heterocyclylalkyl, or Ci-6hydroxyalkyl; when R 1 and R 1 are attached to a nitrogen they are, independently, hydrogen, C 1-6 alkoxy, C3-6 alkoxyalkyl, alkoxycarbonyl, carbonylalkyl, carbonyl aryl, C1-6 alkyl, C 2 -6 alkynyl, C 2 -6 alkenyl, heterocyclylal
• C is phenyl, a six-membered heteroaromatic ring containing one, two, or three nitrogen atoms, a five-membered heteroaromatic ring containing one, two, or three heteroatoms, which are, independently, N, O, or S, a C4-14 bicyclic ring; alkylheteroaryl, or alkylaryl; B is selected from the group consisting of five-membered heteroaromatic rings containing one, two, or three heteroatoms, which are, independently, N, O, or S, six or seven- membered rings or six or seven-membered bridged or spiro-fused rings containing zero, one, or two heteroatoms which are, independently, N, O, or S, five-membered rings containing zero, one, or two heteroatoms which are, independently, N, O, or S; four-membered rings containing zero, one, or two heteroatoms which are, independently, N, O, or S,
• R 12 is H, Ci-6 alkyl, C3-7 cycloalkyl, C1-6 haloalkyl, C2-6 alkenyl, or C2-6 alkynyl,
• R 10 and R n are, independently, H, Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, heteroaryl, alkylaryl, arylalkyl, a six-membered ring or a six-membered bridged or spiro- fused ring containing zero, one, or two heteroatoms which are, independently, N, O, or S, Ci-6 alkoxy, cyano, azido, C2-6 alkynyl, C3- 6 alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, C1-6 alkyl, arylalkoxycarbonyl, carboxy, Ci-6 haloalkyl, heterocyclylalkyl, and C1-6 hydroxyalkyl;
• R 10 and R n are, independently, H, Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alky
• R 10 and R 11 groups can optionally be substituted with one or more substituents, which substituents are, independently, halo, Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 hydroxyalkyl, hydroxyl, carboxyl, acyl, aryl, acyloxy, amino, amido, carboxyl derivatives, alkylamino, dialkylamino, arylamino, alkoxy, alkoxyalkyl, aryloxy, nitro, cyano, sulfonic acid, thiol, imine, sulfonyl, sulfanyl, sulfmyl, sulfamonyl, ester, carboxylic acid, amide, phosphonyl, phosphinyl, phosphoryl, phosphine, thioester, thioether, oxime, hydrazine, carbamate, phosphonic acid,
• the compounds have the following following formula:
• Formula 10 or a pharmaceutically acceptable salt or prodrug thereof wherein when R 1 and R 1 are attached to a carbon they are, independently, hydrogen, halogen, CF3, hydroxy, SF5, N(R’)S(0)2R’, S(0)2R’, S(0)2N(R’)2, C1-6 alkoxy, cyano, C2-6 alkynyl, C3- 6 alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, Ci-6 alkyl, arylalkoxycarbonyl, carboxy, Ci-6 haloalkyl, heterocyclylalkyl, or Ci-6hydroxyalkyl; when R 1 and R 1 are attached to a nitrogen they are, independently, hydrogen, Ci-6 alkoxy, C3-6 alkoxyalkyl, alkoxycarbonyl, carbonylalkyl, carbonyl aryl, Ci-6 alkyl, C2-6 alkynyl, C2-6 alkenyl, heterocyclylalkyl, Ci-6
• E is phenyl, a six-membered heteroaromatic ring containing one, two, or three nitrogen atoms, a five-membered heteroaromatic ring containing one, two, or three heteroatoms, which are, independently, N, O, or S, a C4-14 bicyclic ring; alkylheteroaryl, or alkylaryl;
• D is selected from the group consisting of a five-membered heteroaromatic ring containing one, two, or three heteroatoms, which are, independently, N, O, or S, a six or seven- membered ring or a six or seven-membered bridged or spiro-fused ring containing zero, one, or two heteroatoms which are, independently, N, O, or S, a five-membered ring containing zero, one, or two heteroatoms which are, independently, N, O, or S; and a four-membered ring containing zero, one, or two heteroatoms which are, independently, N, O, or S,
• R 12 is H, Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, or C2-6 alkynyl,
• R 13 is Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, heteroaryl, alkylaryl, arylalkyl, a C4-14 bicyclic ring; a six-membered bridged or spiro-fused ring containing zero, one, or two heteroatoms which are, independently, N, O, S, or a 3-7 membered saturated or partially unsaturated ring containing one or more heteroatoms each independently selected from the group of N, O or S,
• R 13 is optionally substituted with one or more substituents each independently selected
• R 10 and R n are, independently, H, C1-6 alkyl, C1-6 haloalkyl, C 2 -6 alkenyl, C 2 -6 alkynyl, aryl, heteroaryl, alkylaryl, arylalkyl, a six-membered ring or a six-membered bridged or spiro- fused ring containing zero, one, or two heteroatoms which are, independently, N, O, or S, a seven-membered bridged or spiro-fused ring containing zero, one, or two heteroatoms which are, independently, N, O, or S, a five-membered ring containing zero, one, or two heteroatoms which are, independently, N, O, or S; a four-membered ring containing zero, one, or two heteroatoms which are, independently, N, O, or S; or a three membered ring containing zero or one heteroatom which are, independently, N, O, or S, alternatively
• the compounds have the following formula:
• Formula 11 or a pharmaceutically acceptable salt or prodrug thereof wherein when R 1 and R 1 are attached to a carbon they are, independently, hydrogen, halogen, CF3, hydroxy, SF5, N(R’)S(0)2R’, S(0)2R’, S(0)2N(R’)2, C 1-6 alkoxy, cyano, C2-10 alkynyl, C3- 6 alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, C1-6 alkyl, C1-6 haloalkyl, arylalkoxy carbonyl, carboxy, C1-6 haloalkyl, heterocyclylalkyl, or Ci-6 hydroxyalkyl; when R 1 and R 1 are attached to a nitrogen they are, independently, hydrogen, C 1-6 alkoxy, C3-6 alkoxyalkyl, alkoxycarbonyl, carbonylalkyl, carbonyl aryl, C1-6 alkyl, C2-10 alkynyl, C2-6 alkenyl
• G is phenyl, a six-membered heteroaromatic ring containing one, two, or three nitrogen atoms, a five-membered heteroaromatic ring containing one, two, or three heteroatoms, which are, independently, N, O, or S, a C4-14 bicyclic ring; cubane, alkylheteroaryl, or alkylaryl;
• F is selected from the group consisting of a five-membered heteroaromatic ring containing one, two, or three heteroatoms, which are, independently, N, O, or S, a six or seven- membered ring or a six or seven-membered bridged or spiro-fused ring containing zero, one, or two heteroatoms which are, independently, N, O, or S, a five-membered ring containing zero, one, or two heteroatoms which are, independently, N, O, or S; and a four-membered ring containing zero, one, or two heteroatoms which are, independently, N, O, or S,
• R 12 is H, Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, or C2-6 alkynyl,
• R 13 is Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, heteroaryl, alkylaryl, arylalkyl, a C4-14 bicyclic ring; cubane, a six-membered bridged or spiro-fused ring containing zero, one, or two heteroatoms which are, independently, N, O, S, or a 3-7 membered saturated or partially unsaturated ring containing one or more heteroatoms each independently selected from the group of N, O or S,
• R 13 is optionally substituted with one or more substituents each independently selected
• the substituents are selected from the group consisting of R 11 , -NH-C(O)-N(R 10 )2, -
• R 10 and R n are, independently, H, Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, heteroaryl, alkylaryl, arylalkyl, a six-membered ring or a six-membered bridged or spiro- fused ring containing zero, one, or two heteroatoms which are, independently, N, O, or S, a seven-membered bridged or spiro-fused ring containing zero, one, or two heteroatoms which are, independently, N, O, or S, a five-membered ring containing zero, one, or two heteroatoms which are, independently, N, O, or S; a four-membered ring containing zero, one, or two heteroatoms which are, independently, N, O, or S; or a three membered ring containing zero or one heteroatom which are, independently, N, O, or S, alternatively, R
• R 10 and R 11 groups can optionally be substituted with one or more substituents, which substituents are, independently, halo, Ci-6 alkyl, C3-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl,, C 1-6 hydroxy alkyl, hydroxyl, carboxyl, acyl, aryl, acyloxy, amino, amido, carboxyl derivatives, alkylamino, dialkylamino, arylamino, alkoxy, alkoxyalkyl, aryloxy, nitro, cyano, sulfonic acid, thiol, imine, sulfonyl, sulfanyl, sulfmyl, sulfamonyl, ester, carboxylic acid, amide, phosphonyl, phosphinyl, phosphoryl, phosphine, thioester, thioether, oxime, hydrazine, carb
• R 14 and R 15 are independently, H, Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, R 14 and R 15 can come together to form an optionally substituted 3 to 5 membered ring, and
• R 16 is H or Ci-6 alkyl.
• G is phenyl
• F is pyrrolyl.
• the 6 substituent can be directly attached to the ring nitrogen.
• R 1 is selected from the group consisting of F, CN and OH.
• R 1 is methyl
• R 16 is H.
• the compound is a tetramer of the following formula:
• a 1 , B 1 , C 1 and D 1 are, independently, an HBV capsid assembly effector, each A 1 , B 1 , C 1 and D 1 may be the same or different;
• L 1 is a chemical linker selected from the group consisting of -C-((C 2 -6alkyl-0) p ) 4 -, -C- (C i-i6 alky l-) 4 , -C(NR’) 3 -)4, C(Ci-6alkyl-W 1 -) 4 ; -C((CH 2 -CH 2 -0)t-Ci-6alkyl-W 1 -)4; -C((CH 2 -CH 2 - 0) s ) 4 -; C(Ci-3o alkyl-W 1 -) 4 ; C-((C3-6alkyl-0)s-Ci-6alkyl-X-(C3-6alkyl-0) s -Ci-6alkyl-
• W 1 is, independently for each occurrence, aryl, heteroaryl, CHR’, NR’, N, O or S;
• R’ is H, Ci-6 alkyl, optionally unsaturated C3-8 cycloalkyl, C1-6 haloalkyl, C 2 -8 alkoxyalkyl, C 2 -6 alkenyl, C 2 -6 alkynyl, aryl, heteroaryl, alkylaryl, or arylalkyl,
• R 7 and R 8 are, independently, -OH, optionally unsaturated -O-C1-6 alkyl, C1-6 alkyl, C2-
• the compounds are selected from the group consisting of:
• Examples of compounds of Formula 11 include:
• Additional compounds include the following:
• the compounds described herein can have asymmetric centers and occur as racemates, racemic mixtures, individual diastereomers or enantiomers, with all isomeric forms being included in the present invention.
• Compounds of the present invention having a chiral center can exist in and be isolated in optically active and racemic forms. Some compounds can exhibit polymorphism.
• the present invention encompasses racemic, optically-active, polymorphic, or stereoisomeric forms, or mixtures thereof, of a compound described herein, which possess the useful properties described herein.
• optically active forms can be prepared by, for example, resolution of the racemic form by recrystallization techniques, by synthesis from optically-active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary phase or by enzymatic resolution.
• One can either purify the respective compound, then derivatize the compound to form the compounds described herein, or purify the compound themselves.
• Optically active forms of the compounds can be prepared using any method known in the art, including but not limited to by resolution of the racemic form by recrystallization techniques, by synthesis from optically-active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary phase.
• Examples of methods to obtain optically active materials include at least the following. i) physical separation of crystals: a technique whereby macroscopic crystals of the individual enantiomers are manually separated. This technique can be used if crystals of the separate enantiomers exist, i.e., the material is a conglomerate, and the crystals are visually distinct; ii) simultaneous crystallization: a technique whereby the individual enantiomers are separately crystallized from a solution of the racemate, possible only if the latter is a conglomerate in the solid state; iii) enzymatic resolutions: a technique whereby partial or complete separation of a racemate by virtue of differing rates of reaction for the enantiomers with an enzyme; iv) enzymatic asymmetric synthesis: a synthetic technique whereby at least one step of the synthesis uses an enzymatic reaction to obtain an enantiomerically pure or enriched synthetic precursor of the desired enantiomer; v) chemical asymmetric synthesis:
• first- and second-order asymmetric transformations a technique whereby diastereomers from the racemate equilibrate to yield a preponderance in solution of the diastereomer from the desired enantiomer or where preferential crystallization of the diastereomer from the desired enantiomer perturbs the equilibrium such that eventually in principle all the material is converted to the crystalline diastereomer from the desired enantiomer.
• kinetic resolutions this technique refers to the achievement of partial or complete resolution of a racemate (or of a further resolution of a partially resolved compound) by virtue of unequal reaction rates of the enantiomers with a chiral, non- racemic reagent or catalyst under kinetic conditions; ix) enantiospecific synthesis from non-racemic precursors: a synthetic technique whereby the desired enantiomer is obtained from non-chiral starting materials and where the stereochemical integrity is not or is only minimally compromised over the course of the synthesis; x) chiral liquid chromatography: a technique whereby the enantiomers of a racemate are separated in a liquid mobile phase by virtue of their differing interactions with a stationary phase (including but not limited to via chiral HPLC).
• the stationary phase can be made of chiral material or the mobile phase can contain an additional chiral material to provoke the differing interactions;
• chiral gas chromatography a technique whereby the racemate is volatilized and enantiomers are separated by virtue of their differing interactions in the gaseous mobile phase with a column containing a fixed non-racemic chiral adsorbent phase;
• extraction with chiral solvents a technique whereby the enantiomers are separated by virtue of preferential dissolution of one enantiomer into a particular chiral solvent;
• xiii) transport across chiral membranes a technique whereby a racemate is placed in contact with a thin membrane barrier.
• the barrier typically separates two miscible fluids, one containing the racemate, and a driving force such as concentration or pressure differential causes preferential transport across the membrane barrier. Separation occurs as a result of the non-racemic chiral nature of the membrane that allows only one enantiomer of the racemate to pass through.
• Chiral chromatography including but not limited to simulated moving bed chromatography, is used in one embodiment.
• a wide variety of chiral stationary phases are commercially available.
• Suitable inorganic salts can also be formed, including but not limited to, sulfate, nitrate, bicarbonate and carbonate salts. For certain transdermal applications, it can be preferred to use fatty acid salts of the compounds described herein.
• the fatty acid salts can help penetrate the stratum comeum.
• suitable salts include salts of the compounds with stearic acid, oleic acid, lineoleic acid, palmitic acid, caprylic acid, and capric acid.
• Pharmaceutically acceptable salts can be obtained using standard procedures well known in the art, for example by reacting a sufficiently basic compound such as an amine with a suitable acid, affording a physiologically acceptable anion. In those cases where a compound includes multiple amine groups, the salts can be formed with any number of the amine groups.
• Alkali metal e.g., sodium, potassium or lithium
• alkaline earth metal e.g., calcium
• a prodrug is a pharmacological substance that is administered in an inactive (or significantly less active) form and subsequently metabolized in vivo to an active metabolite. Geting more drug to the desired target at a lower dose is often the rationale behind the use of a prodrug and is generally atributed to beter absorption, distribution, metabolism, and/or excretion (ADME) properties.
• Prodrugs are usually designed to improve oral bioavailability, with poor absorption from the gastrointestinal tract usually being the limiting factor. Additionally, the use of a prodrug strategy can increase the selectivity of the drug for its intended target thus reducing the potential for off target effects.
• Compounds described herein include isotopically-labeled compounds, which are identical to those recited in the various formulae and structures presented herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
• isotopes that are incorporated into the present compounds including isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine and chlorine, such as, for example, 2 H, 3 ⁇ 4, 13 C, 14 C, 15 N, 18 0, 17 0, 35 S, 18 F, 36 Cl, respectively.
• isotopically-labeled compounds described herein for example those into which radioactive isotopes such as 2 H are incorporated, are useful in drug and/or substrate tissue distribution assays. Further, in some embodiments, substitution with isotopes such as deuterium, i.e., 2 H, can affords certain therapeutic advantages resulting from greater metabolic stability, such as, for example, increased in vivo half- life or reduced dosage requirements.
• Hosts including but not limited to humans, suffering from one of these cancers, or infected with one of these viruses, such as HBV, or a gene fragment thereof, can be treated by administering to the patient an effective amount of the active compound or a pharmaceutically acceptable prodrug or salt thereof in the presence of a pharmaceutically acceptable carrier or diluent.
• the active materials can be administered by any appropriate route, for example, orally, parenterally, intravenously, intradermally, transdermally, subcutaneously, or topically, in liquid or solid form.
• the compounds described herein can be employed together with at least one other antiviral agent.
• antiviral agents include, but are not limited to, polymerase inhibitors, anti-HBV nucleosides and their prodrugs, viral entry inhibitor, viral maturation inhibitor, literature described capsid assembly modulator, IMPDH inhibitors, protease inhibitors, immune-based therapeutic agents, reverse transcriptase inhibitor, a TLR-agonist, and agents of distinct or unknown mechanism. They can also be used in conjunction with CRISPR/CAS9 approaches, for example, using AAV as the human delivery vector.
• the active compound or its prodrug or pharmaceutically acceptable salt when used to treat or prevent HBV infection, can be administered in combination or alternation with another anti-HBV agent including, but not limited to, those of the formula above.
• another anti-HBV agent including, but not limited to, those of the formula above.
• effective dosages of two or more agents are administered together, whereas during alternation therapy, an effective dosage of each agent is administered serially.
• the dosage will depend on absorption, inactivation and excretion rates of the drug, as well as other factors known to those of skill in the art. It is to be noted that dosage values will also vary with the severity of the condition to be alleviated.
• siRNA and shRNA Therapy siRNA therapy for treating HBV is described, for example, in Chen and Mahato, “siRNA Pool Targeting Different Sites of Human Hepatitis B Surface Antigen Efficiently Inhibits HBV Infection;” J Drug Target. 2008 Feb; 16(2): 140-148 and Morrissey et al, “Potent and persistent in vivo anti-HBV activity of chemically modified siRNAs,” Nature Biotechnology 23, 1002 - 1007 (2005).
• RNAi is a sequence-specific, post-transcriptional gene silencing mechanism, which is triggered by double-stranded synthetic siRNA or short hairpin RNA (shRNA) expressed intracellularly from a vector.
• shRNA short hairpin RNA
• HBV replication and expression can be inhibited by administration of synthetic siRNAs or endogenously expressed shRNAs. See, for example, Giladi et al.,“Small interfering RNA inhibits hepatitis B virus replication in mice,” Mol Ther. 2003;8(5):769-76; McCaffrey et al,“Inhibition of hepatitis B virus in mice by RNA interference,” Nat Biotechnol.
• HBV gene silencing may depend, for example, on siRNA dosing and sequences, and targets for gene silencing include, for example, the inhibition of virus replication, and suppression of HBsAg expression.
• targets for gene silencing include, for example, the inhibition of virus replication, and suppression of HBsAg expression.
• a combination of several siRNAs and/or shRNAs are used, targeting two or more of the HBV S, C, P and X genes. In this manner, multiple targets for inhibition of HBV replication and gene expression can be accessed.
• siRNAs can be designed according to the guide provided by Ambion (http://www.ambion.com/techlib/misc/siRNA_fmder.html) and Invitrogen (https://maidesigner.invitrogen.com/maiexpress/design.do).
• the sequence specificity of siRNAs can be checked by performing a BLAST search (www.ncbi.nlm.nih.gov).
• siRNA sequences can be converted into shRNAs.
• control vectors can be constructed, for example, using psiSTRIKETM, which is a linearized plasmid and contains a U6 RNA polymerase promoter.
• psiSTRIKETM which is a linearized plasmid and contains a U6 RNA polymerase promoter.
• These shRNAs contain two complementary oligonucleotides that can be annealed to form double-stranded DNA for ligation into psiSTRIKETM vector corresponding sites, under a suitable promoter, such as the U6 promoter, using an appropriate ligase, such as T4 DNA ligase.
• Plasmids can be purified, for example, using the QIAGEN® Plasmid Mini Kit (QIAGEN, Valencia, CA).
• targeted endonucleases such as homing endonucleases, zinc-finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs), and the CRISPR (clustered regularly interspaced short palindromic repeats) system can be used.
• ZFNs zinc-finger nucleases
• TALENs transcription activator-like effector nucleases
• CRISPR clustered regularly interspaced short palindromic repeats
• TALENs targeting of the hepatitis B virus (HBV) genome can result in TALEN- induced mutations in the long-lived HBV covalently closed circular DNA (cccDNA). Mutation and/or disruption of cccDNA prevents viral replication by blocking expression of functional viral proteins.
• HBV hepatitis B virus
• CRISPR or clustered regularly interspaced short palindromic repeats
• CRISPR is another way to mutate HBV DNA, by providing targeted genome editing.
• programmable editing tools such as zinc finger nucleases and transcription activator-like effector nucleases (TALENs) described above
• CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9 technology also allows for genome editing, and allows for site-specific genomic targeting in HBV.
• the type II CRISPR/Cas system is a prokaryotic adaptive immune response system that uses non-coding RNAs to guide the Cas9 nuclease to induce site-specific DNA cleavage. This DNA damage is repaired by cellular DNA repair mechanisms, either via the non-homologous end joining DNA repair pathway (NHEJ) or the homology directed repair (HDR) pathway.
• NHEJ non-homologous end joining DNA repair pathway
• HDR homology directed repair
• the CRISPR/Cas9 system provides a simple, RNA-programmable method to generate gene knockouts (via insertion/deletion) or knockins (via HDR), and allows for site-specific genomic targeting in HBV.
• the type II CRISPR/Cas system is a prokaryotic adaptive immune response system that uses non-coding RNAs to guide the Cas9 nuclease to induce site-specific DNA cleavage.
• sgRNA single guide RNA
• INDELs insertions and deletions
• ARCUS is a next-generation genome editing platform derived from a natural genome editing enzyme called a homing endonuclease. They are site-specific DNA- cutting enzymes encoded in the genomes of many eukaryotic species. Homing endonucleases have the unusual ability to precisely recognize long DNA sequences (12- 40 base pairs) that are typically rare enough to occur only once in a complex genome. These non-destructive enzymes trigger gene conversion events that modify the genome in a very precise way, most frequently by the insertion of a new DNA sequence.
• the backbone of the ARCUS technology is the ARC nuclease - a fully synthetic enzyme similar to a homing endonuclease but significantly improved to be the starting point for the first therapeutic-grade genome editing platform.
• the ARC nuclease is small, has unparalleled specificity, and can be customized to recognize a DNA sequence within any target gene.
• ARC nucleases are created using a set of proprietary in silico and lab- based techniques to ensure maximum gene editing efficiency with minimum off-target activity. Importantly, ARC nucleases can be optimized to control potency and specificity based on the analysis of cutting activity in a relevant model organism such as HBY.
• miRNAs are tiny noncoding RNAs that regulate gene expression primarily at the post-transcriptional level by binding to mRNAs. miRNAs contribute to a variety of physiological and pathological processes. A number of miRNAs have been found to play a pivotal role in the host-HBV interaction. HBV infection can change the cellular miRNA expression patterns, and different stages of HBV associated disease have displayed distinctive miRNA profiles. The differential expressed miRNAs are involved in the progression of HBV-related diseases. For instance, some miRNAs are involved in liver tumorigenesis and tumor metastasis. Circulating miRNA in serum or plasma can be a very useful biomarker for the diagnosis and prognosis of HBV-related diseases.
• miRNA-based therapy can be used to treat, prevent, or cure HBV- related diseases. See, for example, Ying-Feng Wei, “MicroRNAs may solve the mystery of chronic hepatitis B virus infection,” World J Gastroenterol. 2013 Aug 14; 19(30): 4867-4876. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC37404l6/
• miRNAs can be divided into cellular miRNAs and viral miRNAs.
• Cellular miRNAs expression profiles change at the infected state, and abnormal miRNAs often closely relate to the viral life cycle as well as the host disorder.
• Viral miRNAs can evolve to regulate both viral and cellular gene expression.
• miR-l22 serves an antiviral role in the HBV life cycle.
• MiR- 122 over-expression inhibits HBV expression, whereas depletion of endogenous miR- 122 results in increased HBV production in transfected cells.
• MiR-l22 inhibitors cause an increase in cellular heme oxygenase- 1, which can decrease HBV covalently closed circular DNA (cccDNA) levels by reducing the stability of the HBV core protein.
• cccDNA HBV covalently closed circular DNA
• MiR-l22 is significantly up-regulated in HBV-infected patients, and can inhibit HBV replication in Huh7 and HepG2 cells.
• Cyclin Gl is a miR-l22 target that specifically interacts with p53, resulting in the specific binding of p53 to the HBV enhancer elements and simultaneous abrogation of the p53-mediated inhibition of HBV transcription.
• HBV is a noncytopathic virus that replicates preferentially in the hepatocytes.
• cccDNA serves as a template for transcription of all viral RNA that is synthetized after HBV DNA enters the hepatocyte nucleus.
• the HBV genome is 3.2 kb in length and contains four overlapping open reading frames. It can transcribe viral pregenomic RNA that reverses transcription to synthesize the viral DNA genome and encode the hepatitis B virus surface antigen (HBsAg), hepatitis B virus core protein, viral reverse DNA polymerase (Pol) and X protein.
• HBV hepatitis B virus surface antigen
• Pol viral reverse DNA polymerase
• Hsa-miR-l25a-5p interferes with HBV translation and down-regulates the expression of the HBV surface antigen. Accordingly, cellular miRNAs can alter HBV gene expression by targeting to HBV transcripts.
• MiR-l4l suppresses HBV replication by reducing HBV promoter activities, by down-regulating peroxisome proliferator-activated receptor alpha. DNA hypermethylation may be closely related to the suppression of HBV cccDNA transcription, and miR-l52 may be a factor involved in the regulation of the methylation of HBV cccDNA.
• miRNAs can directly or indirectly alter HBV replication.
• the close relationship between miRNAs and HBV-related diseases offers an opportunity to use miRNAs or antagomir in combination therapies to treat, cure, or prevent HBV.
• Hosts including but not limited to humans, infected with HBV can be treated by administering to the patient an effective amount of the active compound or a pharmaceutically acceptable prodrug or salt thereof in the presence of a pharmaceutically acceptable carrier or diluent.
• the active materials can be administered by any appropriate route, for example, orally, parenterally, intravenously, intradermally, subcutaneously, or topically, in liquid or solid form.
• a preferred dose of the compound will be in the range of between about 0.01 and about 10 mg/kg, more generally, between about 0.1 and 5 mg/kg, and, preferably, between about 0.5 and about 2 mg/kg, of body weight of the recipient per day.
• the effective dosage range of the pharmaceutically acceptable salts and prodrugs can be calculated based on the weight of the parent compound to be delivered. If the salt or prodrug exhibits activity in itself, the effective dosage can be estimated as above using the weight of the salt or prodrug, or by other means known to those skilled in the art.
• the compound is conveniently administered in unit any suitable dosage form, including but not limited to one containing 7 to 600 mg, preferably 60 to 600 mg of active ingredient per unit dosage form.
• An oral dosage of 1-400 mg is usually convenient.
• the concentration of active compound in the drug composition will depend on absorption, inactivation and excretion rates of the drug as well as other factors known to those of skill in the art. It is to be noted that dosage values will also vary with the severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that the concentration ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed composition.
• the active ingredient can be administered at once, or can be divided into a number of smaller doses to be administered at varying intervals of time.
• a preferred mode of administration of the active compound is oral, although for certain patients a sterile injectable form can be given sc, ip or iv.
• Oral compositions will generally include an inert diluent or an edible carrier. They can be enclosed in gelatin capsules or compressed into tablets.
• the active compound can be incorporated with excipients and used in the form of tablets, troches or capsules. Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition.
• the tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel or com starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.
• a binder such as microcrystalline cellulose, gum tragacanth or gelatin
• an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel or com starch
• a lubricant such as magnesium stearate or Sterotes
• a glidant such as colloidal silicon dioxide
• the compound can be administered as a component of an elixir, suspension, syrup, wafer, chewing gum or the like.
• a syrup can contain, in addition to the active compound(s), sucrose as a sweetening agent and certain preservatives, dyes and colorings and flavors.
• the compound or a pharmaceutically acceptable prodrug or salts thereof can also be mixed with other active materials that do not impair the desired action, or with materials that supplement the desired action, such as antibiotics, antifungals, anti- inflammatories or other antiviral compounds.
• Solutions or suspensions used for parenteral, intradermal, subcutaneous, or topical application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents, such as ethylenediaminetetraacetic acid; buffers, such as acetates, citrates or phosphates, and agents for the adjustment of tonicity, such as sodium chloride or dextrose.
• the parental preparation can be enclosed in ampoules, disposable syringes or multiple
• preferred carriers are physiological saline or phosphate buffered saline (PBS).
• the compositions are present in the form of transdermal formulations, such as that used in the FDA-approved agonist rotigitine transdermal (Neupro patch).
• transdermal formulations such as that used in the FDA-approved agonist rotigitine transdermal (Neupro patch).
• Another suitable formulation is described in U.S. Publication No. 20080050424, entitled “Transdermal Therapeutic System for Treating Parkinsonism.”
• This formulation includes a silicone or acrylate-based adhesive, and can include an additive having increased solubility for the active substance, in an amount effective to increase dissolving capacity of the matrix for the active substance.
• the transdermal formulations can be single-phase matrices that include a backing layer, an active substance-containing self-adhesive matrix, and a protective film to be removed prior to use. More complicated embodiments contain multiple- layer matrices that may also contain non-adhesive layers and control membranes.
• a polyacrylate adhesive is used, it can be crosslinked with multivalent metal ions such as zinc, calcium, aluminum, or titanium ions, such as aluminum acetylacetonate and titanium acetylacetonate.
• silicone adhesives are typically polydimethylsiloxanes. However, other organic residues such as, for example, ethyl groups or phenyl groups may in principle be present instead of the methyl groups. Because the active compounds are amines, it may be advantageous to use amine-resistant adhesives. Representative amine- resistant adhesives are described, for example, in EP 0 180 377.
• acrylate-based polymer adhesives include acrylic acid, acrylamide, hexylacrylate, 2-ethylhexylacrylate, hydroxyethylacrylate, octylacrylate, butyl acrylate, methylacrylate, glycidylacrylate, methacrylic acid, methacrylamide, hexylmethacrylate, 2- ethylhexylmethacrylate, octylmethacrylate, methylmethacrylate, glycidylmethacrylate, vinylacetate, vinylpyrrolidone, and combinations thereof.
• the adhesive must have a suitable dissolving capacity for the active substance, and the active substance most be able to move within the matrix, and be able to cross through the contact surface to the skin.
• Those of skill in the art can readily formulate a transdermal formulation with appropriate transdermal transport of the active substance.
• Certain pharmaceutically acceptable salts tend to be more preferred for use in transdermal formulations, because they can help the active substance pass the barrier of the stratum comeum.
• fatty acid salts such as stearic acid and oleic acid salts.
• Oleate and stearate salts are relatively lipophilic, and can even act as a permeation enhancer in the skin.
• Permeation enhancers can also be used.
• Representative permeation enhancers include fatty alcohols, fatty acids, fatty acid esters, fatty acid amides, glycerol or its fatty acid esters, N-methylpyrrolidone, terpenes such as limonene, alpha-pinene, alpha- terpineol, carvone, carveol, limonene oxide, pinene oxide, and l,8-eucalyptol.
• the patches can generally be prepared by dissolving or suspending the active agent in ethanol or in another suitable organic solvent, then adding the adhesive solution with stirring. Additional auxiliary substances can be added either to the adhesive solution, the active substance solution or to the active substance-containing adhesive solution. The solution can then be coated onto a suitable sheet, the solvents removed, a backing layer laminated onto the matrix layer, and patches punched out of the total laminate.
• Nanoparticulate Compositions The compounds described herein can also be administered in the form of nanoparticulate compositions.
• the controlled release nanoparticulate formulations comprise a nanoparticulate active agent to be administered and a rate-controlling polymer which functions to prolong the release of the agent following administration.
• the compositions can release the active agent, following administration, for a time period ranging from about 2 to about 24 hours or up to 30 days or longer.
• Representative controlled release formulations including a nanoparticulate form of the active agent are described, for example, in U.S. Patent No. 8,293,277.
• Nanoparticulate compositions comprise particles of the active agents described herein, having a non-crosslinked surface stabilizer adsorbed onto, or associated with, their surface.
• the average particle size of the nanoparticulates is typically less than about 800 nm, more typically less than about 600 nm, still more typically less than about 400 nm, less than about 300 nm, less than about 250 nm, less than about 100 nm, or less than about 50 nm. In one aspect of this embodiment, at least 50% of the particles of active agent have an average particle size of less than about 800, 600, 400, 300, 250, 100, or 50 nm, respectively, when measured by light scattering techniques.
• a variety of surface stabilizers are typically used with nanoparticulate compositions to prevent the particles from clumping or aggregating.
• Representative surface stabilizers include gelatin, lecithin, dextran, gum acacia, cholesterol, tragacanth, stearic acid, benzalkonium chloride, calcium stearate, glycerol monostearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters, polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, polyethylene glycols, polyoxyethylene stearates, colloidal silicon dioxide, phosphates, sodium dodecylsulfate, carboxymethylcellulose calcium, carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethyl-cellulose phthalate, noncrystalline cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol, poly
• Lysozymes can also be used as surface stabilizers for nanoparticulate compositions.
• Certain nanoparticles such as poly(lactic-co-glycolic acid) (PLGA)-nanoparticles are known to target the liver when given by intravenous (IV) or subcutaneously (SQ).
• IV intravenous
• SQ subcutaneously
• the nanoparticles or other drug delivery vehicles are targeted to the liver.
• One such type of liver-targeted drug delivery vehicle is described in Park, et al, Mol Imaging. Feb 2011; 10(1): 69-77, and uses Glypican-3 (GPC3) as a molecular target. Park taught using this target for hepatocellular carcinoma (HCC), a primary liver cancer frequently caused by chronic persistent hepatitis.
• GPC3 Glypican-3
• this drug delivery vehicle is also used to target therapeutics to the liver to treat viral infections.
• this type of system can target the compounds to the liver and treat liver cancers or reverse the cancer.
• GPC3 is a heparan sulfate proteoglycan that is not expressed in normal adult tissues, but significantly over expressed in up to 80% of human HCC’s. GPC3 can be targeted, for example, using antibody-mediated targeting and binding (See Hsu, et al, Cancer Res. 1997; 57:5179- 84).
• The‘045 patent discloses a dual-particle tumor or cancer targeting system that includes a first ligand-mediated targeting nanoparticle conjugated with galactosamine, with the ligand being on a target cell.
• the first nanoparticle includes pohfy-glutamic acid)/poly(lactide) block copolymers and n antiviral compound, which in this case is a compound described herein, and in the ‘045 patent, was ganciclovir.
• a second nanoparticle includes pohfy-glutamic acid)/poly(lactide) block copolymers, an endothelial cell-specific promoter, and a (herpes-simplex-virus)-(thymidine kinase) gene constructed plasmid, and provides enhanced permeability and retention-mediated targeting.
• the first and said second nanoparticles are mixed in a solution configured for delivering to the liver.
• the delivery can be directly to, or adjacent to, the liver tumor or cancer.
• Representative rate controlling polymers into which the nanoparticles can be formulated include chitosan, polyethylene oxide (PEO), polyvinyl acetate phthalate, gum arabic, agar, guar gum, cereal gums, dextran, casein, gelatin, pectin, carrageenan, waxes, shellac, hydrogenated vegetable oils, polyvinylpyrrolidone, hydroxypropyl cellulose (HPC), hydroxyethyl cellulose (HEC), hydroxypropyl methylcelluose (HPMC), sodium carboxymethylcellulose (CMC), poly(ethylene) oxide, alkyl cellulose, ethyl cellulose, methyl cellulose, carboxymethyl cellulose, hydrophilic cellulose derivatives, polyethylene glycol, polyvinylpyrrolidone, cellulose acetate, cellulose acetate butyrate, cellulose acetate phthalate, cellulose acetate trimellitate, polyvinyl acetate phthalate, hydroxypropylmethyl
• Nanoparticulate compositions are also described, for example, in U.S. Pat. No. 5,298,262 for "Use of Ionic Cloud Point Modifiers to Prevent Particle Aggregation During Sterilization;” U.S. Pat. No. 5,302,401 for “Method to Reduce Particle Size Growth During Lyophilization;” U.S. Pat. No. 5,318,767 for "X-Ray Contrast Compositions Useful in Medical Imaging;” U.S. Pat. No. 5,326,552 for "Novel Formulation For Nanoparticulate X-Ray Blood Pool Contrast Agents Using High Molecular Weight Non-ionic Surfactants;" U.S. Pat. No.
• nanoparticle formulations including the compounds described herein, and also in the form of a prodrug or a salt, can be used to treat or prevent infections by hepatitis B virus.
• Amorphous small particle compositions are described, for example, in U.S. Pat. No. 4,783,484 for "Particulate Composition and Use Thereof as Antimicrobial Agent;” U.S. Pat. No. 4,826,689 for “Method for Making Uniformly Sized Particles from Water- Insoluble Organic Compounds;” U.S. Pat. No. 4,997,454 for “Method for Making Uniformly-Sized Particles From Insoluble Compounds;” U.S. Pat. No. 5,741,522 for "Ultrasmall, Non-aggregated Porous Particles of Uniform Size for Entrapping Gas Bubbles Within and Methods;" and U.S. Pat. No. 5,776,496, for "Ultrasmall Porous Particles for Enhancing Ultrasound Back Scatter.”
• the active compounds are prepared with carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including but not limited to implants and microencapsulated delivery systems.
• a controlled release formulation including but not limited to implants and microencapsulated delivery systems.
• Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters and polylactic acid.
• enterically coated compounds can be used to protect cleavage by stomach acid. Methods for preparation of such formulations will be apparent to those skilled in the art. Suitable materials can also be obtained commercially.
• Liposomal suspensions including but not limited to liposomes targeted to infected cells with monoclonal antibodies to viral antigens are also preferred as pharmaceutically acceptable carriers.
• liposome formulations can be prepared by dissolving appropriate lipid(s) (such as stearoyl phosphatidyl ethanolamine, stearoyl phosphatidyl choline, arachadoyl phosphatidyl choline, and cholesterol) in an inorganic solvent that is then evaporated, leaving behind a thin film of dried lipid on the surface of the container. An aqueous solution of the active compound is then introduced into the container. The container is then swirled by hand to free lipid material from the sides of the container and to disperse lipid aggregates, thereby forming the liposomal suspension.
• appropriate lipid(s) such as stearoyl phosphatidyl ethanolamine, stearoyl phosphatidyl choline, arachadoyl phosphatidyl choline, and cholesterol
• DIPEA diisopropyl ethyl amine Hiinig’s base
• Scheme 1 is a non-limiting example of the synthesis of intermediate IX and
• Scheme 2 is a non-limiting example of the synthesis of active compounds of the present invention, and in particular, a synthetic approach to compounds of Formulas
• Scheme 3 is an alternate synthetic approach to intermediate IV.
• Scheme 4 is an alternate synthetic approach to intermediate IV.
• Scheme 5 is a synthetic approach to intermediate XXIII
• Scheme 6 is a synthetic approach to intermediate XXIV
• Scheme 7 is a synthetic approach to intermediate XXVII.
• Scheme 8 i s a synthetic approach to compound D, which can be used to make the compounds of Formula 8.
• Scheme 9 is a non-exhaustive list of reagents that can be used to link HBV Capsid Assembly Effectors (“CAE”).
• Schemes 10 and 11 are synthetic approaches to diazo linkers.
• Scheme 12 is a synthetic approach to compounds of Formula HD (dimers where a central linker moiety is attached to two CAE through a heteroaryl moiety formed by coupling an azide with an alkyne).
• Scheme 13 is a synthetic approach to form compounds of formula DAM (dimers where a central linker moiety is attached to two CAE moieties through amide linkages).
• Scheme 14 is a synthetic approach to compounds of Formula DHAR (dimers where a central linker moiety is attached to two CAE through a heteroaryl-alkenyl or alkynyl moiety), formed by coupling a heteroaryl ring to an alkene or alkyne moiety attached to the CAE using transition metal catalyzed coupling chemistry, and Formula DHAR2 (dimers where a central linker moiety is attached to two CAE through a heteroaryl-alkyl moiety) formed by reducing the double or triple bonds in the compounds of Formula DHAR.
• Formula DHAR dimers where a central linker moiety is attached to two CAE through a heteroaryl-alkenyl or alkynyl moiety
• Scheme 15 is a synthetic approach to compounds of Formulas LO and LA (dimers where a central linker moiety which includes two double bonds (Formula LDB) is attached to two CAE via olefin (LO) or alkyl (LA) linkages).
• Formulas LO and LA dimers where a central linker moiety which includes two double bonds (Formula LDB) is attached to two CAE via olefin (LO) or alkyl (LA) linkages).
• Scheme 16 is a synthetic approach to compounds C5-C7.
• Scheme 17 is a synthetic approach to compounds A2-A9.
• Scheme 18 is a synthetic approach to compounds of formulas Bl, B2, B3, B3B, B4, B5, B6, B6B, and B7.
• Scheme 19 is a synthetic approach to compound 8.
• Scheme 20 is a synthetic approach to compound 17.
• Scheme 21 is a synthetic approach to compound 9.
• Scheme 22 is a synthetic approach to compound l6a.
• Scheme 23 is a synthetic approach to compound l7c.
• Scheme 24 is a synthetic approach to compound 20.
• Scheme 25 is a synthetic approach to compound 23.
• Scheme 26 is a synthetic approach to compound 28.
• Scheme 27 is a synthetic approach to compound 33.
• Scheme 28 is a synthetic approach to compound 45.
• Scheme 29 is a synthetic approach to compound 50.
• Scheme 30 is a synthetic approach to compound 53.
• Scheme 31 is a synthetic approach to compounds 58 and 60.
• Scheme 32 is a synthetic approach to compounds 62 and 64.
• intermediates IX and X can be prepared by first reaction of ketoester II with an aldehyde or ketone of general formula III and an ami dine of general formula I to form a dihydropyrimidine of general formula IV.
• Halogenation of the 6-methyl by treatment for example, with N-bromosuccinimide (NBS) or other N-halosuccinimides (NXS) and subsequent reaction with an amine of general formula V in presence of an organic base such as pyridine can afford compound of general formula VI.
• NBS N-bromosuccinimide
• NXS N-halosuccinimides
• Compounds of general formulas A-C can be prepared from intermediates IX and X through a Sonogashira type reation with an alkyne of general formula XI followed by a deprotection step.
• BCb can be used when carbobenzoxy (Cbz) is used as a protecting group.
• Compounds of general formula B can be obtained by reduction of compounds A using, for instance, Fh in the presence of Lindlar catalyst.
• Compounds of general formula C can be synthesized, for example, via a palladium catalyzed reaction with an alkene of general formula XIV under Heck, Suzuki-Myaura or Stille coupling conditions.
• R 9 H, -B(OR) 2 , -Sn(Alk) 3
• intermediate IV can be prepared by first reacting a ketone or aldehyde of general formula II with ketoacid I in presence of a Lewis acid, for example, TiCL. then reaction with amidine XIV to form a thioether intermediate of general formula XV, which can finally react in a transition metal-catalyzed C-C bond formation reaction such as, for example, a Heck type coupling.
• Key intermediate IV can also be prepared by reacting compound XIII with urea, halogenating intermediate XVII with, for instance, POCb and, finally, transition metal- catalyzed coupling reactions such as those described above.
• Intermediates of general formula XXIII can be prepared from compound IV by first halogenating it with, for example, N-bromosuccinimide (NBS) in 1,2- dichloroethane, and then reacting the halogenated compound with a protected amine of general formula XX in the presence of a base such as K2CO3.
• NBS N-bromosuccinimide
• the hydroxyl group in compound XXI can be converted to a leaving group, for example, by reaction with mesyl chloride (MsCl) and an organic base such as triethylamine (Et3N), followed by cyclization in the presence of an inorganic base such as K2CO3.
• MsCl mesyl chloride
• Et3N triethylamine
• Other leaving groups including tosylate, triflate, brosylate, nosylate, and the like, can also be used.
• Intermediates of general formula XXIV can be prepared from compound XIX by first reacting Compound XIX with an amine, such as A-methylamine. in the presence of a base, such as /-BuOK, followed by reaction with 2-chloroacetyl chloride in presence of an organic base such as EbN and final cyclization under basic conditions.
• an amine such as A-methylamine.
• a base such as /-BuOK
• 2-chloroacetyl chloride in presence of an organic base such as EbN and final cyclization under basic conditions.
• Activated compound of general formula XIX can be reacted with a malonate in presence of base such as NaH to from intermediate XXV which can then be reduced with for instance NaBEB.
• Reaction of the resulting diol with MsCl in the presence of an organic base can give access to a cyclized derivative of general formula XXVI which can finally be reacted with a nucleophile, such as NaSMe, to produce a compound of general formula XXVII.
• Bicylic compounds of general structure D can be prepared, for example, from intermediates XXIII, XXIV or XXVII by first deprotecting the ester group with, for instance, BCb in dichloromethane, followed by subsequent halodecarboxylation, using, for example, Nal, oxone and K2CO3, and final transition metal-catalyzed coupling reactions such as Sonogashira, Heck, Suzuki-Myaura or Stille reactions.
• Linked HBV Capsid Assembly Effectors (CAE) of general formula 1 can be prepared using bi or tri functional, homo or heterofunctional linkers and cross linking reagents.
• the preparation of such compounds of general Formula 1 can be accomplished by one of ordinary skill in the art, using, for instance, methods and linkers outlined in TermoFisher Scientific Crosslinking Reagents Technical Handbook (https://tools.thermofisher.com/content/sfs/brochures/l602l63-
• reagents which can be used to link HBV CAE to a central linker.
• LG leaving groups
• Azides on a linker moiety can be reacted with alkyne moieties on an HBV CAE, or on a moiety attached to the HBV CAE, and vice versa.
• Carboxylic acid groups on a linker moiety can be reacted with hydroxyl, thiol, or amine groups on an HBV CAE, or on a moiety attached to the HBV CAE, and vice versa.
• Alkene or alkyne moieties on a linker moiety can be reacted with halides on an HBV CAE, or on a moiety attached to the HBV CAE, for example, using transition metal catalyzed coupling reactions, and vice versa. Double or triple bonds remaining after the coupling step can be reduced, for example, using hydrogen and an appropriate catalyst, should such be desired.
• LG I, Br, Cl, mesyl, tosyl, nosyl, triflate
• Diazido linkers of Formula DAL can be prepared, for example, through the activation of diols of general formula DOL using for instance, mesyl chloride (MesCl) in presence of an organic base such as pyridine, followed by substitution with NaNy for example, in a polar solvent, such as DMF.
• MesCl mesyl chloride
• Diazido linkers of general Formula DAL2 can be prepared, for example, through the activation of diols of general Formula DOL2, using for instance, triflic anhydride (TG2O) in presence of an organic base, such as pyridine, followed by substitution with an azide salt, such as NaNh. in a polar solvent, such as DMF.
• TG2O triflic anhydride
• organic base such as pyridine
• azide salt such as NaNh.
• a polar solvent such as DMF.
• Dimers or heterodimers of general Formula HD can be prepared, for example, through the copper(I)-catalyzed alkyne-azide cycloaddition of a diazido linker of general formula LAZ (azido linker) with an alkyne derivative of a HBV CAE, in the presence, for example, of CuSCL and sodium ascorbate in a mixture of water and tBuOH.
• LAZ azido linker
• Dimers or heterodimers of general Formula DAM can be prepared, for example, through the coupling of a diamino linker of general Formula LAM (linkers with amine groups) with a carboxylic acid derivative of a HBV CAE, in the presence of a peptide coupling reagent like, for example, HATU (1- [Bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate, Hexafluorophosphate Azabenzotriazole Tetramethyl Uronium) in the presence of an organic amine base such as DIPEA (N,N-Diisopropylethylamine, also known as Hunig’s base).
• DIPEA N,N-Diisopropylethylamine, also known as Hunig’s base
• Dimers or heterodimers of general DAM can also be prepared, for example, through the coupling of a diamino linker of general formula LAM with a A-hydroxysuccinimide ester derivative of a HBV CAE in presence of an organic amine base such as DIPEA.
• Dimers or heterodimers of general Formula DHAR (dimer linked through heteroaryl-alkenyl or alkynyl linkages to HBV CAEs) can be prepared, for example, through a transition metal catalyzed coupling reaction, such as a Heck or a Sonogashira reaction, between a correctly functionalized HBV CAE of general Formula AC (alkene/alkyne-functionalized CAE), and a linker with two aromatic or heteroamantic rings subsituted with a leaving group such as I, Br, Cl, mesylate, tosylate or triflate. Reduction of the unsaturation formed, using for instance, H2 and Pd/C in MeOH, can produce compounds of general formula DHAR2 (dimer linked to CAE through a di heteroaryl-alkyl linker).
• a transition metal catalyzed coupling reaction such as a Heck or a Sonogashira reaction
• HBV CAE of general Formula AC alkene/alkyne-
• Dimers or heterodimers of general Formula DO can be prepared, for example, through a ruthenium or tungsten catalyzed cross-metathesis reaction between a correctly functionalized HBV CAE of general Formula CO (CAE attached to an olefin) and a linker with two vinyl or allyl subtitutions (Formula LO, linkers attached to olefins). Reduction of the unsaturation formed, using for instance, H2 and Pd/C in MeOH, can produce compound of general Formula DA (Dimers linked to CAE via alkyl linkages)
• Compounds of general formulas C5-7 can be prepared, for example, by first reaction of a correctly functionalized and protected piperidinone or a correctly functionalized and protected bicyclic piperidinone of general structure Cl with a functionalized acyl chloride derivative in presence of a base such as LiHMDS in a solvent such as THF. Reaction of the diketo intermediate C2 with hydrazine, to form intermediate C3, and subsequent deprotection of the amino group can afford key intermediate C4. Reaction of C4 with a correctly functionalized isocyanate, acyl chloride or sulfonyl chloride reagent in presence of an organic base such as EbN can give compounds of structure C5, C6, and C7. In the generalized reaction scheme shown below, the dashed line symbolizes an optional ring formed by linking R 2 and R 3 via an alkyl bridge, and R'-FC are as defined in the compound section.
• Al can be converted to A2 by treatment with an appropriate alkyl halide such as (3-bromopropoxy)(tert-butyl)diphenylsilane in the presence of a suitable catalyst such as palladium dichloride bis(acetonitrile.
• A2 can be converted to A3 through a deprotection with a suitable reagent such as tetrabutylammonium fluoride and further halogenated to A4 with a suitable reagents such as carbon tetrabromide and triphenylphosphine.
• Cyclization to A5 can be effected with an appropriate radical initiator such as 2,2'-azobis(2-methylpropionitrile) in the presence other reagents such as tributyl tin hydride.
• Ester hydrolysis with a suitable reagent such as lithium hydroxide followed by amide formation via treatment with an appropriate coupling reagent such as HATU and the appropriate aniline or by conversion to the acid chloride with a reagent such a thionyl chloride or oxalyl chloride followed by treatment with the appropriate aniline gives A6.
• the aniline may be varied based on the R4 groups disclosued herein.
• Formation of A7 can be effected by treatment with a suitable reagent such as oxalyl chloride or ethyl2-chloro-2-oxoacetate and may or may not require the addition of catalyst such as aluminum chloride.
• Hydrolysis to AS via a suitable reagent such as lithium hydroxide is followed by preparation of A9 by the coupling of the appropriate amine such as l,l,l-trifluoropropan-2-amine in the presence of a coupling reagent such as HATU.
• the amine may be varied for particular Rl groups disclosed herein.
• Scheme 18 Synthesis of Compounds B2, B3, B3B, B4, B5, B6, B6B, and B7
• Bl can be converted to B2, for example, by treatment with methyl 2-chloro-2-oxoacetate.
• Conversion to B3 can be carried out with an appropriate hydroxide reagent such as lithium hydroxide or in some cases with hydrogen gas and a suitable catalyst if the ester is a benzyl ester.
• B3 can be converted to B4 by treatment with a suitable reagent such as N,N'-diisopropylcarbodiimide and alkyne reagent B3B at elevated temperatures.
• B3 can be treated with oxalyl chloride, worked up and treated with B3B and a suitable base such as 2,6-di- tertbutylpyridine to give B4.
• Hydrolysis to B5 can be effected with a suitable reagent such as lithium hydroxide.
• Conversion to B6 occurs by addition of an appropriate amine (e.g. RI-NH2) and an amide coupling reagent such as HATU.
• B6 can be converted to desired B7 by treatment with a suitable reagent such as lithium hydroxide at elevated temperatures followed a second amide coupling with an appropriate aniline or heteroaryl amine (e.g R4-NtU) and a coupling reagent such as HATU.
• B5 can be treated with an aniline or heteroaryl amine in the presence of a reagent such as Lithium bis(trimethylsilyl)amide to give B6B followed by treatment with an appropriate amine and a coupling reagent such as HATU to give desired B7.
• a reagent such as Lithium bis(trimethylsilyl)amide
• ester such as amino acid ester, sulfate, phosphate and phosphoramidate terminated alkynes.
• Reaction of an acid with an acetylene functionalized with both a hydroxyl and an amine moiety results in formation of the amide linkage to the core molecule, with retention of the hydroxyl group at the terminus of the alkyne.
• This hydroxyl group can then be esterified, sulfated, or phosphorylated using known chemistry.
• Wl can be converted to W2 by reaction with a base such as KOH in presence of the appropriate alkylating agent, such as Mel.
• W2 can then be saponified, in presence of NaOH for instance, and then reacted with a substituted aniline in presence of a coupling agent such as HATU and a base such as DIPEA.
• Conversion of W4 to W5 can be affected by treatment with a suitable reagent such as oxalyl chloride or ethyl2-chloro-2-oxoacetate and may or may not require the addition of catalyst such as aluminum chloride.
• Hydrolysis to W6 via a suitable reagent such as lithium hydroxide is followed by preparation of W7 by the coupling of the appropriate amine such as propargyl amine in the presence of a coupling reagent such as HATU.
• HBV CAE single or multiple replacement of hydrogen with deuterium (carbon-hydrogen bonds to carbon-deuterium bond) at site(s) of metabolism on a HBV CAE, a homo or hetero HBV CAE dimer, a homo or hetero HBV CAE trimer will slow down the rate of metabolism. This can provide a relatively longer half-life, and slower clearance from the body.
• the slow metabolism of a HBV CAE, a homo or hetero HBV CAE dimer or a homo or hetero HBV CAE trimer is expected to add extra advantage to a therapeutic candidate, while other physical or biochemical properties are not affected.
• Anhydrous solvents were purchased from Aldrich Chemical Company, Inc. (Milwaukee, WI) and EMD Chemicals Inc. (Gibbstown, NJ). Reagents were purchased from commercial sources. Unless noted otherwise, the materials used in the examples were obtained from readily available commercial suppliers or synthesized by standard methods known to one skilled in the art of chemical synthesis. 'H and 13 C NMR spectra were taken on a Bruker AscendTM 400 MHz Fourier transform spectrometer at room temperature and reported in ppm downfield from internal tetramethylsilane. Deuterium exchange, decoupling experiments or 2D-COSY were performed to confirm proton assignments.
• Signal multiplicities are represented by s (singlet), d (doublet), dd (doublet of doublets), t (triplet), q (quadruplet), br (broad), bs (broad singlet), m (multiplet). All J- values are in Hz.
• Mass spectra were determined on a Micromass Platform LC spectrometer using electrospray techniques. Analytic TLC were performed on Sigma-Aldrich® aluminum supported silica gel (25 pm) plates. Column chromatography was carried out on Silica Gel or via reverse- phase high performance liquid chromatography.
• Reagents and conditions a) i) benzyl 3-oxobutanoate, AcOH, /PrOH, piperidine, 50°C,
• Reagents and conditions a) benzyl 3-oxobutanoate, /PrOH, AcOH, piperidine, RT, 24 h; b) pyridine-2-carboxamidine hydrochloride, NMI, MeOH, reflux, 18 h; c) i) NBS,
• Reagents and conditions (a) NaOH, Mel, DMSO, rt, 12 h, 94%; (b) 20% NaOH, EtOH, l00°C, 6 h, 40%; (c) Difluoroaniline, HATU, DIPEA, DMF, 80°C, 24 h; (d) ClCOCOOEt, AlCb, DCM, 0°C-rt, 16 h, 72%; (e) 5% NaOH, MeOH, rt, 15 min, 70%; (f) Tris(3- aminopropyl)amine, CDI, DMF, rt, 24 h, 40%.
• Reagents and conditions a) propargylamine, EbN. DMF, rt, 1 h; b) diazidooctane, sodium ascorbate, CUSO4.5H2O, ACN/H2O, rt, 2 h;
• Reagents and conditions c) diazidooctane, sodium ascorbate, CUSO4.5H2O, ACN/H2O, 80°C microwave, 20 min; d) sodium ascorbate, CUSO4.5H2O, ACN/H2O, rt, 1 h
• Reagents and conditions e) NaN . DMF, 80°C, 18 h; f) sodium ascorbate, CuS04.5H20, ACN/H2O, 80°C microwave, 20 min; d) 17b, sodium ascorbate, CUS0 4 .5H 2 0, ACN/H2O, rt, lh; l.l2-Diazidododecane
• Reagents and conditions a) i) NaOH aq, 0°C, 30 min; ii) Cone HC1; b) K2CO3, DMF, 60°C, 24 h; c) AcONa, Ac 2 0, l00°C, 2 h; d) Piperidine, CHCb, rt, 2 h; e) Br 2 , CaCC , CHCb, rt, 24 h. 2-(4-Nilrobenzamido)acelic acid (24)
• Reagents and conditions a) piperidine, AcOH, /PrOH, 24 h; b) thiazole-2-carboximidamide hydrochloride, NMI, THF, 60°C, 65 h; c) N-bromosuccinimide, l,2-DCE, 55°C, 2 h; d) ethyl notroacetate, CS2CO3, DMF, rt, 1.5 h; e) Eh, Raney Ni, B0C2O, EtOH, rt, 48 h; f) NaBFE, EtOH, 50°C, 4 h; g) methanesulfonyl chloride, EbN.
• Methanesulfonyl chloride (0.91 mL, 11.8 mmol) was added to a solution of 39 (3.17 g, 5.9 mmol) and trimethylamine (1.6 mL, 5.9 mmol) in dichloromethane (150 mL) under nitrogen atmosphere. The mixture was stirred at 40°C for 24 h to reach completion. The mixture was then poured into an aqueous solution of NH4CI (200 mL) and extracted with DCM (2 x 100 mL). The combined organic layers were dried over Na 2 S04, filtered and concentrated in vacuo. Purification by column chromatography (7:3 Hex: AcOEt) afforded 41 as ayellow solid (2.00 g, 65%).
• Reagents and conditions a) Tosylchloride, triethylamine, CHCb, RT 2 h; b) sodium azide, DMF, 80°C, 24 h; c) 48, sodium ascorbate, CUSO4.5H2O, ACN/H2O, 80°C microwave, 20 min; d) sodium ascorbate, CUSO4.5H2O, ACN/H20, RT, 3h.
• Triethylamine (0.92 mL, 6.4 mmol) and tosylchloride (0.91 g, 4.8 mmol) were added to a solution of 3,6,9,l2,l5-pentaoxaheptadecane-l,l7-diol 46 (0.4 mL, 1.6 mmol) in chloroform (10 mL) at 0°C.
• the mixture was then stirred at room temperature for 2 h, quenched with a saturated solution of Na2CCb (100 mL) then extracted with DCM (2 x 50 mL). The combined organic layers were dried over Na2SC>4, filtered and concentrated in vaccuo.
• Reagents and conditions a) sodium azide, DMF, 80°C, overnight; b) 7a, sodium ascorbate, CUSO4.5H2O, ACN/H2O, 80°C microwave, 10 min.
• l.lO-Diazidododecane (52) Sodium azide (260 mg) was added to a solution of l,lO-dibromododecane 51 (340 mg) in DMF (2 mL) under nitrogen atmosphere. The mixture was stirred at 80°C overnight.
• Reagents and conditions (b) CDI, , DMF, 45°C, 24 h, 52%; (b) l BuMgCl, THF, r,t, 24h, 40%; (c) HATU, DIPEA, DMF, 45°C, 24h, 50%.
• Reagents and conditions (a) HATU, DIPEA, DMF, r.t, 24 h, 45%; (b) 1N HC1, H2O, THF, 60 °C, 24 h, 70%.
• Reagents and conditions (a) TsCl, Et 3 N, DCM, 0 °C to r.t., 24 h; (b) NaN 3 , (NH+SCri, MeOH, 65 °C, 4 h; (c) CuS0 4 .5H 2 0, Na ascorbate, 100 °C, 2 h.
• Reagents and conditions (a) NaN 3 , DMF/H2O, 90 °C, overnight; (b) CUSO4.5H2O, Na ascorbate, CH3CN/H2O, 90 °C, 8 h.

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