Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/04—Ortho-condensed systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/4353—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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/4353—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
  • A61K31/4375—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 six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—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
  • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—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
  • A61K31/50—Pyridazines; Hydrogenated pyridazines
  • A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/535—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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
  • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
  • A61K38/19—Cytokines; Lymphokines; Interferons
  • A61K38/21—Interferons [IFN]
  • A61K38/212—IFN-alpha
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K39/00—Medicinal preparations containing antigens or antibodies
  • A61K39/12—Viral antigens
  • A61K39/29—Hepatitis virus
  • A61K39/292—Serum hepatitis virus, hepatitis B virus, e.g. Australia antigen
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
• • C—CHEMISTRY; METALLURGY
  • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
  • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
  • C12N7/00—Viruses; Bacteriophages; Compositions thereof; Preparation or purification thereof
• • C—CHEMISTRY; METALLURGY
  • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
  • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
  • C12N2730/00—Reverse transcribing DNA viruses
  • C12N2730/00011—Details
  • C12N2730/10011—Hepadnaviridae
  • C12N2730/10111—Orthohepadnavirus, e.g. hepatitis B virus
• • C—CHEMISTRY; METALLURGY
  • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
  • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
  • C12N2730/00—Reverse transcribing DNA viruses
  • C12N2730/00011—Details
  • C12N2730/10011—Hepadnaviridae
  • C12N2730/10111—Orthohepadnavirus, e.g. hepatitis B virus
  • C12N2730/10134—Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
• • C—CHEMISTRY; METALLURGY
  • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
  • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
  • C12N2730/00—Reverse transcribing DNA viruses
  • C12N2730/00011—Details
  • C12N2730/10011—Hepadnaviridae
  • C12N2730/10111—Orthohepadnavirus, e.g. hepatitis B virus
  • C12N2730/10171—Demonstrated in vivo effect

Definitions

• HBV infection chronic hepatiti s B virus (HBV) infection is a significant global health problem, affecting over 5% of the world population (ov er 350 million people worldwide and 1 .25 million indiv iduals in the U. S.).
• HBV Despite the availability of a prophylactic HBV vaccine, the burden of chronic HBV infection continues to be a significant unmet worldwide medical problem, due to suboptimal treatment options and sustained rates of new infections in most parts of the developing world.
• Current treatments do not prov ide a cure and are limited to only two classes of agents (interferon alpha and nucleoside anal ogues/i nhi bi tors of the viral polymerase); drug resistance, low efficacy, and toierability issues limit their impact.
• the low cure rates of HBV are attributed at least in part to the fact that complete suppression of virus production is difficult to achiev e with a single antiv iral agent.
• the compound of Formula I is a compound of Formula
• the compound of Formula I is a compound of Formula
• the compound of Formula I is a compound of Formula IV :
• compositions comprising a compound of Formula I, II, II I, or IV, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier.
• provided herein is a method of treating an HBV infection in an individual in need thereof, compri sing administering to the individual a therapeutically effective amount of a compound of Formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof.
• provided herein is a method of eradicating an HBV infection in an individual in need thereof, compri sing administering to the individual a therapeutically effective amount of a compound of Formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof.
• provided herein is a method of reducing the viral load associated with an HBV infection in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound of Formula I, I I, 111, or IV, or a pharmaceutically acceptable salt thereof.
• a method of reducing reoccurrence of an HBV infection in an individual in need thereof comprising administering to the individual a therapeutically effective amount of a compound of Formula I, II, III, or IV, or a
• prov ided herein is a method of inhibiting or reducing the formation or presence of HBV DNA-containing particl es or HBV RNA-containing particles in an individual in need thereof, compri sing administering to the individual a therapeutically effective amount of a compound of Formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof.
• prov ided herein is a method of reducing an adverse physiological impact of an HBV infection in an indiv idual in need thereof, comprising administering to the indiv idual a therapeutically effectiv e amount of a compound of Formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof.
• prov ided herein is a method of inducing remission of hepatic injury from an HBV infection in an indiv idual in need thereof, comprising administering to the indiv idual a therapeutically effectiv e amount of a compound of Formula I, I I, 111, or IV, or a pharmaceutically acceptable salt thereof.
• prov ided herein is a method of reducing the physiological impact of long-term antiviral therapy for HBV infection in an indiv idual in need thereof, comprising administering to the indiv idual a therapeutical ly effective amount of a compound of Formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof.
• prov ided herein is a method of prophylactically treating an HBV infection in an indiv idual in need thereof, wherein the indiv idual is afflicted with a latent HBV infection, comprising administering to the i ndiv idual a therapeutically effectiv e amount of a compound of Formula I, I I, III, or IV, or a pharmaceutically acceptabl e salt thereof.
• the methods prov ided herein can further comprise administering to the individual at least one additional therapeutic agent selected from the group consi sting of an HBV polymerase inhibitor, immunomodulatory agents, pegylated interferon, viral entry inhibitor, viral maturation inhibitor, literature-described capsid assembly modulator, rev erse transcriptase inhibitor, a cyciophilin/TNF inhibitor, a TLR-agonist, an HBV vaccine, agents of distinct or unknown mechanism, and a combination thereof.
• the methods provided herein allow for administering of the at least one additional therapeutic agent at a lower dose or frequency as compared to the administering of the at least one additional therapeutic agent alone that is req ired to achieve similar results in prophylactically treating an HBV infection in an individual in need thereof.
• the methods provided herein reduce the viral load in the individual to a greater extent or at a faster rate compared to the administering of a compound selected from the group consisting of an HBV polymerase inhibitor, interferon, viral entry inhibitor, viral maturation inhibitor, di stinct capsid assembly modulator, antiviral compounds of distinct or unknown mechanism, and any combination thereof.
• the methods provided herein cause a lower incidence of viral mutation and/or viral resi stance than the admini stering of a compound selected from the group consisting of an HBV polymerase inhibitor, interferon, viral entry inhibitor, viral maturation inhibitor, di stinct capsid assembly modulator, antiviral compounds of distinct or unknown mechanism, and combination thereof.
• the methods provided herein further comprise admini stering to the individual at least one HBV vaccine, a nucleoside HBV inhibitor, an interferon or any combination thereof.
• a method of treating an HBV infection in an individual in need thereof comprising reducing the HBV viral load by administering to the indiv idual a therapeutical ly effective amount of a compound of Formula 1, I I, III, or IV, or a pharmaceutically acceptable salt thereof, alone or in combination with a reverse transcriptase inhibitor; and further administering to the individual a therapeutical ly effective amount of HBV vaccine.
• the methods provided herein further compri se monitoring the H BV viral load of the subject, wherein the method is carried out for a period of ti me such that the HBV virus is undetectable.
• compounds e.g., the compounds of Formulas I, II, III, or IV, or pharmaceutically acceptable salts thereof, that are useful in the treatment and prevention of HBV infection in subject.
• these compounds may modulate or disrupt HBV assembly and other HBV core protein functions necessary for HBV replication or the generation of infectious particles, may inhibit the production of infectious virus particles or infection or may interact ith HBV capsid to afford defective viral particles with greatly reduced infectivity or replication capacity.
• the compounds provided herein may act as capsid assembly modulators.
• the compounds provided herein have potent antiviral activity, exhibit favorable metabolic properties, tissue distribution, safety and pharmaceutical profiles, and are suitable for use in humans.
• HBV capsid protein plays essential functions during the viral life cycle.
• HBV capsid/core proteins form metastable viral particles or protein shel ls that protect the viral genome during intercellular passage, and al so play a central role in viral replication processes, including genome encapsidation, genome replication, and virion morphogenesis and egress.
• Capsid structures al so respond to environmental cues to allow un-coating after viral entry. Consistently, the appropriate timing of capsid assembly and di s-assembly, the appropriate capsid stability and the function of core protein have been found to be critical for viral infectivity.
• HBV capsid proteins imposes stringent evolutionary constraints on the viral capsid protein sequence, leading to the observed low sequence variability and high conserv ation. Consistently, mutations in HBV capsid that disrupt its assembly are lethal, and mutations that perturb capsid stability severely attenuate viral replication.
• the high functional constraints on the multi-functional HBV core/capsid protein is consi stent with a high sequence conserv ation, as many mutations are deleterious to function. Indeed, the core/capsid protein sequences are >90% identical across HBV genotypes and show only a small number of polymorphic residues. Resi stance selection to HBV core/capsid protein binding compounds may therefore be difficult to select without large impacts on v irus replication fitness.
• the compounds provided herein are useful in HBV treatment by di srupting, accelerating, reducing, delaying and/or inhibiting normal vi al capsid assembly and/or disassembly of immature or mature particles, thereby inducing aberrant capsid morphology and leading to antiv iral effects such as di sruption of virion assembly and/or disassembly, virion maturation, virus egress and/or infection of target cells.
• a disruptor of capsid assembly interacts with mature or immature viral capsid to perturb the stability of the capsid, thus affecting assembly and/or disassembly.
• a di sruptor of capsid assembly perturbs protein folding and/or salt bridges required for stability, function and/or normal morphology of the viral capsi d, thereby disrupting and/or accelerating capsid assembly and/or disassembly.
• the compounds of the inv ention bind capsid and alter metabolism of cellular polyproteins and precursors, leading to abnormal accumulation of protein monomers and/or oligomers and/or abnormal particles, which causes cellular toxicity and death of infected cells.
• the compounds provided herein cause failure of the formation of capsids of optimal stability, affecting efficient uncoating and/or disassembly of viruses (e.g., during infectivity).
• disruption, acceleration, inhibition, delay and/or reduction of capsid assembly and/or disassembly eradicates the virus from the host organism.
• eradication of the HBV from a host advantageously obviates the need for chronic long-term therapy and/or reduces the duration of long-term therapy.
• the compounds described herein are suitable for monotherapy and are effective against natural or native HBV strains and against HBV strains resistant to currently known drugs. In another embodiment, the compounds described herein are suitable for use in combination therapy.
• the compounds proided herein can be used in methods of modulating (e.g., inhibiting or di srupting) the activity, stability, function, and viral replication properties of HBV cccDNA.
• the compounds of the invention can be used in methods of diminishing or preventing the formation of HBV cccDNA.
• the compounds prov ided herein can be used in methods of modulating (e.g., inhibiting or disrupting) the activity of HBV cccDNA.
• the compounds of the inv ention can be used in methods of diminishing the formation of HBV cccDNA.
• the compounds prov ided herein can be used in methods of modulating, inhibiting, or disrupting the generation or release of HBV RNA particles from within the infected cell .
• the total burden (or concentration) of HBV RNA particles is modulated.
• the total burden of HBV RNA is diminished.
• the articles “a” and “an” refer to one or to more than one (i.e. to at least one) of the grammatical object of the article.
• an element means one element or more than one element.
• use of the term “including “ as well as other forms, such as “include “ , “includes, “ and “included, “ is not limiting.
• the term “about” will be understood by persons of ordinary skill in the art and wi ll vary to some extent on the context in hich it is used. As used herein when referring to a measurable value such as an amount, a temporal duration, and the like, the term “about” is meant to encompass variations of ⁇ 20% or ⁇ 10%, including ⁇ 5%, ⁇ 1 %, and ⁇ 0.1% from the specified value, as such variations are appropriate to perform the disclosed methods.
• capsid assembly modulator refers to a compound that disrupts or accelerates or inhibits or hinders or delays or reduces or modifies normal capsid assembly (e.g., during maturation ) or normal capsid disassembly (e.g. , during infectivity) or perturbs capsid stability, thereby inducing aberrant capsid morphology and function.
• a capsid assembly modulator accelerates capsid assembly or disassembly, thereby inducing aberrant capsid morphology.
• a capsid assembly modulator interacts (e.g.
• a capsid assembly modulator causes a perturbation in structure or function of CA (e.g., ability of CA to assemble, disassemble, bind to a substrate, fold into a suitable conformation, or the like), which attenuates viral infectivity and/or is lethal to the virus.
• treatment is defined as the application or administration of a therapeutic agent, i .e., a compound of the invention (alone or in combination with another pharmaceutical agent), to a patient, or application or administration of a therapeutic agent to an isolated tissue or cell line from a patient (e.g., for diagnosis or ex vivo applications), who has an HBV infection, a symptom of HBV infection or the potential to develop an HBV infection, with the purpose to cure, heal, alleviate, relieve, alter, remedy, ameliorate, improve or affect the HBV infection, the symptoms of HBV infection or the potential to develop an HBV infection .
• Such treatments may be speci ically tailored or modified, based on knowledge obtained from the field of pharm acogen om i c s .
• prevent means no disorder or di sease development if none had occurred, or no further di sorder or disease development if there had already been development of the di sorder or disease. Also considered is the ability of one to prevent some or all of the symptoms associated with the di sorder or disease.
• the term "patient, " “individual “ or “subject” refers to a human or a non-human mammal.
• Non-human mammals include, for example, livestock and pets, such as ovine, bovine, porcine, canine, feline and murine mammals.
• the patient, subject or individual is human.
• the terms "effective amount, " “pharmaceutically effective amount” and “therapeutically effective amount” refer to a nontoxic but sufficient amount of an agent to prov ide the desired biological result. That result may be reduction and/or al leviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. An appropriate therapeutic amount in any individual case may be determined by one of ordinary skill in the art using routine experimentation.
• the term “pharmaceutically acceptable” refers to a material, such as a carrier or di luent, which does not abrogate the biological activity or properties of the compound, and is relatively non-toxic, i .e., the material may be administered to an individual without causing undesirable biological effects or i nteracting in a deleterious manner with any of the components of the composition in which it is contained.
• the term "pharmaceutically acceptable salt” refers to derivatives of the disclosed compounds wherein the parent compound is modified by conv erting an existing acid or base moiety to its salt form.
• pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
• the pharmaceutically acceptable salts of the present invention include the conv entional non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
• salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods.
• such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, i sopropanol , or acetonitrile are preferred.
• Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publi shing Company, Easton, Pa., 1985, p. 14 1 8 and Journal of Pharmaceutical Science, 66, 2 (1977), each of which is incorporated herein by reference in its entirety.
• composition refers to a mixture of at least one compound useful within the invention with a pharmaceutically acceptable carrier.
• the pharmaceutical composition facilitates administration of the compound to a patient or subject. Multiple techniques of administering a compound exist in the art including, but not limited to, intravenous, oral , aerosol, parenteral, ophthalmic, pulmonary and topical administration.
• pharmaceutically acceptable carrier means a
• composition or carrier such as a liquid or solid filler, stabilizer, dispersing agent, suspending agent, diluent, excipient, thickening agent, solvent or encapsulating material , involved in carrying or transporting a compound useful w ithin the invention within or to the patient such that it may perform its intended function.
• a pharmaceutically acceptable material , composition or carrier such as a liquid or solid filler, stabilizer, dispersing agent, suspending agent, diluent, excipient, thickening agent, solvent or encapsulating material , involved in carrying or transporting a compound useful w ithin the invention within or to the patient such that it may perform its intended function.
• a compound useful w ithin the invention within or to the patient such that it may perform its intended function.
• Such constructs are carried or transported from one organ, or portion of the body, to another organ, or portion of the body.
• Each carrier must be "acceptable " in the sense of being compatible with the other ingredients of the formulation, including the compound useful within the invention
• materials that may serve as pharmaceutically acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cell lose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin, talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil;
• glycols such as propylene glycol ; polvols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; surface active agents; alginic acid;
• pharmaceutically acceptable carrier also includes any and all coatings, antibacterial and antifungal agents, and absorption delaying agents, and the like that are compatible with the activity of the compound useful within the invention, and are physiologically acceptable to the patient. Supplementary active compounds may also be incorporated into the compositions.
• pharmaceutically acceptable carrier may further include a pharmaceutically acceptable salt of the compound useful within the invention.
• alkyl by itself or as part of another substituent means, unless otherwise stated, a straight or branched chain hydrocarbon having the number of carbon atoms designated (i .e., CYCValkyl means one to six carbon atoms) and includes strai ht, branched chain. Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl, and hexyl. Other examples of Ci-Ce-alkyl include ethyl, methyl, isopropyl, isobutyl , n-pentyl, and n-hexyl .
• alkenyl denotes a monovalent group derived from a hydrocarbon moiety containing at least two carbon atoms and at least one carbon-carbon double bond. The double bond may or may not be the point of attachment to another group.
• Alkenyl groups e.g., CVCValkenvl
• alkenyl groups include, but are not limited to, for example, ethenyl, propenyl, prop- l -en-2-yl, butenyl, 1 -methyl-2-buten- 1 -yl, heptenyl, octenyl and the like.
• halo or halogen alone or as part of another substituent means, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom, preferably, fluorine, chlorine, or bromine, more preferably, fluorine or chlorine.
• haioalkyl refers to alkl radicals wherein any one or more of the alkyl carbon atoms is substituted with halo as defined above. Haioalkyl embraces monohaloalkyl, dihaloalkyl, and polyhaioalkyl radicals.
• haioalkyl includes, but is not limited to, fluorom ethyl, dilluoromethyl , trifl orom ethyl, chloromethyl , dichloromethyl, trichloromethyl, and pentafluoroethyl .
• cycloalkyl refers to a mono cyclic or polycyclic non- aromatic radical, wherein each of the atoms forming the ring (i .e., skeletal atoms) is a carbon atom.
• the cycloalkyl group is saturated or partially unsaturated.
• the cycloalkyl group is fused with an aromatic ring.
• Cycloal kyl groups include groups having 3 to 10 ring atoms iC ⁇ .C in-cycloalkyl ), groups having 3 to 8 ring atoms (CYCVcycloalkyl ), groups having 3 to 7 ring atoms (CYC— cycioalkyl ), and groups having 3 to 6 ring atoms ( C ;.Cv,-cycloalkyl ).
• Illustrative examples of cy cioalkyl groups include, but are not limited to, the following moieties:
• Monocyclic cycioalkyl s include, but are not limited to, cyclopropyl , cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl .
• Di cyclic cycloalkyls include, but are not limited to, tetrahydronaphthyl , indanyl, and tetrahydropentalene.
• Polycyclic cycloalkyls include adamantine and norbornane.
• cycioalkyl includes "unsaturated nonaromatic carbocyclyl” or “nonaromatic unsaturated carbocyclyf " groups, both of which refer to a nonaromatic carbocycle as defined herein, which contains at least one carbon carbon double bond or one carbon carbon triple bond.
• heterocycloalkyf or “heterocyclyl” refers to a
• heteroalicyclic group containing one to four ring heteroatoms each selected from O, S and N.
• each heterocyclyl group has from 3 to 10 atoms in its ring system, with the proviso that the ring of said group does not contain two adjacent O or S atoms.
• Heterocyclyl substituents may be alternatively defined by the number of carbon atoms, e g., CVCx-heterocyclyl indicates the number of carbon atoms contained in the heterocyclic group without including the number of heteroatoms.
• a CVCVheterocycl y 1 will include an additional one to four heteroatoms.
• the hetet ocycloalkyl group is fused with an aromatic ring.
• the nitrogen and sulfur heteroatoms may be optionally oxidized, and the nitrogen atom may be optionally quaternized.
• the heterocyclic system may be attached, unless otherwise stated, at any heteroatom or carbon atom that affords a stable structure.
• An example of a 3-membered heterocycly l group includes, and is not limited to, aziridine.
• 4-membered heterocyclyl groups include, and are not limited to, azetidine and a beta lactam.
• 5-membered heterocyclyl groups include, and are not limited to, pyrrolidine, oxazolidine and thiazolidinedione.
• 6-membered heterocycl oalkyl groups include, and are not limited to, piperidine, morpholine and piperazine.
• heterocycl oal kyl groups are:
• heterocycl es include monocyclic groups such as aziridine, oxirane, thiirane, azetidine, oxetane, thietane, pyrrolidine, pyrrol ine, pyrazolidine, imidazoline, dioxolane, sulfolane, 2,3-dihydrofuran, 2,5-dihydrofuran, tetrahydrofuran, thiophane, piperidine, 1 ,2,3,6-tetrahydropyridine, 1 ,4-dihydropyridine, piperazine, morpholine, thiomorpholine, pyran, 2,3-di hydropyran, tetrahydropyran, 1 ,4-dioxane, 1 ,3-dioxane, homopiperazine, homopiperidine, 1 ,3-dioxepane, 4,7-dihydro- 1 ,3-dioxepin
• aromatic refers to a carbocycle or heterocycl e with one or more polyunsaturated rings and having aromatic character, i.e., having (4n + 2) delocalized ⁇ (pi) electrons, where n i s an integer.
• aryl employed alone or in combination with other terms, means, unless otherwise stated, a carbocyclic aromatic system containing one or more rings (typically one, two, or three rings), wherein such rings may be attached together in a pendent manner, such as a bi phenyl, or may be fused, such as naphthalene.
• aryl groups include phenyl, anthracyl, and naphthyl .
• Preferred examples are phenyl (e.g., (Varyl ) and bi phenyl (e.g., C 12 -aryl).
• aryl groups have from six to sixteen carbon atoms.
• aryl groups have from six to twelve carbon atoms (e.g., C 6 - Ci2-aryl).
• aryl groups have six carbon atoms (e.g., CVaryl ).
• heteroaryl refers to a heterocycle having aromatic character.
• Heteroaryl substituents may be defined by the number of carbon atoms, e.g., Ci-tVheteroaryl indicates the number of carbon atoms contained in the heteroaiyl group without including the number of heteroatoms.
• Ci-tVheteroaryl indicates the number of carbon atoms contained in the heteroaiyl group without including the number of heteroatoms.
• -CV heteroaryl will include an additional one to four heteroatoms.
• a polvcyclic heteroaryl may- include one or more rings that are partially saturated.
• Non-limiting examples of heteroaryls include:
• heteroaryl groups include pyridyl, pyrazinyl pyrimidinyl (including, e.g., 2- and 4-pyrimidinyl), pyndazinyl, thienyl, furyl, pyrrolyl (including, e.g., 2-pyrrolyl), imidazolyl, thiazolyl, oxazolyl, pyrazolyl (including, e.g., 3 5-pyrazolyl), isothiazolyl, 1,2,3-tnazolyl, 1,2,4-triazolyl, 1,3,4-triazolyL tetrazolyl, 1.2.3-thiadia/olyl. 1,2,3-oxadiazolyl, 1.3.4-thiadia/olyl and 1,3,4-oxadiazolyl.
• Non-limiting examples of polvcyclic heterocycles and heteroaryls include indolyl (including, e.g., 3-, 4-, 5-, 6- and 7-indoh I ), mdolinyl, quiiioiyl, tetrahydroquinolyl, isoquinolyl (including, e.g., 1- and 5-isoquinolyl), cinnolinyl, quinoxalinyl (including, e.g., 2- and 5-quinoxaiinyl), quinazolinyl, phthalazinyl,
• substituted means that an atom or group of atoms has replaced hydrogen as the substituent attached to another group.
• W' and W are each independently selected from N, NR a , and CR a , wherein one of W 1 and W is NR a ;
• X is N or CR b ;
• Y is selected from a bond, -C(O)-, and -SO 2 -;
• R 1 is selected from C 6 -Ci 2 -aryi, Ci-C 9 -heteroaryl, (VCVcycloalkyl, C 2 -C 8 - heterocyclyl, OR c , C -CVaikyl, C(0)OR c , C(0)R c , C(0)NR d R e , NR d C(0)R c , OC(0)R c , halo, and CVCx-alkenyl, wherein alkyl, aryi, heteroaryl, cycloalkyl, heterocyclyl, and alkenyl are optionally substituted with 1, 2, 3, or 4 groups each independently selected from -OH, halo, Ci-Ce-aikyl, Ci-CVha!oalkyl, -O-C i-CValkyl, and Ci-Ce-aikyl-OH;
• R is, at each occurrence, independently selected from H, -OH, halo, Ci-C 6 -alkyl, C
• R is, at each occurrence, independently selected from H, -OH, halo, C CValkyl, Cj - Ce-haloalkyl, -Q-Ci-Ce-alkyl, and Ci-Ce-alkyl-OH;
• R 4 is selected from Ci-C 6 -alkyl, (CR 8 R 9 ) p -C 3 -C 8 -cycloaikyi, (CR 8 R 9 ) P -C 2 -C 8 - heterocyclyl, (CR 8 R 9 ) p -C 6 -C 12 -aryl, and (CR 8 R 9 ) p -Ci-C9-heteroaryl, wherein alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with 1, 2, 3, or 4 groups, each independently selected from -OH, halo, CN, Ci-C 6 -aikyl, C
• R 5 is, at each occurrence, independently selected from H, -OH, halo, Ci-C 6 -alkyl, CV C 6 -haloalkyl, -0-C C 6 -alkyl, and G-CValkyl-OH;
• R 4 and R 5 are optionally joined to form a ring
• R" is, at each occurrence, independently selected from H, OH, halo, Ci-Ce-alkyl, C ⁇ - Ce-haloalkyl, -0-Ci-C 6 -alkyl, and
• R is selected from H, G-CValkyl, and Ci-C 6 -alkyl-OH;
• R 8 is, at each occurrence, independently selected from H, -OH, halo, C i-CValkyl, C
• R 9 is, at each occurrence, independently selected from H, -OH, halo, C i-CValkyl, C ⁇ - Ce-haloalkyl, O-d-CV.-alkyl , and d-C 6 -alkyl-OH;
• R a is selected from H, C i-CValkyl, and C
• R b is selected from H and C i-CValkyl
• R c is selected from H, C i-CValkyl, CVCValkyl-OH, C 3 -C 8 -cycloalkyl, CVCV heterocyclyl, C 6 -Ci 2 -aryl, and Cj-Cg-heteroaryl;
• R d is selected from H, C i-CVal kyl , and C " i-CVal kyl-OH;
• R e is selected from H, C i-CValkyl, C i-CValkyl-OH, CVCVcycloalkyl, C 2 -C 8 - heterocyclyl, C 6 -Ci 2 -aiyl, CVCVheteroaryl, and 0-(VC(,-alkyl ;
• R d and R e are optionally joined to form a heterocyclic ring
• R is, at each occurrence, independently selected from H and C i-CValkyl
• n 0, 1 , 2, 3, or 4;
• n 0, 1, 2, or 3;
• p 0, 1, 2, 3, or 4.
• W 1 and W are each independently selected from N, NR a , and CR a , wherein one of W and W is NR a ;
• X is N or CR b ;
• Y is selected from a bond, -C(0)-, and -S0 2 -;
• R 1 is selected from CVCVcycloalkyl, C 2 -C 8 -heterocyclyl, -OR c , CVCValkyl, halo, and CVCValkenyl, wherein alkyl, cycloalkyl, heterocyclyl, and alkenvl are optionally substituted with 1, 2, 3, or 4 groups each independently selected from OH, halo, C 1 -C fl - alkyl, C i-CVhaloa! ky! , -0-CVCValkyl , and CVCVal kyl -OH;
• R is, at each occurrence, independently selected from H, -OH, halo, Ci-C 6 -alkyl, CV
• R 3 is, at each occurrence, independently selected from H, -OH, halo, CVCValkyl, CV G.-haloalkyl , -0-Cj -C 6 -alkyl, and C
• R 4 is selected from C ,-C ( ,-alkyl, (CR 8 R 9 ) p -C 3 -C 8 -cycloalkyl, (CR 8 R 9 ) P -C 2 -C 8 - heterocyclyl, ( C R X R 4 ) P -CVC 1 2-aryl , and ( CR X R'' ) p -C 1 -Cj-heteroary 1 , wherein alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with 1, 2, 3, or 4 groups, each independently selected from OH, halo, CN, CVCValkyl, CVCVhaloalkyl, O- CrCe-alkyl, C(0)N(R f ) 2 , C(0)OR f , -OCH 2 C(0)OR f , » S0 2 R f , and Ci-C 6 -alkyl-OH;
• R 5 is, at each occurrence, independently selected from H, -OH, halo, CVCValkyl, CV CVha!oalkyl, -0-Ci-C 6 -alkyl, and d-C-alkyl-OH;
• R 4 and R are optional ly joined to form a heterocyclic ring
• R 6 is, at each occurrence, independently selected from H, -OH, halo, CVCValkyl, CV CVhaloalkyl , O-d-CV.-alkyl , and d-Ce-alkyl-OH; R is selected from H, C i-CValkyl, and Ci-Ce-alkyl-OH;
• R 8 is, at each occurrence, independently selected from H, Oil, halo, C i-CValkyl, Ci- C 6 -haloaikyl, -0-C
• R 9 is, at each occurrence, independently selected from H, OH, halo, Ci-C 6 -alkyl, C Ce-haloalkyl, -0-Ci-C 6 -alkyl, and C i -Cv.-alkyl-OH;
• R a is selected from H, Ci-C 6 -alkyl, and Ci-C 6 -alkyl-OH;
• R b is selected from H and C i-CValkyl
• R c is selected from H, C i-CValkyl, C
• R is, at each occurrence, independently selected from H and Cj-C 6 -alkyl
• n 0, 1 , 2, 3, or 4;
• n 0, 1, 2, or 3;
• p is O, 1, 2, 3, or 4.
• W 1 and W are each independently selected from N, NR d , and CR d , wherein one of W and W is NR a ;
• X is N or CR b ;
• Y is selected from a bond, -C(O)-, and -S0 2 -;
• R 1 is selected from C -Cg-cycloalkyl, C -Cx-heterocyclyl, Ci-C 6 -alkyl, and C 2 -C 8 - alkenyl, wherein alkyl, cycloalkyl, heterocyclyl, and alkenyl are optionally substituted with 1, 2, 3, or 4 groups each independently selected from -OH, halo, CVCValkv , Ci-CVhaloalkv , -O-Ci-Ce-aikyl, and C C 6 -alkyl ⁇ OH;
• R 2 is, at each occurrence, independently selected from H, -OH, halo, Ci-C 6 -alkyl, Ci- G-haloalkyl, ⁇ -0-Ci-C 6 -alkyl, and d-CValkyl-OH;
• R 3 is, at each occurrence, independently selected from H, Oil, halo, Ci-Ce-alkyl, Ci- CVhaloalkyl, 0-C
• R 4 is selected from C ,-C t -alkyl, (CR 8 R 9 ) p -C 3 -C 8 -cycloalkyl, (CR 8 R 9 ) P -C 2 -C 8 - heterocyclyl, (CR 8 R 9 ) p -C 6 -Ci 2 -aryl, and (CR 8 R 9 ) p -Ci-C9-heteroaryl, wherein alkyl, cycioalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with 1, 2, 3, or 4 groups, each independently selected from -OH, halo, CN, Ci-CValkyl, Ci-Ce-haloalkyl, -O- Ci-Ce-alkyl, C(0)N(R f ) 2 , C(0)OR f , -OCH 2 C(0)OR , -S0 2 R , and Ci-C 6 -alkyl-OH;
• R 5 is, at each occurrence, independently selected from H, -OH, halo, Ci-C 6 -alkyl, Ci- C 6 -haloalkyl, -0-C C 6 -alkyl, and C,-G,-alkyl-OH;
• R 4 and R 5 are optionally joined to form a ring
• R" is, at each occurrence, independently selected from H, OH, halo, Ci-Ce-alkyl, C ⁇ - Ce-haloalkyl, -0-Ci-C 6 -alkyl, and d-d-alkyl-OH;
• R is selected from H, d-CValkyl, and Ci-C 6 -alkyl-OH;
• R 8 is, at each occurrence, independently selected from H, -OH, halo, Ci-G,-alkyl, C
• Ce-haloalkyl -0-Ci-C 6 -alkyl, and Ci-C 6 -alkyl-OH;
• R 9 is, at each occurrence, independently selected from H, -OH, halo, Ci-CValkyl, C ⁇ - Ce-haloalkyl, 0-(VG,-alkyl, and d-Ce-alkyl-OH;
• R a is selected from H, Ci-Ce-alkyl, and C
• R b is selected from H and Ci-Ce-alkyl
• R is, at each occurrence, independently selected from H and C i-CValkyl
• n 0, 1, 2, 3, or 4;
• n 0, 1, 2, or 3;
• p is O, 1, 2, 3, or 4.
• W 1 is R a and W is N or CR '.
• W 1 is NH.
• W 1 is N or CR a and W is NR a .
• X is .
• Y is -C(O)- or -S0 2 -
• Z is -(CR 5 R°) m -
• n 0 or 1
• R 5 is H, -OH, or C C 6 -alkyl
• R 6 is H or Ci-Ce-alkyl
• R is H or Ci-C(,-alkyl.
• R 1 is CVCx-cycloalkyl, C 2 -C 8 - heterocyclyl, Ci-C 6 -alkyl, or C 2 -C 8 -alkenyl, wherein alkyl, cycloalkvl, heterocyclyl, and alkenyl are optionally substituted with 1, 2, 3, or 4 groups each independently selected from - OH, halo, C
• R 1 is (VCVcycloalkyl or C 2 - Cg-heterocyclyl, wherein cycloalkyl and heterocyclyl are optionally substituted with 1, 2, 3, or 4 groups each independently selected from -OH, halo, Ci-C 6 -alkyl, Ci-Ce-hafoalkyl, -O- Ci-C 6 -alkyl, and C ,-C ( ,-alkyl-OH.
• R 1 is CVG.-cycloalkyl or C 2 - Cs-heterocyclyl, wherein cycloalkyl and heterocyclyl are optionally substituted with 1 or 2 groups each independently selected from -OH, halo, Cj-C 6 -alkyl, C
• each R 2 is independently selected from H or Ci-CValkyl . In a further embodiment of the compound of Formula I, R 2 is H.
• R 3 is H.
• R 4 is (CR 8 R 9 ) p -C 3 -C 8 -cycloalkyl, ⁇ C R )p-CVCYheterocycl yl , (CR 8 R 9 ) p -C 6 -Ci 2 -aryl, or ⁇ C Il ) regularly-C i -CVheteroary I , wherein cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with 1, 2, 3, or 4 groups each independently selected from -OH, halo, CN, C CValkyl, Ci-C 6 -haloalkyl, O- CrC 6 -aiky ⁇ , C(0)N(R f ) 2 , C(0)OR f , -OCH 2 C(0)OR f , -S0 2 R f , and Ci-C 6 -alkyl-OH.
• R 4 is (CR 8 R 9 ) p -C6-Ci 2 -aryl, or (CR X R ') P -C I -C)-heteroaryl, wherein aryl, and heteroaryl are optionally substituted with 1, 2, 3, or 4 groups, each independently selected from -OH, halo, CN, Ci-C 6 -alkyl, Ci-C 6 - haloalkyl, -0-C C 6 -alkyL C(0)N(R f ) 2 , C(0)OR f , -OCH 2 C(0)OR f , -S0 2 R f , and C C 6 -aikyl- OH.
• p is 0 or 1;
• R 8 is H, -OH, or C C 6 -alkyl
• R' is H or Ci-CValkyl .
• n 1
• X is N; Y is -C(O)-;
• Z is NR. ;
• R is H or Ci-4-alkyl.
• X is N
• Y is -C(Q)-
• Z is NR 7 ;
• R is H or Cj-4-alkyl
• n 1.
• Y is C(O) or -S0 2 -.
• Z is -(CR 5 R 6 ) m -, -(CR 5 R 6 ) ffi O- or -(CR 5 R 6 ) m -NR 7 -.
• n 0 or 1 ;
• R 5 is II, -OH, or C C 6 -alkyl
• R 6 is I I or Ci-C(,-alkyl
• R is H or Ci-C 6 -alkyl.
• R 1 is CVCVcycloalkyl, C 2 -C 8 - heterocyclyl, Ci-C 6 -aiky ⁇ , and C 2 -C 8 -aikeiiyl, wherein alkyi, cvcloalkyl, heterocyclyl, and alkenyl are optionally substituted with 1, 2, 3, or 4 groups each independently selected from - OH, halo, Ci-CValkyl, C ,-G,-haloalkyl, -0-Ci-C 6 -alkyl, and Ci-C 6 -alkyl-OH.
• R 1 is CVCVcycloalkyl or C 2 - Cg-heterocyclyl, wherein cvcloalkyl and heterocyclyl are optionally substituted with 1, 2, 3, or 4 groups each independently selected from OH, halo, CVCValkyl, C
• Ci-Ce-alkyl and CVCVal kyl -OH.
• R 1 is CVCVcycloalkyl or C -
• C -heterocyclyl wherein cycloalkyl and heterocyclyl are optionally substituted with 1 or 2 groups each independently selected from OH, halo, CVCValkyl, Ci-Ce-haloalkyl, -O-Ci-Ce- alkyl, and CVCe-alkyl-OH.
• R 1 i selected from OH, -Br, methyl, ethyl, ethenyl, propyl, propenyl, isopropyl, butyl, t-butyl, butenyl , pentanyl, 2- methylpentan-2-yl, cyclopropyl, cyclobutyl , cyclopentyl, cyclopentenyl, cyclohexyl , cyclohexenyl, tetrahydrofuranyi, tetraliydropyranyi , dihydropyranyl, pyrrol idinyl,
• OJhexanyl wherein methyl , ethyl, ethenyl, propyl, propenyl , isopropyl, butyl, t- biityl, butenyl, pentanyl, and 2-methylpentan-2-yl are optionally substituted with 1 or 2 groups independently sel ected from OH, and halo, or wherein cyclopropyl, cyclobutyl , cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, tetrahydrofuranyi, tetraliydropyranyi, dihydropyranyl, pyrrol idinyl, and bicyclo[3.1.
• OJhexanyl are optionally substituted with 1 or 2 groups independently selected from OH, halo, CVCValkyl, CVCVhaloalkyi, O-CVCV alkyl, and CVCValkyl -OH.
• R 1 is selected from methyl, ethyl, ethenyl, propyl, propenyl, isopropyl, butyl, t-butyl, butenyl, pentanyl, 2-methylpentan- 2-yl , cyclopropyl , cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cycl ohexenyl , tetrahydrofuranyi, tetraliydropyranyi, dihydropyranyl, pyrrol idinyl, bicyclo[3.1. OJhexanyl, any of which are optionally substituted with 1 or 2 groups independently selected from OH and halo.
• each R 2 i s independently selected from H or CVCValkyl .
• R 2 is H
• R 4 is ( C R X R ' ) p -C -,-CVcy cl oal kyl , (CR 8 R 9 ) p -C 2 -C 3 -heterocyclyl, (CR s R 9 ) p -C 6 -Ci 2 -aiyl, or ( C R X R'' ) favor-C i -C-heteroary 1 , wherein cycloal kyl , heterocyclyl , aryl, and heteroaryl are optionally substituted with 1, 2, 3, or 4 groups, each independently selected from OH, halo, CN, CVCValkyl, CVCVhaloalkyi, O- CVCValkyl, C(0)N(R f ) 2 , C(0)OR f , -OCH 2 C(0)OR , -S0 2 R , and C
• R 4 is (CR 8 R 9 ) p -CVCi 2 -aryl, or (CR X R ') P -C I -Crheteroaryl, and wherein aryl and heteroaryl are optionally substituted with 1, 2, 3, or 4 groups, each independently selected from OH, halo, CN, CVCValkyl, CVCV haloalkyl, - 0-C ,-CValkyl, C(0)N(R ) 2 , C(0)OR f , -OCH 2 C(0)OR f , -S0 2 R f , and G-CValkyl- OH.
• Y is -C(0)-
• Z is -(CR 5 R 6 )m-, -(CR 5 R 6 ) m O- or -(CR 5 R 6 ) m -NR 7 -;
• R 1 is GVCg-cycloalkyl, CVCVheterocyclyl, -OH, CVCe-alkyl, halo, and CVCV alkenyl, wherein alkyi, cycloalkyl, heterocvciyl, and alkenyl are optionally substituted with 1 , 2, 3, or 4 groups each independently selected from -OH, halo, CVCValkyl, G-CVhaloalkyl, -O-d-Ce-alkyl, and d-Cg-alkyl-OH;
• R ⁇ and R 3 are H
• R 4 is ( C R x R ) p -C(,-C 12 -aiy 1 , or (CR 8 R 9 ) p -Ci-C9-heteroaryl, and wherein aryl and heteroaryl are optionally substituted with 1, 2, 3, or 4 groups, each independently selected from -OH, halo, CN, Ci-C 6 -alkyl, G-CVhaloal kyl , -0-Ci-C 6 -alkyl, C(0)N(R f ) 2 , C(0)OR f , -OCH 2 C(0)OR f , -S0 2 R f , and G-CValkyl-OH;
• R 5 is H, -OH, or G-CValkyl
• R" is H or Ci-Ce-alkyl
• R is H or C i-CValkyl
• R 8 is, at each occurrence, independently selected from H, -OH, halo, and Ci-C 6 -alkyl
• R 9 is, at each occurrence, independently selected from H, OH, halo, and CVCValkyl
• R c is Ci-Ce-alkyl
• R is, at each occurrence, independently selected from H and C i-CValkyl
• n 1, or 2;
• n 1 ;
• p 0, 1, or 2.
• R 1 is CVCVcycloalkyl, C 2 -C 8 -heterocyclyl, Ci-C 6 -alkyl, and C 2 -C 8 -alkenyl, wherein alkyl, cycloalkyl, heterocvciyl, and alkenyl are optionally substituted with 1 or 2 groups each independently selected from -OH, halo, CVCValkyl.
• R 4 is (CR 8 R 9 ) p -CVCi 2 -aryi, or (CR 8 R 9 ) P -Cr Cg-heteroaryl, and wherein aryl and heteroaryl are optionally substituted with 1, 2, or 3 groups, each independently selected from -OH, halo, CN, Ci-Ce-alkyl, Ci-Ce-haloalkyl, -O- Ci-Ce-alkyl, and Ci-C 6 -alkyl-OH.
• R 8 is independently selected from H, OH, and CVCValkyl
• R 9 is independently selected from H and CVCValkyl .
• n 1
• Y is -C(O)-
• Z is NR 7 ;
• R is H or Ci-4-alkyl.
• Y is -C(O)-
• Z is NR 7 ;
• R is I I or C i-i-alkyl
• n 1.
• Y is -C(O)- or -SO?-;
• R 1 is Cr s-cycloal kyl , (VCYheterocyclyl, -OH, Ci-C 6 -alkyl, halo, and C 2 -C 8 - alkenyl, wherein alkyl, cycloalkvl, heterocyclyl, and alkenyl are optionally substituted with 1, 2, 3, or 4 groups each independently selected from OH, halo, C i-Ci,-haloalkyl, -0-Ci-C 6 -alkyl, and C
• R 2 is, at each occurrence, independently selected from H, OH, halo, Cj-C 6 -alkyl, C
• R J is selected from H, -OH, halo, Ci-Ce-alkyl, C i-C Too-haloalkyl, -0-C
• R 4 is selected from (CR X R ') P -C I -Crheteroaryl, (CR 8 R 9 ) p -C 6 -Ci 2 -aryl, and C 3 -C 3 - cycloal kyl herein heteroaryl, aryl, and cycloalkvl are optionally substituted with 1 , 2, or 3 groups, each independently selected from OH, halo, CN, CVCValkyl, CVCVhaloalkyl, O- Ci-CValkyl, CVCValkyl -OH, and CVC cycloalkyl.
• R is selected from H, Ci-Ce-alkyl, and CVCValkyl -OH;
• R 8 is, at each occurrence, independently selected from H, OH, halo, CVCValkyl, CV CVhaloalkyl, -O-Ci-CValkyl, and
• R 9 is, at each occurrence, independently selected from H and CVCValkyl; and p is O, l, 2, 3, or 4.
• Y is -C(O)- or -SO,-;
• R 1 is CVCVcycloalkyl, CVCVheterocyclyl, CVCValkyl, and CVCValkenyl, wherein alkyl, cycloalkyl, heterocyclyl, and alkenyl are optionally substituted with 1, 2, 3, or 4 groups each independently selected from -OH, halo, CVCValkyl, CVCVhaloalkyl, -O-CV Valkyl, and C-CValkyl-OH;
• R 2 is, at each occurrence, independently selected from H, -OH, halo, CVCValkyl, C'r Ce-haloalkyl, -0-Ci-C 6 -alkyl, and Ci-C 6 -alkyl-OH;
• R 3 is selected from H, -OH, halo, Ci-Ce-alkyl, CVCVhaloalkyl, -O-CVCValkyl, and CrC 6 -alkyl-OH;
• R 4 is selected from ( CR X R ) P -C i -Orheteroaryl and (CR X R'') P -CV i aryl, wherein heteroaryl and aryl are optionally substituted with 1, 2, or 3 groups, each independently selected from OH, halo, CN, CVCValkyl, CVCVhaloalkyl, O-CVCValkyl, and CVCe- alkyl-OH;
• R is selected from H, CVCValkyl, and Ci-C 6 -alkyl-OH;
• R 8 is, at each occurrence, independently selected from H, -OH, halo, CVCValkyl, CV
• Ce-haloalkyl -0-Ci-C 6 -alkyl, and CVCValkyl -OH;
• R 9 is, at each occurrence, independently selected from H and CVCValkyl; and p is 0, 1, 2, 3, or 4.
• Y is -C(O)-.
• R 1 is CVCVcycloalkyl, C 2 -C 8 - heterocyclyl, -OH, Ci-Ce-alkyl, halo, and C 2 -C 8 -alkenyl, wherein alkyl, cycloalkyl, heterocyclyl, and alkenyl are optionally substituted with 1 or 2 groups each independently selected from -OH, halo, CVCValkyl, CVCVhaloalkyl, -0-Ci-C 6 -aikyl, and Ci-C 6 -alkyl-OH.
• R 1 is Cs-Cs-cycloalkyl, CVCV heterocyclyl, Ci-C 6 -alkyl, and C:>-Cx-alkenyl , wherein alkyl, cycloalkyl, heterocyclyl, and alkenyl are optionally substituted with 1 or 2 groups each independently selected from -OH, halo, CVCValkyl, C ' i-CVha!oalkyl, -O-Ci-Ce-alkyl, and CVG.-alkyl-OH;
• R 1 is CVCVcycloalkyl or C 2 -C 8 - heterocyclyl, wherein cycloalkyl and heterocyclyl are optionally substituted with 1 or 2 groups each independently selected from -OH, halo, CVCValkyl, CVCVhaloalkyl, O-CVCV alkyl, and G-CValkyl-OH
• R 1 is C 3 -C 6 -cycloalkyl or C 2 - Cj-heterocyclyi, wherein cycloalkyl and heterocyclyl are optionally substituted with 1 or 2 groups each independently selected from -OH, halo, CVCValkyl, CVC-haloalkyl, -O-CVCV alkyl, and CVCValkyl -OH.
• R 1 is selected from -OH, - Br, methyl, ethyl, ethenyl, propyl, propenyl, isopropyl, butyl, t-butyl, butenyl, pentanyl, 2- methylpentan-2-yl, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyciohexenyl, tetrahydrofuranvl, tetrahydropyranvl , di hvdropyranyl, pyrrol idinyl,
• bicyclo[3.1.0]hexanyl wherein methyl, ethyl, ethenyl, propyl, propenyl, isopropyl, butyl, t- butyl, butenyl, pentanyl, and 2-methylpentan-2-yl are optionally substituted with 1 or 2 groups independently selected from -OH, and halo, or wherein cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyciohexenyl, tetrahydrofuranvl, tetrahydropyranvl, di hvdropyranyl, pyrrol idinyl, and bicyclo[3.1.0]hexanyl are optionally substituted with 1 or 2 groups independently selected from -OH, halo, CVCValkyl, CVCVhaloalkyl, -O-CVCV al kyl , and CVCValkyl
• R' is selected from methyl, ethyl, ethenyl, propyl, propenyl, isopropyl, butyl, t-butyl, butenyl, pentanyl, 2-methylpentan- 2-yl, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyciohexenyl, tetrahydrofuranvl, tetrahydropyranvl, dihvdropyranyl, pyrrol idinyl, bicyclo[3.1.0]hexanyl, any of which are optionally substituted with 1 or 2 groups independently selected from OH and halo.
• each R 2 is independently selected from H or C i-CValkyl . In a further embodiment of the compound of Formula III, R 2 is H.
• R 3 is H.
• R is H or CrC 4 -alkyl. In a further embodiment, R i s H or -CH 3 . In yet another embodiment, R is I I.
• R 4 is (CR 8 R 9 ) p -Ci-C5-heteroaryl or (CR x R l ') p -C t ,-aryl, or CVCVcycloalkyl, wherein heteroaryl, aryl and cycloalkyl are optionally substituted with 1, 2, or 3 groups, each i ndependently selected from -OH, halo, CN, and C i -CValkyl ,
• R 8 is H or Ci-C 6 -alkyl
• R 9 is I I or Ci-Ce-alkyl
• R 4 is (CR 8 R 9 ) p -Ci-Cs-heteroaryl or (CR s R 9 ) p -C 1 ,-aryl, wherein heteroaryl and aryl are optionally substituted with 1, 2, or 3 groups, each independently selected from OH, halo, CN, and C i-CValkyl;
• R 8 is H or Ci-Ce-alkyl
• R 9 is I I or i-CValkyl
• p is 0 or 1 .
• R 4 i Ci-C 5 -heteroaryl or CVaryl, wherein heteroaryl and aryl are optionally substituted with 1, 2, or 3 groups, each independently selected from -OH, halo, CN, and Ci-Ce-alkyl.
• R 4 i Ci-C 5 -heteroaryl or CVaryl, wherein heteroaryl and aryl are optionally substituted with 1, 2, or 3 groups, each independently selected from -OH, halo, CN, and Ci-Ce-alkyl.
• n 0, 1 , or 2.
• Y is -C(O)-.
• R 1 is CVCYcycloalkyl, C 2 -CV heterocycl l, -OH, CVCValkyl, halo, and C 2 -C 8 -alkenyl, wherein alkyl, cycloalkyl , heterocyclvi, and alkenyl are optionally substituted with 1 or 2 groups each independently selected from OH, halo, CYCValkyl, C
• R 1 is Cs-Cs-cycloalkyl, C 2 -C 8 - heterocyclyl, CVCr.-alkyl, and CVC alkenyl, wherein alkyl, cycloalkyl, heterocyclvi, and al kenyl are optional ly substituted with 1 or 2 groups each independently selected from OH, halo, Ci-Ce-alkyl, C i-CVhaloalkyl, -O-Ci-Ce-alkyl, and Ci-Ce-alkyl-OH;
• each R " is independently selected from I I or C CValkyl .
• R 2 is H
• m is 1, R 5 is H or Ci-C 6 - alkyl, R 6 is H or Ci-Ce-alkyl, and wherein R 5 and R 4 are optionally joined to form a ring.
• m is 1 ; R 5 is Ci-Ce-a!kyl; R 6 is I I or Ci-Ce-alkyl; and R 5 and R 4 are optionally joined to form a ring. For example, in an embodiment.
• R 4 is C i -CValky! or (CR 8 R 9 ) p -C 6 -Ci2-aiyl, wherein alkyl and aryl are optionally substituted with 1, 2, or 3, groups, each independently selected from -OH, halo, CN, Ci-Ce-alkyl, Ci-Ce-haloalkyl, -O- Ci-Ce-alkyl, C(0)N(R ) 2 , C(0)OR f , -OCH 2 C(0)OR f , S0 2 R f , and Ci-C 6 -alkyl-OH.
• the compound of Formula 111 is selected from compounds shown in Table 2 and pharmaceutically acceptable salts thereof
• the compounds of the invention may possess one or more stereocenters, and each stereocenter may exist independently in either the R or S configuration.
• compounds described herein are present in optically active or racemic forms. It i s to be understood that the compounds described herein encompass racemic, optically-active, regioisomeric and stereoi somer ⁇ forms, or combinations thereof that possess the
• optically active forms are achieved in any suitable manner, including by way of non-limiting example, by resolution of the racemic form with recrystal lization techniques, synthesis from optically-active starting materials, chiral synthesis, or
• chromatographic separation using a chiral stationary phase In one embodiment, a mixture of one or more isomer is utilized as the therapeutic compound described herein. In another embodiment, compounds described herein contain one or more chiral centers. These compounds are prepared by any means, including stereoselective synthesis, enantioselective synthesis and/or separation of a mixture of enantiomers and/or diastereomers. Resolution of compounds and isomers thereof is achieved by any means including, by way of non-limiting example, chemical processes, enzymatic processes, fractional crystallization, distillation, and chromatography .
• the compounds of the invention may exist as tautomers. All tautomers are included within the scope of the compounds presented herein.
• Compounds described herein al so include isotopically-labeled compounds wherein one or more atoms is replaced by an atom having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
• isotopes suitable for inclusion in the compounds described herein include and are not limited to L 3 H, U C, 13 C, 14 C, 36 C1, 18 F, 123 I, 125 I, 13 N, 15 N, 15 0, 17 0, 18 0, 32 P, and 35 S.
• isotopically-labeled compounds are useful in drug and/or substrate tissue distribution studies.
• substitution with heavier isotopes such as deuterium affords greater metabolic stability (for example, increased in vivo half-life or reduced dosage requirements).
• substitution with positron emitting isotopes such as U C, 18 F, L, 0 and L, N, is useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.
• Isotopically-labeled compounds are prepared by any suitable method or by processes using an appropriate isotopically-labeled reagent in place of the non-labeled reagent otherwise employed.
• the compounds described herein are labeled by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chem i 1 umi nescent labels.
• reactive functional groups such as hydroxy], amino, imino, thio or carboxy groups
• Protecting groups are used to block some or all of the reactive moieties and prevent such groups from participating in chemical reactions until the protective group is removed.
• each protective group i s removable by a different means.
• Protective groups that are cleaved under totally disparate reaction conditions fulfill the requirement of differential removal .
• the invention provides a method of treating an HBV infection in an individual in need thereof, comprising administering to the individual a therapeutical ly effective amount of a compound of the invention.
• the invention al so provides a method of eradicating an HBV infection in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound of the invention.
• the invention also provides a method of reducing viral load associated with an HBV infection in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound of the invention.
• the invention further prov ides a method of reducing reoccurrence of an HBV infection in an individual in need thereof, comprising admini stering to the indiv idual a therapeutically effectiv e amount of a compound of the invention.
• prov ided herein is a method of inhibiting and/or reducing the formation or presence of HBV DNA-containing particles and/or HBV RNA-containing particles in an indiv idual in need thereof, comprisi ng admini stering to the i ndiv idual a therapeutically effectiv e amount of a compound of the inv ention.
• the inv ention also provides a method of reducing an adverse physiological impact of an HBV infection in an i ndiv idual in need thereof, comprising admini stering to the indiv idual a therapeutically effectiv e amount of a compound of the invention.
• the invention further provides a method of reducing, slowing, or inhibiting an HBV infection in an individual in need thereof, comprising admini stering to the individual a therapeutically effective amount of a compound of the invention.
• the invention al so provides a method of inducing remission of hepatic injury from an HBV infection in an individual in need thereof, compri sing administering to the individual a therapeutically effectiv e amount of a compound of the invention.
• the invention further provides a method of reducing the physiological impact of long- term antiviral therapy for HBV infection in an individual in need thereof, comprising admini stering to the individual a therapeutically effective amount of a compound of the invention.
• the invention further provides a method of prophylactical ly treating an HBV infection in an individual in need thereof, wherein the individual is afflicted with a latent HBV infection, comprisi ng administering to the indiv idual a therapeutically effective amount of a compound of the invention.
• the methods described herein further comprise administering at least one additional therapeutic agent selected from the group consisting of
• the compound of the invention and the at least one additional therapeutic agent are co-formulated.
• the compound of the invention and the at least one additional therapeutic agent are co-administered.
• the individual i s refractory to other therapeutic classes of HBV drugs (e.g, HBV polymerase inhibitors, interferons, viral entry inhibitors, v ital maturation inhibitors, 1 i terature-descri bed capsid assembly modulators, antiviral compounds of distinct or unknown mechanism, and the like, or combinations thereof)-
• the method of the inv ention reduces viral load in an indiv idual suffering from an HBV infection to a greater extent or at a faster rate compared to the extent that other therapeutic classes of HBV drugs reduce viral load in the individual .
• the admini stering of a compound of the inv ention, or a pharmaceutically acceptable salt thereof allows for administering of the at least one additional therapeutic agent at a low er dose or frequency as compared to the admini stering of the at least one additional therapeutic agent alone that is required to achieve similar results in prophylactically treating an HBV infection in an individual in need thereof.
• the administering of a compound of the invention, or a pharmaceutically acceptable salt thereof reduces the viral load in the individual to a greater extent or at a faster rate compared to the administering of a compound selected from the group consisting of an HBV polymerase inhibitor, interferon, viral entry inhibitor, viral maturation inhibitor, distinct capsid assembly modulator, antiviral compounds of distinct or unknown mechanism, and any combination thereof.
• the method of the invention reduces viral load in an individual suffering from an HBV infection, thus allowing lower doses or varying regimens of combination therapies to be used.
• the method of the invention causes a lower incidence of viral mutation and/or viral resi stance compared to other classes of HBV drugs, thereby allowing for long term therapy and minimizing the need for changes in treatment regi mens.
• the method of the invention increases the seroconversion rate beyond that of current treatment regimens.
• the method of the invention increases and/or normalizes and/or restores normal health, elicits full recovery of normal health, restores life expectancy, and/or resolves the viral infection in the individual in need thereof.
• the method of the invention eliminates or decreases the number of HBV RNA particles that are released from HBV infected cells thus enhancing, prolonging, or increasing the therapeutic benefit of the compounds of the invention.
• the method of the invention eradicates HBV from an individual infected with HBV, thereby obviating the need for long term and/or life-long treatment, or shortening the duration of treatment, and/or al lowing for reduction in dosing of other antiviral agents.
• the method of the invention further comprises monitoring the HBV viral load of the subject, and wherein the method i s carried out for a period of time such that the HBV virus is undetectable.
• a method of treating an HBV infection in an individual in need thereof comprising administering to the individual a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof.
• provided herein is a method of treating an HBV infection in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound of Formula II, or a pharmaceutical ly acceptable salt thereof.
• provided herein is a method of treating an HBV infection in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound of Formula III, or a pharmaceutically acceptable salt thereof.
• provided herein is a method of treating an HBV infection in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound of Formula IV, or a pharmaceutically acceptable salt thereof.
• provided herein is a method of treating an HBV infection in an individual in need thereof comprising admini stering to the individual a therapeutically effective amount of a compound of Table 1, or a pharmaceutically acceptable salt thereof.
• prov ided herein is a method of treating an HBV infection in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound of Table 2, or a pharmaceutically acceptable salt thereof.
• the method can further comprise monitoring the HBV viral load of the subject, wherein the method is carried out for a period of time such that the HBV virus is undetectable.
• the compounds of the present inv ention are intended to be useful in combination with one or more additional compounds useful for treating HBV infection.
• additional compounds may comprise compounds of the present inv ention or compounds known to treat, prev ent, or reduce the symptoms or effects of HBV infection.
• Such compounds include but are not limited to HBV polymerase inhibitors, interferons, viral entry inhibitors, viral maturation inhibitors, literature-described capsid assembly modulators, reverse transcriptase inhibitor, i m m un om odul atory agents, a TLR-agonist, and other agents with di stinct or unknown mechanisms that affect the HBV life cycle and/or affect the consequences of HBV infection.
• the compounds of the invention may be used in combination with one or more drugs (or a salt thereof) selected from the group consisting of
• HBV reverse transcriptase inhibitors and DNA and RNA polymerase inhibitors, including but not limited to: lamivudine (3TC, Zeffix, Heptovir, Epivir, and Epivir-FIBV), entecavir (Baraclude, Entav ir), adefov ir dipiv oxil (Hepsara, Preveon, bis-POM PMEA), tenofov ir disoproxil lumarate (Vi ead, TDF or PMPA );
• interferons including but not limited to interferon alpha (IFN-o), interferon beta ( IFN- ⁇ ), interferon lambda ( IFN- ⁇ ), and interferon gamma ( IFN-y);
• IFN-o interferon alpha
• IFN- ⁇ interferon beta
• IFN- ⁇ interferon lambda
• IFN-y interferon gamma
• an i m m u nom odul atory agent such as a TLR-agonist
• agents of distinct or unknown mechanism such as but not limited to AT-6 1 ((E)-N-(l- chloro- -oxo- 1 -phenyl -3 -(piperi din- 1 -yl)prop- 1 -en-2-yl )benzamide), A T- 130 ((E)-N-( 1 - bromo- 1 1 -yl )prop- 1 -en-2-yl )-4-nitrobenzamide), and similar analogs.
• the additional therapeutic agent is an interferon.
• interferon or “IFN” refers to any member the famly of highly homologous species-speci ic proteins that inhibit viral replication and cellular proliferation, and modulate immune response.
• Human interferons are grouped into three classes; Type I, which include interferon-alpha (IFN-a), interferon-beta ( lFN- ⁇ ), and interferon-omega (IF - ⁇ ), Type 11, which includes i nterferon -gam m a ( IFN-y), and Type III, which includes i nterferon-1 ambda ( IFN- ⁇ ).
• interferons Recombinant forms of interferons that hav e been dev eloped and are commercially av ailable are encompassed by the term "interferon " as used herein .
• Chemically modified interferons include pegylated interferons and glycosylated interferons.
• Exampl es of interferons also include, but are not limited to, interferon-alpha-2a, interferon-alpha-2b, interferon-alpha-n 1 , interferon-beta- l a, interferon- beta- 1 b, interferon-lamda- 1 , interferon-lamda-2, and interferon-lamda-3.
• Examples of pegylated interferons incl ude pegylated i nterferon-al pha-2a and pegylated interferson alpha- 2b.
• the compounds of Formula I, II, III, or IV can be administered in combination with an interferon selected from the group consi ting of interferon alpha ( IFN-ot), interferon beta ( IFN- ⁇ ), interferon lambda (IF - ⁇ ), and interferon gamma (IFN- ⁇ ).
• interferon i s interferon-alpha-2a, i n terferon -al ph a-2b , or interferon-alpha-n I .
• the interferon- alpha-2a or interferon-alpha-2b is pegylated.
• the interferon- alpha-2a is pegylated interferon-alpha-2a (PEGASYS).
• the additional therapeutic agent is selected from immune modulator or immune stimulator therapies, which includes biological agents belonging to the interferon class.
• the additional therapeutic agent may be an agent of distinct or unknown mechanism including agents that disrupt the function of other essential viral protein(s) or host proteins required for HBV replication or persistence.
• the additional therapeutic agent is an antiviral agent that blocks viral entry or maturation or targets the HBV polymerase such as nucleoside or nucleotide or non-nucleos(t)ide polymerase inhibitors.
• the reverse transcriptase inhibitor and/or DNA and/or RNA polymerase inhibitor is Zidovudine, Didanosine, Zalcitabine, ddA, Stavudine, Lamiv udine, Abacavir, Emtricitabine, Entecav ir, Apricitabine, Atevi rapine, ribavirin, acyclovir, famciclovir, val acyclovir, ganciclov ir, val ganciclovir, Tenofovir, Adefov ir, PMPA, cidofov ir, Efav irenz, Nevi rapine, Delav irdine, or Etrav i
• the additional therapeutic agent is an i m m un om odul atory agent that induces a natural, limited immune response leading to induction of immune responses against unrelated viruses.
• the i m m unom od ul atory agent can effect maturation of antigen presenting cell s, proliferation of T-cells and cytokine release (e.g., IL- 12, IL- 1 8, IFN-alpha, -beta, and -gamma and TNF-alpha among others),
• the additional therapeutic agent i s a TLR modulator or a TLR agonist, such as a TLR- 7 agonist or TLR-9 agonist.
• the TLR-7 agoni t is selected from the group consisting of SM360320 (9-benzyl-8-hydroxy-2-(2-methoxy-ethoxy)adenine) and AZD 8848 (methyl [3-( ⁇ [3-(6- amino-2 ⁇ butoxy-8-oxo-7,8 ⁇ dihydro-9H-purin ⁇ 9-yl)propyl][3-(4- morpholinyl )propyl Jamino J methyl (phenyl ]acetate).
• the method may further comprise
• the HBV vaccine is at least one of RECOMBIVAX HB, ENGERIX-B, ELOVAC B, GENEVAC-B, or SHANVAC B.
• provided herein is method of treating an HBV infection in an individual in need thereof, comprising reducing the HBV viral load by administering to the indiv idual a therapeutical ly effective amount of a compound of the invention alone or in combination with a reverse transcriptase inhibitor; and further admini stering to the individual a therapeutically effective amount of HBV vaccine.
• the reverse transcriptase inhibitor may be one of Zidov udine, Didanosine, Zalcitabine, ddA, Stav udine, Lamiv udine, Abacav ir, Emtricitabine, Entecavir, Apricitabine, A tev i rapine, ribavirin, acyclovir, famciclovir, val acyclov ir, ganciclov ir, valganciclovir, Tenofov ir, Adefovir, PMPA, cidofov ir, Efavirenz, evi rapine, Delavirdine, or Etravirine.
• synergistic effect may be calculated, for example, using suitable methods such as the Sigmoid-E max equation (Hoi ford & Scheiner, 19981, Clin. Pharmacokinet. 6: 429-453), the equation of Loewe additiv ity (Loewe & Muischnek, 1926, Arch. Exp. Pathol Pharmacol . 1 14: 313-326) and the median-effect equation (Chou & Talalay, 1984, Adv . Enzyme Regul . 22: 27-55).
• Each equation referred to above may be applied to experimental data to generate a corresponding graph to aid in assessing the effects of the drug combination.
• the corresponding graphs associated with the equations referred to abov e are the concentrati on-elYect curve, isobologram curv e and combination index curv e, respectively.
• the method can further compri se monitoring the H BV viral load of the subject, wherein the method is carried out for a period of time such that the HBV virus is undetectable
• prov ided herein is pharmaceutical composition
• a compound of the inv ention or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier.
• Actual dosage levels of the active ingredients in the pharmaceutical compositions of this inv ention may be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.
• the selected dosage level will depend upon a variety of factors including the activity of the particular compound employed, the time of administration, the rate of excretion of the compound, the duration of the treatment, other drugs, compounds or material s used in combination with the compound, the age, sex, weight, condition, general health and prior medi cal hi story of the patient bei ng treated, and like factors well, known in the medical arts.
• a medical doctor e.g., physician or veterinarian, having ordinary skil l in the art may readily determine and prescribe the effective amount of the pharmaceutical composition required.
• physician or veterinari an could start doses of the compounds of the invention employed in the pharmaceutical composition at levels lower than that required in order to achi eve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.
• Dosage unit form refers to physically discrete units suited as unitary dosages for the patients to be treated; each unit containing a predetermined quantity of therapeutic compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical vehicle.
• the dosage unit forms of the invention are dictated by and directly dependent on (a) the unique characteristics of the therapeutic compound and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding/formul ating such a therapeutic compound for the treatment of HBV infection in a patient.
• compositions of the invention are formulated using one or more pharmaceutical ly acceptable excipients or carriers.
• the compositions of the invention are formulated using one or more pharmaceutical ly acceptable excipients or carriers.
• compositions of the invention comprise a therapeutically effective amount of a compound of the invention and a pharmaceutically acceptable carrier.
• the dose of a compound of the inv ention is from about 1 mg to about 2,500 mg. In some embodiments, a dose of a compound of the invention used in compositions described herein is less than about 10,000 mg, or less than about 8,000 mg, or less than about 6,000 mg, or less than about 5,000 mg, or less than about 3,000 mg, or less than about 2,000 mg, or less than about 1,000 mg, or less than about 500 mg, or less than about 200 mg, or less than about 50 mg.
• a dose of a second compound is less than about 1,000 mg, or less than about 800 mg, or less than about 600 mg, or less than about 500 mg, or less than about 400 mg, or less than about 300 mg, or less than about 200 mg, or less than about 100 mg, or less than about 50 mg, or less than about 40 mg, or less than about 30 mg, or less than about 25 mg, or less than about 20 mg, or less than about 15 mg, or less than about 10 mg, or less than about 5 mg, or less than about 2 mg, or less than about 1 mg, or less than about 0.5 mg, and any and all whole or partial increments thereof.
• the present invention is directed to a packaged pharmaceutical composition
• a packaged pharmaceutical composition comprising a container holding a therapeutically effective amount of a compound of the invention, alone or in combination with a second pharmaceutical agent; and instructions for using the compound to treat, prevent, or reduce one or more symptoms of HBV infection in a patient.
• compositions of the invention include oral, nasal, rectal, intravaginal, parenteral , buccal, sublingual or topical .
• the compounds for use in the invention may be formulated for administration by any suitable route, such as for oral or parenteral, for example, transdermal, transmucosal (e.g.
• vaginal e.g., trans- and perivaginally
• intranasal and (trans)rectal intravesical, intrapulmonary, intraduodenal, intragastrical, intrathecal, subcutaneous, intramuscular, intradermal, intra-arterial, intrav enous, intrabronchial, inhalation, and topical administration.
• compositions and dosage forms include, for example, tablets, capsules, caplets, pills, gel caps, troches, dispersions, suspensions, solutions, syrups, granules, beads, transdermal patches, gels, powders, pellets, magmas, lozenges, creams, pastes, plasters, lotions, discs, suppositories, liquid sprays for nasal or oral administration, dry powder or aerosolized formulations for inhalation, compositions and formulations for intravesical admini stration and the like. It should be understood that the formulations and compositions that would be useful in the present invention are not limited to the particular formulations and compositions that are described herein.
• compositions intended for oral use may ⁇ be prepared according to any method known in the art and such compositions may contain one or more agents selected from the group consi sting of inert, non-toxic pharmaceutically excipients that are suitable for the manufacture of tablets.
• excipients include, for example an inert diluent such as lactose; granulating and disintegrating agents such as cornstarch; binding agents such as starch; and lubricating agents such as magnesium stearate.
• the tablets may be uncoated or they may be coated by known techniques for elegance or to delay the release of the active ingredients.
• Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert diluent.
• the compounds of the invention may be formulated for injection or infusion, for example, intravenous, intramuscular or subcutaneous injection or infusion, or for admini stration in a bolus dose and/or continuous infusion.
• Suspensions, solutions or emulsions in an oily or aqueous vehicle, optionally containing other formulatory agents such as suspending, stabilizing and/or dispersing agents may be used.
• Example 1 Procedure for the Preparation of Compounds 040 and 239
• the aqueous phase was extracted with DCM ( 100 mL*2).
• the combined organic phase was washed with saturated brine (50 mL*2), dried over anhydrous a.->S0 , filtered and concentrated in vacuum.
• the reaction vessel was sealed and heated in microwave at 130 °C for 2 hr. LCMS showed the reaction was completed.
• the mixture was poured into water (10 mL) and stirred for 2 min.
• the aqueous phase was extracted with ethyl acetate (10 mL* 2).
• the combined organic phase was washed with brine (10 mL*2), dried with anhydrous Na?S0 4 , filtered and concentrated in
• Step 4 Preapration of Compound 264
• the reaction mixture was diluted with Na 2 S0 3 (Saturated, 60 mL), and extracted with EA (80 mL). The organic layer was concentrated under reduced pressure to give a yellow residue. The residue was purified by Prep-FIPLC(FA) to afford N-(3-chlorophenyl)-3-(2-hydroxy-l-methyl-ethyl)-l, 4,6,7- tetrahydropyrazolo[4,3-c]pyridine-5-carboxamide (15.00 mg, 43.28 umol, 27.42% yield, 96.6% purity) as white solid.
• the pH of the reaction mixture was adjusted to around 5 by adding diluted hydrochloride acid (1 N), then extracted with EA (500 mL*4) and water (300 mL). The organic phase was dried over anhydrous Na 2 S0 4 , filtered and concentrated in vacuum to afford 5-[(3- chiorophenyl)carbamoyl]-l,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-3-carboxylic acid (23.00 g, crude) as light yellow solid. The crude product was used in next step directly without further purification.
• [4,3-c] pyridine-5-carboxamide (60.00 mg, 180.30 umol, 1.00 eq) in DCM (3.00 mL) was added DAST (145.31 mg, 901.50 umol, 1 19.1 1 uL, 5.00 eq) at -40 °C. The mixture was stirred at 15 C for 2 hr. The mixture was extracted with DCM (10 mL*2). The organic layer was washed with saturated aHCO, (10 mL), dried over Na 2 SO.t, filtrated, and concentrated in vacumm.
• 2,2-dimethylbut-3-enoic acid (200,00 nig, 1 .75 mmol, 1.00 eq) was dissolved in SOQ 2 (208.46 mg, 1.75 mmol, 127.1 1 uL, 1.00 eq) and heated to 8 C for 1 hr. The mixture was concentrated in vacumm to get 2, 2-di m eth yl b ut-3 -en oy 1 chloride (190.46 mg), compound 2.
• reaction mixture was warmed to 30 °C and stirred at 30 °C for another 2 hours. TLC showed compound 5 was consumed completely.
• the reaction mixture was added to saturated aqueous of NH 4 C1 (30 mL) and then extracted with EA (50 mL*3), the combined organic phase was dried over anhydrous a 2 S0 4 , filtered and concentrated in vacuum to afford tert-butyi 3-( 1 - methylcyclopentanecarbonyi) -4-oxo-piperidine- 1 -carboxylate (730.00 mg, crude) as yellow oil. The crude product was used in the next step directly without purification.
• the aqueous phase was extracted with ethyl acetate (100 mL*3).
• the combined organic phase was washed with brine (200 mL*2), dried with anhydrous Na 2 S0 4 , filtered and concentrated in vacuum.
• Example 28 Procedure for preparation of Compounds 660, 661, 662, 663, 664, 665, 666, 667, 668, and 669
• reaction mixture was added to aqueous solution of NH 4 C1 (100 mL) and then neutralised by dilute hydrochloric acid (1 N), the aqueous layer was extracted with EA (200 mL*3), the combined organic phase was dried over anhydrous Na?S0 4 , filtered and concentrated in vacuum to afford tert-butyl 3-(cyclobutanecarbonyl )-4-o ⁇ o-piperidine- 1 -carboxylate (5.00 g, crude) as yellow oil. The crude product was used in the next step directly without
• Example 30 Preparation of Compounds 782, 783, 784, 785, 786, 787, 788, 789, 790, 791, and 792
• Example 35 Preparation of ' Compounds ' / 7 04 and 7 7 56, 757, 758, 759, 760, 761, 762, 763, 764, and 765
• Step 1 Preparation of Compounds 2A and 2B

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• 2016
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• 2017
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• 2018
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• 2019
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• 2020
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