NZ724493B2 - Hepatitis B Antiviral Agents - Google Patents

Abstract

The disclosure relates to compounds of general formula (III) and a related family of compounds, and a method for preparing the compounds. These compounds may be used to treat, eradicate, reduce, slow, or inhibit an HBV infection.

Description

HEPATITIS B ANTIVIRAL AGENTS RELATED APPLICATION This application claims priority to U.S. Provisional Patent Application Nos. 61/578,716, filed on December 21, 2011 and 61/709,331, filed on October 3, 2012. The entire contents of these applications are herein incorporated by reference in their entirety.

BACKGROUND OF THE INVENTION Chronic hepatitis B virus (HBV) infection is a significant global health problem, affecting over 5% of the world population (over 350 million people worldwide and 1.25 million individuals in the U.S.).

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 provide a cure and are limited to only two classes of agents (interferon and nucleoside analogues/inhibitors of the viral polymerase); drug resistance, low efficacy, and tolerability issues limit their impact.

The low cure rates of HBV are attributed at least in part to the presence and persistence of covalently closed circular DNA (cccDNA) in the nucleus of infected hepatocytes.

However, persistent suppression of HBV DNA slows liver disease progression and helps to prevent hepatocellular carcinoma. Current therapy goals for HBV-infected patients are directed to reducing serum HBV DNA to low or undetectable levels, and to ultimately reducing or preventing the development of cirrhosis and hepatocellular carcinoma.

There is a need in the art for novel therapeutic agents that treat, ameliorate or prevent HBV infection. Administration of these therapeutic agents to an HBV infected patient, either as monotherapy or in combination with other HBV treatments or ancillary treatments, will lead to significantly improved prognosis, diminished progression of the disease, and enhanced seroconversion rates.

SUMMARY OF THE INVENTION Described herein are compounds useful for the treatment of HBV infection in man.

Accordingly, in one aspect the invention provides a method for preparing a compound of Formula IVc: (IVc); wherein: X is halo; G is hydrogen or halo; G is H, C -C alkyl, or halo; and G is H, halo, C -C alkyl, or OH; the method comprising: a) reacting compound 1: with thionyl chloride to produce compound 2: b) reacting compound 2 with aniline to produce compound 3: c) reacting compound 3 with an amine and TEA to produce a compound of Formula IVc: (IVc).

Certain statements that appear below are broader than what appears in the statements of the invention above. These statements are provided in the interests of providing the reader with a better understanding of the invention and its practice. The reader is directed to the accompanying claim set which defines the scope of the invention.

Also described herein is a compound of formula (I), or a salt, solvate, or N-oxide thereof: (I).

In an embodiment, compounds of formula (I) are of the formula (II): (II) or pharmaceutically acceptable salts thereof.

In an embodiment, compounds of the formula (II) are of the formula (IIa), (IIb), and (IIc).

In another embodiment, the compound of formula (I) has the formula (III): (III).

In another embodiment, described herein are compounds having the formula IV: (IV) or pharmaceutically acceptable salts thereof.

In an embodiment, compounds of formula IV are of the formula IVa, IVb, and IVc, or pharmaceutically acceptable salts of those compounds.

In another embodiment, described herein are compounds of formula V: or pharmaceutically acceptable salts thereof.

In still another embodiment, described herein are compounds of formula VI: (VI) or pharmaceutically acceptable salts thereof.

In an embodiment, compounds of formula VI have the formula VIa or VIb, or pharmaceutically acceptable salts of those compounds, In another embodiment, described herein are compounds of formula VII: (VII) or pharmaceutically acceptable salts thereof.

Also described herein are compositions comprising a compound as described herein (also referred to herein as "a compound as described"). In an embodiment, the composition is pharmaceutical and further comprises at least one pharmaceutically acceptable carrier.

In an embodiment, described herein is a method of treating, eradicating, reducing, slowing, or inhibiting an HBV infection in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound as described.

In another embodiment, described 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 as described.

In still another embodiment, described herein is 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 as described.

In yet another embodiment, described herein is a method of reducing an adverse physiological impact of an HBV infection in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound as described.

Also described herein are methods of inducing remission of hepatic injury from an HBV infection in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound as described.

In another embodiment, described herein is a method of reducing the physiological impact of long-term antiviral therapy for HBV infection in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound as described.

Also described herein is a a method of prophylactically treating an HBV infection in an individual in need thereof, wherein the individual is afflicted with a latent HBV infection, comprising administering to the individual a therapeutically effective amount of a compound as described.

In any above methods, the compound can be administered in combination with an additional therapeutic agent. In an embodiment, the additional therapeutic agent selected from the group consisting of a HBV polymerase inhibitor, interferon, viral entry inhibitor, viral maturation inhibitor, literature-described capsid assembly modulator, reverse transcriptase inhibitor, a TLR-agonist, and agents of distinct or unknown mechanism, and a combination thereof.

In another embodiment, the additional therapeutic agent selected from immune modulator or immune stimulator therapies, which includes biological agents belonging to the interferon class, such as interferon alpha 2a or 2b or modified interferons such as pegylated interferon, alpha 2a, alpha 2b, lamda; or TLR modulators such as TLR-7 agonists or TLR-9 agonists, or antiviral agents that block viral entry or maturation or target the HBV polymerase such as nucleoside or nucleotide or non-nucleos(t)ide polymerase inhibitors, and agents 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.

In an embodiment of the combination therapy, the reverse transcriptase inhibitor is at least one of Zidovudine, Didanosine, Zalcitabine, ddA, Stavudine, Lamivudine, Abacavir, Emtricitabine, Entecavir, Apricitabine, Atevirapine, ribavirin, acyclovir, famciclovir, valacyclovir, ganciclovir, valganciclovir, Tenofovir, Adefovir, PMPA, cidofovir, Efavirenz, Nevirapine, Delavirdine, or Etravirine.

In another embodiment of the combination therapy, the TLR-7 agonist is selected from the group consisting of SM360320 (9-benzylhydroxy(2-methoxy- ethoxy)adenine) and AZD 8848 (methyl [3-({[3-(6-aminobutoxyoxo-7,8-dihydro- 9H-purinyl)propyl][3-(4-morpholinyl)propyl]amino}methyl)phenyl]acetate).

In an embodiment of these combination therapies, the compound and the additional therapeutic agent are co-formulated. In another embodiment, the compound and the additional therapeutic agent are co-administered.

In another embodiment of the combination therapy, administering the compound as described allows for administering of the 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 required to achieve similar results in prophylactically treating an HBV infection in an individual in need thereof.

In another embodiment of the combination therapy, before administering the therapeutically effective amount of the compound as described, the individual is known to be refractory to a compound selected from the group consisting of a HBV polymerase inhibitor, interferon, viral entry inhibitor, viral maturation inhibitor, distinct capsid assembly modulator, antiviral compounds of distinct or unknown mechanism, and combination thereof.

In still another embodiment of the method, administering the compound as described reduces viral load in the individual to a greater extent compared to the administering of a compound selected from the group consisting of a HBV polymerase inhibitor, interferon, viral entry inhibitor, viral maturation inhibitor, distinct capsid assembly modulator, antiviral compounds of distinct or unknown mechanism, and combination thereof.

In another embodiment, administering of the compound as described causes a lower incidence of viral mutation and/or viral resistance than the administering of a compound selected from the group consisting of a HBV polymerase inhibitor, interferon, viral entry inhibitor, viral maturation inhibitor, distinct capsid assembly modulator, antiviral compounds of distinct or unknown mechanism, and combination thereof.

BRIEF DESCRIPTION OF THE DRAWINGS For the purpose of illustrating the invention, there are depicted in the drawings certain embodiments of the invention and/or as described herein. However, the invention is not limited to the precise arrangements and instrumentalities of the embodiments depicted in the drawings.

Figure 1 is a scheme illustrating the fluorescence quenching in vitro HBV assembly assay. This assay utilizes a mutant C150 HBV capsid protein wherein all wild-type cysteines are mutated to alanines, but a C-terminal cysteine residue is preserved and is labeled with fluorescent BoDIPY-FL dye. The fluorescence signal of HBV C150Bo protein decreases during the capsid assembly process, and thus monitoring the fluorescence of the reaction provides a good readout on the extent of the capsid assembly.

DETAILED DESCRIPTION OF THE INVENTION Described herein are compounds that are useful in the treatment and prevention of HBV in man. In a non-limiting embodiment, these compounds modulate and/or disrupt HBV assembly by interacting with HBV capsid to afford defective viral particles with greatly reduced virulence. The compounds as described have potent antiviral activity, exhibit favorable metabolic, tissue distribution, safety and pharmaceutical profiles, and are suitable for use in man.

The HBV capsid protein plays essential functions during the viral life cycle.

HBV capsid/core proteins form metastable viral particles or protein shells that protect the viral genome during intercellular passage, and also play a central role in viral replication processes, including genome encapsidation, genome replication, and virion morphogenesis and egress. Capsid structures also respond to environmental cues to allow un-coating after viral entry. Consistently, proper capsid assembly has been found to be critical for viral infectivity.

The crucial function of HBV capsid proteins imposes stringent evolutionary constraints on the viral capsid protein sequence, leading to the observed low sequence variability and high conservation. Consistently, mutations in HBV capsid that disrupt its assembly are lethal, and mutations that perturb capsid stability severely attenuate viral replication. The more conserved a drug target is, the fewer replication-competent resistance mutations are acquired by patients. Indeed, natural mutations in HBV capsid for chronically infected patients accumulate in only four out of 183 residues in the full length protein. Thus, HBV capsid assembly inhibitors may elicit lower drug resistance emergence rates relative to existing HBV antivirals. Further, drug therapy that targets HBV capsid could be less prone to drug-resistant mutations when compared to drugs that target traditional NA enzyme active sites. Reports describing compounds that bind viral capsids and inhibit replication of HIV, rhinovirus and HBV provide strong pharmacological proof of concept for viral capsid proteins as antiviral drug targets.

In one embodiment, the compounds as described are useful in HBV treatment by disrupting, accelerating, reducing, delaying and/or inhibiting normal viral capsid assembly and/or disassembly of immature or mature particles, thereby inducing aberrant capsid morphology and leading to antiviral effects such as disruption of virion assembly and/or disassembly, virion maturation, and/or virus egress. In one embodiment, 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. In another embodiment, a disruptor of capsid assembly perturbs protein folding and/or salt bridges required for stability, function and /or normal morphology of the viral capsid, thereby disrupting and/or accelerating capsid assembly and/or disassembly. In yet another embodiment, the compounds as described 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. In another embodiment, the compounds as described cause failure of the formation of capsid of optimal stability, affecting efficient uncoating and/or disassembly of viruses (e.g., during infectivity).

In one embodiment, the compounds as described disrupt and/or accelerate capsid assembly and/or disassembly when the capsid protein is immature. In another embodiment, the compounds as described disrupt and/or accelerate capsid assembly and/or disassembly when the capsid protein is mature. In yet another embodiment, the compounds as described disrupt and/or accelerate capsid assembly and/or disassembly during vial infectivity. In yet another embodiment, the disruption and/or acceleration of capsid assembly and/or disassembly attenuates HBV viral infectivity and/or reduces viral load. In yet another embodiment, disruption, acceleration, inhibition, delay and/or reduction of capsid assembly and/or disassembly eradicates the virus from the host organism. In yet another embodiment, 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.

In one embodiment, 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.

In another embodiment, the compounds as described can be used in methods of modulating (e.g., inhibit, disrupt or accelerate) the activity of HBV cccDNA. In yet another embodiment, the compounds as described can be used in methods of diminishing or preventing the formation of HBV cccDNA.

Definitions As used herein, each of the following terms has the meaning associated with it in this section.

Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Generally, the nomenclature used herein and the laboratory procedures in cell culture, molecular genetics, organic chemistry, and peptide chemistry are those well-known and commonly employed in the art.

The term ‘comprising’ as used in this specification and claims means ‘consisting at least in part of’. When interpreting statements in this specification and claims which includes the ‘comprising’, other features besides the features prefaced by this term in each statement can also be present. Related terms such as ‘comprise’ and ‘comprised’ are to be interpreted in similar manner.

As used herein, 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. By way of example, "an element" means one element or more than one element. Furthermore, use of the term "including" as well as other forms, such as "include", "includes," and "included," is not limiting.

As used herein, the term "about" will be understood by persons of ordinary skill in the art and will vary to some extent on the context in which 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%, more preferably ±5%, even more preferably ±1%, and still more preferably ±0.1% from the specified value, as such variations are appropriate to perform the disclosed methods.

As used herein, the term "capsid assembly modulator" refers to a compound that disrupts and/or accelerates and/or inhibits and/or hinders and/or delays and or reduces and/or modifies normal capsid assembly (e.g., during maturation) and/or normal capsid disassembly (e.g., during infectivity) and/or perturbs capsid stability, thereby inducing aberrant capsid morphology and function. In one embodiment, a capsid assembly modulator accelerates capsid assembly and/or disassembly, thereby inducing aberrant capsid morphology. In another embodiment, a capsid assembly modulator interacts (e.g. binds at an active site, binds at an allosteric site, modifies and/or hinders folding and the like) with the major capsid assembly protein (CA), thereby disrupting capsid assembly and/or disassembly. In yet another embodiment, a capsid assembly modulator causes a perturbation in structure and/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.

As used herein, the term "literature-described capsid assembly modulator" refers a capsid assembly modulator that is not a compound as described.

As used herein, the term "treatment" or "treating," is defined as the application or administration of a therapeutic agent, i.e., a compound as described (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 HBV infection, a symptom of HBV infection or the potential to develop HBV infection, with the purpose to cure, heal, alleviate, relieve, alter, remedy, ameliorate, improve or affect HBV infection, the symptoms of HBV infection or the potential to develop HBV infection. Such treatments may be specifically tailored or modified, based on knowledge obtained from the field of pharmacogenomics.

As used herein, the term "prevent" or "prevention" means no disorder or disease development if none had occurred, or no further disorder or disease development if there had already been development of the disorder or disease. Also considered is the ability of one to prevent some or all of the symptoms associated with the disorder or disease.

As used herein, 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. Preferably, the patient, subject or individual is human.

As used herein, the terms "effective amount," "pharmaceutically effective amount" and "therapeutically effective amount" refer to a nontoxic but sufficient amount of an agent to provide the desired biological result. That result may be reduction and/or alleviation 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.

As used herein, the term "pharmaceutically acceptable" refers to a material, such as a carrier or diluent, 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 interacting in a deleterious manner with any of the components of the composition in which it is contained.

As used herein, the language "pharmaceutically acceptable salt" refers to a salt of the administered compounds prepared from pharmaceutically acceptable non-toxic acids, including inorganic acids, organic acids, solvates, hydrates, or clathrates thereof.

Examples of such inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, acetic, hexafluorophosphoric, citric, gluconic, benzoic, propionic, butyric, sulfosalicylic, maleic, lauric, malic, fumaric, succinic, tartaric, amsonic, pamoic, p-tolunenesulfonic, and mesylic. Appropriate organic acids may be selected, for example, from aliphatic, aromatic, carboxylic and sulfonic classes of organic acids, examples of which are formic, acetic, propionic, succinic, camphorsulfonic, citric, fumaric, gluconic, isethionic, lactic, malic, mucic, tartaric, para-toluenesulfonic, glycolic, glucuronic, maleic, furoic, glutamic, benzoic, anthranilic, salicylic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, pantothenic, benzenesulfonic (besylate), stearic, sulfanilic, alginic, galacturonic, and the like. Furthermore, pharmaceutically acceptable salts include, by way of non-limiting example, alkaline earth metal salts (e.g., calcium or magnesium), alkali metal salts (e.g., sodium-dependent or potassium), and ammonium salts.

As used herein, the term "pharmaceutically acceptable carrier" means 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 within the invention within or to the patient such that it may perform its intended function. Typically, 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, and not injurious to the patient. Some examples of 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 cellulose, 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; polyols, 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; pyrogen-free water; isotonic saline; Ringer’s solution; ethyl alcohol; phosphate buffer solutions; and other non-toxic compatible substances employed in pharmaceutical formulations. As used herein, "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. The "pharmaceutically acceptable carrier" may further include a pharmaceutically acceptable salt of the compound useful within the invention. Other additional ingredients that may be included in the pharmaceutical compositions used in the practice of the invention are known in the art and described, for example in Remington's Pharmaceutical Sciences (Genaro, Ed., Mack Publishing Co., 1985, Easton, PA), which is incorporated herein by reference.

As used herein, the term "composition" or "pharmaceutical 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.

As used herein, the term "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., C - means one to six carbon atoms) and includes straight, branched chain, or cyclic substituent groups. Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl, hexyl, and cyclopropylmethyl.

Most preferred is (C -C )alkyl, particularly ethyl, methyl, isopropyl, isobutyl, n-pentyl, n- hexyl and cyclopropylmethyl.

As used herein, the term "substituted alkyl" means alkyl as defined above, substituted by one, two or three substituents selected from the group consisting of halogen, -OH, alkoxy, -NH , -N(CH ) , -C(=O)OH, trifluoromethyl, -C≡N, -C(=O)O(C - 2 3 2 1 C )alkyl, -C(=O)NH , -SO NH , -C(=NH)NH , and -NO , preferably containing one or 4 2 2 2 2 2 two substituents selected from halogen, -OH, alkoxy, -NH , trifluoromethyl, -N(CH ) , 2 3 2 and -C(=O)OH, more preferably selected from halogen, alkoxy and -OH. Examples of substituted alkyls include, but are not limited to, 2,2-difluoropropyl, 2- carboxycyclopentyl and 3-chloropropyl.

As used herein, the term "heteroalkyl" by itself or in combination with another term means, unless otherwise stated, a stable straight or branched chain alkyl group consisting of the stated number of carbon atoms and one or two heteroatoms selected from the group consisting of O, N, and S, and wherein the nitrogen and sulfur atoms may be optionally oxidized and the nitrogen heteroatom may be optionally quaternized. The heteroatom(s) may be placed at any position of the heteroalkyl group, including between the rest of the heteroalkyl group and the fragment to which it is attached, as well as attached to the most distal carbon atom in the heteroalkyl group. Examples include: -O-CH -CH -CH , -CH -CH -CH -OH, -CH -CH -NH-CH , -CH -S-CH -CH , 2 2 3 2 2 2 2 2 3 2 2 3 and -CH CH -S(=O)-CH . Up to two heteroatoms may be consecutive, such as, for 2 2 3 example, -CH -NH-OCH , or -CH -CH -S-S-CH . Preferred heteroalkyl groups have 1- 2 3 2 2 3 carbons.

As used herein, the term "alkoxy" employed alone or in combination with other terms means, unless otherwise stated, an alkyl group having the designated number of carbon atoms, as defined above, connected to the rest of the molecule via an oxygen atom, such as, for example, methoxy, ethoxy, 1-propoxy, 2-propoxy (isopropoxy) and the higher homologs and isomers. Preferred are (C -C ) alkoxy, particularly ethoxy and methoxy.

As used herein, the term "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.

As used herein, the term "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. In one embodiment, the cycloalkyl group is saturated or partially unsaturated. In another embodiment, the cycloalkyl group is fused with an aromatic ring.

Cycloalkyl groups include groups having from 3 to 10 ring atoms. Illustrative examples of cycloalkyl groups include, but are not limited to, the following moieties: Monocyclic cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Dicyclic cycloalkyls include, but are not limited to, tetrahydronaphthyl, indanyl, and tetrahydropentalene. Polycyclic cycloalkyls include adamantine and norbornane. The term cycloalkyl includes "unsaturated nonaromatic carbocyclyl" or "nonaromatic unsaturated carbocyclyl" 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.

As used herein, the term "heterocycloalkyl" or "heterocyclyl" refers to a heteroalicyclic group containing one to four ring heteroatoms each selected from O, Sand N. In one embodiment, each heterocycloalkyl group has from 4 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. In another embodiment, the heterocycloalkyl group is fused with an aromatic ring. In one embodiment, 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. A heterocycle may be aromatic or non-aromatic in nature. In one embodiment, the heterocycle is a heteroaryl.

An example of a 3-membered heterocycloalkyl group includes, and is not limited to, aziridine. Examples of 4-membered heterocycloalkyl groups include, and are not limited to, azetidine and a beta lactam. Examples of 5-membered heterocycloalkyl groups include, and are not limited to, pyrrolidine, oxazolidine and thiazolidinedione.

Examples of 6-membered heterocycloalkyl groups include, and are not limited to, piperidine, morpholine and piperazine. Other non-limiting examples of heterocycloalkyl groups are: Examples of non-aromatic heterocycles include monocyclic groups such as aziridine, oxirane, thiirane, azetidine, oxetane, thietane, pyrrolidine, pyrroline, 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-dihydropyran, tetrahydropyran, 1,4-dioxane, 1,3-dioxane, homopiperazine, homopiperidine, 1,3-dioxepane, 4,7-dihydro-1,3-dioxepin, and hexamethyleneoxide.

As used herein, the term "aromatic" refers to a carbocycle or heterocycle with one or more polyunsaturated rings and having aromatic character, i.e., having (4n + 2) delocalized π (pi) electrons, where n is an integer.

As used herein, the term "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 biphenyl, or may be fused, such as naphthalene.

Examples of aryl groups include phenyl, anthracyl, and naphthyl. Preferred examples are phenyl and naphthyl, most preferred is phenyl.

As used herein, the term "aryl-(C -C )alkyl" means a functional group wherein a one- to three-carbon alkylene chain is attached to an aryl group, e.g., -CH CH -phenyl.

Preferred is aryl-CH - and aryl-CH(CH )-. The term "substituted aryl-(C -C )alkyl" 2 3 1 3 means an aryl-(C -C )alkyl functional group in which the aryl group is substituted.

Preferred is substituted aryl(CH )-. Similarly, the term "heteroaryl-(C -C )alkyl" means 2 1 3 a functional group wherein a one to three carbon alkylene chain is attached to a heteroaryl group, e.g., -CH CH -pyridyl. Preferred is heteroaryl-(CH )-. The term "substituted 2 2 2 heteroaryl-(C -C )alkyl" means a heteroaryl-(C -C )alkyl functional group in which the 1 3 1 3 heteroaryl group is substituted. Preferred is substituted heteroaryl-(CH )-.

As used herein, the term "heteroaryl" or "heteroaromatic" refers to a heterocycle having aromatic character. A polycyclic heteroaryl may include one or more rings that are partially saturated. Examples include the following moieties: Examples of heteroaryl groups also include pyridyl, pyrazinyl, pyrimidinyl (particularly 2- and 4-pyrimidinyl), pyridazinyl, thienyl, furyl, pyrrolyl (particularly 2-pyrrolyl), imidazolyl, thiazolyl, oxazolyl, pyrazolyl (particularly 3- and 5-pyrazolyl), isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,3,4-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,3,4-thiadiazolyl and 1,3,4-oxadiazolyl.

Examples of polycyclic heterocycles and heteroaryls include indolyl (particularly 3-, 4-, 5-, 6- and 7-indolyl), indolinyl, quinolyl, tetrahydroquinolyl, isoquinolyl (particularly 1- and 5-isoquinolyl), 1,2,3,4-tetrahydroisoquinolyl, cinnolinyl, quinoxalinyl (particularly 2- and 5-quinoxalinyl), quinazolinyl, phthalazinyl, 1,8-naphthyridinyl, 1,4-benzodioxanyl, coumarin, dihydrocoumarin, 1,5-naphthyridinyl, benzofuryl (particularly 3-, 4-, 5-, 6- and 7-benzofuryl), 2,3-dihydrobenzofuryl, 1,2-benzisoxazolyl, benzothienyl (particularly 3-, 4-, 5-, 6-, and 7-benzothienyl), benzoxazolyl, benzothiazolyl (particularly 2-benzothiazolyl and 5-benzothiazolyl), purinyl, benzimidazolyl (particularly 2-benzimidazolyl), benzotriazolyl, thioxanthinyl, carbazolyl, carbolinyl, acridinyl, pyrrolizidinyl, and quinolizidinyl.

As used herein, the term "substituted" means that an atom or group of atoms has replaced hydrogen as the substituent attached to another group. The term "substituted" further refers to any level of substitution, namely mono-, di-, tri-, tetra-, or penta- substitution, where such substitution is permitted. The substituents are independently selected, and substitution may be at any chemically accessible position. In one embodiment, the substituents vary in number between one and four. In another embodiment, the substituents vary in number between one and three. In yet another embodiment, the substituents vary in number between one and two.

As used herein, the term "optionally substituted" means that the referenced group may be substituted or unsubstituted. In one embodiment, the referenced group is optionally substituted with zero substituents, i.e., the referenced group is unsubstituted.

In another embodiment, the referenced group is optionally substituted with one or more additional group(s) individually and independently selected from groups described herein.

In one embodiment, the substituents are independently selected from the group consisting of oxo, halogen, -CN, -NH2, -OH, -NH(CH3), -N(CH3)2, alkyl (including straight chain, branched and/or unsaturated alkyl), substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, fluoro alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted alkoxy, fluoroalkoxy, -S-alkyl, S(=O) alkyl, -C(=O)NH[substituted or unsubstituted alkyl, or substituted or unsubstituted phenyl], -C(=O)N[H or alkyl] , -OC(=O)N[substituted or unsubstituted alkyl] , -NHC(=O)NH[substituted or unsubstituted alkyl, or substituted or unsubstituted phenyl], -NHC(=O)alkyl, -N[substituted or unsubstituted alkyl]C(=O)[substituted or unsubstituted alkyl], -NHC(=O)[substituted or unsubstituted alkyl], -C(OH)[substituted or unsubstituted alkyl] , and -C(NH )[substituted or unsubstituted alkyl] . In another 2 2 2 embodiment, by way of example, an optional substituent is selected from oxo, fluorine, chlorine, bromine, iodine, -CN, -NH , -OH, -NH(CH ), -N(CH ) , -CH , -CH CH , - 2 3 3 2 3 2 3 CH(CH ) , -CF , 3 2 3 -CH CF , -OCH , -OCH CH , -OCH(CH ) , -OCF , - OCH CF , -S(=O) -CH , 2 3 3 2 3 3 2 3 2 3 2 3 -C(=O)NH , -C(=O)-NHCH , -NHC(=O)NHCH , -C(=O)CH , and -C(=O)OH. In yet 2 3 3 3 one embodiment, the substituents are independently selected from the group consisting of C alkyl, -OH, C alkoxy, halo, amino, acetamido, oxo and nitro. In yet another 1-6 1-6 embodiment, the substituents are independently selected from the group consisting of C alkyl, C alkoxy, halo, acetamido, and nitro. As used herein, where a substituent is an alkyl or alkoxy group, the carbon chain may be branched, straight or cyclic, with straight being preferred.

Compounds The present invention generally relates to the discovery of compounds that are useful in the treatment and prevention of HBV in man. In one embodiment, the compounds as describedare useful in HBV treatment by disrupting, accelerating, reducing delaying and/or inhibiting normal viral capsid assembly and/or disassembly of immature or mature particles, thereby inducing aberrant capsid morphology and leading to antiviral effects such as disruption of virion assembly and/or disassembly and/or virion maturation, and/or virus egress.

The capsid assembly disruptors disclosed herein may be used as monotherapy and/or in novel cross-class combination regimens for treating HBV infection in man.

Combination therapy with drugs exhibiting different mechanism of action (MOA) that act at different steps in the virus life cycle may deliver greater efficacy due to additive or synergistic antiviral effects. Clinically evaluated HIV treatment regimens have shown that combination therapy improves the efficacy of viral load reduction, and dramatically reduces emergence of antiviral resistance. Combination therapy for the treatment of Hepatitis C (HCV) virus infection has also resulted in significant improvement in sustained antiviral response and eradication rates. Thus, use of the HBV capsid assembly inhibitors as describedin combination with, for example, NA drugs, is likely to deliver a more profound antiviral effect and greater disease eradication rates than current standards of care.

Capsid assembly plays a central role in HBV genome replication. HBV polymerase binds pre-genomic HBV RNA (pgRNA), and pgRNA encapsidation must occur prior to HBV DNA synthesis. Moreover, it is well established that nuclear accumulation of the cccDNA replication intermediate, which is responsible for maintenance of chronic HBV replication in the presence of nucleoside suppressive therapy, requires the capsid for shuttling HBV DNA to the nuclei. Therefore, the HBV capsid assembly disruptors as describedhave the potential to increase HBV eradication rates through synergistic or additive suppression of viral genome replication and to further reduce accumulation of cccDNA when used alone or in combination with existing nucleoside drugs. The capsid assembly disruptors as described may also alter normal core protein degradation, potentially leading to altered MHC-1 antigen presentation, which may in turn increase seroconversion/eradication rates through immuno-stimulatory activity, more effectively clearing infected cells.

In one embodiment, drug resistance poses a major threat to current therapies for chronic HBV infection, and cross-class combination therapy is a proven strategy for delaying emergence of drug resistance strains. The capsid assembly disruptors as describedcan, when administered alone or in combination with other HBV therapy, offer enhanced drug resistant profiles and improved management of chronic HBV.

The compounds useful within the invention may be synthesized using techniques well-known in the art of organic synthesis. The starting materials and intermediates required for the synthesis may be obtained from commercial sources or synthesized according to methods known to those skilled in the art.

In one embodiment, the compound as describedis a compound of formula (I), or a salt, solvate, or N-oxide thereof: (I) wherein: ring A is a monocyclic or bicyclic aryl or a monocyclic or bicyclic heteroaryl ring; ring B is a monocyclic or bicyclic aryl or a monocyclic or bicyclic heteroaryl ring; 1 6 7 6 R is SO N(R )R or C(=O)N(H)R ; R and R are independently selected at each occurrence from the group 8 9 9 9 consisting of halo, -CN, -NO , -(L) -OR , -(L) -SR , -(L) -S(=O)R , -(L) -S(=O) R , - 2 m m m m 2 9 9 9 8 8 (L)m-NHS(=O)2R , -(L)m-C(=O)R , -(L)m-OC(=O)R , -(L)mCO2R , -(L)m-OCO2R , - 8 8 8 8 (L) -CH(R ) , -(L) -N(R ) , -(L) -C(=O)N(R ) , -(L) -OC(=O)N(R ) , -(L) - m 2 m 2 m 2 m 2 m 8 9 9 8 NHC(=O)NH(R ), -(L)m-NHC(=O)R , -(L)m-NHC(=O)OR , -(L)m-C(OH)(R )2, - (L) C(NH )(R ) , -C -C alkyl, -C -C fluoroalkyl and -C -C heteroalkyl; m 2 2 1 6 1 6 1 6 R is C or S(=O); R is H, C -C alkyl, C -C heteroalkyl, -C -C alkyl-(C -C cycloalkyl) or -(L) - 1 6 1 6 1 3 3 6 m aryl, and wherein the alkyl, heteroalkyl, cycloalkyl or aryl group is optionally substituted with 0-5 substituents selected from R ; R and R are independently selected from the group consisting of H, C -C alkyl, C -C fluoroalkyl, C -C heteroalkyl, C -C cycloalkyl, C -C heterocycloalkyl, 1 6 1 6 3 10 2 10 aryl, heteroaryl, -C -C alkyl-(C -C cycloalkyl), -C -C alkyl-(C -C 1 4 3 10 1 4 2 10 heterocycloalkyl), -C -C alkyl-(aryl), or -C -C alkyl(heteroaryl), and wherein the alkyl, 1 4 1 4 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group is optionally 2 6 7 substituted with 0-5 substituents selected from R , or the R and R groups attached to the same N atom are taken together with the N atom to which they are attached to form an optionally substituted C -C heterocycloalkyl ring, wherein the ring optionally 2 10 4 4 4 comprises a moiety selected from O, C=O, S(O) , NR S(O) , NR (C=O) or N-R , and wherein the cycloalkyl or heterocycloalkyl ring is optionally substituted with 0-5 substituents selected from R ; each R is independently, at each occurrence, H, C -C alkyl, C -C fluoroalkyl, 1 6 1 6 C -C heteroalkyl, C -C cycloalkyl, C -C heterocycloalkyl, aryl, heteroaryl, -C -C 1 6 3 10 2 10 1 4 alkyl-(C -C cycloalkyl), -C -C alkyl-(C -C heterocycloalkyl), -C -C alkyl-(aryl), or 3 10 1 4 2 10 1 4 -C -C alkyl(heteroaryl), and wherein the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is optionally substituted with 0-5 substituents selected from R ; or two R groups attached to the same N or C atom are taken together with the N or C atom to which they are attached to form an optionally substituted C -C 2 10 heterocycloalkyl or C3-C10 heterocycloalkyl, wherein the ring optionally comprises a 4 4 4 moiety selected from O, C=O, S(O) , NR S(O) , NR (C=O) or N-R , and wherein the ring is optionally substituted with 0-5 substituents selected from R ; R is C -C alkyl, C -C fluoroalkyl, C -C heteroalkyl, C -C cycloalkyl, a C - 1 6 1 6 1 6 3 10 2 C heterocycloalkyl, aryl, heteroaryl, -C -C alkyl-(C -C cycloalkyl), -C -C alkyl- 1 4 3 10 1 4 (C -C heterocycloalkyl), -C -C alkyl-(aryl), or -C -C alkyl-(heteroaryl), and wherein 2 10 1 4 1 4 the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring is optionally substituted with 0-5 substituents selected from R ; each occurrence of x and y is independently selected from the group consisting of 0, 1, 2, 3 and 4; L is independently, at each occurrence, a bivalent radical selected from -(C -C alkylene) -, -(C -C cycloalkylene), -(C -C alkylene) -O-(C -C alkylene) -, or -(C - m 3 7 1 3 m 1 3 m 1 C alkylene) -NH-(C -C alkylene) -; and, 3 m 1 3 m each occurrence of m is independently 0, 1 or 2.

In one embodiment, ring A is a monocyclic aryl ring optionally substituted with 0-3 substituents selected from R . In another embodiment, ring A is a monocyclic heteroaryl ring optionally substituted with 0-3 substituents selected from R . In yet another embodiment, ring A is a bicyclic aryl ring optionally substituted with 0-3 substituents selected from R . In yet another embodiment, ring A is a bicyclic heteroaryl ring optionally substituted with 0-3 substituents selected from R . In yet another embodiment, ring A is optionally substituted with zero substituents selected from R .

In one embodiment, ring B is a monocyclic aryl ring optionally substituted with 0-3 substituents selected from R . In another embodiment, ring B is a monocyclic heteroaryl ring optionally substituted with 0-3 substituents selected from R . In yet another embodiment, ring B is a bicyclic aryl ring optionally substituted with 0-3 substituents selected from R . In yet another embodiment, ring B is a bicyclic heteroaryl ring optionally substituted with 0-3 substituents selected from R . In yet another embodiment, ring B is optionally substituted with zero substituents selected from R . 1 6 7 In one embodiment, B is phenyl; A is aryl or heteroaryl; R is SO N(R )R or C(=O)N(H)R . 3 1 6 7 In one embodiment, A is phenyl; B is phenyl; R is C; R is SO N(R )R or C(=O)N(H)R .

In one embodiment, A is phenyl; B is phenyl; x is zero; R is C; R is 6 7 6 1 3 SO N(R )R or C(=O)N(H)R ; wherein substituents R and R are in a 1,3-position (or meta-substitution) with respect to each other.

In one embodiment, A is phenyl; B is phenyl; x is zero; R is C; R is 6 7 1 3 SO N(R )R ; wherein substituents R and R are in a 1,3-position (or meta- substitution) with respect to each other.

In one embodiment, A is phenyl; B is phenyl; x is zero; R is C; R is 6 1 3 C(=O)N(H)R ; wherein substituents R and R are in a 1,3-position (or meta- substitution) with respect to each other.

In one embodiment, x is zero. In another embodiment, x is 1 and R is halo.

In one embodiment, the compound as describedis a compound of formula (II), or a salt, solvate, or N-oxide thereof: (II), 4 2 6 wherein ring B, R , y, R , R , x, and R have the definitions provided above for Formula I.

In an embodiment, the compound of formula (II) is a compound of formula (IIa), or a salt, solvate, or N-oxide thereof: (R ) (R ) O S O (R ) (IIa) wherein R , y, R , individually for each occurrence, and x, individually for each occurence, have the definitions provided above for Formula I, and G is carbon or nitrogen.

In another embodiment, the compound of formula (II) is a compound of formula (IIb), or a salt, solvate, or N-oxide thereof: (IIb) 2 6 wherein R , y, R , x, and R have the definitions provided above for Formula I, and wherien the (CH ) group can optionally be further substituted with OH, C alkyl, 2 1-6 1-6 or OC alkyl.

In still another embodiment, the compound of formula (II) is a compound of formula (IIc), or a salt, solvate, or N-oxide thereof: (IIc) wherein R , y, R , individually for each occurrence, and x, individually for each occurence, have the definitions provided above for Formula I, and G is H, alkyl, or substituted alkyl.

In one embodiment, the compound as describedis a compound of formula (III), or a salt, solvate, or N-oxide thereof: (III).

In one embodiment, described herein are compounds having the Formula IV: (IV) or pharmaceutically acceptable salts thereof; wherein R is H or C1-C6 alkyl; wherein each R is independently selected at each occurrence from the group consisting of CH , C -C alkoxy, halo, -CN, -NO , -(L) -SR , -(L) -S(=O)R , -(L) - 3 1 6 2 m m m 9 9 9 9 8 S(=O) R , -(L) -NHS(=O) R , -(L) -C(=O)R , -(L) -OC(=O)R , -(L) CO R , -(L) - 2 m 2 m m m 2 m 8 8 8 8 OCO R , -(L) -N(R ) , -(L) -C(=O)N(R ) , -(L) -OC(=O)N(R ) , -(L) - 2 m 2 m 2 m 2 m 8 9 9 8 NHC(=O)NH(R ), -(L) -NHC(=O)R , -(L) -NHC(=O)OR , -(L) -C(OH)(R ) , - m m m 2 (L) C(NH )(R ) , -C -C haloalkyl, -C -C dihaloalkyl and -C -C trihaloalkyl; m 2 2 1 6 1 6 1 6 L is independently, at each occurrence, a bivalent radical selected from -(C -C alkylene)-, -(C -C cycloalkylene)-, -(C -C alkylene) -O-(C -C alkylene) -, or -(C -C 3 7 1 3 m 1 3 m 1 3 alkylene) -NH-(C -C alkylene) -; m 1 3 m each R is independently, at each occurrence, H, C -C alkyl, -C -C haloalkyl, - 1 6 1 6 C -C dihaloalkyl, -C -C trihaloalkyl, C -C heteroalkyl, C -C cycloalkyl, C -C 1 6 1 6 1 6 3 10 3 10 heterocycloalkyl, aryl, heteroaryl, -C -C alkyl-(C -C cycloalkyl), -C -C alkyl-(C -C 1 4 3 10 1 4 3 10 heterocycloalkyl), -C -C alkyl-(aryl), or -C -C alkyl(heteroaryl), and wherein the alkyl, 1 4 1 4 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is optionally substituted with 1-5 substituents selected from R ; R is C -C alkyl, -C -C haloalkyl, -C -C dihaloalkyl, -C -C trihaloalkyl, C - 1 6 1 6 1 6 1 6 1 C heteroalkyl, C -C cycloalkyl, a C -C heterocycloalkyl, aryl, heteroaryl, -C -C 6 3 10 3 10 1 4 alkyl-(C -C cycloalkyl), -C -C alkyl-(C -C heterocycloalkyl), -C -C alkyl-(aryl), or 3 10 1 4 3 10 1 4 -C -C alkyl-(heteroaryl), and wherein the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring is optionally substituted with 0-5 substituents selected from R ; R is OH, C -C alkyl, C -C alkyl-OH, -C -C haloalkyl, -C -C dihaloalkyl, - 1 6 1 6 1 6 1 6 C -C trihaloalkyl, C -C heteroalkyl, C -C cycloalkyl, a C -C heterocycloalkyl, aryl, 1 6 1 6 3 10 3 10 heteroaryl, -C -C alkyl-(C -C cycloalkyl), -C -C alkyl-(C -C heterocycloalkyl), - 1 4 3 10 1 4 3 10 C -C alkyl-(aryl), or -C -C alkyl-(heteroaryl), and wherein the alkyl, heteroalkyl, 1 4 1 4 cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring is optionally substituted with 1-5 substituents selected from R ; R is a bond or C -C alkylene, wherein the C -C alkylene is optionally 1 3 1 3 substituted with 1-3 substituents selected from R ; R is independently selected at each occurrence from the group consisting of OH, halo, -CN, -NO , -C -C alkyl, -C -C alkoxy, -C -C haloalkyl, -C -C dihaloalkyl, -C - 2 1 6 1 6 1 6 1 6 1 C trihaloalkyl, -C -C heteroalkyl, and C(O) -C -C alkyl; 6 1 6 1 6 w is 0, 1 or 2; each occurrence of x is independently selected from the group consisting of 0, 1, 2, 3 and 4; each occurrence of y is independently selected from the group consisting of 1, 2, and 3; each occurrence of z is independently selected from the group consisting of 0, 1, 2, and 3; each occurrence of m is independently 0, 1 or 2.

In one embodiment of Formula IV, R is independently selected at each , -C -C alkyl, -C -C alkoxy, - occurrence from the group consisting of halo, -CN, -NO2 1 6 1 6 C -C haloalkyl, -C -C dihaloalkyl, -C -C trihaloalkyl, -C -C heteroalkyl, and C(O) - 1 6 1 6 1 6 1 6 C -C alkyl; In one embodiment, compounds of Formula IV are of the Formula IVa: (IVa) or pharmaceutically acceptable salts thereof.

In embodiments of Formulae IV or IVa, each R is independently selected at each occurrence from the group consisting of CH , C -C alkoxy, halo, -CN, -NO , -C -C haloalkyl, -C -C dihaloalkyl, -C -C and 3 1 6 2 1 6 1 6 1 6 trihaloalkyl; R is OH, halo, C -C alkyl, C -C alkyl-OH, -C -C chloroalkyl, -C -C 1 6 1 6 1 6 1 6 dichloroalkyl, -C -C trichloroalkyl, -C -C fluoroalkyl, -C -C difluoroalkyl, -C -C 1 6 1 6 1 6 1 6 trifluoroalkyl, C -C heteroalkyl, C -C cycloalkyl, a C -C heterocycloalkyl, aryl, 1 6 3 10 3 10 heteroaryl, -C -C alkyl-(C -C cycloalkyl), -C -C alkyl-(C -C heterocycloalkyl), - 1 4 3 10 1 4 3 10 C -C alkyl-(aryl), or -C -C alkyl-(heteroaryl), and wherein the alkyl, heteroalkyl, 1 4 1 4 cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring is optionally substituted with 1-5 substituents selected from R ; R is a bond or C1-C3 alkylene, wherein the C1-C3 alkylene is optionally substituted with 1-3 substituents selected from R ; R is independently selected at each occurrence from the group consisting of halo, -CN, -NO , -C -C alkyl, -C -C alkoxy, -C -C fluoroalkyl, -C -C heteroalkyl, 2 1 6 1 6 1 6 1 6 C(O) -C -C alkyl, and C(O) -C -C alkoxy. 1 6 1 6 In other embodiments of Formulae IV or IVa, each R is independently selected at each occurrence from the group consisting of CH , C -C alkoxy, halo, fluoromethyl, 3 1 6 difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, and trichloromethyl; R is OH, halo, C -C alkyl, C -C alkyl-OH, C -C fluoroalkyl, C -C 1 6 1 6 1 6 1 6 difluoroalkyl, C -C trifluoroalkyl, C -C heteroalkyl, C -C cycloalkyl, C -C 1 6 1 6 3 10 3 10 heterocycloalkyl, aryl, heteroaryl, -C -C alkyl-(C -C cycloalkyl), -C -C alkyl-(C -C 1 4 3 10 1 4 3 10 heterocycloalkyl), -C -C alkyl-(aryl), or -C -C alkyl-(heteroaryl), and wherein the 1 4 1 4 alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring is optionally substituted with 1-5 substituents selected from R ; R is a bond or C -C alkylene; R is independently selected at each occurrence from the group consisting of halo, -CN, -NO , -C -C alkyl, -C -C alkoxy, -C -C fluoroalkyl, -C -C heteroalkyl, 2 1 6 1 6 1 6 1 6 and C(O) -C -C alkyl, and C(O) -C -C alkoxy. 1 6 1 6 In other embodiments of Formulae IV and IVa, R (i.e., (R ) ) is 3-F, 3-Cl, 3- CH , 3-CH F, 3-CHF , 4-F, 3-CH F, 3-ClF, 3-BrF, 3,4,5-trifluoro, 3,4,5- 3 2 2 3 trichloro, or 3-chloro-4,5-difluoro. In another embodiment, w is 1 or 2.

In yet other embodiments of Formulae IV and IVa, R is a bond or C -C alkylene; R is OH, halo, C -C alkyl, C -C alkyl-OH, -C -C chloroalkyl, -C -C 1 6 1 6 1 6 1 6 dichloroalkyl, -C -C trichloroalkyl, -C -C fluoroalkyl, -C -C difluoroalkyl, -C -C 1 6 1 6 1 6 1 6 trifluoroalkyl, C3-C10 cycloalkyl, C3-C10 heterocycloalkyl, or phenyl, wherein the C3-C10 cycloalkyl, a C -C heterocycloalkyl, or phenyl groups are optionally substituted with 3 10 1-5 substituents selected from halo, -C1-C6 alkyl, and -C1-C6 alkoxy; and z is 0 or 1.

In another embodiment, compounds of Formula IV are of the Formula IVb: (IVb) or pharmaceutically acceptable salts thereof; wherein G is independently selected at each occurrence from CH3, OCH3, halo, CF , CCl , CH Cl, CCl H, CF H, CH F, and CF ; 3 3 2 2 2 2 3 G is H, C -C alkyl, or halo; G is OH, CH OH, or CH CH OH; 2 2 2 G is H, OH, halo, C -C alkyl, C -C alkyl-OH, -C -C chloroalkyl, -C -C 1 6 1 6 1 6 1 6 dichloroalkyl, -C -C trichloroalkyl, -C -C fluoroalkyl, -C -C difluoroalkyl, -C -C 1 6 1 6 1 6 1 6 trifluoroalkyl, or phenyl, wherein the phenyl group is optionally independently substituted with 1-5 substituents selected from halo, -C -C alkyl, and -C -C alkoxy; 1 6 1 6 y is 1, 2, or 3.

In an embodiment of Formula IVb, wherein G is independently selected at each occurrence from halo, CF , CCl , CH Cl, CCl H, CF H, CH F, and CF ; 3 3 2 2 2 2 3 In another embodiment, compounds of Formula IV are of the Formula IVc: (IVc) or pharmaceutically acceptable salts thereof; wherein X is halo; G is hydrogen or halo; G is H, C -C alkyl, or halo; and G is H, halo, C -C alkyl, or OH.

In one embodiment of Formula IVc, G is C -C alkyl or halo, and wherein G is in the 2, 3, or 4 position of the phenyl ring.

In another embodiment, described herein are compounds of the Formula V: or pharmaceutically acceptable salts thereof; wherein R is H or C -C alkyl; G is H or C -C alkyl; wherein each R is independently selected at each occurrence from the group 8 9 9 consisting of -C -C alkyl, halo, -CN, -NO , -(L) -OR , -(L) -SR , -(L) -S(=O)R , - 1 6 2 m m m 9 9 9 9 8 (L) -S(=O) R , -(L) -NHS(=O) R , -(L) -C(=O)R , -(L) -OC(=O)R , -(L) CO R , - m 2 m 2 m m m 2 8 8 8 8 8 (L) -OCO R , -(L) -CH(R ) , -(L) -N(R ) , -(L) -C(=O)N(R ) , -(L) -OC(=O)N(R ) , m 2 m 2 m 2 m 2 m 2 8 9 9 8 -(L) -NHC(=O)NH(R ), -(L) -NHC(=O)R , -(L) -NHC(=O)OR , -(L) -C(OH)(R ) , - m m m m 2 (L) C(NH )(R ) , -C -C haloalkyl, -C -C dihaloalkyl and -C -C trihaloalkyl; m 2 2 1 6 1 6 1 6 L is independently, at each occurrence, a bivalent radical selected from -(C -C alkylene)-, -(C -C cycloalkylene)-, -(C -C alkylene) -O-(C -C alkylene) -, or -(C -C 3 7 1 3 m 1 3 m 1 3 alkylene) -NH-(C -C alkylene) -; m 1 3 m each R is independently, at each occurrence, H, C -C alkyl, -C -C haloalkyl, - 1 6 1 6 C -C dihaloalkyl, -C -C trihaloalkyl, C -C heteroalkyl, C -C cycloalkyl, C -C 1 6 1 6 1 6 3 10 3 10 heterocycloalkyl, aryl, heteroaryl, -C -C alkyl-(C -C cycloalkyl), -C -C alkyl-(C -C 1 4 3 10 1 4 3 10 heterocycloalkyl), -C -C alkyl-(aryl), or -C -C alkyl(heteroaryl), and wherein the alkyl, 1 4 1 4 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is optionally substituted with 1-5 substituents selected from R ; R is C -C alkyl, -C -C haloalkyl, -C -C dihaloalkyl, -C -C trihaloalkyl, C - 1 6 1 6 1 6 1 6 1 C6 heteroalkyl, C3-C10 cycloalkyl, a C3-C10 heterocycloalkyl, aryl, heteroaryl, -C1-C4 alkyl-(C -C cycloalkyl), -C -C alkyl-(C -C heterocycloalkyl), -C -C alkyl-(aryl), or 3 10 1 4 3 10 1 4 -C -C alkyl-(heteroaryl), and wherein the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring is optionally substituted with 1-5 substituents selected from R ; R is independently selected at each occurrence from the group consisting of halo, -OH, -CN, -NO , -C -C alkyl, -C -C alkoxy, -C -C fluoroalkyl, -C -C 2 1 6 1 6 1 6 1 6 heteroalkyl, and C(O)-C -C alkyl; n is 1, 2, 3, 4, 5, or 6; each occurrence of x is independently selected from the group consisting of 0, 1, 2, 3 and 4; each occurrence of y is independently selected from the group consisting of 1, 2, and 3; and each occurrence of m is independently 0, 1 or 2.

In one embodiment of Formula (V), each R is independently selected at each occurrence from the group consisting of OH, C -C alkyl, C -C alkoxy, halo, -CN, -NO , C -C chloroalkyl, -C -C 1 6 1 6 2 1 6 1 6 dichloroalkyl, -C -C trichloroalkyl, -C -C fluoroalkyl, -C -C difluoroalkyl and -C -C 1 6 1 6 1 6 1 6 trifluoroalkyl; and R is independently selected at each occurrence from the group consisting of halo, -OH, -CN, -NO , -C -C alkyl, -C -C alkoxy, -C -C fluoroalkyl, -C -C 2 1 6 1 6 1 6 1 6 heteroalkyl, and C(O)-C -C alkyl.

In another embodiment of Formula (V), each R is independently selected at each occurrence from the group consisting of –OH, C -C alkyl, C -C alkoxy, halo, fluoromethyl, difluoromethyl, trifluoromethyl, 1 6 1 6 chloromethyl, dichloromethyl, and trichloromethyl; R is independently selected at each occurrence from the group consisting of – OH, halo, -CN, -NO , -C -C alkyl, -C -C alkoxy, -C -C fluoroalkyl, -C -C 2 1 6 1 6 1 6 1 6 heteroalkyl, and C(O)-C -C alkyl.

In still another embodiment of Formula (V), each R is independently selected at each occurrence from the group consisting of –OH, C -C alkyl, halo, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, and trichloromethyl; and each R is independently selected at each occurrence from the group consisting of halo, -C -C alkyl, or -C -C alkoxy. 1 6 1 6 In another embodiment, described herein are compounds of Formula VI: (VI) or pharmaceutically acceptable salts thereof; wherein R is H or C -C alkyl; G is H or C -C alkyl; wherein each R is independently selected at each occurrence from the group consisting of C -C alkyl, C -C alkoxy, halo, -CN, -NO , -(L) -SR , -(L) -S(=O)R , - 1 6 1 6 2 m m 9 9 9 9 8 (L) -S(=O) R , -(L) -NHS(=O) R , -(L) -C(=O)R , -(L) -OC(=O)R , -(L) CO R , - m 2 m 2 m m m 2 8 8 8 8 8 (L) -OCO R , -(L) -CH(R ) , -(L) -N(R ) , -(L) -C(=O)N(R ) , -(L) -OC(=O)N(R ) , m 2 m 2 m 2 m 2 m 2 8 9 9 8 -(L) -NHC(=O)NH(R ), -(L) -NHC(=O)R , -(L) -NHC(=O)OR , -(L) -C(OH)(R ) , - m m m m 2 (L) C(NH )(R ) , -C -C haloalkyl, -C -C dihaloalkyl and -C -C trihaloalkyl; m 2 2 1 6 1 6 1 6 L is independently, at each occurrence, a bivalent radical selected from -(C -C alkylene)-, -(C -C cycloalkylene)-, -(C -C alkylene) -O-(C -C alkylene) -, or -(C -C 3 7 1 3 m 1 3 m 1 3 alkylene) -NH-(C -C alkylene) -; m 1 3 m each R is independently, at each occurrence, H, C -C alkyl, -C -C haloalkyl, - 1 6 1 6 C -C dihaloalkyl, -C -C trihaloalkyl, C -C heteroalkyl, C -C cycloalkyl, C -C 1 6 1 6 1 6 3 10 3 10 heterocycloalkyl, aryl, heteroaryl, -C -C alkyl-(C -C cycloalkyl), -C -C alkyl-(C -C 1 4 3 10 1 4 3 10 heterocycloalkyl), -C -C alkyl-(aryl), or -C -C alkyl(heteroaryl), and wherein the alkyl, 1 4 1 4 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is optionally substituted with 1-5 substituents selected from R ; R is C1-C6 alkyl, -C1-C6 haloalkyl, -C1-C6 dihaloalkyl, -C1-C6 trihaloalkyl, C1- C heteroalkyl, C -C cycloalkyl, a C -C heterocycloalkyl, aryl, heteroaryl, -C -C 6 3 10 3 10 1 4 alkyl-(C3-C10 cycloalkyl), -C1-C4 alkyl-(C3-C10 heterocycloalkyl), -C1-C4 alkyl-(aryl), or -C -C alkyl-(heteroaryl), and wherein the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring is optionally substituted with 1-5 substituents selected from R ; R is OH, C -C alkyl, C -C alkyl-OH, C -C fluoroalkyl, C -C heteroalkyl, 1 6 1 6 1 6 1 6 C -C cycloalkyl, a C -C heterocycloalkyl, aryl, heteroaryl, -C -C alkyl-(C -C 3 10 3 10 1 4 3 10 cycloalkyl), -C -C alkyl-(C -C heterocycloalkyl), -C -C alkyl-(aryl), or -C -C alkyl- 1 4 3 10 1 4 1 4 (heteroaryl), and wherein the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring is optionally substituted with 1-5 substituents selected from R ; R is a bond or C -C alkylene, wherein the C -C alkylene is optionally 1 3 1 3 substituted with 1-3 substituents selected from R ; R is independently selected at each occurrence from the group consisting of halo, -CN, -NO , -C -C alkyl, -C -C alkoxy, -C -C fluoroalkyl, -C -C heteroalkyl, 2 1 6 1 6 1 6 1 6 -C alkyl; and C(O) -C1 6 w is 0, 1 or 2; each occurrence of x is independently selected from the group consisting of 0, 1, 2, 3 and 4; each occurrence of y is independently selected from the group consisting of 0, 1, 2, 3 and 4; each occurrence of z is independently selected from the group consisting of 0, 1, 2, and 3; each occurrence of m is independently 0, 1 or 2.

In certain embodiments of Formula VI, each R is independently selected at each occurrence from the group consisting of C -C alkyl, C -C alkoxy, halo, -CN, -NO , -C -C haloalkyl, -C -C dihaloalkyl, and 1 6 1 6 2 1 6 1 6 -C -C trihaloalkyl; R is OH, halo, C -C alkyl, C -C alkyl-OH, -C -C haloalkyl, -C -C 1 6 1 6 1 6 1 6 dihaloalkyl, -C -C trihaloalkyl, C -C heteroalkyl, C -C cycloalkyl, a C -C 1 6 1 6 3 10 3 10 heterocycloalkyl, aryl, heteroaryl, -C -C alkyl-(C -C cycloalkyl), -C -C alkyl-(C -C 1 4 3 10 1 4 3 10 heterocycloalkyl), -C -C alkyl-(aryl), or -C -C alkyl-(heteroaryl), and wherein the 1 4 1 4 alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring is optionally substituted with 1-5 substituents selected from R ; R is a bond or C1-C3 alkylene, wherein the C1-C3 alkylene is optionally substituted with 1-3 substituents selected from R ; R is independently selected at each occurrence from the group consisting of halo, -CN, -NO , -C -C alkyl, -C -C alkoxy, -C -C fluoroalkyl, -C -C heteroalkyl, 2 1 6 1 6 1 6 1 6 C(O) -C -C alkyl, and C(O) -C -C alkoxy. 1 6 1 6 In another embodiment of Formula VI, each R is independently selected at each occurrence from the group consisting of C -C alkyl, C -C alkoxy, halo, fluoromethyl, difluoromethyl, trifluoromethyl, 1 6 1 6 chloromethyl, dichloromethyl, and trichloromethyl; R is OH, halo, C -C alkyl, C -C alkyl-OH, C -C fluoroalkyl, C -C 1 6 1 6 1 6 1 6 difluoroalkyl, C -C trifluoroalkyl, C -C heteroalkyl, C -C cycloalkyl, a C -C 1 6 1 6 3 10 3 10 heterocycloalkyl, aryl, heteroaryl, -C -C alkyl-(C -C cycloalkyl), -C -C alkyl-(C -C 1 4 3 10 1 4 3 10 heterocycloalkyl), -C -C alkyl-(aryl), or -C -C alkyl-(heteroaryl), and wherein the 1 4 1 4 alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring is optionally substituted with 1-5 substituents selected from R ; is a bond or C -C alkylene; R 1 3 R is independently selected at each occurrence from the group consisting of halo, -CN, -NO , -C -C alkyl, -C -C alkoxy, -C -C fluoroalkyl, -C -C heteroalkyl, 2 1 6 1 6 1 6 1 6 and C(O) -C -C alkyl, and C(O) -C -C alkoxy. 1 6 1 6 In other embodiments of Formula VI, R is 3-F, 3-Cl, 3-CH , 3-CH F, 3-CHF , 3 2 2 4-F, 3-CH F, 3-ClF, 3-BrF, 3,4,5-trifluoro, 3,4,5-trichloro, or 3-chloro-4,5- difluoro. In another embodiment, w is 1 or 2.

In still another embodiment of Formula VI, R is a bond or C -C alkylene; R is OH, halo, C -C alkyl, C -C alkyl-OH, -C -C chloroalkyl, -C -C 1 6 1 6 1 6 1 6 dichloroalkyl, -C -C trichloroalkyl, -C -C fluoroalkyl, -C -C difluoroalkyl, -C -C 1 6 1 6 1 6 1 6 trifluoroalkyl, C -C cycloalkyl, a C -C heterocycloalkyl, or phenyl, wherein the C - 3 10 3 10 3 C cycloalkyl, a C -C heterocycloalkyl, or phenyl groups are optionally substituted 3 10 with 1-5 substituents selected from halo, -C -C alkyl, and -C -C alkoxy; and 1 6 1 6 z is 0 or 1.

In an embodiment, compounds of Formula VI are of the Formula VIa: (VIa) or pharmaceutically acceptable salts thereof; wherein G is independently selected at each occurrence from CH , OCH , halo, CF , CCl , CH Cl, CCl H, CF H, CH F, and CF ; 3 3 2 2 2 2 3 G is H, C -C alkyl, or halo; G is OH, CH OH, or CH CH OH; 2 2 2 G is H, OH, halo, C -C alkyl, C -C alkyl-OH, -C -C chloroalkyl, -C -C 1 6 1 6 1 6 1 6 dichloroalkyl, -C -C trichloroalkyl, -C -C fluoroalkyl, -C -C difluoroalkyl, -C -C 1 6 1 6 1 6 1 6 trifluoroalkyl, or phenyl, wherein the phenyl group is optionally independently substituted with 1-5 substituents selected from halo, -C -C alkyl, and -C -C alkoxy; 1 6 1 6 y is 1, 2, or 3.

In an embodiment, compounds of Formula VI are of the Formula VIaa: (VIaa) or pharmaceutically acceptable salts thereof; wherein G is independently selected at each occurrence from C -C alkyl, OC - 1 6 1 C alkyl, halo, CF , CCl , CH Cl, CCl H, CF H, CH F, and CF ; 6 3 3 2 2 2 2 3 G is H, C -C alkyl, or halo; G is OH, CH2OH, or CH2CH2OH; G is H, OH, halo, C -C alkyl, C -C alkyl-OH, -C -C chloroalkyl, -C -C 1 6 1 6 1 6 1 6 dichloroalkyl, -C1-C6 trichloroalkyl, -C1-C6 fluoroalkyl, -C1-C6 difluoroalkyl, -C1-C6 trifluoroalkyl, or phenyl, wherein the phenyl group is optionally independently substituted with 1-5 substituents selected from halo, -C -C alkyl, and -C -C alkoxy; 1 6 1 6 y is 1, 2, or 3.

In another embodiment, compounds of Formula VI are of the Formula VIb: (VIb) or pharmaceutically acceptable salts thereof; wherein X is halo; G is hydrogen or halo; G is H, C -C alkyl, or halo; and G is H, halo, C -C alkyl, or OH.

In another embodiment, described herein is a compound of Formula VII: (VII) or pharmaceutically acceptable salts thereof; wherein R is H or C -C alkyl; wherein each R is independently selected at each occurrence from the group consisting of C -C alkyl, C -C alkoxy, halo, -CN, -NO , -(L) -SR , -(L) -S(=O)R , - 1 6 1 6 2 m m 9 9 9 9 8 (L)m-S(=O)2R , -(L)m-NHS(=O)2R , -(L)m-C(=O)R , -(L)m-OC(=O)R , -(L)mCO2R , - 8 8 8 8 8 (L) -OCO R , -(L) -CH(R ) , -(L) -N(R ) , -(L) -C(=O)N(R ) , -(L) -OC(=O)N(R ) , m 2 m 2 m 2 m 2 m 2 8 9 9 8 -(L) -NHC(=O)NH(R ), -(L) -NHC(=O)R , -(L) -NHC(=O)OR , -(L) -C(OH)(R ) , - m m m m 2 (L) C(NH )(R ) , -C -C haloalkyl, -C -C dihaloalkyl and -C -C trihaloalkyl; m 2 2 1 6 1 6 1 6 L is independently, at each occurrence, a bivalent radical selected from -(C -C alkylene)-, -(C -C cycloalkylene)-, -(C -C alkylene) -O-(C -C alkylene) -, or -(C -C 3 7 1 3 m 1 3 m 1 3 alkylene) -NH-(C -C alkylene) -; m 1 3 m each R is independently, at each occurrence, H, C -C alkyl, -C -C haloalkyl, - 1 6 1 6 C -C dihaloalkyl, -C -C trihaloalkyl, C -C heteroalkyl, C -C cycloalkyl, C -C 1 6 1 6 1 6 3 10 3 10 heterocycloalkyl, aryl, heteroaryl, -C -C alkyl-(C -C cycloalkyl), -C -C alkyl-(C -C 1 4 3 10 1 4 3 10 heterocycloalkyl), -C -C alkyl-(aryl), or -C -C alkyl(heteroaryl), and wherein the alkyl, 1 4 1 4 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is optionally substituted with 1-5 substituents selected from R ; R is C -C alkyl, -C -C haloalkyl, -C -C dihaloalkyl, -C -C trihaloalkyl, C - 1 6 1 6 1 6 1 6 1 C heteroalkyl, C -C cycloalkyl, a C -C heterocycloalkyl, aryl, heteroaryl, -C -C 6 3 10 3 10 1 4 alkyl-(C -C cycloalkyl), -C -C alkyl-(C -C heterocycloalkyl), -C -C alkyl-(aryl), or 3 10 1 4 3 10 1 4 -C -C alkyl-(heteroaryl), and wherein the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring is optionally substituted with 1-5 substituents selected from R ; R is H, C -C alkyl, -(L) -C(=O)C -C alkyl, -(L) -C(=O)C -C cycloalkyl, - 1 6 m 1 6 m 3 10 (L) -C(=O)OC -C alkyl, -(L) -C(=O)OC -C cycloalkyl wherein the alkyl or m 1 6 m 3 10 cycloalkyl groups are optionally substituted with halo, -C -C haloalkyl, -C -C 1 6 1 6 dihaloalkyl, or -C -C trihaloalkyl; R is a bond or C -C alkylene, wherein the C -C alkylene is optionally 1 3 1 3 substituted with 0-3 substituents selected from R ; R is independently selected at each occurrence from the group consisting of halo, -CN, -NO , -C -C alkyl, -C -C alkoxy, -C -C fluoroalkyl, -C -C heteroalkyl, 2 1 6 1 6 1 6 1 6 and C(O) -C -C alkyl; each occurrence of x is independently selected from the group consisting of 0, 1, 2, 3, or 4; each occurrence of y is independently selected from the group consisting of 1, 2, and 3; z is 0 or 1; and each occurrence of m is independently 0, 1 or 2.

In one embodiment of Formula VII, each R is independently selected at each occurrence from the group consisting of C -C alkyl, C -C alkoxy, halo, -CN, -NO , - 1 6 1 6 2 C -C haloalkyl, -C -C dihaloalkyl, and -C -C trihaloalkyl; 1 6 1 6 1 6 R is a bond or C -C alkylene, wherein the C -C alkylene is optionally 1 3 1 3 substituted with 0-3 substituents selected from R ; R is independently selected at each occurrence from the group consisting of halo, -CN, -NO , -C -C alkyl, -C -C alkoxy, -C -C fluoroalkyl, -C -C heteroalkyl, 2 1 6 1 6 1 6 1 6 C(O) -C -C alkyl, and C(O) -C -C alkoxy. 1 6 1 6 In an embodiment of Formula VII, is independently selected at each occurrence from the group consisting each R of C -C alkyl, C -C alkoxy, halo, fluoromethyl, difluoromethyl, trifluoromethyl, 1 6 1 6 chloromethyl, dichloromethyl, and trichloromethyl; R is a bond or C -C alkylene; R is independently selected at each occurrence from the group consisting of halo, -CN, -NO , -C -C alkyl, -C -C alkoxy, -C -C fluoroalkyl, -C -C heteroalkyl, 2 1 6 1 6 1 6 1 6 and C(O) -C -C alkyl, and C(O) -C -C alkoxy. 1 6 1 6 In an embodiment of Formula VII, R is 3-F, 3-Cl, 3-CH , 3-CH F, 3-CHF , 4-F, 3 2 2 3-CH F, 3-ClF, 3-BrF, 3,4,5-trifluoro, 3,4,5-trichloro, or 3-chloro-4,5-difluoro. 2 10 In another embodiment, R is H, C -C alkyl, or halo. In still another embodiment, R is C(=O)C -C cycloalkyl, wherein the or cycloalkyl group is optionally substituted 3 10 with halo, -C -C haloalkyl, -C -C dihaloalkyl, or -C -C trihaloalkyl. 1 6 1 6 1 6 It will be appreciated that the description of the present invention herein should be construed in congruity with the laws and principals of chemical bonding. In some instances it may be necessary to remove a hydrogen atom in order to accommodate a substitutent at any given location.

It is noted for the generic structures described herein that rings that are substituted by two or more variables (R groups, G groups, etc.) can indicate, for example, either viscinal (e.g., compounds 960D1 and 960D2) or geminal (e.g., compound 916) substitution patterns.

Preferred embodiments of Formulas I-VII, including pharmaceutically acceptable salts thereof, as well as enantiomers, stereoisomers, rotamers, tautomers, diastereomers, atropisomers or racemates thereof, and are shown below in Table 1 and are also considered to be "compounds as described." (Some compounds of Table 1 do not include hydrogens on hydroxyl groups; it is understood that "-O" indicates a hydroxyl substituent at these positions.) Synthetic method codes refer to the synthesis methodologies provided in the experimental section. For example, "A19B03C15" refers the use of intermediate A19 for region A, intermediate B03 for region B, and intermediate C15 for region C, and "GA" refers to general synthesis procedures G and A.

Table 1 Structure Structure Cmp. Cmp.

MS(M+ H) MS(M+ H) ID ID Synthetic method Synthetic method NH F NH OO S OO S 001 002 A01B01C01 A01B01C02 Cl NH OO S OO S 005 006 379/381 379/381 GB GB A01B01C05 A01B01C06 Cl NH OO S OO S 013 014 397/399 A01B01C13 1 397/399 H NMR (400 MHz, DMSO-d6) δ 10.60 (br, 1H), 8.29 (m, 2H), 7.94 (m, 1 H), 7.81 A01B01C14 (m, 1H), 7.52 (m, 1H), 7.50 (m, 1H), 7.22(m, 1H), 2.92(m,4H), 1.53(m, 4H), 1.35(m, 2H), F NH Cl NH OO S OO S 015 016 397/399 397/399 GB GB A01B01C16 A01B01C15 O NH F NH OO S OO S 021 022 A01B01C22 377 1 H NMR (400 MHz, DMSO-d6) δ 10.22 (br, 1H), 8.29 (m, 2H), 7.91 (m, 1 H), 7.78 A01B01C21 (m, 1H), 7.18 (m, 1H), 6.89 (m, 2H), 3.79(s, 3H), 2.92(m,4H), 2.02(s, 3H),1.53(m, 4H), 1.35(m, 2H), Cl NH O S O OO S 413/415 393/395 A01B01C26 A01B01C25 NH F OO S OO S 033 034 397/399 A01B02C03 A01B02C04 Cl NH F NH F OO S 037 038 OO S 431/433 A01B02C26 411/413 H NMR (400 MHz, CD OD) δ 8.11 (m, 1 H), 8.05 (m, 1H), 7.99 (m, 1H), 7.61 (m, A01B02C25 1H), 7.53(m, 2H), 3.05(m,4H), 1.67(m, 4H), 1.48(m, 2H) NH F F NH F 041 042 OO S OO S 395 395 GB GB A01B02C20 A01B02C21 Cl NH F F NH F 049 050 OO S OO S 431/433 A01B02C24 A01B02C89 OO S OO S 053 054 A01B03C03 397/399 H NMR (400 MHz, CDCl ) δ 8.27 (t, 1H), 3 GB 8.18(m 1 H), 7.95 (s, 1H), 7.61 (q, 2H), A01B03C04 7.34 (t, 1H), 7.09(m, 2H), 3.21(t, 4H), 1.65(m, 4H), 1.53(q, 2H), Br NH Br NH OO S OO S 061 062 451/453 437/439 A02B01C31 A03B01C31 Br NH Br NH OO S OO S 063 064 N OH 467/469 453/455 A05B01C31 A04B01C31 Br NH Br NH OO S OO S 065 066 453/455 453/455 A07B01C31 A06B01C31 Br NH Br NH OO S OO S 071 072 O NH 451/453 466/468 GA A13B01C31 A12B01C31 Br NH OO S OO S 073 074 453/455 492/494 A14B01C31 A15B01C31 Br NH OO S OO S 075 076 425/427 528/530 A17B01C31 A16B01C31 Br NH Br NH OO S 077 078 OO S 439/441 411/413 A18B01C31 A19B01C31 Br NH Br NH OO S OO S 079 080 413/415 455/457 A20B01C31 A21B01C31 Br NH Br NH OO S OO S 081 082 O OH 2 424/426 439/441 A23B01C31 A22B01C31 O NH O NH 083 084 S GB A01B01C66 H-NMR (400 MHz, CDCl3): δ ppm: 8.19 (m, 2H), 7.87 (m, 1H), 7.62 (t, 1H), 7.30 (m, 1H), 7.08 (m, 3H), 6.87 (s, 1H), 4.65 A01B01C66 (d, 2H), 2.98 (t, 4H), 1.62 (m, 4H), 1.42 (m, 2H).

O NH O NH Cl 097 098 427/429 311 GB GB A01B01C77 A01B01C32 O NH O NH S 099 100 A01B01C34 H-NMR (400 MHz, CDCl3): δ ppm: 7.98 GB (m, 2H), 7.84 (m, 1H), 7.59 (t, 1H), 7.31 A01B01C33 (m, 2H), 7.24 (m, 3H), 6.42 (d, 1H), 3.72 (m, 2H), 2.95 (m, 6H), 1.62 (m, 4H), 1.40 (m, 2H).

O NH O NH 103 104 GB A01B01C37 A01B01C36 Br NH OO S O N F 115 116 A01B13C24 424/426 A24B01C31 Br NH OO S OO S 117 118 438/440 452/454 A25B01C31 A26B01C31 Br NH Br NH OO S OO S 119 120 466/468 480/482 A27B01C31 A28B01C31 Br NH Br NH OO S OO S N 121 122 494/496 494/496 A29B01C31 A30B01C31 Br NH Br NH OO S OO S 123 124 529/531 542/544 A32B01C31 A31B01C31 Br NH Br NH OO S OO S 125 126 500/502 501/503 A33B01C31 A34B01C31 Br NH Br NH OO S OO S 127 128 507/509 521/523 GA GA A35B01C31 A36B01C31 Br NH Br NH OO S OH OO S 129 130 508/510 A37B01C31 507/509 H NMR (400 MHz, CD OD) δ 8.18 (m, 2H), 8.06(br, 1 H), 7.94 (d, 2H), 7.72 (t, A38B01C31 1H), 7.54 (m, 1H), 7.34 (m, 1H), 3.80(m, 4H), 3.08(m, 4H), 2.87(m, 1H), 1.25 (m, 2H), 1.06 (m, 1H), 0.94 (m, 1H).

Br NH OO S OO S 131 132 560/562 A40B01C31 517/519 H NMR (400 MHz, CD OD) δ 8.33 (s, 1H), 8.16(m, 2 H), 7.88 (m, 2H), 7.69 (t, A39B01C31 1H), 7.62 (d, 1H), 7.32 (m, 1H), 3.71(m, 4H), 3.04(m, 4H), 1.29(m, 2H), 1.07 (m, 2H).

Br NH Br NH OO S OO S 135 136 521/523 506/508 A43B01C31 A45B01C31 OO S OO S 141 142 A15B01C03 H NMR (400 MHz, CDCl ) δ 8.19 (s, 432 3 GB 1H), 8.14 (d, 1H), 7.93 (m, 1 H), 7.85 (s, A15B01C02 1H), 7.72(m, 1H), 7.62(m, 2H), 7.10(t, 2H), 3.76(br,4H), 3.07 (br,4H), 1.62(m, 1H),1.62 (m,1H), 0.93 (m,2H), 0.75(m,2H) F NH OO S OO S 147 148 A15B01C20 H NMR (400 MHz, CDCl ) δ 8.18 (s, 1H), 8.13 (d, 1H), 7.91 (m, 1 H), 7.83(d, A15B01C24 1H), 7.70(t, 1H), 7.50(m, 1H), 7.40(m, 1H), 7.02(t,1H), 3.75 (br,4H), 3.05 (br,4H) 1.62(m, 1H), 0.93 (m,2H), 0.75(m,2H) OO S O OO S 151 152 466/468 A15B01C15 H NMR (400 MHz, CDCl ) δ 8.18 (s, A15B01C82 1H), 8.17(m, 1H), 8.13 (s, 1 H), 7.91(m, 1H), 7.86(m, 1H), 7.71(t, 1H), 7.50(m, 1H), 7.16(t,1H), 3.75 (br,4H), 3.04 (br,4H) 1.62(m,1H), 0.93 (m,2H),0.75(m,2H) OO S OO S 159 160 493/495 491/493 A48B01C31 A15B01C31 Cl NH OO S OO S 168 169 OH OH 367/369 367/369 A19B01C06 A19B01C05 NH F NH OO S OO S 170 171 A19B01C01 A19B01C02 OO S 174 175 OO S A19B01C20 A19B01C21 Cl NH F NH 176 177 OO S OO S OH OH 385/387 369 GB GB A19B01C17 A19B01C24 OO S 178 179 OO S 401/403 A19B01C24 A19B01C79 F NH Cl NH OO S OO S 180 181 385/387 385/387 GB GB A149B01C15 A19B01C15 Cl NH 182 183 OO S OO S 381/383 A19B01C27 A19B01C63 F NH 184 186 OO S OO S 401/403 A19B01C26 A19B01C40 Cl NH OO S OO S 191 192 381/383 A108B01C05 H NMR (400 MHz, CD3OD) δ 8.34 (m, 381/383 2H), 8.024(d, 1 H), 7.98 (d, 2H), 7.83 (s, A108B01C06 1H), 7.74 (m, 2H), 7.55 (m, 1H), 7.32 (m, 1H), 7.14(m, 1H), 4.02(m, 3H), 3.60(m, 2H), 3.16(s, 3H) O NH Cl NH O S O OO S 201 206 395/397 411/413 A18B01C05 A108B16C31 H NMR (400 MHz, CD OD) δ 8.16 (d, 2H), 8.04(br, 1 H), 7.97 (d, 2H), 7.67 (q, 1H), 7.30 (m, 2H), 4.34(m, 1H), 4.00(m, 2H), 3.50(m, 2H).

Cl NH OO S 413/415 A18B01C15 Br NH NH 210 212 OO S OO S 453/455 425/427 A109B01C31 A17B01C31 Cl F 215 216 OO S OO S 381/383 365 GB GB A17B01C02 A17B01C05 NH NH 217 217_R OO S OO S 399/411 399/411 A17B01C15 A17B01C15 217_S 219 OO S OO S 399/411 439/441 A17B01C15 A130B01C31 F NH OO S OO S 224 225 A09B01C02 A09B01C03 Cl NH OO S OO S 226 227 OH OH 423/425 423/425 A09B01C06 A09B01C05 228 229 OO S OO S OH OH 465 466 GB GB A09B01C36 A09B01C45 F NH OO S OO S 230 231 A09B01C24 H NMR (400 MHz, CD OD) δ 8.39 (s, 421 1H), 8.16(m, 2 H), 7.90 (d, 1H), 7.68 (t, A09B01C20 1H), 7.36 (m, 2H), 6.64(m, 1H),3.78 (m, 2H), 3.64 (m, 2H), 2.28 (m, 2H), 1.73 (m, 2H), 1.47 (m, 2H), 1.37 (m, 1H), 1.28 (m, 3H).

Cl NH Cl NH OO S OO S 233 234 441/443 457/459 A09B01C15 A09B01C79 F NH F NH OO S OO S 238 244 443 GB A06B01C02 A09B01C40 F NH OO S OO S 245 250 A06B01C03 A06B01C24 NH Cl NH OO S OO S 251 254 OH OH 407 427/429 GB GB A06B01C20 A06B01C15 F NH OO S OO S 258 263 A08B01C09 H NMR (400 MHz, CD OD) δ 8.33 (s, 1H), 8.23 (d, 1H), 7.98 (t, 1H), 7.78 (t, 1H), 7.59 (d, 2H),7.21(d, 2H), 3.72 (m, 1H), 3.57 (m, 1H), 3.42 (m, 1H), 2.61 (t, A06B01C40 1H), 2.47 (m, 1H), 2.36 (s, 3H), 1.85 (t, 2H), 1.61 (m, 1H), 1.27 (m, 1H) F NH O NH OO S 264 269 OO S A08B01C02 A08B01C45 OO S F NH 270 271 OO S A08B01C20 H NMR (400 MHz, CD OD) δ 8.33 (s, 1H), 8.23 (d, 1H), 8.00 (m, 1H), 7.79 (t, 1H), 7.59 (m, 1H), 7.53 (m, 1H),7.06(t, A08B01C24 1H), 3.72 (m, 1H), 3.59 (m, 1H), 3.43 (m, 1H), 2.60 (m, 1H), 2.45 (m, 1H), 3.31 (d, 3H), 1.84 (m, 2H), 1.60 (m, 1H), 1.26 (m, Cl NH F NH OO S 274 278 OO S 413/415 A08B01C15 A08B01C40 F NH F NH OO S OO S 278_E1 278_E2 A08B01C40 A08B01C40 1H NMR (400 MHz, MeOD) δ 8.33 (s, 1H NMR (400 MHz, MeOD) δ 8.33 (s, 1H), 8.23 (d, J =8.0 Hz, 1H), 8.00 (d, J 1H), 8.23 (d, J =8.0 Hz, 1H), 8.00 (d, J =8.0 Hz, 1H), 7.80 (t, J =8.0 Hz, 1H), 7.63 =8.0 Hz, 1H), 7.80 (t, J =8.0 Hz, 1H), 7.63 (m, 2H), 3.73 (m, 1H), 3.58 (m, 1H), 3.42 (m, 2H), 3.73 (m, 1H), 3.57 (m, 1H), 3.42 (m, 1H), 2.63 (m, 1H), 2.45 (m, 1H), 1.85 (m, 1H), 2.63 (m, 1H), 2.45 (m, 1H), 1.85 (m, 2H), 1.61 (m, 1H), 1.28 (m, 1H). (m, 2H), 1.61 (m, 1H), 1.28 (m, 1H).

F NH NH OO S OO S A04B01C02 A04B01C03 F NH OO S 290 291 OO S A04B01C20 A04B01C24 OO S OO S 291_E1 291_E2 A04B01C20 A04B01C20 Cl NH F NH OO S 294 298 OO S 427/429 A04B01C15 A04B01C40 F NH OO S OO S 302 304 A10B01C08 A10B01C02 Cl NH OO S OO S 305 306 395/397 A10B01C03 H NMR (400 MHz, DMSO-d6) δ 10.57(s, A10B01C05 1H), 8.26 (m, 2H), 7.94 (m, 1 H), 7.81 (m, 3H), 7.23 (m, 2H), 4.70(s, 1H), 3.47(d, 1H), 3.20(m,2H), 2.78(m, 2H), 1.76(m, 2H),1.45(m,2H) F NH OO S OO S 309 310 A10B01C24 A10B01C45 H NMR (400 MHz, DMSO-d6) δ 10.83(s, H NMR (400 MHz, DMSO-d6) δ 10.69(s, 1H), 8.25 (m, 2H), 7.96 (m, 1 H), 7.83 (m, 1H), 8.67 (m, 1H), 8.33 (m, 2H), 8.21 (m, 1H), 7.56 (m, 2H), 7.01(m, 1H), 4.68 (d, 1H), 7.96 (m, 1H), 7.87(m, 2H), 7.68 (m, 1H), 4.54(m,1H),3.17(m, 2H), 1.76(m, 2H), 7.57(m,2H), 3.53(m, 2H), 3.18(m, 2H),1.44(m,2H) 3H), 2.68(m,2H), 1.77(m,2H), 1.45(m,2H) Cl NH OO S OO S 311 314 413/415 A10B01C15 A10B01C20 F NH OO S OO S 318 N 321 A10B01C40 H NMR (400 MHz, DMSO-d6) δ 10.81(s, 466/468 1H), 8.28 (m, 2H), 7.98 (d, 1 H), 7.85 (t, A15B01C83 1H), 7.74 (m, 2H), 4.68(d,1H), 3.54(m,2H), 3.15(m, 2H), 2.81(m, 2H), 1.74(m,2H), 1.42(m,2H).

F NH F NH OO S OO S 322 328 413/415 413/415 A10B01C83 H NMR (400 MHz, DMSO-d6) δ 10.79(s, A04B01C83 1H), 8.27(d, 1H), 7.95 (m, 2 H), 7.83 (m, 1H), 7.59 (d, 2H), 3.16(d, 2H),2.77 (m, 2H), 1.73(m,2H),1.43(m, 2H), 1.17(m, 1H) NH F NH OO S OO S 329 331 A20B01C08 A20B01C02 F NH OO S 332 335 OO S A20B01C03 A20B01C24 336 337 OO S OO S 387/389 387/389 A20B01C15 A20B01C83 F NH OO S 338 341 OO S A50B01C02 A20B01C20 Cl NH OO S OO S 342 343 383/385 A50B01C05 A50B01C03 F NH NH 345 347 OO S OO S 401/403 A50B01C24 A50B01C15 F NH OO S 348 351 OO S A51B01C02 A50B01C20 F NH 352 355 OO S OO S 379 397 GB GB A51B01C24 A51B01C02 NH NH 356 357 OO S OO S 413/415 413/415 A51B01C15 A51B01C83 Br NH OO S 358 359 OO S 444/446 A51B01C20 A52B01C31 Br NH OO S 360 361 427/429 457/459 A53B01C31 A58B01C31 Br NH Cl NH OO S OO S 363 366 399/411 471/473 A52B01C05 A55B01C31 Cl NH Cl NH OO S OO S 371 372 OH O 383/385 397/399 A56B01C05 A57B01C05 Cl NH Cl NH OO S OO S 373 374 417/419 431/433 A52B01C15 A58B01C15 Cl NH Cl NH OO S OO S 375 376 401/403 401/403 GA GA A53B01C15 A54B01C15 O N NH O N NH OO S OO S 380 383 A19B01C46 A10B01C46 O N NH O N NH 386 387 OO S OO S A17B01C46 A06B01C46 H NMR (400 MHz, CD OD) δ 10.91 (s, 1H), 8.68(d, 1 H), 8.32 (d, 1H), 8.26 (m, 1H), 798 (m, 2H), 7.75(t, 1H), 7.64(m, 1H), 4.48(s, 1H) 3.62(m, 2H), 3.28(m, 2H), 2.25(m, 2H), 1.72(m, 2H), 1.32(m, 1H), 1.16(m, 2H) .

O N NH 2 F C NH OO S 388 390 OO S A08B01C46 A18B01C47 F C NH F C NH OO S OO S 391 392 A20B01C47 A10B01C47 F C NH F C NH OO S OO S 395 396 A17B01C47 A06B01C47 O NH O NH OO S OO S 398 401 A19B01C48 A10B01C48 O NH OO S O NH OO S 404 405 A06B01C48 H NMR (400 MHz, CD OD) δ 10.91 (s, 1H), 8.68(d, 1 H), 8.32 (d, 1H), 8.26 (m, A17B01C48 1H), 798 (m, 2H), 7.75(t, 1H), 7.64(m, 1H), 4.48(s, 1H), 3.85(s, 3H), 3.62(m, 2H), 3.28(m, 2H), 2.25(m, 2H), 1.72(m, 2H), 1.32(m, 1H), 1.16(m, 2H) .

Br NH O NH OO S OO S 406 407 429/431 A08B01C48 A19B01C49 Br NH Br NH OO S 408 410 OO S 457/459 OH GA 457/459 A18B01C49 GA A10B01C49 Br NH Br NH O OO S OO S 411 412 471/473 48/487 A04B01C49 A09B01C49 Br NH NC NH OO S 415 OO S 417 457/459 A18B01C52 A08B01C49 NC NH OO S NC NH OO S 418 419 A10B01C52 H NMR (400 MHz, CD OD) δ 10.84 (s, 1H), 8.68(d, 1 H), 8.32 (d, 1H), 8.26 (m, A20B01C52 1H), 798 (m, 2H), 7.75(t, 1H), 7.64(m, 1H), 4.68(s, 1H), 3.52(m, 2H), 3.14(m, 2H), 2.79(m, 2H), 1.74(m, 2H), 1.42(m, 2H).

NC NH OO S OO S 420 425 A04B01C52 A19B01C51 OO S OO S 427 428 A20B01C51 A10B01C51 435 436 OO S OO S 418 392 GA GA A18B01C52 A20B01C52 OO S OO S A17B01A52 GA 1 H NMR (400 MHz, CD OD) δ 8.37 (s, A04B01C52 1H), 8.21(d, 1 H), 8.04 (d, 1H), 7.88 (m, 1H), 7.76 (m, 2H), 7.18(t, 1H), 4.28(m, 1H), 3.92(s, 2H) 3.40(m, 3H), 3.24(m, 1H), 1.88(m, 1H), 1.76(m, 1H).

OO S OO S N 447 448 A19B01C55 A09B01C55 Cl NH Cl NH OO S OO S 455 458 496/498 480/482 A64B01C15 A61B01C15 Br NH OO S OO S 463 467 506/508 GA GA A65B01C31 A65B01C20 OO S 468 OO S 471 460 379 A66B01C20 A17B01C20 OO S 472 473 OO S A18B01C20 A49B01C20 Cl NH OO S 474 N 477 OO S 441/443 A109B01C20 A67B01C15 Br NH OO S OO S 478 479 467/469 A67B01C20 A67B01C31 Cl NH 482 489 OO S OO S 443 455/457 GA GA A67B01C40 A68B01C15 Cl NH NH OO S OO S 501 N 502 443/445 A81B01C20 A81B01C15 Br NH NH OO S OO S N 503 N 505 469/471 A81B01C08 A81B01C31 N Cl O SO F NH OO S 506 507 A82B011C15 OH 1 H NMR (400 MHz, CDCl ) δ 8.21 (s, 1H), 8.19 (d, 1 H), 8.07 (s, 1H), 7.96 (d, 1H), 7.91 (m, 1H), 7.72 (t, 1H), 7.51 (m, 1H), 7.19 (t, 1H), 3.62(d, 2H), 3.36 (s, A81B01C40 3H), 3.28(s, 2H), 3.18 (s, 3H), 2.62 (t, 2H), 1.87(d, 2H), 1.65(d, 2H). 520 521 448/450 A19B05C93 A19B10C31 NH NH 522 523 O S O O S O 421/423 A19B10C15 A19B10C20 F NH 524 526 OO S O S O A17B01C40 A19B10C03 F NH F NH 527 528 OO S OO S A50B01C40 A20B01C40 Cl NH NH OO S OO S 529 530 OH OH 427/429 407 A73B01C15 A73B01C20 Cl NH F NH OO S OO S 531 541 489/491 A75B01C15 A73B01C40 H NMR (400 MHz, CD OD) δ 10.73 (s, H NMR (400 MHz, CD OD) δ 8.30 (s, 1H), 8.33(m, 2 H), 8.04 (d, 2H), 7.38 (t, 1H), 1H), 8.23(d, 1 H), 7.98 (d, 1H), 7.76 (t, 1H), 7.24 (m, 1H), 7.46(m, 3H), 7.33 (m, 2H), 7.58 (m, 2H), 3.48(m, 2H), 2.74 (m, 2H), 7.19(m, 1H), 4.85 (s, 1H), 3.63 (m, 2H), 2.63 1.61(m, 4H), 1.16 (s, 3H). (m, 2H), 1.95 (m, 2H), 1.63 (m, 2H) Br NH Cl NH OO S OO S 544 545 471/473 515/517 A75B01C05 A75B01C31 O SO OO S 546 547 503/505 451 GA GA A79B01C15 A75B01C05 Cl NH OO S OO S 553 554 517/519 A69B01C15 A69B01C20 F NH OO S OO S 555 558 A69B01C08 A69B01C40 Cl NH Cl NH OO S OO S 559 568 531/532 485/487 A72B01C15 A76B01C05 Cl NH Br NH O OO S OO S N OH 569 577 441/443 A74B01C15 529/531 H NMR (400 MHz, CD OD) δ 8.32 (s, 1H), 8.19(d, 1 H), 7.98 (m, 2H), 7.76 (t, A76B01C31 1H), 7.53(m, 1H), 7.23 (t, 1H), 3.55 (m, 2H), 2.68 (m, 2H), 1.58 (m, 4H), 1.42 (q, 2H), 0.84 (t, 3H).

F NH OO S OO S 578 579 A74B01C20 A74B01C40 N Cl O SO Br NH OO S 583 587 455/457 A78B01C15 H NMR (400 MHz, CD OD) δ 8.33 (s, 481/483 1H), 8.25(d, 1 H), 8.00 (d, 2H), 7.80 (t, GA A78B01C31 1H), 7.68(m, 1H), 7.30 (t, 1H), 3.58 (d, 2H), 3.01 (s, 3H), 2.62 (t, 2H), 1.85 (d, 2H), 1.55 (m, 4H), 0.84 (t, 3H).

Cl NH F NH OO S OO S 589 N 593 455/457 A10B01C63 A83B01C15 F NH OO S 594 595 431/432 447/449 A10B01C57 A10B01C58 Cl NH Cl NH OO S OO S N 596-D1 N 596-D2 OH OH 441/443 441/443 GA GA A85B01C15 A85B01C15 597_D1 597_D2 OO S OO S OH OH 421 421 GA GA A85B01C20 A85B01C20 H NMR (400 MHz, CD OD) δ 8.29 (s, H NMR (400 MHz, CD OD) δ 8.29 (s, 1H), 8.20(m, 1 H), 7.94 (m, 1H), 7.72 (m, 1H), 8.20(m, 1 H), 7.94 (m, 1H), 7.72 (m, 1H), 7.50(m, 2H), 7.01 (t, 1H), 3.57 (m, 1H), 7.50(m, 1H), 7.48 (m, 1H), 7.01 (t, 2H), 3.23 (m, 1H), 2.68 (m, 1H), 2.39 (m, 1H), 3.82 (m, 1H), 3.37 (m, 1H), 3.30 (m, 1H), 2.26 (s, 3H), 1.92 (m, 1H), 1.73 (m, 1H), 2.80 (m, 1H), 2.54 (m, 1H), 2.26 (s, 1H), 1.53 (m, 1H), 1.42 (m, 1H), 1.19 (m, 3H), 1.76 (m, 2H), 1.56 (m, 1H), 1.39 (m, 1H), 0.91 (t, 3H). 1H), 1.27 (m, 1H), 0.91 (t, 3H).

NH NH OO S OO S N 601_D1 601_D2 403 403 GA GA A85B01C08 A85B01C08 Cl NH Cl NH OO S OO S 608_D1 608_D2 427/429 427/429 A84B01C15 A84B01C15 F NH F NH OO S OO S 610_D1 610_D2 OH OH 429 429 GA GA A84B01C40 A84B01C40 OO S OO S 615_D1 615_D2 A87B01C20 A87B01C20 H NMR (400 MHz,CDCl3): δppm: 8.17 - 8.13 (m, 2H), 7.99 (s, 1H), 7.90 (d,1H), 7.70 - 7.66 (m, 1H), 7.54 (d, 1H), 7.42 (t, 1H), 7.00 (t, 1H), 3.46 - 3.42(m,2H), 3.38 (s,3H),2.80 - 2.70 (m,2H), 2.45 - 2.40 (m, 1H), 2.40 (s, 1H), 2.07 - 2.00 (m, 1H), 1.85 - 1.81 (m, 1H), 1.57 - 1.54 (m, 1H), 1.00 - 0.99 (m, 3H).

OO S OO S 620 621 427/429 A131B01C15 A108B01C40 OO S 622 623 A52B01C40 A131B01C40 F F NH F NH OO S OO S OH 624 625 A53B01C40 1H NMR (400 MHz, CDCl3) δ 8.25 (s, 1H), 8.14 (d, J =7.6 Hz, 1H), 7.91 (d, J =7.6 Hz, 1H), 7.64 (t, J =7.6 Hz, 1H), 7.49 A58B01C40 (m, 1H), 7.29 (s, 1H), 3.94 (m, 1H), 3.33 (s, 1H), 3.04 (m, 1H), 2.92 (m, 1H), 2.83 (s, 3H), 1.16 (m, 3H).

F NH 626 627 OOO S OO S A55B01C40 A54B01C40 F NH OO S 628 629 OO S A GA 56B01C40 A57B01C40 OO S 630 631 414/416 A49B01C59 A10B01C15 632_R OO S 632_S A18B01C59 A18B01C59 633 634 A10B01C59 H NMR (400 MHz,CDCl3): δppm: 8.20 (s, 1H), 8.15 - 8.13 (m, 1H), 8.07 (s, 1H), 7.94 - 7.92 (m, 1H), 7.74 - 7.63 (m, A20B01C59 3H),7.44 - 7.41 (m, 1H), 7.21 - 7.19 (m, 1H), 5.42 (d, 2H), 3.81 (m, 1H), 3.34 - 3.29 (m, 2H), 2.98 - 2.92 (m, 2H), 1.96 - 1.89 (m, 2H), 1.71 - 1.62 (m, 2H), 1.42 (m,1H).

OO S 641 642 A69B01C59 A75B01C59 644_D2 645 A85B01C59 A81B01C59 646 GA 647_R A18B01C60 H NMR (400 MHz,CDCl3): δ ppm: 8.64 A19B01C60 1 (s, 1H), 8.31 (s, 1H), 8.17 (d, 1H), 7.96 (d, H NMR (400 MHz,CDCl3): δ ppm: 8.34 1H), 7.74 - 7.64 (m, 3H), 7.10 - 7.05 (m, (s, 1H), 8.27 (s, 1H), 8.18 (d, 1H), 7.98 (d, 1H), 7.42 - 7.38 (m, 1H), 5.45 (d, 2H), 1H), 7.73 - 7.67 (m, 3H), 7.11 (t, 1H), 5.47 3.68 - 3.65 (m, 3H), 3.47 - 3. 41 (m, 1H), (d, 2H), 4.49 (m, 1H), 4.06 - 4.02 (m, 2H), 3.27 - 3.21 (m, 1H), 2.88 (br, 1H), 1.85 - 3.63 - 3.59 (m, 2H), 2.51 (br, 2H). 1.76 (m, 2H), 1.74 - 1.64 (m, 2H). 649 650 A04B01C60 A10B01C60 651 652 A06B01C60 A09B01C60 OO S 655 661 A19B01C61 A73B01C60 A18B01C61 662_R OO S 662_S H NMR (400 MHz,CDCl3): δ ppm: 8.38 - 8.35 (m,1H), 8.23 - 8.21 (m,1H), 8.17 (d, 1H), 8.05 - 8.03 (m, 1H), 7.92 (s, 1H), 7.82 (d,1H), 7.75 - 7.51 (m, 1H), 7.74 - 7.64 (m, A18B01C61 3H), 7.10 - 7.05 (m, 1H),7.42 - 7.38 (m, 1H), 5.45 (d, 2H), 3.68 - 3.65 (m, 3H),3.47 - 3. 41 (m, 1H), 3.27 - 3.21 (m, 1H), 2.88 (br, 1H), 1.85 - 1.76 (m, 2H), 1.74 - 1.64 (m, 2H). 663 664 A20B01C61 A10B01C61 667 668 A17B01C61 A06B01C61 675 676 441 O GA 401 A81B01C61 GA A19B01C62 N O N O 677_R 677_S A18B01C62 A19B01C62 678 679 A10B01C62 H NMR (400 MHz, CDCl ) 8.23 ( s, 1H), 8.17- 8.18 ( d, 2H), 7.95- 7.97 ( d, J= 8.0 Hz, 1H), 7.88- 7.89 (d, J= 5.2 Hz, 2H), A20B01C62 7.40- 7.74 ( m, 1H), 7.18-7.23 ( t, J= 18.8 Hz, 1H),6.79- 7.07 ( t, J= 29.6 Hz 1H), 3.82- 3.85 ( m, 1H), 3.30- 3.35 ( m, 2H), 2.96- 3.02 ( m, 2H), 1.92- 1.98 ( m, 2H), 1.61- 1.73 ( m, 2H), 1.42 ( s, 1H).

OO S 680 N 690 A04B01C62 A81B01C62 Cl NH O SO OO S 694 695 457/459 A90B01C20 A90B01C15 F NH O SO OO S 696 700_R A18B01C63 A90B01C40 F NH F NH OO S OO S 700_S 705 A18B01C63 A17B01C63 706 708 397/399 A10B01C58 A75B01C63 F NH OO S O SO 709 712 A81B01C63 A69B01C63 Cl NH Cl NH OO S OO S 713_D1 713-D2 503/505 503/505 A86B01C15 A86B01C15 O SO OO S 714_D1 715_D2 A86B01C20 A86B01C40 Cl NH N Cl O SO OO S 716_D1 719_D1 443/445 485/487 A103B01C15 A86B01C05 Cl N O SO O SO 719_D2 720_D1 443/445 A103B01C20 A103B01C15 O SO O SO 720_D2 N 721_D1 A103B01C20 A103B01C40 O SO N Cl O SO 724_D2 725_D1 A103B01C08 H NMR (400 MHz, CD3OD) δ 8.33 (s, 443/445 1H), 8.24(d, 1 H), 8.02 (d, 1H), 7.80 (t, 1H), 7.58 (m, 2H), 7.29 (t, 1H), 7.03 (d, 1H), A104B01C15 4.61 (s, 2H), 3.91 (s, 1H), 3.67 (m, 1H), 3.60 (m, 1H), 3.53 (m, 2H), 2.80 (m, 1H), 2.61 (t, 1H), 2.38 (s, 3H), 1.91 (m, 1H), 1.76 (m, 2H).

N Cl O SO O SO 725_D2 726_D1 443/445 A104B01C15 H NMR (400 MHz, CD OD) δ 8.34 (s, 1H), 8.25(d, 1 H), 8.00 (m, 2H), 7.78 (t, 1H), 7.67 (m, 1H), 7.27 (t, 1H), 3.88 (m, A104B01C20 1H), 3.80 (m, 1H), 3.75 (m, 1H), 3.56 (m, 2H), 2.34 (t, 1H), 2.13 (t, 1H), 1.90 (m, 1H), 1.48 (m, 1H), 1.33 (m, 1H).

O SO O SO 726_D2 727_D1 A104B01C20 A104B01C40 O SO N Br O SO 727_D2 729_D2 A104B01C40 H NMR (400 MHz, CD OD) δ 8.34 (s, 469/471 1H), 8.25(d, 1 H), 8.03 (d, 1H), 7.82 (t, A104B01C31 1H), 7.65 (m, 2H), 3.91 (m, 1H), 3.82 (m, 1H), 3.73 (m, 1H), 3.57 (m, 2H), 2.35 (t, 1H), 2.13 (m, 1H), 1.89 (m, 1H), 1.47 (m, 1H), 1.31 (m, 1H).

Cl NH O SO 731 741 O SO 485/487 455/457 GA GA A92B01C15 A93B01C15 O SO O SO 742 743_D1 A93B01C20 H NMR (400 MHz, CD3OD) δ 8.31 (m, 1H), 8.22 (d, 1H), 7.98 (m, 1H), 7.76 (m, 1H), 7.61 (d, 1H), 7.55 (m, 1H), 7.03 (t, A93B01C40 1H), 3.70 (m, 4H), 2.52 (d, 1H), 2.31 (s, 3H), 1.92 (m, 2H), 1.50 (m, 4H) , 1.10 (m, 4H).

O SO O SO 743_D2 747_D1 455/457 A95B01C15 A93B01C40 Cl N O SO O SO 747_D2 748_D1 455/457 435 A95B01C20 A95B01C15 H N F O SO O SO 748_D2 749_D1 435 457 GA GA A95B01C20 A95B01C40 N Br O SO O SO 749_D2 751_D1 481/483 A95B01C31 A95B01C40 O SO O SO 751_D2 N 753 481/483 A95B01C31 443/445 H NMR (400 MHz, CD OD) δ 8.37 (s, 1H), 8.22 (d, 1H), 8.06 (m, 2H), 7.78 (t, A17B01C49 1H), 7.68 (d, 1H), 7.33 (m, 2H), 3.86 (m, 1H), 3.55 (m, 2H), 3.22 (m, 1H), 3.05 (m, 1H), 1.82 (m, 1H), 1.75 (d, 1H), 1.47 (m, 3H), 1.36 (d, 3H), 1.23 (m, 2H).

N Br O SO O SO 754 755 533/535 471/473 A75B01C49 A73B01C49 1 H NMR (400 MHz, CD OD) δ 8.39 (s, H NMR (400 MHz, CD OD) δ 8.34 (s, 1H), 8.26(d, 1H), 8.15 (m, 1H), 8.07 (d, 1H), 8.25(d, 1H), 8.14 (m, 1H), 8.02 (d, 1H), 7.84 (t, 1H), 7.74 (m, 1H), 7.47 (m, 1H), 7.79 (t, 1H), 7.70 (m, 1H), 7.27 (t, 2H), 7.28(t, 2H), 7.25 (m, 2H), 3.77 (m, 1H), 3.53 (m, 2H), 2.77 (m, 2H), 1.68 (m, 2H), 2.87 (t, 2H), 2.19 (m, 2H), 1.77 (d, 4H), 1.19 (s, 3H). 2H).

N Br Br O SO O SO 756_D1 756_D2 471/473 471/473 GA GA A84B01C49 A84B01C49 O SO O SO 757 758 487/489 485/487 A81B01C49 A67B01C49 Br NH Br NH O SO O SO 759 760 533/535 533/535 A98B01C31 A97B01C31 F NH Br NH O SO O SO 761 765 OH OH 533/535 F GA 509 A99B01C31 GA A97B01C40 1H NMR (400 MHz, DMSO) δ 10.85 (s, 1H), 8.31 (t, J = 2 Hz, 2H), 8.04 (d, J = 8.0 Hz, 1H), 7.90 (t, J = 8.0 Hz, 1H), 7.74 (dd, J = 6.8, 10.4 Hz, 2H), 7.47 (m, 2H), 7.13 (t, J = 8.8 Hz, 2H), 5.03 (s, 1H), 3.62 (d, J = 10.8 Hz, 2H), 2.62 (t, J = 10.8 Hz, 2H), 1.99 (m, 2H), 1.66 (d, J = 13.2 Hz, 2H).

F NH O SO F NH O SO 766 N 767 A98B01C40 1H NMR (400 MHz, DMSO) δ 1H NMR (400 MHz, DMSO) δ 8.31 (m, 2H), 8.04 509 (d, J = 7.4 Hz, 1H), 7.90 (t, J = 8.0 Hz, GA A99B01C40 1H), 7.74 (dd, J = 6.8, 10.4 Hz, 2H), 7.47 (m, 2H), 7.03 (m, 1H), 5.11 (s, 1H), 3.62 (d, J = 11.2 Hz, 2H), 2.62 (t, J = 11.2 Hz, 2H), 2.03 (dt, J = 4.0,12.8 Hz, 2H), 1.66 (d, J = 12.8 Hz, 2H).

F NH O SO F NH O SO 768 N 769 A100B01C40 1H NMR (400 MHz, MeOD) δ 10.38 (m, 1H), 8.26 (d, J = 7.6 Hz, 1H), 8.06 (d, J = 8.4Hz, 1H), 7.83 (t, J = 8.0 Hz, 1H), 7.65 A101B01C40 (m, 2H), 7.38 (m, 1H), 7.26 (m, 2H), 3.76 (dd, J = 2, 9.2 Hz, 2H), 2.62 (dt, J = 2, 12 Hz, 2H), 2.23 (dt, J = 4.8, 9.2 Hz, 2H), 1.66 (d, J = 12.4 Hz, 2H).

Cl NH O SO O SO 770 771 507/509 A97B01C15 A102B01C40 Cl NH O SO Cl NH O SO 772 773 507/509 A99B01C15 1H NMR (400 MHz, DMSO) δ 10.73 (s, 1H), 8.33 (m, 2H), 8.08 (dd, J = 2.8, 6.8 507/509 Hz, 1H), 8.03 (d, J = 6.8 Hz, 1H), 7.90 (t, J = 8.0 Hz, 1H), 7.75 (m, 1H), 7.57 (m, 1H), A98B01C15 7.46 (t, J = 9.2 Hz, 1 H), 7.29 (m, 1H), 7.16 (m, 2H), 5.23 (s, 1H), 3.62 (d, J = .8 Hz, 2H), 2.62 (t, J = 10.8 Hz, 2H), 2.23 (m, 2H), 1.66 (d, J = 13.2 Hz, 2H).

Cl NH Cl NH O SO O SO 774 775 525/527 A100B01C15 525/527 1H NMR (400 MHz, MeOD) δ 8.46 (s, 1H), A101B01C15 8.27 (d, J =8.0 Hz, 1H), 8.03 (m, 2H), 7.82 (t, J = 8.0 Hz, 1H), 7.68 (m, 1H), 7.37 (m, 1H), 7.24 (m, 3H), 3.76 (dd, J = 2, 8.8 Hz, 2H), 2.62 (dt, J = 2, 12 Hz, 2H), 2.13 (dt, J = 4.4,13.2 Hz, 2H), 1.77 (d, J = 12.4 Hz, 2H).

F NH F Cl N OO S O SO 776 777 A10B02C40 525/527 H NMR (400 MHz, MeOD) δ 8.13 (m, 1H), 8.01 (m, 1H), 7.56 (m, 3H), 3.68 (m, A102B01C15 1H), 3.40 (m, 2H), 2.89 (m, 2H), 1.91 (m, 2H), 1.61 (m, 2H).

O SO O SO 785 786 469/471 449 GA GA A94B01C15 A94B01C20 N F N F O SO O SO 787_D1 787_D2 471 471 GA GA A94B01C40 A94B01C40 792 793 A96B01C20 H NMR (400 MHz, CDCl ) 8.25 ( s, 1H), 8.00- 8.12 ( m, 1H), 7.94- 7.98 ( m, 2H), 7.66- 7.70 (m, 1H), 7.55- 7.56 ( m, 1H), 7.42-7.44 ( m, 1H), 7.02- 7.07 ( t, J= 17.6 GA Hz, 1H), 3.86- 3.92 ( m, 1H), 3.18- 3.38 ( A96B01C40 m, 2H), 3.16 ( s, 3H), 3.12- 3.20 ( m, 1H), 2.93- 2.99 ( m, 1 H), 2.33-2.35 (d, J= 1.6 Hz, 3H), 1.72- 1.82 ( m, 2H), 1.50-1.55 ( m, 3H), 1.49- 1.58 ( m, 5H).

NH F NH O SO O SO 797 799 471/473 473 A91B01C15 A91B01C40 OO S 803 804_R OO S A19B01C65 H NMR (400 MHz, MeOD) δ 8.41 (m, 1H), 8.31 - 8.30 (m, 1H), 8.09 - 8.07 (m, 1H), 7.92 - 7.91 (m, 1H), 7.83 (m, 1H), A18B01C65 7.63 - 7.62 (m, 1H), 5.58 (s, 1H), 5.46 (s, 1H), 4.45 - 4.39 (m, 1H), 4.05 - 4.03 (m, 2H), 3.56 (m, 2H). 804_S 805 OO S OO S A18B01C65 A20B01C65 OO S 806 807 OO S A04B01C65 A10B01C65 NH F OO S OO S 808 809 A06B01C65 A09B01C65 Br NH O SO 810 818_D2 OO S N 475/477 A111B01C49 A17B01C65 F NH F NH O SO O SO 819_D1 819_D2 A111B01C63 OH H NMR (400 MHz, CD OD) δ 8.38 (s, 415 1H), 8.25 (d, J = 8 Hz, 1H), 8.05 (d, J = A111B01C63 2.4 Hz, 1H ), 7.79 (m, 1H), 7.69 (s, 1H), 7.45 (m, 1H), 7.25 (m, 1H), 4.71 (m, 1H), 3.70 (m, 2H), 3.45 (m, 1H), 3.15 (m, 1H), 2.93 (m, 1H), 1.86 (m, 2H) O SO O SO 820_D1 820_D2 A111B01C62 A111B01C62 F NH F NH O SO O SO 821_D1 821_D2 A111B01C40 H NMR (400 MHz, CD OD) δ 8.40 (s, 433 1H), 8.25 (d, J=7.6 Hz, 1H), 8.08 (d, J=7.6 A111B01C40 Hz, 1H), 7.80 (m, 1H), 7.65 (m, 2H), 4.70 (m, 1H), 3.75 (m, 2H), 3.45 (m, 1H), 3.15 (m, 1H), 2.90 (m, 1H), 1.78 (m, 2H) Cl NH Cl NH 822_D1 822_D2 O SO O SO 431/433 431/433 GA GA A111B01C15 A111B01C15 O SO O SO 824_D1 824_D2 A111B01C64 A111B01C64 NH NH O SO O SO 825_D1 825_D2 OH OH 447 447 GA GA A111B01C64 A111B01C64 Br NH F NH O SO O SO 826 HF O 827 HF O 461/463 A110B01C63 A110B01C49 H NMR (400 MHz, CD OD) δ 8.41 (d, H NMR (400 MHz, CD OD) δ 8.30 (s, 3 J=2Hz, 1H), 8.25 (m, 1H), 8.05 (m, 1H), 1H), 8.14 (d, J=7.6Hz, 1H), 8.05 (m, 2H), 7.60 (m, 2H), 7.45 (m, 1H), 7.25 (m, 1H), 7.65 (m, 2H), 7.15 (m, 1H), 4.65 (m, 1H), 4.75 (m, 1H), 4.25 (m, 1H), 3.60 (m, 2H), 4.15 (m, 1H), 3.55 (s, 1H), 3.48 (m, 1H), 3.51 (m, 1H), 3.40 (m, 1H) 3.36 (m, 1H), 3.28 (s, 1H).

O SO 828 829 OO S HF O A110B01C62 A110B01C40 Cl NH O SO O SO 830 834_D1 HF O 417/419 A110B01C15 H NMR (400 MHz, CD OD) δ 8.41 (s, 487/485 1H), 8.25 (d, J=8 Hz, 1H ), 8.01 (m, 2H), 7.75 (m, 1H), 7.60 (m, 1H), 7.21 (m, 1H), A85B01C49 4.75 (m, 1H), 4.24 (m, 1H), 3.66 (m, 1H), 3.57 (m, 1H), 3.45 (m, 1H), 3.36 (m, 1H).

Br NH Br NH O SO O SO 835 843 443/441 457/459 A112B01C49 A113B01C49 F NH O SO 844 846 O SO A113B01C63 A113B01C40 Cl NH O SO O SO 847 848 413/415 A113B01C15 H NMR (400 MHz, CD OD) δ 8.45 (s, A113B01C20 1H), 8.18 (d, 1H), 8.12 (d, 1H), 8.01 (d, 1H), 7.72 (t, 1H), 7.65 (m, 1H), 7.27 (t, 1H), 3.95 (m, 1H), 3.33 (m, 1H), 1.86 (m, 2H), 1.66 (m, 2H), 1.52 (m, 1H), 1.36 (m, 1H).

F NH O SO O SO 849 854 A113B01C64 H NMR (400 MHz, MeOD) δ8.47 (s, 1H), 8.20 - 8.03 (m, 3H), 7.77 - 7.73 (m, 2H), 7.20 - 6.93 (t, 1H), 3.97 - 3.93 (m, 1H), 3.40 - 3.39 (m, 1H), 1.94 - A114B01C40 1.84(m, 2H), 1.68 - 1.63(m, 2H), 1.55 - 1.49 (m, 1H), 1.40 - 1.34(m, 1H).

O SO 459/457 A114B01C49 H NMR (400 MHz, CD OD) δ 8.42 (m, 1H), 8.19 (m, 1H), 8.13 (m, 1H), 8.08 (m, 1H), 7.76 (t, 1H), 7.70 (m, 1H), 7.25 (t, 1H), 4.13 (m, 1H), 3.65 (m, 1H), 2.08 (m, 1H), 1.69 (m, 4H), 1.36 (m, 1H).

Cl NH 862 O SO 863 O SO 413 411/413 GA GA A115B01C40 A115B01C15 Br NH Br NH O SO O SO 867_D1 867_D2 473,471 473,471 A116B01C49 A116B01C49 H NMR (400 MHz, CD OD) δ 8.45 (m, H NMR (400 MHz, CD OD) δ 8.46 (m, 1H), 8.18 (d, 1H), 8.14 (m, 1H), 8.10 (m, 1H), 8.18 (m, 1H), 8.14 (m, 1H), 8.11 (m, 1H), 7.76 (t, 1H), 7.69 (m, 1H), 7.27 (t, 1H), 7.76 (t, 1H), 7.70 (m, 1H), 7.27 (t, 1H), 3.46 (m, 1H), 3.17 (m, 1H), 1.98 (m, 1H), 3.96 (m, 1H), 3.55 (m, 1H), 1.68 (m, 1H), 1.85 (m, 1H), 1.69 (m, 2H), 1.20 (m, 3H), 1.50 (m, 4H), 1.29 (m, 1H). 4H).

F NH O SO O SO 868_D1 871_D1 427/429 A116B01C15 H NMR (400 MHz, CD OD) δ 8.44 (s, 1H), 8.18 (d, 1H), 8.08(d, 1H), 8.00 (m, 1H), 7.76 (t, 1H), 7.65 (m, 1H), 7.30 (t, A116B01C63 1H), 3.47 (m, 1H), 3.16 (m, 1H),1.94 (m, 1H), 1.82 (m, 1H), 1.69 (m, 1H), 1.16 (m, 4H).

Cl NH O SO O SO 871_D2 872_D1 427/429 A116B01C15 H NMR (400 MHz, CD OD) δ 8.45 (s, 1H), 8.18 (d, 1H), 8.11 (d, 1H), 8.01 (m, A116B01C20 1H), 7.76 (t, 1H), 7.65 (m, 1H), 7.30 (t, 1H), 3.96 (m, 1H), 3.53 (m, 1H),1.59 (m, 3H), 1.48 (m, 4H), 1.29 (m, 1H).

Br NH O SO O SO 872_D2 O 875 473/471 A117B01C49 H NMR (400 MHz, CD OD) δ 8.43 (s, 1H), 8.18 (d, 1H), 8.14 (m, 1H), 8.08 (d, A116B01C20 1H), 7.76 (m, 2H), 7.27 (t, 1H), 3.46 (m, 1H), 3.07 (m, 1H), 1.87 (m, 2H), 1.76 (m, 2H), 1.27 (m, 4H).

F NH F NH O SO 876 878 O SO A117B01C63 H NMR (400 MHz, CD3OD) δ 8.43 (s, 1H), 8.18 (d, 1H), 8.08(d, 1H), 7.87 (m, GA 1H), 7.76 (t, 1H), 7.48 (m, 1H), 7.30 (m, A117B01C40 1H), 3.47 (m, 1H), 3.07 (m, 1H),1.87 (m, 2H), 1.77 (m, 2H), 1.27 (m, 4H).

O SO O SO 879 881 A117B01C64 427/429 H NMR (400 MHz, MeOD) δ8.45 (s, 1H), 8.20 - 8.02 (m, 3H), 7.77 - 7.73 (m, 2H), A117B01C15 7.20 - 6.92 (t, 1H), 3.49 - 3.44 (m, 1H), 3.11 - 3.05 (m, 1H), 1.87 - 1.75 (m, 4H), 1.34 - 1.22(m, 4H).

O SO N N F HO H 882 883 GA 379 A117B01C65 GA A10B13C40 H NMR (400 MHz, MeOD) δ8.44 (s, 1H), 8.19 - 8.17 (m, 1H), 8.11 - 8.09 (m, 1H), 7.93 - 7.89 (m, 1H), 7.77 - 7.73 (m, 1H), 7.61 (m, 1H), 5.58(s, 1H), 5.46(s, 1H), 3.49 - 3.44 (m, 1H), 3.11 - 3.05 (m, 1H), 1.88 - 1.75(m, 4H), 1.34 - 1.19(m, 4H).

NH F O SO 385 431/433 A10B01C87 A10B02V15 H NMR (400 MHz, CD OD) δ 8.14 (m, 1H), 8.02 (m, 2H), 7.62 (m, 1H), 7.53 (t, 1H), 7.27 (t, 1H), 3.67 (m, 1H), 3.39 (m, 2H), 2.88 (m, 2H), 1.92 (m, 2H),1.63 (m, 2H).

NH Cl NH F O SO OO S 886 887 475/477 449/451 A10B02C49 A10B02C58 NH F NH F OO S O SO 888 889 A10B02C64 A10B02C63 O SO 890 891 A10B03C40 H NMR (400 MHz, CDCl3) δ 9.71 (s, 431/433 1H), 8.31 (dd, J = 2.0, 6.4 Hz, 1H), 8.21 (m, 1H), 7.49 (dd, J = 6.4, 9.6 Hz, 1H), A10B03C15 7.35 (t, J = 8.8 Hz, 1H), 3.82 (m, 1H), 3.49 (m, 2H),3.12 (m, 2H), 1.92 (m, 2H), 1.66 (m, 2H).

O SO O SO 892 893 449/451 A10B03C58 475/477 H NMR (400 MHz, CD OD) δ 8.44 (m, 1H), 8.27 (m, 1H), 7.74 (m, 2H), 7.55 (t, A10B03C49 1H), 3.76 (m, 1H), 3.58 (s, 2H), 3.06 (m, 2H), 1.93 (m, 2H), 1.60 (m, 2H).

OO S O SO 894 895 A10B03C64 H NMR (400 MHz, MeOD) δ8.46 - 8.44 (m, 1H), 8.30 - 8.27 (m, 1H), 8.05 - 8.01 A10B03C63 (m, 1H), 7.76 (m, 1H), 7.54 - 7.50 (m, 1H),7.19 - 6.92(t, 1H), 3.77 - 3.73 (m, 1H), 3.59 - 3.56 (m, 2H), 3.10 - 3.04(m, 2H), 1.94 - 1.90(m, 2H), 1.64 - 1.56(m, 2H).

NH N OO S OO S 896 898_D1 OH O 447 447 GA GA A10B03C65 A84B03C40 F N F OO S O SO 898_D2 899_D1 A84B03C40 A85B03C40 899_D2 900 OO S O SO 461 461 GA GA A85B03C40 A09B03C40 O SO 901 902 OO S A19B03C40 A114B03C40 OO S 903 904_R OO S A17B03C40 H NMR (400 MHz, CD OD) δ 8.37 (m, A18B03C40 1H), 8.14 (m, 1H), 7.50 (m, 2H), 7.37 (t, 1H), 4.27 (m, 1H), 3.43 (m, 3H), 3.28 (m, 1H), 1.92 (m, 1H), 1.78 (m, 1H).

OO S 904_S 907 OO S A75B03C40 H NMR (400 MHz, CD OD) δ 8.48 (m, A18B03C40 1H), 8.31 (m, 1H), 7.64 (m, 3H), 7.49 (m, 2H), 7.36 (m, 2H), 7.26 (m, 1H), 3.83 (m, 2H), 3.14 (m, 2H), 2.18 (m, 2H), 1.83 (m, F NH OO S 908 916 O SO A81B03C40 H NMR (400 MHz, CD OD) δ 8.44 (m, A110B03C40 1H), 8.26 (m, 1H), 7.63 (m, 2H), 7.52 (t, 1H), 3.72 (m, 2H), 3.35 (s, 2H), 3.01 (t, 2H), 1.73 (m, 2H), 1.63 (m, 2H).

Cl NH O SO 917 910 OO S 417/419 A17B03C15 H NMR (400 MHz, DMSO): δ ppm: .65(s, 1H), 8.40(dd, J = 2.0, 6.4 Hz, 1H), GA 8.27(m, 1H), 8.04 (dd, J = 2.4, 7.2 Hz, A20B03C40 1H), 7.68(m, 2H), 7.44(t, J = 9.0 Hz, 1H), 4.94(d, J = 3.2 Hz, 1H), 4.23(s, 1H), 3.40(m, 2H), 3.18(m, 1H), 1.85(m, 2H).

Cl NH O SO O SO 911 912_D1 445/447 445/447 A73B03C15 A84B03C15 Cl NH Cl NH 912_D2 913_D1 O SO O SO 445/447 459/461 GA GA A85B03C15 A84B03C15 Cl NH Cl NH O SO O SO 913_D2 914 459/461 459/461 A85B03C15 A09B03C15 O SO 461/463 A81B03C15 H NMR (400 MHz, CD OD) δ 8.44 (m, 1H), 8.27 (m, 1H), 7.99 (m, 1H), 7.64 (m, 1H), 7.55(t, 1H), 7.29 (t, 1H), 3.72 (m, 2H), 3.35 (s, 2H), 2.98 (t, 2H), 1.72 (m, 2H), 1.63 (m, 2H).

O SO O SO 922 923_D1 435/437 A110B03C15 449/451 H NMR (400 MHz, CD OD) δ 8.46 (m, 1H), 8.26 (m, 1H), 7.98 (m, 1H), 7.65 (m, A111B03C15 1H), 7.49 (t, 1H), 7.29 (t, 1H), 4.28 (m, 1H), 3.76 (s, 1H), 3.69 (s, 1H), 3.62 (t, 1H), 3.58 (t, 1H), 3.52 (m, 1H), 3.32 (d, 1H).

Cl NH O SO O SO O 923_D2 924 405/407 A20B03C15 H NMR (400 MHz, CD3OD): δ ppm: 449/451 8.44(dd, J = 2.4, 7.2 Hz, 1H), 8.21(m, 1H), 7.95(dd, J = 2.4, 6.4 Hz, 1H), 7.63 (m, A111B03C15 1H), 7.48(t, J = 9.2 Hz, 1H), 7.24(t, J = 9.0 Hz, 1H), 3.70(t, J = 5.8 Hz, 2H), 3.31(m, 2H), 2.97(d, J = 1.6 Hz, 3H).

F NH F NH OO S OO S 925 O 927 A10B17C40 H NMR (400 MHz, DMSO): δ ppm: .86(s, 1H), 8.31(s, 1H), 8.29(s, 1H), 7.85 (d, J = 7.6 Hz, 1H), 7.72(t, J = 5.0 Hz, A10B18C40 2H), 4.73(d, J = 4.0 Hz, 1H), 3.86(s, 3H), 3.61(m, 1H), 3.35(m, 2H), 2.95(m, 2H), 1.75(m, 2H), 1.38(m, 2H),.

Cl NH NH O SO 931 935 O SO 445/447 403/405 A73B01C58 A19B01C58 F NH Cl NH OO S O SO 928 932_D1 429 445/447 GA AGA A84B01C58 A10B17C40 Cl NH Cl NH O SO O SO 933_D1 940_D1 459/461 A85B01C58 H NMR (400 MHz, CD OD) δ 8.34 (s, 1H), 8.24 (d, 1H), 8.03 (d, 1H), 7.80 (m, 521/523 2H), 7.75 (m, 1H), 3.60 (m, 2H), 3.27 (m, GA A86B01C58 1H), 2.74 (m, 1H), 2.47 (m, 1H), 1.96 (m, 1H), 1.75 (m, 1H), 1.59 (m, 1H), 1.44 (m, 1H), 1.27 (m, 1H), 0.99 (t, 3H).

Cl NH O SO O SO 940_D2 943_D1 449/451 521/523 A111B01C58 A86B01C58 Cl NH O SO 435/439 A110B01C58 Cl NH Cl NH O SO O SO 943_D2 945_D2 461/463 449/451 A111B01C58 A104B01C58 F NH F NH O SO 946_D1 946_D2 N O SO A104B01C40 O SO 952 953 403/405 A19B03C15 A113B03C40 H NMR (400 MHz, CD3OD): δ ppm: H NMR (400 MHz, CD OD) δ 8.50 (m, 8.42(dd, J = 2.0, 6.4 Hz, 1H), 8.26(m, 1H), 1H), 8.23 (m, 1H), 7.63 (m, 2H), 7.45 (m, 7.96(dd, J = 2.4, 6.8 Hz, 1H), 7.62 (m, 1H), 3.96 (m, 1H), 3.45 (m, 1H), 1.91 (m, 1H), 7.54(t, J = 9.2 Hz, 1H), 7.25(t, J = 9.0 2H), 1.68 (m, 2H), 1.48 (m, 2H).

Hz, 1H), 4.45(m, 1H), 4.12(t, J = 7.8 Hz, 2H), 3.72(t, J = 6.8 Hz, 2H).

O SO 954 955_D1 475/477 461/463 A113B03C49 1 A104B01C15 H NMR (400 MHz, CD OD) δ 8.49 (m, H NMR (400 MHz, CD OD) δ 8.42 (m, 1H), 8.25 (m, 1H), 8.13 (m, 1H), 7.69 (m, 1H), 8.25 (m, 1H), 7.95 (m, 1H), 7.61 (m, 1H), 7.47 (t, 1H), 7.25 (t, 1H), 3.96 (m, 1H), 7.51 (t, 1H), 7.25 (t, 1H), 3.94 (m, 1H), 3.46 (m, 1H), 1.93 (m, 2H), 1.69 (m, 1H), 3.86 (d, 1H), 3.75 (m, 1H), 3.57 (m, 2H), 1.47 (m, 2H). 1H), 3.48 (m, 1H), 2.59 (t, 1H), 2.47 (t, 1H), 1.87 (m, 1H), 1.42 (m, 2H).

F NH O SO 955_D2 956 461/463 O A104B01C15 H NMR (400 MHz, CD OD) δ 8.42 (m, A113B03C63 1H), 8.25 (m, 1H), 7.95 (m, 1H), 7.61 (m, 1H), 7.51 (t, 1H), 7.25 (t, 1H), 3.94 (m, 1H), 3.86 (d, 1H), 3.75 (m, 1H), 3.57 (m, 1H), 3.48 (m, 1H), 2.59 (t, 1H), 2.47 (t, 1H), 1.87 (m, 1H), 1.42 (m, 2H).

F NH Cl NH O SO O SO 957 N 958 431/433 A114B03C40 H NMR (400 MHz, CD3OD) δ 8.48 (m, A114B03C15 1H), 8.23 (m, 1H), 7.63 (m, 1H), 7.52 (t, 1H), 4.13 (m, 1H), 3.71 (m, 1H), 2.09 (m, 1H), 1.68 (m, 4H), 1.44 (m, 1H).

Br NH O SO 959 960_D1 475/477 A114B03C49 A111B03C40 O SO 960_D2 961 A114B03C63 A111B03C40 F NH F NH O SO O SO 962_D1 962_D2 A116B03C40 H NMR (400 MHz, CD OD) δ 8.48 (m, 1H), 8.25 (m, 1H), 7.63 (m, 1H), 7.52 (t, A116B03C40 1H), 3.46 (m, 1H), 3.24 (m, 1H), 2.05 (m, 1H), 1.84 (m, 1H), 1.73 (m, 2H), 1.24 (m, 4H).

Cl NH Cl NH O SO O SO 963_D1 963_D2 445/447 445/447 A116B03C15 A116B03C15 Br NH O O SO O SO 964_D1 964_D2 489/491 A116B03C49 489/491 H NMR (400 MHz, CD3OD) δ 8.49 (m, A116B03C15 1H), 8.23 (m, 1H), 8.13 (m, 1H), 7.68 (m, 1H), 7.48 (m, 1H), 7.25 (t, 1H), 3.99 (m, 1H), 3.61 (m, 1H), 1.57 (m, 8H).

F NH F NH 972_D1 972_D2 OO S OO S A118B03C40 A118B03C40 Cl NH Cl NH O OO S OO S 973_D1 973_D2 445/447 OH GA 445/447 A118B03C15 H NMR (400 MHz, CD3OD) δ 8.49 (m, A118B03C15 1H), 8.23 (m, 1H), 7.98 (m, 1H), 7.63 (m, 1H), 7.48 (m, 1H), 7.27 (t, 1H), 3.78 (m, 1H), 1.58 (m, 9H).

F NH F NH OO S 976_D1 977_D2 OO S A118B03C63 A119B03C40 H NMR (400 MHz, CD OD) δ 8.49 (m, 1H), 8.21 (m, 1H), 7.83 (m, 1H), 7.42 (t, 2H), 7.27 (m, 1H), 3.00 (m, 1H), 1.91 (m, 2H), 1.67 (m, 2H), 1.27 (m, 5H).

Cl NH Cl NH 978_CT 978_CT OO S OO S NH NH HO HO 417/419 GA GA A119B03C15 A119B03C15 Br NH F NH 979_CT 981_CT OO S OO S 462/464 401 A119B03C63 A119B03C49 F NH Cl NH OO S OO S 981_D1 990_D1 NH NH 477/479 A119B03C63 A121B03C58 Cl NH Cl NH OO S OO S 988_D1 988_D2 NH NH HO HO 459/461 459/461 A121B03C15 A121B03C15 Cl NH Cl NH 990_D2 998_D1 OO S OO S HO NH 477/479 461/463 GA GA A121B03C58 A123B03C15 Cl NH F NH OO S OO S 998_D2 1007 HO NH 461/463 A123B03C15 A125B03C40 Cl NH OO S F NH 1008 1017 461/463 OO S A125B03C15 H NMR (400 MHz, MeOD) δ 8.51 - 8.49 433/435 (m, 2H), 7.99 - 7.96 (m, 1H), 7.63 - 7.62 (m, 1H), 7.50 - 7.45 (m, 1H), 7.28 - 7.24 A112B07C40 (m, 1H), 3.77 - 3.76 (m, 1H), 3.65 - 3.62 (m, 1H), 3.56 - 3.54 (m, 1H), 1.79 - 1.73 (m, 2H), 1.49 - 1.42 (m, 2H), 1.41 - 1.38 (m, 2H).

Cl NH Br NH Cl Cl OO S OO S 1018 1019 NH NH 431/435 476/478 GA GA A112B07C15 A112B07C49 Cl NH F NH OO S 1021 1022 OO S 447/449 A113B07C15 449/451 A113B07C40 F NH F NH OO S 1033 1057 OO S 463/465 449/451 A117B07C40 A10B07C40 Cl NH Br NH Cl Cl OO S OO S 1058 1059 OH OH 447/449 492/494 GA GA A10B07C15 A10B07C49 1060 1061 421/423 A19B07C40 465/467 H NMR (400 MHz, CD OD) δ 8.56 (d, 1 H), 8.15 (m, 1H), 7.81 (d, 1H), 7.61 (m, A10B07C58 2H), 4.53 (m, 1H), 4.16 (m, 2H), 3.89 (m, 2H). 1062 1070 419/421 A19B07C15 451/453 H NMR (400 MHz, CD OD) δ 8.56 (d, 1 H), 8.15 (d, 1H), 7.99 (m, 1H), 7.82 (m, A110B07C15 1H), 7.63 (m, 1H), 7.25 (m, 1H), 4.53 (m, 1H), 4.17 (m, 2H), 3.89 (m, 2H).

Cl NH OO S 1078_D 461/463 A84B07C15 H NMR (400 MHz, CD3OD) δ 8.48 (d, J = 2 Hz, 1H), 8.08 (m, 1H), 8.01 (s, 1H), 7.88 (d, J = 6.4 Hz, 1H), 7.68 (m, 1H), 7.50 (m, 1H), 7.17 (m, 1H), 3.75 (m, 2H), 3.30 (m, 1H), 3.01 (m, 1H), 2.65 (m, 1H), 2.01 (m, 1H), 1.68 (m, 2H), 1.10 (d, J = 6.4 Hz, 3H) Br NH Cl NH Cl Cl OO S OO S 1078_D 1079 461/463 506/508 GA GA A84B07C15 A84B07C49 F NH F NH 1081_D 1081_D OO S OO S 1 N 2 477/479 477/479 A85B07C40 A85B07C40 Cl NH F NH OO S OO S 1089 1090 433/435 435/437 A17B07C15 A17B07C40 Br NH OO S 1095_R 492/494 A18B07C49 Br NH OO S 1095_S 1096_R 465/467 491/493 A18B07C49 A18B07C58 1096_S 1098 465/467 477/479 A18B07C58 A81B07C15 Br NH OO S 1099 1107 466/468 523/521 A20B07C49 A81B07C49 Cl NH 1114 1116 OO S 447/449 A113B06C15 469/471 H NMR (400 MHz, CD OD) δ 8.06 (d, J= 2 Hz, 1 H), 7.99 (m, 2 H), 7.75 (m, 1 H), 7.30 (m, 1 H), 7.25 (m, 1 H), 3.93 (m, 1 A110B07C58 H), 3.35 (m, 1 H),1.93 (m, 2 H), 1.88 (m, 2 H), 1.68 (m, 1 H), 1.52 (m, 1 H).

Cl NH Cl OO S 1126 1130 461/463 479/481 A117B06C15 GAA81B07C40 Cl NH Cl Cl NH Cl 1134_C 1134_C OO S OO S T1 T2 NH NH 433/435 433/435 A119B06C15 A119B06C15 Cl NH Cl NH 1135_D 1135_D OO S OO S N 1 N 2 467/469 467/469 A111B03C58 A111B03C58 F NH Cl Cl NH Cl OO S OO S 1149 1150 449/451 447/449 A10B06C40 A10B06C15 H NMR (400 MHz, CD OD) δ 7.95 (s, 1 H), 7.88 (d, J= 2 Hz, 1 H ), 7.81 (d, J= 4.4 Hz, 1 H), 7.53 (m, 2 H), 3.69 (m, 1 H), 3.40 (m, 2 H), 2.91 (m, 2 H), 1.88 (m, 2 H), 1.60 (m, 2 H).

Cl NH Cl OO S 1154 1157 419/421 413/415 GA GA A19B06C15 A114B01C15 Cl NH OO S 1170_D OO S 1161 461/463 A84B06C15 A73B03C40 Cl NH Cl Cl NH OO S OO S 1170_D N 1178 461/463 475/477 A84B06C15 A09B06C15 Cl NH Cl Cl NH Cl OO S OO S 1182 1194 433/435 523/525 A17B06C15 A75B06C15 F NH F Cl NH Cl O OO S OO S 1198 1201 421/423 A10B08C40 H NMR (400 MHz, CD OD) δ 8.24 (t, A20B06C15 3 1H), 7.57 (m, 2H), 7.42 (t, 1H), 3.76 (m, 1H), 3.53 (m, 1H), 3.08 (m, 2H), 1.92 (m, 2H), 1.60 (m, 2H).

Cl F F NH F OO S 1202 OO S 1205 449/451 A10B08C15 H NMR (400 MHz, CD OD) δ 8.25 (t, 1H), 7.97 (m, 1H), 7.58(m, 1H), 7.47 (t, A19B08C40 1H), 7.27 (t, 1H), 3.75 (m, 1H), 3.55 (m, 1H), 3.06 (m, 1H), 1.91(m, 2H), 1.60 (m,2H).

Cl NH F Br NH F OO S OO S 1206 1207 466/468 421/423 GA GA A19B08C49 A19B08C15 F NH F Cl NH F F 1209_C 1208 OO S OO S 439/441 A119B08C40 A19B08C58 H NMR (400 MHz, CD OD) δ 8.24 (t, H NMR (400 MHz, CD OD) δ 8.26 (t, 1H), 7.58 (m, 2H), 7.44 (m, 1H), 4.34 (m, 1H), 7.74 (m, 1H), 7.66 (m, 1H), 7.51 (t, 1H), 4.05 (m, 1H), 2.20 (m, 4H). 1H), 4.49 (m, 1H), 4.13 (m, 2H), 3.73 (m, 2H).

F NH F 1209_C OO S A119B08C40 Br NH F F NH F OO S 1231 OO S 1241 507/509 A84B08C49 A17B08C40 F NH F Cl NH F OO S OO S 1242 1249 OH HO 435/437 A17B08C15 A81B08C40 Br N F Cl NH F O S O OO S 1250 1251 GA A81B08C49 H NMR (400 MHz, CD OD) δ 8.25 (t, 479/481 1H), 8.08 (m, 1H), 7.65 (m, 1H), 7.43 (t, 1H), 7.27 (t, 1H), 3.66 (m, 2H), 3.38 (s, A81B08C15 2H), 2.97 (t, 2H), 1.75 (m, 2H), 1.60 (m, 2H).

Br NH F F NH F OO S OO S N 1253 1255 569/571 A75B08C49 A75B08C40 F NH F F NH F 1257 OO S 1261 OO S OH OH 425 451 A20B08C40 A113B08C40 Br NH F F NH F 1273_D OO S 1263 OO S 493 /495 A113B08C49 A118B08C40 F NH F Br NH F OO S 1273_D OO S 1275 507/509 A118B08C40 H NMR (400 MHz, CD3OD) δ 8.29 (t, A118B08C49 1H), 7.57 (m, 2H), 7.35 (t, 1H), 2.98 (m, 1H), 1.91 (m, 2H), 1.67 (m, 2H), 1.25 (m, 5H).

Br NH Br NH OO S OO S 1281_D 1281_D 493/495 493/495 A111B03C49 A111B03C49 F NH F NH 1001_D 1001_D OO S OO S HO NH HO NH GA A123B03C63 GA A123B03C63 F NH F NH OO S O HO NH 1002_D 1002_D OO S HO NH GA A124B03C40 1H NMR (400MHz, METHANOL-d4) ℃ = 8.47 (m, 1H), 8.23 (m, 1H), 7.61 (m, GA A124B03C40 2H), 7.49 (m, 1H), 3.78 - 3.72 (m, 1H), 3.58 - 3.49 (m, 1H), 3.32 - 3.27 (m, 1H), 1.83 - 1.75 (m, 1H), 1.74 - 1.56 (m, 3H), 1.51 - 1.36 (m, 2H) Cl NH Cl NH 1003_D 1003_D OO S OO S HO NH HO NH 461/163 461/463 GA A124B03C15 A124B03C15 Br NH Br NH 1004_D 1004_D OO S OO S HO NH HO NH HO HO 505/507 505/507 GA GA A124B03C49 A124B03C49 Cl NH Cl NH 1005_D 1005_D OO S OO S HO NH HO NH HO HO 479/481 479/481 GA GA A124B03C58 A124B03C58 F NH Cl F NH Cl 1006_D 1006_D OO S OO S NH NH HO HO 445/446 445/446 GA GA A121B06C40 A121B06C40 Cl NH Br NH OO S OO S 1009 1010 479/481 A125B03C58 H NMR (400MHz, METHANOL-d4) ℃ = 505/507 8.58 - 8.48 (m, 1H), 8.26 - 8.17 (m, 1H), A125B03C49 7.83 - 7.71 (m, 2H), 7.48 - 7.43 (m, 1H), 3.98 - 3.91 (m, 1H), 3.45 (m, 1H), 3.36 - 3.34 (m, 1H), 1.89 - 1.71 (m, 2H), 1.68 - 1.55 (m, 1H), 1.44 (m, 2H), 1.37 - 1.26 (m, F NH OO S 1011 A125B03C63 Br NH OO S 1020 1023 449/451 491/493 A112B07C49 A113B07C49 F NH OO S 1025 1024 447/449 A115B07C40 465/467 GA H NMR (400 MHz, CD3OD) δ 8.62 (d, J= A113B07C58 2Hz, 1H), 8.11 (d, J= 2.4Hz, 1H ), 7.66 (d, J= 8Hz, 1H), 7.61 (m, 2H), 3.10 (m, 1H), 1.67 (m, 4H), 1.55 (m, 1H), 1.26 (m, 5H).

Cl NH Br NH Cl Cl OO S OO S 1026 1027 NH NH 445/447 489/491 GA GA A115B07C15 A115B07C49 F NH 1029_D 1028 OO S HO NH 463/465 463/465 A115B07C58 A116B07C40 Cl NH F NH 1029_D 1030_D OO S OO S HO NH HO NH 461/463 463/465 A116B07C15 A116B07C40 1030_D 1031_D 507/505 A116B07C49 461/463 H NMR (400 MHz, CD OD) δ 8.62 (d, 1 H), 8.12 (m, 1H), 7.76 (m, 1H), 7.68 (m, A116B07C15 1H), 7.25 (m, 1H), 3.47 (m, 1H), 3.15 (m, 1H), 1.96 (m, 1H), 1.80 (m, 1H), 1.73 (m, 2H), 1.25 (m, 4H). 1031_D 1032_D 507/505 479/481 A116B07C49 A116B07C58 F NH 1032_D 1033 OO S 479/481 463/465 A116B07C58 A117B07C40 Br NH Cl NH OO S OO S 1034 1035 506/508 A117B07C49 461/463 H NMR (400 MHz, CD OD) δ 8.63 (d, J= 2Hz, 1H), 8.12 (m, 2H), 7.76 (d, J= 8.4 A117B07C15 Hz, 1H ), 7.60 (m, 1H), 7.25 (m, 1H), 3.48 (m, 1H), 3.12 (m, 1H), 1.79 (m, 4H), 1.36 (m, 2H), 1.24 (m, 2H). 1036 1037 479/481 463/465 GA GA A118B07C40 A117B07C58 Br NH OO S 1038 1039 461/463 506/508 A118B07C15 A118B07C49 1040 1041 479/481 452/454 A119B07C40 A118B07C58 1042 1043 479/481 433/435 A119B07C49 A119B07C15 1044 1049 459/461 A122B07C40 451/453 H NMR (400 MHz, CD OD) δ 8.62 (d, 1 H), 8.05 (m, 1H), 7.75 (d, 1H), 7.61 (m, A119B07C58 2H), 7.53(m, 2H), 3.18(m, 1H), 1.76(m, 1H), 1.64(m, 3H), 1.40 (m, 4H), 1.15 (s, 3H). 1050 1051 503/501 A122B07C49 457/459 H NMR (400 MHz, CD OD) δ 8.62 (d, 1 H), 8.11 (m, 2H), 7.75 (m, 2H), 7.25 (m, A122B07C15 1H), 3.18(m, 1H), 1.64(m, 4H), 1.37 (m, 4H), 1.15 (s, 3H). 1052 1053 459/461 475/477 A121B07C40 A122B07C58 1054 1055 503/501 A121B07C49 457/459 H NMR (400 MHz, CD OD) δ 8.63 (d, 1 H), 8.13 (m, 1H), 7.68 (m, 2H), 7.25 (m, A121B07C15 1H), 3.25 (m, 1H), 1.73 (m, 2H), 1.64 (m, 2H), 1.48 (m, 4H), 1.20 (s, 3H).

F NH 1056_D OO S 1057 475/477 449/451 A121B07C58 A10B07C40 1061 1063 465/463 421/423 A19B07C49 A19B07C40 1 H NMR (400 MHz, CD3OD) δ 8.56 (d, 1 H NMR (400 MHz, CD OD) δ 8.56 (d, H), 8.15 (m, 2H), 7.82 (m, 1H), 7.68 (m, 1 H), 8.15 (m, 1H), 7.81 (d, 1H), 7.61 1H), 7.25 (m, 1H), 4.53 (m, 1H), 4.17 (m, (m, 2H), 4.53 (m, 1H), 4.16 (m, 2H), 2H), 3.89 (m, 2H). 3.89 (m, 2H). 1064 1065 437/439 475/477 A19B07C58 A91B07C40 1066 1067 519/517 473/475 A91B07C49 A91B07C15 1068 1069 453/455 491/493 GA A110B07C40 A91B07C58 1070 1071 451/453 497/495 A110B07C15 A110B07C49 F NH OO S 1073 463/465 A73B07C40 Br NH Cl NH OO S OO S 1074 1075 461/463 506/508 A73B07C15 A73B07C49 F NH 1077_D OO S 1076 461/463 463/465 A73B07C58 A84B07C40 1077_D 463/465 A84B07C40 Cl NH OO S 1082_D 1080 475/477 A85B07C15 H NMR (400 MHz, CD OD) δ 8.59 (d, J= 479/481 2.4 Hz, 1H), 8.15 (m, 1H), 7.99 (d, J= 8.4 Hz, 1H), 7.78 (m, 1 H), 7.63 (m, 1H), 7.27 A84B07C58 (m, 1H), 3.81 (m, 1H), 3.78 (m, 1 H), 3.39 (m, 1 H), 3.07 (m, 1H), 2.77 (m, 1H), 1.95 (m, 1 H), 1.75 (m, 1 H), 1.56 (m, 1H), 1.43 (m, 1 H), 1.24 (m, 1 H), 0.93 (m, 3 H).

Cl NH Br NH Cl Cl OO S OO S 1082_D 1083_D OH OH 475/479 520/522 GA GA A85B07C15 A85B07C49 1084_D 1084_D 493/495 493/495 GA GA A85B07C58 A85B07C58 Cl NH F NH OO S OO S N 1085 1086 475/477 477/479 A09B07C15 H NMR (400 MHz, CD OD) δ 8.57 (d, J= A09B07C40 6.4 Hz, 1 H), 8.14 (m, 1 H), 8.12 (m, 1 H), 7.99 (m, 1 H), 7.63 (m, 1 H), 7.27 (m, 1H), 3.84 (m, 2H), 3.64 (m, 2 H), 2.82 (m, 2H), 1.79 (m, 2H), 1.60 (m, 1 H), 1.50 (m, 2H), 1.26 (m, 2H).

Br NH OO S 1087 1088 519/521 493/495 A09B07C49 A09B07C58 Br NH OO S 1091 1092 477/479 A17B07C49 451/453 H NMR (400 MHz, CD OD) δ 8.61 (d, J= 2.4 Hz, 1 H), 8.14 (m, 2 H), 7.80 (m, 1H), A17B07C58 7.68 (m, 1 H), 7.22 (m, 1 H), 4.45 (m, 1 H), 3.59 (m, 3H), 3.38 (m, 1 H), 2.05 (m, 2H).

F NH F NH Cl Cl 1093_R 1093_S OO S OO S 449/451 449/451 A18B07C40 A18B07C40 Cl NH Cl NH Cl Cl OO S OO S 1094_R 1094_S OH OH 447/449 447/449 A18B07C15 A18B07C15 1100 495/497 A81B07C58 Cl NH F NH OO S OO S N 1101 1102 523/525 525/527 A75B07C15 A75B07C40 H NMR (400 MHz, CD OD) δ 8.63 (d, J= H NMR (400 MHz, CD OD) δ 8.62 (d, J= 2.4 Hz, 1H), 8.17 (m, 1H), 7.98 (m, 1 H), 2 Hz, 1 H), 8.15 (m, 1H), 7.82 (d, J= 8.4 7.82 (d, J= 8 Hz, 1 H), 7.49 (m, 1H), 7.47 Hz, 1 H), 7.62 (m, 2 H), 7.49 (m, 2 H), (m, 1 H), 7.35 (m, 2 H), 7.25 (m, 2 H), 7.35 (m, 2 H), 7.25 (m, 1 H), 3.84 (m, 2 7.22 (m, 2 H), 3.81 (m, 2 H), 3.31 (m, 2 H), 2.15 (m, 4H), 1.82 (m, 2 H).

H), 2.21 (m, 2 H), 1.81 (m, 2 H).

Br NH OO S 1103 1104 567/569 523/525 GA GA A75B07C49 A75B07C58 Cl NH F NH OO S 1105 1106 OO S 421/423 OH GA A20B07C15 423/425 A20B07C40 H NMR (400 MHz, CD OD) δ 8.60 (d, J= 2 Hz, 1 H), 8.12 (m, 1 H), 7.98 (d, J= 8 Hz, 1 H), 7.61 (m, 2 H), 3.71 (m, 2 H), 3.42 (m, 2 H), 3.02 (s, 3 H). 1108 439/441 A20B07C58 Cl NH OO S 1110 1109 431/433 A112B06C15 433/435 H NMR (400 MHz, CD OD) δ 8.03 (d, J= 2 Hz, 1 H), 7.92 (m, 2 H), 7.84 (m, 1 H), A112B07C40 7.75 (m, 1 H), 7.25 (m, 1 H), 3.58 (m, 1 H), 1.80 (m, 2 H), 1.66 (m, 2 H), 1.51 (m, 4 H). 1111 1112 477/475 449/451 A112B07C49 A112B07C58 1113 449/451 A113B07C40 1115 1433 493/491 465/467 A113B07C49 A113B07C58 Cl NH OO S 1117 1118 447/449 445/447 A115B06C15 A115B07C40 1119 1120 491/489 463/465 A115B07C49 A115B07C58 1121_D 1121_D 463/465 A116B07C40 463/465 H NMR (400 MHz, CD OD) δ 8.03 (d, 1 H), 7.96 (m, 1H), 7.76 (d, 1H), 7.54 (m, A116B07C40 2H), 3.47 (m, 1H), 3.15 (m, 1H), 2.17 (m, 1H), 1.86 (m, 1H), 1.73 (m, 2H), 1.15 (m, 4H). 1122_D 1122_D 461/463 461/463 GA GA A116B07C15 A116B07C15 1123_D 1123_D 507/505 507/505 GA GA A116B07C49 A116B07C49 1124_D 1124_D 479/481 479/481 GA GA A116B07C58 A116B07C58 Cl NH Cl OO S 1125 1126 445/447 461/463 A117B07C40 H NMR (400 MHz, CD OD) δ 8.03 (d, 1 A117B06C15 H), 7.95 (m, 1H), 7.74 (m, 1H), 7.54 (m, 2H), 3.47 (m, 2H), 3.06 (m, 1H), 1.86 (m, 4H), 1.26 (m, 4H). 1127 1128 507/505 A117B07C49 461/463 A117B07C58 Cl NH Cl OO S 1129 1444 461/463 463/465 A118B06C15 A118B07C40 Br NH Cl 1131_D 1131_D OO S 507/505 507/505 GA GA A118B07C49 A118B07C49 1132_D 1132_D 479/481 479/481 GA GA A118B07C58 A118B07C58 F NH Cl 1133 1445 OO S 479/481 345/347 A119B07C49 A19B07C40 1136_C 1136_C T1 T2 451/453 451/453 GA GA A119B07C58 A119B07C58 1141 1142 457/459 459/461 A122B07C15 A122B07C40 1143 1144 503/501 GA 475/477 A122B07C49 A122B07C58 Br NH Cl OO S 1146 1147 457/459 521/519 A121B07C15 A121B07C49 Br NH Cl OO S 1148 1151 475/477 A121B07C58 492 /494 H NMR (400 MHz, CD OD) δ 8.05 (d, 1 3 GA H), 7.99 (m, 1H), 7.76 (m, 2H), 7.64 (m, A10B07C49 1H), 3.20 (m, 1H), 1.73 (m, 2H), 1.64 (m, 2H), 1.44 (m, 4H), 1.20 (s, 3H). 1152 1153 421/423 465/467 A19B07C40 A10B07C58 1155 465/463 A19B07C49 1156 1421 437/439 A19B07C58 H NMR (400 MHz, CD OD) δ 8.03 (d, 1 475/477 H), 7.97 (m, 1H), 7.84(m, 1H), 7.75 (m, A91B07C40 1H), 7.66 (m, 1H), 3.55(m,2H), 4.45 (m, 1H), 4.03 (m, 2H), 3.57 (m, 2H). 1158 1160 473/475 491/493 A91B07C15 A91B07C58 1422 1162 451/453 453/455 A110B07C15 A110B07C40 1163 1164 497/495 469/471 A110B07C49 A110B07C58 1165 1166 443/445 A73B07C15 H NMR (400 MHz, CD OD) δ 8.10 (d, 1 445/447 H), 8.01 (d, 1H), 7.95 (m, 1H), 7.88 (m, 1H), 7.63 (m, 1H), 7.22 (m, 1H), 3.50 (m, A73B07C40 2H), 2.77 (m, 2H), 1.68 (m, 4H), 1.21 (s, 3H). 1167 1168 489/487 A73B07C49 461/463 H NMR (400 MHz, CD OD) δ 7.97 (d, 1 H), 7.95 (d, 1H), 7.90 (m, 1H), 7.88 (m, A73B07C58 1H), 7.57 (m, 1H), 7.27 (m, 1H), 3.49 (m, 2H), 2.77 (m, 2H), 1.68 (m, 4H), 1.21 (s, 3H). 1169_D 1169_D 463/465 463/465 GA GA A84B07C40 A84B07C40 1171_D 1171_D 507/505 507/505 GA GA A84B07C49 A84B07C49 1172_D 1172_D 479/481 479/481 GA GA A84B07C58 A84B07C5 1173_D 1173_D 477/479 477/479 GA GA A85B07C40 A85B07C40 Cl NH Cl OO S Cl NH OH OO S 1174_D 1174_D 475/477 A85B06C15 1 OH H NMR (400 MHz, CD OD) δ 7.97 (m, 2 475/477 H), 7.89 (d, J= 4.4 Hz, 1 H), 7.80 (m, 1 H), 7.57 (m, 1 H), 7.27 (m, 1 H), 3.60 (m, 2 A85B06C15 H), 3.30 (m, 1 H), 2.75 (m, 1 H), 2.47 (m, 1 H), 1.95 (m, 1 H), 1.75 (m, 1 H), 1.58 (m, 1 H), 1.44 (m, 1 H), 1.21 (m, 1 H), 0.93 (m, 3 H). 1175_D 1175_D 521/519 A85B07C49 H NMR (400 MHz, CD OD) δ 8.10 (d, 1 521/519 H), 7.95 (m, 1H), 7.88 (m, 1H), 7.78 (m, 1H), 7.68 (m, 1H), 7.25 (m, 1H), 3.55 (m, A85B07C49 2H), 3.29 (m, 1H), 2.76(m, 1H), 2.45 (m, 1H), 1.96 (m, 1H), 1.74 (m, 1H), 1.55(m, 2H), 1.24 (m, 1H), 0.98 (m, 3H). 1176_D 1176_D 493/495 A85B07C58 H NMR (400 MHz, CD OD) δ 7.97 (d, 1 493/495 H), 7.93 (m, 1H), 7.81(m, 1H), 7.75 (m, 1H), 7.68(m, 1H), 3.55(m,2H), 3.41(m, A85B07C58 1H), 2.76(m, 1H), 2.45 (m, 1H), 1.96(m, 1H), 1.74 (m, 1H), 1.55(m, 2H), 1.24 (m, 1H), 0.98 (m, 3H).

Cl NH Cl OO S 1178 1177 475/477 477/479 A09B06C15 A09B07C40 1179 1180 493/495 A09B07C58 521/519 H NMR (400 MHz, CD OD) δ 7.95 (d, 1 GA 3 A09B07C49 H), 7.87 (m, 1H), 7.81 (m, 1H), 7.79 (m, H), 7.78 (m, 1H), 3.77 (m,2H), 3.59 (m, 2H), 2.38 (m, 2H), 1.83 (m, 2H), 1.47 (m, 2H), 1.38 (m, 2H) 1181 435/437 A17B07C40 1183 1184 479/477 451/453 A17B07C49 A17B07C58 1185_R 1185_S 449/451 A18B07C40 449/451 H NMR (400 MHz, CD OD) δ 8.05 (m, 1 H), 7.97 (d, 1H), 8.01 (m, 1H), 7.79 (d, A18B07C40 1H), 7.54 (m, 2H), 3.73 (m, 2H), 3.69 (m, 1H), 3.48 (m, 1H), 3.25 (m, 1H), 1.83 (m, 2H), 1.64 (m, 2H).

Cl NH Cl Cl NH Cl OO S 1186_R OO S 1186_S 447/449 A18B06C15 1 447/449 H NMR (400 MHz, CD OD) δ 8.04 (d, J=2.0 Hz, 1 H), 7.98 (m, 2 H), 7.80 (m, 1 A18B06C15 H), 7.57 (m, 1 H),7.28 (m, 1 H), 3.75 (m, 2 H), 3.60 (m, 1 H), 3.48 (m, 1 H), 3.27 (m, 1 H), 1.93 (m, 2 H), 1.60 (m, 2 H). 1187_R 1187_S 493/491 A18B07C49 493/491 H NMR (400 MHz, CD OD) δ 8.11 (d, 1 H), 8.08 (d, 1H), 8.01 (m, 1H), 7.78 (m, A18B07C49 1H), 7.68 (m, 1H), 7.25 (m, 1H), 3.73 (m, 2H), 3.69 (m, 1H), 3.48 (m, 1H), 3.25 (m, 1H), 1.83 (m, 2H), 1.68 (m, 2H). 1188_R 1188_S 465/467 465/467 GA GA A18B07C58 A18B07C58 F NH Cl OO S 1189 1190 477/479 479/481 A81B07C15 A81B07C40 1191 1192 505/503 GA 477/479 A81B07C49 GA A81B07C58 1193 1197 507/509 A75B07C40 423/425 H NMR (400 MHz, CD OD) δ 8.01 (d, 1 A20B07C40 H), 7.84 (m, 1H), 7.82 (m, 1H), 7.55 (m, 2H), 7.46 (m, 2H), 7.32 (m, 2H), 7.24 (m, 1H), 3.72 (m, 2H), 2.86 (m, 2H), 2.17 (m, 2H), 1.79 (m, 2H). 1195 1196 551/549 523/525 A75B07C49 A75B07C58 1199 1200 467/465 439/441 A20B07C49 A20B07C58 H NMR (400 MHz, CD OD) δ 8.09 (d, 1 H NMR (400 MHz, CD OD) δ 8.01 (d, 1 H), 7.99 (m, 1H), 7.91 (m, 1H), 7.77 (m, H), 7.93 (m, 1H), 7.77 (m, 1H), 7.66 (m, 1H), 7.25 (m, 1H), 3.70 (m, 2H), 3.22 1H), 7.64(m,1H), 3.70 (m, 2H), 3.22 (m,2H), 2.89 (s, 3H) (m,2H), 2.89(s, 3H) Br NH F Cl NH F OO S N OO S 1203 1204 494/496 OH 467/469 A10B08C49 H NMR (400 MHz, CD OD) δ 8.25 (t, A10B08C58 1H), 8.10 (m, 1H), 7.64 (m, 1H), 7.47 (t, H NMR (400 MHz, CD OD) δ 8.25 (t, 1H), 7.25 (t, 1H), 3.75 (m, 1H), 3.54 (m, 1H), 7.75 (m, 1H), 7.67 (m, 1H), 7.48 (t, 2H), 3.08 (m, 2H), 1.92 (m, 2H), 1.60 (m, 1H), 3.76 (m, 1H), 3.52 (m, 2H), 3.08 (m, 2H). 2H), 1.91 (m, 2H), 1.60 (m, 2H).

Br NH F Br NH F 1211_C 1211_C F T1 F T2 OO S OO S 479/481 479/481 GA GA A119B08C49 A119B08C49 Br NH F F NH F 1217 1219 OO S OO S 477/479 A112B08C4 A112B08C40 Br NH F F NH F OO S 1221 1223 OO S 491/493 A115B08C49 449 1 H NMR (400 MHz, CD OD) δ 8.29 (t, 1H), 8.10 (m, 1H), 7.63 (m, 1H), 7.43 (t, A115B08C40 1H), 7.27 (t, 1H), 3.17 (m, 1H), 1.76 (m, 4H), 1.59 (m, 1H), 1.30 (m, 4H), 1.16 (m, 1H).

Cl NH F NH F OO S OO S 1225 1226 463/465 A73B08C15 A73B08C40 Br NH F F NH F OO S 1229_D 1227 OO S 507/509 A73B08C49 A84B08C40 F NH F 1229_D OO S A84B08C40 Br NH F OO S OO S 1237 1239 521/523 A09B08C49 A09B08C40 Br NH F OO S F 1243 1245_R N OO S 479/481 A17B08C49 A18B08C40 Br NH F F NH F 1245_S 1247_R OO S OO S 493/495 A18B08C49 A18B08C40 Br NH F OO S 1247_S 1252 493/495 A18B08C49 H NMR (400 MHz, CD OD) δ 8.31 (t, 1H), 8.10 (m, 1H), 7.65 (m, 1H), 7.45 (t, 497/499 1H), 7.25 (t, 1H), 3.87 (m, 1H), 3.70 (m, GA A81B08C58 1H), 3.57 (m, 1H), 3.48 (m, 1H), 3.38 (m, 1H), 1.98 (m, 4H).

F NH F Br NH F OO S HO NH 1265 OO S 1267 HO NH A116B08C40 507/509 H NMR (400 MHz, CD OD) δ 8.25 (t, A116B08C49 1H), 7.57 (m, 2H), 7.40 (t, 1H), 3.48 (m, 1H), 3.22 (m, 1H), 1.99 (m, 1H), 1.83 (m, 1H), 1.71 (m, 2H), 1.27 (m, 4H).

Br NH F F NH F OO S 1269 1271 OO S 507/509 A117B08C49 H NMR (400 MHz, CD OD) δ 8.29 (t, 1H), 8.10 (m, 1H), 7.65 (m, 1H), 7.41 (t, A117B08C40 1H), 7.25 (t, 1H), 3.48 (m, 1H), 3.16 (m, 1H), 1.87 (m, 4H), 1.30 (m, 4H).

F NH 1283 OO S A127B03C40 H NMR (400 MHz, MeOD) δ 8.45 - 8.43 (m, 1H), 8.29 - 8.26 (m, 1H), 7.64 - 7.61 (m, 2H), 7.59 - 7.51 (m, 1H), 3.78 - 3.73 (m, 3H), 3.62 - 3.52 (m, 1H), 3.01 - 2.98 (m, 1H), 2.88 - 2.85 (m, 1H), 2.14 - 1.98 (m, 1H), 1.87 - 1.82 (m, 1H). 1334 1335 467/469 465/467 A10B09C40 H NMR (400 MHz,CD3OD) δ 8.05 (d, A10B09C15 1H), 7.70 (d, 1H), 7.55 (dd, 1H), 3.77 (m, 1H), 3.56 (m, 2H), 3.09 (td, 2H), 1.94 (m, 2H), 1.60 (m, 2H). 1336 1337 509/512 483/485 A10B09C49 A10B09C58 1338 1339 439/441 449/451 A19B09C40 H NMR (400 MHz,CD3OD) δ 8.06 (d, A10B09C63 1H), 7.75 (d, 1H), 7.54 (dd, 2H), 4.50 (t, 1H), 4.13 (t, 2H), 3.73 (t, 2H). 1340 1345 439/441 437/439 A20B09C15 A19B09C15 1347 1349 453/455 A17B09C40 457/459 H NMR (400 MHz,CD3OD) δ 8.09 (d, 1H), 7.67 (d, 1H), 7.53 (dd, 2H), 4.38 (d, A20B09C58 1H), 3.51 (m, 3H), 3.39 (m, 1H), 2.02 (m, 2H). 1352 1354_R 467/469 469/471 A18B09C40 A17B09C58 1354_S 1355_R 465/467 467/469 A18B09C15 A18B09C40 1359 1361 537/539 A09B09C49 H NMR (400 MHz,CD3OD) δ 8.09 (dd, 495/497 GA 1H), 8.03 (d, 1H), 7.67 (d, 1H), 7.61 (m, A09B09C40 1H), 7.27 (t, 1H),3.83 (d, 2H), 3.62 (t, 2H), 2.66 (t, 2H), 1.83 (d, 2H), 1.51 (m, 3H), 1.28 (m, 2H).

F NH Cl OO S 1363 1364 477/479 A09B09C63 481/483 H NMR (400 MHz,CD3OD) δ 8.03 (d, 1H), 7.84 (m, 1H), 7.68 (d, 1H), 7.36 (m, A73B09C40 1H), 7.30 (q, 1H), 3.86 (d, 2H), 3.62 (t, 2H), 2.67 (t, 2H), 1.83 (d, 2H), 1.50 (m, 3H), 1.28 (m, 2H). 1374_C 1365 479/481 453/455 A73B09C15 A119B09C40 1374_C 1375 453/455 451/453 GA GA A119B09C40 A119B09C15 1379 1380 495/497 497/499 A81B09C15 H NMR (400 MHz, CD3OD-d4) δ8.02 – A81B09C40 8.04 (m, 1H), 7.92 – 7.95 (m, 1H), 7.65 – H NMR (400 MHz, CD3OD-d4) δ8.02 – 7.68 (m, 1 H), 7.54 – 7.56 (m, 1H), 7.23 – 8.04 (m, 1H), 7.65 – 7.69 (m, 1H), 7.49 – 7.28 (m, 1H),3.65 – 3.68 (m, 2H), 3.34 (s, 7.53 (m, 2H), 3.64 – 3.68 (m, 2H), 3.34 (s, 2H), 2.94 – 3.00(m, 2H), 1.57 – 1.71(m, 2H), 2.93 – 2.99 (m, 2H), 1.57 – 1.71(m, 4H). 4H). 1386 1387 509/511 483/485 A113B09C49 A113B09C58 Br NH Cl F NH Cl OO S 1389_D 1391_D OO S OH 525/523 A116B09C49 H NMR (400MHz, METHANOL-d4) ℃ = 481/483 8.13 - 8.04 (m, 2H), 7.68 - 7.59 (m, 2H), 7.30 - 7.21 (m, 1H), 3.53 - 3.44 (m, 1H), A116B09C40 3.28 - 3.20 (m, 1H), 2.08 - 1.97 (m, 1H), 1.91 - 1.81 (m, 1H), 1.77 - 1.70 (m, 2H), 1.22 (s, 4H) Br NH Cl OO S 1391_D 1396 2 523/525 525/523 A117B09C49 A116B09C49 1 H NMR (400 MHz, CD3OD-d4) δ8.04 – H NMR (400MHz, METHANOL-d4) ℃ = 8.08 (m, 2H), 7.60 – 7.64 (m, 2H), 7.21 – 8.11 - 8.06 (m, 2H), 7.63 (d, J=9.7 Hz, 7.26 (m, 1H), 3.40 – 3.50 (m, 1H), 3.10 – 2H), 7.25 (m, 1H), 4.01 (m, 1H), 3.65 - 3.20 (m, 1H),1.75 – 1.92 (m, 4H), 1.20 – 3.55 (m, 1H), 1.80 - 1.61 (m, 3H), 1.61 - 1.37(m, 4H). 1.05 (m, 5H) 1398 1400 479/481 A118B09C15 463/465 H NMR (400 MHz, CD3OD-d4) δ8.06 – 8.08 (m, 1H), 7.92 – 7.95 (m, 1H), 7.54 – A117B09C63 7.62 (m, 2 H), 7.23 – 7.28 (m, 1H), 3.74 – 3.76 (m, 1H),3.30 – 3.34 (m, 1H), 1.23 – 1.73(m, 8H). 1401 1402 523/525 497/499 A118B09C49 A118B09C58 H NMR (400 MHz, CD3OD-d4) δ8.06 – H NMR (400 MHz, CD3OD-d4) δ8.07 – 8.08 (m, 1H), 7.59 – 7.63 (m, 2H), 7.21 – 8.09 (m, 1H), 7.68 – 7.71 (m, 1H), 7.60 – 7.26 (m, 1 H), 3.74 – 3.76 (m, 1H),3.30 – 7.64 (m, 2 H), 3.74 – 3.76 (m, 1H),3.30 – 3.34 (m, 1H), 1.23 – 1.73(m, 8H). 3.34 (m, 1H), 1.23 – 1.73(m, 8H). 1404 1405 469/471 467/469 GA GA A129B09C40 A129B09C15 H NMR (400 MHz, CD3OD-d4) δ8.07 – 8.10 (m, 1H), 7.63 – 7.66 (m, 1H), 7.49 – 7.54 (m, 2 H), 4.16 – 4.18 (m, 1H),3.91 – 3.96 (m, 2H), 3.65 – 3.70 (m, 1H), 3.50 – 3.60 (m, 2H). 1410 1413 469/471 453/455 A110B09C15 A110B09C63 391/393 1419 1420 A128B03C15 A01B21C40 H NMR (400 MHz, CD3OD-d4) δ8.41 – H NMR (400 MHz, CD3OD-d4) δ 8.44 – 8.42 (m, 1H), 8.21 -8.23 (m, 1H), 8.05 - 8.46 (m, 1H), 8.20 -8.30 (m, 1H), 7.94 - 8.07 (m, 1 H), 7.61 -7.65 (m, 2H), 5.06 (s, 7.97 (m, 1 H), 7.60 -7.62 (m, 1H), 7.44 – 2H), 3.74 – 3.77 (m, 1H), 3.52 – 3.56 (m, 7.49 (m, 1H), 7.22 – 7.26 (m, 1H), 3.55 – 2H), 3.03 – 3.06 (m, 2H), 1.87 – 1.92 (m, 3.58 (m, 2H), 3.09 – 3.12 (m, 2H). 2H), 1.57 – 1.62 (m, 2H). 1378_C 435/437 A119B09C63 Also described is a composition comprising a compound of formula (I), or a salt, solvate, or N-oxide thereof. In one embodiment, the composition is pharmaceutical and further comprises at least one pharmaceutically acceptable carrier.

Preparation of the Compounds as described herein Compounds of formula (II) may be prepared by the reaction sequence that is illustrated in Scheme 1.

Scheme 1.

The compound of formula (IV) may be reacted with chlorosulfonic acid to yield the sulfonyl chloride of formula (V). The compound of formula (V) may be reacted with a secondary or primary amine of formula HNR R , in a solvent such as but not limited to tetrahydrofuran, dichloromethane, ethyl ether or a mixture thereof, preferably in the presence of a tertiary base such as but not limited to triethylamine, diisopropylethylamine or pyridine, to yield the compound of formula (VI), which may be coupled to an amine via an amide bond, yielding the compound of formula (II). The amide coupling may be performed in the presence of a coupling agent, such as but not limited to DCC (N,N'-dicyclohexyl carbodiimide), DIC (N,N'-diisopropylcarbodiimide), EDC (1-ethyl(3-dimethylaminopropyl) carbodiimide), HBTU (O-benzotriazole- N,N,N',N'-tetramethyl-uronium-hexafluoro-phosphate), HATU (2-(1H azabenzotriazolyl)-1,1,3,3-tetramethyl uronium hexafluorophosphate methanaminium), HCTU ((2-(6-chloro-1H-benzotriazoleyl)-1,1,3,3- tetramethylaminium hexafluorophosphate), TBTU (O-(benzotriazolyl)-N,N,N',N'- tetramethyluronium tetrafluoroborate), or PyBOP (benzotriazolyl-oxytripyrrolidino- phosphonium hexafluorophosphate), in a solvent such as but not limited to tetrahydrofuran, dichloromethane, or a mixture thereof, and in the optional presence of a tertiary base, such as but not limited to triethylamine, diisopropylethylamine or pyridine.Alternatively, the sulfonyl chloride of formula (V) may be reacted with a chlorinating reagent, such as but not limited to thionyl chloride, phosgene, diphosgene or triphosgene, to yield the acyl chloride of formula (VII). The compound of formula (VII) may then be reacted with an amine in a solvent such as but not limited to tetrahydrofuran, dichloromethane, ethyl ether or a mixture thereof, under conditions that do not promote the reaction of the sulfonyl chloride group with the amine, to yield the compound of formula (VIII), which may then be reacted with the amine HNR R in a solvent such as but not limited to tetrahydrofuran, toluene, dichloromethane, or a mixture thereof, and in the presence of a tertiary base, such as but not limited to triethylamine, diisopropylethylamine or pyridine, to yield the compound of formula (II).

Compounds of formula (III) may be prepared by the reaction scheme that is illustrated in Scheme 2.

Scheme 2.

The compound of formula (IX) may be reacted with a secondary or primary amine of formula HNR R , in a solvent such as but not limited to tetrahydrofuran, dichloromethane, ethyl ether or a mixture thereof, in the presence of a coupling agent, such as but not limited to DCC, EDC, HBTU, HATU, HCTU, TBTU, or PyBOP, in a solvent such as but not limited to tetrahydrofuran, dichloromethane, or a mixture thereof, and in the optional presence of a tertiary base, such as but not limited to triethylamine, diisopropylethylamine or pyridine, to yield the compound of formula (X). The compound of formula (X) may be treated with a base, such as but not limited to lithium hydroxide, sodium hydroxide or potassium hydroxide, to yield the compound of formula (XI). The compound of formula (XI) may be reacted with a secondary or primary amine, in a solvent such as but not limited to tetrahydrofuran, dichloromethane, ethyl ether or a mixture thereof, in the presence of a coupling agent, such as but not limited to DCC, EDC, HBTU, HATU, HCTU, TBTU, or PyBOP, in a solvent such as but not limited to tetrahydrofuran, dichloromethane, or a mixture thereof, and in the optional presence of a tertiary base, such as but not limited to triethylamine, diisopropylethylamine or pyridine, to yield the compound of formula (III).

The compounds as described may possess one or more stereocenters, and each stereocenter may exist independently in either the R or S configuration. In one embodiment, compounds described herein are present in optically active or racemic forms. It is to be understood that the compounds described herein encompass racemic, optically-active, regioisomeric and stereoisomeric forms, or combinations thereof that possess the therapeutically useful properties described herein.

Preparation of optically active forms is achieved in any suitable manner, including by way of non-limiting example, by resolution of the racemic form with recrystallization 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 methods and formulations described herein include the use of N-oxides (if appropriate), crystalline forms (also known as polymorphs), solvates, amorphous phases, and/or pharmaceutically acceptable salts of compounds having the structure of any compound as described, as well as metabolites and active metabolites of these compounds having the same type of activity. Solvates include water, ether (e.g., tethrahydrofuran, methyl tert-butyl ether) or alcohol (e.g., ethanol) solvates, acetates and the like. In one embodiment, the compounds described herein exist in solvated forms with pharmaceutically acceptable solvents such as water, and ethanol. In another embodiment, the compounds described herein exist in unsolvated form.

In one embodiment, the compounds as described may exist as tautomers. All tautomers are included within the scope of the compounds presented herein.

In one embodiment, compounds described herein are prepared as prodrugs. A "prodrug" refers to an agent that is converted into the parent drug in vivo. In one embodiment, upon in vivo administration, a prodrug is chemically converted to the biologically, pharmaceutically or therapeutically active form of the compound. In another embodiment, a pro drug is enzymatically metabolized by one or more steps or processes to the biologically, pharmaceutically or therapeutically active form of the compound.

In one embodiment, sites on, for example, the aromatic ring portion of compounds as described are susceptible to various metabolic reactions. Incorporation of appropriate substituents on the aromatic ring structures may reduce, minimize or eliminate this metabolic pathway. In one embodiment, the appropriate substituent to decrease or eliminate the susceptibility of the aromatic ring to metabolic reactions is, by way of example only, a deuterium, a halogen, or an alkyl group.

Compounds described herein also 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. Examples of isotopes suitable for inclusion in the compounds described 2 3 11 13 14 36 18 123 125 13 15 herein include and are not limited to H, H, C, C, C, Cl, F, I, I, N, N, 17 18 32 35 O, O, O, P, and S. In one embodiment, isotopically-labeled compounds are useful in drug and/or substrate tissue distribution studies. In another embodiment, substitution with heavier isotopes such as deuterium affords greater metabolic stability (for example, increased in vivo half-life or reduced dosage requirements). In yet another 11 18 15 13 embodiment, substitution with positron emitting isotopes, such as C, F, O and 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.

In one embodiment, the compounds described herein are labeled by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.

The compounds described herein, and other related compounds having different substituents are synthesized using techniques and materials described herein and as described, for example, in Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989), March, Advanced Organic Chemistry 4 Ed., (Wiley 1992); Carey and Sundberg, Advanced Organic Chemistry 4th Ed., Vols. A and B (Plenum 2000,2001), and Green and Wuts, Protective Groups in Organic Synthesis 3rd Ed., (Wiley 1999) (all of which are incorporated by reference for such disclosure). General methods for the preparation of compound as described herein are modified by the use of appropriate reagents and conditions, for the introduction of the various moieties found in the formula as provided herein.

Compounds described herein are synthesized using any suitable procedures starting from compounds that are available from commercial sources, or are prepared using procedures described herein.

In one embodiment, reactive functional groups, such as hydroxyl, amino, imino, thio or carboxy groups, are protected in order to avoid their unwanted participation in reactions. 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. In another embodiment, each protective group is removable by a different means. Protective groups that are cleaved under totally disparate reaction conditions fulfill the requirement of differential removal.

In one embodiment, protective groups are removed by acid, base, reducing conditions (such as, for example, hydrogenolysis), and/or oxidative conditions. Groups such as trityl, dimethoxytrityl, acetal and t-butyldimethylsilyl are acid labile and are used to protect carboxy and hydroxy reactive moieties in the presence of amino groups protected with Cbz groups, which are removable by hydrogenolysis, and Fmoc groups, which are base labile. Carboxylic acid and hydroxy reactive moieties are blocked with base labile groups such as, but not limited to, methyl, ethyl, and acetyl, in the presence of amines that are blocked with acid labile groups, such as t-butyl carbamate, or with carbamates that are both acid and base stable but hydrolytically removable.

In one embodiment, carboxylic acid and hydroxy reactive moieties are blocked with hydrolytically removable protective groups such as the benzyl group, while amine groups capable of hydrogen bonding with acids are blocked with base labile groups such as Fmoc. Carboxylic acid reactive moieties are protected by conversion to simple ester compounds as exemplified herein, which include conversion to alkyl esters, or are blocked with oxidatively-removable protective groups such as 2,4-dimethoxybenzyl, while co-existing amino groups are blocked with fluoride labile silyl carbamates.

Allyl blocking groups are useful in the presence of acid- and base- protecting groups since the former are stable and are subsequently removed by metal or pi-acid catalysts. For example, an allyl-blocked carboxylic acid is deprotected with a palladium-catalyzed reaction in the presence of acid labile t-butyl carbamate or base- labile acetate amine protecting groups. Yet another form of protecting group is a resin to which a compound or intermediate is attached. As long as the residue is attached to the resin, that functional group is blocked and does not react. Once released from the resin, the functional group is available to react.

Typically blocking/protecting groups may be selected from: Other protecting groups, plus a detailed description of techniques applicable to the creation of protecting groups and their removal are described in Greene and Wuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley & Sons, New York, NY, 1999, and Kocienski, Protective Groups, Thieme Verlag, New York, NY, 1994, which are incorporated herein by reference for such disclosure.

Assays HBV Capsid Protein Assembly Testing The fluorescence quenching in vitro assembly HBV assay was developed according to a method described by Zlotnick and coworkers (Nature Biotechnology 2006, 24:358). The assay is based on the observation that the C-termini of the HBV core protein cluster together during capsid formation. This assay utilizes a mutant C150 HBV capsid protein where all wild-type cysteines are mutated to alanines, but a C- terminal cysteine residue is preserved and is labeled with fluorescent BoDIPY-FL dye.

HBV C150Bo protein is highly fluorescent, however the fluorescence is drastically reduced during the capsid assembly process. Thus, the assay measures the ability and potency of test compounds to modulate capsid assembly by monitoring the fluorescence of the labeled capsid C150Bo protein.

In a typical assay, the mutant HBV C150 protein (amino acids 1-150, C49A, C61A, C107A, 150C) is cloned into a T7 RNA-polymerase based expression vector, expressed in E.coli and purified to homogeneity as a dimer. The purified HBV core protein is desalted and labeled with BODIPY-FL Dye.

In a non-limiting embodiment, the assembly assay is conducted in 96-well plate format. The assembly reactions are carried out in 50 mM Hepes buffer, pH 7.5 and 150 mM NaCl. The compounds are pre-incubated with the HBV CA protein for 15 min, and the assembly reactions are initiated by addition of NaCl. The reaction is allowed to continue for 1 hour at room temperature.

To determine the effect on capsid assembly, each test compound is initially screened at 4 different concentrations: 10 μM, 3 μM, 1 μM and 0.3 μM in duplicates.

Primary hits are compounds that show activity in the assembly assay at 10 uM and a representative group of these active compounds is shown in Table 1. Identified primary hits are confirmed in follow-up studies as described elsewhere herein. Known modulators of HBV CA assembly, such as HAP-1 and BAY 41-4109, are used as control compounds in these experiments and exhibited EC values consistent with the literature. EC values for test compounds are determined via analysis of the dose- response curve.

HBV Antiviral Testing Compounds active in the HBV assembly assay are tested for their activity and toxicity in cellular assay. In the first anti-viral assay, the ability of compounds to inhibit HBV replication in an HBV-producing hepatoma cell line using the dot-blot method is evaluated.

Briefly, confluent monolayers of HepG2-2.2.15 cells are incubated with complete medium containing various concentrations of a test compound. Three days later, the culture medium is replaced with fresh medium containing the appropriately diluted test compound. Six days following the initial administration of the test compound, the cell culture supernatant is collected, and cell lysis is performed. The samples are applied onto Nylos membranes and DNA is immobilized to the membrane by UV cross-linking. After pre-hybridization, the HBV probe is added and the hybridization is performed overnight. The membranes are exposed to the Kodak films; antiviral activity is calculated from the reduction in HBV DNA levels (EC ). The EC 50 50 for antiviral activity is calculated from the dose response curves of active compounds.

Assay performance over time is monitored by the use of the standard positive control compounds ETV, BAY 41-4109, and HAP-1.

Compound cytotoxity (TC ) is measured in this same HepG2-2.2.15 cell line using a CellTiter Blue-based cytotoxicity assay employed as recommended by manufacturer (Promega). To confirm and expand these results, a second antiviral assay is carried out on active compounds using the stable HBV cell line HepG2.2.15 and measuring anti-HBV potency by real-time PCR and cytotoxicity by CellTiter Blue. In this assay, 24 hours after cell seeding, HepG2-2.2.15 cells are incubated with complete medium containing various concentrations of a test compound with BAY 41-4109 and HAP-1 used as positive controls. After three days, the culture medium is replaced with fresh medium containing the appropriately diluted test compound. The cell culture is collected six days following the initial administration of the test compound, followed by HBV DNA extraction using QIAamp 96 DNA Blood Kit (Qiagen). The extracted HBV DNA is diluted and analyzed by Real-Time PCR. A standard curve is generated by plotting Ct value vs the amount of HBV plasmid standard. Cytotoxicity is determined similarly to the above described method by applying a dye uptake method (CellTiter Blue kit, Promega).

Prevention of HBV Pre-Genomic RNA (pgRNA) Incorporation.

The anti-viral activity of the compounds as described is assessed based on their ability to suppress both extracellular and intracellular HBV DNA production in two different cell culture models of HBV replication. To assess if these effects are due to disruption of intracellular capsid assembly, a particle-gel assay that allows quantitation of intracellular viral capsids, as well as encapsidated pre-genomic RNA and DNA, is performed. The assay relies on agarose gel separation of viral capsid from free capsid/core subunits and viral pg-RNA and DNA.

Methods of Treatment Also described is a method of treatment of an HBV infection in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound as described.

Also described is 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 as described.

Also described is 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 as described.

Also described is a method of reducing the physiological impact of an HBV infection in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound as described.

Also described is a method of reducing, slowing, or inhibiting an HBV infection in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound as described.

Also described is a method of inducing remission of hepatic injury from an HBV infection in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound as described.

Also described is a method of reducing the physiological impact of long-term antiviral therapy for HBV infection in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound as described.

Also described is 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 as described.

Also described is a method of prophylactically treating an HBV infection in an individual in need thereof, wherein the individual is afflicted with a latent HBV infection, comprising administering to the individual a therapeutically effective amount of a compound as described.

In one embodiment, the methods described herein further comprise administering at least one therapeutic agent selected from the group consisting of nucleotide/nucleoside analogs, entry inhibitors, fusion inhibitors, and any combination of these or other antiviral mechanisms. In another embodiment, the compound as described and the at least one additional therapeutic agent are co-formulated. In yet another embodiment, the compound as describedand the at least one additional therapeutic agent are co-administered.

In one embodiment, the individual is refractory to other therapeutic classes of HBV drugs (e.g, HBV polymerase inhibitors, interferons, viral entry inhibitors, viral maturation inhibitors, literature-described capsid assembly modulators, antiviral compounds of distinct or unknown mechanism, and the like, or combinations thereof).

In another embodiment, the method as describedreduces viral load in an individual suffering from an HBV infection to a greater extent compared to the extent that other therapeutic classes of HBV drugs reduce viral load in the individual.

In onw embodiment, the method as describedreduces viral load in an individual suffering from an HBV infection, thus allowing lower doses or varying regimens of combination therapies to be used.

In one embodiment, the method as describedcauses a lower incidence of viral mutation and/or viral resistance compared to other classes of HBV drugs, thereby allowing for long term therapy and minimizing the need for changes in treatment regimens.

In one embodiment, the method as describedincreases the seroconversion rate beyond that of current treatment regimens.

In one embodiment, the method as describedincreases 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.

In one embodiment, the method as describederadicates 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 allowing for reduction in dosing of other antiviral agents.

Accordingly, in one embodiment, described 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 I, or a pharmaceutically acceptable salt thereof.

In another embodiment, described 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 compound of formula II, or a pharmaceutically acceptable salt thereof.

In another embodiment, described 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 compound of formula IIa, or a pharmaceutically acceptable salt thereof.In another embodiment, described 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 compound of formula IIb, or a pharmaceutically acceptable salt thereof.

In another embodiment, described 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 compound of formula IIc, or a pharmaceutically acceptable salt thereof.

In another embodiment, described 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 compound of formula III, or a pharmaceutically acceptable salt thereof.

In another embodiment, described 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 compound of formula IV, or a pharmaceutically acceptable salt thereof.

In another embodiment, described 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 compound of formula IVa, or a pharmaceutically acceptable salt thereof.

In another embodiment, described 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 compound of formula IVb, or a pharmaceutically acceptable salt thereof.

In another embodiment, described 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 compound of formula IVc, or a pharmaceutically acceptable salt thereof.

In another embodiment, described 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 compound of formula V, or a pharmaceutically acceptable salt thereof.

In another embodiment, described 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 compound of formula VI, or a pharmaceutically acceptable salt thereof.

In another embodiment, described 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 compound of formula VIa, or a pharmaceutically acceptable salt thereof.

In another embodiment, described 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 compound of formula VIb, or a pharmaceutically acceptable salt thereof.

In another embodiment, described 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 compound of formula VII, or a pharmaceutically acceptable salt thereof.

Accordingly, in one embodiment, described 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 compound 318.

In another embodiment, described 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 compound 890.

In another embodiment, described 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 compound 826.

In another embodiment, described 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 compound 891.

In another embodiment, described 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 compound 903.

In another embodiment, described 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 compound 917.

In another embodiment, described 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 compound 924.

In another embodiment, described 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 compound 922 In another embodiment, described 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 compound 955D1.

In another embodiment, described 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 compound 955D2 In another embodiment, described 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 compound 129.

In another embodiment, described 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 compound 132.

In another embodiment, described 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 compound 142.

In another embodiment, described 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 compound 278.

In another embodiment, described 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 compound 305.

In another embodiment, described 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 compound 318.

In another embodiment, described 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 compound 404.

In another embodiment, described 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 compound 507.

In another embodiment, described 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 compound 531.

In another embodiment, described 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 compound 597D1.

In another embodiment, described 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 compound 634.

In another embodiment, described 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 compound 694.

In another embodiment, described 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 compound 754.

In another embodiment, described 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 compound 758.

In another embodiment, described 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 compound 768.

In another embodiment, described 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 compound 803.

In another embodiment, described 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 compound 820.

In another embodiment, described 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 compound 919.

In another embodiment, described 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 compound 824_D1.

In another embodiment, described 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 compound 824_D2.

In another embodiment, described 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 compound 825_D1.

In another embodiment, described 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 compound 825_D2.

In another embodiment, described 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 compound 826.

In another embodiment, described 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 compound 843.

In another embodiment, described 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 compound 851.

In another embodiment, described 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 compound 1157.

In another embodiment, described 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 compound 867_D1.

In another embodiment, described 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 compound 867_D2.

In another embodiment, described 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 compound 875.

In another embodiment, described 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 compound 1161.

In another embodiment, described 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 compound 901.

In another embodiment, described 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 compound 903.

In another embodiment, described 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 compound 916.

In another embodiment, described 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 compound 960D1.

In another embodiment, described 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 compound 960D2.

In another embodiment, described 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 compound 953.

In another embodiment, described 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 compound 922.

In another embodiment, described 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 compound 924.

In another embodiment, described 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 compound 927.

In another embodiment, described 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 compound 931.

In another embodiment, described 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 compound 935.

In another embodiment, described 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 compound 942.

In another embodiment, described 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 compound 946D1.

In another embodiment, described 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 compound 946D2.

In another embodiment, described 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 compound 955D1.

In another embodiment, described 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 compound 955D2.

In another embodiment, described 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 compound 952.

In another embodiment, described 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 compound 958.

In another embodiment, described 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 compound 964D1.

In another embodiment, described 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 compound 964D2.

In another embodiment, described 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 compound 976D1.

In another embodiment, described 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 compound 988.

In another embodiment, described 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 compound 1008.

In another embodiment, described 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 compound 1021.

In another embodiment, described 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 compound 1022.

In another embodiment, described 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 compound 1035.

In another embodiment, described 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 compound 1078D1.

In another embodiment, described 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 compound 1086.

In another embodiment, described 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 compound 1091.

In another embodiment, described 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 compound 1105.

In another embodiment, described 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 compound 1114.

In another embodiment, described 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 compound 1126.

In another embodiment, described 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 compound 1134CT1.

In another embodiment, described 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 compound 1134CT2.

In another embodiment, described 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 compound 1149.

In another embodiment, described 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 compound 1281D1.

In another embodiment, described 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 compound 1281D2.

In another embodiment, described 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 compound 1116.

In another embodiment, described 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 compound 1130.

In another embodiment, described 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 compound 1135D1.

Combination Therapies The compounds as describedare intended to be useful in combination with one or more additional compounds useful for treating HBV infection. These additional compounds may comprise compounds as describedor compounds known to treat, prevent, 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, and other agents with distinct or unknown mechanisms that affect the HBV life cycle and/or affect the consequences of HBV infection.

In non-limiting examples, the compounds as describedmay be used in combination with one or more drugs (or a salt, solvate or prodrug thereof) selected from the group consisting of HBV reverse transcriptase inhibitors, and DNA and RNA polymerase inhibitors, including but are not limited to: lamivudine (3TC, Zeffix, Heptovir, Epivir, and Epivir- HBV), entecavir (Baraclude, Entavir), adefovir dipivoxil (Hepsara, Preveon, bis-POM PMEA), tenofovir disoproxil fumarate (Viread, TDF or PMPA); interferons, including but not limited to interferon alpha (IFN-α), interferon lambda (IFN-λ), and interferon gamma (IFN-γ); viral entry inhibitors; viral maturation inhibitors; literature-described capsid assembly modulators, such as but not limited to BAY 41-4109; compounds of distinct or unknown mechanism, such as but not limited to AT-61 ((E)-N-(1-chlorooxophenyl(piperidinyl)propenyl)benzamide), AT-130 ((E)-N-(1-bromo(2-methoxyphenyl)oxo(piperidinyl)propenyl) nitrobenzamide), and similar analogs.

In another embodiment, the additional therapeutic agent selected from immune modulator or immune stimulator therapies, which includes biological agents belonging to the interferon class, such as interferon alpha 2a or 2b or modified interferons such as pegylated interferon, alpha 2a, alpha 2b, lamda; or TLR modulators such as TLR-7 agonists or TLR-9 agonists, or antiviral agents that block viral entry or maturation or target the HBV polymerase such as nucleoside or nucleotide or non-nucleos(t)ide polymerase inhibitors, and agents 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.

In an embodiment of the combination therapy, the reverse transcriptase inhibitor and/or DNA and/or RNA polymerase inhibitor Zidovudine, Didanosine, Zalcitabine, ddA, Stavudine, Lamivudine, Abacavir, Emtricitabine, Entecavir, Apricitabine, Atevirapine, ribavirin, acyclovir, famciclovir, valacyclovir, ganciclovir, valganciclovir, Tenofovir, Adefovir, PMPA, cidofovir, Efavirenz, Nevirapine, Delavirdine, or Etravirine.

In another embodiment of the combination therapy, the TLR-7 agonist is selected from the group consisting of SM360320 (9-benzylhydroxy(2-methoxy- ethoxy)adenine) and AZD 8848 (methyl [3-({[3-(6-aminobutoxyoxo-7,8-dihydro- 9H-purinyl)propyl][3-(4-morpholinyl)propyl]amino}methyl)phenyl]acetate).

A synergistic effect may be calculated, for example, using suitable methods such as, for example, the Sigmoid-E equation (Holford & Scheiner, 19981, Clin.

Pharmacokinet. 6: 429-453), the equation of Loewe additivity (Loewe & Muischnek, 1926, Arch. Exp. Pathol Pharmacol. 114: 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 above are the concentration-effect curve, isobologram curve and combination index curve, respectively.

Administration/Dosage/Formulations The regimen of administration may affect what constitutes an effective amount.

The therapeutic formulations may be administered to the patient either prior to or after the onset of a HBV infection. Further, several divided dosages, as well as staggered dosages may be administered daily or sequentially, or the dose may be continuously infused, or may be a bolus injection. Further, the dosages of the therapeutic formulations may be proportionally increased or decreased as indicated by the exigencies of the therapeutic or prophylactic situation.

Administration of the compositions as describedto a patient, preferably a mammal, more preferably a human, may be carried out using known procedures, at dosages and for periods of time effective to treat HBV infection in the patient. An effective amount of the therapeutic compound necessary to achieve a therapeutic effect may vary according to factors such as the state of the disease or disorder in the patient; the age, sex, and weight of the patient; and the ability of the therapeutic compound to treat HBV infection in the patient. Dosage regimens may be adjusted to provide the optimum therapeutic response. For example, several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation. A non-limiting example of an effective dose range for a therapeutic compound as describedis from about 1 and 5,000 mg/kg of body weight/per day. One of ordinary skill in the art would be able to study the relevant factors and make the determination regarding the effective amount of the therapeutic compound without undue experimentation.

Actual dosage levels of the active ingredients in the pharmaceutical compositions as describedmay 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.

In particular, 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 materials used in combination with the compound, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well, known in the medical arts.

A medical doctor, e.g., physician or veterinarian, having ordinary skill in the art may readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician or veterinarian could start doses of the compounds as describedemployed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.

In particular embodiments, it is especially advantageous to formulate the compound in dosage unit form for ease of administration and uniformity of dosage.

Dosage unit form as used herein 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 as describedare 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/formulating such a therapeutic compound for the treatment of HBV infection in a patient.

In one embodiment, the compositions as describedare formulated using one or more pharmaceutically acceptable excipients or carriers. In one embodiment, the pharmaceutical compositions as describedcomprise a therapeutically effective amount of a compound as describedand a pharmaceutically acceptable carrier.

The carrier may be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils. The proper fluidity may be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prevention of the action of microorganisms may be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, sodium chloride, or polyalcohols such as mannitol and sorbitol, in the composition. Prolonged absorption of the injectable compositions may be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate or gelatin. In one embodiment, the pharmaceutically acceptable carrier is not DMSO alone.

In one embodiment, the compositions as describedare administered to the patient in dosages that range from one to five times per day or more. In another embodiment, the compositions as describedare administered to the patient in range of dosages that include, but are not limited to, once every day, every two, days, every three days to once a week, and once every two weeks. It will be readily apparent to one skilled in the art that the frequency of administration of the various combination compositions as describedwill vary from individual to individual depending on many factors including, but not limited to, age, disease or disorder to be treated, gender, overall health, and other factors. Thus, the present description should not be construed to be limited to any particular dosage regime and the precise dosage and composition to be administered to any patient will be determined by the attending physical taking all other factors about the patient into account.

Compounds as describedfor administration may be in the range of from about 1 μg to about 10,000 mg, about 20 μg to about 9,500 mg, about 40 μg to about 9,000 mg, about 75 μg to about 8,500 mg, about 150 μg to about 7,500 mg, about 200 μg to about 7,000 mg, about 3050 μg to about 6,000 mg, about 500 μg to about 5,000 mg, about 750 μg to about 4,000 mg, about 1 mg to about 3,000 mg, about 10 mg to about 2,500 mg, about 20 mg to about 2,000 mg, about 25 mg to about 1,500 mg, about 30 mg to about 1,000 mg, about 40 mg to about 900 mg, about 50 mg to about 800 mg, about 60 mg to about 750 mg, about 70 mg to about 600 mg, about 80 mg to about 500 mg, and any and all whole or partial increments therebetween.

In some embodiments, the dose of a compound as describedis from about 1 mg and about 2,500 mg. In some embodiments, a dose of a compound as described 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. Similarly, in some embodiments, a dose of a second compound (i.e., a drug used for treating Parkinson’s Disease ) as described herein 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.

In one embodiment, described is a packaged pharmaceutical composition comprising a container holding a therapeutically effective amount of a compound as described, 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.

Formulations may be employed in admixtures with conventional excipients, i.e., pharmaceutically acceptable organic or inorganic carrier substances suitable for oral, parenteral, nasal, intravenous, subcutaneous, enteral, or any other suitable mode of administration, known to the art. The pharmaceutical preparations may be sterilized and if desired mixed with auxiliary agents, e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure buffers, coloring, flavoring and/or aromatic substances and the like. They may also be combined where desired with other active agents, e.g., other analgesic agents.

Routes of administration of any of the compositions as describedinclude oral, nasal, rectal, intravaginal, parenteral, buccal, sublingual or topical. The compounds for use as describedmay be formulated for administration by any suitable route, such as for oral or parenteral, for example, transdermal, transmucosal (e.g., sublingual, lingual, (trans)buccal, (trans)urethral, vaginal (e.g., trans- and perivaginally), (intra)nasal and (trans)rectal), intravesical, intrapulmonary, intraduodenal, intragastrical, intrathecal, subcutaneous, intramuscular, intradermal, intra-arterial, intravenous, intrabronchial, inhalation, and topical administration.

Suitable 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 administration 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.

Oral Administration For oral application, particularly suitable are tablets, dragees, liquids, drops, suppositories, or capsules, caplets and gelcaps. The 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 consisting of inert, non-toxic pharmaceutically excipients that are suitable for the manufacture of tablets. Such 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.

For oral administration, the compounds as describedmay be in the form of tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g., polyvinylpyrrolidone, hydroxypropylcellulose or hydroxypropylmethylcellulose); fillers (e.g., cornstarch, lactose, microcrystalline cellulose or calcium phosphate); lubricants (e.g., magnesium stearate, talc, or silica); disintegrates (e.g., sodium starch glycollate); or wetting agents (e.g., sodium lauryl sulphate). If desired, the tablets may be coated using suitable methods and coating materials such as OPADRY™ film coating systems available from Colorcon, West Point, Pa. (e.g., OPADRY™ OY Type, OYC Type, Organic Enteric OY-P Type, Aqueous Enteric OY-A Type, OY-PM Type and OPADRY™ White, 32K18400).

Liquid preparation for oral administration may be in the form of solutions, syrups or suspensions. The liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, methyl cellulose or hydrogenated edible fats); emulsifying agent (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters or ethyl alcohol); and preservatives (e.g., methyl or propyl p-hydroxy benzoates or sorbic acid).

Granulating techniques are well known in the pharmaceutical art for modifying starting powders or other particulate materials of an active ingredient. The powders are typically mixed with a binder material into larger permanent free-flowing agglomerates or granules referred to as a "granulation." For example, solvent-using "wet" granulation processes are generally characterized in that the powders are combined with a binder material and moistened with water or an organic solvent under conditions resulting in the formation of a wet granulated mass from which the solvent must then be evaporated.

Melt granulation generally consists in the use of materials that are solid or semi- solid at room temperature (i.e. having a relatively low softening or melting point range) to promote granulation of powdered or other materials, essentially in the absence of added water or other liquid solvents. The low melting solids, when heated to a temperature in the melting point range, liquefy to act as a binder or granulating medium.

The liquefied solid spreads itself over the surface of powdered materials with which it is contacted, and on cooling, forms a solid granulated mass in which the initial materials are bound together. The resulting melt granulation may then be provided to a tablet press or be encapsulated for preparing the oral dosage form. Melt granulation improves the dissolution rate and bioavailability of an active (i.e. drug) by forming a solid dispersion or solid solution.

U.S. Patent No. 5,169,645 discloses directly compressible wax-containing granules having improved flow properties. The granules are obtained when waxes are admixed in the melt with certain flow improving additives, followed by cooling and granulation of the admixture. In certain embodiments, only the wax itself melts in the melt combination of the wax(es) and additives(s), and in other cases both the wax(es) and the additives(s) will melt.

The present description also includes a multi-layer tablet comprising a layer providing for the delayed release of one or more compounds as described, and a further layer providing for the immediate release of a medication for treatment of Parkinson’s Disease. Using a wax/pH-sensitive polymer mix, a gastric insoluble composition may be obtained in which the active ingredient is entrapped, ensuring its delayed release.

Parenteral Administration For parenteral administration, the compounds as describedmay be formulated for injection or infusion, for example, intravenous, intramuscular or subcutaneous injection or infusion, or for administration 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.

Additional Administration Forms Additional dosage forms include dosage forms as described in U.S. Patents Nos. 6,340,475; 6,488,962; 6,451,808; 5,972,389; 5,582,837; and 5,007,790. Additional dosage forms also include dosage forms as described in U.S. Patent Applications Nos. 20030147952; 20030104062; 20030104053; 20030044466; 20030039688; and 20020051820. Additional dosage forms also include dosage forms as described in PCT Applications Nos. WO 03/35041; WO 03/35040; WO 03/35029; WO 03/35177; WO 03/35039; WO 02/96404; WO 02/32416; WO 01/97783; WO 01/56544; WO 01/32217; WO 98/55107; WO 98/11879; WO 97/47285; WO 93/18755; and WO 90/11757.

Controlled Release Formulations and Drug Delivery Systems In one embodiment, the formulations as describedmay be, but are not limited to, short-term, rapid-offset, as well as controlled, for example, sustained release, delayed release and pulsatile release formulations.

The term sustained release is used in its conventional sense to refer to a drug formulation that provides for gradual release of a drug over an extended period of time, and that may, although not necessarily, result in substantially constant blood levels of a drug over an extended time period. The period of time may be as long as a month or more and should be a release which is longer that the same amount of agent administered in bolus form.

For sustained release, the compounds may be formulated with a suitable polymer or hydrophobic material which provides sustained release properties to the compounds.

As such, the compounds for use the method as describedmay be administered in the form of microparticles, for example, by injection or in the form of wafers or discs by implantation.

In one embodiment, the compounds as describedare administered to a patient, alone or in combination with another pharmaceutical agent, using a sustained release formulation.

The term delayed release is used herein in its conventional sense to refer to a drug formulation that provides for an initial release of the drug after some delay following drug administration and that mat, although not necessarily, includes a delay of from about 10 minutes up to about 12 hours.

The term pulsatile release is used herein in its conventional sense to refer to a drug formulation that provides release of the drug in such a way as to produce pulsed plasma profiles of the drug after drug administration.

The term immediate release is used in its conventional sense to refer to a drug formulation that provides for release of the drug immediately after drug administration.

As used herein, short-term refers to any period of time up to and including about 8 hours, about 7 hours, about 6 hours, about 5 hours, about 4 hours, about 3 hours, about 2 hours, about 1 hour, about 40 minutes, about 20 minutes, or about 10 minutes and any or all whole or partial increments thereof after drug administration after drug administration.

As used herein, rapid-offset refers to any period of time up to and including about 8 hours, about 7 hours, about 6 hours, about 5 hours, about 4 hours, about 3 hours, about 2 hours, about 1 hour, about 40 minutes, about 20 minutes, or about 10 minutes, and any and all whole or partial increments thereof after drug administration.

Dosing The therapeutically effective amount or dose of a as described will depend on the age, sex and weight of the patient, the current medical condition of the patient and the progression of HBV infection in the patient being treated. The skilled artisan will be able to determine appropriate dosages depending on these and other factors.

A suitable dose of a compound as describedmay be in the range of from about 0.01 mg to about 5,000 mg per day, such as from about 0.1 mg to about 1,000 mg, for example, from about 1 mg to about 500 mg, such as about 5 mg to about 250 mg per day. The dose may be administered in a single dosage or in multiple dosages, for example from 1 to 4 or more times per day. When multiple dosages are used, the amount of each dosage may be the same or different. For example, a dose of 1 mg per day may be administered as two 0.5 mg doses, with about a 12-hour interval between doses.

It is understood that the amount of compound dosed per day may be administered, in non-limiting examples, every day, every other day, every 2 days, every 3 days, every 4 days, or every 5 days. For example, with every other day administration, a 5 mg per day dose may be initiated on Monday with a first subsequent 5 mg per day dose administered on Wednesday, a second subsequent 5 mg per day dose administered on Friday, and so on.

In the case wherein the patient's status does improve, upon the doctor's discretion the administration of the inhibitor as describedis optionally given continuously; alternatively, the dose of drug being administered is temporarily reduced or temporarily suspended for a certain length of time (i.e., a "drug holiday"). The length of the drug holiday optionally varies between 2 days and 1 year, including by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days, 180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days, or 365 days. The dose reduction during a drug holiday includes from 10%-100%, including, by way of example only, 10%, %,20%,25%,30%, 35%,40%,45%,50%,55%,60%,65%,70%,75%,80%,85%,90%, 95%, or 100%.

Once improvement of the patient's conditions has occurred, a maintenance dose is administered if necessary. Subsequently, the dosage or the frequency of administration, or both, is reduced, as a function of the viral load, to a level at which the improved disease is retained. In one embodiment, patients require intermittent treatment on a long-term basis upon any recurrence of symptoms and/or infection.

The compounds for use in the method as describedmay be formulated in unit dosage form. The term "unit dosage form" refers to physically discrete units suitable as unitary dosage for patients undergoing treatment, with each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, optionally in association with a suitable pharmaceutical carrier. The unit dosage form may be for a single daily dose or one of multiple daily doses (e.g., about 1 to 4 or more times per day). When multiple daily doses are used, the unit dosage form may be the same or different for each dose.

Toxicity and therapeutic efficacy of such therapeutic regimens are optionally determined in cell cultures or experimental animals, including, but not limited to, the determination of the LD (the dose lethal to 50% of the population) and the ED (the 50 50 dose therapeutically effective in 50% of the population). The dose ratio between the toxic and therapeutic effects is the therapeutic index, which is expressed as the ratio between LD and ED . Capsid assembly inhibitors exhibiting high therapeutic indices 50 50 are preferred. The data obtained from cell culture assays and animal studies is optionally used in formulating a range of dosage for use in human. The dosage of such capsid assembly inhibitors lies preferably within a range of circulating concentrations that include the ED with minimal toxicity. The dosage optionally varies within this range depending upon the dosage form employed and the route of administration utilized.

Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, numerous equivalents to the specific procedures, embodiments, claims, and examples described herein. Such equivalents were considered to be within the scope of this invention and covered by the claims appended hereto. For example, it should be understood, that modifications in reaction conditions, including but not limited to reaction times, reaction size/volume, and experimental reagents, such as solvents, catalysts, pressures, atmospheric conditions, e.g., nitrogen atmosphere, and reducing/oxidizing agents, with art-recognized alternatives and using no more than routine experimentation, are within the scope of the present application.

It is to be understood that wherever values and ranges are provided herein, all values and ranges encompassed by these values and ranges, are meant to be encompassed within the scope of the present invention. Moreover, all values that fall within these ranges, as well as the upper or lower limits of a range of values, are also contemplated by the present application.

In this specification where reference has been made to patent specifications, other external documents, or other sources of information, this is generally for the purpose of providing a context for discussing the features of the invention. Unless specifically stated otherwise, reference to such external documents is not to be construed as an admission that such documents, or such sources of information, in any jurisdiction, are prior art, or form part of the common general knowledge in the art.

The following examples further illustrate aspects of the present invention.

However, they are in no way a limitation of the teachings or disclosure of the present invention as set forth herein.

EXAMPLES The invention is now described with reference to the following Examples. These Examples are provided for the purpose of illustration only, and the invention is not limited to these Examples, but rather encompasses all variations that are evident as a result of the teachings provided herein.

Materials: Unless otherwise noted, all starting materials and resins were obtained from commercial suppliers and used without purification.

Library General Design Region A (amines and amino alcohols): Region B (core variation) ： Region C (anilines, amines and aryl carboxylic acids): F F F F F F F N N N N N H H H H H F F F F F C60 C61 C62 C63 C64 C65 Part I Intermediate Synthesis (Regions A, B &C) 1 Preparation of Region A intermediates 1.1 Preparation of A46/47/48 1.1.1 Synthetic procedure for preparation 2 To a solution of Compound 1 (5 g, 21.8 mmol) and N,O_Dimethylhydroxylamine (1.6 g, 26.2 mmol) in DCM (50 mL) was added HATU (9.9 g, 26.2 mmol) and Et N (2.65 g, 26.2 mmol) at rt. The formed mixture was stirred at rt overnight. The mixture was washed with water, and purified by column chromatography to give the desired product (3 g, 51%). 1.1.2 Preparation of Compound 3 To a solution of Compound 2 (500 mg, 1.84 mmol) in anhydrous THF (5 mL) was added CH3MgBr (0.8 mL, 2.4 mmol) at 0 ℃. The formed mixture was allowed to warm to room temperature. The reaction was quenched with aqueous NH Cl solution.

The organic layer was separated and extracted with EtOAc (10 mLx2). The combined organic layers were concentrated to give the crude product, which was purified by column chromatography to give the desired product (300 mg, 72%). H NMR (400 MHz, CDCl ): δ ppm: 4.04(br, 2H), 2.73(t, 2H), 2.43(m, 1H), 2.15(s, 3H), 1.82(m, 2H), 1.53(m, 2H), 1.45(s, 9H). 1.2.3 Preparation of A46 To a solution of Compound 3 (350 mg, 1.54 mmol) in anhydrous DCM (5 mL) was added HCl in dioxane (2 mL) at 0 C. The formed mixture was stirred for 2 h. The formed mixture was concectrated to give the desired product which was used for the next step (260 mg, 100%).

A47/48 were preparaed following the similar procedure as A46. 1.2 Preparation of A73-80 2.1 Preparation of compound 2 To RMgBr (0.5 M, 20 mmol) in THF was added a solution of Compound 1 (2.0 g, 10.56 mmol) in THF (20 mL) at 0-4 ℃. The formed mixture was stirred at rt for 3 h.

The reaction was quenched by NH Cl solution, and the mixture was extracted with EtOAc (20 mLx3). The organic layer was concentrated to give the crude product, which was purified by column chromatography to give the desired product. 2.2 Preparation of compound 3 NaH, MeI R OH To a solution of Compound 2 (10 mmol) in DMF (40 mL) was added NaH (10 mmol) at 0 ℃, After stirring for 30 min, a solution of MeI (10 mmol) in DMF(5 mL) was added dropwise, and stirred at rt for 4 h. The mixture was poured into water and extracted with EA. The combined organic phase was washed with brine, dried over Na SO , and concentrated in vacuo. The residue was purified through column chromatography to give the desired product. 2.3 Preparation of A73-80 To a solution of Compound 2 or 3 in MeOH was added Pd(OH) /C (100 mg), and the formed mixture was stirred under H at 50 psi overnight. The Pd was filtered and the filtrate was concentrated to give the desired product. 1.3 Preparation of A81/82 1.3.1 Preparation of Compound 2 To a solution of Compound 1 (1.9 g, 10 mmol) in DMSO (30 mL) was added Me SOI (3.3 g, 15 mmol), followed by NaH (0.6 g, 16 mmol) at 0 ℃. The formed mixture was stirred at rt overnight. The mixture was poured into water and extracted with EA. The combined organic phases were washed with brine, dried over Na SO , and concentrated in vacu. The residue was purified through column chromatography to give the desired product. (0.46 g, 23%). H NMR (400 MHz, CDCl ): δ: 7.34(m, 4H), 7.30(m, 1H), 3.55(s, 2H), 2.62(s, 2H), 2.55 (m, 4H), 1.83(m, 2H), 1.52(m, 2H). 1.3.2 Preparation of Compound 3 A mixture of Compound 2 (3.0 g, 14.76 mmol) in H SO (60 mL, 0.2 M) was stirred at rt overnight. The mixture was neutralized with NaOH solution to pH8. The formed mixture was extracted with EtOAc. The combined organic layers were concentrated to give the desired product (1.5 g, 46%). H NMR (400 MHz, CDCl ): δ ppm: 7.32(m, 4H), 7.27(m, 1H), 3.52(s, 2H), 3.44(s, 2H), 2.64 (m, 2H), 2.36(m, 2H), 2.03(m, 2H), 1.59(m, 4H). 1.3.3 Preparation of A81 To a solution of Compound 3 (500 mg, 2 mmol) in CH OH (5 mL) was added Pd(OH) /C (50 mg). The formed mixture was hydrogenated overnight under H atmosphere. The catalyst was filtered and the filtrate was concentrated to give the desired product (200 mg, 68%). 1.3.4 Preparation of compound 4 To a solution of A12 (100 mg, 0.762 mmol) and Et N (116 mg, 1.14 mmol) in MeOH (3 mL) was added Boc O (200 mg, 0.915 mmol) at rt. The formed mixture was stirred overnight. The mixture was concentrated and diluted with DCM (20 ml). The resulting mixture was washed with water. The organic layer was concentrated to give the crude product which was used for the next step (180 mg, 68%). 1.3.5 Preparation of compound 5 To a suspension of NaH (125 mg, 3.11 mmol) in THF (3 mL) was added a solution of compound 4 (240 mg, 1.04 mmol) at rt. The formed mixture was stirred for minutes. Then CH I (736 mg, 5.19 mmol) was added to the above mixture. The mixture was stirred overnight. The reaction was quenched by water, and the formed mixture was concentrated to give the crude product, which was purified by column chromatography to give the desired product (200 mg, 74%). H NMR (400 MHz, CDCl ): δ ppm: 3.72(m, 2H), 3.35(s, 3H), 3.29(s, 2H), 3.24(s, 3H), 3.06 (m, 2H), 1.74(m, 2H), 1.47(m, 1H), 1.46(s, 9H), 1.42(m, 1H). 1.3.6 Preparation of A82 Compound 5 (200 mg, 0.77 mmol) was treated with 4 N HCl in methanol (10 mL), and stirred at rt for 20 min. The mixture was concentrated in vacuo to give a HCl salt (150 mg, 99 %). 1.4 Preparation of A67-72 Boc Boc H N N N HCl LiAlH 1. LDA Boc O 2. RX O O O O OH 12 3 A67/68/69 Boc Boc H N N N NaH, MeI R R R R=Me, Et, PhCH OH O O 4 A70/71/72 1.4.1 Preparation of compound 2 LDA (4 mmol) was added to a solution of dry THF (20 mL) slowly at -30℃ .

The solution was chilled to -75℃ and then Compound 1 (1.00 g, 3.89 mmol) in THF (10 mL) was added dropwise. After addition, the reaction mixture was stirred for 1h at -30 ℃. RX (5 mmol) in THF (10 mL) was added dropwise. The resulted mixture was stirred at RT overnight. Aqueous NH Cl (30 mL) was added and the aqueous layer was extracted with ethyl acetate (20 mL 3). The organic layer was dried and concentrated to give the crude product, which was purified by column on silica gel to give the product. 1.4.2 Preparation of compound 3 Compound 2 (4.87 mmol) was dissolved in HCl/dioxane (20 mL). The mixture was stirred at RT for 2 h. The solvent was removed to give the product. 1.4.3 Preparation of A67/68/69 LiAlH (367.80 mg, 9.93 mmol) was suspended in dry THF (30 mL) at 0 ℃ .

Compound 3 (4.96 mmol) in dry THF (10 mL) was added slowly. The reaction mixture was stirred at RT overnight. The reaction mixture was quenched with water (0.37 mL) and 10% NaOH (0.37 mL), then water (1.11 mL) was added. The mixture was stirred at RT for 30 min and filtered. The filtrate was concentrated to give the product. 1.4.4 Preparation of compound 4 To a mixture of TEA (6 mmol) and Boc O (5 mmol) in DCM (40 mL) was added A14/15/16 (4.2 mmol), and stirred at rt overnight. The mixture was washed with 1N HCl, NaHCO3 and brine, dried over Na SO , and concentrated in vacuo. The residue was purified through column chromatography to give the desired product. 1.4.5 Preparation of compound 5 NaH (13 mmol) was suspended in dry THF (10 mL) and cooled to 0℃. A solution of compound 4 (6.55 mmol) in dry THF (10 mL) was added slowly. The reaction mixture was stirred at 0℃ for 20 min and then MeI (1.4 g, 9.8 mmol) was added dropwise. The resulted mixture was stirred at RT overnight. The reaction mixture was washed with water and concentrated. The residue was purified through column chromatography to give the desired product. 1.4.6 Preparation of A70/71/72 Compound 5 (3.4 mmol) was dissolved in HCl/dioxane (20 mL) . The mixture was stirred at RT for 2h. The solvent was removed to give the product. 1.5 Preparation of A84-89 1.5.1 Preparation of compound 2 To a solution of compound 1 (2.0 g, 7.37 mmol) and K CO (3.06 g, 22.11 mmol) in acetone (80 mL) was added RX (2.30 g, 14.74mmol) slowly at RT. The reaction mixture was stirred under reflux overnight. The reaction mixture was filtered and concentrated. The residue was dissolved in water (50 mL) and extracted with ethyl acetate (50 mL2). The organic layer was dried and concentrated to give the product. 1.5.2 Preparation of compound 3 Compound 2 (13.36 mmol) was dissolved in 20% HCl (50 mL). The reaction mixture was stirred under reflux for 2 days. The solvent was removed and the crude product was dissolved in THF (100 mL) and H O (20 mL). Boc O (5.83 g, 26.73 mmol ) and Na CO (4.25 g, 40.10 mmol) was added. The reaction mixture was stirred at RT overnight. The crude product was purified by column to give the product. 1.5.3 Preparation of compound 4 To a solution of compound 3 (11.00 mmol) in ethanol (50 mL) was added KBH (0.712 g, 13.20mmol) slowly at 0 ℃. The reaction mixture was stirred at 0 ℃for 0.5 h and the stirred at RT for 2 h. The reaction mixture was pure into water (50 mL) and extracted with DCM (50 mL3). The organic layer was dried and concentrated to give the product. 1.5.4 Preparation of A84/85/86 Compound 4 (4.36 mmol) was dissolved in HCl/dioxane (20 mL). The mixture was stirred at RT for 2 h. The solvent was removed to give the product. 1.5.5 Preparation of compound 5 To a solution of Compound 4 (17 mmol) in dry THF (10 mL) was added NaH (20mmol) at 0ºC slowly. The reaction mixture was stirred at 0℃ slowly, then MeI (20 mmol) was added dropwise. The resulted mixture was stirred at RT overnight. The reaction mixture was washed with water and concentrated. Purification by chromatograph gave the product. 1.5.4 Preparation of A87/88/89 Compound 5 (5.5 mmol) was dissolved in HCl/dioxane (25 mL). The mixture was stirred at RT for 2 h. The solvent was removed to give the product. 1.6 Preparation of A103/104 1.6.1 Preparation of compound 2 To a solution of compound 1 (1.9 mmol) was added NaOH (1.9 mmol) in MeOH (20 ml), and stirred at rt for 30 min. NaBH4 (14.4 mmol) was added in portions, and the mixture was stirred at rt overnight. Water was added slowly, and stirred at rt for 30 min.

The mixture was extracted with EA. The combined organic phase was washed with brine, dried over Na SO , and concentrated in vacuo. The residue was purified through column chromatography to give the desired product. 1.6.2 Preparation of A104 To a solution of compound 2 (450 mg, 2 mmol) in MeOH (50 mL) was added Pd(OH) /C (100 mg), and the formed mixture was stirred under H at 50psi overnight.

The catalyst was filtered and the filtrate was concentrated to give the desired product (230 mg, 88 %).

A103 was prepared following the same procedure with A104. 1.7 Preparation of A90/91/92 1.7.1 Preparation of compound 2 A solution of ethyl acetate (2.11 g, 24 mmol) in THF (30 mL) was added to lithium diisopropylamide solution (13 mL, 2.0 M in THF, 26 mmol) at -78 C. After stirring at the same temperature for 30 min, a solution of Compound 1 (3.8 g, 20 mmol) in THF (30 mL) was added and the mixture was stirred for 15 h at -40 C. The reaction solution was quenched with saturated NH Cl (100 mL) and extracted with ethyl acetate (250 mL 2). The combined organic layers were dried (Na SO ) and concentrated in vacuum. Column chromatography of the residue, using petroleum ether/ethyl acetate (2:1) as eluent, gave Compound 2 as white solid. (4.2 g, yield: 80%). 1.7.2 Preparation of compound 3 Compound 2 (2.63 g, 10 mmol) was dissolved in THF (40 mL), then LiAlH (380 mg, 10 mmol) was added, the mixture was stirred at rt for 1 h. Water (0.4 g) was added, then NaOH (0.4 mL, 10%) was added, the mixture was stirred for 30 min, water (1.2 mL) was added, the solid was filtered, the filtrate was concentrated and extracted with EtOAc (100 mL), the organic layer was concentrated to give desired Compound 3 (2.1 g, yield: 90%) 1.7.3 Preparation of A90 To a solution of compound 3 (460 mg, 2 mmol) in CH OH (5 mL) was added Pd(OH) /C (50 mg). The formed mixture was hydrogenated overnight under H atmosphere. The catalyst was filtered and the filtrate was concentrated to give the desired product A90 (190 mg, 68%). 1.7.4 Preparation of compound 4 A90 (1.45 g, 10 mmol) was dissolved in MeOH (20 mL), then Boc O (2.16 g, 10 mmol) and TEA (1.5 g, 15 mmol) was added. The mixture was stirred at rt for 3 h. The solution was concentrated and dissolved with EA, washed with 1N HCl and NaHCO3, concentrated in vacuo to give desired compound 2 (2.3 g, yield: 100 %). 1.7.5 Preparation of compound 5 To a suspension of NaH (240 mg, 6 mmol) in THF (10 mL) was added a solution of Compound 4 (490 mg, 2 mmol) at rt. The formed mixture was stirred for 10 minutes. Then CH I (852 mg, 6 mmol) was added to the above mixture. The mixture was stirred overnight. The reaction was quenched by water, and the formed mixture was concentrated to give the crude product, which was purified by column chromatography (PE: EtOAc = 10: 1) to give the desired product (437 mg, 80 %). 1.7.6 Preparation of A92 A92 Compound 5 (2.73 g, 10 mmol) was dissolved in DCM (20 mL), Then CF COOH (20 mL) was added, the mixture stirred at room temperature for 2 hours. The solution was concentrated to give desired A92 (1.6 g, 91 %). 1.7.7 Preparation of compound 2: To a solution of Compound 6 (2.4 g, 10 mmol) in DMF (30 mL) was added TEA (2.02 g, 20 mmol) and TBSCl (1.5 g, 10 mmol) at rt. The formed mixture was stirred for 12 hours. The reaction was quenched by water (100 mL), and extracted by EtOAc (100 mL). The organic layer was concentrated to give the crude product, which was purified by column chromatography (PE:EtOAc = 10:1) to give the desired product (2.0 g, 80 %). 1.7.8 Preparation of compound 8 Pd(OH) Boc O OTBS OTBS To a solution of compound 7 (700 mg, 2 mmol) in CH OH (5 mL) was added Pd(OH) /C (250 mg) and Boc O (512 mg, 2mmol). The formed mixture was hydrogenated overnight under H atmosphere. The catalyst was filtered and the filtrate was concentrated to give the desired product 4 (575 mg, 81%). 1.7.9 Preparation of compound 9 To a suspension of NaH (240 mg, 6 mmol) in THF (10 mL) was added a solution of compound 8 (720 mg, 2 mmol) at rt. The formed mixture was stirred for 10 minutes.

Then CH I (852 mg, 6 mmol) was added to the above mixture. The mixture was stirred overnight. The reaction was quenched by water, and the formed mixture was concentrated to give the crude product, which was purified by column chromatography (PE: EtOAc = 10: 1) to give the desired product 9 (520 mg, 69 %). 1.7.10 Preparation of A91 Compound 9 (373 mg, 1 mmol) was dissolved in DCM (5 mL), Then CF COOH (5 mL) was added, the mixture stirred at room temperature for 2 hours. The solution was concentrated to give desired compound A91 (273 mg, 100 %). 1.8 Preparation of A93/94 1.8.1 Preparation of compound 2 To a solution of (Diethoxy-phosphoryl)-acetic acid ethyl ester (4.5 g, 20 mmol) in THF (50 mL) was added NaH (960 mg, 24 mmol) at 0 C. The formed mixture was stirred for 10 minutes. Then Compound 1 (4.1 g, 20 mmol) was added to the above mixture. The mixture was stirred overnight. The reaction was quenched by water, and the formed mixture was extracted with EtOAc (200 mL). The organic layer was concentrated to give the crude product, which was purified by column chromatography (PE: EtOAc = 5: 1) to give the desired product 2 (3.36 g, 71 %). 1.8.2 Preparation of compound 3 Compound 2 (2.59 g, 10 mmol) was dissolved in THF (40 mL), then LiAlH (380 mg, 10 mmol) was added, the mixture was stirred at room temperature for 1 hour.

Water (0.4 g) was added, then NaOH (0.4 mL, 10%) was added, the mixture was stirred for 30 min, water (1.2 mL) was added, the solid was filtered, the filtrate was concentrated and extracted with EtOAc (100 mL), the organic layer was concentrated to give desired compound 5 (2.07 g, yield: 90%). 1.8.3 Preparation of A93 To a solution of Compound 3 (2.31 g, 10 mmol) in CH OH (30 mL) was added Pd/C (1.0 g). The formed mixture was hydrogenated overnight under H atmosphere.

The catalyst was filtered and the filtrate was concentrated to give the desired product A93 (1.28 g, 90 %). 1.8.4 Preparation of Compound 4 A93 (1.43 g, 10 mmol) was dissolved in MeOH (20 mL), then Boc O (2.16 g, 10 mmol) and TEA (1.5 g, 15 mmol) was added. The mixture was stirred at room temperature for 3 hours. The solution was concentrated in vacuo. The residue was dissolved with EA, washed with 1N HCl and saturated NaHCO , dried over Na SO and 3 2 4 concentrated in vacuo to give desired Compound 4 (2.43 g, yield: 100%). 1.8.5 Preparation of Compound 5 To a suspension of NaH (1.2 g, 30 mmol) in THF (50 mL) was added a solution of Compound 4 (2.43 g, 10 mmol) at rt. The formed mixture was stirred for 10 minutes. Then CH I (4.2 g, 30 mmol) was added to the above mixture. The mixture was stirred overnight. The reaction was quenched by water, and the formed mixture was concentrated to give the crude product, which was purified by column chromatography (PE: EtOAc = 10: 1) to give the desired product (2.05 g, 80 %). 1.8.6 Preparation of A94 Compound 5 (2.57 g, 10 mmol) was dissolved in DCM (20 mL), Then CF COOH (20 mL) was added, the mixture stirred at room temperature for 2 hours. The solution was concentrated in vauco to give desired A94 (1.57 g, 100 %). 1.9 Preparation of A95/96 Pd/C LiAlH CbzCl, Wittig Zn, AcOH CH MgBr Cbz Cbz 1 2 3 4 5 A95 1.9.1 Preparation of compound 2 To a solution of Compound 1 (10.9 g, 100 mmol) in THF (100 mL) was added ℃. The formed mixture was stirred for 10 minutes.

CbzCl (17.6 g, 100 mmol), at 0 Then CH MgBr (100 mL, 100 mmol) was added to the above mixture. The mixture was stirred overnight. The reaction was quenched by water, and the formed mixture was extracted with EtOAc (200 mL). The organic layer was concentrated to give the crude product, which was purified by column chromatography (PE: EtOAc = 4: 1) to give the desired product 2 (14.7 mg, 58 %). 1.9.2 Preparation of compound 3 To a suspension of Zn (6.5 g, 100 mmol) in AcOH (50 mL) was added a solution of compound 2 (4.9 g, 20 mmol) at rt. The mixture was stirred overnight. The reaction was filtered and concentrated to give the crude product, which was purified by column chromatography (PE: EtOAc = 5: 1) to give the desired product 3 (2.9 g, 62 %). 1.9.3 Preparation of compound 4 To a solution of (Diethoxy-phosphoryl)-acetic acid ethyl ester (4.5 g, 20 mmol) in THF (50 mL) was added NaH (960 mg, 24 mmol) at 0 C. The formed mixture was stirred for 10 minutes. Then Compound 3 (4.94 g, 20 mmol) was added to the above mixture. The mixture was stirred overnight. The reaction was quenched by water, and the formed mixture was extracted with EtOAc (200 mL). The organic layer was concentrated to give the crude product, which was purified by column chromatography (PE: EtOAc = 5: 1) to give the desired product 4 (3.94 g, 62 %). 1.9.4 Preparation of compound 5 Compound 4 (3.17 g, 10 mmol) was dissolved in THF (40 mL), then LiAlH (380 mg, 10 mmol) was added, the mixture was stirred at room temperature for 1 hour.

Water (0.4 g) was added, then NaOH (0.4 mL, 10%) was added, the mixture was stirred for 30 min, water (1.2 mL) was added, the solid was filtered, the filtrate was concentrated and extracted with EtOAc (100 mL), the organic layer was concentrated to give desired Compound 5 (2.47 g, yield: 90%). 1.9.5 Preparation of A95 To a solution of Compound 5 (2.75 g, 10 mmol) in CH OH (30 mL) was added Pd/C (1.0 g). The formed mixture was hydrogenated overnight under H atmosphere.

The catalyst was filtered and the filtrate was concentrated to give the desired product A33 (1.28 g, 90 %). 1.9.6 Preparation of Compound 6 To a solution of Compound 5 (2.31 g, 10 mmol) in CH OH (30 mL) was added Pd/C (1.0 g). The formed mixture was hydrogenated overnight under H atmosphere.

The catalyst was filtered and the filtrate was concentrated to give the desired product (1.28 g, 90 %). 1.9.7 Preparation of compound 7 Compound 6 (1.43 g, 10 mmol) was dissolved in MeOH (20 mL), then Boc O (2.16 g, 10 mmol) and TEA (1.5 g, 15 mmol) was added. The mixture was stirred at room temperature for 3 hours. The solution was concentrated in vacuo, dissolved with EA, washed with 1N HCl and NaHCO3, dried over Na SO , and concentrated in vacuo to give desired Compound 7 (2.43 g, yield: 100%). 1.9.8 Preparation of compound 8 To a suspension of NaH (1.2 g, 30 mmol) in THF (50 mL) was added a solution of Compound 7 (2.43 g, 10 mmol) at rt. The formed mixture was stirred for 10 minutes. Then CH I (4.2 g, 30 mmol) was added to the above mixture. The mixture was stirred overnight. The reaction was quenched by water, and the formed mixture was concentrated to give the crude product, which was purified by column chromatography (PE: EtOAc = 10: 1) to give the desired product (2.05 g, 80 %). 1.9.9 Preparation of A96 Compound 8 (2.57 g, 10 mmol) was dissolved in DCM (20 mL), Then CF COOH (20 mL) was added, the mixture stirred at room temperature for 2 hours. The solution was concentrated to give desired compound H (1.57 g, 100 %). 1.10 Preparation of A53/58 A mixture of compound 1 (1.2 g, 20 mmol) and MeNH2 in THF was heated to 70ºC in a sealed tube overnight. The mixture was concentrated in vacuo. The residue was re-dissolved in toluene, and concentrated in vacuo to give the desired product A53 (1.8 g, 98 %). H NMR (400 MHz, CDCl ): δ ppm: 3.79 - 3.84(m, 1H), 2.42 - 2.46 (m, 2H), 3.35(s, 3H), 1.16 (d, 2H).

A58 was prepared following the same procedure as A53. 1.11 Preparation of A98 1.11.1 Preparation of compound 3 To a solution of compound 2 (10 mL, 1 M, 10 mmol) in THF was added a solution of Compound 1 (0.95 g, 5 mmol) in THF (20 mL) at 0 ℃. The formed mixture was stirred at rt for 3 h. The reaction was quenched by NH Cl solution, and the mixture was extracted with EtOAc (20 mLx3). The organic layer was concentrated to give the crude product, which was purified by column chromatography to give the desired product (1.1 g, 78 %). LCMS: 286.3 [M+1]. 1.11.2 Preparation of A98 To a solution of Compound 3 (1.1 g, 3.8 mmol) in MeOH was added Pd(OH) /C (100 mg), and the formed mixture was stirred under H balloon overnight. The Pd was filtered and the filtrate was concentrated to give the desired product (680 mg, 90 %). H NMR (400 MHz, CDCl3): δ ppm: 7.24 - 7.38 (m, 3H), 6.95 - 7.00 (m, 1H), 3.10 - 3.17 (m, 2H), 2.98 -3.01 (m, 2 H), 1.99 - 2.06 (m, 2H), 1.72 - 1.79 (m, 2H). 1.12 Preparation of A97/99/101 1.12.1 Preparation of compound 2 To a solution of 1-bromofluorobenzene (1.75 g, 10 mmol) in THF was added n-BuLi (4 mL, 10 mmmol, 2.5 M) at -78 ℃ under N2. After stirring for 15 min, a solution of Compound 1 (0.95 g, 5 mmol) in THF (20 mL) was added dropwise at -78 ℃. The formed mixture was stirred at rt for 3 h. The reaction was quenched by NH4Cl solution, and the mixture was extracted with EtOAc (20 mLx3). The organic layer was concentrated to give the crude product, which was purified by column chromatography to give the desired product (0.9 g, 64 %). LCMS: 286.3 [M+1]. 1.12.2 Preparation of A97 To a solution of Compound 2 (0.9 g, 3.1 mmol) in MeOH was added Pd(OH) /C (100 mg), and the formed mixture was stirred under H balloon overnight. The Pd was filtered and the filtrate was concentrated to give the desired product (0.5 g, 82 %).

LCMS: 196.2 [M+1].

A99/101 were prepared following the same procedure as A97. 1.13 Preparation of A100/102 1.12.1 Preparation of compound 2 To a solution of 4-bromo-1,2-difluorobenzene (3.86 g, 20 mmol) in THF (50 mL) was added I2 (64 mg , 0.25 mmol), followed by Mg (0.48 g, 20 mmol) at rt under N2. After stirring for 1 h, the Mg was disappeared, a solution of Compound 1 (1.9 g, 10 mmol) in THF (20 mL) was added dropwise at 0 ℃. The formed mixture was stirred at rt for 3 h. The reaction was quenched by NH Cl solution, and the mixture was extracted with EtOAc (500 mLx3). The organic layer was concentrated to give the crude product, which was purified by column chromatography to give the desired product (2.8 g, 93 %).

LCMS: 304.1 [M+1]. 1.12.2 Preparation of A100 To a solution of Compound 2 (2.8 g, 9.3 mmol) in MeOH (200 mL) was added Pd(OH) /C (0.5 g), and the formed mixture was stirred under H balloon overnight. The Pd was filtered and the filtrate was concentrated to give the desired product (1.6 g, 80 %). LCMS: 214.1 [M+1].

A102 was prepared following the same procedure as A100. 1.14 Preparation of A114 1.14.1 Preparation of compound 2 To a slurry of Compound 1 (6.5 g, 79 mmol) and Compound 2 (10.2 g, 69 mmol) in MeOH (100 mL) was added a aqueous Na2CO3 (6 mL, 2 N, 12 mmol), and stirred at rt for 24 h. The solid was collected by filteration, washed with MeoH and dried in vacuo, which was used in the next step (14 g, crude). LCMS: 230.2 [M+1]. 1.14.1 Preparation of compound 4 O NaBH O NH MeOH, THF To a mixture of Compound 3 (14 g, 61 mmol) in MeOH/THF (300 mL/50mL) was added NaBH4 (3.4 g, 90 mmol) at 0 ℃, and stirred at rt overnight. 1 N HCl was added slowly to quenched the reaction. The mixture was concentrated in vacuo, and and the mixture was extracted with EtOAc (500 mLx3). The organic layer was concentrated to give the crude product, which was purified by column chromatography to give the compound 4 (8.0 g, 57 %). LCMS: 236.1 [M+1]. 1.14.3 Preparation of A114 A mixture of compound 4 (8.0 g, 34 mmol) in MeOH (100 mL) was added concentrated HCl (10 mL), and heated to reflux for 2 h. The mixture was concentrated in vacuo. The residue was dissolved with water and washed with EA. The aqueous phase was concentrated in vacuo to give the desired product with HCl salt (2.8 g, 82 %). H NMR (400 MHz, CDCl3): δ ppm: 4.33 (bs, 1H), 3.66 (bs, 1H), 2.08 - 2.16 (m, 2H), 1.74 -1.90 (m, 4 H). 1.15 Preparation of A113 A mixture of Compound 1 (4.2 g, 50 mmol) and ammonia (25 %, 20 mL) in MeOH(100 mL) was heated to 60 ℃ in a sealed tube overnight. The mixture was concentrated in vacuo. The residue was dissolved with 0.5 N HCl (20mL) and washed with EA. The aqueous phase was concentrated in vacuo to give the desired product A44, which was used in the next step directly (3.0 g, 59 %). 1.16 Preparation of A121 1.16.1 Preparation of compound 2 To MeMgBr (3 mL, 12 mmol) in THF was added dropwise a solution of Compound 1 (1.0 g, 4.7 mmol) in THF (20 mL) at 0-4 ℃. The formed mixture was stirred at rt for 3 h. The reaction was quenched by NH Cl solution, and the mixture was extracted with EtOAc (20 mLx3). The organic layer was concentrated to give the desired product 2, used directly in the next step without further purification (0.97 g, 94%). 1.16.2 Preparation of A121 To a solution of Compound 2 (970 mg, 4.43 mmol) in DCM (10 mL) was added TFA (5 mL). The formed mixture was stirred overnight at rt. The reaction mixture was concentrated to give the product A121 (1.3 g,), which was used in the next step directly. 1.17 Preparation of A125 1.17.1 Preparation of compound 2 To a solution of Compound 1 (8.2 g, 0.1 mol) and NBS (21.4 g, 0.12 mol) in CCl (100 mL), was added AIBN (3.3 g, 20 mmol) at rt, and heated to reflux for 3 h.

The mixture was washed with Na SO , sat. NaHCO and brine, dried over Na SO , and 2 3 3 2 4 concentrated to afford desired product 2 (8.5 g, 53 %), used in the next step directly. 1.17.2 Preparation of compound 3 To a solution of Compound 2 (4.0g, 24.8 mmol) and phenylmethanamine (3.2 g, 29.8 mmol) in anhydrous THF (60 mL), was added K CO (5.1 g, 37.2 mmol), and heated to 60 C for 5 h. After cooling to rt, the mixture was diluted with EA, and H O (80 mL). The aqueous phase was extracted with EA (100 mL3). The combined organic phase was washed with brine, dried over Na SO , concentrated to afford crude product which was purified by silica gel column chromatography (20-50% EtOAc in PE) to afford 3 (3.1 g, 68 yield). LCMS: 187 [M+1]. 1.17.3 Preparation of compound 4 Compound 3 (1.0 g, 5.3 mmol) was dissolved in DCM (20 mL), CF COOH (3.0 g, 26.7 mmol) was added and stirred for 30 minutes at rt. m-CPBA (1.5 g, 8.6 mmol) was added and the mixture stirred at rt overnight. Aqueous NaHCO was added to the reaction mixture and the phases separated and extracted with DCM (3 50 mL). The combined organic extracts were dried, filtered and concentrated in vacuo to yield the crude amino diol. Purification bychromatography on SiO (EA) gave 4 (600 mg, 51 %) as acolourless oil. LCMS: 222 [M+1]. 1.17.4 Preparation of A125 To a solution of compound 5 (600 mg, 2.7 mmol) in CH OH (8 mL) was added Pd(OH) /C (60 mg). The formed mixture was hydrogenated overnight under H atmosphere. The catalyst was filtered and the filtrate was concentrated to give the desired product (340 mg, 95%). 1.18 Preparation of A127 1.18.1 Preparation of Compound 2 To a solution of compound 1 (7.0 g, 25.8 mmol) in EtOH (100 mL) was added NaBH4 (9.8 g, 258 mmol) in portions at 0 C. The reaction mixture was stirred at 0 ℃ for 0.5 h and then stirred at RT overnight. The reaction mixture was poured into water (100 mL) and extracted with DCM (100 mL3). The organic layer was dried and concentrated to give the product 2 (4.5 g, 75%). 1.18.3 Preparation of Compound 3 To a solution of Compound 2 (2.5 g, 10.8 mmol) and imidazole (0.9 g, 12 mmol) in anhydrous DCM (30 mL), TBSCl (1.7 g, 11.4 mmol) was added dropwise at 0 C. After complete addition, the solution was allowed to warm to rt, and stirred for 2 h.

The reaction mixture was dissolved with DCM, washed with 1N HCl, saturated NaH CO3 and brine, dried over Na SO , and concentrated to afford desired product 3 (3.3 g, 89%). LCMS: 345 [M+1]. 1.18.4 Preparation of Compound 4 To a solution of Compound 3 (3.3 g, 9.6 mmol) and TEA(1.16 g, 11.5 mmol) in anhydrous THF (30 mL), AcCl(0.83 g, 11.6 mmol) was added dropwise at 0 C. After complete addition, the solution was allowed to warm to rt, and stirred for 2 h. The reaction mixture was dissolved with DCM, washed with 1N HCl, saturated Na2 CO3 and brine, dried over Na SO , and concentrated to afford desired product 4 (3.5 g, 95%).

LCMS: 388 [M+1] 1.18.5 Preparation of Compound 5 To a solution of compound 4 (3.5 g, 9.0 mmol) in THF (40 mL) was added TBAF (2.75 g, 10 mmol). The formed mixture was stirred at rt overnight. The mixture was poured into water and extracted with EA. The combined organic phase was washed with 1N HCl ，saturated NaHCO3 and brine, dried over Na SO , and concentrated in vacuo. The residue was purified through column chromatography to give the desired product 5. (2.4 g, 96%). 1.18.6 Preparation of Compound 6 To a solution of Compound 5 (1.0 g, 3.7 mmol) in anhydrous DCM (15 mL), DAST(1.19 g, 7.4 mmol, 2.0 eq) was added dropwise at -78 C under N . After addition the solution was warmed to rt gradually and stirred for 2 h. Quenched the reaction with sat. NaHCO (30 mL), extracted with DCM (30 mL3), combined the organic layer, washed with brine, dried over Na SO , and concentrated to afford desired product 6 (870 mg, 87%). 1.18.7 Preparation of Compound 7 To a solution of Compound 6 (870 mg, 3.2 mmol) and NaOH (256 mg, 6.4 mmol) in MeOH/H O (10 mL, v:v =4:1). The formed mixture was stirred overnight at rt. The reaction mixture was nuetralized with 1N HCl solution and concentrated to give the crude product (720 mg, 96%). 1.18.7 Preparation of A127 To a solution of Compound 7(720 mg, 3.1 mmol) in DCM (6 mL) was added TFA (5 mL). The formed mixture was stirred overnight at rt. The reaction mixture was concentrated to give the crude product (800 mg, crude), used in the next step directly. 1.19 Preparation of A119 1.19.1 Preparation of compound 2 To a solution of compound 1 (4.0 g, 21.6 mmol) in ethanol (40 mL) was added NaBH (1.64 g, 43.2 mmol) slowly at 0 ℃. The reaction mixture was stirred at RT for 5 h. The reaction mixture was quenched with NH Cl (50 mL) and extracted with ethyl acetate (50 mL3). The organic layer was dried and concentrated to give the product. 1.19.2 Preparation of A119 Compound 2 (4g 21.6 mmol) was dissolved in HCl/EA (25 mL). The mixture was stirred at RT for 2 h. The solvent was removed to give the product. 1.20 Preparation of A110 1.20.1 Preparation of compound 2 To a solution of Compound 1 (4.0 g ，0.024 mmol) in CH Cl (40 mL) was added m-CPBA (0.3 mol) at room temperature, and the mixture was stirred at rt for 12 hours. The mixture was quenched with Na SO , washed with NaHCO , and 2 3 3 concentrated to give the compound 2 (4.4 g, 100 %). H NMR (400 MHz, CDCl ): δ ppm: 3.73 (m, 2H), 3.60 (m, 2H), 3.23 (m, 2H), 1.37 (s, 9H). 1.20.2 Preparation of compound 3 To a solution of Compound 2 (2.0 g ，0.01 mmol) in Et N (20 mL) was added pyridine. HF Py (3 mL) at 0 C, and the mixture was heated to 80 C for 12 hours. Then the mixture was concentrated in vacuo. The residue was diluted with AcOEt, washed with aqueous NH Cl solution and brine, dried over Na2SO4 and concentrated in vacuo.

The residue was purified by column chromatography (PE: EA=4:1) to give the desired product. 1.20.3 Preparation of A110 To a solution of compound 3 (0.5g, 0.002 mol) in anhydrous DCM (2 mL) was added TFA (2 mL) at 0 C. The formed mixture was stirred for 2 h, and concentrated to give the desired product which was used for the next step (500 mg, 100%). 1.21 Preparation of A111 1.21.1 Preparation of compound 2 To a solution of compound 1 (4 g, 0.02 mol) in DCM (40 mL) was added TMSOTf (6.6 g, 0.03 mol), Et N (6.0 g, 0.06 mol) at room temperature. The reaction mixture was stirred for 1 hour. Then the mixture reaction was concentrated, purified by column chromatography (PE: AcOEt =10:1) to give the compound 2 (4.3 g, 80%). H NMR (400 MHz, CDCl ): δ ppm: 4.79 (s, 1H), 3.87 (m, 2H), 3.52 (m, 2H), 2.11 (s, 1H), 1.43 (s, 9H), 0.16 (s, 9H). 1.21.2 Preparation of compound 3 A mixture of Compound 2 (250 mg, 0.92 mmol), select F (360 mg, 0.92 mmol) in MeCN (20 mL) was stirred for 4 hours. The mixture was concentrated and purified by column chromatography (PE: AcOEt = 4:1) to give the compound 3 (180 mg, 90%). H NMR (400 MHz, CDCl3): δ ppm: 4.10 ～4.84 (m, 1H), 3.63 ～3.66 (m, 1H), 3.14 ～3.21 (m, 1H), 2.48 ～2.52 (m, 1H), 2.35 ～2.39 (m, 2H), 1.42 (s, 9H). 1.21.3 Preparation of compound 4 To a solution of Compound 3 (1 g, 4.6 mmol) in ethanol (10 mL) was added NaBH (0.3 g, 7.8 mmol) slowly at 0 C. The reaction mixture was stirred at 0 C for 0.5 h and the stirred at room temperature for 4 hours. The reaction mixture was quenched with aqueous NH4Cl solution and extracted with AcOEt. The organic layer was dried and concentrated to give the desired product. 1.21.4 Preparation of compound A111 To a solution of compound 4 (0.6 g, 2.7 mmol) in anhydrous DCM (4 mL) was added TFA (4 mL) at 0 C. The formed mixture was stirred for 2 h, and concentrated to give the desired product which was used for the next step (600 mg, 100%). 2 Preparation of Region B intermediates 2.1 Preparation of B02,03,06,07,08,09,17,18 To chlorosulfonic acid (23.8 mL, 350 mmol) cooled to 0 C was added portionwise 2-fluorobenzoic acid (5 g, 35 mmol). After complete addition, the yellow solution was allowed to warm to room temperature, then heated to 75 C overnight. The reaction mixture was cooled to room temperature and then added dropwise to ice-water (150 mL). The white precipitate was filtered, washed with water, and dried in vacuo to afford the desired product B02 as a white solid (3.37 g, 40.4 %).

B03,06,07,08,09,17,18 were prepared following the same procedure as B02.

B06/07/08/09 were produced under much higher temperature, such as 140-150 ℃, and longer reaction time, such as 6-12 h. 2.2 Preparation of B11 O ClSO H O -50 C-rt Chlorosulphonic acid (8.5 mL, 130 mmol) was added to a solution of compound 1 (5.0 g, 34 mmol) in DCM (30 mL) at – 50 ℃ under N2, and stirred at rt overnight. The reaction mixture was then poured into ice water, extracted with DCM, and the organic phase was dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography to give a mixture of desired product (1.6 g, containing an 3-position isomeric side product ，which was used in the next step without separation). 3 Preparation of Region C intermediates 3.1 Preparation of C59 3.1.1 Preparation of compound 2 To a solution of Compound 1 (5.0 g, 32.7 mmol) in anhydrous DCM (50 mL) was added DAST (5.5 g, 34.3 mmol) drop-wise at -78 C under N . After addition, the reaction mixture is allowed to warm back to rt and poured into a beaker containing 30 g of ice, decomposing any unreacted DAST. The organic layer is separated, and the water layer is extracted twice with 45 mL portions of DCM. The combined organic layer was washed with 50 mL of water, and dried over anhydrous magnesium sulfate. Evaporation to dryness under reduced pressure gives crude product which was purified by silica gel chromatography (eluted with PE: EA=100: 1) to afford Compound 2. (3.5 g, yield: 70%) 3.1.2 Preparation of C59 A solution of Compound 2 (3.5 g, 22.6 mmol), Fe powder (6.3 g, 0.11 mol, 5 eq.) and NH Cl (5.9 g, 0.11mol) in MeOH (40 mL) and water (10 mL) was heated to reflux for 3 h. The mixture was filtered. The filtrate was concentrated in vacuo, and extracted with DCM. The organic phase was concentrated in vacuo, and purified through column chromatography. 3.2 Preparation of C60 3.2.1 Preparation of compound 2 A mixture of Compound 1 (9.6 g, 56.8 mmol) in MeOH (100 mL) was added NaBH in portions at 0 C. After addition, the reaction mixture was stirred for 1 h at rt.

The reaction mixture was quenched with 1 N HCl, and concentrated in vacuo.

The residue was extracted with EtOAc (100 mL3). The organic layer was concentrated to give the crude product, which was used for the next step directly. (9.8 g, crude) 3.2.2 Preparation of compound 3 To a solution of Compound 2 (6.2 g, 36.3 mmol) in anhydrous DCM (80 mL) was added DAST (11.7 g, 34.3 mmol) drop-wise at -78 C under N2. The reaction mixture was stirred at rt for 2 h, and poured into a beaker containing 30 g of ice, decomposing any unreacted DAST. Mixture was extracted twice with 45 mL portions of DCM. The combined organic layer was washed with 50 mL of water, and dried over anhydrous magnesium sulfate. Evaporation to dryness under reduced pressure gives crude product which was purified by silica gel chromatography (eluted with PE: EA=from100: 1 to 50: 1) to afford Compound 3. (4.5 g, yield: 71%) 3.2.3 Preparation of C60 A solution of Compound 2 (4.2 g, 24.3 mmol) Fe powder (7.0 g, 0.12 mol, 5 eq.) and NH Cl (6.8 g, 0.12mol) in MeOH (40 mL) and water (10 mL) was heated to reflux for 3 hours. Filtered, the filtrate concentrated in vacuo to give a solid, which was used for the next step directly. 3.3 Preparation of C61 3.3.1 Preparation of compound 2 To a solution of Compound 1 (0.5 g, 3.3 mmol) in anhydrous DCM (10 mL) was added DAST(1.3 g, 7.95 mmol) drop-wise at -78 C under N . The reaction mixture was stirred at rt for 2 h, and poured into a beaker containing 5 g of ice, decomposing any unreacted DAST. The mixture was extracted twice with DCM (45 mL). The combined organic layer was washed with 50 mL of water, and dried over anhydrous magnesium sulfate. Evaporation to dryness under reduced pressure gives crude product which was purified by silica gel chromatography (eluted with PE: EA=100: 1) to afford Compound 2 (0.45 g, yield: 79%). 3.3.2 Preparation of C61 A solution of Compound 2 (0.45 g, 2.9 mmol) and Pd/C(50 mg) in EtOH (5 mL) was stirred at rt under H2 atmosphere overnight. The Pd/C was removed by filtered.

The filtrate was concentrated in vacuo to give the desired product, which was used for the next step directly. 3.4 Preparation of C62 3.4.1 Preparation of compound 2 To a solution of compound 1 (3.0 g, 17.8 mmol) in anhydrous DCM (50 ml) was added DAST (6.3 g, 39.0 mmol) at 0 ℃ under N . The formed mixture was stirred at rt for 2 h, quenched by saturated NaHCO solution, and diluted with EA (100 mL). The organic layer was separated, dried over Na SO and concentrated under reduced pressure. The residue was purified by flash column chromatograph on silica gel (PE: EA 5:1 to 3:1) to give compound 2 (3.2 g, 94.1%). 3.4.2 Preparation of C62 A solution of compound 2 (3.2 g, 16.8 mmol), Zn ((10.9 g, 168 mmol), and NH4Cl (9.0 g, 168 mmol) was stirred in water (20 mL) and methanol (50 mL) at 50 ℃ for 4 h. The mixture was filtrated, and concentrated under vacuum. The residue was purified by silica gel chromatography to give desired product (2.6 g, 96.3%). LCMS: 162 [M+1]. 3.5 Preparation of C58 A solution of Compound 1 (5.0 g, 25.83 mmol), Fe powder (14.47 g, 258.3mmol, 10 eq.) and NH Cl (13.95 g, 258.3 mmol) in EtOH (80 mL) and water (10 mL) was heated to reflux for 3 h. The reaction mixture was filtered and concentrated.

The residue was dissolved in water (50 mL) and extracted with ethyl acetate (50 mL2).

The organic layer was dried and concentrated to give the product used in the next step directly. LCMS: 164[M+1]. 3.6 Preparation of C64/65 3.6.1 Preparation of Compound 2 Compound 1 (5.0 g, 3.5 mmol) was dissolved in concentrated H SO (16 mL) and heated to 60 C. N-bromosuccinimide (7.5, 4.2 mmol) was added in three portions over a period of 30 min. After being heated for 3 h under N , the reaction mixture was poured into ice water. The product was extracted with EtOAc, washed with water and brine, and dried over Na SO . Purification by silica gel column chromatography (0-10% EtOAc in PE) yielded an orange liquid as product 2 in 45% yield. H NMR (400 MHz, CDCl ) δ 10.31 (d, 1H, J = 1.2 Hz), 7.80 - 7.99 (m, 1H), 7.64 - 7.60 (m, 1H). 3.6.2 Preparation of Compound 3 A mixture of compound 2 (1.0 g, 4.5 mmol), NH Boc (660 mg, 5.7 mmol), Cs CO (2.05 g, 6.3 mmol), Pd (dba) (124 mg, 0.135 mmol) and X-Phos (193 mg, 2 3 2 3 0.405 mmol) in 30 mL of dioxane was heated to 100 C overnight. After cooling to rt, the aqueous was extracted with EA for three times. The organic layer was washed with water and brine, dried over Na SO , filtered and evaporated to give crude product, which was purified by silica gel column chromatography (0-10% EtOAc in PE) to give 3 (300 mg, 13%). LCMS: 258 [M+1]. 3.6.3 Preparation of Compound 4 To a solution of Compound 3 (500 mg, 1.95 mmol) in anhydrous DCM ( 10 mL), was added DAST(1.25 g, 7.78 mmol, 4.0 eq ) dropwise at -78 C under N . After addition, the solution was warmed to rt gradually and stirred for 2 h. The mixture was quenched with saturated NaHCO (30 mL), extracted with DCM (10 mL3). The combined the organic phase was washed with brine, dried over Na SO and concentrated in vacuo to afford desired product 4 (380 mg, 70%). LCMS: 280.1 [M+1]. 3.6.4 Preparation of C64 To a solution of Compound 4 (280 mg, 1.0 mmol) in DCM (5 mL) was added TFA(5 ml) .The formed mixture was stirred overnight at room temperature. The reaction mixture was concentrated to give the crude product G(145 mg, 81%). H NMR (400 MHz, CDCl ) δ 6.94-6.67 (t, 1H), 5.58-6.54 (m, 2H), 3.75 (br, 2H) LCMS: 180.1 [M+1]. 3.6.5 Preparation of Compound 5 To a solution of compound 2 (1.0 g, 3.5 mmol) in MeOH (20 mL) was added NaBH (200 mg, 5.0 mmol) slowly at 0 ℃. The reaction mixture was stirred at 0 ℃ for 0.5 h and then stirred at RT for 2 h. The reaction mixture was quenched with 1N HCl (20 mL) and concentrated in vacuo. The residue was extracted with DCM (30 mL3). The organic layer was dried and concentrated to give the product 5 (1.05 g, crude). 3.6.6 Preparation of Compound 6 To a solution of Compound 5 (2.0 g, 9.0 mmol) and TEA (1.36 g, 13.5 mmol) in anhydrous THF (20 mL), AcCl(0.85 g, 10.8 mmol) was added dropwise at 0 C. After addition, the solution was allowed to warm to rt, and stirred for 2 h. The reaction was dissolved with EtOAc (100 mL), washed with 1 N HCl, 5 % NaOH and brine, dried over Na SO and concentrated in vacuo to afford desired product 6 (2.3 g, 96%). LCMS: 265/267 [M+1]. 3.3.7 Preparation of Compound 7 A mixture of Compound 6 (6.0 g, 22.3 mmol), NH Boc (3.3 g, 27.9 mmol, 1.2 eq.), Cs CO (10.2 g, 31.2 mmol), Pd (dba) (613 mg, 0.7 mmol, 3%) and Xant- 2 3 2 3 Phos(955 mg, 2.01 mmol, 9%) in 200 mL of dioxane was heated to 100 C for overnight. After cooling to rt, the mixture was filtered, and the filterate was concentrated in vacuo. The residue was purified by silica gel column chromatography (0-10% EtOAc in PE) to afford 7 (4.5 g, 66% yield). LCMS: 302 [M+1]. 3.3.8 Preparation of Compound 8 To a solution of Compound 7 (490 mg, 1.63 mmol) in THF (50 mL) was added aqueous solution of NaOH (80 mg, 2.0 mmol, 10 %), and stirred overnight at rt. The reaction mixture was acidified by 1N HCl solution and concentrated in vacuo. The residue was extracted with EA. The organic layer was washed with water and brine, dried over Na SO and concentrated in vacuo to afford desired product 8 (380 mg, 90%).

H NMR (400 MHz, CDCl ) δ 7.38-7.33 (m, 1H), 7.07-7.05 (m, 1H), 4.75 (s, 2H), 1.51 (s, 9H). LCMS: 260 [M+1]. 3.3.9 Preparation of Compound 9 To a solution of Compound 8 (380 mg, 1.47 mmol) in anhydrous DCM (5 mL), DAST (473 mg, 2.94 mmol, 2.0 eq) was added dropwise at -78 ℃ under N . After addition, the solution was warmed to rt gradually and stirred for 2 h. The reaction mixture was poured into sat. NaHCO (20 mL) at 0 ℃, extracted with DCM (10 mL3).

The combined organic phase was washed with brine, dried over Na SO , and concentrated to afford desired product 9 (370 mg, 96 %). LCMS: 262 [M+1]. 3.3.10 Preparation of C65 To a solution of Compound 9 (370 mg, 1.7 mmol) in DCM (5 mL) was added TFA (5 mL). The formed mixture was stirred overnight at rt. The reaction mixture was concentrated in vacuo to give the crude product C65 (130 mg, 58 %). H NMR (400 MHz, CDCl ) δ 6.42-6.38 (m, 2H), 5.38 (d, J=1.2 Hz,1H), 5.26 (d, 2 H, J=1.2 Hz) LCMS: 162 [M+1].

Part II General Procedure for Targets General procedure A 1.1 General procedure for preparation of compound 2 A mixture of Compound 1 (4.53 mmol) in SOCl (10 mL) was heated to reflux overnight. The mixture was concentrated to give the crude product, which was used for the next step directly. 1.2. General procedure for preparation of compound 3 To a boiled solution of Compound 2 (1.08 g, 4.52 mmol) in toluene (10 mL) was added aniline (4.52 mmol), and refluxed for 2 h. The mixture was concentrated in vacuo to give a solid, which was used for the next step directly. 1.3 General procedure for preparation of iii To a solution of Compound 3 (0.3 mmol) in CH Cl (3 mL) was added amine (0.3 mmol) and Et N (30 mg, 0.33 mmol) at rt, and the mixture was stirred at rt for 2 h.

The mixture was diluted with CH Cl (20 mL) and washed with water. The organic phase was concentrated in vacuo to give the crude product, which was purified by prep- HPLC to give the desired product.

General procedure B 1.1 General procedure for preparation of compound 2 To a solution of Compound 1 (10 mmol) in CH Cl (50 mL) was added amine (10 mmol) and TEA (11 mmol), and stirred at rt overnight. The mixture was washed with 1 N HCl and saturated NaHCO3, and concentrated in vacuo. The residue was purified by chromatography to give the desire product. 1.2 General procedure for preparation of compound 3 To a solution of Compound 2 (5 mmol) in MeOH (40mL) was added an aqueous solution of NaOH (7 mmol, 1N), and stirred at rt overnight. The reaction mixture was acidified by 1N HCl solution to pH 6 and extracted with DCM. The combined organic phase was concentrated in vacuo to give the product. 1.3 General procedure for preparation of iii To a solution of Compound 3 (1 mmol) and aniline (1 mmol) in DCM (10 mL) was added HATU (1.1 mmol), followed by DIPEA (1.5 mmol). The formed mixture was stirred at rt overnight. The mixture was diluted with CH Cl (20 mL) and washed with water. The organic layer was concentrated to give the crude product, which was purified by preparative HPLC to give the desired product.

General procedure C 1.1 General procedure for preparation of compound 2 To a solution of Compound 1 (1.80 g, 10 mmol) and piperidine (2.1 g, 25 mmol) in DCM (50 mL) was added HATU (3.8 g, 10 mmol) a at rt. The formed mixture was stirred overnight. The mixture was washed with 1N HCl, NaOH (5 %) and brine, and concentrated in vacuo to give the desired product (2.1 g, 85 %). LCMS: 248 [M+1]. 1.2 General procedure for preparation of compound 3 N LiOH N O OMe O OH To a solution of methyl Compound 2 (2.1 g, 8.5 mmol) in CH OH (40 mL) and H2O (10 mL) was added LiOH H O (0.6 g, 15 mmol). The formed mixture was stirred overnight. The resulting mixture was acidified by 1N HCl and concentrated in vacuo.

The residue was extracted DCM. The combined organic phase was concentrated in vacuo to give the crude product, which was used for the next step directly (1.7 g, 86 %).

LCMS: 234 [M+1]. 1.3 General procedure for preparation of iii To a solution of Compound 3 (0.3 mmol), amine (0.3 mmol) and Et N (30 mg, 0.33 mmol) in CH Cl (3 mL) was added HATU (0.33 mmol), and the mixture was stirred at rt for 2 h. The mixture was diluted with CH Cl (20 mL) and washed with water. The organic phase was concentrated in vacuo to give the crude product, which was purified preparative HPLC to give the desired product.

General procedure D 1.1 General procedure for preparation of compound 2 To a solution of methyl 4-formylbenzoate (150 mg, 0.914 mmol), azetidinol hydrochloride (120 mg, 1.10 mmol) and Et N (111 mg, 1.10 mmol) in CH Cl (3 mL) 3 2 2 was added NaBH(OAc) (580 mg, 2.74 mmpl). The formed mixture was stirred at rt overnight. The reaction was quenched by NaHCO solution, and the formed mixture was extracted with CH Cl (10 mL x 3). The organic layer was concentrated to give the crude product, which was purified preparative TLC to give the desired product (150 mg, 74%). H NMR (400 MHz, CDCl ): δ ppm: 7.97(d, 2H), 7.34(d, 2H), 3.89(s, 3H), 3.68(s, 2H), 3.63(m, 2H), 3.04(m, 2H). 1.2 General procedure for preparation of compound 3 LiOH OH OH O HO To a solution of methyl 4-((3-hydroxyazetidinyl)methyl)benzoate (150 mg, 0.68 mmol) in CH OH (3 mL) and H2O (1 mL) was added LiOH H O (57 mg, 1.36 mmpl). The formed mixture was stirred overnight. The resulting mixture was acidified by 1N HCl and concentrated in vacuo. The residue was extracted DCM. The combined organic phase was concentrated in vacuo to give the crude product, which was used for the next step directly (150 mg, crude). 1.3 General procedure for preparation of iii To a solution of ((3-hydroxyazetidinyl)methyl)benzoic acid (150 mg, 0.723 mmol) and 3-bromoamine (187 mg, 1.09 mmol) in DMF (3 mL) was added HATU (413 mg, 1.09 mmol) and DIEA (187 mg, 1.45 mmol) at rt. The formed mixture was stirred overnight. The mixture was diluted with CH Cl (20 mL) and washed with water (5 mL x 2). The organic layer was concentrated to give the crude product, which was purified preparative HPLC to give the desired product (15 mg, 6%). H NMR (400 MHz, CDCl ): δ ppm: 11.03(br, 1H), 10.49(s, 1H), 8.11(s, 1H), 7.98 (d, 2H), 7.75(m, 1H), 7.67(d, 2H), 7.29(m, 2H), 4.45(m, 3H), 4.16(m, 2H), 3.87(m, 2H). LCMS: 361/363 [M+1/M+1+2].

General procedure E 1.1 General procedure for preparation of compound 2 Compound 1 (1.0 g, 3.54 mmol) was dissolved in 10 g (65.22 mmol) of POCl , then, the mixture was warmed to 100 C and stirred for overnight. Solvent was evaporated in vacuo and the residue was prepared for next step. 1.2 General procedure for preparation of compound 3 To a solution of compound 2 (138 mg, 050 mmol) in 5 mL of DCM, aniline (0.55 mmol) and Et3N (51 mg, 050 mmol) was added. The mixture was stirred at rt for overnight. Water was added to the mixture and extracted with DCM, the organic layer was washed with brine, dried over Na2SO4, filtered and solvent was evaporated in vacuo. The residue was prepared for next step. 1.3 General procedure for preparation of iii To a solution of Compound 3 (0.3 mmol) in CH Cl (3 mL) was added amine (0.3 mmol) and Et N (30 mg, 0.33 mmol) at rt, and the mixture was stirred at rt for 2 h.

The mixture was diluted with CH Cl (20 mL) and washed with water. The organic phase was concentrated in vacuo to give the crude product, which was purified preparative HPLC to give the desired product.

General procedure F 1.1 Preparation of compound 2 To chlorosulfonic acid (65 g, 0.56 mol) cooled to 0 C was added portionwise Compound 1 (10.2 g, 73 mmol). After complete addition, the yellow solution was warmed to room temperature, then heated to 70 C overnight. The reaction mixture was cooled to room temperature and then added drop-wise to ice (0.5 L). The white precipitate was filtered, washed with water, and dried in vacuo to afford the desired product as a white solid (13.7 g, 80%). 1.2 Preparation of compound 3 HO Cl SOCl O S O O S O Cl Cl A mixture of Compound 2(13.7 g, 57.6 mmol) in SOCl2 (60 mL) was heated to reflux overnight. The mixture was concentrated to give the crude product, which was used for the next step directly. 1.3 Preparation of compound 4 To a boiled solution of compound 3 (5.5 g, 21 mmol) in anhydrous toluene (50 mL) was added a solution of aniline (2.0 mg, 21 mmol). The formed mixture was stirred for another 30 minutes. The mixture was allowed to cool to room temperature, and diluted with EtOAc (50 mL). The mixture was washed with ice-water (20 mL). The organic layer was concentrated to give the desired product, which was used for the next step directly (7.0 g, 67%). 1.4 Preparation of compound 5 To a solution of Compound 4 (7.0 g, 22 mmol) in dry CH Cl (80 mL) was added piperidinol (2.2 g, 22 mmol) and Et N (3 mL) at rt. The formed mixture was stirred overnight. The mixture was diluted with CH Cl (100 mL) and washed with water (50 mL 2). The organic layer was concentrated to give the crude product, which was purified by silica chromatography gel to give the desired product (4.5 g, 53%). 1.5 Preparation of compound 6 To a solution of Compound 5 (4.5 g, 12.1 mmol) in CH Cl (50 mL) was added Et N (2.5 mL), followed by CH COCl (1.2 g, 12.1 mmol) at 0 C. The formed mixture was stirred overnight at room temperature. The mixture was washed with aqueous Na CO solution, and the aqueous layer was acidified by 1N HCl. The formed mixture was extracted with CH Cl (100 mL 3). The combined organic layers were concentrated to give crude product which was purified by silica chromatography gel to give the desired product (3.0 g, 60%). 1.6 Preparation of compound 7 A solution of Compound 6 (310 mg, 0.73 mmol) in POCl (3.5 mL) was heated to 80 C for 3 hours. The organic layer was concentrated to give the desired product, which was used for the next step directly (340mg, crude) 1.7 Preparation of compound 8 To a solution of Compound 7 (340 mg, 0.73 mmol) in anhydrous THF (5 mL) was added O-(trimethylsilyl)hydroxylamine (94 mg, 0.9 mmol) drop-wise at 0 C. The formed mixture was stirred overnight at room temperature. The mixture was washed with 1N HCl solution, and the aqueous layer was acidified by aqueous Na CO . The formed mixture was extracted with CH Cl (10 mL 3). The combined organic layers were concentrated to give crude product. (360 mg, crude) 1.8 Preparation of compound 9 To a solution of Compound 8 (360 mg) in NMP (3 mL) was added t-BuOK (80 mg, 0.71 mmol) at rt, and the mixture was heated to 80 C for 3 h. The mixture was diluted with EtOAc (20 mL) and washed with water. The organic phase was concentrated in vacuo to give the crude product, which was purified by preparative HPLC to give the desired product. (50 mg, yield: 20%) 1.9 Preparation of 738 A solution of Compound 9 (50 mg, 0.12mmol), NaOH (10 mg, 0.24 mml), in 1 mL of MeOH and 1ml of water was stirred at room temperature for 16 hours. The solvent was removed off and purified by Prep-HPLC to afford 20 mg of 738 (20 mg, 40%). LCMS: 374 [M+1]. 737 was prepared following the similar procedure with 738.

General procedure G 1.1 Preparation of compound 2 To chlorosulfonic acid (82.4 g, 0.71 mol) cooled to 0 C was added portionwise Compound 1 (5.0 g, 25 mmol). After complete addition, the yellow solution was warmed to room temperature, then heated to 150 C for 5 h. The reaction mixture was cooled to room temperature and then added drop-wise to ice (60 g). The white precipitate was filtered, washed with water, and dried in vacuo to afford the desired product as a yellow solid (6.0 g, 80%).

H NMR (400 MHz, CDCl ): δ ppm: 8.89(d, J = 2.0 Hz 1H), 8.25(dd, J = 2.0, 8.4 Hz, 1H), 8.02(d, J = 8.4 Hz, 1H). 1.2 Preparation of compound 3 A mixture of Compound 2 (6.0 g, 20.1 mmol) in SOCl (60 mL) was heated to reflux for 3h. The mixture was concentrated to give the crude product, which was used for the next step directly. To a boiled solution of compound 3 (6.4 g, 20.1 mmol) in anhydrous toluene (60 mL) was added 3,4,5-trifluoroaniline (2.9 g, 20.1 mmol). The formed mixture was heated to 100 C for 6 h. The mixture was allowed to cool to room temperature, and then concentrated to give the desired product, which was used for the next step directly (7.5 g, 87%).

H NMR (400 MHz, DMSO): δ ppm: 10.78(s, 1H), 8.45(d, J = 2.0 Hz, 1H), 7.75(m, 4H). 1.3 Preparation of compound 6 To a solution of Compound 4 (2.0 g, 4.7 mmol) in MeCN (20 mL) was added piperidinol (0.47 g, 4.7 mmol) and Et N (1.4 mL) at rt. The formed mixture was stirred for 2 h. The mixture was diluted with EA (150 mL) and washed with water (50 mL 2). The organic layer was concentrated to give the crude product, which was purified by silica chromatography gel to give the desired product (1.7 g, 74%). 1.4 Preparation of 927 To a solution of Compound 6 (200 mg, 0.41 mmol) in MeOH (10 mL) was added Et N (165 mg, 1.62 mmol) and Pd(dppf)Cl (33 mg, 0.04 mmol) under N . The 3 2 2 formed mixture was stirred at 80 C under CO of 50 Psi pressure for 12 h. The mixture was allowed to cool to room temperature and filtered. The filtration was concentrated and purified by silica chromatography gel to give the desired product (150 mg, 79%).

LCMS: 473.1 [M+1].

H NMR (400 MHz, DMSO): δ ppm: 10.86(s, 1H), 8.31(s, 1H), 8.29(s, 1H), 7.85 (d, J = 7.6 Hz, 1H), 7.72(t, J = 5.0 Hz, 2H), 4.73(d, J = 4.0 Hz, 1H), 3.86(s, 3H), 3.61(m, 1H), 3.35(m, 2H), 2.95(m, 2H), 1.75(m, 2H), 1.38(m, 2H),. 1.5 Preparation of 1420 To a solution of Compound 927 (200 mg, 0.42mmol) in THF (10 mL) was added LiBH (38 mg, 1.72 mmol) under N at 0 C, the formed mixture was stirred at room temperature overnight. The reaction mixture was diluted with EA (100 mL) and washed with brine (50 mL 2). The organic layer were dried over Na SO , concentrated and purified by silica chromatography gel to give the desired product (45 mg, 24 %). LCMS: 445.1 [M+1].

H NMR (400 MHz, CD3OD): δ ppm: 8.42(d, J = 2.0 Hz, 1H), 8.21(dd, J = 2.0, 8.4 Hz, 1H), 8.06(d, J = 8.0 Hz, 1H), 7.63 (m, 2H), 5.06(s, 2H), 3.76(m, 1H), 3.53(m, 2H), 3.05(m, 2H), 1.90(m, 2H) 1.59(m, 2H).

Specific Experimental Procedure for Preparation of 777 1.1 Preparation of Compound 2 To chlorosulfonic acid (23.8 mL, 350 mmol) was added portionwise 2- fluorobenzoic acid (5 g, 35 mmol) at 0 C. After addition, the yellow solution was allowed to warm to room temperature, and then heated at 75 C for 12 h. The reaction mixture was cooled to room temperature and then poured onto ice water (150 mL). The white precipitate was filtered, washed with water, and dried in vacuo to afford the desired product (3.37 g, 40.4 %). 1.2 Preparation of Compound 3 A mixture of Compound 2 (238 mg, 1 mmol) in SOCl (10 mL) was heated at reflux for 12h. The mixture was concentrated to give the crude product, which was used for the next step directly. 1.3 Preparation of Compound 5 To a solution of Compound 3 (260 mg, 1 mmol) in refluxing toluene (10 mL) was added Compound 4 (147 mg, 1 mmol). The resulting solution was heated at reflux for 2 h and then concentrated in vacuo to give a solid, which was used for the next step directly without purification. 1.4 Preparation of 777 To a solution of crude Compound 5 (370 mg, 1 mmol) and Compound 6 (101 mg, 1 mmol) in MeCN (15 mL) was added Et3N (150 mg, 1.5 mmol) at room temperature. After addition, the resulting mixture was stirred for 2 h, at which time LCMS indicated the completion of the reaction. The solution was evaporated and the residue was purified by preparative HPLC to give the desired product 777 (251 mg, 61%).

H NMR (400 MHz, MeOD) δ 8.11-8.14 (m, 1H), 8.00-8.03 (m, 1H), 7.51-7.59 (m, 3H), 3.66-3.71 (m, 1H), 3.36-3.42 (m, 2H), 2.85-2.91 (m, 2H), 1.89-1.94 (m, 2H), 1.15-1.64 (m, 2H). LCMS: 433 [M+1].

Specific Experimental Procedure for Preparation of Compound 890 1.1 Procedure for preparation of compound 2 A mixture of Compound 1 (10.0 g, 42.0 mmol) in SOCl (60 mL) was heated to reflux overnight. The mixture was concentrated in vacuo. The residue was dissolved with toluene (30 mL), and concentrated in vacuo to give the crude product, which was used for the next step directly. 1.2 Procedure for preparation of compound 3 To a boiled solution of crude Compound 2 (42 mmol) in toluene (100 mL) was added a suspension of aniline (6.17 g, 42 mmol) in toluene (40 mL) slowly, and refluxed for 2 h. The mixture was concentrated in vacuo to give a solid, which was used for the next step directly. 1.3 Procedure for preparation of 890 To a solution of Compound 3 (42 mmol) in MeCN (250 mL) was added amine 4 (4.3 g, 42 mmol) and Et N (6.18 g, 61.2 mmol) at rt, and the mixture was stirred at rt for 3 h. The solution was concentrated in vacuo. The residue was purified by silica gel chromatography to give the desired product as white solid (15.7 g, 86.5 %).

H-NMR (Methanol-d4 400MHz): 8.41-8.39 (dd, J=6.5, 2.4 Hz, 1H), 8.26-8.23 (m, 1H), 7.61-7.50 (m, 3H), 3.74-3.72 (m, 1H), 3.56-3.52 (m, 2H), 3.06-3.01 (m, 2H), 1.91-1.87 (m, 2H), 1.59-1.56 (m, 2H).

LCMS: 433.0 [M+1].

Specific Experimental Procedure for Preparation of 894 1.1 Procedure for preparation of compound 2 A mixture of Compound 1 (3.0 g, 12.6 mmol) in SOCl (80 mL) was heated to reflux overnight. The mixture was concentrated in vacuo. The residue was re-dissolved with toluene (30 mL), and concentrated in vacuo to give the crude product, which was used for the next step directly. 1.2 Procedure for preparation of compound 3 To a solution of crude Compound 2 (12.6 mmol) in refluxing toluene (10 mL) was added 3,4-difluoroaniline (1.6 g, 12.6 mmol). The resulting solution was heated at reflux for 2 h and then concentrated in vacuo to give a solid, which was used for the next step directly without purification. 1.3 Procedure for preparation of 894 To a solution of crude Compound 3 (600 mg, 2.0 mmol) and Compound 4 (203 mg, 2.0 mmol) in MeCN (10 mL) was added Et N (303 mg, 3.0 mmol) at room temperature. The mixture was stirred at rt for 3 h, at which time LCMS indicated the completion of the reaction. The solution was concentrated in vacuo. The residue was purified by prep-HPLC to give the desired product as white solid (430 mg, 60.3 %).

H-NMR (Methanol-d4 400MHz): 8.40-8.42 (m, 1H), 8.23-8.25 (m, 1H), 7.75-7.82 (m, 1H), 7.42-7.52 (m, 2H), 7.25-7.28 (m, 1H), 3.74-3.74 (m, 1H), 3.52-3.56 (m, 2H), 3.01- 3.07 (m, 2H), 1.1.87-1.91 (m, 2H), 1.56-1.59 (m, 2H). LCMS: 415.0 [M+1].

Experimental Procedure for Preparation of Compound 891 1.1 Procedure for preparation of compound 2 A mixture of Compound 1 (20.0 g, 84.0 mmol) in SOCl (120 mL) was heated at reflux for 3 h. The mixture was concentrated in vacuo. The residue was dissolved with toluene (60 mL), and concentrated in vacuo to give the crude product, which was used for the next step directly. 1.2 Procedure for preparation of compound 3 To a solution of crude Compound 2 (84 mmol) in refluxing toluene (200 mL) was added 3-chlorofluoroaniline (12.3 g, 42 mmol). The resulting mixture was refluxed for for 5 h. The mixture was concentrated in vacuo to give a solid, which was used for the next step directly. 1.3 Procedure for preparation of Compound 891 Compound 3 (2.0 g, 5.5 mmol) and Compound 4 (0.55 g, To a solution of curde .5 mmol) in MeCN (30 mL) was added Et N (0.83 g, 8.2 mmol) at rt. The mixture was stirred at rt for 2 h, at which time LCMS indicated the completion of the reaction. The solution was concentrated in vacuo. The residue was purified by silica gel chromatography to give the desired product as white solid (1.41 g, 60.3 %).

H-NMR (DMSO-d6 400MHz): 10.66 (s, 1H), 8.37-8.33 (m, 2H), 8.04-8.02 (m, 1H), 7.72-7.62 (m, 2H), 7.47-7.38 (m, 1H), 4.75-4.74 (d, J=4.0 Hz, 1H),3.65-3.55 (m, 1H), 3.37-3.27(m, 2H), 2.98-2.88(m, 2H), 1.75-1.65 (m, 2H), 1.45-1.35(m, 2H). LCMS: 431.0 [M+1].

Specific Experimental Procedure for Preparation of Compound 903 To a solution of Compound 1 (4.5 g, 12.2 mmol) and Compound 2 (1.5 g, 12.2 mmol) in MeCN (70 mL) was added Et3N (3.1 g, 30.7 mmol) at rt. The mixture was stirred at rt for 2 h, at which time LCMS indicated the completion of the reaction. The solution was concentrated in vacuo. The residue was purified by silica gel chromatography to give the desired product as white solid (2.69 g, 52.7 %).

H-NMR (Methanol-d4 400MHz): 8.59-8.33 (m, 1H), 8.13-8.10 (m, 1H), 7.51- 7.42 (m, 2H), 7.41-7.35 (m, 1H), 4.27-4.24 (m, 1H), 3.42-3.37 (m, 3H), 3.25-3.20 (m, 1H), 1.90-1.86 (m, 1H) , 1.82-1.78 (m, 1H).

LCMS: 419.0 [M+1].

Experimental Procedure for Preparation of Compund 953 To a solution of Compound 1 (5.5 g, 15.1 mmol) and Compound 2 (1.6 g, 14.7 mmol) in MeCN (80 mL) was added Et N (3.8 g, 37.7 mmol) at rt. The mixture was stirred at rt for 2 h, at which time LCMS indicated the completion of the reaction. The solution was concentrated in vacuo. The residue was purified by silica gel chromatography to give the pure product as white solid (1.1 g, 18.3 %) and impure product (about 1.0 g).

H-NMR (Methanol-d4 400MHz): 8.46-8.41 (m, 1H), 8.35-8.25 (m, 1H), 7.99- 7.92 (m, 1H), 7.68-7.52 (m, 2H), 7.29-7.24 (t, J=8.4 Hz, 1H), 4.55-4.45 (m, 1H), 4.16- 4.12 (m, 2H), 3.76-3.71 (m, 2H). LCMS: 403.0 [M+1].

Experimental Procedure for Preparation of Compound 960_D1 and Compound 960_D2 1.1 Preparation of compound 2 To a solution of Compound 1 (40 g, 188 mmol) in DCM (400 mL) was added TMSOTf (44 g, 198 mmol), followed by Et N (38.0 g, 0.377 mol) at room temperature.

The reaction mixture was stirred for 1 hour. Then the reaction was concentrated to give the crude product Compound 2 (48.0g, 88.8%).

H NMR (400 MHz, CDCl ): δ ppm: 4.79 (s, 1H), 3.87 (m, 2H), 3.52 (m, 2H), 2.11 (s, 1H), 1.43 (s, 9H), 0.16 (s, 9H). 1.2 Preparation of compound 3 A mixture of Compound 2 (48 g, 167 mmol) and select-F (69 g, 184 mmol) in MeCN (500 mL) was stirred for 4 hours. The mixture was concentrated and purified by column chromatography (PE: AcOEt = 5:1) to give the compound 3 (14 g, 36%).

H NMR (400 MHz, CDCl ): δ ppm: 4.10-4.84 (m, 1H), 3.63-3.66 (m, 1H), 3.14-3.21 (m, 1H), 2.48-2.52 (m, 1H), 2.35-2.39 (m, 2H), 1.42 (s, 9H). 1.3 Preparation of compound 4 To a solution of Compound 3 (8.6 g, 36.1 mmol) in ethanol (90 mL) was added NaBH (2.13 g, 56.7 mmol) slowly at 0 C. The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was quenched with aqueous NH Cl solution and extracted with AcOEt. The organic layer was dried and concentrated in vacuo. The residue was purified by column chromatography to give the desired product as a mixture of cis and trans isomers (8.3 g, 97.6%). 1.4 Preparation of compound 5 To a solution of compound 4 (650 mg, 2.73 mmol) in anhydrous DCM (6 mL) was added TFA (4 mL). The mixture was stirred for 2 h, and concentrated to give the desired product which was used for the next step (300 mg, 80%). 1.5 Preparation of 960_D1 To a solution of Compound 6 (1.54 g, 4.2 mmol) and Compound 5 (500 mg, 4.2 mmol) in MeCN (25 mL) was added Et N (848 mg, 8.4 mmol) at rt. The mixture was stirred at rt for 3 h, at which time LCMS indicated the completion of the reaction. The solution was concentrated in vacuo. The residue was purified by preparative HPLC to give the desired product as white solid (580 mg, 42.3 %). The first peak in HPLC is named as 960_D1, while the second peak is 960_D2 (12.83 mg, 21.2%). 960_D1: H-NMR (DMSO-d6 400MHz): 10.79 (s, 1H) ，8.37-8.29 (m, 2H), 7.72- 7.68 (m, 3H), 5.17-5.16 (d, J=4.0Hz,1H), 4.71-4.58(m, 1H), 3.69-3.53 (m, 3H), 3.200- 3.10 (m, 1H), 2.95-2.93 (m, 1H), 1.71-1.66(m, 2H).

LCMS: 451.1 [M+1]. 960_D2: H-NMR (DMSO-d6 400MHz):10.82(s, 1H), 8.38-8.32(m, 2H), 7.75- 7.69(m, 3H), 5.39-5.38(d, J=4.0 Hz, 1H), 4.48-4.67(d, J=4.0 Hz, 1H), 3.71(s, 1H), 3.35(s, 2H), 3.23-3.20(t, J=4.0Hz, 2H), 1.88-1.85(m, 1H), 1.56-1.52(m, 1H).

LCMS: 451.1 [M+1].

Specific Experimental Procedures for Preparation of Compounds 1161/911 1.1 Preparation of compound 2 To CH MgBr (3 M, 60 mmol) in THF (50 mL) was added a solution of Compound 1 (10.0 g, 53 mmol) in THF (50 mL) slowly at 0-4 ℃. The resulting mixture was stirred at rt for 1 h. The reaction mixture was quenched by NH Cl solution, and extracted with EtOAc (100 mLx3). The organic layer was concentrated to give the crude product, which was purified by column chromatography to give the desired product (2.24g, Yield: 20.7%). LCMS: 206.0 [M+1]. 1.2 Preparation of compound 3 To a solution of Compound 2 (2.26 g, 11 mmol) in MeOH (40mL) was added Pd(OH) (350 mg), and was stirred under H2 at 50 psi for 72 h. The mixture was filtered and the filtrate was concentrated to give the desired product (1.26 g, Yield: 100%).

H-NMR (CDCl3 400MHz): 2.85-2.91 (m, 2H), 2.70-2.76 (m, 2H), 2.47-2.51 (m, 4H), 1.18 (s, 3H). 1.3 Procedure for preparation of Compound 1161 To a solution of Compound 3 (350 mg, 3 mmol) and Compound 4 (1.28 g, 3.5 mmol) in MeCN (15 mL) was added Et N (2 mL) at rt. The mixture was stirred at rt for 1 h. The reaction mixture was dissolved with EA (150 mL) and washed with brine (70 mL * 2). The organic layer were dried over Na SO , concentrated in vacuo and purified by silica chromatography gel to give the desired product (652 mg, 48.7 %).

H NMR (Methanol-d4 400MHz): 8.43-8.41 (dd, J=6.5, 2.4 Hz, 1H), 8.27-8.25 (m, 1H), 7.65-7.60 (m, 2H), 7.55-7.50 (dd, J=9.8, 8.8 Hz, 1H) ，3.60-3.57 (m, 2H), 3.04-2.97 (m, 2H), 1.68-1.63 (m, 4H), 1.22 (s, 3H).

LCMS: 447.0 [M+1]. 1.4 Procedure for preparation of 911 To a solution of Compound 3 (335 mg, 2.9 mmol) in MeCN (14 mL) was added Compound 5 (1.22 g, 3.4 mmol) and Et N (2 mL) at rt, and the mixture was stirred at rt for 1 h. The reaction mixture was diluted with EA (150 mL) and washed with brine (70 mL * 2). The organic layer were dried over Na SO , concentrated and purified by silica chromatography gel to give the desired product (686 mg, 54.9 %).

H-NMR (Methanol-d4 400MHz): 8.44-8.41 (dd, J=6.5, 2.1 Hz, 1H), 8.28-8.25 (m, 1H), 7.99-7.97 (dd, J=6.8, 2.5 Hz, 1H), 7.65-7.62 (m, 1H) ，7.54-7.50 (t, J=9.3 Hz, 1H) ，7.29-7.24 (t, J=9.0 Hz, 1H) ，3.60-3.57 (m, 2H), 3.04-2.98 (m, 2H), 1.72-1.65 (m, 4H), 1.22 (s, 3H). LCMS: 445.0 [M+1] /447.0 [M+3].

Experimental Procedure for Preparation of Compound 916 1.1 Preparation of Compound 2 To a solution of Me SOI (87.5 g, 396 mmol) in DMSO (400 mL) was added NaH (17 g, 706 mmol) at 0 ℃, and stirred at room temperature for 1 h. Then Bu NBr (8.05 g, 26 mmol) was added to the solution, followed by a solution of Compound 1 (50.0 g, 265 mmol) in DMSO (200 mL), and the mixture was stirred at room temperature for 1.5 h. The mixture was poured into water slowly and extracted with EA.

The combined organic phases were washed with brine, dried over Na SO , and concentrated in vacuo to give the desired product (50.5 g, 93 %).

H NMR (400 MHz, CDCl ): δ: 7.28-7.17 (m, 5H), 2.57-2.45(m, 6H), 1.77-1.74(m, 2H), 1.50-1.46 (m, 2H), 1.20-1.17(m, 2H). 1.2 Preparation of Compound 3 A mixture of Compound 2 (30.5 g, 150 mmol) in H SO (37.5 g, 380 mmol, 0.2 M) was stirred at rt overnight. The mixture was neutralized with Na CO to pH10 and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated to give the desired product (20.0 g, 58%). H NMR (400 MHz, CD3OD): δ ppm: 7.29-7.22(m, 5H), 3.50(s, 2H), 3.44(s, 2H), 3.31-3.27 (m, 2H), 2.61-2.58(m, 2H), 2.41-2.36(m, 2H), 1.69-1.64(m, 2H), 1.51-1.49(m, 2H). 1.3 Preparation of Compound 4 To a solution of Compound 3 (20 g, 90 mmol) in CH3OH (800 mL) was added dry Pd(OH)2 (2 g). The formed mixture was hydrogenated under H2 atmosphere of 15 Psi pressure overnight. The catalyst was filtered and the filtrate was concentrated to give the desired product (12 g, 98%). 1.4 Preparation of Compound 916 To a solution of Compound 5 (7.8 g, 21.2 mmol) in MeCN (100 mL) was added amine 4 (2.8 g, 21.2 mmol) and Et N (4.3 g, 42.4 mmol) at rt, and the mixture was stirred at rt for 3 h. The solution was concentrated in vacuo. The residue was purified by silica gel chromatography eluted with PE ： EA= from 3:1 to 1:2 to give the desired product as white solid (6.2 g), which was purified by re-crystallization from EA (30 mL) to afford pure product as white solid (4.1 g, yield: 41%).

H NMR (400MHz, METHANOL-d4): 8.48-8.39 (m, 1H), 8.33-8.21 (m, 1H), 7.63-7.59 (m, 2H), 7.59-7.52 (m, 1H), 3.72-3.69 (m, 2H), 3.35 (s, 2H), 3.03-2.94 (m, 2H), 1.78- 1.67 (m, 2H), 1.63-1.60 (m, 2H) LCMS: 463.1[M+1].

Specific Experimental Procedure for Preparation of Compounds 826/922 Experimental Data ： 1.1 Preparation of compound 2 To a solution of Compound 1 (10 g 0.06 mol) in CH Cl (40 mL) was added m- CPBA (9.0 g, 0.66 mol) at room temperature, and the mixture was stirred at rt for 12 hours. The mixture was quenched with Na SO , washed with NaHCO , and 2 3 3 concentrated to give the compound 2 (10 g, 90 %).

H NMR (400 MHz, CDCl ): δ ppm: 3.73-3.75 (m, 2H), 3.59-3. 60(m, 2H), 3.20- 3.25 (m, 2H), 1.37 (s, 9H). 1.2 Preparation of compound 3 To a solution of Compound 2 (10.0 g ，0.054 mol) in Et N (60 mL) was added Py HF (20 mL) at 0 ℃, and the mixture was heated to 80℃ for 12 hours. Then the mixture was concentrated in vacuo . The residue was diluted with AcOEt, washed with aqueous NH4Cl solution and brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (PE: EA=4:1) to give the the compound 3 (4 g, 36 %).

H NMR (400 MHz, CDCl3): δ ppm: 4.79-4.90 (m, 1H), 4.31-4.34 (m, 1H), 3.46- 3.56 (m, 4H), 2.25(s, 1H), 1.40 (s, 9H). 1.3 Preparation of Compound 4 To a solution of compound 3 (2 g, 0.01 mol) in anhydrous DCM (10 mL) was added TFA (10 mL) at 0 ℃. The formed mixture was stirred for 2 h, and concentrated to give the desired product as a TFA salt which was used for the next step (2.4 g). 1.4 Preparation of 826 To a solution of Compound 5 (900 mg, 2.3 mmol) and Compound 4 (580 mg) in MeCN (50 mL) was added Et N (690 mg, 6.9 mmol) at room temperature. The mixture was stirred at rt for 3 hours. The solution was concentrated in vacuo. The residue was purified by silica gel chromatography (PE:EA=3:1) to give 826 as white solid (0.6 g, 60 H NMR (400 MHz, Methanol-d4): δ ppm: 8.40 (s, 1H), 8.21-8.23 (d, J= 7.6Hz,1H), 8.06-8.13 (m, 2H), 7.69-8.06 (m, 2H), 4.77-4.88 (m, 1H), 4.23-4.25 (m, 1H), 3.43-3.66 (m, 3H), 3.32-3.33 (m, 1 H). 1.5 Preparation of 922 To a solution of Compound 6 (900 mg, 2.47 mmol) and Compound 4 (620 mg) in MeCN (50 mL) was added Et N (750 mg, 7.41 mmol) at room temperature. The mixture was stirred at rt for 3 hours. The solution was diluted with AcOEt, washed with water, dried with anhydrous Na SO and concentrated in vacuo. The residue was purified by silica gel chromatography (PE: EA =3:1) to give 922 as white solid (0.6 g, 50 %).

H NMR (400 MHz, DMSO-d6): δ ppm: 8.40 (s, 1H), 10.68 (s, 1H), 8.39-8.42 (m, 2H), 8.03-8.05 (m, 1H), 7.68-7.70 (m, 1H), 7.43-7.48 (m, 1H), 5.61-5.62 (d, J= 3.6Hz 1H), 4.87-5.01(m, 1H), 4.20-4.22 (m,1H), 3.57-3.65 (m, 2H), 3.48-3.49 (m, 1H), 3.45-3.47 (m,1H). LCMS: 435.0[M+1].

Specific Experimental Procedure for Compound 958 1.1 Preparation of Compound 2 To a slurry of Compound 1 (6.5 g, 79 mmol) and Compound 2 (10.2 g, 69 mmol) in MeOH (100 mL) was added an aqueous Na CO (6 mL, 2 N, 12 mmol), and stirred at rt for 24 h. The solid was collected by filtration, washed with MeOH and dried in vacuo, which was used in the next step (14 g, crude).

LCMS: 230.2 [M+1]. 1.2 Preparation of Compound 4 O NaBH O NH MeOH, THF To a mixture of Compound 3 (14 g, 61 mmol) in MeOH/THF (300 mL/50mL) was added NaBH (3.4 g, 90 mmol) at 0 ℃, and stirred at rt overnight. 1 N HCl was added slowly to quench the reaction. The resulting mixture was concentrated in vacuo.

The residue was dissolve with water and EtOAc. The aqueous phase was extracted with EtOAc (500 mLx2). The combined organic phase was concentrated to give the crude product, which was purified by column chromatography to give the Compound 4 (8.0 g, 57 %). LCMS: 236.1 [M+1]. 1.3 Preparation of Compound 5 A mixture of Compound 4 (8.0 g, 34 mmol) in MeOH (100 mL) was added concentrated HCl (10 mL), and heated to reflux for 2 h. The mixture was concentrated in vacuo. The residue was dissolved with water and washed with EA. The aqueous phase was concentrated in vacuo to give the desired product with HCl salt (2.8 g, 82 %).

H NMR (400 MHz, CDCl ): δ ppm: 4.33 (bs, 1H), 3.66 (bs, 1H), 2.08 - 2.16 (m, 2H), 1.74 -1.90 (m, 4 H). 1.4 Preparation of 958 To a solution of Compound 6 (626 mg, 1.72 mmol) and Compound 5 (174 mg, 1.72 mmol) in MeCN (7 mL) was added Et N (260 mg, 2.58 mmol) at rt, and the mixture was stirred at rt for 2 h. The solution was concentrated in vacuo. The organic phase was concentrated in vacuo to give the crude product, which was purified by prep- HPLC to give the desired product (355 mg, 48%).

H NMR (MeOD-d4 400MHz): 8.47-8.45(m, 1H) ，8.230-8.22 (m, 1H), 7.98-7.96 (m, 1H), 7.62-7.61 (m, 1H), 7.50-7.48 (m, 1H), 7.46-7.26(m, 1H), 4.13-4.10 (m, 1H), 3.72- 3.68 (m, 1H), 2.10-2.08 (m, 1H), 1.08-1.64 (m, 4H).1.64-1.43 (m, 1H).

LCMS: 431.0 [M+1].

Example: HBV Assembly Assay Selected compounds as described were assayed in the HBV assembly assay, as described elsewhere herein. The assembly assay was conducted in 96-well plate format.

The assembly reactions were carried out in 50 mM Hepes buffer, pH 7.5 and 150 mM NaCl. The compounds were pre-incubated with the HBV CA protein for 15 min, and the assembly reactions were initiated by addition of NaCl. The reaction was allowed to continue for 1 hour at room temperature. The 96-well plate assembly assay consistently had Z’ factors greater than 0.7 and were robust and reproducible both from plate-to-plate and day-to-day.

To determine the effect on capsid assembly, each test compound was initially screened at 4 different concentrations: 10 μM, 3 μM, 1 μM and 0.3 μM in duplicates.

Primary hits were compounds that show >50% activity in the assembly assay at 10 μM and a representative group of these active compounds is illustrated in Table 2.

Table 2.

"Activity" represents activity in HBV assembly assay (‘+’ indicates >50% activity at μM) Compound Activity Compound Activity 065 + 078 + 079 + 119 + 121 + 126 + 129 + 148 + 191 + 208 + 242 + 258 + 282 + 318 + 332 + 349 + 366 + 407 + 419 + 451 + 462 + 478 + 501 + 541 + 553 + 595 + 610D2 + 646 + 659D2 + 677R + 688 + 713D2 + 719D1 + 725D1 + 743D1 + 758 + 765 + 775 + 803 + 820D2 + 824D2 + 826 + 843 + 867D2 + 885 + 890 + 900 + 901 + 903 + 914 + 916 + 927 + 928 + 935 + 946D2 + 953 + 955D1 + 955D2 + 958 + 959 + 960D1 + 960D2 + 989D1 + 1042 + 1057 + 1087 + 1094S + 1099 + 1106 + 1113 + 1114 + 1116 + 1129 + 1130 + 1134CT2 + 1135D1 + 1149 + 1153 + 1157 + 1161 + 1189 + 1283 + 1338 + 1339 + 1345 + 1374CT1 + 1374CT2 + 1378CT2 + 1379 + 1380 + 1404 + 1410 + 1413 + 1420 + Example: Dot-blot Assay Selected compounds, which were shown to be active in the HBV assembly assay, were tested for their activity and toxicity in cellular assay. In the first anti-viral assay, the ability of compounds to inhibit HBV replication in an HBV-producing hepatoma cell line using the dot-blot method was evaluated.

Confluent monolayers of HepG2-2.2.15 cells were incubated with complete medium containing various concentrations of a test compound. Three days later, the culture medium was replaced with fresh medium containing the appropriately diluted test compound. Six days following the initial administration of the test compound, the cell culture supernatant was collected, and cell lysis was performed. The samples were applied onto Nylos membranes and DNA was immobilized to the membrane by UV cross-linking. After pre-hybridization, the HBV probe was added and the hybridization was performed overnight. The membranes were exposed to the Kodak films; antiviral activity was calculated from the reduction in HBV DNA levels (EC ). The EC for 50 50 antiviral activity was calculated from the dose response curves of active compounds.

Assay performance over time was monitored by the use of the standard positive control compounds ETV, BAY 41-4109, and HAP-1. Results are illustrated in Table 3.

Cytotoxity (CC ) was measured in this same HepG2-2.2.15 cell line using a CellTiter Blue-based cytotoxicity assay employed as recommended by manufacturer (Promega). All compounds in Table 3 demonstrated low toxicity at 5 μM.

Table 3 "Activity" represents activity in dot-blot-assay (‘+’ indicates >50% activity at 10 μM) Compound Activity Compound Activity 065 + 078 + 079 + 119 + 121 + 126 + 129 + 148 + 191 + 208 + 242 + 258 + 282 + 318 + 332 + 349 + 366 + 407 + 419 + 451 + 462 + 478 + 501 + 541 + 553 + 595 + 610D2 + 646 + 659D2 + 677R + 688 + 713D2 + 719D1 + 725D1 + 743D1 + 758 + 765 + 775 + 803 + 820D2 + 826 + 843 + 867D2 + 885 + 890 + 900 + 901 + 903 + 914 + 916 + 927 + 928 + 935 + 946D2 + 953 + 955D1 + 955D2 + 958 + 959 + 960D1 + 960D2 + 989D1 + 1042 + 1057 + 1087 + 1094S + 1099 + 1106 + 1113 + 1114 + 1116 + 1129 + 1130 + 1134CT2 + 1135D1 + 1149 + 1153 + 1157 + 1161 + 1189 + 1283 + 1338 + 1339 + 1345 + 1374CT1 + 1374CT2 + 1378CT2 + 1379 + 1380 + 1404 + 1410 + 1413 + 1420 + 824D2 + Example: Prevention of HBV Pre-Genomic RNA (pgRNA) Incorporation The compounds as described were assessed for their ability to suppress both extracellular and intracellular HBV DNA production in two different cell culture models of HBV replication. A particle-gel assay that allows quantitation of intracellular viral capsids, as well as encapsidated pre-genomic RNA and DNA, was performed. The assay relied on agarose gel separation of viral capsid from free capsid/core subunits and viral pg-RNA and DNA.

This assay revealed that the compounds as described prevent packaging of pre- genomic RNA into the viral capsid without significant effect on intracellular core particle levels. This effect is consistent with the biochemical activity of the compounds as described, which act as allosteric effectors that misdirect in vitro assembly leading to formation of aberrant, non-functional particles. The potent antiviral effect is due to that pg-RNA encapsidation is required for viral DNA synthesis.

The disclosures of each and every patent, patent application, and publication cited herein are hereby incorporated herein by reference in their entirety.

While the invention has been disclosed with reference to specific embodiments, it is apparent that other embodiments and variations of this invention may be devised by others skilled in the art without departing from the true spirit and scope of the invention.

The appended claims are intended to be construed to include all such embodiments and equivalent variations.

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Claims (10)

CLAIM

1. A method for preparing a compound of Formula IVc: O S O H N H (IVc); 5 wherein: X is halo; G is hydrogen or halo; G is H, C -C alkyl, or halo; and G is H, halo, C -C alkyl, or OH; the method comprising: a) reacting compound 1: 10 with thionyl chloride to produce compound 2: b) reacting compound 2 with aniline to produce compound 3: c) reacting compound 3 with an amine and TEA to produce a compound of Formula IVc: O S O H N H 5 (IVc).

2. The method of claim 1, wherein G is H, methyl, or halo.

3. The method of claim 1, wherein G is halo.

4. The method of claim 1, wherein G is halo.

5. The method of claim 1, wherein G is H.

6. The method of claim 1, wherein compound 1 in step a) is selected from the group consisting of: OO S , , , , , , and .

7. The method of claim 1, wherein the aniline in step b) is selected from the group consisting of: , , , , , , and

8. The method of claim 1, wherein the amine in step c) is selected from the group consisting of: , , , , , , , , , , , , , , , , , , and 15 .

9. The method of claim 1, wherein the compound of Formula IVc is selected from the group consisting of: Cl NH F NH Cl NH F NH OO S OO S OO S N OO S F F F Cl NH Cl NH F NH F NH OO S OO S OO S OO S OH OH Cl NH F NH F NH F NH OO S OO S OO S OO S Br NH Br NH Br NH O OO S OO S OO S OO S Cl NH Cl NH Cl NH F NH OO S OO S OO S OO S OH OH Cl NH Cl NH F NH F NH OO S OO S OO S OO S OH OH F NH F NH Cl NH OO S OO S OO S Cl NH Cl NH Cl NH F NH OO S OO S OO S OO S F NH N Cl O SO O SO OO S O OH Cl H O SO O SO O SO O SO O O O H N Br O SO O SO O SO O SO N Br F NH O SO O SO O SO OO S F NH Cl NH F NH O SO O SO O SO O SO OH OH Cl NH F F NH F NH F O O O O O SO O SO OO S O SO OH O NH NH O O O F F F O SO O SO O SO NH F NH F F F OO S O SO OO S O SO Cl NH Cl NH O SO O SO O SO O SO F NH Cl NH O SO OO S O SO O SO NH Cl NH F Cl NH NH O O O O OO S O SO O SO O SO F NH Cl NH O SO O SO NH NH Cl Br F NH Cl Cl OO S OO S OO S OH OH Cl NH Br NH F NH Cl Cl OO S OO S OO S F NH Cl Cl NH OO S OO S Cl NH Cl Cl NH Cl Cl NH Cl OO S OO S OO S OO S O OH Br NH Cl NH F NH F NH F Cl Cl Cl OO S OO S OO S OO S Br NH F NH OO S OO S F NH Br NH Cl NH Cl Cl OO S OO S OO S Cl NH Br NH Cl Cl OO S OO S Br NH Cl OO S Cl NH Cl OO S Cl NH Cl OO S

10. The method of any one of claims 1 to 9, substantially as herein described with reference to any example thereof.