HK1217330B - N-phenyl-carboxamide derivatives and the use thereof as medicaments for the treatment of hepatitis b - Google Patents

Description

N-phenyl-carbamyl derivatives and their use as drugs for treating hepatitis B

Background Art

Hepatitis B virus (HBV) is an enveloped, partially double-stranded DNA (dsDNA) virus of the hepadnaviridae family. Its genome consists of four overlapping reading frames: the precore/core gene; the polymerase gene; the L, M, and S genes, which encode three envelope proteins; and the X gene.

During infection, the partial double-stranded DNA genome (loose circular DNA; rcDNA) is converted into covalently closed circular DNA (cccDNA) in the host cell nucleus and the viral mRNA is transcribed. Once encapsidated, the pregenomic RNA (pgRNA) (which also encodes core protein and Pol) serves as a template for reverse transcription, which regenerates the partial dsDNA genome (rcDNA) in the nucleocapsid.

HBV is endemic in parts of Asia and Africa and is endemic in China. HBV has infected approximately 2 billion people worldwide, of whom approximately 350 million develop chronic infection. The virus causes the disease hepatitis B, and chronic infection is associated with a strongly increased risk of developing cirrhosis and hepatocellular carcinoma.

Hepatitis B virus is transmitted through exposure to infectious blood or body fluids, and viral DNA has been detected in the saliva, tears, and urine of chronic carriers with high titers of DNA in the serum.

An effective and well-tolerated vaccine exists, but immediate treatment options are currently limited to interferon and the following antiviral drugs: tenofovir, lamivudine, adefovir, entecavir, and telbivudine.

Additionally, heteroaryldihydropyrimidines (HAPs) were identified as a class of HBV inhibitors in tissue culture and animal models (Weber et al., Antiviral Res. 54:69-78).

WO/2013/006394 published on January 10, 2013 relates to a subclass of sulfamoyl-arylamide active against HBV.

Among the problems that may be encountered with these direct HBV antivirals are toxicity, mutagenicity, lack of selectivity, poor efficacy, poor bioavailability, and synthetic difficulties.

There is a need for additional HBV inhibitors that overcome at least one of these disadvantages or that possess additional advantages, such as increased potency or an increased safety window.

Description of the Invention

The present invention relates to a compound having the chemical formula (I)

or one of its stereoisomers or tautomeric forms, wherein:

represent:

X represents -(SO ₂ )- or a single bond, wherein

When X represents -(SO ₂ )-:

R ⁴ is selected from the group consisting of: -NR ⁵ R ⁶ , C ₁ -C ₆ alkyl, a 3-7 membered saturated ring optionally containing one or more heteroatoms each independently selected from the group consisting of O, S and N, such 3-7 membered saturated ring or C ₁ -C ₆ alkyl is substituted with one or more substituents each independently selected from the group consisting of hydrogen, fluoro, C ₁ -C ₄ alkoxy, OH, oxo, C ₁ -C ₄ alkyl, and cyclopropyl, and R ¹ , R ² and R ³ are independently selected from the group consisting of hydrogen, halogen, CN, chloro, CHF ₂ , CH ₂ F, CF ₃ and C ₁ -C ₃ alkyl and cyclopropyl;

When X represents a single bond:

R ⁴ is -C(=O)OR ⁷ ,

and R ¹ , R ² and R ³ are independently selected from the group consisting of hydrogen, halogen, CN, chlorine, CHF ₂ , CH ₂ F, CF ₃ , C ₁ -C ₃ alkyl, and cyclopropyl; such that at least one of R ¹ , R ² and R ³ is fluorine, and the other of R ¹ , R ² and R ³ is hydrogen, halogen, CN, chlorine, CHF ₂ , CH ₂ F, CF ₃ , C ₁ -C ₃ alkyl, and cyclopropyl;

R ⁵ is selected from the group consisting of hydrogen or methyl;

R ⁶ is selected from the group consisting of: C ₁ -C ₆ alkyl or a 3-7 membered saturated ring optionally containing one or more heteroatoms each independently selected from the group consisting of: O, S and N, such 3-7 membered saturated ring or C ₁ -C ₆ alkyl is optionally substituted with one or more substituents each independently selected from the group consisting of hydrogen, fluorine, CN, OH, oxo, -NHC(=O)OC ₁ -C ₄ alkyl, C ₁ -C ₄ alkyl optionally substituted with R ⁸ , C ₁ -C ₄ alkyloxy,

R ⁷ is selected from the group consisting of: C ₁ -C ₆ alkyl or a 3-7 membered saturated ring optionally containing one or more heteroatoms each independently selected from the group consisting of: O, S and N;

R ⁸ is selected from the group consisting of hydrogen, OH, C ₁ -C ₄ alkyl or CN;

or a pharmaceutically acceptable salt or solvate thereof.

The present invention further relates to a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable carrier.

The present invention also relates to compounds of formula (I) for use as a medicament, preferably for use in the prevention and treatment of HBV infection in mammals.

In another aspect, the invention relates to a combination of a compound of formula (I) and another HBV inhibitor.

definition

The term "Ci _-3 alkyl" as a group or part of a group refers to a hydrocarbon group of the formula _{CnH2n +1} , where n is a number ranging from 1 to 3. In the case where the Ci _-3 alkyl group is coupled to another group, _it refers to a chemical formula _CnH2n . _Ci-3 alkyl groups include from 1 to 3 carbon atoms, more preferably 1 to 2 carbon atoms. _Ci-3 alkyl includes all linear or branched alkyl groups having between 1 and 3 carbon atoms, and thus includes, for example, methyl, ethyl, n-propyl and isopropyl.

_C1-4 alkyl as a group or part of a group defines a straight or branched chain saturated hydrocarbon group having from 1 to 4 carbon atoms, such as the groups defined for _C1-3 alkyl and butyl etc.

_C1-6 alkyl as a group or part of a group defines a straight or branched chain saturated hydrocarbon group having from 1 to 6 carbon atoms, such as the groups defined for _C1-4 alkyl and pentyl, hexyl, 2-methylbutyl and the like.

The term "C _1-3 alkyloxy" as a group or part of a group refers to a group of formula --OR ^c , wherein R ^c is C _1-3 alkyl. Non-limiting examples of suitable C _1-3 alkoxy groups include methyloxy (also methoxy), ethyloxy (also ethoxy), propoxy, and isopropoxy.

The term oxo, C(=O), or carbonyl refers to a group consisting of one carbon atom double-bonded to an oxygen atom.

As used herein, the term "3-7 membered saturated ring" means a saturated cyclic hydrocarbon having 3, 4, 5, 6 or 7 carbon atoms, and is general to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

Such saturated rings may optionally contain one or more heteroatoms such that at least one carbon atom is replaced by a heteroatom selected from N, O and S, in particular from N and O. Examples include oxetane, tetrahydro-2H-pyranyl, piperidinyl, tetrahydrofuranyl, morpholinyl, thiolane 1,1-dioxide and pyrrolidinyl. Preferably, the saturated cyclic hydrocarbon has 3 or 4 carbon atoms and 1 oxygen atom. Examples include oxetane and tetrahydrofuranyl.

It should be noted that different isomers of different heterocycles may exist in the definitions as used throughout this specification.For example, pyrrolyl may be 1H-pyrrolyl or 2H-pyrrolyl.

The terms halo and halogen are generic for fluorine, chlorine, bromine or iodine. Preferred halogens are fluorine and chlorine.

It should also be noted that the residue positions on any molecular moiety used in the definitions may be any position on such moiety as long as it is chemically stable. For example, pyridyl includes 2-pyridyl, 3-pyridyl, and 4-pyridyl; pentyl includes 1-pentyl, 2-pentyl, and 3-pentyl.

The positions indicated on the phenyl group (e.g., ortho, meta, and/or para) are indicated relative to the bond connecting the phenyl group to the main structure. As an example of the position of R ¹ , any position is indicated relative to the nitrogen (*) connected to the main structure:

When any variable (eg, halogen or C _1-4 alkyl) occurs more than one time in any constituent, each definition is independent.

For therapeutic use, salts of compounds of formula (I) are those in which the counterion is pharmaceutically or physiologically acceptable. However, for example, in the preparation or purification of pharmaceutically acceptable compounds of formula (I), the use of salts with non-pharmaceutically acceptable counterions may also be found. All salts, whether pharmaceutically acceptable or unacceptable, are included within the scope of the present invention.

The pharmaceutically acceptable or physiologically tolerable addition salt forms that the compounds of the present invention are able to form can be conveniently prepared using appropriate acids, such as, for example, inorganic acids, such as hydrohalic acids, for example, hydrochloric acid or hydrobromic acid; sulfuric acid; hemisulfuric acid, nitric acid; phosphoric acid and the like; or organic acids, such as, for example, acetic acid, aspartic acid, dodecylsulfuric acid, heptanoic acid, hexanoic acid, nicotinic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclamic acid, salicylic acid, p-aminosalicylic acid, pamoic acid and the like.

Conversely said acid addition salt forms can be converted by treatment with an appropriate base into the free base form.

The term "salts" also comprises the hydrates and solvent addition forms that the compounds of the present invention are able to form. Examples of such forms are, for example, hydrates, alcoholates and the like.

The compounds of the present invention may also exist in their tautomeric forms, for example, the tautomeric form of an amide (-C(=O)-NH-) group is an imino alcohol (-C(OH)=N-). Tautomeric forms, although not explicitly indicated in the structural formulas represented herein, are also intended to be included within the scope of the present invention.

As used herein, the term "stereochemically isomeric forms of the compounds of the present invention" defines all possible compounds consisting of the same atoms bonded by the same sequence of bonds but having different three-dimensional structures that are not interchangeable, and the compounds of the present invention may have these characteristics. Unless otherwise mentioned or indicated, the chemical nomenclature of a compound encompasses a mixture of all possible stereochemically isomeric forms that the compound may have. The mixture may contain all diastereomers and/or enantiomers of the basic molecular structure of the compound. All stereochemically isomeric forms of the compounds of the present invention, either in pure form or admixed with each other, are intended to be encompassed within the scope of the present invention.

As used herein, pure stereoisomeric forms of the compounds and intermediates are defined as being substantially free of other enantiomeric or diastereomeric forms of the same basic molecular structure of the compound or intermediate. In particular, the term 'stereoisomerically pure' relates to compounds or intermediates having a stereoisomeric excess of at least 80% (i.e., a minimum of 90% of one isomer and 10% of other possible isomers) to 100% (i.e., 100% of one isomer and no other isomers), more particularly compounds or intermediates having a stereoisomeric excess of 90% to 100%, even more particularly 94% to 100% and most particularly 97% to 100%. The terms 'enantiomerically pure' and 'diastereomerically pure' should be understood in a similar manner, but the discussion is about enantiomeric excess and diastereomeric excess, respectively, in a mixture.

Pure stereoisomeric forms of the compounds of the present invention and intermediates can be obtained by the application of procedures known in the art. For example, enantiomers can be separated from each other by selective crystallization of their diastereomeric salts with optically active acids or bases. Examples thereof are tartaric acid, dibenzoyltartaric acid, ditoluoyltartaric acid, and camphorsulfonic acid. Alternatively, enantiomers can be separated by chromatography techniques using chiral stationary phases. The pure stereochemically isomeric forms can also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction is carried out stereospecifically. Preferably, if a specific stereoisomer is desired, the compound will be synthesized by a stereospecific method of preparation. These methods will advantageously use enantiomerically pure starting materials.

The diastereoisomeric forms of formula (I) can be obtained separately by conventional methods. Suitable physical separation methods that may be advantageously employed are, for example, selective crystallization and chromatography (eg column chromatography).

The present invention is also intended to include all isotopes of atoms present in the compounds of the present invention. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium. Isotopes of carbon include C-13 and C-14.

Detailed Description of the Invention

Whenever used hereinafter, the term "compound of formula (I)"

or "compounds of the present invention" or similar terms are meant to include compounds having the general formula (I), (Ib), their salts, stereoisomeric forms and racemic mixtures or any subgroups thereof.

The compounds for use in the prevention and treatment of HBV infection in mammals are disclosed as the compounds themselves and are not limited to such uses unless limited by the claims.

In a first aspect, the present invention provides a compound having the formula (I)

or one of its stereoisomers or tautomeric forms, wherein:

represent:

X represents -(SO ₂ )- or a single bond, wherein

When X represents -(SO ₂ )-:

R ⁴ is selected from the group consisting of: -NR ⁵ R ⁶ , C ₁ -C ₆ alkyl, a 3-7 membered saturated ring optionally containing one or more heteroatoms each independently selected from the group consisting of O, S and N, such 3-7 membered saturated ring or C ₁ -C ₆ alkyl is substituted with one or more substituents each independently selected from the group consisting of hydrogen, fluoro, C ₁ -C ₄ alkoxy, OH, oxo, C ₁ -C ₄ alkyl, and cyclopropyl, and R ¹ , R ² and R ³ are independently selected from the group consisting of hydrogen, halogen, CN, chloro, CHF ₂ , CH ₂ F, CF ₃ and C ₁ -C ₃ alkyl and cyclopropyl;

When X represents a single bond:

R ⁴ is -C(=O)OR ⁷ ,

and R ¹ , R ² and R ³ are independently selected from the group consisting of hydrogen, halogen, CN, chlorine, CHF ₂ , CH ₂ F, CF ₃ , C ₁ -C ₃ alkyl, and cyclopropyl; such that at least one of R ¹ , R ² and R ³ is fluorine, and the other of R ¹ , R ² and R ³ is hydrogen, halogen, CN, chlorine, CHF ₂ , CH ₂ F, CF ₃ , C ₁ -C ₃ alkyl, and cyclopropyl;

R ⁵ is selected from the group consisting of hydrogen or methyl;

R ⁶ is selected from the group consisting of: C ₁ -C ₆ alkyl or a 3-7 membered saturated ring optionally containing one or more heteroatoms each independently selected from the group consisting of: O, S and N, such 3-7 membered saturated ring or C ₁ -C ₆ alkyl is optionally substituted with one or more substituents each independently selected from the group consisting of hydrogen, fluorine, CN, OH, oxo, -NHC(=O)OC ₁ -C ₄ alkyl, C ₁ -C ₄ alkyl optionally substituted with R ⁸ , C ₁ -C ₄ alkyloxy,

R ⁷ is selected from the group consisting of: C ₁ -C ₆ alkyl or a 3-7 membered saturated ring optionally containing one or more heteroatoms each independently selected from the group consisting of: O, S and N;

R ⁸ is selected from the group consisting of hydrogen, OH, C ₁ -C ₄ alkyl or CN;

or a pharmaceutically acceptable salt or solvate thereof.

In a further aspect, the present invention relates to compounds of formula (I)

or one of its stereoisomers or tautomeric forms, wherein:

represent:

X represents -(SO ₂ )- or a single bond, wherein

When X represents -(SO ₂ )-;

^R4 is selected from the group consisting of ^-NR5R6 , _C1 - _C6 alkyl, ^a 3-7 membered saturated ring optionally containing one or more heteroatoms each independently selected from the group consisting of O, S and N, such 3-7 membered saturated ring or _C1 - _C6 alkyl is substituted with one or more substituents each independently selected from the group consisting of hydrogen, fluoro, _C1 - _C4 alkoxy, OH, oxo, _C1 - _C4 alkyl, and cyclopropyl,

and R ¹ , R ² and R ³ are independently selected from the group consisting of hydrogen, fluorine, chlorine, CHF ₂ , CH ₂ F, CF ₃ and methyl;

When X represents a single bond:

R ⁴ is -C(=O)OR ⁷ ,

and ^R1 , ^R2 and ^R3 are independently selected from the group consisting of hydrogen, fluorine, chlorine, _CHF2 , _CH2F , _CF3 and methyl, such that at least one of ^R1 , ^R2 and ^R3 is fluorine and another of ^R1 , ^R2 and ^R3 is fluorine, _CHF2 , _CH2F , _CF3 or methyl.

R ⁵ is selected from the group consisting of hydrogen or methyl;

R ⁶ is selected from the group consisting of: C ₁ -C ₆ alkyl or a 3-7 membered saturated ring optionally containing one or more heteroatoms each independently selected from the group consisting of: O, S and N, such 3-7 membered saturated ring or C ₁ -C ₆ alkyl is optionally substituted with one or more substituents each independently selected from the group consisting of: hydrogen, or C ₁ -C ₄ alkyl;

R ⁷ is selected from the group consisting of: C ₁ -C ₆ alkyl or a 3-7 membered saturated ring optionally containing one or more heteroatoms each independently selected from the group consisting of: O, S and N;

or a pharmaceutically acceptable salt or solvate thereof.

In one embodiment of the present invention,

In another embodiment of the present invention, the compound is represented by the following chemical formula (Ib):

or one of its stereoisomers or tautomeric forms, or a pharmaceutically acceptable salt or solvate.

In a preferred embodiment, compounds of formula (I) or (Ib) are envisaged, wherein R ¹ is selected from fluoro or methyl, and R ² is fluoro.

In yet another embodiment, compounds of formula (I) or (Ib) are contemplated, wherein X is -(SO ₂ )-, R ⁴ is NR ⁵ R ⁶ and R ⁵ and R ⁶ are as defined above.

In a further embodiment, compounds of formula (I) or (Ib) are contemplated wherein R ⁴ comprises a 3-7 membered saturated ring optionally comprising an oxygen.

Another embodiment of the present invention relates to those compounds of formula (I) or any subgroup thereof, as mentioned in any other embodiment, wherein one or more of the following limitations apply:

(a) R ⁶ is C ₁ -C ₆ alkyl, optionally substituted by one or more fluorine groups.

(b) R ¹ is methyl.

(c) ^R2 and ^R3 are independently selected from the group consisting of hydrogen, fluoro and methyl.

(d) R ⁶ contains a 3-7 membered saturated ring optionally containing one oxygen, more specifically, R ⁶ is a 4- or 5-membered saturated ring containing one oxygen, and such 4- or 5-membered saturated ring is optionally substituted by methyl.

(e) ^R6 comprises a branched _C3 - _C6 alkyl group optionally substituted with one or more fluorine groups, or ^R6 comprises a _C3 - _C6 cycloalkyl group, wherein the _C3 - _C6 cycloalkyl group is substituted with one or more fluorine groups or is substituted with a _C1 - _C4 group substituted with one or more fluorine groups. More specifically, ^R6 is a branched _C3 - _C6 alkyl group substituted with one or more fluorine groups.

(f) R ⁶ is selected from the group consisting of C ₂ -C ₆ alkyl optionally substituted with one or more fluorines.

Further combinations of any sub-embodiments or preferred embodiments are also contemplated to be within the scope of the present invention.

Preferred compounds according to the present invention are compounds having a formula selected from Table 1 or stereoisomers or tautomeric forms thereof.

In another aspect, the present invention pays attention to a kind of pharmaceutical composition, and the pharmaceutical composition includes the compound with chemical formula (I) of effective amount in the treatment specified here or prevention, and pharmaceutically acceptable carrier.In this background, a kind of prevention effective amount is the amount that is enough to prevent the HBV infection of the experimenter in the risk of being infected.In this background, a kind of treatment effective amount is a kind of amount that is enough to stabilizing HBV infection, alleviating HBV infection or eradicating HBV infection in the experimenter that has been infected.Still in another aspect, the present invention relates to the method for preparing the pharmaceutical composition specified here, it includes closely by pharmaceutically acceptable carrier and the compound with chemical formula (I) of effective amount in the treatment specified here or prevention effective amount mixing.

Therefore, the compounds of the present invention or any subgroup thereof can be formulated into different pharmaceutical forms for administration purposes. As appropriate compositions, all compositions commonly used for systemic administration can be cited. In order to prepare the pharmaceutical compositions of the present invention, an effective amount of a specific compound (optionally in the form of an addition salt) as an active ingredient is combined in a uniform blend with a pharmaceutically acceptable carrier, which can take a variety of forms depending on the form of the desired formulation for administration. It is desirable that these pharmaceutical compositions are in a unit dosage form suitable for, in particular suitable for, oral, rectal, transdermal or parenteral administration. For example, in the preparation of pharmaceutical compositions in oral dosage forms, any common pharmaceutical media can be used, such as water, glycols, oils, alcohols and the like in the case of oral liquid preparations (such as suspensions, syrups, elixirs, emulsions and solutions); or solid carriers such as starch, sugar, kaolin, lubricants, binders, disintegrants and the like in the case of powders, pills, capsules and tablets. Because they are easy to administer, tablets and capsules represent the most advantageous oral unit dosage forms, in which case solid pharmaceutical carriers are used. For parenteral compositions, the carrier will typically include at least a large portion of sterile water, but may also include other ingredients such as to assist solubility. For example, injectable solutions can be prepared in which the carrier includes saline and glucose solutions of physiological saline solutions, glucose solutions, or any two or more mixtures thereof. Injectable suspensions can also be prepared, in which case appropriate liquid carriers, suspending agents, etc. can be used. Also included are solid form products that are expected to be converted into liquid form products shortly before use. In the composition suitable for transdermal administration, the carrier may optionally include a penetration enhancer and/or a suitable wetting agent, optionally in combination with a small proportion of any property in suitable additives that do not introduce significant adverse effects on the skin. The compounds of the present invention can also be administered by oral inhalation or insufflation in the form of a solution, suspension, or dry powder using any delivery system known in the art.

For ease of administration and uniformity of dosage, it is particularly advantageous to formulate the above-described pharmaceutical compositions in unit dosage form. As used herein, a unit dosage form refers to a physically discrete unit suitable as a unit dosage, each unit containing a predetermined amount of the active ingredient calculated to produce the desired therapeutic effect in combination with the required pharmaceutical carrier. Examples of such unit dosage forms are tablets (including scored or coated tablets), capsules, pills, suppositories, powder packets, wafers, injectable solutions or suspensions, and the like, and separate multiples thereof.

The compounds of formula (I) are active as inhibitors of the HBV replication cycle and can be used to treat and prevent HBV infection or HBV-related diseases, including progressive liver fibrosis, inflammation and necrosis leading to cirrhosis, end-stage liver disease, and hepatocellular carcinoma.

Due to their antiviral properties, in particular their anti-HBV properties, the compounds of formula (I) or any subgroup thereof are useful in the inhibition of the HBV replication cycle, in particular in the treatment of warm-blooded animals infected with HBV (in particular humans) and for the prevention of HBV infection. The present invention further relates to a method for treating warm-blooded animals infected with HBV or at risk of being infected with HBV (in particular humans), which method comprises administering a therapeutically effective amount of a compound of formula (I).

As specified herein, the compound of formula (I) can therefore be used as a drug, particularly as a drug for treating or preventing HBV infection. The use or treatment method as a drug comprises systemically administering an amount effective to combat HBV infection-related conditions or an amount effective to prevent HBV infection to a subject infected by HBV or a subject susceptible to HBV infection.

The present invention also relates to the use of the compound of the present invention in the manufacture of a medicament for treating or preventing HBV infection.

In general, it is contemplated that the effective antiviral daily dose will be from about 0.01 mg/kg to about 50 mg/kg body weight, or from about 0.01 mg/kg to about 30 mg/kg body weight. The desired dose may be suitably administered in two, three, four, or more sub-doses at appropriate intervals throughout the day. The sub-doses may be formulated as unit dosage forms, for example, containing from about 1 mg to about 500 mg, or from about 1 mg to about 300 mg, or from about 1 mg to about 100 mg, or from about 2 mg to about 50 mg of active ingredient per unit dosage form.

The present invention also concerns combinations of compounds of formula (I) or any subgroup thereof as specified herein with other anti-HBV agents. The term "combination" also relates to a product or kit comprising (a) a compound of formula (I) as specified above, and (b) at least one other compound capable of treating HBV infection (referred to herein as an anti-HBV agent), as a combined preparation for simultaneous, separate or sequential treatment of HBV infection. In one embodiment, the present invention concerns combinations of compounds of formula (I) or any subgroup thereof with at least one anti-HBV agent. In a specific embodiment, the present invention concerns combinations of compounds of formula (I) or any subgroup thereof with at least two anti-HBV agents. In a specific embodiment, the present invention concerns combinations of compounds of formula (I) or any subgroup thereof with at least three anti-HBV agents. In a specific embodiment, the present invention concerns combinations of compounds of formula (I) or any subgroup thereof with at least four anti-HBV agents.

The combination of previously known anti-HBV agents (such as interferon-α (IFN-α), pegylated interferon-α, 3TC, adefovir or a combination thereof) and a compound of formula (I) or any subgroup thereof can be used as one drug in combination therapy.

General synthesis:

Substituents expressed in this general synthesis section are intended to include any substituent or reactive species suitable for conversion into any substituent according to the present invention without undue burden to one of ordinary skill in the art.

The general synthesis of compounds of formula (I) is described in Scheme 1 and Scheme 2. As described in Scheme 1, an amino acid of formula (II) is reacted with a reagent of formula ^R4 -XY in the presence of a base such as, for example, DIPEA. In the context of Scheme 1, examples of such reagents of formula ^R4 -XY are, but are not limited to

ClC(=O)OR ⁷ , and R ⁴ SO ₂ Cl. The resulting carboxylic acid III is reacted with an aniline of formula (IV) under typical amide forming conditions such as HATU and DIPEA in CH ₂ Cl ₂ at room temperature to give compounds of formula (I).

Solution 1

Another possible synthetic route to compounds of general formula (I) is depicted in Scheme 2. In this case, compound V (an amino acid with a protecting group PG on nitrogen, where PG can be, for example, Boc (tert-butyloxy)carbonyl) or Cbz (benzyloxycarbonyl)) is reacted with an aniline compound of formula (IV) under typical amide-forming conditions, such as, for example, HATU and DIPEA in _CH2Cl2 . The resulting compound of general formula VI _is deprotected, for example, by treatment with HCl in iPrOH/ _CH2Cl2 or TFA _{in CH2Cl2} when PG is equal to Boc, to give a compound of formula VII. Further reaction of the compound of general formula VII with a compound of general formula _R4 -XY (in the context of Scheme 2 _, examples of R4 _- XY are, but are not limited to _, ClC(=O) ^OR7 , _R4SO2Cl , and ) is likely carried out in the presence of a base, such as, for example, _NEt3 , to give compounds of general formula (I).

Option 2

Another possible route to compounds of formula (I)c is described in Scheme 3. A compound of formula VII is reacted with a reagent of formula VIII. Examples of such reagents VIII are, but are not limited to, NH ₂ SO ₂ NH ₂ and

In the case of the following: reaction with VII followed by methylation with, for example, MeOTf, a compound of the following general formula (IXa) is obtained:

Further reaction with an amine of formula XI leads to the formation of a compound of formula (Ic).

Option 3

General Procedure LCMS Method

High performance liquid chromatography (HPLC) measurements were performed using an LC pump, a diode array (DAD) or UV detector and a column as specified in the corresponding methods. Additional detectors were included if necessary (see Methods table below).

The flow from the column is taken to a mass spectrometer (MS) equipped with an atmospheric pressure ion source. Setting the tuning parameters (e.g., scan range, dwell time, etc.) to obtain ions with nominal monoisotopic molecular weights (MW) that allow identification of the compound is within the knowledge of the skilled person. Data acquisition is performed using appropriate software.

Compounds are described by experimental retention time ( _Rt ) and ion. If not specified differently in the data table, the reported molecular ions correspond to [M+H] ⁺ (protonated molecule) and/or [MH] ⁻ (deprotonated molecule). In cases where the compound is not directly ionizable, the type of adduct is specified (i.e., [M+NH ₄ ] ⁺ , [M+HCOO] ⁻ , etc.). All results obtained are subject to the experimental uncertainty generally associated with the methods used.

Hereinafter, “SQD” means single quadrupole detector, “MSD” mass selective detector, “RT” room temperature, “BEH” bridged ethylsiloxane/silica hybrid, “DAD” diode array detector, “HSS” high intensity silica, “Q-Tof” quadrupole time-of-flight mass spectrometer, “CLND” chemiluminescent nitrogen detector, “ELSD” evaporative light scanning detector,

LCMS method (flow rate in mL/min; column temperature (T) in °C; run time in minutes).

Synthesis of compounds:

Compound 1: N-(4-fluoro-3-methyl-phenyl)-1-isobutylsulfonyl-pyrrolidine-3-carboxamide

To a stirred solution of 4-fluoro-3-methyl-aniline (2.0 g, 15.98 mmol), 1-tert-butoxycarbonylpyrrolidine-3-carboxylic acid (3.44 g, 15.98 mmol) and DIPEA (6.2 g, 47.9 mmol) in CH ₂ Cl ₂ (30 mL) at 0° C. was added HATU (7.29 g, 19.2 mmol). The resulting mixture was stirred at 18° C. overnight. The reaction mixture was washed with 1N HCl (30 mL) and saturated aqueous NaHCO ₃ (30 mL), dried over Na ₂ SO ₄ and concentrated in vacuo to give tert-butyl-3-[(4-fluoro-3-methyl-phenyl)carbamoyl]pyrrolidine-1-carboxylate (3.1 g). To a solution of tert-butyl 3-[(4-fluoro-3-methyl-phenyl)carbamoyl]pyrrolidine-1-carboxylate (3.1 g, 9.62 mmol) in _CH₂Cl₂ (30 _mL ) was added trifluoroacetic acid (20 mL). The resulting mixture was stirred at 18°C for 3 hours. The reaction mixture was adjusted to pH 7-8 with saturated aqueous _NaHCO₃ . The organic layer was separated, washed with brine, and dried _{over Na₂SO₄} . The solvent was removed in vacuo, and the obtained residue (1.8 g) was used as such in the next step. To a portion of the above-obtained residue (500 mg) and DIPEA (576 mg, 4.46 mmol) in _CH₂Cl₂ (10 _mL ) at 0°C was added 2-methylpropane-1-sulfonyl chloride (257 mg, 1.64 mmol). The resulting mixture was stirred at 18°C for 4 hours. The reaction mixture was washed with 1N HCl (15 mL) and saturated aqueous _NaHCO₃ (15 mL), dried over _Na₂SO₄ , and concentrated in _vacuo . The crude product was purified by reverse-phase preparative high-performance liquid chromatography (eluent: _CH₃CN (0.05% _NH₃.H₂O ) in _H₂O from 40% to 70%, v/v). Pure fractions were collected and volatiles were removed in vacuo. The aqueous layer was lyophilized to dryness _to afford compound 1 (40 mg).

Synthesis of enantiomers of compound 1:

Compound 2: (3S)-N-(4-Fluoro-3-methyl-phenyl)-1-isobutylsulfonyl-pyrrolidine-3-carboxamide

Prepared similarly as described for compound 1, starting from (3S)-1-tert-butoxy-carbonylpyrrolidine-3-carboxylic acid instead of 1-tert-butoxycarbonylpyrrolidine-3-carboxylic acid. Method A; Rt: 5.43 min. m/z: 343.3 (M+H) ⁺ exact mass: 342.1. ¹ H NMR (400MHz, chloroform-d) δppm 1.13 (d, J = 6.8Hz, 6H) 2.22-2.37 (m, 6H) 2.83-3.00 (m, 2H) 3.10 (quin, J = 7.3Hz, 1H) 3.42-3.59 (m, 3H) 3 .73 (dd, J=10.0, 7.5Hz, 1H) 6.94 (t, J=8.9Hz, 1H) 7.22-7.30 (m, 1H) 7.36-7.41 (m, 1H) 7.73 (br.s, 1H). (c0.26w/v%, DMF).

Compound 3: (3R)-N-(4-fluoro-3-methyl-phenyl)-1-isobutylsulfonyl-pyrrolidine-3-carboxamide

Prepared similarly as described for compound 1, starting with (3R)-1-tert-butoxy-carbonylpyrrolidine-3-carboxylic acid instead of 1-tert-butoxycarbonylpyrrolidine-3-carboxylic acid. Method B; Rt: 5.54 min. m/z: 343.3 (M+H) + exact mass: 342.1. (c 0.46 w/v%, DMF)

Synthesis of (3S)-N-(4-fluoro-3-methyl-phenyl)pyrrolidine-3-carboxamide hydrochloride:

4-Fluoro-3-methylaniline (5.81 g, 46.5 mmol), Boc-(3S)-1-pyrrolidine-3-carboxylic acid (10 g, 46.5 mmol) and DIPEA (24 mL, 139.4 mmol) were dissolved in CH ₂ Cl ₂ (30 mL). HATU (21.2 g, 55.7 mmol) was added in small portions and the resulting mixture was stirred at room temperature overnight. The reaction mixture was washed with 1 M HCl (20 mL) and the organic layer was evaporated to dryness. The residue was purified by silica gel column chromatography using a heptane to EtOAc gradient to produce tert-butyl (3S)-3-[(4-fluoro-3-methyl-phenyl)carbamoyl]pyrrolidine-1-carboxylate (14.7 g) as a light brown oil. (3S)-3-[(4-Fluoro-3-methyl-phenyl)carbamoyl]pyrrolidine-1-carboxylate (14.7 g) was dissolved in CH ₂ Cl ₂ (100 mL) and HCl (6 M in iPrOH, 76 mL) was added. The reaction mixture was stirred at room temperature overnight. The volatiles were removed under reduced pressure and the obtained residue was triturated in diethyl ether, filtered and dried in vacuo overnight to give (3S)-N-(4-fluoro-3-methyl-phenyl)pyrrolidine-3-carboxamide hydrochloride (11.2 g) as a powder.

General synthetic procedure A:

(3S)-N-(4-Fluoro-3-methyl-phenyl)pyrrolidine-3-carboxamide hydrochloride (200 mg, 0.77 mmol) and DIPEA (2.5 eq) were dissolved in _CH2Cl2 (5 mL). Reagent A (Procedure A1: 0.140 _mL ; Procedure A2: 0.150 mL if liquid, 1.1 eq if solid) was added and the reaction mixture was stirred at room temperature overnight (Procedures A1, A2, and A3) or for 30 minutes (Procedure A4).

Work-up procedures A1, A2 and A4: The mixture was washed with 1 M HCl (5 mL) and the organic layer was loaded onto a silica column and purified using a gradient from heptane to EtOAc.

Work-up procedure A3: The organic layer was loaded onto a silica column and purified using a gradient from heptane to EtOAc.

Compound 6: (3S)-N-(4-Fluoro-3-methyl-phenyl)-1-propylsulfonyl-pyrrolidine-3-carboxamide.

¹ H NMR (400MHz, DMSO-d ₆ ) δppm 1.00(t, J=7.5Hz, 3H), 1.66-1.77(m, 2H), 2.01-2.12(m, 1H), 2.12-2.19(m, 1H), 2.20 (d, J=1.8Hz, 3H), 3.04-3.11 (m, 2H), 3.17 (quin, J=7.4Hz, 1H), 3. 27-3.31 (m, 1H), 3.34-3.43 (m, 2H), 3.56 (dd, J=10.0, 7.8Hz, 1H), 7.07 (t, J =9.2Hz, 1H), 7.34-7.43 (m, 1H), 7.50 (dd, J=7.0, 2.4Hz, 1H), 10.02 (s, 1H).

Compound 8: (3S)-1-(cyclopropylmethylsulfonyl)-N-(4-fluoro-3-methyl-phenyl)pyrrolidine-3-carboxylate amine.

¹ H NMR (400MHz, DMSO-d ₆ ) δppm 0.31-0.39(m, 2H), 0.55-0.64(m, 2H), 0.97-1.10(m, 1H), 2.01-2.12(m, 1H), 2. 12-2.19 (m, 1H), 2.20 (d, J=1.8Hz, 3H), 3.07 (d, J=7.0Hz, 2H), 3.18 (quin, J=7.6 Hz, 1H), 3.33-3.38 (m, 1H), 3.38-3.47 (m, 2H), 3.59 (dd, J=9.7, 7.9Hz, 1H), 7.07 (t, J=9.2Hz, 1H), 7.35-7.43 (m, 1H), 7.50 (dd, J=7.0, 2.2Hz, 1H), 10.02 (s, 1H).

Compound 9: (3S)-N-(4-Fluoro-3-methyl-phenyl)-1-tetrahydropyran-4-ylsulfonyl-pyrrolidine-3-carboxylate amine.

¹ H NMR (400MHz, DMSO-d ₆ ) δppm 1.59-1.75 (m, 2H), 1.81-1.94 (m, 2H), 2.02-2.19 (m, 2H), 2.20 (d, J=1.8Hz, 3H), 3.18 (quin, J=7.4Hz, 1H), 3.32-3.56 (m, 6H), 3.6 2 (dd, J=9.7, 7.9Hz, 1H), 3.87-3.98 (m, 2H), 7.07 (t, J=9.1Hz, 1H), 7.34-7.43 (m, 1H), 7.50 (dd, J=7.0, 2.4Hz, 1H), 10.02 (s, 1H).

Compound 10: (3S)-1-Cyclopentylsulfonyl-N-(4-fluoro-3-methyl-phenyl)pyrrolidine-3-carboxamide.

¹ H NMR (400MHz, DMSO-d ₆ ) δppm 1.49-1.61(m, 2H), 1.61-1.73(m, 2H), 1.77-1.89(m, 2H), 1.89-2.01(m, 2H) , 2.03-2.18 (m, 2H), 2.20 (d, J=1.8Hz, 3H), 3.16 (quin, J=7.5Hz, 1H), 3.33- 3.46 (m, 3H), 3.60 (dd, J=9.7, 7.9Hz, 1H), 3.71 (quin, J=8.1Hz, 1H), 7.07 (t , J=9.2Hz, 1H), 7.35-7.42 (m, 1H), 7.50 (dd, J=7.0, 2.4Hz, 1H), 10.02 (s, 1H)

Compound 24: (3S)-1-(2-Ethylcyclopropyl)sulfonyl-N-(4-fluoro-3-methyl-phenyl)pyrrolidine-3-carboxylate Amide.

¹ H NMR (400MHz, DMSO-d ₆ ) δppm 0.81-0.90(m, 1H), 0.92-0.98(m, 3H), 1.05-1.13(m, 1H), 1.28-1.42(m , 3H), 2.01-2.19(m, 2H), 2.19-2.23(m, 3H), 2.52-2.54(m, 1H), 3.13-3. 24(m, 1H), 3.33-3.38(m, 1H), 3.38-3.48(m, 2H), 3.54-3.63(m, 1H), 7.0 7(t, J=9.2Hz, 1H), 7.36-7.43(m, 1H), 7.48-7.54(m, 1H), 10.02(s, 1H).

The mixture 24 was separated into two isomers by preparative SFC (stationary phase: Chiralcel Diacel OJ 20 x 250 mm; mobile phase: _CO2 , iPrOH with 0.2% _iPrNH2 ). OJ-H 250 mm x 4.6 mm, flow rate: 5 mL/min, mobile phase: 15% EtOH (containing 0.2% _iPrNH2 ) for 4 minutes. Rt: 24a: 1.68 min, 24b: 2.04 min.

Compound 25: (3S)-N-(4-Fluoro-3-methyl-phenyl)-1-sec-butylsulfonyl-pyrrolidine-3-carboxamide.

¹ H NMR (400MHz, DMSO-d ₆ ) δppm 0.96 (t, J = 7.5Hz, 3H) 1.22-1.26 (m, 3H) 1.36-1.54 (m, 1H) 1.81-1.97 (m, 1H) 2.02-2.18 (m, 2H) 2.20 (d, J = 1.8Hz, 3H) 3.09-3.2 6 (m, 2H) 3.33-3.48 (m, 3H) 3.57-3.66 (m, 1H) 7.06 (t, J = 9.2Hz, 1H) 7.33-7.43 (m, 1H) 7.51 (dd, J = 7.0, 2.6Hz, 1H) 10.02 (s, 1H)

Compound 26: (3S)-3-[(4-Fluoro-3-methyl-phenyl)carbamoyl]pyrrolidine-1-carboxylic acid isobutyl ester.

¹ H NMR (400MHz, DMSO-d ₆ ) δppm 0.89 (d, J=6.6Hz, 6H), 1.80-1.92 (m, 1H), 1.94-2.18 (m, 2H), 2.18-2.24 (m, 3H), 3.04-3.21 (m, 1H), 3.24-3.38 (m, 1H), 3.35-3. 50 (m, 2H), 3.50-3.63 (m, 1H), 3.77 (d, J=6.4Hz, 2H), 7.06 (t, J=9.2Hz, 1H), 7.35-7.42 (m, 1H), 7.49-7.52 (m, 1H), 10.00 (s, 1H).

Compound 27: (1S,5S)-N-(4-fluoro-3-methyl-phenyl)-3-isobutylsulfonyl-3-azabicyclo [3.1.0] Hexane-1-carboxamide.

3-benzyl-3-azabicyclo [3.1.0] hexane-5-ethyl formate (1.03g, 4.2mmol) is dissolved in THF (40mL). Add water (10mL) and LiOH (0.5g, 20.9mmol). The reaction mixture is stirred at room temperature for 12 hours and then refluxed for 24 hours. The reaction mixture is concentrated to dryness in a vacuum, and residual water and toluene (2x 20mL) coevaporation are removed to obtain a kind of residue. The residue obtained is suspended in CH ₂ Cl ₂ (50mL, anhydrous) and NEt ₃ .HCl (5.8g, 42.0mmol), 4-fluoro-3-methyl-aniline (0.79g) and HATU (4.8g, 12.6mmol) are added successively. The reaction mixture is stirred at room temperature for 2 hours. DMF (100mL) and more 4-fluoro-3-methyl-aniline (0.53g) are added to the reaction mixture. The reaction mixture was further stirred at room temperature over the weekend. The reaction mixture was diluted with CH ₂ Cl ₂ (100 mL), washed with saturated aqueous sodium bicarbonate (2 x 50 mL), dried (Na ₂ SO ₄ ), and concentrated in vacuo to give a residue. The obtained residue was purified using silica gel column chromatography by eluting with a gradient of ethyl acetate in heptane from 0 to 100% and then ethyl acetate in heptane from 20% to 25% to produce 3-benzyl-N-(4-fluoro-3-methyl-phenyl)-3-azabicyclo[3.1.0]hexane-5-carboxamide (400 mg). Method C; Rt: 1.17 min. m/z: 325.2 (M+H) ⁺ exact mass: 324.2.

3-Benzyl-N-(4-fluoro-3-methyl-phenyl)-3-azabicyclo[3.1.0]hexane-5-carboxamide (400 mg) was dissolved in methanol (50 mL) and Pd/C 10% (262 mg) was added. The solution was stirred under an _H atmosphere at room temperature for 1 hour. After filtering on celite, the mixture was concentrated in vacuo to give N-(4-fluoro-3-methyl-phenyl)-3-azabicyclo[3.1.0]hexane-5-carboxamide (282 mg). Method C; Rt: 0.60 min. m/z: 235.2 (M+H) ⁺ exact mass: 234.1. To a solution of N-(4-fluoro-3-methyl-phenyl)-3-azabicyclo[3.1.0]hexane-5-carboxamide (142 mg, 0.606 mmol) in CH ₂ Cl ₂ (5 mL) was added DIPEA (0.84 mL, 4.85 mmol) and 2-methylpropane-1-sulfonyl chloride (142.4 mg, 0.91 mmol). The reaction mixture was stirred at room temperature for 30 minutes and then diluted with CH ₂ Cl ₂ (10 mL), washed with aqueous HCl (1 N, 10 mL), brine, and dried (Na ₂ SO ₄ ). After removing the volatiles in vacuo, the obtained residue was purified using silica gel column chromatography (ethyl acetate in heptane from 20% to 30%) to give a viscous residue. The residue was triturated in diisopropyl ether and the obtained white solid was filtered, washed with petroleum ether, and dried in vacuo to give compound 27 (124 mg) as a white powder. Method C; Rt: 1.02 min. m/z: 372.2 (M+NH ₄ ) ⁺ exact mass: 354.1. ¹ H NMR (400 MHz, chloroform-d) δ ppm 1.11 (d, J=6.8 Hz, 6H), 1.17 (t, J=5.2 Hz, 1H), 1.52 (dd, J=8.4, 5.3 Hz, 1H), 2.17 (ddd, J=8.4, 5.0, 3.9 Hz, 1H), 2.21-2.33 (m, 4H), 2.87 (d, J=6.6 Hz, 2H), 3.48 (dd, J=9.7, 3.7Hz, 1H), 3.62 (d, J=9.5Hz, 1H), 3.74 (d, J=9.0Hz, 1H), 3.82 (d, J=8.8Hz, 1H), 6.9 5 (t, J=8.9Hz, 1H), 7.03 (br.s, 1H), 7.17-7.24 (m, 1H), 7.34 (dd, J=6.6, 2.6Hz, 1H).

Compound 28: N-(4-Fluoro-3-methyl-phenyl)-1-isobutylsulfonyl-indoline-3-carboxamide.

Indoline-3-carboxylic acid (1g, 6.13mmol) is dissolved in DMF (10mL) and water (5mL) is added. After adding DIPEA (2.4mL, 14.1mmol), the reaction mixture is stirred for 10 minutes. Then, 2-methylpropane-1-sulfonyl chloride (0.96g, 6.128mmol) is added dropwise and the reaction mixture is stirred at room temperature overnight. The reaction mixture is segmented between CH ₂ Cl ₂ and water and is set to pH=10 with 1M NaOH. The organic layer is removed and the aqueous layer is acidified to pH=1 with concentrated HCl. The product is extracted with CH ₂ Cl _2. The organic layer is dried with MgSO ₄ , filtered and concentrated to dryness in a vacuum to obtain 1-isobutylsulfonylindoline-3-carboxylic acid (600mg) as an oil, which is used in the next step as such. 1-Isobutylsulfonylindoline-3-carboxylic acid (600 mg), 4-fluoro-3-methylaniline (265 mg, 2.12 mmol) and DIPEA (1.1 mL, 6.35 mmol) were dissolved in CH ₂ Cl ₂ (20 mL). HATU (966.2 mg, 2.54 mmol) was added and the resulting mixture was stirred at room temperature overnight. The reaction mixture was washed with 1 M HCl (15 mL) and the organic layer was evaporated to dryness. The obtained residue was purified by silica gel column chromatography using a heptane to EtOAc gradient to produce compound 28 (36.2 mg) as an off-white powder. Method E; Rt: 2.03 min. m/z: 391.0 (M+H) ⁺ exact mass: 390.1. ^1H NMR(400MHz, DMSO-d ₆ )ppm 1.04 (d, J=6.8Hz, 3H), 1.03 (d, J=6.6Hz, 3H), 2.11-2.19 (m, 1H), 2.21 (d, J=1.3Hz, 3H), 3.00-3.17 (m, 2H), 4.14-4.22 (m, 1H), 4.23- 4.31 (m, 1H), 4.31-4.38 (m, 1H), 7.01-7.13 (m, 2H), 7.23-7.34 (m, 2H), 7.38-7.48 (m, 2H), 7.52 (dd, J=7.0, 2.4Hz, 1H), 10.42 (s, 1H)

Compound 29: N-(4-Fluoro-3-methyl-phenyl)-1-isobutylsulfonyl-3-methyl-pyrrolidine-3-carboxamide.

Synthesized similarly as described for compound 28 using 3-methyl-pyrrolidine-3-carboxylic acid instead of indoline-3-carboxylic acid. Method C; Rt: 1.04 min. m/z: 374.3 (M+NH ₄ ) ⁺ exact mass: 356.2. ¹ H NMR (400 MHz, DMSO-d ₆ ) ppm 0.97-1.03(m, 6H), 1.39(s, 3H), 1.81-1.92(m, 1H), 2.03-2.15(m, 1H), 2.21 (d, J=1.8Hz, 3H), 2.38-2.47 (m, 1H), 2.93 (d, J=6.6Hz, 2H), 3.20 (d, J=9.9H z, 1H), 3.23-3.30 (m, 1H), 3.33-3.41 (m, 1H), 3.75 (d, J=9.9Hz, 1H), 7.07 (t , J=9.1Hz, 1H), 7.38-7.47 (m, 1H), 7.52 (dd, J=7.0, 2.4Hz, 1H), 9.56 (s, 1H). The racemic mixture 29 was separated into enantiomers 29a and 29b by preparative SFC (stationary phase: Chiralpak DiacelAS 20 x 250 mm; mobile phase: _CO2 , MeOH with 0.4% _iPrNH2 ). AS-H 250 mm x 4.6 mm, flow rate: 5 mL/min, mobile phase: 20% MeOH (containing 0.2% _iPrNH2 ) for 7 min. Rt: 29a: 1.36 min, 29b: 1.72 min.

Compound 30: N-(4-Fluoro-3-methyl-phenyl)-7-isobutylsulfonyl-7-azabicyclo[2.2.1]heptane-3- Formamide (racemic mixture, pure diastereomers).

4-Fluoro-3-methylaniline (0.622 g, 4.97 mmol) was dissolved in _CH₂Cl₂ ( ₆₀ mL). (+/-)-7-tert-butoxycarbonyl-7-azabicyclo[2.2.1]heptane-3-carboxylic acid (1 g, 4.14 mmol) was then added, followed by DIPEA (2.14 mL, 12.4 mmol), and the mixture was stirred for 10 minutes. HATU (2.36 g, 6.12 mmol) was then added portionwise. The resulting mixture was stirred for 1.5 hours. NaOH (1 M in _H₂O , 16.6 mL) was then added. The resulting mixture was extracted _{with CH₂Cl₂} (3 x 25 mL), and the combined organic layers were dried ( _MgSO₄ ), filtered, and concentrated in vacuo. The crude product was purified using silica gel column chromatography (gradient elution: EtOAc-heptane 0:100 to 30:70) to give tert-butyl 3-[(4-fluoro-3-methyl-phenyl)-carbamoyl]-7-azabicyclo[2.2.1]heptane-7-carboxylate (77 mg). tert-Butyl 3-[(4-fluoro-3-methyl-phenyl)carbamoyl]-7-azabicyclo[2.2.1]heptane-7-carboxylate (77 mg) was dissolved in 1,4-dioxane (2 mL) and HCl (4 M in dioxane, 0.88 mL) was added in three portions over 1 hour. 30 minutes after the last addition, the mixture was concentrated at 50° C. under a gentle nitrogen stream. The crude product was used as is. Method C; Rt: 0.58 min. m/z: 249.2 (M+H) ⁺ exact mass: 248.1. The crude product obtained above was stirred in CH ₂ Cl ₂ (2 mL) and DIPEA (0.30 mL, 1.8 mmol) was added, followed by 2-methylpropane-1-sulfonyl chloride (43 μL, 0.331 mL). The reaction mixture was stirred overnight. The reaction mixture was poured into dichloromethane (5 mL) and treated with HCl (1 M in H ₂ O, 2.2 mL). The layers were separated and the organics were dried over MgSO ₄ , filtered and concentrated in vacuo. The crude product was chromatographed using silica gel column chromatography (gradient elution: EtOAc-heptane 0:100 to 20:80). The combined fractions were concentrated and the residue was dried in vacuo to give compound 30 (32.1 mg). Method C; Rt: 1.04 min. m/z: 386.3 (M+NH 4 )+ exact mass: 368.2. ¹ H NMR (400 MHz, chloroform-d) δ ppm 1.10 (d, J = 6.5 Hz, 6H), 1.56-1.64 (m, 2H), 1.92 (dd, J = 12.3, 9.5 Hz, 1H), 2.01-2.14 (m, 2H), 2.14-2.20 (m, 1H), 2.25 (d, J = 2.0 Hz, 3H), 2.33 (spt, J = 6.7 Hz, 1H), 2.60 (dd, J=9.1, 5.0Hz, 1H), 2.92-3.05 (m, 2H), 4.31 (t, J=4.4Hz, 1H), 4.47 (d, J=4.4Hz, 1H ), 6.93 (t, J=8.9Hz, 1H), 7.21-7.30 (m, 1H), 7.35 (dd, J=6.9, 2.4Hz, 1H), 7.76 (br.s., 1H).

Compound 31: (3S)-N-(4-Fluoro-3-methyl-phenyl)-1-(isobutylsulfamoyl)pyrrolidine-3-carboxamide

_In a sealed microwave tube, (3S)-N-(4-fluoro-3-methyl-phenyl)pyrrolidine-3-carboxamide hydrochloride (50 mg, 0.193 mmol) and _NH2SO2NH2 (93 mg, 0.966 mmol) were suspended in _dioxane (3 mL). The tube was heated at 100°C overnight. The reaction mixture was used as such in the next reaction. Isobutylamine (1 mL) was added to the above reaction mixture. The tube was heated at 100°C overnight. The reaction mixture was evaporated to dryness and purified on silica using a heptane to EtOAc gradient followed by preparative HPLC (RP Vydac Denali _C18-10 μm, 250 g, 5 cm). Mobile phase (0.25% _NH4HCO3 solution in water, MeOH), the desired fractions were collected, evaporated, dissolved in MeOH and evaporated again to give compound 31 (3.5 mg). Method C; Rt: 0.98 min. m/z: 375.2 (M+NH ₄ ) ⁺ exact mass: 357.2. ¹ HNMR (400MHz, DMSO-d ₆ ) δppm 0.86 (d, J=6.8Hz, 6H), 1.62-1.74 (m, 1H), 1.99-2.18 (m, 2H), 2.20 (d, J=1.8Hz, 3H), 2.73 (d, J=6.8Hz, 2H), 3.09-3.30 (m, 4H), 3.47 (dd, J=9.5, 8.1Hz, 1H), 7.06 (t, J=9.1Hz, 1H), 7.17 (br.s., 1H), 7.35-7.44 (m, 1H), 7.51 (dd, J=7.2, 2.3Hz, 1H), 10.02 (br.s., 1H).

Compound 32: (3S)-N-(4-Fluoro-3-methyl-phenyl)-1-(isopropylsulfamoyl)pyrrolidine-3-carboxamide.

Catechol (10 g, 90.8 mmol) and pyridine (14.6 mL, 181.6 mmol) dissolved in heptane (60 mL) were stirred at -5°C. Sulfuryl chloride (12.26 g, 90.8 mmol) dissolved in heptane (20 mL) was added dropwise while maintaining the temperature at -5°C. After completion of the addition, the reaction mixture was stirred at -5°C for 2 hours. The reaction mixture was allowed to reach room temperature and used in the next step. Isopropylamine (7.7 mL, 90.8 mmol) and then NEt ₃ (12.6 mL, 90.8 mmol) were added to the reaction mixture obtained above at room temperature. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into a CH ₂ Cl ₂ /water mixture. The organic layer was separated and evaporated to dryness. The obtained residue was purified by silica gel column chromatography using a gradient elution from heptane to EtOAc. The product fractions were collected and evaporated to dryness to yield (2-hydroxyphenyl) N-isopropylsulfamate (3.28 g). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.14 (d, J=6.6 Hz, 6H), 3.56-3.68 (m, 1H), 6.77-6.83 (m, 1H), 6.95 (dd, J=8.0, 1.7 Hz, 1H), 7.05-7.12 (m, 1H), 7.25 (dd, J=8.1, 1.8 Hz, 1H), 8.05 (d, J=7.0 Hz, 1H), 9.75 (s, 1H). (3S)-N-(4-Fluoro-3-methyl-phenyl)pyrrolidine-3-carboxamide hydrochloride, (2-hydroxyphenyl) N-isopropylsulfamate (300 mg, 1.30 mmol) and NEt ₃ (0.134 mL, 0.966 mmol) were dissolved in CH ₃ CN (3 mL) and heated in a microwave at 100° C. for 10 minutes. The tube was heated again at 100° C. for 15 minutes. More NEt ₃ (0.1 mL) was added and the tube was heated again for 30 minutes. The volatiles were removed under reduced pressure and the residue was purified by silica gel column chromatography using a heptane to EtOAc gradient followed by HPLC (RP Vydac Denali C18-10 μm, 250 g, 5 cm). Mobile phase (0.25% NH ₄ HCO ₃ solution in water, MeOH), the desired fractions were collected, evaporated, dissolved in MeOH and evaporated again, and the obtained residue was crystallized from CH ₃ CN/diisopropyl ether to give compound 32 (95.8 mg). Method C; Rt: 0.91 min. m/z: 344.2 (M+H) ⁺ exact mass: 343.1. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.09-1.13 (m, 6H), 1.98-2.18 (m, 2H), 2.20 (d, J=1.8 Hz, 3H), 3.09-3.29 (m, 4H), 3.34-3.50 (m, 2H), 7.02-7.11 (m, 2H), 7.34-7.42 (m, 1H), 7.50 (dd, J=7.0, 2.4 Hz, 1H), 10.00 (s, 1H); Differential scanning calorimetry (30° C. to 300° C. at 10° C./min), peak: 101.1° C. (c 0.54 w/v%, DMF)

Compound 33: (3S)-N-(4-Fluoro-3-methyl-phenyl)-1-[[(3S)-tetrahydrofuran-3-yl]sulfamoyl]pyrrolidone Pyrrolidine-3-carboxamide.

(S)-(-)-3-Aminotetrahydrofuran p-toluenesulfonate (301.3 mg, 1.16 mmol) was added to a stirred mixture of 1,3,2-benzodioxathiophene 2,2-dioxide (200 mg, 1.16 mmol) and _NEt₃ (484 μL, 3.49 mmol) in 1,4-dioxane (10 mL). (3S)-N-(4-Fluoro-3-methyl-phenyl)pyrrolidine-3-carboxamide hydrochloride (258 mg) was added to the reaction mixture. The mixture was heated at 100°C for 10 minutes, cooled to room temperature, heated at 100°C for 30 minutes longer, and cooled to room temperature. The reaction mixture was stored at room temperature over the weekend. The mixture was filtered, the filtrate was concentrated, and the resulting residue was diluted with _CH₂Cl₂ (10 _mL ). The organic layer was washed with aqueous hydrochloric acid (1N, 2 x 10 _mL ), dried ( _Na₂SO₄ ), and evaporated to dryness. The residue was purified using silica gel column chromatography with a gradient of ethyl acetate in heptane to give compound 33 (51 mg). Method C; Rt: 0.80 min. m/z: 372.2 (M+H) ⁺ exact mass: 371.1. ¹ H NMR (400MHz, DMSO-d ₆ ) δppm 1.75-1.88 (m, 1H), 1.98-2.18 (m, 3H), 2.20 (d, J=1.8Hz, 3H), 3.10-3.35 (m, 4H), 3.41-3.54 (m, 2H), 3.65 (td, J=8.0, 5.9Hz, 1H), 3.70-3 .81 (m, 2H), 3.82-3.92 (m, 1H), 7.06 (t, J=9.1Hz, 1H), 7.35-7.43 (m, 1H), 7.46 (br.s, 1H), 7.51 (dd, J=7.0, 2.2Hz, 1H), 10.02 (br.s, 1H). (c 0.63 w/v%, DMF).

Compound 34: (3S)-N-(4-Fluoro-3-methyl-phenyl)-1-[(3-methyloxetan-3-yl)sulfamoyl] Pyrrolidine-3-carboxamide.

2,3-Dimethyl-1-[(2-methyl-1H-imidazol-1-yl)sulfonyl]-1H-imidazol-3-ium trifluoromethanesulfonate (1.51 g, 3.87 mmol), (3S)-N-(4-fluoro-3-methyl-phenyl)pyrrolidine-3-carboxamide hydrochloride (500 mg, 1.93 mmol) and DIPEA (1.67 mL, 9.66 mmol) were dissolved in _CH3CN (5 mL) and stirred at room temperature for 30 minutes. The volatiles were removed under reduced pressure and the obtained residue was purified by silica gel column chromatography with a gradient from heptane to EtOAc to give (3S)-N-(4-fluoro-3-methyl-phenyl)-1-(2-methylimidazol-1-yl)sulfonyl-pyrrolidine-3-carboxamide (387 mg).

(3S)-N-(4-Fluoro-3-methyl-phenyl)-1-(2-methylimidazol-1-yl)sulfonyl-pyrrolidine-3-carboxamide (387 mg, 1.056 mmol) was dissolved in CH ₂ Cl ₂ (10 mL) and the mixture was cooled with an ice bath. Methyl trifluoromethanesulfonate (190.7 mg, 1.16 mmol) was added and the reaction mixture was stirred at 0° C. for 2 hours. The volatiles were removed under reduced pressure, and the obtained residue was dissolved in CH ₃ CN (10 mL) along with 3-methyl-3-oxetaneamine hydrochloride (1:1) (163.1 mg, 1.32 mmol) and DIPEA (0.364 mL, 2.11 mmol). The mixture was stirred at 80° C. for 1 hour. The volatiles were removed under reduced pressure and the obtained residue was purified by silica gel column chromatography with a gradient from heptane to EtOAc to give compound 34 (244 mg). ¹ H NMR (400MHz, DMSO-d ₆ ) δppm 1.60 (s, 3H), 2.00-2.19 (m, 2H), 2.20 (d, J=1.8Hz, 3H), 3.11-3.30 (m, 4H), 3.49 (dd, J=9.6, 8.3Hz, 1H), 4.21 (d, J=6.3Hz, 2H ), 4.65 (d, J=6.3Hz, 2H), 7.06 (t, J=9.2Hz, 1H), 7.34-7.43 (m, 1H), 7.51 (dd, J=7.0, 2.4Hz, 1H), 7.62 (s, 1H), 10.02 (s, 1H). Method C; Rt: 0.81min. m/z: 389.2 (M+NH ₄ ) ⁺ exact mass: 371.1.

Compound 35: 3-Fluoro-N-(4-fluoro-3-methyl-phenyl)-1-(isopropylsulfamoyl)pyrrolidine-3-carboxamide.

To a solution of 1-benzyl-3-fluoro-pyrrolidine-3-carboxylic acid (3.06 g, 13.7 mmol) (synthesis described in Tetrahedron Letters (2011), 52(12), 1300-1302) in DMF (30 mL) was added triethylamine hydrochloride (9.43 g, 68.5 mmol), triethylamine (5.71 mL, 41.1 mmol), HATU (4.83 g, 20.6 mmol) and 4-fluoro-3-methyl-aniline (1.71 g, 13.7 mmol). The reaction mixture was stirred at room temperature for 1 hour and diluted with water (200 ml). The solid was filtered and washed with water to provide 1-benzyl-3-fluoro-N-(4-fluoro-3-methyl-phenyl)pyrrolidine-3-carboxamide (2.65 g) as a light purple powder. A second batch (120 mg) was separated from the filtrate. The two powders were combined and used in the next step.

1-Benzyl-3-fluoro-N-(4-fluoro-3-methyl-phenyl)pyrrolidine-3-carboxamide (2.77 g, 8.37 mmol) was dissolved in MeOH (150 mL) and 10% palladium on carbon (0.89 g) was added. This mixture was hydrogenated at room temperature under 1 atm of H ₂ pressure for 30 minutes. The solid was filtered off and the filtrate was evaporated under reduced pressure to provide 3-fluoro-N-(4-fluoro-3-methyl-phenyl)pyrrolidine-3-carboxamide (1.21 g) as an off-white solid. Method E; Rt: 1.23 min. m/z: 241.4 (M+H) ⁺ exact mass: 240.1.

3-Fluoro-N-(4-fluoro-3-methyl-phenyl)pyrrolidine-3-formamide (250mg, 0.98mmol), (2-hydroxyphenyl) N-isopropylaminosulfonate (294mg, 1.27mmol) and triethylamine (0.27mL, 1.96mmol) are dissolved in ACN (3mL) and heated at 100 ℃ for 10 minutes in microwave. Volatiles are removed under reduced pressure. Residue is dissolved in DCM (20mL) and washed with aqueous HCl (1N) (2x 5mL) and salt solution (5mL). The organic layer is concentrated to dryness, and residue is purified by silica gel chromatography by the gradient elution of ethyl acetate in heptane, produces a viscous oil. This oil is dissolved in methanol (2mL). In this solution, water (8mL) is added. This suspension is heated under reflux and this emulsion becomes suspension and spends the night. The solid was filtered and washed with methanol in water (20%, 2 x 2 mL) to provide compound 35 as a white solid, which was dried in a vacuum oven at 50 °C over the weekend (210 mg). ¹ H NMR (400MHz, DMSO-d ₆ )δppm1.13 (dd, J=6.5, 0.8Hz, 6H), 2.21 (d, J=1.8Hz, 3H), 2.27-2.41 (m, 1H), 2.41-2.61 (m, 1H), 3.34-3.52 (m, 3H), 3.53-3.73 (m, 2H) , 7.10 (t, J=9.2Hz, 1H), 7.26 (br.d, J=7.3Hz, 1H), 7.50 (ddd, J=8.7, 4.7, 2.9Hz, 1H), 7.63 (dd, J=7.0, 2.2Hz, 1H), 10.21 (br.s., 1H). Method C; Rt: 0.96min. m/z: 379.2 (M+NH ₄ ) ⁺ exact mass: 361.1.

The racemic mixture 35 was separated into its enantiomers by preparative SFC (stationary phase: Chiralcel Diacel OD 20 x 250 mm; mobile phase: _CO2 , iPrOH with 0.4% _iPrNH2 ). OD-H 250 mm x 4.6 mm, flow rate: 5 mL/min, mobile phase: 35% MeOH (containing 0.2% _iPrNH2 ) for 4 min. Rt: 35a: 2.39 min, 35b: 2.87 min.

Compound 36: N-(4-fluoro-3-methyl-phenyl)-2-(isopropylsulfamoyl)-2-azabicyclo[3.1.0]hexane Alkane-4-carboxamide.

To a solution of 2-tert-butoxycarbonyl-2-azabicyclo[3.1.0]hexane-4-carboxylic acid (1000 mg, 4.4 mmol) in DMF (10 mL) was added triethylamine (1.83 mL, 13.2 mmol), HATU (2.51 g, 6.60 mmol), followed by 4-fluoro-3-methyl-aniline (716 mg, 5.72 mmol). The reaction mixture was stirred at room temperature for 1 hour and diluted with water (100 mL). The solid was filtered and washed with water to provide tert-butyl 4-[(4-fluoro-3-methyl-phenyl)carbamoyl]-2-azabicyclo[3.1.0]hexane-2-carboxylate as a brown, sticky solid. This was redissolved in DCM, dried over _MgSO₄ , filtered, and used as such in the next step. Method C; Rt: 1.02 min and 1.05 min. m/z: 335.2 (M+H) ⁺ exact mass: 334.2.

To a solution of tert-butyl 4-[(4-fluoro-3-methyl-phenyl)carbamoyl]-2-azabicyclo[3.1.0]hexane-2-carboxylate (1.47 g, 4.4 mmol) in DCM (200 mL) was added TFA (6.73 mL, 88 mmol). The reaction mixture was stirred at room temperature for 5 hours. The reaction mixture was evaporated to dryness to give N-(4-fluoro-3-methyl-phenyl)-2-azabicyclo[3.1.0]hexane-4-carboxamide as a brown oil. Method C; Rt: 0.58 min and 0.60 min. m/z: 235.2 (M+H) ⁺ exact mass: 234.1.

N-(4-Fluoro-3-methyl-phenyl)-2-azabicyclo[3.1.0]hexane-4-carboxamide (300 mg, 0.86 mmol), (2-hydroxyphenyl) N-isopropylsulfamate (259 mg, 1.12 mmol) and triethylamine (0.36 mL, 2.58 mmol) were dissolved in ACN (5 mL) and heated in a microwave at 100 ° C for 10 minutes. The volatiles were removed under reduced pressure and the residue was dissolved in DCM (20 mL), washed with aqueous HCl (1 M) (2 x 5 mL) and brine (5 mL). The organic layer was concentrated to dryness and the residue was purified using silica gel chromatography using a gradient of ethyl acetate in heptane (from 20% to 100%) to give compound 36a (trans-isomer) (36 mg) as a white powder. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ ppm 0.62 (dt, J=8.7, 5.9Hz, 1H), 0.94 (ddd, J=6.0, 4.7, 2.6Hz, 1H), 1.12 (dd, J=6.6, 1.6Hz, 6H), 1.7 8 (ddd, J=8.8, 6.0, 64.8Hz, 1H), 2.20 (d, J=1.8Hz, 3H), 2.95 (dd, J=10.5, 7.8Hz, 1H), 3.12 (td, J= 5.9, 2.7 Hz, 1H), 3.22 (dd, J = 7.8, 1.1 Hz, 1H), 3.43 (q, J = 6.5 Hz, 1H), 3.47 (d, J = 10.4 Hz, 1H), 7.07 (t, J = 9.2 Hz, 1H), 7.15 (br. s., 1H), 7.38-7.41 (m, 1H), 7.51 (dd, J = 7.0, 2.2 Hz, 1H), 9.99 (s, 1H). Method C; Rt: 0.90 min. m/z: 356.1 (M+H) ⁺ exact mass: 355.1. and impure compound 36b as a colorless oil. This was further purified using preparative LCMS. (Hypersyl C18BDS-3 μm, 100 x 4.6 mm) mobile phase (NH ₄ HCO ₃ 0.2% in water, acetonitrile). The desired fractions were combined and evaporated to dryness, redissolved in methanol and evaporated to dryness, and dried in a vacuum oven overnight to produce compound 36b (CIS-isomer) (40 mg). ¹ H NMR (600 MHz, DMSO-d ₆ ) δ ppm 0.50 (dt, J = 8.4, 6.1 Hz, 1H), 1.11 (ddd, J = 6.3, 4.4, 2.9 Hz, 1H), 1.14 (dd, J = 6.6, 2.9 Hz, 6H), 1.85-1.96 (m, 1H), 6 3.21 (d, J = 1.8 Hz, 3H), 3.06-3.13 (m, 1H), 3.16 (td, J = 6.1, 2.7 Hz, 1H), 3.28-3.31 (m, 1H), 3.33-3.35 (m, 1H), 3.39 (s, 1H), 3.41-3.50 (m, 1H), 7.07 (t, J = 9.2 Hz, 1H), 7.21 (br. s., 1H), 7.39 (ddd, J = 8.5, 4.6, 2.8 Hz, 1H), 7.53 (dd, J = 7.1, 2.3 Hz, 1H), 10.07 (s, 1H). Method C; Rt: 0.92 min. m/z: 356.1 (M+H) ⁺ exact mass: 355.1

Compound 37: (3S)-N-(4-Fluoro-3-methyl-phenyl)-1-[[(1R,2R)-2-hydroxyindan-]-yl]sulfamoyl 1-[4 ...(4-amino-2-yl)pyrrolidine-3-

Compound 37 was prepared similarly to compound 34, using (1R,2R)-1-amino-2,3-dihydro-1H-inden-2-ol instead of 3-methyl-3-oxetanamine hydrochloride (1:1). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.05-2.18 (m, 2H), 2.20 (s, 3H), 2.67 (dd, J=15.5, 6.9 Hz, 1H), 3.06-3.25 (m, 2H), 3.33-3.43 (m, 3H), 3.61 (t, J=8.8 Hz, 1H), 4.22 (quin, J=6.4 Hz, 1H), 4.49 (t, J= δ: 7.0 Hz, 1H), 5.30 (d, J = 5.7 Hz, 1H), 7.07 (t, J = 9.2 Hz, 1H), 7.14-7.29 (m, 3H), 7.32-7.45 (m, 2H), 7.52 (dd, J = 6.9, 2.3 Hz, 1H), 7.63 (d, J = 8.1 Hz, 1H), 10.01 (s, 1H). Method C; Rt: 0.91 min. m/z: 434.2 (M+H) ⁺ exact mass: 433.1.

Compound 38: N-[2-[[(3S)-3-[(4-fluoro-3-methyl-phenyl)carbamoyl]pyrrolidin-1-yl]sulfonylamino tert-butyl]propyl]carbamate.

Compound 38 was prepared similarly to compound 34 using N-(2-aminopropyl)-, 1,1-dimethylethyl carbamate instead of 3-methyl-3-oxetaneamine hydrochloride (1:1). ¹ H NMR (400MHz, DMSO-d ₆ ) δppm 1.05 (d, J=6.6Hz, 3H), 1.37 (s, 9H), 1.97-2.17 (m, 2H), 2.17-2.23 (m, 3H), 2.88 (dt, J=13.4, 6.5Hz, 1H), 2.96-3.08 (m, 1H), 3.09- 3.29 (m, 5H), 3.42-3.51 (m, 1H), 6.79 (br.s., 1H), 7.00-7.11 (m, 2H), 7.34-7.42 (m, 1H), 7.50 (dd, J=6.9, 2.1Hz, 1H), 9.99 (s, 1H). Method C; Rt: 0.99min. m/z: 459.2 (M+H) ⁺ exact mass: 458.2.

Compound 39: (3S)-N-(4-Fluoro-3-methyl-phenyl)-1-[[(1R)-2-hydroxy-1-methyl-ethyl]sulfamoyl 1-[4 ...(4-amino-2-yl)pyrrolidine-3-

Compound 39 was prepared similarly to compound 34 using D-alaninol instead of 3-methyl-3-oxetanamine hydrochloride (1:1). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.10 (d, J=6.4 Hz, 3H), 1.98-2.18 (m, 2H), 2.20 (d, J=1.8 Hz, 3H), 3.09-3.31 (m, 6H), 3.39-3.53 (m, 2H), 4.70 (t, J=5.6 Hz, 1H), 6.98 (d, J=5.7 Hz, 1H), 7.06 (t, J=9.2 Hz, 1H), 7.34-7.44 (m, 1H), 7.51 (dd, J=7.0, 2.4 Hz, 1H), 10.00 (s, 1H). Method C; Rt: 0.75 min. m/z: 360.2 (M+H) ⁺ exact mass: 359.1.

Compound 40: (3S)-1-[(2-cyano-1-methyl-ethyl)sulfamoyl]-N-(4-fluoro-3-methyl-phenyl)pyrrolidone Pyrrolidine-3-carboxamide.

Compound 40 was prepared similarly to compound 34, using 3-aminobutyronitrile instead of 3-methyl-3-oxetanamine hydrochloride (1:1). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.23 (dd, J=6.7, 2.1 Hz, 3H), 2.00-2.12 (m, 1H), 2.12-2.19 (m, 1H), 2.20 (d, J=1.5 Hz, 3H), 2.60-2.79 (m, 2H), 3.11-3.22 (m, 1H), 3.22-3.28 (m, 1H), 3.28-3.31 (m, 1H). 3.38 (m, 2H), 3.45-3.54 (m, 1H), 3.54-3.66 (m, 1H), 7.06 (t, J=9.1 Hz, 1H), 7.36-7.43 (m, 1H), 7.51 (dd, J=7.0, 2.2 Hz, 1H), 7.62 (br. s, 1H), 10.02 (s, 1H). Method C; Rt: 0.83 min. m/z: 386.3 (M+NH ₄ ) ⁺ exact mass: 368.1.

Compound 41: trans-N-(4-fluoro-3-methyl-phenyl)-1-(isopropylsulfamoyl)-4-methyl-pyrrolidine- 3-Formamide.

Methyl crotonate (3.7g, 15.6mmol) is dissolved in DCM (50ml) and merged with TFA (200 μ l, 0.79mmol).Then, in 20 minutes, dropwise add a solution of N-methoxymethyl-N-trimethylsilylmethyl-benzylamine (1.56g, 15.6mmol) in DCM (10ml).This reaction mixture is stirred for 16 and then concentrated in a vacuum.Resistates is pressed and used in the next step like this.

The crude product mentioned above is dissolved among the THF (40mL) and merges with the solution of lithium hydroxide (3.74g, 156mmol) in water (10mL).This mixture was at room temperature stirred 24 hours.The reaction mixture is evaporated to drying, and water is removed with toluene (2x 50mL).Resistates is pressed for the next step like this.

The above-mentioned crude product is dissolved in DMF (30mL). Triethylamine hydrochloride (25.77g, 187mmol), triethylamine (6.51mL, 46.8mmol) and HATU are added, followed by 4-fluoro-3-methyl-aniline (2.54g, 20.3mmol). The reaction mixture is stirred at room temperature for 1 hour. The reaction mixture is filtered under a nitrogen atmosphere and diluted with water (200mL). The solid is filtered and washed with water to provide a brown sticky solid. The organic matter in the filtrate is extracted with diethyl ether. The combined organic layer is merged with the brown sticky solid, washed with brine and evaporated to dryness. The residue is purified using silica gel column chromatography (ethyl acetate in heptane from 0 to 100%) to provide (3S, 4S)-1-benzyl-N-(4-fluoro-3-methyl-phenyl)-4-methyl-pyrrolidine-3-carboxamide (1400mg) as a brown oil. Method C; Rt: 1.06min. m/z: 327.2 (M+H) ⁺ exact mass: 326.1 This was used as such in the next step.

(3S, 4S) -1- benzyl -N- (4- fluoro -3- methyl - phenyl) -4- methyl - pyrrolidine -3- formamide (1.40g, 2.83mmol) is dissolved in MeOH (50mL) and 10% palladium on carbon (3.01g) is added. This mixture is hydrogenated under pressure for 90 minutes at room temperature under 1atm of _H . Solid is filtered out and the filtrate is evaporated under reduced pressure to provide (3S, 4S) -N- (4- fluoro -3- methyl - phenyl) -4- methyl - pyrrolidine -3- formamide (547mg) as a colorless oil (547mg).

(3S,4S)-N-(4-Fluoro-3-methyl-phenyl)-4-methyl-pyrrolidine-3-carboxamide (274 mg, 1.16 mmol), (2-hydroxyphenyl) N-isopropylsulfamate (349 mg, 1.51 mmol) and triethylamine (0.48 mL, 3.48 mmol) were dissolved in ACN (3 mL) and heated in a microwave at 100° C. for 10 minutes. The volatiles were removed under reduced pressure and the residue was purified using preparative LCMS (Hypersyl C18 BDS-3 μm, 100 x 4.6 mm), mobile phase (NH ₄ HCO ₃ 0.2% in water, methanol). The desired fractions were combined and evaporated to dryness, redissolved in methanol and evaporated to dryness to give a crude product that was repurified using preparative LCMS. (Hypersyl C18BDS-3μm, 100x4.6mm), mobile phase ( _{NH4HCO3 0.2} % in water, acetonitrile). The desired fractions were combined and evaporated to dryness, redissolved in methanol and evaporated to dryness, and dried in a vacuum oven overnight to provide compound 41 (trans-isomer). ^1H NMR (600MHz, DMSO- _d6 ) δppm 1.04 (d, J=6.6Hz, 3H), 1.12 (dd, J=6.5, 2.1Hz, 6H), 2.20 (d, J=1.8Hz, 3H), 2.41-2.48 ( m, 1H), 2.71 (q, J=9.1Hz, 1H), 2.80 (t, J=9.4Hz, 1H), 3.25 (t, J=9.4Hz, 1H), 3.39 (sxt, 3.45 (dd, J = 9.5, 7.5 Hz, 1H), 3.52 (dd, J = 9.7, 8.2 Hz, 1H), 7.07 (t, J = 9.2 Hz, 2H), 7.40 (ddd, J = 8.6, 4.5, 2.8 Hz, 1H), 7.53 (dd, J = 7.0, 2.2 Hz, 1H), 10.05 (s, 1H). Method E; Rt: 1.73 min. m/z: 358.4 (M+H) ⁺ exact mass: 357.1.

Compound 42: 3-Fluoro-N-(4-fluoro-3-methyl-phenyl)-1-[[(3S)-tetrahydrofuran-3-yl]sulfamoyl]pyrrolidone Pyrrolidine-3-carboxamide.

(S)-(-)-3-Aminotetrahydrofuran p-toluenesulfonate (5.0 g, 19.3 mmol) was added to a stirred mixture of 1,3,2-benzodioxathiophene 2,2-dioxide (4.26 g, 19.3 mmol) and triethylamine (5.36 μL, 38.6 mmol) in ACN (50 mL). The reaction mixture was stirred for 18 hours. The reaction mixture was evaporated to dryness at 25° C. to give a residue, which was purified using silica gel column chromatography (ethyl acetate in heptane from 20% to 60%) to give (2-hydroxyphenyl) N-[(3S)-tetrahydrofuran-3-yl]sulfamate (2.4 g) as a light green viscous oil. ¹ H NMR (400MHz, DMSO-d ₆ )δppm1.77-1.93 (m, 1H), 2.02-2.20 (m, 1H), 3.57 (dd, J=9.1, 4.1Hz, 1H), 3.66 (td, J=8.2, 5.6Hz, 1H), 3.70-3.80 (m, 2H), 4.02-4.23 (m, 1H), 6.78-6.84 (m, 1H), 6.96 (dd, J=8.1, 1.5Hz, 1H), 7.07-7.15 (m, 1H), 7.23 (dd, J=7.9, 1.5Hz, 1H), 8.46 (d, J=5.5Hz, 1H), 9.85 (s, 1H).

3-Fluoro-N-(4-fluoro-3-methyl-phenyl)pyrrolidine-3-carboxamide (400mg, 1.57mmol), (2-hydroxyphenyl) N-[(3S)-tetrahydrofuran-3-yl] sulfamate (487mg, 1.88mmol) and triethylamine (0.44mL, 3.13mmol) are dissolved in ACN (5mL) and deheated in microwave at 100 DEG C for 10 minutes. Volatiles are removed under reduced pressure. Residue is dissolved in DCM (20mL) and washed with aqueous HCl (1M) (2x 5mL) and brine (5mL). The organic layer is concentrated to dryness, and residue is purified using silica gel column chromatography (ethyl acetate in heptane from 5% to 100%) to produce compound 42 (361mg) as a viscous oil. ¹ H NMR (400MHz, DMSO-d ₆ ) δppm 1.73-1.90(m, 1H), 2.03-2.16(m, 1H), 2.22(s, 3H), 2.27-2.63(m, 2H), 3.37-3.56(m, 3H), 3.58-3.84(m, 5H), 63.85-3.98 (m, 1H), 7.11 (t, J=9.1Hz, 1H), 7.44-7.54 (m, 1H), 7.56-7.77 (m, 2H), 10.22 (br.s., 1H).

The racemic mixture 42 was separated into its enantiomers by preparative SFC (stationary phase: Chiralcel Diacel OJ 20 x 250 mm; mobile phase: _CO2 , iPrOH with 0.2% _iPrNH2 ). OJ-H 250 mm x 4.6 mm, flow rate: 5 mL/min, mobile phase: 10% MeOH (containing 0.2% _iPrNH2 ) for 4 min. Rt: 42a: 3.66 min, 42b: 4.26 min.

Compound 43: N-(4-Fluoro-3-methyl-phenyl)-3-[[(3S)-tetrahydrofuran-3-yl]sulfamoyl]-3-aza Bicyclo[3.1.0]hexane-1-carboxamide.

3-benzyl-3-azabicyclo [3.1.0] hexane-1-ethyl formate (being described in the synthesis among WO 201233956 A1) (1.03g, 4.2mmol) is dissolved in THF.Water (10mL) and LiOH (0.50g, 21mmol) are added in the reaction mixture, and it is stirred at room temperature for 12 hours.The reaction mixture is heated under reflux for 48 hours.The reaction mixture is evaporated to dryness.With toluene (2x 20mL) azeotropic removal water, to obtain a kind of crude product, it is pressed and used in the next step like this.

The above-mentioned crude product is suspended in DMF (50mL).Add triethylamine hydrochloride (5.78g, 42.0mmol), 4-fluoro-3-methyl-aniline (788mg, 6.3mmol) and HATU.The reaction mixture is stirred at room temperature for 2 hours.Add DMF (100mL) and 4-fluoro-3-methyl-aniline (525mg, 4.2mmol), and the reaction mixture is stirred for 72 hours.The reaction mixture is diluted with DCM (100mL), washed with saturated aqueous sodium bicarbonate (2x 50mL), dried (Na ₂ SO ₄ ), filtered and evaporated.The crude product is purified using silica gel column chromatography (ethyl acetate/heptane from 0 to 100%), to provide 3-benzyl-N-(4-fluoro-3-methyl-phenyl)-3-azabicyclo [3.1.0] hexane-1-methane amide (420mg) as a colorless viscous oil, which is used in the next step as such. Method C; Rt: 1.17 min. m/z: 325.2 (M+H) ⁺ exact mass: 324.1

3-Benzyl-N-(4-fluoro-3-methyl-phenyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide (400 mg) was dissolved in MeOH (50 mL) and 10% palladium on carbon (262 mg) was added. This mixture was hydrogenated at room temperature under 1 atm of H ₂ pressure for 60 minutes. The solid was filtered off and the filtrate was evaporated under reduced pressure to provide (1S,5S)-N-(4-fluoro-3-methyl-phenyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide (282 mg) as a colorless oil. Method C; Rt: 0.60 min. m/z: 235.2 (M+H) ⁺ exact mass: 234.1.

N-(4-fluoro-3-methyl-phenyl)-3-azabicyclo[3.1.0]hexane-1-carboxamide (141 mg, 0.58 mmol), (2-hydroxyphenyl) N-[(3S)-tetrahydrofuran-3-yl]sulfamate (180 mg, 0.70 mmol) and triethylamine (0.16 mL, 1.16 mmol) were dissolved in ACN (3 mL) and heated in a microwave at 100 ° C for 10 minutes. The volatiles were removed under reduced pressure. The residue was dissolved in DCM (20 mL) and washed with aqueous HCl (1 M) (2 x 5 mL) and brine (5 mL). The organic layer was concentrated to dryness, and the residue was purified using silica gel column chromatography (ethyl acetate in heptane from 30% to 100%) to produce compound 43 (138 mg) as a viscous oil. ¹ H NMR (400 MHz, DMSO-d ₆ )δppm1.03 (t, J=4.6Hz, 1H), 1.41 (dd, J=8.1, 4.8Hz, 1H), 1.76-1.86 (m, 1H), 2.03-2.14 (m, 1H), 2.17 (ddd, J=8.5, 5.0, 3.4Hz, 1H), 2.20 (d, J=1.6Hz, 3H), 3.27-3.38 (m, 2H), 3.50 (dd, J=8.9, 4.4Hz, 1H), 3 3.56 (dd, J = 9.3, 2.8 Hz, 1H), 3.62-3.66 (m, 1H), 3.64-3.69 (m, 1H), 3.73-3.80 (m, 2H), 3.81-3.89 (m, 1H), 7.05 (t, J = 9.3 Hz, 1H), 7.42 (ddd, J = 8.7, 4.6, 2.8 Hz, 1H), 7.50 (dd, J = 7.3, 2.4 Hz, 1H), 9.30 (s, 1H). Method C; Rt: 0.83 min. m/z: 401.3 (M+NH ₄ ) ⁺ exact mass: 383.1.

Compound 44: (3S)-N-(3,4-difluorophenyl)-1-[(3-methyloxetan-3-yl)sulfamoyl]pyrrole Alkane-3-carboxamide.

(3S)-N-(3,4-Difluorophenyl)pyrrolidine-3-carboxamide hydrochloride was prepared analogously to (3S)-N-(4-fluoro-3-methyl-phenyl)pyrrolidine-3-carboxamide hydrochloride using 3,4-difluoroaniline instead of 4-fluoro-3-methylaniline. Compound 44 was prepared analogously to compound 34. ¹ H NMR (400MHz, DMSO-d ₆ ) δppm 1.60 (s, 3H), 2.00-2.22 (m, 2H), 3.11-3.30 (m, 4H), 3.49 (dd, J=9.6, 8.0Hz, 1H), 4.21 (d, J=6.4Hz, 2H), 4.65 (d, J=5.9H z, 2H), 7.25-7.33 (m, 1H), 7.38 (dt, J=10.5, 9.1Hz, 1H), 7.63 (s, 1H), 7.78 (ddd, J=13.3, 7.5, 2.5Hz, 1H), 10.28 (s, 1H). Method C; Rt: 0.78min. m/z: 393.1 (M+NH ₄ ) ⁺ exact mass: 375.1.

Compound 45: (3S)-N-(3,4-difluorophenyl)-1-[[(1R)-1-methylpropyl]sulfamoyl]pyrrolidine-3-yl Formamide.

(3S)-N-(3,4-difluorophenyl)pyrrolidine-3-carboxamide hydrochloride was prepared similarly to (3S)-N-(4-fluoro-3-methyl-phenyl)pyrrolidine-3-carboxamide hydrochloride, using 3,4-difluoroaniline instead of 4-fluoro-3-methylaniline. Compound 45 was prepared similarly to compound 34, using (R)-(-)-2-aminobutane instead of 3-methyl-3-oxetanamine hydrochloride (1:1). ¹ H NMR (400MHz, DMSO-d ₆ ) δppm 0.86 (t, J=7.5Hz, 3H), 1.10 (d, J=6.6Hz, 3H), 1.31-1.51 (m, 2H), 1.98-2.21 (m, 2H), 3.10-3.29 (m, 5H), 3.47 (dd, J=9.6, 8.0Hz, 1H), 7.02 (d, J=8.1Hz, 1H), 7.24-7.32 (m, 1H), 7.38 (dt, J=10.6, 9.1Hz, 1H), 7.78 (ddd, J=13.3, 7.5, 2.5Hz, 1H), 10.26 (s, 1H). Method C; Rt: 0.95min. m/z: 362.2 (M+H) ⁺ exact mass: 361.1.

Compound 46: (3S)-N-(3,4-difluorophenyl)-1-[[(3S)-tetrahydrofuran-3-yl]sulfamoyl]pyrrole Alkane-3-carboxamide.

(3S)-N-(3,4-Difluorophenyl)pyrrolidine-3-carboxamide hydrochloride was prepared similarly to (3S)-N-(4-fluoro-3-methyl-phenyl)pyrrolidine-3-carboxamide hydrochloride, using 3,4-difluoroaniline instead of 4-fluoro-3-methylaniline. Compound 46 was prepared similarly to compound 34, using ((S)-(-)-3-aminotetrahydrofuran-4-toluene-sulfonate instead of 3-methyl-3-oxetanamine hydrochloride (1:1). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.75-1.86(m, 1H), 2.01-2.12(m, 2H), 2.12-2.22(m, 1H), 3.12-3.30(m, 4H), 3. 44-3.54(m, 2H), 3.65(td, J=8.0, 5.9Hz, 1H), 3.71-3.81(m, 2H), 3.81-3.92(m, 1 H), 7.24-7.33 (m, 1H), 7.38 (dt, J = 10.6, 9.0 Hz, 1H), 7.47 (br. s., 1H), 7.78 (ddd, J = 13.3, 7.5, 2.5 Hz, 1H), 10.28 (br. s., 1H). Method C; Rt: 0.80 min. m/z: 376.0 (M+H) ⁺ exact mass: 375.1.

Compound 47: (3S)-N-(4-Fluoro-3-methyl-phenyl)-1-[[3-(2-hydroxyethyl)oxetan-3-yl]amino [sulfonyl]pyrrolidine-3-carboxamide.

Compound 47 was prepared similarly to compound 34 using 2-(3-aminooxetan-3-yl)ethanol instead of 3-methyl-3-oxetanamine hydrochloride (1:1). ¹ H NMR (400MHz, DMSO-d ₆ ) δppm 2.01-2.18 (m, 4H), 2.20 (d, J=1.8Hz, 3H), 3.10-3.30 (m, 4H), 3.51 (dd, J=9.5, 8.1Hz, 1H), 3.56-3.64 (m, 2H), 4.39 (d, J=6.6Hz , 2H), 4.47 (t, J=5.1Hz, 1H), 4.64 (d, J=6.4Hz, 2H), 7.07 (t, J=9.2Hz, 1H), 7.36-7.43 (m, 1H), 7.48-7.55 (m, 2H), 10.02 (s, 1H). Method C; Rt: 0.72min. m/z: 402.1 (M+H) ⁺ exact mass: 401.1.

Compound 48: (3S)-N-(4-Fluoro-3-methyl-phenyl)-1-[(1-methyl-2-oxo-pyrrolidin-3-yl)sulfamate [acyl]pyrrolidine-3-carboxamide.

Compound 48 was prepared similarly to compound 34, using 3-amino-1-methyl-2-pyrrolidinone instead of 3-methyl-3-oxetanamine hydrochloride (1:1). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.71-1.85 (m, 1H), 2.00-2.10 (m, 1H), 2.10-2.18 (m, 1H), 2.20 (d, J=1.8 Hz, 3H), 2.29-2.40 (m, 1H), 2.74 (s, 3H), 3.12-3.30 (m, 5H), 3.33-3.41 (m, 1H), 3.55 (td, J= 8.7, 3.9 Hz, 1H), 3.98 (qd, J = 9.1, 5.8 Hz, 1H), 7.06 (t, J = 9.1 Hz, 1H), 7.35-7.43 (m, 1H), 7.52 (d, J = 7.0 Hz, 1H), 7.56 (dd, J = 13.8, 8.9 Hz, 1H), 9.99 (d, J = 7.5 Hz, 1H). Method C; Rt: 0.75 min. m/z: 399.2 (M+H) ⁺ exact mass: 398.1.

Compound 49: (3S)-N-(4-Fluoro-3-methyl-phenyl)-1-(6-oxa-2-azaspiro[3.3]heptane-2-ylsulfonyl)- acyl)pyrrolidine-3-carboxamide.

Compound 49 was prepared similarly to compound 34 using 2-oxa-6-azaspiro[3.3]heptane instead of 3-methyl-3-oxetanamine hydrochloride (1:1). ¹ H NMR (400MHz, DMSO-d ₆ ) δppm 1.99-2.18 (m, 2H), 2.20 (d, J=1.5Hz, 3H), 3.09-3.21 (m, 2H), 3.22-3.30 (m, 1H), 3.33-3.40 (m, 1H), 3.51 (dd, J=9.7, 7.9 Hz, 1H), 4.00 (s, 4H), 4.65 (s, 4H), 7.07 (t, J=9.2Hz, 1H), 7.35-7.44 (m, 1H), 7.51 (dd, J=7.0, 2.4Hz, 1H), 10.02 (s, 1H). Method C; Rt: 0.81min. m/z: 384.1 (M+H) ⁺ exact mass: 383.1.

Compound 50: (3S)-N-(4-Fluoro-3-methyl-phenyl)-1-[(1-methyl-5-oxo-pyrrolidin-3-yl)sulfamate [acyl]pyrrolidine-3-carboxamide.

Compound 50 was prepared similarly to compound 34 using 4-amino-1-methyl-pyrrolidin-2-one hydrochloride instead of 3-methyl-3-oxetanamine hydrochloride (1:1). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.00-2.11 (m, 1H), 2.11-2.19 (m, 1H), 2.20 (d, J=1.8 Hz, 3H), 2.23 (d, J=5.5 Hz, 1H), 2.56 (dd, J=16.8, 8.5 Hz, 1H), 2.69 (d, J=4.2 Hz, 3H), 3.10-3.20 (m, 1H), 3.20-3.26 (m, 2H), 3.26-3.30 ( m, 2H), 3.43-3.52 (m, 1H), 3.55-3.64 (m, 1H), 3.90-4.02 (m, 1H), 7.07 (t, J = 9.1 Hz, 1H), 7.33-7.44 (m, 1H), 7.51 (dd, J = 7.0, 2.6 Hz, 1H), 7.63 (dd, J = 7.0, 3.1 Hz, 1H), 10.01 (d, J = 2.6 Hz, 1H). Method C; Rt: 0.72 min. m/z: 399.2 (M+H) ⁺ exact mass: 398.1.

Compound 51: N-[(2R)-2-[[(3S)-3-[(4-fluoro-3-methyl-phenyl)carbamoyl]pyrrolidin-1-yl] [Methyl]sulfonylamino]propyl]carbamate.

Tert-butyl N-[(2R)-2-[[(3S)-3-[(4-Fluoro-3-methyl-phenyl)carbamoyl]pyrrolidin-1-yl]sulfonylamino]propyl]carbamate was prepared similarly to the compound using 1,1-dimethylethyl N-[(2R)-2-aminopropyl]-carbamate instead of 3-methyl-3-oxetaneamine hydrochloride (1:1).

Tert-butyl N-[(2R)-2-[[(3S)-3-[(4-fluoro-3-methyl-phenyl)carbamoyl]pyrrolidin-1-yl]sulfonylamino]propyl]carbamate (2.07 g, 4.52 mmol) was dissolved in DCM (25 mL). HCl (6 M in iPrOH) (25 mL) was added and the reaction mixture was stirred at room temperature overnight. The volatiles were removed under reduced pressure and the residue was used as is in the next step.

The crude product mentioned above is dissolved in DCM (20mL) together with DIPEA (3.11mL, 18.1mmol). Dropwise add methyl chloroformate (0.52mL, 6.77mmol) and the reaction mixture is at room temperature stirred overnight. Volatiles are under reduced pressure removed, and resistates is used heptane to EtOAc gradient to purify on silica, produces the product that is a kind of oil, is solidified into a kind of white powder (394mg) when standing. ¹ H NMR (400MHz, DMSO-d ₆ ) δppm 1.07 (d, J=6.6Hz, 3H), 1.99-2.18 (m, 2H), 2.20 (d, J=1.8Hz, 3H), 2.93 (dt, J=13.5, 6.8Hz, 1H), 3.02-3.30 (m, 5H), 3.32 (s, 3H), 3 .34-3.39 (m, 1H), 3.48 (dd, J=9.5, 8.4Hz, 1H), 7.02-7.10 (m, 2H), 7.12 (t, J=5.9Hz, 1H), 7.35-7.42 (m, 1H), 7.51 (dd, J=7.0, 2.4 Hz , 1H), 10.00 (s, 1H). Method C; Rt: 0.81 min. m/z: 417.1 (M+H) ⁺ exact mass: 416.2. (c 0.52 w/v%, DMF).

Biological Example - Anti-HBV Activity of Compounds of Formula (I)

Anti-HBV activity was measured using the stably transfected cell line HepG2.2.15, which has been described as secreting relatively consistently high levels of HBV virion particles and has been shown to cause acute and chronic infection and disease in chimpanzees.

For antiviral activity, cells were treated twice in 96-well plates with a dilution series of compounds in duplicate for three days. After 6 days of treatment, purified HBV DNA from secreted virions was quantified using real-time PCR and HBV-specific primer sets and probes to determine antiviral activity.

Anti-HBV activity was also determined using the HepG2.117 cell line, a stable, HBV-inducible cell line that replicates HBV in the absence of doxycycline (a Tet-off system). For antiviral assays, HBV replication was induced and then treated with a series of diluted compounds in duplicate in 96-well plates. After 3 days of treatment, antiviral activity was determined by quantification of intracellular HBV DNA using real-time PCR and HBV-specific primer sets and probes.

The cytotoxicity of these compounds was tested using HepG2 cells, which were incubated in the presence of the compounds for 4 days. Cell viability was assessed using the resazurin assay. The results are shown in Table 1.

Table 1.

Claims (12)

1. A compound having the chemical formula (I) Or its stereoisomers or tautomers, wherein: represent: X represents -( _SO₂ )- or a single bond, where, When X represents –( _SO₂ )-: ^R4 is selected from the group consisting of: ^-NR5R6 , ^C1 _{- C6} alkyl, a 3-7 membered saturated ring optionally containing one or more heteroatoms independently selected from the group consisting of: O, S, and N, wherein such 3-7 membered saturated ring or _C1 - _C6 alkyl is substituted by one or more substituents independently selected from the group consisting of: hydrogen, fluorine, _C1 - _C4 alkoxy, OH, oxo, _C1 - _C4 alkyl, and cyclopropyl. Furthermore, ^R1 , ^R2 , and ^R3 are independently selected from the group consisting of: hydrogen, halogen, CN, _CHF2 , _CH2F , _CF3 , and _C1 - _C3 alkyl and cyclopropyl groups; When X represents a single bond: R ⁴ is -C(=O)OR ⁷ , Furthermore, ^R1 , ^R2 , and ^R3 are independently selected from the group consisting of: hydrogen, halogen, CN, _CHF2 , _CH2F , _CF3 , and _C1 - _C3 alkyl and cyclopropyl; such that at least one of ^R1 , ^R2 , and ^R3 is fluorine, and the other of ^R1 , ^R2 , and ^R3 is hydrogen, halogen, CN, _CHF2 , _CH2F , _CF3 , and _C1 - _C3 alkyl and cyclopropyl; R ⁵ is selected from the group consisting of hydrogen or methyl; ^R6 is selected from the group consisting of: _C1 - _C6 alkyl or optionally a 3-7 membered saturated ring comprising one or more heteroatoms each independently selected from the group consisting of: O, S, and N, such 3-7 membered saturated ring or _C1 - _C6 alkyl being optionally substituted by one or more substituents each independently selected from the group consisting of: hydrogen, fluorine, CN, OH, oxo, -NHC(=O)O- _C1 - _C4 alkyl, _C1 - _C4 alkyl optionally substituted with ^R8 , _C1 - _C4 alkoxy, or; R ⁷ is selected from the group consisting of: _C1 - _C6 alkyl or optionally containing one or more heteroatoms selected independently from the group consisting of: O, S and N; ^R8 is selected from the group consisting of: hydrogen, OH, _C1 - _C4 alkyl or CN; Or its pharmaceutically acceptable salt. 2. The compound according to claim 1, wherein... represent. 3. The compound according to claim 1, wherein the halogen is chlorine. 4. The compound according to claim 1 or 2, wherein the compound is represented by the following chemical formula (Ib). Or its stereoisomers or tautomers, or pharmaceutically acceptable salts. 5. The compound according to claim 1 or 2, wherein R ¹ is selected from fluorine or methyl, and R ² is fluorine. 6. ^The compound according to claim 1 or 2, wherein X is –( _SO₂ )-, ^R₄ is ^NR₅R₆ and ^R₅ and ^R₆ are as defined above. 7. The compound according to claim 1 or 2, wherein R ⁴ comprises a 3-7 member saturated ring optionally containing an oxygen atom. 8. The compound according to claim 1 or 2, wherein R ⁶ comprises a branched _C3 - _C6 alkyl group optionally substituted with one or more fluorine groups, or wherein the 3-7 membered saturated ring is a _C3 - _C6 cycloalkyl group, wherein such C3 _- C6 _cycloalkyl group is substituted with one or more fluorine groups or is substituted with a _C1 - _C4 alkyl group. 9. The compound according to claim 8, wherein ^R6 is a branched _C3 - _C6 alkyl group substituted with one or more fluorine molecules. 10. Use of the compound according to any one of the preceding claims in the preparation of a medicament for the prevention or treatment of HBV infection in mammals. 11. A pharmaceutical composition comprising a compound according to any one of claims 1 to 9, and a pharmaceutically acceptable carrier. 12. A product comprising (a) a compound having chemical formula (I) as defined in any one of claims 1 to 9, and (b) another HBV inhibitor, as a combination formulation for simultaneous, separate or sequential use in the treatment of HBV infection.