Pregenomic RNA encapsidation inhibitors and their method of use

Abstract

Pharmaceutical compositions comprising a 4-sulfamoyl-heteroaryl-2-carboxamides that are useful as pregenomic RNA encapsidation inhibitors of HBV for the treatment of Hepatitis B virus (HBV) infection and related conditions are disclosed herein.

Description

PREGENOMIC RNA ENCAPSIDATION INHIBITORS AND THEIR METHOD OF USEFEDERALLY SPONSORED RESEARCH AND DEVELOPMENT

[0001] The invention was made with government support under grant number All 13267 awarded by the National Institutes of Health and under grant number W81XWH2110587 awarded by U.S. Army Medical Research and Development Command. The government has certain rights in the invention.CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of priority from U.S. Provisional Patent Application No. 63 / 656,907, filed June 6, 2024, titled Novel Pregenomic RNA Encapsidation Inhibitors and Their Method of Use, which is hereby incorporated herein by reference in its entirety for all purposes.BACKGROUND OF THE INVENTION

[0003] Hepatitis B virus (HBV) is a member of the Hepadnaviridae family and contains a 3.2 kb, partially double-stranded, relaxed circular (rc) DNA genome. Hepatitis B virus (HBV) has infected one-third of world population, and 240 million people are chronic carriers, to whom a curative therapy is still not available.Approximately one-third of these individuals will die from serious liver diseases, such as cirrhosis and hepatocellular carcinoma, if left untreated (Lee. 1997; Lok. 2004).

[0004] Seven drugs are currently available for the management of chronic hepatitis B, which include two formulations of alpha-interferon (standard and pegylated) and five nucleos(t)ide analogues (lamivudine, adefovir, entecavir, telbivudine, and tenofovir) that inhibit HBV DNA polymerase (Keeffe et al., 2008). At present, the preferred first-line treatment choices are entecavir, tenofovir or peg-interferon alfa-2a.However, even with the first-line treatment options, peg-interferon alfa-2a is effective in achieving certain serological milestones in only one-third of treated patients and frequently associated with severe side effects (Janssen et al., 2005; Lau et al., 2005; Perrillo, 2009). Entecavir and tenofovir are highly potent HBV inhibitors, but a longterm or possibly life-time treatment is required to continuously suppress HBV replication, which may eventually fail due to emergence of drug resistant viruses (Dienstag, 2009).Hence, there is a pressing need for the introduction of novel, safeand effective therapies for chronic hepatitis B, which is listed by National Institute of Allergy and Infectious Diseases (NIAID) as a High Priority Area of Interest.

[0005] Hepatitis B virus (HBV) core protein assembles viral pre-genomic (pg) RNA and D A polymerase into nucleocapsids for reverse transcriptional DNA replication io take place. Pregenomic (pg) RNA is the template for reverse transcriptional replication of HBV DNA and its encapsidation, together with viral DNA polymerase, into nucleocapsid is essential for the subsequent viral DNA synthesis. Inhibition of pregenomic RNA (pg) encapsidation would block HBV replication and provide a new therapeutic approach to the treatment of HBV.

[0006] There is a long felt need for new antiviral drugs that are both diseasemodifying and effective in treating patients that are infected with hepatitis B virus. There is also a clear and present need for new antiviral drugs that are both disease modifying and effective in treating patients that are infected with drug resistant hepatitis B virus. The present invention addresses the need for new antiviral drugs that are both disease-modifying and effective in treating patients that are infected with hepatitis B virus.SUMMARY OF THE INVENTION

[0007] Aspects of the present invention are directed towards 4-sulfamoyl-heteroaryl- 2-carboxamide of the formula (1), useful as pregenomic RNA encapsidation inhibitors of HBV for the treatment of Hepatitis B virus (HBV) infection and related conditions.

[0009] Including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, isotopic analogs, prodrugs and complexes thereof, wherein:

[0010] X1is selected from the group consisting of nitrogen and CR4a;

[0011] R1is selected from the group consisting of C4-8 branched alkyl, C1-8 fluoroalkyl, Ci-s chloroalkyl, Ci-s bromoalkyl,s-salkenyl, Cs-salkynyl andC4-8 alkyl wherein the C4-8 alkyl is optionally substituted with one or more moi etiesselected from the group consisting of halogens, -OH, NH2, -CN, -CHF2, -CH2F, and - CFs;

[0012] R2is selected from the group consisting of C3-8 branched alkyl, C3-8 branched haloalkyl, Cs-iocycloalkyl, Cs-iocycloalkenyl, Ce-io bicycle wherein the C3- locycloalkyl, Cs-iocycloalkenyl, Ce-io bicycle optionally contain a group selected from O , S and N;

[0013] And R2is optionally being substituted with one or more substituents each independently selected from the group consisting of -OH, Fluoro, oxo, NH2, -CN, - CHF2, -CH2F or -CFs;

[0014] R2ais selected from the group consisting of hydrogen,, and, C1-8 alk l wherein the C1-8 alkyl is optionally substituted with one or more moieties selected from the group consisting of halogens, -OH, NH2, -CN, -CHF2, -CH2F, and - CFs;

[0015] R3is selected from the group consisting-memnbered heteroaryl, and 6-membered heteroaryl wherein the 5-memnbered heteroaryl, and 6- membered heteroaryl are optionally substituted with one or more moieties selected from the group consisting of halogen, C1-6 alkyl, C1-4 fluoroalkyl, cyano, -CHF2, - CF2CH3, -CH2F, -CF3, -OCF3, Ci-3alkyl and C3-6 cycloalkyl ;

[0016] Rais selected from the group consisting of hydrogen, halogen, C1-6 alkyl, Ci-4 fluoroalkyl, cyano, -CHF2, -CF2CH3, -CH2F, -CFs, -OCFs, Ci-3alkyl and Cs- ecycloalkyl;

[0017] Rbis selected from the group consisting of hydrogen, halogen, C1-6 alkyl, C1-4 fluoroalkyl, cyano. -CHF2. -CF2CH3, -CH2F, -CF3, -OCF3, Ci-3alkyl and C3- ecycloalkyl;

[0018] Rcis selected from the group consisting of hydrogen, halogen, C1-6 alkyl, C1-4 fluoroalkyl, cyano, -CHF2, -CF2CH3, -CH2F, -CF3, -OCF3, Ci-3alkyl and C3- ecycloalkyl;

[0019] Rdis selected from the group consisting of hydrogen, halogen, C1-6 alkyl, C1-4 flouroalkyl, cyano, -CHF2, -CF2CH3, -CH2F, -CFs, -OCFs, Ci salkyl and Cs-6 cycloalkyl;

[0020] Reis selected from the group consisting of hydrogen, halogen, Ci-6 alkyl, Ci-4 flouroalkyl, cyano, -CHF2. -CF2CH3, -CH2F, -CF3, -OCF3, Ci-3alkyl and Cs- ecycloalkyl:

[0021] R4is selected from the group consisting of hydrogen, halogen, C1-6 alky l, C3-7 branched alky l, C1-4 flouroalkyl, and C3-7 branched fluoroalkyl, -CN, -CHF2, - CF2CH3, -CH2F, -CF3, C2-3alkenyl, Cs-scycloalkyl, Ci-3alkyl, and -O-Ci-ealky wherein the Ci-3alkyl is optionally substituted with methoxy and the -O-Ci-salkyl is optionally substituted with moieties selected from the group consisting of halogen, -CHF2, -CF2- methyl, -CH2F, -CFs, -OCFs, and -CN;

[0022] In some embodiments R2'1and R4are taken together with the atoms to which they are bound to form a 7 to 9 membered ring;

[0023] R4ais selected from the group consisting of hydrogen, halogen, C1-6 alkyl, C3-7 branched alkyl, C1-4 haloalkyl, and C3-7 branched haloalky 1;

[0024] R5is selected from the group consisting of hydrogen, C1-4 alkyl, and

[0025] R6is selected from the group consisting of hydrogen and C1-4 alkyl;

[0026] m is 1, 2, 3. 4, 5, 6. 7, or 8;

[0027] n is 1, 2, 3, 4, 5, 6, 7, or 8;

[0028] q is 1, 2, 3, 4, 5, 6, 7, or 8;

[0029] u is 1, 2, 3, 4, 5, 6, 7, or 8;.

[0030] x is 1. 2, 3, 4, 5, 6, 7, or 8;

[0031] z is 1. 2, 3, 4. 5, 6, 7. or 8;

[0032] e is 1, 2, 3, 4, 5, 6, 7, or 8;

[0033] Aspects of the present invention further relate to compositions comprising:

[0034] an effective amount of one or more compounds according to the present invention and an excipient.

[0035] Aspects of the present invention also relates to a method for treating or preventing diseases that involve pregenomic RNA encapsidation, including, for example, HBV infection, said method comprising administering to a subject an effective amount of a compound or composition according to aspects of the present invention.

[0036] Yet further aspects of the present invention relate to a method for treating or preventing diseases that involve pregenomic RNA encapsidation, including, forexample, HBV infection, wherein said method comprises administering to a subject a composition comprising an effective amount of one or more compounds according to aspects of the present invention and an excipient.

[0037] Aspects of the present invention also relates to a method for treating or preventing disease or conditions associated with HBV infection, and diseases that involve pregenomic RNA encapsidation. Said methods comprise administering to a subject an effective amount of a compound or composition according to aspects of the present invention.

[0038] Aspects of the present invention yet further relate to a method for treating or preventing disease or conditions associated with HBV infection, and diseases that involve pregenomic RNA encapsidation, wherein said method comprises administering to a subject a composition comprising an effective amount of one or more compounds according to the present invention and an excipient.

[0039] Aspects of the present invention further relate to a process for preparing the pregenomic RNA encapsidation inhibitors of HBV of the present invention.

[0040] These and other objects, features, and advantages will become apparent to those of ordinary skill in the art from a reading of the following detailed description and the appended claims. All percentages, ratios and proportions herein are by weight, unless otherwise specified. All temperatures are in degrees Celsius (° C) unless otherwise specified. All documents cited are in relevant part, incorporated herein by reference; the citation of any document is not to be construed as an admission that it is prior art with respect to the present invention.BRIEF DESCRIPTION OF DRAWINGS

[0041] FIG. 1 is a graph of the mean plasma concentration versus time profile of (R)- N-(3,4-difluorophenyl)-3-fluoro-l -methyl-4-(N-(l , 1, 1 -trifluoropropan-2- yl)sulfamoyl)-lH-pyrrole-2-carboxamide after 3 mg / kg (IV) and 10 mg / kg (PO) to CD1 mice.

[0042] FIG. 2 is a graph of the mean plasma concentration versus time profile of (R)- N-(3,4-difluorophenyl)-3-fluoro-l-(2-fluoroethyl)-4-(N-(l,l,l-trifluoropropan-2- yl)sulfamoyl)-lH-pyrrole-2-carboxamide after 3 mg / kg IV and 10 mg / kg (PO) to CD1 mice.

[0043] FIG. 3 is a graph of the mean plasma concentration versus time profile of 72006 after 3 mg / kg (IV) and 10 mg / kg (PO) to CD1 mice.

[0044] FIG. 4 is a graph of the mean plasma concentration versus time profile of (R)-1-(2,2-difluoroethyl)-3-fluoro-N-(3,4,5-trifluorophenyl)-4-(N-(l,l,l-trifluoropropan-2-yl)sulfamoyl)-lH-pyrrole-2-carboxamide after 3 mg / kg (IV) and 10 mg / kg (PO) to CD1 mice.

[0045] FIGS. 5A-5F are graphs of the evaluation of the anti-HBV efficacy of (R)-l- (2,2-difluoroethyl)-3-fluoro-N-(3,4,5-trifluorophenyl)-4-(N-(l,l,l-trifluoropropan-2- yl)sulfamoyl)-lH-pyrrole-2-carboxamide in AAV / HBV mouse model.DETAILED DESCRIPTION OF THE INVENTION

[0046] The pregenomic RNA encapsidation inhibitors according to aspects of the present invention are capable of treating and preventing diseases associated with pregenomic RNA encapsidation, for example HBV infection. Pregenomic (pg) RNA is the template for reverse transcriptional replication of HBV DNA and its encapsidation, together with viral DNA polymerase, into nucleocapsid is essential for the subsequent viral DNA synthesis. Without wishing to be limited by theory, it is believed that inhibition of pregenomic RNA encapsidation can ameliorate, abate, or otherwise cause to be controlled, diseases associated with pregenomic RNA encapsidation, for example HBV infection. Pregenomic RNA encapsidation inhibitors according to aspects of the present invention address the clear and unmet need to identify novel and safe antiviral agents for the treatment of HBV infection that are chemically and mechanistically distinct from HBV antiviral drugs in current clinical use.

[0047] Clinically, the pregenomic RNA encapsidation inhibitors according to aspects of the present invention complement the current medications by providing an additional option for a subpopulation of patients that do not tolerate or benefit from the current medications (Akbar et al., 2009; Liaw, 2009; Peters, 2009; Wiegand, van Bommel, and Berg). In addition, the pregenomic RNA encapsidation inhibitors according to aspects of the present invention may be effective on HBV variants that are resistant to the currently available DNA polymerase inhibitors (Zouhm and Locamini, 2009). Further, combination therapies of the pregenomic RNA encapsidation inhibitors according to aspects of the present invention with DNA polymerase inhibitors may synergistically suppress HBV replication and prevent the emergence of drug resistance, offering a safer and more effective treatment for chronic hepatitis B (Billioud et al., 2011).

[0048] Throughout the description, where compositions are described as having, including, or comprising specific components, or where processes are described as having, including, or comprising specific process steps, it is contemplated that compositions of the present teachings also consist essentially of, or consist of, the recited components, and that the processes of the present teachings also consist essentially of, or consist of, the recited processing steps.

[0049] In the application, where an element or component is said to be included in and / or selected from a list of recited elements or components, it should be understood that the element or component can be any one of the recited elements or components and can be selected from a group consisting of two or more of the recited elements or components.

[0050] The use of the singular herein includes the plural (and vice versa) unless specifically stated otherwise. In addition, where the use of the term “about” is before a quantitative value, the present teachings also include the specific quantitative value itself, unless specifically stated otherwise.

[0051] It should be understood that the order of steps or order for performing certain actions is immaterial so long as the present teachings remain operable. Moreover, two or more steps or actions can be conducted simultaneously

[0052] As used herein, the term "halogen" shall mean chlorine, bromine, fluorine and iodine.

[0053] As used herein, unless otherwise noted, “alkyl” and / or “aliphatic” whether used alone or as part of a substituent group refers to straight and branched carbon chains having 1 to 20 carbon atoms or any number within this range, for example 1 to 6 carbon atoms or 1 to 4 carbon atoms. Designated numbers of carbon atoms (e.g. Ci- 6) shall refer independently to the number of carbon atoms in an alkyl moiety or to the alkyl portion of a larger alkyl-containing substituent. Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tertbutyl. and the like. Alkyl groups can be optionally substituted. Non-limiting examples of substituted alkyl groups include hydroxymethyl, chloromethyl, trifluoromethyl, aminomethyl, 1 -chloroethyl, 2 -hydroxyethyl, 1,2-difluoroethyl, 3- carboxypropyl, and the like. In substituent groups with multiple alkyl groups such as (Ci-6alkyl)2amino, the alkyl groups may be the same or different.

[0054] As used herein, the terms “alkenyl” and “alkynyl” groups, whether used alone or as part of a substituent group, refer to straight and branched carbon chains having 2or more carbon atoms, preferably 2 to 20, wherein an alkenyl chain has at least one double bond in the chain and an alkynyl chain has at least one triple bond in the chain. Alkenyl and alkynyl groups can be optionally substituted. Nonlimiting examples of alkenyl groups include ethenyl, 3-propenyl, 1 -propenyl (also 2-methylethenyl), isopropenyl (also 2-methylethen-2-yl), buten-4-yl, and the like. Nonlimiting examples of substituted alkenyl groups include 2-chloroethenyl (also 2-chlorovinyl), 4-hydroxybuten-l-yl, 7-hydroxy-7-methyloct-4-en-2-yl. 7-hydroxy-7-methyloct-3.5- dien-2-yl, and the like. Nonlimiting examples of alkynyl groups include ethynyl, prop-2-ynyl (also propargy l), propyn-l-yl, and 2-methyl-hex-4-yn-l-yl. Nonlimiting examples of substituted alkynyl groups include, 5-hydroxy-5-methylhex-3-ynyl, 6- hydroxy-6-methylhept-3-yn-2-yl, 5-hydroxy-5-ethylhept-3-ynyl, and the like.

[0055] As used herein, “cycloalkyl,’’ whether used alone or as part of another group, refers to a non-aromatic carbon-containing ring including cyclized alkyl, alkenyl, and alky nyl groups, e.g., having from 3 to 14 ring carbon atoms, preferably from 3 to 7 or 3 to 6 ring carbon atoms, or even 3 to 4 ring carbon atoms, and optionally containing one or more (e.g., 1, 2. or 3) double or triple bond. Cycloalkyl groups can be monocyclic (e g., cyclohexyl) or polycyclic (e.g., containing fused, bridged, and / or spiro ring systems), wherein the carbon atoms are located inside or outside of the ring system. Any suitable ring position of the cycloalkyl group can be covalently linked to the defined chemical structure. Cycloalkyl rings can be optionally substituted. Nonlimiting examples of cycloalkyl groups include: cyclopropyl, 2-methyl- cyclopropyl, cyclopropenyl, cyclobutyl, 2,3-dihydroxycyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclopentadienyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctanyl. decalinyl, 2,5-dimethylcyclopentyl, 3.5-dichlorocyclohexyl, 4- hydroxy cyclohexyl, 3,3,5-trimethylcyclohex-l-yl, octahydropentalenyl, octahydro- IH-indenyl, 3a,4,5,6,7,7a-hexahydro-3H-inden-4-yl, decahydroazulenyl; bicyclo[6.2.0]decanyl, decahydronaphthalenyl, and dodecahydro-lH-fluorenyl. The term “cycloalkyl” also includes carbocyclic rings which are bicyclic hydrocarbon rings, non-limiting examples of which include, bicyclo-[2.1.1]hexanyl, bicyclo[2.2.1]heptanyl, bicyclo[3.1.1]heptanyl, l,3-dimethyl[2.2.1]heptan-2-yl, bicyclo[2.2.2]octanyl, and bicyclo[3.3.3]undecanyl.

[0056] “Haloalkyl” is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with 1 or more halogen. Haloalkyl groups include perhaloalkyl groups,wherein all hydrogens of an alkyl group have been replaced with halogens (e.g., -CF3, CF2CF3). Haloalkyl groups can optionally be substituted with one or more substituents in addition to halogen. Examples of haloalkyl groups include, but are not limited to, fluoromethyl, dichloroethyl, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl groups.

[0057] The term “alkoxy” refers to the group -O-alkyl, wherein the alkyl group is as defined above. Alkoxy groups optionally may be substituted. The term C3-6 cyclic alkoxy refers to a ring containing 3 to 6 carbon atoms and at least one oxygen atom (e.g., tetrahydrofuran, tetrahydro-2H-pyran). C3-6 cyclic alkoxy groups optionally may be substituted.

[0058] The term “aryl.” wherein used alone or as part of another group, is defined herein as a an unsaturated, aromatic monocyclic ring of 6 carbon members or to an unsaturated, aromatic polycyclic ring of from 10 to 14 carbon members. Aryl rings can be, for example, pheny l or naphthyl ring each optionally substituted with one or more moieties capable of replacing one or more hydrogen atoms. Non-limiting examples of aryl groups include: phenyl, naphthylen-l-yl. naphthylen-2-yl. 4- fluorophenyl, 2-hydroxyphenyl, 3-methylphenyl, 2-amino-4-fluorophenyl, 2-(N,N- diethylamino)phenyl, 2-cyanophenyl, 2,6-di-tert-butylphenyl, 3 -methoxy phenyl, 8- hydroxynaphthylen-2-yl 4,5-dimethoxynaphthylen-l-yl, and 6-cyano-naphthylen-l- yl. Aryl groups also include, for example, phenyl or naphthyl rings fused with one or more saturated or partially saturated carbon rings (e.g., bicyclo[4.2.0]octa-l , 3,5- trienyl, indanyl), which can be substituted at one or more carbon atoms of the aromatic and / or saturated or partially saturated rings.

[0059] The term “arylalkyl” or “aralkyl” refers to the group -alkyl-aryl, where the alkyl and aryl groups are as defined herein. Aralkyl groups of the present invention are optionally substituted. For instance, in some embodiments the aralkyl groups may be substituted while in other embodiments the aralkyl groups may be unsubstituted. Examples of arylalkyl groups include, for example, benzyl, 1 -phenylethyl, 2- phenylethyl, 3-phenylpropyL 2-phenylpropyl, fluorenylmethyl and the like.

[0060] The terms “heterocyclic” and / or “heterocycle” and / or “heterocylyl,” whether used alone or as part of another group, are defined herein as one or more ring having from 3 to 20 atoms wherein at least one atom in at least one ring is a heteroatom selected from nitrogen (N), oxygen (O), or sulfur (S), and wherein further the ring that includes the heteroatom is non-aromatic. In heterocycle groups that include 2 or morefused rings, the non-heteroatom bearing ring may be aryl (e.g., indolinyl, tetrahydroquinolinyl. chromanyl). Exemplary heterocycle groups have from 3 to 14 ring atoms of which from 1 to 5 are heteroatoms independently selected from nitrogen (N), oxygen (O), or sulfur (S). One or more N or S atoms in a heterocycle group can be oxidized. Heterocycle groups can be optionally substituted.

[0061] Non-limiting examples of heterocyclic units having a single ring include: diazirinyl, aziridinyl. urazolyl. azetidinyl, pyrazolidinyl. imidazolidinyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolidinyl, isothiazolyl, isothiazolinyl oxathiazolidinonyl, oxazolidinonyl, hydantoinyl, tetrahydrofuranyl, pyrrolidinyl, morpholinyl, piperazinyl, piperidinyl, dihydropyranyl, tetrahydropyranyl, piperidin-2-onyl (valerolactam). 2,3,4,5-tetrahydro-lH-azepinyl, 2.3 -dihydro- IH-indole. and 1 ,2,3,4- tetrahydro-quinoline. Non-limiting examples of heterocyclic units having 2 or more rings include: hexahydro-lH-pyrrolizinyl, 3a,4,5,6,7,7a-hexahydro-lH- benzo[d]imidazolyl, 3a,4,5,6,7,7a-hexahydro-lH-indolyl, 1, 2,3,4- tetrahydroquinolinyl. chromanyl, isochromanyl, indolinyl, isoindolinyl. and decahydro-lH-cycloocta[b]pyrrolyl.

[0062] The term '‘heteroaryl,” whether used alone or as part of another group, is defined herein as one or more rings having from 5 to 20 atoms wherein at least one atom in at least one ring is a heteroatom chosen from nitrogen (N), oxygen (O). or sulfur (S), and wherein further at least one of the rings that includes a heteroatom is aromatic. In heteroaryl groups that include 2 or more fused rings, the non-heteroatom bearing ring may be a carbocycle (e.g., 6,7-Dihydro-5H-cyclopentapyrimidine) or aryl (e.g., benzofuranyl, benzothiophenyl, indolyl). Exemplary heteroaryl groups have from 5 to 14 ring atoms and contain from 1 to 5 ring heteroatoms independently selected from nitrogen (N), oxygen (O), or sulfur (S). One or more N or S atoms in a heteroaryl group can be oxidized. Heteroaryl groups can be substituted. Non-limiting examples of heteroary l rings containing a single ring include: 1,2,3,4-tetrazolyl, [l,2,3]triazolyl, [l,2,4]triazolyl, triazinyl, thiazolyl, IH-imidazolyl, oxazolyl, furanyl, thiopheneyl, pyrimidinyl, 2-phenylpyrimidinyl, pyridinyl. 3-methylpyridinyl. and 4- dimethylaminopyridinyl. Non-limiting examples of heteroary l rings containing 2 or more fused rings include: benzofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, cinnolinyl, naphthyridinyl, phenanthridinyl, 7H-purinyl. 9H-purinyl, 6-amino-9H-purinyl, 5H-pyrrolo[3,2-d]pyrimidinyl, 7H-pyrrolo[2.3- d] pyrimidinyl, pyrido[2,3-d]pyrimidinyl, 2-phenylbenzo[d]thiazolyl, IH-indolyl,4,5,6,7-tetrahydro-l-H-indolyl, quinoxalinyl, 5-methylquinoxalinyl, quinazolinyl, quinolinyl, 8-hydroxy-quinolinyl, and isoquinolinyl.

[0063] One non-limiting example of a heteroaryl group as described above is C1-5 heteroaryl, which has 1 to 5 carbon ring atoms and at least one additional ring atom that is a heteroatom (preferably 1 to 4 additional ring atoms that are heteroatoms) independently selected from nitrogen (N), oxygen (O), or sulfur (S). Examples of C 1-5 heteroaryl include, but are not limited to, tnazinyl, thiazol-2-yl. thiazol-4-yl, imidazol-l-yl, lH-imidazol-2-yl, lH-imidazol-4-yl, isoxazolin-5-yl, furan-2-yl, furan- 3-yl, thiophen-2-yl, thiophen-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyridin-2-yl, pyridin-3-yl, and pyridin-4-yl.

[0064] Unless otherwise noted, when two substituents are taken together to form a ring having a specified number of ring atoms (e.g., R2 and R3 taken together with the nitrogen (N) to which they are attached to form a ring having from 3 to 7 ring members), the ring can have carbon atoms and optionally one or more (e.g., 1 to 3) additional heteroatoms independently selected from nitrogen (N), oxygen (O), or sulfur (S). The ring can be saturated or partially saturated and can be optionally substituted.

[0065] For the purposed of the present invention fused ring units, as well as spirocyclic rings, bicyclic rings and the like, which comprise a single heteroatom will be considered to belong to the cyclic family corresponding to the heteroatom containing ring. For example, 1 ,2,3,4-tetrahydroquinoline having the formula: rposes of the present invention, considered a heterocyclic unit. clopentapyrimidine having the formula:

[0069] is, for the purposes of the present invention, considered a heteroaryl unit.When a fused ring unit contains heteroatoms in both a saturated and an aryl ring, the aryl ring will predominate and determine the type of category to which the ring is assigned. For example, l,2,3,4-tetrahydro-[l,8]naphthyridine having the formula:

[0070]

[0071] is, for the purposes of the present invention, considered a heteroaryl unit.

[0072] Whenever a term or either of their prefix roots appear in a name of a substituent, the name is to be interpreted as including those limitations provided herein. For example, whenever the term “alkyl’’ or “aryl” or either of their prefix roots appear in a name of a substituent (e.g., arylalkyd, alkylamino) the name is to be interpreted as including those limitations given above for “alkyl” and “aryl.”

[0073] The term “substituted” is used throughout the specification. The term “substituted” is defined herein as a moiety, whether acyclic or cyclic, which has one or more hydrogen atoms replaced by a substituent or several (e.g., 1 to 10) substituents as defined herein below. The substituents are capable of replacing one or two hydrogen atoms of a single moiety’ at a time. In addition, these substituents can replace two hydrogen atoms on two adjacent carbons to form said substituent, new moiety or unit. For example, a substituted unit that requires a single hydrogen atom replacement includes halogen, hydroxyl, and the like. A two hydrogen atom replacement includes carbonyl, oximino, and the like. A two hydrogen atom replacement from adjacent carbon atoms includes epoxy, and the like. The term “substituted” is used throughout the present specification to indicate that a moiety can have one or more of the hydrogen atoms replaced by a substituent. When a moiety' is described as “substituted” any number of the hydrogen atoms may be replaced. For example, difluoromethyl is a substituted Ci alkyl; trifluoromethyl is a substituted Ci alkyl; 4-hydroxyphenyl is a substituted aromatic ring; (N,N-dimethyl-5-amino)octanyl is a substituted Cs alky l; 3-guanidinopropyl is a substituted C3 alkyl; and 2- carboxypyridinyl is a substituted heteroaryl.

[0074] The variable groups defined herein, e.g., alkyl, alkenyl, alkynyl. cycloalkyl, alkoxy, aryloxy, aryl, heterocycle and heteroaryl groups defined herein, whether used alone or as part of another group, can be optionally substituted. Optionally’ substituted groups will be so indicated.

[0075] The following are non-limiting examples of substituents which can substitute for hydrogen atoms on a moiety: halogen (chlorine (Cl), bromine (Br), fluorine (F) and iodine(I), -CN, -NO2, oxo (=0), -OR7, -SR7, -N(R7)2, -NR7C(O)R7, -SO2R7, - SO2OR7, -SO2N(R7)2, C(O)R7, C(O)OR7, C(O)N(R7)2, C1-6 alkyl, C1-6 haloalky 1, C1-6 alkoxy, C'2-x alkenyl, C2-8 alkynyl, C3-14 cycloalkyl, aryl, heterocycle, or heteroaryl, wherein each of the alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, cycloalky l. aryl, heterocycle, and heteroaryl groups is optionally substituted with 1-10 (e.g., 1-6or 1-4) groups selected independently from halogen, -CN, -NO2, oxo, and R7; wherein R7, at each occurrence, independently is hydrogen, -OR8, -SR8, -C(O)R8, - C(O)OR8, -C(O)N(R8)2, -SO2R8, S(O)2OR8, -N(R8)2, -NR8C(O)R8, C1-6 alkyl, C1-6 haloalkyl, C2-8 alkenyl, C2-8 alkynyl, cycloalkyl (e.g., C3-6 cycloalkyd), ary l, heterocycle, or heteroary l, or two R7units taken together with the atom(s) to which they are bound form an optionally substituted carbocycle or heterocycle wherein said carbocycle or heterocycle has 3 to 7 ring atoms; wherein R8, at each occurrence, independently is hydrogen, C1-6 alkyl, C1-6 haloalky 1, C2-8 alkenyl, C2-8 alkynyl, cycloalky 1 (e.g., Cs-6 cycloalkyl), ary l, heterocycle, or heteroaryl, or two R8units taken together with the atom(s) to which they are bound form an optionally substituted carbocycle or heterocycle wherein said carbocycle or heterocycle preferably has 3 to 7 ring atoms.

[0076] In some embodiments, the substituents are selected from

[0077] i) -OR9; for example, -OH, -OCH3, -OCH2CH3, -OCH2CH2CH3;

[0078] ii) -C(O)R9; for example, -COCH3, -COCH2CH3. -COCH2CH2CH3;

[0079] 111) -C(O)OR9; for example, -CO2CH3, -CO2CH2CH3, -CO2CH2CH2CH3;

[0080] iv) -C(O)N(R9)2; for example, -CONH2, -CONHCHs, -CON(CH3)2;

[0081] v) -N(R9)2; for example, -NH2, -NHCH3, -N(CH3)2, -NH(CH2CH3);

[0082] vi) halogen: -F, -Cl, -Br, and -I;

[0083] vii) -CHeXg; wherein X is halogen and e+g =3; for example, -CH2F, -CHF2, - CF3, -CCI3, or -CBrs;

[0084] -SO2R9; for example, -SO2H; -SO2CH3; -SO2C6H5;

[0085] C1-6 linear, branched, or cyclic alkyl;

[0086] Cyano;

[0087] Nitro;

[0088] N(R9)C(O)R9;

[0089] Oxo (=0);

[0090] Heterocycle; and

[0091] Heteroaryl.

[0092] wherein each R9is independently hydrogen, optionally substituted C1-6 linear or branched alkyl (e.g., optionally substituted C1-4 linear or branched alkyl), or optionally substituted C3-6 cycloalkyl (e.g optionally substituted C3-4 cycloalkyl); or two R9units can be taken together to form a ring comprising 3-7 ring atoms. Incertain aspects, each R9is independently hydrogen, Ci-6 linear or branched alkyl optionally substituted with halogen or C'3-6 cycloalkyl or C3-6 cycloalkyl.

[0093] At various places in the present specification, substituents of compounds are disclosed in groups or in ranges. It is specifically intended that the description include each and every individual subcombination of the members of such groups and ranges. For example, the term “C1-6 alkyd” is specifically intended to individually disclose Ci, C2, C3. C4. C5. C6, C1-6, C1-5, Ci-4, C1-3, C1-2, C2-6. C2-5, C2-4. C2-3, C3-6, C3- 5, C3-4, C4-6, C4-5, and C5-6, alkyl.

[0094] For the purposes of the present invention the terms “compound,” “analog,” and “composition of matter” stand equally well for the pregenomic RNA encapsidation inhibitors agent described herein, including all enantiomeric forms, diastereomeric forms, salts, and the like, and the terms “compound,” “analog,” and “composition of matter” are used interchangeably throughout the present specification.

[0095] Compounds described herein can contain an asymmetric atom (also referred as a chiral center), and some of the compounds can contain one or more asymmetric atoms or centers, which can thus give rise to optical isomers (enantiomers) and diastereomers. The present teachings and compounds disclosed herein include such enantiomers and diastereomers, as well as the racemic and resolved, enantiomerically pure R and S stereoisomers, as well as other mixtures of the R and S stereoisomers and pharmaceutically acceptable salts thereof. Optical isomers can be obtained in pure form by standard procedures known to those skilled in the art, which include, but are not limited to, diastereomeric salt formation, kinetic resolution, and asymmetric synthesis. The present teachings also encompass cis and trans isomers of compounds containing alkenyl moieties (e.g., alkenes and imines). It is also understood that the present teachings encompass all possible regioisomers, and mixtures thereof, which can be obtained in pure form by standard separation procedures known to those skilled in the art, and include, but are not limited to, column chromatography, thin- layer chromatography, and high-performance liquid chromatography.

[0096] Pharmaceutically acceptable salts of compounds of the present teachings, which can have an acidic moiety7, can be formed using organic and inorganic bases. Both mono and poly anionic salts are contemplated, depending on the number of acidic hydrogens available for deprotonation. Suitable salts formed with bases include metal salts, such as alkali metal or alkaline earth metal salts, for examplesodium, potassium, or magnesium salts; ammonia salts and organic amine salts, such as those formed with morpholine, thiomorpholine, piperidine, pyrrolidine, a mono-, di- or tri-lower alkylamine (e.g., ethyl-tert-butyl-, diethyl-, diisopropyl-, triethyl-, tributyl- or dimethylpropylamine), or a mono-, di-, or trihydroxy lower alkydamine (e.g., mono-, di- or triethanolamine). Specific non-limiting examples of inorganic bases include NaHCOs, Na2CO3. KHCOs, K2CO3. CS2CO3, LiOH, NaOH, KOH, NaH2PO4, Na2HPO4. and NasPOr. Internal salts also can be formed. Similarly, when a compound disclosed herein contains a basic moiety, salts can be formed using organic and inorganic acids. For example, salts can be formed from the following acids: acetic, propionic, lactic, benzenesulfonic, benzoic, camphorsulfonic, citric, tartaric, succinic, dichloroacetic, ethenesulfonic, formic, fumaric, gluconic, glutamic, hippuric, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, malonic, mandelic, methanesulfonic, mucic, napthalenesulfonic, nitric, oxalic, pamoic, pantothenic, phosphoric, phthalic, propionic, succinic, sulfuric, tartaric, toluenesulfonic, and camphorsulfonic as well as other known pharmaceutically acceptable acids.

[0097] When any variable occurs more than one time in any constituent or in any formula, its definition in each occurrence is independent of its definition at every' other occurrence (e.g., in N(RX)2, each Rxmay be the same or different than the other). Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0098] The terms “treat” and “treating” and “treatment” as used herein, refer to partially or completely alleviating, inhibiting, ameliorating and / or relieving a condition from which a patient is suspected to suffer.

[0099] As used herein, “therapeutically effective” and “effective dose” refer to a substance or an amount that elicits a desirable biological activity or effect.

[0100] Except when noted, the terms “subject” or “patient” are used interchangeably and refer to mammals such as human patients and non-human primates, as well as experimental animals such as rabbits, rats, and mice, and other animals. Accordingly, the term “subject” or “patient” as used herein means any mammalian patient or subject to which the compounds of the invention can be administered. In an exemplary embodiment of the present invention, to identify subject patients for treatment according to the methods of the invention, accepted screening methods are employed to determine risk factors associated with a targeted or suspected disease orcondition or to determine the status of an existing disease or condition in a subject. These screening methods include, for example, conventional work-ups to determine risk factors that may be associated with the targeted or suspected disease or condition. These and other routine methods allow the clinician to select patients in need of therapy using the methods and compounds according to aspects of the present invention.

[0101] The pregen omic RNA encapsidation inhibitors

[0102] The pregenomic RNA encapsidation inhibitors according to aspects of the present invention useful for the treatment of Hepatitis B virus (HBV) infection and related conditions are functionalized benzamide derivatives, and include all enantiomeric and diastereomeric forms and pharmaceutically accepted salts thereof having the formula (I):

[0104] Including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, isotopic analogs, prodrugs and complexes thereof, wherein:

[0105] X1is selected from the group consisting of nitrogen and CR4a;

[0106] R1is selected from the group consisting of C4-8 branched alkyl, C1-8 fluoroalkyl, C1-8 chloroalkyl, Ci-s bromoalkyl,, C2-8hydroxyalkyl, C2-saminoalkyl, Cs-salkenyl, CAsalkynyl. andC4-8 alkyl wherein the C4-8 alkyd is optionally substituted with one or more moieties selected from the group consisting of halogens, -OH, NH2, -CN, -CHF2, -CH2F, and -CF3;

[0107] R2is selected from the group consisting of C3-8 branched alkyl, C3-8 branched haloalkyl, Cs-iocycloalkyl, C3-iocycloalkenyl, Ce-io bicycle wherein the C3- locycloalkyl, Cs-iocycloalkenyl, Ce-io bicycle optionally contain a group selected from O , S and N;

[0108] And R2is optionally being substituted with one or more substituents each independently selected from the group consisting of -OH, Fluoro, oxo, NH2, -CN, - CHF2, -CH2F or -CF3;

[0109] R2ais selected from the group consisting of hydrogen., and. C1-8 alkyl wherein the Ci-s alkyl is optionally substituted with one or more moieties selected from the group consisting of halogens, -OH, NH2, -CN, -CHF2, -CH2F, and - CF3;

[0110] R3is selected from the group consisting-memnbered heteroaryl, and 6-membered heteroaryl wherein the 5-memnbered heteroaryl, and 6- membered heteroaryl are optionally substituted with one or more moieties selected from the group consisting of halogen, C1-6 alkyl, C1-4 fluoroalkyl, cyano, -CHF2, - CF2CH3, -CH2F, -CF3, -OCF3, Ci-salkyl and C3-6 cycloalkyl;

[0111] Rais selected from the group consisting of hydrogen, halogen, C1-6 alkyl, C1-4 fluoroalkyl, cyano, -CHF2. -CF2CH3, -CH2F, -CF3, -OCF3, Ci-3alkyl and C3- 6cycloalkyl;

[0112] Rbis selected from the group consisting of hydrogen, halogen, C1-6 alky l, C1-4 fluoroalkyl, cyano, -CHF2, -CF2CH3, -CH2F, -CF3, -OCF3, Ci-3alkyl and C3- ecycloalkyl;

[0113] Rcis selected from the group consisting of hydrogen, halogen, C1-6 alkyl, Ci-4 fluoroalkyl, cyano, -CHF2, -CF2CH3, -CH2F, -CFs, -OCFs, Ci-3alkyl and Cs- ecycloalkyl;

[0114] Rdis selected from the group consisting of hydrogen, halogen, C1-6 alkyl, C1-4 fluoroalkyl, cyano. -CHF2. -CF2CH3, -CH2F, -CF3, -OCF3, Ci-3alkyl and C3- ecycloalkyl;

[0115] Reis selected from the group consisting of hydrogen, halogen, C1-6 alkyl, C1-4 fluoroalkyl, cyano, -CHF2, -CF2CH3, -CH2F, -CF3, -OCF3, Ci-3alkyl and C3- ecycloalkyl;

[0116] R4is selected from the group consisting of hydrogen, halogen, C1-6 alkyl, C3-7 branched alkyl, C1-4 flouroalkyl, and C3-7 branched fluoroalkyl, -CN, -CHF2, - CF2CH3, -CH2F, -CF3, C2-3alkenyl, Cs-scycloalkyl, Ci-3alkyl, and -O-Ci-ealky wherein the Ci-3alkyl is optionally substituted with methoxy and the -O-Ci-ealkyl is optionally substituted with moieties selected from the group consisting of halogen, - CHF2, -CF2-methyl, -CH2F, -CF3, -OCF3, and -CN;

[0117] In some embodiments R2aand R4are taken together with the atoms to which they are bound to form a 7 to 9 membered ring;

[0118] R4ais selected from the group consisting of hydrogen, halogen, C1-6 alkyl, C3-7 branched alkyl. Ci-4 haloalkyL and C3-7 branched haloalkyl;

[0119] R5is selected from the group consisting of hydrogen, Ci-4 alkyd, and

[0120] R6is selected from the group consisting of hydrogen and C1-4 alky 1;

[0121] m is 1, 2, 3, 4, 5, 6, 7, or 8;

[0122] n is i. 2, 3, 4, 5, 6, 7, or 8;

[0123] q is 1. 2, 3, 4. 5, 6, 7. or 8;

[0124] u is 1, 2, 3, 4, 5, 6, 7, or 8;

[0125] x is 1, 2, 3, 4, 5, 6, 7, or 8;

[0126] z is 1, 2, 3, 4, 5, 6, 7, or 8;

[0127] e is 1. 2, 3, 4, 5, 6, 7, or 8;

[0128] The compounds of the present invention, in certain embodiments, include compounds having formula (II):

[0130] including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof.

[0131] The compounds of the present invention, in certain embodiments, include compounds having formula (III):

[0133] including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof.

[0134] The compounds of the present invention, in certain embodiments, include compounds having formula (IV):

[0135]

[0136] including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof.

[0137] The compounds of the present invention, in certain embodiments, include compounds having formula (V):

[0139] including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof.

[0140] The compounds of the present invention, in certain embodiments, include compounds having formula (VI):

[0142] including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof.

[0143] The compounds of the present invention, in certain embodiments, include compounds having formula (VII):

[0144]

[0145] including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof.

[0146] The compounds of the present invention, in certain embodiments, include compounds having formula (VIII):

[0148] including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof.

[0149] The compounds of the present invention, in certain embodiments, include compounds having formula (IX):

[0150]

[0151] including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof.

[0152] The compounds of the present invention, in certain embodiments, include compounds having formula (X):

[0153]

[0154] including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof.

[0155] The compounds of the present invention, in certain embodiments, include compounds having formula (XI):

[0157] including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof.

[0158] The compounds of the present invention, in certain embodiments, include compounds having formula (XII):

[0159]

[0160] including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof.

[0161] The compounds of the present invention, in certain embodiments, include compounds having formula (XIII):

[0162]

[0163] including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof.

[0164] The compounds of the present invention, in certain embodiments, include compounds having formula (XIV):

[0166] including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof.

[0167] The compounds of the present invention, in certain embodiments, include compounds having formula (XV):

[0169] including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof.

[0170] In some embodiments X1is nitrogen.

[0171] In some embodiments X1is CR4a.

[0172] In some embodiments R1is C3-7 branched alkyl.

[0173] In some embodiments R1is C1-4 fluoroalkyl.

[0174] In some embodiments R1is C1-4 chloroalkyl.

[0175] In some embodiments

[0176] In some embodiments

[0177] In some embodiments

[0178] In some embodiments

[0179] In some embodiments

[0180] In some embodiments R1is C2-8hydroxyalkyl.

[0181] In some embodiments R1is C2-8aminoalkyl.

[0182] In some embodiments R1is Cs-salkenyl.

[0183] In some embodiments R1is Cs-salkynyl.

[0184] In some embodiments R1is C4-8 alkyl.

[0185] In some embodiments R1is C4-8 alkyl that is substituted with one or more moieties selected from the group consisting of halogens, -OH, NH2. -CN. -CHF2. -CH2F, and -CF3

[0186] In some embodiments R2is C3-8 branched alkyl.

[0187] In some embodiments R2is C3-8 branched haloalkyl.

[0188] In some embodiments R2is Cs-iocycloalkyl.

[0189] In some embodiments R2is C3-iocycloalkyl containing an O.

[0190] In some embodiments R2is Cs-iocycloalkyl containing an S.

[0191] In some embodiments R2is Cs-iocycloalkyl containing an N.

[0192] In some embodiments R2is Cs-iocycloalkenyl.

[0193] In some embodiments R2is Cs-iocycloalkenyl containing an O.

[0194] In some embodiments R2is Cs-iocycloalkenyl containing an S.

[0195] In some embodiments R2is Cs-iocycloalkenyl containing an N.

[0196] In some embodiments R2is Ce-io bicycle.

[0197] In some embodiments R2is Ce-io bicycle containing an O.

[0198] In some embodiments R2is Ce-io bicycle containing an S.

[0199] In some embodiments R2is Ce-io bicycle containing an N.

[0200] In some embodiments R2is substituted with one or more substituents each independently selected from the group consisting of -OH, Fluoro, oxo, NH2, -CN, - CHF2, -CH2F or -CF3

[0201] In some embodiments R23is hydrogen.

[0202] In some embodiments R2ais C1-8 alky l.

[0203] In some embodiments R23is C1-8 alkyl that is substituted with one or more moieties selected from the group consisting of halogens, -OH. NH2. -CN. -CHF2. - CH2F, and -CF3

[0204] In some embodiments

[0205] In some embodiments

[0206] In some embodiments R3is 5-memnbered heteroaryl.

[0207] In some embodiments R3is 5-memnbered heteroaryl that is substituted with one or more moieties selected from the group consisting of halogen, C1-6 alkyl, C1-4 fluoroalkyl, cyano, -CHF2. -CF2CH3, -CH2F, -CF3, -OCF3, Ci-3alkyl and C -6 cycloalkyd.

[0208] In some embodiments R3is 6-membered heteroaryl.

[0209] In some embodiments R3is 6-membered heteroaryl that is substituted with one or more moieties selected from the group consisting of halogen. C1-6 alkyl, Ci-4 fluoroalkyl, cyano, -CHF2, -CF2CH3, -CH2F, -CF3, -OCF3, Ci-3alkyl and C3-6 cycloalky 1 ;

[0210] In some embodiments R3is hydrogen.

[0211] In some embodiments R3is halogen.

[0212] In some embodiments R3is C1-6 alkyl.

[0213] In some embodiments R3is C1-4 fluoroalkyl

[0214] In some embodiments R3is C1-4 cyano.

[0215] In some embodiments R3is -CHF2.

[0216] In some embodiments R3is -CF2CH3.

[0217] In some embodiments Rais -CH2F.

[0218] In some embodiments Rais -CF3.

[0219] In some embodiments Rais -OCF3.

[0220] In some embodiments Rais Ci-3alkyl.

[0221] In some embodiments Rais C3-6cycloalkyl.

[0222] In some embodiments Rbis hydrogen.

[0223] In some embodiments Rbis halogen.

[0224] In some embodiments Rbis Ci-6 alkyl.

[0225] In some embodiments Rbis Ci-4 fluoroalkyl.

[0226] In some embodiments Rbis cyano.

[0227] In some embodiments Rbis -CHF2.

[0228] In some embodiments Rbis -CF2CH3.

[0229] In some embodiments Rbis -CH2F.

[0230] In some embodiments Rbis -CF3.

[0231] In some embodiments Rbis -OCF3.

[0232] In some embodiments Rbis Ci salkyl.

[0233] In some embodiments Rbis Cs-ecycloalkyl.

[0234] In some embodiments Rcis hydrogen

[0235] In some embodiments Rcis halogen.

[0236] In some embodiments Rcis C1-6 alkyl.

[0237] In some embodiments Rcis C1-4 fluoroalkyl.

[0238] In some embodiments Rcis cyano.

[0239] In some embodiments Rcis -CHF2.

[0240] In some embodiments Rcis -CF2CH3.

[0241] In some embodiments Rcis -CH2F.

[0242] In some embodiments Rcis -CF3.

[0243] In some embodiments Rcis -OCF3.

[0244] In some embodiments Rcis Ci-3alkyl.

[0245] In some embodiments Rcis Cs-ecycloalkyl.

[0246] In some embodiments Rdis hydrogen.

[0247] In some embodiments Rdis halogen.

[0248] In some embodiments Rdis C1-6 alkyl.

[0249] In some embodiments Rdis C1-4 flouroalkyl.

[0250] In some embodiments Rdis cyano.

[0251] In some embodiments Rdis -CHF2.

[0252] In some embodiments Rdis -CF2CH3.

[0253] In some embodiments Rdis -CH2F.

[0254] In some embodiments Rdis -CF3.

[0255] In some embodiments Rdis -OCF3.

[0256] In some embodiments Rdis Ci-3alkyl.

[0257] In some embodiments Rdis Cs-ecycloalkyl.

[0258] In some embodiments Reis hydrogen.

[0259] In some embodiments Reis halogen.

[0260] In some embodiments Reis C1-6 alkyl.

[0261] In some embodiments Reis C1-4 flouroalkyl.

[0262] In some embodiments Reis cyano.

[0263] In some embodiments Reis -CHF2.

[0264] In some embodiments Reis -CF2CH3.

[0265] In some embodiments Reis -CH2F.

[0266] In some embodiments Reis -CFs.

[0267] In some embodiments Reis -OCF3.

[0268] In some embodiments Reis Ci-3alkyl.

[0269] In some embodiments Reis Cs-ecycloalkyl.

[0270] In some embodiments R4is hydrogen.

[0271] In some embodiments R4is halogen.

[0272] In some embodiments R4is C1-6 alkyl.

[0273] In some embodiments R4is C3-7 branched alkyl.

[0274] In some embodiments R4is C1-4 flouroalkyl.

[0275] In some embodiments R4is C3-7 branched fluoroalkyl.

[0276] In some embodiments R4is -CN.

[0277] In some embodiments R4is -CHF2.

[0278] In some embodiments R4is -CF2CH3.

[0279] In some embodiments R4is -CH2F.

[0280] In some embodiments R4is -CF3.

[0281] In some embodiments R4is C2-3alkenyl.

[0282] In some embodiments R4is Cs-scycloalkyl.

[0283] In some embodiments R4is Ci-3alkyl.

[0284] In some embodiments R4is Ci-3alkyl that is substituted with methoxy.

[0285] In some embodiments R4is -O-Ci-6alky.

[0286] In some embodiments R4is -O-C i-salkyl that is substituted with moieties selected from the group consisting of halogen. -CHF 2. -CF2-methyL -CH2E -CF3, - OCF3, and -CN.

[0287] In some embodiments R2aand R4are taken together with the atoms to which they are bound to form a 6 membered ring.

[0288] In some embodiments R2aand R4are taken together with the atoms to which they are bound to form a 7 membered ring.

[0289] In some embodiments R23and R4are taken together with the atoms to which they are bound to form a 8 membered ring.

[0290] In some embodiments R2aand R4are taken together with the atoms to w hich they are bound to form a 9 membered ring.

[0291] In some embodiments R4ais hydrogen.

[0292] In some embodiments R4ais halogen.

[0293] In some embodiments R4ais C1-6 alky l.

[0294] In some embodiments R4ais C3-7 branched alkyl.

[0295] In some embodiments R4ais C1-4 haloalkyl.

[0296] In some embodiments R4ais C3-7 branched fluoroalkyl.

[0297] In some embodiments R5is hydrogen.

[0298] In some embodiments R5is C1-4 alkyl.

[0299] In some embodiments

[0300] In some embodiments R6is hydrogen.

[0301] In some embodiments R6is C1-4 alkyl.

[0302] In some embodiments m is 1.

[0303] In some embodiments m is 2.

[0304] In some embodiments m is 3.

[0305] In some embodiments m is 4.

[0306] In some embodiments m is 5.

[0307] In some embodiments m is 6.

[0308] In some embodiments m is 7.

[0309] In some embodiments m is 8.

[0310] In some embodiments n is 1.

[0311] In some embodiments n is 2.

[0312] In some embodiments n is 3.

[0313] In some embodiments n is 4.

[0314] In some embodiments n is 5.

[0315] In some embodiments n is 6.

[0316] In some embodiments n is 7.

[0317] In some embodiments n is 8.

[0318] In some embodiments q is 1.

[0319] In some embodiments q is 2.

[0320] In some embodiments q is 3.

[0321] In some embodiments q is 4.

[0322] In some embodiments q is 5.

[0323] In some embodiments q is 6.

[0324] In some embodiments q is 7.

[0325] In some embodiments q is 8.

[0326] In some embodiments u is 1.

[0327] In some embodiments u is 2.

[0328] In some embodiments u is 3.

[0329] In some embodiments u is 4.

[0330] In some embodiments u is 5.

[0331] In some embodiments u is 6.

[0332] In some embodiments u is 7.

[0333] In some embodiments u is 8.

[0334] In some embodiments x is 1.

[0335] In some embodiments x is 2.

[0336] In some embodiments x is 3.

[0337] In some embodiments x is 4.

[0338] In some embodiments x is 5.

[0339] In some embodiments x is 6.

[0340] In some embodiments x is 7.

[0341] In some embodiments x is 8.

[0342] In some embodiments z is 1.

[0343] In some embodiments z is 2.

[0344] In some embodiments z is 3.

[0345] In some embodiments z is 4.

[0346] In some embodiments z is 5.

[0347] In some embodiments z is 6.

[0348] In some embodiments z is 7.

[0349] In some embodiments z is 8.

[0350] In some embodiments e is 1.

[0351] In some embodiments e is 2.

[0352] In some embodiments e is 3.

[0353] In some embodiments e is 4.

[0354] In some embodiments e is 5.

[0355] In some embodiments e is 6.

[0356] In some embodiments e is 7.

[0357] In some embodiments e is 8.

[0358] Compounds of the present invention, in certain embodiments, include compounds having the formula (XVI) or a pharmaceutically acceptable salt form thereof:

[0359]

[0360] wherein non-limiting examples of R3, R5and X1are defined herein below inTable 1.

[0361] Table 1: Exemplary' compound of the structure (XVI)

[0362] Compounds of the present invention, in certain embodiments, include compounds having the formula (XVII) or a pharmaceutically acceptable salt form thereof:

[0364] wherein non-limiting examples of R1, R3and X1are defined herein below inTable 2.

[0365] Table 2: Exemplary' compound of the structure (XVII)

[0366] Compounds of the present invention, in certain embodiments, include compounds having the formula (XVIII) or a pharmaceutically acceptable salt form

[0368] wherein non-limiting examples of R1, R2, R2a, R3, and R5are defined herein below in Table 3.

[0369] Table 3: Exemplary compound of the structure (XVIII)

[0370] Compounds of the present invention, in certain embodiments, include compounds having the formula (XIX) or a pharmaceutically acceptable salt form thereof:

[0372] wherein non-limiting examples of R1, R2, R2a, R3, and R5are defined herein below in Table 4.

[0373] Table 4: Exemplary' compound of the structure (XIX)

[0374] For the purposes of demonstrating the manner in which the compounds of the present invention are named and referred to herein, the compound having the formula:

[0375]

[0376] has the chemical name (R)-N-(3,4-difluorophenyl)-3-fluoro-l-(2-fluoroethyl)-4-(N-(l,l,l-trifluoropropan-2-yl)sulfamoyl)-lH-pyrrole-2-carboxamide.

[0377] For the purposes of demonstrating the manner in which the compounds of the present invention are named and referred to herein, the compound having the formula:

[0378]

[0379] has the chemical name (R)-4-(N-(sec-butyl)sulfamoyl)-l-(cyanomethyl)-N-(3,4-difluorophenyl)-lH-pyrrole-2-carboxamide.

[0380] For the purposes of demonstrating the manner in which the compounds of the present invention are named and referred to herein, the compound having the formula:

[0381]

[0382] has the chemical name (R)-N-(3,4-difluorophenyl)-4-fluoro-l-(2-fluoroethyl)- 3-(N-(l,l,l-trifluoropropan-2-yl)sulfamoyl)-lH-pyrazole-5-carboxamide.

[0383] For the purposes of demonstrating the manner in which the compounds of the present invention are named and referred to herein, the compound having the formula:

[0384]

[0385] has the chemical name (R)-3-(N-(sec-butyl)sulfamoyl)-l-(cyanomethyl)-N- (3,4-difluorophenyl)-lH-pyrazole-5-carboxamide.

[0386] For the purposes of the present invention, a compound depicted by the racemic formula, for example:

[0387]

[0388] will stand equally well for either of the two enantiomers having the formula:

[0392] or mixtures thereof, or in the case where a second chiral center is present, all diastereomers.

[0393] In all of the embodiments provided herein, examples of suitable optional substituents are not intended to limit the scope of the claimed invention. The compounds of the invention may contain any of the substituents, or combinations of substituents, provided herein.

[0394] PROCESS

[0395] Aspects of the present invention further relate to a process for preparing the pregenomic RNA encapsidation inhibitors according to aspects of the present invention.

[0396] Compounds of the present teachings can be prepared in accordance with the procedures outlined herein, from commercially available starting materials, compounds known in the literature, or readily prepared intermediates, by employing standard synthetic methods and procedures known to those skilled in the art. Standard synthetic methods and procedures for the preparation of organic molecules and functional group transformations and manipulations can be readily obtained from the relevant scientific literature or from standard textbooks in the field. It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions can vary’ with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures. Those skilled in the art of organic synthesis will recognize that the nature and order of the synthetic steps presented can be varied for the purpose of optimizing the formation of the compounds described herein.

[0397] The processes described herein can be monitored according to any suitable method known in the art. For example, product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g.,JH or 1?C), infrared spectroscopy, spectrophotometry' (e.g., UV-visible), mass spectrometry, or by chromatography such as high pressure liquid chromatograpy (HPLC), gas chromatography (GC), gel-permeation chromatography (GPC), or thin layer chromatography (TLC).

[0398] Preparation of the compounds can involve protection and deprotection of various chemical groups. The need for protection and deprotection and the selection of appropriate protecting groups can be readily determined by one skilled in the art. The chemistry of protecting groups can be found, for example, in Greene et al., Protective Groups in Organic Synthesis, 2d. Ed. (Wiley & Sons, 1991), the entire disclosure of which is incorporated by reference herein for all purposes.

[0399] The reactions or the processes described herein can be carried out in suitable solvents which can be readily selected by one skilled in the art of organic synthesis.Suitable solvents typically are substantially nonreactive with the reactants, intermediates, and / or products at the temperatures at which the reactions are carried out, i.e., temperatures that can range from the solvent’s freezing temperature to the solvent’s boiling temperature. A given reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the particular reaction step, suitable solvents for a particular reaction step can be selected.

[0400] The compounds of these teachings can be prepared by methods known in the art of organic chemistry. The reagents used in the preparation of the compounds of these teachings can be either commercially obtained or can be prepared by standard procedures described in the literature. For example, compounds according to aspects of the present invention can be prepared according to the method illustrated in the General Synthetic Schemes.

[0401] GENERAL SYNTHETIC SCHEMES FOR PREPARATION OF COMPOUNDS.

[0402] The reagents used in the preparation of the compounds of this invention can be either commercially obtained or can be prepared by standard procedures described in the literature. In accordance with this invention, compounds in the genus may be produced by one of the following reaction schemes.

[0403] Compounds of formula (I) may be prepared according to the process outlined in schemes 1-9.Scheme 1

[0405] Accordingly, a suitably substituted compound of the formula (1), a known compound or compound prepared by known methods wherein Z1is a Ci-6 alkyl, is reacted with a compound of the formula (2) wherein LG is a leaving group such as chlorine, bromine, iodine, tosylate, mesylate, and the like, in the presence of a base such as sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, and the like, in a solvent such as methylene chloride, 1,2-di chloroethane, tetrahydrofuran, 1,4-di oxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (3). A compound of the formula (3)is reacted with sulfurochloridic acid optionally in the presence of a solvent such as methylene chloride, 1 ,2-di chloroethane, tetrahydrofuran, 1,4-di oxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (4).

[0407] A compound of the formula (4) is reacted with thionyl chloride, optionally in the presence of a solvent such as methylene chloride, 1 ,2-di chloroethane, tetrahydrofuran, 1.4-di oxane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (5). A compound of the formula (5) is reacted with a compound of the formula (6), a know n compound or a compound prepared by known methods, optionally in the presence of a base such as triethylamine, N.N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1 ,2-di chloroethane, tetrahydrofuran, 1,4-di oxane, acetonitrile, 1,2-dimethoxy ethane, and the like, optionally with heating, optionally w ith microwave irradiation to provide a compound of the formula (7).

[0408]

[0409] A compound of the formula (7) is reacted with a base such as sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, and the like, in a solvent such as methylene chloride, 1 ,2-di chloroethane, tetrahydrofuran, 1,4-di oxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microw ave irradiation to provide a compound of the formula (8). A compound of the formula (8) is reacted with a compound of the formula (9), a known compound or compound prepared by known methods, in the presence of a coupling agent such as di cyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, O-Benzotriazole-N,N,N’,N’- tetramethyl-uronium-hexafluoro-phosphate, O-(7-azabenzotriazol-l-yl)-N,N.N',N'- tetramethyluronium hexafluorophosphate, Benzotriazole-1 -yl-oxy-tris- (dimethylamino)-phosphonium hexafluorophosphate, benzotriazol- 1 -yl- oxytripyrrolidinophosphonium hexafluorophosphate, and the like, optionally in the presence of hydroxy benzotriazole, optionally in the presence of a base such as triethylamine, N.N-diisopropylethylamine, pyridine. 2,6-dimethylpyridine, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1,2-dimethoxy ethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (10).Scheme 4

[0410]

[0411] A compound of the formula (11), a known compound or a compound prepared by known methods wherein Z2is a Cl -6 alkyl, is reacted with sulfurochloridic acid optionally in the presence of a solvent such as methylene chloride, 1,2-di chloroethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microw ave irradiation to provide a compound of the formula (12). A compound of the formula (12) is reacted w ith a compound of the formula (13) n the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and the like, in the presence of a solvent such as N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, methylene chloride, chloroform, 1 ,2-di chloroethane, tetrahydrofuran, 1,4-dioxane. acetonitrile, 1,2- dimethoxyethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (14).

[0413] A compound of the formula (14) is reacted with a compound of the formula (15) wherein LG1is a leaving group such as chlorine, bromine, iodine, tosylate, mesylate, and the like, in the presence of a base such as sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, and the like, in a solvent such as methylene chloride, 1.2-di chloroethane, tetrahydrofuran, 1.4-di oxane, methanol, ethanol, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide. and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (16). A compound of the formula (16) is reacted with a base such as sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, and the like, in a solvent such as methylene chloride, 1,2-di chloroethane, tetrahydrofuran, 1,4-di oxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (17).

[0415] A compound of the formula (18) is reacted with a base such as sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, and the like, in a solvent such as methylene chloride, 1 ,2-di chloroethane, tetrahydrofuran, 1,4-di oxane, methanol, ethanol, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (19). A compound of the formula (19) is reacted with a compound of the formula (20). a known compound or compound prepared by know n methods, in the presence of coupling agent such as di cyclohexylcarbodiimide, 1- ethyl-3-(3-dimethylaminopropyl)carbodiimide, O-Benzotriazole-N,N,N’,N’- tetramethyl-uronium-hexafluoro-phosphate, O-(7-azabenzotriazol-l-yl)-N,N,N',N'- tetramethyluronium hexafluorophosphate, Benzotri azole- 1 -yl-oxy-tris- (dimethy lamino)-phosphonium hexafluorophosphate, benzo triazol- 1 -yl- oxytripyrrolidinophosphonium hexafluorophosphate, and the like, optionally in thepresence of hydroxy benzotriazole, optionally in the presence of a base such as triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, in the presence of a solvent such as methylene chloride, chloroform, 1,2- dichloroethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, 1 ,2-dimethoxy ethane, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (21).

[0416]

[0417] A compound of the formula (21) is reacted with a compound of the formula(22) wherein LG2is a leaving group such as chlorine, bromine, iodine, tosylate, mesylate, and the like, in the presence of a base such as sodium carbonate, lithium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, and the like, in a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, 1.4-di oxane, methanol, ethanol, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (23).Scheme 8

[0419] A compound of the formula (24) is reacted with a compound of the formula (25) in the presence of a solvent such as methylene chloride, 1 ,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, dimethylsulfoxide, N,N- dimethylacetamide, and the like, in the presence of a base such as 1,8- diazabicyclo[5.4.0]undec-7-ene, triethylamine, N,N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (26).

[0420]

[0421] A compound of the formula (27) is reacted with cesium fluoride in the presence of a solvent such as tetrahydrofuran, 1,4-dioxane, methanol, ethanol, N,N- dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (28).Scheme 10

[0422]

[0423] A compound of the formula (29) is reacted with a ruthenium catalyst such as benzylidene-bis(tricyclohexylphosphine)dichlororuthenium, (1,3-Bis(2,4,6- trimethylphenyl)-2-imidazolidinylidene)dichloro(phenylmethylene)(tri cyclohexyl phosphine)ruthenium, (l,3-bis-(2,4,6-trimethylphenyl)-2- imidazolidinylidene)dichloro(o-isopropoxy phenylmethylene)ruthenium, dichloro(2- isopropoxyphenylmethylene) (tricyclohexylphosphine) ruthenium(II), [1 ,3-bis(2- methylphenyl)-2-imidazolidinylidene] dichloro(phenylmethylene)(tricyclohexyl phosphine) ruthenium(II), dichloro[l,3-bis(2,4,6-trimethylphenyl)-2- imidazolidinylidene](benzylidene) bis(3-bromopyridine) ruthenium(II), dichloro[l,3- bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene](3-methyl-2-butenylidene) (tricy clohexylphosphine)ruthenium(II), dichlorofl ,3-bis(2-methyl phenyl)-2- imidazolidinylidene](2-isopropoxyphenylmethylene)ruthenium(II), [l,3-dimesityl-2- imidazolidinylidene] dichloro[3-(2-pyridinyl)propylidene]ruthenium(II), dichloro[l,3- bis(2,6-isopropylphenyl)-2-imidazolidinylidene](2-isopropoxyphenyl methylene)ruthenium(II), dichloro(tricyclohexylphosphine) [(tricyclohexylphosphoranyl) methylidene] ruthenium tetrafl uoroborate, dichloro[l,3- bis(2.4.6-trimethyl phenyl)-2- imidazolidinylidene] [(tricyclohexylphosphoranyl)methylidene]ruthenium(II)tetrafluoroborate. [2-(l-methylethoxy-O)phenylmethyl-C](nitrato-O,O'){rel- (2R,5R,7R)-adamantane-2,l-diyl[3-(2.4.6-trimethylphenyl)-l-imidazolidinyl-2- ylidene] } ruthenium, dichloro[l,3-bis(2,6-isopropylphenyl)-2- imidazolidinylidene](benzylidene)(tricyclohexyl phosphine)ruthenium(II), [1 ,3-bis(2- methylphenyl)-2-imidazolidinylidene]dichloro (phenylmethylene)(tricyclohexylphosphine)ruthenium(II), dichloro[l,3-bis(2,4,6- trimethylphenyl)-2-imidazolidinylidene][3-(2-pyridinyl)propylidene]ruthenium(II), and the like in the presence of a solvent such as methylene chloride, 1,2- di chloroethane, tetrahydrofuran, 1,4-di oxane, 1 ,2-dimethoxy ethane, 1,2- diethoxyethane, N,N-dimethyl formamide, N,N-dimethylacetamide, dimethylsulfoxide, and the like, optionally with heating, optionally with microwave irradiation to provide a compound of the formula (30). A compound of the formula (30) is reacted with hydrogen gas in the presence of a palladium catalyst such as palladium on carbon, palladium on barium sulfate, palladium (II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis (triphenylphosphine) palladium(II), palladium on carbon, bis(acetonitnle)dichloropalladium(II), and the like, in an organic solvent such as methanol, ethanol, ethyl acetate, tetrahydrofuran, 1,4-di oxane, dichloromethane, chloroform, 1 ,2-di chloroethane, N,N- dimethylformamide, and the like, optionally with heating, to provide a compound of the formula (31).

[0424] The Examples provided below provide representative methods for preparing exemplary compounds according to aspects of the present invention. The skilled practitioner will know how to substitute the appropriate reagents, starting materials and purification methods known to those skilled in the art, in order to prepare the compounds according to aspects of the present invention.

[0425] The following LC / MS procedure was used for the analysis of the examples described herein. LC / MS data were determined with a Waters Alliance 2695 HPLC / MS (Waters Symmetry Cis. 4.6 x 75 mm, 3.5 pm) with a 2996 diode array detector from 210-400 nm; the solvent system is 5-95% acetonitrile in water (with 0.1% trifluoroacetic acid) over nine minutes using a linear gradient, and retention times are in minutes. Mass spectrometry was performed on a Waters ZQ using electrospray in positive mode.

[0426] Preparative reverse phase HPLC was performed on a Phenomenex LUNA column (19 x 100 mm, Cis, 5 pm) with a 10 minute mobile phase gradient of 10%acetonitrile / water to 90% acetonitrile / water with 0. 1% trifluoroacetic acid as buffer using 214 and 254 nm as detection wavelengths. Injection and fraction collection were performed with a Gilson 215 liquid handling apparatus using Trilution LC software.

[0427] 'H-NMR's were taken on a Varian 300 or 400 MHz NMR using tetramethylsilane (TMS) as internal standard (5 = 0.00) with peaks reported downfield from TMS.

[0428] The examples provided methods for preparing representative compounds of formulas (I) through (XIX). The skilled practitioner will know how to substitute the appropriate reagents, starting materials and purification methods known to those skilled in the art, in order to prepare additional compounds according to aspects of the present invention.

[0429] Examples 1-65 provide methods for preparing representative compounds of formula (I). The skilled practitioner will know' how to substitute the appropriate reagents, starting materials and purification methods known to those skilled in the art, in order to prepare additional compounds according to aspects of the present invention.

[0430] Example 1 Synthesis of (R)-N-(3,4-difluorophenyl)-3-fluoro-l-(2- fluoroethy l)-4-(N-( 1,1,1 -trifluoropropan-2-y l)s ulfamoy 1)- IH-py rrole-2-carboxamide

[0432] Step 1 : Synthesis of ethyl 3 -fluoro- 1 -(2 -fluoroethyl)- lH-pyrrole-2- carboxylate: A solution of ethyl 3-fluoro-lH-pyrrole-2-carboxylate (12.0 g, 76.4 mmol, 1.00 eq) and CS2CO3 (49.7 g, 153 mmol, 2.00 eq) in N,N-dimethylformamide (100 mL) under nitrogen was cooled to 0 °C and 1 -fluoro-2-iodo-ethane (19.9 g, 115 mmol, 1.50 eq) was added while maintaining the reaction temperature between 0 °C and 10 °C. The reaction mixture was stirred at 20 °C for 16 hours and a white suspension was obtained. The reaction mixture was quenched by addition water 800 mL, then extracted with ethyl acetate (100 mL x 3). The combined organic phase was washed with brine (50.0 mL x 1), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by flash silica gel chromatography (0% to 5% Ethyl acetate / Petroleum ether gradient) which provided ethyl 3-fluoro-l-(2-fluoroethyl)-lH-pyrrole-2-carboxylate as a light yellow oil.JH NMR: 400 MHz, Chloroform-^ 5 6.69 (dd, J= 4.57. 3.44 Hz, 1 H) 5.89 (d, J= 3.13 Hz, 1 H) 4.68 - 4.72 (m, 1 H) 4.56 (dt, J= 14.16, 4.49 Hz, 2 H) 4.46 - 4.49 (m, 1 H) 4.30 (q, J= 7. 13 Hz, 2 H) 1.35 (t, J = 7.13 Hz, 3 H); HPLCMS: MS (ESI) m z = 204.1 [M+H]+.

[0434] Step 2: Synthesis of 5-(ethoxycarbonyl)-4-fluoro-l-(2-fluoroethyl)-lH- pyrrole-3-sulfonic acid: A solution of ethyl 3-fluoro-l-(2-fluoroethyl)-lH-pyrrole-2- carboxylate (5.00 g, 24.6 mmol, 1.00 eq) in methylene chloride (50.0 mL) under nitrogen was cooled to 0 °C and sulfurochloridic acid (3.73 g, 32.0 mmol, 2.13 mL, 1.30 eq) in methylene chloride (25.0 mL) was added while maintaining the reaction temperature between 0 °C and 5 °C. The reaction mixture was then stirred at 0 °C for 3 hours under nitrogen and a brown suspension was obtained. The reaction mixture was concentrated under reduced pressure to obtain 5-(ethoxycarbonyl)-4-fluoro-l-(2- fluoroethyl)-lH-pyrrole-3-sulfonic acid as a brown oil which was used without further purification. 'H NMR: 400 MHz, Chloroform- S 9.93 - 10.91 (m, 6 H) 8.30 - 8.75 (m. 2 H) 7. 19 - 7.26 (m, 1 H) 4.68 - 4.75 (m, 1 H) 4.48 - 4.63 (m. 4 H) 4.33 (q. J = 7.13 Hz, 3 H) 3.65 - 3.67 (m, 1 H) 1.36 (br t, J= 6.94 Hz, 3 H); HPLCMS: MS (ESI) m'z - 301.1 [M+H]+.

[0436] Step 3: Synthesis of ethyl 4-(chlorosulfonyl)-3-fluoro-l-(2-fluoroethyl)-lH- pyrrole-2-carboxylate: A solution of 5-(ethoxycarbonyl)-4-fluoro-l-(2-fluoroethyl)- lH-pyrrole-3-sulfonic acid (7.80 g, 27.5 mmol, 1.00 eq) in SOCh (98.3 g, 826 mmol, 59.9 mL, 30.0 eq) was stirred at 80 °C for 6 hours under N2. The green mixture was allowed to cool and was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (0% to 20% Ethyl acetate / Petroleum ether gradient) to provide ethyl 4-(chlorosulfonyl)-3-fluoro-l-(2-fluoroethyl)-lH-pyrrole-2- carboxylate (6.30 g, 20.9 mmol, 75.8% yield) as a light yellow^ solid. 'H NMR: 400MHz, Chloroform-^ 5 7.39 (d, J= 3.63 Hz, 1 H) 4.76 - 4.79 (m, 1 H) 4.64 - 4.69 (m, 2H) 4.60 - 4.63 (m, 1 H) 4.38 (q, J= 7. 13 Hz. 2 H) 1.40 (t, J= 7.13 Hz, 3 H);HPLCMS: MS (ESI) m / z = 373.4 [M+H]+

[0437]

[0438] Step 4: Synthesis of ethyl (R)-3-fluoro- l-(2-fluoroethyl)-4-(N-( 1,1,1- trifluoropropan-2-yl)sulfamoyl)-lH-pyrrole-2-carboxylate: To a solution of ethyl 4- (chlorosulfonyl)-3-fluoro-l-(2-fluoroethyl)-lH-pyrrole-2-carboxylate (6.30 g, 20.9 mmol, 1.00 eq) and pyridine (4.96 g, 62.6 mmol, 5.06 mL, 3.00 eq) in acetonitrile (85.0 rnL) under nitrogen was added (R)- 1,1,1 -trill uoropropan-2-amine (5.00 g, 33.4 mmol, 1.60 eq) and 4-dimethylaminopyridine (383 mg, 3.13 mmol, 0.15 eq). The reaction mixture was stirred at 85 °C for 20 hours and yellow solution was obtained. The reaction mixture was allowed to cool and was then concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (0% to 30% Ethyl acetate / Petroleum ether gradient) to provide ethyl (R)-3-fluoro-l-(2- fluoroethyl)-4-(N-(l.l.l-trifluoropropan-2-yl)sulfamoyl)-lH-pyrrole-2-carboxylate as a light yellow solid. 'H NMR: 400 MHz, Chloroform- 5 7.20 (d, J= 4.25 Hz, 1 H) 4.80 (d, J= 9.63 Hz, 1 H) 4.70 - 4.75 (m, 1 H) 4.61 (t, J= 4.38 Hz, 2 H) 4.52 - 4.56 (m, 1 H) 4.34 (q, J= 7.13 Hz, 2 H) 3.98 - 4.10 (m, 1 H) 1.35 - 1.40 (m, 7 H);HPLCMS: MS (ESI) m / z = 379.2 [M+H]+.

[0439]

[0440] Step 5: Synthesis of (R)-3 -fluoro- l-(2-fluoroethyl)-4-(N-( 1.1.1- trifluoropropan-2-yl)sulfamoyl)-lH-pyrrole-2-carboxylic acid: A solution of ethyl (R)-3-fluoro-l-(2-fluoroethyl)-4-(N-(l,l,l-trifluoropropan-2-yl)sulfamoyl)-lH- pyrrole-2-carboxylate (3.00 g, 7.93 mmol, 1.00 eq) and LiOH H2O (998 mg, 23.8 mmol, 3.00 eq) in in tetrahydrofuran (24.0 rnL) and H2O (8.00 mL) was stirred at 20 °C for 16 hours. The reaction mixture was concentrated under reduced pressure to remove tetrahydrofuran, 40 mL water was added, and the pH was adjusted pH = 3with 1 M HC1. Then resulting suspension was filtered to provide (R)-3-fluoro-l-(2- fluoroethyl)-4-(N-(LLI-trifluoropropan-2-yl)sulfamoyl)-IH-pyrrole-2-carboxylic acid as a white solid. 'H NMR: 400 MHz, DMSO-ak 5 8.65 (d, J= 8.76 Hz, 1 H) 7.61 (d, J= 4.63 Hz, 1 H) 4.68 - 4.77 (m, 1 H) 4.54 - 4.66 (m, 3 H) 3.96 (dq, J= 15.34, 7.52 Hz, 1 H) 1.14 (d, J= 7.00 Hz, 3 H); HPLCMS: MS (ESI) m,z = 235.2 [M+H]+.

[0441]

[0442] Step 5: Synthesis of (R)-N-(3,4-difluorophenyl)-3-fluoro-l-(2-fluoroethyl)-4- (N-( 1 , 1 , 1 - trifl uoropropan-2-yl)sulfamoy 1)- 1 H-pyrrole-2-carboxamide: (R)-3 -fluoro- 1 - (2-fluoroethyl)-4-(N-(l,l,l-tnfluoropropan-2-yl)sulfamoyl)-lH-pyrrole-2-carboxyhc acid (300 mg, 0.86 mmol, 1.00 eq), hydroxybenzotriazole (139 mg, 1.03 mmol, 1.20 eq), l-ethyl-3-(3-dimethylaminopropyl)carbodiimide HC1 (197 mg, 1.03 mmol, 1.20 eq) and N,N-diisopropylethylamine (553 mg, 4.28 mmol, 0.75 mL, 5.00 eq) were dissolved in methylene chloride (9.00 mL) and 3,4-difluoroaniline(166 mg. 1.28 mmol, 1.50 eq) was added. The reaction mixture was stirred at 40 °C for 10 hours. The reaction mixture was then cooled and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (0% to 40% Ethyl acetate / Petroleum ether gradient) to obtained (R)-N-(3,4-difluorophenyl)-3-fluoro-l- (2-fluoroethyl)-4-(N-(l,l,l-trifluoropropan-2-yl)sulfamoyl)-lH-pyrrole-2- carboxamide as a white solid. 'H NMR: 400 MHz, DMSO-tL 5 10.38 (s, 1 H) 8.68 (d, J= 8.51 Hz, 1 H) 7.76 - 7.85 (m, 1 H) 7.59 (d, J = 4.50 Hz, 1 H) 7.37 - 7.47 (m, 2 H) 4.72 (t, J= 4.50 Hz, 1 H) 4.58 - 4.63 (m, 2 H) 4.51 - 4.56 (m, 1 H) 3.93 - 4.06 (m, 1 H) 1.18 (d. J= 7.00 Hz, 3 H); HPLCMS: MS (ESI) mz = 462.3 [M+H]+.

[0443] Example 2: Synthesis of (R)-4-(N-(sec-butyl)sulfamoyl)-N-(3-chloro-4- fluorophenyl)-l-(2-fluoroethyl)-lH-pyrrole-2-carboxamide

[0445] Step 1 : Synthesis of Methyl 4-(chlorosulfonyl)-lH-pyrrole-2-carboxylate:Methyl lH-pyrrole-2-carboxylate (2 g. 0.015 mol) was added to chlorosulfuric acid(8.5 mL, 0.127 mol) at 0 °C, and the reaction mixture was stirred at 22 °C for 4 hours. The reaction was then cooled to 0 °C and then quenched by adding ice water. The mixture was filtered and the resulting solid was dissolved in CH2CI2 The solution was then dried over Na2SC>4„ filtered and the solvent was removed under reduced pressure to provide Methyl 4-(chlorosulfonyl)-lH-pyrrole-2-carboxylate as an off-white solid, which was used for the next step without further purification.JH NMR (300 MHz, CDCh): 5 (ppm) 10.13 (br. s„ 1 H), 7.65 - 7.68 (m, 1 H), 7.32 - 7.35 (m, 1 H), 3.94 (s, 224.4. [M+H]+

[0447] Step 2: Synthesis of (R)-Methyl 4-(N-(sec-butyl)sulfamoyl)-lH-pyrrole-2- carboxylate: A solution of (R)-butan-2-amine (0.076 mL, 0.751 mmol) and triethylamine (0.209 mL, 1.502 mmol) in anhydrous CH2CI2 (5 mL) was stirred at 0 °C for 20 minutes. Methyl 4-(chlorosulfonyl)-lH-pyrrole-2-carboxylate (2, 168 mg, 0.751 mmol) was added and the resulting reaction mixture was warmed to 22 °C and stirred for 18 hours. The reaction mixture was then diluted with CH2CI2, washed with brine solution. The organic layer was dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by flash silica gel chromatography (0-40% ethyl acetate in hexanes gradient) to provide (R)-Methyl 4-(N-(sec-butyl)sulfamoyl)-lH- pyrrole-2-carboxylate as white solid. 'H NMR (300 MHz, CDCh): 5 (ppm) 9.78 (br.s., 1 H), 7.45 (dd, J = 3.22, 1.47 Hz, 1 H), 7.14 (dd, J = 2.93, 1.76 Hz, 1 H), 4.48 (d, J = 7.62 Hz, 1 H), 3.89 (s, 3 H), 3.19 - 3.32 (m, 1 H), 1.37 - 1.50 (m, 2 H), 1.08 (d, .7= 7.03 Hz, 3 H), 0.84 (t, J = 7.33 Hz, 3 H); HPLCMS: MS (ESI) m / z = 261.5 [M+H]+.

[0449] Step 3: Synthesis of (R)-Methyl 4-(N-(sec-butyl)sulfamoyl)-l-(2-fluoroethyl)- lH-pyrrole-2-carboxylate: A solution of (R)-Methyl 4-(N-(sec-butyl)sulfamoyl)-lH- pyrrole-2-carboxylate (3, 60 mg, 0.23 mmol) in anhydrous N,N-dimethylformamide(2.5 mL) was treated with CS2CO3 (149 mg, 0.46 mmol). After stirring the reaction mixture at 22 °C for 15 minutes, 1 -fluoro-2-iodoethane (0.037 mL, 0.46 mmol) was added. The reaction mixture was stirred at 22 °C for 18 hours, quenched with ice water and extracted with ethyl acetate. The organic fraction was washed with brine solution, dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified by flash silica gel chromatography (0-40% ethyl acetate in hexanes gradient) to provide (R)-Methyl 4-(N-(sec-butyl)sulfamoyl)-l-(2-fluoroethyl)-lH-pyrrole-2- carboxylate as a colorless liquid.NMR (300 MHz, CDCI3): 5 (ppm) 7.38 - 7.40 (m, 1 H), 7.23 (d, J= 1.76 Hz, 1 H), 4.74 - 4.79 (m, 1 H), 4.67 - 4.71 (m, 1 H), 4.60 (s, 2 H), 4.38 (d. J= 7.62 Hz, 1 H), 3.83 (s, 3 H), 3.18 - 3.30 (m, 1 H), 1.43 (quin, J= 7.18 Hz. 2 H). 1.08 (d, J= 7.03 Hz. 3 H). 0.80 - 0.87 (m, 3 H); HPLCMS: MS (ESI) m / z = 307.4

[0450]

[0451] Step 4: Synthesis of (R)-4-(N-(sec-butyl)sulfamoyl)-l-(2-fluoroethyl)-lH- pyrrole-2-carboxylic acid: A solution of (R)-Methyl 4-(N-(sec-butyl)sulfamoyl)-l-(2- fluoroethyl)-lH-pyrrole-2-carboxylate (46 mg, 0.15 mmol) in tetrahydrofuran (3 mL) was treated with LiOH H2O (1 M) (0.450 mL. 0.450 mmol). The resulting reaction mixture was stirred at 22 °C for 24 hours. The reaction mixture was acidified to a pH of 3.0 by the slow addition of aqueous 1 N HC1 and extracted with ethyl acetate. The organic portions were washed with saturated aqueous NaCl, dried over Na2SO4, filtered, evaporated under reduced pressure. The residue was dried under vacuum 18 hours to (R)-4-(N-(sec-butyl)sulfamoyl)-l-(2-fluoroethyl)-lH-pyrrole-2-carboxylic acid as a colorless gum which was used without further purification. HPLCMS: MS (ESI) m / z = 293.6 [M+H]+.

[0453] Step 5: Synthesis of (R)-4-(N-(sec-butyl)sulfamoyl)-N-(3-chloro-4- fluorophenyl)-l-(2-fluoroethyl)-lH-pyrrole-2-carboxamide: A solution of (R)-4-(N- (sec-butyl)sulfamoyl)-l-(2-fluoroethyl)-lH-pyrrole-2-carboxylic acid (20 mg, 0.068 mmol) in anhydrous CH2CI2 (1.2 mL), was treated with l-ethyl-3-(3- dimethylaminopropyl)carbodiimide HC1 (26 mgr, 0.136 mmol), hydroxybenzotriazole (21 mg, 0.136 mmol), and N,N-diisopropylethylamine (0.035 ml, 0.204 mmol) and stirred at 22 °C for 10 minutes and then 3-chloro-4-fluoroaniline (20 mg, 0. 136 mmol) was added. The resulting reaction mixture was stirred at 22 °C for 24 hours, diluted with ethyl acetate, and washed successively with aqueous saturated NH4CI and aqueous NaCl. The organic portion was dried over Na2SC>4, filtered, and evaporated under reduced pressure. The residue was purified by preparative HPLC (10-90% acetonitrile in water 0.1% trifluoroacetic acid over 30 minutes, Phenomenex Luna LC Column (5 pm C18 100 A, 150 x 21.2 mm)) to provide (R)-4-(N-(sec-butyl)sulfamoyl)-N-(3- chloro-4-fluorophenyl)-l-(2-fluoroethyl)-lH-py rrole-2-carboxamide as white solid. 'H NMR (300 MHz. DMSO-rfc): 5 (ppm) 10.26 (br.s, 1 H), 7.99 (dd, J =6.74, 2.64 Hz, 1 H), 7.63 (ddd, J =8.94, 4.25, 2.64 Hz, 1 H), 7.57 (d, J= 1.76 Hz, 1 H), 7.34 - 7.42 (m, 2 H), 7.20 (d, J= 7.62 Hz, 1 H), 4.75 (br.s., 2 H), 4.63 (dd, J =9.38, 3.52 Hz, 2 H), 3.00 - 3.11 (m, 1 H), 1.32 (quin, J = 7.33 Hz, 2 H), 0.94 (d, J= 7.03 Hz, 3 H), 0.68 - 0.79 (m, 3 H); HPLCMS: MS (ESI) m / z = 420.7 [M+H]+.

[0454] Example 3: Synthesis of (R)-4-(N-(sec-butyl)sulfamoyl)-N-(3,4- difluorophenyl)-l-(2-fluoroethyl)-lH-pyrrole-2-carboxamide

[0456] Synthesis of (R)-4-(N-(sec-butyl)sulfamoyl)-N-(3,4-difluorophenyl)-l-(2-Huoroethyl)-lH-pyrrole-2-carboxamide: A solution of (R)-4-(N-(sec- butyl)sulfamoyl)-l-(2-fluoroethyl)-lH-pyrrole-2-carboxylic acid (23 mg, 0.078 mmol) in anhydrous CH2CI2 (1.2 mL), was treated with l-ethyl-3-(3- dimethylaminopropyl)carbodiimide HC1 (45 mgr, 0.234 mmol), hydroxybenzotriazole (36 mgr, 0.234 mmol), and N,N-diisopropylethylamine (0.068 ml, 0.39 mmol) and stirred at 22 °C for 10 minutes, and then 3,4-difluoroaniline (0.023 ml, 0.234 mmol)was added. The resulting reaction mixture was stirred at 22 °C for 24 hours, diluted with ethyl acetate, and washed successively with aqueous saturated NH4CI and aqueous NaCl. The organic portion was dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified by preparative HPLC (10-90% acetonitrile in water 0.1% trifluoroacetic acid over 30 minutes, Phenomenex Luna LC Column (5 pm C18 100 A, 150 x 21.2 mm)) to provide (R)-4-(N-(sec-butyl)sulfamoyl)-N-(3,4- difluorophenyl)-l-(2-fluoroethyl)-lH-pyrrole-2-carboxamide as white solid.NMR (300 MHz, DMSO-t / e): 5 (ppm) 10.28 (br.s, 1 H), 7.84 (ddd, J=13.48, 7.62, 2.34 Hz, 1 H), 7.57 (d, J= 1.76 Hz, 1 H), 7.39 - 7.48 (m, 2 H), 7.37 (d, J= 1.76 Hz, 1 H), 7.20 (d, J= 7.62 Hz, 1 H), 4.72 - 4.79 (m, 2 H), 4.58 - 4.67 (m, 2 H), 2.98 - 3.13 (m, 1 H), 1.28 - 1.36 (m, 2 H), 0.94 (d, J = 7.03 Hz. 3 H). 0.73 (t. J= 7.33 Hz, 3 H); HPLCMS: MS (ESI) m / z = 404.8 [M+H]+.

[0457] Example 4: Synthesis of (R)-methyl 4-(N-(sec-butyl)sulfamoyl)-l- (difluoromethyl)-lH-pyrrole-2-carboxylate

[0459] Step 1: Synthesis of (R)-methyl 4-(N-(sec-butyl)sulfamoyl)-l- (difluoromethyl)-lH-pyrrole-2-carboxylate: A solution of (R)-Methyl 4-(N-(sec- butyl)sulfamoyl)-lH-pyrrole-2-carboxylate (130 mg, 0.499 mmol) in anhydrous N,N- dimethylformamide (3 m ) was treated with CS2CO3 (488 mg, 1.497 mmol). After stirring the reaction mixture at 22 °C for 15 minutes, sodium 2 -chi oro-2, 2- difluoroacetate (228 mg, 1.497 mmol) was added. The reaction mixture was stirred at 60 °C for 15 hours, allowed to cool to 22 °C, quenched with ice water, and extracted with ethyl acetate. The organic fraction was washed with brine solution, dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified by flash silica gel chromatography (0-30% ethyl acetate in hexanes gradient) to provide (R)-methyl 4-(N-(sec-butyl)sulfamoyl)-l-(difluoromethyl)-lH-pyrrole-2-carboxylate as a white semi solid. 'H NMR (300 MHz, CDCI3): 5 (ppm) 8.05 - 8.30 (m, 1 H), 7.75 - 7.90 (m, 2 H), 4.54 (d, J= 7.62 Hz, 1 H), 3.89 (s, 3 H), 3.26 - 3.34 (m, 1 H), 1.43 - 1.49 (m, 2 H), 1.10 - 1.13 (m, 3 H), 0.82 - 0.87 (m, 3 H); HPLCMS: MS (ESI) m / z = 311.6 [M+H]+.

[0460]

[0461] Step 2: Synthesis of (R)-4-(N-(sec-butyl)sulfamoyl)-l-(difluoromethyl)-lH- pyrrole-2-carboxylic acid: A solution of (R)-methyl 4-(N-(sec-butyl)sulfamoyl)-l- (difluoromethyl)-lH-pyrrole-2-carboxylate (25 mg, 0.08 mmol) in tetrahydrofuran (1.5 mL) was treated with LiOH hbO (1 M) (0.240 mL, 0.240 mmol). The resulting reaction mixture was stirred at 22 °C for 18 hours. The reaction mixture was acidified to a pH of 3.0 by the slow addition of aqueous 1 N HC1, and extracted with ethyl acetate. The organic portions were washed with saturated aqueous NaCl, dried (Na2SO4), evaporated under reduced pressure, and the residue was dried under high vacuum 18 hours to yield (R)-4-(N-(sec-butyl)sulfamoyl)-l -(difluoromethyl)- lH-pyrrole-2-carboxylic acid as a white semi solid. HPLCMS: MS (ESI) m / z = 297.6 [M+H]+.

[0463] Step 3: (R)-4-(N-(sec-butyl)sulfamoyl)-N-(3-chloro-4-fluorophenyl)-l- (difluoromethyl)-lH-pyrrole-2-carboxamide: A solution of (R)-4-(N-(sec- butyl)sulfamoyl)-l-(difluoromethyl)-lH-pyrrole-2-carboxylic acid (23 mg. 0.077 mmol) in anhydrous CH2CI2 (1.5 mL), was treated with l-ethyl-3-(3- dimethylaminopropyl)carbodiimide HC1 (29 mgr, 0.154 mmol), hydroxybenzotriazole (23 mgr, 0.154 mmol), and N,N-diisopropylethylamine (0.040 ml, 0.230 mmol) and stirred at 22 °C for 10 min, 3-chloro-4-fluoroaniline (22 mg, 0.154 mmol) was added. The resulting reaction mixture was stirred at 22 °C for 18 hours, diluted with ethyl acetate, and washed successively with aqueous saturated. NH4CI and aqueous NaCl. The organic portion was dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified by preparative HPLC (10-90% acetonitrile in water 0.1% trifluoroacetic acid over 30 minutes. Phenomenex Luna LC Column (5 pm C18 100 A, 150 x 21.2 mm))to provide (R)-4-(N-(sec-butyl)sulfamoyl)-N-(3-chloro-4- fluorophenyl)-l -(difluoromethyl)- lH-pyrrole-2 -carboxamide as white solid. 'H NMR (300 MHz, DMSO-O: 5 (ppm) 10.51 (br.s, 1 H), 7.96 - 8.04 (m, 1 H), 7.92 (d, J= 1.76Hz, 1 H), 7.63 (ddd, J= 9.08, 4.10, 2.64 Hz, 1 H), 7.51 (s, 1 H), 7.38 - 7.47 (m, 2 H), 3.13 - 3.18 (m. 1 H). 1.34 (quin. J = 7.18 Hz. 2 H). 0.96 (d, J = 6.45 Hz, 3 H), 0.71 - 0.78 (m, 3 H); HPLCMS: MS (ESI) m / z = 424.7 [M+H]+.

[0464] Example 5: Synthesis of (R)-4-(N-(sec-butyl)sulfamoyl)-N-(3-chloro-4- fluorophenyl)-l-(2,2,3,3-tetrafluoropropyl)-lH-pyrrole-2-carboxamide

[0466] Step 1: Synthesis of (R)-methyl 4-(N-(sec-butyl)sulfamoyl)-l-(2,2,3,3- tetrafluoropropyl)-lH-pyrrole-2 -carboxylate: A solution of (R)-Methyl 4-(N-(sec- butyl)sulfamoyl)-lH-pyrrole-2-carboxylate (230 mg, 0.883 mmol) in anhydrous tetrahydrofuran (6.5 mL) was treated with l,8-diazabicyclo[5.4.0]undec-7-ene (0.64 ml, 4.417 mmol). After stirring the reaction mixture at 22 °C for 15 min, 1, 1,2,2- tetrafluoro-3-iodopropane (0.30 ml, 2.649 mmol) was added. The reaction mixture was stirred at 60 °C for 48 hours, cooled to 22 °C, quenched with 1 N HC1, and extracted with ethyl acetate. The organic fraction was washed with brine solution, dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified by flash silica gel chromatography (0-30% ethyl acetate in hexanes gradient) to provide (R)-methyl 4-(N-(sec-butyl)sulfamoyl)-l-(2,2,3,3-tetrafluoropropyl)-lH-pyrrole-2- carboxylate as colorless liquid. 'H NMR (300 MHz, CDCls): 5 (ppm) 7.40 (s, 1 H), 7.25 (d. J= 2.34 Hz. 1 H). 5.68 - 6.10 (m. 1 H). 5.10 ft. J = 14.95 Hz, 2 H), 4.47 (d. J = 7.62 Hz, 1 H), 3.85 (s, 3 H), 3. 19 - 3.29 (m, 1 H), 1.42 (quin, J = 7.18 Hz, 2 H), 1.07 (d, J= 6.45 Hz, 3 H), 0.79 - 0.85 (m, 3 H); HPLCMS: MS (ESI) m / z = 375.7 [M+H]+.

[0468] Step 2: Synthesis of (R)-4-(N-(sec-butyl)sulfamoyl)-l-(2, 2,3,3- tetrafluoropropyl)-lH-pyrrole-2-carboxylic acid: A solution of (R)-methyl 4-(N-(sec- butyl)sulfamoyl)-l -(2,2,3,3-tetrafluoropropyl)-lH-pyrrole-2-carboxylate (70 mg,0.186 mmol) in tetrahydrofuran (3 rnL) was treated with LiOH H2O (1 M) (0.56 mL, 0.56 mmol). The resulting reaction mixture was stirred at 22 °C for 22 hours. The reaction mixture was acidified to a pH of 3.0 by the slow addition of aqueous 1 N HC1 and extracted with Ethyl acetate. The organic portions were washed with aqueous NaCl, dried over Na2SO4, filtered, and evaporated under reduced pressure to provide (R)-4- (N-(sec-butyl)sulfamoyl)-l-(2.2,3,3-tetrafluoropropyl)-lH-pyrrole-2-carboxylic acid as a white semi solid. HPLCMS: MS (ESI) m / z = 361.7 [M+H]+.

[0469]

[0470] Step 3: (R)-4-(N-(sec-butyl)sulfamoyl)-N-(3-chloro-4-fluorophenyl)-l- (2,2,3,3-tetrafluoropropyl)-lH-pyrrole-2-carboxamide: A solution of (R)-4-(N-(sec- butyl)sulfamoyl)-l-(2,2,3,3-tetrafluoropropyl)-lH-pyrrole-2-carboxylic acid (20 mg, 0.055 mmol) in anhydrous CH2CI2 (1.5 mL), was treated with l-ethyl-3-(3- dimethylaminopropyl)carbodiimide HC1 (21 mgr, 0.11 mmol), hydroxybenzotriazole (17 mgr, 0.11 mmol), and N,N-diisopropylethylamine (0.028 ml. 0.165 mmol) and stirred at 22 °C for 10 minutes, and then 3-chloro-4-fluoroaniline (16 mg, 0.11 mmol) was added. The resulting reaction mixture was stirred at 22 °C for 18 hours, diluted with ethyl acetate, and washed successively with aqueous saturated NH4CI, aqueous NaCl. The organic portion was dried over Na2SO4, fdtered, and evaporated under reduced pressure. The residue was purified by preparative HPLC (10-90% acetonitrile in water 0.1% trifluoroacetic acid over 30 minutes, Phenomenex Luna LC Column (5 pm C18 100 A, 150 x 21.2 mm)) to provide (R)-4-(N-(sec-butyl)sulfamoyl)-N-(3- chloro-4-fluorophenyl)-l-(2,2,3,3-tetrafluoropropyl)-lH-pyrrole-2-carboxamide as white solid. *H NMR (300 MHz, DMSO-Js): 5 (ppm) 10.37 (s, 1 H), 7.98 (dd. J= 6.74, 2.64 Hz, 1 H), 7.64 (dt, J= 4.54, 2.64 Hz, 1 H), 7.60 (s, 1 H), 7.35 - 7.43 (m, 2 H), 7.31 (d, J= 7.62 Hz, 1 H), 6.41 - 6.80 (m, 1 H), 5.32 (t, J= 15.82, 2 H), 3.06 (td, J= 13.48, 6.74 Hz, 1 H), 1.27 - 1.39 (m, 2 H), 0.94 (d, J = 6.45 Hz, 3 H), 0.69 - 0.79 (m, 3 H); HPLCMS: MS (ESI) m / z = 488.8 [M+H]+.

[0471] Example 6: Synthesis of (R)-4-(N-(sec-butyl)sulfamoyl)-N-(3,4- difluorophenyl)-l-(2,2,3,3-tetrafluoropropyl)-lH-pyrrole-2-carboxamide

[0472]

[0473] A solution of (R)-4-(N-(sec-butyl)sulfamoyl)-l-(2.2.3.3-tetrafluoropropyl)- lH-pyrrole-2-carboxylic acid (25 mg, 0.069 mmol) in anhydrous CH2CI2 (1.5 mL), was treated with l-ethyl-3-(3-dimethylaminopropyl)carbodiimide HC1 (40 mgr, 0.207 mmol), hydroxybenzotriazole (32 mgr, 0.207 mmol), and N,N-diisopropylethylamine (0.060 ml. 0.345 mmol) and stirred at 22 °C for 10 minutes, and then 3. 4- difluoroaniline (27 mg, 0.207 mmol) was added. The resulting reaction mixture was stirred at 22 °C for 18 hours, diluted with ethyl acetate, and washed successively with aqueous saturated NH4CI, aqueous NaCl. The organic portion was dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified by preparative HPLC (10-90% acetonitrile in water 0.1% trifluoroacetic acid over 30 minutes, Phenomenex Luna LC Column (5 pm C18 100 A, 150 x 21.2 mm)) and (R)- 4-(N-(sec-butyl)sulfamoyl)- N-(3,4-difluorophenyl)-l -(2,2,3, 3-tetrafluoropropyl)-lH- pyrrole-2-carboxamide was obtained as white solid.JH NMR (300 MHz, DMSO-c / fi): 5 (ppm) 10.39 (s, 1 H), 7.82 (ddd. J = 13.04. 7.47. 2.34 Hz, 1 H). 7.60 (s, 1 H), 7.44 - 7.50 (m, 1 H), 7.34 - 7.43 (m, 2 H), 7.31 (d, J = 7.62 Hz, 1 H), 6.39 - 6.82 (m, 1 H), 5.31 (t, J= 16.41, 2 H), 3.05 (dt, J= 13.77, 6.59, 1 H), 1.33 (quin, J = 7.18 Hz, 2 H), 0.94 (d. J= 6.45 Hz, 3 H), 0.66 - 0.80 (m, 3 H); HPLCMS: MS (ESI) m / z = 472.8.

[0474] Example 7: Synthesis of (R)-4-(N-(sec-butyl)sulfamoyl)-N-(3- (difluoromethyl)-4-fluorophenyl)-l-(2,2,3,3-tetrafluoropropyl)-lH-pyrrole-2- carboxamide

[0475]

[0476] A solution of (R)-4-(N-(sec-butyl)sulfamoyl)-l-(2.2.3.3-tetrafluoropropyl)- lH-pyrrole-2-carboxylic acid (20 mg, 0.055 mmol) in anhydrous CH2CI2 (1.5 mL), wastreated with l-ethyl-3-(3-dimethylaminopropyl)carbodiimide HC1 (31 mgr. 0.165 mmol), hydroxybenzotriazole (25 mgr, 0.165 mmol), and N,N-diisopropylethylamine (0.047 ml, 0.275 mmol) and stirred at 22 °C for 10 minutes, and then 3- (difluoromethyl)-4-fluoroaniline (26 mg, 0.165 mmol) was added. The resulting reaction mixture was stirred at 22 °C for 18 hours, diluted with ethyl acetate, and washed successively with aqueous saturated NH4CI, aqueous NaCl. The organic portion was dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified by preparative HPLC (10-90% acetonitrile in water 0.1% trifluoroacetic acid over 30 minutes, Phenomenex Luna LC Column (5 pm C18 100 A, 150 x 21.2 mm)) to provide (R)-4-(N-(sec-butyl)sulfamoyl)-N-(3-(difluoromethyl)-4- fluorophenyl)-l-(2,2.3.3-tetrafluoropropyl)-lH-pyrrole-2-carboxamide as white solid. 'H NMR (300 MHz, DMSO-rfc): 8 (ppm) 10.41 (s, 1 H), 8.01 (d, J = 5.86 Hz, 1 H), 7.80 - 7.90 (m, 1 H), 7.60 (s, 1 H), 7.34 - 7.41 (m, 2 H), 7.31 (d, J= 7.62 Hz, 1 H), 6.99 - 7.24 (m, 1 H), 6.40 - 6.79 (m, 1 H), 5.33 (t, J= 15.82 Hz, 2 H), 3.00 - 3.12 (m, 1 H), 1.27 - 1.40 (m, 2 H), 0.95 (d, J= 6.45 Hz. 3 H). 0.74 (t. J = 7.33 Hz, 3 H); HPLCMS: MS (ESI) m / z = 504.9 [M+H]+.

[0477] Example 8: Synthesis of (R)-4-(N-(sec-butyl)sulfamoyl)-l-(cyanomethyl)-N- (3,4-difluorophenyl)-lH-pyrrole-2-carboxamide

[0478]

[0479] Step 1 : Synthesis of (R)-4-(N-(sec-butyl)sulfamoyl)-lH-pyrrole-2-carboxylic acid: A solution of (R)-methyl 4-(N-(sec-butyl)sulfamoyl)-lH-pyrrole-2-carboxylate (260 mg, 0.998 mmol) in a tetrahydrofuran:H2O: methanol mixture (8: 1.6: 1.6 mL) was treated with LiOH H2O (1 M) (5 mL, 5 mmol). The resulting reaction mixture was stirred at 50 °C for 18 hours. The reaction mixture was concentrated on rotavapor. acidified to a pH of 3.0 by the slow addition of aqueous KHSO4 (0.8 M), and extracted with ethyl acetate. The organic portions were dried overNa2SC>4, filtered, evaporated under reduced pressure to provide (R)-4-(N-(sec-butyl)sulfamoyl)-lH-pyrrole-2- carboxylic acid as an off-white solid. HPLCMS: MS (ESI) m / z = 247.5 [M+H]+.

[0480]

[0481] Step 2: Synthesis of (R)-4-(N-(sec-butyl)sulfamoyl)-N-(3,4-difluorophenyl)- lH-pyrrole-2-carboxamide: A solution of (R)-4-(N-(sec-butyl)sulfamoyl)-lH-pyrrole- 2-carboxylic acid (234 mg, 0.95 mmol) in anhydrous CH2CI2 (10 mL), was treated with l-ethyl-3-(3-dimethylaminopropyl)carbodiimide HC1 (364 mgr, 1.9 mmol), hydroxybenzotriazole (290 mgr, 1.9 mmol), and N,N-diisopropylethylamine (0.49 ml, 2.85 mmol) and stirred at 22 °C for 10 minutes, and then 3, 4-difluoroaniline (0. 188 ml, 1.9 mmol) was added. The resulting reaction mixture was stirred at 22 °C for 18 hours, diluted with ethyl acetate, and washed successively with aqueous saturated NH4CI, aqueous NaCl. The organic portion was dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was triturated with hexane (X 3 times), CH2C12:hexane (1 :2, X 2 times) and dried under high vacuum to yield the (R)-4-(N- (sec-butyl)sulfamoyl)-N-(3,4-difluorophenyl)-lH-pyrrole-2-carboxamide as pink solid.1H NMR (300 MHz, DMSO-Je): 5 (ppm) 12.41 (br. s, 1 H), 10.21 (s, 1 H), 7.88 (ddd, J = 13.33, 7.47, 2.64 Hz, 1 H), 7.45 - 7.51 (m, 1 H), 7.38 - 7.45 (m. 1 H), 7.35 (dd. J= 5.28. 2.34 Hz, 2 H), 7.12 (d, J= 7.62 Hz, 1 H), 2.99 - 3.09 (m. 1 H). 1.31 (quin. J= 7. 18 Hz, 2 H), 0.92 (d, J= 7.03 Hz, 3 H), 0.69 - 0.76 (m, 3 H); HPLCMS: MS (ESI) m / z - 358.7 [M+H]+.

[0483] Step 3: Synthesis of (R)-4-(N-(sec-butyl)sulfamoyl)-l-(cyanomethyl)-N-(3,4- difluorophenyl)-lH-pyrrole-2-carboxamide: A solution of (R)-4-(N-(sec- butyl)sulfamoyl)-N-(3,4-difluorophenyl)-lH-pyrrole-2-carboxamide (25 mg, 0.069 mmol) in anhydrous N.N-dimethylformamide (1 mL) was treated with CS2CO3 (57 mg, 0.172 mmol). After stirring the reaction mixture at 22 °C for 15 minutes, 2- bromoacetonitrile (0.006 ml, 0.082 mmol) was added. The reaction mixture was stirred at 22 °C for 18 hours, quenched with ice water, and extracted with ethyl acetate. The organic fraction was washed with brine solution, dried over Na2SO4, filtered, andconcentrated under reduced pressure. The residue was purified by prep-HPLC (10-90% acetonitrile in water 0.1% trifluoroacetic acid over 30 minutes, Phenomenex Luna LC Column (5 pm C18 100 A, 150 x 21.2 mm)) to provide (R)-4-(N-(sec-butyl)sulfamoyl)- l-(cyanomethyl)-N-(3,4-difluorophenyl)-lH-pyrrole-2-carboxamide as a pale yellow solid. 'H NMR (300 MHz, MeOD): 5 (ppm) 7.78 (ddd, J= 12.89, 7.33, 2.64 Hz, 1 H), 7.64 (d. J= 1.76 Hz, 1 H), 7.35 - 7.45 (m, 2 H), 7. 18 - 7.29 (m, 1 H), 5.53 (s, 2 H), 3.17 - 3.26 (m, 1 H), 1.37 - 1.51 (m, 2 H), 1.06 (d, J= 6.45 Hz, 3 H), 0.81 - 0.89 (m, 3 H); HPLCMS: MS (ESI) m / z = 397.7 [M+H]+.

[0484] Example 9: Synthesis of (R)-4-(N-(sec-butyl)sulfamoyl)-l-(2,2-difluoroethyl)- N-(3,4-difluorophenyl)-lH-pyrrole-2-carboxamide

[0486] A solution of (R)-4-(N-(sec-butyl)sulfamoyl)-N-(3,4-difluorophenyl)-lH- pyrrole-2-carboxamide (25 mg, 0.069 mmol) in anhydrous tetrahydrofuran (1 mL) was treated with l,8-diazabicyclo[5.4.0]undec-7-ene (0.061 ml, 0.414 mmol). After stirring the reaction mixture at 22 °C for 15 minutes, l,l-difluoro-2-iodoethane (0.027 ml, 0.310 mmol) was added. The reaction mixture was stirred at 60 °C for 48 hours, cooled to 22 °C, diluted with ethyl acetate, and washed successively with aqueous IN HC1, aqueous NaCl. The organic portion was dried over Na2SC>4, filtered, and concentrated under reduced pressure. The residue was purified by prep-HPLC (10-90% acetonitrile in water 0. 1 % trifluoroacetic acid over 30 minutes, Phenomenex Luna LC Column (5 pm C18 100 A, 150 x 21.2 mm)) to provide (R)-4-(N-(sec-butyl)sulfamoyl)-N-(3,4- difluorophenyl)-lH-pyrrole-2-carboxamide as a white solid. 'H NMR (300 MHz. DMSO-O: 5 (ppm) 10.34 (s, 1 H), 7.83 (dd, J = 13.48, 7.62, 1 H), 7.60 (s, 1H), 7.35 - 7.48 (m, 3 H), 7.27 (d, J = 7.62 Hz, 1 H), 6.13 - 6.54 (m, 1 H), 4.81 - 4.96 (m, 2 H), 3.04 (quin, J = 6.89 Hz, 1 H), 1.32 (quin, J= 7.18 Hz, 2 H), 0.93 (d, J= 7.03 Hz, 3 H), 0.68 - 0.76 (m, 3 H); HPLCMS: MS (ESI) m / z = 422.8 [M+H]+.

[0487] Example 10: Synthesis of (R)-4-(N-(sec-butyl)sulfamoyl)-l-(2-cyanoethyl)-N- (3,4-difluorophenyl)-lH-pyrrole-2-carboxamide

[0488]

[0489] A solution of (R)-4-(N-(sec-butyl)sulfamoyl)-N-(3,4-difluorophenyl)-lH- pyrrole-2-carboxamide (30 mg, 0.083 mmol) in anhydrous tetrahydrofuran (1 mL) was treated with l,8-Diazabicyclo[5.4.0]undec-7-ene (0.003 ml, 0.024 mmol). After stirring the reaction mixture at 22 °C for 10 minutes, acrylonitrile (0.032 ml, 0.498 mmol) was added. The reaction mixture was stirred at 22 °C for 24 hours, diluted with ethyl acetate, and washed with aqueous NH4CI. The organic portion was dried over Na2SC>4, filtered, and concentrated under reduced pressure. The residue was purified by prep-HPLC (10- 90% acetonitrile in water 0.1% trifluoroacetic acid over 30 minutes, Phenomenex Luna LC Column (5 pm C18 100 A, 150 x 21.2 mm)) to provide (R)-4-(N-(sec- butyl)sulfamoyl)-l-(2-cyanoethyl)-N-(3,4-difluorophenyl)-lH-pyrrole-2-carboxamide as a white solid. 'H NMR (300 MHz, DMSO-rie): 5 (ppm) 10.30 (br. s, 1 H), 7.79 - 7.91 (m, 1 H), 7.68 (s, 1 H), 7.43 - 7.50 (m, 1 H), 7.33 - 7.42 (m, 2 H), 7.24 (d, J= 7.62 Hz, 1 H), 4.61 (t, J= 6.15 Hz, 2 H), 2.99 - 3.11 (m, 3 H), 1.26 - 1.38 (m, 2 H), 0.93 (d, J = 6.45 Hz, 3 H), 0.68 - 0.79 (m, 3 H); HPLCMS: MS (ESI) m / z = 411.7 [M+H]+.

[0490] Example 11 : Synthesis of (R)-4-(N-(sec-butyl)sulfamoyl)-N-(3,4- difluorophenyl)-l-(2-hydroxyethyl)-lH-pyrrole-2-carboxamide

[0492] Step 1 : Synthesis of (R)-4-(N-(sec-butyl)sulfamoyl)-l-(2-((tert- butyldimethylsilyl)oxy)ethyl)-N-(3,4-difluorophenyl)-lH-pyrrole-2-carboxamide: A solution of (R)-4-(N-(sec-butyl)sulfamoyl)-N-(3,4-difluorophenyl)-lH-pyrrole-2- carboxamide (50 mg. 0. 139 mmol) in anhydrous N,N-dimethylformamide (1.5 mL) was treated with K2CO3 (58 mg, 0.417 mmol). After stirring the reaction mixture at 22 °C for 10 minutes, (2-bromoethoxy)(tert-butyl)dimethylsilane (0.059 ml, 0.278 mmol) was added. The reaction mixture was stirred at 60 °C for 18 hours, cooled to 22 °C, quenchedwith ice water and extracted with ethyl acetate. The organic fraction was washed with brine solution, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by Combi-flash (0-30% ethyl acetate in Hexanes) to provide (R)-4-(N-(sec-butyl)sulfamoyl)-l-(2-((tert-butyldimethylsilyl)oxy)ethyl)-N-(3,4- difluorophenyl)-lH-pyrrole-2-carboxamide (38 mg, 53%) as white solid. HPLCMS: MS (ESI) m / z = 517.0 [M+H]+.

[0494] Step 2: Synthesis of (R)-4-(N-(sec-butyl)sulfamoyl)-N-(3,4-difluorophenyl)-l- (2-hydroxyethyl)-lH-pyrrole-2-carboxamide: A solution of (R)-4-(N-(sec- butyl)sulfamoyl)-l-(2-((tert-butyldimethylsilyl)oxy)ethyl)-N-(3,4-difluorophenyl)- lH-pyrrole-2-carboxamide (26 mg, 0.050 mmol) in HC1 in methanol (0.9 M) (2 mL) was kept at 22 °C for 18 hours without stirring and then concentrated under reduced pressure. The residue was purified by prep-HPLC (10-90% acetonitrile in water 0.1% trifluoroacetic acid over 30 minutes, Phenomenex Luna LC Column (5 pm Cl 8 100 A, 150 x 21.2 mm)) to provide (R)-4-(N-(sec-butyl)sulfamoyl)-N-(3.4-difluorophenyl)-l- (2-hydroxyethyl)-lH-pyrrole-2-carboxamide as a white solid. Tl NMR (300 MHz, DMSO-O: 3 (ppm) 10.23 (br. s, 1 H), 7.85 (ddd, J = 13.33, 7.47, 2.64 Hz, 1 H), 7.49 (d, J= 1.76 Hz, 1 H), 7.45 (dd, J = 3.52, 1.76 Hz, 1 H), 7.33 - 7.43 (m, 1 H), 7.30 (d, J = 1.76 Hz, 1 H), 7. 15 (d, J= 7.62 Hz, 1 H), 4.84 (br. s, 1 H), 4.40 (t, J= 5.28 Hz, 2 H), 3.63 (t, J = 5.21 Hz, 2 H), 3.04 (dt, J = 13.77, 6.59 Hz, 1 H), 1.26 - 1.38 (m, 2 H), 0.93 (d, J= 6.45 Hz, 3 H), 0.69 - 0.80 (m, 3 H); HPLCMS: MS (ESI) m / z = 402.8 [M+H]+.

[0495] Example 12: Synthesis of (R)-4-(N-(sec-butyl)sulfamoyl)-N-(3,4- difluorophenyl)-l-(3-hydroxypropyl)-lH-pyrrole-2-carboxamide

[0497] Step 1 : Synthesis of (R)-4-(N-(sec-butyl)sulfamoyl)-l-(3-((tert- butyldimethylsilyl)oxy)propyl)-N-(3,4-difluorophenyl)-lH-pyrrole-2-carboxamide: A solution of (R)-4-(N-(sec-butyl)sulfamoyl)-N-(3,4-difluorophenyl)-lH-pyrrole-2- carboxamide (40 mg, 0. 112 mmol) in anhydrous N.N-dimethylformamide (1.2 mL) was treated with K2CO3 (46 mg, 0.336 mmol). After stirring the reaction mixture at 22 °C for 10 minutes (3-bromopropoxy)(tert-butyl)dimethylsilane (0.052 ml, 0.224 mmol) was added. The reaction mixture was stirred at 60 °C for 22 hours, cooled to 22 °C. quenched with ice water, and extracted with ethyl acetate. The organic fraction was washed with brine solution, dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified by flash silica gel chromatography (0-30% ethyl acetate in hexanes gradient) to provide (R)-4-(N-(sec-butyl)sulfamoyl)-l-(3-((tert- butyldimethylsilyl)oxy)propyl)-N-(3,4-difluorophenyl)-lH-pyrrole-2-carboxamide as white semi solid. HPLCMS: MS (ESI) m / z = 531.0 [M+H]+.

[0498]

[0499] Step 2: Synthesis of (R)-4-(N-(sec-butyl)sulfamoyl)-N-(3,4-difluorophenyl)-l- (3-hydroxypropyl)-lH-pyrrole-2-carboxamide: A solution of (R)-4-(N-(sec- butyl)sulfamoyl)-l-(3-((tert-butyldimethylsilyl)oxy)propyl)-N-(3,4-di fluorophenyl)- lH-pyrrole-2-carboxamide (36 mg, 0.067 mmol) in HC1 in Methanol (0.9 M) (3 mL) was kept at 22 °C for 18 hours without stirring and then evaporated under reduced pressure. The residue was purified by prep-HPLC (10-90% acetonitrile in water 0.1% trifluoroacetic acid over 30 minutes, Phenomenex Luna LC Column (5 pm Cl 8 100 A, 150 x 21.2 mm)) to provide (R)-4-(N-(sec-butyl)sulfamoyl)-N-(3,4-difluorophenyl)-l- (3-hydroxypropyl)-lH-pyrrole-2-carboxamide as a white solid. 'H NMR (400 MHz, DMSO- s): 6 (ppm) 10.26 (br.s, 1 H), 7.87 (ddd, J = 13.33, 7.46, 2.45 Hz, 1 H), 7.55 (d, J= 1.71 Hz, 1 H). 7.47 - 7.52 (m. 1 H). 7.37 - 7.45 (m. 1 H), 7.33 (d, J= 1.71 Hz, 1 H), 7.18 (d, J = 7.58 Hz, 1 H), 4.59 (br.s, 1 H), 4.41 (t, J = 6.85 Hz, 2 H), 3.34 (t, J = 6.11 Hz, 2 H), 3.07 (dt, J = 13.69, 6.85 Hz, 1 H), 1.84 (quin, J = 6.54 Hz, 2 H), 1.34 (quin, J= 7. 15 Hz, 2 H), 0.95 (d, J= 6.60 Hz, 3 H), 0.75 (t, J= 7.34 Hz, 3 H); HPLCMS: MS (ESI) m / z = 416.8 [M+H]+.

[0500] Example 13: Synthesis of (R)-4-(N-(sec-butyl)sulfamoyl)-N-(3,4- difluorophenyl)-l-(4-hydroxybutyl)-lH-pyrrole-2-carboxamide

[0502] Step 1 : Synthesis of (R)-4-(N-(sec-butyl)sulfamoyl)-l-(4-((tert- butyldimethylsilyl)oxy)butyl)-N-(3,4-difluorophenyl)-lH-pyrrole-2-carboxamide: A solution of (R)-4-(N-(sec-butyl)sulfamoyl)-N-(3,4-difluorophenyl)-lH-pyrrole-2- carboxamide (37 mg. 0. 103 mmol) in anhydrous N,N-dimethylformamide (1.2 mL) was treated with K2CO3 (57 mg, 0.412 mmol). After stirring the reaction mixture at 22 °C for 10 minutes, tert-butyl(4-iodobutoxy)dimethylsilane (0.080 ml, 0.309 mmol) was added. The reaction mixture was stirred at 60 °C for 24 hours, cooled to 22 °C, quenched with ice water, and extracted with ethyl acetate. The organic fraction was washed with brine solution, dried over Na2SC>4, filtered, and evaporated under reduced pressure. The residue was purified by flash silica gel chromatography (0-30% ethyl acetate in hexanes gradient) to provide (R)-4-(N-(sec-butyl)sulfamoyl)-l-(4-((tert- butyldimethylsilyl)oxy)butyl)-N-(3,4-difluorophenyl)-lH-pyrrole-2-carboxamide as white solid. HPLCMS: MS (ESI) m / z = 545.1 [M+H]+.

[0503]

[0504] Step 2: Synthesis of (R)-4-(N-(sec-butyl)sulfamoyl)-N-(3,4-difluorophenyl)-l- (4-hydroxybutyl)-lH-pyrrole-2-carboxamide: A solution of (R)-4-(N-(sec- butyl)sulfamoyl)-l-(4-((tert-butyldimethylsilyl)oxy)butyl)-N-(3,4-difluorophenyl)- lH-pyrrole-2-carboxamide (25 mg, 0.045 mmol) in HC1 in Methanol (0.9 M) (2.5 mL) was kept at 22 °C for 18 hours without stirring, and then evaporated under reduced pressure. The residue was purified by prep-HPLC (10-90% acetonitrile in water 0.1%trifluoroacetic acid over 30 minutes, Phenomenex Luna LC Column (5 pm Cl 8 100 A, 150 x 21.2 mm)) to provide Synthesis of (R)-4-(N-(sec-butyl)sulfamoyl)-N-(3,4- difluorophenyl)-l-(4-hydroxybutyl)-lH-pyrrole-2-carboxamide as a white solid. 'H NMR (400 MHz, DMSO- e): 8 (ppm) 10.21 (br.s, 1 H), 7.84 (ddd, J = 13.47, 7.62, 2.34 Hz, 1 H), 7.57 (d, J = 1.95 Hz, 1 H), 7.44 - 7.51 (m, 1 H), 7.34 - 7.42 (m, 1 H), 7.30 (d, J= 1.95 Hz, 1 H), 7.13 (d, 7.42 Hz, 1 H), 4.36 (t, J= 7.03 Hz, 2 H), 3.33 - 3.37(m. 2 H). 3.00 - 3.10 (m. 1 H), 1.64 - 1.73 (m, 2 H), 1.27 - 1.35 (m, 4 H), 0.93 (d. J = 6.64 Hz, 3 H), 0.73 (t, J= 7.42 Hz, 3 H); HPLCMS: MS (ESI) m / z = 430.8 [M+H]+.

[0505] Example 14: Synthesis of (R)-4-(N-(sec-butyl)sulfamoyl)-N-(3,4- difluorophenyl)-l-(5-hydroxypentyl)-lH-pyrrole-2-carboxamide

[0507] Step 1 : Synthesis of (R)-4-(N-(sec-butyl)sulfamoyl)-l-(5-((tert- butyldimethylsilyl)oxy)pentyl)-N-(3,4-difluorophenyl)-lH-pyrrole-2-carboxamide: A solution of (R)-4-(N-(sec-butyl)sulfamoyl)-N-(3,4-difluorophenyl)-lH-pyrrole-2- carboxamide (50 mg, 0. 139 mmol) in anhydrous N,N-dimethylformamide (1.5 mL) was treated with K2CO3 (58 mg, 0.417 mmol). After stirring the reaction mixture at 22 °C for 10 minutes ((5-bromopentyl)oxy)(tert-butyl)dimethylsilane (78 mg, 0.278 mmol) was added. The reaction mixture was stirred at 60 °C for 18 hours, cooled to 22 °C, quenched with ice water, and extracted with Ethyl acetate. The organic fraction was washed with brine solution, dried over Na2SC>4, filtered, and evaporated under reduced pressure. The residue was purified by flash silica gel chromatography (0-30% ethyl acetate in Hexanes) to provide (R)-4-(N-(sec-butyl)sulfamoyl)-l-(5-((tert- butyldimethylsilyl)oxy)pentyl)-N-(3,4-difluorophenyl)-lH-pyrrole-2-carboxamide as white semi solid. HPLCMS: MS (ESI) m / z = 559.1 [M+H]+.

[0508]

[0509] Step 2: Synthesis of (R)-4-(N-(sec-butyl)sulfamoyl)-N-(3,4-difluorophenyl)-l-(5-hydroxypentyl)-lH-pyrrole-2-carboxamide: A solution of (R)-4-(N-(sec- butyl)sulfamoyl)-l-(5-((tert-butyldimethylsilyl)oxy)pentyl)-N-(3,4-di fluorophenyl)- lH-pyrrole-2-carboxamide (40 mg, 0.071 mmol) in HC1 in methanol (0.9 M) (3 ml) was kept at 22 °C for 18 hours without stirring, and then evaporated under reduced pressure. The residue was purified by prep-HPLC (10-90% acetonitrile in water 0.1 % trifluoroacetic acid over 30 minutes, Phenomenex Luna LC Column (5 pm Cl 8 100 A, 150 x 21.2 mm)) to provide (R)-4-(N-(sec-butyl)sulfamoyl)-N-(3.4-difluorophenyl)-l- (5-hydroxypentyl)-lH-pyrrole-2-carboxamide as a white solid. 'H NMR (400 MHz, DMSO-O: 5 (ppm) 10.25 (br.s, 1 H), 7.86 (ddd, J = 13.27, 7.52, 2.45 Hz, 1 H), 7.59 (d, J= 1.71 Hz, 1 H), 7.46 - 7.53 (m, 1 H), 7.36 - 7.45 (m, 1 H), 7.32 (d, J= 1.71 Hz, 1 H), 7.17 (d, J = 7.83 Hz, 1 H), 4.36 (t, J= 6.85 Hz, 2 H), 3.33 - 3.36 (m, 2 H), 3.06 (dt, J = 13.63, 6.76 Hz, 1 H), 1.68 (quin, J = 7.34 Hz, 2 H), 1.29 - 1.44 (m. 4 H), 1.16 - 1.25 (m. 2 H). 0.95 (d, J = 6.60 Hz, 3 H), 0.75 (t, J = 7.34 Hz, 3 H); HPLCMS: MS (ESI) m / z = 444.9 [M+H]+.

[0510] Example 15: Synthesis of (R)-l-(2,2-difluoroethyl)-N-(3,4-difluorophenyl)-4- (N-(l, 1 ,1 -trifluoropropan-2-yl)sulfamoyl)-lH-pyrrole-2-carboxamide

[0512] Step 1 : Synthesis of (R)-methyl 4-(N-( 1,1,1 -trifl uoropropan-2-yl)sulfamoyl)- lH-pyrrole-2-carboxylate: A solution of methyl 4-(chlorosulfonyl)-lH-pyrrole-2- carboxylate (150 mg, 0.67 mmol) in anhydrous CH3CN (6.5 mL) was treated with pyridine (0.163 ml, 2.01 mmol) and 4-dimethylaminopyridine (10 mg, 0.08 mmol). After stirring the reaction mixture at 22 °C for 10 minutes, (R)- 1,1,1 -trifluoropropan-2-amine hydrochloride (160 mg, 1.07 mmol) was added. The reaction mixture was stirred at 90 °C for 18 hours, cooled to 22 °C and concentrated under reduced pressure. The residue was dissolved in CH2CI2,. and washed with aqueous NaCl. The organic fraction was dried over Na2SC>4, filtered, and evaporated under reduced pressure. The residue was purified by flash silica gel chromatography (0-40% ethyl acetate in hexanes gradient) to provide (R)-methyl 4-(N-(l,l,l-trifluoropropan-2-yl)sulfamoyl)-lH- pyrrole-2-carboxylate as white solid. HPLCMS: MS (ESI) m / z = 301.5 [M+H]L

[0513]

[0514] Step 2: Synthesis of (R)-methyl l-(2,2-difluoroethyl)-4-(N-(l,l,l- trifluoropropan-2-yl)sulfamoyl)-lH-pyrrole-2-carboxylate: A solution of (R)-methyl 4- (N-(l,l,l-trifluoropropan-2-yl)sulfamoyl)-lH-pyrrole-2-carboxylate (130 mg, 0.432 mmol) in anhydrous tetrahydrofuran (4.5 mL) was treated with 1,8- diazabicyclo[5.4.0]undec-7-ene (0.322 ml, 2.16 mmol). After stirring the reaction mixture at 22 °C for 15 minutes, 1,1 -dill uoro-2-iodoethane (0. 152 ml, 1.728 mmol) was added. The reaction mixture was stirred at 60 °C for 30 hours, cooled to 22 °C, diluted with ethyl acetate, and washed successively with aqueous IN HC1, aqueous NaCl. The organic portion was dried over Na2SC>4, filtered, and evaporated under reduced pressure. The residue was purified by flash silica gel chromatography (0-20% ethyl acetate in hexanes gradient) to provide (R)-methyl l-(2,2-difluoroethyl)-4-(N-( 1,1,1- trifluoropropan-2-yl)sulfamoyl)-lH-pyrrole-2-carboxylate as colorless oil. HPLCMS: MS (ESI) m / z = 365.6 [M+H]+.

[0515]

[0516] Step 3: Synthesis of (R)-l-(2,2-difluoroethyl)-4-(N-(l,l,l-trifluoropropan-2- yl)sulfamoyl)-lH-pyrrole-2-carboxylic acid: A solution of (R)-methyl 1 -(2,2-difluoroethyl)-4-(N-(l,l,l-trifluoropropan-2-yl)sulfamoyl)-lH-pyrrole-2-carboxylate (113 mg. 0.310 mmol) in tetrahydrofuran: H2O mixture (4: 1 ml) was treated with LiOH H2O (1 M) (1.4 mL, 1.4 mmol). The resulting reaction mixture was stirred at 22 °C for 18 hours. The reaction mixture was acidified to a pH of 3.0 by the slow addition of aqueous 1 N HC1 and extracted with ethyl acetate. The organic portions were washed with aqueous NaCl, dried over Na2SO4, filtered, concentrated under reduced pressure to provide (R)-l-(2.2-difluoroethyl)-4-(N-( 1.1.1 -trifluoropropan-2-yl)sulfamoyl)-lH- pyrrole-2-carboxylic acid as a white solid. HPLCMS: MS (ESI) m / z = 351.6 [M+H]+.

[0517]

[0518] Step 4: Synthesis of (R)-l-(2.2-difluoroethyl)-N-(3,4-difluorophenyl)-4-(N- (l,l,l-trifluoropropan-2-yl)sulfamoyl)-lH-pyrrole-2-carboxamide: A solution of (R)- 1 -(2,2-difluoroethy l)-4-(N-( 1,1,1 -trifluoropropan-2-yl)sulfamoy 1)- 1 H-pyrrole-2- carboxylic acid (30 mg, 0.085 mmol) in anhydrous N,N-dimethylformamide (1 mL), was treated with l-ethyl-3-(3-dimethylaminopropyl)carbodiimide HC1 (49 mgr, 0.255 mmol), hydroxybenzotriazole (39 mgr, 0.255 mmol), and N,N-diisopropylethylamine (0.075 ml, 0.425 mmol) and stirred at 22 °C for 10 minutes, and then 3, 4- difluoroaniline (0.025 ml, 0.255 mmol) was added. The resulting reaction mixture was stirred at 22 °C for 20 hours, quenched with ice water, and extracted with ethyl acetate. The organic fraction was washed successively with aqueous sat. NH4CI. aqueous NaCl. The organic portion was dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified by prep-HPLC (10-90% acetonitrile in water 0.1% trifluoroacetic acid over 30 minutes, Phenomenex Luna LC Column (5 pm Cl 8 100 A, 150 x 21.2 mm)) to provide (R)-l-(2,2-difluoroethyl)-N-(3,4-difluorophenyl)-4-(N- (l,l,l-trifluoropropan-2-yl)sulfamoyl)-lH-pyrrole-2-carboxamide as a white solid. 'H NMR (400 MHz, DMSO- e): 5 (ppm) 10.41 (br.s, 1 H), 8.31 (d, J =8.56 Hz, 1 H), 7.86 (ddd, J= 13.33, 7.46, 2.45 Hz, 1 H), 7.74 (d, J = 1.71 Hz, 1 H), 7.46 - 7.51 (m, 1 H), 7.39 - 7.45 (m. 2 H), 6.23 - 6.54 (m, 1 H), 4.84 - 4.98 (m, 2 H), 3.95 (dq. J = 15.31, 7.53 Hz, 1 H), 1.07 (d. J= 7.09 Hz, 3 H); HPLCMS: MS (ESI) m / z = 462.8 [M+H]+.

[0519] Example 16: Synthesis of (R)-l-(2.2-difluoroethyl)-N-(3-(difluoromethyl)-4- fluorophenyl)-4-(N-(L 1 , 1 -trifluoropropan-2-yl)sulfamoyl)- lH-pyrrole-2-carboxamide

[0521] Synthesis of (R)-l-(2,2-difluoroethyl)-N-(3-(difluoromethyl)-4-fluorophenyl)- 4-(N-(l,l,l-trifluoropropan-2-yl)sulfamoyl)-lH-pyrrole-2-carboxamide: A solution of (R)- 1 -(2,2-difluoroethy l)-4-(N-( 1,1, 1 -trifluoropropan-2-yl)sulfamoy 1)- 1 H-py rrole-2- carboxylic acid (30 mg, 0.085 mmol) in anhydrous N,N-dimethylformamide (1.5 mL), was treated with l-ethyl-3-(3-dimethylaminopropyl)carbodiimide HC1 (49 mgr, 0.255 mmol), hydroxybenzotriazole (39 mgr, 0.255 mmol), and N,N-diisopropylethylamine (0.075 ml, 0.425 mmol) and stirred at 22 °C for 10 minutes. 3-(difluoromethyl)-4- fluoroaniline (47 mg, 0.289 mmol) was added. The resulting reaction mixture was stirred at 22 °C for 20 hours, quenched with ice water, and extracted with ethyl acetate. The organic fraction was washed successively with aqueous saturated NH4CI and aqueous NaCl. The organic portion was dried over Na2SO4, filtered, and concenrated under reduced pressure. The residue w as purified by prep-HPLC (10-90% acetonitrile in water 0.1% trifluoroacetic acid over 30 minutes, Phenomenex Luna LC Column (5 pm C18 100 A, 150 x 21.2 mm)) to provide (R)-l-(2,2-difluoroethyl)-N-(3- (difluoromethy l)-4-fluorophenyl)-4-(N-(l , 1 , 1 -trifluoropropan-2-yl)sulfamoyl)- 1H- pyrrole-2-carboxamide as a white solid.1H NMR (400 MHz. DMSO-rfc): 6 (ppm) 10.42 (br.s, 1 H), 8.32 (d, J = 8.80 Hz, 1 H), 8.05 (dd, J =6. 1 1, 2.45 Hz, 1 H), 7.87 (dt, J = 8.07, 4.03 Hz, 1 H), 7.74 (d, J= 1.71 Hz, 1 H), 7.45 (d, J= 1.71 Hz, 1 H), 7.34 - 7.41 (m, 1 H), 7.10 - 7.26 (m, 1 H), 6.23 - 6.56 (m, 1 H), 4.85 - 4.99 (m, 2 H), 3.95 (dq, J = 15.19, 7.49 Hz, 1 H), 1.08 (d. J = 6.85 Hz, 3 H); HPLCMS: MS (ESI) m / z = 494.8 [M+H]’.494.8.

[0522] Example 17: Synthesis of (R)-N-(3-cyano-4-fluorophenyl)-l-(2,2- difluoroethyl)-4-(N-(l,l,l-trifluoropropan-2-yl)sulfamoyl)-lH-pyrrole-2- carboxamide:

[0523]

[0524] Synthesis of (R)-N-(3-cyano-4-fluorophenyl)-l-(2,2-difluoroethyl)-4-(N-(l,l,l-trifluoropropan-2-yl)sulfamoyl)-lH-pyrrole-2-carboxamide: A solution of (R)- 1 -(2,2-difluoroethy l)-4-(N-( 1 , 1 , 1 -trifluoropropan-2-yl)sulfamoy 1)- lH-pyrrole-2- carboxylic acid (38 mg, 0. 108 mmol) in anhydrous N,N-dimethylformamide (1.5 mL), was treated with l-ethyl-3-(3-dimethylaminopropyl)carbodiimide HC1 (62 mgr, 0.324 mmol), hydroxybenzotriazole (50 mgr, 0.324 mmol), and N,N-diisopropylethylamine (0.094 ml, 0.54 mmol) and stirred at 22 °C for 10 minutes, and then 5-amino-2- fluorobenzonitrile (44 mg, 0.324 mmol) was added. The resulting reaction mixture was stirred at 22 °C for 20 hours, quenched with ice water, and extracted with ethyl acetate. The organic fraction was washed successively with aqueous saturated NH4CI and aqueous NaCl. The organic portion was dried over Na2SOr, filtered, and evaporated under reduced pressure. The residue was purified by prep-HPLC (10-90% acetonitrile in water 0.1% trifluoroacetic acid over 30 minutes, Phenomenex Luna LC Column (5 pm C18 100 A, 150 x 21.2 mm)) to provide (R)-N-(3-cyano-4-fhiorophenyl)-l-(2,2- difluoroethyl)-4-(N-( 1,1,1 -trifl uoropropan-2-y l)sulfamoy 1)- 1 H-py rrole-2-carboxamide as a pale orange solid.!H NMR (400 MHz, DMSO-rfc): 5 (ppm) 10.54 (br.s, 1 H), 8.34 (d, 8.80 Hz, 1 H), 8.21 (dd, J = 5.87. 2.69 Hz, 1 H), 8.00 (ddd, J = 9.29, 4.89, 2.69Hz. 1 H). 7.76 (d, J= 1.96 Hz. 1 H). 7.55 (t. J= 9.17 Hz, 1 H), 7.45 (d. J= 1.71 Hz, 1 H), 6.24 - 6.55 (m, 1 H), 4.85 - 4.98 (m, 2 H), 3.95 (dq, J= 15.25, 7.39 Hz, 1 H), 1.08 (d, J= 7.09 Hz, 3 H); HPLCMS: MS (ESI) m / z = 469.8 [M+H]+.

[0525] Example 18: Synthesis of (S)-l-(2,2-difluoroethyl)-N-(3.4-difluorophenyl)-4-(N-( 1 , 1 , 1 -trifluoropropan-2-yl)sulfamoy 1)- 1 H-pyrrole-2-carboxamideF3CX ..<''HN„ / OMe0O

[0526] H

[0527] Step 1 : Synthesis of methyl (S)-4-(N-( 1,1,1 -trifluoropropan-2-yl)sulfamoyl)- lH-pyrrole-2-carboxylate: The title compounds was prepared according to theprocedure of (R)-methyl 4-(N-(l,l,l-trifluoropropan-2-yl)sulfamoyl)-lH-pyrrole-2- carboxylate except that (R)-l,l,l-trifluoropropan-2-amine hydrochloride was replaced with (S)- 1,1,1 -trifl uoropropan-2-amine hydrochloride.

[0528]

[0529] Step 2: Synthesis of methyl (S)-l-(2,2-difluoroethyl)-4-(N-(l,l,l- trifluoropropan-2-yl)sulfamoyl)-lH-pyrrole-2-carboxylate: The title compound was prepared according to the procedure of methyl (R)-l-(2,2-difluoroethyl)-4-(N-(l,l,l- trifluoropropan-2-yl)sulfamoyl)-lH-pyrrole-2-carboxylate except that methyl (R)-4-(N-(l,l,l-trifluoropropan-2-yl)sulfamoyl)-lH-pyrrole-2-carboxylate was replaced with methyl (S)-4-(N-(l,l,l-trifluoropropan-2-yl)sulfamoyl)-lH-pyrrole-2- carboxylate.

[0531] Step 3: Synthesis of (S)-l-(2,2-difluoroethyl)-4-(N-(l,l,l-trifluoropropan-2- yl)sulfamoyl)-lH-pyrrole-2-carboxylic acid: The title compound was prepared according to the procedure of (R)-l-(2,2-difluoroethyl)-4-(N-(l,l,l-trifluoropropan-2- yl)sulfamoyl)-lH-pyrrole-2-carboxylic acid except that methyl (R)-l-(2,2- difluoroethyl)-4-(N-(l,l,l-trifluoropropan-2-yl)sulfamoyl)-lH-pyrrole-2-carboxylate was replaced with methyl (S)-l-(2,2-difluoroethyl)-4-(N-(l,l,l-trifluoropropan-2- yl)sulfamoyl)-lH-pyrrole-2-carboxylate.

[0532]

[0533] Step 4: Synthesis of (S)-l-(2,2-difluoroethyl)-N-(3,4-difluorophenyl)-4-(N- (l,l,l-trifluoropropan-2-yl)sulfamoyl)-lH-pyrrole-2-carboxamide: A solution of (S)- l-(2,2-difluoroethyl)-4-(N-(l,l,l-trifluoropropan-2-yl)sulfamoyl)-lH-pyrrole-2- carboxylic acid (20 mg, 0.057 mmol) in anhydrous N,N-dimethylformamide (1 rnL), was treated with l-ethyl-3-(3-dimethylaminopropyl)carbodiimide HC1 (33 mgr, 0.171 mmol), hydroxybenzotriazole (26 mgr, 0.171 mmol), and N,N-diisopropylethylamine (0.050 ml. 0.285 mmol) and stirred at 22 °C for 10 minutes, and then 3. 4- difluoroaniline (0.017 ml, 0.171 mmol) was added. The resulting reaction mixture was stirred at 22 °C for 20 hours, quenched with ice water, and extracted with ethyl acetate. The organic fraction was washed successively with aqueous saturated NH4CI and aqueous NaCl. The organic portion was dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue w as purified by prep-HPLC (10-90% acetonitrile in water 0.1% trifluoroacetic acid over 30 minutes, Phenomenex Luna LC Column (5 pm C18 100 A, 150 x 21.2 mm)) to provide (S)-l-(2,2-difluoroethyl)-N-(3,4- difluorophenyl)-4-(N-( 1,1,1 -trifluoropropan-2-y l)sulfamoyl)- IH-py rrole-2- carboxamide as an off-white solid.!H NMR (400 MHz, DMSO-ufe): 5 (ppm) 10.39 (br.s, 1 H), 8.29 (d, J = 8.59 Hz, 1 H), 7.85 (ddd, J= 13.28, 7.42, 2.34 Hz, 1 H), 7.73 (d, J= 1.95 Hz, 1 H), 7.46 - 7.50 (m, 1 H), 7.38 - 7.44 (m, 2 H), 6.22 - 6.53 (m, 1 H), 4.85 - 4.98 (m, 2 H), 3.89 - 3.99 (m, 1 H), 1.08 (d, J = 7.03 Hz, 3 H); HPLCMS: MS (ESI) m / z = 462.1 [M+H] ' .

[0534] Example 19: Synthesis of (S)-l-(2,2-difluoroethyl)-N-(3-(difluoromethyl)-4- fluorophenyl)-4-(N-(l,l,l-trifluoropropan-2-yl)sulfamoyl)-lH-pyrrole-2-carboxamide

[0536] Synthesis of (S)-l-(2,2-difluoroethyl)-N-(3-(difhioromethyl)-4-fluorophenyl)- 4-(N-(l,l,l-trifluoropropan-2-yl)sulfamoyl)-lH-pyrrole-2-carboxamide: A solution of (S)- 1 -(2,2-difluoroethy l)-4-(N-(l ,1,1 -trifl uoropropan-2-y l)sulfamoyl)- IH-py rrole-2- carboxylic acid (20 mg, 0.057 mmol) in anhydrous N,N-dimethylformamide (1 mL), was treated with l-ethyl-3-(3-dimethylaminopropyl)carbodiimide HC1 (33 mgr, 0.171 mmol), hydroxybenzotriazole (26 mgr, 0.171 mmol), and N,N-diisopropylethylamine(0.050 ml, 0.285 mmol) and stirred at 22 °C for 10 minutes, and then 3- (difluoromethyl)-4-fluoroaniline (27 mg. 0.171 mmol) was added. The resulting reaction mixture was stirred at 22 °C for 20 hours, quenched with ice water, and extracted with ethyl acetate. The organic fraction was washed successively with aqueous saturated NH4CI and aqueous NaCl. The organic portion was dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified by prep-HPLC (10-90% acetonitrile in water 0.1% trifluoroacetic acid over 30 minutes. Phenomenex Luna LC Column (5 pm C18 100 A, 150 x 21.2 mm)) to provide (S)-l- (2,2-difluoroethyl)-N-(3-(difluoromethyl)-4-fluorophenyl)-4-(N-(l,l,l- trifluoropropan-2-yl)sulfamoyl)-lH-pyrrole-2-carboxamide as a pale orange solid. ’H NMR (400 MHz. DMSO- e): 5 (ppm) 10.41 (br.s, 1 H), 8.30 (d, J= 8.59 Hz, 1 H), 8.05 (dd, J= 6.25, 2.73 Hz, 1 H), 7.84 - 7.90 (m, 1 H), 7.73 (d, J= 1.95 Hz, 1 H), 7.45 (d, J = 1.56 Hz, 1 H), 7.35 - 7.40 (m, 1 H), 7.08 - 7.25 (m, 1 H), 6.23 - 6.53 (m, 1 H), 4.86 - 4.98 (m, 2 H), 3.89 - 3.99 (m, 1 H), 1.08 (d, J = 7.03 Hz, 3 H); HPLCMS: MS (ESI) m / z = 494.2 [M+H]+.

[0537] Example 20: Synthesis of (S)-N-(3-cyano-4-fluorophenyl)-l-(2,2- difluoroethyl)-4-(N-( 1,1,1 -trifl uoropropan-2-y l)sulfamoy 1)- 1 H-py rrole-2- carboxamide:

[0538]

[0539] Synthesis of (S)-N-(3-cyano-4-fluorophenyl)-l-(2,2-difluoroethyl)-4-(N-(l,l,l-trifluoropropan-2-yl)sulfamoyl)-lH-pyrrole-2-carboxamide: A solution of (S)- 1 -(2,2-difluoroethy l)-4-(N-( 1,1,1 -trifluoropropan-2-yl)sulfamoy 1)- lH-pyrrole-2- carboxylic acid (32 mg, 0.091 mmol) in anhydrous N,N-dimethylformamide (1.5 mb), was treated with l-ethyl-3-(3-dimethylaminopropyl)carbodiimide HC1 (52 mgr, 0.273 mmol), hydroxybenzotriazole (42 mgr, 0.273 mmol), and N,N-diisopropylethylamine (0.079 ml, 0.455 mmol) and stirred at 22 °C for 10 minutes, 5-amino-2- fluorobenzonitrile (37 mg, 0.273 mmol) was added. The resulting reaction mixture was stirred at 22 °C for 20 hours, quenched with ice water, and extracted with ethyl acetate. The organic fraction was washed successively with aqueous saturated NH4CI andaqueous NaCl. The organic portion was dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified by prep-HPLC (10-90% acetonitrile in water 0.1% trifluoroacetic acid over 30 minutes, Phenomenex Luna LC Column (5 pm C18 100 A, 150 x 21.2 mm)) to provide (S)-N-(3-cyano-4-fluorophenyl)-l-(2,2- difluoroethyl)-4-(N-(l,l,l-trifluoropropan-2-yl)sulfamoyl)-lH-pyrrole-2-carboxamide as a light brown solid.!H NMR (400 MHz, DMSO-<fe): 5 (ppm) 10.52 (br.s, 1 H), 8.32 (d, J= 8.59 Hz, 1 H), 8.21 (dd, J = 5.47. 2.73 Hz. 1 H). 8.00 (ddd, J = 9.18, 4.88, 2.73 Hz, 1 H), 7.75 (d, J= 1.95 Hz, 1 H), 7.55 (t, J= 8.98 Hz, 1 H), 7.45 (d, J= 1.95 Hz, 1 H), 6.23- 6.54 (m, 1 H), 4.86 - 4.98 (m, 2 H), 3.90 - 3.99 (m, 1 H), 1.08 (d, J= 7.03 Hz, 3 H); HPLCMS: MS (ESI) m / z = 469.1 [M+H]+.

[0540] Example 21 : Synthesis of l-(2.2-difluoroethyl)-N-(3,4- difluorophenyl)-3- fluoro-4-[[(lR)-2,2,2-trifluoro-l-methyl-ethyl]sulfamoyl]pyrrole-2-carboxamide

[0541] Step 1 : Synthesis of ethyl l-(2,2-difluoroethyl)-3-fluoro-pyrrole-2-carboxylate

[0543] To a solution of ethyl 3-fluoro-lH-pyrrole-2-carboxylate (4.50 g, 28.6 mmol) and CS2CO3 (18.6 g. 57.2 mmol) in N,N-dimethylformaide (50 mL) was added 1,1- difluoro-2-iodo-ethane (8.24 g, 42.9 mmol). The reaction mixture was stirred at 20 °C for 16 hours under nitrogen, quenched by addition water (250 mL), and extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with brine (50 mL x 3), dried with anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by column chromatography (S1O2. Petroleum ether / Ethyl acetate=l / O to 5 / 1) to give ethyl l-(2,2-difluoroethyl)-3-fluoro-pyrrole-2-carboxylate as a yellow oil. 'H NMR: (400 MHz, CDCh): 5 6.73 - 6.63 (m, 1H), 6.22 - 5.87 (m, 2H), 4.55 (dt. J= 4.0, 13.2 Hz, 2H), 4.34 (q, J= 7.2 Hz. 2H), 1.38 (t, J= 7.2 Hz, 3H).

[0544] Step 2: Synthesis of l-(2,2-difluoroethyl)-5-ethoxycarbonyl-4-fluoro-pyrrole- 3-sulfonic acid:ethyl l-(2,2-difluoroethyl)-3-fluoro-pyrrole-2-carboxylate(6.00 g, 27. 1 mmol) in dichloromethane (50 mL) was added sulfurochloridic acid (4.1 1 g, 35.2 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 2.5 hours under nitrogen and then the mixture was concentrated in vacuum to give l-(2,2- difluoroethyl)-5 -ethoxy carbonyl-4-fluoro-pyrrole-3- sulfonic acid as a yellow oil. The resulting material was used without further purification.

[0547] Step 3: Synthesis of ethyl 4-chlorosulfonyl-l-(2,2-difluoroethyl)-3-fluoro- pyrrole-2- carboxylate

[0549] A solution of l-(2,2-difluoroethyl)-5-ethoxycarbonyl-4-fluoro-pyrrole-3- sulfonic acid (8.00 g, 26.5 mmol) in thionyl chloride (63.2 g, 531 mmol) was stirred at 80 °C for 6 hours under nitrogen. The mixture was then cooled, concentrated under vacuum, and the residue was purified by column chromatography (S1O2. Petroleum ether / Ethyl acetate=20 / l to 3 / 1, Rf=0.40) to give ethyl 4-chlorosulfonyl-l-(2,2- difluoroethyl)-3-fluoro-pyrrole-2-carboxylate as a light yellow solid.!H NMR: (400 MHz, DMSO- >): 5 7.20 - 7.04 (m, 1H), 6.43 - 6.03 (m, 1H), 4.68 (dt, J= 3.6, 14.8 Hz, 2H), 4.32 - 4.12 (m, 2H). 1.31 - 1.16 (m. 3H).

[0550] Step 4: Sysnthesis of ethyl l-(2,2-difluoroethyl)-3-fluoro-4-[[(lR)-2,2,2- trifluoro- 1 -methyl- ethyl] sulfamoyl] pyrrole-2-carboxylate

[0552] To a solution of ethyl 4-chlorosulfonyl-l-(2,2-difluoroethyl)-3-fluoro-pyrrole- 2-carboxylate (7.20 g. 22.5 mmol) and pyridine (5.34 g, 67.5 mmol, 5.45 mL) in acetonitrile (50 mL) was added N,N-demethylaminopyridine (412 mg, 3.38 mmol) and (2R)-l,l,l-trifluoropropan-2-amine;hydrochloride (5.39 g, 36.0 mmol).The reaction mixture was stirred at 85 °C for 16 hours under N2. The reaction mixture was the cooled and concentrated under vacuum. The residue was purified by column chromatography (S1O2. Petroleum ether / Ethyl acetate=20 / l to 3 / 1) to give ethyl l-(2.2-difluoroethyl)-3- fluoro-4-[[(lR)-2,2,2-trifluoro-l -methyl-ethyl]sulfamoyl]pyrrole-2-carboxylate as a white solid. 'H NMR: (400 MHz, DMSO-rie): 58.74 (d, J = 8.8 Hz, 1H), 7.69 (d, J = 4.8 Hz, 1H), 6.53 - 6.14 (m, 1H), 4.91 - 4.69 (m, 2H), 4.29 (q, J = 7.2 Hz, 2H), 4.06 - 3.92 (m, 1H). 1.28 (t. J = 7.2 Hz, 3H), 1.16 (d. J= 6.8 Hz, 3H).

[0553] Step 5: Synthesis of l-(2,2-difluoroethyl)-3-fluoro-4-[[(lR)-2,2,2-trifluoro-l- methyl-ethyl] sulfamoyl]pyrrole-2-carboxylic acid

[0555] To a solution of ethyl l-(2.2-difluoroethyl)-3-fluoro-4-[[(lR)-2.2.2-trifluoro-l- methyl-ethyl] sulfamoyl]pyrrole-2-carboxylate (6.50 g, 16.4 mmol) in tetrahydrofuran (60 mL) was added a solution of LiOH.H2O (2.06 g, 49.2 mmol) in H2O (20 mL). The reaction mixture was stirred at 20 °C for 16 hours and concentrated under vacuum to remove tetrahydrofuran, then extracted with ethyl acetate (20 mL x 3). The aqueous phase was adjusted pH = 3 with HC1 solution (1 M). The resulting suspension was filtered to give l-(2,2-difluoroethyl)-3-fluoro-4-[[(lR)-2,2,2-trifluoro-l-methyl- ethyl]sulfamoyl]pyrrole-2-carboxylic acid as a white solid, ’l l NMR: (400 MHz, DMSO-O: 5 13.46 (s, J = 2.3 Hz, 1H), 8.71 (d, J = 8.8 Hz, 1H), 7.64 (d, J = 4.8 Hz, 1H), 6.53 - 6.13 (m, 1H), 4.90 - 4.70 (m, 2H), 4.08 - 3.87 (m, 1H), 1.15 (d, J = 6.8 Hz, 3H).

[0556] Step 6: Synthesis of l-(2,2-difluoroethyl)-N-(3,4-difluorophenyl)-3-fluoro-4- [[(lR)-2,2,2- trifluoro-l-methyl-ethyl]sulfamoyl]pyrrole-2-carboxamide.

[0558] To a solution of l-(2,2-difluoroethyl)-3-fluoro-4-[[(lR)-2,2,2-trifluoro-l- methyl-ethyl]sulfamoyl]pyrrole-2-carboxylic acid (3.00 g, 8.15 mmol) and N,N- diisopropylethyl amine (5.26 g, 40.7 mmol), hydroxybenzotriazole (1.32 g, 9.78 mmol), l-ethyl-3-(3-dimethylaminopropyl)carbodiimide (1.87 g, 9.78 mmol) in methylene chloride (40 mL) was added 3,4-difluoroaniline (1.37 g, 10.6 mmol), the reaction mixture was stirred at 40 °C for 10 hours. Then, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiCh, Petroleum ether / Ethyl acetate=20 / l to 3 / 1). The resulting material was triturated with petroleum ether (30 mL) at 25 °C for 30 mins and toluene (20 mL) at 80 °C for 10 minutes to give l-(2,2-difluoroethyl)-N-(3,4-difluorophenyl)-3-fluoro-4-[[(lR)-2,2,2- trifluoro- 1 -methyl-ethyl] sulfamoyl] pyrrole -2-carboxamide as a white solid.!H NMR: (400 MHz, DMSO-cL): 5 10.44 (s, 1H), 8.74 (d, J = 8.8 Hz, 1H), 7.86 - 7.75 (m, 1H), 7.62 (d. J= 4.4 Hz, 1H), 7.47 - 7.37 (m, 2H), 6.54 - 6.20 (m, 1H). 4.91 - 4.58 (m. 2H), 4. 11 - 3.86 (m, 1H), 1.19 (d, J = 6.8 Hz. 3H). HPLCMS : MS (ESI) m z = 480.1 [M+H]+.

[0559] Example 22: Synthesis of l-(2,2-difluoroethyl)-N-(2,3-difluorophenyl)-3- fluoro-4-[[(lR)-2,2,2- trifluoro-l-methyl-ethyl]sulfamoyl]pyrrole-2-carboxamide

[0561] To a solution of l-(2,2-difluoroethyl)-3-fluoro-4-[[(lR)-2,2,2-trifluoro-l- methyl-ethyl]sulfamoyl]pyrrole-2-carboxylic acid (80.0 mg, 217 pmol). N,N- diisopropylethyl amine (112 mg, 868 pmol), hydroxybenzotriazole (35.2 mg, 260 pmol) and l-ethyl-3-(3-dimethylaminopropyl)carbodiimide (49.9 mg, 260 pmol) in methylene chloride (2 mL) was added 2,3-difluoroaniline (30.8 mg, 238 pmol). The reaction mixture was stirred at 40 °C for 16 hours, cooled, diluted with water (5 mL), and extracted with methylene chloride (5 mL x 3). The combined organic layers were dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated undervacuum, and the residue was purified by prep-HPLC (column: Phenomenex luna Cl 8 150*25 mm* 10 um; mobile phase: [water (HC1)- acetonitrile]; gradient: 42%-72% B over 9 minutes) to give l-(2,2-difluoroethyl)-N-(2,3-difluorophenyl)-3-fluoro-4- [[(lR)-2,2,2-trifluoro-l-methyl-ethyl]sulfamoyl]pyrrole-2-carboxamide as an off- white solid. 'H NMR: (400 MHz, CDCh): 5 8.11 (d, J = 8.0 Hz, 1H), 8.08 - 8.02 (m, 1H), 7.23 (d, J = 4.8 Hz, 1H). 7.17 - 7.07 (m, 1H). 7.05 - 6.93 (m, 1H), 6.16 (tt, J = 56.0, 4.0 Hz. 1H), 4.91 (d. J = 8.0 Hz, 1H). 4.76 - 4.68 (m, 2H). 4.17 - 4.01 (m. 1H). 1.44 (d, J= 6.8 Hz, 3H); HPLC / MS product retention time = 2.203 minutes, MS (ESI) m'z = 480.1 [M+H]+.

[0562] Example 23: Synthesis of l-(2,2-difluoroethyl)-3-fluoro-4-[[(lR)-2,2,2- trifluoro-l-methyl-ethyl]sulfamoyl]-N-(3,4,5-trifluorophenyl)pyrrole-2-carboxamide.

[0564] To a solution of l-(2,2-difluoroethyl)-3-fluoro-4-[[(lR)-2,2,2-trifluoro-l- methyl-ethyl]sulfamoyl]pyrrole-2-carboxylic acid (80.0 mg, 217 pmol), N,N- diisopropylethyl amine (140 mg, 1.09 mmol), hydroxybenzotriazole (35.2 mg, 260 pmol) and l-ethyl-3-(3-dimethylaminopropyl)carbodiimide (49.9 mg. 260 pmol) in methylene chloride (3 mL) was added 3,4,5-trifluoroaniline (38.3 mg, 260 pmol). The reaction mixture was stirred at 40 °C for 16 hours, cooled, diluted with H2O (5 mL) and extracted with methylene chloride (5 mL x 3). The organic layers were combined, dried with anhy drous sodium sulfate, filtered and the filtrate was concentrated under vacuum. The resulting material was purified by prep-HPLC (column: Phenomenex luna Cl 8 150*25 mm* 10 um; mobile phase: [water (HCl)-acetonitrile]; gradient: 47%-77% B over 9 minutes) to give l-(2,2-difluoroethyl)-3-fluoro-4-[[(lR)-2,2,2-trifluoro-l- methyl-ethyl |sulfamoyl |-A / -(3.4.5-trifluorophenyl)pyrrole-2-carbo.\amide as an off- white solid. 'H NMR: (400 MHz, CDCh): 5 7.74 (d, J = 9.6 Hz, 1H), 7.32 - 7.28 (m, 2H), 7.23 (d, J= 4.8 Hz, 1H), 6.15 (tt, J= 56.0, 4.0 Hz, 1H), 4.87 (d, J = 9.6 Hz, 1H), 4.76 - 4.66 (m, 2H), 4.16 - 4.01 (m, 1H), 1.45 (d, J= 7.2 Hz, 3H); HPLC / MS: product: retention time = 2.329 minutes, MS (ESI) m / z = 498.0 [M+H]+.

[0565] Example 24: Synthesis of N-(3-chlorophenyl)-l-(2,2-difluoroethyl)-3-fluoro-4- [[(lR)-2,2,2- trifluoro-l-methyl-ethyl]sulfamoyl]pyrrole-2-carboxamide

[0567] To a solution of l-(2.2-difluoroethyl)-3-fluoro-4-[[(lR)-2.2.2-trifluoro-l- methyl-ethyl] sulfamoyl]pyrrole-2-carboxylic acid (80.0 mg, 217 pmol) and N,N- diisopropylethyl amine (140 mg, 1.09 mmol), hydroxybenzotriazole (35.2 mg, 260 pmol), l-ethyl-3-(3-dimethylaminopropyl)carbodiimide (49.9 mg, 260 pmol) in methylene chloride (3 mL) was added 3 -chloroaniline (27.7 mg, 217 pmol). The reaction mixture was stirred at 40 °C for 16 hours, cooled, diluted with H2O (5 mL), and extracted with methylene chloride (5 mL x 2). The organic layers were combined and dried with anhydrous sodium sulfate, filtered and the filtrate was concentrated under vacuum. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150*25 mm* 10 urn; mobile phase: [water (HCl)-acetocitrileJ; gradient: 47%-77% B over 9 minutes) to give A^-(3-chlorophenyl)-l-(2,2-difluoroethyl)-3-fluoro-4-[[(77?)-2.2.2-trifluoro-l-methyl-ethyl] sulfamoyl] pyrrole-2-carboxamide as an off-white solid. 'H NMR: (400 MHz, CDCh): 5 7.79 (d, J= 9.6 Hz, 1H), 7.74 - 7.69 (m, 1H), 7.38 - 7.34 (m, 1H), 7.34 - 7.29 (m, 1H). 7.22 (d, J= 4.8 Hz, 1H), 7.20 - 7.15 (m, 1H), 6.17 (tt, J= 56.0, 4.0 Hz, 1H), 4.86 (d, J= 9.6 Hz, 1H), 4.76 - 4.66 (m, 2H), 4.16 - 4.02 (m, 1H), 1.44 (d, J= 6.8 Hz, 3H); HPLC / MS: product retention time = 2.286 minutes, MS (ESI) / « : = 478.0 [M+H]+.

[0568] Example 25: Synthesis of l-(2,2-difluoroethyl)-3-fluoro-N-phenyl-4-[[(lR)-2.2.2-trifluoro-l-methyl-ethyl]sulfamoyl]pyrrole-2-carboxamide

[0570] To a solution of l-(2,2-difluoroethyl)-3-fluoro-4-[[(lR)-2,2,2-trifluoro-l- methyl-ethyl]sulfamoyl]pyrrole-2-carboxylic acid (80.0 mg, 217 pmol) and N,N- diisopropylethyl amine (140 mg, 1.09 mmol), hydroxybenzotriazole (35.2 mg, 260 pmol), l-ethyl-3-(3-dimethylaminopropyl)carbodiimide (49.9 mg, 260 pmol) in methylene chloride (3 mL) was added aniline (24.3 mg, 260 pmol). The reactionmixture was stirred at 40 °C for 16 hours, cooled, diluted with H2O (5 mL), then extracted with methylene chloride (5 mL / 3). The organic layers were combined and dried with anhydrous sodium sulfate, filtered and the filtrate was concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150*25 mm* 10 um; mobile phase: [water (HCl)-acetonitrile] ; gradient:40%-70% B over 9 minutes) to give l-(2,2-difluoroethyl)-3-fluoro-N-phenyl-4-[[(lR)-2,2,2-trifluoro-l-methyl- ethyl]sulfamoyl]pyrrole-2-carboxamide as an off-white solid.XH NMR: (400 MHz. CDCh): 57.80 (d, J = 8.4 Hz, 1H), 7.54 (d, J = 7.6 Hz, 2H), 7.40 (t, J = 7.6 Hz, 2H), 7.24 - 7.17 (m, 2H), 6.19 (tt, J= 56.0, 4.0 Hz, 1H), 4.87 (d, J= 9.6 Hz, 1H), 4.76 - 4.66 (m, 2H), 4.16 - 4.02 (m, 1H), 1.44 (d. J = 6.8 Hz, 3H); HPLC / MS: product retention time = 2.119 minutes, MS (ESI) m 'z = 444.1 [M+H]+.

[0571] Example 26: Synthesis of l-(2,2-difluoroethyl)-3-fluoro-4-[[(lR)-2,2,2- trifluoro-l-methyl-ethyl]sulfamoyl]-N-(2,4,5-trifluorophenyl)pyrrole-2-carboxamide

[0572] Step 1 : Preparation of l-(2,2-difluoroethyl)-3-fluoro-4-[[(lR)-2,2,2-trifluoro-l- methyl-ethyl]sulfamoyl]pyrrole-2-carboxylate

[0574] To a solution of l-(2,2-difluoroethyl)-3-fluoro-4-[[(lR)-2,2,2-trifluoro-l- methyl-ethyl]sulfamoyl]pyrrole-2-carboxylic acid (200 mg, 543 pmol) and N,N- dimethylformamide (3.97 mg. 54.3 pmol) in methylene chloride (2 mL) was added (COC1)2 (103 mg, 814 pmol) at 0 °C. The mixture was stirred at 25 °C for 10 minutes. Then the resulting mixture was added dropwise into MeOH (8 mL), and the reaction mixture was stirred at 25 °C for 15 minutes. The reaction mixture was then diluted with H2O (20 mL) and extracted with methylene chloride (15 mL x 3). The organic layers were combined and dried with anhydrous sodium sulfate, filtered and the filtrate was concentrated in vacuo to give methyl l-(2,2-difluoroethyl)-3-fluoro-4-[[(lR)-2,2,2- trifluoro-l-methyl-ethyl]sulfamoyl]pyrrole-2-carboxylate (200 mg, 0.52 mmol, 96% yield) as a white solid. ’H NMR: (400 MHz, CDCh): 5 7.21 (d, J= 4.4 Hz, 1H), 6.05 (tt, J= 56.0, 4.0 Hz, 1H), 5.02 (d, J= 9.6 Hz, 1H), 4.67 - 4.58 (m, 2H), 4.11 - 4.00 (m, 1H), 3.92 (s, 3H), 1.39 (d, J= 7.2 Hz, 3H); HPLC / MS: product retention time = 0.826 minutes, MS (ESI) m / z = 383.1[M+H]+.

[0575] Step 2: Preparation of l-(2,2-difluoroethyl)-3-fluoro-4-[[(lR)-2,2,2-trifluoro-l- methyl-ethyl]sulfamoyl]-N-(2.4,5-trifluorophenyl)pyrrole-2-carboxamide

[0577] To a solution of methyl l-(2,2-difluoroethyl)-3-fluoro-4-[[(lR)-2,2,2-trifluoro- l-methyl-ethyl]sulfamoyl]pyrrole-2-carboxylate (80.0 mg, 209 pmol) and 2,4,5- trifluoroaniline (40.0 mg, 272 pmol) in toluene (1.5 mL) was added AlMes (2 M in toluene, 0.63 mmol, 0.31 mL). the reaction mixture was stirred at 80 °C for 12 hours. The reaction was cooled, the mixture was diluted with saturated NH4Q solution (5 mL), and extracted with ethyl acetate (10 mL x 2). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by prep-HPLC (column: Waters xbridge 150*25 mm 10 um; mobile phase: [water (NH4HCO3)- acetonitrile]; gradient: 53%-73% B over 8 min) to give l-(2,2-difluoroethyl)-3-fluoro-4-[[(lR)-2,2,2-trifluoro-l-methyl- ethyl]sulfamoyl]-N-(2,4,5-trifluorophenyl)pyrrole-2-carboxamide as ayellow solid.JH NMR: (400 MHz, CDCh): 58.34 - 8.24 (m, 1H), 8.05 (br d, J= 7.6 Hz, 1H), 7.23 (d, J = 4.8 Hz. 1H), 7.10 - 7.02 (m, 1H), 6. 15 (ft, J = 56.0, 4.0 Hz, 1H), 5.01 (d, J = 9.2 Hz, 1H), 4.76 - 4.67 (m, 2H), 4.16 - 4.02 (m, 1H), 1.44 (d, J = 6.8 Hz, 3H); HPLC / MS: product retention time = 2.332 minutes, MS (ESI) mJz = 498.1 [M+H]+.

[0578] Example 27: Synthesis of l-(2.2-difluoroethyl)-N-[3-(difluoromethyl)-4- fluoro-phenyl]-3-fluoro-4-[[(lR)-2,2,2-trifluoro-l-methyl-ethyl]sulfamoyl]pyrrole-2- carboxamide.

[0579]

[0580] To a solution of l -(2,2-difluoroethyl)-3-fluoro-4-[[(lR)-2,2,2-trifluoro-l - methyl-ethyl]sulfamoyl]pyrrole-2-carboxylic acid (80.0 mg, 217 pmol) and N,N- diisopropylethyl amine (140 mg, 1.09 mmol), hydroxybenzotriazole (35.2 mg, 260 pmol), l-ethyl-3-(3-dimethylaminopropyl)carbodiimide (49.9 mg. 260 pmol) in methylene chloride (3 mL) was added 3-(difluoromethyl)-4-fluoro-aniline (42.0 mg.260 pmol), the reaction mixture was stirred at 40 °C for 16 hours. The reaction was cooled, diluted with H2O (5 mL), and extracted with methylene chloride (5 mL* 2). The organic layers were combined and dried with anhydrous sodium sulfate, filtered and the filtrate was concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150*25 mm* 10 um; mobile phase: [water (HC1)- acetonitrile] ; gradient:44%-74% B over 9 minutes) to give l-(2,2-difluoroethyl)-JV-[3- (difluoromethyl)-4-fluoro-phenyl]-3-fluoro-4-[[(lR)-2,2,2-trifluoro-l-methyl- ethyl]sulfamoyl]pyrrole-2-carboxamide as an off-white solid.!H NMR: (400 MHz, CDCI3): 57.84 (d, J = 9.6 Hz, 1H), 7.80 - 7.74 (m, 1H), 7.73 - 7.65 (m, 1H), 7.22 (d, J = 4.8 Hz, 1H), 7.17 (t, 7 = 9.2 Hz. 1H), 6.91 (t, J= 54.8 Hz, 1H), 6.16 (tt, 7= 56.0, 4.0 Hz. 1H), 4.89 (d, J= 9.2 Hz, 1H), 4.76 - 4.68 (m, 2H). 4. 18 - 4.00 (m. 1H), 1.45 (d, J = 6.8 Hz, 3H); HPLC / MS: product retention time = 2.246 minutes, MS (ESI) m / z = 512.1 [M+H]’.

[0581] Example 28: Synthesis of l-(2,2-difluoroethyl)-3-fluoro-N-[4-fluoro-3- (trifluoromethy l)pheny 1] -4- [[( 1 R)-2,2,2-trifluoro- 1 -methy 1-ethy 1] sulfamoyl] py rrole-2- carboxamide

[0582]

[0583] To a solution of l-(2,2-difluoroethyl)-3-fluoro-4-[[(lR)-2,2,2-trifluoro-l- methyl-ethyl]sulfamoyl]pyrrole-2-carboxylic acid (80.0 mg, 217 pmol) and N,N- diisopropylethyl amine (140 mg, 1.09 mmol), hydroxybenzotriazole (35.2 mg, 260 pmol), l-ethyl-3-(3-dimethylaminopropyl)carbodiimide (49.9 mg, 260 pmol) in methylene chloride (3 mL) was added 4-fluoro-3-(trifluoromethyl)aniline (42.8 mg,238 pmol). The reaction mixture was stirred at 40 °C for 16 hours, cooled, diluted with H2O (5 mL), then extracted with methylene chloride (5 mL x 2). The organic layers were combined and dried with anhydrous sodium sulfate, filtered and the filtrate was concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex luna C 18 150*25 mm* lO um; mobile phase: [water (HCl)-acetonitrile]; gradient: 48%- 78% B over 9 minutes) to give l-(2,2-difluoroethyl)-3-fluoro-N-[4-fluoro-3- (trifluoromethyl)phenyl]-4-[[(lR)-2,2,2-trifluoro-l-methyl-ethyl]sulfamoyl]pyrrole-2- carboxamide as an off-white solid. 'HNMR: (400 MHz, CDCL): 57.92 - 7.79 (m. 2H),7.76 - 7.69 (m, 1H), 7.26 - 7.20 (m, 2H), 6.16 (tt, J = 56.0, 4.0 Hz, 1H), 4.88 (d, J = 10.0 Hz, 1H), 4.76 - 4.67 (m, 2H). 4.19 - 4.03 (m, 1H), 1.45 (d, J = 6.8 Hz. 3H); HPLC / MS: product retention time = 2.452 minutes, MS (ESI) m / z = 530.2 [M+H]+.

[0584] Example 29: Synthesis of l-(2,2-difluoroethyl)-3-fluoro-N-(4-fluoro-3-methyl- phenyl)-4-[[(lR)-2,2,2-trifluoro-l-methyl-ethyl]sulfamoyl]pyrrole-2-carboxamide

[0586] To a solution of l-(2,2-difluoroethyl)-3-fluoro-4-[[(lR)-2,2,2-trifluoro-l- methyl-ethyl]sulfamoyl]pyrrole-2-carboxylic acid (80.0 mg, 217 pmol) and N,N- diisopropylethyl amine (140 mg, 1.09 mmol), hydroxybenzotriazole (35.2 mg, 260 pmol), l-ethyl-3-(3-dimethylaminopropyl)carbodiimide (49.9 mg, 260 pmol) in methylene chloride (3 mL) was added 4-fluoro-3-methyl-aniline (40.7 mg, 325 pmol). The reaction mixture was stirred at 40 °C for 16 hours, cooled, diluted with H2O (5 mL), and extracted with methylene chloride (5 mL x 2). The organic layers were combined and dried with anhydrous sodium sulfate, filtered and the filtrate was concentrated tn vacuo. The residue was purified by prep-HPLC (column: Waters xbridge 150*25 mm 10 urn; mobile phase: [water (NH4HCO3)-acetonitrile]; gradient: 55%-75% B over 8 minutes) to give l-(2,2-difluoroethyl)-3-fluoro-JV-(4-fluoro-3- methyl-phenyl)-4-[[(lR)-2,2,2-trifluoro-l-methyl-ethyl]sulfamoyl]pyrrole-2- carboxamide as an off-white solid. 'H NMR: (400 MHz, CDCh): 57.72 (d, J= 9.2 Hz, 1H), 7.38 (dd, J= 2.4, 6.4 Hz, 1H), 7.32 - 7.28 (m, 1H), 7.20 (d, J= 4.8 Hz, 1H), 7.02 (t, J= 8.8 Hz, 1H), 6.17 (tt, J= 56.0, 4.0 Hz, 1H), 5.19 - 4.77 (m, 1H), 4.76 - 4.67 (m, 2H), 4.15 - 4.03 (m, 1H), 2.31 (s, 3H), 1.44 (d. J = 6.8 Hz, 3H); HPLC / MS: product retention time = 2.261 minutes, MS (ESI) m 'z = 476.1 [M+H]+.

[0587] Example 30: Synthesis of N-(3-cyano-4-fluoro-phenyl)-l-(2,2-difluoroethyl)-3-fluoro-4-[[(lR)-2,2,2-trifluoro-l-methyl-ethyl]sulfamoyl]pyrrole-2-carboxamide

[0588]

[0589] To a solution of l-(2,2-difluoroethyl)-3-fluoro-4-[[(lR)-2,2,2-trifluoro-l- methyl-ethyl]sulfamoyl]pyrrole-2-carboxylic acid (20.0 mg, 54.3 pmol) and N,N- diisopropylethyl amine (28.0 mg, 217 pmol), hexafluorophosphate azabenzotriazole tetramethyl uronium (26.8 mg, 70.6 pmol) in N,N-dimethylformamide (2 mL) was added 5-amino-2-fluoro-benzonitrile (14.7 mg, 108 pmol). The reaction mixture was stirred at 60 °C for 16 hours, cooled, diluted with H2O (5 mL), and then extracted with methylene chloride (5 mL x 2). The organic layers were combined and dried with anhydrous sodium sulfate, fdtered and the fdtrate was concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150*25 mm* 10 um; mobile phase: [column: Phenomenex Luna Cl 8 150*25 mm* 10 um; mobile phase: [water (formic acid)-acetonitrile] ; gradient: 42%-72% B over 10 minutes) to give N-(3- cyano-4-fluoro-phenyl)-l-(2,2-difluoroethyl)-3-fluoro-4-[[(lR)-2,2,2-trifluoro-l- methyl-ethyl]sulfamoyl]pyrrole-2-carboxamide as a yellow solid. 'HNMR: (400 MHz, CDCh): 6 8.02 (dd, J= 2.8, 5.6 Hz, 1H), 7.85 (d, J= 9.6 Hz, 1H), 7.73 - 7.65 (m. 1H), 7.26 - 7.21 (m, 2H), 6.15 (tt, J= 56.0, 4.0 Hz, 1H). 4.93 (d, J= 9.2 Hz, 1H), 4.76 - 4.67 (m, 2H), 4.16 - 3.99 (m, 1H), 1.45 (d, J = 7.2 Hz, 3H); HPLC / MS: product retention time = 2.163 minutes, MS (ESI) m / z = 509.1 [M+Na]+.

[0590] Example 31: Synthesis of l-(2,2-difluoroethyl)-N-(2,4-difluorophenyl)-3- fluoro-4-[[(lR)-2,2,2- trifluoro-l-methyl-ethyl]sulfamoyl]pyrrole-2-carboxamide

[0592] To a solution of l-(2,2-difluoroethyl)-3-fluoro-4-[[(lR)-2,2,2-trifluoro-l- methyl-ethyl]sulfamoyl]pyrrole-2-carboxylic acid (80.0 mg, 217 pmol) and N,N- diisopropylethyl amine (140 mg, 1.09 mmol), hydroxybenzotriazole (35.2 mg, 260 pmol), l-ethyl-3-(3-dimethylaminopropyl)carbodiimide (49.9 mg, 260 pmol) in methylene chloride (3 mL) was added 2,4-difluoroaniline (33.6 mg, 260 pmol). The reaction mixture was stirred at 40 °C for 16 hours cooled, diluted with H2O (5 mL), and then extracted with methylene chloride (5 mL x 2). The organic layers were combined and dried with anhydrous sodium sulfate, filtered and the filtrate was concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150*25 mm* 10 um; mobile phase: [water (HCl)-acetonitrile]; gradient: 41%-71% Bover 9 minutes) to give l-(2.2-difluoroethyl)-JV-(2,4-difluorophenyl)-3-fluoro-4- [[(lR)-2,2,2-trifluoro-l-methyl-ethyl]sulfamoyl]pyrrole-2-carboxamide as an off- white solid. 'H NMR: (400 MHz, CDCh): 5 8.24 - 8.18 (m, 1H), 7.99 (br d, J= 8.4 H, 1H), 7.22 (d, J= 4.8 Hz, 1H), 6.98 - 6.89 (m, 2H), 6.16 (t, J= 56.0, 4.0 Hz, 1H), 4.96 (d, J= 9.2 Hz, 1H), 4.76 - 4.67 (m, 2H), 4.16 - 4.02 (m, 1H), 1.44 (d, J = 6.8 Hz, 3H); HPLC / MS: product retention time = 2.266 minutes, MS (ESI) m / z = 480.1 [M+H]+.

[0593] Example 32: Synthesis of N-(3-chloro-4-fluoro-phenyl)-l-(2.2-difluoroethyl)- 3-fluoro-4-[[(lR)- 2,2,2-trifluoro-l-methyl-ethyl]sulfamoyl]pyrrole-2-carboxamide

[0594]

[0595] To a solution of l -(2,2-difluoroethyl)-3-fluoro-4-[[(lR)-2,2,2-trifluoro-l - methyl-ethyl]sulfamoyl]pyrrole-2-carboxylic acid (80.0 mg, 217 pmol) and N,N- diisopropylethyl amine (140 mg, 1.09 mmol), hydroxybenzotriazole (35.2 mg, 260 pmol), l-ethyl-3-(3-dimethylaminopropyl)carbodiimide (49.9 mg. 260 pmol) in methylene chloride (3 mL) was added 3-chloro-4-fluoro-aniline (47.4 mg, 325 pmol). The reaction mixture was stirred at 40 °C for 16 hours, cooled, diluted with H2O (5 mL), and then extracted with methylene chloride (5 mL x 2). The organic layers were combined and dried with anhydrous sodium sulfate, filtered and the filtrate was concentrated in vacuo. The residue was purified by prep-HPLC (column: Waters xbridge 150*25 mm 10 um; mobile phase: [water (NH4HCO3)-acetonitrile]; gradient: 57%-77% B over 8 minutes) to give 7V-(3-chloro-4-fluoro-phenyl)-l-(2,2- difluoroethyl)-3-fluoro-4-[[(lR)-2.2,2-trifluoro-l-methyl-ethyl]sulfamoyl]pyrrole-2- carboxamide as a white solid. 'H NMR: (400 MHz, CDCh): 57.92 - 7.55 (m, 2H), 7.38 -7.30 (m, 1H), 7.22 (d, J= 4.4 Hz, 1H), 7. 16 (t, J= 8.8 Hz, 1H), 6. 16 (tt, J= 56.0, 4.0 Hz, 1H), 5.40 - 4.79 (m, 1H), 4.76 - 4.67 (m, 2H), 4.13 - 4.05 (m, 1H), 1.44 (d, J= 6.8 Hz, 3H); HPLC / MS: product retention time = 2.326 minutes, MS (ESI) m / z = 496.0 [M+H]~.

[0596] Example 33: Synthesis ofN-(3,4-difluorophenyl)-3-fluoro-l-(2-methoxyethyl)- 4-[[(lR)-2,2,2-trifluoro-l-methyl-ethyl]sulfamoyl]pyrrole-2-carboxamide

[0597] Step 1 : Preparation of ethyl 3 -fluoro- l-(2-methoxyethyl)pyrrole-2-carboxy late

[0599] To a solution of ethyl 3-fluoro-lH-pyrrole-2-carboxylate (1.00 g, 6.36 mmol) and CS2CO3 (4.15 g. 12.7 mmol) in N,N-dimethylformamide (15 mL) was added 1- iodo-2-methoxy-ethane (1.78 g, 9.55 mmol) at 0 °C. The reaction mixture was stirred at 20 °C for 16 hours under nitrogen, quenched by addition water (100 mL), and then extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with brine (50.0 mL), dried with anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiCh. Petroleum ether / Ethyl acetate=l / O to 5 / 1) to give ethyl 3-fluoro-l-(2-methoxyethyl)pyrrole-2- carboxylate as a colorless oil.JH NMR: (400 MHz, CDCh): 56.70 (dd, J = 3.2, 4.8 Hz, 1H), 5.87 (d. J = 2.8 Hz, 1H), 4.40 (t, J = 5.2 Hz, 2H), 4.32 (q, J = 7.2 Hz, 2H), 3.63 (t, J = 5.2 Hz, 2H), 3.30 (s, 3H), 1.37 (t, J = 7.2 Hz, 3H): HPLC / MS: product retention time = 0.584 minutes, MS (ESI) m / z = 216.1 [M+H]+.

[0600] Step 2: Preparation of 5-ethoxycarbonyl-4-fluoro-l-(2-methoxyethyl)pyrrole- 3-sulfonic acid

[0602] To a solution of ethyl 3-fluoro-l-(2-methoxyethyl)pyrrole-2-carboxylate (1.33 g. 6.18 mmol) in methylene chloride (13 mL) was added sulfurochloridic acid (936 mg, 8.03 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 2 hours under nitrogen and then concentrated under vacuum to give 5-ethoxycarbonyl-4-fluoro-l-(2- methoxyethyl) pyrrole-3-sulfonic acid as a yellow oil which was used without further purification. HPLC / MS: product retention time = 0.377 minutes, MS (ESI) m / z = 296.0 [M+H]’.

[0603] Step 3: Preparation of ethyl 4-chlorosulfonyl-3 -fluoro- 1 -(2- methoxyethyl)pyrrole-2-carboxylate

[0605] A solution of 5-ethoxycarbonyl-4-fluoro-l-(2-methoxyethyl)pyrrole-3-sulfonic acid (1.80 g, 6. 10 mmol) in SOCI2 (24.5 g, 206 mmol) was stirred at 80 °C for 6 hours under nitrogen, cooled, and concentrated in vacuo. The residue was purified by column chromatography (SiCh, Petroleum ether / Ethyl acetate=20 / l to 3 / 1) to give ethyl 4- chlorosulfonyl-3-fluoro-l-(2-methoxyethyl)pyrrole-2-carboxylate as a yellow oil. 'HNMR: (400 MHz, CDCh): 5 7.39 (d, J= 3.6 Hz, 1H). 4.50 (t. J= 4.8 Hz. 2H), 4.37 (q. J= 7.2 Hz, 2H), 3.65 (t, J= 4.8 Hz, 2H), 3.33 (s, 3H), 1.39 (t, J= 7.2 Hz, 3H).

[0606] Step 4: Preparation of ethyl 3-fluoro-l-(2-methoxyethyl)-4-[[(lR)-2,2,2- trifluoro-l-methyl-ethyl]sulfamoyl]pyrrole-2-carboxylate

[0608] To a solution of ethyl 4-chlorosulfonyl-3-fluoro-l -(2 -methoxy ethyl)pyrrole-2- carboxylate (0.40 g, 1.27 mmol) and pyridine (302 mg, 3.82 mmol) in acetonitrile (5 mL) was added 4-dimethylaminopyridine (23.3 mg. 191 pmol) and (2 )-1,1,1- trifluoropropan-2-amine;hydrochloride (286 mg, 1.91 mmol). The reaction mixture was stirred at 85 °C for 16 hours under nitrogen, cooled, and concentrated in vacuo. The residue was purified by column chromatography (SiCh, Petroleum ether / Ethyl acetate=20 / l to 3 / 1) to give ethyl 3-fluoro-l-(2-methoxyethyl)-4-[[(lR)-2.2,2-trifluoro- l-methyl-ethyl]sulfamoyl]pyrrole-2-carboxylate as a colorless oil. 'H NMR: (400 MHz, CDCk): 87.21 (d, J= 4.0 Hz, 1H), 4.77 (d, J= 9.6 Hz, 1H), 4.44 (t, J= 4.8 Hz, 2H), 4.34 (q, J= 7.2 Hz, 2H), 4.07 - 4.00 (m, 1H), 3.62 (t, J= 4.8 Hz, 2H), 3.30 (s, 3H), 1.44 - 1.33 (m, 6H); HPLC / MS: product retention time = 0.574 minutes, MS (ESI) m'z = 391.2 [M+H]+.

[0609] Step 5: Preparation of 3-fluoro-l-(2-methoxyethyl)-4-[[(lR)-2,2,2-trifluoro-l- methyl-ethyl]sulfamoyl]pyrrole-2-carboxylic acid

[0611] To a solution of ethyl 3-fluoro-l-(2-methoxyethyl)-4-[[(lR)-2,2,2-trifluoro-l- methyl-ethyl]sulfamoyl]pyrrole-2-carboxylate (330 mg. 845 pmol) in tetrahydrofuran (9 mL) was added a solution of LiOHTbO (106 mg, 2.54 mmol) in H2O (3 mL). The reaction mixture was stirred at 20 °C for 16 hours, concentrated under reduced pressure, water (10 mL) was added, and the solution was adjusted to pH = 3 with HC1 solution (1 M). The resulting suspension was filtered. The filtered cake was collected and dried to give 3-fluoro-l-(2-methoxyethyl)-4-[[(lR)-2.2.2-trifluoro-l-methyl- ethyl]sulfamoyl]pyrrole-2-carboxylic acid as a white solid. 'H NMR: (400 MHz, DMSO-^6): 3 13.70 - 12.66 (m, 1H), 8.60 (d, J= 8.8 Hz, 1H), 7.52 (d, J= 4.8 Hz, 1H), 4.43 (t, J= 4.4 Hz, 2H), 4.02 - 3.89 (m, 1H), 3.56 (t, J= 5.2 Hz, 2H), 3.21 (s, 3H), 1. 14 (d, J = 6.8 Hz, 3H).

[0612] Step 6: Preparation of N-(3,4-difluorophenyl)-3-fluoro-l-(2-methoxyethyl)-4- [[( 1 R)-2,2,2-trifluoro- 1 -methy 1-ethyl] sulfamoyl] py rrole-2-carboxamide

[0613]

[0614] To a solution of 3-fluoro-l-(2-methoxyethyl)-4-[[(lR)-2.2.2-trifluoro-l- methyl-ethyl]sulfamoyl]pyrrole-2-carboxylic acid (35.0 mg, 96.6 pmol) and N,N- diisopropylethyl amine (37.5 mg, 289 pmol). hexafluorophosphate azabenzotriazole tetramethyl uronium (44. Img, 116 pmol) in N,N-dimethylformamide (1 mL) was added 3.4-difluoroaniline (14.9 mg, 115 pmol). The reaction mixture was stirred at 45 °C for 4 hours, cooled, and concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150*25 mm* 10 um; mobile phase: [water (formic acid)-acetonitrile] ; gradient: 42%-72% B over 10 minutes) to give 7V-(3,4- difluorophenyl)-3-fluoro-l-(2-methoxyethyl)-4-[[(7.R)-2,2,2-trifluoro-l-methyl- ethyl]sulfamoyl]pyrrole-2-carboxamide as a yellow solid. 'H NMR: (400 MHz. CDCh): 57.81 (d, J= 9.6 Hz, 1H), 7.71 - 7.63 (m, 1H), 7.24 (d, J = 4.8 Hz, 1H), 7.20- 7.06 (m, 2H), 4.93 (d, J = 9.6 Hz, 1H). 4.54 (t, J= 4.4 Hz, 2H), 4.14 - 3.99 (m. 1H), 3.73 - 3.59 (m, 2H), 3.31 (s, 3H), 1.42 (d. J= 7.2 Hz, 3H); HPLC / MS: product retention time = 2. 143 minutes, MS (ESI) m / z = 474. 1 [M+H]+.

[0615] Example 34: Synthesis of 3-fluoro-l-(2-methoxyethyl)-4-[[(lR)-2,2,2- trifluoro-l-methyl-ethyl]sulfamoyl]-N-(3,4,5-trifluorophenyl)pyrrole-2-carboxamide

[0617] To a solution of 3-fluoro-l-(2-methoxyethyl)-4-[[(lR)-2,2,2-trifluoro-l- methyl-ethyl]sulfamoyl]pyrrole-2-carboxylic acid (35.0 mg, 96.6 pmol) and N,N- diisopropylethyl amine (37.4 mg, 289 pmol), hexafluorophosphate azabenzotriazole tetramethyl uronium (44.0 mg, 115pmol) in N,N-dimethylformamide ( 1 mL) was added 3.4.5-trifluoroanihne (17.0 mg, 115 pmol). The reaction mixture was stirred at 45 °C for 16 hours, cooled, and concentrated in vacuo. The residue was purified by prep- HPLC (column: Phenomenex Luna C18 150*25 mm* 10 um; mobile phase: [water (formic acid)-acetonitrile]; gradient: 44%-74% B over 10 minutes) to give 3-fluoro-l- (2-methoxyethyl)-4-[[(lR)-2,2,2-trifluoro-l-methyl-ethyl]sulfamoyl]-N-(3.4.5- trifluorophenyl)pyrrole-2-carboxamide as an off-white solid. 'H NMR: (400 MHz, CDCh): 5 7.77 (d, J= 10.0 Hz, 1H), 7.37 - 7.28 (m, 2H), 7.25 (d, J= 4.4 Hz, 1H), 4.85 (d, J = 9.6 Hz, 1H), 4.54 (t, J = 4.4 Hz, 2H), 4.14 - 3.96 (m, 1H), 3.67 (t, J = 4.4 Hz, 2H), 3.31 (s, 3H), 1.43 (d, J= 7.2 Hz, 3H); HPLC / MS: product retention time = 2.244 minutes, MS (ESI) m / z = 492.1 [M+H]+.

[0618] Example 35: Synthesis of N-(3-chloro-4-fluoro-phenyl)-3-fluoro-l-(2- methoxyethyl)-4-[[(lR)-2,2,2-trifluoro-l-methyl-ethyl]sulfamoyl]pyrrole-2- carboxamide

[0619]

[0620] To a solution of 3-fluoro-l-(2-methoxyethyl)-4-[[(lR)-2,2,2-trifluoro-l- methyl-ethyl]sulfamoyl]pyrrole-2-carboxylic acid (35.0 mg, 96.6 pmol) and N,N-diisopropylethyl amine (37.4 mg, 289 pmol). hexafluorophosphate azabenzotriazole tetramethyl uronium (44.0 mg, 115 pmol) in N,N-dimethylformamide (1 mL) was added 3-chloro-4-fluoro-aniline (16.8 mg, 116 pmol). The reaction mixture was stirred at 45 °C for 4 hours, cooled, and concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex LunaC18 150*25 mm*10 urn; mobile phase: [water (formic acid)-acetonitrile] ; gradient:47%-77% B over 10 minutes) to give N-(3-chloro- 4-fluoro-phenyl)-3-fluoro-l-(2-methoxyethyl)-4-[[(lR)-2.2.2-trifluoro-l-methyl- ethyl]sulfamoyl]pyrrole-2-carboxamide as a yellow solid.NMR: (400 MHz, CDCh): 57.88 - 7.75 (m, 2H), 7.36 - 7.29 (m, 1H), 7.25 (d, J = 4.8 Hz, 1H), 7.14 (t, J = 8.8 Hz, 1H), 4.96 (d. J = 9.6 Hz, 1H), 4.54 (t. J = 4.4 Hz, 2H), 4.14 - 3.98 (m. 1H), 3.67 (t. J = 4.8 Hz, 2H), 3.31 (s, 3H), 1.42 (d, J = 6.8 Hz, 3H). HPLC / MS: product retention time = 2.219 minutes, MS (ESI) m'z = 490.1 [M+H]+.

[0621] Example 36: Synthesis of N-(3-chlorophenyl)-3-fluoro-l-(3-methoxypropyl)- 4-[[(lR)-2,2,2-trifluoro-l-methyl-ethyl]sulfamoyl]pyrrole-2-carboxamide

[0623] To a solution of 3-fluoro-l-(3-methoxypropyl)-4-[[(lR)-2,2,2-trifluoro-l- methyl-ethyl]sulfamoyl]pyrrole-2-carboxylic acid (40.0 mg, 106 pmol) and hexafluorophosphate azabenzotriazole tetramethyl uronium (48.5 mg, 127 pmol), N,N- diisopropylethyl amine (41.2 mg, 318 pmol) in N,N-dimethylformamide (1 mL) was added 3-chloroaniline (16.2 mg, 127 pmol). The reaction mixture was stirred at 45 °C for 4 hours, cooled, and concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 150*25 mm* 10 um; mobile phase: [water (formic acid)-acetonitrile] ; gradient: 42%-72% B over 10 minutes) to give N-(3-chlorophenyl)- 3-fluoro-l-(3-methoxypropyl)-4-[[(lR)-2,2,2-trifluoro-l-methyl- ethyl]sulfamoyl]pyrrole-2-carboxamide as a white solid. 'HNMR: (400 MHz, CDCh): 57.85 - 7.76 (m, 1H), 7.76 - 7.72 (m, 1H), 7.38 - 7.32 (m, 1H), 7.32 - 7.28 (m, 1H), 7.21 - 7.12 (m, 2H), 4.85 (d, J = 9.6 Hz, 1H), 4.48 (t, J= 6.8 Hz, 2H), 4.15 - 3.99 (m, 1H), 3.33 (s, 3H), 3.30 (t. J= 5.6 Hz. 2H), 1.99 - 2. 12 (m, 2H). 1.43 (d, J= 6.8 Hz. 3H); HPLC / MS: product retention time = 2.252 minutes, MS (ESI) m / z = 486.1 [M+H]+.

[0624] Example 37: Synthesis of N-[3-(difluoromethyl)-4-fluoro-phenyl]-3-fluoro-l-(2-methoxyethyl)-4-[[(lR)-2,2,2-trifluoro-l-methyl-ethyl]sulfamoyl]pyrrole-2- carboxamide

[0626] To a solution of 3-fluoro-l-(2-methoxyethyl)-4-[[(lR)-2,2,2-trifluoro-l- methyl-ethyl]sulfamoyl]pyrrole-2-carboxylic acid (35.0 mg, 96.6 pmol) and N,N- diisopropylethyl amine (37.4 mg, 289 pmol), hexafluorophosphate azabenzotriazole tetramethyl uronium (44.0 mg, 115 pmol) in N,N-dimethylformamide (1 mL) was added 3-(difluoromethyl)-4-fluoro-aniline (18.6 mg, 115 pmol.). The reaction mixture was stirred at 45 °C for 4 hours, cooled, and concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 150*25 mm*10 urn; mobile phase: [water (formic acid)-acetonitrile] ; gradient: 45%-75% B over 10 minutes) to give N-[3-(difluoromethyl)-4-fluoro-phenyl]-3-fluoro-l-(2-methoxyethyl)-4-[[(lR)-2.2.2- trifluoro-l-methyl-ethyl]sulfamoyl]pyrrole-2-carboxamide as a yellow solid. 'H NMR: (400 MHz, CDCh): 57.88 (d, J = 10.0 Hz, 1H), 7.82 - 7.74 (m, 1H), 7.71 - 7.62 (m, 1H), 7.25 (d, J= 4.8 Hz, 1H), 7.15 (t, J= 9.2 Hz, 1H), 7.06 - 6.72 (m, 1H), 4.97 (d, J = 9.6 Hz, 1H), 4.55 (t, J= 4.4 Hz, 2H). 4.14 - 3.99 (m. 1H), 3.67 (t, J= 4.4 Hz, 2H), 3.31 (s, 3H). 1.42 (d, J = 7.2 Hz. 3H) HPLC / MS: product retention time = 2.155 minutes. MS (ESI) m / z = 506. 1 [M+H]+.

[0627] Example 38: Synthesis of 3-fluoro-l-(2-methoxyethyl)-N-phenyl-4-[[(lR)- 2.2.2-trifluoro-l-methyl-ethyl]sulfamoyl]pyrrole-2-carboxamide

[0629] To a solution of 3-fluoro-l-(2-methoxyethyl)-4-[[(lR)-2,2,2-trifluoro-l- methyl-ethyl]sulfamoyl]pyrrole-2-carboxylic acid (35.0 mg, 96.6 pmol) and N,N- diisopropylethyl amine (37.4 mg, 289 pmol), hexafluorophosphate azabenzotriazole tetramethyl uronium (44.0 mg, 115 pmol) in N,N-dimethylformamide (1 mL) wasadded aniline (10.8 mg, 115 pmol). The reaction mixture was stirred at 45°C for 4 hours, cooled, and concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex luna Cl 8 150*25 mm* 10 um; mobile phase: [water (formic acid)-acetonitrile] ; gradient: 42%-72% B over 10 minutes) to give 3-fluoro-l-(2- methoxyethyl)-N-phenyl-4-[[(lR)-2,2,2-trifluoro-l-methyl-ethyl]sulfamoyl]pyrrole-2- carboxamide as ayellow solid.JH NMR: (400 MHz, CDCh): 57.84 (d, J= 9.2 Hz, 1H), 7.55 (d. J= 7.6 Hz, 2H). 7.37 (t. J = 8.0 Hz. 2H), 7.23 (d. J= 4.8 Hz. 1H). 7.20 - 7.13 (m, 1H), 5.03 (d, J= 9.6 Hz, 1H), 4.56 (t, J= 4.8 Hz, 2H), 4.15 - 3.99 (m, 1H), 3.68 (t, J = 4.8 Hz, 2H), 3.30 (s, 3H), 1.41 (d, J = 6.8 Hz, 3H); HPLC / MS: product retention time RT = 2.025 minutes, MS (ESI) m.'z = 438.1 [M+H]+.

[0630] Example 39: Synthesis of N-(3.4-difluorophenyl)-3-fluoro-l-(3- methoxypropyl)-4-[[(lR)-2,2,2-trifluoro-l-methyl-ethyl]sulfamoyl]pyrrole-2- carboxamide

[0631] Step 1 : Preparation of ethyl 3-fluoro-l-(3-methoxypropyl)pyrrole-2- carboxylate

[0633] To a solution of ethyl 3-fluoro-lH-pyrrole-2-carboxylate (1.00 g, 6.36 mmol), KI (1.16 g, 7.00 mmol) and CS2CO3 (4.15 g, 12.7 mmol) in N.N-dimethylformamide (15 mL) was added l-bromo-3-methoxy-propane (1.46 g, 9.55 mmol). The reaction mixture was stirred at 20 °C for 16 hours under nitrogen, quenched by addition water (100 mL), and the resulting solution was extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with brine (50 mL), dried with anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (Si O2. Petroleum ether / Ethyl acetate=l / 0 to 5 / 1) to give ethyl 3-fluoro- l-(3-methoxypropyl)pyrrole-2-carboxylate as a colorless oil. 'H NMR: (400 MHz, CDCh): 5 6.62 (dd, J= 3.2, 5.2 Hz, 1H), 5.86 (d, J= 2.8 Hz, 1H), 4.39 - 4.24 (m, 4H), 3.32 (s, 3H), 3.28 (t, J= 6.0 Hz, 2H), 1.98 (q, J= 6.4 Hz, 2H), 1.37 (t. J= 7.2 Hz. 3H).

[0634] Step 2: Preparation of 5-ethoxycarbonyl-4-fluoro-l-(3-methoxypropyl)pyrrole- 3-sulfomc acid

[0636] To a solution of ethyl 3-fluoro-l-(3-methoxypropyl)pyrrole-2-carboxylate (1.42 g, 6.19 mmol) in methylene chloride (14 mL) was added sulfurochloridic acid (938 mg, 8.05 mmol) at 0 °C, the reaction mixture was stirred at 0 °C for 2.5 hours under N2, and then the mixture was concentrated in vacuum to give 5-ethoxycarbonyl-4-fluoro-l-(3- methoxypropyl)pyrrole-3-sulfonic acid as a yellow oil which was used without further purification. HPLCMS: product retention time = 0.383 minutes, MS (ESI) m / z = 310.0 [M+H]’.

[0637] Step 3: Preparation of ethyl 4-chlorosulfonyl-3-fluoro-l-(3- methoxypropyl)pyrrole-2-carboxylate

[0639] A solution of 5-ethoxycarbonyl-4-fluoro-l-(3-methoxypropyl)pyrrole-3- sulfonic acid (1.90 g, 6.14 mmol) in SOCh (32.7 g, 275 mmol) was stirred at 80 °C for 6 hours under nitrogen. Then the mixture was cooled and concentrated in vacuo and the residue was purified by column chromatography (SiCh. Petroleum ether / Ethyl acetate=20 / l to 3 / 1) to give ethyl 4-chlorosulfonyl-3-fluoro-l -(3- methoxypropyl)pyrrole-2-carboxylate as a yellow oil. 'H NMR: (400 MHz, CDCh): 5 7.32 (d, J = 3.2 Hz, 1H), 4.43 (t, J= 6.8 Hz, 2H), 4.39 - 4.35 (m, 2H), 3.33 (s, 3H), 3.30 (t, J= 5.6 Hz, 2H), 2.06 - 2.01 (m. 2H), 1.39 (t, J = 6.8 Hz, 3H).

[0640] Step 4 Preparation of ethyl 3-fluoro-l-(3-methoxypropyl)-4-[[(lR)-2,2,2- trifluoro- 1 -methyl-ethyl]sulfamoyl]pyrrole-2-carboxylate

[0642] To a solution of ethyl 4-chlorosulfonyl-3-fluoro-l-(3-methoxypropyl)pyrrole- 2-carboxylate (700 mg, 2.14 mmol) and pyridine (506 mg, 6.41 mmol) in acetonitrile (8 mL) was added 4-dimethylaminopyridine (39.1 mg, 320 pmol) and (2R)-1,1,1- trifluoropropan-2-amine;hydrochloride (479 mg, 3.20 mmol). The reaction mixture was stirred at 85 °C for 16 hours under nitrogen, cooled, and concentrated in vacuo. The residue was purified by column chromatography (SiCh, Petroleum ether / Ethyl acetate=20 / l to 3 / 1) to give ethyl 3-fluoro-l-(3-methoxypropyl)-4-[[(lR)-2,2,2- trifluoro-l-methyl-ethyl]sulfamoyl]pyrrole-2-carboxylate as a white solid. 'H NMR: (400 MHz, CDCh): 57.13 (d, J= 4.4 Hz, 1H), 4.87 (d, J= 9.6 Hz, 1H), 4.44 - 4.29 (m, 4H), 4.09 - 3.98 (m, 1H), 3.32 (s. 3H), 3.27 (t, J = 5.6 Hz. 2H), 2.04 - 1.95 (m. 2H). 1.43 - 1.33 (m, 6H). HPLCMS product retention time = 0.586 minutes, MS (ESI) m = 405.2 [M+H]+.

[0643] Step 5: Preparation of 3-fluoro-l-(3-methoxypropyl)-4-[[(lR)-2,2,2-trifluoro- l-methyl-ethyl]sulfamoyl]pyrrole-2 -carboxylic acid

[0645] To a solution of ethyl 3-fluoro-l-(3-methoxypropyl)-4-[[(lR)-2,2,2-trifluoro-l- methyl-ethyl]sulfamoyl]pyrrole-2-carboxylate (460 mg, 1.14 mmol) in tetrahydrofuran (9 mL) was added a solution of LiOH.H2O (143 mg. 3.41 mmol) in H2O (3 mL), the reaction mixture was stirred at 20 °C for 16 hours, and then concentrated under reduced pressure to remove the tetrahydrofuran. Water (10 mL) was added, and the pH was adjusted to pH = 3 with HC1 solution (1 mol / L). The resulting suspension was filtered and the filtered cake was collected and dried to give 3-fluoro-l-(3-methoxypropyl)-4- [[(lR)-2,2,2-trifluoro-l-methyl-ethyl]sulfamoyl]pyrrole-2-carboxylic acid as a white solid. 'H NMR: (400 MHz, DMSO- e): 5 13.63 - 12.65 (m, 1H), 8.60 (d, J = 8.8 Hz,1H), 7.52 (d, J= 4.4 Hz, 1H), 4.36 - 4.23 (m, 2H), 4.04 - 3.88 (m, 1H), 3.24 (t, J= 6.0Hz. 2H), 3.20 (s, 3H), 1.98 - 1.83 (m, 2H). 1.15 (d, J= 6.8 Hz, 3H).

[0646] Step 6 Preparation of N-(3,4-difluorophenyl)-3-fluoro-l-(3-methoxypropyl)-4-[[( 1 R)-2,2,2-trifluoro- 1 -methy 1 -ethyl] sulfamoyl] py rrole-2-carboxamide

[0648] To a solution of 3-fluoro-l-(3-methoxypropyl)-4-[[(lR)-2.2,2-trifluoro-l- methyl-ethyl]sulfamoyl]pyrrole-2-carboxylic acid (40.0 mg, 106 pmol), N,N- diisopropylethyl amine (41.2 mg, 318 pmol) and hexafluorophosphate azabenzotriazole tetramethyl uronium (48.5 mg, 127 pmol) in N,N-dimethylformamide (1 mL) was added 3,4-difluoroaniline (16.4 mg, 127 pmol). The reaction mixture was stirred at 45 °C for 3 hours, cooled, and concentrated in vacuo. The residue was purified by prep- HPLC (column: Phenomenex Luna C18 150*25 mm* 10 um; mobile phase: [water (formic acid)-acetonitrile]; gradient: 40%-70% B over 10 minutes) to give N-(3,4- difluorophenyl)-3-fluoro-l-(3-methoxypropyl)-4-[[(lR)-2,2,2-trifluoro-l-methyl- ethyl]sulfamoyl]pyrrole-2-carboxamide as a white solid. 'HNMR: (400 MHz, CDCh): 5 7.78 (d, J = 10.0 Hz, 1H), 7.72 - 7.64 (m, 1H), 7.21 - 7.07 (m, 3H), 4.89 (d, J = 9.6 Hz, 1H), 4.55 - 4.37 (m, 2H), 4. 14 - 3.99 (m, 1H), 3.33 (s, 3H), 3.30 (t, J= 5.6 Hz, 2H), 2.13 - 1.97 (m, 2H), 1.43 (d, J= 6.8 Hz, 3H). HPLCMS product retention time = 2.175 minutes, MS (ESI) m / z = 488.1 [M+H]+.

[0649] Example 40: Synthesis of 3-fluoro-l-(3-methoxypropyl)-4-[[(lR)-2,2,2- trifluoro-l-methyl-ethyl]sulfamoyl]-N-(3,4,5-trifluorophenyl)pyrrole-2-carboxamide

[0651] To a solution of 3-fluoro-l-(3-methoxypropyl)-4-[[(lR)-2,2,2-trifluoro-l- methyl-ethyl]sulfamoyl]pyrrole-2-carboxylic acid (40.0 mg, 106 pmol) and N,N- diisopropylethyl amine (41.2 mg, 318 pmol), hexafluorophosphate azabenzotriazoletetramethyl uronium (48.5 mg, 127 pmol) in N,N-dimethylformamide (1 mL) was added 3,4,5-trifluoroaniline (18.7 mg, 127 pmol). The reaction mixture was stirred at 45 °C for 16 hours, cooled, and concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex LunaC18 150*25 mm*10 um; mobile phase: [water (formic acid)-acetonitrile] ; gradient:46%-76% B over 10 minutes) to give 3-fluoro-l- (3-methoxypropyl)-4-[[(lR)-2.2.2-trifluoro-l-methyl-ethyl]sulfamoyl]-N-(3,4,5- trifluorophenyl)pyrrole-2-carboxamide as ayellow solid. 'H NMR: (400 MHz, CDCh): 57.75 (d, J = 10.4 Hz, 1H), 7.34 - 7.28 (m, 2H), 7.18 (d, J = 4.8 Hz, 1H), 4.93 (d, J = 9.6 Hz, 1H), 4.46 (t, J= 6.8 Hz, 2H), 4.19 - 3.96 (m, 1H), 3.33 (s, 3H), 3.30 (t, J = 5.6 Hz, 2H), 2.10 - 2.00 (m. 2H), 1.43 (d, J = 12 Hz, 3H). HPLCMS: product retention time = 2.267 minutes, MS (ESI) m2 = 506. 1 [M+H]+.

[0652] Example 41 : Synthesis of N-(3-chloro-4-fluoro-phenyl)-3-fluoro-l-(3- methoxypropyl)-4-[[(lR)-2,2,2-trifluoro-l-methyl-ethyl]sulfamoyl]pyrrole-2- carboxamide

[0654] To a solution of 3-fluoro-l-(3-methoxypropyl)-4-[[(lR)-2.2.2-trifluoro-l- methyl-ethyl]sulfamoyl]pyrrole-2-carboxylic acid (40.0 mg, 106 pmol) and hexafluorophosphate azabenzotriazole tetramethyl uronium (48.5 mg, 127 pmol), N,N- diisopropylethyl amine (41.2 mg, 318 pmol) in N,N-dimethylformamide (1 mL) was added 3-chloro-4-fluoro-aniline (18.5 mg, 127 pmol). The reaction mixture was stirred at 45 °C for 4 hours, cooled, and concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex LunaC18 150*25 mm*10 um; mobile phase: [water (formic acid)-acetonitrile] ; gradient:43%-73% B over 10 minutes) to giveN-(3-chloro- 4-fluoro-phenyl)-3-fluoro-l-(3-methoxypropyl)-4-[[(lR)-2,2,2-trifluoro-l -methyl- ethyl]sulfamoyl]pyrrole-2-carboxamide as a white solid. 'H NMR: (400 MHz, CDCh): 57.89 - 7.65 (m, 2H), 7.39 - 7.30 (m, 1H), 7.20 - 7.10 (m, 2H), 4.91 (d, J= 9.6 Hz, 1H), 4.47 (t, J= 6.4 Hz, 2H), 4. 15 - 3.95 (m, 1H), 3.33 (s, 3H), 3.30 (t, J= 5.6 Hz, 2H), 2. 17 - 1.98 (m, 2H), 1.43 (d, J = 6.8 Hz, 3H). HPLCMS: product retention time = 2.256 minutes, MS (ESI) m / z = 504.1 [M+H]+.

[0655] Example 42: Synthesis of N-(3-chlorophenyl)-3-fluoro-l-(3-methoxypropyl)- 4-[[(lR)-2,2,2-trifluoro-l-methyl-ethyl]sulfamoyl]pyrrole-2-carboxamide

[0657] To a solution of 3-fluoro-l-(3-methoxypropyl)-4-[[(lR)-2,2,2-trifluoro-l- methyl-ethyl]sulfamoyl]pyrrole-2-carboxylic acid (40.0 mg, 106 pmol) and hexafluorophosphate azabenzotriazole tetramethyl uronium (48.5 mg, 127 pmol), N,N- diisopropylethyl amine (41.2 mg, 318 pmol) in N,N-dimethylformamide (1 mL) was added 3-chloroaniline (16.2 mg, 127 pmol). The reaction mixture was stirred at 45 °C for 4 hours, cooled, and concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex Luna Cl 8 150*25 mm* 10 um; mobile phase: [water (formic acid)-acetonitrile]; gradient: 42 %-72% B over 10 minutes) to give N-(3-chlorophenyl)- 3-fluoro-l-(3-methoxypropyl)-4-[[(lR)-2,2,2-trifluoro-l-methyl- ethyl]sulfamoyl]pyrrole-2-carboxamide as a white solid. 'HNMR: (400 MHz, CDCh): 57.85 - 7.76 (m, 1H), 7.76 - 7.72 (m, 1H), 7.38 - 7.32 (m, 1H), 7.32 - 7.28 (m, 1H), 7.21 - 7.12 (m, 2H), 4.85 (d, J = 9.6 Hz. 1H), 4.48 (t, J = 6.8 Hz, 2H), 4.15 - 3.99 (m, 1H), 3.33 (s, 3H), 3.30 (t. J= 5.6 Hz. 2H), 2. 12 - 2.00 (m, 2H). 1.43 (d, J= 6.8 Hz, 3H). HPLCMS: product retention time = 2.252 minutes, MS (ESI) m / z = 486.1 [M+H]+.

[0658] Example 43: Synthesis of N-[3-(difluoromethyl)-4-fluoro-phenyl]-3-fluoro-l- (3-methoxypropyl)-4-[[(lR)-2,2,2-trifluoro-l-methyl-ethyl]sulfamoyl]pyrrole-2- carboxamide

[0659]

[0660] To a solution of 3-fluoro-l-(3-methoxypropyl)-4-[[(lR)-2,2,2-trifluoro-l- methyl-ethyl]sulfamoyl]pyrrole-2-carboxylic acid (40.0 mg, 106 pmol) and hexafluorophosphate azabenzotriazole tetramethyl uronium (48.5 mg, 127 pmol), N,N- diisopropylethyl amine (41.2 mg, 318 pmol) in N,N-dimethylformamide (1 mL) was added 3-(difluoromethyl)-4-fluoro-aniline (20.5 mg, 127 pmol). The reaction mixturewas stirred at 45 °C for 4 hours, cooled, and concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 150*25 mm*10 um; mobile phase: [water (formic acid)-acetonitrile]; gradient: 40%-70% B over 10 minutes) to give N-[3-(difluoromethyl)-4-fluoro-phenyl]-3-fluoro-l-(3-methoxypropyl)-4-[[(lR)-2,2,2- trifluoro-l-methyl-ethyl]sulfamoyl]pyrrole-2-carboxamide as a pink solid. 'H NMR: (400 MHz, CDCh): 5 7.89 - 7.75 (m, 2H), 7.74 - 7.65 (m, 1H), 7.20 - 7.12 (m. 2H), 7.04 - 6.74 (m. 1H), 4.82 (d, J = 9.2 Hz. 1H), 4.56 - 4.40 (m, 2H). 4.14 - 3.98 (m. 1H). 3.33 (s, 3H), 3.30 (t, J = 5.6 Hz, 2H), 2.12 - 2.01 (m, 2H), 1.44 (d, J = 6.8 Hz, 3H). HPLCMS: product retention time = 2.210 minutes, MS (ESI) m / z = 520.2 [M+H]+.

[0661] Example 44: Synthesis of 3-fluoro-l-(3-methoxypropyl)-N-phenyl-4-[[(lR)- 2.2.2-trifluoro-l-methyl-ethyl]sulfamoyl]pyrrole-2-carboxamide

[0663] To a solution of 3-fluoro-l-(3-methoxypropyl)-4-[[(lR)-2,2,2-trifluoro-l- methyl-ethyl]sulfamoyl]pyrrole-2-carboxylic acid (40.0 mg, 106 pmol) and hexafluorophosphate azabenzotriazole tetramethyl uronium (48.5 mg, 127 pmol), N,N- diisopropylethyl amine (41.2 mg, 318 pmol) in N,N-dimethylformamide (1 mL) was added aniline (11.8 mg, 127 pmol). The reaction mixture was stirred at 45 °C for 4 hours, cooled, and concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 150*25 mm*10 um; mobile phase: [water (formic acid)-acetonitrile]; gradient: 40%-70% B over 10 minutes) to give 3-fluoro-l-(3- methoxypropyl)-N-phenyl-4-[[(lR)-2,2,2-trifluoro-l-methyl-ethyl]sulfamoyl]pyrrole- 2-carboxamide as a white solid. 'H NMR: (400 MHz, CDCI3): 3 7.81 (d, J = 9.6 Hz, 1H), 7.55 (d, J= 8.0 Hz, 2H), 7.38 (t, J= 7.6 Hz, 2H), 7.22 - 7.12 (m, 2H), 4.94 (d, J= 9.2 Hz, 1H), 4.57 - 4.36 (m, 2H). 4. 19 - 3.94 (m, 1H), 3.33 (s, 3H), 3.32 - 3.27 (m, 2H), 2. 12 - 2.02 (m, 2H), 1.42 (d, J= 6.8 Hz, 3H). HPLCMS: product retention time = 2.082 minutes, MS (ESI) m / z = 452.1 [M+H]+.

[0664] Example 45: Synthesis of l-(2,2-difluoroethyl)-N-(3,4-difluorophenyl)-3- fluoro-4-[[(lR)-2,2,2- trifluoro-l-methyl-ethyl]sulfamoyl]pyrrole-2-carboxamide

[0666] Step 1 : Preparation of ethyl l-(2,2-difluoroethyl)-3-£luoro-pyrrole-2- carboxylate:

[0667] To a solution of ethyl 3-fluoro-lH-pyrrole-2-carboxylate (4.50 g, 28.6 mmol) and CS2CO3 (18.6 g, 57.2 mmol) in N,N-dimethylformamide (50 mL) was added 1,1- difluoro-2-iodo-ethane (8.24 g, 42.9 mmol), the reaction mixture was stirred at 20 °C for 16 hours under nitrogen. The reaction was quenched by addition water (250 mL), then extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with brine (50 mL x 3). dried with anhydrous sodium sulfate, fdtered and concentrated in vacum. The residue was purified by column chromatography (SiCh, Petroleum ether / Ethyl acetate=l / O to 5 / 1) to give ethyl l-(2,2-difluoroethyl)-3-fluoro-pyrrole-2- carboxylate as a yellow oil. 'H NMR: (400 MHz, CDCh): 5 6.73 - 6.63 (m. 1H), 6.22 - 5.87 (m, 2H), 4.55 (dt, J = 4.0, 13.2 Hz, 2H), 4.34 (q, J = 7.2 Hz, 2H), 1.38 (t, J = 7.2 Hz, 3H).

[0669] Step 2: Preparation of 1 -(2.2-difluoroethyl)-5-ethoxycarbonyl-4-fluoro-pyrrole- 3-sulfonic acid: To a solution of ethyl l-(2,2-difluoroethyl)-3-fluoro-pyrrole-2- carboxylate (6.00 g, 27.1 mmol) in dichloromethane (50 mL) was added sulfurochloridic acid (4.11 g, 35.2 mmol) at 0 °C, the reaction mixture was stirred at 0 °C for 2.5 hours under nitrogen. The reaction was concentrated in vacuum to give 1- (2,2-difluoroethyl)-5-ethoxycarbonyl-4-fluoro-pyrrole-3- sulfonic acid as a yellow oil which was used without further purification.

[0671] Step 3: Preparation of ethyl 4-chlorosulfonyl-l-(2,2-difluoroethyl)-3-fluoro- pyrrole-2- carboxylate: A solution of l-(2.2-difluoroethyl)-5-ethoxycarbonyl-4-fluoro- pyrrole-3-sulfonic acid (8.00 g, 26.5 mmol) in thionyl chloride (63.2 g, 531 mmol) was stirred at 80 °C for 6 hours under nitrogen. The reaction was cooled and concentrated in vacuo. The residue was purified by column chromatography (SiCh, Petroleum ether / Ethyl acetate=20 / l to 3 / 1, Rf=0.40) to give ethyl 4-chlorosulfonyl-l-(2,2-

[0673] Step 4: Preparation of ethyl l-(2,2-difluoroethyl)-3-fluoro-4-[[(lR)-2,2,2- trifluoro-1 -methyl- ethyl]sulfamoyl]pyrrole-2-carboxylate: To a solution of ethyl 4- chlorosulfonyl-l-(2,2-difluoroethyl)-3-fluoro-pyrrole-2-carboxylate (7.20 g, 22.5 mmol) and pyridine (5.34 g, 67.5 mmol, 5.45 mL) in acetonitrile (50 mL) was added 4- dimethylaminopyridine (412 mg, 3.38 mmol) and (2R)- 1,1,1 -trifluoropropan-2- amine;hydrochloride (5.39 g. 36.0 mmol), the reaction mixture was stirred at 85 °C for 16 hours under N2. The reaction mixture was cooled and concentrated in vacuo. The residue was purified by column chromatography (SiCh. Petroleum ether / Ethyl acetate=20 / l to 3 / 1) to give ethyl l-(2,2-difluoroethyl)-3-fluoro-4-[[(lR)-2,2,2- trifluoro- 1 -methyl-ethyl] sulfamoyl] pyrrole-2-carboxy late as a white solid. 'H NMR: (400 MHz, DMSO-c / e): 68.74 (d, J= 8.8 Hz, 1H), 7.69 (d, J= 4.8 Hz, 1H), 6.53 - 6.14 (m, 1H), 4.91 - 4.69 (m, 2H), 4.29 (q, J= 12 Hz, 2H), 4.06 - 3.92 (m, 1H), 1.28 (t, J= 7.2 Hz, 3H), 1.16 (d, J = 6.8 Hz, 3H).

[0675] Step 5: Preparation of To a solution of ethyl l-(2,2-difluoroethyl)-3-fluoro-4-[[(lR)-2,2,2-trifluoro-l -methyl-ethyl] sulfamoyl]pyrrole-2-carboxylate (6.50 g. 16.4mmol) in THF (60 mL) was added a solution of LiOf I.I EO (2.06 g, 49.2 mmol) in H2O (20 mL), the reaction mixture was stirred at 20 °C for 16 hours. The reaction was then concentrated in vacuo to remove tetrahydrofuran, extracted with ethyl acetate (20 mL x 3), the aqueous phase was adjusted to pH = 3 with HC1 solution (1 mol / L). The resulting suspension was filtered to give l-(2,2-difluoroethyl)-3-fluoro-4-[[(lR)-2,2,2- trifluoro-l-methyl-ethyl]sulfamoyl]pyrrole-2-carboxylic acid as a white solid. 'H NMR: (400 MHz, DMSO-t / e): 5 13.46 (s. J = 2.3 Hz. 1H), 8.71 (d. J= 8.8 Hz, 1H), 7.64 (d, J= 4.8 Hz, 1H), 6.53 - 6.13 (m, 1H), 4.90 - 4.70 (m, 2H), 4.08 - 3.87 (m, 1H), 1.15 (d, J = 6.8 Hz, 3H).

[0677] Step 6: Preparation of l-(2,2-difluoroethyl)-N-(3,4-difluorophenyl)-3-fluoro-4- [[(1 R)-2,2,2- trifluoro-l-methyl-ethyl]sulfamoyl]pyrrole-2-carboxamide: To a solution of l-(2,2-difluoroethyl)-3-fluoro-4-[[(lR)-2,2,2-trifluoro-l-methyl- ethyl]sulfamoyl]pyrrole-2-carboxylic acid (3.00 g, 8.15 mmol) and N,N- diisopropylethylamine (5.26 g. 40.7 mmol), hydroxy benzotriazole (1.32 g, 9.78 mmol). l-ethyl-3-(3-dimethylaminopropyl)carbodiimide (1.87 g, 9.78 mmol) in methylene chloride (40 mL) was added 3,4-difluoroaniline (1.37 g, 10.6 mmol). The reaction was stirred at 40 °C for 10 hours, cooled, and concentrated in vacuo. The residue was purified by column chromatography (SiCh, Petroleum ether / Ethyl acetate=20 / l to 3 / 1) The fractions containing the title compounds were combined and concentrated in vacuo. The residue was triturated with petroleum ether (30 mL) at 25 °C for 30 minutes and toluene (20 mL) at 80 °C for 10 minutes to give l-(2,2-difluoroethyl)-N-(3,4- difluorophenyl)-3-fluoro-4-[[(lR)-2.2.2-trifluoro-l-methyl-ethyl]sulfamoyl]pyrrole-2- carboxamide as a white solid. 'H NMR: (400 MHz, DMSO-rfc): 5 10.44 (s, 1H), 8.74 (d, J= 8.8 Hz, 1H), 7.86 - 7.75 (m, 1H), 7.62 (d, J= 4.4 Hz, 1H), 7.47 - 7.37 (m, 2H), 6.54 - 6.20 (m, 1H), 4.91 - 4.58 (m, 2H), 4.11 - 3.86 (m, 1H), 1.19 (d, J= 6.8 Hz, 3H). HPLCMS: product retention time = 2.343 minutes, MS (ESI) m / z = 480.1 [M+H]+.

[0678] Example 46: Synthesis of (R)-N-(3,4-difluorophenyl)-l-(prop-2-yn-l-yl)-4-(N- (1 ,1,1 -trifluoropropan-2-yl)sulfamoyl)-l H-pyrrole-2-carboxamide

[0680] Step 1 : Preparation of methyl l-(prop-2-yn-l-yl)-lH-pyrrole-2-carboxylate: To a stirred solution of methyl lH-pyrrole-2-carboxylate (225 mg. 1.83 mmol, 1 eq) and CS2CO3 (1.19 g, 3.65 mmol, 2 eq) in N.N-dimethylformamide (3.5 mL) was added propargyl bromide (80% wt in toluene, 0.41 mL, 3.65 mmol, 2 eq). The reaction was stirred at 55 °C for 16 hours, cooled, and diluted with ethyl acetate. The organic layer washed with sat. brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography with ethyl acetate in hexane from 0: 1 to 1 :3 to afford methyl l-(prop-2-yn-l-yl)-lH-pyrrole-2-carboxylate as a light yellow oil. MS (ESI) m / z = 164.1 [M+H]+.

[0682] Step 2: Preparation of 5-(methoxycarbonyl)-l-(prop-2-yn-l-yl)-lH-pyrrole-3- sulfonic acid: To a solution of methyl l-(prop-2-yn-l-yl)-lH-pyrrole-2-carboxylate (50 mg, 0.306 mmol, 1 eq) in methylene chloride (0.8 mL) at 0 °C was added CISO3H (0.031 mL, 0.466 mmol, 1.5 eq). The reaction was slowly warmed to 23 °C and stirred for 2 hours. The suspension was concentrated under reduced pressure to give 5- (methoxycarbonyl)-l-(prop-2-yn-l-yl)-lH-pyrrole-3-sulfonic acid, which was used in the next step without further purification. MS (ESI) m / z = 244. 1 [M+H]+.

[0684] Step 3: Preparation of methyl 4-(chlorosulfonyl)-l-(prop-2-yn-l-yl)-lH- pyrrole-2-carboxylate: 5-(methoxycarbonyl)-l-(prop-2-yn-l-yl)-lH-pyrrole-3- sulfonic acid was dissolved in CH3CN (0.5 mL) under argon atmosphere, SOCI2 (1 mL) was added, and the solution was stirred at 75°C for 2.5 hours. The reaction cooled, concentrated under reduced pressure. The residue was filtered through 4g ISCO silicagel column (flow rate 100 mL / min) on silica gel chromatography with 25% ethyl acetate in hexane to give methyl 4-(chlorosulfonyl)-l-(prop-2-yn-l-yl)-lH-pyrrole-2- carboxylate as a brown oil.

[0685]

[0686] Step 4: Preparation of methyl (R)- 1 -(prop-2-yn- 1 -yl)-4-(N-( 1,1,1- trifluoropropan-2-yl)sulfamoyl)-lH-pyrrole-2-carboxylate: To a stirred solution of methyl 4-(chlorosulfonyl)-l-(prop-2-yn-l-yl)-lH-pyrrole-2-carboxylate (65 mg, 0.248 mmol, 1 eq) in a mixture of MeCN (1 mL) and pyridine (0. 1 mL) was added (R)- 1,1,1 - trifluoropropan-2-amine hydrochloride (60 mg, 0.401 mmol, 1.6 eq) and 4- dimethylaminopyridine (9. 1 mg, 0.0745 mmol, 0.3 eq). The reaction was stirred at 80°C for 4 hours, cooled, and concentrated under reduced pressure. The residue was purified by silica gel chromatography with ethyl acetate in methylene chloride from 0: 1 to 3: 17 to afford methyl (R)-l-(prop-2-yn-l-yl)-4-(N-(l,l,l-trifluoropropan-2-yl)sulfamoyl)- lH-pyrrole-2-carboxylate as a brown oil. MS (ESI) m / z = 339.2 [M+H]+.

[0687]

[0688] Step 5: Preparation of (R)-l-(prop-2-yn-l-yl)-4-(N-( 1,1,1 -trifluoropropan-2- yl)sulfamoyl)-lH-pyrrole-2-carboxyhc acid: To a stirred solution of methyl (R)-l- (prop-2-yn-l-yl)-4-(N-(l,l,l-trifluoropropan-2-yl)sulfamoyl)-lH-pyrrole-2- carboxylate (68.5 mg, 0.202 mmol, 1 eq) in tetrahydrofuran (1 mL) was added aq. LiOH (IM, 0.5 mL, 2.5 eq). The reaction mixture was stirred at 23 °C for 16 hours. The reaction was then acidified with 10% aq. citric acid and extracted with ethyl acetate.The organic layer was separated, washed with sat. brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to afford (R)-l-(prop-2-yn-l-yl)-4-(N-(l,l,l- trifluoropropan-2-yl)sulfamoyl)-lH-pyrrole-2-carboxylic acid as a white solid, which was used without further purification. MS (ESI) m / z = 325.2 [M+H]+.

[0689]

[0690] Step 6: Preparation of (R)-N-(3,4-difluorophenyl)-l-(prop-2-yn-l-yl)-4-(N- (l,l,l-trifluoropropan-2-yl)sulfamoyl)-lH-pyrrole-2-carboxamide: To a dried vessel with a magnetic stir bar was subsequently added (R)-l-(prop-2-yn-l-yl)-4-(N-(l,l,l- trifluoropropan-2-yl)sulfamoyl)-lH-pyrrole-2-carboxylic acid (51.3 mg, 0.158 mmol, 1 eq,), l-ethyl-3-(3-dimethylaminopropyl)carbodiimide (39 mg, 0.203 mmol, 1.3 eq), hydroxybenzotriazole (39.4 mg, , 0.206 mmol, 1.3 eq) and methylene chloride (1 mL). N,N-diisopropylethylamine (0.137 mL, 0.788 mmol, 5 eq) and 3,4-difluoroaniline (30.6 mg. 0.237 mmol, 1.5 eq) were added, the reaction was stirred at 35°C for 16 hours, concentrated under reduced pressure, the resulting residue was purified by SiCh chromatography with ethyl acetate in methylene chloride from 0: 1 to 1 :4 to afford (R)- N-(3,4-difluorophenyl)- 1 -(prop-2-yn-l -yl)-4-(N-(l , 1 , 1 -trifluoropropan-2- yl)sulfamoyl)-lH-pyrrole-2-carboxamide as a white solid.JH NMR (400 MHz, DMSO-d6) d 10.33 (s, 1H), 8.24 (d, .7 = 8.59 Hz, 1H), 7.84 (ddd, J= 2.34, 7.52, 13.18 Hz, 1H), 7.76 (d, .7 = 1 .95 Hz, 1H), 7.39-7.49 (m, 2H), 7.37 (d, J= 1.95 Hz, 1H), 5.20- 5.32 (m, 2H), 3.94 (qd, J= 7.49, 15.43 Hz, 1H), 3.47 (t, J = 2.54 Hz, 1H), 1.06 (d, J= 7.03 Hz, 3H). MS (ESI) m / z = 436.2 [M+H]+.

[0691] Example 47: Synthesis of (R)-N-(3,4-difluorophenyl)-3-fluoro-l-(prop-2-yn-l- yl)-4-(N-(l , 1 , 1 -trifluoropropan-2-yl)sulfamoyl)- lH-pyrrole-2-carboxamide

[0693] Step 1 : Preparation of ethyl 3-fluoro-l-(prop-2-yn-l-yl)-lH-pyrrole-2- carboxylate: To a stirred solution of ethyl 3 -fluoro- lH-pyrrole-2-carboxylate (250 mg, 1.59 mmol, 1 eq) and CS2CO3 (1.04 g, 3.18 mmol, 2 eq) in N.N-dimethylformamide (3.5 mL) was added propargy l bromide (80% wt in toluene, 0.36 mL, 3.18 mmol, 2 eq). The reaction was stirred at 55 °C for 16 hours, cooled, and diluted with ethyl acetate. The organic layer washed with sat. brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography withethyl acetate in hexane from 0:1 to 1:3 to afford ethyl 3-fluoro-l-(prop-2-yn-l-yl)-lH- pyrrole-2-carboxylate as a light yellow oil. MS (ESI) m / z = 196.2 [M+H]+.

[0694]

[0695] Step 2 Synthesis of 5-(ethoxycarbonyl)-4-fluoro-l-(prop-2-yn-l-yl)-lH- pyrrole-3 -sulfonic acid: To a solution of ethyl 3-fluoro-l-(prop-2-yn-l-yl)-lH-pyrrole- 2-carboxylate (120 mg, 0.615 mmol, 1 eq) in methylene chloride (1.5 mL) at 0°C was added CISO3H (0.061 mL, 0.916 mmol, 1.5 eq). The reaction was slowly warmed to 23 °C, stirred for 2 hours, and concentrated under reduced pressure to give crude 5-(ethoxycarbonyl)-4-fluoro-l-(prop-2-yn-l-yl)-lH-pyrrole-3-sulfonic acid which was used without further purification. MS (ESI) m / z = 276.1 [M+H]+.

[0696]

[0697] Step 3: Synthesis of ethyl 4-(chlorosulfonyl)-3-fluoro-l-(prop-2-yn-l-yl)-lH- pyrrole-2-carboxylate: 5-(ethoxycarbonyl)-4-fluoro-l -(prop-2 -yn-1 -yl)-lH-pyrrole-3- sulfonic acid was dissolved in CHsCN (0.5 mL) under and argon atmosphere, SOCh (2 mL) was added and the reaction was stirred at 75°C for 5.5 hours. The reaction was then concentrated under reduced pressure and chased with methylene chloride. The residue was purified with a 4g ISCO silica gel column (flow rate 50 mL / min) on CombiFlash with 25% ethyl acetate in hexane to give ethyl 4-(chlorosulfonyl)-3-fluoro- l-(prop-2-yn-l-yl)-lH-pyrrole-2-carboxylate as a brown oil.

[0698]

[0699] Step 4: Synthesis of ethyl (R)-3 -fluoro- l-(prop-2-yn-l-yl)-4-(N-( 1,1,1- trifluoropropan-2-yl)sulfamoyl)-lH-pyrrole-2-carboxylate: To a stirred solution of ethyl 4-(chlorosulfonyl)-3-fluoro- 1 -(prop-2-yn- 1 -y 1)- 1 H-py rrole-2-carboxy late (49.5mg) in a mixture of acetonitrile (1 mL) and pyridine (0.05 mL) was added (R)-l,l,l- trifluoropropan-2-amine hydrochloride (30 mg. 0.2 mmol. 1.6 eq) and 4- dimethylaminopyridine (4.5 mg, 0.0369 mmol, 0.3 eq). The reaction was stirred at 70°C for 16 hours, cooled, and concentrated under reduced pressure. The residue was purified by silica gel chromatography with ethyl acetate in hexane from 0: 1 to 3:7 to afford ethyl (R)-3-fluoro- 1 -(prop-2-yn- 1 -y l)-4-(N-(l , 1 , 1 -trifluoropropan-2- yl)sulfamoyl)-lH-pyrrole-2-carboxylate as a brown oil. MS (ESI) m / z = 371.2 [M+EI]+.

[0700]

[0701] Step 5: Synthesis of (R)-3 -fluoro- 1 -(prop-2 -yn-l-yl)-4-(N-( 1,1,1 - trifluoropropan-2-yl)sulfamoyl)-lH-pyrrole-2-carboxylic acid: To a stirred solution of ethyl (R)-3 -fluoro- 1 -(prop-2-yn- 1 -yl)-4-(N-( 1,1,1 -trifl uoropropan-2-yl)sulfamoyl)- lH-pyrrole-2-carboxylate (31 mg, 0.0837 mmol, 1 eq) in tetrahydrofuran (1 mL) was added aq. LiOH (IM, 0.25 mL, 3 eq). The reaction was stirred at 23 °C for 16 hours, acidified with a mixture of 2M HC1 and sat. brine ( 1 : 1), and extracted with ethyl acetate. The organic layer was separated, washed with sat. brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to afford (R)-3 -fluoro- l-(prop-2-yn-l-y l)-4- (N-(l,l,l-trifluoropropan-2-yl)sulfamoyl)-lH-pyrrole-2-carboxylic acid as a yellow solid, which was used step without further purification. MS (ESI) m / z = 343.2 [M+H]+.

[0703] Step 6: Synthesis of (R)-N-(3,4-difluorophenyl)-3-fluoro-l-(prop-2-yn-l-yl)-4- (N-(l,l,l-trifluoropropan-2-yl)sulfamoyl)-lH-pyrrole-2-carboxamide: To a dried vessel with a magnetic stir bar was subsequently added (R)-3-fluoro-l-(prop-2-yn-l- yl)-4-(N-(l,l,l-trifluoropropan-2-yl)sulfamoyl)-lH-pyrrole-2-carboxylic acid (0.0837 mmol, 1 eq), l-ethyl-3-(3-dimethylaminopropyl)carbodiimide (21 mg, 0.11 mmol, 1.3 eq), hydroxbenzotriazole (21 mg, with no less than 20% water, 0. 11 mmol, 1.3 eq) and methylene chloride (0.8 mL). N,N-diisopropylethylamine (0.073 mL, 0.42 mmol, 5 eq)and 3,4-difluoroaniline (16 mg. 0.124 mmol, 1.5 eq) were added subsequently, the reaction mixture was stirred at 35°C for 16 hours, cooled, and concentrated under vacuum. The residue was purified by silica gel chromatography with ethyl acetate in methylene chloride from 0: 1 to 1:3. Fractions containing the title compound were concentrated under reduced pressure and the resulting residue was further purified by silica gel chromatography with ethyl acetate in hexane from 0: 1 to 3:7 to afford (R)-N- (3 ,4-difluoropheny l)-3 -fluoro- 1 -(prop-2-yn- 1 -yl)-4-(N-( 1.1.1 - trifl uoropropan-2- yl)sulfamoyl)-lH-pyrrole-2-carboxamide as a white solid. 'H NMR (400 MHz,DMSO-d6) 8 10.42 (s, 1H), 8.68 (d, J= 8.98 Hz, 1H), 7.76-7.83 (m, 1H), 7.64 (d, J = 4.30 Hz, 1H), 7.39-7.44 (m, 2H), 5.11 (t, J = 2.93 Hz, 2H), 3.94-4.05 (m, 1H), 3.51- 3.53 (m, 1H). 1.17 (d, J = 7.03 Hz. 3H). MS (ESI) m / z = 454.2 [M+H]+.

[0704] Example 48: (R)-N-(3,4-difluorophenyl)-3-fluoro-l-methyl-4-(N-(l,l,l- trifluoropropan-2-yl)sulfamoyl)-lH-pyrrole-2-carboxamide.

[0706] The title compound was prepared using the methods described in WO2014 / 184350A1 which is incorporated herein by reference. MS (ESI) m / z = 430.3 [M+H]’.

[0707] The following compounds were prepared using chemistry analogous to that described in Examples 1 through 47. One skilled in the art would know and understand which starting material to use to prepare the following compounds.

[0708]

[0709] Example 49: (R)-4-(N-(sec-butyl)sulfamoyl)-N-(3-chloro-4-fluorophenyl)-l-(2-chloroethyl)-lH-pyrrole-2-carboxamide

[0710]

[0711] MS (ESI) m / z = 436.3 [M+H]+.

[0712] Example 50: (R)-N-(3-chlorophenyl)-3-fluoro-l-(2-fluoroethyl)-4-(N-(l,l,l- trifluoropropan-2-yl)sulfamoyl)-lH-pyrrole-2-carboxamide

[0713]

[0714] MS (ESI) m / z = 460 [M+H]+.

[0715] Example 51 : (R)-N-(3-(difluoromethyl)-4-fluorophenyl)-3-fluoro-l-(2- fluoroethyl)-4-(N-(l ,1,1 -trifluoropropan-2-yl)sulfamoyl)- lH-pyrrole-2-carboxamide

[0716]

[0717] MS (ESI) m / z = 494 [M+H]+.

[0718] Example 52: (R)-3-fluoro-N-(4-fluoro-3-(trifluoromethyl)phenyl)-l-(2- fluoroethyl)-4-(N-(l , 1 , 1 -trifluoropropan-2-yl)sulfamoyl)- lH-pyrrole-2-carboxamide

[0719]

[0720] MS (ESI) m / z = 512 [M+H]+.

[0721] Example 53: (R)-N-(3-cyano-4-fluorophenyl)-3-fluoro-l-(2-fluoroethyl)-4-(N-(1 , 1 , 1 -trifluoropropan-2-yl)sulfamoyl)-lH-py rrole-2-carboxamide

[0722]

[0723] MS (ESI) m / z = 469 [M+H]+.

[0724] Example 54: (R)-3-fluoro-N-(4-fluoro-3-methylphenyl)-l-(2-fluoroethyl)-4-(N-(l,l,l-trifluoropropan-2-yl)sulfamoyl)-lH-pyrrole-2-carboxamide

[0738] MS (ESI) m / z = 486 [M+H]+.

[0739] Example 59: (R)-l-allyl-N-(3,4-difluorophenyl)-3-fluoro-4-(N-(l,l,l-trifluoro propan-2-yl)sulfamoyl)-lH-pyrrole-2-carboxamide

[0750] MS (ESI) m / z = 526 [M+H]+.

[0751] Example 63: (S)-N-(3-cyano-4-fluorophenyl)-l-methyl-4-(N-(l,l,l-trifluoro propan-2-yl)sulfamoyl)-lH-pyrrole-2-carboxamide

[0752] compound

[0753] MS (ESI) m / z = 419 [M+H]+.

[0754] Examples 64 and 65: Synthesis of (R)-4-(N-(sec-butyl)-N-(2- cyanoethyl)sulfamoyl)-N-(3,4-difluorophenyl)-l-(2-cyanoethyl)-lH-pyrrole-2- carboxamide and (R)-4-(N-(sec-butyl)-N-(2-cyanoethyl)sulfamoyl)-N-(3,4- difluorophenyl)-N, 1 -bis(2-cy anoethyl)- IH-py rrole-2-carboxamide

[0756] A solution of (R)-4-(N-(sec-butyl)sulfamoyl)-N-(3,4-difluorophenyl)-lH- pyrrole-2-carboxamide (22, 30 mg, 0.083 mmol) in anhydrous tetrahydrofuran (1 mL) was treated with l,8-diazabicyclo[5.4.0]undec-7-ene (0.043 ml). After stirring the reaction mixture at 23 °C for 10 minutes, acrylonitrile (27, 0.5 ml) was added. The reaction was stirred at 23 °C for 2 hours, diluted with ethyl acetate, and washed with aqueous NEECl. The organic portion was dried (Na2SO4), and evaporated under reduced pressure. The residue was purified by prep-HPLC to provide (R)-4-(N-(sec- butyl)-N-(2-cyanoethyl)sulfamoyl)-N-(3,4-difluorophenyl)-l-(2-cyanoethyl)-lEI- pyrrole-2-carboxamide as a off-white solid (MS (ESI) m / z = 464.8 [M+H]+) and (R)- 4-(N-(sec-butyl)-N-(2-cyanoethyl)sulfamoyl)-N-(3,4-difluorophenyl)-N,l-bis(2- cyanoethyl)-lH-pyrrole-2-carboxamide (MS (ESI) m / z = 518.0 [M+H]+) as a off-white solid.

[0757] FORMULATIONS

[0758] Aspects of the present invention also relates to compositions or formulations which comprise the pregenomic RNA encapsidation inhibitors according to aspects of the present invention. In general, the compositions according to aspects of the present invention comprise an effective amount of one or more functionalized benzamide derivatives and salts thereof according to aspects of the present invention which are effective for useful for the treatment of Hepatitis B virus (HBV) infection and related conditions; and one or more excipients.

[0759] For the purposes of the present invention the term “excipient’' and “carrier’" are used interchangeably throughout the description of the present invention and said terms are defined herein as, “ingredients which are used in the practice of formulating a safe and effective pharmaceutical composition.”

[0760] The formulator will understand that excipients are used primarily to serve in delivering a safe, stable, and functional pharmaceutical, serving not only as part of the overall vehicle for delivery but also as a means for achieving effective absorption by the recipient of the active ingredient. An excipient may fill a role as simple and direct as being an inert filler, or an excipient as used herein may be part of a pH stabilizing system or coating to insure delivery of the ingredients safely to the stomach. The formulator can also take advantage of the fact the compounds according to aspects of the present invention have improved cellular potency, pharmacokinetic properties, as well as improved oral bioavailability.

[0761] The present teachings also provide pharmaceutical compositions that include at least one compound described herein and one or more pharmaceutically acceptable earners, excipients, or diluents. Examples of such carriers are well known to those skilled in the art and can be prepared in accordance with acceptable pharmaceutical procedures, such as, for example, those described in Remington’s Pharmaceutical Sciences, 17th edition, ed. Alfonoso R. Gennaro, Mack Publishing Company, Easton, PA (1985). the entire disclosure of which is incorporated by reference herein for all purposes. As used herein, “pharmaceutically acceptable” refers to a substance that is acceptable for use in pharmaceutical applications from a toxicological perspective and does not adversely interact with the active ingredient. Accordingly, pharmaceutically acceptable carriers are those that are compatible with the other ingredients in the formulation and are biologically acceptable. Supplementary active ingredients can also be incorporated into the pharmaceutical compositions.

[0762] Compounds of the present teachings can be administered orally or parenterally, neat or in combination with conventional pharmaceutical carriers. Applicable solid carriers can include one or more substances which can also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet-disintegrating agents, or encapsulating materials. The compounds can be formulated in a conventional manner, for example, in a manner similar to that used for known antiviral agents. Oral formulations containing a compound disclosed herein can comprise any conventionally used oral form,including tablets, capsules, buccal forms, troches, lozenges and oral liquids, suspensions or solutions. In powders, the carrier can be a finely divided solid, which is an admixture with a finely divided compound. In tablets, a compound disclosed herein can be mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired. The powders and tablets can contain up to 99 % of the compound.

[0763] Capsules can contain mixtures of one or more compound(s) disclosed herein with inert filler(s) and / or diluent(s) such as pharmaceutically acceptable starches (e.g., com, potato or tapioca starch), sugars, artificial sw eetening agents, powdered celluloses (e.g., crystalline and microcrystalline celluloses), flours, gelatins, gums, and the like.

[0764] Useful tablet formulations can be made by conventional compression, wet granulation or dry granulation methods and utilize pharmaceutically acceptable diluents, binding agents, lubricants, disintegrants, surface modifying agents (including surfactants), suspending or stabilizing agents, including, but not limited to, magnesium stearate, steanc acid, sodium laur l sulfate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, microcrystalline cellulose, sodium carboxymethyl cellulose, carboxymethylcellulose calcium, poly vinylpyrrolidine, alginic acid, acacia gum, xanthan gum, sodium citrate, complex silicates, calcium carbonate, glycine, sucrose, sorbitol, dicalcium phosphate, calcium sulfate, lactose, kaolin, mannitol, sodium chloride, low melting waxes, and ion exchange resins. Surface modifying agents include nonionic and anionic surface modifying agents. Representative examples of surface modifying agents include, but are not limited to, poloxamer 188, benzalkonium chloride, calcium stearate, cetostearl alcohol, cetomacrogol emulsifying wax, sorbitan esters, colloidal silicon dioxide, phosphates, sodium dodecylsulfate, magnesium aluminum silicate, and triethanolamine. Oral formulations herein can utilize standard delay or time-release formulations to alter the absorption of the compound(s). The oral formulation can also consist of administering a compound disclosed herein in water or fruit juice, containing appropriate solubilizers or emulsifiers as needed.

[0765] Liquid carriers can be used in preparing solutions, suspensions, emulsions, syrups, elixirs, and for inhaled delivery'. A compound of the present teachings can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, or a mixture of both, or a pharmaceutically acceptable oils or fats.The liquid carrier can contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers, and osmo-regulators. Examples of liquid carriers for oral and parenteral administration include, but are not limited to, water (particularly containing additives as described herein, e.g., cellulose derivatives such as a sodium carboxy methyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols, e.g.. glycols) and their derivatives, and oils (e g., fractionated coconut oil and arachis oil). For parenteral administration, the carrier can be an oily ester such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are used in sterile liquid form compositions for parenteral administration. The liquid carrier for pressurized compositions can be halogenated hydrocarbon or other pharmaceutically acceptable propellants.

[0766] Liquid pharmaceutical compositions, which are sterile solutions or suspensions, can be utilized by, for example, intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously. Compositions for oral administration can be in either liquid or solid form.

[0767] Preferably the pharmaceutical composition is in unit dosage form, for example, as tablets, capsules, powders, solutions, suspensions, emulsions, granules, or suppositories. In such form, the pharmaceutical composition can be sub-divided in unit dose(s) containing appropriate quantities of the compound. The unit dosage forms can be packaged compositions, for example, packeted powders, vials, ampoules, prefilled syringes or sachets containing liquids. Alternatively, the unit dosage form can be a capsule or tablet itself, or it can be the appropriate number of any such compositions in package form. Such unit dosage form can contain from about 1 mg / kg of compound to about 500 mg / kg of compound, and can be given in a single dose or in two or more doses. Such doses can be administered in any manner useful in directing the compound(s) to the recipient’s bloodstream, including orally, via implants, parenterally (including intravenous, intraperitoneal and subcutaneous injections), rectally, vaginally. and transdermally.

[0768] When administered for the treatment or inhibition of a particular disease state or disorder, it is understood that an effective dosage can vary depending upon the particular compound utilized, the mode of administration, and severity' of the condition being treated, as well as the various physical factors related to the individual being treated. In therapeutic applications, a compound of the present teachings can beprovided to a patient already suffering from a disease in an amount sufficient to cure or at least partially ameliorate the symptoms of the disease and its complications. The dosage to be used in the treatment of a specific individual typically must be subjectively determined by the attending physician. The variables involved include the specific condition and its state as well as the size, age and response pattern of the patient.

[0769] In some cases it may be desirable to administer a compound directly to the airways of the patient, using devices such as, but not limited to, metered dose inhalers, breath-operated inhalers, multidose dry-powder inhalers, pumps, squeeze-actuated nebulized spray dispensers, aerosol dispensers, and aerosol nebulizers. For administration by intranasal or intrabronchial inhalation, the compounds of the present teachings can be formulated into a liquid composition, a solid composition, or an aerosol composition. The liquid composition can include, by way of illustration, one or more compounds of the present teachings dissolved, partially dissolved, or suspended in one or more pharmaceutically acceptable solvents and can be administered by, for example, a pump or a squeeze-actuated nebulized spray dispenser. The solvents can be, for example, isotonic saline or bacteriostatic water. The solid composition can be, by way of illustration, a pow der preparation including one or more compounds of the present teachings intermixed w ith lactose or other inert powders that are acceptable for intrabronchial use, and can be administered by. for example, an aerosol dispenser or a device that breaks or punctures a capsule encasing the solid composition and delivers the solid composition for inhalation. The aerosol composition can include, by way of illustration, one or more compounds of the present teachings, propellants, surfactants, and co-solvents, and can be administered by, for example, a metered device. The propellants can be a chlorofluorocarbon (CFC), a hydrofluoroalkane (HF A), or other propellants that are physiologically and environmentally acceptable.

[0770] Compounds described herein can be administered parenterally or intraperitoneally. Solutions or suspensions of these compounds or a pharmaceutically acceptable salts, hydrates, or esters thereof can be prepared in w ater suitably mixed with a surfactant such as hydroxyl-propylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations typically contain a preservative to inhibit the growth of microorganisms.

[0771] The pharmaceutical forms suitable for injection can include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In some embodiments, the form can sterile and its viscosity permits it to flow through a syringe. The form preferably is stable under the conditions of manufacture and storage and can be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.

[0772] Compounds described herein can be administered transdermally, i.e., administered across the surface of the body and the inner linings of bodily passages including epithelial and mucosal tissues. Such administration can be carried out using the compounds of the present teachings including pharmaceutically acceptable salts, hydrates, or esters thereof, in lotions, creams, foams, patches, suspensions, solutions, and suppositories (rectal and vaginal).

[0773] Transdermal administration can be accomplished through the use of a transdermal patch containing a compound, such as a compound disclosed herein, and a carrier that can be inert to the compound, can be non-toxic to the skin, and can allow delivery- of the compound for systemic absorption into the blood stream via the skin. The carrier can take any number of forms such as creams and ointments, pastes, gels, and occlusive devices. The creams and ointments can be viscous liquid or semisolid emulsions of either the oil-in-water or water-in-oil type. Pastes comprised of absorptive powders dispersed in petroleum or hydrophilic petroleum containing the compound can also be suitable. A variety of occlusive devices can be used to release the compound into the blood stream, such as a semi-permeable membrane covering a reservoir containing the compound with or without a carrier, or a matrix containing the compound. Other occlusive devices are known in the literature.

[0774] Compounds described herein can be administered rectally or vaginally in the form of a conventional suppository-. Suppository formulations can be made from traditional materials, including cocoa butter, with or without the addition of waxes to alter the suppository’s melting point, and glycerin. Water-soluble suppository bases, such as polyethylene glycols of various molecular weights, can also be used.

[0775] Lipid formulations or nanocapsules can be used to introduce compounds of the present teachings into host cells either in vitro or in vivo. Lipid formulations and nanocapsules can be prepared by methods known in the art.

[0776] To increase the effectiveness of compounds of the present teachings, it can be desirable to combine a compound with other agents effective in the treatment of the target disease. For example, other active compounds (i.e. , other active ingredients or agents) effective in treating the target disease can be administered with compounds of the present teachings. The other agents can be administered at the same time or at different times than the compounds disclosed herein.

[0777] Compounds of the present teachings can be useful for the treatment or inhibition of a pathological condition or disorder in a mammal, for example, a human subject. The present teachings accordingly provide methods of treating or inhibiting a pathological condition or disorder by providing to a mammal a compound of the present teachings including its pharmaceutically acceptable salt) or a pharmaceutical composition that includes one or more compounds of the present teachings in combination or association with pharmaceutically acceptable carriers. Compounds of the present teachings can be administered alone or in combination with other therapeutically effective compounds or therapies for the treatment or inhibition of the pathological condition or disorder.

[0778] Non-limiting examples of compositions according to aspects of the present invention include from about 0.001 mg to about 1000 mg of one or more compounds of the disclosure according to aspects of the present invention and one or more excipients; from about 0.01 mg to about 100 mg of one or more compounds of the disclosure according to aspects of the present invention and one or more excipients; and from about 0. 1 mg to about 10 mg of one or more compounds of the disclosure according to aspects of the present invention; and one or more excipients.EXAMPLES AND PROCEDURES

[0779] The following procedures can be utilized in evaluating and selecting compounds as pregenomic RNA encapsidation inhibitors of HBV.Example 1

[0780] The HBV replication inhibitors according to aspects of the present invention are capable of treating and preventing diseases associated with HBV infection. The results presented in Tables 5-7 demonstrated that compounds according to aspects of thepresent invention inhibit HBV replication in human hepatoblastoma cell line (HepG2)- derived cell line HepDES19 cells that support robust HBV DNA replication in a tetracycline inducible manner (Guo, H. et al. 2007).

[0781] Determination of antiviral activity of compounds of the disclosure, as presented in Table 2, in human hepatoblastoma (HepG2)-derived cell line HepDES19 cells: HepDES19 cells were seeded into 24-well plates at a density of 2 x 105cells per well and cultured in tetracycline-free complete DMEM / F-12 medium. Twenty-four hours after seeding, the cells were mock treated or treated with a serial 1:2 dilution of testing compound at concentrations for 6 days. Intracellular HBV core DNA was extracted as described in (1). HBV core DNA was quantified by a real-time PCR assay using a LightCycler 480 SYBR green I Master PCR kit (Roche) with primers 5=- GGCTTTCGGAAAATTCCTA TG-3’ (sense) and 5’- AGCCCTACGAACCACTGAAC-3’ (antisense). The PCR was carried out as follows: denaturing at 95°C for 5 min, followed by 40 cycles of amplification at 95°C for 15 s and at 60°C for 30 s. The centration that reduces HBV DNA by 50% (EC so) was calculated by plotting dose response curves and using GraphPad Prism 9.

[0782] Determination of cytotoxicity of compounds of the disclosure in human hepatoma-derived cell lines, HepDES19 cells were seeded into 96- well plates at a density of 6 x 104cells per well and cultured in DMEM / F-12 medium with 10% fetal bovine serum in the absence of tetracycline. One day after seeding, cells were mock- treated or treated with a serial 1 :2 dilution of testing compounds for 6 days. The cytotoxic effects of the testing compounds were determined by alamarBlue HS Cell Viability assay by following manufacturer’s instruction (Invitrogen). Specifically, in each well, 90 pL of medium and 10 pL of alamar blue reagent was added and incubated for 1-4 hours at 37°C and fluorescence intensity measurement was carried out using the Tecan plate scanner. The cytotoxicity of a compound was expressed as the concentration of compound that reduced the viability of the cells by 50% (CC50). CC50 were calculated by using GraphPad Prism 9.

[0783] Table 5: Exemplary in vitro screening data for compounds of the formula (XX).

[0785] Table 6: Exemplary in vitro screening data for compounds of the formula(XXI);

[0786] Table 7: Exemplary in vitro screening data for compounds of the formula(XXII);

[0787] Protocol for pharmacokinetic and tissue distribution studies. The pharmacokinetics of the compounds was studied in CD1 mice after intravenous (IV) and oral gavage (PO) administration. Mouse PK studies was conducted at 3 mg / kg (IV) and 10 mg / kg (PO). Plasma samples obtained from dosed animals, at ten time points, including 5, 15 and 30 minutes and 1, 1.5, 2, 4, 6, 8 and 24 hr post-dose for processing to plasma, were prepared for analysis by means of a single step protein precipitation technique, by adding 200 pL of acetonitrile containing an IS mixture (labetalol, imipramine and diclofenac) to 50 pL aliquots of individual subject samples. Samples were mixed by vortex for homogeneity and then subjected to centrifugation at 4000 rpm for 10 min. The supernatant (200 pL) was collected and injected into the LC- MS / MS for analysis. Pharmacokinetic parameters will be calculated using established non-compartmental methods.

[0788] Exemplary results for PK studies for compounds of the disclosure are show n in tables 8 through 11.

[0789] Table 8: Pharmacokinetic data (R)-N-(3,4-difluorophenyl)-3-fluoro-l-methyl- 4-(N-(l,l,l-trifluoropropan-2-yl)sulfamoyl)-IH-pyrrole-2-carboxamide when doses at 3 mg / kg IV and 10 mg / kg PO.yl)sulfamoyl)-lH-pyrrole-2-carboxamide was doses at 3 mg / kg IV 1.5 mg / mL solution of "NMP / Solutol HS15 / saline (10 / 10 / 80)".

[0792] (R)-N-(3,4-difluorophenyl)-3-fluoro-l -methyl-4-(N-(l , 1, l-trifluoropropan-2- yl)sulfamoyl)-lH-pyrrole-2-carboxamide was doses at 10 mg / kg PO 1 mg / mL solution of "NMP / Solutol HS15 / saline (10 / 10 / 80).

[0793] Table 9: Pharmacokinetic data (R)-N-(3,4-difluorophenyl)-3-fluoro-l-(2- fluoroethyl)-4-(N-(l ,1,1 -trifluoropropan-2-yl)sulfamoyl)- lH-pyrrole-2-carboxamide when doses at 3 mg / kg IV and 10 mg / kg PO.

[0794]

[0795] (R)-N-(3,4-difluorophenyl)-3-fluoro-l-(2-fluoroethyl)-4-(N-(l,l,l- trifluoropropan-2-yl)sulfamoyl)-lH-pyrrole-2-carboxamide was dosed 3 mg / kg IV dosing 1.5 mg / mL solution of 5%NMP, 60% Propylene glycol, 35% 20% HP-0-CD in water.

[0796] (R)-N-(3,4-difluorophenyl)-3-fluoro-l-(2-fluoroethyl)-4-(N-(l,l,l- trifluoropropan-2-yl)sulfamoyl)-lH-pyrrole-2-carboxamide was dosed 10 mg / kg POdosing 1 mg / mL solution of 5%NMP, 60% Propylene glycol. 35% "20% HP-0-CD in water.

[0797] Table 10: Pharmacokinetic data (R)-l-(2,2-difluoroethyl)-N-(3,4- difluorophenyl)-3-fluoro-4-(N-(l,l,l-trifluoropropan-2-yl)sulfamoyl)-lH-pyrrole-2- carboxamide when doses at 3 mg / kg IV and 10 mg / kg PO.

[0799] (R)-l-(2,2-difluoroethyl)-N-(3,4-difluorophenyl)-3-fluoro-4-(N-(l,l,l- trifluoropropan-2-yl)sulfamoyl)-lH-pyrrole-2-carboxamide was dosed 3 mg / kg IV dosing 1.5 mg / mL solution of 5%NMP, 60% Propylene glycol, 35% 20% HP-0-CD in water.

[0800] (R)-l-(2,2-difluoroethyl)-N-(3,4-difluorophenyl)-3-fluoro-4-(N-(l,Ll- trifluoropropan-2-yl)sulfamoyl)-lH-pyrrole-2-carboxamide was 10 mg / kg PO dosing 1 mg / mL solution of "5%NMP, 60% Propylene glycol, 35% 20% HP-fl-CD in water.

[0801] Table 11: Pharmacokinetic data (R)-l-(2,2-difluoroethyl)-3-fluoro-N-(3,4,5- trifluorophenyl)-4-(N-(l,Ll-trifluoropropan-2-yl)sulfamoyl)-lH-pyrrole-2- carboxamide when doses at 3 mg / kg IV and 10 mg / kg PO.

[0803] (R)- 1 -(2,2-difluoroethyl)-3-fluoro-N-(3,4,5-trifluorophenyl)-4-(N-(l,l ,l - trifluoropropan-2-yl)sulfamoyl)-IH-pyrrole-2-carboxamide was dosed at 3 mg / kg IV 5% NMP and 95% Propylene glycol (1.5 mg / mL).

[0804] (R)- 1 -(2,2-difluoroethyl)-3-fluoro-N-(3,4,5-trifluorophenyl)-4-(N-( 1,1,1- trifluoropropan-2-yl)sulfamoyl)-lH-pyrrole-2-carboxamide was dosed at 10 mg / kg PO 5% NMP and 95% Propylene glycol (2.0 mg / mL).

[0805] As seen in table 8, the T1 / 2 of (R)-N-(3,4-difluorophenyl)-3-fluoro-l-methyl-4- (N-(l,l,l-trifluoropropan-2-yl)sulfamoyl)-lH-pyrrole-2-carboxamide when dosed to CD1 mice either via IV (3 mg / kg) or PO (10 mg / kg) is less than 1 hour. We have discovered that the 4-sulfamoyl-heteroaryl-2-carboxamides of the disclosure have significantly longer T1 / 2S than (R)-N-(3,4-difluorophenyl)-3-fluoro-l-methyl-4-(N- (l,l,l-trifluoropropan-2-yl)sulfamoyl)-lH-pyrrole-2-carboxamide. As shown in tables 9-11, the T1 / 2S of (R)-N-(3.4-difluorophenyl)-3-fluoro-l-(2-fluoroethyl)-4-(N-(l,l,l- trifluoropropan-2-yl)sulfamoyl)-lH-pyrrole-2-carboxamide, (R)-l-(2,2-difluoroethyl)- N-(3,4-difluorophenyl)-3-fluoro-4-(N-(l ,1,1 -trifl uoropropan-2-yl)sulfamoyl)-lH- pyrrole-2-carboxamide, and (R)-l-(2,2-difluoroethyl)-3-fluoro-N-(3,4,5- trifluorophenyl)-4-(N-( 1.1.1 -trifl uoropropan-2-yl)sulfamoyl)- 1 H-pyrrole-2- carboxamide are 8.86 hours, 5.78 hours and >14 hours respectively. This surprising andunexpected finding would not have been predicted by one skilled in the art at the time of invention, and the increased T1 / 2 of the compounds of the disclosure support their utility as pregenomic RNA encapsidation inhibitors of HBV useful for the treatment of Hepatitis B virus (HBV) infection and related conditions.Example 2

[0806] Evaluation of the anti -HBV efficacy of this compound, (R)-l-(2,2- difluoroethyl)-3-fluoro-N-(3.4.5-trifluorophenyl)-4-(N-(l .1.1 -trifluoropropan-2- yl)sulfamoyl)-lH-pyrrole-2-carboxamide, in AAV / HBV mouse model.

[0807] Study procedures: C57BL / 6 mice (male) were injected with rAAV8-1.3HBV (1.0X1010 genome copy, genotype D) via tail veins. On days 14 and day 21 post infection (or -14 and -7 post dosing) blood was collected from all mice. Plasma samples were prepared for measurements of HBV DNA by qPCR, HBsAg and HBeAg by ELISA. On day 28 post infection, 25 mice were selected and divided into 5 groups with 5 mice in each group with matching infection parameters, according to plasma HBV DNA, HBsAg and HBeAg results on days -14 and -7. On day 28 post infection, mice were administered with the first dose of the test article, which is defined as day 0. As shown in Table 12, there were three dose groups: 10, 30 and 100 mg / kg. The animals were treated via oral route once daily for 21 days. A vehicle group and a positive control group treated with entecavir at 0.1 mg / kg were also included. Daily body weight was recorded for all animals. Blood samples were collected on day 0. 7, 14. On day 21, animals were terminated to collect blood samples and livers. HBV DNA, HBsAg, HBeAg as well as ALT were determined using plasma samples. HBV DNA was determined using liver samples by qPCR assay.

[0808] Table 12. AAV / HBV animal study design

[0809] FIGS. 5A-5F are graphs of the evaluation of the anti -HBV efficacy of (R)-l- (2,2-difluoroethyl)-3-fluoro-N-(3,4,5-trifluorophenyl)-4-(N-(l,l,l-trifluoropropan-2- yl)sulfamoyl)-lH-pyrrole-2-carboxamide in AAV / HBV mouse model. FIG. 5A is a graph of the plasma HBV DNA, FIG. 5B is a graph of the plasma HBsAg, FIG. 5C isa graph of the ) Plasma HBeAg, FIG. 5D is of HBV DNA in liver at day 21 post dosing, and FIG. 5E is of daily body weight and FIG. 5F is of ALT. As shown in FIG. 5A, in animals treated with (R)-l-(2,2-difluoroethyl)-3-fluoro-N-(3,4,5-trifluorophenyl)-4- (N-(l,l,l-trifluoropropan-2-yl)sulfamoyl)-lH-pyrrole-2-carboxamide with as low as 10 mg / kg dose, plasma HBV DNA was significantly reduced by 2.68 logio.

[0810] Animals treated with 30 or 100 mg / kg showed similar efficacy, with plasma HBV DNA reduced by 3.07 or 3.19 logio. respectively. Compared to entecavir treated animals, (R)-l-(2,2-difluoroethyl)-3-fluoro-N-(3,4,5-trifluorophenyl)-4-(N-(l,l,l- trifluoropropan-2-yl)sulfamoyl)-IH-pyrrole-2-carboxamide showed similar efficacy in reducing HBV DNA in the liver at day 21 (see FIG. 5D). Plasma HBsAg and HBeAg levels were unchanged (see FIG. 5B and 5C). The treatment with (R)-l-(2,2- difluoroethyl)-3-fluoro-N-(3,4,5-trifluorophenyl)-4-(N-(l,l,l-trifluoropropan-2- yl)sulfamoyl)-lH-pyrrole-2-carboxamide with up to 100 mg / kg for 21 days was well tolerated without obvious body weight loss (see FIG. 5E). In addition, treatment did not result in ALT flares in all animals (see FIG. 5F).

[0811] (R)- 1 -(2,2-difluoroethyl)-3-fluoro-N-(3,4,5-trifluoropheny l)-4-(N-( 1,1.1- trifluoropropan-2-yl)sulfamoyl)-lH-pyrrole-2-carboxamide was well tolerated at up to 100 mg / kg QD for 21 days in AAV / HBV mice. Treatment with (R)-l-(2,2- difluoroethyl)-3-fluoro-N-(3.4.5-trifluorophenyl)-4-(N-(l,Ll-trifluoropropan-2- yl)sulfamoyl)-lH-pyrrole-2-carboxamide at 10 mg / kg dose reduced plasma HBV DNA by 2.68 logio. Treatment with (R)-l -(2,2-difluoroethyl)-3-fluoro-N-(3,4,5- trifluorophenyl)-4-(N-(l,I,l-trifluoropropan-2-yl)sulfamoyl)-lH-pyrrole-2- carboxamide at 30 and 100 mg / kg doses reduced plasma HBV DNA at similar level by >3 logio.

Claims

CLAIMS1. A compound of formula (I) :an enantiomer thereof, a diastereomer thereof, a hydrate thereof, a solvate thereof, a pharmaceutically acceptable salt thereof, an isotopic analog thereof, a prodrug thereof, and / or a complex thereof, wherein:X1is selected from the group consisting of nitrogen and CR4a;R1is selected from the group consisting of C4-8 branched alkyl, Ci-s fluoroalkyl, Ci-s chloroalkyl, C 1-8 bromoalkyl,, . , ,, C2-8 hydroxyalkyl, C2-8 aminoalkyl, C3-8 alkenyl, and C3-8 alkynyl, and C4-8 alkyd, wherein the C4-8 alky 1 is optionally substituted with one or more moieties selected from the group consisting of halogens, -OH, NH2, -CN, -CHF2, -CH2F, and - CF3;R2is selected from the group consisting of C3-8 branched alkyl, C3-8 branched haloalkyl, C3-10 cycloalky 1, C3-10 cycloalkenyl, and Ce-io bicycle, wherein the C3-10 cycloalkyl, the C3-10 cycloalkenyl, and / or the Ce-io bicycle optionally contain a group selected from O, S and N; andR2is optionally being substituted with one or more substituents each independently selected from the group consisting of -OH, fluoro, oxo, NH2, -CN, -CHF2, -CH2F, or - CF3;R2ais selected from the group consisting of hydrogen,, and C1-8 alkyl, wherein the C1-8 alkyl is optionally substituted with one or more moieties selected from the group consisting of halogens. -OH. NH2. -CN, -CHF2, -CH2F, and -CF3. or R2aand R4are taken together with the atoms to which they are bound to form a 7 to 9 membered ring;R3is selected from the group consisting-memnbered heteroaryl, and 6-membered heteroaryl, wherein the 5-memnbered heteroaryl and the 6- membered heteroaryl are optionally substituted with one or more moieties selected from the group consisting of a halogen, Ci-6 alkyl. Ci-4 fluoroalkyl, cyano, -CHF2, - CF2CH3, -CH2F, -CFs, -OCF3, C1.3 alkyl, and C3-6 cycloalkyl;Rais selected from the group consisting of hydrogen, halogen, C1-6 alkyl, C1-4 fluoroalkyl, cyano, -CHF2, -CF2CH3, -CH2F, -CF3, -OCF3, C1-3 alkyl, and C3-6 cycloalkyl;Rbis selected from the group consisting of hydrogen, halogen, C1-6 alkyl, Ci-4 fluoroalkyl, cyano, -CHF2, -CF2CH3, -CH2F, -CFs, -OCFs, C1-3 alkyl, and C3-6 cycloalkyl;Rcis selected from the group consisting of hydrogen, halogen, C1-6 alkyl, C1-4 fluoroalkyl, cyano. -CHF2. -CF2CH3, -CH2F, -CF3, -OCF3, C1-3 alkyl, and C3-6 cycloal kyl;Rdis selected from the group consisting of hydrogen, halogen, C1-6 alkyl, C1-4 flouroalkyl, cyano, -CHF2, -CF2CH3, -CH2F, -CF3, -OCF3, Ci-3alkyl, and C3-6 cycloalkyl;Reis selected from the group consisting of hydrogen, halogen, C1-6 alkyl, Ci-4 flouroalkyl, cyano, -CHF2, -CF2CH3, -CH2F, -CFs, -OCFs, C1-3 alky l, and C3-6 cycloalkyl;R4is selected from the group consisting of hydrogen, halogen, C1-6 alkyl, C3-7 branched alkyl, C1-4 flouroalkyl, C3-7 branched fluoroalkyl, -CN, -CHF2, - CF2CH3, - CH2F, -CFs, C2-3 alkenyl, C3-5 cycloalkyl, C1-3 alkyl, and -O-C1-6 alky, wherein the C1-3 alkyd is optionally substituted with methoxy and the -O-C1-6 alkyd is optionally substituted with moieties selected from the group consisting of halogen, -CHF2, -CF2- methyl. -CH2F. -CF3. -OCF3, and -CN, or R4and R2aare taken together with the atoms to which they are bound to form a 7 to 9 membered ring;R4ais selected from the group consisting of hydrogen, halogen, C1-6 alkyd, C3-7 branched alkyd. Ci-4 haloalkyl, and C3-7 branched haloalkyl;R5is selected from the group consisting of hydrogen, Ci-4 alkyl, and;R6is selected from the group consisting of hydrogen and C1-4 alkyl; m is 1, 2, 3, 4, 5, 6. 7, or 8; n is 1, 2, 3, 4. 5, 6, 7. or 8; q is 1, 2, 3, 4, 5, 6, 7, or 8; u is 1, 2, 3, 4, 5, 6, 7, or 8; x is 1, 2, 3, 4, 5, 6, 7, or 8; z is 1, 2, 3, 4. 5, 6, 7, or 8; and e is 1, 2, 3, 4, 5, 6, 7, or 8.

2. The compound according to claim 1, wherein the compound of formula (I) has a structure according to formula (II)an enantiomer thereof, a diastereomer thereof, a hydrate thereof, a solvate thereof, a pharmaceutically acceptable salt thereof, and / or a complex thereof.

3. The compound according to claim 1, wherein the compound of formula (I) has a structure according to formula (III)an enantiomer thereof, a diastereomer thereof, a hydrate thereof, a solvate thereof, a pharmaceutically acceptable salt thereof, and / or a complex thereof.

4. The compound according to claim 1, wherein the compound of formula (I) has a structure according to formula (IV)an enantiomer thereof, a diastereomer thereof, a hydrate thereof, a solvate thereof, a pharmaceutically acceptable salt thereof, and / or a complex thereof.

5. The compound according to claim 1, wherein the compound of formula (I) has a structure according to formula (V)an enantiomer thereof, a diastereomer thereof, a hydrate thereof, a solvate thereof, a pharmaceutically acceptable salt thereof, and / or a complex thereof.

6. The compound according to claim 1. wherein the compound of formula (I) has a structure according to having formula (VI)an enantiomer thereof, a diastereomer thereof, a hydrate thereof, a solvate thereof, a pharmaceutically acceptable salt thereof, and / or a complex thereof.

7. The compound according to claim 1, wherein the compound of formula (I) has a structure according to formula (VII)an enantiomer thereof, a diastereomer thereof, a hydrate thereof, a solvate thereof, a pharmaceutically acceptable salt thereof, and / or a complex thereof.

8. The compound according to claim 1, wherein the compound of formula (I) has a structure according to formula (VIII)R4 O3p2 ,S R "NX1-N R5C3.7branched alkylR2a(VIII)an enantiomer thereof, a diastereomer thereof, a hydrate thereof, a solvate thereof, a pharmaceutically acceptable salt thereof, and / or a complex thereof.

9. The compound according to claim 1, wherein the compound of formula (I) has a structure according to formula (IX) oalkylan enantiomer thereof, a diastereomer thereof, a hydrate thereof, a solvate thereof, a pharmaceutically acceptable salt thereof, and / or a complex thereof.

10. The compound according to claim 1, wherein the compound of formula (I) has a structure according to formula (X)R4O R3loroalkylR2a(X) an enantiomer thereof, a diastereomer thereof, a hydrate thereof, a solvate thereof, a pharmaceutically acceptable salt thereof, and / or a complex thereof.

11. The compound according to claim 1, wherein the compound of formula (I) has a structure according to formula (XI)an enantiomer thereof, a diastereomer thereof, a hydrate thereof, a solvate thereof, a pharmaceutically acceptable salt thereof, and / or a complex thereof.

12. The compound according to claim 1, wherein the compound of formula (I) has a structure according to formula (XII)an enantiomer thereof, a diastereomer thereof, a hydrate thereof, a solvate thereof, a pharmaceutically acceptable salt thereof, and / or a complex thereof.

13. The compound according to claim 1, wherein the compound of formula (I) has a structure according to formula (XIII)an enantiomer thereof, a diastereomer thereof, a hydrate thereof, a solvate thereof, a pharmaceutically acceptable salt thereof, and / or a complex thereof.

14. The compound according to claim 1, wherein the compound of formula (I) has a structure according to formula (XIV)an enantiomer thereof, a diastereomer thereof, a hydrate thereof, a solvate thereof, a pharmaceutically acceptable salt thereof, and / or a complex thereof.

15. The compound according to claim 1, wherein the compound of formula (I) has a structure according to formula (XV)an enantiomer thereof, a diastereomer thereof, a hydrate thereof, a solvate thereof, a pharmaceutically acceptable salt thereof, and / or a complex thereof.

16. The compound according to claim 1, wherein the compound of formula (I) is selected from:(R)-N-(3,4-difluorophenyl)-3-fluoro-l-(2-fluoroethyl)-4-(N-(l,l,l-trifluoropropan-2- yl)sulfamoyl)-lH-pyrrole-2-carboxamide;(R)-4-(N-(sec-butyl)sulfamoyl)-N-(3-chloro-4-fluorophenyl)-l-(2-fluoroethyl)-lH- pyrrole-2-carboxamide;(R)-4-(N-(sec-butyl)sulfamoyl)-N-(3,4-difluorophenyl)-l-(2-fluoroethyl)-lH-pyrrole- 2-carboxamide;(R)-methyl 4-(N-(sec-butyl)sulfamoyl)-l -(difluoromethyl)- lH-pyrrole-2 -carboxy late (R)-4-(N-(sec-butyl)sulfamoyl)-N-(3-chloro-4-fluorophenyl)-l-(2, 2,3,3- tetrafluoropropyl)-lH-pyrrole-2 -carboxamide;(R)-4-(N-(sec-butyl)sulfamoyl)-N-(3,4-difluorophenyl)-l-(2,2,3,3-tetrafluoropropyl)- lH-pyrrole-2-carboxamide;(R)-4-(N-(sec-butyl)sulfamoyl)-N-(3-(difluoromethyl)-4-fluorophenyl)-l-(2,2,3,3- tetrafluoropropyl)-lH-pyrrole-2 -carboxamide;(R)-4-(N-(sec-butyl)sulfamoyl)-l-(cyanomethyl)-N-(3,4-difluorophenyl)-lH-pyrrole- 2-carboxamide;(R)-4-(N-(sec-butyl)sulfamoyl)-l-(2,2-difluoroethyl)-N-(3,4-difluorophenyl)-lH- pyrrole-2-carboxamide;(R)-4-(N-(sec-butyl)sulfamoyl)-l-(2-cyanoethyl)-N-(3,4-difluorophenyl)-lH-pyrrole- 2-carboxamide;(R)-4-(N-(sec-butyl)sulfamoyl)-N-(3,4-difluorophenyl)-l-(2-hydroxyethyl)-lH- pyrrole-2-carboxamide;(R)-4-(N-(sec-butyl)sulfamoyl)-N-(3,4-difluorophenyl)-l-(3-hydroxypropyl)-lH- pyrrole-2-carboxamide;(R)-4-(N-(sec-butyl)sulfamoyl)-N-(3,4-difluorophenyl)-l-(4-hydroxybutyl)-lH- pyrrole-2-carboxamide;(R)-4-(N-(sec-butyl)sulfamoyl)-N-(3,4-difluorophenyl)-l-(5-hydroxypentyl)-lH- pyrrole-2-carboxamide;(R)- 1 -(2,2-difluoroethy l)-N-(3 ,4-difluoropheny l)-4-(N-( 1.1.1 -trifluoropropan-2- yl)sulfamoyl)-lH-pyrrole-2-carboxamide;(R)-l-(2,2-difluoroethyl)-N-(3-(difluoromethyl)-4-fluorophenyl)-4-(N-(l,l,l- trifluoropropan-2-yl)sulfamoyl)-lH-pyrrole-2-carboxamide;(R)-N-(3-cy ano-4-fluoropheny 1)- 1 -(2,2-difluoroethyl)-4-(N-(l , 1 , 1 -trifluoropropan-2- yl)sulfamoyl)-lH-pyrrole-2-carboxamide;(S)-l-(2,2-difluoroethyl)-N-(3,4-difluorophenyl)-4-(N-(l,l,l-trifluoropropan-2- yl)sulfamoyl)-lH-pyrrole-2-carboxamide;(S)-l -(2,2-difluoroethy l)-N-(3-(difluoromethy l)-4-fluorophenyl)-4-(N-(l, 1,1- trifluoropropan-2-yl)sulfamoyl)-lH-pyrrole-2-carboxamide;(S)-N-(3-cyano-4-fluorophenyl)-l-(2,2-difluoroethyl)-4-(N-(l,l,l-trifluoropropan-2- yl)sulfamoyl)-lH-pyrrole-2-carboxamide; l-(2,2-difluoroethyl)-N-(3,4- difluorophenyl)-3-fluoro-4-[[(lR)-2,2,2-trifluoro-l- methyl-ethyl]sulfamoyl]pyrrole-2-carboxamide; l-(2,2-difluoroethyl)-N-(2,3-difluorophenyl)-3-fluoro-4-[[(lR)-2,2,2- trifluoro-1- methyl-ethyl]sulfamoyl]pyrrole-2-carboxamide; l-(2,2-difluoroethyl)-3-fluoro-4-[[(lR)-2,2,2-trifluoro-l-methyl-ethyl]sulfamoyl]-N-(3,4,5-trifluorophenyl)pyrrole-2-carboxamide;N-(3-chlorophenyl)-l-(2,2-difluoroethyl)-3-fluoro-4-[[(lR)-2,2,2- trifluoro- 1-methyl- ethyl]sulfamoyl]pyrrole-2-carboxamide; l-(2,2-difluoroethyl)-3-fluoro-N-phenyl-4-[[(lR)-2.2.2-trifluoro-l-methyl- ethyl]sulfamoyl]pyrrole-2-carboxamide; l-(2,2-difluoroethyl)-3-fluoro-4-[[(lR)-2,2,2-trifluoro-l-methyl-ethyl]sulfamoyl]-N- (2,4,5-trifluorophenyl)pyrrole-2-carboxamide; l-(2,2-difluoroethyl)-N-[3-(difluoromethyl)-4-fluoro-phenyl]-3-fluoro-4-[[(lR)-2,2,2- trifluoro- 1 -methyl-ethylJsulfamoyl]pyrrole-2-carboxamide; l-(2,2-difluoroethyl)-3-fluoro-N-[4-fluoro-3-(trifluoromethyl)phenyl]-4-[[(lR)-2,2,2- trifluoro-l-methyl-ethyl]sulfamoyl]pyrrole-2-carboxamide; l-(2,2-difluoroethyl)-3-fluoro-N-(4-fluoro-3-methyl-phenyl)-4-[[(lR)-2,2,2-trifluoro- l-methyl-ethyl |sulfamovl |pvrrole-2 -carboxamide;N-(3-cyano-4-fluoro-phenyl)-l-(2,2-difluoroethyl)-3-fluoro-4-[[(lR)-2,2,2-trifluoro- l-methyl-ethyl]sulfamoyl]pyrrole-2 -carboxamide; l-(2,2-difluoroethyl)-N-(2,4-difluorophenyl)-3-fluoro-4-[[(lR)-2,2,2- trifluoro-1- methyl-ethyl]sulfamoyl]pyrrole-2-carboxamide;N-(3-chloro-4-fluoro-phenyl)-l-(2,2-difluoroethyl)-3-fluoro-4-[[(lR)- 2,2,2-trifluoro- l-methyl-ethyl]sulfamoyl]pyrrole-2 -carboxamide;N-(3,4-difluorophenyl)-3-fluoro-l-(2-methoxyethyl)-4-[[(lR)-2,2,2-trifluoro-l- methyl-ethyl]sulfamoyl]pyrrole-2-carboxamide;3-fluoro-l-(2-methoxyethyl)-4-[[(lR)-2.2.2-trifluoro-l-methyl-ethyl]sulfamoyl]-N-(3,4,5-trifluorophenyl)pyrrole-2-carboxamide;N-(3-chloro-4-fluoro-phenyl)-3-fluoro-l-(2-methoxyethyl)-4-[[(lR)-2,2,2-trifluoro-l- methyl-ethyl]sulfamoyl]pyrrole-2-carboxamide;N-(3-chlorophenyl)-3-fluoro-l-(3-methoxypropyl)-4-[[(lR)-2,2,2-trifluoro-l -methyl- ethyl]sulfamoyl]pyrrole-2-carboxamide;N-[3-(difluoromethyl)-4-fluoro-phenyl]-3-fluoro-l -(2 -methoxy ethyl)-4-[[(lR)-2, 2,2- trifluoro-l-methyl-ethyl]sulfamoyl]pyrrole-2-carboxamide;3-fluoro-l-(2-methoxyethyl)-N-phenyl-4-[[(lR)-2,2,2-trifluoro-l-methyl- ethyl]sulfamoyl]pyrrole-2-carboxamide;N-(3,4-difluorophenyl)-3-fluoro-l-(3-methoxypropyl)-4-[[(lR)-2,2,2-trifluoro-l- methyl-ethyl]sulfamoyl]pyrrole-2-carboxamide;3-fluoro-l-(3-methoxypropyl)-4-[[(lR)-2.2,2-trifluoro-l-methyl-ethyl]sulfamoyl]-N- (3,4,5-trifluorophenyl)pyrrole-2-carboxamide;N-(3 -chloro-4-fluoro-phenyl)-3-fluoro- 1 -(3 -methoxypropyl)-4- [ [( 1 R)-2,2,2-trifluoro- 1 -methy 1 - ethyl] sulfamoyl] pyrrole-2 -carboxamide;N-(3-chlorophenyl)-3-fluoro-l-(3-methoxypropyl)-4-[[(lR)-2,2,2-trifluoro-l -methyl- ethyl]sulfamoyl]pyrrole-2-carboxamide;N-[3-(difluoromethyl)-4-fluoro-phenyl]-3-fluoro-l-(3-methoxypropyl)-4-[[(lR)-2,2,2- trifluoro-l-methyl-ethyl]sulfamoyl]pyrrole-2-carboxamide;3-fluoro-l-(3-methoxypropyl)-N-phenyl-4-[[(lR)-2.2.2-trifluoro-l-methyl- ethylJsulfamoyl]pyrrole-2-carboxamide;(R)-N-(3 ,4-difluoropheny 1)- 1 -(prop-2 -yn- 1 -yl)-4-(N-( 1 , 1 , 1 -trifluoropropan-2- yl)sulfamoyl)-lH-pyrrole-2-carboxamide;(R)-N-(3,4-difluorophenyl)-3-fluoro-l-(prop-2-yn-l-yl)-4-(N-(l,l,l-trifluoropropan- 2-yl)sulfamoyl)-lH-pyrrole-2-carboxamide;(R)-4-(N-(sec-butyl)sulfamoyl)-N-(3,4-difluorophenyl)-lH-pyrrole-2-carboxamide;(R)-4-(N-(sec-butyl)sulfamoyl)-N-(3-chloro-4-fluorophenyl)-l-(2-chloroethyl)-lH- pyrrole-2-carboxamide;(R)-N-(3 -chloropheny l)-3 -fluoro- 1 -(2-fluoroethyl)-4-(N-( 1,1,1 -trifluoropropan-2- yl)sulfamoyl)-lH-pyrrole-2-carboxamide;(R)-N-(3-(difluoromethyl)-4-fluorophenyl)-3-fluoro- 1 -(2-fluoroethyl)-4-(N-(l , 1,1- trifluoropropan-2-yl)sulfamoyl)-lH-pyrrole-2-carboxamide;(R)-3 -fluoro-N-(4-fluoro-3-(trifluoromethyl)pheny 1)- 1 -(2-fluoroethyl)-4-(N-( 1,1,1- trifluoropropan-2-yl)sulfamoyl)-lH-pyrrole-2-carboxamide;(R)-N-(3-cy ano-4-fluorophenyl)-3 -fluoro- 1 -(2-fluoroethyl)-4-(N-(l ,1,1- trifluoropropan-2-yl)sulfamoyl)-lH-pyrrole-2-carboxamide;(R)-3-fluoro-N-(4-fluoro-3-methylphenyl)-l-(2-fluoroethyl)-4-(N-(l,l,l- trifluoropropan-2-yl)sulfamoyl)-lH-pyrrole-2-carboxamide;(R)-3-fluoro-l-(2-fluoroethyl)-N-(3,4,5-trifluorophenyl)-4-(N-(l,l,l-trifluoropropan- 2-yl)sulfamoyl)-lH-pyrrole-2-carboxamide;(R)-N-(3-chloro-4-fluorophenyl)-3-fluoro-l-(2-fluoroethyl)-4-(N-(l,l,l- trifluoropropan-2-yl)sulfamoyl)-lH-pyrrole-2-carboxamide;(R)-N-(3,4-difluorophenyl)-3-fluoro-l-((tetrahydro-2H-pyran-4-yl)methyl)-4-(N- (l,l,l-trifluoropropan-2-yl)sulfamoyl)-lH-pyrrole-2-carboxamide;(R)-N-(3.4-difluorophenyl)-3-fluoro- 1 -isopentyl-4-(N-( 1,1, 1 -trifluoropropan-2- yl)sulfamoyl)-lH-pyrrole-2-carboxamide;(R)-l-allyl-N-(3,4-difluorophenyl)-3-fluoro-4-(N-(l,l,l-trifluoro propan-2- yl)sulfamoyl)-lH-pyrrole-2-carboxamide;(R)-N-(3.4-difluorophenyl)-3-fluoro-l-(2,2,2-trifluoroethyl)-4-(N-(l,l,l- trifluoropropan-2-yl)sulfamoyl)-lH-pyrrole-2-carboxamide;(R)-N-(3,4-difluorophenyl)-3-fluoro-l-(3-fluoropropyl)-4-(N-(l,l,l-trifluoropropan- 2-yl)sulfamoyl)-lH-pyrrole-2-carboxamide;(R)-N-(3.4-difluorophenyl)-3-fluoro-l-(4,4,4-trifluorobutyl)-4-(N-(l,l,l- trifluoropropan-2-yl)sulfamoyl)-lH-pyrrole-2-carboxamide;(S)-N-(3-cyano-4-fluorophenyl)-l-methyl-4-(N-(l,l,l-trifluoropropan-2- yl)sulfamoyl)-lH-pyrrole-2-carboxamide;(R)-4-(N-(sec-butyl)-N-(2-cyanoethyl)sulfamoyl)-N-(3,4-fluorophenyl)-l-(2- cy anoethyl)- lH-pyrrole-2-carboxamide;(R)-4-(N-(sec-butyl)-N-(2-cyanoethyl)sulfamoyl)-N-(3,4-fluorophenyl)-N,l-bis(2- cyanoethyl)-lH-pyrrole-2-carboxamide;(R)-l -(2,2-difluoroethyl)-N-(3,4-difluorophenyl)-3-fluoro-4-(N-(l , 1,1- trifluoropropan-2-yl)sulfamoyl)-lH-pyrrole-2-carboxamide;(R)-l-(2,2-difluoroethyl)-3-fluoro-N-(3,4,5-trifluorophenyl)-4-(N-( 1,1,1 - trifluoropropan-2-yl)sulfamoyl)-lH-pyrrole-2-carboxamide; an enantiomer thereof, a diastereomer thereof, a hydrate thereof, a solvate thereof, a pharmaceutically acceptable salt thereof, a complex thereof, and a combination of two or more thereof.

17. A composition comprising an effective amount of at least one compound according to claim 1.

18. The composition according to claim 17 further comprising at least one excipient.

19. A method for treating or preventing hepatitis B, said method comprising administering to a subject an effective amount of at least one compound according to claim 1 to ameliorate, reduce, treat, and / or prevent hepatitis B.

20. A method for treating or preventing hepatitis B, said method comprising administering to a subject an effective amount of at least one compound according to claim 1 to ameliorate and / or reduce hepatitis B.

21. The method of claim 19, wherein the at least one compound is administered in a composition further comprising at least one pharmaceutically acceptable excipient.

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