Azetidine compounds for treatment of hsv

Abstract

The present disclosure provides, in part, azetidine compounds, and pharmaceutical compositions thereof, and methods of the treatment and prophylaxis of HSV infections.

Description

[0001] AZETIDINE COMPOUNDS FOR TREATMENT OF HSV CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No.63 / 602,173, filed November 22, 2023, which is incorporated by reference in its entirety. BACKGROUND Human herpes viruses are large-enveloped double-stranded DNA viruses that share the characteristic of establishing life-long infections in humans. This is accomplished by their ability to exist in the host either as a symptom free latent infection, where the virus lies dormant or, following activation, as a lytic infection with associated symptoms. These viral infections have widespread, worldwide prevalence and it is notable that over 90% of all humans are chronically infected with more than one human herpes virus. Human herpes viruses are classified into three subfamilies (i.e., α, β and γ) based upon their biological characteristics and the family consists of eight members, i.e., Herpes Simplex Virus subtype type 1 and 2 (HSV1, HSV2), Varicella Zoster Virus (VZV), Epstein-Barr virus (EBV), Cytomegalovirus (CMV), and human herpes viruses 6-8 (HHV 6-8). HSV1 and 2 infections can cause disease in immune competent individuals. Both subtypes cause cutaneous genital / anal and orolabial / nasal cavity (cold sore) lesions, although HSV2 is more commonly associated with the former and HSV1 the latter such that >80% of genital infections are believed to be caused by HSV2. Globally, over 500 million people have genital herpes infections. Symptoms vary but are typically most severe on first time of infection and can last for weeks to months. Approximately 50 to 80% of the world’s population have orolabial HSV infection, which is the main cause of cold sores. HSV, and particularly HSV1, can also cause lesions on the fingers (Whitlows) and other areas of the skin. The vast majority of HSV infected individuals will not experience any noticeable symptoms. However, some will experience recurrent outbreaks of infection. In the USA, 20 to 40% of the population will get recurrent labial HSV lesions. Significantly, orolabial cold sores and Whitlow’s provide a very easy route for transmission of the virus to other individuals which can lead to rarer but much more serious HSV-related pathologies. For example, HSV-related ocular keratitis is a major cause of blindness. HSV can also cause encephalitis in neonates which is a life-threatening condition. Other disorders also believed to be caused by HSV include herpes gladiatorum, Mollaret's meningitis and possibly Bell's palsy. Primary infection with, or reactivation of an existing herpes virus infection, can be a major cause of disease in immunocompromised individuals. Key at-risk immunocompromised populations include patients undergoing solid organ or stem cell transplantation, individuals with HIV / AIDS, and ICU patients. Presently, there is no cure for HSV. Medicines have been developed that can to some degree prevent or shorten outbreaks, but there is a need for improved therapies for treating HSV infection and inhibiting viral replication. Currently, nucleoside analogues, such as acyclovir and its prodrugs, e.g., valacyclovir and famciclovir, are used as agents against herpes viruses such as HSV. In order to exert their effects, these nucleoside analogues must first be phosphorylated by viral thymidine kinase (TK) and then subsequently converted by cellular kinases to the nucleoside triphosphate, which inhibits the activity of the viral DNA polymerase. If the virus has no functionally active TK, as is the case, for example, with resistant HHV1 mutants or with TK-negative viruses, the active substance is unable to exert its effects. Nucleoside analogues are clinically administered at a dose as high as several hundred in mg to several grams per day and even in high doses, and over long treatment durations, these compounds do not completely prevent recurrent outbreaks of symptoms from HSV infection. High doses also lead to increased levels of adverse effects. Viral shedding is also common in HSV patients and can asymptomatically facilitate the transmission of HSV to more individuals. Nucleoside analogues do little to address this and long-term suppressive treatment, e.g., with valacyclovir has been shown to reduce transmission risk only by 46%. Since the nucleoside analogues can incorporate into the genome DNA of a host via the host DNA polymerase, the mutagenicity of these agents is also a concern, as documented for the nucleoside analogue, ganciclovir. Given the inadequacy of existing treatments, there is an urgent medical need to develop improved, well-tolerated anti-herpes treatments. A class of compounds being investigated for HSV treatment are the helicase-primase inhibitors. Helicase-primase inhibitors are antiviral agents with a novel mechanism of action against HSV1 and 2. They inhibit the viral heterotrimeric complex consisting of helicase, primase, and cofactor subunits that have functions essential for viral DNA replication. They are not nucleoside analogues and do not require phosphorylation by TK to inhibit HSV replication and they are therefore potentially active against TK-deficient HSV, which as described above, is a major mechanism of resistance to nucleoside analogues, such as acyclovir. Two examples of helicase-primase inhibitors are BILS-179 BS and amenamevir (Katsumata et al. (2018) Biochem Pharm 158 p201-206). BILS-179 BS has been dosed orally but was suspended from early clinical trials due to adverse events. One example of a helicase-primase inhibitor is pritelivir, a thiazolylamide derivative with the chemical name N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2- pyridinyl)-phenyl] acetamide. This compound has been disclosed in WO200053591. WO2001047904 discloses thiazolyl amide derivatives and their use as antiviral medicaments. WO2000053591 discloses thiazolyl derivatives and their utilization as antiviral agents. WO2017174640 discloses aminothiazole derivatives useful as antiviral agents. WO2019068817 discloses enantiomers of substituted thiazoles as antiviral compounds. There is still a need for additional antiviral compounds for the treatment and prophylaxis of HSV infections that have an improved profile with respect to safety, potency, selectivity and / or bioavailability. SUMMARY OF THE INVENTION In one aspect, the present disclosure provides a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein the variables are as described herein. In another aspect, the disclosure provides pharmaceutical compositions comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In another aspect, the disclosure provides a method of treating an HSV infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of compound of Formula I, or a pharmaceutically acceptable salt thereof. In another aspect, the disclosure provides a method of treating an HSV infection in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. DETAILED DESCRIPTION OF THE INVENTION The features and other details of the disclosure will now be more particularly described. Before further description of the present disclosure, certain terms employed in the specification, examples and appended claims are collected here. These definitions should be read in light of the remainder of the disclosure and as understood by a person of skill in the art. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by a person of ordinary skill in the art. Definitions The term “alkyl” as used herein refers to a saturated straight or branched hydrocarbon. Exemplary alkyl groups include, but are not limited to, straight or branched hydrocarbons of 1-6 or 1-4 carbon atoms, referred to herein as C1-6 alkyl and C1-4 alkyl, respectively. Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-butyl, 3-methyl-2- butyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2- pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, neopentyl, and n-hexyl. The term “alkylene” as used herein refers to a biradical alkyl group. The term “alkenyl” as used herein refers to an unsaturated straight or branched hydrocarbon having at least one carbon-carbon double bond. Exemplary alkenyl groups include, but are not limited to, a straight or branched group of 2-6 carbon atoms, referred to herein as C2-6alkenyl. Examples include, but are not limited to, vinyl, allyl, butenyl, and pentenyl. The term “alkynyl” as used herein refers to an unsaturated straight or branched hydrocarbon having at least one carbon-carbon triple bond. Exemplary alkynyl groups include, but are not limited to, straight or branched groups of 2-6 carbon atoms, referred to herein as C2-6alkynyl. Examples include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and methylpropynyl. The term “alkoxy” as used herein refers to a straight or branched alkyl group attached to oxygen (i.e., alkyl-O-). Exemplary alkoxy groups include, but are not limited to, alkoxy groups of 1-6 or 1-4 carbon atoms, referred to herein as C1-6alkoxy and C1-4alkoxy, respectively. Examples include, but are not limited to, methoxy, ethoxy, and isopropoxy. The term “alkoxyalkyl” as used herein refers to an alkyl group substituted with an alkoxy group. Exemplary alkoxyalkyl groups include, but are not limited to, a C1-6alkyl group substituted with a C1-3alkoxy or C1-4alkoxy group, referred to herein as C1-3alkoxyC1-6alkyl and C1-4alkoxyC1-6alkyl, respectively. Examples include, but are not limited to, CH3CH2OCH2-, CH3OCH2CH2- and CH3OCH2-. The term “cyano” as used herein refers to CN. The term “monocycloalkyl” as used herein refers to a saturated monocyclic hydrocarbon group of, for example, 3-6 carbons, referred to herein as C3-6monocycloalkyl. Examples include, btu are not limited to, cyclooctyl, cycloheptyl. cyclohexyl, cyclopentenyl, cyclobutyl and cyclopropyl. The terms “halo” or “halogen” as used herein refer to F, Cl, Br or I. The term “haloalkyl” as used herein refers to an alkyl group substituted with one or more halogen atoms. Exemplary haloalkyl groups include, but are not limited to, a C1-6alkyl or C1-4alkyl substituted with one or more halo groups, referred to herein as haloC1-6alkyl and haloC1- 4alkyl, respectively. For example, haloC1-6alkyl refers to a straight or branched alkyl group of 1-6 carbon atoms substituted with one or more halogen atoms. Examples include, but are not limited to, -CH2F, -CHCl2, -CHF2, -CF3, CF3CH2-, CH3CF2-, CF3CCl2- and CF3CF2-. The term “haloalkoxy” as used herein refers to an alkoxy group substituted with one or more halogen atoms. Exemplary alkoxy groups include, but are not limited to, a C1-6alkoxy or C1-4alkoxy substituted with one or more halo groups, referred to herein as haloC1-6alkoxy and haloC1-4alkoxy, respectively. Examples include, but are not limited to, CCl3O-, CF3O-, CHF2O- CF3CH2O-, and CF3CF2O-. The terms “hydroxy” and “hydroxyl” as used herein refer to OH. The term “hydroxyalkyl” as used herein refers to an alkyl group substituted with one or more hydroxy groups. Exemplary hydroxyalkyl groups include, but are not limited to, a C1-6alkyl or C1-4alkyl substituted with one or more hydroxy groups, referred to herein as hydroxyC1-6alkyl and hydroxyC1-4alkyl, respectively. Examples include, but are not limited to, HOCH2-, HOCH2CH2-, CH3CH(OH)CH2-, (CH3)2C(OH)CH2-, and HOCH2CH(OH)CH2-. The term “hydroxyalkoxy” as used herein refers to an alkoxy group substituted with one or more hydroxy groups. Exemplary hydroxyalkoxy groups include, but are not limited to, a C1-6alkoxy or C1-4alkoxy substituted with one or more hydroxy groups, referred to herein as hydroxyC1-6alkoxy and hydroxyC1-4alkoxy, respectively. Examples include, but are not limited to HOCH2O-, HOCH2CH2O-, CH3CH(OH)CH2O-, (CH3)2C(OH)CH2O-, and HOCH2CH(OH)CH2O-. The term “RnRmNalkyl-,” as used herein refers to an alkyl group substituted with a RnRmN- group, as defined herein. Exemplary RnRmNalkyl- groups include, but are not limited to, a C1-6alkyl or C1-4alkyl substituted with one or more RnRmN- group groups, referred to herein as RnRmNC1-6alkyl and RnRmNC1-4alkyl, respectively. Examples include, but are not limited to NH2CH2-, NH(CH3)CH2-, N(CH3)2CH2CH2- and CH3CH(NH2)CH2-. The term “RnRmNalkoxy,” as used herein refers to an alkoxy group substituted with a RnRmN- group, as defined herein. Exemplary RnRmNalkoxy groups include, but are not limited to, a C1-6alkoxy or C1-4alkoxy substituted with one or more RnRmN- groups, referred to herein as RnRmNC1-6alkoxy and RnRmNC1-4alkoxy, respectively. Examples include, but are not limited to, NH2CH2-, NH(CH3)CH2O-, N(CH3)2CH2CH2O-, and CH3CH(NH2)CH2O-. As used herein, when a bicyclic ring is shown with a floating point of attachment and / or floating substituents, for example as in , it signifies that the bicyclic ring can be attached via a carbon atom on either ring, and that the substituents (e.g., the R33group(s)) can be independently attached to either or both rings. The terms “Individual,” “patient,” or “subject” are used interchangeably and include any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans. The compounds or pharmaceutical compositions of the disclosure can be administered to a mammal, such as a human, but can also be administered to other mammals such as an animal in need of veterinary treatment, e.g., domestic animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, sheep, pigs, horses, and the like) and laboratory animals (e.g., rats, mice, guinea pigs, dogs, primates, and the like). The mammal treated in the methods of the disclosure is desirably a mammal in which treatment of HSV infection is desired. The term “modulation” includes antagonism (e.g., inhibition), agonism, partial antagonism and / or partial agonism. The term “Pharmaceutically acceptable” includes molecular entities and compositions that do not produce an adverse, allergic, or other untoward reaction when administered to an animal, or a human, as appropriate. For human administration, preparations should meet sterility, pyrogenicity, and general safety and purity standards as required by FDA Office of Biologics standards. The term “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” as used herein refers to any and all solvents, dispersion media, coatings, isotonic and absorption delaying agents, fillers, and the like, that are compatible with pharmaceutical administration. The use of such media and agents for pharmaceutically active substances is well known in the art. The compositions may also contain other active compounds providing supplemental, additional, or enhanced therapeutic functions. The term “pharmaceutical composition” as used herein refers to a composition comprising at least one compound as disclosed herein formulated together with one or more pharmaceutically acceptable excipients. The term "pharmaceutically acceptable salt(s)" as used herein refers to salts of acidic or basic groups that may be present in compounds used in the compositions. Compounds included in the present compositions that are basic in nature can form a wide variety of salts with various inorganic and organic acids. The acids that may be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, including, but not limited to, malate, oxalate, chloride, bromide, iodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)) salts. Compounds included in the present compositions that are acidic in nature are capable of forming base salts with various pharmacologically acceptable cations. Examples of such salts include alkali metal or alkaline earth metal salts, particularly calcium, magnesium, sodium, lithium, zinc, potassium, and iron salts. Compounds included in the present compositions that include a basic or acidic moiety may also form pharmaceutically acceptable salts with various amino acids. The compounds of the disclosure may contain both acidic and basic groups; for example, one amino and one carboxylic acid group. In such a case, the compound can exist as an acid addition salt, a zwitterion, or a base salt. The term “therapeutically effective amount” or “effective amount” as used herein refers to the amount of the subject compound that will elicit the biological or medical response of a tissue, system or animal, (e.g., mammal or human) that is being sought by the researcher, veterinarian, medical doctor or other clinician. The compounds or pharmaceutical compositions of the disclosure are administered in therapeutically effective amounts to treat a disease. Alternatively, a therapeutically effective amount of a compound is the quantity required to achieve a desired therapeutic and / or prophylactic effect. The term “treating” includes any effect, e.g., lessening, reducing, modulating, or eliminating, a viral infection, that results in the improvement of the disease. The compounds of the disclosure may contain one or more chiral centers and, therefore, exist as stereoisomers. The term “stereoisomers” when used herein consist of all enantiomers or diastereomers. These compounds may be designated by the symbols “(+),” “ ),” “R” or “S,” depending on the configuration of substituents around the stereogenic carbon atom, but the skilled artisan will recognize that a structure may denote a chiral center implicitly. The present disclosure encompasses various stereoisomers of these compounds and mixtures thereof. Mixtures of enantiomers or diastereomers may be designated “(±)” in nomenclature, but the skilled artisan will recognize that a structure may denote a chiral center implicitly. The compounds of the disclosure may contain one or more double bonds and, therefore, exist as geometric isomers resulting from the arrangement of substituents around a carbon- carbon double bond. The symbol denotes a bond that may be a single, double or triple bond as described herein. Substituents around a carbon-carbon double bond are designated as being in the “Z” or “E” configuration wherein the terms “Z” and “E” are used in accordance with IUPAC standards. Unless otherwise specified, structures depicting double bonds encompass both the “E” and “Z” isomers. Substituents around a carbon-carbon double bond alternatively can be referred to as “cis” or “trans,” where “cis” represents substituents on the same side of the double bond and “trans” represents substituents on opposite sides of the double bond. Compounds of the disclosure may contain a carbocyclic or heterocyclic ring and therefore, exist as geometric isomers resulting from the arrangement of substituents around the ring. The arrangement of substituents around a carbocyclic or heterocyclic ring are designated as being in the “Z” or “E” configuration wherein the terms “Z” and “E” are used in accordance with IUPAC standards. Unless otherwise specified, structures depicting carbocyclic or heterocyclic rings encompass both “Z” and “E” isomers. Substituents around a carbocyclic or heterocyclic ring may also be referred to as “cis” or “trans”, where the term “cis” represents substituents on the same side of the plane of the ring and the term “trans” represents substituents on opposite sides of the plane of the ring. Mixtures of compounds wherein the substituents are disposed on both the same and opposite sides of plane of the ring are designated “cis / trans.” Individual enantiomers and diastereomers of compounds of the present disclosure can be prepared synthetically from commercially available starting materials that contain asymmetric or stereogenic centers, or by preparation of racemic mixtures followed by resolution methods well known to those of ordinary skill in the art. These methods of resolution are exemplified by (1) attachment of a mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography and liberation of the optically pure product from the auxiliary, (2) salt formation employing an optically active resolving agent, (3) direct separation of the mixture of optical enantiomers on chiral liquid chromatographic columns or (4) kinetic resolution using stereoselective chemical or enzymatic reagents. Racemic mixtures can also be resolved into their component enantiomers by well-known methods, such as chiral- phase liquid chromatography or crystallizing the compound in a chiral solvent. Stereoselective syntheses, a chemical or enzymatic reaction in which a single reactant forms an unequal mixture of stereoisomers during the creation of a new stereocenter or during the transformation of a pre- existing one, are well known in the art. Stereoselective syntheses encompass both enantiomeric and diastereoselective transformations and may involve the use of chiral auxiliaries. For examples, see Carreira and Kvaerno, Classics in Stereoselective Synthesis, Wiley-VCH: Weinheim, 2009. The compounds disclosed herein can exist in solvated as well as unsolvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the disclosure embrace both solvated and unsolvated forms. In one embodiment, the compound is amorphous. In one embodiment, the compound is a single polymorph. In another embodiment, the compound is a mixture of polymorphs. In another embodiment, the compound is in a crystalline form. The disclosure also embraces isotopically labeled compounds of the disclosure which are identical to those recited herein, except that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as2H,3H,13C,14C,15N,18O,17O,31P,32P,35S,18F, and36Cl, respectively. For example, a compound of the disclosure may have one or more H atom replaced with deuterium. Certain isotopically labeled disclosed compounds (e.g., those labeled with3H and14C) are useful in compound and / or substrate tissue distribution assays. Tritiated (i.e.,3H) and carbon- 14 (i.e.,14C) isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e.,2H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances. Isotopically labeled compounds of the disclosure can generally be prepared by following procedures analogous to those disclosed in the examples herein by substituting an isotopically labeled reagent for a non-isotopically labeled reagent. The term “prodrug” refers to compounds that are transformed in vivo to yield a disclosed compound or a pharmaceutically acceptable salt, hydrate or solvate of the compound. The transformation may occur by various mechanisms (such as by esterase, amidase, phosphatase, oxidative and or reductive metabolism) in various locations (such as in the intestinal lumen or upon transit of the intestine, blood or liver). Prodrugs are well known in the art (for example, see Rautio, Kumpulainen, et al., Nature Reviews Drug Discovery 2008, 7, 255). Azetidine Compounds In one aspect, the present disclosure provides a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein: is selected from the group consisting of: , , ,, , and ; is selected from the group consisting of: , , , , , , , , , , and ;X is CR2or N; X1, X2and X4are independently selected from the group consisting of O and S; X3is CH2, O, or NRx;Rais hydrogen, C1-4alkyl, cyclopropyl, cyclobutyl or oxetanyl; Rbis hydrogen, halo, cyano, OH, C1-4alkyl, haloC1-4alkyl; or Raand Rbtogether form a - CH2CH2X3- or -CH2X3- group; Rxand Ryare independently selected from the group consisting of is hydrogen, C1-4alkyl, and acetyl; R1is or ; R2is hydrogen, halo, C1-4alkyl, haloC1-4alkyl, C1-4alkoxy or haloC1-4alkoxy; R3is independently selected for each occurrence from the group consisting of halo and cyano; R3a, R4aand R11aare independently selected from the group consisting of hydrogen, C1-4alkyl, halo C1-4alkyl and hydroxyC1-4alkyl; R4is independently selected for each occurrence from the group consisting of halo, CN, OH, NRnRm, C1-4alkyl, haloC1-4alkyl, C2-4alkenyl, C2-4alkynyl optionally substituted with hydroxyC1-3alkyl, cyclopropyl optionally substituted with halo or cyano, and R4b, provided that only one R4group can be R4b; R4bis selected from the group consisting of: , , , , , ,

[0002] , , and ;R7and R8are independently selected from the group consisting of hydrogen, C1-4alkyl, acetyl, C3-6monocycloalkyl, phenyl, and pyridyl; or R7and R8together with the N atom to which they are attached form an arizidinyl, azetidinyl, pyrrolidinly, piperidinyl, morpholinyl or thiomorpholinyl group; R7aand R8aare independently selected from the group consisting of hydrogen, C1-4alkyl and C3-6monocycloalkyl, or R7and R8together with the N atom to which they are attached form an arizidinyl, azetidinyl, pyrrolidinyl, or piperidinyl morpholinyl or thiomorpholinyl group; R9and R9aare independently selected from the group consisting or C1-4alkyl and haloC1- 4alkyl; R10and R10aare independently selected from the group consisting of hydrogen and C1-4alkyl; R11is independently selected for each occurrence from the group consisting of halo, CN, OH, NRnRm, C1-4alkyl, haloC1-4alkyl, C2-4alkenyl, C2-4alkynyl, and cyclopropyl; q, r and x are independently selected from the group consisting of 0 and 1; s, w and z are independently selected from the group consisting of 0, 1 and 2; and u, v and y are independently selected from the group consisting of 0, 1, 2 and 3. The following embodiments further describe a compound of Formula I, or a pharmaceutically acceptable salt thereof. It will be appreciated that all chemically allowable combinations of the embodiments described herein are envisioned as further embodiments of the invention. In certain embodiments, is F Cl In certain embodiments, is or . In certain embodiments, is In certain embodiments, is 15 In certain embodiments, is selected from the group consisting of and . In certain embodiments, is . In certain embodiments, is or . In certain embodiments, is . In certain embodiments, is In certain embodiments, is selected from the group consisting of and .In certain embodiments, is selected from the group consisting of , , , , , , , , , , , and . In certain embodiments: is ; and is selected from the group consisting of and In certain embodiments: is ; and is . In certain embodiments: is ; and is 18 In certain embodiments: is and is selected from the group consisting of ,, , , , , , , , , , , and .In certain embodiments, X isCR2. In Certain embodiments, X is C(CH3). In certain embodiments: Rais hydrogen or C1-4alkyl; and Rbis hydrogen, halo, cyano, OH, C1-4alkyl, haloC1-4alkyl. In certain embodiments: Rais hydrogen or C1-4alkyl; and Rbis hydrogen. In certain embodiments, Raand Rbare hydrogen. In certain embodiments, Raand Rbtogether form a -CH2CH2X3- or -CH2X3- group. For clarity, when Raand Rbtogether form a -CH2CH2X3- or -CH2X3- group, the Compound of Formula I can be depicted as Formula Ia: or a pharmaceutically acceptable salet thereof. In certain embodiments, R1is , , or In certain embodiments, R1 is or .In certain embodiments, R1is . In certain embodiments, In certain embodiments, In certain embodiment .In certain embodiments, In certain embodiments, In certain embodiments, . In certain embodiments, . In certain embodiments: R2is H, Cl, F, CH3 or CF3. In certain embodiments: R2is CH3. In certain embodiments, R3is halo for each occurrence and u is 1, 2 or 3. In certain embodiments,R3is F for each occurrence and u is 1, 2 or 3. In certain embodiments, R4is independently selected for each occurrence from the group consisting of halo, CN, methyl, CHF2, CF3, acetylenyl, and cyclopropyl. In certain embodiments, R4is independently selected for each occurrence from the group consisting of halo, CN, OH, NH2, NH(CH3), N(CH3)2, C1-4alkyl, haloC1-4alkyl, C2-4alkenyl, C2- 4alkynyl optionally substituted with hydroxyC1-3alkyl, and cyclopropyl optionally substituted with halo or cyano. In certain embodiments: R4is independently selected for each occurrence from the group consisting of halo, CN, methyl, CHF2, CF3, acetylenyl, and cyclopropyl. In certain embodiments: R4is independently selected from halo for all occurrences. In certain embodiments, R4bis selected from the group consisting of , , In certain embodiments, R4bis selected from the group consisting of , Methods of Use The compounds according to the present invention are useful for the treatment and prophylaxis of disorders caused by herpes viruses, in particular Herpes simplex viruses. In one aspect, the present invention provides a method for the treatment or prophylaxis of an HSV infection in a subject in need thereof, the method comprising: administering to the subject a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof. In some embodiment, the infection is a Herpes simplex infection. In some embodiment, the infection is an HSV-1 infection. In some embodiment, the infection is an HSV-2 infection. In some embodiments, the infection is a Herpes simplex infection and the subject displays symptoms such as Herpes labialis, Herpes genitalis, HSV-related keratitis, encephalitis, or pneumonia. In another embodiment, the infection is a Herpes simplex infection and the subject displays symptoms such as suppressed immune system (for example AIDS patients, cancer patients, patients having a genetic immunodeficiency, transplant patients). In another embodiment, the infection is a Herpes simplex infection, and the subject is a new-born child or infant. In another aspect, the present invention provides a method for suppressing recurrence of HSV symptoms or outbreaks in a subject in need thereof, the method comprising: administering to the subject a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof. In some embodiment, the infection is a Herpes simplex infection. In some embodiment, the infection is an HSV-1 infection. In some embodiment, the infection is an HSV-2 infection. In some embodiment, the subject is a herpes-positive patient. In some embodiment, the subject is a herpes-simplex-positive patient. In another aspect, the present invention provides a method for the treatment or prophylaxis of an HSV infection in a subject in need thereof, the method comprising: administering to the subject a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, wherein: the infection is resistant to nucleosidic antiviral therapy. In one embodiment, the infection is a Herpes simplex infection. In some embodiment, the infection is a Herpes simplex infection. In another embodiment, the subject is a herpes-positive patient. In another embodiment, the nucleosidic antiviral therapy is selected from the group consisting of acyclovir, penciclovir, famciclovir, ganciclovir and valacyclovir. In another aspect, the present invention provides a compound for the use as a medicament. Combination Therapies The compounds according to the present invention are also useful for the treatment and prophylaxis of disorders caused by herpes viruses, in particular Herpes simplex viruses, in combination with other active ingredients. In one aspect, the present invention provides a method for the treatment or prophylaxis of an HSV infection in a subject in need thereof, the method comprising: administering to the subject a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, in combination with an antiviral agent. In some embodiments, the antiviral agent is selected from the group consisting of acyclovir, penciclovir, famciclovir, ganciclovir and valacyclovir, foscarnet and trifluridine. In some embodiment, the infection is a Herpes simplex infection. In some embodiment, the infection is an HSV-1 infection. In some embodiment, the infection is an HSV-2 infection. In some embodiments, the infection is a Herpes simplex infection and the subject displays symptoms such as Herpes labialis, Herpes genitalis, HSV-related keratitis, encephalitis, or pneumonia. In another embodiment, the infection is a Herpes simplex infection and the subject displays symptoms such as suppressed immune system (for example AIDS patients, cancer patients, patients having a genetic immunodeficiency, transplant patients). In another embodiment, the infection is a Herpes simplex infection, and the subject is a new-born child or infant. In another aspect, the present invention provides a method for suppressing recurrence of HSV symptoms or outbreaks in a subject in need thereof, the method comprising: administering to the subject a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, in combination with an antiviral agent. In some embodiments, the antiviral agent is selected from the group consisting of acyclovir, penciclovir, famciclovir, ganciclovir and valacyclovir, foscarnet and trifluridine. In some embodiment, the infection is a Herpes simplex infection. In some embodiment, the infection is an HSV-1 infection. In some embodiment, the infection is an HSV-2 infection. In some embodiment, the subject is a herpes-positive patient. In some embodiment, the subject is a herpes-simplex-positive patient. In another aspect, the present invention provides a compound for the use as a medicament. In another aspect, the present invention provides a method for the treatment or prophylaxis of an HSV infection in a subject in need thereof, the method comprising: administering to the subject a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, in combination with a corticosteroid. In some embodiment, the infection is a Herpes simplex infection. In some embodiment, the infection is an HSV-1 infection. In some embodiment, the infection is an HSV-2 infection. In some embodiments, the infection is a Herpes simplex infection and the subject displays symptoms such as Herpes labialis, Herpes genitalis, HSV-related keratitis, encephalitis, or pneumonia. In another embodiment, the infection is a Herpes simplex infection and the subject displays symptoms such as suppressed immune system (for example AIDS patients, cancer patients, patients having a genetic immunodeficiency, transplant patients). In another embodiment, the infection is a Herpes simplex infection, and the subject is a new-born child or infant. In another aspect, the present invention provides a method for suppressing recurrence of HSV symptoms or outbreaks in a subject in need thereof, the method comprising: administering to the subject a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, in combination with a corticosteroid. In some embodiment, the infection is a Herpes simplex infection. In some embodiment, the infection is an HSV-1 infection. In some embodiment, the infection is an HSV-2 infection. In some embodiment, the subject is a herpes-positive patient. In some embodiment, the subject is a herpes-simplex-positive patient. In another aspect, the present invention provides a compound for the use as a medicament. Formulations and Administration The compounds on the invention can be converted in a known manner into the customary formulations, such as tablets, sugar-coated tablets, pills, granules, aerosols, syrups, emulsions, suspensions, and solutions, using inert, nontoxic, pharmaceutically suitable carriers and solvents. Here, the therapeutically active compound should in each case be present in a concentration of about 0.5 to 90% by weight of the total mixture, i.e., in amounts which are sufficient to achieve the dosage range indicated. The formulations are prepared, for example, by extending the active compounds with solvents and / or excipients, if appropriate using emulsifiers and / or dispersants, it being possible, for example, if the diluent used is water, to use, if appropriate, organic solvents as auxiliary solvents. Administration is carried out in a customary manner, including orally, parenterally, topically, perlingually or intravenously. In the case of parenteral administration, solutions or suspensions of the active compounds using suitable liquid carrier and excipients can be employed. In general, it has proved advantageous in the case of intravenous administration to administer amounts of from approximately 0.001 to 20 mg / kg, preferably approximately 0.01 to 10 mg / kg, of bodyweight to achieve effective results, and in the case of oral administration the dose is approximately 0.01 to 30 mg / kg, preferably 0.1 to 20 mg / kg, of bodyweight. In some instances, it may be necessary to depart from the amounts mentioned, namely depending on the bodyweight or on the type of administration route, on the individual response to the medicament, the manner of its formulation and the time or interval at which administration takes place. Thus, in some cases it may be adequate to manage with less than the abovementioned minimum amount, while in other cases the upper limit mentioned must be exceeded. In the case of the administration of relatively large amounts, it may be advisable to divide this into several individual administrations over the course of the day. If appropriate, it may be useful to combine the compounds according to the invention with other active substances, in particular antiviral active substances. The compounds used in the present invention can be in the form of a pharmaceutically acceptable salt, cocrystal or a solvate. The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids, including inorganic bases or acids and organic bases or acids. In case the compounds of the present invention contain one or more acidic or basic groups, the invention also comprises their corresponding pharmaceutically or toxicologically acceptable salts, in particular their pharmaceutically utilizable salts. Thus, the compounds of the present invention which contain acidic groups can be used according to the invention, for example, as alkali metal salts, alkaline earth metal salts or ammonium salts. More precise examples of such salts include sodium salts, potassium salts, calcium salts, magnesium salts or salts with ammonia or organic amines such as, for example, ethylamine, ethanolamine, triethanolamine or amino acids. The compounds of the present invention which contain one or more basic groups, i.e., groups which can be protonated, can be used according to the invention in the form of their addition salts with inorganic or organic acids. Examples of suitable acids include hydrogen chloride, hydrogen bromide, phosphoric acid, sulfuric acid, nitric acid, methanesulfonic acid, p-toluenesuifonic acid, naphthalenedisulfonic acids, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid, sulfaminic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, citric acid, adipic acid, and other acids known to the person skilled in the art. If the compounds of the present invention simultaneously contain acidic and basic groups in the molecule, the invention also includes, in addition to the salt forms mentioned, inner salts or betaines (zwitterions). The respective salts can be obtained by customary methods which are known to the person skilled in the art like, for example, by contacting these with an organic or inorganic acid or base in a solvent or dispersant, or by anion exchange or cation exchange with other salts. The present invention also includes all salts of the compounds of the present invention which, owing to low physiological compatibility, are not directly suitable for use in pharmaceuticals but which can be used, for example, as intermediates for chemical reactions or for the preparation of pharmaceutically acceptable salts. Depending on the substitution pattern, the compounds according to the invention can exist in stereoisomeric forms which either behave as image and mirror image (enantiomers), or which do not behave as image and mirror image (diastereomers). The invention relates both to the enantiomers or diastereomers and their respective mixtures. Like the diastereomers, the racemic forms can be separated into the stereoisomerically uniform components in a known manner. The scope of the invention includes those compounds which are only converted into the actual active compounds of the Formulas I and once inside the body (so-called prodrugs). In practical use, the compounds used in the present invention can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral, or parenteral {including intravenous). In preparing the compositions for oral dosage form, any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols, flavouring agents, preservatives, coloring agents and the like in the case of oral liquid preparations, such as, for example, suspensions, elixirs and solutions; or carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solid preparations such as, for example, powders, hard and soft capsules and tablets, with the solid oral preparations being preferred over the liquid preparations. Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be coated by standard aqueous or non-aqueous techniques. Such compositions and preparations should contain at least 0.1 percent of active compound. The percentage of active compound in these compositions may, of course, be varied and may conveniently be between about 2 percent to about 60 percent of the weight of the unit. The amount of active compound in such therapeutically useful compositions is such that an effective dosage will be obtained. The active compounds can also be administered intranasally as, for example, liquid drops or spray or as eye drops. The tablets, pills, capsules, and the like may also contain a binder such as hydroxypropyl methylcellulose, or polyvinylpyrrolidone; diluent or fillers such as microcrystalline cellulose, dicalcium phosphate, lactose, or mannitol; a disintegrating agent such as croscarmellose sodium, polyvinylpyrrolidone, or sodium starch glycolate; a lubricant such as magnesium stearate or sodium stearyl fumarate; a glidant such as silicon dioxide; and a sweetening agent such as sucrose or saccharin. When a dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as a fatty oil. Various other materials may be present as coatings or to modify the physical form of the dosage unit. For instance, tablets may be coated with shellac, sugar or both. A syrup or elixir may contain, in addition to the active ingredient, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and a flavoring such as cherry or orange flavor. The compounds used in the present invention may also be administered parenterally. Solutions or suspensions of these active compounds can be prepared in water suitably mixed with a surfactant such as hydroxypropyl cellulose, sodium lauryl sulfate, or polysorbate. Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms. The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must 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. Any suitable route of administration may be employed for providing a mammal, especially a human, with an effective dose of a compound of the present invention. For example, oral, rectal, topical, parenteral (including intravenous), ocular, pulmonary, nasal, and the like may be employed. Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols, and the like. Compounds of the present invention can be administered orally or as eye drop. The compounds of the present invention can also be administered orally. The effective dosage of active ingredient employed may vary depending on the particular compound employed, the mode of administration, the condition being treated, and the severity of the condition being treated. Such dosage may be ascertained readily by a person skilled in the art. The compounds of the present invention can also be present in combination with additional active ingredients, in particular, with one or more active ingredients exhibiting advantageous effects in the treatment of any of the disorders or diseases as described herein. The compounds of the present invention can be present in a composition in combination with at least one further active substance being effective in treating a disease or disorder associated with viral infections (antiviral active compounds), preferably a disease or disorder being associated with viral infections caused by herpes viruses, such as in particular by Herpes simplex viruses (i.e., combination therapy). The at least one further active substance being effective in treating a disease or disorder associated with viral infections (antiviral active compounds) are preferably selected from the group consisting of nucleosidic drugs such as acyclovir, valacyclovir, penciclovir, ganciclovir, famciclovir and trifluridine, as well as compounds such as foscarnet and cidofovir. Accordingly, the present invention further relates to a pharmaceutical composition comprising one or more of the compounds as described herein and at least one pharmaceutically acceptable carrier and / or excipient and / or at least one further active substance being effective in treating a disease or disorder associated with viral infections (antiviral active compounds). The novel active compounds can be converted in a known manner into customary formulations, such as tablets, caplets, sugar-coated tablets, pills, granules, aerosols, syrups, pharmaceutically suitable carriers, and solvents. Here, the therapeutically active compound should in each case be present in a concentration of about 0.1 to 90% by weight of the total mixture, i.e., in amounts which are sufficient to achive the dosage range indicated. The formulations are prepared, for example, by extending the active compounds with solvents and / or excipients, if appropriate using emulsifiers and / or dispersants, if being possible, for example, if the diluent used is water, to use, if appropriate, organic solvents as auxiliary solvents. Administration is carried out in a customary manner, preferably orally, parenterally or topically, in particular perlingually or intravenously. In the case of parenteral administration, solutions or suspensions of the active compounds using suitable liquid carrier materials can be employed. In general, it has proved advantageous in the case or intravenous administration to administer amounts of from approx. 0.001 to 20 mg / kg, preferably approx. 0.01 to 10 mg / kg of bodyweight to achieve effective results, and in the case of oral administration the dose is approx. 0.01 to 30 mg / kg, preferably 0.1 to 20 mg / kg of body weight. In spite of this, it may be necessary, if appropriate, to depart from the amounts mentioned, namely depending on the bodyweight or on the type of the administration route, on the individual response to the medicament, the manner of its formulation and the time or interval at which administration takes place. Thus, in some cases it may be adequate to manage with less than the abovementioned minimum amount, while in other cases the upper limit mentioned must be exceeded. In the case of administration of relatively large amounts it may be advisable to divide this into several individual administrations over the course of the day. Examples of the Invention The compounds described herein can be prepared in several ways based on the teachings contained herein and synthetic procedures known in the art. In the description of the synthetic methods described below, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and workup procedures, can be chosen to be the conditions standard for that reaction, unless otherwise indicated. It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule should be compatible with the reagents and reactions proposed. Substituents not compatible with the reaction conditions will be apparent to one skilled in the art, and alternate methods are therefore indicated. The starting materials for the examples are either commercially available or are readily prepared by standard methods from known materials. At least some of the compounds identified as “intermediates” herein are contemplated as compounds of the disclosure. Abbreviations: AcOH Acetic acid ACN Acetonitrile Boc2O Di-tert-butyl dicarbonate nBuLi n-Butyllithium DCM Dichloromethane DIAD Diisopropyl azodicarboxylate DIEA Diisopropyl ethylamine DMF N, N-Dimethylformamide DMSO Dimethyl sulfoxide DPPF 1,1’-Bis(diphenylphosphino)ferrocene EtOAc Ethyl acetate Et3N Triethylamine HATU Hexafluorophosphate Azabenzotriazole Tetramethyl Uronium h, hr Hour(s) HPLC High performance liquid chromatography LCMS Liquid chromatography–mass spectrometry MeOH Methanol NMO / NMMO N-Methyl morpholine-N-Oxide NBS N-Bromosuccinimide PE Petroleum ether iPrOH Isopropanol rt, r.t. Room temperature SFC Supercritical Fluid Chromatography TEA Triethylamine TBAI Tetrabutylammonium iodide TBAB Tetrabutylammonium bromide TFA Trifluoroacetic acid THF Tetrahydrofuran TLC Thin-layer chromatography XPhos 2-Dicyclohexylphosphino-2’,4’,6’-triisopropylbiphenyl Following LCMS methods have been used for the analysis of final compounds: Method A: X-Bridge BEH C-18 (3x50 mmx2.5mm); Mobile phase: A; 0.025% formic acid in H2O; B; CH3CN; Injection voloume:2 µL; Flow rate:1.2 mL / min, column temperature: 50oC; Gradient program: 2% B to 98% B in 2.2 min, held 3 min, at 3.2 min B conc. is held at 2 % for 4 min. Method B: X-select CSH 18 (3x50 mmx2.5mm); Mobile phase: A; 0.025% formic acid in H2O; B; CH3CN; Injection voloume:2 µL; Flow rate:1.2 mL / min, column temperature: 50oC; Gradient program: 0% B to 98% B in 2 min, hold for 3 min, at 3.2 min B conc. is held at 0 % for 4 min. Method C: X-select CSH 18 (3x50 mmx2.5mm); Mobile phase: A; 0.05% formic acid in H2O:CH3CN (95:5); B; 0.05% formic acid in CH3CN; Injection volume: 2 µL; Flow rate: 1.2 mL / min, column temperature: 50oC; Gradient program: 0% B to 98% B in 2 min, hold for 3 min, at 3.2 min B conc. is held at 0 % for 4 min. Method D: X-select CSH C18 (3x50 mmx2.5µm); Mobile phase: A; 2mM in Ammonium Bicarbonate; B; CH3CN; Injection voloume:2 µL; Flow rate:1.2 mL / min, column temperature: 50oC; Gradient program: 0% B to 98% B in 2 min, hold for 3 min, at 3.2 min B conc. is held at 0 % for 4 min. Method E: X-select CSH 18 (3x50 mmx2.5mm); Mobile phase: A; 0.05% formic acid in H2O; B; CH3CN; Injection volume: 2µL; Flow rate:1.5 mL / min, column temperature: 50oC; Gradient program: 0% B to 100% B in 1.5 min, hold 2.2 min, at 2.6 min B conc. is held at 0 % for 3 min. Example 1. Synthesis of 1-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-N-methyl-N-(4-methyl-5- sulfamoylthiazol-2-yl)azetidine-3-carboxamide (1) Synthesis of methyl azetidine-3-carboxylate hydrochloride (1-2) To a stirred solution of compound 1-1 (2.0 g, 9.29 mmol) in DCM (10 mL) was added 4M HCl in dioxane (10 mL) at 0 °C. The resulting reaction mixture was slowly warmed to room temperature and allowed to stir for 4 h. After completion of the reaction, the mixture was concentrated under reduced pressure to dryness. The crude residue obtained was purified by trituration with diethyl ether and stirred for 5-10 min. The obtained solid was filtered off and dried in vacuo to afford the title compound 1-2 (1.40 g, crude) as an off-white solid, which was used in the next step without further purification. Synthesis of methyl 1-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)azetidine-3-carboxylate (1-3) To a stirred solution of compound 1-2 (1.31 g, 8.36 mmol) in 1,4 dioxane (30 mL) was added 4'- bromo-2,5-difluoro-1,1'-biphenyl (1.50 g, 8.36 mmol) followed by CS2CO3(4.55 g, 13.9 mmol). The reaction mixture was purged under nitrogen for 10 min. To this solution, Xantphos (0.66 g, 1.11 mmol) and Pd2(dba)3 (0.52 g, 0.56 mmol) were added under nitrogen atmosphere. The reaction mixture was then heated at 100 °C for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to room temperature, filtered through a pad of Celite and washed with ethyl acetate. The filtrate was diluted with water and extracted with EtOAc followed by brine. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by CombiFlash column chromatography [eluting with 20-30% EtOAc in heptane] to afford the title compound 1-3 (0.6 g, 40%) as an off white solid. Synthesis of 1-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)azetidine-3-carboxylic acid (1-4) To a stirred solution of compound 1-3 (0.2 g, 0.66 mmol) in THF: H2O (8:2 mL) was added Lithium hydroxide (32 mg, 1.32 mmol). The resulting reaction mixture was allowed to stir for 2 hrs at room temperature. After completion of the reaction (monitored by TLC), the reaction mixture was acidified with 1M HCl, and extracted with EtOAc. The combined organic layers were washed with water, dried over anhydrous Na2SO4,filtered, and concentrated under reduced pressure to afford the title compound 1-4 (0.15 g, crude) as a pale-yellow solid, which was used in the next step without further purification. Synthesis of 1-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-N-methyl-N-(4-methyl-5- sulfamoylthiazol-2-yl)azetidine-3-carboxamide (1) To a stirred solution of compound 1-4 (0.2 g, 0.72 mmol) in DMF (5 mL) under nitrogen atmosphere, was added HOBt (0.2 g, 1.45 mmol) followed by EDC.HCl (0.27 g, 1.45 mmol) at 0 °C. The resulting reaction mixture was stirred at 0 °C for 5-10 min. To this reaction mixture, 4- methyl-2-(methylamino)thiazole-5-sulfonamide (0.15 g, 0.72 mmol) was added at 0 °C and the reaction mixture was slowly warmed to room temperature and stirred for 12 h. After completion of the reaction (monitored by TLC), the mixture was quenched with water and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude compound was purified by CombiFlash chromatography [eluting with 60-70% EtOAc in heptane] followed by preparative HPLC to afford the title compound 1 (25 mg, 6.9%) as an off white solid. Example 2: Synthesis of N-methyl-N-(4-methyl-5-sulfamoylthiazol-2-yl)-1-(4-(4- methylthiazol-2-yl)phenyl)azetidine-3-carboxamide (77) Synthesis of 2-(4-bromophenyl)-4-methylthiazole (2-2) To a stirred solution of compound 2-1 (1 g, 5.62 mmol) in 1,4 dioxane: H2O (10:3 mL) was added 2-(4-bromophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.7 g, 8.42 mmol) followed by K3PO4(3.76 g, 16.85 mmol). The reaction mixture was purged under nitrogen for 10 min. To the resulting solution, Pd (dppf)Cl2 (0.43 g, 0.56 mmol) was added under nitrogen atmosphere. The reaction mixture was heated at 100 °C for 12 h. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to room temperature, filtered through a pad of Celite®545 and washed with ethyl acetate. The filtrate was diluted with water and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by CombiFlash column chromatography, eluting with 30-40% EtOAc in heptane, to afford the title compound 2-2 (0.5 g, 35%) as an off-white solid. Synthesis of methyl 1-(4-(4-methylthiazol-2-yl)phenyl)azetidine-3-carboxylate (2-3) To a stirred solution of compound 2-2 (0.5 g, 1.97 mmol) in DMF (5 mL) was added methyl azetidine-3-carboxylate TFA salt (0.67 g, 2.95 mmol) followed by K2CO3(0.68 g, 4.92 mmol). The reaction mixture was purged under nitrogen for 10 min. To the resulting solution, CuI (38 mg, 0.19 mmol) and L-Proline (45 mg, 0.39 mmol) were added under nitrogen atmosphere. The reaction mixture was heated at 100 °C for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to room temperature, filtered through a pad of Celite and washed with ethyl acetate. The filtrate was diluted with water and extracted with EtOAc.. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by CombiFlash column chromatography, eluting with 40-50% EtOAc in heptane, to afford the title compound 2-3 (0.1 g, 17.6%) as an off white solid. Synthesis of 1-(4-(4-methylthiazol-2-yl)phenyl)azetidine-3-carboxylic acid (2-4) To a stirred solution of compound 2-3 (0.1 g, 0.35 mmol) in THF: MeOH: H2O (3:1:1 mL) at 0 °C, Lithium hydroxide monohydrate (25 mg, 1.04 mmol) was added. The resulting reaction mixture was slowly warmed to room temperature and stirred for 12 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to dryness. The crude residue obtained was treated with 1M HCl solution and the resulting suspension was allowed to stir for 5-10 min. The precipitated solid obtained was collected by filtration and dried in vacuo. The crude residue obtained was purified by trituration with pentane. The obtained solid was filtered off and dried in vacuo to afford the title compound 2-4 (80 mg, crude) as an off-white solid, which was used in the next step without further purification. Synthesis of N-methyl-N-(4-methyl-5-sulfamoylthiazol-2-yl)-1-(4-(4-methylthiazol-2- yl)phenyl)azetidine-3-carboxamide (77) To a stirred solution of compound 2-4 (80 mg, 0.29 mmol) in DMF (3 mL) at 0 °C under nitrogen atmosphere, was added HOBt (80 mg, 0.58 mmol) followed by EDC.HCl (0.11 g, 0.58 mmol). The resulting reaction mixture was stirred at the same temperature for 5-10 min. To this reaction mixture, 4-methyl-2-(methylamino)thiazole-5-sulfonamide (90 mg, 0.43 mmol) was added at 0 °C and then the reaction mixture was slowly warmed to room temperature and stirred for 2 h. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with water and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude compound was purified by preparative HPLC to afford the title compound 77 (15 mg, 11%) as an off white solid. Example 3: Synthesis of 1-(5-(2,5-difluorophenyl)pyridin-2-yl)-N-methyl-N-(4-methyl-5- sulfamoylthiazol-2-yl)azetidine-3-carboxamide (85) F Synthesis of methyl 1-(5-bromopyridin-2-yl)azetidine-3-carboxylate (3-2) To a stirred solution of compound 3-1 (2 g, 11.36 mmol) in acetonitrile (25 mL) at 0 °C under nitrogen atmosphere, was added K2CO3 (7.86 g, 56.82 mmol). The resulting reaction mixture was stirred at the same temperature for 5-10 min. To this reaction mixture, methyl azetidine-3- carboxylate TFA salt (3.12 g, 13.64 mmol) was added at 0 °C. The reaction mixture was slowly warmed to room temperature and allowed to stir at 100 °C for 1 h. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to room temperature, filtered through a pad of Celite and washed with ethyl acetate and the filtrate was concentrated under reduced pressure. The crude product was purified by CombiFlash column chromatography, eluting with 10-20% EtOAc in heptane, to afford the title compound 3-2 (0.65 g, 20.9%) as an off white solid. Synthesis of methyl 1-(5-(2,5-difluorophenyl)pyridin-2-yl)azetidine-3-carboxylate (3-3) To a stirred solution of compound 3-2 (0.65 g, 2.37 mmol) in 1,4 dioxane: H2O (4: 1 mL) was added (2,5-difluorophenyl)boronic acid (0.45 g, 2.85 mmol) followed by K3PO4 (1.6 g, 7.12 mmol). The reaction mixture was purged under nitrogen for 10 min. To this resulting solution Pd (dppf)Cl2(88 mg, 0.12 mmol) was added under nitrogen atmosphere. The reaction mixture was then heated at 110 °C for 16 h. After completion (monitored by TLC), the reaction mixture was cooled to room temperature, filtered through a pad of Celite®545 and washed with ethyl acetate. The filtrate was diluted with water and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by CombiFlash column chromatography [eluting with 30-40% EtOAc in heptane] to afford the title compound 3-3 (0.5 g, 54%) as an off-white solid. Synthesis of 1-(5-(2,5-difluorophenyl)pyridin-2-yl)azetidine-3-carboxylic acid (3-4) To a stirred solution of compound 3-3 (0.5 g, 1.63 mmol) in THF: MeOH: H2O (4: 4: 2 mL) at 0 °C, Lithium hydroxide monohydrate (0.2 g, 8.13 mmol) was added. The resulting reaction mixture was slowly warmed to room temperature and stirred for 1 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to dryness. The crude residue obtained was treated with 1M aq. HCl solution and the resulting suspension was allowed to stir for 5-10 min. The precipitated solid obtained was collected by filtration and dried in vacuo. The crude residue obtained was purified by trituration with pentane. The obtained solid was filtered off and dried in vacuo to afford the title compound 3-4, which was used in the next step without further purification. Synthesis of 1-(5-(2,5-difluorophenyl)pyridin-2-yl)-N-methyl-N-(4-methyl-5- sulfamoylthiazol-2-yl)azetidine-3-carboxamide (85) To a stirred solution of compound 3-4 (0.25 g, 0.84 mmol) in DMF (3 mL) at 0 °C under nitrogen atmosphere, was added HOBt (0.23 g, 1.69 mmol) followed by EDC.HCl (0.25 g, 1.27 mmol). The resulting reaction mixture was stirred at the same temperature for 5-10 min. To this reaction mixture, 4-methyl-2-(methylamino)thiazole-5-sulfonamide (0.28 g, 1.27 mmol) was added at 0 °C. The reaction mixture was slowly warmed to room temperature and stirred for 1 h. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with water and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4,filtered, and concentrated under reduced pressure. The crude product was purified by CombiFlash column chromatography, eluting with 60-70% EtOAc in heptane, to afford the title compound 85 (10 mg, 1.9%) as an off-white solid. Example 4: Synthesis of 1-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-N-(methyl-d3)-N-(4-methyl- 5-sulfamoylthiazol-2-yl) azetidine-3-carboxamide (60) Synthesis of 4-methyl-2-((methyl-d3) amino) thiazole-5-sulfonamide (4-2) To a stirred solution of compound 4-1 (1 g, 5 mmol) in ACN (10 mL) under nitrogen atmosphere, was added methan-d3-amine (0.7 g, 9 mmol) followed by K2CO3(2 g, 10 mmol) at room temperature. The resulting solution stirred at 75 ⁰C for 12 h. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to room temperature, diluted with water, and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by CombiFlash column chromatography [eluting with 80-90% EtOAc in heptane] to afford the title compound 4-2 (0.4 g, 40%) as a white solid. Synthesis of 1-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-N-(methyl-d3)-N-(4-methyl-5- sulfamoylthiazol-2-yl) azetidine-3-carboxamide (60) To a stirred solution of 1-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)azetidine-3-carboxylic acid (0.2 g, 0.69 mmol) in DMF (5 mL) at 0 °C under nitrogen atmosphere, was added HOBt (0.191 g, 1.38 mmol) followed by EDC.HCl (0.27 g, 1.38 mmol). The resulting reaction mixture was stirred at 0 °C for 5-10 min. To this reaction mixture, compound 4-2 (0.17 g, 0.83 mmol) was added at 0 °C and then the reaction mixture was slowly warmed to room temperature and stirred for 2 h. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude compound was purified by preparative HPLC to afford the title compound 60 (40 mg, 12%) as an off-white solid. Example 5: Synthesis of 1-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-N-methyl-N-(4-(methyl-d3)-5- sulfamoylthiazol-2-yl)azetidine-3-carboxamide (44 Synthesis of 1-bromopropan-2-one-1,1,3,3,3-d5 (5-2) A solution of compound 5-1 (10 g, 156 mmol) in bromine (10 mL) was allowed to stir at room temperature for 2 h. The reaction mixture was used for the next step immediately. Synthesis of N-methyl-4-(methyl-d3)thiazol-2-amine (5-3) To a stirred a solution of compound 5-2 (10 g, 70.4 mmol) in ethanol (100 mL) at 0 ºC under nitrogen atmosphere, was added 1-methylthiourea (8.89 g, 98.6 mmol). The reaction mixture was slowly warmed to room temperature and allowed to stir at 75 ºC for 12 h. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to room temperature, quenched with saturated NaHCO3solution, and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by CombiFlash column chromatography, eluting with 30-35% EtOAc in heptane, to afford the title compound 5-3 (0.8 g, 8.7%) as a pale-yellow oil. Synthesis of 4-(methyl-d3)-2-(methylamino)thiazole-5-sulfonic acid (5-4) To a stirred solution of compound 5-3 (0.7 g, 5.34 mmol) in DCM (10 mL) at 0 ºC under nitrogen atmosphere, was added Chlorosulfonic acid (3.1 g, 26.67 mmol). The resulting reaction mixture was slowly warmed to room temperature and allowed to stir for 22 h. After completion of the reaction (monitored by TLC) the reaction mixture was quenched with ice cold and concentrated under reduced pressure to afford the title compound 5-3 (0.55 g, crude) as a pale- yellow colored oil, which was used in the next step without further purification. Synthesis of 4-(methyl-d3)-2-(methylamino)thiazole-5-sulfonyl chloride (5-5) A solution of compound 5-4 (0.55 g, 2.60 mmol) in thionyl chloride (10.0 mL, 136 mmol) under nitrogen atmosphere was allowed to stir at 80 ºC for 12 h. After completion of the reaction (monitored by TLC) the reaction mixture was concentrated under reduced pressure to afford the title compound 5-5 (0.3 g, crude) as a pale-yellow oil, which was used in the next step without further purification. Synthesis of 4-(methyl-d3)-2-(methylamino)thiazole-5-sulfonamide (5-6) To a stirred solution of compound 5-5 (0.3 g, 1.31 mmol) in THF (5.0 mL) at 0 ºC was added an aqueous ammonia solution (4 mL). The resulting reaction mixture was slowly warmed to room temperature and allowed to stir for 2 h. After completion of the reaction (monitored by TLC) the reaction mixture was diluted with water and extracted with ethyl acetate followed by brine. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude compound obtained was purified by CombiFlash chromatography,eluting with 90-95% EtOAc in heptane, to afford the title compound 5-6 (0.12 g, 43.7%) as a yellow solid. Synthesis of 1-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-N-methyl-N-(4-(methyl-d3)-5- sulfamoylthiazol-2-yl)azetidine-3-carboxamide (44) To a stirred solution of 1-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)azetidine-3-carboxylic acid (0.1 g, 0.34 mmol) in DMF (5 mL) at 0 °C under nitrogen atmosphere, was added HOBt (95 mg, 0.69 mmol) followed by EDC.HCl (0.13 g, 0.69 mmol). The resulting reaction mixture was stirred at 0 °C for 5-10 min. To this reaction mixture, compound 5-6 (87 mg, 0.41 mmol) was added at 0 °C and then the reaction mixture was slowly warmed to room temperature and stirred for 2 h. The reaction mixture was diluted with water and extracted with EtOAc followed by brine. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude compound was purified by preparative HPLC to afford the title compound 44 (12 mg, 7.2%) as an off white solid. Example 6: Synthesis of 2-(2-(5'- Synthesis-2'-fluoro-[1,1'-biphenyl]-4-yl)-5-oxo-2,6- diazaspiro[3.5]nonan-6-yl)-4-methylthiazole-5-sulfonamide (113)

[0003] Synthesis of 1-tert-butyl 3-methyl 3-(2-cyanoethyl)azetidine-1,3-dicarboxylate (6-1) To dry THF (600 mL) was added di-isopropyl amine (43.4 mL, 0.307 mol) at -60 °C under Ar atm, n-Butyllithium (122.7 mL, 2.5 M solution in hexane, 0.307 mol) was added. Compound 1-1 (25.1 mL, 0.307 mol) in THF (50 mL) was dropwise added to the solution at -80 °C. The reaction mixture was stirred for 1 hr at that temperature.3-Bromopropanenitrile (25.1 mL, 0.307 mol) in THF (50 mL) was dropwise added to the solution at -80 °C. The mixture was allowed to warm to rt and stirred for 16 h. The reaction mixture was poured into an aqueous ammonium chloride saturated solution (1 L). The resulting mixture was extracted with MTBE (300 mL × 3). The combined organic layers were washed with brine (300 mL x 2), dried over anhydrous Na2SO4, filtered, and evaporated under reduced pressure. The resulting residue was purified by column chromatography to afford 6-1 (8 g (contaminated with 1-1), 60% purity, 6.4%).1H NMR (400 MHz, CDCl3): δ 4.24 (d, J = 8.8 Hz, 2H), 3.81 (s, 3H), 3.79 (d, J = 8.8 Hz, 2H), 2.45 - 2.36 (m, 2H), 2.36 - 2.27 (m, 2H), 1.46 (s, 9H) ppm. Synthesis of tert-butyl 5-oxo-2,6-diazaspiro[3.5]nonane-2-carboxylate (6-2) Compound 6-1 (8 g, 18 mmol) was dissolved in methanol (200 mL). Raney nickel (10 g) was added to the solution and the mixture was stirred at rt for 48 h under hydrogen pressure (50 atm). The reaction mixture was filtered and evaporated. The residue was treated with petroleum ether and grey precipitate was collected and dried. The crude product was purified by flash- chromatography to afford 6-2 (3.6 g, 90%).1H NMR (500 MHz, d6-DMSO): δ 7.58 (s, 1H), 4 (s, 2H), 3.49 (s, 2H), 3.13 - 3.03 (m, 2H), 2 - 1.88 (m, 2H), 1.66 - 1.55 (m, 2H), 1.43 - 1.29 (m, 9H) ppm. Synthesis of 2,6-diazaspiro[3.5]nonan-5-one (6-3) Compound 6-2 (3.6 g, 15 mmol) was dissolved in ice-cold trifluoroacetic acid (30 mL). The solution was stirred for 2 h. The reaction mixture was evaporated, and the residue was treated with MTBE (3^×^30 mL) and petroleum ether (50 mL). The white precipitate was collected and dried to give 6-3 (3.5 g (trifluoroacetate), 92%^).1H NMR (400 MHz, d6-DMSO): δ 9.07 - 8.67 (m, 2H), 7.85 (s, 1H), 4.16 - 4.03 (m, 2H), 3.69 (d, J = 6.5 Hz, 2H), 3.1 (s, 2H), 2.06 (s, 2H), 1.63 (d, J = 4.3 Hz, 2H) ppm. Synthesis of 2-(4-nitrophenyl)-2,6-diazaspiro[3.5]nonan-5-one (6-4) To a stirred solution of 6-3 (4.1 g (hydrochloride), 23.2 mmol) and 1-fluoro-4-nitrobenzene (2.44 mL, 23.^ mmol) in DMF (50 mL) was added cesium carbonate (15 g, 46 mmol) at RT. The reaction mixture was stirred at 50 °C for 16 h. The reaction mixture was poured in water (200 mL) and yellow precipitate was filtered, washed with water, and dried to give 6-4 (5.8 g, 95%). MS calcd. for C13H15N3O3: 261, Found: 262 [M + 1]+.1H NMR (400 MHz, d6-DMSO): δ 8.06 (d, J = 8.8 Hz, 2H), 7.7 (s, 1H), 6.46 (d, J = 9.3 Hz, 2H), 4.17 (d, J = 7.8 Hz, 2H), 3.78 (d, J = 8.3 Hz, 2H), 3.17 (t, J = 4.6 Hz, 2H), 2.15 - 2.03 (m, 2H), 1.76 - 1.63 (m, 2H) ppm. Synthesis of N-(tert-butyl)-4-methyl-2-(2-(4-nitrophenyl)-5-oxo-2,6-diazaspiro[3.5]nonan- 6-yl)thiazole-5-sulfonamide (6-5) To a stirred solution of 6-4 (3 g, 11.5 mmol), 2-bromo-N-(tert-butyl)-4-methylthiazole-5- sulfonamide (4.32^g, 13.8 mmol) and cesium carbonate (7.48 g, 23 mmol) in 1,4-dioxane (60 mL) were added Pd2(dba)3 (0.525 g, 0.57^mmol) and XanthPhos (0.664 g, 1.15 mmol) under Ar atm. The mixture was stirred at 90 ℃ overnight. The mixture was filtered and evaporated. The residue was purified by column chromatography to give 6-5 (0.5 g, 9%^).MS (ESI): calcd. for C21H27N5O5S2: 493, Found: 494 [M + 1 - 18]+.1H NMR (400 MHz,CDCl3): δ 8.24 - 8.06 (m, 2H), 6.49 - 6.32 (m, 2H), 4.59 (s, 1H), 4.48 (d, J = 7.3 Hz, 2H), 4.22 (t, J = 6.1 Hz, 2H), 3.9 (d, J = 7.3 Hz, 2H), 2.59 (s, 3H), 2.44 - 2.32 (m, 2H), 2.17 - 2.03 (m, 2H), 1.32 (s, 9H) ppm. Synthesis of 2-(2-(4-aminophenyl)-5-oxo-2,6-diazaspiro[3.5]nonan-6-yl)-N-(tert-butyl)-4- methylthiazole-5-sulfonamide (6-6) То а stirred solution of 6-5 (2.3 mg, 4.7 mmol) in DMF (30 mL) were added 4,4`-bipyridile (36 mg, 0.2^mmol) and hypodiboric acid (1.26 g, 14 mmol) at RT. The solution was stirred for 2 h. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (3^×^100 mL). The combined organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4, and evaporated to dryness to give 6-6 (1.6 g, 74%).MS (ESI): calcd. for C21H29N5O3S2: 463, Found: 464 [M + 1]+.1H NMR (500 MHz, d6-DMSO): δ 7.77 (s, 1H), 6.49 (d, J = 8.5 Hz, 2H), 6.24 (d, J = 8.5 Hz, 2H), 4.42 (s, 2H), 4.02 - 3.96 (m, 2H), 3.87 (d, J = 6.8 Hz, 2H), 3.58 (d, J = 6.3 Hz, 2H), 2.45 (s, 3H), 2.25 (d, J = 5.7 Hz, 2H), 1.95 (s, 2H), 1.13 (s, 9H) ppm. Synthesis of N-(tert-butyl)-4-methyl-2-(5-oxo-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)phenyl)-2,6-diazaspiro[3.5]nonan-6-yl)thiazole-5-sulfonamide (6-7) To a stirred solution of 6-6 (1.1 g, 2.37 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2- dioxaborolane) (0.784 g, 3.08 mmol) in acetonitrile (20 mL) was added dropwise tert-butyl nitrite (0.34 mL, 2.85 mmol) at RT. The mixture was stirred for 16 h. The mixture was evaporated and subjected to column chromatography to give 6-7 (100 mg, 50% purity (contaminated with deborylation product), 3.7%).MS (ESI): calcd. for C27H39BN4O5S2: 574, Found: 575 [M + 1]+. Synthesis of N-(tert-butyl)-2-(2-(5'-cyano-2'-fluoro-[1,1'-biphenyl]-4-yl)-5-oxo-2,6- diazaspiro[3.5]nonan-6-yl)-4-methylthiazole-5-sulfonamide (6-8) To a stirred solution of 6-7 (0.1 g, 0.17 mmol), 3-bromo-4-fluorobenzonitrile (34.6 mg, 0.17 mmol) and potassium phosphate (0.15 g, 0.7 mmol) in 1,4-dioxane (2 mL) was added Pd(dppf)Cl2 (7.1 mg, 0.07 mmol) under Ar atm. The mixture was stirred at 90℃ overnight. The mixture was filtered and purified by HPLC to give 6-8 (34^mg, 34%).MS (ESI): calcd. for C28H30FN5O3S2: 567, Found: 568 [M + 1]+. Synthesis of 2-(2-(5'- Synthesis-2'-fluoro-[1,1'-biphenyl]-4-yl)-5-oxo-2,6- diazaspiro[3.5]nonan-6-yl)-4-methylthiazole-5-sulfonamide (113) Compound 6-8 (34 mg, 0.06 mmol) was dissolved in trifluoroacetic acid (0.5 mL) and the solution was stirred at rt for 16 h. The solution evaporated, and the residue was subjected to HPLC to give 113 (13 mg, 42%). Example 7: Synthesis of 2-(2-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-5-oxo-2,6- diazaspiro[3.4]octan-6-yl)-4-methylthiazole-5-sulfonamide (127) Synthesis of tert-butyl 5-oxo-2,6-diazaspiro[3.4]octane-2-carboxylate (7-2) To а stirred solution of compound 7-1 (0.4 g, 2.4 mmol) in dioxane / H2O, Boc2O (0.64 g, 2.9 mmol) and NaOH (0.1 g, 2.7 mmol) were added, the reaction mixture was stirred 8 h at room temperature. After completion of the reaction, the reaction mixture was diluted with ice cold water. The organic part was dried over anhydrous Na2SO4 and concentrated under vacuum. The resulting crude material was purified by flash column chromatography to obtain 7-2 (0.5 g, 90%). Synthesis of tert-butyl 6-(5-(N-(tert-butyl)sulfamoyl)-4-methylthiazol-2-yl)-5-oxo-2,6- diazaspiro[3.4]octane-2-carboxylate (7-3) To a stirred solution of compound 7-2 (0.5 g, 2.2 mmol) in dioxane (20 mL), 2-bromo-N-(tert- butyl)-4-methylthiazole-5-sulfonamide (82 mg, 2.5 ^mmol) and Cs2CO3 (1.44g, 4.25 mmol) were added. The reaction mixture was purged under nitrogen for 10 min. To this resulting solution Xantphos (177 mg, 0.14 eq.) and Pd2(dba)3 (140 mg, 0.07 eq.) were added under nitrogen atmosphere. The reaction mixture was heated at 100 °C for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to room temperature, filtered through a pad of Celite and washed with ethyl acetate. The filtrate was diluted with water and extracted with EtOAc (10 mL x 2). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by HPLC to afford 7-3 (0.45 g, 45%). Synthesis of N-(tert-butyl)-4-methyl-2-(5-oxo-2,6-diazaspiro[3.4]octan-6-yl)thiazole-5- sulfonamide (7-4) То а stirred solution of compound 7-3 (0.45 g, 0.98 mmol) in DCM, was added TFA (5 eq.), and then the reaction mixture was stirred overnight. After completion of the reaction, the reaction mixture was concentrated under vacuum. The resulting crude material was purified by HPLC to obtain compound 7-4 (180 mg, 51%). Synthesis of N-(tert-butyl)-2-(2-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-5-oxo-2,6- diazaspiro[3.4]octan-6-yl)-4-methylthiazole-5-sulfonamide (7-5) To a stirred solution of compound 7-4 (180 mg, 0.5 mmol) in 1,4 dioxane (10 mL), 4'-bromo- 2,5-difluoro-1,1'-biphenyl (148 mg, 0.55 mmol) and Cs2CO3(245 mg, 0.75 mmol) were added. The reaction mixture was purged under nitrogen for 10 min. To this resulting solution Xantphos (40 mg, 0.14^eq.) and Pd2(dba)3 (32 mg, 0.07 eq.) were added under nitrogen atmosphere. The reaction mixture was heated at 100 °C for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to room temperature, filtered through a pad of Celite and washed with ethyl acetate. The filtrate was diluted with water and extracted with EtOAc (5 mL x 2) and washed with brine. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by HPLC to afford compound 7-5 (55^mg, 20%) as an off white solid.^ Synthesis of 2-(2-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-5-oxo-2,6-diazaspiro[3.4]octan-6-yl)-4- methylthiazole-5-sulfonamide (127) То а stirred solution of compound 7-5 (55 mg, 0.1 mmol) in DCE, TFA (5 eq.) was added, and then the reaction mixture was stirred overnight at 60°C. After completion of the reaction, the reaction mixture was concentrated under vacuum. The resulting crude material was purified by HPLC to obtain 127 (11 mg, 22%). Example 8: Synthesis of 2-(2-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-5-methyl-9-oxo-2,5,8- triazaspiro[3.5]nonan-8-yl)-4-methylthiazole-5-sulfonamide (125) Synthesis of tert-butyl 9-oxo-2,5,8-triazaspiro[3.5]nonane-2-carboxylate (8-2) Ethane-1,2-diamine (13.17 g, 219.2 mmol, 14.63 mL, 1.5 equiv) and benzyltriethylammonium chloride (1.66 g, 7.3 mmol) were dissolved in chloroform (125 mL), and compound 8-1 (25.0 g, 146.1 mmol) was added while stirring. This solution was cooled to 0 °C. A solution of sodium hydroxide (29.2 g, 0.73 mol, 5.00 eq) in water (29.2 mL) was added dropwise to the above solution, controlling the temperature below 10 °C. The reaction was then carried out at 25 °C for 16^hours. After completion, the organic layer was separated. The aqueous phase was extracted three times with chloroform, and the organic phases were combined, dried over Na2SO4, and concentrated. The crude product was purified by column chromatography to give 8-2 (1.26 g, 3.6%). MS (ESI): calcd. for C11H19N3O3: 241.14, Found: 142.2 [(M-Boc) + 1]+. Synthesis of tert-butyl 5-methyl-9-oxo-2,5,8-triazaspiro[3.5]nonane-2-carboxylate (8-3) To a solution of compound 8-2 (1.26 g, 5.23 mmol) in dichloroethane (30 mL), acetic acid (345 mg, 5.75 mmol) and aq. formaldehyde (0.47 mL, 37% soln, 5.75 mmol) were added successively at 0 °C. After 5 min NaBH(OAc)3 (3.32 g, 15.67 mmol) was added in one portion. The resulting suspension was stirred at r.t. overnight. Then it was quenched with sat NaHCO3soln. (30 mL) and extracted with DCM (3 × 30^mL). The combined organic extract was dried over Na2SO4 and concentrated in vacuo to give pure tert-butyl 5-methyl-9-oxo-2,5,8-triazaspiro[3.5]nonane-2- carboxylate 8-3 (1.12 g, 84%) as a colorless oil, which was solidified on standing. MS (ESI): calcd. for C12H21N3O3: 255.16, Found: 156.2 [(M-Boc) + 1]+. Synthesis of 5-methyl-2,5,8-triazaspiro[3.5]nonan-9-one (8-4) To a solution of compound 8-3 (400.0^mg, 1.57 mmol) in dioxane (10 mL), 10% solution of HCl in dioxane (4 eq.) was added. The resulting mixture was stirred at 60 °C overnight. The resulting precipitate was filtered, washed with dioxane and MTBE, and dried at 60 °C in the oven to give dihydrochloride 8-4 (360 mg, crude), which was used in the next step without additional purification. MS (ESI): calcd. for C7H13N3O: 155.11, MS Found: 156.0 [M + 1]+. Synthesis of 2-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-5-methyl-2,5,8-triazaspiro[3.5]nonan-9- one (8-5) A suspension of compound 8-4 (200.0 mg, 876.7^µmol), 4'-bromo-2,5-difluoro-1,1'-biphenyl (117.45 mg, 438.3 µmol), Cs2CO3 (1000 mg, 3.07^mmol), Pd2dba3 (56.09 mg, 61.36 µmol) and XanthPhos (70.96 mg, 122.72 µmol) in a degassed dioxane (15 mL) was stirred under argon at 100 °C overnight. After completion of the reaction (monitored by LCMS), the mixture was evaporated in vacuo, diluted with water (10 mL) and extracted with ethyl acetate (25 mL x 2). The combined organic solution was washed with water (10 mL) and brine (10 mL), dried over Na2SO4, and evaporated in vacuo to give crude product, which was purified with prep-HPLC to give 8-5 (36.0 mg, 12%). MS (ESI): calcd. for C19H19F2N3O: 343.15, MS Found: 344.2 [M + 1]+. Synthesis of N-(tert-butyl)-2-(2-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-5-methyl-9-oxo-2,5,8- triazaspiro[3.5]nonan-8-yl)-4-methylthiazole-5-sulfonamide (8-6) A suspension of compound 8-5 (38.0 mg, 110.7 µmol), 2-bromo-N-tert-butyl-4-methyl-1,3- thiazole-5-sulfonamide (52 mg, 166 µmol), Cs2CO3(108.1 mg, 331.9 µmol), Pd2dba3(7.08 mg, 7.7 µmol) and XanthPhos (8.96^mg, 15.5 µmol) in a degassed dioxane (15 mL) was stirred under argon at 100 °C overnight. After completion of the reaction (monitored by LCMS), the mixture was evaporated in vacuo, diluted with water (10 mL) and extracted with ethyl acetate (25 mL x 2). The combined organic solution was washed with water (10 mL) and brine (10 mL), dried over Na2SO4, and evaporated in vacuo to give crude product, which was purified with prep- HPLC to give 8-6 (25.0 mg, 39%^). MS (ESI): calcd. for C27H31F2N5O3S2: 575.2, MS Found: 576.2 [M + 1]+. Synthesis of 2-(2-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-5-methyl-9-oxo-2,5,8- triazaspiro[3.5]nonan-8-yl)-4-methylthiazole-5-sulfonamide (125) Compound 8-6 (25.0 mg, 43.4 µmol) was dissolved in neat TFA (0.5 mL). The resulting solution was stirred overnight at r.t. Then it was concentrated in vacuo, quenched with sat. aq. NaHCO3solution, extracted with EtOAc (^10 mL x 2). The combined organic extracts were dried over Na2SO4and evaporated in vacuo to give the crude product, which was purified by prep-HPLC to give the pure compound 125 (6.2 mg, 27%). Example 8: Synthesis of 2-2-[4-(2,5-difluorophenyl)-1,3-thiazol-2-yl]-5-oxo-2,6- diazaspiro[3.5]nonan-6-yl-4-methyl-1,3-thiazole-5-sulfonamide (111) Synthesis of 2-[4-(2,5-difluorophenyl)-1,3-thiazol-2-yl]-2,6-diazaspiro[3.5]nonan-5-one (9- 1) To solution of compound 6-3 (202.13 mg, 1.15 mmol) in ethanol (2 mL), trimethylsilyl isothiocyanate (150.41 mg, 1.15 mmol) was added dropwise at 0°C over a period of 15 minutes. The reaction mixture was stirred at rt for 30 minutes. Then 2-chloro-1-(2,5-difluorophenyl)ethan- 1-one (218.12 mg, 1.15 mmol) and triethylamine (116.16 mg, 1.15 mmol) were added sequentially to the mixture, and the resulting mixture was stirred at rt overnight. After consumption of starting material (by LCMS), the residue was filtered and washed with ethanol (^4 mL x 2). The mother liquor was evaporated under reduced pressure and the resulting crude oil was purified by flash chromatography to afford compound 9-1 (80 mg, 19.7%). MS (ESI): calcd. for C16H15F2N3OS: 335.1, Found: 336.0 [M + H]+. Synthesis of N-tert-butyl-2-2-[4-(2,5-difluorophenyl)-1,3-thiazol-2-yl]-5-oxo-2,6- diazaspiro[3.5]nonan-6-yl-4-methyl-1,3-thiazole-5-sulfonamide (9-2) In 10 mL flask, compound 9-2 (80.0 mg, 238.5 µmol) and 2-bromo-N-tert-butyl-4-methyl-1,3- thiazole-5-sulfonamide (96.84 mg, 309.15 µmol) were suspended in IPA:water (3:1) (6 mL) and degassed by vacuum / argon purge cycle. In a flow of Ar,^Pd2(dba)3 (10.87 mg, 11.89 µmol) and Xantphos (13.75 mg, 23.78 µmol) were added, followed by Cs2CO3(154.95 mg, 475.61 µmol). The reaction mixture was refluxed for 12h, then cooled to rt, concentrated, and partitioned between EtOAc (5 mL) and water (5 mL). The organic layer was separated, dried over Na2SO4, and concentrated in vacuo. The crude product was purified by HPLC to afford compound 9-2 (20.0 mg, 14%). MS (ESI): calcd. for C24H27F2N5O3S3: 567.1, MS Found: 566.0 [M + H]+. Synthesis of 2-2-[4-(2,5-difluorophenyl)-1,3-thiazol-2-yl]-5-oxo-2,6-diazaspiro[3.5]nonan-6- yl-4-methyl-1,3-thiazole-5-sulfonamide (111) A solution of compound 9-2 (19.86 mg, 34.99 µmol) in CH2Cl2 (5^mL) / TFA (5 mL) was stirred overnight at rt. The mixture was evaporated and purified by HPLC to afford 111 (6.9 mg, 36.6%). Biological Assay Data Cell culture Vero cells were cultured in Dulbecco’s Modified Eagle Medium (DMEM) supplemented with 10% fetal bovine serum and 100 units / mL penicillin and streptomycin. The cells were passaged 2-3 times per week to maintain sub-confluent densities. Assays HSV-1 antiviral assay Vero cells were seeded into 96-well plates at a density of 2.5 × 103cells per well and allowed to attach overnight. Following attachment, the media was replaced with 50 uL of infection medium (DMEM supplemented with 2% fetal bovine serum and 100 units / mL penicillin and streptomycin). A Tecan D300e digital dispenser was then used to add compounds to the culture using an 8-point 3-fold serial dilution format. The DMSO concentration was normalized to 0.5% for all treatments. Following compound addition, 50 uL of infection medium containing 80 TCID50 HSV-1 was added to the cells and incubated at 37⁰C for 4 days. After the incubation, the plates were equilibrated to room temperature, the media was removed, and 60 of a 1:1 dilution of Cell titer glow and phosphate buffered saline was added to the cells. Following a 5-minute incubation, cell viability was quantified by measuring luminance using a Tecan Infinite M1000 Pro plate reader. HSV-2 antiviral assay Vero cells were seeded into 96-well plates at a density of 1.0 × 104cells per well and allowed to attach overnight. Following attachment, the media was replaced with 50 uL of infection medium (DMEM supplemented with 2% fetal bovine serum and 100 units / mL penicillin and streptomycin). A Tecan D300e digital dispenser was then used to add compounds to the culture using an 8-point 3-fold serial dilution format. The DMSO concentration was normalized to 0.5% for all treatments. Following compound addition, 50 uL of infection medium containing 160 TCID50HSV-2 G strain was added to the cells and incubated at 37⁰C for 5 days. After the incubation, 10 µL / well of WST-8 chromogenic reagent was added and the plates incubated at 37⁰C for 3 hours. Following the incubation, cell viability was quantified by measuring the absorbance at 460 nm and 620 nm using a Tecan Infinite M1000 Pro plate reader. Table 2 provides assay data for exemplified compounds of the invention grouped in the following ranges: A indicates EC50< 100 nM; B indicates EC50of ≥100 to <1,000 nM; C indicates EC50 of ≥1,000 to <5,000 nM; NA indicates not available. Table 2. Assay data for exemplified compounds of the invention.

[0004] All publications, patents, and patent applications cited in this specification are incorporated herein by reference for the teaching to which such citation is used. Test compounds for the experiments described herein were employed in free or salt form. The specific responses observed may vary according to and depending on the particular active compound selected or whether there are present carriers, as well as the type of formulation and mode of administration employed, and such expected variations or differences in the results are contemplated in accordance with practice of the present invention. Although specific embodiments of the present invention are herein illustrated and described in detail, the invention is not limited thereto. The above detailed descriptions are provided as exemplary of the present invention and should not be construed as constituting any limitation of the invention. Modifications will be obvious to those skilled in the art, and all modifications that do not depart from the spirit of the invention are intended to be included with the scope of the appended claims.

Claims

CLAIMS:

1. A compound of Formula Ior a pharmaceutically acceptable salt thereof, wherein:is selected from the group consisting of, , ,, ,andis selected from the group consisting ofand;X is CR2or N; X1, X2and X4are independently selected from the group consisting of O and S; X3is CH2, O, or NRx; X5is CH2, CF2, O, S or NRy, Rais hydrogen, C1-4alkyl, cyclopropyl, cyclobutyl or oxetayl; Rbis hydrogen, halo, cyano, OH, C1-4alkyl, haloC1-4alkyl; or Raand Rbtogether form a - CH2CH2X3- or -CH2X3- group; Rxand Ryare independently selected from the group consisting of is hydrogen, C1-4alkyl, and acetyl;R1isor; R2is hydrogen, halo, C1-4alkyl, haloC1-4alkyl, C1-4alkoxy or haloC1-4alkoxy; R3is independently selected for each occurrence from the group consisting of halo and cyano; R3a, R4aand R11aare independently selected from the group consisting of hydrogen, C1-4alkyl, halo C1-4alkyl and hydroxyC1-4alkyl; R4is independently selected for each occurrence from the group consisting of halo, CN, OH, NRnRm, C1-4alkyl, haloC1-4alkyl, C2-4alkenyl, C2-4alkynyl optionally substituted with hydroxyC1-3alkyl, cyclopropyl optionally substituted with halo or cyano, and R4b, provided that only one R4group can be R4b; R4bis selected from the group consisting of ,,and;R7and R8are independently selected from the group consisting of hydrogen, C1-4alkyl, acetyl, C3-6monocycloalkyl, phenyl, and pyridyl; or R7and R8together with the N atom to which they are attached form an arizidinyl, azetidinyl, pyrrolidinly, piperidinyl, morpholinyl or thiomorpholinyl group; R7aand R8aare independently selected from the group consisting of hydrogen, C1-4alkyl and C3-6monocycloalkyl, or R7and R8together with the N atom to which they are attached form an arizidinyl, azetidinyl, pyrrolidinyl, or piperidinyl morpholinyl or thiomorpholinyl group; R9and R9aare independently selected from the group consisting or C1-4alkyl and haloC1- 4alkyl; R10and R10aare independently selected from the group consisting of hydrogen and C1-4alkyl; R11is independently selected for each occurrence from the group consisting of halo, CN, OH, NRnRm, C1-4alkyl, haloC1-4alkyl, C2-4alkenyl, C2-4alkynyl, and cyclopropyl; q, r and x are independently selected from the group consisting of 0 and 1; s, w and z are independently selected from the group consisting of 0, 1 and 2; andu, v and y are independently selected from the group consisting of 0, 1, 2 and 3.

2. The compound of Claim 1, or a pharmaceutically acceptable salt thereof, wherein:is ; andis selected from the group consisting of:and3. The compound of Claim 2, or a pharmaceutically acceptable salt thereof, wherein:is; andisor4. The compound of Claim 1, or a pharmaceutically acceptable salt thereof, wherein:isandis selected from the group consisting of:and.

5. The compound according to any one of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein: Rais hydrogen or C1-4alkyl; and Rbis hydrogen, halo, cyano, OH, C1-4alkyl, haloC1-4alkyl.

6. The compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein: Rais hydrogen or C1-4alkyl; and Rbis hydrogen.

7. The compound of claim 6, or a pharmaceutically acceptable salt thereof, wherein Raand Rbare hydrogen.

8. The compound according to any one of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein Raand Rbtogether form a -CH2CH2X3- or -CH2X3- group9. The compound according to any one of claims 1-8, or a pharmaceutically acceptable salt thereof, wherein: R2is H, Cl, F, CH3 or CF3.

10. The compound of claim 9, or a pharmaceutically acceptable salt thereof, wherein: R2is CH3.

11. The compound according to any one of claims 1-10, or a pharmaceutically acceptablesalt thereof, wherein: R1 isor.

12. The compound of claim 11, or a pharmaceutically acceptable salt thereof, wherein: R1is.

13. The compound of claim 12, or a pharmaceutically acceptable salt thereof, wherein: R1is R1is.

14. The compound of claim 11, or a pharmaceutically acceptable salt thereof, wherein: R1is15. The compound of claim 14, or a pharmaceutically acceptable salt thereof, wherein:R1 is .

16. The compound of claim 11, or a pharmaceutically acceptable salt thereof, wherein: R1is17. The compound of claim 16, or a pharmaceutically acceptable salt thereof, wherein:R1 is.

18. The compound of claim 11, or a pharmaceutically acceptable salt thereof, wherein: R1is19. The compound of claim 18, or a pharmaceutically acceptable salt thereof, wherein:R1 is .

20. The compound according to any one of claims 1-19, or a pharmaceutically acceptable salt thereof, wherein: R3is halo for each occurrence and u is 0, 1, 2 or 3.

21. The compound of claim 20, or a pharmaceutically acceptable salt thereof, wherein: u is 0.

22. The compound according to any one of claims 1-21, or a pharmaceutically acceptable salt thereof, wherein: R4is independently selected for each occurrence from the group consisting of halo, CN, methyl, CHF2, CF3, acetylenyl, and cyclopropyl.

23. The compound according of claim 22, or a pharmaceutically acceptable salt thereof, wherein: R4is independently selected from halo for all occurrences.

24. A pharmaceutical composition comprising a compound according to any one of claims 1-23, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

25. A method for the treatment or prophylaxis of an HSV infection in a subject in need thereof, the method comprising: administering to the subject a therapeutically effective amount of a compound according to any one of claims 1-23, or a pharmaceutically acceptable salt thereof.

26. A method for the treatment or prophylaxis of an HSV infection in a subject in need thereof, the method comprising: administering to the subject a therapeutically effective amount of a pharmaceutical composition of claim 24.

27. The method of claim 25 or 26, wherein infection is an HSV-1 infection.

28. The method of claim 25 or 26, wherein infection is an HSV-2 infection.

29. The compound according to any one of claims 1-23 for the use as a medicament.

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