WO2024049803A1

WO2024049803A1 - Bicyclic heterocycle compounds for treatment of herpes viruses

Info

Publication number: WO2024049803A1
Application number: PCT/US2023/031369
Authority: WO
Inventors: Jiaxin Yu; Min Zhong; Michael Walker; Hassan Pajouhesh; Mark Bures
Original assignee: Assembly Biosciences, Inc.
Priority date: 2022-08-29
Filing date: 2023-08-29
Publication date: 2024-03-07

Abstract

The present disclosure provides, in part, novel bicyclic heterocycle compounds of Formula (I), pharmaceutical compositions thereof, and methods for the treatment and prophylaxis of herpes viruses. Formula (I)

Description

BICYCLIC HETEROCYCLE COMPOUNDS FOR TREATMENT OF HERPES VIRUSES

CROSS-REFERENCE TO RELATED APPLICATION

This application claims benefit of U.S. Provisional Application No. 63/401,890, filed August 29, 2022, the contents of which are hereby incorporated by reference.

BACKGROUND OF THE INVENTION

Human herpes viruses (Herpesviridae) are responsible for causing a wide variety of diseases in humans. Infection with herpes viruses can occur early in life and by adulthood over 95% of the population is infected by at least one herpes virus. These viruses establish a persistent life -long infection through viral latency in neuronal, lymphoid, or myeloid cells. Recurrent episodes of herpes virus disease can be triggered by numerous stimuli, including concurrent viral infections, stress, fatigue, allergies, pregnancy, sunlight, or fever. Herpes virus infection in immune competent individuals generally causes mild self-limiting disease, such as: oral (HSV- 1), and genital (HSV-2) ulcers, chicken pox (VZV), flu-like syndrome (CMV), and mononucleosis (EBV). In immunocompromised individuals however, primary infection with, or reactivation of an existing herpes virus infection is a major cause of disease and death. Key at risk immunocompromised populations include patients undergoing solid organ or stem cell transplants, individuals with HIV/AIDS, and ICU patients.

Herpesviridae comprise a diverse family of double- stranded DNA viruses that are classified into three subfamilies ( i.e., a, ' and y) based upon biological characteristics such as cell tropism, diseases caused, viral life-cycle, and site of viral persistence and latency. The family consists of eight members: Herpes Simplex Virus type I and 2 (HSV-1, HSV-2), Varicella Zoster Virus (VZV), Epstein-Barr virus (EBV), Cytomegalovirus (CMV), and human herpes viruses 6-8 (HHV6-8). tx-herpes viruses include herpes simplex virus types I and 2 (HSVI and HSV2), and varicella-zoster virus (VZV). HSVI causes orofacial lesions, commonly known as fever blisters or cold sores. Approximately 30% of the United States population suffers from recurrent episodes of HSVI. HSV2, which is less common than HSVI, causes genital lesions. Primary infection with VZV causes varicella, commonly known as chicken pox. Reactivation of latent VZV manifests as herpes zoster or shingles. Cytomegalovirus (CMV) is a prototypical herpes virus. Seroprevalance to CMV in the adult population is approximately 60%, but certain endemic areas of the world have rates closer to 100%. CMV represents the leading viral cause of morbidity and mortality in at-risk immunocompromised patients. EBV, a y-herpes virus, causes infectious mononucleosis and is responsible for lymphoid cancers such as Burkitt' s and Hodgkin's lymphoma.

Presently, there is no cure for herpes. Medicines have been developed that can prevent or shorten outbreaks, but there is a need for improved therapies for treating herpes virus infection and inhibiting viral replication. The current standard of care for immunocompromised patients at risk for herpes virus disease is pre-emptive treatment with high-dose nucleoside/nucleotide analog drugs such as acyclovir, (val)ganciclovir, and cidofovir, all of which target the viral DNA polymerase. In general, current treatments are virus specific (not broad spectrum), and in the case of (val)ganciclovir and cidofovir cannot be administered prophylactic ally due to dose -related toxicities including bone marrow suppression and renal toxicity. Although efficacious in many settings, the current nucleos(t)ide drugs are also limited by drug-resistant viral variants and existing cross-resistant variants which may lead to treatment failure.

W02020053654 discloses pyridopyrazinedione compounds for treating viral infections, particularly infections caused by herpesviruses. WO2021061898 discloses pyrazolopyridinone compounds for treating viral infections, particularly infections caused by herpesviruses. WO2021127071 discloses novel bicyclic heterocycle compounds for treating or preventing a herpesvirus infection in a patient. WO2022146755 discloses amido- substituted heterocycle compounds for treating or preventing a herpesvirus infection in a patient.

There is still a need for additional antiviral compounds for the treatment and prophylaxis of viral infections, particularly herpes infections, which have an improved profile with respect to safety, potency, selectivity and/or bioavailability.

SUMMARY OF THE INVENTION

In one embodiment, 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 a herpes virus 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.

Tn another aspect, the disclosure provides a method of treating a herpes virus 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 C_1-6 alkyl and C_1-4 alkyl, respectively. Exemplary alkyl groups 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, etc. 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 C_2-6alkenyl. Exemplary alkenyl groups include, but are not limited to, vinyl, allyl, butenyl, and pentenyl, etc ....

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 C_2-6alkynyl. Exemplary alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pcntynyl, hcxynyl, and mcthylpropynyl, etc ....

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 C_1-6alkoxy and C_1-4alkoxy, respectively. Exemplary alkoxy groups include, but are not limited to methoxy, ethoxy, and isopropoxy, etc.

The term “alkoxyalkyl” as used herein refers to an alkyl group substituted with an alkoxy group. Examples include, but are not limited to, CH₃CH₂OCH₂-, CH₃OCH₂CH₂- and CH₃OCH₂-, etc....

The term “cyano” as used herein refers to the radical -CN.

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. For example, haloC_1-6alkyl 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-, CHCI₂-, -CHF₂, CF₃-, CF₃CH₂-, CH₃CF₂, CF₃CC1₂- and CF₃CF₂-.

The term “haloalkoxy” as used herein refers to an alkoxy group substituted with one or more halogen atoms. Examples include, but are not limited to, CCI₃O-, CF₃O-, CHF₂O- CF₃CH₂O-, and CF₃CF₂O-.

The terms “hydroxy” and “hydroxyl” as used herein refers to the radical -OH. The term “hydroxy alkyl” as used herein refers to an alkyl group substituted with one or more hydroxy groups. Examples include, but are not limited to, HOCH₂-, HOCH₂CH₂-, CH₃CH(OH)CH₂- and HOCH₂CH(OH)CH₂-.

The term “hydroxyalkoxy” as used herein refers to an alkoxy group substituted with one or more hydroxy groups. Examples include but are not limited to HOCH₂O-, HOCH₂CH₂O-, CH₃CH(OH)CH₂O- and HOCH₂CH(OH)CH₂O-.

The term “R^aR^bNC_1-6 alkyl-,” as used herein refers to an alkyl group substituted with a R^aR^bN- group, as defined herein. Examples include but are not limited to NH₂CH₂-, NH(CH₃)CH₂-, N(CH₃)₂CH₂CH₂- and CH₃CH(NH₂)CH₂-.

The term “R^aR^bNC_1-6alkoxy,” as used herein refers to an alkoxy group substituted with a R^aR^bN- groups, as defined herein. 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

signifies that the bicyclic ring can be attached via a carbon atom on either ring, and that the substituents (e.g., the R³³ group(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 HBV infection is desired.

The term “modulation” includes antagonism (e.g., inhibition), agonism, partial antagonism and/or partial agonism.

The term “Pharmaceutically acceptable” include 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 Biologies 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 are capable of forming 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., l , l '-mcthylcnc-h/.s-(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 non 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 stcrcogcnic 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 carboncarbon double bond. The symbol 7=: 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 preexisting 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 Kvaemo, 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 as ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶C1, 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 with ³H and ¹⁴C) are useful in compound and/or substrate tissue distribution assays. Tritiated (i.e., ³H) and carbon- 14 (z.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).

Bicyclic Heterocycle Compounds

In one aspect, the present disclosure provides a compound of Formula I

Formula I or a pharmaceutically acceptable salt thereof, wherein:

R¹ and R² are independently selected from the group consisting of hydrogen, halo, cyano, and nitro;

R⁴ is selected from the group consisting of hydrogen, halo, cyano, nitro, hydroxyl, NR^aR^b, C_1-4alkyl, C_2-4alkenyl, C_2-4alkynyl and C_1-4alkoxyC_1-4alkyl, wherein the C_1-4alkyl. C2- 4alkenyl, C_2-4alkynyl or C_1-4alkoxyC_1-4alkyl is optionally substituted with 1-3 substituents independently selected from the group consisting of halo, hydroxy, nitro, NR^aR^b and NHC(O)OCi-₄alkyl;

R⁶ and R⁷ are independently selected from the group consisting of Chalkyl. hydroxyCi- 4alkyl and C_1-4alkoxyC_1-4alkyl-;

R⁸ is hydrogen, C(O)NR^aR^b, C_1-4alkyl, C_2-4alkenyl, C_2-4alkynyl, C_1-4alkoxyC_1-4alkyl, R¹⁰ or C(O)R¹⁰, wherein the C_1-4alkyl, C_2-4alkenyl, C_2-4alkynyl or C_1-4alkoxyC_1-4alkyl is optionally substituted with 1-3 substituents independently selected from the group consisting of halo, hydroxy, nitro, NR^aR^b and NHC(O)OC_1-4alkyl;

R⁹ is independently selected for each occurrence from the group consisting of halo, cyano, nitro, hydroxyl, NR^aR^b, C_1-4alkyl, C_2-4alkenyl, C_2-4alkynyl and C_1-4alkoxyC_1-4alkyl, wherein the C_1-4alkyl. C_2-4alkenyl, C_2-4alkynyl or C_1-4alkoxyC_1-4alkyl is optionally substituted with 1-3 substituents; independently selected from the group consisting of halo, hydroxy, nitro, NR^aR^b and NHC(O)O C_1-4alkyl;

R^9a is hydrogen or C_1-4alkyl;

R^a and R^b for each occurrence are independently selected from the group consisting of hydrogen and C_1-4alkyl;

X is O or S; w is 0, 1 or 2; x is 0 or 1 ; and y is 0, 1, 2 or 3.

In one embodiment, the compound of Formula I is of Formula la

Formula la.

In another embodiment, the compound of Formula I is of Formula lb

Formula lb.

In another embodiment, the compound of Formula I is of Formula Ic

The following embodiments further describe a compound of Formula I, la, lb, or Ic, 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, R¹ is Cl or CN. In certain embodiments, R² is hydrogen or F.

In certain embodiments, R¹ is Cl or CN and R² is hydrogen.

In certain embodiments, R¹ is Cl and R² is F.

In certain embodiments, R³ is

In certain embodiments, R³ is selected from the group consisting of

In certain embodiments, R³ is selected from the group consisting of

In certain embodiments, R³ is

In certain embodiments, R³ is

In certain embodiments, R³ is selected from the group consisting of

In certain embodiments, R³ is selected from the group consisting of

In certain embodiments, R³ is

Tn certain embodiments, R³ is selected from the group consisting

In certain embodiments, R³ is

In certain embodiments, R⁶and R⁷ are independently selected from the group consisting of CH₃, CH₂OH and CH₂OCH₃;

Tn certain embodiments, R⁶and R⁷ are CH₃;

In certain embodiments, R⁸ is cyano, CH₃, CH₂F, CH₂OH, vinyl, CH₂CHF2, CH(OH)CH₃, CH(OH)CH₂OH, CH(OH)CH₂NO₂, CH(OH)CH₂NH₂, or CH₂OCH₃.

Methods of Use

The Compounds of the invention are useful in human and veterinary medicine for treating or preventing a viral infection in a patient. In one embodiment, the Compounds of the invention can be inhibitors of viral replication. In another embodiment, the Compounds of the invention can be inhibitors of herpesvirus replication. Accordingly, the Compounds of the invention are useful for treating viral infections, such as herpesvirus. In accordance with the invention, the Compounds of the invention can be administered to a patient in need of treatment or prevention of a viral infection.

In one aspect, the invention provides methods for treating or preventing a viral infection in a patient comprising administering to the patient an effective amount of at least one Compound of the invention or a pharmaceutically acceptable salt thereof.

The Compounds of the invention are useful in the inhibition of herpesvirus replication, the treatment of herpesvirus infection and/or reduction of the likelihood or severity of symptoms of herpesvirus infection and the inhibition of herpesvirus viral replication and/or herpesvirus viral production in a cell-based system. For example, the Compound of the invention are useful in treating infection by herpesvirus after suspected past exposure to herpesvirus by such means as blood transfusion, exchange of body fluids, bites, accidental needle stick, or exposure to patient blood during surgery or other medical procedures.

In one embodiment, the invention provides a method for treating herpesvirus infection in a patient, the method comprising administering to the patient an effective amount of at least one Compound of the invention, or a pharmaceutically acceptable salt thereof.

In another embodiment, the herpesvirus being treated or prevented is of the family cc- herpesviridae. Herpesviruses of the family α-herpesviridae include, but are not limited to, herpes simplex virus 1 (HSV-1 or HSV1), herpes simplex 2 (HSV-2 or HSV2), and varicella zoster virus (VZV).

In another embodiment, the herpesvirus being treated or prevented is of the family P - herpesviridae. Herpesviruses of the family -herpes viridae include, but are not limited to, human cytomegalovirus (CMV), human herpesvirus 6 (HHV6), and human herpesvirus 7 (HHV7).

In another embodiment, the herpesvirus being treated or prevented is of the family y- herpesviridae. Herpesviruses of the family y-herpesviridae include, but are not limited to, Epstein-Barr virus (EBV), human herpesvirus 4 (HHV4), and Kaposi's sarcoma-associated herpesvirus (KHSV), also known as human herpesvirus 8 (HHV8).

In another embodiment, the herpesvirus being treated or prevented is HSV-1.

In another embodiment, the herpesvirus being treated or prevented is HSV-2.

In another embodiment, the herpesvirus being treated or prevented is VZV.

In another embodiment, the herpesvirus being treated or prevented is CMV.

In a further embodiment, the herpesvirus being treated or prevented is HHV4.

In another embodiment, the herpesvirus being treated or prevented is HHV6.

In another embodiment, the herpesvirus being treated or prevented i s HHV7.

In another embodiment, the herpesvirus being treated or prevented is EBV.

In another embodiment, the herpesvirus being treated or prevented is KSHV.

In another embodiment, the amount administered is effective to treat or prevent infection by herpesvirus in the patient. In another embodiment, the amount administered is effective to inhibit herpesvirus viral replication and/or viral production in the patient.

The compositions and combinations of the present invention can be useful for treating a patient suffering from infection related to any herpesvirus infection. Herpesvirus types may differ in their antigenicity, level of viremia, severity of disease produced, and response to therapy. See Poole et al., Clinical Therapeutics, 40:8 (2018), 1282-1298.

Combination Therapy

In another aspect, the present methods for treating or preventing herpesvirus infection can further comprise the administration of one or more additional therapeutic agents which are not Compounds of the invention.

In one embodiment, the additional therapeutic agent is an antiviral agent.

In another embodiment, the additional therapeutic agent is an anti-herpes agent.

Anti-herpes agents useful in the present compositions and methods include, but are not limited to, nucleoside polymerase inhibitors, such as acyclovir, valaciclovir, famciclovir, penciclovir, cidofovir, brincidofovir (CMX-001), valmanciclovir, ganciclovir, valganciclovir, and N-methanocarbathymidine (N-MCT); pyrophosphate polymerase inhibitors, such as foscarnet; CMV terminase inhibitors, such as letermovir; viral kinase inhibitors, such as maribavir; and helicase-primase inhibitors, such as pritelivir (AIC-316), and amenamevir (ASP- 2151).

In another embodiment, the additional therapeutic agent is an immunomodulatory agent, such as an immunosuppressive agent. Immunosuppressant agents useful in the present compositions and methods include, but are not limited to, cytotoxic agents, such as cyclophosphamide and cyclosporin A; corticosteroids, such as hydrocortisone and dexamethasone, and non-steroidal anti-inflammatory agents (NSAID).

In another aspect, the present invention provides methods for treating a herpesvirus infection in a patient, the method comprising administering to the patient: (i) at least one Compound of the invention, or a pharmaceutically acceptable salt thereof, and (ii) at least one additional therapeutic agent that is other than Compound of the invention, wherein the amounts administered are together effective to treat or prevent the herpesvirus infection.

When administering a combination therapy of the invention to a patient, therapeutic agents in the combination, or a pharmaceutical composition or compositions comprising therapeutic agents, may be administered in any order such as, for example, sequentially, concurrently, together, simultaneously and the like. The amounts of the various actives in such combination therapy may be different amounts (different dosage amounts) or same amounts (same dosage amounts). Thus, for non-limiting illustration purposes, a Compound of the invention and an additional therapeutic agent may be present in fixed amounts (dosage amounts) in a single dosage unit (e.g., a capsule, a tablet and the like).

In one embodiment, the at least one Compound of the invention is administered during a time when the additional therapeutic agent(s) exert their prophylactic or therapeutic effect, or vice versa.

In another embodiment, the at least one Compound of the invention and the additional therapeutic agent(s) are administered in doses commonly employed when such agents are used as monotherapy for treating a herpesvirus infection.

In another embodiment, the at least one Compound of the invention and the additional therapeutic agent(s) are administered in doses lower than the doses commonly employed when such agents are used as monotherapy for treating a herpesvirus infection.

In another embodiment, the at least one Compound of the invention and the additional therapeutic agent(s) act synergistically and are administered in doses lower than the doses commonly employed when such agents arc used as monotherapy for treating a herpesvirus infection.

In one embodiment, the at least one Compound of the invention and the additional therapeutic agent(s) are present in the same composition. In one embodiment, this composition is suitable for oral administration. In another embodiment, this composition is suitable for intravenous administration. In another embodiment, this composition is suitable for subcutaneous administration. In still another embodiment, this composition is suitable for parenteral administration.

The at least one Compound of the invention and the additional therapeutic agent(s) can act additively or synergistically. A synergistic combination may allow the use of lower dosages of one or more agents and/or less frequent administration of one or more agents of a combination therapy. A lower dosage or less frequent administration of one or more agents may lower toxicity of therapy without reducing the efficacy of therapy.

In one embodiment, the administration of at least one Compound of the invention and the additional therapeutic agent(s) may inhibit the resistance of a herpesvirus infection to these agents.

The doses and dosage regimen of the other agents used in the combination therapies of the present invention for the treatment or prevention of herpesvirus infection can be determined by the attending clinician, taking into consideration the approved doses and dosage regimen in the package insert; the age, sex and general health of the patient; and the type and severity of the viral infection or related disease or disorder. When administered in combination, the Compound(s) of the invention, and the other agent(s) can be administered simultaneously (i.e., in the same composition or in separate compositions one right after the other) or sequentially. This particularly useful when the components of the combination are given on different dosing schedules, e.g., one component is administered once daily and another component is administered every six hours, or when the preferred pharmaceutical compositions are different, e.g., one is a tablet and one is a capsule. A kit comprising the separate dosage forms is therefore advantageous.

In one embodiment, one or more compounds of the present invention are administered with one or more additional therapeutic agents selected from: an immunomodulator, an antiherpes agent, a viral replication inhibitor, an antisense agent, a therapeutic vaccine, a virion production inhibitor, a viral entry inhibitor, a viral assembly inhibitor, an antibody therapy (monoclonal or polyclonal), and any agent useful for treating any type of herpesvirus infection.

Compositions and Administration

Due to their activity, the Compounds of the invention are useful in veterinary and human medicine. As described above, the Compounds of the invention are useful for treating or preventing herpesvirus infection in a patient in need thereof.

In another aspect, the present invention provides pharmaceutical compositions comprising an effective amount of a Compound of the invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In another aspect, the present invention provides pharmaceutical compositions comprising (i) an effective amount of a Compound of the invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier; and (ii) one or more additional therapeutic agents, wherein said additional therapeutic agents are selected from anti-herpes agents and immunomodulators.

When administered to a patient, the Compounds of the invention can be administered as a component of a composition that comprises a pharmaceutically acceptable carrier or vehicle. The present invention provides pharmaceutical compositions comprising an effective amount of at least one Compound of the invention and a pharmaceutically acceptable carrier. In the pharmaceutical compositions and methods of the present invention, the active ingredients will typically be administered in admixture with suitable carrier materials suitably selected with respect to the intended form of administration, i.e., oral tablets, capsules (either solid-filled, semi-solid filled or liquid filled), powders for constitution, oral gels, elixirs, dispersible granules, syrups, suspensions, and the like, and consistent with conventional pharmaceutical practices. For example, for oral administration in the form of tablets or capsules, the active drug component may be combined with any oral non-toxic pharmaceutically acceptable inert carrier, such as lactose, starch, sucrose, cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, talc, mannitol, ethyl alcohol (liquid forms), and the like. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories. Powders and tablets may be comprised of from about 0.5 to about 95 percent inventive composition. Tablets, powders, cachets, and capsules can be used as solid dosage forms suitable for oral administration.

Moreover, when desired or needed, suitable binders, lubricants, disintegrating agents and coloring agents may also be incorporated in the mixture. Suitable binders include starch, gelatin, natural sugars, corn sweeteners, natural and synthetic gums such as acacia, sodium alginate, carboxymethylcellulose, polyethylene glycol and waxes. Among the lubricants there may be mentioned for use in these dosage forms, boric acid, sodium benzoate, sodium acetate, sodium chloride, and the like. Disintegrants include starch, methylcellulose, guar gum, and the like. Sweetening and flavoring agents and preservatives may also be included where appropriate. Liquid form preparations include solutions, suspensions and emulsions and may include water or water-propylene glycol solutions for parenteral or intravenous injection.

Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration. Such liquid forms include solutions, suspensions, and emulsions.

For preparing suppositories, a low melting wax such as a mixture of fatty acid glycerides or cocoa butter is first melted, and the active ingredient is dispersed homogeneously therein as by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool and thereby solidify.

Additionally, the compositions of the present invention may be formulated in sustained release form to provide the rate-controlled release of any one or more of the components or active ingredients to optimize therapeutic effects, i.e., antiviral activity and the like. Suitable dosage forms for sustained release include layered tablets containing layers of varying disintegration rates or controlled release polymeric matrices impregnated with the active components and shaped in tablet form or capsules containing such impregnated or encapsulated porous polymeric matrices.

In one embodiment, the one or more Compounds of the invention are administered orally.

In another embodiment, the one or more Compounds of the invention are administered intravenously.

In another embodiment, the one or more Compounds of the invention are administered sublingually.

In another embodiment, a pharmaceutical preparation comprising at least one Compound of the invention is in unit dosage form. In such form, the preparation is subdivided into unit doses containing effective amounts of the active components.

Compositions can be prepared according to conventional mixing, granulating, or coating methods, respectively, and the present compositions can contain, in one embodiment, from about 0.1 %, to about 99% of the Compound(s) of the invention by weight or volume. In various embodiments, the present compositions can contain, in one embodiment, from about 1%, to about 70% or from about 5%, to about 60% of the Compound(s) of the invention by weight or volume. The amount and frequency of administration of the Compounds of the invention will be regulated according to the judgment of the attending clinician considering such factors as age, condition and size of the patient as well as severity of the symptoms being treated. Generally, a total daily dosage of the at least one Compound(s) of the invention alone, or when administered as combination therapy, can range from about 1 to about 2500 mg per day, although variations will necessarily occur depending on the target of therapy, the patient and the route of administration. In one embodiment, the dosage is from about 10 to about 1000 mg/day, administered in a single dose or in 2-4 divided doses. In another embodiment, the dosage is from about 1 to about 500 mg/day, administered in a single dose or in 2-4 divided doses. In still another embodiment, the dosage is from about 1 to about 100 mg/day, administered in a single dose or in 2-4 divided doses. In yet another embodiment, the dosage is from about 1 to about 50 mg/day, administered in a single dose or in 2-4 divided doses. In another embodiment, the dosage is from about 500 to about 1500 mg/day, administered in a single dose or in 2-4 divided doses. In still another embodiment, the dosage is from about 500 to about 1000 mg/day, administered in a single dose or in 2-4 divided doses. In yet another embodiment, the dosage is from about 100 to about 500 mg/day, administered in a single dose or in 2-4 divided doses.

The compositions of the invention can further comprise one or more additional therapeutic agents, selected from those listed above herein. Accordingly, in one embodiment, the present invention provides compositions comprising: (i) at least one Compound of the invention or a pharmaceutically acceptable salt thereof; (ii) one or more additional therapeutic agents that are not a Compound of the invention; and (iii) a pharmaceutically acceptable carrier, wherein the amounts in the composition are together effective to treat herpesvirus infection.

In one embodiment, the present invention provides compositions comprising a Compound of the invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

In another embodiment, the present invention provides compositions comprising a Compound of the invention, or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable carrier, and a second therapeutic agent selected from the group consisting of antiherpes agents and immunomodulators. In another embodiment, the present invention provides compositions comprising a Compound of the invention, or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable carrier, and two additional therapeutic agents, each of which are independently selected from the group consisting of anti-herpes agents and immunomodulators.

Examples

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

BociO 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

LC-MS Liquid chromatography-mass spectrometry

MeOH Methanol

NMON Methyl morpholine-N-Oxide

NBS N-Bromo succinimide

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

Preparation of Intermediates:

N-(4-Chlorobenzyl)-8-oxo-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-3-carboxamide hydrochloride (INT-1)

Step 1. Synthesis of ethyl 2-oxo-2-((pyrazin-2-ylmethyl)amino)acetate. To a stirred solution of pyrazin-2-ylmethanamine (10 g, 90 mmol) in THF (100 mL) at 0 °C was added TEA (38.3 ml, 269 mmol) followed by ethyl 2-chloro-2-oxoacetate (13.76 g, 99 mmol) The resulting reaction mixture was slowly wanned to room temperature and stirred for 2 h. The reaction mixture was filtered and washed with THF (200 mL). The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography, eluting with 50-80% ethyl acetate in petroleum ether to afford ethyl 2-oxo-2-((pyrazin-2- ylmethyl)amino)acetate (17 g, 89%) as an off-white solid. LC-MS: 210.1 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆): δ 9.53 (s, 1H), 8.61 (d, J = 7.20 Hz, 1H), 8.55 (d, J = 2.80 Hz, 1H), 4.51 (s, 1H), 4.26 (q, J = 6.80 Hz, 2H), 1.28 (t, J = 7.20 Hz, 3H) ppm.

Step 2. Synthesis of ethyl imidazo[1,5-a]pyrazine-3-carboxylate. To a stirred solution of ethyl 2-oxo-2-((pyrazin-2-ylmethyl)amino)acetate (17 g, 80 mmol) in DCE (250 mL) was added POCI₃ (25.09 g, 160 mmol) and phosphorus pentoxide (17.42 g, 120 mmol) at rt. The resulting reaction mixture was stirred at 100 °C for 16 h. The reaction mixture was quenched with sodium bicarbonate solution (10%) and extracted with DCM (300 mLx 2). The organic layers dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford ethyl imidazo[l,5- a]pyrazine-3-carboxylate (9 g, 50%) as a brown solid. LC-MS: 192.1 [M+H]⁺. Step 3. Synthesis of ethyl 5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-3-carboxylate: An autoclave was charged with a solution of ethyl imidazo[1,5-a]pyrazinc-3-carboxylatc (9 g, 39.5 mmol) in ethanol (200 mL) under a nitrogen atmosphere for 10 min. To this resulting solution was added palladium on carbon (7.56 g, 7.11 mmol) at room temperature under an inert atmosphere. The resulting reaction mixture was stirred under 80 psi hydrogen pressure at room temperature for 12 h. The reaction mixture was filtered through a celite pad. The filtrate was concentrated under reduced pressure to provide ethyl 5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine- 3-carboxylate (10 g), which was used for the next step without further purifications.

Step 4. Synthesis of 7-(tert-butyl)-3-ethyl-5,6-dihydroimidazo[1,5-a]pyrazine-3,7(8H)- dicarboxylate. To a stirred solution of ethyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-3- carboxylate (10 g, 46.2 mmol) in DCM (300 mL) were added triethylamine (10.3 ml, 102.4 mmol) followed by Boc-anhydride (22.3 g, 102.4 mmol) at 0 °C. The reaction mixture was stirred at rt for 16 h. The reaction mixture was diluted with DCM and washed with water. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography, eluting with 50-60% ethyl acetate in petroleum ether to afford 7-(tert-butyl)-3-ethyl-5,6-dihydroimidazo[1,5-a]pyrazine- 3,7(8H)-dicarboxylate (12 g) as a pale oil. LC-MS: 296.3 [M-1]⁺; ¹H NMR (300 MHz, DMSO- d₆): δ 7.01 (s, 1H), 4.62 (s, 2H), 4.35 (t, J = 5.70 Hz, 2H), 4.29 (t, J = 7.20 Hz, 2H), 3.71 (t, J = 5.40 Hz, 2H), 3.71 (s, 9H), 1.30 (t, J = 6.90 Hz, 3H) ppm.

Step 5. Synthesis of lithium 7-(tert-butoxycarbonyl)-5,6,7,8-tetrahydroimidazo[l,5- a]pyrazine-3-carboxylate. To a stirred solution of 7 -(tert- butyl) 3-ethyl 5,6-dihydroimidazo[l,5- a]pyrazine-3,7(8H)-dicarboxylate (1 g, 3.39 mmol) in Tetrahydrofuran (7 mL), Water (1 mL) and EtOH (2 mL) was added LiOH (0.162 g, 6.77 mmol). The reaction was stirred at rt for 2 h. The reaction mixture was evaporated and co-distilled with dioxane (4 mL x 2) under reduced pressure to afford lithium 7-(tert-butoxycarbonyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-3-carboxylate (0.97 g) as an off-white solid. LC-MS: 269.1 [M+H]⁺; ¹H NMR: (400 MHz, DMSO-d₆): δ 6.73 (s, 1H), 4.54 (s, 2H), 4.43 (t, J = 7.60 Hz, 2H), 3.64 (t, J = 7.20 Hz, 2H), 1.43 (s, 9H) ppm. Step 6. Synthesis of tert-butyl 3-((4-chlorobenzyl)carbamoyl)-5,6-dihydroimidazo[l,5- a]pyrazine-7(8H)-carboxylate. A solution of lithium 7-(tcrt-butoxycarbonyl)-5, 6,7,8- tetrahydroimidazo[1,5-a]pyrazine-3-carboxylate (2 g, 7.32 mmol), (4-chlorophenyl)methanamine (1.34 g, 9.52 mmol), BOP (6.47 g, 14.6 mmol) and DIPEA (3.78 g, 29.30 mmol) in DMF (20 mL) was stirred at rt overnight. Tire reaction mixture was partitioned between water (20 mL) and EtOAc. The organic layer was dried over Na₂SO₄, filtered, and concentrated. The resulting residue was purified by column chromatography eluting with 30% EtOAc in petroleum ether to afford tert-butyl 3-((4-chlorobenzyl)carbamoyl)-5,6-dihydroimidazo[1,5-a]pyrazine-7(8H)- carboxylate (1.8 g, 64%) as a pale yellow gum. LC-MS: 391.2 [M-1]⁺;

NMR: (400 MHz, DMSO-d₆): δ 9.00 (t, J = 8.40 Hz, 1H), 7.38-7.30 (m, 4H), 6.93 (s, 1H), 4.60 (s, 2H), 4.42-4.36 (m, 4H), 3.68 (t, J = 6.80 Hz, 2H), 1.43 (s, 9H) ppm.

Step 7. Synthesis of tert-butyl-3-((4-chlorobenzyl)carbamoyl)-8-oxo-5,6- dihydroimidazo[1,5-a]pyrazine-7(8H)-carboxylate. To a solution of tert-butyl-3-((4- chlorobenzyl)carbamoyl)-5,6-dihydroimidazo[1,5-a]pyrazine-7(8H)-carboxylate (1.7 g, 4.35 mmol) in dioxane (32 mL) and water (8 mL) was added sodium chlorite (1.17 g, 13.07 mmol). The reaction mixture was heated to 60 °C and stirred for 16 h. The reaction mixture was diluted with EtOAc (30 mL). The organic layer was dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The resulting residue was triturated with pet ether and filtered. The filter was dried under reduced pressure to afford tcrt-butyl-3-((4-chlorobcnzyl)carbamoyl)-8-oxo-5,6- dihydroimidazo[1,5-a]pyrazine-7(8H)-carboxylate (1.1 g, 65%) as a white solid. LC-MS: 403.1 [M-1]⁺; ¹H NMR: (400 MHz, DMSO-d₆): δ 9.40 (t, 7 = -5.20 Hz, 1H), 7.77 (s, 1H), 7.40-7.33 (m, 4H), 4.66 (t, J = 5.60 Hz, 2H), 4.41 (d, J = 6.40 Hz, 2H), 4.07 (t, J = 5.60 Hz, 2H), 1.26 (s, 9H) ppm.

Step 8. Synthesis of N-(4-chlorobenzyl)-8-oxo-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-3- carboxamide hydrochloride (INT-1). To a solution of tert-butyl 3-((4- chlorobenzyl)carbamoyl)-8-oxo-5,6-dihydroimidazo[1,5-a]pyrazine-7(8H)-carboxylate (1.1 g, 2.72 mmol) in DCM (20 mL) at 0 °C, was 4 N HC1 in dioxane (13.61 mL, 54.45 mmol). The reaction mixture was warmed to rt and stirred for 12 h. The progress of the reaction was monitored by LC-MS. The solvent was evaporated. The residue was neutralized with 10 % NaHCO₃ (20 mL), stirred for 10 min and filtered. The filter was washed with water (10 mL) and dried under reduced pressure to afford N-(4-chlorobenzyl)-8-oxo-5,6,7,8-tetrahydroimidazo[1,5- a]pyrazine-3-carboxamide (INT-1) (0.9 g, 99%) as a pale yellow solid. LC-MS: 305.1 [M-1]⁺; 1H NMR: (400 MHz, DMSO-d₆): δ 9.31 (t, J = 8.00 Hz, 1H), 8.12 (s, 1H), 7.56 (s, 1H), 7.40-

7.29 (m, 4H), 4.59 (t, J - 8.00 Hz, 2H), 4.40 (d, J = 8.40 Hz, 2H), (t, J = Hz, 2H) ppm.

N-(4-Chlorobenzyl)-7-oxo-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (INT-2)

Step 1. Synthesis of 6-(tert-butyl) 3-ethyl 2-amino-4,7-dihydrothieno[2,3-c]pyridine- 3,6(5H)-dicarboxylate. To a stirred solution of tcrt-butyl 4-oxopipcridinc-1-carboxylate (5 g, 24.59 mmol) in ethanol (50 mL) was added TEA (3.50 ml, 24.59 mmol) and sulphur (1.610 g,

49.2 mmol) and stirred for 20 min. Ethyl 2-cyanoacetate (3.21 ml, 29.5 mmol) was added and the reaction mixture was stirred at rt for 23 h. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by column chromatography to afford 6-(tert-butyl) 3-ethyl 2-amino-4,7-dihydrothieno[2,3-c]pyridine-3,6(5H)-dicarboxylate (7.5 g, 66%) as a yellow solid. LC-MS: 327.1 [M-1]⁺; ¹H NMR (400 MHz, DMSO-d₆): δ 7.33 (s, 2H), 4.25 (s, 2H), 4.18 - 4.13 (m, 2H), 3.51 (t, 7 = 4.8 Hz, 2H), 2.67 (t, 7 = 5.6 Hz, 2H), 1.25 (t, 7= 14.0 Hz, 3H) ppm.

Step 2. Synthesis of 6-(tert-butyl) 3-ethyl 4,7-dihydrothieno[2,3-c]pyridine-3,6(5H)- dicarboxylate. To a preheated stirred solution of tert-Butyl nitrite (2.89 ml, 23.82 mmol) in THF (350 mL) was added 6-(tert-butyl) 3-ethyl 2-amino-4,7-dihydrothieno[2,3-c]pyridine-3,6(5H)- dicarboxylate (7.5 g, 22.69 mmol) dissolved in THF (350 mL). The reaction mixture was stirred at 60 °C for 10 h. The reaction was monitored by TLC. The reaction mixture was diluted with water and extracted with EtOAc (50 mL x 2). The combined organic layers were dried over sodium sulfate, fdtered, and concentrated. The resulting residue was purified by column chromatography eluting with 20% EA in PE to afford 6-(tcrt-butyl) 3-cthyl 4,7- dihydrothieno[2,3-c]pyridine-3,6(5H)-dicarboxylate (1.95 g, 28%). LC-MS: 211.9 [M+l]⁺.

Step 3. Synthesis of 6-(tert-butyl) 3-ethyl 7-oxo-4,7-dihydrothieno[2,3-c]pyridine-3,6(5H)- dicarboxylate. To the stirred solution of 6-(tert-butyl) 3-ethyl 4,7-dihydrothieno[2,3-c]pyridine- 3,6(5H)-dicarboxylate (570 mg, 1.556 mmol) in dioxane (4 mL) and water (1 ml) was added sodium chlorite (431 mg, 4.67 mmol) at rt. The reaction mixture was stirred at 60 °C for 3 h. The reaction was monitored by TLC. The reaction mixture was diluted with water and extracted with ethyl acetate (10 ml x 2). The combined organic layers were washed with 10% NaHCO₃ solution, dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by trituration with ethyl acetate and petroleum ether to afford 6-(tert-butyl) 3-ethyl 7-oxo-4,7-dihydrothieno[2,3-c]pyridine-3,6(5H)-dicarboxylate (0.4 g) as an off-white solid. LC- MS: 270.1 [M+l]⁺.

Step 4. Synthesis of 6-(tert-butoxycarbonyl)-7-oxo-4,5,6,7-tetrahydrothieno[2,3-c]pyridine- 3-carboxylic acid. To the stirred solution of 6-(tert-butyl) 3-ethyl 7-oxo-4,7-dihydrothieno[2,3- c]pyridine-3,6(5H)-dicarboxylate (100 mg, 0.270 mmol) in THF ( 2 mL), methanol (0.222 mL) and NaOH (12.14 mg, 0.297 mmol) in water (0.222 ml) was added dropwise 0 - 5 °C. The resulting reaction mixture was stirred at rt for 3 h and then concentrated under reduced pressure. The residue was used for next step without further purifications. LC-MS: 295.9 [M-l]’.

Step 5. Synthesis of tert-butyl 3-((4-chlorobenzyl)carbamoyl)-7-oxo-4,7-dihydrothieno[2,3- c]pyridine-6(5H)-carboxylate. To the stirred solution of 6-(tert-butoxycarbonyl)-4, 5,6,7- tetrahydrothieno[2,3-c]pyridine-3-carboxylic acid (440 mg, 0.745 mmol) in DMF (5 mL) was added (4-chlorophenyl)methanamine (162 mg, 1.118 mmol), HATU (434 mg, 1.118 mmol) followed by DIPEA (0.266 ml, 1.491 mmol) at 0 °C. The resulting reaction mixture was stirred at rt for 4 h. The reaction was monitored by HPLC. The reaction mixture was diluted with water and extracted with ethyl acetate (10 mL x 2). The combined organic layers were dried over sodium sulphate, filtered, and concentrated in vacuo. The residue was purified by column chromatography to afford tert-butyl 3-((4-chlorobenzyl)carbamoyl)-7-oxo-4,7- dihydrothicno[2,3-c]pyridinc-6(5H)-carboxylatc (0.35 g, 79%) as an off-white solid. LC-MS: 351.0 [M+l]⁺.

Step 6. Synthesis of N-(4-chlorobenzyl)-7-oxo-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3- carboxamide. To the stirred solution of tert-butyl 3-((4-chlorobenzyl)carbamoyl)-7-oxo-4,7- dihydrothieno[2,3-c]pyridine-6(5H)-carboxylate (110 mg, 0.225 mmol) in DCM (5 mL) was added 4N HC1 in 1,4-dioxane (0.056 ml, 0.225 mmol) at 0 °C. The resulting reaction mixture was stirred at rt for 1 h. The reaction was monitored by UPLC. The reaction mixture was concentrated and diluted with water, and extracted with DCM (20 mL x 2). The combined organic layers were washed with NaHCO₃ solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford N-(4-chlorobenzyl)-7-oxo-4, 5,6,7- tetrahydrothieno[2,3-c]pyridine-3-carbox amide (INT-2) (0.27 g, 77%) as an off-white solid. LC-MS: 321.0 [M+l]⁺.

N-(4-Chlorobenzyl)-2-methyl-7-oxo-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (1NT-3)

Step 1. Synthesis 6-(tert-butyl) 3-ethyl 2-amino-4,7-dihydrothieno[2,3-c]pyridine-3,6(5H)- dicarboxylate. To the stirred solution of tert-butyl 4-oxopiperidine- 1 -carboxylate (5 g, 24.59 mmol) in Ethanol (50 mL) was added TEA (3.50 ml, 24.59 mmol) and sulphur (1.610 g, 49.2 mmol) and stirred for 20 min. Ethyl 2-cyanoacetate (3.23 ml, 29.5 mmol) was added, and the reaction mixture was stirred at rt for 21 h. The precipitate was filtered off. The filtrate was concentrated in vacuo to afford 6-(tert-butyl) 3-ethyl 2-amino-4,7-dihydrothieno[2,3-c]pyridine- 3,6(5H)-dicarboxylate (7.46 g, 93%) as a yellow solid. LC-MS: 327.1 [M-1]⁺; ¹H NMR (400 MHz, DMSO-d₆): δ 7.33 (s, 2H), 4.25 (s, 2H), 4.13-4.18 (m, 2H), 3.51 (t, J = 5.60 Hz, 2H), 2.66 (t, J = 5.60 Hz, 2H), 1.42 (s, 9H), 1.25 (t, J = 6.80 Hz, 3H) ppm.

Step 2. Synthesis 6-(tert-butyl) 3-ethyl 4,7-dihydrothieno[2,3-c]pyridine-3,6(5H)- dicarboxylate. To a pre-heated stirred solution of tert-butyl nitrite (2.87 ml, 23.57 mmol) in THF (200 mL) was added a solution of 6-(tert-butyl) 3-ethyl 2-amino-4,7-dihydrothieno[2,3- c]pyridine-3,6(5H)-dicarboxylate (7.4 g, 22.44 mmol) in THF (200 mL), The reaction mixture was stirred the reaction mixture at 60 °C for 12 h. The reaction mixture was diluted with water and extracted with EtOAc (50 mL x 2). The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The resulting residue was purified by column chromatography (20% EA in PE) to afford 6-(tert-butyl) 3-ethyl 4,7-dihydrothieno[2,3-c]pyridine-3,6(5H)- dicarboxylate (El g, 12%) as a yellow liquid. LC-MS: 212.1 [M+l]⁺.

Step 3. Synthesis 6-(tert-butyl) 3-ethyl 2-bromo-4,7-dihydrothieno[2,3-c]pyridine-3,6(5H)- dicarboxylate. To a stirred solution of 6- (tert-butyl) 3-ethyl 4,7-dihydrothieno[2,3-c]pyridine- 3,6(5H)-dicarboxylate (2.34 g, 7.51 mmol) in DMF (25 mL) were added 1-bromopyrrolidine- 2, 5-dione (2.67 g, 15.03 mmol) at rt. The reaction mixture was stirred at rt for 12 h. After the completion of the reaction, the reaction mixture was evaporated under reduced pressure. The resulting residue was purified by column chromatography eluting with 20-30% EA in PE to afford 6-(tert-butyl) 3-ethyl 2-bromo-4,7-dihydrothieno[2,3-c]pyridine-3,6(5H)-dicarboxylate (1.5 g, 47%) as a yellow oil. LC-MS: 292.0 [M-1]⁺;

NMR (400 MHz, DMSO-d₆): δ 4.48 (s, 2H), 4.24-4.31 (m, 2H), 3.56 (t, J = 7.60 Hz, 2H), 2.76 (t, J = 7.60 Hz, 2H), 1.42 (s, 9H), 1.31 (t, J = 9.60 Hz, 3H) ppm.

Step 4. Synthesis of 6-(tert-butyl) 3-ethyl 2-methyl-4,7-dihydrothieno[2,3-c]pyridine- 3,6(5H)-dicarboxylate. To a stirred solution of 6-(tert-butyl) 3-ethyl 2-bromo-4,7- dihydrothieno[2,3-c]pyridine-3,6(5H)-dicarboxylate (1.5 g, 3.84 mmol) in DMF (20 mL) was degassed with nitrogen for 10 min, then added bis(triphenylphosphine)palladium(II) chloride (0.270 g, 0.384 mmol) and tetramethyltin (1.031 g, 5.76 mmol). The reaction mixture was stirred at 100 °C for 16 h and then evaporated under reduced pressure. The resulting residue was purified by column chromatography eluting with 25-35% EA in PE to afford 6-(tert-butyl) 3- ethyl 2-methyl-4,7-dihydrothieno[2,3-c]pyridine-3,6(5H)-dicarboxylate (1.1 g, 77%) as a yellow oil. LC-MS: 226.1 [M+l]⁺.

Step 5. Synthesis 2-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylic acid. To a stirred solution of 6-(tert-butyl) 3-ethyl 2-methyl-4,7-dihydrothieno[2,3-c]pyridine-3,6(5H)- dicarboxylate (1 g, 3.07 mmol) in dioxane (10 mL) and water (4 mL) was added KOH (0.259 g, 4.61 mmol) and stirred at 60 °C for 16 h. After the completion of the reaction, the reaction mixture was evaporated under reduced pressure to afford 2-methyl-4,5,6,7-tetrahydrothieno[2,3- c]pyridine-3 -carboxylic acid (0.60 g, 76%) as a yellow oil. LC-MS: 198.1 [M-56]⁺. Step 6. Synthesis tert-butyl 3-((4-chlorobenzyl)carbamoyl)-2-methyl-4,7-dihydrothieno[2,3- c]pyridine-6(5H)-carboxylate. To a stirred solution of 6-(tert-butoxycarbonyl)-2-methyl- 4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylic acid (0.7 g, 2.354 mmol) in DMF (10 mL) was added DIPEA (1.217 g, 9.42 mmol) and HATU (1.343 g, 3.53 mmol) followed by the addition of (4-chlorophenyl)methanamine (0.400 g, 2.82 mmol) at rt. The reaction mixture was stirred at rt overnight. After the completion of the reaction, the reaction mixture was evaporated under reduced pressure. The resulting residue was purified by column chromatography eluting with a 25-30% EA in PE to afford tert-butyl 3-((4-chlorobenzyl)carbamoyl)-2-methyl-4,7- dihydrothieno[2,3-c]pyridine-6(5H)-carboxylate (0.6 g, 52%) as a yellow oil. LC-MS: 365.1 [M- 56]⁺.

Step 7. Synthesis tert-butyl 3-((4-chlorobenzyl)carbamoyl)-2-methyl-7-oxo-4,7- dihydrothieno[2,3-c]pyridine-6(5H)-carboxylate. To a stirred solution of tert-butyl 3-((4- chlorobenzyl)carbamoyl)-2-methyl-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylate (0.6 g, 1.425 mmol) in dioxane (8.0 mL) and water (2.0 mL) was added sodium chlorite (0.258 g, 2.85 mmol) and stirred at 60 °C for 12 h. After the completion of the reaction, the reaction mixture was diluted with water and extracted with EtOAc (30 mL x 3). The combined organic extracts were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography eluting with EA in PE (0 to 60%) to afford tert-butyl 3-((4-chlorobenzyl)carbamoyl)-2-methyl-7- oxo-4, 7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylate (0.6 g, 88%) as a yellow oil. LC-MS: 335.2 [M-56]⁺.

Step 8. Synthesis N-(4-chlorobenzyl)-2-methyl-7-oxo-4,5,6,7-tetrahydrothieno[2,3- c]pyridine-3-carboxamide. To a stirred solution of tert-butyl 3-((4-chlorobenzyl)carbamoyl)-2- methyl-7-oxo-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylate (0.6 g, 1.380 mmol) in dioxane (8 mL) was added 4N HC1 (4.14 mL, 16.55 mmol) and stirred at rt for 3 h. The reaction mixture was evaporated under reduced pressure. The residue was diluted with DCM (lOmL) and washed with saturated sodium bicarbonate solution (15 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford N-(4- chlorobenzyl)-2-methyl-7-oxo-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (INT-3)

(0.3 g, 60%) as an off-white solid. LC-MS: 335.1 [M+l]⁺.

N-(4-Chlorobenzyl)-2-methyl-7-oxo-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (INT-4)

Step 1. Synthesis of Ethyl 5-formyl-1H-pyrrole-2-carboxylate. The Vilsmeier reagent was prepared by adding POCI₃ (3.35 ml, 35.9 mmol) dropwise to ice-cold, dry DMF (3.35 mL) under stirring. The mixture was then stirred for 15 min at 0 °C. Then ethy1lH- pyrrole-2-carboxylate (1 g, 7.19 mmol) in DCE (3.35 mL) was added dropwise. The reaction mixture was stirred at 100 °C for Ih. The reaction mixture was poured into an ice-cold saturated solution of NaCl. The mixture was extracted with dichloromethane (20 mL x 3). The combined organic layers were washed with water (20 mL x 3), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography eluting 15-20 % EA in PE to afford ethyl 5 -formyl- 1H-pyrrole-2-carboxylate (870 mg, 68%) as a light- yellow solid. LC-MS: 167 [M+l ]⁺; ¹H-NMR (400 MHz, DMSO-d₆): δ 9.94 (br s, 1H), 9.69 (s, 1H), 6.97 (s, 2H), 4.43 - 4.39 (m, 2H), 1.42 (t, J = 7.2 Hz, 3H) ppm. Step 2. Synthesis of 5-(Ethoxycarbonyl)-1H-pyrrole-2-carboxylic acid. To a stirred solution of ethyl 5-formyl-1H-pyrrole-2-carboxylate (0.55 g, 3.29 mmol) in acetone (39 mL) at 0 °C was added KMnO₄ (1.04 g, 6.58 mmol) in acetone (13 mL) and water (13 mL). The reaction mixture was stirred at rt for 16 h. The reaction mixture was poured into a saturated solution of Na₂SO₃ (2.0 g), then IM HC1 (22.3 mL) was added dropwise at 0 °C. The resulting mixture was extracted with chloroform (20 mL x 3). The combined organic extracts were washed with water (10 mL) and brine (5.0 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give 5-(ethoxy carbonyl1)H- - pyrrole-2 -carboxylic acid (0.5 g, 74%) as an off-white solid. LC-MS: 182.1 [M-1]-; ¹H-NMR (400 MHz, DMSO-d₆): δ 12.42 (s, 1H), 12.22 (br s, 1H), 7.49 (d, J = 4.4 Hz, 1H), 7.05 (d, J = 3.6 Hz, 1H), 4.28 - 4.24 (m, 2H), 1.29 (t, J = 9.2 Hz, 3H) ppm.

Step 3. Synthesis of Ethyl 5-((4-chlorobenzyl)carbamoyl)-1H-pyrrole-2-carboxylate. To a stirred solution of 5-(ethoxycarbonyl)-1H-pyrrole-2-carboxylic acid (300 mg, 1.63 mmol) in DMF (8 mL) was added DIPEA (1.512 ml, 8.19 mmol) and HATU (1449 mg, 3.28 mmol) followed by(4-chlorophenyl) methanamine (232 mg, 1.638 mmol). The reaction mixture was stirred at rt for 2 h. The reaction mixture was diluted with ice-cold water (10 mL) and extracted with ethyl acetate (10 x 2 mL). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography eluting with 30-35 % EA in PE to afford ethyl 5-((4-chlorobenzyl)carbamoyl)-1H-pyrrole-2-carboxylate (0.35 g, 66%) as an off- white solid. LC-MS: 307.1 [M-1]⁺; ¹H-NMR (400 MHz, DMSO-d₆): δ 12.11 (s, 1H), 8.86 (t, J = 8.0 Hz, 1H), 7.42 - 7.40 (m, 4H), 6.83 (d, J = 5.2 Hz, 1H), 6.79 (d, J = 5.2 Hz, 1H), 4.45 (d, J = 7.6 Hz, 2H), 4.30 - 4.25 (m, 2H), 1.30 (t, J = 9.2 Hz, 3H) ppm.

Step 4. Synthesis of Ethyl 1-(2-((tert-butoxycarbonyl)amino)ethyl)-5-((4- chlorobenzyl)carbamoyl)-1H-pyrrole-2-carboxylate. To a stirred solution of ethyl 5-((4- chlorobenzyl)carbamoyl)-1H-pyrrole-2-carboxylate (0.35 g, 1.141 mmol) in DMF (50 mL) were added K₂CO₃ (0.158 g, 1 .141 mmol) followed by tert-butyl (2-bromoethyl)carbamate (0.287 g, 1.255 mmol) at 0 - 5 °C-and stirred at rt for 48 h. The reaction mixture was diluted with water (3.0 mL) and extracted with ethyl acetate (5 ml x 2). The combined organic extracts were washed with brine (1 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography by eluting with 15- 20 % EA in PE to afford ethyl 1-(2-((tert-methoxycarbonyl)amino)ethyl)-5-((4- chlorobenzyl)carbamoyl)-1H-pyrrole-2-carboxylate (0.4 g, 68%) as a brown solid. LC-MS: 447.9 [M-l]’.

Step 5. Synthesis of Ethyl 1-(2-aminoethyl)-5-((4-chlorobenzyl)carbamoyl)-1H-pyrrole-2- carboxylate. To a stirred solution of ethyl 1-(2-((tert-butoxycarbonyl)amino)ethyl)-5-((4- chlorobenzyl)carbamoyl)-1H-pyrrole-2-carboxylate (350 mg, 0.719 mmol) in dioxane (10 mL) under nitrogen atmosphere was added 4N HC1 in dioxane (0.022 mL, 0.719 mmol) at 0 °C. Then reaction mixture was stirred at rt for 2 h. The reaction mixture was concentrated under reduced pressure to afford ethyl 1-(2-aminoethyl)-5-((4-chlorobenzyl)carbamoyl)-1H-pyrrole-2- carboxylate (0.32 g), which was used for nest step without further purifications. LC-MS: 348.1 [M-l]’.

Step 6. Synthesis of N-(4-chlorobenzyl)-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-6- carboxamide. To a stirred solution of ethyl 1-(2-aminoethyl)-5-((4-chlorobenzyl) carbamoyl)- 1H-pyrrole-2-carboxylate (0.320 g, 0.915 mmol) in dioxane (2 mL) was added saturated solution of Na₂CO₃ ( 10 mL) and stirred at room temperature for 12 h. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography eluting with 0-5% methanol in DCM to afford N-(4-chlorobenzyl)-1-oxo- l,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-6-carboxamide (INT-4) (0.16 g, 55%) as an off-white solid. LC-MS: 304.0 [M+l]⁺.

N-(4-Chlorobenzyl)-2-methyl-7-oxo-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (1NT-5) KM O

Step 1. Synthesis of methyl 4-bromo-5-formyl-1H-pyrrole-2-carboxylate. To a stirred solution of dry DMF (9.1 mL), POCI₃ (9.16 ml, 98 mmol) dropwise at 0 °C. The reaction mixture was stirred at the same temperature for 15 min. Then methyl 4-bromo-1H-pyrrole-2- carboxylate (4 g, 19.61 mmol) in DCE (9.1 mL) was added to the above reaction mixture. The reaction mixture was stirred at 100 °C for 2 h. The reaction mixture was poured into an ice-cold saturated solution of NaCl and extracted with dichloromethane (20 mL x 3). The combined organic layers were washed with water (20 mL x 3), dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford methyl 4-bromo-5-formyl-1H-pyrrole-2- carboxylate (6.0 g, 86%) as yellow solid. LC-MS: 232.0 [M-l]-; ¹H-NMR (400 MHz, DMSO- d₆): δ 9.72 (s, 1H), 7.02 (s, 1H), 3.84 (s, 3H) ppm.

Step 2. Synthesis of 3-bromo-5-(methoxycarbonyl)-1H-pyrrole-2-carboxylic acid. To a stirred solution of methyl 4-bromo-5-formyl-1H-pyrrole-2-carboxylate (6.0 g, 16.81 mold) in acetone (156 mL) at 0 °C was added dropwise a solution of KMnO₄ (5.42 g, 33.6 mol) in acetone (52 mL) and water (52 mL). The reaction mixture was stirred rt for 12 h. The reaction mixture was poured into a saturated solution of Na₂SO₃ (2.0 g), then IM HC1 (22.3 mL) was added dropwise at 0 °C. The resulting mixture was extracted with chloroform (20 mL x 3). The combined organic extracts were washed with water (10 mL) and brine (5.0 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to afford 3-bromo-5- (methoxycarbonyl)-1H-pyrrole-2-carboxylic acid (3.1 g, 65%) as an off-white solid. LC-MS: 247.9 [M-l]-; ¹H-NMR (400 MHz, DMSO-d₆): δ 9.72 (s, 1H), 7.02 (s, 1H), 3.84 (s, 3H) ppm.

Step 3. Synthesis of methyl 4-bromo-5-((4-chlorobenzyl)carbamoyl)-1H-pyrrole-2- carboxylate. To a stirred solution of 3-bromo-5-(methoxycarbonyl)-1H-pyrrole-2-carboxylic acid (2.4 g, 6.48 mmol) in DMF (15 mLl) was added (4-chlorophenyl) methanamine (1.124 g, 7.78 mmol) and HATU (3.77 g, 9.72 mmol) followed by DIPEA (2.165 ml, 12.97 mmol). The reaction mixture was stirred at rt for 2h. After the completion reaction, the reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (70 mL x 2). The combined organic extracts were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography eluting with EA in PE (20 to 30%) to afford methyl 4-bromo-5-((4- chlorobenzyl)carbamoyl)-1H-pyrrole-2-carboxylate (2.0 g, 81%). LC-MS: 373.0 [M-1]⁺; ¹H- NMR (400 MHz, DMSO-d₆): δ 8.67 (t, J = 6.0Hz, 1H), 7.43-7.37 (m, 4H), 6.91 (s, 1H), 4.44 (d, J = 5.6 Hz, 2H), 3.81 (s, 3H) ppm.

Step 4. Synthesis of methyl 4-bromo-1-(2-((tert-butoxycarbonyl)amino)ethyl)-5-((4- chlorobenzyl) carbamoyl)-1H-pyrrole-2-carboxylate. To a stirred solution of methyl 4-bromo- 5-((4-chlorobenzyl)carbamoyl)-1H-pyrrole-2-carboxylate (3.7 g, 9.96 mmol) in DMF (5.0 mL) were added K₂CO₃ (4.13 g, 29.9 mmol) and tert-butyl (2-bromoethyl)carbamate (3.35 g, 14.93 mmol) at rt. The reaction mixture was stirred at 70 °C for 16 h. After the completion of the reaction, the reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (80 ml x 2). The combined organic extracts were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography eluting with EA in PE (10 to 20%) to afford methyl 4-bromo- 1 -(2-((tert-butoxycarbonyl)amino)ethyl)-5-((4-chlorobenzyl)carbamoyl)- 1H-pyrrole-2-carboxylate (2.8 g, 35%) as off-white solid. LC-MS: 373.0 [M-Boc]⁺.

Step 5. Synthesis of methyl 1-(2-aminoethyl)-4-bromo-5-((4-chlorobenzyl)carbamoyl)-1H- pyrrole-2-carboxylate. A solution of methyl 4-bromo- 1-(2-((tert-butoxycarbonyl)amino)ethyl)-

5-((4-chlorobenzyl)carbamoyl)-1H-pyrrole-2-carboxylate (2.8 g, 5.44 mmol) in dioxane (15 mL) and 4N HC1 (13.6 mL, 54.4 mmol) at 0 °C was stirred at rt for 3 hr. After the completion of the reaction, the reaction mixture was concentrated under reduced pressure to afford methyl 1-(2- aminoethyl)-4-bromo-5-((4-chlorobenzyl)carbamoyl)-1H-pyrrole-2-carboxylate HC1 salt (2.8 g, 53% yield) as a yellow oil, which was used for the next step without further purifications. LC- MS: 416.0 [M+l]⁺.

Step 6. Synthesis of 7-bromo-N-(4-chlorobenzyl)-1-oxo-1,2,3,4-tetrahydropyrrolo[l,2- a]pyrazine-6-carboxamide. To a stirred solution of methyl 1-(2-aminoethyl)-4-bromo-5-((4- chlorobenzyl)carbamoyl)-1H-pyrrole-2-carboxylate HC1 salt (2.88 g, 6.38 mmol) in dioxane (20 mL) was added a solution of sodium carbonate (1.353 g, 12.77 mmol) in water (15 mL). The reaction mixture was stirred at 70 °C 12 h. After the completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate (80 ml x 2). The combined organic extracts were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (silica gel, 100-200 mesh size) eluting with EA in PE (10 to 20%) to afford 7- bromo-N-(4-chlorobenzyl)-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-6-carboxamide (1.2 g, 49%) as an off white solid. LC-MS: 382.0 [M-1]⁺; ¹H-NMR (400 MHz, DMSO-d₆): δ 8.74 (t, J = 6.00 Hz, 1H), 8.02 (s, 1H), 7.40 (m, 4H), 6.75 (s, 1H), 4.46 (d, J = 6.00 Hz, 2H), 4.21 (t, J = 6.0 Hz, 2H), 3.52-3.48 (m, 2H) ppm.

Step 7. Synthesis of tert-butyl 7-bromo-6-((tert-butoxycarbonyl)(4- chlorobenzyl)carbamoyl)-1-oxo-3,4-dihydropyrrolo[1,2-a]pyrazine-2(lH)-carboxylate. To a stirred solution of 7-bromo-N-(4-chlorobenzyl)-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-

6-carboxamide (1.2 g, 3.14 mmol) in THF (15 mL) was added DMAP (0.192 g, 1.568 mmol), TEA (1.31 1 ml, 9.41 mmol) and Boc-anhydride (1 .820 ml, 7.84 mmol) at 0 °C. The reaction mixture was heated at 60 °C for 5 h. After completing the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate (30 mL x 2). The combined organic extracts were washed with brine (50 mL), dried over Na₂SO₄. and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (silica gel, 100-200 mesh size) eluting with EA in PE (10 to 20%) to afford tert-butyl-7-bromo-6-((tert-butoxycarbonyl)(4- chlorobenzyl)carbamoyl)-1-oxo-3,4-dihydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate (1.7 g, 78%) as a yellow oil. LC-MS: 526.1 [M-35]⁺; ¹H-NMR (400 MHz, DMSO-d₆): δ 7.40 (d, J= 8.40 Hz, 2H), 7.32 (d, J = 1.60 Hz, 2H), 7.04 (s, 1H), 5.32 (s, 1H), 4.91-4.91 (m, 2H), 4.51-4.48 (m, 1H), 4.12-4.26 (m, 1H), 4.08-4.06 (m, 2H), 1.59 (s, 11H), 1.38-1.26 (m, 11H) ppm

Step 8. Synthesis of tert-butyl 6-((tert-butoxycarbonyl)(4-chlorobenzyl)carbamoyl)-7- methyl-1 -oxo-3, 4-dihydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate. To a stirred solution of tcrt-butyl-7-bromo-6-((tcrt-butoxycarbonyl)(4-chlorobcnzyl)carbamoyl)-1-oxo-3,4- dihydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate (1.2 g, 1.750 mmol) in DMF (10 mL) and degassed with nitrogen for 15 min then added bis(triphenylphosphine)palladium(II) chloride (0.368 g, 0.525 mmol) and tetramethyltin (0.626 g, 3.50 mmol). The reaction mixture was stirred at 100 °C for 16 h. After completing the reaction, the reaction mixture was filtered through celite pad and washed with ethyl acetate (50 mL). The filtrate was diluted with ethyl acetate and washed with water (30 mL) and brine (10 mL). The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (silica gel, 100-200 mesh size) eluting with EA in PE (10 to 20%) to afford tert-butyl 6-((tert-butoxycarbonyl)(4- chlorobenzyl)carbamoyl)-7-methyl-1-oxo-3,4-dihydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate (0.65 g, 61%) as a solid. LC-MS: 461.9 [M-35]⁺; ¹H-NMR (400 MHz, DMSO-d₆): δ 7.46-7.45 (m, 3H), 7.38-7.36 (m, 3H), 6.71 (s, 1H), 4.84 (d, J = 7.20 Hz, 2H), 4.33 (s, 1H), 4.06-3.95 (m, 3H), 1.98 (s, 3H), 1.49 (s, 10H), 1.20 (s, 9H) ppm.

Step 9. Synthesis of N-(4-chlorobenzyl)-7-methyl-1-oxo-1,2,3,4-tetrahydropyrrolo[l,2- a]pyrazine-6-carboxamide. To a stirred solution of tert-butyl 6-((tert-butoxycarbonyl)(4- chlorobenzyl)carbamoyl)-7-methyl-1-oxo-3,4-dihydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate (0.650 g, 1 .255 mmol) in dioxane (10 mL) was added 4N HC1 (3.14 ml, 12.55 mmol). The reaction mixture was stirred for 8 h at rt. After completing the reaction, the reaction mixture was concentrated under reduced pressure to afford to N-(4-chlorobenzyl)-7-methyl-1-oxo-1,2,3,4- tetrahydropyrrolo[1,2-a]pyrazine-6-carboxamide (INT-5) (0.32 g, 54%) as a yellow solid. LC- MS: 318.2 [M+1]⁺; ¹H-NMR (400 MHz, DMSO-d₆): δ 8.43 (t, J = 6.00 Hz, 1H), 8.43 (s, 1H), 7.39-7.34 (m, 6H), 6.49 (s, 1H), 4.44 (d, J = 6.00 Hz, 2H), 4.19 (t, J = 6.00 Hz, 2H), 3.48-3.46

(m, 2H), 2.20 (s, 3H) ppm.

N-(4-Chlorobenzyl)-8-oxo-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-3-carboxamide hydrochloride (INT-6)

Step 8

INT-6

Step 1. Synthesis of ethyl 2-(acetylthio)-2-methylpropanoate. To a stirred solution of ethyl 2- bromo-2-methylpropanoate (17.86 ml, 127 mmol) in acetone (500 mL) was added potassium thioacetate (16.27 g, 140 mmol) at rt and the resulting reaction mixture was allowed to stir at 60 °C for 16 h. The reaction mixture was concentrated. The residue was diluted with water (70 mL) and extracted with DCM (100 mL x 2). The combined organic extract was washed with water (60 mL), dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure to afford ethyl 2-(acetylthio)-2-methylpropanoate (25 g, 84%). LC-MS: 191[M+1]⁺; ¹H- NMR (400 MHz, CDCl₃): δ 4.21 (q, J = 6.80 Hz, 2H), 2.29 (s, 3H), 1.59 (s, 6H), 1.28 (t, J = 7.20 Hz, 3H) ppm.

Step 2: Synthesis of 2-mercapto-2-methylpropan-1-ol. A round bottom flask (1 L, three necks) attached with a condenser and temperature sensor was charged with THF (258mL) under a nitrogen atmosphere, and LAH in THF (38.2 ml, 76 mmol) was added, cooled to 0 °C, and stirred for 10 min. To this reaction mixture, methyl 2-(acetylthio)-2-methylpropanoate (8.3 g, 38.2 mmol) in THF (86 mL) was added dropwise at 0 °C over a period of 10 min. After complete addition, the resulting reaction mixture was stirred at rt for 2 h and then at 60 °C for 17 h. The reaction mixture was cooled to 0 °C, quenched with EtOAc (200 ml), and then 1.5 N aq HC1 (100 mL). The organic layer was filtered through celite and was washed with EtOAc (500 mL). The combined organic extract was washed with water (300 mL), brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford 2- mercapto-2-methylpropan-1-ol (3.4 g, 79%) as a pale-yellow liquid, which was used in the next step without further purifications. ¹H-NMR (400 MHz, CDCI3): δ 3.45 (s, 2H), 2.14 (s, 1H), 1.38 (s, 6H) ppm.

Step 3: Synthesis of tert-butyl 2-((1-hydroxy-2-methylpropan-2-yl)thio)acetate. To a stirred solution of 2-mercapto-2-methylpropan-1-ol (5.0 g, 44.3 mmol) in MeOH (54 mL) was added TEA (7.62 mL, 53.1 mmol) followed by tert-butyl bromoacetate (6.67 mL, 44.3 mmol) dropwise at 0 °C. The resulting reaction mixture was slowly warmed to rt and stirred for 16 h. The reaction mixture was concentrated. The residue was diluted with water (70 mL) and extracted with EtOAc (100 mL x 2). The combined organic extract was washed with brine (60 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford the tertbutyl 2-((1-hydroxy-2-methylpropan-2-yl)thio)acetate (9.1 g, 91%) a colorless oil, which was used in the next step without further purifications. ¹H NMR (400 MHz, CDCI3): δ 3.36 (s, 2H), 3.17 (s, 2H), 1.47 (S, 9H), 1.27 (s, 6H) ppm. Step 4: Synthesis of tert-butyl 2-((1-hydroxy-2-methylpropan-2-yl)sulfonyl)acetate. To a stirred solution of tert-butyl 2-((1-hydroxy-2-methylpropan-2-yl)thio)acetate (6 g, 27.2 mmol) in acetone (60 mL) and water (60 mL) was added Oxone (38.0 g, 59.9 mmol). The resulting reaction mixture was allowed to stir at rt for 12 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with EtOAc (20 mL) and filtered. The filtrate was washed with water (50 mL) and extracted with EtOAc (50 mL x 2). The combined organic extract was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford tert-butyl 2-((1-hydroxy-2-methylpropan-2-yl)sulfonyl)acetate (4.9 g, 71%) as a colorless liquid, which was used in the next step without further purifications. LC-MS: 251.3 [M-1]⁺; ¹H-NMR (400 MHz, CDCl₃ ): δ 4.14 (s, 2H), 3.85 (s, 2H), 1.51 (s, 9H), 1.43 (s, 6H) ppm.

Step 5: Synthesis of tert-butyl 2-((2-methyl-1-((tetrahydro-2H-pyran-2-yl)oxy)propan-2- yl)sulfonyl)acetate. To a stirred solution of tert-butyl 2-((1-hydroxy-2-mcthylpropan-2- yl) sulfonyl) acetate (4.9 g, 19.23 mmol) in DCM (50 mL) was added pyridinium p- toluenesulfonate (0.488 g, 1.923 mmol) followed by pyridinium p-toluenesulfonate (0.488 g, 1.923 mmol) dropwise at 0 °C. The resulting reaction mixture was slowly warmed to rt and stirred for 16 h. The reaction mixture was cooled, diluted with DCM (100 mL), quenched with sat NaHCO₃ solution (30 ml), and extracted with DCM (100 mL x 2). The combined organic extract was washed with water (70 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography eluting with EtOAc in Hexane (25-35%) to afford tert-butyl 2-((2-methyl-1-((tetrahydro-2H- pyran-2-yl)oxy)propan-2-yl)sulfonyl)acetate (6 g, 93%) as a liquid. LC-MS: 354.4 [M+18]⁺; ¹ H- NMR (400 MHz, CDCI3): δ 4.70-4.69 (m, 1H), 4.19-4.10 (m, 2H), 3.94 (d, J = 7.80 Hz, 1H), 3.84-3.81 (m, 1H), 3.61-3.58 (m, 2H), 1.80-1.77 (m, 2H), 1.67-1.65 (m, 4H), 1.54 (s, 9H), 1.52 (s, 3H), 1.52 (s, 3H) ppm.

Step 6: Synthesis of tert-butyl 1-((2-methyl-1-((tetrahydro-2H-pyran-2-yl)oxy)propan-2- yl)sulfonyl)cyclopropane-1-carboxylate. To a stirred solution of tert-butyl 2-((2-methyl-1- ((tetrahydro-2H-pyran-2-yl)oxy)propan-2-yl)sulfonyl)acetate (6.0 g, 17.66 mmol) in DMF (4.4 mL) were added TBAI (0.998 g, 2.65 mmol) and K₂CO₃ (8.71 g, 61.8 mmol) followed by 1,2- dibromoethane (4.34 ml, 35.3 mmol). The resulting reaction mixture was heated at 60 °C for 12 h. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL x 2). The combined organic extract was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (silica gel, 60-100 mesh size) eluting with EtOAc/Hexane (20- 30%) to afford tert-butyl 1-((2-methyl-1-((tetrahydro-2H-pyran-2-yl)oxy)propan-2- yl)sulfonyl)cyclopropane-1-carboxylate (2.7 g, 42%) as a pale oil. LC-MS: 380.2 [M+18]⁺; ¹H NMR (400 MHz, CDCl₃): δ 4.65-4.63 (m, 1H), 3.93-3.83 (m, 2H), 3.64-3.62 (m, 2H), 1.83-1.78 (m, 2H), 1.76-1.74 (m, 2H), 1.65-1.52 (m, 19 H), 1.50-1.47 (m, 2 H) ppm.

Step 7: Synthesis of (1-((2-methyl-1-((tetrahydro-2H-pyran-2-yl)oxy)propan-2- yl)sulfonyl)cyclopropyl)methanol. To a stirred solution of tert-butyl 1-((2-methyl-1- ((tetrahydro-2H-pyran-2-yl)oxy)propan-2-yl)sulfonyl)cyclopropane-1-carboxylate (5.3 g, 14.48 mmol) in THF (50 mL) was added LAH (18.09 ml, 36.2 mmol) at 0 °C and stirred at rt for Ih. The reaction mixture was cooled, quenched with EtOAc (20 mL), sat sodium sulfate (10 mL), and extracted with EtOAc (50mL). The combined organic layers were washed with water (50mL), brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (silica-gel, mesh size) using EtOAc/PE (30-35 %) as an eluent to afford (1-((2-methyl-1-((tetrahydro-2H- pyran-2-yl)oxy)propan-2-yl)sulfonyl)cyclopropyl)methanol (2.6 g,.61%) as a yellow liquid. LC- MS: 310.1 [M+18]⁺; ¹H-NMR (400 MHz, CDCl₃): δ 4.64-4.61 (m, 1H), 3.97-0.93 (m, 3H), 3.90- 3.81 (m, 2H), 3.67-3.53 (m, 1H), 1.79-1.76 (m, 2H), 1.60-1.55 (m, 4H), 1.53-1.51 (m, 3H), 1.50- 1.47 (m, 6H), 1.06-1.04 (m, 2H) ppm.

Step 8: Synthesis of 2-(2-((1-(bromomethyl)cyclopropyl)sulfonyl)-2- methylpropoxy)tetrahydro-2H-pyran. To a stirred solution of (1-((2-methyl-1-((tetrahydro- 2H-pyran-2-yl)oxy)propan-2-yl)sulfonyl)cyclopropyl)methanol (2.7 g, 9.05 mmol) and DPPE (7.36 g, 18.10 mmol)) and IH-imidazole (6.00 g, 86 mmol) in THF ( 25 mL) was added CBr4 (6.12 g, 18.10 mmol) in THF (lOmL) drop wise at 0 °C. The resulting reaction mixture was warmed slowly to rt and the reaction mass was stirred for 12 h at rt. After completion of the reaction. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL x 2). The combined organic layers were washed with brine solution (30 mL), dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The resulting residure was purified by column chromatography on silica gel [100 - 200 mesh, eluting with 0-20% EtOAc in hexane] to afford the 2-(2-((1-(bromomethyl)cyclopropyl)sulfonyl)-2-methylpropoxy)tetrahydro- 2H-pyran (INT-6) (2.1 g, 65%) as a colorless oil. LC-MS: 355.3 [M+18]⁺; ¹HNMR (400 MHz, DMSO-d₆): δ 4.68 - 4.61 (m, 1H), 4.15 - 4.02 (m, 3H), 3.96 - 3.94 (m, 1H), 3.88 - 3.78 (m, 1H), 3.66 - 3.64 (m, 1H), 3.59 - 3.50 (m, 1H), 1.92 - 1.60 (m, 10H), 1.50 (s, 3H), 1.32 - 1.20 (m, 2H) ppm.

1 -(Bromomethyl)- 1-(cyclopropylsulfonyl)cyclopropane (INT-7)

LiBH₄ (2M in THF), CBr₄, DPPE THF, 0 °C-RT, 20 h THF, RT, 2h

Step 3

Step 4

INT-7

Step 1. Synthesis of benzyl 2-(cyclopropylsulfonyl)acetate. To a slurry of sodium cyclopropanesulfinate (5.48 g, 41.9 mmol) in DMF (60 mL) was added benzyl 2-bromoacetate (10 g, 41.9 mmol). The resulting mixture was stirred at 25 °C for 18 h. Then sodium cyclopropanesulfinate (2.74 g, 20.95 mmol) was added and the reaction mixture was stirred at rt for 4 h. Sodium cyclopropancsulfinatc (2.74 g, 20.95 mmol) was then added and continued stirring at rt for 17 h. The reaction mixture was diluted with water and extracted with MTBE (100 mL x 2). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated to afford benzyl 2-(cyclopropylsulfonyl)acetate (11 g, 89%) as a colorless oil. LC-MS: 2.17 min, 86.29 %, 253.1 [M-l]-.

Step 2. Synthesis of_benzyl 1-(cyclopropylsulfonyl)cyclopropane-1-carboxylate. To a solution of benzyl 2-(cyclopropylsulfonyl)acetate (11 g, 37.3 mmol) in DMF (350 mL) was added K₂CO₃ (15.79 g, 112 mmol) and 1 ,2-dibromoethane (4.95 ml, 56.0 mmol), and tetrabutylammonium iodide (0.141 g, 0.373 mmol). The resulting mixture was stirred at 60 °C for 18 h. The solids were removed by filtration. The filtrate was diluted with water and extracted with MTBE (200 mL x 2). The combined organic layers were washed with brine (100 mL), dried over sodium sulfate, filtered, and concentrated to afford benzyl 1- (cyclopropylsulfonyl)cyclopropane-1-carboxylate (7.62 g, 61%).

Step 3. Synthesis of (1-(cyclopropylsulfonyl)cyclopropyl)methanol. To a solution of benzyl 1- (cyclopropylsulfonyl)cyclopropanc-1-carboxylate (7.62 g, 22.59 mmol) in THF (100 mL) was added LiBH4 (11.29 ml, 22.59 mmol). The resulting solution was stirred at 25 °C for 20 h. The reaction mixture was cooled to 0 °C and quenched with 1.5N HC1. The resulting solution was extracted with DCM (100 mL x 3). The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The resulting residue was purified by column chromatography (50% EA in PE). LC-MS: 177.1 [M+l]⁺.

Step 4. Synthesis of 1-(bromomethyl)-1-(cyclopropylsulfonyl)cyclopropane. A solution of (1- (cyclopropylsulfonyl)cyclopropyl)methanol (2 g, 11.31 mmol) and dppe (3.22 g, 7.92 mmol) in THF (20 mL) and was added a solution of CBr₄ (7.66 g, 22.62 mmol) in THF (4 mL) dropwise at 0 °C. The reaction mixture was stirred at rt for 1 h. The solid was removed by filtration. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography (20% EA in PE) to afford 1-(bromomethyl)-1- (cyclopropylsulfonyl)cyclopropanc (INT-7). LC-MS: 239.1 [M+l]⁺.

1 -(Bromomethyl)- 1-(tert-butylsulfonyl) cyclopropane (INT-8)

INT-8

Step 1. Synthesis of methyl 2-(tert-butylthio)acetate. To a stirred solution of 2- methylpropane-2-thiol (6.25 ml, 55.4 mmol) in DMF (40 mL) was added K₂CO₃ (15.32 g, 111 mmol) and methyl 2-bromoacetate (6.36 ml, 66.5 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with ice-cold water (50 mL) and extracted with EtOAc (50 mL x 2). The combined organic extracts were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (silica gel, 230- 400) eluting with EA in PE (0 to 20%) to afford methyl 2-(tert-butylthio) acetate (3.5 g, 56%) as a colorless oil. ¹H-NMR (400 MHz, CDCl)₃: 400 MHz, DMSO-d6: δ 3.76 (s, 3H), 3.33 (s, 2H), 1.36 (s, 9H) ppm.

Step 2. Synthesis of methyl 2-(tert-butylsulfonyl)acetate. To a stirred solution of methyl 2- (tert-butylthio) acetate (1.0 g, 6.16 mmol) in CH₂CI₂ (30 mL) was added mCPBA (2.340 g, 13.56 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 16 h. After completion of the reaction, the reaction mixture was quenched with saturated NaHCO₃ and extracted with DCM (30 mL x 2). The combined organic layers were washed with brine solution (20 mL) and water (20 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated in vacuo to afford methyl 2-(tert-butylsulfonyl)acetate (1.2 g, 84%) as colorless oil. ¹H-NMR (400 MHz, CDCI₃): δ 4.00 (s, 2H), 3.83 (s, 3H), 1.49 (s, 9H) ppm.

Step 3. Synthesis of methyl 1-(tert-butylsulfonyl)cyclopropane-1-carboxylate. To a solution of methyl 2-(tert-butylsulfonyl)acetate (1.1 g, 5.66 mmol) in DMF (10 mL) was added K₂CO₃ (2.348 g, 16.99 mmol) and 1 ,2-dibromoethane (0.735 ml, 8.49 mmol) and tetrabutylammonium iodide (0.021 g, 0.057 mmol). The resulting mixture was stirred at 60 °C for 12 h. The solid was removed by filtration. The filtrate was diluted with water and extracted with EtOAc (30 mL x 3). The combined organic extracts were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (silica gel, 230-400 size) eluting with EA in PE (0 to 60%) to afford methyl 1-(tert-butylsulfonyl)cyclopropane-1-carboxylate (2 g, 89%) as a yellow oil. ¹H- NMR (400 MHz, CDCl₃): δ 3.80 (s, 3H), 1.83 (t, J = 7.2 Hz, 2H), 1.66 (t, J = 5.6 Hz, 2H), 1.48 (s, 9H) ppm. Step 4. Synthesis of (1-(tert-butylsulfonyl) cyclopropyl)methanol. To a solution of methyl 1- (tert-butylsulfonyl)cyclopropane- 1 -carboxylate (2.0 g, 9.08 mmol) in THF (30 mL) was added LiBH4 (4.99 ml, 9.99 mmol) at 0 °C. The resulting solution was stirred at RT for 16 h. The reaction was cooled to 0 °C and quenched with 1.5 N HC1. The resulting solution was extracted with EtOAc (30 ml x 2). The combined organic extracts were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (silica gel, 230-400 size) using EtOAc- Pet Ether (0 to 40%) as an eluent to afford (1-(tert-butylsulfonyl) cyclopropyl)methanol (1.2 g, 60%) as an off-white solid. ¹H-NMR (400 MHz, CDCl₃): δ 3.90 (s, 2H), 2.91 (br s, 1H), 1.59 (t, J = 2.0 Hz, 2H), 1.53 (s, 9H), 1.08 (t, J = 2.0 Hz, 2H) ppm.

Step 5. Synthesis of 1-(bromomethyl)-1-(tert-butylsulfonyl)cyclopropane. To a stirred solution of (1-(tert-butylsulfonyl) cyclopropyl)methanol (1.2 g, 4.10 mmol) in THF (5 mL) was added CBr₄ (2.7 g, 8.21 mmol) in THF (5.00 mL) dropwise at 0 °C followed by DPPE (2.4 g, 6.16 mmol). The resulting reaction mixture was stirred at rt for 1 h and filtered through a celite pad to remove the solid. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography (ELSD) using 5% EA in PE as an eluent to afford 1-(bromomethyl)-1-(tert-butylsulfonyl) cyclopropane (INT-8) (0.55 g, 45%) as an off- white solid. ¹H-NMR (400 MHz, CDCl₃): δ 4.02 (s, 2H), 1.82 -1.79 (m, 2H), 1.54 (s, 9H), 1.30 - 1.27 (m, 2H) ppm. 1-(Bromomethyl)-1-((2-methylbut-3-en-2-yl)sulfonyl)cyclopropane (INT-9)

LDA (2.0 M in THF) CBr₄, DPPE,

HCHO, THF, -70 °C, 2h THF, 0 °C-RT, 2h

Step 3

Step 4

lnt-9 Step 1. Synthesis of (allylsulfonyl)cyclopropane. To a stirred solution of sodium cyclopropanesulfinate (10.01 g, 78 mmol) and tetrabutylammonium bromide (1.199 g, 3.72 mmol) in water (60 mL) was added 3 -bromoprop- 1-ene (6.42 ml, 74.4 mmol). The reaction mixture was stirred at rt for 24h. The reaction mixture was diluted with water (10 mL) and extracted with EtOA_c (30 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford (allylsulfonyl)cyclopropane as a yellow oil, which was used for next step without further purifications. ¹H-NMR (400 MHz, DMSO-d₆): δ 6.03-5.95 (m, 1H), 5.52-5.47 (m, 2H), 3.78 (d, J = 0.80 Hz, 2H), 2.46-2.41 (m, 1H), 1.29-1.25 (m, 2H), 1.08-1.03 (m, 2H) ppm.

Step 2. Synthesis of ((2-methylbut-3-en-2-yl)sulfonyl)cyclopropane. To a stirred solution of(allylsulfonyl)cyclopropane (8.6 g, 58.8 mmol) in THF (60 mL) was added LiHMDS (132 ml, 132 mmol) slowly at -78 °C. The reaction mixture was stirred at the same temperature for 25 min. To this was added iodomethane (8.06 ml, 129 mmol) and stirred at -78 °C for 2 h. The reaction mixture was quenched with sat NH4CI (50 mL) and extracted with EtOAc (120 mL x 2). The combined organic extracts were washed with brine (120 mL), dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure to afford ((2-methylbut-3-en-2- yl)sulfonyl) cyclopropane as a brown oil, which was used for next step without further purifications. ¹H-NMR (400 MHz, DMSO-d₆): δ 6.20-6.13 (m, 1H), 5.42 (d, J = 1.60 Hz, 2H), 2.39-0.36 (m, 1H), 0.59 (s, 6H), 1.28-0.19 (m, 2H), 1.04-1.00 (m, 2H) ppm.

Step 3. Synthesis of (1-((2-methylbut-3-en-2-yl)sulfonyl)cyclopropyl)methanol. To a stirred solution of((2-methylbut-3-en-2-yl)sulfonyl)cyclopropane (10 g, 57.4 mmol) in THF (100 mL) was added LDA (57.4 mL, 115 mmol) slowly at -78 °C and reaction mixture was stirred at the same temperature for 45 min. To this was added paraformaldehyde (8.62 g, 287 mmol) and stirred at -78 °C for 20 min. The reaction mixture was stirred at rt for 45 min. The reaction mixture was quenched with saturated NH4CI (150 mL) and extracted with EtOAc (100 mL x 3). The combined organic extracts were washed with brine (80 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (silica gel, 230-400 size) eluting with EA in PE (0 to 60%) to afford (1 -((2-methylbut-3-en-2-yl)sulfonyl) cyclopropyl)methanol (5g, 43%) as a colourless oil. ¹H-NMR (400 MHz, DMSO-d₆): δ 6.31 (q, J = 10.40 Hz, 1H), 5.45-5.41 (m, 2H), 3.83 (m, 2H), 1.58 (s, 6H), 1.57-1.55 (m, 2H), 1.33-1.26 (m, 1H), 1.06 (t, J = 0.80 Hz, 2H) ppm.

Step 4. Synthesis of 1-(bromomethyl)-1-((2-methylbut-3-en-2-yl)sulfonyl)cyclopropane. To a stirred solution of (1-((2-methylbut-3-en-2-yl)sulfonyl)cyclopropyl)methanol (3.5 g, 17.12 mmol) and dppe (10.44 g, 25.7 mmol) in THF (30 mL) was added dropwise CBr4 (11.59 g, 34.2 mmol) in THF (10 mL) at 0 °C. The reaction mixture was stirred at rt for 2 h and then diluted with ethyl acetate and filtered through the celite pad. The filtrate was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (100-200, mesh size) using EtOAc in Petroleum ether as an eluent to afford 1 -(bromo methyl)- 1-((2-methylbut-3 - en-2-yl)sulfonyl)cyclopropane (INT-9) (3.0 g, 57%) as a brown oil. ¹H-NMR (400 MHz, DMSO-d₆): δ 6.32-6.25 (m, 1H), 5.47-5.41 (m, 2H), 3.96 (s, 2H), 1.71-1.68 (m, 2H), 1.58 (s, 6H), 1.26-1.23 (m, 2H) ppm.

1 -(Bromomethyl)- 1 -(( 1 -(fluoromethyl)cyclopropyl)sulfonyl) cyclopropane (INT- 10)

Pd/C, AcOH, DPP MeOH, RT, 36 h THF, 0 °C

Step 10 Step

INT-10

Step 1. Synthesis of butyl 1-((benzyloxy)methyl)cyclopropane-1-sulfonate. To a stirred solution of butyl cyclopropanesulfonate (10 g, 56.1 mmol) in THF (150 mL) was added nBuLi (24.04 ml, 67.3 mmol) slowly at - 78 °C. Then the reaction mixture was stirred for 15 min. To this was added ((chloromethoxy)methyl)benzene (10.54 g, 67.3 mmol) at - 78 °C. The reaction mixture was stirred at rt for 16 h and quenched with saturated NH4CI solution (100 mL) and extracted with ethyl acetate (200 mL x 2). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (silica gel, 230-400 size) using EA in PE (0 to 20%) as an eluent to afford butyl 1-((benzyloxy)methyl)cyclopropane- 1-sulfonate (13.7 g, 77%) as a colorless oil. LC-MS: 316.3 [M-1]⁺; ¹H-NMR (400 MHz, DMSO-d₆): δ 7.39-7.28 (m, 5H), 4.57 (s, 2H), 4.25 (t, J = 6.40 Hz, 2H), 3.82 (s, 2H), 1.70-1.65 (m, 2H), 1.58-1.50 (m, 2H), 1.42-1.37 (m, 2H), 1.14-1.11 (m, 2H), 0.94 (t, J = 30.80 Hz, 3H) ppm.

Step 2. Synthesis of 1-((benzyloxy)methyl)cyclopropane-1-sulfonic acid. To a stirred solution of butyl 1-((benzyloxy)methyl)cyclopropane-1-sulfonate (13.7 g, 45.9 mmol) in DME (120 mL) and water (120 mL) was added potassium thiocyanate (4.77 g, 49.1 mmol) at rt slowly. The reaction mixture was stirred at 95 °C for 16 h. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (30 mL). The aqueous layer was concentrated under reduced pressure to afford 1-((benzyloxy)methyl)cyclopropane-1-sulfonic acid (10 g, 90%) as an off- white solid. LC-MS: 241.1 [M-1]-; ¹H-NMR (400 MHz, DMSO-d₆): δ 7.37-7.27 (m, 5H), 4.48 (s, 2H), 3.75 (s, 2H), 0.83-0.81 (m, 2H), 0.62-0.61 (m, 2H) ppm.

Step 3. Synthesis of 1-((benzyloxy)methyl)cyclopropane-1-sulfonyl chloride. To a stirred suspension of 1-((benzyloxy)methyl)cyclopropane-1-sulfonic acid (12 g, 41.0 mmol) in SOCI₂ (89 mL, 1.23 mol) was added DMF (10.0 mL) slowly at 0 °C. Then the reaction mixture was stirred at 75 °C for 45 min. The reaction mixture was diluted with ethyl acetate (150 mL) and washed with brine (50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford 1-((benzyloxy)methyl)cyclopropane-1- sulfonyl chloride as a brown crude oil, which was used for the next step without further purification. ¹H-NMR (400 MHz, DMSO-d₆): δ 7.41-7.28 (m, 5H), 4.64 (s, 2H), 4.03 (s, 2H), 4.03 (t, J = 5.20 Hz, 2H), 1.43 (t, J= 5.20 Hz, 2H) ppm. Step 4. Synthesis of sodium 1-((benzyloxy)methyl)cyclopropane-1-sulfinate. To a stirred solution of sodium sulfite (4.83 g, 38.4 mmol) in water (70 mL) was added sodium bicarbonate (6.44 g, 77 mmol) slowly at rt. The reaction mixture was heated at 50 °C for 45 min. To the above reaction mixture was added 1-((benzyloxy)methyl)cyclopropane-1- sulfonyl chloride (10 g, 38.4 mmol). The reaction mixture was heated at 50 °C for 18 h. The reaction mixture was concentrated under reduced pressure. The residue was triturated with MeOH to afford sodium 1- ((benzyloxy)methyl)cyclopropane-1-sulfinate (7 g, 66%), which was used for the next step without further purification. ¹H-NMR (400 MHz, DMSO-d₆): δ 7.35-7.26 (m, 5H), 4.50 (s, 2H), 3.66 (s, 2H), 0.76-0.68 (m, 2H), 0.30-0.29 (m, 2H) ppm.

Step 5. Synthesis of ethyl 2-((1-((benzyloxy)methyl)cyclopropyl)sulfonyl)acetate. To a stirred solution of sodium 1-((benzyloxy)methyl)cyclopropane-1-sulfinate (4.6 g, 18.53 mmol) in DMF (40 mL) under a nitrogen atmosphere was added ethyl 2-bromoacetate (1.79 ml, 16.18 mmol) slowly at rt. The reaction mixture was stirred at rt for 16 h. The reaction mixture was diluted with MTBE (50 ML), filtered through celite pad, and washed with MTBE. The filtrate was washed with brine (20 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford ethyl 2-((1- ((benzyloxy)methyl)cyclopropyl)sulfonyl)acetate (4.52 g, 70%) as a brown oil. which was used for the next step without further purification. ¹H-NMR (400 MHz, DMSO-d₆): δ 7.41-7.28 (m, 5H), 4.60 (s, 2H), 4.31 (s, 2H), 4.27 (q, J = 5.20 Hz, 3H), 3.81 (s, 2H), 1.62-0.00 (m, 2H), 1.05- 0.00 (m, 2H) ppm.

Step 6. Synthesis of ethyl 1-((1-((benzyloxy)methyl)cyclopropyl)sulfonyl)cyclopropane-1- carboxylate. To a stirred solution of ethyl 2-((1- ((benzyloxy)methyl)cyclopropyl)sulfonyl)acetate (4.5 g, 14.41 mmol) in DMF (40 mL) were added K₂CO₃ (3.98 g, 28.8 mmol), 1 ,2-dibromoethane (1.497 mL, 17.29 mmol) and TBAI (0.532 g, 1.441 mmol) at rt . The resulting reaction mixture was stirred at 60 °C for 16 h. The reaction mixture was cooled to RT, diluted with MTBE ( 50 mL), and filtered through a celite pad. The solid was washed with MTBE. The filtrate was washed with water (30 mL), brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue! was purified by flash column chromatography (silica gel, 230-400 size) using EA in PE (20-30%) as an eluent to afford ethyl 1- ((l((benzyloxy)methyl)cyclopropyl)sulfonyl)cyclopropane-1-carboxylate (2.5 g, 51%) as a yellow oil. ¹H-NMR (400 MHz, DMSO-d₆): δ 4.50 (s, 2H), 4.16 (q, J = 7.20 Hz, 2H), 3.74 (s, 2H), 1.85-1.83 (m, 2H), 1.82-1.82 (m, 2H), 1.77-1.76 (m, 2H), 1.25 (t, 7 - 7.20 Hz, 3H), 1.11- 1.07 (m, 2H) ppm.

Step 7. Synthesis of (1-((1-((benzyloxy)methyl)cyclopropyl)sulfonyl)cyclopropyl)methanol.

To a stirred solution of ethyl 1-((1-((benzyloxy)methyl)cyclopropyl)sulfonyl)cyclopropane-1- carboxylate (2.5 g, 7.39 mmol) in THE (25 mL) under nitrogen atmosphere was added LiBH4 (2M in THF) (4.06 mL, 8.13 mmol) slowly at 0 °C . The resulting solution was stirred at rt for 48 h. The reaction was cooled to 0 °C and quenched with 1.5 N HC1. The resulting solution was extracted with EtOAc (30 mL x 2). The combined organic extracts were washed with brine (50 mL), dried over anhydrous sodium sulfate, and filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography eluting with 30-40% EA in PE to afford (1-((1-((benzyloxy)methyl)cyclopropyl)sulfonyl)cyclopropyl)methanol (1.42 g, 65%) as a colorless solid. LC-MS: 297.0 [M-1]⁺; ¹H-NMR (400 MHz, DMSO-d₆): δ 7.42-7.32 (m, 5H), 4.57 (s, 2H), 3.85 (s, 2H), 3.77 (d, 7 = 3.60 Hz, 2H), 3.49 (t, 7 = 2.00 Hz, 1H), 1.67 (t, 7 = 5.20 Hz, 2H), 1.54 (t, 7 = 4.80 Hz, 2H), 1.12-1.08 (m, 2H), 1.01 (t, 7 = 0.80 Hz, 2H) ppm.

Step 8. Synthesis of (1-((1-((benzyloxy)methyl)cyclopropyl)sulfonyl)cyclopropyl)methyl methanesulfonate. To a stirred solution of (1-((1-

((benzyloxy)methyl)cyclopropyl)sulfonyl)cyclopropyl)methanol (500 mg, 1.687 mmol) in DCM (4 mL) under nitrogen atmosphere were added TEA (0.461 mL, 3.37 mmol) and mesyl-Cl (0.16 mL, 2.067 mmol) at 0 °C. Then the reaction mixture was stirred at rt for 3 h. The reaction mixture was diluted with cold water (20 mL) and extracted with DCM (15 mL x 2). The organic layer was washed with 1.5 N HC1 (15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford (1-((1-((benzyloxy)methyl)cyclopropyl) sulfonyl)cyclopropyl)methyl methanesulfonate as a colorless oil. which was used for the next step without further purification. ¹ H-NMR (400 MHz, DMSO-d₆): δ 7.39-7.28 (m, 5H), 4.56 (s, 2H), 4.53 (s, 2H), 3.78 (s, 2H), 3.03 (s, 3H), 1.68-1.57 (m, 4H), 1.12-1.06 (m, 4H) ppm.

Step 9. Synthesis of (((1-((1- (fluoromethyl)cyclopropyl)sulfonyl)cyclopropyl)methoxy)methyl)benzene. To a stirred solution of (1-((1-((benzyloxy)methyl)cyclopropyl)sulfonyl)cyclopropyl)methyl mcthancsulfonatc (650 mg, 1.736 mmol) in THF (5 mL) was added TBAF (IM in THF) (8.68 mL, 8.68 mmol) at rt. Then the reaction mixture was stirred at 70 °C for 15h. The reaction mixture cooled to rt, diluted with cold water (20 mL), and extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with brine (15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography eluting with 20-30% EA in PE to afford (((1-((1- (fluoromethyl)cyclopropyl)sulfonyl)cyclopropyl)methoxy) methyl)benzene (390 mg, 75%) as a colorless gummy solid. LC-MS: 299.0 [M-1]⁺; ¹H-NMR (400 MHz, DMSO-d₆): δ 7.40-7.36 (m, 5H), 4.67 (d, 7 = 48.80 Hz, 2H), 4.55 (s, 2H), 3.80 (s, 2H), 1.65-1.58 (m, 4H), 1.14-1.11 (m, 4H) ppm.

Step 10. Synthesis of (1-((1-(fhioromethyl)cyclopropyl)sulfonyl)cyclopropyl)methanol. In a tiny clave, a solution of (((1-((1-(fluoromethyl)cyclopropyl)sulfonyl)cyclopropyl) methoxy)methyl)benzene (350 mg, 1.173 mmol) was dissolved in MeOH (15 mL) and degassed with nitrogen gas for a 5 min. 10% Pd/C (250 mg, 0.234 mmol) was added to the above reaction mixture. The reaction mixture was stirred under a hydrogen gas atmosphere using 5 Kg pressure at rt for 36 h. After completing the reaction, the reaction mixture was filtered through the Celite pad and washed with methanol (150 mL). The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography eluting with 20-30% EA in PE to afford (1-((1-(fhroromethyl)cyclopropyl)sulfonyl)cyclopropyl)methanol (220 mg, 68%) as a colorless solid. ¹H-NMR (400 MHz, DMSO-d₆): δ 4.67 (d, 7 = 48.80 Hz, 2H), 3.91 (m, 2H), 1.64-1.59 (m, 4H), 1.22-1.20 (m, 4H) ppm. Step 11. Synthesis of 1-(bromomethyl)-1-((1- (fluoromethyl)cyclopropyl)sulfonyl)cyclopropane. To a stirred solution of

(fluoromethyl)cyclopropyl)sulfonyl)cyclopropyl)methanol (220 mg, 1.056 mmol) in THF (6 mL) were added DPPF (644 mg, 1.585 mmol) and a solution of CBr4 (715 mg, 2.113 mmol) in THF (1.5 mL) slowly at 0 °C. The reaction mixture was stirred at rt for 1 h and filtered through the celite pad. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography eluting with 10% EA in PE to afford 1-(bromomethyl)-1- ((1-(fluoromethyl)cyclopropyl)sulfonyl)cyclopropane (Int-10) (200 mg, 56%) as a colorless solid. ¹H-NMR (400 MHz, DMSO-d₆): δ 4.68 (d, J- 48.80 Hz, 2H), 3.89 (s, 2H), 1.81-1.72 (m, 4H), 1.32-1.24 (m, 4H) ppm.

(2-((1-(Bromomethyl)cyclopropyl)sulfonyl) propan-2-yl)benzene (INT-11)

Step 1. Synthesis of ethyl 2-((2-phenylpropan-2-yl)thio)acetate. To a stirred solution of 2- phenylpropan-2-ol (2.0 g, 14.68 mmol) in DCM (20 mL) was added BF₃OEt₂ (2.047 ml, 16.15 mmol) at -70 °C and stirred for 20 minutes. Then added ethyl 2-mercaptoacetate (1.941 g, 16.15 mmol) to the reaction mixture. The reaction mixture was stirred at rt for 1 h. The reaction mixture was diluted with MTBE (25 mL) and washed with water (20 mL x 2). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography to afford pure ethyl 2-((2-phenylpropan-2- yl)thio)acetate (2.7 g, 77%) as a colorless oil. GCMS: 238.0 [M-1]⁺; ¹H-NMR (400 MHz, DMSO-d₆): δ 7.51 (d, J= 1.2 Hz, 2H), 7.35 (t, J = 2.0 Hz. 2H), 7.26-7.22 (m, 1H), 3.94 (dd, J = 7.2, 14.2 Hz, 2H), 3.06 (s, 2H), 1.66 (s, 6H), 1.19 (t, J = 2.4 Hz, 3H) ppm.

Step 2. Synthsis of ethyl 2-((2-phenylpropan-2-yl)sulfonyl)acetate. To a stirred solution of ethyl 2-((2-phenylpropan-2-yl)thio)acetate (1.0 g, 4.20 mmol) in a mixture of methanol (10 mL) and water (3.0 mL) was added oxone (5.16 g, 8.39 mmol). The reaction mixture was stirred at rt for 12 h. The reaction mixture was filtered through celite pad. The filtrate was extracted with DCM (10 mL x 2). The combined organic layers were washed with water, brine, dried over sodium sulfate, filtered, and concentrated in vacuo to afford ethyl 2-((2-phenylpropan-2- yl) sulfonyl) acetate, which was used for the next step without further purifications. ¹H-NMR (400 MHz, DMSO-d₆): δ 7.64-7.61 (m, 2H), 7.44-7.41 (m, 3H), 4.08 (dd, J = 14.0, 7.2 Hz, 2H), 3.99 (s, 2H), 1.80 (s, 6H), 1.16 (t, J = 6.8 Hz, 3H) ppm.

Step 3. Synthesis of ethyl 1-((2-phenylpropan-2-yl)sulfonyl)cyclopropane-1-carboxylate. To a solution of ethyl 2-((2-phenylpropan-2-yl)sulfonyl)acetate (1.1 g, 4.07 mmol) in DMF (15 mL) was added K₂CO₃ (1.125 g, 8.14 mmol), 1,2-dibromoethane (0.352 mL, 4.07 mmol) and TBAI (0.150 g, 0.407 mmol). The resulting mixture was heated to 60 °C for 12 h. The solid obtained was filtered off. The filtrate was diluted with water and extracted with MTBE (30 mL x 3). The combined organic layers were washed with water, brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (silica gel, 230-400 size) using EA in PE (0 to 60%) as an eluent to afford ethyl l -((2-phenylpropan-2-yl)sulfonyl)cyclopropane-1-carboxylate (0.7 g, 58%) as yellow oil. ¹ H-NMR (400 MHz, DMSO-d₆): δ 7.59-7.57 (m, 2H), 7.43-7.39 (m, 3H), 3.97-3.91 (m, 2H), 1.83 (s, 6H), 1.42-1.35 (m, 2H), 1.34-1.32 (m, 2H), 1.23-1.12 (m, 3H) ppm.

Step 4. Synthesis of (1-((2-phenylpropan-2-yl)sulfonyl)cyclopropyl)methanol. To a solution of ethyl 1-((2-phenylpropan-2-yl)sulfonyl)cyclopropane-1-carboxylate (700 mg, 2.362 mmol) in THF (10 mL) was added LiBH4 (1.299 mL, 2.60 mmol) at 0-5 °C. The resulting mixture was stirred at rt for 8 h. The reaction mixture was cooled to 0-5 °C and quenched with 1.5 N HC1. The resulting solution was extracted with EtOAc (30 mL x 2). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by Isolera column chromatography eluting with 30-40% EA in PE to afford (1-((2-phenylpropan-2- yl)sulfonyl)cyclopropyl)methanol (400 mg, 67%) as a colorless solid. ¹H-NMR (400 MHz, DMSO-d₆): δ 7.66-7.61 (m, 2H), 7.43-7.37 (m, 3H), 5.04 (t, J - 8.4 Hz, 1H), 3.45 (d, J - 8.0 Hz, 2H), 1.82 (s, 6H), 0.90 (s, 4H) ppm.

Step 5. Synthesis of (2-((1-(bromomethyl)cyclopropyl)sulfonyl)propan-2-yl)benzene. To a stirred solution of (1-((2-phenylpropan-2-yl)sulfonyl)cyclopropyl)methanol (400 mg, 1.573 mmol) and DPPF (959 mg, 2.359 mmol) in THF (lOmL) was added a solution of CBr4 (1064 mg, 3.15 mmol) in THF (2 mL) at 0 °C. Then the reaction mixture was stirred at rt for 1 h. The reaction mixture was filtered through celite pad. The filtrate was concentrated under reduced pressure. The resulting residue was purified by Isolera column chromatography eluting with 10% EA in PE to afford (2-((1-(bromomethyl)cyclopropyl)sulfonyl) propan-2-yl)benzene (INT 11) (450 mg, 90%) as a white solid. ¹H-NMR (400 MHz, DMSO-d₆): δ 7.73-7.69 (m, 2H), 7.46-7.43 (m, 3H), 3.34 (d, J = 6.80 Hz, 2H), 1.78 (s, 6H), 1.35-1.32 (m, 2H), 1.10-1.07 (m, 2H) ppm.

(2-((1-(Bromomethyl)cyclopropyl)sulfonyl) propan-2-yl)benzene (INT-12)

OH 8 h

INT-12

Step 1. Synthesis of 3-((1-((benzyloxy)methyl)cyclopropyl)sulfonyl)oxetane. In a 50 mL seal tube, a stirred solution of sodium 1-((benzyloxy)methyl)cyclopropane-1-sulfinate (3 g, 12.08 mmol) in DMF (10 mL) was added 3-iodooxetane (8.89 g, 48.3 mmol). The reaction mixture was stirred at 50 °C for 48 h. The reaction mixture was diluted with MTBE (50 mL), filtered through a celite pad, washed with MTBE. The filtrate was washed with brine (20 ml x 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford 3-((1-((benzyloxy)methyl)cyclopropyl)sulfonyl)oxetane (2.2 g, 65%) as a brown oil, which was used for the next step without further purifications. ¹ H-NMR (400 MHz, CDCl₃): δ 7.42-7.30 (m, 5H), 5.06-4.98 (m, 2H), 4.76-4.67 (m, 3H), 4.49 (s, 2H), 3.69 (s, 2H), 1.53 (t, J = 4.80 Hz, 2H), 0.98 (t, J = 0.80 Hz, 2H) ppm.

Step 2. Synthesis of ethyl 3-((1-((benzyloxy)methyl)cyclopropyl)sulfonyl)oxetane-3- earboxylate. To a stirred solution of 3-((1-((benzyloxy)methyl)cyclopropyl)sulfonyl)oxetane (2.6 g, 9.21 mmol) in THF (30 mL) under nitrogen atmosphere was added LiHMDS (18.42 mL, 18.42 mmol) slowly at -78 °C and stirred it for 30 mins. To this was added ethyl carbonochloridate (4.38 mL, 46.0 mmol) at -78 °C. The reaction mixture was stirred at rt for 3 h. The reaction was quenched with saturated NH4CI solution (30 mL) and extracted with EtOAc (100 mL x 2). The combined organic extracts were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by Isolera column chromatography eluting with 20% EA in PE to afford ethyl 3-((1-((benzyloxy)methyl) cyclopropyl)sulfonyl)oxetane-3-carboxylate (2.61 g, 79%) as a colorless solid. LC-MS: 354.9 [M-1]⁺; ¹H-NMR (400 MHz, CDCl₃): δ 7.40-7.28 (m, 5H), 5.20 (d, 7 = 7.60 Hz, 2H), 4.89 (d, 7 = 8.00 Hz, 2H), 4.49 (s, 2H), 4.31 (q, 7 = 7.20 Hz, 2H), 3.67 (s, 2H), 1.33 (t, 7 = 10.40 Hz, 3H), 1.28 (t, 7 = 6.00 Hz, 2H), 1.03 (t, 7 = 5.20 Hz, 2H) ppm.

Step 3. Synthesis of 2-((1-((benzyloxy)methyl)cyclopropyl)sulfonyl)-2-methylpropane-l,3- diol. To a stirred solution of lithium aluminum hydride (2M in THF) (5.64 mL, 11.29 mmol) was added ethyl 3-((1-((benzyloxy)methyl)cyclopropyl)sulfonyl)oxetane-3-carboxylate (1 g, 2.82 mmol) in THF (20 mL); and the reaction mixture was stirred at rt for 12 h. The reaction mixture was cooled to 0 °C and quenched with 1 .5 N HC1 to pH ~ 1 to 2 and extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with brine (15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by Isolera column chromatography eluting with 40-50% EA in PE to afford 2-((1-((benzyloxy)methyl)cyclopropyl) sulfonyl)-2-methylpropane- 1,3 -diol (450 mg, 43%) as a colorless g solid. ¹H-NMR (400 MHz, CD₃OD): δ 7.38-7.30 (m, 5H), 4.55 (s, 2H), 4.00 (d, 7 = 12.00 Hz, 2H), 3.91-3.87 (m, 4H), 1.58-1.55 (m, 2H), 1.41 (s, 3H), 1.14-1.13 (m, 2H) ppm.

Step 4. Synthesis of (((1-((1, 3-dimethoxy-2-methylpropan-2- yl)sulfonyl)cyclopropyl)methoxy )methyl)benzene. To a stirred solution of 2-((1- ((benzyloxy)methyl)cyclopropyl)sulfonyl)-2-methylpropane-l,3-diol (200 mg, 0.636 mmol) in THF (5 mL) were added Mel (0.060 mL, 0.954 mmol) and cesium carbonate (207 mg, 0.636 mmol). Then the reaction mixture was stirred at rt for 18 h. After completion, the reaction mixture was diluted with cold water (20 mL) and extracted with ethyl acetate (25 mL x 2). The combined organic layers were washed with brine (15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by Isolera column chromatography eluting with 20-50% EA in PE to afford (((1-((l,3-dimethoxy-2-methylpropan-2- yl)sulfonyl)cyclopropyl)methoxy)methyl)benzene (150 mg, 69%) as a colorless solid. LC-MS: 343.1 [M+H]⁺; ¹H-NMR (400 MHz, CDCI3): δ7.38-7.32 (m, 5H), 4.54 (s, 2H), 3.87 (s, 2H), 3.79 (d, J = 9.60 Hz, 2H), 3.66 (d, J = 10.00 Hz, 2H), 3.34 (s, 6H), 1.62-1.59 (m, 2H), 1.45 (s, 3H), 1.11-1.10 (m, 2H) ppm.

Step 5. Synthesis of (1-((l,3-dimethoxy-2-methylpropan-2- yl)sulfonyl)cyclopropyl)methanol. In an 25 mL tiny clave glass, a solution of ((( 1-(( 1 ,3- dimethoxy-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methoxy)methyl)benzene (81 mg, 0.237 mmol) and acetic acid (0.068 mL, 1.183 mmol) were dissolved in MeOH (5 mL). To this reaction mixture, 10% Pd/C (76 mg, 0.071 mmol) was added under a nitrogen atmosphere. The reaction mixture was stirred under Hydrogen gas 5 kg atmosphere at rt for 18 h. The reaction mixture was filtered through the Celite pad and washed with methanol (50 mL). The filtrate was evaporated under reduced pressure. The resulting residue was purified by Isolera column chromatography eluting with 50-60% EA in PE to afford (1 -((1 ,3-dimethoxy-2-methylpropan-2- yl)sulfonyl) cyclopropyl)mcthanol (70 mg, 94%) as a colorless solid. ¹H-NMR (400 MHz, CDCl₃): δ 3.79 (s, 2H), 3.70-3.66 (m, 2H), 3.60-3.56 (m, 2H), 3.27 (s, 6H), 1.32 (s, 3H), 1.28- 1.24 (m, 2H), 1.08-1.04 (m, 2H) ppm.

Step 6. Synthesis of 1-(bromomethyl)-1-((l,3-dimethoxy-2-methylpropan-2- yl)sulfonyl)cyclopropane. To a stirred solution of (1-((l,3-dimethoxy-2-methylpropan-2- yl)sulfonyl)cyclopropyl) methanol (70 mg, 0.277 mmol) in THF (2.5 mL) under nitrogen atmosphere were added DPPE (169 mg, 0.416 mmol) and a solution of CBr₄ (188 mg, 0.555 mmol) in THF (1.5 mL). The reaction mixture was stirred at rt for 2 h. The reaction mixture was diluted with cold water (20 mL) and extracted with ethyl acetate (25 mL x 2). The combined organic layers were washed with brine (15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by Isolera column chromatography eluting with 20-30% EA in PE to afford 1 -(bromomethyl)- 1-((1, 3-dimethoxy-2- methylpropan-2-yl)sulfonyl)cyclopropane (INT-12) (60 mg, 68%) as a colorless solid. ¹H-NMR (400 MHz, CDCl₃): δ 4.09 (s, 2H), 3.76-3.74 (m, 2H), 3.67-3.65 (m, 2H), 3.41 (s, 6H), 1.71-1.70 (m, 2H), 1.59 (s, 3H), 1.28-1.24 (m, 2H) ppm. tert-Butyl 2-((1-(bromomethyl)cyclopropyl)sulfonyl)-2-methylpropanoate (INT-13)

Step 1. Synthesis of tert-butyl 2-((2-methoxy-2-oxoethyl)thio)-2-methylpropanoate. To a stirred solution of compound methyl 2-mercaptoacetate (3.0g, 28.3 mmol) in MeOH (40 mL) was added TEA (2.92 g, 28.3 mmol) followed by tcrt-butyl-2-bromoisobutyratc (6.43 g, 28.3 mmol) dropwise at 0 °C. The resulting reaction mixture was stirred at rt for 16 h and concentrated. The residue was diluted with water (70 mL) and extracted with EtOAc (50 mL x 2). The combined organic extracts were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford tert-butyl 2-((2- methoxy-2-oxoethyl)thio)-2-methylpropanoate (6.3 g, 83%) as a colorless oil, which was used for the next step without further purifications. LC-MS: 248 [M-1]⁺; ¹ H-NMR (400 MHz, CDCl₃): δ 3.75 (d, J = 10.40 Hz, 3H), 3.47 (s, 2H), 1.50 (s, 6H), 1.48 (d, J = 2.80 Hz, 9H) ppm.

Step 2. Synthesis of tert-butyl 2-((2-methoxy-2-oxoethyl)sulfonyl)-2-methylpropanoate. To a stirred solution of tert-butyl 2-((2-methoxy-2-oxoethyl)thio)-2-methylpropanoate (6.3 g, 25.4 mmol) in acetone (50 mL) and water (50 mL) was added oxone monopersulfate (35.4 g, 55.8 mmol). The resulting reaction mixture was stirred at rt for 12 h and filtered through celite pad and washed with ethyl acetate. The organic layer was washed with water (150 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford tert-butyl 2-((2- methoxy-2-oxoethyl)sulfonyl)-2-methylpropanoate (3.5 g, 46%) as a colorless liquid. ¹H-NMR (400 MHz, DMSO-d₆): δ 4.52 (d, J = 12.00 Hz, 2H), 3.72 (d, J = 5.20 Hz, 2H), 1.88 (t, J = 6.40 Hz, 1H), 1.52 (s, 6H), 1.44 (t, J = 11.60 Hz, 9H) ppm.

Step 3. Synthesis of methyl 1-((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)sulfonyl)cyclo propane-1-carboxylate. To a stirred solution of tert-butyl 2-((2-methoxy-2-oxoethyl)sulfonyl)- 2-methylpropanoate (3.5 g, 12.49 mmol) in DMF (40 mL) were added TBAI (0.706 g, 1.873 mmol) and K₂CO₃ (6.16 g, 43.7 mmol) followed by 1,2-dibromoethane (4.79 g, 24.97 mmol). The resulting reaction mixture was heated at 60 °C for 12 h. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (100 mL x 2). The combined organic extracts were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (silica gel, 60-100 mesh size) using EA/PE (20 to 30%) as an eluent to afford methyl 1 -(( 1 -(tert- butoxy)-2-mcthyl-1-oxopropan-2-yl)sulfonyl)cyclopropanc-1-carboxylate (3.5 g, 90%) as a pale yellow oil. LC-MS: 306.3 [M+18]⁺; ¹H-NMR (400 MHz, DMSO-d₆): δ 3.78 (s, 2H), 1.85 (s, 1H), 1.84 (t, J = 4.80 Hz, 6H), 1.51 (d, J = 6.80 Hz, 9H) ppm.

Step 4. Synthesis of tert-butyl 2-((1-(hydroxymethyl)cyclopropyl)sulfonyl)-2- methylpropanoate. To a stirred solution of methyl 1-((1-(tert-butoxy)-2-methyl-1-oxopropan-2- yl)sulfonyl)cyclopropane-1-carboxylate (3.5 g, 11.42 mmol) in THF (20 mL) was added LlAlH₄(Ot-Bu)₃ (28.6 ml 1 M in THF, 28.6 mmol) dropwise at 0 °C. The reaction mixture was stirred at 60 °C for 12 h. The reaction mixture was cooled to °C and quenched with saturated with ammonium chloride and extracted with ethyl acetate. The organic layer was separated, washed with water, brine solution, dried over sodium sulfate, filtered, and concentrated at reduced pressure. The resulting residue was purified by silica gel column chromatography using 10-50% EA in PE as an eluent to afford tert-butyl 2-((1-(hydroxymethyl)cyclopropyl)sulfonyl)- 2-methylpropanoate (1.6 g, 50%) as a colorless oil. LC-MS: 306.1 [M+l]+.

Step 5. Synthesis of tert-butyl 2-((1-(bromomethyl)cyclopropyl)sulfonyl)-2- methylpropanoate. To a stirred solution of tert-butyl 2-((1- (hydroxymethyl)cyclopropyl)sulfonyl)-2-methylpropanoate (1.0 g, 3.59 mmol) in THF (20 mL) were added DPPE (2.147 g, 5.39 mmol) and CBiv (2.383 g, 7.18 mmol) at 0 °C. Then the reaction mixture was stirred at rt for 2 h. The reaction mixture was filtered through celite pad and washed with ethyl acetate (100 mL). The filtrate was concentrated under reduced pressure. The resulting residue was purified by Isolera column chromatography eluting with 20-30% EAA in PE to afford tert-butyl 2-((1-(bromomethyl)cyclopropyl)sulfonyl)-2-methylpropanoate (INT-13) (700 mg, 57%) as a colorless solid.¹H -NMR (400 MHz, DMSO-d₆): δ 4.06 (s, 2H), 1.72-1.71 (m, 2H), 1.69 (s, 6H), 1.54 (s, 9H), 1.31-1.30 (m, 2H) ppm.

(1-((2,2,5-Trimethyl-l,3-dioxan-5-yl)sulfonyl)cyclopropyl)methyl-4-methylbenzenesulfonate (INT-14)

Step 1. Synthesis of 5-((1-((benzyloxy)methyl)cyclopropyl)sulfonyl)-2,2,5-trimethyl-l,3- dioxane. To a stirred solution of 2-((1-((benzyloxy)methyl)cyclopropyl)sulfonyl)-2- methylpropane-1,3-diol (400 mg, 1.272 mmol) in acetone (5 mL) was added 2,2- dimethoxypropane (1325 mg, 12.72 mmol) and p-toluenesulfonic acid monohydrate (50 mg, 0.263 mmol). Then the reaction mixture was stirred at rt for 20 h. The reaction mixture was diluted with cold water (20 mL) and extracted with ethyl acetate (25 mL x 2). The combined organic layers were washed with brine (15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by Isolera column chromatography eluting with 20-30% EA in PE to afford purc5-((1- ((benzyloxy)methyl)cyclopropyl)sulfonyl)-2,2,5-trimethyl-l,3-dioxane (250 mg, 47%) as a colorless solid. ¹H-NMR (400 MHz, CDCl)₃: 57.40-7.30 (m, 5H), 4.54 (s, 2H), 4.47 (d, J = 12.00 Hz, 2H), 3.83 (d, J = 12.00 Hz, 2H), 3.77 (s, 2H), 1.68 (s, 3H), 1.61-1.59 (m, 2H), 1.42 (s, 3H), 1.28 (s, 3H), 1.08-1.07 (m, 2H) ppm.

Step 2. Synthesis of (1-((2,2,5-trimethyl-l,3-dioxan-5-yl)sulfonyl)cyclopropyl)methanol. In an 25 mL tiny clave glass, a solution of 5-((1-((benzyloxy)methyl)cyclopropyl)sulfonyl)-2,2,5- trimethyl-l,3-dioxane (250 mg, 0.705 mmol) and acetic acid (1 mL, 17.48 mmol) in MeOH (20 mL) was bubbled with nitrogen gas for period of 2 min. To this reaction mixture, Pd/C (50% wet) (1g, 0.940 mmol) was added. The reaction mixture was stirred under hydrogen gas 5 kg atmosphere at rt for 20 h. The reaction mixture was filtered through the Celite pad and washed bed with methanol (50 mL). The filtrate was evaporated under reduced pressure. The resulting residue was purified by Isolera column chromatography eluting with 20% EA in PE to afford (1- ((2,2,5-trimethyl-1,3-dioxan-5-yl)sulfonyl)cyclopropyl)methanol (130 mg, 70%) as a colorless solid. ¹ H-NMR (400 MHz, CDC)l:₃ δ 4.43 (d, J = 12.80 Hz, 2H), 3.99 (s, 2H), 3.87 (d, J = 13.20 Hz, 2H), 1.68-1.66 (m, 2H), 1.51 (s, 3H), 1.47 (s, 6H), 1.16-1.14 (m, 2H) ppm.

Step 3. Synthesis of (1-((2,2,5-trimethyl-l,3-dioxan-5-yl)sulfonyl)cyclopropyl)methyl 4- methylbenzenesulfonate. To a stirred solution of (1-((2,2,5-trimethyl-l,3-dioxan-5- yl)sulfonyl)cyclopropyl)methanol (100 mg, 0.378 mmol) in DCM (2 mL) were added TEA (0.155 mL, 1.135 mmol) and 4-methylbenzenesulfonyl chloride (72.1 mg, 0.378 mmol) at 0 °C. Then the reaction mixture was stirred at rt for 20 h. The reaction mixture was diluted with cold water (20 mL) and extracted with DCM (15 mL x 2). The combined organic layers were washed with 10% NaHCO₃ solution (15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by Isolera column chromatography eluting with 20-30% EA in PE to afford (1-((2,2,5-trimethyl-l,3-dioxan-5- yl)sulfonyl)cyclopropyl)methyl -4-methylbenzenesulfonate (INT-14) (78 mg, 49%) as colorless gummy solid. ¹H-NMR (400 MHz, CDCI3): δ 7.81 (d, J = 8.40 Hz, 2H), 7.40 (d, J = 0.40 Hz, 2H), 4.48 (s, 2H), 4.30 (d, J = 12.80 Hz, 2H), 3.77 (d, J = 12.40 Hz, 2H), 2.49 (s, 3H), 1.71-1.70 (m, 2H), 1.49 (s, 3H), 1.43 (s, 3H), 1.43 (s, 3H), 1.22-1.21 (m, 2H) ppm. 1-((1-(Bromomethyl)cyclopropyl)sulfonyl)azetidine (INT-15)

Step 1. Synthesis 1-((1-((benzyloxy)methyl)cyclopropyl)sulfonyl)azetidine. To a stirred solution of 1 -((benzyloxy )methyl)cyclopropane-1- sulfonyl chloride (600 mg, 2.255 mmol) in DCM (6 mL) was added TEA (699 mg, 6.77 mmol) and azetidine (131 mg, 2.255 mmol). The resulting solution was stirred at rt for 12 h. The reaction mixture was diluted with water and extracted with DCM (20 mL x 2). The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The resulting residue was purified by column chromatography (20% EA in PE) to afford 1-((1-((bcnzyloxy)mcthyl) cyclopropyl) sulfonyl) azctidinc. LC-MS: 282.0 [M+l]⁺.

Step 2. Synthesis (1-(azetidin-1-ylsulfonyl)cyclopropyl)methanol. In a 25 mL tiny clave glass, a solution of 1-((1-((benzyloxy)methyl)cyclo propyl)sulfonyl)azetidine (385 mg, 1.355 mmol) in acetic acid (0.791 mL, 13.55 mmol) and MeOH (15 mL) was added palladium on carbon (10% dry basis) (360 mg, 0.339 mmol). The reaction mixture was stirred under hydrogen gas 5 kg atmosphere at 60 °C for 65 h. The reaction mass was filtered through a celite bed. The filtrate was concentrated to afford (1-(azetidin-1-ylsulfonyl)cyclopropyl)methanol (140 mg, 54%). ¹H- NMR (400 MHz, CDCl₃): δ 4.04-4.00 (m, 4H), 3.81 (d, J = 8.8 Hz, 2H), 3.51 (s, 1H), 2.35-2.27 (m, 2H), 1.41-1.38 (m, 2H), 1.02- 1.01 (m, 2H) ppm.

Step 3. Synthesis 1-((1-(bromomethyl)cyclopropyl)sulfonyl)azetidine. To a stirred solution of (1-(azetidin-1-ylsulfonyl)cyclopropyl)methanol (140 mg, 0.695 mmol) in THF (5 mL) was added CB1-4 (471 mg, 1.391 mmol) in THF (2 ml) at 0 °C. The resulting reaction mixture was stirred at rt for 1 h. The reaction mixture was filtered through a celite bed. The filtrate was concentrated. The resulting residue was purified by column chromatography to afford 1-((1- (bromomethyl)cyclopropyl)sulfonyl)azetidine (INT-15) (127 mg, 72%) as a colorless solid. LC- MS: 292.0 [M-1]⁺; ¹H-NMR (400 MHz, DMSO-d₆): δ 4.54 (s, 1H), 3.83-3.84 (m, 2H), 3.53 (t, J = 6.40 Hz, 2H), 3.36-3.41 (m, 2H), 2.11-2.18 (m, 2H), 1.73-1.76 (m, 2H), 1.17-1.19 (m, 2H) ppm.

1 -(Bromomethyl)- 1 -(( 1 -(methoxymethyl)cyclopropyl) sulfonyl)cyclopropane (INT - 16)

Step 1. Synthesis of (((1-((1-(methoxymethyl)cyclopropyl)sulfonyl)cyclopropyl) methoxy)methyl)benzene. To a stirred solution of (1-((1- ((benzyloxy)methyl)cyclopropyl)sulfonyl)cyclopropyl)methanol (200 mg, 0.675 mmol) in DMF (10 mL) was added NaH (17.81 mg, 0.742 mmol) portion wise followed by Mel (0.084 ml, 1.350 mmol) at 0 °C. The reaction mixture was stirred for rt for 2 h. The reaction mixture was diluted with saturated ammonium chloride (10 mL) and extracted with ethyl acetate (20 mL x 2). The combined organic extracts were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford (((1-((1- (methoxymethyl)cyclopropyl)sulfonyl)cyclopropyl)methoxy)methyl)benzene (200 mg, 93%), which was used for the next step without any further purifications.

Step 2. Synthesis of (1-((1-(methoxymethyl)cydopropyl)sulfonyl)cyclopropyl)methanol. To a stirred solution of (((1-((1-(methoxymethyl)cyclopropyl)sulfonyl)cyclopropyl)methoxy) methyl)benzene (200 mg, 0.644 mmol) in MeOH (8.0 mL) and acetic acid (0.369 pl, 6.44 pmol) was added 10% Pd/C (686 mg, 6.44 mmol). The reaction mixture was stirred under hydrogen pressure (6 kg) and heated at 70 °C for 12 h. The reaction mixture was filtered through a celite pad, and washed with ethyl acetate (70 mL). The filtrate was concentrated under reduced pressure. The resulting residue was dissolved in water (10 mL) and washed with saturated bicarbonate solution (10 mL) and brine (10 mL). The organic extract was dried over anhydrous sodium sulfate, fdtered, and concentrated under reduced pressure to afford (1-((1- (methoxymethyl)cyclopropyl)sulfonyl)cyclopropyl)methanol (200 mg) as a solid, which was used for the next step without any further purifications. LC-MS: 220 [M+l]⁺.

Step 3. Synthesis of 1-(bromomethyl)-1-((1-

(methoxymethyl)cyclopropyl)sulfonyl)cyclopropane. To a stirred solution of (1-((1- (methoxymethyl)cyclopropyl)sulfonyl)cyclopropyl)methanol (200 mg, 0.908 mmol) in THF (2.0 mL) under nitrogen atmosphere were added DDPE (543 mg, 1.362 mmol) and CB14 (602 mg, 1.816 mmol) at 0 °C. Then the reaction mixture was stirred at rt for 2 h. The reaction mixture was filtered on a celite pad and washed with ethyl acetate (100 mL). The filtrate was concentrated under reduced pressure. The resulting residue was purified by Isolera column chromatography eluting with 20-30% EA in PE to afford 1 -(bromomethyl)- 1-((1- (methoxymethyl)cyclopropyl)sulfonyl)cyclopropane (INT-16) (256 mg, 89%) as a colorless solid. LC-MS: 220 [M+l]⁺. tert-Butyl 4-(2-((1-(bromomethyl)cyclopropyl)sulfonyl)propan-2-yl)-2,2-dimethyloxazolidine-3- carboxylate (INT-17)

Step 1. Synthesis of 3-((2-(tert-butoxy)-2-oxoethyl)thio)-2-((tert-butoxycarbonyl)amino)-3- methylbutanoic acid. To a stirred solution of 2-amino-3-mercapto-3-methylbutanoic acid (3 g, 20.11 mmol) in dioxane (20 mL) was added NaOH (40.2 ml, 40.2 mmol) and Boc-anhydride (4.67 ml, 20.11 mmol) at 0 °C and stirred RT for 1.5 h, then tert-butyl 2-bromoacetate (3.92 g, 20.11 mmol) was added. The resulting mixture was stirred at rt for 16 h. The reaction mixture was diluted with water (20 mL) and acidified with IN aqueous hydrochloric acid (lOmL), and extracted with ethyl acetate (30 mL x 2). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford (S)-3-((2-(tert-butoxy)-2-oxoethyl)thio)-2-((tert-butoxycarbonyl)amino)-3- methylbutanoic acid (6 g, 79%) as a yellow liquid.-LC-MS: 363 [M+l]⁺.

Step 2. Synthesis of tert-butyl 2-((3-((tert-butoxycarbonyl)amino)-4-hydroxy-2- methylbutan-2yl)thio)acetate. A solution of 3-((2-(tert-butoxy)-2-oxoethyl)thio)-2-((tert- butoxycarbonyl)amino)-3-methylbutanoic acid (4.0 g, 10.90 mmol), TEA (1.684 ml, 11.98 mmol), and isobutyl chloroformate (1.574 ml, 11.98 mmol) was stirred at -10 °C for 30 min. The reaction mixture was filtered. The filtrate was added dropwise to a stirred solution of NaBH i (1.237 g, 32.7 mmol) in water (10 mL) and stirred at 0 °C for 15 min The reaction mixture was quenched with 1.5 N HC1 (20 mL), extracted with ethyl acetate(100 mL). The organic extract was washed with brine (70 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford tert-butyl 2-((3-((tert-butoxycarbonyl)amino)-4-hydroxy-2- methylbutan-2-yl)thio)acetate (4.0 g, 53%) as a solid. LC-MS: 340 [M+l]⁺.

Step 3. Synthesis of tert-butyl 4-(2-((2-(tert-butoxy)-2-oxoethyl)thio)propan-2-yl)-2,2- dimethyloxazolidine-3-carboxylate. A solution of tert-butyl 2-((3-((tert- butoxycarbonyl)amino)-4-hydroxy-2-mcthylbutan-2-yl)thio)acctatc (3.0 g, 8.58 mmol), 2,2- dimethoxypropane (4.47 g, 42.9 mmol), and p-TsOH (0.163 g, 0.858 mmol) in toluene (30 mL) was stirred at rt for 16 h. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure to afford tert-butyl 4-(2-((2-(tert-butoxy)-2-oxoethyl)thio)propan-2-yl)-2,2-dimethyloxazolidine-3- carboxylate (2.5 g, 23%). LC-MS: 390 [M+l]⁺.

Step 4. Synthesis of tert-butyl 4-(2-((2-(tert-butoxy)-2-oxoethyl)sulfonyl)propan-2-yl)-2,2- dimethyloxazolidine-3-carboxylate. To a mixture of tert-butyl 4-(2-((2-(tert-butoxy)-2- oxoethyl)thio)propan-2-yl)-2,2-dimethyloxazolidine-3-carboxylate (2.5 g, 6.42 mmol) and sodium bicarbonate (4.31 g, 51.3 mmol) ) in acetone (20 mL) at 0 °C was added portion- wise oxone mono persulphate (9.07 g, 14.76 mmol) and water (7.0 ml). The resulting reaction mixture was stirred at rt for 60 min. The reaction mixture was quenched with 10 % NaiSCh (15 mL), then neutralized with 1.5N HC1 (50 mL), extracted with ethyl acetate (30 mL). The organic layer was washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to afford tert-butyl 4-(2-((2-(tert-butoxy)-2-oxoethyl)sulfonyl)propan-2-yl)-2,2-dimethyl- oxazolidinc-3-carboxylatc (1.2 g, 44%) as an oil , which was used for next step without further purification. LC-MS: 222.2 [M+l]⁺.

Step 5. Synthesis of tert-butyl 4-(2-((1-(tert-butoxycarbonyl)cyclopropyl)sulfonyl)propan-2- yl)-2,2-dimethyloxazolidine-3-carboxylate. A solution of tert-butyl 4-(2-((2-(tert-butoxy)-2- oxoethyl)sulfonyl)propan-2-yl)-2,2-dimethyloxazolidine-3-carboxylate (1.2 g, 2.85 mmol) in DMF (10 mL) was added K₂CO₃ (1.180 g, 8.54 mmol) and 1 ,2-dibromoethane (1.070 g, 5.69 mmol). The reaction mixture was stirred at 100 °C for 16 h and diluted with water (30 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic extracts were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford tert-butyl 4-(2-((1-(tert-butoxycarbonyl)cyclopropyl)sulfonyl)propan-2-yl)-2,2- dimethyloxazolidine-3-carboxylate (1.0 g, 78%) as a brown liquid. LC-MS: 447.5 [M+l]⁺.

Step 6. Synthesis of tert-butyl 4-(2-((1-(hydroxymethyl)cyclopropyl)sulfonyl)propan-2-yl)- 2,2-dimethyloxazolidine-3-carboxylate. To a stirred solution of tert-butyl 4-(2-((1-(tert- butoxycarbonyl)cyclopropyl)sulfonyl)propan-2-yl)-2,2-dimethyloxazolidine-3-carboxylate (300 mg, 0.670 mmol) in THF (5.0 mL) was added dropwise LiAlFL (1.341 ml, 1.341 mmol) at 0 °C. The resulting reaction mixture was stirred 0 °C for 3 h and then quenched by the addition of water (1 mL). The slurry was stirred at rt for 15 min, then sodium sulfate was added, and the solid was removed by filtration through a celite pad and washed with ethyl acetate. The filtrate was concentrated to afford tert-butyl 4-(2-((1-(hydroxymethyl)cyclopropyl)sulfonyl)propan-2- yl)-2,2-dimethyloxazolidine-3-carboxylate (130 mg, 49%). LC-MS: 377 [M+l]⁺.

Step 7. Synthesis of tert-butyl 4-(2-((1-(bromomethyl)cyclopropyl)sulfonyl)propan-2-yl)- 2,2-dimethyloxazolidine-3-carboxylate. To a stirred solution of tert-butyl 4-(2-((1- (hydroxymethyl)cyclopropyl)sulfonyl)propan-2-yl)-2,2-dimethyloxazolidine-3-carboxylate (130 mg, 0.344 mmol) in THF (2.0 mL) were added DPPE (206 mg, 0.517 mmol) and CBr4 (228 mg, 0.689 mmol) at 0 °C. Then the reaction mixture was stirred at rt for 1 h. The reaction mixture was filtered through a celite pad and washed with ethyl acetate (100 mL). The filtrate was concentrated under reduced pressure. The resulting residue was purified by Isolera column chromatography eluting with 20-30% EA in PE to afford tert-butyl 4-(2-(( 1 - (bromomcthyl)cyclopropyl)sulfonyl)propan-2-yl)-2,2-dimcthyloxazolidinc-3-carboxylatc (INT- 17) as a colorless solid. LC-MS: 440 [M+l]⁺.

Preparation of Representative Compounds of the Invention:

N-(4-Chlorobenzyl)-8-oxo-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-3-carboxamide hydrochloride (Example 1)

Step 1. Synthesis of N-(4-chlorobenzyl)-7-((1-((2-methyl-1-((tetrahydro-2H-pyran-2-yl)oxy) propan-2-yl)sulfonyl)cyclopropyl)methyl)-8-oxo-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine- 3-carboxamide (1-1): To a stirred solution of N-(4-chlorobenzyl)-8-oxo-5, 6,7,8- tetrahydroimidazo[1,5-a]pyrazine-3-carboxamide (INT-1) (100 mg, 0.328 mmol) in DMF (3 mL) was added 2-(2-((1-(bromomethyl)cyclopropyl)sulfonyl)-2-methylpropoxy)tetrahydro-2H- pyran (INT-6) (175 mg, 0.492 mmol) and cesium carbonate (428 mg, 1.313 mmol) at rt. The reaction mixture was stirred at 60 °C overnight. The reaction mixture was diluted with water (20 mL), extracted with EtOAc (10 mL x 2). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography, eluting in 50% EtOAc in petroleum ether to get N-(4-chlorobenzyl)-7-((1-((2- methyl-1-((tetrahydro-2H-pyran-2-yl)oxy)propan-2-yl)sulfonyl)cyclopropyl)methyl)-8-oxo-

5.6.7.8-tetrahydro-imidazo[1,5-a]pyrazine-3-carboxamide (1-1) (80 mg, 38%) as an off-white solid. LC-MS: 579.1 [M-1]⁺; ¹H-NMR: (400 MHz, DMSO-d₆): δ 9.32 (t, 7 - 8.40 Hz, 1H), 7.59 (s, 1H), 7.36 (d, J = 11.60 Hz, 4H), 4.46-4.67 (m, 4H), 4.41 (d, 7 = 8.40 Hz, 2H), 4.07 (d, J = 21.20 Hz, 2H), 3.82-3.76 (m, 5H), 3.60 (d, J = 14.40 Hz, 1H), 3.48 (d, J = 14.80 Hz, 2H), 1.61- 1.55 (m, 3H), 1.55-1.38 (m, 3H), 1.38-1.21 (m, 5H), 1.08-1.06 (m, 2H) ppm.

Step 2. Synthesis of N-(4-chlorobenzyl)-7-((1-((l-hydroxy-2-methylpropan-2-yl)sulfonyl) cyclopropyl)methyl)-8-oxo-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-3-carboxamide (Example 1): A mixture of N-(4-chlorobenzyl)-7-((1-((2-methyl-1-((tetrahydro-2H-pyran-2- yl)oxy)propan-2-yl)sulfonyl)cyclopropyl)methyl)-8-oxo-5,6,7,8-tetrahydroimidazo[l,5- a]pyrazine-3-carboxamide (1-1) (80 mg, 0.138 mmol) and PTSA (34.2 mg, 0.180 mmol) in methanol (3 mL) was stirred at rt for 2 h. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by reverse phase HPLC to afford N-(4- chlorobenzyl)-7-((1-((1-hydroxy-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-8-oxo-

5.6.7.8-tetrahydroimidazo[1,5-a]pyrazine-3-carboxamide (Example 1) (28 mg, 40%) as an off- white solid. LC-MS: 495.0 [M+l] ⁺; HPLC: RT = 3.69 min, 97.9% (Max), column: X Bridge C8 (50X4.6) mm, 3-5 μm, Mobile phase A: 0.1% FA in water Mobile phase B: ACN Flow: 2.0 mL/min; ¹H-NMR: (400 MHz, DMSO-d₆): δ 9.33 (t, J = 6.40 Hz, 1H), 7.59 (s, 1H), 7.40-7.33 (m, 4H), 5.33 (t, J = 5.60 Hz, 1H), 4.66 (t, J = 6.40 Hz, 2H), 4.41 (d, J = 6.40 Hz, 2H), 4.10 (s, 2H), 3.76 (t, J = 5.60 Hz, 2H), 3.65 (d, 7 = 5.60 Hz, 2H), 1.31-1.34 (m, 8H), 1.04-1.04 (m, 2H) ppm.

N-(4-Chlorobenzyl)-6-(( 1-(cyclopropylsulfonyl)cyc lopropyl)methyl)-7-oxo-4, 5,6,7- tetrahydrothieno[2,3-c]pyridine-3-carboxamide (Example 2)

Step 1. Synthesis of N-(4-chlorobenzyl)-6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-7- oxo-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide. To a stirred solution of N-(4- chlorobenzyl)-7-oxo-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (45 mg, 0.137 mmol) in DMF (2 mL) was added CS2CO3 (183 mg, 0.550 mmol) and 1-(bromomethyl)-1- (cyclopropylsulfonyl)cyclopropane (INT-7) (67.1 mg, 0.275 mmol). The resulting reaction mixture was heated to 60 °C for 12 h. The reaction mixture was filtered through celite pad and washed with EtOAc (5 mL x 2). The filtrate was evaporated under reduced pressure. The resulting residue was purified by reverse HPLC to afford N-(4-chlorobenzyl)-6-((1- (cyclopropylsulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3- carboxamide (Example 2) (25 mg, 38%) as a white solid. LC-MS: 478.9 [M-1]⁺; HPLC: RT = 4.19 min, 99.8% (Max), Column: X-Bridge C8(50X4.6) mm, 3.5pm, Mobile phase A: 0.1% FA in water Mobile phase B: ACN, Flow:2.0mL/min); ¹H-NMR (400 MHz, DMSO-d₆): δ 8.95 (t, J = 6.0 Hz, 1H), 8.34 (s, 1H), 7.40 (d, J = 8.4 Hz, 2H), 7.35 (d, J = 8.4 Hz, 2H), 4.42 (d, J = 6.0 Hz, 2H), 4.02 (s, 2H), 3.69 (t, J = 6.8 Hz, 2H), 3.14 (t, J = 6.8 Hz, 2H), 2.99 - 2.95 (m, 1H), 1.29 - 1.24 (m, 2H), 1.11 - 1.06 (m, 2H), 1.05 - 1.01 (m, 4H) ppm.

6-((1-(tert-Butylsulfonyl)cyc lopropyl)methyl)-N-(4-chlorobenzyl)-2-methyl-7-oxo-4, 5,6,7- tetrahydrothieno[2,3-c]pyridine-3-carboxamide (Example 3)

Step 1. Synthesis of 6-((1-(tert-butylsulfonyl)cyclopropyl)methyl)-N-(4-chlorobenzyl)-2- methyl-7-oxo-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide. To a stirred solution of N-(4-chlorobenzyl)-2-methyl-7-oxo-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (INT-3) (0.05 g, 0.149 mmol), 1 -(bromomethyl)- 1-(tert-butylsulfonyl)cyclopropane (INT-8) (0.057 g, 0.224 mmol) in DMF (2 mL) was added cesium carbonate (0.195 g, 0.597 mmol). The reaction mixture was stirred at 60 °C for 16 h and evaporated under reduced pressure. The resulting residue was purified by reverse phase HPLC to afford 6-((1-(tert- butylsulfonyl)cyclopropyl)methyl)-N-(4-chlorobenzyl)-2-methyl-7-oxo-4, 5,6,7- tetrahydrothieno[2,3-c]pyridine-3-carboxamide (Example 3) (10 mg, 13%) as an off-white solid. LC-MS: 509.1[M-1]⁺; HPLC: RT = 4.5 min, 95.9% (Max), Column: X-Bridge C8 (50x4.6) mm, 3.5pm, Mobile phase A: 0.1% FA in water, Mobile phase B: ACN, Flow: 2.0mL/min; ¹H- NMR (400 MHz, DMSO-A): δ 8.70 (t, J = 6.00 Hz, 1H), 7.40-7.43 (m, 2H), 7.34-7.37 (m, 2H), 4.42 (d, J = 6.00 Hz, 2H), 4.03-4.06 (m, 2H), 3.62 (t, J = 6.80 Hz, 2H), 2.87 (t, J = 6.80 Hz, 2H), 2.55-2.63 (m, 3H), 1.42 (s, 9H), 1.31-1.31 (m, 2H), 0.99-0.99 (m, 2H) ppm.

N-(4-Chlorobenzyl)-2-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-oxo-1,2,3,4- tetrahydropyrrolo[1,2-a]pyrazine-6-carboxamide (Example 4)

Step 1. Synthesis of N-(4-chlorobenzyl)-2-((l-(cyclopropylsulfonyl)cyclopropyl)methyl)-1- oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-6-carboxamide: To a stirred solution of N-(4- chlorobenzyl)-l-oxo-l,2,3,4-tetrahydropyrrolo[l,2-a]pyrazine-6-carboxamide (INT-4) (0.05 g, 0.165 mmol) in DMF (3 mL) were added CS₂CO₃ (0.268 g, 0.823 mmol) and l-(bromomethyl)-

1-(cyclopropylsulfonyl)cyclopropane (INT-7) (0.079 g, 0.329 mmol) at 0 °C. The reaction mixture was then stirred at 60 °C for 16 h. The reaction mixture was evaporated under reduced pressure. The resulting residue was purified by reverse HPLC to afford N-(4-chlorobenzyl)-2- ((1 -(cycloprop ylsulfonyl)cyc lopropyl)methyl)- 1-oxo- 1.2.3.4-tetrahydropyrrolo[l,2-a]pyrazine-6- carboxamide (Example 4) (25.9 mg, 33%) as an off-white solid. LC-MS: 462.1 [M+l]⁺; HPLC: RT = 4.09 min, 97.8% (Max), Column: X-Bridge C8 (50x4.6) mm, 3-5 μm, Mobile phase:

A:0.1 % TFA in water Mobile phase: B: ACN, Flow:2.0mL/min); ¹ H-NMR (400 MHz, DMSO- d₆): δ 8.93 (t, J = 6.0 Hz, 1H), 7.40 (d, J = 8.4 Hz, 2H), 7.33 (d, J = 8.4 Hz, 2H), 6.93 (d, J = 4.0 Hz, 1H), 6.71 (d, J = 4.0 Hz, 1H), 4.59 (t, J = 6.0 Hz, 2H), 4.41 (d, J = 6.0 Hz, 2H), 4.03 (s, 2H), 3.76 (t, J = 6.0 Hz, 2H), 3.01 - 2.97 (m, 1H), 1.29 - 1.24 (m, 2H), 1.12 - 1.05 (m, 6H) ppm.

N-(4-chlorobenzyl)-7-methyl-2-((l-((2-methylbut-3-en-2-yl)sulfonyl)cyclopropyl)methyl)-l- oxo-1,2,3,4-tetrahydropyrrolo[l,2-a]pyrazine-6-carboxamide (Example 5), N-(4-chlorobenzyl)-

2-(( 1 -((3 ,4-dihydroxy-2-methylbutan-2-yl)sulfonyl)cyclopropyl)methyl)-7 -methyl- 1 -oxo- 1 ,2,3 ,4- tetrahydropyrrolo[l,2-a]pyrazine-6-carboxamide (Example 6), (R)-N-(4-chlorobenzyl)-2-((l- ((3,4-dihydroxy-2-methylbutan-2-yl)sulfonyl)cyclopropyl)methyl)-7-methyl-l-oxo-1,2,3,4- tetrahydropyrrolo[l,2-a]pyrazine-6-carboxamide (Example 7), and (S)-N-(4-chlorobenzyl)-2-((l- ((3,4-dihydroxy-2-methylbutan-2-yl)sulfonyl)cyclopropyl)methyl)-7-methyl-l-oxo-l,2,3,4- tetrahydropyrrolo[l,2-a]pyrazine-6-carboxamide (Example 8)

Step 1. Synthesis of N-(4-chlorobenzyl)-7-methyl-2-((1-((2-methylbut-3-en-2-yl)sulfonyl) cyclopropyl)methyl)-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-6-carboxamide. To a stirred solution of N-(4-chlorobenzyl)-7-methyl-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine- 6-carboxamide (0.170 g, 0.535 mmol) in DMF (4 mL) were added cesium carbonate (0.697 g, 2.140 mmol) and 1-(bromomcthyl)-1-((2-mcthylbut-3-cn-2-yl)sulfonyl)cyclopropanc (0.214 g, 0.802 mmol) at rt. The reaction mixture was stirred at 60 °C for 16 h. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by reverse phase HPLC to afford N-(4-chlorobenzyl)-7-methyl-2-((1-((2-methylbut-3-en-2- yl)sulfonyl)cyclopropyl)methyl)-1-oxo-l,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-6-carboxamide (Example 5) (5.4 mg, 2%) as an off-white solid. LC-MS: 504.0 [M-1]⁺; HPLC: RT = 4.6 min, 96% (Max), Column: X-Bridge C8 (50 x 4.6) mm, 3.5 pm, Mobile phase A: 0.1% FA in water, Mobile phase B: ACN, Flow:2.0mL/min); ¹H-NMR (400 MHz, DMSO-d₆): δ 8.44 (t, J = 6.00 Hz, 1H), 7.42 (d, J = 2.00 Hz, 2H), 7.36 (d, J = 8.80 Hz, 2H), 6.52 (s, 1H), 6.16 (dd, J = 10.40, 17.40 Hz, 1H), 5.49-5.40 (m, 2H), 4.44 (d, J = 6.00 Hz, 2H), 4.25 (t, J = 6.40 Hz, 2H), 3.98 (s, 2H), 3.65 (t, J = 6.00 Hz, 2H), 2.19 (s, 3H), 1.48 (s, 6H), 1.30-1.29 (m, 2H), 0.99-0.99 (m, 2H) ppm. Step 2. Synthesis of N-(4-chlorobenzyl)-2-((1-((3,4-dihydroxy-2-methylbutan-2- yl)sulfonyl)cyclo propyl)methyl)-7-methyl-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine- 6-carboxamide. To a stirred solution of N-(4-chlorobenzyl)-7-methyl-2-((1-((2-methylbut-3-en- 2-yl)sulfonyl)cyclopropyl)methyl)- 1 -oxo- 1 ,2,3 ,4-tetrahydropyrrolo[ 1 ,2-a]pyrazine-6- carboxamide (0.08 g, 0.159 mmol) in acetone (3 mL) and water (0.375 mL) were added osmium tetroxide (0.199 ml, 0.016 mmol) and NMO (0.056 g, 0.476 mmol) at rt. The reaction mixture was stirred at rt for 12 h. The reaction mixture was evaporated under reduced pressure. The resulting residue was purified by reverse phase prep HPLC to afford N-(4-chlorobenzyl)-2-((1- ((3,4-dihydroxy-2-methylbutan-2-yl)sulfonyl)cyclopropyl)methyl)-7-methyl-1-oxo-l,2,3,4- tetrahydropyrrolo[1,2-a]pyrazine-6-carboxamide (Example 6) (7.5 mg, 9%) as an off-white solid. LC-MS: 538.2 [M-1]⁺; HPLC: RT = 3.76 min, 99%(Max), Column: X-Bridge C8(50X4.6) mm, 3.5pm, Mobile phase A: 0.1 % FA in water Mobile phase B: ACN, Flow:2.0mL/min); ¹H- NMR (400 MHz, DMSO-d₆): δ 8.44 (t, J = 6.0 Hz, 1H), 7.41 (d, J = 2.0 Hz, 2H), 7.36 (d, J = 8.4 Hz, 2H), 6.52 (s, 1H), 5.26 (d, J = 5.20 Hz, 1H), 4.69 (t, J = 5.60 Hz, 3H), 4.44 (d, J = 6.0Hz, 2H), 4.27-4.30 (m, 2H), 4.14 (d, J = 14.40 Hz, 1H), 4.02 (d, J = 14.80 Hz, 1H), 3.88-3.84 (m, 1H), 3.69-3.62 (m, 2H), 2.19 (s, 3H), 1.41 (s, 3H), 1.35-1.29 (m, 5H), 1.01-0.97 (m, 2H) ppm.

Step 3. Synthesis of (S)-N-(4-chlorobenzyl)-2-((1-((3,4-dihydroxy-2-methylbutan-2- yl)sulfonyl)cyclopropyl)methyl)-7-methyl-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine- 6-carboxamide and (R)-N-(4-chlorobenzyl)-2-((1-((3,4-dihydroxy-2-methylbutan-2- yl)sulfonyl)cyclopropyl)methyl)-7-methyl-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine- 6-carboxamide. N-(4-chlorobenzyl)-2-((1-((3,4-dihydroxy-2-methylbutan-2- yl)sulfonyl)cyclopropyl)methyl)-7-methyl- 1-oxo- 1,2,3, 4-tetrahydropyrrolo[1,2-a]pyrazine-6- carboxamide (0.03 g, 0.056 mmol) was separated by SFC to afford (S)-N-(4-chlorobenzyl)-2-((1- ((3,4-dihydroxy-2-methylbutan-2-yl)sulfonyl)cyclopropyl)methyl)-7-methyl-1-oxo-l,2,3,4- tetrahydropyrrolo[1,2-a]pyrazine-6-carboxamide carboxamide (Example 7) (2.8 mg, 9%) as an off-white solid. LC-MS: 538.0 [M-1]⁺; HPLC: RT = 3.76 min, 97.5% (Max), Column: X-Bridge C8(50X4.6) mm, 3.5pm, Mobile phase A: 0.1% FA in water Mobile phase B: ACN, Flow:2.0mL/min); ¹H-NMR (400 MHz, DMSO-d₆): δ 8.45 (t, J = 6.00 Hz, 1H), 7.42-7.35 (m, 4H), 6.52 (s, 1H), 5.28 (d, J = 5.20 Hz, 1H), 4.70 (t, J = 5.60 Hz, 1H), 4.44 (d, J = 5.60 Hz, 2H), 4.30-4.20 (m, 2H), 4.14 (d, J = 14.80 Hz, 1H), 4.02 (d, J = 14.80 Hz, 1H), 3.88-3.84 (m, 1H), 3.70-3.62 (m, 3H), 2.19 (s, 3H), 1.41 (s, 3H), 1.35-1.29 (m, 5H), 0.99-0.97 (m, 2H) ppm and (R)- N-(4-chlorobenzyl)-2-((1-((3,4-dihydroxy-2-methylbutan-2-yl)sulfonyl)cyclopropyl)methyl)-7- methyl-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-6-carboxamide (Example 8) (3.0 mg, 10% yield) as an off-white solid. LC-MS: 538.0 [M-1]⁺; HPLC: RT = 3.764 min, 98.5% (Max), Column: X-Bridge C8 (50x4.6) mm, 3.5 pm, Mobile phase A: 0.1% FA in water Mobile phase B: ACN, Flow:2.0mL/min); ¹H-NMR (400 MHz, DMSO-d₆): δ 8.44 (t, J = 6.00 Hz, 1H), 7.42-7.35 (m, 4H), 6.52 (s, 1H), 5.27 (d, J = 5.20 Hz, 1H), 4.69 (t, J = 5.60 Hz, 1H), 4.44 (d, J = 6.00 Hz, 2H), 4.30-4.21 (m, 2H), 4.14 (d, J = 14.80 Hz, 1H), 4.02 (d, J = 14.80 Hz, 1H), 3.88-3.84 (m, 1H), 3.69-3.62 (m, 3H), 2.19 (s, 3H), 1.41 (s, 3H), 1.35-1.29 (m, 5H), 0.99-0.97 (m, 2H) ppm.

N-(4-Chlorobenzyl)-7-((1-((2-methylbut-3-en-2-yl) sulfonyl) cyclopropyl) methyl)-8-oxo- 5,6,7,8-tetrahydroimidazo[1 ,5-a] pyrazine-3-carboxamide (Example 9), N-(4-chlorobenzyl)-7- ((1-((3, 4-dihydroxy-2-mcthylbutan-2-yl)sulfonyl)cyclopropyl)mcthyl)-8-oxo-5, 6,7,8- tetrahydroimidazo[1,5-a]pyrazine-3-carboxamide (Example 10), and (N-(4-chlorobenzyl)-7-((1- ((3-hydroxy-2-methylbutan-2-yl)sulfonyl)cyclopropyl)methyl)-8-oxo-5, 6,7,8- tetrahydroimidazo[1,5-a]pyrazine-3-carboxamide (Example 11)

Step 1. Synthesis of N-(4-chlorobenzyl)-7-((1-((2-methylbut-3-en-2-yl) sulfonyl) cyclopropyl) methyl)-8-oxo-5,6,7,8-tetrahydroimidazo[1,5-a] pyrazine-3-carboxamide. To a stirred solution of N-(4-chlorobenzyl)-8-oxo-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-3- carboxamide hydrochloride (90 mg, 0.264 mmol) in DMF (2 mL) were added CS₂CO₃ (344 mg, 1.055 mmol) and 1-(bromomethyl)-1-((2-methylbut-3-en-2-yl)sulfonyl)cyclopropane (Int-94) (92 mg, 0.343 mmol) at 0 °C. The reaction mixture was stirred at 60 °C for 5 h. The reaction mixture was diluted with ice water (10 mL) and extracted with EtOAc (5 mL x 2). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated in vacuo. The resulting residue was purified by reverse phase HPLC using buffer 0.1% aq FA in CAN to afforded N-(4- chlorobenzyl)-7-((1-((2-methylbut-3-en-2-yl)sulfonyl)cyclopropyl)methyl)-8-oxo-5, 6,7,8- tetrahydroimidazo[1,5-a]pyrazine-3-carboxamide (Example 9) (50 mg, 38%) as an off-white solid. LC-MS: 490.9 [M-1]⁺; HPLC: RT - 4.50 min, 99.6% (Max), Column: X-Bridge C8 (50 x 4.6) mm, 3.5 μm Mobile phase A:0.1% TFA in water Mobile phase B: ACN, Flow:2.0mL/min; ¹H-NMR (400 MHz, DMSO-d₆): δ 9.33 (t, J = 6.40 Hz, 1H), 7.59 (s, 1H), 7.39-7.32 (m, 4H), 6.20-6.13 (m, 1H), 5.50-5.40 (m, 2H), 4.65 (t, J = 6.00 Hz, 2H), 4.40 (d, J = 6.40 Hz, 2H), 4.01 (s, 2H), 3.72 (t, J = 5.60 Hz, 2H), 1.48 (s, 6H), 1.48-0.29 (m, 2H), 1.05-1.03 (m, 2H) ppm.

Step 2. Synthesis of N-(4-chlorobenzyl)-7-((1-((3,4-dihydroxy-2-methylbutan-2- yl)sulfonyl)cyclopropyl)methyl)-8-oxo-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-3- carboxamide. To a solution of N-(4-chlorobenzyl)-7-((1-((2-methylbut-3-en-2- yl)sulfonyl)cyclopropyl)methyl)-8-oxo-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-3-carboxamide (40 mg, 0.081 mmol) in acetone (5 mL) and water (0.57 mL) was added NMO (28.6 mg, 0.244 mmol) and osmium tetroxide (2.5% in BuOH, 0.102 ml, 8.15 pmol) at rt. The reaction mixture was stirred overnight. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by reverse phase HPLC using 0.1% aq FA in CAN to afford N-(4- chlorobenzyl)-7-((1-((3,4-dihydroxy-2-methylbutan-2-yl)sulfonyl)cyclopropyl)methyl)-8-oxo- 5,6,7,8-tetra hydroimidazo[1,5-a]pyrazine-3-carboxamide (Example 10) (13 mg, 28 %) an off white solid. LC-MS: 525.2 [M-1]⁺; HPLC: RT = 3.53 min, 92.1% (Max), Column: X-Bridge C8 (50 x 4.6) mm, 3.5pm, Mobile phase A: 0.1% FA in water, Mobile phase B: ACN, Flow: 2.0mL/min; ¹H-NMR (400 MHz, DMSO-d₆): δ 9.33 (t, J = 6.40 Hz, 1H), 7.60 (s, 1H), 7.33-7.35 (m, 4H), 5.29 (d, J = 5.20 Hz, 1H), 4.72-4.64 (m, 3H), 4.41 (d, J = 6.40 Hz, 2H), 4.17 (d, J = 14.40 Hz, 2H), 4.06 (d, J = 14.80 Hz, 1H), 3.91 (t, J = 2.40 Hz, 2H), 3.85-3.85 (m, 1H), 3.77- 3.76 (m, 1H), 1.40 (s, 3H), 1.37-1.35 (m, 2H), 1.34 (s, 3H), 1.03-1.01 (m, 2H) ppm.

Step 3. Synthesis of N-(4-chlorobenzyl)-7-((1-((2-methyl-1-oxopropan-2- yl)sulfonyl)cyclopropyl)methyl)-8-oxo-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-3 carboxamide. To a stirred solution of N-(4-chlorobenzyl)-7-((1-((3,4-dihydroxy-2-methylbutan- 2-yl)sulfonyl)cyclopropyl)methyl)-8-oxo-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-3- carboxamide (140 mg, 0.261 mmol) in DCM (30 mL) was added sodium periodate-silicon bounded (419 mg, 0.392 mmol) at rt. The reaction mixture was stirred at rt for 2h. The reaction mixture was filtered and washed with DCM (10 mL). The filtrate was concentrated under reduced pressure to afford N-(4-chlorobenzyl)-7-((1-((2-methyl-1-oxopropan-2- yl)sulfonyl)cyclopropyl)methyl)-8-oxo-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-3-carboxamide (85 mg, 65%) as an off white solid. LC-MS: 493.1 [M-1]⁺; ¹H-NMR (400 MHz, DMSO-d₆): δ 9.75 (s, 1H), 9.32 (t, J = 9.2 Hz, 1H), 7.60 (s, 1H), 7.40 - 7.32 (m, 4H), 4.65 (t, J = 8.0 Hz, 2H), 4.41 (d, 7= 8.4 Hz, 2H), 3.94 (s, 2H), 3.73 (t, 7 = 7.6 Hz, 2H), 1.54 (s, 6H), 1.31 - 1.24 (m, 2H), 1.15 - 1.13 (m, 2H) ppm.

Step 4. Synthesis of N-(4-chlorobenzyl)-7-((1-((3-hydroxy-2-methylbutan-2-yl)sulfonyl) cyclopropyl)methyl)-8-oxo-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-3-carboxamide. To a stirred solution of N-(4-chlorobenzyl)-7-((1-((2-methyl-1-oxopropan-2-yl)sulfonyl)cyclo propyl)methyl)-8-oxo-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-3-carboxamide (25 mg, 0.050 mmol) in Dry THF (5 mL) was added methylmagnesium bromide (0.124 ml, 0.248 mmol) at 0 °C. The reaction mixture was stirred at rt for 2h. The reaction mixture was quenched with saturated ammonium chloride solution (5 mL) and extracted with EtOAc (15 mL x 2). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by reverse phase HPLC to afford N-(4- chlorobenzyl)-7-((1-((3-hydroxy-2-methylbutan-2-yl)sulfonyl)cyclopropyl)methyl)-8-oxo- 5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-3-carboxamide (Example 11) (6 mg, 23%) as a white solid. LC-MS: 508.9 [M-1]⁺; HPLC: RT = 3.92 min, 96.7%, Column: X-Bridge C8 (50 x 4.6) mm, 3.5 μm, Mobile phase A: 0.1% FA in water, Mobile phase B: ACN, Flow: 2.0mL/min; ¹H- NMR (400 MHz, DMSO-d₆): δ 9.32 (t, 7 = 6.4 Hz, 1H), 7.60 (s, 1H), 7.40 - 7.33 (m, 4H), 5.16 (d, 7 = 5.2 Hz, 1H), 4.70 - 4.63 (m, 2H), 4.41 (d, 7 = 6.4 Hz, 2H), 4.17 - 4.04 (m, 3H), 3.77 - 3.73 (m, 2H), 1.38 - 1.30 (m, 5H), 1.24 (s, 3H), 1.15 (d, 7 = 6.4 Hz, 3H), 1.08 - 1.01 (m, 2H) ppm.

7-((1-((4-Amino-3-hydroxy-2-methylbutan-2-yl)sulfonyl)cyclopropyl)methyl)-N-(4- chlorobenzyl)-8-oxo-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-3-carboxamide (Example 12), (S)-7-((1-((4-amino-3-hydroxy-2-methylbutan-2-yl)sulfonyl)cyclopropyl)methyl)-N-(4- chlorobenzyl)-8-oxo-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-3-carboxamide (Example 13) and (R)-7-((1-((4-amino-3-hydroxy-2-methylbutan-2-yl)sulfonyl)cyclopropyl)methyl)-N-(4 chlorobenzyl)-8-oxo-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-3-carboxamide (Example 14)

Step 1. Synthesis of N-(4-chlorobenzyl)-7-((1-((2-(oxiran-2-yl)propan-2- yl)sulfonyl)cyclopropyl)methyl)-8-oxo-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-3- carboxamide. To a stirred solution of N-(4-chlorobenzyl)-7-((1-((2-methylbut-3-en-2- yl)sulfonyl)cyclopropyl)methyl)-8-oxo-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-3-carboxamide (220 mg, 0.439 mmol) in DCM (2 mL) was added pyrazole (6.10 mg, 0.088 mmol), hydrogen peroxide (100 mg, 0.878 mmol) and methyltrioxorhenium(vii) (8.38 mg, 0.033 mmol). Then the reaction mixture was stirred rt for 24 h. The reaction mixture was quenched with water (5 mL) and extracted with ethyl acetate (5 mL x 2). The combined organic layers were washed with water, brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure, which was used for next step without further purifications._LC-MS: 506.1 [M+l]⁺.

Step 2. Synthesis of 7-((1-((4-amino-3-hydroxy-2-methylbutan-2- yl)sulfonyl)cyclopropyl)methyl)-N-(4-chlorobenzyl)-8-oxo-5,6,7,8-tetrahydroimidazo|T,5- a]pyrazine-3-carboxamide. In a tiny cleave reactor, was added N-(4-chlorobenzyl)-7-((1-((2- (oxiran-2-yl)propan-2-yl)sulfonyl)cyclopropyl)methyl)-8-oxo-5,6,7,8-tetrahydroimidazo[l,5- a]pyrazine-3-carboxamide (100 mg, 0.099 mmol) followed by 1,4-dioxane (0.5 mL) and ammonium hydroxide (5 ml, 0.099 mmol). Then the reaction mixture was heated to 80 °C under 5 kg pressure for 16 h. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by reverse phase HPLC to afford 7-((1-((4-amino-3-hydroxy-2- methylbutan-2-yl)sulfonyl)cyclopropyl)methyl)-N-(4-chlorobenzyl)-8-oxo-5, 6,7,8- tetrahydroimidazo[1,5-a]pyrazine-3-carboxamide (Example 12) (2.0 mg, 4%) as a white solid. LC-MS: 525.2 [M-1]⁺; HPLC: RT = 4.73 min, 98.1%, (Column: X-Bridge C8 (50 x 4.6) mm, 3-5 μm, Mobile phase A: lOmM Ammonium bicarbonate in water, Mobile phase B: ACN, Flow: 2.0mL/min); ¹H-NMR (400 MHz, DMSO-d₆): δ 9.32 (t, J = 6.4 Hz, 1H), 7.59 (s, 1H), 7.40-7.33 (m, 4H), 5.27 (d, J= 5.2 Hz, 1H), 4.71-4.66 (m, 3H), 4.41 (d, J = 6.4 Hz, 2H), 4.20-4.04 (m, 2H), 3.76-3.35 (m, 6H), 1 .41-1 .37 (m, 3H), 1 .36-1 .35 (m, 2H), 1 .34-1 .29 (m, 3H), 1 .03-1 .01 (m, 2H) ppm.

Step 3. Synthesis of (S)-7-((1-((4-amino-3-hydroxy-2-methylbutan-2- yl)sulfonyl)cyclopropyl) methyl)-N-(4-chlorobenzyl)-8-oxo-5,6,7,8-tetrahydroimidazo[l,5- a]pyrazine-3-carboxamide and (R)-7-((1-((4-amino-3-hydroxy-2-methylbutan-2- yl)sulfonyl)cyclopropyl)methyl)-N-(4-chlorobenzyl)-8-oxo-5,6,7,8-tetrahydroimidazo[l,5- a]pyrazine-3-carboxamide. 7-((1-((4-amino-3-hydroxy-2-methylbutan-2- yl)sulfonyl)cyclopropyl)methyl)-N-(4-chlorobenzyl)-8-oxo-5,6,7,8-tetrahydroimidazo[l,5- a]pyrazine-3-carboxamide (32 mg, 0.061 mmol) was separated by SFC to afford (S)-7-((1-((4- amino-3-hydroxy-2-methylbutan-2-yl)sulfonyl)cyclopropyl)methyl)-N-(4-chlorobenzyl)-8-oxo- 5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-3-carboxamide (Example 13) (7.3 mg, 23%) as a white solid. LC-MS: 524.1 [M-1]⁺; HPLC: RT = 2.80 min, 99.7%, (Column: X-Bridge C8 (50 x 4.6)mm, 3-5 μm, Mobile phase A: 0.1% FA in water, Mobile phase B : ACN, Flow: 2.0mL/min); Chiral SFC: 1.94 min, 100%, (Method: Chiralpak AS-H, Co-Solvent: 40% Co-Solvent Name: 0.5% isopropylamine in IPA); ¹H-NMR (400 MHz, DMSO-d₆): δ 9.35 - 9.32 (m, 1H), 7.59 (s, 1H), 7.39 - 7.33 (m, 4H), 5.50 (brs, 1H), 4.66 - 4.64 (m, 2H), 4.41 (d, J = 6.4 Hz, 2H), 4.19 - 4.05 (m, 2H), 3.82 - 3.74 (m, 3H), 2.90 - 2.86 (m, 1H), 2.55 - 2.52 (m, 1H), 1.41 (s, 3H), 1.37 - 1.35 (m, 2H), 1.29 (s, 3H), 1.06 - 1.02 (m, 2H) ppm and (R)-7-((1-((4-amino-3-hydroxy-2- methylbutan-2-yl)sulfonyl)cyclopropyl)methyl)-N-(4-chlorobenzyl )-8-oxo-5, 6,7,8- tetrahydroimidazo[1,5-a]pyrazine-3-carboxamide (Example 14) (6.3 mg, 20%) as a white solid. LC-MS: 524.0 [M-1]⁺; HPLC: RT = 2.78 min, 99.7%, (Column: X-Bridge C8 (50 x 4.6) mm, 3-5 μm, Mobile phase A: 0.1% FA in water, Mobile phase B: ACN, Flow: 2.0mL/min); Chiral SFC: 2.89 min, 99.20%, (Method: Chiralpak AS-H, Co-Solvent: 40% Co-Solvent Name: 0.5% isopropylamine in IPA); ¹H-NMR (400 MHz, DMSO-d₆): δ 9.32 - 9.31 (m, 1H), 7.59 (s, 1H), 7.40 - 7.33 (m, 4H), 5.60 (brs, 1H), 4.69 - 4.64 (m, 2H), 4.41 (d, J = 6.0 Hz, 2H), 4.18 - 4.06 (m, 2H), 3.84 - 3.73 (m, 3H), 2.93 - 2.90 (m, 1H), 2.58 - 2.53 (m, 1H), 1.42 (s, 3H), 1.40 - 1.36 (m, 2H), 1.29 (s, 3H), 1.07 - 1.04 (m, 2H) ppm.

7-((1-((4-Amino-3-hydroxy-2-methylbutan-2-yl)sulfonyl)cyclopropyl)methyl)-N-(4- chlorobenzyl)-8-oxo-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-3-carboxamide (Example 15), N- (4-chlorobenzyl)-7-((1-((2-cyanopropan-2-yl)sulfonyl)cyclopropyl)methyl)-8-oxo-5, 6,7,8- tctrahydroimidazo[1,5-a]pyrazinc-3-carboxamidc (Example 16), 7-((1-((2-(lH-tctrazol-5- yl)propan-2-yl)sulfonyl)cyclopropyl)methyl)-N-(4-chlorobenzyl)-8-oxo-5, 6,7,8- tetrahydroimidazo[1,5-a]pyrazine-3-carboxamide (Example 17), N-(4-chlorobenzyl)-7-((1-((2- (1-methyl-1H-tetrazol-5-yl)propan-2-yl)sulfonyl)cyclopropyl)methyl)-8-oxo-5, 6,7,8- tetrahydroimidazoll,5-aJpyrazine-3-carboxamide (Example 18), and N-(4-chlorobenzyl)-7-((1- ((2-(2-methyl-2H-tetrazol-5-yl)propan-2-yl)sulfonyl)cyclopropyl)methyl)-8-oxo-5, 6,7,8- tetrahydro imidazo[1,5-a]pyrazine-3-carboxamide (Example 19)

Step 1. Synthesis of tert-butyl 2-((1-((3-((4-chlorobenzyl)carbamoyl)-8-oxo-5,6-dihydro imidazo[1,5-a]pyrazin-7(8H)-yl)methyl)cyclopropyl)sulfonyl)-2-methylpropanoate. To a stirred solution of N-(4-chlorobenzyl)-8-oxo-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-3- carboxamide (INT-1) (200 mg, 0.656 mmol) in DMF (8 mL) were added CS₂CO₃ (855 mg, 2.63 mmol), tert-butyl 2-((1-(bromomethyl)cyclopropyl)sulfonyl)-2-methylpropanoate (INT-13) (336 mg, 0.984 mmol). Then the reaction mixture was heated at 60 °C for 16 h. The reaction mixture was diluted with cold water (50 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by reverse phase HPLC to afford tert-butyl 2-((1-((3-((4-chlorobenzyl)carbamoyl)-8-oxo-5,6-dihydroimidazo[l,5- a]pyrazin-7(8H)-yl)methyl)cyclopropyl)sulfonyl)-2-methylpropanoate (300 mg, 79%). LC-MS: 565.2 [M-1]⁺; ¹H-NMR (400 MHz, DMSO-d₆): δ 9.33 (t, J = 6.40 Hz, 1H), 7.60 (s, 1H), 7.40- 7.33 (m, 4H), 4.67 (t, J = 6.00 Hz, 2H), 4.41 (d, J = 6.40 Hz, 2H), 4.10 (d, J = 5.20 Hz, 2H), 3.75 (t, 7= 6.00 Hz, 2H), 1.59 (s, 6H), 1.47 (d, 7 = 3.20 Hz, 9H), 1.36-1.32 (m, 2H), 1.13 (1, 7 = 2.40 Hz, 2H) ppm.

Step 2. Synthesis of2-((1-((3-((4-chlorobenzyl)carbamoyl)-8-oxo-5,6-dihydroimidazo[1,5-a] pyrazin-7(8H)-yl)methyl)cyclopropyl)sulfonyl)-2-methylpropanoic acid. To a stirred solution of tert-butyl 2-((1-((3-((4-chlorobenzyl)carbamoyl)-8-oxo-5,6-dihydroimidazo[1,5-a]pyrazin- 7(8H)-yl)methyl)cyclopropyl)sulfonyl)-2-methylpropanoate (280 mg, 0.496 mmol) in DCM (6 mL) was added TFA (282 mg, 2.478 mmol) at 0 °C. Then reaction mixture was stirred at rt for 12 h. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by HPLC to afford 2-((1-((3-((4-chlorobenzyl)carbamoyl)-8-oxo-5,6- dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)methyl)cyclopropyl)sulfonyl)-2-methylpropanoic acid (201 mg, 79%). LC-MS: 509.1 [M-1]⁺; ¹H-NMR (400 MHz, DMSO-d₆): δ 13.72 (s, 1H), 9.33 (t, 7 = 6.40 Hz, 1H), 7.60 (s, 1H), 7.33-7.35 (m, 4H), 4.67 (t, 7 = 6.40 Hz, 2H), 4.41 (d, 7 = 6.40 Hz, 2H), 4.08 (s, 2H), 3.74 (t, 7 = 5.20 Hz, 2H), 1.60 (d, 7 = 3.20 Hz, 6H), 1.36 (dd, 7 = 4.40, 6.80 Hz, 2H), 1.12 (t, 7 = 2.00 Hz, 2H) ppm.

Step 3. Synthesis of 7-((1-((1-amino-2-methyl-1-oxopropan-2- yl)sulfonyl)cyclopropyl)methyl)-N-(4-chlorobenzyl)-8-oxo-5,6,7,8-tetrahydroimidazo[l,5- a]pyrazine-3-carboxamide. To a stirred solution of 2-((1-((3-((4-chlorobenzyl)carbamoyl)-8- oxo-5, 6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)methyl)cyclopropyl)sulfonyl)-2- methylpropanoic acid (600 mg, 0.849 mmol) dissolved in DMF (6 mL) were added HATU (645 mg, 1.698 mmol), ammonium chloride (363 mg, 6.79 mmol), and DIPEA (0.741 mL, 4.24 mmol) at 0 °C. The reaction mixture was stirred at rt for 20 h. The reaction mixture was diluted with cold water (50 mL) and extracted with DCM (50 mL x 2). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by reverse-phase HPLC to afford 7- ((1-((1-amino-2-methyl-1-oxopropan-2-yl)sulfonyl)cyclopropyl)methyl)-N-(4-chlorobenzyl)-8- oxo-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-3-carboxamide (Example 15) (270 mg, 63%) as a white solid. LC-MS: 508.1 [M-1]⁺; HPLC: RT = 3.75 min, 99.8%; Column: X Bridge C8 (50 x 4.6) mm, 3-5 μm Mobile phase A: 0.1% FA in water Mobile phase B: ACN, Flow:2.0 mL/min; ^!H-NMR (400 MHz, DMSO-d₆): δ 9.33 (t, J = 6.40 Hz, 1H), 7.67 (s, 1H), 7.59 (s, 2H), 7.40-7.33 (m, 4H), 4.66 (t, J = 6.00 Hz, 2H), 4.41 (d, J = 6.00 Hz, 2H), 4.05 (s, 2H), 1.57 (s, 6H), , 3.75 (t, J = 6.00 Hz, 2H), 1.35 (t, J = 4.40 Hz, 2H), 1.10 (t, J = 5.60 Hz, 2H) ppm.

Step 4. Synthesis of N-(4-chlorobenzyl)-7-((1-((2-cyanopropan-2- yl)sulfonyl)cyclopropyl)methyl)-8-oxo-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-3- carboxamide. To a stirred solution of 7-((1-((1-amino-2-mcthyl-1-oxopropan-2- yl)sulfonyl)cyclopropyl)methyl)-N-(4-chlorobenzyl)-8-oxo-5,6,7,8-tetrahydroimidazo[l,5- a]pyrazine-3-carboxamide (50 mg, 0.098 mmol) in DMF (1 mL) was added thionyl chloride (0.014 ml, 0.197 mmol) at 0-5 °C. The reaction mixture was stirred at rt for 4 h. The reaction mixture was concentrated under reduced pressure. The resulting residue was diluted with water (5 mL) and extracted with Ethyl acetate (5 mL x 2). The combined organic layers were washed with water (5 mL), brine (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by reverse phase HPLC to afford N- (4-chlorobenzyl)-7-((1-((2-cyanopropan-2-yl)sulfonyl)cyclopropyl)methyl)-8-oxo-5, 6,7,8- tetrahydroimidazo[1,5-a]pyrazine-3-carboxamide (Example 16) (10 mg, 21%) as an off-white solid. LC-MS: 489.9 [M-1]⁺; HPLC: RT = 4.49 min, 99.9%, (Column: X-Bridge C8 (50 x 4.6) mm, 3-5 μm, Mobile phase A: 0.1% FA in water, Mobile phase B: ACN, Flow: 2.0mL/min); ^rH- NMR (400 MHz, DMSO-d₆): δ 9.34 (t, J = 6.4 Hz, 1H), 7.62 (s, 1H), 7.40-7.33 (m, 4H), 4.67 (t, 7 = 6.0 Hz, 2H), 4.41 (d, 7 = 6.4 Hz, 2H), 4.21 (s, 2H), 3.80 (t, 7= 6.0 Hz, 2H), 1.82 (s, 6H), 1.49 (t, 7 = 4.8 Hz, 2H), 1.28 (t, 7 = 2.0 Hz, 2H) ppm.

Step 5. Synthesis of 7-((1-((2-(lH-tetrazol-5-yl)propan-2-yl)sulfonyl)cyclopropyl)methyl)-N- (4-chlorobenzyl)-8-oxo-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-3-carboxamide. To a stirred solution of N-(4-chlorobenzyl)-7-(( 1-((2-cyanopropan-2-yl)sulfonyl)cyclopropyl )methyl)-8-oxo-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-3-carboxamide (300 mg, 0.612 mmol) in DMSO (4 mL) were added sodium azide (60 mg, 0.923 mmol) and copper(II) sulfate pentahydrate (229 mg, 0.918 mmol). The reaction mixture was stirred at 120 °C for 20 h. The reaction mixture was quenched with 1.5M HC1 (10 mL), diluted with water (10 mL), and extracted with ethyl acetate (25 mL x 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by reverse phase HPLC to afford 7-((1-((2-(lH-tetrazol-5-yl)propan-2- yl)sulfonyl)cyclopropyl)methyl)-N-(4-chlorobenzyl)-8-oxo-5,6,7,8-tetrahydroimidazo[l,5- a]pyrazine-3-carboxamide (Example 17) (200 mg, 74%) as a white solid. LC-MS: 532.9 [M-1]⁺; HPLC: RT = 3.90 min, 99%, (Column: X Bridge C8 (50x4.6) mm, 3-5 μm, Mobile phase A: 0.1% FA in water, Mobile phase B: CAN, Flow:2.0 mL/min); ¹H-NMR (400 MHz, DMSO-d₆): δ 9.32 (t, J = 6.40 Hz, 1H), 7.58 (s, 1H), 7.39-7.32 (m, 4H), 4.63 (t, J = 6.40 Hz, 2H), 4.40 (d, J = 6.40 Hz, 2H), 3.70 (s, 2H), 3.61 (t, J = 6.00 Hz, 2H), 1.93 (s, 6H), 0.99 (s, 4H) ppm.

Step 6. Synthesis of N-(4-chlorobenzyl)-7-((1-((2-(1-methyl-1H-tetrazol-5-yl)propan-2- yl)sulfonyl)cyclopropyl)methyl)-8-oxo-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-3- carboxamide and N-(4-chlorobenzyl)-7-((1-((2-(2-methyl-2H-tetrazol-5-yl)propan-2- yl)sulfonyl)cyclopropyl)methyl)-8-oxo-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-3- carboxamide. To a stirred solution of 7-((1-((2-(lH-tetrazol-5-yl)propan-2- yl)sulfonyl)cyclopropyl)methyl)-N-(4-chlorobenzyl)-8-oxo-5,6,7,8-tetrahydroimidazo[l,5- a]pyrazine-3-carboxamide (50 mg, 0.075 mmol) in DMF (2 mL) was added NaH (4 mg, 0.1 mmol) at 0 °C and stirred for 20 min. To this mixture, methyl iodide (13 mg, 0.092 mmol) was added. The reaction mixture was stirred at rt for 20 h. The reaction mixture was diluted with cold water (20 mL) and extracted with ethyl acetate (25 mL x 2). The combined organic layers were washed with brine (15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by reverse phase prep HPLC to afford N-(4-chlorobenzyl)-7 -(( 1 -((2-( 1 -methyl- 1 H-tetrazol-5-yl)propan-2- yl)sulfonyl)cyclopropyl)methyl)-8-oxo-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-3-carboxamide (Example 18) (6 mg, 14%) as a white solid. LC-MS: 548.0 [M-1]⁺; HPLC: RT = 4.17 min, 95.9%; Column: X-Bridge C8 (50 x 4.6) mm, 3-5 μm Flow Rate: 2.0ml/min, Mobile Phase A: 0.1%FA in water, Mobile Phase B: Acetonitrile; ¹H-NMR (400 MHz, DMSO-d₆): δ 9.33 (t, J = 6.40 Hz, 1H), 7.58 (s, 1H), 7.40-7.32 (m, 4H), 4.63 (t, J = 6.00 Hz, 2H), 4.45 (s, 3H), 4.40 (d, J = 6.40 Hz, 2H), 3.74 (s, 2H), 3.64 (t, J = 6.00 Hz, 2H), 1.90 (s, 6H), 1.01 (t, J = 3.60 Hz, 2H), 0.95 (t, J= 8.00 Hz, 2H) ppm and N-(4-chlorobenzyl)-7-((1-((2-(2-methyl-2H-tetrazol-5-yl)propan-2- yl)sulfonyl)cyclopropyl)methyl)-8-oxo-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-3-carboxamide (Example 19) (6 mg, 14% yield) as white solid. LC-MS: 578.0 [M-1]⁺; HPLC: RT = 4.16 min, 95.2%; (Column: X-Bridge C8 (50x 4.6) mm, 3-5 μm, Flow Rate : 2.0ml/min, Mobile Phase A: 0.1%FA in water Mobile Phase B: Acetonitrile); ¹H-NMR (400 MHz, DMSO-d₆): δ 9.33 (t, J - 6.40 Hz, 1H), 7.59 (s, 1H), 7.39-7.32 (m, 4H), 4.63 (t, J = 6.40 Hz, 2H), 4.40 (d, J = 6.40 Hz, 2H), 4.26 (s, 3H), 3.77 (s, 2H), 3.62 (t, J = 6.40 Hz, 2H), 2.02 (s, 6H), 1.06-0.84 (m, 4H) ppm.

N-(4-Chlorobenzyl)-7-((1-((1-fluoro-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-8-oxo-

5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-3-carboxamide (Example 20)

Step 1. Synthesis of N-(4-chlorobenzyl)-7-((1-((l-fluoro-2-methylpropan-2-yl)sulfonyl) cyclopropyl)methyl)-8-oxo-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-3-carboxamide. To a stirred solution of N-(4-chlorobenzyl)-7-((1-((1-hydroxy-2-methylpropan-2- yl)sulfonyl)cyclopropyl)methyl)-8-oxo-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-3-carboxamide (60 mg, 0.121 mmol) in DCM (1 mL) was added DAST (0.024 ml, 0.182 mmol) dropwise at 0 °C. The reaction mixture was stirred at rt for 32 h. The reaction mixture was diluted with water (5.0 ml) and extracted with DCM (5 mL x 3). The combined organic extracts were washed with a solution of 10% sodium bicarbonate (5.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by HPLC to afford N- (4-chlorobenzyl)-7-((1-((1-fluoro-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-8-oxo- 5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-3-carboxamide (Example 20) as an off-white solid. LC-MS: 497 [M-1]⁺; HPLC: RT = 5.62 min, 98.4%, (Column: X-Bridge C8 (50 x 4.6) mm, 3.5 pm, Mobile phase A: lOmM ammonium bicarbonate in water, Mobile phase B: Acetonitrile Flow:1.0mL/min; H-NMR (400 MHz, DMSO-d₆): δ 9.33 (t, J = 6.40 Hz, 1H), 7.60 (s, 1H), 7.39 (q, J = 2.40 Hz, 2H), 7.35 (q, J = 2.00 Hz, 2H), 4.73 (s, 1H), 4.66 (t, J = 6.40 Hz, 2H), 4.62 (s, 1H), 4.41 (d, J = 6.40 Hz, 2H), 4.06 (s, 2H), 3.75 (t, J = 6.00 Hz, 2H), 1.42 (d, J = 2.00 Hz, 6H), 1.37 (t, J = 4.40 Hz, 2H), 1.14 (t, J = 2.00 Hz, 2H) ppm.

N-(4-Chlorobenzyl)-7-((1-((l,3-dihydroxy-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-

8-oxo-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-3-carboxamide (Example 21)

Step 1. Synthesis N-(4-chlorobenzyl)-8-oxo-7-((1-((2,2,5-trimethyl-l,3-dioxan-5- yl)sulfonyl)cyclopropyl)methyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-3-carboxamide.

To a stirred solution of N-(4-chlorobenzyl)-8-oxo-5, 6,7, 8-tetrahydroimidazo[1,5-a]pyrazine-3- carboxamide (INT-1) (50 mg, 0.164 mmol) in DMF (2 mL) were added (1-((2,2,5-trimethyl-l,3- dioxan-5-yl)sulfonyl)cyclopropyl)methyl 4-methylbenzenesulfonate (INT-14) (76 mg, 0.180 mmol and cesium carbonate (160 mg, 0.492 mmol). Then reaction mixture was stirred at 60 °C for 18 h. The reaction mixture was diluted with cold water (10 mL) and extracted with ethyl acetate (15 mL x 2). The combined organic layers were washed with brine (15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by reverse phase HPLC to afford N-(4-chlorobenzyl)-8-oxo-7-((1-((2,2,5- trimethyl-l,3-dioxan-5-yl)sulfonyl)cyclopropyl)methyl)-5,6,7,8-tetrahydroimidazo[l,5- a]pyrazine-3-carboxamide as a white solid. LC-MS: 551.3 [M-1]⁺; ¹H-NMR (400 MHz, DMSO- d₆): δ 9.32 (t, J = 6.40 Hz, 1H), 7.59 (s, 1H), 7.40-7.33 (m, 4H), 4.66 (t, J = 7.20 Hz, 2H), 4.41 (d, J = 6.40 Hz, 2H), 4.28 (d, J = 13.20 Hz, 2H), 4.15 (s, 2H), 3.88 (d, J = 12.80 Hz, 2H), 3.77 (t, J = 5.60 Hz, 2H), 3.77 (s, 9H), 1.36 (m, 2H), 1.15-1.14 (m, 2H) ppm.

Step 2. Synthesis of N-(4-chlorobenzyl)-7-((1-((l,3-dihydroxy-2-methylpropan-2- yl)sulfonyl) cyclopropyl)methyl)-8-oxo-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-3- carboxamide. To a stirred solution of N-(4-chlorobcnzyl)-8-oxo-7-((1-((2,2,5-trimcthyl-l,3- dioxan-5-yl)sulfonyl)cyclopropyl)methyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-3- carboxamide (50 mg, 0.036 mmol) in dioxane (0.5 mL) was added 4N HC1 in water (0.5 mL, 16.46 mmol). The reaction mixture was stirred at 60 °C for 3 h. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by HPLC to afford N- (4-chlorobenzyl)-7-((1-((l,3-dihydroxy-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-8- oxo-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-3-carboxamide (Example 21) (5 mg, 27%) as a white solid. LC-MS: 511.0 [M-1]⁺; HPLC: RT - 3.47 min, 98.7%; Column: X-Bridge C8(50 x 4.6) mm, 3-5 μm, Mobile phase A: 0.1% FA in water, Mobile phase B: ACN, Flow: 2.0 mL/min; ¹H-NMR (400 MHz, DMSO-d₆): δ 9.32 (t, J = 6.40 Hz, 1H), 7.59 (s, 1H), 7.40-7.33 (m, 4H), 5.17 (t, J = 5.60 Hz, 2H), 4.65 (t, J = 6.00 Hz, 2H), 4.41 (d, J = 6.40 Hz, 2H), 4.14 (s, 2H), 3.80- 3.75 (m, 4H), 3.71-3.66 (m, 2H), 3.68 (t, J = 5.60 Hz, 2H), 1.27 (s, 3H), 1.04 (t, J = 4.80 Hz, 2H) ppm.

7-((1-((3-Amino-4-hydroxy-2-methylbutan-2-yl)sulfonyl)cyclopropyl)methyl)-N-(4- chlorobenzyl)-8-oxo-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-3-carboxamide (Example 22),

(S)-7-((1-((3-amino-4-hydroxy-2-methylbutan-2-yl)sulfonyl)cyclopropyl)methyl)-N-(4- chlorobenzyl)-8-oxo-5,6,7,8-tetrahydroimidazo[l,5-aJpyrazine-3-carboxamide (Example 23), and (R)-7-((1-((3-amino-4-hydroxy-2-methylbutan-2-yl)sulfonyl)cyclopropyl)methyl)-N-(4- chlorobenzyl)-8-oxo-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-3-carboxamide (Example 24)

Step 1. Synthesis of tert-butyl 4-(2-((1-((3-((4-chlorobenzyl)carbamoyl)-8-oxo-5,6- dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)methyl)cyclopropyl)sulfonyl)propan-2-yl)-2,2- dimethyloxazolidine-3-carboxylate. To a stirred solution of N-(4-chlorobenzyl)-8-oxo-5, 6,7,8- tetrahydroimidazo[1,5-a]pyrazine-3-carboxamide (100 mg, 0.328 mmol) in DMF (2 mL) were added CS₂CO₃ (428 mg, 1.31 mmol) and tert-butyl 4-(2-((1- (bromomethyl)cyclopropyl)sulfonyl)propan-2-yl)-2,2-dimethyl-oxazolidine-3-carboxylate (217 mg, 0.492 mmol). The reaction mixture was stirred at 60 °C for 16 h. The reaction mixture was evaporated under reduced pressure to afford tert-butyl 4-(2-((1-((3-((4-chlorobenzyl)carbamoyl)- 8-oxo-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)methyl)cyclopropyl)sulfonyl)propan-2-yl)- 2,2-dimethyloxazolidine-3-carboxylate (250 mg, 68%). LC-MS: 664 [M+l]⁺.

Step 2. Synthesis of 7-((1-((3-amino-4-hydroxy-2-methylbutan-2- yl)sulfonyl)cyclopropyl)methyl)-N-(4-chlorobenzyl)-8-oxo-5,6,7,8-tetrahydroimidazo[l,5- a]pyrazine-3-carboxamide. To a stirred solution of tert-butyl 4-(2-((1-((3-((4- chlorobenzyl)carbamoyl)-8-oxo-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)- yl)methyl)cyclopropyl)sulfonyl)propan-2-yl)-2,2-dimethyl oxazolidine-3-carboxylate (200 mg, 0.301 mmol) in MeOH (2.0 mL) was added 4 N HC1 in water (1 ml). The reaction mixture was stirred at rt for 6 h. The reaction mixture was concentrated in vacuo. The resulting residue was purified by reverse phase HPLC to afford 7-((1-((3-amino-4-hydroxy-2-methylbutan-2- yl)sulfonyl)cyclopropyl)methyl)-N-(4-chlorobenzyl)-8-oxo-5,6,7,8-tetrahydroimidazo[l,5- a]pyrazine-3 -carboxamide (Example 22) (55 mg, 35%) as an off white solid. LC-MS: 524 [M-1]⁺; HPLC: RT = 2.67 min, 99.5%, Column: X-Bridge C8 (50 x 4.6) mm, 3-5 μm, Mobile phase A: 0.1% FA in water, Mobile phase B: ACN, Flow: 2.0 mL/min; ¹H-NMR (400 MHz, DMSO-d₆): δ 9.33 (t, J = 6.40 Hz, 1H), 8.27 (s, 1H), 7.59 (s, 1H), 7.40-7.33 (m, 4H), 4.66 (t, J = 6.80 Hz, 3H), 4.41 (d, J = 6.40 Hz, 2H), 4.13 (s, 2H), 3.76 (t. 7 - 6.00 Hz, 2H), 3.66 (t, J - 2.80 Hz, 1H), 3.30-2.68 (m, 1H), 1.42 (s, 3H), 1.36 (t, J = 4.40 Hz, 5H), 1.05 (t, J = 4.00 Hz, 2H) ppm.

Step 3. Synthesis of S)-7-((1-((3-amino-4-hydroxy-2-methylbutan-2- yl)sulfonyl)cyclopropyl) methyl)-N-(4-chlorobenzyl)-8-oxo-5,6,7,8-tetrahydroimidazo[l,5- a]pyrazine-3-carboxamide and (R)-7- (( 1 -((3-amino-4-hydroxy-2-methylbutan-2- yl)sulfonyl)cyclopropyl)methyl)-N-(4-chlorobenzyl)-8-oxo-5,6,7,8-tetrahydroimidazo[l,5- a]pyrazine-3-carboxamide. 7-((1-((3-amino-4-hydroxy-2-methylbutan-2-yl)sulfonyl)cyclo propyl)methyl)-N-(4-chlorobenzyl)-8-oxo-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-3- carboxamide (55 mg, 0.105 mmol) was separated by SFC to afford (S)-7-((1-((3-amino-4- hydroxy-2-methylbutan-2-yl)sulfonyl)cyclopropyl)methyl)-N-(4-chlorobenzyl)-8-oxo-5, 6,7,8- tetrahydroimidazo[1,5-a]pyrazine-3-carboxamide (Example 23) (15.6 mg, 28% yield). LC-MS: 524 [M-1]⁺; HPLC: RT = 4.65 min, 97.1 %, Column: X-Bridge C8 (50 x 4.6)mm, 3-5 μm, Mobile phase A: 10 mM ammonium bicarbonate in water, Mobile phase: B Acetonitrile; ¹-H NMR (400 MHz, DMSO-d₆): δ 9.34 (d, J = 6.40 Hz, 1H), 7.59 (s, 1H), 7.40-7.33 (m, 4H), 4.71- 4.65 (m, 3H), 4.41 (d, J = 6.40 Hz, 2H), 4.13 (s, 2H), 3.75 (t, J = 6.00 Hz, 2H), 3.67 (t, J = 3.60 Hz, 1H), 3.31 (t, J = 7.60 Hz, 1H), 3.21 (q, J = 3.20 Hz, 1H), 2.06 (d, 7 = 19.20 Hz, 2H), 1.42 (s, 6H), 1.36 (t, J = 4.00 Hz, 2H), 1.05 (d, J = 3.20 Hz, 2H) ppm and (R)-7-((1-((3-amino-4- hydroxy-2-methylbutan-2-yl)sulfonyl)cyclopropyl)methyl)-N-(4-chlorobenzyl)-8-oxo-5, 6,7,8- tetrahydroimidazo[1,5-a]pyrazine-3-carboxamide (Example 24) (12.3 mg, 22%). LC-MS: 524 [M-1]⁺; HPLC: RT = 3.21 min, 97.4%, Column: X-Bridge C8 (50 x 4.6)mm, 3-5 μm, Mobile phase A: 0.1% TFA in water, Mobile phase B: CAN, Flow: 2.0 mL/min; ¹H-NMR (400 MHz, DMSO-d₆): δ 9.33 (s, 1H), 7.60 (s, 1H), 7.40-7.37 (m, 2H), 7.35 (s, 2H), 4.72 (s, 1H), 4.68-4.65 (m, 2H), 4.41 (d, J = 6.40 Hz, 2H), 4.13 (s, 2H), 3.76 (t, J = 6.00 Hz, 2H), 3.67 (d, J = 10.00 Hz, 1H), 3.28 (s, 1H), 3.22 (t, 7= 4.00 Hz, 1H), 1.43 (s, 6H), 1.36 (t, 7 = 4.40 Hz, 2H), 1.06 (d, 7 = 3.20 Hz, 2H) ppm.

6-((1-(tert-Butylsulfonyl)cyc lopropyl)methyl)-N-(4-chlorobenzyl)-7-oxo-4, 5,6,7- tetrahydrothieno[2,3-c] pyridine-3 -carboxamide (Example 25)

Step 1. Synthesis of 6-((1-(tert-butylsulfonyl)cyclopropyl)methyl)-N-(4-chlorobenzyl)-7-oxo- 4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide. To a stirred solution of N-(4- chlorobenzyl)-7-oxo-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide (INT-2) (0.032 g, 0.100 mmol) in DMF (2 mL) were added cesium carbonate (0.130 g, 0.399 mmol) and 1- (bromomethyl)-1-(tert-butylsulfonyl)cyclopropane (INT-8) (0.038 g, 0.150 mmol) at rt. The reaction mixture was stirred at 60 °C for 16 h. The reaction mixture was evaporated under reduced pressure. The resulting residue was purified by HPLC to afford 6-((1-(tert- butylsulfonyl)cyclopropyl)methyl)-N-(4-chlorobenzyl)-7-oxo-4,5,6,7-tetrahydrothieno[2,3-c] pyridine-3-carboxamide (Example 25) (7.7 mg, 15%) as an off white solid. LC-MS: 494.9 [M-1]⁺; HPLC: RT = 4.49 min, 98.8% (Max), Column: X-Bridge C8 (50 x 4.6) mm, 3-5 μm, Mobile phase A: 0.1% FA in water, Mobile phase B: ACN, Flow:2.0mL/min; ¹H-NMR (400 MHz, DMSO-d₆): δ 8.96 (t, J = 5.60 Hz, 1H), 8.35 (s, 1H), 7.40 (d, J = 8.80 Hz, 2H), 7.34 (d, J = 8.40 Hz, 2H), 4.41 (d, J = 6.00 Hz, 2H), 4.06 (s, 2H), 3.64 (t, J = 7.20 Hz, 2H), 3.13 (t, J = 6.80 Hz, 2H), 1.42 (s, 9H), 1.31 (d, J = 2.40 Hz, 2H), 1.01-1.01 (m, 2H) ppm.

2-((1-(tert-Butylsulfonyl)cyc lopropyl)methyl)-N-(4-chlorobenzyl)- 1-oxo- 1,2, 3,4- tetrahydropyrrolo[1,2-a]pyrazine-6-carboxamide (Example 26)

Step 1. Synthesis of 2-((1-(tert-butylsulfonyl)cyclopropyl)methyl)-N-(4-chlorobenzyl)-1-oxo- l,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-6-carboxamide. To a stirred solution of N-(4- chlorobenzyl)-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-6-carboxamide (INT-4) (0.05 g, 0.165 mmol) in DMF (3 mL) were added cesium carbonate (0.268 g, 0.823 mmol) and 1- (bromomethyl)-1-(tert-butylsulfonyl)cyclopropane (INT-8) (0.063 g, 0.247 mmol). The reaction mixture was stirred at 60 °C for 16 h. The reaction mixture was evaporated under reduced pressure. The resulting residue was purified by reverse phase HPLC to afford 2-((1-(tert- butylsulfonyl)cyclo propyl)methyl)-N-(4-chlorobenzyl)- 1-oxo- 1,2,3, 4-tetrahydropyrrolo[ 1,2- a]pyrazine-6-carboxamide (Example 26) (28.1 mg, 36%) as an off white solid. LC-MS: 477.9 [M-1]⁺; HPLC: RT = 4.39 min, 99.8% (Max), Column: X-Bridge C8 (50 x 4.6) mm, 3.5 pm, Mobile phase: A: 0.1% FA in water, Mobile phase B: ACN, Flow: 2.0mL/min; ¹H-NMR (400 MHz, DMSO-d₆): δ 8.93 (t, J = 6.00 Hz, 1H), 7.39 (d, J = 2.00 Hz, 2H), 7.33 (d, J = 8.40 Hz, 2H), 6.92 (d, J = 4.00 Hz, 1H), 6.71 (d, J = 4.00 Hz, 1H), 4.58 (t, J = 6.40 Hz, 2H), 4.41 (d, J = 6.00 Hz, 2H), 4.06 (s, 2H), 3.71 (t, J = 6.00 Hz, 2H), 1.42 (s, 9H), 1.31-1.31 (m, 2H), 1.05- 1.03 (m, 2H) ppm.

Table 1 shows structures and analytical data for representative Examples of the present invention. These compounds can be prepared according to the synthetic schemes described above and using procedures known to those of ordinary skill in the art.

Table 1: Representative Examples of the Invention

Ill

Biological Data

Cell culture

MRC-5 fibroblast cells were cultured in Eagle’s Minimum Essential Medium (MEM) supplemented with 1.5 g/L sodium bicarbonate, non-essential amino acids, 292 mg/L L- glutamine, 110 mg/L sodium pyruvate, 10% fetal bovine serum and 100 units/mL penicillin and streptomycin. The cells are incubated at 37°C and 5% CO₂ and passaged 2-3 times per week to maintain sub-confluent densities.

Assay

AD-169 HCMV antiviral assay

MRC-5 cells were seeded into transparent 96-well plates at a density of 5.0 x 10³ cells per well and allowed to attach overnight. Following attachment, the media was replaced with 50 uL of infection medium (MEM 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 4-fold serial dilution format. The DMSO concentration was normalized to 0.5% for all treatments. Following compound addition, 50 uL of infection medium containing a 1:200 dilution of a HCMV stock (1.6 x 10⁷ TCID₅₀/mL) was added to the cells for a final dilution of 1:400 and incubated at 37°C for 7 days. After the incubation, 10 uL of WST-1 was added to each well and incubated for 4 hours at 37°C. The absorbance was then measured at a wavelength of 450 nm using a Tecan Infinite M1000 Pro plate reader and the cytopathic effect (CPE) was then quantified relative to the full inhibition achieved with 0.5 uM of Letermovir. 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 x 10³ cells 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 37°C 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 x 10⁴ cells 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 TCID50 HSV-2 G strain was added to the cells and incubated at 37°C for 5 days. After the incubation, 10 μL/well of WST-8 chromogenic reagent was added and the plates incubated at 37°C 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 antiviral activity for exemplified compounds of the invention grouped in the following ranges: A indicates EC₅₀ < 100 nM; B indicates EC₅₀ of >100 to <1000 nM; C indicates EC₅₀ of >1,000 to <10,000 nM.

Table 2: Biological assay data for representative Compounds of the invention

It will be understood that various details of the presently disclosed subject matter may be changed without departing from the scope of the presently disclosed subject matter. Furthermore, the foregoing description is for the purpose of illustration only, and not for the purpose of limitation.

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 disclosure.

Although specific embodiments of the present disclosure are herein illustrated and described in detail, the disclosure is not limited thereto. The above detailed descriptions are provided as exemplary of the present disclosure and should not be construed as constituting any limitation of the disclosure. Modifications will be obvious to those skilled in the art, and all modifications that do not depart from the spirit of the disclosure are intended to be included with the scope of the appended claims.

Claims

CLAIMS: That which is claimed is:

1. A compound of Formula I

or a pharmaceutically acceptable salt thereof, wherein:

R⁴ is selected from the group consisting of hydrogen, halo, cyano, nitro, hydroxyl, NR^aR^b, C_1-4alkyl, C_2-4alkcnyl, C_2-4alkynyl and C_1-4alkoxyC_1-4alkyl, wherein the C_1-4alkyl. C2- 4alkenyl, C_2-4alkynyl or C_1-4alkoxyC_1-4alkyl is optionally substituted with 1-3 substituents independently selected from the group consisting of halo, hydroxy, nitro, NR^aR^b and NHC(O)OC_1-4alkyl; R⁶ and R⁷ are independently selected from the group consisting of C_1-4alkyl. hydroxyCi- 4alkyl and C_1-4alkoxyC_1-4alkyl-;

R⁸ is hydrogen, C(O)NR^aR^b, C_1-4alkyl, C_2-4alkenyl, C_2-4alkynyl, C_1-4alkoxyC_1-4alkyl, R¹⁰ or C(O)R¹⁰, wherein the C_1-4alkyl, C_2-4alkenyl, C_1-4alkynyl or C_1-4alkoxyC_1-4alkyl is optionally substituted with 1-3 substituents independently selected from the group consisting of halo, hydroxy, nitro, NR^aR^b and NHC(O)OC_1-4alkyl;

R⁹ is independently selected for each occurrence from the group consisting of halo, cyano, nitro, hydroxyl, NR^aR^b, C_1-4alkyl, C_2-4alkcnyl, C_2-4alkynyl and C_1-4alkoxyC_1-4alkyl, wherein the C_1-4alkyl. C_2-4alkenyl, C_2-4alkynyl or C_1-4alkoxyC_1-4alkyl is optionally substituted with 1-3 substituents; independently selected from the group consisting of halo, hydroxy, nitro, NR^aR^b and NHC(O)OC_1-4alkyl;

R^9a is hydrogen or C_1-4alkyl;

X is O or S; w is 0, 1 or 2; x is 0 or 1 ; and y is 0, 1, 2 or 3.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, of Formula la

Formula la.

3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, of Formula lb

Formula lb.

4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, of Formula

Ic

Formula Ic.

5. The compound according to any one of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein R¹ is Cl or CN.

6. The compound according to any one of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein R² is hydrogen or F.

7. The compound according to any one of claims 1-6, or a pharmaceutically acceptable salt thereof, wherein

8. The compound of claim 7, or a pharmaceutically acceptable salt thereof, wherein R⁶ and R⁷ are independently selected from the group consisting of CH₃, CH₂OH and CH₂OCH₃.

9. The compound of claim 8, or a pharmaceutically acceptable salt thereof, wherein R⁶ and R⁷ are CH₃.

10. The compound according to any one of claims 7-9, or a pharmaceutically acceptable salt thereof, wherein R⁸ is cyano, CH₃, CH₂F, CH₂OH, vinyl, CH₂CHF₂, CH(OH)CH₃, CH(OH)CH₂OH, CH(OH)CH₂NO₂, CH(OH)CH₂NH₂, or CH₂OCH₃.

11. The compound according to any one of claims 1-6, or a pharmaceutically acceptable salt thereof, wherein R³ is selected from the group consisting of

12. The compound of claim 1 1 , or a pharmaceutically acceptable salt thereof, wherein R³ is selected from the group consisting of

13. The compound of claim 12, or a pharmaceutically acceptable salt thereof, wherein R³ is selected from the group consisting of

14. The compound of claim 11, or a pharmaceutically acceptable salt thereof, wherein R³ is

15. The compound of claim 14, or a pharmaceutically acceptable salt thereof, wherein R³ is selected from the group consisting of

16. The compound according to any one of claims 1-6, or a pharmaceutically acceptable salt

17. The compound of claims 16, or a pharmaceutically acceptable salt thereof, wherein R³ is

18. The compound according to any one of claims 1-6, or a pharmaceutically acceptable salt thereof, wherein R is selected from the group consisting

19. The compound of claim 18, or a pharmaceutically acceptable salt thereof, wherein R³ is

20. A pharmaceutical composition comprising a compound according to any one of claims 1-19, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

21. The pharmaceutical composition of claim 20, further comprising one or more additional therapeutic agents, wherein said additional therapeutic agents are selected from anti-herpes agents, and immunomodulators.

22. A method for the treatment or prophylaxis of a herpes virus 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 1-19, or a pharmaceutically acceptable salt thereof.

23. A method for the treatment or prophylaxis of a herpes virus infection in a subject in need thereof, the method comprising: administering to the subject a therapeutically effective amount of a pharmaceutical composition of claim 21.

24. The method of claim 22 or 23, wherein infection is an HSV-1 infection.

25. The method of claim 22 or 23, wherein infection is an HSV-2 infection.

26. The method of claim 22 or 23, wherein infection is an CMV infection.

27. The compound according to any one of claims 1-19 for use as a medicament.

28. The compound according to any one of claims 1-19 for the use in therapy.