Antiviral indolinyl compounds and uses thereof

Abstract

The present disclosure relates to indolinyl compounds. The present disclosure further relates to compounds that inhibit viral helicase-primase. The present disclosure further relates to the use of the compounds for preparing medicaments for the treatment of diseases and / or conditions by inhibiting viral helicase-primase. The present disclosure also relates to the use of these compounds in the treatment of viral infections. The present disclosure further relates to intermediates for the preparation, and pharmaceutical compositions containing the compounds.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 63 / 344,487, filed May 20, 2022, which is incorporated herein in its entirety for all purposes.

[0002] Sequence Listing This application contains a Sequence Listing that has been submitted electronically in XML file format, which is incorporated herein by reference in its entirety. The above .XML copy, created on April 10, 2023, is named 1422-WO-PCT.xml and is 3,468 bytes in size.

[0003] The present disclosure relates to indolinyl compounds. The present disclosure also relates to the use of these compounds in the treatment of viral infections. The present disclosure further relates to intermediates for their preparation, and pharmaceutical compositions containing these compounds. [Background technology]

[0004] Herpes viruses have a very high global prevalence and disease burden. They include herpes simplex virus 1 (HSV-1), herpes simplex virus 2 (HSV-2), varicella zoster virus, Epstein-Barr virus, and cytomegalovirus. HSV-1 and HSV-2 are contagious human pathogens. HSV-1 is primarily transmitted by oral contact and causes oral herpes, while HSV-2 is a sexually transmitted infection that causes genital herpes. These infections are lifelong and characterized by periodic reactivation and viral shedding, which can cause symptoms such as painful blisters or ulcers, and transmission to others. Currently available drugs to treat these infections are primarily based on nucleoside analogues such as acyclovir, famciclovir, and valacyclovir. These compounds are effective in reducing the severity and frequency of symptoms, but do not eliminate viral shedding and therefore the risk of transmission. In addition, the administration regimen is complicated and inconvenient.

[0005] Herpesviruses encode their own helicase and primase for the synthesis of viral DNA. The helicase-primase complex plays an important role in viral DNA replication. The helicase separates the viral DNA double helix, and the primase synthesizes an RNA primer on the single-stranded DNA that initiates DNA synthesis directed by DNA polymerase (Kleymann G. 2004).

[0006] There is a need for new, more effective and safer drugs with improved pharmacokinetics. Inhibition of viral helicase-primase can prevent viral replication and thus lead to the development of drugs with desirable selectivity, potency, metabolic stability, or reduced adverse effects. Summary of the Invention

[0007] The present disclosure relates to indolinyl compounds. The present disclosure also relates to compounds that inhibit viral helicase-primase. The present disclosure further relates to the use of the compounds for the treatment and / or prevention of diseases and / or conditions.

[0008] In one embodiment, the compound of formula (I) [ka] , or a pharma- ceutically acceptable salt thereof, wherein: R 1 but, [ka] and R 2a , R 2b , and R 2c are each independently H, halogen, or C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, -CN, C 1~6 Haloalkoxy, or -SCF 3 and R 3a and R 3b are each independently H, halogen, or C 1~6 Alkyl or C 1~6 Is it a haloalkyl? or R 3a and R 3b However, together with the carbon to which they are attached, C 3~6 Form a cycloalkyl, R 3a and R 3b The cycloalkyl formed from the formula (I) is a cycloalkyl group having 1 to 3 Z 3 and optionally substituted with X a and X b each independently represents O or CR 7a R 7b and R 7a and R 7b However, independently, H, C 1~6Alkyl or C 1~6 Is it a haloalkyl? or R 7a and R 7b However, together with the carbon to which they are attached, C 3~6 Form a cycloalkyl, R 7a and R 7b C formed from 3~6 Cycloalkyl may be the same or different, and may have 1 to 3 Z 7 and optionally substituted with R 4a , R 4b , and R 4c are each independently H, halogen, or C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, -CN, -SCF 3 , or Z 4 C optionally substituted with 3~6 is cycloalkyl, R 5 But, C 6~10 aryl or heteroaryl, R 5 The aryl or heteroaryl may be the same or different, and may be 1 to 3 Z 5 and optionally substituted with R 5 each heteroaryl is independently a 5- to 10-membered heteroaryl having 1 to 3 heteroatoms selected from N, O, and S; R 6 But, H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~8 Alkoxyalkyl, or C 3~6 cycloalkyl, R 6 Cycloalkyl is 1 to 3 Z 6 and optionally substituted with each Z 3 , Z 4 , Z 5 , Z 6 , and Z 7 are independently halogen, -CN, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6Alkoxy or C 1~6 Provided herein are compounds, or a pharma- ceutically acceptable salt thereof, which are haloalkoxy.

[0009] In some embodiments, provided herein is a pharmaceutical composition comprising a compound provided herein or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable excipient or carrier. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of a compound provided herein or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable excipient or carrier.

[0010] In some embodiments, the pharmaceutical compositions provided herein further comprise one or more (e.g., 1, 2, 3, 4, 1 or 2, 1 to 3, or 1 to 4) additional therapeutic agents, or pharma- ceutically acceptable salts thereof. In some embodiments, the pharmaceutical compositions further comprise a therapeutically effective amount of one or more (e.g., 1, 2, 3, 4, 1 or 2, 1 to 3, or 1 to 4) additional therapeutic agents, or pharma- ceutically acceptable salts thereof.

[0011] In some embodiments, the disclosure provides a method of inhibiting herpesvirus helicase-primase in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound provided herein (e.g., a compound of (I), (IIa), (IIb), (IIc), (IId), (IIe), or (IIf)), or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition provided herein.

[0012] In some embodiments, the disclosure provides a method of treating a patient having a herpes virus-mediated condition, comprising administering to the patient a therapeutically effective amount of a compound provided herein (e.g., a compound of Formula (I), (IIa), (IIb), (IIc), (IId), (IIe), or (IIf)), or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition provided herein. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0013] The present disclosure relates to compounds that inhibit herpes virus helicase primase. In one embodiment, the disclosure relates to indolinyl compounds. The disclosure further relates to the use of the compounds for treating and / or preventing diseases and / or conditions with the compounds. The disclosure also relates to compositions and methods for treating and / or preventing viral infections comprising an inhibitor of herpes virus helicase primase in combination with one or more additional therapeutic agents.

[0014] Patients infected with herpes viruses may benefit from treatment with an inhibitor of herpes virus helicase primase and, optionally, one or more additional therapeutic agents.

[0015] Definitions and general parameters The following description is made with the understanding that the disclosure should be considered as an illustration of the subject matter recited in the claims, and is not intended to limit the scope of the appended claims to the specific embodiments illustrated. The headings used throughout this disclosure are for convenience only and should not be construed as limiting the scope of the claims in any way. An embodiment illustrated under any heading may be combined with an embodiment illustrated under any other heading.

[0016] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art. Please note that as used in this specification and the appended claims, the singular forms "a", "and" and "the" include plural referents unless the context clearly indicates otherwise. Thus, for example, a reference to a "compound" includes a plurality of such compounds, and a reference to an "assay" includes a reference to one or more assays and equivalents thereof known to those skilled in the art, etc.

[0017] As used herein, the following words and phrases are intended to have the meanings generally set forth below, unless a different meaning is suggested by the context in which they are used.

[0018] A dash ("-") that is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, -CONH 2 is attached through a carbon atom. Dashes at the front or end of chemical groups are for convenience and chemical groups may be depicted with or without one or more dashes without losing their ordinary meaning. A wavy line drawn across a line in a structure indicates the point of attachment of the group. No directionality is indicated or implied by the order in which chemical groups are written or named, unless chemically or structurally required. A solid line projecting from the center of a ring indicates that the point of attachment of a substituent on that ring may be at any ring atom. For example, R in the structure below a can be attached to any of the five carbon ring atoms, or R a may replace the hydrogen attached to the nitrogen ring atom: [ka]

[0019] "C u-v " prefix indicates that the following group has u to v carbon atoms. For example, "C 1-6 "Alkyl group" indicates that the alkyl group has 1 to 6 carbon atoms. Similarly, the term "xy-membered" ring, where x and y are numerical ranges (e.g., "3-12-membered heterocyclyl") refers to a ring having from x to y (e.g., 3 to 12) atoms, up to 80% of which may be heteroatoms such as N, O, S, P, etc., and the remaining atoms are carbon.

[0020] Also, certain commonly used alternative chemical nomenclature may or may not be used. For example, divalent groups such as divalent "alkyl" groups, divalent "aryl" groups, etc. may also be referred to as "alkylene" or "alkylenyl" groups, or alkylyl groups, "arylene" or "arylenyl" groups, or arylyl groups, respectively.

[0021] "Compounds disclosed herein" or "compounds of the disclosure" or "compounds provided herein" or "compounds described herein" refer to compounds of formula (I), (IIa), (IIb), (IIc), (IId), (IIe), or (IIf). Also included are specific compounds provided herein.

[0022] Reference herein to "about" a value or parameter includes (and describes) embodiments directed to the value or parameter itself. In certain embodiments, the term "about" includes the indicated amount ±10%. In other embodiments, the term "about" includes the indicated amount ±5%. In certain other embodiments, the term "about" includes the indicated amount ±1%. Additionally, the term "about X" includes a description of "X." Additionally, the singular forms "a" and "the" include plural referents unless the context clearly indicates otherwise. Thus, for example, reference to "a compound" includes a plurality of such compounds, and reference to "an assay" includes reference to one or more assays and equivalents thereof known to those of skill in the art.

[0023] "Alkyl" refers to an unbranched or branched saturated hydrocarbon chain. As used herein, alkyl refers to a group having 1 to 20 carbon atoms (i.e., C 1~20 alkyl), 1 to 8 carbon atoms (i.e., C 1~8 alkyl), 1 to 6 carbon atoms (i.e., C 1~6 alkyl), 1 to 4 carbon atoms (i.e., C 1~4 alkyl), or 1 to 3 carbon atoms (i.e., C 1~3 Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. When an alkyl group having a particular number of carbons is named by a chemical name or specified by a molecular formula, all positional isomers having that number of carbons may be included. Thus, for example, "butyl" includes n-butyl (i.e., -(CH2 ) 3 CH 3 ), sec-butyl (i.e., -CH(CH 3 )CH 2 CH 3 ), isobutyl (i.e., -CH 2 CH(CH 3 ) 2 ) and tert-butyl (i.e., -C(CH 3 ) 3 ), and "propyl" includes n-propyl (i.e., -(CH 2 ) 2 CH 3 ) and isopropyl (i.e., -CH(CH 3 ) 2 ) are included.

[0024] "Alkenyl" refers to an alkyl group containing at least one carbon-carbon double bond and having 2 to 20 carbon atoms (i.e., C 2~20 alkenyl), having 2 to 8 carbon atoms (i.e., C 2~8 alkenyl), having 2 to 6 carbon atoms (i.e., C 2~6 alkenyl), or having 2 to 4 carbon atoms (i.e., C 2~4 Alkenyl refers to an aliphatic group. Examples of alkenyl groups are ethenyl, propenyl, and butadienyl (including 1,2-butadienyl and 1,3-butadienyl).

[0025] "Alkynyl" refers to an alkyl group containing at least one carbon-carbon triple bond and having 2 to 20 carbon atoms (i.e., C 2~20 alkynyl), having 2 to 8 carbon atoms (i.e., C 2~8 alkynyl), having 2 to 6 carbon atoms (i.e., C 2~6 alkynyl), or having 2 to 4 carbon atoms (i.e., C 2~4 alkynyl), an aliphatic group. The term "alkynyl" also includes alkynyl groups having one triple bond and one double bond.

[0026] "Acyl" refers to the group -C(=O)R, where R is hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be optionally substituted as defined herein. Examples of acyls include formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethyl-carbonyl, and benzoyl.

[0027] "Alkoxy" refers to an alkyl group having an oxygen atom connecting the alkyl group to the point of attachment, alkyl-O-. 16 Alkoxy groups include, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, 2 butoxy, isobutoxy, sec butoxy, tert butoxy, pentoxy, hexoxy, and the like. Alkoxy groups can be further substituted with a variety of substituents as described herein. Alkoxy groups can be substituted or unsubstituted.

[0028] "Alkoxyalkyl" refers to an alkoxy group linked to an alkyl group which is linked to the remainder of the compound. Alkoxyalkyl has 2 to 6 (C 2~6 Alkoxyalkyl), 2 to 5 (C 2~5 Alkoxyalkyl), 2 to 4 (C 2~4 alkoxyalkyl), or 2 to 3 (C 2~3 The number of carbons refers to the total number of carbons in the alkoxy and alkyl groups. For example, in some embodiments, C 6 Alkoxyalkyl is butyl (C 4 Ethoxy (C alkyl) 2 alkoxy), and in other embodiments, isopropyl (C 3 n-propoxy (C 3 Alkoxy and alkyl are as defined above, where alkyl is divalent, including but not limited to methoxymethyl (CH 3 OCH 2), methoxyethyl (CH 3 OCH 2 CH 2 ) etc. may be mentioned.

[0029] "Amino" is -NR y R z R y and R z is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl, each of which may be optionally substituted.

[0030] As used herein, "aryl" refers to an all-carbon aromatic monocyclic ring or an all-carbon polycyclic ring system in which at least one of the rings is aromatic. For example, in some embodiments, an aryl group has 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 12 carbon atoms. Aryl includes phenyl radicals. Aryl also includes polycyclic ring systems (e.g., ring systems containing 2, 3, or 4 rings) having 9 to 20 carbon atoms, e.g., 9 to 16 carbon atoms, in which at least one ring is aromatic and the other rings may or may not be aromatic (i.e., carbocyclic). Such polycyclic ring systems are optionally substituted with one or more (e.g., 1, 2, or 3) oxo groups on any carbocyclic moiety of the polycyclic ring system. The rings of a polycyclic ring system may be connected to each other by fused bonds, spiro bonds, and bridged bonds, where valency requirements permit. When referring to an aryl with a particular range of atom members (e.g., 6-10 membered aryl), it is also understood that the atom range is for the total ring atoms of the aryl. For example, 6 membered aryl includes phenyl, and 10 membered aryl includes naphthyl and 1,2,3,4-tetrahydronaphthyl. Non-limiting examples of aryl groups include, but are not limited to, phenyl, indenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, anthracenyl, and the like.

[0031] "Cyano" or "carbonitrile" refers to the group CN.

[0032] "Cycloalkyl" refers to saturated or partially saturated cyclic alkyl groups having single or multiple rings, including fused, bridged, and spiro ring systems. The term "cycloalkyl" includes cycloalkenyl groups (i.e., cyclic groups having at least one double bond). As used herein, cycloalkyl refers to groups having 3 to 20 ring carbon atoms (i.e., C 3~20 cycloalkyl), having 3 to 12 ring carbon atoms (i.e., C 3~12 cycloalkyl), having 3 to 10 ring carbon atoms (i.e., C 3~10 cycloalkyl), having 3 to 8 ring carbon atoms (i.e., C 3~8 cycloalkyl), or having 3 to 6 ring carbon atoms (i.e., C 3~6 Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0033] "Fused" refers to a ring that is bonded to an adjacent ring. In some embodiments, the fused ring system is heterocyclyl. In some embodiments, the fused ring system is oxabicyclohexanyl. In some embodiments, the fused ring system is [ka] It is.

[0034] "Bridged" refers to a ring fusion in which non-adjacent atoms on the rings are linked by a divalent substituent, such as an alkylenyl group, an alkylenyl group containing one or two heteroatoms, or a single heteroatom. Quinuclidinyl and admantanyl are examples of bridged ring systems. In some embodiments, the bridged ring is bicyclopentyl (e.g., bicyclo[1.1.1]pentyl), bicycloheptyl (e.g., bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl), or bicyclooctyl (e.g., bicyclo[2.2.2]octyl). In some embodiments, the bridged ring is [ka] It is.

[0035] "Spiro" refers to a ring substituent that is joined by two bonds at the same carbon atom. Examples of spiro groups include 1,1-diethylcyclopentane, dimethyl-dioxolane, and 4-benzyl-4-methylpiperidine, where cyclopentane and piperidine are each spiro substituents. In some embodiments, the spiro substituent is spiropentanyl (spiro[ab]pentanyl), spirohexanyl, spiroheptanyl, spirooctyl (e.g., spiro[2.5]octyl), spirononanyl (e.g., spiro[3.5]nonanyl), spirodecanyl (e.g., spiro[4.5]decanyl), or spiroundecanyl (e.g., spiro[5.5]undecanyl). In some embodiments, the spiro substituent is [ka] It is.

[0036] "Halogen" or "halo" includes fluoro, chloro, bromo, and iodo.

[0037] As used herein, "haloalkyl" refers to an alkyl, as defined herein, in which one or more hydrogen atoms of the alkyl are independently replaced by halo substituents, which may be the same or different. For example, C 1~4 Haloalkyl is C 1~4 one or more of the alkyl hydrogen atoms are replaced by a halo substituent; 1~4 Examples of haloalkyl groups include, but are not limited to, fluoromethyl, fluorochloromethyl, difluoromethyl, difluorochloromethyl, trifluoromethyl, 1,1,1-trifluoroethyl, and pentafluoroethyl.

[0038] "Haloalkoxy" refers to an alkoxy group in which some or all of the hydrogen atoms are replaced with halogen atoms. With respect to an alkyl group, a haloalkoxy group is a C 16 The alkoxy group may have any suitable number of carbon atoms, such as 1, 2, 3, or more halogens. If all hydrogens are replaced by halogens, such as fluorine, the compound is persubstituted, such as perfluorinated. Haloalkoxy includes, but is not limited to, trifluoromethoxy, 2,2,2, trifluoroethoxy, perfluoroethoxy, and the like.

[0039] As used herein, the term "heteroaryl" refers to a monocyclic aromatic ring or a polycyclic ring. The term encompasses monocyclic aromatic monocycles of 1-6 carbon atoms and about 1-4 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur in the ring. The sulfur and nitrogen atoms may be present in oxidized form, provided that the ring is aromatic. Such rings include, but are not limited to, pyridyl, pyrimidinyl, oxazolyl, or furyl. The term also includes polycyclic ring systems (e.g., ring systems containing two or three rings), in which a heteroaryl group as defined above can be fused with one or more heteroaryl (e.g., naphthyridinyl), carbocycle (e.g., 5,6,7,8-tetrahydroquinolyl), or aryl (e.g., indazolyl) to form a polycyclic ring. Such polycyclic rings may be optionally substituted with one or more (e.g., one, two, or three) oxo groups on the carbon moieties of the polycyclic ring. It is understood that the attachment point of a heteroaryl polycyclic ring may be at any position of the ring, including the heteroaryl, aryl, or carbocyclic portions of the ring, as defined above. Exemplary heteroaryls include, but are not limited to, pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, thienyl, indolyl, imidazolyl, oxazolyl, isoxazolyl, furyl, oxadiazolyl, thiadiazolyl, quinolyl, isoquinolyl, benzothiazolyl, benzoxazolyl, indazolyl, quinoxalyl, quinazolyl, 5,6,7,8-tetrahydroisoquinolinyl, benzofuranyl, benzimidazolyl, and thianaphthenyl.

[0040] As used herein, "heterocyclyl" or "heterocyclic ring" or "heterocycle" refers to a single saturated or partially unsaturated ring or polycyclic ring. The term includes saturated or partially unsaturated monocyclic rings (e.g., 3-, 4-, 5-, 6-, or 7-membered rings) of about 1-6 carbon atoms and 1-3 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur in the ring. The ring may be substituted with one or more (e.g., 1, 2, or 3) oxo groups, and the sulfur and nitrogen atoms may be present in their oxidized forms. Such rings include, but are not limited to, azetidinyl, tetrahydrofuranyl, or piperidinyl. The term also includes polycyclic ring systems (e.g., ring systems containing two or three rings) in which a heterocyclic group (as defined above) can be connected to two adjacent atoms (fused heterocycles) with one or more heterocyclic (e.g., decahydronaphthyridinyl), heteroaryl (e.g., 1,2,3,4-tetrahydronaphthyridinyl), carbocyclic (e.g., decahydroquinolyl), or aryl. It is understood that the point of attachment of a heterocyclic polycyclic ring can be at any position of the ring, including the heterocyclic, heteroaryl, aryl, or carbocyclic portions of the ring, as defined above. Exemplary heterocycles include, but are not limited to, aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, tetrahydrofuranyl, dihydrooxazolyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1,2,3,4-tetrahydroquinolyl, benzoxazinyl, dihydrooxazolyl, chromanyl, 1,2-dihydropyridinyl, 2,3-dihydrobenzofuranyl, 1,3-benzodioxolyl, and 1,4-benzodioxanyl. Exemplary fused bicyclic heterocycles include, but are not limited to, [ka]

[0041] "Hydroxy" or "hydroxyl" refers to an OH group.

[0042] "Oxo" refers to the (=O) or (O) radical.

[0043] "Sulfonyl" is S(O) 2 R c R c is alkyl, heterocyclyl, cycloalkyl, heteroaryl, or aryl. Examples of sulfonyl are methylsulfonyl, ethylsulfonyl, phenylsulfonyl, and toluenesulfonyl.

[0044] Whenever the graphical representation of a group terminates in a singly bonded nitrogen atom, the group is represented as -NH 2 Similarly, unless otherwise specified, hydrogen atom(s) are implied and considered to be present where necessary to complete valence or provide stability, given the knowledge of one of ordinary skill in the art.

[0045] The term "optionally" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances when the event or circumstance occurs and instances when the event or circumstance is absent. Also, the term "optionally substituted" means that any one or more hydrogen atoms on a specified atom or group may or may not be replaced by a non-hydrogen moiety.

[0046] The term "substituted" means that any one or more hydrogen atoms on the designated atom or group are replaced with one or more substituents other than hydrogen, provided that the normal valence of the designated atom is not exceeded. The one or more substituents include, but are not limited to, alkyl, alkenyl, alkynyl, alkoxy, acyl, amino, amido, amidino, aryl, azido, carbamoyl, carboxyl, carboxyl ester, cyano, guanidino, halo, haloalkyl, heteroalkyl, heteroaryl, heterocyclyl, hydroxy, hydrazino, imino, oxo, nitro, alkylsulfinyl, sulfonic acid, alkylsulfonyl, thiocyanato, thiol, thione, or combinations thereof. Polymers or similarly indefinite structures obtained by defining the substituents with an infinite number of additional substituents (e.g., substituted aryl with a substituted alkyl, which is itself substituted with a substituted aryl group, which is further substituted with a substituted heteroalkyl group, etc.) are not intended to be included herein. Unless otherwise stated, the maximum number of consecutive substitutions in the compounds described herein is 3. For example, consecutive substitution of a substituted aryl group with two other substituted aryl groups is limited to [(substituted aryl)substituted aryl]substituted aryl. Similarly, the above definition is not intended to include impermissible substitution patterns (e.g., methyl substituted with 5 fluorines or a heteroaryl group with two adjacent oxygen ring atoms). Such impermissible substitution patterns are well known to those skilled in the art. When used to modify a chemical group, the term "substituted" can describe other chemical groups defined herein. For example, the term "substituted aryl" includes, but is not limited to, "alkylaryl". Unless otherwise specified, when a group is described as optionally substituted, any substituents of the group are themselves unsubstituted.

[0047] In some embodiments, the term "substituted alkyl" refers to an alkyl group having one or more substituents including hydroxyl, halo, amino, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl. In additional embodiments, "substituted cycloalkyl" refers to a cycloalkyl group having one or more substituents including alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, amino, alkoxy, halo, oxo, and hydroxyl; "substituted heterocyclyl" refers to a heterocyclyl group having one or more substituents including alkyl, amino, haloalkyl, heterocyclyl, cycloalkyl, aryl, heteroaryl, alkoxy, halo, oxo, and hydroxyl; "substituted aryl" refers to an aryl group having one or more substituents including halo, alkyl, amino, haloalkyl, cycloalkyl, heterocyclyl, heteroaryl, alkoxy, and cyano; "substituted heteroaryl" refers to a heteroaryl group having one or more substituents including halo, amino, alkyl, haloalkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, alkoxy, and cyano; and "substituted sulfonyl" refers to -S(O) 2 Refers to the R group, where R is substituted with one or more substituents including alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl. In other embodiments, one or more of the substituents may be further substituted with halo, alkyl, haloalkyl, hydroxyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is substituted. In other embodiments, the substituents may be further substituted with halo, alkyl, haloalkyl, alkoxy, hydroxyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is unsubstituted.

[0048] In some embodiments, the substituted cycloalkyl, substituted heterocyclyl, substituted aryl, and / or substituted heteroaryl include cycloalkyl, heterocyclyl, aryl, and / or heteroaryl having substituents on the ring atoms to which the cycloalkyl, heterocyclyl, aryl, and / or heteroaryl are attached to the remainder of the compound. For example, in the moiety below, the cyclopropyl is substituted with a methyl group: [ka]

[0049] The disclosure illustratively described herein may suitably be practiced in the absence of any element or elements, limitation or limitations not specifically disclosed herein. Thus, for example, terms such as "comprising," "including," "containing," etc., should be read broadly and without limitation. Furthermore, the terms and expressions used herein are used as terms of description and not of limitation, and there is no intention to use such terms and expressions to exclude any equivalents of the features shown and described, or any portion thereof, but it is recognized that various modifications are possible within the scope of the disclosure as claimed.

[0050] The compounds of the present disclosure may be in the form of pharmaceutically acceptable salts. The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids, including inorganic bases or acids and organic bases or acids. When the compounds of the present disclosure contain one or more acidic or basic groups, the present disclosure also includes the corresponding pharmaceutically or toxicologically acceptable salts of the compounds, or pharmaceutically available salts of the compounds. Thus, compounds of the present disclosure that contain acidic groups may exist in these groups and may be used in accordance with the present disclosure, for example, as alkali metal salts, alkaline earth metal salts, or ammonium salts. More precise examples of such salts include sodium salts, potassium salts, calcium salts, magnesium salts, or salts with ammonia or organic amines, such as ethylamine, ethanolamine, triethanolamine, amino acids, or other bases known to those skilled in the art. Compounds of the present disclosure that contain one or more basic groups, i.e., groups that can be protonated, may exist and may be used in accordance with the present disclosure in the form of their addition salts with inorganic or organic acids. Examples of suitable acids include hydrogen chloride, hydrogen bromide, phosphoric acid, sulfuric acid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acid, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid, sulfamic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, citric acid, adipic acid, and other acids known to those skilled in the art.

[0051] In the case where the compounds of the present disclosure simultaneously contain acidic and basic groups in the molecule, the present disclosure also includes, in addition to the salt forms mentioned, inner salts or betaines (zwitterions). The respective salts can be obtained by conventional methods known to those skilled in the art, for example, by contacting these salts with organic or inorganic acids or bases in a solvent or dispersant, or by anion or cation exchange with other salts.

[0052] The present disclosure also includes all salts of the compounds of the present disclosure that are not directly suitable for use in pharmaceuticals due to poor physiological compatibility, but can be used, for example, as intermediates for chemical reactions or for the preparation of pharmaceutically acceptable salts. Acids and bases useful for reacting with base compounds to form pharmaceutically acceptable salts (acid addition salts or base addition salts, respectively) are known to those skilled in the art. Similarly, methods for preparing pharmaceutically acceptable salts from base compounds (at the time of disclosure) are known to those skilled in the art and are disclosed, for example, in Berge, at al. Journal of Pharmaceutical Science, Jan. 1977 vol. 66, No. 1, and other sources.

[0053] Furthermore, the compounds disclosed herein may be subject to tautomerism. Where tautomerism, e.g., keto-enol tautomerism, of the compounds or their prodrugs may occur, each of the individual forms, e.g., keto and enol forms, is within the scope of the present disclosure, as are mixtures thereof in any ratio. The same applies to stereoisomers, e.g., enantiomers, cis / trans isomers, diastereomers, conformers, etc.

[0054] The term "protecting group" refers to a moiety of a compound that masks or changes the properties of a functional group or the compound as a whole. Chemical protecting groups and strategies for protection / deprotection are well known in the art (see, for example, Protective Groups in Organic Chemistry, Theodora W. Greene, John Wiley & Sons, Inc., New York, 1991). Protecting groups are often used to mask the reactivity of certain functional groups to aid in the effectiveness of desired chemical reactions, for example, to create and break chemical bonds in an orderly and planned manner. The term "deprotection" refers to the removal of a protecting group.

[0055] Those of skill in the art will understand that if the list of alternative substituents includes members that cannot be used to replace a particular group due to the members' valence requirements or for other reasons, the list is intended to be read with the knowledge of those of skill in the art to include only those members of the list that are suitable to replace the particular group.

[0056] Additionally, the compounds of the present disclosure may exist in the form of solvates, such as solvates that include pharma- ceutically acceptable solvates such as water of solvation or alcohols, particularly ethanol. A "solvate" is formed by the interaction of a solvent with a compound.

[0057] In certain embodiments, optical isomers, racemates, or other mixtures thereof (e.g., scalemic mixtures) of the compounds described herein or pharma- ceutically acceptable salts thereof, or mixtures thereof, are provided. If desired, isomers can be separated by methods well known in the art, for example, liquid chromatography. In these situations, single enantiomers or diastereomers, i.e., optically active forms, can be obtained by asymmetric synthesis or by resolution. Resolution can be achieved by conventional methods, such as, for example, crystallization in the presence of a resolving agent, or chromatography, for example, using a chiral high pressure liquid chromatography (HPLC) column.

[0058] "Stereoisomer" refers to a compound that is composed of the same atoms bonded by the same bonds, but has different three-dimensional structures that are not interchangeable. The present invention contemplates various stereoisomers and mixtures thereof, including "enantiomers" which refer to two stereoisomers whose molecules are non-superimposable mirror images of one another. "Diastereomers" are stereoisomers that have at least two asymmetric atoms, but are not mirror images of each other. Unless otherwise specified, the description is intended to include individual stereoisomers and mixtures. Methods for the determination of stereochemistry and the separation of stereoisomers are well known in the art (see, for example, Chapter 4 of Advanced Organic Chemistry, 4th ed., J. March, John Wiley and Sons, New York, 1992).

[0059] The compounds disclosed herein and their pharma- ceutically acceptable salts may, in some embodiments, contain asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined with respect to absolute stereochemistry as (R)- or (S)-, or, in the case of amino acids, as (D)- or (L)-. Some embodiments include all such possible isomers, as well as their racemic, scalemic, and optically pure forms. Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents and resolved using conventional techniques, e.g., chromatography and fractional crystallization. Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from suitable optically pure precursors or resolution of the racemates (or racemates of salts or derivatives) using, e.g., chiral high-pressure liquid chromatography (HPLC). When compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless otherwise specified, these compounds are intended to include both E and Z geometric isomers. Likewise, all tautomeric forms are intended to be included. When compounds are represented in their chiral form, it is understood that the embodiments include, but are not limited to, the specific diastereomerically or enantiomerically enriched forms. When chirality is not specified, it is understood that the embodiments are directed to either the specific diastereomerically or enantiomerically enriched forms, or racemic or scalemic mixtures of such compound(s). As used herein, a "scalemic mixture" is a mixture of stereoisomers in a ratio other than 1:1.

[0060] Compositions provided herein that contain the compounds described herein, or pharma- ceutically acceptable salts, isomers, or mixtures thereof, may include racemic mixtures, or mixtures containing an enantiomeric excess of one enantiomer or a single diastereomer, or diastereomeric mixtures. All such isomeric forms of these compounds are expressly included herein as if each and every isomeric form were specifically and individually listed.

[0061] Any formula or structure given herein is also intended to represent unlabeled and isotopically labeled forms of the compound. Isotopically labeled compounds have the structure shown by the formula given herein, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into the compounds of the present disclosure include: 2 H (deuterium, D), 3 H (tritium), 11 C. 13 C. 14 C. 15 N, 18 F, 31 P, 32 P, 35 S, 36 Cl, and 125 I and isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, including, but not limited to, I. Various isotopically labeled compounds of the present disclosure include, for example, 3 H, 13 C and 14 A radioisotope such as C is incorporated. Such isotopically labeled compounds may be useful in detection or imaging techniques, including metabolic studies, reaction kinetic studies, drug or substrate tissue distribution assays, such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), or in radiotherapy of patients. The isotopically labeled compounds of the present disclosure and their prodrugs can generally be prepared by carrying out the procedures disclosed in the schemes or examples and preparations described below, by substituting readily available isotopically labeled reagents with non-isotopically labeled reagents.

[0062] The present disclosure also includes "deuterated analogs" of the compounds disclosed herein in which 1 to n hydrogens attached to a carbon atom have been replaced by deuterium, where n is the number of hydrogens in the molecule. Such compounds may exhibit increased resistance to metabolism and thus may be useful, for example, for increasing the half-life of any compound of formula (I) when administered to a mammal, such as a human. See, for example, Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism", Trends Pharmacol.Sci.5(12):524-527 (1984). Such compounds are synthesized by means well known in the art, for example, by employing starting materials in which one or more hydrogens have been replaced by deuterium.

[0063] Deuterium-labeled or deuterium-substituted therapeutic compounds of the present disclosure may have improved DMPK (drug metabolism and pharmacokinetic) properties with respect to distribution, metabolism and excretion (ADME). Substitution with heavier isotopes such as deuterium may confer certain therapeutic advantages due to greater metabolic stability, such as increased in vivo half-life, reduced dosage requirements and / or improved therapeutic index. 18 F-labeled compounds may be useful in PET or SPECT studies.

[0064] The concentration of such heavier isotopes, specifically deuterium, can be defined by the isotopic enrichment factor. In the compounds of the present disclosure, any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom. Unless otherwise stated, when a position is specifically designated as "H" or "hydrogen", the position is understood to have that hydrogen in the natural abundance isotopic composition of hydrogen. Thus, in the compounds of the present disclosure, any atom specifically designated as deuterium (D) is meant to represent deuterium.

[0065] Further, the present disclosure provides a pharmaceutical composition comprising, as an active ingredient, a compound of the present disclosure, or a prodrug compound thereof, or a pharma- ceutically acceptable salt or solvate thereof, together with a pharma- ceutically acceptable carrier.

[0066] "Pharmaceutical composition" refers to one or more active ingredients and one or more inactive ingredients that make up the carrier, as well as any product that results directly or indirectly from the combination, complexation or aggregation of any two or more of the ingredients, or from the dissociation of one or more of the ingredients, or from any other type of reaction or interaction of one or more of the ingredients. Thus, the pharmaceutical composition of the present disclosure can include any composition made by mixing at least one compound of the present disclosure with a pharma-ceutically acceptable carrier.

[0067] As used herein, "pharmaceutically acceptable carriers" include excipients or agents, such as solvents, diluents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, that are not deleterious to the disclosed compounds or their use. The use of such carriers and agents to prepare compositions of pharma- ceutically active substances is well known in the art (see, for example, Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, PA 17th Ed. (1985), and Modern Pharmaceutics, Marcel Dekker, Inc. 3rd Ed. (G.S. Banker & C.T. Rhodes, Eds.).

[0068] "Treatment" or "treating" is an approach for obtaining beneficial or desired results, including clinical results. Beneficial or desired clinical results may include one or more of the following: a) inhibiting the disease or condition (e.g., reducing one or more symptoms resulting from the disease or condition and / or lessening the severity of the disease or condition), b) delaying or preventing the onset of one or more clinical symptoms associated with the disease or condition (e.g., stabilizing the disease or condition, preventing or slowing the worsening or progression of the disease or condition, and / or preventing or slowing the spread (e.g., metastasis) of the disease or condition), and / or c) palliating the disease, i.e., causing regression of clinical symptoms (e.g., improving the disease state, providing partial or total recovery of the disease or condition, enhancing the effect of another medication, delaying disease progression, improving quality of life, and / or prolonging survival. In some embodiments, the term "treatment" or "treating" refers to the administration of a compound of Formula (I), (IIa), (IIb), (IIc), (IId), (IIe), or (IIf) or a pharma- ceutically acceptable salt thereof, to (i) delay the onset of the disease, i.e., to prevent or delay the onset of clinical symptoms of the disease, (ii) inhibit the disease, i.e., to prevent the onset of clinical symptoms, and / or (iii) palliate the disease, i.e., to cause regression of clinical symptoms or their severity.

[0069] "Prevention" or "preventing" refers to any treatment of a disease or condition that does not result in the development of clinical symptoms of the disease or condition. In some embodiments, the compounds may be administered to subjects (including humans) who are at risk or have a family history of the disease or condition.

[0070] "Subject" refers to an animal, such as a mammal (including a human), that has been or is the object of treatment, observation, or experiment. The methods described herein may be useful in human therapy and / or veterinary applications. In some embodiments, the subject is a mammal. In some embodiments, the subject is a human.

[0071] The term "therapeutically effective amount" or "effective amount" of a compound described herein or a pharma- ceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analogue thereof means an amount sufficient to effect treatment and provide a therapeutic benefit, such as amelioration of symptoms or slowing of disease progression, upon administration to a subject. For example, a therapeutically effective amount can be an amount sufficient to reduce symptoms of a disease or condition in response to a herpesvirus helicase-primase inhibitor. A therapeutically effective amount may vary depending on the subject, the disease or condition being treated, the weight and age of the subject, the severity of the disease or condition, and the mode of administration, and can be readily determined by one of skill in the art.

[0072] compound In one embodiment, the present disclosure provides a compound of formula (I) [ka] , or a pharma- ceutically acceptable salt thereof, wherein: R 1 but, [ka] and R 2a , R 2b , and R 2c are each independently H, halogen, or C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, -CN, C 1~6 Haloalkoxy, or -SCF 3 and R 3a and R 3bare each independently H, halogen, or C 1~6 Alkyl or C 1~6 Is it a haloalkyl? or R 3a and R 3b However, together with the carbon to which they are attached, C 3~6 Form a cycloalkyl, R 3a and R 3b The cycloalkyl formed from the formula (I) is a cycloalkyl group having 1 to 3 Z 3 and optionally substituted with X a and X b each independently represents O or CR 7a R 7b and R 7a and R 7b However, independently, H, C 1~6 Alkyl or C 1~6 Is it a haloalkyl? or R 7a and R 7b However, together with the carbon to which they are attached, C 3~6 Form a cycloalkyl, R 7a and R 7b C formed from 3~6 Cycloalkyl may be the same or different, and may have 1 to 3 Z 7 and optionally substituted with R 4a , R 4b , and R 4c are each independently H, halogen, or C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, -CN, -SCF 3 , or Z 4 C optionally substituted with 3~6 is cycloalkyl, R 5 But, C 6~10 aryl or heteroaryl, R 5 The aryl or heteroaryl may be the same or different, and may be 1 to 3 Z 5 and optionally substituted with R5 each heteroaryl is independently a 5- to 10-membered heteroaryl having 1 to 3 heteroatoms selected from N, O, and S; R 6 But, H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~8 Alkoxyalkyl, or C 3~6 cycloalkyl, R 6 Cycloalkyl is 1 to 3 Z 6 and optionally substituted with each Z 3 , Z 4 , Z 5 , Z 6 , and Z 7 are independently halogen, -CN, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy or C 1~6 The present invention provides a compound, or a pharma- ceutically acceptable salt thereof, which is haloalkoxy.

[0073] In some embodiments, the compound of formula (I) is a compound of formula (IIa) [ka] or a pharma- ceutically acceptable salt thereof.

[0074] In some embodiments, the compound of formula (I) is a compound of formula (IIb) [ka] or a pharma- ceutically acceptable salt thereof.

[0075] In some embodiments, the compound of formula (I) is a compound of formula (IIc) [ka] or a pharma- ceutically acceptable salt thereof.

[0076] In some embodiments, the compound of formula (I) is a compound of formula (IId) [ka] or a pharma- ceutically acceptable salt thereof.

[0077] In some embodiments, the compound of Formula (I) is a compound of Formula (IIe), or a pharma- ceutically acceptable salt thereof: [ka] In the formula, R 7a1 and R 7b1 However, independently, H, C 1~6 Alkyl or C 1~6 haloalkyl or R 7a1 and R 7b1 However, together with the carbon to which they are attached, C 3~6 Form a cycloalkyl, R 7a1 and R 7b1 C formed from 3~6 Cycloalkyl may be the same or different, and may have 1 to 3 Z 7 may be optionally substituted with

[0078] In some embodiments, the compound of formula (I) is a compound of formula (IIf), or a pharma- ceutically acceptable salt thereof: [ka] In the formula, R 7a1 and R 7b1 However, independently, H, C 1~6 Alkyl or C 1~6 haloalkyl or R 7a1 and R 7b1 However, together with the carbon to which they are attached, C 3~6 Form a cycloalkyl, R 7a1 and R 7b1 C formed from 3~6 Cycloalkyl may be the same or different, and may have 1 to 3 Z 7 may be optionally substituted with

[0079] In some embodiments, the compound is a compound of Formula (IIe) or Formula (IIf).

[0080] In some embodiments, a compound of Formula (I), (IIa), (IIb), (IIc), (IId), (IIe), or (IIf), or a pharma- ceutically acceptable salt thereof, is [ka] It is a compound wherein

[0081] In some embodiments, the compound of Formula (I), (IIa), (IIb), (IIc), (IId), (IIe), or (IIf), or a pharma- ceutically acceptable salt thereof, is 1 but [ka] In some embodiments, R 1 teeth, [ka] It is.

[0082] In some embodiments, the compound of Formula (I), (IIa), (IIb), (IIc), (IId), (IIe), or (IIf), or a pharma- ceutically acceptable salt thereof, is 2a is H. In some embodiments, R 2a is halogen or C 1~6 In some embodiments, R 2a is F, Cl, or Br. In some embodiments, R 2a is F. In some embodiments, R 2a is C 1~3 In some embodiments, R 2a is methyl.

[0083] In some embodiments, the compound of Formula (I), (IIa), (IIb), (IIc), (IId), (IIe), or (IIf), or a pharma- ceutically acceptable salt thereof, is 2b is H. In some embodiments, R 2b is halogen or C 1~6 In some embodiments, R 2b is F, Cl, or Br. In some embodiments, R 2b is F. In some embodiments, R 2b is C 1~3 In some embodiments, R 2b is methyl.

[0084] In some embodiments, the compound of Formula (I), (IIa), (IIb), (IIc), (IId), (IIe), or (IIf), or a pharma- ceutically acceptable salt thereof, is 2c is H. In some embodiments, R 2c is halogen or C 1~6 In some embodiments, R 2c is F, Cl, or Br. In some embodiments, R 2c is F. In some embodiments, R 2c is C 1~3 In some embodiments, R 2c is methyl.

[0085] In some embodiments, the compound of Formula (I), (IIa), (IIb), (IIc), (IId), (IIe), or (IIf), or a pharma- ceutically acceptable salt thereof, is 3a is H. In some embodiments, R 3a is C 1~6 In some embodiments, R 3a is C 1~3 In some embodiments, R 3a is methyl.

[0086] In some embodiments, the compound of Formula (I), (IIa), (IIb), (IIc), (IId), (IIe), or (IIf), or a pharma- ceutically acceptable salt thereof, is 3b is H. In some embodiments, R 3b is C 1~6 In some embodiments, R 3b is C 1~3 In some embodiments, R 3b is methyl.

[0087] In some embodiments, the compound of Formula (I), (IIa), (IIb), (IIc), (IId), (IIe), or (IIf), or a pharma- ceutically acceptable salt thereof, is 3a and R 3b However, together with the carbon to which they are attached, C 3~6 In some embodiments, R 3a and R 3b together with the carbon to which they are attached form a cyclopropyl.

[0088] In some embodiments, the compound of Formula (I), (IIa), (IIb), (IIc), (IId), (IIe), or (IIf), or a pharma- ceutically acceptable salt thereof, is 4a is H. In some embodiments, R 4a is halogen. In some embodiments, R 4a is F, Cl, or Br. In some embodiments, R 4a is F.

[0089] In some embodiments, the compound of Formula (I), (IIa), (IIb), (IIc), (IId), (IIe), or (IIf), or a pharma- ceutically acceptable salt thereof, is 4b is H. In some embodiments, R 4b is halogen. In some embodiments, R 4b is F, Cl, or Br. In some embodiments, R 4bis F.

[0090] In some embodiments, the compound of Formula (I), (IIa), (IIb), (IIc), (IId), (IIe), or (IIf), or a pharma- ceutically acceptable salt thereof, is 4c is H. In some embodiments, R 4c is halogen. In some embodiments, R 4c is F, Cl, or Br. In some embodiments, R 4c is F.

[0091] In some embodiments, the compound of Formula (I), (IIa), (IIb), (IIc), (IId), (IIe), or (IIf), or a pharma- ceutically acceptable salt thereof, is 5 is 1 to 3 Z, which may be the same or different 5 C optionally substituted with 6~10 aryl, and each Z 5 are independently halogen, -CN, C 1~6 Alkyl or C 1~6 In some embodiments, R 5 is phenyl optionally substituted with 1 to 3 halo. In some embodiments, R 5 is phenyl optionally substituted with 1-3 F. In some embodiments, R 5 is phenyl, [ka] It is.

[0092] In some embodiments, the compound of Formula (I), (IIa), (IIb), (IIc), (IId), (IIe), or (IIf), or a pharma- ceutically acceptable salt thereof, is 5 is 1 to 3 Z, which may be the same or different 5 In some embodiments, R is a heteroaryl optionally substituted with 5is a heteroaryl selected from thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrrolyl, pyrazolyl, triazolyl, pyridyl, pyrazinyl, and pyrimidinyl; R 5 The heteroaryl may have 1 to 3 Z 5 In some embodiments, R 5 is 1 to 3 Z, which may be the same or different 5 In some embodiments, R is pyridyl optionally substituted with 5 is 1 to 3 Z, which may be the same or different 5 In some embodiments, R is diazinyl optionally substituted with 5 is triazolyl or pyrazolyl, each of which may be the same or different, and may be 1 to 3 Z 5 In some embodiments, R 5 is thiazolyl, isothiazolyl, oxazolyl, or isoxazolyl; R 5 Thiazolyl, isothiazolyl, oxazolyl, and isoxazolyl each may be the same or different, and each may have 1 to 3 Z 5 In some embodiments, each Z 5 are independently halogen, -CN, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy or C 1~6 In some embodiments, each Z 5 are independently halogen, C 1~3 Alkyl, -CN, or -OCH 3 In some embodiments, Z 5 is F.

[0093] In some embodiments, the compound of Formula (I), (IIa), (IIb), (IIc), (IId), (IIe), or (IIf), or a pharma- ceutically acceptable salt thereof, is 5 But pyridyl, [ka] In some embodiments, R 5 is pyridyl. In some embodiments, R 5 teeth, [ka] In some embodiments, R 5 teeth, [ka] In some embodiments, R 5 teeth, [ka] In some embodiments, R 5 teeth, [ka] It is.

[0094] In some embodiments, the compound of Formula (I), (IIa), (IIb), (IIc), (IId), (IIe), or (IIf), or a pharma- ceutically acceptable salt thereof, is 7a and R 7b are each independently H or C 1~6 In some embodiments, R 7a is H. In some embodiments, R 7a is C 1~3 In some embodiments, R 7a is methyl. In some embodiments, R 7b is H. In some embodiments, R 7b is C 1~3 In some embodiments, R 7b is methyl.

[0095] In some embodiments, the compound of Formula (IIe) or (IIf), or a pharma- ceutically acceptable salt thereof, is 7a and R 7b are each independently H or C 1~6 In some embodiments, R 7a1 is H. In some embodiments, R 7a1 is C 1~3 In some embodiments, R 7a1 is methyl. In some embodiments, R 7b1 is H. In some embodiments, R 7b1 is C 1~3 In some embodiments, R 7b1 is methyl.

[0096] In some embodiments, the compound of formula (I), or a pharma- ceutically acceptable salt thereof, is a and X b is O.

[0097] In some embodiments, the compound of Formula (I), (IIa), (IIb), (IIc), (IId), (IIe), or (IIf), or a pharma- ceutically acceptable salt thereof, is 6 is H. In some embodiments, R 6 is C 1~6 Alkyl or C 1~6 In some embodiments, R 6 is hydrogen, C 1~3 Alkyl or C 1~3 In some embodiments, R 6 is -CH optionally substituted with 1 to 3 halo 3 In some embodiments, R 6 is -CH 3 , -CHF 2 , -CH 2 F, -CF 3 , -CHCl 2 , or -CH 2 In some embodiments, R 6is -CH 3 It is.

[0098] In some embodiments, the compound of Formula (I), (IIa), (IIb), (IIc), (IId), (IIe), or (IIf), or a pharma- ceutically acceptable salt thereof, is 1 but, [ka] and R 2a , R 2b , and R 2c are each independently H or halogen; R 3a and R 3b are H and R 4a , R 4b , and R 4c are H and R 5 is 1 to 3 Z, which may be the same or different 5 R is heteroaryl optionally substituted with 6 But, C 1~6 Alkyl or C 1~6 A compound that is a haloalkyl.

[0099] In some embodiments, the compound of Formula (I), (IIa), (IIb), (IIc), (IId), (IIe), or (IIf), or a pharma- ceutically acceptable salt thereof, is 1 but, [ka] and R 2a , R 2b , and R 2c are each independently H or halogen; R 3a and R 3b are H and R 4a , R 4b , and R 4c are H and R 5 is 1 to 3 Z, which may be the same or different 5is a heteroaryl selected from thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrrolyl, pyrazolyl, triazolyl, pyridyl, pyrazinyl, and pyrimidinyl, optionally substituted with R 6 But, C 1~3 Alkyl or C 1~3 A compound that is a haloalkyl.

[0100] In some embodiments, the compound of Formula (I), (IIa), (IIb), (IIc), (IId), (IIe), or (IIf), or a pharma- ceutically acceptable salt thereof, is 1 but, [ka] and R 2a , R 2b , and R 2c are each independently H or F; R 3a and R 3b are H and R 4a , R 4b , and R 4c are H and R 5 is 1 to 3 Z, which may be the same or different 5 pyridyl optionally substituted with R 6 But -CH 3 , -CHF 2 , -CH 2 F, -CF 3 , -CHCl 2 , or -CH 2 It is a compound that is Cl.

[0101] In some embodiments, the compound of Formula (I), (IIa), (IIb), (IIc), (IId), (IIe), or (IIf), or a pharma- ceutically acceptable salt thereof, is 1 but, [ka] and R 2a , R 2b , and R 2care each independently H or F; R 3a and R 3b are H and R 4a , R 4b , and R 4c are H and R 5 But pyridyl, [ka] and R 6 is optionally substituted with 1 to 3 halo; 3 is a compound.

[0102] In some embodiments, the compound is of formula (IIe), or a pharma- ceutically acceptable salt thereof, wherein R 1 but, [ka] and R 2a , R 2b , and R 2c are each independently H or halogen; R 3a and R 3b are H and R 4a , R 4b , and R 4c are H and R 5 is 1 to 3 Z, which may be the same or different 5 R is heteroaryl optionally substituted with 6 But, C 1~6 Alkyl or C 1~6 It is haloalkyl.

[0103] In some embodiments, the compound is of formula (IIe), or a pharma- ceutically acceptable salt thereof, wherein R 1 but, [ka] and R 2a , R 2b , and R 2c are each independently H or halogen; R3a and R 3b are H and R 4a , R 4b , and R 4c are H and R 5 is 1 to 3 Z, which may be the same or different 5 is a heteroaryl selected from thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrrolyl, pyrazolyl, triazolyl, pyridyl, pyrazinyl, and pyrimidinyl, optionally substituted with R 6 But, C 1~3 Alkyl or C 1~3 It is haloalkyl.

[0104] In some embodiments, the compound is of formula (IIe), or a pharma- ceutically acceptable salt thereof, wherein R 1 but, [ka] and R 2a , R 2b , and R 2c are each independently H or F; R 3a and R 3b are H and R 4a , R 4b , and R 4c are H and R 5 is 1 to 3 Z, which may be the same or different 5 pyridyl optionally substituted with R 6 But -CH 3 , -CHF 2 , -CH 2 F, -CF 3 , -CHCl 2 , or -CH 2 It is Cl.

[0105] In some embodiments, the compound is of formula (IIe), or a pharma- ceutically acceptable salt thereof, wherein R 1 but, [ka] and R 2a , R 2b , and R 2c are each independently H or F; R 3a and R 3b are H and R 4a , R 4b , and R 4c are H and R 5 But pyridyl, [ka] and R 6 is optionally substituted with 1 to 3 halo; 3 It is.

[0106] In some embodiments, the compound is of formula (IIf), or a pharma- ceutically acceptable salt thereof, wherein R 1 but, [ka] and R 2a , R 2b , and R 2c are each independently H or halogen; R 3a and R 3b are H and R 4a , R 4b , and R 4c are H and R 5 is 1 to 3 Z, which may be the same or different 5 R is heteroaryl optionally substituted with 6 But, C 1~6 Alkyl or C 1~6 It is haloalkyl.

[0107] In some embodiments, the compound is of formula (IIf), or a pharma- ceutically acceptable salt thereof, wherein R 1 but, [ka] and R 2a , R2b , and R 2c are each independently H or halogen; R 3a and R 3b are H and R 4a , R 4b , and R 4c are H and R 5 is 1 to 3 Z, which may be the same or different 5 is a heteroaryl selected from thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrrolyl, pyrazolyl, triazolyl, pyridyl, pyrazinyl, and pyrimidinyl, optionally substituted with R 6 But, C 1~3 Alkyl or C 1~3 It is haloalkyl.

[0108] In some embodiments, the compound is of formula (IIf), or a pharma- ceutically acceptable salt thereof, wherein R 1 but, [ka] and R 2a , R 2b , and R 2c are each independently H or F; R 3a and R 3b are H and R 4a , R 4b , and R 4c are H and R 5 is 1 to 3 Z, which may be the same or different 5 pyridyl optionally substituted with R 6 But -CH 3 , -CHF 2 , -CH 2 F, -CF 3 , -CHCl 2 , or -CH 2 It is Cl.

[0109] In some embodiments, the compound is of formula (IIf), or a pharma- ceutically acceptable salt thereof, wherein R 1 but, [ka] and R 2a , R 2b , and R 2c are each independently H or F; R 3a and R 3b are H and R 4a , R 4b , and R 4c are H and R 5 But pyridyl, [ka] and R 6 is optionally substituted with 1 to 3 halo; 3 It is.

[0110] In some embodiments, the present disclosure provides: [ka] [ka] [ka] [ka] or a pharma- ceutically acceptable salt thereof.

[0111] In some embodiments, the present disclosure provides: [ka] [ka] [ka] or a pharma- ceutically acceptable salt thereof.

[0112] In some embodiments, the disclosure provides a racemic mixture comprising a compound of formula (I), (IIa), (IIb), (IIc), (IId), (IIe), or (IIf), or a pharma- ceutically acceptable salt thereof. In some embodiments, the disclosure provides a racemic mixture comprising a compound disclosed herein, or a pharma- ceutically acceptable salt thereof. In some embodiments, the disclosure provides a scalemic mixture comprising a compound of formula (I), (IIa), (IIb), (IIc), (IId), (IIe), or (IIf), or a pharma- ceutically acceptable salt thereof. In some embodiments, the disclosure provides a scalemic mixture comprising a compound disclosed herein, or a pharma- ceutically acceptable salt thereof.

[0113] Those of skill in the art will recognize the groups disclosed herein (e.g., R 1 Each and every embodiment of the remaining groups (e.g., R 2a , R 2b , R 2c , R 3a , R 3b It is understood that each of the above-mentioned embodiments (e.g., each of the above-mentioned formulas) may be combined with any other embodiment to produce the complete compound of formula (I) or any formula described herein, or a pharma- ceutically acceptable salt, stereoisomer, mixture of stereoisomers, or tautomer thereof, each of which is considered to be within the scope of this disclosure.

[0114] Compositions and kits The compounds provided herein, or their pharmaceutically acceptable salts, are usually administered in the form of pharmaceutical compositions.Therefore, pharmaceutical compositions are also provided herein, comprising one or more of the compounds provided herein, or their pharmaceutically acceptable salts, isomers, or mixtures thereof, and one or more pharmaceutically acceptable vehicles selected from carriers, adjuvants, and excipients. The compounds provided herein, or their pharmaceutically acceptable salts, may be the only active ingredient or one of the active ingredients of the pharmaceutical composition.Suitable pharmaceutically acceptable vehicles may include, for example, inert solid diluents and fillers, diluents including sterile aqueous solutions and various organic solvents, permeation enhancers, solubilizers, and adjuvants.Such compositions are prepared by methods well known in the pharmaceutical art. See, e.g., Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa. 17th Ed. (1985), and Modern Pharmaceutics, Marcel Dekker, Inc. 3rd Ed. (G.S. Banker & C.T. Rhodes, Eds.).

[0115] In some embodiments, provided herein is a pharmaceutical composition comprising a compound provided herein (i.e., a compound of Formula (I), (IIa), (IIb), (IIc), (IId), (IIe), or (IIf), or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient or carrier. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of a compound provided herein, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient or carrier.

[0116] In some embodiments, the pharmaceutical compositions provided herein further comprise one or more (i.e., 1, 2, 3, 4, 1 or 2, 1-3, or 1-4) additional therapeutic agents, or pharma- ceutically acceptable salts thereof. In some embodiments, the pharmaceutical compositions further comprise a therapeutically effective amount of one or more (i.e., 1, 2, 3, 4, 1 or 2, 1-3, or 1-4) additional therapeutic agents, or pharma- ceutically acceptable salts thereof. In some embodiments, one of the more therapeutic agents is a complement receptor 2 antagonist, a Duffy antigen chemokine receptor modulator, an envelope glycoprotein GP350 modulator, a glucocorticoid receptor agonist, a helicase inhibitor, a helicase-primase inhibitor, an HIV gp160 protein inhibitor, an HIV gp41 protein inhibitors, HIV-1 reverse transcriptase inhibitors, HLA class I antigen A-2 alpha modulators, HLA class I antigen A-24 alpha modulators, human cytomegalovirus glycoprotein B modulators, human cytomegalovirus glycoprotein H modulators, human cytomegalovirus glycoprotein inhibitors, human cytomegalovirus glycoprotein L modulators, immunoglobulin G agonists, interferon alpha 2 ligands, interferon gamma receptor antagonists, latent membrane protein 1 modulators, latent membrane protein 2 regulators, latent membrane protein 2 stimulators, progesterone receptor agonists, secreted protein BARF1 regulators, serine threonine protein kinase UL97 regulators, T cell surface glycoprotein CD8 stimulators, thymidine kinase inhibitors, trans-acting transcription protein ICP4 regulators, transferase inhibitors, non-specific gene inhibitors, adenosylhomocysteinase inhibitors, basigin inhibitors, basigin regulators, CCR5 chemokine regulators, CD4 agonists, CD4 regulators, CD89 agonists, CMV 65kDa lower matrix phosphoprotein regulators, CRISPR associated endonuclease Cas9 regulators, cyclin dependent kinase inhibitors, cyclin dependent kinase inhibitors, cyclin dependent kinase-9 inhibitors, DNA polymerase inhibitors, DNA primase inhibitors, endonucleasesmodulators, Epstein-Barr nuclear antigen 1 inhibitors, Epstein-Barr nuclear antigen 1 modulators, Epstein-Barr nuclear antigen 1 stimulators, fatty acid synthase inhibitors, herpesvirus envelope glycoprotein B stimulators, herpesvirus envelope glycoprotein D inhibitors, herpesvirus envelope glycoprotein D modulators, HIV gp120 protein inhibitors, HLA class I antigen A-11 alpha modulators, Hsp 90 inhibitors, human cytomegalovirus glycoprotein B inhibitors, human cytomegalovirus glycoprotein B modulators, human cytomegalovirus glycoprotein inhibitors, hyaluronidase inhibitors, immunoglobulin agonists, interferon alpha 1 ligands, interferon alpha 2 ligands, interferon alpha ligand inhibitors, interferon alpha ligand modulators, interferon beta ligands, large terminase terminase protein inhibitors, LAT gene inhibitors, NAD-dependent deacetylase sirtuin modulators, nicotinic acetylcholine receptor antagonists, NKG2D ligand modulators, nucleotidyl transferase inhibitors, protein Jumonji inhibitors, ribonuclease stimulators, serine threonine protein kinase UL97 inhibitors, syntaxin-5 inhibitors, TAT protein modulators, T cell surface glycoprotein CD8 stimulators, TLR-4 agonists, and viral ribonucleotide reductase inhibitors. In some embodiments, one of the more therapeutic agents is selected from famciclovir, acyclovir, and valacyclovir.

[0117] In some embodiments, provided herein is a pharmaceutical composition comprising a therapeutically effective amount of a compound provided herein, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient.

[0118] The pharmaceutical composition may be administered in either a single dose or multiple doses. The pharmaceutical composition may be administered by a variety of methods, including, for example, rectal, oral, intranasal, and transdermal routes. In some embodiments, the pharmaceutical composition may be administered by intraarterial injection, intravenous, intraperitoneal, parenteral, intramuscular, subcutaneous, oral, topical, or as an inhalant.

[0119] One mode of administration is parenteral, for example, by injection.The form that the pharmaceutical composition described herein can be incorporated into for administration by injection includes, for example, sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixir, mannitol, dextrose, or sterile aqueous solution, and similar pharmaceutical vehicle, aqueous or oily suspension, or emulsion.In some embodiments, the compound disclosed herein or its pharmaceutically acceptable salt and pharmaceutical composition are administered by subcutaneous injection.

[0120] The pharmaceutical compositions of the present disclosure may be in the form of a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension. The suspension may be formulated according to known techniques using those suitable dispersing or wetting agents and suspending agents mentioned herein. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol, or may be prepared as a lyophilized powder. Among the acceptable vehicles and solvents that may be used are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixed oils may conventionally be used as a solvent or suspending medium. For this purpose, any non-irritating fixed oil may be used, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid may also be used in the preparation of injectables.

[0121] In some embodiments, the sterile injectable preparation disclosed herein may also be a sterile injectable solution or suspension prepared from a lyophilized powder reconstituted in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be used are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixed oils may be conventionally used as a solvent or suspending medium. For this purpose, any non-irritating fixed oil may be used, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid may also be used in the preparation of injectables.

[0122] Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain antioxidants, buffers, bacteriophages, and solutes that render the formulation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions which may contain suspending agents and thickening agents. In certain embodiments, the suspension is a microsuspension. In certain embodiments, the suspension is a nanosuspension.

[0123] In some embodiments, formulations suitable for parenteral administration (e.g., intramuscular (IM) and subcutaneous (SC) administration) include one or more excipients. The excipient must be compatible with other components of the formulation and physiologically harmless to the recipient. Examples of suitable excipients are well known to those skilled in the art of parenteral formulations and can be found, for example, in Handbook of Pharmaceutical Excipients (eds. Rowe, Sheskey & Quinn), 6th edition 2009. Examples of solubilizing excipients in parenteral formulations (e.g., SC or IM formulations) include, but are not limited to, polysorbates (such as polysorbate 20 or 80) and poloxamers (such as poloxamer 338, 188, or 207). In some embodiments, the compounds disclosed herein, or pharma- ceutically acceptable salts thereof, and pharmaceutical compositions are administered with an implant.

[0124] Oral administration may be another route for administration of the compounds provided herein or their pharma- ceutically acceptable salts. Administration may be, for example, via capsules or enteric-coated tablets. In preparing pharmaceutical compositions containing at least one compound provided herein, or its pharma- ceutically acceptable salts, isomers, or mixtures thereof, the active ingredient (such as the compounds provided herein) is usually diluted with an excipient and / or enclosed within such a carrier, which may be in the form of a capsule, sachet, paper, or other container. When the excipient functions as a diluent, it may be in the form of a solid, semi-solid, or liquid material that acts as a vehicle, carrier, or medium for the active ingredient. Thus, the pharmaceutical composition may be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as solids or in liquid media), ointments, containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, sterile injection solutions, and sterile packaged powders.

[0125] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum acacia, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methylcellulose, or any combination thereof.In addition, the pharmaceutical composition may include lubricants such as talc, magnesium stearate, and mineral oil, wetting agents, emulsifying and suspending agents, preserving agents such as methyl and propylhydroxybenzoates, sweeteners, and flavoring agents, or any combination thereof.

[0126] Pharmaceutical compositions comprising at least one compound described herein, or pharma- ceutically acceptable salts, isomers, or mixtures thereof, can be formulated to provide rapid, sustained, or delayed release of the active ingredient (such as the compounds provided herein) after administration to a subject by using procedures known in the art. Controlled release drug delivery systems for oral administration include osmotic pump systems and dissolution systems that include polymer-coated reservoirs or drug-polymer matrix formulations. Examples of controlled release systems are shown in U.S. Patent Nos. 3,845,770, 4,326,525, 4,902,514, and 5,616,345. Another formulation for use in the methods of the present disclosure employs transdermal delivery devices ("patches"). Such transdermal patches can be used to provide continuous or discontinuous infusion of the compounds provided herein in controlled amounts. The construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art. See, for example, US Patent Nos. 5,023,252, 4,992,445 and 5,001,139.Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.

[0127] To prepare solid compositions such as tablets, the principal active ingredient may be mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogenous mixture of the compound described herein, or a pharma- ceutically acceptable salt, isomer, or mixture thereof. When these preformulation compositions are referred to as homogenous, the active ingredient may be evenly dispersed throughout the composition such that the composition may be readily subdivided into equally effective unit dosage forms, such as tablets, pills, and capsules.

[0128] The tablets or pills of the compounds provided herein or their pharma- ceutically acceptable salts can be coated or otherwise compounded to provide a dosage form that provides the advantage of prolonged action or to protect against the acidic conditions of the stomach.For example, the tablet or pill can be composed of an inner dosage component and an outer dosage component, the outer dosage component being in the form of an envelope over the inner dosage component.The two components can be separated by an enteric layer, which serves to resist disintegration in the stomach and allow the inner component to pass intact into the duodenum or to be delayed in release.A variety of materials can be used for such enteric layers or coatings, including many polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol, and cellulose acetate.

[0129] Pharmaceutical compositions for inhalation or insufflation may include solutions and suspensions in pharma- ceutically acceptable aqueous or organic solvents, or mixtures thereof, as well as powders. Liquid or solid compositions may include suitable pharma- ceutically acceptable excipients as described above. In some embodiments, the compositions are administered by the oral or nasal respiratory route for local or systemic effect. In other embodiments, compositions in pharma- ceutically acceptable solvents may be nebulized by use of an inert gas. Nebulized solutions may be inhaled directly from the nebulizing device, or the nebulizing device may be attached to a face mask, obturator, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered orally or nasally, preferably from a device that delivers the formulation in an appropriate manner.

[0130] In one embodiment, provided herein is a kit comprising a compound provided herein (i.e., a compound of Formula (I), (IIa), (IIb), (IIc), (IId), (IIe), or (IIf)), or a pharma- ceutically acceptable salt, stereoisomer, prodrug, or solvate thereof, and suitable packaging. In some embodiments, the kit further comprises instructions for use. In some embodiments, the kit comprises a compound provided herein (i.e., a compound of Formula (I), (IIa), (IIb), (IIc), (IId), (IIe), or (IIf)), or a pharma- ceutically acceptable salt, stereoisomer, prodrug, or solvate thereof, and a label and / or instructions for use of the compound in the treatment of an indication, including a disease or condition described herein.

[0131] In some embodiments, the kit further comprises one or more (i.e., 1, 2, 3, 4, 1 or 2, 1-3, or 1-4) additional therapeutic agents, or pharma- ceutically acceptable salts thereof.

[0132] In one embodiment, provided herein is an article of manufacture comprising a compound described herein, or a pharma- ceutically acceptable salt, isomer, or mixture thereof, in a suitable container, hi some embodiments, the container can be a vial, bottle, ampoule, pre-filled syringe, or intravenous bag.

[0133] method The methods provided herein may be applied to in vivo or ex vivo cell populations. "In vivo" means within a living individual, such as within an animal or human. In this context, the methods provided herein may be used therapeutically in an individual. "Ex vivo" means outside a living individual. Examples of ex vivo cell populations include in vitro cell cultures and biological samples, including fluid or tissue samples obtained from an individual. Such samples may be obtained by methods well known in the art. Exemplary biological fluid samples include blood, cerebrospinal fluid, urine, and saliva. Exemplary tissue samples include tumors and their biopsies. In this context, the present disclosure may be used for a variety of purposes, including therapeutic and experimental purposes. For example, the present disclosure may be used ex vivo to determine optimal schedules and / or dosing of the compounds disclosed herein for a given cell type, individual, and other parameters. Information gathered from such use may be used for experimental purposes or in the clinic to set up protocols for in vivo treatment. Other ex vivo uses for which the present disclosure may be suitable are described below or will become apparent to those of skill in the art. Selected compounds may be further characterized to determine safety or tolerated dosages in human or non-human subjects. Such properties may be determined using methods commonly known to those of skill in the art.

[0134] In one embodiment, the disclosure provides a method of treating or preventing a herpes virus infection in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound provided herein, or a pharma- ceutical acceptable salt thereof, or a pharmaceutical composition provided herein.

[0135] In some embodiments, the methods provided herein further comprise administering a therapeutically effective amount of one, two, three, or four additional therapeutic agents, or pharma- ceutically acceptable salts thereof.

[0136] The present disclosure further relates to the use of the compounds disclosed herein for the treatment and / or prevention of diseases and / or conditions by inhibiting the helicase primase of herpes virus with the compounds described above. Furthermore, the present disclosure relates to the use of the compounds disclosed herein for the preparation of a medicament for the treatment and / or prevention of diseases and / or conditions associated with herpes virus by inhibiting the helicase primase of herpes virus with the compounds described above. In some embodiments, the disease or condition associated with herpes virus is alleviated by inhibiting herpes virus helicase primase. In some embodiments, the present disclosure relates to the use of the compounds disclosed herein for the preparation of a medicament for the treatment and / or prevention of diseases and / or conditions associated with HSV-1 or HSV-2 by inhibiting the helicase primase with the compounds described above.

[0137] The medicaments referred to herein can be prepared by conventional processes involving combining a compound according to the present disclosure with a pharma- ceutically acceptable carrier.

[0138] In some embodiments, provided herein is a method of inhibiting herpes virus helicase primase, the method comprising administering to a patient in need thereof (e.g., a patient having a disease or condition associated with a herpes virus) a therapeutically effective amount of a compound of Formula (I), (IIa), (IIb), (IIc), (IId), (IIe), or (IIf), or a pharma- ceutically acceptable salt thereof, or a composition comprising a compound of Formula (I), (IIa), (IIb), (IIc), (IId), (IIe), or (IIf), or a pharma- ceutically acceptable salt thereof.

[0139] In some embodiments, provided herein are methods of inhibiting HSV-1 or HSV-2 helicase primase comprising administering to a patient in need thereof (e.g., a patient having a disease or condition associated with HSV-1 or HSV-2) a therapeutically effective amount of a compound of Formula (I), (IIa), (IIb), (IIc), (IId), (IIe), or (IIf), or a pharma- ceutically acceptable salt thereof, or a composition comprising a compound of Formula (I), (IIa), (IIb), (IIc), (IId), (IIe), or (IIf), or a pharma- ceutically acceptable salt thereof. In some embodiments, provided herein are methods of inhibiting HSV-1 or HSV-2 helicase primase comprising administering to a patient in need thereof (e.g., a patient having a disease or condition associated with HSV-1 or HSV-2) a therapeutically effective amount of a compound disclosed herein, or a pharma- ceutically acceptable salt thereof, or a composition comprising a compound disclosed herein, or a pharma- ceutically acceptable salt thereof.

[0140] In some embodiments, provided herein is a method of reducing the proliferation of a virus, comprising contacting the virus with a compound of formula (I), (IIa), (IIb), (IIc), (IId), (IIe), or (IIf), or a pharmaceutically acceptable salt thereof, and inhibiting helicase primase in the virus. In some embodiments, provided herein is a method of reducing the proliferation of a herpes virus, comprising contacting the virus with a compound of formula (I), (IIa), (IIb), (IIc), (IId), (IIe), or (IIf), or a pharmaceutically acceptable salt thereof, and inhibiting helicase primase in the virus. In some embodiments, provided herein is a method of reducing the proliferation of HSV-1 or HSV-2, comprising contacting the virus with a compound disclosed herein, or a pharmaceutically acceptable salt thereof, and inhibiting helicase primase in the virus.

[0141] In some embodiments, provided herein is a method of treating a disorder induced, exacerbated, or promoted by a herpes virus, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula (I), (IIa), (IIb), (IIc), (IId), (IIe), or (IIf), or a pharma- ceutically acceptable salt thereof, or a composition comprising a compound of Formula (IIa), (IIb), (IIc), (IId), (IIe), or (IIf), or a pharma- ceutically acceptable salt thereof. In some embodiments, provided herein is a method of treating a disorder induced, exacerbated, or promoted by HSV-1 or HSV-2, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), (IIa), (IIb), (IIc), (IId), (IIe), or (IIf), or a pharma- ceutically acceptable salt thereof, or a composition comprising a compound of formula (IIa), (IIb), (IIc), (IId), (IIe), or (IIf), or a pharma- ceutically acceptable salt thereof. In some embodiments, the disorder is genital herpes, herpes labialis, HSV keratitis, HSV encephalitis, or disseminated HSV. In some embodiments, the disorder is genital herpes.

[0142] In some embodiments, provided herein is the use of a compound of formula (I), (IIa), (IIb), (IIc), (IId), (IIe), or (IIf), or a pharma- ceutically acceptable salt thereof, in the treatment of a viral infection. In some embodiments, provided herein is the use of a compound of formula (I), (IIa), (IIb), (IIc), (IId), (IIe), or (IIf), or a pharma- ceutically acceptable salt thereof, in the treatment of a viral infection caused by a herpes virus. In some embodiments, provided herein is the use of a compound of formula (I), (IIa), (IIb), (IIc), (IId), (IIe), or (IIf), or a pharma- ceutically acceptable salt thereof, in the treatment of a viral infection caused by HSV-1 or HSV-2.

[0143] In some embodiments, provided herein is the use of a compound of formula (I), (IIa), (IIb), (IIc), (IId), (IIe), or (IIf), or a pharma- ceutically acceptable salt thereof, for the preparation of a medicament for preventing / treating a viral infection. In some embodiments, provided herein is the use of a compound of formula (I), (IIa), (IIb), (IIc), (IId), (IIe), or (IIf), or a pharma- ceutically acceptable salt thereof, for the preparation of a medicament for preventing / treating a viral infection caused by a herpes virus. In some embodiments, provided herein is the use of a compound of formula (I), (IIa), (IIb), (IIc), (IId), (IIe), or (IIf), or a pharma- ceutically acceptable salt thereof, for the preparation of a medicament for preventing / treating a viral infection caused by HSV-1 or HSV-2.

[0144] In some embodiments, provided herein is a compound of Formula (I), (IIa), (IIb), (IIc), (IId), (IIe), or (IIf), or a pharma- ceutically acceptable salt thereof, for use in therapy. In some embodiments, provided herein is a compound of Formula (I), (IIa), (IIb), (IIc), (IId), (IIe), or (IIf), or a pharma- ceutically acceptable salt thereof, for use in a method of treating a viral infection caused by HSV-1 or HSV-2.

[0145] Administration The compounds of the present disclosure, or pharma- ceutically acceptable salts thereof (also referred to herein as active ingredients), can be administered by any route appropriate to the condition to be treated. Suitable routes include oral, rectal, nasal, topical (including buccal and sublingual), transdermal, vaginal, and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal, and epidural). It will be understood that the preferred route may vary, for example, depending on the condition of the recipient. An advantage of certain compounds disclosed herein, or pharma- ceutically acceptable salts thereof, is that they are orally bioavailable and can be administered orally.

[0146] The compounds of the present disclosure, or pharma- ceutically acceptable salts thereof, may be administered to an individual according to an effective dosing regimen for a desired period or duration, such as at least about 1 day, at least about 2 days, at least about 3 days, at least about 4 days, at least about 5 days, at least about 6 days, at least about 1 week, at least about 2 weeks, at least about 3 weeks, at least about 1 month, at least about 2 months, at least about 3 months, at least about 6 months, or at least about 12 months or more. In some embodiments, the compounds, or pharma- ceutically acceptable salts thereof, are administered on a daily or intermittent schedule for the duration of the individual's life.

[0147] The specific dosage level of the compound of the present disclosure or a pharma- ceutically acceptable salt thereof for any particular subject will depend on a variety of factors, including the activity of the particular compound used, age, body weight, general health, sex, diet, time of administration, route of administration, and excretion rate, drug combination, and the severity of the particular disease in the subject receiving the therapy. For example, dosages may be expressed as milligrams of the compound provided herein or a pharma- ceutically acceptable salt thereof per kilogram of subject body weight (mg / kg). Dosages of about 0.1-150 mg / kg may be appropriate. In some embodiments, about 0.1-100 mg / kg may be appropriate. In other embodiments, dosages of 0.5-60 mg / kg may be appropriate. Normalizing according to subject body weight is particularly useful when adjusting dosages between subjects of widely differing sizes, such as when using drugs in both children and adults, or when converting effective dosages in non-human subjects, such as dogs, to dosages appropriate for human subjects.

[0148] Dosages may also be described as the total amount of a compound described herein, or a pharma- ceutically acceptable salt thereof, administered per dose. The dosage or frequency of administration of a compound of the present disclosure, or a pharma- ceutically acceptable salt thereof, may be adjusted over the course of treatment based on the judgment of the administering physician.

[0149] The compounds of the present disclosure, or pharma- ceutically acceptable salts thereof, may be administered to an individual (e.g., a human) in a therapeutically effective amount. In some embodiments, the compound of formula (I), (IIa), (IIb), (IIc), (IId), (IIe), or (IIf), or a pharma- ceutically acceptable salt thereof, is administered once a day, once a week, once a month, once every two months, once every three months, or once every six months. In some embodiments, the compound of formula (I), (IIa), (IIb), (IIc), (IId), (IIe), or (IIf), or a pharma- ceutically acceptable salt thereof, is administered once a day. In some embodiments, the compound of formula (I), (IIa), (IIb), (IIc), (IId), (IIe), or (IIf), or a pharma- ceutically acceptable salt thereof, is administered once a week. In some embodiments, the compound of formula (I), (IIa), (IIb), (IIc), (IId), (IIe), or (IIf), or a pharma- ceutically acceptable salt thereof, is administered once a month. In some embodiments, the compound of formula (I), (IIa), (IIb), (IIc), (IId), (IIe), or (IIf), or a pharma- ceutically acceptable salt thereof, is administered once every two months. In some embodiments, the compound of formula (I), (IIa), (IIb), (IIc), (IId), (IIe), or (IIf), or a pharma- ceutically acceptable salt thereof, is administered once every three months. In some embodiments, the compound of formula (I), (IIa), (IIb), (IIc), (IId), (IIe), or (IIf), or a pharma- ceutically acceptable salt thereof, is administered once every six months.

[0150] The compounds provided herein, or pharma- ceutically acceptable salts thereof, can be administered by any useful route and means, such as oral or parenteral (e.g., intravenous) administration. The therapeutically effective amount of the compound, or pharma- ceutically acceptable salts thereof, can include from about 0.00001 mg / kg body weight per day to about 10 mg / kg body weight per day, for example, from about 0.0001 mg / kg body weight per day to about 10 mg / kg body weight per day, or for example, from about 0.001 mg / kg body weight per day to about 1 mg / kg body weight per day, or for example, from about 0.01 mg / kg body weight per day to about 1 mg / kg body weight per day, or for example, from about 0.05 mg / kg body weight per day to about 0.5 mg / kg body weight per day. In some embodiments, a therapeutically effective amount of a compound provided herein, or a pharma- ceutically acceptable salt thereof, can be from about 30 μg to about 300 μg per day, from about 0.3 mg to about 30 mg per day, or from about 30 mg to about 300 mg per day, or from about 300 mg to about 1000 mg per day.

[0151] The compounds of the present disclosure, or pharma- ceutically acceptable salts thereof, may be combined with one or more additional therapeutic agents in any dosage of the compounds of the present disclosure, or pharma- ceutically acceptable salts thereof (e.g., from about 1 mg to 1000 mg of compound). The therapeutically effective amount may include from about 0.1 mg per dose to about 1000 mg per dose, for example from about 50 mg per dose to about 500 mg per dose, or for example from about 100 mg per dose to about 400 mg per dose, or for example from about 150 mg per dose to about 350 mg per dose, or for example from about 200 mg per dose to about 300 mg per dose, or for example from about 0.01 mg per dose to about 1000 mg per dose, or for example from about 0.01 mg per dose to about 100 mg per dose, or for example from about 0.1 mg per dose to about 100 mg per dose, or for example from about 1 mg per dose to about 100 mg per dose, or for example from about 1 mg per dose to about 10 mg per dose, or for example from about 1 mg per dose to about 1000 mg per dose. Other therapeutically effective amounts of a compound of Formula (I), (IIa), (IIb), (IIc), (IId), (IIe), or (IIf), or a pharma- ceutically acceptable salt thereof, are about 50, 100, 125, 150, 175, 200, 225, 250, 275, or 300 mg per dose. Other therapeutically effective amounts of a compound of Formula (I), (IIa), (IIb), (IIc), (IId), (IIe), or (IIf), or a pharma- ceutically acceptable salt thereof, are about 300, 325, 350, 375, 400, 425, 450, 475, 500, 525, 550, 575, 600, 625, 650, 675, 700, 725, 750, 775, 800, 825, 850, 875, 900, 925, 950, 975, or about 1000 mg per dose.

[0152] In some embodiments, the therapeutically effective amount of the compound of formula (I), (IIa), (IIb), (IIc), (IId), (IIe), or (IIf), or other therapeutically effective amounts of pharmaceutically acceptable salts thereof, is about 1 mg to about 1000 mg. In some embodiments, the therapeutically effective amount of the compound of formula (I), (IIa), (IIb), (IIc), (IId), (IIe), or (IIf), or other therapeutically effective amounts of pharmaceutically acceptable salts thereof, is about 1 mg to about 900 mg. In some embodiments, the therapeutically effective amount of the compound of formula (I), (IIa), (IIb), (IIc), (IId), (IIe), or (IIf), or other therapeutically effective amounts of pharmaceutically acceptable salts thereof, is about 1 mg to about 800 mg. In some embodiments, the therapeutically effective amount of the compound of formula (I), (IIa), (IIb), (IIc), (IId), (IIe), or (IIf), or other therapeutically effective amounts of pharmaceutically acceptable salts thereof, is about 1 mg to about 700 mg. In some embodiments, the therapeutically effective amount of the compound of formula (I), (IIa), (IIb), (IIc), (IId), (IIe), or (IIf), or other therapeutically effective amounts of pharmaceutically acceptable salts thereof, is about 1 mg to about 600 mg. In some embodiments, the therapeutically effective amount of the compound of formula (I), (IIa), (IIb), (IIc), (IId), (IIe), or (IIf), or other therapeutically effective amounts of pharmaceutically acceptable salts thereof, is about 1 mg to about 500 mg. In some embodiments, the therapeutically effective amount of the compound of formula (I), (IIa), (IIb), (IIc), (IId), (IIe), or (IIf), or other therapeutically effective amounts of pharmaceutically acceptable salts thereof, is about 1 mg to about 400 mg. In some embodiments, the therapeutically effective amount of the compound of formula (I), (IIa), (IIb), (IIc), (IId), (IIe), or (IIf), or other therapeutically effective amounts of pharmaceutically acceptable salts thereof, is about 1 mg to about 300 mg. In some embodiments, the therapeutically effective amount of the compound of formula (I), (IIa), (IIb), (IIc), (IId), (IIe), or (IIf), or other therapeutically effective amounts of pharmaceutically acceptable salts thereof, is about 1 mg to about 200 mg.In some embodiments, the therapeutically effective amount of the compound of formula (I), (IIa), (IIb), (IIc), (IId), (IIe), or (IIf), or other therapeutically effective amounts of its pharma- ceutically acceptable salt, is about 1 mg to about 100 mg. In some embodiments, the therapeutically effective amount of the compound of formula (I), (IIa), (IIb), (IIc), (IId), (IIe), or (IIf), or other therapeutically effective amounts of its pharma- ceutically acceptable salt, is about 1 mg to about 75 mg. In some embodiments, the therapeutically effective amount of the compound of formula (I), (IIa), (IIb), (IIc), (IId), (IIe), or (IIf), or other therapeutically effective amounts of its pharma- ceutically acceptable salt, is about 1 mg to about 50 mg. In some embodiments, the therapeutically effective amount of the compound of formula (I), (IIa), (IIb), (IIc), (IId), (IIe), or (IIf), or other therapeutically effective amounts of pharmaceutically acceptable salts thereof, is about 1 mg to about 25 mg. In some embodiments, the therapeutically effective amount of the compound of formula (I), (IIa), (IIb), (IIc), (IId), (IIe), or (IIf), or other therapeutically effective amounts of pharmaceutically acceptable salts thereof, is about 1 mg to about 20 mg. In some embodiments, the therapeutically effective amount of the compound of formula (I), (IIa), (IIb), (IIc), (IId), (IIe), or (IIf), or other therapeutically effective amounts of pharmaceutically acceptable salts thereof, is about 1 mg to about 15 mg. In some embodiments, the therapeutically effective amount of a compound of Formula (I), (IIa), (IIb), (IIc), (IId), (IIe), or (IIf), or other therapeutically effective amount of a pharma- ceutically acceptable salt thereof, is from about 1 mg to about 10 mg. In some embodiments, the therapeutically effective amount of a compound of Formula (I), (IIa), (IIb), (IIc), (IId), (IIe), or (IIf), or other therapeutically effective amount of a pharma- ceutically acceptable salt thereof, is from about 1 mg to about 5 mg.

[0153] In some embodiments, the therapeutically effective amount of a compound of Formula (I), (IIa), (IIb), (IIc), (IId), (IIe), or (IIf), or other therapeutically effective amount of a pharma- ceutically acceptable salt thereof, is about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 275 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1000 mg, or about 1050 mg. In some embodiments, the therapeutically effective amount of the compound of formula (I), (IIa), (IIb), (IIc), (IId), (IIe), or (IIf), or other therapeutically effective amount of a pharma- ceutically acceptable salt thereof, is about 5 mg. In some embodiments, the therapeutically effective amount of the compound of formula (I), (IIa), (IIb), (IIc), (IId), (IIe), or (IIf), or other therapeutically effective amount of a pharma- ceutically acceptable salt thereof, is about 100 mg. In some embodiments, the therapeutically effective amount of the compound of formula (I), (IIa), (IIb), (IIc), (IId), (IIe), or (IIf), or other therapeutically effective amount of a pharma- ceutically acceptable salt thereof, is about 150 mg. In some embodiments, the therapeutically effective amount of the compound of formula (I), (IIa), (IIb), (IIc), (IId), (IIe), or (IIf), or other therapeutically effective amount of a pharma- ceutically acceptable salt thereof, is about 200 mg. In some embodiments, the therapeutically effective amount of the compound of formula (I), (IIa), (IIb), (IIc), (IId), (IIe), or (IIf), or other therapeutically effective amount of a pharma- ceutically acceptable salt thereof, is about 250 mg. In some embodiments, the therapeutically effective amount of the compound of formula (I), (IIa), (IIb), (IIc), (IId), (IIe), or (IIf), or other therapeutically effective amount of a pharma- ceutically acceptable salt thereof, is about 300 mg. In some embodiments, the therapeutically effective amount of a compound of Formula (I), (IIa), (IIb), (IIc), (IId), (IIe), or (IIf), or other pharma- ceutically acceptable salt thereof, is about 350 mg.In some embodiments, the therapeutically effective amount of the compound of formula (I), (IIa), (IIb), (IIc), (IId), (IIe), or (IIf), or other therapeutically effective amount of a pharma- ceutically acceptable salt thereof, is about 400 mg. In some embodiments, the therapeutically effective amount of the compound of formula (I), (IIa), (IIb), (IIc), (IId), (IIe), or (IIf), or other therapeutically effective amount of a pharma- ceutically acceptable salt thereof, is about 450 mg. In some embodiments, the therapeutically effective amount of the compound of formula (I), (IIa), (IIb), (IIc), (IId), (IIe), or (IIf), or other therapeutically effective amount of a pharma- ceutically acceptable salt thereof, is about 500 mg. In some embodiments, the therapeutically effective amount of the compound of formula (I), (IIa), (IIb), (IIc), (IId), (IIe), or (IIf), or other therapeutically effective amount of a pharma- ceutically acceptable salt thereof, is about 550 mg. In some embodiments, the therapeutically effective amount of the compound of formula (I), (IIa), (IIb), (IIc), (IId), (IIe), or (IIf), or other therapeutically effective amount of a pharma- ceutically acceptable salt thereof, is about 600 mg. In some embodiments, the therapeutically effective amount of the compound of formula (I), (IIa), (IIb), (IIc), (IId), (IIe), or (IIf), or other therapeutically effective amount of a pharma- ceutically acceptable salt thereof, is about 650 mg. In some embodiments, the therapeutically effective amount of the compound of formula (I), (IIa), (IIb), (IIc), (IId), (IIe), or (IIf), or other therapeutically effective amount of a pharma- ceutically acceptable salt thereof, is about 700 mg. In some embodiments, the therapeutically effective amount of the compound of formula (I), (IIa), (IIb), (IIc), (IId), (IIe), or (IIf), or other therapeutically effective amount of a pharma- ceutically acceptable salt thereof, is about 750 mg. In some embodiments, the therapeutically effective amount of the compound of formula (I), (IIa), (IIb), (IIc), (IId), (IIe), or (IIf), or other therapeutically effective amount of a pharma- ceutically acceptable salt thereof, is about 800 mg.In some embodiments, the therapeutically effective amount of the compound of formula (I), (IIa), (IIb), (IIc), (IId), (IIe), or (IIf), or other therapeutically effective amount of a pharma- ceutically acceptable salt thereof, is about 850 mg. In some embodiments, the therapeutically effective amount of the compound of formula (I), (IIa), (IIb), (IIc), (IId), (IIe), or (IIf), or other therapeutically effective amount of a pharma- ceutically acceptable salt thereof, is about 900 mg. In some embodiments, the therapeutically effective amount of the compound of formula (I), (IIa), (IIb), (IIc), (IId), (IIe), or (IIf), or other therapeutically effective amount of a pharma- ceutically acceptable salt thereof, is about 950 mg. In some embodiments, the therapeutically effective amount of a compound of Formula (I), (IIa), (IIb), (IIc), (IId), (IIe), or (IIf), or other therapeutically effective amount of a pharma- ceutically acceptable salt thereof, is about 1000 mg. In some embodiments, the therapeutically effective amount of a compound of Formula (I), (IIa), (IIb), (IIc), (IId), (IIe), or (IIf), or other therapeutically effective amount of a pharma- ceutically acceptable salt thereof, is about 1050 mg. When administered orally, the total weekly dosage for a human subject may be about 1 mg to 1,000 mg / week, about 10 to 500 mg / week, about 50 to 300 mg / week, about 75 to 200 mg / week, or about 100 to 150 mg / week. In some embodiments, the total weekly dosage for a human subject may be about 100, 200, 300, 400, 500, 600, 700, 800, 900, or 1000 mg / week administered in a single dose. In some embodiments, the total weekly dosage for a human subject of a compound of formula (I), (IIa), (IIb), (IIc), (IId), (IIe), or (IIf), or a pharma- ceutically acceptable salt thereof, may be about 100 mg administered in a single dose. In some embodiments, the total weekly dosage for a human subject of a compound of formula (I), (IIa), (IIb), (IIc), (IId), (IIe), or (IIf), or a pharma- ceutically acceptable salt thereof, may be about 150 mg administered in a single dose.In some embodiments, the total weekly dosage for a human subject of a compound of Formula (I), (IIa), (IIb), (IIc), (IId), (IIe), or (IIf), or a pharma- ceutically acceptable salt thereof, may be about 200 mg administered in a single dose. In some embodiments, the total weekly dosage for a human subject of a compound of Formula (I), (IIa), (IIb), (IIc), (IId), (IIe), or (IIf), or a pharma- ceutically acceptable salt thereof, may be about 250 mg administered in a single dose. In some embodiments, the total weekly dosage for a human subject of a compound of Formula (I), (IIa), (IIb), (IIc), (IId), (IIe), or (IIf), or a pharma- ceutically acceptable salt thereof, may be about 300 mg administered in a single dose. In some embodiments, the total weekly dosage for a human subject of a compound of formula (I), (IIa), (IIb), (IIc), (IId), (IIe), or (IIf), or a pharma- ceutically acceptable salt thereof, may be about 350 mg administered in a single dose. In some embodiments, the total weekly dosage for a human subject of a compound of formula (I), (IIa), (IIb), (IIc), (IId), (IIe), or (IIf), or a pharma- ceutically acceptable salt thereof, may be about 400 mg administered in a single dose. In some embodiments, the total weekly dosage for a human subject of a compound of formula (I), (IIa), (IIb), (IIc), (IId), (IIe), or (IIf), or a pharma- ceutically acceptable salt thereof, may be about 450 mg administered in a single dose. In some embodiments, the total weekly dosage for a human subject of a compound of Formula (I), (IIa), (IIb), (IIc), (IId), (IIe), or (IIf), or a pharma- ceutically acceptable salt thereof, may be about 500 mg administered in a single dose. In some embodiments, the total weekly dosage for a human subject of a compound of Formula (I), (IIa), (IIb), (IIc), (IId), (IIe), or (IIf), or a pharma- ceutically acceptable salt thereof, may be about 600 mg administered in a single dose.In some embodiments, the total weekly dosage for a human subject of a compound of Formula (I), (IIa), (IIb), (IIc), (IId), (IIe), or (IIf), or a pharma- ceutically acceptable salt thereof, may be about 700 mg administered in a single dose. In some embodiments, the total weekly dosage for a human subject of a compound of Formula (I), (IIa), (IIb), (IIc), (IId), (IIe), or (IIf), or a pharma- ceutically acceptable salt thereof, may be about 800 mg administered in a single dose. In some embodiments, the total weekly dosage for a human subject of a compound of Formula (I), (IIa), (IIb), (IIc), (IId), (IIe), or (IIf), or a pharma- ceutically acceptable salt thereof, may be about 900 mg administered in a single dose. In some embodiments, the total weekly dosage for a human subject of a compound of Formula (I), (IIa), (IIb), (IIc), (IId), (IIe), or (IIf), or a pharma- ceutically acceptable salt thereof, may be about 1000 mg administered in a single dose.

[0154] When administered orally, the total weekly dosage for a human subject of a compound of Formula (I), (IIa), (IIb), (IIc), (IId), (IIe), or (IIf), or a pharma- ceutically acceptable salt thereof, may be about 500 mg to 1,000 mg / week, about 600 to 900 mg / week, or about 700 to 800 mg / week. In some embodiments, the total weekly dosage for a human subject of a compound of Formula (I), (IIa), (IIb), (IIc), (IId), (IIe), or (IIf), or a pharma- ceutically acceptable salt thereof, may be about 100, 200, 300, 400, 500, 600, 700, 800, 900, or 1000 mg / week administered in a single dose. In some embodiments, the total monthly dosage for a human subject of a compound of Formula (I), (IIa), (IIb), (IIc), (IId), (IIe), or (IIf), or a pharma- ceutically acceptable salt thereof, may be about 500 mg administered in a single dose. In some embodiments, the total monthly dosage for a human subject of a compound of Formula (I), (IIa), (IIb), (IIc), (IId), (IIe), or (IIf), or a pharma- ceutically acceptable salt thereof, may be about 550 mg administered in a single dose. In some embodiments, the total monthly dosage for a human subject of a compound of Formula (I), (IIa), (IIb), (IIc), (IId), (IIe), or (IIf), or a pharma- ceutically acceptable salt thereof, may be about 600 mg administered in a single dose. In some embodiments, the total monthly dosage for a human subject of a compound of Formula (I), (IIa), (IIb), (IIc), (IId), (IIe), or (IIf), or a pharma- ceutically acceptable salt thereof, may be about 650 mg administered in a single dose. In some embodiments, the total monthly dosage for a human subject of a compound of Formula (I), (IIa), (IIb), (IIc), (IId), (IIe), or (IIf), or a pharma- ceutically acceptable salt thereof, may be about 700 mg administered in a single dose. In some embodiments, the total monthly dosage for a human subject of a compound of Formula (I), (IIa), (IIb), (IIc), (IId), (IIe), or (IIf), or a pharma- ceutically acceptable salt thereof, may be about 750 mg administered in a single dose.In some embodiments, the total monthly dosage for a human subject of a compound of Formula (I), (IIa), (IIb), (IIc), (IId), (IIe), or (IIf), or a pharma- ceutically acceptable salt thereof, may be about 800 mg administered in a single dose. In some embodiments, the total monthly dosage for a human subject of a compound of Formula (I), (IIa), (IIb), (IIc), (IId), (IIe), or (IIf), or a pharma- ceutically acceptable salt thereof, may be about 850 mg administered in a single dose. In some embodiments, the total monthly dosage for a human subject of a compound of Formula (I), (IIa), (IIb), (IIc), (IId), (IIe), or (IIf), or a pharma- ceutically acceptable salt thereof, may be about 900 mg administered in a single dose. In some embodiments, the total monthly dosage for a human subject of a compound of Formula (I), (IIa), (IIb), (IIc), (IId), (IIe), or (IIf), or a pharma- ceutically acceptable salt thereof, may be about 950 mg administered in a single dose. In some embodiments, the total monthly dosage for a human subject of a compound of Formula (I), (IIa), (IIb), (IIc), (IId), (IIe), or (IIf), or a pharma- ceutically acceptable salt thereof, may be about 1000 mg administered in a single dose.

[0155] A single dose may be administered hourly, daily, weekly, or monthly. For example, a single dose may be administered about once every hour, 2, 3, 4, 6, 8, 12, 16 hours, or once every 24 hours. A single dose may also be administered daily, once every 2, 3, 4, 5, 6 days, or once every 7 days. A single dose may also be administered once every 1, 2, 3 weeks, or once every 4 weeks. In certain embodiments, a single dose may be administered about once every week. A single dose may also be administered about once every month. In some embodiments, a compound provided herein, or a pharma- ceutically acceptable salt thereof, is administered once a day in the methods disclosed herein. In some embodiments, a compound provided herein, or a pharma- ceutically acceptable salt thereof, is administered twice a day in the methods disclosed herein.

[0156] In some embodiments, the compound provided herein, or a pharma- ceutically acceptable salt thereof, is administered in the methods disclosed herein once a day. In some embodiments, the compound provided herein, or a pharma- ceutically acceptable salt thereof, is administered in the methods disclosed herein once a week. In some embodiments, the compound provided herein, or a pharma- ceutically acceptable salt thereof, is administered in the methods disclosed herein once a month. In some embodiments, the compound provided herein, or a pharma- ceutically acceptable salt thereof, is administered in the methods disclosed herein once every two months. In some embodiments, the compound provided herein, or a pharma- ceutically acceptable salt thereof, is administered in the methods disclosed herein once every three months. In some embodiments, the compound provided herein, or a pharma- ceutically acceptable salt thereof, is administered in the methods disclosed herein once every six months.

[0157] In some embodiments, the compound provided herein, or a pharma- ceutically acceptable salt thereof, is orally administered once a week in a single dose of about 100 mg. In some embodiments, the compound provided herein, or a pharma- ceutically acceptable salt thereof, is orally administered once a week in a single dose of about 150 mg. In some embodiments, the compound provided herein, or a pharma- ceutically acceptable salt thereof, is orally administered once a week in a single dose of about 200 mg. In some embodiments, the compound provided herein, or a pharma- ceutically acceptable salt thereof, is orally administered once a week in a single dose of about 250 mg. In some embodiments, the compound provided herein, or a pharma- ceutically acceptable salt thereof, is orally administered once a week in a single dose of about 300 mg. In some embodiments, the compound provided herein, or a pharma- ceutically acceptable salt thereof, is orally administered once a week in a single dose of about 350 mg. In some embodiments, the compound provided herein, or a pharma- ceutically acceptable salt thereof, is orally administered once a week in a single dose of about 400 mg. In some embodiments, the compound provided herein, or a pharma- ceutically acceptable salt thereof, is orally administered once a week in a single dose of about 450 mg. In some embodiments, the compound provided herein, or a pharma- ceutically acceptable salt thereof, is orally administered once a week in a single dose of about 500 mg. In some embodiments, the compound provided herein, or a pharma- ceutically acceptable salt thereof, is orally administered once a week in a single dose of about 600 mg.

[0158] In some embodiments, the compound provided herein, or a pharma- ceutically acceptable salt thereof, is orally administered in a single dose of about 500 mg once a month. In some embodiments, the compound provided herein, or a pharma- ceutically acceptable salt thereof, is orally administered in a single dose of about 550 mg once a month. In some embodiments, the compound provided herein, or a pharma- ceutically acceptable salt thereof, is orally administered in a single dose of about 600 mg once a month. In some embodiments, the compound provided herein, or a pharma- ceutically acceptable salt thereof, is orally administered in a single dose of about 650 mg once a month. In some embodiments, the compound provided herein, or a pharma- ceutically acceptable salt thereof, is orally administered in a single dose of about 700 mg once a month. In some embodiments, the compound provided herein, or a pharma- ceutically acceptable salt thereof, is orally administered in a single dose of about 750 mg once a month. In some embodiments, the compound provided herein, or a pharma- ceutically acceptable salt thereof, is orally administered once a month in a single dose of about 800 mg. In some embodiments, the compound provided herein, or a pharma- ceutically acceptable salt thereof, is orally administered once a month in a single dose of about 850 mg. In some embodiments, the compound provided herein, or a pharma- ceutically acceptable salt thereof, is orally administered once a month in a single dose of about 900 mg. In some embodiments, the compound provided herein, or a pharma- ceutically acceptable salt thereof, is orally administered once a month in a single dose of about 950 mg. In some embodiments, the compound provided herein, or a pharma- ceutically acceptable salt thereof, is orally administered once a month in a single dose of about 1000 mg.

[0159] The frequency of administration of the compound of the present disclosure, or a pharma- ceutically acceptable salt thereof, is determined by the needs of each individual patient, and may be, for example, once a day, once a week, once a month, once every two months, once every three months, or once every six months. Administration of the compound or a pharma- ceutically acceptable salt thereof continues as long as necessary to treat herpes virus infection, including HSV-1 and HSV-2 infection, or any other indication described herein. For example, the compound or a pharma- ceutically acceptable salt thereof may be administered to a person suffering from herpes virus infection, including HSV-1 and HSV-2 infection, for the life of the person.

[0160] Administration may be intermittent, with a period of several days or more during which the patient receives a daily dose of the compound of the present disclosure, or a pharma- ceutically acceptable salt thereof, followed by a period of several days or more during which the patient does not receive a daily dose of the compound, or a pharma- ceutically acceptable salt thereof. For example, the patient may receive a dose of the compound, or a pharma- ceutically acceptable salt thereof, every other day, or three times per week. As a further example, the patient may be administered a dose of the compound, or a pharma- ceutically acceptable salt thereof, daily for a period of 1 to 14 days, followed by a period of 7 to 21 days during which the patient does not receive a dose of the compound, or a pharma- ceutically acceptable salt thereof, followed by a subsequent period (e.g., 1 to about 14 days) during which the patient again receives a daily dose of the compound, or a pharma- ceutically acceptable salt thereof. Alternating periods of administration of the compound, or a pharma- ceutically acceptable salt thereof, followed by periods of not administering the compound, or a pharma- ceutically acceptable salt thereof, can be repeated as clinically required to treat the patient.

[0161] The compound of the present application, or a pharma- ceutically acceptable salt thereof, or the pharmaceutical composition of the present disclosure may be administered once, twice, three times, or four times a day, using any suitable mode described above. Administration or treatment with the compound, or a pharma- ceutically acceptable salt thereof, may also continue for several days, for example, treatment will typically continue for at least 7 days, 14 days, or 28 days for one cycle of treatment. Treatment cycles are well known for herpes virus infections, including HSV-1 and HSV-2 infections. In some embodiments, treatment cycles alternate periodically with rest periods of about 1 to 28 days, usually about 7 days or about 14 days, between cycles. Treatment cycles may also be continuous in other embodiments.

[0162] The effective dosage of the active ingredient used may vary depending on the particular compound used, the mode of administration, the condition being treated, and the severity of the condition being treated. Such dosages may be readily ascertained by one skilled in the art.

[0163] combination In some embodiments, a compound of Formula (I), (IIa), (IIb), (IIc), (IId), (IIe), or (IIf) provided herein, or a pharma- ceutically acceptable salt thereof, is administered in combination with one or more additional therapeutic agents for treating or preventing a disease or condition disclosed herein. In some embodiments, the one or more additional therapeutic agents are 1, 2, 3, or 4 additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents are 1 additional therapeutic agent. In some embodiments, the one or more additional therapeutic agents are 2 additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents are 3 additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents are 4 additional therapeutic agents.

[0164] In some embodiments, the pharmaceutical compositions provided herein comprise a compound of Formula (I), (IIa), (IIb), (IIc), (IId), (IIe), or (IIf) provided herein, or a pharma- ceutically acceptable salt thereof, and one or more additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents are 1, 2, 3, or 4 additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents are 1 additional therapeutic agent. In some embodiments, the one or more additional therapeutic agents are 2 additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents are 3 additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents are 4 additional therapeutic agents.

[0165] In some embodiments, the one or more additional therapeutic agents include, for example, a DNA polymerase inhibitor, such as brincidofovir; a protein Jumonji inhibitor, such as ML-324, dimethyloxaloylglycine; an interferon alpha 2 ligand modulator, such as interferon alpha-2b, Alpharekin®, recombinant human interferon alpha-2b biosimilar, Herpferon®, Anterferon®; a nicotinic acetylcholine receptor antagonist, such as RPI-MN; a virus-specific T cell therapy, such as off-the-shelf single virus-specific T cell (VST) therapy, ALVR-108, multiple virus-specific T cell TI1; another drug for the treatment of herpes virus infection, such as BOR-15001L7, lidocaine, Bryostatin-23, or any combination thereof.

[0166] In some embodiments, the one or more additional therapeutic agents include an anti-herpes virus envelope glycoprotein D antibody, such as m27f; a progesterone receptor agonist, such as levonorgestrel; or an HIV-1 reverse transcriptase inhibitor, such as tenofovir, or any combination thereof.

[0167] In some embodiments, the one or more additional therapeutic agents include, for example, an endonuclease modulator, such as a meganuclease; an interferon alpha ligand / interferon gamma receptor antagonist, such as Anaferon®, or any combination thereof.

[0168] In some embodiments, the one or more additional therapeutic agents include, for example, a CCR5 chemokine modulator, a DNA polymerase inhibitor, a DNA primase inhibitor, a fatty acid synthase inhibitor, a glucocorticoid receptor agonist, a helicase inhibitor, a herpes virus envelope glycoprotein D inhibitor, an Hsp90 inhibitor, a human cytomegalovirus glycoprotein inhibitor, a hyaluronidase inhibitor, an interferon alpha 1 ligand, an interferon alpha 2 ligand, an interferon beta ligand, a T cell surface glycoprotein CD8 stimulator, or a cyclin dependent kinase inhibitor, or any combination thereof.

[0169] In some embodiments, the one or more additional therapeutic agents include, for example, DNA primase-helicase inhibitors, such as amenamevir, priterivir, IM-250; DNA polymerase inhibitors, such as famciclovir, penciclovir, valacyclovir, acyclovir, foscarnet sodium; CCR5 chemokine modulators / human cytomegalovirus glycoprotein inhibitors, such as MB-66; Hsp 90 inhibitors, such as BJ-B11; glucocorticoid receptor agonists, such as hydrocortisone; interferon alpha 1 ligand modulators, such as interferon alpha 1b, recombinant human interferon alpha 1b; interferon alpha 2 ligand modulators, such as recombinant human interferon alpha-2b, KW-045; interferon beta ligand modulators, such as interferon beta-1a (RebiSmart™); anti-HSV envelope glycoprotein D antibodies, e.g., UB-621; T cell surface glycoprotein CD8 stimulators, e.g., immunogenic peptides, fatty acid synthase inhibitors, e.g., TVB-2640; anti-herpes simplex virus monoclonal antibodies, e.g., HDIT-101; or other drugs for the treatment of herpes simplex virus infection, e.g., idoxuridine, BTL-TML-HSV, docosanol, MAR-8644, MAR-8658, NV-HHV-101, PRL-01, HN-0037, or any combination thereof.

[0170] In some embodiments, the one or more additional therapeutic agents include, for example, a hyaluronidase inhibitor, such as astodrimer (SPL-7013); a live attenuated HSV vaccine, such as RVx-101 HSV-1; a live attenuated HSV vaccine having deletions in UL20 and UL53, such as VC2; a live attenuated HSV vaccine mutated in the R2 coding region of UL37, such as R2; or an HSV-2 subunit trivalent vaccine (containing gC2, gD2, gE2), such as an HSV-2 trivalent vaccine, or any combination thereof.

[0171] In some embodiments, the one or more additional therapeutic agents include, for example, a live attenuated recombinant vaccine, such as AuroVax; a UL5 and UL29 deleted HSV-2 replication-deficient vaccine, such as HSV-529; an mRNA vaccine targeting HSV-2 disease, such as mRNA-1608, or any combination thereof.

[0172] In some embodiments, the one or more additional therapeutic agents include, for example, a CD4 agonist, a CD89 agonist, a Duffy antigen chemokine receptor modulator, a herpes virus envelope glycoprotein D inhibitor, an HIV gp120 protein inhibitor, an HIV gp160 protein inhibitor, an HIV gp41 protein inhibitor, an immunoglobulin G agonist, a nicotinic acetylcholine receptor antagonist, a TAT protein modulator, a T cell surface glycoprotein CD8 stimulator, or a TLR-4 agonist, or any combination thereof.

[0173] In some embodiments, the one or more additional therapeutic agents include, for example, a nicotinic acetylcholine receptor antagonist, such as RPI-78M; an anti-herpes simplex virus monoclonal antibody, such as HDIT-101; an anti-herpes virus envelope glycoprotein D antibody, such as UB-621; a TLR-4 agonist, such as IDC-G103 vaccine; an inactivated HSV-1 and HSV-2 vaccine, such as Vitaherpavac®; a live inactivated HSV-1 and HSV-2 vaccine, such as Theravax-HSV-2 vaccine; a formalin-inactivated herpesvirus (FI-HSV2) vaccine; or an RBT-26 T cell line subunit vaccine; a DNA vaccine, such as a pDNA / rVSV vector vaccine; or other drugs for the treatment of HSV-2, such as EBT-105, Alloferon™, or any combination thereof.

[0174] In some embodiments, the one or more additional therapeutic agents include, for example, an HIV gp120 / gp160 / gp41 protein inhibitor, such as Griffithsin; a hyaluronidase inhibitor, such as Astodrimer (SPL-7013); a CD4 agonist / T cell surface glycoprotein CD8 vaccine, such as GENO-2; a TAT protein modulator, such as HerpesVaxTat® vaccine; a CD89 agonist / Duffy antigen chemokine receptor modulator / immunoglobulin G agonist, such as glycoprotein D + liposome encapsulated glycoprotein D boost vaccine; or a vaccine, such as Profavax-HSV-2 vaccine; an HSV-2 mRNA vaccine; a glycoprotein D DNA vaccine, or any combination thereof.

[0175] In some embodiments, the one or more additional therapeutic agents include, for example, a DNA vaccine, such as the HSV-2 vaccine Admedus; an RNA vaccine, such as GSK-4108771A; a live attenuated viral vaccine, such as EXD-12; a live attenuated delta-gD2-based viral vaccine; a vaccine, such as the NE-gD2 intranasal nanoemulsion NE-based adjuvanted HSV-2 vaccine; or other drugs for the treatment of HSV-2, such as EBT-105, Alloferon™, or any combination thereof.

[0176] In some embodiments, the one or more additional therapeutic agents include, for example, an antimicrobial peptoid, a CD4 modulator, a CRISPR-associated endonuclease Cas9 modulator, a cyclin-dependent kinase-9 inhibitor, a DNA polymerase inhibitor, a nicotinic acetylcholine receptor antagonist, a TAT protein modulator, a thymidine kinase inhibitor, or a viral envelope protein inhibitor, or any combination thereof.

[0177] In some embodiments, the one or more additional therapeutic agents include, for example, a DNA polymerase inhibitor / thymidine kinase inhibitor, such as acyclovir; a CRISPR-associated endonuclease Cas9 modulator, such as EBT-104; a nicotinic acetylcholine receptor antagonist, such as RPI-78M; a cyclin-dependent kinase-9 inhibitor, such as FIT-039; other drugs for HSV-1 treatment, such as ZEP-3Na, MXB-009; a CD4 modulator peptide vaccine, such as CEL-1000; a vaccine, such as an inactivated HSV-1 and HSV-2 vaccine, such as Vitaherpavac® (anti-herpes vaccine); a live inactivated HSV-1 and HSV-2 vaccine, such as Theravax-HSV-1 vaccine; or a viral envelope protein inhibitor, such as MXB-005, or a combination thereof.

[0178] In some embodiments, the one or more additional therapeutic agents include, for example, a TAT protein modulator, such as the HerpesVaxTat® vaccine; or a vaccine, such as the Profavax-HSV-1 vaccine, or a combination thereof.

[0179] In some embodiments, the one or more additional therapeutic agents include, for example, a live attenuated viral vaccine, such as EXD-12; or a live attenuated delta-gD2-based viral vaccine, or a combination thereof.

[0180] In some embodiments, the one or more additional therapeutic agents include, for example, a DNA polymerase inhibitor, a herpes virus envelope glycoprotein D inhibitor, or an interferon alpha 2 ligand, or any combination thereof.

[0181] In some embodiments, the one or more additional therapeutic agents include, for example, a DNA polymerase inhibitor, such as famciclovir, penciclovir; an interferon alpha 2 ligand modulator, such as Yallaferon®; an anti-herpes virus envelope glycoprotein D antibody, such as UB-621; or other drugs for the treatment of genital herpes, such as interferon gamma, Alloferon™, ZEP-3Na, or any combination thereof.

[0182] In some embodiments, the one or more additional therapeutic agents include, for example, a vaccine, such as a NE-gD2 intranasal nanoemulsion NE-based adjuvant vaccine; or other drugs for the treatment and prevention of genital herpes, such as SQX-77, anti-STI antibodies, or any combination thereof.

[0183] In some embodiments, the one or more additional therapeutic agents include, for example, a SAPN (self-assembling protein nanoparticle)-based herpes vaccine.

[0184] In some embodiments, the one or more additional therapeutic agents include, for example, a CMV 65 kDa lower matrix phosphoprotein modulator, a DNA polymerase inhibitor, a G protein-coupled receptor homolog US28 antagonist, a herpes virus envelope glycoprotein B stimulator, an HLA class I antigen A-11 alpha modulator, an HLA class I antigen A-2 alpha modulator, an HLA class I antigen A-24 alpha modulator, a human cytomegalovirus glycoprotein B inhibitor, a human cytomegalovirus glycoprotein B modulator, a human cytomegalovirus glycoprotein H modulator, a human cytomegalovirus glycoprotein inhibitor, a large terminase protein inhibitor, a ribonuclease stimulator, a serine threonine protein kinase UL97 modulator, a syntaxin-5 inhibitor, a transferase inhibitor, or a viral ribonucleotide reductase inhibitor, or a combination thereof.

[0185] In some embodiments, the one or more additional therapeutic agents include, for example, a DNA polymerase inhibitor, such as ganciclovir, fomivirsen, fomivirsen sodium, valganciclovir; a DNA polymerase inhibitor / serine threonine protein kinase UL97 modulator, such as filociclovir; a G protein-coupled receptor homolog US28 antagonist, such as SYN-002; a large terminase protein inhibitor, such as AIC-387, AIC-476; a serine threonine protein kinase UL97 inhibitor, such as marivacic. viral ribonucleotide reductase inhibitors, e.g., didox; ribonuclease stimulators, e.g., ranpirnase; HLA class I antigen A-11 alpha modulators / HLA class I antigen A-2 alpha modulators / HLA class I antigen A-24 alpha modulators, e.g., allogeneic anti-CMV-TCR-T cell therapy, YT-CMV-22, YT-CMV-27 and YT-CMV-45; human cytomegalovirus glycoprotein B inhibitors, e.g., CMV-345; other drugs for the treatment of CMV, e.g., USC-505, USC-596, CMV Examples of therapeutic agents include pp65 and ppM83 derived peptides, artemiphon (BAY-44-9585), PG-36, CMX-16669, HN-0141, ALVR-105, NPP-669, CMV pH4 human immunoglobulin, Cytovir™, antiviral cytotoxic T cell therapy, CMV TCR transduced T cells, adimulcleucel; or polyclonal antibodies, such as Cytogam®, or combinations thereof.

[0186] In some embodiments, the one or more additional therapeutic agents include, for example, a Syntaxin-5 inhibitor, such as Retro-94; a large terminase protein inhibitor, such as letermovir; a DNA polymerase inhibitor, such as valganciclovir; an anti-CMV antibody, such as BT-084 (Cytotect® CP); a human cytomegalovirus glycoprotein B and glycoprotein H modulator vaccine, such as mRNA-1647; a CMV 65 kDa lower matrix phosphoprotein vaccine, such as IRB-12022; or a vaccine, such as an mRNA-based vaccine; BD-03 plasmid DNA vaccine; V-212 heat-treated varicella zoster virus vaccine; a protein subunit vaccine, such as VBI-1501A; a CMV-MVA pentamer vaccine (RhUL128C-MVA); a CMV-MVA Triplex vaccine; a VLP-based vaccine SPYVLP-102, or any combination thereof.

[0187] In some embodiments, the one or more additional therapeutic agents include, for example, a human cytomegalovirus glycoprotein inhibitor, e.g., CMV-IVIG; an additional drug for the treatment or prevention of CMV, e.g., an artemisinin derivative, NPC-21; a herpesvirus envelope glycoprotein B stimulating vaccine, e.g., HB-101; a CMV 65 kDa lower matrix phosphoprotein modulator vaccine, e.g., AVX-601; a vaccine, e.g., a CMV vaccine; a CMVpp65 peptide vaccine; V-160; or a multivirus-specific cytotoxic T cell therapy, or any combination thereof.

[0188] In some embodiments, the one or more additional therapeutic agents include a DNA polymerase inhibitor, such as ganciclovir, fomivirsen, cidofovir, valganciclovir, foscarnet sodium.

[0189] In some embodiments, the one or more additional therapeutic agents include, for example, a DNA polymerase inhibitor, a helicase inhibitor, an immunoglobulin agonist, an interferon alpha 2 ligand, an interferon alpha ligand modulating agent, an interferon beta ligand, or a TLR-4 agonist, or any combination thereof.

[0190] In some embodiments, the one or more additional therapeutic agents include, for example, a DNA polymerase inhibitor, such as penciclovir, famciclovir, valacyclovir, acyclovir, USC-373; a DNA primase inhibitor-helicase inhibitor, such as amenamevir; an interferon alpha 2 ligand modulator, such as interferon alpha-2b, Yallaferon®, pegylated interferon alpha-1b, INTEFEN®, interferon alpha-2a, Anterferon®; an interferon beta ligand modulator, such as RebiSmart™; an immunoglobulin agonist, such as Varicellon®, varicella immunoglobulin-VF; a vaccine, such as varicella vaccine (live attenuated); an MMRV vaccine; a herpes zoster vaccine; a varicella zoster recombinant adjuvant vaccine; or a drug for the treatment of varicella zoster virus infection, such as HerpeCide™, or any combination thereof.

[0191] In some embodiments, the one or more additional therapeutic agents include, for example, a vaccine, such as ProQuad®; Priorix-Tetra® (MeMuRu-OKA); a protein subunit TLR-4 agonist vaccine, such as CRV-101; VZV ORF29 mutant-based vaccines; chickenpox vaccines (live attenuated); chickenpox vaccine Sinovac; Varilrix® vaccine (VZV-OKA strain); attenuated recombinant subunit vaccines containing gE, e.g., GSK-137173A; protein subunit vaccines, e.g., SP-0204; pneumococcal conjugate vaccines, e.g., SP-0202; triple attenuated live vaccines, e.g., MM-RvaxPRO®; adenovirus vector vaccines, e.g., VTP-400; recombinant varicella zoster virus vaccines; recombinant herpes zoster vaccines; inactivated varicella zoster vaccines; live attenuated virus vaccines, e.g., NBP-608, Suduvax® II, VZV-7D; or anti-varicella zoster virus antibodies, e.g., VariZIG®, or any combination thereof.

[0192] In some embodiments, the one or more additional therapeutic agents include, for example, a drug for the treatment or prevention of Varicella Zoster virus infection, such as OV-02; or a vaccine, such as EG-HZ; or any combination thereof.

[0193] In some embodiments, the one or more additional therapeutic agents include, for example, an interferon alpha 2 ligand; a DNA polymerase inhibitor; a transferase inhibitor; a CRISPR-associated endonuclease Cas9 modulator; a LAT gene inhibitor; or a gene inhibitor, or any combination thereof.

[0194] In some embodiments, the one or more additional therapeutic agents include, for example, a DNA polymerase inhibitor, such as acyclovir, ganciclovir; an interferon alpha 2 ligand modulator, such as interferon alpha-2b, Anterferon®; a CRISPR-associated endonuclease Cas9 modulator / gene inhibitor, such as HSV-1 targeted CRISPR / Cas9 gene therapy; a LAT gene inhibitor, such as IFNγ / LAT siRNA gene therapy (rdHSV1 vector, herpes simplex keratitis); an additional agent for the treatment of herpes keratitis, such as EKC-Cide™, or any combination thereof.

[0195] In some embodiments, the one or more additional therapeutic agents include, for example, a Basigin inhibitor, an envelope glycoprotein GP350 modulator, an Epstein-Barr nuclear antigen 1 inhibitor, an Epstein-Barr nuclear antigen 1 stimulator, an HLA class I antigen A-11 alpha modulator, an HLA class I antigen A-2 alpha modulator, an HLA class I antigen A-24 alpha modulator, a human cytomegalovirus glycoprotein B modulator, a human cytomegalovirus glycoprotein H modulator, a human cytomegalovirus glycoprotein L modulator, a latent membrane protein 1 modulator, a latent membrane protein 2 stimulator, an NKG2D ligand modulator, or a secreted protein BARF1 modulator, or any combination thereof.

[0196] In some embodiments, the one or more additional therapeutic agents include, for example, an NKG2D ligand modulator, such as pamidronate; an Epstein-Barr nuclear antigen 1 inhibitor, such as VK-2019, an anti-Epstein-Barr virus (EBV) peptide; an HLA class I antigen A-11 alpha / HLA class I antigen A-2 alpha / HLA class I antigen A-24 alpha modulator, such as allogeneic anti-EBV-TCR-T cells, YT-EBV-44; an additional drug for EBV treatment, such as ALVR-105, an antiviral cytotoxic T cell therapy; an Epstein-Barr nuclear antigen / latency membrane protein 1 and protein 2 / secreted protein BARF1 modulator, such as bartalucel-T (CMD-003); or an mRNA vaccine, such as mRNA-1195, or any combination thereof.

[0197] In some embodiments, the one or more additional therapeutic agents include, for example, a basigin modulator, such as an EBV gH / gL / gp42 vaccine; or a basigin modulator / envelope glycoprotein GP350 modulator / human cytomegalovirus glycoprotein B modulator / human cytomegalovirus glycoprotein H modulator / human cytomegalovirus glycoprotein L modulator, such as an mRNA-1189 vaccine; a vaccine, such as an EBV gH / gL vaccine; P-989; an mRNA vaccine; or an EBV cancer vaccine (mRNA, LPP nanoparticles), or any combination thereof.

[0198] In some embodiments, the one or more additional therapeutic agents include, for example, an Epstein-Barr nuclear antigen 1 / latent membrane protein 2 stimulatory agent, such as an MVA-based vaccine; a multivirus-specific cytotoxic T cell therapy; or a vaccine, such as an EBV-VLP vaccine, or any combination thereof.

[0199] In some embodiments, the one or more additional therapeutic agents include, for example, a DNA polymerase inhibitor.

[0200] In some embodiments, the one or more additional therapeutic agents include, for example, a DNA polymerase inhibitor, such as brincidofovir; a drug for treating herpes virus type 6, such as ALVR-105; a multivirus-specific cytotoxic T cell therapy; or an HHV-6B glycoprotein complex gH / gL / gQ1 / gQ2 subunit vaccine, or any combination thereof. EXAMPLES

[0201] The following examples are included to demonstrate specific embodiments of the present disclosure. It should be understood by those skilled in the art that the techniques disclosed in the following examples represent techniques that work well in the implementation of the present disclosure, and therefore can be considered as constituting specific modes for its implementation. However, those skilled in the art should understand that in light of the present disclosure, these examples are illustrative and not exhaustive. Many modifications can be made in the specific embodiments disclosed and still obtain similar or similar results without departing from the spirit and scope of the present disclosure.

[0202] The compounds disclosed herein can be prepared according to the procedures of the following schemes and examples using appropriate materials, and are further illustrated by the following specific examples. Furthermore, by utilizing the procedures described herein in conjunction with one of ordinary skill in the art, additional compounds of the present disclosure claimed herein can be readily prepared. The examples further provide details for the preparation of the compounds of the present disclosure. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds. To synthesize compounds that are embodiments described in the present disclosure, inspection of the structure of the compound to be synthesized provides the identity of each of the substituents. In some cases, the identity of the final product can be revealed by the inspection process of the identity of the necessary starting materials in light of the examples herein. The compounds can be isolated in the form of their pharma-ceutically acceptable salts, such as those described above. The compounds described herein are typically stable and isolatable at room temperature and pressure.

[0203] Illustrative preparations of the compounds disclosed herein are set forth below. Unless otherwise indicated, the variables have the same meanings as above. The examples provided below are intended to illustrate certain embodiments of the disclosure. Suitable starting materials, building blocks, and reagents used in the syntheses described below are commercially available from, for example, AbovChem, Acros Organics, Astatech, Combi Blocks, Oakwood Chemical, or Sigma-Aldrich, or can be found in, for example, "March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure", 5 th Edition, John Wiley & Sons or T. Eicher, S. Hauptmann “The Chemistry of Heterocycles;Structures, Reactions, Synthesis and Application”,2 nd These can usually be synthesized according to the procedures described in literature such as "Fiesers' Reagents for organic Synthesis" John Wiley & Sons, 2000, and the like. [Table 4]

[0204] General Procedure A [ka] Compounds of formula A.3 can be produced from intermediates A.1 and A.2 by amide coupling (similar reaction described in Chem. Soc. Rev., 2009, 38, 606-631, Amide Bond Formation: Beyond Traditional Coupling Reagents). An exemplary procedure is as follows: Intermediates A.1 (1 eq.) and A.2 (1 eq.) are suspended in acetonitrile (10V). TCFH (1.2 eq.) is then added, followed by dropwise addition of N-methylimidazole (3 eq.) while maintaining the internal temperature below 25° C. After complete consumption of the starting material, the reaction mixture is purified by reverse phase HPLC to give the title compound of type A.3.

[0205] General Procedure B [ka] Intermediates of type B.1 are protected with a suitable protecting group (e.g., Boc, PMB, DMB, DMFDMA, etc.) to give intermediate B.2. In the subsequent amide coupling step, intermediate B.2 (1 eq.) and intermediate B.3 (1 eq.) are suspended in acetonitrile (10 V). TCFH (1.2 eq.) is then added, followed by dropwise addition of N-methylimidazole (3 eq.) while maintaining the internal temperature below 25° C. After consumption of intermediates B.2 and B.3 and conversion to intermediates of type B.4, removal of the relevant protecting groups is carried out in the same pot using suitable conditions (e.g., TFA, hydrazine, etc.). After complete removal of the protecting groups, addition of water (30 V) may result in precipitation of a solid material, which is filtered, washed and dried to give compounds of type B.5.

[0206] General Procedure C [ka] Intermediates of type C.1 (1 eq.) and type C.2 (1 eq.) are suspended in acetonitrile (10 V). TCFH (1.2 eq.) is then added, followed by dropwise addition of N-methylimidazole (3 eq.) while maintaining the internal temperature below 25° C. After consumption of intermediates C.1 and C.2, silica gel is added, the solvent is removed under reduced pressure, and the resulting compound is adsorbed onto silica gel and purified by flash column chromatography to provide compounds of type intermediate C.3. Intermediate C.3 is then dissolved in chloroform (5 V) and chlorosulfonic acid (5 V). The mixture is then stirred at 65° C. until consumption of intermediate C.3 is observed, at which point the mixture is carefully poured onto ice. The resulting precipitated solid of intermediate C.4 is filtered, dissolved in dichloromethane (5 V), and 6N ammonium hydroxide is added (25 eq.). After complete consumption of intermediate C.4, the mixture is diluted with dichloromethane (25 V) and the organic phase is washed successively with water (10 V) and brine (10 V) and then dried over magnesium sulfate. After filtration and concentration, the crude residue is purified using reverse phase HPLC to give compounds of type C.5.

[0207] Preparation of intermediate 1: 7-methylindoline-6-sulfonamide [ka] Preparation of Intermediate 1.1: 6-Bromo-7-methylindoline (100 mg, 0.47 mmol) and 4-dimethylaminopyridine (12 mg, 0.2 equiv.) were taken up in tetrahydrofuran (5 mL). The solution was cooled to 0° C. and then di-tert-butyl dicarbonate (134 mg, 1.3 equiv.) was added in one portion. The mixture was allowed to warm to room temperature and stirred overnight, at which point silica gel was added and the solvent was removed under reduced pressure. The resulting crude material was purified by flash column chromatography on silica gel (0-20% ethyl acetate in hexanes) to give Intermediate 1.1. LCMS: 312.1 [M+H].

[0208] Preparation of intermediate 1.2: Intermediate 1.1 (110 mg, 0.35 mmol) was taken up in tetrahydrofuran (5 mL) and cooled to -78 °C. Then, n-butyl lithium (2.4 M in hexanes, 0.22 mL, 1.5 eq.) was added dropwise and stirred at the same temperature for 5 min. Then, 2-methyl-2-(sulfinylamino)oxypropane (95 mg, 2 eq.) was added in one portion and the mixture was allowed to warm to room temperature and stirred overnight. Silica gel was then added and the solvent was removed under reduced pressure. The resulting crude material was purified by flash column chromatography on silica gel (0-10% methanol in dichloromethane) to give intermediate 1.2. LCMS: 313.1 [M+H].

[0209] Preparation of intermediate 1: Intermediate 1.2 (45 mg, 0.21 mmol) was taken up in trifluoroacetic acid (2 mL) and stirred for 1 h. The solvent was then removed under reduced pressure to give intermediate 1. LCMS: 213.1 [M+H].

[0210] Preparation of intermediate 2: 5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carboxylic acid [ka] Preparation of intermediate 2.1: To a stirred suspension of 60% NaH (22.72 g, 2 eq.) in THF (1000 mL) was added diethyl carbonate (86 mL, 1.5 eq.) at 0° C. To this was added 5-bromo-indan-1-one (100 g, 473.1 mmol) portionwise at this temperature. The reaction mixture was kept stirred at this temperature until gas evolution subsided. The reaction mixture was slowly heated to 50° C. and stirring was maintained for 2 h. The progress of the reaction was monitored by TLC and after consumption of starting material, the reaction mixture was allowed to cool to room temperature. The reaction was diluted with EtOAc (10 V). To this was added 3N aqueous HCl solution dropwise. Both layers were separated. The aqueous layer was extracted with EtOAc (2×5 V). The combined organic layers were washed with brine solution (5 V), dried (Na 2 SO 4) and evaporated to give the crude material which was purified by column chromatography on silica gel to give intermediate 2.1. LCMS: 283.0 [M+H].

[0211] Preparation of intermediate 2.2: To a solution of intermediate 2.1 (56 g, 197.9 mmol) in TFA (280 mL) at 0° C., triethylsilane (224 mL) was added dropwise and the reaction mixture was stirred at room temperature for 24 h. The reaction progress was monitored by TLC. After consumption of the starting material, the reaction mixture was evaporated to dryness under reduced pressure to give the crude material. The crude material was purified by column chromatography on silica gel to give intermediate 2.2. LC / MS: 269.0 [M+H].

[0212] Preparation of Intermediate 2.3: A stirred solution of Intermediate 2.2 (40 g, 148.7 mmol) and 2-tributylstannylpyridine (57.5 g, 1.05 equiv.) in 1,4 dioxane (400 mL) was degassed with argon for 10 min, at which point Pd(PPh 3 ) 4 (8.6 g, 5 mol%) was added and degassed again for another 10 min. The reaction mixture was heated to 90° C. for 16 h. The reaction mixture was filtered through a Celite pad and the Celite pad was washed twice with ethyl acetate. The combined filtrate was evaporated to dryness to give the crude material. The crude material was purified by column chromatography on silica gel to give intermediate 2.3. LC / MS: 268.1 [M+H].

[0213] Preparation of intermediate 2: To a stirred solution of intermediate 2.3 (35 g, 131.1 mmol) in methanol (350 mL) at 0° C., 2N aqueous NaOH (140 mL, 2.2 eq.) was added and the reaction mixture was stirred at room temperature for 4 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to 100 mL. The residue was diluted with water (10 V) and the aqueous layer was washed with ethyl acetate (2×2 V). The aqueous phase was neutralized with 2N aqueous HCl and extracted with 10% methanol / DCM (3×5 V). The organic layer was dried over sodium sulfate and concentrated to give the crude material. The crude material was then taken up in 10% isopropanol / toluene (10 V) solution and treated with activated charcoal. The solvent was then removed under reduced pressure. The residue was taken up in 30% toluene / hexane, stirred for 30 min, filtered, and then dried under high vacuum. This process was repeated two more times to give intermediate 2. LC / MS: 238.1 [MH].

[0214] Preparation of intermediate 3: 4-methylindoline-6-sulfonamide [ka] Intermediate 3.1 was prepared in a similar manner to Intermediate 1.1, utilizing 6-bromo-4-methylindoline instead of 6-bromo-7-methylindoline as the starting material. LCMS: 312.1 [M+H].

[0215] Intermediate 3.2 was prepared in a similar manner to Intermediate 1.2, using Intermediate 3.1 instead of compound Intermediate 1.1 as the starting material. LCMS: 313.1 [M+H].

[0216] Intermediate 3 was prepared in a similar manner to intermediate 1, using intermediate 3.2 instead of intermediate 1.2 as the starting material. LCMS: 213.1 [M+H].

[0217] The intermediates in Table 1A were prepared in a similar manner to Intermediates 1 and 3. [Table 1A]

[0218] The intermediates in Table 1B were prepared in a similar manner to Intermediate 2. [Table 1B]

[0219] Preparation Example Preparation of Example 1: 4-Methyl-3-(5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)-2,3-dihydro-1H-indene-5-sulfonamide (General Procedure A) [ka] Intermediate 1 (25 mg, 0.12 mmol) and intermediate 2 (34 mg, 1.2 eq.) were taken up in acetonitrile (2 mL). 1-Methylimidazole (48 mg, 5 eq.) and TCFH (chloro(dimethylamino)-N,N-dimethylmethaniminium hexafluorophosphate, 33 mg, 1 eq.) were then added sequentially and the reaction mixture was stirred at room temperature overnight, after which the solvent was removed under reduced pressure. The crude residue was purified by reverse phase HPLC to give Example 1. 1 H NMR(400 MHz,DMSO-d6)δ 8.69-8.59(m,1H),7.99-7.85(m,4H),7.69(d,J=7.8 Hz,1H),7.37(s,2H),7.33(d,J=10.9 Hz,2H),7.29(d,J=7.9 Hz,1H),6.53(m,4H),4.26(d,J=8.0 Hz,2H),3.91(m,1H),3.12(t,J=7.4 Hz,2H),2.28(s,3H).LCMS:434.1[M+H].

[0220] Preparation of Example 2: [ka] Example 2 was prepared in a similar manner to Example 1, utilizing Intermediate 3 instead of Intermediate 1 as the starting material. 1 H NMR (400 MHz, DMSO-d 6)δ 8.68(dt,J=5.0,1.4 Hz,1H),8.44(d,J=1.7 Hz,1H),7.98(dd,J=15.6,7.9 Hz,3H),7.89(dd,J=7.9,1.7 Hz,1H),7.46-7.40(m,1H),7.38(d,J=7.8 Hz,1H),7.33(d,J=1.6 Hz,1H),7.23(s,2H),4.36(t,J=8.5 Hz,2H),3.78(q,J=8.1 Hz,1H),3.44-3.22(m,4H),3.18(t,J=8.3 Hz,2H),2.29(s,3H).LCMS:434.1[M+H].

[0221] The following examples in Table 1C were prepared in a similar manner to Example 1 (General Procedure A). [Table 1C-1] [Table 1C-2] [Table 1C-3]

[0222] Preparations 14, 15, 16 and 17: [ka] Example 14 was obtained from the first eluate of the chiral SFC purification of Example 3 using an OJ-H 4.6×100 mm column with 50% ethanol as a co-solvent. 1H NMR(400 MHz,DMSO-d6)δ 8.69(dd,J=4.8,1.5 Hz,1H),8.58(s,1H),8.07-7.91(m,3H),7.89(dd,J=7.9,1.7 Hz,1H),7.57-7.35(m,4H),7.29(s,2H),4.90(t,J=7.5 Hz,1H),3.90-3.69(m,1H),3.46(tt,J=16.9,8.4 Hz,3H),3.28(dd,J=15.8,8.5 Hz,1H),3.14(dd,J=16.3,7.7 Hz,1H),2.80(d,J=16.6 Hz,1H),1.30(d,J=6.2 Hz,3H).LC / MS:434.1[M+H].

[0223] Example 15 was obtained from the second eluate of the chiral SFC purification of Example 3 using an OJ-H 4.6×100 mm column with 50% ethanol as a co-solvent. 1 H NMR(400 MHz,DMSO-d6)δ 8.75-8.67(m,1H),8.58(s,1H),8.06(d,J=4.1 Hz,2H),7.97(s,1H),7.88(dd,J=7.9,1.7 Hz,1H),7.58-7.37(m,4H),7.29(s,2H),4.90(t,J=7.5 Hz,1H),3.78(q,J=8.2 Hz,1H),3.47(tt,J=18.5,8.9 Hz,3H),3.29(dd,J=15.9,8.5 Hz,1H),3.14(dd,J=16.3,7.7 Hz,1H),2.81(d,J=16.6 Hz,1H),1.30(d,J=6.2 Hz,3H).LC / MS:434.1[M+H].

[0224] Example 16 was obtained from the third eluate of the chiral SFC purification of Example 3 using an OJ-H 4.6×100 mm column with 50% ethanol as a co-solvent. 1H NMR(400 MHz,DMSO-d6)δ 8.70(dd,J=5.0,1.4 Hz,1H),8.58(s,1H),8.04(d,J=4.1 Hz,2H),7.99-7.84(m,2H),7.61-7.39(m,4H),7.29(s,2H),4.91(q,J=7.0 Hz,1H),3.78(q,J=8.1 Hz,1H),3.60-3.33(m,3H),3.27(dd,J=16.2,8.5 Hz,1H),3.16(dd,J=16.0,7.6 Hz,1H),2.81(d,J=16.6 Hz,1H),1.30(d,J=6.2 Hz,3H).LC / MS:434.1[M+H].

[0225] Example 17 was obtained from the fourth eluate of the chiral SFC purification of Example 3 using an OJ-H 4.6×100 mm column with 50% ethanol as a co-solvent. 1 H NMR(400 MHz,DMSO-d6)δ 8.70(dd,J=5.1,1.4 Hz,1H),8.58(s,1H),8.14-8.01(m,2H),7.97-7.82(m,2H),7.61-7.37(m,4H),7.29(s,2H),4.90(t,J=7.5 Hz,1H),3.86-3.73(m,1H),3.62-3.36(m,3H),3.27(dd,J=16.2,8.5 Hz,1H),3.16(dd,J=16.0,7.6 Hz,1H),2.81(d,J=16.6 Hz,1H),1.30(d,J=6.2 Hz,3H).LC / MS:434.1[M+H].

[0226] Alternative preparation of Example 15 starting from 5-bromo-(R)-2-methylindoline Preparation of intermediate 49: (R)-2-methylindoline-6-sulfonamide [ka] Intermediate 49.2 was prepared in a similar manner to Intermediate 42.3 utilizing (R)-5-bromo-2-methylindoline as the starting material instead of Intermediate 42.1.

[0227] Preparation of 49.3: (2R)-1-acetyl-5-bromo-2-methyl-indoline-6-sulfonamide 49.2 (145 mg, 0.44 mmol) in EtOH (10 mL) was added to a suspension of 10% Pd / C (93 mg, 0.2 equiv.) and EtOH (10 mL). 3 N (0.18 mg, 3 equiv.) was added. The reaction mixture was evacuated and H 2 Purge (4 times) and 2 The mixture was stirred under reduced pressure. LCMS showed complete conversion after stirring overnight. The mixture was filtered through a pad of Celite, washing the pad with EtOH, and the filtrate was concentrated to near dryness. Water was added to the residue, the mixture was sonicated, and the white solid was collected by filtration, washing the solid with water (3 times), and further drying the solid under high vacuum.

[0228] Intermediate 49 was prepared in a similar manner to intermediate 42, utilizing 49.3 instead of 42.3 as the starting material. 1 H NMR (400 MHz, DMSO-d 6 )δ 7.14-7.06(m,3H),6.95(dd,J=7.6,1.7 Hz,1H),6.83(d,J=1.6 Hz,1H),6.04(d,J=1.9 Hz,1H),4.01-3.85(m,1H),3.18-3.03(m,1H),2.59-2.51(m,1H),1.18(d,J=6.2 Hz,3H).LCMS:213.026[M+H].

[0229] Example 15 was then prepared by Method A using Intermediate 49 and Intermediate 19. The retention time of this product from analytical chiral column chromatography was identical to that of the material obtained from the preparative chiral SFC purification of Example 3.

[0230] Preparation of intermediate 18: 1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide [ka] To a solution of intermediate 35 (750 mg, 1.78 mmol) in 1,4-dioxane (10 mL) was added bis(pinacolato)diboron (1.2 equiv), potassium acetate (3.0 equiv), and (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride (20 mol%). The mixture was sparged with nitrogen for 5 min and then heated to 95 °C. After stirring for 4 h, the reaction was partitioned between water (25 mL) and EtOAc (25 mL). The aqueous phase was extracted twice with EtOAc (25 mL) and the combined organic layers were dried over magnesium sulfate. The solvent was removed under reduced pressure and the crude residue was purified using flash column chromatography (0-100% EtOAc in hexanes) to give intermediate 18. LC / MS: 469.2 [M+H].

[0231] Preparation of Example 18 [ka] To a solution of Intermediate 18 (20 mg, 0.043 mmol) in 9:1 1,4-dioxane:water (1 mL) was added 2-bromo-6-fluoropyrazine (1.2 equiv), potassium carbonate (3.0 equiv), and (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride (20 mol%). The mixture was sparged with nitrogen and stirred for 5 min and then heated to 95°C. After stirring for 4 h, the reaction was concentrated and the crude residue was purified using reverse phase HPLC to provide Example 18. 1 H NMR (400 MHz, DMSO-d 6 )δ 9.25(d,J=5.1 Hz,1H),8.69-8.53(m,2H),8.02(s,1H),7.97(d,J=8.0 Hz,1H),7.48(dd,J=7.8,1.7 Hz,1H),7.42(dd,J=8.0,3.7 Hz,2H),7.28(s,2H),4.35(t,J=8.5 Hz,2H),3.83-3.72(m,1H),3.23-3.34(m,6H).LC / MS:439.1[M+H].

[0232] The following examples in Table 1D were prepared in a similar manner to Example 18 using the appropriate aryl bromide coupling partners. [Table 1D-1] [Table 1D-2]

[0233] Preparation of intermediate 19: (R)-5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carboxylic acid [ka] Intermediate 19 was obtained as the first eluate of SFC purification of intermediate 2 using a Chiralpak AD-H column with 20% methanol as co-solvent. LC / MS: 238.1 [MH].

[0234] Preparation of Example 28: [ka] Example 28 was prepared in a similar manner to Example 1 using Intermediate 19 and Intermediate 9 (General Procedure A). 1 H NMR(400 MHz,DMSO-d6)δ 8.70(dd,J=5.0,1.4 Hz,1H),8.57(d,J=6.7 Hz,1H),8.04(d,J=4.1 Hz,2H),7.94(s,1H),7.88(dd,J=7.8,1.7 Hz,1H),7.57(s,2H),7.48(q,J=4.6 Hz,1H),7.37(dd,J=16.6,8.8 Hz,2H),4.34(t,J=8.5 Hz,2H),3.76(t,J=8.0 Hz,1H),3.41-3.22(m,6H).LC / MS:438.1[M+H].

[0235] Preparation of intermediate 20: Imino(indolin-6-yl)(methyl)-λ 6 -Sulfanone [ka] Preparation of intermediate 20.1: A solution of 6-bromo-1H-indole (5.0 g, 25.5 mmol, 1.0 equiv) in THF (100 mL) was added with N 2 NaH (2.0 g, 51.0 mmol, 2.0 equiv) was added at 0° C. under reduced pressure. The reaction was stirred for 30 min, then it was cooled to −65° C. and t-BuLi (58.8 mL, 1.3 N, 3.0 equiv) was added. It was stirred for 30 min, dimethyl disulfide (7.2 g, 76.5 mmol, 3.0 equiv) was added, the reaction was stirred for 2 h, warmed to room temperature over 1 h, then quenched with water and extracted with EtOAc. The organic extract was concentrated and the residue was purified by column chromatography to give compound intermediate 20.1. LC / MS: 160.4 [M+H].

[0236] Preparation of Intermediate 20.2: A solution of Intermediate 20.1 (8.2 g, 50.3 mmol, 1.0 equiv) in AcOH (80 mL) was added with NaBH 3 CN (9.5 g, 150.9 mmol, 3.0 equiv) was added in portions at 10° C. The reaction was stirred for 1 h, quenched with water, and 2 CO 3 The pH was adjusted to 6 with ethyl acetate and extracted with EtOAc (150 mL x 2). The combined organic fractions were washed with Na 2 SO 4 The mixture was dried at 40° C., concentrated and the residue was purified by column chromatography to give Intermediate 20.2. LC / MS: 166.2 [M+H].

[0237] Preparation of Intermediate 20.3: To a solution of Intermediate 20.2 (6.2 g, 37.6 mmol, 1.0 equiv) in DCM (60 mL) was added Boc 2 O (16.4 g, 75.2 mmol, 2.0 equiv.) and DMAP (4.6 g, 37.6 mmol) were added in portions at room temperature. The reaction was stirred overnight, poured into water, extracted with EtOAc (50 mL×2), the combined organic fractions were concentrated, and the residue was purified by column chromatography to give compound intermediate 20.3. LC / MS: 265.9 [M+H].

[0238] Preparation of Intermediate 20.4: A solution of Intermediate 20.3 (6.7 g, 25.3 mmol, 1.0 equiv) in DCM (60 mL) was treated with tert-butyl carbonazidate (9.0 g, 63.2 mmol, 2.5 equiv) and FeCl 2 (3.2 g, 25.3 mmol, 1.0 equiv.) was reacted with N 2 The mixture was added under 0° C. The reaction was allowed to warm to room temperature overnight, then poured into water and extracted with EtOAc. The organic fraction was concentrated and the residue was purified by column chromatography (DCM / MeOH=40:1) to give Intermediate 20.4. LC / MS: 381.1 [M+H].

[0239] Preparation of intermediate 20.5: Dissolve intermediate 20.4 (5.8 g, 15.3 mmol, 1.0 equiv) in THF / H 2 To a solution of NaIO in 20O (4 / 1, 75 mL) 4 (16.4 g, 76.5 mmol, 5.0 equiv.) and RuCl 3 H 2 O (172 mg, 0.77 mmol, 0.05 equiv) was added portionwise at room temperature. The reaction mixture was stirred for 10 min, poured into water and extracted with EtOAc (50 mL×2). The combined organic extracts were concentrated and the residue was purified by column chromatography (petroleum ether / EtOAc=2:1) ​​to give intermediate 20.5. LC / MS: 397.1 [M+H].

[0240] Preparation of intermediate 20: Intermediate 20.5 (4.0 g) was dissolved in HCl / dioxane (40 mL, 4N) and stirred overnight. The resulting solid was filtered and dissolved in water. The pH was then adjusted to 7 using sodium bicarbonate, and the residue was purified by reverse phase HPLC to give intermediate 20. LC / MS: 197.1 [M+H].

[0241] Preparation of Example 29 (General Procedure A): Imino(methyl)(1-(5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indolin-6-yl)-λ 6 -Sulfanone [ka] To a solution of intermediate 2 (30 mg, 0.15 mmol) and intermediate 20 (91 mg, 3 eq.) in acetonitrile (40V) was added 1-methylimidazole (3 eq.) and TCFH (2 eq.). After stirring at room temperature for 1 h, the reaction was diluted with EtOAc and water was added. The resulting aqueous layer was extracted twice with EtOAc and the pooled organic fractions were dried over magnesium sulfate. The solvent was removed under reduced pressure and then reconstituted in THF (2 mL) and 2N NaOH (2 mL). The mixture was then heated at 75° C. for 6 h, after which the pH was adjusted to 7 using 1N HCl. The mixture was extracted with EtOAc (3×25 mL) and the combined organic fractions were dried over magnesium sulfate. After removing the solvent under reduced pressure, the crude residue was purified by flash column chromatography (10% methanol in EtOAc) to give Example 29. LC / MS: 418.2 [M+H].

[0242] Preparation of Examples 31 and 33: [ka] Example 31 was obtained from the fourth eluate of the chiral SFC purification of Example 29 using a CCO-F2 column with 40% methanol as co-solvent. 1 H NMR (400 MHz, DMSO-d 6 )δ 8.65(q,J=2.1 Hz,2H),7.98-7.81(m,4H),7.59(dd,J=7.8,1.8 Hz,1H),7.46(d,J=7.8 Hz,1H),7.38-7.29(m,2H),4.36(t,J=8.5 Hz,2H),4.09(s,1H),3.75(q,J=8.2 Hz,1H),3.30-3.19(m,6H),3.00(s,3H).LC / MS:418.2[M+H].

[0243] Example 33 was obtained from the third eluate of the chiral SFC purification of Example 29 using a CCO-F2 column with 40% methanol as co-solvent. 1 H NMR (400 MHz, DMSO-d 6)δ 8.65(q,J=2.1 Hz,2H),8.02-7.77(m,4H),7.59(dd,J=7.8,1.8 Hz,1H),7.46(d,J=7.8 Hz,1H),7.40-7.27(m,2H),4.36(t,J=8.6 Hz,2H),4.09(s,1H),3.76(p,J=8.0 Hz,1H),3.32-3.21(m,6H),3.00(s,3H).LC / MS:418.2[M+H].

[0244] Preparation of intermediate 21: [ka] Preparation of intermediate 21.1: 5-Fluoro-2-methylindoline (40 g, 268 mmol, 1 equiv.) was taken up in acetic acid (200 mL, 5 V). NaBH 3 CN (50 g, 815 mmol, 3 equiv) was added in portions while maintaining the temperature below 10° C. The resulting solution was allowed to warm to room temperature and stirred for 3 h, at which point the reaction was diluted with ice-cold water (500 mL). The reaction was then extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine (750 mL) and diluted with Na 2 SO 4 The mixture was dried at 40° C. and concentrated in high vacuum. The crude intermediate 21.1 was isolated as a thick yellow oil and used in the next step without further purification. LC / MS: 151.2 [M+H].

[0245] Preparation of Intermediate 21.2: To a stirred solution of Intermediate 21.1 (35 g, 86.6 mmol) in DCM (300 mL) was added triethylamine (35 mL, 1 vol) followed by acetyl chloride (35 mL, 1 vol) at 0° C. The reaction mixture was stirred at room temperature for 2 h. The residue was quenched with cold water (200 mL) and extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine (750 mL) and diluted with Na 2 SO 4 The mixture was dried at 40° C. and concentrated in high vacuum. The crude residue was purified by column chromatography (100-200 silica gel, eluted with 8% EtOAc-hexanes) to give Intermediate 21.2. LC / MS: 193.2 [M+H].

[0246] Preparation of Intermediate 21.3: A stirred solution of Intermediate 21.2 (35 g, 0.011 mol) in chlorosulfonic acid (250 mL, 10 V) was added at 0° C. under nitrogen and the reaction mixture was stirred at 50° C. for 3 h. Upon completion of the reaction, the mixture was diluted with ice-cold water. The precipitate was filtered, taken up in dichloromethane (50 mL) and added to concentrated ammonium hydroxide solution (20 mL). After vigorous stirring at room temperature for 15 min, the solvent was removed under pressure and the resulting solid was filtered and rinsed with water to give Intermediate 21.3. LC / MS: 272.3 [M+H].

[0247] Preparation of intermediates (R)-21 and (S)-21: A racemic mixture of intermediate 21.3 (30 g, 110 mmol, 1 equiv.) in 500 mL of 2N sodium hydroxide was heated at 100° C. for 3 h. The reaction was cooled to room temperature and the pH was adjusted to 7 with acetic acid. The precipitate was filtered, washed with water, and dried under high vacuum. The resulting deacetylated racemic mixture was then subjected to chiral SFC purification using a ChiralPak IG 240×4.6 mm column with a mobile phase consisting of 70:20:10 hexanes:methanol:MTBE. Intermediate (R)-21 was collected as the second eluent (retention time 13.1 min). LC / MS: 230.1 [M+H]. Intermediate (S)-21 was collected as the first eluent (retention time 10.5 min). LC / MS: 230.1 [M+H].

[0248] Preparation of Example 34: [ka] Example 34 was prepared in a similar manner to Example 1 using intermediate (S)-21 and intermediate 19 (general procedure A). 1H NMR(400 MHz,DMSO-d6)δ 8.72-8.62(m,1H),8.54(d,J=6.7 Hz,1H),8.02-7.81(m,4H),7.58(s,2H),7.39(d,J=8.8 Hz,3H),4.90(t,J=7.5 Hz,1H),3.77(t,J=8.4 Hz,1H),3.48-3.09(m,6H),1.30(d,J=6.2 Hz,3H).LC / MS:452.1[M+H].

[0249] Preparation of Example 35 (General Procedure B): [ka] Intermediate (R)-21 was taken up in THF (10V) and dimethylformamide dimethyl acetal (1.2 equiv.) was added in one portion. The solution was stirred at room temperature for 30 min, then the solvent was removed under reduced pressure to give the crude residue intermediate (R)-21a (LC / MS: 286.1 [M+H]), which was used directly in the next step without further purification.

[0250] Intermediate (R)-21a was taken up in acetonitrile (10V). Intermediate 19 (1 eq) was added followed by TCFH (2 eq). The suspension was placed in a room temperature water bath and N-methylimidazole (5 eq) was added dropwise. The solution was stirred at room temperature for 1 hour, at which point LC / MS analysis showed complete conversion to intermediate (R)-21b (LC / MS: 507.2 [M+H]). Hydrazine hydrate (50 eq) was then added in one portion and allowed to stir at room temperature for 30 minutes, after which water was added (5V). The resulting precipitate was filtered and dried under reduced pressure to give Example 35. 1H NMR(400 MHz,DMSO-d6)δ 8.69(d,J=4.9 Hz,1H),8.54(d,J=6.6 Hz,1H),8.10-7.84(m,4H),7.58(s,2H),7.51-7.24(m,3H),4.90(t,J=7.5 Hz,1H),3.77(p,J=8.2 Hz,1H),3.46(ddt,J=34.0,17.5,8.7 Hz,3H),3.20(ddd,J=59.1,16.3,8.3 Hz,2H),2.80(d,J=16.9 Hz,1H),1.30(d,J=6.2 Hz,3H).LC / MS:452.1[M+H].

[0251] Preparation of intermediate 22: [ka] Intermediate 22 was prepared in a similar manner to Example 1 (Method A) using indoline-6-sulfonamide instead of intermediate 1 and 5-bromo-2,3-dihydrobenzofuran-2-carboxylic acid instead of intermediate 2. LC / MS: 423.0 [M+H].

[0252] Preparation of Example 36: [ka] Example 36 was prepared in a similar manner to Example 71 using Intermediate 22 instead of Intermediate 35. 1 H NMR(400 MHz,DMSO-d6)δ 8.63(dd,J=4.8,1.4 Hz,1H),8.54(d,J=1.7 Hz,1H),8.01(d,J=1.8 Hz,1H),7.92(d,J=5.6 Hz,2H),7.89(d,J=2.1 Hz,1H),7.52(dd,J=7.8,1.7 Hz,1H),7.45(d,J=7.8 Hz,1H),7.34(t,J=5.8 Hz,1H),7.31(s,2H),6.98(d,J=8.4 Hz,1H),5.78(dd,J=9.7,6.5 Hz,1H),4.47-4.27(m,2H),3.69-3.60(m,2H),3.30(t,J=8.6 Hz,2H).LC / MS:422.1[M+H].

[0253] Preparation of intermediate 23: [ka] Intermediate 23 was prepared in a similar manner to intermediate 22, using intermediate 9 instead of indoline-6-sulfonamide. LC / MS: 441.0 [M+H].

[0254] Preparation of Example 37: [ka] Example 37 was prepared in a similar manner to Example 71 using Intermediate 23 instead of Intermediate 22. 1 H NMR(400 MHz,DMSO-d6)δ 8.65(dt,J=5.1,1.4 Hz,1H),8.51(d,J=6.7 Hz,1H),7.99(dd,J=7.9,2.8 Hz,3H),7.90(dd,J=8.4,2.0 Hz,1H),7.60(s,2H),7.40(t,J=6.7 Hz,2H),7.00(d,J=8.4 Hz,1H),5.78(dd,J=9.7,6.5 Hz,1H),4.47-4.24(m,2H),3.67-3.56(m,2H),3.31(t,J=8.7 Hz,2H).LC / MS:440.1[M+H].

[0255] Preparation of Example 38: (R)-5-bromo-2-methyl-1-((R)-5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide [ka] Intermediate 24.1 was prepared in a similar manner to Intermediate 21.2, using (R)-5-bromo-2-methylindoline as the starting material instead of Intermediate 21.1. LC / MS: 254.0 [M+H].

[0256] Intermediate 24.2 was prepared in a similar manner to Intermediate 21.3, using Intermediate 24.1 instead of Intermediate 21.2 as the starting material. LC / MS: 333.0 [M+H].

[0257] Intermediate 24.3 was prepared in a similar manner to Intermediate 21.4, using Intermediate 24.2 instead of Intermediate 21.3 as the starting material. LC / MS: 291.0 [M+H].

[0258] Example 38 was prepared in a similar manner to Example 35 using Intermediate 24.3 instead of Intermediate (R)-21 as the starting material. 1 H NMR(400 MHz,DMSO-d6)δ 8.80(s,1H),8.69(d,J=4.9 Hz,1H),8.10-7.91(m,3H),7.88(d,J=7.8 Hz,1H),7.73(s,1H),7.50(s,2H),7.45(q,J=6.1,4.3 Hz,1H),7.36(d,J=7.9 Hz,1H),4.90(p,J=6.6 Hz,1H),3.77(p,J=8.3 Hz,1H),3.46-3.38(m,1H),3.47-3.32(m,3H),3.13(dd,J=16.2,7.6 Hz,1H),2.81(d,J=16.8 Hz,1H),1.30(d,J=6.3 Hz,3H).LC / MS:512.1[M+H].

[0259] Preparation of intermediate 25: tert-butyl ((5-fluoroindolin-6-yl)(methyl)(oxo)-16-sulfanylidene)carbamate [ka] Preparation of Intermediate 25.1: To a solution of 5,6-difluoroindoline-2,3-dione (200 g, 1.09 mol) in DMF (5 V) was added sodium methanethiolate (153 g, 2.0 equiv). The solution was stirred at 80° C. for 16 h, at which point water (15 V) was added and the mixture was extracted with EtOAc (2×600 mL). The pooled organic fractions were washed with brine, dried over sodium sulfate, filtered and concentrated to give Intermediate 25.1, which was used without further purification. LC / MS: 212.0 [M+H].

[0260] Preparation of Intermediate 25.2: To a solution of Intermediate 25.1 (100 g, 473 mmol) in THF (6V) at 0° C. was added lithium aluminum hydride (35.9 g, 2.0 equiv.). The mixture was allowed to warm to room temperature and stirred for 16 h, at which point the reaction was carefully quenched by sequential addition of water (38 mL), 15% aqueous sodium hydroxide (38 mL), and water (114 mL). The crude residue was extracted with EtOAc (2×300 mL) and the combined organic fractions were washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude residue was purified using flash column chromatography on silica gel to give Intermediate 25.2. LC / MS: 182.0 [M+H].

[0261] Preparation of Intermediate 25.3: To a solution of Intermediate 25.2 (26 g, 143 mmol) in acetic acid (5V) was added sodium cyanoborohydride (27.1 g, 3.0 equiv). The mixture was allowed to stir at room temperature for 1 h, at which point water (400 mL) was added and the mixture was extracted with EtOAc (2×150 mL). The combined organic fractions were washed with brine, dried over sodium sulfate, filtered and concentrated. The crude residue was purified by flash column chromatography on silica gel to give Intermediate 25.3. LC / MS: 184.1 [M+H].

[0262] Preparation of Intermediate 25.4: To a solution of Intermediate 25.3 (20.0 g, 109 mmol) in THF (6V) was added 1-[2-(trimethylsilyl)ethoxycarbonyloxy]pyrrolidine-2,5-dione (56.6 g, 2.0 equiv.) and DMAP (13.3 g, 1.0 equiv.). The solution was stirred at room temperature for 16 h, at which point water was added (100 mL) and the residue was extracted with dichloromethane (2×50 mL). The combined organic fractions were washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude residue was then purified by flash column chromatography on silica gel to give Intermediate 25.4. LC / MS: 328.1 [M+H].

[0263] Preparation of Intermediate 25.5: To a solution of Intermediate 25.4 (20.0 g, 61 mmol) in dichloromethane (6V) at 0° C. was added m-chloroperoxybenzoic acid (13.6 g, 1.1 equiv.). The solution was allowed to warm to room temperature and stirred for 2 h, at which point the reaction was filtered and the resulting filtrate was quenched with saturated sodium sulfite solution (100 mL). The resulting residue was extracted with dichloromethane (2×50 mL). The combined organic fractions were washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude residue was purified by flash column chromatography on silica gel to give Intermediate 25.5. LC / MS: 344.1 [M+H].

[0264] Preparation of Intermediate 25.6: To a solution of Intermediate 25.5 (14.0 g, 40.7 mmol) in dichloromethane (6V) was added magnesium oxide (8.21 g, 5.0 equiv), (diacetoxyiodo)benzene (19.7 g, 1.5 equiv), tert-butyl carbamate (9.55 g, 2.0 equiv), and dirhodium tetraacetate (900 mg, 0.05 equiv). The mixture was stirred at 40° C. for 16 h, at which point water was added and the mixture was extracted with dichloromethane (2×30 mL). The combined organic fractions were washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude residue was purified by flash column chromatography on silica gel to give Intermediate 25.6. LC / MS: 459.2 [M+H].

[0265] Preparation of intermediate 25: To a solution of intermediate 25.6 (2.0 g, 4.4 mmol) in THF (10V) was added tetrabutylammonium fluoride (1.0 M solution in THF, 4.8 mL, 1.1 equiv). The solution was stirred at room temperature for 1 h, then water was added (10 mL). The mixture was extracted with EtOAc (2×50 mL). The combined organic fractions were washed with brine, dried over sodium sulfate, filtered, and contracted. The crude residue was purified using flash column chromatography on silica gel to give intermediate 25. LC / MS: 315.1 [M+H].

[0266] Preparation of Example 39 (General Procedure B): (5-Fluoro-1-((R)-5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indolin-6-yl)(imino)(methyl)-λ 6 -Sulfanone [ka] To a suspension of Intermediate 25 (500 mg, 1.6 mmol), Intermediate 19 (381 mg, 1.0 equiv), and TCFH (535 mg, 1.2 equiv) in acetonitrile (10V) was added N-methylimidazole (0.63 mL, 5.0 equiv). The resulting solution was stirred at room temperature for 15 min, concentrated, and purified by flash column chromatography on silica gel to give Intermediate 25.7. LC / MS: 536.2 [M+H].

[0267] A solution of intermediate 25.7 (980 mg, 1.8 mmol) in dichloromethane (10 V) and trifluoroacetic acid (10 V) was stirred at room temperature for 1 h and then concentrated. The resulting residue was purified by reverse phase HPLC to give Example 39. 1H NMR(400 MHz,DMSO-d6)δ 8.70(d,J=5.0 Hz,1H),8.63(d,J=6.6 Hz,1H),8.02(d,J=4.1 Hz,2H),7.95(s,1H),7.88(d,J=7.9 Hz,1H),7.50-7.42(m,2H),7.39(d,J=7.9 Hz,1H),4.36(t,J=8.6 Hz,2H),3.83-3.71(m,1H),3.33-3.22(m,9H).LC / MS:436.1[M+H].

[0268] Preparation of Example 40 (R)-(5-fluoro-1-((R)-5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indolin-6-yl)(imino)(methyl)-16-sulfanone and 41 (S)-(5-fluoro-1-((R)-5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indolin-6-yl)(imino)(methyl)-16-sulfanone: [ka] Chiral SFC separation was performed on Example 39 using an OJ-H 4.6×100 mm column with 50% EtOH as a co-solvent. Example 40 was obtained as the first eluent. 1 H NMR (400 MHz, DMSO-d6) δ 8.64 (dt, J=9.7, 4.0 Hz, 2H), 8.01-7.86 (m, 4H), 7.44-7.23 (m, 3H), 4.57 (s, 1H), 4.35 (t, J=8.5 Hz, 2H), 3.75 (p, J=8.2 Hz, 1H), 3.32-3.22 (m, 5H), 3.13 (s, 3H). LC / MS: 436.1 [M+H]. Example 41 was obtained as the second eluate. 1H NMR(400 MHz,DMSO-d6)δ 8.70-8.65(m,1H),8.62(d,J=6.7 Hz,1H),8.01-7.93(m,3H),7.93-7.86(m,1H),7.45-7.27(m,3H),4.35(t,J=8.6 Hz,2H),3.75(p,J=8.1 Hz,1H),3.30(p,J=7.7 Hz,5H),3.22(s,3H).LC / MS:436.1[M+H].

[0269] Preparation of intermediate 26 [ka] Intermediate 26 was prepared in a similar manner to intermediate 23, using intermediate (R)-21 as the starting material instead of intermediate 9. LC / MS: 455.0 [M+H].

[0270] Preparation of Example 42: (2R)-5-fluoro-2-methyl-1-(5-(pyridin-2-yl)-2,3-dihydrobenzofuran-2-carbonyl)indoline-6-sulfonamide [ka] Example 42 was prepared in a similar manner to Example 36 using Intermediate 26 instead of Intermediate 22 as the starting material (General Procedure A). 1 H NMR(400 MHz,DMSO-d6)δ 8.67(d,J=5.0 Hz,1H),8.47(d,J=6.5 Hz,1H),8.03(t,J=9.0 Hz,3H),7.98(s,1H),7.88(d,J=8.6 Hz,1H),7.60(s,2H),7.50-7.40(m,2H),7.00(t,J=11.4,8.5 Hz,1H),5.87-5.76(m,1H),5.05(p,J=6.8 Hz,1H),4.90(p,J=6.7 Hz,1H),3.72-3.45(m,3H),2.84(d,J=16.9 Hz,1H),1.36(d,J=6.3 Hz,2H),1.32(d,J=6.5 Hz,1H).LC / MS:454.1[M+H].

[0271] Preparation of Examples 43 and 44: [ka] For Example 42, chiral SFC purification was performed using an OD-H 4.6×100 mm column with 50% MeOH as a co-solvent.

[0272] Example 43 was obtained as the first eluate. 1 H NMR(400MHz,DMSO-d6)δ 8.63(dd,J=4.7,1.5Hz,1H),8.48(d,J=6.6Hz,1H),7.99(s,1H),7.96-7.88(m,3H),7.61(s,2H),7.43(d,J=9.7Hz,1H),7.38-7.33(m, 1H),6.98(d,J=8.4Hz,1H),5.79(dd,J=9.9,6.2Hz,1H),4.96-4.86(m,1H),2.84(d,J=16.9Hz,1H),1.36(d,J=6.3Hz,3H),3H below water peak. LC / MS:454.1[M+H].

[0273] Example 44 was obtained as the second eluate. 1 H NMR(400MHz,DMSO-d6)δ 8.63(dd,J=4.7,1.6Hz,1H),8.49(d,J=6.7Hz,1H),8.03(s,1H),7.95-7.86(m,3H),7.62(s,2H),7.44(d,J=9.7Hz,1H),7.34(ddd,J=6.7,4.8,1 .8Hz,1H),6.95(d,J=8.3Hz,1H),5.81(dd,J=9.5,6.6Hz,1H),5.05(t,J=7.4Hz,1H),2.85(d,J=17.0Hz,1H),1.32(d,J=6.4Hz,3H),3H below water peak. LC / MS: 454.1[M+H].

[0274] Preparation of Example 45: (R)-1-(5-(2,5-difluorophenyl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide [ka] Example 45 was prepared in a similar manner to Example 71 using intermediate 37 instead of intermediate 35 and 2,5-difluorophenylboronic acid instead of phenylboronic acid as starting materials. 1 H NMR (400 MHz, DMSO-d6) δ 8.59 (s, 1H), 7.46 (s, 1H), 7.44-7.38 (m, 2H), 7.35 (s, 4H), 7.27 (s, 2H), 4.33 (t, J = 8.5 Hz, 2H), 3.75 (t, J = 8.0 Hz, 1H), 6H below the water peak. LC / MS: 455.0 [M+H].

[0275] Preparation of intermediate 27: [ka] A solution of 5-fluoro-2,3-dimethyl-1H-indole (2 g, 12.3 mmol, 1 equiv.) in AcOH (7 V) was treated with NaBH 3 CN (2 equiv.) was added. The mixture was stirred at 20° C. for 3 h. The reaction mixture was concentrated to dryness and the crude product was purified by flash column chromatography on silica gel to give the trans racemic intermediate 27. LC / MS: 166.1 [M+H].

[0276] Intermediate 27 was subjected to chiral SFC purification using an OJ-H column with 10% heptane-MTBE as a co-solvent to give intermediate (2R,3S)-27 (first eluent, LC / MS: 166.1 [M+H]) and intermediate (2S,3R)-27 (second eluent, LC / MS: 166.1 [M+H]).

[0277] Preparation of Example 46 (General Procedure C): (2R,3S)-5-Fluoro-2,3-dimethyl-1-((R)-5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide [ka] Intermediate 27.1 was prepared in a manner similar to that of Example 1 using intermediate (2R,3S)-27 and intermediate 19 as starting materials. LC / MS: 387.2 [M+H].

[0278] Example 46 was prepared in a similar manner to Intermediate 21.3 using Intermediate 27.1 instead of Intermediate 21.2 as the starting material. 1 H NMR(400 MHz,DMSO-d6)δ 8.70(d,J=5.0 Hz,1H),8.54(d,J=6.6 Hz,1H),8.05-7.95(m,3H),7.89(dd,J=7.9,1.7 Hz,1H),7.58(s,2H),7.45(d,J=9.2 Hz,2H),7.37(d,J=7.9 Hz,1H),4.44(d,J=6.4 Hz,1H),3.74(t,J=8.4 Hz,1H),3.47(dd,J=16.0,8.9 Hz,2H),3.26(dd,J=16.0,8.5 Hz,1H),3.12-3.02(m,2H),1.30(d,J=6.3 Hz,3H),1.25(d,J=7.0 Hz,3H).LC / MS:466.2[M+H].

[0279] Preparation of Example 47: (2S,3R)-5-Fluoro-2,3-dimethyl-1-((R)-5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide [ka] Example 47 was synthesized in a similar manner to Example 46, using intermediate (2S,3R)-27 as the starting material instead of intermediate (2R,3S)-27 (General Procedure C). 1H NMR(400 MHz,DMSO-d6)δ 8.65(d,J=4.9 Hz,1H),8.54(d,J=6.6 Hz,1H),7.91(dd,J=19.6,9.4 Hz,4H),7.58(s,2H),7.45(d,J=9.8 Hz,1H),7.41-7.30(m,2H),4.44(d,J=6.4 Hz,1H),3.73(s,1H),3.27-2.99(m,5H),1.29(d,J=6.4 Hz,3H),1.25(d,J=6.7 Hz,3H).LC / MS:466.2[M+H].

[0280] Preparation of intermediate 28: [ka] AcOH (30 mL) and HClO 4 To a solution of 5-fluoro-2,3-dimethyl-1H-indole (5 g, 30.6 mmol, 1 equiv.) in 1H-indole (30.8 g, 306.4 mmol, 18.5 mL, 10 equiv.) was added Pd / C (20 mol%). The mixture was degassed and diluted with H 2 Purge the mixture three times with H. 2 The mixture was stirred at 50° C. under atmosphere (15 psi) for 24 h. After cooling to 0° C., the mixture was made basic with 6N NaOH until pH=9. The mixture was extracted with DCM (40 mL×2). The organic layer was washed with brine (30 mL) and diluted with Na 2 SO 4 The mixture was dried at 40° C. and concentrated to give the crude product, which was purified by flash column chromatography on silica gel to give the cis racemic intermediate 28. LC / MS: 166.1 [M+H].

[0281] Intermediate 28 was subjected to chiral SFC purification using an OJ-H column with 10% heptane-MTBE as a co-solvent to give intermediate (2R,3R)-28 (first eluent, LC / MS: 166.1 [M+H]) and intermediate (2S,3S)-28 (second eluent, LC / MS: 166.1 [M+H]).

[0282] Preparation of Example 48: (2R,3R)-5-Fluoro-2,3-dimethyl-1-((R)-5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide [ka] Example 48 was prepared in a similar manner to Example 46 using intermediate (2R,3R)-28 instead of intermediate (2R,3S)-27 as the starting material (General Procedure C). 1 H NMR(400 MHz,DMSO-d6)δ 8.73(d,J=5.1 Hz,1H),8.48(dd,J=6.6,4.8 Hz,1H),8.21-8.00(m,2H),7.96(s,1H),7.87(dd,J=7.9,1.7 Hz,1H),7.58(s,2H),7.53-7.43(m,1H),7.38(dd,J=9.1,4.1 Hz,2H),4.89(p,J=6.8 Hz,1H),3.76(ddd,J=25.1,15.6,9.2 Hz,2H),3.55-3.34(m,2H),3.28(dd,J=16.0,8.6 Hz,1H),3.14(dd,J=16.4,7.6 Hz,1H),1.33(t,J=7.0 Hz,3H),1.14(t,J=6.4 Hz,3H).LC / MS:466.2[M+H].

[0283] Preparation of Example 49 (General Procedure C): (2S,3S)-5-Fluoro-2,3-dimethyl-1-((R)-5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide [ka] Example 49 was prepared in a similar manner to Example 46 using intermediate (2S,3S)-28 instead of intermediate (2R,3S)-27 as the starting material. 1H NMR(400 MHz,DMSO-d6)δ 8.72(d,J=5.0 Hz,1H),8.48(d,J=6.5 Hz,1H),8.15-8.03(m,2H),7.96-7.82(m,2H),7.58(s,2H),7.55-7.50(m,1H),7.40(dd,J=21.6,8.8 Hz,2H),4.90(t,J=7.2 Hz,1H),3.75(dp,J=15.3,7.8,7.4 Hz,2H),3.45(ddd,J=31.5,16.2,8.1 Hz,2H),3.21(ddd,J=36.4,16.1,8.0 Hz,2H),1.32(d,J=7.1 Hz,3H),1.14(d,J=6.4 Hz,3H).LC / MS:466.2[M+H].

[0284] Preparation of intermediate 29: [ka] Preparation of Intermediate 29.1: 5-Bromo-2,3-dihydro-1H-indene-2-carboxylic acid was subjected to chiral SFC purification using an IB column with 5% MeOH as co-solvent. The second eluent was collected to give Intermediate 29.1. LC / MS: 263.0 [M+Na].

[0285] Preparation of Intermediate 29.2: Intermediate 29.2 was prepared in a similar manner to Intermediate (R)-21b, using Intermediate 29.1 as the starting material instead of Intermediate 19. LC / MS: 508.1 [M+H].

[0286] Preparation of intermediate 29: To a solution of intermediate 29.2 (1.0 g, 1.98 mmol) in THF (5V) was added hydrazine hydrate (50 equiv.). The solution was stirred at room temperature for 30 min and then concentrated under reduced pressure. The crude residue was purified using flash column chromatography on silica gel to give intermediate 29. LC / MS: 453.0 [M+H].

[0287] Preparation of Example 50: (R)-1-((R)-5-(2-chloro-5-fluorophenyl)-2,3-dihydro-1H-indene-2-carbonyl)-5-fluoro-2-methylindoline-6-sulfonamide [ka] Example 50 was prepared in a similar manner to Example 69 using intermediate 29 and 2-chloro-5-fluorophenylboronic acid as starting materials. 1 H NMR(400 MHz,DMSO-d6)δ 8.54(d,J=6.5 Hz,1H),7.57(s,2H),7.38(d,J=9.8 Hz,1H),7.29(t,3H),7.23(d,J=10.0 Hz,2H),4.89(q,J=7.7,7.1 Hz,1H),3.76(p,J=8.2 Hz,1H),3.51(dd,J=16.9,9.0 Hz,1H),3.23(dd,J=15.6,8.4 Hz,1H),3.11(dd,J=16.2,7.7 Hz,1H),2.79(d,J=16.9 Hz,1H),1.28(d,J=6.1 Hz,3H).LC / MS:503.1[M+H].

[0288] Preparation of Example 51 (General Procedure B): (1-((R)-5-(2,5-difluorophenyl)-2,3-dihydro-1H-indene-2-carbonyl)-5-fluoroindolin-6-yl)(imino)(methyl)-λ 6 -Sulfanone [ka] Intermediate 30.1 was prepared in a similar manner to Intermediate 25.8, using Intermediate 29.1 as starting material instead of Intermediate 19. LC / MS: 537.1 [M+H].

[0289] Intermediate 30.2 was prepared in a similar manner to Example 69 using Intermediate 30.1 and 2,5-difluorophenylboronic acid as starting materials. LC / MS: 571.2 [M+H].

[0290] Intermediate 30.2 (106 mg, 0.19 mmol) was dissolved in dichloromethane (5 V) and trifluoroacetic acid (5 V). The solution was stirred at room temperature for 5 minutes and concentrated under reduced pressure. The resulting residue was purified using reverse phase HPLC to give Example 51. 1 H NMR(400 MHz,DMSO-d6)δ 8.63(d,J=6.6 Hz,1H),7.48-7.30(m,7H),7.30-7.15(m,1H),4.35(t,J=8.6 Hz,2H),3.75(p,J=7.9 Hz,1H),3.44-3.14(m,9H).LC / MS:471.2[M+H].

[0291] Preparation of Examples 52 and 53: [ka] Example 51 was subjected to chiral SFC purification using an OJ-H column with 40% EtOH as a co-solvent. Example 52 was obtained as the first eluent. 1 H NMR (400 MHz, DMSO-d6) δ 8.62 (d, J=6.7 Hz, 1H), 7.47-7.29 (m, 7H), 7.29-7.15 (m, 1H), 4.34 (t, J=8.5 Hz, 2H), 3.75 (p, J=8.0 Hz, 1H), 3.28 (q, J=7.6, 6.5 Hz, 6H), 3.15 (s, 3H). LC / MS: 471.2 [M+H]. Example 53 was obtained as the second eluate. 1 H NMR(400 MHz,DMSO-d6)δ 8.62(d,J=6.7 Hz,1H),7.47-7.28(m,7H),7.28-7.15(m,1H),4.34(t,J=8.6 Hz,2H),3.75(p,J=8.0 Hz,1H),3.30-3.19(m,6H),3.14(s,3H).LC / MS:471.2[M+H].

[0292] Preparation of intermediate 31: [ka] Intermediate 31.1 was prepared in a similar manner to intermediate 22, using intermediate 4 instead of indoline-6-sulfonamide as the starting material. LC / MS: 437.0 [M+H].

[0293] Intermediate 31 was prepared in a similar manner to Example 71, using Intermediate 31.1 as the starting material instead of Intermediate 35. LC / MS: 436.1 [M+H].

[0294] Preparation of Examples 56 and 57: [ka] Intermediate 31 was subjected to chiral SFC purification using an OJ-H 4.6×100 mm column with 45% MeOH-DEA as a co-solvent.

[0295] Example 56 was obtained as the second eluate. 1 H NMR(400 MHz,DMSO-d6)δ 8.61(ddd,J=4.8,1.8,1.0 Hz,1H),8.52(s,1H),8.00(d,J=1.8 Hz,1H),7.93-7.88(m,1H),7.87(t,J=1.2 Hz,1H),7.83(td,J=7.7,1.8 Hz,1H),7.56(dd,J=7.8,1.7 Hz,1H),7.49(d,J=7.8 Hz,1H),7.30(s,2H),7.28(ddd,1H),6.96(d,J=8.4 Hz,1H),5.79(dd,J=10.0,6.2 Hz,1H),4.91(p,J=6.5 Hz,1H),3.68(dd,J=15.8,9.8 Hz,1H),3.50(dt,J=14.9,6.8 Hz,2H),2.84(d,J=16.6 Hz,1H),1.37(d,J=6.3 Hz,3H).LC / MS:436.1[M+H].

[0296] Example 57 was obtained as the first eluate. 1H NMR(400 MHz,DMSO-d6)δ 8.61(ddd,J=4.9,1.8,1.0 Hz,1H),8.53(s,1H),8.04(d,J=1.8 Hz,1H),7.93-7.88(m,1H),7.87(t,J=1.2 Hz,1H),7.83(td,J=7.6,1.8 Hz,1H),7.57(dd,J=7.9,1.7 Hz,1H),7.50(d,J=7.8 Hz,1H),7.32(s,2H),7.28(ddd,J=7.2,4.8,1.3 Hz,1H),6.93(d,J=8.6 Hz,1H),5.82(dd,J=9.6,6.6 Hz,1H),5.06(t,J=7.5 Hz,1H),3.67(dd,J=15.8,6.5 Hz,1H),3.59(dd,J=17.8,9.4 Hz,1H),3.52(d,J=8.6 Hz,1H),2.85(d,J=16.4 Hz,1H),1.33(d,J=6.3 Hz,3H).LC / MS:436.1[M+H].

[0297] Preparation of Example 58: (R)-1-(5-(2,5-difluorophenyl)-2,3-dihydro-1H-indene-2-carbonyl)-5-fluoroindoline-6-sulfonamide [ka] Intermediate 32 was prepared in a similar manner to Intermediate 29 using Intermediate 9 and Intermediate 29.1 as starting materials. LC / MS: 439.0 [M+H].

[0298] Example 58 was prepared in a similar manner to Example 50 using Intermediate 32 and 2,5-difluorophenylboronic acid as starting materials. 1 H NMR (400MHz, DMSO-d 6 ) δ 8.56(d,J=6.7Hz,1H), 7.57(s,2H), 7.43(s,1H), 7.41-7.32(m,5H), 7.25(dq,J=8.9,5.1,4.3Hz,1H), 4.33(t,J=8.5Hz,2H), 3.73(d,J=8.0Hz,1H), 6H below water peak. LC / MS: 473.1[M+H].

[0299] Preparation of intermediate 33: [ka] Intermediate 32 was prepared in a similar manner to intermediate 21, using 5-chloro-2-methylindole instead of 5-fluoro-2-methylindole as the starting material. LC / MS: 247.0 [M+H].

[0300] Intermediate 32 was subjected to chiral SFC separation using a ChiralPak IG column with 60 MeOH as a co-solvent.

[0301] Intermediate (R)-32 was obtained as the first eluent. LC / MS: 247.0 [M+H].

[0302] Intermediate (S)-32 was obtained as the second eluent. LC / MS: 247.0 [M+H].

[0303] Preparation of Example 59 (General Procedure B): (S)-5-chloro-2-methyl-1-((R)-5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide [ka] Example 59 was prepared in a similar manner to Example 35 using Intermediate (S)-32 and Intermediate 19 as starting materials. 1 H NMR(400 MHz,DMSO-d6)δ 8.76(s,1H),8.72-8.62(m,1H),8.05-7.85(m,4H),7.59-7.32(m,5H),4.91(t,J=7.3 Hz,1H),3.53-3.06(m,6H),2.81(d,J=16.9 Hz,1H),1.30(d,J=6.3 Hz,3H).LC / MS:468.2[M+H].

[0304] Preparation of Example 60 (General Procedure B): (R)-5-chloro-2-methyl-1-((R)-5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide [ka] Example 60 was prepared in a similar manner to Example 35 using intermediate (R)-32 and intermediate 19 as starting materials. 1 H NMR(400 MHz,DMSO-d6)δ 8.75(s,1H),8.70(dt,J=5.0,1.4 Hz,1H),8.11-7.80(m,4H),7.62-7.26(m,5H),4.90(t,J=7.5 Hz,1H),3.78(p,J=8.1 Hz,1H),3.46(dtd,J=22.5,15.3,13.7,8.1 Hz,3H),3.28(dd,J=16.1,8.5 Hz,1H),3.13(dd,J=16.3,7.7 Hz,1H),2.81(d,J=16.8 Hz,1H),1.30(d,J=6.3 Hz,3H).LC / MS:468.2[M+H].

[0305] Preparation of Example 61: (R)-1-((R)-5-(2,5-difluorophenyl)-2,3-dihydro-1H-indene-2-carbonyl)-5-fluoro-2-methylindoline-6-sulfonamide [ka] Example 61 was prepared in a similar manner to Example 50 using 2,5-difluorophenylboronic acid instead of 2-chloro-5-fluorophenylboronic acid as the starting material. 1H NMR(400MHz,DMSO-d6)δ 8.54(d,J=6.7Hz,1H),7.58(s,2H),7.45(s,1H),7.42-7.30(m,5H),7.28-7.21(m,1H),4.88(q,J=7.1Hz,1H),3.81-3.71(m,1H),3.51(dd, 2H below the water peak. LC / MS:487.1[M+H].

[0306] Preparation of Example 62: (R)-5-fluoro-2-methyl-1-((R)-5-(2,3,5-trifluorophenyl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide [ka] Example 62 was prepared in a similar manner to Example 50 using 2,3,5-trifluorophenylboronic acid instead of 2-chloro-5-fluorophenylboronic acid as the starting material. 1 H NMR(400MHz,DMSO-d6)δ 8.54(d,J=6.7Hz,1H),7.58(s,2H),7.54(dd,J=9.7,5.1Hz,1H),7.40(s,1H),7.36(d,J=6.8Hz,2H),7.27(dd,J=9.2,4.0Hz,2H),4.89(t,J=7.6Hz ,1H),3.77(q,J=8.3Hz,1H),3.52(dd,J=16.8,8.8Hz,1H),3.13(dd,J=16.1,7.8Hz,1H),2.80(d,J=16.8Hz,1H),1.29(d,J=6.3Hz,3H),3H below water peak. LC / MS: 505.1[M+H].

[0307] Preparation of Example 63: (R)-2,5-dimethyl-1-((R)-5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide [ka] To a solution of Example 38 (40 mg, 0.047 mmol) in DMF (10 V) was added tetramethyltin (5 equiv.). The mixture was sparged with argon for 10 min and then heated to 90° C. After stirring at that temperature for 1 h, the solution was cooled to room temperature, filtered, and purified by reverse phase HPLC to give Example 63.

[0308] Preparation of intermediate 33: [ka] To a solution of 6-bromoindolin-2-one (10 g, 47.2 mmol, 1 equiv.) and diisopropylamine (10.5 g, 103.7 mmol, 14.6 mL, 2.2 equiv.) in THF (100 mL) was added dropwise at −40° C. n-BuLi (2.5 M in hexanes, 41.5 mL, 2.2 equiv.) was added dropwise. The mixture was stirred at −40° C. for 45 min, then 1,2-dibromoethane (26.5 g, 141.4 mmol, 10.6 mL, 3 equiv.) was added dropwise and stirring was continued for 16 h while the temperature was slowly raised to 20° C. The reaction mixture was diluted with 2N NH 4 The mixture was then extracted with ethyl acetate (100 mL×2). The combined organic layers were washed with brine (50 mL) and concentrated with Na 2 SO 4 The mixture was dried at rt. The combined organic layers were concentrated to dryness to give a residue. The residue was purified by reverse MPLC (Agela C18 800 g silica, 35-65% ethanol in hexanes, gradient over 30 min) to give Intermediate 33.1. LC / MS: 238.0 [M+H].

[0309] To a solution of intermediate 33.1 (3 g, 12.6 mmol, 1 equiv) in THF (60 mL) was added LiAlH 4(1.4 g, 37.8 mmol, 3 equiv) was added at 0° C. The mixture was stirred at 60° C. for 1 h. After cooling to 0-10° C., 1.5 mL of water, 1.5 mL of 1N NaOH, and 4.5 mL of water were added to the solution. The mixture was filtered through diatomaceous earth and the filtrate was concentrated under high vacuum to give Intermediate 33.2 (LC / MS: 224.0 [M+H]), which was used in the next step without further purification.

[0310] A solution of intermediate 32.2 (1.9 g, 8.4 mmol, 1 eq.) in THF (20 mL) was added with TEA (1.3 g, 12.7 mmol, 1.7 mL, 1.5 eq.) and Boc. 2 0 (2.7 g, 12.7 mmol, 2.9 mL, 1.5 equiv) was added. The mixture was stirred at 30° C. for 12 h. The reaction mixture was concentrated to dryness to give the crude product. The crude product was purified by flash column chromatography on silica gel to give intermediate 33.3 LC / MS: 324.0 [M+H].

[0311] A solution of intermediate 33.3 (2.6 g, 8.1 mmol, 1 equiv.) in dioxane (50 mL) was added to a solution of BnSH (1.5 g, 12.0 mmol, 1.4 mL, 1.5 equiv.), DIEA (2.0 g, 16.0 mmol, 2.7 mL, 2 equiv.), Pd 2 (dba) 3 (367.1 mg, 400.9 umol, 0.05 equiv) and Xantphos (464.0 mg, 801.9 umol, 0.1 equiv) were added. The mixture was stirred at 120° C. under argon atmosphere for 12 hours. The reaction mixture was concentrated to dryness to give the crude product, which was purified by flash column chromatography on silica gel to give Intermediate 33.4. LC / MS: 368.2 [M+H].

[0312] To a solution of intermediate 33.4 (1.5 g, 4.0 mmol, 1 equiv.) in AcOH (15 mL) and water (5 mL) was added NCS (1.6 g, 12.2 mmol, 3 equiv.). The mixture was stirred at 20° C. for 5 h. 30 mL of water was added to the reaction and the reaction mixture was extracted with ethyl acetate (40 mL×2). The combined organic layers were washed with brine (30 mL) and extracted with Na2 SO 4 The combined organic layers were concentrated to dryness to give a crude residue which was purified by flash column chromatography on silica gel to give intermediate 33.5. LC / MS: 344.1 [M+H].

[0313] A solution of intermediate 33.5 (1.0 g, 3.0 mmol, 1 equiv) in THF (10 mL) and NH 3 H 2 0 (5 mL, 30% purity) was stirred at 20° C. for 12 h. The reaction mixture was concentrated to remove THF. Then, 10 mL of water was added to the reaction mixture to form a precipitate, which was collected by filtration, and the filter cake was washed with water (10 mL×2) and dried under reduced pressure to give intermediate 33.6. LC / MS: 325.1 [M+H].

[0314] A solution of intermediate 33.6 (880 mg, 2.7 mmol) in 4M HCl / EtOAc (20 mL) was stirred at 20° C. for 1 h. The reaction mixture was filtered, and the filter cake was washed with EtOAc (5 mL×2) and dried under reduced pressure to give intermediate 33. LC / MS: 225.1 [M+H].

[0315] Preparation of Example 64 (General Procedure A): (R)-1'-(5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)spiro[cyclopropane-1,3'-indoline]-6'-sulfonamide [ka] Example 64 was prepared by the method for Example 60 using Intermediate 19 and Intermediate 33 as starting materials. 1H NMR(400 MHz,DMSO-d6)δ 8.65(ddd,J=4.7,1.9,0.9 Hz,1H),8.59(d,J=1.8 Hz,1H),8.01-7.81(m,4H),7.45(dd,J=7.9,1.7 Hz,1H),7.41-7.30(m,2H),7.26(s,2H),6.99(d,J=7.9 Hz,1H),4.37(s,2H),3.68(p,J=8.1 Hz,1H),3.42-3.20(m,4H),1.33-1.09(m,4H).LC / MS:446.2[M+H].

[0316] Preparation of intermediate 34: [ka] Intermediate 34 was prepared in a similar manner to Example 36 using 6-bromo-2,3-dihydrobenzofuran-2-carboxylic acid and intermediate 9 as starting materials. LC / MS: 440.1 [M+H].

[0317] Preparation of Example 65: (S)-5-Fluoro-1-(6-(pyridin-2-yl)-2,3-dihydrobenzofuran-2-carbonyl)indoline-6-sulfonamide [ka] Intermediate 34 was subjected to chiral SFC purification using an OD-H column with 50% MeOH as a co-solvent.

[0318] Example 65 was obtained as the first eluate. 1H NMR (400MHz, DMSO-d6) δ 8.68(dt,J=4.9,1.4Hz,1H),8.51(d,J=6.6Hz,1H),8.04-7.99(m,1H),7.97(dd ,J=8.1,1.8Hz,1H),7.63(dd,J=7.8,1.6Hz,1H),7.60(s,2H),7.54(d,J=1.5Hz ,1H),7.44(ddd,J=6.8,4.9,1.7Hz,1H),7.40(s,1H),7.38(d,J=3.1Hz,1H),5. 75(dd,J=9.7,6.4Hz,1H),3.66-3.51(m,2H),3.31(t,J=8.6Hz,2H),2H below water peak. LC / MS: 440.1[M+H].

[0319] Preparation of intermediates (R)-17 and (S)-17: [ka] Intermediate 17 was subjected to chiral SFC purification using a ChiralPak IG column with 45% MeOH as a co-solvent.

[0320] Intermediate (R)-17 was obtained as the first eluent. LC / MS: 227.1 [M+H].

[0321] Intermediate (S)-17 was obtained as the second eluent. LC / MS: 227.1 [M+H].

[0322] Preparation of Example 68 (General Procedure A): (R)-2-Ethyl-1-((R)-5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide [ka] Example 68 was prepared in a similar manner to Example 35 using intermediate (R)-17. 1H NMR(400 MHz,DMSO-d6)δ 8.71(dq,J=4.8,1.6 Hz,1H),8.60-8.48(m,1H),8.05(td,J=4.6,4.2,1.5 Hz,2H),7.99-7.85(m,2H),7.51(td,J=6.8,5.9,2.9 Hz,2H),7.44(d,J=7.9 Hz,1H),7.37(d,J=7.9 Hz,1H),7.29(s,2H),4.72(td,J=8.5,3.4 Hz,1H),3.78(p,J=8.2 Hz,1H),3.55-3.34(m,3H),3.26(dt,J=17.1,8.7 Hz,1H),3.13(dd,J=16.3,7.8 Hz,1H),2.96(d,J=16.8 Hz,1H),1.78-1.46(m,2H),0.89(t,J=7.3 Hz,3H).LC / MS:448.2[M+H].

[0323] Preparation of intermediate 35: 1-(5-bromo-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide [ka] Intermediate 35 was prepared according to general procedure A using 5-bromo-2,3-dihydro-1H-indene-2-carboxylic acid and indoline-6-sulfonamide. 1 H NMR(400 MHz,DMSO-d6)δ 8.57(d,J=1.7 Hz,1H),7.54-7.23(m,6H),7.20(d,J=8.1 Hz,1H),4.30(t,J=8.5 Hz,2H),3.72(p,J=8.0 Hz,1H),3.21(dt,J=26.0,7.5 Hz,6H).LCMS:420.96[M+H].

[0324] Preparation of Example 69: 1-(5-phenyl-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide [ka] To a stirred solution of intermediate 35 (30 mg, 0.071 mmol) in DMF (1 ml) and water (0.2 ml) was added phenylboronic acid (10.5 mg, 1.2 eq), tetrakis(triphenylphosphine)palladium(0) (12.3 mg, 0.15 eq), potassium carbonate (24.6 mg, 2.5 eq). The mixture was purged with argon and then heated to 90° C. Upon completion of the reaction (as judged by LCMS). The mixture was allowed to cool to room temperature. The mixture was diluted with EtOAc (10 V) and water (10 V). The organic layer was dried (MgSO 4 ) and evaporated in high vacuum to give the crude material. The crude residue was purified by reverse phase HPLC to give Example 69. 1 H NMR(400 MHz,DMSO-d6)δ 8.60(d,J=1.6 Hz,1H),7.68-7.59(m,2H),7.55-7.20(m,10H),4.34(t,J=8.5 Hz,2H),3.75(p,J=8.0 Hz,1H),3.33-3.20(m,6H).LCMS:419.06[M+H].

[0325] Preparation of Example 70: 1-(5-(2-fluorophenyl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide [ka] Example 70 was prepared in a similar manner to Example 69 utilizing (2-fluorophenyl)boronic acid instead of phenylboronic acid as the starting material. 1 H NMR (400 MHz, DMSO-d 6 )δ 8.60(d,J=1.6 Hz,1H),7.59-7.19(m,11H),4.34(t,J=8.5 Hz,2H),3.75(q,J=8.1 Hz,1H),3.41-3.12(m,6H).LCMS:437.04[M+H].

[0326] Preparation of Example 71: 1-(5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide [ka] To a stirred suspension of intermediate 35 (30 mg, 0.071 mmol) in 1,4-dioxane (1 ml) was added tributyl(2-pyridyl)stannane (41.8 mg, 1.6 eq.), bis(tri-t-butylphosphine)palladium(0) (3.6 mg, 0.1 eq.). The mixture was purged with argon and then heated to 90° C. Upon completion of the reaction (as judged by LCMS). The mixture was allowed to cool to room temperature. The mixture was diluted with EtOAc (10 V) and water (10 V). The organic layer was dried (MgSO 4 ) and evaporated in high vacuum to give the crude material. The crude residue was purified by reverse phase HPLC to give Example 71. 1 H NMR(400 MHz,DMSO-d6)δ 8.67(d,J=4.9 Hz,1H),8.60(s,1H),8.02-7.82(m,4H),7.55-7.33(m,4H),7.28(s,2H),4.35(t,J=8.5 Hz,2H),3.76(q,J=8.1 Hz,1H),3.35-3.22(m,6H).LCMS:420.19[M+H].

[0327] The following examples in Table 1E were prepared in a similar manner to Example 71, utilizing the appropriate arylstannane as the starting material in place of tributyl(2-pyridyl)stannane. [Table 1E-1] [Table 1E-2]

[0328] Preparation of Example 78: 1-(5-(1H-pyrazol-1-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide [ka] To a stirred solution of intermediate 35 (50 mg, 0.12 mmol) in DMF (1 mL) was added 1H-pyrazole (16.2 mg, 2 equiv.), copper(I) iodide (45.2 mg, 2.0 equiv.), trans-N,N'-dimethyl-1,2-cyclohexanediamine (67.5 mg, 2.0 equiv.), K 2 CO 3 (29.4 mg, 4.0 equiv.) was added. The mixture was purged with argon and then heated at 105° C. overnight. The mixture was then cooled to room temperature and diluted with EtOAc (10V) and H 2 The organic layer was dried (MgSO 4 ) and evaporated in high vacuum to give the crude material. The crude residue was purified by reverse phase HPLC to give Example 78. 1 H NMR(400 MHz,DMSO-d6)δ 8.60(d,J=1.6 Hz,1H),8.44(d,J=2.5 Hz,1H),7.71(t,J=2.7 Hz,2H),7.63(dd,J=8.2,2.1 Hz,1H),7.48(dd,J=7.9,1.7 Hz,1H),7.42(d,J=7.8 Hz,1H),7.34(d,J=8.2 Hz,1H),7.28(s,2H),6.52(t,J=2.1 Hz,1H),4.34(t,J=8.5 Hz,2H),3.77(p,J=8.1 Hz,1H),3.29-3.13(m,6H).LCMS:409.21[M+H].

[0329] Preparation of Example 79: 1-(5-(1H-1,2,4-triazol-1-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide [ka] Example 79 was prepared in a similar manner to Example 78 utilizing 1H-1,2,4-triazole as the starting material instead of 1H-pyrazole. 1H NMR(400 MHz,DMSO-d6)δ 9.24(s,1H),8.59(s,1H),8.22(s,1H),7.73(d,J=2.0 Hz,1H),7.65(dd,J=8.1,2.0 Hz,1H),7.48(dd,J=7.9,1.7 Hz,1H),7.41(dd,J=8.0,3.2 Hz,2H),7.28(s,2H),4.34(t,J=8.5 Hz,2H),3.78(p,J=7.9 Hz,1H),3.36-3.14(m,6H).LCMS:410.13[M+H].

[0330] Example 80: Preparation of (S)-1-(5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide, and Example 81: Preparation of (R)-1-(5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide [ka] These two single isomers were separated by CCO-F2 column, NH 3 Prepared by separating the racemic mixture Example 71 by SFC using 50% MeOH containing: The first peak was assigned as Example 80 and the second peak was assigned as Example 81.

[0331] Example 82: Preparation of (S)-1-(5-(2-fluorophenyl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide, and Example 83: Preparation of (R)-1-(5-(2-fluorophenyl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide [ka] These two single isomers were prepared by separating the racemic mixture Example 70 by SFC using a CCO-F2 column, 50% MeOH. The first peak was assigned as Example 82 and the second peak was assigned as Example 83.

[0332] Preparation of Example 85: (R)-1-(5-(6-fluoropyridin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide [ka] These two single isomers were prepared by separating the racemic mixture Example 75 by SFC using a CCO-F2 column, 50% MeOH. The second peak fraction was assigned as Example 85.

[0333] Preparation of intermediate 36: (S)-1-(5-bromo-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide, and intermediate 37: (R)-1-(5-bromo-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide [ka] These two single isomers were prepared by separating the racemic mixture Example 35 by SFC using an IB column, 30% MeOH with DEA. The first peak was assigned as intermediate 36 and the second peak as intermediate 37. The absolute stereochemistry of intermediate 37 was confirmed by coupling with tributyl(2-pyridyl)stannane using the same procedure as Example 71. The product was co-eluted with Example 81 using the chiral separation conditions of Example 71.

[0334] Example 86: Preparation of (S)-1-(5-(pyrazin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide, and Example 87: Preparation of (R)-1-(5-(pyrazin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide [ka] Examples 86 and 87 were prepared from enantiopure intermediate 36 and intermediate 37 using the same procedure as example 71.

[0335] Example 88: Preparation of (S)-1-(5-(3-fluoropyridin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide, and Example 89: Preparation of (R)-1-(5-(3-fluoropyridin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide [ka] Examples 88 and 89 were prepared using the same procedure as Example 71 from enantiopure intermediates 36 and 37, respectively.

[0336] Preparation of Example 90: (R)-1-(5-(6-methylpyridin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide [ka] Example 90 was prepared in a similar manner to Example 71 utilizing Intermediate 37 and 2-methyl-6-(tributylstannyl)pyridine as starting materials. 1 H NMR(400 MHz,DMSO-d6)δ 8.60(d,J=1.7 Hz,1H),8.04-7.73(m,3H),7.56-7.19(m,7H),4.35(t,J=8.5 Hz,2H),3.76(q,J=8.1 Hz,1H),3.26(d,J=8.5 Hz,6H),2.59(s,3H).LCMS:434.280[M+H].

[0337] Preparation of Example 91: (R)-1-(5-(1H-pyrazol-1-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide [ka] Example 91 was prepared in a similar manner to Example 78 utilizing Intermediate 37 instead of Intermediate 35.

[0338] Preparation of intermediate 38 and its diastereomers (38.3 and 38.4): [ka] Preparation of intermediate 38.1: To a stirred suspension of sodium hydride (0.68 g, 60% dispersion in oil, 2 eq.) in Me-THF (15 mL) was charged diethyl carbonate (3.2 mL, 3 eq.) at 0° C. 6-Bromo-3-methyl-2,3-dihydro-1H-inden-1-one (2.0 g, 8.9 mmol) in Me-THF (5 ml) was added dropwise to the mixture. The resulting mixture was kept stirred at 0° C. until gas evolution ceased. The reaction mixture was then slowly raised to 70° C. Upon completion of the reaction, the reaction mixture was then allowed to cool to room temperature and then diluted with EtOAc (8 V). The resulting mixture was further cooled at 0° C. to which was added dropwise aqueous HCl (3N, 10 ml). The aqueous layer was extracted with EtOAc (2×5 V). The combined organic layers were washed with brine and purified by HPLC. 2 SO 4 The mixture was dried at 40° C., filtered and concentrated in high vacuum. The residue was purified by silica gel column chromatography to give Intermediate 38.1 (1.7 g, 64% yield).

[0339] Preparation of Intermediate 38.2: Triethylsilane (4V) and trifluoroacetic acid (5V) were added to ethyl 5-bromo-1-methyl-3-oxo-2,3-dihydro-1H-indene-2-carboxylate (1.7 g, 5.7 mmol). The reaction mixture was stirred at room temperature for 5 days. The mixture was then concentrated to dryness and the resulting residue was purified by silica gel chromatography to give Intermediate 38.2 (1.1 g. 69%). 1H NMR(400 MHz,chloroform-d)δ 7.37-7.31(m,2H),7.09-6.95(m,1H),4.22(qd,J=7.2,1.5 Hz,2H),3.52-3.31(m,1H),3.26-3.06(m,2H),2.86(q,J=9.1 Hz,1H),1.40(d,J=6.8 Hz,3H),1.32(t,J=7.1 Hz,3H).

[0340] Preparation of intermediate 38: Ethyl 5-bromo-1-methyl-2,3-dihydro-1H-indene-2-carboxylate (1.1 g, 3.9 mmol) was dissolved in THF (8 ml) and treated with 2N NaOH (aq, 6 ml). The mixture was left stirring at room temperature. Upon completion of the reaction, 2N HCl (aq) was added to adjust the pH to 5. EtOAc (2×5 V) was added to extract the mixture. The organic layers were combined and washed with Mg 2 SO 4 Drying at 40° C., filtering and concentrating in high vacuum gave intermediate 38 as crude material. LCMS: 253.620 [MH].

[0341] Preparation of Intermediate 38.3 and 38.4: These two single isomers were prepared by separating the racemic mixture Example 38 by SFC using an IG column, 10% MeOH containing DEA. The first peak was assigned as intermediate 38.3 and the second peak was assigned as intermediate 38.4. The absolute stereochemistry of these two compounds was confirmed by the biochemical activity of the compound synthesized from these two isomers.

[0342] Preparation of Example 92: 1-(5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide [ka] Intermediate 39 was prepared in a similar manner to Example 1 using indoline-6-sulfonamide and intermediate 38. LCMS: 435.012 [M+H].

[0343] Example 92 was prepared in a similar manner to Example 71, utilizing Intermediate 39 instead of Intermediate 35 as the starting material. 1 H NMR(400 MHz,DMSO-d6)δ 8.66(dd,J=8.3,3.3 Hz,2H),8.06-7.82(m,4H),7.56-7.32(m,4H),7.29(s,2H),4.44-4.26(m,2H),3.67(q,J=7.0 Hz,1H),332-3.19(m,4H),3.08(dd,J=15.0,8.0 Hz,1H),1.37(d,J=6.9 Hz,3H).LCMS:434.259[M+H].

[0344] Example 93: Preparation of 1-((1S,2R)-1-methyl-5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide, and Example 94: Preparation of 1-((1R,2S)-1-methyl-5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide [ka] These two single isomers were prepared by separating the racemic mixture Example 92 by SFC using a CCO-F2 column, 50% EtOH with TFA. The first peak was assigned as Example 93 and the second peak was assigned as Example 94. The absolute stereochemistry of these two compounds was confirmed by their biochemical activity.

[0345] Example 93: 1 H NMR(400 MHz,DMSO-d6)δ 8.66(dd,J=8.3,3.2 Hz,2H),7.94(t,J=7.2 Hz,4H),7.49(dd,J=7.8,1.7 Hz,1H),7.46-7.33(m,3H),7.29(s,2H),4.48-4.26(m,2H),3.67(q,J=7.4 Hz,1H),3.33-3.18(m,4H),3.08(dd,J=15.0,8.0 Hz,1H),1.38(d,J=6.9 Hz,3H).LCMS:434.288[M+H].

[0346] Example 94: 1 H NMR(400 MHz,DMSO-d6)δ 8.66(dd,J=9.3,3.3 Hz,2H),8.02-7.87(m,4H),7.49(dd,J=7.8,1.7 Hz,1H),7.46-7.33(m,3H),7.29(s,2H),4.49-4.21(m,2H),3.69(q,J=7.1 Hz,1H),3.32-3.20(m,4H),3.08(dd,J=15.0,8.0 Hz,1H),1.37(d,J=6.9 Hz,3H).LCMS:434.278[M+H].

[0347] Preparation of intermediate 40: 6-bromo-1-methyl-2,3-dihydro-1H-indene-2-carboxylic acid [ka] Intermediate 40 was prepared in a similar manner to intermediate 38, utilizing 5-bromo-3-methyl-2,3-dihydro-1H-inden-1-one instead of 6-bromo-3-methyl-2,3-dihydro-1H-inden-1-one. LCMS: 253.620 [MH]. [ka]

[0348] Preparation of Example 95: 1-(1-methyl-6-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide Example 95 was prepared in a similar manner to Example 92, utilizing Intermediate 40 instead of Intermediate 38 as the starting material. 1H NMR(400 MHz,DMSO-d6)δ 8.70(d,J=4.9 Hz,1H),8.65(s,1H),8.10-7.83(m,4H),7.54-7.33(m,4H),7.29(s,2H),4.35(td,J=9.0,6.0 Hz,2H),3.70(t,J=7.1 Hz,1H),3.42-3.22(m,4H),3.06(dd,J=14.5,7.1 Hz,1H),1.41(d,J=6.9 Hz,3H).LCMS:434.280[M+H].

[0349] Preparation of Example 96: 5-Fluoro-1-(1-methyl-5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide [ka] Example 96 was prepared in a similar manner to Example 92 utilizing Intermediate 9 instead of indoline-6-sulfonamide as the starting material. 1 H NMR(400 MHz,DMSO-d6)δ 8.66(d,J=4.8 Hz,1H),8.62(d,J=6.7 Hz,1H),8.05-7.84(m,4H),7.58(s,2H),7.36(dd,J=11.5,8.2 Hz,3H),4.42-4.26(m,2H),3.65(q,J=7.3 Hz,1H),3.35-3.20(m,4H),3.06(dd,J=15.0,8.0 Hz,1H),1.36(d,J=6.9 Hz,3H).LCMS:452.301[M+1].

[0350] Example 97: Preparation of 5-fluoro-1-((1R,2S)-1-methyl-5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide, and Example 98: Preparation of 5-fluoro-1-((1S,2R)-1-methyl-5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide [ka] These two single isomers were prepared by separating the racemic mixture Example 96 by SFC using a CCO-F2 column, 50% MeOH. The second peak was assigned as Example 97 and the first peak was assigned as Example 98. The absolute stereochemistry of these two compounds was confirmed by their biochemical activity.

[0351] Example 97: 1 H NMR(400 MHz,DMSO-d6)δ 8.71-8.64(m,1H),8.62(d,J=6.7 Hz,1H),8.00-7.83(m,4H),7.58(s,2H),7.42-7.27(m,3H),4.35(td,J=9.2,6.5 Hz,2H),3.65(q,J=7.1 Hz,1H),3.32-3.23(m,4H),3.06(dd,J=15.0,8.1 Hz,1H),1.36(d,J=6.9 Hz,3H).LCMS:452.206[M+H].

[0352] Example 98: 1 H NMR(400 MHz,DMSO-d6)δ 8.71-8.63(m,1H),8.62(d,J=6.6 Hz,1H),8.04-7.85(m,4H),7.58(s,2H),7.36(dt,J=8.2,4.2 Hz,3H),4.44-4.23(m,2H),3.66(t,J=7.2 Hz,1H),3.32-3.21(m,4H),3.06(dd,J=14.9,8.1 Hz,1H),1.36(d,J=6.9 Hz,3H).LCMS:452.212[M+H].

[0353] Preparation of Example 99: 5-Fluoro-1-(1-methyl-5-(6-methylpyridin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide [ka] Example 99 was prepared in a similar manner to Example 71 utilizing Intermediate 41, 2-methyl-6-(tributylstannyl)pyridine as the starting material instead of Intermediate 35, 2-(tributylstannyl)pyridine. 1 H NMR(400 MHz,DMSO-d6)δ 8.62(d,J=6.7 Hz,1H),8.03-7.74(m,4H),7.58(s,2H),7.42-7.21(m,3H),4.46-4.22(m,2H),3.65(q,J=7.1 Hz,1H),3.32-3.15(m,4H),3.07(dd,J=15.1,8.0 Hz,1H),2.59(s,3H),1.37(d,J=6.9 Hz,3H).LCMS:466.196[M+H].

[0354] Preparation of Example 100: 5-Fluoro-1-(1-methyl-5-(6-methylpyridin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide [ka] Example 100 was prepared in a similar manner to Example 78, utilizing Intermediate 41 instead of Intermediate 35 as the starting material. 1 H NMR(400 MHz,DMSO-d6)δ 8.61(d,J=6.7 Hz,1H),8.44(d,J=2.5 Hz,1H),7.72(d,J=1.7 Hz,1H),7.67(d,J=8.2 Hz,2H),7.58(s,2H),7.34(dd,J=12.6,8.8 Hz,2H),6.52(t,J=2.2 Hz,1H),4.34(td,J=9.0,4.6 Hz,2H),3.88-3.51(m,1H),3.44-3.20(m,4H),3.06(dd,J=14.8,7.5 Hz,1H),1.35(d,J=6.9 Hz,3H).LCMS:441.181[M+H].

[0355] Preparation of Example 101: 3-methyl-1-((1S,2R)-1-methyl-5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide [ka] Example 101 was prepared in a similar manner to Example 92 utilizing intermediate 38.4, 3-methylindoline-6-sulfonamide, as the starting material instead of intermediate 38, indoline-6-sulfonamide. 1 H NMR(400 MHz,DMSO-d6)δ 8.70(d,J=5.0 Hz,1H),8.63(s,1H),8.04(d,J=4.2 Hz,2H),7.92(d,J=6.1 Hz,2H),7.61-7.42(m,3H),7.39(d,J=8.3 Hz,1H),7.30(s,2H),4.55(q,J=10.2 Hz,1H),3.77-3.52(m,3H),3.49-3.23(m,2H),3.09(ddd,J=14.0,7.7,5.3 Hz,1H),1.44-1.31(m,6H).LCMS:448.225[M+H].

[0356] Preparation of Example 102: 3-methyl-1-((1R,2S)-1-methyl-5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide [ka] Example 102 was prepared in a similar manner as Example 92 utilizing intermediate 38.3 and 3-methylindoline-6-sulfonamide instead of indoline-6-sulfonamide as starting materials. 1H NMR(400 MHz,DMSO-d6)δ 8.70(dt,J=5.0,1.4 Hz,1H),8.63(d,J=1.7 Hz,1H),8.01(dd,J=4.8,1.9 Hz,2H),7.92(dd,J=5.7,1.9 Hz,2H),7.53(dd,J=7.8,1.7 Hz,1H),7.46(d,J=7.5 Hz,2H),7.38(d,J=8.3 Hz,1H),7.30(s,2H),4.54(t,J=10.2 Hz,1H),3.97-3.80(m,1H),3.68(p,J=7.4 Hz,1H),3.64-3.55(m,1H),3.43(dd,J=15.2,8.3 Hz,1H),3.37-3.27(m,1H),3.09(ddd,J=14.2,7.9,5.4 Hz,1H),1.46-1.31(m,6H).LCMS:448.177[M+H].

[0357] Preparation of Example 103: 5-Fluoro-3-methyl-1-((1R,2S)-1-methyl-5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide [ka] Example 103 was prepared in a similar manner as Example 92, except utilizing Intermediate 38.3 and Intermediate 42 as starting materials. 1 H NMR(400 MHz,DMSO-d6)δ 8.71(d,J=5.0 Hz,1H),8.60(d,J=6.6 Hz,1H),8.06(d,J=4.3 Hz,2H),7.97-7.86(m,2H),7.58(s,2H),7.50(q,J=4.8 Hz,1H),7.40(t,J=9.9 Hz,2H),4.54(q,J=9.8 Hz,1H),3.87(td,J=10.4,6.9 Hz,1H),3.63(dt,J=27.4,7.3 Hz,2H),3.48-3.22(m,2H),3.08(ddd,J=15.0,7.9,4.6 Hz,1H),1.36(td,J=7.1,1.8 Hz,6H).LCMS:466.220[M+H].

[0358] Preparation of intermediate 42: 5-fluoro-3-methylindoline-6-sulfonamide [ka] Preparation of intermediate 42.1: 5-Fluoro-3-methyl-1H-indole (1.5 g, 10 mmol) was dissolved in acetic acid (5 V). 3 CN (632 mg, 3 equiv.) was added portionwise to the reaction flask while maintaining the temperature below 10 °C. The resulting solution was allowed to warm to room temperature and stirred for 3 h. The solution was then diluted with ice-cold water and neutralized with 2N NaOH until the pH of the solution rose to between 5-6. The reaction mixture was extracted with EtOAc (4 x 20 V). The combined organic layers were washed with brine and diluted with MgSO 4 The crude material was used directly in the next step.

[0359] Preparation of Intermediate 42.2: 5-Fluoro-3-methyl-indoline (10 mmol, crude) was dissolved in dichloromethane (10V) and triethylamine (2.8 ml, 3 equiv.) and acetyl chloride (0.78 ml, 1 equiv.) were added at 0° C. The reaction was stirred at 0° C. for 15 min, at which point it was quenched with sodium bicarbonate (sat. aq.) and extracted with EtOAc (3×10V). The organic layer was dried (MgSO 4 ) and concentrated in high vacuum. The residue was purified by column chromatography on silica gel to give the product as a white solid (1.72 g, 90% yield over two steps). 1 H NMR (400 MHz, chloroform-d) δ 8.17 (dd, J=8.8, 4.9 Hz, 1H), 6.96-6.79 (m, 2H), 4.26 (t, J=9.8 Hz, 1H), 3.63 (dd, J=10.2, 6.8 Hz, 1H), 3.57-3.43 (m, 1H), 1.38 (d, J=6.9 Hz, 3H). LCMS: 194.014 [M+H].

[0360] Preparation of intermediate 42.3: 1-(5-Fluoro-3-methyl-indolin-1-yl)ethanone (0.5 g, 2.6 mmol) was taken up in dichloroethane (5 V) and chlorosulfonic acid (10 V). The reaction was sealed and warmed to 65 °C overnight, after which the reaction was carefully poured onto ice. After extraction with EtOAc (2 x 10 V), the combined organic layers were dried (MgSO 4 ) and concentrated under high vacuum. The crude material was dissolved in 1,4-dioxane (4V) and a solution of concentrated ammonium hydroxide was added and the mixture was stirred at room temperature for 1 h. The volatiles were evaporated under high vacuum and dilute hydrochloric acid was added. The white solid was collected by filtration. The solid was washed with water and a minimum amount of dichloromethane and the solid was further dried by lyo. 0.57 g, 81% yield for two steps. 1 H NMR(400 MHz,DMSO-d6)δ 8.46(d,J=6.6 Hz,1H),7.56(s,2H),7.36(d,J=9.7 Hz,1H),4.33(t,J=10.0 Hz,1H),3.70(dd,J=10.3,6.8 Hz,1H),3.53(dt,J=9.5,6.9 Hz,1H),2.17(s,3H),1.31(d,J=6.9 Hz,3H).LCMS:272.956[M+H].

[0361] Preparation of intermediate 42: 1-Acetyl-5-fluoro-2-methyl-indoline-6-sulfonamide (0.57 g, 2.1 mmol) was dissolved in 2N NaOH (aq, 6 ml, 6 eq). The mixture was heated at 100° C. for 3 h. The reaction was cooled and the pH was adjusted to 7 with acetic acid. The resulting precipitate was collected by filtration. The solid was washed with water and dried by lyophilization. Off-white powder, 0.42 g, 88% yield. 1 H NMR(400 MHz,DMSO-d6)δ 7.38(s,2H),7.07(d,J=9.9 Hz,1H),6.80(d,J=5.9 Hz,1H),5.71(s,1H),3.62(td,J=9.0,1.4 Hz,1H),3.33-3.23(m,1H),3.03(td,J=8.6,2.6 Hz,1H),1.24(d,J=6.8 Hz,3H).LCMS:231.034[M+H].

[0362] Example 103 was prepared in a similar manner as Example 92, utilizing Intermediate 38.3, Intermediate 42 instead of Intermediate 38, Indoline-6-sulfonamide as starting materials. 1 H NMR(400 MHz,DMSO-d6)δ 8.71(d,J=5.0 Hz,1H),8.60(d,J=6.6 Hz,1H),8.06(d,J=4.3 Hz,2H),7.97-7.86(m,2H),7.58(s,2H),7.50(q,J=4.8 Hz,1H),7.40(t,J=9.9 Hz,2H),4.54(q,J=9.8 Hz,1H),3.87(td,J=10.4,6.9 Hz,1H),3.63(dt,J=27.4,7.3 Hz,2H),3.48-3.22(m,2H),3.08(ddd,J=15.0,7.9,4.6 Hz,1H),1.36(td,J=7.1,1.8 Hz,6H).LCMS:466.220[M+H].

[0363] Example 104: Preparation of (R)-5-fluoro-3-methyl-1-((1R,2S)-1-methyl-5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide, and Example 105: Preparation of (S)-5-fluoro-3-methyl-1-((1R,2S)-1-methyl-5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide [ka] These two single isomers were prepared by separating the racemic mixture Example 103 by SFC using a CCO-F2 column, 35% MeOH. The first peak was assigned as Example 104 and the second peak was assigned as Example 105.

[0364] Example 104: 1H NMR(400 MHz, DMSO-d6)δ 8.66(d,J=4.9 Hz,1H),8.60(d,J=6.6 Hz,1H),7.94(q,J=6.8,5.7 Hz,4H),7.58(s,2H),7.45-7.29(m,3H),4.56(t,J=9.9 Hz,1H),3.86(dd,J=10.3,7.0 Hz,1H),3.63(dq,J=15.9,7.4 Hz,2H),3.34-3.22(m,2H),3.16-2.97(m,1H),1.36(t,J=6.2 Hz,6H).LCMS:466.24[M+H].

[0365] Example 105: 1 H NMR(400 MHz, DMSO-d6)δ 8.66(d,J=4.9 Hz,1H),8.60(d,J=6.6 Hz,1H),8.03-7.80(m,4H),7.58(s,2H),7.48-7.29(m,3H),4.53(t,J=10.0 Hz,1H),3.89(dd,J=10.4,6.9 Hz,1H),3.64(dp,J=16.2,7.3 Hz,2H),3.34-3.22(m,2H),3.07(dd,J=14.9,7.9 Hz,1H),1.36(t,J=6.2 Hz,6H).LCMS:466.23[M+H].

[0366] Preparation of Example 106: 3-メチル-1-[5-(2-ピリジル)インダン-2-カルボニル]インドリン-6-スルホンアミド

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[0367] Example 107: Preparation of (R)-3-methyl-1-((R)-5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide, and Example 108: Preparation of (S)-3-methyl-1-((R)-5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide [ka] The chiral separation of Example 106 gave four fractions. Example 107 was obtained from the third fraction, and Example 108 was obtained from the fourth fraction. The NMR of these two compounds was the same as that of Example 106.

[0368] Preparation of Example 109: 3-Methyl-1-[5-(2-pyridyl)indan-2-carbonyl]indoline-6-sulfonamide [ka] 3,3-Dimethylindoline-6-sulfonamide (66 mg, 0.25 mmol), 5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carboxylic acid (60 mg, 0.25 mmol) were suspended in acetonitrile (2.5 mL) and 1-methylimidazole (72 mg, 3.5 equiv.) was added followed by chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (TCFH, 84 mg, 1.2 equiv.) in one portion. The reaction mixture was stirred at room temperature overnight and then the solvent was removed under reduced pressure. The crude residue was purified by reverse phase HPLC to give Example 109. 1 H NMR (400 MHz, methanol-d 4 )δ 8.82-8.75(m,1H),8.70(d,J=1.7 Hz,1H),8.54(td,J=8.0,1.6 Hz,1H),8.30(d,J=8.2 Hz,1H),7.91(ddd,J=7.3,5.8,1.1 Hz,1H),7.84(d,J=1.7 Hz,1H),7.78(dd,J=7.9,1.8 Hz,1H),7.67(dd,J=7.9,1.7 Hz,1H),7.55(d,J=7.9 Hz,1H),7.43(d,J=7.9 Hz,1H),4.15(s,2H),3.95-3.81(m,1H),3.56-3.39(m,4H),1.46(s,6H).LCMS:448.32[M+H].

[0369] Preparation of Example 110: 5-Bromo-1-(5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide [ka] Example 110 was prepared in a similar manner to Example 106 utilizing 5-bromoindoline-6-sulfonamide and 5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carboxylic acid as starting materials. 1 H NMR (400 MHz, methanol-d 4 )δ 8.95(s,1H),8.80(dd,J=6.0,1.5 Hz,1H),8.67(td,J=8.0,1.6 Hz,1H),8.39(dd,J=8.2,1.1 Hz,1H),8.02(m,1H),7.83(d,J=1.8 Hz,1H),7.77(dd,J=7.9,1.8 Hz,1H),7.68(s,1H),7.57(d,J=7.9 Hz,1H),4.41(m,3H),3.92-3.81(m,1H),3.46(m,5H).445.31[M+H].

[0370] Preparation of Example 111: 5-Methoxy-1-[5-(2-pyridyl)indan-2-carbonyl]indoline-6-sulfonamide [ka] To a solution of 5-bromo-1-[5-(2-pyridyl)indan-2-carbonyl]indoline-6-sulfonamide Example 110 (80 mg, 0.16 mmol) in MeOH (1.5 mL) was added copper iodide (31 mg, 1 eq.) and 25% sodium methoxide in methanol (73 uL, 2 eq.), followed by heating at 70° C. for 12 h. The reaction mixture was filtered and concentrated. The crude residue was purified by preparative HPLC to give the product. 1 H NMR (400 MHz, methanol-d 4 )δ 8.79(s,1H),8.71-8.59(m,2H),8.38(t,J=6.6 Hz,1H),8.01(t,J=6.8 Hz,1H),7.82(s,1H),7.75(m,1H),7.55(t,J=6.9 Hz,1H),7.18(s,1H),4.37(m,1H),3.98(s,3H),3.90-3.78(m,2H),3.73(s,2H),3.54-3.38(m,4H).LCMS:450.31[M+H].

[0371] Preparation of intermediate 43: (2-ethyl-5-fluoro-indolin-1-yl)-[(2R)-5-(2-pyridyl)indan-2-yl]methanone [ka] Preparation of intermediate 43.1 (2-ethyl-5-fluoro-indoline): Sodium cyanoborohydride (776 mg, 12 mmol) is added in portions to a solution of 2-ethyl-5-fluoro-1H-indole (1 g, 6.2 mmol) in glacial acid (5 mL) at 0° C. The mixture is stirred at room temperature for 2 h. After cooling in an ice bath, the reaction mixture is diluted with water (15 mL). The reaction mixture is made basic with 40% aqueous NaOH. The reaction mixture is extracted with DCM (2×15 mL). The organic extracts are dried, filtered and concentrated. The residue is purified by flash chromatography to give intermediate 43.1. LC / MS: 166.00 [M+H].

[0372] Intermediate 43 was prepared by Method A utilizing 2-ethyl-5-fluoro-indoline intermediate 43.1, (R)-5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carboxylic acid intermediate 19 as starting materials. LC / MS: 387.32 [M+H].

[0373] Preparation of Example 112: 2-Ethyl-5-fluoro-1-[(2R)-5-(2-pyridyl)indan-2-carbonyl]indoline-6-sulfonamide: [ka] Chlorosulfonic acid (0.9 mL) was cooled in an ice bath and (2-ethyl-5-fluoro-indolin-1-yl)-[(2R)-5-(2-pyridyl)indan-2-yl]methanone (Intermediate 43) in DCM (1 mL) was added portionwise under stirring. Stirring was continued for 20 min, after which the ice bath was removed and the mixture was heated to 70° C. for 1 h. After cooling to room temperature, the mixture was carefully poured into ice water and extracted twice with DCM. The combined organic layers were washed with Na 2 SO4 The triturated intermediate was then diluted with dioxane (1.5 mL) and 28% NH 4 OH (1.5 mL) and stirred at room temperature for 10 min. The reaction was complete. The mixture was concentrated. The residue was washed with saturated NaHCO 3 The organic phase was diluted with aqueous ethyl acetate and extracted twice with EtOAc. 2 SO 4 The residue was purified by flash chromatography to give the title compound. 1 H NMR (400 MHz, DMSO-d 6 )δ 8.72 -8.61(m,1H),8.51(m,1H),8.06-7.77(m,4H),7.57(s,2H),7.44(d,J=9.6 Hz,1H),7.41-7.25(m,2H),4.44(q,J=6.3 Hz,1H),3.73(p,J=8.3 Hz,2H),3.45(m,2H),3.30-3.17(m,1H),3.07(m,2H),1.38-1.19(m,5H).LC / MS:466.35[M+1].

[0374] Example 113: Preparation of (R)-2-ethyl-1-((R)-5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide, and Example 114: Preparation of (S)-2-ethyl-1-((R)-5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide [ka] Chiral separation of Example 112 gave two fractions. Example 113 was obtained from the first fraction and Example 114 was obtained from the second fraction. Example 113: 1 H NMR (400 MHz, DMSO-d 6)δ 8.65(ddd,J=4.9,3.0,2.0 Hz,1H),8.54(d,J=6.6 Hz,1H),8.48(d,J=6.5 Hz,0H),8.05-7.79(m,4H),7.56(s,2H),7.44(d,J=9.6 Hz,1H),7.40-7.27(m,2H),4.98-4.82(m,0H),4.44(q,J=6.4 Hz,1H),4.09(d,J=5.3 Hz,0H),3.74(q,J=8.5 Hz,1H),3.45(dd,J=16.1,8.5 Hz, 2H), 3.27-2.94 (m, 2H), 1.43-1.19 (m, 5H), 1.14 (d, J = 6.4 Hz, 1H). Example 114: 1 H NMR (400 MHz, DMSO-d 6 )δ 8.64(ddd,J=4.8,1.9,1.0 Hz,1H),8.51(dd,J=23.5,6.6 Hz,1H),7.97-7.79(m,4H),7.55(m,2H),7.44(m,2H),7.40-7.23(m,1H),4.44(q,J=6.4 Hz,1H),3.74(dd,J=16.6,8.5 Hz,2H),3.45(m,3H),3.18-2.92(m,2H),1.39-1.15(m,5H).LCMS:466.39[M+H].

[0375] Intermediate 45: 1-(6-ブロモ-2,3-ジヒドロベンゾフラン-2-カルボニル)インドリン-6-スルホンアミドの Modulation:

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[0376] Preparation of Example 115: 1-(6-(pyridin-2-yl)-2,3-dihydrobenzofuran-2-carbonyl)indoline-6-sulfonamide [ka] Intermediate 45 (73.3 mg, 0.173 mmol) was taken up in dioxane (2 mL) and combined with bis(tri-tert-butylphosphine)palladium(0) (8.85 mg, 0.1 equiv.) followed by 2-(tributylstannyl)pyridine (63.8 mg, 1 equiv.). The mixture was stirred at 95° C. for 1 h, then the crude material was purified by reverse phase HPLC. The collected fractions were lyophilized to give Example 115. 1 H NMR (400 MHz, DMSO-d6) δ 8.67-8.63 (m, 1H), 8.54 (d, J = 1.6 Hz, 1H), 7.96 (d, J = 8.0 Hz, 1H), 7.92-7.87 (m, 1H), 7.66-7.62 (m, 1H), 7.55 (d, J = 1.5 Hz, 1H), 7.54-7.50 (m, 1H), 7.45 (d, J = 8.0 Hz, 1H), 7.37 (d, J = 7.6 Hz, 2H), 7.30 (s, 2H), 5.76 (dd, J = 9.6, 6.5 Hz, 1H), 4.43 (d, J = 9.1 Hz, 1H), 4.32 (q, J = 9.1 Hz, 1H), 6H below the water peak. LC / MS: 422.2[M+H].

[0377] Intermediate 46: Preparation of 1-(6-bromo-2,3-dihydrobenzofuran-2-carbonyl)-5-fluoroindoline-6-sulfonamide [ka] The preparation of intermediate 46 involved the same method as for intermediate 45, using 5-fluoroindoline-6-sulfonamide instead of starting indoline-6-sulfonamide. LC / MS: 440.6 [M+H].

[0378] Preparation of Example 116: 5-Fluoro-1-(6-(pyridin-2-yl)-2,3-dihydrobenzofuran-2-carbonyl)indoline-6-sulfonamide [ka] Example 116 was prepared similarly to Example 115 using Intermediate 46 instead of Intermediate 45 with a reaction time of 48 hours. 1 H NMR (400MHz, DMSO-d6) δ 8.67(d,J=4.9Hz,1H),8.51(d,J=6.6Hz,1H),7.99(d,J=7.9Hz,1H),7.94(dd,J=8 .3,6.6Hz,1H),7.64(dd,J=7.8,1.6Hz,1H),7.60(s,2H),7.55(d,J=1.5Hz,1H),7 .40(d,J=3.7Hz,2H),7.38(s,1H),5.75(dd,J=9.6,6.5Hz,1H),4.42(dd,J=18.0, 9.1Hz, 1H), 4.32 (dd, J = 9.3Hz, 1H), 3.58 (t, J = 8.8Hz, 2H), 3.31 (t, J = 8.6Hz, 2H). LC / MS: 440.0[M+H].

[0379] Preparation of intermediate 47: 1-((2R)-5-bromoindane-2-carbonyl)-2-methyl-indoline-6-sulfonamide [ka] Intermediate 47 was prepared using a similar procedure towards intermediate 45 using (2R)-5-bromoindane-2-carboxylic acid and 2-methylindoline-6-sulfonamide as starting materials. The reaction mixture was stirred overnight and then purified by reverse phase HPLC. The resulting desired fractions were combined and lyophilized to give intermediate 47. LC / MS: 435.0 [M+H].

[0380] Preparation of Example 117: 1-((2R)-5-(2,5-difluorophenyl)indan-2-carbonyl)-2-methyl-indoline-6-sulfonamide [ka] Intermediate 47 (42 mg, 0.096 mmol) was dissolved in a solution of 9:1 dioxane:water (1 mL) and then combined with (2,5-difluorophenyl)boronic acid (30 mg, 2 equiv.), (1,1′-bis(diphenylphosphino)ferrocene)-dichloropalladium(II) (27 mg, 0.4 equiv.), and potassium carbonate (40 mg, 3 equiv.). The reaction mixture was purged with nitrogen gas before being stirred at 95° C. for 4 h. The crude material was then purified via reverse phase HPLC and lyophilized to provide Example 117. 1 H NMR (400MHz, DMSO-d 6 ) δ 8.57(s,1H), 7.51(dd,J=7.9,1.6Hz,1H), 7.45(d,J=6.9Hz,1H), 7.41-7.32(m,3H), 7.28(s,2H), 4.93-4.83(m,1H), 3.82-3.70(m,1H), 2.79(d,J=16.6Hz,1H), 2.70-2.30(m,1H), 1.29(d,J=6.3Hz,3H), 4H below water peak. LC / MS: 440.0[M+H].

[0381] Example 118: Preparation of (R)-1-((R)-5-(2,5-difluorophenyl)-2,3-dihydro-1H-indene-2-carbonyl)-2-methylindoline-6-sulfonamide, and Example 119: Preparation of (S)-1-((R)-5-(2,5-difluorophenyl)-2,3-dihydro-1H-indene-2-carbonyl)-2-methylindoline-6-sulfonamide [ka] Example 118 was obtained from racemic Example 117 via chiral SFC separation (45% isopropyl alcohol and ammonia on an AD-H 4.6×100 mm column) with a retention time of 3.54 minutes. 1 H NMR (400MHz, DMSO-d 6 ) δ 8.58(s,1H), 7.54-7.50(m,1H), 7.46(d,J=5.7Hz,1H), 7.42-7.31(m,4H), 7.29(s,1H), 7.10(s,4H), 4.89(t,J=7.4Hz,1H), 3.83-3.72(m,1H), 2.80(d,J=16.6Hz,1H), 1.30(d,J=6.3Hz,3H), 5H below water peak. LC / MS: 440.0[M+H].

[0382] Example 119 was obtained from racemic Example 117 via chiral SFC separation (45% isopropyl alcohol and ammonia on an AD-H 4.6×100 mm column) with a retention time of 5.12 minutes. 1 H NMR (400MHz, DMSO-d 6 ) δ 8.58(s,1H), 7.52(dd,J=7.9,1.6Hz,1H), 7.45(d,J=7.7Hz,1H), 7.41(s,1H), 7.37(d,J=6.7Hz,4H), 7.29(s,2H), 4.89(t,1H), 3.83-3.72(m,1H), 2.80(d,J=16.6Hz,1H), 1.30(d,J=6.3Hz,3H), 5H below water peak. LC / MS: 440.0[M+H].

[0383] Preparation of intermediate 48: 1-(5-bromo-2,3-dihydrobenzofuran-2-carbonyl)-2-methylindoline-6-sulfonamide [ka] Intermediate 48 was obtained using the same method as intermediate 45, with 5-bromo-2,3-dihydrobenzofuran-2-carboxylic acid and 2-methylindoline-6-sulfonamide as reactants. The crude material was purified using reverse phase HPLC and then lyophilized to give intermediate 48. LC / MS: 437.0 [M+H].

[0384] Preparation of Example 120: 1-(5-(2,5-difluorophenyl)-2,3-dihydrobenzofuran-2-carbonyl)-2-methylindoline-6-sulfonamide [ka] Example 120 was prepared using the same procedure as Example 117, using intermediate 48 instead of intermediate 47. 1 H NMR(400 MHz,DMSO-d6)δ 8.52(s,1H),7.56(t,J=6.9 Hz,1H),7.50(s,1H),7.47(s,0H),7.40-7.34(m,1H),7.31(d,J=7.3 Hz,1H),7.25-7.17(m,1H),6.96(t,J=9.5 Hz,1H),5.85-5.75(m,1H),5.10-4.84(m,1H),3.74-3.42(m,3H),2.84(d,J=16.3 Hz,1H),1.36(d,J=6.3 Hz,1H),1.32(d,J=6.5 Hz,2H).LC / MS:471.0[M+H].

[0385] Preparation of Example 123: (R)-1-((R)-5-(2,5-difluorophenyl)-2,3-dihydrobenzofuran-2-carbonyl)-2-methylindoline-6-sulfonamide [ka] Example 123 was obtained from racemic Example 120 via chiral SFC separation (25% ethanol and ammonia on an OJ-H 4.6×100 mm column) with a retention time of 13.05 minutes. 1 H NMR (400MHz, DMSO-d 6 ) δ 8.52(s,1H), 7.59-7.54(m,1H), 7.50(d,J=6.4Hz,2H), 7.39-7.34(m,3H), 7.32(s,2H), 7.22(td,J=8.7,8.2,4.0Hz,1H), 6.94(d,J=8.5Hz,1H), 5.81(dd,J=9.6,6.6Hz,1H), 5.04(d,J=7.9Hz,1H), 1.32(d,J=6.4Hz,3H), 3H below water peak. LC / MS: 471.0[M+H].

[0386] Preparation of intermediate 60: 5-fluoro-2-(fluoromethyl)indoline-6-sulfonamide [ka] Preparation of intermediate 60.1 (N-allyl-4-fluoroaniline) A solution of 4-fluoroaniline (50 g, 449.9 mmol, 43.10 mL, 1 equiv.) in DMF (500 mL) was treated with 3-bromoprop-1-ene (48.9 g, 404.9 mmol, 0.9 equiv.) and K 2 CO 3 (93.2 g, 674.9 mmol, 1.5 equiv.) was added. The reaction mixture was stirred at 20° C. for 12 h. The reaction mixture was quenched with water (500 mL) and extracted with ethyl acetate (1000 mL×2). The combined organics were washed with brine (1500 mL) and diluted with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash column chromatography on silica gel (eluting with 0-20% ethyl acetate in petroleum ether) to give Intermediate 60.1. LC / MS: 152.1 [M+H].

[0387] Preparation of intermediate 60.2 (2-allyl-4-fluoroaniline) To a solution of intermediate 60.1 (20 g, 132.3 mmol, 1 equiv.) in m-xylene (150 mL), BF 3 Et 2 2H2O (56.3 g, 396.8 mmol, 48.9 mL, 3 equiv.) was added and the reaction mixture was stirred at 170° C. for 2 h. After cooling to room temperature, the reaction mixture was treated with 2M NaOH until pH=7 and extracted with EtOAc (1 L×2). The combined organics were washed with brine (1.5 L) and diluted with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash column chromatography on silica gel (eluting with 0-20% ethyl acetate in petroleum ether) to give Intermediate 60.2. LC / MS: 152.1 [M+H].

[0388] Preparation of intermediate 60.3 (N-(2-allyl-4-fluorophenyl)acetamide) To a solution of intermediate 60.2 (15 g, 99.2 mmol, 1 equiv) in DCM (200 mL) was added Ac 2 O (30.3 g, 297.6 mmol, 27.8 mL, 3 equiv.) was added. The mixture was stirred at 20° C. for 12 h. Water (150 mL) was added and the reaction mixture was extracted with DCM (150 mL×2). The combined organic layers were washed with brine (150 mL) and diluted with Na 2 SO 4 The combined organic layers were concentrated to dryness to give Intermediate 60.3, which was used directly without purification. LC / MS: 194.1 [M+H].

[0389] Preparation of intermediate 60.4 (1-acetyl-5-fluoroindolin-2-yl)methyl acetate Intermediate 60.3 (20 g, 103.5 mmol, 1 equiv.) in AcOH (300 mL) and Ac 2 To a solution of Pd(CH 3 CN) 2 Cl 2 (1.3 g, 5.1 mmol, 0.05 equiv.) and Cu(NO 3 ) 2 *3H 2O (1.2 g, 5.1 mmol, 0.05 equiv.) was added. The reaction mixture was degassed and O 2 3 times, then O 2 The mixture was stirred at 25° C. under atmospheric pressure (15 psi) for 15 hours. The reaction mixture was concentrated to dryness. Dichloromethane (200 mL) was then added and the resulting mixture was diluted with saturated NaHCO 3 (200 mL). The aqueous layer was extracted with dichloromethane (2×200 mL) and the combined organic layers were washed with Na 2 SO 4 The mixture was dried at rt. The solvent was removed under reduced pressure. The crude product was purified by flash column chromatography on silica gel (eluting with 10-50% ethyl acetate in petroleum ether) to give intermediate 60.4. LC / MS: 252.1 [M+H].

[0390] Preparation of intermediate 60.5 (1-(5-fluoro-2-(hydroxymethyl)indolin-1-yl)ethan-1-one) A solution of intermediate 60.4 (7.4 g, 29.4 mmol, 1 equiv.) in MeOH (70 mL) was added with LiOH H 2 0 (1M, 35.3 mL, 1.2 equiv.) was added. The mixture was stirred at 0° C. for 1 h. The mixture was acidified with 2M HCl until pH=3. The reaction mixture was filtered, and the filter cake was washed with water (10 mL×2) and dried under reduced pressure to give intermediate 60.5. LC / MS: 210.1 [M+H].

[0391] Preparation of intermediate 60.6 ((1-acetyl-5-fluoroindolin-2-yl)methyl methanesulfonate) To a solution of intermediate 60.5 (3 g, 14.3 mmol, 1 equiv) in DCM (40 mL) was added DIPEA (7.4 g, 57.3 mmol, 9.9 mL, 4 equiv) and methylsulfonylmethanesulfonate (5.0 g, 28.6 mmol, 2 equiv). The mixture was stirred at 20° C. for 2 h. The reaction mixture was concentrated and then purified by flash column chromatography on silica gel (eluting with 10-50% ethyl acetate in petroleum ether) to give intermediate 60.6. LC / MS: 288.1 [M+H].

[0392] Preparation of intermediate 60.7 (1-(5-fluoro-2-(fluoromethyl)indolin-1-yl)ethan-1-one) A solution of intermediate 60.6 (2.5 g, 8.7 mmol, 1 equiv) in TBAF (1 M, 43.5 mL, 5 equiv) in THF was stirred at 70° C. for 36 h. Water (30 mL) was added to the reaction and the resulting mixture was extracted with ethyl acetate (30 mL×2). The combined organic layers were washed with brine (20 mL) and diluted with Na 2 SO 4 The combined organic layers were concentrated to dryness to give a residue. The crude product was purified by flash column chromatography using silica gel (eluting with 0-30% ethyl acetate in petroleum ether) to give intermediate 60.7. LC / MS: 212.1 [M+H].

[0393] Preparation of intermediate 60.8 (1-acetyl-5-fluoro-2-(fluoromethyl)indoline-6-sulfonyl chloride) HSO 3 A solution of Cl (2 mL) was cooled to 5° C. Then, intermediate 60.7 (600 mg, 2.8 mmol, 1 equiv) was added to the mixture in three portions. The reaction mixture was then stirred at 50° C. for 5 h. After cooling to 20° C., the mixture was poured into ice water (20 mL), and then the mixture was extracted with DCM (30 mL×2). The combined organic layers were washed with brine (20 mL) and Na 2 SO 4The combined organic layers were concentrated to dryness to give intermediate 60.8, which was used in the next step without further purification. LC / MS: 310.0 [M+H].

[0394] Preparation of intermediate 60.9 (1-acetyl-5-fluoro-2-(fluoromethyl)indoline-6-sulfonamide) To a solution of intermediate 60.8 (750 mg, 2.4 mmol, 1 equiv) in THF (8 mL) was added NH 3 H 2 0 (4 mL, 30% w / v) was added. The mixture was stirred at 20° C. for 12 h and then concentrated under reduced pressure to give intermediate 60.9, which was used in the next step without further purification. LC / MS: 291.1 [M+H].

[0395] Preparation of intermediate 60 (5-fluoro-2-(fluoromethyl)indoline-6-sulfonamide) To a solution of intermediate 60.9 (650 mg, 2.2 mmol, 1 equiv) in EtOH (7 mL) was added HCl (12 M, 1.3 mL, 7 equiv). The mixture was stirred at 80° C. for 2 h. The reaction mixture was concentrated to dryness and then dissolved in water (20 mL). The mixture was made basic with ammonia (3 mL) and extracted with ethyl acetate (20 mL×2). The combined organic layers were washed with brine (15 mL) and diluted with Na 2 SO 4 The combined organic layers were concentrated to dryness to give intermediate 60. LC / MS: 249.0 [M+H].

[0396] For intermediate 60, DAICEL CHIRALPAK IF (250 mm x 30 mm, 10 μm) column, mobile phase: [0.1% NH 3 Chiral SFC separation was carried out using 100% hexanes (MeOH), B%: 40% to 40%, 5 min). (S)-Intermediate 60 was obtained as the first eluate, and (R)-Intermediate 60 was obtained as the second eluate.

[0397] Preparation of Example 125: (S)-5-fluoro-2-(fluoromethyl)-1-((R)-5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide: [ka] Example 125 was prepared in a similar manner to Example 35 using (S)-Intermediate 60 and Intermediate 19 (General Procedure B). 1 H NMR(400 MHz,DMSO-d6)δ 8.68(d,J=4.9 Hz,1H),8.52(d,J=6.6 Hz,1H),8.05-7.94(m,2H),7.94-7.83(m,2H),7.59(s,2H),7.42(ddd,J=20.6,8.9,6.3 Hz,3H),5.28-5.07(m,1H),4.75-4.33(m,2H),3.83(p,J=8.0 Hz,1H),3.76-3.06(m,5H),2.99(d,J=17.3 Hz,1H).LC / MS:470.2[M+H].

[0398] Preparation of Example 126: (R)-5-fluoro-2-(fluoromethyl)-1-((R)-5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide: [ka] Example 126 was prepared in a similar manner to Example 35 using (R)-Intermediate 60 and Intermediate 19 (General Procedure B). 1H NMR(400 MHz,DMSO-d6)δ 8.70(dd,J=5.0,1.5 Hz,1H),8.51(d,J=6.6 Hz,1H),8.09-7.98(m,2H),7.96(s,1H),7.88(dd,J=7.9,1.7 Hz,1H),7.60(s,2H),7.48(td,J=5.1,3.4 Hz,1H),7.37(t,J=9.5 Hz,2H),5.17(dt,J=18.9,7.9 Hz,1H),4.80-4.35(m,2H),3.83(p,J=8.3 Hz,1H),3.53-3.31(m,3H),3.24(dd,J=16.1,8.4 Hz,1H),3.09(dd,J=16.2,7.8 Hz,1H),2.99(d,J=17.3 Hz,1H).LC / MS:470.2[M+H].

[0399] Preparation of intermediate 50 (2-(difluoromethyl)-5-fluoroindoline-6-sulfonamide): [ka] Preparation of intermediate 50.1 (5-fluoro-1-tosyl-1H-indole): To a solution of 5-fluoro-1H-indole (50 g, 369.9 mmol, 1 equiv.) in THF (600 mL), NaH (19.2 g, 480.9 mmol, 60% purity, 1.3 equiv.) was added and the resulting mixture was cooled to 37° C. for 1 hour. 2 At 0° C., 4-methylbenzenesulfonyl chloride (84.6 g, 443.9 mmol, 1.2 equiv) was added in portions. The mixture was warmed to 20° C. and stirred at 20° C. for 14 h. The residue was then added to water (500 mL) and the solid was collected by filtration, washed with water (50 mL×3), petroleum ether (50 mL×3) and dried under reduced pressure to give Intermediate 50.1. LC / MS: 290.1 ​​[M+H].

[0400] Preparation of intermediate 50.2 (5-fluoro-1-tosyl-1H-indole-2-carbaldehyde) To a solution of intermediate 50.1 (50 g, 172.8 mmol, 1 equiv.) in THF (500 mL), n-BuLi (2.5 M, 96.78 mL, 1.4 equiv.) was added 2 The mixture was stirred at -70°C under atmospheric pressure for 1 h. Then DMF (25.90 g, 354.27 mmol, 27.26 mL, 2.05 equiv) was added to the mixture and stirred at -70°C for 0.5 h. The mixture was diluted with saturated NH 4 The mixture was quenched with aqueous Cl (500 mL) and extracted with ethyl acetate (500 mL x 3). The combined organics were washed with brine (200 mL) and diluted with Na 2 SO 4 The solid was triturated with 1000 mL of petroleum ether, the solid was collected by filtration, rinsed with petroleum ether (50 mL×3), and dried under reduced pressure to give Intermediate 50.2. LC / MS: 318.1 [M+H].

[0401] Preparation of intermediate 50.3 (2-(difluoromethyl)-5-fluoro-1-tosyl-1H-indole) To a solution of intermediate 50.2 (58 g, 182.7 mmol, 1 equiv) in DCM (580 mL), 2 DAST (58.92 g, 365.55 mmol, 48.30 mL, 2 equiv) was added dropwise under atmosphere at -70°C. The mixture was then warmed to 20°C over 16 h. The mixture was cooled to 0°C, quenched with water (500 mL) and extracted with DCM (500 mL x 3). The combined organics were washed with brine (300 mL) and diluted with Na 2 SO 4 The mixture was dried at 40° C., filtered, concentrated under reduced pressure, and the residue was purified by flash column chromatography on silica gel (eluting with 5-10% EtOAc in petroleum ether) to give Intermediate 50.3. LC / MS: 340.1 [M+H].

[0402] Preparation of intermediate 50.4 (2-(difluoromethyl)-5-fluoro-1-tosylindoline): To a suspension of Pd / C (8 g, 10% purity, 1.00 equiv.) in EtOAc (500 mL) was added Intermediate 50.3 (14.5 g, 42.73 mmol, 1 equiv.). The suspension was degassed and diluted with H 2 The mixture was purged with H 2 (30 Psi) at 60° C. for 2 h, at which time it was filtered through a pad of Celite and the Celite was rinsed with ethyl acetate (100 mL×3). The filtrate was concentrated under reduced pressure to give Intermediate 50.4. LC / MS: 342.1 [M+H].

[0403] Preparation of intermediate 50.5 (2-(difluoromethyl)-5-fluoroindoline): To a solution of intermediate 50.4 (16.3 g, 47.75 mmol, 1 equiv) in MeOH (300 mL) was added Mg (11.61 g, 477.52 mmol, 10 equiv) in small portions. The mixture was then stirred at 20° C. for 4 h. The reaction was washed with saturated NH 4 The mixture was quenched with aqueous Cl (100 mL) and diluted with water (300 mL) and EtOAc (300 mL). The resulting mixture was filtered and the filter cake was rinsed with EtOAc (50 mL×3). The combined filtrate was then extracted with ethyl acetate (200 mL×3). The combined organics were washed with brine (150 mL) and diluted with Na 2 SO 4 Drying at 40° C., filtering and concentrating under reduced pressure gave intermediate 50.5, which was used directly in the next step without further purification. LC / MS: 188.0 [M+H].

[0404] Preparation of intermediate 50.6 (1-(2-(difluoromethyl)-5-fluoroindolin-1-yl)ethan-1-one) To a solution of intermediate 50.5 (17 g, 90.83 mmol, 1 equiv) in DCM (200 mL) was added acetyl chloride (10.69 g, 136.25 mmol, 9.72 mL, 1.5 equiv) and TEA (27.57 g, 272.49 mmol, 37.93 mL, 3 equiv). The mixture was stirred at 20° C. for 16 h. The reaction was quenched with water (200 mL) and extracted with DCM (200 mL×3). The combined organics were washed with brine (100 mL) and diluted with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure. The residue was then purified by flash column chromatography on silica gel (eluting with 10-15% ethyl acetate in petroleum ether) to give Intermediate 50.6. LC / MS: 230.0 [M+H].

[0405] Preparation of intermediate 50.7 (1-acetyl-2-(difluoromethyl)-5-fluoroindoline-6-sulfonyl chloride) Intermediate 50.6 (10 g, 43.63 mmol, 1 equiv.) of HSO 3 Cl solution (105.00 g, 901.10 mmol, 60 mL, 20.65 equiv) was stirred at 55° C. for 5 h. The reaction mixture was cooled to room temperature, quenched slowly with ice water (300 mL), and extracted with ethyl acetate (100 mL×3). The combined organic phase was washed with saturated NaHCO 3 Wash with aqueous solution (200 mL x 2) and brine (200 mL), and add Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure. The resulting residue was purified using flash column chromatography on silica gel (eluting with 40-50% EtOAc in petroleum ether) to give Intermediate 50.7. LC / MS: 328.0 [M+H].

[0406] Preparation of intermediate 50.8 (1-acetyl-2-(difluoromethyl)-5-fluoroindoline-6-sulfonamide) Intermediate 50.7 (4.5 g, 13.73 mmol, 1 equiv.) and NH 3 H 2A mixture of O (16.04 g, 137.32 mmol, 17.63 mL, 30% purity, 10 equiv) in THF (40 mL) was stirred at 20° C. for 1 h. The reaction was concentrated under reduced pressure to give intermediate 50.8, which was used directly in the next step without purification. LC / MS: 309.0 [M+H].

[0407] Preparation of intermediate 50 (2-(difluoromethyl)-5-fluoroindoline-6-sulfonamide) A mixture of intermediate 50.8 (5 g, 16.22 mmol, 1 equiv) and HCl (12 M, 9.46 mL, 7 equiv) in EtOH (50 mL) was stirred at 80° C. for 6 h. The mixture was cooled to 20° C. and concentrated under reduced pressure to give a residue. The residue was dissolved in water (30 mL) and stirred at 0° C. for 1 h. 2 CO 3 The pH was adjusted to 9 by slow addition of ethyl acetate (20 mL x 3). The mixture was extracted with ethyl acetate (20 mL x 3). The combined organics were washed with brine (15 mL) and diluted with Na 2 SO 4 Drying at 40° C., filtering and concentrating under reduced pressure gave intermediate 50. LC / MS: 267.1 [M+H].

[0408] For intermediate 50, DAICEL CHIRALPAK IG (250 mm x 50 mm, 10 μm) column, mobile phase: [0.1% NH 3 Chiral SFC separation was performed using 100% COOH, B%: 40% to 40%, 5 min. (R)-intermediate 50 was obtained as the first eluent, and (S)-intermediate 50 was obtained as the second eluent.

[0409] Preparation of Example 127 ((R)-2-(difluoromethyl)-5-fluoro-1-((R)-5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide) [ka] Example 127 was prepared in a similar manner to Example 35 using (R)-Intermediate 50 and Intermediate 19 (General Procedure B). 1H NMR (400 MHz, DMSO-d 6 )δ 8.70(dt,J=5.0,1.4 Hz,1H),8.48(d,J=6.5 Hz,1H),8.08-8.02(m,2H),7.92-7.86(m,2H),7.62(s,2H),7.49(td,J=5.2,3.2 Hz,1H),7.45-7.40(m,2H),5.33(q,J=11.8 Hz,1H),3.85(p,J=8.2 Hz,1H),3.61(dd,J=17.6,9.7 Hz,1H),3.49(dd,J=15.9,8.8 Hz,1H),3.39(dd,J=16.2,7.4 Hz,1H),3.29-3.16(m,2H),3.10(dd,J=15.8,7.7 Hz,1H),2.70(s,1H).LC / MS:488.1[M+H].

[0410] Preparation of Example 128: (S)-2-(difluoromethyl)-5-fluoro-1-((R)-5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide [ka] Example 128 was prepared in a similar manner to Example 35 using (S)-Intermediate 50 and Intermediate 19 (General Procedure B). 1 H NMR (400 MHz, DMSO-d 6 )δ 8.72(dt,J=5.2,1.4 Hz,1H),8.47(d,J=6.6 Hz,1H),8.12-8.06(m,2H),7.96(s,1H),7.87(dd,J=7.9,1.7 Hz,1H),7.62(s,2H),7.52(td,J=5.5,2.6 Hz,1H),7.39(dd,J=17.9,8.8 Hz,2H),5.33(q,J=11.9 Hz,1H),5.14(s,1H),3.85(p,J=8.3 Hz,1H),3.60(dd,J=17.6,9.7 Hz,1H),3.45(ddd,J=22.6,16.1,8.1 Hz,2H),3.32-3.14(m,2H),3.08(dd,J=16.3,7.7 Hz,1H).LC / MS:488.1[M+H].

[0411] Preparation of Example 129: (R)-1-(5-(pyrimidin-4-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide: [ka] Example 129 was prepared in a similar manner to Example 71 using intermediate 37 and 4-(tributylstannyl)pyrimidine. 1 H NMR(400 MHz,DMSO-d6)δ 9.22(d,J=1.3 Hz,1H),8.84(d,J=5.4 Hz,1H),8.59(d,J=1.7 Hz,1H),8.16-7.96(m,3H),7.45(ddd,J=24.9,7.8,2.3 Hz,3H),7.28(s,2H),4.35(t,J=8.5 Hz,2H),3.78(p,J=8.0 Hz,1H),3.37-3.12(m,6H).LC / MS:421.1[M+H].

[0412] Preparation of Example 130: (R)-1-(5-(pyridin-3-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide: [ka] Example 130 was prepared in a similar manner to Example 69 using intermediate 37 and pyridin-3-ylboronic acid. 1 H NMR(400 MHz,DMSO-d6)δ 8.99(d,J=2.2 Hz,1H),8.66(dd,J=5.1,1.5 Hz,1H),8.59(d,J=1.7 Hz,1H),8.32(dt,J=8.1,1.9 Hz,1H),7.76-7.61(m,2H),7.61-7.52(m,1H),7.48(dd,J=7.8,1.8 Hz,1H),7.41(t,J=7.4 Hz,2H),7.28(s,2H),4.35(t,J=8.5 Hz,2H),3.77(p,J=8.0 Hz,1H),3.39-3.20(m,6H).LC / MS:420.2[M+H].

[0413] Preparation of Example 131: (R)-1-(5-(pyridin-4-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide: [ka] Example 131 was prepared in a similar manner to Example 69 using Intermediate 37 and pyridin-4-ylboronic acid. 1 H NMR(400 MHz,DMSO-d6)δ 8.84-8.70(m,2H),8.59(d,J=1.7 Hz,1H),8.04(d,J=5.6 Hz,2H),7.81(s,1H),7.73(dd,J=7.9,1.8 Hz,1H),7.53-7.36(m,3H),7.28(s,2H),4.34(t,J=8.5 Hz,2H),3.78(p,J=7.9 Hz,1H),3.31-3.12(m,6H).LC / MS:420.2[M+H].

[0414] Preparation of Example 132: (R)-1-(5-(quinolin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide: [ka] Example 132 was prepared in a similar manner to Example 71 using Intermediate 37 and 2-(tributylstannyl)quinoline. 1 H NMR(400 MHz,DMSO-d6)δ 8.61(d,J=1.7 Hz,1H),8.50(d,J=8.7 Hz,1H),8.17(dd,J=5.1,3.6 Hz,2H),8.10(dd,J=7.8,1.7 Hz,2H),8.03(dd,J=8.2,1.4 Hz,1H),7.81(ddd,J=8.5,6.9,1.5 Hz,1H),7.62(ddd,J=8.1,6.8,1.2 Hz,1H),7.56-7.37(m,3H),7.29(s,2H),4.36(t,J=8.5 Hz,2H),3.80(p,J=8.1 Hz,1H),3.43-3.23(m,6H).LC / MS:470.3[M+H].

[0415] Preparation of Example 133: (R)-1-(5-(pyrimidin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide: [ka] Example 133 was prepared in a similar manner to Example 71 using Intermediate 37 and 2-(tributylstannyl)pyrimidine. 1 H NMR(400 MHz,DMSO-d6)δ 8.89(d,J=4.8 Hz,2H),8.60(d,J=1.7 Hz,1H),8.32-8.17(m,2H),7.56-7.34(m,4H),7.28(s,2H),4.35(t,J=8.5 Hz,2H),3.78(p,J=8.1 Hz,1H),3.42-3.18(m,6H).LC / MS:421.1[M+H].

[0416] Preparation of Example 134: (R)-1-(5-(naphthalen-1-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide: [ka] Example 134 was prepared in a similar manner to Example 69 using Intermediate 37 and naphthalen-1-ylboronic acid. 1 H NMR(400 MHz,DMSO-d6)δ 8.63(d,J=1.7 Hz,1H),8.00(dd,J=8.0,1.5 Hz,1H),7.95(d,J=8.2 Hz,1H),7.84(d,J=8.3 Hz,1H),7.65-7.19(m,11H),4.36(t,J=8.5 Hz,2H),3.80(p,J=8.1 Hz,1H),3.41-3.21(m,6H).LC / MS:469.1[M+H].

[0417] Preparation of Example 135: (R)-1-(5-(naphthalen-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide: [ka] Example 135 was prepared in a similar manner to example 69 using intermediate 37 and naphthalen-2-ylboronic acid. 1 H NMR(400 MHz,DMSO-d6)δ 8.61(d,J=1.7 Hz,1H),8.20(d,J=1.8 Hz,1H),8.04-7.98(m,2H),7.94(dd,J=7.4,1.9 Hz,1H),7.84(dd,J=8.6,1.9 Hz,1H),7.69(d,J=1.7 Hz,1H),7.62(dd,J=7.8,1.7 Hz,1H),7.59-7.32(m,5H),7.29(s,2H),4.36(t,J=8.5 Hz,2H),3.78(p,J=8.1 Hz,1H),3.39-3.17(m,6H).LC / MS:469.1[M+H].

[0418] Preparation of intermediate 51 (5-fluoro-1-(6-fluoro-5-(pyridin-2-yl)-2,3-dihydrobenzofuran-2-carbonyl)-3-methylindoline-6-sulfonamide): [ka] Intermediate 51 was prepared in a similar manner to Example 101 using 5-fluoro-3-methylindoline-6-sulfonamide and 5-bromo-6-fluoro-2,3-dihydrobenzofuran-2-carboxylic acid (General Procedure B). LC / MS: (General Procedure B). LC / MS: 472.2 [M+H].

[0419] Preparation of Example 136 and Example 137 ((S)-5-fluoro-1-((R)-6-fluoro-5-(pyridin-2-yl)-2,3-dihydrobenzofuran-2-carbonyl)-3-methylindoline-6-sulfonamide), (R)-5-fluoro-1-((R)-6-fluoro-5-(pyridin-2-yl)-2,3-dihydrobenzofuran-2-carbonyl)-3-methylindoline-6-sulfonamide [ka] Intermediate 51 was subjected to chiral SFC separation using an AD-H column (250×21 mm 5 um) with 45% EtOH as a co-solvent.

[0420] The third eluate was collected and concentrated to give Example 136. 1 H NMR(400 MHz,DMSO-d6)δ 8.68(dd,J=5.0,1.9 Hz,1H),8.49(d,J=6.6 Hz,1H),7.88(td,J=7.7,1.9 Hz,1H),7.81(d,J=8.0 Hz,1H),7.77-7.68(m,1H),7.61(s,2H),7.45(d,J=9.7 Hz,1H),7.36(ddd,J=7.5,4.8,1.1 Hz,1H),6.93(d,J=11.8 Hz,1H),5.83(dd,J=10.0,6.1 Hz,1H),4.48(t,J=9.9 Hz,1H),3.93(dd,J=10.4,6.8 Hz,1H),3.70-3.48(m,3H),1.36(d,J=6.9 Hz,3H).LC / MS:472.2[M+H].

[0421] The fourth eluent was collected and concentrated to give Example 137. 1 H NMR(400 MHz,DMSO-d6)δ 8.74-8.67(m,1H),8.49(d,J=6.6 Hz,1H),7.91(td,J=7.7,1.9 Hz,1H),7.81(d,J=8.0 Hz,1H),7.74(dd,J=8.0,2.3 Hz,1H),7.61(s,2H),7.45(d,J=9.6 Hz,1H),7.38(ddd,J=7.5,4.8,1.2 Hz,1H),6.93(d,J=11.8 Hz,1H),5.83(dd,J=10.0,6.1 Hz,1H),4.58(t,J=9.9 Hz,1H),3.83(dd,J=10.3,7.0 Hz,1H),3.74-3.54(m,3H),1.36(d,J=6.9 Hz,3H).LC / MS:472.2[M+H].

[0422] Preparation of intermediate 52 (5-fluoro-3-(trifluoromethyl)indoline-6-sulfonamide): [ka] Preparation of intermediate 52.1 (5-bromo-4-fluoro-2-iodoaniline): To a solution of 3-bromo-4-fluoroaniline (25 g, 131.6 mmol, 1 equiv.) in acetic acid (130 mL) was added NIS (31.1 g, 138.1 mmol, 1.1 equiv.) in small portions. The mixture was stirred at 20° C. for 2 h. The mixture was concentrated under reduced pressure and the resulting residue was dissolved in EtOAc (200 mL), washed with saturated sodium carbonate (100 mL), brine (50 mL), and diluted with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure. The resulting residue was purified using flash column chromatography on silica gel (eluting with 10-20% EtOAc in petroleum ether) to give Intermediate 52.1. LC / MS: 315.9 [M+H].

[0423] Preparation of Intermediate 52.2 (N-(5-bromo-4-fluoro-2-iodophenyl)-4-methylbenzenesulfonamide): To a solution of Intermediate 52.1 (25.3 g, 80.1 mmol, 1 eq.) and pyridine (15.8 g, 200.4 mmol, 16.18 mL, 2.5 eq.) in DCM (300 mL) was added 4-methylbenzenesulfonyl chloride (30.5 g, 160.3 mmol, 2 eq.). The mixture was stirred at 20° C. for 16 h. The reaction was quenched with water (300 mL) and extracted with DCM (300 mL×3). The combined organics were washed with brine (150 mL) and diluted with Na 2 SO 4 The mixture was dried at 40° C., filtered, concentrated under reduced pressure, and the resulting residue was purified by flash column chromatography on silica gel (eluting with 5% EtOAc in petroleum ether) to give Intermediate 52.2. LC / MS: 469.9 [M+H].

[0424] Preparation of Intermediate 52.3 (N-(5-bromo-4-fluoro-2-(3,3,3-trifluoroprop-1-en-2-yl)phenyl)-4-methylbenzenesulfonamide): H of Intermediate 52.2 (23.1 g, 49.1 mmol, 1 equiv.)2 A solution of 4,4,6-trimethyl-2-[1-(trifluoromethyl)vinyl]-1,3,2-dioxaborinane (12 g, 54.05 mmol, 1.1 equiv.), Pd(dppf)Cl in 2H2O (70 mL) and toluene (280 mL) was 2 ·CH 2 Cl 2 (2.0 g, 2.4 mmol, 0.05 equiv.) and Cs 2 CO 3 (48.0 g, 147.4 mmol, 3 equiv.) was added. The mixture was degassed and N 2 The mixture was heated to 90 °C and purged with N 2 The reaction was stirred under ambient atmosphere for 16 h. The reaction was cooled to 20° C., diluted with water (200 mL), filtered, and the filter cake was rinsed with EtOAc (50 mL×3). The combined filtrate was then extracted with EtOAc (200 mL×3). The combined organics were washed with brine (50 mL) and diluted with Na 2 SO 4 The mixture was dried at 40° C., filtered, concentrated under reduced pressure, and the resulting residue was purified by flash column chromatography on silica gel (eluting with 5% EtOAc in petroleum ether) to give Intermediate 52.3. LC / MS: 438.0 [M+H].

[0425] Preparation of Intermediate 52.4 (6-Bromo-5-fluoro-1-tosyl-3-(trifluoromethyl)indoline): To a solution of Intermediate 52.3 (8.3 g, 18.9 mmol, 1 equiv) in DMF (80 mL) was added DBU (864.9 mg, 5.6 mmol, 856.4 uL, 0.3 equiv) and the mixture was stirred at 120° C. for 1 h. The reaction was cooled to 20° C., quenched with water (100 mL), and extracted with ethyl acetate (150 mL×3). The combined organics were washed with water (100 mL×3), brine (100 mL), and diluted with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel (eluting with 7% EtOAc in petroleum ether) to give Intermediate 52.4. LC / MS: 438.0 [M+H].

[0426] Preparation of intermediate 52.5 (6-(benzylthio)-5-fluoro-1-tosyl-3-(trifluoromethyl)indoline): A solution of intermediate 52.4 (6.2 g, 14.3 mmol, 1 equiv.) in dioxane (80 mL) was added to Pd 2 (dba) 3 (524.0 mg, 572.3 umol, 0.04 equiv), Xantphos (662.2 mg, 1.1 mmol, 0.08 equiv), DIEA (3.7 g, 28.6 mmol, 4.9 mL, 2 equiv), and BnSH (1.8 g, 15.0 mmol, 1.7 mL, 1.05 equiv) were added. The mixture was degassed and flushed with N 2 The mixture was heated to 100 °C and purged with N 2 The mixture was stirred under atmospheric pressure for 16 h. The reaction mixture was cooled to room temperature, quenched with water (80 mL) and extracted with ethyl acetate (100 mL×3). The combined organics were washed with brine (50 mL) and diluted with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel (eluting with 10% EtOAc in petroleum ether) to give intermediate 52.5. LC / MS: 482.1 [M+H].

[0427] Preparation of intermediate 52.6 (5-fluoro-1-tosyl-3-(trifluoromethyl)indoline-6-sulfonyl chloride): Dissolve intermediate 52.5 (5.5 g, 11.4 mmol, 1 equiv.) in AcOH (60 mL) and H 2 To a solution in 200 (20 mL) was added NCS (4.6 g, 34.4 mmol, 3 equiv.) in small portions. The mixture was stirred at 20° C. for 16 h. The reaction was quenched with water (50 mL) and extracted with ethyl acetate (50 mL×3). The combined organics were washed with brine (30 mL) and diluted with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel (eluting with 15% EtOAc in petroleum ether) to give intermediate 52.6. LC / MS: 458.0 [M+H].

[0428] Preparation of Intermediate 52.7 (5-Fluoro-1-tosyl-3-(trifluoromethyl)indoline-6-sulfonamide): Mix Intermediate 52.6 (4.5 g, 9.8 mmol, 1 equiv.) and NH 3 H 2 A solution of O (22.9 g, 196.5 mmol, 25.2 mL, 30% purity, 20 equiv) in THF (45 mL) was stirred at 20° C. for 2 h. The mixture was concentrated under reduced pressure to give intermediate 52.7, which was used in the next step without purification. LC / MS: 439.0 [M+H].

[0429] Preparation of intermediate 52 (5-fluoro-3-(trifluoromethyl)indoline-6-sulfonamide): A mixture of Mg (6.2 g, 256.1 mmol, 31.2 equiv.) in MeOH (280 mL) was reacted with H 2 The mixture was stirred at 20° C. until the formation of was observed. Then, a solution of intermediate 52.7 (3.6 g, 8.2 mmol, 1 equiv) in MeOH (35 mL) was added dropwise to the mixture. The mixture was stirred at 20° C. for 3 h. The reaction was diluted with saturated NH 4 The mixture was quenched with aqueous Cl (300 mL) and extracted with DCM (300 mL x 5). The combined organics were washed with brine (100 mL) and diluted with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel (eluted with 40% EtOAc in petroleum ether) to give intermediate 52. LC / MS: 285.0 [M+H].

[0430] Intermediate 52 was subjected to chiral SFC separation using a ChiralPak IH, 250×30 mm, 10 um. Mobile phase: 0.1% NH 3 with 33% MeOH. The first eluent was collected and concentrated to give (S)-intermediate 52. LC / MS: 285.0 [M+H]. The second eluent was collected and concentrated to give (R)-intermediate 52. LC / MS: 285.0 [M+H].

[0431] Example 138 Preparation of (S)-5-fluoro-1-((1R,2S)-1-methyl-5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)-3-(trifluoromethyl)indoline-6-sulfonamide: [ka] Example 138 was prepared in a similar manner to Example 92 using (S)-Intermediate 52 and Intermediate 38.3 as starting materials. 1 H NMR(400 MHz,DMSO-d6)δ 8.70(ddd,J=6.7,4.2,2.8 Hz,2H),8.03(d,J=4.2 Hz,2H),7.93(d,J=8.3 Hz,2H),7.73(s,2H),7.61-7.43(m,2H),7.38(d,J=7.8 Hz,1H),4.86-4.40(m,3H),3.74-3.61(m,1H),3.51-3.34(m,2H),3.07(dd,J=14.7,7.1 Hz,1H),1.38(d,J=6.9 Hz,3H).LC / MS:520.2[M+H].

[0432] Example 139 Preparation of (R)-5-fluoro-1-((1R,2S)-1-methyl-5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)-3-(trifluoromethyl)indoline-6-sulfonamide: [ka] Example 139 was prepared in a similar manner to Example 92 using (R)-Intermediate 52 and Intermediate 38.3 as starting materials. 1 H NMR(400 MHz,DMSO-d6)δ 8.75-8.65(m,2H),8.02(d,J=3.8 Hz,2H),7.96-7.88(m,2H),7.73(s,2H),7.61-7.32(m,3H),4.81-4.43(m ,3H),3.74-3.61(m,1H)(m,1H),3.50-3.36(m,2H),3.09(tt,J=12.0,5.2 Hz,1H),1.38(d,J=6.9 Hz,3H).LC / MS:520.2[M+H].

[0433] Preparation of intermediate 53: (S)-5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carboxylic acid [ka] Intermediate 53 was obtained as the second eluate of SFC purification of intermediate 2 using a Chiralpak AD-H column with 20% methanol as co-solvent. LC / MS: 238.1 [MH].

[0434] Example 140 (Preparation of (S)-5-fluoro-2-methyl-1-((S)-5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide) [ka] Example 140 was prepared in a similar manner to Example 35 using (S)-Intermediate 21 and Intermediate 53 (General Procedure B). 1 H NMR (400 MHz, DMSO-d 6 )δ 8.71(d,J=5.0 Hz,1H),8.54(d,J=6.6 Hz,1H),8.05(s,1H),7.92(s,1H),7.88(d,J=8.2 Hz,1H),7.58(s,2H),7.50(td,J=5.4,2.6 Hz,1H),7.40(dd,J=12.5,8.8 Hz,2H),4.90(p,J=6.6 Hz,1H),3.56-3.35(m,3H),3.26(dd,J=16.4,8.5 Hz,1H),3.15(dd,J=15.9,7.6 Hz,1H),2.81(d,J=16.9 Hz,1H),1.30(d,J=6.2 Hz,3H).LC / MS:452.0[M+H].

[0435] Preparation of Example 141 ((R)-5-fluoro-2-methyl-1-((S)-5-(pyridin-2-yl)-2,3-dihydro-1H-indene-2-carbonyl)indoline-6-sulfonamide): [ka] Example 141 was prepared in a similar manner to Example 35 using (R)-Intermediate 21 and Intermediate 53 (General Procedure B). 1 H NMR(400 MHz,DMSO-d6)δ 8.68(dd,J=4.8,1.5 Hz,1H),8.54(d,J=6.6 Hz,1H),7.99(dd,J=6.2,1.8 Hz,2H),7.95-7.83(m,2H),7.58(s,2H),7.52-7.33(m,3H),4.91(q,J=7.5,7.0 Hz,1H),3.77-3.31(m,5H),3.42(ddd,J=29.3,16.2,8.2 Hz,2H),3.20(ddd,J=40.2,16.0,8.1 Hz,2H),2.81(d,J=16.9 Hz,1H),1.30(d,J=6.3 Hz,3H).LC / MS:452.1[M+H].

[0436] Biological assays HSV-2 Cellomics Assay Compounds were tested for their ability to inhibit HSV-2 replication by monitoring the expression of HSV protein gD using a high-throughput immunofluorescence-based assay. Ten-dose, 3-fold serial dilutions of compounds were prepared at starting concentrations of 0.2 mM or 2 mM in 100% DMSO. 250 nl of compound was spotted in quadruplicate onto a black collagen-coated 384-well microplate with clear bottom (Greiner catalog number 781956) using a Labcyte ECHO acoustic dispenser. The final starting concentration in the assay was either 1 μM or 10 μM. DMSO (no compound) and pritelivir were included in each microplate as negative and positive controls, respectively.

[0437] ARPE-19 cells (ATCC Catalog No. CRL-2302) were maintained in DMEM / F-12 Glutamax medium (Thermo Fisher Scientific Catalog No. 10565018) supplemented with 10% FBS (Corning Catalog No. 35-011-CV) and 1% penicillin-streptomycin (Cat. No. 30-002-CI). Prior to confluence, cells were transferred to a centrifuge tube and spun at 1000 rpm for 5 minutes. Cells were resuspended in assay medium (DMEM / F-12 Glutamax, 2% FBS, 1% penicillin-streptomycin) and counted. Cell density was adjusted to 150,000 cells / ml and infected with HSV-2 virus (MS strain, ATCC Catalog No. VR-540) at an MOI of 0.06 in a 50 ml conical tube for 1 hour under constant rocking. The cells were then spun at 1000 rpm for 5 minutes and the medium was replaced with assay medium containing either 2% FBS or 10% human serum (EMD Millipore Cat. No. S1-100ML). 50 μl of infection suspension was added to compound pre-spotted microplate wells (7,500 cells per well). Plates were incubated at 37° C. for 16 hours.

[0438] The cell culture medium was aspirated using a Biomek Fx and 50 μl of paraformaldehyde solution (Electron Microscopy Sciences Cat. No. 15712-S) diluted to 4% in DPBS (Corning Cat. No. 21-031-CM) was added per well. After 30 min incubation at room temperature, the plates were washed 4 times with 100 μl / well of PBS using a Biotek plate washer. A 1:500 solution of the primary antibody (anti-HSV gD, Virusys Cat. No. P1103) was prepared in permeabilization buffer (Invitrogen Cat. No. 00-8333-56) and 50 μl was added to the wells. After 1 hour incubation at room temperature, 50 μl of a 1:1000 solution of secondary antibody (Alexa Fluor 488 goat anti-mouse, Thermo Fisher Scientific Catalog No. A11001) and DAPI (Thermo Fisher Scientific Catalog No. 62248) in permeabilization buffer was added to the wells and the plate was incubated for 1 hour at room temperature in the dark. The plate was washed again 4 times and 50 μl of DPBS was added to all wells before sealing the plate with a black adhesive seal. Fluorescence was measured on a Cellomics plate reader.

[0439] Data analysis was performed using Thermo Scientific HCS Studio software. Briefly, cells were identified using DAPI nuclear staining and a threshold was set to filter cells based on shape and size. A second threshold based on green fluorescence intensity (detection of HSV-2 gD) was set to identify HSV-2 infected cells. Data was reported as the mean fluorescence intensity of HSV-2 infected cells. EC50 values ​​were defined as the compound concentration that reduced the mean fluorescence intensity by 50% and were calculated using a sigmoidal dose-response model to generate curve fitting. The EC50 of pritelivir in this assay was 150 nM. Data for specific compounds are reported in Table 1 below. [Table 1-1] [Table 1-2] [Table 1-3]

[0440] MT-4 CC50 assay Compounds were tested in 384-well plates. 18 compounds in duplicate. Compounds were diluted 7-fold, 3-fold in DMSO by Bravo. Assay plates containing 20uL of medium with compound were seeded with 2000 MT-4 cells at 20uL / well by Multi-drop to initiate the assay. Plates were incubated at 37°C for 5 days. On day 6, 40uL of CellTiter Glo was added to each well. Luminescence was read by Victor II. CC 50 The value was defined as the compound concentration causing a 50% decrease in luminescence signal and was calculated using a sigmoidal dose-response model to generate a curve fit. Data for specific compounds are reported in Table 1 above.

[0441] HSV qPCR assay HSV replication in the presence or absence of compounds was measured by qPCR according to the following procedure: DMSO stock compound solutions (1-10 mM) were serially diluted (2.5-fold) in DMSO in clear round-bottom 96-well plates. Compounds were then diluted 1:20 in assay medium (DMEM / F12 Glutamax+2% fetal bovine serum+1% penicillin-streptomycin) and 10 μL of these dilutions were added to 96-well tissue culture plates for final starting concentrations of 0.5-5 μM.

[0442] ARPE-19 cells (ATCC Catalog No. CRL-2302) maintained in growth medium (DMEM / F12 Glutamax+10%FBS+1%Penicillin-Streptomycin) were transferred to a centrifuge tube and spun at 1000 rpm for 5 minutes. Cells were resuspended in assay medium, counted, and cell density was adjusted to 2.8E+05 cells / ml with assay medium. Cells were then infected with HSV-1 (KOS strain, ATCC Catalog No. VR-1493) or HSV-2 virus (MS strain, ATCC Catalog No. VR-540) at MOI 0.05 in a 50 ml conical tube for 1 hour under constant rocking. 90 μL of infection suspension (25,000 cells) was added to the assay plate where the compound was already added. After overnight incubation at 37°C, cell culture medium was removed and cell lysis was performed using the prepGEM Universal kit (MicroGEM Cat. No. PUN1000). Specifically, 100 μL of prepGEM master mix (94.75 μL water, 5 μL buffer, 0.25 μL enzyme stock) was added to each well and the plate was incubated at room temperature for 15 min (last 5 min on a plate shaker). The cell lysates were then transferred to a 96-well PCR-compatible microplate (Applied Biosystems, Cat. No. N8010560). The plate was sealed with a heat-resistant plastic sealer and heated in a thermal cycler using the following conditions: 75°C for 10 min, 95°C for 5 min. Finally, the plate was cooled to room temperature with gentle shaking before proceeding to the qPCR setup.

[0443] qPCR reactions were performed using QuantiNova multiplex PCR kit (Qiagen catalog number 208456) in a total reaction volume of 20 μL. To the wells of a 96-well rapid optical microplate (Applied Biosystems catalog number 4246906) 15 μL of reagent mix (5 μL 4X QuantiNova Master Mix, 0.1 μL QN Rox reference dye, 1 μL 20X HSV primer / probe mix and 8.9 μL PCR grade water) and 5 μL of cell lysate were added. The plate was sealed with a clear sealer, spun down and the qPCR reaction was performed on an Applied Biosystems Quantstudio 7 Flex instrument using the following conditions: 95°C for 2 minutes, then 40 cycles alternating between 95°C for 5 seconds and 60°C for 30 seconds.

[0444] Analysis was performed using the dCT method: dCT = CT (test) - CT (DMSO). Fold changes were calculated as 2^ -dCT The fold change was then converted to a percentage compared to the DMSO control (no drug). The EC50 was determined by nonlinear regression analysis using GraphPad Prism software. [Table 5]

[0445] The EC50 for pritelivir and amenamevir in this assay was both 14 nM. The EC50 for acyclovir was 1250 nM. Data for specific compounds is reported in Table 2 below. [Table 2]

[0446] Carbonic anhydrase (esterase) biochemical assay Compounds were tested in a high-throughput 384-well assay format for their ability to inhibit human carbonic anhydrase (hCA)-mediated hydrolysis of 4-nitrophenyl acetate (4NPA) (Verpoorte et al, JBC, 1967). Ten-dose, 3-fold serial dilutions of compounds were prepared at a starting concentration of 10 mM in 100% DMSO. 200 nl of compound was then spotted in quadruplicate onto clear 384-well microplates (Perkin Elmer catalog number 6007640) using a Labcyte ECHO acoustic dispenser. The final starting concentration in the assay was 50 μM. DMSO (no compound) and acetazolamide were included in each microplate as negative and positive controls, respectively.

[0447] A 1.5 μM solution of hCAI (R&D systems catalog number 2180-CA) or a 1 μM solution of hCAII (Genscript catalog number U3256FL150-4 / P5GA002) was prepared in assay buffer (25 mM Tris pH 7.5, 100 mM NaCl, 1% DMSO) and 20 μl was added to the compounds using a Biotek Micro Flo. After 15 minutes of preincubation at room temperature, the reaction was started by adding 20 μl of a 4 mM solution of 4NPA substrate (Sigma catalog number N8130) in assay buffer. The microplate was incubated for 60 minutes at room temperature after which the absorbance at 405 nM was read on an Envision plate reader. IC50 values ​​were defined as the compound concentration causing a 50% decrease in absorbance signal and were calculated using a sigmoidal dose-response model to generate curve fitting. The IC50 for acetazolamide was 0.04 uM in the hCAII assay and 1.1 uM in the hCAI assay. Data for specific compounds are reported in Table 2 above.

[0448] Plasma stability assay Test compounds were incubated at 2 μM in either rat or human plasma (BioIVT, Westbury, NY) for up to 4 hours at 37° C. At the designated time points, aliquots from the incubations were quenched by the addition of 9 volumes of 100% acetonitrile containing an internal standard. After the final collection, samples were centrifuged at 4500 rpm for 10 minutes and the supernatants were transferred to a new plate containing an equal volume of water for analysis by liquid chromatography coupled to triple quadrupole mass spectrometry (LC-MS / MS). The percentage of test compound remaining in plasma after incubation (peak area ratio of analyte to internal standard) was plotted against incubation time and the plasma half-life (t1 / 2) was calculated from a linear fit of the natural logarithm of the curve.

[0449] Stability assay for cryopreserved hepatocytes Test compounds were incubated at 1 μM with either rat or human cryopreserved hepatocytes (BioIVT, Westbury, NY) in a 24-well plate format (1 × 10 per well). 6 The samples were incubated at 37°C for up to 6 hours at 1000 x g / mL (cells / mL). At the indicated time points, samples were transferred to a 96-well plate and quenched with two volumes of a solution containing 90% acetonitrile, 10% methanol, 0.1% formic acid, and an internal standard. The sample plate was centrifuged at 3200 rpm for 15 minutes and the supernatant was transferred to a new plate containing half the volume of water. The resulting solution was analyzed by LC-MS / MS. The data (peak area ratio of analyte to internal standard) were plotted on a semi-logarithmic scale and fitted using an exponential fit. Half-lives (t1 / 2) and metabolic rates were determined assuming first-order kinetics. Predicted hepatic clearance was calculated from the half-lives using a well-stirred model. Data for specific compounds are reported in Table 3 below. [Table 3]

[0450] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0451] Thus, although the present disclosure has been specifically disclosed in terms of preferred embodiments, it is to be understood that optional features, modifications, improvements, and variations of the disclosure embodied herein disclosed herein may be utilized by those skilled in the art, and such modifications, improvements, and variations are deemed to be within the scope of the present disclosure. The materials, methods, and examples provided herein are representative of preferred embodiments, are illustrative, and are not intended as limitations on the scope of the present disclosure.

[0452] The present disclosure has been described broadly and generically herein. Each of the narrower species and subgeneric groupings falling within the generic disclosure also form part of the present disclosure. This includes the general description of the present disclosure with any conditional or negative limitation removing any subject matter from the genus, regardless of whether the excised material is specifically set forth herein.

[0453] Additionally, when features or aspects of the disclosure are described in terms of a Markush group, those skilled in the art will recognize that the disclosure is thereby also described in terms of any individual member or subgroup of members of the Markush group.

[0454] While the present disclosure has been described in conjunction with the above embodiments, it should be understood that the foregoing description and examples are intended to be illustrative and not limiting of the scope of the present disclosure. Other aspects, advantages, and modifications within the scope of the present disclosure will be apparent to those skilled in the art to which this disclosure pertains.

Claims

1. Compounds of formula (I): 【Chemistry 1】 、 or a pharma- ceutically acceptable salt thereof, wherein: R １ but, 【Chemistry 2】 and R ２ａ , R ２ｂ , and R ２ｃ are each independently H, a halogen, or C １～６ Alkyl, C １～６ Haloalkyl, C １～６ Alkoxy, -CN, C １～６ Haloalkoxy, or -SCF ３ and R ３ａ and R ３ｂ are each independently H, a halogen, or C １～６ Alkyl or C １～６ Is it a haloalkyl? Or R ３ａ and R ３ｂ together with the carbon to which they are attached, C ３～６ Form a cycloalkyl, R ３ａ and R ３ｂ The cycloalkyl formed from the formula (I) may be the same or different and may have 1 to 3 Z ３ and optionally substituted with X ａ and X ｂ each independently represents O or CR ７ａ R ７ｂ and R ７ａ and R ７ｂ are each independently H, C １～６ Alkyl or C １～６ Is it a haloalkyl? Or R ７ａ and R ７ｂ together with the carbon to which they are attached, C ３～６ Form a cycloalkyl, R ７ａ and R ７ｂ The C formed from ３～６ Cycloalkyl may be the same or different and may have 1 to 3 Z ７ and optionally substituted with R ４ａ , R ４ｂ , and R ４ｃ are each independently H, a halogen, or C １～６ Alkyl, C １～６ Haloalkyl, C １～６ Alkoxy, -CN, -SCF ３ , or Z ４ C optionally substituted with ３～６ is cycloalkyl, R ５ But, C ６～１０ aryl or heteroaryl; R ５ The aryl or heteroaryl may be the same or different, and may be 1 to 3 Z ５ and R is optionally substituted with ５ wherein the heteroaryl is a 5- to 10-membered heteroaryl having 1 to 3 heteroatoms, each of which is independently N, O, or S; R ６ But, H, C １～６ Alkyl, C １～６ Haloalkyl, C ２～８ Alkoxyalkyl, or C ３～６ cycloalkyl, R ６ The cycloalkyl is selected from the group consisting of 1 to 3 Z ６ and optionally substituted with Each Z ３ , Z ４ , Z ５ , Z ６ , and Z ７ are independently halogen, -CN, C １～６ Alkyl, C １～６ Haloalkyl, C １～６ Alkoxy or C １～６ A compound, or a pharma- ceutically acceptable salt thereof, which is haloalkoxy.

2. The compound according to claim 1, wherein the compound of formula (I) is represented by formula (IIa): 【Chemistry 3】

3. The compound according to claim 1 or 2, wherein the compound of formula (I) is represented by formula (IIb): or a pharma- ceutically acceptable salt thereof. 【Chemistry 4】

4. The compound according to claim 1, wherein the compound of formula (I) is represented by formula (IIc): 【Chemistry 5】

5. The compound according to claim 1 or 4, wherein the compound of formula (I) is represented by formula (IId): or a pharma- ceutically acceptable salt thereof. 【Chemistry 6】

6. The compound of formula (I) is represented by formula (IIe): 【Chemistry 7】 In the formula, R ７ａ１ and R ７ｂ１ are each independently H, C １～６ Alkyl or C １～６ haloalkyl or R ７ａ１ and R ７ｂ１ together with the carbon to which they are attached, C ３～６ Form a cycloalkyl, R ７ａ１ and R ７ｂ１ The C formed from ３～６ Cycloalkyl may be the same or different and may have 1 to 3 Z ７ 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, optionally substituted with:

7. The compound according to claim 6, wherein the compound of formula (I) is represented by formula (IIf): or a pharma- ceutically acceptable salt thereof. 【Chemistry 8】

8. 【Fig. 9】 8. The compound according to any one of claims 1 to 7, wherein:

9. R １ but, 【Chemistry 10】 9. The compound according to any one of claims 1 to 8, wherein:

10. R １ but, 【Chemistry 11】 9. The compound according to any one of claims 1 to 8, wherein:

11. R ２ａ The compound according to any one of claims 1 to 10, wherein is H, or a pharma- ceutically acceptable salt thereof.

12. R ２ａ is halogen or C １～６ The compound according to any one of claims 1 to 10, or a pharma- ceutically acceptable salt thereof, wherein R is an alkyl group.

13. R ２ｂ The compound according to any one of claims 1 to 12, wherein is H, or a pharma- ceutically acceptable salt thereof.

14. R ２ｂ The compound according to any one of claims 1 to 12, or a pharma- ceutically acceptable salt thereof, wherein is halogen.

15. R ２ｂ The compound according to any one of claims 1 to 12 and 14, or a pharma- ceutically acceptable salt thereof, wherein is F, Cl, or Br.

16. R ２ｂ The compound according to any one of claims 1 to 12, 14, and 15, wherein is F, or a pharma- ceutically acceptable salt thereof.

17. R ２ｃ is H; or a pharma- ceutically acceptable salt thereof.

18. R ２ｃ is halogen or C １～６ 17. The compound of any one of claims 1 to 16, or a pharma- ceutically acceptable salt thereof, wherein: R is an alkyl group;

19. R ２ｃ The compound according to any one of claims 1 to 16 and 18, wherein is F, or a pharma- ceutically acceptable salt thereof.

20. R ３ａ is H; or a pharma- ceutically acceptable salt thereof.

21. R ３ａ But, C １～６ 20. The compound of any one of claims 1 to 19, or a pharma- ceutically acceptable salt thereof, wherein R is an alkyl group.

22. R ３ｂ is H; or a pharma- ceutically acceptable salt thereof.

23. R ３ｂ But, C １～６ 22. The compound of any one of claims 1 to 21, or a pharma- ceutically acceptable salt thereof, which is alkyl.

24. R ３ａ and R ３ｂ together with the carbon to which they are attached, C ３～６ 22. The compound according to any one of claims 1 to 21, or a pharma- ceutically acceptable salt thereof, which forms a cycloalkyl.

25. R ４ａ is H; or a pharma- ceutically acceptable salt thereof.

26. R ４ａ The compound according to any one of claims 1 to 24, or a pharma- ceutically acceptable salt thereof, wherein is halogen.

27. R ４ｂ is H; or a pharma- ceutically acceptable salt thereof.

28. R ４ｂ The compound according to any one of claims 1 to 26, or a pharma- ceutically acceptable salt thereof, wherein is halogen.

29. R ４ｃ is H; or a pharma- ceutically acceptable salt thereof.

30. R ４ｃ The compound according to any one of claims 1 to 28, or a pharma- ceutically acceptable salt thereof, wherein is halogen.

31. R ５ is 1 to 3 Z which may be the same or different; ５ C optionally substituted with ６～１０ aryl, and each Z ５ are independently halogen, -CN, C １～６ Alkyl, or C １～６ 31. The compound of any one of claims 1 to 30, or a pharma- ceutically acceptable salt thereof, which is haloalkyl.

32. R ５ But phenyl, 【Chemistry 12】 32. The compound according to any one of claims 1 to 31, wherein:

33. R ５ is heteroaryl, R ５ The heteroaryl of the formula (I) is selected from the group consisting of 1 to 3 Z ５ 31. The compound according to any one of claims 1 to 30, or a pharma- ceutically acceptable salt thereof, optionally substituted with

34. R ５ is a heteroaryl selected from thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrrolyl, pyrazolyl, triazolyl, pyridyl, pyrazinyl, and pyrimidinyl; R ５ The heteroaryl of the formula (I) is selected from the group consisting of 1 to 3 Z ５ 34. The compound according to any one of claims 1 to 30 and 33, or a pharma- ceutically acceptable salt thereof, optionally substituted with

35. R ５ is 1 to 3 Z which may be the same or different; ５ 35. The compound of any one of claims 1 to 30, 33, and 34, which is pyridyl optionally substituted with: or a pharma- ceutically acceptable salt thereof.

36. R ５ But halogen, C １～３ Alkyl, -CN, or -OCH ３ 36. The compound of any one of claims 1 to 30 and 33 to 35, which is pyridyl optionally substituted with

37. R ５ But pyridyl, 【Chemistry 13】 37. The compound according to any one of claims 1 to 30 and 33 to 36, wherein:

38. R ５ but, 【Chemistry 14】 38. The compound according to any one of claims 1 to 30 and 33 to 37, wherein:

39. R ５ But halogen, C １～３ Alkyl, -CN, or -OCH ３ 35. The compound of any one of claims 1 to 30, 33, and 34, which is diazinyl optionally substituted with, or a pharma- ceutically acceptable salt thereof.

40. R ５ but, 【Chemistry 15】 40. The compound according to any one of claims 1 to 30, 33, 34, and 39, which is: or a pharma- ceutically acceptable salt thereof.

41. R ５ is triazolyl or pyrazolyl, and the triazolyl or pyrazolyl is halogen, —CN, C １～３ Alkyl, or -OCH ３ 35. The compound of any one of claims 1 to 30, 33, and 34, optionally substituted with:

42. R ５ but, 【Chemistry 16】 42. The compound according to any one of claims 1 to 30, 33, 34, and 41, which is: or a pharma- ceutically acceptable salt thereof.

43. R ５ is thiazolyl, isothiazolyl, oxazolyl, or isoxazolyl; R ５ The thiazolyl, isothiazolyl, oxazolyl and isoxazolyl are each independently selected from halogen, C １～３ Alkyl, -CN, or -OCH ３ 35. The compound of any one of claims 1 to 30, 33, and 34, optionally substituted with:

44. R ５ but, 【Chemistry 17】 44. The compound according to any one of claims 1 to 30, 33, 34, and 43, or a pharma- ceutically acceptable salt thereof.

45. R ７ａ and R ７ｂ are each independently H or C １～６ 45. The compound of any one of claims 1 to 44, or a pharma- ceutically acceptable salt thereof, which is alkyl.

46. R ７ａ is H; or a pharma- ceutically acceptable salt thereof.

47. R ７ａ But, C １～３ 46. ​​The compound of any one of claims 1 to 45, or a pharma- ceutically acceptable salt thereof, wherein: R is an alkyl group;

48. R ７ｂ is H; or a pharma- ceutically acceptable salt thereof.

49. R ７ｂ But, C １～３ 48. The compound of any one of claims 1 to 47, or a pharma- ceutically acceptable salt thereof, wherein: R is an alkyl group;

50. R ７ｂ But -CH ３ 48. The compound according to any one of claims 1 to 47, wherein:

51. R ７ａ１ and R ７ｂ１ are each independently H or C １～６ 51. The compound of any one of claims 1, 6 to 50, or a pharma- ceutically acceptable salt thereof, wherein: R is an alkyl group;

52. R ７ａ１ or a pharma- ceutically acceptable salt thereof. The compound according to any one of claims 6 to 51, wherein

53. R ７ａ１ But, C １～３ 52. The compound of any one of claims 6 to 51, or a pharma- ceutically acceptable salt thereof, which is alkyl.

54. R ７ｂ１ or a pharma- ceutically acceptable salt thereof. The compound according to any one of claims 6 to 53, wherein

55. R ７ｂ１ But, C １～３ 54. The compound of any one of claims 6 to 53, or a pharma- ceutically acceptable salt thereof, which is alkyl.

56. R ７ｂ１ But -CH ３ 54. The compound according to any one of claims 6 to 53, wherein:

57. X ａ and X ｂ is O; or a pharma- ceutically acceptable salt thereof.

58. R ６ is H; or a pharma- ceutically acceptable salt thereof.

59. R ６ But, C １～６ Alkyl or C １～６ 58. The compound of any one of claims 1 to 57, or a pharma- ceutically acceptable salt thereof, which is haloalkyl.

60. R ６ is —CH optionally substituted with 1 to 3 halo ３ 60. The compound of any one of claims 1 to 57 and 59, which is: or a pharma- ceutically acceptable salt thereof.

61. R ６ But -CH ３ , -CHF ２ , -CH ２ F, -CF ３ , -CHCl ２ , or -CH ２ 61. The compound of any one of claims 1 to 57, 59, and 60, wherein R is C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, C25, C26, C2

62. R ６ But -CH ３ 62. The compound according to any one of claims 1 to 57 and 59 to 61, which is: or a pharma- ceutically acceptable salt thereof.

63. 【Fig. 18-1】 【Chemistry 18-2】 【Chemistry 18-3】 【Chemistry 18-4】 or a pharma- ceutically acceptable salt thereof.

64. 【Fig. 19-1】 【Chemistry 19-2】 【Chemistry 19-3】 A compound selected from or a pharma- ceutically acceptable salt thereof.

65. A compound selected from Examples 1 to 20, 22 to 29, 31, 33 to 41, 43 to 53, 56 to 65, 68 to 83, 85 to 119, 123, and 125 to 141, or a pharma- ceutically acceptable salt thereof.

66. A compound selected from Examples 1-20, 22-29, 31, 33-41, 43-53, 56-65, 68-83, 85-119, 123, and 125-141.

67. 67. A pharmaceutical composition comprising a compound according to any one of claims 1 to 66, or a pharma- ceutically acceptable salt thereof, and at least one pharma- ceutically acceptable carrier.

68. 68. The pharmaceutical composition of claim 67, further comprising one, two, three, or four additional therapeutic agents.

69. 69. The pharmaceutical composition of claim 68, wherein the additional therapeutic agent is selected from famciclovir, acyclovir, and valacyclovir.

70. 70. A method of treating a herpes virus infection comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 66, or a pharma- ceutically acceptable salt thereof, or a composition according to any one of claims 67 to 69.

71. 71. The method of claim 70, wherein the method comprises administering any one of claims 1-65, or a pharma- ceutically acceptable salt thereof, or any one of claims 66-68, in combination with one, two, three, or four additional therapeutic agents.

72. 72. The method of claim 70 or 71, wherein the herpes virus is HSV-1 or HSV-2.

73. 70. A method of treating a disorder induced, exacerbated or promoted by a herpes virus, comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 66, or a pharma- ceutically acceptable salt thereof, or a composition according to any one of claims 67 to 69.

74. 74. The method of claim 73, wherein the method comprises administering any one of claims 1-65, or a pharma- ceutically acceptable salt thereof, or any one of claims 66-68, in combination with one, two, three, or four additional therapeutic agents.

75. 75. The method of claim 73 or 74, wherein the disorder is genital herpes, herpes labialis, HSV keratitis, HSV encephalitis, or disseminated HSV.

76. 70. Use of a compound according to any one of claims 1 to 66, or a pharma- ceutically acceptable salt thereof, in the treatment of a viral infection.

77. 67. Use of a compound according to any one of claims 1 to 66, or a pharma- ceutically acceptable salt thereof, in the treatment of a viral infection caused by a herpes virus.

78. 67. Use of a compound according to any one of claims 1 to 66, or a pharma- ceutically acceptable salt thereof, in the treatment of a viral infection caused by HSV-1 or HSV-2.

79. 70. Use of a compound according to any one of claims 1 to 66, or a pharma- ceutically acceptable salt thereof, for the preparation of a medicament for the prophylaxis / treatment of viral infections.

80. 70. Use of a compound according to any one of claims 1 to 66, or a pharma- ceutically acceptable salt thereof, for the preparation of a medicament for the prophylaxis / treatment of viral infections caused by herpes viruses.

81. 67. Use of a compound according to any one of claims 1 to 66, or a pharma- ceutically acceptable salt thereof, for the preparation of a medicament for the prophylaxis / treatment of viral infections caused by HSV-1 or HSV-2.

82. A compound according to any one of claims 1 to 66, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to any one of claims 67 to 69, for use in a method for treating a viral infection caused by HSV-1 or HSV-2.

83. 83. The compound, a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition for use according to claim 82, wherein the viral infection is genital herpes, herpes labialis, HSV keratitis, HSV encephalitis, or disseminated HSV.

84. 84. The compound, or a pharma- ceutically acceptable salt thereof, or pharmaceutical composition for use according to claim 82 or 83, wherein the compound, or a pharma- ceutically acceptable salt thereof, is administered in combination with an additional therapeutic agent.

85. 67. A compound according to any one of claims 1 to 66, or a pharma- ceutically acceptable salt thereof, for use in therapy.

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