Prodrugs of benzimidazol-1,2-YL amide compounds

Abstract

Provided for herein are prodrug compounds of benzimidazol-1,2-yl amide Kv7 activators. Particularly, the prodrug compounds have improved properties for stable formulation for treatment of Kv7 associated disorders, including seizure disorders. Also provided for are pharmaceutical compositions of said prodrug compounds and methods of treatment for seizure disorders including status epilepticus and others.

Description

PRODRUGS OF BENZIMIDAZOL-1,2-YL AMIDE COMPOUNDSCROSS-REFERENCE TO RELATED APPLICATION

[0001] This international application claims priority to U.S. Provisional Patent Application No. 63 / 684,398, filed August 18, 2024, hereby incorporated by reference herein in its entirety.TECHNICAL FIELD OF THE INVENTION

[0002] Provided for herein are prodrug compounds of benzimidazol- 1,2-yl amide Kv7 activators. Particularly, the prodrug compounds have improved properties for stable formulation for treatment of Kv7 associated disorders, including seizure disorders. Also provided for are pharmaceutical compositions of said prodrug compounds and methods of treatment for seizure disorders including status epilepticus and others.BACKGROUND OF THE INVENTION

[0003] The Kv7 subfamily of voltage-gated potassium (K+) channels includes five homologous pore-forming a-subunits denoted Kv7.1 to Kv7.5. These subunits have a structure including 6 transmembrane spanning units (denoted SI to S6) flanked by intracellular N-terminal and C-terminal domains. Subunit S4 includes a voltage-sensor domain having alternating, positively-charged residues and a pore region is located between subunits S5 and S6 of each subunit. Kv7 K+channels are formed as tetramers of Kv7.1 to Kv7.5 a-subunits, either as homotetramers or heterotetramers.

[0004] Neurons are known to express Kv7.2, Kv7.3, Kv7.4, and Kv7.5 a-subunits. Kv7.2 and Kv7.3 are exclusively neuronal while Kv7.4 and Kv7.5 can be found in other tissues such as smooth and skeletal muscle. Of particular interest in the context of neurological diseases are Kv7.2 and Kv7.3, which have a role in resistance to depolarizing excitatory influences. For example, Kv7.2 / Kv7.3 activators such as benzimidazol- 1,2-yl amides among others are described in WO 2014 / 145852 A2, published September 18, 2014 corresponding to PCT / US2014 / 030686, filed March 17, 2014; WO 2018 / 209074 Al, published November 15, 2018 corresponding to PCT / US2018 / 032050, filed May 10, 2018; WO 2016 / 040952 A2, published March 17, 2016 corresponding to PCT / US2015 / 050027, filed September 14, 2015; WO 2018 / 081825 Al, published May 3, 2018 corresponding to PCT / US2017 / 059393, filed October 31, 2017; and WO 2019 / 183148 Al, published September 26, 2019 corresponding to PCT / US2019 / 023039, filed March 19, 2019, the entireties of which are incorporated by130175-101610 / 20289-WO-PCTreference herein. These compounds and others capable of activating Kv7.2 / Kv7.3 have promise as potent anticonvulsants for treatment of epileptic seizures and for treatment of other Kv7 associated diseases. While there is some overlap with epilepsy patients, a different condition known as status epilepticus can place epileptic and non-epileptic patients in continuous or rapidly-succeeding seizures for which current treatments are limited and relatively ineffective. Moreover, patients with status epilepticus face severe risks for death or permanent disability if effective treatment, such as an intravenous, subcutaneous, or other parenteral therapy, is not rendered.

[0005] For patients requiring anticonvulsant treatments, such as in status epilepticus, Kv7.2 / 7.3 activators, including benzimidazol- 1,2-yl amides, may be promising therapeutic compounds. However, these compounds may have unsuitable aqueous solubility for intravenous, subcutaneous, or other parenteral formulation as an anticonvulsant therapy. Provided herein are prodrug compounds having improved or favorable aqueous solubility for intravenous, subcutaneous, or other parenteral administration routes, as well as favorable in vitro and in vivo characteristics for release of the pharmaceutically-active compound.SUMMARY OF THE INVENTION

[0006] Provided for herein are prodrugs of benzimidazol- 1,2-yl amide Kv7 activator compounds. The prodrugs generally contain a cleavable moiety which is removed chemically or enzymatically in vivo to release a pharmaceutically-active Kv7 activator compound. The prodrugs may have improved characteristics such as improved physiochemical properties, improved pharmacological properties, and / or improved toxicity profiles. For example, the prodrugs may advantageously have improved aqueous solubility and stability and may effectively release a pharmaceutically-active Kv7 activator in plasma.

[0007] For example, in an embodiment, the benzimidazol- 1,2-yl amide prodrug may be a compound according to Formula I:or a pharmaceutically acceptable salt thereof, wherein:230175-101610 / 20289-WO-PCTD is C2-C5 alkyl or phenyl, wherein said C2-5 alkyl or phenyl is optionally substituted with one or more substituents independently selected from -CH3 and F;A is Ci-Ce alkyl;X is -H, -F, -CH3, -CF3, -CF2H, -CFH2, -SCF3, pyridinyl, C1-C3 alkyl, phenyl, or cyclobutyl, wherein said C1-C3 alkyl, phenyl, or cyclobutyl is optionally substituted with one or more F; Y is -H, -F, -OH, or -CH3;Q is -SO3H, -SO2R5, -P(=O)(OH)2, -R6-O(P=O)(OH)2, -R6-O(P=O)(OH)-O-R7, -(C=O)- NR8R9, -R6-NR8R9, -R6-O(C=O)-NR8R9, -R6-O(C=O)-R10-R11, -R6-O(C=O)-O-R10-R11, -R6- O(C=O)-O-Rn, -(C=O)-O-Rn, -(C=O)-O-R10-Rn, -(C=O)-Rn, -(C=O)-R10-R1\ -R10-Rn, or -R11;R1is -H, C3-C4 hydroxyalkyl, -CN, -OH, -CF3, -OCHF2, NRARB, halogen, C3-C5 heterocycloalkyl, C1-C7 alkoxy, or C1-C5 alkyl, wherein said C3-C5 heterocycloalkyl C1-C7 alkoxy, or C1-C5 alkyl is optionally substituted with one or more substituents independently selected from -OH and -F;R2is -H, halogen, -CN, -OCH3, -CORA, -CF3, -OCF3, or C1-C2 alkyl, wherein said C1-C2 alkyl is optionally substituted with one or more substituents independently selected from - OCH3 and -CORA;R3is -H, halogen, -CF3, -OCHF2, -OCF3, -OCFH2or -OCH3;R4is -H, halogen, or C3 hydroxyalkyl;R5and R7are each independently Ci-Ce alkyl optionally substituted with one or more substituents independently selected from -OH; =0, and -NH2;R6is methylene optionally substituted with one or more substituents independently selected from C1-C5 alkyl, cyclopropyl, gem-cyclopropyl, and carbonyl, wherein any two C1-C5 alkyl groups, when present, may form a 3-6 membered ring;R8and R9are independently -H, Ci-Ce alkyl, C2-C10 heteroalkyl, phenyl, or C5-C10 heteroaryl, optionally substituted with one or more substituents independently selected from -OH, =0, - NH2, -CH2-O-(C=O)-CH2-RCCI-C6alkyl, Ci-C6heteroalkyl, -(CH2)m-O(P=O)(OH)2, - (CH2)m-OS(=O)2(OH), said one or more substituents of R8or R9optionally further substituted with -OH, Ci-C5alkyl, Ci-C5heteroalkyl, -(CH2)m-O(P=O)(OH)2 or-(CH2)m-OS(=O)2(OH), orR8and R9together with the nitrogen to which they are attached form a C4-C7 cycloalkyl, C4- C7 heterocycloalkyl, or C5-C10 heteroaryl optionally substituted with one or more substituents independently selected from C1-C10 alkyl, C2-C14 heteroalkyl, C4-C7 cycloalkyl or C4-C7 heterocycloalkyl;330175-101610 / 20289-WO-PCTR10is Ci-C5alkyl, -(CH2-CH2-O)n-, -CH2-(CH2-CH2-O)n-, -(CH2)k-C4-C7 cycloalkyl, or -(CH2)k-C4-C? heterocycloalkyl;R11is -H, -OH, C1-C10 alkyl, C2-C10 heteroalkyl, C4-C7 cycloalkyl, C4-C7 heterocycloalkyl, C4-C7 heteroaryl, phenyl, -(CH2)m-O(P=O)(OH)2, -(CH2)m-O(PO3)2-, -(CH2)m-O(P=O)(NH2)2,NH(CH3), -(CH2)m-N(CH3)2, -NH3+, -N(CH3)£ -N(CH2-CH3)3+, -(CH2)m-O-(C=O)-O-(CH2- CH2-O)n-CH3. and -(CH2)n-RD, optionally substituted with one or more substituents independently selected from -NH2, -(CH2)m-O(P=O)(OH)2, =NH, -NH(CH3), -N(CH3)2, -NH3+, -N(CH3)3+, =0, -OH, Ci-C3alkyl, -(CH2)m0H, -(CH2)mC00H, -(C=O)-O-C-(CH3)3, - (CH2)m-OS(=O)2(OH), -(C=0)-RDor -RD, or whereinwhen R10is -(CH2-CH2-O)n-, k is an integer from 0 to 3; m is an integer from 0 to 3; n is an integer from 0 to 6;RAand RBare -CH3;Rcis Ci-Ce alkyl, Ci-Ce heteroalkyl, C4-C10 cycloalkyl, C4-C10 heterocycloalkyl, phenyl, C5-C10 heteroaryl, or -NR8R9andRDis a monosaccharide or an amino acid including salts thereof.

[0008] In a further embodiment, the benzimidazol- 1,2-yl amide prodrug may be a compound according to Formula II:Formula II,430175-101610 / 20289-WO-PCTor a pharmaceutically acceptable salt thereof, where Q is defined as above in Formula I.

[0009] In a further embodiment, the benzimidazol- 1,2-yl amide prodrug may be a compound according to Formula IV:Formula IV, or a pharmaceutically acceptable salt thereof, wherein:D is C2-C5 alkyl or phenyl, wherein said C2-5 alkyl or phenyl is optionally substituted with one or more substituents independently selected from -CH3 and -F;A is Ci-Ce alkyl;X is -H, -F, -CH3, -CF3, -CF2H, -CFH2, -SCF3, pyridinyl, C1-C3 alkyl, phenyl, or cyclobutyl, wherein said C1-C3 alkyl, phenyl, or cyclobutyl is optionally substituted with one or more -F;Y is -H, -F, -OH, or -CH3;Q is -P(=O)(OH)2, -R6-O(P=O)(OH)2, -R6-O(P=O)(OH)-O-R7, -(C=O)-NR8R9, -R6-NR8R9, -R6-O(C=O)-NR8R9, -R6-O(C=O)-R10-R11, -R6-O(C=O)-O-R10-R11, -R6-O(C=O)-O-Rn, - (C=O)-O-Rn, -(C=O)-O-R10-R11, -(C=O)-Rn, -(C=O)-R10-R1\ -R10-Rn, or -R11;R1is -H, C3-C4 hydroxyalkyl, -CN, -OH, -CF3, -OCHF2, -NRARB, halogen, C3-C5 heterocycloalkyl, C1-C7 alkoxy, or C1-C5 alkyl, wherein said C3-C5 heterocycloalkyl C1-C7 alkoxy, or C1-C5 alkyl is optionally substituted with one or more substituents independently selected from -OH and -F;R2is -H, halogen, -CN, -OCH3, -CORA, -CF3, -OCF3, or C1-C2 alkyl, wherein said C1-C2 alkyl is optionally substituted with one or more substituents independently selected from - OCH3 and -CORA;R3is -H, halogen, -CF3, -OCHF2, -OCF3, -OCFH2or -OCH3;R4is -H, halogen, or C3 hydroxyalkyl;R5and R7are each independently Ci-Ce alkyl optionally substituted with one or more substituents independently selected from -OH; =0, and -NH2;R6is C1-C3 alkylene, preferably methylene, optionally substituted with one or more substituents independently selected from C1-C5 alkyl, cyclopropyl, gem-cyclopropyl, and carbonyl, wherein any two C1-C5 alkyl groups, when present, may form a 3-6 membered ring;530175-101610 / 20289-WO-PCTR8and R9are independently -H, Ci-Ce alkyl, C2-Cio heteroalkyl, phenyl, or Cs-Cioheteroaryl, optionally substituted with one or more substituents independently selected from -OH, =0, - NH2, -CH2-O-(C=O)-CH2-RCCI-C6alkyl, Ci-C6heteroalkyl, -(CH2)m-O(P=O)(OH)2, - (CH2)m-OS(=O)2(OH), said one or more substituents of R8or R9optionally further substituted with -OH, Ci-C5alkyl, Ci-C5heteroalkyl, -(CH2)m-O(P=O)(OH)2or-(CH2)m-OS(=O)2(OH), orR8and R9together with the nitrogen to which they are attached form a C4-C7 cycloalkyl, C4- C7 heterocycloalkyl, or C5-C10 heteroaryl optionally substituted with one or more substituents independently selected from C1-C10 alkyl, C2-Ci4 heteroalkyl, C4-C7 cycloalkyl or C4-C7 heterocycloalkyl;R10is Ci-C5alkyl, -(CH2-CH2-O)n-, -CH2-(CH2-CH2-O)n-, -(CH2)k-C4-C7cycloalkyl, or - (CH2)k-C4-C7 heterocycloalkyl;R11is -H, -OH, C1-C10 alkyl, C2-Cio heteroalkyl, C4-C7 cycloalkyl, C4-C7 heterocycloalkyl, C4-C7 heteroaryl, phenyl, -(CH2)m-O(P=O)(OH)2, -(CH2)m-O(PO3)2-, -(CH2)m-O(P=O)(NH2)2,NH(CH3), -(CH2)m-N(CH3)2, -NH3+, -N(CH3)3+, -N(CH2-CH3)3+, -(CH2)m-O-(C=O)-O-(CH2- CH2-O)n-CH3. and -(CH2)n-RD, optionally substituted with one or more substituents independently selected from -NH2, -(CH2)m-O(P=O)(OH)2, =NH, -NH(CH3), -N(CH3)2, - NH3+, -N(CH3)3+, =0, -OH, -Ci-C3alkyl, -(CH2)m0H, -(CH2)mCOOH, -(C=O)-O-C-(CH3)3, , -(CH2)m-OS(=O)2(OH), -(C=O)-RDor RD, or whereinwhen R10is -(CH2-CH2-O)n-, k is an integer from 0 to 3; m is an integer from 0 to 3; n is an integer from 0 to 6;RAand RBare -CH3;Rcis Ci-Ce alkyl, Ci-Ce heteroalkyl, C4-C10 cycloalkyl, C4-C10 heterocycloalkyl, phenyl, C5-C10 heteroaryl, or -NR8R9and630175-101610 / 20289-WO-PCTRDis a monosaccharide or an amino acid including salts thereof.

[0010] In a further embodiment, the benzimidazol- 1,2-yl amide prodrug may be a compound according to Formula V:or a pharmaceutically acceptable salt thereof, where Q is defined as above in Formula IV.

[0011] In further embodiments, provided for are pharmaceutical compositions comprising a compound according to one or more of Formula I, Formula II, Formula IV, and / or Formula V. Pharmaceutical compositions may comprise one or more excipients for formulation including but not limited to a carrier, surfactant, lubricant, glidant, stabilizer, antioxidant, preservative, binder, diluent, disintegrant, wetting agents, among others. Pharmaceutical compositions may be formulated for various administration routes including but not limited to intravenous, other parenteral, intranasal, inhalant, suppository, oral, and others. Certain formulations include stable aqueous formulations for intravenous administration.

[0012] In further embodiments, provided for are methods of treating a Kv7 associated disorder comprising administration of a compound according to one or more of Formula I, Formula II, Formula IV, and / or Formula V. Kv7 associated disorders may generally be treated by activating Kv7 channels. In particular, the disclosed methods may include treating tinnitus or a seizure disorder comprising administration of a compound according to one or more of I, Formula II, Formula IV, and / or Formula V. In an embodiment, the seizure disorder is any seizure disorder having involvement or association with Kv7 channel activity and particularly those which may be treated or improved by activation of Kv7 channels in the nervous system. In an embodiment, the seizure disorder is an epileptic seizure disorder. In an embodiment, the seizure disorder is a non-epileptic seizure disorder. In an embodiment, the seizure disorder is status epilepticus. In an embodiment, the administration is intravenous or other parenteral administration.

[0013] These and other embodiments should be apparent from the accompanying disclosure. While particular embodiments are described in detail, it should be appreciated that other embodiments within the scope and spirit of the disclosure are contemplated, and elements or730175-101610 / 20289-WO-PCTaspects of the various embodiments are not limited to those particular embodiments but may be combined as additional embodiments.BRIEF DESCRIPTION OF THE DRAWINGS

[0014] Aspects and advantages of the present disclosure will become apparent from the following exemplary embodiments taken in conjunction with the accompanying drawings, of which:

[0015] FIG. 1 depicts mean plasma concentration vs time profiles of formation of pharmaceutically-active compound from exemplary prodrugs in male rats;

[0016] FIG. 2 A depicts a mean plasma concentration vs time profile of formation of pharmaceutically-active compound from exemplary prodrug compound 30 in male dogs;

[0017] FIG. 2B depicts a mean plasma concentration vs time profile of formation of pharmaceutically-active compound from exemplary prodrug compound 56 in male dogs; and

[0018] FIG. 2C depicts a mean plasma concentration vs time profile of formation of pharmaceutically-active compound from exemplary prodrug compound 86 in male dogs.DETAILED DESCRIPTION OF THE INVENTION

[0019] In an aspect, this disclosure provides for prodrugs of amide-bearing Kv7.2 / 7.3 activators. In an aspect, the amide-bearing Kv7.2 / 7.3 activator is a benzimidazol- 1,2-yl amide compound. The Kv7.2 / 7.3 activators may have selectivity for Kv7.2 / 7.3 over Kv7.4 and / or Kv7.5. In further aspects, provided for are methods for treating neurological conditions such as conditions involving convulsions or seizures by administration of a prodrug of a benzimidazol- 1,2-yl amide compound. The benzimidazol- 1,2-yl amide compound prodrugs may have improved aqueous solubility compared with the base compound for intravenous, subcutaneous, or other parenteral administration. In an aspect, the neurological condition is status epilepticus. In further aspects, the neurological condition is tinnitus. In yet further aspects, provided for are aqueous pharmaceutical compositions comprising a prodrug of a benzimidazol- 1,2-yl amide compound, including their use in methods for treating neurological conditions involving convulsions or seizures including but not limited to status epilepticus.

[0020] In an embodiment, the benzimidazol- 1,2-yl amide prodrug is a compound according to Formula I:830175-101610 / 20289-WO-PCTor a pharmaceutically acceptable salt thereof, wherein:D is C2-C5 alkyl or phenyl, wherein said C2-5 alkyl or phenyl is optionally substituted with one or more substituents independently selected from -CH3 and -F;A is Ci-Ce alkyl;X is -H, -F, -CH3, -CF3, -CF2H, -CFH2, -SCF3, pyridinyl, C1-C3 alkyl, phenyl, or cyclobutyl, wherein said C1-C3 alkyl, phenyl, or cyclobutyl is optionally substituted with one or more -F;Y is -H, -F, -OH, or -CH3;Q is -SO3H, -SO2R5, -P(=O)(OH)2, -R6-O(P=O)(OH)2, -R6-O(P=O)(OH)-O-R7, -(C=O)- NR8R9, -R6-NR8R9, -R6-O(C=O)-NR8R9, -R6-O(C=O)-R10-R11, -R6-O(C=O)-O-R10-R11, -R6- O(C=O)-O-Rn, -(C=O)-O-Rn, -(C=O)-O-R10-Rn, -(C=O)-Rn, -(C=O)-R10-R1\ -R10-Rn, or -R11;R1is -H, C3-C4 hydroxyalkyl, -CN, -OH, -CF3, -OCHF2, -NRARB, halogen, C3-C5 heterocycloalkyl, C1-C7 alkoxy, or C1-C5 alkyl, wherein said C3-C5 heterocycloalkyl C1-C7 alkoxy, or C1-C5 alkyl is optionally substituted with one or more substituents independently selected from -OH and -F;R2is -H, halogen, -CN, -OCH3, -CORA, -CF3, -OCF3, or C1-C2 alkyl, wherein said C1-C2 alkyl is optionally substituted with one or more substituents independently selected from - OCH3 and -CORA;R3is -H, halogen, -CF3, -OCHF2, -OCF3, -OCFH2or -OCH3;R4is -H, halogen, or C3 hydroxyalkyl;R5and R7are each independently Ci-Ce alkyl optionally substituted with one or more substituents independently selected from -OH; =0, and -NH2;R6is methylene optionally substituted with one or more substituents independently selected from C1-C5 alkyl, cyclopropyl, gem-cyclopropyl, and carbonyl, wherein any two C1-C5 alkyl groups, when present, may form a 3-6 membered ring;R8and R9are independently -H, Ci-Ce alkyl, C2-C10 heteroalkyl, phenyl, or Cs-Cioheteroaryl, optionally substituted with one or more substituents independently selected from -OH, =0, - NH2, -CH2-O-(C=O)-CH2-RCCI-C6alkyl, Ci-C6heteroalkyl, -(CH2)m-O(P=O)(OH)2, -930175-101610 / 20289-WO-PCT(CH2)m-OS(=O)2(OH), said one or more substituents of R8or R9optionally further substituted with -OH, Ci-C5alkyl, Ci-C5heteroalkyl, -(CH2)m-O(P=O)(OH)2or-(CH2)m-OS(=O)2(OH), orR8and R9together with the nitrogen to which they are attached form a C4-C7 cycloalkyl, C4- C7 heterocycloalkyl, or C5-C10 heteroaryl optionally substituted with one or more substituents independently selected from C1-C10 alkyl, C2-C14 heteroalkyl, C4-C7 cycloalkyl or C4-C7 heterocycloalkyl;R10is Ci-C5alkyl, -(CH2-CH2-O)n-, -CH2-(CH2-CH2-O)n-, -(CH2)k-C4-C7 cycloalkyl, or - (CH2)k-C4-C7 heterocycloalkyl;R11is -H, -OH, C1-C10 alkyl, C2-Cio heteroalkyl, C4-C7 cycloalkyl, C4-C7 heterocycloalkyl, C4-C7 heteroaryl, phenyl, -(CH2)m-O(P=O)(OH)2, -(CH2)m-O(PO3)2-, -(CH2)m-O(P=O)(NH2)2,k is an integer ranging from 0 to 3; m is an integer ranging from 0 to 3; n is an integer ranging from 0 to 6;RAand RBare -CH3;Rcis Ci-Ce alkyl, Ci-Ce heteroalkyl, C4-C10 cycloalkyl, C4-C10 heterocycloalkyl, phenyl, C5-C10 heteroaryl, or -NR8R9andRDis a monosaccharide or an amino acid including salts thereof.

[0021] In an embodiment, R6is substituted with methyl, ethyl, propyl, or butyl.

[0022] In an embodiment, the Ci-Ce heteroalkyl of R8and / or R9is -CH2-CH2-NH21030175-101610 / 20289-WO-PCT

[0023] In an embodiment, the Ci-Ce heteroalkyl of R8and / or R9is -CH2-CH2-OH

[0024] In an embodiment, the C5-C10 heteroaryl of R8and / or R9is pyridyl.

[0025] In an embodiment, R8and / or R9are optionally substituted with a Ci-Ce heteroalkyl selected from the group consisting of -CH2-OH, -CH2-N(CH3)2, -CH2-CH2-N(CH3)2, -CH2- CH2-CH2-N(CH3)2

[0026] In an embodiment, R8and R9together form N-methylpiperazine, piperazine, morpholine, piperidine, or azetidine.

[0027] In an embodiment, the C4-C7 heteroalkyl of R10is -CH2-CH2-S-S-CH2-CH2.

[0028] In an embodiment, the C4-C7 heterocycloalkyl of R10is oxetane.£ lb. ( 'l l.:

[0029] In an alternative embodiment, R10is -(6H2-O)U

[0030] In an embodiment, the Ci-Ce alkyl of R11is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.

[0031] In an embodiment, the C2-C10 heteroalkyl of R11is selected from the group consisting of: -O-CH3, -CH2-O-CH3, -CH2-CH2-O-CH3, -O-CH2-CH3, -CH2-O-CH2-CH3, and -CH2- CH2-O-CH2-CH3

[0032] In an embodiment, the C4-C7 heterocycloalkyl of R11is selected from the group consisting of azetidine, piperazine, morpholine, N-methyl piperidine N-methyl piperazine, and piperidine.

[0033] In an embodiment, the C2-C10 heteroalkyl of R11is -CH2-CH2-S-S-CH2-CH2.

[0034] In an embodiment, the Ci-Ce heteroalkyl of RC is -NH-CH3.

[0035] In an embodiment, the monosaccharide of RDhas the chemical formula CeHnOe.

[0036] In an embodiment, the monosaccharide of RDhas a chemical structure selected from:stereoisomers thereof, and connectivity through any -OH moiety thereof.1130175-101610 / 20289-WO-PCT

[0037] In an embodiment, the amino acid of RDis serine, optionally linked to the prodrug compound at the primary alcohol or amine position.

[0038] In an embodiment, R1is -CN.

[0039] In an embodiment, R2and R3are halogen, optionally -F.

[0040] In an embodiment, R4is selected from -H and -OH. In an embodiment, R4is -H.

[0041] In an embodiment, D is selected from methyl, ethyl, propyl, and butyl.

[0042] In an embodiment, D is selected from isopropyl and tert-butyl. In an embodiment, D is tert-butyl.

[0043] In an embodiment, A is C3 alkyl.

[0044] In an embodiment, X and Y are selected from methyl, ethyl, propyl, and butyl.

[0045] In an embodiment, X and Y are methyl. In an embodiment, X and Y, together with A, form tert-pentyl.

[0046] In an embodiment, the benzimidazol- 1,2-yl amide prodrug is a compound according to Formula II:or a pharmaceutically acceptable salt thereof, wherein:Q is -SO3H, -SO2R5, -P(=O)(OH)2, -R6-O(P=O)(OH)2, -R6-O(P=O)(OH)-O-R7, -(C=O)- NR8R9, -R6-NR8R9, -R6-O(C=O)-NR8R9, -R6-0(C=0)-R10-R11, -R6-0(C=0)-0-R10-R11, -R6- O(C=O)-O-Rn, -(C=O)-O-Rn, -(C=O)-O-R10-Rn, -(C=O)-Rn, -(C=O)-R10-Rn, -R10-Rn, or -R11;R5and R7are each independently Ci-Ce alkyl optionally substituted with one or more substituents independently selected from -OH; =0, and -NH2;R6is methylene optionally substituted with one or more substituents independently selected from C1-C5 alkyl, cyclopropyl, gem-cyclopropyl, and carbonyl, wherein any two C1-C5 alkyl groups, when present, may form a 3-6 membered ring;R8and R9are independently -H, Ci-Ce alkyl, C2-Cio heteroalkyl, phenyl, or Cs-Cioheteroaryl, optionally substituted with one or more substituents independently selected from -OH, =0, - NH2, -CH2-O-(C=O)-CH2-RCCI-C6alkyl, Ci-C6heteroalkyl, -(CH2)m-O(P=O)(OH)2, -1230175-101610 / 20289-WO-PCT(CH2)m-OS(=O)2(OH), said one or more substituents of R8or R9optionally further substituted with -OH, Ci-C5alkyl, Ci-C5heteroalkyl, -(CH2)m-O(P=O)(OH)2or-(CH2)m-OS(=O)2(OH), orR8and R9together with the nitrogen to which they are attached form a C4-C7 cycloalkyl, C4- C7 heterocycloalkyl, or C5-C10 heteroaryl optionally substituted with one or more substituents independently selected from C1-C10 alkyl, C2-C14 heteroalkyl, C4-C7 cycloalkyl or C4-C7 heterocycloalkyl;R10is Ci-C5alkyl, -(CH2-CH2-O)n-, -CH2-(CH2-CH2-O)n-, -(CH2)k-C4-C7 cycloalkyl, or - (CH2)k-C4-C7 heterocycloalkyl;R11is - H, -OH, Ci-C 10 alkyl, C2-Cio heteroalkyl, C4-C7 cycloalkyl, C4-C7 heterocycloalkyl, C4-C7 heteroaryl, phenyl, -(CH2)m-O(P=O)(OH)2, -(CH2)m-O(PO3)2-, -(CH2)m-O(P=O)(NH2)2,k is an integer ranging from 0 to 3; m is an integer ranging from 0 to 3; n is an integer ranging from 0 to 6;Rcis Ci-Ce alkyl, Ci-Ce heteroalkyl, C4-C10 cycloalkyl, C4-C10 heterocycloalkyl, phenyl, C5-C10 heteroaryl, or -NR8R9andRDis a monosaccharide or an amino acid including salts thereof.

[0047] In an embodiment, Q is -R6-O(C=O)-R10-Rnor-R6-O(C=O)-O-R10-R11.

[0048] In an embodiment, Q is -R6-O(C=O)-R10-R11.

[0049] In an embodiment, Q is -R6-O(C=O)-O-R10-R11.1330175-101610 / 20289-WO-PCT

[0050] In an embodiment, R10is selected from -(CH2-CH2-O)n, C1-C5 alkyl, and C4-C7 cycloalkyl.

[0051] In an embodiment, R10is-(CH2-CH2-O)n.

[0052] In an embodiment, n is 2, 3, 4, 5, or 6.

[0053] In an embodiment, n is 2. In an embodiment, n is 3. In an embodiment, n is 4, in an embodiment, n is 5, in an embodiment, n is 6.

[0054] In an embodiment, R10is C1-C5 alkyl. In an embodiment, the C1-C5 alkyl of R10is optionally substituted with one or more R11.

[0055] In an embodiment, the C1-C5 alkyl of R10is -(CH2)-.

[0056] In an embodiment, the C1-C5 alkyl of R10is -(CH2-CH2)-.

[0057] In an embodiment, the C1-C5 alkyl of R10is -(CH2-CH2-CH2)-.

[0058] In an embodiment, the C1-C5 alkyl of R10is -(CH2- CH2-CH2-CH2)-.

[0059] In an embodiment, the C1-C5 alkyl of R10is -(CH2- CH2-CH2-CH2-CH2)-.

[0060] In an embodiment, R10is C4-C7 cycloalkyl. In an embodiment, the C4-C7 cycloalkyl of R10is optionally substituted with one or more R11.

[0061] In an embodiment, the C4-C7 cycloalkyl or R10is cyclohexyl.

[0062] In an embodiment, R11is selected from C1-C10 alkyl, -(CH2)m-O(P=O)(OH)2, -(CH2)m- O(PO3)2’, and C4-C7 heterocycloalkyl.

[0063] In an embodiment, the C1-C10 alkyl of R11is methyl, ethyl, propyl, or butyl.

[0064] In an embodiment, the C1-C10 alkyl of R11is methyl.

[0065] In an embodiment, the C1-C10 alkyl of R11is ethyl.

[0066] In an embodiment, the C1-C10 alkyl of R11is propyl, optionally isopropyl.

[0067] In an embodiment, the C1-C10 alkyl of R11is butyl, optionally tert-butyl.

[0068] In an embodiment, R11is selected from -(CH2)m-O(PO3)2' and m is 0, 1, or 2. In an embodiment, m is 0. In an embodiment, m is 1. In an embodiment, m is 2.

[0069] In an embodiment, R11is C4-C7 heterocycloalkyl. In an embodiment, the C4-C7 heterocycloalkyl is C4 heterocycloalkyl or C5 heterocycloalkyl. In an embodiment, the C4 heterocycloalkyl is azetidine.

[0070] In an embodiment, the C4-C7 heterocycloalkyl1430175-101610 / 20289-WO-PCT

[0071] In an embodiment, the compound is a prodrug of the compound according to FormulaIII:dimethylbutanamide.

[0072] In an embodiment, the compound is selected from the group consisting of the following compounds of Table 1:Table 1: Exemplary Prodrug Compounds1530175-101610 / 20289-WO-PCT1630175-101610 / 20289-WO-PCT1730175-101610 / 20289-WO-PCT1830175-101610 / 20289-WO-PCT1930175-101610 / 20289-WO-PCT2030175-101610 / 20289-WO-PCT2130175-101610 / 20289-WO-PCT30175-101610 / 20289-WO-PCT30175-101610 / 20289-WO-PCT30175-101610 / 20289-WO-PCT30175-101610 / 20289-WO-PCT

[0073] In further embodiments, the benzimidazol- 1,2-yl amide prodrug is a compound according to Formula IV:2630175-101610 / 20289-WO-PCTor a pharmaceutically acceptable salt thereof, wherein:D is C2-C5 alkyl or phenyl, wherein said C2-5 alkyl or phenyl is optionally substituted with one or more substituents independently selected from -CH3 and -F;A is Ci-Ce alkyl;X is -H, -F, -CH3, -CF3, -CF2H, -CFH2, -SCF3, pyridinyl, C1-C3 alkyl, phenyl, or cyclobutyl, wherein said C1-C3 alkyl, phenyl, or cyclobutyl is optionally substituted with one or more -F; Y is -H, -F, -OH, or -CH3;Q is -P(=O)(OH)2, -R6-O(P=O)(OH)2, -R6-O(P=O)(OH)-O-R7, -(C=O)-NR8R9, -R6-NR8R9, - R6-O(C=O)-NR8R9, -R6-0(C=0)-R10-R11, -R6-0(C=0)-0-R10-R11, -R6-O(C=O)-O-Rn, - (C=O)-O-Rn, -(C=O)-O-R10-R11, -(C=O)-Rn, -(C=O)-R10-R1\ -R10-Rn, or -R11;R1is H, C3-C4 hydroxyalkyl, -CN, -OH, -CF3, -OCHF2, NRARB, halogen, C3-C5 heterocycloalkyl, C1-C7 alkoxy, or C1-C5 alkyl, wherein said C3-C5 heterocycloalkyl C1-C7 alkoxy, or C1-C5 alkyl is optionally substituted with one or more substituents independently selected from -OH and -F;R2is H, halogen, -CN, -OCH3, -CORA, -CF3, -OCF3, or C1-C2 alkyl, wherein said C1-C2 alkyl is optionally substituted with one or more substituents independently selected from -OCH3 and -CORA;R3is H, halogen, -CF3, -OCHF2, -OCF3, -OCFH2or -OCH3;R4is H, halogen, or C3 hydroxyalkyl;R5and R7are each independently Ci-Ce alkyl optionally substituted with one or more substituents independently selected from -OH; =0, and -NH2;R6is C1-C3 alkylene, preferably methylene, optionally substituted with one or more substituents independently selected from C1-C5 alkyl, cyclopropyl, gem-cyclopropyl, and carbonyl, wherein any two C1-C5 alkyl groups, when present, may form a 3-6 membered ring; R8and R9are independently -H, Ci-Ce alkyl, C2-C10 heteroalkyl, phenyl, or Cs-Cioheteroaryl, optionally substituted with one or more substituents independently selected from -OH, =0, - NH2, -CH2-O-(C=O)-CH2-RCCI-C6alkyl, Ci-C6heteroalkyl, -(CH2)m-O(P=O)(OH)2, -2730175-101610 / 20289-WO-PCT(CH2)m-OS(=O)2(OH), said one or more substituents of R8or R9optionally further substituted with -OH, Ci-C5alkyl, Ci-C5heteroalkyl, -(CH2)m-O(P=O)(OH)2or-(CH2)m-OS(=O)2(OH), orR8and R9together with the nitrogen to which they are attached form a C4-C7 cycloalkyl, C4- C7 heterocycloalkyl, or C5-C10 heteroaryl optionally substituted with one or more substituents independently selected from C1-C10 alkyl, C2-C14 heteroalkyl, C4-C7 cycloalkyl or C4-C7 heterocycloalkyl;R10is Ci-C5alkyl, -(CH2-CH2-O)n-, -CH2-(CH2-CH2-O)n-, -(CH2)k-C4-C7 cycloalkyl, or - (CH2)k-C4-C7 heterocycloalkyl;R11is -H, -OH, C1-C10 alkyl, C2-Cio heteroalkyl, C4-C7 cycloalkyl, C4-C7 heterocycloalkyl, C4-C7 heteroaryl, phenyl, -(CH2)m-O(P=O)(OH)2, -(CH2)m-O(PO3)2-, -(CH2)m-O(P=O)(NH2)2,k is an integer ranging from 0 to 3; m is an integer ranging from 0 to 3; n is an integer ranging from 0 to 6;RAand RBare -CH3;Rcis Ci-Ce alkyl, Ci-Ce heteroalkyl, C4-C10 cycloalkyl, C4-C10 heterocycloalkyl, phenyl, C5- C10 heteroaryl, or -NR8R9andRDis a monosaccharide or an amino acid including salts thereof.

[0074] In further embodiments, the benzimidazol- 1,2-yl amide prodrug is a compound according to Formula V:2830175-101610 / 20289-WO-PCTQ is -P(=O)(OH)2, -R6-O(P=O)(OH)2, -R6-O(P=O)(OH)-O-R7, -(C=O)-NR8R9, -R6-NR8R9, - R6-O(C=O)-NR8R9, -R6-0(C=0)-R10-R11, -R6-0(C=0)-0-R10-R11, -R6-O(C=O)-O-Rn, - (C=O)-O-Rn, -(C=O)-O-R10-R11, -(C=O)-Rn, -(C=O)-R10-Rn, -R10-Rn, or -R11;R5and R7are each independently Ci-Ce alkyl optionally substituted with one or more substituents independently selected from -OH; =0, and -NH2;R6is C1-C3 alkylene, preferably methylene, optionally substituted with one or more substituents independently selected from C1-C5 alkyl, cyclopropyl, gem-cyclopropyl, and carbonyl, wherein any two C1-C5 alkyl groups, when present, may form a 3-6 membered ring; R8and R9are independently -H, Ci-Ce alkyl, C2-Cio heteroalkyl, phenyl, or Cs-Cioheteroaryl, optionally substituted with one or more substituents independently selected from -OH, =0, - NH2, -CH2-O-(C=O)-CH2-RCCI-C6alkyl, Ci-C6heteroalkyl, -(CH2)m-O(P=O)(OH)2, - (CH2)m-OS(=O)2(OH), said one or more substituents of R8or R9optionally further substituted with -OH, Ci-C5alkyl, Ci-C5heteroalkyl, -(CH2)m-O(P=O)(OH)2or-(CH2)m-OS(=O)2(OH),R8and R9together with the nitrogen to which they are attached form a C4-C7 cycloalkyl, C4- C7 heterocycloalkyl, or C5-C10 heteroaryl optionally substituted with one or more substituents independently selected from C1-C10 alkyl, C2-Ci4 heteroalkyl, C4-C7 cycloalkyl or C4-C7 heterocycloalkyl;R10is Ci-C5alkyl, -(CH2-CH2-O)n-, -CH2-(CH2-CH2-O)n-, -(CH2)k-C4-C7cycloalkyl, or -(CH2)k-C4-C7 heterocycloalkyl;R11is -H, -OH, C1-C10 alkyl, C2-Cio heteroalkyl, C4-C7 cycloalkyl, C4-C7 heterocycloalkyl, C4-C7 heteroaryl, phenyl, -(CH2)m-O(P=O)(OH)2, -(CH2)m-O(PO3)2’, -(CH2)m-O(P=O)(NH2)2,2930175-101610 / 20289-WO-PCTNH(CH3), -(CH2)m-N(CH3)2, -NH3+, -N(CH3)3+, -N(CH2-CH3)3+, -(CH2)m-O-(C=O)-O-(CH2- CH2-O)n-CH3. and -(CH2)n-RD, optionally substituted with one or more substituents independently selected from -NH2, -(CH2)m-O(P=O)(OH)2, =NH, NH(CH3), -N(CH3)2, - NH3+, -N(CH3)3+, =0, -OH, -Ci-C3alkyl, -(CH2)m0H, -(CH2)mCOOH, -(C=O)-O-C-(CH3)3, , -(CH2)m-OS(=O)2(OH), -(C=O)-RDor RD, or whereinwhen R10is -(CH2-CH2-O)n- k is an integer ranging from 0 to 3; m is an integer ranging from 0 to 3; n is an integer ranging from 0 to 6;Rcis Ci-Ce alkyl, Ci-Ce heteroalkyl, C4-C10 cycloalkyl, C4-C10 heterocycloalkyl, phenyl, C5-C10 heteroaryl, or -NR8R9andRDis a monosaccharide or an amino acid including salts thereof.

[0075] In an embodiment, the compound is selected from the group consisting of the following compounds of Table 2:3030175-101610 / 20289-WO-PCT3130175-101610 / 20289-WO-PCT3230175-101610 / 20289-WO-PCT

[0076] In the various embodiments described herein, the compound is a prodrug compound according to Formula I, Formula II, Formula IV, or Formula V. In various embodiments described herein, the compound is a prodrug compound according to Formula I. In various3330175-101610 / 20289-WO-PCTembodiments described herein, the compound is a prodrug compound according to Formula II. In various embodiments described herein, the compound is a prodrug compound according to Formula IV. In various embodiments described herein, the compound is a prodrug compound according to Formula V. In further embodiments, the compound is a prodrug compound according to one or more of Formula I, Formula II, Formula III, and / or Formula IV.

[0077] In this disclosure, where compositions or processes are described as having, including, or comprising specific components or steps, it is contemplated that said compositions or processes also may consist essentially of, or consist of, the recited components or steps. Where a composition or process consists essentially of a number of recited components or steps, it is contemplated that the composition or process may include additional components or steps which are routine or which do not materially alter the composition or process as would be understood by a person of ordinary skill in the art. The order of steps or order for performing certain actions is immaterial so long as the present teachings remain operable. Moreover, two or more steps or actions can be conducted simultaneously.

[0078] The use of the singular herein includes the plural, and the use of the plural includes the singular, unless specifically stated otherwise. In addition, the use of the term “about” before a quantitative value should be taken to include the specific quantitative value itself unless specifically stated otherwise. Where the term “about” is used without any other specific description before a quantitative value, values within 10% of the quantitative value are generally contemplated.

[0079] As used herein, the term “halogen” means chlorine, bromine, fluorine, and iodine. It is specifically contemplated that the term “halogen” may be replaced by any one or more of chlorine, bromine, fluorine, or iodine in any described embodiment.

[0080] As used herein, the symbol and abbreviation “fBu”, such as in a chemical formula or text shorthand, means “tert-butyl” and is represented by the formula:. As used herein, the abbreviation “Me” such as in a chemical formula or text shorthand, means “methyl” and is represented by the formula -CHa. As used herein, the abbreviation “Et” such as in a chemical formula or text shorthand, means “ethyl” and is represented by the formula -3430175-101610 / 20289-WO-PCTCH2-CH3. As used herein, the chemical abbreviation -OPO3H2 represents a phosphate group, having the structure

[0081] As used herein, the term “gem-cyclopropyl” refers to a linking cyclopropyl represented by the structure:. Unless otherwise specified, the gem-cyclopropyl group may be further substituted with methyl, ethyl, halogen, halomethyl (e.g., -CF3), or haloethyl.

[0082] As used herein, the term “alkyl” or refers to straight and branched carbon chains. The term may be preceded by a range of carbon atoms (e.g., C1-C10 alkyl) which means that the straight or branched chain may include from 1 to 10 carbon atoms, not accounting for those which may also be present in a substituent to the carbon chain at any position. It should be appreciated that while a range of atom numbers is given for the purposes of defining embodiments of the present invention, a small number of additional atoms outside of the range (such as one, two, three, or four) may be contemplated in other embodiments of the present invention. Alkyl groups may also contain one or more (e.g., one, two, or three) unsaturations such as double or triple bonds, which may be alternatively referred to as alkenyl or alkynyl groups, respectively. Alkyl groups may generally be substituted at one or more positions to replace a hydrogen atom with a different atom or constituent atom of another group. One example of a substituted alkyl group is “hydroxyalkyl” which contains one or more hydroxyl (-OH) substituents. As would be apparent from the context, in some cases “alkyl” is also intended to encompass internal linking groups which bridge two substituents. Such internal alkyl linking groups may be alternatively referred to as alkylene groups, which are bivalent saturated aliphatic radicals such as in the context of linking groups. An example of an alkylene group is methylene, i.e., -CH2-.

[0083] As used herein, the term “heteroalkyl” refers to straight and branched carbon chains including at least one heteroatom independently selected from S, N, or O. For example, “C2- C10 heteroalkyl” means linear or branched chain of two to ten atoms where at least one of the atoms is a heteroatom (such as S, N, or O) while the other atoms are carbon. Branched groups may include one or more C or heteroatoms (e.g., methyl, ethyl, propyl, carbonyl, hydroxyl, amine, etc.). In some embodiments, a heteroalkyl may contain one, two, three, or four heteroatoms. It should be appreciated that while a range of atom numbers is given for the purposes of defining embodiments of the present invention, a small number of additional3530175-101610 / 20289-WO-PCTatoms outside of the range (such as one, two, three, or four) may be contemplated in other embodiments of the present invention. Heteroalkyl groups may also contain one or more (e.g., one, two, or three) unsaturations such as double or triple bonds, which may be alternatively referred to as heteroalkenyl or heteroalkynyl groups, respectively. Heteroalkyl groups may generally be substituted at one or more positions to replace a hydrogen atom or lone electron pair with a different atom or constituent atom of another group. One specific type of heteroalkyl is an “alkoxy” group containing one or more oxygen atoms in the chain. As would be apparent from the context, in some cases “heteroalkyl” is also intended to encompass internal linking groups which bridge two substituents.

[0084] As used herein, the term “cycloalkyl” refers to one or more rings of carbon atoms. For example, “C4-C7 cycloalkyl” means one or more rings having between 4 to 7 carbon atoms total (by way of non-limiting example, cyclobutyl having 4 carbon atoms, cyclohexyl having 6 carbon atoms, norbomane having 7 carbon atoms as a bridged ring system, and spiro[2.3]hexane having 6 carbon atoms as a spiro system). It should be appreciated that while a range of atom numbers is given for the purposes of defining embodiments of the present invention, a small number of additional atoms outside of the range (such as one, two, three, or four) may be contemplated in other embodiments of the present invention.Cycloalkyl groups may also contain one or more (e.g., one, two, or three) unsaturations such as double bonds. Cycloalkyl groups may generally be substituted at one or more positions to replace a hydrogen atom with a different atom or constituent atom of another group. As would be apparent from the context, in some cases “cycloalkyl” is also intended to encompass internal linking groups which bridge two substituents.

[0085] As used herein, the term “heterocycloalkyl” refers to one or more rings including at least one heteroatom independently selected from S, N, or O. For example, C4-C7 heterocycloalkyl means one or more rings having between 4 and 7 atoms total, where at least one atom is a heteroatom other than C, such as S, N, or O. In some embodiments, a heterocycloalkyl may contain one, two, three, or four heteroatoms. It should be appreciated that while a range of atom numbers is given for the purposes of defining embodiments of the present invention, a small number of additional atoms outside of the range (such as one, two, three, or four) may be contemplated in other embodiments of the present invention.Heterocycloalkyl groups may also contain phosphorous such as in the group:3630175-101610 / 20289-WO-PCTHeterocycloalkyl groups may also contain one or more (e.g., one, two, or three) unsaturations such as double bonds. Heterocycloalkyl groups may generally be substituted at one or more positions to replace a hydrogen atom or lone electron pair with a different atom or constituent atom of another group. As would be apparent from the context, in some cases “heterocycloalkyl” is also intended to encompass internal linking groups which bridge two substituents.

[0086] As used herein, the term “heteroaryl” means an aromatic ring system including at least one heteroatom independently selected from S, N, or O. Included are unsaturated, aromatic monocyclic rings and unsaturated, polycyclic rings. For example, C5-C10 heteroaryl means one or more rings having between 5 and 10 atoms total, where at least one atom is a heteroatom other than C, such as S, N, or O. In some embodiments, a heteroaryl may contain one, two, three, or four heteroatoms. It should be appreciated that while a range of atom numbers is given for the purposes of defining embodiments of the present invention, a small number of additional atoms outside of the range (such as one, two, three, or four) may be contemplated in other embodiments of the present invention. Heteroaryl groups may generally be substituted at one or more positions to replace a hydrogen atom or lone electron pair with a different atom or constituent atom of another group. As would be apparent from the context, in some cases “heteroaryl” is also intended to encompass internal linking groups which bridge two substituents.

[0087] As used herein, the term “compound” or “prodrug compound” includes all enantiomeric forms, diastereomeric forms, stereoisomers, salts, solvates, and esters thereof. Also encompassed are all isotopic variants having natural or enriched isotopic content such as deuterated compounds or other isotopically enriched forms.

[0088] In various embodiments, a number of atoms in a particular group or substituent is denoted by a range (e.g. C1-C10 alkyl). It is specifically intended that each and every individual numbers of atoms in the range are contemplated, as are each and every subcombination of numbers within the ranges. For example “C1-C10” in the context of alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, heteroaryl, and others would include Ci, C2, C3, C4, C5, Ce, C7, C8, C9, and C10 groups, as well as sub-combinations such as C1-C9, Ci-C8, C1-C7, Ci-C6, Ci-C5, C1-C4, C1-C3, C1-C2, C2-C10, C2-C9, C2-C8, C2-C7, C2-C6, C2-C5, C2-C4, C2-C3, C3-C10, C3-C9, C3-C8, C3-C7, C3-C6, C3-C5, C3-C4, C4-C10, C4-C9, C4-C8, C4-C7, C4-C6, c4-c5, C5-Cio, C5-C9, C5-C8, C5-C7, C5-C6, C6-C10, C6-C9, C6-C8, C6-C7, C7-C10, C7-C9, c7-c8, c8- C10, C8-C9, and C9-C10. Other ranges given herein likewise include the individual numbers and all sub-combinations.3730175-101610 / 20289-WO-PCT

[0089] The prodrug compounds described herein may contain one or more chiral centers, and may therefore include optical isomers, i.e. enantiomers, and diastereomers. The compounds may be obtained as racemic mixtures or enantiomerically pure R and S stereoisomers and pharmaceutically acceptable salts thereof. Cis and trans isomers of alkenes and imines or other double-bonded species are also contemplated. Certain stereoisomers may be obtained by standard techniques known in the art such as asymmetric synthesis, diastereomeric recrystallization, kinetic resolution, chromatographic or other separation techniques, etc. Chromatographic techniques may include column chromatography, thin-layer chromatography, and high-performance liquid chromatography (HPLC), and may incorporate chiral columns which generally have a chiral stationary phase. Chromatographic and other separation techniques are well-known in the art and standard procedures may be followed to obtain enantiomerically-pure or diastereomerically-pure compounds.

[0090] Pharmaceutically-acceptable salts of compounds of the present teachings can be formed using organic and inorganic bases, or organic and inorganic acids. Both mono and polyanionic salts, or mono and polycationic salts, are contemplated, depending on the number of charges available on the compound. Suitable salts formed with bases include metal salts, such as alkali metal or alkaline earth metal salts, for example sodium, potassium, or magnesium salts; ammonia salts and organic amine salts, such as those formed with morpholine, thiomorpholine, piperidine, pyrrolidine, a mono-, di- or tri-lower alkylamine (e.g., ethyl-tert-butyl-, diethyl-, diisopropyl-, triethyl-, tributyl-, tert-butyl-, or dimethylpropylamine), or a mono-, di-, or trihydroxy lower alkylamine (e.g., mono-, di- or triethanolamine) or amino acids (e.g. arginine). Specific non-limiting examples of inorganic bases include NaHCC , Na2CO3, KHCO3, K2CO3, CsCO3, LiOH, NaOH, KOH, NaH2PO4, Na2HPO4, and Na3PO4. Internal salts also can be formed. Similarly, when a compound disclosed herein contains a basic moiety, salts can be formed using organic and inorganic acids. For example, salts can be formed from the following acids: acetic, trifluoroacetic, propionic, lactic, benzenesulfonic, benzoic, camphorsulfonic, citric, tartaric, succinic, di chloroacetic, ethenesulfonic, formic, fumaric, gluconic, glutamic, hippuric, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, malonic, mandelic, methanesulfonic, mucic, napthalenesulfonic, nitric, oxalic, pamoic, pantothenic, phosphoric, phthalic, propionic, succinic, sulfuric, tartaric, toluenesulfonic, and camphorsulfonic as well as other known pharmaceutically acceptable acids.

[0091] As used herein, the phrase “Kv7 associated disease” is a disease, disorder, or condition: associated with a mutation in the KCNQ2 gene; associated with a mutation in the3830175-101610 / 20289-WO-PCTKCNQ3 gene; associated with a mutation in the KCNQ4 gene; associated with a mutation in the KCNQ5 gene; associated with genes encoding Kv7 potassium channels; associated with a non-mutated Kv7 potassium channel, but dysfunctional Kv7 potassium channel; associated with the hyperexcitability of cells that are believed to cause the disease, disorder or condition; or a combination thereof. Regardless of causation, these Kv7 associated diseases, disorders or conditions can be treated by the activation of the Kv7 potassium channel, even though the Kv7 potassium channel may not be a direct or indirect cause of the disease, disorder or condition.

[0092] Examples of a “Kv7 associated disease” in relation to a mutation in the KCNQ2 gene include but are not limited to benign familial neonatal seizures (BFNS) or KCNQ2 encephalopathy (also known as KCNQ2 neonatal epileptic encephalopathy). Examples of a Kv7 associated disorder in relation to a mutation in the KCNQ3 gene include but are not limited to BFNS or KCNQ3-related developmental disability. Examples of a Kv7 associated disorder in relation to a mutation in the KCNQ4 gene include but are not limited to autosomal dominant nonsyndromic hearing loss. Examples of a Kv7 associated disorder in relation to a mutation in the KCNQ5 gene include but are not limited to nonsyndromic intellectual disability or epileptic encephalopathy. Examples of a disorder associated with the hyperexcitability of cells that are believed to cause the disease, disorder or condition include but are not limited to focal clonic seizures, generalized tonic-clonic seizures, neuropathic pain, overactive bladder; or smooth muscle disorders, or a combination thereof. The Kv7 activator compounds herein are useful as anticonvulsants for treatment of epileptic seizures or other seizure conditions. For example, Kv7 activators are useful for the treatment of status epilepticus.

[0093] In each of the embodiments disclosed herein, the compositions and methods may be utilized with or on a subject in need of such treatment, which may also be referred to as “in need thereof,” means that the subject has been identified as having a need for the particular method or treatment.

[0094] As used herein, the term “therapeutic” means an agent utilized to treat, combat, ameliorate, or prevent, or any combination thereof, an unwanted condition, disorder or disease of a subject or patient.

[0095] As used herein, the term “patient” and “subject” are interchangeable and may be taken to mean any living organism, which may be treated with compounds of the present invention. As such, the terms “patient” and “subject” may include, but are not limited to, any nonhuman mammal, primate or human. In some embodiments, the “patient” or “subject” is an3930175-101610 / 20289-WO-PCTadult, child, infant, or fetus. In some embodiments, the “patient” or “subject” is a human. In some embodiments, the “patient” or “subject” is a mammal, such as mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, primates, or humans.

[0096] The terms “therapeutically effective amount” or “therapeutic dose” as used herein are interchangeable and may refer to the amount of an active agent or pharmaceutical compound or composition that elicits a clinical, biological or medicinal response in a tissue, system, animal, individual or human that is being sought by a researcher, veterinarian, medical doctor or other clinical professional. A clinical, biological or medical response may include, for example, one or more of the following: (1) preventing a disease, condition or disorder in an individual that may be predisposed to the disease, condition or disorder but does not yet experience or display pathology or symptoms of the disease, condition or disorder, (2) inhibiting a disease, condition or disorder in an individual that is experiencing or displaying the pathology or symptoms of the disease, condition or disorder or arresting further development of the pathology and / or symptoms of the disease, condition or disorder, and (3) ameliorating a disease, condition or disorder in an individual that is experiencing or exhibiting the pathology or symptoms of the disease, condition or disorder or reversing the pathology and / or symptoms experience or exhibited by the individual.

[0097] The terms “treat,” “treated,” or “treating” may be taken to mean prophylaxis of a specific disorder, disease or condition, alleviation of the symptoms associated with a specific disorder, disease or condition and / or prevention of the symptoms associated with a specific disorder, disease or condition. In some embodiments, the term refers to slowing the progression of the disorder, disease or condition or alleviating the symptoms associated with the specific disorder, disease or condition. In some embodiments, the term refers to alleviating the symptoms of a disease or condition. In some disorder, disease or condition. In some embodiments, the term refers to restoring function which was impaired or lost due to a specific disorder, disorder or condition.

[0098] Another aspect of the disclosure is a pharmaceutical composition comprising a compound of Formula I or Formula II with a pharmaceutically acceptable adjuvant, carrier, or diluent. Another aspect of the disclosure is a pharmaceutical composition comprising a compound of Formula IV or Formula V with a pharmaceutically acceptable adjuvant, carrier, or diluent.

[0099] Further aspects of the disclosure are methods for treating a Kv7 associated disorder in a subject in need thereof by administration of a prodrug compound according to Formula I or Formula II. The administration route may be intravenous or other parenteral route, or any other4030175-101610 / 20289-WO-PCTappropriate route. As described herein, prodrug compounds according to Formula I or Formula II have advantageous properties for intravenous formulation including solubility, aqueous stability, and plasma instability, among others, compared to non-prodrug compounds (such as the compound of Formula III) bearing a non-functionalized amide group.

[0100] In some embodiments, the Kv7 associated disorder is tinnitus. Tinnitus affects roughly 10% of the population and results in the debilitating false perception of sounds such as ringing or rushing sounds. Tinnitus is associated with neuronal hyperactivity in the cochlea and reduced Kv7 activity, particularly with respect to Kv7.2 / 3 channel activity. The Kv7 activators herein are useful for the treatment and / or prevention of tinnitus. Provided for are methods for treating tinnitus in a subject in need thereof by administration of a prodrug compound according to Formulae I, II, IV, or V.

[0101] Also provided for are methods for treating a seizure disorder in a subject in need thereof by intravenous administration of a prodrug compound according to Formula I or Formula II. Also provided for are methods for treating status epilepticus in a subject in need thereof by intravenous administration of a prodrug compound according to Formula I or Formula II. In addition to intravenous administration, other parenteral administration routes are contemplated.

[0102] Further aspects of the disclosure are methods for treating a Kv7 associated disorder in a subject in need thereof by administration of a prodrug compound according to Formula IV or Formula V. The administration route may be intravenous or other parenteral route, or any other appropriate route. As described herein, prodrug compounds according to Formula IV or Formula V have advantageous properties for intravenous formulation including solubility, aqueous stability, and plasma instability, among others, compared to non-prodrug compounds (such as the compound of Formula III) bearing a non-functionalized amide group. Also provided for are methods for treating a seizure disorder in a subject in need thereof by intravenous administration of a prodrug compound according to Formula IV or Formula V. Also provided for are methods for treating status epilepticus in a subject in need thereof by intravenous administration of a prodrug compound according to Formula IV or Formula V. In addition to intravenous administration, other parenteral administration routes are contemplated.

[0103] Compounds are generally given as pharmaceutical compositions comprised of a therapeutically effective amount of one or more of a compound of Formula I or II, or Formula IV or Formula V, or pharmaceutically acceptable salt(s) thereof, and a pharmaceutically acceptable carrier, further optionally containing conventional excipients. A therapeutically effective amount is the amount needed to provide a meaningful patient benefit as determined4130175-101610 / 20289-WO-PCTby practitioners in that art. Pharmaceutically acceptable carriers are those conventionally known carriers having acceptable safety profiles. Compositions encompass all common solid and liquid forms including capsules, tablets, lozenges, and powders as well as liquid suspensions, syrups, elixirs, and solutions. Solid compositions may by formed in timed or sustained released formulations. Compositions are made using common formulation techniques and conventional excipients (such as binding and wetting agents) and / or vehicles (such as water and alcohols).

[0104] The disclosure and methods encompass all conventional modes of administration including oral, parenteral, intranasal, sublingual, topical, and transdermal methods. Typically, the daily dose may be 0.01-100 mg / kg body weight daily. Generally, more compound is required orally and less parenterally. The specific dosing regime, however, should be determined by a physician using sound medical judgement.Among other routes of administration, the standard routes of administration described by the FDA are contemplated herein (FDA Routes of Administration; retrieved from the official FDA website). These routes include auricular (otic), buccal, conjunctival, cutaneous, dental, electroosmosis, endocervical, endosinusial, endotracheal, enteral, epidural, extra amniotic, extracorporeal, hemodialysis, infiltration, interstitial, intra-abdominal, intra-amniotic, intraarterial, intra-articular, intrabiliary, intrabronchial, intrabursal, intracardiac, intracartilaginous, intracaudal, intracavernous, intracavitary, intracerebral, intracisternal, intracorneal, intracoronal, dental, intracoronary, intracorporus cavernosum, intradermal, intradiscal, intraductal, intraduodenal, intradural, intraepidermal, intraesophageal, intragastric, intragingival, intraileal, intralesional, intraluminal, intralymphatic, intramedullary, intrameningeal, intramuscular, intraocular, intraovarian, intrapericardial, intraperitoneal, intrapleural, intraprostatic, intrapulmonary, intrasinal, intraspinal, intrasynovial, intratendinous, intratesticular, intrathecal, intrathoracic, intratubular, intratumor, intratympanic, intrauterine, intravascular, intravenous, intravenous bolus, intravenous drip, intraventricular, intravesical, intravitreal, iontophoresis, irrigation, laryngeal, nasal, nasogastric, not applicable, occlusive dressing technique, ophthalmic, oral, oropharyngeal, parenteral, percutaneous, periarticular, peridural, perineural, periodontal, rectal, respiratory (inhalation), retrobulbar, soft tissue, subarachnoid, subconjunctival, subcutaneous, sublingual, submucosal, topical, transdermal, transmucosal, transplacental, transtracheal, transtympanic, ureteral, urethral, and / or vaginal.

[0105] In some embodiments, the route of administration for compounds of Formula I or II may be intravenous or other parenteral. In some embodiments, the route of administration4230175-101610 / 20289-WO-PCTfor compounds of Formula IV or Formula V may be intravenous or other parenteral. In other embodiments, the administration route may be intranasal or inhalant. In other embodiments, the administration route may be oral.

[0106] The formulator will understand that excipients are used primarily to serve in delivering a safe, stable, and functional pharmaceutical, serving not only as part of the overall vehicle for delivery but also as a means for achieving effective absorption by the recipient of the active ingredient. An excipient may fill a role as simple and direct as being an inert filler, or an excipient as used herein may be part of a pH stabilizing system or coating.

[0107] Pharmaceutical compositions may comprise one or more pharmaceutically acceptable carriers, excipients, or diluents. Examples of such carriers are well known to those skilled in the art and can be prepared in accordance with acceptable pharmaceutical procedures, such as, for example, those described in Remington's Pharmaceutical Sciences, 17th edition, ed. Alfonoso R. Gennaro, Mack Publishing Company, Easton, Pa. (1985), the entire disclosure of which is incorporated by reference herein for all purposes. As used herein, “pharmaceutically acceptable” refers to a substance that is acceptable for use in pharmaceutical applications from a toxicological perspective and does not adversely interact with the active ingredient. Accordingly, pharmaceutically acceptable carriers are those that are compatible with the other ingredients in the formulation and are biologically acceptable. Supplementary active ingredients can also be incorporated into the pharmaceutical compositions.

[0108] While parenteral is preferred in some embodiments, compounds of the present teachings can be administered orally or parenterally, neat or in combination with conventional pharmaceutical carriers. Applicable solid carriers can include one or more substances which can also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet-disintegrating agents, or encapsulating materials. Oral formulations containing a compound disclosed herein can comprise any conventionally used oral form, including tablets, capsules, buccal forms, troches, lozenges and oral liquids, suspensions or solutions. In powders, the carrier can be a finely divided solid, which is an admixture with a finely divided compound. In tablets, a compound disclosed herein can be mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired. The powders and tablets can contain up to 99% of the compound.

[0109] Capsules can contain mixtures of one or more compound(s) disclosed herein with inert filler(s) and / or diluent(s) such as pharmaceutically acceptable starches (e.g., corn,4330175-101610 / 20289-WO-PCTpotato or tapioca starch), sugars, artificial sweetening agents, powdered celluloses (e.g., crystalline and microcrystalline celluloses), flours, gelatins, gums, and the like.

[0110] Useful tablet formulations can be made by conventional compression, wet granulation or dry granulation methods and utilize pharmaceutically acceptable diluents, binding agents, lubricants, disintegrants, surface modifying agents (including surfactants), suspending or stabilizing agents, including, but not limited to, magnesium stearate, stearic acid, sodium lauryl sulfate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, microcrystalline cellulose, sodium carboxymethyl cellulose, carboxymethylcellulose calcium, polyvinylpyrrolidine, alginic acid, acacia gum, xanthan gum, sodium citrate, complex silicates, calcium carbonate, glycine, sucrose, sorbitol, dicalcium phosphate, calcium sulfate, lactose, kaolin, mannitol, sodium chloride, low melting waxes, ion exchange resins, benzyl alcohol, eucalyptol, gelatin, limonene, mannitol, menthol, menthone, menthyl acetate, sucralose, and vanillin. Surface modifying agents include nonionic and anionic surface modifying agents. Representative examples of surface modifying agents include, but are not limited to, pol oxamer 188, benzalkonium chloride, calcium stearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters, colloidal silicon dioxide, phosphates, sodium dodecyl sulfate, magnesium aluminum silicate, and triethanolamine. Oral formulations herein can utilize standard delay or time-release formulations to alter the absorption of the compound(s). The oral formulation can also consist of administering a compound disclosed herein in water or fruit juice, containing appropriate solubilizers or emulsifiers as needed.

[0111] Liquid carriers can be used in preparing solutions for oral or parenteral administration (such as intravenous, intramuscular, or other injections), including suspensions, emulsions, syrups, elixirs, and additionally for inhaled delivery. A compound of the present teachings can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, or a mixture of both, or pharmaceutically acceptable oils or fats. The liquid carrier can contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers, and osmo-regulators. Examples of liquid carriers for oral and parenteral administration include, but are not limited to, water (particularly containing additives as described herein, e.g., cellulose derivatives such as a sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols, e.g., glycols) and their derivatives, and oils (e.g., fractionated coconut oil and arachis oil). For parenteral administration, the carrier can be an oily ester such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are used in sterile liquid form compositions for4430175-101610 / 20289-WO-PCTparenteral administration. The liquid carrier for pressurized compositions can be halogenated hydrocarbon or other pharmaceutically acceptable propellants.

[0112] Liquid pharmaceutical compositions, which are sterile solutions or suspensions, can be utilized by, for example, intramuscular, intraperitoneal or subcutaneous injection. Sterile injectable solutions can also be administered intravenously. Compositions for oral administration can be in either liquid or solid form.

[0113] Preferably the pharmaceutical composition is in unit dosage form, for example, as tablets, capsules, powders, solutions, suspensions, emulsions, granules, or suppositories. In such form, the pharmaceutical composition can be further sub-divided to contain appropriate quantities of the compound. The unit dosage forms can be packaged compositions, for example, packeted powders, vials, ampoules, prefilled syringes or sachets containing liquids. Alternatively, the unit dosage form can be a capsule or tablet itself, or it can be the appropriate number of any such compositions in package form. Such doses can be administered in any manner useful in directing the compound(s) to the recipient's bloodstream, including orally, via implants, parenterally (including intravenous, intraperitoneal and subcutaneous injections), rectally, vaginally, and transdermally.

[0114] When administered for the treatment or inhibition of a particular disease state or disorder, it is understood that an effective dosage can vary depending upon the particular compound utilized, the pharmaceutical composition formulated, the mode of administration, and severity of the condition being treated, as well as the various physical factors related to the individual being treated. In therapeutic applications, a compound of the present teachings can be provided to a patient already suffering from a disease in an amount sufficient to cure or at least partially ameliorate the symptoms of the disease and its complications. The dosage to be used in the treatment of a specific individual typically must be subjectively determined by the attending physician. The variables involved include the specific condition and its state as well as the size, age and response pattern of the patient.

[0115] In some cases it may be desirable to administer a compound directly to the airways of the patient, using devices such as, but not limited to, metered dose inhalers, breath- operated inhalers, multidose dry-powder inhalers, pumps, squeeze-actuated nebulized spray dispensers, aerosol dispensers, and aerosol nebulizers. For administration by intranasal or intrabronchial inhalation, the compounds of the present teachings can be formulated into a liquid composition, a solid composition, or an aerosol composition. The liquid composition can include, by way of illustration, one or more compounds of the present teachings dissolved, partially dissolved, or suspended in one or more pharmaceutically acceptable solvents and can4530175-101610 / 20289-WO-PCTbe administered by, for example, a pump or a squeeze-actuated nebulized spray dispenser. The solvents can be, for example, isotonic saline or bacteriostatic water. The solid composition can be, by way of illustration, a powder preparation including one or more compounds of the present teachings intermixed with lactose or other inert powders that are acceptable for intrabronchial use, and can be administered by, for example, an aerosol dispenser or a device that breaks or punctures a capsule encasing the solid composition and delivers the solid composition for inhalation. The aerosol composition can include, by way of illustration, one or more compounds of the present teachings, propellants, surfactants, and co-solvents, and can be administered by, for example, a metered device. The propellants can be a chlorofluorocarbon (CFC), a hydrofluoroalkane (HFA), or other propellants that are physiologically and environmentally acceptable.

[0116] Compounds described herein can be administered parenterally or intraperitoneally. Solutions or suspensions of these compounds or pharmaceutically acceptable salts, hydrates, or esters thereof can be prepared in water suitably mixed with a surfactant such as hydroxyl-propylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations typically contain a preservative to inhibit the growth of microorganisms.

[0117] The pharmaceutical forms suitable for injection can include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In some embodiments, the form can be sterile and its viscosity permits it to flow through a syringe. The form preferably is stable under the conditions of manufacture and storage and can be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.SYNTHETIC SCHEMES

[0118] The following synthetic schemes may be generally followed to prepare compounds of the present disclosure, further in view of the experimental descriptions to follow. It should be appreciated that variations of these schemes are contemplated to produce the various compounds described herein.

[0119] SCHEME 1: Preparation of compounds of the formula (I)4630175-101610 / 20289-WO-PCT

[0120] Compounds described herein can be synthesized according to scheme 1. Step 1 consists of an acylation procedure of an alcohol with chloromethyl chloroformate or derivatives thereof. Step 2 represents the coupling of the chloromethyl derivative with the oxygen or nitrogen of the amide of the aminobenzimidazole heterocycle.

[0121] SCHEME 2: Preparation of compounds of the formula (I)

[0122] Compounds described herein can be synthesized according to scheme 2. Step 1 consists of an activation procedure of a carboxylic acid with an activation agent such as (COC1)2. Step 2 represents the coupling of the activated acid derivative with the oxygen or nitrogen of the amide function of the aminobenzimidazole heterocycle.

[0123] SCHEME 3a: Preparation of compounds of the formula (I)

[0124] Compounds described herein can be synthesized according to scheme 3a. In scheme 3a, “R” may be a substituent as defined by “R8” herein for other structures. Step 1 consists of the coupling of the chloroalkyl derivative with the nitrogen of the amide function of the aminobenzimidazole heterocycle. Step 2 is the deprotection of the protecting group (PG) by classical procedure (For example Boc group with acidic condition like TFA, or Fmoc group by basic condition like piperidine).

[0125] SCHEME 3b: Preparation of compounds of the formula (I)4730175-101610 / 20289-WO-PCT

[0126] Compounds described herein can be synthesized according to scheme 3b.Step 1 consists of the coupling of the chloroalkyl derivative with the nitrogen of the amide function of the aminobenzimidazole heterocycle. Step 2 is the deprotection of the protecting group (PG) by classical procedure (For example Boc group with acidic condition like TFA, or Fmoc group by basic condition like piperidine, silicon group with fluorine source or acidic condition). Step 3 represents an esterification reaction between an alcohol and a carboxylic acid derivatives, activated or not with a coupling agent.

[0127] SCHEME 4: Preparation of compounds of the formula (I)

[0128] Compounds described herein can be synthesized according to scheme 4. Step 1 represents the formation of a phosphate derivative using a phosphorus reagent like phosphorus oxychloride followed by a hydrolysis using water.

[0129] SCHEME 5a: Preparation of compounds of the formula (I)

[0130] Compounds described herein can be synthesized according to scheme 5a. Step 1 consists of an acylation procedure of an amine with chloromethylchloroformate or derivatives thereof. Step 2 represents the coupling of the chloroalkyl derivative with the oxygen or nitrogen of the amide function of the aminobenzimidazole heterocycle.

[0131] SCHEME 5b: Preparation of compounds of the formula (I)4830175-101610 / 20289-WO-PCT

[0132] Compounds described herein can be synthesized according to scheme 5b. Step 1 consists of the coupling of the chloromethyl phenyl carbonate with the nitrogen of the amide of the aminobenzimidazole heterocycle. Step 2 is the reaction of the carbonate with an amine to generate a carbamate.[0

[0134] Compounds described herein can be synthesized according to scheme 6. Step 1 consists of an acylation procedure of a carboxylic acid with a chloroalkyl chlorosulfate. Step 2 represents the coupling of the chloroalkyl derivative with the oxygen or nitrogen of the amide function of the aminobenzimidazole heterocycle. Step 3 is the deprotection of the protecting group (PG) by classical procedure (For example Boc group with acidic condition like TFA, or Fmoc group by basic condition like piperidine).

[0135] SCHEME 7a: Preparation of compounds of the formula (I)

[0136] Compounds described herein can be synthesized according to scheme 7a. Step 1 consists of an activation of an amide function with phosgene or a similar reagent to form an imidoyl chloride intermediate. Step 2 represents the coupling of the imidoyl chloride intermediate with an alcohol to form an imidic acid ester.

[0137] SCHEME 7b: Preparation of compounds of the formula (I)4930175-101610 / 20289-WO-PCT

[0138] Compounds described herein can be synthesized according to scheme 7b. Step 1 consists of an activation of an amide function with phosgene or a similar reagent to form an imidoyl chloride intermediate. Step 2 represents the coupling of the imidoyl chloride intermediate with an alcohol to form an imidic acid ester. Step 3 is the deprotection of the protecting group (PG) by classical procedure (For example Boc group with acidic condition like TFA, or Fmoc group by basic condition like piperidine)

[0139] SCHEME 8: Preparation of compounds of the formula (I)

[0140] Compounds described herein can be synthesized according to scheme 8. Step 1 represents the coupling of the chloroformate derivative with the oxygen or nitrogen of the amide function of the aminobenzimidazole heterocycle.

[0141] SCHEME 9a: Preparation of compounds of the formula (I)5030175-101610 / 20289-WO-PCT

[0142] Compounds described herein can be synthesized according to scheme 9a. Step 1 consists of an acylation procedure of an alcohol with chloroalkyl chloroformate derivatives. Step 2 represents the alkylation of the chloromethyl derivative with the oxygen or nitrogen of the amide function of the aminobenzimidazole heterocycle. The ratio between N and O alkylated products can vary from 0 / 100 to 100 / 0. Step 3 is the deprotection of the protecting group (PG) by classical procedure (For example Boc group with acidic condition like TFA, or Fmoc group by basic condition like piperidine, silicon group with fluorine source or acidic condition). Step 4 is the formation of a phosphate derivative using a phosphorus reagent like phosphorus oxychloride followed by hydrolysis using water. N and O alkylated derivatives can be separated at step 2, 3 or 4.

[0143] SCHEME 9b: Preparation of compounds of the formula (I)

[0144] Compounds described herein can be synthesized according to scheme 9b.Step 1 consists of an alkylation procedure of a carboxylic acid with a chloroalkyl chlorosulfate derivative. Step 2 represents the alkylation of the chloroalkyl derivative with the oxygen or nitrogen of the amide function of the aminobenzimidazole heterocycle. Step 3 is the deprotection of the protecting group (PG) by classical procedure (For example Boc group with acidic condition like TFA, or Fmoc group by basic condition like piperidine, silicon group with fluorine source or acidic condition). Step 4 is the formation of a phosphate derivative using a phosphorus reagent like phosphorus oxychloride followed by a hydrolysis using water.

[0145] SCHEME 9c: Preparation of compounds of the formula (I)

[0146] Compounds described herein can be synthesized according to scheme 9c.Step 1 depicts the sulfonation of alcohol to sulfate derivatives.

[0147] SCHEME 10a: Preparation of compounds of the formula (I)5130175-101610 / 20289-WO-PCT

[0148] Compounds described herein can be synthesized according to scheme 10a. Step 1 consists in an acylation procedure of an alcohol with chloromethylchloroformate or derivatives thereof. Step 2 represents the alkylation of the chloroalkyl derivative with the oxygen or nitrogen of the amide function of the aminobenzimidazole heterocycle. The ratio between N and O alkylated products can vary from 0 / 100 to 100 / 0. Step 3 is the deprotection of the protecting group (PG) by classical procedure (For example Boc group with acidic condition like TFA, or Fmoc group by basic condition like piperidine). The N and O alkylated derivatives can be separated at step 2 or 3.

[0149] SCHEME 10b: Preparation of compounds of the formula (I)

[0150] Compounds described herein can be synthesized according to scheme 10b. Step 1 consists of an acylation procedure of an alcohol with a chloroalkyl chloroformate derivative. Step 2 represents the alkylation of the chloromethyl derivative with the oxygen or nitrogen of the amide function of the aminobenzimidazole heterocycle. The ratio between N and O alkylated products can vary from 0 / 100 to 100 / 0. Step 3 is the deprotection of the protecting group (PG) by classical procedure (For example Boc group with acidic condition like TFA, or Fmoc group by basic condition like piperidine). The N and O alkylated derivatives can be separated at step 2 or 3.

[0151] SCHEME Ila: Preparation of compounds of the formula (I)5230175-101610 / 20289-WO-PCT

[0152] Compounds described herein can be synthesized according to scheme I la. Step 1 consists in an acylation procedure of an alcohol with chloromethylchloroformate or derivatives thereof. Step 2 represents the alkylation of the chloromethyl derivative with the oxygen or nitrogen of the amide function of the aminobenzimidazole heterocycle. The ratio between N and O alkylated products can vary from 0 / 100 to 100 / 0. Step 3 is the deprotection of the protecting group (PG) by classical procedure (for example Boc group with acidic condition like TFA, or Fmoc group by basic condition like piperidine, silicon group with fluorine source or acidic condition). Step 4 is the formation of a cyclic phosphate derivative using a phosphorus reagent like phosphorus oxychloride followed by a hydrolysis using water. The N and O alkylated derivatives can be separated at step 2, 3 or 4.

[0153] SCHEME 11b: Preparation of compounds of the formula (I)5330175-101610 / 20289-WO-PCT

[0154] Compounds described herein can be synthesized according to scheme 11b. Step 1 consists of an acylation procedure of an alcohol with chloromethylchloroformate or derivatives thereof. Step 2 represents the alkylation of the chloromethyl derivative with the oxygen or nitrogen of the amide function of the aminobenzimidazole heterocycle. The ratio between N and O alkylated products can vary from 0 / 100 to 100 / 0. Step 3 is the deprotection of the protecting group (PG) by classical procedure (For example Boc group with acidic condition like TFA, or Fmoc group by basic condition like piperidine, silicon group with fluorine source or acidic condition). Step 4 is the formation of a cyclic phosphate derivative or a bis phosphate derivative using a phosphorus reagent like phosphorus oxychloride followed by a hydrolysis using water. The N and O alkylated derivatives can be separated at step 2, 3 or 4. The ratio between cyclic phosphate and bis phosphate derivatives can vary from 0 / 100 to100 / 0.

[0155] SCHEME 12: Preparation of compounds of the formula (I)

[0156] Compounds described herein can be synthesized according to scheme 12.Step 1 consists of an acylation procedure of an alcohol with chloromethylchloroformate or derivatives thereof. Step 2 represents the alkylation of the chloromethyl derivative with the oxygen or nitrogen of the amide function of the aminobenzimidazole heterocycle. The ratio between N and O alkylated products can vary from 0 / 100 to 100 / 0. Step 3 is the deprotection of the protecting group (PG) by classical procedure (For example Boc group with acidic condition like TFA, or Fmoc group by basic condition like piperidine, silicon group with fluorine source or acidic condition). Step 4 is the formation of a phosphoramidate derivative using a phosphorus reagent like phosphorus oxychloride followed by adding an amine. The N and O alkylated derivatives can be separated at step 2, 3 or 4.

[0157] SCHEME 13a: Preparation of compounds of the formula (I)5430175-101610 / 20289-WO-PCT

[0158] Compounds described herein can be synthesized according to scheme 13a.Step 1 consists of an acylation procedure of an alcohol with chloromethylchloroformate or derivatives thereof. Step 2 represents the alkylation of the chloromethyl derivative with the nitrogen of the amide function of the aminobenzimidazole heterocycle. Step 3 is the nucleophilic substitution of the bromine atom with the amino function of an amino acid, for example sarcosine.

[0159] SCHEME 13b: Preparation of compounds of the formula (I)

[0160] Compounds described herein can be synthesized according to scheme 13b.Step 1 consists of an acylation procedure of an alcohol with chloromethylchloroformate or derivatives thereof. Step 2 represents the alkylation of the chloromethyl derivative with the nitrogen of the amide function of the aminobenzimidazole heterocycle. Step 3 is the nucleophilic substitution of the bromine atom with the amino function of an amino acid, for example sarcosine.

[0161] SCHEME 14a: Preparation of compounds of the formula (I)

[0162] Compounds described hereinafter can be synthesized according to scheme 14a. Step 1 is an acylation of an alcohol with chloromethylchloroformate or derivatives thereof. Step 2 represents the alkylation of chloromethyl derivative with the nitrogen or oxygen of the amide function of the aminobenzimidazole heterocycle. The ratio between N and O alkylated products can vary from 0 / 100 to 100 / 0. Step 3 is the deprotection of the protecting group (PG) by classical procedure (for example, benzyl group is via Pd-mediated hydrogenation).

[0163] SCHEME 14b: Preparation of building block for Scheme 145530175-101610 / 20289-WO-PCT. ,O-R10-OHPGO'Step-2 PGO y OPGOPG

[0164] Compounds described herein can be synthesized according to scheme 14b. Step 1 is protection of sugar hydroxyls (for example- alkylation with benzyl halide or allyl halide and base). Step 2 represents the selective deprotection of side chain protected hydroxyl moiety (for example- cleavage of silicon group with fluoride source or acidic condition). EXPERIMENTAL

[0165] Synthesis of (2-(((l-(N-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH- benzo[d]imidazol-2-yl)-3,3-dimethylbutanamido)ethoxy)carbonyl) (methyl)amino)pyridin-3-yl)methyl methylglycinate (Cmpd. 25)

[0166] Step-1: (2-((( l-(7V-(l-(tert-butyl)-6-cyano-4,7-difluoro-l H- benzo[d]imidazol-2-yl)-3,3-dimethylbutanamido)ethoxy)carbonyl) (methyl)amino)pyridin-3-yl)methyl \-( / cr / -butoxycarbonyl)- \-methylglycinate (2)

[0167] To a solution of N-( l -( / c / 7-butyl)-6-cyano-4,7-difluoro- I H-benzo[d]imidazol- 2-yl) -3,3-dimethylbutanamide (Formula III) (300 mg, 0.86 mmol) in acetonitrile (8 mL) was added (2-(((l -chi oroethoxy)carbonyl)(methyl)amino)pyri din-3 -yl)methyl N-(tert- butoxycarbonyl)-N-methylglycinate (1, 537 mg, 1.29 mmol) and cesium carbonate (842 mg, 2.58 mmol) at 25 °C. The resulting mixture was stirred at 85 °C for 5 h. Upon completion, as indicated by UPLC, the reaction mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL X 3). The combined organic extract was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure (bath temperature: 35 °C). The crude was purified by flash column chromatography (silica-gel, 230-400) using EtOAc- petroleum ether (10 to 80%) as an eluent to obtain (2-(((l-(A-(l-(terLbutyl)-6-cyano- 4,7-difluoro-lH-benzo[d]imidazol-2-yl)-3,3- dimethylbutanamido)ethoxy)carbonyl)(methyl)amino)pyridin-3-yl)methyl N-(tert- butoxycarbonyl)-A-methylglycinate (2) as a colorless gel (370 mg, 51%). LCMS (ES+): m / z728.3 [M + H]+.5630175-101610 / 20289-WO-PCT

[0168] Step-2: (2-(((l-(N-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH- benzo[d]imidazol-2-yl)-3,3-dimethylbutanamido)ethoxy)carbonyl) (methyl)amino)pyridin-3-yl)methyl methylglycinate (Cmpd. 25)

[0169] To a solution of (2-(((l-(N-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH- benzo[d]imidazol-2-yl)-3,3-dimethylbutanamido)ethoxy)carbonyl)(methyl)amino)pyridin-3- yl)methyl N-(tert-butoxycarbonyl)-N-methylglycinate (2, 350 mg, 0.48 mmol) in DCM (1 mL) was added TFA (274 mg, 5 eq.) at 0 °C. The resulting mixture was stirred at 25 °C for 10 min. Upon completion, as indicated by UPLC, the mixture was neutralized with aq. NaHCCf (10%, 10 mL) and extracted with DCM (15 mL X 2). Combined organic extract was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure (bath temperature: 30 °C). The crude was purified by reverse phase prep HPLC to afford (2-(((l-(N-(l-(tert-butyl)- 6-cyano-4,7-difluoro-lH-benzo[d]imidazol-2-yl)-3,3- dimethylbutanamido)ethoxy)carbonyl)(methyl)amino)pyridin-3-yl)methyl methylglycinate (Cmpd. 25) as an off-white solid (210 mg, 68%). LCMS (ES+): m / z 628.3 [M + H]+.

[0170] Synthesis of (2-((((N-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH- benzo [d] imidazol-2-yl)-3,3- dimethylbutanamido)methoxy)carbonyl)(methyl)amino)pyridin-3-yl)methyl methylglycinate (Cmpd. 55)

[0171] Cmpd. 55 was prepared with an analogous procedure to Cmpd 25, but with (2- (((chloromethoxy)carbonyl)(methyl)amino)pyridin-3-yl)methyl N-(tert-butoxycarbonyl)-N- methylglycinate as the starting material in step 1.

[0172] Synthesis of butvD-6-cvano-4.7-difluoro-lH-benzo[d]imidazol-2-vh-3.3-dimethylbutanamido)methyl (2.5.8J l-tetraoxatridecan-13-yl) carbonate (Cmpd. 30)

[0173] Step-1: Chloromethyl (2,5,8,ll-tetraoxatridecan-13-yl) carbonate (3)

[0174] To a stirred solution of 2,5,8, 11 -tetraoxatridecan- 13 -ol (1) (1 g, 4.80 mmol) inDCM (11 mL) were added pyridine (0.777 mL, 9.60 mmol) and chloromethyl5730175-101610 / 20289-WO-PCTcarbonochloridate (2) (1.24 g, 9.60 mmol) at 0 °C. The reaction was then slowly warmed to ambient temperature and stirred for an hour. After completion of the reaction as indicated by TLC and LCMS-ELSD, the mixture was quenched with 20 mL of water and extracted with DCM (3 x 30 mL). The combined organic phase was washed with aq. HC1 (1 M, 20 mL) followed by brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford chloromethyl (2,5,8, 11 -tetraoxatridecan- 13 -yl) carbonate (3) as colorless oil (1.39 g, crude) which was directly used in the next step without further purification. LCMS (ES+): m / z 301.1 [M + H]+.

[0175] Step-2: Synthesis of (7V-(l-(tert-Butyl)-6-cyano-4,7-difluoro-lH- benzo[d]imidazol-2-yl)-3,3-dimethylbutanamido)methyl (2,5,8,ll-tetraoxatridecan-13- yl) carbonate (Cmpd. 30)

[0176] To a stirred solution of 7V-(l-(terLbutyl)-6-cyano-4,7-difluoro-lH- benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide (Formula III) (800 mg, 2.30 mmol) in acetonitrile (10.0 mL) were added cesium carbonate (1.12 g, 3.44 mmol) and chloromethyl (2,5,8,l l,14-pentaoxahexadecan-16-yl) carbonate (3) (1.04 g, 3.44 mmol) at room temperature. The reaction mixture was stirred at 80 °C for an hour. After completion of the reaction as indicated by UPLC, the mixture was cooled to ambient temperature and quenched with 20 mL of water. The mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic phase was washed with brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude was purified by reverse phase prep-HPLC to afford (A-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH-benzo[d]imidazol-2-yl)-3,3- dimethylbutanamido)methyl (2,5,8, 11 -tetraoxatridecan- 13 -yl) carbonate (Cmpd. 30) as pale yellow gummy liquid (420.5 mg, 30% yield). LCMS (ES+): m / z 613.2 [M + H]+; 557.1 [M - 'Bu + 2H]+

[0177] Synthesis of l-(N-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH- benzo[d]imidazol-2-yl)-3,3-dimethylbutanamido)ethyl (2,5,8,ll-tetraoxatridecan-13-yl) carbonate (Cmpd. 163)

[0178] Cmpd. 163 was prepared with an analogous procedure to that described for Cmpd. 30.

[0179] Synthesis of N-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH-benzo[d]imidazol- 2-yl)-N-(3,3-dimethylbutanoyl)-l-methylpiperidine-4-carboxamide (Cmpd. 51)5830175-101610 / 20289-WO-PCT

[0180] Step-1: l-methylpiperidine-4-carbonyl chloride (2)

[0181] To a stirred solution of l-methylpiperidine-4-carboxylic acid (1, 500 mg, 3.49 mmol) in di chloromethane (10 mL) at 0 °C was added oxalyl chloride (0.397 mL, 4.54 mmol) and a catalytic amount of DMF (2 drops). After stirring at 0 °C for 5 mins, the reaction mixture was heated to 45 °C for 2 h. After completion, as indicated by TLC, the reaction mixture was concentrated under reduced pressure to afford l-methylpiperidine-4-carbonyl chloride (2) (550 mg, crude) as a pale-yellow solid, which was directly used in the next step without further purification.

[0182] Step-2: N-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH-benzo[d]imidazol-2-yl)- N-(3,3-dimethylbutanoyl)-l-methylpiperidine-4-carboxamide (Cmpd. 51):

[0183] To a stirred solution of 7V-(l-(terLbutyl)-6-cyano-4,7-difluoro-lH- benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide (Formula III) (300 mg, 0.86 mmol) in acetonitrile (10 mL) was added cesium carbonate (561 mg, 1.72 mmol) and 1- methylpiperidine-4-carbonyl chloride [2, 209 mg, 1.29 mmol (in 2 mL of acetonitrile and DIPEA (111 mg, 0.86 mmol)] at 0 °C. The reaction mixture was heated to 50 °C for 1 h. Upon completion, as indicated by UPLC, the reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (3 X 10 mL). The organic layer was dried over sodium sulfate, filtered through a cotton plug, and concentrated under reduced pressure. The crude was purified by reverse phase prep HPLC to afford N-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH- benzo[d]imidazol-2-yl)-N-(3,3-dimethylbutanoyl)-l-methylpiperidine-4-carboxamide (Cmpd. 51) as an off-white solid (65 mg, 16%). LCMS (ES+): m / z 474.1 [M + H]+.

[0184] Synthesis of (Z)-(Z)-N-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH- benzo[d]imidazol-2-yl)-3,3-dimethylbutanimidic 2-morpholinoacetic anhydride (Cmpd.61)

[0185] Cmpd 61 was prepared with an analogous procedure to Cmpd. 51 but with 2- morpholinoacetic acid as the starting material in step 1 and 2-morpholinoacetyl chloride as the starting material in step 2.5930175-101610 / 20289-WO-PCT

[0186] Synthesis of \-( l-( / c / 7-Butyl)-6-cvaiio-4.7-diniioro-l H-2-yl)-3,3-dimethylbutanamido)methyl (2-(Dhosphonooxy)ethyl) carbonate (Cmpd. 54)

[0187] [1] Step-1: 2-((tert-Butyldimethylsilyl)oxy)ethyl (chloromethyl) carbonate (3)

[0188] To a stirred solution of 2-((terLbutyldimethylsilyl)oxy)ethan-l-ol (1) (3.0 g, 17.01 mmol) in DCM (15 mL) were added pyridine (2.02 ml, 25.5 mmol) and chloromethyl carbonochloridate (2) (2.63 g, 20.42 mmol) at 0 °C. The reaction was then slowly warmed to ambient temperature and stirred for 2 h. After completion of the reaction as indicated by TLC and LCMS-ELSD, the mixture was quenched with 20 mL of water and extracted with DCM (3 x 20 mL). The combined organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford 2-(( / c / 7-butyldirnethylsilyl)oxy)ethyl (chloromethyl) carbonate (3) as colorless oil (4.6 g, crude) which was directly used in the next step without further purification. LCMS (ES+): m / z 269.0 [M]+.

[0189] Step-2: (7V-(l-(tert-Butyl)-6-cyano-4,7-difluoro-lH-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamido)methyl (2-((tert-butyldimethylsilyl)oxy)ethyl) carbonate (4)

[0190] To a stirred solution of M( l -( / c / 7-butyl)-6-cyano-4,7-difluoro- I H- benzo[d]imidazol-2-yl) -3,3-dimethylbutanamide (Formula III) (600 mg, 1.72 mmol) in acetonitrile (5 mL) were added cesium carbonate (842 mg, 2.58 mmol) and 2-(( / c77- butyldimethylsilyl)oxy)ethyl (chloromethyl) carbonate (3) (1.39 g, 5.17 mmol) at room temperature. The reaction mixture was stirred at 85 °C for 2 h. After completion of the reaction as indicated by UPLC, the mixture was cooled to ambient temperature and quenched with 20 mL of water. The mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The6030175-101610 / 20289-WO-PCTcrude was purified by silica gel (230-400 mesh) chromatography using ethyl acetate / petroleum ether (10-15%) as to afford (A-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH-benzo[d]imidazol-2- yl)-3,3-dimethylbutanamido)methyl (2-(( / c / 7-butyldimethylsilyl)oxy)ethyl) carbonate (4) as colorless gum (300 mg, 28% yield). LCMS (ES+): m / z 581.3 [M + H]+.

[0191] Step-3: (7V-(l-(tert-Butyl)-6-cyano-4,7-difluoro-lH-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamido)methyl (2-hydroxyethyl) carbonate (5)

[0192] To a stirred solution of (A-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH- benzo[d]imidazol-2-yl)-3,3-dimethylbutanamido)methyl (2-(( / c77- butyldimethylsilyl)oxy)ethyl) carbonate (4) (150 mg, 0.258 mmol) in MeOH (1.5 mL) was added / ?-toluenesulfonic acid monohydrate (4.45 mg, 0.026 mmol) at room temperature. The reaction mixture was stirred at room temperature for 2 h. After completion of the reaction as indicated by UPLC, the mixture was quenched with 10% aq. sodium bicarbonate and extracted with DCM (3 x 10 mL). The combined organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure to afford (A-(l -( / c / 7-butyl)-6-cy ano-4, 7-difluoro-lH- benzo[d]imidazol-2-yl)-3,3-dimethylbutanamido)methyl (2-hydroxyethyl) carbonate (5) as colorless gum (120 mg, crude) which was directly used in the next step without further purification. LCMS (ES+): m / z 467.2 [M + H]+.

[0193] Step-4: (7V-(l-(tert-Butyl)-6-cyano-4,7-difluoro-lH-benzo[d]imidazol-2-yl)- 3,3-dimethylbutanamido)methyl (2-(phosphonooxy)ethyl) carbonate (Cmpd. 54)

[0194] To a stirred solution of (A-( l -( / c / 7-butyl)-6-cy ano-4, 7-difluoro-lH- benzo[d]imidazol-2-yl)-3,3-dimethylbutanamido)methyl (2-hydroxyethyl) carbonate (5) (120 mg, 0.257 mmol) in DCM (1.2 mL) was added A-ethyl-A-isopropylpropan-2-amine (199 mg, 1.54 mmol) and the reaction mixture was cooled at 0 °C. Then, POCL (59.2 mg, 0.386 mmol) was added, and the mixture stirred for 45 minutes at 0 °C. After completion of the reaction as indicated by UPLC, the mixture was quenched with 0.3 mL of water and stirred for an additional 10 minutes. The organic layer was separated, and the aqueous layer was extracted with DCM (1 x 3 mL). The combined organic phase was concentrated under reduced pressure at room temperature. The crude was purified by reverse phase prep-HPLC to afford (N-( \ -(lerl- butyl)-6-cyano-4,7-difluoro-lH-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamido)methyl (2- (phosphonooxy)ethyl) carbonate (Cmpd. 54) as white solid (11 mg, 8% yield). [*Compound Cmpd. 54 was possibly isolated as ammonium salt as ammonium bicarbonate buffer was used for prep-HPLC], LCMS (ES+): m / z 547.2 [M + H]+.

[0195] (A-(l-(fert-Butyl)-6-cvano-4,7-difluoro-lH-benzo[d]imidazol-2-yl)-3,3- dimethylbutanamidolmethyl (3-(phosphonooxy)propyl) carbonate (Cmpd. 56)6130175-101610 / 20289-WO-PCT

[0196] Step-1: Chloromethyl (2,5,8,ll,14-pentaoxahexadecan-16-yl) carbonate (3)

[0197] To a stirred solution of 3-((terLbutyldimethylsilyl)oxy)propan-l-ol (1) (2.00 g, 10.51 mmol) in DCM (10 mL) were added pyridine (1.7 ml, 21.01 mmol) and chloromethyl carbonochloridate (2) (2.71 g, 21.01 mmol) at 0 °C. The reaction was then slowly warmed to ambient temperature and stirred for an hour. After completion of the reaction as indicated by TLC and LCMS-ELSD, the mixture was quenched with 20 mL of water and extracted with DCM (3 x 30 mL). The combined organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford 3-(( / c / 7-butyldirnethylsilyl)oxy)propyl (chloromethyl) carbonate (3) as a colorless oil (2.43 g, crude) which was directly used in the next step without further purification. LCMS (ES+): m / z 282.1 [M]+.

[0198] Step-2: (7V-(l-(tert-Butyl)-6-cyano-4,7-difluoro-lH-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamido)methyl (3-((tert-butyldimethylsilyl)oxy)propyl) carbonate (4)

[0199] To a stirred solution of A-(l-(terLbutyl)-6-cyano-4,7-difluoro-lH- benzo[d]imidazol-2-yl) -3,3-dimethylbutanamide (Formula III) (500 mg, 1.513 mmol) in acetonitrile (20 mL) were added cesium carbonate (493 mg, 1.51 mmol) and 3-(( / c77- butyldimethylsilyl)oxy)propyl (chloromethyl) carbonate (3) (428 mg, 1.51 mmol) at room temperature. The reaction mixture was stirred at 85 °C for an hour. After completion of the reaction as indicated by UPLC, the mixture was cooled to ambient temperature and quenched with 50 mL of water. The mixture was extracted with ethyl acetate (2 * 100 mL). The combined organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude was purified by silica gel (60-100 mesh) chromatography using ethyl acetate / petroleum ether (10-15%) to afford (A-(l -(te / 7-butyl)-6-cy ano-4, 7-difluoro-lH- benzo[d]imidazol-2-yl)-3,3-dimethylbutanamido)methyl (3-(( / c77-6230175-101610 / 20289-WO-PCTbutyldimethylsilyl)oxy)propyl) carbonate (4) as a colorless gum (330 mg, 33% yield). LCMS (ES+): m / z 595.3 [M + H]+; 539.2 [M -'Bu + 2H]+

[0200] Step-3: (7V-(l-(tert-Butyl)-6-cyano-4,7-difluoro-lH-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamido)methyl (3-hydroxypropyl) carbonate (Cmpd. 102)

[0201] To a stirred solution of (A-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH- benzo[d]imidazol-2-yl)-3,3-dimethylbutanamido)methyl (3-(( / c77- butyldimethylsilyl)oxy)propyl) carbonate (4) (300 mg, 0.555 mmol) in MeOH (5.0 mL) was added / ?-toluenesulfonic acid monohydrate (10.5 mg, 0.055 mmol) at room temperature. The reaction mixture was stirred at room temperature for 30 minutes. After completion of the reaction as indicated by UPLC, the mixture was quenched with 10% aq. sodium bicarbonate and extracted with DCM (2 x 10 mL). The combined organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford (A-( l -( / c / 7-butyl)-6-cyano- 4,7-difhioro-lH-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamido)methyl(3-hydroxypropyl) carbonate (Cmpd. 102) as colorless gum (240 mg, crude) which was directly used in the next step without further purification. LCMS (ES+): m / z 481.1 [M + H]+; 425.2 [M -*Bu + 2H]+.

[0202] Step-4: (7V-(l-(tert-Butyl)-6-cyano-4,7-difluoro-lH-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamido)methyl (3-(phosphonooxy)propyl) carbonate (Cmpd. 56)

[0203] To a stirred solution of (A-(l-(terLbutyl)-6-cyano-4,7-difluoro-lH- benzo[d]imidazol-2-yl)-3, 3 -dimethylbutanamido)methyl(3 -hydroxypropyl) carbonate (Cmpd. 102) (230 mg, 0.479 mmol) in DCM (3.0 mL) was added A-ethyl-A-isopropylpropan-2-amine (371 mg, 2.87 mmol) and the reaction mixture was cooled to 0 °C. Then, POCL (110 mg, 0.718 mmol) was added, and the mixture stirred for 30 minutes at 0 °C. After completion of the reaction as indicated by UPLC, the mixture was quenched with 1 mL of water and stirred for additional 5 minutes. The organic layer was separated, and the aqueous layer was extracted with DCM (1 x 5 mL). The combined organic phase was concentrated under reduced pressure. The crude was purified by reverse phase prep-HPLC to afford (A-(l-(tert-butyl)-6-cyano-4,7- difluoro-lH-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamido)methyl (3-(phosphonooxy)propyl) carbonate (Cmpd. 56) as white solid (38 mg, 14% yield). [*Compound Cmpd. 56 was possibly isolated as ammonium salt as ammonium bicarbonate buffer was used for prep-HPLC] LCMS (ES+): m / z 561.1 [M + H]+(free acid).

[0204] Synthesis of (A-(l-(ferCButyl)-6-cyano-4,7-difluoro-lH-benzo[d]imidazol- 2-yl)-3,3-dimethylbutanamido)methyl (4-(phosDhonooxy)butyl) carbonate (Cmpd. 57)6330175-101610 / 20289-WO-PCT

[0205] Step-1: 4-((tert-Butyldimethylsilyl)oxy)butyl (chloromethyl) carbonate (3)

[0206] To a stirred solution of 4-((te / 7-butyldimethylsilyl)oxy)butan-l-ol (1) (3.00 g, 14.7 mmol) in DCM (15 mL) were added pyridine (2.37 ml, 29.4 mmol) and chloromethyl carbonochloridate (2) (3.79 g, 29.4 mmol) at 0 °C. The reaction was then slowly warmed to ambient temperature and stirred for an hour. After completion of the reaction as indicated by TLC and LCMS-ELSD, the mixture was quenched with 20 mL of water and extracted with DCM (3 x 30 mL). The combined organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford 4-((te / 7-butyldimethylsilyl)oxy)butyl (chloromethyl) carbonate (3) as colorless oil (3.66 g, crude) which was directly used in the next step without further purification. LCMS (ES+): m / z mass not observed.1H-NMR (400 MHz, DMSO-t / 6): 5 5.89 (s, 2H), 4.25-4.18 (m, 2H), 3.61 (t, J = 6.2 Hz, 2H), 1.72-1.64 (m, 2H), 1.55-1.47 (m, 2H), 0.86 (s, 9H), 0.03 (s, 6H).

[0207] Step-2: (7V-(l-(tert-Butyl)-6-cyano-4,7-difluoro-lH-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamido)methyl (4-((tert-butyldimethylsilyl)oxy)butyl) carbonate (4)

[0208] To a stirred solution of 7V-(l-(terLbutyl)-6-cyano-4,7-difluoro-lH- benzo[d]imidazol-2-yl) -3,3-dimethylbutanamide (Formula III) (500 mg, 1.51 mmol) in acetonitrile (6 mL) were added cesium carbonate (935 mg, 2.87 mmol) and 4-(( / c / 7- butyldimethylsilyl)oxy)butyl (chloromethyl) carbonate (3) (1.28 g, 4.31 mmol) at room temperature. The reaction mixture was stirred at 80 °C for 3 h. After completion of the reaction as indicated by UPLC, the mixture was cooled to ambient temperature and quenched with 20 mL of water. The mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure. The crude was purified by silica gel (230-400 mesh) chromatography using ethyl acetate / petroleum ether (10-15%) to afford (7V-(l-(te / 7-butyl)-6-cyano-4,7-difluoro-lH-benzo[d]imidazol-2-yl)-6430175-101610 / 20289-WO-PCT3,3-dimethylbutanamido)methyl (4-((terLbutyldimethylsilyl)oxy)butyl) carbonate (4) as colorless gum (430 mg, 49% yield). LCMS (ES+): m / z 609.2 [M + H]+.

[0209] Step-3: (7V-(l-(tert-Butyl)-6-cyano-4,7-difluoro-lH-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamido)methyl (4-hydroxybutyl) carbonate (5)

[0210] To a stirred solution of (A-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH- benzo[d]imidazol-2-yl)-3,3-dimethylbutanamido)methyl (4-(( / erl- butyldimethylsilyl)oxy)butyl) carbonate (4) (200 mg, 0.329 mmol) in MeOH (2.0 mL) was added / ?-toluenesulfonic acid monohydrate (11.3 mg, 0.066 mmol) at room temperature. The reaction mixture was stirred at room temperature for 30 minutes. After completion of the reaction as indicated by UPLC, the mixture was quenched with 10% aq. sodium bicarbonate and extracted with DCM (2 x 10 mL). The combined organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford (A-( l -( / c / 7-butyl)-6-cyano- 4,7-difhioro-lH-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamido)methyl (4-hydroxybutyl) carbonate (5) as colorless gum (145 mg, crude) which was directly used in the next step without further purification. LCMS (ES+): m / z 495.1 [M + H]+.

[0211] Step-4: (7V-(l-(tert-Butyl)-6-cyano-4,7-difluoro-lH-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamido)methyl (4-(phosphonooxy)butyl) carbonate (Cmpd. 57)

[0212] To a stirred solution of (A-(l-(terLbutyl)-6-cyano-4,7-difluoro-lH- benzo[d]imidazol-2-yl)-3,3-dimethylbutanamido)methyl (4-hydroxybutyl) carbonate (5) (145 mg, 0.293 mmol) in DCM (1.5 mL) was added A-ethyl-A-isopropylpropan-2-amine (0.307 mL, 1.76 mmol) and the reaction mixture was cooled at 0 °C. Then, POCL (67.4 mg, 0.440 mmol) was added, and the mixture stirred for 45 min at 0 °C. After completion of the reaction as indicated by UPLC, the mixture was quenched with 0.5 mL of water and stirred for an additional 10 min. The organic layer was separated, and the aqueous layer was extracted with DCM (1 x 5 mL). The combined organic phase was concentrated under reduced pressure. The crude was purified by reverse phase prep-HPLC to afford (A-(l-(tert-butyl)-6-cyano-4, 7- difluoro-lH-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamido)methyl (4-(phosphonooxy)butyl) carbonate (Cmpd. 57) as a white solid (14 mg, 8% yield). [*Compound Cmpd. 57 was possibly isolated as ammonium salt as ammonium bicarbonate buffer was used for prep-HPLC], LCMS (ES+): m / z 575.2 [M + H]+.

[0213] Synthesis of (A-(l-(fert-Butyl)-6-cvano-4,7-difluoro-lH-benzo[d]imidazol- 2-yl)-3,3-dimethylbutanamido)methyl (2-(2-(Dhosphonooxy)ethoxy)ethyl) carbonate (Cmpd. 59)6530175-101610 / 20289-WO-PCT

[0214] Step-1: 2-(2-((tert-Butyldimethylsilyl)oxy)ethoxy)ethyl (chloromethyl) carbonate (3)

[0215] To a stirred solution of 2-(2-((tert-butyldimethyl silyl )oxy)ethoxy)ethan- 1 -ol (1) (3.80 g, 17.2 mmol) in DCM (15 mL) were added A-ethyl-A-isopropylpropan-2-amine (2.67 g, 20.7 mmol) and chloromethyl carb onochlori date (2) (0.726 g, 5.63 mmol) at 0 °C. The reaction was then slowly warmed at ambient temperature and stirred for an hour. After completion of the reaction as indicated by TLC and LCMS-ELSD, the mixture was quenched with 20 mL of water and extracted with DCM (3 x 30 mL). The combined organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude was purified by silica gel (230-400 mesh) chromatography using ethyl acetate / petroleum ether (10%) as to afford 2-(2-((te / 7-butyldimethylsilyl)oxy)ethoxy)ethyl (chloromethyl) carbonate (3) as a colorless oil (1.62 g, 30% yield). LCMS (ES+): m / z not observed. 'H-NMR (400 MHz, DMSO-t / 6): 5 5.75 (s, 2H), 4.41-4.35 (m, 2H), 3.82-3.74 (m, 4H), 3.62-3.56 (m, 2H), 0.91 (s, 9H), 0.08 (s, 6H).

[0216] Step-2: (7V-(l-(tert-Butyl)-6-cyano-4,7-difluoro-lH-benzo[d]imidazol-2-yl)- 3,3-dimethylbutanamido)methyl (2-(2-((tert-butyldimethylsilyl)oxy)ethoxy)ethyl) carbonate (4)

[0217] To a stirred solution of 7V-(l-(terLbutyl)-6-cyano-4,7-difluoro-lH- benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide (Formula III) (720 mg, 2.07 mmol) in acetonitrile (7 mL) were added cesium carbonate (1.01 g, 3.10 mmol) and 2-(2-((terL butyldimethylsilyl)oxy)ethoxy)ethyl (chloromethyl) carbonate (3) (1.62 mg, 5.17 mmol) at room temperature. The reaction mixture was stirred at 85 °C for 2 h. After completion of the reaction as indicated by UPLC, the mixture was cooled to ambient temperature and quenched with 20 mL of water. The mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure.6630175-101610 / 20289-WO-PCTThe crude was purified by silica gel (230-400 mesh) chromatography using ethyl acetate / petroleum ether (10-30%) as to afford (A-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH- benzo[d]imidazol-2-yl)-3,3-dimethylbutanamido)methyl (2-(2-(( / c / 7- butyldimethylsilyl)oxy)ethoxy)ethyl) carbonate (4) as colorless gum (300 mg, 21% yield).LCMS (ES+): m / z 625.3 [M + H]+

[0218] Step-3: (7V-(l-(ter / -Butyl)-6-cyano-4,7-difluoro-lH-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamido)methyl (2-(2-hydroxyethoxy)ethyl) carbonate (5)

[0219] To a stirred solution of (A-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH- benzo[d]imidazol-2-yl)-3,3-dimethylbutanamido)methyl (2-(2-(( / c77- butyldimethylsilyl)oxy)ethoxy)ethyl) carbonate (4) (150 mg, 0.24 mmol) in MeOH (1.0 mL) was added / ?-toluenesulfonic acid monohydrate (4.13 mg, 0.024 mmol) at room temperature. The reaction mixture was stirred at room temperature for 2 h. After completion of the reaction as indicated by UPLC, the mixture was quenched with 10% aq. sodium bicarbonate and extracted with DCM (3 * 10 mL). The combined organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure to afford (7V-(l-(tert-butyl)-6-cyano-4,7- difluoro-lH-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamido)methyl (2-(2- hydroxyethoxy)ethyl) carbonate (5) as a colorless gum (100 mg, crude) which was directly used in the next step without further purification. LCMS (ES+): m / z 511.2 [M + H]+.

[0220] Step-4: (7V-(l-(ter / -Butyl)-6-cyano-4,7-difluoro-lH-benzo[d]imidazol-2-yl)- 3,3-dimethylbutanamido)methyl (2-(2-(phosphonooxy)ethoxy)ethyl) carbonate (Cmpd. 59)

[0221] To a stirred solution of (A-(l-(terLbutyl)-6-cyano-4,7-difluoro-lH- benzo[d]imidazol-2-yl)-3,3-dimethylbutanamido)methyl (2-(2-hydroxyethoxy)ethyl) carbonate (5) (100 mg, 0.196 mmol) in DCM (1.0 mL) was added Methyl -Mi sopropyl propan - 2-amine (127 mg, 0.979 mmol) and the reaction mixture was cooled at 0 °C. Then, POCL (45.0 mg, 0.294 mmol) was added, and the mixture stirred for 45 minutes at 0 °C. After completion of the reaction as indicated by UPLC, the mixture was quenched with 0.5 mL of water and stirred for an additional 10 minutes. The organic layer was separated, and the aqueous layer was extracted with DCM (1 x 5 mL). The combined organic phase was concentrated under reduced pressure. The crude was purified by reverse phase prep-HPLC to afford (N- l- tert- butyl)-6-cyano-4,7-difluoro-lH-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamido)methyl (2- (2-(phosphonooxy)ethoxy)ethyl) carbonate (Cmpd. 59) as a white solid (35 mg, 30% yield). [*Compound 59 was possibly isolated as an ammonium salt as ammonium bicarbonate buffer was used for prep-HPLC], LCMS (ES+): m / z 591.1 [M + H]+.6730175-101610 / 20289-WO-PCT

[0222] The following compounds were prepared with analogous procedures to that described for Cmpd. 59, but with appropriate starting material 1:(N-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH-benzo[d]imidazol-2-yl)-3,3- dimethylbutanamido)m ethyl (2-methyl-4-(phosphonooxy)butan-2-yl) carbonate (Cmpd. 135) (N-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH-benzo[d]imidazol-2-yl)-3,3- dimethylbutanamido)m ethyl ((1 s,4s)-4-((phosphonooxy)methyl)cyclohexyl) carbonate(Cmpd. 136)(N-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH-benzo[d]imidazol-2-yl)-3,3- dimethylbutanamido)m ethyl ((lr,4r)-4-((phosphonooxy)methyl)cyclohexyl) carbonate(Cmpd. 137)(N-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH-benzo[d]imidazol-2-yl)-3,3- dimethylbutanamido)m ethyl (3-(2-(phosphonooxy)ethyl)oxetan-3-yl) carbonate (Cmpd. 138) (N-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH-benzo[d]imidazol-2-yl)-3,3- dimethylbutanamido)methyl ((lr,4r)-4-(phosphonooxy)cyclohexyl) carbonate (Cmpd. 152) (N-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH-benzo[d]imidazol-2-yl)-3,3- dimethylbutanamido)methyl ((ls,3s)-3-(phosphonooxy)cyclobutyl) carbonate (Cmpd. 154) (N-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH-benzo[d]imidazol-2-yl)-3,3- dimethylbutanamido)methyl ((lr,3r)-3-((phosphonooxy)methyl)cyclobutyl) carbonate (Cmpd. 155)((((2-methyl-4-(phosphonooxy)butan-2-yl)oxy)carbonyl)oxy)methyl (Z)-N-(l-(tert-butyl)-6- cyano-4,7-difluoro-lH-benzo[d]imidazol-2-yl)-3,3-dimethylbutanimidate (Cmpd. 159) (N-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH-benzo[d]imidazol-2-yl)-3,3- dimethylbutanamido)methyl (2-(2-(2-(2-(phosphonooxy)ethoxy)ethoxy)ethoxy)ethyl) carbonate (Cmpd. 162)(((4-(phosphonooxy)butoxy)carbonyl)oxy)methyl (Z)-N-(l-(tert-butyl)-6-cyano-4,7-difluoro- lH-benzo[d]imidazol-2-yl)-3,3-dimethylbutanimidate (Cmpd. 165)(((((lr,4r)-4-(phosphonooxy)cyclohexyl)oxy)carbonyl)oxy)methyl (Z)-N-(l-(tert-butyl)-6- cyano-4,7-difluoro-lH-benzo[d]imidazol-2-yl)-3,3-dimethylbutanimidate (Cmpd. 166) l-(N-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH-benzo[d]imidazol-2-yl)-3,3- dimethylbutanamido)ethyl (3-(phosphonooxy)propyl) carbonate (Cmpd. 167) (N-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH-benzo[d]imidazol-2-yl)-3,3- dimethylbutanamido)m ethyl ((3-((phosphonooxy)methyl)bicyclo[l .1. l]pentan-l-yl)m ethyl) carbonate (Cmpd. 170)6830175-101610 / 20289-WO-PCT((((3-((phosphonooxy)methyl)bicyclo[l .1. l]pentan-l-yl)methoxy)carbonyl)oxy)methyl (Z)- N-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH-benzo[d]imidazol-2-yl)-3,3-dimethylbutanimidate (Cmpd. 171)(((((ls,4s)-4-((phosphonooxy)methyl)cyclohexyl)oxy)carbonyl)oxy)methyl (Z)-N-(l-(tert- butyl)-6-cyano-4,7-difluoro-lH-benzo[d]imidazol-2-yl)-3,3-dimethylbutanimidate (Cmpd. 172)3-oxo-15-(phosphonooxy)-2,4,7,10,13-pentaoxapentadecyl (Z)-N-(l-(tert-butyl)-6-cyano-4,7- difluoro-lH-benzo[d]imidazol-2-yl)-3,3-dimethylbutanimidate (Cmpd. 173)(((((lr,3r)-3-(phosphonooxy)cyclobutyl)methoxy)carbonyl)oxy)methyl (Z)-N-(l-(tert-butyl)- 6-cyano-4,7-difluoro-lH-benzo[d]imidazol-2-yl)-3,3-dimethylbutanimidate (Cmpd. 183) (N-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH-benzo[d]imidazol-2-yl)-3,3- dimethylbutanamido)methyl (((lr,3r)-3-(phosphonooxy)cyclobutyl)methyl) carbonate (Cmpd. 185)((((lr,3r)-3-((phosphonooxy)methyl)cyclobutoxy)carbonyl)oxy)methyl (Z)-N-(l-(tert-butyl)- 6-cyano-4,7-difluoro-lH-benzo[d]imidazol-2-yl)-3,3-dimethylbutanimidate (Cmpd. 186) (l-((l-(tert-butyl)-6-cyano-4,7-difluoro-lH-benzo[d]imidazol-2-yl)amino)-3,3- dimethylbutoxy)methyl ((lr,3r)-3-(phosphonooxy)cyclobutyl) carbonate (Cmpd. 187) ((((3-(2-(phosphonooxy)ethyl)oxetan-3-yl)oxy)carbonyl)oxy)methyl (Z)-N-(l-(tert-butyl)-6- cyano-4,7-difluoro-lH-benzo[d]imidazol-2-yl)-3,3-dimethylbutanimidate (Cmpd. 188) (N-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH-benzo[d]imidazol-2-yl)-3,3- dimethylbutanamido)m ethyl (l-(phosphonooxy)propan-2-yl) carbonate (Cmpd. 190) (N-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH-benzo[d]imidazol-2-yl)-3,3- dimethylbutanamido)m ethyl (2-(phosphonooxy)propyl) carbonate (Cmpd. 191)

[0223] Synthesis of (N-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH-benzo[d]imidazol- 2-yl)-3,3-dimethylbutanamido)methyl piperazine-l-carboxylate (Cmpd. 68)

[0224] Step-1: chloromethyl phenyl carbonate (3)6930175-101610 / 20289-WO-PCT

[0225] To a stirred solution of phenol (1.00 g, 10.6 mmol) in DCM (15 mL) was added triethylamine (2.24 mL, 15.9 mmol) and chloromethyl carb onochlori date (1.42 ml, 15.9 mmol) at 0 °C and the mixture was stirred at 25 °C for 1 h. Upon completion, as indicated by UPLC, the reaction mixture was quenched with water (20 mL) and extracted using DCM (3 X 30 mL). The combined organic phases were washed with brine (20 mL), dried over sodium sulfate, and concentrated under reduced pressure to afford chloromethyl phenyl carbonate (3; 2.2 g) as a colourless viscous liquid, which was used in the next step without further purification.

[0226] Step-2: (N-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH-benzo[d]imidazol-2- yl)-3,3-dimethylbutanamido)methyl phenyl carbonate (4)

[0227] To a stirred solution of 7V-(l-(terLbutyl)-6-cyano-4,7-difluoro-lH- benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide (Formula III) (300 mg, 0.860 mmol) in acetonitrile (3 mL) was added cesium carbonate (421 mg, 1.29 mmol) and chloromethyl phenyl carbonate (241 mg, 1.29 mmol) at ambient temperature. The reaction mixture was then heated at 80 °C for 1 h. After 1 h, additional chloromethyl phenyl carbonate (241 mg, 1.29 mmol) was added to the reaction mixture and it was heated for 2 h. Upon completion, as indicated by UPLC, the reaction mixture was quenched by ice cooled water (10 mL) and extracted using ethyl acetate (3 X 20 mL). The combined organic phases were washed with brine (10 mL), dried over sodium sulfate, and concentrated under reduced pressure. The crude was eluted through a silica plug (silica-gel, 230-400) using EtOAc- Petroleum ether (35%) to afford crude (N-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH-benzo[d]imidazol-2-yl)-3,3- dimethylbutanamido)methyl phenyl carbonate (4) as white solid (170 mg), which was used in the next step without further purification.

[0228] Step-3: (N-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH-benzo[d]imidazol-2-yl)- 3,3-dimethylbutanamido)methyl piperazine-l-carboxylate (Cmpd.68)

[0229] To a stirred solution of piperazine (51.8 mg, 0.60 mmol) and DIPEA (51.9 mg, 0.401 mmol) in tetrahydrofuran (1 mL) was added (N-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH- benzo[d]imidazol-2-yl)-3,3-dimethylbutanamido)methyl phenyl carbonate (4; 100 mg, 0.20 mmol) at 25 °C. The reaction mixture was then heated at 50 °C for 6 h. Upon completion, as indicated by UPLC, the reaction mixture was cooled to ambient temperature and directly concentrated under reduced pressure. The crude was purified by reverse phase prep HPLC to afford (N-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH-benzo[d]imidazol-2-yl)-3,3- dimethylbutanamido)m ethyl piperazine-l-carboxylate (Cmpd. 68) as a white solid (8.2 mg, 8%) LCMS (ES+): m / z 491.2 [M + H]+7030175-101610 / 20289-WO-PCT

[0230] The following compounds were prepared with procedures analogous to those described for Cmpd. 68:(N-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH-benzo[d]imidazol-2-yl)-3,3- dimethylbutanamido)m ethyl (2-aminoethyl)carbamate (Cmpd. 71) (N-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH-benzo[d]imidazol-2-yl)-3,3- dimethylbutanamido)methyl (2-hydroxyethyl)carbamate (Cmpd. 74)

[0231] Synthesis of 2-morpholinoethyl (Z)-N-(l-(tert-butyl)-6-cyano-4,7-difluoro- lH-benzo[d]imidazol-2-yl)-3,3-dimethylbutanimidate (Cmpd. 84)

[0232] Step-1: 2-morpholinoethyl (Z)-N-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH- benzo[d]imidazol-2-yl)-3,3-dimethylbutanimidate (Cmpd. 84)

[0233] To a stirred solution of TV-(l-(te / 7-butyl)-6-cyano-4,7-difluoro-lH- benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide (Formula III) (150 mg, 0.43 mmol) in DCM (8 mL) at 0 °C was added triethylamine (131 mg, 1.29 mmol) and phosgene (426 mg, 0.861 mmol) under nitrogen. The mixture was stirred at 0 °C for 30 min and 2-morpholinoethan-l-ol (2; 85 mg, 0.65 mmol) was added. The reaction mixture was heated at 50 °C for 2 h. Upon completion, as indicated by UPLC, the reaction mixture was quenched with water (10 mL) and extracted with DCM (2 X 10 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude was purified by reverse phase prep-HPLC to afford 2-morpholinoethyl (Z)-N-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH-benzo[d]imidazol- 2-yl)-3,3-dimethylbutanimidate (Cmpd. 84) as a colorless gum (30 mg, 15%). LCMS (ES+): m / z 462.2 [M + H]+

[0234] Synthesis of (7V-(l-(tert-Butyl)-6-cyano-4.7-difluoro-l H-benzo[d]imidazol- 2-yl)-3,3-dimethylbntanamido)methyl (2, 5, 8,1 l,14-pentaoxahexadecan-16-yl) carbonate (Cmpd. 85)7130175-101610 / 20289-WO-PCT

[0235] Step-1: Chloromethyl (2,5,8,ll,14-pentaoxahexadecan-16-yl) carbonate (3)

[0236] To a stirred solution of 2,5,8, 1 l,14-pentaoxahexadecan-16-ol (1) (1.00 g, 3.96 mmol) in DCM (10 mL) were added pyridine (0.627 g, 7.93 mmol) and chloromethyl carbonochloridate (2) (1.02 g, 7.93 mmol) at 0 °C. The reaction was then slowly warmed to ambient temperature and stirred for an hour. After completion of the reaction as indicated by TLC and LCMS-ELSD, the mixture was quenched with 20 mL of water and extracted with DCM (3 x 30 mL). The combined organic phase was washed with dilute aq. HC1 (1 M, 20 mL) followed by brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford chloromethyl (2,5,8, 11,14-pentaoxahexadecan- 16-yl) carbonate (3) as a colorless oil (920 mg, crude) which was directly used in the next step without further purification. LCMS (ES+): m / z 345.1 [M + H]+.

[0237] Step-2: (7V-(l-(tert-Butyl)-6-cyano-4,7-difluoro-lH-benzo[d]imidazol-2-yl)- 3,3-dimethylbutanamido)methyl (2,5,8,ll,14-pentaoxahexadecan-16-yl) carbonate (Cmpd. 85)

[0238] To a stirred solution of A-(l-(terLbutyl)-6-cyano-4,7-difluoro-lH- benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide (Formula III) (200 mg, 0.574 mmol) in acetonitrile (5.0 mL) were added cesium carbonate (281 mg, 0.861 mmol) and chloromethyl (2, 5, 8,11,14-pentaoxahexadecan- 16-yl) carbonate (3) (297 mg, 0.861 mmol) at room temperature. The reaction mixture was stirred at 80 °C for 2 h. After completion of the reaction as indicated by UPLC, the mixture was cooled to ambient temperature and quenched with 20 mL of water. The mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure. The crude was purified by reverse phase prep-HPLC to afford (A-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH-benzo[d]imidazol-2-yl)-3,3- dimethylbutanamido)methyl (2,5,8, 11,14-pentaoxahexadecan- 16-yl) carbonate (Cmpd. 85) as colorless gummy liquid (64.0 mg, 17% yield). LCMS (ES+): m / z 657.2 [M + H]+; 601.2 [M - 'Bu + 2H]+7230175-101610 / 20289-WO-PCT

[0239] Synthesis of ( biityl)-6-cvano-4.7-dinuoro-l H-beiizo|d|-iinidazol-2-yl)-3,3-dimethylbutanamido)methyl (2,5,8,ll,14,17-hexaoxanonadecan-19-yl) carbonate (Cmpd. 86)

[0240] Step-1: Synthesis of chloromethyl (2,5,8,ll,14,17-hexaoxanonadecan-19- yl) carbonate (3)

[0241] To a stirred solution of 2,5,8, 11,14, 17-hexaoxanonadecan-19-ol (1) (1.0 g, 3.37 mmol) in DCM (11 mL) were added pyridine (534 mg, 6.75 mmol) and chloromethyl carbonochloridate (870 mg, 6.75 mmol) at 0 °C. The reaction was then slowly warmed to ambient temperature and stirred for an hour. After completion of the reaction as indicated by TLC and LCMS-ELSD, the mixture was quenched with 20 mL of water and extracted with DCM (3 x 30 mL). The combined organic phase was washed with dilute aq. HC1 (1 M, 20 mL) followed by brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford chloromethyl (2,5,8, 11,14, 17-hexaoxanonadecan- 19-yl) carbonate (3) as a colorless oil (1.1 g, crude) which was directly used in the next step without further purification. LCMS (ES+): m / z 389.1 [M + H]+.

[0242] Step-2: Synthesis of ( V-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH-benzo[d]- imidazol-2-yl)-3,3-dimethylbutanamido)methyl (2,5,8,ll,14,17-hexaoxanonadecan-19- yl) carbonate (Cmpd. 86)

[0243] To a stirred solution of A-(l-(terLbutyl)-6-cyano-4,7-difluoro-lH- benzo[d]imidazol-2-yl) -3,3-dimethylbutanamide (Formula III) (400 mg, 1.15 mmol) in acetonitrile (5.0 mL) were added cesium carbonate (561 mg, 1.72 mmol) and chloromethyl (2, 5, 8,11,14, 17-hexaoxanonadecan- 19-yl) carbonate (3) (893 mg, 2.30 mmol) at room temperature. The reaction mixture was stirred at 80 °C for 2 h. After completion of the reaction as indicated by UPLC, the mixture was cooled to ambient temperature and quenched with 20 mL of water. The mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude was purified by reverse phase prep-HPLC to afford (A-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH-benzo[d]imidazol-2-yl)-3,3-7330175-101610 / 20289-WO-PCTdimethylbutanamido)methyl (2,5,8, 11,14, 17-hexaoxanonadecan- 19-yl) carbonate (Cmpd. 86) as colorless gummy liquid (164.4 mg, 20% yield). LCMS (ES+): m / z 701.2 [M + H]+; 645.3 [M -'Bn + 2H]+

[0244] Synthesis of N-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH-benzo[d]imidazol- 2-yl)-N-(3,3-dimethylbutanoyl)-[l,4'-bipiperidine]-l'-carboxamide (Cmpd. 89) and (Z)- [l,4'-bipiperidine]-l'-carboxylic (Z)-N-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH- benzo[d]imidazol-2-yl)-3,3-dimethylbutanimidic anhydride (Cmpd. 88)Step-1: N-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH-benzo[d]imidazol-2-yl)-N-(3,3- dimethylbutanoyl)-[l,4'-bipiperidine]-l'-carboxamide (Cmpd. 89) and (Z)-[l,4'- bipiperidinej-l'-carboxylic (Z)-N-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH- benzo[d]imidazol-2-yl)-3,3-dimethylbutanimidic anhydride (Cmpd. 88)

[0245] To a stirred solution of 7V-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH- benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide (Formula III) (250 mg, 0.72 mmol) in acetonitrile (8 mL) was added cesium carbonate (468 mg, 1.44 mmol) and [l,4'-bipiperidine]- l'-carbonyl chloride (1; 248 mg, 1.08 mmol). The reaction mixture was heated at 100 °C for 2 h. Upon completion, as indicated by UPLC, the reaction mixture was concentrated under vacuo. The crude was purified by reverse phase prep-HPLC to afford N-(l-(tert-butyl)-6-cyano-4,7- difluoro-lH-benzo[d]imidazol-2-yl)-N-(3,3-dimethylbutanoyl)-[l,4'-bipiperidine]-T- carboxamide (Cmpd. 89) as an off-white solid (120 mg, 29%) LCMS (ES+): m / z 543.2 [M + H]+and (Z)-[l,4'-bipiperidine]-l'-carboxylic (Z)-N-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH- benzo[d]imidazol-2-yl)-3,3-dimethylbutanimidic anhydride (Cmpd. 88) as off white solid (10 mg, 2.5%). LCMS (ES+): m / z 543.2 [M + H]+.

[0246] Synthesis of (Z)-(Z)-N-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH- benzo[d]imidazol-2-yl)-3,3-dimethylbutanimidic 4-methylpiperazine-l-carboxylic anhydride (Cmpd. 92)

[0247] Cmpd. 92 was prepared with an analogous procedure to Cmpd. 89 but with 4- methyl-1 -piperazinecarbonyl chloride in step 1.

[0248] Synthesis of N-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH-benzo[d]imidazol- 2-yl)-N-(3,3-dimethylbutanoyl)-4-methylpiperazine-l-carboxamide (Cmpd. 93)7430175-101610 / 20289-WO-PCT

[0249] Cmpd. 93 was prepared with an analogous procedure to Cmpd. 89 but with 4- methyl-1 -piperazinecarbonyl chloride in step 1.

[0250] Synthesis of piperidin-4-ylmethyl (Z)-N-(l-(tert-butyl)-6-cyano-4,7- difluoro-lH-benzo[d]imidazol-2-yl)-3,3-dimethylbutanimidate (Cmpd. 99)

[0251] Step-1: tert-butyl (Z)-4-((l-((l-(tert-butyl)-6-cyano-4,7-difluoro-lH- benzo [d] imidazol-2-yl)imino)-3,3-dimethylbutoxy)methyl)piperidine-l-carboxylate (3)

[0252] To a stirred solution of 7V-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH- benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide (Formula III) (150 mg, 0.43 mmol) in DCM (8 mL) at 0 °C was added tri ethylamine (0.18 ml, 1.3 mmol) and phosgene (0.10 ml, 0.86 mmol) [under nitrogen]. The mixture was stirred at 0 °C for 30 min and tert-butyl 4- (hydroxymethyl)piperidine-l -carboxylate (2; 139 mg, 0.65 mmol) was added at 0 °C. The reaction mixture was heated to 50 °C for 2 h. Upon completion, as indicated by UPLC, the reaction mixture was quenched with water (10 mL) and extracted with DCM (2 X 10 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude was purified by silica gel (60-120 mesh) chromatography using ethyl acetate / petroleum ether (0-20%) as eluent to afford (Z)-4-((l-((l-(tert-butyl)-6-cyano-4,7- difluoro-lH-benzo[d]imidazol-2-yl)imino)-3,3-dimethylbutoxy)methyl)piperidine-l- carboxylate (3) as a colorless gum (75 mg, 26%). LCMS (ES+): m / z 546.3 [M + H]+.

[0253] Step-2: piperidin-4-ylmethyl (Z)-N-(l-(tert-butyl)-6-cyano-4,7-difluoro- lH-benzo[d]imidazol-2-yl)-3,3-dimethylbutanimidate (Cmpd. 99)

[0254] To a stirred solution of tert-butyl (Z)-4-((l-((l-(tert-butyl)-6-cyano-4,7- difluoro-lH-benzo[d]imidazol-2-yl)imino)-3,3-dimethylbutoxy)methyl)piperidine-l- carboxylate (3; 70 mg, 0.128 mmol) in DCM (3.5 ml) at 0 °C was added TFA (0.35 mL, 4.5 mmol). The reaction was stirred at 0 °C for 30 min. Upon completion, as indicated by UPLC, the reaction mixture was quenched with 10% aq. sodium bicarbonate solution (10 mL) and extracted with DCM (3 X 10 mL). DCM layer was concentrated under vacuum and the crude was purified by reverse phase prep-HPLC to afford (Z)-N-(l-(tert-butyl)-6-cyano-4,7-difhioro- lH-benzo[d]imidazol-2-yl)-3,3-dimethylbutanimidate (Cmpd. 99) as an off-white solid (15 mg, 26%). LCMS (ES+): m / z 446.2 [M + H]+. [*Compound Cmpd. 99 was possibly isolated as formate salt as HCOOH buffer was used for prep-HPLC],7530175-101610 / 20289-WO-PCT

[0255] Synthesis of (N-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH-benzo[d]imidazol- 2-yl)-3,3-dimethylbutanamido)methyl 4-methylpiperazine-l-carboxylate (Cmpd. 69) and (Z)-(l-((l-(tert-butyl)-6-cyano-4,7-difluoro-lH-benzo[d]imidazol-2-yl)imino)-3,3- dimethylbutoxy)methyl 4-methylpiperazine-l-carboxylate ( Cmpd. 100)Step-1: chloromethyl 4-methylpiperazine-l-carboxylate (3)To a stirred solution of 1 -methylpiperazine (1, 500 mg, 4.99 mmol) in DCM (4 mL) was added DIPEA (1.31 mL, 7.49 mmol) at 0 °C. After 5 min, chloromethyl carb onochlori date (965 mg, 7.49 mmol) was added dropwise and the reaction was continued for 1 h at 25 °C. Upon completion, as indicated by UPLC, the reaction mixture was quenched by ice cooled water (20 mL) and extracted with ethyl acetate (3 X 20 mL). Combined organic phases was washed with brine solution (20 mL), dried over sodium sulfate, and concentrated under reduced pressure to obtain chloromethyl 4-methylpiperazine-l -carboxylate (3) (260 mg), which was directly used in the next step without further purification. LCMS (ES+): m / z 193.1 [M + H]+.Step-2: (N-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH-benzo[d]imidazol-2-yl)-3,3- dimethylbutanamido)methyl 4-methylpiperazine-l-carboxylate (Cmpd. 69) and (Z)-(l- ((l-(tert-butyl)-6-cyano-4,7-difluoro-lH-benzo[d]imidazol-2-yl)imino)-3,3- dimethylbutoxy)methyl 4-methylpiperazine-l-carboxylate (Cmpd. 100)

[0256] To a stirred solution of A-(l-(terLbutyl)-6-cyano-4,7-difluoro-lH- benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide (Formula III) (200 mg, 0.57 mmol) in acetonitrile (3 mL) was added cesium carbonate (281 mg, 0.86 mmol) and chloromethyl 4- m ethylpiperazine- 1 -carboxylate (3, 166 mg, 0.86 mmol) at 25 °C. The reaction mixture was then heated at 80 °C for 3 h. Upon completion, as indicated by UPLC, the reaction mixture was quenched by ice cooled water (10 mL) and extracted with ethyl acetate (3 X 10 mL). The combined organic phases were washed with brine (10 mL), dried over sodium sulfate, and concentrated under reduced pressure. The crude was purified by reverse phase prep7630175-101610 / 20289-WO-PCTHPLC to afford (N-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH-benzo[d]imidazol-2-yl)-3,3- dimethylbutanamido)m ethyl 4-m ethylpiperazine- 1 -carboxylate (Cmpd. 69) as a white solid (8.5 mg, 3%) LCMS (ES+): m / z 505.2 [M + H]+and (Z)-(l-((l-(tert-butyl)-6-cyano-4,7- difluoro-lH-benzo[d]imidazol-2-yl)imino)-3,3-dimethylbutoxy)methyl 4-methylpiperazine-1-carboxylate (Cmpd. 100) as white solid (3.3 mg, 1%). LCMS (ES+): m / z 505.2 [M + H]+.

[0257] Synthesis of (N-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamido)methyl morpholine-4-carboxylate (Cmpd. 70)

[0258] Cmpd 70 was prepared with an analogous procedure to Cmpd. 69, but with morpholine as the starting material in step 1 and chloromethyl 4-methyl-morpholine-4- carboxylate as the starting material in step 2.

[0259] Synthesis of (N-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH-benzo[d]imidazol- 2-yl)-3,3-dimethylbutanamido)methyl (2-(dimethylamino)ethyl)carbamate (Cmpd. 72)

[0260] Cmpd 72 was prepared with an analogous procedure to Cmpd. 69, but with N,N-dimethylethylenediamine as the starting material in step 1 and chloromethyl (2- (dimethylamino)ethyl)carbamate as the starting material in step 2.

[0261] Synthesis of (N-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH-benzo[d]imidazol- 2-yl)-3,3-dimethylbutanamido)methyl [l,4'-bipiperidine]-l'-carboxylate formate (Cmpd. 78)

[0262] Cmpd 78 was prepared with an analogous procedure to Cmpd. 69, but with l,4'-bipiperidine as the starting material in step 1 and chloromethyl [ 1 ,4'-bipiperidine]- 1 '- carboxylate as the starting material in step 2.

[0263] Synthesis of (N-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH-benzo[d]imidazol- 2-yl)-3,3-dimethylbutanamido)methyl 4-(4-methylpiperazin-l-yl)piperidine-l- carboxylate hydrochloride (Cmpd. 87)

[0264] Cmpd 87 was prepared with an analogous procedure to Cmpd. 69, but with 1- methyl-4-(piperidin-4-yl)piperazine as the starting material in step 1 and chloromethyl 4-(4- methylpiperazin-l-yl)piperidine-l -carboxylate as the starting material in step 2.7730175-101610 / 20289-WO-PCT

[0265] Synthesis of (N-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH-benzo[d]imidazol- 2-yl)-3,3-dimethylbutanamido)methyl methyl(3-((phosphonooxy)methyl)pyridin-2- yl)carbamate (Cmpd. 107)

[0266] Step 1: (N-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH-benzo[d]imidazol-2-yl)- 3,3-dimethylbutanamido)methyl methyl(3-((phosphonooxy)methyl)pyridin-2- yl)carbamate (Cmpd. 107)

[0267] To a solution of (N-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH-benzo[d]imidazol- 2-yl)-3,3-dimethylbutanamido)methyl (3-(hydroxymethyl)pyridin-2-yl)(methyl)carbamate (Cmpd. 101, 200 mg, 0.37 mmol) in DCM (1 mL) was added phosphoryl trichloride (85 mg, 0.55 mmol) and DIPEA (95 mg, 0.74 mmol) at 0 °C. The resulting mixture was stirred at 25 °C for 30 min. The mixture was then quenched with water (0.5 mL). The progress of the reaction was monitored by UPLC. The mixture was extracted with DCM (2 x 5 mL) and the combined organic layers were washed with brine. The separated organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude was purified by reverse phase prep HPLC to afford (N-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH- benzo[d]imidazol-2-yl)-3,3-dimethylbutanamido)methyl methyl(3-((phosphonooxy)methyl)pyridin-2-yl)carbamate (Cmpd. 107) as a white solid (5.2 mg, 2%). [*Compound Cmpd. 107 was possibly isolated as ammonium salt as ammonium bicarbonate buffer was used for prep-HPLC], LCMS (ES+): m / z 623.1 [M + H]+.Synthesis of l-(N-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH-benzo[d]imidazol-2-yl)-3,3- dimethylbutanamido)ethyl methyl(3-((phosphonooxy)methyl)pyridin-2-yl)carbamate (Cmpd. 26)Cmpd. 26 was prepared with an analogous procedure to Cmpd. 107, but with l-(N-(l-(tert- butyl)-6-cyano-4,7-difluoro-lH-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamido)ethyl (3- (hydroxymethyl)pyridin-2-yl)(methyl)carbamate as the starting material.

[0268] Synthesis of (7V-(l-(tert-Butyl)-6-cyano-4.,7-difluoro-lH-benzo[d]imidazol-2-yl)-3.,3-dimethylbutanamido)methyl 2-(azetidin-3-yl)acetate (Cmpd. 112)7830175-101610 / 20289-WO-PCT

[0269] Step-1: te / 7- Butyl 3-(2-(chloromethoxy)-2-oxoethyl)azetidine-l- carboxylate (3)

[0270] To a stirred solution of 2-(l-(tert-butoxycarbonyl)azeti din-3 -yl)acetic acid (1) (500 mg, 2.32 mmol) in a biphasic mixture of DCMTLO (1 : 1, 16 mL) were added potassium carbonate (963 mg, 6.97 mmol) and tetrabutylammonium hydrogen sulfate (237 mg, 0.697 mmol) at room temperature. The reaction was then cooled to -5 °C and chloromethyl sulfurochloridate (2) (575 mg, 3.48 mmol) was added. Then the mixture was slowly warmed to ambient temperature and stirred vigorously for 5 h. After completion of the reaction as indicated by TLC and LCMS, the organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford tert-butyl 3-(2-(chloromethoxy)-2- oxoethyl)azetidine-l -carboxylate (3) as colorless oil (640 mg, crude) which was directly used in the next step without further purification. GCMS (ES+): m / z 163.0 [M - Boc]-.

[0271] Step-2: te / 7- Butyl 3-(2-((A-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH- benzo[d]imidazol-2-yl)-3,3-dimethylbutanamido)methoxy)-2-oxoethyl)azetidine-l- carboxylate (4)

[0272] To a stirred solution of 7V-(l-(terZ-butyl)-6-cyano-4,7-difluoro-lH- benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide (Formula III) (175 mg, 0.502 mmol) in acetonitrile (7.0 mL) were added cesium carbonate (196 mg, 0.603 mmol) and tert-butyl 3-(2- (chloromethoxy)-2-oxoethyl)azetidine-l -carboxylate (3) (265 mg, 1.01 mmol) at room temperature. The reaction mixture was stirred at 85 °C for 2 h. After completion of the reaction as indicated by UPLC, the mixture was cooled to ambient temperature and quenched with 20 mL of water. The mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic phase was washed with brine (20 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure. The crude was purified by silica gel (230-400 mesh) chromatography using ethyl acetate / petroleum ether (20-50%) as eluent to afford tert-butyl 3- (2-((7V-(l-(terZ-butyl)-6-cyano-4,7-difluoro-lH-benzo[d]imidazol-2-yl)-3,3-7930175-101610 / 20289-WO-PCTdimethylbutanamido)methoxy)-2-oxoethyl)azetidine-l -carboxylate (4) as a colorless gum (190 mg, 53% yield). LCMS (ES+): m / z 576.2 [M + H]+

[0273] Step-2: (7V-(l-(tert-Butyl)-6-cyano-4,7-difluoro-lH- benzo [d] imidazol-2-yl)-3,3-dimethylbutanamido)methyl 2-(azetidin-3-yl)acetate (Cmpd. 112)

[0274] To a stirred solution of tert-butyl 3-(2-((7V-(l-(tert-butyl)-6-cyano-4,7-difluoro- lH-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamido)methoxy)-2-oxoethyl)azetidine-l- carboxylate (4) (95 mg, 0.165 mmol) in DCM (l.O mL) were added 2,6-dimethylpyridine (0.15 mL, 1.3 mmol) and trimethyl silyl trifluoromethanesulfonate (0.18 ml, 0.99 mmol) at 0 °C. After 1 h, completion of the reaction was indicated by UPLC and the mixture was quenched with 3 mL of water and instantly lyophilized. The crude was purified by reverse phase prep-HPLC to afford (7V-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH-benzo[d]imidazol-2-yl)-3,3- dimethylbutanamido)methyl 2-(azeti din-3 -yl)acetate (Cmpd. 112) as a white solid (8 mg, 10% yield) [*Partial formate salt was observed in 'H-NMR, which is expected from prep-HPLC purification with formic acid buffer], LCMS (ES+): m / z 476.1 [M + H]+.

[0275] The following compounds were prepared with procedures analogous to those described for Cmpd. 112:(Z)-(l-((l-(tert-butyl)-6-cyano-4,7-difluoro-lH-benzo[d]imidazol-2-yl)imino)-3,3- dimethylbutoxy)methyl 2-(azeti din-3 -yl)acetate (Cmpd. 150) (N-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH-benzo[d]imidazol-2-yl)-3,3- dimethylbutanamido)methyl 2-(piperidin-4-yl)acetate (Cmpd. 31)

[0276] Synthesis of (2-((((N-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH- benzo [d] imidazol-2-yl)-3,3- dimethylbutanamido)methoxy)carbonyl)(methyl)amino)pyridin-3-yl)methyl 2-(4- methylpiperazin-l-yl)acetate (Cmpd. 113) and (N-(l-(tert-butyl)-6-cyano-4,7-difluoro- lH-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamido)methyl (3-(hydroxymethyl)pyridin- 2-yl)(methyl)carbamate (Cmpd. 101)8030175-101610 / 20289-WO-PCT

[0277] Step-1: (N-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH-benzo[d]imidazol-2-yl)- 3,3-dimethylbutanamido)methyl (3-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2- yl)(methyl)carbamate (2)

[0278] To a solution of 7V-(l-(terLbutyl)-6-cyano-4,7-difluoro-lH-benzo[d]imidazol- 2-yl)-3,3-dimethylbutanamide (Formula III) (500 mg, 1.44 mmol) in acetonitrile (5 mL) was added cesium carbonate (701 mg, 2.15 mmol) and chloromethyl (3-(((terL butyldimethylsilyl)oxy)methyl)pyri din-2 -yl)(methyl)carbamate (1, 742 mg, 2.15 mmol). The resulting mixture was stirred at 85 °C for 2 h. Upon completion, as indicated by UPLC, the reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (3 x 20 mL). Combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude was purified by column chromatography (silica-gel, 230-400) using EtOAc- petroleum ether (0 to 40%) to get (N-(l-(tert-butyl)-6- cyano-4,7-difhioro-lH-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamido)methyl (3-(((tert- butyldimethylsilyl)oxy)methyl)pyridin-2-yl)(methyl)carbamate (2) as a colorless gel (650 mg, 48%). LCMS (ES+): m / z 657.3 [M + H]+.

[0279] Step-2: (N-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH-benzo[d]imidazol-2-yl)- 3,3-dimethylbutanamido)methyl (3-(hydroxymethyl)pyridin-2-yl)(methyl)carbamate (Cmpd. 101)

[0280] To a solution of (N-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH-benzo[d]imidazol- 2-yl)-3,3-dimethylbutanamido)methyl (3-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2- yl)(methyl)carbamate (Cmpd. 101, 600 mg, 0.91 mmol) in methanol (2.0 ml) was added 4- methylbenzenesulfonic acid (79 mg, 0.46 mmol). The resulting mixture was stirred at 25 °C for 2 h. Upon completion, as indicated by UPLC, the reaction mixture was quenched with water (10 mL) and extracted with DCM (3 x 20 mL). Combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to get (N-(l-(tert-butyl)-6-cyano-4,7- difluoro-lH-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamido)methyl (3-(hydroxymethyl)pyridin-2-yl)(methyl)carbamate (Cmpd. 101) as a pale-yellow gel (600 mg),8130175-101610 / 20289-WO-PCTwhich was directly used in the next step without further purification. LCMS (ES+): m / z 543.2 [M + H]+

[0281]

[0282] Step 3: (2-((((N-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH-benzo[d]imidazol- 2-yl)-3,3-dimethylbutanamido)methoxy)carbonyl)(methyl)amino)pyridin-3-yl)methyl 2- (4-methylpiperazin-l-yl)acetate (Cmpd.113)

[0283] To a solution of 2-(4-methylpiperazin-l-yl)acetic acid (3; 262 mg, 1.66 mmol) in DCM (4.0 ml) was added 3-(((ethylimino)methylene)amino)-N,N-dimethylpropan-l-amine (515 mg, 3.32 mmol) and N,N-dimethylpyridin-4-amine (675 mg, 5.53 mmol). The resulting mixture was stirred at 25 °C for 10 min. Finally, (N-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH- benzo[d]imidazol-2-yl)-3,3-dimethylbutanamido)methyl (3-(hydroxymethyl)pyridin-2- yl)(methyl)carbamate (Cmpd. 101, 600 mg, 1.11 mmol) was added. The resulting mixture was stirred at 25 °C for 1 h. Upon completion, as indicated by UPLC, the reaction mixture was quenched with water (10 mL). The reaction mixture was extracted with DCM (3 x 20 mL). Combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude was purified by reverse phase prep HPLC to afford (2-((((N-(l- (tert-butyl)-6-cyano-4,7-difluoro-lH-benzo[d]imidazol-2-yl)-3,3- dimethylbutanamido)methoxy)carbonyl)(methyl)amino)pyridin-3-yl)methyl 2-(4- methylpiperazin-l-yl)acetate (Cmpd. 113) as a white solid (50 mg, 6%). LCMS (ES+): m / z683.2 [M + H]+.

[0284] Synthesis of l-(N-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH- benzo [d] imidazol-2-yl)-3,3-dimethylbutanamido)ethyl (3-(hydroxymethyl)pyridin-2- yl)(methyl)carbamate (Cmpd. 108)

[0285] Cmpd. 108 was prepared with an analogous procedure to Cmpd. 101, but with1-chloroethyl (3-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)(methyl)carbamate as starting material 1 in step 1.

[0286] Synthesis of (N-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamido)methyl 4-(phosphonooxy)butanoate (Cmpd. 123)8230175-101610 / 20289-WO-PCT

[0287] Step-1: chloromethyl 4-((tert-butyldimethylsilyl)oxy)butanoate (3)

[0288] To a stirred solution of 4-((tert-butyldimethylsilyl)oxy)butanoic acid (1.92 g, 8.79 mmol) in DCM (20 mL) and water (20 mL) was added K2CO3 (4.86 g, 35.2 mmol), tetrabutyl ammonium hydrogen sulfate (TBAHS; 896 mg, 2.64 mmol) and chloromethyl chlorosulfate (1.86 mL, 17.6 mmol) at 0 °C. The reaction was stirred at ambient temperature for 16 h. Upon completion, as indicated by TLC, 20 mL water was added and the mixture was extracted with DCM (3 x 20 mL). Combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure to afford chloromethyl 4-((tert- butyldimethylsilyl)oxy)butanoate (3) as a yellow colored liquid (1.8 g, crude), which was directly used in the next step without further purification.

[0289] Step-2: (N-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH-benzo[d]imidazol-2- yl)-3,3-dimethylbutanamido)methyl 4-((tert-butyldimethylsilyl)oxy)butanoate (4)

[0290] To a solution of 7V-(l-(terLbutyl)-6-cyano-4,7-difluoro-lH-benzo[d]imidazol- 2-yl) -3,3-dimethylbutanamide (Formula III) (2.0 g, 5.7 mmol) in acetonitrile (20 mL) was added cesium carbonate (2.81 g, 8.61 mmol) and chloromethyl 4-((tert- butyldimethylsilyl)oxy)butanoate (4.6 g, 17 mmol). The resulting mixture was heated at 85 °C for 2 h. After completion, as indicated by UPLC, the reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (3 x 20 mL). Combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The crude was purified by silica gel (230-400 mesh) chromatography using ethyl acetate / petroleum ether (10- 40%) as to afford (N-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH-benzo[d]imidazol-2-yl)-3,3- dimethylbutanamido)methyl 4-((tert-butyldimethylsilyl)oxy)butanoate (4) as a white solid (740 mg, 21%). LCMS (ES+): m / z 579.3 [M + H]+.

[0291] Step-3: (N-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH-benzo[d]imidazol-2- yl)-3,3-dimethylbutanamido)methyl 4-hydroxybutanoate (5)

[0292] To a stirred solution of (N-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH- benzo[d]imidazol-2-yl)-3,3-dimethylbutanamido)methyl 4-((tert- butyldimethylsilyl)oxy)butanoate (4; 660 mg, 1.14 mmol) in methanol (7 mL) was added p- toluenesulfonic acid monohydrate (32.5 mg, 0.17 mmol) and stirred at ambient temperature for 15 min. Upon completion, as indicated by UPLC, the reaction was quenched with 10% aq. sodium bicarbonate solution (10 mL) and extracted with DCM 3 X 10 mL). Organic layer was concentrated under reduce pressure to afford (N-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH- benzo[d]imidazol-2-yl)-3,3-dimethylbutanamido)methyl 4-hydroxybutanoate (5) as pale8330175-101610 / 20289-WO-PCTyellow gum (440 mg), which was used in the next step without further purification. LCMS (ES+): m / z 465.3 [M + H]+.

[0293] Step-4: (N-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH-benzo[d]imidazol-2- yl)-3,3-dimethylbutanamido)methyl 4-(phosphonooxy)butanoate (Cmpd. 123)

[0294] To a stirred solution of (N-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH- benzo[d]imidazol-2-yl)-3,3-dimethylbutanamido)methyl 4-hydroxybutanoate (5; 440 mg, 0.95 mmol) in DCM (5 mL) was added DIPEA (0.83 mL, 4.7 mmol) and POCL (0.13 mL, 1.4 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 20 min and then quenched with water (3 mL). The organic volatile was removed under reduced pressure and purified by reverse phase (C18 column) purification to afford (N-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH- benzo[d]imidazol-2-yl)-3,3-dimethylbutanamido)methyl 4-(phosphonooxy)butanoate (Cmpd. 123) as white solid (150 mg, 29%). LCMS (ES+): m / z 545.2 [M + H]+. [*Compound Cmpd. 123 was possibly isolated as ammonium salt as ammonium bicarbonate buffer was used for prep-HPLC],

[0295] Synthesis of 2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethyl ((N-(l-(tert- butyl)-6-cyano-4,7-difluoro-lH-benzo[d]imidazol-2-yl)-3,3- dimethylbutanamido)methyl) carbonate (Cmpd. 146)

[0296] Step-1: tert-butyl (l-chloro-3-oxo-2,4,7,10,13-pentaoxapentadecan-15- yl)carbamate (3)

[0297] To a stirred solution of tert-butyl (2-(2-(2-(2- hydroxyethoxy)ethoxy)ethoxy)ethyl)carbamate (1; 1 g, 3.41 mmol) in DCM (15 mL) at 0 °C was added pyridine (1.10 mL, 13.6 mmol) and chloromethyl carbonochloridate (0.88 g, 6.82 mmol). The reaction mixture was stirred at ambient temperature for 45 min. Upon completion, as indicated by TLC, the reaction mixture was quenched with (20 mL) and extracted with DCM (2 X 20 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude was purified by silica gel (230-400 mesh) chromatography using ethyl acetate / petroleum ether (5-10%) as to afford tert-butyl (l-chloro-3-oxo-2,4,7,10,13-8430175-101610 / 20289-WO-PCTpentaoxapentadecan- 15-yl)carbamate (3) as colorless liquid (1 g, 76%). LCMS (ES+): m / z286.1 [(M + H)-Boc]+.

[0298] Step-2: tert-butyl (16-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH- benzo[d]imidazol-2-yl)-19,19-dimethyl-13,17-dioxo-3,6,9,12,14-pentaoxa-16- azaicosyl)carbamate (4)

[0299] To a stirred solution of 7V-(l-(terLbutyl)-6-cyano-4,7-difluoro-lH- benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide (Formula III) (300 mg, 0.86 mmol) in acetonitrile (6 mL) was added cesium carbonate (561 mg, 1.72 mmol) and tert-butyl (1-chloro- 3-oxo-2,4,7,10,13-pentaoxapentadecan-15-yl)carbamate (3; 498 mg, 1.29 mmol). The reaction mixture was heated at 85 °C for 1 h. Upon completion, as indicated by UPLC, the reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (2 X 100 mL). The obtained organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude was purified by silica gel (230-400 mesh) chromatography using ethyl acetate / petroleum ether (5-15%) as to afford tert-butyl (16-(l-(tert-butyl)-6-cyano-4,7- difluoro-lH-benzo[d]imidazol-2-yl)-19,19-dimethyl-13,17-dioxo-3,6,9,12,14-pentaoxa-16- azaicosyl)carbamate (4) as colorless gum (400 mg, 20%). LCMS (ES+): m / z 698.2 [M + H]+.

[0300] Step-3: 2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethyl ((N-(l-(tert-butyl)-6- cyano-4,7-difluoro-lH-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamido)methyl) carbonate (Cmpd. 146)

[0301] To a stirred solution of tert-butyl (16-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH- benzo[d]imidazol-2-yl)-19,19-dimethyl-13,17-dioxo-3,6,9,12,14-pentaoxa-16- azaicosyl)carbamate (4; 380 mg, 0.16 mmol) in DCM (4 mL) at 0 °C was added TFA (0.13 mL, 1.63 mmol). The reaction mixture was stirred at 0 °C for 10 min. Upon completion, as indicated by UPLC, the reaction mixture was quenched with water and directly lyophilized. The crude was purified by reverse phase prep-HPLC to afford 2-(2-(2-(2- aminoethoxy)ethoxy)ethoxy)ethyl ((N-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH- benzo[d]imidazol-2-yl)-3,3-dimethylbutanamido)methyl) carbonate (Cmpd. 146) as a white solid (5 mg, 5% yield). LCMS (ES+): m / z 598.3 [M + H]+. [*Compound Cmpd. 146 was possibly isolated as TFA salt as trifluoroacetic acid buffer was used for prep-HPLC],

[0302] Synthesis of (N-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH-benzo[d]imidazol- 2-yl)-3,3-dimethylbutanamido)methyl (3-(4-methylpiperazin-l-yl)propyl) carbonate (Cmpd. 161)8530175-101610 / 20289-WO-PCT

[0303] Step-1: 3-bromopropyl (chloromethyl) carbonate (3)

[0304] To a solution of 3 -bromopropan- l-ol (1; 1 g, 7.19 mmol) in DCM (10 mL) was added pyridine (1.14 g, 14.4 mmol) and chloromethyl carb onochlori date (1.39 g, 10.8 mmol). The resulting mixture was stirred at ambient temperature for 1 h. After completion of the reaction as indicated by TLC, the mixture was quenched with 20 mL of water and extracted with DCM (3 x 20 mL). The combined organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford 3-bromopropyl (chloromethyl) carbonate (3) as colorless liquid (1.5 g, crude), which was used in the next step without further purification.

[0305] Step-2: 3-bromopropyl ((N-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH- benzo [d] imidazol-2-yl)-3,3-dimethylbutanamido)methyl) carbonate (4)

[0306] To a solution of N-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH-benzo[d]imidazol- 2-yl)-3,3-dimethylbutanamide (Formula III) (1 g, 2.87 mmol) in acetonitrile (10 mL) was added cesium carbonate (1.4 g, 4.31 mmol) and 3-bromopropyl (chloromethyl) carbonate (3; 1.33 g, 5.74 mmol). The resulting mixture was stirred at 85 °C for 2 h. After completion of the reaction as indicated by UPLC, the mixture was quenched with water (20 mL) and extracted with ethyl acetate (3 x 20 mL). Combined organic layers was dried over sodium sulfate and concentrated under reduced pressure to get 600 mg of 3-bromopropyl ((N-(l-(tert-butyl)-6- cyano-4,7-difhioro-lH-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamido)methyl) carbonate (4, crude). LCMS (ES+): m / z 545.0 [M + 2H]+.

[0307] Step-3: (N-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH-benzo[d]imidazol-2- yl)-3,3-dimethylbutanamido)methyl (3-(4-methylpiperazin-l-yl)propyl) carbonate (Cmpd. 161)

[0308] To a solution of crude 3-bromopropyl ((N-(l-(tert-butyl)-6-cyano-4,7-difluoro- lH-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamido)methyl) carbonate (4; 200 mg, 0.368 mmol) in acetonitrile (5 mL) was added cesium carbonate (180 mg, 0.552 mmol) and 1- methylpiperazine (5; 73.7 mg, 0.736 mmol). The resulting mixture was stirred at 85 °C for 1 h. After completion of the reaction as indicated by LCMS, organic volatiles were evaporated8630175-101610 / 20289-WO-PCTunder reduced pressure and the crude was purified by reverse phase prep-HPLC to afford (N- (l-(tert-butyl)-6-cyano-4,7-difluoro-lH-benzo[d]imidazol-2-yl)-3,3- dimethylbutanamido)methyl (3-(4-methylpiperazin-l-yl)propyl) carbonate (Cmpd. 161) as white solid (8 mg, 4%). LCMS (ES+): m / z 563.3 [M + H]+. [*Compound Cmpd. 161 was possibly isolated as formate salt as formic acid buffer was used for prep-HPLC],

[0309] The following compounds were prepared with procedures analogous to those described for Cmpd. 161, but with appropriate starting materials:(N-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH-benzo[d]imidazol-2-yl)-3,3- dimethylbutanamido)m ethyl (2-(dimethylamino)ethyl) carbonate (Cmpd. 37) (N-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH-benzo[d]imidazol-2-yl)-3,3- dimethylbutanamido)methyl (2-morpholinoethyl) carbonate diformate (Cmpd. 40) (N-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH-benzo[d]imidazol-2-yl)-3,3- dimethylbutanamido)methyl (2-(4-methylpiperazin-l-yl)ethyl) carbonate (Cmpd. 53) (N-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH-benzo[d]imidazol-2-yl)-3,3- dimethylbutanamido)m ethyl (2-(piperazin-l-yl)ethyl) carbonate (Cmpd. 147) (N-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH-benzo[d]imidazol-2-yl)-3,3- dimethylbutanamido)m ethyl (3 -morpholinopropyl) carbonate formate (Cmpd. 164)

[0310] Preparation of 2-methylpropan-2-aminium 4-((((N-(l-(tert-butyl)-6- cyano-4,7-difluoro-lH-benzo [d] imidazol-2-yl)-3,3- dimethylbutanamido)methoxy)carbonyl)oxy)butyl hydrogen phosphate (Cmpd. 57- Erbumine salt)Cmpd. 57 ammonium salt Cmpd. 57 erbumine salt

[0311] Dowex 50W-X8 (0.5 g) resin was washed with H2O (20 mL). To the resin was added a solution of 2-methylpropan-2-amine (0.1 g, 1.25 mmol) in H2O / MeCN (2:3, 10 mL) and the suspension was stirred for 1 h. Next, the mixture was filtered through a Buchner funnel and the resin was washed with a solution of H2O / MeCN (1 : 1, 40 mL) to remove excess amine. To a solution of ammonium 4-((((N-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH- benzo[d]imidazol-2-yl)-3,3-dimethylbutanamido)methoxy)carbonyl)oxy)butyl hydrogen phosphate (Cmpd. 57-ammonium salt; 0.07 g, 0.122 mmol) in H2O / MeCN (1 :3, 4 mL) was added the prepared resin and the mixture was stirred for 1 h. The mixture was filtered through8730175-101610 / 20289-WO-PCTa Buchner funnel and the resin was washed with FLO / MeCN (1 : 1, 3 x 10 mL). The filtrate was lyophilized to afford 2-methylpropan-2-aminium 4-((((N-(l-(tert-butyl)-6-cyano-4,7-difhioro- lH-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamido)methoxy)carbonyl)oxy)butyl hydrogen phosphate (Cmpd. 57-erbumine salt; 0.048 g, 61%) as white solid.

[0312] Preparation of Sodium 4-((((N-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH- benzo [d] imidazol-2-yl)-3,3-dimethylbutanamido)methoxy)carbonyl)oxy)butyl phosphate (Cmpd. 57-di-Na salt)

[0313] Dowex 50W-X8 (0.5 g) resin was washed with H2O (20 mL). To the resin was added a solution of NaCl (0.5 g) in water (10 mL) and the mixture was stirred for 1 h. Next, the resin was filtered through a Buchner funnel and then washed with H2O (60 mL). The resulting resin was added to a solution of ammonium 4-((((N-(l-(tert-butyl)-6-cyano-4,7- difluoro-lH-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamido)methoxy)carbonyl)oxy)butyl hydrogen phosphate (Cmpd 57-di-Na salt; 0.07 g, 0.122 mmol) in H2O / MeCN (2:3, 5 mL) and the mixture was stirred for 1 h. The mixture was filtered through Buchner funnel and resin was washed with FLO / MeCN (1 : 1, 3 x 10 mL). The filtrate was lyophilized to afford sodium 4-((((N-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH-benzo[d]imidazol-2-yl)-3,3- dimethylbutanamido)methoxy)carbonyl)oxy)butyl phosphate (Cmpd. 57-di-Na salt; 0.05 g, 66%) as white solid. The di-sodium salt was characterized by IC and CHN analysis. Elemental analysis: Calculated for C24H3iF2N4Na2O8P: C, 46.61; H, 5.05; N, 9.06. Found: C, 46.55; H, 5.67; N, 9.29.

[0314] Synthesis of (N-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH-benzo[d]imidazol- 2-yl)-3,3-dimethylbutanamido)methyl (2-hydroxy-2-oxido-l,3,2-dioxaphosphinan-5-yl) carbonate (Cmpd.-168) and ((((2-hydroxy-2-oxido-l,3,2-dioxaphosphinan-5- yl)oxy)carbonyl)oxy)methyl (Z)-N-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH- benzo[d]imidazol-2-yl)-3,3-dimethylbutanimidate (Cmpd. 169)8830175-101610 / 20289-WO-PCT

[0315] Step-1: chloromethyl (2,2,3,3,9,9,10,10-octamethyl-4,8-dioxa-3,9- disilaundecan-6-yl) carbonate (3)

[0316] To a stirred solution of 2,2,3,3,9,9,10,10-octamethyl-4,8-dioxa-3,9- disilaundecan-6-ol (1; 1.5 g, 4.68 mmol) in DCM (20 mL) at 0 °C was added pyridine (1.16 mL, 14.0 mmol) and chloromethyl carb onochlori date (905 mg, 7.02 mmol). The reaction mixture was stirred at ambient temperature for 45 min. Upon completion, as indicated by TLC, to the reaction mixture was added DCM (40 mL) and water (40 mL). The organic layer was separated, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude was purified by silica gel (230-400 mesh) chromatography using ethyl acetate / petroleum ether (5-10%) as to afford chloromethyl (2,2,3,3,9,9,10,10-octamethyl-4,8-dioxa-3,9- disilaundecan-6-yl) carbonate (3) as colorless liquid (1.2 g, 78%). 'H-NMR (400 MHz, DMSO-t / 6): 5 5.91 (s, 2H), 4.78-4.71 (m, 1H), 3.82-3.68 (m, 4H), 0.86 (s, 18H), 0.04 (s, 12H).

[0317] Step-2: (N-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH-benzo[d]imidazol-2- yl)-3,3-dimethylbutanamido)methyl (2,2,3,3,9,9,10,10-octamethyl-4,8-dioxa-3,9- disilaundecan-6-yl) carbonate (4a) and 5-(((tert-butyldimethylsilyl)oxy)methyl)-8, 8,9,9- tetramethyl-3-oxo-2,4,7-trioxa-8-siladecyl (Z)-N-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH- benzo [d] imidazol-2-yl)-3,3-dimethylbutanimidate (4b)

[0318] To a stirred solution of 7V-(l-(terLbutyl)-6-cyano-4,7-difluoro-lH- benzo[d]imidazol-2-yl) -3,3-dimethylbutanamide (Formula III) (400 mg, 1.15 mmol) in8930175-101610 / 20289-WO-PCTacetonitrile (8 mL) was added cesium carbonate (561 mg, 1.72 mmol) and chloromethyl (2,2,3,3,9,9,10,10-octamethyl-4,8-dioxa-3,9-disilaundecan-6-yl) carbonate (3; 711 mg, 1.72 mmol). Then the reaction mixture was heated to 85 °C for 1 h. Upon completion, as indicated by UPLC, the reaction mixture was quenched with water (30 mL) and extracted with ethyl acetate (2 X 50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude was purified by silica gel (230-400 mesh) chromatography using ethyl acetate / petroleum ether (5-10%) as to afford (N-(l-(tert-butyl)-6- cyano-4,7-difhioro-lH-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamido)methyl (2,2,3,3,9,9,10,10-octamethyl-4,8-dioxa-3,9-disilaundecan-6-yl) carbonate (4a) as a colorless viscous liquid (210 mg, 23%) and 5-(((tert-butyldimethylsilyl)oxy)methyl)-8, 8,9,9- tetramethyl-3-oxo-2,4,7-trioxa-8-siladecyl (Z)-N-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH- benzo[d]imidazol-2-yl)-3,3-dimethylbutanimidate (4b) as colorless viscous liquid (170 mg, 19%). ). LCMS (ES+): m / z 725.4 [M + H]+.

[0319] Step-3a: (N-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH-benzo[d]imidazol-2- yl)-3,3-dimethylbutanamido)methyl (l,3-dihydroxypropan-2-yl) carbonate (5a)

[0320] To a stirred solution of (N-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH- benzo[d]imidazol-2-yl)-3,3-dimethylbutanamido)methyl (2,2,3,3,9,9,10,10-octamethyl-4,8- dioxa-3,9-disilaundecan-6-yl) carbonate (4a; 180 mg, 0.248 mmol) in methanol (4 mL) at 0 °C was added p-toluenesulfonic acid monohydrate (23.6 mg, 0.124 mmol). The reaction mixture was stirred at ambient temperature for 15 min. Upon completion, as indicated by TLC, the reaction mixture was quenched with 10% aq. sodium bicarbonate solution and extracted with DCM (2 X 10 mL). Organic layer was concentrated under reduced pressure to afford vacuum to afford (N-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH-benzo[d]imidazol-2-yl)-3,3- dimethylbutanamido)m ethyl (l,3-dihydroxypropan-2-yl) carbonate (5a) as colorless gum (100 mg, crude), which was used for the next step without further purification. LCMS (ES+): m / z 497.5 [M + H]+.

[0321] Step-4a: (N-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH-benzo[d]imidazol-2- yl)-3,3-dimethylbutanamido)methyl (2-hydroxy-2-oxido-l,3,2-dioxaphosphinan-5-yl) carbonate (Cmpd. 168)

[0322] To a stirred solution of (N-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH- benzo[d]imidazol-2-yl)-3,3-dimethylbutanamido)methyl (l,3-dihydroxypropan-2-yl) carbonate (5a; 100 mg, 0.201 mmol) in DCM (3 mL) at 0 °C was added DIPEA (0.181 ml, 1.007 mmol) and POCL (0.028 ml, 0.302 mmol). The reaction mixture was stirred at 0 °C for 20 min. Upon completion, as indicated by UPLC, the reaction mixture was quenched with9030175-101610 / 20289-WO-PCTwater (2 mL). The organic volatiles were removed under reduced pressure and directly purified by reverse phase (C18 column) purification to afford (N-(l-(tert-butyl)-6-cyano-4,7-difhioro- lH-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamido)methyl (2-hydroxy-2-oxido- 1,3,2- dioxaphosphinan-5-yl) carbonate (Cmpd. 168) as a white solid (4.5 mg, 4%). LCMS (ES+): m / z 559.2 [M + H]+. [*Compound Cmpd. 168 was possibly isolated as ammonium salt as ammonium bicarbonate buffer was used for prep-HPLC],

[0323] Step-3b: Synthesis of ((((l,3-dihydroxypropan-2- yl)oxy)carbonyl)oxy)methyl (Z)-N-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH- benzo [d] imidazol-2-yl)-3,3-dimethylbutanimidate (5b)

[0324] To a stirred solution of 5-(((tert-butyldimethylsilyl)oxy)methyl)-8, 8,9,9- tetramethyl-3-oxo-2,4,7-trioxa-8-siladecyl (Z)-N-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH- benzo[d]imidazol-2-yl)-3,3-dimethylbutanimidate (4b; 170 mg, 0.23 mmol) in methanol (4 mL) at 0 °C was added p-toluenesulfonic acid monohydrate (22.3 mg, 0.12 mmol). The reaction mixture was stirred at ambient temperature for 15 min. Upon completion, as indicated by TLC, the reaction mixture was quenched with 10% aq. sodium bicarbonate solution and extracted with DCM (2 X 5 mL). The organic layer was concentrated under reduced pressure to afford vacuum to afford ((((l,3-dihydroxypropan-2-yl)oxy)carbonyl)oxy)methyl (Z)-N-(l-(tert- butyl)-6-cyano-4,7-difluoro-lH-benzo[d]imidazol-2-yl)-3,3-dimethylbutanimidate (5b) as colorless gum (100 mg, crude), which was used in the next step without further purification.LCMS (ES+): m / z 497.5 [M + H]+.

[0325] Step-4b: ((((2-hydroxy-2-oxido-l,3,2-dioxaphosphinan-5- yl)oxy)carbonyl)oxy)methyl (Z)-N-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH- benzo[d]imidazol-2-yl)-3,3-dimethylbutanimidate (Cmpd. 169)

[0326] To a stirred solution of ((((l,3-dihydroxypropan-2-yl)oxy)carbonyl)oxy)methyl (Z)-N-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH-benzo[d]imidazol-2-yl)-3,3- dimethylbutanimidate (5b; 100 mg, 0.201 mmol) in DCM (3 mL) at 0 °C was added DIPEA (0.18 mL, 1.01 mmol) and POCL (0.03 ml, 0.302 mmol). The reaction mixture was stirred at 0 °C for 20 min. Upon completion, as indicated by UPLC, the reaction mixture was quenched with water (2 mL). Organic volatiles were removed under reduced pressure and directly purified by reverse phase (C18 column) purification to afford ((((2-hydroxy-2-oxido- 1,3,2- dioxaphosphinan-5-yl)oxy)carbonyl)oxy)methyl (Z)-N-(l-(tert-butyl)-6-cyano-4,7-difhioro- lH-benzo[d]imidazol-2-yl)-3,3-dimethylbutanimidate (Cmpd. 169) as a white solid (4.5 mg, 4%). LCMS (ES+): m / z 559.2 [M + H]+. [*Compound Cmpd. 169 was possibly isolated as ammonium salt as ammonium bicarbonate buffer was used for prep-HPLC],9130175-101610 / 20289-WO-PCT

[0327] Synthesis of H-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH-benzo[d]imidazol- 2-yl)-3,14,14-trimethyl-8,12-dioxo-7,9-dioxa-3,ll-diazapentadecanoic acid (Cmpd. 180)

[0328] Step-1 and 2 : The synthesis of intermediates 3 and 4 are described in procedure for synthesis of Cmpd. 161.

[0329] Step-3: H-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH-benzo[d]imidazol-2- yl)-3,14,14-trimethyl-8,12-dioxo-7,9-dioxa-3,ll-diazapentadecanoic acid (Cmpd. 180)

[0330] To a solution of 3-bromopropyl ((N-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH- benzo[d]imidazol-2-yl)-3,3-dimethylbutanamido)methyl) carbonate (4; 300 mg, 0.552 mmol) in acetonitrile (4 mL) was added cesium carbonate (180 mg, 0.552 mmol) and methylglycine (492 mg, 5.52 mmol). The resulting mixture was stirred at 85 °C for 2 h. After completion of the reaction as indicated by LCMS, organic volatiles were evaporated under reduced pressure and the crude was purified by reverse phase prep-HPLC to afford l l-(l-(tert-butyl)-6-cyano- 4,7-difhioro-lH-benzo[d]imidazol-2-yl)-3,14,14-trimethyl-8,12-dioxo-7,9-dioxa-3,l 1- diazapentadecanoic acid (Cmpd. 180) as a white solid (5 mg, 2%). LCMS (ES+): m / z 552.3 [M + H]+. [*Compound Cmpd. 180 was possibly isolated as formate salt as formic acid buffer was used for prep-HPLC],

[0331] Synthesis of (N-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH-benzo[d]imidazol- 2-yl)-3,3-dimethylbutanamido)methyl (3-hydroxypropyl) carbonate (7V-(l-(tert-Butyl)-6- cyano-4,7-difluoro-lH-benzo [d] imidazol-2-yl)-3,3-dimethylbutanamido)methyl (3- hydroxypropyl) carbonate (Cmpd. 102), (((3-hydroxypropoxy)carbonyl)oxy)methyl (Z)- N-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH-benzo[d]imidazol-2-yl)-3,3- dimethylbutanimidate (Cmpd. 104), (N-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH- benzo [d] imidazol-2-yl)-3,3-dimethylbutanamido)methyl (3-((dimorpholinophosphoryl)oxy)propyl) carbonate (Cmpd. 176) and (((3- ((dimorpholinophosphoryl)oxy)propoxy)carbonyl)oxy)methyl (Z)-N-(l-(tert-butyl)-6- cyano-4,7-difluoro-lH-benzo[d]imidazol-2-yl)-3,3-dimethylbutanimidate (Cmpd. 181)9230175-101610 / 20289-WO-PCT

[0332] Step-1: Chloromethyl (2,5,8,ll,14-pentaoxahexadecan-16-yl) carbonate (3)

[0333] To a stirred solution of 3-((tert-butyldimethylsilyl)oxy)propan-l-ol (1) (2 g, 10.5 mmol) in DCM (10 mL) were added pyridine (1.7 ml, 21.01 mmol) and chloromethyl carbonochloridate (2) (2.71 g, 21.01 mmol) at 0 °C. The reaction was then slowly warmed at ambient temperature and stirred for an hour. After completion of the reaction as indicated by TLC and LCMS-ELSD, the mixture was quenched with 20 mL of water and extracted with DCM (3 x 30 mL). The combined organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford 3-(( / c / 7-butyldirnethylsilyl)oxy)propyl (chloromethyl) carbonate (3) as colorless oil (2.43 g, crude) which was directly used in the next step without further purification. LCMS (ES+): m / z 282.1 [M]+.

[0334] Step-2: (7V-(l-(tert-Butyl)-6-cyano-4,7-difluoro-lH-benzo[d]imidazol-2-yl)- 3,3-dimethylbutanamido)methyl (3-((tert-butyldimethylsilyl)oxy)propyl) carbonate (4a) and 9,9,10,10-tetramethyl-3-oxo-2,4,8-trioxa-9-silaundecyl (Z)-N-(l-(tert-butyl)-6-cyano- 4,7-difluoro-lH-benzo[d]imidazol-2-yl)-3,3-dimethylbutanimidate (4b)

[0335] To a stirred solution of A-(l-(terLbutyl)-6-cyano-4,7-difluoro-lH- benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide (Formula III) (500 mg, 1.51 mmol) in acetonitrile (20 mL) were added cesium carbonate (493 mg, 1.51 mmol) and 3-(( / c77- butyldimethylsilyl)oxy)propyl (chloromethyl) carbonate (3) (428 mg, 1.51 mmol) at room temperature. The reaction mixture was stirred at 85 °C for an hour. After completion of the reaction as indicated by UPLC, the mixture was cooled to ambient temperature and quenched with 50 mL of water. The mixture was extracted with ethyl acetate (2 * 100 mL). The combined organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude was purified by silica gel (60-100 mesh) chromatography using ethyl acetate / petroleum ether (10-15%) to afford a mixture of (A-(l-(tert-butyl)-6-cyano-4,7- difluoro-lH-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamido)methyl (3-((tert- butyldimethylsilyl)oxy)propyl) carbonate (4a) and 9,9,10,10-tetramethyl-3-oxo-2,4,8-trioxa-9330175-101610 / 20289-WO-PCT9-silaundecyl (Z)-N-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH-benzo[d]imidazol-2-yl)-3,3- dimethylbutanimidate (4b) as a colorless gum (330 mg, 33% yield). LCMS (ES+): m / z 595.3 [M + H]+; 539.2 [M -"Bn + 2H]+

[0336] Step-3: (7V-(l-(tert-Butyl)-6-cyano-4,7-difluoro-lH-benzo[d]imidazol-2-yl)- 3,3-dimethylbutanamido)methyl (3-hydroxypropyl) carbonate (Cmpd. 102) and (((3- hydroxypropoxy)carbonyl)oxy)methyl (Z)-N-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH- benzo[d]imidazol-2-yl)-3,3-dimethylbutanimidate (Cmpd. 104)

[0337] To a stirred solution of [(A-(l-(terLbutyl)-6-cyano-4,7-difluoro-lH- benzo[d]imidazol-2-yl)-3,3-dimethylbutanamido)methyl (3-((terL butyldimethylsilyl)oxy)propyl) carbonate (4a) and 9,9,10,10-tetramethyl-3-oxo-2,4,8-trioxa- 9-silaundecyl (Z)-N-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH-benzo[d]imidazol-2-yl)-3,3- dimethylbutanimidate (4b) (300 mg, 0.555 mmol) in MeOH (5.0 mL) was added p- toluenesulfonic acid monohydrate (10.5 mg, 0.055 mmol) at room temperature. The reaction mixture was stirred at room temperature for 30 minutes. After completion of the reaction as indicated by UPLC, the mixture was quenched with 10% aq. sodium bicarbonate and extracted with DCM (2 x 10 mL). The combined organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure to afford (7V-(l-(terLbutyl)-6-cyano-4,7-difluoro-lH- benzo[d]imidazol-2-yl)-3, 3 -dimethylbutanamido)methyl(3 -hydroxypropyl) carbonate (Cmpd. 102) and (((3-hydroxypropoxy)carbonyl)oxy)methyl (Z)-N-(l-(tert-butyl)-6-cyano-4,7- difluoro-lH-benzo[d]imidazol-2-yl)-3,3-dimethylbutanimidate (Cmpd. 104) as a colorless gum (240 mg, crude) which was directly used in the next step without further purification.LCMS (ES+): m / z 481.1 [M + H]+; 425.2 [M -"Bn + 2H]+

[0338] Step-4: (N-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH-benzo [d] imidazol-2- yl)-3,3-dimethylbutanamido)methyl (3-((dimorpholinophosphoryl)oxy)propyl) carbonate (Cmpd. 176) and (((3-((dimorpholinophosphoryl)oxy)propoxy)carbonyl)oxy)methyl (Z)-N-(l-(tert-butyl)-6- cyano-4,7-difluoro-lH-benzo[d]imidazol-2-yl)-3,3-dimethylbutanimidate (Cmpd. 181)

[0339] To a stirred solution of [(A-(l-(te / 7-butyl)-6-cyano-4,7-difluoro-lH- benzo[d]imidazol-2-yl)-3, 3 -dimethylbutanamido)methyl(3 -hydroxypropyl) carbonate (Cmpd. 102) and (((3-hydroxypropoxy)carbonyl)oxy)methyl (Z)-N-(l-(tert-butyl)-6-cyano-4,7- difhioro-lH-benzo[d]imidazol-2-yl)-3,3-dimethylbutanimidate (Cmpd. 104)] (50 mg, 0.104 mmol) in DCM (3 mL) at 0 °C was added DIPEA (0.091 mL, 0.52 mmol) and POCL (0.015 mL, 0.156 mmol). The reaction mixture was stirred at 0 °C for 20 min. Then, morpholine (0.018 mL, 0.208 mmol) was added and stirred at ambient temperature for 5 min. Upon completion,9430175-101610 / 20289-WO-PCTas indicated by UPLC, the reaction was concentrated under reduced pressure. The crude was purified by reverse phase prep-HPLC to afford (N-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH- benzo[d]imidazol-2-yl)-3,3-dimethylbutanamido)methyl (3-((dimorpholinophosphoryl)oxy)propyl) carbonate (Cmpd. 176) as a white solid (20 mg, 27%) and (((3-((dimorpholinophosphoryl)oxy)propoxy)carbonyl)oxy)methyl (Z)-N-(l-(tert-butyl)- 6-cyano-4,7-difluoro-lH-benzo[d]imidazol-2-yl)-3,3-dimethylbutanimidate (Cmpd. 181) as a colorless gum (10 mg, 13%). LCMS (ES+): m / z 699.3 [M + H]+.

[0340] Synthesis of (N-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH-benzo[d]imidazol- 2-yl)-3,3-dimethylbutanamido)methyl (3-((dimorpholinophosphoryl)oxy)propyl) carbonate (Cmpd. 175)

[0341] Cmpd. 175 was prepared with an analogous procedure to Cmpd. 176, but with appropriate amine source in step 4.

[0342] Synthesis of 3-((((N-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH- benzo[d]imidazol-2-yl)-3,3-dimethylbutanamido)methoxy)carbonyl)oxy)propyl hydrogen sulfate (Cmpd. 182)

[0343] Step-1 : 3-((((N-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH-benzo [d] imidazol- 2-yl)-3,3-dimethylbutanamido)methoxy)carbonyl)oxy)propyl hydrogen sulfate (Cmpd. 182)

[0344] To a solution of (N-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH-benzo[d]imidazol- 2-yl)-3,3-dimethylbutanamido)methyl (3-hydroxypropyl) carbonate (Cmpd. 102; 200 mg, 0.42 mmol) in pyridine (2 ml) was added pyridine-sulfur trioxide (1 : 1) complex (132 mg, 0.83 mmol) at 0 °C. The resulting mixture was stirred at 25 °C for 2 h. Upon completion, as indicated by UPLC, the reaction mixture was quenched with water (0.5 mL) and directly purified by reverse phase (Cl 8 column) purification to afford 3-((((N-(l-(tert-butyl)-6-cyano- 4,7-difhioro-lH-benzo[d]imidazol-2-yl)-3,3- dimethylbutanamido)methoxy)carbonyl)oxy)propyl hydrogen sulfate (Cmpd. 182) as a white solid (29 mg, 12%). LCMS (ES+): m / z 561.3 [M + H]+. [*Compound Cmpd. 182 was possibly isolated as ammonium salt as ammonium bicarbonate buffer was used for prep- HPLC],9530175-101610 / 20289-WO-PCT

[0345] Synthesis of (N-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH-benzo[d]imidazol- 2-yl)-3,3-dimethylbutanamido)methyl (3-(phosphonooxy)-2-((phosphonooxy)methyl)propyl) carbonate (Cmpd. 184), (N-(l-(tert-butyl)-6-cyano-4,7- difluoro-lH-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamido)methyl ((2-hydroxy-2- oxido-l,3,2-dioxaphosphinan-5-yl)methyl) carbonate (Cmpd. 177) and ((((2-hydroxy-2- oxido-l,3,2-dioxaphosphinan-5-yl)methoxy)carbonyl)oxy)methyl (Z)-N-(l-(tert-butyl)-6- cyano-4,7-difluoro-lH-benzo[d]imidazol-2-yl)-3,3-dimethylbutanimidate (Cmpd. 178)

[0346] Step-1: 3-((tert-butyldimethylsilyl)oxy)-2-(((tert- butyldimethylsilyl)oxy)methyl)propyl (chloromethyl) carbonate (3)

[0347] To a stirred solution of 3-((tert-butyldimethylsilyl)oxy)-2-(((tert- butyldimethylsilyl)oxy)methyl)propan-l-ol (1; 1.4 g, 4.18 mmol) in DCM (20 mL) at 0 °C were added pyridine (830 g, 10.5 mmol) and chloromethyl carb onochlori date (809 mg, 6.28 mmol). The reaction mixture was stirred at ambient temperature for 45 min. Upon completion, as indicated by TLC, to the reaction mixture was added DCM (25 mL) and water (15 mL). The organic layer was separated, dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford 3-((tert-butyldimethylsilyl)oxy)-2-(((tert-9630175-101610 / 20289-WO-PCTbutyldimethylsilyl)oxy)methyl)propyl (chloromethyl) carbonate (3) as a colorless liquid (1.5 g, crude), which was used in next step without further purification.Step-2: (N-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH-benzo[d]imidazol-2-yl)-3,3- dimethylbutanamido)methyl (3-((tert-butyldimethylsilyl)oxy)-2-(((tert- butyldimethylsilyl)oxy)methyl)propyl) carbonate (4a) and 6-(((tert- butyldimethylsilyl)oxy)methyl)-9,9,10,10-tetramethyl-3-oxo-2,4,8-trioxa-9-silaundecyl (Z)-N-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH-benzo[d]imidazol-2-yl)-3,3- dimethylbutanimidate (4b)

[0348] To a stirred solution of N-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH- benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide (Formula III) (500 mg, 1.44 mmol) in acetonitrile (10 mL) at 85°C were added CS2CO3 (701 mg, 2.15 mmol) and 3-((tert- butyldimethylsilyl)oxy)-2-(((tert-butyldimethylsilyl)oxy)methyl)propyl (chloromethyl) carbonate (3; 919 mg, 2.15 mmol). Then the reaction mixture was heated to 85 °C for 1 h. Upon completion, as indicated by TLC, the reaction mixture was quenched with water (30 mL), then extracted with ethyl acetate (2 X 50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude was purified by silica gel (60-120 mesh) chromatography using ethyl acetate / petroleum ether (5-10%) to afford (N-(l-(tert- butyl)-6-cyano-4,7-difluoro-lH-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamido)methyl (3- ((tert-butyldimethylsilyl)oxy)-2-(((tert-butyldimethylsilyl)oxy)methyl)propyl) carbonate (4a) as a colorless gel (200 mg, 17%) and 6-(((tert-butyldimethylsilyl)oxy)methyl)-9,9, 10,10- tetramethyl-3-oxo-2,4,8-trioxa-9-silaundecyl (Z)-N-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH- benzo[d]imidazol-2-yl)-3,3-dimethylbutanimidate (4b) as a colorless gel (100 mg, 9%).LCMS (ES+): m / z 683.3 [(M + H)-tBu]+.

[0349] Step-3a: (N-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH-benzo[d]imidazol-2- yl)-3,3-dimethylbutanamido)methyl (3-hydroxy-2-(hydroxymethyl)propyl) carbonate (5a)

[0350] To a solution of (N-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH-benzo[d]imidazol- 2-yl)-3,3-dimethylbutanamido)methyl (3-((tert-butyldimethylsilyl)oxy)-2-(((tert- butyldimethylsilyl)oxy)methyl)propyl) carbonate (4a; 100 mg, 0.135 mmol) in methanol (2 mL) was added 4-methylbenzenesulfonic acid (5.82 mg, 0.034 mmol) and the resulting mixture was stirred at ambient temperature for 20 min. Upon completion, as indicated by UPLC, the reaction was quenched with aq. sodium bicarbonate solution and the mixture was extracted with DCM (3 x 20 mL). Combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to afford (N-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH-9730175-101610 / 20289-WO-PCTbenzo[d]imidazol-2-yl)-3,3-dimethylbutanamido)methyl (3-hydroxy-2-(hydroxymethyl)propyl) carbonate (5a) as colorless gum (60 mg, crude), which was used in the next step without further purification. LCMS (ES+): m / z 511.3 [M + H]+.

[0351] Step-4a: (N-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH-benzo [d] imidazol-2- yl)-3,3-dimethylbutanamido)methyl (3-(phosphonooxy)-2-((phosphonooxy)methyl)propyl) carbonate (Cmpd. 184)

[0352] To a solution of (N-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH-benzo[d]imidazol- 2-yl)-3,3-dimethylbutanamido)methyl (3-hydroxy-2-(hydroxymethyl)propyl) carbonate (5a; 60 mg, 0.12 mmol) in ethyl acetate (3 mL) was added DIPEA (0.06 ml, 0.35 mmol) and POCh (0.11 ml, 1.2 mmol) at 0 °C. The resulting mixture was stirred at 0 °C for 10 min. Upon completion, as indicated by UPLC, the reaction mixture was quenched with water (1 mL). Organic volatiles were removed under reduced pressure and directly purified by reverse phase (C18 column) purification to afford (N-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH- benzo[d]imidazol-2-yl)-3,3-dimethylbutanamido)methyl (3-(phosphonooxy)-2-((phosphonooxy)methyl)propyl) carbonate (Cmpd. 184) as a white solid (10 mg, 12%). LCMS (ES+): m / z 671.0 [M + H]+. [*Compound Cmpd. 184 was possibly isolated as ammonium salt as ammonium bicarbonate buffer was used for prep-HPLC],

[0353] Step-4b: (N-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH-benzo[d]imidazol-2- yl)-3,3-dimethylbutanamido)methyl ((2-hydroxy-2-oxido-l,3,2-dioxaphosphinan-5- yl)methyl) carbonate (Cmpd. 177)

[0354] To a solution of (N-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH-benzo[d]imidazol- 2-yl)-3,3-dimethylbutanamido)methyl (3-hydroxy-2-(hydroxymethyl)propyl) carbonate (5a; 80 mg, 0.16 mmol) in DCM (2 mL) was added DIPEA (122 mg, 0.94 mmol) and POCh (36 mg, 0.24 mmol) at 0 °C. The resulting mixture was stirred at 0 °C for 20 min. Upon completion, as indicated by UPLC, the reaction mixture was quenched with water (1 mL). Organic volatiles were removed under reduced pressure and directly purified by reverse phase (Cl 8 column) purification to afford (N-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH-benzo[d]imidazol-2-yl)-3,3- dimethylbutanamido)methyl ((2-hydroxy-2-oxido-l,3,2-dioxaphosphinan-5-yl)methyl) carbonate (Cmpd. 177) as a white solid (12 mg, 13%). LCMS (ES+): m / z 573.2 [M + H]+. [*Compound Cmpd. 177 was possibly isolated as ammonium salt as ammonium bicarbonate buffer was used for prep-HPLC],

[0355] Step-3b: (((3-hydroxy-2-(hydroxymethyl)propoxy)carbonyl)oxy)methyl (Z)-N-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH-benzo[d]imidazol-2-yl)-3,3- dimethylbutanimidate (5b)9830175-101610 / 20289-WO-PCT

[0356] To a solution of 6-(((tert-butyldimethylsilyl)oxy)methyl)-9,9, 10,10- tetramethyl-3-oxo-2,4,8-trioxa-9-silaundecyl (Z)-N-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH- benzo[d]imidazol-2-yl)-3,3-dimethylbutanimidate (4b; 100 mg, 0.135 mmol) in methanol (3 mL) was added 4-methylbenzenesulfonic acid (7.72 mg, 0.041 mmol) and the resulting mixture was stirred at ambient temperature for 15 min. Upon completion, as indicated by UPLC, the reaction was quenched with aq. sodium bicarbonate solution and the mixture was extracted with DCM (3 x 20 mL). Combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to afford (((3-hydroxy-2- (hydroxymethyl)propoxy)carbonyl)oxy)methyl (Z)-N-(l-(tert-butyl)-6-cyano-4,7-difluoro- lH-benzo[d]imidazol-2-yl)-3,3-dimethylbutanimidate (5b) as colorless gum (100 mg, crude), which was used in the next step without further purification. LCMS (ES+): m / z 511.1 [M + H]+

[0357] Step-4c: ((((2-hydroxy-2-oxido-l,3,2-dioxaphosphinan-5- yl)methoxy)carbonyl)oxy)methyl (Z)-N-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH- benzo[d]imidazol-2-yl)-3,3-dimethylbutanimidate (Cmpd. 178)

[0358] To a solution of (((3-hydroxy-2-(hydroxymethyl)propoxy)carbonyl)oxy)methyl (Z)-N-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH-benzo[d]imidazol-2-yl)-3,3- dimethylbutanimidate (5b; 100 mg, 0.2 mmol) in DCM (2 mL) was added DIPEA (152 mg, 1.18 mmol) and POCL (45 mg, 0.29 mmol) at 0 °C. The resulting mixture was stirred at 0 °C for 20 min. Upon completion, as indicated by UPLC, the reaction mixture was quenched with water (1 mL). Organic volatiles were removed under reduced pressure and directly purified by reverse phase (C18 column) purification to afford ((((2-hydroxy-2-oxido- 1,3,2- dioxaphosphinan-5-yl)methoxy)carbonyl)oxy)methyl (Z)-N-(l-(tert-butyl)-6-cyano-4,7- difluoro-lH-benzo[d]imidazol-2-yl)-3,3-dimethylbutanimidate (Cmpd. 178) as a white solid (5.5 mg, 5%). LCMS (ES+): m / z 573.3 [M + H]+. [*Compound Cmpd. 178 was possibly isolated as ammonium salt as ammonium bicarbonate buffer was used for prep-HPLC],

[0359] Synthesis of 3-(2-((tert-butyldimethylsilyl)oxy)ethyl)oxetan-3-ol (3) imidazole (2 eq) i DMAP (0.05 eq) .. Q ^J '' O SiDMF, rt, 15 h \Z OH / \Step-1 o1 2 (1 eq)4

[0360] Step-1: 3-(2-((tert-butyldimethylsilyl)oxy)ethyl)oxetan-3-ol (3)

[0361] To a solution of 3-(2-hydroxyethyl)oxetan-3-ol (1; 1.4 g, 12 mmol) in DMF (10 mL) and was added IH-imidazole (1.61 g, 23.7 mmol), N,N-dimethylpyridin-4-amine (0.072 g, 0.593 mmol), and tert-butylchlorodimethylsilane (1.79 g, 11.9 mmol). The resulting mixture9930175-101610 / 20289-WO-PCTwas stirred at ambient temperature for 15 h. Upon completion, the reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (3 x 10 mL). Combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The crude was purified by silica gel (230-400 mesh) chromatography using ethyl acetate / petroleum ether (5-30%) to afford 3-(2-((tert-butyldimethylsilyl)oxy)ethyl)oxetan-3-ol (3) as colorless liquid (1.29 g, 47%). *H-NMR (400 MHz, DMSO-t / 6): 5 5.56 (s, 1H), 4.47- 4.34 (m, 4H), 3.73 (t, J= 6.4 Hz, 2H), 1.91 (t, J= 6.4 Hz, 2H), 0.87 (s, 9H), 0.06 (s, 6H).

[0362] Synthesis of (N-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH-benzo[d]imidazol- 2-yl)-3,3-dimethylbutanamido)methyl (4-(((2R,3R,4S,5R,6R)-3,4,5-trihydroxy-6- (hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)butyl) carbonate (Cmpd. 189)

[0363] Step-1: tert-butyldimethyl(4-(((2R,3R,4S,5S,6R)-3,4,5-tris(benzyloxy)-6- ((benzyloxy)methyl)tetrahydro-2H-pyran-2-yl)oxy)butoxy)silane (2)

[0364] To a stirred solution of (2S,3R,4S,5R,6R)-2-(4-((tert- butyldimethylsilyl)oxy)butoxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (1; 450 mg, 1.23 mmol) in tetrahydrofuran (8 mL) was added sodium hydride (295 mg, 7.37 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 45 min, then benzyl bromide (1050 mg, 6.14 mmol) was added to the reaction mixture and stirred at ambient temperature for 16 h. Upon completion, as indicated by TLC, the reaction mixture was quenched with aq. ammonium chloride (10 mL) and extracted using ethyl acetate (3 X 15 mL). Combined organic phases were washed with brine (10 mL), dried over sodium sulfate, and concentrated under reduced pressure to obtain tert-butyldimethyl(4-(((2R,3R,4S,5S,6R)-3,4,5-tris(benzyloxy)-6-10030175-101610 / 20289-WO-PCT((benzyloxy)methyl)tetrahydro-2H-pyran-2-yl)oxy)butoxy)silane (1 g, crude), which was used in the next step without further purification.

[0365] Step-2: 4-(((2R,3R,4S,5S,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-pyran-2-yl)oxy)butan-l-ol (3)

[0366] To a stirred solution of tert-butyldimethyl(4-(((2R,3R,4S,5S,6R)-3,4,5- tris(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-pyran-2-yl)oxy)butoxy)silane (1.00 g, 1.38 mmol) in MeOH (15 mL). 4-methylbenzenesulfonic acid hydrate (0.052 g, 0.275 mmol) was added at 0 °C. The reaction mixture was stirred at ambient temperature for 2 h. Upon completion, as indicated by LCMS, the reaction mixture was quenched by water (5 mL) and extracted with DCM (3 X 10 mL). Combined organic phases were washed with brine (10 mL), dried over sodium sulfate, and concentrated under reduced pressure. The crude was purified by reverse phase (C-18 column) purification to afford 4-(((2R,3R,4S,5S,6R)-3,4,5- tris(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-pyran-2-yl)oxy)butan-l-ol (300 mg, 36%) LCMS (ES+): m / z 630.4 [M + NH4]+.

[0367] Step-3: chloromethyl (4-(((2R,3R,4S,5S,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-pyran-2-yl)oxy)butyl) carbonate (3)

[0368] To a stirred solution of 4-(((2R,3R,4S,5S,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)tetr ahydro-2H-pyran-2-yl)oxy)butan-l-ol (1; 300 mg, 0.49 mmol) in DCM (5 mL) was added pyridine (77 mg, 0.98 mmol) and chloromethyl carb onochlori date (76 mg, 0.59 mmol) at 0 °C. The reaction mixture was stirred at ambient temperature for 2 h. Upon completion, as indicated by LCMS, the mixture was quenched by water (3 mL) and extracted with DCM (3 X 7 mL). Combined organic phases were washed with brine (5 mL), dried over sodium sulfate, and concentrated under reduced pressure to afford chloromethyl (4- (((2R,3R,4S,5S,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-pyran-2- yl)oxy)butyl) carbonate (320 mg, crude), which was used in the next step without further purification.

[0369] Step-4: (N-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH-benzo[d]imidazol-2- yl)-3,3-dimethylbutanamido)methyl (4-(((2R,3R,4S,5S,6R)-3,4,5-tris(benzyloxy)-6- ((benzyloxy)methyl)tetrahydro-2H-pyran-2-yl)oxy)butyl) carbonate (4)

[0370] To a stirred solution of N-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH- benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide (Formula III) (150 mg, 0.431 mmol) in acetonitrile (3 mL) was added cesium carbonate (210 mg, 0.646 mmol) and chloromethyl (4-(((2R,3R,4S,5S,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-pyran-2- yl)oxy)butyl) carbonate (3; 304 mg, 0.431 mmol). The reaction mixture was heated at 80 °C10130175-101610 / 20289-WO-PCTfor 5 h. Upon completion, as indicated by LCMS, the mixture was quenched with water (3 mL) and extracted with ethyl acetate (3 x 3 mL). Combined organic phases were washed with brine (2 mL), dried over sodium sulfate, and concentrated under reduced pressure. The crude was purified by reverse phase chromatography (using C-18; 100 g column) using a mixture of acetonitrile and 0.1 M aq. ammonium bicarbonate to afford (N-(l-(tert-butyl)-6-cyano-4,7- difluoro-lH-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamido)methyl (4-(((2R,3R,4S,5S,6R)- 3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-pyran-2-yl)oxy)butyl) carbonate (4) as white solid (85 mg, 19%).

[0371] Step-5: (N-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH-benzo [d] imidazol-2- yl)-3,3-dimethylbutanamido)methyl (4-(((2R,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)butyl) carbonate (Cmpd. 189)

[0372] To a stirred solution of (N-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH- benzo[d]imidazol-2-yl)-3,3-dimethylbutanamido)methyl (4-(((2R,3R,4S,5S,6R)-3,4,5- tris(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-pyran-2-yl)oxy)butyl) carbonate (4; 80 mg, 0.079 mmol) in ethyl acetate (10 mL) was added palladium on carbon (Pd / C) (167 mg, 0.157 mmol). The mixture was stirred at ambient temperature under H2 atmosphere (hydrogen gas balloon) for 2 h. The reaction mixture was filtered through celite and concentrated under reduced pressure. The crude was purified by reverse phase (Cl 8 column) purification to afford (N-(l-(tert-butyl)-6-cyano-4,7-difluoro-lH-benzo[d]imidazol-2-yl)-3,3- dimethylbutanamido)methyl (4-(((2R,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)butyl) carbonate (Cmpd. 189) as white solid (18.2 mg, 35%). LCMS (ES+): m / z 657.3 [M + H]+.

[0373] Synthesis of 4-(((2R,3R,4S,5S,6R)-3,4,5-tris(benzyloxy)-6- ((benzyloxy)methyl)tetrahydro-2H-pyran-2-yl)oxy)butan-l-ol (3)Table 4: Analytical Data10230175-101610 / 20289-WO-PCT10330175-101610 / 20289-WO-PCT10430175-101610 / 20289-WO-PCT10530175-101610 / 20289-WO-PCT10630175-101610 / 20289-WO-PCT10730175-101610 / 20289-WO-PCT10830175-101610 / 20289-WO-PCT10930175-101610 / 20289-WO-PCT11030175-101610 / 20289-WO-PCT11130175-101610 / 20289-WO-PCT11230175-101610 / 20289-WO-PCT11330175-101610 / 20289-WO-PCT11430175-101610 / 20289-WO-PCT11530175-101610 / 20289-WO-PCT11630175-101610 / 20289-WO-PCT11730175-101610 / 20289-WO-PCT11830175-101610 / 20289-WO-PCTLCMS method:11930175-101610 / 20289-WO-PCTAbbreviations: ACN = acetonitrile, TFA = trifluoroacetic acid, DMSO = dimethyl sulfoxide, DCM = dichloromethane.EXAMPLES

[0374] Example 1: Aqueous Solubility, Aqueous Chemical Stability, and Lipophilicity

[0375] 1.1 Aqueous Solubility

[0376] For IV formulation, enhanced aqueous solubility is generally desirable to avoid formulation challenges. To assess the aqueous solubility of the prodrug compounds described herein, a thermodynamic solubility assay was performed at three different pH values of 3.0, 5.0, and 7.4.

[0377] The following general, exemplary experimental procedures were followed.The test buffer systems were generally prepared as in the following preparations. The pH 3.0 phosphate buffer was prepared by dissolving 3.40 g of potassium dihydrogen phosphate in 900 mL of Milli-Q water, adjusting the pH to 3.0 using phosphoric acid, and diluting to 1000 mL with Milli-Q water. The pH 5.0 acetate buffer was prepared by dissolving 8.08 g of NaOH, 17.5 g of glacial acetic acid, and 23.75 g of NaCl in 900 mL of Milli-Q water with stirring to dissolve, followed by final dilution to 2L and pH adjustment, if necessary, with IN NaOH or IN HC1. The pH 7.4 phosphate buffer was prepared by dissolving 2.79 g of12030175-101610 / 20289-WO-PCTK2HPO4 and 0.54 g of KH2PO4 in 90 mL of Milli-Q water, followed by adjusting the pH to 7.4 using IN HCL / 1N NaOH and diluting to 200 mL with Milli-Q water.

[0378] The test compounds were prepared at a concentration of 50 mM in 100% DMSO using volumetric glassware. To perform the assay(s), master stock solution (100 mM) of test compound (2.5 pL ) was added to 247.5 pL of respective buffer and incubated for 24 h at 37 °C on a thermomixer at a shaking speed of 1000 rpm. Final DMSO concentration in the incubations was 1% v / v. At 24 h, samples were centrifuged at 4000 rpm for 10 min and filtered using 0.45 pm PVDF filter. Filtrate was collected, then analyzed using HPLC. Test samples were analyzed against eight point calibration curve. (Cone, from 1200 pM to 3 pM). Solubility values (pM) were calculated with the slope generated against the HPLC calibration curve. The solubilities were classified as “Low” or “L” for concentrations <25 pM, “Moderate” or “M” for concentrations from 25 - 150 pM, or “High” or “H” for concentrations > 150 pM. The solubility results obtained are depicted in Table 5 below, along with the chemical stability results.

[0379] 1.2 - Aqueous Chemical Stability

[0380] In addition to aqueous solubility, chemical stability is also advantageous to ensure that the prodrug compounds remain intact.. To assess the chemical stability of the prodrug compounds described herein, an aqueous chemical stability assay was performed at three different pH values of 3.0, 5.0, and 7.4.

[0381] The following general, exemplary experimental procedures were followed. The test buffer systems were generally prepared as in the following preparations. The pH 3.0 phosphate buffer was prepared by dissolving 3.40 g of potassium dihydrogen phosphate in 900 mL of Milli-Q water, adjusting the pH to 3.0 using phosphoric acid, and diluting to 1000 mL with Milli-Q water. The pH 5.0 acetate buffer was prepared by dissolving 8.08 g of NaOH, 17.3 g of glacial acetic acid, and 23.75 g of NaCl in 900 mL of Milli-Q water with stirring to dissolve, followed by final dilution to 2L and pH adjustment, if necessary, with IN NaOH or IN HC1. The pH 7.4 phosphate buffer was prepared by first preparing two solutions A and B. Solution A was prepared by dissolving 8.7 g of K2HPO4 in 50 mL of Milli-Q water. Solution B was prepared by dissolving 6.8 g of KH2PO4 in 50 mL of Milli-Q water. The buffer was prepared by combining 8.02 mL of solution A and 1.98 mL of solution B, followed by dilution to 100 mL with Milli-Q water.

[0382] A quenching solution was prepared in acetonitrile containing the internal standards tolbutamide and telmisartan. A stock tolbutamide solution (40 mg / mL in DMSO) and telmisartan (10 mg / mL in DMSO) were prepared. 10 pL of the tolbutamide stock and 2512130175-101610 / 20289-WO-PCTpL of the telmisartan stock were added to 1 L of acetonitrile to prepare the quenching solution having 400 ng / mL tolbutamide and 250 ng / mL telmisartan internal standards. A portion of the quenching solution was chilled for subsequent steps.

[0383] The test compounds were prepared first as 10 mM stock solutions in DMSO. From the stock solutions, ImM solutions in DMSO were prepared. The following steps a-e.) were then performed, a.) Add master stock solution (1 mM in DMSO) of test compound (1 pL) to 99 pL of buffer and incubate for 0, 1, 2, 4, 6 and 24 hr (600 rpm) at 37°C (N=2) separately, b.) Final DMSO concentration in the incubations is 1% v / v. c.) Collect the samples at 0, 1, 2, 4, 6 and 24 hr and mix the samples with 300 uL of ice cold quenching solution containing the internal standards d.) Centrifuge samples for 20 min at 4000 rpm. e) After centrifugation, transfer 100 pL of supernatant to a 96-well plate and dilute with 100 pL of water, vortex mix for 30 sec on Eppendorf mix mate at 600 RPM. Take an aliquot of 100 pL of this sample and dilute with 100 pL of water, vortex again for 30 sec on Eppendorf mix mate at 600 RPM and analyze via LC-MS / MS. The percent compound remaining (PCR; % remaining) = (Area ratio of test sample at respective time point / Area ratio of test sample at 0 min time point) X 100. Table 5 below shows the stability at 24 hours where a PCR of >70% is denoted “S” for “Stable” and a PCR of < 70% is denoted “U” for “Unstable” at each pH.Table 5. Aqueous Solubility and Aqueous Stability at 24 hours.12230175-101610 / 20289-WO-PCT12330175-101610 / 20289-WO-PCT

[0384] From these results, it can be seen that Formula III has low aqueous solubility at each pH tested, and is generally unstable except for at pH 7.4. Conversely, various prodrug compounds have the advantages of being highly soluble and / or stable at most if not all pH values tested. In view of these results, the prodrug compounds overcome a technical challenge of preparing aqueous pharmaceutical compositions, such as intravenous or other parenteral formulations, of Formula III.

[0385] 1.3 Lipophilicity

[0386] A pH 7.4 phosphate buffer was prepared by mixing 19 mL of a IM KH2PO4 solution and 81 mL of a IM K2HPO4 solution, made up to IL in Milli-Q water with pH adjustment to pH 7.4, as necessary. A portion of phosphate buffer (pH 7.4) was mixed with an equal quantity of octanol and mechanically shaken for 24 hours. After shaking, the mixture was allowed to settle for 48 hours without disturbing. After 48 hours, the layers were separated, the upper layer containing saturated octanol and the lower layer containing saturated phosphate buffer.12430175-101610 / 20289-WO-PCT

[0387] An internal standard solution was obtained by the following procedure: prepare 40 mg / mL stock solution of tolbutamide and 10 mg / mL stock of telmisartan in DMSO. Add 10 pL of 40 mg / mL stock solution of tolbutamide and 25 pL of telmisartan to 1 L of acetonitrile for preparing 400 ng / mL tolbutamide and 250 ng / mL of telmisartan as an internal standard in acetonitrile.

[0388] The lipophilicity assay was performed according to the following procedure: 10 pL of 10 mM DMSO stock is spiked in 2 mL 96 deep well plate. To the compound spiked 96 deep well plate is added 495 pL of saturated octanol and the plate is mixed for 5 min at 1000 rpm. Saturated phosphate buffer (495 pL) is added to 96 deep well plate containing reference / test compound in saturated octanol. The plates are shaken at RT for 2 hr at 1000 rpm on Thermomixer. After 2 hr of shaking, the plates are centrifuged at 4000 rpm for 10 min. After centrifugation, 200 pL of octanol (upper layer) is separated. After removing remaining octanol layer, 200 pL of buffer layer is collected. Both the samples are processed for LCMS analysis.

[0389] The lipophilicity was determined by the following Log-D sample preparation for LC-MS / MS: Log-D Sample 10 pL of Octanol was added to 30 pL of blank Buffer and 30 pL of Buffer Sample was added to 10 pL of blank Octanol (Matrix Match) and vortexed for 5 min and mixed with 260 pL of acetonitrile containing internal standard (400 ng / mL Tolbutamide and 250ng / mL Telmisartan). Samples were centrifuged at 4000 rpm for 10 min and 200 pL supernatant was separated. Both the octanol and buffer fractions were diluted 5 times with acetonitrile containing internal standard (400 ng / mL Tolbutamide and 250ng / mL Telmisartan) due to high response. Samples were analyzed by LC-MS / MS. Further 10 times dilution was performed by taking 20 pL of supernatant and 180 pL of acetonitrile for control samples. Log D values were calculated using the log of ratio of octanol area ratio normalized with injection volume to buffer area ratio normalized with injection volume. LogD values < 1 correspond to a “Low” partition coefficient, values from 1 - 3 correspond to a “Moderate” partition coefficient, and values > 3 correspond to a “High” partition coefficient. A high partition coefficient indicates relatively high lipophilicity and a low partition coefficient indicates relatively low lipophilicity. These results are shown in Table 6 below:Table 6: LogD and partition coefficients.12530175-101610 / 20289-WO-PCT

[0390] From the above lipophilicity results, it can be seen that various prodrugs exhibit lipophilicity which differs from the active pharmaceutical compound Formula III. Particularly, many prodrugs exhibit moderate or low lipophilicity compared to the high12630175-101610 / 20289-WO-PCTlipophilicity observed for the active pharmaceutical compound. These results indicate that prodrugs may advantageously modify the lipophilicity for formulation, delivery, and / or pharmacokinetic advantages.

[0391] Example 2: Plasma Stability

[0392] While aqueous stability is generally advantageous for the prodrug compounds, as analyzed in Example 1 above, it is generally advantageous for prodrug compounds to have poor plasma stability. Poor plasma stability is generally advantageous to facilitate release of the active pharmaceutical compound. Therefore, a plasma stability assay was performed to analyze plasma stability in rat, human, and / or dog plasma.

[0393] The following general, exemplary procedures were followed for each of the rat, human, and dog plasma stability experiments. Plasma was removed from deep freeze and allowed to thaw at room temperature. Once thawed, the plasma was centrifuged at 4000 rpm for 10 minutes, and the collected supernatant was used for the assay. For each tested compound, a master 10 mM stock solution was prepared in 100% DMSO. A working stock solution (100 pM) was then prepared from each stock by diluting 2 pL of the 10 mM master stock with 198 pL of acetonitrile: water (1 : 1 v / v). Internal standards were prepared as follows: 6.25 pL tolbutamide (40 mg / mL) and 25 pL telmisartan (10 mg / mL) to IL acetonitrile to prepare 250 ng / mL tolbutamide and 250 ng / mL telmisartan. A portion of the acetonitrile with internal standard was then chilled on ice. Working stock solution (100 pM) of test compound (4 pL) was spiked to 396 pL of plasma and incubated for 5 h at 37 °C. At each time point (0, 15, 30, 60, 120 and 300 min), 50 pL of incubation mixture was precipitated with 300 pL of ice cold acetonitrile containing the internal standards. Samples were vortexed for 10 min at 1000 rpm and centrifuged at 4000 rpm for 10 min. After centrifugation, 100 pL of supernatant was diluted with 100 pL of water and analyzed by LC-MS / MS. The Percent Compound Remaining (PCR) was determined and Table 7 below shows the stability at 300 minutes where a PCR of >70% is denoted “S” for “Stable” and a PCR of < 70% is denoted “U” for “Unstable” for each plasma type.Table 7: Plasma Stability at 300 Minutes12730175-101610 / 20289-WO-PCT12830175-101610 / 20289-WO-PCT

[0394] From these results, it can be seen that most of the prodrugs tested exhibited plasma instability, which should be generally advantageous for release of the active pharmaceutical ingredient in vivo.

[0395] Example 3: Rat Pharmacokinetics

[0396] IV Pharmacokinetics

[0397] To evaluate release of the active pharmaceutical ingredient from the prodrug in vivo, rat pharmacokinetic data was collected. Rats were dosed intravenously through the tail vein with Img / kg of Formula III (active pharmaceutical ingredient) or prodrug, corrected to 1 mg / kg of active pharmaceutical ingredient. Plasma samples were typically collected from the jugular vein at time points of 5 min, 15 min, 30 min, 1 hr, 2 hr, 4 hr, 6 hr, 8 hr, 12 hr and 24 hr. The anticoagulant used for blood samples was 200 mM K2 EDTA (20 pL / mL of blood) with 0.1% paraxon. The IV formulation used was DMSO: Tween 80: PEG200: Saline (5%: 5%: 30%: 60%). Concentrations of prodrug and Formula III were detected via LC- MS / MS. In most examples, rapid degradation of the prodrug was observed (i.e., within first hour), and in all cases the released active pharmaceutical compound Formula III was detected.

[0398] FIG. 1 shows a comparison of Formula III detected after administration of the compound, or after administration of a prodrug compound of the present invention. From this comparison, it can be seen that the prodrugs of the present invention effectively release the active pharmaceutical composition in vivo.

[0399] Example 4: Dog Pharmacokinetics

[0400] Male beagle dogs were obtained from PalamurBio Sciences, aged 1 to 3 years. Dogs were dosed intravenously via IV infusion (10 minutes) through the cephalic vein. Blood12930175-101610 / 20289-WO-PCTsamples were collected at pre-dose, 0.083 (during infusion), 0.167 (end of infusion), 0.33, 0.67, 1, 2, 4, 6, 8, 12, and 24 hours. The formulation vehicle for test compounds was PEG400: PG: 20% HPBCD in PBS (7.4 pH) (20:20:60 % by volume). The dosage was 0.3 mg / kg, administered at a dose of 1 mL / kg from a 0.3 mg / mL formulation of the test compound. For each test compound, three animals were treated. The treatment was well- tolerated with no serious adverse effects.

[0401] FIGs. 2A, 2B, and 2C show representative pharmacokinetic data for compounds 30, 56, and 86. For each compound administered, disappearance of the prodrug can be observed with concomitant formation the active pharmaceutical ingredient. The mean half-life of these compounds was 0.45 hours, 0.04 h, and 0.28 h, respectively to yield the active pharmaceutical compound of Formula III.

[0402] From these results, it can be seen that formulations of the prodrugs of the present invention can be administered to effectively release the active pharmaceutical compound of Formula III. These characteristics, along with one or more other improved characteristics of lipophilicity, solubility and / or chemical stability, make the prodrugs of the present invention an advantageous improvement over the active pharmaceutical composition of Formula III.Incorporation by Reference

[0403] The entire disclosure of each of the patent documents, including certificates of correction, patent application documents, scientific articles, governmental reports, websites, and other references referred to herein is incorporated by reference herein in its entirety for all purposes. In case of a conflict in terminology, the present specification controls.Equivalents

[0404] The invention can be embodied in other specific forms without departing from the spirit or essential characteristics thereof. The foregoing embodiments are to be considered in all respects illustrative rather than limiting on the invention described herein. In the various embodiments of the compositions and methods, where the term comprises is used with respect to the components of the compositions or the recited steps of the methods, it is also contemplated that the compositions and methods consist essentially of, or consist of, the recited components or steps. Furthermore, it should be understood that the order of steps or order for performing certain actions is immaterial so long as the invention remains operable. Moreover, two or more steps or actions can be conducted simultaneously.

[0405] In the specification, the singular forms also include the plural forms, unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific13030175-101610 / 20289-WO-PCTterms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In the case of conflict, the present specification will control.

[0406] Furthermore, it should be recognized that in certain instances a composition can be described as being composed of the components prior to mixing, because upon mixing certain components can further react or be transformed into additional materials.

[0407] All percentages and ratios used herein, unless otherwise indicated, are by weight. It is recognized the mass of an object is often referred to as its weight in everyday usage and for most common scientific purposes, but that mass technically refers to the amount of matter of an object, whereas weight refers to the force experienced by an object due to gravity. Also, in common usage the “weight” (mass) of an object is what one determines when one “weighs” (masses) an object on a scale or balance.13130175-101610 / 20289-WO-PCT

Claims

CLAIMSWHAT IS CLAIMED IS:

1. A benzimidazol- 1,2-yl amide prodrug compound according to Formula I:Formula I, or a pharmaceutically acceptable salt thereof, wherein:D is C2-C5 alkyl or phenyl, wherein said C2-5 alkyl or phenyl is optionally substituted with one or more substituents independently selected from -CH3 and -F;A is Ci-Ce alkyl;X is -H, -F, -CH3, -CF3, -CF2H, -CFH2, -SCF3, pyridinyl, C1-C3 alkyl, phenyl, or cyclobutyl, wherein said C1-C3 alkyl, phenyl, or cyclobutyl is optionally substituted with one or more F;Y is H, F, -OH, or -CH3;Q is -SO3H, -SO2R5, -P(=O)(OH)2, -R6-O(P=O)(OH)2, -R6-O(P=O)(OH)-O-R7, - (C=O)-NR8R9, -R6-NR8R9, -R6-O(C=O)-NR8R9, -R6-O(C=O)-R10-Rn-R6-O(C=O)- O-R10-Rn, -R6-O(C=O)-O-Rn, -(C=O)-O-Rn, -(C=O)-O-R10-Rn, -(C=O)-Rn, - (C=O)-R10-Rn, -R10-Rn, and -R11,R1is H, C3-C4 hydroxyalkyl, -CN, -OH, -CF3, -OCHF2, NRARB, halogen, C3-C5 heterocycloalkyl, C1-C7 alkoxy, or C1-C5 alkyl, wherein said C3-C5 heterocycloalkyl C1-C7 alkoxy, or C1-C5 alkyl is optionally substituted with one or more substituents independently selected from -OH or F;R2is H, halogen, -CN, -OCH3, -CORA, -CF3, -OCF3, or C1-C2 alkyl, wherein said Ci- C2 alkyl is optionally substituted with one or more substituents independently selected from -OCH3 and -CORA;R3is H, halogen, -CF3, -OCHF2, -OCF3, -OCFH2or -OCH3;R4is H, halogen, or C3 hydroxyalkyl;R5and R7are each independently Ci-Ce alkyl optionally substituted with one or more substituents independently selected from -OH; =0, and -NH2;13230175-101610 / 20289-WO-PCTR6is methylene optionally substituted with one or more substituents independently selected from C1-C5 alkyl, cyclopropyl, gem-cyclopropyl, and carbonyl, optionally wherein two of said C1-C5 alkyl substituents form a 3-6 membered ring;R8and R9are independently -H, Ci-Ce alkyl, C2-C10 heteroalkyl, phenyl, or C5- Cioheteroaryl, optionally substituted with one or more substituents independently selected from -OH, =0, -NH2, -CH2-O-(C=O)-CH2-RcCi-C6alkyl, Ci-C6heteroalkyl, -(CH2)m-O(P=O)(OH)2, -(CH2)m-OS(=O)2(OH), said one or more substituents of R8or R9optionally further substituted with -OH, C1-C5 alkyl, C1-C5 heteroalkyl, -(CH2)m-O(P=O)(OH)2or-(CH2)m-OS(=O)2(OH), orR8and R9together with the nitrogen to which they are attached form a C4-C7 cycloalkyl, C4-C7 heterocycloalkyl, or C5-C10 heteroaryl optionally substituted with one or more substituents independently selected from C1-C10 alkyl, C2-C14 heteroalkyl, C4-C7 cycloalkyl or C4-C7 heterocycloalkyl;R10is Ci-C5alkyl, -(CH2-CH2-O)n-, -CH2-(CH2-CH2-O)n-:-(CH2)k-C4-C7 cycloalkyl, or -(CH2)k-C4-C? heterocycloalkyl;R11is - H, -OH, C1-C10 alkyl, C2-C10 heteroalkyl, C4-C7 cycloalkyl, C4-C7 heterocycloalkyl, C4-C7 heteroaryl, phenyl, -(CH2)m-O(P=O)(OH)2, -(CH2)m-O(PO3)2',(CH2)m-NH2, -(CH2)m-NH(CH3), -(CH2)m-N(CH3)2, -NH3+, -N(CH3)3+, -N(CH2- CH3)3+, -(CH2)m-O-(C=O)-O-(CH2-CH2-O)n-CH3, and -(CH2)n-RD, optionally substituted with one or more substituents independently selected from -NH2, -(CH2)m- O(P=O)(OH)2, =NH, NH(CH3), -N(CH3)2, -NH3+, -N(CH3)3+, =0, -OH, -C1-C3alkyl,-(CH2)mOH, -(CH2)mCOOH, -(C=O)-O-C-(CH3)3, , -(CH2)m-OS(=O)2(OH), -(C=O)-RDor -RD, or whereinwhen R10is -(CH2-CH2-O)n-, k is an integer from 0 to 3; m is an integer from 0 to 3; n is an integer from 0 to 6; RAand RBare -CH3;13330175-101610 / 20289-WO-PCTRcis Ci-Ce alkyl, Ci-Ce heteroalkyl, C4-C10 cycloalkyl, C4-C10 heterocycloalkyl, phenyl, C5-C10 heteroaryl, or -NR8R9andRDis a monosaccharide or an amino acid including salts thereof.

2. A benzimidazol- 1,2-yl amide prodrug compound according to claim 1, wherein R1is - CN.

3. A benzimidazol- 1,2-yl amide prodrug compound according to claim 1, wherein R2and R3are halogen.

4. A benzimidazol- 1,2-yl amide prodrug compound according to claim 1, wherein R2and R3are -F.

5. A benzimidazol- 1,2-yl amide prodrug compound according to claim 1, wherein R4is selected from -H and -OH.

6. A benzimidazol- 1,2-yl amide prodrug compound according to claim 1, wherein R4is - H.

7. A benzimidazol- 1,2-yl amide prodrug compound according to claim 1, wherein D is selected from methyl, ethyl, propyl, and butyl.

8. A benzimidazol- 1,2-yl amide prodrug compound according to claim 1, wherein D is tert-butyl.

9. A benzimidazol- 1,2-yl amide prodrug compound according to claim 1, wherein A is C3 alkyl.

10. A benzimidazol- 1,2-yl amide prodrug compound according to claim 1, wherein X andY are selected from methyl, ethyl, propyl, and butyl.

11. A benzimidazol- 1,2-yl amide prodrug compound according to claim 1, wherein X andY are methyl.13430175-101610 / 20289-WO-PCT12. A benzimidazol- 1,2-yl amide prodrug compound according to claim 1, wherein R6is substituted with methyl, ethyl, propyl, or butyl.

13. A benzimidazol- 1,2-yl amide prodrug compound according to claim 1, wherein the Ci-C6heteroaryl of R8and / or R9is -CH2-CH2-NH2 or -CH2-CH2-OH.

14. A benzimidazol- 1,2-yl amide prodrug compound according to claim 1, wherein R8and / or R9are optionally substituted with a Ci-Ce heteroalkyl selected from the group consisting of -CH2-OH, -CH2-N(CH3)2, -CH2-CH2-N(CH3)2, -CH2-CH2-CH2-N(CH3)215. A benzimidazol- 1,2-yl amide prodrug compound according to claim 1, wherein R8and R9together form N-methylpiperazine, piperazine, morpholine, piperidine, or azetidine.

16. A benzimidazol- 1,2-yl amide prodrug compound according to claim 1, wherein the C4-C7 heteroalkyl of R10is -CH2-CH2-S-S-CH2-CH2 or oxetane.

17. A benzimidazol- 1,2-yl amide prodrug compound according to claim 1, wherein the C2-C10 heteroalkyl of R11is selected from the group consisting of: -O-CH3, -CH2-O- CH3, -CH2-CH2-O-CH3, -O-CH2-CH3, -CH2-O-CH2-CH3, and -CH2-CH2-O-CH2-CH318. A benzimidazol- 1,2-yl amide prodrug compound according to claim 1, wherein the C4-C7 heterocycloalkyl of R11is selected from the group consisting of azetidine, piperazine, morpholine, N-methyl piperidine N-methyl piperazine, and piperidine.

19. A benzimidazol- 1,2-yl amide prodrug compound according to claim 1, wherein the C2-C10 heteroalkyl of R11is -CH2-CH2-S-S-CH2-CH2.

20. A benzimidazol- 1,2-yl amide prodrug compound according to claim 1, wherein the Ci-Ce heteroalkyl of Rcis -NH-CH321. A benzimidazol- 1,2-yl amide prodrug compound according to claim 1, wherein RDis a monosaccharide having the chemical formula G>H 12O6, or wherein RDis the amino acid serine or a derivative thereof.13530175-101610 / 20289-WO-PCT22. A benzimidazol- 1,2-yl amide prodrug compound according to Formula II:Formula II, or a pharmaceutically acceptable salt thereof, wherein:Q is -SO3H, -SO2R5, -P(=O)(OH)2, -R6-O(P=O)(OH)2, -R6-O(P=O)(OH)-O-R7, - (C=O)-NR8R9, -R6-NR8R9, -R6-O(C=O)-NR8R9, -R6-O(C=O)-R10-Rn, -R6-O(C=O)- O-R10-Rn, -R6-O(C=O)-O-Rn, -(C=O)-O-Rn, -(C=O)-O-R10-Rn, -(C=O)-Rn, - (C=O)-R10-Rn, -R10-Rn, or -R11;R5and R7are each independently Ci-Ce alkyl optionally substituted with one or more substituents independently selected from -OH; =0, and -NH2;R6is methylene optionally substituted with one or more substituents independently selected from C1-C5 alkyl, cyclopropyl, gem-cyclopropyl, and carbonyl, optionally wherein two of said C1-C5 alkyl substituents form a 3-6 membered ring;R8and R9are independently -H, Ci-Ce alkyl, C2-Cio heteroalkyl, phenyl, or C5- Cioheteroaryl, optionally substituted with one or more substituents independently selected from -OH, =0, -NH2, -CH2-O-(C=O)-CH2-RcCi-C6alkyl, Ci-C6heteroalkyl, -(CH2)m-O(P=O)(OH)2, -(CH2)m-OS(=O)2(OH), said one or more substituents of R8or R9optionally further substituted with -OH, C1-C5 alkyl, C1-C5 heteroalkyl, -(CH2)m-O(P=O)(OH)2or-(CH2)m-OS(=O)2(OH), orR8and R9together with the nitrogen to which they are attached form a C4-C7 cycloalkyl, C4-C7 heterocycloalkyl, or C5-C10 heteroaryl optionally substituted with one or more substituents independently selected from C1-C10 alkyl, C2-Ci4 heteroalkyl, C4-C7 cycloalkyl or C4-C7 heterocycloalkyl;R10is Ci-C5alkyl, -(CH2-CH2-O)n-, -CH2-(CH2-CH2-O)n-, -(CH2)k-C4-C7 cycloalkyl, or -(CH2)k-C4-C7 heterocycloalkyl;Rnis -H, -OH, C1-C10 alkyl, C2-Cio heteroalkyl, C4-C7 cycloalkyl, C4-C7 heterocycloalkyl, C4-C7 heteroaryl, phenyl, -(CH2)m-13630175-101610 / 20289-WO-PCTk is an integer from 0 to 3; m is an integer from 0 to 3; n is an integer from 0 to 6;Rcis Ci-Ce alkyl, Ci-Ce heteroalkyl, C4-C10 cycloalkyl, C4-C10 heterocycloalkyl, phenyl, C5-C10 heteroaryl, or -NR8R9andRDis a monosaccharide or an amino acid including salts thereof.

23. A benzimidazol- 1,2-yl amide prodrug compound according to claim 22, wherein Q is -R6-O(C=O)-R10-R11or -R6-O(C=O)-O-R10-R11.

24. A benzimidazol- 1,2-yl amide prodrug compound according to claim 22, wherein R10is selected from -(CH2-CH2-O)n, C1-C5 alkyl, and C4-C7 cycloalkyl.

25. A benzimidazol- 1,2-yl amide prodrug compound according to claim 22, wherein R10is C1-C5 alkyl or C4-C7 cycloalkyl, optionally substituted with one or more R11.

26. A benzimidazol- 1,2-yl amide prodrug compound according to claim 25, wherein R10is selected from -(CH2)-, -(CH2-CH2)-, -(CH2-CH2-CH2)-, -( CH2- CH2-CH2-CH2)-, and -(CH2- CH2-CH2-CH2-CH2)-.13730175-101610 / 20289-WO-PCT27. A benzimidazol- 1,2-yl amide prodrug compound according to claim 25, wherein R10is cyclohexyl.

28. A benzimidazol- 1,2-yl amide prodrug compound according to claim 22, wherein R11is selected from Ci-Cio alkyl, -(CH2)m-O(P=O)(OH)2, -(CH2)m-O(PO3)2', and C4-C7 heterocycloalkyl.

29. A benzimidazol- 1,2-yl amide prodrug compound according to claim 28, wherein R11is methyl, ethyl, propyl, or butyl.

30. A benzimidazol- 1,2-yl amide prodrug compound according to claim 28, wherein R11is azetidine.

31. A benzimidazol- 1,2-yl amide prodrug compound according to claim 22 selected from the group consisting of:pharmaceutically-acceptable salts thereof.13830175-101610 / 20289-WO-PCT32. A benzimidazol- 1,2-yl amide prodrug compound according to claim 22, having the structure:pharmaceutically-acceptable salt thereof.

33. A benzimidazol- 1,2-yl amide prodrug compound according to claim 22, having the structure:pharmaceutically-acceptable salt thereof.

34. A benzimidazol- 1,2-yl amide prodrug compound according to claim 22, having the structure:pharmaceutically-acceptable salt thereof.

35. A benzimidazol- 1,2-yl amide prodrug compound according to claim 22, having the structure:pharmaceutically-acceptable salt thereof.

36. A benzimidazol- 1,2-yl amide prodrug compound according to claim 22, having the structure:pharmaceutically-acceptable salt thereof.13930175-101610 / 20289-WO-PCT37. A benzimidazol- 1,2-yl amide prodrug compound according to claim 22, having the structure:pharmaceutically-acceptable salt thereof.

38. A benzimidazol- 1,2-yl amide prodrug compound selected from the group consisting<img src='' class="img-anchor img-center" img-id="IMGF000141_0002" / >14030175-101610 / 20289-WO-PCT14130175-101610 / 20289-WO-PCT14230175-101610 / 20289-WO-PCT14330175-101610 / 20289-WO-PCT14430175-101610 / 20289-WO-PCT14530175-101610 / 20289-WO-PCT14630175-101610 / 20289-WO-PCT30175-101610 / 20289-WO-PCT30175-101610 / 20289-WO-PCT30175-101610 / 20289-WO-PCT15030175-101610 / 20289-WO-PCT39. A benzimidazol- 1,2-yl amide prodrug compound according to Formula IV:D is C2-C5 alkyl or phenyl, wherein said C2-5 alkyl or phenyl is optionally substituted with one or more substituents independently selected from -CH3 and -F;A is Ci-Ce alkyl;X is -H, -F, -CH3, -CF3, -CF2H, -CFH2, -SCF3, pyridinyl, C1-C3 alkyl, phenyl, or cyclobutyl, wherein said C1-C3 alkyl, phenyl, or cyclobutyl is optionally substituted with one or more -F;Y is -H, -F, -OH, or -CH3;15130175-101610 / 20289-WO-PCTQ is -P(=O)(OH)2, -R6-O(P=O)(OH)2, -R6-O(P=O)(OH)-O-R7, -(C=O)-NR8R9, -R6- NR8R9, -R6-O(C=O)-NR8R9, -R6-O(C=O)-R10-R11, -R6-O(C=O)-O-R10-R11, -R6- O(C=O)-O-Rn, -(C=O)-O-Rn, -(C=O)-O-R10-Rn, -(C=O)-Rn, -(C=O)-R10-Rn, - R10-Rn, or -R11;R1is H, C3-C4 hydroxyalkyl, -CN, -OH, -CF3, -OCHF2, NRARB, halogen, C3-C5 heterocycloalkyl, C1-C7 alkoxy, or C1-C5 alkyl, wherein said C3-C5 heterocycloalkyl C1-C7 alkoxy, or C1-C5 alkyl is optionally substituted with one or more substituents independently selected from -OH and -F;R2is -H, halogen, -CN, -OCH3, -CORA, -CF3, -OCF3, or Ci-C2alkyl, wherein said Ci- C2alkyl is optionally substituted with one or more substituents independently selected from -OCH3 and -CORA;R3is -H, halogen, -CF3, -OCHF2, -OCF3, -OCFH2or -OCH3;R4is -H, halogen, or C3 hydroxyalkyl;R5and R7are each independently Ci-Ce alkyl optionally substituted with one or more substituents independently selected from -OH; =0, and -NH2;R6is methylene optionally substituted with one or more substituents independently selected from C1-C5 alkyl, cyclopropyl, gem-cyclopropyl, and carbonyl, optionally wherein two of said C1-C5 alkyl substituents form a 3-6 membered ring ;R8and R9are independently -H, Ci-Ce alkyl, C2-Cio heteroalkyl, phenyl, or C5- Cioheteroaryl, optionally substituted with one or more substituents independently selected from -OH, =0, -NH2, -CH2-O-(C=O)-CH2-RcCi-C6alkyl, Ci-C6heteroalkyl, -(CH2)m-O(P=O)(OH)2, -(CH2)m-OS(=O)2(OH), said one or more substituents of R8or R9optionally further substituted with -OH, C1-C5 alkyl, C1-C5 heteroalkyl, -(CH2)m-O(P=O)(OH)2or-(CH2)m-OS(=O)2(OH), orR8and R9together with the nitrogen to which they are attached form a C4-C7 cycloalkyl, C4-C7 heterocycloalkyl, or C5-C10 heteroaryl optionally substituted with one or more substituents independently selected from C1-C10 alkyl, C2-Ci4 heteroalkyl, C4-C7 cycloalkyl or C4-C7 heterocycloalkyl;R10is Ci-C5alkyl, -(CH2-CH2-O)n-, -CH2-(CH2-CH2-O)n-, -(CH2)k-C4-C7cycloalkyl, or -(CH2)k-C4-C? heterocycloalkyl;R11is -H, -OH, C1-C10 alkyl, C2-Cio heteroalkyl, C4-C7 cycloalkyl, C4-C7 heterocycloalkyl, C4-C7 heteroaryl, phenyl, -(CH2)m-O(P=O)(OH)2, -(CH2)m-O(PO3)2',15230175-101610 / 20289-WO-PCTN(CH3)2, -(CH2)m-NH2, -(CH2)m-NH(CH3), -(CH2)m-N(CH3)2, -NH3+, -N(CH3)3+, - N(CH2-CH3)3+, -(CH2)m-O-(C=O)-O-(CH2-CH2-O)n-CH3, and -(CH2)n-RD, optionally substituted with one or more substituents independently selected from -NH2, -(CH2)m- O(P=O)(OH)2, =NH, -NH(CH3), -N(CH3)2, -NH3+, -N(CH3)3+, =0, -OH, -C1-C3alkyl, -(CH2)m0H, -(CH2)mC00H, -(C=O)-O-C-(CH3)3, , -(CH2)m-OS(=O)2(OH), - (C=O)-RDor -RD, or whereinwhen R10is -(CH2-CH2-O)n- k is an integer from 0 to 3; m is an integer from 0 to 3; n is an integer from 0 to 6;RAand RBare -CH3;Rcis Ci-Ce alkyl, Ci-Ce heteroalkyl, C4-C10 cycloalkyl, C4-C10 heterocycloalkyl, phenyl, C5-C10 heteroaryl, or -NR8R9andRDis a monosaccharide or an amino acid including salts thereof.

40. A benzimidazol- 1,2-yl amide prodrug is a compound according to Formula V:or a pharmaceutically acceptable salt thereof, wherein:Q is -P(=O)(OH)2, -R6-O(P=O)(OH)2, -R6-O(P=O)(OH)-O-R7, -(C=O)-NR8R9, -R6-NR8R9, -R6-O(C=O)-NR8R9, -R6-O(C=O)-R10-R11, -R6-O(C=O)-O-R10-R11, -R6-15330175-101610 / 20289-WO-PCTO(C=O)-O-Rn, -(C=O)-O-Rn, -(C=O)-O-R10-Rn, -(C=O)-Rn, -(C=O)-R10-Rn, - R10-Rn, or -R11;R5and R7are each independently Ci-Ce alkyl optionally substituted with one or more substituents independently selected from -OH; =0, and -NH2;R6is methylene optionally substituted with one or more substituents independently selected from C1-C5 alkyl, cyclopropyl, gem-cyclopropyl, and carbonyl, optionally wherein two of said C1-C5 alkyl substituents form a 3-6 membered ring;R8and R9are independently -H, Ci-Ce alkyl, C2-C10 heteroalkyl, phenyl, or C5- Cioheteroaryl, optionally substituted with one or more substituents independently selected from -OH, =0, -NH2, -CH2-O-(C=O)-CH2-RcCi-C6alkyl, Ci-C6heteroalkyl, -(CH2)m-O(P=O)(OH)2, -(CH2)m-OS(=O)2(OH), said one or more substituents of R8or R9optionally further substituted with -OH, C1-C5 alkyl, C1-C5 heteroalkyl, -(CH2)m-O(P=O)(OH)2or-(CH2)m-OS(=O)2(OH), orR8and R9together with the nitrogen to which they are attached form a C4-C7 cycloalkyl, C4-C7 heterocycloalkyl, or C5-C10 heteroaryl optionally substituted with one or more substituents independently selected from C1-C10 alkyl, C2-C14 heteroalkyl, C4-C7 cycloalkyl or C4-C7 heterocycloalkyl;R10is Ci-C5alkyl, -(CH2-CH2-O)n-, -CH2-(CH2-CH2-O)n-, -(CH2)k-C4-C7 cycloalkyl, or -(CH2)k-C4-C7 heterocycloalkyl;R11is - H, -OH, C1-C10 alkyl, C2-C10 heteroalkyl, C4-C7 cycloalkyl, C4-C7 heterocycloalkyl, C4-C7 heteroaryl, phenyl, -(CH2)m-O(P=O)(OH)2, -(CH2)m-O(PO3)2',N(CH3)2, -(CH2)m-NH2, -(CH2)m-NH(CH3), -(CH2)m-N(CH3)2, -NH3+, -N(CH3)3+, - N(CH2-CH3)3+, -(CH2)m-O-(C=O)-O-(CH2-CH2-O)n-CH3, and -(CH2)n-RD, optionally substituted with one or more substituents independently selected from -NH2, -(CH2)m- 0(P=0)(0H)2, =NH, -NH(CH3), -N(CH3)2, -NH3+, -N(CH3)3+, =0, -OH, -C1-C3alkyl, -(CH2)m0H, -(CH2)mC00H, -(C=O)-O-C-(CH3)3, , -(CH2)m-OS(=O)2(OH), - (C=0)-RDor -RD,15430175-101610 / 20289-WO-PCTor wherein R11is -(P=O)(OH)2 or when R10is -(CH2-CH2-O)n-, k is an integer ranging from 0 to 3; m is an integer ranging from 0 to 3; n is an integer ranging from 0 to 6;Rcis Ci-Ce alkyl, Ci-Ce heteroalkyl, C4-C10 cycloalkyl, C4-C10 heterocycloalkyl, phenyl, C5-C10 heteroaryl, or -NR8R9andRDis a monosaccharide or an amino acid including salts thereof.

41. A benzimidazol- 1,2-yl amide prodrug selected from the group consisting of:15530175-101610 / 20289-WO-PCT15630175-101610 / 20289-WO-PCT30175-101610 / 20289-WO-PCT42. A pharmaceutical composition comprising a benzimidazol- 1,2-yl amide prodrug according to any one of claims 1 to 41.

43. A method of treating a Kv7 associated disorder comprising administering to a subject in need thereof a therapeutically-effective amount of a benzimidazol- 1,2-yl amide15830175-101610 / 20289-WO-PCTprodrug according to any one of claims 1 to 41, or a pharmaceutical composition according to claim 42.

44. The method of claim 43, wherein the administration is intravenous.

45. The method of claim 43, wherein the subject is mammalian.

46. The method of claim 45, wherein the mammalian subject is human.

47. The method of claim 43, wherein the Kv7 associated disorder is a seizure disorder.

48. The method of claim 47, wherein the seizure disorder is status epilepticus.

49. A use of a benzimidazol- 1,2-yl amide prodrug according to any one of claims 1 to 41, or a pharmaceutical composition according to claim 42, for treating a Kv7 associated disorder in a subject in need thereof.

50. The use of claim 49, wherein the Kv7 associated disorder is a seizure disorder.

51. The use of claim 50, wherein the seizure disorder is status epilepticus.

52. A use of a benzimidazol- 1,2-yl amide prodrug according to any one of claims 1 to 41, or a pharmaceutical composition according to claim 42, in the manufacture of a medicament for treating a Kv7 associated disorder in a subject in need thereof.

53. The use of claim 52, wherein the Kv7 associated disorder is a seizure disorder.

54. The use of claim 53, wherein the seizure disorder is status epilepticus.15930175-101610 / 20289-WO-PCT

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