Imidazole modulators for the treatment of pain and hypertension

Abstract

The present disclosure relates to compounds of the formula (I) and pharmaceutically acceptable salts thereof, to processes for the preparation of, intermediates used in the preparation of, and compositions containing such compounds and the uses of such compounds for the treatment of pain or hypertension.

Description

[0001] IMIDAZOLE MODULATORS FOR THE TREATMENT OF PAIN AND HYPERTENSION

[0002] Inventors: John E. Donello, Donald E. Frail, Daniel W. Gil, Bruce D. Roth, and Robert A. Volkmann

[0003] CROSS REFERENCE TO RELATED APPLICATIONS

[0004] This application claims the benefit of U.S. Provisional Application No. 63 / 709,336, filed October 18, 2024, which is incorporated by reference herein in its entirety.

[0005] Background

[0006] There is an ongoing need for new compounds that are effective in the treatment of pain. There is also an ongoing need for new compounds that are effective in the treatment of hypertension.

[0007] Summary

[0008] This disclosure relates to compounds of the Formula: or pharmaceutically acceptable salts thereof, wherein:

[0009] R1is alk-(O)x-Y, wherein alk is C1-4 alkyl, =CH, or C1-4 =CH-alkyl; x is 0 or 1 ; and Y is H, C1-6 alkyl, C3-6 cycloalkyl, C3-6 heterocyclyl, amino, Ci-e alkylamino or -CEN, wherein Y is optionally substituted with CH3, -OCHs, tert-butoxycarbonyl, or 1 , 2, or 3 fluoro atoms, or a combination thereof;

[0010] R2is H, F, Cl, Br, alkyl, fluoroalkyl, alkoxy, cyclopropoxy or fluoroalkoxy;

[0011] R3is H, F, Cl, Br, alkyl, fluoroalkyl, alkoxy, cyclopropoxy or fluoroalkoxy; or R2and R3may be taken together with the carbon atoms to which they are attached to form a 5-8 membered heterocyclic ring system that is optionally substituted with 0, 1 , or 2 R4substituents and 0 or 1 R5substituents;

[0012] R4is H, F, Cl, Br, =O, alkyl, fluoroalkyl, alkoxy or fluoroalkoxy; and

[0013] In some embodiments, R5is H, alkyl, fluoroalkyl (such as C1-6 fluoroalkyl, e.g., -CH2F, -CHF2,- CFs, -CH2CH2F, etc.) or deuterio-alkyl (e.g., CD3). In some embodiments, if R5is directly attached to a carbon atom, R5is H, F, Cl, Br, alkyl, fluoroalkyl, alkoxy or fluoroalkoxy; or, if R5is directly attached to a nitrogen atom, R5is H, F, Cl, Br, or alkyl.

[0014] In some embodiments:

[0015] R1is alkyl optionally substituted with one to three substituents independently selected from the group H, F, Cl, Br, alkyl, cyclopropyl, [1 .1 .1 ]bicyclopentyl, alkoxy[1.1.1]bicyclopentyl, alkoxy (such as C1-6 alkoxy, e.g , -OCHs, -OC2H5, etc.), cyclopropoxy, fluoroalkoxy (such as Ci-s fluoroalkoxy, e.g., - OCH2F, -OCHF2, -OCF3, -OCH2CH2F, etc.), amino, alkylamino and dialkylamino; or the dashed line represents an optional double bond, and R1is a methylene group optionally substituted with alkoxy (such as C1-6 alkoxy, e g., -OCHs, -OC2H5, etc.);

[0016] R2is H, F, Cl, Br, alkyl, fluoroalkyl (such as C1-6 flouroalkyl, e g., -CH2F, -CHF2.-CF3, - CH2CH2F, etc.), alkoxy (such as C1-6 alkoxy, e.g., -OCHs, -OC2H5, etc.), cyclopropoxy or fluoroalkoxy (such as C1 6 fluoroalkoxy, e.g., -OCH2F, -OCHF2, -OCF3, -OCH2CH2F, etc.);

[0017] R3is H, F, Cl, Br, alkyl, fluoroalkyl (such as C1-6 flouroalkyl, e g., -CH2F, -CHF2.-CF3, - CH2CH2F, etc.), alkoxy (such as C1-6 alkoxy, e.g., -OCHs, -OC2H5, etc.), cyclopropoxy or fluoroalkoxy (such as C1-6 fluoroalkoxy, e.g., -OCH2F, -OCHF2, -OCF3, -OCH2CH2F, etc.); or R2and R3may be taken together with the carbon atoms to which they are attached to form a 5-7 membered heterocyclic ring system having 1 or 2 substituents R4and 1 substituent R5;

[0018] Each R4is independently H, F, Cl, Br, alkyl, fluoroalkyl (such as C1-6 flouroalkyl, e.g., -CH2F, - CHF2.-CF3, -CH2CH2F, etc.), alkoxy (such as C1-6 alkoxy, e.g., -OCHs, -OC2H5, etc.) or fluoroalkoxy (such as C1-6 fluoroalkoxy, e.g., -OCH2F, -OCHF2, -OCF3, -OCH2CH2F, etc.); and

[0019] In some embodiments, R5is H, alkyl, fluoroalkyl (such as C1-6 fluoroalkyl, e.g., -CH2F, -CHF2,- CFs, -CH2CH2F, etc.) or deuterio-alkyl (e.g., CD3).

[0020] In some embodiments, if R5is directly attached to a carbon atom, R5is H, F, Cl, Br, alkyl, fluoroalkyl, alkoxy or fluoroalkoxy; or, if R5is directly attached to a nitrogen atom, R5is H, F, Cl, Br, or alkyl.

[0021] This disclosure also relates to compounds of Formula l(i) to l(xvi), wherein R2and R3are taken together to form a bicyclic ring of the formulae:

[0022]

[0023] Some embodiments include a compound of Formula l(i to xvi) wherein R1is alkyl (such as Ci-e alkyl, e.g., methyl, ethyl, etc.) optionally substituted with one to three substituents independently selected from the group H, alkyl (such as Ci-e alkyl), cyclopropyl, F, Cl, Br, alkoxy (such as CI-B alkoxy, e.g., - OCHs, -OC2H5, etc.), cyclopropoxy and fluoroalkoxy (such as C1-6 fluoroalkoxy, e.g., -OCH2F, -OCHF2, -OCF3, -OCH2CH2F, etc.).

[0024] Some embodiments include a compound of Formula I wherein the dashed line represents an optional double bond, and R1represents methylene optionally substituted with alkoxy (such as C1-6 alkoxy, e.g., -OCHs, -OC2H5, etc.).

[0025] Some embodiments include a compound of Formula I wherein R2is independently H, F, Cl, Br, alkyl (such as Ci e alkyl), fluoroalkyl (such as C e flouroalkyl, e.g., -CH2F, -CHF2.-CF3, -CH2CH2F, etc.), alkoxy (such as C1-6 alkoxy, e g , -OCH3, -OC2H5, etc ), cyclopropoxy or fluoroalkoxy (such as C1-6 fluoroalkoxy, e.g., -OCH2F, -OCHF2, -OCF3. -OCH2CH2F, etc ).

[0026] Some embodiments include a compound of Formula I wherein R3is independently H, F, Cl, Br, alkyl (such as C1-6 alkyl), fluoroalkyl (such as C1-6 flouroalkyl, e.g., -CH2F, -CHF2.-CF3, -CH2CH2F, etc.), alkoxy (such as C1-6 alkoxy, e.g., -OCH3, -OC2H5, etc.), cyclopropoxy or fluoroalkoxy (such as C1-6 fluoroalkoxy, e.g., -OCH2F, -OCHF2, -OCFs. -OCFbCFhF, etc ).

[0027] Some embodiments include a compound of Formula I including Formula l(i to xvi) wherein R2and R3are taken together with the carbon atoms to which they are attached to form a 5-7 membered heterocyclic ring system that is optionally substituted with substituents R4and R5.

[0028] Some embodiments include a compound of Formula l(i to xvi) wherein each R4is independently H, F, Cl, Br, alkyl (such as C1-6 alkyl), fluoroalkyl (such as C1-6 flouroalkyl, e.g., -CH2F, -CHF2.-CF3, - CH2CH2F, etc.), alkoxy (such as Ci-e alkoxy, e.g., -OCHs, -OC2H5, etc.) or fluoroalkoxy (such as C1-6 fluoroalkoxy, e.g., -OCH2F, -OCHF2, -OCF3, -OCH2CH2F, etc ). In the above Formula l(i-xvi), a second independent R4may be present where the structure allows.

[0029] Some embodiments include a compound of Formula l(i to xvi) wherein R5is H, alkyl, fluoroalkyl (such as C1-6 fluoroalkyl, e.g., -CH2F, -CHF2.-CF3, -CH2CH2F, etc.) or deuterio-alkyl (e.g , CD3).

[0030] In some embodiments, R5is independently H, alkyl (such as C1-6 alkyl), fluoroalkyl (such as C1-6 flouroalkyl, e.g., -CH2F, -CHF2,-CF3, -CH2CH2F, etc.), alkoxy (such as Ci-s alkoxy, e g., -OCH3, - OC2H5, etc.) or fluoroalkoxy (such as C1-6 fluoroalkoxy, e.g., -OCH2F, -OCHF2, -OCF3, -OCH2CH2F, etc.).

[0031] Some embodiments include a compound of Formula l(i to xvi) wherein R4is H, F, Cl, methyl, or ethyl.

[0032] Some embodiments include a compound of Formula l(i to xvi) wherein R5is H or methyl.

[0033] Some embodiments include a pharmaceutical composition comprising a compound of Formula l(i to xvi) described herein and a pharmaceutically acceptable carrier.

[0034] Some embodiments include the use of a compound described herein in the manufacture of a medicament to treat pain or hypertension.

[0035] Some embodiments include a method of treating pain or hypertension comprising administering, to a mammal in need thereof, a therapeutically effective amount of a compound described herein.

[0036] Some embodiments include a kit comprising 1 ) a compound described herein, and 2) instructions to use the compound to treat pain or hypertension.

[0037] Detailed Description

[0038] This present disclosure relates to novel compounds of Formula I, Formula l(i), Formula l(ii) Formula l(iii), Formula l(iv), Formula l(v), Formula l(vi), Formula l(vii), Formula l(viii), Formula l(x), Formula l(xi), Formula l(xii), Formula l(xiii), Formula l(xiv), Formula l(xv), and Formula l(xvi), or pharmaceutically acceptable salts thereof.

[0039] With respect to any relevant structural representation, such as Formula I, Formula l(i to xvi): R1is alkyl, such as C1-6 alkyl (such as methyl, -CH3) optionally substituted with one to three substituents independently selected from the group H, alkyl (such as C1-6 alkyl), cyclopropyl, halo, alkoxy (such as C1-6 alkoxy, e.g., -OCHs, -OC2H5, etc.), cyclopropoxy or fluoroalkoxy (such as C1-6 fluoroalkoxy, e.g., - OCH2F, -OCHF2, -OCFs, -OCH2CH2F, etc.). In some embodiments, R1is methyl. In some embodiments, R1is -CH2F. In some embodiments, R1is ethyl. In some embodiments, R1is - CH2OCH3. In some embodiments, R1is -CH2-O-cyclopropyl. In some embodiments, R1is -CH2-O- CH2CHF2. In some embodiments, R1is -CH2CHF2. In some embodiments, R1is methoxy bicyclo[1.1.1 ]pent-1-y I. In some embodiments, R1is -CH2-O-CHF2. In some embodiments, R1is -CHF2. With respect to any relevant structural representation, such as Formula I, Formula l(i to xvi): alternatively the dashed line represents an optional double (unsaturated) bond and R1is methylene (such as >C=C<) optionally substituted with alkoxy (such as Ci-e alkoxy, e.g., -OCH3, -OC2H5, etc.). In some embodiments, R1is unsubstituted. In some embodiments, R1is =CH-OCH3.

[0040] With respect to any relevant structural representation, such as Formula I, Formula l(i to xvi), in some embodiments, R1is =CH2, CH3, =CHOCH3, =CHCH3, -CH2-O-cyclobutyl-F, =CHF, -CH2-O-(oxetan-3- yl), -CH2F, -(CH2)2-O-cyclopropyl, -(CH2)2OCF3, -(CH2)2C=N, -CH2C=N, -CH2-(oxetan-3-yl), - (CH2)2OCH3, oxetan-3-yl, -CH2-(oxetan-2-yl), -CH2-(azetidine-2-yl)-N-BOC, -CH2-(1-methylazetidine- 2-yl), -CH2-(2-fluoroazetidine-2-yl), -CH2OCH2CH3, -CH2-O-(2,2-difluorocycloprop-1-yl), -CH2N(CH3)2, or -CH2-(3,3-difluoroazetidine-1-yl)

[0041] With respect to any relevant structural representation, such as Formula I, Formula l(i to xvi), in some embodiments, R1is =CH2. In some embodiments, R1is CH3. In some embodiments, R1is =CHOCH3In some embodiments, R1is =CHCH3In some embodiments, R1is -CH2-O-cyclobutyl-F, In some embodiments, R1is =CHF In some embodiments, R1is -CH2-O-(oxetan-3-yl), In some embodiments, R1is -CH2F. In some embodiments, R1is -(CH2)2-0-cyclopropyl. In some embodiments, R1is - (CH2)2OCF3In some embodiments, R1is -(CH2)2C N In some embodiments, R1is -CH2C N In some embodiments, R1is -CH2-(oxetan-3-yl), In some embodiments, R1is -(CH2)2OCH3. In some embodiments, R1is oxetan-3-yl, In some embodiments, R1is -CH2-(oxetan-2-yl), In some embodiments, R1is -CH2-(azetidine-2-yl)-N-BOC. In some embodiments, R1is -CH2-(1- methylazetidine-2-yl). In some embodiments, R1is -CH2-(2-fluoroazetidine-2-yl), In some embodiments, R1is -CH2OCH2CH3. In some embodiments, R1is -CH2-0-(2,2-difluorocycloprop-1-yl). In some embodiments, R1is -CH2N(CH3)2. In some embodiments, R1is -CH2-(3,3-difluoroazetidine-1- yi). oxetan-3-yl oxetan-2-yl bicyclo[1 1.1 ]pent-1-yl azetidine-2-yl 2-fluoroazetidine-2-yl 3,3-difluoroazetidine-1-yl (azetidine-2-yl)-N-BOC

[0042] With respect to any relevant structural representation, such as Formula I, Formula l(i to xvi), R2is independently H, F, Cl, Br, alkyl (such as C-I-B alkyl), fluoroalkyl (such as Ci-e flouroalkyl, e.g., -CH2F, - OHF2.-CF3, -CH2CH2F, etc.), alkoxy (such as C1-6 alkoxy, e.g., -OCH3, -OC2H5, etc.) or fluoroalkoxy (such as C1-6 fluoroalkoxy, e.g., -OCH2F, -OCHF2, -OCF3, -OCH2CH2F, etc.). In some embodiments, R2is CHs. In some embodiments, R2is -O-cyclopropyl. In some embodiments, R2is F. In some embodiments, R2is -OCHs. In some embodiments, R2is -OCF3. In some embodiments, R2is H

[0043] With respect to any relevant structural representation, such as Formula I, Formula l(i to xvi), R3is independently H, F, Cl, Br, alkyl (such as C-I-B alkyl), fluoroalkyl (such as C1-6 flouroalkyl, e.g., -CH2F, - CHF2.-CF3, -CH2CH2F, etc.), alkoxy (such as C1-6 alkoxy, e.g., -OCHs, -OC2H5, etc.) or fluoroalkoxy (such as C1-6 fluoroalkoxy, e.g., -OCH2F, -OCHF2, -OCF3, -OCH2CH2F, etc.). In some embodiments, R3is H. In some embodiments, R3is CHs. In some embodiments, R3is Cl. In some embodiments, R3is F.

[0044] In some embodiments, R2is CHs and R3is CH3. In some embodiments, R2is -OCHs and R3is -CHs. In some embodiments, R2is -OCHs and R3is Cl. In some embodiments, R2is F and R3is -CHs. In some embodiments, R2is -O-cyclopropyl and R3is H.

[0045] With respect to any relevant structural representation, such as Formula I, Formula l(i to xvi), in some embodiments, R2and R3may be taken together with the carbon atoms to which they are attached to form a 5-7 membered heterocyclic ring system that is optionally substituted with substituents R4and R5.

[0046] In some embodiments, R2and R3, together with the carbon atoms to which they are attached, form the one of the rings or ring systems below. The R4groups and R5group are also present, but not depicted in the structures.

[0047] With respect to any relevant structural representation, such as Formula I, Formula l(i to xvi), in some embodiments each R4is independently H, F, Cl, Br, alkyl (such as Ci-e alkyl ), fluoroalkyl (such as Ci-e flouroalkyl, e.g., -CH2F, -CHF2,-CFs, -CH2CH2F, etc.), alkoxy (such as Cvs alkoxy, e g., -OCH3, - OC2H5, etc.) or fluoroalkoxy (such as C1-6 fluoroalkoxy, e.g., -OCH2F, -OCHF2, -OCFs, -OCH2CH2F, etc )

[0048] With respect to any relevant structural representation, such as Formula I, Formula l(i to xvi), in some embodiments R5is H, alkyl, fluoroalkyl (such as Ove fluoroalkyl, e.g., -CH2F, -CHF2,-CF3, -CH2CH2F, etc.) or deuterio-alkyl (e.g., CD3). In some embodiments, R5is independently H, alkyl, fluoroalkyl (such as C1-6 flouroalkyl, e.g., -CH2F, -CHF2,-CF3, -CH2CH2F, etc.), alkoxy (such as C1-6 alkoxy, e.g., - OCH3, -OC2H5, etc.) or fluoroalkoxy (such as C1.6 fluoroalkoxy, e.g., -OCH2F, -OCHF2, -OCF3, - OCH2CH2F, etc.).

[0049] With respect to any relevant structural representation, such as Formula I, Formula l(i to xvi), in some embodiments R4is H, F, Cl, methyl, or ethyl. In some embodiments, R4is H. In some embodiments, R4is methyl. In some embodiments, R4is F

[0050] With respect to any relevant structural representation, such as Formula I, Formula l(i to xvi), in some embodiments, R4is -CH2CH3, -CH2CHF2, -CH2CH2F, or is -CF3.

[0051] With respect to any relevant structural representation, such as Formula I, Formula l(i to xvi), in some embodiments, R4is -CH2CH3 In some embodiments, R4is -CH2CHF2 In some embodiments, R4is - CH2CH2F In some embodiments, R4is -CF3.

[0052] In some embodiments, there are two R4groups, such as in the structures of Compound 90 and Compound 91 , and each R4is independently H, F, Cl, methyl, ethyl, -CH2CHF2. -CH2CH2F, or R4is - CFs

[0053] With respect to any relevant structural representation, such as Formula I, Formula l(i to xvi), in some embodiments R5is H or methyl. In some embodiments, R5is H. In some embodiments, R5is methyl. In some embodiments, R5is ethyl. In some embodiments, R5is CD3. In some embodiments, R5is F. In some embodiments, R4is H and R5is methyl. In some embodiments, R4is methyl and R5is methyl. In some embodiments, R4is H and R5is ethyl. In some embodiments, R4is H and R5is CD3. In some embodiments, R4is H, and R5is H. In some embodiments, R4is F and R5is F.

[0054] As used herein, the term “alkyl" includes saturated aliphatic hydrocarbons including straight chains and branched chains and 1, 2, 3, 4, 5, or 6 carbon atoms. For example, as used herein, the term “alkyl,” as well as the alkyl moieties of other groups referred to herein (e.g., alkoxy), refers to linear or branched moieties of 1 to 6, carbon atoms, e.g., 1 , 2, 3, 4, 5, or 6 carbon atoms (e.g., methyl, ethyl, n- propyl, isopropyl, n-butyl, iso-butyl, secondary-butyl, tertiary-butyl), optionally substituted by 1 , 2, 3, 4, or 5 suitable substituents. Methyl (-CH3) is one particular alkyl embodiment that may be optionally substituted.

[0055] Whenever a numerical range is used in this application, for example when 1 to 6 is used in the definition of “alkyl” means that the alkyl group may contain 1 , 2, 3, 4, 5, or 6 carbon atoms

[0056] As used herein, the term "alkenyl" is defined to include aliphatic hydrocarbons having at least one carbon-carbon double bond, including straight chains and branched chains having at least one carbon-carbon double bond and 2 to 6 carbon atoms. For example, as used herein, the term "alkenyl" means straight or branched chain unsaturated radicals of 2 to 6 carbon atoms, including, but not limited to ethenyl, 1-propenyl, 2-propenyl (allyl), iso-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2- butenyl, and the like; optionally substituted by 1 to 5 suitable substituents.

[0057] As used herein, the term “alkynyl” includes aliphatic hydrocarbons having at least one carbon-carbon triple bond, including straight chains and branched chains having at least one carbon-carbon triple bond and 2, 3, 4, 5 or 6 carbon atoms. For example, as used herein, the term “alkynyl” is used herein to mean straight or branched hydrocarbon chain alkynyl moiety as defined above having 2, 3, 4, 5 or 6 carbon atoms and one triple bond; optionally substituted by 1, 2, 3, 4, or 5 suitable substituents.

[0058] As used herein, the term “cycloalkyl” includes saturated or unsaturated (non-aromatic) monocyclic or bicyclic hydrocarbon rings (e g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl); optionally substituted by 1 , 2, or 3 suitable substituents. The cycloalkyl group has 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms. One group of monocyclic cycloalkyl rings have 3, 4, 5, or 6 carbon atoms. In another embodiment the cycloalkyl may optionally contain one, two or more non-cumulative nonaromatic double or triple bonds.

[0059] As used herein, the term “bicycloalkyl” is defined to include a cycloalkyl as defined above which is bridged to a second carbocyclic ring (e.g., [1 .1.1 ]bicyclopentyl, bicyclo[2.2.1]heptanyl, bicyclo[3.2.1]octanyl and bicyclo[5.2.0]nonanyl, etc.). Preferably, the bicycloalkyl group has 5 to 20 carbon atoms. More preferably, the bicycloalkyl group has 5 to 10 carbon atoms. The bicycloalkyl is optionally substituted by 1 to 3 suitable substituents such as alkyl, alkoxy or halo. In one embodiment the bicycloalkyl may optionally contain one, two or more non cumulative non aromatic double or triple bonds. As used herein, the term “heterocyclic” includes monocyclic or fused-ring polycyclic groups with one or more heteroatoms selected from O, S and N in the ring. The heterocyclic group has 4 to 12 ring atoms, or 4, 5, 6, 7, 8, 9, 10, 11 , or 12 ring atoms, including one to five heteroatoms, (or 1 , 2, 3, 4, or 5 heteroatoms) selected from O, S, and N. For example, as used herein, the term “5 to 12 membered heterocyclic” means aromatic or nonaromatic moieties containing at least one ring heteroatom selected from O, S and N and from 1 to 11 carbon atoms, or 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11 carbon atoms, such as such as dihydrobenzofuranyl, benzodioxolyl, indolinyl, isoindolinyl, quinuclidinyl, chromanyl, isochromanyl, benzoxazinyl and the like. The heterocyclic group is optionally substituted by 1 , 2, 3, 4, or 5 suitable substituents such as R4and R5.

[0060] The compounds of Formula I, Formula l(i to xvi) may exist in the form of pharmaceutically acceptable salts such as, e.g., acid addition salts and base addition salts. The phrase “pharmaceutically acceptable salt(s)”, as used herein, unless otherwise indicated, includes salts of acidic or basic groups that are acceptable for pharmaceutical use. Reference to any compound herein, by name, structure, or any other means, includes pharmaceutically acceptable salts of the compound.

[0061] As used herein, any reference to a compound by structure, name, or any other indicator, is intended to include all forms of the compound, including hydrates, solvates, isomers (including optical, geometric and tautomeric isomers), crystalline and non-crystalline forms, isomorphs, polymorphs, metabolites, prodrugs, atropisomers and isotopically enriched compounds thereof.

[0062] The present invention includes all pharmaceutically acceptable isotopically-labelled compounds of formula I wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number which predominates in nature.

[0063] Examples of isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, such as2H and3H, carbon, such as11C,13C and14C, chlorine, such as36CI, fluorine, such as18F, iodine, such as123l and125l, nitrogen, such as13N and15N, oxygen, such as15O,17O and18O, phosphorus, such as32P, and sulphur, such as35S.

[0064] Certain isotopically-labelled compounds of Formula I or Formula l(i to xvi), for example, those incorporating a radioactive isotope, are useful in drug and / or substrate tissue distribution studies. The radioactive isotopes tritium, i.e.3H, and carbon-14, i.e.14C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.

[0065] Substitution with heavier isotopes such as deuterium, i.e.2H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances

[0066] Substitution with positron emitting isotopes, such as11C,18F,15O and13N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.

[0067] Isotopically-labeled compounds of Formula I can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using an appropriate isotopically-labeled reagent in place of the nonlabeled reagent previously employed.

[0068] As used herein, any reference to a compound by structure, name, or any other indicator, is intended to include all deuterated forms of the compound. Deuterated compounds are those in which one or more of the hydrogen atoms in the drug molecule have been replaced by its heavier stable isotope deuterium.

[0069] Compounds 1-58, depicted in Tables A-D, and pharmaceutically acceptable salts thereof, are specifically contemplated herein.

[0070] Some embodiments include Compound 1 or a pharmaceutical acceptable salt thereof.

[0071] Some embodiments include Compound 2 or a pharmaceutical acceptable salt thereof.

[0072] Some embodiments include Compound 3 or a pharmaceutical acceptable salt thereof.

[0073] Some embodiments include Compound 4 or a pharmaceutical acceptable salt thereof.

[0074] Some embodiments include Compound 5 or a pharmaceutical acceptable salt thereof.

[0075] Some embodiments include Compound 6 or a pharmaceutical acceptable salt thereof

[0076] Some embodiments include Compound 7 or a pharmaceutical acceptable salt thereof.

[0077] Some embodiments include Compound 8 or a pharmaceutical acceptable salt thereof.

[0078] Some embodiments include Compound 9 or a pharmaceutical acceptable salt thereof.

[0079] Some embodiments include Compound 10 or a pharmaceutical acceptable salt thereof.

[0080] Some embodiments include Compound 11 or a pharmaceutical acceptable salt thereof.

[0081] Some embodiments include Compound 12 or a pharmaceutical acceptable salt thereof.

[0082] Some embodiments include Compound 13 or a pharmaceutical acceptable salt thereof

[0083] Some embodiments include Compound 14 or a pharmaceutical acceptable salt thereof.

[0084] Some embodiments include Compound 15 or a pharmaceutical acceptable salt thereof.

[0085] Some embodiments include Compound 16 or a pharmaceutical acceptable salt thereof.

[0086] Some embodiments include Compound 17 or a pharmaceutical acceptable salt thereof.

[0087] Some embodiments include Compound 18 or a pharmaceutical acceptable salt thereof.

[0088] Some embodiments include Compound 19 or a pharmaceutical acceptable salt thereof.

[0089] Some embodiments include Compound 20 or a pharmaceutical acceptable salt thereof.

[0090] Some embodiments include Compound 21 or a pharmaceutical acceptable salt thereof. Some embodiments include Compound 22 or a pharmaceutical acceptable salt thereof.

[0091] Some embodiments include Compound 23 or a pharmaceutical acceptable salt thereof.

[0092] Some embodiments include Compound 24 or a pharmaceutical acceptable salt thereof.

[0093] Some embodiments include Compound 25 or a pharmaceutical acceptable salt thereof.

[0094] Some embodiments include Compound 26 or a pharmaceutical acceptable salt thereof.

[0095] Some embodiments include Compound 27 or a pharmaceutical acceptable salt thereof.

[0096] Some embodiments include Compound 28 or a pharmaceutical acceptable salt thereof.

[0097] Some embodiments include Compound 29 or a pharmaceutical acceptable salt thereof.

[0098] Some embodiments include Compound 30 or a pharmaceutical acceptable salt thereof.

[0099] Some embodiments include Compound 31 or a pharmaceutical acceptable salt thereof.

[0100] Some embodiments include Compound 32 or a pharmaceutical acceptable salt thereof.

[0101] Some embodiments include Compound 33 or a pharmaceutical acceptable salt thereof.

[0102] Some embodiments include Compound 34 or a pharmaceutical acceptable salt thereof.

[0103] Some embodiments include Compound 35 or a pharmaceutical acceptable salt thereof.

[0104] Some embodiments include Compound 36 or a pharmaceutical acceptable salt thereof.

[0105] Some embodiments include Compound 37 or a pharmaceutical acceptable salt thereof

[0106] Some embodiments include Compound 38 or a pharmaceutical acceptable salt thereof.

[0107] Some embodiments include Compound 39 or a pharmaceutical acceptable salt thereof.

[0108] Some embodiments include Compound 40 or a pharmaceutical acceptable salt thereof.

[0109] Some embodiments include Compound 41 or a pharmaceutical acceptable salt thereof.

[0110] Some embodiments include Compound 42 or a pharmaceutical acceptable salt thereof.

[0111] Some embodiments include Compound 43 or a pharmaceutical acceptable salt thereof.

[0112] Some embodiments include Compound 44 or a pharmaceutical acceptable salt thereof

[0113] Some embodiments include Compound 45 or a pharmaceutical acceptable salt thereof.

[0114] Some embodiments include Compound 46 or a pharmaceutical acceptable salt thereof.

[0115] Some embodiments include Compound 47 or a pharmaceutical acceptable salt thereof.

[0116] Some embodiments include Compound 48 or a pharmaceutical acceptable salt thereof.

[0117] Some embodiments include Compound 49 or a pharmaceutical acceptable salt thereof. Some embodiments include Compound 50 or a pharmaceutical acceptable salt thereof.

[0118] Some embodiments include Compound 51 or a pharmaceutical acceptable salt thereof.

[0119] Some embodiments include Compound 52 or a pharmaceutical acceptable salt thereof.

[0120] Some embodiments include Compound 53 or a pharmaceutical acceptable salt thereof.

[0121] Some embodiments include Compound 54 or a pharmaceutical acceptable salt thereof.

[0122] Some embodiments include Compound 55 or a pharmaceutical acceptable salt thereof.

[0123] Some embodiments include Compound 56 or a pharmaceutical acceptable salt thereof.

[0124] Some embodiments include Compound 57 or a pharmaceutical acceptable salt thereof.

[0125] Some embodiments include Compound 58 or a pharmaceutical acceptable salt thereof.

[0126] Some embodiments include Compound 59 or a pharmaceutical acceptable salt thereof.

[0127] Some embodiments include Compound 60 or a pharmaceutical acceptable salt thereof.

[0128] Some embodiments include Compound 61 or a pharmaceutical acceptable salt thereof.

[0129] Some embodiments include Compound 62 or a pharmaceutical acceptable salt thereof.

[0130] Some embodiments include Compound 63 or a pharmaceutical acceptable salt thereof.

[0131] Some embodiments include Compound 64 or a pharmaceutical acceptable salt thereof.

[0132] Some embodiments include Compound 65 or a pharmaceutical acceptable salt thereof

[0133] Some embodiments include Compound 66 or a pharmaceutical acceptable salt thereof.

[0134] Some embodiments include Compound 67 or a pharmaceutical acceptable salt thereof.

[0135] Some embodiments include Compound 68 or a pharmaceutical acceptable salt thereof.

[0136] Some embodiments include Compound 69 or a pharmaceutical acceptable salt thereof.

[0137] Some embodiments include Compound 70 or a pharmaceutical acceptable salt thereof.

[0138] Some embodiments include Compound 71 or a pharmaceutical acceptable salt thereof.

[0139] Some embodiments include Compound 72 or a pharmaceutical acceptable salt thereof

[0140] Some embodiments include Compound 73 or a pharmaceutical acceptable salt thereof.

[0141] Some embodiments include Compound 74 or a pharmaceutical acceptable salt thereof.

[0142] Some embodiments include Compound 75 or a pharmaceutical acceptable salt thereof.

[0143] Some embodiments include Compound 76 or a pharmaceutical acceptable salt thereof.

[0144] Some embodiments include Compound 77 or a pharmaceutical acceptable salt thereof. Some embodiments include Compound 78 or a pharmaceutical acceptable salt thereof.

[0145] Some embodiments include Compound 79 or a pharmaceutical acceptable salt thereof.

[0146] Some embodiments include Compound 80 or a pharmaceutical acceptable salt thereof.

[0147] Some embodiments include Compound 81 or a pharmaceutical acceptable salt thereof.

[0148] Some embodiments include Compound 82 or a pharmaceutical acceptable salt thereof.

[0149] Some embodiments include Compound 83 or a pharmaceutical acceptable salt thereof.

[0150] Some embodiments include Compound 84 or a pharmaceutical acceptable salt thereof.

[0151] Some embodiments include Compound 85 or a pharmaceutical acceptable salt thereof.

[0152] Some embodiments include Compound 86 or a pharmaceutical acceptable salt thereof.

[0153] Some embodiments include Compound 87 or a pharmaceutical acceptable salt thereof.

[0154] Some embodiments include Compound 88 or a pharmaceutical acceptable salt thereof.

[0155] Some embodiments include Compound 89 or a pharmaceutical acceptable salt thereof.

[0156] Some embodiments include Compound 90 or a pharmaceutical acceptable salt thereof.

[0157] Some embodiments include Compound 91 or a pharmaceutical acceptable salt thereof.

[0158] Some embodiments include Compound 92 or a pharmaceutical acceptable salt thereof.

[0159] Some embodiments include Compound 93 or a pharmaceutical acceptable salt thereof

[0160] Some embodiments include Compound 94 or a pharmaceutical acceptable salt thereof.

[0161] Some embodiments include Compound 95 or a pharmaceutical acceptable salt thereof.

[0162] Some embodiments include Compound 96 or a pharmaceutical acceptable salt thereof.

[0163] Some embodiments include Compound 97 or a pharmaceutical acceptable salt thereof.

[0164] Some embodiments include Compound 98 or a pharmaceutical acceptable salt thereof.

[0165] Some embodiments include Compound 99 or a pharmaceutical acceptable salt thereof.

[0166] Some embodiments include Compound 100 or a pharmaceutical acceptable salt thereof

[0167] Some embodiments include Compound 101 or a pharmaceutical acceptable salt thereof.

[0168] Some embodiments include Compound 102 or a pharmaceutical acceptable salt thereof.

[0169] Some embodiments include Compound 103 or a pharmaceutical acceptable salt thereof.

[0170] Some embodiments include Compound 104 or a pharmaceutical acceptable salt thereof.

[0171] Some embodiments include Compound 105 or a pharmaceutical acceptable salt thereof. Some embodiments include Compound 106 or a pharmaceutical acceptable salt thereof,

[0172] Some embodiments include Compound 107 or a pharmaceutical acceptable salt thereof,

[0173] Some embodiments include Compound 108 or a pharmaceutical acceptable salt thereof,

[0174] Some embodiments include Compound 109 or a pharmaceutical acceptable salt thereof,

[0175] Some embodiments include Compound 110 or a pharmaceutical acceptable salt thereof,

[0176] Some embodiments include Compound 111 or a pharmaceutical acceptable salt thereof,

[0177] Some embodiments include Compound 112 or a pharmaceutical acceptable salt thereof,

[0178] Some embodiments include Compound 113 or a pharmaceutical acceptable salt thereof,

[0179] Some embodiments include Compound 114 or a pharmaceutical acceptable salt thereof,

[0180] Some embodiments include Compound 115 or a pharmaceutical acceptable salt thereof,

[0181] Some embodiments include Compound 116 or a pharmaceutical acceptable salt thereof,

[0182] Some embodiments include Compound 117 or a pharmaceutical acceptable salt thereof,

[0183] Some embodiments include Compound 118 or a pharmaceutical acceptable salt thereof,

[0184] Some embodiments include Compound 119 or a pharmaceutical acceptable salt thereof,

[0185] Some embodiments include Compound 120 or a pharmaceutical acceptable salt thereof,

[0186] Some embodiments include Compound 121 or a pharmaceutical acceptable salt thereof

[0187] Some embodiments include Compound 122 or a pharmaceutical acceptable salt thereof,

[0188] Some embodiments include Compound 123 or a pharmaceutical acceptable salt thereof,

[0189] Some embodiments include Compound 124 or a pharmaceutical acceptable salt thereof,

[0190] Some embodiments include Compound 125 or a pharmaceutical acceptable salt thereof,

[0191] Some embodiments include Compound 126 or a pharmaceutical acceptable salt thereof,

[0192] Some embodiments include Compound 127 or a pharmaceutical acceptable salt thereof,

[0193] Some embodiments include Compound 128 or a pharmaceutical acceptable salt thereof

[0194] Some embodiments include Compound 129 or a pharmaceutical acceptable salt thereof,

[0195] Some embodiments include Compound 130 or a pharmaceutical acceptable salt thereof,

[0196] Some embodiments include Compound 131 or a pharmaceutical acceptable salt thereof,

[0197] Some embodiments include Compound 132 or a pharmaceutical acceptable salt thereof,

[0198] Some embodiments include Compound 133 or a pharmaceutical acceptable salt thereof. Some embodiments include Compound 134 or a pharmaceutical acceptable salt thereof,

[0199] Some embodiments include Compound 135 or a pharmaceutical acceptable salt thereof,

[0200] Some embodiments include Compound 136 or a pharmaceutical acceptable salt thereof,

[0201] Some embodiments include Compound 137 or a pharmaceutical acceptable salt thereof,

[0202] Some embodiments include Compound 138 or a pharmaceutical acceptable salt thereof,

[0203] Some embodiments include Compound 139 or a pharmaceutical acceptable salt thereof,

[0204] Some embodiments include Compound 140 or a pharmaceutical acceptable salt thereof,

[0205] Some embodiments include Compound 141 or a pharmaceutical acceptable salt thereof,

[0206] Some embodiments include Compound 142 or a pharmaceutical acceptable salt thereof,

[0207] Some embodiments include Compound 143 or a pharmaceutical acceptable salt thereof,

[0208] Some embodiments include Compound 144 or a pharmaceutical acceptable salt thereof,

[0209] Some embodiments include Compound 145 or a pharmaceutical acceptable salt thereof,

[0210] Some embodiments include Compound 146 or a pharmaceutical acceptable salt thereof,

[0211] Some embodiments include Compound 147 or a pharmaceutical acceptable salt thereof,

[0212] Some embodiments include Compound 148 or a pharmaceutical acceptable salt thereof,

[0213] Some embodiments include Compound 149 or a pharmaceutical acceptable salt thereof

[0214] Some embodiments include Compound 150 or a pharmaceutical acceptable salt thereof,

[0215] Some embodiments include Compound 151 or a pharmaceutical acceptable salt thereof,

[0216] Some embodiments include Compound 152 or a pharmaceutical acceptable salt thereof,

[0217] Some embodiments include Compound 153 or a pharmaceutical acceptable salt thereof,

[0218] Some embodiments include Compound 154 or a pharmaceutical acceptable salt thereof,

[0219] Some embodiments include Compound 155 or a pharmaceutical acceptable salt thereof,

[0220] Some embodiments include Compound 156 or a pharmaceutical acceptable salt thereof

[0221] Some embodiments include Compound 157 or a pharmaceutical acceptable salt thereof,

[0222] Some embodiments include Compound 158 or a pharmaceutical acceptable salt thereof,

[0223] Some embodiments include Compound 159 or a pharmaceutical acceptable salt thereof,

[0224] Some embodiments include Compound 160 or a pharmaceutical acceptable salt thereof,

[0225] Some embodiments include Compound 161 or a pharmaceutical acceptable salt thereof. Some embodiments include Compound 162 or a pharmaceutical acceptable salt thereof.

[0226] Some embodiments include Compound 163 or a pharmaceutical acceptable salt thereof.

[0227] Some embodiments include Compound 164 or a pharmaceutical acceptable salt thereof.

[0228] Some embodiments include Compound 165 or a pharmaceutical acceptable salt thereof.

[0229] Some embodiments include Compound 166 or a pharmaceutical acceptable salt thereof.

[0230] Some embodiments include Compound 167 or a pharmaceutical acceptable salt thereof.

[0231] Some embodiments include Compound 168 or a pharmaceutical acceptable salt thereof.

[0232] Some embodiments include Compound 169 or a pharmaceutical acceptable salt thereof.

[0233] Some embodiments include Compound 170 or a pharmaceutical acceptable salt thereof.

[0234] Some embodiments include Compound 171 or a pharmaceutical acceptable salt thereof.

[0235] Some embodiments include Compound 172 or a pharmaceutical acceptable salt thereof.

[0236] Some embodiments include Compound 173 or a pharmaceutical acceptable salt thereof.

[0237] Some embodiments include Compound 174 or a pharmaceutical acceptable salt thereof.

[0238] Some embodiments include Compound 175 or a pharmaceutical acceptable salt thereof.

[0239] Some embodiments include Compound 176 or a pharmaceutical acceptable salt thereof.

[0240] Some embodiments include Compound 177 or a pharmaceutical acceptable salt thereof

[0241] The compounds of the disclosure may also exist in a mesomorphic state (mesophase or liquid crystal) when subjected to suitable conditions. The mesomorphic state is intermediate between the true crystalline state and the true liquid state (either melt or solution). Mesomorphism arising as the result of a change in temperature is described as ‘thermotropic’ and that resulting from the addition of a second component, such as water or another solvent, is described as ‘lyotropic’. Compounds that have the potential to form lyotropic mesophases are described as ‘amphiphilic’ and consist of molecules which possess an ionic (such as -COO Na+, -COO K+, or -SO3‘Na+) or non-ionic (such as - N'N+(CH3)3) polar head group. For more information, see Crystals and the Polarizing Microscope by N. H. Hartshorne and A. Stuart, 4thEdition (Edward Arnold, 1970).

[0242] Hereinafter all references to compounds of Formula I, Formula l(i), Formula l(ii), Formula l(iii), Formula l(iv), Formula l(v), Formula l(vi), Formula l(vii), Formula l(viii), Formula l(x), Formula l(xi), Formula l(xii), Formula l(xiii), Formula l(xiv), Formula l(xv), and Formula l(xvi), include references to salts, solvates, multi-component complexes and liquid crystals thereof and to solvates, multicomponent complexes and liquid crystals of salts thereof.

[0243] The compounds of Formula I, Formula l(i to xvi) may have asymmetric carbon atoms and may exist as two or more stereoisomers. The carbon-carbon bonds may be depicted herein using a solid line ( - ), a solid wedge ( ), or a dotted wedge ( ). The use of a solid line to depict bonds to asymmetric carbon atoms is meant to indicate that all possible stereoisomers (e.g., specific enantiomers, racemic mixtures, etc ) at that carbon atom are included. In each of these stereoisomers an H (hydrogen) atom is not always expressly recited. The use of either a solid or dotted wedge to depict bonds to asymmetric carbon atoms is meant to indicate that the single isomer depicted is contemplated, that an excess of a single isomer has been obtained, but with unknown stereochemistry, or that an excess of a single isomer has been obtained and identified as that isomer. Stereoisomers of Formula I, include Formula I’ (i to xvi):

[0244]

[0245] The compounds of Formula I, Formula l(i to xvi) or Formula I’ (i to xvi) or an acceptable salt thereof may be included in a useful composition such as a pharmaceutical composition. Accordingly, in one embodiment, such a pharmaceutical composition comprises a compound described herein and a pharmaceutically acceptable carrier. In some embodiments, a pharmaceutical composition contains a single active pharmaceutical ingredient.

[0246] The pharmaceutical acceptable carrier may comprise any conventional pharmaceutical carrier or excipient. Suitable pharmaceutical carriers include inert diluents or fillers, water and various organic solvents (such as hydrates and solvates). The pharmaceutical compositions may, if desired, contain additional ingredients such as flavorings, binders, excipients and the like. Thus, for oral administration, tablets containing various excipients, such as citric acid may be employed together with various disintegrants such as starch, alginic acid and certain complex silicates and with binding agents such as sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often useful for tableting purposes Solid compositions of a similar type may also be employed in soft and hard filled gelatin capsules. Non-limiting examples of materials, therefore, include lactose or milk sugar and high molecular weight polyethylene glycols. When aqueous suspensions or elixirs are desired for oral administration, the active compound therein may be combined with various sweetening or flavoring agents, coloring matters or dyes and, if desired, emulsifying agents or suspending agents, together with diluents such as water, ethanol, propylene glycol, glycerin, or combinations thereof.

[0247] The pharmaceutical composition may, for example, be in a form suitable for oral administration as a tablet, capsule, pill, powder, sustained release formulations, solution suspension, for parenteral injection as a sterile solution, suspension or emulsion, for topical administration as an ointment or cream or for rectal administration as a suppository.

[0248] Exemplary parenteral administration forms include solutions or suspensions of active compounds in sterile aqueous solutions, for example, aqueous propylene glycol or dextrose solutions. Such dosage forms may be suitably buffered, if desired

[0249] The pharmaceutical composition may be in unit dosage forms suitable for single administration of precise dosages.

[0250] In one preferred embodiment the composition comprises a therapeutically effective amount of a compound of Formula I, Formula l(i), Formula l(ii), Formula l(iii), Formula l(iv), Formula l(v), Formula l(vi), Formula l(vii), Formula l(viii), Formula l(x), Formula l(xi), Formula l(xii), Formula l(xiii), Formula l(xiv), Formula l(xv), or Formula l(xvi), and a pharmaceutically acceptable carrier.

[0251] Another embodiment of the disclosure is directed to a method for treating pain or hypertension in a mammal, such as a human, comprising administering to said mammal a therapeutically effective amount of a compound described herein.

[0252] The term “therapeutically effective amount” as used herein refers to that amount of the compound being administered which will relieve to some extent one or more of the symptoms of the disorder being treated. The terms “treating,” or “treatment” broadly includes any kind of treatment activity, including the diagnosis, cure, mitigation, or prevention of disease in man or other animals, or any activity that otherwise affects the structure or any function of the body of man or other animals.

[0253] Administration of the compounds of Formula I, Formula l(i), Formula l(ii), Formula l(iii), Formula l(iv), Formula l(v), Formula l(vi), Formula l(vii), Formula l(viii), Formula l(x), Formula l(xi), Formula l(xii), Formula l(xiii), Formula l(xiv), Formula l(xv), and Formula l(xvi) may be effected by any method that enables delivery of the compounds to the site of action. These methods include oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion), topical, and rectal administration.

[0254] Dosage regimens may be adjusted to provide the optimum desired response. For example, a single bolus may be administered, several divided doses may be administered over time, or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. It is especially advantageous to formulate parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form, as used herein, refers to physically discrete units suited as unitary dosages for the mammalian subjects to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier

[0255] Thus, the skilled artisan would appreciate, based upon the disclosure provided herein, that the dose and dosing regimen is adjusted in accordance with methods well-known in the therapeutic arts. That is, the maximum tolerable dose can be readily established, and the effective amount providing a detectable therapeutic benefit to a patient may also be determined, as can the temporal requirements for administering each agent to provide a detectable therapeutic benefit to the patient. Accordingly, while certain dose and administration regimens are exemplified herein, these examples in no way limit the dose and administration regimen that may be provided to a patient in practicing the present disclosure.

[0256] It is to be noted that dosage values may vary with the type and severity of the condition to be alleviated, and may include single or multiple doses. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that dosage ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed composition. For example, doses may be adjusted based on pharmacokinetic or pharmacodynamic parameters, which may include clinical effects such as toxic effects and / or laboratory values. Thus, the present disclosure encompasses intra-patient doseescalation as determined by the skilled artisan. Determining appropriate dosages and regimens for administration of the active agent are well-known in the relevant art and would be understood to be encompassed by the skilled artisan once provided the teachings disclosed herein.

[0257] The amount of the compound of Formula I, Formula l(i), Formula l(ii), Formula l(iii), Formula l(iv), Formula l(v), Formula l(vi), Formula l(vii), Formula l(viii), Formula l(viii), Formula l(x), Formula l(xi), Formula l(xii), Formula l(xiii), Formula l(xiv), Formula l(xv), and Formula l(xvi) administered will be dependent on the subject being treated, the severity of the disorder or condition, the rate of administration, the disposition of the compound and the discretion of the prescribing physician. However, an effective dosage is in the range of about 0.001 to about 100 mg per kg body weight per day, preferably about 1 to about 35 mg / kg / day, in single or divided doses For a 70 kg human, this would amount to about 0.05 to about 7 g / day, preferably about 0.1 to about 2.5 g / day. In some instances, dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effect, provided that such larger doses are first divided into several small doses for administration throughout the day.

[0258] Compounds of the Formula I, Formula l(i), Formula l(ii), Formula l(iii), Formula l(iv), Formula l(v), Formula l(vi), Formula l(vii), Formula l(viii), Formula l(viii), Formula l(x), Formula l(xi), Formula l(xii), Formula l(xiii), Formula l(xiv), Formula l(xv), and Formula l(xvi) may be prepared according to the following reaction schemes and accompanying discussion. Unless otherwise indicated, R1through R6, A, are as defined above in the reaction schemes and discussion that follow. In general, the compounds of this disclosure may be made by processes which include processes analogous to those known in the chemical arts, particularly in light of the description contained herein. Certain processes for the manufacture of the compounds of this disclosure are provided as further features of the disclosure and are illustrated by the following reaction schemes. Other processes may be described in the experimental section.

[0259] As an initial note, in the preparation of the compounds of Formula I, Formula l(i), Formula l(ii), Formula l(iii), Formula l(iv), Formula l(v), Formula l(vi), Formula l(vii), Formula l(viii), Formula l(viii), Formula l(x), Formula l(xi), Formula l(xii), Formula l(xiii), Formula l(xiv), Formula l(xv), and Formula l(xvi) it is noted that some of the preparation methods useful for the preparation of the compounds described herein may require protection of remote functionality (e.g., primary amine, secondary amine, carboxyl). The need for such protection will vary depending on the nature of the remote functionality and the conditions of the preparation methods. The need for such protection is readily determined by one skilled in the art The use of such protection / deprotection methods is also within the skill in the art. For a general description of protecting groups and their use, see T.W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991

[0260] For example, certain compounds contain primary amines or carboxylic acid functionalities which may interfere with reactions at other sites of the molecule if left unprotected. Accordingly, such functionalities may be protected by an appropriate protecting group which may be removed in a subsequent step Suitable protecting groups for amine and carboxylic acid protection include those protecting groups commonly used in peptide synthesis (such as N-t-butoxycarbonyl, benzyloxycarbonyl, and 9-fluorenylmethylenoxycarbonyl for amines and lower alkyl or benzyl esters for carboxylic acids) which are generally not chemically reactive under the reaction conditions described and can typically be removed without chemically altering other functionality in the Formula I, Formula l(i), Formula l(ii), Formula l(iii), Formula l(iv), Formula l(v), Formula l(vi), Formula l(vii), Formula l(viii), Formula l(x), Formula l(xi), Formula l(xii), Formula l(xiii), Formula l(xiv), Formula l(xv), or Formula l(xvi).

[0261] Compounds of Formula I, Formula l(i), Formula l(ii), Formula l(iii), Formula l(iv), Formula l(v), Formula l(vi), Formula l(vii), Formula l(viii), Formula l(x), Formula l(xi), Formula l(xii), Formula l(xiii), Formula l(xiv), Formula l(xv), and Formula l(xvi)have chiral centers and thus exist as stereoisomers, such as racemates, enantiomers, or diastereomers (Formula I’ (i to xvi) depicting R1with a solid wedge or alternatively wherein R1may have the opposite hashed wedge orientation) Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate using, for example, chiral high pressure liquid chromatography (HPLC) Alternatively, the racemate (or a racemic precursor) may be reacted with a suitable optically active compound, for example, an alcohol, or, in the case where the compound contains an acidic or basic moiety, an acid or base such as tartaric acid or 1 -phenylethylamine. The resulting diastereomeric mixture may be separated by chromatography and / or fractional crystallization and one or both of the diastereoisomers converted to the corresponding pure enantiomer(s) by means well known to one skilled in the art. Chiral compounds of Formula I (and chiral precursors thereof) may be obtained in enantiomerically-enriched form using chromatography, typically HPLC, on an asymmetric resin with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from 0 to 50% isopropanol, typically from 2 to 20%, and from 0 to 5% of an alkylamine, typically 0.1% diethylamine. Concentration of the eluate affords the enriched mixture. Stereoisomeric conglomerates may be separated by conventional techniques known to those skilled in the art. See, e.g., “Stereochemistry of Organic Compounds” by E L. Eliel (Wiley, New York, 1994), the disclosure of which is incorporated herein by reference in its entirety.

[0262] In the present case, compounds of Formula I exist as a mixture of enantiomers of Formulae la and lb

[0263] This mixture of isomers can be resolved through conventional methods described above or via chiral resolution by protection of the imidazole nitrogen followed by resolution through a chiral column followed by deprotection. Protection of the imidazole compounds of Formula la and lb is performed according to methods well known to those skilled in the art. More specifically, to a stirred solution of compound of Formula I (i.e. , a mixture of enantiomers of Formula la and lb) (1.0 equiv.) in dichloromethane (10 vol.), was added triethylamine (3 equiv.) and BOC anhydride (1.5 equiv). The mixture was stirred at room temperature for 4 hours. The progress of the reaction was monitored by TLC, after completion of reaction, the mixture was diluted with water and extracted with dichloromethane. The organic layer was washed with brine solution, dried over anhydrous sodium sulphate, filtered & concentrated under reduced pressure to obtain crude, which was purified by flash column chromatography using ethyl acetate in hexane as an eluent to obtain BOC protected derivatives of Formula I.

[0264] Most of the enantiomers (la and lb) were separated as racemic compounds at this stage. Afew enantiomers may be separated without BOC protection. Chiral methods used for separation are mentioned below.

[0265] Method 1 :

[0266] Analytical conditions: Column: CHIRALPAK IG (100 mm X 4.6 mm X 3 pm).

[0267] Mobile phase:- n-Hexane : Ethanol with 0.1% DEA.

[0268] Method 2:

[0269] Analytical conditions: Column: CHIRALPAK IG (100 mm X 4.6 mm X 3 pm).

[0270] Mobile phase: - n-Hexane: IPAwith 0.1 % DEA.

[0271] Method 3:

[0272] Analytical conditions: Column: CHIRALPAK IC (100 mm X 4.6 mm X 3 pm)

[0273] Mobile phase: - n-Hexane: Ethanol with 0.1 % DEA.

[0274] Method 4:

[0275] Analytical conditions: Column: CHIRALPAK IC (100 mm X 4.6 mm X 3 pm)

[0276] Mobile phase: - n-Hexane: IPAwith 0.1 % DEA.

[0277] Method 5:

[0278] Analytical conditions: Column: CHIRALPAK IC (100 mm X 4.6 mm X 3 pm)

[0279] Mobile phase: - MTBE: Ethanol with 0.1 % DEA

[0280] Method 6:

[0281] Analytical conditions: Column: CHIRALCEL OJ-H (250 mm x 4 6 mm x5 pm)

[0282] Mobile phase: - n-Hexane: Ethanol with 0.1 % DEA

[0283] Method 7:

[0284] Analytical conditions: Column: CHIRALPAK IA (100 mm X 4.6 mm X 3 pm)

[0285] Mobile phase: - n-Hexane: IPAwith 0.1 % DEA.

[0286] The resolved compounds of Formula la and lb may be deprotected according to methods well known to those skilled in the art. Specifically, to a stirred solution of compound la or lb (1.0 equiv ) in methanol (10 vol.), was added sodium carbonate (2 equiv.) at room temperature and the mixture was stirred for 2 hours. The progress of the reaction was monitored by TLC, after completion of reaction, the mixture was concentrated The obtained crude was dissolved with water and extracted with ethyl acetate The organic layer was washed with brine solution, dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to obtain crude, which was purified by flash column chromatography using methanol in dichloromethane as an eluent to obtain single enantiomer compound of Formula la or Formula lb. Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC).

[0287] Alternatively, the racemate (or a racemic precursor) may be reacted with a suitable optically active compound, for example, an alcohol, or, in the case where the compound of formula I contains an acidic or basic moiety, a base or acid such as 1-phenylethylamine or tartaric acid. The resulting diastereomeric mixture may be separated by chromatography and / or fractional crystallization and one or both of the diastereoisomers converted to the corresponding pure enantiomer(s) by means well known to a skilled person.

[0288] Chiral compounds of the disclosure (and chiral precursors thereof) may be obtained in enantiomerically-enriched form using chromatography, typically HPLC, on an asymmetric resin with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from 0 to 50% by volume of isopropanol, typically from 2% to 20%, and from 0 to 5% by volume of an alkylamine, typically 0.1% diethylamine. Concentration of the eluate affords the enriched mixture.

[0289] All publications, including but not limited to, issued patents, patent applications, and journal articles, cited in this application are each herein incorporated by reference in their entirety

[0290] Although the disclosure has been described above with reference to the disclosed embodiments, those skilled in the art will readily appreciate that the specific experiments detailed below are only illustrative of the disclosure. It should be understood that various modifications can be made without departing from the spirit of the disclosure. Accordingly, the disclosure is limited only by the claims.

[0291] In the following Examples and Preparations, “BOC”, “Boc” or “boc” means N-terf- butoxycarbonyl, “DCM” (CH2CI2) means methylene chloride, “DIPEA” or“DIEA” means diisopropyl ethyl amine, “DMA” means N,N-dimethylacetamide, “DMF” means N-N-dimethyl formamide, “DMSO” means dimethylsulfoxide, “DPPP” means 1,3-bis(diphenylphosphino)propane, “HOAc” means acetic acid, “IPA” means isopropyl alcohol. “MTBE" means methyl t-butyl ether, “NMP” means 1-methyl 2- pyrrolidinone, “TEA” means triethyl amine, “TFA" means trifluoroacetic acid, “DCM” means dichloromethane, “EtOAc” means ethyl acetate, “MgSCU” means magnesium sulphate, “NaSOT means sodium sulphate, “MeOH” means methanol, “EtOH” means ethanol, “H2O” means water, “HCI” means hydrochloric acid, “POCI3” means phosphorus oxychloride, “DMSO” means dimethyl sulfoxide, “K2CO3” means potassium carbonate, “N” means Normal, “M” means molar, “mL” means millilitre, “mmol” means millimoles, “pmol” means micromoles, “eq.” means equivalent, “°C” means degrees Celsius, “Pa” means pascals.

[0292] Methods and Procedures

[0293] Procedure A

[0294] Synthesis of Compounds 1, 3 and 3

[0295] Compound 2 Compound 3

[0296] Experimental Details

[0297] Step 1 . Synthesis of 4

[0298] 1-(1-Methylindol-4-yl)-1-[1 -(triphenylmethyl)imidazol-4-yl]ethanol:

[0299] Under the protection of nitrogen, magnesium (97 mg, 3.99 mmol, 1.2 equiv) and iodine (42 mg, 0.17 mmol, 0.05 equiv) was added to the reaction vial. Dissolve 4-bromo-1-methylindole (700 mg, 3.33 mmol, 1.0 equiv) in tetrahydrofuran (3 mL), then take 0.5 ml_ of 4-bromo-1-methylindole in tetrahydrofuran and add to the above reaction liquid The bottom of the reaction flask is heated with a heatgun to initiate the reaction. The remaining 4-bromo-1-methylindole in tetrahydrofuran solution was added dropwise to keep the reaction liquid slightly boiling. The mixture was stirred at 60 °C for another 30 min to give a gray solution which was used for the next step directly.

[0300] To a solution of 1-[1-(triphenylmethyl)imidazol-4-yl]ethanone (704 mg, 1.99 mmol, 0 6 equiv) in tetrahydrofuran (10 mL) was added the (1-methyl-1 / - / -indol-4-yl)magnesium bromide solution prepared above dropwise. The mixture was stirred at 0 °C for 1 h under nitrogen atmosphere. The reaction was quenched with sat. ammonium chloride (aq.) at 0 °C. The resulting mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with water (3 x 20 mL), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petroleum ether / ethyl acetate (2:1 ) to afford 1-(1-methylindol-4-yl)-1-[1-(triphenylmethyl)imidazol-4- yl]ethanol (280 mg, 17 38% yield) as a yellow solid. LCMS (ESI) [M+H]+: 484

[0301] Step 2. Synthesis of Compound 1

[0302] 4-[1-(1H-imidazol-4-yl)ethenyl]-1-methylindole:

[0303] To a solution of 1-(1-methylindol-4-yl)-1-[1-(triphenylmethyl)imidazol-4-yl]ethanol (270 mg, 0 56 mmol, 1.0 equiv) in trifluoroacetic acid (3 mL) was added triethylsilane (1 mL). The solution was stirred at 80

[0304] °C for 1 h under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under vacuum to give a residue, which was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, acetonitrile in water (10 mmol / L NH4HCO3), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in 4-[1 -(1 / -7-imidazol-4-yl)ethenyl]-1 -methylindole (120 mg, 96.27% yield) as a yellow solid. LCMS (ESI) [M+H]+: 224.

[0305] Step 3. Synthesis of 5 ompoun

[0306] 4-[1-(1 H-imidazol-4-yl)ethyl]-1-methylindole:

[0307] To a solution of 4-[1-(1 / - / -imidazol-4-yl)ethenyl]-1-methylindole (60 mg, 0 27 mmol, 1 0 equiv) in methanol (5 ml_) was added Pd / C (15 mg) under nitrogen atmosphere. The mixture was stirred at room temperature under hydrogen atmosphere. The mixture was filtered through a Celite pad. The filtrate was concentrated to give a residue, which was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, acetonitrile in water (10 mmol / L NH4HCO3), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in 4-[1-(1 / - / -imidazol-4-yl)ethyl]-1-methylindole (37.3 mg, 61.61% yield) as a white solid. LCMS (ESI) [M+H]+: 226

[0308] Step 4. Chiral Resolution: Isolation of Compounds 2 and 3

[0309] 4-[(1 R)-1 -(1 H-imidazol-4-yl)ethyl]-1 -methylindole & 4-[(1 S)-1 -(1 H-imidazol-4-yl)ethyl]-1 - methylindole:

[0310] The racemate 4-[1-(1 / - / -imidazol-4-yl)ethyl]-1-methylindole (31 mg, 0.14 mmol, 1.0 equiv) was separated by Prep-Chiral HPLC with the following conditions (Column: CHIRALPAK-IK, 3*25mm, 5pm; Mobile Phase A: Hex(0 1% DEA)-HPLC, Mobile Phase B: EtOH-HPLC; Flow rate: 40 mL / min; Gradient: isocratic 10%; Wave Length: 214 / 230 nm; RT1(min): 9.1 ; RT2(min): 13.8; Sample Solvent: EtOH-HPLC; Injection Volume: 1 mL; Number Of Runs: 3) to afford 4-[(1R)-1-(1H-imidazol-4- yl)ethyl]-1 -methylindole (12.3 mg, 38.80% yield) as a white solid. LCMS (ESI) [M+H]+: 226.10.1H NMR (400 MHz, DMSO-de) 5 11.72 (s, 1 H), 7.46 (s, 1 H), 7.32 - 7.14 (m, 2H), 7 14 - 6.98 (m, 1 H), 6.81 (d, J = 7.3 Hz, 1 H), 6.74 (s, 1H), 6.53 - 6.38 (m, 1 H), 4.52 - 4.32 (m, 1H), 3.75 (s, 3H), 1.59 (d, J = 7.2 Hz, 3H).

[0311] 4-[(1 S)-1 -( 1 / - / -imidazol-4-yl)ethyl]-1 -methylindole (13.1 mg, 41.32% yield) as a white solid. LCMS (ESI) [M+H]+: 226.10.1H NMR (400 MHz, DMSO-de) 5 11.72 (s, 1 H), 7.46 (s, 1 H), 7.34 - 7.17 (m, 2H), 7.12 - 6.94 (m, 1 H), 6.81 (d, J = 7.2 Hz, 1 H), 6.74 (s, 1H), 6.47 (dd, J = 3.1, 0.9 Hz, 1H), 4.42 (d, J = 7.3 Hz, 1 H), 3.75 (s, 3H), 1.59 (d, J = 7.2 Hz, 3H).

[0312] Table A (Compounds prepared using procedure A)

[0313] Procedure B

[0314] Synthesis of Compounds 55, 56, 57 & 58

[0315]

[0316] Experimental Details

[0317] Step 1 . Synthesis of 2

[0318] (2,3-dihydrobenzofuran-7-yl)(1-trityl-1 H-imidazol-4-yl)methanol:

[0319] To a stirred solution of 7-bromo-2,3-dihydrobenzofuran (15.0 g, 75.77 mmol, 1.0 equiv) in THF (150 ml_) was added n-BuLi (45 5 ml_, 113 66 mmol, 1 5 equiv) dropwise at -78 °C The solution was stirred at this temperature for 30 min to give solution A. To a stirred solution of 1 -trityl- 1 H-imidazole-4- carbaldehyde (25.6 g, 75.77 mmol, 1 .0 equiv) in THF (200 ml_) was added solution A dropwise at -78 °C. The mixture was stirred at this temperature for 1 h. The reaction mixture was quenched by the addition of 100 mL saturated NFkCI aqueous. The aqueous solution was extracted with EtOAc (100 mL x 3). The combined organic solution was dried over Na2SC>4 and concentrated to give the residue which was triturated with MeOH to afford (2,3-dihydrobenzofuran-7-yl)(1-trityl-1 H-imidazol-4- yl)methanol (14g, 40% yield) as white solid. LCMS (ESI) [M+H]+: 459.1H NMR (400 MHz, Chloroform- d) 5 7.50 (s, 1H), 7.35 - 7.28 (m, 10H), 7.15 - 7.03 (m, 7H), 6.94 (d, J = 7.7 Hz, 1H), 6.68 (d, J = 7.9 Hz, 1 H), 6.51 (s, 1H), 5.78 (s, 1H), 4.43 (t, J = 8 7 Hz, 2H), 2.98 (t, J = 8.7 Hz, 2H).

[0320] Step 2. Synthesis of 3

[0321] (2,3-dihydrobenzofuran-7-yl)(1-trityl-1 H-imidazol-4-yl)methanone:

[0322] A mixture of (2,3-dihydrobenzofuran-7-yl)(1-trityl-1H-imidazol-4-yl)methanol (14 g, 30.55 mmol, 1.0 equiv) and MnC>2 (26.6 g, 305.54 mmol, 10.0 equiv) in DCM (300 mL) was stirred at 40 °C overnight. The mixture was filtered. The filtrate was concentrated to give the residue which was purified by flash column with 0- 30% EtOAc in petroleum ether to afford (2,3-dihydrobenzofuran-7-yl)(1-trityl-1H- imidazol-4-yl)methanone (12 5 g, 90% yield) as white solid. LCMS (ESI) [M+H]+: 457.1H NMR (400 MHz, Chloroform-d) 5 7.72 (d, J = 7.8 Hz, 1 H), 7.67 (s, 1H), 7.53 (s, 1 H), 7.38 - 7.32 (m, 9H), 7.20 - 7.11 (m, 7H), 6.93 (d, J = 7.9 Hz, 1 H), 4.58 (t, J = 8.8 Hz, 2H), 3.48 (t, J = 8.8 Hz, 2H)

[0323] Step 3. Synthesis of 4

[0324] 4-(1-(2,3-dihydrobenzofuran-7-yl)-2-methoxyvinyl)-1-trityl-1H-imidazole:

[0325] To a stirred solution of 4-(2,3-dihydro-1-benzofuran-7-carbonyl)-1-(triphenylmethyl)imidazole (2.0 g, 4.38 mmol, 1.0 equiv) and (methoxymethyl)triphenylphosphonium chloride (2.3 g, 6.57 mmol, 1.5 equiv) in THF (10 mL) was added sodium bis(trimethylsilyl)amide (3.3 mL, 6.57 mmol, 1 5 equiv) at room temperature under nitrogen atmosphere. After 2 h at 60 °C, the reaction was quenched with sat. ammonium chloride (aq.) at room temperature. The aqueous layer was extracted with ethyl acetate (3 x 20 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, acetonitrile in water (10 mmol / L NH4HCO3), 10% to 50% gradient in 10 min; detector, UV 254 nm to afford 4-(1-(2,3-dihydrobenzofuran-7-yl)-2-methoxyvinyl)-1-trityl-1 / - / -imidazole (1 g, 47 11% yield, 92.1% purity) as a light yellow solid. LCMS (ESI) [M+H]+: 485.

[0326] Step 5. Synthesis of Compounds 55 and 56

[0327] 4-[(Z)-1-(2,3-dihydro-1-benzofuran-7-yl)-2-methoxyethenyl]-1H-imidazole and (E)-4-(1 -(2,3- dihydrobenzofuran-7-yl)-2-methoxyvinyl)-1H-imidazole:

[0328] A solution of 4-(1-(2,3-dihydrobenzofuran-7-yl)-2-methoxyvinyl)-1-trityl-1 / 7-imidazole (600 mg, 1.23 mmol, 1.0 equiv) in acetic acid (10 mL) was stirred at 60 °C for 1 h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed- phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, acetonitrile in water (10 mmol / L NH4HCO3), 10% to 50% gradient in 10 min; detector, UV 254 nm. to give (180 mg crude) as a brown solid The crude (60 mg) product was purified by Prep-HPLC with the following conditions (Column: Xbridge Phenyl OBD Column, 30*150mm 5pm; Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient (B%): 22% B to 57 % B in 17 min; Wave Length: 254nm / 220nm; RT1(min): 8.57) to afford (Z)-4-(1-(2,3-dihydrobenzofuran-7- yl)-2-methoxyvinyl)-1 / - / -imidazole (37.4 mg, 99.2% purity) as a white solid. LCMS (ESI) [M+H]+: 243.15.1H NMR (400 MHz, DMSO-de) 5 11.62 (d, J = 168.4 Hz, 1H), 7 41 (s, 1 H), 7.08 (s, 1H), 6.98 - 6.78 (m, 1H), 6.64 (d, J = 64.5 Hz, 2H), 6.29 (s, 1H), 4.38 (t, J = 8.7 Hz, 2H), 3.69 (s, 3H), 3.11 (t, J = 8.7 Hz, 2H).

[0329] (E)-4-(1-(2,3-dihydrobenzofuran-7-yl)-2-methoxyvinyl)-1H-imidazole (8.9 mg, 98.6% purity) as a white solid. LCMS (ESI) [M+H]+: 243.15.1H NMR (400 MHz, DMSO-de) 5 11.77 (d, J = 43.5 Hz, 1 H), 7.50 (s, 1 H), 7.13 (d, J = 7.2 Hz, 1H), 7.04 - 6.85 (m, 2H), 6.78 (t, J = 7.4 Hz, 1 H), 6.36 (s, 1 H), 4 41 (t, J = 8.7 Hz, 2H), 360 (s, 3H), 3.17 (t, J = 8.7 Hz, 2H).

[0330] Step 6. Synthesis of Compound 5 p p

[0331] 4-(1-(2,3-dihydrobenzofuran-7-yl)-2-methoxyethyl)-1 W-imidazole:

[0332] To a solution of crude mixture of 4-[(Z)-1-(2,3-dihydro-1-benzofuran-7-yl)-2-methoxyethenyl]-1 / 7- imidazole and (E)-4-(1-(2,3-dihydrobenzofuran-7-yl)-2-methoxyvinyl)-1 / - / -imidazole (120 mg, 0.50 mmol, 1.0 equiv) in methanol (5 mL) was added Pd / C (20 mg). The resulting mixture was stirred at room temperature for 1 h under hydrogen atmosphere The resulting mixture was filtered, the filter cake was washed with methanol (15 mL). The filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: YMC-Actus Triart C18 ExRS, 30*150 mm, 5 u m; Mobile Phase A: water(10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 17% B to 32% B in 14 min; Wave Length: 254nm / 220nm; RTi(min): 10.12) to afford 4-[1-(2,3-dihydro-1-benzofuran-7-yl)-2-methoxyethyl]-1 / 7-imidazole (42.6 mg, 34.81% yield, 99.1% purity) as a white solid. LCMS (ESI) [M+H]+: 245.051H NMR (400 MHz, DMSO-cfe) 5 11.76 (s, 1 H), 7.49 (d, J = 8.3 Hz, 1H), 7.23 - 6.83 (m, 2H), 6.85 - 6.42 (m, 2H), 4.50 (td, J = 8.8, 3.9 Hz, 2H), 4.43 - 4.24 (m, 1 H), 3.98 - 3.62 (m, 2H), 3.18 (d, J = 10.8 Hz, 5H).

[0333] Step 7: Resolution to afford Compounds 57 and 58

[0334] ( / ?)-4-(1-(2,3-dihydrobenzofuran-7-yl)-2-methoxyethyl)-1H-imidazole & (S)-4-(1 -(2,3- dihydrobenzofuran-7-yl)-2-methoxyethyl)-1H-imidazole:

[0335] The racemate 4-[1-(2,3-dihydro-1-benzofuran-7-yl)-2-methoxyethyl]-1 / - / -imidazole (28 mg, 0.14 mmol, 1 .0 equiv) was separated by Prep-Chiral HPLC with the following conditions (Column: NB-Chiral NX(2), 50*4.6MM 3u; Mobile Phase A: Hex(10 mM NHs-MeOH), Mobile Phase B: EtOH; Flow rate: 40 mL / min; Gradient (B%): isocratic 30%; Wave Length: 220 / 254 nm; RT1(min): 5.29; RT2(min): 10.48; Sample Solvent: MeOH; Injection Volume: 1.0 mL; Number Of Runs: 2): 13.8; Sample Solvent: EtOH- -HPLC; Injection Volume: 1 mL; Number Of Runs: 3) to afford (R)-4-(1-(2,3-dihydrobenzofuran-7-yl)-2- methoxyethyl)-1H-imidazole (7.9 mg, 28.20% yield) as a white solid. LCMS (ESI) [M+H]+: 245.10.1H NMR (400 MHz, DMSO-de) 6 11.78 (s, 1 H), 7.50 (s, 1 H), 7.02 (dd, J = 23 3, 7.4 Hz, 2H), 6.85 - 6.62 (m, 2H), 4.51 (td, J = 8.8, 3.4 Hz, 2H), 4.34 (t, J = 7.3 Hz, 1H), 3.82 - 3 66 (m, 2H), 3.18 (d, J = 14.1 Hz, 5H)

[0336] (S)-4-(1-(2,3-dihydrobenzofuran-7-yl)-2-methoxyethyl)-1 H-imidazole (7.4 mg, 26.42% yield) as a white solid. LCMS (ESI) [M+H]+: 245.10.1H NMR (400 MHz, DMSO-de) 5 11.78 (s, 1 H), 7 50 (s, 1H), 7.02 (dd, J = 23.3, 7.4 Hz, 2H), 6.85 - 6.62 (m, 2H), 4.51 (td, J = 8.8, 3.4 Hz, 2H), 4.34 (t, J = 7 3 Hz, 1 H), 3.82 - 3.66 (m, 2H), 3.18 (d, J = 14.1 Hz, 5H).

[0337] Synthesis of Compounds 118 and 119

[0338] Experimental Details

[0339] Step 1 . Synthesis of 7 4-Bromo-l,2-dimethylindole 7:

[0340] To a stirred solution of 4-bromo-2-methyl-127-indole (5.0 g, 23.80 mmol, 1.0 equiv) in tetrahydrofuran (50 mL) was added sodium hydride (1.9 g, 47.60 mmol, 2.0 equiv, 60%) in portions at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at 0 °C for 30 min under nitrogen atmosphere. To the above mixture was added iodomethane (1.77 mL, 28.56 mmol, 1.2 equiv) at 0 °C. The resulting mixture was stirred at room temperature for additional 1 h. Desired product could be detected by LCMS. The reaction was quenched with ice water (50 mL) at 0 °C. The resulting mixture was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine (2 x 50 mL). dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petroleum ether / ethyl acetate (10: 1). This resulted in 4-bromo-l,2-dimethylindole (4.8 g, 96.02% yield) as a yellow solid. LCMS (ESI) [M+H]+: 224.

[0341] Step 2: Synthesis of 8

[0342] (l,2-Dimethylindol-4-yl)[l-(triphenylmethyl)imidazol-4-yl]methanol:

[0343] A mixture of 4-bromo-l,2-dimethylindole (4.8 g, 21.41 mmol, 1.0 equiv) in THF (50 mL) was stirred at -78 °C for 5 min under nitrogen atmosphere. To the above mixture was added n- BuLi (10.3 mL, 25.70 mmol, 1.2 equiv) dropwise at -78 °C. The resulting mixture was stirred at -78 °C for additional 30 min. To the above mixture was added 1 -(triphenylmethyl)imidazole- 4-carbaldehyde (5.8 g, 17.12 mmol, 0.8 equiv) dropwise at -78 °C. The resulting mixture was stirred at -78 °C for additional 30 min. Desired product could be detected by LCMS. The reaction was quenched with sat. NH4CI (aq.) at room temperature. The resulting mixture was diluted with water (50 mL). The resulting mixture was extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine (2 x 100 mL), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The resulting mixture was washed with 3 x 50 mL of ether. This resulted in (L2-dimethylindol-4- yl)[l-(triphenylmethyl)imidazol-4-yl]methanol (4.5 g, 93.75% yield) as an off-white solid. LCMS (ESI) [M+H]+: 484.

[0344] Step 3: Synthesis of 9

[0345] 1 ,2-Dimethyl-4- [ 1 -(triphenylmethyl)imid azole-4-carb onyl] indole :

[0346] A solution of (l,2-dimethylindol-4-yl)[l-(triphenylmethyl)imidazol-4-yl]methanol (4.5 g, 9.30 mmol, 1.0 equiv) and MnCh (4.0g, 46.51 mmol, 5.0 equiv) in trichloromethane (10 mL) was stirred at 70 °C for 2 h under nitrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with tri chloromethane (2 x 50 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petroleum ether I ethyl acetate (1:1). This resulted in l,2-dimethyl-4-[l- (triphenylmethyl)imidazole-4-carbonyl]indole (4.0 g, 88.89% yield) as a yellow solid. LCMS (ESI) | M+H | : 482.

[0347] Step 4: Synthesis of 10

[0348] 4- {2-Methoxy- 1- [ l-(triphenylmethyl)imidazol-4-yl] etheny l}-l-methy lindole:

[0349] To a stirred solution of l-methyl-4-[l-(triphenylmethyl)imidazole-4-carbonyl]indole (3.0 g, 6.41 mmol, 1.0 equiv) and (methoxymethyl)triphenylphosphanium chloride (3.2 g, 9.34 mmol, 1.5 equiv) in tetrahydrofuran (50 mL) was added NaHMDS (9.3 mL, 18.69 mmol, 3.0 equiv) dropwise at 60 °C under nitrogen atmosphere. The resulting mixture was stirred at 60 °C for 2 h under nitrogen atmosphere. Desired product could be detected by LCMS. The reaction was quenched with sat. ammonium chloride (aq.) (50 mL) at room temperature. The resulting mixture was extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with water (2 x 100 mL), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petroleum ether / ethyl acetate (1 : 1). This resulted in 4- {2-methoxy-l-[l-(triphenylmethyl)imidazol-4-yl]ethenyl}-l-methylindole (2.4 g, 80.57% yield) as a yellow solid. LCMS (ESI) [M+H]+: 510.

[0350] Step 5: Synthesis of 11

[0351] 4-[l-(l / / -imidazol-4-yl)-2-methoxyethenyl|-l,2-dimethylindole:

[0352] A solution of 4-{2-methoxy-l-[l-(triphenylmethyl)imidazol-4-yl]ethenyl}-l,2- dimethylindole (2.4 g, 4.61 mmol, 1 equiv) in acetic acid (50 mL) was stirred at 60 °C for 4 h under nitrogen atmosphere. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with dichloromethane / methyl alcohol (12: 1). This resulted in 4-[l- ( l / / -imidazol-4-yl)-2-methoxy ethenyl] -1,2-dimethylindole (750 mg, 60.84% yield) as a yellow solid. LCMS (ESI) [M+H]+: 268.

[0353] Step 6: Synthesis of 12

[0354] 4-[l-(l / / -imidazol-4-yl)-2-methoxyethyl|-l,2-diniethylindole:

[0355] A solution of 4-{2-methoxy-l-[l-(triphenylmethyl)imidazol-4-yl]ethyl}-l,2- dimethylindole (700 mg, 2.68 mmol, 1 equiv) in acetic acid (20 mL) was stirred at 60 °C for 1 h under nitrogen atmosphere. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (10 mmol / L NH4HCO3), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in 4-[l-(177-imidazol-4-yl)-2-methoxyethyl]-l,2-dimethylindole (500 mg, 71.42% yield) as a yellow solid. LCMS (ESI) [M+H]+: 270 Step 7 : Synthesis of 13

[0356] 3-Fhioro-4-| l-(l / / -imidazol-4-yl)-2-methoxyethyl|-l, 2-dimethylindole:

[0357] To a stirred solution of 4-[l-(177-imidazol-4-yl)-2 -methoxyethyl]-!, 2-dimethylindole (100 mg, 0.37 mmol, 1.0 equiv) in acetonitrile (4 mb) was added 4-(chloromethyl)-l-fluoro- l,4-diazabicyclo[2.2.2]octane-l,4-diium; bis(tetrafluoroboranuide) (157 mg, 0.44 mmol, 1.2 equiv) in portions at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at 0 °C for 15 min under nitrogen atmosphere. Desired product could be detected by LCMS. The crude product ( 100 mg) was purified by Prep-HPLC with the following conditions (Column: XBridge Shield RP18 OBD Column 30*150 mm, 5pm; Mobile Phase A: Water(10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient (B%): 24% B to 39 % B in 17 min; Wave Length: 254 nm / 220 nm; RTl(min): 6.423 min). This resulted in 3-fluoro-4-[l-(17 / - imidazol-4-yl)-2-methoxyethyl]-l, 2-dimethylindole (24 mg, 24.00% yield) as a yellow solid. LCMS (ESI) [M+H]+: 288.

[0358] Step 8: Synthesis of Compounds 118 and 119

[0359] 3-Fluoro-4-[( ! / ?)-! -(LH-imidazol-4-yl)-2-methoxyethyl]-l,2-dimethylindole & 3-Fluoro-

[0360] 4-[(LS')-l-(l / / -imidazol-4-yl)-2-methoxyethyl]-l, 2-dimethylindole:

[0361] The racemate 3-fluoro-4-[l-(177-imidazol-4-yl)-2-methoxy ethyl] -1, 2-dimethylindole (36 mg, 0.12 mmol, 1.0 equiv) was purified by Prep-CHIRAL with the following conditions (Column: CHIRALPAK IG. 3*25 cm, 5 pm; Mobile Phase A: Hex(0.5% 2M NHs-MeOH)- HPLC, Mobile Phase B: EtOH: ACN=5 : 1 ; Flow rate: 40 mL / min; Gradient (B%)50% B; Wave Length: 220 / 254 nm; RTl(min): 4.097; RT2(min): 6.455; Sample Solvent: EtOH— HPLC; Injection Volume: 1.0 mL; Number Of Runs: 6). This resulted in 3-fluoro-4-[(17?)-l -(177- imidazol-4-yl)-2-methoxyethyl]-l,2-dimethylindole (12.4 mg, 20.67% yield, 96.7% purity, 100% e.e) as a yellow solid. LCMS (ESI) [M+H]~: 288.10. 'H NMR (400 MHz, DMSO-Je) 5 11.81 (d, J= 43.6 Hz, 1H), 7.50 (s, 1H), 7.32 - 7.18 (m. 1H), 7.08 - 6.91 (m, 2H), 6.71 (d, J= 41.6 Hz, 1H), 4.80 (d. J = 27.7 Hz, 1H), 3.97 - 3.78 (m. 2H), 3.61 (s. 3H), 3.21 (d. J = 13.7 Hz, 3H), 2.34 (d, J= 2.0 Hz, 3H).

[0362] And 3-fluoro-4-[(lS)-l-(177-imidazol-4-yl)-2 -methoxyethyl]-!, 2-dimethylindole (11.5 mg, 19.17% yield, 99.6% purity, 100% e.e) as a light yellow solid. LCMS (ESI) [M+H]+: 288.10. ‘H NMR (400 MHz, DMSO-t / e) 5 11.80 (d, J = 48.1 Hz, 1H), 7.49 (d, J = 10.1 Hz, 1H), 7.32 - 7.18 (m, 1H), 7.07 - 6.97 (m, 1H), 6.97 - 6.64 (m, 2H), 4.87 - 4.72 (m, 1H), 3.96 - 3.77 (m, 2H), 3.61 (d, J = 5.4 Hz, 3H), 3.24 - 3.18(d, J = 5.4 Hz, 3H), 2.34 (d, J = 2.1 Hz, 3H).

[0363] Table B (Compounds prepared using Procedure B)

[0364] Procedure C Trt

[0365] Synthesis of Compounds 124 and 125

[0366] Compound 124 Compound 125

[0367] Experimental Details

[0368] Step 1 . Synthesis of 2

[0369] 4-(2,3-Dihydro-1 -benzofuran-7-ylmethyl)-1H-imidazole:

[0370] A mixture of 2,3-dihydro-1-benzofuran-7-yl[1-(triphenylmethyl)imidazol-4-yl]methanol (10.0 g, 21.8 mmol, 1.0 equiv) and triethylsilane (7.6 g, 65.43 mmol, 3.0 equiv) in trifluoroacetic acid (100 mL) and dichloromethane (150 mL) was stirred at 60 °C for 1 h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. This resulted in 4-(2,3-dihydro-1-benzofuran-7- y Imethy l)-1 / - / -imidazole (3.2 g crude) as a yellow oil. The crude product was used for the next step directly without further purification. LCMS (ESI) [M+H]+: 201

[0371] Step 2. Synthesis of 3

[0372] 4-(2,3-Dihydro-1 -benzofuran-7-ylmethyl)-1 -(triphenylmethyl)imidazole:

[0373] To a stirred solution of 4-(2,3-dihydro-1-benzofuran-7-ylmethyl)-1 / - / -imidazole (3.2 g, 15.98 mmol, 1.0 equiv) and triethylamine (4 8 g, 47.94 mmol, 3.0 equiv) in dichloromethane (100 mL) was added triphenylmethyl chloride (5.3 g, 19.17 mmol, 1.2 equiv) in portions at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 1 h under nitrogen atmosphere. The reaction was quenched with ice water (100 mL) at 0 °C. The resulting mixture was extracted with dichloromethane (3 x 100 mL). The combined organic layers were washed with water (2 x 100 mL), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petroleum ether / ethyl acetate (1 :1 ). This resulted in 4-(2,3-dihydro-1-benzofuran-7-ylmethyl)-1- (triphenylmethyl)imidazole (3.2 g, 45.25% yield, 90% purity) as a white solid. LCMS (ESI) [M+H]+: 443 Step 3. Synthesis of 4

[0374] 4-[1-(2,3-Dihydro-1 -benzofuran-7-yl)-2-fluoroethyl]-1-(triphenylmethyl)imidazole:

[0375] To a stirred solution of 4-(2,3-dihydro-1-benzofuran-7-ylmethyl)-1-(triphenylmethyl)imidazole (2.1 g, 4.74 mmol, 1.0 equiv) in tetrahydrofuran (50 ml_) was added LDA (4.7 mL, 9.5 mmol, 2.0 equiv, 2M in tetrahydrofuran) dropwise at -78 °C under nitrogen atmosphere. The resulting mixture was stirred at - 78 °C for 30 min under nitrogen atmosphere To the above mixture was added fluoroiodomethane (1.51 g, 9.48 mmol, 2.0 equiv) at -78 °C. The resulting mixture was stirred at -78 °C for additional 30 min. Desired product could be detected by LCMS. The reaction was quenched with sat. NH4CI (aq.) at -78 °C. The resulting mixture was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with water (2 x 50 mL), dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petroleum ether / ethyl acetate (1 :1). This resulted in 4-[1-(2,3-dihydro-1- benzofuran-7-yl)-2-fluoroethyl]-1-(triphenylmethyl)imidazole (630 mg, 28 0% yield) as a yellow solid LCMS (ESI) [M+H]+: 475

[0376] Step 4. Synthesis of 5

[0377] 4-[1-(2,3-Dihydro-1 -benzofuran-7-yl)-2-fluoroethyl]-1 H-imidazole:

[0378] A solution of 4-[1-(2,3-dihydro-1-benzofuran-7-yl)-2-fluoroethyl]-1-(triphenylmethyl)imidazole (850 mg, 1.79 mmol, 1.0 equiv) in acetic acid (30 mL) was stirred at 60 °C for 1 h under nitrogen atmosphere. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, acetonitrile in water (10 mmol / L NH4HCO3), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in 4-[1-(2,3-dihydro-1-benzofuran-7-yl)-2- fluoroethyl]-1 / - / -imidazole (350 mg, 84.14% yield, 98% purity) as a white solid. LCMS (ESI) [M+H]+: 233.0.

[0379] Step 5. Resolution of 5 to afford Compounds 124 and 125

[0380] 5 Compound 124 Compound 125

[0381] 4-[(1R)-1-(2,3-dihydro-1-benzofuran-7-yl)-2-fluoroethyl]-1H-imidazole & 4-[(1S)-1 -(2,3-dihydro-1- benzofuran-7-yl)-2-fluoroethyl]-1H-imidazole:

[0382] The racemate 4-[1-(2,3-dihydro-1-benzofuran-7-yl)-2-fluoroethyl]-1 / - / -imidazole (350 mg) was separated by Prep-Chiral HPLC Column: CHIRALPAK IA, 3*25 cm, 5 pm; Mobile Phase A: Hex: MtBE=1: 1(0.5% 2 M NH3-MEOH), Mobile Phase B: MeOH; Flow rate: 40 mL / min; Gradient: isocratic 8%; Wave Length: 284 / 218 nm; RT1(min): 6.114; RT2(min): 8.64; Sample Solvent: MeOH; Injection Volume: 04 mL; Number Of Runs: 10 This resulted in 4-[(1R)-1-(2,3-dihydro-1-benzofuran-7-yl)-2- fluoroethyl]-1 / - / -imidazole (152.5 mg, 43.57% yield, 92.5% purity) as a white semi-solid. LCMS (ESI) [M+H]+: 233.15.1H NMR (400 MHz, DMSO-cfe) 611.89 (s, 1H), 756 (d, J =1.1 Hz, 1H), 7.15-6.94 (m, 2H), 6.86 (s, 1H), 6.79-6.69(m, 1H), 4.90 -4.79 (m, 1H), 4.78-4.68(m, 1H), 4.59-4.39(m, 3H), 3.23- 3.14 (m, 2H).

[0383] 4-[(1 S)-1-(2,3-dihydro-1-benzofuran-7-yl)-2-fluoroethyl]-1 / - / -imidazole (113.3 mg, 3237% yield, 99.7% purity) as a white semi-solid LCMS (ESI) [M+H]+: 233101H NMR (400 MHz, DMSO-ds) 51189 (s, 1H), 7.56 (s, 1H), 7.19-6.94 (m, 2H), 6.86 (s, 1H), 6.79-6.70 (m, 1H), 4.90-4.78 (m, 1H), 4.77- 4.67 (m, 1H), 4.59-4.37 (m, 3H), 3.24-3.12 (m, 2H)

[0384] Synthesis of Compound 139 ii, lr[dF(CF3)ppy]2(dtbbpy)PF6, quinuclidine, DMSO iii, Ni(acac)2, BPO, 450nm Blue LEDs Experimental Details

[0385] Step 1. Synthesis of 8 ii, lr[dF(CF3)ppy]2(dtbbpy)PF6, quinuclidine, DMS iii, Ni(acac)2, BPO, 450nm Blue LEDs

[0386] 7e / / -butyl 4-[3-methoxy-l-(l-methylindol-4-yl)propyl]imidazole-l-carboxylate:

[0387] To a stirred mixture of / e / 7-butyl 4-[hydroxy(l-methylindol-4-yl)methyl]imidazole-l- carboxylate (500 mg, 1.52 mmol, 1.0 equiv) and 2-methoxyethan-l-ol (174 mg, 2.28 mmol, 1.5 equiv), NHC-1 (1.6 g, 4.12 mmol, 2.7 equiv) in tert-butyl methyl ether (20 mL) was added pyridine (326 mg, 4.12 mmol, 2.7 equiv). The resulting mixture was stirred at room temperature for 10 min under nitrogen atmosphere. The resulting mixture was filtered. A new bottle was added the filtrate, Ir[dF(CF3)ppy]2(dtbpy))PFe (17 mg, 0.01 mmol, 0.01 equiv), Ni(acac)2 (98 mg, 0.38 mmol, 0.25 equiv), l-azabicyclo[2.2.2]octane (849 mg, 7.63 mmol, 5.0 equiv) and benzoyl benzenecarboperoxoate (554 mg, 2.29 mmol, 1.5 equiv) in DMSO (20 mL). The resulting mixture was stirred under the irradiation of blue LEDs (450 nm, 100% light, 1500 rpm) for 2 h at room temperature under nitrogen atmosphere. Desired product could be detected by LCMS. The reaction was quenched with sat. ammonium chloride (aq.) at room temperature. The resulting mixture was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with water (3 x 50 mL), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, acetonitrile in Water (10 mmol / L NH4HCO3), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in tert-butyl 4-[3-methoxy-l-(l-methylindol-4- yl)propyl]imidazole-l-carboxylate (70 mg crude) as ayellow solid. LCMS (ESI) [M+H]+: 370.

[0388] Step 2. Synthesis of Compound 139 ompoun

[0389] 4-[l-(17 / -imidazol-4-yl)-3-methoxypi opyl|-l-methylindole:

[0390] A solution of 4-{3-methoxy-l-[l-(triphenylmethyl)imidazol-4-yl]propyl}-l- methylindole (200 mg. 0.391 mmol. 1.0 equiv) in acetic acid (10 mL) was stirred at 60 °C for 1 h under nitrogen atmosphere. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The crude product (200 mg) was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column 30*150 mm, 5pm; Mobile Phase A: Water(10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient (B%): 18% B to 33% B in 10 min; Wave Length: 254nm / 220 nm; RTl(min): 11.05 min). This resulted in 4-[l-(177-imidazol-4-yl)-3-methoxypropyl]-l- methylindole (27.1 mg, 26.31% yield) as a light yellow solid. LCMS (ESI) [M+H]+: 270.20. 'H NMR (300 MHz, DMSO-tL) 5 11.74 (d, J= 29.9 Hz, 1H), 7.46 (d, J = 14.2 Hz, 1H), 7.32 - 7.17 (m, 2H). 7.13 - 6.99 (m, 1H), 6.97 - 6.72 (m, 2H), 6.51 (d, J= 3.4 Hz, 1H), 4.51 - 4.28 (m. 1H), 3.75 (s, 3H), 3.24 - 3.17 (m, 2H), 3.15 (d, J= 3.9 Hz, 3H), 2.43 - 2.08 (m, 2H).

[0391] Table C (Compounds prepared using Procedure C)

[0392]

[0393] Procedure D

[0394] Synthesis of Compound 170 Experimental Details

[0395] Step 1 . Synthesis of 5

[0396] 4-(2-cyclopropoxy-1 -(2,3-dihydrobenzofuran-7-yl)ethyl)-1-trityl-1H-imidazole:

[0397] NHC condensation: A 40-mL vial was charged with 2,3-dihydro-1-benzofuran-7-yl[1- (triphenylmethyl)imidazol-4-yl]methanol (400 mg, 0.88 mmol, 1.0 equiv), 5,7-di-tert-butyl-3- phenylbenzo[d]oxazol-3-ium tetrafluorobor (NHC) (0 9 g, 2 36 mmol, 2 7 equiv) and tert-butyl methyl ether (10 mL). Pyridine (186 mg, 2.36 mmol, 2.7 equiv) was added slowly via syringe. The heterogeneous mixture was vigorously stirred at room temperature for 45 minutes. During this time a white solid precipitated out

[0398] A second 40-mL was charged with 2-iodosyl-1 ,3,5-trimethylbenzene (456 mg, 1.77 mmol, 0.5 equiv), cyclopropoxyacetic acid (400 mg, 3.45 mmol, 1.0 equiv) and magnesium sulfate (0.6 g, 5.17 mmol, 1 5 equiv) in dichloromethane (10 ml_) was stirred at room temperature for 30 min under nitrogen atmosphere . The resulting mixture was filtered and concentrated the filtrate. Add DMSO (7 mL) and tert-butyl methyl ether (7 mL) to the filtrate as Stock Solution 1.

[0399] Upon completion of NHC condensation, the methyl tert-butyl ether suspension was transferred to a 6 mL syringe under air. Then a syringe filter and new needle were installed on the syringe, before the methyl tert-butyl ether solution was injected through the syringe filter into the a new vial and introduce Ni(TMHD)2 (0 36 mg, 0 08 mmol, 0 1 equiv) and lr[dF(Me)ppy2]2(dtbbpy)PFe (9 5 mg, 0 01 mmol, 0 01 equiv) and Stock Solution 1 via syringe. The final reaction mixture was then stirred or sonicated for ~1 minute to afford a homogeneous light green solution before it was irradiated with 450 nm LED modules at 100% light intensity with maximum fan speed and 500 rpm stir rate in a PennOC Integrated Photoreactor for 1 h

[0400] The resulting mixture was quenched by the addition of water. The aqueous solution was extracted with ethyl acetate (3 x 20 mL) The combined organic layers were washed with water (3 x 20 mL), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (petroleum ether / ethyl acetate = 2:1.5) to afford 4- (2-cyclopropoxy-1-(2,3-dihydrobenzofuran-7-yl)ethyl)-1-trityl-1 / 7-imidazole (75 mg, crude) as a yellow solid. LCMS (ESI) [M+H]+: 513. Step 2. Synthesis of Compound 170 p

[0401] 4-[2-cyclopropoxy-1 -(2,3-dihydro-1 -benzofuran-7-yl)ethyl]-1 H-imidazole:

[0402] A solution of 4-[2-cyclopropoxy-1 -(2, 3-dihydro-1-benzofuran-7-yl)ethyl]-1 -(triphenyl methyl)! midazole (70 mg, 0.14 mmol, 1.0 equiv) in acetate acid (1 ml_) was stirred at 60 °C for 1 h under nitrogen atmosphere The resulting mixture was concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column 30*150 mm, 5pm; Mobile Phase A: water(10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient (B%): 18% B to 48% B in 10 min; Wave Length: 254 nm / 220 nm; RT1 (min): 9.20 min) to afford 4-[2-cyclopropoxy-1-(2,3-dihydro-1-benzofuran-7-yl)ethyl]-1 / 7-imidazole (5.2 mg, 14 09% yield) as a yellow semi-solid. LCMS (ESI) [M+H]+: 271.10.1H NMR (400 MHz, DMSO-de) 6 11 78 (d, J = 21.0 Hz, 1H), 7.50 (s, 1 H), 7.15 - 6.85 (m, 2H), 6.79 - 6.50 (m, 2H), 4.65 - 4.42 (m, 2H), 4.42 - 4.25 (m, 1 H), 3.97 - 3.77 (m, 2H), 3 29 - 3.12 (m, 3H), 0.65 - 0.17 (m, 4H) Synthesis of Compound 173 Compound 173 iiiJr(ppy)2(dtbbpy)PF6, TBAOBz, DMSO

[0403] 450 nm Blue LEDs

[0404] Experimental Details

[0405] Step 1 . Synthesis of 3 iii,lr(ppy)2(dtbbpy)PF6, TBAOBz, DMSO

[0406] 450 nm Blue LEDs

[0407] 4-[1-(2,3-dihydro-1-benzofuran-7-yl)-2,2-difluoroethyl]-1-(triphenylmethyl)imidazole:

[0408] NHC condensation: A 40-mL vial was charged with 5,7-di-terf-butyl-3-phenylbenzo[d]oxazol-3-ium tetrafluoroborate (0.36 g, 0.92 mmol, 1.2 equiv), 2,3-dihydro-1-benzofuran-7-yl[1- (triphenylmethyl)imidazol-4-yl]methanol (350 mg, 0.76 mmol, 1.0 equiv). Tert-butyl methyl ether (6 mL) was added via syringe under air. Pyridine (91 uL, 2.06 mmol, 2.7 equiv) in tert-butyl methyl ether (0.2 mL) was added slowly via syringe. The heterogeneous mixture was vigorously stirred at room temperature for 30 minutes. The resulting mixture was filtered; the filter cake was washed with tertbutyl methyl ether (2 x 0.5 mL).

[0409] A mixture of (4Z)-2,2,6,6-tetramethyl-5-[({[(3Z)-2,2,6,6-tetramethyl-5-oxohept-3-en-3- yl]oxy}cuprio)oxy]hept-4-en-3-one (16 mg, 0.04 mmol, 0.05 equiv) and 4-tert-butyl-2,6-bis(4-tert- butylpyridin-2-yl)pyridine (15 mg, 0.04 mmol, 0.05 equiv) in tert-butyl methyl ether (1.5 mL) was sonicated until homogenous. The vial was opened to introduce DMSO (20 mL), lr(ppy)2(dtbbpy)PFs (6.9 mg, 0.015 mmol, 0.02 equiv), 2-((difluoromethyl)sulfonyl)benzo[d]thiazole (197 mg, 0.80 mmol, 1.05 equiv), tetrabutylammonium benzoate (327 mg, 0.91 mmol, 1.2 equiv) and the NHC condensation. The resulting mixture was stirred at room temperature for additional 1 h under nitrogen atmosphere (450 nm, 100% light, 1500 rpm).

[0410] The operation was repeated for two times. The three batches were combined and quenched with water The resulting mixture was extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with water (3 x 30 mL), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC petroleum ether I ethyl acetate to afford 4-[1-(2,3-dihydro-1-benzofuran-7-yl)-2,2-difluoroethyl]-1- (triphenylmethyl)imidazole (102 mg, crude) as a yellow solid. LCMS (ESI) [M+H]+: 493. Step 2. Synthesis of Compound 173

[0411] 4-[1-(2,3-dihydro-1-benzofuran-7-yl)-2,2-difluoroethyl]-1H-imidazole:

[0412] A solution of 4-[1-(2,3-dihydro-1-benzofuran-7-yl)-2,2-difluoroethyl]-1-(triphenylmethyl)imidazole (127 mg, 026 mmol, 1 0 equiv) in acetate acid (1 ml_) was stirred at 60 °C for 1 h under nitrogen atmosphere The resulting mixture was concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD 018 Column, 30*150 mm, 5pm; Mobile Phase A: Water(10 nmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 15% B to45 % B in 10 min; Wave Length: 254nm / 220nm; RT1(min): 8.98) to afford 4-[1- (2,3-dihydro-1-benzofuran-7-yl)-2,2-difluoroethyl]-1 / - / -imidazole (8.4 mg, 13.02% yield) as a light yellow solid. LCMS (ESI) [M+H]+: 251.15.1H NMR (400 MHz, DMSO-de) 5 7.60 (s, 1 H), 7.26 - 6 90 (m, 3H), 6 86 - 6 71 (m, 1 H), 6 71 - 6 27 (m, 1 H), 4 70 - 442 (m, 3H), 3 22 - 3 13 (m, 2H)

[0413] Table D (Compounds prepared using Procedure D)

[0414] Procedure E

[0415] Synthesis of Compounds 176 and 177

[0416] Experimental Details

[0417] Step 1. Synthesis of 3

[0418] 2-(2,3-dihydrobenzofuran-7-yl)-7V,7V-dimethyl-2-(l-trityl-l / 7-imidazol-4-yl)acetamide: To a stirred solution of 4-(2,3-dihydro-l-benzofuran-7-ylmethyl)-l- (triphenylmethyl)imidazole (800 mg, 1.80 mmol, 1.0 equiv) in tetrahydrofuran (15 mL) was added lithium diisopropylamide (1.8 mL, 3.62 mmol, 2.0 equiv) dropwise at -78 °C under nitrogen atmosphere. The resulting mixture was stirred at -78 °C for additional 30 min. To the above mixture was added dimethylcarbamyl chloride (195 mg, 1.80 mmol, 1.0 equiv) at -78 °C. The resulting mixture was stirred at -78 °C for additional 30 min. Desired product could be detected by LCMS. The reaction was quenched with sat. ammonium chloride (aq.) at room temperature. The resulting mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with water (2 x 20 mL), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petroleum ether / ethyl acetate (1 : 1). This resulted in 2-(2.3-dihydrobenzofuran-7-yl)- / V.A-dimethyl-2-( l -trityl- I H-imidazol-4- yl)acetamide (280 mg, crude, 40.62% yield) as a yellow solid. LCMS (ESI) [M+H]+: 514

[0419] Step 2. Synthesis of 4

[0420] 2-(2,3-dihydrobenzofuran-7-yl)-'V, / V-dimethyl-2-(l-trityl-l / / -iniidazol-4-yl)ethan-l- amine:

[0421] To a stirred solution of 2-(2,3-dihydrobenzofuran-7-yl)-A(Ar-dimethyl-2-(l-trityl-17 / - imidazol-4-yl)acetamide (280 mg, 0.54 mmol. 1.0 equiv) in tetrahydrofuran (5 mL) was added lithium aluminum hydride (0.33 mL, 0.81 mmol, 1.5 equiv) dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 30 min under nitrogen atmosphere. Desired product could be detected by LCMS. The reaction was quenched with sodium sulfate decahydrate at 0 °C. The resulting mixture was filtered, the filter cake was washed with tetrahydrofuran (3 x 10 mL). The filtrate was concentrated under reduced pressure to give the residue which was purified by prep-TLC (petroleum ether: ethyl acetate= 1 : 1 ) to give 2-(2,3-dihydrobenzofuran-7-yl)-jV,jV-dimethyl-2-(l-trityl-l / 7-imidazol-4-yl)ethan-l- amine (50 mg, crude) as a yellow solid. LCMS (ESI) [M+H]+: 500.0

[0422] Step 3. Synthesis of Compound 176 ompoun

[0423] 2-(2,3-dihydrobenzofuran-7-yl)-2-(T / / -imidazol-4-yl)-A', ’V-dimethylethan-l -amine:

[0424] A solution of 2-(2.3-dihydrobenz.ofuran-7-yl)-yVjV-dimethyl-2-( 1 -trityl- l / / -imidazol-4- yl)ethan-l -amine (50 mg, 0.12 mmol, 1.0 equiv) in acetic acid (5 mL) was stirred at 60 °C for Ih under nitrogen atmosphere. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep- HPLC with the following conditions (Column: YMC-Actus Triart C18 ExRS, 30* 150 mm, 5pm; Mobile Phase A: Water(10 mmol / L NH4HC03+0.05%NH3.H20), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 11 % B to 26 %B in 60min; Wave Length: 254nm / 220 nm; RTl(min): 13.02). This resulted in 2-(2.3-dihydrobenzofuran-7-yl)-2-( l / / -imidazol-4-yl)-A,. / V- dimethylethan-1 -amine (7.2 mg, 24.92%yield) as a white solid. LCMS (ESI) [M+H]+: 258.00. 'H NMR (400 MHz, DMSO-Js) 5 11.68 (s, 1H), 7.47 (d, J= 1.2 Hz, 1H), 7.07 - 6.95 (m, 2H), 6.76 - 6.64 (m, 2H), 4.56 - 4.43 (m, 2H), 4.33 - 4.23 (m, 1H), 3.20 - 3.11 (m, 2H), 2.74 (d, J = 7.8 Hz, 2H), 2.12 (s, 6H).

[0425] Step 4. Synthesis of 5

[0426] 2-(2,3-dihydrobenzofuran-7-yl)-2-( l-trityl-l / / -imidazol-4-yl)acetaldehyde:

[0427] To a stirred solution of 4-(2,3-dihydro-l-benzofuran-7-ylmethyl)-l- (triphenylmethyl)imidazole (600 mg, 1.38 mmol, 1.0 equiv) in tetrahydrofuran (10 mL) was added lithium diisopropylamide (1.4 mL, 2.78 mmol, 2.0 equiv) dropwise at -78 °C under nitrogen atmosphere. The resulting mixture was stirred at -78 °C for additional 30 min. To the above mixture was added methyl formate (82.8 mg, 1.38 mmol, 1.0 equiv) at -78 °C. The resulting mixture was stirred at -78 °C for additional 30 min. Desired product could be detected by LCMS. The reaction was quenched with sat. ammonium chloride (aq.) at room temperature. The resulting mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with water (2 x 20 mL), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petroleum ether / ethyl acetate (1 : 1). This resulted in 2-(2.3-dihydrobenzofuran-7-yl)-2-( l -trityl- l / 7-imidazol-4-yl)acetaldehyde (300 mg, 47.01% yield) as a yellow solid. LCMS (ESI) [M+HJT 471.

[0428] Step 5. Synthesis of 6 l-(2-(2,3-dihydi’obenzofiiran-7-yl)-2-(l-tntyl-l / / -imidazol-4-yl)ethylidene)-3,3- difluoroazetidin- 1-ium :

[0429] To a stirred solution of 2-(2,3-dihydro-l-benzofuran-7-yl)-2-[l- (triphenylmethyl)imidazol-4-yl]acetaldehyde (300 mg, 0.63 mmol, 1.0 equiv) and 3,3- difluoroazetidine hydrochloride (120 mg, 0.94 mmol, 1.5 equiv) in toluene (5 mL) was added tetrakis(propan-2-yloxy)titanium (361 mg, 1.27 mmol, 2.0 equiv) dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 100 °C for Ih under nitrogen atmosphere. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petroleum ether I ethyl acetate (1: 1). This resulted in l-(2-(2,3- dihydrobenzofuran-7-yl)-2-(l-trityl-17 / -imidazol-4-yl)ethylidene)-3,3-difluoroazetidin-l-ium (200 mg, crude) as a yellow solid. LCMS (ESI) [M+H]+: 546.

[0430] Step 6. Synthesis of Compound 177

[0431] 4-[2-(3,3-difliioioazetidin-l-yl)-l-(2,3-dihydio-l-benzofuran-7-yl)ethyl|-l / / -imidazole; formic acid:

[0432] To a solution of l-[2-(2,3-dihydro-l-benzofuran-7-yl)-2-[l-(triphenylmethyl)imidazol-4- yl]ethylidene]-3,3-difluoro-llambda5-azetidin-l-ylium (180 mg, 0.33 mmol, 1.0 equiv) in methyl alcohol (10 mL) was added Pd / C (35 mg) under nitrogen atmosphere in a 50 mL roundbottom flask. The mixture was hydrogenated at room temperature for Ih under hydrogen atmosphere using a hydrogen balloon. The mixture was filtered through a Celite pad and concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5pm; Mobile Phase A: Water(10nmol / LNH4HCO?). Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 49% B to49 % B in 10 min; Wave Length: 254nm / 220nm; RTl(min): 7.73). This resulted in 4-[2-(3,3-difluoroazeti din-1 -yl)-l-(2,3-dihydro-l-benzofuran-7-yl)ethyl]-l / 7-imidazole; formic acid (17.9 mg, 17.80% yield) as a white solid. LCMS (ESI) [M+H]+: 306.00.JH NMR (400 MHz, DMSO-O 5 8.17 (s, 1H), 7.52 (s. 1H), 7.08 - 7.00 (m. 2H), 6.79 - 6.69 (m. 2H), 4.51 (m, 2H), 4.12 - 4.05 (m, 1H). 3.41 (m, 2H) 3.20 - 3.13 (m. 4H), 3.10 - 3.05 (m, 1H), 3.03 - 2.97 (m, 1H).

[0433] Table E (Compounds prepared using Procedure E

[0434] Activity Table ADRA2A and ADRA2B Arrestin Agonist Assay Method

[0435] Columns 3, 4 and 5 in the Table above recite the data from an arrestin assay which used frozen CHO- K1 cell lines stably expressing human ADRA2A and ADRA2B receptors. Cells are frozen following normal cell freezing protocols. Briefly, cells are washed with PBS and then dissociated with 0.25% trypsin. Dissociated cells are quenched in full media and then collected by centrifugation at 290 x g for 5 minutes. Cells are resuspended in cell freeze media (10% DMSO, 90% Avantor Seradigm FB Essence Cat# 10803-034) to a concentration of 2x107cells / mL. One miliLiter of cells are dispensed into cryovial tubes and frozen in a controlled rate cryo-freezer container at -80°C. Cells are stored at -80°C (or in liquid N2 if stored > 6 months) until the day of the assay.

[0436] On the day before the assay, frozen cells are thawed in a 37°C water bath, brought up in 20 ml_ of full media, and collected via centrifugation at 290 x g for 5 minutes. Cells are washed in PBS by centrifugation and resuspended in Opti-MEM (Gibco Cat# 31985070) to a concentration of 1x10scells / mL. 10 .l / well of cells (10,000 cells / well) are dispensed into 384 well corning plates, in triplicate. Cells are incubated overnight in a 37°C, 5% CO2 cell incubator.

[0437] On the day of the assay, agonists are diluted in Opti-MEM to 3.5x of the final assay concentration. 4 gL of agonists are added to the cells and incubated for 2 hours at 37°C in a 5% CO2 cell incubator 6 uL of arrestin detection reagents are dispensed onto the cells and the plates are incubated for 2 hours at room temperature. Arrestin detection reagent consists of 1 -part Galacton-star substrate (Thermo Fisher Cat# T2739), 5-parts Emerald-Il enhancer concentrate (Thermo Fisher Cat# T2382C) and in 25-parts buffer (100 mM Dibasic Potassium phosphate, 10 mM Monobasic Potassium Phosphate at pH 7.8) with 0.35% Triton X-100 (w / v). Plates are read on an Envision luminescence plate reader.

[0438] If stereochemistry is not indicated, a name or structural depiction includes any stereoisomer or any mixture of stereoisomers.

[0439] Unless otherwise indicated, all numbers expressing quantities of ingredients, properties such as amounts, percentage, and so forth used in the specification and claims are to be understood in all instances as indicating both the exact values as shown and as being modified by the term “about.” Accordingly, unless indicated to the contrary, the numerical parameters set forth in the specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Rounding any value to fewer significant digits is specifically contemplated herein. For example, the term “about 1.1” is intended to contemplate a value of “about 1.” Similarly, a value such as “about 100” is intended to contemplate a value of “about 1 x 102, ” indicating only a single significant digit, and that values should be rounded so that there is only a single significant digit.

[0440] The terms “a,” “an,” “the” and similar referents used in the context of describing the embodiments (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context The use of any and all examples, or exemplary language (e.g. , “such as”) provided herein is intended merely to better illuminate the embodiments and does not pose a limitation on the scope of any claim. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the claims.

[0441] Groupings of alternative elements or embodiments disclosed herein are not to be construed as limitations. Each group member may be referred to and claimed individually or in any combination with other members of the group or other elements found herein. It is anticipated that one or more members of a group may be included in, or deleted from, a group for reasons of convenience and / or to expedite prosecution. When any such inclusion or deletion occurs, the specification is deemed to contain the group as modified thus fulfilling the written description of all Markush groups if used in the appended claims.

[0442] Any use of the terms “comprising,” “comprises,” “having,” “includes,” “including,” or the like is intended to also contemplate use of “consisting essentially of,” “consists essentially of,” “consisting of,” or “consists of ”

[0443] Certain embodiments are described herein, including the best mode known to the inventors for carrying out the claimed embodiments. Of course, variations on these described embodiments will become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventor expects skilled artisans to employ such variations as appropriate, and the inventors intend for the claimed embodiments to be practiced otherwise than specifically described herein. Accordingly, the claims include all modifications and equivalents of the subject matter recited in the claims as permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof is contemplated unless otherwise indicated herein or otherwise clearly contradicted by context. In closing, it is to be understood that the embodiments disclosed herein are illustrative of the principles of the claims. Other modifications that may be employed are within the scope of the claims. Thus, by way of example, but not of limitation, alternative embodiments may be utilized in accordance with the teachings herein. Accordingly, the claims are not limited to embodiments precisely as shown and described

Claims

CLAIMS1. A compound of Formula I:or a pharmaceutically acceptable salt thereof, wherein:R1is alkyl optionally substituted with one to three substituents, wherein each substituent is independently H, F, Cl, Br, alkyl, cyclopropyl, [1 .1 .1 ]bicyclopentyl, alkoxy[1 .1 .1 ]bicyclopentyl, alkoxy, cyclopropoxy, fluoroalkoxy, amino, alkylamino, or dialkylamino; or the dashed line represents an optional double bond, and R1is a methylene group optionally substituted with alkoxy;R2is H, F, Cl, Br, alkyl, fluoroalkyl, alkoxy, cyclopropoxy or fluoroalkoxy;R3is H, F, Cl, Br, alkyl, fluoroalkyl, alkoxy, cyclopropoxy or fluoroalkoxy; or R2and R3may be taken together with the carbon atoms to which they are attached to form a 5-7 membered heterocyclic ring system that is optionally substituted with substituents R4and R5;R4is H, F, Cl, Br, alkyl, fluoroalkyl, alkoxy or fluoroalkoxy; andR5is H, alkyl, fluoroalkyl (such as Ci-e fluoroalkyl, e.g., -CH2F, -CHF2.-CF3, -CH2CH2F, etc.) or deuterio-alkyl (e g., CD3).

2. A compound of Formula I:or a pharmaceutically acceptable salt thereof, wherein:R1is alk-(O)x-Y, wherein alk is C1-4 alkyl, =CH, or C1-4 =CH-alkyl; x is 0 or 1 ; and Y is H, C1-6 alkyl, C3-6 cycloalkyl, C3-6 heterocyclyl, amino, C1-6 alkylamino or -C N, wherein Y is optionally substituted with CH3, -OCH3, tert-butoxycarbonyl, or 1 , 2, or 3 fluoro atoms, or a combination thereof;R2is H, F, Cl, Br, alkyl, fluoroalkyl, alkoxy, cyclopropoxy or fluoroalkoxy;R3is H, F, Cl, Br, alkyl, fluoroalkyl, alkoxy, cyclopropoxy or fluoroalkoxy; or R2and R3may be taken together with the carbon atoms to which they are attached to form a 5-8 membered heterocyclic ring system that is optionally substituted with 0, 1 , or 2 R4substituents and 0 or 1 R5substituents;R4is H, F, Cl, Br, =O, alkyl, fluoroalkyl, alkoxy or fluoroalkoxy; andR5is H, alkyl, fluoroalkyl (such as C1-6 fluoroalkyl, e.g., -CH2F, -CHF2.-CF3, -CH2CH2F, etc.) or deuterio-alkyl (e g., CD3).

3. The compound of any preceding claim, wherein R1is alkyl optionally substituted with one to three substituents independently selected from the group H, alkyl, cyclopropyl, F, Cl, alkoxy, cyclopropoxy and fluoroalkoxy.

4. The compound of any preceding claim, wherein R2is independently H, F, Cl, alkyl, fluoroalkyl, alkoxy, cyclopropoxy or fluoroalkoxy5. The compound of any preceding claim, wherein R3is independently H, F, Cl, alkyl, fluoroalkyl, alkoxy, cyclopropoxy or fluoroalkoxy 6. The compound of any preceding claim, wherein R2and R3are taken together with the carbon atoms to which they are attached to form a 5-7 membered heterocyclic ring system that is optionally substituted with substituents R4and R5.

7. The compound of any preceding claim, further represented by a formula:

8. The compound of any preceding claim, wherein R4is independently H, F, Cl, alkyl, fluoroalkyl, alkoxy or fluoroalkoxy.

9. The compound of any preceding claim, wherein R5is independently H, F, Cl, alkyl, fluoroalkyl, alkoxy or fluoroalkoxy.

10. The compound of any preceding claim, wherein R4is H, F, Cl, methyl, or ethyl11. The compound of any preceding claim, wherein R5is H or methyl,12 A pharmaceutical composition comprising a compound of any preceding claim, and a pharmaceutically acceptable carrier.

13. The use of a compound of any preceding claim in the manufacture of a medicament to treat pain or hypertension.

14. A method of treating pain or hypertension comprising administering, to a mammal in need thereof, a therapeutically effective amount of a compound of any one of claims 1-11.

15. A kit comprising 1 ) a compound of any one of claims 1-11 , and 2) instructions to use the compound to treat pain or hypertension

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