Pyrazol-5-amine agonists of alpha-2 adrenergic receptors

Abstract

The present disclosure relates to compounds of the formula: 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] PCT Application

[0002] Attorney Docket No. 134063-0004W001

[0003] PYRAZOL-5-AMINE AGONISTS OF ALPHA-2 ADRENERGIC RECEPTORS Background

[0004] 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.

[0005] Summary

[0006] This disclosure relates to compounds of the Formula: or a pharmaceutically acceptable salt thereof, wherein:

[0007] Ring A is a heteroaryl, such as a 5-6 membered heteroaryl, such as pyrazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1 ,3a-diazindienyl, 1 ,3,4-oxadiazolyl, 1 ,2,4 thiadiazolyl, pyridyl, pyrazinyl, or pyrimidinyl, or any Ring A depicted in Compounds 1-84;

[0008] R1is H, F, Cl, Br, I, OH, or a moiety of a formula C1-15H0-35N0-5O0-6S0-2F0-16 which attaches to the phenyl ring with a carbon atom, a nitrogen atom, an oxygen atom, or a sulfur atom;

[0009] R2is H, F, Cl, Br, I, OH, or a moiety of a formula C1-15H0-35N0-5O0-6S0-2F0-16 which attaches to the phenyl ring with a carbon atom, a nitrogen atom, an oxygen atom, or a sulfur atom; when R1and R2are on adjacent carbon atoms they, together with the phenyl ring to which they are attached, may form a bicyclic heteroaryl ring system that is optionally substituted with 1 or 2 substituents, wherein the substituents of the bicyclic heteroaryl ring system are independently F, Cl, Br, I, OH, NH2, -OCH3, -OCH2CH3, -CH3,-CECH, -OCF3, -OCHF2, or -CF3;

[0010] R3is independently H, F, Cl, Br, I, OH, or a moiety of a formula C1-15H0-35N0-5O0-6S0-2F0-16;

[0011] R4is independently H, F, Cl, Br, I, OH, or a moiety of a formula C1-15H0-35N0-5O0-6S0-2F0-16 which attaches to the phenyl ring with a carbon atom, a nitrogen atom, an oxygen atom, or a sulfur atom; when R3and R4are on adjacent ring atoms they, together with A, may form a bicyclic heteroaryl ring system that is optionally substituted with 1 or 2 substituents, wherein the substituents of the bicyclic PCT Application

[0012] Attorney Docket No. 134063-0004W001 heteroaryl ring system are independently F, Cl, Br, I, OH, NH2, -OCH3, -OCH2CH3, -CH3,-CECH, - OCF3, -OCHF2, or -CF3;

[0013] R5is independently H or alkyl, wherein R5, together with A and the nitrogen to which it is attached, may form a bicyclic heteroaryl ring system, wherein the substituents of the bicyclic heteroaryl ring system are independently F, Cl, Br, I, OH, NH2, -OCH3, -OCH2CH3, -CH3,-CECH, -OCF3, -OCHF2, or - CF3; and

[0014] R6is independently H or alkyl.

[0015] This disclosure also relates to compounds of Formula l(i) or l(ii), wherein R1and R2are taken together to form a ring:

[0016] This disclosure also relates to compounds of Formula l(iii), I (iv) , l(v), I (vi) , and l(vii):

[0017] PCT Application

[0018] Attorney Docket No. 134063-0004W001

[0019] This disclosure also relates to compounds of Formula l(viii), l(ix), or l(x):

[0020] This disclosure also relates to compounds of Formula l(xi), l(xii), or I (xiii) , PCT Application

[0021] Attorney Docket No. 134063-0004W001

[0022] This disclosure also relates to compounds of Formula l(xiv), l(xv) and l(xvi):

[0023] This disclosure also relates to compounds of Formula I (xvii) , (xviii), (xix), (xx), (xxi) or (xxii):

[0024] PCT Application

[0025] Attorney Docket No. 134063-0004W001

[0026] Some embodiments include a compound of Formula I (i to xxii) wherein each of R1and R2is independently H, halo, alkyl, alkoxy, perfluoroalkyl, or perfluroalkoxy.

[0027] Some embodiments include a compound of Formula I (i to xxii) wherein each of R3and R4is independently H, halo, -CN, alkyl, cycloalkyl, perfluoroalkyl, perfluoroalkoxy, alkoxyalkyl or perfluroalkoxyalkyl.

[0028] Some embodiments include a compound of Formula I (i to xxii) wherein R5is H.

[0029] Some embodiments include a compound of Formula I (i to xxii) wherein R6is H,

[0030] Some embodiments include a pharmaceutical composition comprising a compound described herein and a pharmaceutically acceptable carrier.

[0031] Some embodiments include the use of a compound described herein in the manufacture of a medicament to treat pain or hypertension.

[0032] 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.

[0033] Some embodiments include a kit comprising 1) a compound described herein, and 2) instructions to use the compound to treat pain or hypertension. PCT Application

[0034] Attorney Docket No. 134063-0004W001

[0035] Detailed Description

[0036] This present disclosure relates to novel compounds of Formula I, Formula I (I - xxii) or pharmaceutically acceptable salts thereof.

[0037] With respect to any relevant structural representation, such as 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(ix), Formula l(x), Formula l(xi), Formula l(xii), Formula l(xiii), Formula l(xiv), Formula l(xv), Formula l(xvi), Formula l(xvii), Formula l(xviii), Formula l(xix), Formula l(xx), Formula l(xxi), or Formula l(xxii): R1is H, F, Cl, Br, I, OH, or a moiety of a formula C1-15H0-35N0-5O0-6S0-2F0-16, C1-6H0-15N0-2O0-3F0-7, or C1-3H0- 7O0-3F0-4, which attaches to the phenyl ring with a carbon atom, such as C1-6 alkyl (e.g., -CH3), C1-6 alkynyl (e.g., -CECH), -CN, or Ci-6 perfluoroalkyl (e.g., -CF3, -CH2CHF), attaches to the phenyl ring with a nitrogen atom (e.g., -NHCH3), attaches to the phenyl ring with an oxygen atom, such as C1-6 - O-alkyl (e.g., -OCH3, -OCH2CH3, etc.) or C1-6 -O-fluoroalkyl (e.g., -OCF3, -OCHF2, etc.), or attaches to the phenyl ring with a sulfur atom (e.g., -SCH3, -SCH2CH3, etc.).

[0038] With respect to any relevant structural representation, such as 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(ix), Formula l(x), Formula l(xi), Formula l(xii), Formula l(xiii), Formula l(xiv), Formula l(xv), Formula l(xvi), Formula l(xvii), Formula l(xviii), Formula l(xix), Formula l(xx), Formula l(xxi), Formula l(xxii): R2is H, F, Cl, Br, I, OH, or a moiety of a formula C1-15H0-35N0-5O0-6S0-2F0-16, C1-6H0-15N0-2O0-3F0-7, or C1-3H0-7O0- 3F0-4, which attaches to the phenyl ring with a carbon atom, such as C1-6 alkyl (e.g., -CH3), C1-6 alkynyl (e.g., -CECH), -CN, or C1-6 perfluoroalkyl (e.g., -CF3, -CH2CHF), attaches to the phenyl ring with a nitrogen atom (e.g., -NHCH3), attaches to the phenyl ring with an oxygen atom, such as C1-6 -O-alkyl (e.g., -OCH3, -OCH2CH3, etc.) or C1-6 -O-perfluoroalkyl (e.g., -OCF3, -OCHF2, etc.), or attaches to the phenyl ring with a sulfur atom (e.g., -SCH3, -SCH2CH3, etc.).

[0039] With respect to any relevant structural representation, such as 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(ix), Formula l(x), Formula l(xi), Formula l(xii), Formula l(xiii), Formula l(xiv), Formula l(xv), Formula l(xvi), Formula I (xvii), Formula I (xviii) , Formula l(xix), Formula l(xx), Formula l(xxi), Formula l(xxii): in some embodiments, when R1and R2are on adjacent carbon atoms they, together with the phenyl ring to which they are attached, may form a bicyclic heteroaryl ring system, such as a dihydrobenzofuranyl or a benzodioxolyl, that is optionally substituted with 1 or 2 substituents, wherein the substituents of the bicyclic heteroaryl ring system are independently F, Cl, Br, I, OH, NH2, -OCH3, -OCH2CH3, -CH3,-CECH, - OCF3, -OCHF2, or -CF3 PCT Application

[0040] Attorney Docket No. 134063-0004W001

[0041] With respect to any relevant structural representation, such as 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(ix), Formula l(x), Formula l(xi), Formula l(xii), Formula l(xiii), Formula l(xiv), Formula l(xv), Formula l(xvi), Formula I (xvii), Formula I (xviii) , Formula l(xix), Formula l(xx), Formula l(xxi), Formula l(xxii), R3is independently H, F, Cl, Br, I, OH, CN, or a moiety of a formula C1-15H0-35N0-5O0-6S0-2F0-16; C1-6H0-15N0- 2O0-3F0-7, or C1-3H0-7O0-3F0-4, C1-6 alkyl (e.g., -CH3), C3-6 cycloalkyl (e.g., cyclopropyl), -C(=O)NH2, or C1- 6 perfluoroalkyl (e.g., -CF3, -CH2CHF, -CH2CH2F, -cyclopropyl-CFs, etc.), C1-6 -O-alkyl (e.g., -OCH3, - OCH2CH3, etc.), C1-6 -alkyl-O-alkyl (e.g., -CH2-O-CH3, -CH2-CH2-O-CH3, -C(CH3)2-O-CH3, etc), - NH(CH2)I-5OCH3(e.g., -NHCH2CH2OCH3), -SCH3, -SCH2CH3), or a C3-6 cyclic ether (e.g., oxetanyl)

[0042] With respect to any relevant structural representation, such as Formula I, Formula l(i), Formula l(ii), Formula l(iii), Formula l(iiia), Formula l(iv), Formula l(v), Formula l(vi), Formula l(vii), Formula l(viii), Formula l(ix), Formula l(x), Formula l(xi), Formula l(xii), Formula l(xiii), Formula l(xiv), Formula l(xv), Formula l(xvi), Formula l(xvii), Formula l(xviii), Formula l(xix), Formula l(xx), Formula l(xxi), Formula l(xxii), R4is independently H, F, Cl, Br, I, OH, CN, or a moiety of a formula C1-15H0-35N0-5O0-6S0-2F0-16; C1-6H0-15N0-2O0-3F0-7, or C1-3H0-7O0-3F0-4, C1-6 alkyl (e.g., -CH3), C3-6 cycloalkyl (e.g., cyclopropyl), - C(=O)NH2, or C1-6 fluoroalkyl (e.g., -CF3, -CH2CHF, -CH2CH2F, -cyclopropyl-CFs, etc.), C1-6 -O-alkyl (e.g., -OCH3, -OCH2CH3, etc.), C1-6 -alkyl-O-alkyl (e.g., -CH2-O-CH3, -C(CH3)2-O-CH3, etc), -NH(CH2)I-5OCH3(e.g., -NHCH2CH2OCH3), -SCH3, -SCH2CH3), Ci-6-alkyl-OH (e.g., -C(CH3)2-OH) or a C3-6 cyclic ether (e.g., oxetanyl)

[0043] With respect to any relevant structural representation, such as Formula I, Formula l(i), Formula l(ii), Formula l(iii), Formula l(iiia), Formula l(iv), Formula l(v), Formula l(vi), Formula l(vii), Formula l(viii), Formula l(ix), Formula l(x), Formula l(xi), Formula l(xii), Formula l(xiii), Formula l(xiv), Formula l(xv), Formula l(xvi), Formula l(xvii), Formula l(xviii), Formula l(xix), Formula l(xx), Formula l(xxi), Formula l(xxii), when R3and R4are on adjacent ring atoms they, together with A, may form a bicyclic heteroaryl ring system that is optionally substituted with 1 or 2 substituents, wherein the substituents of the bicyclic heteroaryl ring system are independently F, Cl, Br, I, OH, NH2, -OCH3, -OCH2CH3, - CH3.-CECH, -OCF3, -OCHF2, or -CFs. In some embodiments, A, R3and R4, together with A, form a ring system such as: , that is optionally substituted with 1 or 2 substituents, wherein the substituents of the bicyclic heteroaryl ring system are independently F, Cl, Br, I, OH, NH2, -OCH3, - OCH2CH3, -CH3,-CECH, -OCF3, -OCHF2, or -CF3 PCT Application

[0044] Attorney Docket No. 134063-0004W001

[0045] With respect to any relevant structural representation, such as 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(ix), Formula l(x), Formula l(xi), Formula l(xii), Formula l(xiii), Formula l(xiv), Formula l(xv), Formula l(xvi), Formula l(xvii), Formula l(xviii), Formula l(xix), Formula l(xx), Formula l(xxi), Formula l(xxii), Ring “A” is a 5 or 6 membered heteroaryl group with one or more ring heteroatoms selected from O, S and N. In some embodiments, “A” has 5 to 6 ring atoms including one to three heteroatoms independently selected from O, S, or N. In some embodiments, “A” is pyrazolyl, isoxazolyl, oxazolyl, thiadiazolyl, thiazolyl, isoxazolyl, oxadiazolyl, ortriazolyl. In some embodiments, “A” is pyridyl, pyrimidinyl, or pyridazinyl.

[0046] In some embodiments, A is pyrazolyl.

[0047] In some embodiments, A is isoxazolyl.

[0048] In some embodiments, A is pyridyl.

[0049] In some embodiments, A is pyrazinyl.

[0050] In some embodiments, A is pyrimidinyl.

[0051] In some embodiments, A is oxazolyl.

[0052] In some embodiments, A is thiazolyl.

[0053] In some embodiments, A is isothiazolyl.

[0054] In some embodiments, A is diazindienyl.

[0055] In some embodiments, A is oxadiazolyl.

[0056] In some embodiments, A is thiadiazolyl.

[0057] 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 “(Ci-C6)alkyl,” as well as the alkyl moieties of other groups referred to herein (e.g., (Ci-Ce)alkyl), 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.

[0058] 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.

[0059] 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 “(C2-C6)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. PCT Application

[0060] Attorney Docket No. 134063-0004W001

[0061] 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.

[0062] As used herein, the term “heteroaryl” includes monocyclic or fused-ring polycyclic aromatic heterocyclic groups with one or more heteroatoms selected from O, S and N in the ring. The heteroaryl group has 5 to 12 ring atoms, or 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 heteroaryl” means aromatic 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 pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, thienyl, furyl, imidazolyl, oxazolyl (e.g., 1 ,3-oxazolyl, 1 ,2-oxazolyl), thiazolyl (e.g., 1 ,2-thiazolyl, 1 ,3-thiazolyl), pyrazolyl, tetrazolyl, triazolyl (e.g., 1 ,2,3-triazolyl, 1 ,2,4-triazolyl), diazindienyl (e.g., 1 ,3a-diazindienyl), oxadiazolyl (e.g., 1 ,2,3-oxadiazolyl), thiadiazolyl (e.g., 1 ,3,4-thiadiazolyl), quinolyl, isoquinolyl, benzothienyl, benzofuryl, indolyl, and the like. The heteroaryl group is optionally substituted by 1 , 2, 3, 4, or 5 suitable substituents.

[0063] The compounds of Formula I, Formula l(i), Formula l(ii), Formula l(iv), Formula l(v), Formula l(vi), Formula l(vii), Formula l(viii), Formula l(ix), Formula l(x), Formula l(xi), Formula l(xii), Formula l(xiii), Formula l(xiv), Formula l(xv), Formula l(xvi), Formula l(xvii), Formula l(xviii), Formula l(xix), Formula l(xx), Formula l(xxi), Formula l(xxii), 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.

[0064] 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.

[0065] Compounds 1-84, depicted in Table A, Table B, Table C, Table D, Table E and pharmaceutically acceptable salts thereof, are specifically contemplated herein.

[0066] Some embodiments include Compound 1 or a pharmaceutical acceptable salt thereof.

[0067] Some embodiments include Compound 2 or a pharmaceutical acceptable salt thereof.

[0068] Some embodiments include Compound 3 or a pharmaceutical acceptable salt thereof.

[0069] 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 PCT Application

[0070] Attorney Docket No. 134063-0004W001 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 -S03Na+) 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).

[0071] 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(ix), Formula l(x), Formula l(xi), Formula l(xii), Formula l(xiii), Formula l(xiv), Formula l(xv), Formula l(xvi), Formula l(xvii), Formula l(xviii), Formula l(xix), Formula l(xx), Formula l(xxi), Formula l(xxii), include references to salts, solvates, multi-component complexes and liquid crystals thereof and to solvates, multicomponent complexes and liquid crystals of salts thereof.

[0072] 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(ix), Formula l(x), Formula l(xi), Formula l(xii), Formula l(xiii), Formula l(xiv), Formula l(xv), Formula l(xvi), Formula l(xvii), Formula l(xviii), Formula l(xix), Formula l(xx), Formula l(xxi), Formula l(xxii), 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:

[0073] PCT Application

[0074] Attorney Docket No. 134063-0004W001

[0075] 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(ix), Formula l(x), Formula l(xi), Formula l(xii), Formula l(xiii), Formula l(xiv), Formula l(xv), Formula l(xvi), Formula l(xvii), Formula l(xviii), Formula l(xix), Formula l(xx), Formula l(xxi), Formula l(xxii), 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.

[0076] 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 PCT Application

[0077] Attorney Docket No. 134063-0004W001 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.

[0078] 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.

[0079] 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.

[0080] The pharmaceutical composition may be in unit dosage forms suitable for single administration of precise dosages.

[0081] 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(ix), Formula l(x), Formula l(xi), Formula l(xii), Formula l(xiii), Formula l(xiv), Formula l(xv), Formula l(xvi), Formula l(xvii), Formula l(xviii), Formula l(xix), Formula l(xx), Formula l(xxi), Formula l(xxii), and a pharmaceutically acceptable carrier.

[0082] 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.

[0083] 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.

[0084] 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.

[0085] 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(ix), Formula l(x), Formula l(xi), Formula l(xii), Formula l(xiii), Formula l(xiv), Formula l(xv), Formula l(xvi), Formula l(xvii), Formula I (xviii) , Formula l(xix), Formula l(xx), Formula l(xxi), Formula I (xxii), 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.

[0086] Dosage regimens may be adjusted to provide the 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 PCT Application

[0087] Attorney Docket No. 134063-0004W001 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.

[0088] Thus, the skilled artisan would appreciate, based upon the disclosure provided herein, that the dose and dosing regimen may be adjusted in accordance with methods described in this disclosure or apparent from this disclosure. 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.

[0089] 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 readily apparent from this disclosure and would be understood to be encompassed by the skilled artisan once provided the teachings disclosed herein.

[0090] The amount of the compound of Formula I, Formula l(i), Formula l(ii), Formula l(iii), Formula I (iv), Formula l(v), Formula l(vi), Formula l(vii), Formula l(viii), Formula l(ix), Formula l(x), Formula l(xi), Formula l(xii), Formula l(xiii), Formula l(xiv), Formula l(xv), Formula l(xvi), Formula l(xvii), Formula I (xviii) , Formula I (xix) , Formula l(xx), Formula l(xxi), Formula I (xxii), 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 unacceptable side effect, provided that such larger doses are first divided into several small doses for administration throughout the day.

[0091] 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(ix), Formula l(x), Formula l(xi), Formula l(xii), PCT Application

[0092] Attorney Docket No. 134063-0004W001

[0093] Formula l(xiii), Formula l(xiv), Formula l(xv), Formula l(xvi), Formula l(xvii), Formula l(xviii), Formula l(xix), Formula l(xx), Formula l(xxi), Formula I (xxii), 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.

[0094] 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(ix), Formula l(x), Formula l(xi), Formula l(xii), Formula l(xiii), Formula l(xiv), Formula l(xv), Formula l(xvi), Formula I (xvii), Formula I (xviii) , Formula l(xix), Formula l(xx), Formula l(xxi), Formula l(xxii), 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 informed by the present disclosure. The use of such protection / deprotection methods is also within the skill in the art informed by the present disclosure. 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 .

[0095] 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(ix), Formula l(x), Formula l(xi), Formula l(xii), Formula l(xiii), Formula l(xiv), Formula l(xv), Formula l(xvi), Formula l(xvii), Formula l(xviii), Formula l(xix), Formula l(xx), Formula l(xxi), Formula l(xxii).

[0096] Methods and Procedures

[0097] Procedure A PCT Application

[0098] Attorney Docket No. 134063-0004W001

[0099] Synthesis of Compounds 1 and 2

[0100] PCT Application

[0101] Attorney Docket No. 134063-0004W001

[0102] Experimental Details

[0103] Step 1. Synthesis of 3

[0104] (2,3-dimethylphenyl)(1-trityl-1 H-imidazol-4-yl)methanol:

[0105] Under the protection of nitrogen, magnesium (1.4 g, 87.22 mmol, 1.2 equiv) and iodine (130 mg, 19.70 mmol, 0.01 equiv) was added to tetra hydrofuran (5 mL). Dissolve 3-bromo-1 ,2- dimethylbenzene(10.0 g, 54.03 mmol, 1.0 equiv) in tetrahydrofuran (50 mL), then take 10 mL of 3- bromo-1 ,2-dimethylbenzene 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 3-bromo-1 ,2- dimethylbenzene 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 was used for the next step directly without purification.

[0106] To the above mixture was added 1-(triphenylmethyl)imidazole-4-carbaldehyde (10.1 g, 27.74 mmol, 0.6 equiv) in THF (50 mL) dropwise over 15 min at 0 °C. The resulting mixture was stirred for at 0 °C for additional 1 h. The reaction was quenched by the addition of water (100 mL). The resulting mixture was extracted with ethyl acetate (3 x 100 mL). The combined organic layers were dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by trituration with ethyl acetate (100 mL). This resulted in (2,3-dimethylphenyl)(1- trityl-1 / 7-imidazol-4-yl)methanol (12.0 g, 49.4% yield) as a white solid. LCMS (ESI) [M+H]+: 445.

[0107] PCT Application

[0108] Attorney Docket No. 134063-0004W001

[0109] Step 2. Synthesis of 4

[0110] (2,3-dimethylphenyl)(1 -trityl-1 H-imidazol-4-yl)methanone:

[0111] To a mixture of (2,3-dimethylphenyl)[1-(triphenylmethyl)imidazol-4-yl]methanol (10.0 g, 22.49 mmol, 1.0 equiv) in trichloromethane (250 mL) was added dioxide (15.6 g, 179.94 mmol, 8.0 equiv). The resulting mixture was stirred at 70 °C for additional 1 h. The resulting mixture was filtered, the filter cake was washed with dichloromethane (3 x 50 mL). The filtrate was concentrated under reduced pressure. The residue was purified by trituration with ethyl acetate (100 mL). This resulted in (2,3- dimethylphenyl)(1 -trityl-1 / 7-imidazol-4-yl)methanone (9.5 g, 95.9% yield) as a white solid. LCMS (ESI) [M+H]+: 443.

[0112] PCT Application

[0113] Attorney Docket No. 134063-0004W001

[0114] Step 3. Synthesis of 6

[0115] N-((2,3-dimethylphenyl)(1H-imidazol-4-yl)methyl)-1 -methyl-1H-pyrazol-5-amine:

[0116] To a stirred solution of 4-(2,3-dimethylbenzoyl)-1-(triphenylmethyl)imidazole (1 .0 g, 2.26 mmol, 1 .0 equiv) in dichloromethane (10 mL) was added titanium tetrachloride (430 mg, 2.26 mmol, 1.0 equiv) dropwise and 2-methylpyrazol-3-amine (440 mg, 4.52 mmol, 2.0 equiv) in dichloromethane (10 mL) dropwise at 0 °C. The resulting mixture was stirred at room temperature for additional 1 h. To the above mixture was added methyl alcohol (5 mL) followed by sodium cyanoborohydride (350 mg, 5.65 mmol, 2.5 equiv) at room temperature. The resulting mixture was stirred at room temperature for additional 4 h. The reaction was quenched with water (10 mL) at 0 °C. The aqueous layer was extracted with dichloromethane (3 x 10 mL). The combined organic solution was concentrated under reduced pressure to give the residue which was purified by Prep-HPLC with the following conditions (Column: YMC-Actus Triart C18 ExRS 30*150 mm, 5m; Mobile Phase A: Water(1 Ommol / L NH4HCO3), Mobile Phase E3: ACN; Flow rate: 60 mL / min; Gradient: 15% E3 to 42% B in 7 min; Wave Length: 254nm / 220nm; RT1 (min): 6.72). This resulted in A / -((2,3-dimethylphenyl)(1 / 7-imidazol-4-yl)methyl)-1-methyl-1 / 7-pyrazol-5-amine (114.0 mg, 17.88% yield) as a white solid. LCMS (ESI) [M+H]+: 282.15.1H NMR (400 MHz, DMSO-c / e) 6 11.95 (d, J = 73.0 Hz, 1 H), 7.56 (d, J = 1.3 Hz, 1 H), 7.29 (s, 1 H), 7.15 - 6.91 (m, 3H), 6.58 (d, J = 115.4 Hz, 1 H), 6.13 - 5.75 (m, 1 H), 5.62 - 5.48 (m, 1 H), 5.04 (d, J = 1.9 Hz, 1 H), 3.59 (s, 3H), 2.23 (d, J = 10.4 Hz, 6H).

[0117] PCT Application

[0118] Attorney Docket No. 134063-0004W001

[0119] 4. Separation of 1 and 2

[0120] W-[( / ?)-(2,3-dimethylphenyl)(1H-imidazol-4-yl)methyl]-2-methylpyrazol-3-amine & / V-[(S)-(2,3- dimethylphenyl)(1 H-imidazol-4-yl)methyl]-2-methylpyrazol-3-amine:

[0121] A / -[1 A7-imidazol-4-yl(2-methylphenyl)methyl]-2-methylpyrazol-3-amine (106 mg) was separated by Prep-Chiral-HPLC with the following conditions Column: CHIRAL ART Cellulose-SZ, 3*25 cm, 5 pm; Mobile Phase A: Hex(10mM NHs-MeOH), Mobile Phase B: EtOH; Flow rate: 40 mL / min; Gradient (B%): isocratic 10%; Wave Length: 220 / 254 nm; RT1 (min): 11 .0; RT2(min): 17.0; Sample Solvent: EtOH: DCM=1 : 1 ; Injection Volume: 1.0 mL; Number Of Runs: 3. This resulted in A / -[(R)-(2,3- dimethylphenyl)(1 / 7-imidazol-4-yl)methyl]-2-methylpyrazol-3-amine (44.0 mg, 41.47% yield) as a white solid. LCMS (ESI) [M+H]+: 282.05.1H NMR (400 MHz, DMSO-c / 6) 6 11.89 (s, 1 H), 7.56 (d, J = 1.2 Hz, 1 H), 7.33 - 7.25 (m, 1 H), 7.07 - 6.97 (m, 2H), 6.95 (d, J = 1 .9 Hz, 1 H), 6.68 (s, 1 H), 5.80 (s, 1 H), 5.52 (d, J = 6.2 Hz, 1 H), 5.05 (d, J = 1 .9 Hz, 1 H), 3.59 (s, 3H), 2.24 (s, 3H), 2.21 (s, 3H).

[0122] A / -[(S)-(2,3-dimethylphenyl)(1 / 7-imidazol-4-yl)methyl]-2-methylpyrazol-3-amine (42.4 mg, 41 .00% yield) as a white solid. LCMS (ESI) [M+H]+: 282.15.1H NMR (400 MHz, DMSO-cfe) 6 1 1 .95 (d, J = 69.9 Hz, 1 H), 7.56 (d, J = 1 .2 Hz, 1 H), 7.34 - 7.23 (m, 1 H), 7.01 (s, 2H), 6.95 (d, J = 1 .8 Hz, 1 H), 6.72 (s, 1 H), 5.93 (d, J = 142.8 Hz, 1 H), 5.50 (s, 1 H), 5.05 (d, J = 1.9 Hz, 1 H), 3.59 (s, 3H), 2.24 (s, 3H), 2.21 (s, 3H).

[0123] PCT Application

[0124] Attorney Docket No. 134063-0004W001

[0125] Table A (Compounds prepared using Procedure A) PCT Application

[0126] Attorney Docket No. 134063-0004W001 PCT Application

[0127] Attorney Docket No. 134063-0004W001 PCT Application

[0128] Attorney Docket No. 134063-0004W001 PCT Application

[0129] Attorney Docket No. 134063-0004W001 PCT Application

[0130] Attorney Docket No. 134063-0004W001

[0131] Procedure B

[0132] Synthesis of Compound 42

[0133] PCT Application

[0134] Attorney Docket No. 134063-0004W001

[0135] PCT Application

[0136] Attorney Docket No. 134063-0004W001

[0137] Experimental Details

[0138] Step 1. Synthesis of 3

[0139] Trt

[0140] (1Z)- / V-(4-fluoro-2,5-dimethylpyrazol-3-yl)-1 -[1 -(triphenylmethyl)imidazol-4-yl]methanimine:

[0141] A solution of 1-(triphenylmethyl)imidazole-4-carbaldehyde (120 mg, 0.355 mmol, 1 equiv), tetrakis(propan-2-yloxy)titanium (120.94 mg, 0.426 mmol, 1 .2 equiv) and 4-fluoro-2,5-dimethylpyrazol- 3-amine (54.95 mg, 0.426 mmol, 1 .2 equiv) in toluene (3 mL) was stirred at 100 °C for 1 h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure to give the residue which was purified by silica gel column chromatography, eluted with petroleum ether I ethyl acetate (1 :1) to afford (1 Z)- / V-(4-fluoro-2,5-dimethylpyrazol-3-yl)-1 -[1 -(triphenylmethyl)imidazol-4-yl]methanimine (130 mg, 81 .55% yield) as a light yellow solid. LCMS (ESI) [M+H]+: 450. 1 PCT Application

[0142] Attorney Docket No. 134063-0004W001

[0143] Step 2. Synthesis of 5

[0144] / V-[(2,3-dimethylphenyl)[1 -(triphenylmethyl)imidazol-4-yl]methyl]-4-fluoro-2,5-dimethylpyrazol- 3-amine:

[0145] Under the protection of nitrogen, magnesium (24 mg, 1.00 mmol, 1.5 equiv) and iodine (1.8 mg, 0.006 mmol, 0.01 equiv) was added to tetrahydrofuran (0.2 mL). Dissolve 3-bromo-1 ,2- dimethylbenzene (59.28 mg, 0.320 mmol, 1.2 equiv) in tetra hydrofuran (1 mL), then take 0.2 mL of 3- bromo-1 ,2-dimethylbenzene 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 3-bromo-1 ,2- dimethylbenzene 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 was used for the next step directly without purification.

[0146] To a stirred solution of (1Z)- / V-(4-fluoro-2,5-dimethylpyrazol-3-yl)-1-[1 -(triphenylmethyl)imidazol-4- yl]methanimine (120 mg, 0.267 mmol, 1 equiv) in THF (1 mL) was added the 1-bromo-2,3- dimethylbenzene solution prepared above dropwise at 0 °C. The solution was stirred at this temperature for 1 h. The reaction was quenched with sat. ammonia chloride (aq.) at room temperature. The resulting mixture was extracted with ethyl acetate (2 x 10 mL). The combined organic layers were 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 dichloromethane I methanol (5:1) to afford A / -[(2,3-dimethylphenyl)[1-(triphenylmethyl)imidazol-4-yl]methyl]-4-fluoro-2,5-dimethylpyrazol- 3-amine (100 mg, 67.41 % yield) as a yellow solid. LCMS (ESI) [M+H]+: 556.

[0147] PCT Application

[0148] Attorney Docket No. 134063-0004W001

[0149] Step 3. Synthesis of Compound 42

[0150] N-[(2,3-dimethylphenyl)(1H-imidazol-4-yl)methyl]-4-fluoro-2,5-dimethylpyrazol-3 -amine:

[0151] A solution of A / -[(2,3-dimethylphenyl)[1-(triphenylmethyl)imidazol-4-yl]methyl]-4-fluoro-2,5- dimethylpyrazol-3-amine (100 mg, 0.180 mmol, 1 equiv) and trifluoroacetic acid (2 mL) in dichloromethane (6 mL) was stirred at room temperature for 1 h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The crude product was purified by reverse phase flash with the following conditions (Column: XSelect CSH Fluoro Phenyl 30*150 mm, 5m; Mobile Phase A: water(0.1 % FA), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 2%B to 2% B in 2 min, 2% B to 13% B in 10 min; Wave Length: 254nm / 220nm nm; RT1 (min): 8.95) to afford N- [(2,3-dimethylphenyl)(1 / 7-imidazol-4-yl)methyl]-4-fluoro-2,5-dimethylpyrazol-3-amine (crude) as a white solid. The crude product was purified by Prep-TLC (dichloromethane I methanol = 10:1) to afford N- [(2,3-dimethylphenyl)(1 / 7-imidazol-4-yl)methyl]-4-fluoro-2,5-dimethylpyrazol-3-amine (13.0 mg, 98.3% purity) as a white solid. LCMS (ESI) [M+H]+: 314.10.1H NMR (400 MHz, DMSO-c / e) 6 11.90 (s, 1 H), 7.56 (d, J = 1 .3 Hz, 1 H), 7.43 - 7.30 (m, 1 H), 7.03 (d, J = 6.7 Hz, 2H), 6.59 (d, J = 54.9 Hz, 1 H), 5.82 (d, J = 7.0 Hz, 1 H), 5.53 (s, 1 H), 3.50 (s, 3H), 2.22 (s, 3H), 2.16 (s, 3H), 1.92 (s, 3H).

[0152] PCT Application

[0153] Attorney Docket No. 134063-0004W001

[0154] Table B (Compounds prepared using Procedure B) PCT Application

[0155] Attorney Docket No. 134063-0004W001

[0156] Synthesis of Compound 52

[0157] Compound 52

[0158] Experimental Details

[0159] Step 1. Synthesis of 3 PCT Application

[0160] Attorney Docket No. 134063-0004W001

[0161] (2,3-dimethylphenyl)(1-trityl-1 H-imidazol-4-yl)methanol:

[0162] Under the protection of nitrogen, magnesium (1.4 g, 87.22 mmol, 1.2 equiv) and iodine (130 mg, 19.70 mmol, 0.01 equiv) was added to tetra hydrofuran (5 mL). Dissolve 3-bromo-1 ,2- dimethylbenzene(10.0 g, 54.03 mmol, 1.0 equiv) in tetrahydrofuran (50 mL), then take 10 mL of 3- bromo-1 ,2-dimethylbenzene 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 3-bromo-1 ,2- dimethylbenzene 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 was used for the next step directly without purification.

[0163] To the above mixture was added 1-(triphenylmethyl)imidazole-4-carbaldehyde (10.1 g, 27.74 mmol, 0.6 equiv) in THF (50 mL) dropwise over 15 min at 0 °C. The resulting mixture was stirred for at 0 °C for additional 1 h. The reaction was quenched by the addition of water (100 mL). The resulting mixture was extracted with ethyl acetate (3 x 100 mL). The combined organic layers were dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by trituration with ethyl acetate (100 mL). This resulted in (2,3-dimethylphenyl)(1- trityl-1 / 7-imidazol-4-yl)methanol (12.0 g, 49.4% yield) as a white solid. LCMS (ESI) [M+H]+: 445.

[0164] Step 2. Synthesis of Compound 52

[0165] Compound 52

[0166] W-[(2,3-dimethylphenyl)(1H-imidazol-4-yl)methyl]-4,5-dimethyl-1 ,2-oxazol-3-amine:

[0167] A solution of (2,3-dimethylphenyl)[1-(triphenylmethyl)imidazol-4-yl]methanol (500 mg, 1.12 mmol, 1.0 equiv) and dimethyl-1 ,2-oxazol-3-amine (126 mg, 1.12 mmol, 1.0 equiv) in toluene (5 mL) was added 4-methylbenzene-1 -sulfonic acid hydrate (107 mg, 0.56 mmol, 0.5 equiv). The solution was stirred for 1 h at 100 °C under nitrogen atmosphere. The resulting mixture was quenched by the addition of water (10 mL). The aqueous solution was extracted with ethyl acetate (3 x 20 mL). The organic layers were combined and 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 (10mmol / L NH4HCO3), 10% to 50% gradient in 30 min; detector, UV 220 nm to afford A / -[(2,3- dimethylphenyl)(1 / 7-imidazol-4-yl)methyl]-4,5-dimethyl-1 ,2-oxazol-3-amine (66.1 mg, 19.75% yield) as a white solid. LCMS (ESI) [M+H]+: 297.10.1H NMR (400 MHz, DMSO-cfe) 6 12.02 - 11.83 (m, 1 H), 7.55 PCT Application

[0168] Attorney Docket No.134063-0004W001

[0169] (s, 1H), 7.29-7.17 (m, 1H), 7.07-6.93 (m, 2H), 6.68-5.83 (m, 3H), 2.25-2.23 (m, 3H), 2.18-2.14 (m, 3H), 2.10-2.07 (m, 3H), 1.80 (s, 3H).

[0170] Table C (Compounds prepared using Procedure C) PCT Application

[0171] Attorney Docket No. 134063-0004W001

[0172] Procedure D

[0173] Synthesis of Compound 62 PCT Application

[0174] Attorney Docket No. 134063-0004W001

[0175] Experimental Details

[0176] Step 1. Synthesis of 2

[0177] Bromo(2,3-dimethylphenyl)magnesium:

[0178] Under the protection of nitrogen, magnesium (980 mg, 40.52 mmol, 1.5 equiv) and iodine (60 mg, 0.26 mmol, 0.01 equiv) was added to tetra hydrofuran (20 mL). Dissolve 3-bromo-1 ,2- dimethylbenzene(5.0 g, 27.01 mmol, 1.0 equiv) in tetrahydrofuran (30 mL), then take 6 mL of 3-bromo- 1 ,2-dimethylbenzene 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 3-bromo-1 ,2-dimethylbenzene 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 was used for the next step directly without purification.

[0179] PCT Application

[0180] Attorney Docket No. 134063-0004W001

[0181] Step 2. Synthesis of 4

[0182] 1-(2,3-Dimethylphenyl)-1 -[1 -(triphenylmethyl)imidazol-4-yl]methanamine:

[0183] To a solution of 1-(triphenylmethyl)imidazole-4-carbonitrile (9.6 g, 28.65 mmol, 1 .2 equiv) in tetrahydrofuran (50 mL) was added bromo(2,3-dimethylphenyl)magnesium (24 mL, 23.88 mmol, 1 .0 equiv) dropwise. The mixture was stirred at 0 °C for 1 h under nitrogen atmosphere. Desired product could be detected by LCMS. The resulting mixture was quenched by the addition of methyl alcohol (50 mL). To the mixture was added sodium cyanoborohydride (9.03 g, 238.81 mmol, 10.0 equiv) in portions over 5min at 0 °C. The resulting mixture was stirred at room temperature for additional 1 h. The reaction was quenched with sat. ammonia chloride (aq.) at 0 °C. The resulting mixture was extracted with ethyl acetate (3 x 50 mL). The combined organic solution was dried over anhydrous sodium sulfate and 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 1 -(2,3-dimethylphenyl)-1-[1 - (triphenylmethyl)imidazol-4-yl]methanamine (3.2 g, 30.21 % yield) as a white solid. LCMS (ESI) [M+H]+: 444.

[0184] PCT Application

[0185] Attorney Docket No. 134063-0004W001

[0186] Step 3. Synthesis of 6

[0187] / V-[(2,3-dimethylphenyl)[1 -(triphenylmethyl)imidazol-4-yl]methyl]-6-methylpyridin-2 -amine:

[0188] A mixture of 1-(2,3-dimethylphenyl)-1-[1-(triphenylmethyl)imidazol-4-yl]methanamine (300 mg, 0.67 mmol, 1.0 equiv), 2-bromo-6-methylpyridine (232 mg, 1.35 mmol, 2.0 equiv), Pd2(dba)3(61 mg, 0.06 mmol, 0.1 equiv), DavePhos (26.62 mg, 0.068 mmol, 0.1 equiv) and sodium 2-methylpropan-2- olate (194 mg, 2.03 mmol, 3.0 equiv) in dioxane (5 mL) was stirred at 90 °C for 1 h under nitrogen atmosphere. The reaction was quenched with sat. water (10 mL) at room temperature. The resulting mixture was extracted with dichloromethane (3 x 10 mL). The combined organic layers were washed with water (2 x 10 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 (10mmol / L NH4HCO3), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in A / -[(2,3-dimethylphenyl)[1- (triphenylmethyl)imidazol-4-yl]methyl]-6-methylpyridin-2-amine (150 mg, 41.48% yield) as a yellow solid. LCMS (ESI) [M+H]+: 535.

[0189] PCT Application

[0190] Attorney Docket No. 134063-0004W001

[0191] 4. Synthesis of Compound 62

[0192] Compound 62

[0193] / V-[(2,3-dimethylphenyl)(1H-imidazol-4-yl)methyl]-6-methylpyridin-2 -amine:

[0194] A solution of A / -[(2,3-dimethylphenyl)[1-(triphenylmethyl)imidazol-4-yl]methyl]-6-methylpyridin-2- amine (218 mg, 0.408 mmol, 1 equiv) in trifluoroacetic acid (2 mL) and dichloromethane(4 mL) was stirred at room temperature 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 (1 Ommol / L NH4HCO3), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in A / -[(2,3-dimethylphenyl)(1 / 7- imidazol-4-yl)methyl]-6-methylpyridin-2-amine (88.0 mg, 72.64% yield) as a white solid. LCMS (ESI) [M+H]+: 293.101H NMR (400 MHz, DMSO-c / 6) 6 14.24 (s, 1 H), 9.10 - 8.90 (m, 1 H), 7.76 (s, 1 H), 7.55 - 7.38 (m, 1 H), 7.26 - 7.00 (m, 4H), 6.67 - 6.42 (m, 3H), 2.26 (d, J = 17.4 Hz, 9H).

[0195] Table D (Compounds prepared using Procedure D) PCT Application

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[0198] Attorney Docket No. 134063-0004W001 PCT Application

[0199] Attorney Docket No. 134063-0004W001

[0200] ADRA2A and ADRA2B Arrestin Agonist Assay Method

[0201] The arrestin assay uses 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. 1 mL 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.

[0202] 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 1x106cells / mL. 10 pil / 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.

[0203] On the day of the assay, agonists are diluted in Opti-MEM to 3.5x of the final assay concentration. 4 iiL of agonists are added to the cells and incubated for 2 hours at 37°C in a 5% CO2 cell incubator. 6DpL 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.

[0204] PCT Application

[0205] Attorney Docket No. 134063-0004W001

[0206] Activity Table

Claims

PCT ApplicationAttorney Docket No. 134063-0004W001CLAIMS1. A compound of Formula I:or a pharmaceutically acceptable salt thereof, wherein:Ring A is a 5-6 membered heteroaryl selected from: pyrazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1 ,3a- diazindienyl, 1 ,3,4-oxadiazolyl, 1 ,2,4 thiadiazolyl, pyridyl, pyrazinyl, and pyrimidinyl;R1is H, F, Cl, Br, I, OH, or a moiety of a formula C1-15H0-35N0-5O0-6S0-2F0-16 which attaches to the phenyl ring with a carbon atom, a nitrogen atom, an oxygen atom, or a sulfur atom;R2is H, F, Cl, Br, I, OH, or a moiety of a formula C1-15H0-35N0-5O0-6S0-2F0-16 which attaches to the phenyl ring with a carbon atom, a nitrogen atom, an oxygen atom, or a sulfur atom; when R1and R2are on adjacent carbon atoms they, together with the phenyl ring to which they are attached, may form a bicyclic heteroaryl ring system that is optionally substituted with 1 or 2 substituents, wherein the substituents of the dihydrobenzofuranyl or the benzodioxolyl are independently F, Cl, Br, I, OH, NH2, -OCH3, -OCH2CH3, -CH3,-CECH, -OCF3, -OCHF2, or -CF3;R3is H, F, Cl, Br, I, OH, or a moiety of a formula C1-15H0-35N0-5O0-6S0-2F0-16;R4is H, F, Cl, Br, I, OH, or a moiety of a formula C1-15H0-35N0-5O0-6S0-2F0-16;R5is H, or alkyl; andR6is H, or alkyl.

2. A compound according to claim 1 wherein R1and R2are taken together to form a ring:PCT ApplicationAttorney Docket No. 134063-0004W0013. A compound according to claim 1 wherein ring A is a 5 membered heterocycle of FormulaI(iii), l(iv), l(v), l(vi), and l(vii):

4. A compound of Formula l(viii), l(ix), and l(x) wherein ring A is a 5 membered heterocycle with Nitrogen and Sulfur heteroatoms:PCT ApplicationAttorney Docket No. 134063-0004W0015. A compound of Formula l(xi), l(xii): or I (xiii) wherein ring A is a 5 membered heterocycle with nitrogen and oxygen heteroatoms:

6. A compound of Formula l(xiv), l(xv) or l(xvi), wherein ring A is a 5 membered heterocycle with Nitrogen and Sulfur heteroatoms:I(xiv), I(xv), or I(xvi).PCT ApplicationAttorney Docket No. 134063-0004W0017. A compound of Formula l(xvii), (xviii), (xix), (xx), (xxi) and (xxii) wherein ring A is a six membered heterocyclic ring with 1 or 2 nitrogen heteroatoms:

8. A compound of any of the proceeding claims wherein each of R1and R2is independently H, halo, alkyl, alkoxy, perfluoroalkyl, or perfluroalkoxy.

9. A compound of any of the proceeding claims wherein each of R3and R4is independently H, halo, -CN, alkyl, cycloalkyl, perfluoroalkyl, perfluoroalkoxy, alkoxyalkyl or perfluroalkoxyalkyl.

10. A compound of any of the proceeding claims wherein R5is H,11. A compound of any of the proceeding claims wherein R6is H,12. A pharmaceutical composition comprising a compound of any preceding claim, and a pharmaceutically acceptable carrier.

13. The use of a compound of any one of the preceding claims 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.PCT Application Attorney Docket No. 134063-0004W00115. 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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