Prodrugs of compounds that inhibit trpv1 receptor   

Abstract: wherein A, R1, R2, and R3 are defined in the specification, and which are useful as therapeutic compounds particularly for treating disorders or conditions associated with inflammation, pain, bladder overactivity, urinary incontinence, and other disorders caused by or exacerbated by TRPV1. Compounds of formula (I)

This application claims priority to the provisional application Ser. No. 60/730,991 filed on Oct. 28, 2005.

The present invention relates to prodrugs of urea containing compounds, pharmaceutically acceptable salts and pharmaceutical compositions thereof, which are useful for treating pain, bladder overactivity, urinary incontinence, and other disorders caused by or exacerbated by vanilloid receptor activity. The compounds of the present invention have better physicochemical properties permitting more active drug to be available.

BACKGROUND OF THE INVENTION

Nociceptors are primary sensory afferent (C and AS fibers) neurons that are activated by a wide variety of noxious stimuli including chemical, mechanical, thermal, and proton (pH<6) modalities. The lipophillic vanilloid, capsaicin, activates primary sensory fibers via a specific cell surface capsaicin receptor, cloned as TRPV1. The intradermal administration of capsaicin is characterized by an initial burning or hot sensation followed by a prolonged period of analgesia. The analgesic component of TRPV1 receptor activation is thought to be mediated by a capsaicin-induced desensitization of the primary sensory afferent terminal. Thus, the long lasting anti-nociceptive effects of capsaicin have prompted the clinical use of capsaicin analogs as analgesic agents. Further, capsazepine, a capsaicin receptor antagonist can reduce inflammation-induced hyperalgesia in animal models. TRPV1 receptors are also localized on sensory afferents, which innervate the bladder. Capsaicin or resiniferatoxin has been shown to ameliorate incontinence symptoms upon injection into the bladder.

The TRPV1 receptor has been called a “polymodal detector” of noxious stimuli since it can be activated in several ways. The receptor channel is activated by capsaicin and other vanilloids and thus is classified as a ligand-gated ion channel. TRPV1 receptor activation by capsaicin can be blocked by the competitive TRPV1 receptor antagonist, capsazepine. The channel can also be activated by protons and heat. Under mildly acidic conditions (pH 6-7), the affinity of capsaicin for the receptor is increased, whereas at pH<6, direct activation of the channel occurs. In addition, when membrane temperature reaches 43° C., the channel is opened. Thus heat can directly gate the channel in the absence of ligand. The capsaicin analog, capsazepine, which is a competitive antagonist of capsaicin, blocks activation of the channel in response to capsaicin, acid, or heat.

The channel is a nonspecific cation conductor. Both extracellular sodium and calcium enter through the channel pore, resulting in cell membrane depolarization. This depolarization increases neuronal excitability, leading to action potential firing and transmission of a noxious nerve impulse to the spinal cord. In addition, depolarization of the peripheral terminal can lead to release of inflammatory peptides such as, but not limited to, substance P and CGRP, leading to enhanced peripheral sensitization of tissue.

Recently, two groups have reported the generation of a “knock-out” mouse lacking the TRPV1 receptor (TRPV1 (−/−)). Electrophysiological studies of sensory neurons (dorsal root ganglia) from these animals revealed a marked absence of responses evoked by noxious stimuli including capsaicin, heat, and reduced pH. These animals did not display any overt signs of behavioral impairment and showed no differences in responses to acute non-noxious thermal and mechanical stimulation relative to wild-type mice. The TRPV1 (−/−) mice also did not show reduced sensitivity to nerve injury-induced mechanical or thermal nociception. However, the TRPV1 knock-out mice were insensitive to the noxious effects of intradermal capsaicin, exposure to intense heat (50-55° C.), and failed to develop thermal hyperalgesia following the intradermal administration of carrageenan.

The compounds of the present invention are novel TRPV1 antagonists and have utility in for treating pain, bladder overactivity, urinary incontinence, and other disorders associated with pain that are caused by or exacerbated by vanilloid receptor activity.

SUMMARY

The present invention discloses prodrugs of urea containing compounds, pharmaceutically acceptable salts and pharmaceutical compositions thereof. More particularly, the present invention is directed to compounds of formula (1),

or a pharmaceutically acceptable salt, prodrug, salt of a prodrug or a combination thereof, wherein

A is

R1 is alkyl, cycloalkyl, alkenyl; halogen or haloalkyl;

R2 is hydrogen or heterocyclealkyl wherein the heterocycle moiety of the heterocyclealkyl is unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from the group consisting of alkyl, -alkyl-ORB, and -alkyl-N(RB)2;

R3 is

wherein R4 is —C(O)—O—(CH2)mR5, —C(O)(CH2)n—R6, —(CH2)r—R7, —C(O)R8, or —CH2C(H)(OH)R9 when R2 is hydrogen; or R4 is hydrogen when R2 is heterocyclealkyl; wherein the heterocycle moiety of the heterocyclealkyl is unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from the group consisting of alkyl, -alkyl-ORB, and -alkyl-N(RB)2;

m is 1, 2, or 3;

n is 1, 2 or 3;

r is 1, 2 or 3;

t is 0, 1, 2, 3 or 4;

u is 0, 1, 2 or 3;

R5 is alkyl, —O—P(O)(ORA)(ORA), —P(O)(ORA)(ORA), —ORA, —OC(O)(RA), heterocycle, —C(O)ORA, —C(O)N(RB)2, —C(O)(RA), —NRARB, or -N(RB)C(O)ORA,

R6 is alkyl, —OC(O)(RA), —ORA, —C(O)ORA, —NRARB, —OP(O)(ORA)(ORA), or —P(O)(ORA)(ORA);

R7 is alkoxy, heterocycle, —OC(O)(RA), —OC(O)(hydroxyalkyl), —OP(O)(ORA)(ORA), or —P(O)(ORA)(ORA),

R8 is heterocycle or N(R8a)(R8b) wherein R8a and R8b are independently hydrogen or alkyl;

R9 is alkoxyalkyl, —C(O)ORA, -alkyl-N(RB)C(O)ORA, or heterocyclealkyl;

R10 is alkyl;

each occurence of R11 are independently hydrogen, alkyl or aryl, or two R11 groups that are attached to a single carbon atom together form a cycloalkyl ring;

RA is hydrogen, alkyl, alkoxyalkyl, aryl or arylalkyl;

RB is hydrogen or alkyl;

the heterocycle and the heterocycle moiety of the heterocyclealkyl, represented by R5, R7, R8, and R9, are each independently substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of alkyl, haloalkyl, alkoxy, haloalkoxy, —C(O)OH, -alkyl-C(O)OH, and —N(ZA)(ZB);

ZA and ZB are each independently hydrogen, alkyl, —C(O)alkyl, formyl, aryl, or arylalkyl; and

the aryl and the aryl moiety of the arylalkyl, represented by RA, ZA and ZB are each independently substituted with 0, 1, 2 or 3 substituents selected from the group consisting of alkyl, haloalkyl, alkoxy and haloalkoxy.

The compounds of the present invention are useful for treating pain, bladder overactivity, urinary incontinence, and other disorders caused by or exacerbated by vanilloid receptor activity.

Also described are pharmaceutical compositions comprising a therapeutically effective amount of one or more compounds of formula (I), or a therapeutically acceptable salt, solvate, or combination thereof, and a pharmaceutically acceptable carrier.

One particular embodiment of the present invention describes a method of treating a disease or preventing disorders that may be ameliorated by inhibiting vanilloid receptor subtype 1 activity in a mammal comprising administering a therapeutically effective amount of one or more compounds of formula (I) or a pharmaceutically acceptable salt thereof.

The compounds of formula (I) may be used in the manufacture of a medicament for the treatment or prevention of a disease or disorder that may be ameliorated by inhibiting vanilloid receptor subtype 1 activity.

Furthermore, the disclosed compounds of formula (I) are useful in treating a disease or a disorder, wherein the disease or disorder is associated with pain, inflammation, urinary incontinence and bladder dysfunction.

The disclosed methods of treating or preventing disease or disorder associated with pain wherein the pain is neuropathic pain, inflammatory pain, or both, which method comprises administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

There is also disclosed methods of treating or preventing a disease or disorder associated with bladder overactivity or urinary incontinence, or both, which method comprises administering a therapeutically effective amount of a compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof.

DETAILED DESCRIPTION

Compounds of the invention have the formula (I) as described above. In general, the compounds of formula (I) can include, but are not limited to, compounds in which A is

More particularly, compounds of formula (I) contain A which is

In another series of embodiments, compounds of formula (I) contain A which is

In a further series of embodiments, compounds of formula (I) contain A which is

In yet another series of embodiments, compounds of formula (I) contain A which is

Lastly in yet another series of embodiments, compounds of formula (1) contain A which is

For each substructure as defined by ring A, there exist the following embodiments which further define the scope of the compounds of the present invention. These further embodiments are contemplated to apply to each series of compounds of the present invention defined under ring A.

In one embodiment there is described compounds of formula (I) wherein R1 is alkyl, cycloalkyl, halogen or haloalkyl, R2 is hydrogen or heterocyclealkyl, R3 is selected from the groups

and R4 is selected form the group consisting of —C(O)—O—(CH2)mR5, —C(O)(CH2)n—R6, —(CH2)r—R7, —C(O)R8, or —CH2C(H)(OH)R9 when R2 is hydrogen.

Compounds of the invention include those wherein R1 is alkyl, cycloalkyl, halogen or haloalkyl, preferably alkyl, R2 is hydrogen, R3 is

and R4 is —(CH2)r—R7, in which R7 selected from the group consisting of heterocycle, —OC(O)(RA), —OC(O)(hydroxyalkyl), and —P(O)(ORA)(ORA). Preferred compounds include those in which R7 is —OC(O)(RA), and RA is hydrogen or those in which R7 is —OC(O)(hydroxyalkyl).

Other compounds of the present invention include those wherein R1 is alkyl, cycloalkyl, halogen or haloalkyl, preferably alkyl, R2 is hydrogen, R3 is

and R4 is —C(O)(CH2)n—R6, wherein R6 is selected from the group consisting of is —OC(O)(RA), —ORA, —C(O)ORA, —NRARB, —OP(O)(ORA)(ORA) or —P(O)(ORA)(ORA). Examples of compounds of the present invention are those in which RA is hydrogen, alkyl, aryl or arylalkyl.

Other compounds of the present invention include those wherein R1 is alkyl, cycloalkyl, halogen or haloalkyl, preferably alkyl, R2 is hydrogen, R3 is

and R4 is —CH2C(H)(OH)R9, wherein R9 is selected from the group consisting of alkoxyalkyl, —C(O)ORA, -alkyl-N(RB)C(O)ORA, and heterocyclealkyl. Examples of compounds of the present invention are those in which R9 is alkoxyalkyl, —C(O)ORA, and heterocyclealkyl, and RA is hydrogen, alkyl, aryl or arylalkyl.

Other compounds included in the present invention are those in which R1 is alkyl, cycloalkyl, halogen or haloalkyl, preferably alkyl, R2 is hydrogen, R3 is

and R4 is —C(O)R8 , wherein R8 is heterocycle or N(R8a)(R8b). Examples of compounds of the present invention are those in which R8 is heterocycle.

Other compounds included in the present invention are those in which R1 is alkyl, cycloalkyl, halogen or haloalkyl, preferably alkyl, R2 is heterocyclealkyl, R3 is

and R4 is hydrogen. Examples of the present invention comprise compounds in which the heterocycle moiety of the heterocyclealkyl is unsubstituted. However, compounds in which the heterocycle moiety of the heterocyclealkyl is substituted with 1, 2, 3 or 4 substituents selected from the group consisting of alkyl, -alkyl-ORB, and -alkyl-N(RB)2, are also comprised in the present invention.

Other compounds included in the present invention are those in which R1 is alkyl, cycloalkyl, halogen or haloalkyl, R2 is heterocyclealkyl, R3 is

and R4 is hydrogen.

Compounds of the present invention include those wherein R1 is alkyl, cycloalkyl, halogen or haloalkyl, preferably alkyl, R2 is hydrogen, R3 is

and R4 is —C(O)—O—(CH2)mR5, wherein R5 is selected from the group consisting of —O—P(O)(ORA)(ORA), —P(O)(ORA)(ORA), —ORA, —OC(O)(RA), heterocycle, —C(O)ORA, —C(O)N(RB)2, —C(O)(RA), and —N(RB)C(O)ORA. Examples of these compounds include those in which R5 is —O—P(O)(ORA)(ORA), and RA is independently selected from the group consisting of hydrogen, alkyl, aryl or arylalkyl. Other examples include those compounds in which R5 is —P(O)(ORA)(ORA), and RA is independently selected from the group consisting of hydrogen, alkyl, aryl or arylalkyl. Examples of compounds include those in which R5 is ORA and RA is independently selected from the group consisting of hydrogen, alkyl, aryl or arylalkyl. Other examples include those in which R5 is heterocycle. Examples include compounds in which R5 is OC(O)(RA), and RA is independently selected from the group consisting of hydrogen, alkyl, aryl or arylalkyl. Other examples include those compounds in which R5 is —C(O)ORA, and RA is independently selected from the group consisting of hydrogen, alkyl, aryl or arylalkyl. Other compounds included in the examples of the present invention are those in which R5 is —C(O)N(RB)2, and RB is selected between hydrogen and alkyl. Other compounds included in the examples of the present invention are those in which R5 is —N(RB)C(O)ORA wherein RB is selected between hydrogen and alkyl, and RA is independently selected from the group consisting of hydrogen, alkyl, aryl or arylalkyl.

Other compounds of the present invention are those in which R1 is alkyl, cycloalkyl, halogen or haloalkyl, preferably alkyl, R2 is hydrogen, R3 is

and R4 is —C(O)R8, in which R8 is heterocycle or N(R8a)(R8b) wherein R8a and R8b are independently hydrogen or alkyl. Examples of the present invention include compounds in which Rg is heterocycle.

Other compounds of the present invention are those in which R1 is alkyl, cycloalkyl, halogen or haloalkyl, preferably alkyl, R2 is hydrogen, R3 is

and R4 is —CH2C(H)(OH)R9, wherein R9 is selected from the group consisting of alkoxyalkyl, —C(O)ORA, -alkyl-N(RB)C(O)ORA, and heterocyclealkyl. Examples of the present invention include compounds in which R9 is alkoxyalkyl. Other examples include compounds in which R9 is —C(O)ORA and RA is alkyl. Other examples include compounds in which R9 is heterocyclealkyl.

Other compounds of the present invention include compounds in which R1 is alkyl, cycloalkyl, halogen or haloalkyl, preferably alkyl, R2 is hydrogen, R3 is

and R4 is —C(O)—O—(CH2)mR5. Other compounds included in the invention are those in which, R1 is alkyl, cycloalkyl, halogen or haloalkyl, preferably alkyl, R2 is hydrogen, R3 is

and R4 is —(O)(CH2)n—R6. Other compounds included in the invention are those in which, R1 is alkyl, cycloalkyl, halogen or haloalkyl, preferably alkyl, R2 is hydrogen, R3 is

and R4 is and —(CH2)n—R7. Other compounds included in the present invention have R1 is alkyl or alkenyl, preferably alkyl, R2 is heterocyclealkyl, R3 is

and R4 is hydrogen.

Furthermore, compounds of formula (II) are considered within the scope of the present invention,

wherein R1, R2, R3 and t are defined in compounds of formula (I).

Other compounds of the present invention include compounds of formula (III)

wherein R1, R2, R3 and t are defined in compounds of formula (I).

Other compounds of the present invention include compounds of formula (IV)

wherein R1, R2, R3 and t are defined in compounds of formula (I).

Other compounds of the present invention include compounds of formula (V)

wherein R1, R2, R3 and t are defined in compounds of formula (I).

The following compounds are contemplated to be within the scope of the present invention:

It is contemplated that any of the embodiments described above may be combined and the scope of the compounds of the present invention defined under formula (I) is described by any such combinations. Compounds and compositions of the invention are useful for modulating the effects of vanilloid receptor activity, and more particularly the receptor type TRPV1. In particular, the compounds and compositions of the invention can be used for treating and preventing disorders modulated by TRPV1. Typically, such disorders can be ameliorated by selectively modulating the TRPV1 receptor in a mammal, preferably by administering a compound or composition of the invention, either alone or in combination with another active agent, for example, as part of a therapeutic regimen. The compounds of the invention, including but not limited to those specified in the examples, possess an affinity for TRPV1′s. As TRPV1 ligands, the compounds of the invention can be useful for the treatment and prevention of a number of diseases or conditions mediated by the TRPV1 activity.

For example, TRPV1 have been shown to play a significant role in the release of inflammatory peptides such as, but not limited to, substance P and CGRP, leading to enhanced peripheral sensitization of tissue. As such, TRPV1 ligands are suitable for the treatment of disorders associated with pain and inflammation. Further, capsazepine, a capsaicin receptor antagonist can reduce inflammation-induced hyperalgesia in animal models.

TRPV1 receptors are also localized on sensory afferents, which innervate the bladder. Capsaicin or resiniferatoxin has been shown to ameliorate incontinence symptoms upon injection into the bladder. Therefore, TRPV1 ligands are suitable for the treatment of disorders associated with urinary incontinence and bladder dysfunction.

As used throughout this specification and the appended claims, the following terms have the following meanings:

The term “alkenyl” as used herein, means a straight or branched chain hydrocarbon containing from 2 to 10 carbons and containing at least one carbon-carbon double bond formed by the removal of two hydrogens. Representative examples of alkenyl include, but are not limited to, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl-1-heptenyl, and 3-decenyl.

The term “alkoxy” as used herein, means an alkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, and hexyloxy.

The term “alkoxyalkyl” as used herein, means an alkoxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of alkoxyalkyl include, but are not limited to, tert-butoxymethyl, 2-ethoxyethyl, 2-methoxyethyl, and methoxymethyl.

The term “alkyl” as used herein, means a straight or branched chain hydrocarbon containing from 1 to 10 carbon atoms. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, and n-decyl.

The term “aryl” as used herein, means phenyl or a bicyclic aryl. The bicyclic aryl is naphthyl, or a phenyl fused to a monocyclic cycloalkyl, or a phenyl fused to a monocyclic cycloalkenyl. The phenyl and the bicyclic aryl groups of the present invention are unsubstituted or substituted. The bicyclic aryl is attached to the parent molecular moiety through any carbon atom contained within the bicyclic aryl. Representative examples of the aryl groups include, but are not limited to, dihydroindenyl, indenyl, naphthyl, dihydronaphthalenyl, 1,3-benzodioxolyl, 2,3-dihydro-1,4-benzodioxin-6-yl, and 5,6,7,8-tetrahydronaphthalenyl.

The term “arylalkyl” as used herein, means an aryl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of arylalkyl include, but are not limited to, benzyl, 2-phenylethyl, 3-phenylpropyl, and 2-naphth-2-ylethyl.

The term “halo” or “halogen” as used herein, means —Cl, —Br, —I or —F.

The term “haloalkoxy” as used herein, means an alkoxy group as defined herein, wherein one to six hydrogen atoms are replaced by halogens. Representative examples of haloalkoxy include, but are not limited to, chloromethoxy, 2-fluoroethoxy, trifluoromethoxy, 2-chloro-3-fluoropentyloxy, and pentafluoroethoxy.

The term “haloalkyl” as used herein, means an alkyl group as defined herein, wherein one to six hydrogen atoms are replaced by halogens. Representative examples of haloalkyl include, but are not limited to, chloromethyl, 2-fluoroethyl trifluoromethyl, pentafluoroethyl, and 2-chloro-3-fluoropentyl.

The term “heterocycle” or “heterocyclic” as used herein, means a monocyclic three-, four-, five-, six-, seven- or eight-membered ring containing at least one heteroatom independently selected from the group consisting of O, N, and S. The three- or four-membered ring contains zero or one double bond, and one heteroatom selected from the group consisting of O, N and S. The five-membered ring contains zero or one double bond and one, two or three heteroatoms selected from the group consisting of O, N and S. The six-membered ring contains zero, one or two double bonds and one, two or three heteroatoms selected from the group consisting of O, N and S. The seven-membered ring contains zero, one, two, or three double bonds and one, two or three heteroatoms selected from the group consisting of O, N and S. The monocyclic heterocycle is unsubstituted or substituted and is connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the monocyclic heterocycle. Representative examples of monocyclic heterocycle include, but are not limited to, azetidinyl, azepanyl, aziridinyl, diazepanyl, 1,3-dioxanyl, 1,3-dioxolan-4-yl, 1,3-dithiolanyl, 1,3-dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl, morpholinyl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl, thiazolinyl, thiazolidinyl, thiomorpholinyl, 1,1-dioxidothiomorpholinyl (thiomorpholine sulfone), thiopyranyl, and trithianyl.

The term “heterocyclealkyl” as used herein, means a heterocycle group, as defined herein, appended to the parent moiety through an alkyl group, as defined herein. Examples of heterocyclealkyl of the present invention include, but not limited to, 2-morpholin-4-yl-ethyl and 2-piperidin-1-yl-ethyl.

The term “hydroxy” as used herein, means an —OH group.

The term “hydroxyalkyl” as used herein, means at least one hydroxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.

Representative examples of hydroxyalkyl include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2,3-dihydroxypentyl, and 2-ethyl-4-hydroxyheptyl.

The term “oxo” as used herein, means ═O.

Compounds of the present invention may exist as stereoisomers wherein, asymmetric or chiral centers are present. These stereoisomers are “R” or “S” depending on the configuration of substituents around the chiral carbon atom. The terms “R” and “S” used herein are configurations as defined in IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem., 1976, 45: 13-30. The present invention contemplates various stereoisomers and mixtures thereof and these are specifically included within the scope of this invention. Stereoisomers include enantiomers and diastereomers, and mixtures of enantiomers or diastereomers. Individual stereoisomers of compounds of the present invention may be prepared synthetically from commercially available starting materials that contain asymmetric or chiral centers or by preparation of racemic mixtures followed by resolution which is well known to those of ordinary skill in the art. These methods of resolution are exemplified by (1) attachment of a mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography and liberation of the optically pure product from the auxiliary, (2) direct separation of the mixture of optical enantiomers on chiral chromatographic columns, or fractional recrystalization of salt of the compounds of the present invention with chrial carboxylic acids followed by neutralization to obtain the pure steroisomer of the compound of the present invention.

The compounds and processes of the present invention will be better understood by reference to the following Examples, which are intended as an illustration of and not a limitation upon the scope of the invention. Further, all citations herein are incorporated by reference.

Compounds of the invention were named by ACD/ChemSketch version 5.01 (developed by Advanced Chemistry Development, Inc., Toronto, ON, Canada) or were given names consistent with ACD nomenclature. Alternatively, compounds were assigned names using ChemDraw Ultra 9.0 (or higher version) (Cambridgesoft). The practice of assigning names to chemical compounds from structures, and of assigning chemical structures from given chemical names is well known to those of ordinary skill in the art.

The compounds of this invention can be prepared by a variety of synthetic procedures. Representative procedures are shown in, but are not limited to, Schemes 1-11.

As outlined in Scheme 1, ketone containing compounds of formula (3) may be converted into compounds of formula (8) which are used in the synthesis of compounds of formula (I). Compounds of formula (3) when heated in the presence of a compound of formula (4) or similar chiral amine containing compound in toluene under Dean-Stark conditions with or without a catalytic amount of acid, followed by treatement with reducing conditions such as but not limited to sodium borohydride in ethanol will provide a compounds of formula (5). Compounds of formula (5) when treated with an atmosphere of hydrogen in the presence of a palladium catalyst such as palladium on carbon in solvents such as but not limited to methanol or ethanol with our without a catalytic amount of an acid such as acetic acid will provide compounds of formula (8) wherein R1 is as defined in formula (I).

Alternatively, compounds of formula (3) when treated with an hydroxylamine or O-substituted hydroxylamines such as, but not limited to methoxyamine, in the presence of a solvent such as, but not limited to, pyridine or mixtures of ethanol and pyridine at a temperature from about room temperature to about 50° C. will provide oximes of formula (6). Oximes of formula (6) can be reduced in the presence of an atmosphere of hydrogen gas from about 40 to about 60 psi and a catalyst such as, but not limited to palladium on carbon at a temperature from about 50° C. to about 70° C. to provide compounds of formula (7). Compounds of formula (7) made through this method exist as a mixture of enantiomers that may be resolved by fractional crystallization when converted to salt with chiral carboxylic acid. Chiral carboxylic acids useful in forming salts with compounds of formula (7) include chiral amino acids such as, but not limited to, N-acetyl-(D)-leucine and N-tert-butyloxycarbonyl phenylalanine. The fractional crystallization of compounds of formula (7) with chiral carboxylic acids will provide after neutralization the individual isomers of (R) or the (S) form of the amine of formula (8).

Ureas of general formula (14) wherein R1 and R2 are as defined in formula (I) can be prepared as described in Scheme 2. Indazoles of general formula (10), prepared using the procedures as described in Example 56C, when treated with a compound of formula (11), in solvents such as but not limited to acetonitrile will provide a compound of formula (12). Compounds of formula (12) when treated with compounds of formula (9) in the presence of a base such as but not limited to diisopropylethylamine will provide ureas of formula (13). Typical solvents include but are not limited to acetonitrile or N,N-dimethylformamide. Ureas of general formula (13) when treated with sodium hydroxide or potassium hydroxide will provide indazoles of general formula (14). Typical solvents include but are not limited to methanol, ethanol and mixtures of solvents such as N,N-dimethylformamide and methanol. Compounds of formula (13) and of formula (14) described in Scheme 2 are drawn to represent chiral compounds which are the product of using the chiral compound of formula (9). Alternatively, the use of racemic compounds of formula (7) in this synthetic pathway will produce racemic mixtures of compounds of formula (13) and racemic mixtures of compounds of formula (14).

Alternatively, compounds of formula (10) can be treated with phosgene or triphosgene and 4-dimethylaminopyridine in a solvent such as, but not limited to, dichloromethane, followed by treatment with amines of general formula (9) in a solvent such as, but not limited to, toluene or tetrahydrofuran or a combination thereof to provide ureas of general formula (13) wherein R2 is hydrogen or heterocyclealkyl.

It is also known to one skilled in the art that compounds of formula (10) can be treated with trichloroacetyl chloride and a base such as, but not limited to, triethylamine in a solvent such as dichloromethane to provide trichloroacetamides, which in turn can be treated with amines of formula (9) and a non-nucleophilic base such as, but not limited to, 1,8-diazabicyclo[5.4.0]undec-7-ene in a solvent such as, but not limited to, acetonitrile, to provide ureas of general formula (13) wherein R2 is hydrogen or heterocyclealkyl. Compounds of formula (9) wherein R2 is heterocyclealkyl can be obtained from amines of formula (8) by treatment with halides of formula R2X wherein X is Cl, Br or I, in the presence of a base such as but not limited to sodium carbonate or potassium carbonate, optioanally in the presence of catalytic amount of tetrabutylammonium iodide. The reaction is generally performed in solvents such as but not limited to N,N-dimethylformamide, methanol, ethanol, and mixtures thereof.

Compounds of formula (13) wherein R2 is heterocyclealkyl can also be prepared from compounds of formula (13) wherein R2 is hydrogen employing the reaction conditions for the transformation of compounds of formula (8) to compounds of formula (9).

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