Methods for treating alcohol addiction, alcohol-use disorders and alcohol-related inflammatory diseases

Abstract

Therapeutic methods and models for use of compounds represented by Structural Formula l-VIII and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, enantiomers, diastereomers, geometric isomers, racemates, tautomers, rotamers, atropisomers, isotopic variations including at least one deuterium atom, and N-oxide thereof for treating alcohol abuse, alcohol addiction or alcohol dependency, alcohol-use disorders and their consequences especially cardiometabolic abnormalities, and fibrotic and inflammatory conditions related to the liver and pancreas in an animal or individual. The therapeutic methods and models relate to use of compounds with favorable in vivo pharmacodynamic profiles towards reducing voluntary alcohol (ethanol) intake and seeking behavior in both male and female subjects.

Description

[0001] METHODS FOR TREATING ALCOHOL ADDICTION, ALCOHOL-USE DISORDERS AND ALCOHOL-RELATED INFLAMMATORY DISEASES

[0002] STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH

[0003] This invention was made with government support under U01AA028963 (Project title: CB1 Neutral Antagonists for Alcohol Use Disorder) awarded by the National Institute on Alcohol Abuse and Alcoholism, National Institute of Health. The government has certain rights in the invention.

[0004] BACKGROUND OF THE INVENTION

[0005] Alcohol use disorder (AUD) is a complex and devastating disorder that causes several medical, psychological, social, economic, and personal problems. According to the 2023 National Survey on Drug Use and Health (NSDUH), 224 million people ages 12 and older (79% in this age group) reported that they drank alcohol at some point in their lifetime. Among these, 29.5 million people ages 12 and older (10.6% in this age group) had AUD, comprising 16.6 million males ages 12 and older (12.1 % in this age group) and 13.0 million females ages 12 and older (9.1 % in this age group). Like other drugs of abuse, the economic burden from AUD is enormous. Moreover, it is estimated that alcohol use is one of the primary causes for preventable death worldwide . Existing therapies for AUD include behavioral interventions or have been limited to a few clinically available drugs that may not be effective. Moreover, these treatments are limited to restrictive patient populations in terms of their therapeutic effects. Given the epidemiological and economic issues related with AUD, there is an urgent need for novel interventions which may treat the most serious symptoms of AUD. Consequently, the current pharmacological interventions to treat AUD are limited, and there is an urgent need for a novel pharmacological therapy which can also be effective and safe across the a broader patient population.

[0006] As defined in the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), AUD is a maladaptive pattern of substance use leading to clinically significant impairment or distress, as manifested by two or more of the following occurring at any time in the same 12-month period comprising - alcohol is often taken in larger amounts or over a longer period than was intended; there is a persistent desire or unsuccessful efforts to cut down or control alcohol use; a great deal of time is spent in activities necessary to obtain alcohol, use alcohol, or recover from its effects; craving, or a strong desire or urge to use alcohol; recurrent alcohol use resulting in a failure to fulfill major role obligations at work, school, or home; continued alcohol use despite having persistent or recurrent social or interpersonal problems caused or exacerbated by the effects of alcohol; important social, occupational, or recreational activities are given up or reduced because of alcohol use; recurrent alcohol use in situations in which it is physically hazardous; alcohol use is continued despite knowledge of having a persistent or recurrent physical or psychological problem that is likely to have been caused or exacerbated by alcohol; tolerance, as defined by either of the following - a need for markedly increased amounts of alcohol to achieve intoxication or desired effect or a markedly diminished effect with continued use of the same amount of alcohol; and lastly withdrawal, as manifested by either of the following - the characteristic withdrawal syndrome for alcohol or alcohol (or a closely related substance, such as a benzodiazepine) is taken to relieve or avoid withdrawal symptoms.

[0007] Alcohol addiction can be framed as a repeating addiction cycle involving three stages that in turn involve three other domains: incentive salience, negative emotional states, and executive function with each stage being linked to and feeding on the others. The domains are reflected in three key regions of the brain: the basal ganglia, the extended amygdala, and the prefrontal cortex, respectively. A person who is addicted to alcohol may go through this three-stage cycle over the course of weeks or months, or progress through it several times in a day with the person entering the cycle of addiction at any one of the following stages: a) Binge / lntoxication Stage: reward, incentive salience, and pathological habits During this stage, a person experiences the rewarding effects of alcohol, such as euphoria, the reduction of anxiety, and the easing of social interactions. Repeated activation of the basal ganglia’s reward system reinforces alcohol drinking behavior, increasing the likelihood of repeated consumption. The basal ganglia play an important role in motivation as well as in the formation of habits and other routine behaviors. This repeated activation of the basal ganglia also ultimately triggers changes in the way a person responds to stimuli associated with drinking alcohol, such as specific people, places, or alcohol-associated cues such as certain glassware or images or descriptions of drinking. Over time, these stimuli can trigger powerful urges to drink alcohol. Repeated alcohol consumption also results in changes in the basal ganglia that lead to habit formation, ultimately contributing to compulsive use. b) Negative Affect / Withdrawal Stage: reward deficits and stress surfeit - When a person who is addicted to alcohol stops drinking, they experience withdrawal symptoms — or symptoms that are opposite to the positive effects of alcohol that are experienced when drinking it. These symptoms can be physical (sleep disturbances, pain, feelings of illness) and emotional (dysphoria, irritability, anxiety, and emotional pain). The negative feelings associated with alcohol withdrawal are thought to come from two sources. First, a diminished activation in the reward systems — or a reward deficit — of the basal ganglia makes it difficult for people to experience the pleasures of everyday living. Second, an increased activation of the brain’s stress systems — or a stress surfeit — in the extended amygdala contributes to anxiety, irritability, and unease. At this stage, the person no longer drinks alcohol for the pleasurable effects (“high”), but rather to escape the “low” feelings to which chronic alcohol misuse has contributed. c) Preoccupation / Anticipation Stage: craving, impulsivity, and executive function

[0008] This is the stage at which an individual seeks alcohol again after a period of abstinence. A person becomes preoccupied with alcohol and how to get more of it, and looks forward to the next time he or she will consume it. The prefrontal cortex — an area of the brain responsible for executive function, including the ability to organize thoughts and activities, prioritize tasks, manage time, and make decisions — is compromised in people experiencing alcohol addiction. As a result, this area of the brain plays a key role in this stage.

[0009] Alcohol (ethyl alcohol or ethanol) has a low molecular weight and readily cross the blood brain barrier, and as with water, its distribution throughout the body can be as ubiquitous, given its highly hydrophilic nature. In early alcohol research, it was believed that alcohol may exert its psychotropic effects by modulating lipid bilayer membranes. With advancement in behavioral and biochemical research techniques, it was shown that alcohol exerts its effects in brain through specific molecular targets. Among others, molecular targets include activation of pentameric cys-loop ligandgated ion channels, i.e. cation permeable excitatory nicotinic acetylcholine (nAChR) and serotonin3 (5-HT3) receptors, as well as anion permeable inhibitory y- aminobutyric acid (GABAA), and strychnine-sensitive glycine (GlyR) receptors, and inhibition of ionotropic glutamate receptors especially n-methyl -d- aspartate receptors (NMDARs). Alcohol produces its reinforcing, and other central effects through allosteric modulation of above-mentioned ion channels in a concentration dependent manner.

[0010] Like other drugs of abuse, alcohol’s reinforcing effect is mediated by modulation of the mesolimbic dopamine pathway. Acute experimenter-administered alcohol primarily increases dopamine levels in the Nucleus Accumbens (NAc) shell. The mechanism by which alcohol increases dopamine levels in NAc shell is not clearly understood, but it is speculated that alcohol reduces the firing of GABAergic neurons from NAc to ventral tegmental area (VTA), which leads to disinhibition of the dopaminergic neurons from VTA to NAc. Increase in dopamine levels in NAc shell upon acute alcohol administration is also regulated by glutaminergic inputs from prefrontal cortex (PFC), bed nucleus of stria terminalis (BNST), and the lateral hypothalamus, the exact role of these glutaminergic inputs to NAc shell is not clear as alcohol at lower concentration initially increases the glutamate levels but with increasing alcohol concentrations decrease glutamate levels. Apart from its effects on modulating ion channel permeability, alcohol also interacts with centrally expressed GPCRs especially MOR, and the cannabinoid receptor 1 CB1 R.

[0011] Before the discovery of individual facets of the endocannabinoid system (eCB), it was known through behavioral studies in rodents and humans that alcohol interacts with cannabis to produce synergistic effects on sleep, locomotion, and cognition. With the discovery of two cannabinoid receptors CB1 R and CB2R, and their endogenous ligands, 2-arachidonoylglycerol (2AG) and anandamide (N- arachidonoylethanolamine, AEA), the interaction between the eCB system and alcohol became more apparent. Short-term as well as chronic alcohol application to cultured neuronal cells increases AEA and 2-AG production through Ca2+ dependent increase in activity of PLA2 and NAPE-PLD. In contrast to alcohol increasing the endocannabinoid tone, some studies have found opposite effects, wherein acute alcohol treatment decreases eCB signaling in multiple brain areas with no effect on FAAH activity. The eCB system also interacts with alcohol in modulating its reinforcing effects. CB1 R are not expressed on VTA dopaminergic neurons, but they are present on GABAergic presynaptic interneurons, and on presynaptic terminals of GABAergic neurons from RMTg . It has been shown in the Sardinian alcohol preferring rats (sP), there is an increased spontaneous firing of VTA dopaminergic neurons, and this is linked to endocannabinoid mediated reduction in GABA release from RMTg GABAergic neurons. The role of eCB in modulating reinforcing effects of alcohol and other drugs of abuse is more complex than just modulating GABAergic neurons, as much is not known about how endocannabinoids modulate the glutaminergic neurons from PFC on to NaC. The activation of this pathway has recently been shown to reduce dopamine levels in NaC which might play a role in regulating rewarding effects of drugs of abuse including alcohol .

[0012] Modulating individual components of the eCB system using exogenous compounds have been shown to have differential effects on alcohol intake. Systemic administration of CB1 R agonists like CP 55,940, and WIN 55,212-2 have been shown to increase alcohol intake in two bottle choice as well as in operant selfadministration procedures. Anatomical site-specific microinjections of a CB1 R agonist (WIN 55,212-2) in VTA have also been shown to increase alcohol intake at lower doses. The side effect profiles of CBR1 agonists, especially their psychotropic and hypomotility effects may interfere with alcohol intake in preclinical laboratory animals.

[0013] Activating CB1 R by increasing endogenous levels of endocannabinoids i.e. AEA, and 2-AG by inhibiting their respective metabolic enzymes (FAAH and MAGL) have also been evaluated for regulating alcohol intake. Like activating CB1 R with synthetic agonists, FAAH inhibitor URB597 increases alcohol preference in wild type mice. Deletion of the FAAH enzyme also increases preference for alcohol in mice, and alcohol preferring AA rats have lower levels of FAAH enzyme in the PFC area as compared to the non-alcohol preferring nonAA rats. FAAH inhibitors show similar effects in mice and rats experiencing withdrawal from alcohol. URB597, not only reduces the alcohol withdrawal induced anxiety but also blocks cue-induced reinstatement of alcohol drinking in rats. Like the effects observed in rats, URB597 also reduces alcohol seeking behavior in mice undergoing alcohol deprivation. Unlike the studies performed with FAAH inhibitors, not much is known about effects of inhibiting MAGL on alcohol intake, with only one study so far showing that inhibiting MAGL with JZL-184 mitigates the behavioral symptoms in mice undergoing protracted alcohol withdrawal.

[0014] Notably, blocking cannabinoid receptors especially CB1 R has been evaluated in various reward related behaviors. It is now known that blocking CB1 R effectively reduces the rewarding effects of drugs like nicotine, alcohol, and natural rewards like food intake . The benefit of blocking CB1 R signaling in reducing alcohol intake was first observed in preclinical studies of rimonabant, a CB1 antagonist / inverse agonist. In one of the early studies, it was found that rimonabant decreased alcohol intake rats without affecting water intake. Expanding upon this work, studies were performed to show that rimonabant reduces acute voluntary alcohol consumption in multiple preclinical rodent models when administered systematically. Rimonabant was also found to be effective in decreasing alcohol intake in chronic drinking models and showed promising effects in maintaining abstinence in animal models of relapse. Moreover, site specific microinjections of rimonabant in the posterior region of VTA markedly reduces alcohol intake in rats showing the exact neuroanatom ical site of action of rimonabant for its effects in reducing alcohol intake in rodents. Following this, SR147778 (surinabant), a CB1 cannabinoid receptor antagonist and an analog of rimonabant, was also shown to suppress ethanol preference in chronically alcoholized Wistar rats . These promising pre-clinical studies with rimonabant and analogs culminated in a clinical trial evaluating CB1 inverse agonist effects in maintaining abstinence from alcohol drinking. However, in a specified clinical trial, rimonabant failed to produce significant effects on maintaining abstinence from alcohol drinking as compared to placebo. In addition, the adverse neuropsychiatric side effects associated with chronic use of rimonabant, led to its withdrawal from the market. In this context, a promising alternative to rimonabant for treating various health-related outcomes comprise brain penetrant neutral antagonists and / or periphero-neutral antagonists, i.e., these are the ligands that bind to the CB1 receptor with high affinity, but they do not alter secondary signaling protein levels i.e. cAMP and GTPYS levels .

[0015] It would thus be useful to have compounds with activity and methods of use for treating alcohol misuse, alcohol addiction alcohol dependency, alcohol-use disorders, and especially for reducing voluntary ethanol intake and seeking, in both males and females.

[0016] SUMMARY OF THE INVENTION

[0017] Briefly stated, the disclosed embodiments provide a method of use of new and improved compounds that can act on the cannabinoid receptors for treating alcohol abuse, alcohol addiction or alcohol dependency, alcohol-use disorders and their consequences especially cardiometabolic abnormalities, and fibrotic and inflammatory conditions related to the liver and pancreas in an animal or individual. The inventive cannabimimetic ligands of this embodiment can be represented by general Formula I and their pharmaceutically acceptable salts, solvates, hydrates, polymorphs, enantiomers, diastereomers, geometric isomers, racemates, tautomers, rotamers, atropisomers, isotopic variations comprising one deuterium atom or more, or N-oxides thereof: wherein: the ring system can contain 1 or 2 double bonds; any one of Z1 , Z2, Z3 and Z4 can be C, N, 0, S or >C(=0);

[0018] A is N(R5) or a direct bond,

[0019] B is optionally present and if present comprises N(R5),

[0020] R5 is hydrogen, OH, alkyl or substituted alkyl;

[0021] Z5 is optionally present and if present comprises >C(=0) or >C(alkyl);

[0022] R1 comprises -T-(CH2)m- Q -(CH2)n-Z, m and n independently comprises an integer from 0 to about 7;

[0023] T comprises a an aromatic ring having 5 to about 8 carbon atoms as ring members, a heteroaromatic ring having 5 to about 8 ring members

[0024] Q comprises C^C;

[0025] Z comprises H, halogen, CF3, CF2H, N3, NCS, ON, N02, NX1X2, 0X3, SX3, OAc, OSO2X3, O-acyl, S-acyl, SO2-alkyl, SO-alkyl, SC(CH3)2COOX8, OC(CH3)2COOX8, C(CH3)2COOX8, Si(alkyl)3, alkyl-CN, O-aroyl, O(CH2)jOX3, O(CH2)jNXiX2, NH- acyl, NH-aroyl, CHO, C(halogen)3, C00X3, SO3H, SO2NX1X2, CONX1X2, NHC(O)O- alkyl, NHS02-alkyl, alkoxy, alkyl, alcohol, alkylmercapto, alkylamino, di-alkylamino, alkylsulfinyl or alkylsulfonyl, CX4X5X6, -CH=CHX8, -C=CX8;

[0026] Xi and X2 each independently comprise H or alkyl, or

[0027] Xi and X2together comprise part of a heterocyclic ring having about 4 to about 7 ring members and optionally one additional heteroatom selected from 0, N or S, or

[0028] Xi and X2together comprise part of an imide ring having about 5 to about 6 members,

[0029] X3 comprises H, alkyl, NO2, (CH2)mCN, hydroxyloweralkyl, or alkyl-NXiX2,

[0030] X4, Xs, and Xe each independently comprise H, alkyl, carbocyclic ring, hydroxyloweralkyl, alkyl-OH, halogen, CN, SNO, S(S02)alkyl, NX1X2, COOX3, CONX3, OX7, or O-alkyl-X? wherein

[0031] X7comprises H, alkyl, NO2, NO, P(O)(OX8)2, PH(0)(0X8), S(O)kN(alkyl)2, S(0)kX8, S(O)kOX8, COOXs, CONXs, SO3H, C0X8, wherein

[0032] X8comprises H, alkyl, carbocyclic ring, heterocyclic ring, aromatic ring, heteroaromatic ring, or -CXg=CHXio wherein

[0033] X9 and X10 each independently comprise H or alkyl

[0034] Wherein m is an integer from 0 to 7 j is an integer from 0 to about 6, or k is an integer from 0 to about 2; or

[0035] R1 comprises -T-(CH2)m- Q -(CH2)n-Z; m and n independently comprises an integer from 0 to about 7;

[0036] T comprises, an aromatic ring having 5 to about 8 carbon atoms as ring members, a heteroaromatic ring having 5 to about 8 ring members;

[0037] Q comprises C=C; and

[0038] Z comprises a carbocyclic ring having about 4 to about 7 ring members, a heterocyclic ring having about 4 to about 7 ring members, an aromatic ring having about 5 to about 7 ring members, a heteroaromatic ring having about 5 to about 7 ring members, a bicyclic ring, a heterobicyclic ring, a tricyclic ring, a heterotricyclic ring, a polycyclic ring, a heteropolycyclic ring; or any above group substituted on at least one available ring atom by an alkyl group; or any above group substituted on at least one available ring nitrogen atom by a benzyl group, a substituted benzyl group, an alkoxybenzyl group, a substituted alkoxybenzyl group, a benzhydryl group or a substituted benzhydryl group; and wherein the connecting point between the -(CH2)n- group and the Z group can be any available ring carbon atom or any available ring nitrogen atom; or

[0039] R1 comprises -T-(CH2)m- Q -(CH2)n-Z; m and n independently comprises an integer from 0 to about 7;

[0040] T comprises an aromatic ring having 5 to about 8 carbon atoms as ring members, a heteroaromatic ring having 5 to about 8 ring members;

[0041] Q comprises C=C; and

[0042] Z comprises 1 -, 2- or 3-pyrrolidinyl, 1 -, 2-, 3- or 4-piperidinyl, 2-, 3- or 4- morpholinyl, 2-, 3- or 4-thiomorpholinyl, 1 -, 2- or 3-azetidinyl, 1 - or 2-piperazinyl, 2- or 3-tetrahydrofuranyl; or any above group substituted on at least one available ring atom by an alkyl group; or any above group substituted on at least one available ring nitrogen atom by a benzyl group, a substituted benzyl group, an alkoxybenzyl group, a substituted alkoxybenzyl group, a benzhydryl group or a substituted benzhydryl group; and wherein the connecting point between the -(CH2)n- group and the Z group can be any available ring carbon atom or any available ring nitrogen atom; or

[0043] R1 comprises -T-(CH2)m- Q -(CH2)n-Z; m and n independently comprises an integer from 0 to about 7;

[0044] T comprises an aromatic ring having 5 to about 8 carbon atoms as ring members, a heteroaromatic ring having 5 to about 8 ring members;

[0045] Q comprises C=C; and

[0046] Z comprises

[0047] wherein X and Y each independently comprise

[0048] H, halogen, CF3, CF2H, N3, NCS, CN, NO2, NX1X2, OX3, SX3, OAc, OSO2X3, O-acyl, S-acyl, SO2-alkyl, SO-alkyl, SC(CH3)2COOX8, OC(CH3)2COOX8, C(CH3)2COOX8, Si(alkyl)3, alkyl-CN, O-aroyl, O(CH2)jOX3, O(CH2)jNXiX2, NH-acyl, NH-aroyl, CHO, C(halogen)3, COOX3, SO3H, SO2NX1X2, CONX1X2, NHC(O)O-alkyl, NHSO2-alkyl, alkoxy, alkyl, alcohol, alkylmercapto, alkylamino, di-alkylamino, alkylsulfinyl or alkylsulfonyl, CX4X5X6, -CH=CHX8, -C=CX8;

[0049] Xi and X2each independently comprise H or alkyl, or

[0050] Xi and X2together comprise part of a heterocyclic ring having about 4 to about 7 ring members and optionally one additional heteroatom selected from 0, N or S, or

[0051] Xi and X2together comprise part of an imide ring having about 5 to about 6 members,

[0052] X3comprises H, alkyl, NO2, (CH2)mCN, hydroxyloweralkyl, or alkyl-NXiX2,

[0053] X4, Xs, and Xe each independently comprise H, alkyl, carbocyclic ring, hydroxyloweralkyl, alkyl-OH, halogen, CN, SNO, S(SO2)alkyl, NX1X2, C00X3, CONX3, OX7, or O-alkyl-X? wherein

[0054] X7comprises H, alkyl, NO2, NO, P(O)(OX8)2, PH(O)(OX8), S(O)kN(alkyl)2, S(O)kX8, S(O)kOX8, COOXs, CONXs, SO3H, COXS, wherein

[0055] X8comprises H, alkyl, carbocyclic ring, heterocyclic ring, aromatic ring, heteroaromatic ring, or -CXg=CHXio wherein

[0056] X9 and X10 each independently comprise H or alkyl

[0057] Wherein m is an integer from 0 to 7 j is an integer from 0 to about 6, k is an integer from 0 to about 2,

[0058] W comprises H or alkyl; or

[0059] R1 comprises -T-(CH2)m- Q -(CH2)n-Z; m and n independently comprises an integer from 0 to about 7;

[0060] T comprises an aromatic ring having 5 to about 8 carbon atoms as ring members, a heteroaromatic ring having 5 to about 8 ring members;

[0061] Q comprises C=C; and

[0062] Z comprises an unsaturated ring having 5 ring atoms and 0 to 2 independently selected heteroatoms as ring members fused to an unsaturated ring having 5 ring atoms and 0 to 4 independently selected heteroatoms as ring members, an unsaturated ring having 5 ring atoms and 0 to 2 independently selected heteroatoms as ring members fused to an unsaturated ring having 6 or 7 ring atoms and 0 to 4 independently selected heteroatoms as ring members or an unsaturated ring having 6 ring atoms and 0 to 3 independently selected heteroatoms as ring members fused to an unsaturated ring having 6 or 7 ring atoms and 0 to 4 independently selected heteroatoms as ring members; or

[0063] R1 comprises -T-(CH2)m- Q -(CH2)n-Z;

[0064] T comprises an aromatic ring having 5 to about 8 carbon atoms as ring members, a heteroaromatic ring having 5 to about 8 ring members; m and n independently comprises an integer from 0 to about 7;

[0065] Q comprises C=C;

[0066] Z comprises

[0067] E comprises a C1 to about C4, linear or branched alkyl group, a phenyl group, a substituted phenyl group, a benzyl group or a substituted benzyl group; or

[0068] R1 comprises -T-(CH2)m- Q -(CH2)n-Z; T comprises an aromatic ring having 5 to about 8 carbon atoms as ring members, a heteroaromatic ring having 5 to about 8 ring members; m and n independently comprises an integer from 0 to about 7;

[0069] Q comprises C=C; and

[0070] Z comprises k is an integer from 1 to about 5

[0071] R2 comprises -(CH2)n-Z; n is an integer from 0 to about 7; wherein Z comprises, H, halogen, CF3, CF2H, N3, NCS, CN, NO2, NX1X2, OX3, SX3, OAc, OSO2X3, O-acyl, S-acyl, SO2-alkyl, SO-alkyl, SC(CH3)2COOX8, OC(CH3)2COOX8, C(CH3)2COOX8, Si(alkyl)3, alkyl-CN, O-aroyl, O(CH2)jOX3, O(CH2)jNXiX2, NH-acyl, NH-aroyl, CHO, C(halogen)3, COOX3, SO3H, SO2NX1X2, CONXIX2, NHC(O)O-alkyl, NHSO2-alkyl, alkoxy, alkyl, alcohol, alkylmercapto, alkylamino, di-alkylamino, alkylsulfinyl or alkylsulfonyl, CX4X5X6, -CH=CHXs , - C CXs:

[0072] Xi and X2each independently comprise H or alkyl, or

[0073] Xi and X2together comprise part of a heterocyclic ring having about 4 to about 7 ring members and optionally one additional heteroatom selected from 0, N or S, or

[0074] Xi and X2together comprise part of an imide ring having about 5 to about 6 members,

[0075] X3 comprises H, alkyl, aryl, N02, (CH2)mCN, hydroxyloweralkyl, or alkyl-NXiX2,

[0076] X4, Xs, and Xe each independently comprise H, alkyl, carbocyclic ring, hydroxyloweralkyl, alkyl-OH, halogen, CN, SNO, S(SO2)alkyl, NXIX2, COOX3, CONX3, OX7, or O-alkyl-X? wherein

[0077] X7comprises H, alkyl, N02, NO, P(O)(OX8)2, PH(O)(OXs), S(O)kN(alkyl)2, S(O)kX8, S(O)kOX8, C00X8, CONXs, SO3H, C0X8, wherein Xs comprises H, alkyl, carbocyclic ring, heterocyclic ring, aromatic ring, heteroaromatic ring, or -CXg=CHXio wherein

[0078] X9 and X10 each independently comprise H or alkyl

[0079] Wherein m is an integer from 0 to 7 j is an integer from 0 to about 6, or k is an integer from 0 to about 2; or

[0080] R2 comprises -(CH2)n-Z; n is an integer from 0 to about 7; and

[0081] Z comprises a carbocyclic ring having about 4 to about 7 ring members, a heterocyclic ring having about 4 to about 7 ring members, an aromatic ring having about 5 to about 7 ring members, a heteroaromatic ring having about 5 to about 7 ring members, a bicyclic ring, a heterobicyclic ring, a tricyclic ring, a heterotricyclic ring, a polycyclic ring, a heteropolycyclic ring; or any above group substituted on at least one available ring atom by an alkyl group; or any above group substituted on at least one available ring nitrogen atom by a benzyl group, a substituted benzyl group, an alkoxybenzyl group, a substituted alkoxybenzyl group, a benzhydryl group or a substituted benzhydryl group; and wherein the connecting point between the -(CH2)n- group and the Z group can be any available ring carbon atom or any available ring nitrogen atom; or

[0082] R2 comprises -(CH2)n-Z; n is an integer from 0 to about 7; and

[0083] Z comprises a 5 member unsaturated ring having 0 to 4 independently selected heteroatoms as ring members, a substituted 5 member unsaturated ring having 0 to 4 independently selected heteroatoms as ring members, a 6 member aromatic ring having 0 to 5 independently selected heteroatoms as ring members or a substituted 6 member aromatic ring having 0 to 5 independently selected heteroatoms; and wherein the connecting point between the -(CH2)n- group and the Z group can be any available ring carbon atom or any available ring nitrogen atom; or R2 comprises -(CH2)n-Z; n is an integer from 0 to about 7; and

[0084] Z comprises 1-, 2- or 3-pyrrolidinyl, 1-, 2- 3- or 4-piperidinyl, 2- 3- or 4-morpholinyl, 2-, 3- or 4-thiomorpholinyl, 1 -, 2- or 3-azetidinyl, 1 - or 2-piperazinyl, 2- or 3- tetrahydrofuranyl; or any above group substituted on at least one available ring atom by an alkyl group; or any above group substituted on at least one available ring nitrogen atom by a benzyl group, a substituted benzyl group, an alkoxybenzyl group, a substituted alkoxybenzyl group, a benzhydryl group or a substituted benzhydryl group; and wherein the connecting point between the -(CH2)n- group and the Z group can be any available ring carbon atom or any available ring nitrogen atom; or

[0085] R2 comprises -(CH2)n-Z; n is an integer from 0 to about 7; and

[0086] Z comprises wherein X and Y each independently comprise, H, halogen, CF3, CF2H, N3, NCS, CN, NO2, NX1X2, OX3, SX3, OAc, OSO2X3, O-acyl, S-acyl, SO2-alkyl, SO-alkyl, SC(CH3)2COOX8, OC(CH3)2COOX8, C(CH3)2COOX8, Si(alkyl)3, alkyl-CN, O-aroyl, O(CH2)jOX3, O(CH2)jNXiX2, NH-acyl, NH-aroyl, CHO, C(halogen)3, COOX3, SO3H, SO2NX1X2, CONX1X2, NHC(O)O-alkyl, NHSO2-alkyl, alkoxy, alkyl, alcohol, alkylmercapto, alkylamino, di-alkylamino, alkylsulfinyl or alkylsulfonyl, CX4X5X6, - CH=CHX8, -C=CX8; Xi and X2 each independently comprise H or alkyl, or

[0087] Xi and X2 together comprise part of a heterocyclic ring having about 4 to about 7 ring members and optionally one additional heteroatom selected from 0, N or S, or

[0088] Xi and X2 together comprise part of an imide ring having about 5 to about 6 members,

[0089] X3 comprises H, alkyl, aryl, NO2, (CH2)mCN, hydroxyloweralkyl, or alkyl-NXiX2,

[0090] X4, Xs, and Xe each independently comprise H, alkyl, carbocyclic ring, hydroxyloweralkyl, alkyl-OH, halogen, CN, SNO, S(S02)alkyl, NX1X2, COOX3, CONX3, OX7, or O-alkyl-X? wherein

[0091] X7comprises H, alkyl, NO2, NO, P(O)(OX8)2, PH(O)(OXs), S(O)kN(alkyl)2, S(0)kX8, S(0)k0X8, COOXs, CONXs, SO3H, COXs, wherein

[0092] X8comprises H, alkyl, carbocyclic ring, heterocyclic ring, aromatic ring, heteroaromatic ring, or -CXg=CHXio wherein

[0093] X9 and X10 each independently comprise H or alkyl

[0094] Wherein m is an integer from 0 to 7 j is an integer from 0 to about 6, or k is an integer from 0 to about 2

[0095] W comprises H or alkyl; or

[0096] R2 comprises -(CH2)n-Z; n is an integer from 0 to about 7; and

[0097] Z comprises a carbocyclic ring having 6 ring atoms fused to a heterocyclic ring having from 5 to 7 ring atoms, a carbocyclic ring having 6 ring atoms fused to a heteroaromatic ring having from 5 to 7 ring atoms, a heterocyclic ring having 6 ring atoms fused to a heterocyclic ring having from 5 to 7 ring atoms, an heterocyclic ring having 6 ring atoms fused to a heteroaromatic ring having from 5 to 7 ring atoms, an aromatic ring having 6 ring atoms fused to a heterocyclic ring having from 5 to 7 ring atoms, an aromatic ring having 6 ring atoms fused to a heteroaromatic ring having from 5 to 7 ring atoms, a heteroaromatic ring having 6 ring atoms fused to a heterocyclic ring having from 5 to 7 ring atoms or a heteroaromatic ring having 6 ring atoms fused to a heteroaromatic ring having from 5 to 7 ring atoms; or R2 comprises -(CH2)n-Z; n comprises an integer from 0 to about 7; and

[0098] Z comprises an unsaturated ring having 5 ring atoms and 0 to 2 independently selected heteroatoms as ring members fused to an unsaturated ring having 5 ring atoms and 0 to 4 independently selected heteroatoms as ring members, an unsaturated ring having 5 ring atoms and 0 to 2 independently selected heteroatoms as ring members fused to an unsaturated ring having 6 or 7 ring atoms and 0 to 3 independently selected heteroatoms as ring members or an unsaturated ring having 6 ring atoms and 0 to 4 independently selected heteroatoms as ring members fused to an unsaturated ring having 6 or 7 ring atoms and 0 to 4 independently selected heteroatoms as ring members; or

[0099] R2 comprises -(CH2)m -Qi-(CH2)n-Z;

[0100] Qi comprises NH, 0, S,-CH=CH- -C=C-, -CO, SO2 or OSO2; m is an integer from 1 to about 7; n is an integer from 0 to about 7; and wherein Z comprises, H, halogen, CF3, CF2H, N3, NCS, CN, NO2, NX1X2, OX3, SX3, OAc, OSO2X3, 0-acyl, S-acyl, SO2-alkyl, SO-alkyl, SC(CH3)2COOX8, OC(CH3)2COOX8 , C(CH3)2COOX8, Si(alkyl)3, alkyl-CN, O-aroyl, O(CH2)jOX3, O(CH2)jNXiX2, NH-acyl, NH-aroyl, CHO, C(halogen)3, COOX3, SO3H, SO2NX1X2, CONX1X2, NHC(O)O-alkyl, NHS02-alkyl, alkoxy, alkyl, alcohol, alkylmercapto, alkylamino, di-alkylamino, alkylsulfinyl or alkylsulfonyl, CX4X5X6, -CH=CHXs , -C=CX8;

[0101] Xi and X2 each independently comprise H or alkyl, or

[0102] Xi and X2 together comprise part of a heterocyclic ring having about 4 to about 7 ring members and optionally one additional heteroatom selected from 0, N or S, or

[0103] Xi and X2 together comprise part of an imide ring having about 5 to about 6 members,

[0104] X3 comprises H, alkyl, aryl, NO2, (CH2)mCN, hydroxyloweralkyl, or alkyl-NXiX2, X4, Xs, and Xs each independently comprise H, alkyl, carbocyclic ring, hydroxyloweralkyl, alkyl-OH, halogen, CN, SNO, S(SO2)alkyl, NX1X2, COOX3, CONX3, OX7, or O-alkyl-X? wherein

[0105] X7comprises H, alkyl, NO2, NO, P(O)(OX8)2, PH(O)(OX8), S(O)kN(alkyl)2, S(O)kX8, S(O)kOX8, COOXs, CONXs, SO3H, COXs, wherein

[0106] X8comprises H, alkyl, carbocyclic ring, heterocyclic ring, aromatic ring, heteroaromatic ring, or -CXg=CHXio wherein

[0107] X9 and X10 each independently comprise H or alkyl

[0108] Wherein m is an integer from 0 to 7 j is an integer from 0 to about 6, or k is an integer from 0 to about 2; or

[0109] R2 comprises -Q2-(CH2)n-Z;

[0110] Q2 is optionally present and if present comprises -CH2-NH, -CH2-O, -CH2-S, -CH2- SO2 or -CH2-OSO2; n is an integer from 0 to about 7; wherein Z comprises, H, halogen, CF3, CF2H, N3, NCS, CN, NO2, NX1X2, OX3, SX3, OAc, OSO2X3, O-acyl, S-acyl, SO2-alkyl, SO-alkyl, SC(CH3)2COOX8, OC(CH3)2COOX8 , C(CH3)2COOX8, Si(alkyl)3, alkyl-CN, O-aroyl, O(CH2)jOX3, O(CH2)jNXiX2, NH-acyl, NH-aroyl, CHO, C(halogen)3, COOX3, SO3H, SO2NX1X2, CONX1X2, NHC(O)O-alkyl, NHSO2-alkyl, alkoxy, alkyl, alcohol, alkylmercapto, alkylamino, di-alkylamino, alkylsulfinyl or alkylsulfonyl, CX4X5X6, -CH=CHX8, -C=CX8

[0111] Xi and X2 each independently comprise H or alkyl, or

[0112] Xi and X2 together comprise part of a heterocyclic ring having about 4 to about 7 ring members and optionally one additional heteroatom selected from 0, N or S, or

[0113] Xi and X2 together comprise part of an imide ring having about 5 to about 6 members,

[0114] X3 comprises H, alkyl, aryl, NO2, (CH2)mCN, hydroxyloweralkyl, or alkyl-NXiX2, X4, Xs, and Xs each independently comprise H, alkyl, carbocyclic ring, hydroxyloweralkyl, alkyl-OH, halogen, CN, SNO, S(SO2)alkyl, NX1X2, COOX3, CONX3, OX7, or O-alkyl-X? wherein

[0115] X7comprises H, alkyl, NO2, NO, P(O)(OX8)2, PH(O)(OX8), S(O)kN(alkyl)2, S(O)kX8, S(O)kOX8, COOXs, CONXs, SO3H, COXs, wherein

[0116] X8comprises H, alkyl, carbocyclic ring, heterocyclic ring, aromatic ring, heteroaromatic ring, or -CXg=CHXio wherein

[0117] X9 and X10 each independently comprise H or alkyl

[0118] Wherein m is an integer from 0 to 7 j is an integer from 0 to about 6, k is an integer from 0 to about 2; or

[0119] R2 comprises -(CH2)m - Qi -(CH2)n-Z;

[0120] Qi comprises NH, 0, S, CH=CH, C=C, CO, SO2 or OSO2; m is an integer from 1 to about 7; n is an integer from 0 to about 7;

[0121] Z comprises a bicyclic ring, a heterobicyclic ring, a tricyclic ring, a heterotricyclic ring, a polycyclic ring or a heteropolycyclic ring; or

[0122] R2 comprises -(CH2)m - Qi -(CH2)n-Z;

[0123] Qi comprises NH, 0, S, CH=CH, C=C, CO, SO2 or OSO2; m is an integer from 1 to about 7; n is an integer from 0 to about 7;

[0124] Z comprises a carbocyclic ring having about 4 to about 7 ring members, a heterocyclic ring having about 4 to about 7 ring members, an aromatic ring having about 5 to about 7 ring members, a heteroaromatic ring having about 5 to about 7 ring members; a bicyclic ring, a heterobicyclic ring, a tricyclic ring, a heterotricyclic ring, a polycyclic ring, a heteropolycyclic ring or any above group substituted on at least one available ring atom by an alkyl group or any above group substituted on at least one available ring nitrogen atom by a benzyl group, a substituted benzyl group, an alkoxybenzyl group, a substituted alkoxybenzyl group, a benzhydryl group or a substituted benzhydryl group; and wherein the connecting point between the -(CH2)n- group and the Z group can be any available ring carbon atom or any available ring nitrogen atom; or

[0125] R2 comprises -(CH2)m - Qi -(CH2)n-Z;

[0126] Qi comprises NH, 0, S, CH=CH, C=C, CO, SO2 or OSO2; m is an integer from 1 to about 7; n is an integer from 0 to about 7; and

[0127] Z comprises a 5 member unsaturated ring having 0 to 4 independently selected heteroatoms as ring members, a substituted 5 member unsaturated ring having 0 to 4 independently selected heteroatoms as ring members, a 6 member aromatic ring having 0 to 5 independently selected heteroatoms as ring members or a substituted 6 member aromatic ring having 0 to 5 independently selected heteroatoms; and wherein the connecting point between the -(CH2)n- group and the Z group can be any available ring carbon atom or any available ring nitrogen atom; or

[0128] R2 comprises -(CH2)m - Qi -(CH2)n-Z;

[0129] Qi comprises NH, 0, S, CH=CH, C=C, CO, SO2 or OSO2; m is an integer from 1 to about 7; n is an integer from 0 to about 7;

[0130] Z comprises 1 -, 2- or 3-pyrrolidinyl, 1 -, 2-, 3- or 4-piperidinyl, 2-, 3- or 4- morpholinyl, 2-, 3- or 4-thiomorpholinyl, 1 -, 2- or 3-azetidinyl, 1 - or 2-piperazinyl, 2- or 3-tetrahydrofuranyl; or any above group substituted on at least one available ring atom by an alkyl group; or any above group substituted on at least one available ring nitrogen atom by a benzyl group, a substituted benzyl group, an alkoxybenzyl group, a substituted alkoxybenzyl group, a benzhydryl group or a substituted benzhydryl group; and wherein the connecting point between the -(CH2)n- group and the Z group can be any available ring carbon atom or any available ring nitrogen atom; or

[0131] R2 comprises -(CH2)m - Qi -(CH2)n-Z;

[0132] Qi comprises NH, 0, S, CH=CH, C=C, CO, SO2 or OSO2; m is an integer from 1 to about 7; n is an integer from 0 to about 7; and

[0133] Z comprises wherein X and Y each independently comprise

[0134] H, halogen, CF3, CF2H, N3, NCS, CN, NO2, NX1X2, OX3, SX3, OAc, OSO2X3, 0- acyl, S-acyl, SO2-alkyl, SO-alkyl, SC(CH3)2COOX8, OC(CH3)2COOX8, C(CH3)2COOX8, Si(alkyl)3, alkyl-CN, O-aroyl, O(CH2)jOX3, O(CH2)jNXiX2, NH- acyl, NH-aroyl, CHO, C(halogen)3, COOX3, SO3H, SO2NX1X2, CONX1X2, NHC(O)O- alkyl, NHSO2-alkyl, alkoxy, alkyl, alcohol, alkylmercapto, alkylamino, di-alkylamino, alkylsulfinyl or alkylsulfonyl, CX4X5X6, -CH=CHXs , -C=CX8;

[0135] Xi and X2each independently comprise H or alkyl, or

[0136] Xi and X2together comprise part of a heterocyclic ring having about 4 to about 7 ring members and optionally one additional heteroatom selected from 0, N or S, or

[0137] Xi and X2together comprise part of an imide ring having about 5 to about 6 members,

[0138] X3comprises H, alkyl, aryl, NO2, (CH2)mCN, hydroxyloweralkyl, or alkyl-NXiX2,

[0139] X4, Xs, and Xe each independently comprise H, alkyl, carbocyclic ring, hydroxyloweralkyl, alkyl-OH, halogen, CN, SNO, S(SO2)alkyl, NX1X2, C00X3, C0NX3, OX7, or O-alkyl-X? wherein

[0140] X7comprises H, alkyl, NO2, NO, P(O)(OX8)2, PH(O)(OX8), S(O)kN(alkyl)2, S(0)kX8, S(O)kOX8, COOXs, CONXs, SO3H, COXs, wherein Xs comprises H, alkyl, carbocyclic ring, heterocyclic ring, aromatic ring, heteroaromatic ring, or -CXg=CHXio wherein

[0141] X9 and X10 each independently comprise H or alkyl

[0142] Wherein m is an integer from 0 to 7 j is an integer from 0 to about 6, k is an integer from 0 to about 2

[0143] W comprises H or alkyl; or

[0144] R2 comprises -(CH2)m - Qi -(CH2)n-Z;

[0145] Qi comprises NH, 0, S, CH=CH, C=C, CO, SO2 or OSO2; m is an integer from 1 to about 7; n is an integer from 0 to about 7; and

[0146] Z comprises an unsaturated ring having 5 ring atoms and 0 to 2 independently selected heteroatoms as ring members fused to an unsaturated ring having 5 ring atoms and 0 to 4 independently selected heteroatoms as ring members, an unsaturated ring having 5 ring atoms and 0 to 2 independently selected heteroatoms as ring members fused to an unsaturated ring having 6 or 7 ring atoms and 0 to 4 independently selected heteroatoms as ring members or an unsaturated ring having 6 ring atoms and 0 to 4 independently selected heteroatoms as ring members fused to an unsaturated ring having 6 or 7 ring atoms and 0 to 4 independently selected heteroatoms as ring members; or

[0147] R2 comprises -(CH2)m - Qi -(CH2)n-Z;

[0148] Qi comprises NH, 0, S, CH=CH, C=C, CO, SO2 or OSO2; m is an integer from 1 to about 7; n is an integer from 0 to about 7; and

[0149] Z comprises

[0150]

[0151] R2 comprises -T-(CH2)n-Z; n comprises an integer from 0 to about 7;

[0152] T comprises a carbocyclic ring having 3 to about 8 ring members, an unsaturated ring having 3 to about 8 carbon atoms as ring members, an aromatic ring having 5 to about 8 carbon atoms as ring members, a heterocyclic ring having 3 to about 8 ring members, a heteroaromatic ring having 5 to about 8 ring members, a bicyclic ring, a heterobicyclic ring, a tricyclic ring, a heterotricyclic ring, a polycyclic ring or a heteropolycyclic ring; and

[0153] Z comprises, H, halogen, CF3, CF2H, N3, NCS, CN, NO2, NX1X2, OX3, SX3, OAc, OSO2X3, O-acyl, S-acyl, SO2-alkyl, SO-alkyl, SC(CH3)2COOX8, OC(CH3)2COOX8, C(CH3)2COOX8, Si(alkyl)3, alkyl-CN, O-aroyl, O(CH2)jOX3, O(CH2)jNXiX2, NH- acyl, NH-aroyl, CHO, C(halogen)3, COOX3, SO3H, SO2NX1X2, CONX1X2, NHC(O)O- alkyl, NHSO2-alkyl, alkoxy, alkyl, alcohol, alkylmercapto, alkylamino, di-alkylamino, alkylsulfinyl or alkylsulfonyl, CX4X5X6, -CH=CHXs , -C=CX8;

[0154] Xi and X2 each independently comprise H or alkyl, or

[0155] Xi and X2together comprise part of a heterocyclic ring having about 4 to about 7 ring members and optionally one additional heteroatom selected from 0, N or S, or

[0156] Xi and X2 together comprise part of an imide ring having about 5 to about 6 members,

[0157] X3comprises H, alkyl, aryl, NO2, (CH2)mCN, hydroxyloweralkyl, or alkyl-NXiX2,

[0158] X4, Xs, and Xe each independently comprise H, alkyl, carbocyclic ring, hydroxyloweralkyl, alkyl-OH, halogen, CN, SNO, S(SO2)alkyl, NX1X2, COOX3, CONX3, OX7, or O-alkyl-X? wherein X7comprises H, alkyl, NO2, NO, P(O)(OX8)2, PH(O)(OX8), S(O)kN(alkyl)2, S(O)kX8, S(O)kOX8, COOX8, CONXs, SO3H, COX8, wherein

[0159] X8comprises H, alkyl, carbocyclic ring, heterocyclic ring, aromatic ring, heteroaromatic ring, or -CXg=CHXio wherein

[0160] X9 and X10 each independently comprise H or alkyl

[0161] Wherein m is an integer from 0 to 7 j is an integer from 0 to about 6, k is an integer from 0 to about 2; or

[0162] R2 comprises -T-(CH2)n-Z; n comprises an integer from 0 to about 7;

[0163] T comprises a carbocyclic ring having 3 to about 8 ring members, an unsaturated ring having 3 to about 8 carbon atoms as ring members, an aromatic ring having 5 to about 8 carbon atoms as ring members, a heterocyclic ring having 3 to about 8 ring members, a heteroaromatic ring having 5 to about 8 ring members, a bicyclic ring, a heterobicyclic ring, a tricyclic ring, a heterotricyclic ring, a polycyclic ring or a heteropolycyclic ring; and

[0164] Z comprises a carbocyclic ring having about 4 to about 7 ring members, a heterocyclic ring having about 4 to about 7 ring members, an aromatic ring having about 5 to about 7 ring members, a heteroaromatic ring having about 5 to about 7 ring members, a bicyclic ring, a heterobicyclic ring, a tricyclic ring, a heterotricyclic ring, a polycyclic ring, a heteropolycyclic ring; or any above group substituted on at least one available ring atom by an alkyl group; or any above group substituted on at least one available ring nitrogen atom by a benzyl group, a substituted benzyl group, an alkoxybenzyl group, a substituted alkoxybenzyl group, a benzhydryl group or a substituted benzhydryl group; and wherein the connecting point between the -(CH2)n- group and the Z group can be any available ring carbon atom or any available ring nitrogen atom; or

[0165] R2 comprises -T-(CH2)n-Z; n comprises an integer from 0 to about 7; T comprises a carbocyclic ring having 3 to about 8 ring members, an unsaturated ring having 3 to about 8 carbon atoms as ring members, an aromatic ring having 5 to about 8 carbon atoms as ring members, a heterocyclic ring having 3 to about 8 ring members, a heteroaromatic ring having 5 to about 8 ring members, a bicyclic ring, a heterobicyclic ring, a tricyclic ring, a heterotricyclic ring, a polycyclic ring or a heteropolycyclic ring; and

[0166] Z comprises 1 -, 2- or 3-pyrrolidinyl, 1 -, 2-, 3- or 4-piperidinyl, 2-, 3- or 4- morpholinyl, 2-, 3- or 4-thiomorpholinyl, 1 -, 2- or 3-azetidinyl, 1 - or 2-piperazinyl, 2- or 3-tetrahydrofuranyl; or any above group substituted on at least one available ring atom by an alkyl group; or any above group substituted on at least one available ring nitrogen atom by a benzyl group, a substituted benzyl group, an alkoxybenzyl group, a substituted alkoxybenzyl group, a benzhydryl group or a substituted benzhydryl group; and wherein the connecting point between the -(CH2)n- group and the Z group can be any available ring carbon atom or any available ring nitrogen atom; or

[0167] R2 comprises -T-(CH2)n-Z; n comprises an integer from 0 to about 7;

[0168] T comprises a carbocyclic ring having 3 to about 8 ring members, an unsaturated ring having 3 to about 8 carbon atoms as ring members, an aromatic ring having 5 to about 8 carbon atoms as ring members, a heterocyclic ring having 3 to about 8 ring members, a heteroaromatic ring having 5 to about 8 ring members, a bicyclic ring, a heterobicyclic ring, a tricyclic ring, a heterotricyclic ring, a polycyclic ring or a heteropolycyclic ring; and

[0169] Z comprises wherein X and Y each independently comprise

[0170] H, halogen, CF3, CF2H, N3, NCS, CN, NO2, NX1X2, OX3, SX3, OAc, OSO2X3, 0- acyl, S-acyl, SO2-alkyl, SO-alkyl, SC(CH3)2COOX8, OC(CH3)2COOX8, C(CH3)2COOX8, Si(alkyl)3, alkyl-CN, O-aroyl, O(CH2)jOX3, O(CH2)jNXiX2, NH- acyl, NH-aroyl, CHO, C(halogen)3, COOX3, SO3H, SO2NX1X2, CONX1X2, NHC(O)O- alkyl, NHS02-alkyl, alkoxy, alkyl, alcohol, alkylmercapto, alkylamino, di-alkylamino, alkylsulfinyl or alkylsulfonyl, CX4X5X6, -CH=CHXs , -C=CX8;

[0171] Xi and X2each independently comprise H or alkyl, or

[0172] Xi and X2together comprise part of a heterocyclic ring having about 4 to about 7 ring members and optionally one additional heteroatom selected from 0, N or S, or

[0173] Xi and X2together comprise part of an imide ring having about 5 to about 6 members,

[0174] X3comprises H, alkyl, aryl, N02, (CH2)mCN, hydroxyloweralkyl, or alkyl-NXiX2,

[0175] X4, Xs, and Xe each independently comprise H, alkyl, carbocyclic ring, hydroxyloweralkyl, alkyl-OH, halogen, CN, SNO, S(SO2)alkyl, NX1X2, C00X3, C0NX3, OX7, or O-alkyl-X? wherein

[0176] X7comprises H, alkyl, N02, NO, P(O)(OX8)2, PH(O)(OX8), S(O)kN(alkyl)2, S(0)kX8, S(O)kOX8, COOXs, CONXs, SO3H, COXs, wherein

[0177] X8comprises H, alkyl, carbocyclic ring, heterocyclic ring, aromatic ring, heteroaromatic ring, or -CXg=CHXio wherein

[0178] X9 and X10 each independently comprise H or alkyl

[0179] Wherein m is an integer from 0 to 7 j is an integer from 0 to about 6, k is an integer from 0 to about 2

[0180] W comprises H or alkyl; or

[0181] R2 comprises -T-(CH2)n-Z; n comprises an integer from 0 to about 7;

[0182] T comprises a carbocyclic ring having 3 to about 8 ring members, an unsaturated ring having 3 to about 8 carbon atoms as ring members, an aromatic ring having 5 to about 8 carbon atoms as ring members, a heterocyclic ring having 3 to about 8 ring members, a heteroaromatic ring having 5 to about 8 ring members, a bicyclic ring, a heterobicyclic ring, a tricyclic ring, a heterotricyclic ring, a polycyclic ring or a heteropolycyclic ring; and

[0183] Z comprises an unsaturated ring having 5 ring atoms and 0 to 2 independently selected heteroatoms as ring members fused to an unsaturated ring having 5 ring atoms and 0 to 4 independently selected heteroatoms as ring members, an unsaturated ring having 5 ring atoms and 0 to 2 independently selected heteroatoms as ring members fused to an unsaturated ring having 6 or 7 ring atoms and 0 to 4 independently selected heteroatoms as ring members or an unsaturated ring having 6 ring atoms and 0 to 3 independently selected heteroatoms as ring members fused to an unsaturated ring having 6 or 7 ring atoms and 0 to 4 independently selected heteroatoms as ring members; or

[0184] R2 comprises -T-(CH2)m- Qi -(CH2)n-Z; m and n independently comprises an integer from 0 to about 7;

[0185] T comprises a carbocyclic ring having 3 to about 8 ring members, an unsaturated ring having 3 to about 8 carbon atoms as ring members, an aromatic ring having 5 to about 8 carbon atoms as ring members, a heterocyclic ring having 3 to about 8 ring members, a heteroaromatic ring having 5 to about 8 ring members, a bicyclic ring, a heterobicyclic ring, a tricyclic ring, a heterotricyclic ring, a polycyclic ring or a heteropolycyclic ring;

[0186] Qi comprises NH, 0, S, CH=CH, C=C, CO, SO2 or OSO2; and

[0187] Z comprises, H, halogen, CF3, CF2H, N3, NCS, CN, NO2, NX1X2, 0X3, SX3, OAc, OSO2X3, 0-acyl, S-acyl, SO2-alkyl, SO-alkyl, SC(CH3)2COOX8, OC(CH3)2COOX8, C(CH3)2COOX8, Si(alkyl)3, alkyl-CN, O-aroyl, O(CH2)jOX3, O(CH2)jNXiX2, NH- acyl, NH-aroyl, CHO, C(halogen)3, C00X3, SO3H, SO2NX1X2, CONX1X2, NHC(O)O- alkyl, NHS02-alkyl, alkoxy, alkyl, alcohol, alkylmercapto, alkylamino, di-alkylamino, alkylsulfinyl or alkylsulfonyl, CX4X5X6, -CH=CHXs , -C=CX8;

[0188] Xi and X2 each independently comprise H or alkyl, or

[0189] Xi and X2 together comprise part of a heterocyclic ring having about 4 to about 7 ring members and optionally one additional heteroatom selected from 0, N or S, or Xi and X2 together comprise part of an imide ring having about 5 to about 6 members,

[0190] X3 comprises H, alkyl, aryl, NO2, (CH2)mCN, hydroxyloweralkyl, or alkyl-NXiX2,

[0191] X4, Xs, and Xe each independently comprise H, alkyl, carbocyclic ring, hydroxyloweralkyl, alkyl-OH, halogen, CN, SNO, S(SO2)alkyl, NX1X2, COOX3, CONX3, OX7, or O-alkyl-X? wherein

[0192] X7comprises H, alkyl, NO2, NO, P(O)(OX8)2, PH(O)(OX8), S(O)kN(alkyl)2, S(O)kX8, S(O)kOX8, COOXs, CONXs, SO3H, COXs, wherein

[0193] X8comprises H, alkyl, carbocyclic ring, heterocyclic ring, aromatic ring, heteroaromatic ring, or -CXg=CHXio wherein

[0194] X9 and X10 each independently comprise H or alkyl

[0195] Wherein m is an integer from 0 to 7 j is an integer from 0 to about 6, k is an integer from 0 to about 2; or

[0196] R2 comprises -T-(CH2)m- Qi -(CH2)n-Z; m and n independently comprises an integer from 0 to about 7;

[0197] T comprises a carbocyclic ring having 3 to about 8 ring members, an unsaturated ring having 3 to about 8 carbon atoms as ring members, an aromatic ring having 5 to about 8 carbon atoms as ring members, a heterocyclic ring having 3 to about 8 ring members, a heteroaromatic ring having 5 to about 8 ring members, a bicyclic ring, a heterobicyclic ring, a tricyclic ring, a heterotricyclic ring, a polycyclic ring or a heteropolycyclic ring;

[0198] Qi comprises NH, 0, S, CH=CH, C=C, CO, SO2 or OSO2; and

[0199] Z comprises a carbocyclic ring having about 4 to about 7 ring members, a heterocyclic ring having about 4 to about 7 ring members, an aromatic ring having about 5 to about 7 ring members, a heteroaromatic ring having about 5 to about 7 ring members, a bicyclic ring, a heterobicyclic ring, a polycyclic ring, a heteropolycyclic ring; or any above group substituted on at least one available ring atom by an alkyl group; or any above group substituted on at least one available ring nitrogen atom by a benzyl group, a substituted benzyl group, an alkoxybenzyl group, a substituted alkoxybenzyl group, a benzhydryl group or a substituted benzhydryl group; and wherein the connecting point between the -(CH2)n- group and the Z group can be any available ring carbon atom or any available ring nitrogen atom; or

[0200] R2 comprises -T-(CH2)m- Qi -(CH2)n-Z; m and n independently comprises an integer from 0 to about 7;

[0201] T comprises a carbocyclic ring having 3 to about 8 ring members, an unsaturated ring having 3 to about 8 carbon atoms as ring members, an aromatic ring having 5 to about 8 carbon atoms as ring members, a heterocyclic ring having 3 to about 8 ring members, a heteroaromatic ring having 5 to about 8 ring members, a bicyclic ring, a heterobicyclic ring, a tricyclic ring, a heterotricyclic ring, a polycyclic ring or a heteropolycyclic ring;

[0202] Qi comprises NH, 0, S, CH=CH, C=C, CO, SO2 or OSO2; and

[0203] Z comprises 1 -, 2- or 3-pyrrolidinyl, 1 -, 2-, 3- or 4-piperidinyl, 2-, 3- or 4- morpholinyl, 2-, 3- or 4-thiomorpholinyl, 1 -, 2- or 3-azetidinyl, 1 - or 2-piperazinyl, 2- or 3-tetrahydrofuranyl; or any above group substituted on at least one available ring atom by an alkyl group; or any above group substituted on at least one available ring nitrogen atom by a benzyl group, a substituted benzyl group, an alkoxybenzyl group, a substituted alkoxybenzyl group, a benzhydryl group or a substituted benzhydryl group; and wherein the connecting point between the -(CH2)n- group and the Z group can be any available ring carbon atom or any available ring nitrogen atom; or

[0204] R2 comprises -T-(CH2)m- Qi -(CH2)n-Z; m and n independently comprises an integer from 0 to about 7;

[0205] T comprises a carbocyclic ring having 3 to about 8 ring members, an unsaturated ring having 3 to about 8 carbon atoms as ring members, an aromatic ring having 5 to about 8 carbon atoms as ring members, a heterocyclic ring having 3 to about 8 ring members, a heteroaromatic ring having 5 to about 8 ring members, a bicyclic ring, a heterobicyclic ring, a tricyclic ring, a heterotricyclic ring, a polycyclic ring or a heteropolycyclic ring;

[0206] Qi comprises N, 0, S, CH=CH, C=C, CO, SO2 or OSO2; and Z comprises wherein X and Y each independently comprise

[0207] H, halogen, CF3, CF2H, N3, NCS, CN, NO2, NX1X2, OX3, SX3, OAc, OSO2X3, 0- acyl, S-acyl, SO2-alkyl, SO-alkyl, SC(CH3)2COOX8, OC(CH3)2COOX8, C(CH3)2COOX8, Si(alkyl)3, alkyl-CN, O-aroyl, O(CH2)jOX3, O(CH2)jNXiX2, NH- acyl, NH-aroyl, CHO, C(halogen)3, COOX3, SO3H, SO2NX1X2, CONX1X2, NHC(O)O- alkyl, NHSO2-alkyl, alkoxy, alkyl, alcohol, alkylmercapto, alkylamino, di-alkylamino, alkylsulfinyl or alkylsulfonyl, CX4X5X6, -CH=CHXs , -C=CX8;

[0208] Xi and X2 each independently comprise H or alkyl, or

[0209] Xi and X2together comprise part of a heterocyclic ring having about 4 to about 7 ring members and optionally one additional heteroatom selected from 0, N or S, or

[0210] Xi and X2 together comprise part of an imide ring having about 5 to about 6 members,

[0211] X3comprises H, alkyl, aryl, NO2, (CH2)mCN, hydroxyloweralkyl, or alkyl-NXiX2,

[0212] X4, Xs, and Xe each independently comprise H, alkyl, carbocyclic ring, hydroxyloweralkyl, alkyl-OH, halogen, CN, SNO, S(SO2)alkyl, NX1X2, COOX3, CONX3, OX7, or O-alkyl-X? wherein

[0213] X7comprises H, alkyl, NO2, NO, P(O)(OX8)2, PH(O)(OXs), S(O)kN(alkyl)2, S(O)kX8, S(O)kOX8, COOXs, CONXs, SO3H, COXs, wherein

[0214] X8comprises H, alkyl, carbocyclic ring, heterocyclic ring, aromatic ring, heteroaromatic ring, or -CXg=CHXio wherein

[0215] X9 and X10 each independently comprise H or alkyl Wherein m is an integer from 0 to 7 j is an integer from 0 to about 6, k is an integer from 0 to about 2

[0216] W comprises H or alkyl; or

[0217] R2 comprises -T-(CH2)m- Qi -(CH2)n-Z; m and n independently comprises an integer from 0 to about 7;

[0218] T comprises a carbocyclic ring having 3 to about 8 ring members, an unsaturated ring having 3 to about 8 carbon atoms as ring members, an aromatic ring having 5 to about 8 carbon atoms as ring members, a heterocyclic ring having 3 to about 8 ring members, a heteroaromatic ring having 5 to about 8 ring members, a bicyclic ring, a heterobicyclic ring, a tricyclic ring, a heterotricyclic ring, a polycyclic ring or a heteropolycyclic ring;

[0219] Qi comprises NH, 0, S, CH=CH, C=C, CO, SO2 or OSO2; and

[0220] Z comprises an unsaturated ring having 5 ring atoms and 0 to 2 independently selected heteroatoms as ring members fused to an unsaturated ring having 5 ring atoms and 0 to 2 independently selected heteroatoms as ring members, an unsaturated ring having 5 ring atoms and 0 to 2 independently selected heteroatoms as ring members fused to an unsaturated ring having 6 or 7 ring atoms and 0 to 4 independently selected heteroatoms as ring members or an unsaturated ring having 6 ring atoms and 0 to 3 independently selected heteroatoms as ring members fused to an unsaturated ring having 6 or 7 ring atoms and 0 to 4 independently selected heteroatoms as ring members, or

[0221] R2 comprises -T-(CH2)m- Qi -(CH2)n-Z;

[0222] T comprises a carbocyclic ring having 3 to about 8 ring members, an unsaturated ring having 3 to about 8 carbon atoms as ring members, an aromatic ring having 5 to about 8 carbon atoms as ring members, a heterocyclic ring having 3 to about 8 ring members, a heteroaromatic ring having 5 to about 8 ring members, a bicyclic ring, a heterobicyclic ring, a tricyclic ring, a heterotricyclic ring, a polycyclic ring or a heteropolycyclic ring; m and n independently comprises an integer from 0 to about 7; Qi comprises NH, 0, S, CH=CH, C=C, CO, SO2 or OSO2; and Z comprises:

[0223] E comprises a C1 to about C4, linear or branched alkyl group, a phenyl group, a substituted phenyl group, a benzyl group or a substituted benzyl group; or

[0224] R2 comprises -T-(CH2)m- Qi -(CH2)n-Z;

[0225] T comprises a carbocyclic ring having 3 to about 8 ring members, an unsaturated ring having 3 to about 8 carbon atoms as ring members, an aromatic ring having 5 to about 8 carbon atoms as ring members, a heterocyclic ring having 3 to about 8 ring members, a heteroaromatic ring having 5 to about 8 ring members, a bicyclic ring, a heterobicyclic ring, a tricyclic ring, a heterotricyclic ring, a polycyclic ring or a heteropolycyclic ring; m and n independently comprises an integer from 0 to about 7;

[0226] Qi comprises NH, 0, S, CH=CH, C=C, CO, SO2 or OSO2;

[0227] Z comprises k is an integer from 1 to about 5,

[0228] R3 comprises wherein G comprises CH, C(CH3), C(CN) or N,

[0229] L, K and J each independently comprise (CH2)n, (CHs)2, C=O, 0, -CHOH, C(CH3)0MI , C(CH2)n(X)Y, NM1, SO2, SO, or S, n is an integer from 0 to about 7;

[0230] Mi is H, alkyl, C(0)M2 where

[0231] M2 is H, alkyl, NM3M4, OMs and M3, M4 and Ms are independently H, OH or alkyl and X and Y each independently comprise, H, halogen, CF3, CF2H, N3, NCS, CN, NO2, NX1X2, OX3, SX3, OAc, OSO2X3, O-acyl, S-acyl, SO2-alkyl, SO-alkyl, SC(CH3)2COOX8, OC(CH3)2COOX8 , C(CH3)2COOX8, Si(alkyl)3, alkyl-CN, 0- aroyl, O(CH2)jOX3, O(CH2)jNXiX2, NH-acyl, NH-aroyl, CHO, C(halogen)3, COOX3, SO3H, SO2NX1X2, CONX1X2, NHC(O)O-alkyl, NHS02-alkyl, alkoxy, alkyl, alcohol, alkylmercapto, alkylamino, di-alkylamino, alkylsulfinyl or alkylsulfonyl, CX4X5X6, - CH=CHX8, -C^CXs ;

[0232] Xi and X2 each independently comprise H or alkyl, or

[0233] Xi and X2 together comprise part of a heterocyclic ring having about 4 to about 7 ring members and optionally one additional heteroatom selected from 0, N or S, or

[0234] Xi and X2 together comprise part of an imide ring having about 5 to about 6 members,

[0235] X3 comprises H, alkyl, NO2, (CH2)mCN, hydroxyloweralkyl, or alkyl-NXiX2,

[0236] X4, Xs, and Xe each independently comprise H, alkyl, carbocyclic ring, hydroxyloweralkyl, alkyl-OH, halogen, CN, SNO, S(S02)alkyl, NX1X2, COOX3, CONX3, OX7, or O-alkyl-X? wherein

[0237] X7comprises H, alkyl, NO2, NO, P(O)(OX8)2, PH(O)(OXs), S(O)kN(alkyl)2, S(0)kX8, S(O)kOX8, C00X8, CONXs, SO3H, C0X8, wherein

[0238] Xs comprises H, alkyl, carbocyclic ring, heterocyclic ring, aromatic ring, heteroaromatic ring, or -CXg=CHXio wherein

[0239] X9 and X10 each independently comprise H or alkyl

[0240] Wherein m is an integer from 0 to 7 j is an integer from 0 to about 6, or k is an integer from 0 to about 2;

[0241] R4 comprises

[0242] H, halogen, CF3, CF2H, N3, NCS, CN, NO2, NX1X2, OH, ONO2, SX3, OAc, OSO2X3, O-acyl, S-acyl, SO2-alkyl, SO-alkyl, SC(CH3)2COOX8, OC(CH3)2COOX8 , C(CH3)2COOX8, Si(alkyl)3, alkyl-CN, O-aroyl, O(CH2)jOX3, O(CH2)jNXiX2, NH- acyl, NH-aroyl, CHO, C(halogen)3, COOX3, SO3H, SO2NXIX2, CONXiX2, NHC(O)O- alkyl, NHSO2-alkyl, alkoxy, alkyl, alcohol, alkylmercapto, alkylamino, di-alkylamino, alkylsulfinyl or alkylsulfonyl, CX4X5X6, -CH=CHX8, -C=CX8;

[0243] Xi and X2each independently comprise H or alkyl, or

[0244] Xi and X2together comprise part of a heterocyclic ring having about 4 to about 7 ring members and optionally one additional heteroatom selected from 0, N or S, or

[0245] Xi and X2together comprise part of an imide ring having about 5 to about 6 members,

[0246] X3comprises H, alkyl, N02, (CH2)mCN, hydroxyloweralkyl, or alkyl-NXiX2,

[0247] X4, Xs, and Xe each independently comprise H, alkyl, carbocyclic ring, hydroxyloweralkyl, alkyl-OH, halogen, CN, SNO, S(SO2)alkyl, NXiX2, COOX3, CONX3, OX7, or O-alkyl-X? wherein

[0248] X7 comprises H, alkyl, N02, NO, P(O)(OX8)2, PH(O)(OXs), S(O)kN(alkyl)2, S(O)kX8, S(O)kOX8, COOXs, CONXs, SO3H, C0X8, wherein

[0249] X8comprises H, alkyl, carbocyclic ring, heterocyclic ring, aromatic ring, heteroaromatic ring, or -CXg=CHXio wherein

[0250] X9 and X10 each independently comprise H or alkyl

[0251] Wherein m is an integer from 0 to 7 j is an integer from 0 to about 6, or k is an integer from 0 to about 2; or

[0252] R4 comprises a carbocyclic ring having about 4 to about 7 ring members, a heterocyclic ring having about 4 to about 7 ring members, an aromatic ring having about 5 to about 7 ring members, a heteroaromatic ring having about 5 to about 7 ring members, a bicyclic ring, a heterobicyclic ring, a tricyclic ring, a heterotricyclic ring, a polycyclic ring or a heteropolycyclic ring; or

[0253] R4 comprises

[0254]

[0255] R4 comprises -(CH2)d-Z; d is an integer from 1 to about 6;

[0256] Z comprises H, halogen, CF3, CF2H, N3, NCS, CN, NO2, NX1X2, OX3, SX3, OAc, OSO2X3, O-acyl, S-acyl, SO2-alkyl, SO-alkyl, SC(CH3)2COOX8, OC(CH3)2COOX8, C(CH3)2COOX8, Si(alkyl)3, alkyl-CN, O-aroyl, O(CH2)jOX3, O(CH2)jNXiX2, NH- acyl, NH-aroyl, CHO, C(halogen)3, COOX3, SO3H, SO2NXIX2, CONX1X2, NHC(O)O- alkyl, NHSO2-alkyl, alkoxy, alkyl, alcohol, alkylmercapto, alkylamino, di-alkylamino, alkylsulfinyl or alkylsulfonyl, CX4X5X6, -CH=CHX8, -C=CX8;

[0257] Xi and X2each independently comprise H or alkyl, or

[0258] Xi and X2together comprise part of a heterocyclic ring having about 4 to about 7 ring members and optionally one additional heteroatom selected from 0, N or S, or

[0259] Xi and X2together comprise part of an imide ring having about 5 to about 6 members,

[0260] X3comprises H, alkyl, NO2, (CH2)mCN, hydroxyloweralkyl, or alkyl-NXiX2,

[0261] X4, Xs, and Xe each independently comprise H, alkyl, carbocyclic ring, hydroxyloweralkyl, alkyl-OH, halogen, CN, SNO, S(SO2)alkyl, NX1X2, C00X3, CONX3, OX7, or O-alkyl-X?, wherein

[0262] X7comprises H, alkyl, NO2, NO, P(O)(OX8)2, PH(O)(OX8), S(O)kN(alkyl)2, S(O)kX8, S(O)kOX8, COOXs, CONXs, SO3H, COXS, wherein

[0263] X8comprises H, alkyl, carbocyclic ring, heterocyclic ring, aromatic ring, heteroaromatic ring, or -CX9=CHXIO, wherein

[0264] X9 and X10 each independently comprise H or alkyl, m is an integer from 0 to 7, j is an integer from 0 to about 6, k is an integer from 0 to about 2; or

[0265] R4 comprises -(CH2)d-Z; d is an integer from 1 to about 6; and

[0266] Z comprises a carbocyclic ring having about 4 to about 7 ring members, a heterocyclic ring having about 4 to about 7 ring members, an aromatic ring having about 5 to about 7 ring members, a heteroaromatic ring having about 5 to about 7 ring members, a bicyclic ring, a heterobicyclic ring, a tricyclic ring, a heterotricyclic ring, a polycyclic ring, a heteropolycyclic ring; or any above group substituted on at least one available ring atom by an alkyl group; or any above group substituted on at least one available ring nitrogen atom by a benzyl group, a substituted benzyl group, an alkoxybenzyl group, a substituted alkoxybenzyl group, a benzhydryl group or a substituted benzhydryl group; and wherein the_connecting point between the -(CH2)d- group and the Z group can be any available ring carbon atom or any available ring nitrogen atom; or

[0267] R4 comprises -(CH2)d-Z; d is an integer from 1 to about 6; and

[0268] Z comprises 1-, 2- or 3-pyrrolidinyl, 1-, 2-, 3- or 4-piperidinyl, 2-, 3- or 4-morpholinyl, 2-, 3- or 4-thiomorpholinyl, 1 -, 2- or 3-azetidinyl, 1 - or 2-piperazinyl, 2- or 3- tetrahydrofuranyl; or any above group substituted on at least one ring atom by an alkyl group; or any above group substituted on at least one available ring nitrogen atom by a benzyl group, a substituted benzyl group, an alkoxybenzyl group, a substituted alkoxybenzyl group, a benzhydryl group or a substituted benzhydryl group; and wherein the connecting point between the -(CH2)d- group and the Z group can be any available ring carbon atom or any available ring nitrogen atom; or

[0269] R4 comprises -(CH2 )m - Qi -(CH2)n-Z;

[0270] Qi comprises NH, 0, S, CH=CH, C=C, CO, SO2 or OSO2; m is an integer from 1 to about 7; n is an integer from 0 to about 7; and

[0271] Z comprises

[0272] H, halogen, CF3, CF2H, N3, NCS, CN, NO2, NX1X2, OX3, SX3, OAc, OSO2X3, O-acyl, S-acyl, SO2-alkyl, SO-alkyl, SC(CH3)2COOX8, OC(CH3)2COOX8, C(CH3)2COOX8, Si(alkyl)3, alkyl-CN, O-aroyl, O(CH2)JOX3, O(CH2)jNXiX2, NH-acyl, NH-aroyl, CHO, C(halogen)3, COOX3, SO3H, SO2NX1X2, CONX1X2, NHC(O)O-alkyl, NHSO2-alkyl, alkoxy, alkyl, alcohol, alkylmercapto, alkylamino, di-alkylamino, alkylsulfinyl or alkylsulfonyl, CX4X5X6, -CH=CHXs , -C=CX8;

[0273] Xi and X2each independently comprise H or alkyl, or

[0274] Xi and X2together comprise part of a heterocyclic ring having about 4 to about 7 ring members and optionally one additional heteroatom selected from 0, N or S, or

[0275] Xi and X2together comprise part of an imide ring having about 5 to about 6 members,

[0276] X3comprises H, alkyl, N02, (CH2)mCN, hydroxyloweralkyl, or alkyl-NXiX2,

[0277] X4, Xs, and Xe each independently comprise H, alkyl, carbocyclic ring, hydroxyloweralkyl, alkyl-OH, halogen, CN, SNO, S(SO2)alkyl, NX1X2, C00X3, C0NX3, OX7, or O-alkyl-X? wherein

[0278] X7comprises H, alkyl, N02, NO, P(O)(OX8)2, PH(O)(OXs), S(O)kN(alkyl)2, S(0)kX8, S(O)kOX8, COOXs, CONXs, SO3H, COXS, wherein

[0279] X8comprises H, alkyl, carbocyclic ring, heterocyclic ring, aromatic ring, heteroaromatic ring, or -CXg=CHXio, wherein

[0280] X9 and X10 each independently comprise H or alkyl, wherein m is an integer from 0 to 7, j is an integer from 0 to about 6, k is an integer from 0 to about 2; or

[0281] R4 comprises -(CH2)m- Qi -(CH2)n-Z;

[0282] Qi comprises NH, 0, S, CH=CH, C=C, CO, S02or 0S02; m is an integer from 1 to about 7; n is an integer from 0 to about 7; and Z comprises a carbocyclic ring having about 4 to about 7 ring members, a heterocyclic ring having about 4 to about 7 ring members, an aromatic ring having about 5 to about 7 ring members, a heteroaromatic ring having about 5 to about 7 ring members; a bicyclic ring, a heterobicyclic ring, a tricyclic ring, a heterotricyclic ring, a polycyclic ring, a heteropolycyclic ring; or any above group substituted on at least one available ring atom by an alkyl group; or any above group substituted on at least one available ring nitrogen atom by a benzyl group, _a substituted benzyl group, an alkoxybenzyl group, a substituted alkoxybenzyl group, a benzhydryl group or a substituted benzhydryl group; and wherein the connecting point between the -(CH2)n- group and the Z group can be any available ring carbon atom or any available ring nitrogen atom; or

[0283] R4 comprises -(CH2)m - Qi -(CH2)n-Z;

[0284] Qi comprises NH, 0, S, CH=CH, C=C, CO, SO2 or OSO2; m is an integer from 1 to about 7; n is an integer from 0 to about 7; and

[0285] Z comprises 1-, 2- or 3-pyrrolidinyl, 1-, 2-, 3- or 4-piperidinyl, 2-, 3- or 4-morpholinyl, 2-, 3- or 4-thiomorpholinyl, 1 -, 2- or 3-azetidinyl, 1 - or 2-piperazinyl, 2- or 3- tetrahydrofuranyl; or any above group substituted on at least one available ring atom by an alkyl; or any above group substituted on at least one available ring nitrogen atom by a benzyl group, a substituted benzyl group, an alkoxybenzyl group, a substituted alkoxybenzyl group, a benzhydryl group or a substituted benzhydryl group; and wherein the connecting point between the -(CH2)n- group and the Z group can be any available ring carbon atom or any available ring nitrogen atom; or

[0286] R4 comprises -(CH2)m - Qi -(CH2)n-Z;

[0287] Qi comprises NH, 0, S, CH=CH, C=C, CO, SO2 or OSO2; m is an integer from 1 to about 7; n is an integer from 0 to about 7; and

[0288] Z comprises

[0289] wherein X and Y each independently comprise

[0290] H, halogen, CF3, CF2H, N3, NCS, CN, NO2, NX1X2, OX3, SX3, OAc, OSO2X3, O-acyl, S-acyl, SO2-alkyl, SO-alkyl, SC(CH3)2COOX8, OC(CH3)2COOX8, C(CH3)2COOX8, Si(alkyl)3, alkyl-CN, O-aroyl, O(CH2)jOX3, O(CH2)jNXiX2, NH-acyl, NH-aroyl, CHO, C(halogen)3, COOX3, SO3H, SO2NX1X2, CONX1X2, NHC(O)O-alkyl, NHSO2-alkyl, alkoxy, alkyl, alcohol, alkylmercapto, alkylamino, di-alkylamino, alkylsulfinyl or alkylsulfonyl, CX4X5X6, -CH=CHX8, -C=CX8;

[0291] Xi and X2each independently comprise H or alkyl, or

[0292] Xi and X2 together comprise part of a heterocyclic ring having about 4 to about 7 ring members and optionally one additional heteroatom selected from 0, N or S, or

[0293] Xi and X2 together comprise part of an imide ring having about 5 to about 6 members,

[0294] X3comprises H, alkyl, NO2, (CH2)mCN, hydroxyloweralkyl, or alkyl-NXiX2,

[0295] X4, Xs, and Xe each independently comprise H, alkyl, carbocyclic ring, hydroxyloweralkyl, alkyl-OH, halogen, CN, SNO, S(SO2)alkyl, NX1X2, C00X3, CONX3, OX7, or O-alkyl-X? wherein

[0296] X7comprises H, alkyl, NO2, NO, P(O)(OX8)2, PH(O)(OX8), S(O)kN(alkyl)2, S(O)kX8, S(O)kOX8, COOX8, CONXs, SO3H, COXS, wherein

[0297] X8comprises H, alkyl, carbocyclic ring, heterocyclic ring, aromatic ring, heteroaromatic ring, or -CXg=CHXio wherein

[0298] X9 and X10 each independently comprise H or alkyl

[0299] Wherein m is an integer from 0 to 7 j is an integer from 0 to about 6, k is an integer from 0 to about 2, W comprises H or alkyl.

[0300] A variation of formula I comprises cannabimimetic imidazole ligands represented by Formula II and their pharmaceutically acceptable salts, solvates, hydrates, polymorphs, enantiomers, diastereomers, geometric isomers, racemates, tautomers, rotamers, atropisomers, isotopic variations comprising at least one deuterium atom, or N-oxides thereof:

[0301] II

[0302] A variation of Formula I comprises cannabimimetic thiazole and oxazole ligands represented by Formula III and their and their pharmaceutically acceptable salts, solvates, hydrates, polymorphs, enantiomers, diastereomers, geometric isomers, racemates, tautomers, rotamers, atropisomers, isotopic variations comprising at least one deuterium atom, or N-oxides thereof:

[0303] III

[0304] A variation of Formula I comprises cannabimimetic triazole ligands represented by Formula IV and their and their pharmaceutically acceptable salts, solvates, hydrates, polymorphs, enantiomers, diastereomers, geometric isomers, racemates, tautomers, rotamers, atropisomers, isotopic variations comprising at least one deuterium atom, or N-oxides thereof:

[0305] A variation of Formula I comprises cannabimimetic pyrazoline or chiral dihydropyrazole ligands represented by Formula V and their and their pharmaceutically acceptable salts, solvates, hydrates, polymorphs, enantiomers, diastereomers, geometric isomers, racemates, tautomers, rotamers, atropisomers, isotopic variations comprising at least one deuterium atom, or N-oxides thereof:

[0306] V

[0307] A variation of Formula I comprises cannabimimetic pyrazoline or chiral dihydropyrazole ligands represented by Formula VI and their and their pharmaceutically acceptable salts, solvates, hydrates, polymorphs, enantiomers, diastereomers, geometric isomers, racemates, tautomers, rotamers, atropisomers, isotopic variations comprising at least one deuterium atom, or N-oxides thereof:

[0308] VI wherein R4a and R4b are each independently H, alkyl or halogen. A variation of Formula I comprises cannabimimetic pyrazole ligands represented by Formula VII and their and their pharmaceutically acceptable salts, solvates, hydrates, polymorphs, enantiomers, diastereomers, geometric isomers, racemates, tautomers, rotamers, atropisomers, isotopic variations comprising at least one deuterium atom, or N-oxides thereof:

[0309] A variation of Formula I comprises cannabimimetic pyrrolidinone ligands represented by Formula VIII and their and their pharmaceutically acceptable salts, solvates, hydrates, polymorphs, enantiomers, diastereomers, geometric isomers, racemates, tautomers, rotamers, atropisomers, isotopic variations comprising at least one deuterium atom, or N-oxides thereof:

[0310] VIII

[0311] The inventive compounds in any formula, embodiment or variation include any and all possible isomers and steroisomers. In general, the compositions of the invention may be alternately formulated to comprise, consist of, or consist essentially of, any appropriate components herein disclosed. The compositions of the invention may additionally, or alternatively, be formulated so as to be devoid, or substantially free, of any components, materials, ingredients, adjuvants or species used in the prior art compositions or that are otherwise not necessary to the achievement of the function and / or objectives of the present invention. Unless otherwise specifically defined, “acyl” refers to the general formula -C(O)alkyl.

[0312] Unless otherwise specifically defined, “acyloxy” refers to the general formula 0 acyl.

[0313] Unless otherwise specifically defined, “alcohol” refers to the general formula alkyl-OH and includes primary, secondary and tertiary variations.

[0314] Unless otherwise specifically defined, “alkyl” or “lower alkyl” refers to a linear, branched or cyclic alkyl group having from 1 to about 10 carbon atoms, and advantageously 1 to about 7 carbon atoms including, for example, methyl, ethyl, propyl, butyl, hexyl, octyl, isopropyl, isobutyl, tert-butyl, cyclopropyl, cyclohexyl, cyclooctyl, vinyl and allyl. The alkyl group can be saturated or unsaturated. The alkyl group can be unsubstituted, singly substituted or, if possible, multiply substituted, with substituent groups in any possible position. Unless otherwise specifically limited, a cyclic alkyl group includes monocyclic, bicyclic, tricyclic, tetracyclic and polycyclic rings, for example norbornyl, adamantyl and related terpenes.

[0315] Unless otherwise specifically defined, “alkoxy” refers to the general formula -O-alkyl.

[0316] Unless otherwise specifically defined, “alkylmercapto” refers to the general formula —S— alkyl.

[0317] Unless otherwise specifically defined, “alkylamino” refers to the general formula -(NH)-alkyl.

[0318] Unless otherwise specifically defined, “di-alkylamino” refers to the general formula -N-(alkyl)2. Unless otherwise specifically limited di-alkylamino includes cyclic amine compounds such as piperidine and morpholine.

[0319] Unless otherwise specifically defined, an aromatic ring is an unsaturated ring structure having about 5 to about 7 ring members and including only carbon as ring atoms. The aromatic ring structure can be unsubstituted, singly substituted or, if possible, multiply substituted, with substituent groups in any possible position.

[0320] Unless otherwise specifically defined, “aryl” refers to an aromatic ring system that includes only carbon as ring atoms, for example phenyl, biphenyl or naphthyl. The aryl group can be unsubstituted, singly substituted or, if possible, multiply substituted, with substituent groups in any possible position.

[0321] Unless otherwise specifically defined, “aroyl” refers to the general formula -C(=O)-aryl.

[0322] Unless otherwise specifically defined, a bicyclic ring structure comprises 2 fused or bridged rings that include only carbon as ring atoms. The bicyclic ring structure can be saturated or unsaturated. The bicyclic ring structure can be unsubstituted, singly substituted or, if possible, multiply substituted, with substituent groups in any possible position. The individual rings may or may not be of the same type. Examples of bicyclic ring structures include naphthalene and bicyclooctane.

[0323] Unless otherwise specifically defined, a carbocyclic ring is a non-aromatic ring structure, saturated or unsaturated, having about 3 to about 8 ring members that includes only carbon as ring atoms, for example, cyclohexadiene or cyclohexane. The carbocyclic ring can be unsubstituted, singly substituted or, if possible, multiply substituted, with substituent groups in any possible position.

[0324] Unless otherwise specifically defined, “halogen” refers to an atom selected from fluorine, chlorine, bromine and iodine.

[0325] Unless otherwise specifically defined, a heteroaromatic ring is an unsaturated ring structure having about 5 to about 8 ring members independently selected from carbon atoms and one or more heteroatoms, including oxygen, nitrogen and / or sulfur, for example, pyridine, furan, quinoline, and their derivatives. The heteroaromatic ring can be unsubstituted, singly substituted or, if possible, multiply substituted, with substituent groups in any possible position.

[0326] Unless otherwise specifically defined, a heterobicyclic ring structure comprises 2 fused or bridged rings having ring members independently selected from carbon and one or more heteroatoms, including oxygen, nitrogen and / or sulfur. The heterobicyclic ring structure can be saturated or unsaturated. The heterobicyclic ring can be unsubstituted, singly substituted or, if possible, multiply substituted, with substituent groups in any possible position. The individual rings may or may not be of the same type. Examples of heterobicyclic ring structures include isobenzofuran and indole. Unless otherwise specifically defined, a heterocyclic ring is a saturated or unsaturated ring structure having about 3 to about 8 ring members independently selected from carbon atoms and one or more heteroatoms, including oxygen, nitrogen and / or sulfur; for example, piperidine, morpholine, piperazine, pyrrolidine, thiomorpholine, 1 ,1 -dioxothiomorpholine and their derivatives. The heterocyclic ring can be unsubstituted, singly substituted or, if possible, multiply substituted, with substituent groups in any possible position.

[0327] Unless otherwise specifically defined, a heterotricyclic ring structure comprises 3 fused, bridged, or both fused and bridged rings having ring members independently selected from carbon and one or more heteroatoms, including oxygen, nitrogen and / or sulfur. The heterotricyclic ring structure may be saturated or unsaturated. The heterotricyclic ring structure can be unsubstituted, singly substituted or, if possible, multiply substituted, with substituent groups in any possible position. The individual rings may or may not be of the same type. Examples of heterotricyclic ring structures include carbazole, phenanthroline, phenazine, 2,4,10-trioxaadamantane and tetradecahydro-phenanthroline.

[0328] Unless otherwise specifically defined, a heteropolycyclic ring structure comprises more than 3 rings that may be fused, bridged or both fused and bridged and that have ring members independently selected from carbon and one or more heteroatoms, including oxygen, nitrogen and / or sulfur. The heteropolycyclic ring structure can be saturated or unsaturated. The heteropolycyclic ring structure can be unsubstituted, singly substituted or, if possible, multiply substituted, with substituent groups in any possible position. The individual rings may or may not be of the same type. Examples of heteropolycyclic ring structures include azaadamantine, tropane, homotropane and 5-norbomene-2,3-dicarboximide.

[0329] Unless otherwise specifically defined, the term “phenacyl” refers to the general formula -phenyl-acyl.

[0330] Unless otherwise specifically defined, a polycyclic ring structure comprises more than 3 rings that may be fused, bridged or both fused and bridged, and that includes carbon as ring atoms. The polycyclic ring structure can be saturated or unsaturated. The polycyclic ring structure can be unsubstituted, singly substituted or, if possible, multiply substituted, with substituent groups in any possible position. The individual rings may or may not be of the same type. Examples of polycyclic ring structures include adamantine, bicyclooctane, norbornane and bicyclononanes.

[0331] Unless otherwise specifically defined, a spirocycle refers to a ring system wherein a single atom is the only common member of two rings. A spirocycle can comprise a saturated carbocyclic ring comprising about 3 to about 8 ring members, a heterocyclic ring comprising about 3 to about 8 ring atoms wherein up to about 3 ring atoms may be N, S, or 0 or a combination thereof.

[0332] Unless otherwise specifically defined, a tricyclic ring structure comprises 3 rings that may be fused, bridged or both fused and bridged, and that includes carbon as ring atoms. The tricyclic ring structure can be saturated or unsaturated. The tricyclic ring structure can be unsubstituted, singly substituted or, if possible, multiply substituted, with substituent groups in any possible position, and may be substituted or unsubstituted. The individual rings may or may not be of the same type. Examples of tricyclic ring structures include fluorene and anthracene.

[0333] Unless otherwise specifically limited the term substituted means substituted by a below-described substituent group in any possible position. Substituent groups for the above moieties useful in the invention are those groups that do not significantly diminish the biological activity of the inventive compound. Substituent groups that do not significantly diminish the biological activity of the inventive compound include, for example, H, halogen, N3, NCS, CN, NO2, NX1X2, OX3, C(Xs)3, OAc, O-acyl, O-aroyl, NH-acyl, NH-aroyl, NHCOalkyl, CHO, C(halogen)3, COOX3, SO3H, PO3H2, SO2NX1X2, CONX1X2, alkyl, alcohol, alkoxy, alkylmercapto, alkylamino, dialkylamino, sulfonamide, thioalkoxy or methylene dioxy when the substituted structure has two adjacent carbon atoms, wherein Xi and X2 each independently comprise H or alkyl, or Xi and X2 together comprise part of a heterocyclic ring having about 4 to about 7 ring members and optionally one additional heteroatom selected from 0, N or S, or Xi and X2 together comprise part of an imide ring having about 5 to about 6 members and X3 comprises H, alkyl, hydroxyloweralkyl, or alkyl-NXiX2. Unless otherwise specifically limited a substituent group may be in any possible position. Some of the inventive compounds show a high affinity for at least one of the cannabinoid receptors. Thus, another aspect of the invention is use of at least one of the inventive compounds to interact with a cannabinoid receptor.

[0334] Some of the novel heteropyrrole derivatives show selectivity for the CB1 cannabinoid receptor. These inventive CB1 selective analogs are able to interact with the CB1 cannabinoid receptors present in the CNS as well as the periphery without affecting the CB2 receptors to the same degree. Therefore, still another aspect of the invention is use of at least one of the inventive compounds to preferentially interact with a CB1 cannabinoid receptors present either in the CNS or the periphery.

[0335] Another aspect of the invention is use of at least one of the inventive compounds to interact with both CB1 and CB2 cannabinoid receptors present either in the CNS or the periphery.

[0336] The inventive heteropyrrole analogs described herein, and physiologically acceptable salts thereof, have pharmacological properties when administered in therapeutically effective amounts for providing a physiological response. Thus, another aspect of the invention is the administration of a therapeutically effective amount of at least one of the inventive compounds, or a physiologically acceptable salt thereof, to an individual or animal to provide a physiological response.

[0337] The subject matter of this invention also discloses novel processes and methods to synthesize compounds.

[0338] A better understanding of the invention will be obtained from the following detailed description of the article and the desired features, properties, characteristics, and the relation of the elements as well as the process steps, one with respect to each of the others, as set forth and exemplified in the description, illustrative embodiments and examples.

[0339] BRIEF DESCRIPTION OF THE DRAWINGS

[0340] Figure 1 is a drawing depicting the chemical structures of compounds referred to herein as COMPOUNDS 1 , 2 and 3; Figure 2 shows the effects of COMPOUND 2 in the DID assay wherein ost hoc analysis revealed that two highest doses of COMPOUND 2 (3 and 10mg / kg) significantly reduced ethanol intake as compared to vehicle treatment in both males and females at 2-hour and 4-hour, post access;

[0341] Figure 3 shows the effects of acamprosate in the DID assay wherein Post hoc analysis revealed that the reduction in ethanol intake when using high doses of acamprosate (100, 200, 300 and 400 mg / kg) was significantly less when compared to that of COMPOUND 2 in both males and females at 2-hour and 4-hour, post access;

[0342] Figure 4 shows that COMPOUND 2 (3mg / kg) when administered repeatedly over a period of 21 days, produced a significant reduction in ethanol intake (g / kg) as compared to vehicle treatment over a period of three DID cycles;

[0343] Figure 5 shows that COMPOUND 2 (3 mg / kg and 10 mg / kg) produced a significant dose-related reduction in ethanol drinking per unit of body weight (gram / kilogram) in male and female mice at 2-hour, 4-hour and 24-hour, post access. Post-hoc analysis also showed that the highest two doses of COMPOUND 2 (3 mg / kg and 10 mg / kg) significantly increased water intake in both male and female mice as compared to vehicle treatment at 24-hour post ethanol access;

[0344] Figure 6 shows that acamprosate (100, 200, 300 and 400 mg / kg) produced a dose- related reduction in ethanol drinking per unit of body weight (gram / kilogram) in male and female mice, at 2-hour, 4-hour and 24-hour, post access. Post-hoc analysis also showed that the highest doses of acamprosate (100, 200, 300 and 400 mg / kg) did not increase water intake in both male and female mice as compared to vehicle treatment at 24-hour post ethanol access when compared to COMPOUND 2;

[0345] Figure 7 shows the blood ethanol content (BEC) for COMPOUND 3 (3 mg / kg) after 4- hour post access in male and female mice; Figure 8 shows that COMPOUND 2 (3 mg / kg and 10 mg / kg) produced a dose-related decrease in the Fl (fixed-interval) link of the chain schedule and produced a dose- related significant reduction in Fl responding in animals trained to self-administer ethanol + supersac solution under a chain FI-FR (fixed-interval-fixed-ratio) schedule. Additionally, as opposed to effects observed during the Fl link, all three doses of COMPOUND 2 (1 , 3, and 10 mg / kg) significantly reduced super sac solution containing ethanol self-administration as compared to vehicle;

[0346] Figure 9 shows that COMPOUND 2 can modulate ethanol withdrawal wherein COMPOUND 2 reduces the HIC scores in male mice and COMPOUND 2 produces non-statistical trend of reduction of HIC scores;

[0347] Figure 10 shows that COMPOUND 2 can modulate ethanol withdrawal wherein COMPOUND 2 reduces the HIC scores in female mice and COMPOUND 2 produces non-statistical trend of reduction of HIC scores; and

[0348] Figure 11 shows the graphical summary of the results wherein the average ethanol drinking (g / kg) in vehicle treated and COMPOUND 2 treated mice is shown across various drinking procedures.

[0349] DETAILED DESCRIPTION OF THE INVENTION

[0350] As used herein a "therapeutically effective amount" of a compound, is the quantity of a compound which, when administered to an individual or animal, results in a sufficiently high level of that compound in the individual or animal to cause a physiological response, for example a discernible increase or decrease in stimulation of cannabinoid receptors. The inventive compounds described herein, and physiologically acceptable salts thereof, have pharmacological properties when administered in therapeutically effective amounts individually or in combination for providing a physiological response useful to treat fibrosis of the liver, and related inflammatory conditions. Typically, a "therapeutically effective amount" of an inventive compound is believed to range from about 0.01 mg / day to about 1 ,000 mg / day.

[0351] As used herein, an "individual" refers to a human. An "animal" refers to, for example nonhuman-primates such as squirrel monkeys, rhesus monkeys, marmosets, baboons, veterinary animals, such as rodents, dogs, cats, horses and the like, and farm animals, such as cows, pigs and the like.

[0352] In certain embodiments, the compound disclosed in the invention can be used in combination with other acceptable pharmaceutical substances.

[0353] In embodiments in which compounds of the disclosure is used in combination with rimonabant (Accomplia, Sanofi-Aventis) or other CB1 antagonists or inberse agonists, it will be possible to reduce or even eliminate one or more of these sideeffects, particularly nausea. That is, it is possible to reduce the amount of Rimonabant or other CB1 antagonists administered to the individual who has had, is receiving or is about to receive a therapeutically effective amount of the compound of the disclosure. In one embodiment, the amount of rimonabant administered to the individual is reduced by 1.5 to 5-fold compared to the accepted therapeutic amount. The individual is then dosed with a therapeutically effective amount of at least one of the compounds of the disclosure. Of course, it is also possible to increase the length of time between doses of rimonabant with the same or similar effect.

[0354] Accordingly, one embodiment provides for a method for reducing unwanted sideeffects (one or more of nausea, dizziness, diarrhea, and anxiety) typically associated with administration of SR141716A (accompliaTM / rimonabant) or other CB1 antagonists or inverse agonists to certain individuals.

[0355] As will be apparent, the compounds of the invention can be used alone or in combination with disulfiram, acamprosate, naltrexone, nalmefene, topiramate, gabapentin, pregabalin, varenicline, baclofen, sodium oxybate, aripiprazole, ondansetron, quetiapine, duloxetine, venlafaxine, ondansetron, pexacerfont, Org- 25935, fenofibrate, memantine, oxytocin, ghrelin, orexin, varenicline, bupropion, cytisine / lobeline, ibudilast, suvorexant, prazosin, doxazosin, / V-acetylcysteine, tirzepatide, semaglutide, liraglutidein, A / -[(4-trifluoromethyl)benzyl]4- methoxybutyramide, 4-((6-(4,4-dimethylcyclohexyl)-2-methylthieno[2;3-c / ]pyrimidin-4- yl)methyl)thiomorpholine 1 ,1 -dioxide, ABT-436, 2-(2-methylimidazo[2, 7-b][1 ,3]thiazol- 6-yl)-1-{2-[(1 R)-5-(6-methylpyrimidin-4-yl)-2,3-dihydro-1 H-inden-1-yl]-2,7- diazaspiro[3.5]non-7-ylethanone, psilocybin, cannabidiol, and compounds that act via related biological mechanisms.

[0356] Compounds of the invention can also be used in combination with aldehyde dehydrogenase inhibitor, dopamine beta-hydroxylase inhibitor, modulator of glutamatergic activity, opioid receptor antagonist, opioid receptor antagonist and partial agonist, GABAB agonist, modulator of GABA activity, inhibitor of glutamatergic activity and modulator of GABA activity, nicotinic acetylcholine receptor agonist, dopamine receptor partial agonist and 5-HT2A receptor antagonist, 5-HT3 receptor antagonist, glucocorticoid receptor antagonist, selective phosphodiesterase inhibitor and macrophage migration inhibitory factor inhibitor, adrenergic alpha-1 antagonist, modulator of synaptic glutamatergic activity, dual orexin antagonist, vasopressin type 1 B receptor antagonist, gamma-hydroxy-butyrate analogue, negative allosteric modulator at mGluR5, positive allosteric modulator of GABAB receptor, ghrelin receptor inverse agonist, a potassium channel opener, anticonvulsant agent, contraceptive agent, antipsychotic agent, anticonstipation agent, nicotine receptor agonist or partial agonist, CB1 antagonist, CB1 or CB2 agonist, melaninconcentrating hormone receptor antagonist, an anti-psychotic agent, a peroxisome proliferator-activated receptor modulator, an inhibitor of the BET (bromodomain and extra terminal) domain protein, nitric oxide synthase inhibitor, a farnesoid X receptor agonists, a ghrelin antagonist, a GLP-1 agonist, a fatty acid amide hydrolase inhibitor, an intestinal-acting microsomal triglyceride transfer protein inhibitor, a dipeptidyl-peptidase IV inhibitor, an angiotensin-converting-enzyme inhibitor, a statin, a sterol absorption inhibitor, a beta-3 adrenergic agonist, a biguanide, a sodium glucose transport antagonist, a CCR2 and CCR5 receptor antagonists, a cyclooxygenase-2 inhibitor, a renin inhibitor, a monoamine oxidase inhibitor, a CETP inhibitor, a ACAT inhibitor, a DGAT-1 inhibitor, a mitochondrial transfer protein inhibitor, a noradrenalin-serotonin-dopamine reuptake inhibitor or a lipase inhibitor.

[0357] In one embodiment, less than five compounds of the disclosure, preferably one or two of same is used in combination with less than five of the known CB1 antagonists, preferably one or two of same.

[0358] By “physiologically acceptable salts” is meant, salts typically useful for pharmaceutical applications including acid addition salts and basic salts. Examples of acid addition salts are hydrochloride salts, hydrobromide salts, methane sulfonate salts etc. Examples of basic salts are salts where the cation is selected from alkali metals, such as sodium and potassium, alkaline earth metals, such as calcium, and ammonium ions. Other examples of physiologically acceptable salts can be found in "Remington's Pharmaceutical Sciences" 17. Ed. Alfonso R. Gennaro (Ed.), Mark Publishing Company, Easton, Pa., U.S.A., 1985 and more recent editions, and in Encyclopedia of Pharmaceutical Technology.

[0359] Polymorphic forms show improved physiochemical properties and stability. In one embodiment, the compounds disclosed in the invention could exist in various solid forms. The solid forms can be crystalline and amorphous forms, but not limited to, solvates, hydrates, hydrolyzable esters and N-oxides of the compounds defined in the specification. These solid forms can be obtained by treating either the free base or their salts at a certain adjusted pH and certain temperature with an solvent or a combination of solvents. The solvents can be and not limited to a hydrocarbon solvent such as toluene, xylene, hexanes, heptane, or petroleum ether, alcohol such as methanol, ethanol, n-butanol, n-propanol and 2-propanol, di-isopropyl ether, ethylacetate, dichloromethane, acetic acid, acetone, tetrahydrofuran, dichloromethane, and water. In one embodiment, in order to improve the dehepaticability of the compound disclosed in the present invention for the required physiological effect, a “pro-drug” of the same can be made available. For example, the pro-drug can be a obtained by conjugation of the parent drug with polyethylene glycol(PEG).

[0360] In one embodiment, the compounds in the present invention could exist as enantiomers, diastereomers, geometric isomers, racemates, tautomers, rotamers, atropisomers or metabolites.

[0361] In some embodiments, the compounds have at least one fluorine atom incorporated at or adjacent to a site that is susceptible to metabolism. The fluorine atom can be part or adjacent to a substituent group as defined.

[0362] In one embodiment, some compounds disclosed in the invention can be “neutral antagonists”. These agents are said to have no effect on intrinsic receptor activity at least in certain test systems. However, these agents may be able to block receptor binding and activation, usually by a competitive agonist.

[0363] In some embodiments, it would be desirable to have “neutral” antagonists that exhibit essentially no constitutive CB1 receptor activity and which block or significantly reduce receptor activation induced by a suitable agonist. It would be further desirable to have neutral antagonists of the CB1 receptor that can be used to prevent, treat, or reduce the severity of symptoms of certain medical conditions. It would be especially desirable to have neutral antagonists that exhibit no or minimal side-effects in vivo.

[0364] In another embodiment, the compound disclosed in the present invention may act preferentially at the CB1 receptors located in the periphery. In certain embodiments, the compounds do not penetrate the blood-brain-barrier, have restricted penetration or have slow or delayed penetration. In certain embodiments, peripherally acting compounds that are excluded from the CNS may have advantages over centrally acting compounds, for example, reduced adverse effects including psychiatric effects such as anxiety and depression, diarrhea, nausea, vomiting, anhedonia and reduced water intake.

[0365] A compound acting on the CB1 receptors located in the periphery could be behave either as a neutral antagonist or an inverse agonist.

[0366] A compound acting on the CB1 receptors located centrally, could behave as a neutral antagonist or an inverse agonist.

[0367] In another embodiment, the compounds disclosed in the invention could act either as neutral antagonists or as inverse agonists with no or reduced side effects.

[0368] The CB1 cannabinoid receptor binding affinities (Ki) for some of the compounds disclosed in the invention range between 0.1 nM and less than 100 nM. For example, CB1 cannabinoid receptor binding affinity (Ki) for compound 1 is 1 nM and the CB2 cannabinoid receptor binding affinity (Ki) is greater than 1000 nM. The CB1 selectivity for some of the compounds range from 5 to greater than 5000.

[0369] The compounds of the present invention can be administered by a variety of known methods, including orally, rectally, or by parenteral routes (e g., intramuscular, intravenous, subcutaneous, nasal or topical). The form in which the compounds are administered will be determined by the route of administration. Such forms include, mixtures for oral and rectal administration, liquid mixtures for oral, intravenous, intramuscular, subcutaneous, ocular, intranasal, inhalation-based and transdermal administration and slow microcarriers for rectal, intramuscular or intravenous administration. Suitable physiologically acceptable vehicles for inclusion with mixtures include, for example, saline, sterile water, Ringer's solution and isotonic sodium chloride solutions. The specific dosage level of active ingredient will depend upon a number of factors, including, for example, biological activity of the particular preparation, age, body weight, sex and general health of the individual being treated. In another embodiment, the compounds of the present disclosure can also comprise isotopes at one or more of their atoms. For example, the compounds can be radiolabeled with isotopes, such as2H (deuterium written as D).

[0370] In some embodiments, the compounds have at least one deuterium atom incorporated at or adjacent to a site that is susceptible to metabolism. The deuterium atom can be part or adjacent to a substituent group as defined.

[0371] As used herein, an "inflammatory condition" refers to a condition involving hepatic disease or acute and chronic pancreatitis.

[0372] In a particular embodiment, the hepatic disease may be alcoholic or non-alcoholic steatohepatitis.

[0373] In a particular embodiment, the hepatic disease may be alcoholic or non-alcoholic cirrhosis.

[0374] In a particular embodiment, the hepatic disease may be liver cancer.

[0375] In a particular embodiment, the "inflammatory condition" can be relate to fibrosis of the liver or pancreas.

[0376] In a particular embodiment, fibrosis can be a condition related to the liver, or pancreas.

[0377] An "animal" refers to, for example nonhuman-primates such as squirrel monkeys, rhesus monkeys, marmosets, baboons, veterinary animals, such as rodents, dogs, cats, horses and the like, and farm animals, such as cows, pigs and the like.

[0378] Several embodiments of the invention are further described in the Specification. It will be recognized that one or more features of any embodiments disclosed herein may be combined and / or rearranged within the scope of the invention to produce further embodiments that are also within the scope of the invention.

[0379] Still other objects and advantages of the invention will become apparent by those of skill in the art from the disclosure herein, which are simply illustrative and not restrictive. Thus, other embodiments will be recognized by the ordinarily skilled artisan without departing from the spirit and scope of the invention.

[0380] In some embodiments, the following compounds are effective at treating alcohol misuse, alcohol addiction alcohol dependency, alcohol-use disorders, and especially for reducing voluntary ethanol intake and seeking: 5-[4-(4-Cyano-but-1-ynyl)-phenyl]- 1-(2,4-dichloro-phenyl)-4-methyl-1 H-pyrazole-3-carboxylic acid morpholin-4-ylamide (Compound 2);

[0381] 5-[4-(4-Cyano-but-1 -yny l)-phenyl]-1 -(2,4-dichloro-phenyl)-4-methyl-1 H-pyrazole-3- carboxylic acid piperidin-1-ylamide (Compound 3);

[0382] 1 -(2,4-Dichloro-phenyl)-5-[4-(4-hydroxy-but-1 -ynyl)-phenyl]-4-methyl-1 H-pyrazole-3- carboxylic acid piperidin-1-ylamide;

[0383] 1 -(2,4-Dichloro-phenyl)-5-[4-(4-fluoro-but-1 -ynyl)-phenyl]-4-methyl-1 H-pyrazole-3- carboxylic acid piperidin-1-ylamide;

[0384] 1 -(2,4-Dichloro-phenyl)-4-methyl-5-[4-(4-nitrooxy-but-1 -ynyl)-phenyl]-1 H-pyrazole-3- carboxylic acid piperidin-1-ylamide;

[0385] 5-[4-(4-Cyano-but-1 -ynyl)-phenyl]-1 -(2,4-dichloro-phenyl)-4-ethyl-1 H-pyrazole-3- carboxylic acid piperidin-1-ylamide;

[0386] 1 -(2,4-Dichloro-phenyl)-4-ethyl-5-[4-(4-hydroxy-but-1 -ynyl)-phenyl]-1 H-pyrazole-3- carboxylic acid piperidin-1-ylamide;

[0387] 1 -(2,4-Dichloro-phenyl)-4-ethyl-5-[4-(4-fluoro-but-1 -yny l)-pheny l]-1 H-pyrazole-3- carboxylic acid piperidin-1-ylamide;

[0388] 1 -(2,4-Dichloro-phenyl)-4-ethyl-5-[4-(4-nitrooxy-but-1 -yny l)-pheny l]-1 H-pyrazole-3- carboxylic acid piperidin-1-ylamide;

[0389] 1 -(2,4-Dichloro-phenyl)-5-[4-(4-hydroxy-but-1 -ynyl)-phenyl]-4-methyl-1 H-pyrazole-3- carboxylic acid morpholin-4-ylamide; 1 -(2,4-Dichloro-phenyl)-5-[4-(4-fluoro-but-1 -ynyl)-phenyl]-4-methyl-1 H-pyrazole-3- carboxylic acid morpholin-4-ylamide;

[0390] 1 -(2,4-Dichloro-phenyl)-4-methyl-5-[4-(4-nitrooxy-but-1 -yny l)-phenyl]-1 H-pyrazole-3- carboxylic acid morpholin-4-ylamide;

[0391] 1 -(2,4-Dichloro-phenyl)-4-ethyl-5-[4-(4-nitrooxy-but-1 -ynyl)-phenyl]-1 H-pyrazole-3- carboxylic acid morpholin-4-ylamide;

[0392] 1 -(2,4-Dichloro-phenyl)-4-ethyl-5-[4-(4-fluoro-but-1 -ynyl)-phenyl]-1 H-pyrazole-3- carboxylic acid morpholin-4-ylamide;

[0393] 1 -(2,4-Dichloro-phenyl)-4-ethyl-5-[4-(4-hydroxy-but-1 -yny l)-pheny l]-1 H-pyrazole-3- carboxylic acid morpholin-4-ylamide;

[0394] 5-[4-(4-Cyano-but-1 -ynyl)-phenyl]-1 -(2,4-dichloro-phenyl)-4-ethyl-1 H-pyrazole-3- carboxylic acid morpholin-4-ylamide;

[0395] 5-[4-(4-Cyano-but-1 -ynyl)-phenyl]-1 -(2,4-dichloro-phenyl)-4-methyl-1 H-pyrazole-3- carboxylic acid (1 ,1-dioxo-1A6-thiomorpholin-4-yl)-amide;

[0396] 1 -(2,4-Dichloro-phenyl)-5-[4-(4-hydroxy-but-1 -ynyl)-phenyl]-4-methyl-1 H-pyrazole-3- carboxylic acid (1 ,1-dioxo-1 A6-thiomorpholin-4-yl)-amide;

[0397] 1 -(2,4-Dichloro-phenyl)-5-[4-(4-fluoro-but-1 -ynyl)-phenyl]-4-methyl-1 H-pyrazole-3- carboxylic acid (1 ,1-dioxo-1 A66-thiomorpholin-4-yl)-amide;

[0398] 1 -(2,4-Dichloro-phenyl)-4-methyl-5-[4-(4-nitrooxy-but-1 -ynyl)-phenyl]-1 H-pyrazole-3- carboxylic acid (1 ,1-dioxo-1 A6-thiomorpholin-4-yl)-amide;

[0399] 1 -(2,4-Dichloro-phenyl)-4-ethyl-5-[4-(4-nitrooxy-but-1 -ynyl)-phenyl]-1 H-pyrazole-3- carboxylic acid (1 ,1-dioxo-1 A6-thiomorpholin-4-yl)-amide;

[0400] 1 -(2,4-Dichloro-phenyl)-4-ethyl-5-[4-(4-fluoro-but-1 -ynyl)-phenyl]-1 H-pyrazole-3- carboxylic acid (1 ,1-dioxo-1 A6-thiomorpholin-4-yl)-amide;

[0401] 1 -(2,4-Dichloro-phenyl)-4-ethyl-5-[4-(4-hydroxy-but-1 -ynyl)-phenyl]-1 H-pyrazole-3- carboxylic acid (1 ,1-dioxo-1 A6-thiomorpholin-4-yl)-amide;

[0402] 5-[4-(4-Cyano-but-1 -ynyl)-phenyl]-1 -(2,4-dichloro-phenyl)-4-ethyl-1 H-pyrazole-3- carboxylic acid (1 ,1-dioxo-1 A6-thiomorpholin-4-yl)-amide;

[0403] 5-[4-(5-Cyano-pent-1 -ynyl)-phenyl]-1 -(2,4-dichloro-phenyl)-4-ethyl-1 H-pyrazole-3- carboxylic acid piperidin-1-ylamide; 1 -(2,4-Dichloro-phenyl)-4-ethyl-5-[4-(5-hydroxy-pent-1 -ynyl)-phenyl]-1 H-pyrazole-3- carboxylic acid piperidin-1-ylamide;

[0404] 1 -(2,4-Dichloro-phenyl)-4-ethyl-5-[4-(5-fluoro-pent-1 -yny l)-pheny l]-1 H-pyrazole-3- carboxylic acid piperidin-1-ylamide;

[0405] 1 -(2,4-Dichloro-phenyl)-4-ethyl-5-[4-(5-nitrooxy-pent-1 -ynyl)-phenyl]-1 H-pyrazole-3- carboxylic acid piperidin-1-ylamide;

[0406] 1 -(2,4-Dichloro-phenyl)-4-ethyl-5-[4-(5-nitrooxy-pent-1 -ynyl)-phenyl]-1 H-pyrazole-3- carboxylic acid morpholin-4-ylamide;

[0407] 1 -(2,4-Dichloro-phenyl)-4-ethyl-5-[4-(5-fluoro-pent-1 -ynyl)-phenyl]-1 H-pyrazole-3- carboxylic acid morpholin-4-ylamide;

[0408] 1 -(2,4-Dichloro-phenyl)-4-ethyl-5-[4-(5-hydroxy-pent-1 -yny l)-pheny l]-1 H-pyrazole-3- carboxylic acid morpholin-4-ylamide;

[0409] 5-[4-(5-Cyano-pent-1 -ynyl)-phenyl]-1 -(2,4-dichloro-phenyl)-4-ethyl-1 H-pyrazole-3- carboxylic acid morpholin-4-ylamide;

[0410] 5-[4-(5-Cyano-pent-1 -ynyl)-phenyl]-1 -(2,4-dichloro-phenyl)-4-ethyl-1 H-pyrazole-3- carboxylic acid (1 ,1-dioxo-1 A6-thiomorpholin-4-yl)-amide;

[0411] 1 -(2,4-Dichloro-phenyl)-4-ethyl-5-[4-(5-fluoro-pent-1 -yny l)-pheny l]-1 H-pyrazole-3- carboxylic acid (1 ,1-dioxo-1 A6-thiomorpholin-4-yl)-amide;

[0412] 1 -(2,4-Dichloro-phenyl)-4-ethyl-5-[4-(5-hydroxy-pent-1 -ynyl)-phenyl]-1 H-pyrazole-3- carboxylic acid (1 ,1-dioxo-1 A6-thiomorpholin-4-yl)-amide;

[0413] 1 -(2,4-Dichloro-phenyl)-4-ethyl-5-[4-(5-nitrooxy-pent-1 -ynyl)-phenyl]-1 H-pyrazole-3- carboxylic acid (1 ,1-dioxo-1 A6-thiomorpholin-4-yl)-amide;

[0414] 1 -(2,4-Dichloro-phenyl)-4-methyl-5-[4-(5-nitrooxy-pent-1 -ynyl)-phenyl]-1 H-pyrazole-3- carboxylic acid (1 ,1-dioxo-1 A6-thiomorpholin-4-yl)-amide;

[0415] 1 -(2,4-Dichloro-phenyl)-5-[4-(5-fluoro-pent-1 -ynyl)-phenyl]-4-methyl-1 H-pyrazole-3- carboxylic acid (1 ,1-dioxo-1 A6-thiomorpholin-4-yl)-amide;

[0416] 1 -(2,4-Dichloro-phenyl)-5-[4-(5-hydroxy-pent-1 -ynyl)-phenyl]-4-methyl-1 H-pyrazole-3- carboxylic acid (1 ,1-dioxo-1 A6-thiomorpholin-4-yl)-amide;

[0417] 5-[4-(5-Cyano-pent-1 -ynyl)-phenyl]-1 -(2,4-dichloro-phenyl)-4-methyl-1 H-pyrazole-3- carboxylic acid (1 ,1-dioxo-1 A6-thiomorpholin-4-yl)-amide; 5-[4-(5-Cyano-pent-1 -ynyl)-phenyl]-1 -(2,4-dichloro-phenyl)-4-methyl-1 H-pyrazole-3- carboxylic acid piperidin-1-ylamide;

[0418] 1 -(2,4-Dichloro-phenyl)-5-[4-(5-hydroxy-pent-1 -ynyl)-phenyl]-4-methyl-1 H-pyrazole-3- carboxylic acid piperidin-1-ylamide;

[0419] 1 -(2,4-Dichloro-phenyl)-5-[4-(5-fluoro-pent-1 -ynyl)-phenyl]-4-methyl-1 H-pyrazole-3- carboxylic acid piperidin-1-ylamide;

[0420] 1 -(2,4-Dichloro-phenyl)-4-methyl-5-[4-(5-nitrooxy-pent-1 -ynyl)-phenyl]-1 H-pyrazole-3- carboxylic acid piperidin-1-ylamide;

[0421] 1 -(2,4-Dichloro-phenyl)-4-methyl-5-[4-(5-nitrooxy-pent-1 -ynyl)-phenyl]-1 H-pyrazole-3- carboxylic acid morpholin-4-ylamide;

[0422] 1 -(2,4-Dichloro-phenyl)-5-[4-(5-hydroxy-pent-1 -ynyl)-phenyl]-4-methyl-1 H-pyrazole-3- carboxylic acid morpholin-4-ylamide;

[0423] 1 -(2,4-Dichloro-phenyl)-5-[4-(5-fluoro-pent-1 -ynyl)-phenyl]-4-methyl-1 H-pyrazole-3- carboxylic acid morpholin-4-ylamide;

[0424] 5-[4-(5-Cyano-pent-1 -ynyl)-phenyl]-1 -(2,4-dichloro-phenyl)-4-methyl-1 H-pyrazole-3- carboxylic acid morpholin-4-ylamide;

[0425] 5-[4-(5-Cyano-pent-1 -ynyl)-phenyl]-1 -(2,4-dichloro-phenyl)-4-hydroxymethyl-1 H- pyrazole-3-carboxylic acid piperidin-1-ylamide;

[0426] 1 -(2,4-Dichloro-phenyl)-4-hydroxymethyl-5-[4-(5-hydroxy-pent-1 -ynyl)-phenyl]-1 H- pyrazole-3-carboxylic acid piperidin-1-ylamide;

[0427] 1 -(2,4-Dichloro-phenyl)-5-[4-(5-fluoro-pent-1 -ynyl)-phenyl]-4-hydroxymethyl-1 H- pyrazole-3-carboxylic acid piperidin-1-ylamide;

[0428] 1 -(2,4-Dichloro-phenyl)-4-hydroxymethyl-5-[4-(5-nitrooxy-pent-1 -ynyl)-phenyl]-1 H- pyrazole-3-carboxylic acid piperidin-1-ylamide;

[0429] 1 -(2,4-Dichloro-phenyl)-4-hydroxymethyl-5-[4-(5-nitrooxy-pent-1 -yny l)-pheny l]-1 H- pyrazole-3-carboxylic acid morpholin-4-ylamide;

[0430] 1 -(2,4-Dichloro-phenyl)-4-hydroxymethyl-5-[4-(5-hydroxy-pent-1 -ynyl)-phenyl]-1 H- pyrazole-3-carboxylic acid morpholin-4-ylamide;

[0431] 1 -(2,4-Dichloro-phenyl)-5-[4-(5-fluoro-pent-1 -ynyl)-phenyl]-4-hydroxymethyl-1 H- pyrazole-3-carboxylic acid morpholin-4-ylamide; 5-[4-(5-Cyano-pent-1 -ynyl)-phenyl]-1 -(2,4-dichloro-phenyl)-4-hydroxymethyl-1 H- pyrazole-3-carboxylic acid morpholin-4-ylamide;

[0432] 5-[4-(5-Cyano-pent-1 -yny l)-pheny l]-1 -(2,4-dichloro-phenyl)-4-hydroxymethyl-1 H- pyrazole-3-carboxylic acid (1 , 1 -dioxo-1 A6-thiomorpholin-4-yl)-amide;

[0433] 1 -(2,4-Dichloro-phenyl)-4-hydroxymethyl-5-[4-(5-hydroxy-pent-1 -ynyl)-phenyl]-1 H- pyrazole-3-carboxylic acid (1 , 1 -dioxo-1 A6-thiomorpholin-4-yl)-amide;

[0434] 1 -(2,4-Dichloro-phenyl)-5-[4-(5-fluoro-pent-1 -ynyl)-phenyl]-4-hydroxymethyl-1 H- pyrazole-3-carboxylic acid (1 ,1-dioxo-1 A6-thiomorpholin-4-yl)-amide;

[0435] 1 -(2,4-Dichloro-phenyl)-4-hydroxymethyl-5-[4-(5-nitrooxy-pent-1 -yny l)-pheny l]-1 H- pyrazole-3-carboxylic acid (1 ,1-dioxo-1 A6-thiomorpholin-4-yl)-amide;

[0436] 5-[4-(4-Cyano-but-1 -ynyl)-phenyl]-1 -(2,4-dichloro-phenyl)-4-hydroxymethyl-1 H- pyrazole-3-carboxylic acid (1 ,1-dioxo-1 A6-thiomorpholin-4-yl)-amide;

[0437] 1 -(2,4-Dichloro-phenyl)-5-[4-(4-fluoro-but-1 -ynyl)-phenyl]-4-hydroxymethyl-1 H- pyrazole-3-carboxylic acid (1 , 1 -dioxo-1 A6-thiomorpholin-4-yl)-amide;

[0438] 1 -(2,4-Dichloro-phenyl)-5-[4-(4-hydroxy-but-1 -ynyl)-phenyl]-4-hydroxymethyl-1 H- pyrazole-3-carboxylic acid (1 ,1-dioxo-1 A6-thiomorpholin-4-yl)-amide;

[0439] 1 -(2,4-Dichloro-phenyl)-4-hydroxymethyl-5-[4-(4-nitrooxy-but-1 -ynyl)-phenyl]-1 H- pyrazole-3-carboxylic acid (1 ,1-dioxo-1 A6-thiomorpholin-4-yl)-amide;

[0440] 1 -(2,4-Dichloro-phenyl)-4-hydroxymethyl-5-[4-(4-nitrooxy-but-1 -yny l)-pheny l]-1 H- pyrazole-3-carboxylic acid piperidin-1-ylamide;

[0441] 1 -(2,4-Dichloro-phenyl)-5-[4-(4-fluoro-but-1 -ynyl)-phenyl]-4-hydroxymethyl-1 H- pyrazole-3-carboxylic acid piperidin-1-ylamide;

[0442] 1 -(2,4-Dichloro-phenyl)-5-[4-(4-hydroxy-but-1 -ynyl)-phenyl]-4-hydroxymethyl-1 H- pyrazole-3-carboxylic acid piperidin-1-ylamide;

[0443] 5-[4-(4-Cyano-but-1 -ynyl)-phenyl]-1 -(2,4-dichloro-phenyl)-4-hydroxymethyl-1 H- pyrazole-3-carboxylic acid piperidin-1-ylamide;

[0444] 5-[4-(4-Cyano-but-1 -ynyl)-phenyl]-1 -(2,4-dichloro-phenyl)-4-hydroxymethyl-1 H- pyrazole-3-carboxylic acid morpholin-4-ylamide;

[0445] 1 -(2,4-Dichloro-phenyl)-5-[4-(4-fluoro-but-1 -ynyl)-phenyl]-4-hydroxymethyl-1 H- pyrazole-3-carboxylic acid morpholin-4-ylamide; 1 -(2,4-Dichloro-phenyl)-5-[4-(4-hydroxy-but-1 -ynyl)-phenyl]-4-hydroxymethyl-1 H- pyrazole-3-carboxylic acid morpholin-4-ylamide;

[0446] 1 -(2,4-Dichloro-phenyl)-4-hydroxymethyl-5-[4-(4-nitrooxy-but-1 -ynyl)-phenyl]-1 H- pyrazole-3-carboxylic acid morpholin-4-ylamide;

[0447] 1-[4-(4-Cyano-but-1 -ynyl)-phenyl]-2-(2,4-dichloro-phenyl)-5-methyl-1 H-imidazole-4- carboxylic acid piperidin-1-ylamide;

[0448] 2-(2,4-Dichloro-phenyl)-1 -[4-(4-fluoro-but-1 -ynyl)-phenyl]-5-methyl-1 H-imidazole-4- carboxylic acid piperidin-1-ylamide;

[0449] 2-(2,4-Dichloro-phenyl)-1 -[4-(4-hydroxy-but-1 -ynyl)-phenyl]-5-methyl-1 H-imidazole-4- carboxylic acid piperidin-1-ylamide;

[0450] 2-(2,4-Dichloro-phenyl)-5-methyl-1 -[4-(4-nitrooxy-but-1 -ynyl)-phenyl]-1 H-imidazole-4- carboxylic acid piperidin-1-ylamide;

[0451] 2-(2,4-Dichloro-phenyl)-5-methyl-1 -[4-(4-nitrooxy-but-1 -ynyl)-phenyl]-1 H-imidazole-4- carboxylic acid morpholin-4-ylamide;

[0452] 2-(2,4-Dichloro-phenyl)-1 -[4-(4-hydroxy-but-1 -ynyl)-phenyl]-5-methyl-1 H-imidazole-4- carboxylic acid morpholin-4-ylamide;

[0453] 2-(2,4-Dichloro-phenyl)-1 -[4-(4-fluoro-but-1 -ynyl)-phenyl]-5-methyl-1 H-imidazole-4- carboxylic acid morpholin-4-ylamide;

[0454] 1-[4-(4-Cyano-but-1 -ynyl)-phenyl]-2-(2,4-dichloro-phenyl)-5-methyl-1 H-imidazole-4- carboxylic acid morpholin-4-ylamide;

[0455] 1-[4-(4-Cyano-but-1 -ynyl)-phenyl]-2-(2,4-dichloro-phenyl)-5-methyl-1 H-imidazole-4- carboxylic acid (1 ,1-dioxo-1 A6-thiomorpholin-4-yl)-amide;

[0456] 2-(2,4-Dichloro-phenyl)-1 -[4-(4-fluoro-but-1 -ynyl)-phenyl]-5-methyl-1 H-imidazole-4- carboxylic acid (1 ,1-dioxo-1 A6-thiomorpholin-4-yl)-amide;

[0457] 2-(2,4-Dichloro-phenyl)-1 -[4-(4-hydroxy-but-1 -ynyl)-phenyl]-5-methyl-1 H-imidazole-4- carboxylic acid (1 ,1-dioxo-1 A6-thiomorpholin-4-yl)-amide;

[0458] 2-(2,4-Dichloro-phenyl)-5-methyl-1 -[4-(4-nitrooxy-but-1 -ynyl)-phenyl]-1 H-imidazole-4- carboxylic acid (1 ,1-dioxo-1 A6-thiomorpholin-4-yl)-amide;

[0459] 2-(2,4-Dichloro-phenyl)-5-ethyl-1-[4-(4-nitrooxy-but-1 -ynyl)-phenyl]-1 H-imidazole-4- carboxylic acid (1 ,1-dioxo-1 A6-thiomorpholin-4-yl)-amide; 2-(2,4-Dichloro-phenyl)-5-ethyl-1-[4-(4-hydroxy-but-1 -ynyl)-phenyl]-1 H-imidazole-4- carboxylic acid (1 ,1-dioxo-1 A6-thiomorpholin-4-yl)-amide;

[0460] 2-(2,4-Dichloro-phenyl)-5-ethyl-1-[4-(4-fluoro-but-1-ynyl)-phenyl]-1 H-imidazole-4- carboxylic acid (1 ,1-dioxo-1 A6-thiomorpholin-4-yl)-amide;

[0461] 1-[4-(4-Cyano-but-1 -ynyl)-phenyl]-2-(2,4-dichloro-phenyl)-5-ethyl-1 H-imidazole-4- carboxylic acid (1 ,1-dioxo-1 A6-thiomorpholin-4-yl)-amide;

[0462] 1-[4-(4-Cyano-but-1 -ynyl)-phenyl]-2-(2,4-dichloro-phenyl)-5-ethyl-1 H-imidazole-4- carboxylic acid morpholin-4-ylamide;

[0463] 2-(2,4-Dichloro-phenyl)-5-ethyl-1-[4-(4-hydroxy-but-1 -ynyl)-phenyl]-1 H-imidazole-4- carboxylic acid morpholin-4-ylamide;

[0464] 2-(2,4-Dichloro-phenyl)-5-ethyl-1-[4-(4-fluoro-but-1-ynyl)-phenyl]-1 H-imidazole-4- carboxylic acid morpholin-4-ylamide;

[0465] 2-(2,4-Dichloro-phenyl)-5-ethyl-1-[4-(4-nitrooxy-but-1 -ynyl)-phenyl]-1 H-imidazole-4- carboxylic acid morpholin-4-ylamide;

[0466] 2-(2,4-Dichloro-phenyl)-5-ethyl-1-[4-(4-nitrooxy-but-1 -ynyl)-phenyl]-1 H-imidazole-4- carboxylic acid piperidin-1-ylamide;

[0467] 2-(2,4-Dichloro-phenyl)-5-ethyl-1-[4-(4-hydroxy-but-1 -ynyl)-phenyl]-1 H-imidazole-4- carboxylic acid piperidin-1-ylamide;

[0468] 2-(2,4-Dichloro-phenyl)-5-ethyl-1-[4-(4-fluoro-but-1-ynyl)-phenyl]-1 H-imidazole-4- carboxylic acid piperidin-1-ylamide;

[0469] 1-[4-(4-Cyano-but-1 -ynyl)-phenyl]-2-(2,4-dichloro-phenyl)-5-ethyl-1 H-imidazole-4- carboxylic acid piperidin-1-ylamide;

[0470] 1 -[4-(4-Cyano-but-1 -ynyl)-phenyl]-2-(2,4-dichloro-phenyl)-5-hydroxymethyl-1 H- imidazole-4-carboxylic acid piperid in-1 -ylamide;

[0471] 2-(2,4-Dichloro-phenyl)-1 -[4-(4-fluoro-but-1 -ynyl)-phenyl]-5-hydroxymethyl-1 H- imidazole-4-carboxylic acid piperidin-1 -ylamide;

[0472] 2-(2,4-Dichloro-phenyl)-1 -[4-(4-hydroxy-but-1 -ynyl)-phenyl]-5-hydroxymethyl-1 H- imidazole-4-carboxylic acid piperidin-1 -ylamide;

[0473] 2-(2,4-Dichloro-phenyl)-5-hydroxymethyl-1 -[4-(4-nitrooxy-but-1 -ynyl)-phenyl]-1 H- imidazole-4-carboxylic acid piperidin-1 -ylamide; 2-(2,4-Dichloro-phenyl)-5-hydroxymethyl-1 -[4-(4-nitrooxy-but-1 -ynyl)-phenyl]-1 H- imidazole-4-carboxylic acid morpholin-4-ylamide;

[0474] 2-(2,4-Dichloro-phenyl)-1 -[4-(4-hydroxy-but-1 -ynyl)-phenyl]-5-hydroxymethyl-1 H- imidazole-4-carboxylic acid morpholin-4-ylamide;

[0475] 2-(2,4-Dichloro-phenyl)-1 -[4-(4-fluoro-but-1 -ynyl)-phenyl]-5-hydroxymethyl-1 H- imidazole-4-carboxylic acid morpholin-4-ylamide;

[0476] 1 -[4-(4-Cyano-but-1 -ynyl)-phenyl]-2-(2,4-dichloro-phenyl)-5-hydroxymethyl-1 H- imidazole-4-carboxylic acid morpholin-4-ylamide;

[0477] 1 -[4-(4-Cyano-but-1 -ynyl)-phenyl]-2-(2,4-dichloro-phenyl)-5-hydroxymethyl-1 H- imidazole-4-carboxylic acid (1 ,1 -dioxo-1 A6-thiomorpholin-4-yl)-amide;

[0478] 2-(2,4-Dichloro-phenyl)-1 -[4-(4-fluoro-but-1 -ynyl)-phenyl]-5-hydroxymethyl-1 H- imidazole-4-carboxylic acid (1 ,1 -dioxo-1 A6-thiomorpholin-4-yl)-amide;

[0479] 2-(2,4-Dichloro-phenyl)-1 -[4-(4-hydroxy-but-1 -ynyl)-phenyl]-5-hydroxymethyl-1 H- imidazole-4-carboxylic acid (1 ,1 -dioxo-1 A6-thiomorpholin-4-yl)-amide;

[0480] 2-(2,4-Dichloro-phenyl)-5-hydroxymethyl-1 -[4-(4-nitrooxy-but-1 -ynyl)-phenyl]-1 H- imidazole-4-carboxylic acid (1 ,1 -dioxo-1 A6-thiomorpholin-4-yl)-amide;

[0481] 1-[4-(5-Cyano-pent-1-ynyl)-phenyl]-2-(2,4-dichloro-phenyl)-5-methyl-1 H-imidazole-4- carboxylic acid (1 ,1-dioxo-1 A6-thiomorpholin-4-yl)-amide;

[0482] 2-(2,4-Dichloro-phenyl)-1 -[4-(5-hydroxy-pent-1 -ynyl)-phenyl]-5-methyl-1 H-imidazole- 4-carboxylic acid (1 ,1 -dioxo-1 A6-thiomorpholin-4-yl)-amide;

[0483] 2-(2,4-Dichloro-phenyl)-1 -[4-(5-fluoro-pent-1-ynyl)-phenyl]-5-methyl-1 H-imidazole-4- carboxylic acid (1 ,1-dioxo-1 A6-thiomorpholin-4-yl)-amide;

[0484] 2-(2,4-Dichloro-phenyl)-5-methyl-1 -[4-(5-nitrooxy-pent-1-ynyl)-phenyl]-1 H-imidazole- 4-carboxylic acid (1 ,1 -dioxo-1 A6-thiomorpholin-4-yl)-amide;

[0485] 2-(2,4-Dichloro-phenyl)-5-ethyl-1-[4-(5-nitrooxy-pent-1-ynyl)-phenyl]-1 H-imidazole-4- carboxylic acid (1 ,1-dioxo-1 A6-thiomorpholin-4-yl)-amide;

[0486] 2-(2,4-Dichloro-phenyl)-5-ethyl-1-[4-(5-hydroxy-pent-1-ynyl)-phenyl]-1 H-imidazole-4- carboxylic acid (1 ,1-dioxo-1 A6-thiomorpholin-4-yl)-amide;

[0487] 2-(2,4-Dichloro-phenyl)-5-ethyl-1 -[4-(5-fluoro-pent-1 -ynyl)-phenyl]-1 H-imidazole-4- carboxylic acid (1 ,1-dioxo-1 l6-thiomorpholin-4-yl)-amide; 1-[4-(5-Cyano-pent-1-ynyl)-phenyl]-2-(2,4-dichloro-phenyl)-5-ethyl-1 H-imidazole-4- carboxylic acid (1 ,1-dioxo-1 l6-thiomorpholin-4-yl)-amide;

[0488] 1-[4-(5-Cyano-pent-1-ynyl)-phenyl]-2-(2,4-dichloro-phenyl)-5-methyl-1 H-imidazole-4- carboxylic acid piperidin-1-ylamide;

[0489] 2-(2,4-Dichloro-phenyl)-1 -[4-(5-fluoro-pent-1-ynyl)-phenyl]-5-methyl-1 H-imidazole-4- carboxylic acid piperidin-1-ylamide;

[0490] 2-(2,4-Dichloro-phenyl)-1 -[4-(5-hydroxy-pent-1 -ynyl)-phenyl]-5-methyl-1 H-imidazole- 4-carboxylic acid piperidin-1 -ylamide;

[0491] 2-(2,4-Dichloro-phenyl)-5-methyl-1 -[4-(5-nitrooxy-pent-1-ynyl)-phenyl]-1 H-imidazole- 4-carboxylic acid piperidin-1 -ylamide;

[0492] 2-(2,4-Dichloro-phenyl)-5-methyl-1 -[4-(5-nitrooxy-pent-1-ynyl)-phenyl]-1 H-imidazole- 4-carboxylic acid morpholin-4-ylamide;

[0493] 2-(2,4-Dichloro-phenyl)-1 -[4-(5-hydroxy-pent-1 -ynyl)-phenyl]-5-methyl-1 H-imidazole- 4-carboxylic acid morpholin-4-ylamide;

[0494] 2-(2,4-Dichloro-phenyl)-1 -[4-(5-fluoro-pent-1-ynyl)-phenyl]-5-methyl-1 H-imidazole-4- carboxylic acid morpholin-4-ylamide;

[0495] 1-[4-(5-Cyano-pent-1-ynyl)-phenyl]-2-(2,4-dichloro-phenyl)-5-methyl-1 H-imidazole-4- carboxylic acid morpholin-4-ylamide;

[0496] 1-[4-(5-Cyano-pent-1-ynyl)-phenyl]-2-(2,4-dichloro-phenyl)-5-ethyl-1 H-imidazole-4- carboxylic acid morpholin-4-ylamide;

[0497] 2-(2,4-Dichloro-phenyl)-5-ethyl-1 -[4-(5-fluoro-pent-1 -ynyl)-phenyl]-1 H-imidazole-4- carboxylic acid morpholin-4-ylamide;

[0498] 2-(2,4-Dichloro-phenyl)-5-ethyl-1-[4-(5-hydroxy-pent-1-ynyl)-phenyl]-1 H-imidazole-4- carboxylic acid morpholin-4-ylamide;

[0499] 2-(2,4-Dichloro-phenyl)-5-ethyl-1-[4-(5-nitrooxy-pent-1-ynyl)-phenyl]-1 H-imidazole-4- carboxylic acid morpholin-4-ylamide;

[0500] 2-(2,4-Dichloro-phenyl)-5-ethyl-1-[4-(5-nitrooxy-pent-1-ynyl)-phenyl]-1 H-imidazole-4- carboxylic acid piperidin-1-ylamide;

[0501] 2-(2,4-Dichloro-phenyl)-5-ethyl-1-[4-(5-hydroxy-pent-1-ynyl)-phenyl]-1 H-imidazole-4- carboxylic acid piperidin-1-ylamide; 2-(2 , 4-D ich loro-pheny l)-5-ethy 1-1 -[4-(5-fluoro-pent-1 -ynyl)-phenyl]-1 H-imidazole-4- carboxylic acid piperidin-1-ylamide; and 1-[4-(5-Cyano-pent-1-ynyl)-phenyl]-2-(2,4-dichloro-phenyl)-5-ethyl-1 H-imidazole-4- carboxylic acid piperidin-1-ylamide.

[0502] The disclosure is further illustrated by the following examples, which are not to be construed as limiting this disclosure in scope or spirit to the specific procedures described in this disclosure. It is to be understood that the examples are provided to illustrate certain embodiments and that no limitation to the scope of the disclosure is intended thereby. It is to be further understood that resort may be had to various other embodiments, modifications, and equivalents thereof which may suggest themselves to those skilled in the art without departing from the spirit of the present disclosure and / or scope of the appended claims.

[0503] EXAMPLES

[0504] Eight-week-old adult male and female C57BL / 6J mice (Jackson Laboratories, Bar Harbor, Maine) weighing between 20-25 g served as subjects in all Examples. Animals were singly housed for the entire duration of experiments in polycarbonate cages (28 x 17 x 12 cm) lined with corn cob bedding in a climate (22.1 ± 1 °C, 30 - 40 % humidity) controlled vivarium under a reverse 12-h light / dark cycle (lights off at 10.00 A.M.). Food (Purina LabDiet 5001 ) and tap water was available without restriction, except for 2, or 4 hours in the DID experiment wherein water bottles were replaced with ethanol bottles (see below). All experiments were approved by the Animal Care and Use Committees of Northeastern and Tufts Universities in accordance with the Guide for the care and use of laboratory animals, 8thedition (National Research Council, 2011 ).

[0505] COMPOUND 2 (5-(4-(4-cyanobut-1 -yn-1 -yl)pheny l)-1 -(2,4-dichlorophenyl)-4-methyl- / V-morpholino-1 / - / -pyrazole-3-carboxamide) was synthesized as per procedures described US8,084,451 and US8,293,211. On the day of the experiment a specific amount of COMPOUND 2 was weighed out, and dissolved in 4% DMSO, and 8% Tween-80 followed by slow addition of sterile 0.9% saline to make the drug suspension. Acamprosate Calcium (Biosynth International, Oakbrook Terrace, IL) was weighed and dissolved in sterile 0.9 % saline to prepare the final drug solution. Either of the drugs, or their corresponding vehicles were administered 20-45 mins prior to ethanol access. Both the drugs were administered intraperitoneally (i.p.) at a volume of 10 ml / kg.

[0506] Drinking in the Dark (DID) Model: Effects of COMPOUND 2 on reducing binge ethanol drinking was assessed using a repeated DID procedure. The experimental design for the DID procedure was adapted from a previous publication (Rhodes et al., 2005) and further modifications in the experimental design were made for accommodating drug injections in mice (Hwa et al., 2014). Each experimental cycle was performed over a period of four days. On each test day, three hours into the dark cycle, the water bottles were replaced with 50 ml polypropylene plastic centrifuge tubes (Fisher Scientific. Waltham, MA) containing 20 % w / v ethanol prepared by mixing 200 proof, anhydrous, >99.5% ethyl ethanol (Millipore Sigma, Billerica, MA) in tap water. Centrifuge tubes were sealed with pre-assembled rubber stoppers (5 1 , Ancare Corp., Bellmore, NY) fitted with double ball bearing sipper tubes (TD-100, Ancare Corp., Bellmore, NY). A drip cage with no animal present was used to record ethanol loss due to spillage from handling and evaporation. Ethanol loss in the control drip cage was subtracted from each animal’s ethanol intake. On test days 1 -3, mice were given access to ethanol for 2 hours. On test day 4, mice were weighed, and injected with the respective drug dose, or vehicle treatment 20 minutes prior to ethanol access. Ethanol intake was monitored at 2, and 4 hours after access on test day 4. The four test days were followed by three days of a washout period during which mice had no access to ethanol. The 7 days of testing comprised one DID cycle. In the current work, 6 DID cycles were conducted over a period of six weeks, wherein the first cycle consisted of habituation to drinking ethanol, and the second cycle included habituation to handling, and injections. Over the course of the next 4 DID sessions, mice (n=12 / group) were treated with counterbalanced doses of COMPOUND 2 (1 , 3, 10 mg / kg) and its respective vehicle (4% DMSO, 8 % Tween- 80). COMPOUND 2 or its respective vehicle was administered on the fourth day of each cycle. A separate group (n=12 / group) of mice was treated with counterbalanced doses of acamprosate (100, 200, 300, and 400 mg / kg) and its respective vehicle (0.9 % saline) administered across 7 DID cycles.

[0507] Assessment of tolerance to the effects of COMPOUND 2 upon repeated administration on binge drinking using the DID model:

[0508] Two separate groups of male C57BL / 6J mice (n=6 / group) underwent 5 repeated DID cycles (each cycle comprised of seven days with 4 days of ethanol access and 3 non-ethanol days). After two habituation sessions, starting with the third cycle, one group of mice received daily COMPOUND 2 (3 mg / kg) injections for three weeks and a second group of mice received daily vehicle injections for three weeks. COMPOUND 2 (3 mg / kg) or its vehicle were administered 20 minutes prior to ethanol access via the i.p. route of administration (10 mg / kg; volume of injection). Like the procedure described in the DID section (see above), mice had access to ethanol for 2 hours on days 1-3, and for 4 hours on day 4, during each DID cycle. For the remaining three days of the DID cycle animals received COMPOUND 2 (3 mg / kg) or vehicle injections but had no access to ethanol. Ethanol bottles were weighed at the end of the 2-hour post access to drinking on test days 1 -3; and on test day 4, ethanol bottles were weighed at 2-, and 4-hours post access to monitor ethanol intake.

[0509] Intermittent access alcohol (IAA) drinking model: To assess the effects of COMPOUND 2 on excessive ethanol drinking, animals were given 24 hour access to ethanol on an intermittent schedule. IAA drinking procedure was based on a method described by (Hwa et al., 2011 ; Hwa et al., 2014). Three hours into the dark cycle, mice (n=12 / group) were given access to two bottles with one containing 20% w / v ethanol mixed in drinking water and the other bottle containing tap water. Mice had access to ethanol for a period of 24 hours, three days a week (Tuesday, Thursday, and Friday) and the other four days (Wednesday, Friday, Sunday, and Monday) mice had access to two bottles of tap water; cage and bedding changes occurred on every Monday. The water and ethanol bottles along with the sipper tubes used in the IAA procedure were identical to the bottles, and sipper tubes used in the DID experiment. Animals were habituated to the IAA drinking procedure for 3 weeks till a stable drinking pattern was observed. From the fourth week onwards, animals were habituated to handling, and injection procedures on every ethanol day, with saline injections being administered 20 minutes prior to ethanol access. From the fifth week onwards, saline injections were replaced with vehicle injections (4 % DMSO and 8% Tween 80) administered 20 minutes prior to ethanol access. After 5 weeks of IAA drinking, mice were treated with counterbalanced doses of COMPOUND 2 (1 , 3, or 10 mg / kg) or acamprosate (100, 200, 300, or 400 mg / kg). Mice received drug injections once per week, and the remaining ethanol days were preceded by respective vehicle injections. Ethanol, and water bottles were weighed every 2, 4, and 24 hours to monitor ethanol, and water intake. A separate empty cage served as “drip cage” to record spillage as a result of handling and evaporation.

[0510] Blood ethanol concentration (BEC) measurements: Based on the findings (dose response, and time course results) in IAA, 3mg / kg COMPOUND 2 was most effective in reducing ethanol intake at 4 hour post access. Separate groups of mice (n=6 / group) were given access to ethanol for 4 weeks using the IAA procedure. Mice were then treated with 3 mg / kg COMPOUND 2 or its respective vehicle, 20 minutes prior to ethanol access. 4 hour post ethanol access trunk blood was collected, and immediately centrifuged at 10,000 g for 10 minutes. Separated supernatant plasma was then flash frozen and stored at -80 °C. Blood ethanol content (BEC) was then analyzed by injecting 5 pl of plasma into Analox AM1 analyzer (Analox Instruments, Sturbridge, UK).

[0511] Effects of COMPOUND 2 on reinforcing effects of ethanol: To assess the effects of COMPOUND 2 on reinforcing effects of ethanol, separate groups (n=12 / group) of mice were trained to self-administer supersac solution (4% glucose, and 0.125% saccharin) containing ethanol using a custom-built octagon apparatus as taught by Klaus A. Miczek et al., 2022; K. A. Miczek et al., 2022. The self-administration apparatus consisted of eight side panels made of plexiglass. One panel was installed with two nose poke response units and another separate panel was installed with a nose poke unit containing a trough for fluid delivery. Illumination of LED lights above the nose poke indicated the unit was active. In the beginning of the procedure mice were conditioned to respond on an active nose poke response unit using a chain Fl FR schedule of reinforcement. The response requirement for the initial Fl link of the chain schedule gradually increased from 0.1 minutes to 5 minutes. During each training session, the last poke on the Fl schedule was reinforced with access to the separate nose poke response unit equipped with a trough. Responding on the second link was reinforced according to an FR schedule with super sac solution. Once stable responding was established during 5 minutes Fl followed by FR1 reinforced with super sac solution animals were reinforced with 12% w / v ethanol mixed in super sac solution. The number of responses during FR1 schedule was adjusted for each mouse according to its body weight to deliver maximally 1.8g / kg of ethanol. After stable responding was observed during the chain Fl 5 [FR1 ] schedule, mice were adapted to vehicle injections for one week. Mice were then treated with counterbalanced doses of COMPOUND 2 (1 , 3, and 5.6 mg / kg) or its respective vehicle once a week. Animals were injected 20-45 minutes before the experiment. For reinforcement studies, the rate of responses as well as the amount of ethanol consumed were the dependent variables.

[0512] Effects of COMPOUND 2 on animals undergoing ethanol withdrawal: To examine effects of COMPOUND 2 on animals undergoing ethanol withdrawal, animals were subjected to drink ethanol under two experimental procedures, i.e., intermittent alcohol access (IAA); n=50 and continuous alcohol access (CAA); n=49. Experimental set up for IAA was similar to the one described above in the IAA drinking section. For animals drinking under the CAA procedure bottle containing 20% w / v ethanol, was available 24 hours on all days of the week along with an additional tap water bottle. Animals in IAA, and CAA groups were allowed to drink ethanol for eight weeks. Following this drinking period, animals were subjected to ethanol withdrawal once a week wherein instead of an ethanol bottle, animals received two bottles of water. Withdrawal was assessed in mice by measuring handling induced convulsions (HIC) which is a neurological sign of ethanol dependence(Goldstein, 1972; Goldstein & Pal, 1971 ). HIC scores were evaluated in mice 6-8 hours after removal of ethanol bottle, as it has been shown in the past that peak HIC occurs during this period of withdrawal (Hwa et al., 2015). HIC scores were assigned on an ordinal scale ranging from 0-4 with 0 showing no withdrawal and scores of greater than 3 indicating a full body tonic-clonic convulsion. Mice were treated with counterbalanced doses of COMPOUND 2 (1 , 3, and 5.6 mg / kg) or its respective vehicle 15-45 mins prior to undergoing HIC assessment.

[0513] Statistical Analysis: Ethanol intake is reported as per body weight (g / kg) for DID, IAA, CAA, and FI-FR procedures. Additionally, for the IAA procedure, ethanol intake is also reported as total ethanol consumed (ml). Water intake is also reported in the IAA procedure as total water consumed (ml). All the intake data reported here are based on bottle weights at 2, and 4 hours for DID, and an additional time point of 24 hours for IAA, and CAA. For ethanol reinforcement experiment, number of nose pokes during FI-FR sessions are reported as responses per minute. Data are expressed as mean ± standard error of mean (SEM). Ethanol intake (g / kg & ml), water intake (ml) ethanol intake over time (g / kg) in withdrawal experiment were analyzed using mixed effect model analysis, Dunnett’s post hoc comparison tests were performed when applicable (p< 0.05). FI-FR response data were analyzed for significant changes using one-way repeated measures ANOVA followed by Bonferroni’s post hoc analysis (p<0.05). Ethanol intake was analyzed by two-way repeated measures ANOVA followed by Holm-Sidak’s post hoc analysis (p<-0.005) when COMPOUND 2 was administered on a daily basis. To measure effects of COMPOUND 2 on HIC scores, two-way repeated measures ANOVA followed by Bonferroni’s post hoc analysis (p<0.05) was used. The comparison between BEC (vehicle vs. COMPOUND 2) was performed using Student’s t test. A simple linear regression (SLR) was performed to determine the relationship between ethanol intake and BEC.

Claims

CLAIMSWhat is claimed is:

1. A method of treating or reducing a condition chosen from one or more of alcohol abuse, alcohol addiction, alcohol dependency, alcohol-use disorders and related consequences in an animal or individual having that condition comprising: administering to the individual or animal a therapeutically effective amount of one or more compounds of Formula 1 and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, enantiomers, diastereomers, geometric isomers, racemates, tautomers, rotamers, atropisomers, isotopic variations including at least one deuterium atom, and N-oxides thereof:wherein: the 5-membered core ring system includes 0, 1 or 2 double bonds; any one of Z1 , Z2, Z3 and Z4 can be C, N, 0, S or >C(=O);A is N(R5) or a direct bond;B is optionally present, and if present is N(R5);R5 is hydrogen, OH, alkyl or substituted alkyl;Z5 is optionally present, and if present is >C(=O) or >C(alky I);R1 is - T- (CH2)m- Q - (CH2)n- Z, wherein each of m and n is independently an integer from 0 to 7;T is selected from an aromatic ring having 5 to 8 carbon atoms as ring members and a heteroaromatic ring having 5 to 8 ring members;Q is C=C;Z is selected from the group consisting of H, halogen, CF3, CF2H, N3, NCS, CN, NO2, NX1X2, OX3, SX3, OAc, OSO2X3, O-acyl, S-acyl, SO2-alkyl, SO-alkyl, SC(CH3)2COOX8, OC(CH3)2COOX8 , C(CH3)2COOX8, Si(alkyl)3, alkyl-CN, 0- aroyl, O(CH2)jOX3, O(CH2)jNXiX2, NH-acyl, NH-aroyl, CHO, C(halogen)3, COOX3, SO3H, SO2NXIX2, C0NXIX2, NHC(O)O-alkyl, NHS02-alkyl, alkoxy, alkyl, alcohol, alkylmercapto, alkylamino, di-alkylamino, alkylsulfinyl, alkylsulfonyl, -CX4X5X6, - CH=CHXs and -C=CX8, whereinXi and X2 are independently selected from H and alkyl, orXi and X2together comprise part of a heterocyclic ring having 4 to 7 ring members and optionally one additional heteroatom selected from 0, N and S, orXi and X2together comprise part of an imide ring having 5 to 6 members,X3 is selected from the group consisting of H, alkyl, NO2, (CH2)mCN, hydroxyloweralkyl, and alkyl-NXiX2, each of X4, X5, and Xe is independently selected from the group consisting of H, alkyl, carbocyclic ring, hydroxyloweralkyl, alkyl-OH, halogen, CN, SNO, S(SO2)alkyl, NX1X2, COOX3, CONX3, OX7, and O-alkyl-X7, whereinX7 is selected from the group consisting of H, alkyl, NO2, NO, P(O)(OX8)2, PH(0)(0X8), S(O)kN(alkyl)2, S(0)kX8, S(O)kOX8, COOXs, CONXs, SO3H, and COXs,Xs is selected from the group consisting of H, alkyl, carbocyclic ring, heterocyclic ring, aromatic ring, heteroaromatic ring, and -CXg=CHXw, wherein each of X9 and X10 is independently H or alkyl, m is an integer from 0 to 7, j is an integer from 0 to 6, k is an integer from 0 to 2; orR1 is -T-(CH2)m- Q -(CH2)n-Z; each of m and n is independently an integer from 0 to 7;T is an aromatic ring having 5 to 8 carbon atoms as ring members or a heteroaromatic ring having 5 to 8 ring members;Q is C=C; andZ is selected from the group consisting of a carbocyclic ring having 4 to 7 ring members, a heterocyclic ring having 4 to 7 ring members, an aromatic ring having 5 to 7 ring members, a heteroaromatic ring having 5 to 7 ring members, a bicyclic ring, a heterobicyclic ring, a tricyclic ring, a heterotricyclic ring, a polycyclic ring, and a heteropolycyclic ring; or any above group substituted on at least one available ring atom by an alkyl group; or any above group substituted on at least one available ring nitrogen atom by a benzyl group, a substituted benzyl group, an alkoxybenzyl group, a substituted alkoxybenzyl group, a benzhydryl group or a substituted benzhydryl group; and wherein the connecting point between the -(CH2)n- group and the Z group can be any available ring carbon atom or any available ring nitrogen atom; orR1 is -T-(CH2)m- Q -(CH2)n-Z; each of m and n is independently an integer from 0 to 7;T is an aromatic ring having 5 to 8 carbon atoms as ring members or a heteroaromatic ring having 5 to 8 ring members;Q is C=C; andZ is selected from the group consisting of 1 -, 2- or 3-pyrrolidinyl, 1 -, 2-, 3- or 4- piperidinyl, 2-, 3- or 4-morpholinyl, 2-, 3- or 4-thiomorpholinyl, 1 -, 2- or 3-azetidinyl, 1 - or 2-piperazinyl, and 2- or 3-tetrahydrofuranyl; or any above group substituted on at least one available ring atom by an alkyl group; or any above group substituted on at least one available ring nitrogen atom by a benzyl group, a substituted benzyl group, an alkoxybenzyl group, a substituted alkoxybenzyl group, a benzhydryl group or a substituted benzhydryl group; and wherein the connecting point between the -(CH2)n- group and the Z group can be any available ring carbon atom or any available ring nitrogen atom; orR1 is -T-(CH2)m- Q -(CH2)n-Z; each of m and n is independently an integer from 0 to 7;T is an aromatic ring having 5 to 8 carbon atoms as ring members or a heteroaromatic ring having 5 to 8 ring members;Q iss C=C; andZ is selected from the group consisting ofwherein each of X and Y each is independently selected from H, halogen, CF3, CF2H, N3, NCS, CN, NO2, NX1X2, OX3, SX3, OAc, OSO2X3, O-acyl, S-acyl, SO2- alkyl, SO-alkyl, SC(CH3)2COOX8, OC(CH3)2COOX8 , C(CH3)2COOX8, Si(alkyl)3, alkyl-CN, O-aroyl, O(CH2)jOX3, O(CH2)jNXiX2, NH-acyl, NH-aroyl, CHO, C(halogen)3, COOX3, SO3H, SO2NX1X2, CONX1X2, NHC(O)O-alkyl, NHSO2-alkyl, alkoxy, alkyl, alcohol, alkylmercapto, alkylamino, di-alkylamino, alkylsulfinyl, alkylsulfonyl, CX4X5X6, -CH=CHX8, and -C=CX8; each of Xi and X2 is independently H or alkyl, orXi and X2 together comprise part of a heterocyclic ring having 4 to 7 ring members and optionally one additional heteroatom selected from 0, N and S, orXi and X2 together comprise part of an imide ring having 5 to 6 members,X3 is selected from the group consisting of H, alkyl, NO2, (CH2)mCN, hydroxyloweralkyl, and alkyl-NXiX2, each of X4, X5, and Xe is independently selected from the group consisting of H, alkyl, carbocyclic ring, hydroxyloweralkyl, alkyl-OH, halogen, CN, SNO, S(SO2)alkyl, NX1X2, COOX3, CONX3, OX7, and O-alkyl-X7, whereinX7 is selected from the group consisting of H, alkyl, NO2, NO, P(O)(OXs)2, PH(O)(OX8), S(O)kN(alkyl)2, S(O)kX8, S(O)kOX8, COOXs, CONXs, and SO3H, COXs,Xs is selected from the group consisting of H, alkyl, carbocyclic ring, heterocyclic ring, aromatic ring, heteroaromatic ring, and -CX9=CHXIO,X9 and X10 each independently comprise H or alkyl, m is an integer from 0 to 7, j is an integer from 0 to 6, k is an integer from 0 to 2,W is H or alkyl; orR1 is - T- (CH2)m- Q -(CH2)n-Z; wherein each of m and n is independently an integer from 0 to 7;T is an aromatic ring having 5 to 8 carbon atoms as ring members or a heteroaromatic ring having 5 to 8 ring members;Q is C=C; andZ is selected from the group consisting of an unsaturated ring having 5 ring atoms and 0 to 2 independently selected heteroatoms as ring members fused to an unsaturated ring having 5 ring atoms and 0 to 4 independently selected heteroatoms as ring members, an unsaturated ring having 5 ring atoms and 0 to 2 independently selected heteroatoms as ring members fused to an unsaturated ring having 6 or 7 ring atoms and 0 to 4 independently selected heteroatoms as ring members, and an unsaturated ring having 6 ring atoms and 0 to 3 independently selected heteroatoms as ring members fused to an unsaturated ring having 6 or 7 ring atoms and 0 to 4 independently selected heteroatoms as ring members; orR1 is -T-(CH2)m- Q -(CH2)n-Z;T is an aromatic ring having 5 to 8 carbon atoms as ring members and a heteroaromatic ring having 5 to 8 ring members; each of m and n is independently an integer from 0 to 7;Q comprises C=C;wherein E is selected from the group consisting of a C1 to C4 linear or branched alkyl group, a phenyl group, a substituted phenyl group, a benzyl group and a substituted benzyl group; orR1 is -T-(CH2)m- Q -(CH2)n-Z;T is an aromatic ring having 5 to 8 carbon atoms as ring members or a heteroaromatic ring having 5 to 8 ring members; each of m and n is independently an integer from 0 to 7;Q is C=C; andZ is selected from the group consisting ofwherein k is an integer from 1 to 5,R2 is -(CH2)n-Z; n is an integer from 0 to 7; whereinZ is selected from the group consisting of H, halogen, CF3, CF2H, N3, NCS, CN, NO2, NXIX2, OX3, SX3, OAc, OSO2X3, O-acyl, S-acyl, SO2-alkyl, SO-alkyl, SC(CH3)2COOX8, OC(CH3)2COOX8 , C(CH3)2COOX8, Si(alkyl)3, alkyl-CN, O-aroyl, O(CH2)jOX3, O(CH2)jNXiX2, NH-acyl, NH-aroyl, CHO, C(halogen)3, COOX3, SO3H, SO2NXiX2, CONXIX2, NHC(O)O-alkyl, NHSO2-alkyl, alkoxy, alkyl, alcohol, alkylmercapto, alkylamino, di-alkylamino, alkylsulfinyl, alkylsulfonyl, CX4X5X6, - CH=CHX8, and -C^CXs; each of Xi and X2is independently H or alkyl, orXi and X2together comprise part of a heterocyclic ring having 4 to 7 ring members and optionally one additional heteroatom selected from 0, N and S, orXi and X2together comprise part of an imide ring having 5 to 6 members,X3 is selected from the group consisting of H, alkyl, aryl, N02, (CH2)mCN, hydroxyloweralkyl, and alkyl-NXiX2,each of X4, X5, and Xe is independently selected from the group consisting of H, alkyl, carbocyclic ring, hydroxyloweralkyl, alkyl-OH, halogen, CN, SNO, S(SO2)alkyl, NX1X2, COOX3, CONX3, OX7, and O-alkyl-X7, whereinX7 is selected from the group consisting of H, alkyl, NO2, NO, P(O)(OX8)2, PH(O)(OX8), S(O)kN(alkyl)2, S(O)kX8, S(O)kOX8, COOXs, CONX8, SO3H, and COX8, whereinX8is selected from the group consisting of H, alkyl, carbocyclic ring, heterocyclic ring, aromatic ring, heteroaromatic ring, and -CXg=CHXio wherein each of Xg and X10 is independently H or alkyl, m is an integer from 0 to 7, j is an integer from 0 to 6, k is an integer from 0 to 2; orR2 is -(CH2)n-Z; wherein n is an integer from 0 to 7; andZ is selected from the group consisting of a carbocyclic ring having 4 to 7 ring members, a heterocyclic ring having 4 to 7 ring members, an aromatic ring having 5 to 7 ring members, a heteroaromatic ring having 5 to 7 ring members, a bicyclic ring, a heterobicyclic ring, a tricyclic ring, a heterotricyclic ring, a polycyclic ring, and a heteropolycyclic ring; or any above group substituted on at least one available ring atom by an alkyl group; or any above group substituted on at least one available ring nitrogen atom by a benzyl group, a substituted benzyl group, an alkoxybenzyl group, a substituted alkoxybenzyl group, a benzhydryl group or a substituted benzhydryl group; and wherein the connecting point between the -(CH2)n- group and the Z group can be any available ring carbon atom or any available ring nitrogen atom; orR2 is -(CH2)n-Z; wherein n is an integer from 0 to 7; andZ is selected from the group consisting of a 5 member unsaturated ring having 0 to 4 independently selected heteroatoms as ring members, a substituted 5 member unsaturated ring having 0 to 4 independently selected heteroatoms as ring members,a 6 member aromatic ring having 0 to 5 independently selected heteroatoms as ring members or a substituted 6 member aromatic ring having 0 to 5 independently selected heteroatoms; and wherein the connecting point between the -(CH2)n- group and the Z group can be any available ring carbon atom or any available ring nitrogen atom; orR2 is -(CH2)n-Z; n is an integer from 0 to 7; andZ is selected from the group consisting of 1 -, 2- or 3-pyrrolidinyl, 1 -, 2- 3- or 4- piperidinyl, 2-, 3- or 4-morpholinyl, 2-, 3- or 4-thiomorpholinyl, 1 -, 2- or 3-azetidinyl, 1 - or 2-piperazinyl, 2- or 3-tetrahydrofuranyl; or any above group substituted on at least one available ring atom by an alkyl group; or any above group substituted on at least one available ring nitrogen atom by a benzyl group, a substituted benzyl group, an alkoxybenzyl group, a substituted alkoxybenzyl group, a benzhydryl group or a substituted benzhydryl group; and wherein the connecting point between the -(CH2)n- group and the Z group can be any available ring carbon atom or any available ring nitrogen atom; orR2 is -(CH2)n-Z; wherein n is an integer from 0 to 7; andZ is selected from the group consisting ofwherein each of X and Y is independently selected from H, halogen, CF3,CF2H, N3, NCS, CN, NO2, NX1X2, OX3, SX3, OAc, OSO2X3, O-acyl, S-acyl, SO2-alkyl, SO-alkyl, SC(CH3)2COOX8, OC(CH3)2COOX8 , C(CH3)2COOX8, Si(alkyl)3, alkyl-CN, O-aroyl, O(CH2)jOX3, O(CH2)jNXiX2, NH-acyl, NH-aroyl, CHO, C(halogen)3, COOX3, SO3H, SO2NXIX2, CONXIX2, NHC(O)O-alkyl, NHSO2-alkyl, alkoxy, alkyl, alcohol, alkylmercapto, alkylamino, di-alkylamino, alkylsulfinyl or alkylsulfonyl, CX4X5X6, -CH=CHXs , and -C=CX8;each of Xi and X2is H or alkyl, orXi and X2together comprise part of a heterocyclic ring having 4 to 7 ring members and optionally one additional heteroatom selected from 0, N and S, orXi and X2together comprise part of an imide ring having 5 to 6 members,X3is selected from the group consisting of H, alkyl, aryl, N02, (CH2)mCN, hydroxyloweralkyl, and alkyl-NXiX2, each of X4, Xs, and Xe is selected from the group consisting of H, alkyl, carbocyclic ring, hydroxyloweralkyl, alkyl-OH, halogen, CN, SNO, S(SO2)alkyl, NXIX2, C00X3, C0NX3, 0X7, and O-alkyl-X7, whereinX7is selected from the group consisting of H, alkyl, N02, NO, P(O)(OX8)2, PH(0)(0X8), S(O)kN(alkyl)2, S(O)kX8, S(O)kOX8, COOXs, CONXs, SO3H, and COXs, whereinX8is selected from the group consisting of H, alkyl, carbocyclic ring, heterocyclic ring, aromatic ring, heteroaromatic ring, and -CX9=CHXIO, wherein each of X9 and X10 is independently H or alkyl, m is an integer from 0 to 7, j is an integer from 0 to 6, or k is an integer from 0 to 2,W is H or alkyl; orR2 is -(CH2)n-Z; n is an integer from 0 to 7; andZ is selected from the group consisting of a carbocyclic ring having 6 ring atoms fused to a heterocyclic ring having from 5 to 7 ring atoms, a carbocyclic ring having 6 ring atoms fused to a heteroaromatic ring having from 5 to 7 ring atoms, a heterocyclic ring having 6 ring atoms fused to a heterocyclic ring having from 5 to 7ring atoms, an heterocyclic ring having 6 ring atoms fused to a heteroaromatic ring having from 5 to 7 ring atoms, an aromatic ring having 6 ring atoms fused to a heterocyclic ring having from 5 to 7 ring atoms, an aromatic ring having 6 ring atoms fused to a heteroaromatic ring having from 5 to 7 ring atoms, a heteroaromatic ring having 6 ring atoms fused to a heterocyclic ring having from 5 to 7 ring atoms, and a heteroaromatic ring having 6 ring atoms fused to a heteroaromatic ring having from 5 to 7 ring atoms; orR2 is -(CH2)n-Z; n is an integer from 0 to 7; andZ is selected from the group consisting of an unsaturated ring having 5 ring atoms and 0 to 2 independently selected heteroatoms as ring members fused to an unsaturated ring having 5 ring atoms and 0 to 4 independently selected heteroatoms as ring members, an unsaturated ring having 5 ring atoms and 0 to 2 independently selected heteroatoms as ring members fused to an unsaturated ring having 6 or 7 ring atoms and 0 to 3 independently selected heteroatoms as ring members, and an unsaturated ring having 6 ring atoms and 0 to 4 independently selected heteroatoms as ring members fused to an unsaturated ring having 6 or 7 ring atoms and 0 to 4 independently selected heteroatoms as ring members; orR2 is -(CH2)m -Qi-(CH2)n-Z;Qi is selected from the group consisting of NH, 0, S,-CH=CH-, -C=C-, -CO, S02and 0S02; m is an integer from 1 to 7; n is an integer from 0 to 7; whereinZ is selected from the group consisting of H, halogen, CF3, CF2H, N3, NCS, CN, NO2, NX1X2, OX3, SX3, OAc, OSO2X3, 0-acyl, S-acyl, SO2-alkyl, SO-alkyl, SC(CH3)2COOX8, OC(CH3)2COOX8 , C(CH3)2COOX8, Si(alkyl)3, alkyl-CN, 0- aroyl, O(CH2)jOX3, O(CH2)jNXiX2, NH-acyl, NH-aroyl, CHO, C(halogen)3, COOX3, SO3H, SO2NX1X2, CONX1X2, NHC(O)O-alkyl, NHS02-alkyl, alkoxy, alkyl, alcohol,alkylmercapto, alkylamino, di-alkylamino, alkylsulfinyl, alkylsulfonyl, CX4X5X6, - CH=CHX8, and -C=CX8; each of Xi and X2 is independently H or alkyl, orXi and X2 together comprise part of a heterocyclic ring having 4 to 7 ring members and optionally one additional heteroatom selected from 0, N and S, orXi and X2 together comprise part of an imide ring having 5 to 6 members,X3 is selected from the group consisting of H, alkyl, aryl, NO2, (CH2)mCN, hydroxyloweralkyl, and alkyl-NXiX2, each of X4, Xs, and Xe is independently selected from the group consisting of H, alkyl, carbocyclic ring, hydroxyloweralkyl, alkyl-OH, halogen, CN, SNO, S(SO2)alkyl, NX1X2, COOX3, CONX3, OX7, and O-alkyl-X7, whereinX7 is selected from the group consisting of H, alkyl, NO2, NO, P(O)(OX8)2, PH(O)(OXs), S(O)kN(alkyl)2, S(0)kX8, S(O)kOX8, COOXs, CONXs, SO3H and C0X8, whereinX8is selected from the group consisting of H, alkyl, carbocyclic ring, heterocyclic ring, aromatic ring, heteroaromatic ring, and -CX9=CHXIO, wherein each of Xg and Xi is H or alkyl, m is an integer from 0 to 7, j is an integer from 0 to 6, or k is an integer from 0 to 2; orR2 is -Q2-(CH2)n-Z; whereinQ2 is optionally present, and if present, is selected from the group consisting of -CH2-NH, -CH2-O, -CH2-S, -CH2-SO2, and -CH2-OSO2; n is an integer from 0 to 7;Z is selected from the group consisting of H, halogen, CF3, CF2H, N3, NCS, CN, NO2, NX1X2, OX3, SX3, OAc, OSO2X3, 0-acyl, S-acyl, SO2-alkyl, SO-alkyl, SC(CH3)2COOX8, OC(CH3)2COOX8, C(CH3)2COOX8, Si(alkyl)3, alkyl-CN, O-aroyl, O(CH2)jOX3, O(CH2)jNXiX2, NH-acyl, NH-aroyl, CHO, C(halogen)3, COOX3, SO3H, SO2NX1X2, CONX1X2, NHC(O)O-alkyl, NHS02-alkyl, alkoxy, alkyl, alcohol,alkylmercapto, alkylamino, di-alkylamino, alkylsulfinyl, alkylsulfonyl, CX4X5X6, - CH=CHX8, and -C=CX8; each of Xi and X2 is independently H or alkyl, orXi and X2 together comprise part of a heterocyclic ring having 4 to 7 ring members and optionally one additional heteroatom selected from 0, N and S, orXi and X2 together comprise part of an imide ring having 5 to 6 members,X3 is selected from the group consisting of H, alkyl, aryl, NO2, (CH2)mCN, hydroxyloweralkyl, and alkyl-NXiX2, each of X4, Xs, and Xe is independently selected from the group consisting of H, alkyl, carbocyclic ring, hydroxyloweralkyl, alkyl-OH, halogen, CN, SNO, S(SO2)alkyl, NX1X2, COOX3, CONX3, OX7, and O-alkyl-X7, whereinX7 is selected from the group consisting of H, alkyl, NO2, NO, P(O)(OX8)2, PH(O)(OXs), S(O)kN(alkyl)2, S(0)kX8, S(O)kOX8, COOXs, CONXs, SO3H and C0X8, whereinX8is selected from the group consisting of H, alkyl, carbocyclic ring, heterocyclic ring, aromatic ring, heteroaromatic ring, and -CX9=CHXIO, each of Xg and X10 is independently H or alkyl, m is an integer from 0 to 7, j is an integer from 0 to 6, k is an integer from 0 to 2; orR2 is -(CH2)m - Qi -(CH2)n-Z;Qi is selected from the group consisting of NH, 0, S, CH=CH, C=C, CO, SO2 or OSO2; m is an integer from 1 to 7; n is an integer from 0 to 7;Z is selected from the group consisting of a bicyclic ring, a heterobicyclic ring, a tricyclic ring, a heterotricyclic ring, a polycyclic ring, and a heteropolycyclic ring; orR2 is -(CH2)m - Qi -(CH2)n-Z;Qi is selected from the group consisting of NH, 0, S, CH=CH, C=C, CO, SO2 and OSO2; m is an integer from 1 to 7; n is an integer from 0 to 7;Z is selected from the group consisting of a carbocyclic ring having 4 to 7 ring members, a heterocyclic ring having 4 to 7 ring members, an aromatic ring having 5 to 7 ring members, a heteroaromatic ring having 5 to 7 ring members; a bicyclic ring, a heterobicyclic ring, a tricyclic ring, a heterotricyclic ring, a polycyclic ring, a heteropolycyclic ring or any above group substituted on at least one available ring atom by an alkyl group or any above group substituted on at least one available ring nitrogen atom by a benzyl group, a substituted benzyl group, an alkoxybenzyl group, a substituted alkoxybenzyl group, a benzhydryl group or a substituted benzhydryl group; and wherein the connecting point between the -(CH2)n- group and the Z group can be any available ring carbon atom or any available ring nitrogen atom; orR2 is -(CH2)m - Qi -(CH2)n-Z;Qi is selected from the group consisting of NH, 0, S, CH=CH, C=C, CO, SO2 and OSO2; m is an integer from 1 to 7; n is an integer from 0 to 7; andZ is selected from the group consisting of a 5 member unsaturated ring having 0 to 4 independently selected heteroatoms as ring members, a substituted 5 member unsaturated ring having 0 to 4 independently selected heteroatoms as ring members, a 6 member aromatic ring having 0 to 5 independently selected heteroatoms as ring members or a substituted 6 member aromatic ring having 0 to 5 independently selected heteroatoms; and wherein the connecting point between the -(CH2)n- group and the Z group can be any available ring carbon atom or any available ring nitrogen atom; orR2 is -(CH2)m - Qi -(CH2)n-Z;Qi is selected from the group consisting of NH, 0, S, CH=CH, C=C, CO, SO2 and OSO2; m is an integer from 1 to 7; n is an integer from 0 to 7;Z is selected from the group consisting of 1 -, 2- or 3-pyrrolidinyl, 1 -, 2- 3- or 4- piperidinyl, 2-, 3- or 4-morpholinyl, 2-, 3- or 4-thiomorpholinyl, 1 -, 2- or 3-azetidinyl, 1 - or 2-piperazinyl, 2- or 3-tetrahydrofuranyl; or any above group substituted on at least one available ring atom by an alkyl group; or any above group substituted on at least one available ring nitrogen atom by a benzyl group, a substituted benzyl group, an alkoxybenzyl group, a substituted alkoxybenzyl group, a benzhydryl group and a substituted benzhydryl group; and wherein the connecting point between the -(CH2)n- group and the Z group can be any available ring carbon atom or any available ring nitrogen atom; orR2 is -(CH2)m - Qi -(CH2)n-Z;Qi is selected from the group consisting of NH, 0, S, CH=CH, C=C, CO, SO2 and OSO2; m is an integer from 1 to 7; n is an integer from 0 to 7; andZ is selected from the group consisting ofwherein each of X and Y is independently selected from the group consisting of H, halogen, CF3, CF2H, N3, NCS, CN, NO2, NX1X2, OX3, SX3, OAc, OSO2X3, 0-acyl, S-acyl, SO2-alkyl, SO-alkyl, SC(CH3)2COOX8, OC(CH3)2COOX8, C(CH3)2COOX8, Si(alkyl)3, alkyl-CN, O-aroyl, O(CH2)jOX3, O(CH2)jNXiX2, NH- acyl, NH-aroyl, CHO, C(halogen)3, COOX3, SO3H, SO2NXIX2, CONXIX2, NHC(O)O- alkyl, NHSO2-alkyl, alkoxy, alkyl, alcohol, alkylmercapto, alkylamino, di-alkylamino, alkylsulfinyl, alkylsulfonyl, CX4X5X6, -CH=CHX8 , and -C=CX8; each of Xi and X2is independently H or alkyl, orXi and X2together comprise part of a heterocyclic ring having 4 to 7 ring members and optionally one additional heteroatom selected from 0, N and S, orXi and X2together comprise part of an imide ring having 5 to 6 members,X3is selected from the group consisting of H, alkyl, aryl, N02, (CH2)mCN, hydroxyloweralkyl, and alkyl-NXiX2, each of X4, X5, and Xe is independently selected from the group consisting of H, alkyl, carbocyclic ring, hydroxyloweralkyl, alkyl-OH, halogen, CN, SNO, S(SO2)alkyl, NXIX2, C00X3, C0NX3, OX7, and O-alkyl-X7, whereinX7 is selected from the group consisting of H, alkyl, N02, NO, P(O)(OXs)2, PH(0)(0X8), S(O)kN(alkyl)2, S(O)kX8, S(O)kOX8, COOXs, CONXs, SO3H, and C0X8, whereinX8is selected from the group consisting of H, alkyl, carbocyclic ring, heterocyclic ring, aromatic ring, heteroaromatic ring, and -CX9=CHXIO, wherein each of X9 and X10 is independently H or alkyl, m is an integer from 0 to 7, j is an integer from 0 to 6, k is an integer from 0 to 2,W is H or alkyl; orR2 is -(CH2)m- Qi -(CH2)n-Z;Qi is selected from the group consisting of NH, O, S, CH=CH, C=C, CO, S02and 0S02; m is an integer from 1 to 7; n is an integer from 0 to 7; andZ is selected from the group consisting of an unsaturated ring having 5 ring atoms and 0 to 2 independently selected heteroatoms as ring members fused to an unsaturated ring having 5 ring atoms and 0 to 4 independently selected heteroatoms as ring members, an unsaturated ring having 5 ring atoms and 0 to 2 independently selected heteroatoms as ring members fused to an unsaturated ring having 6 or 7 ring atoms and 0 to 4 independently selected heteroatoms as ring members or an unsaturated ring having 6 ring atoms and 0 to 4 independently selected heteroatoms as ring members fused to an unsaturated ring having 6 or 7 ring atoms and 0 to 4 independently selected heteroatoms as ring members; orR2 is -(CH2)m - Qi -(CH2)n-Z;Qi is selected from the group consisting of NH, 0, S, CH=CH, C=C, CO, SO2and OSO2; m is an integer from 1 to 7; n is an integer from 0 to 7; andZ is selected from the group consisting ofR2 is -T-(CH2)n-Z; n is an integer from 0 to 7;T is selected from the group consisting of a carbocyclic ring having 3 to 8 ring members, an unsaturated ring having 3 to 8 carbon atoms as ring members, an aromatic ring having 5 to 8 carbon atoms as ring members, a heterocyclic ring having 3 to 8 ring members, a heteroaromatic ring having 5 to 8 ring members, abicyclic ring, a heterobicyclic ring, a tricyclic ring, a heterotricyclic ring, a polycyclic ring or a heteropolycyclic ring; andZ is selected from the group consisting of H, halogen, CF3, CF2H, N3, NCS, CN, NO2, NX1X2, OX3, SX3, OAc, OSO2X3, O-acyl, S-acyl, SO2-alkyl, SO-alkyl, SC(CH3)2COOX8, OC(CH3)2COOX8 , C(CH3)2COOX8, Si(alkyl)3, alkyl-CN, O-aroyl, O(CH2)jOX3, O(CH2)jNXiX2, NH-acyl, NH-aroyl, CHO, C(halogen)3, COOX3, SO3H, SO2NX1X2, CONX1X2, NHC(O)O-alkyl, NHSO2-alkyl, alkoxy, alkyl, alcohol, alkylmercapto, alkylamino, di-alkylamino, alkylsulfinyl or alkylsulfonyl, CX4X5X6, - CH=CHX8, and -C=CX8; each of Xi and X2 is independently H or alkyl, orXi and X2 together comprise part of a heterocyclic ring having 4 to 7 ring members and optionally one additional heteroatom selected from 0, N and S, orXi and X2 together comprise part of an imide ring having 5 to 6 members,X3 is selected from the group consisting of H, alkyl, aryl, NO2, (CH2)mCN, hydroxyloweralkyl, and alkyl-NXiX2, each of X4, X5, and Xe is independently selected from the group consisting of H, alkyl, carbocyclic ring, hydroxyloweralkyl, alkyl-OH, halogen, CN, SNO, S(SO2)alkyl, NX1X2, COOX3, CONX3, OX7, and O-alkyl-X7, whereinW7 is selected from the group consisting of H, alkyl, NO2, NO, P(0)(0Xs)2, PH(0)(0X8), S(O)kN(alkyl)2, S(0)kX8, S(O)kOX8, C00X8, CONXs, SO3H, C0X8, wherein X8comprises H, alkyl, carbocyclic ring, heterocyclic ring, aromatic ring, heteroaromatic ring, and -CXg=CHXio, wherein each of X9 and X10 is independently H or alkyl, m is an integer from 0 to 7, j is an integer from 0 to 6, k is an integer from 0 to 2; orR2 is -T-(CH2)n-Z; n is an integer from 0 to 7;T is selected from the group consisting of a carbocyclic ring having 3 to 8 ring members, an unsaturated ring having 3 to 8 carbon atoms as ring members, anaromatic ring having 5 to 8 carbon atoms as ring members, a heterocyclic ring having 3 to 8 ring members, a heteroaromatic ring having 5 to 8 ring members, a bicyclic ring, a heterobicyclic ring, a tricyclic ring, a heterotricyclic ring, a polycyclic ring and a heteropolycyclic ring; andZ is selected from the group consisting of a carbocyclic ring having 4 to 7 ring members, a heterocyclic ring having 4 to 7 ring members, an aromatic ring having 5 to 7 ring members, a heteroaromatic ring having 5 to 7 ring members, a bicyclic ring, a heterobicyclic ring, a tricyclic ring, a heterotricyclic ring, a polycyclic ring, a heteropolycyclic ring; or any above group substituted on at least one available ring atom by an alkyl group; or any above group substituted on at least one available ring nitrogen atom by a benzyl group, a substituted benzyl group, an alkoxybenzyl group, a substituted alkoxybenzyl group, a benzhydryl group and a substituted benzhydryl group; and wherein the connecting point between the -(CH2)n- group and the Z group can be any available ring carbon atom or any available ring nitrogen atom; orR2 is -T-(CH2)n-Z; n is an integer from 0 to 7;T is selected from the group consisting of a carbocyclic ring having 3 to 8 ring members, an unsaturated ring having 3 to 8 carbon atoms as ring members, an aromatic ring having 5 to 8 carbon atoms as ring members, a heterocyclic ring having 3 to 8 ring members, a heteroaromatic ring having 5 to 8 ring members, a bicyclic ring, a heterobicyclic ring, a tricyclic ring, a heterotricyclic ring, a polycyclic ring and a heteropolycyclic ring; andZ is selected from the group consisting of 1 -, 2- or 3-pyrrolidinyl, 1 -, 2-, 3- or 4- piperidinyl, 2-, 3- or 4-morpholinyl, 2-, 3- or 4-thiomorpholinyl, 1 -, 2- or 3-azetidinyl, 1 - or 2-piperazinyl, 2- or 3-tetrahydrofuranyl; or any above group substituted on at least one available ring atom by an alkyl group; or any above group substituted on at least one available ring nitrogen atom by a benzyl group, a substituted benzyl group, an alkoxybenzyl group, a substituted alkoxybenzyl group, a benzhydryl group or a substituted benzhydryl group; and wherein the connecting point between the -(CH2)n-group and the Z group can be any available ring carbon atom or any available ring nitrogen atom; orR2 is -T-(CH2)n-Z; n is an integer from 0 to 7;T is selected from the group consisting of a carbocyclic ring having 3 to 8 ring members, an unsaturated ring having 3 to 8 carbon atoms as ring members, an aromatic ring having 5 to 8 carbon atoms as ring members, a heterocyclic ring having 3 to 8 ring members, a heteroaromatic ring having 5 to 8 ring members, a bicyclic ring, a heterobicyclic ring, a tricyclic ring, a heterotricyclic ring, a polycyclic ring and a heteropolycyclic ring; andZ is selected from the group consisting ofwherein each of X and Y each is independently selected from the group consisting of H, halogen, CF3, CF2H, N3, NCS, CN, NO2, NX1X2, OX3, SX3, OAc, OSO2X3, O-acyl, S-acyl, SO2-alkyl, SO-alkyl, SC(CH3)2COOX8, OC(CH3)2COOX8, C(CH3)2COOX8, Si(alkyl)3, alkyl-CN, O-aroyl, O(CH2)jOX3, O(CH2)jNXiX2, NH- acyl, NH-aroyl, CHO, C(halogen)3, COOX3, SO3H, SO2NXIX2, CONXIX2, NHC(O)O- alkyl, NHSO2-alkyl, alkoxy, alkyl, alcohol, alkylmercapto, alkylamino, di-alkylamino, alkylsulfinyl or alkylsulfonyl, CX4X5X6, -CH=CHX8, and -C=CX8; each of Xi and X2is independently H or alkyl, orXi and X2together comprise part of a heterocyclic ring having 4 to 7 ring members and optionally one additional heteroatom selected from 0, N and S, orXi and X2 together comprise part of an imide ring having 5 to 6 members,X3 is selected from the group consisting of H, alkyl, aryl, NO2, (CH2)mCN, hydroxyloweralkyl, and alkyl-NXiX2, each of X , Xs, and Xe is independently selected from the group consisting of H, alkyl, carbocyclic ring, hydroxyloweralkyl, alkyl-OH, halogen, CN, SNO, S(SO2)alkyl, NX1X2, COOX3, CONX3, OX7, and O-alkyl-X7, whereinX7comprises H, alkyl, NO2, NO, P(O)(OX8)2, PH(O)(OXs), S(O)kN(alkyl)2, S(O)kX8, S(O)kOX8, COOX8, CONXs, SO3H, and COX8, whereinX8is selected from the group consisting of H, alkyl, carbocyclic ring, heterocyclic ring, aromatic ring, heteroaromatic ring, and -CXg=CHXio, wherein each of X9 and X10 is independently H or alkyl, m is an integer from 0 to 7, j is an integer from 0 to 6, k is an integer from 0 to 2,W is H or alkyl; orR2 is -T-(CH2)n-Z; n is an integer from 0 to 7;T is selected from the group consisting of a carbocyclic ring having 3 to 8 ring members, an unsaturated ring having 3 to 8 carbon atoms as ring members, an aromatic ring having 5 to 8 carbon atoms as ring members, a heterocyclic ring having 3 to 8 ring members, a heteroaromatic ring having 5 to 8 ring members, a bicyclic ring, a heterobicyclic ring, a tricyclic ring, a heterotricyclic ring, a polycyclic ring or a heteropolycyclic ring; andZ is selected from the group consisting of an unsaturated ring having 5 ring atoms and 0 to 2 independently selected heteroatoms as ring members fused to an unsaturated ring having 5 ring atoms and 0 to 4 independently selected heteroatoms as ring members, an unsaturated ring having 5 ring atoms and 0 to 2 independently selected heteroatoms as ring members fused to an unsaturated ring having 6 or 7 ring atoms and 0 to 4 independently selected heteroatoms as ring members or an unsaturated ring having 6 ring atoms and 0 to 3 independently selected heteroatomsas ring members fused to an unsaturated ring having 6 or 7 ring atoms and 0 to 4 independently selected heteroatoms as ring members; orR2 is -T-(CH2)m- Qi -(CH2)n-Z; each of m and n is independently an integer from 0 to 7;T is selected from the group consisting of a carbocyclic ring having 3 to 8 ring members, an unsaturated ring having 3 to 8 carbon atoms as ring members, an aromatic ring having 5 to 8 carbon atoms as ring members, a heterocyclic ring having 3 to 8 ring members, a heteroaromatic ring having 5 to 8 ring members, a bicyclic ring, a heterobicyclic ring, a tricyclic ring, a heterotricyclic ring, a polycyclic ring and a heteropolycyclic ring;Qi m and n independently comprises NH, O, S, CH=CH, C=C, CO, SO2and OSO2; andZ is selected from the group consisting of, H, halogen, CF3, CF2H, N3, NCS, CN, NO2, NX1X2, OX3, SX3, OAc, OSO2X3, O-acyl, S-acyl, SO2-alkyl, SO-alkyl, SC(CH3)2COOX8, OC(CH3)2COOX8, C(CH3)2COOX8, Si(alkyl)3, alkyl-CN, 0- aroyl, O(CH2)jOX3, O(CH2)jNXiX2, NH-acyl, NH-aroyl, CHO, C(halogen)3, COOX3, SO3H, SO2NX1X2, CONX1X2, NHC(O)O-alkyl, NHS02-alkyl, alkoxy, alkyl, alcohol, alkylmercapto, alkylamino, di-alkylamino, alkylsulfinyl, alkylsulfonyl, CX4X5X6, - CH=CHX8, and -C=CX8; each of Xi and X2is independently H or alkyl, orXi and X2together comprise part of a heterocyclic ring having 4 to 7 ring members and optionally one additional heteroatom selected from 0, N and S, orXi and X2together comprise part of an imide ring having 5 to 6 members, X3 comprises H, alkyl, aryl, NO2, (CH2)mCN, hydroxyloweralkyl, and alkyl-NXiX2, each of X4, X5, and Xe is independently selected from the group consisting of H, alkyl, carbocyclic ring, hydroxyloweralkyl, alkyl-OH, halogen, CN, SNO, S(SO2)alkyl, NX1X2, COOX3, CONX3, OX7, and O-alkyl-X7, whereinX7 is selected from the group consisting of H, alkyl, N02, NO, P(O)(OX8)2, PH(0)(0X8), S(O)kN(alkyl)2, S(O)kX8, S(O)kOX8, COOXs, CONXs, SO3H, and COXs, whereinXs is selected from the group consisting of H, alkyl, carbocyclic ring, heterocyclic ring, aromatic ring, heteroaromatic ring, and -CX9=CHXIO, wherein each of X9 and X10 is independently H or alkyl, m is an integer from 0 to 7, j is an integer from 0 to 6, k is an integer from 0 to 2; orR2 is -T-(CH2)m- Qi -(CH2)n-Z; each of m and n is independently an integer from 0 to 7;T is selected from the group consisting of a carbocyclic ring having 3 to 8 ring members, an unsaturated ring having 3 to 8 carbon atoms as ring members, an aromatic ring having 5 to 8 carbon atoms as ring members, a heterocyclic ring having 3 to 8 ring members, a heteroaromatic ring having 5 to 8 ring members, a bicyclic ring, a heterobicyclic ring, a tricyclic ring, a heterotricyclic ring, a polycyclic ring, and a heteropolycyclic ring;Qi is selected from the group consisting of NH, 0, S, CH=CH, C=C, CO, S02and 0S02; andZ is selected from the group consisting of a carbocyclic ring having 4 to 7 ring members, a heterocyclic ring having 4 to 7 ring members, an aromatic ring having 5 to 7 ring members, a heteroaromatic ring having 5 to 7 ring members, a bicyclic ring, a heterobicyclic ring, a polycyclic ring, a heteropolycyclic ring; or any above group substituted on at least one available ring atom by an alkyl group; or any above group substituted on at least one available ring nitrogen atom by a benzyl group, a substituted benzyl group, an alkoxybenzyl group, a substituted alkoxybenzyl group, a benzhydryl group or a substituted benzhydryl group; and wherein the connecting point between the -(CH2)n- group and the Z group can be any available ring carbon atom or any available ring nitrogen atom; orR2 is -T-(CH2)m- Qi -(CH2)n-Z; each of m and n is independently an integer from 0 to 7;T is selected from the group consisting of a carbocyclic ring having 3 to 8 ring members, an unsaturated ring having 3 to 8 carbon atoms as ring members, an aromatic ring having 5 to 8 carbon atoms as ring members, a heterocyclic ring having 3 to 8 ring members, a heteroaromatic ring having 5 to 8 ring members, a bicyclic ring, a heterobicyclic ring, a tricyclic ring, a heterotricyclic ring, a polycyclic ring or a heteropolycyclic ring;Qi is selected from the group consisting of NH, 0, S, CH=CH, C=C, CO, SO2 and OSO2; andZ is selected from the group consisting of 1 -, 2- or 3-pyrrolidinyl, 1 -, 2-, 3- or 4- piperidinyl, 2-, 3- or 4-morpholinyl, 2-, 3- or 4-thiomorpholinyl, 1 -, 2- or 3-azetidinyl, 1 - or 2-piperazinyl, 2- or 3-tetrahydrofuranyl; or any above group substituted on at least one available ring atom by an alkyl group; or any above group substituted on at least one available ring nitrogen atom by a benzyl group, a substituted benzyl group, an alkoxybenzyl group, a substituted alkoxybenzyl group, a benzhydryl group or a substituted benzhydryl group; and wherein the connecting point between the -(CH2)n- group and the Z group can be any available ring carbon atom or any available ring nitrogen atom; orR2 is -T-(CH2)m- Qi -(CH2)n-Z; each of m and n is independently an integer from 0 to 7;T is selected from the group consisting of a carbocyclic ring having 3 to 8 ring members, an unsaturated ring having 3 to 8 carbon atoms as ring members, an aromatic ring having 5 to 8 carbon atoms as ring members, a heterocyclic ring having 3 to 8 ring members, a heteroaromatic ring having 5 to 8 ring members, a bicyclic ring, a heterobicyclic ring, a tricyclic ring, a heterotricyclic ring, a polycyclic ring or a heteropolycyclic ring;Qi is selected from the group consisting of N, O, S, CH=CH, C=C, CO, SO2 and OSO2; andZ is selected from the group consisting ofwherein each of X and Y is independently selected from the group consisting of H, halogen, CF3, CF2H, N3, NCS, CN, NO2, NX1X2, OX3, SX3, OAc, OSO2X3, 0- acyl, S-acyl, SO2-alkyl, SO-alkyl, SC(CH3)2COOX8, OC(CH3)2COOX8, C(CH3)2COOX8, Si(alkyl)3, alkyl-CN, O-aroyl, O(CH2)jOX3, O(CH2)jNXiX2, NH- acyl, NH-aroyl, CHO, C(halogen)3, C00X3, SO3H, SO2NX1X2, CONX1X2, NHC(O)O- alkyl, NHSO2-alkyl, alkoxy, alkyl, alcohol, alkylmercapto, alkylamino, di-alkylamino, alkylsulfinyl or alkylsulfonyl, CX4X5X6, -CH=CHXs , and -C^CXs: each of Xi and X2 is independently selected from the group consisting of comprise H and alkyl, orXi and X2 together comprise part of a heterocyclic ring having 4 to 7 ring members and optionally one additional heteroatom selected from 0, N and S, or Xi and X2 together comprise part of an imide ring having 5 to 6 members, X3comprises H, alkyl, aryl, NO2, (CH2)mCN, hydroxyloweralkyl, and alkyl-NXiX2, each of X4, X5, and Xe is independently selected from the group consisting of H, alkyl, carbocyclic ring, hydroxyloweralkyl, alkyl-OH, halogen, CN, SNO, S(SO2)alkyl, NX1X2, C00X3, C0NX3, OX7, and O-alkyl-X7, whereinX7 is selected from the group consisting of H, alkyl, NO2, NO, P(O)(OX8)2, PH(O)(OX8), S(O)kN(alkyl)2, S(0)kX8, S(O)kOX8, COOXs, CONXs, SO3H, COXs, wherein X8comprises H, alkyl, carbocyclic ring, heterocyclic ring, aromatic ring, heteroaromatic ring, and -CXg=CHXio, wherein each of X9 and X10 is independently H or alkyl, m is an integer from 0 to 7, j is an integer from 0 to 6,k is an integer from 0 to 2,W is H or alkyl; orR2 is -T-(CH2)m- Qi -(CH2)n-Z; each of m and n is independently an integer from 0 to 7;T is selected from the group consisting of a carbocyclic ring having 3 to 8 ring members, an unsaturated ring having 3 to 8 carbon atoms as ring members, an aromatic ring having 5 to 8 carbon atoms as ring members, a heterocyclic ring having 3 to 8 ring members, a heteroaromatic ring having 5 to 8 ring members, a bicyclic ring, a heterobicyclic ring, a tricyclic ring, a heterotricyclic ring, a polycyclic ring and a heteropolycyclic ring;Qi is selected from the group consisting of NH, 0, S, CH=CH, C=C, CO, S02and 0S02; andZ is selected from the group consisting of an unsaturated ring having 5 ring atoms and 0 to 2 independently selected heteroatoms as ring members fused to an unsaturated ring having 5 ring atoms and 0 to 2 independently selected heteroatoms as ring members, an unsaturated ring having 5 ring atoms and 0 to 2 independently selected heteroatoms as ring members fused to an unsaturated ring having 6 or 7 ring atoms and 0 to 4 independently selected heteroatoms as ring members or an unsaturated ring having 6 ring atoms and 0 to 3 independently selected heteroatoms as ring members fused to an unsaturated ring having 6 or 7 ring atoms and 0 to 4 independently selected heteroatoms as ring members, orR2 is -T-(CH2)m- Qi -(CH2)n-Z;T is selected from the group consisting of a carbocyclic ring having 3 to 8 ring members, an unsaturated ring having 3 to 8 carbon atoms as ring members, an aromatic ring having 5 to 8 carbon atoms as ring members, a heterocyclic ring having 3 to 8 ring members, a heteroaromatic ring having 5 to 8 ring members, a bicyclic ring, a heterobicyclic ring, a tricyclic ring, a heterotricyclic ring, a polycyclic ring or a heteropolycyclic ring; each of m and n is independently an integer from 0 to 7;Qi is selected from the group consisting of NH, 0, S, CH=CH, C=C, CO, SO2 and OSO2; andZ isE is selected from the group consisting of a C1 to C4, linear or branched alkyl group, a phenyl group, a substituted phenyl group, a benzyl group and a substituted benzyl group; orR2 is -T-(CH2)m- Qi -(CH2)n-Z;T is selected from the group consisting of a carbocyclic ring having 3 to 8 ring members, an unsaturated ring having 3 to 8 carbon atoms as ring members, an aromatic ring having 5 to 8 carbon atoms as ring members, a heterocyclic ring having 3 to 8 ring members, a heteroaromatic ring having 5 to 8 ring members, a bicyclic ring, a heterobicyclic ring, a tricyclic ring, a heterotricyclic ring, a polycyclic ring or a heteropolycyclic ring; each of m and n is independently an integer from 0 to 7;Qi is selected from the group consisting of NH, 0, S, CH=CH, C=C, CO, SO2 and OSO2;Z is selected from the group consisting ofk is an integer from 1 to 5,J— KR3 is 1 -1wherein G is selected from the group consisting of CH, C(CHs), C(CN) and N,each of L, K and J is independently selected from the group consisting of (CH2)n, (CH3)2, C=O, 0, -CHOH, C(CH3)0MI , C(CH2)n(X)Y, NMi, SO2, SO, and S, n is an integer from 0 to 7;Mi is H, alkyl, or C(0)M2, whereinM2is selected from the group consisting of H, alkyl, NM3M4, OMs, each of M3, M4 and Ms is independently selected from the group consisting of H, OH and alkyl, each of X and Y is independently selected from the group consisting of H, halogen, CF3, CF2H, N3, NCS, CN, N02, NXiX2, 0X3, SX3, OAc, OSO2X3, 0-acyl, S- acyl, SO2-alkyl, SO-alkyl, SC(CH3)2COOX8, OC(CH3)2COOX8, C(CH3)2COOX8, Si(alkyl)3, alkyl-CN, O-aroyl, O(CH2)jOX3, O(CH2)jNXiX2, NH-acyl, NH-aroyl, CHO, C(halogen)3, C00X3, SO3H, SO2NXIX2, C0NXIX2, NHC(O)O-alkyl, NHS02-alkyl, alkoxy, alkyl, alcohol, alkylmercapto, alkylamino, di-alkylamino, alkylsulfinyl, alkylsulfonyl, CX4X5X6, -CH=CHXs , and -C=CX8; each of Xi and X2is independently H or alkyl, orXi and X2together comprise part of a heterocyclic ring having 4 to 7 ring members and optionally one additional heteroatom selected from 0, N and S, orXi and X2together comprise part of an imide ring having 5 to 6 members, X3comprises H, alkyl, NO2, (CH2)mCN, hydroxyloweralkyl, and alkyl-NXiX2, each of X4, Xs, and Xe is independently selected from the group consisting of H, alkyl, carbocyclic ring, hydroxyloweralkyl, alkyl-OH, halogen, CN, SNO, S(SO2)alkyl, NXIX2, C00X3, C0NX3, OX7, and O-alkyl-X7, whereinX7 is selected from the group consisting of H, alkyl, N02, NO, P(O)(OX8)2, PH(O)(OXs), S(O)kN(alkyl)2, S(O)kX8, S(O)kOX8, COOXs, CONXs, SO3H, C0X8, wherein X8comprises H, alkyl, carbocyclic ring, heterocyclic ring, aromatic ring, heteroaromatic ring, and -CXg=CHXio, each of X9 and X10 is independently H or alkyl, m is an integer from 0 to 7, j is an integer from 0 to 6, or k is an integer from 0 to 2;R4 is selected from the group consisting of H, halogen, CF3, CF2H, N3, NCS, CN, NO2, NX1X2, OH, ONO2, SX3, OAc, OSO2X3, O-acyl, S-acyl, SO2-alkyl, SO-alkyl, SC(CH3)2COOX8, OC(CH3)2COOX8, C(CH3)2COOX8, Si(alkyl)3, alkyl-CN, O-aroyl, O(CH2)jOX3, O(CH2)jNXiX2, NH-acyl, NH-aroyl, CHO, C(halogen)3, COOX3, SO3H, SO2NX1X2, CONX1X2, NHC(O)O-alkyl, NHSO2-alkyl, alkoxy, alkyl, alcohol, alkylmercapto, alkylamino, di-alkylamino, alkylsulfinyl, alkylsulfonyl, CX4X5X6, - CH=CHXs , and -C=CX8; each of Xi and X2 is independently H or alkyl, orXi and X2 together comprise part of a heterocyclic ring having 4 to 7 ring members and optionally one additional heteroatom selected from 0, N and S, orXi and X2 together comprise part of an imide ring having 5 to 6 members,X3 is selected from the group consisting of H, alkyl, NO2, (CH2)mCN, hydroxyloweralkyl, and alkyl-NXiX2, each of X4, Xs, and Xs is independently selected from the group consisting of H, alkyl, carbocyclic ring, hydroxyloweralkyl, alkyl-OH, halogen, CN, SNO, S(SO2)alkyl, NX1X2, COOX3, CONX3, OX7, and O-alkyl-X7, whereinX7 is selected from the group consisting of H, alkyl, NO2, NO, P(O)(OX8)2, PH(0)(0X8), S(O)kN(alkyl)2, S(0)kX8, S(O)kOX8, C00X8, C0NX8, SO3H, and C0X8, whereinX8is selected from the group consisting of H, alkyl, carbocyclic ring, heterocyclic ring, aromatic ring, heteroaromatic ring, and -CX9=CHXw, wherein each of X9 and X10 is independently H or alkyl, m is an integer from 0 to 7, j is an integer from 0 to 6, or k is an integer from 0 to 2; orR4 is selected from the group consisting of a carbocyclic ring having 4 to 7 ring members, a heterocyclic ring having 4 to 7 ring members, an aromatic ring having 5 to 7 ring members, a heteroaromatic ring having 5 to 7 ring members, a bicyclic ring, a heterobicyclic ring, a tricyclic ring, a heterotricyclic ring, a polycyclic ring, and a heteropolycyclic ring; orR4 is selected from the group consisting ofR4 is selected from the group consisting of -(CH2)d-Z; wherein d is an integer from 1 to 6;Z is selected from the group consisting of H, halogen, CF3, CF2H, N3, NCS, CN, NO2, NX1X2, OX3, SX3, OAc, OSO2X3, O-acyl, S-acyl, SO2-alkyl, SO-alkyl, SC(CH3)2COOX8, OC(CH3)2COOX8 , C(CH3)2COOX8, Si(alkyl)3, alkyl-CN, 0- aroyl, O(CH2)jOX3, O(CH2)jNXiX2, NH-acyl, NH-aroyl, CHO, C(halogen)3, COOX3, SO3H, SO2NX1X2, CONX1X2, NHC(O)O-alkyl, NHSO2-alkyl, alkoxy, alkyl, alcohol, alkylmercapto, alkylamino, di-alkylamino, alkylsulfinyl, alkylsulfonyl, CX4X5X6, - CH=CHX8, and -C=CX8; each of Xi and X2 is independently H or alkyl, orXi and X2 together comprise part of a heterocyclic ring having 4 to 7 ring members and optionally one additional heteroatom selected from 0, N and S, orXi and X2 together comprise part of an imide ring having 5 to 6 members,X3 is selected from the group consisting of H, alkyl, NO2, (CH2)mCN, hydroxyloweralkyl, and alkyl-NXiX2, each of X4, X5, and Xe is independently selected from the group consisting of H, alkyl, carbocyclic ring, hydroxyloweralkyl, alkyl-OH, halogen, CN, SNO, S(SO2)alkyl, NX1X2, COOX3, CONX3, OX7, and O-alkyl-X7, whereinX7 is selected from the group consisting of H, alkyl, NO2, NO, P(O)(OXa)2, PH(O)(OXs), S(O)kN(alkyl)2, S(O)kX8, S(O)kOX8, COOXs, CONXs, SO3H, and C0X8, whereinXs is selected from the group consisting of H, alkyl, carbocyclic ring, heterocyclic ring, aromatic ring, heteroaromatic ring, and -CX9=CHXIO, wherein each of X9 and X10 is independently H or alkyl, m is an integer from 0 to 7, j is an integer from 0 to 6, k is an integer from 0 to 2; orR4 is -(CH2)d-Z; d is an integer from 1 to 6; andZ is selected from the group consisting of a carbocyclic ring having 4 to 7 ring members, a heterocyclic ring having 4 to 7 ring members, an aromatic ring having 5 to 7 ring members, a heteroaromatic ring having 5 to 7 ring members, a bicyclic ring, a heterobicyclic ring, a tricyclic ring, a heterotricyclic ring, a polycyclic ring, a heteropolycyclic ring; or any above group substituted on at least one available ring atom by an alkyl group; or any above group substituted on at least one available ring nitrogen atom by a benzyl group, a substituted benzyl group, an alkoxybenzyl group, a substituted alkoxybenzyl group, a benzhydryl group, and a substituted benzhydryl group; and wherein the_connecting point between the -(CH2)d- group and the Z group can be any available ring carbon atom or any available ring nitrogen atom; orR4 is -(CH2)d-Z; wherein d is an integer from 1 to 6; andZ is selected from the group consisting of 1 -, 2- or 3-pyrrolidinyl, 1 -, 2-, 3- or 4- piperidinyl, 2-, 3- or 4-morpholinyl, 2-, 3- or 4-thiomorpholinyl, 1 -, 2- or 3-azetidinyl, 1 - or 2-piperazinyl, 2- or 3-tetrahydrofuranyl; or any above group substituted on at least one ring atom by an alkyl group; or any above group substituted on at least one available ring nitrogen atom by a benzyl group, a substituted benzyl group, an alkoxybenzyl group, a substituted alkoxybenzyl group, a benzhydryl group, and a substituted benzhydryl group; and wherein the connecting point between the -(CH2)d- group and the Z group can be any available ring carbon atom or any available ring nitrogen atom; orR4 is -(CH2)m - Qi -(CH2)n-Z;Qi is NH, 0, S, CH=CH, C=C, CO, S02, and 0S02; m is an integer from 1 to 7; n is an integer from 0 to 7; andZ is selected from the group consisting of H, halogen, CF3, CF2H, N3, NCS, CN, NO2, NX1X2, OX3, SX3, OAc, OSO2X3, 0-acyl, S-acyl, SO2-alkyl, SO-alkyl, SC(CH3)2COOX8, OC(CH3)2COOX8 , C(CH3)2COOX8, Si(alkyl)3, alkyl-CN, O-aroyl, O(CH2)jOX3, O(CH2)jNXiX2, NH-acyl, NH-aroyl, CHO, C(halogen)3, COOX3, SO3H, SO2NX1X2, CONX1X2, NHC(O)O-alkyl, NHS02-alkyl, alkoxy, alkyl, alcohol, alkylmercapto, alkylamino, di-alkylamino, alkylsulfinyl or alkylsulfonyl, CX4X5X6, - CH=CHX8, and -C^CXs; each of Xi and X2is independently H or alkyl, orXi and X2 together comprise part of a heterocyclic ring having 4 to 7 ring members and optionally one additional heteroatom selected from 0, N and S, orXi and X2together comprise part of an imide ring having 5 to 6 members,X3 is selected from the group consisting of H, alkyl, NO2, (CH2)mCN, hydroxyloweralkyl, and alkyl-NXiX2, each of X4, Xs, and Xe is independently selected from the group consisting of H, alkyl, carbocyclic ring, hydroxyloweralkyl, alkyl-OH, halogen, CN, SNO, S(SO2)alkyl, NX1X2, COOX3, CONX3, 0X7, and O-alkyl-X7, whereinX7comprises H, alkyl, NO2, NO, P(O)(OX8)2, PH(O)(OXs), S(O)kN(alkyl)2, S(O)kX8, S(O)kOX8, C00X8, CONXs, SO3H, and COXs, whereinXs is selected from the group consisting of H, alkyl, carbocyclic ring, heterocyclic ring, aromatic ring, heteroaromatic ring, and -CXg=CHXio, wherein each of X9 and X10 is independently H or alkyl, m is an integer from 0 to 7, j is an integer from 0 to 6, k is an integer from 0 to 2; orR4 is -(CH2)m - Qi -(CH2)n-Z;Qi is selected from the group consisting of NH, 0, S, CH=CH, C=C, CO, SO2 and OSO2; m is an integer from 1 to 7; n is an integer from 0 to 7; andZ is selected from the group consisting of a carbocyclic ring having 4 to 7 ring members, a heterocyclic ring having 4 to 7 ring members, an aromatic ring having 5 to 7 ring members, a heteroaromatic ring having 5 to 7 ring members; a bicyclic ring, a heterobicyclic ring, a tricyclic ring, a heterotricyclic ring, a polycyclic ring, a heteropolycyclic ring; or any above group substituted on at least one available ring atom by an alkyl group; or any above group substituted on at least one available ring nitrogen atom by a benzyl group, a substituted benzyl group, an alkoxybenzyl group, a substituted alkoxybenzyl group, a benzhydryl group, and a substituted benzhydryl group; and wherein the connecting point between the -(CH2)n- group and the Z group can be any available ring carbon atom or any available ring nitrogen atom; orR4 is -(CH2)m - Qi -(CH2)n-Z;Qi is selected from the group consisting of NH, 0, S, CH=CH, C=C, CO, SO2 and OSO2; m is an integer from 1 to 7; n is an integer from 0 to 7; andZ is selected from the group consisting of 1 -, 2- or 3-pyrrolidinyl, 1 -, 2-, 3- or 4- piperidinyl, 2-, 3- or 4-morpholinyl, 2-, 3- or 4-thiomorpholinyl, 1 -, 2- or 3-azetidinyl, 1 - or 2-piperazinyl, and 2- or 3-tetrahydrofuranyl; or any above group substituted on at least one available ring atom by an alkyl; or any above group substituted on at least one available ring nitrogen atom by a benzyl group, a substituted benzyl group, an alkoxybenzyl group, a substituted alkoxybenzyl group, a benzhydryl group or a substituted benzhydryl group; and wherein the connecting point between the -(CH2)n- group and the Z group can be any available ring carbon atom or any available ring nitrogen atom; orR4 is -(CH2)m - Qi -(CH2)n-Z;Qi is selected from the group consisting of NH, 0, S, CH=CH, C=C, CO, SO2 and OSO2; m is an integer from 1 to 7; n is an integer from 0 to 7; andZ is selected from the group consisting ofwherein each of X and Y is independently selected from the group consisting of H, halogen, CF3, CF2H, N3, NCS, CN, NO2, NX1X2, OX3, SX3, OAc, OSO2X3, 0- acyl, S-acyl, SO2-alkyl, SO-alkyl, SC(CH3)2COOX8, OC(CH3)2COOX8, C(CH3)2COOX8, Si(alkyl)3, alkyl-CN, O-aroyl, O(CH2)jOX3, O(CH2)jNXiX2, NH- acyl, NH-aroyl, CHO, C(halogen)3, C00X3, SO3H, SO2NX1X2, CONX1X2, NHC(O)O- alkyl, NHSO2-alkyl, alkoxy, alkyl, alcohol, alkylmercapto, alkylamino, di-alkylamino, alkylsulfinyl or alkylsulfonyl, CX4X5X6, -CH=CHX8, and -C=CX8; each of Xi and X2is independently H or alkyl, orXi and X2 together comprise part of a heterocyclic ring having 4 to 7 ring members and optionally one additional heteroatom selected from 0, N and S, orXi and X2 together comprise part of an imide ring having 5 to 6 members,X3is selected from the group consisting of H, alkyl, NO2, (CH2)mCN, hydroxyloweralkyl, and alkyl-NXiX2, each of X4, X5, and Xe is independently selected from the group consisting of H, alkyl, carbocyclic ring, hydroxyloweralkyl, alkyl-OH, halogen, CN, SNO, S(SO2)alkyl, NXIX2, C00X3, C0NX3, OX7, and O-alkyl-X7, whereinX7 is selected from the group consisting of H, alkyl, NO2, NO, P(O)(OX8)2, PH(0)(0X8), S(O)kN(alkyl)2, S(0)kX8, S(O)kOX8, COOXs, CONXs, SO3H, C0X8,wherein Xs comprises H, alkyl, carbocyclic ring, heterocyclic ring, aromatic ring, heteroaromatic ring, and -CXg=CHXio, wherein each of X9 and X10 is H or alkyl, wherein m is an integer from 0 to 7, j is an integer from 0 to 6, k is an integer from 0 to 2, and W is H or alkyl.

2. The method of claim 1 , wherein the condition includes one or more symptom from the group consisting of alcohol seeking, alcohol dependency, alcohol craving, binge craving, binge-like consumption, reinforcing, and withdrawal.

3. The method of claim 1 , wherein the condition includes one or more symptom including alcohol dependency that is post-withdrawal or relapse craving.

4. The method of claim 1 , wherein the condition includes alcohol-related withdrawal symptoms.

5. The method of claim 1 , wherein the condition includes heavy alcohol drinking.

6. The method of claim 1 , wherein the condition includes alcoholic impulse control disorder.

7. The method of claim 1 , wherein the condition includes relapse use of alcohol.

8. The method of claim 1 , wherein the condition includes one or more symptom from the group consisting of an inflammatory condition related to liver disease selected from alcohol-related hepatic steatosis, alcohol-related steatohepatitis, alcohol-related fibrosis, alcohol-related cirrhosis and alcohol-related cancer.

9. The method of claim 1 , wherein the condition includes one or more symptom from the group consisting of inflammatory condition related to pancreatic disease selected from alcohol-induced pancreatitis.

10. The method of claim 1 , wherein the one or more compounds includes one or more cannabimimetic imidazole ligand represented by Formula II:II and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, enantiomers, diastereomers, geometric isomers, racemates, tautomers, rotamers, atropisomers, and isotopic variations including at least one deuterium atom and N-oxides thereof.

11. The method of claim 1 , wherein the one or more compounds includes one or more cannabimimetic thiazole and oxazole ligands represented by Formula III:and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, enantiomers, diastereomers, geometric isomers, racemates, tautomers, rotamers, atropisomers, and isotopic variations including at least one deuterium atom and N-oxides thereof.

12. The method of claim 1 , wherein the one or more compounds includes one or more cannabimimetic triazole ligands represented by Formula IV:IV and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, enantiomers, diastereomers, geometric isomers, racemates, tautomers, rotamers, atropisomers, and isotopic variations including at least one deuterium atom and N-oxides thereof.

13. The method of claim 1 , wherein the one or more compounds includes one or more cannabimimetic pyrazoline or chiral dihydropyrazole ligands represented by Formula V:V and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, enantiomers, diastereomers, geometric isomers, racemates, tautomers, rotamers, atropisomers, and isotopic variations including at least one deuterium atom and N-oxides thereof.

14. The method of claim 1 , wherein the one or more compounds includes one or more cannabimimetic pyrazoline or chiral dihydropyrazole ligands represented by Formula VI:VI and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, enantiomers, diastereomers, geometric isomers, racemates, tautomers, rotamers, atropisomers, and isotopic variations including at least one deuterium atom and N-oxides thereof.

15. The method of claim 1 , wherein the one or more compounds includes one or more cannabimimetic pyrazole ligands represented by Formula VII:VII and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, enantiomers, diastereomers, geometric isomers, racemates, tautomers, rotamers, atropisomers, and isotopic variations including at least one deuterium atom and N-oxides thereof.

16. The method of claim 1 , wherein the one or more compounds includes one or more cannabimimetic pyrrolidone ligands represented by Formula VIII:VIII and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, enantiomers, diastereomers, geometric isomers, racemates, tautomers, rotamers, atropisomers, and isotopic variations including at least one deuterium atom and N-oxides thereof.

17. The method of claim 1 , wherein the one or more compounds are independently selected from:5-[4-(4-Cyano-but-1 -ynyl)-phenyl]-1 -(2,4-dichloro-phenyl)-4-methyl-1 H-pyrazole-3- carboxylic acid morpholin-4-ylamide (Compound 2);5-[4-(4-Cyano-but-1 -ynyl)-phenyl]-1 -(2,4-dichloro-phenyl)-4-methyl-1 H-pyrazole-3- carboxylic acid piperidin-1-ylamide (Compound 3);1 -(2,4-Dichloro-phenyl)-5-[4-(4-hydroxy-but-1 -ynyl)-phenyl]-4-methyl-1 H-pyrazole-3- carboxylic acid piperidin-1-ylamide;5-[4-(4-Cyano-but-1 -ynyl)-phenyl]-1 -(2,4-dichloro-phenyl)-4-methyl-1 H-pyrazole-3- carboxylic acid (1 ,1-dioxo-1 l6-thiomorpholin-4-yl)-amide;5-[4-(4-Cyano-but-1 -ynyl)-phenyl]-1 -(2,4-dichloro-phenyl)-4-hydroxymethyl-1 H- pyrazole-3-carboxylic acid morpholin-4-ylamide;1 -(2,4-Dichloro-phenyl)-4-methyl-5-[4-(4-nitrooxy-but-1 -ynyl)-phenyl]-1 H-pyrazole-3- carboxylic acid piperidin-1-ylamide;1-[4-(4-Cyano-but-1 -ynyl)-phenyl]-2-(2,4-dichloro-phenyl)-5-methyl-1 H-imidazole-4- carboxylic acid (1 ,1-dioxo-1 l6-thiomorpholin-4-yl)-amide;5-[4-(4-Cyano-but-1 -ynyl)-phenyl]-1 -(2,4-dichloro-phenyl)-4-ethyl-1 H-pyrazole-3- carboxylic acid morpholin-4-ylamideand pharmaceutically acceptable salts, solvates, hydrates, polymorphs, enantiomers, diastereomers, geometric isomers, racemates, tautomers, rotamers, atropisomers, and isotopic variations including at least one deuterium atom, and N-oxides thereof.

18. The method of claim 1 , wherein the one or more compounds are independently selected from:5-[4-(4-Cyano-but-1 -ynyl)-phenyl]-1 -(2,4-dichloro-phenyl)-4-methyl-1 H-pyrazole-3- carboxylic acid morpholin-4-ylamide (Compound 2);5-[4-(4-Cyano-but-1 -ynyl)-phenyl]-1 -(2,4-dichloro-phenyl)-4-methyl-1 H-pyrazole-3- carboxylic acid piperidin-1-ylamide (Compound 3);1 -(2,4-Dichloro-phenyl)-5-[4-(4-hydroxy-but-1 -ynyl)-phenyl]-4-methyl-1 H-pyrazole-3- carboxylic acid piperidin-1-ylamide;1 -(2,4-Dichloro-phenyl)-5-[4-(4-fluoro-but-1 -ynyl)-phenyl]-4-methyl-1 H-pyrazole-3- carboxylic acid piperidin-1-ylamide;1 -(2,4-Dichloro-phenyl)-4-methyl-5-[4-(4-nitrooxy-but-1 -ynyl)-phenyl]-1 H-pyrazole-3- carboxylic acid piperidin-1-ylamide;5-[4-(4-Cyano-but-1 -ynyl)-phenyl]-1 -(2,4-dichloro-phenyl)-4-ethyl-1 H-pyrazole-3- carboxylic acid piperidin-1-ylamide;1 -(2,4-Dichloro-phenyl)-4-ethyl-5-[4-(4-hydroxy-but-1 -ynyl)-phenyl]-1 H-pyrazole-3- carboxylic acid piperidin-1-ylamide;1 -(2,4-Dichloro-phenyl)-4-ethyl-5-[4-(4-fluoro-but-1 -ynyl)-phenyl]-1 H-pyrazole-3- carboxylic acid piperidin-1-ylamide;1 -(2,4-Dichloro-phenyl)-4-ethyl-5-[4-(4-nitrooxy-but-1 -ynyl)-phenyl]-1 H-pyrazole-3- carboxylic acid piperidin-1-ylamide;1 -(2,4-Dichloro-phenyl)-5-[4-(4-hydroxy-but-1 -ynyl)-phenyl]-4-methyl-1 H-pyrazole-3- carboxylic acid morpholin-4-ylamide;1 -(2,4-Dichloro-phenyl)-5-[4-(4-fluoro-but-1 -ynyl)-phenyl]-4-methyl-1 H-pyrazole-3- carboxylic acid morpholin-4-ylamide;1 -(2,4-Dichloro-phenyl)-4-methyl-5-[4-(4-nitrooxy-but-1 -ynyl)-phenyl]-1 H-pyrazole-3- carboxylic acid morpholin-4-ylamide;1 -(2,4-Dichloro-phenyl)-4-ethyl-5-[4-(4-nitrooxy-but-1 -ynyl)-phenyl]-1 H-pyrazole-3- carboxylic acid morpholin-4-ylamide;1 -(2,4-Dichloro-phenyl)-4-ethyl-5-[4-(4-fluoro-but-1 -yny l)-pheny l]-1 H-pyrazole-3- carboxylic acid morpholin-4-ylamide;1 -(2,4-Dichloro-phenyl)-4-ethyl-5-[4-(4-hydroxy-but-1 -ynyl)-phenyl]-1 H-pyrazole-3- carboxylic acid morpholin-4-ylamide;5-[4-(4-Cyano-but-1 -ynyl)-phenyl]-1 -(2,4-dichloro-phenyl)-4-ethyl-1 H-pyrazole-3- carboxylic acid morpholin-4-ylamide;5-[4-(4-Cyano-but-1 -ynyl)-phenyl]-1 -(2,4-dichloro-phenyl)-4-methyl-1 H-pyrazole-3- carboxylic acid (1 ,1-dioxo-1A6-thiomorpholin-4-yl)-amide;1 -(2,4-Dichloro-phenyl)-5-[4-(4-hydroxy-but-1 -ynyl)-phenyl]-4-methyl-1 H-pyrazole-3- carboxylic acid (1 ,1-dioxo-1 A6-thiomorpholin-4-yl)-amide;1 -(2,4-Dichloro-phenyl)-5-[4-(4-fluoro-but-1 -ynyl)-phenyl]-4-methyl-1 H-pyrazole-3- carboxylic acid (1 ,1-dioxo-1 A66-thiomorpholin-4-yl)-amide;1 -(2,4-Dichloro-phenyl)-4-methyl-5-[4-(4-nitrooxy-but-1 -ynyl)-phenyl]-1 H-pyrazole-3- carboxylic acid (1 ,1-dioxo-1 A6-thiomorpholin-4-yl)-amide;1 -(2,4-Dichloro-phenyl)-4-ethyl-5-[4-(4-nitrooxy-but-1 -yny l)-pheny l]-1 H-pyrazole-3- carboxylic acid (1 ,1-dioxo-1 A6-thiomorpholin-4-yl)-amide;1 -(2,4-Dichloro-phenyl)-4-ethyl-5-[4-(4-fluoro-but-1 -ynyl)-phenyl]-1 H-pyrazole-3- carboxylic acid (1 ,1-dioxo-1 A6-thiomorpholin-4-yl)-amide;1 -(2,4-Dichloro-phenyl)-4-ethyl-5-[4-(4-hydroxy-but-1 -ynyl)-phenyl]-1 H-pyrazole-3- carboxylic acid (1 ,1-dioxo-1 A6-thiomorpholin-4-yl)-amide;5-[4-(4-Cyano-but-1 -ynyl)-phenyl]-1 -(2,4-dichloro-phenyl)-4-ethyl-1 H-pyrazole-3- carboxylic acid (1 ,1-dioxo-1 A6-thiomorpholin-4-yl)-amide;5-[4-(5-Cyano-pent-1 -yny l)-pheny l]-1 -(2,4-dichloro-phenyl)-4-ethyl-1 H-pyrazole-3- carboxylic acid piperidin-1-ylamide;1 -(2,4-Dichloro-phenyl)-4-ethyl-5-[4-(5-hydroxy-pent-1 -ynyl)-phenyl]-1 H-pyrazole-3- carboxylic acid piperidin-1-ylamide;1 -(2,4-Dichloro-phenyl)-4-ethyl-5-[4-(5-fluoro-pent-1 -ynyl)-phenyl]-1 H-pyrazole-3- carboxylic acid piperidin-1-ylamide;1 -(2,4-Dichloro-phenyl)-4-ethyl-5-[4-(5-nitrooxy-pent-1 -ynyl)-phenyl]-1 H-pyrazole-3- carboxylic acid piperidin-1-ylamide;1 -(2,4-Dichloro-phenyl)-4-ethyl-5-[4-(5-nitrooxy-pent-1 -yny l)-pheny l]-1 H-pyrazole-3- carboxylic acid morpholin-4-ylamide;1 -(2,4-Dichloro-phenyl)-4-ethyl-5-[4-(5-fluoro-pent-1 -ynyl)-phenyl]-1 H-pyrazole-3- carboxylic acid morpholin-4-ylamide;1 -(2,4-Dichloro-phenyl)-4-ethyl-5-[4-(5-hydroxy-pent-1 -ynyl)-phenyl]-1 H-pyrazole-3- carboxylic acid morpholin-4-ylamide;5-[4-(5-Cyano-pent-1 -yny l)-pheny l]-1 -(2,4-dichloro-phenyl)-4-ethyl-1 H-pyrazole-3- carboxylic acid morpholin-4-ylamide;5-[4-(5-Cyano-pent-1 -ynyl)-phenyl]-1 -(2,4-dichloro-phenyl)-4-ethyl-1 H-pyrazole-3- carboxylic acid (1 ,1-dioxo-1 A6-thiomorpholin-4-yl)-amide;1 -(2,4-Dichloro-phenyl)-4-ethyl-5-[4-(5-fluoro-pent-1 -ynyl)-phenyl]-1 H-pyrazole-3- carboxylic acid (1 ,1-dioxo-1 A6-thiomorpholin-4-yl)-amide;1 -(2,4-Dichloro-phenyl)-4-ethyl-5-[4-(5-hydroxy-pent-1 -ynyl)-phenyl]-1 H-pyrazole-3- carboxylic acid (1 ,1-dioxo-1 A6-thiomorpholin-4-yl)-amide;1 -(2,4-Dichloro-phenyl)-4-ethyl-5-[4-(5-nitrooxy-pent-1 -yny l)-pheny l]-1 H-pyrazole-3- carboxylic acid (1 ,1-dioxo-1 A6-thiomorpholin-4-yl)-amide;1 -(2,4-Dichloro-phenyl)-4-methyl-5-[4-(5-nitrooxy-pent-1 -yny l)-pheny l]-1 H-pyrazole-3- carboxylic acid (1 ,1-dioxo-1 A6-thiomorpholin-4-yl)-amide;1 -(2,4-Dichloro-phenyl)-5-[4-(5-fluoro-pent-1 -ynyl)-phenyl]-4-methyl-1 H-pyrazole-3- carboxylic acid (1 ,1-dioxo-1 A6-thiomorpholin-4-yl)-amide;1 -(2,4-Dichloro-phenyl)-5-[4-(5-hydroxy-pent-1 -ynyl)-phenyl]-4-methyl-1 H-pyrazole-3- carboxylic acid (1 ,1-dioxo-1 A6-thiomorpholin-4-yl)-amide;5-[4-(5-Cyano-pent-1 -yny l)-pheny l]-1 -(2,4-dichloro-phenyl)-4-methyl-1 H-pyrazole-3- carboxylic acid (1 ,1-dioxo-1 A6-thiomorpholin-4-yl)-amide;5-[4-(5-Cyano-pent-1 -ynyl)-phenyl]-1 -(2,4-dichloro-phenyl)-4-methyl-1 H-pyrazole-3- carboxylic acid piperidin-1-ylamide;1 -(2,4-Dichloro-phenyl)-5-[4-(5-hydroxy-pent-1 -ynyl)-phenyl]-4-methyl-1 H-pyrazole-3- carboxylic acid piperidin-1-ylamide;1 -(2,4-Dichloro-phenyl)-5-[4-(5-fluoro-pent-1 -ynyl)-phenyl]-4-methyl-1 H-pyrazole-3- carboxylic acid piperidin-1-ylamide;1 -(2,4-Dichloro-phenyl)-4-methyl-5-[4-(5-nitrooxy-pent-1 -ynyl)-phenyl]-1 H-pyrazole-3- carboxylic acid piperidin-1-ylamide;1 -(2,4-Dichloro-phenyl)-4-methyl-5-[4-(5-nitrooxy-pent-1 -ynyl)-phenyl]-1 H-pyrazole-3- carboxylic acid morpholin-4-ylamide;1 -(2,4-Dichloro-phenyl)-5-[4-(5-hydroxy-pent-1 -ynyl)-phenyl]-4-methyl-1 H-pyrazole-3- carboxylic acid morpholin-4-ylamide;1 -(2,4-Dichloro-phenyl)-5-[4-(5-fluoro-pent-1 -ynyl)-phenyl]-4-methyl-1 H-pyrazole-3- carboxylic acid morpholin-4-ylamide;5-[4-(5-Cyano-pent-1 -ynyl)-phenyl]-1 -(2,4-dichloro-phenyl)-4-methyl-1 H-pyrazole-3- carboxylic acid morpholin-4-ylamide;5-[4-(5-Cyano-pent-1 -ynyl)-phenyl]-1 -(2,4-dichloro-phenyl)-4-hydroxymethyl-1 H- pyrazole-3-carboxylic acid piperidin-1-ylamide;1 -(2,4-Dichloro-phenyl)-4-hydroxymethyl-5-[4-(5-hydroxy-pent-1 -ynyl)-phenyl]-1 H- pyrazole-3-carboxylic acid piperidin-1-ylamide;1 -(2,4-Dichloro-phenyl)-5-[4-(5-fluoro-pent-1 -ynyl)-phenyl]-4-hydroxymethyl-1 H- pyrazole-3-carboxylic acid piperidin-1-ylamide;1 -(2,4-Dichloro-phenyl)-4-hydroxymethyl-5-[4-(5-nitrooxy-pent-1 -ynyl)-phenyl]-1 H- pyrazole-3-carboxylic acid piperidin-1-ylamide;1 -(2,4-Dichloro-phenyl)-4-hydroxymethyl-5-[4-(5-nitrooxy-pent-1 -ynyl)-phenyl]-1 H- pyrazole-3-carboxylic acid morpholin-4-ylamide;1 -(2,4-Dichloro-phenyl)-4-hydroxymethyl-5-[4-(5-hydroxy-pent-1 -ynyl)-phenyl]-1 H- pyrazole-3-carboxylic acid morpholin-4-ylamide;1 -(2,4-Dichloro-phenyl)-5-[4-(5-fluoro-pent-1 -ynyl)-phenyl]-4-hydroxymethyl-1 H- pyrazole-3-carboxylic acid morpholin-4-ylamide;5-[4-(5-Cyano-pent-1 -ynyl)-phenyl]-1 -(2,4-dichloro-phenyl)-4-hydroxymethyl-1 H- pyrazole-3-carboxylic acid morpholin-4-ylamide;5-[4-(5-Cyano-pent-1 -ynyl)-phenyl]-1 -(2,4-dichloro-phenyl)-4-hydroxymethyl-1 H- pyrazole-3-carboxylic acid (1 ,1-dioxo-1 A6-thiomorpholin-4-yl)-amide;1 -(2,4-Dichloro-phenyl)-4-hydroxymethyl-5-[4-(5-hydroxy-pent-1 -ynyl)-phenyl]-1 H- pyrazole-3-carboxylic acid (1 ,1-dioxo-1 A6-thiomorpholin-4-yl)-amide;1 -(2,4-Dichloro-phenyl)-5-[4-(5-fluoro-pent-1 -ynyl)-phenyl]-4-hydroxymethyl-1 H- pyrazole-3-carboxylic acid (1 , 1 -dioxo-1 A6-thiomorpholin-4-yl)-amide;1 -(2,4-Dichloro-phenyl)-4-hydroxymethyl-5-[4-(5-nitrooxy-pent-1 -ynyl)-phenyl]-1 H- pyrazole-3-carboxylic acid (1 , 1 -dioxo-1 A6-thiomorpholin-4-yl)-amide;5-[4-(4-Cyano-but-1 -ynyl)-phenyl]-1 -(2,4-dichloro-phenyl)-4-hydroxymethyl-1 H- pyrazole-3-carboxylic acid (1 ,1-dioxo-1 A6-thiomorpholin-4-yl)-amide;1 -(2,4-Dichloro-phenyl)-5-[4-(4-fluoro-but-1 -ynyl)-phenyl]-4-hydroxymethyl-1 H- pyrazole-3-carboxylic acid (1 ,1-dioxo-1 A6-thiomorpholin-4-yl)-amide;1 -(2,4-Dichloro-phenyl)-5-[4-(4-hydroxy-but-1 -ynyl)-phenyl]-4-hydroxymethyl-1 H- pyrazole-3-carboxylic acid (1 ,1-dioxo-1 A6-thiomorpholin-4-yl)-amide;1 -(2,4-Dichloro-phenyl)-4-hydroxymethyl-5-[4-(4-nitrooxy-but-1 -ynyl)-phenyl]-1 H- pyrazole-3-carboxylic acid (1 , 1 -dioxo-1 A6-thiomorpholin-4-yl)-amide;1 -(2,4-Dichloro-phenyl)-4-hydroxymethyl-5-[4-(4-nitrooxy-but-1 -ynyl)-phenyl]-1 H- pyrazole-3-carboxylic acid piperidin-1-ylamide;1 -(2,4-Dichloro-phenyl)-5-[4-(4-fluoro-but-1 -ynyl)-phenyl]-4-hydroxymethyl-1 H- pyrazole-3-carboxylic acid piperidin-1-ylamide;1 -(2,4-Dichloro-phenyl)-5-[4-(4-hydroxy-but-1 -ynyl)-phenyl]-4-hydroxymethyl-1 H- pyrazole-3-carboxylic acid piperidin-1-ylamide;5-[4-(4-Cyano-but-1 -ynyl)-phenyl]-1 -(2,4-dichloro-phenyl)-4-hydroxymethyl-1 H- pyrazole-3-carboxylic acid piperidin-1-ylamide;5-[4-(4-Cyano-but-1 -ynyl)-phenyl]-1 -(2,4-dichloro-phenyl)-4-hydroxymethyl-1 H- pyrazole-3-carboxylic acid morpholin-4-ylamide;1 -(2,4-Dichloro-phenyl)-5-[4-(4-fluoro-but-1 -ynyl)-phenyl]-4-hydroxymethyl-1 H- pyrazole-3-carboxylic acid morpholin-4-ylamide;1 -(2,4-Dichloro-phenyl)-5-[4-(4-hydroxy-but-1 -ynyl)-phenyl]-4-hydroxymethyl-1 H- pyrazole-3-carboxylic acid morpholin-4-ylamide;1 -(2,4-Dichloro-phenyl)-4-hydroxymethyl-5-[4-(4-nitrooxy-but-1 -ynyl)-phenyl]-1 H- pyrazole-3-carboxylic acid morpholin-4-ylamide;1-[4-(4-Cyano-but-1 -ynyl)-phenyl]-2-(2,4-dichloro-phenyl)-5-methyl-1 H-imidazole-4- carboxylic acid piperidin-1-ylamide;2-(2,4-Dichloro-phenyl)-1 -[4-(4-fluoro-but-1 -ynyl)-phenyl]-5-methyl-1 H-imidazole-4- carboxylic acid piperidin-1-ylamide;2-(2,4-Dichloro-phenyl)-1 -[4-(4-hydroxy-but-1 -ynyl)-phenyl]-5-methyl-1 H-imidazole-4- carboxylic acid piperidin-1-ylamide;2-(2,4-Dichloro-phenyl)-5-methyl-1 -[4-(4-nitrooxy-but-1 -ynyl)-phenyl]-1 H-imidazole-4- carboxylic acid piperidin-1-ylamide;2-(2,4-Dichloro-phenyl)-5-methyl-1 -[4-(4-nitrooxy-but-1 -ynyl)-phenyl]-1 H-imidazole-4- carboxylic acid morpholin-4-ylamide;2-(2,4-Dichloro-phenyl)-1 -[4-(4-hydroxy-but-1 -ynyl)-phenyl]-5-methyl-1 H-imidazole-4- carboxylic acid morpholin-4-ylamide;2-(2,4-Dichloro-phenyl)-1 -[4-(4-fluoro-but-1 -ynyl)-phenyl]-5-methyl-1 H-imidazole-4- carboxylic acid morpholin-4-ylamide;1-[4-(4-Cyano-but-1 -ynyl)-phenyl]-2-(2,4-dichloro-phenyl)-5-methyl-1 H-imidazole-4- carboxylic acid morpholin-4-ylamide;1-[4-(4-Cyano-but-1 -ynyl)-phenyl]-2-(2,4-dichloro-phenyl)-5-methyl-1 H-imidazole-4- carboxylic acid (1 ,1-dioxo-1 A6-thiomorpholin-4-yl)-amide;2-(2,4-Dichloro-phenyl)-1 -[4-(4-fluoro-but-1 -ynyl)-phenyl]-5-methyl-1 H-imidazole-4- carboxylic acid (1 ,1-dioxo-1 A6-thiomorpholin-4-yl)-amide;2-(2,4-Dichloro-phenyl)-1 -[4-(4-hydroxy-but-1 -ynyl)-phenyl]-5-methyl-1 H-imidazole-4- carboxylic acid (1 ,1-dioxo-1 A6-thiomorpholin-4-yl)-amide;2-(2,4-Dichloro-phenyl)-5-methyl-1 -[4-(4-nitrooxy-but-1 -ynyl)-phenyl]-1 H-imidazole-4- carboxylic acid (1 ,1-dioxo-1 A6-thiomorpholin-4-yl)-amide;2-(2,4-Dichloro-phenyl)-5-ethyl-1-[4-(4-nitrooxy-but-1 -ynyl)-phenyl]-1 H-imidazole-4- carboxylic acid (1 ,1-dioxo-1 A6-thiomorpholin-4-yl)-amide;2-(2,4-Dichloro-phenyl)-5-ethyl-1-[4-(4-hydroxy-but-1 -ynyl)-phenyl]-1 H-imidazole-4- carboxylic acid (1 ,1-dioxo-1 A6-thiomorpholin-4-yl)-amide;2-(2,4-Dichloro-phenyl)-5-ethyl-1-[4-(4-fluoro-but-1-ynyl)-phenyl]-1 H-imidazole-4- carboxylic acid (1 ,1-dioxo-1 A6-thiomorpholin-4-yl)-amide;1-[4-(4-Cyano-but-1 -ynyl)-phenyl]-2-(2,4-dichloro-phenyl)-5-ethyl-1 H-imidazole-4- carboxylic acid (1 ,1-dioxo-1 A6-thiomorpholin-4-yl)-amide;1-[4-(4-Cyano-but-1 -ynyl)-phenyl]-2-(2,4-dichloro-phenyl)-5-ethyl-1 H-imidazole-4- carboxylic acid morpholin-4-ylamide;2-(2,4-Dichloro-phenyl)-5-ethyl-1-[4-(4-hydroxy-but-1 -ynyl)-phenyl]-1 H-imidazole-4- carboxylic acid morpholin-4-ylamide;2-(2,4-Dichloro-phenyl)-5-ethyl-1-[4-(4-fluoro-but-1-ynyl)-phenyl]-1 H-imidazole-4- carboxylic acid morpholin-4-ylamide;2-(2,4-Dichloro-phenyl)-5-ethyl-1-[4-(4-nitrooxy-but-1 -ynyl)-phenyl]-1 H-imidazole-4- carboxylic acid morpholin-4-ylamide;2-(2,4-Dichloro-phenyl)-5-ethyl-1-[4-(4-nitrooxy-but-1 -ynyl)-phenyl]-1 H-imidazole-4- carboxylic acid piperidin-1-ylamide;2-(2,4-Dichloro-phenyl)-5-ethyl-1-[4-(4-hydroxy-but-1 -ynyl)-phenyl]-1 H-imidazole-4- carboxylic acid piperidin-1-ylamide;2-(2,4-Dichloro-phenyl)-5-ethyl-1-[4-(4-fluoro-but-1-ynyl)-phenyl]-1 H-imidazole-4- carboxylic acid piperidin-1-ylamide;1-[4-(4-Cyano-but-1 -ynyl)-phenyl]-2-(2,4-dichloro-phenyl)-5-ethyl-1 H-imidazole-4- carboxylic acid piperidin-1-ylamide;1 -[4-(4-Cyano-but-1 -ynyl)-phenyl]-2-(2,4-dichloro-phenyl)-5-hydroxymethyl-1 H- imidazole-4-carboxylic acid piperid in-1 -ylamide;2-(2,4-Dichloro-phenyl)-1 -[4-(4-fluoro-but-1 -ynyl)-phenyl]-5-hydroxymethyl-1 H- imidazole-4-carboxylic acid piperid in-1 -ylamide;2-(2,4-Dichloro-phenyl)-1 -[4-(4-hydroxy-but-1 -ynyl)-phenyl]-5-hydroxymethyl-1 H- imidazole-4-carboxylic acid piperid in-1 -ylamide;2-(2,4-Dichloro-phenyl)-5-hydroxymethyl-1 -[4-(4-nitrooxy-but-1 -ynyl)-phenyl]-1 H- imidazole-4-carboxylic acid piperidin-1 -ylamide;2-(2,4-Dichloro-phenyl)-5-hydroxymethyl-1 -[4-(4-nitrooxy-but-1 -ynyl)-phenyl]-1 H- imidazole-4-carboxylic acid morpholin-4-ylamide;2-(2,4-Dichloro-phenyl)-1 -[4-(4-hydroxy-but-1 -ynyl)-phenyl]-5-hydroxymethyl-1 H- imidazole-4-carboxylic acid morpholin-4-ylamide;2-(2 , 4-D ich loro-pheny l)-1 -[4-(4-fluoro-but-1 -ynyl)-phenyl]-5-hydroxymethyl-1 H- imidazole-4-carboxylic acid morpholin-4-ylamide;1 -[4-(4-Cyano-but-1 -ynyl)-phenyl]-2-(2,4-dichloro-phenyl)-5-hydroxymethyl-1 H- imidazole-4-carboxylic acid morpholin-4-ylamide;1 -[4-(4-Cyano-but-1 -ynyl)-phenyl]-2-(2,4-dichloro-phenyl)-5-hydroxymethyl-1 H- imidazole-4-carboxylic acid (1 ,1 -dioxo-1 A6-thiomorpholin-4-yl)-amide;2-(2,4-Dichloro-phenyl)-1 -[4-(4-fluoro-but-1 -ynyl)-phenyl]-5-hydroxymethyl-1 H- imidazole-4-carboxylic acid (1 ,1 -dioxo-1 A6-thiomorpholin-4-yl)-amide;2-(2,4-Dichloro-phenyl)-1 -[4-(4-hydroxy-but-1 -ynyl)-phenyl]-5-hydroxymethyl-1 H- imidazole-4-carboxylic acid (1 ,1 -dioxo-1 A6-thiomorpholin-4-yl)-amide;2-(2,4-Dichloro-phenyl)-5-hydroxymethyl-1 -[4-(4-nitrooxy-but-1 -ynyl)-phenyl]-1 H- imidazole-4-carboxylic acid (1 ,1 -dioxo-1 A6-thiomorpholin-4-yl)-amide;1-[4-(5-Cyano-pent-1-ynyl)-phenyl]-2-(2,4-dichloro-phenyl)-5-methyl-1 H-imidazole-4- carboxylic acid (1 ,1-dioxo-1 A6-thiomorpholin-4-yl)-amide;2-(2,4-Dichloro-phenyl)-1 -[4-(5-hydroxy-pent-1 -ynyl)-phenyl]-5-methyl-1 H-imidazole- 4-carboxylic acid (1 ,1 -dioxo-1 A6-thiomorpholin-4-yl)-amide;2-(2,4-Dichloro-phenyl)-1 -[4-(5-fluoro-pent-1-ynyl)-phenyl]-5-methyl-1 H-imidazole-4- carboxylic acid (1 ,1-dioxo-1 A6-thiomorpholin-4-yl)-amide;2-(2,4-Dichloro-phenyl)-5-methyl-1 -[4-(5-nitrooxy-pent-1-ynyl)-phenyl]-1 H-imidazole- 4-carboxylic acid (1 ,1 -dioxo-1 A6-thiomorpholin-4-yl)-amide;2-(2,4-Dichloro-phenyl)-5-ethyl-1-[4-(5-nitrooxy-pent-1-ynyl)-phenyl]-1 H-imidazole-4- carboxylic acid (1 ,1-dioxo-1 A6-thiomorpholin-4-yl)-amide;2-(2,4-Dichloro-phenyl)-5-ethyl-1-[4-(5-hydroxy-pent-1-ynyl)-phenyl]-1 H-imidazole-4- carboxylic acid (1 ,1-dioxo-1 A6-thiomorpholin-4-yl)-amide;2-(2,4-Dichloro-phenyl)-5-ethyl-1 -[4-(5-fluoro-pent-1 -ynyl)-phenyl]-1 H-imidazole-4- carboxylic acid (1 ,1-dioxo-1 l6-thiomorpholin-4-yl)-amide;1-[4-(5-Cyano-pent-1-ynyl)-phenyl]-2-(2,4-dichloro-phenyl)-5-ethyl-1 H-imidazole-4- carboxylic acid (1 ,1-dioxo-1 l6-thiomorpholin-4-yl)-amide;1-[4-(5-Cyano-pent-1-ynyl)-phenyl]-2-(2,4-dichloro-phenyl)-5-methyl-1 H-imidazole-4- carboxylic acid piperidin-1-ylamide;2-(2,4-Dichloro-phenyl)-1 -[4-(5-fluoro-pent-1-ynyl)-phenyl]-5-methyl-1 H-imidazole-4- carboxylic acid piperidin-1-ylamide;2-(2,4-Dichloro-phenyl)-1 -[4-(5-hydroxy-pent-1 -ynyl)-phenyl]-5-methyl-1 H-imidazole- 4-carboxylic acid piperidin-1 -ylamide;2-(2,4-Dichloro-phenyl)-5-methyl-1 -[4-(5-nitrooxy-pent-1-ynyl)-phenyl]-1 H-imidazole- 4-carboxylic acid piperidin-1 -ylamide;2-(2,4-Dichloro-phenyl)-5-methyl-1 -[4-(5-nitrooxy-pent-1-ynyl)-phenyl]-1 H-imidazole- 4-carboxylic acid morpholin-4-ylamide;2-(2,4-Dichloro-phenyl)-1 -[4-(5-hydroxy-pent-1 -ynyl)-phenyl]-5-methyl-1 H-imidazole- 4-carboxylic acid morpholin-4-ylamide;2-(2,4-Dichloro-phenyl)-1 -[4-(5-fluoro-pent-1-ynyl)-phenyl]-5-methyl-1 H-imidazole-4- carboxylic acid morpholin-4-ylamide;1-[4-(5-Cyano-pent-1-ynyl)-phenyl]-2-(2,4-dichloro-phenyl)-5-methyl-1 H-imidazole-4- carboxylic acid morpholin-4-ylamide;1-[4-(5-Cyano-pent-1-ynyl)-phenyl]-2-(2,4-dichloro-phenyl)-5-ethyl-1 H-imidazole-4- carboxylic acid morpholin-4-ylamide;2-(2,4-Dichloro-phenyl)-5-ethyl-1 -[4-(5-fluoro-pent-1 -ynyl)-phenyl]-1 H-imidazole-4- carboxylic acid morpholin-4-ylamide;2-(2,4-Dichloro-phenyl)-5-ethyl-1-[4-(5-hydroxy-pent-1-ynyl)-phenyl]-1 H-imidazole-4- carboxylic acid morpholin-4-ylamide;2-(2,4-Dichloro-phenyl)-5-ethyl-1-[4-(5-nitrooxy-pent-1-ynyl)-phenyl]-1 H-imidazole-4- carboxylic acid morpholin-4-ylamide;2-(2,4-Dichloro-phenyl)-5-ethyl-1-[4-(5-nitrooxy-pent-1-ynyl)-phenyl]-1 H-imidazole-4- carboxylic acid piperidin-1-ylamide;2-(2,4-Dichloro-phenyl)-5-ethyl-1-[4-(5-hydroxy-pent-1-ynyl)-phenyl]-1 H-imidazole-4- carboxylic acid piperidin-1-ylamide;2-(2,4-Dichloro-phenyl)-5-ethyl-1 -[4-(5-fluoro-pent-1 -ynyl)-phenyl]-1 H-imidazole-4- carboxylic acid piperidin-1-ylamide; and 1-[4-(5-Cyano-pent-1-ynyl)-phenyl]-2-(2,4-dichloro-phenyl)-5-ethyl-1 H-imidazole-4- carboxylic acid piperidin-1-ylamide, and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, enantiomers, diastereomers, geometric isomers, racemates,tautomers, rotamers, atropisomers, and isotopic variations including at least one deuterium atom, and N-oxides thereof.

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