BACKGROUND OF THE INVENTION
In 1999, 61% of adults, 13% of children aged 6 to 11 years and 14% of adolescents aged 12 to 19 years in the United States were overweight. Increases in occurrence of overweight and obesity has been seen in all age, racial and ethnic groups, and in both men and women.
Epidemiological studies show an increase in mortality associated with overweight and obesity. Individuals who are obese (body mass index (“BMI”)>30) have a 50-100% increased risk of premature death from all causes compared to individuals with a BMI in the range of 20 to 25. BMI is calculated according to the formula:
An estimated 300,000 deaths a year in the United States may be attributable to obesity. Overweight and obesity are associated with an increased risk for coronary heart disease; type 2 diabetes; endometrial, colon, postmenopausal breast, and other cancers; and certain musculoskeletal disorders, such as knee osteoarthritis.
Both modest and large weight gains are associated with significantly increased risk of disease. For example, a weight gain of 11 to 18 pounds increases a person's risk of developing type 2 diabetes to twice that of individuals who have not gained weight, while those who gain 44 pounds or more have four times the risk of type 2 diabetes. A gain of approximately 10 to 20 pounds results in an increased risk of coronary heart disease (nonfatal myocardial infarction and death) of 1.25 times in women and 1.6 times in men. Higher levels of body weight gain of 22 pounds in men and 44 pounds in women result in an increased coronary heart disease risk of 1.75 and 2.65, respectively. In women with a BMI of 34 or greater, the risk of developing endometrial cancer is increased by more than six times. Overweight and obesity are also known to exacerbate many chronic conditions such as hypertension and elevated cholesterol. Overweight and obese individuals also may suffer from social stigmatization, discrimination, and poor body image. Although obesity-associated morbidities occur most frequently in adults, important consequences of excess weight as well as antecedents of adult disease occur in overweight children and adolescents. Overweight children and adolescents are more likely to become overweight or obese adults; this concern is greatest among adolescents. Type 2 diabetes, high blood lipids, and hypertension as well as early maturation and orthopedic problems also occur with increased frequency in overweight youth. A common consequence of childhood overweight is psychosocial-specifically discrimination. See The Surgeon General's Call To Action To Prevent and Decrease Overweight and Obesity, U.S. Dept. of Health and Human Services, 2001. Thus, the need exists for methods of controlling weight and treating obesity.
Melanin-concentrating hormone (MCH) is a cyclic, 19-amino acid hypothalamic neuropeptide derived from a larger pro-hormone precursor of MCH, Pmch. Pmch-deficient mice are lean, hypophagic, and have an increased metabolic rate. Transgenic mice over-expressing Pmch are hyperphagic and develop mild obesity. Consequently, MCH has been implicated in the regulation of energy homeostasis, through actions on motor activity, metabolism, food intake and neuroendocrine function.
Two receptors have been identified in MCH, and are designated MCH 1 receptor and MCH 2 receptor. The MCH 1 and MCH 2 receptors are G protein-coupled receptors (GPCRs) believed to be responsible for the actions of MCH. G proteins are heterotrimeric proteins that control cellular responses to stimuli by cycling between a GTP-bound active state, which regulates the activity of a number of effector proteins, and a GDP-bound inactive state. GPCRs accelerate activation of the G protein by increasing the GDP/GTP exchange rate.
MCH 1 receptor-deficient mice have normal body weights, yet are lean and have reduced fat mass. Surprisingly, MCH 1 receptor-deficient mice are hyperphagic when maintained on regular chow, and their leanness is a consequence of hyperactivity and altered metabolism. Consistent with the hyperactivity, MCH 1 receptor-deficient mice are less susceptible to diet-induced obesity. Importantly, chronic central infusions of MCH induce hyperphagia and mild obesity in wild-type mice, but not in MCH 1 receptor-deficient mice. Marsh et al., Proc. Nat. Acad. Sci., 99(5), 3241 (2002).
Because MCH has been shown to be an important regulator of food intake and energy balance, compounds capable of modulating the activity of MCH receptors, particularly MCH 1 receptors, are highly desirable for the treatment of eating disorders and metabolic disorders.
PCT Publication No. WO 02/04433 describes phenylcycloalkylmethylamino and phenylalkenylamino derivatives as modulators of MCH 1 receptors useful in the treatment of certain metabolic, feeding and sexual disorders.
U.S. Pat. No. 6,472,394 describes the use of amide derivatives of 1,4-disubstituted piperidine as MCH antagonists for the treatment of obesity and diabetes.
SUMMARY OF THE INVENTION
Among the several objects of certain embodiments of the present invention, therefore, may be noted the provision of melanin concentrating hormone receptor antagonists; the provision of pharmaceutical compositions comprising melanin concentrating hormone receptor antagonists; the provision of methods of treating, preventing, or otherwise ameliorating melanin concentrating hormone-mediated disorders in a subject; the provision of methods for treating, preventing or otherwise ameliorating obesity in a subject; and the provision of methods of achieving sustained body weight loss in a subject.
Briefly therefore, the present invention is directed to a melanin concentrating hormone receptor antagonist of Formula I as defined herein.
The present invention is also directed to pharmaceutical compositions comprising a compound of Formula I, as defined herein, and a pharmaceutically acceptable carrier, adjuvant, or diluent.
The present invention is also directed to a method of inhibiting a GPCR, comprising contacting a compound of Formula I, as defined herein, with a GPCR, wherein the compound of Formula I is present at a concentration sufficient to inhibit the binding of a GPCR ligand in vitro. This method includes inhibiting a GPCR in vivo, e.g., in a subject given an amount of a compound of Formula I that would be sufficient to inhibit the binding of a ligand to the GCPR in vitro. Examples of GPCRs which may be inhibited according to the present invention include, but are not limited to the following GPCR families: Acetylcholine muscarinic, Adenosine, adrenergic, adrenergic, alpha-adrenergic, angiotensin, AR, Cannabinoid, DA, dopamine, His, imidazoline, Leukotriene, mAch, MCH, Opioid, serotonergic, serotonin, and Somatostatin.
Inhibition of the binding of a GPCR ligand to GPCRs is useful in the treatment of numerous disorders, including digestive tract disorders; mucolytic asthma; arrhythmia; ischemia; reperfusion injury; bronchospasm associated with asthma, emphysema and chronic bronchitis; acute and chronic respiratory diseases, including cystic fibrosis; cardiostimulant; chronic bronchitis; neurological depression; heart failure; benign prostate hypertrophy; diabetes; muscle spasm; myocardial infarction; stroke; Alzheimer's disease; anorexia; cachexia; multiple sclerosis; hyperprolactinemia; psychotropism; mydriasis in ocular examination and surgery; deficitary and productive schizophrenia, psychasthenia and non-endogenous depression; kidney disease; vasodilation; chronic gastritis; glaucoma; depression; rhinitis, including allergic rhinitis; pain, including cancer pain, musculoskeletal pain, post-operative pain; eye disease; dyspepsia; cough; ulcer, including gastrointestinal, gastric and esophageal ulcers; helicobacter pylori prophylaxis infection; oesophagitis; allergies, including non-asthma allergies; cold; asthma; conjuctivitis; urticaria; diarrhea; Creutzfeldt-Jakob disease; dysmenorrhoea; drug addiction and drug overdose; septic shock treatment; cerebral ischaemia; drug posoning; head trauma; inflammation; pruritus; tardive dyskinesia; emesis; anxiety; motility dysfunction; cluster headaches; hypertension; cancer; irritable bowel syndrome; hemotherapy-induced nausea and vomiting; thrombosis; dementia; opiate-induced nausea and vomiting; bipolar depression; migraine; sleep disorders; traumatic shock; gastritis; gastro-oesophageal reflux; psychosis; Parkinson disease; Dependence treatment; Pre-eclampsia; Raynaud's disease; Vasospasm; haemostasis; nausea and vomiting; spasms; post-operative nausea and vomiting; alcoholism, alcohol addiction; bulimia; nicotine addiction; obsessive-compulsive disorder; panic disorder; post-traumatic stress disorder; premenstrual syndrome; and dermatitis, including allergic dermatitis.
The present invention is also directed to methods of inhibiting the binding of MCH to MCH receptors comprising contacting a compound of Formula I with cells expressing MCH receptors, wherein the compound is present at a concentration sufficient to inhibit MCH binding to MCH receptors in vitro. This method includes inhibiting the binding of MCH to MCH receptors in vivo, e.g., in a subject given an amount of a compound of Formula I that would be sufficient to inhibit the binding of MCH to the MCH receptors in vitro. The amount of a compound of Formula I that would be sufficient to inhibit the binding of MCH to the MCH receptor in vitro may be readily determined via a MCH receptor binding assay, such as the assay described hereinbelow in Example 24.
The present invention is also directed to methods for altering the signal-transducing activity of MCH receptors, particularly the MCH receptor-mediated release of intracellular calcium, said method comprising exposing cells expressing such receptors to an effective amount of a compound of the invention. This method includes altering the signal-transducing activity of MCH receptors in vivo, e.g., in a subject given an amount of a compound of Formula I that would be sufficient to alter the signal-transducing activity of MCH receptors in vitro. The amount of a compound that would be sufficient to alter the signal-transducing activity of MCH receptors may be determined via a MCH receptor signal transduction assay, such as the calcium mobilization assay described hereinbelow in Example 23.
The present invention is also directed to methods of using compounds of Formula I and appropriately labeled derivatives thereof as standards and reagents in determining the ability of a potential pharmaceutical to bind to MCH receptor.
The present invention is also directed to methods of treating, preventing, or otherwise ameliorating melanin concentrating hormone-mediated disorders in a subject, the method comprising administering a compound of Formula I or a pharmaceutical composition comprising a compound of Formula I and a pharmaceutically-acceptable carrier, adjuvant, or diluent to said subject.
The present invention is also directed to methods of treating or preventing obesity in a subject, the method comprising administering a compound of Formula I or a pharmaceutical composition comprising a compound of Formula I and a pharmaceutically-acceptable carrier, adjuvant, or diluent to said subject.
The present invention is also directed to methods of treating or preventing conditions such as feeding disorders, including obesity, bulimia and bulimia nervosa; sexual or reproductive disorders; depression and anxiety; epileptic seizure; hypertension; cerebral hemorrhage; congestive heart failure; sleep disturbances; or any condition in which antagonism of an MCH receptor is beneficial.
The present invention is also directed to methods of treating eating disorders, particularly obesity and bulimia nervosa, comprising administering to a subject in need of such treatment a compound of Formula I in combination with leptin, a leptin receptor agonist, or a melanocortin receptor 4 (MC4) agonist.
The present invention is also directed to methods of using compounds of Formula I as positive controls in assays for activity of GPCRs, particularly MCH.
The present invention is also directed to methods of using appropriately labeled compounds of Formula I as probes for the localization of GPCRs, particularly MCH, in tissue sections.
Other objects and features will be in part apparent and in part pointed out hereinafter.
Abbreviations and Definitions
The term “alkyl”, where used alone or within other terms such as “haloalkyl”, “alkylsulfonyl”, “alkoxyalkyl” and “hydroxyalkyl”, is a linear or branched radical having one to about twenty carbon atoms or, preferably, one to about twelve carbon atoms. More preferred alkyl radicals are “lower alkyl” radicals having one to about ten carbon atoms. Most preferred are lower alkyl radicals having one to about six carbon atoms. Examples of such radicals include methyl, ethyl, propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, sec-butyl, and tert-butyl), pentyl (e.g., n-pentyl and iso-amyl), hexyl, and the like.
The term “cycloalkyl” is a saturated carbocyclic radical having three to twelve carbon atoms. The cycloalkyl radical may be mono-, bi-, or tricyclic. More preferred cycloalkyl radicals are “lower cycloalkyl” radicals having three to about eight carbon atoms. Examples of such radicals include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
The term “alkenyl” is a linear or branched radical having at least one carbon-carbon double bond and having two to about twenty carbon atoms or, preferably, two to about twelve carbon atoms. More preferred alkyl radicals are “lower alkenyl” radicals having two to about six carbon atoms. Examples of alkenyl radicals include ethenyl, propenyl, allyl, butenyl and 4-methylbutenyl. The terms “alkenyl” and “lower alkenyl” also are radicals having “cis” and “trans” orientations, or alternatively, “E” and “Z” orientations.
The term “cycloalkenyl” is a partially unsaturated carbocyclic radical having three to twelve carbon atoms. The cycloalkenyl radicals may be mono-, bi-, or tricyclic. More preferred cycloalkenyl radicals are “lower cycloalkenyl” radicals having four to about eight carbon atoms. Examples of such radicals include cyclobutenyl, cyclopentenyl, cyclopentadienyl, and cyclohexenyl.
The term “alkynyl” is a linear or branched radical having at least one carbon-carbon triple bond and having two to about twenty carbon atoms or, preferably, two to about twelve carbon atoms. More preferred alkynyl radicals are “lower alkynyl” radicals having two to about ten carbon atoms. Most preferred are lower alkynyl radicals having two to about six carbon atoms. Examples of such radicals include propargyl, butynyl, and the like.
The terms “carboxy” or “carboxyl”, whether used alone or with other terms, such as “carboxyalkyl”, is —CO2H.
The term “carboxyalkyl” is an alkyl radical as defined above substituted with a carboxy radical. More preferred are “lower carboxyalkyl” radicals, which are lower alkyl radicals as defined above substituted with a carboxy radical, and may be additionally substituted on the alkyl radical with halo. Examples of such lower carboxyalkyl radicals include carboxymethyl, carboxyethyl and carboxypropyl.
The term “halo” is a halogen such as fluorine, chlorine, bromine or iodine.
The term “haloalkyl” is an alkyl radical as defined above wherein any one or more of the carbon atoms is substituted with halo as defined above. Specifically included are monohaloalkyl, dihaloalkyl and polyhaloalkyl radicals. A monohaloalkyl radical, for one example, may have either an iodo, bromo, chloro or fluoro atom within the radical. Dihalo and polyhaloalkyl radicals may have two or more of the same halo atoms or a combination of different halo radicals. More preferred haloalkyl radicals are “lower haloalkyl” having one to six carbon atoms. Examples of lower haloalkyl radicals include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl.
The terms “alkoxy” and “alkyloxy” are linear or branched oxy-containing radicals each having alkyl portions of one to about ten carbon atoms. More preferred alkoxy radicals are “lower alkoxy” radicals having one to six carbon atoms. Examples of such radicals include methoxy, ethoxy, propoxy, butoxy and tert-butoxy. The “alkoxy” radicals may be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide haloalkoxy radicals. More preferred haloalkoxy radicals are “lower haloalkoxy” radicals having one to six carbon atoms and one or more halo radicals. Examples of such radicals include fluoromethoxy, chloromethoxy, trifluoromethoxy, trifluoroethoxy, fluoroethoxy and fluoropropoxy.
The term “alkoxyalkyl” is an alkyl radical having one or more alkoxy radicals attached to the alkyl radical, that is, to form monoalkoxyalkyl and polyalkoxyalkyl radicals. More preferred alkoxyalkyl radicals are “lower alkoxyalkyl” radicals having two to twelve carbon atoms. Examples of such radicals include methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, dimethoxymethyl, dimethoxyethyl, methoxy(ethoxy)ethyl, dimethoxypropyl, and methoxy(ethoxy)propyl.
The term “alkoxycarbonyl” is a radical containing an alkoxy radical, as defined above, attached via an oxygen atom to a carbonyl radical, i.e., an ester radical. More preferred are “lower alkoxycarbonyl” radicals with alkyl portions having one to six carbons. Examples of such lower alkoxycarbonyl radicals include substituted or unsubstituted methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl and hexyloxycarbonyl.
The term “hydroxyalkyl” is a linear or branched alkyl radical having one to about ten carbon atoms, any one of which may be substituted with one or more hydroxyl radicals. More preferred hydroxyalkyl radicals are “lower hydroxyalkyl” radicals having one to six carbon atoms and one or more hydroxyl radicals. Examples of such radicals include hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl and hydroxyhexyl.
The term “alkylamino” is an amino group that has been substituted with one or two alkyl radicals. Preferred are “lower N-alkylamino” radicals having alkyl portions having one to six carbon atoms. Suitable lower alkylamino may be mono- or dialkylamino, such as N-methylamino, N-ethylamino, N,N-dimethylamino, N,N-diethylamino or the like.
The term “alkylaminoalkyl” is a radical having one or more alkyl radicals attached to the nitrogen atom of an aminoalkyl radical.
The term “alkylaminocarbonyl” is an aminocarbonyl group that has been substituted with one or two alkyl radicals on the amino nitrogen atom. Preferred are “N-alkylaminocarbonyl” “N,N-dialkylaminocarbonyl” radicals. More preferred are “lower N-alkylaminocarbonyl” and “lower N,N-dialkylaminocarbonyl” radicals with lower alkyl portions as defined above.
The term “alkylthio” is a radical containing an alkyl radical of one to about ten carbon atoms attached to a divalent sulfur atom. More preferred alkylthio radicals are “lower alkylthio” radicals having alkyl radicals of one to six carbon atoms. Examples of such lower alkylthio radicals are methylthio, ethylthio, propylthio, butylthio and hexylthio.
The term “alkylthioalkyl” is a radical containing an alkylthio radical attached through the divalent sulfur atom to an alkyl radical of one to about ten carbon atoms. More preferred alkylthioalkyl radicals are “lower alkylthioalkyl” radicals having alkyl radicals of one to six carbon atoms. Examples of such lower alkylthioalkyl radicals include methylthiomethyl, methylthioethyl, ethylthioethyl, and ethylthiopropyl.
The term “alkylsulfinyl” is a radical containing a linear or branched alkyl radical, of one to ten carbon atoms, attached to a divalent —S(═O)— radical. More preferred alkylsulfinyl radicals are “lower alkylsulfinyl” radicals having alkyl radicals of one to six carbon atoms. Examples of such lower alkylsulfinyl radicals include methylsulfinyl, ethylsulfinyl, butylsulfinyl and hexylsulfinyl.
The term “aminoalkyl” is an alkyl radical substituted with one or more amino radicals. More preferred are “lower aminoalkyl” radicals of one to six carbon atoms. Examples of such radicals include aminomethyl, aminoethyl, and the like.
The term “aminocarbonyl” is an amide group of the formula —C(═O)NH2.
The term “carbonyl”, whether used alone or with other terms, such as “alkoxycarbonyl”, is —(C═O)—.
The term “aryl”, alone or in combination, is a carbocyclic aromatic system containing one, two or three rings wherein such rings may be attached together in a pendent manner or may be fused, and wherein at least one of the rings is aromatic. The term “aryl” includes aromatic radicals such as phenyl, naphthyl, tetrahydronaphthyl, indane and biphenyl. Aryl moieties may also be substituted at a substitutable position with one or more substituents selected independently from alkyl, alkoxyalkyl, alkylaminoalkyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, alkoxy, aralkoxy, hydroxyl, amino, halo, nitro, alkylamino, acyl, cyano, carboxy, aminocarbonyl, alkoxycarbonyl and aralkoxycarbonyl.
The terms “heterocyclyl” and “heterocyclo” are saturated or partially unsaturated heteroatom-containing ring-shaped radicals having one, two, or three rings wherein such rings may be attached together in a pendent manner or may be fused, where the heteroatoms may be selected from nitrogen, sulfur and oxygen. Examples of saturated heterocyclyl and heterocyclo radicals include saturated 3- to 6-membered heteromonocylic radicals containing one to four nitrogen atoms (e.g., pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl, etc.); saturated 3- to 6-membered heteromonocyclic group containing one to two oxygen atoms and one to three nitrogen atoms (e.g., morpholinyl, etc.); saturated 3- to 6-membered heteromonocyclic group containing one to two sulfur atoms and one to three nitrogen atoms (e.g., thiazolidinyl, etc.). Examples of partially unsaturated heterocyclyl and heterocyclo radicals include dihydrothiophene, dihydropyran, dihydrofuran and dihydrothiazole.
The term “heteroaryl” is an aromatic heteroatom-containing ring-shaped radical having one, two, or three rings wherein at least one ring is aromatic. Examples of heteroaryl radicals include unsaturated 3- to 6-membered heteromonocyclic group containing one to four nitrogen atoms, e.g., pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl (e.g., 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.) tetrazolyl (e.g. 1H-tetrazolyl, 2H-tetrazolyl, etc.), etc.; unsaturated condensed heterocyclyl group containing one to five nitrogen atoms, e.g., indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl (e.g., tetrazolo[1,5-b]pyridazinyl, etc.), etc.; unsaturated 3- to 6-membered heteromonocyclic group containing an oxygen atom, e.g., pyranyl, furyl, etc.; unsaturated 3- to 6-membered heteromonocyclic group containing a sulfur atom, e.g., thienyl, etc.; unsaturated 3- to 6-membered heteromonocyclic group containing one to two oxygen atoms and one to three nitrogen atoms, e.g., oxazolyl, isoxazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.) etc.; unsaturated condensed heterocyclyl group containing one to two oxygen atoms and one to three nitrogen atoms (e.g., benzoxazolyl, benzoxadiazolyl, etc.); unsaturated 3- to 6-membered heteromonocyclic group containing one to two sulfur atoms and one to three nitrogen atoms, e.g., thiazolyl, thiadiazolyl (e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, etc.) etc.; unsaturated condensed heterocyclyl group containing one to two sulfur atoms and one to three nitrogen atoms (e.g., benzothiazolyl, benzothiadiazolyl, etc.) and the like. The term “heteroaryl” also includes radicals where heteroaryl radicals are fused with aryl radicals. Examples of such fused bicyclic radicals include benzofuran, benzothiophene, and the like. Said heterocyclyl group may be substituted at a substitutable position with one or more substituents selected independently from alkyl, hydroxyl, halo, alkoxy, oxo, amino and alkylamino.
The terms “heterocyclylalkyl” and “heterocycloalkyl” are saturated and partially unsaturated heterocyclyl-substituted alkyl radicals, such as pyrrolidinylmethyl, and heteroaryl-substituted alkyl radicals, such as pyridylmethyl, quinolylmethyl, thienylmethyl, furylethyl, and quinolylethyl. The heteroaryl in said heteroaralkyl may be additionally substituted with halo, alkyl, alkoxy, halkoalkyl and haloalkoxy.
The term “acyl” is a radical provided by the residue after removal of hydroxyl from an organic acid. Examples of such acyl radicals include alkanoyl and aroyl radicals.
The term “alkanoyl” or “alkylcarbonyl” are alkyl radicals as defined herein attached to a carbonyl radical. Examples of such alkanoyl radicals include formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, and trifluoroacetyl.
The terms “arylcarbonyl” (also called “aroyl”) and “aralkylcarbonyl” include radicals having aryl or aralkyl radicals, as defined herein, attached to a carbonyl radical. Examples of such radicals include substituted or unsubstituted phenylcarbonyl, naththoyl, and benzylcarbonyl. The aryl in said aroyl and aralkylcarbonyl radicals may be additionally substituted.
The term “aralkoxy” is an aralkyl radical as defined herein attached through an oxygen atom to other radicals.
The term “aralkoxyalkyl” is an aralkoxy radical as defined herein attached through an oxygen atom to an alkyl radical.
The terms “aralkyl” and “arylalkyl” are aryl-substituted alkyl radicals such as benzyl, diphenylmethyl, triphenylmethyl, phenylethyl, and diphenylethyl. The aryl in said aralkyl may be additionally substituted with halo, alkyl, alkoxy, halkoalkyl and haloalkoxy. The terms benzyl and phenylmethyl are interchangeable.
The term “aralkylamino” is an aralkyl radical as defined herein attached through an amino nitrogen atom to other radicals. The terms “N-arylaminoalkyl” and “N-aryl-N-alkyl-aminoalkyl” are amino groups which have been substituted with one aryl radical or one aryl and one alkyl radical, respectively, and having the amino group attached to an alkyl radical. Examples of such radicals include N-phenylaminomethyl and N-phenyl-N-methylaminomethyl.
The term “aralkylthio” is an aralkyl radical attached to a sulfur atom.
The term “aralkylthioalkyl” is an aralkylthio radical attached through a sulfur atom to an alkyl radical.
The term “arylamino” is an amino group that has been substituted with one or two aryl radicals. An example of such arylamino radicals is N-phenylamino. The “arylamino” radicals may be further substituted on the aryl ring portion of the radical.
The term “aryloxyalkyl” is a radical having an aryl radical attached to an alkyl radical through a divalent oxygen atom.
The term “arylthioalkyl” is a radical having an aryl radical attached to an alkyl radical through a divalent sulfur atom.
The term “sulfonyl”, whether used alone or linked to other terms such as alkylsulfonyl, is a divalent —SO2— radical.
The term “alkylsulfonyl” is an alkyl radical attached to a sulfonyl radical, where alkyl is defined as above. More preferred alkylsulfonyl radicals are “lower alkylsulfonyl” radicals having one to six carbon atoms. Examples of such lower alkylsulfonyl radicals include methylsulfonyl, ethylsulfonyl and propylsulfonyl. The “alkylsulfonyl” radicals may be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide haloalkylsulfonyl radicals.
The terms “sulfamyl”, “aminosulfonyl” and “sulfonamidyl” are —SO2NH2.
The term “pharmaceutically acceptable” is used adjectivally herein to mean that the modified noun is appropriate for use in a pharmaceutical product; that is the “pharmaceutically-acceptable” material is relatively safe and/or non-toxic, though not necessarily providing a separable therapeutic benefit by itself. Pharmaceutically-acceptable cations include metallic ions and organic ions. More preferred metallic ions include, but are not limited to, appropriate alkali metal salts, alkaline earth metal salts and other physiologically-acceptable metal ions. Exemplary ions include aluminum, calcium, lithium, magnesium, potassium, sodium and zinc, in their usual valences. Preferred organic ions include protonated tertiary amines and quaternary ammonium cations, including in part, trimethylamine, diethylamine, N,N′-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine. Exemplary pharmaceutically acceptable acids include without limitation hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, methanesulfonic acid, acetic acid, formic acid, tartaric acid, maleic acid, malic acid, citric acid, isocitric acid, succinic acid, lactic acid, gluconic acid, glucuronic acid, pyruvic acid, oxalacetic acid, fumaric acid, propionic acid, aspartic acid, glutamic acid, benzoic acid, and the like.
The term “prodrug” refers to a chemical compound that can be converted into a therapeutic compound by metabolic or simple chemical processes within the body of the subject.
The term “subject” for purposes of treatment or prevention includes any human or animal subject who is in need of treatment. The subject can be a domestic livestock species, a laboratory animal species, a zoo animal or a companion animal. In one embodiment, the subject is a mammal. In another embodiment, the mammal is a human being.
The term “PBS” stands for phosphate buffered saline.
The term “HEPES” stands for N-2-hydroxyethylpiperazine-N′-2-ethanesulfonic acid.
The term “BSA” stands for bovine serum albumin.
The term “STI” stands for soybean trypsin inhibitor.
The term “Pefabloc” stands for (4-(2-aminoethyl)benzenesulfonylfluoride, HCl salt.
The term “Phosphoramidon” stands for N-α-L-rhamnopyranosyloxy(hydroxyphosphinyl)-L-leucyl-L-tryptophan.
The term “FCC” stands for flash column chromatography.
The term “Ki” stands for inhibitory rate constant.
The term “FLIPR” stands for fluorometric imaging plate reader.
The term “HEK 293” stands for the human embryonic kidney 293 cell line.
The term “Boc” stands for tert-butoxycarbonyl.
The term “DIC” stands for diisopropylcarbodiimide.
The term “DCM” stands for dichloromethane.
The term “DBU” stands for 1,8-diazabicyclo[5.4.0]undec-7-ene.
The term “phosgene” stands for COCl2.
The term “DCE” stands for dichloroethane.
The term “DMF” stands for dimethylformamide.
The term “EtOAc” stands for ethyl acetate.
The term “HOBt” stands for 1-Hydroxybenzotriazole hydrate.
The term “MeOH” stands for methanol.
The term “TFA” stands for trifluoroacetic acid.
The MCH receptor antagonists employed in the present invention can exist in tautomeric, geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis- and trans-geometric isomers, E- and Z-geometric isomers, R- and S-enantiomers, diastereomers, d- and l-isomers, the racemic mixtures thereof and other mixtures thereof. Pharmaceutically acceptable salts of such tautomeric, geometric or stereoisomeric forms are also included within the invention. The terms “cis” and “trans”, as used herein, denote a form of geometric isomerism in which two carbon atoms connected by a double bond and each substituted by a hydrogen and another group, will each have a hydrogen atom on the same side of the double bond (“cis”) or on opposite sides of the double bond (“trans”). Some of the compounds described herein contain alkenyl groups, and are meant to include both cis and trans or “E” and “Z” geometric forms. Furthermore, some of the compounds described herein contain one or more stereocenters and are meant to include R, S, and mixtures or R and S forms for each stereocenter present.
The MCH receptor antagonists utilized in the present invention may be in the form of free bases or pharmaceutically-acceptable acid addition salts thereof. The term “pharmaceutically-acceptable salts” are salts commonly used to form alkali metal salts and to form addition salts of free acids or free bases. The nature of the salt may vary, provided that it is pharmaceutically acceptable. Suitable pharmaceutically-acceptable acid addition salts of compounds for use in the present methods may be prepared from an inorganic acid or from an organic acid. Examples of such inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric acid. Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, examples of which are formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, 4-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, 2-hydroxyethanesulfonic, toluenesulfonic, sulfanilic, cyclohexylaminosulfonic, stearic, algenic, hydroxybutyric, salicylic, galactaric and galacturonic acid. Suitable pharmaceutically-acceptable base addition salts of compounds of use in the present methods include metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from N,N′-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), and procaine. All of these salts may be prepared by conventional means from the corresponding compound by reacting, for example, the appropriate acid or base with the compound of any Formula set forth herein.
The MCH receptor antagonists useful in the practice of the present invention can be formulated into pharmaceutical compositions and administered by any means that will deliver a therapeutically effective dose. Such compositions can be administered orally, parenterally, by inhalation spray, rectally, intradermally, transdermally, or topically, in dosage unit formulations containing conventional nontoxic pharmaceutically-acceptable carriers, adjuvants, and vehicles as desired. Topical administration may also involve the use of transdermal administration such as transdermal patches or iontophoresis devices. The term parenteral as used herein includes subcutaneous, intravenous, intramuscular, or intrasternal injection, or infusion techniques. Formulation of drugs is discussed in, e.g., Hoover, Remington's Pharmaceutical Sciences, (1975), and Liberman & Lachman, Eds., Pharmaceutical Dosage Forms, (1980).
Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions, can be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally-acceptable diluent or solvent. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are useful in the preparation of injectables. Dimethyl acetamide, surfactants including ionic and non-ionic detergents, and polyethylene glycols can be used. Mixtures of solvents and wetting agents such as those discussed above are also useful.
Suppositories for rectal administration of the compounds discussed herein can be prepared by mixing the active agent with a suitable non-irritating excipient such as cocoa butter, synthetic mono-, di-, or triglycerides, fatty acids, or polyethylene glycols, which are solid at ordinary temperatures but liquid at the rectal temperature, and which will therefore melt in the rectum and release the drug.
Solid dosage forms for oral administration may include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the compounds are ordinarily combined with one or more adjuvants appropriate to the indicated route of administration. If administered per os, the compounds can be admixed with lactose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, acacia gum, sodium alginate, polyvinylpyrrolidone, and/or polyvinyl alcohol, and then tableted or encapsulated for convenient administration. Such capsules or tablets can contain a controlled-release formulation as can be provided in a dispersion of active compound in hydroxypropylmethyl cellulose. In the case of capsules, tablets, and pills, the dosage forms can also comprise buffering agents such as sodium citrate, or magnesium or calcium carbonate or bicarbonate. Tablets and pills can additionally be prepared with enteric coatings.
For therapeutic purposes, formulations for parenteral administration can be in the form of aqueous or non-aqueous isotonic sterile injection solutions or suspensions. These solutions and suspensions can be prepared from sterile powders or granules having one or more of the carriers or diluents mentioned for use in the formulations for oral administration. The compounds can be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, and/or various buffers. Other adjuvants and modes of administration are well and widely known in the pharmaceutical art.
Liquid dosage forms for oral administration can include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art, such as water. Such compositions can also comprise adjuvants, such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring, and perfuming agents.
The amount of active ingredient that can be combined with the carrier materials to produce a single dosage of the MCH receptor antagonist will vary depending upon the patient and the particular mode of administration. In general, the pharmaceutical compositions may contain an MCH receptor antagonist in the range of about 1 to about 250 mg, more typically, in the range of about 10 to about 200 mg and still more typically, between about 25 to about 150 mg. A daily dose of about 0.01 to about 80 mg/kg body weight, or more typically, between about 0.5 to about 50 mg/kg body weight and even more typically, from about 1 to about 25 mg/kg body weight, may be appropriate. The daily dose can be administered in one to about four doses per day.
The MCH receptor antagonists are administered in such amount as will be therapeutically effective in the treatment or control of the disorder or condition being treated. It will be appreciated that the amount of active ingredients contained in an individual dose of each dosage form need not in itself constitute an effective amount, as the necessary effective amount could be reached by administration of a number of individual doses. Those skilled in the art will appreciate that the quantity of active MCH receptor antagonist to be administered will vary depending upon the age, sex, and body weight of the subject to be treated, the type of disease, or syndrome to be treated, the particular method and scheduling of administration, and what other MCH receptor antagonist, if any, is co-administered. Dosage amounts for an individual patient may thus be above or below the typical dosage ranges. Generally speaking, the MCH receptor antagonist can be employed in any amount known to be effective at treating, preventing or controlling the disorder or condition being treated. The doses may be single doses or multiple doses per day, with the number of doses taken per day and the time allowed between doses varying depending on the individual needs of the patient. Optimization of treatment, including dosage amount, method and time of administration, is thus best determined by a skilled practitioner through close monitoring of patients on an individual basis. Those skilled in the art will appreciate that dosages may also be determined with guidance from Goodman & Goldman, The Pharmacological Basis of Therapeutics, 9th Ed. (1996), App. II, pp. 1707-1711 and from Goodman & Goldman, The Pharmacological Basis of Therapeutics, 10th Ed. (2001), App. II, pp. 475-493.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
In one embodiment of the present invention, the MCH receptor antagonist is a compound of Formula I, or a pharmaceutically-acceptable salt, tautomer or prodrug thereof, having the following structure:
- wherein:
- W is selected from the group consisting of hydrogen, hydroxy, alkyl, cycloalkyl, aryl, halo, alkoxy, hydroxyalkyl, alkoxyalkyl, aryloxy, carboxyl, carboxyalkyl, and cyano;
- X is selected from the group consisting of —OR1, —NR1R10, and —SR1;
- Y is selected from the group consisting of hydrogen, —N(R7)C(O)NR2R8, —N(R7)C(O)OR2, —N(R7)C(O)R2, —N(R7)SO2R2, and —NR2R7;
- Z is selected from the group consisting of —CH═CH—, —CH2N(R9)—, —C(O)—, —CH2N(R9)—, and —N(R12)C(O)N(R9)—;
- R1 is selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, and heteroarylalkyl, wherein R1 is optionally substituted with one or more substituents selected from the group consisting of alkyl, hydroxy, alkoxy, carboxyl, aryloxy, oxo, and halo;
- R2 is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, aralkyl, cycloalkylalkyl, aralkenyl, arylcycloalkyl, and heteroarylalkyl, or R2 together with R8 and the nitrogen to which they are attached may form an unsaturated fused heterocyclic ring system, wherein R2 or the unsaturated fused heterocyclic ring formed with R8 is optionally substituted with one or more substituents selected from the group consisting of alkyl, hydroxy, alkoxy, carboxyl, aryloxy, oxo, and halo;
- R3 is selected from the group consisting of hydrogen, hydroxy, alkyl, cycloalkyl, aryl, aralkyl, halo, alkoxy, hydroxyalkyl, alkoxyalkyl, aryloxy, carboxyl, carboxyalkyl, and cyano;
- R4 is selected from the group consisting of a bond, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, aralkyl, cycloalkylalkyl, aralkenyl, and heteroarylalkyl, or R4 together with R9 and the nitrogen to which they are attached may form a saturated 5- or 6-membered heterocyclic ring, wherein R4 or the ring formed with R9 is optionally substituted with one or more substituents selected from the group consisting of alkyl, hydroxy, alkoxy, carboxyl, aryloxy, oxo, alkoxycarbonyl, and halo;
- R5 is selected from the group consisting of hydrogen, hydroxy, alkyl, cycloalkyl, aryl, aralkyl, halo, alkoxy, hydroxyalkyl, alkoxyalkyl, aryloxy, carboxyl, carboxyalkyl, and cyano, or R5 together with R6 and the nitrogen to which they are attached may form a saturated 5- or 6-membered heterocyclic ring;
- R6 is selected from the group consisting of hydrogen, hydroxy, alkyl, cycloalkyl, aryl, aralkyl, halo, alkoxy, hydroxyalkyl, alkoxyalkyl, aryloxy, carboxyl, carboxyalkyl, and cyano, or R6 together with R5 and the nitrogen to which they are attached may form a saturated 5- or 6-membered heterocyclic ring;
- R7 is selected from the group consisting of hydrogen, hydroxy, alkyl, cycloalkyl, aryl, aralkyl, halo, alkoxy, hydroxyalkyl, alkoxyalkyl, aryloxy, carboxyl, carboxyalkyl, and cyano;
- R8 is selected from the group consisting of hydrogen, hydroxy, alkyl, cycloalkyl, aryl, aralkyl, halo, alkoxy, hydroxyalkyl, alkoxyalkyl, aryloxy, carboxyl, carboxyalkyl, and cyano, or R8 together with R2 and the nitrogen to which they are attached may form an unsaturated fused heterocyclic ring system;
- R9 is selected from the group consisting of hydrogen, hydroxy, alkyl, cycloalkyl, aryl, aralkyl, halo, alkoxy, hydroxyalkyl, alkoxyalkyl, aryloxy, carboxyl, carboxyalkyl, and cyano, or R9 together with R4 and the nitrogen to which they are attached may form a saturated 5- or 6-membered heterocyclic ring;
- R10 is selected from the group consisting of hydrogen, hydroxy, alkyl, cycloalkyl, aryl, aralkyl, halo, alkoxy, hydroxyalkyl, alkoxyalkyl, aryloxy, carboxyl, carboxyalkyl, and cyano;
- R11 is selected from the group consisting of hydrogen, hydroxy, alkyl, cycloalkyl, aryl, aralkyl, halo, alkoxy, hydroxyalkyl, alkoxyalkyl, aryloxy, carboxyl, carboxyalkyl, and cyano; and
- R12 is selected from the group consisting of hydrogen, hydroxy, alkyl, cycloalkyl, aryl, aralkyl, halo, alkoxy, hydroxyalkyl, alkoxyalkyl, aryloxy, carboxyl, carboxyalkyl, and cyano.
In another embodiment, the MCH receptor antagonist consists of compounds of Formula I, or a pharmaceutically-acceptable salt, tautomer or prodrug thereof, wherein:
- W is selected from the group consisting of hydrogen, hydroxy, lower alkyl, lower cycloalkyl, aryl, halo, lower alkoxy, lower hydroxyalkyl, lower alkoxyalkyl, aryloxy, carboxyl, lower carboxyalkyl, and cyano;
- X is selected from the group consisting of —OR1, —NR1R10, and —SR1;
- Y is selected from the group consisting of hydrogen, —N(R7)C(O)NR2R8, —N(R7)C(O)OR2, —N(R7)C(O)R2, —N(R7)SO2R2, and —NR2R7;
- Z is selected from the group consisting of —CH═CH—, —CH2N(R9)—, —C(O)—, —C(O)N(R9)—, and —N(R12)C(O)N(R9)—;
- R1 is selected from the group consisting of lower alkyl, lower cycloalkyl, lower cycloalkylalkyl, aryl, lower aralkyl, heteroaryl, and lower heteroarylalkyl, wherein R1 is optionally substituted with one or more substituents selected from the group consisting of lower alkyl, hydroxy, lower alkoxy, carboxyl, aryloxy, oxo, and halo;
- R2 is selected from the group consisting of lower alkyl, lower cycloalkyl, aryl, heteroaryl, lower aralkyl, lower cycloalkylalkyl, lower aralkenyl, lower arylcycloalkyl, and lower heteroarylalkyl, or R2 together with R8 and the nitrogen to which they are attached may form an unsaturated fused heterocyclic ring system, wherein R2 or the unsaturated fused heterocyclic ring formed with R8 is optionally substituted with one or more substituents selected from the group consisting of lower alkyl, hydroxy, lower alkoxy, carboxyl, aryloxy, oxo, and halo;
- R3 is selected from the group consisting of hydrogen, hydroxy, lower alkyl, lower cycloalkyl, aryl, lower aralkyl, halo, lower alkoxy, lower hydroxyalkyl, lower alkoxyalkyl, aryloxy, carboxyl, lower carboxyalkyl, and cyano;
- R4 is selected from the group consisting of a bond, lower alkyl, lower alkenyl, lower alkynyl, lower cycloalkyl, aryl, heteroaryl, lower aralkyl, lower cycloalkylalkyl, lower aralkenyl, and lower heteroarylalkyl, or R4 together with R9 and the nitrogen to which they are attached may form a saturated 5- or 6-membered heterocyclic ring, wherein R4 or the ring formed with R9 is optionally substituted with one or more substituents selected from the group consisting of lower alkyl, hydroxy, lower alkoxy, carboxyl, aryloxy, oxo, lower alkoxycarbonyl, and halo;
- R5 is selected from the group consisting of hydrogen, hydroxy, lower alkyl, lower cycloalkyl, aryl, lower aralkyl, halo, lower alkoxy, lower hydroxyalkyl, lower alkoxyalkyl, aryloxy, carboxyl, lower carboxyalkyl, and cyano, or R5 together with R6 and the nitrogen to which they are attached may form a saturated 5- or 6-membered heterocyclic ring;
- R6 is selected from the group consisting of hydrogen, hydroxy, lower alkyl, lower cycloalkyl, aryl, lower aralkyl, halo, lower alkoxy, lower hydroxyalkyl, lower alkoxyalkyl, aryloxy, carboxyl, lower carboxyalkyl, and cyano, or R6 together with R5 and the nitrogen to which they are attached may form a saturated 5- or 6-membered heterocyclic ring;
- R7 is selected from the group consisting of hydrogen, hydroxy, lower alkyl, lower cycloalkyl, aryl, lower aralkyl, halo, lower alkoxy, lower hydroxyalkyl, lower alkoxyalkyl, aryloxy, carboxyl, lower carboxyalkyl, and cyano;
- R8 is selected from the group consisting of hydrogen, hydroxy, lower alkyl, lower cycloalkyl, aryl, lower aralkyl, halo, lower alkoxy, lower hydroxyalkyl, lower alkoxyalkyl, aryloxy, carboxyl, lower carboxyalkyl, and cyano, or R8 together with R2 and the nitrogen to which they are attached may form an unsaturated fused heterocyclic ring system;
- R9 is selected from the group consisting of hydrogen, hydroxy, lower alkyl, lower cycloalkyl, aryl, lower aralkyl, halo, lower alkoxy, lower hydroxyalkyl, lower alkoxyalkyl, aryloxy, carboxyl, lower carboxyalkyl, and cyano, or R9 together with R4 and the nitrogen to which they are attached may form a saturated 5- or 6-membered heterocyclic ring;
- R10 is selected from the group consisting of hydrogen, hydroxy, lower alkyl, lower cycloalkyl, aryl, lower aralkyl, halo, lower alkoxy, lower hydroxyalkyl, lower alkoxyalkyl, aryloxy, carboxyl, lower carboxyalkyl, and cyano;
- R11 is selected from the group consisting of hydrogen, hydroxy, lower alkyl, lower cycloalkyl, aryl, lower aralkyl, halo, lower alkoxy, lower hydroxyalkyl, lower alkoxyalkyl, aryloxy, carboxyl, lower carboxyalkyl, and cyano; and
- R12 is selected from the group consisting of hydrogen, hydroxy, lower alkyl, lower cycloalkyl, aryl, lower aralkyl, halo, lower alkoxy, lower hydroxyalkyl, lower alkoxyalkyl, aryloxy, carboxyl, lower carboxyalkyl, and cyano.
In another embodiment, the MCH receptor antagonist consists of compounds of Formula I, or a pharmaceutically-acceptable salt, tautomer or prodrug thereof, wherein:
- W is selected from the group consisting of hydrogen, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, tetrahydronaphthyl, biphenyl, chloro, bromo, fluoro, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, hydroxyhexyl, methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, methoxypentyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, ethoxybutyl, ethoxypentyl, propoxymethyl, propoxyethyl, propoxypropyl, propoxybutyl, propoxypentyl, butoxymethyl, butoxyethyl, butoxypropyl, butoxybutyl, butoxypentyl, pentoxymethyl, pentoxyethyl, pentoxypropyl, pentoxybutyl, pentoxypentyl, phenoxy, naphthyloxy, tetrahydronaphthyloxy, biphenylyloxy, carboxyl, carboxymethyl, carboxyethyl, carboxypropyl, carboxybutyl, carboxypentyl, carboxyhexyl, and cyano;
- X is selected from the group consisting of —OR1, —NR1R10, and —SR1;
- Y is selected from the group consisting of hydrogen, —N(R7)C(O)NR2R8, —N(R7)C(O)OR2, —N(R7)C(O)R2, —N(R7)SO2R2, and —NR2R7;
- Z is selected from the group consisting of —CH═CH—, —CH2N(R9)—, —C(O)—, —C(O)N(R9)—, and —N(R12)C(O)N(R9)—;
- R1 is selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclopropylethyl, cyclopropylpropyl, cyclopropylbutyl, cyclopropylpentyl, cyclobutylmethyl, cyclobutylethyl, cyclobutylpropyl, cyclobutylbutyl, cyclobutylpenyyl, cyclopentylmethyl, cyclopentylethyl, cyclopentylpropyl, cyclopentylbutyl, cyclopentylpentyl, cyclohexylmethyl, cyclohexylethyl, cyclohexylpropyl, cyclohexylbutyl, cyclohexylpentyl, phenyl, naphthyl, tetrahydronaphthyl, biphenyl, benzyl, diphenylmethyl, triphenylmethyl, phenylethyl, diphenylethyl, furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, isoxazolyl, oxazolyl, indolyl, thiazolyl, isothiazolyl, oxadiazolyl, oxatriazolyl, dioxazole, tetrazolyl, benzodioxolyl, wherein R1 is optionally substituted with one or more substituents selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl, hexyl, hydroxy, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, carboxyl, phenoxy, naphthyloxy, tetrahydronaphthyloxy, biphenylyloxy, oxo, chloro, bromo, and fluoro;
- R2 is selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, tetrahydronaphthyl, biphenyl, furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, isoxazolyl, oxazolyl, indolyl, thiazolyl, isothiazolyl, oxadiazolyl, oxatriazolyl, dioxazole, tetrazolyl, benzodioxolyl, benzyl, diphenylmethyl, triphenylmethyl, phenylethyl, diphenylethyl, cyclopropylmethyl, cyclopropylethyl, cyclopropylpropyl, cyclopropylbutyl, cyclopropylpentyl, cyclobutylmethyl, cyclobutylethyl, cyclobutylpropyl, cyclobutylbutyl, cyclobutylpenyyl, cyclopentylmethyl, cyclopentylethyl, cyclopentylpropyl, cyclopentylbutyl, cyclopentylpentyl, cyclohexylmethyl, cyclohexylethyl, cyclohexylpropyl, cyclohexylbutyl, cyclohexylpentyl, phenylethenyl, phenylpropenyl, phenylallyl, phenylbutenyl, phenylpentenyl, phenylcyclopropyl, phenylcyclobutyl, phenylcyclopentyl, phenylcyclohexyl, biphenylcyclopropyl, biphenylcyclobutyl, biphenylcyclopentyl, biphenylcyclohexyl, naphthylcyclopropyl, naphthylcyclobutyl, naphthylcyclopentyl, naphthylcyclohexyl, or R2 together with R8 and the nitrogen to which they are attached may form a ring selected from the group consisting of hexahydroisoindolyl, tetrahydroisoindolyl, dihydroisoindolyl, isoindolinyl, hexahydroindolyl, tetrahydroindolyl, dihydroindolyl, indolinyl, octahydroquinolinyl, hexahydroquinolinyl, tetrahydroquinolinyl, dihydroquinolinyl, and quinolinyl, wherein R2 or the ring formed with R8 is optionally substituted with one or more substituents selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl, hexyl, hydroxy, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, carboxyl, phenoxy, naphthyloxy, tetrahydronaphthyloxy, biphenylyloxy, oxo, chloro, bromo, and fluoro;
- R3 is selected from the group consisting of hydrogen, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, tetrahydronaphthyl, biphenyl, benzyl, diphenylmethyl, triphenylmethyl, phenylethyl, diphenylethyl, chloro, bromo, fluoro, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, hydroxyhexyl, methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, methoxypentyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, ethoxybutyl, ethoxypentyl, propoxymethyl, propoxyethyl, propoxypropyl, propoxybutyl, propoxypentyl, butoxymethyl, butoxyethyl, butoxypropyl, butoxybutyl, butoxypentyl, pentoxymethyl, pentoxyethyl, pentoxypropyl, pentoxybutyl, pentoxypentyl, phenoxy, naphthyloxy, tetrahydronaphthyloxy, biphenylyloxy, carboxyl, carboxymethyl, carboxyethyl, carboxypropyl, carboxybutyl, carboxypentyl, carboxyhexyl, and cyano;
- R4 is selected from the group consisting of a bond, methyl, ethyl, propyl, butyl, pentyl, hexyl, ethenyl, propenyl, allyl, butenyl, pentenyl, acetylenyl, propynyl, butynyl, pentynyl, hexynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, tetrahydronaphthyl, biphenyl, furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, isoxazolyl, oxazolyl, indolyl, thiazolyl, isothiazolyl, oxadiazolyl, oxatriazolyl, dioxazole, tetrazolyl, benzodioxolyl, benzyl, diphenylmethyl, triphenylmethyl, phenylethyl, diphenylethyl, cyclopropylmethyl, cyclopropylethyl, cyclopropylpropyl, cyclopropylbutyl, cyclopropylpentyl, cyclobutylmethyl, cyclobutylethyl, cyclobutylpropyl, cyclobutylbutyl, cyclobutylpenyyl, cyclopentylmethyl, cyclopentylethyl, cyclopentylpropyl, cyclopentylbutyl, cyclopentylpentyl, cyclohexylmethyl, cyclohexylethyl, cyclohexylpropyl, cyclohexylbutyl, cyclohexylpentyl, phenylethenyl, phenylpropenyl, phenylallyl, phenylbutenyl, phenylpentenyl, or R4 together with R9 and the nitrogen to which they are attached may form a pyrrolidinyl or a piperidinyl ring, wherein R4 or the ring formed with R9 is optionally substituted with one or more substituents selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl, hexyl, hydroxy, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, carboxyl, phenoxy, naphthyloxy, tetrahydronaphthyloxy, biphenylyloxy, oxo, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, chloro, bromo, and fluoro;
- R5 is selected from the group consisting of hydrogen, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, tetrahydronaphthyl, biphenyl, benzyl, diphenylmethyl, triphenylmethyl, phenylethyl, diphenylethyl, chloro, bromo, fluoro, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, hydroxyhexyl, methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, methoxypentyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, ethoxybutyl, ethoxypentyl, propoxymethyl, propoxyethyl, propoxypropyl, propoxybutyl, propoxypentyl, butoxymethyl, butoxyethyl, butoxypropyl, butoxybutyl, butoxypentyl, pentoxymethyl, pentoxyethyl, pentoxypropyl, pentoxybutyl, pentoxypentyl, phenoxy, naphthyloxy, tetrahydronaphthyloxy, biphenylyloxy, carboxyl, carboxymethyl, carboxyethyl, carboxypropyl, carboxybutyl, carboxypentyl, carboxyhexyl, and cyano, or R5 together with R6 and the nitrogen to which they are attached may form a pyrrolidinyl or a piperidinyl ring;
- R6 is selected from the group consisting of hydrogen, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, tetrahydronaphthyl, biphenyl, benzyl, diphenylmethyl, triphenylmethyl, phenylethyl, diphenylethyl, chloro, bromo, fluoro, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, hydroxyhexyl, methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, methoxypentyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, ethoxybutyl, ethoxypentyl, propoxymethyl, propoxyethyl, propoxypropyl, propoxybutyl, propoxypentyl, butoxymethyl, butoxyethyl, butoxypropyl, butoxybutyl, butoxypentyl, pentoxymethyl, pentoxyethyl, pentoxypropyl, pentoxybutyl, pentoxypentyl, phenoxy, naphthyloxy, tetrahydronaphthyloxy, biphenylyloxy, carboxyl, carboxymethyl, carboxyethyl, carboxypropyl, carboxybutyl, carboxypentyl, carboxyhexyl, and cyano, or R6 together with R5 and the nitrogen to which they are attached may form a pyrrolidinyl or a piperidinyl ring;
- R7 is selected from the group consisting of hydrogen, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, tetrahydronaphthyl, biphenyl, benzyl, diphenylmethyl, triphenylmethyl, phenylethyl, diphenylethyl, chloro, bromo, fluoro, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, hydroxyhexyl, methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, methoxypentyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, ethoxybutyl, ethoxypentyl, propoxymethyl, propoxyethyl, propoxypropyl, propoxybutyl, propoxypentyl, butoxymethyl, butoxyethyl, butoxypropyl, butoxybutyl, butoxypentyl, pentoxymethyl, pentoxyethyl, pentoxypropyl, pentoxybutyl, pentoxypentyl, phenoxy, naphthyloxy, tetrahydronaphthyloxy, biphenylyloxy, carboxyl, carboxymethyl, carboxyethyl, carboxypropyl, carboxybutyl, carboxypentyl, carboxyhexyl, and cyano;
- R8 is selected from the group consisting of hydrogen, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, tetrahydronaphthyl, biphenyl, benzyl, diphenylmethyl, triphenylmethyl, phenylethyl, diphenylethyl, chloro, bromo, fluoro, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, hydroxyhexyl, methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, methoxypentyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, ethoxybutyl, ethoxypentyl, propoxymethyl, propoxyethyl, propoxypropyl, propoxybutyl, propoxypentyl, butoxymethyl, butoxyethyl, butoxypropyl, butoxybutyl, butoxypentyl, pentoxymethyl, pentoxyethyl, pentoxypropyl, pentoxybutyl, pentoxypentyl, phenoxy, naphthyloxy, tetrahydronaphthyloxy, biphenylyloxy, carboxyl, carboxymethyl, carboxyethyl, carboxypropyl, carboxybutyl, carboxypentyl, carboxyhexyl, and cyano, or R8 together with R2 and the nitrogen to which they are attached may form an isoindolinyl ring;
- R9 is selected from the group consisting of hydrogen, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, tetrahydronaphthyl, biphenyl, benzyl, diphenylmethyl, triphenylmethyl, phenylethyl, diphenylethyl, chloro, bromo, fluoro, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, hydroxyhexyl, methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, methoxypentyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, ethoxybutyl, ethoxypentyl, propoxymethyl, propoxyethyl, propoxypropyl, propoxybutyl, propoxypentyl, butoxymethyl, butoxyethyl, butoxypropyl, butoxybutyl, butoxypentyl, pentoxymethyl, pentoxyethyl, pentoxypropyl, pentoxybutyl, pentoxypentyl, phenoxy, naphthyloxy, tetrahydronaphthyloxy, biphenylyloxy, carboxyl, carboxymethyl, carboxyethyl, carboxypropyl, carboxybutyl, carboxypentyl, carboxyhexyl, and cyano, or R9 together with R4 and the nitrogen to which they are attached may form a pyrrolidinyl or a piperidinyl ring;
- R10 is selected from the group consisting of hydrogen, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, tetrahydronaphthyl, biphenyl, benzyl, diphenylmethyl, triphenylmethyl, phenylethyl, diphenylethyl, chloro, bromo, fluoro, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, hydroxyhexyl, methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, methoxypentyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, ethoxybutyl, ethoxypentyl, propoxymethyl, propoxyethyl, propoxypropyl, propoxybutyl, propoxypentyl, butoxymethyl, butoxyethyl, butoxypropyl, butoxybutyl, butoxypentyl, pentoxymethyl, pentoxyethyl, pentoxypropyl, pentoxybutyl, pentoxypentyl, phenoxy, naphthyloxy, tetrahydronaphthyloxy, biphenylyloxy, carboxyl, carboxymethyl, carboxyethyl, carboxypropyl, carboxybutyl, carboxypentyl, carboxyhexyl, and cyano;
- R11 is selected from the group consisting of hydrogen, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, tetrahydronaphthyl, biphenyl, benzyl, diphenylmethyl, triphenylmethyl, phenylethyl, diphenylethyl, chloro, bromo, fluoro, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, hydroxyhexyl, methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, methoxypentyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, ethoxybutyl, ethoxypentyl, propoxymethyl, propoxyethyl, propoxypropyl, propoxybutyl, propoxypentyl, butoxymethyl, butoxyethyl, butoxypropyl, butoxybutyl, butoxypentyl, pentoxymethyl, pentoxyethyl, pentoxypropyl, pentoxybutyl, pentoxypentyl, phenoxy, naphthyloxy, tetrahydronaphthyloxy, biphenylyloxy, carboxyl, carboxymethyl, carboxyethyl, carboxypropyl, carboxybutyl, carboxypentyl, carboxyhexyl, and cyano; and
- R12 is selected from the group consisting of hydrogen, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, tetrahydronaphthyl, biphenyl, benzyl, diphenylmethyl, triphenylmethyl, phenylethyl, diphenylethyl, chloro, bromo, fluoro, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, hydroxyhexyl, methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, methoxypentyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, ethoxybutyl, ethoxypentyl, propoxymethyl, propoxyethyl, propoxypropyl, propoxybutyl, propoxypentyl, butoxymethyl, butoxyethyl, butoxypropyl, butoxybutyl, butoxypentyl, pentoxymethyl, pentoxyethyl, pentoxypropyl, pentoxybutyl, pentoxypentyl, phenoxy, naphthyloxy, tetrahydronaphthyloxy, biphenylyloxy, carboxyl, carboxymethyl, carboxyethyl, carboxypropyl, carboxybutyl, carboxypentyl, carboxyhexyl, and cyano.
In another embodiment, the MCH receptor antagonist consists of compounds of Formula I, or a pharmaceutically-acceptable salt, tautomer or prodrug thereof, wherein:
- W is selected from the group consisting of hydrogen, hydroxy, alkyl, cycloalkyl, aryl, halo, alkoxy, hydroxyalkyl, alkoxyalkyl, aryloxy, carboxyl, carboxyalkyl, and cyano;
- X is —OR1;
- Y is selected from the group consisting of hydrogen, —N(R7)C(O)NR2R8, —N(R7)C(O)OR2, —N(R7)C(O)R2, —N(R7)SO2R2, and —NR2R7;
- Z is selected from the group consisting of —CH═CH—, —CH2N(R9)—, —C(O)—, —C(O)N(R9)—, and —N(R12)C(O)N(R9)—;
- R1 is selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, and heteroarylalkyl, wherein R1 is optionally substituted with one or more substituents selected from the group consisting of alkyl, hydroxy, alkoxy, carboxyl, aryloxy, oxo, and halo;
- R2 is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, aralkyl, cycloalkylalkyl, aralkenyl, arylcycloalkyl, and heteroarylalkyl, or R2 together with R8 and the nitrogen to which they are attached may form an unsaturated fused heterocyclic ring system, wherein R2 or the unsaturated fused heterocyclic ring formed with R8 is optionally substituted with one or more substituents selected from the group consisting of alkyl, hydroxy, alkoxy, carboxyl, aryloxy, oxo, and halo;
- R3 is selected from the group consisting of hydrogen, hydroxy, alkyl, cycloalkyl, aryl, aralkyl, halo, alkoxy, hydroxyalkyl, alkoxyalkyl, aryloxy, carboxyl, carboxyalkyl, and cyano;
- R4 is selected from the group consisting of a bond, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, aralkyl, cycloalkylalkyl, aralkenyl, and heteroarylalkyl, or R4 together with R9 and the nitrogen to which they are attached may form a saturated 5- or 6-membered heterocyclic ring, wherein R4 or the ring formed with R9 is optionally substituted with one or more substituents selected from the group consisting of alkyl, hydroxy, alkoxy, carboxyl, aryloxy, oxo, alkoxycarbonyl, and halo;
- R5 is selected from the group consisting of hydrogen, hydroxy, alkyl, cycloalkyl, aryl, aralkyl, halo, alkoxy, hydroxyalkyl, alkoxyalkyl, aryloxy, carboxyl, carboxyalkyl, and cyano, or R5 together with R6 and the nitrogen to which they are attached may form a saturated 5- or 6-membered heterocyclic ring;
- R6 is selected from the group consisting of hydrogen, hydroxy, alkyl, cycloalkyl, aryl, aralkyl, halo, alkoxy, hydroxyalkyl, alkoxyalkyl, aryloxy, carboxyl, carboxyalkyl, and cyano, or R6 together with R5 and the nitrogen to which they are attached may form a saturated 5- or 6-membered heterocyclic ring;
- R7 is selected from the group consisting of hydrogen, hydroxy, alkyl, cycloalkyl, aryl, aralkyl, halo, alkoxy, hydroxyalkyl, alkoxyalkyl, aryloxy, carboxyl, carboxyalkyl, and cyano;
- R8 is selected from the group consisting of hydrogen, hydroxy, alkyl, cycloalkyl, aryl, aralkyl, halo, alkoxy, hydroxyalkyl, alkoxyalkyl, aryloxy, carboxyl, carboxyalkyl, and cyano, or R8 together with R2 and the nitrogen to which they are attached may form an unsaturated fused heterocyclic ring system;
- R9 is selected from the group consisting of hydrogen, hydroxy, alkyl, cycloalkyl, aryl, aralkyl, halo, alkoxy, hydroxyalkyl, alkoxyalkyl, aryloxy, carboxyl, carboxyalkyl, and cyano, or R9 together with R4 and the nitrogen to which they are attached may form a saturated 5- or 6-membered heterocyclic ring;
- R10 is selected from the group consisting of hydrogen, hydroxy, alkyl, cycloalkyl, aryl, aralkyl, halo, alkoxy, hydroxyalkyl, alkoxyalkyl, aryloxy, carboxyl, carboxyalkyl, and cyano;
- R11 is selected from the group consisting of hydrogen, hydroxy, alkyl, cycloalkyl, aryl, aralkyl, halo, alkoxy, hydroxyalkyl, alkoxyalkyl, aryloxy, carboxyl, carboxyalkyl, and cyano; and
- R12 is selected from the group consisting of hydrogen, hydroxy, alkyl, cycloalkyl, aryl, aralkyl, halo, alkoxy, hydroxyalkyl, alkoxyalkyl, aryloxy, carboxyl, carboxyalkyl, and cyano.
In another embodiment, the MCH receptor antagonist consists of compounds of Formula I, or a pharmaceutically-acceptable salt, tautomer or prodrug thereof, wherein:
- W is selected from the group consisting of hydrogen, hydroxy, lower alkyl, lower cycloalkyl, aryl, halo, lower alkoxy, lower hydroxyalkyl, lower alkoxyalkyl, aryloxy, carboxyl, lower carboxyalkyl, and cyano;
- X is —OR1;
- Y is selected from the group consisting of hydrogen, —N(R7)C(O)NR2R8, —N(R7)C(O)OR2, —N(R7)C(O)R2, —N(R7)SO2R2, and —NR2R7;
- Z is selected from the group consisting of —CH═CH—, —CH2N(R9)—, —C(O)—, —C(O)N(R9)—, and —N(R12)C(O)N(R9)—;
- R1 is selected from the group consisting of lower alkyl, lower cycloalkyl, lower cycloalkylalkyl, aryl, lower aralkyl, heteroaryl, and lower heteroarylalkyl, wherein R1 is optionally substituted with one or more substituents selected from the group consisting of lower alkyl, hydroxy, lower alkoxy, carboxyl, aryloxy, oxo, and halo;
- R2 is selected from the group consisting of lower alkyl, lower cycloalkyl, aryl, heteroaryl, lower aralkyl, lower cycloalkylalkyl, lower aralkenyl, lower arylcycloalkyl, and lower heteroarylalkyl, or R2 together with R8 and the nitrogen to which they are attached may form an unsaturated fused heterocyclic ring system, wherein R2 or the unsaturated fused heterocyclic ring formed with R8 is optionally substituted with one or more substituents selected from the group consisting of lower alkyl, hydroxy, lower alkoxy, carboxyl, aryloxy, oxo, and halo;
- R3 is selected from the group consisting of hydrogen, hydroxy, lower alkyl, lower cycloalkyl, aryl, lower aralkyl, halo, lower alkoxy, lower hydroxyalkyl, lower alkoxyalkyl, aryloxy, carboxyl, lower carboxyalkyl, and cyano;
- R4 is selected from the group consisting of a bond, lower alkyl, lower alkenyl, lower alkynyl, lower cycloalkyl, aryl, heteroaryl, lower aralkyl, lower cycloalkylalkyl, lower aralkenyl, and lower heteroarylalkyl, or R4 together with R9 and the nitrogen to which they are attached may form a saturated 5- or 6-membered heterocyclic ring, wherein R4 or the ring formed with R9 is optionally substituted with one or more substituents selected from the group consisting of lower alkyl, hydroxy, lower alkoxy, carboxyl, aryloxy, oxo, lower alkoxycarbonyl, and halo;
- R5 is selected from the group consisting of hydrogen, hydroxy, lower alkyl, lower cycloalkyl, aryl, lower aralkyl, halo, lower alkoxy, lower hydroxyalkyl, lower alkoxyalkyl, aryloxy, carboxyl, lower carboxyalkyl, and cyano, or R5 together with R6 and the nitrogen to which they are attached may form a saturated 5- or 6-membered heterocyclic ring;
- R6 is selected from the group consisting of hydrogen, hydroxy, lower alkyl, lower cycloalkyl, aryl, lower aralkyl, halo, lower alkoxy, lower hydroxyalkyl, lower alkoxyalkyl, aryloxy, carboxyl, lower carboxyalkyl, and cyano, or R6 together with R5 and the nitrogen to which they are attached may form a saturated 5- or 6-membered heterocyclic ring;
- R7 is selected from the group consisting of hydrogen, hydroxy, lower alkyl, lower cycloalkyl, aryl, lower aralkyl, halo, lower alkoxy, lower hydroxyalkyl, lower alkoxyalkyl, aryloxy, carboxyl, lower carboxyalkyl, and cyano;
- R8 is selected from the group consisting of hydrogen, hydroxy, lower alkyl, lower cycloalkyl, aryl, lower aralkyl, halo, lower alkoxy, lower hydroxyalkyl, lower alkoxyalkyl, aryloxy, carboxyl, lower carboxyalkyl, and cyano, or R8 together with R2 and the nitrogen to which they are attached may form an unsaturated fused heterocyclic ring system;
- R9 is selected from the group consisting of hydrogen, hydroxy, lower alkyl, lower cycloalkyl, aryl, lower aralkyl, halo, lower alkoxy, lower hydroxyalkyl, lower alkoxyalkyl, aryloxy, carboxyl, lower carboxyalkyl, and cyano, or R9 together with R4 and the nitrogen to which they are attached may form a saturated 5- or 6-membered heterocyclic ring;
- R10 is selected from the group consisting of hydrogen, hydroxy, lower alkyl, lower cycloalkyl, aryl, lower aralkyl, halo, lower alkoxy, lower hydroxyalkyl, lower alkoxyalkyl, aryloxy, carboxyl, lower carboxyalkyl, and cyano;
- R11 is selected from the group consisting of hydrogen, hydroxy, lower alkyl, lower cycloalkyl, aryl, lower aralkyl, halo, lower alkoxy, lower hydroxyalkyl, lower alkoxyalkyl, aryloxy, carboxyl, lower carboxyalkyl, and cyano; and
- R12 is selected from the group consisting of hydrogen, hydroxy, lower alkyl, lower cycloalkyl, aryl, lower aralkyl, halo, lower alkoxy, lower hydroxyalkyl, lower alkoxyalkyl, aryloxy, carboxyl, lower carboxyalkyl, and cyano.
In another embodiment, the MCH receptor antagonist consists of compounds of Formula I, or a pharmaceutically-acceptable salt, tautomer or prodrug-thereof, wherein:
- W is selected from the group consisting of hydrogen, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, tetrahydronaphthyl, biphenyl, chloro, bromo, fluoro, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, hydroxyhexyl, methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, methoxypentyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, ethoxybutyl, ethoxypentyl, propoxymethyl, propoxyethyl, propoxypropyl, propoxybutyl, propoxypentyl, butoxymethyl, butoxyethyl, butoxypropyl, butoxybutyl, butoxypentyl, pentoxymethyl, pentoxyethyl, pentoxypropyl, pentoxybutyl, pentoxypentyl, phenoxy, naphthyloxy, tetrahydronaphthyloxy, biphenylyloxy, carboxyl, carboxymethyl, carboxyethyl, carboxypropyl, carboxybutyl, carboxypentyl, carboxyhexyl, and cyano;
- X is —OR1;
- Y is selected from the group consisting of hydrogen, —N(R7)C(O)NR2R8, —N(R7)C(O)OR2, —N(R7)C(O)R2, —N(R7)SO2R2, and —NR2R7;
- Z is selected from the group consisting of —CH═CH—, —CH2N(R9)—, —C(O)—, —C(O)N(R9)—, and —N(R12)C(O)N(R9)—;
- R1 is selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclopropylethyl, cyclopropylpropyl, cyclopropylbutyl, cyclopropylpentyl, cyclobutylmethyl, cyclobutylethyl, cyclobutylpropyl, cyclobutylbutyl, cyclobutylpenyyl, cyclopentylmethyl, cyclopentylethyl, cyclopentylpropyl, cyclopentylbutyl, cyclopentylpentyl, cyclohexylmethyl, cyclohexylethyl, cyclohexylpropyl, cyclohexylbutyl, cyclohexylpentyl, phenyl, naphthyl, tetrahydronaphthyl, biphenyl, benzyl, diphenylmethyl, triphenylmethyl, phenylethyl, diphenylethyl, furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, isoxazolyl, oxazolyl, indolyl, thiazolyl, isothiazolyl, oxadiazolyl, oxatriazolyl, dioxazole, tetrazolyl, benzodioxolyl, wherein R1 is optionally substituted with one or more substituents selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl, hexyl, hydroxy, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, carboxyl, phenoxy, naphthyloxy, tetrahydronaphthyloxy, biphenylyloxy, oxo, chloro, bromo, and fluoro;
- R2 is selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, tetrahydronaphthyl, biphenyl, furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, isoxazolyl, oxazolyl, indolyl, thiazolyl, isothiazolyl, oxadiazolyl, oxatriazolyl, dioxazole, tetrazolyl, benzodioxolyl, benzyl, diphenylmethyl, triphenylmethyl, phenylethyl, diphenylethyl, cyclopropylmethyl, cyclopropylethyl, cyclopropylpropyl, cyclopropylbutyl, cyclopropylpentyl, cyclobutylmethyl, cyclobutylethyl, cyclobutylpropyl, cyclobutylbutyl, cyclobutylpenyyl, cyclopentylmethyl, cyclopentylethyl, cyclopentylpropyl, cyclopentylbutyl, cyclopentylpentyl, cyclohexylmethyl, cyclohexylethyl, cyclohexylpropyl, cyclohexylbutyl, cyclohexylpentyl, phenylethenyl, phenylpropenyl, phenylallyl, phenylbutenyl, phenylpentenyl, phenylcyclopropyl, phenylcyclobutyl, phenylcyclopentyl, phenylcyclohexyl, biphenylcyclopropyl, biphenylcyclobutyl, biphenylcyclopentyl, biphenylcyclohexyl, naphthylcyclopropyl, naphthylcyclobutyl, naphthylcyclopentyl, naphthylcyclohexyl, or R2 together with R8 and the nitrogen to which they are attached may form a ring selected from the group consisting of hexahydroisoindolyl, tetrahydroisoindolyl, dihydroisoindolyl, isoindolinyl, hexahydroindolyl, tetrahydroindolyl, dihydroindolyl, indolinyl, octahydroquinolinyl, hexahydroquinolinyl, tetrahydroquinolinyl, dihydroquinolinyl, and quinolinyl, wherein R2 or the ring formed with R8 is optionally substituted with one or more substituents selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl, hexyl, hydroxy, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, carboxyl, phenoxy, naphthyloxy, tetrahydronaphthyloxy, biphenylyloxy, oxo, chloro, bromo, and fluoro;
- R3 is selected from the group consisting of hydrogen, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, tetrahydronaphthyl, biphenyl, benzyl, diphenylmethyl, triphenylmethyl, phenylethyl, diphenylethyl, chloro, bromo, fluoro, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, hydroxyhexyl, methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, methoxypentyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, ethoxybutyl, ethoxypentyl, propoxymethyl, propoxyethyl, propoxypropyl, propoxybutyl, propoxypentyl, butoxymethyl, butoxyethyl, butoxypropyl, butoxybutyl, butoxypentyl, pentoxymethyl, pentoxyethyl, pentoxypropyl, pentoxybutyl, pentoxypentyl, phenoxy, naphthyloxy, tetrahydronaphthyloxy, biphenylyloxy, carboxyl, carboxymethyl, carboxyethyl, carboxypropyl, carboxybutyl, carboxypentyl, carboxyhexyl, and cyano;
- R4 is selected from the group consisting of a bond, methyl, ethyl, propyl, butyl, pentyl, hexyl, ethenyl, propenyl, allyl, butenyl, pentenyl, acetylenyl, propynyl, butynyl, pentynyl, hexynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, tetrahydronaphthyl, biphenyl, furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, isoxazolyl, oxazolyl, indolyl, thiazolyl, isothiazolyl, oxadiazolyl, oxatriazolyl, dioxazole, tetrazolyl, benzodioxolyl, benzyl, diphenylmethyl, triphenylmethyl, phenylethyl, diphenylethyl, cyclopropylmethyl, cyclopropylethyl, cyclopropylpropyl, cyclopropylbutyl, cyclopropylpentyl, cyclobutylmethyl, cyclobutylethyl, cyclobutylpropyl, cyclobutylbutyl, cyclobutylpenyyl, cyclopentylmethyl, cyclopentylethyl, cyclopentylpropyl, cyclopentylbutyl, cyclopentylpentyl, cyclohexylmethyl, cyclohexylethyl, cyclohexylpropyl, cyclohexylbutyl, cyclohexylpentyl, phenylethenyl, phenylpropenyl, phenylallyl, phenylbutenyl, phenylpentenyl, or R4 together with R9 and the nitrogen to which they are attached may form a pyrrolidinyl or a piperidinyl ring, wherein R4 or the ring formed with R9 is optionally substituted with one or more substituents selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl, hexyl, hydroxy, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, carboxyl, phenoxy, naphthyloxy, tetrahydronaphthyloxy, biphenylyloxy, oxo, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, chloro, bromo, and fluoro;
- R5 is selected from the group consisting of hydrogen, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, tetrahydronaphthyl, biphenyl, benzyl, diphenylmethyl, triphenylmethyl, phenylethyl, diphenylethyl, chloro, bromo, fluoro, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, hydroxyhexyl, methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, methoxypentyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, ethoxybutyl, ethoxypentyl, propoxymethyl, propoxyethyl, propoxypropyl, propoxybutyl, propoxypentyl, butoxymethyl, butoxyethyl, butoxypropyl, butoxybutyl, butoxypentyl, pentoxymethyl, pentoxyethyl, pentoxypropyl, pentoxybutyl, pentoxypentyl, phenoxy, naphthyloxy, tetrahydronaphthyloxy, biphenylyloxy, carboxyl, carboxymethyl, carboxyethyl, carboxypropyl, carboxybutyl, carboxypentyl, carboxyhexyl, and cyano, or R5 together with R6 and the nitrogen to which they are attached may form a pyrrolidinyl or a piperidinyl ring;
- R6 is selected from the group consisting of hydrogen, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, tetrahydronaphthyl, biphenyl, benzyl, diphenylmethyl, triphenylmethyl, phenylethyl, diphenylethyl, chloro, bromo, fluoro, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, hydroxyhexyl, methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, methoxypentyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, ethoxybutyl, ethoxypentyl, propoxymethyl, propoxyethyl, propoxypropyl, propoxybutyl, propoxypentyl, butoxymethyl, butoxyethyl, butoxypropyl, butoxybutyl, butoxypentyl, pentoxymethyl, pentoxyethyl, pentoxypropyl, pentoxybutyl, pentoxypentyl, phenoxy, naphthyloxy, tetrahydronaphthyloxy, biphenylyloxy, carboxyl, carboxymethyl, carboxyethyl, carboxypropyl, carboxybutyl, carboxypentyl, carboxyhexyl, and cyano, or R6 together with R5 and the nitrogen to which they are attached may form a pyrrolidinyl or a piperidinyl ring;
- R7 is selected from the group consisting of hydrogen, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, tetrahydronaphthyl, biphenyl, benzyl, diphenylmethyl, triphenylmethyl, phenylethyl, diphenylethyl, chloro, bromo, fluoro, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, hydroxyhexyl, methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, methoxypentyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, ethoxybutyl, ethoxypentyl, propoxymethyl, propoxyethyl, propoxypropyl, propoxybutyl, propoxypentyl, butoxymethyl, butoxyethyl, butoxypropyl, butoxybutyl, butoxypentyl, pentoxymethyl, pentoxyethyl, pentoxypropyl, pentoxybutyl, pentoxypentyl, phenoxy, naphthyloxy, tetrahydronaphthyloxy, biphenylyloxy, carboxyl, carboxymethyl, carboxyethyl, carboxypropyl, carboxybutyl, carboxypentyl, carboxyhexyl, and cyano;
- R8 is selected from the group consisting of hydrogen, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, tetrahydronaphthyl, biphenyl, benzyl, diphenylmethyl, triphenylmethyl, phenylethyl, diphenylethyl, chloro, bromo, fluoro, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, hydroxyhexyl, methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, methoxypentyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, ethoxybutyl, ethoxypentyl, propoxymethyl, propoxyethyl, propoxypropyl, propoxybutyl, propoxypentyl, butoxymethyl, butoxyethyl, butoxypropyl, butoxybutyl, butoxypentyl, pentoxymethyl, pentoxyethyl, pentoxypropyl, pentoxybutyl, pentoxypentyl, phenoxy, naphthyloxy, tetrahydronaphthyloxy, biphenylyloxy, carboxyl, carboxymethyl, carboxyethyl, carboxypropyl, carboxybutyl, carboxypentyl, carboxyhexyl, and cyano, or R8 together with R2 and the nitrogen to which they are attached may form an isoindolinyl ring;
- R9 is selected from the group consisting of hydrogen, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, tetrahydronaphthyl, biphenyl, benzyl, diphenylmethyl, triphenylmethyl, phenylethyl, diphenylethyl, chloro, bromo, fluoro, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, hydroxyhexyl, methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, methoxypentyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, ethoxybutyl, ethoxypentyl, propoxymethyl, propoxyethyl, propoxypropyl, propoxybutyl, propoxypentyl, butoxymethyl, butoxyethyl, butoxypropyl, butoxybutyl, butoxypentyl, pentoxymethyl, pentoxyethyl, pentoxypropyl, pentoxybutyl, pentoxypentyl, phenoxy, naphthyloxy, tetrahydronaphthyloxy, biphenylyloxy, carboxyl, carboxymethyl, carboxyethyl, carboxypropyl, carboxybutyl, carboxypentyl, carboxyhexyl, and cyano, or R9 together with R4 and the nitrogen to which they are attached may form a pyrrolidinyl or a piperidinyl ring;
- R10 is selected from the group consisting of hydrogen, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, tetrahydronaphthyl, biphenyl, benzyl, diphenylmethyl, triphenylmethyl, phenylethyl, diphenylethyl, chloro, bromo, fluoro, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, hydroxyhexyl, methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, methoxypentyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, ethoxybutyl, ethoxypentyl, propoxymethyl, propoxyethyl, propoxypropyl, propoxybutyl, propoxypentyl, butoxymethyl, butoxyethyl, butoxypropyl, butoxybutyl, butoxypentyl, pentoxymethyl, pentoxyethyl, pentoxypropyl, pentoxybutyl, pentoxypentyl, phenoxy, naphthyloxy, tetrahydronaphthyloxy, biphenylyloxy, carboxyl, carboxymethyl, carboxyethyl, carboxypropyl, carboxybutyl, carboxypentyl, carboxyhexyl, and cyano;
- R11 is selected from the group consisting of hydrogen, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, tetrahydronaphthyl, biphenyl, benzyl, diphenylmethyl, triphenylmethyl, phenylethyl, diphenylethyl, chloro, bromo, fluoro, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, hydroxyhexyl, methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, methoxypentyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, ethoxybutyl, ethoxypentyl, propoxymethyl, propoxyethyl, propoxypropyl, propoxybutyl, propoxypentyl, butoxymethyl, butoxyethyl, butoxypropyl, butoxybutyl, butoxypentyl, pentoxymethyl, pentoxyethyl, pentoxypropyl, pentoxybutyl, pentoxypentyl, phenoxy, naphthyloxy, tetrahydronaphthyloxy, biphenylyloxy, carboxyl, carboxymethyl, carboxyethyl, carboxypropyl, carboxybutyl, carboxypentyl, carboxyhexyl, and cyano; and
- R12 is selected from the group consisting of hydrogen, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, tetrahydronaphthyl, biphenyl, benzyl, diphenylmethyl, triphenylmethyl, phenylethyl, diphenylethyl, chloro, bromo, fluoro, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, hydroxyhexyl, methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, methoxypentyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, ethoxybutyl, ethoxypentyl, propoxymethyl, propoxyethyl, propoxypropyl, propoxybutyl, propoxypentyl, butoxymethyl, butoxyethyl, butoxypropyl, butoxybutyl, butoxypentyl, pentoxymethyl, pentoxyethyl, pentoxypropyl, pentoxybutyl, pentoxypentyl, phenoxy, naphthyloxy, tetrahydronaphthyloxy, biphenylyloxy, carboxyl, carboxymethyl, carboxyethyl, carboxypropyl, carboxybutyl, carboxypentyl, carboxyhexyl, and cyano.
In another embodiment, the MCH receptor antagonist is selected from a subclass of compounds of Formula I represented by Formula II:
- wherein:
- W is selected from the group consisting of hydrogen, hydroxy, alkyl, and alkoxy;
- X is selected from the group consisting of —OR1, —NR1R10, and —SR1;
- Y is selected from the group consisting of hydrogen, —N(R7)C(O)NR2R8, —N(R7)C(O)OR2, —N(R7)C(O)R2, —N(R7)SO2R2, and —NR2R7;
- Z is selected from the group consisting of —CH═CH—, —CH2N(R9)—, —C(O)—, —C(O)N(R9)—, and —N(R12)C(O)N(R9)—;
- R1 is selected from the group consisting of alkyl, cycloalkyl, aryl, and heteroaryl, wherein R1 is optionally substituted with one or more substituents selected from the group consisting of alkyl, hydroxy, alkoxy, carboxyl, aryloxy, oxo, and halo;
- R2 is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, aralkyl, cycloalkylalkyl, aralkenyl, and arylcycloalkyl, or R2 together with R8 and the nitrogen to which they are attached may form an unsaturated fused heterocyclic ring system, wherein R2 or the unsaturated fused heterocyclic ring formed with R8 is optionally substituted with one or more substituents selected from the group consisting of alkyl, hydroxy, alkoxy, carboxyl, aryloxy, oxo, and halo;
- R4 is selected from the group consisting of a bond, alkyl, alkenyl, and cycloalkyl, or R4 together with R9 and the nitrogen to which they are attached may form a saturated 5- or 6-membered heterocyclic ring, wherein R4 or the ring formed with R9 is optionally substituted with one or more substituents selected from the group consisting of alkyl, hydroxy, and halo;
- R5 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, aralkyl, and alkoxyalkyl, or R5 together with R6 and the nitrogen to which they are attached may form a saturated 5- or 6-membered heterocyclic ring;
- R6 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, aralkyl, and alkoxyalkyl, or R6 together with R5 and the nitrogen to which they are attached may form a saturated 5- or 6-membered heterocyclic ring;
- R7 is selected from the group consisting of hydrogen, alkyl, and aryl;
- R8 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, aralkyl, hydroxyalkyl, alkoxyalkyl, and carboxyalkyl, or R8 together with R2 and the nitrogen to which they are attached may form an unsaturated fused heterocyclic ring system;
- R9 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, aralkyl, hydroxyalkyl, alkoxyalkyl, and carboxyalkyl, or R9 together with R4 and the nitrogen to which they are attached may form a saturated 5- or 6-membered heterocyclic ring;
- R10 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, aralkyl, hydroxyalkyl, alkoxyalkyl, and carboxyalkyl; and
- R12 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, aralkyl, hydroxyalkyl, alkoxyalkyl, and carboxyalkyl;
- or a pharmaceutically-acceptable salt, tautomer or prodrug thereof.
In another embodiment, the MCH receptor antagonist consists of compounds of Formula II, or a pharmaceutically-acceptable salt, tautomer or prodrug thereof, wherein:
- W is selected from the group consisting of hydrogen, hydroxy, lower alkyl, and lower alkoxy;
- X is selected from the group consisting of —OR1, —NR1R10, and —SR1;
- Y is selected from the group consisting of hydrogen, —N(R7)C(O)NR2R8, —N(R7)C(O)OR2, —N(R7)C(O)R2, —N(R7)SO2R2, and —NR2R7;
- Z is selected from the group consisting of —CH═CH—, —CH2N(R9)—, —C(O)—, —C(O)N(R9)—, and —N(R12)C(O)N(R9)—;
- R1 is selected from the group consisting of lower alkyl, lower cycloalkyl, aryl, and heteroaryl, wherein R1 is optionally substituted with one or more substituents selected from the group consisting of lower alkyl, hydroxy, lower alkoxy, carboxyl, aryloxy, oxo, and halo;
- R2 is selected from the group consisting of lower alkyl, lower cycloalkyl, aryl, heteroaryl, lower aralkyl, lower cycloalkylalkyl, lower aralkenyl, and lower arylcycloalkyl, or R2 together with R8 and the nitrogen to which they are attached may form an unsaturated fused heterocyclic ring system, wherein R2 or the unsaturated fused heterocyclic ring formed with R8 is optionally substituted with one or more substituents selected from the group consisting of lower alkyl, hydroxy, lower alkoxy, carboxyl, aryloxy, oxo, and halo;
- R4 is selected from the group consisting of a bond, lower alkyl, lower alkenyl, and lower cycloalkyl, or R4 together with R9 and the nitrogen to which they are attached may form a saturated 5- or 6-membered heterocyclic ring, wherein R4 or the ring formed with R9 is optionally substituted with one or more substituents selected from the group consisting of lower alkyl, hydroxy, and halo;
- R5 is selected from the group consisting of hydrogen, lower alkyl, lower cycloalkyl, aryl, lower aralkyl, and lower alkoxyalkyl, or R5 together with R6 and the nitrogen to which they are attached may form a saturated 5- or 6-membered heterocyclic ring;
- R6 is selected from the group consisting of hydrogen, lower alkyl, lower cycloalkyl, aryl, lower aralkyl, and lower alkoxyalkyl, or R6 together with R5 and the nitrogen to which they are attached may form a saturated 5- or 6-membered heterocyclic ring;
- R7 is selected from the group consisting of hydrogen, lower alkyl, and aryl;
- R8 is selected from the group consisting of hydrogen, lower alkyl, lower cycloalkyl, aryl, lower aralkyl, lower hydroxyalkyl, lower alkoxyalkyl, and lower carboxyalkyl, or R8 together with R2 and the nitrogen to which they are attached may form an unsaturated fused heterocyclic ring system;
- R9 is selected from the group consisting of hydrogen, lower alkyl, lower cycloalkyl, aryl, lower aralkyl, lower hydroxyalkyl, lower alkoxyalkyl, and lower carboxyalkyl, or R9 together with R4 and the nitrogen to which they are attached may form a saturated 5- or 6-membered heterocyclic ring;
- R10 is selected from the group consisting of hydrogen, lower alkyl, lower cycloalkyl, aryl, lower aralkyl, lower hydroxyalkyl, lower alkoxyalkyl, and lower carboxyalkyl; and
- R12 is selected from the group consisting of hydrogen, lower alkyl, lower cycloalkyl, aryl, lower aralkyl, lower hydroxyalkyl, lower alkoxyalkyl, and lower carboxyalkyl.
In another embodiment, the MCH receptor antagonist consists of compounds of Formula II, or a pharmaceutically-acceptable salt, tautomer or prodrug thereof, wherein:
- W is selected from the group consisting of hydrogen, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, and hexyloxy;
- X is selected from the group consisting of —OR1, —NR1R10, and —SR1;
- Y is selected from the group consisting of hydrogen, —N(R7)C(O)NR2R8, —N(R7)C(O)O R2, —N(R7)C(O)R2, —N(R7)SO2R2, and —NR2R7;
- Z is selected from the group consisting of —CH═CH—, —CH2N(R9)—, —C(O)—, —C(O)N(R9)—, and —N(R12)C(O)N(R9);
- R1 is selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, tetrahydronaphthyl, biphenyl, benzyl, furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, isoxazolyl, oxazolyl, indolyl, thiazolyl, isothiazolyl, oxadiazolyl, oxatriazolyl, dioxazole, tetrazolyl, and benzodioxolyl, wherein R1 is optionally substituted with one or more substituents selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl, hexyl, hydroxy, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, carboxyl, phenoxy, naphthyloxy, tetrahydronaphthyloxy, biphenylyloxy, oxo, chloro, bromo, and fluoro;
- R2 is selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, tetrahydronaphthyl, biphenyl, furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, isoxazolyl, oxazolyl, indolyl, thiazolyl, isothiazolyl, oxadiazolyl, oxatriazolyl, dioxazole, tetrazolyl, benzodioxolyl, benzyl, diphenylmethyl, triphenylmethyl, phenylethyl, diphenylethyl, cyclopropylmethyl, cyclopropylethyl, cyclopropylpropyl, cyclopropylbutyl, cyclopropylpentyl, cyclobutylmethyl, cyclobutylethyl, cyclobutylpropyl, cyclobutylbutyl, cyclobutylpenyyl, cyclopentylmethyl, cyclopentylethyl, cyclopentylpropyl, cyclopentylbutyl, cyclopentylpentyl, cyclohexylmethyl, cyclohexylethyl, cyclohexylpropyl, cyclohexylbutyl, cyclohexylpentyl, phenylethenyl, phenylpropenyl, phenylallyl, phenylbutenyl, phenylpentenyl, phenylcyclopropyl, phenylcyclobutyl, phenylcyclopentyl, phenylcyclohexyl, biphenylcyclopropyl, biphenylcyclobutyl, biphenylcyclopentyl, biphenylcyclohexyl, naphthylcyclopropyl, naphthylcyclobutyl, naphthylcyclopentyl, naphthylcyclohexyl, or R2 together with R8 and the nitrogen to which they are attached may form a ring selected from the group consisting of hexahydroisoindolyl, tetrahydroisoindolyl, dihydroisoindolyl, isoindolinyl, hexahydroindolyl, tetrahydroindolyl, dihydroindolyl, indolinyl, octahydroquinolinyl, hexahydroquinolinyl, tetrahydroquinolinyl, dihydroquinolinyl, and quinolinyl, wherein R2 or the ring formed with R8 is optionally substituted with one or more substituents selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl, hexyl, hydroxy, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, carboxyl, phenoxy, naphthyloxy, tetrahydronaphthyloxy, biphenylyloxy, oxo, chloro, bromo, and fluoro;
- R3 is selected from the group consisting of hydrogen, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, tetrahydronaphthyl, biphenyl, benzyl, diphenylmethyl, triphenylmethyl, phenylethyl, diphenylethyl, chloro, bromo, fluoro, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, hydroxyhexyl, methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, methoxypentyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, ethoxybutyl, ethoxypentyl, propoxymethyl, propoxyethyl, propoxypropyl, propoxybutyl, propoxypentyl, butoxymethyl, butoxyethyl, butoxypropyl, butoxybutyl, butoxypentyl, pentoxymethyl, pentoxyethyl, pentoxypropyl, pentoxybutyl, pentoxypentyl, phenoxy, naphthyloxy, tetrahydronaphthyloxy, biphenylyloxy, carboxyl, carboxymethyl, carboxyethyl, carboxypropyl, carboxybutyl, carboxypentyl, carboxyhexyl, and cyano;
- R4 is selected from the group consisting of a bond, methyl, ethyl, propyl, butyl, pentyl, hexyl, ethenyl, propenyl, allyl, butenyl, pentenyl, acetylenyl, propynyl, butynyl, pentynyl, hexynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, tetrahydronaphthyl, biphenyl, furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, isoxazolyl, oxazolyl, indolyl, thiazolyl, isothiazolyl, oxadiazolyl, oxatriazolyl, dioxazole, tetrazolyl, benzodioxolyl, benzyl, diphenylmethyl, triphenylmethyl, phenylethyl, diphenylethyl, cyclopropylmethyl, cyclopropylethyl, cyclopropylpropyl, cyclopropylbutyl, cyclopropylpentyl, cyclobutylmethyl, cyclobutylethyl, cyclobutylpropyl, cyclobutylbutyl, cyclobutylpenyyl, cyclopentylmethyl, cyclopentylethyl, cyclopentylpropyl, cyclopentylbutyl, cyclopentylpentyl, cyclohexylmethyl, cyclohexylethyl, cyclohexylpropyl, cyclohexylbutyl, cyclohexylpentyl, phenylethenyl, phenylpropenyl, phenylallyl, phenylbutenyl, phenylpentenyl, or R4 together with R9 and the nitrogen to which they are attached may form a pyrrolidinyl or a piperidinyl ring, wherein R4 or the ring formed with R9 is optionally substituted with one or more substituents selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl, hexyl, hydroxy, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, carboxyl, phenoxy, naphthyloxy, tetrahydronaphthyloxy, biphenylyloxy, oxo, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, chloro, bromo, and fluoro;
- R5 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, tetrahydronaphthyl, biphenyl, benzyl, diphenylmethyl, triphenylmethyl, phenylethyl, diphenylethyl, methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, methoxypentyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, ethoxybutyl, ethoxypentyl, butoxybutyl, butoxypentyl, pentoxymethyl, pentoxyethyl, pentoxypropyl, pentoxybutyl, and pentoxypentyl, or R5 together with R6 and the nitrogen to which they are attached may form a pyrrolidinyl or a piperidinyl ring;
- R6 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, tetrahydronaphthyl, biphenyl, benzyl, diphenylmethyl, triphenylmethyl, phenylethyl, diphenylethyl, methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, methoxypentyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, ethoxybutyl, ethoxypentyl, butoxybutyl, butoxypentyl, pentoxymethyl, pentoxyethyl, pentoxypropyl, pentoxybutyl, and pentoxypentyl, or R6 together with R5 and the nitrogen to which they are attached may form a pyrrolidinyl or a piperidinyl ring;
- R7 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, phenyl, naphthyl, tetrahydronaphthyl, and biphenyl;
- R8 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, tetrahydronaphthyl, biphenyl, benzyl, diphenylmethyl, triphenylmethyl, phenylethyl, diphenylethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, hydroxyhexyl, methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, methoxypentyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, ethoxybutyl, ethoxypentyl, propoxymethyl, propoxyethyl, propoxypropyl, propoxybutyl, propoxypentyl, butoxymethyl, butoxyethyl, butoxypropyl, butoxybutyl, butoxypentyl, pentoxymethyl, pentoxyethyl, pentoxypropyl, pentoxybutyl, pentoxypentyl, carboxymethyl, carboxyethyl, carboxypropyl, carboxybutyl, carboxypentyl, and carboxyhexyl, or R8 together with R2 and the nitrogen to which they are attached may form an isoindolinyl ring;
- R9 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, tetrahydronaphthyl, biphenyl, benzyl, diphenylmethyl, triphenylmethyl, phenylethyl, diphenylethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, hydroxyhexyl, methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, methoxypentyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, ethoxybutyl, ethoxypentyl, propoxymethyl, propoxyethyl, propoxypropyl, propoxybutyl, propoxypentyl, butoxymethyl, butoxyethyl, butoxypropyl, butoxybutyl, butoxypentyl, pentoxymethyl, pentoxyethyl, pentoxypropyl, pentoxybutyl, pentoxypentyl, carboxymethyl, carboxyethyl, carboxypropyl, carboxybutyl, carboxypentyl, and carboxyhexyl, or R9 together with R4 and the nitrogen to which they are attached may form a pyrrolidinyl or a piperidinyl ring;
- R10 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, tetrahydronaphthyl, biphenyl, benzyl, diphenylmethyl, triphenylmethyl, phenylethyl, diphenylethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, hydroxyhexyl, methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, methoxypentyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, ethoxybutyl, ethoxypentyl, propoxymethyl, propoxyethyl, propoxypropyl, propoxybutyl, propoxypentyl, butoxymethyl, butoxyethyl, butoxypropyl, butoxybutyl, butoxypentyl, pentoxymethyl, pentoxyethyl, pentoxypropyl, pentoxybutyl, pentoxypentyl, carboxymethyl, carboxyethyl, carboxypropyl, carboxybutyl, carboxypentyl, and carboxyhexyl; and
- R12 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, tetrahydronaphthyl, biphenyl, benzyl, diphenylmethyl, triphenylmethyl, phenylethyl, diphenylethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, hydroxyhexyl, methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, methoxypentyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, ethoxybutyl, ethoxypentyl, propoxymethyl, propoxyethyl, propoxypropyl, propoxybutyl, propoxypentyl, butoxymethyl, butoxyethyl, butoxypropyl, butoxybutyl, butoxypentyl, pentoxymethyl, pentoxyethyl, pentoxypropyl, pentoxybutyl, pentoxypentyl, carboxymethyl, carboxyethyl, carboxypropyl, carboxybutyl, carboxypentyl, and carboxyhexyl.
In another embodiment, the MCH receptor antagonist is selected from a subclass of compounds of Formula I represented by Formula III:
- wherein:
- X is selected from the group consisting of —OR1 and —SR1;
- Y is selected from the group consisting of hydrogen, —N(R7)C(O)NR2R8, —N(R7)C(O)OR2, —N(R7)C(O)R2, —N(R7)SO2R2, and —NR2R7;
- Z is selected from the group consisting of —CH═CH—, —CH2N(R9)—, —C(O)N(R9)—, and —NHC(O)NR9—;
- R1 is selected from the group consisting of alkyl, cycloalkyl, aryl, and heteroaryl, wherein R1 is optionally substituted with one or more substituents selected from the group consisting of alkyl, hydroxy, alkoxy, carboxyl, aryloxy, oxo, and halo;
R2 is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, aralkyl, cycloalkylalkyl, aralkenyl, and arylcycloalkyl, or R2 together with R8 and the nitrogen to which they are attached may form an unsaturated fused heterocyclic ring system, wherein R2 or the unsaturated fused heterocyclic ring formed with R8 is optionally substituted with one or more substituents selected from the group consisting of alkyl, hydroxy, alkoxy, carboxyl, aryloxy, oxo, and halo;
- R4 is selected from the group consisting of a bond, alkyl, alkenyl, and cycloalkyl, or R4 together with R9 and the nitrogen to which they are attached may form a saturated 5- or 6-membered heterocyclic ring, wherein R4 or the ring formed with R9 is optionally substituted with one or more substituents selected from the group consisting of alkyl, hydroxy, and halo;
- R5 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, aralkyl, and alkoxyalkyl, or R5 together with R6 and the nitrogen to which they are attached may form a saturated 5- or 6-membered heterocyclic ring;
- R6 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, aralkyl, and alkoxyalkyl, or R6 together with R5 and the nitrogen to which they are attached may form a saturated 5- or 6-membered heterocyclic ring;
- R7 is selected from the group consisting of hydrogen, alkyl, and aryl;
- R8 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, aralkyl, hydroxyalkyl, alkoxyalkyl, and carboxyalkyl, or R8 together with R2 and the nitrogen to which they are attached may form an unsaturated fused heterocyclic ring system;
- R9 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, aralkyl, hydroxyalkyl, alkoxyalkyl, and carboxyalkyl, or R9 together with R4 and the nitrogen to which they are attached may form a saturated 5- or 6-membered heterocyclic ring;
- R10 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, aralkyl, hydroxyalkyl, alkoxyalkyl, and carboxyalkyl; and
- R12 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, aralkyl, hydroxyalkyl, alkoxyalkyl, and carboxyalkyl;
- or a pharmaceutically-acceptable salt, tautomer or prodrug thereof.
In another embodiment, the MCH receptor antagonist consists of compounds of Formula III, or a pharmaceutically-acceptable salt, tautomer or prodrug thereof, wherein:
- X is selected from the group consisting of —OR1 and —SR1;
- Y is selected from the group consisting of hydrogen, —N(R7)C(O)NR2R8, —N(R7)C(O)OR2, —N(R7)C(O)R2, —N(R7)SO2R2, and —NR2R7;
- Z is selected from the group consisting of —CH═CH—, —CH2N(R9)—, —C(O)N(R9)—, and —NHC(O)NR9—;
- R1 is selected from the group consisting of lower alkyl, lower cycloalkyl, aryl, and heteroaryl, wherein R1 is optionally substituted with one or more substituents selected from the group consisting of lower alkyl, hydroxy, lower alkoxy, carboxyl, aryloxy, oxo, and halo;
- R2 is selected from the group consisting of lower alkyl, lower cycloalkyl, aryl, heteroaryl, lower aralkyl, lower cycloalkylalkyl, lower aralkenyl, and lower arylcycloalkyl, or R2 together with R8 and the nitrogen to which they are attached may form an unsaturated fused heterocyclic ring system, wherein R2 or the unsaturated fused heterocyclic ring formed with R8 is optionally substituted with one or more substituents selected from the group consisting of lower alkyl, hydroxy, lower alkoxy, carboxyl, aryloxy, oxo, and halo;
- R4 is selected from the group consisting of a bond, lower alkyl, lower alkenyl, and lower cycloalkyl, or R4 together with R9 and the nitrogen to which they are attached may form a saturated 5- or 6-membered heterocyclic ring, wherein R4 is optionally substituted with one or more substituents selected from the group consisting of lower alkyl, hydroxy, and halo;
- R5 is selected from the group consisting of hydrogen, lower alkyl, lower cycloalkyl, aryl, lower aralkyl, and lower alkoxyalkyl, or R5 together with R6 and the nitrogen to which they are attached may form a saturated 5- or 6-membered heterocyclic ring;
- R6 is selected from the group consisting of hydrogen, lower alkyl, lower cycloalkyl, aryl, lower aralkyl, and lower alkoxyalkyl, or R6 together with R5 and the nitrogen to which they are attached may form a saturated 5- or 6-membered heterocyclic ring;
- R7 is selected from the group consisting of hydrogen, lower alkyl, and aryl;
- R8 is selected from the group consisting of hydrogen, lower alkyl, lower cycloalkyl, aryl, lower aralkyl, lower hydroxyalkyl, lower alkoxyalkyl, and lower carboxyalkyl, or R8 together with R2 and the nitrogen to which they are attached may form an unsaturated fused heterocyclic ring system;
- R9 is selected from the group consisting of hydrogen, lower alkyl, lower cycloalkyl, aryl, lower aralkyl, lower hydroxyalkyl, lower alkoxyalkyl, and lower carboxyalkyl, or R9 together with R4 and the nitrogen to which they are attached may form a saturated 5- or 6-membered heterocyclic ring;
- R10 is selected from the group consisting of hydrogen, lower alkyl, lower cycloalkyl, aryl, lower aralkyl, lower hydroxyalkyl, lower alkoxyalkyl, and lower carboxyalkyl; and
- R12 is selected from the group consisting of hydrogen, lower alkyl, lower cycloalkyl, aryl, lower aralkyl, lower hydroxyalkyl, lower alkoxyalkyl, and lower carboxyalkyl.
In another embodiment, the MCH receptor antagonist consists of compounds of Formula III, or a pharmaceutically-acceptable salt, tautomer or prodrug thereof, wherein:
- X is selected from the group consisting of —OR1 and —SR1;
- Y is selected from the group consisting of hydrogen, —N(R7)C(O)NR2R8, —N(R7)C(O)OR2, —N(R7)C(O)R2, —N(R7)SO2R2, and —NR2R7;
- Z is selected from the group consisting of —CH═CH—, —CH2N(R9)—, —C(O)N(R9)—, and —NHC(O)NR9—;
- R1 is selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, tetrahydronaphthyl, biphenyl, benzyl, furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, isoxazolyl, oxazolyl, indolyl, thiazolyl, isothiazolyl, oxadiazolyl, oxatriazolyl, dioxazole, tetrazolyl, and benzodioxolyl, wherein R1 is optionally substituted with one or more substituents selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl, hexyl, hydroxy, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, carboxyl, phenoxy, naphthyloxy, tetrahydronaphthyloxy, biphenylyloxy, oxo, chloro, bromo, and fluoro;
- R2 is selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, tetrahydronaphthyl, biphenyl, furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, isoxazolyl, oxazolyl, indolyl, thiazolyl, isothiazolyl, oxadiazolyl, oxatriazolyl, dioxazole, tetrazolyl, benzodioxolyl, benzyl, diphenylmethyl, triphenylmethyl, phenylethyl, diphenylethyl, cyclopropylmethyl, cyclopropylethyl, cyclopropylpropyl, cyclopropylbutyl, cyclopropylpentyl, cyclobutylmethyl, cyclobutylethyl, cyclobutylpropyl, cyclobutylbutyl, cyclobutylpenyyl, cyclopentylmethyl, cyclopentylethyl, cyclopentylpropyl, cyclopentylbutyl, cyclopentylpentyl, cyclohexylmethyl, cyclohexylethyl, cyclohexylpropyl, cyclohexylbutyl, cyclohexylpentyl, phenylethenyl, phenylpropenyl, phenylallyl, phenylbutenyl, phenylpentenyl, phenylcyclopropyl, phenylcyclobutyl, phenylcyclopentyl, phenylcyclohexyl, biphenylcyclopropyl, biphenylcyclobutyl, biphenylcyclopentyl, biphenylcyclohexyl, naphthylcyclopropyl, naphthylcyclobutyl, naphthylcyclopentyl, naphthylcyclohexyl, or R2 together with R8 and the nitrogen to which they are attached may form a ring selected from the group consisting of hexahydroisoindolyl, tetrahydroisoindolyl, dihydroisoindolyl, isoindolinyl, hexahydroindolyl, tetrahydroindolyl, dihydroindolyl, indolinyl, octahydroquinolinyl, hexahydroquinolinyl, tetrahydroquinolinyl, dihydroquinolinyl, and quinolinyl, wherein R2 or the ring formed with R8 is optionally substituted with one or more substituents selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl, hexyl, hydroxy, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, carboxyl, phenoxy, naphthyloxy, tetrahydronaphthyloxy, biphenylyloxy, oxo, chloro, bromo, and fluoro;
- R3 is selected from the group consisting of hydrogen, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, tetrahydronaphthyl, biphenyl, benzyl, diphenylmethyl, triphenylmethyl, phenylethyl, diphenylethyl, chloro, bromo, fluoro, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, hydroxyhexyl, methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, methoxypentyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, ethoxybutyl, ethoxypentyl, propoxymethyl, propoxyethyl, propoxypropyl, propoxybutyl, propoxypentyl, butoxymethyl, butoxyethyl, butoxypropyl, butoxybutyl, butoxypentyl, pentoxymethyl, pentoxyethyl, pentoxypropyl, pentoxybutyl, pentoxypentyl, phenoxy, naphthyloxy, tetrahydronaphthyloxy, biphenylyloxy, carboxyl, carboxymethyl, carboxyethyl, carboxypropyl, carboxybutyl, carboxypentyl, carboxyhexyl, and cyano;
- R4 is selected from the group consisting of a bond, methyl, ethyl, propyl, butyl, pentyl, hexyl, ethenyl, propenyl, allyl, butenyl, pentenyl, acetylenyl, propynyl, butynyl, pentynyl, hexynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, tetrahydronaphthyl, biphenyl, furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, isoxazolyl, oxazolyl, indolyl, thiazolyl, isothiazolyl, oxadiazolyl, oxatriazolyl, dioxazole, tetrazolyl, benzodioxolyl, benzyl, diphenylmethyl, triphenylmethyl, phenylethyl, diphenylethyl, cyclopropylmethyl, cyclopropylethyl, cyclopropylpropyl, cyclopropylbutyl, cyclopropylpentyl, cyclobutylmethyl, cyclobutylethyl, cyclobutylpropyl, cyclobutylbutyl, cyclobutylpenyyl, cyclopentylmethyl, cyclopentylethyl, cyclopentylpropyl, cyclopentylbutyl, cyclopentylpentyl, cyclohexylmethyl, cyclohexylethyl, cyclohexylpropyl, cyclohexylbutyl, cyclohexylpentyl, phenylethenyl, phenylpropenyl, phenylallyl, phenylbutenyl, phenylpentenyl, or R4 together with R9 and the nitrogen to which they are attached may form a pyrrolidinyl or a piperidinyl ring, wherein R4 or the ring formed with R9 is optionally substituted with one or more substituents selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl, hexyl, hydroxy, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, carboxyl, phenoxy, naphthyloxy, tetrahydronaphthyloxy, biphenylyloxy, oxo, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, chloro, bromo, and fluoro;
- R5 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, tetrahydronaphthyl, biphenyl, benzyl, diphenylmethyl, triphenylmethyl, phenylethyl, diphenylethyl, methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, methoxypentyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, ethoxybutyl, ethoxypentyl, butoxybutyl, butoxypentyl, pentoxymethyl, pentoxyethyl, pentoxypropyl, pentoxybutyl, and pentoxypentyl, wherein R5 together with R6 and the nitrogen to which they are attached may form a pyrrolidinyl or a piperidinyl ring;
- R6 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, tetrahydronaphthyl, biphenyl, benzyl, diphenylmethyl, triphenylmethyl, phenylethyl, diphenylethyl, methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, methoxypentyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, ethoxybutyl, ethoxypentyl, butoxybutyl, butoxypentyl, pentoxymethyl, pentoxyethyl, pentoxypropyl, pentoxybutyl, and pentoxypentyl, or R6 together with R5 and the nitrogen to which they are attached may form a pyrrolidinyl or a piperidinyl ring;
- R7 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, phenyl, naphthyl, tetrahydronaphthyl, and biphenyl;
- R8 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, tetrahydronaphthyl, biphenyl, benzyl, diphenylmethyl, triphenylmethyl, phenylethyl, diphenylethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, hydroxyhexyl, methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, methoxypentyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, ethoxybutyl, ethoxypentyl, propoxymethyl, propoxyethyl, propoxypropyl, propoxybutyl, propoxypentyl, butoxymethyl, butoxyethyl, butoxypropyl, butoxybutyl, butoxypentyl, pentoxymethyl, pentoxyethyl, pentoxypropyl, pentoxybutyl, pentoxypentyl, carboxymethyl, carboxyethyl, carboxypropyl, carboxybutyl, carboxypentyl, and carboxyhexyl, or R8 together with R2 and the nitrogen to which they are attached may form an isoindolinyl ring;
- R9 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, tetrahydronaphthyl, biphenyl, benzyl, diphenylmethyl, triphenylmethyl, phenylethyl, diphenylethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, hydroxyhexyl, methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, methoxypentyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, ethoxybutyl, ethoxypentyl, propoxymethyl, propoxyethyl, propoxypropyl, propoxybutyl, propoxypentyl, butoxymethyl, butoxyethyl, butoxypropyl, butoxybutyl, butoxypentyl, pentoxymethyl, pentoxyethyl, pentoxypropyl, pentoxybutyl, pentoxypentyl, carboxymethyl, carboxyethyl, carboxypropyl, carboxybutyl, carboxypentyl, and carboxyhexyl, or R9 together with R4 and the nitrogen to which they are attached may form a pyrrolidinyl or a piperidinyl ring;
- R10 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, tetrahydronaphthyl, biphenyl, benzyl, diphenylmethyl, triphenylmethyl, phenylethyl, diphenylethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, hydroxyhexyl, methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, methoxypentyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, ethoxybutyl, ethoxypentyl, propoxymethyl, propoxyethyl, propoxypropyl, propoxybutyl, propoxypentyl, butoxymethyl, butoxyethyl, butoxypropyl, butoxybutyl, butoxypentyl, pentoxymethyl, pentoxyethyl, pentoxypropyl, pentoxybutyl, pentoxypentyl, carboxymethyl, carboxyethyl, carboxypropyl, carboxybutyl, carboxypentyl, and carboxyhexyl; and
- R12 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, tetrahydronaphthyl, biphenyl, benzyl, diphenylmethyl, triphenylmethyl, phenylethyl, diphenylethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, hydroxyhexyl, methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, methoxypentyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, ethoxybutyl, ethoxypentyl, propoxymethyl, propoxyethyl, propoxypropyl, propoxybutyl, propoxypentyl, butoxymethyl, butoxyethyl, butoxypropyl, butoxybutyl, butoxypentyl, pentoxymethyl, pentoxyethyl, pentoxypropyl, pentoxybutyl, pentoxypentyl, carboxymethyl, carboxyethyl, carboxypropyl, carboxybutyl, carboxypentyl, and carboxyhexyl.
In another embodiment, the MCH receptor antagonist is selected from a subclass of compounds of Formula I represented by Formula IV:
- wherein:
- X is selected from the group consisting of —OR1 and —SR1;
- Z is selected from the group consisting of —CH═CH—, —CH2N(R9)—, —C(O)N(R9)—, and —NHC(O)NR9—;
- R1 is selected from the group consisting of alkyl, cycloalkyl, aryl, and heteroaryl, wherein R1 is optionally substituted with one or more substituents selected from the group consisting of alkyl, hydroxy, alkoxy, carboxyl, aryloxy, oxo, and halo;
- R2 is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, aralkyl, cycloalkylalkyl, aralkenyl, and arylcycloalkyl, or R2 together with R8 and the nitrogen to which they are attached may form an unsaturated fused heterocyclic ring system, wherein R2 or the unsaturated fused heterocyclic ring formed with R8 is optionally substituted with one or more substituents selected from the group consisting of alkyl, hydroxy, alkoxy, carboxyl, aryloxy, oxo, and halo;
- R4 is selected from the group consisting of a bond, alkyl, alkenyl, and cycloalkyl, or R4 together with R9 and the nitrogen to which they are attached may form a saturated 5- or 6-membered heterocyclic ring, wherein R4 or the ring formed with R9 is optionally substituted with one or more substituents selected from the group consisting of alkyl, hydroxy, and halo;
- R5 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, aralkyl, and alkoxyalkyl, or R5 together with R6 and the nitrogen to which they are attached may form a saturated 5- or 6-membered heterocyclic ring;
- R6 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, aralkyl, and alkoxyalkyl, or R6 together with R5 and the nitrogen to which they are attached may form a saturated 5- or 6-membered heterocyclic ring;
- R7 is selected from the group consisting of hydrogen, alkyl, and aryl;
- R8 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, aralkyl, hydroxyalkyl, alkoxyalkyl, and carboxyalkyl, or R5 together with R2 and the nitrogen to which they are attached may form an unsaturated fused heterocyclic ring system;
- R9 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, aralkyl, hydroxyalkyl, alkoxyalkyl, and carboxyalkyl, or R9 together with R4 and the nitrogen to which they are attached may form a saturated 5- or 6-membered heterocyclic ring;
- R10 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, aralkyl, hydroxyalkyl, alkoxyalkyl, and carboxyalkyl; and
- R12 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, aralkyl, hydroxyalkyl, alkoxyalkyl, and carboxyalkyl;
- or a pharmaceutically-acceptable salt, tautomer or prodrug thereof.
In another embodiment, the MCH receptor antagonist consists of compounds of Formula IV, or a pharmaceutically-acceptable salt, tautomer or prodrug thereof, wherein:
- X is selected from the group consisting of —OR1 and —SR1;
- Z is selected from the group consisting of —CH═CH—, —CH2N(R9)—, —C(O)N(R9)—, and —NHC(O)NR9—;
- R1 is selected from the group consisting of lower alkyl, lower cycloalkyl, aryl, and heteroaryl, wherein R1 is optionally substituted with one or more substituents selected from the group consisting of lower alkyl, hydroxy, lower alkoxy, carboxyl, aryloxy, oxo, and halo;
- R2 is selected from the group consisting of lower alkyl, lower cycloalkyl, aryl, heteroaryl, lower aralkyl, lower cycloalkylalkyl, lower aralkenyl, and lower arylcycloalkyl, or R2 together with R8 and the nitrogen to which they are attached may form an unsaturated fused heterocyclic ring system, wherein R2 or the unsaturated fused heterocyclic ring formed with R8 is optionally substituted with one or more substituents selected from the group consisting of lower alkyl, hydroxy, lower alkoxy, carboxyl, aryloxy, oxo, and halo;
- R4 is selected from the group consisting of a bond, lower alkyl, lower alkenyl, and lower cycloalkyl, or R4 together with R9 and the nitrogen to which they are attached may form a saturated 5- or 6-membered heterocyclic ring, wherein R4 or the ring formed with R9 is optionally substituted with one or more substituents selected from the group consisting of lower alkyl, hydroxy, and halo;
- R5 is selected from the group consisting of hydrogen, lower alkyl, lower cycloalkyl, aryl, lower aralkyl, and lower alkoxyalkyl, or R5 together with R6 and the nitrogen to which they are attached may form a saturated 5- or 6-membered heterocyclic ring;
- R6 is selected from the group consisting of hydrogen, lower alkyl, lower cycloalkyl, aryl, lower aralkyl, and lower alkoxyalkyl, or R6 together with R5 and the nitrogen to which they are attached may form a saturated 5- or 6-membered heterocyclic ring;
- R7 is selected from the group consisting of hydrogen, lower alkyl, and aryl;
- R8 is selected from the group consisting of hydrogen, lower alkyl, lower cycloalkyl, aryl, lower aralkyl, lower hydroxyalkyl, lower alkoxyalkyl, and lower carboxyalkyl, or R8 together with R2 and the nitrogen to which they are attached may form an unsaturated fused heterocyclic ring system;
- R9 is selected from the group consisting of hydrogen, lower alkyl, lower cycloalkyl, aryl, lower aralkyl, lower hydroxyalkyl, lower alkoxyalkyl, and lower carboxyalkyl, or R9 together with R4 and the nitrogen to which they are attached may form a saturated 5- or 6-membered heterocyclic ring;
- R10 is selected from the group consisting of hydrogen, lower alkyl, lower cycloalkyl, aryl, lower aralkyl, lower hydroxyalkyl, lower alkoxyalkyl, and lower carboxyalkyl; and
- R12 is selected from the group consisting of hydrogen, lower alkyl, lower cycloalkyl, aryl, lower aralkyl, lower hydroxyalkyl, lower alkoxyalkyl, and lower carboxyalkyl.
In another embodiment, the MCH receptor antagonist consists of compounds of Formula IV, or a pharmaceutically-acceptable salt, tautomer or prodrug thereof, wherein:
- X is selected from the group consisting of —OR1 and —SR1;
- Z is selected from the group consisting of —CH═CH—, —CH2N(R9)—, —C(O)N(R9)—, and —NHC(O)NR9—;
- R1 is selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, tetrahydronaphthyl, biphenyl, benzyl, furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, isoxazolyl, oxazolyl, indolyl, thiazolyl, isothiazolyl, oxadiazolyl, oxatriazolyl, dioxazole, tetrazolyl, and benzodioxolyl, wherein R1 is optionally substituted with one or more substituents selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl, hexyl, hydroxy, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, carboxyl, phenoxy, naphthyloxy, tetrahydronaphthyloxy, biphenylyloxy, oxo, chloro, bromo, and fluoro;
- R2 is selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, tetrahydronaphthyl, biphenyl, furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, isoxazolyl, oxazolyl, indolyl, thiazolyl, isothiazolyl, oxadiazolyl, oxatriazolyl, dioxazole, tetrazolyl, benzodioxolyl, benzyl, diphenylmethyl, triphenylmethyl, phenylethyl, diphenylethyl, cyclopropylmethyl, cyclopropylethyl, cyclopropylpropyl, cyclopropylbutyl, cyclopropylpentyl, cyclobutylmethyl, cyclobutylethyl, cyclobutylpropyl, cyclobutylbutyl, cyclobutylpenyyl, cyclopentylmethyl, cyclopentylethyl, cyclopentylpropyl, cyclopentylbutyl, cyclopentylpentyl, cyclohexylmethyl, cyclohexylethyl, cyclohexylpropyl, cyclohexylbutyl, cyclohexylpentyl, phenylethenyl, phenylpropenyl, phenylallyl, phenylbutenyl, phenylpentenyl, phenylcyclopropyl, phenylcyclobutyl, phenylcyclopentyl, phenylcyclohexyl, biphenylcyclopropyl, biphenylcyclobutyl, biphenylcyclopentyl, biphenylcyclohexyl, naphthylcyclopropyl, naphthylcyclobutyl, naphthylcyclopentyl, naphthylcyclohexyl, or R2 together with R8 and the nitrogen to which they are attached may form a ring selected from the group consisting of hexahydroisoindolyl, tetrahydroisoindolyl, dihydroisoindolyl, isoindolinyl, hexahydroindolyl, tetrahydroindolyl, dihydroindolyl, indolinyl, octahydroquinolinyl, hexahydroquinolinyl, tetrahydroquinolinyl, dihydroquinolinyl, and quinolinyl, wherein R2 or ring formed with R8 is optionally substituted with one or more substituents selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl, hexyl, hydroxy, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, carboxyl, phenoxy, naphthyloxy, tetrahydronaphthyloxy, biphenylyloxy, oxo, chloro, bromo, and fluoro;
- R3 is selected from the group consisting of hydrogen, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, tetrahydronaphthyl, biphenyl, benzyl, diphenylmethyl, triphenylmethyl, phenylethyl, diphenylethyl, chloro, bromo, fluoro, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, hydroxyhexyl, methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, methoxypentyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, ethoxybutyl, ethoxypentyl, propoxymethyl, propoxyethyl, propoxypropyl, propoxybutyl, propoxypentyl, butoxymethyl, butoxyethyl, butoxypropyl, butoxybutyl, butoxypentyl, pentoxymethyl, pentoxyethyl, pentoxypropyl, pentoxybutyl, pentoxypentyl, phenoxy, naphthyloxy, tetrahydronaphthyloxy, biphenylyloxy, carboxyl, carboxymethyl, carboxyethyl, carboxypropyl, carboxybutyl, carboxypentyl, carboxyhexyl, and cyano;
- R4 is selected from the group consisting of a bond, methyl, ethyl, propyl, butyl, pentyl, hexyl, ethenyl, propenyl, allyl, butenyl, pentenyl, acetylenyl, propynyl, butynyl, pentynyl, hexynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, tetrahydronaphthyl, biphenyl, furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, isoxazolyl, oxazolyl, indolyl, thiazolyl, isothiazolyl, oxadiazolyl, oxatriazolyl, dioxazole, tetrazolyl, benzodioxolyl, benzyl, diphenylmethyl, triphenylmethyl, phenylethyl, diphenylethyl, cyclopropylmethyl, cyclopropylethyl, cyclopropylpropyl, cyclopropylbutyl, cyclopropylpentyl, cyclobutylmethyl, cyclobutylethyl, cyclobutylpropyl, cyclobutylbutyl, cyclobutylpenyyl, cyclopentylmethyl, cyclopentylethyl, cyclopentylpropyl, cyclopentylbutyl, cyclopentylpentyl, cyclohexylmethyl, cyclohexylethyl, cyclohexylpropyl, cyclohexylbutyl, cyclohexylpentyl, phenylethenyl, phenylpropenyl, phenylallyl, phenylbutenyl, phenylpentenyl, or R4 together with R9 and the nitrogen to which they are attached may form a pyrrolidinyl or a piperidinyl ring, wherein R4 or the ring formed with R9 is optionally substituted with one or more substituents selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl, hexyl, hydroxy, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, carboxyl, phenoxy, naphthyloxy, tetrahydronaphthyloxy, biphenylyloxy, oxo, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, chloro, bromo, and fluoro;
- R5 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, tetrahydronaphthyl, biphenyl, benzyl, diphenylmethyl, triphenylmethyl, phenylethyl, diphenylethyl, methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, methoxypentyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, ethoxybutyl, ethoxypentyl, butoxybutyl, butoxypentyl, pentoxymethyl, pentoxyethyl, pentoxypropyl, pentoxybutyl, and pentoxypentyl, or R5 together with R6 and the nitrogen to which they are attached may form a pyrrolidinyl or a piperidinyl ring;
- R6 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, tetrahydronaphthyl, biphenyl, benzyl, diphenylmethyl, triphenylmethyl, phenylethyl, diphenylethyl, methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, methoxypentyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, ethoxybutyl, ethoxypentyl, butoxybutyl, butoxypentyl, pentoxymethyl, pentoxyethyl, pentoxypropyl, pentoxybutyl, and pentoxypentyl, or R6 together with R5 and the nitrogen to which they are attached may form a pyrrolidinyl or a piperidinyl ring;
- R7 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, phenyl, naphthyl, tetrahydronaphthyl, and biphenyl;
- R8 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, tetrahydronaphthyl, biphenyl, benzyl, diphenylmethyl, triphenylmethyl, phenylethyl, diphenylethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, hydroxyhexyl, methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, methoxypentyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, ethoxybutyl, ethoxypentyl, propoxymethyl, propoxyethyl, propoxypropyl, propoxybutyl, propoxypentyl, butoxymethyl, butoxyethyl, butoxypropyl, butoxybutyl, butoxypentyl, pentoxymethyl, pentoxyethyl, pentoxypropyl, pentoxybutyl, pentoxypentyl, carboxymethyl, carboxyethyl, carboxypropyl, carboxybutyl, carboxypentyl, and carboxyhexyl, or R8 together with R2 and the nitrogen to which they are attached may form an isoindolinyl ring;
- R9 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, tetrahydronaphthyl, biphenyl, benzyl, diphenylmethyl, triphenylmethyl, phenylethyl, diphenylethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, hydroxyhexyl, methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, methoxypentyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, ethoxybutyl, ethoxypentyl, propoxymethyl, propoxyethyl, propoxypropyl, propoxybutyl, propoxypentyl, butoxymethyl, butoxyethyl, butoxypropyl, butoxybutyl, butoxypentyl, pentoxymethyl, pentoxyethyl, pentoxypropyl, pentoxybutyl, pentoxypentyl, carboxymethyl, carboxyethyl, carboxypropyl, carboxybutyl, carboxypentyl, and carboxyhexyl, or R9 together with R4 and the nitrogen to which they are attached may form a pyrrolidinyl or a piperidinyl ring;
- R10 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, tetrahydronaphthyl, biphenyl, benzyl, diphenylmethyl, triphenylmethyl, phenylethyl, diphenylethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, hydroxyhexyl, methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, methoxypentyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, ethoxybutyl, ethoxypentyl, propoxymethyl, propoxyethyl, propoxypropyl, propoxybutyl, propoxypentyl, butoxymethyl, butoxyethyl, butoxypropyl, butoxybutyl, butoxypentyl, pentoxymethyl, pentoxyethyl, pentoxypropyl, pentoxybutyl, pentoxypentyl, carboxymethyl, carboxyethyl, carboxypropyl, carboxybutyl, carboxypentyl, and carboxyhexyl; and
- R12 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, tetrahydronaphthyl, biphenyl, benzyl, diphenylmethyl, triphenylmethyl, phenylethyl, diphenylethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, hydroxyhexyl, methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, methoxypentyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, ethoxybutyl, ethoxypentyl, propoxymethyl, propoxyethyl, propoxypropyl, propoxybutyl, propoxypentyl, butoxymethyl, butoxyethyl, butoxypropyl, butoxybutyl, butoxypentyl, pentoxymethyl, pentoxyethyl, pentoxypropyl, pentoxybutyl, pentoxypentyl, carboxymethyl, carboxyethyl, carboxypropyl, carboxybutyl, carboxypentyl, and carboxyhexyl.
In another embodiment, the MCH receptor antagonist is selected from a subclass of compounds of Formula I represented by Formula V:
- wherein:
- X is selected from the group consisting of —OR1 and —SR1;
- Z is selected from the group consisting of —CH═CH—, —CH2N(R9)—, —C(O)N(R9)—, and —NHC(O)NR9—;
- R1 is selected from the group consisting of alkyl, cycloalkyl, aryl, and heteroaryl, wherein R1 is optionally substituted with one or more substituents selected from the group consisting of alkyl, hydroxy, alkoxy, carboxyl, aryloxy, oxo, and halo;
- R2 is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, aralkyl, cycloalkylalkyl, aralkenyl, and arylcycloalkyl, or R2 together with R8 and the nitrogen to which they are attached may form an unsaturated fused heterocyclic ring system, wherein R2 or the unsaturated fused heterocyclic ring formed with R8 is optionally substituted with one or more substituents selected from the group consisting of alkyl, hydroxy, alkoxy, carboxyl, aryloxy, oxo, and halo;
- R4 is selected from the group consisting of a bond, alkyl, alkenyl, and cycloalkyl, or R4 together with R9 and the nitrogen to which they are attached may form a saturated 5- or 6-membered heterocyclic ring, wherein R4 or the ring formed with R9 is optionally substituted with one or more substituents selected from the group consisting of alkyl, hydroxy, and halo;
- R5 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, aralkyl, and alkoxyalkyl, or R5 together with R6 and the nitrogen to which they are attached may form a saturated 5- or 6-membered heterocyclic ring;
- R6 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, aralkyl, and alkoxyalkyl, or R6 together with R5 and the nitrogen to which they are attached may form a saturated 5- or 6-membered heterocyclic ring;
- R7 is selected from the group consisting of hydrogen, alkyl, and aryl;
- R8 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, aralkyl, hydroxyalkyl, alkoxyalkyl, and carboxyalkyl, or R8 together with R2 and the nitrogen to which they are attached may form an unsaturated fused heterocyclic ring system; and
- R9 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, aralkyl, hydroxyalkyl, alkoxyalkyl, and carboxyalkyl, or R9 together with R4 and the nitrogen to which they are attached may form a saturated 5- or 6-membered heterocyclic ring;
- or a pharmaceutically-acceptable salt, tautomer or prodrug thereof.
In another embodiment, the MCH receptor antagonist consists of compounds of Formula V, or a pharmaceutically-acceptable salt, tautomer or prodrug thereof, wherein:
- X is selected from the group consisting of —OR1 and —SR1;
- Z is selected from the group consisting of —CH═CH—, —CH2N(R9)—, —C(O)N(R9)—, and —NHC(O)NR9—;
- R1 is selected from the group consisting of lower alkyl, lower cycloalkyl, aryl, and heteroaryl, wherein R1 is optionally substituted with one or more substituents selected from the group consisting of lower alkyl, hydroxy, lower alkoxy, carboxyl, aryloxy, oxo, and halo;
- R2 is selected from the group consisting of lower alkyl, lower cycloalkyl, aryl, heteroaryl, lower aralkyl, lower cycloalkylalkyl, lower aralkenyl, and lower arylcycloalkyl, or R2 together with R8 and the nitrogen to which they are attached may form an unsaturated fused heterocyclic ring system, wherein R2 or the unsaturated fused heterocyclic ring formed with R8 is optionally substituted with one or more substituents selected from the group consisting of lower alkyl, hydroxy, lower alkoxy, carboxyl, aryloxy, oxo, and halo;
- R4 is selected from the group consisting of a bond, lower alkyl, lower alkenyl, and lower cycloalkyl, or R4 together with R9 and the nitrogen to which they are attached may form a saturated 5- or 6-membered heterocyclic ring, wherein R4 or the ring formed with R9 is optionally substituted with one or more substituents selected from the group consisting of lower alkyl, hydroxy, and halo;
- R5 is selected from the group consisting of hydrogen, lower alkyl, lower cycloalkyl, aryl, lower aralkyl, and lower alkoxyalkyl, or R5 together with R6 and the nitrogen to which they are attached may form a saturated 5- or 6-membered heterocyclic ring;
- R6 is selected from the group consisting of hydrogen, lower alkyl, lower cycloalkyl, aryl, lower aralkyl, and lower alkoxyalkyl, or R6 together with R5 and the nitrogen to which they are attached may form a saturated 5- or 6-membered heterocyclic ring;
- R7 is selected from the group consisting of hydrogen, lower alkyl, and aryl;
- R8 is selected from the group consisting of hydrogen, lower alkyl, lower cycloalkyl, aryl, lower aralkyl, lower hydroxyalkyl, lower alkoxyalkyl, and lower carboxyalkyl, or R8 together with R2 and the nitrogen to which they are attached may form an unsaturated fused heterocyclic ring system; and
- R9 is selected from the group consisting of hydrogen, lower alkyl, lower cycloalkyl, aryl, lower aralkyl, lower hydroxyalkyl, lower alkoxyalkyl, and lower carboxyalkyl, or R9 together with R4 and the nitrogen to which they are attached may form a saturated 5- or 6-membered heterocyclic ring.
In another embodiment, the MCH receptor antagonist consists of compounds of Formula V, or a pharmaceutically-acceptable salt, tautomer or prodrug thereof, wherein:
- X is selected from the group consisting of —OR1 and —SR1;
- Z is selected from the group consisting of —CH═CH—, —CH2N(R9)—, —C(O)N(R9)—, and —NHC(O)NR9—;
- R1 is selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, tetrahydronaphthyl, biphenyl, benzyl, furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, isoxazolyl, oxazolyl, indolyl, thiazolyl, isothiazolyl, oxadiazolyl, oxatriazolyl, dioxazole, tetrazolyl, and benzodioxolyl, wherein R1 is optionally substituted with one or more substituents selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl, hexyl, hydroxy, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, carboxyl, phenoxy, naphthyloxy, tetrahydronaphthyloxy, biphenylyloxy, oxo, chloro, bromo, and fluoro;
- R2 is selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, tetrahydronaphthyl, biphenyl, furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, isoxazolyl, oxazolyl, indolyl, thiazolyl, isothiazolyl, oxadiazolyl, oxatriazolyl, dioxazole, tetrazolyl, benzodioxolyl, benzyl, diphenylmethyl, triphenylmethyl, phenylethyl, diphenylethyl, cyclopropylmethyl, cyclopropylethyl, cyclopropylpropyl, cyclopropylbutyl, cyclopropylpentyl, cyclobutylmethyl, cyclobutylethyl, cyclobutylpropyl, cyclobutylbutyl, cyclobutylpenyyl, cyclopentylmethyl, cyclopentylethyl, cyclopentylpropyl, cyclopentylbutyl, cyclopentylpentyl, cyclohexylmethyl, cyclohexylethyl, cyclohexylpropyl, cyclohexylbutyl, cyclohexylpentyl, phenylethenyl, phenylpropenyl, phenylallyl, phenylbutenyl, phenylpentenyl, phenylcyclopropyl, phenylcyclobutyl, phenylcyclopentyl, phenylcyclohexyl, biphenylcyclopropyl, biphenylcyclobutyl, biphenylcyclopentyl, biphenylcyclohexyl, naphthylcyclopropyl, naphthylcyclobutyl, naphthylcyclopentyl, naphthylcyclohexyl, or R2 together with R8 and the nitrogen to which they are attached may form a ring selected from the group consisting of hexahydroisoindolyl, tetrahydroisoindolyl, dihydroisoindolyl, isoindolinyl, hexahydroindolyl, tetrahydroindolyl, dihydroindolyl, indolinyl, octahydroquinolinyl, hexahydroquinolinyl, tetrahydroquinolinyl, dihydroquinolinyl, and quinolinyl, wherein R2 or the ring formed with R8 is optionally substituted with one or more substituents selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl, hexyl, hydroxy, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, carboxyl, phenoxy, naphthyloxy, tetrahydronaphthyloxy, biphenylyloxy, oxo, chloro, bromo, and fluoro;
- R4 is selected from the group consisting of a bond, methyl, ethyl, propyl, butyl, pentyl, hexyl, ethenyl, propenyl, allyl, butenyl, pentenyl, acetylenyl, propynyl, butynyl, pentynyl, hexynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, tetrahydronaphthyl, biphenyl, furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, isoxazolyl, oxazolyl, indolyl, thiazolyl, isothiazolyl, oxadiazolyl, oxatriazolyl, dioxazole, tetrazolyl, benzodioxolyl, benzyl, diphenylmethyl, triphenylmethyl, phenylethyl, diphenylethyl, cyclopropylmethyl, cyclopropylethyl, cyclopropylpropyl, cyclopropylbutyl, cyclopropylpentyl, cyclobutylmethyl, cyclobutylethyl, cyclobutylpropyl, cyclobutylbutyl, cyclobutylpenyyl, cyclopentylmethyl, cyclopentylethyl, cyclopentylpropyl, cyclopentylbutyl, cyclopentylpentyl, cyclohexylmethyl, cyclohexylethyl, cyclohexylpropyl, cyclohexylbutyl, cyclohexylpentyl, phenylethenyl, phenylpropenyl, phenylallyl, phenylbutenyl, phenylpentenyl, or R4 together with R9 and the nitrogen to which they are attached may form a pyrrolidinyl or a piperidinyl ring, wherein R4 or the ring formed with R9 is optionally substituted with one or more substituents selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl, hexyl, hydroxy, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, carboxyl, phenoxy, naphthyloxy, tetrahydronaphthyloxy, biphenylyloxy, oxo, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, chloro, bromo, and fluoro;
- R5 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, tetrahydronaphthyl, biphenyl, benzyl, diphenylmethyl, triphenylmethyl, phenylethyl, diphenylethyl, methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, methoxypentyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, ethoxybutyl, ethoxypentyl, butoxybutyl, butoxypentyl, pentoxymethyl, pentoxyethyl, pentoxypropyl, pentoxybutyl, and pentoxypentyl, or R5 together with R6 and the nitrogen to which they are attached may form a pyrrolidinyl or a piperidinyl ring;
- R6 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, tetrahydronaphthyl, biphenyl, benzyl, diphenylmethyl, triphenylmethyl, phenylethyl, diphenylethyl, methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, methoxypentyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, ethoxybutyl, ethoxypentyl, butoxybutyl, butoxypentyl, pentoxymethyl, pentoxyethyl, pentoxypropyl, pentoxybutyl, and pentoxypentyl, or R6 together with R5 and the nitrogen to which they are attached may form a pyrrolidinyl or a piperidinyl ring;
- R7 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, phenyl, naphthyl, tetrahydronaphthyl, and biphenyl;
- R8 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, tetrahydronaphthyl, biphenyl, benzyl, diphenylmethyl, triphenylmethyl, phenylethyl, diphenylethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, hydroxyhexyl, methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, methoxypentyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, ethoxybutyl, ethoxypentyl, propoxymethyl, propoxyethyl, propoxypropyl, propoxybutyl, propoxypentyl, butoxymethyl, butoxyethyl, butoxypropyl, butoxybutyl, butoxypentyl, pentoxymethyl, pentoxyethyl, pentoxypropyl, pentoxybutyl, pentoxypentyl, carboxymethyl, carboxyethyl, carboxypropyl, carboxybutyl, carboxypentyl, and carboxyhexyl, or R8 together with R2 and the nitrogen to which they are attached may form an isoindolinyl ring; and
- R9 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, tetrahydronaphthyl, biphenyl, benzyl, diphenylmethyl, triphenylmethyl, phenylethyl, diphenylethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, hydroxyhexyl, methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, methoxypentyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, ethoxybutyl, ethoxypentyl, propoxymethyl, propoxyethyl, propoxypropyl, propoxybutyl, propoxypentyl, butoxymethyl, butoxyethyl, butoxypropyl, butoxybutyl, butoxypentyl, pentoxymethyl, pentoxyethyl, pentoxypropyl, pentoxybutyl, pentoxypentyl, carboxymethyl, carboxyethyl, carboxypropyl, carboxybutyl, carboxypentyl, and carboxyhexyl, or R9 together with R4 and the nitrogen to which they are attached may form a pyrrolidinyl or a piperidinyl ring.
In another embodiment, the MCH receptor antagonist is selected from a subclass of compounds of Formula I represented by Formula VI:
- wherein:
- X is selected from the group consisting of —OR1 and —SR1;
- Z is selected from the group consisting of —CH═CH—, —CH2N(R9)—, —C(O)N(R9)—, and —NHC(O)NR9—;
- R1 is selected from the group consisting of alkyl, cycloalkyl, aryl, and heteroaryl, wherein R1 is optionally substituted with one or more substituents selected from the group consisting of alkyl, hydroxy, alkoxy, carboxyl, aryloxy, oxo, and halo;
- R2 is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, aralkyl, cycloalkylalkyl, aralkenyl, and arylcycloalkyl, or R2 together with R8 and the nitrogen to which they are attached may form an unsaturated fused heterocyclic ring system, wherein R2 or the unsaturated fused heterocyclic ring formed with R8 is optionally substituted with one or more substituents selected from the group consisting of alkyl, hydroxy, alkoxy, carboxyl, aryloxy, oxo, and halo;
- R4 is selected from the group consisting of a bond, alkyl, alkenyl, and cycloalkyl, or R4 together with R9 and the nitrogen to which they are attached may form a saturated 5- or 6-membered heterocyclic ring, wherein R4 or the ring formed with R9 is optionally substituted with one or more substituents selected from the group consisting of alkyl, hydroxy, and halo;
- R5 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, aralkyl, and alkoxyalkyl, or R5 together with R6 and the nitrogen to which they are attached may form a saturated 5- or 6-membered heterocyclic ring;
- R6 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, aralkyl, and alkoxyalkyl, or R6 together with R5 and the nitrogen to which they are attached may form a saturated 5- or 6-membered heterocyclic ring;
- R7 is selected from the group consisting of hydrogen, alkyl, and aryl; and
- R9 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, aralkyl, hydroxyalkyl, alkoxyalkyl, and carboxyalkyl, or R9 together with R4 and the nitrogen to which they are attached may form a saturated 5- or 6-membered heterocyclic ring;
- or a pharmaceutically-acceptable salt, tautomer or prodrug thereof.
In another embodiment, the MCH receptor antagonist consists of compounds of Formula VI, or a pharmaceutically-acceptable salt, tautomer or prodrug thereof, wherein:
- X is selected from the group consisting of —OR1 and —SR1;
- Z is selected from the group consisting of —CH═CH—, —CH2N(R9)—, —C(O)N(R9)—, and —NHC(O)NR9—;
- R1 is selected from the group consisting of lower alkyl, lower cycloalkyl, aryl, and heteroaryl, wherein R1 is optionally substituted with one or more substituents selected from the group consisting of lower alkyl, hydroxy, lower alkoxy, carboxyl, aryloxy, oxo, and halo;
- R2 is selected from the group consisting of lower alkyl, lower cycloalkyl, aryl, heteroaryl, lower aralkyl, lower cycloalkylalkyl, lower aralkenyl, and lower arylcycloalkyl, or R2 together with R8 and the nitrogen to which they are attached may form an unsaturated fused heterocyclic ring system, wherein R2 or the unsaturated fused heterocyclic ring formed with R8 is optionally substituted with one or more substituents selected from the group consisting of lower alkyl, hydroxy, lower alkoxy, carboxyl, aryloxy, oxo, and halo;
- R4 is selected from the group consisting of a bond, lower alkyl, lower alkenyl, and lower cycloalkyl, or R4 together with R9 and the nitrogen to which they are attached may form a saturated 5- or 6-membered heterocyclic ring, wherein R4 or the ring formed with R9 is optionally substituted with one or more substituents selected from the group consisting of lower alkyl, hydroxy, and halo;
- R5 is selected from the group consisting of hydrogen, lower alkyl, lower cycloalkyl, aryl, lower aralkyl, and lower alkoxyalkyl, or R5 together with R6 and the nitrogen to which they are attached may form a saturated 5- or 6-membered heterocyclic ring;
- R6 is selected from the group consisting of hydrogen, lower alkyl, lower cycloalkyl, aryl, lower aralkyl, and lower alkoxyalkyl, or R6 together with R5 and the nitrogen to which they are attached may form a saturated 5- or 6-membered heterocyclic ring;
- R7 is selected from the group consisting of hydrogen, lower alkyl, and aryl;
- R8 is selected from the group consisting of hydrogen, lower alkyl, lower cycloalkyl, aryl, lower aralkyl, lower hydroxyalkyl, lower alkoxyalkyl, and lower carboxyalkyl, or R8 together with R2 and the nitrogen to which they are attached may form an unsaturated fused heterocyclic ring system; and
- R9 is selected from the group consisting of hydrogen, lower alkyl, lower cycloalkyl, aryl, lower aralkyl, lower hydroxyalkyl, lower alkoxyalkyl, and lower carboxyalkyl, or R9 together with R4 and the nitrogen to which they are attached may form a saturated 5- or 6-membered heterocyclic ring.
In another embodiment, the MCH receptor antagonist consists of compounds of Formula VI, or a pharmaceutically-acceptable salt, tautomer or prodrug thereof, wherein:
- X is selected from the group consisting of —OR1 and —SR1;
- Z is selected from the group consisting of —CH═CH—, —CH2N(R9)—, —C(O)N(R9)—, and —NHC(O)NR9—;
- R1 is selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, tetrahydronaphthyl, biphenyl, benzyl, furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, isoxazolyl, oxazolyl, indolyl, thiazolyl, isothiazolyl, oxadiazolyl, oxatriazolyl, dioxazole, tetrazolyl, and benzodioxolyl, wherein R1 is optionally substituted with one or more substituents selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl, hexyl, hydroxy, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, carboxyl, phenoxy, naphthyloxy, tetrahydronaphthyloxy, biphenylyloxy, oxo, chloro, bromo, and fluoro;
- R2 is selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, tetrahydronaphthyl, biphenyl, furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, isoxazolyl, oxazolyl, indolyl, thiazolyl, isothiazolyl, oxadiazolyl, oxatriazolyl, dioxazole, tetrazolyl, benzodioxolyl, benzyl, diphenylmethyl, triphenylmethyl, phenylethyl, diphenylethyl, cyclopropylmethyl, cyclopropylethyl, cyclopropylpropyl, cyclopropylbutyl, cyclopropylpentyl, cyclobutylmethyl, cyclobutylethyl, cyclobutylpropyl, cyclobutylbutyl, cyclobutylpenyyl, cyclopentylmethyl, cyclopentylethyl, cyclopentylpropyl, cyclopentylbutyl, cyclopentylpentyl, cyclohexylmethyl, cyclohexylethyl, cyclohexylpropyl, cyclohexylbutyl, cyclohexylpentyl, phenylethenyl, phenylpropenyl, phenylallyl, phenylbutenyl, phenylpentenyl, phenylcyclopropyl, phenylcyclobutyl, phenylcyclopentyl, phenylcyclohexyl, biphenylcyclopropyl, biphenylcyclobutyl, biphenylcyclopentyl, biphenylcyclohexyl, naphthylcyclopropyl, naphthylcyclobutyl, naphthylcyclopentyl, naphthylcyclohexyl, or R2 together with R8 and the nitrogen to which they are attached may form a ring selected from the group consisting of hexahydroisoindolyl, tetrahydroisoindolyl, dihydroisoindolyl, isoindolinyl, hexahydroindolyl, tetrahydroindolyl, dihydroindolyl, indolinyl, octahydroquinolinyl, hexahydroquinolinyl, tetrahydroquinolinyl, dihydroquinolinyl, and quinolinyl, wherein R2 or the ring formed with R8 is optionally substituted with one or more substituents selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl, hexyl, hydroxy, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, carboxyl, phenoxy, naphthyloxy, tetrahydronaphthyloxy, biphenylyloxy, oxo, chloro, bromo, and fluoro;
- R4 is selected from the group consisting of a bond, methyl, ethyl, propyl, butyl, pentyl, hexyl, ethenyl, propenyl, allyl, butenyl, pentenyl, acetylenyl, propynyl, butynyl, pentynyl, hexynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, tetrahydronaphthyl, biphenyl, furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, isoxazolyl, oxazolyl, indolyl, thiazolyl, isothiazolyl, oxadiazolyl, oxatriazolyl, dioxazole, tetrazolyl, benzodioxolyl, benzyl, diphenylmethyl, triphenylmethyl, phenylethyl, diphenylethyl, cyclopropylmethyl, cyclopropylethyl, cyclopropylpropyl, cyclopropylbutyl, cyclopropylpentyl, cyclobutylmethyl, cyclobutylethyl, cyclobutylpropyl, cyclobutylbutyl, cyclobutylpenyyl, cyclopentylmethyl, cyclopentylethyl, cyclopentylpropyl, cyclopentylbutyl, cyclopentylpentyl, cyclohexylmethyl, cyclohexylethyl, cyclohexylpropyl, cyclohexylbutyl, cyclohexylpentyl, phenylethenyl, phenylpropenyl, phenylallyl, phenylbutenyl, phenylpentenyl, or R4 together with R9 and the nitrogen to which they are attached may form a pyrrolidinyl or a piperidinyl ring, wherein R4 or the ring formed with R9 is optionally substituted with one or more substituents selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl, hexyl, hydroxy, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, carboxyl, phenoxy, naphthyloxy, tetrahydronaphthyloxy, biphenylyloxy, oxo, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, chloro, bromo, and fluoro;
- R5 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, tetrahydronaphthyl, biphenyl, benzyl, diphenylmethyl, triphenylmethyl, phenylethyl, diphenylethyl, methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, methoxypentyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, ethoxybutyl, ethoxypentyl, butoxybutyl, butoxypentyl, pentoxymethyl, pentoxyethyl, pentoxypropyl, pentoxybutyl, and pentoxypentyl, or R5 together with R6 and the nitrogen to which they are attached may form a pyrrolidinyl or a piperidinyl ring;
- R6 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, tetrahydronaphthyl, biphenyl, benzyl, diphenylmethyl, triphenylmethyl, phenylethyl, diphenylethyl, methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, methoxypentyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, ethoxybutyl, ethoxypentyl, butoxybutyl, butoxypentyl, pentoxymethyl, pentoxyethyl, pentoxypropyl, pentoxybutyl, and pentoxypentyl, or R6 together with R5 and the nitrogen to which they are attached may form a pyrrolidinyl or a piperidinyl ring;
- R7 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, phenyl, naphthyl, tetrahydronaphthyl, and biphenyl;
- R8 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, tetrahydronaphthyl, biphenyl, benzyl, diphenylmethyl, triphenylmethyl, phenylethyl, diphenylethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, hydroxyhexyl, methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, methoxypentyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, ethoxybutyl, ethoxypentyl, propoxymethyl, propoxyethyl, propoxypropyl, propoxybutyl, propoxypentyl, butoxymethyl, butoxyethyl, butoxypropyl, butoxybutyl, butoxypentyl, pentoxymethyl, pentoxyethyl, pentoxypropyl, pentoxybutyl, pentoxypentyl, carboxymethyl, carboxyethyl, carboxypropyl, carboxybutyl, carboxypentyl, and carboxyhexyl, or R8 together with R2 and the nitrogen to which they are attached may form an isoindolinyl ring; and
- R9 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, tetrahydronaphthyl, biphenyl, benzyl, diphenylmethyl, triphenylmethyl, phenylethyl, diphenylethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, hydroxyhexyl, methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, methoxypentyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, ethoxybutyl, ethoxypentyl, propoxymethyl, propoxyethyl, propoxypropyl, propoxybutyl, propoxypentyl, butoxymethyl, butoxyethyl, butoxypropyl, butoxybutyl, butoxypentyl, pentoxymethyl, pentoxyethyl, pentoxypropyl, pentoxybutyl, pentoxypentyl, carboxymethyl, carboxyethyl, carboxypropyl, carboxybutyl, carboxypentyl, and carboxyhexyl, or R9 together with R4 and the nitrogen to which they are attached may form a pyrrolidinyl or a piperidinyl ring.
In another embodiment, the MCH receptor antagonist is selected from a subclass of compounds of Formula I represented by Formula VII:
- wherein:
- R1 is selected from the group consisting of cycloalkyl and aryl, wherein R1 is optionally substituted with one or more substituents selected from the group consisting of alkyl, hydroxy, alkoxy, and halo;
- R2 is selected from the group consisting of alkyl, aryl, aralkyl, cycloalkylalkyl, aralkenyl, and arylcycloalkyl, or R2 together with R8 and the nitrogen to which they are attached may form an unsaturated fused heterocyclic ring system, wherein R2 or the unsaturated fused heterocyclic ring formed with R8 is optionally substituted with one or more substituents selected from the group consisting of alkyl, hydroxy, alkoxy, aryloxy, and halo;
- R5 is selected from the group consisting of hydrogen and alkyl, or R5 together with R6 and the nitrogen to which they are attached may form a saturated 5- or 6-membered heterocyclic ring;
- R6 is selected from the group consisting of hydrogen and alkyl, or R6 together with R5 and the nitrogen to which they are attached may form a saturated 5- or 6-membered heterocyclic ring; and
- R8 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, and aryl, or R8 together with R2 and the nitrogen to which they are attached may form an unsaturated fused heterocyclic ring system;
- or a pharmaceutically-acceptable salt, tautomer or prodrug thereof.
In another embodiment, the MCH receptor antagonist consists of compounds of Formula VII, or a pharmaceutically-acceptable salt, tautomer or prodrug thereof, wherein:
- R1 is selected from the group consisting of lower cycloalkyl and aryl, wherein R1 is optionally substituted with one or more substituents selected from the group consisting of lower alkyl, hydroxy, lower alkoxy, and halo;
- R2 is selected from the group consisting of lower alkyl, aryl, lower aralkyl, lower cycloalkylalkyl, lower aralkenyl, and lower arylcycloalkyl, or R2 together with R8 and the nitrogen to which they are attached may form an unsaturated fused heterocyclic ring system, wherein R2 or the unsaturated fused heterocyclic ring formed with R8 is optionally substituted with one or more substituents selected from the group consisting of lower alkyl, hydroxy, lower alkoxy, aryloxy, and halo;
- R5 is selected from the group consisting of hydrogen and lower alkyl, or R5 together with R6 and the nitrogen to which they are attached may form a saturated 5- or 6-membered heterocyclic ring;
- R6 is selected from the group consisting of hydrogen and lower alkyl, or R6 together with R5 and the nitrogen to which they are attached may form a saturated 5- or 6-membered heterocyclic ring; and
- R8 is selected from the group consisting of hydrogen, lower alkyl, lower cycloalkyl, and aryl, or R8 together with R2 and the nitrogen to which they are attached may form an unsaturated fused heterocyclic ring system.
In another embodiment, the MCH receptor antagonist consists of compounds of Formula VII, or a pharmaceutically-acceptable salt, tautomer or prodrug thereof, wherein:
- R1 is selected from the group consisting of cyclopentyl, cyclohexyl, phenyl, naphthyl, and biphenyl, wherein R1 is optionally substituted with one or more substituents selected from the group consisting of methyl, ethyl, propyl, hydroxy, methoxy, ethoxy, propoxy, chloro, bromo, and fluoro;
- R2 is selected from the group consisting of methyl, ethyl, propyl, butyl, phenyl, naphthyl, tetrahydronaphthyl, biphenyl, benzyl, phenylethyl, cyclopentylmethyl, cyclopentylethyl, cyclopentylpropyl, cyclohexylmethyl, cyclohexylethyl, cyclohexylpropyl, phenylethenyl, phenylpropenyl, phenylcyclopropyl, biphenylcyclopropyl, and naphthylcyclopropyl, or R2 together with R8 and the nitrogen to which they are attached may form a ring selected from the group consisting of dihydroisoindolyl, dihydroindolyl, tetrahydroisoquinolinyl, and tetrahydroquinolinyl, wherein R2 or the ring formed with R8 is optionally substituted with one or more substituents selected from the group consisting of methyl, ethyl, propyl, butyl, hydroxy, methoxy, ethoxy, propoxy, phenoxy, naphthyloxy, biphenylyloxy, chloro, bromo, and fluoro;
- R5 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, butyl, pentyl, and hexyl, or R5 together with R6 and the nitrogen to which they are attached may form a pyrrolidinyl or a piperidinyl ring;
- R6 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, butyl, pentyl, and hexyl, or R6 together with R5 and the nitrogen to which they are attached may form a pyrrolidinyl or a piperidinyl ring; and
- R8 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, and biphenyl, or R8 together with R2 and the nitrogen to which they are attached may form a ring selected from the group consisting of dihydroisoindolyl, dihydroindolyl, tetrahydroisoquinolinyl, and tetrahydroquinolinyl.
In another embodiment, the MCH receptor antagonist consists of compounds of Formula VII, or a pharmaceutically-acceptable salt, tautomer or prodrug thereof, wherein:
- R1 is selected from the group consisting of phenyl, and naphthyl, wherein R1 is optionally substituted with one or more substituents selected from the group consisting of methyl, chloro, and fluoro;
- R2 is selected from the group consisting of methyl, ethyl, phenyl, naphthyl, biphenyl, benzyl, phenylethyl, cyclopentylethyl, phenylethenyl, phenylcyclopropyl, or R2 together with R8 and the nitrogen to which they are attached may form a dihydroisoindolyl ring, wherein R2 or the ring formed with R6 is optionally substituted with one or more substituents selected from the group consisting of methyl, propyl, methoxy, phenoxy, chloro, bromo, and fluoro;
- R5 is hydrogen or R5 together with R6 and the nitrogen to which they are attached form a pyrrolidinyl ring;
- R6 is hydrogen or R6 together with R5 and the nitrogen to which they are attached form a pyrrolidinyl ring; and
- R8 is selected from the group consisting of hydrogen, methyl, and phenyl, or R8 together with R2 and the nitrogen to which they are attached may form a dihydroisoindolyl ring.
In another embodiment, the compound of Formula I is selected from the group of compounds listed in Table 1.
TABLE 1
|
|
Compound
No.Structure
|
|
|
1
4-[(3,4-dimethylphenyl)oxy]-3-
{[(phenylamino)carbonyl]amino}-N-(2-(1-
pyrrolidinyl)ethyl)benzamide
MS m/z 473 (M + H); MW 472
|
5
4-[(3,4-dimethylphenyl)oxy]-3-[(3-
phenylpropanoyl)amino]-N-(2-(1-
pyrrolidinyl)ethyl)benzamide
MS m/z 486 (M + H); MW 485
|
6
4-[(3,4-dimethylphenyl)oxy]-3-
({[(phenylmethyl)amino]carbonyl}amino)-N-
(2-(1-pyrrolidinyl)ethyl)benzamide
MS m/z 487 (M + H); MW 486
|
8
4-(phenyloxy)-N-(2-(1-
pyrrolidinyl)ethyl)benzamide
MS m/z 311.4 (M + H); MW 310.4
|
10
3-acetylamino-4-(3,4-dimethylphenoxy)-N-(2-
pyrrolidin-1-yl-ethyl)benzamide
MS m/z 396 (M + H); MW 395
|
11
4-(3,4-dimethylphenoxy)-3-propionylamino-N-
(2-pyrrolidin-1-yl-ethyl)benzamide
MS m/z 400 (M + H); MW 409
|
12
3-(3-cyclopentylpropionylamino)-4-(3,4-
dimethylphenoxy)-N-(2-pyrrolidin-1-yl-
ethyl)benzamide
MS m/z 478 (M + H); MW 477
|
13
4-(3,4-dimethylphenoxy)-3-
phenylacetylarnino-N-(2-pyrrolidin-1-yl-
ethyl)benzamide
MS m/z 472 (M + H); MW 471
|
15
4-(3,4-dimethylphenoxy)-3-(3-phenyl-
acryloylamino)-N-(2-pyrrolidin-1-yl-
ethyl)benzamide
MS m/z 484 (M + H); MW 483
|
16
4-(3,4-dimethylphenoxy)-3-[(2-phenyl-
cyclopropanecarbonyl)amino]-N-(2-
pyrrolidin-1-yl-ethyl)benzamide
MS m/z 498 (M + H); MW 497
|
17
naphthalene-2-carboxylic acid [2-(3,4-
dimethylphenoxy)-5-(2-pyrrolidin-1-yl-
ethylcarbamoyl)phenyl]amide
MS m/z 508 (M + H); MW 507
|
18
4-(3,4-dimethylphenoxy)-3-(3-ethylureido)-
N-(2-pyrrolidin-1-yl-ethyl)benzamide
MS m/z 425 (M + H); MW 424
|
20
N-(2-aminoethyl)-4-(3,4-dimethylphenoxy)-3-
(3-phenylpropionylamino)benzamide
MS m/z 432 (M + H); MW 431
|
22
4-methoxy-3-(3-phenylpropionylamino)-N-(2-.
pyrrolidin-1-yl-ethyl)benzamide
MS m/z 508 (M + H); MW 507
|
27
4-(naphthalen-2-yl-oxy)-3-(3-
phenylpropionylamino)-N-(2-pyrrolidin-1-yl-
ethyl)benzamide
MS m/z 502 (M + H); MW 501
|
30
4-(3,4-dimethylphenoxy)-3-[3-(2-
methoxyphenyl)ureido]-N-(2-pyrroliidin-1-yl-
ethyl)benzamide
MS m/z 503 (M + H); MW 502
|
31
3-[3-(2,4-dichlorophenyl)ureido]-4-(3,4-
dimethylphenoxy)-N-(2-pyrrolidin-1-yl-
ethyl)benzamide
MS m/z 542 (M + H); MW 541
|
32
4-(3,4-dimethylphenoxy)-3-[3-(4-
phenoxyphenyl)ureido]-N-(2-pyrrolidin-1-yl-
ethyl)benzamide
MS m/z 565 (M + H); MW 564
|
33
3-(3-biphenyl-4-yl-ureido)-4-(3,4-
dimethylphenoxy)-N-(2-pyrrolidin-1-yl-
MS m/z 549 (M + H); MW 548
|
34
4-(3,4-dimethylphenoxy)-3-[3-(4-
isopropylphenyl)ureido]-N-(2-pyrrolidin-1-
yl-ethyl)benzamide
MS m/z 515 (M + H); MW 514
|
35
4-(3,4-dimethylphenoxy)-3-[3-(2,6-
dimethylphenyl)ureido]-N-(2-pyrrolidin-1-
yl-ethyl)benzamide
MS m/z 501 (M + H); MW 500
|
36
4-(3,4-dimethylphenoxy)-3-(3-naphthalen-1-
yl-ureido)-N-(2-pyrrolidin-1-yl-
ethyl)benzamide
MS m/z 523 (M + H); MW 522
|
37
3-[3-(2,6-diisopropylphenyl)ureido]-4-(3,4-
dimethylphenoxy)-N-(2-pyrrolidin-1-yl-
ethyl)benzamide
MS m/z 557 (M + H); MW 556
|
38
3-[3-(4-bromophenyl)ureido]-4-(3,4-
dimethylpherioxy)-N-(2-pyrrolidin-1-yl-
ethyl)benzamide
MS m/z 553 (M + H); MW 552
|
39
4-(3,4-dimethylphenoxy)-3-[3-(3-
fluorophenyl)ureido]-N-(2-pyrrolidin-1-yl-
ethyl)benzamide
MS m/z 491 (M + H); MW 490
|
40
4-(3,4-dimethylphenoxy)-3-[3-(3-
methoxyphenyl)ureido]-N-(2-pyrrolidin-1-yl-
ethyl)benzamide
MS m/z 503 (M + H); MW 502
|
41
3-[3-(2-chlorophenyl)ureido]-4-(3,4-
dimethylphenoxy)-N-(2-pyrrolidin-1-yl-
ethyl)benzamide
MS m/z 507 (M + H); MW 506
|
42
4-(3,4-dimethylphenoxy)-3-(3,3-
diphenylureido)-N-(2-pyrrolidin-1-yl-
ethyl)benzamide
MS m/z 549 (M + H); MW 548
|
43
4-(3,4-dimethylphenoxy)-3-(3-methyl-3-
phenylureido)-N-(2-pyrrolidin-1-yl-
ethyl)benzamide
MS m/z 487 (M + H); MW 486
|
50
1,3-dihydroisoindole-2-carboxylic acid [2-
(3,4-dimethylphenoxy)-5-(2-pyrrolidin-1-yl-
ethylcarbamoyl)phenyl]amide
MS m/z 499 (M + H); MW 498
|
51
4-(4-fluoro-3-methylphenoxy)-3-[3-(3-
fluorophenyl)ureido]-N-(2-pyrrolidin-1-yl-
ethyl)benzamide
MS m/z 495 (M + H); MW 494
|
52
4-(3,4-dichlorophenoxy)-3-[3-(3-
fluorophenyl)ureido]-N-(2-pyrrolidin-1-yl-
ethyl)benzamide
MS m/z 531 (M + H); MW 530
|
53
4-(3,4-difluorophenoxy)-3-[3-(3-
fluorophenyl)ureido]-N-(2-pyrrolidin-1-yl-
ethyl)benzamide
MS m/z 499 (M + H); MW 498
|
54
4-(4-fluorophenoxy)-3-[3-(3-
fluorophenyl)ureido]-N-(2-pyrrolidin-1-yl-
ethyl)benzamide
MS m/z 481 (M + H); MW 480
|
55
4-(3-fluorophenoxy)-3-[3-(3-
fluorophenyl)ureido]-N-(2-pyrrolidin-1-yl-
ethyl)benzamide
MS m/z 481 (M + H); MW 480
|
56
3-[3-(3-fluorophenyl)ureido]-N-(2-
pyrrolidin-1-yl-ethyl)-4-p-
tolyloxybenzamide
MS m/z 477 (M + H); MW 476
|
57
3-[3-(3-fluorophenyl)ureidol-N-(2-
pyrrolidin-1-yl-ethyl)-4-m-
tolyloxybenzamide
MS m/z 477 (M + H); MW 476
|
58
3-[3-(3,5-difluorophenyl)ureido]-4-(3,4-
dimethylphenoxy)-N-(2-pyrrolidin-1-yl-
ethyl)benzamide
MS m/z 509 (M + H); MW 508
|
59
3-[3-(3,5-dichlorophenyl)ureido]-4-(3,4-
dimethylphenoxy)-N-(2-pyrrolidin-1-yl-
ethyl)benzamide
MS m/z 541 (M + H); MW 540
|
61
3-[3-(3-fluorophenyl)ureido]-4-phenoxy-N-
(2-pyrrolidin-1-yl-ethyl)benzamide
MS m/z 463 (M + H); MW 462
|
63
1-(2-(3,4-dimethylphenoxy)-5-(2-pyrrolidin-
1-yl-methylpyrrolidine-1-carbonyl)phenyl]-
3-phenylurea
MS m/z 513 (M + H); MW 512
|
64
1-{2-(3,4-dimethylphenoxy)-5-[(2-
pyrrolidin-1-yl-ethylamino)-methyl]phenyl}-
3-(3-fluorophenyl)urea
MS m/z 477 (M + H); MW 476
|
65
1-[2-(3,4-dimethylphenoxy)-5-(2-pyrrolidin-
1-yl-methylpyrrolidine-1-carbonyl)phenyl]-
3-phenylurea
MS m/z 513 (M + H); MW 512
|
66
4-(3,4-dichlorophenoxy)-3-[3-(3,5-
difluorophenyl)ureido]-N-(2-pyrrolidin-1-
yl-ethyl)benzamide
MS m/z 549 (M + H); MW 548
|
In another embodiment, the compound of Formula I is selected from the group of compounds of Formula V having the structure:
wherein R2a, R2b, R2c, R2d, and R2e are as defined in Table 2.
TABLE 2
|
|
Compound
No.R2aR2bR2cR2dR2e
|
|
200HCH3CH3HH
201HCH3CH3CH3H
202HCH3CH3OCH3H
203HCH3CH3ClH
204HCH3CH3BrH
205HCH3CH3FH
206HCH3CH3HCH3
207HCH3CH3CH3CH3
208HCH3CH3HOCH3
209HCH3CH3CH3OCH3
210HCH3CH3OCH3OCH3
211HCH3CH3ClOCH3
212HCH3CH3BrOCH3
213HCH3CH3FOCH3
214HCH3CH3HCl
215HCH3CH3CH3Cl
216HCH3CH3OCH3Cl
217HCH3CH3ClCl
218HCH3CH3BrCl
219HCH3CH3FCl
220HCH3CH3HBr
221HCH3CH3CH3Br
222HCH3CH3OCH3Br
223HCH3CH3ClBr
224HCH3CH3BrBr
225HCH3CH3FBr
226HCH3CH3HF
227HCH3CH3CH3F
228HCH3CH3OCH3F
229HCH3CH3ClF
230HCH3CH3BrF
231HCH3CH3FF
232HCH3OCH3HH
233HCH3OCH3CH3H
234HCH3OCH3OCH3H
235HCH3OCH3ClH
236HCH3OCH3BrH
237HCH3OCH3FH
238HCH3OCH3HCH3
239HCH3OCH3CH3CH3
240HCH3OCH3OCH3CH3
241HCH3OCH3ClCH3
242HCH3OCH3BrCH3
243HCH3OCH3FCH3
244HCH3OCH3HOCH3
245HCH3OCH3OCH3OCH3
246HCH3OCH3HCl
247HCH3OCH3CH3Cl
248HCH3OCH3OCH3Cl
249HCH3OCH3ClCl
250HCH3OCH3BrCl
251HCH3OCH3FCl
252HCH3OCH3HBr
253HCH3OCH3CH3Br
254HCH3OCH3OCH3Br
255HCH3OCH3ClBr
256HCH3OCH3BrBr
257HCH3OCH3FBr
258HCH3OCH3HF
259HCH3OCH3CH3F
260HCH3OCH3OCH3F
261HCH3OCH3ClF
262HCH3OCH3BrF
263HCH3OCH3FF
264HCH3ClHH
265HCH3ClCH3H
266HCH3ClOCH3H
267HCH3ClClH
268HCH3ClBrH
269HCH3ClFH
270HCH3ClHCH3
271HCH3ClCH3CH3
272HCH3ClOCH3CH3
273HCH3ClClCH3
274HCH3ClBrCH3
275HCH3ClFCH3
276HCH3ClHOCH3
277HCH3ClCH3OCH3
278HCH3ClOCH3OCH3
279HCH3ClClOCH3
280HCH3ClBrOCH3
281HCH3ClFOCH3
282HCH3ClHCl
283HCH3ClClCl
284HCH3ClHBr
285HCH3ClCH3Br
286HCH3ClOCH3Br
287HCH3ClClBr
288HCH3ClBrBr
289HCH3ClFBr
290HCH3ClHF
291HCH3ClCH3F
292HCH3ClOCH3F
293HCH3ClClF
294HCH3ClFF
295HCH3BrHH
296HCH3BrCH3H
297HCH3BrOCH3H
298HCH3BrClH
299HCH3BrBrH
300HCH3BrFH
301HCH3BrHCH3
302HCH3BrCH3CH3
303HCH3BrOCH3CH3
304HCH3BrClCH3
305HCH3BrBrCH3
306HCH3BrFCH3
307HCH3BrHOCH3
308HCH3BrCH3OCH3
309HCH3BrOCH3OCH3
310HCH3BrClOCH3
311HCH3BrBrOCH3
312HCH3BrFOCH3
313HCH3BrHCl
314HCH3BrCH3Cl
315HCH3BrOCH3Cl
316HCH3BrClCl
317HCH3BrBrCl
318HCH3BrFCl
319HCH3BrHBr
320HCH3BrBrBr
321HCH3BrHF
322HCH3BrCH3F
323HCH3BrOCH3F
324HCH3BrClF
325HCH3BrBrF
326HCH3BrFF
327HCH3FHH
328HCH3FCH3H
329HCH3FOCH3H
330HCH3FClH
331HCH3FBrH
332HCH3FFH
333HCH3FHCH3
334HCH3FCH3CH3
335HCH3FOCH3CH3
336HCH3FClCH3
337HCH3FBrCH3
338HCH3FFCH3
339HCH3FHOCH3
340HCH3FCH3OCH3
341HCH3FOCH3OCH3
342HCH3FClOCH3
343HCH3FBrOCH3
344HCH3FFOCH3
345HCH3FHCl
346HCH3FCH3Cl
347HCH3FOCH3Cl
348HCH3FClCl
349HCH3FBrCl
350HCH3FFCl
351HCH3FHBr
352HCH3FCH3Br
353HCH3FOCH3Br
354HCH3FClBr
355HCH3FBrBr
356HCH3FFBr
357HCH3FHF
358HCH3FFF
359HOCH3CH3HH
360HOCH3CH3HCH3
361HOCH3CH3HOCH3
362HOCH3CH3HCl
363HOCH3CH3HBr
364HOCH3CH3HF
365HOCH3CH3CH3H
366HOCH3CH3CH3CH3
367HOCH3CH3CH3OCH3
368HOCH3CH3CH3Cl
369HOCH3CH3CH3Br
370HOCH3CH3CH3F
371HOCH3CH3OCH3H
372HOCH3CH3OCH3OCH3
373HOCH3CH3OCH3Cl
374HOCH3CH3OCH3Br
375HOCH3CH3OCH3F
376HOCH3CH3ClH
377HOCH3CH3ClOCH3
378HOCH3CH3ClCl
379HOCH3CH3ClBr
380HOCH3CH3ClF
381HOCH3CH3BrH
382HOCH3CH3BrOCH3
383HOCH3CH3BrCl
384HOCH3CH3BrBr
385HOCH3CH3BrF
386HOCH3CH3FH
387HOCH3CH3FOCH3
388HOCH3CH3FCl
389HOCH3CH3FBr
390HOCH3CH3FF
391HOCH3OCH3HH
392HOCH3OCH3HCH3
393HOCH3OCH3HOCH3
394HOCH3OCH3HCl
395HOCH3OCH3HBr
396HOCH3OCH3HF
397HOCH3OCH3CH3H
398HOCH3OCH3CH3CH3
399HOCH3OCH3CH3Cl
400HOCH3OCH3CH3Br
401HOCH3OCH3CH3F
402HOCH3OCH3OCH3H
403HOCH3OCH3OCH3CH3
404HOCH3OCH3OCH3OCH3
405HOCH3OCH3OCH3Cl
406HOCH3OCH3OCH3Br
407HOCH3OCH3OCH3F
408HOCH3OCH3ClH
409HOCH3OCH3ClCH3
410HOCH3OCH3ClCl
411HOCH3OCH3ClBr
412HOCH3OCH3ClF
413HOCH3OCH3BrH
414HOCH3OCH3BrCH3
415HOCH3OCH3BrCl
416HOCH3OCH3BrBr
417HOCH3OCH3BrF
418HOCH3OCH3FH
419HOCH3OCH3FCH3
420HOCH3OCH3FCl
421HOCH3OCH3FBr
422HOCH3OCH3FF
423HOCH3ClHH
424HOCH3ClHCH3
425HOCH3ClHOCH3
426HOCH3ClHCl
427HOCH3ClHBr
428HOCH3ClHF
429HOCH3ClCH3H
430HOCH3ClCH3CH3
431HOCH3ClCH3OCH3
432HOCH3ClCH3Br
433HOCH3ClCH3F
434HOCH3ClOCH3H
435HOCH3ClOCH3CH3
436HOCH3ClOCH3OCH3
437HOCH3ClOCH3Br
438HOCH3ClOCH3F
439HOCH3ClClH
440HOCH3ClClCH3
441HOCH3ClClOCH3
442HOCH3ClClCl
443HOCH3ClClBr
444HOCH3ClClF
445HOCH3ClBrH
446HOCH3ClBrCH3
447HOCH3ClBrOCH3
448HOCH3ClBrBr
449HOCH3ClFH
450HOCH3ClFCH3
451HOCH3ClFOCH3
452HOCH3ClFBr
453HOCH3ClFF
454HOCH3BrHH
455HOCH3BrHCH3
456HOCH3BrHOCH3
457HOCH3BrHCl
458HOCH3BrHBr
459HOCH3BrHF
460HOCH3BrCH3H
461HOCH3BrCH3CH3
462HOCH3BrCH3OCH3
463HOCH3BrCH3Cl
464HOCH3BrCH3F
465HOCH3BrOCH3H
466HOCH3BrOCH3CH3
467HOCH3BrOCH3OCH3
468HOCH3BrOCH3Cl
469HOCH3BrOCH3F
470HOCH3BrClH
471HOCH3BrClCH3
472HOCH3BrClOCH3
473HOCH3BrClCl
474HOCH3BrClF
475HOCH3BrBrH
476HOCH3BrBrCH3
477HOCH3BrBrOCH3
478HOCH3BrBrCl
479HOCH3BrBrBr
480HOCH3BrBrF
481HOCH3BrFH
482HOCH3BrFCH3
483HOCH3BrFOCH3
484HOCH3BrFCl
485HOCH3BrFF
486HOCH3FHH
487HOCH3FHCH3
488HOCH3FHOCH3
489HOCH3FHCl
490HOCH3FHBr
491HOCH3FHF
492HOCH3FCH3H
493HOCH3FCH3CH3
494HOCH3FCH3OCH3
495HOCH3FCH3Cl
496HOCH3FCH3Br
497HOCH3FOCH3H
498HOCH3FOCH3CH3
499HOCH3FOCH3OCH3
500HOCH3FOCH3Cl
501HOCH3FOCH3Br
502HOCH3FClH
503HOCH3FClCH3
504HOCH3FClOCH3
505HOCH3FClCl
506HOCH3FClBr
507HOCH3FBrH
508HOCH3FBrCH3
509HOCH3FBrOCH3
510HOCH3FBrCl
511HOCH3FBrBr
512HOCH3FFH
513HOCH3FFCH3
514HOCH3FFOCH3
515HOCH3FFCl
516HOCH3FFBr
517HOCH3FFF
518HClCH3HH
519HClCH3HCH3
520HClCH3HOCH3
521HClCH3HCl
522HClCH3HBr
523HClCH3HF
524HClCH3CH3H
525HClCH3CH3CH3
526HClCH3CH3OCH3
527HClCH3CH3Cl
528HClCH3CH3Br
529HClCH3CH3F
530HClCH3OCH3H
531HClCH3OCH3OCH3
532HClCH3OCH3Cl
533HClCH3OCH3Br
534HClCH3OCH3F
535HClCH3ClH
536HClCH3ClOCH3
537HClCH3ClCl
538HClCH3ClBr
539HClCH3ClF
540HClCH3BrH
541HClCH3BrOCH3
542HClCH3BrCl
543HClCH3BrBr
544HClCH3BrF
545HClCH3FH
546HClCH3FOCH3
547HClCH3FCl
548HClCH3FBr
549HClCH3FF
550HClOCH3HH
551HClOCH3HCH3
552HClOCH3HOCH3
553HClOCH3HCl
554HClOCH3HBr
555HClOCH3HF
556HClOCH3CH3H
557HClOCH3CH3CH3
558HClOCH3CH3Cl
559HClOCH3CH3Br
560HClOCH3CH3F
561HClOCH3OCH3H
562HClOCH3OCH3CH3
563HClOCH3OCH3OCH3
564HClOCH3OCH3Cl
565HClOCH3OCH3Br
566HClOCH3OCH3F
567HClOCH3ClH
568HClOCH3ClCH3
569HClOCH3ClCl
570HClOCH3ClBr
571HClOCH3ClF
572HClOCH3BrH
573HClOCH3BrCH3
574HClOCH3BrCl
575HClOCH3BrBr
576HClOCH3BrF
577HClOCH3FH
578HClOCH3FCH3
579HClOCH3FCl
580HClOCH3FBr
581HClOCH3FF
582HClClHH
583HClClHCH3
584HClClHOCH3
585HClClHCl
586HClClHBr
587HClClHF
588HClClCH3H
589HClClCH3CH3
590HClClCH3OCH3
591HClClCH3Br
592HClClCH3F
593HClClOCH3H
594HClClOCH3CH3
595HClClOCH3OCH3
596HClClOCH3Br
597HClClOCH3F
598HClClClH
599HClClClCH3
600HClClClOCH3
601HClClClCl
602HClClClBr
603HClClClF
604HClClBrH
605HClClBrCH3
606HClClBrOCH3
607HClClBrBr
608HClClFH
609HClClFCH3
610HClClFOCH3
611HClClFBr
612HClClFF
613HClBrHH
614HClBrHCH3
615HClBrHOCH3
616HClBrHCl
617HClBrHBr
618HClBrHF
619HClBrCH3H
620HClBrCH3CH3
621HClBrCH3OCH3
622HClBrCH3Cl
623HClBrCH3F
624HClBrOCH3H
625HClBrOCH3CH3
626HClBrOCH3OCH3
627HClBrOCH3Cl
628HClBrOCH3F
629HClBrClH
630HClBrClCH3
631HClBrClOCH3
632HClBrClCl
633HClBrClF
634HClBrBrH
635HClBrBrCH3
636HClBrBrOCH3
637HClBrBrCl
638HClBrBrBr
639HClBrBrF
640HClBrFH
641HClBrFCH3
642HClBrFOCH3
643HClBrFCl
644HClBrFF
645HClFHH
646HClFHCH3
647HClFHOCH3
648HClFHCl
649HClFHBr
650HClFHF
651HClFCH3H
652HClFCH3CH3
653HClFCH3OCH3
654HClFCH3Cl
655HClFCH3Br
656HClFOCH3H
657HClFOCH3CH3
658HClFOCH3OCH3
659HClFOCH3Cl
660HClFOCH3Br
661HClFClH
662HClFClCH3
663HClFClOCH3
664HClFClCl
665HClFClBr
666HClFBrH
667HClFBrCH3
668HClFBrOCH3
669HClFBrCl
670HClFBrBr
671HClFFH
672HClFFCH3
673HClFFOCH3
674HClFFCl
675HClFFBr
676HClFFF
677HBrCH3HH
678HBrCH3HCH3
679HBrCH3HOCH3
680HBrCH3HCl
681HBrCH3HBr
682HBrCH3HF
683HBrCH3CH3H
684HBrCH3CH3CH3
685HBrCH3CH3OCH3
686HBrCH3CH3Cl
687HBrCH3CH3Br
688HBrCH3CH3F
689HBrCH3OCH3H
690HBrCH3OCH3OCH3
691HBrCH3OCH3Cl
692HBrCH3OCH3Br
693HBrCH3OCH3F
694HBrCH3ClH
695HBrCH3ClOCH3
696HBrCH3ClCl
697HBrCH3ClBr
698HBrCH3ClF
699HBrCH3BrH
700HBrCH3BrOCH3
701HBrCH3BrCl
702HBrCH3BrBr
703HBrCH3BrF
704HBrCH3FH
705HBrCH3FOCH3
706HBrCH3FCl
707HBrCH3FBr
708HBrCH3FF
709HBrOCH3HH
710HBrOCH3HCH3
711HBrOCH3HOCH3
712HBrOCH3HCl
713HBrOCH3HBr
714HBrOCH3HF
715HBrOCH3CH3H
716HBrOCH3CH3CH3
717HBrOCH3CH3Cl
718HBrOCH3CH3Br
719HBrOCH3CH3F
720HBrOCH3OCH3H
721HBrOCH3OCH3CH3
722HBrOCH3OCH3OCH3
723HBrOCH3OCH3Cl
724HBrOCH3OCH3Br
725HBrOCH3OCH3F
726HBrOCH3ClH
727HBrOCH3ClCH3
728HBrOCH3ClCl
729HBrOCH3ClBr
730HBrOCH3ClF
731HBrOCH3BrH
732HBrOCH3BrCH3
733HBrOCH3BrCl
734HBrOCH3BrBr
735HBrOCH3BrF
736HBrOCH3FH
737HBrOCH3FCH3
738HBrOCH3FCl
739HBrOCH3FBr
740HBrOCH3FF
741HBrClHH
742HBrClHCH3
743HBrClHOCH3
744HBrClHCl
745HBrClHBr
746HBrClHF
747HBrClCH3H
748HBrClCH3CH3
749HBrClCH3OCH3
750HBrClCH3Br
751HBrClCH3F
752HBrClOCH3H
753HBrClOCH3CH3
754HBrClOCH3OCH3
755HBrClOCH3Br
756HBrClOCH3F
757HBrClClH
758HBrClClCH3
759HBrClClOCH3
760HBrClClCl
761HBrClClBr
762HBrClClF
763HBrClBrH
764HBrClBrCH3
765HBrClBrOCH3
766HBrClBrBr
767HBrClFH
768HBrClFCH3
769HBrClFOCH3
770HBrClFBr
771HBrClFF
772HBrBrHH
773HBrBrHCH3
774HBrBrHOCH3
775HBrBrHCl
776HBrBrHBr
777HBrBrHF
778HBrBrCH3H
779HBrBrCH3CH3
780HBrBrCH3OCH3
781HBrBrCH3Cl
782HBrBrCH3F
783HBrBrOCH3H
784HBrBrOCH3CH3
785HBrBrOCH3OCH3
786HBrBrOCH3Cl
787HBrBrOCH3F
788HBrBrClH
789HBrBrClCH3
790HBrBrClOCH3
791HBrBrClCl
792HBrBrClF
793HBrBrBrH
794HBrBrBrCH3
795HBrBrBrOCH3
796HBrBrBrCl
797HBrBrBrBr
798HBrBrBrF
799HBrBrFH
800HBrBrFCH3
801HBrBrFOCH3
802HBrBrFCl
803HBrBrFF
804HBrFHH
805HBrFHCH3
806HBrFHOCH3
807HBrFHCl
808HBrFHBr
809HBrFHF
810HBrFCH3H
811HBrFCH3CH3
812HBrFCH3OCH3
813HBrFCH3Cl
814HBrFCH3Br
815HBrFOCH3H
816HBrFOCH3CH3
817HBrFOCH3OCH3
818HBrFOCH3Cl
819HBrFOCH3Br
820HBrFClH
821HBrFClCH3
822HBrFClOCH3
823HBrFClCl
824HBrFClBr
825HBrFBrH
826HBrFBrCH3
827HBrFBrOCH3
828HBrFBrCl
829HBrFBrBr
830HBrFFH
831HBrFFCH3
832HBrFFOCH3
833HBrFFCl
834HBrFFBr
835HBrFFF
836HFCH3HH
837HFCH3HCH3
838HFCH3HOCH3
839HFCH3HCl
840HFCH3HBr
841HFCH3HF
842HFCH3CH3H
843HFCH3CH3CH3
844HFCH3CH3OCH3
845HFCH3CH3Cl
846HFCH3CH3Br
847HFCH3CH3F
848HFCH3OCH3H
849HFCH3OCH3OCH3
850HFCH3OCH3Cl
851HFCH3OCH3Br
852HFCH3OCH3F
853HFCH3ClH
854HFCH3ClOCH3
855HFCH3ClCl
856HFCH3ClBr
857HFCH3ClF
858HFCH3BrH
859HFCH3BrOCH3
860HFCH3BrCl
861HFCH3BrBr
862HFCH3BrF
863HFCH3FH
864HFCH3FOCH3
865HFCH3FCl
866HFCH3FBr
867HFCH3FF
868HFOCH3HH
869HFOCH3HCH3
870HFOCH3HOCH3
871HFOCH3HCl
872HFOCH3HBr
873HFOCH3HF
874HFOCH3CH3H
875HFOCH3CH3CH3
876HFOCH3CH3Cl
877HFOCH3CH3Br
878HFOCH3CH3F
879HFOCH3OCH3H
880HFOCH3OCH3CH3
881HFOCH3OCH3OCH3
882HFOCH3OCH3Cl
883HFOCH3OCH3Br
884HFOCH3OCH3F
885HFOCH3ClH
886HFOCH3ClCH3
887HFOCH3ClCl
888HFOCH3ClBr
889HFOCH3ClF
890HFOCH3BrH
891HFOCH3BrCH3
892HFOCH3BrCl
893HFOCH3BrBr
894HFOCH3BrF
895HFOCH3FH
896HFOCH3FCH3
897HFOCH3FCl
898HFOCH3FBr
899HFOCH3FF
900HFClHH
901HFClHCH3
902HFClHOCH3
903HFClHCl
904HFClHBr
905HFClHF
906HFClCH3H
907HFClCH3CH3
908HFClCH3OCH3
909HFClCH3Br
910HFClCH3F
911HFClOCH3H
912HFClOCH3CH3
913HFClOCH3OCH3
914HFClOCH3Br
915HFClOCH3F
916HFClClH
917HFClClCH3
918HFClClOCH3
919HFClClCl
920HFClClBr
921HFClClF
922HFClBrH
923HFClBrCH3
924HFClBrOCH3
925HFClBrBr
926HFClFH
927HFClFCH3
928HFClFOCH3
929HFClFBr
930HFClFF
931HFBrHH
932HFBrHCH3
933HFBrHOCH3
934HFBrHCl
935HFBrHBr
936HFBrHF
937HFBrCH3H
938HFBrCH3CH3
939HFBrCH3OCH3
940HFBrCH3Cl
941HFBrCH3F
942HFBrOCH3H
943HFBrOCH3CH3
944HFBrOCH3OCH3
945HFBrOCH3Cl
946HFBrOCH3F
947HFBrClH
948HFBrClCH3
949HFBrClOCH3
950HFBrClCl
951HFBrClF
952HFBrBrH
953HFBrBrCH3
954HFBrBrOCH3
955HFBrBrCl
956HFBrBrBr
957HFBrBrF
958HFBrFH
959HFBrFCH3
960HFBrFOCH3
961HFBrFCl
962HFBrFF
963HFFHH
964HFFHCH3
965HFFHOCH3
966HFFHCl
967HFFHBr
968HFFHF
969HFFCH3H
970HFFCH3CH3
971HFFCH3OCH3
972HFFCH3Cl
973HFFCH3Br
974HFFOCH3H
975HFFOCH3CH3
976HFFOCH3OCH3
977HFFOCH3Cl
978HFFOCH3Br
979HFFClH
980HFFClCH3
981HFFClOCH3
982HFFClCl
983HFFClBr
984HFFBrH
985HFFBrCH3
986HFFBrOCH3
987HFFBrCl
988HFFBrBr
989HFFFH
990HFFFCH3
991HFFFOCH3
992HFFFCl
993HFFFBr
994HFFFF
995CH3CH3CH3HH
996CH3CH3CH3CH3H
997CH3CH3CH3OCH3H
998CH3CH3CH3ClH
999CH3CH3CH3BrH
1000CH3CH3CH3FH
1001CH3CH3CH3HCH3
1002CH3CH3CH3CH3CH3
1003CH3CH3CH3HOCH3
1004CH3CH3CH3CH3OCH3
1005CH3CH3CH3OCH3OCH3
1006CH3CH3CH3ClOCH3
1007CH3CH3CH3BrOCH3
1008CH3CH3CH3FOCH3
1009CH3CH3CH3HCl
1010CH3CH3CH3CH3Cl
1011CH3CH3CH3OCH3Cl
1012CH3CH3CH3ClCl
1013CH3CH3CH3BrCl
1014CH3CH3CH3FCl
1015CH3CH3CH3HBr
1016CH3CH3CH3CH3Br
1017CH3CH3CH3OCH3Br
1018CH3CH3CH3ClBr
1019CH3CH3CH3BrBr
1020CH3CH3CH3FBr
1021CH3CH3CH3HF
1022CH3CH3CH3CH3F
1023CH3CH3CH3OCH3F
1024CH3CH3CH3ClF
1025CH3CH3CH3BrF
1026CH3CH3CH3FF
1027CH3CH3OCH3HH
1028CH3CH3OCH3CH3H
1029CH3CH3OCH3OCH3H
1030CH3CH3OCH3ClH
1031CH3CH3OCH3BrH
1032CH3CH3OCH3FH
1033CH3CH3OCH3HCH3
1034CH3CH3OCH3CH3CH3
1035CH3CH3OCH3OCH3CH3
1036CH3CH3OCH3ClCH3
1037CH3CH3OCH3BrCH3
1038CH3CH3OCH3FCH3
1039CH3CH3OCH3HOCH3
1040CH3CH3OCH3OCH3OCH3
1041CH3CH3OCH3HCl
1042CH3CH3OCH3CH3Cl
1043CH3CH3OCH3OCH3Cl
1044CH3CH3OCH3ClCl
1045CH3CH3OCH3BrCl
1046CH3CH3OCH3FCl
1047CH3CH3OCH3HBr
1048CH3CH3OCH3CH3Br
1049CH3CH3OCH3OCH3Br
1050CH3CH3OCH3ClBr
1051CH3CH3OCH3BrBr
1052CH3CH3OCH3FBr
1053CH3CH3OCH3HF
1054CH3CH3OCH3CH3F
1055CH3CH3OCH3OCH3F
1056CH3CH3OCH3ClF
1057CH3CH3OCH3BrF
1058CH3CH3OCH3FF
1059CH3CH3ClHH
1060CH3CH3ClCH3H
1061CH3CH3ClOCH3H
1062CH3CH3ClClH
1063CH3CH3ClBrH
1064CH3CH3ClFH
1065CH3CH3ClHCH3
1066CH3CH3ClCH3CH3
1067CH3CH3ClOCH3CH3
1068CH3CH3ClClCH3
1069CH3CH3ClBrCH3
1070CH3CH3ClFCH3
1071CH3CH3ClHOCH3
1072CH3CH3ClCH3OCH3
1073CH3CH3ClOCH3OCH3
1074CH3CH3ClClOCH3
1075CH3CH3ClBrOCH3
1076CH3CH3ClFOCH3
1077CH3CH3ClHCl
1078CH3CH3ClClCl
1079CH3CH3ClHBr
1080CH3CH3ClCH3Br
1081CH3CH3ClOCH3Br
1082CH3CH3ClClBr
1083CH3CH3ClBrBr
1084CH3CH3ClFBr
1085CH3CH3ClHF
1086CH3CH3ClCH3F
1087CH3CH3ClOCH3F
1088CH3CH3ClClF
1089CH3CH3ClFF
1090CH3CH3BrHH
1091CH3CH3BrCH3H
1092CH3CH3BrOCH3H
1093CH3CH3BrClH
1094CH3CH3BrBrH
1095CH3CH3BrFH
1096CH3CH3BrHCH3
1097CH3CH3BrCH3CH3
1098CH3CH3BrOCH3CH3
1099CH3CH3BrClCH3
1100CH3CH3BrBrCH3
1101CH3CH3BrFCH3
1102CH3CH3BrHOCH3
1103CH3CH3BrCH3OCH3
1104CH3CH3BrOCH3OCH3
1105CH3CH3BrClOCH3
1106CH3CH3BrBrOCH3
1107CH3CH3BrFOCH3
1108CH3CH3BrHCl
1109CH3CH3BrCH3Cl
1110CH3CH3BrOCH3Cl
1111CH3CH3BrClCl
1112CH3CH3BrBrCl
1113CH3CH3BrFCl
1114CH3CH3BrHBr
1115CH3CH3BrBrBr
1116CH3CH3BrHF
1117CH3CH3BrCH3F
1118CH3CH3BrOCH3F
1119CH3CH3BrClF
1120CH3CH3BrBrF
1121CH3CH3BrFF
1122CH3CH3FHH
1123CH3CH3FCH3H
1124CH3CH3FOCH3H
1125CH3CH3FClH
1126CH3CH3FBrH
1127CH3CH3FFH
1128CH3CH3FHCH3
1129CH3CH3FCH3CH3
1130CH3CH3FOCH3CH3
1131CH3CH3FClCH3
1132CH3CH3FBrCH3
1133CH3CH3FFCH3
1134CH3CH3FHOCH3
1135CH3CH3FCH3OCH3
1136CH3CH3FOCH3OCH3
1137CH3CH3FClOCH3
1138CH3CH3FBrOCH3
1139CH3CH3FFOCH3
1140CH3CH3FHCl
1141CH3CH3FCH3Cl
1142CH3CH3FOCH3Cl
1143CH3CH3FClCl
1144CH3CH3FBrCl
1145CH3CH3FFCl
1146CH3CH3FHBr
1147CH3CH3FCH3Br
1148CH3CH3FOCH3Br
1149CH3CH3FClBr
1150CH3CH3FBrBr
1151CH3CH3FFBr
1152CH3CH3FHF
1153CH3CH3FFF
1154CH3OCH3CH3HH
1155CH3OCH3CH3HCH3
1156CH3OCH3CH3HOCH3
1157CH3OCH3CH3HCl
1158CH3OCH3CH3HBr
1159CH3OCH3CH3HF
1160CH3OCH3CH3CH3H
1161CH3OCH3CH3CH3CH3
1162CH3OCH3CH3CH3OCH3
1163CH3OCH3CH3CH3Cl
1164CH3OCH3CH3CH3Br
1165CH3OCH3CH3CH3F
1166CH3OCH3CH3OCH3H
1167CH3OCH3CH3OCH3OCH3
1168CH3OCH3CH3OCH3Cl
1169CH3OCH3CH3OCH3Br
1170CH3OCH3CH3OCH3F
1171CH3OCH3CH3ClH
1172CH3OCH3CH3ClOCH3
1173CH3OCH3CH3ClCl
1174CH3OCH3CH3ClBr
1175CH3OCH3CH3ClF
1176CH3OCH3CH3BrH
1177CH3OCH3CH3BrOCH3
1178CH3OCH3CH3BrCl
1179CH3OCH3CH3BrBr
1180CH3OCH3CH3BrF
1181CH3OCH3CH3FH
1182CH3OCH3CH3FOCH3
1183CH3OCH3CH3FCl
1184CH3OCH3CH3FBr
1185CH3OCH3CH3FF
1186CH3OCH3OCH3HH
1187CH3OCH3OCH3HCH3
1188CH3OCH3OCH3HOCH3
1189CH3OCH3OCH3HCl
1190CH3OCH3OCH3HBr
1191CH3OCH3OCH3HF
1192CH3OCH3OCH3CH3H
1193CH3OCH3OCH3CH3CH3
1194CH3OCH3OCH3CH3Cl
1195CH3OCH3OCH3CH3Br
1196CH3OCH3OCH3CH3F
1197CH3OCH3OCH3OCH3H
1198CH3OCH3OCH3OCH3CH3
1199CH3OCH3OCH3OCH3OCH3
1200CH3OCH3OCH3OCH3Cl
1201CH3OCH3OCH3OCH3Br
1202CH3OCH3OCH3OCH3F
1203CH3OCH3OCH3ClH
1204CH3OCH3OCH3ClCH3
1205CH3OCH3OCH3ClCl
1206CH3OCH3OCH3ClBr
1207CH3OCH3OCH3ClF
1208CH3OCH3OCH3BrH
1209CH3OCH3OCH3BrCH3
1210CH3OCH3OCH3BrCl
1211CH3OCH3OCH3BrBr
1212CH3OCH3OCH3BrF
1213CH3OCH3OCH3FH
1214CH3OCH3OCH3FCH3
1215CH3OCH3OCH3FCl
1216CH3OCH3OCH3FBr
1217CH3OCH3OCH3FF
1218CH3OCH3ClHH
1219CH3OCH3ClHCH3
1220CH3OCH3ClHOCH3
1221CH3OCH3ClHCl
1222CH3OCH3ClHBr
1223CH3OCH3ClHF
1224CH3OCH3ClCH3H
1225CH3OCH3ClCH3CH3
1226CH3OCH3ClCH3OCH3
1227CH3OCH3ClCH3Br
1228CH3OCH3ClCH3F
1229CH3OCH3ClOCH3H
1230CH3OCH3ClOCH3CH3
1231CH3OCH3ClOCH3OCH3
1232CH3OCH3ClOCH3Br
1233CH3OCH3ClOCH3F
1234CH3OCH3ClClH
1235CH3OCH3ClClCH3
1236CH3OCH3ClClOCH3
1237CH3OCH3ClClCl
1238CH3OCH3ClClBr
1239CH3OCH3ClClF
1240CH3OCH3ClBrH
1241CH3OCH3ClBrCH3
1242CH3OCH3ClBrOCH3
1243CH3OCH3ClBrBr
1244CH3OCH3ClFH
1245CH3OCH3ClFCH3
1246CH3OCH3ClFOCH3
1247CH3OCH3ClFBr
1248CH3OCH3ClFF
1249CH3OCH3BrHH
1250CH3OCH3BrHCH3
1251CH3OCH3BrHOCH3
1252CH3OCH3BrHCl
1253CH3OCH3BrHBr
1254CH3OCH3BrHF
1255CH3OCH3BrCH3H
1256CH3OCH3BrCH3CH3
1257CH3OCH3BrCH3OCH3
1258CH3OCH3BrCH3Cl
1259CH3OCH3BrCH3F
1260CH3OCH3BrOCH3H
1261CH3OCH3BrOCH3CH3
1262CH3OCH3BrOCH3OCH3
1263CH3OCH3BrOCH3Cl
1264CH3OCH3BrOCH3F
1265CH3OCH3BrClH
1266CH3OCH3BrClCH3
1267CH3OCH3BrClOCH3
1268CH3OCH3BrClCl
1269CH3OCH3BrClF
1270CH3OCH3BrBrH
1271CH3OCH3BrBrCH3
1272CH3OCH3BrBrOCH3
1273CH3OCH3BrBrCl
1274CH3OCH3BrBrBr
1275CH3OCH3BrBrF
1276CH3OCH3BrFH
1277CH3OCH3BrFCH3
1278CH3OCH3BrFOCH3
1279CH3OCH3BrFCl
1280CH3OCH3BrFF
1281CH3OCH3FHH
1282CH3OCH3FHCH3
1283CH3OCH3FHOCH3
1284CH3OCH3FHCl
1285CH3OCH3FHBr
1286CH3OCH3FHF
1287CH3OCH3FCH3H
1288CH3OCH3FCH3CH3
1289CH3OCH3FCH3OCH3
1290CH3OCH3FCH3Cl
1291CH3OCH3FCH3Br
1292CH3OCH3FOCH3H
1293CH3OCH3FOCH3CH3
1294CH3OCH3FOCH3OCH3
1295CH3OCH3FOCH3Cl
1296CH3OCH3FOCH3Br
1297CH3OCH3FClH
1298CH3OCH3FClCH3
1299CH3OCH3FClOCH3
1300CH3OCH3FClCl
1301CH3OCH3FClBr
1302CH3OCH3FBrH
1303CH3OCH3FBrCH3
1304CH3OCH3FBrOCH3
1305CH3OCH3FBrCl
1306CH3OCH3FBrBr
1307CH3OCH3FFH
1308CH3OCH3FFCH3
1309CH3OCH3FFOCH3
1310CH3OCH3FFCl
1311CH3OCH3FFBr
1312CH3OCH3FFF
1313CH3ClCH3HH
1314CH3ClCH3HCH3
1315CH3ClCH3HOCH3
1316CH3ClCH3HCl
1317CH3ClCH3HBr
1318CH3ClCH3HF
1319CH3ClCH3CH3H
1320CH3ClCH3CH3CH3
1321CH3ClCH3CH3OCH3
1322CH3ClCH3CH3Cl
1323CH3ClCH3CH3Br
1324CH3ClCH3CH3F
1325CH3ClCH3OCH3H
1326CH3ClCH3OCH3OCH3
1327CH3ClCH3OCH3Cl
1328CH3ClCH3OCH3Br
1329CH3ClCH3OCH3F
1330CH3ClCH3ClH
1331CH3ClCH3ClOCH3
1332CH3ClCH3ClCl
1333CH3ClCH3ClBr
1334CH3ClCH3ClF
1335CH3ClCH3BrH
1336CH3ClCH3BrOCH3
1337CH3ClCH3BrCl
1338CH3ClCH3BrBr
1339CH3ClCH3BrF
1340CH3ClCH3FH
1341CH3ClCH3FOCH3
1342CH3ClCH3FCl
1343CH3ClCH3FBr
1344CH3ClCH3FF
1345CH3ClOCH3HH
1346CH3ClOCH3HCH3
1347CH3ClOCH3HOCH3
1348CH3ClOCH3HCl
1349CH3ClOCH3HBr
1350CH3ClOCH3HF
1351CH3ClOCH3CH3H
1352CH3ClOCH3CH3CH3
1353CH3ClOCH3CH3Cl
1354CH3ClOCH3CH3Br
1355CH3ClOCH3CH3F
1356CH3ClOCH3OCH3H
1357CH3ClOCH3OCH3CH3
1358CH3ClOCH3OCH3OCH3
1359CH3ClOCH3OCH3Cl
1360CH3ClOCH3OCH3Br
1361CH3ClOCH3OCH3F
1362CH3ClOCH3ClH
1363CH3ClOCH3ClCH3
1364CH3ClOCH3ClCl
1365CH3ClOCH3ClBr
1366CH3ClOCH3ClF
1367CH3ClOCH3BrH
1368CH3ClOCH3BrCH3
1369CH3ClOCH3BrCl
1370CH3ClOCH3BrBr
1371CH3ClOCH3BrF
1372CH3ClOCH3FH
1373CH3ClOCH3FCH3
1374CH3ClOCH3FCl
1375CH3ClOCH3FBr
1376CH3ClOCH3FF
1377CH3ClClHH
1378CH3ClClHCH3
1379CH3ClClHOCH3
1380CH3ClClHCl
1381CH3ClClHBr
1382CH3ClClHF
1383CH3ClClCH3H
1384CH3ClClCH3CH3
1385CH3ClClCH3OCH3
1386CH3ClClCH3Br
1387CH3ClClCH3F
1388CH3ClClOCH3H
1389CH3ClClOCH3CH3
1390CH3ClClOCH3OCH3
1391CH3ClClOCH3Br
1392CH3ClClOCH3F
1393CH3ClClClH
1394CH3ClClClCH3
1395CH3ClClClOCH3
1396CH3ClClClCl
1397CH3ClClClBr
1398CH3ClClClF
1399CH3ClClBrH
1400CH3ClClBrCH3
1401CH3ClClBrOCH3
1402CH3ClClBrBr
1403CH3ClClFH
1404CH3ClClFCH3
1405CH3ClClFOCH3
1406CH3ClClFBr
1407CH3ClClFF
1408CH3ClBrHH
1409CH3ClBrHCH3
1410CH3ClBrHOCH3
1411CH3ClBrHCl
1412CH3ClBrHBr
1413CH3ClBrHF
1414CH3ClBrCH3H
1415CH3ClBrCH3CH3
1416CH3ClBrCH3OCH3
1417CH3ClBrCH3Cl
1418CH3ClBrCH3F
1419CH3ClBrOCH3H
1420CH3ClBrOCH3CH3
1421CH3ClBrOCH3OCH3
1422CH3ClBrOCH3Cl
1423CH3ClBrOCH3F
1424CH3ClBrClH
1425CH3ClBrClCH3
1426CH3ClBrClOCH3
1427CH3ClBrClCl
1428CH3ClBrClF
1429CH3ClBrBrH
1430CH3ClBrBrCH3
1431CH3ClBrBrOCH3
1432CH3ClBrBrCl
1433CH3ClBrBrBr
1434CH3ClBrBrF
1435CH3ClBrFH
1436CH3ClBrFCH3
1437CH3ClBrFOCH3
1438CH3ClBrFCl
1439CH3ClBrFF
1440CH3ClFHH
1441CH3ClFHCH3
1442CH3ClFHOCH3
1443CH3ClFHCl
1444CH3ClFHBr
1445CH3ClFHF
1446CH3ClFCH3H
1447CH3ClFCH3CH3
1448CH3ClFCH3OCH3
1449CH3ClFCH3Cl
1450CH3ClFCH3Br
1451CH3ClFOCH3H
1452CH3ClFOCH3CH3
1453CH3ClFOCH3OCH3
1454CH3ClFOCH3Cl
1455CH3ClFOCH3Br
1456CH3ClFClH
1457CH3ClFClCH3
1458CH3ClFClOCH3
1459CH3ClFClCl
1460CH3ClFClBr
1461CH3ClFBrH
1462CH3ClFBrCH3
1463CH3ClFBrOCH3
1464CH3ClFBrCl
1465CH3ClFBrBr
1466CH3ClFFH
1467CH3ClFFCH3
1468CH3ClFFOCH3
1469CH3ClFFCl
1470CH3ClFFBr
1471CH3ClFFF
1472CH3BrCH3HH
1473CH3BrCH3HCH3
1474CH3BrCH3HOCH3
1475CH3BrCH3HCl
1476CH3BrCH3HBr
1477CH3BrCH3HF
1478CH3BrCH3CH3H
1479CH3BrCH3CH3CH3
1480CH3BrCH3CH3OCH3
1481CH3BrCH3CH3Cl
1482CH3BrCH3CH3Br
1483CH3BrCH3CH3F
1484CH3BrCH3OCH3H
1485CH3BrCH3OCH3OCH3
1486CH3BrCH3OCH3Cl
1487CH3BrCH3OCH3Br
1488CH3BrCH3OCH3F
1489CH3BrCH3ClH
1490CH3BrCH3ClOCH3
1491CH3BrCH3ClCl
1492CH3BrCH3ClBr
1493CH3BrCH3ClF
1494CH3BrCH3BrH
1495CH3BrCH3BrOCH3
1496CH3BrCH3BrCl
1497CH3BrCH3BrBr
1498CH3BrCH3BrF
1499CH3BrCH3FH
1500CH3BrCH3FOCH3
1501CH3BrCH3FCl
1502CH3BrCH3FBr
1503CH3BrCH3FF
1504CH3BrOCH3HH
1505CH3BrOCH3HCH3
1506CH3BrOCH3HOCH3
1507CH3BrOCH3HCl
1508CH3BrOCH3HBr
1509CH3BrOCH3HF
1510CH3BrOCH3CH3H
1511CH3BrOCH3CH3CH3
1512CH3BrOCH3CH3Cl
1513CH3BrOCH3CH3Br
1514CH3BrOCH3CH3F
1515CH3BrOCH3OCH3H
1516CH3BrOCH3OCH3CH3
1517CH3BrOCH3OCH3OCH3
1518CH3BrOCH3OCH3Cl
1519CH3BrOCH3OCH3Br
1520CH3BrOCH3OCH3F
1521CH3BrOCH3ClH
1522CH3BrOCH3ClCH3
1523CH3BrOCH3ClCl
1524CH3BrOCH3ClBr
1525CH3BrOCH3ClF
1526CH3BrOCH3BrH
1527CH3BrOCH3BrCH3
1528CH3BrOCH3BrCl
1529CH3BrOCH3BrBr
1530CH3BrOCH3BrF
1531CH3BrOCH3FH
1532CH3BrOCH3FCH3
1533CH3BrOCH3FCl
1534CH3BrOCH3FBr
1535CH3BrOCH3FF
1536CH3BrClHH
1537CH3BrClHCH3
1538CH3BrClHOCH3
1539CH3BrClHCl
1540CH3BrClHBr
1541CH3BrClHF
1542CH3BrClCH3H
1543CH3BrClCH3CH3
1544CH3BrClCH3OCH3
1545CH3BrClCH3Br
1546CH3BrClCH3F
1547CH3BrClOCH3H
1548CH3BrClOCH3CH3
1549CH3BrClOCH3OCH3
1550CH3BrClOCH3Br
1551CH3BrClOCH3F
1552CH3BrClClH
1553CH3BrClClCH3
1554CH3BrClClOCH3
1555CH3BrClClCl
1556CH3BrClClBr
1557CH3BrClClF
1558CH3BrClBrH
1559CH3BrClBrCH3
1560CH3BrClBrOCH3
1561CH3BrClBrBr
1562CH3BrClFH
1563CH3BrClFCH3
1564CH3BrClFOCH3
1565CH3BrClFBr
1566CH3BrClFF
1567CH3BrBrHH
1568CH3BrBrHCH3
1569CH3BrBrHOCH3
1570CH3BrBrHCl
1571CH3BrBrHBr
1572CH3BrBrHF
1573CH3BrBrCH3H
1574CH3BrBrCH3CH3
1575CH3BrBrCH3OCH3
1576CH3BrBrCH3Cl
1577CH3BrBrCH3F
1578CH3BrBrOCH3H
1579CH3BrBrOCH3CH3
1580CH3BrBrOCH3OCH3
1581CH3BrBrOCH3Cl
1582CH3BrBrOCH3F
1583CH3BrBrClH
1584CH3BrBrClCH3
1585CH3BrBrClOCH3
1586CH3BrBrClCl
1587CH3BrBrClF
1588CH3BrBrBrH
1589CH3BrBrBrCH3
1590CH3BrBrBrOCH3
1591CH3BrBrBrCl
1592CH3BrBrBrBr
1593CH3BrBrBrF
1594CH3BrBrFH
1595CH3BrBrFCH3
1596CH3BrBrFOCH3
1597CH3BrBrFCl
1598CH3BrBrFF
1599CH3BrFHH
1600CH3BrFHCH3
1601CH3BrFHOCH3
1602CH3BrFHCl
1603CH3BrFHBr
1604CH3BrFHF
1605CH3BrFCH3H
1606CH3BrFCH3CH3
1607CH3BrFCH3OCH3
1608CH3BrFCH3Cl
1609CH3BrFCH3Br
1610CH3BrFOCH3H
1611CH3BrFOCH3CH3
1612CH3BrFOCH3OCH3
1613CH3BrFOCH3Cl
1614CH3BrFOCH3Br
1615CH3BrFClH
1616CH3BrFClCH3
1617CH3BrFClOCH3
1618CH3BrFClCl
1619CH3BrFClBr
1620CH3BrFBrH
1621CH3BrFBrCH3
1622CH3BrFBrOCH3
1623CH3BrFBrCl
1624CH3BrFBrBr
1625CH3BrFFH
1626CH3BrFFCH3
1627CH3BrFFOCH3
1628CH3BrFFCl
1629CH3BrFFBr
1630CH3BrFFF
1631CH3FCH3HH
1632CH3FCH3HCH3
1633CH3FCH3HOCH3
1634CH3FCH3HCl
1635CH3FCH3HBr
1636CH3FCH3HF
1637CH3FCH3CH3H
1638CH3FCH3CH3CH3
1639CH3FCH3CH3OCH3
1640CH3FCH3CH3Cl
1641CH3FCH3CH3Br
1642CH3FCH3CH3F
1643CH3FCH3OCH3H
1644CH3FCH3OCH3OCH3
1645CH3FCH3OCH3Cl
1646CH3FCH3OCH3Br
1647CH3FCH3OCH3F
1648CH3FCH3ClH
1649CH3FCH3ClOCH3
1650CH3FCH3ClCl
1651CH3FCH3ClBr
1652CH3FCH3ClF
1653CH3FCH3BrH
1654CH3FCH3BrOCH3
1655CH3FCH3BrCl
1656CH3FCH3BrBr
1657CH3FCH3BrF
1658CH3FCH3FH
1659CH3FCH3FOCH3
1660CH3FCH3FCl
1661CH3FCH3FBr
1662CH3FCH3FF
1663CH3FOCH3HH
1664CH3FOCH3HCH3
1665CH3FOCH3HOCH3
1666CH3FOCH3HCl
1667CH3FOCH3HBr
1668CH3FOCH3HF
1669CH3FOCH3CH3H
1670CH3FOCH3CH3CH3
1671CH3FOCH3CH3Cl
1672CH3FOCH3CH3Br
1673CH3FOCH3CH3F
1674CH3FOCH3OCH3H
1675CH3FOCH3OCH3CH3
1676CH3FOCH3OCH3OCH3
1677CH3FOCH3OCH3Cl
1678CH3FOCH3OCH3Br
1679CH3FOCH3OCH3F
1680CH3FOCH3ClH
1681CH3FOCH3ClCH3
1682CH3FOCH3ClCl
1683CH3FOCH3ClBr
1684CH3FOCH3ClF
1685CH3FOCH3BrH
1686CH3FOCH3BrCH3
1687CH3FOCH3BrCl
1688CH3FOCH3BrBr
1689CH3FOCH3BrF
1690CH3FOCH3FH
1691CH3FOCH3FCH3
1692CH3FOCH3FCl
1693CH3FOCH3FBr
1694CH3FOCH3FF
1695CH3FClHH
1696CH3FClHCH3
1697CH3FClHOCH3
1698CH3FClHCl
1699CH3FClHBr
1700CH3FClHF
1701CH3FClCH3H
1702CH3FClCH3CH3
1703CH3FClCH3OCH3
1704CH3FClCH3Br
1705CH3FClCH3F
1706CH3FClOCH3H
1707CH3FClOCH3CH3
1708CH3FClOCH3OCH3
1709CH3FClOCH3Br
1710CH3FClOCH3F
1711CH3FClClH
1712CH3FClClCH3
1713CH3FClClOCH3
1714CH3FClClCl
1715CH3FClClBr
1716CH3FClClF
1717CH3FClBrH
1718CH3FClBrCH3
1719CH3FClBrOCH3
1720CH3FClBrBr
1721CH3FClFH
1722CH3FClFCH3
1723CH3FClFOCH3
1724CH3FClFBr
1725CH3FClFF
1726CH3FBrHH
1727CH3FBrHCH3
1728CH3FBrHOCH3
1729CH3FBrHCl
1730CH3FBrHBr
1731CH3FBrHF
1732CH3FBrCH3H
1733CH3FBrCH3CH3
1734CH3FBrCH3OCH3
1735CH3FBrCH3Cl
1736CH3FBrCH3F
1737CH3FBrOCH3H
1738CH3FBrOCH3CH3
1739CH3FBrOCH3OCH3
1740CH3FBrOCH3Cl
1741CH3FBrOCH3F
1742CH3FBrClH
1743CH3FBrClCH3
1744CH3FBrClOCH3
1745CH3FBrClCl
1746CH3FBrClF
1747CH3FBrBrH
1748CH3FBrBrCH3
1749CH3FBrBrOCH3
1750CH3FBrBrCl
1751CH3FBrBrBr
1752CH3FBrBrF
1753CH3FBrFH
1754CH3FBrFCH3
1755CH3FBrFOCH3
1756CH3FBrFCl
1757CH3FBrFF
1758CH3FFHH
1759CH3FFHCH3
1760CH3FFHOCH3
1761CH3FFHCl
1762CH3FFHBr
1763CH3FFHF
1764CH3FFCH3H
1765CH3FFCH3CH3
1766CH3FFCH3OCH3
1767CH3FFCH3Cl
1768CH3FFCH3Br
1769CH3FFOCH3H
1770CH3FFOCH3CH3
1771CH3FFOCH3OCH3
1772CH3FFOCH3Cl
1773CH3FFOCH3Br
1774CH3FFClH
1775CH3FFClCH3
1776CH3FFClOCH3
1777CH3FFClCl
1778CH3FFClBr
1779CH3FFBrH
1780CH3FFBrCH3
1781CH3FFBrOCH3
1782CH3FFBrCl
1783CH3FFBrBr
1784CH3FFFH
1785CH3FFFCH3
1786CH3FFFOCH3
1787CH3FFFCl
1788CH3FFFBr
1789CH3FFFF
1790OCH3CH3CH3HH
1791OCH3CH3CH3CH3H
1792OCH3CH3CH3OCH3H
1793OCH3CH3CH3ClH
1794OCH3CH3CH3BrH
1795OCH3CH3CH3FH
1796OCH3CH3CH3HCH3
1797OCH3CH3CH3CH3CH3
1798OCH3CH3CH3HOCH3
1799OCH3CH3CH3CH3OCH3
1800OCH3CH3CH3OCH3OCH3
1801OCH3CH3CH3ClOCH3
1802OCH3CH3CH3BrOCH3
1803OCH3CH3CH3FOCH3
1804OCH3CH3CH3HCl
1805OCH3CH3CH3CH3Cl
1806OCH3CH3CH3OCH3Cl
1807OCH3CH3CH3ClCl
1808OCH3CH3CH3BrCl
1809OCH3CH3CH3FCl
1810OCH3CH3CH3HBr
1811OCH3CH3CH3CH3Br
1812OCH3CH3CH3OCH3Br
1813OCH3CH3CH3ClBr
1814OCH3CH3CH3BrBr
1815OCH3CH3CH3FBr
1816OCH3CH3CH3HF
1817OCH3CH3CH3CH3F
1818OCH3CH3CH3OCH3F
1819OCH3CH3CH3ClF
1820OCH3CH3CH3BrF
1821OCH3CH3CH3FF
1822OCH3CH3OCH3HH
1823OCH3CH3OCH3CH3H
1824OCH3CH3OCH3OCH3H
1825OCH3CH3OCH3ClH
1826OCH3CH3OCH3BrH
1827OCH3CH3OCH3FH
1828OCH3CH3OCH3HCH3
1829OCH3CH3OCH3CH3CH3
1830OCH3CH3OCH3OCH3CH3
1831OCH3CH3OCH3ClCH3
1832OCH3CH3OCH3BrCH3
1833OCH3CH3OCH3FCH3
1834OCH3CH3OCH3HOCH3
1835OCH3CH3OCH3OCH3OCH3
1836OCH3CH3OCH3HCl
1837OCH3CH3OCH3CH3Cl
1838OCH3CH3OCH3OCH3Cl
1839OCH3CH3OCH3ClCl
1840OCH3CH3OCH3BrCl
1841OCH3CH3OCH3FCl
1842OCH3CH3OCH3HBr
1843OCH3CH3OCH3CH3Br
1844OCH3CH3OCH3OCH3Br
1845OCH3CH3OCH3ClBr
1846OCH3CH3OCH3BrBr
1847OCH3CH3OCH3FBr
1848OCH3CH3OCH3HF
1849OCH3CH3OCH3CH3F
1850OCH3CH3OCH3OCH3F
1851OCH3CH3OCH3ClF
1852OCH3CH3OCH3BrF
1853OCH3CH3OCH3FF
1854OCH3CH3ClHH
1855OCH3CH3ClCH3H
1856OCH3CH3ClOCH3H
1857OCH3CH3ClClH
1858OCH3CH3ClBrH
1859OCH3CH3ClFH
1860OCH3CH3ClHCH3
1861OCH3CH3ClCH3CH3
1862OCH3CH3ClOCH3CH3
1863OCH3CH3ClClCH3
1864OCH3CH3ClBrCH3
1865OCH3CH3ClFCH3
1866OCH3CH3ClHOCH3
1867OCH3CH3ClCH3OCH3
1868OCH3CH3ClOCH3OCH3
1869OCH3CH3ClClOCH3
1870OCH3CH3ClBrOCH3
1871OCH3CH3ClFOCH3
1872OCH3CH3ClHCl
1873OCH3CH3ClClCl
1874OCH3CH3ClHBr
1875OCH3CH3ClCH3Br
1876OCH3CH3ClOCH3Br
1877OCH3CH3ClClBr
1878OCH3CH3ClBrBr
1879OCH3CH3ClFBr
1880OCH3CH3ClHF
1881OCH3CH3ClCH3F
1882OCH3CH3ClOCH3F
1883OCH3CH3ClClF
1884OCH3CH3ClFF
1885OCH3CH3BrHH
1886OCH3CH3BrCH3H
1887OCH3CH3BrOCH3H
1888OCH3CH3BrClH
1889OCH3CH3BrBrH
1890OCH3CH3BrFH
1891OCH3CH3BrHCH3
1892OCH3CH3BrCH3CH3
1893OCH3CH3BrOCH3CH3
1894OCH3CH3BrClCH3
1895OCH3CH3BrBrCH3
1896OCH3CH3BrFCH3
1897OCH3CH3BrHOCH3
1898OCH3CH3BrCH3OCH3
1899OCH3CH3BrOCH3OCH3
1900OCH3CH3BrClOCH3
1901OCH3CH3BrBrOCH3
1902OCH3CH3BrFOCH3
1903OCH3CH3BrHCl
1904OCH3CH3BrCH3Cl
1905OCH3CH3BrOCH3Cl
1906OCH3CH3BrClCl
1907OCH3CH3BrBrCl
1908OCH3CH3BrFCl
1909OCH3CH3BrHBr
1910OCH3CH3BrBrBr
1911OCH3CH3BrHF
1912OCH3CH3BrCH3F
1913OCH3CH3BrOCH3F
1914OCH3CH3BrClF
1915OCH3CH3BrBrF
1916OCH3CH3BrFF
1917OCH3CH3FHH
1918OCH3CH3FCH3H
1919OCH3CH3FOCH3H
1920OCH3CH3FClH
1921OCH3CH3FBrH
1922OCH3CH3FFH
1923OCH3CH3FHCH3
1924OCH3CH3FCH3CH3
1925OCH3CH3FOCH3CH3
1926OCH3CH3FClCH3
1927OCH3CH3FBrCH3
1928OCH3CH3FFCH3
1929OCH3CH3FHOCH3
1930OCH3CH3FCH3OCH3
1931OCH3CH3FOCH3OCH3
1932OCH3CH3FClOCH3
1933OCH3CH3FBrOCH3
1934OCH3CH3FFOCH3
1935OCH3CH3FHCl
1936OCH3CH3FCH3Cl
1937OCH3CH3FOCH3Cl
1938OCH3CH3FClCl
1939OCH3CH3FBrCl
1940OCH3CH3FFCl
1941OCH3CH3FHBr
1942OCH3CH3FCH3Br
1943OCH3CH3FOCH3Br
1944OCH3CH3FClBr
1945OCH3CH3FBrBr
1946OCH3CH3FFBr
1947OCH3CH3FHF
1948OCH3CH3FFF
1949OCH3OCH3CH3HH
1950OCH3OCH3CH3HCH3
1951OCH3OCH3CH3HOCH3
1952OCH3OCH3CH3HCl
1953OCH3OCH3CH3HBr
1954OCH3OCH3CH3HF
1955OCH3OCH3CH3CH3H
1956OCH3OCH3CH3CH3CH3
1957OCH3OCH3CH3CH3OCH3
1958OCH3OCH3CH3CH3Cl
1959OCH3OCH3CH3CH3Br
1960OCH3OCH3CH3CH3F
1961OCH3OCH3CH3OCH3H
1962OCH3OCH3CH3OCH3OCH3
1963OCH3OCH3CH3OCH3Cl
1964OCH3OCH3CH3OCH3Br
1965OCH3OCH3CH3OCH3F
1966OCH3OCH3CH3ClH
1967OCH3OCH3CH3ClOCH3
1968OCH3OCH3CH3ClCl
1969OCH3OCH3CH3ClBr
1970OCH3OCH3CH3ClF
1971OCH3OCH3CH3BrH
1972OCH3OCH3CH3BrOCH3
1973OCH3OCH3CH3BrCl
1974OCH3OCH3CH3BrBr
1975OCH3OCH3CH3BrF
1976OCH3OCH3CH3FH
1977OCH3OCH3CH3FOCH3
1978OCH3OCH3CH3FCl
1979OCH3OCH3CH3FBr
1980OCH3OCH3CH3FF
1981OCH3OCH3OCH3HH
1982OCH3OCH3OCH3HCH3
1983OCH3OCH3OCH3HOCH3
1984OCH3OCH3OCH3HCl
1985OCH3OCH3OCH3HBr
1986OCH3OCH3OCH3HF
1987OCH3OCH3OCH3CH3H
1988OCH3OCH3OCH3CH3CH3
1989OCH3OCH3OCH3CH3Cl
1990OCH3OCH3OCH3CH3Br
1991OCH3OCH3OCH3CH3F
1992OCH3OCH3OCH3OCH3H
1993OCH3OCH3OCH3OCH3CH3
1994OCH3OCH3OCH3OCH3OCH3
1995OCH3OCH3OCH3OCH3Cl
1996OCH3OCH3OCH3OCH3Br
1997OCH3OCH3OCH3OCH3F
1998OCH3OCH3OCH3ClH
1999OCH3OCH3OCH3ClCH3
2000OCH3OCH3OCH3ClCl
2001OCH3OCH3OCH3ClBr
2002OCH3OCH3OCH3ClF
2003OCH3OCH3OCH3BrH
2004OCH3OCH3OCH3BrCH3
2005OCH3OCH3OCH3BrCl
2006OCH3OCH3OCH3BrBr
2007OCH3OCH3OCH3BrF
2008OCH3OCH3OCH3FH
2009OCH3OCH3OCH3FCH3
2010OCH3OCH3OCH3FCl
2011OCH3OCH3OCH3FBr
2012OCH3OCH3OCH3FF
2013OCH3OCH3ClHH
2014OCH3OCH3ClHCH3
2015OCH3OCH3ClHOCH3
2016OCH3OCH3ClHCl
2017OCH3OCH3ClHBr
2018OCH3OCH3ClHF
2019OCH3OCH3ClCH3H
2020OCH3OCH3ClCH3CH3
2021OCH3OCH3ClCH3OCH3
2022OCH3OCH3ClCH3Br
2023OCH3OCH3ClCH3F
2024OCH3OCH3ClOCH3H
2025OCH3OCH3ClOCH3CH3
2026OCH3OCH3ClOCH3OCH3
2027OCH3OCH3ClOCH3Br
2028OCH3OCH3ClOCH3F
2029OCH3OCH3ClClH
2030OCH3OCH3ClClCH3
2031OCH3OCH3ClClOCH3
2032OCH3OCH3ClClCl
2033OCH3OCH3ClClBr
2034OCH3OCH3ClClF
2035OCH3OCH3ClBrH
2036OCH3OCH3ClBrCH3
2037OCH3OCH3ClBrOCH3
2038OCH3OCH3ClBrBr
2039OCH3OCH3ClFH
2040OCH3OCH3ClFCH3
2041OCH3OCH3ClFOCH3
2042OCH3OCH3ClFBr
2043OCH3OCH3ClFF
2044OCH3OCH3BrHH
2045OCH3OCH3BrHCH3
2046OCH3OCH3BrHOCH3
2047OCH3OCH3BrHCl
2048OCH3OCH3BrHBr
2049OCH3OCH3BrHF
2050OCH3OCH3BrCH3H
2051OCH3OCH3BrCH3CH3
2052OCH3OCH3BrCH3OCH3
2053OCH3OCH3BrCH3Cl
2054OCH3OCH3BrCH3F
2055OCH3OCH3BrOCH3H
2056OCH3OCH3BrOCH3CH3
2057OCH3OCH3BrOCH3OCH3
2058OCH3OCH3BrOCH3Cl
2059OCH3OCH3BrOCH3F
2060OCH3OCH3BrClH
2061OCH3OCH3BrClCH3
2062OCH3OCH3BrClOCH3
2063OCH3OCH3BrClCl
2064OCH3OCH3BrClF
2065OCH3OCH3BrBrH
2066OCH3OCH3BrBrCH3
2067OCH3OCH3BrBrOCH3
2068OCH3OCH3BrBrCl
2069OCH3OCH3BrBrBr
2070OCH3OCH3BrBrF
2071OCH3OCH3BrFH
2072OCH3OCH3BrFCH3
2073OCH3OCH3BrFOCH3
2074OCH3OCH3BrFCl
2075OCH3OCH3BrFF
2076OCH3OCH3FHH
2077OCH3OCH3FHCH3
2078OCH3OCH3FHOCH3
2079OCH3OCH3FHCl
2080OCH3OCH3FHBr
2081OCH3OCH3FHF
2082OCH3OCH3FCH3H
2083OCH3OCH3FCH3CH3
2084OCH3OCH3FCH3OCH3
2085OCH3OCH3FCH3Cl
2086OCH3OCH3FCH3Br
2087OCH3OCH3FOCH3H
2088OCH3OCH3FOCH3CH3
2089OCH3OCH3FOCH3OCH3
2090OCH3OCH3FOCH3Cl
2091OCH3OCH3FOCH3Br
2092OCH3OCH3FClH
2093OCH3OCH3FClCH3
2094OCH3OCH3FClOCH3
2095OCH3OCH3FClCl
2096OCH3OCH3FClBr
2097OCH3OCH3FBrH
2098OCH3OCH3FBrCH3
2099OCH3OCH3FBrOCH3
2100OCH3OCH3FBrCl
2101OCH3OCH3FBrBr
2102OCH3OCH3FFH
2103OCH3OCH3FFCH3
2104OCH3OCH3FFOCH3
2105OCH3OCH3FFCl
2106OCH3OCH3FFBr
2107OCH3OCH3FFF
2108OCH3ClCH3HH
2109OCH3ClCH3HCH3
2110OCH3ClCH3HOCH3
2111OCH3ClCH3HCl
2112OCH3ClCH3HBr
2113OCH3ClCH3HF
2114OCH3ClCH3CH3H
2115OCH3ClCH3CH3CH3
2116OCH3ClCH3CH3OCH3
2117OCH3ClCH3CH3Cl
2118OCH3ClCH3CH3Br
2119OCH3ClCH3CH3F
2120OCH3ClCH3OCH3H
2121OCH3ClCH3OCH3OCH3
2122OCH3ClCH3OCH3Cl
2123OCH3ClCH3OCH3Br
2124OCH3ClCH3OCH3F
2125OCH3ClCH3ClH
2126OCH3ClCH3ClOCH3
2127OCH3ClCH3ClCl
2128OCH3ClCH3ClBr
2129OCH3ClCH3ClF
2130OCH3ClCH3BrH
2131OCH3ClCH3BrOCH3
2132OCH3ClCH3BrCl
2133OCH3ClCH3BrBr
2134OCH3ClCH3BrF
2135OCH3ClCH3FH
2136OCH3ClCH3FOCH3
2137OCH3ClCH3FCl
2138OCH3ClCH3FBr
2139OCH3ClCH3FF
2140OCH3ClOCH3HH
2141OCH3ClOCH3HCH3
2142OCH3ClOCH3HOCH3
2143OCH3ClOCH3HCl
2144OCH3ClOCH3HBr
2145OCH3ClOCH3HF
2146OCH3ClOCH3CH3H
2147OCH3ClOCH3CH3CH3
2148OCH3ClOCH3CH3Cl
2149OCH3ClOCH3CH3Br
2150OCH3ClOCH3CH3F
2151OCH3ClOCH3OCH3H
2152OCH3ClOCH3OCH3CH3
2153OCH3ClOCH3OCH3OCH3
2154OCH3ClOCH3OCH3Cl
2155OCH3ClOCH3OCH3Br
2156OCH3ClOCH3OCH3F
2157OCH3ClOCH3ClH
2158OCH3ClOCH3ClCH3
2159OCH3ClOCH3ClCl
2160OCH3ClOCH3ClBr
2161OCH3ClOCH3ClF
2162OCH3ClOCH3BrH
2163OCH3ClOCH3BrCH3
2164OCH3ClOCH3BrCl
2165OCH3ClOCH3BrBr
2166OCH3ClOCH3BrF
2167OCH3ClOCH3FH
2168OCH3ClOCH3FCH3
2169OCH3ClOCH3FCl
2170OCH3ClOCH3FBr
2171OCH3ClOCH3FF
2172OCH3ClClHH
2173OCH3ClClHCH3
2174OCH3ClClHOCH3
2175OCH3ClClHCl
2176OCH3ClClHBr
2177OCH3ClClHF
2178OCH3ClClCH3H
2179OCH3ClClCH3CH3
2180OCH3ClClCH3OCH3
2181OCH3ClClCH3Br
2182OCH3ClClCH3F
2183OCH3ClClOCH3H
2184OCH3ClClOCH3CH3
2185OCH3ClClOCH3OCH3
2186OCH3ClClOCH3Br
2187OCH3ClClOCH3F
2188OCH3ClClClH
2189OCH3ClClClCH3
2190OCH3ClClClOCH3
2191OCH3ClClClCl
2192OCH3ClClClBr
2193OCH3ClClClF
2194OCH3ClClBrH
2195OCH3ClClBrCH3
2196OCH3ClClBrOCH3
2197OCH3ClClBrBr
2198OCH3ClClFH
2199OCH3ClClFCH3
2200OCH3ClClFOCH3
2201OCH3ClClFBr
2202OCH3ClClFF
2203OCH3ClBrHH
2204OCH3ClBrHCH3
2205OCH3ClBrHOCH3
2206OCH3ClBrHCl
2207OCH3ClBrHBr
2208OCH3ClBrHF
2209OCH3ClBrCH3H
2210OCH3ClBrCH3CH3
2211OCH3ClBrCH3OCH3
2212OCH3ClBrCH3Cl
2213OCH3ClBrCH3F
2214OCH3ClBrOCH3H
2215OCH3ClBrOCH3CH3
2216OCH3ClBrOCH3OCH3
2217OCH3ClBrOCH3Cl
2218OCH3ClBrOCH3F
2219OCH3ClBrClH
2220OCH3ClBrClCH3
2221OCH3ClBrClOCH3
2222OCH3ClBrClCl
2223OCH3ClBrClF
2224OCH3ClBrBrH
2225OCH3ClBrBrCH3
2226OCH3ClBrBrOCH3
2227OCH3ClBrBrCl
2228OCH3ClBrBrBr
2229OCH3ClBrBrF
2230OCH3ClBrFH
2231OCH3ClBrFCH3
2232OCH3ClBrFOCH3
2233OCH3ClBrFCl
2234OCH3ClBrFF
2235OCH3ClFHH
2236OCH3ClFHCH3
2237OCH3ClFHOCH3
2238OCH3ClFHCl
2239OCH3ClFHBr
2240OCH3ClFHF
2241OCH3ClFCH3H
2242OCH3ClFCH3CH3
2243OCH3ClFCH3OCH3
2244OCH3ClFCH3Cl
2245OCH3ClFCH3Br
2246OCH3ClFOCH3H
2247OCH3ClFOCH3CH3
2248OCH3ClFOCH3OCH3
2249OCH3ClFOCH3Cl
2250OCH3ClFOCH3Br
2251OCH3ClFClH
2252OCH3ClFClCH3
2253OCH3ClFClOCH3
2254OCH3ClFClCl
2255OCH3ClFClBr
2256OCH3ClFBrH
2257OCH3ClFBrCH3
2258OCH3ClFBrOCH3
2259OCH3ClFBrCl
2260OCH3ClFBrBr
2261OCH3ClFFH
2262OCH3ClFFCH3
2263OCH3ClFFOCH3
2264OCH3ClFFCl
2265OCH3ClFFBr
2266OCH3ClFFF
2267OCH3BrCH3HH
2268OCH3BrCH3HCH3
2269OCH3BrCH3HOCH3
2270OCH3BrCH3HCl
2271OCH3BrCH3HBr
2272OCH3BrCH3HF
2273OCH3BrCH3CH3H
2274OCH3BrCH3CH3CH3
2275OCH3BrCH3CH3OCH3
2276OCH3BrCH3CH3Cl
2277OCH3BrCH3CH3Br
2278OCH3BrCH3CH3F
2279OCH3BrCH3OCH3H
2280OCH3BrCH3OCH3OCH3
2281OCH3BrCH3OCH3Cl
2282OCH3BrCH3OCH3Br
2283OCH3BrCH3OCH3F
2284OCH3BrCH3ClH
2285OCH3BrCH3ClOCH3
2286OCH3BrCH3ClCl
2287OCH3BrCH3ClBr
2288OCH3BrCH3ClF
2289OCH3BrCH3BrH
2290OCH3BrCH3BrOCH3
2291OCH3BrCH3BrCl
2292OCH3BrCH3BrBr
2293OCH3BrCH3BrF
2294OCH3BrCH3FH
2295OCH3BrCH3FOCH3
2296OCH3BrCH3FCl
2297OCH3BrCH3FBr
2298OCH3BrCH3FF
2299OCH3BrOCH3HH
2300OCH3BrOCH3HCH3
2301OCH3BrOCH3HOCH3
2302OCH3BrOCH3HCl
2303OCH3BrOCH3HBr
2304OCH3BrOCH3HF
2305OCH3BrOCH3CH3H
2306OCH3BrOCH3CH3CH3
2307OCH3BrOCH3CH3Cl
2308OCH3BrOCH3CH3Br
2309OCH3BrOCH3CH3F
2310OCH3BrOCH3OCH3H
2311OCH3BrOCH3OCH3CH3
2312OCH3BrOCH3OCH3OCH3
2313OCH3BrOCH3OCH3Cl
2314OCH3BrOCH3OCH3Br
2315OCH3BrOCH3OCH3F
2316OCH3BrOCH3ClH
2317OCH3BrOCH3ClCH3
2318OCH3BrOCH3ClCl
2319OCH3BrOCH3ClBr
2320OCH3BrOCH3ClF
2321OCH3BrOCH3BrH
2322OCH3BrOCH3BrCH3
2323OCH3BrOCH3BrCl
2324OCH3BrOCH3BrBr
2325OCH3BrOCH3BrF
2326OCH3BrOCH3FH
2327OCH3BrOCH3FCH3
2328OCH3BrOCH3FCl
2329OCH3BrOCH3FBr
2330OCH3BrOCH3FF
2331OCH3BrClHH
2332OCH3BrClHCH3
2333OCH3BrClHOCH3
2334OCH3BrClHCl
2335OCH3BrClHBr
2336OCH3BrClHF
2337OCH3BrClCH3H
2338OCH3BrClCH3CH3
2339OCH3BrClCH3OCH3
2340OCH3BrClCH3Br
2341OCH3BrClCH3F
2342OCH3BrClOCH3H
2343OCH3BrClOCH3CH3
2344OCH3BrClOCH3OCH3
2345OCH3BrClOCH3Br
2346OCH3BrClOCH3F
2347OCH3BrClClH
2348OCH3BrClClCH3
2349OCH3BrClClOCH3
2350OCH3BrClClCl
2351OCH3BrClClBr
2352OCH3BrClClF
2353OCH3BrClBrH
2354OCH3BrClBrCH3
2355OCH3BrClBrOCH3
2356OCH3BrClBrBr
2357OCH3BrClFH
2358OCH3BrClFCH3
2359OCH3BrClFOCH3
2360OCH3BrClFBr
2361OCH3BrClFF
2362OCH3BrBrHH
2363OCH3BrBrHCH3
2364OCH3BrBrHOCH3
2365OCH3BrBrHCl
2366OCH3BrBrHBr
2367OCH3BrBrHF
2368OCH3BrBrCH3H
2369OCH3BrBrCH3CH3
2370OCH3BrBrCH3OCH3
2371OCH3BrBrCH3Cl
2372OCH3BrBrCH3F
2373OCH3BrBrOCH3H
2374OCH3BrBrOCH3CH3
2375OCH3BrBrOCH3OCH3
2376OCH3BrBrOCH3Cl
2377OCH3BrBrOCH3F
2378OCH3BrBrClH
2379OCH3BrBrClCH3
2380OCH3BrBrClOCH3
2381OCH3BrBrClCl
2382OCH3BrBrClF
2383OCH3BrBrBrH
2384OCH3BrBrBrCH3
2385OCH3BrBrBrOCH3
2386OCH3BrBrBrCl
2387OCH3BrBrBrBr
2388OCH3BrBrBrF
2389OCH3BrBrFH
2390OCH3BrBrFCH3
2391OCH3BrBrFOCH3
2392OCH3BrBrFCl
2393OCH3BrBrFF
2394OCH3BrFHH
2395OCH3BrFHCH3
2396OCH3BrFHOCH3
2397OCH3BrFHCl
2398OCH3BrFHBr
2399OCH3BrFHF
2400OCH3BrFCH3H
2401OCH3BrFCH3CH3
2402OCH3BrFCH3OCH3
2403OCH3BrFCH3Cl
2404OCH3BrFCH3Br
2405OCH3BrFOCH3H
2406OCH3BrFOCH3CH3
2407OCH3BrFOCH3OCH3
2408OCH3BrFOCH3Cl
2409OCH3BrFOCH3Br
2410OCH3BrFClH
2411OCH3BrFClCH3
2412OCH3BrFClOCH3
2413OCH3BrFClCl
2414OCH3BrFClBr
2415OCH3BrFBrH
2416OCH3BrFBrCH3
2417OCH3BrFBrOCH3
2418OCH3BrFBrCl
2419OCH3BrFBrBr
2420OCH3BrFFH
2421OCH3BrFFCH3
2422OCH3BrFFOCH3
2423OCH3BrFFCl
2424OCH3BrFFBr
2425OCH3BrFFF
2426OCH3FCH3HH
2427OCH3FCH3HCH3
2428OCH3FCH3HOCH3
2429OCH3FCH3HCl
2430OCH3FCH3HBr
2431OCH3FCH3HF
2432OCH3FCH3CH3H
2433OCH3FCH3CH3CH3
2434OCH3FCH3CH3OCH3
2435OCH3FCH3CH3Cl
2436OCH3FCH3CH3Br
2437OCH3FCH3CH3F
2438OCH3FCH3OCH3H
2439OCH3FCH3OCH3OCH3
2440OCH3FCH3OCH3Cl
2441OCH3FCH3OCH3Br
2442OCH3FCH3OCH3F
2443OCH3FCH3ClH
2444OCH3FCH3ClOCH3
2445OCH3FCH3ClCl
2446OCH3FCH3ClBr
2447OCH3FCH3ClF
2448OCH3FCH3BrH
2449OCH3FCH3BrOCH3
2450OCH3FCH3BrCl
2451OCH3FCH3BrBr
2452OCH3FCH3BrF
2453OCH3FCH3FH
2454OCH3FCH3FOCH3
2455OCH3FCH3FCl
2456OCH3FCH3FBr
2457OCH3FCH3FF
2458OCH3FOCH3HH
2459OCH3FOCH3HCH3
2460OCH3FOCH3HOCH3
2461OCH3FOCH3HCl
2462OCH3FOCH3HBr
2463OCH3FOCH3HF
2464OCH3FOCH3CH3H
2465OCH3FOCH3CH3CH3
2466OCH3FOCH3CH3Cl
2467OCH3FOCH3CH3Br
2468OCH3FOCH3CH3F
2469OCH3FOCH3OCH3H
2470OCH3FOCH3OCH3CH3
2471OCH3FOCH3OCH3OCH3
2472OCH3FOCH3OCH3Cl
2473OCH3FOCH3OCH3Br
2474OCH3FOCH3OCH3F
2475OCH3FOCH3ClH
2476OCH3FOCH3ClCH3
2477OCH3FOCH3ClCl
2478OCH3FOCH3ClBr
2479OCH3FOCH3ClF
2480OCH3FOCH3BrH
2481OCH3FOCH3BrCH3
2482OCH3FOCH3BrCl
2483OCH3FOCH3BrBr
2484OCH3FOCH3BrF
2485OCH3FOCH3FH
2486OCH3FOCH3FCH3
2487OCH3FOCH3FCl
2488OCH3FOCH3FBr
2489OCH3FOCH3FF
2490OCH3FClHH
2491OCH3FClHCH3
2492OCH3FClHOCH3
2493OCH3FClHCl
2494OCH3FClHBr
2495OCH3FClHF
2496OCH3FClCH3H
2497OCH3FClCH3CH3
2498OCH3FClCH3OCH3
2499OCH3FClCH3Br
2500OCH3FClCH3F
2501OCH3FClOCH3H
2502OCH3FClOCH3CH3
2503OCH3FClOCH3OCH3
2504OCH3FClOCH3Br
2505OCH3FClOCH3F
2506OCH3FClClH
2507OCH3FClClCH3
2508OCH3FClClOCH3
2509OCH3FClClCl
2510OCH3FClClBr
2511OCH3FClClF
2512OCH3FClBrH
2513OCH3FClBrCH3
2514OCH3FClBrOCH3
2515OCH3FClBrBr
2516OCH3FClFH
2517OCH3FClFCH3
2518OCH3FClFOCH3
2519OCH3FClFBr
2520OCH3FClFF
2521OCH3FBrHH
2522OCH3FBrHCH3
2523OCH3FBrHOCH3
2524OCH3FBrHCl
2525OCH3FBrHBr
2526OCH3FBrHF
2527OCH3FBrCH3H
2528OCH3FBrCH3CH3
2529OCH3FBrCH3OCH3
2530OCH3FBrCH3Cl
2531OCH3FBrCH3F
2532OCH3FBrOCH3H
2533OCH3FBrOCH3CH3
2534OCH3FBrOCH3OCH3
2535OCH3FBrOCH3Cl
2536OCH3FBrOCH3F
2537OCH3FBrClH
2538OCH3FBrClCH3
2539OCH3FBrClOCH3
2540OCH3FBrClCl
2541OCH3FBrClF
2542OCH3FBrBrH
2543OCH3FBrBrCH3
2544OCH3FBrBrOCH3
2545OCH3FBrBrCl
2546OCH3FBrBrBr
2547OCH3FBrBrF
2548OCH3FBrFH
2549OCH3FBrFCH3
2550OCH3FBrFOCH3
2551OCH3FBrFCl
2552OCH3FBrFF
2553OCH3FFHH
2554OCH3FFHCH3
2555OCH3FFHOCH3
2556OCH3FFHCl
2557OCH3FFHBr
2558OCH3FFHF
2559OCH3FFCH3H
2560OCH3FFCH3CH3
2561OCH3FFCH3OCH3
2562OCH3FFCH3Cl
2563OCH3FFCH3Br
2564OCH3FFOCH3H
2565OCH3FFOCH3CH3
2566OCH3FFOCH3OCH3
2567OCH3FFOCH3Cl
2568OCH3FFOCH3Br
2569OCH3FFClH
2570OCH3FFClCH3
2571OCH3FFClOCH3
2572OCH3FFClCl
2573OCH3FFClBr
2574OCH3FFBrH
2575OCH3FFBrCH3
2576OCH3FFBrOCH3
2577OCH3FFBrCl
2578OCH3FFBrBr
2579OCH3FFFH
2580OCH3FFFCH3
2581OCH3FFFOCH3
2582OCH3FFFCl
2583OCH3FFFBr
2584OCH3FFFF
2585ClCH3CH3HH
2586ClCH3CH3CH3H
2587ClCH3CH3OCH3H
2588ClCH3CH3ClH
2589ClCH3CH3BrH
2590ClCH3CH3FH
2591ClCH3CH3HCH3
2592ClCH3CH3CH3CH3
2593ClCH3CH3HOCH3
2594ClCH3CH3CH3OCH3
2595ClCH3CH3OCH3OCH3
2596ClCH3CH3ClOCH3
2597ClCH3CH3BrOCH3
2598ClCH3CH3FOCH3
2599ClCH3CH3HCl
2600ClCH3CH3CH3Cl
2601ClCH3CH3OCH3Cl
2602ClCH3CH3ClCl
2603ClCH3CH3BrCl
2604ClCH3CH3FCl
2605ClCH3CH3HBr
2606ClCH3CH3CH3Br
2607ClCH3CH3OCH3Br
2608ClCH3CH3ClBr
2609ClCH3CH3BrBr
2610ClCH3CH3FBr
2611ClCH3CH3HF
2612ClCH3CH3CH3F
2613ClCH3CH3OCH3F
2614ClCH3CH3ClF
2615ClCH3CH3BrF
2616ClCH3CH3FF
2617ClCH3OCH3HH
2618ClCH3OCH3CH3H
2619ClCH3OCH3OCH3H
2620ClCH3OCH3ClH
2621ClCH3OCH3BrH
2622ClCH3OCH3FH
2623ClCH3OCH3HCH3
2624ClCH3OCH3CH3CH3
2625ClCH3OCH3OCH3CH3
2626ClCH3OCH3ClCH3
2627ClCH3OCH3BrCH3
2628ClCH3OCH3FCH3
2629ClCH3OCH3HOCH3
2630ClCH3OCH3OCH3OCH3
2631ClCH3OCH3HCl
2632ClCH3OCH3CH3Cl
2633ClCH3OCH3OCH3Cl
2634ClCH3OCH3ClCl
2635ClCH3OCH3BrCl
2636ClCH3OCH3FCl
2637ClCH3OCH3HBr
2638ClCH3OCH3CH3Br
2639ClCH3OCH3OCH3Br
2640ClCH3OCH3ClBr
2641ClCH3OCH3BrBr
2642ClCH3OCH3FBr
2643ClCH3OCH3HF
2644ClCH3OCH3CH3F
2645ClCH3OCH3OCH3F
2646ClCH3OCH3ClF
2647ClCH3OCH3BrF
2648ClCH3OCH3FF
2649ClCH3ClHH
2650ClCH3ClCH3H
2651ClCH3ClOCH3H
2652ClCH3ClClH
2653ClCH3ClBrH
2654ClCH3ClFH
2655ClCH3ClHCH3
2656ClCH3ClCH3CH3
2657ClCH3ClOCH3CH3
2658ClCH3ClClCH3
2659ClCH3ClBrCH3
2660ClCH3ClFCH3
2661ClCH3ClHOCH3
2662ClCH3ClCH3OCH3
2663ClCH3ClOCH3OCH3
2664ClCH3ClClOCH3
2665ClCH3ClBrOCH3
2666ClCH3ClFOCH3
2667ClCH3ClHCl
2668ClCH3ClClCl
2669ClCH3ClHBr
2670ClCH3ClCH3Br
2671ClCH3ClOCH3Br
2672ClCH3ClClBr
2673ClCH3ClBrBr
2674ClCH3ClFBr
2675ClCH3ClHF
2676ClCH3ClCH3F
2677ClCH3ClOCH3F
2678ClCH3ClClF
2679ClCH3ClFF
2680ClCH3BrHH
2681ClCH3BrCH3H
2682ClCH3BrOCH3H
2683ClCH3BrClH
2684ClCH3BrBrH
2685ClCH3BrFH
2686ClCH3BrHCH3
2687ClCH3BrCH3CH3
2688ClCH3BrOCH3CH3
2689ClCH3BrClCH3
2690ClCH3BrBrCH3
2691ClCH3BrFCH3
2692ClCH3BrHOCH3
2693ClCH3BrCH3OCH3
2694ClCH3BrOCH3OCH3
2695ClCH3BrClOCH3
2696ClCH3BrBrOCH3
2697ClCH3BrFOCH3
2698ClCH3BrHCl
2699ClCH3BrCH3Cl
2700ClCH3BrOCH3Cl
2701ClCH3BrClCl
2702ClCH3BrBrCl
2703ClCH3BrFCl
2704ClCH3BrHBr
2705ClCH3BrBrBr
2706ClCH3BrHF
2707ClCH3BrCH3F
2708ClCH3BrOCH3F
2709ClCH3BrClF
2710ClCH3BrBrF
2711ClCH3BrFF
2712ClCH3FHH
2713ClCH3FCH3H
2714ClCH3FOCH3H
2715ClCH3FClH
2716ClCH3FBrH
2717ClCH3FFH
2718ClCH3FHCH3
2719ClCH3FCH3CH3
2720ClCH3FOCH3CH3
2721ClCH3FClCH3
2722ClCH3FBrCH3
2723ClCH3FFCH3
2724ClCH3FHOCH3
2725ClCH3FCH3OCH3
2726ClCH3FOCH3OCH3
2727ClCH3FClOCH3
2728ClCH3FBrOCH3
2729ClCH3FFOCH3
2730ClCH3FHCl
2731ClCH3FCH3Cl
2732ClCH3FOCH3Cl
2733ClCH3FClCl
2734ClCH3FBrCl
2735ClCH3FFCl
2736ClCH3FHBr
2737ClCH3FCH3Br
2738ClCH3FOCH3Br
2739ClCH3FClBr
2740ClCH3FBrBr
2741ClCH3FFBr
2742ClCH3FHF
2743ClCH3FFF
2744ClOCH3CH3HH
2745ClOCH3CH3HCH3
2746ClOCH3CH3HOCH3
2747ClOCH3CH3HCl
2748ClOCH3CH3HBr
2749ClOCH3CH3HF
2750ClOCH3CH3CH3H
2751ClOCH3CH3CH3CH3
2752ClOCH3CH3CH3OCH3
2753ClOCH3CH3CH3Cl
2754ClOCH3CH3CH3Br
2755ClOCH3CH3CH3F
2756ClOCH3CH3OCH3H
2757ClOCH3CH3OCH3OCH3
2758ClOCH3CH3OCH3Cl
2759ClOCH3CH3OCH3Br
2760ClOCH3CH3OCH3F
2761ClOCH3CH3ClH
2762ClOCH3CH3ClOCH3
2763ClOCH3CH3ClCl
2764ClOCH3CH3ClBr
2765ClOCH3CH3ClF
2766ClOCH3CH3BrH
2767ClOCH3CH3BrOCH3
2768ClOCH3CH3BrCl
2769ClOCH3CH3BrBr
2770ClOCH3CH3BrF
2771ClOCH3CH3FH
2772ClOCH3CH3FOCH3
2773ClOCH3CH3FCl
2774ClOCH3CH3FBr
2775ClOCH3CH3FF
2776ClOCH3OCH3HH
2777ClOCH3OCH3HCH3
2778ClOCH3OCH3HOCH3
2779ClOCH3OCH3HCl
2780ClOCH3OCH3HBr
2781ClOCH3OCH3HF
2782ClOCH3OCH3CH3H
2783ClOCH3OCH3CH3CH3
2784ClOCH3OCH3CH3Cl
2785ClOCH3OCH3CH3Br
2786ClOCH3OCH3CH3F
2787ClOCH3OCH3OCH3H
2788ClOCH3OCH3OCH3CH3
2789ClOCH3OCH3OCH3OCH3
2790ClOCH3OCH3OCH3Cl
2791ClOCH3OCH3OCH3Br
2792ClOCH3OCH3OCH3F
2793ClOCH3OCH3ClH
2794ClOCH3OCH3ClCH3
2795ClOCH3OCH3ClCl
2796ClOCH3OCH3ClBr
2797ClOCH3OCH3ClF
2798ClOCH3OCH3BrH
2799ClOCH3OCH3BrCH3
2800ClOCH3OCH3BrCl
2801ClOCH3OCH3BrBr
2802ClOCH3OCH3BrF
2803ClOCH3OCH3FH
2804ClOCH3OCH3FCH3
2805ClOCH3OCH3FCl
2806ClOCH3OCH3FBr
2807ClOCH3OCH3FF
2808ClOCH3ClHH
2809ClOCH3ClHCH3
2810ClOCH3ClHOCH3
2811ClOCH3ClHCl
2812ClOCH3ClHBr
2813ClOCH3ClHF
2814ClOCH3ClCH3H
2815ClOCH3ClCH3CH3
2816ClOCH3ClCH3OCH3
2817ClOCH3ClCH3Br
2818ClOCH3ClCH3F
2819ClOCH3ClOCH3H
2820ClOCH3ClOCH3CH3
2821ClOCH3ClOCH3OCH3
2822ClOCH3ClOCH3Br
2823ClOCH3ClOCH3F
2824ClOCH3ClClH
2825ClOCH3ClClCH3
2826ClOCH3ClClOCH3
2827ClOCH3ClClCl
2828ClOCH3ClClBr
2829ClOCH3ClClF
2830ClOCH3ClBrH
2831ClOCH3ClBrCH3
2832ClOCH3ClBrOCH3
2833ClOCH3ClBrBr
2834ClOCH3ClFH
2835ClOCH3ClFCH3
2836ClOCH3ClFOCH3
2837ClOCH3ClFBr
2838ClOCH3ClFF
2839ClOCH3BrHH
2840ClOCH3BrHCH3
2841ClOCH3BrHOCH3
2842ClOCH3BrHCl
2843ClOCH3BrHBr
2844ClOCH3BrHF
2845ClOCH3BrCH3H
2846ClOCH3BrCH3CH3
2847ClOCH3BrCH3OCH3
2848ClOCH3BrCH3Cl
2849ClOCH3BrCH3F
2850ClOCH3BrOCH3H
2851ClOCH3BrOCH3CH3
2852ClOCH3BrOCH3OCH3
2853ClOCH3BrOCH3Cl
2854ClOCH3BrOCH3F
2855ClOCH3BrClH
2856ClOCH3BrClCH3
2857ClOCH3BrClOCH3
2858ClOCH3BrClCl
2859ClOCH3BrClF
2860ClOCH3BrBrH
2861ClOCH3BrBrCH3
2862ClOCH3BrBrOCH3
2863ClOCH3BrBrCl
2864ClOCH3BrBrBr
2865ClOCH3BrBrF
2866ClOCH3BrFH
2867ClOCH3BrFCH3
2868ClOCH3BrFOCH3
2869ClOCH3BrFCl
2870ClOCH3BrFF
2871ClOCH3FHH
2872ClOCH3FHCH3
2873ClOCH3FHOCH3
2874ClOCH3FHCl
2875ClOCH3FHBr
2876ClOCH3FHF
2877ClOCH3FCH3H
2878ClOCH3FCH3CH3
2879ClOCH3FCH3OCH3
2880ClOCH3FCH3Cl
2881ClOCH3FCH3Br
2882ClOCH3FOCH3H
2883ClOCH3FOCH3CH3
2884ClOCH3FOCH3OCH3
2885ClOCH3FOCH3Cl
2886ClOCH3FOCH3Br
2887ClOCH3FClH
2888ClOCH3FClCH3
2889ClOCH3FClOCH3
2890ClOCH3FClCl
2891ClOCH3FClBr
2892ClOCH3FBrH
2893ClOCH3FBrCH3
2894ClOCH3FBrOCH3
2895ClOCH3FBrCl
2896ClOCH3FBrBr
2897ClOCH3FFH
2898ClOCH3FFCH3
2899ClOCH3FFOCH3
2900ClOCH3FFCl
2901ClOCH3FFBr
2902ClOCH3FFF
2903ClClCH3HH
2904ClClCH3HCH3
2905ClClCH3HOCH3
2906ClClCH3HCl
2907ClClCH3HBr
2908ClClCH3HF
2909ClClCH3CH3H
2910ClClCH3CH3CH3
2911ClClCH3CH3OCH3
2912ClClCH3CH3Cl
2913ClClCH3CH3Br
2914ClClCH3CH3F
2915ClClCH3OCH3H
2916ClClCH3OCH3OCH3
2917ClClCH3OCH3Cl
2918ClClCH3OCH3Br
2919ClClCH3OCH3F
2920ClClCH3ClH
2921ClClCH3ClOCH3
2922ClClCH3ClCl
2923ClClCH3ClBr
2924ClClCH3ClF
2925ClClCH3BrH
2926ClClCH3BrOCH3
2927ClClCH3BrCl
2928ClClCH3BrBr
2929ClClCH3BrF
2930ClClCH3FH
2931ClClCH3FOCH3
2932ClClCH3FCl
2933ClClCH3FBr
2934ClClCH3FF
2935ClClOCH3HH
2936ClClOCH3HCH3
2937ClClOCH3HOCH3
2938ClClOCH3HCl
2939ClClOCH3HBr
2940ClClOCH3HF
2941ClClOCH3CH3H
2942ClClOCH3CH3CH3
2943ClClOCH3CH3Cl
2944ClClOCH3CH3Br
2945ClClOCH3CH3F
2946ClClOCH3OCH3H
2947ClClOCH3OCH3CH3
2948ClClOCH3OCH3OCH3
2949ClClOCH3OCH3Cl
2950ClClOCH3OCH3Br
2951ClClOCH3OCH3F
2952ClClOCH3ClH
2953ClClOCH3ClCH3
2954ClClOCH3ClCl
2955ClClOCH3ClBr
2956ClClOCH3ClF
2957ClClOCH3BrH
2958ClClOCH3BrCH3
2959ClClOCH3BrCl
2960ClClOCH3BrBr
2961ClClOCH3BrF
2962ClClOCH3FH
2963ClClOCH3FCH3
2964ClClOCH3FCl
2965ClClOCH3FBr
2966ClClOCH3FF
2967ClClClHH
2968ClClClHCH3
2969ClClClHOCH3
2970ClClClHCl
2971ClClClHBr
2972ClClClHF
2973ClClClCH3H
2974ClClClCH3CH3
2975ClClClCH3OCH3
2976ClClClCH3Br
2977ClClClCH3F
2978ClClClOCH3H
2979ClClClOCH3CH3
2980ClClClOCH3OCH3
2981ClClClOCH3Br
2982ClClClOCH3F
2983ClClClClH
2984ClClClClCH3
2985ClClClClOCH3
2986ClClClClCl
2987ClClClClBr
2988ClClClClF
2989ClClClBrH
2990ClClClBrCH3
2991ClClClBrOCH3
2992ClClClBrBr
2993ClClClFH
2994ClClClFCH3
2995ClClClFOCH3
2996ClClClFBr
2997ClClClFF
2998ClClBrHH
2999ClClBrHCH3
3000ClClBrHOCH3
3001ClClBrHCl
3002ClClBrHBr
3003ClClBrHF
3004ClClBrCH3H
3005ClClBrCH3CH3
3006ClClBrCH3OCH3
3007ClClBrCH3Cl
3008ClClBrCH3F
3009ClClBrOCH3H
3010ClClBrOCH3CH3
3011ClClBrOCH3OCH3
3012ClClBrOCH3Cl
3013ClClBrOCH3F
3014ClClBrClH
3015ClClBrClCH3
3016ClClBrClOCH3
3017ClClBrClCl
3018ClClBrClF
3019ClClBrBrH
3020ClClBrBrCH3
3021ClClBrBrOCH3
3022ClClBrBrCl
3023ClClBrBrBr
3024ClClBrBrF
3025ClClBrFH
3026ClClBrFCH3
3027ClClBrFOCH3
3028ClClBrFCl
3029ClClBrFF
3030ClClFHH
3031ClClFHCH3
3032ClClFHOCH3
3033ClClFHCl
3034ClClFHBr
3035ClClFHF
3036ClClFCH3H
3037ClClFCH3CH3
3038ClClFCH3OCH3
3039ClClFCH3Cl
3040ClClFCH3Br
3041ClClFOCH3H
3042ClClFOCH3CH3
3043ClClFOCH3OCH3
3044ClClFOCH3Cl
3045ClClFOCH3Br
3046ClClFClH
3047ClClFClCH3
3048ClClFClOCH3
3049ClClFClCl
3050ClClFClBr
3051ClClFBrH
3052ClClFBrCH3
3053ClClFBrOCH3
3054ClClFBrCl
3055ClClFBrBr
3056ClClFFH
3057ClClFFCH3
3058ClClFFOCH3
3059ClClFFCl
3060ClClFFBr
3061ClClFFF
3062ClBrCH3HH
3063ClBrCH3HCH3
3064ClBrCH3HOCH3
3065ClBrCH3HCl
3066ClBrCH3HBr
3067ClBrCH3HF
3068ClBrCH3CH3H
3069ClBrCH3CH3CH3
3070ClBrCH3CH3OCH3
3071ClBrCH3CH3Cl
3072ClBrCH3CH3Br
3073ClBrCH3CH3F
3074ClBrCH3OCH3H
3075ClBrCH3OCH3OCH3
3076ClBrCH3OCH3Cl
3077ClBrCH3OCH3Br
3078ClBrCH3OCH3F
3079ClBrCH3ClH
3080ClBrCH3ClOCH3
3081ClBrCH3ClCl
3082ClBrCH3ClBr
3083ClBrCH3ClF
3084ClBrCH3BrH
3085ClBrCH3BrOCH3
3086ClBrCH3BrCl
3087ClBrCH3BrBr
3088ClBrCH3BrF
3089ClBrCH3FH
3090ClBrCH3FOCH3
3091ClBrCH3FCl
3092ClBrCH3FBr
3093ClBrCH3FF
3094ClBrOCH3HH
3095ClBrOCH3HCH3
3096ClBrOCH3HOCH3
3097ClBrOCH3HCl
3098ClBrOCH3HBr
3099ClBrOCH3HF
3100ClBrOCH3CH3H
3101ClBrOCH3CH3CH3
3102ClBrOCH3CH3Cl
3103ClBrOCH3CH3Br
3104ClBrOCH3CH3F
3105ClBrOCH3OCH3H
3106ClBrOCH3OCH3CH3
3107ClBrOCH3OCH3OCH3
3108ClBrOCH3OCH3Cl
3109ClBrOCH3OCH3Br
3110ClBrOCH3OCH3F
3111ClBrOCH3ClH
3112ClBrOCH3ClCH3
3113ClBrOCH3ClCl
3114ClBrOCH3ClBr
3115ClBrOCH3ClF
3116ClBrOCH3BrH
3117ClBrOCH3BrCH3
3118ClBrOCH3BrCl
3119ClBrOCH3BrBr
3120ClBrOCH3BrF
3121ClBrOCH3FH
3122ClBrOCH3FCH3
3123ClBrOCH3FCl
3124ClBrOCH3FBr
3125ClBrOCH3FF
3126ClBrClHH
3127ClBrClHCH3
3128ClBrClHOCH3
3129ClBrClHCl
3130ClBrClHBr
3131ClBrClHF
3132ClBrClCH3H
3133ClBrClCH3CH3
3134ClBrClCH3OCH3
3135ClBrClCH3Br
3136ClBrClCH3F
3137ClBrClOCH3H
3138ClBrClOCH3CH3
3139ClBrClOCH3OCH3
3140ClBrClOCH3Br
3141ClBrClOCH3F
3142ClBrClClH
3143ClBrClClCH3
3144ClBrClClOCH3
3145ClBrClClCl
3146ClBrClClBr
3147ClBrClClF
3148ClBrClBrH
3149ClBrClBrCH3
3150ClBrClBrOCH3
3151ClBrClBrBr
3152ClBrClFH
3153ClBrClFCH3
3154ClBrClFOCH3
3155ClBrClFBr
3156ClBrClFF
3157ClBrBrHH
3158ClBrBrHCH3
3159ClBrBrHOCH3
3160ClBrBrHCl
3161ClBrBrHBr
3162ClBrBrHF
3163ClBrBrCH3H
3164ClBrBrCH3CH3
3165ClBrBrCH3OCH3
3166ClBrBrCH3Cl
3167ClBrBrCH3F
3168ClBrBrOCH3H
3169ClBrBrOCH3CH3
3170ClBrBrOCH3OCH3
3171ClBrBrOCH3Cl
3172ClBrBrOCH3F
3173ClBrBrClH
3174ClBrBrClCH3
3175ClBrBrClOCH3
3176ClBrBrClCl
3177ClBrBrClF
3178ClBrBrBrH
3179ClBrBrBrCH3
3180ClBrBrBrOCH3
3181ClBrBrBrCl
3182ClBrBrBrBr
3183ClBrBrBrF
3184ClBrBrFH
3185ClBrBrFCH3
3186ClBrBrFOCH3
3187ClBrBrFCl
3188ClBrBrFF
3189ClBrFHH
3190ClBrFHCH3
3191ClBrFHOCH3
3192ClBrFHCl
3193ClBrFHBr
3194ClBrFHF
3195ClBrFCH3H
3196ClBrFCH3CH3
3197ClBrFCH3OCH3
3198ClBrFCH3Cl
3199ClBrFCH3Br
3200ClBrFOCH3H
3201ClBrFOCH3CH3
3202ClBrFOCH3OCH3
3203ClBrFOCH3Cl
3204ClBrFOCH3Br
3205ClBrFClH
3206ClBrFClCH3
3207ClBrFClOCH3
3208ClBrFClCl
3209ClBrFClBr
3210ClBrFBrH
3211ClBrFBrCH3
3212ClBrFBrOCH3
3213ClBrFBrCl
3214ClBrFBrBr
3215ClBrFFH
3216ClBrFFCH3
3217ClBrFFOCH3
3218ClBrFFCl
3219ClBrFFBr
3220ClBrFFF
3221ClFCH3HH
3222ClFCH3HCH3
3223ClFCH3HOCH3
3224ClFCH3HCl
3225ClFCH3HBr
3226ClFCH3HF
3227ClFCH3CH3H
3228ClFCH3CH3CH3
3229ClFCH3CH3OCH3
3230ClFCH3CH3Cl
3231ClFCH3CH3Br
3232ClFCH3CH3F
3233ClFCH3OCH3H
3234ClFCH3OCH3OCH3
3235ClFCH3OCH3Cl
3236ClFCH3OCH3Br
3237ClFCH3OCH3F
3238ClFCH3ClH
3239ClFCH3ClOCH3
3240ClFCH3ClCl
3241ClFCH3ClBr
3242ClFCH3ClF
3243ClFCH3BrH
3244ClFCH3BrOCH3
3245ClFCH3BrCl
3246ClFCH3BrBr
3247ClFCH3BrF
3248ClFCH3FH
3249ClFCH3FOCH3
3250ClFCH3FCl
3251ClFCH3FBr
3252ClFCH3FF
3253ClFOCH3HH
3254ClFOCH3HCH3
3255ClFOCH3HOCH3
3256ClFOCH3HCl
3257ClFOCH3HBr
3258ClFOCH3HF
3259ClFOCH3CH3H
3260ClFOCH3CH3CH3
3261ClFOCH3CH3Cl
3262ClFOCH3CH3Br
3263ClFOCH3CH3F
3264ClFOCH3OCH3H
3265ClFOCH3OCH3CH3
3266ClFOCH3OCH3OCH3
3267ClFOCH3OCH3Cl
3268ClFOCH3OCH3Br
3269ClFOCH3OCH3F
3270ClFOCH3ClH
3271ClFOCH3ClCH3
3272ClFOCH3ClCl
3273ClFOCH3ClBr
3274ClFOCH3ClF
3275ClFOCH3BrH
3276ClFOCH3BrCH3
3277ClFOCH3BrCl
3278ClFOCH3BrBr
3279ClFOCH3BrF
3280ClFOCH3FH
3281ClFOCH3FCH3
3282ClFOCH3FCl
3283ClFOCH3FBr
3284ClFOCH3FF
3285ClFClHH
3286ClFClHCH3
3287ClFClHOCH3
3288ClFClHCl
3289ClFClHBr
3290ClFClHF
3291ClFClCH3H
3292ClFClCH3CH3
3293ClFClCH3OCH3
3294ClFClCH3Br
3295ClFClCH3F
3296ClFClOCH3H
3297ClFClOCH3CH3
3298ClFClOCH3OCH3
3299ClFClOCH3Br
3300ClFClOCH3F
3301ClFClClH
3302ClFClClCH3
3303ClFClClOCH3
3304ClFClClCl
3305ClFClClBr
3306ClFClClF
3307ClFClBrH
3308ClFClBrCH3
3309ClFClBrOCH3
3310ClFClBrBr
3311ClFClFH
3312ClFClFCH3
3313ClFClFOCH3
3314ClFClFBr
3315ClFClFF
3316ClFBrHH
3317ClFBrHCH3
3318ClFBrHOCH3
3319ClFBrHCl
3320ClFBrHBr
3321ClFBrHF
3322ClFBrCH3H
3323ClFBrCH3CH3
3324ClFBrCH3OCH3
3325ClFBrCH3Cl
3326ClFBrCH3F
3327ClFBrOCH3H
3328ClFBrOCH3CH3
3329ClFBrOCH3OCH3
3330ClFBrOCH3Cl
3331ClFBrOCH3F
3332ClFBrClH
3333ClFBrClCH3
3334ClFBrClOCH3
3335ClFBrClCl
3336ClFBrClF
3337ClFBrBrH
3338ClFBrBrCH3
3339ClFBrBrOCH3
3340ClFBrBrCl
3341ClFBrBrBr
3342ClFBrBrF
3343ClFBrFH
3344ClFBrFCH3
3345ClFBrFOCH3
3346ClFBrFCl
3347ClFBrFF
3348ClFFHH
3349ClFFHCH3
3350ClFFHOCH3
3351ClFFHCl
3352ClFFHBr
3353ClFFHF
3354ClFFCH3H
3355ClFFCH3CH3
3356ClFFCH3OCH3
3357ClFFCH3Cl
3358ClFFCH3Br
3359ClFFOCH3H
3360ClFFOCH3CH3
3361ClFFOCH3OCH3
3362ClFFOCH3Cl
3363ClFFOCH3Br
3364ClFFClH
3365ClFFClCH3
3366ClFFClOCH3
3367ClFFClCl
3368ClFFClBr
3369ClFFBrH
3370ClFFBrCH3
3371ClFFBrOCH3
3372ClFFBrCl
3373ClFFBrBr
3374ClFFFH
3375ClFFFCH3
3376ClFFFOCH3
3377ClFFFCl
3378ClFFFBr
3379ClFFFF
3380BrCH3CH3HH
3381BrCH3CH3CH3H
3382BrCH3CH3OCH3H
3383BrCH3CH3ClH
3384BrCH3CH3BrH
3385BrCH3CH3FH
3386BrCH3CH3HCH3
3387BrCH3CH3CH3CH3
3388BrCH3CH3HOCH3
3389BrCH3CH3CH3OCH3
3390BrCH3CH3OCH3OCH3
3391BrCH3CH3ClOCH3
3392BrCH3CH3BrOCH3
3393BrCH3CH3FOCH3
3394BrCH3CH3HCl
3395BrCH3CH3CH3Cl
3396BrCH3CH3OCH3Cl
3397BrCH3CH3ClCl
3398BrCH3CH3BrCl
3399BrCH3CH3FCl
3400BrCH3CH3HBr
3401BrCH3CH3CH3Br
3402BrCH3CH3OCH3Br
3403BrCH3CH3ClBr
3404BrCH3CH3BrBr
3405BrCH3CH3FBr
3406BrCH3CH3HF
3407BrCH3CH3CH3F
3408BrCH3CH3OCH3F
3409BrCH3CH3ClF
3410BrCH3CH3BrF
3411BrCH3CH3FF
3412BrCH3OCH3HH
3413BrCH3OCH3CH3H
3414BrCH3OCH3OCH3H
3415BrCH3OCH3ClH
3416BrCH3OCH3BrH
3417BrCH3OCH3FH
3418BrCH3OCH3HCH3
3419BrCH3OCH3CH3CH3
3420BrCH3OCH3OCH3CH3
3421BrCH3OCH3ClCH3
3422BrCH3OCH3BrCH3
3423BrCH3OCH3FCH3
3424BrCH3OCH3HOCH3
3425BrCH3OCH3OCH3OCH3
3426BrCH3OCH3HCl
3427BrCH3OCH3CH3Cl
3428BrCH3OCH3OCH3Cl
3429BrCH3OCH3ClCl
3430BrCH3OCH3BrCl
3431BrCH3OCH3FCl
3432BrCH3OCH3HBr
3433BrCH3OCH3CH3Br
3434BrCH3OCH3OCH3Br
3435BrCH3OCH3ClBr
3436BrCH3OCH3BrBr
3437BrCH3OCH3FBr
3438BrCH3OCH3HF
3439BrCH3OCH3CH3F
3440BrCH3OCH3OCH3F
3441BrCH3OCH3ClF
3442BrCH3OCH3BrF
3443BrCH3OCH3FF
3444BrCH3ClHH
3445BrCH3ClCH3H
3446BrCH3ClOCH3H
3447BrCH3ClClH
3448BrCH3ClBrH
3449BrCH3ClFH
3450BrCH3ClHCH3
3451BrCH3ClCH3CH3
3452BrCH3ClOCH3CH3
3453BrCH3ClClCH3
3454BrCH3ClBrCH3
3455BrCH3ClFCH3
3456BrCH3ClHOCH3
3457BrCH3ClCH3OCH3
3458BrCH3ClOCH3OCH3
3459BrCH3ClClOCH3
3460BrCH3ClBrOCH3
3461BrCH3ClFOCH3
3462BrCH3ClHCl
3463BrCH3ClClCl
3464BrCH3ClHBr
3465BrCH3ClCH3Br
3466BrCH3ClOCH3Br
3467BrCH3ClClBr
3468BrCH3ClBrBr
3469BrCH3ClFBr
3470BrCH3ClHF
3471BrCH3ClCH3F
3472BrCH3ClOCH3F
3473BrCH3ClClF
3474BrCH3ClFF
3475BrCH3BrHH
3476BrCH3BrCH3H
3477BrCH3BrOCH3H
3478BrCH3BrClH
3479BrCH3BrBrH
3480BrCH3BrFH
3481BrCH3BrHCH3
3482BrCH3BrCH3CH3
3483BrCH3BrOCH3CH3
3484BrCH3BrClCH3
3485BrCH3BrBrCH3
3486BrCH3BrFCH3
3487BrCH3BrHOCH3
3488BrCH3BrCH3OCH3
3489BrCH3BrOCH3OCH3
3490BrCH3BrClOCH3
3491BrCH3BrBrOCH3
3492BrCH3BrFOCH3
3493BrCH3BrHCl
3494BrCH3BrCH3Cl
3495BrCH3BrOCH3Cl
3496BrCH3BrClCl
3497BrCH3BrBrCl
3498BrCH3BrFCl
3499BrCH3BrHBr
3500BrCH3BrBrBr
3501BrCH3BrHF
3502BrCH3BrCH3F
3503BrCH3BrOCH3F
3504BrCH3BrClF
3505BrCH3BrBrF
3506BrCH3BrFF
3507BrCH3FHH
3508BrCH3FCH3H
3509BrCH3FOCH3H
3510BrCH3FClH
3511BrCH3FBrH
3512BrCH3FFH
3513BrCH3FHCH3
3514BrCH3FCH3CH3
3515BrCH3FOCH3CH3
3516BrCH3FClCH3
3517BrCH3FBrCH3
3518BrCH3FFCH3
3519BrCH3FHOCH3
3520BrCH3FCH3OCH3
3521BrCH3FOCH3OCH3
3522BrCH3FClOCH3
3523BrCH3FBrOCH3
3524BrCH3FFOCH3
3525BrCH3FHCl
3526BrCH3FCH3Cl
3527BrCH3FOCH3Cl
3528BrCH3FClCl
3529BrCH3FBrCl
3530BrCH3FFCl
3531BrCH3FHBr
3532BrCH3FCH3Br
3533BrCH3FOCH3Br
3534BrCH3FClBr
3535BrCH3FBrBr
3536BrCH3FFBr
3537BrCH3FHF
3538BrCH3FFF
3539BrOCH3CH3HH
3540BrOCH3CH3HCH3
3541BrOCH3CH3HOCH3
3542BrOCH3CH3HCl
3543BrOCH3CH3HBr
3544BrOCH3CH3HF
3545BrOCH3CH3CH3H
3546BrOCH3CH3CH3CH3
3547BrOCH3CH3CH3OCH3
3548BrOCH3CH3CH3Cl
3549BrOCH3CH3CH3Br
3550BrOCH3CH3CH3F
3551BrOCH3CH3OCH3H
3552BrOCH3CH3OCH3OCH3
3553BrOCH3CH3OCH3Cl
3554BrOCH3CH3OCH3Br
3555BrOCH3CH3OCH3F
3556BrOCH3CH3ClH
3557BrOCH3CH3ClOCH3
3558BrOCH3CH3ClCl
3559BrOCH3CH3ClBr
3560BrOCH3CH3ClF
3561BrOCH3CH3BrH
3562BrOCH3CH3BrOCH3
3563BrOCH3CH3BrCl
3564BrOCH3CH3BrBr
3565BrOCH3CH3BrF
3566BrOCH3CH3FH
3567BrOCH3CH3FOCH3
3568BrOCH3CH3FCl
3569BrOCH3CH3FBr
3570BrOCH3CH3FF
3571BrOCH3OCH3HH
3572BrOCH3OCH3HCH3
3573BrOCH3OCH3HOCH3
3574BrOCH3OCH3HCl
3575BrOCH3OCH3HBr
3576BrOCH3OCH3HF
3577BrOCH3OCH3CH3H
3578BrOCH3OCH3CH3CH3
3579BrOCH3OCH3CH3Cl
3580BrOCH3OCH3CH3Br
3581BrOCH3OCH3CH3F
3582BrOCH3OCH3OCH3H
3583BrOCH3OCH3OCH3CH3
3584BrOCH3OCH3OCH3OCH3
3585BrOCH3OCH3OCH3Cl
3586BrOCH3OCH3OCH3Br
3587BrOCH3OCH3OCH3F
3588BrOCH3OCH3ClH
3589BrOCH3OCH3ClCH3
3590BrOCH3OCH3ClCl
3591BrOCH3OCH3ClBr
3592BrOCH3OCH3ClF
3593BrOCH3OCH3BrH
3594BrOCH3OCH3BrCH3
3595BrOCH3OCH3BrCl
3596BrOCH3OCH3BrBr
3597BrOCH3OCH3BrF
3598BrOCH3OCH3FH
3599BrOCH3OCH3FCH3
3600BrOCH3OCH3FCl
3601BrOCH3OCH3FBr
3602BrOCH3OCH3FF
3603BrOCH3ClHH
3604BrOCH3ClHCH3
3605BrOCH3ClHOCH3
3606BrOCH3ClHCl
3607BrOCH3ClHBr
3608BrOCH3ClHF
3609BrOCH3ClCH3H
3610BrOCH3ClCH3CH3
3611BrOCH3ClCH3OCH3
3612BrOCH3ClCH3Br
3613BrOCH3ClCH3F
3614BrOCH3ClOCH3H
3615BrOCH3ClOCH3CH3
3616BrOCH3ClOCH3OCH3
3617BrOCH3ClOCH3Br
3618BrOCH3ClOCH3F
3619BrOCH3ClClH
3620BrOCH3ClClCH3
3621BrOCH3ClClOCH3
3622BrOCH3ClClCl
3623BrOCH3ClClBr
3624BrOCH3ClClF
3625BrOCH3ClBrH
3626BrOCH3ClBrCH3
3627BrOCH3ClBrOCH3
3628BrOCH3ClBrBr
3629BrOCH3ClFH
3630BrOCH3ClFCH3
3631BrOCH3ClFOCH3
3632BrOCH3ClFBr
3633BrOCH3ClFF
3634BrOCH3BrHH
3635BrOCH3BrHCH3
3636BrOCH3BrHOCH3
3637BrOCH3BrHCl
3638BrOCH3BrHBr
3639BrOCH3BrHF
3640BrOCH3BrCH3H
3641BrOCH3BrCH3CH3
3642BrOCH3BrCH3OCH3
3643BrOCH3BrCH3Cl
3644BrOCH3BrCH3F
3645BrOCH3BrOCH3H
3646BrOCH3BrOCH3CH3
3647BrOCH3BrOCH3OCH3
3648BrOCH3BrOCH3Cl
3649BrOCH3BrOCH3F
3650BrOCH3BrClH
3651BrOCH3BrClCH3
3652BrOCH3BrClOCH3
3653BrOCH3BrClCl
3654BrOCH3BrClF
3655BrOCH3BrBrH
3656BrOCH3BrBrCH3
3657BrOCH3BrBrOCH3
3658BrOCH3BrBrCl
3659BrOCH3BrBrBr
3660BrOCH3BrBrF
3661BrOCH3BrFH
3662BrOCH3BrFCH3
3663BrOCH3BrFOCH3
3664BrOCH3BrFCl
3665BrOCH3BrFF
3666BrOCH3FHH
3667BrOCH3FHCH3
3668BrOCH3FHOCH3
3669BrOCH3FHCl
3670BrOCH3FHBr
3671BrOCH3FHF
3672BrOCH3FCH3H
3673BrOCH3FCH3CH3
3674BrOCH3FCH3OCH3
3675BrOCH3FCH3Cl
3676BrOCH3FCH3Br
3677BrOCH3FOCH3H
3678BrOCH3FOCH3CH3
3679BrOCH3FOCH3OCH3
3680BrOCH3FOCH3Cl
3681BrOCH3FOCH3Br
3682BrOCH3FClH
3683BrOCH3FClCH3
3684BrOCH3FClOCH3
3685BrOCH3FClCl
3686BrOCH3FClBr
3687BrOCH3FBrH
3688BrOCH3FBrCH3
3689BrOCH3FBrOCH3
3690BrOCH3FBrCl
3691BrOCH3FBrBr
3692BrOCH3FFH
3693BrOCH3FFCH3
3694BrOCH3FFOCH3
3695BrOCH3FFCl
3696BrOCH3FFBr
3697BrOCH3FFF
3698BrClCH3HH
3699BrClCH3HCH3
3700BrClCH3HOCH3
3701BrClCH3HCl
3702BrClCH3HBr
3703BrClCH3HF
3704BrClCH3CH3H
3705BrClCH3CH3CH3
3706BrClCH3CH3OCH3
3707BrClCH3CH3Cl
3708BrClCH3CH3Br
3709BrClCH3CH3F
3710BrClCH3OCH3H
3711BrClCH3OCH3OCH3
3712BrClCH3OCH3Cl
3713BrClCH3OCH3Br
3714BrClCH3OCH3F
3715BrClCH3ClH
3716BrClCH3ClOCH3
3717BrClCH3ClCl
3718BrClCH3ClBr
3719BrClCH3ClF
3720BrClCH3BrH
3721BrClCH3BrOCH3
3722BrClCH3BrCl
3723BrClCH3BrBr
3724BrClCH3BrF
3725BrClCH3FH
3726BrClCH3FOCH3
3727BrClCH3FCl
3728BrClCH3FBr
3729BrClCH3FF
3730BrClOCH3HH
3731BrClOCH3HCH3
3732BrClOCH3HOCH3
3733BrClOCH3HCl
3734BrClOCH3HBr
3735BrClOCH3HF
3736BrClOCH3CH3H
3737BrClOCH3CH3CH3
3738BrClOCH3CH3Cl
3739BrClOCH3CH3Br
3740BrClOCH3CH3F
3741BrClOCH3OCH3H
3742BrClOCH3OCH3CH3
3743BrClOCH3OCH3OCH3
3744BrClOCH3OCH3Cl
3745BrClOCH3OCH3Br
3746BrClOCH3OCH3F
3747BrClOCH3ClH
3748BrClOCH3ClCH3
3749BrClOCH3ClCl
3750BrClOCH3ClBr
3751BrClOCH3ClF
3752BrClOCH3BrH
3753BrClOCH3BrCH3
3754BrClOCH3BrCl
3755BrClOCH3BrBr
3756BrClOCH3BrF
3757BrClOCH3FH
3758BrClOCH3FCH3
3759BrClOCH3FCl
3760BrClOCH3FBr
3761BrClOCH3FF
3762BrClClHH
3763BrClClHCH3
3764BrClClHOCH3
3765BrClClHCl
3766BrClClHBr
3767BrClClHF
3768BrClClCH3H
3769BrClClCH3CH3
3770BrClClCH3OCH3
3771BrClClCH3Br
3772BrClClCH3F
3773BrClClOCH3H
3774BrClClOCH3CH3
3775BrClClOCH3OCH3
3776BrClClOCH3Br
3777BrClClOCH3F
3778BrClClClH
3779BrClClClCH3
3780BrClClClOCH3
3781BrClClClCl
3782BrClClClBr
3783BrClClClF
3784BrClClBrH
3785BrClClBrCH3
3786BrClClBrOCH3
3787BrClClBrBr
3788BrClClFH
3789BrClClFCH3
3790BrClClFOCH3
3791BrClClFBr
3792BrClClFF
3793BrClBrHH
3794BrClBrHCH3
3795BrClBrHOCH3
3796BrClBrHCl
3797BrClBrHBr
3798BrClBrHF
3799BrClBrCH3H
3800BrClBrCH3CH3
3801BrClBrCH3OCH3
3802BrClBrCH3Cl
3803BrClBrCH3F
3804BrClBrOCH3H
3805BrClBrOCH3CH3
3806BrClBrOCH3OCH3
3807BrClBrOCH3Cl
3808BrClBrOCH3F
3809BrClBrClH
3810BrClBrClCH3
3811BrClBrClOCH3
3812BrClBrClCl
3813BrClBrClF
3814BrClBrBrH
3815BrClBrBrCH3
3816BrClBrBrOCH3
3817BrClBrBrCl
3818BrClBrBrBr
3819BrClBrBrF
3820BrClBrFH
3821BrClBrFCH3
3822BrClBrFOCH3
3823BrClBrFCl
3824BrClBrFF
3825BrClFHH
3826BrClFHCH3
3827BrClFHOCH3
3828BrClFHCl
3829BrClFHBr
3830BrClFHF
3831BrClFCH3H
3832BrClFCH3CH3
3833BrClFCH3OCH3
3834BrClFCH3Cl
3835BrClFCH3Br
3836BrClFOCH3H
3837BrClFOCH3CH3
3838BrClFOCH3OCH3
3839BrClFOCH3Cl
3840BrClFOCH3Br
3841BrClFClH
3842BrClFClCH3
3843BrClFClOCH3
3844BrClFClCl
3845BrClFClBr
3846BrClFBrH
3847BrClFBrCH3
3848BrClFBrOCH3
3849BrClFBrCl
3850BrClFBrBr
3851BrClFFH
3852BrClFFCH3
3853BrClFFOCH3
3854BrClFFCl
3855BrClFFBr
3856BrClFFF
3857BrBrCH3HH
3858BrBrCH3HCH3
3859BrBrCH3HOCH3
3860BrBrCH3HCl
3861BrBrCH3HBr
3862BrBrCH3HF
3863BrBrCH3CH3H
3864BrBrCH3CH3CH3
3865BrBrCH3CH3OCH3
3866BrBrCH3CH3Cl
3867BrBrCH3CH3Br
3868BrBrCH3CH3F
3869BrBrCH3OCH3H
3870BrBrCH3OCH3OCH3
3871BrBrCH3OCH3Cl
3872BrBrCH3OCH3Br
3873BrBrCH3OCH3F
3874BrBrCH3ClH
3875BrBrCH3ClOCH3
3876BrBrCH3ClCl
3877BrBrCH3ClBr
3878BrBrCH3ClF
3879BrBrCH3BrH
3880BrBrCH3BrOCH3
3881BrBrCH3BrCl
3882BrBrCH3BrBr
3883BrBrCH3BrF
3884BrBrCH3FH
3885BrBrCH3FOCH3
3886BrBrCH3FCl
3887BrBrCH3FBr
3888BrBrCH3FF
3889BrBrOCH3HH
3890BrBrOCH3HCH3
3891BrBrOCH3HOCH3
3892BrBrOCH3HCl
3893BrBrOCH3HBr
3894BrBrOCH3HF
3895BrBrOCH3CH3H
3896BrBrOCH3CH3CH3
3897BrBrOCH3CH3Cl
3898BrBrOCH3CH3Br
3899BrBrOCH3CH3F
3900BrBrOCH3OCH3H
3901BrBrOCH3OCH3CH3
3902BrBrOCH3OCH3OCH3
3903BrBrOCH3OCH3Cl
3904BrBrOCH3OCH3Br
3905BrBrOCH3OCH3F
3906BrBrOCH3ClH
3907BrBrOCH3ClCH3
3908BrBrOCH3ClCl
3909BrBrOCH3ClBr
3910BrBrOCH3ClF
3911BrBrOCH3BrH
3912BrBrOCH3BrCH3
3913BrBrOCH3BrCl
3914BrBrOCH3BrBr
3915BrBrOCH3BrF
3916BrBrOCH3FH
3917BrBrOCH3FCH3
3918BrBrOCH3FCl
3919BrBrOCH3FBr
3920BrBrOCH3FF
3921BrBrClHH
3922BrBrClHCH3
3923BrBrClHOCH3
3924BrBrClHCl
3925BrBrClHBr
3926BrBrClHF
3927BrBrClCH3H
3928BrBrClCH3CH3
3929BrBrClCH3OCH3
3930BrBrClCH3Br
3931BrBrClCH3F
3932BrBrClOCH3H
3933BrBrClOCH3CH3
3934BrBrClOCH3OCH3
3935BrBrClOCH3Br
3936BrBrClOCH3F
3937BrBrClClH
3938BrBrClClCH3
3939BrBrClClOCH3
3940BrBrClClCl
3941BrBrClClBr
3942BrBrClClF
3943BrBrClBrH
3944BrBrClBrCH3
3945BrBrClBrOCH3
3946BrBrClBrBr
3947BrBrClFH
3948BrBrClFCH3
3949BrBrClFOCH3
3950BrBrClFBr
3951BrBrClFF
3952BrBrBrHH
3953BrBrBrHCH3
3954BrBrBrHOCH3
3955BrBrBrHCl
3956BrBrBrHBr
3957BrBrBrHF
3958BrBrBrCH3H
3959BrBrBrCH3CH3
3960BrBrBrCH3OCH3
3961BrBrBrCH3Cl
3962BrBrBrCH3F
3963BrBrBrOCH3H
3964BrBrBrOCH3CH3
3965BrBrBrOCH3OCH3
3966BrBrBrOCH3Cl
3967BrBrBrOCH3F
3968BrBrBrClH
3969BrBrBrClCH3
3970BrBrBrClOCH3
3971BrBrBrClCl
3972BrBrBrClF
3973BrBrBrBrH
3974BrBrBrBrCH3
3975BrBrBrBrOCH3
3976BrBrBrBrCl
3977BrBrBrBrBr
3978BrBrBrBrF
3979BrBrBrFH
3980BrBrBrFCH3
3981BrBrBrFOCH3
3982BrBrBrFCl
3983BrBrBrFF
3984BrBrFHH
3985BrBrFHCH3
3986BrBrFHOCH3
3987BrBrFHCl
3988BrBrFHBr
3989BrBrFHF
3990BrBrFCH3H
3991BrBrFCH3CH3
3992BrBrFCH3OCH3
3993BrBrFCH3Cl
3994BrBrFCH3Br
3995BrBrFOCH3H
3996BrBrFOCH3CH3
3997BrBrFOCH3OCH3
3998BrBrFOCH3Cl
3999BrBrFOCH3Br
4000BrBrFClH
4001BrBrFClCH3
4002BrBrFClOCH3
4003BrBrFClCl
4004BrBrFClBr
4005BrBrFBrH
4006BrBrFBrCH3
4007BrBrFBrOCH3
4008BrBrFBrCl
4009BrBrFBrBr
4010BrBrFFH
4011BrBrFFCH3
4012BrBrFFOCH3
4013BrBrFFCl
4014BrBrFFBr
4015BrBrFFF
4016BrFCH3HH
4017BrFCH3HCH3
4018BrFCH3HOCH3
4019BrFCH3HCl
4020BrFCH3HBr
4021BrFCH3HF
4022BrFCH3CH3H
4023BrFCH3CH3CH3
4024BrFCH3CH3OCH3
4025BrFCH3CH3Cl
4026BrFCH3CH3Br
4027BrFCH3CH3F
4028BrFCH3OCH3H
4029BrFCH3OCH3OCH3
4030BrFCH3OCH3Cl
4031BrFCH3OCH3Br
4032BrFCH3OCH3F
4033BrFCH3ClH
4034BrFCH3ClOCH3
4035BrFCH3ClCl
4036BrFCH3ClBr
4037BrFCH3ClF
4038BrFCH3BrH
4039BrFCH3BrOCH3
4040BrFCH3BrCl
4041BrFCH3BrBr
4042BrFCH3BrF
4043BrFCH3FH
4044BrFCH3FOCH3
4045BrFCH3FCl
4046BrFCH3FBr
4047BrFCH3FF
4048BrFOCH3HH
4049BrFOCH3HCH3
4050BrFOCH3HOCH3
4051BrFOCH3HCl
4052BrFOCH3HBr
4053BrFOCH3HF
4054BrFOCH3CH3H
4055BrFOCH3CH3CH3
4056BrFOCH3CH3Cl
4057BrFOCH3CH3Br
4058BrFOCH3CH3F
4059BrFOCH3OCH3H
4060BrFOCH3OCH3CH3
4061BrFOCH3OCH3OCH3
4062BrFOCH3OCH3Cl
4063BrFOCH3OCH3Br
4064BrFOCH3OCH3F
4065BrFOCH3ClH
4066BrFOCH3ClCH3
4067BrFOCH3ClCl
4068BrFOCH3ClBr
4069BrFOCH3ClF
4070BrFOCH3BrH
4071BrFOCH3BrCH3
4072BrFOCH3BrCl
4073BrFOCH3BrBr
4074BrFOCH3BrF
4075BrFOCH3FH
4076BrFOCH3FCH3
4077BrFOCH3FCl
4078BrFOCH3FBr
4079BrFOCH3FF
4080BrFClHH
4081BrFClHCH3
4082BrFClHOCH3
4083BrFClHCl
4084BrFClHBr
4085BrFClHF
4086BrFClCH3H
4087BrFClCH3CH3
4088BrFClCH3OCH3
4089BrFClCH3Br
4090BrFClCH3F
4091BrFClOCH3H
4092BrFClOCH3CH3
4093BrFClOCH3OCH3
4094BrFClOCH3Br
4095BrFClOCH3F
4096BrFClClH
4097BrFClClCH3
4098BrFClClOCH3
4099BrFClClCl
4100BrFClClBr
4101BrFClClF
4102BrFClBrH
4103BrFClBrCH3
4104BrFClBrOCH3
4105BrFClBrBr
4106BrFClFH
4107BrFClFCH3
4108BrFClFOCH3
4109BrFClFBr
4110BrFClFF
4111BrFBrHH
4112BrFBrHCH3
4113BrFBrHOCH3
4114BrFBrHCl
4115BrFBrHBr
4116BrFBrHF
4117BrFBrCH3H
4118BrFBrCH3CH3
4119BrFBrCH3OCH3
4120BrFBrCH3Cl
4121BrFBrCH3F
4122BrFBrOCH3H
4123BrFBrOCH3CH3
4124BrFBrOCH3OCH3
4125BrFBrOCH3Cl
4126BrFBrOCH3F
4127BrFBrClH
4128BrFBrClCH3
4129BrFBrClOCH3
4130BrFBrClCl
4131BrFBrClF
4132BrFBrBrH
4133BrFBrBrCH3
4134BrFBrBrOCH3
4135BrFBrBrCl
4136BrFBrBrBr
4137BrFBrBrF
4138BrFBrFH
4139BrFBrFCH3
4140BrFBrFOCH3
4141BrFBrFCl
4142BrFBrFF
4143BrFFHH
4144BrFFHCH3
4145BrFFHOCH3
4146BrFFHCl
4147BrFFHBr
4148BrFFHF
4149BrFFCH3H
4150BrFFCH3CH3
4151BrFFCH3OCH3
4152BrFFCH3Cl
4153BrFFCH3Br
4154BrFFOCH3H
4155BrFFOCH3CH3
4156BrFFOCH3OCH3
4157BrFFOCH3Cl
4158BrFFOCH3Br
4159BrFFClH
4160BrFFClCH3
4161BrFFClOCH3
4162BrFFClCl
4163BrFFClBr
4164BrFFBrH
4165BrFFBrCH3
4166BrFFBrOCH3
4167BrFFBrCl
4168BrFFBrBr
4169BrFFFH
4170BrFFFCH3
4171BrFFFOCH3
4172BrFFFCl
4173BrFFFBr
4174BrFFFF
4175FCH3CH3HH
4176FCH3CH3CH3H
4177FCH3CH3OCH3H
4178FCH3CH3ClH
4179FCH3CH3BrH
4180FCH3CH3FH
4181FCH3CH3HCH3
4182FCH3CH3CH3CH3
4183FCH3CH3HOCH3
4184FCH3CH3CH3OCH3
4185FCH3CH3OCH3OCH3
4186FCH3CH3ClOCH3
4187FCH3CH3BrOCH3
4188FCH3CH3FOCH3
4189FCH3CH3HCl
4190FCH3CH3CH3Cl
4191FCH3CH3OCH3Cl
4192FCH3CH3ClCl
4193FCH3CH3BrCl
4194FCH3CH3FCl
4195FCH3CH3HBr
4196FCH3CH3CH3Br
4197FCH3CH3OCH3Br
4198FCH3CH3ClBr
4199FCH3CH3BrBr
4200FCH3CH3FBr
4201FCH3CH3HF
4202FCH3CH3CH3F
4203FCH3CH3OCH3F
4204FCH3CH3ClF
4205FCH3CH3BrF
4206FCH3CH3FF
4207FCH3OCH3HH
4208FCH3OCH3CH3H
4209FCH3OCH3OCH3H
4210FCH3OCH3ClH
4211FCH3OCH3BrH
4212FCH3OCH3FH
4213FCH3OCH3HCH3
4214FCH3OCH3CH3CH3
4215FCH3OCH3OCH3CH3
4216FCH3OCH3ClCH3
4217FCH3OCH3BrCH3
4218FCH3OCH3FCH3
4219FCH3OCH3HOCH3
4220FCH3OCH3OCH3OCH3
4221FCH3OCH3HCl
4222FCH3OCH3CH3Cl
4223FCH3OCH3OCH3Cl
4224FCH3OCH3ClCl
4225FCH3OCH3BrCl
4226FCH3OCH3FCl
4227FCH3OCH3HBr
4228FCH3OCH3CH3Br
4229FCH3OCH3OCH3Br
4230FCH3OCH3ClBr
4232FCH3OCH3BrBr
4232FCH3OCH3FBr
4233FCH3OCH3HF
4234FCH3OCH3CH3F
4235FCH3OCH3OCH3F
4236FCH3OCH3ClF
4237FCH3OCH3BrF
4238FCH3OCH3FF
4239FCH3ClHH
4240FCH3ClCH3H
4241FCH3ClOCH3H
4242FCH3ClClH
4243FCH3ClBrH
4244FCH3ClFH
4245FCH3ClHCH3
4246FCH3ClCH3CH3
4247FCH3ClOCH3CH3
4248FCH3ClClCH3
4249FCH3ClBrCH3
4250FCH3ClFCH3
4251FCH3ClHOCH3
4252FCH3ClCH3OCH3
4253FCH3ClOCH3OCH3
4254FCH3ClClOCH3
4255FCH3ClBrOCH3
4256FCH3ClFOCH3
4257FCH3ClHCl
4258FCH3ClClCl
4259FCH3ClHBr
4260FCH3ClCH3Br
4261FCH3ClOCH3Br
4262FCH3ClClBr
4263FCH3ClBrBr
4264FCH3ClFBr
4265FCH3ClHF
4266FCH3ClCH3F
4267FCH3ClOCH3F
4268FCH3ClClF
4269FCH3ClFF
4270FCH3BrHH
4271FCH3BrCH3H
4272FCH3BrOCH3H
4273FCH3BrClH
4274FCH3BrBrH
4275FCH3BrFH
4276FCH3BrHCH3
4277FCH3BrCH3CH3
4278FCH3BrOCH3CH3
4279FCH3BrClCH3
4280FCH3BrBrCH3
4281FCH3BrFCH3
4282FCH3BrHOCH3
4283FCH3BrCH3OCH3
4284FCH3BrOCH3OCH3
4285FCH3BrClOCH3
4286FCH3BrBrOCH3
4287FCH3BrFOCH3
4288FCH3BrHCl
4289FCH3BrCH3Cl
4290FCH3BrOCH3Cl
4291FCH3BrClCl
4292FCH3BrBrCl
4293FCH3BrFCl
4294FCH3BrHBr
4295FCH3BrBrBr
4296FCH3BrHF
4297FCH3BrCH3F
4298FCH3BrOCH3F
4299FCH3BrClF
4300FCH3BrBrF
4301FCH3BrFF
4302FCH3FHH
4303FCH3FCH3H
4304FCH3FOCH3H
4305FCH3FClH
4306FCH3FBrH
4307FCH3FFH
4308FCH3FHCH3
4309FCH3FCH3CH3
4310FCH3FOCH3CH3
4311FCH3FClCH3
4312FCH3FBrCH3
4313FCH3FFCH3
4314FCH3FHOCH3
4315FCH3FCH3OCH3
4316FCH3FOCH3OCH3
4317FCH3FClOCH3
4318FCH3FBrOCH3
4319FCH3FFOCH3
4320FCH3FHCl
4321FCH3FCH3Cl
4322FCH3FOCH3Cl
4323FCH3FClCl
4324FCH3FBrCl
4325FCH3FFCl
4326FCH3FHBr
4327FCH3FCH3Br
4328FCH3FOCH3Br
4329FCH3FClBr
4330FCH3FBrBr
4331FCH3FFBr
4332FCH3FHF
4333FCH3FFF
4334FOCH3CH3HH
4335FOCH3CH3HCH3
4336FOCH3CH3HOCH3
4337FOCH3CH3HCl
4338FOCH3CH3HBr
4339FOCH3CH3HF
4340FOCH3CH3CH3H
4341FOCH3CH3CH3CH3
4342FOCH3CH3CH3OCH3
4343FOCH3CH3CH3Cl
4344FOCH3CH3CH3Br
4345FOCH3CH3CH3F
4346FOCH3CH3OCH3H
4347FOCH3CH3OCH3OCH3
4348FOCH3CH3OCH3Cl
4349FOCH3CH3OCH3Br
4350FOCH3CH3OCH3F
4351FOCH3CH3ClH
4352FOCH3CH3ClOCH3
4353FOCH3CH3ClCl
4354FOCH3CH3ClBr
4355FOCH3CH3ClF
4356FOCH3CH3BrH
4357FOCH3CH3BrOCH3
4358FOCH3CH3BrCl
4359FOCH3CH3BrBr
4360FOCH3CH3BrF
4361FOCH3CH3FH
4362FOCH3CH3FOCH3
4363FOCH3CH3FCl
4364FOCH3CH3FBr
4365FOCH3CH3FF
4366FOCH3OCH3HH
4367FOCH3OCH3HCH3
4368FOCH3OCH3HOCH3
4369FOCH3OCH3HCl
4370FOCH3OCH3HBr
4371FOCH3OCH3HF
4372FOCH3OCH3CH3H
4373FOCH3OCH3CH3CH3
4374FOCH3OCH3CH3Cl
4375FOCH3OCH3CH3Br
4376FOCH3OCH3CH3F
4377FOCH3OCH3OCH3H
4378FOCH3OCH3OCH3CH3
4379FOCH3OCH3OCH3OCH3
4380FOCH3OCH3OCH3Cl
4381FOCH3OCH3OCH3Br
4382FOCH3OCH3OCH3F
4383FOCH3OCH3ClH
4384FOCH3OCH3ClCH3
4385FOCH3OCH3ClCl
4386FOCH3OCH3ClBr
4387FOCH3OCH3ClF
4388FOCH3OCH3BrH
4389FOCH3OCH3BrCH3
4390FOCH3OCH3BrCl
4391FOCH3OCH3BrBr
4392FOCH3OCH3BrF
4393FOCH3OCH3FH
4394FOCH3OCH3FCH3
4395FOCH3OCH3FCl
4396FOCH3OCH3FBr
4397FOCH3OCH3FF
4398FOCH3ClHH
4399FOCH3ClHCH3
4400FOCH3ClHOCH3
4401FOCH3ClHCl
4402FOCH3ClHBr
4403FOCH3ClHF
4404FOCH3ClCH3H
4405FOCH3ClCH3CH3
4406FOCH3ClCH3OCH3
4407FOCH3ClCH3Br
4408FOCH3ClCH3F
4409FOCH3ClOCH3H
4410FOCH3ClOCH3CH3
4411FOCH3ClOCH3OCH3
4412FOCH3ClOCH3Br
4413FOCH3ClOCH3F
4414FOCH3ClClH
4415FOCH3ClClCH3
4416FOCH3ClClOCH3
4417FOCH3ClClCl
4418FOCH3ClClBr
4419FOCH3ClClF
4420FOCH3ClBrH
4421FOCH3ClBrCH3
4422FOCH3ClBrOCH3
4423FOCH3ClBrBr
4424FOCH3ClFH
4425FOCH3ClFCH3
4426FOCH3ClFOCH3
4427FOCH3ClFBr
4428FOCH3ClFF
4429FOCH3BrHH
4430FOCH3BrHCH3
4431FOCH3BrHOCH3
4432FOCH3BrHCl
4433FOCH3BrHBr
4434FOCH3BrHF
4435FOCH3BrCH3H
4436FOCH3BrCH3CH3
4437FOCH3BrCH3OCH3
4438FOCH3BrCH3Cl
4439FOCH3BrCH3F
4440FOCH3BrOCH3H
4441FOCH3BrOCH3CH3
4442FOCH3BrOCH3OCH3
4443FOCH3BrOCH3Cl
4444FOCH3BrOCH3F
4445FOCH3BrClH
4446FOCH3BrClCH3
4447FOCH3BrClOCH3
4448FOCH3BrClCl
4449FOCH3BrClF
4450FOCH3BrBrH
4451FOCH3BrBrCH3
4452FOCH3BrBrOCH3
4453FOCH3BrBrCl
4454FOCH3BrBrBr
4455FOCH3BrBrF
4456FOCH3BrFH
4457FOCH3BrFCH3
4458FOCH3BrFOCH3
4459FOCH3BrFCl
4460FOCH3BrFF
4461FOCH3FHH
4462FOCH3FHCH3
4463FOCH3FHOCH3
4464FOCH3FHCl
4465FOCH3FHBr
4466FOCH3FHF
4467FOCH3FCH3H
4468FOCH3FCH3CH3
4469FOCH3FCH3OCH3
4470FOCH3FCH3Cl
4471FOCH3FCH3Br
4472FOCH3FOCH3H
4473FOCH3FOCH3CH3
4474FOCH3FOCH3OCH3
4475FOCH3FOCH3Cl
4476FOCH3FOCH3Br
4477FOCH3FClH
4478FOCH3FClCH3
4479FOCH3FClOCH3
4480FOCH3FClCl
4481FOCH3FClBr
4482FOCH3FBrH
4483FOCH3FBrCH3
4484FOCH3FBrOCH3
4485FOCH3FBrCl
4486FOCH3FBrBr
4487FOCH3FFH
4488FOCH3FFCH3
4489FOCH3FFOCH3
4490FOCH3FFCl
4491FOCH3FFBr
4492FOCH3FFF
4493FClCH3HH
4494FClCH3HCH3
4495FClCH3HOCH3
4496FClCH3HCl
4497FClCH3HBr
4498FClCH3HF
4499FClCH3CH3H
4500FClCH3CH3CH3
4501FClCH3CH3OCH3
4502FClCH3CH3Cl
4503FClCH3CH3Br
4504FClCH3CH3F
4505FClCH3OCH3H
4506FClCH3OCH3OCH3
4507FClCH3OCH3Cl
4508FClCH3OCH3Br
4509FClCH3OCH3F
4510FClCH3ClH
4511FClCH3ClOCH3
4512FClCH3ClCl
4513FClCH3ClBr
4514FClCH3ClF
4515FClCH3BrH
4516FClCH3BrOCH3
4517FClCH3BrCl
4518FClCH3BrBr
4519FClCH3BrF
4520FClCH3FH
4521FClCH3FOCH3
4522FClCH3FCl
4523FClCH3FBr
4524FClCH3FF
4525FClOCH3HH
4526FClOCH3HCH3
4527FClOCH3HOCH3
4528FClOCH3HCl
4529FClOCH3HBr
4530FClOCH3HF
4531FClOCH3CH3H
4532FClOCH3CH3CH3
4533FClOCH3CH3Cl
4534FClOCH3CH3Br
4535FClOCH3CH3F
4536FClOCH3OCH3H
4537FClOCH3OCH3CH3
4538FClOCH3OCH3OCH3
4539FClOCH3OCH3Cl
4540FClOCH3OCH3Br
4541FClOCH3OCH3F
4542FClOCH3ClH
4543FClOCH3ClCH3
4544FClOCH3ClCl
4545FClOCH3ClBr
4546FClOCH3ClF
4547FClOCH3BrH
4548FClOCH3BrCH3
4549FClOCH3BrCl
4550FClOCH3BrBr
4551FClOCH3BrF
4552FClOCH3FH
4553FClOCH3FCH3
4554FClOCH3FCl
4555FClOCH3FBr
4556FClOCH3FF
4557FClClHH
4558FClClHCH3
4559FClClHOCH3
4560FClClHCl
4561FClClHBr
4562FClClHF
4563FClClCH3H
4564FClClCH3CH3
4565FClClCH3OCH3
4566FClClCH3Br
4567FClClCH3F
4568FClClOCH3H
4569FClClOCH3CH3
4570FClClOCH3OCH3
4571FClClOCH3Br
4572FClClOCH3F
4573FClClClH
4574FClClClCH3
4575FClClClOCH3
4576FClClClCl
4577FClClClBr
4578FClClClF
4579FClClBrH
4580FClClBrCH3
4581FClClBrOCH3
4582FClClBrBr
4583FClClFH
4584FClClFCH3
4585FClClFOCH3
4586FClClFBr
4587FClClFF
4588FClBrHH
4589FClBrHCH3
4590FClBrHOCH3
4591FClBrHCl
4592FClBrHBr
4593FClBrHF
4594FClBrCH3H
4595FClBrCH3CH3
4596FClBrCH3OCH3
4597FClBrCH3Cl
4598FClBrCH3F
4599FClBrOCH3H
4600FClBrOCH3CH3
4601FClBrOCH3OCH3
4602FClBrOCH3Cl
4603FClBrOCH3F
4604FClBrClH
4605FClBrClCH3
4606FClBrClOCH3
4607FClBrClCl
4608FClBrClF
4609FClBrBrH
4610FClBrBrCH3
4611FClBrBrOCH3
4612FClBrBrCl
4613FClBrBrBr
4614FClBrBrF
4615FClBrFH
4616FClBrFCH3
4617FClBrFOCH3
4618FClBrFCl
4619FClBrFF
4620FClFHH
4621FClFHCH3
4622FClFHOCH3
4623FClFHCl
4624FClFHBr
4625FClFHF
4626FClFCH3H
4627FClFCH3CH3
4628FClFCH3OCH3
4629FClFCH3Cl
4630FClFCH3Br
4631FClFOCH3H
4632FClFOCH3CH3
4633FClFOCH3OCH3
4634FClFOCH3Cl
4635FClFOCH3Br
4636FClFClH
4637FClFClCH3
4638FClFClOCH3
4639FClFClCl
4640FClFClBr
4641FClFBrH
4642FClFBrCH3
4643FClFBrOCH3
4644FClFBrCl
4645FClFBrBr
4646FClFFH
4647FClFFCH3
4648FClFFOCH3
4649FClFFCl
4650FClFFBr
4651FClFFF
4652FBrCH3HH
4653FBrCH3HCH3
4654FBrCH3HOCH3
4655FBrCH3HCl
4656FBrCH3HBr
4657FBrCH3HF
4658FBrCH3CH3H
4659FBrCH3CH3CH3
4660FBrCH3CH3OCH3
4661FBrCH3CH3Cl
4662FBrCH3CH3Br
4663FBrCH3CH3F
4664FBrCH3OCH3H
4665FBrCH3OCH3OCH3
4666FBrCH3OCH3Cl
4667FBrCH3OCH3Br
4668FBrCH3OCH3F
4669FBrCH3ClH
4670FBrCH3ClOCH3
4671FBrCH3ClCl
4672FBrCH3ClBr
4673FBrCH3ClF
4674FBrCH3BrH
4675FBrCH3BrOCH3
4676FBrCH3BrCl
4677FBrCH3BrBr
4678FBrCH3BrF
4679FBrCH3FH
4680FBrCH3FOCH3
4681FBrCH3FCl
4682FBrCH3FBr
4683FBrCH3FF
4684FBrOCH3HH
4685FBrOCH3HCH3
4686FBrOCH3HOCH3
4687FBrOCH3HCl
4688FBrOCH3HBr
4689FBrOCH3HF
4690FBrOCH3CH3H
4691FBrOCH3CH3CH3
4692FBrOCH3CH3Cl
4693FBrOCH3CH3Br
4694FBrOCH3CH3F
4695FBrOCH3OCH3H
4696FBrOCH3OCH3CH3
4697FBrOCH3OCH3OCH3
4698FBrOCH3OCH3Cl
4699FBrOCH3OCH3Br
4700FBrOCH3OCH3F
4701FBrOCH3ClH
4702FBrOCH3ClCH3
4703FBrOCH3ClCl
4704FBrOCH3ClBr
4705FBrOCH3ClF
4706FBrOCH3BrH
4707FBrOCH3BrCH3
4708FBrOCH3BrCl
4709FBrOCH3BrBr
4710FBrOCH3BrF
4711FBrOCH3FH
4712FBrOCH3FCH3
4713FBrOCH3FCl
4714FBrOCH3FBr
4715FBrOCH3FF
4716FBrClHH
4717FBrClHCH3
4718FBrClHOCH3
4719FBrClHCl
4720FBrClHBr
4721FBrClHF
4722FBrClCH3H
4723FBrClCH3CH3
4724FBrClCH3OCH3
4725FBrClCH3Br
4726FBrClCH3F
4727FBrClOCH3H
4728FBrClOCH3CH3
4729FBrClOCH3OCH3
4730FBrClOCH3Br
4731FBrClOCH3F
4732FBrClClH
4733FBrClClCH3
4734FBrClClOCH3
4735FBrClClCl
4736FBrClClBr
4737FBrClClF
4738FBrClBrH
4739FBrClBrCH3
4740FBrClBrOCH3
4741FBrClBrBr
4742FBrClFH
4743FBrClFCH3
4744FBrClFOCH3
4745FBrClFBr
4746FBrClFF
4747FBrBrHH
4748FBrBrHCH3
4749FBrBrHOCH3
4750FBrBrHCl
4751FBrBrHBr
4752FBrBrHF
4753FBrBrCH3H
4754FBrBrCH3CH3
4755FBrBrCH3OCH3
4756FBrBrCH3Cl
4757FBrBrCH3F
4758FBrBrOCH3H
4759FBrBrOCH3CH3
4760FBrBrOCH3OCH3
4761FBrBrOCH3Cl
4762FBrBrOCH3F
4763FBrBrClH
4764FBrBrClCH3
4765FBrBrClOCH3
4766FBrBrClCl
4767FBrBrClF
4768FBrBrBrH
4769FBrBrBrCH3
4770FBrBrBrOCH3
4771FBrBrBrCl
4772FBrBrBrBr
4773FBrBrBrF
4774FBrBrFH
4775FBrBrFCH3
4776FBrBrFOCH3
4777FBrBrFCl
4778FBrBrFF
4779FBrFHH
4780FBrFHCH3
4781FBrFHOCH3
4782FBrFHCl
4783FBrFHBr
4784FBrFHF
4785FBrFCH3H
4786FBrFCH3CH3
4787FBrFCH3OCH3
4788FBrFCH3Cl
4789FBrFCH3Br
4790FBrFOCH3H
4791FBrFOCH3CH3
4792FBrFOCH3OCH3
4793FBrFOCH3Cl
4794FBrFOCH3Br
4795FBrFClH
4796FBrFClCH3
4797FBrFClOCH3
4798FBrFClCl
4799FBrFClBr
4800FBrFBrH
4801FBrFBrCH3
4802FBrFBrOCH3
4803FBrFBrCl
4804FBrFBrBr
4805FBrFFH
4806FBrFFCH3
4807FBrFFOCH3
4808FBrFFCl
4809FBrFFBr
4810FBrFFF
4811FFCH3HH
4812FFCH3HCH3
4813FFCH3HOCH3
4814FFCH3HCl
4815FFCH3HBr
4816FFCH3HF
4817FFCH3CH3H
4818FFCH3CH3CH3
4819FFCH3CH3OCH3
4820FFCH3CH3Cl
4821FFCH3CH3Br
4822FFCH3CH3F
4823FFCH3OCH3H
4824FFCH3OCH3OCH3
4825FFCH3OCH3Cl
4826FFCH3OCH3Br
4827FFCH3OCH3F
4828FFCH3ClH
4829FFCH3ClOCH3
4830FFCH3ClCl
4831FFCH3ClBr
4832FFCH3ClF
4833FFCH3BrH
4834FFCH3BrOCH3
4835FFCH3BrCl
4836FFCH3BrBr
4837FFCH3BrF
4838FFCH3FH
4839FFCH3FOCH3
4840FFCH3FCl
4841FFCH3FBr
4842FFCH3FF
4843FFOCH3HH
4844FFOCH3HCH3
4845FFOCH3HOCH3
4846FFOCH3HCl
4847FFOCH3HBr
4848FFOCH3HF
4849FFOCH3CH3H
4850FFOCH3CH3CH3
4851FFOCH3CH3Cl
4852FFOCH3CH3Br
4853FFOCH3CH3F
4854FFOCH3OCH3H
4855FFOCH3OCH3CH3
4856FFOCH3OCH3OCH3
4857FFOCH3OCH3Cl
4858FFOCH3OCH3Br
4859FFOCH3OCH3F
4860FFOCH3ClH
4861FFOCH3ClCH3
4862FFOCH3ClCl
4863FFOCH3ClBr
4864FFOCH3ClF
4865FFOCH3BrH
4866FFOCH3BrCH3
4867FFOCH3BrCl
4868FFOCH3BrBr
4869FFOCH3BrF
4870FFOCH3FH
4871FFOCH3FCH3
4872FFOCH3FCl
4873FFOCH3FBr
4874FFOCH3FF
4875FFClHH
4876FFClHCH3
4877FFClHOCH3
4878FFClHCl
4879FFClHBr
4880FFClHF
4881FFClCH3H
4882FFClCH3CH3
4883FFClCH3OCH3
4884FFClCH3Br
4885FFClCH3F
4886FFClOCH3H
4887FFClOCH3CH3
4888FFClOCH3OCH3
4889FFClOCH3Br
4890FFClOCH3F
4891FFClClH
4892FFClClCH3
4893FFClClOCH3
4894FFClClCl
4895FFClClBr
4896FFClClF
4897FFClBrH
4898FFClBrCH3
4899FFClBrOCH3
4900FFClBrBr
4901FFClFH
4902FFClFCH3
4903FFClFOCH3
4904FFClFBr
4905FFClFF
4906FFBrHH
4907FFBrHCH3
4908FFBrHOCH3
4909FFBrHCl
4910FFBrHBr
4911FFBrHF
4912FFBrCH3H
4913FFBrCH3CH3
4914FFBrCH3OCH3
4915FFBrCH3Cl
4916FFBrCH3F
4917FFBrOCH3H
4918FFBrOCH3CH3
4919FFBrOCH3OCH3
4920FFBrOCH3Cl
4921FFBrOCH3F
4922FFBrClH
4923FFBrClCH3
4924FFBrClOCH3
4925FFBrClCl
4926FFBrClF
4927FFBrBrH
4928FFBrBrCH3
4929FFBrBrOCH3
4930FFBrBrCl
4931FFBrBrBr
4932FFBrBrF
4933FFBrFH
4934FFBrFCH3
4935FFBrFOCH3
4936FFBrFCl
4937FFBrFF
4938FFFHH
4939FFFHCH3
4940FFFHOCH3
4941FFFHCl
4942FFFHBr
4943FFFHF
4944FFFCH3H
4945FFFCH3CH3
4946FFFCH3OCH3
4947FFFCH3Cl
4948FFFCH3Br
4949FFFOCH3H
4950FFFOCH3CH3
4951FFFOCH3OCH3
4952FFFOCH3Cl
4953FFFOCH3Br
4954FFFClH
4955FFFClCH3
4956FFFClOCH3
4957FFFClCl
4958FFFClBr
4959FFFBrH
4960FFFBrCH3
4961FFFBrOCH3
4962FFFBrCl
4963FFFBrBr
4964FFFFH
4965FFFFCH3
4966FFFFOCH3
4967FFFFCl
4968FFFFBr
4969FFFFF
|
In another embodiment, the compound of Formula I is selected from the group of compounds of Formula V having the structure:
- wherein R2a, R2b, R2c, R2d, and R2e are as defined in Table 2.
In another embodiment, the compound of Formula I is selected from the group of compounds of Formula V having the structure:
- wherein R2a, R2b, R2c, R2d, and R2e are as defined in Table 2.
In another embodiment, the compound of Formula I is selected from the group of compounds of Formula V having the structure:
- wherein R2a, R2b, R2c, R2d, and R2e are as defined in Table 2.
In another embodiment, the compound of Formula I is selected from the group of compounds of Formula V having the structure:
- wherein R2a, R2b, R2c, R2d, and R2e are as defined in Table 2.
In another embodiment, the compound of Formula I is selected from the group of compounds of Formula V having the structure:
- wherein R2a, R2b, R2c, R2d, and R2e are as defined in Table 2.
In another embodiment, the compound of Formula I is selected from the group of compounds of Formula V having the structure:
- wherein R2a, R2b, R2c, R2d, and R2e are as defined in Table 2.
In another embodiment, the compound of Formula I is selected from the group of compounds of Formula V having the structure:
- wherein R2a, R2b, R2c, R2d, and R2e are as defined in Table 2.
In another embodiment, the compound of Formula I is selected from the group of compounds of Formula V having the structure:
- wherein R2a, R2b, R2c, R2d, and R2e are as defined in Table 2.
In another embodiment, the compound of Formula I is selected from the group of compounds of Formula V having the structure:
- wherein R2a, R2b, R2c, R2d, and R2e are as defined in Table 2.
In another embodiment, the compound of Formula I is selected from the group of compounds of Formula V having the structure:
- wherein R2a, R2b, R2c, R2d, and R2e are as defined in Table 2.
In another embodiment, the compound of Formula I is selected from the group of compounds of Formula V having the structure:
- wherein R2a, R2b, R2c, R2d, and R2e are as defined in Table 2.
In another embodiment, the compound of Formula I is selected from the group of compounds of Formula V having the structure:
- wherein R2a, R2b, R2c, R2d, and R2e are as defined in Table 2.
In another embodiment, the compound of Formula I is selected from the group of compounds of Formula V having the structure:
- wherein R2a, R2b, R2c, R2d, and R2e are as defined in Table 2.
In another embodiment, the compound of Formula I is selected from the group of compounds of Formula V having the structure:
- wherein R2a, R2b, R2c, R2d, and R2e are as defined in Table 2.
In another embodiment, the compound of Formula I is selected from the group of compounds of Formula V having the structure:
- wherein R2a, R2b, R2c, R2d, and R2e are as defined in Table 2.
The compounds of Formula I are MCH receptor antagonists, as demonstrated by the ligand binding assays described hereinbelow. MCH receptor antagonist activity has been correlated with pharmaceutical activity for the treatment of eating disorders such as obesity and hyperphagia, and diabetes. Compounds of Formula I exhibit good activity in standard in vitro MCH calcium mobilization assays and/or receptor binding assays, specifically in the assays described hereinbelow, see Examples 23 and 24. Generally, compounds of Formula I have an Ki of about 10 μM or less, preferably about 1 μM or less, more preferably about 100 nM or less, or even more preferably about 10 nM or less, as determined by a standard in vitro MCH receptor mediated calcium mobilization assay as exemplified by Example 23, hereinbelow. Generally compounds of Formula I are MCH receptor antagonists and exhibit IC50 values of about 10 μM or less, preferably about 1 μM or less, more preferably about 100 nM or less, or even more preferably about 10 nM or less, as determined by a standard in vitro MCH receptor binding assay such as is described hereinbelow in Example 24.
Preferably, the MCH receptor antagonists of Formula I bind specifically, and still more preferably with high affinity, to MCH receptors.
The following examples illustrate the invention.
EXAMPLE 1
To a 2 L glass bottle was added 4-formyl-3-methoxyphenoxy-polystyrene resin (100-180 mesh, 1.1 mmol/g loading, 20 g, 22 mmol), amine (5 eq, 110 mmol), and anhydrous DCE (500 mL). The resulting mixture was shaken for one hour at room temperature. Then, Na(OAc)3BH (5 eq, 110 mmol) was added and the mixture was shaken overnight at room temperature. The mixture was degassed every half-hour for the first three hours. The resin was filtered and washed with MeOH (2×) and DCM (2×) to afford 1.
Step 2
To a 2 L glass bottle was added 1, 4-fluoro-3-nitrobenzoic acid (24.4 mmol, 132 mmol), HOBt (18 g, 132 mmol), DIC (42 mL, 264 mmol), and DMF (500 mL). The resulting mixture was shaken overnight at room temperature. The resin was filtered and washed with DMF (2×), MeOH (2×), and DCM (2×) to afford 2.
Step 3
To a 2 L glass bottle was added 2, phenol (27 g, 220 mmol), DBU (20 mL, 132 mmol), and DMF (400 mL). The resulting mixture was shaken overnight at room temperature. Then, the resin was filtered and washed with DMF (2×) and DCM (2×) to afford 3.
Step 4
To a 2 L glass bottle was added 3, Tin(II)Cl.2H2O (49.5 g, 220 mmol) and DMF (400 mL). The resulting mixture was then shaken overnight at room temperature. The resin was filtered and washed with DMF (2×) and DCM (2×) to afford 4.
EXAMPLE 2
Method 1
Starting material (10 mg, 0.021 mmol) was combined with 1,2-dibromoethane (2.3 μL, 0.025 mmol) and NaH (1 mg, 0.042 mmol) in 0.5 mL DMF at room temperature. The mixture was then heated to 80° C. for 1 hour. The reaction mixture was worked up with water and EtOAc.
Method 2
Starting material (20 mg, 0.04 mmol) was combined with 1,2-diiodoethane (14.3 mg, 0.05 mmol) and NaH (2 mg, 0.08 mmol) in 0.5 mL DMF, then reacted as described above.
EXAMPLE 3
To a peptide vessel was added resin (1.1 mmol/g loading, 100 mg, 0.11 mmol), 2-methoxyphenylisocyanate (1.1 mmol), and pyridine: DCM (5 mL, 1:1 ratio). The resulting mixture was shaken overnight at room temperature. The resin was washed with DCM (2×). Then, 30% TFA in DCM (10 mL) was added and the resulting mixture was shaken for 45 min. at room temperature. The resin was filtered and washed with DCM (2×). The filtrate was concentrated to afford 30.
Examples 4-16 were prepared according to the procedure shown in Example 3.
EXAMPLE 4
EXAMPLE 5
EXAMPLE 6
EXAMPLE 7
EXAMPLE 8
EXAMPLE 9
EXAMPLE 10
EXAMPLE 11
EXAMPLE 12
EXAMPLE 13
EXAMPLE 14
EXAMPLE 15
EXAMPLE 16
EXAMPLE 17
To a round bottom flask was added resin (500 mg, 0.55 mmol) and DCM (15 mL). The resulting mixture was cooled to −78° C. Then, 20% phosgene in toluene (540 mg) was added dropwise. The resulting mixture was warmed to room temperature and shaken for 3 hours. The resin was filtered and washed with DCM (2×). The resin was transferred to a peptide vessel and excess (10-15 eq) of aminopyridine along with 15 mL of DCM were added. The resulting mixture was shaken overnight at room temperature. The resin was washed with DCM (2×). Then, 30% TFA in DCM (50 mL) was added and the resulting mixture was shaken for 45 min. at room temperature. The resin was filtered and washed with DCM (2×). The filtrate was concentrated to afford 44.
EXAMPLE 18
To a peptide vessel was added resin (1.1 mmol/g, 200 mg, 0.22 mmol), phenylchloroformate (143 μL, 1.1 mmol), and DCM:pyridine (7 mL, 1:1 ratio). The resulting mixture was shaken overnight at room temperature. The resin was washed with DCM (2×). Then, 30% TFA in DCM (50 mL) was added and the resulting mixture was shaken for 45 min. at room temperature. The resin was filtered and washed with DCM (2×). The filtrate was concentrated to afford 45.
EXAMPLE 19
To a peptide vessel was added resin (1.1 mmol/g, 1.1 g, 1.21 mmol), 1,1-dimethylethyl 2-oxoethyl(phenyl)carbamate (490 mg, 3.63 mmol), and DCM:DMF (10 mL, 1:1 ratio). The mixture was shaken for 30 min. at room temperature. Then, Na(OAc)3BH (1.27 g, 6.05 mmol) was added and the mixture was shaken overnight at room temperature. The mixture was degassed every half hour for the first 3 hours. The resin was washed with MeOH (2×) and DCM (2×). Then, 30% TFA in DCM (50 mL) was added and resulting mixture was shaken for 45 min. at room temperature. The resin was filtered and washed with DCM (2×). The filtrate was concentrated and dried. Then, phosgene (27.1 μL, 0.274 mmol) and DCM:pyridine (5 mL, 1:1 ratio) were added to the crude mixture. The resulting mixture was stirred at room temperature for 45 min. The mixture was concentrated and purified by column chromatography to afford 62.
EXAMPLE 20
To a peptide vessel was added resin (1.1 mmol/g, 500 mg, 0.55 mmol), acetaldehyde (93 μL, 1.65 mmol), and DCM:DMF (8 mL, 1:1 ratio). The mixture was shaken for 30 min. at room temperature. Then, Na(OAc)3BH (580 mg, 2.75 mmol) was added and the mixture was shaken overnight at room temperature. The mixture was degassed every half hour for the first three hours. The resin was washed with MeOH (2×) and DCM (2×). Then, isocyanatobenzene (327 μL, 2.75 mmol) and DCM (10 mL) were added to the resin in the peptide vessel. The resulting mixture was shaken overnight at room temperature. The resin was washed with DCM (2×). Then, 30% TFA in DCM (50 mL) was added and resulting mixture was shaken for 45 min. at room temperature. The resin was filtered and washed with DCM (2×). The filtrate was concentrated to afford 49.
EXAMPLE 21
To a round bottom flask was added resin (1.1 mmol/g, 400 mg, 0.44 mmol) and DCM (7 mL). The resulting mixture was stirred at −78° C. and phosgene (217 mg, 2.2 mmol) was added dropwise. The mixture was warmed up to room temperature and shaken for 3 hours. The resin was washed with DCM (2×) and transferred to a peptide vessel. Then, 1,2,3,4-tetrahydroquinoline (585 μL, 4.4 mmol) was added to the vessel. The resulting mixture was shaken for 2 hours. The resin was washed with DCM (2×). Then, 30% TFA in DCM (30 mL) was added and resulting mixture was shaken for 45 min. at room temperature. The resin was filtered and washed with DCM (2×). The filtrate was concentrated to afford 46.
EXAMPLE 22
To a 20 ml vial was added 1-((4-fluoro-3-nitrophenyl)carbonyl)-2-(1-pyrrolidinylmethyl)pyrrolidine (520 mg, 1.62 mmol), 3,4-dimethylphenol (237 mg, 1.94 mmol), DBU (271 μL, 1.78 mmol), and DMF (10 mL). The resulting mixture was stirred overnight at room temperature. The mixture was extracted with H2O and EtOAc. The organic layers were combined, dried with MgSO4, and concentrated to give a crude intermediate. The intermediate was purified by column chromatography to give a pure intermediate. Then, EtOH:H2O (3:1) and Na2S2O4 (10 eq) were added to the intermediate. The resulting mixture was refluxed overnight. Then, the mixture was cooled to room temperature and extracted with H2O and EtOAc. The organic layers were combined, dried with MgSO4, and concentrated to give a crude intermediate. The crude intermediate was purified by column chromatography to give a pure intermediate. The purified intermediate was placed in a round bottom flask and DCM and phenylisocyanate (1 eq) were added. The resulting mixture was stirred at room temperature for 1 hour. The solvent was removed and the crude desired product was purified by column chromatography to afford 63.
EXAMPLE 23
Functional Assay
Human embryonic kidney cells (293 total) expressing either human, rat, or mouse MCH receptor were harvested from 150 mm culture dishes using PBS. Spinning at 1500 rpm for 2 minutes initially pelleted cells. The resulting pellet was then homogenized in 15 mL ice cold sucrose buffer (25 mM HEPES, 0.3 M sucrose, pH 7.4) with a motorized, glass fitted, Teflon® homogenizer. The homogenate was centrifuged at 48,000×g at 4° C. for 10 minutes, resuspended in 15 mL assay buffer (25 mM HEPES, 10 mM MgCl2, 0.2% BSA, 0.1 mg/mL STI, 0.1 mg/mL Pefabloc®, 1 μM Phosphoramidon, pH 7.4) with a Tissue-Tearor® (Biospec Products) and centrifuged again at 48,000×g for 10 minutes. The pellet was homogenized for a third time in 15 mL assay buffer using the Tissue-Tearor® and again centrifuged at 48,000×g for 10 minutes. The resulting pellet was resuspended in assay buffer at a wet weight concentration of 10-20 mg/mL.
Pharmacological analyses were conducted using either a HT-PS100 device (Axiom Biotechnologies, San Diego, Calif.), which provides high-resolution dose-response fluorometric measurements of [Ca++]i mobilization, or using a FLIPR® device (Molecular Devices, Sunnyvale, Calif.).
HT-PS100 Protocol:
Materials: HEK 293 cells were stably transfected with the rat MCH 1 receptor and maintained under G418 antibiotic pressure. HT-PS100 assay buffer consisted of Physiological Saline Solution (145 mM NaCl, 5.4 mM KCL, 1.0 mM NaH2PO4, 1.8 mM CaCl2, 0.8 mM MgSO4, 15.0 mM HEPES, pH 7.4, 11.2 mM glucose)+50 μM Pluronic-F127. MCH peptide (Amgen, Inc.) was reconstituted in assay buffer and served as the positive agonist control for all experiments. Test compounds were prepared as 10 mM stocks in 100% DMSO and diluted to a top end working concentration of 100 μM in 96 well plates.
Methods: HEK 293 stably expressing MCH1R were maintained in Dulbeco's modified Eagle's medium (GIBCO/Life Technologies, Rockville, Md.) supplemented with 2 mM glutamine and 10% dialyzed fetal bovine serum (HyClone, Logan, Utah) at 37° C., 5% CO2. Cells were harvested by 10′ treatment with Versene (GIBCO/Life Technologies) followed by trituration, washing twice with cold (4° C.) hybridoma medium (Serum/Protein free, with L-glutamine, sodium bicarbonate, MOPS buffer) (Sigma-Aldrich Corp, St. Louis, Mo.) and resuspended at 2×106 cells/mL in the same medium. The resuspended cells were loaded with the fluorescent calcium indicator Fura-2 by incubating with Fura-2AM (Molecular Probes, Eugene, Oreg.) at 1.6 μM for 60′ at room temperature. The loaded cells were then washed twice with hybridoma medium, adjusted to 2×105 cells/mL and kept at ambient temperature in a spinner flask under gentle stirring for up to 6 hours during the experiment.
Receptor-stimulated intracellular calcium responses were detected in the flow-through detector cuvette of the HT-PS100 by monitoring increases in the ratio of Fura-2 fluorescence intensities R340/380 measured at alternating 340/380 nm excitation and 510 nm emission.
Preliminary static experiments, conducted to determine the kinetics of MCH1R's dose response to MCH peptide, indicated the optimum time point to capture the maximum Ca++ transients was 30 s. No interference with DMSO was seen up to 1%. Based on these observations, subsequent experiments were conducted on the HT-PS100 to generate high resolution dose response curves, characterize agonist/antagonist properties, and evaluate antagonist potencies via Schild experiments. During HT-PS100 validation, reproducible EC50s for MCH of 10 nM were generated within a broad range of cell passage and harvest density. HT-PS100 gradient generation was calibrated with a standardized stock of fluorescein.
Test compounds were screened for MCH1R activity in the HT-PS100 for both agonist and antagonist action. Agonist mode challenges were conducted at a maximum gradient concentration of 100 μM. Antagonist activity was tested by 30 s pre-incubation of cells at a compound concentration of 100 μM, with subsequent introduction of MCH at a concentration 5-fold of EC50 as determined in preliminary experiments. Compounds that showed inhibition of the MCH-induced Ca++ response were automatically tagged for re-interrogation, IC50 generation, and Schild analysis.
Schild experiments were conducted on the HT-PS100 for selected compounds by 30 s pre-incubation of cells with antagonist compounds prior to administering MCH peptide. Several fixed concentrations of antagonist compounds were prepared in 10-fold increments, and presented to the cells 30 s before introducing a gradient of increasing MCH concentration. Values for compound pA2 were calculated by linear regression of Log(DR−1) MCH EC50 as a function of Log(antagonist concentration), where DR is the dose ratio of MCH EC50 values determined in the presence and absence of antagonist.
The following compounds had Ki values of 100 μM or less in the HT-PS100 assay: Compound Nos. ______. Of these, Compound Nos. ______ had Ki values of 100 nM or less in this assay.
FLIPR® Protocol:
Materials: Pharmacological analysis was conducted using a FLIPR® device (Molecular Devices, Sunnyvale, Calif.). CHOK1-Gqi cells were stably transfected with the rat MCH1 receptor and maintained under G418 antibiotic pressure. FLIPR® assay buffer consisted of phenol red-free DMEM+2.5 mM probenecid. MCH peptide (Amgen, Inc.) was reconstituted in assay buffer and served as the positive agonist control for all experiments. Test compounds were prepared as 10 mM stocks in 100% DMSO and diluted to a top end working concentration of 10 μM in 96 well black, flat bottom, collagen-I coated plates (Becton Dickinson, Bedford, Mass.).
Methods: CHOK1-Gqi cells stably expressing MCH1R were maintained in Dulbeco's modified Eagle's medium (GIBCO/Life Technologies, Rockville, Md.) supplemented with 2 mM glutamine and 10% dialyzed fetal bovine serum (HyClone, Logan, Utah) at 37° C., 5% CO2. Cells were harvested by 10′ treatment with Versene (GIBCO/Life Technologies) followed by trituration, washing twice with cold (4° C.) hybridoma medium (Serum/Protein free, with L-glutamine, sodium bicarbonate, MOPS buffer) (Sigma-Aldrich Corp, St. Louis, Mo.) and replated onto 96 well black, flat bottom, collagen-I coated plates to a density of 10,000 cells/well. The cells were then loaded with the fluorescent calcium indicator Fura-2 (Molecular Probes, Eugene, Oreg.) at 1.6 μM for 60′ at room temperature. The loaded cells were then washed twice with 90 μl/well of wash buffer (1×HBSS, 20 mM HEPES, 2.5 mM probenecid).
Receptor-stimulated intracellular calcium responses were detected using FLIPR® by monitoring increases in the Fura-2 fluorescence response.
Test compounds were screened for MCH1R activity in the FLIPR® for both agonist and antagonist action. Agonist mode challenges were conducted at a maximum gradient concentration of 1 μM. Antagonist activity was tested by 10 min pre-incubation of cells at a compound concentration of defined to be 300× the EC50 of MCH (typically 1 μM), with subsequent introduction of MCH at a concentration 5-fold of EC50 as determined in preliminary experiments. Compounds that showed inhibition of MCH induced MCH1R dependant Ca++ responses were automatically tagged for re-interogation, IC50 generation, and Schild analysis.
Schild experiments were conducted on the FLIPR® for selected compounds by co-administering antagonist compounds together with MCH peptide. Several fixed concentrations of antagonist compounds were prepared in 10-fold increments, and presented to the cells in a gradient of increasing MCH concentration. Values for compound pA2 were calculated by linear regression of MCH EC50s as a function of antagonist concentration.
The following compounds had Ki values of 100 μM or less in the rMCH FLIPR® assay: Compound Nos. 1, 5, 6, 15, 22, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 51, 53, 54, 55, 56, 57, 58, 59, and 64. Of these, Compound Nos. 1, 6, 15, 31, 32, 38, 39, 40, and 41 had Ki values of 100 nM or less in this assay.
The following compounds had Ki values of 100 μM or less in the hMCH FLIPR® assay: Compound Nos. 1, 5, 6, 34, 35, 36, 37, 38, 40, 41, 51, 52, 53, 54, 55, 56, 57, 58, 59, and 64. Of these, Compound Nos. 1, 6, 34, 35, 38, 40, 41, 51, 56, and 57 had Ki values of 100 nM or less in this assay.
EXAMPLE 24
Ligand Binding Assay
Binding assays were determined as described below using mouse, rat or human MCH 1 receptors (mMCH1R, rMCH1R, and hMCH1R, respectively) expressed in HEK 293; IC50 values were calculated.
Binding assays were performed in 96-well U-bottom plates. Membranes (100 μg tissue) were incubated at 30° C. for 90 minutes in assay buffer with various peptides in the presence of 0.2 nM 125I native-MCH (Perkin-Elmer Life Sciences, Boston, Mass.) in 100 μL total volume. Non-specific binding was assessed in the presence of 1 μM cold native-MCH. The reaction was terminated by rapid filtration through Unfilter-96 GF/C glass fiber filter plates (FilterMate® 196 Harvester, Packard Instrument Co., Meriden, Conn.) pre-soaked in PBS/0.5% BSA, followed by three washes with 300 μL ice-cold water. Bound radioactivity was determined using a TopCount® microplate scintillation and luminescence counter (Packard Instrument Co., Meriden, Conn.). Nonlinear regression analyses of drug concentration curves were performed using GraphPad Prism® (GraphPad Software, Inc., San Diego, Calif.).
The following compounds had IC50 values of 100 μM or less in the rMCH assay: Compound Nos. 1, 10, 12, 13, 15, 16, 17, 18, 22, 27, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 51, 52, 53, 54, 55, 56, 57, 58, 59, 61, 63, 64, 65, and 66. Of these, Compound Nos. 1, 31, 38, 39, 40, 41, 51, 52, 53, 54, 55, 56, 57, 58, 59, 61, and 66 had IC50 values of 100 nM or less in the rMCH assay.
The following compounds had IC50 values of 100 μM or less in the hMCH assay: Compound Nos. 1, 5, 6, 8, 10, 12, 13, 15, 16, 17, 18, 20, 22, 27, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 58, 59, 64, 65, and 66. Of these, Compound Nos. 1, 6, 31, 32, 33, 34, 36, 37, 38, 39, 40, 41, 58, 59, and 66 had IC50 values of 100 nM or less in the hMCH assay.
In view of the above, it will be seen that the several objects of the invention are achieved.
The above description of the embodiments and examples are intended only to acquaint others skilled in the art with the invention, its principles, and its practical application, so that others skilled in the art may adapt and apply the invention in its numerous forms, as may be best suited to the requirements of a particular use. The present invention, therefore, is not limited to the above embodiments, and may be variously modified.
With reference to the use of the word(s) “comprise” or “comprises” or “comprising” or “including” or “having” in the above description and/or in the following claims, it should be noted that unless the context requires otherwise, those words are used on the basis and clear understanding that they are to be interpreted inclusively, rather than exclusively, and that each of those words is to be so interpreted in construing the above description and/or the following claims. When introducing elements of the present invention or the preferred embodiment(s) thereof, the articles “a,” “an,” “the,” and “said” are intended to mean that there are one or more of the elements.
In view of the above, it will be seen that the several objects of the invention are achieved and other advantageous results attained.
As various changes could be made in the above compounds and methods without departing from the scope of the invention, it is intended that all matter contained in the above description shall be interpreted as illustrative and not in a limiting sense.
The entire texts of all U.S. patents and other references cited herein are hereby incorporated by reference into this patent.