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Title:
HETEROCYCLIC COMPOUNDS, AND THEIR USE AS ALLOSTERIC MODULATORS OF 5-HYDROXYTRYPTAMINE 2C RECEPTOR (5-HT2CR)
Document Type and Number:
WIPO Patent Application WO/2021/028935
Kind Code:
A1
Abstract:
The present invention relates to compounds of formula (I): or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R1, R2, R3, R4, X, m and n are as defined in the specification. The present invention also relates to compositions comprising such compounds, use of such compounds and methods of treating a condition, disease or disorder using such compounds and/or compositions.

Inventors:
JETTA SANDEEP KUMAR (IN)
RAPAKA NAIMISHA (IN)
YADAV PREM NARAYAN (IN)
MISRA PARIMAL (IN)
PAL MANOJIT (IN)
Application Number:
PCT/IN2020/050048
Publication Date:
February 18, 2021
Filing Date:
January 16, 2020
Export Citation:
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Assignee:
DR REDDYS INST OF LIFE SCIENCES (IN)
International Classes:
C07H15/16; A61K31/4985
Domestic Patent References:
WO2007093366A12007-08-23
Other References:
KIM JUNG WHA; CHOI HYUN GYU; SONG JI HOON; KANG KI SUNG; SHIM SANG HEE: "Bioactive secondary metabolites from an endophytic fungus Phoma sp. PF2 derived from Artemisia princeps Pamp", THE JOURNAL OF ANTIBIOTICS, vol. 72, no. 3, 12 December 2018 (2018-12-12), pages 174 - 177, XP036693085, DOI: https://doi.org/10.1038/s41429-018-0131-2
Attorney, Agent or Firm:
BHATTACHARYYA, Goutam et al. (IN)
Download PDF:
Claims:
THE CLAIMS:

1. A compound of formula (I): or a pharmaceutically acceptable salt or a stereoisomer thereof; wherein,

R1, at each occurrence, is independently selected from hydrogen, halogen, - N(R1a)R1b, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl and optionally substituted heteroaryl; wherein the optional substituent, at each occurrence, is one or more of the groups selected from hydroxyl, halogen, oxo (=O), alkyl, alkoxy, haloalkyl, and haloalkoxy;

R2 and R3, independently, are selected from hydrogen, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl and optionally substituted heteroaryl; wherein the optional substituent, at each occurrence, is one or more of the groups selected from hydroxyl, halogen, oxo (=O), alkyl, alkoxy, haloalkyl, and haloalkoxy;

R4 is selected from hydrogen, halogen, hydroxyl, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl and optionally substituted heteroaryl; wherein the optional substituent, at each occurrence, is one or more of the groups selected from hydroxyl, halogen, oxo (=O), alkyl, alkoxy, haloalkyl, and haloalkoxy; or

R3 and R4 together form a cyclic ring, wherein the cyclic ring, at each occurrence, is optionally substituted with one or more groups selected from hydroxyl, oxo (=O), alkyl, alkoxy, haloalkyl, and haloalkoxy;

X is -NR5, oxygen, or sulfur; R5 is selected from hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, optionally substituted aralkenoyl, and optionally substituted aralkanoyl; wherein the optionally substituent, at each occurrence, is one or more of the groups selected from hydroxyl, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy and - N(R1a)R1b; R1a and R1b, independently, are selected from hydrogen, optionally substituted alkyl, alkylsulfonyl, arylsulfonyl and optionally substituted aryl; wherein the optional substituent, at each occurrence, is one or more of the groups selected from hydroxyl, halogen, alkyl, alkoxy, haloalkyl, and haloalkoxy; m is 1, 2, 3 or 4; and n is 1 or 2.

2. The compound as claimed in claim 1, wherein the compound is a compound of formula (IA): or a pharmaceutically acceptable salt or a stereoisomer thereof; wherein R1, R2, R3, R4, R5, m and n are same as defined in claim 1.

3. The compound as claimed in claim 1, wherein the compound is a compound of formula (IB): or a pharmaceutically acceptable salt or a stereoisomer thereof; wherein R1, R2, R3, R4, m and n are same as defined in claim 1.

4. The compound as claimed in claim 1 or claim 2, wherein R5 is hydrogen, optionally substituted alkyl, optionally substituted aryl and optionally substituted heteroaralkyl; wherein the optional substituent, at each occurrence, is one or more of the groups selected from hydroxyl, halogen, and -N(R1a)R1b where R1a and R1b are same as defined in claim 1.

5. The compound as claimed in claim 4, wherein R1a and R1b, independently, are selected from hydrogen, alkyl, and alkylsulfonyl.

6. The compound as claimed in claim 1 or claim 2, wherein R5 is selected from hydrogen, methyl, phenyl and indolinylalkyl; wherein the phenyl, at each occurrence, is optionally substituted by one or more of the groups selected from hydroxyl, fluorine, chlorine, and -NH(SO2CH3).

7. The compound as claimed in claim 3, wherein R3 and R4 together form a cyclic ring A as shown in a compound of formula (K) below:

8. The compound as claimed in any of claims 1-7, wherein R1, at each occurrence, is independently selected from hydrogen, halogen, -N(R1a)R1b, alkyl and alkoxy, wherein R1a and R1b are same as defined in claim 1. 9. The compound as claimed in any of claims 1-8, wherein R1 is selected from hydrogen, fluorine, chlorine, -NH(SO2CH3), -CH3, and -OCH3.

10. The compound as claimed in any of claims 1-9, wherein each of R2, R3, and R4 is hydrogen.

11. The compound as claimed in any of claims 1-10, wherein m is 1 or 2.

12. The compound as claimed in any of claims 1-11, wherein n is 1.

13. The compound as claimed in claim 1, is selected from:

or a pharmaceutically acceptable salt or a stereoisomer thereof.

14. A pharmaceutical composition comprising a compound as claimed in any of claims 1-13, or a pharmaceutically acceptable salt or a stereoisomer thereof, and optionally, admixed with a pharmaceutically acceptable excipient. 15. Use of a compound as claimed in any of claims 1-13, or a pharmaceutically acceptable salt or a stereoisomer thereof, in the manufacture of a medicament for use in treating a subject of a condition, disease or disorder responsive to modulation of the 5- HT2C receptor.

16. A compound as claimed in any of claims 1-13, or a pharmaceutically acceptable salt or a stereoisomer thereof, for use in treating a condition, disease or disorder in a subject wherein modulation of 5-HT2c receptor(s) provides a benefit.

17. A method of treating a condition, disease or disorder in a subject wherein modulation of 5-HT2c receptor(s) provides a benefit, comprising administering a therapeutically effective amount of a compound as claimed in any of claims 1-13 to the subject in need thereof. 18. The method as claimed in claim 17, wherein the 5-HT2c receptor(s) are activated or stimulated.

19. The method as claimed in claim 17, wherein the condition, disease or disorder is obesity, addiction, anxiety, depression and obesity related comorbidities.

20. A method of treating or preventing obesity in a subject, comprising administering a therapeutically effective amount of a compound as claimed in any of claims 1-13 to the subject in need thereof.

21. A method of controlling food intake of a subject comprising administering a therapeutically effective amount of a compound as claimed in any of claims 1-13 to the subject in need thereof. 22. A method of controlling weight gain of a subject comprising administering a therapeutically effective amount of a compound as claimed in any of claims 1-13 to the subject in need thereof.

Description:
HETEROCYCLIC COMPOUNDS, AND THEIR USE AS ALLOSTERIC MODULATORS OF 5-HYDROXYTRYPTAMINE 2C RECEPTOR (5-HT2CR)

RELATED APPLICATION

This application claims the benefit of Indian provisional application number 201941032593, filed on August 12, 2019; the contents of which are hereby incorporated by reference in their entirety.

TECHNICAL FIELD

The disclosure generally relates to 5 -hydroxy tryptamine 2 receptor (5-HT 2 R) modulators, pharmaceutical compositions comprising the 5-HT 2 R modulators, and their uses.

BACKGROUND

5-HT 2 receptors (5-HT 2 R) family play critical role in large array of physiological and behavioral functions in humans and animals via three important and distinct subtypes: 5-HT 2A R, 5-HT 2B R, and 5-HT 2c R. The 5-HT 2c R is involved in a diversity of physiological functions, such as nociception, motor behavior, endocrine secretion, thermoregulation, appetite modulation, and the control of exchanges between the central nervous system and the cerebrospinal fluid. This receptor has also been implicated in numerous pathologies, and the modulation of 5-HT 2c R function holds a tremendous amount of therapeutic promise for the treatment of diseases such as addiction, anxiety, depression, and obesity/eating disorders.

Obesity being a global epidemic health problem has received considerable attention as a major public hazard. Obesity is a chronic pathological and costly disease of abnormal or excessive fat accumulation in the body. Various studies indicated that 5- HT 2C R activation would regulate appetite and food consumption, probably by promoting satiety. Given this appetite suppression by activation of 5-HT 2c , selective agents with high affinity for this receptor over 5-HT 2B and 5-HT 2A are being developed for the treatment of obesity. Allosteric modulators of 5-HT 2c R present a novel and attractive drug design strategy to augment the response to endogenous 5-HT and to achieve high receptor subtype selectivity and specificity with ligand binding to an allosteric site rather than to the orthosteric binding site that binds the endogenous agonist. It is therefore desirable to identify novel, positive agonist and allosteric modulators (PAAM) of the 5- HT 2C R with high potency, specificity, and drug like properties. So far Lorcaserin (Belviq) is the only agent that has been approved by the FDA and being marketed by Arena/ Esai. However, Lorcaserin cause only 5-10% of weight loss and moderate improvement of co- morbidity. Moreover, it is not a PAAM of 5-HT 2c R. The discovery and development of a small molecule that is PAAM of 5-HT 2c R may result in 15-25% weight loss and improvement in one or more co-morbid risk factors or complications at commensurate with the observed weight reduction. Thus, there is a need in the art for molecules that are PAAM, and/or react selectively with 5-HT 2 R subtypes, particularly selective 5-HT 2c R agonists, which exhibit no or minimal effect on 5-HT 2A R and/or 5-HT 2B R.

SUMMARY OF THE INVENTION

The present invention provides heterocyclic compounds including their analogues, derivatives, tautomers, prodrugs, stereoisomers, enantiomers, diastereomers, polymorphs, pharmaceutically acceptable salts, pharmaceutically acceptable hydrates, pharmaceutically acceptable solvates and bioisosteres.

In one aspect, the present invention provides a compound of formula (I): or a pharmaceutically acceptable salt or a stereoisomer thereof; wherein,

R 1 , at each occurrence, is independently selected from hydrogen, halogen, - N(R 1a )R 1b , optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl and optionally substituted heteroaryl; wherein the optional substituent, at each occurrence, is one or more of the groups selected from hydroxyl, halogen, oxo (=0), alkyl, alkoxy, haloalkyl, and haloalkoxy; R 2 and R 3 , independently, are selected from hydrogen, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl and optionally substituted heteroaryl; wherein the optional substituent, at each occurrence, is one or more of the groups selected from hydroxyl, halogen, oxo (=0), alkyl, alkoxy, haloalkyl, and haloalkoxy;

R 4 is selected from hydrogen, halogen, hydroxyl, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl and optionally substituted heteroaryl; wherein the optional substituent, at each occurrence, is one or more of the groups selected from hydroxyl, halogen, oxo (=0), alkyl, alkoxy, haloalkyl, and haloalkoxy; or

R 3 and R 4 together form a cyclic ring, wherein the cyclic ring, at each occurrence, is optionally substituted with one or more groups selected from hydroxyl, oxo (=0), alkyl, alkoxy, haloalkyl, and haloalkoxy;

X is -NR 5 , oxygen, or sulfur;

R 5 is selected from hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, optionally substituted aralkenoyl, and optionally substituted aralkanoyl; wherein the optionally substituent, at each occurrence, is one or more of the groups selected from hydroxyl, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy and - N(R 1a )R 1b ; R 1a and R 1b , independently, are selected from hydrogen, optionally substituted alkyl, alkylsulfonyl, arylsulfonyl and optionally substituted aryl; wherein the optional substituent, at each occurrence, is one or more of the groups selected from hydroxyl, halogen, alkyl, alkoxy, haloalkyl, and haloalkoxy; m is 1, 2, 3 or 4; and n is 1 or 2.

In another aspect, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or a stereoisomer thereof, and one or more pharmaceutically acceptable excipient. In another aspect, the present invention provides a method of treating or preventing obesity in a subject, comprising administering a therapeutically effective amount of a compound of formula (I) to the subject in need thereof.

In yet another aspect, the present invention provides a method of treating a disease or disorder in a subject wherein modulation of 5-HT 2c R provides a benefit, comprising administering a therapeutically effective amount of a compound of formula (I) to the subject in need thereof.

BRIEF DESCRIPTION OF ACCOMPANYING DRAWINGS

FIG. 1 illustrates 5-HT 2A , 5-HT 2B and 5-HT 2c agonism and 5-HT 2c PAAM activities of compound 9 of the present invention.

FIG. 2 illustrates mean concentration-time profile of Compound 1 after oral administration at a dose of 30 mg/kg to mice (a) brain and (b) plasma.

FIG. 3 illustrates acute food intake study in intracerebroventricular (icv) rats. DETAILED DESCRIPTION OF THE INVENTION

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art to which the invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, preferred methods and materials are described. For the purposes of the present invention, the following terms are defined below.

The articles "a" and "an" are used herein to refer to one or to more than one (i.e. to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element.

The term "alkyl" refers to a straight or branched chain saturated aliphatic hydrocarbon that may be substituted or unsubstituted. In certain embodiments, the alkyl is C 1 -C 6 alkyl. Examples of "alkyl" include but are not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl, isobutyl and the likes thereof.

The term “alkylsulfonyl” refers to a group -S(O 2 )-alkyl, where alkyl is as defined above. Examples of "alkylsulfonyl" include, but are not limited to, methylsulfonyl, ethylsufonyl, and propylsufonyl. The term "alkoxy" refers to a group -O-alkyl, wherein alkyl is as defined above. Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, t- butoxy and the likes thereof.

The term "alkynyl" refers to an unsaturated hydrocarbon group which is linear or branched and has at least one carbon-carbon triple bond. In certain embodiments, an alkynyl group has 2 to 20 carbon atoms and in other embodiments, has 2 to 6 carbon atoms. An alkynyl group having 2 to 6 carbon atoms may be referred to as a -(C 2 - C 6 )alkynyl group. The alkynyl group may contain 1 , 2 or 3 carbon-carbon triple bonds, or more. Preferably, alkynyl groups contain one or two triple bonds, most preferably one triple bond. In some instances, alkynyl moiety may be coupled to the remainder of the molecule through an alkyl linkage. Examples of alkynyl include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl or 3-butynyl, 2-pentynyl, 3- pentynyl, 2-hexynyl, 3-hexynyl and the like.

The term "aryl" refers to optionally substituted unsaturated or partially saturated aromatic ring system having five to ten carbon atoms which are monocyclic, bicyclic or polycyclic and may optionally be replaced by one or more hetero atoms selected from N, O and S. Exemplary aryl groups include phenyl, naphthyl, indanyl, biphenyl and the likes thereof.

The term "arylalkyl" refers to an alkyl group substituted by one or more aryl groups, wherein the alkyl and aryl are same as defined above. Non-limiting examples of the arylalkyl group include phenylmethyl, phenylethyl, and the like.

The term “arylsulfonyl” refers to a group -S(0 2 )-aryl, where aryl is as defined above. Examples of "arylsulfonyl" include, but are not limited to, phenylsulfonyl and tolylsulfonayl.

The term "bioisosteres" refers to compounds or groups that possess near molecular shapes and volumes, approximately the same distribution of electrons and which exhibit similar physical properties such as hydrophobicity. Bioisostereic compounds affect the same biochemically associated systems as agonist or antagonists and thereby produce biological properties that are related to each other. As used herein, the term 'compound(s)' comprises the compounds disclosed in the present invention.

As used herein, the term "comprises" or "comprising" is generally used in the sense of include, that is to say permitting the presence of one or more features or components.

As used herein, "compounds of the present invention" or "compound of the disclosure" refers to compounds of formula (I), (IA), and/or (IB) as herein defined, their derivatives, their analogs, their tautomeric forms, their stereoisomers, their bioisosters, their diastereomers, their polymorphs, their enantiomers, their appropriate N-oxides, their pharmaceutically acceptable salts, their pharmaceutically acceptable hydrates, their pharmaceutically acceptable solvates and pharmaceutically acceptable compositions containing them.

As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. By "pharmaceutically acceptable" it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

As used herein, the term "cycloalkyl" used herein, either alone or in combination with other radicals, denotes mono, bicyclic or polycyclic saturated, partially saturated hydrocarbon ring system of about 3 to 12 carbon atoms which may be substituted or unsubstituted. Exemplary "cycloalkyl" groups include but are not limited to cyclopopyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, perhydronapthyl, adamantyl, noradamantyl and spirobicyclic groups such as spiro (4,4)non-2-yl.

As used herein, the term "halogen" refers to fluorine, chlorine, bromine or iodine.

As used herein, the term "heteroaryl" refers to monocyclic aromatic ring systems or fused bicyclic aromatic ring systems comprising two or more aromatic rings, preferably two to three ring systems. These heteroaryl rings contain one or more nitrogen, sulfur and/or oxygen atoms where N-oxides sulfur oxides and dioxides are permissible heteroatom substitutions. The term includes ring(s) optionally substituted with halogens, nitro, amino, alkoxy, alkyl sulfonyl amino, alkylcarbonylamino, carboxy, alkyl carbonoyl, hydroxy, and alkyl. Examples of heteroaryl groups include furan, thiophene, pyrrole, imidazole, pyrazole, triazole, tetrazole, thiazole, oxazole, isoxazole, oxadiazole, thiadiazole, isothiazole, pyridine, pyridazine, pyrazine, pyrimidine, quinoline, isoquinoline, benzofuran, benzo thiophene, indole, indazole, chromanyl, isochromanyl and the likes thereof.

The term “heteroaralkyl” or “heteroarylalkyl” refers to an alkyl group substituted by one or more heteroaryl groups, wherein the alkyl and heteroaryl are same as defined above. Examples of heteroaralkyl include, but are not limited to, 4-methoxy-l-pyridin-3- ylmethyl, 2-pyridinylmethyl, 3-pyridinylmethyl, 4-pyridinylmethyl, 3-(2-pyridinyl)- propyl, and thienylmethyl, indolinylalkyl ( such as 2-indolinylmethyl, 2-(3- indolinyl)ethyl, l-(4-indolinyl)ethyl, 3-(5-indolinyl)propyl, 4-(6-indolinyl)butyl, 5-(7- indolinyl)pentyl, 6-(l-indolinyl)hexyl, 2-methyl-3-(3-indolinyl)propyl, 1 , 1 -dimethyl-2- (2-indolinyl)-ethyl, 3,3-dimethyl-5-indolinylmethyl, l,3,3-trimethyl-5-indolinylmethyl, 1- ethyl-3,3-dimethyl-5-indolinylmethyl, l-methyl-5-indolinymethyl, 1 ,3-dimethyl-5- indolinylmethyl, or the like).

The term "heterocyclyl" refers to a stable 3 to 15 membered ring that is either saturated or has one or more degrees of unsaturation or unsaturated. These heterocyclic rings contain one or more heteroatoms selected from the group consisting of nitrogen, sulfur and oxygen where N-oxides, sulfur oxides and dioxides are permissible heteroatom substitutions. Such a ring is optionally fused to one or more of another heterocyclic ring(s), aryl ring(s) or cycloalkyl ring(s). Examples of such groups are selected from the group consisting of azetidinyl, acridinyl, pyrazolyl, imidazolyl, triazolyl, pyrrolyl, thiophenyl, thiazolyl, oxazolyl, isoxazolyl, furanyl, pyrazinyl, tetrahydroisoquinolinyl, piperidinyl, piperazinyl, morpholinyl, thiomorphonilyl, pyridazinyl, indolyl, isoindolyl, quinolinyl, chromanyl and the likes thereof. "Heterocyclylalkyl" refers to a heterocyclic ring radical defined above, directly bonded to an alkyl group. The heterocyclylalkyl radical is attached to the main structure at carbon atom in the alkyl group that results in the creation of a stable structure. The term “heterocyclylalkyl” used herein refers to one or more heterocyclyl groups appended to an alkyl radical. Examples of heterocyclylalkyl include, but are not limited to, piperidinylmethyl, piperidinylethyl, morpholinylmethyl, morpholinylethyl, and the like.

As used herein, the term "hydroxyl" refers to -OH group.

The expression "obesity related comorbidities" includes arthritis, cardiovascular disease, certain types of cancer, dyslipidemia, gall bladder disease, hypertension, hyperuricemia, insulin resistance, metabolic syndrome, menstrual irregularities, sleep apnea and type 2 diabetes.

As used herein, the terms "optional" or "optionally" mean that the subsequently described event or circumstance may occur or may not occur, and that the description includes instances where the event or circumstance occurs as well as instances in which it does not. For example, "optionally substituted alkyl" refers to the alkyl may be substituted as well as the event or circumstance where the alkyl is not substituted.

As used herein, the term "oxo" refers to =0 group.

"Pharmaceutically acceptable" means that, which is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable and includes that which is acceptable for veterinary as well as human pharmaceutical use.

"Pharmaceutically acceptable salt" refers to the salts of the compounds, that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. Such salts include: salts derived from inorganic bases such as Li, Na, K, Ca, Mg, Fe, Cu, Zn, Al, Mn; salts of organic bases such as N,N'-diacetylethylenediamine, 2- dimethylaminoethanol, isopropylamine, morpholine, piperazine, piperidine, procaine, diethylamine, triethylamine, trimethylamine, tripropylamine, tromethamine, choline hydroxide, dicyclohexylamine, metformin, benzylamine, phenylethylamine, dialkylamine, trialkylamine, thiamine, aminopyrimidine, aminopyridine, purine, pyrimidine, spermidine, and the like; chiral bases like alkylphenylamine, glycinol, phenyl glycinol and the like, salts of natural amino acids such as glycine, alanine, valine, leucine, isoleucine, lysine, arginine, serine, threonine, phenylalanine; unnatural amino acids such as D-isomers or substituted amino acids; salts of acidic amino acids such as aspartic acid, glutamic acid; guanidine, substituted guanidine wherein the substituents are selected from nitro, amino, alkyl, alkenyl, alkynyl, ammonium or substituted ammonium salts. Salts may include acid addition salts where appropriate which are sulphates, nitrates, phosphates, perchlorates, borates, hydrohalides, acetates, tartrates, maleates, citrates, succinates, methanesulfonates, benzoates, salicylates, hydroxynaphthoates, benzenesulfonates, ascorbates and the likes thereof.

"Pharmaceutically acceptable solvates" may be hydrates or comprising other solvents of crystallization such as alcohols.

As used herein, the term "prevents", "preventing" and "prevention" refer to a method of preventing the onset of a disease and/or its attendant symptoms or barring a subject from acquiring a disease. As used herein, "prevent", "preventing" and "prevention" also include delaying the onset of a disease and/or its attendant symptoms and reducing a subject's risk of acquiring a disease.

The term "agonist" refers generally to a compound that interacts with and activates a receptor, such as one or more of the receptors of the 5-HT 2 family of receptors, and initiates a physiological or pharmacological response characteristic of that receptor.

The term "antagonist" refers generally to a compound that binds to the receptor at the same site as an agonist, but which does not activate the intracellular response initiated by the active form of the receptor, and as such an antagonist can inhibit the intracellular responses by agonists.

As used herein the term "selective 5-HT 2c R agonist" means an agonist compound that is selective for binding and activation of 5-HT 2c R compared to the other receptors of the 5-HT 2 family of receptors. An agonist of this invention can be selective for the 5- thcR receptor over the 5-HT 2B R, be selective for the 5-HT 2c R over the 5-HT 2A R or be selective for the 5-HT 2c R receptor over both the 5-HT 2A R and 5-HT 2B R. In some instances, a present 5-HT 2c R agonist can exhibit agonist activity with respect to the 5- HT 2A R. In further instances, a present 5-HT 2c R agonist can exhibit agonist activity with respect to the 5-HT 2B R. In certain embodiments, 5-HT 2c R agonists of this invention may exhibit selectivity over receptors of 5-HT families other than those of the 5 -HT2 family. The selectivity can be assessed by using any method known in the art, for example, by determining EC 50 ratios for different receptors. In some instances, selectivity can be determined using a receptor binding assay or a functional assay.

Unless otherwise specified, the term "substituted" as used herein refers to mono, bi, tri or tetra substitution with any one or more combination of the following substituents: hydroxy, halogen, carboxyl, cyano, nitro, oxo (=0), thio (=S), substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclylalkyl ring, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic ring, substituted or unsubstiuted guanidine, -COOR 6 , -C(O) R 6 , -C(S)R 6 , -C(O)N(R7)R 8 , -C(O)ON(R7)R 8 , -NR 6 CO(R 7 )R 8 , -N(R 6 )SOR 7 , -

N(R 6 )SO 2 R 7 , -(=N-N(R 7 )R 8 ), -NR 6 C(O)OR 7 , -NR7R 8 , -NR6C(O)R 7 , - NR 6 C(S)R 7 , - NR 6 C(S)NR7R 8 , -SONR7R 8 , -SO 2 NR7R 8 , -OR 6 , -OR 6 C(O)NR 7 R 8 , - OR 6 C(O)OR 7 , - OC(O)R 6 , -OC(O)NR 7 R 8 , -R 6 NR 7 C(O)R 8 , -R6OR 7 , -R 6 C(O)OR 7 , -R 6 C(O)NR 7 R 8 , - R 6 C(O)R 7 , -R 6 OC(O)R 7 , -SR 6 , -SOR 6 , -SO2R 6 , and -ONO2, wherein R 6 , R 7 and R 8 are independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted heterocyclylalkyl ring, substituted or unsubstituted heteroarylalkyl, or substituted or unsubstituted heterocyclic ring. Alternatively, R 7 and R 8 together with the nitrogen they are attached with, form a 4 to 8 membered ring which can be substituted or unsubstituted. According to one embodiment, the substituents in the aforementioned "substituted" groups cannot be further substituted. For example, when the substituent on "substituted alkyl" is "substituted aryl" the substituent on "substituted aryl" cannot be "substituted alkenyl".

The term "stereoisomer" or "stereoisomers" refers to any enantiomers, diastereomers or geometrical isomers of the compounds of formula (I), (IA), or (IB), wherever they are chiral or when they bear one or more double bond. When the compounds of the formula (I) and related formulae are chiral, they can exist in racemic or in optically active form. It should be understood that the invention encompasses all stereochemical isomeric forms, including diastereomeric, enantiomeric and epimeric forms, as well as -isomers and /-isomers and mixtures thereof. Individual stereoisomers of compounds can be prepared synthetically from commercially available starting materials which contain chiral centers or by preparation of mixtures of enantiomeric products followed by separation such as conversion to a mixture of diastereomers followed by separation or recrystallization, chromatographic techniques, direct separation of enantiomers on chiral chromatographic columns, or any other appropriate method known in the art. Starting compounds of particular stereochemistry are either commercially available or can be made and resolved by techniques known in the art. Additionally, the compounds of the present invention may exist as geometric isomers. The present invention includes all cis, trans, syn, anti, entgegen (E) and zusammen (Z) isomers as well as the appropriate mixtures thereof.

The stereoisomers of the compounds forming part of this invention may be prepared by using reactants in their single enantiomeric form in the process wherever possible or by conducting the reaction in the presence of reagents or catalysts in their single enantiomer form or by resolving the mixture of stereoisomers by conventional methods. Some of the preferred methods include use of microbial resolution, resolving the diastereomeric salts formed with chiral acids such as mandelic acid, camphorsulfonic acid, tartaric acid, lactic acid, and the like wherever applicable or chiral bases such as brucine, cinchona alkaloids and their derivatives and the like. Different polymorphs of a compound of formula (I), (IA), (IB) and/or (IC) of present invention may be prepared by crystallization of the corresponding compound of formula (I), (IA), (IB) and/or (IC) under different conditions. For example, making use of commonly used solvents or their mixtures for recrystallization, crystallization at different temperature ranges, different cooling techniques like very fast to very slow cooling during crystallization procedure, by exposing to room temp, by heating or melting the compound followed by gradual cooling and the like. The presence of polymorphs may be determined by one or more methods like solid probe NMR spectroscopy, DSC, TGA, Powder X-Ray diffraction and IR.

As used herein, the term "therapeutically effective amount" refers to that amount of the compound being administered sufficient to prevent development of or alleviate to some extent one or more of the symptoms of the condition or disorder being treated.

As used herein, the term "treat", "treating" and "treatment" refer to a method of alleviating or abrogating a disease and/or its attendant symptoms.

Each embodiment is provided by way of explanation of the invention and not by way of limitation of the invention. In fact, it will be apparent to those skilled in the art that various modifications and variations can be made to the compounds, compositions and methods described herein without departing from the scope or spirit of the invention. For instance, features illustrated or described as part of one embodiment can be applied to another embodiment to yield a still further embodiment. Thus, it is intended that the present invention includes such modifications and variations and their equivalents. Other objects, features and aspects of the present invention are disclosed in or are obvious from, the following detailed description. It is to be understood by one of ordinary skill in the art that the present discussion is a description of exemplary embodiments only and is not to be construed as limiting the broader aspects of the present invention.

In an embodiment, the present invention provides a compound of formula (I): or a pharmaceutically acceptable salt or a stereoisomer thereof; wherein, R 1 , at each occurrence, is independently selected from hydrogen, halogen, - N(R 1a )R 1b , optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl and optionally substituted heteroaryl; wherein the optional substituent, at each occurrence, is one or more of the groups selected from hydroxyl, halogen, oxo (=O), alkyl, alkoxy, haloalkyl, and haloalkoxy;

R 2 and R 3 , independently, are selected from hydrogen, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl and optionally substituted heteroaryl; wherein the optional substituent, at each occurrence, is one or more of the groups selected from hydroxyl, halogen, oxo (=O), alkyl, alkoxy, haloalkyl, and haloalkoxy;

R 4 is selected from hydrogen, halogen, hydroxyl, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl and optionally substituted heteroaryl; wherein the optional substituent, at each occurrence, is one or more of the groups selected from hydroxyl, halogen, oxo (=O), alkyl, alkoxy, haloalkyl, and haloalkoxy; or

R 3 and R 4 together form a cyclic ring, wherein the cyclic ring, at each occurrence, is optionally substituted with one or more groups selected from hydroxyl, oxo (=0), alkyl, alkoxy, haloalkyl, and haloalkoxy;

X is -NR 5 , oxygen, or sulfur;

R 5 is selected from hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, optionally substituted aralkenoyl, and optionally substituted aralkanoyl; wherein the optionally substituent, at each occurrence, is one or more of the groups selected from hydroxyl, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy and - N(R 1a )R 1b ; R 1a and R 1b , independently, are selected from hydrogen, optionally substituted alkyl, alkylsulfonyl, arylsulfonyl and optionally substituted aryl; wherein the optional substituent, at each occurrence, is one or more of the groups selected from hydroxyl, halogen, alkyl, alkoxy, haloalkyl, and haloalkoxy; m is 1, 2, 3 or 4; and n is 1 or 2.

In certain embodiments, the compound of formula (I) is a compound of formula

(IA): or a pharmaceutically acceptable salt or a stereoisomer thereof; wherein R 1 , R 2 , R 3 , R 4 , R 5 , m and n are same as defined in formula (I).

In certain embodiments, the compound of formula (I) is a compound of formula

(IB): or a pharmaceutically acceptable salt or a stereoisomer thereof; wherein R 1 , R 2 , R 3 , R 4 , m and n are same as defined in formula (I).

In certain embodiments, R 5 , in the compound of formula (I) and/or (IA), or a pharmaceutically acceptable salt or a stereoisomer thereof, is hydrogen, optionally substituted alkyl, optionally substituted aryl and optionally substituted heteroaralkyl; wherein the optional substituent, at each occurrence, is one or more of the groups selected from hydroxyl, halogen, or -N(R 1a )R 1b , where R 1a and R 1b are same as defined in formula (I). In some instances, R 1a and R 1b , independently, are selected from hydrogen, alkyl, and alkylsulfonyl. In certain embodiments, R 5 , in the compound of formula (I) and/or (IA), or a pharmaceutically acceptable salt or a stereoisomer thereof, is hydrogen, methyl, phenyl and indolinylalkyl (such as indolinylethyl); wherein the phenyl, at each occurrence, is optionally substituted by one or more of the groups selected from hydroxyl, fluorine, chlorine, and -NH(SO 2 CH 3 ).

In certain embodiments, R 3 and R 4 in the compound of formula (I), (IA) and/or (IB), or a pharmaceutically acceptable salt or a stereoisomer thereof, together form a cyclic ring A as shown in formula (K) below: wherein R 1 , m and n are same as defined in formula (I); and ring A is

In certain embodiments, R 1 , at each occurrence, in the compound of formula (I), (IA) and/or (IB), or a pharmaceutically acceptable salt or a stereoisomer thereof, is independently selected from hydrogen, halogen, -N(R 1a )R 1b , alkyl and alkoxy, wherein R 1a and R 1b are same as defined in formula (I) or as in the embodiments described above. In some instances, R 1 is selected from hydrogen, fluorine, chlorine, -NH(SO 2 CH 3 ), -CH 3 , and -OCH 3 .

In certain embodiments, each of R 2 , R 3 , and R 4 , in the compound of formula (I), (IA) and/or (IB), or a pharmaceutically acceptable salt or a stereoisomer thereof, is hydrogen.

In certain embodiments, m, in the compound of formula (I), (IA) and/or (IB), or a pharmaceutically acceptable salt or a stereoisomer thereof, 1 or 2. In some instances, m is 1. In further instances, m is 2.

In certain embodiments, n, in the compound of formula (I), (IA) and/or (IB), or a pharmaceutically acceptable salt or a stereoisomer thereof, is 1 or 2. In some instances, n is 1. In further instances, n is 2.

In certain embodiments of the compound of formula (IA) or a pharmaceutically acceptable salt or a stereoisomer thereof, R 1 , at each occurrence, is selected from hydrogen, halogen, and -N(R 1a )R 1b ; R 2 R 3 , and R 4 , independently, are hydrogen; R 5 is aryl optionally substituted with one or more halogen or -N(R 1a )R 1b ; and n is 1, where R 1a and R 1b , independently, are selected from hydrogen, and alkylsulfonyl.

In certain embodiments of the compound of formula (IB) or a pharmaceutically acceptable salt or a stereoisomer thereof, R 1 , at each occurrence, is hydrogen or halogen; R 2 is hydrogen; R 3 and R 4 together form a cyclic ring as shown formula (K) above; and n is 1.

In certain embodiments, the compounds of the present invention can also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the present invention also embraces isotopically-labeled variants of the present invention which are identical to those recited herein, but for the fact that one or more atoms of the compound are replaced by an atom having the atomic mass or mass number different from the predominant atomic mass or mass number usually found in nature for the atom. All isotopes of any particular atom or element as specified are contemplated within the scope of the compounds of the invention and their uses. Exemplary isotopes that can be incorporated in to compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, chlorine and iodine, such as 2 H ("D"), 3 H, n C, 13 C, 14 C, 13 N, 15 N, 15 0, 17 0, 18 0, 35 S, 18 F, 36 C1, 123 I and 125 I. Isotopically labeled compounds of the present inventions can generally be prepared by following procedures analogous to those disclosed in the schemes and/or in the examples herein below, by substituting an isotopically labeled reagent for a non- isotopically labeled reagent.

In certain embodiments, the present invention provides a compound selected from: or a pharmaceutically acceptable salt or a stereoisomer thereof.

In certain embodiments, the present invention provides a pharmaceutical composition comprising a compound of formula (I), (IA), and/or (IB) or a pharmaceutically acceptable salt or a stereoisomer thereof, optionally admixed with a pharmaceutically acceptable excipient or carrier or diluent.

The present invention also provides methods for formulating the disclosed compounds for pharmaceutical administration.

The compositions and methods of the present invention may be utilized to treat a subject in need thereof. In certain embodiments, the subject is a mammal such as a human or a non-human mammal. When administered to an animal, such as a human, the composition or the compound is preferably administered as a pharmaceutical composition comprising, for example, a compound of the invention and a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers are well known in the art and include, for example, aqueous solutions such as water or physiologically buffered saline or other solvents or vehicles such as glycols, glycerol and oils such as olive oil or injectable organic esters. In a preferred embodiment, when such pharmaceutical compositions are for human administration, particularly for invasive routes of administration (i.e., routes, such as injection or implantation, that circumvent transport or diffusion through an epithelial barrier), the aqueous solution is pyrogen-free or substantially pyrogen-free. The excipients can be chosen, for example, to effect delayed release of an agent or to selectively target one or more cells, tissues or organs. The pharmaceutical composition can be in dosage unit form such as tablet, capsule (including sprinkle capsule and gelatin capsule), granule, and lyophile for reconstitution, powder, solution, syrup, suppository, injection or the like. The composition can also be present in a transdermal delivery system, e.g., a skin patch. The composition can also be present in a solution suitable for topical administration, such as an eye drop.

A pharmaceutically acceptable carrier can contain physiologically acceptable agents that act, for example, to stabilize, increase solubility or to increase the absorption of a compound such as a compound of the invention. Such physiologically acceptable agents include, for example, carbohydrates, such as glucose, sucrose or dextrans, antioxidants, such as ascorbic acid or glutathione, chelating agents, low molecular weight proteins or other stabilizers or excipients. The choice of a pharmaceutically acceptable carrier, including a physiologically acceptable agent, depends, for example, on the route of administration of the composition. The preparation of pharmaceutical composition can be a self-emulsifying drug delivery system or a self-microemulsifying drug delivery system. The pharmaceutical composition (preparation) also can be a liposome or other polymer matrix, which can have incorporated therein, for example, a compound of the invention. Liposomes, for example, which comprise phospholipids or other lipids, are nontoxic, physiologically acceptable and metabolizable carriers that are relatively simple to make and administer.

The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problem or complication, commensurate with a reasonable benefit/risk ratio.

The phrase "pharmaceutically acceptable carrier" as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials which can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances employed in pharmaceutical formulations.

A pharmaceutical composition (preparation) can be administered to a subject by any of a number of routes of administration including, for example orally (for example, drenches as in aqueous or non-aqueous solutions or suspensions, tablets, capsules (including sprinkle capsules and gelatin capsules), boluses, powders, granules, pastes for application to the tongue); absorption through the oral mucosa (e.g., sublingually); anally, rectally or vaginally (for example, as a pessary, cream or foam); parenterally (including intramuscularly, intravenously, subcutaneously or intrathecally as, for example, a sterile solution or suspension); nasally; intraperitoneally; subcutaneously; transdermally (for example as a patch applied to the skin); and topically (for example, as a cream, ointment or spray applied to the skin or as an eye drop). The compound may also be formulated for inhalation. In yet another embodiment, a compound may be simply dissolved or suspended in sterile water.

The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, the particular mode of administration. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. Generally, out of one hundred percent, this amount will range from about 1 percent to about ninety-nine percent of active ingredient, preferably from about 5 percent to about 70 percent, most preferably from about 10 percent to about 30 percent.

Methods of preparing these formulations or compositions include the step of bringing into association an active compound, such as a compound of the invention, with the carrier and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product.

Formulations of the invention suitable for oral administration may be in the form of capsules (including sprinkle capsules and gelatin capsules), cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), lyophile, powders, granules or as a solution or a suspension in an aqueous or non-aqueous liquid or as an oil-in-water or water-in-oil liquid emulsion or as an elixir or syrup or as pastilles (using an inert base, such as gelatin and glycerin or sucrose and acacia) and/or as mouth washes and the like, each containing a predetermined amount of a compound of the present invention as an active ingredient. Compositions or compounds may also be administered as a bolus, electuary or paste.

To prepare solid dosage forms for oral administration (capsules (including sprinkle capsules and gelatin capsules), tablets, pills, dragees, powders, granules and the like), the active ingredient is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example, cetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such a talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate and mixtures thereof; (10) complexing agents, such as, modified and unmodified cyclodextrins; and (11) coloring agents. In the case of capsules (including sprinkle capsules and gelatin capsules), tablets and pills, the pharmaceutical compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.

A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

The tablets and other solid dosage forms of the pharmaceutical compositions, such as dragees, capsules (including sprinkle capsules and gelatin capsules), pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres. They may be sterilized by, for example, filtration through a bacteria- retaining filter or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved in sterile water or some other sterile injectable medium immediately before use. These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. The active ingredient can also be in microencapsulated form, if appropriate, with one or more of the above-described excipients.

Liquid dosage forms useful for oral administration include pharmaceutically acceptable emulsions, lyophiles for reconstitution, microemulsions, suspensions, solutions, syrups and elixirs. In addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, cyclodextrins and derivatives thereof, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan and mixtures thereof.

Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.

Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth and mixtures thereof.

Formulations of the pharmaceutical compositions for rectal, vaginal or urethral administration may be presented as a suppository, which may be prepared by mixing one or more active compounds with one or more suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active compound. Formulations of the pharmaceutical compositions for administration to the mouth may be presented as a mouthwash or an oral spray or an oral ointment.

Alternatively, or additionally, compositions can be formulated for delivery via a catheter, stent, wire or other intraluminal device. Delivery via such devices may be especially useful for delivery to the bladder, urethra, ureter, rectum or intestine.

Formulations which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be appropriate.

Dosage forms for the topical or transdermal administration include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier and with any preservatives, buffers or propellants that may be required.

The ointments, pastes, creams and gels may contain, in addition to an active compound, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide or mixtures thereof.

Powders and sprays can contain, in addition to an active compound, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder or mixtures of these substances. Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

Transdermal patches have the added advantage of providing controlled delivery of a compound of the present invention to the body. Such dosage forms can be made by dissolving or dispersing the active compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate of such flux can be controlled by either providing a rate controlling membrane or dispersing the compound in a polymer matrix or gel.

Ophthalmic formulations, eye ointments, powders, solutions and the like, are also contemplated as being within the scope of this invention. If desired, liquid ophthalmic formulations have properties similar to that of lacrimal fluids, aqueous humor or vitreous humor or are compatable with such fluids. A preferred route of administration is local administration (e.g., topical administration, such as eye drops or administration via an implant).

The phrases "parenteral administration" and "administered parenterally" as used herein means modes of administration other than enteral and topical administration, usually by injection and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion.

Pharmaceutical compositions suitable for parenteral administration comprise one or more active compounds in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.

Examples of suitable aqueous and nonaqueous carriers that may be employed in the pharmaceutical compositions of the invention include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol and the like) and suitable mixtures thereof, vegetable oils, such as olive oil and injectable organic esters, such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants.

These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents that delay absorption such as aluminium monostearate and gelatin.

In some cases, in order to prolong the effect of a drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material having poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution, which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.

Injectable depot forms are made by forming microencapsulated matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissue.

For use in the methods of this invention, active compounds can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably, 0.5 to 90%) of active ingredient in combination with a pharmaceutically acceptable carrier.

Methods of introduction may also be provided by rechargeable or biodegradable devices. Various slow release polymeric devices have been developed and tested in vivo in recent years for the controlled delivery of drugs, including proteinaceous biopharmaceuticals. A variety of biocompatible polymers (including hydrogels), including both biodegradable and non-degradable polymers, can be used to form an implant for the sustained release of a compound at a particular target site.

Actual dosage levels of the active ingredients in the pharmaceutical compositions may be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition and mode of administration, without being toxic to the patient. The selected dosage level will depend upon a variety of factors including the activity of the particular compound or combination of compounds employed or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion of the particular compound(s) being employed, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compound(s) employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated and like factors well known in the medical arts.

A physician or veterinarian having ordinary skill in the art can readily determine and prescribe the therapeutically effective amount of the pharmaceutical composition required. For example, the physician or veterinarian could start doses of the pharmaceutical composition or compound at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved. By "therapeutically effective amount" is meant the concentration of a compound that is sufficient to elicit the desired therapeutic effect. It is generally understood that the effective amount of the compound will vary according to the weight, sex, age and medical history of the subject. Other factors which influence the effective amount may include, but are not limited to, the severity of the patient's condition, the disorder being treated, the stability of the compound and, if desired, another type of therapeutic agent being administered with the compound of the invention. A larger total dose can be delivered by multiple administrations of the agent. Methods to determine efficacy and dosage are known to those skilled in the art (Isselbacher et al. (1996) Harrison's Principles of Internal Medicine 13 ed., 1814-1882, herein incorporated by reference).

In general, a suitable daily dose of an active compound used in the compositions and methods of the invention will be that amount of the compound that is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above.

If desired, the effective daily dose of the active compound may be administered as one, two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms. In yet another embodiment of the present invention, the active compound may be administered two or three times daily. In preferred embodiments, the active compound will be administered once daily.

The patient receiving this treatment is any animal in need, including primates, in particular humans and other mammals such as equines, cattle, swine and sheep; and poultry and pets in general.

Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, coating agents, release agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.

Examples of pharmaceutically acceptable antioxidants include: (1) water-soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol and the like; and (3) metal-chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid and the like.

In certain embodiments, the compounds of the present invention can be formulated and administered in a prodrug form. In general, prodrugs comprise functional derivatives of the claimed compounds, which are capable of being enzymatically activated or converted into the more active parent form. Thus, in the treatment methods of the present invention, the term "administering" encompasses the treatment of the various disorders described with the compound specifically disclosed or with a compound which may not be specifically disclosed, but which converts to the specified compound in vivo after administration to the patient. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in Wihnan, 14 Biochem. Soc. Trans. 375-82 (1986); Stella et al, Prodrugs: A Chemical Approach to Targeted Drug Delivery in Directed Drug Delivery 247-67 (1985).

The present disclosure further provides use of a compound of the present invention for the manufacture of a medicament. In some instances, the disclosure provides use of a compound of the present invention, or a pharmaceutically acceptable salt or a stereoisomer thereof, in the manufacture of a medicament for use in treating a subject of a condition, disease or disorder responsive to modulation of the 5- HT 2C receptor. In certain embodiments, the condition, disease or disorder is selected from a group comprising obesity, addiction, anxiety, depression, obesity related comorbidities. In a further embodiment, the condition, disease or disorder is obesity.

The compounds of the present invention modulate receptors of the 5-HT 2 family of receptors, and particularly 5-HT 2c R. In certain embodiments, the compounds of the present invention selectively modulate the 5-HT 2c R, while exhibiting significantly no or minimal effect on 5-HT 2A R. In some embodiments, the compounds of the present invention selectively modulate the 5-HT 2c R, while exhibiting significantly no or minimal effect on 5-HT 2B R. In certain embodiments, the compounds of the present invention are positive agonist and allosteric modulators (PAAM) of the 5-HT 2c R.

In certain embodiments, the present invention provides a method of treating a condition, disease or disorder in a subject, wherein modulation of 5-HT 2c R provides a benefit, comprising administering a therapeutically effective amount of a compound of formula (I), (IA) and/or (IB) or a pharmaceutically acceptable salt or a stereoisomer thereof, to the subject in need thereof. In some embodiments, the disease or disorder is selected from a group comprising obesity, addiction, anxiety, depression and obesity related comorbidities.

In some embodiments, the present invention provides a method of treating or preventing obesity in a subject, comprising administering a therapeutically effective amount of a compound of formula (I), (IA) and/or (IB) or a pharmaceutically acceptable salt or a stereoisomer thereof to the subject in need thereof.

In further embodiments, the present invention provides a method of controlling food intake of a subject comprising administering a therapeutically effective amount of a compound of formula (I), (IA) and/or (IB) or a pharmaceutically acceptable salt or a stereoisomer thereof to the subject in need thereof. In some instances, the “method of controlling food intake” refers to “method of decreasing food intake”. In yet further embodiments, the present invention provides a method of controlling weight gain of a subject comprising administering a therapeutically effective amount of a compound of formula (I), (IA) and/or (IB) or a pharmaceutically acceptable salt or a stereoisomer thereof to the subject in need thereof.

The present invention also discloses a method for modulating a 5-HT 2c R receptor in vivo or in vitro comprising contacting the receptor with one or more compounds of formula (I), (IA) and/or (IB) or a or a pharmaceutically acceptable salt or a stereoisomer thereof. In certain embodiments, the method stimulates or activates the 5-HT 2c R.

The compounds of the present invention may be used as single drugs (monotherapy) or conjointly with one or more other agents (conjoint therapy). The compounds may be used by themselves or, preferably, in a pharmaceutical composition in which the compound is mixed with one or more pharmaceutically acceptable materials. The dosage of the compounds of the present invention varies depending on a patient's age, weight or symptoms, as well as the compound's potency or therapeutic efficacy, the dosing regimen and/or treatment time. Generally, suitable routes of administration may, for example, include oral, eyedrop, rectal, transmucosal, topical or intestinal administration; parenteral delivery, including intramuscular, subcutaneous, intramedullary injections, as well as intrathecal, direct intraventricular, intravenous, intraperitoneal, intranasal or intraocular injections. The compounds of the invention may be administered in an amount of 0.5 mg or 1 mg up to 500 mg, 1 g or 2 g per dosage regimen. The dosage may be administered once per week, once per three days, once per two days, once per day, twice per day, three times per day or more often. In alternative embodiments, in certain adults the compound can be continuously administered by intravenous administration for a period of time designated by a physician. Since the dosage is affected by various conditions, an amount less than or greater than the dosage ranges contemplated about may be implemented in certain cases. A physician can readily determine the appropriate dosage for a patient undergoing therapeutic treatment.

The compounds of the present invention may be administered in combination with one or more other drugs (1) to complement and/or enhance effect of the compound of the present invention, (2) to modulate pharmacodynamics, improve absorption or reduce dosage of the compound of the present invention and/or (3) to reduce or ameliorate the side effects of the compound of the present invention. As used herein, the phrase "conjoint administration" refers to any form of administration of two or more different therapeutic compounds such that the second compound is administered while the previously administered therapeutic compound is still effective in the body (e.g., the two compounds are simultaneously effective in the patient, which may include synergistic effects of the two compounds). For example, the different therapeutic compounds can be administered either in the same formulation or in a 24-separate formulation, either concomitantly or sequentially. In yet another embodiment, the different therapeutic compounds can be administered within one hour, 12 h, 24 h, 36 h, 48 h, 72 h or a week of one another. Thus, an individual who receives such treatment can benefit from a combined effect of different therapeutic compounds. The respective compounds may be administered by the same or different route and the same or different method.

The dosage of the other drug can be a dosage that has been clinically used or may be a reduced dosage that is effective when administered in combination with a compound of the present invention. The ratio of the compound of the present invention and the other drug can vary according to age and weight of a subject to be administered, administration method, administration time, disorder to be treated, symptom and combination thereof. For example, the other drug may be used in an amount of 0.01 to 100 parts by mass, based on 1 part by mass of the compound of the present invention.

In certain embodiments, different compounds of the invention may be conjointly administered with one or more other compounds of the invention. Moreover, such combinations may be conjointly administered with other therapeutic agents, such as other agents suitable for the treatment of diseases and/or disorders described herein.

The present invention also provides a process for the preparation of the compounds of formula (I) are set forth in the below Examples and generalized Scheme. One of skill in the art will recognize that scheme can be adapted to produce the compounds of general formula (I) and pharmaceutically acceptable salts or stereo isomers of compounds of general formula (I) according to the present invention.

The schemes are given for the purpose of illustrating the invention and are not intended to limit the scope or spirit of the invention. Starting materials shown in the schemes can be obtained from commercial sources or prepared based on procedures described in the literature. Furthermore, in the following schemes, where specific acids, bases, reagents, coupling agents, solvents, etc. are mentioned, it is understood that other suitable acids, bases, reagents, coupling agents etc. may be used and are included within the scope of the present invention. Modifications to reaction conditions, for example, temperature, duration of the reaction or combinations thereof, are envisioned as part of the present invention. All possible stereoisomers are envisioned within the scope of this invention.

The intermediates required for the synthesis are commercially available or alternatively, these intermediates can be prepared using known literature methods. The invention is described in greater detail by way of specific examples.

It is contemplated that some of the intermediates disclosed in the present invention are used for the next step without any characterization data.

It is meant to be understood that the order of the steps in the processes may be varied, that reagents, solvents and reaction conditions may be substituted for those specifically mentioned, and that vulnerable moieties may be protected and deprotected, as necessary. The variables “X”, R 1 , R 2 , R 3 , R 4 , R 5 , m and n independently represent all the possible substitutions as disclosed in compound of formula (I).

General Synthetic Scheme(s):

The compounds of formula (I) are prepared by reacting a compound of formula (II) with the compound of formula (III) in the absence or presence of a suitable palladium catalyst selected from PdC1 2 , (PPh 3 ) 2 PdC1 2 , Pd(OAc) 2 , (PPh 3 ) 4 Pd, Pd/C and the likes thereof, and a copper catalyst selected from CuC1, CuBr, Cul and the likes thereof and a base selected from NaHCO 3 , K 2 CO 3 , Na 2 CO 3 , Cs 2 CO 3 , Et 3 N, DIPEA, DBU and the likes thereof, in a solvent selected from benzene, toluene, xylene, THF, 1,4-dioxane, diethyl ether, diphenyl ether, dichlorome thane, acetonitrile, chloroform, 1 ,2-dichloroethane, methanol, ethanol, n-butanol, iso-propanol, polyethylene glycol, dimethylformamide, dimethylsulfoxide and the likes thereof.

EXAMPLES

The following examples are given by way of illustration of the working of the invention in actual practice and therefore should not be construed to limit the scope of present invention.

General method(s): Unless stated otherwise, reactions were performed under nitrogen atmosphere using oven dried glassware. Reactions were monitored by thin layer chromatography (TLC) on silica gel plates (60 F254), visualizing with ultraviolet light or iodine spray. Flash chromatography was performed on silica gel (230-400 mesh) using distilled hexane, ethyl acetate. 1 H NMR and 13 C NMR spectra were recorded in DMSO- de solution by using 400 and 100 MHz spectrometers, respectively. Proton chemical shifts (d) are relative to tetramethylsilane (TMS, d 0.00) as internal standard and expressed in ppm. Spin multiplicities are given as s (singlet), d (doublet), dd (doublet of doublet), t (triplet) and m (multiplet) as well as b (broad). Coupling constants ( J) were given in hertz. MS spectra were obtained on a Agilent 6430 series Triple Quard LC-MS / MS spectrometer. Melting points (mp) were measured by using Buchi B-540 melting point apparatus and are uncorrected. Chromatographic purity by HPLC (Agilent 1200 series Chem Station software) was determined by using area normalization method and the condition specified in each case: column, mobile phase (range used), flow rate, detection wavelength, and retention times.

Preparation of compounds of formula (I)

EXAMPLE 1:

A mixture of compound of formula (II) (1.0 equiv), compound of formula (III) (1.5 equiv), copper acetate (0.5 equiv) and Cs 2 CO 3 (2.0 equiv) in dry acetonitrile (5 mL) was stirred at 80 °C for 1-1.5 h under nitrogen atmosphere. After completion of the reaction (monitored by TLC), the mixture was poured into water (15 mL), and then extracted with ethyl acetate (3 x 15 mL). The organic layers were collected, combined, dried over anhydrous Na 2 SO 4 , filtered and concentrated under vacuum. The residue obtained was purified by column chromatography using ethyl acetate/hexene to give the compound of formula (I).

The compounds appearing in the following Table 1 were prepared by analogy to the procedure described above. The requisite starting materials (e.g., compound of formula (II), compound of formula (III) were described herein. The starting materials were commercially available, known in the literature or can be readily synthesized by one skilled in the art. The characterization data of the compounds was summarized herein the Table 2.

Table 1

Table 2

Some of the compounds of formula (I) (such as formula (IB)) are prepared by using a procedure described in Example 2 below. The reactions are performed using a standard ultrasonic bath instrument (SONOREX SUPER RK 510H model) producing irradiation of 35 KHz. Reactions were monitored by thin layer chromatography (TLC) on silica gel plates (60 F254), visualized with ultraviolet light or iodine spray. Flash chromatography was performed on silica gel (230-400 mesh) using distilled hexane, ethyl acetate, dichloromethane. 1 H and 13 C NMR spectra were determined in CDCI3 solution by using 400 and 100 MHz spectrometers, respectively. Proton chemical shifts (d) are relative to tetramethylsilane (TMS, d = 0.00) as internal standard and expressed in ppm. Spin multiplicities are given as s (singlet), d (doublet), t (triplet), q (quartet) and m (multiplet) as well as bm (broad multiplet). Coupling constants ( J) are given in hertz. Melting points were determined using melting point apparatus and are uncorrected. MS spectra were obtained on a mass spectrometer (Agilent 6430 Triple Quadrupole LC/MS). Chromatographic purity by HPLC (Agilent 1200 series Chem Station software) was determined by using area normalization method and the condition specified in each case: column, mobile phase (range used), flow rate, detection wavelength, and retention times.

Example 2: 3-((3S,3aS,9aS,9bS)-3-hydroxy-3a,6-dimethyl-7-oxo- 2,3,3a,4,5,7,8,9,9a,9b-decahydro-1H-cyclopenta[a]naphthalen- 3-yl)-1H-isochromen- 1-one (Compound-12) A mixture of 2-iodobenzoic acid (1.2 mmol), terminal alkyne (1.0 mmol), K 2 CO 3 (2.0 mmol) and Cul (20 mo1%) in polyethylene glycol (PEG-400, 5.0 ml) was sonicated at room temperature for 3 h under nitrogen atmosphere. The progress of the reaction was monitored by TLC. After completion of the reaction, the mixture was diluted with EtOAc (10 ml) passed through celite bed. The filtrate was collected, washed with water (20 ml), and then extracted into EtOAc. All organic layers were collected, combined and dried over anhydrous Na 2 S0 4 . Then filtered and concentrated under low vacuum. The residue obtained was purified by column chromatography using silica gel (230-400 mesh) as a stationary phase and distilled 5% ethyl acetate/hexane as a mobile phase to give the desired product.

White solid; Yield: 60%; mp 106-108 °C; R f (30% EtOAc/Hexane) 0.15; 1 H NMR (400 MHz, CDC1 3 ): d 8.27 (d, J = 8.0 Hz, 1H), 7.76-7.71 (m, 1H), 7.54-7.50 (m, 1H), 7.46 (d,J = 7.6 Hz, 1H), 6.45 (s, 1H), 2.83 (s, 1H), 2.72 (dd, J = 17.0, 4.6 Hz, 1H), 2.53-2.47 (m, 1H), 2.43-2.36 (m, 2H), 2.33-2.21 (m, 3H), 2.09-2.03 (m, 1H), 1.94-1.82 (m, 2H), 1.70 (s, 3H), 1.64-1.60 (m, 2H), 1.16 (s, 3H), 1.02-0.94 (m, 1H), 0.90-0.85(m, 1H); 13 C NMR (100 MHz, CDCE): d 198.7, 161.5, 159.1, 157.2, 136.5, 135.0, 130.3, 129.5, 128.4, 126.0, 119.9, 103.7, 84.4, 49.6, 47.4, 39.6, 37.0, 35.0, 32.6, 27.2, 27.0, 23.8, 13.6, 11.0; MS (ES mass): m/z 379.2 (M+l); HPLC: 96.23 %; column: Symmetry C-18 75*4.6 mm 3.5mm, mobile phase A: 0.1% HCOOH in water, mobile phase B: CH3CN (gradient) T/B%: 0/50, 0.5/50, 4/95, 10/95, 10.5/50, 12/50; flow rate: 1.0 mL/min; Diluent: ACN: WATER (80:20) UV 230 nm, retention time 2.5 min.

The compounds listed in the Table 3 below were prepared by a procedure similar to the one described in Example-2 with appropriate variations in reactants, quantities of reagents, and reaction conditions. The requisite starting materials were described herein. The starting materials were commercially available, known in the literature or can be readily synthesized by one skilled in the art. The characterization data of the compounds were summarized herein the Table 4.

Note: All the reactions were carried out using alkyne 1 (1.0 mmol), 2 (1.2 mmol), Cul (20 mole %) and K 2 CO 3 (2 mmol) under ultrasound irradiation (35 KHz) at room temperature.

Table 4

Pharmacological assay

In vitro screening and assay systems

NFAT-RE Assay based screening on 5-HT2A, 5-HT2B and 5-HT2C, and 5-HT2C PAAM:

For 5-HT 2 family, NFAT-RE assay was used. In the assay, HEK 293T cells were transiently transfected with 5-HT 2A, 5-HT 2B and 5-HT 2c plasmid, and NFAT-RE plasmid in 96 well plate. 16-18 hours post transfection, Lorcaserin and test compounds were added at a concentration of 10 mM, 1 mM, 100 nM, 10 nM, 1 nM, 0.1 nM and 0.01 nM in triplicates for 5-6 hours. After incubation of compounds for 5-6 hours, the media of the plates was discarded and BrightGlo substrate solution (1 mg/ml, final concentration) was added and luminescence was measured immediately using multi-mode plate reader (BMG, Labtech). The relative luminescence units (RLU) values obtained from reading were analyzed using Prism, Graph pad (Version V). The compounds were further profiled for PAAM assay for 5-HT 2c in presence of 10 mM of serotonin following the same protocol. The results are summarized in Table 5. The 5-HT 2A , 5-HT 2B and 5-HT 2c agonism and 5-HT 2c PAAM activity of Compound 9 is shown in FIG. 1.

Table 5

In vivo Assay:

Brain and systemic PK

To determine the oral and intravenous pharmacokinetic profile and parameters of 5-HT 2c PAAM, the FDA bioanalytical guidelines for bioanalytical method validation were implemented. In brief, the test molecule was administered orally and intravenously at a single dose to Sprague Dawley rats. Blood samples were collected at different time intervals. Plasma was separated by centrifugation at 2000xg for 5 min at 4 °C. On completion of study animals were euthanized as per IAEC guidelines. All the samples were stored at -80 °C and analysis was done using validated bioanalytical method. The pharmacokinetic parameters were estimated using WinNonlin software through non- compartment modeling. Different parameters viz. Cmax (pg/mL)- maximum plasma concentration; t max (h)- time to reach C max ; (mg h/mL)-area under concentration versus time curve extrapolated to infinity; and t ½ (h)- elimination half-life were calculated. The results are summarized in Table 6, Table 7 and FIG. 2. Table 6: Pharmacokinetic parameters of Compound 1 following oral administration

(30mg/kg) to mice (n=4)

Each value represents the mean ± SEM. AUC 0-t : Area under the plasma concentration time curve up to last sampling time; Cl/F: Clearance; C max : Plasma peak concentration; t ½ · Terminal half-life; t max : Time to Cmax; Vz/F: Volume of distribution.

Table 7: Brain to Plasma Ratio of Compound 1 following oral administration (30mg/kg) to mice (n=4)

*Each value represents the mean ± SEM Stability in liver microsomes

To know the metabolic stability, the compound was incubated in 50 mM potassium phosphate buffer, pH 7.4 with rat liver microsomes in presence or absence of cofactors. The final incubation mixture in presence of cofactors was containing 5 mM of the test compound, 0.25 mg/mL of rat liver microsomes, ImM NADP+, 5 mM Glucose-6- phosphate, 2 mM magnesium chloride and 0.6 IU/mL of enzyme glucose-6-phospahte dehydrogenase. The reaction was initiated by addition of the compound to the pre warmed mixture and incubated at 37°C with brief agitation. Samples were withdrawn at a time interval of 0, 15, 30, 60 and 120 minutes, and added with twice the volume of cold acetonitrile, mixed thoroughly and centrifuged to collect the supernatant. The samples were analyzed using LCMS/MS and the obtained peak areas were compared with that of zero-minute sample to calculate % of compound remaining. The time vs % compound remaining linear regression curve was plotted to know the elimination rate constant ‘k’ (slope). The slope was used to calculate the half-life and in vitro metabolic clearance of the compound. The results are summarized in Tables 8-12.

Table 8: Metabolic stability of Compound 1 and Compound 9 in Rat liver

Microsomes -With Cofactors Table 9: Half-life (t 1/2 , min) and Intrinsic clearance (CL int , mL/min/mg) in Rat Liver

Microsomes Table 10: Metabolic Stability of Compound 1 and Compound 9 in Rat Liver

Microsomes - Without Cofactors

Table 11

Comparative Data: Metabolic Stability of Compound 7 and Compound 8 in Rat

Liver Microsomes - With Cofactors Table 12: Metabolic Stability of Compound 7 and Compound 8 in Rat Liver microsomes - Without Cofactors

Stability in brain homogenate A 20% (w/v) mice brain homogenate was prepared in normal saline. For incubations in presence of protease inhibitor, each mL of brain homogenate was added with 10 mL of 100 X EDTA free protease inhibitor cocktail prepared in phosphate buffer, pH 7.0. The DMSO stock of the compound was spiked into brain homogenate in presence or absence of protease inhibitor to obtain the final concentration of 10 mM and incubated at 37°C with brief agitation. Samples were withdrawn at a time interval of 0, 15, 30, 60 and 120 minutes, and added with twice the volume of cold acetonitrile, mixed thoroughly and centrifuged to collect the supernatant. The samples were analyzed using LCMS/MS, the peak areas were compared to 0 minute to know the stability of test compound. The results are summarized in Table 13.

Table 13: Stability of Compound 1 and in Mice Brain homogenate in absence and presence of Protease inhibitors

Acute Food intake study in rats

To evaluate food intake, mice/rats were starved for twelve hours (from 9 am to 9 pm), while water was remaining available. After 12 h of food deprivation, drug as well as vehicle were injected and 30 minutes after drug injection, a weighed amount of standard chow pellets was placed in the clean food rack and food remaining in the cage (including spillage in the cage) was collected and weighed at various time points (FIG. 4). Food consumption was evaluated as the difference in weight between that of initially provided food and that left in the rack. 8 cannulated rats were given vehicle treatment and food intake was measured after 3 h, 6 h and 24 h. After washing period of 24 h, the animals were treated with Compound 1 (1 mM) via icv route and food intake was measured after 3 h, 6 h and 24 h.

After washing period of 48 h, the animals were treated with Lorcaserin ( 1 mM) via icv route and food intake was measured after 3 h, 6 h and 24 h. As can be seen form FIG. 4, the reduction of food intake by Compound 1 and Lorcaserin were comparable and significant compared to vehicle treated control mice (both post 3 h and 6 h post compound treatment).