3-PHENYL-PYRAZOLE DERIVATIVES AS MODULATORS OF THE 5-HT2A SEROTONIN RECEPTOR USEFUL FOR THE TREATMENT OF DISORDERS RELATED THERETO

• US 20110105456A1
• Filed: 12/22/2010
• Published: 05/05/2011
• Est. Priority Date: 11/19/2004
• Status: Abandoned Application

• Current Assignee: Arena Pharmaceuticals Incorporated
• Original Assignee: Arena Pharmaceuticals Incorporated
• Inventors: Casper, Matin, Jones, Robert M., Feichtinger, Konrad, Unett, David J., Teegarden, Bradley, Choi, Jin Sun Karoline, Dosa, Peter I., Xiong, Yifeng, Strah-Pleynet, Sonja, Jayakumar, Honnappa, Lehmann, Juerg
• Application Number:
  US12/976,887
• Publication Number:
  US 20110105456A1
• Time in Patent Office: Days
• US Class Current: 514/210.2
• CPC Class Codes: A61K 31/5377 not condensed and containing further heterocyclic rings, e.g. timolol
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/20 Hypnotics; Sedatives
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/02 Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: A61P 9/12 Antihypertensives
• CPC Class Codes: C07D 231/12 with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 231/16 Halogen atoms or nitro radicals
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 403/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 409/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/10 : linked by a carbon chain containing aromatic rings
• CPC Class Codes: C07D 413/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 417/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 487/08 : Bridged systems
• CPC Class Codes: Y02A 50/30 : Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

The present invention relates to certain 3-phenyl-pyrazole derivatives of Formula (Ia) and pharmaceutical compositions thereof that modulate the activity of the 5-HT_2A serotonin receptor.

Compounds and pharmaceutical compositions thereof are directed to methods useful in the treatment of platelet aggreagation, coronary artery disease, myocardial infarction, transient ischemic attack, angina, stroke, atrial fibrillation, reducing the risk of blood clot formation, asthma or symptoms thereof, agitation or a symptom, behavioral disorders, drug induced psychosis, excitative psychosis, Gilles de la Tourette'"'"'s syndrome, manic disorder, organic or NOS psychosis, psychotic disorder, psychosis, acute schizophrenia, chronic schizophrenia, NOS schizophrenia and related disorders, and sleep disorders, sleep disorders, diabetic-related disorders, progressive multifocal leukoencephalopathy and the like.

The present invention also relates to the methods for the treatment of 5-HT_2A serotonin receptor mediated disorders in combination with other pharmaceutical agents administered separately or together.

Claims

1. A compound of Formula (Ia):

2. The compound according to claim 1 having Formula (Ic):

3. The compound according to claim 1, wherein V is O.

4. The compound according to claim 1 wherein W is —

CH₂—

, —

CH₂CH₂—

, —

CH₂C(═

O)—

, —

CH₂CH₂CH₂—

, —

C(CH₃)₂C(═

O)—

, —

CH₂CH(CH₃)—

, —

CH(CH₃)CH₂—

, —

C(CH₃)₂CH₂—

, or —

CH₂C(CH₃)₂—

.

5. The compound according to claim 1, wherein W is absent.

6. The compound according to claim 1, wherein X is C(═

O).

7. The compound according to claim 1, wherein X is absent.

8. The compound according to claim 1, wherein Y is NH, O or absent.

9. The compound according to claim 1, wherein Z is absent, —

CH₂—

, —

CH(OH)—

, —

CF₂—

, —

C(CH₃)₂—

, 1,1-cyclopropyl, —

CH₂CH₂—

, —

CH₂CH₂CH₂—

, —

CH(CH₃)—

, or —

C(═

O)—

.

10. The compound according to claim 1, wherein R₁ is —

CH₃.

11. The compound according to claim 1, wherein R₂ is H.

12. The compound according to claim 1, wherein R₃ is H, F, Cl or Br.

13. The compound according to claim 1, wherein R₄ is heterobicyclic, heterocyclic, or heteroaryl each optionally substituted with substituents selected independently from the group consisting of C_1-6 acyl, C_1-12 acyloxy, C_1-6 alkoxycarbonylamino, C_1-4 alkoxy, C_1-6 alkyl, C_1-4 alkylcarboxamide, C_1-4 alkylsulfonamide, C_1-4 alkylsulfonyl, C_1-4 alkylureyl, amino, carbo-C_1-6-alkoxy, carboxamide, carboxy, C_2-6 dialkylcarboxamide, formyl, halogen, C_1-4 haloalkyl, heteroaryl, hydroxyl and phenyl;

wherein said C_1-5 acyl, C_1-5 acyloxy, C_1-4 alkoxy, C_1-6 alkyl, C_1-4 alkylcarboxamide, amino, carbo-C_1-6-alkoxy and heteroaryl are each optionally substituted with substituents selected independently from the group consisting of C_1-6 alkyl, carbo-C_1-6-alkoxy, carboxy, and phenyl.

14. The compound according to claim 1, wherein R₄ is selected from the group consisting of pyrrolidin-1-yl, pyrrolidin-2-yl, piperidin-1-yl, piperidin-4-yl, piperidin-3-yl, morpholin-4-yl, piperazin-1-yl, pyridin-3-yl, pyridin-2-yl, pyridin-4-yl, azetidin-1-yl, thiomorpholin-4-yl, morpholin-2-yl, 2,5-diaza-bicyclo[2.2.1]hept-2-yl, [1,4]oxazepan-4-yl, 1,1-dioxo-1λ

⁶-thiomorpholin-4-yl, piperidin-2-yl, azepan-1-yl, pyrrolidin-3-yl, 3-oxo-piperazin-1-yl, 7-aza-bicyclo[2.2.1]hept-7-yl, and imidazol-1-yl each optionally substituted with substituents selected independently from the group consisting of CH₃, C(═

O)O-t-butyl, C(═

O)OH, C(═

O)OEt, NHC(═

O)O-t-butyl, OH, C(═

O)NHCH₂C(═

O)OCH₃, NHC(═

O)CH₂C(═

O)OCH₃, C(═

O)NHCH₂C(═

O)OH, NHC(═

O)CH₂C(═

O)OH, C(═

O)OCH₃, OC(═

O)CH₂CH₂C(═

O)OCH₃, OC(═

O)CH₂CH₂CH₂CH₂CH₃, CH₂C(═

O)OCH₂CH₃, OCH₃, CH₂C(═

O)OH, OC(═

O)CH₂CH₂C(═

O)OCH₃, CH₂CH₂C(═

O)OCH₃, C(═

O)CH₃, and C(═

O)OCH₂-phenyl, C(═

O)CH₂CH₂C(═

O)OCH₃, C(═

O)CH₂CH₂C(═

O)OH, F, phenyl, CH₂C(═

O)OCH₃, S(═

O)₂CH₃, OCH₂-phenyl, CH₂-phenyl, C(═

O)NH₂, CHO, —

NH₂, NHC(═

O)CH₃, C(═

O)N(CH₃)₂, NHS(═

O)₂CH₃, —

CF₃, 3-methyl-[1,2,4]oxadiazol-5-yl, and CH(CH₃)₂.

15. The compound according to claim 1, wherein R₅, R₆ and R₇ are all H.

16. The compound according to claim 1, wherein R₈ is C_1-8 alkyl, C_2-6 alkenyl, aryl, C_3-7 cycloalkyl, or heteroaryl each optionally substituted with substituents selected independently from the group consisting of C_1-6 acyl, C_1-6 alkoxy, C_1-6 alkyl, cyano, halogen, C_1-6 haloalkoxy, C_1-6 haloalkyl, and hydroxyl, or two adjacent substituents together with said aryl or said heteroaryl form a C_5-7 cycloalkyl optionally comprising 1 to 2 oxygen atoms and optionally substituted with F.

17. The compound according to claim 1, wherein R₈ is selected from the group consisting of methyl, iso-propyl, iso-butyl, n-propyl, n-butyl, 2-methyl-propenyl, phenyl, naphthalen-1-yl, cyclopropyl, cyclobutyl, cyclopentyl, pyridin-2-yl, pyridin-3-yl, 1H-benzoimidazol-2-yl, benzooxazol-2-yl, benzothiazol-2-yl, thiophen-2-yl, furan-2-yl, benzothiophen-2-yl, thiazol-2-yl, isoxazol-3-yl, and pyridin-4-yl each optionally substituted with substituents selected independently from the group consisting of C(═

O)CH₃, OCH₃, CH₃, F, Cl, Br, CF₃, hydroxyl, OCF₃, and CN, or two adjacent substituents together with said phenyl form a C₅ cycloalkyl comprising 2 oxygen atoms and optionally substituted with F.

18. The compound according to claim 1, wherein R₈ is selected from the group consisting of 4-chloro-phenyl, 2,4-difluoro-phenyl, 4-fluoro-phenyl, 3-chloro-phenyl, 2,2-difluoro-benzo[1,3]dioxol-5-yl, 4-hydroxy-phenyl, 4-chloro-2-hydroxy-phenyl, phenyl, 3-fluoro-phenyl, 2-fluoro-phenyl, 2-chloro-phenyl, 4-bromo-phenyl, 4-methoxy-phenyl, 4-trifluoromethyl-phenyl, 3,5-bis-trifluoromethyl-phenyl, 2-fluoro-5-methyl-phenyl, 3-methoxy-phenyl, 3-acetyl-phenyl, 4-methyl-phenyl, 3-trifluoromethyl-phenyl, 3,5-difluoro-phenyl, 2,4-dichloro-phenyl, 4-chloro-2-trifluoromethyl-phenyl, 3,4-difluoro-phenyl, 2,5-difluoro-phenyl, 2,6-difluoro-phenyl, naphthalen-1-yl, 4-trifluoromethoxy-phenyl, 3-cyano-phenyl, 2-trifluoromethoxy-phenyl, 4-chloro-2-fluoro-phenyl, 2,3-difluoro-phenyl, 2,4,5-trifluoro-phenyl, 2,3,4-trifluoro-phenyl, 3,4-dichloro-phenyl, 4-fluoro-3-trifluoromethyl-phenyl, 5-fluoro-2-trifluoromethyl-phenyl, 2-trifluoromethyl-phenyl, 3-methyl-phenyl, 2-fluoro-4-trifluoromethyl-phenyl, 4-chloro-3-fluoro-phenyl, 3-fluoro-4-methyl-phenyl, 4-fluoro-3-methyl-phenyl, 3-fluoro-4-trifluoromethyl-phenyl, 3-chloro-4-fluoro-phenyl, 2,6-dichloro-phenyl, 4-cyano-phenyl, 2,5-dichloro-phenyl, and benzo[1,3]dioxol-5-yl.

19. The compound according to claim 1, wherein R₈ is selected from the group consisting of methyl, iso-propyl, iso-butyl, n-propyl, n-butyl, 2-methyl-propenyl, 3-methyl-butyl, cyclopropyl, cyclobutyl, and cyclopentyl.

20. The compound according to claim 1, wherein R₈ is selected from the group consisting of pyridin-3-yl, 6-trifluoromethyl-pyridin-3-yl, 3-hydroxy-pyridin-2-yl, 6-methyl-pyridin-3-yl, 6-hydroxy-pyridin-3-yl, 1H-benzoimidazol-2-yl, benzooxazol-2-yl, benzothiazol-2-yl, thiophen-2-yl, furan-2-yl, 5-chloro-thiophen-2-yl, benzothiophen-2-yl, thiazol-2-yl, 5-methyl-isoxazol-3-yl, and pyridin-4-yl.

21. The compound according to claim 1, wherein R₉ is H.

22. The compound according to claim 1, wherein R₁₁ is H.

23. The compound according to claim 1 having Formula (Ik):

24. The compound according to claim 1 having Formula (Ik):

25. The compound according to claim 1 having Formula (Io):

26. The compound according to claim 1, wherein the compound is selected from the group consisting of:

1-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-3-(4-chloro-phenyl)-urea (Compound

     1);

N-(3-(4-chloro-1-methyl-1H-pyrazol-5-yl)-4-(2-morpholinoethoxy)phenyl)cyclopropanecarboxamide (Compound

     271);

N-{3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-[2-(4-methoxy-piperidin-1-yl)-ethoxy]-phenyl}-3-fluoro-benzamide (Compound

     637);

N-[3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-3-fluoro-4-methyl-benzamide (Compound

     559);

1-(3-(4-chloro-1-methyl-1H-pyrazol-5-yl)-4-(2-morpholinoethoxy)phenyl)-3-(3-chlorophenyl)urea (Compound

     231);

1-(4-Chloro-benzyl)-3-[3-(2-methyl-2H-pyrazol-3-yl)-4-(3-morpholin-4-yl-propoxy)-phenyl]-urea (Compound

     666);

3-Chloro-N-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-benzamide (Compound

     512);

3-Fluoro-N-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-4-trifluoromethyl-benzamide (Compound

     487);

1-{3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-[2-(3-hydroxy-azetidin-1-yl)-ethoxy]-phenyl}-3-(4-chloro-phenyl)-urea (Compound

     298);

1-[4-[2-(7-Aza-bicyclo[2.2.1]hept-7-yl)-ethoxy]-3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-phenyl]-3-(3-trifluoromethyl-benzyl)-urea (Compound

     710);

1-[4-[2-(7-Aza-bicyclo[2.2.1]hept-7-yl)-ethoxy]-3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-phenyl]-3-(2,4-difluoro-benzyl)-urea (Compound

     734);

4-Fluoro-N-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-benzamide (Compound

     281);

N-[3-(2-Methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-4-trifluoromethyl-benzamide (Compound

     282);

N-[3-(2-Methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-3-trifluoromethyl-benzamide (Compound

     435);

N-[4-[2-(3,3-Difluoro-pyrrolidin-1-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-4-fluoro-3-methyl-benzamide (Compound

     546);

4-Fluoro-3-methyl-N-[3-(2-methyl-2H-pyrazol-3-yl)-4-(1-methyl-pyrrolidin-2-ylmethoxy)-phenyl]-benzamide (Compound

     547);

N-{3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-[2-(2-methyl-pyrrolidin-1-yl)-ethoxy]-phenyl}-3,4-difluoro-benzamide (Compound

     579);

N-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-(1-methyl-pyrrolidin-3-yloxy)-phenyl]-3,4-difluoro-benzamide (Compound

     585);

N-[4-[2-(3-Hydroxy-pyrrolidin-1-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-4-trifluoromethyl-benzamide (Compound

     586);

3-Fluoro-N-[4-[2-(4-formyl-piperazin-1-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-benzamide (Compound

     752);

N-[4-[2-(4-Acetyl-piperazin-1-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-methoxy-benzamide (Compound

     755);

N-[3-(2-Methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-2-phenyl-acetamide) (Compound

     762);

2-(3-Fluoro-phenyl)-N-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-acetamide (Compound

     766);

2-(3-Chloro-phenyl)-N-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-acetamide (Compound

     767);

N-[3-(2-Methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-2-(3-trifluoromethyl-phenyl)-acetamide (Compound

     768);

2-(3-Methoxy-phenyl)-N-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-acetamide (Compound

     769);

N-[3-(2-Methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-2-m-tolyl-acetamide (Compound

     770);

N-[3-(2-Methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-2-p-tolyl-acetamide (Compound

     771);

2-Benzo[1,3]dioxol-5-yl-N-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-acetamide (Compound

     772);

N-[3-(2-Methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-2-(4-trifluoromethyl-phenyl)-acetamide (Compound

     794);

N-[3-(2-Methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-2-thiophen-2-yl-acetamide (Compound

     795);

1-[4-(2-Azetidin-1-yl-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-(2,4-difluoro-phenyl)-urea (Compound

     86);

1-{3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-[2-(3-methoxy-azetidin-1-yl)-ethoxy]-phenyl}-3-(4-chloro-phenyl)-urea (Compound

     267);

N-{3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-[2-(3-methoxy-azetidin-1-yl)-ethoxy]-phenyl}-3-methyl-butyramide (Compound

     326);

Benzooxazol-2-yl-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-yl-ethoxy)-phenyl]-amine (Compound

     199);

5-Chloro-thiophene-2-carboxylic acid[3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-amide (Compound

     333);

3,4-Difluoro-N-[4-[2-(2-methyl-piperidin-1-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-benzamide (Compound

     459);

N-[3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-(1-methyl-piperidin-4-yloxy)-phenyl]-4-fluoro-3-methyl-benzamide (Compound

     745);

1-(2-Fluoro-phenyl)-3-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-piperidin-1-yl-ethoxy)-phenyl]-urea (Compound

     65);

N-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-3-fluoro-benzamide (Compound

     455);

Cyclopentanecarboxylic acid[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-amide (Compound

     310);

N-[3-(2-Methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-4-trifluoromethyl-benzamide (Compound

     343);

N-{3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-[2-(3-fluoro-pyrrolidin-1-yl)-ethoxy]-phenyl}-3-fluoro-benzamide (Compound

     475);

3-Chloro-4-fluoro-N-[4-[2-(4-fluoro-piperidin-1-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-benzamide (Compound

     538);

N-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-(piperidin-3-yloxy)-phenyl]-4-fluoro-benzamide (Compound

     396);

N-[4-[2-(4-Acetyl-piperazin-1-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-fluoro-benzamide (Compound

     660);

N-[4-[2-(4,4-Difluoro-piperidin-1-yl)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-fluoro-benzamide (Compound

     778);

3-Fluoro-N-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-benzamide (Compound

     729);

3-Methoxy-N-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-benzamide (Compound

     733);

1-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-3-(2,4-difluoro-phenyl)-urea (Compound

     5);

1-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-pyridin-4-yl-ethoxy)-phenyl]-3-(4-chloro-phenyl)-urea (Compound

     145);

1-(2,4-Difluoro-phenyl)-3-[4-(2-imidazol-1-yl-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-urea (Compound

     219);

[4-(2-Azepan-1-yl-ethoxy)-3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-phenyl]-carbamic acid isopropyl ester (Compound

     352);

N-[3-(2-Methyl-2H-pyrazol-3-yl)-4-(2-[1,4]oxazepan-4-yl-ethoxy)-phenyl]-3-trifluoromethyl-benzamide (Compound

     568);

N-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-[1,4]oxazepan-4-yl-ethoxy)-phenyl]-3-fluoro-4-trifluoromethyl-benzamide (Compound

     606);

[3-(2-Methyl-2H-pyrazol-3-yl)-4-(2-thiomorpholin-4-yl-ethoxy)-phenyl]-carbamic acid isopropyl ester (Compound

     214);

[3-(2-Methyl-2H-pyrazol-3-yl)-4-(2-[1,4]oxazepan-4-yl-ethoxy)-phenyl]-carbamic acid isopropyl ester (Compound

     215); and

N-[3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-3-trifluoromethyl-benzamide (Compound

     527);

or a pharmaceutically acceptable salt, hydrate or solvate thereof.

27. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier.

28. A method for treating a 5-HT_2A mediated disorder in an individual comprising administering to said individual in need thereof a therapeutically effective amount of a compound according to claim 1 or a pharmaceutical composition according to claim 27.

29. The method according to claim 28, wherein said 5-HT_2A mediated disorder is selected from the group consisting of coronary artery disease, myocardial infarction, transient ischemic attack, angina, stroke, and atrial fibrillation.

30. A method for treating a condition associated with platelet aggregation in an individual comprising administering to said individual in need thereof a therapeutically effective amount of a compound according to claim 1 or a pharmaceutical composition according to claim 27.

31. A method for reducing the risk of blood clot formation in an angioplasty or coronary bypass surgery individual comprising administering to said individual in need thereof a therapeutically effective amount of a compound according to claim 1 or a pharmaceutical composition according to claim 27.

32. A method for reducing the risk of blood clot formation in an individual suffering from atrial fibrillation, comprising administering to said individual in need thereof a therapeutically effective amount of a compound according to claim 1 or a pharmaceutical composition according to claim 27.

33. A method for treating a sleep disorder in an individual comprising administering to said individual in need thereof a therapeutically effective amount of a compound according to claim 1 or a pharmaceutical composition according to claim 27.

34. The method according to claim 33, wherein said sleep disorder is a dyssomnia.

35. The method according to claim 33, wherein said sleep disorder is a parasomnia.

36. A method for treating a diabetic-related disorder in an individual comprising administering to said individual in need thereof a therapeutically effective amount of a compound according to claim 1 or a pharmaceutical composition according to claim 27.

37. A method for treating progressive multifocal leukoencephalopathy in an individual comprising administering to said individual in need thereof a therapeutically effective amount of a compound according to claim 1 or a pharmaceutical composition according to claim 27.

38. A method for treating hypertension in an individual comprising administering to the individual in need thereof a therapeutically effective amount of a compound according to claim 1 or a pharmaceutical composition according to claim 27.

66. A process for preparing a composition comprising admixing a compound according to claim 1 and a pharmaceutically acceptable carrier.

39. A method for treating pain in an individual comprising administering to the individual in need thereof a therapeutically effective amount of a compound according to claim 1 or a pharmaceutical composition according to claim 27.

39-65. -65. (canceled)