NO336267B1 - Condensed heterocyclic compounds having serotonin receptor modulation activity, pharmaceutical compositions comprising such, and the use of the compounds. - Google Patents

Description

The present invention relates to compounds which are serotonin receptor modulators. More particularly, the present invention provides condensed heterocyclic compounds which are serotonin receptor modulators and which are useful for the treatment of disease states mediated by serotonin receptor activity. The invention further relates to pharmaceutical compositions comprising such compounds as well as the use of the compounds for the production of therapeutic compositions.

Serotonin (5-hydroxytryptamine, 5-HT) is an important neurotransmitter that exhibits effects via a multiplicity of receptors. To date, at least fifteen different 5-HT receptors have been identified, primarily as a result of cloning cDNAs, and these receptors have been grouped into seven families (5-HT and 5-HT7) (D. Hoyer, et al. Pharmacol. Biochem. Behav. (2002) 71, 533-554). Fourteen of the fifteen cloned 5-HT receptors are expressed in the brain. 5-HT is implicated in many disease states, particularly states of the central nervous system: depression, anxiety, schizophrenia, eating disorders, obsessive compulsive disorder, learning and memory dysfunction, migraine, chronic pain, sensory perception, motor activity, temperature regulation, conception, sexual behavior, hormone secretion and cognition. Identification of multiple 5-HT receptors has provided the opportunity to characterize existing therapeutic agents believed to act via the serotonergic system. As a result, it has been recognized that many drugs have non-selective properties (B.L. Roth et al., Neuroscientist (2000) 6(4) 252-262). For example, antipsychotic drugs, clozapine, chlorpromazine, haloperidol and olanzapine exhibit affinities for multiple serotonin receptors in addition to other family of receptors. Similar behaviors have been reported for antidepressants, which include imipramine, nortriptaline, fluoxetine and sertraline. Similarly, the antimigraine drug sumatriptan exhibits a high affinity for several serotonin receptors. While lack of selectivity often contributes to a beneficial therapeutic outcome, it can also cause unwanted and dose-limiting side effects (S.M. Stahl, EssentialPsychopharmacology, 2nd ed., Cambridge University Press, Cambridge, U.K., 2000). Thus, inhibition of serotonin and norepinephrine uptake together with 5-HT2 receptor blockade is responsible for the therapeutic effects of tricyclic antidepressants. In contrast, their blocking of histamine Hi, muscarinic and α-adrenergic receptors can lead to sedation, blurred vision and orthostatic hypertension respectively. Likewise, atypical antipsychotics, which include olanzapine and clozapine, are considered to have positive therapeutic effects attributed to their actions at the 5-HT2, D2, and 5-HT7 receptors. Conversely, their propensity for side effects is due to their affinities for a number of dopaminergic, serotonergic and adrenergic receptors.

More selective ligands therefore have the potential to alleviate adverse pharmacology and provide new therapies. More importantly, the ability to obtain compounds with known receptor selectivities provides the prospect of targeting multiple therapeutic mechanisms and improving clinical responses with a single drug.

The present invention relates to a compound of formula (I), (Tf) and (US):

in which

m is 1 or 2;

n is 1, 2 or 3;

p is 1, 2 or 3;

m+n is less than or equal to 4;

m+p is less than or equal to 4;

q is 0 or 1;

r is 0 or 1;

R<3> is -C1-4 alkyl, optionally substituted with -OH or halo;

Ar is an aryl or heteroaryl ring selected from the group consisting of: a) phenyl, optionally mono-, di- or tri-substituted with R<r>or disubstituted on adjacent carbons with -OCi^alkyleneO-;

R<r> is selected from the group consisting of -OH, -C 1-6 alkyl, -OC 1-6 alkyl, -CN, -NO 2 , halo and -CF 3 ;

b) a monocyclic aromatic hydrocarbon group having five ring atoms, having a carbon atom as the point of attachment, having a carbon atom replaced by >0 or

>S, which has up to one additional carbon atom replaced by a -N= optionally mono- or disubstituted with R<r>;

ALK is a branched or unbranched C 1-6 alkylene, C 2-8 alkenylene, optionally mono-, di- or tri-substituted with a substituent selected from the group consisting of: -OH, -OC 1-6 alkyl;

CYC is hydrogen or a carbocyclic or heterocyclic ring selected from the group consisting of: i) phenyl, optionally mono-, di- or tri-substituted by R<q>or disubstituted on

adjacent carbons with -OCi^alkyleneO-;

R<q>is selected from the group consisting of -OH, -Ci-6alkyl, -OCi-6alkyl, -CN, -NO2, - N(R<a>)R<b>or -(NR<c>) SO 2 C 1-6 alkyl (where Ra, R<b>and R<c>are independently selected from H or C 1-6 alkyl), -SO 2 N(Ra)R<b>, halo and -CF 3 ;

v) a monocyclic aromatic hydrocarbon group having five ring atoms, having a carbon atom as the point of attachment, having a carbon atom replaced by

>0 or >S;

vi) a monocyclic aromatic hydrocarbon group such as here six ring atoms, which has a carbon atom which is the point of attachment, which has one or two carbon atoms replaced by -N= optionally mono- or disubstituted with R<q>;

vii) a 3- to 8-membered non-aromatic carbocyclic or heterocyclic ring, said ring having 0, 1 or 2 non-adjacent heteroatom members selected from O, or S, -, having 0, 1 or 2 unsaturated bonds, having 0, 1 or 2 carbon members that are a carbonyl;

R 1 is selected from the group consisting of H, C 1-4 alkyl, and benzofused C 4-7 cycloalkyl, each optionally mono-, di- or tri-substituted with R<p>;

R<p>is selected from the group consisting of -OH, -OCi-alkyl;

R<2> is selected from the group consisting of H or C1-6 alkyl;

and enantiomers, diastereomers, hydrates, solvates and pharmaceutically acceptable salts thereof.

The compounds can be used in pharmaceutical compositions for the treatment or prevention of disease states mediated by serotonin receptors, in particular 5-HT7 and/or 5-HT2 receptor subtypes.

The present invention further relates to pharmaceutical compositions comprising such a compound as well as the use of the compounds for the production of pharmaceutical compositions.

Preferred is m 1.

Preferred is n 1 or 2.

P 1 or 2 is preferred.

Preferred is m+n 2 or 3.

Preferred is m+p 2 or 3.

Preferred is q 1.

Preferred is R<3>, optionally substituted, selected from the group consisting of methyl, ethyl, propyl, isopropyl and butyl.

Preferred is R<3>methyl.

Preferred is Ar, optionally substituted, selected from the group consisting of:

phenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 4-ethylphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 4-fluorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 2-trifluoromethylphenyl, 3- trifluoromethylphenyl, 4-trifluoromethylphenyl, 3-trifluoromethoxyphenyl, 4-trifluoromethoxyphenyl, 3-cyanophenyl, 4-cyanophenyl, 3, 4-difluorophenyl, 3,4-dichlorophenyl, 2,3-difluorophenyl, 2,3-dichlorophenyl, 2,4-difluorophenyl, 2,4-dichlorophenyl, 3-nitrophenyl, 4-nitrophenyl, 3-chloro-4-fluorophenyl, 3-fluoro-4-chlorophenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 4-hydroxy-2-methylphenyl, 4-hydroxy-3-fluorophenyl, 3,4-dihydroxyphenyl, 4-fluoro-3-methylphenyl, furan-2- yl, furan-3-yl, thiophen-2-yl, thiophen-3-yl, 5-chlorothiophen-2-yl, 5-methylthiophen-2-yl, 5-chlorothiophen-3-yl and 5-methylthiophen-3- yl.

Preferred is ALK, optionally substituted, selected from the group consisting of methylene, ethylene, propylene, tert-butylene, pentylene, 1-ethylpropylene, 2-ethylpropylene, 2-ethylbutylene, isopropylene, but-3-enylene, isobutylene, 3-methylbutylene and the allyl.

Specifically, ALK can be selected from the group consisting of methylene, ethylene, propylene, tert-butylene, 4-hydroxybutylene, pentylene, 5-hydroxypentylene, 1-ethylpropylene, 2-ethylpropylene, 2-ethylbutylene, isopropylene, but-3-enylene, isobutylene and 3-methylbutylene.

Preferred is CYC, optionally substituted, selected from the group consisting of hydrogen, phenyl, pyridyl, thiophen-2-yl, thiophen-3-yl, tetrahydropyranyl, furan-2-yl and furan-3-yl.

Specifically, CYC may be selected from the group consisting of hydrogen, phenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 4-ethylphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, 3,4-difluorophenyl, 3,4- dichlorophenyl, 2,3-difluorophenyl, 2,3-dichlorophenyl, 2,4-difluorophenyl, 2,4-dichlorophenyl, 2,6-difluorophenyl, 2,6-dichlorophenyl, 2,6-dimethylphenyl, 2,4,6- trifluorophenyl, 2,4,6-trichlorophenyl, 3,4,5-trimethoxyphenyl, 3-nitrophenyl, 4-nitrophenyl, 3,4-dimethylphenyl, 3-aminophenyl, 4-aminophenyl, thiophen-2-yl, thiophen-3- yl, tetrahydropyran-2,3-or 4-yl, furan-2-yl, furan-3-yl, 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, and 3,4-dihydroxyphenyl.

Preferably, R<1> is selected from the group consisting of hydrogen, C1-3alkyl, each optionally mono-, di- or tri-substituted with R<p>.

More preferably, R<1>, optionally R<p->substituted, is selected from the group consisting of hydrogen, methyl, ethyl, propyl and isopropyl.

Specifically, R<1> can be selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, 3-hydroxypropyl and hydroxyethyl.

Preferred is R<2>hydrogen or C1-6 alkyl.

More preferably, R<2> is hydrogen or methyl.

It is to be understood that some compounds referred to herein are chiral and/or have geometric isomeric centers, for example E and Z isomers. The present invention includes all such optical ones, which include stereoisomers and racemic mixtures, diastereomers and geometric isomers which exhibit the activity that characterizes the compounds according to the invention. In addition, certain compounds referred to herein may result in solvated as well as non-solvated forms. It is to be understood that the present invention includes all such solvated and non-solvated forms which display the activity which characterizes the compounds according to the invention.

Compounds according to the invention can be modified to become detectable by any analytical technique. The compounds according to the invention can be labeled with radioactive elements such as 1251,18F, nC, <64>Cu and the like for use in imaging or for radioactive treatment of patients. An example of such compounds is an isotopically labeled compound, such as a<18>F-isotopically labeled compound that can be used as a probe in detection and/or imaging techniques, such as positron emission tomography (PET) and single photon emission computed tomography (SPECT). Advantageously, compounds according to the invention labeled with<18>F or<n>C can be used as a positron emission tomography (PET) molecular probe to study serotonin-mediated disorders. Another example of such compounds is an isotopically labeled compound, such as a deuterium and/or lithium labeled compound that can be used in reaction kinetics studies. The compounds described herein can be reacted with appropriate functionalized radioactive reagents using known chemistry to give radiolabeled compounds.

Pharmaceutically acceptable salts, esters, and amides include carboxylate salts (eg, C 1-6 alkyl, C 6-6 cycloalkyl, aryl, C 2 -ioheteroaryl, or C 2-10 nonaromatic heterocyclic compounds), amino addition salts, acid addition salts, esters, and amides that are within a reasonable benefit/risk ratio , pharmaceutically effective and suitable for contact with patient tissues without undue toxicity, irritation or allergic response. Representative addition salts of the compounds of formula (I) exhibiting basic functionality include a hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate , maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lacthiobionate and lauryl sulfonate. Representative addition salts of compounds of formula (I) exhibiting acidic functionality are those which form non-toxic base salts with such compounds. These salts may include alkali metal and alkaline earth metal cations such as sodium, potassium, calcium and magnesium, as well as non-toxic ammonium, quaternary ammonium and amine cations such as tetramethylammonium, methylamine, trimethylamine and ethylamine. See, for example, S.M. Berge et al., "Pharmaceutical Salts", J. Pharm. Sci., 1977, 66:1-19.

Representative pharmaceutically acceptable amides include those derived from ammonia, primary C 1-6 alkylamines and secondary di(C 1-6 alkyl)amines. Secondary amines include 5- or 6-membered heterocyclic or heteroaromatic ring constituents containing at least one nitrogen atom and optionally between 1 and 2 additional heteroatoms. Preferred amines are derived from ammonia, C 1-3 alkyl primary amines and di(C 1-2 alkyl)amines. Representative pharmaceutically acceptable esters include C 1-6 alkyl, C 5-7 cycloalkyl, phenyl and phenyl(C 1-6 ) alkyl esters. Preferred esters include methyl esters.

Preferred compounds, which are condensed pyrroles, are selected from the group consisting of:

Preferred compounds which are fused 1-substituted pyrazoles are selected from the group consisting of:

Preferred compounds, which are fused 2-substituted pyrazoles, are selected from the group consisting of:

In another embodiment according to the invention, preferred compounds are selected from the group consisting of:

In another embodiment according to the invention, preferred compounds are selected from the group consisting of:

In a further other embodiment according to the invention, preferred compounds are selected from the group consisting of:

Features and advantages of the present invention will be obvious to the person skilled in the art. Based on the present description, the person skilled in the art will be able to make modifications and adaptations to the various conditions and application.

The condensed heterocyclic compounds of formula (I), (n) and (HI) can be prepared by a number of reaction schemes. Access to compounds of formula (I) is described in scheme 1. Preparation of compounds of formula (II) is described in schemes 2, 3, 5 and 6. Synthesis of compounds of formula (HI) is shown in schemes 3 and 4. Those skilled in the art will see that certain compounds are more advantageously produced by one scheme compared to another.

Referring to Scheme 1, compounds of formula (I) can be prepared from compounds of formula (IV). The amine moiety of the compounds of formula (IV) may be suitably protected, shown by substituent G, as an alkyl or benzylamine, carbamate or other groups such as those described in "Protecting Groups in Organic Synthesis", 2nd ed., T.W. Green and P.G.M. Wuts, John Wiley & Sons, 1999 (G is -C 1-6 alkyl, -COOC 1-6 alkyl, -(C=O)C 1-6 alkyl or benzyl unsubstituted or substituted with -OC 1-6 alkyl or -C 1-6 alkyl). A preferred protecting group will be the t-butyl carbamate (Boe) group. The carbonyl functional group of compound (IV) can be treated with a primary amine of type (V), in a suitable solvent such as THF, toluene, benzene, methanol or ethanol at temperatures between 20 and 110°C, with removal of water by either Dean -Stark apparatus or by the addition of dehydrating agents such as SiO2, MgSO2, Q1SO4, Ti(0-iPr4 or 4 Å molecular sieve to form the corresponding imines of type (VI). Preferred solvents are toluene and ethanol and preferred dehydrating agents are SiC>2 and 4 Å molecular sieves. Those skilled in the art will appreciate that the imines of type (VI) can exist as more than one tautomeric form. Compounds of type (VI) can then be treated with nitroolefin of type (VU) to give pyrrole compounds of formula (VIII). Those skilled in the art will recognize that imines of formula (VI), which exist as more than enamine tautomers, will give rise to regioisomers upon treatment with a nitroolefin of type (VU) depending on the structure of the compound of formula (IV).The protecting group on the nitrogen may either n is removed using generally accepted methods or, depending on the type of group involved, can be converted directly to compounds of formula (I). More specifically, a group, such as a t-butyl carbamate, can be removed with an acid, such as trifluoroacetic acid or hydrochloric acid, and the like in a solvent such as CH 2 Cl 2 , ethanol or methanol, to give compounds of formula (IX). It will generally be understood that compounds of formula (IX) represent a subset of compounds of formula (I) wherein R<1> is equal to H. Compounds of formula (IX) and (I) may be converted to their corresponding salts by use of known procedures in the literature.

Compounds such as (I) can be prepared from compounds of type (IX) using common synthetic procedures such as alkylation or reductive amination. Thus, treatment of compounds of formula (IX) with a compound of formula (X) containing a carbonyl group in the presence of a reducing agent such as NaBFL,, NaBH3CN, NaBH(OAc)3 or hydrogen gas in the presence of a catalyst in a solvent, such such as CH2CI2, DCE, THF, ethanol, methanol or the like, result in compounds of formula (I). Those skilled in the art will see that addition of acid to reduce the pH of the reaction mixture to less than pH 7 may be required. Examples of acids may include AcOH, Ti(0-iPr) 4 , trifluoroacetic acid or hydrochloric acid and the like. In addition, compounds such as (IX) can be treated with an alkylating agent of type (XI). For example, treatment with an alkyl chloride, bromide, iodide, mesylate or tosylate (wherein X is Cl, Br, I, OMs, OTs or the like) in a solvent such as DMF, DMA, THF or ethanol and in the presence of a base such as NaHCO3, Na2CO3, K2CO3 or CS2CO3 give compounds of formula (I).

With reference to Scheme 2, compounds of formula (II) can be prepared from compounds of formula (XII). As in Scheme 1, the amine moiety in compounds of formula (XII) may be suitably protected, as shown by substituent G, as an alkyl or benzylamine, amide, carbamate or other groups such as those described in "Protecting Groups In Organic Synthesis ", 3rd ed., T.W. Greene and P.G.M. Wuts, John Wiley & Sons, 1999. A preferred protecting group would be the t-butyl carbamate (Boe) group. Condensation of hydrazine with compounds of formula (XII) in a solvent such as methanol, ethanol, isopropanol or t-butyl alcohol at temperatures from 20 to 80°C will give compounds of type (XIII). Those skilled in the art will recognize that compounds of formula (XIII) can exist in more than one resonance form. More specifically, compounds of formula (XIII) are tautomeric with the corresponding 3-hydroxypyrazoles. Compounds such as (XIII) can be treated with an alkylating agent such as (XIV) to give compounds of type (XV). For example, treatment with an alkyl or benzyl chloride, bromide, iodide, mesylate or tosylate (wherein X is Cl, Br, I, OMs, OTs or the like) in DMF, DMA, THF or ethanol in the presence of a base such as NaHCO 3 , Na2C03, K2CO3, NaH, potassium tert-butoxide or CS2CO3 give compounds of formula (XV). The person skilled in the art will see that alkylation of compounds of formula (XIII) can give rise to regioisomers. Compounds of type (XV) can be converted into a precursor for transition metal catalyzed cross-coupling reactions, such as Stille, Suzuki, Negishi or other such coupling reactions known to those skilled in the art. For example, treatment with POCl3, PC13, PC15, PBr3 or POB3 can give the corresponding 3-halopyrazoles. A preferred method involves treatment with a triflating agent, such as trifluoromethanesulfonic anhydride or N-phenyltrifluoromethanesulfonimide in DCE, CH2Cl2, THF or the like in the presence of a base, such as pyridine, triethylamine or diisopropylethylamine to give pyrazole triflates of formula (XVI). Treatment of triflates of formula (XVI) with an organoboron compound of formula (XVII) in the presence of a catalyst such as Pd(PPh3)4, PdCl2(PPh3)2, PdCl2(Po-tol3)2, PdCl2(dppe) or PdCl2(dppf ) in a solvent such as THF, 1,4-dioxane, DMA, DMF, DME, toluene, toluene/ethanol, or toluene/H20 mixtures, in the presence of a base such as Na2CO3, K2CO3, CS2CO3, K3PO4, KF, CsF, KOAc or the like will give compounds of formula (XVIII). Preferred catalysts are Pd(PPh3)4 and PdCl2(dppf), with or without additives such as dppf and catalytic Bu4NBr. Preferred solvents include THF, 1,4-dioxane, toluene and toluene/H 2 O mixtures, the preferred bases being Na 2 CO 3 , CS 2 CO 3 and K 3 PO 4 . The protecting group on the nitrogen of the compound of formula (XVIII) can be removed using generally accepted methods, which those skilled in the art will discover. More specifically, a group such as a t-butyl carbamate can be removed with an acid such as trifluoroacetic acid or hydrochloric acid and the like in a solvent such as CH 2 Cl 2 , ethanol or methanol to give compounds of formula (XIX). Compounds of formula (XIX) or (II) can be converted into their corresponding salts using methods known to those skilled in the art. For example, amines of formula (XIX) can be treated with citric acid in a solvent such as ethanol to give the corresponding citrate salt. It will be generally understood that compounds of formula (XIX) represent a subset of compounds of formula (H) in which R<1> is equal to H.

Compounds such as (II) can be prepared from compounds of type (XIX) using common synthetic procedures such as alkylation or reductive amination. Thus, treatment of compounds of formula (XIX) with a compound of formula (X) containing a carbonyl group in the presence of a reducing agent, such as NaBFL,, NaBH3CN, NaBH(OAc)3 or a hydrogen gas in the presence of a catalyst in a solvent, such as CH2CI2, DCE, THF, ethanol, methanol or equivalent give compounds of formula (Tf). The person skilled in the art will see that the addition of acid to reduce the pH of the reaction mixture to below pH 7 may be required. Examples of acids may include AcOH, Ti(P-iPr) 4 , trifluoroacetic acid or hydrochloric acid and the like. In addition, compounds such as (XIX) can be treated with an alkylating agent of type (XT). For example, treatment with an alkyl chloride, bromide, iodide, mesylate or tosylate (wherein X is Cl, Br, I, OMs, OTs or the like) in a solvent, such as DMF, DMA, THF or ethanol and in the presence of a base such as NaHC03, Na2C03, K2C03 or Cs2C03 will give compounds of formula (ff). With reference to scheme 3, compounds of formula (II), (HI), (XXVII) and (XXVIII) can be prepared as described. The amine moiety of the compounds of formula (XX) may be suitably protected, shown by substituent G, as an alkyl or benzylamine, amide, carbamate or other groups such as those described in "Protecting Groups In Organic Synthesis", 3rd ed.; T.W. Greene and P.G.M. Wuts, John Wiley & Sons, 1999. A preferred protecting group would be the t-butyl carbamate (Boe) group. The carbonyl functional group of compound (XX) can be treated with a saturated secondary amine, such as morpholine, in a suitable solvent, such as toluene or benzene, at a temperature between 20 and 110°C by removing water with a Dean-Stark apparatus with or without an acid catalyst, such as TsOH, which will give the corresponding enamines of type (XXI). Those skilled in the art will appreciate that enamines of type (XXI) can exist as more than one enamine regioisomer depending on the structure of the compound of formula (XX). Treatment of enamines (XXI) with a benzoyl chloride will give the diketone compounds of formula (XXTV). In addition, the carbonyl functional group of compound (XX) can be treated with a diazo ketone in the presence of a Lewis acid, such as BF 3 , to give the diketone compounds (XXIV) directly. Condensation of the hydrazine with compounds of formula (XXTV) in a solvent such as methanol, ethanol, isopropanol or t-butyl alcohol at temperatures of from 20-80°C will give pyrazole compounds of type (XXV). Compounds, such as (XXV), can be treated with an alkylating agent of formula (XIV). For example, treatment with an alkyl or benzyl chloride, bromide, iodide, mesylate or tosylate (wherein X is Cl, Br, I, OMs, OTs or the like) in DMF, DMA, THF or ethanol in the presence of a base such as NaHCO 3 , Na2C03, NaH, potassium tert-butoxide, K2C03 or Cs2C03 give a mixture of compounds of formula (XXVI) and (XVIII). Those skilled in the art will recognize that a mixture of compounds of formula (XXVI) and (XVIII) can be separated by chromatographic or crystallization techniques. The protecting group on the nitrogen can be removed using generally accepted methods, which those skilled in the art will know. More specifically, a group such as a t-butyl carbamate can be removed from compounds of formula (XXVI) and (XVIII) with an acid, such as trifluoroacetic acid or hydrochloric acid and the like, in a solvent such as CH 2 Cl 2 , ethanol or methanol to give compounds of formula (XXVII) and (XIX) respectively. Compounds of formulas (XXVII), (XIX), (II) or (Ul) can be converted into their corresponding salts using methods known to those skilled in the art. It will generally be understood that compounds of formula (XXVII) and (XIX) represent subsets of compounds of formula (III) and (II) respectively, in which R<1> is equal to H.

Compounds such as (II) and (ISS) can be prepared from compounds of formula (XIX) and (XXVII) respectively, using synthetic methods such as alkylation or reductive amination. Thus, treatment of compounds of formula (XIX) with a compound of formula (X) containing a carbonyl group in the presence of a reducing agent, such as NaBFL,, NaBH3CN, NaBH(OAc)3 or hydrogen gas in the presence of a catalyst in a solvent, such as CH2CI2, DCE, THF, ethanol, methanol or equivalent give compounds of formula (SS). Those skilled in the art will appreciate that addition of acid to reduce the pH of the reaction mixture to less than pH 7 may be required. Examples of acids may include AcOH, Ti(0-iPr) 4 , trifluoroacetic acid or hydrochloric acid and the like. In addition, compounds such as (XIX) can be treated with an alkylating agent of type (XI). For example, treatment with an alkyl chloride, bromide, iodide, mesylate or tosylate (wherein X is Cl, Br, I, OMs, OTs or the like) in a solvent, such as DMF, DMA, THF or ethanol, in the presence of a base , such as NaHC03, Na2C03, K2CO3or Cs2C03, give compounds of formula (SS).

With reference to Scheme 4, compounds of formula (III) can be prepared as indicated. The amine component of a compound of formula (XII) may be suitably protected, shown by substituent G, as an alkyl or benzylamine, amide, carbamate or other groups such as those described in "Protecting Group in Organic Syntehsis", 3rd ed. ; T.W. Greene and P.G.M. Wuts, John Wiley & Sons, 1999. Condensation of an alkyl or arylhydrazine of type (XXVIII), or a salt thereof, with compounds of formula (XII) in a solvent, such as methanol, ethanol, isopropanol or t-butyl alcohol, at temperatures from 20-80°C with or without a base, such as NaHCO 3 , Na 2 CO 3 , K 2 CO 3 , Cs 2 CO 3 , triethylamine or diisopropylethylamine, will give compounds of formula (XXIX). Preferred solvents are ethanol and t-butyl alcohol, the preferred bases being triethylamine and diisopropylethylamine. Compounds of formula (XXIX) can be converted into a precursor for transition metal catalyzed cross-coupling reactions, such as Stille, Suzuki, Negjshi or other such coupling reactions known in the literature. For example, treatment with POCl3, PC13, PC15, PBr3 or POBr3 can give the corresponding 3-halopyrazoles. A preferred method will involve treatment with a triflating agent such as trifluoromethanesulfonic anhydride or an N-phenyltrifluoromethanesulfonimide in DCE, CH 2 Cl 2 , THF or the like in the presence of a base such as pyridine, triethylamine or diisopropylamine to give pyrazole triflates of formula (XXX). Treatment of triflates of formula (XXX) with an organoboron compound of formula (XVII) in the presence of a catalyst such as Pd(PPh3)4, PdCl2(PPh3)2, PdCl2(Po-tol3)2, PdCl2(dppe) or PdCl2(dppf ) in a solvent such as THf, 1,4-dioxane, DMA, DMF, DME, toluene, toluene/ethanol or toluene/H20 mixtures, in the presence of a base such as Na2CO3, K2CO3, Cs2CO3, K3PO4, KF, CsF , KOAc or the like will give compounds of formula (XXVI). Preferred catalysts are Pd(PPh3)4 and PdCl2(dppf), with or without additives, such as dppf and catalytic Bu4NBr. Preferred solvents are THF, 1,4-dioxane, toluene and toluene/H 2 O mixtures, the preferred bases being Na 2 CO 3 , K 2 CO 3 , Cs 2 CO 3 and K 3 PO 4 . The protecting group on the nitrogen of compounds of formula (XXVI) can be removed using generally accepted methods, which those skilled in the art will know. More specifically, a group such as t-butyl carbamate can be removed with an acid such as trifluoroacetic acid or hydrochloric acid and the like in a solvent such as CH 2 Cl 2 , ethanol or methanol to give compounds of formula (XXVII). Compounds of formula (XXVII) or (ISS) can be converted to their corresponding salts using methods known to those skilled in the art. It will generally be understood that compounds of formula (XXVII) represent a subset of compounds of formula (SIS) in which R<1> is equal to H.

Compounds such as formula (ISS) can be prepared from compounds of type (XXVII) using known synthetic methods such as alkylation or reductive amination. Thus, treatment of compounds of formula (XXVII) with a compound of formula (X) containing a carbonyl group in the presence of a reducing agent, such as NaBFL,, NaBH3CN, NaBH(OAc)3 or hydrogen gas in the presence of a catalyst in a solvent, such as CH 2 Cl 2 , DCE, THF, ethanol, methanol or equivalent give compounds of formula (Ul). The person skilled in the art will see that the addition of acid to reduce the pH of the reaction mixture to less than pH 7 may be required. Examples of acids include AcOH, Ti(0-iPr) 4 , trifluoroacetic acid or hydrochloric acid and the like. In addition, compounds such as (XXVII) can be treated with an alkylating agent of type (XI). For example, treatment with an alkyl chloride, bromide, iodide, mesylate or tosylate (wherein X is Cl, Br, I, OMs, OTs or the like) in a solvent such as DMF, DMA, THF or ethanol in the presence of a base, which NaHC03, Na2C03, K2C03 or Cs2C03 give compounds of formula (US).

Referring to Scheme 5, in an alternative embodiment, compounds of formula (SS) can be prepared from a ketone of formula (XXXI). A ketone of formula (XXXI) can be converted to the pyrazole of formula (XXXII) according to the procedure shown in scheme 3 for converting a compound of formula (XX) into a compound of formula (XVIII). A compound of formula (XXXIII) can be prepared from a compound of formula (XXXII) after treatment with aqueous acid. For example, treatment of a compound of formula (XXXII) with HCl in aqueous THF at elevated temperatures will give compounds of formula (XXXIII). A ketone of formula (XXXIII) can be converted into an oxime of formula (XXXIV) by treatment with hydroxylamine, preferably after treatment with hydroxylamine in pyridine. Compounds of formula (XXXIV) may exist as a single isomer or mixture of stereoisomers. Treatment of an oxime of formula (XXXTV) with a hydride reducing agent can give compounds of formula (XIX). In a preferred embodiment, the reducing agent is diisobutyl aluminum hydride in CH2C12. Conversion of the compounds of formula (XIX) to compounds of formula (II) can be carried out by the methods described in scheme 3. With reference to scheme 6, in an alternative embodiment, compounds of formula (XIX) can also be prepared as indicated. The amine moiety in compounds of formula (Xffl) may suitably be protected, as shown by substituent G, as an alkyl or benzylamine, amide, carbamate or other groups, such as those described in "Protecting Groups In Organic Synthesis", 3rd ed. .; T.W. Greene and P.G.M. Wuts, John Wiley & Sons, 1999. Preferably, the sequence indicated in scheme 6 can be used for compounds where p = 1, m = 2 and G = t-butylcarbamoyl. Treatment of pyrazolones of formula (Xffl) with a triflating agent, such as N-phenyltrifluoromethanesulfonimide or trifluoromethanesulfonic anhydride in pyridine or other non-nucleophilic amine base gives pyrazole triflates of formula (XTV). Compounds such as (XXXV) can be treated with an alkylating agent of formula (XIV). For example, treatment with an alkyl or benzyl chloride, bromide, iodide, mesylate or tosylate (wherein X is Cl, Br, I, OMs, OTs or the like) in DMF, DMA, THF or ethanol in the presence of a base such as NaHCO 3 , Na2CO3, NaH, K2CO3, CS2CO3 or potassium tert-butoxide give compounds of formula (XVI). Preferably, the alkylation is carried out using alkylating agents such as benzyl bromide in the presence of a suitable base such as potassium tert-butoxide. Pyrazoles of formula (XVI) can be taken further as described in scheme 2 to give compounds of formula (XIX) and (II).

The compounds according to the invention are serotonin receptor modulators, and as such the compounds are useful in the treatment of serotonin-mediated disease states. In particular, the compounds can be used in the treatment or prevention of CNS disorders, such as sleep disorders, depression/anxiety, general anxiety disorders, schizophrenia, bipolar disorders, psychotic disorders, obsessive compulsive disorder, mood disorders, post-traumatic stress and other stress-related disorders, migraine, pain, eating disorders , obesity, sexual dysfunction, metabolic disorders, hormone imbalance, alcohol abuse, addiction disorders, nausea, inflammation, centrally mediated hypertension, sleep/wake disorders, jet lag and heart rhythm abnormalities. The compounds can also be used in the treatment or prevention of hypotension, peripheral vascular disorders, cardiovascular shock, renal disorders, gastric motility, diarrhea, spastic colon, irritable bowel disorder, ischemia, septic shock, urinary incontinence and other disorders related to the gastrointestinal and vascular systems. In addition, the compounds according to the invention can be used in the treatment or prevention of a number of ocular disorders which include glaucoma, optic neuritis, diabetic retinopathy, retinal edema and age-related macular degeneration.

The compounds according to the inventions are 5-HT7 modulators and many are 5-HT7 antagonists. As such, the compounds are useful in the treatment of 5-HT7 mediated disease states. Where the compounds exhibit substantially 5-HT7-antagonistic activity, they may be particularly useful in the treatment or prevention of depression/anxiety, sleep/wake disorders, jet lag, migraine, urinary incontinence, gastric motility and irritable bowel disorders.

Many of the compounds according to the invention are 5-HT2 modulators, and many are 5-HT2 antagonists. As such, the compounds are useful in the treatment of 5-HT 2 -mediated diseases or conditions. If the compounds exhibit substantial 5-HT2 antagonist activity, they may be particularly useful in the treatment or prevention of depression/anxiety, generalized anxiety disorder, schizophrenia, bipolar disorders, psychotic disorders, obsessive-compulsive disorders, mood disorders, post-traumatic stress disorders, sleep disorders, sexual dysfunction, eating disorders, migraine, addiction disorders and peripheral vascular disorders.

It is to be understood that the compound of the invention can be administered orally or parenterally, which includes intravenous, intramuscular, intraperitoneal, subcutaneous, rectal and topical administration, and by inhalation. For oral administration, the compounds according to the invention will generally be provided in the form of tablets or capsules, or as an aqueous solution or suspension. Tablets for oral use may include the active ingredient mixed with pharmaceutically acceptable excipients such as inert diluents, disintegrants, binders, lubricants, sweeteners, flavorings, coloring agents and preservatives. Suitable inert diluents include sodium and calcium carbonate, sodium and calcium phosphate, and lactose. Corn starch and alginic acid are suitable disintegrants. Binders can include starch and gelatin. The lubricant, if present, will generally be magnesium stearate, stearic acid or talc. If desired, the tablets can be coated with a material, such as glyceryl monostearate or glyceryl distearate, to delay absorption in the gastrointestinal tract. Capsules for oral use include hard gelatin capsules in which the active ingredient is mixed with a solid diluent and soft gelatin capsules in which the active ingredient is mixed with water or an oil, such as peanut oil, liquid paraffin or olive oil. For intramuscular, intraperitoneal, subcutaneous and intravenous use, the compounds of the invention will generally be provided in sterile aqueous solutions or suspensions, buffered to an appropriate pH and isotonicity. Suitable aqueous vehicles include Ringer's solution and isotonic sodium chloride. Aqueous suspensions according to the invention may include suspending agents, such as cellulose derivatives, sodium alginate, polyvinyl pyrrolidone and gum tragacanth, and a wetting agent, such as lecithin. Suitable preservatives for aqueous suspensions include ethyl and n-propyl p-hydroxybenzoate.

Effective doses of the compound according to the invention can be determined by usual methods. The specific dosage level required for a particular patient will depend on a number of factors including the severity of the condition being treated, the route of administration and the weight of the patient. Generally, however, it is intended that the daily dose (whether administered as a single dose or as divided doses) will be in the range of 0.01 to 1,000 mg/day, more commonly from 1 to 500 mg/day and most commonly from 10 to 200 mg/day. Expressed as a dosage per unit of body weight, a typical dose would be expected to be between 0.0001 mg/kg and 15 mg/kg, particularly between 0.01 mg/kg and 7 mg/kg, and most suitably between 0.15 mg/kg and 2.5 mg/kg.

EXAMPLES

To illustrate the invention, the following examples are included.

Protocol for preparative reverse-phase HPLC

Gilson®

Column: YMC-Pack OD S-A, 5 um, 75x30 mm

Flow rate: 25 ml/min

Detection: y = 220% 254 nm

Gradient (acetonitrile/water, 0.05% trifluoroacetic acid)

1) 0.0 min. 15% acetonitrile/85% water

2) 20.0 min. 99% acetonitrile/1% water

Procedure A:

Protocol for HPLC (reverse phase)

Hewlett Packard Series 1100

Column: Agilent ZORBAX® Bonus RP, 5 um, 4.6x250 mm Flow rate: 1 ml/min

Detection: y = 220 & 254 nm

Gradient (acetonitrile/water, 0.05% trifluoroacetic acid)

1) 0.0 min. 1% acetonitrile/99% water

2) 20.0 min. 99% acetonitrile/1% water

Method B:

Protocol for HPLC

Hewlett Packard Series 1100

Column: Agilent ZORBAX® Eclipse XDB-C8, 5 µm, 4.6x150 mm Flow rate: 1 ml/min

Detection: y = 220 & 254 nm

Gradient (acetonitrile/water, 0.05% trifluoroacetic acid)

1) 0.0 min. 1% acetonitrile/99% water

2) 8.0 min. 99% acetonitrile/1% water

3) 12.0 min. 99% acetonitrile/1% water

Protocol for preparative SFC

Thar Technologies®

Column: Chiracel AD, 10 µm, 250x20 mm

Flow rate: 37 gm/min

Detection: y = 220 & 254 nm

Mobile phase: Isocratic 30% IPA/70% C02

Pressure: 150 Bar

Temperature: 35°C

Protocol for Analytical SFC

Jasco®

Column: Chiracel AD, 10 µm, 250 x 4.6 mm Flow rate: 1 gm/min.

Detection: y = 220 & 254 nm

Mobile phase: Isocratic 30% IPA/70% C02

Pressure: 150 bar

Temperature: 335°C

Mass spectra were recorded on an Agilent series 1100 MSD using electrospray ionization (ESI) in either positive or negative mode as indicated.

Thin layer chromatography was performed using Merck silica gel 60 F2542.5 cm x 7.5 cm 250 µm or 5.0 cm x 10.0 cm 250 µm precoated silica gel plates. Preparative thin-layer chromatography was performed using a Science silica gel 60 F2542O cm x 20 cm 0.5 mm precoated plates with a 20 cm x 4 cm

concentration zone.

NMR spectra were obtained using a user model DPX 400 (400 MHz), DPX500 (500 MHz) or DPX600 (600 MHz) spectrometer. The format of ^NMR data below is: chemical layer in ppm embedded in tetramethylsilane reference (multiplicity, coupling constant, J in Hz, integration).

Example 1

1-Benzyl-3-(4-nitrophenyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine.

Step A: 1-benzyl-3-(4-nitrophenyl)-1,4,6,7-tetrahydro-pyrrolo[3,2-c]pyridine-5-carboxylic acid tert-butyl ester.

To a stirred solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (0.69 g) in toluene (5 ml) was added 378 µL of benzylamine. The mixture was stirred for 10 min and then 0.70 g of silica gel (SiCl 2 ) was added. After stirring at room temperature for 8 hours, 0.77 g of 1-nitro-4-(2-nitrovinyl)-benzene in toluene (5 ml) was added, and the mixture was stirred for 14 hours at room temperature. The mixture was then filtered through diatomaceous earth and the filtrate concentrated in vacuo. Chromatography on SiC>2 (8 to 20% EtOAc/hexane) gave 0.48 g of the desired compound.

MS (ESI): exact mass calculated for C 25 H 27 N 3 O 4 , 433.20;

found, m/z 434.2 [M+H]<+>, 456.2 [M+Na]<+>.

Step B:

To a stirred solution of 0.20 g of the above compound in a 10:1 mixture of CH 2 Cl 2 /MeOH (6 mL) was added 1.9 mL of 1.0 M HCl in Et 2 O. After stirring for 12 hours at room temperature, a white solid formed which was collected by filtration to give 0.11 g of the title compound.

MS (ESI): exact mass calculated for C20H19N3O2, 333.15;

found, m/z 334.2 [M+H]<+>.

*HNMR (500 MHz, CD3OD): 8.26-8.21 (m, 2H), 7.59-7.55 (m, 2H), 7.42 (s, 1H), 7.36 (t, J=7.4 Hz, 2H), 7.30 (t, J=7.4 Hz, 1 Hz), 7.20 (d, J=7.4 Hz, 2H), 5.19 (s, 2H ), 4.44 (s, 2H), 3.53 (t, J=6.3 Hz, 2H), 2.89 (t, J=6.3 Hz, 2H).

Examples 17-22 were prepared according to the procedure described in Example 1, with changes as noted.

Example 17

1-Benzyl-2-methyl-3-phenyl-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine.

The title compound (89.4 g) was prepared from 0.51 g of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester, 272 µL of benzylamine and 0.41 g of (2-nitropropenyl)-benzene.

MS (ESI): exact mass calculated for C21H22N2, 302.18;

found, m/z 303.2 [M+H]<+>.

<*>HNMR (400 MHz, CD3OD): 7.41-7.36 (m, 2H), 7.35-7.30 (m, 2H), 7.28-7.21 (m, 4H), 7.05-7.01 (m, 2H), 5.16 (s, 2H), 4.18 (s, 2H), 3.52 (t, J=6.3 Hz, 2H), 2.89 (t, J=6.3 Hz, 2H).

Example 18

1-benzyl-3-p-tolyl-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine.

The title compound (89.7 g) was prepared from 0.51 g of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester, 272 µL of benzylamine and 0.41 g of 1-methyl-4-(2-nitrovinyl)-benzene.

MS (ESI): exact mass calculated for C21H22N2, 302.18;

found, m/z 303.2 [M+H]<+>.

<*>HNMR (400 MHz, CD3OD):7.35-7.31 (m, 2H), 7.29-7.25 (m, 1H), 7.23-7.20 (m, 2H), 7.18- .14 (m, 4H), 7.06 (s, 1H), 5.13 (s, 2H), 4.33 (s, 2H), 3.49 (t, J=6.3 Hz, 2H) , 2.86 (t, J=6.3 Hz, 2H).

Example 22

1-butyl-3-p-tolyl-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine.

The title compound (292.8 mg) was prepared from 0.56 g of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester, 260 µL of butylamine and 0.45 g of 1-methyl-4-(2-nitrovinyl)-benzene.

MS (ESI): exact mass calculated for Ci8H24N2, 268.19;

found, m/z 269.2 [M+H]<+>.

*HNMR (500 MHz, CD3OD): 7.20-7.14 (m, 4H), 6.93 (s, 1H), 4.32 (s, 2H), 3.88 (t, J=7, l Hz, 2H), 3.56 (t, J=6.0 Hz, 2H), 3.00 (t, J=6.0 Hz, 2H), 2.32 (s, 3H), 1.77 -170 (m, 2H), 1.41-1.33 (m, 2H), 0.97 (t, J=7.4 Hz, 3H).

Example 26

1-Benzyl-3-phenyl-1,4,5,6,7,8-hexahydro-pyrrolo[2,3-d]azepine.

Step A: 1-benzyl-3-phenyl-4,5,7,8-tetrahydro-1H-pyrrolo[2,3-d]azepine-6-carboxylic acid tert-butyl ester.

A solution of the compound (0.53 g) from Example 59, Step B, and 272 µL of benzylamine in benzene (10 mL) was heated to reflux for 24 hours using a Dean-Stark apparatus. The solvent was removed, the crude material dissolved in toluene (10 mL), and 0.38 g of (2-nitrovinyl)benzene added. The mixture was stirred for 24 hours at room temperature, and concentrated in vacuo. Chromatography on SiC>2 (1 to 20% EtOAc/hexane) gave 108.0 mg of the desired compound.

MS (ESI): exact mass calculated for C26H30N2O2, 402.53;

found, m/z 403.2 [M+H]<+->

Step B:

To a stirred solution of the compound from Step A (108.0 mg) in CH 2 Cl 2 (5 mL) was added TFA (1 mL). The mixture was stirred at room temperature for 12 hours and then concentrated in vacuo. The residue was partitioned between CH 2 Cl 2 (10 mL) and 1M NaOH (10 mL). The layers were separated and the aqueous layer extracted with CH 2 Cl 2 (2 x 10 mL). The combined organic layers were concentrated. Chromatography on SiC>2 (5% 2 M NH 3 in MeOH/CH 2 Cl 2 ) gave 66.5 mg of the title compound.

MS (ESI): exact mass calculated for C21H22N2, 302.41;

found, m/z 303.2 [M+H]<+>.

*H NMR (500 MHz, CDCl 3 ): 7.42-7.22 (m, 8H), 7.08 (m, 2H), 6.67 (s, 1H), 5.08 (s, 2H), 3.06-2.91 (m, 4H), 2.90-2.82 (m, 2H), 2.77-2.68 (m, 2H), 2.25 (br s, 1H).

Example 35 (Reference example)

1-Benzyl-3-(4-chlorophenyl)-5-ethyl-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine.

To a solution of 1-benzyl-3-(4-chlorophenyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine (Example 25; 0.11 g) in 1.2 -dichloromethane (5 ml) 18 uL of acetic acid, 26 uL of acetaldehyde and 0.10 g of NaBH(OAc)3 were added. The mixture was stirred at room temperature for 15 hours. The mixture was diluted with CH 2 Cl 2 , and washed with saturated aqueous NaHCO 3 (2x). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated in vacuo. Chromatography on SiO 2 (1% 2M NH 3 in MeOH/CH 2 Cl 2 ) gave 0.02 g of the title compound. The product was dissolved in Et 2 O and treated with excess 1.0 M HCl in Et 2 O which gave 0.02 g of the corresponding HCl salt.

MS (ESI): exact mass calculated for C 22 H 23 CIN 2 , 350.15;

found, m/z 351.2 [M+H]<+>, 353.2 [M+H]<+>.

*HNMR (500 MHz, CD3OD): 7.37-7.27 (m, 7H), 7.19-7.17 (m, 3H), 5.17-5.13 (m, 2H), 4, 48-4.37 (m, 2H), 3.85-3.76 (m, 2H), 3.45-3.23 (m, 2H), 3.00-2.84 (m, 2H), 1.38 (t, J=7.1 Hz, 3H).

Example 38

1-Benzyl-3-(4-chlorophenyl)-5-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine.

Step A: 1-benzyl-3-(4-chlorophenyl)-1,4,6,7-tetrahydro-pyrrolo[3,2-c]pyridine-5-carboxylic acid ethyl ester.

To a stirred solution of 3.0 g of 4-oxo-piperidine-1-carboxylic acid ethyl ester in benzene (35 ml) was added 1.91 ml of benzylamine. The mixture was heated to reflux for 24 hours at

application of a Dean-Stark apparatus. The solvent was removed to give a dull yellow oil. A portion of the crude product (0.50 g) was dissolved in toluene (4 ml) and 0.35 g of 1-chloro-4-(2-nitrovinyl)benzene was added followed by 0.7 g of 4P molecular sieve. The resulting mixture was stirred for 12 hours at room temperature. The mixture was then filtered through diatomaceous earth and the filtrate washed with saturated aqueous NH 4 Cl (3x). The combined organic extracts were dried over Na 2 SO 4 , filtered and concentrated in vacuo. Chromatography on SiO 2 (8% EtOAc/hexane) gave 0.25 g of the title compound. TLC (SiO 2 , 25% EtOAc/hexane): Rf = 0.34.

MS (ESI): exact mass calculated for C 23 H 23 CIN 2 O 2 , 394.14;

found, m/z 395.2 [M+H]<+>, 397.2 [M+H]<+>, 417.1 [M+Na]<+>.

Step B:

To a stirred solution of the above compound (0.25 g) in toluene (20 mL) was added 571 µL of sodium bis(-2-methoxyethoxy)aluminum hydride (Red-Al, 1.5M in toluene). The mixture was stirred for 48 hours at room temperature, and the reaction was then quenched by the addition of saturated aqueous potassium sodium tartrate. The organic layer was separated and dried over Na 2 SO 4 , filtered and concentrated in vacuo to give 0.16 g of the title compound.

TLC (SiO 2 , 10% MeHO/EtOAc): Rf = 0.14.

MS (ESI): exact mass calculated for C2iH2iCTN2, 336.14;

found, m/z 337.2 [M+H]<+>, 339.2 [M+H]<+>.

*H NMR (500 MHz, CDCl 3 ): 7.31-7.24 (m, 7H), 7.07-7.06 (m, 2H), 6.76 (s, 1H), 4.98 (s, 2H), 3.56 (s, 2H), 2.72 (t, J=6.3 Hz, 2H), 2.60 (t, J=6.3 Hz, 2H).

Example 43 (Reference example)

1-Benzyl-3-(4-trifluoromethylphenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene.

Step A: 3-oxo-23,4,5,7,8-hexahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester.

To a solution of 5-oxo-azepane-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (Example 59, Step A; 8.29 g) in 80 mL of EtOH was added 1.5 mL of hydrazine hydrate. The solution was heated to reflux for two days and then cooled to room temperature. The solvent volume was reduced to about 20 ml, and the resulting solution was stored at -15°C for 16 hours. Water was added and the solids were collected by filtration, washed with water and dried to give 4.99 g of the desired compound as a white crystalline solid.

MS (ESI): exact mass calculated for C12H19N3O3, 253.14;

found, m/z 254.1 [M+H]<+>.

Step B: 1-benzyl-3-oxo-2,3,4,5,7,8-hexahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester.

To a stirred solution of 1.16 g of the compound from step Ai in 15 ml of DMF, 1.80 g of CS 2 CO 3 was added. The suspension was stirred at room temperature for 20 minutes. Benzyl bromide (0.6 mL) was added and the mixture was stirred at room temperature for an additional 12 h. The mixture was diluted with water and extracted with Et 2 O. The combined organic layers were washed with water, brine, dried over Na 2 SO 4 , and concentrated to give 1.77 g of a colorless partial solid. Chromatography on SiC>2 (15 to 50% EtOAc/hexane) gave in 1 hour 1.21 g of a desired compound as a mixture of mono-benzylated isomers.

TLC (SiO 2 , 50% EtOAc/hexane): Rf = 0.34.

MS (ESI): exact mass calculated for C19H25N3O3, 343.19,

found, m/z 344.2 [M+H]<+>, 366.2 [M+Na]<+>.

Step C: 1-benzyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester.

To a stirred solution of the above mixture of regioisomers (1.21 g) in 35 mL of CH 2 Cl 2 , 1.93 mL of i-Pr 2 NEt and 1.58 g of N-phenyltrifluoromethanesulfonimide were added. The mixture was heated to reflux for 12 hours and then cooled and concentrated in vacuo. Chromatography on SiC>2 (5 to 20% EtOAc/hexane) gave 0.63 g of the desired compound. TLC (SiO 2 , 25% EtOAc/hexane): Rf = 0.37.

MS (ESI): exact mass calculated for C20H24F3N3O5S, 475.14;

found, m/z 476.2 [M+H]<+>.

In addition, 0.68 g of the undesired monobenzylated 3-benzyloxy-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester was obtained.

Step D: 1-Benzyl-3-(4-trifluoromethylphenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester.

To a solution of the compound from step C (0.17 g) in 5 mL THF was added 0.12 g K3PO4, 0.08 g 4-trifluoromethylphenylboronic acid and 0.03 g PdC^dppf The mixture was heated to reflux for 12 h . The mixture was cooled, filtered through diatomaceous earth and concentrated in vacuo. Chromatography on SiO 2 (5 to 40% EtOAc/hexane) gave 0.05 g of the desired compound. TLC (SiO 2 , 25% EtOAc/hexane): Rf = 0.49.

Step E: 1-benzyl-3-(4-trifluoromethylphenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene.

To a stirred solution of the compound from step D (0.05 g) in 2 mL of CH 2 Cl 2 was added 2.0 mL of TF A. The mixture was stirred at room temperature for 2 h and concentrated in vacuo. The crude product was redissolved in CH 2 Cl 2 and treated with Dowex<®>550A resin. After stirring for 2 hours, the mixture was filtered and concentrated in vacuo to give 0.04 g of the title compound. The product was dissolved in Et 2 O and treated with excess 1.0 M HCl in Et 2 O for 30 minutes. The solvent was removed in vacuo to give 0.05 g of the corresponding HCl salt.

MS (ESI): exact mass calculated for C21H20F3N3, 371.16;

found, m/z 372.2 [M+H]<+>.

*H NMR (500 MHz, CD3OD): 7.78-7.74 (m, 4H), 7.37-7.28 (m, 3H), 7.20 (t, J=6.9 Hz, 2H), 5.46 (br s, 2H), 4.65 ( br s, 1H), 3.40-3.37 (m, 3H), 3.17-3.10 (m, 4H).

The title compounds of Examples 44 and 47 were prepared according to the general procedure indicated in Example 43, steps D and E, unless otherwise indicated.

Example 44 (Reference example)

1-Benzyl-3-phenyl-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene.

The title compound (0.07 g) was prepared from the compound of Example 43, Step C (0.16 g) and 0.05 g of phenylboric acid.

MS (ESI): exact mass calculated for C20H-21N3, 303.17;

found, m/z 304.2 [M+H]<+>.

<*>HNMR (500 MHz, CD3OD): 7.56-7.54 (m, 2H), 7.51-7.43 (m, 3H), 7.39-7.36 (m, 2H), 7.33-7.29 (m, 1H), 7.21 (d , J=6.9 Hz), 5.50 (s, 2H), 3.43-3.38 (m, 4H), 3.22-3.20 (m, 2H), 3.12-3.10 (m, 2H).

Example 47

1-Benzyl-3-(4-fluorophenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene.

The title compound (0.07 g) was prepared from the compound of Example 43, Step C (0.22 g), and 0.20 g of 4-fluorophenylboronic acid by adding 9.1 mg of dppf and using a hexane solvent.

MS (ESI): exact mass calculated for C20H20FN3, 321.16;

found, m/z 322.2 [M+H]<+>.

<*>HNMR (500 MHz, CDC13): 7.54-7.51 (m, 2H), 7.33-7.30 (m, 2H), 7.28-7.24 (m, 1H), 7.12-7.07 (m, 4H), 5.35 (s , 2H), 2.98-2.95 (m, 2H), 2.94-2.92 (m, 2H), 2.80-2.77 (m, 2H), 2.76-2.74 (m, 2H).

Example 57 1-Benzyl-3-phenyl-6-propyl-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene.

The title compound (0.05 g) was prepared from 1-benzyl-3-phenyl-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene (Example 44, 0.09 g) and 23 µL of propionaldehyde as in Example 35. MS (ESI): exact mass calculated for C 23 H- 27 N 3 , 345.22;

found, m/z 346.3 [M+H]<+>.

<*>HNMR (400 MHz, CD3OD): 7.56-7.54 (m, 2H), 7.47-7.28 (m, 6H), 7.21-7.19 (m, 2H), 5.44 (s, 2H), 3.70-3.66 (m , 2H), 3.41-3.07 (m, 8H), 1.86-1.76 (m, 2H), 1.03 (t, J=7.3 Hz, 3H).

Example 59

1-Benzyl-3-(4-chlorophenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene.

Step A: 5-oxo-azepane-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester.

A solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (35 mmol, 7.0 g) in anhydrous Et 2 O (50 mL) was stirred in a 200 mL 3-necked flask equipped with two addition funnels. The solution was cooled to -25°C. Ethyl diazoacetate (46.5 mmol, 4.89 mL) in anhydrous Et 2 O (10 mL) and BF 3 OEt 2 (36.7 mmol, 4.65 mL) in anhydrous Et 2 O (10 mL) were simultaneously, but independently, added to the solution in during 90 minutes. The mixture was stirred further for 1 hour and was slowly warmed to room temperature. Then 30% aqueous K2CO3 was added dropwise to the mixture until gas evolution stopped. The organic layer was separated, dried over Na2SO4 and concentrated. The residue was purified by chromatography (SiO 2 , 5 to 20% EtOAc/hexane) to give the desired compound (7.5 g).

Step B: 4-oxo-azepane-1-carboxylic acid tert-butyl ester.

To a solution of the product of step A in 1,4-dioxane (50 mL) was added 1N NaOH (40.83 mmol, 40.83 mL). The mixture was stirred at room temperature overnight. The solution was then acidified to pH 4-5 with 3 N HCl. The mixture was extracted with Et 2 O followed by CH 2 Cl 2 until TLC showed no product remaining in the aqueous layer. The combined organic layers were dried over Na 2 SO 4 and concentrated in vacuo to give the desired compound (7.46 g).

MS (ESI): exact mass calculated for C11H19NO3, 214.14;

found, m/z 236.2 [M+Na]<+>.

Step C: 3-(4-Chlorophenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester.

p-Toluenesulfonic acid (0.033 mg, 0.18 mmol) and morpholine (3.4 mL, 38 mmol) were added to a solution of the product of Step B (7.46 g, 35.0 mmol) in benzene (15 mL) .

The reaction mixture was heated to reflux for 20 hours using a Dean-Stark trap. The reaction mixture was cooled to room temperature and concentrated in vacuo to give the intermediate enamine, which was used without further purification. To a 0°C solution of the enamine in CH 2 Cl 2 (30 mL) was added triethylamine (27.5 mmol, 3.80 mL) followed by a solution of 4-chlorobenzoyl chloride (27.5 mmol, 3.50 mL) in CH 2 Cl 2 (10ml). The reaction mixture was warmed to room temperature and stirred for 16 hours. The mixture was poured into water and the layers were separated. The organic layer was dried over Na2SO4 and concentrated. The resulting oil was diluted with EtOH (120 mL), cooled to 0 °C and treated with hydrazine (75 mmol, 2.4 mL). The reaction mixture was warmed to room temperature and stirred for 16 hours. The mixture was concentrated and the residue purified by SFC purification to give the desired compound (1.2 g).

MS (ESI): exact mass calcd for C 12 H 2 CIN 2 O 3 347.14;

found, m/z 346.0 [M-H]".

<*>HNMR (500 MHz, CD3OD): 7.40-7.35 (m, 4H), 3.62-3.59 (m, 2H), 3.54-3.51 (m, 2H), 2.96-2.93 (m, 2H), 2.81-2.77 (m, 2H), 1.20 (s, 9H).

The reaction sequence also gave 3-(4-chlorophenyl)-4,6,7,8-tetrahydro-1H-1,2,5-triaza-azulene-5-carboxylic acid tert-butyl ester (1.5 g).

MS (ESI): exact mass calcd for C 12 Cl 12 O 347.14;

found, m/z 346.0 [M-H]".

JH NMR (500 MHz, CD3OD): 7.65 (d, J=8.2 Hz, 1H), 7.47-7.41 (m, 3H), 4.67-4.45 (m, 2H), 3.71-3.65 (m, 2H), 2.90- 2.89 (m, 2H), 1.90-1.87 (m, 2H), 1.18 (s, 9H).

Step D: 1-benzyl-3-(4-chlorophenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester.

To a 0 °C solution of the product of step C (0.10 g, 0.29 mmol) in DMF (2 mL) was added NaH (60% dispersion in oil, 92 mg, 2.3 mmol). The solution was warmed to room temperature over 1 hour, and benzyl chloride (2.3 mmol) was then added. The reaction mixture was stirred for 16 hours and then concentrated. The residue was diluted with water and extracted with CH 2 Cl 2 . The organic layer was washed with brine, dried over Na2SO4 and concentrated. The impure product was purified by SiCV chromatography which gave the desired ester which was taken directly to the next step. 2-Benzyl-3-(4-chlorophenyl)-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester was also obtained.

MS (ESI): exact mass calculated for C25H-28CIN3O2, 437.19;

found, m/z 438.4 [M+H]<+>.

*H NMR (500 MHz, CDCl 3 ): 7.50-7.48 (m, 2H), 7.40-7.38 (m, 2H), 7.33-7.26 (m, 3H), 7.13-7.11 (m, 2H), 5.33 (s, 2H), 3.55-3.51 (m, 4H), 2.86-2.77 (m, 4H), 1.47 (s, 9H).

Step E:

The product from step D was dissolved in 9:1 CH 2 Cl 2 /MeOH (4 mL). An excess of 1 N HCl in Et 2 O was added and the resulting mixture was stirred for 2 h. Progress of the reaction was monitored by MS until no more starting material remained. The reaction mixture was concentrated to give the desired product (51 mg).

MS (ESI): exact mass calculated for C20H20CIN3, 337.13;

found, m/z 338.2 [M+H]<+>.

JH NMR (500 MHz, CD3OD): 7.56-7.53 (m, 2H), 7.51-7.48 (m, 2H), 7.38-7.29 (m, 3H), 7.20-7.19 (m, 2H), 5.48 (s, 2H ), 3.42-3.37 (m, 4H), 3.20-3.18 (m, 2H), 3.10-3.08 (m, 2H).

An alternative procedure set out in Scheme 5 is shown below:

Step F: 3-(4-chlorophenyl)-1,4,6,7-tetrahydro-indazole-5-[1,31-dioxolane.

The desired compound (5.0 g) was prepared from 5.0 g of 1,4-dioxa-spiro[4.5]decan-8-one, 4.5 ml of 4-chlorobenzoyl chloride and 3.0 ml of hydrazine according to the procedure given in step C above.

JH NMR (500 MHz, CDCl 3 ): 7.53-7.50 (m, 2H), 7.36-7.33 (m, 2H), 4.02 (s, 4H), 2.91 (s, 2H), 2.89 (t, J=6.6 Hz, 2H), 2.01 (t, J=6.6 Hz, 2H).

Step G: 1-benzyl-3-(4-chlorophenyl)-1,4,6,7-tetrahydro-indazole-5-[1,3]dioxolane. The desired compound (3.93 g) was prepared from 4.0 g of the compound from Step F as indicated in Step D, using benzyl bromide (1.9 mL) in place of benzyl chloride and K 2 CO 3 (6.1 g) in instead of NaH.

*HNMR (500 MHz, CDC13): 7.67-7.64 (m, 2H), 7.39-7.27 (m, 5H), 7.21-7.18 (m, 2H), 5.29 (s, 2H), 4.05-3.98 (m, 4H ), 2.95 (s, 2H), 2.71 (t, J=6.6 Hz, 2H), 1.98 (t, J=6.6 Hz, 2H).

Step H: 1-benzyl-3-(4-chlorophenyl)-1,4,6,7-tetrahydro-indazol-5-one oxime.

A solution of 3.87 g of the compound from Step G in 80 mL of THF with 5 mL of 1M HCl was heated to reflux for 16 hours. The volatile compounds were removed in vacuo and water was added (300 mL). The mixture was adjusted to pH 9 by addition of 1 M NaOH and then extracted with CH 2 Cl 2 . The combined extracts were washed with brine and the solvent removed in vacuo to give 1-benzyl-3-(4-chlorophenyl)-1,4,6,7-tetrahydro-indazol-5-one. This product (3.13 g) was treated with hydroxylamine hydrochloride (3.0 g) in 20 ml of pyridine. The reaction mixture was stirred at room temperature for 14 hours, and was then diluted with water (300 mL) and stirred for an additional 1 hour. The mixture was filtered on paper and the solids were washed with EtOAc and dried in vacuo to give 2.48 g of the desired compound.

*HNMR (500 MHz, acetone-d6): 10.24 (s, 1H), 7.30-7.26 (m, 2H), 7.06-7.02 (m, 2H), 6.91-9.87 (m, 2H), 6.85-6.81 (m , 1H), 6.77-6.73 (m, 2H), 3.21 (s, 2H), 2.31 (t, J=6.6 Hz, 2H), 2.09 (t, J=6.6 Hz, 2H).

Step I. 1-Benzyl-3-(4-chlorophenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene.

A solution of the compound from Step H (78.2 mg) in 15 mL of CH 2 Cl 2 was cooled to 0°C and diisobutylaluminum hydride (1.5 M in toluene, 0.75 mL) was added. The mixture was warmed to room temperature and stirred for 12 hours. Water (0.2 mL) and NaF (0.40 g) were added and the mixture was stirred for 1 h. The mixture was filtered through diatomaceous earth and the filtrate concentrated to give 66.7 mg of a mixture of the title compound and 1-benzyl-3-(4-chlorophenyl)-1,4,5,6,7,8-hexahydro-1,2, 5-triaza-azul one.

MS (ESI): exact mass calculated for C20H20CIN3, 337.13;

found, m/z 338.0 [M+H]<+>.

Examples 60 through 102 were prepared using the procedures described in Example 59, steps D and E, unless otherwise noted.

Example 64

3-(4-Chlorophenyl)-2-ethyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene.

The title compound (0.021 g) was prepared from 3-(4-chlorophenyl)-2-ethyl-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 63) according to Example 59, step E.

MS (ESI): exact mass calculated for CisHigCINs, 275.12;

found, m/z 276.1 [M+H]<+>.

<*>HNMR (500 MHz, CD3OD): 7.46 (d, J=8.6 Hz, 2H), 7.24 (d, J=8.6 Hz, 2H), 3.90 (q, J=7.2 Hz, 2H), 3.31-3.29 (m, 2H), 3.20-3.19 (m, 2H), 3.06-3.04 (m, 2H), 2.69-2.67 (m, 2H), 1.17 (t, J=7.2Hz, 3H).

Example 74

3-(4-Chlorophenyl)-1-(3-methylbenzyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene.

The title compound (0.004 g) was prepared from 3-(4-chlorophenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 59, Step C ; 0.1 g) using 3-methylbenzyl chloride (0.6 ml) instead of benzyl chloride.

MS (ESI): exact mass calculated for C2iH22CIN3, 351.15;

found, m/z 352.2 [M+H]<+>.

<*>HNMR (500 MHz, CD3OD): 7.31-7.26 (m, 2H), 7.26-7.21 (m, 2H), 6.99 (t, J=7.5 Hz, 1H), 6.88 (d, J=7.1 Hz, 1H), 6.76 (s, !H), 6.67 (d, J=7.1 Hz, 1H), 5.13 (s, 2H), 2.79-2.73 (m, 4H), 2.69-2.65 (m, 2H), 2.63- 2.60 (m, 2H), 2.09 (s, 3H).

Example 75

3-(4-Chlorophenyl)-1-(4-fluorobenzyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene.

The title compound (0.003 g) was prepared from 3-(4-chlorophenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 59, Step C ; 0.1 g) using 4-fluorobenzyl chloride (0.5 ml) instead of benzyl chloride.

MS (ESI): exact mass calculated for C20H19CIFN3, 355.13;

found, m/z 356.2 [M+H]<+>.

<*>HNMR (500 MHz, CD3OD): 7.40-7.37 (m, 2H), 7.35-7.32 (m, 2H), 7.08-7.04 (m, 2H), 6.98-6.94 (m, 2H), 5.26 (s , 2H), 2.89-2.86 (m, 4H), 2.80-2.78 (m, 2H), 2.73-2.70 (m, 2H).

Example 76

3-(4-Chlorophenyl)-1-(3-fluorobenzyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene.

The title compound (0.01 g) was prepared from 3-(4-chlorophenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 59, step C; 0.1 g) using 3-fluorobenzyl chloride (0.5 ml) instead of benzyl chloride.

MS (ESI): exact mass calculated for C20H19CIFN3, 355.13;

found, m/z 356.1 [M+H]<+>.

<*>HNMR (500 MHz, CD3OD): 7.42-7.37 (m, 2H), 7.35-7.32 (m, 2H), 7.28-7.21 (m, 1H), 6.93-6.88 (m, 1H), 6.84 (d , J=7.7 Hz, 1H), 6.75-6.71 (m, 1H), 5.29 (s, 2H), 2.89-2.85 (m, 4H), 2.79-2.76 (m, 2H), 2.74-2.70 (m, 2H ).

Example 82 (Reference example)

5-[3-(4-Chlorophenyl)-5,6,7,8-tetrahydro-4H-1,2,6-triaza-azulen-2-yl]-pentanoic acid methyl ester.

The title compound (0.0042 g) was prepared from 3-(4-chlorophenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 59, step C; 0.15 g) using methyl 5-chlorovalerate (0.90 ml) in place of benzyl chloride. The reaction sequence also results in 3-(4-chlorophenyl)-1-(4-methoxycarbonylbutyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester in the alkylation step .

MS (ESI): exact mass calculated for C19H24CIN3C>2, 361.16;

found, m/z 362.2 [M+H]<+>.

*HNMR (500 MHz, CD3OD): 7.54-7.51 (m, 2H), 7.31-7.29 (m, 2H), 3.95 (t, J==7.0 Hz, 2H), 3.60 (s, 3H), 3.03-3.01 (m, 2H), 2.93-2.91 (m, 4H), 2.56-2.53 (m, 2H), 2.16 (t, J=7.4 Hz, 2H), 1.67-1.62 (m, 2H), 1.41-1.38 (m , 2H).

Example 84 (Reference example)

5-[3-(4-chlorophenyl)-5,6,7,8-tetrahydro-4H-1,2,6-triaza-azulen-2-yl]-pentan-1-ol.

5-[3-(4-Chlorophenyl)-5,6,7,8-tetrahydro-4H-1,2,6-triaza-azulen-2-yl]-pentanoic acid methyl ester (Example 82, 0.009 g) was dissolved in 9:1 Et 2 O/CH 2 Cl 2 (3 mL) and the solution was slowly added to a stirred suspension of lithium aluminum hydride (2 mg) in 5 mL anhydrous Et 2 O. After stirring at room temperature for 6 hours, the reaction was stopped with 2 ml of water. The mixture was treated with 2 mL of 1 N NaOH, followed by an additional 2 mL of water. The mixture was then filtered through kieselguhr. The organic layer was separated,

dried over MgSC>4 and concd. After further drying via vacuum, the resulting oil was dissolved in 2 mL of 9:1 CH 2 Cl 2 /MeOH and treated with 3 mL of 1 N HCl in Et 2 O. After 4 hours, the volatile compounds were removed in vacuo. The crude oil was purified by preparative TLC (9:1 CH 2 Cl 2 /2 M NH 3 i MeOH) to give 0.001 of the title compound as a colorless oil.

MS (ESI): exact mass calcd for C 12 H 2 Cl 2 O, 333.16;

found, m/z 334.2 [M+H]<+>.

<*>HNMR (500 MHz, CD3OD): 7.54-7.52 (m, 2H), 7.32-7.30 (m, 2H), 3.95 (t, J=7.1 Hz, 2H), 3.44 (t, J=6.6 Hz, 2H), 3.13-3.09 (m, 2H), 3.03-3.00 (m, 2H), 2.98-2.95 (m, 2H), 2.61-2.58 (m, 2H), 1.70-1.64 (m, 2H), 1.40- 1.35 (m, 2H), 1.20-1.16 (m, 2H).

Example 85 (Reference example)

5-[3-(4-Chlorophenyl)-5,6,7,8-tetrahydro-4H-1,2,6-triaza-azulen-1-yl]-pentanoic acid methyl ester.

The title compound (0.0051 g) was prepared from 3-(4-chlorophenyl)-1-(4-methoxycarbonyl-butyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene- 6-carboxylic acid tert-butyl ester (Example 82) according to Example 59, step E.

MS (ESI): exact mass calculated for C19H24CIN3O2, 361.16;

found, m/z 362.2 [M+H]<+>.

<*>HNMR (500 MHz, CD3OD): 7.45-7.40 (m, 4H), 4.13 (t, J=7.0 Hz, 2H), 3.63 (s, 3H), 3.04-3.03 (m, 2H), 2.98- 2.95 (m, 4H), 2.79-2.76 (m, 2H), 2.34 (t, J=7.4 Hz, 2H), 1.81-1.77 (m, 2H), 1.61-1.58 (m, 2H).

Example 87

5-[3-(4-chlorophenyl)-5,6,7,8-tetrahydro-4H-1,2,6-triaza-azulen-1-yl]-pentan-1-ol.

5-[3-(4-Uorphen<y>1)-5,6,7,8-tetrahydro-4H-1,2,6-triaza-azulen-1-yl]-pentan<y> re methyl ester (Example 85, 0.015 g) was reduced as in Example 84 to give the title compound (0.0063

g) as a colorless oil.

MS (ESI): exact mass calcd for C 12 H 2 Cl 2 O, 333.16;

found, m/z 334.1 [M+H]<+>.

<*>HNMR (500 MHz, CD3OD): 7.45-7.40 (m, 4H), 4.13 (t, J=7.2 Hz, 2H), 3.53 (t, J=6.4 Hz, 2H), 3.04-3.01 (m, 2H), 2.97-2.92 (m, 4H), 2.78-2.75 (m, 2H), 1.82-1.75 (m, 2H), 1.57-1.51 (m, 2H), 1.41-1.34 (m, 2H).

Example 96 (Reference example)

3-(4-Chlorophenyl)-1-(3-fluoro-4-methoxybenzyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene.

The title compound (0.021 g) was prepared from 3-(4-chlorophenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 59, Step C ; 0.35 g) using 3-fluoro-4-methoxybenzyl bromide (0.25 g) instead of benzyl chloride. The reaction sequence also provides 3-(4-chlorophenyl)-2-(3-fluoro-4-methoxybenzyl)-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert -butyl ester in the alkylation step.

MS (ESI): exact mass calculated for C21H21CIN3O, 385.14;

found, m/z 386.1 [M+H]<+>.

*H NMR (500 MHz, CD3OD): 7.50-7.47 (m, 2H), 7.47-7.42 (m, 2H), 7.06-7.02 (m, 1H), 6.90-6.86 (m, 2H), 5.29 (s, 2H), 3.84 (s, 3H), 3.35-3.29 (m, 2H), 2.94-2.92 (m, 4H), 2.88-2.85 (m, 2H), 2.80-2.77 (m, 2H).

<13> CNMR (125 MHz, CD3OD): 154.2, 152.2, 149.1, 148.1, 143.5, 134.2, 132.9, 131.1, 131.0, 130.5, 129.1, 123.3.3, 118.7, 115.0, 114, 114, 114, 114, 114, 114. , 27.3.

Example 98

3-(Chlorophenyl)-1-(4-nitrobenzyl)-1,4,5,6,7,8-hexahydro-1,2,6-triazaazulene.

The title compound (0.004 g) was prepared from 3-(4-chlorophenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 59, Step C ; 0.3 g) using 4-nitrobenzyl bromide (0.3 g) instead of benzyl chloride.

MS (ESI): exact mass calculated for C20H19CIN4O2, 382.12;

found, m/z 383.1 [M+H]<+>.

*HNMR (400 MHz, CD3OD): 8.23-8.19 (m, 2H), 7.51-7.47 (m, 2H), 7.45-7.47 (m, 2H), 7.32 (d, J=8.6 Hz, 2H), 5.52 ( s, 2H), 2.98-2.95 (m, 4H), 2.89-2.85 (m, 2H), 2.83-2.79 (m, 2H).

Example 99 (Reference example)

4-(3-phenyl-5,6,7,8-tetrahydro-4H-1,2,6-triaza-azulen-1-ylmethyl)-phenylamine.

3-(4-Chlorophenyl)-1-(4-nitrobenzyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 98, 70 mg ) was dissolved in 25 mL of anhydrous EtOH and treated with 10% palladium on carbon (20 mg). The mixture was then hydrogenated for 4 hours at 30 psi. The mixture was filtered through kieselguhr. The filtrate was concentrated and dried via vacuum to give 55 mg of 1-(4-aminobenzyl)-3-phenyl-4,5,7,8-tetrahydro-1H,1,2,6-triaza-azulene-6-carboxylic acid tert- butyl ester. The intermediate aniline was then dissolved in 1 mL of MeOH and treated with 5 mL of 1 N HCl in Et 2 O. After 6 hours, the volatile compounds were removed in vacuo. The resulting yellow partial solid was purified by preparative TLC (9:1 CH 2 Cl 2 /2 M NH 3 i MeOH) to give 0.007 g of the title compound as a pale yellow solid.

MS (ESI): exact mass calculated for C20H22N4, 318.18;

found, m/z 319.2 [M+H]+ .

<*>HNMR (500 MHz, CD3OD): 7.50-7.47 (m, 2H), 7.44-7.41 (m, 2H), 7.37-7.34 (m, 1H), 6.94-6.90 (m, 2H), 6.68-6.65 (m, 2H), 5.23 (s, 2H), 3.11-3.06 (m, 4H), 2.99-2.96 (m, 2H), 2.91-2.88 (m, 2H).

Example 100

N-[4-(3-phenyl-5,6,7,8-tetrahydro-4H-1,2,6-triaza-azulen-1-ylmethyl)-phenyl]-methanesulfonamide.

To a solution of 0.022 g of 1-(4-aminobenzyl)-3-phenyl-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 99) in DMF (1 ml) was added 1 equivalent of triethylamine. After 5 min. 1 equivalent of methanesulfonyl chloride was added and the mixture was stirred overnight. The reaction was quenched with water and extracted with EtOAc (3x). The combined organic layers were dried over Na2SO4 and concentrated. The resulting oil was purified by preparative TLC (50% EtOAc/hexanes) to give 1-(4-methanesulfonylamino-benzyl)-3-phenyl-4,5,7,8-tetrahydro-1H-1,2,6-triaza -azulene-6-carboxylic acid tert-butyl ester. This monomesylate was then dissolved in 9:1 CF 2 Cl 2 /MeOH (2 mL) and treated with 3 mL 1 N HCl in Et 2 O. After 6 hours, the volatile part was removed in vacuo. The resulting oil was purified by preparative TLC (9:1 CH 2 Cl 2 /2 M NH 3 i MeOH) to give 0.004 g of the title compound as a white solid.

MS (ESI): exact mass calculated for C21H24N4O2S, 396.16;

found, m/z 397.1 [M+H]+ .

*H NMR (500 MHz, CD3OD): 7.50-7.47 (m, 2H), 7.42 (t, J=7.7 Hz, 2H), 7.37-7.34 (m, 1H), 7.22-7.20 (m, 2H), 7.13 -7.10 (m, 2H), 5.34 (s, 2H), 2.97-2.93 (m, 4H), 2.92 (s, 3H), 2.90-2.87 (m, 2H), 2.82-2.78 (m, 2H).

Example 103

3-(4-Chlorophenyl)-1-thiophen-2-ylmethyl-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene.

Step A: 1-(4-chlorophenyl)-2-diazo-ethanone.

To a solution of diazomethane (33.2 mmol) in Et 2 O (70 mL) was added triethylamine (33.2 mmol). The mixture was cooled to 0°C and 4-chlorobenzoyl chloride (30 mmol) in Et 2 O (30 mL) was slowly added. The mixture was then warmed to room temperature for 1 hour. After filtering the mixture, the clear filtrate was concentrated to obtain the desired crude compound (5.4 g).

Step B: 3-(4-chlorophenyl-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester).

To a 0°C mixture of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (20 mmol) in Et 2 O (150 mL) was added a solution of BF 3 E 2 O (30 mmol) in Et 2 O (150 mL) followed by a solution of the product from step A (21 mmol) in Et 2 O (150 mL). After the addition is complete, the mixture was heated to 25°C and stirred for 1 hour. Saturated aqueous NaHCO 3 (200 mL) was added and the layers were separated. The organic layer was concentrated and the resulting residue was diluted with MeOH (100 mL). Hydrazine (3 mL) was added and the mixture was stirred at 25°C for 16 h. Purification by flash chromatography (EtOAc/CH 2 Cl 2 ) afforded the desired compound (1.8 g).

Step C:

The product from step B (0.2 mmol) was mixed with 2-chloromethylthiophene (0.3 mmol) in DMF (2 mL), and Cs 2 CO 3 (0.3 mmol) was then added. The mixture was stirred at 25°C for 16 hours. After concentration and purification by SiO 2 chromatography (EtOAc/hexane), 3-(4-chlorophenyl)-1-thiophen-2-ylmethyl-1,4,5,6,7,8-hexahydro-azulene was obtained. The intermediate was treated with TF A (1 mL) in CH 2 Cl 2 (10 mL) for 4 h. After concentration of the reaction mixture, the title compound was obtained (0.029 g). The reaction sequence also gave 3-(4-chlorophenyl)-2-thiophen-2-ylmethyl-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester in the alkylation step.

MS (ESI): exact mass calculated for Ci8Hi8ClN3O, 343.09;

found, m/z 344.1 [M+H]<+>. 317.19;

*H NMR (500 MHz, CD3OD): 7.46-7.44 (m, 2H), 7.41-7.39 (m, 2H), 7.29 (dd, J=5.1, 1.1 Hz, 1H), 7.00 (dd, J=3.5, 1.1 Hz, 1H), 6.91 (dd, J=5.1, 3.5 Hz, 1H), 5.52 (s, 2H), 3.36-3.34 (m, 2H), 3.30-3.28 (m, 2H), 3.24-3.18 (m , 2H), 2.99-2.97 (m, 2H).

Examples 104 through 155 were prepared using the method described in Example 103 unless otherwise indicated.

Example 104

1-Benzyl-3-thiophen-2-yl-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene.

The title compound (28 mg) was prepared from 3-thiophen-2-yl-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester as described in Example 103, using thiophene-2-carbonyl chloride (5 mmol) instead of 4-chlorobenzoyl chloride, and benzyl chloride (0.3 mmol) instead of 2-chloromethylthiophene.

MS (ESI): exact mass calculated for Ci8Hi9N3S, 309.13;

found, m/z 310.1 [M+H]<+>.

*HNMR (500 MHz, CD3OD): 7.27-7.01 (m, 8H), 5.28 (s, 2H), 3.26-3.24 (br m, 2H), 3.18-3.16 (br m, H), 3.11-3.09 (br m, 2H), 2.96-2.94 (br m, 2H).

Example 108

3-(4-Chlorophenyl)-1-(2,4-difluorobenzyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene.

The title compound (0.030 g) was prepared from 3-(4-chlorophenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 103, Step B ; 0.2 mmol) using 2,4-difluorobenzyl bromide (0.3 mmol) instead of 2-chloromethylthiophene. The reaction sequence also gave 3-(4-chlorophenyl)-2-(2,4-difluorobenzyl)-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester in the alkylation step.

MS (ESI): exact mass calculated for C 2 oHi 8 CIF 2 N 3 , 373.12;

found, m/z 374.1 [M+H]<+>.

*HNMR (400 MHz, CD3OD): 7.52-7.49 (br m, 4H), 7.27-7.24 (br m, 1H), 7.01-6.99 (br m, 2H), 5.52 (s, 2H), 3.51-3.49 ( brm, 2H), 3.43-3.40 (brm, 2H), 3.34-3.31 (brm, 2H), 3.11-3.09 (br m, 2H).

Example 111

1-but-3-enyl-3-(4-chlorophenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene.

The title compound (0.028 g) was prepared from 3-(4-chlorophenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 103, Step B ; 0.2 mmol) using 1-but-3-enyl chloride (0.3 mmol) instead of 2-chloromethylthiophene.

MS (ESI): exact mass calculated for Ci7H22CrN30, 301.13;

found, m/z 302.1 [M+H]<+>.

<*>HNMR (500 MHz, CDCl3):7.40-7.37 (m, 2H), 7.31-7.28 (m, 2H), 6.75-6.67 (m, 1H), 5.02-5.00 (br m, 2H), 4.07 ( t, J=7.2 Hz, 2H), 2.99-2.97 (br m, 2H), 2.91-2.89 (br m, 2H), 2.80-2.78 (br m, 2H), 2.71-2.69 (br m, 2H), 2.48 (q, J=7.3 Hz, 2H).

Example 114

3-(4-Chlorophenyl)-1-(2-ethyl-butyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene.

The title compound (0.010 g) was prepared from 3-(4-chlorophenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 103, Step B ; 0.2 mmol) by using 1-bromo-2-ethylbutane (0.3 mmol) instead of 2-chloromethyl-thiophene. The reaction sequence also gave 3-(4-chlorophenyl)-2-(2-ethyl-butyl)-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester in the alkylation step.

MS (ESI): exact mass calculated for C19H26CIN3, 331.18;

found, m/z 332.3 [M+H]<+>.

<*>HNMR (400 MHz, CD3OD): 7.50-7.48 (brm, 4H), 4.11-4.09 (brm, 2H), 3.71-3.69 (br m, 2H), 3.33-3.31 (brm, 2H), 3.26- 3.24 (brm, 2H), 3.06-3.04 (brm, 2H), 1.91-1.89 (m, 1H), 1.36-1.34 (m, 4H), 0.93 (t, J=7.3 Hz, 6H).

Example 117

3-(4-Chlorophenyl)-1-cyclohexylmethyl-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene.

The title compound (0.09 g) was prepared from 3-(4-chlorophenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 103, step B; 170 mg) using cyclohexylmethyl bromide (2 mmol) instead of 2-chloromethylthiophene. The reaction sequence also gave 3-(4-chlorophenyl)-2-cyclohexylmethyl-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester in the alkylation step.

MS (ESI): exact mass calculated for C20H-26CIN3, 343.18;

found, m/z 344.3 [M+H]<+>.

<*>HNMR (500 MHz, CD3OD): 7.37 (d, J=6.6 Hz, 2H), 7.32 (d, J=6.6 Hz, 2H), 3.94 (d, J=7.3 Hz, 2H); 3.44-3.40 (br m, 2H), 3.35-3.32 (br m, 2H), 3.17-3.14 (br m, 2H), 3.01-2.99 (brm, 2H), 1.74-1.53 (m, 4H), 1.52 ( d, J=11.2Hz, 2H), 1.17-1.10 (m, 3H), 0.94-0.90 (m, 2H).

Example 118

3-(4-Chlorophenyl)-1-isobutyl-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene.

The title compound (0.031 g) was prepared from 3-(4-chlorophenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 103, Step B ; 0.2 mmol) using isobutyl bromide (0.3 mmol) instead of 2-chloromethylthiophene. The reaction sequence also gave 3-(4-chlorophenyl)-2-isobutyl-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester from the alkylation step.

MS (ESI): exact mass calculated for C17H22CIN3, 303.15;

found, m/z 304.1 [M+H]<+>.

JH NMR (500 MHz, CD3OD): 7.64 (d, J=6.6 Hz, 2H), 7.56 (d, J=6.6 Hz, 2H), 4.20 (d, J=7.4 Hz, 2H), 3.72-3.69 (br m, 2H), 3.62-3.60 (br m, 2H), 3.44-3.42 (br m, 2H), 3.29-3.27 (br m, 2H), 2.35 (m, 1H), 1.14 (d, J=6.7 Hz , 6H).

Example 119

1-Benzo[1,3]dioxol-5-ylmethyl-3-(4-chlorophenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene.

The title compound (0.035 g) was prepared from 3-(4-chlorophenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 103, Step B ; 0.2 mmol) using benzo[1,3]dioxol-5-ylmethyl chloride (0.3 mmol) instead of 2-chloromethylthiophene. The reaction sequence also gave 2-benzo[1,3]dioxol-5-ylmethyl-3-(4-chlorophenyl)-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester in the alkylation step.

MS (ESI): exact mass calculated for C2iH20CIN3O2, 381.12;

found, m/z 382.1 [M+H]<+>.

*H NMR (500 MHz, CD3OD): 7.39-7.32 (m, 4H), 6.67-6.65 (m, 1H), 6.54-6.61 (m, 2H), 5.81 (s, 2H), 5.16 (s, 2H) , 2.81-2.79 (m, 4H), 2.76-2.74 (m, 2H), 2.68-2.66 (m, 2H).

Example 120

3-(4-Chlorophenyl)-1-(tetrahydro-pyran-4-ylmethyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene.

The title compound was prepared from 3-(4-chlorophenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 103, Step B; 0.2 mmol) by using toluene-4-sulfonic acid tetrahydropyran-3-ylmethyl ester (0.3 mmol) instead of 2-chloromethyl-thiophene. The title compound was obtained as a 2:1 mixture (25 mg) with 3-(4-chlorophenyl)-2-(tetrahydro-pyran-4-ylmethyl)-2,4,5,6,7,8-hexahydro-1 ,2,6-triaza-azulene. Data for the mixture: MS (ESI): exact mass calculated for C19H24CIN3O, 345.16;

found, m/z 346.1 [M+H]<+>.

*HNMR (500 MHz, CD3OD): 7.47-7.23 (m, 4H), 4.10-3.78 (m, 4H), 3.37-3.14 (m, 8H), 3.06-2.67 (m, 2H), 2.02-1.93 (m , 1H), 1.42-0.97 (m, 4H).

Example 131

3-(4-Chlorophenyl)-2-isobutyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene.

The title compound (0.010 g) was prepared from 3-(4-chlorophenyl)-2-isobutyl-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 118, step C) according to the deprotection method from example 103, step C.

MS (ESI): exact mass calculated for C17H22CIN3, 303.15;

found, m/z 304.1 [M+H]<+>.

<*>HNMR (400 MHz, CD3OD): 7.58-7.56 (m, 2H), 7.37-7.34 (m, 2H), 3.81 (d, J=7.5 Hz, 2H), 3.42-3.40 (m, 2H), 3.34-3.30 (m, 2H), 3.18-3.15 (m, 2H), 2.81-2.78 (m, 2H), 2.02-2.00 (m, 1H), 0.74 (d, J=6.7 Hz, 6H).

Example 133

2-Benzyl-3-phenyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene.

To a solution of 2-benzyl-3-(4-chlorophenyl)-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (0.1 mmol) (Example 59, Step D) in THF (25 mL) was added lithium aluminum hydride (100 mg). The mixture was heated to reflux for 4 hours. Water, 1 ml, was added, the mixture was filtered and the filtrate was concentrated. After purification (SiO 2 , EtOAc/hexane), 2-benzyl-3-phenyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester was obtained.

Example 160

4-[3-(4-Uophenyl)-5,6,7,8-tetrahydro-4H-1,2,6-triaza-azulen-1-ylmethyl]-2-fluorophenyl.

BBr3 (0.13 mL) was slowly added to a 0°C solution of 0.022 g of 3-(4-chlorophenyl)-1-(3-fluoro-4-methoxybenzyl)-1,4,5,6,7, 8-Hexahydro-1,2,6-triaza-azulene (Example 96) in CH 2 Cl 2 (20 mL). After 1 hour, the mixture was warmed to room temperature and stirred for 18 hours. The reaction was then cooled to 0°C and quenched by the addition of 5 mL of saturated aqueous NaHCO 3 . The aqueous layer was extracted with methanol CH 2 Cl 2 (2x). The combined organic layers were dried over Na2SO4 and concentrated. The crude oil was purified by preparative TLC (9:1 CH 2 Cl 2 /2 M NH 3 i MeOH) to give the title compound (0.16 g) as a tan solid.

MS (ESI): exact mass calculated for C20H19CIN3O, 371.12;

found, m/z 372.1 [M+H]<+>.

<*>HNMR (400 MHz, CD3OD): 7.50-7.42 (m, 4H), 6.86-6.79 (m, 3H), 5.26 (s, 2H), 3.31-3.26 (m, 2H), 2.96-2.95 (m , 4H), 2.90-2.87 (m, 2H), 2.81-2.79 (m, 2H). 13C NMR (100 MHz, CD3OD): 154.2, 151.8, 149.6, 146.1, 146.0, 143.8, 134.8, 133.4, 131.1, 130.3, 130.3.2, 129.7, 124.0, 118.1, 115.6, 115.4, 50.1, 50.4, 50.4, 50.1, 50.4.

Example 165

1-Benzyl-3-(4-chlorophenyl)-6-methyl-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene.

To a solution of 1-benzyl-3-(4-chlorophenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene (Example 59, Step E; 0.1 mmol ) in 1,2-dichloroethane (5 ml) was added acetic acid (0.2 mmol), formaldehyde (37% aqueous solution, 0.037 ml) and NaBH(OAc)3 (0.2 mmol). The mixture was stirred at room temperature for 15 hours. The mixture was diluted with CH 2 Cl 2 and washed with saturated aqueous NaHCO 3 (2x). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated in vacuo. Chromatography on SiO 2 (2 M NH 3 in MeOH/CH 2 Cl 2 ) gave 0.015 g of the title compound.

MS (ESI): exact mass calculated for C21H22CIN3, 351.15;

found, m/z 352.2 [M+H]<+>.

*H NMR (400 MHz, CDCl 3 ): 7.45-7.42 (m, 2H), 7.32-7.29 (m, 2H), 7.26-7.19 (m, 3H), 7.03-7.01 (br m, 2H), 5.27 (s , 2H), 2.75-2.68 (m, 4H), 2.64-2.58 (m, 4H), 2.36 (s, 3H). Examples 166 and 167 were synthesized using the procedure described in Example 165 unless otherwise noted.

Example 166 1-Benzyl-3-(4-chlorophenyl)-6-ethyl-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene.

The title compound (18 mg) was prepared using acetaldehyde (0.2 mmol) instead of formaldehyde.

MS (ESI): exact mass calculated for C 22 H 24 CIN 3 , 365.17;

found, m/z 366.2 [M+H]<+>.

*H NMR (400 MHz, CDCl 3 ): 7.45-7.43 (m, 2H), 7.31-7.29 (m, 2H), 7.26-7.19 (m, 3H), 7.03-7.01 (brm, 2H), 5.26 (s, 2H), 2.74-2.71 (m, 10H), 1.01 (t, J=7.1 Hz, 3H).

Example 167

3-(4-Chlorophenyl)-6-(3,4-dimethoxybenzyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene.

To a solution of 3-(4-chlorophenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 59, Step C; 0.1 mmol) in CH 2 Cl 2 (5 mL) was added TFA (1 mL). The mixture was stirred at room temperature for 16 hours. After concentration, the intermediate 3-(4-chlorophenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene was obtained. The intermediate (0.1 mmol) was converted to the title compound (16 mg) according to the procedure described in Example 165 using 3,4-dimethoxybenzaldehyde (0.2 mmol) instead of formaldehyde.

MS (ESI): exact mass calculated for C 22 H 24 CIN 3 O 2 , 397.16;

found, m/z 398.2 [M+H]<+>.

*H NMR (500 MHz, CD3OD): 7.38-7.35 (br m, 4H), 7.91 (d, J=1.8 Hz), 6.82-6.80 (dd, J=8.1, 1.8 Hz, 1H), 6.76-6.74 ( d, J=8.1, 1H), 3.83-3.80 (s, 6H), 2.84-2.82 (m, 4H), 2.71-2.69 (m, 4H).

Example 172

3-(4-Chlorophenyl)-1-phenyl-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene.

A solution of 3-(4-chlorophenyl)-4,5,7,8-tetrahydro-1H-1,2,6-thiraza-azulene-6-carboxylic acid tert-butyl ester (Example 59, step C; 0.3 mmol ) in CH 2 Cl 2 (5 mL) was treated with phenylboric acid (0.6 mmol), pyridine (0.6 mmol) and copper(II) acetate (4.5 mmol). The mixture was stirred at room temperature for 16 hours. After concentration and purification (SiO 2 , EtOAc/hexane), 3-(4-chlorophenyl)-1-phenyl-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene-6 -carboxylic acid tert-butyl ester obtained. This intermediate was then diluted with CH 2 Cl 2 (10 mL) and TFA (1 mL) was added. The mixture was stirred at room temperature for 4 hours. The mixture was concentrated and the residue was purified (SiO 2 , 2 M NH 3 in MeOH/CH 2 Cl 2 ) to give the title compound (40 mg).

MS (ESI): exact mass calcd for C 1 H 2 Cl 3 ), 323.12;

found, m/z 324.1 [M+H]<+>.

<*>HNMR (500 MHz, CDC13): 7.46-7.40 (m, 4H), 7.36-7.32 (m, 5H), 3.09-3.07 (br m, 4H), 3.00-2.98 (br m, 2H), 3.92 -2.90 (br m, 2H).

Example 173 (Reference example)

3-(4-Chlorophenyl)-1-(2-methylbenzyl)-4,5,6,7,8,9-hexahydro-1H-1,2,6-triaza-cyclopentacyclooctene.

Step A: 3-(4-chlorophenyl)-1,4,5,7,8,9-hexahydro-1,2,6-triaza-cyclopentacyclooctene-6-carboxylic acid tert-butyl ester.

To a 0°C solution of 4-oxo-azepane-1-carboxylic acid tert-butyl ester (Example 59, Step B; 0.915 g) in Et 2 O (30 mL) was added BF 3 Et 2 O (0.733 mL) followed by the solution of 1-( 4-Chlorophenyl)-2-diazoethanone (Example 103, Step A; 4.5 mmol) in Et 2 O (30 mL). The mixture was heated to 25°C and stirred for 1 hour. Saturated aqueous NaHCO 3 (40 mL) was added and the organic layer was separated and concentrated. The resulting residue was diluted with MeOH (50 mL) and treated with hydrazine (1.5 mL). The reaction mixture was stirred at 25°C for 16 hours. Concentration and purification by flash chromatography (SiO 2 , EtOAc/CH 2 Cl 2 ) afforded the desired ester.

Step B: 3-(4-Chlorophenyl)-1-(2-nietylbenzyl)-1,4,5J,8,9-hexahydro-1,2,6-triaza-cyclopentacyclooctene-6-carboxylic acid tert- butyl ester.

A solution of the product from Step A (0.2 mmol) in DMF (2 mL) was treated with 2-methylbenzyl chloride (0.3 mmol) followed by CS 2 CO 3 (0.3 mmol). The mixture was stirred at 25°C for 16 hours. Concentration and purification by chromatography (SiO 2 , EtOAc/hexane) afforded the target intermediate.

Step C:

A solution of the product from Step B in MeOH (20 mL) was treated with HCl (2 M in Et 2 O, 1 mL) for 16 h. After concentration and purification by chromatography (SiO 2 , 2 M NH 3 in MeOH/CH 2 Cl 2 ) the title compound was obtained (24 mg). The reaction sequence also gave 3-(4-chlorophenyl)-1-(2-methylbenzyl)-4,5,6,7,8,9-hexahydro-1H-1,2,7-triaza-cyclopentacyclooctene (20 mg).

MS (ESI): exact mass calculated for C 22 H 24 CIN 3 , 365.17;

found, m/z 366.2 [M+H]<+>.

*H NMR (500 MHz, CD3OD): 7.51-7.50 (m, 2H), 7.42-7.40 (m, 2H), 7.14-7.05 (m, 3H), 6.58 (d, J=7.6 Hz, 1H), 5.42 (s, 2H), 3.25 (t, J=5.6 Hz, 2H), 3.13 (t, J=5.6 Hz, 2H), 3.01 8t, J=5.6 Hz, 2H), 2.89 (t, J=5.6 Hz, 2H), 2.30 (s, 3H), 1.78-1.76 (m, 2H).

Example 174

3-(4-Chlorophenyl)-1-(2-methyl-benzyl)-4,5,6,7,8,9-hexahydro-1H-1,2,7-triaza-cyclopentacyclooctene.

The title compound (20 mg) was obtained as in Example 173.

MS (ESI): exact mass calculated for C 22 H 24 CIN 3 , 365.17;

found, m/z 366.2 [M+H]<+>.

*H NMR (500 MHz, CD3OD): 7.48-7.46 (m, 2H), 7.39-7.36 (m, 2H), 7.14-7.05 (m, 3H), 6.55-6.54 (m, 1H), 5.39 (s, 2H), 3.02-3.00 (m, 2H), 2.98-2.96 (m, 4H), 2.80-2.78 (m, 2H), 2.30-2.28 (s, 3H), 1.99-1.97 (m, 2H).

Example 176 (Reference example)

2,3-diphenyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene.

Step A: 3-oxo-2-phenyl-2,3,4,5,7,8-hexahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester.

To a solution of the compound (3.13 g) from Example 59, Step A in 80 mL of EtOH was added 1.2 mL of phenylhydrazine. The resulting solution was heated to reflux for 3 days and then cooled to room temperature, and the solvent was removed in vacuo. The residue was chromatographed on SiC>2 (0 to 80% EtOAc/hexane) to give 3.13 g of the desired compound.

MS (ESI): exact mass calculated for C18H23N3O3, 329.17;

found, m/z 330.2 [M+H]<+>.

Step B: 2-phenyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester.

To a stirred solution of the above compound (1.79 g) in 35 ml of CH 2 Cl 2 was added 3.0 ml of i-Pr 2 NEt and 3.05 g of N-phenyltrifluoromethanesulfonimide. The mixture was heated to reflux for 24 hours and then concentrated in vacuo. Chromatography on SiO 2 (0 to 75% EtOAc/hexane) gave 1.88 g of the desired compound.

MS (ESI): exact mass calculated for C19H22F3N3O5S, 461.12;

found, m/z 407.1 [M+H]<+>.

Step C: 2,3-diphenyl-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester.

To a solution of the above compound (0.28 g) in 5 ml of 1,4-dioxane was added 0.29 g of K3PO4, 104.3 mg of phenylboric acid and 43.0 mg of PdCl2dppf. The mixture was heated at 80°C for 3 hours . More phenylboronic acid (0.10 g) and PdC2dppf (26 mg) were added and the temperature was increased to 100°C. After an additional 12 hours, the mixture was poured into water (100 mL) and extracted with CH 2 Cl 2 (3 x 20 mL). The combined layers were filtered through kieselguhr and the filtrate was concentrated in vacuo. Chromatography on SiC>2 (0 to 20% EtOAc/hexane) gave 158.8 mg of the desired compound.

MS (ESI): exact mass calculated for C24H27N3O2, 389.21;

found, m/z 390.2 [M+H]<+>.

Step D:

To a stirred solution of the above compound (158.8 mg) in 5 mL of EtOH was added 2 mL of 1.0 M HCl in Et 2 O. The mixture was stirred at room temperature for 12 hours and concentrated in vacuo to give 75.6 mg of the title compound.

MS (ESI): exact mass calculated for C19H19N3, 289.16;

found, m/z 290.2 [M+H]<+>.

XH NMR (500 MHz, CD3OD): 7.41-7.38 (m, 3H), 7.36-7.32 (m, 3H), 7.23-7.18 (m, 4H), 3.49-3.45 (m, 2H), 3.38-3.34 (m , 2H), 3.26-2.32 (m, 2H), 2.96-2.93 (m, 2H).

Example 177

2-cyclohexyl-3-phenyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene.

Step A: Cyclohexyl-hydrazine hydrochloride.

To a solution of cyclohexanone (1.25 ml) in hexane (8 ml) was added 1.59 g of tert-butyl carbamate. The mixture was heated to reflux for 10 min. and then allowed to cool to room temperature. The white precipitate was then treated with BH 3 (1.0 M in THF, 12 mL). After stirring at room temperature for 20 min. the mixture was treated with 16 mL of 6 N HCl. The mixture was heated to 110°C for 20 min. and then concentrated in vacuo. The residue was treated with 30 ml of THF. The title compound (1.82 g), a white solid, was collected from the mixture by filtration.

MS (ESI): exact mass calculated for C6Hi4N2, 114.12;

found, m/z 115.1 [M+H]<+>.

<X>HNMR (500 MHz, CDC13): 3.05-2.99 (m, 1H), 2.11-2.09 (m, 2H), 1.88-1.86 (m, 2H), 1.72-1.69 (m, 1H), 1.37-1.19 (m, 5H).

Step B: 2-cyclohexyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester.

The desired compound was prepared as in steps A and B of Example 176, with cyclohexylhydrazine hydrochloride from step A in place of phenylhydrazine. The hydrazine salt was neutralized with Dowex<®>550 resin pre-use.

Step C: 2-cyclohexyl-3-phenyl-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester.

To a solution of 126 mg of the compound from step A in 3 mL of 1,4-dioxane was added 299 mg of K3PO4, 131 mg of phenylboric acid and 7.5 mg of dppf PdCl2dppf (22 mg) was then added and the mixture was heated to reflux over the night. The mixture was concentrated in vacuo and the residue was dissolved in toluene. The solution was filtered through diatomaceous earth and the filtrate was concentrated to give 202 mg of an oil. Chromatography on SiO 2 (5 to 25% EtOAc/hexane) gave 98.7 mg of the desired compound.

MS (ESI): exact mass calculated for C 24 H 33 N 3 O 2 , 395.26;

found, m/z 396.2 [M+H]<+>.

Step D:

The above compound (98.7 mg) was converted to the title compound (71.0 mg) as in Example 43, Step E, and the crude product was chromatographed on SiO 2 (2 to 8% 2 M NH 3 in MeOH/EtOAc).

MS (ESI): exact mass calculated for Ci9H25N3, 295.20;

found, m/z 296.2 [M+H]<+>.

<*>HNMR (500 MHz, CDC13): 7.59-7.49 (m, 3H), 7.35-7.29 (m, 2H), 3.97-3.88 (m, 1H), 3.44-3.38 (m, 2H), 3.34-3.27 (m, 2H), 3.20-3.14 (m, 2H), 2.81-2.73 (m, 2H), 1.99-176 (m, 6H), 1.65 (br s, 1H), 1.28-1.17 (m, 3H).

Example 178

3-(4-Chlorophenyl)-2-cyclohexyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene.

The title compound (48 mg) was prepared as in Example 177, steps C and D, using 129 mg of 2-cyclohexyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza- azulene-6-carboxylic acid tert-butyl ester (Example 177, Step B) and 173 mg of 4-chlorophenylboronic acid.

MS (ESI): exact mass calculated for C19H24CIN3, 329.17;

found, m/z 330.1 [M+H]<+>.

<*>HNMR (500 MHz, CDC13): 7.60-7.53 (m, 2H), 7.36-7.27 (m, 2H), 3.94-3.83 (m, 1H), 3.43-3.36 (m, 2H), 3.34-3.26 (m, 2H), 3.2-3.12 (m, 2H), 2.80-2.72 (m, 2H), 1.98-1.76 (m, 6H), 1.67 (br s, 1H), 1.32-1.17 (m, 3H).

Example 180

2-cyclopentyl-3-phenyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene.

Step A: 2-cyclopentyl-3-trifluoromethanesulfonylcyclo-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester.

The desired triflate was prepared as in steps A and B of Example 176 using cyclopentylhydrazine hydrochloride (prepared according to the procedure of Example 177, step A using cyclopentanone instead of cyclohexanone) in place of phenylhydrazine, t-butanol instead for EtOH, with the addition of 3 equiv. triethylamine.

Step B:

The title compound (52 mg) was prepared from the product of Step A (101 mg) according to the procedure of Example 177, Steps C and D, using 109 mg of phenylboric acid.

MS (ESI): exact mass calculated for Ci8H23N3, 281.19;

found, m/z 282.1 [M+H]<+>.

*H NMR (500 MHz, CDCl 3 ): 7.58-7.48 (m, 3H), 7.36-7.30 (m, 2H), 4.50 (m, 1H), 3.44-3.38 (m, 2H9, 3.34-3.27 (m, 2H ), 3.22-3.16 (m, 2H), 2.81-2.75 (m, 2H), 2.06-1.84 (m, 6H), 1.65-1.54 (m, 2H).

Example 181

3-(4-Chlorophenyl)-2-cyclopentyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene.

The title compound (74 mg) was prepared as in Example 177, steps C and D, using 215 mg of 2-cyclopentyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza- azulene-6-carboxylic acid tert-butyl ester (Example 180, Step A) and 296 mg of 4-chlorophenylboronic acid.

MS (ESI): exact mass calculated for Ci8H22CIN3, 315.15;

found, m/z 316.1 [M+H]<+>.

*HNMR (500 MHz, CDC13): 7.59-7.53 (m, 2H), 7.36-7.30 (m, 2H), 4.48 (m, 1H), 3.44-3.37 (m, 2H), 3.34-3.27 (m, 2H ), 3.22-3.15 (m, 2H), 2.81-2.74 (m, 2H), 2.06-1.84 (m, 6H), 1.65-1.55 (m, 2H).

Example 182

2-Cyclopentyl-3-(4-fluorophenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene.

The title compound (113 mg) was prepared as in Example 177, steps C and D, using 2-cyclopentyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene- 6-carboxylic acid tert-butyl ester (Example 180, step A) and 185 mg of 4-fluorophenylboronic acid.

MS (ESI): exact mass calculated for Ci8H22FN3,299.18;

found, m/z 300.5 [M+H]<+>.

*H NMR (500 MHz, CDCl 3 ): 7.45-7.39 (m, 2H), 7.35-7.29 (m, 2H), 4.53 (m, 1H), 3.48-3.42 (m, 2H), 3.36-3.28 (m, 2H), 3.28-3.23 (m, 2H), 2.84-2.78 (m, 2H), 2.08-1.85 (m, 6H), 1.67-1.56 (m, 2H).

Example 183

2-(1-ethylpropyl)-3-(3-fluorophenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene.

Step A: 2-(1-ethylpropyl)-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester.

The desired triflate was prepared as in Steps A and B of Example 176, using (1-ethyl-propyl)-hydrazine hydrochloride (made from 3-pentanone as described in Example 177, Step A) in place of phenylhydrazine. The hydrazine was neutralized with NaH in DMF use.

Step B:

The title compound (82 mg) was prepared as in Example 177, steps C and D, using 150 g of the triflate from step A and 138 mg of 3-fluorophenylboronic acid.

MS (ESI): exact mass calculated for Ci8H24FN3, 301.20;

found, m/z 302.4 [M+H]<+>.

*H NMR (500 MHz, CDCl 3 ): 7.61-7.55 (m, 1H), 7.31-7.25 (m, 1H), 7.16-7.12 (m, 1H), 7.10-7.05 (m, 1H), 3.85-3.77 ( m, 1H), 3.45-3.40 (m, 2H), 3.35-3.29 (m, 2H), 3.23-3.18 (m, 2H), 2.82-2.76 (m, 2H), 1.97-1.80 (m, 2H), 1.79-1.70 (m, 2H), 0.71 (t, J=7.4 Hz, 3H).

Example 184

2-(1-ethyl-propyl)-3-(4-fluorophenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene.

The title compound (93 mg) was prepared as in Example 177, steps C and D, using 150 mg of 2-(1-ethylpropyl)-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2, 6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 183, Step A) and 138 mg of 3-fluorophenylboronic acid.

MS (ESI): exact mass calculated for Ci8H24FN3, 301.20;

found, m/z 302.5 [M+H]<+>.

XHNMR (500 MHz, CDC13): 7.44-7.30 (m, 4H), 3.92-3.85 (m, 1H), 3.51-3.43 (m, 2H), 3.38-3.33 (m, 2H), 3.30-3.24 (m, 2H), 2.86-2.78 (m, 2H), 1.98-1.85 (m, 2H), 1.84-1.73 (m, 2H), 0.73 (t, J=7.4 Hz, 3H).

Example 186

2-(1-ethylpropyl)-3-phenyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene.

The title compound (40 mg) was prepared as in Example 177, steps C and D, using 150 mg of 2-(1-ethyl-propyl)-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1, 2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 183, Step A) and 120 mg of phenylboric acid.

MS (ESI): exact mass calculated for Ci8H25N3, 283.20;

found, m/z 284.4 [M+H]<+>.

<*>HNMR (500 MHz, CDC13): 7.48-7.38 (m, 3H), 7.24-7.19 (m, 2H), 3.77-3.70 (m, 1H), 3.36-3.31 (m, 2H), 3.24-3.19 (m, 2H), 3.14-3.09 (m, 2H), 2.71-2.65 (m, 2H), 1.85-1.75 (m, 2H), 1.68-1.58 (m, 2H), 0.61 (t, J=7.4 Hz , 3H).

Example 189 (Reference example)

2-isopropyl-3-phenyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene.

Step A: 2-isopropyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester.

The desired triphate was prepared as in steps A and B of Example 176, using isopropylhydrazine hydrochloride in place of phenylhydrazine, t-butanol in place of EtOH with the addition of 3 equiv. triethylamine.

Step B:

The title compound (93 mg) was prepared as in Example 177, steps C and D, using 172 mg of the triflate from step A and 147 mg of phenylboric acid.

MS (ESI): exact mass calculated for d6H2iN3, 255.17;

found, m/z 256.5 [M+H]<+>.

<*>HNMR (500 MHz, CDC13): 7.58-7.49 (m, 3H), 7.36-7.30 (m, 2H), 4.40 (m, 1H), 3.45-3.40 (m, 2H), 3.34-3.28 (m , 2H), 3.23-3.18 (m, 2H), 2.82-2.75 (m, 2H), 1.40 (d, J=6.9 Hz, 6H).

Example 190

3-(4-Fluorophenyl)-2-isopropyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene.

The title compound (92 mg) was prepared in Example 177, steps C and D, using 159 mg of 2-isopropyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene -6-carboxylic acid tert-butyl ester (Example 189, Step A) and 156 mg of 4-fluorophenylboronic acid.

MS (ESI): exact mass calculated for Ci6H20FN3,273.16;

found, m/z 274.4 [M+H]<+>.

*H NMR (500 MHz, CDCl 3 ): 7.42-7.35 (m, 2H), 7.33-7.27 (m, 2H), 4.37 (m, 1H), 3.46-3.39 (m, 2H), 3.34-3.28 (m, 2H), 3.23-3.18 (m, 2H), 2.81-2.74 (m, 2H), 1.41 (d, J=6.9 Hz, 6H).

Example 191

2-(1-ethylpropyl)-3-thiophen-2-yl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene.

The title compound (35 mg) was prepared as in Example 177, steps C and D, using 148 mg of 2-(1-ethylpropyl)-3-trifluoromethanesulfonoxy-4,5,7,8-tetrahydro-2H-1,2, 6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 183, Step A) and 122 mg of 2-thiopheneboronic acid.

MS (ESI): exact mass calculated for C16H23N3S, 289.16;

found, m/z 290.5 [M+H]<+>.

*H NMR (500 MHz, CDCl3): 7.72-7.67 (m, 1H), 7.25-7.21 (m, 1H), 7.13-7.09 (m, 1H), 4.01-3.94 (m, !H), 3.43-3.38 (m, 2H), 3.34-3.28 (m, 2H), 3.20-3.14 (m, 2H), 2.86-2.80 (m, 2H), 1.95-1.85 (m, 2H), 179-1.69 (m, 2H) , 0.71 (t, J=7.4 Hz, 3H).

Example 192

2-cyclopentyl-3-thiophen-3-yl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene.

The title compound (114 mg) was prepared as in Example 177, steps C and D, using 200 mg of 2-cyclopentyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza- azulene-6-carboxylic acid tert-butyl ester (Example 180, Step A) and 169 mg of 3-thiopheneboronic acid.

MS (ESI): exact mass calculated for Ci6H2iN3S 287.15;

found, m/z 288.4 [M+H]<+>.

*H NMR (500 MHz, CDCl3): 7.68-7.63 (m, 1H), 7.56-7.51 (m, 1H), 7.17-7.12 (m, 1H), 4.58 (m, 1H), 3.43-3.37 (m, 2H), 3.34-3.28 (m, 2H9, 3.19-3.14 (m, 2H), 2.86-2.80 (m, 2H), 2.04-1.85 (m, 6H), 1.67-1.57 (m, 2H).

Example 193 (Reference example O

2-Ethyl-3-phenyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene.

Step A: 2-ethyl-3-trifluoromethanesulfonylcyclo-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester.

The desired triflate was prepared as in steps A and B of Example 176, using ethyl hydrazine oxalate in place of phenylhydrazine, t-butanol in place of EtOH, with the addition of 3 equiv. triethylamine.

Step B:

The title compound (106 mg) was prepared as in Example 177, Steps C and D, using 198 mg of the triflate from Step A and 122 mg of phenylboric acid.

MS (ESI): exact mass calculated for C15H19N3, 241.16;

found, m/z 242.4 [M+H]<+>.

*H NMR (500 MHz, CDCl 3 ): 7.61-7.54 (m, 3H), 7.43-7.39 (m, 2H), 4.11 (q, J=7.1 Hz, 2H), 3.49-3.44 (m, 2H), 3.37 -3.32 (m, 2H), 3.28-3.22 (m, 2H), 2.89-2.82 (m, 2H), 1.33 (t, J=7.1Hz, 3H).

Example 209

2-isopropyl-3-p-tolyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene.

The title compound (129 mg) was prepared as in Example 177, steps C and D, using 204 mg of 2-isopropyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza- azulene-6-carboxylic acid tert-butyl ester (Example 189, Step A) and 194 mg of 4-methylphenylboronic acid.

MS (ESI): exact mass calculated for C17H23N3, 269.19;

found, m/z 270.5 [M+H]<+>.

*H NMR (500 MHz, CDCl 3 ): 7.28 (d, J=7.7 Hz, 2H), 7.12 (d, J=7.7 Hz, 2H), 4.32 (m, 1H), 3.34-3.33 (m, 2H), 3.12-3.10 (m, 2H), 2.70-2.68 (m, 2H), 2.33 (s, 3H), 1.30 (d, J=6.6 Hz, 6H).

Example 210

3-(4-Ethylphenyl)-2-isopropyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene.

The title compound (134 mg) was prepared as in Example 177, steps C and D, using 202 mg of 2-isopropyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza- azulene-6-carboxylic acid tert-butyl ester (Example 189, step A) and 212 mg of 4-ethylphenylboronic acid.

MS (ESI): exact mass calculated for Ci8H25N3, 283.20;

found, m/z 284.5 [M+H]<+>.

*H NMR (500 MHz, CD3OD): 7.44 (d, J=7.7 Hz, 2H), 7.31 (d, J=7.7 Hz, 2H), 4.52 (m, 1H), 3.50-3.48 (m, 2H), 3.36-3.34 (m, 2H), 2.85-2.83 (m, 2H), 2.75 (q, J=7.7 Hz, 2H), 1.47 (d, J=6.6 Hz, 6H), 1.29 (t, J=7.7 Hz , 3H).

Example 211

3-(4-Chlorophenyl)-2-isopropyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene.

The title compound (82 mg) was prepared as in Example 177, steps C and D, using 205 mg of 2-isopropyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza- azulene-6-carboxylic acid tert-butyl ester (Example 189, Step A) and 332 mg of 2-(4-chlorophenyl)-benzo[1,3,2]dicaborole.

MS (ESI): exact mass calculated for Ci6H20CIN3, 289.13;

found, m/z 290.4 [M+H]<+>, 2.92.4 [M+H]<+>.

*H NMR (500 MHz, CD3OD): 7.57 (d, J=8.5 Hz, 2H), 7.33 (d, J=8.5 Hz, 2H), 4.36 (m, 1H), 3.44-3.40 (m 2H), 3.20 -3.18 (m, 2H), 2.81-2.76 (m, 2H), 1.40 (d, J=6.6 Hz, 6H).

Example 212

4-(2-isopropyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulen-3-yl)-benzonitrile.

The title compound (95 mg) was prepared as in Example 177, steps C and D, using 205 mg of 2-isopropyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene -6-carboxylic acid tert-butyl ester (Example 189, Step A) and 211 mg of 4-cyanophenylboronic acid.

MS (ESI): exact mass calculated for C17H20N4, 280.17;

found, m/z 281.4 [M+H]<+>.

*H NMR (500 MHz, CD3OD): 7.57 (d, J=8.5 Hz, 2H), 7.33 (d, J=8.5 Hz, 2H), 4.36 (m, 1H), 3.42-3.40 (m, 2H), 3.19-3.17 (m, 2H), 7.33 (d, J=8.5 Hz, 2H), 4.36 (m, 1H), 3.42-3.40 (m, 2H), 3.19-3.17 (m, 2H), 2.79-2.77 ( m, 2H), 1.40 (d, J=6.6 Hz, 6H).

Example 213

2-Isopropyl-3-(4-trifluoromethylphenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene.

The title compound (103 mg) was prepared as in Example 177, steps C and D, using 199 mg of 2-isopropyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza- azulene-6-carboxylic acid tert-butyl ester (Example 189, Step A) and 265 mg of 4-trifluoromethylphenylboronic acid.

MS (ESI): exact mass calculated for C17H20F3N3, 323.16;

found, m/z 324.4 [M+H]<+>.

*H NMR (500 MHz, CD3OD): 7.86 (d, J=8.0 Hz, 2H), 7.55 (d, J=8.0 Hz, 2H), 4.34 (m, 1H), 3.43-3.40 (m, 2H), 3.20-3.18 (m, 2H), 2.80-2.78 (m, 2H), 1.40 (d, J=6.6 Hz, 6H).

Example 214

2-Ethyl-3-p-tolyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene.

The title compound (136 mg) was prepared as in Example 177, steps C and D, using 201 mg of 2-ethyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza- azulene-6-carboxylic acid tert-butyl ester (Example 193, Step A) and 198 mg of 4-trifluoromethylphenylboronic acid.

MS (ESI): exact mass calculated for Ci6H2iN3, 255.17;

found, m/z 265.5 [M+H]<+>.

*H NMR (500 MHz, CD3OD): 7.38 (d, J=8.0 Hz, 2H), 7.25 (d, J=8.0 Hz, 2H), 4.67 (br s, 1H), 4.05 (q, J=7.1 Hz , 2H), 3.92-3.41 (m, 2H), 3.28-2.18 (m, 3H), 2.89-2.80 (m, 2H), 2.43 (s, 3H), 1.29 (t, J=7.1 Hz, 3H).

Example 215

2-tert-butyl-3-phenyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene.

Step A: 2-(tert-butyl)-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester.

The desired triflate was prepared as in steps A and B of Example 176, using tert-butylhydrazine hydrochloride in place of phenylhydrazine, t-butanol in place of EtOH, with the addition of 3 equiv. triethylamine.

Step B:

The title compound (53 mg) was prepared as in Example 177, steps C and D, using 200 mg of the triflate from step A and 166 mg of phenylboric acid.

MS (ESI): exact mass calculated for C17H23N3, 269.19;

found, m/z 270.5 [M+H]<+>, 214.4 [M-<t>Bu]<+>.

*HNMR (500 MHz, CD3OD): 7.49-7.47 (m, 3H), 7.32-7.30 (m, 2H), 3.41-3.39 (m, 2H), 3.25-3.23 (m, 2H), 3.18-3.15 (m , 2H), 2.52-2.520 (m, 2H), 1.41 (s, 9H).

Example 216

2-tertbutyl-3-(4-fluorophenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene.

The title compound (88 mg) was prepared as in Example 177, steps C and D, using 204 mg of 2-(tert-butyl)-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2, 6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 215, Step A) and 194 mg of 4-fluorophenylboronic acid.

MS (ESI): exact mass calculated for C17H22FN3, 287.18;

found, m/z 288.4 [M+H]<+>, 232.4 [M-<t>Bu]<+>.

*H NMR (500 MHz, CD3OD): 7.37-7.33 (m, 2H), 7.26-7.22 (m, "H), 3.41-3.38 (m, 2H), 3.26-3.24 (m, 2H), 3.18-3.15 (m, 2H), 2.53-2.51 (m, 2H), 1.42 (s, 9H).

Example 217

2-cyclopentyl-3-p-tolyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene.

The title compound (70.4 mg) was prepared as in Example 177, steps C and D, using 204.3 mg of 2-cyclopentyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2, 6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 180, Step A) and 204.1 mg of 4-methylphenylboronic acid.

MS (ESI): exact mass calculated for C19H25N3, 295.42;

found, m/z 296.5 [M+H]<+>, 232.4 [M-<t>Bu]<+>.

*H NMR (500 MHz, CD3OD): 7.37 (d, J=7.9 Hz, 2H), 7.21 (d, J=7.9 Hz, 2H), 4.50 (m, 1H), 3.43-3.40 (m, 2H), 3.32-3.28 (m, 2H), 3.20-3.17 (m, 2H), 2.80-2.77 (m, 2H), 2.43 (s, 3H), 2.04-1.86 (m, 6H), 1.64-1.55 (m, 2H ).

Example 218

2-Cyclopentyl-3-(4-trifluoromethyl-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene.

The title compound (45.2 mg) was prepared as in Example 177, steps C and D, by

using 269.2 mg of 2-cyclopentyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 180, step A) and 359.2 mg of 4-trifluoromethylphenylboronic acid.

MS (ESI): exact mass calculated for C19H22F3N3, 349.49;

found, m/z 350.3 [M+H]<+>.

*H NMR (500 MHz, CD3OD): 7.87 (d, J=7.0 Hz, 2H), 7.55 (d, J=7.9 Hz, 2H), 4.48 (m, 1H), 3.43-3.40 (m, 2H), 3.21-3.17 (m, 2H), 2.81-2.77 (m, 2H), 2.07-1.86 (m, 6H), 1.66-1.57 (m, 2H).

Example 220

2-Cyclopentyl-3-(4-methoxyphenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene.

The title compound (34.9 mg) was prepared as in Example 177, steps C and D, using 299.2 mg of 2-cyclopentyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2, 6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 180, Step A) and 329.2 mg of 4-methoxyphenylboronic acid.

MS (ESI): exact mass calculated for C19H25N3O, 311.42;

found, m/z 312.3 [M+H]<+>.

<X>HNMR (500 MHz, CD3OD): 7.26-7.23 (m, 2H), 7.11-7.08 (m, 2H), 4.51 (m, 1H), 3.87 (s, 3H), 3.43-3.40 (m, 2H ), 3.20-3.16 (m, 2H), 2.80-2.76 (m, 2H), 2.02-1.86 (m, 6H), 1.64-1.55 (m, 2H).

Example 232

2-cyclopentyl-3-furan-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene.

The title compound (101 mg) was prepared as in Example 180 using 202 mg of 2-cyclopentyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert -butyl ester (Example 180, step A) and 149 mg of 3-furanboric acid.

MS (ESI): exact mass calculated for Ci 6 H 2 iN 3 O, 272.5;

found, m/z 330.5 [M+H]<+>.

*H NMR (500 MHz, CD3OD): 7.73-7.72 (m, 2H), 6.57-6.56 (m, 1H), 4.64 (m, 1H), 3.40-3.38 (m, 2H), 3.16-3.14 (m, 2H), 2.86-2.84 (m, 2H), 2.03-1.91 (m, 6H), 1.66-1.64 (m, 2H).

Example 233

2-cyclopentyl-3-thiophen-2-yl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene.

The title compound (83 mg) was prepared as in Example 180 using 200 mg of 2-cyclopentyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert -butyl ester (Example 180, step A) and 282 mg of 2-thiopheneboric acid.

MS (ESI): exact mass calculated for Ci 6 H 2 iN 3 O, 287.15;

found, m/z 288.4 [M+H]<+>.

*H NMR (500 MHz, CD3OD): 7.70-7.68 (m, 1H), 7.24-7.22 (m, 1H), 7.15-7.14 (m, 1H), 4.64 (m, 1H), 3.41-3.39 (m, 2H), 3.16-3.15 (m, 2H), 2.85-2.83 (m, 2H), 2.01-1.88 (m, 6H), 1.63-1.60 (m, 2H).

Example 236

2-Cyclopentyl-3-(3,4-difluorophenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene.

The title compound (70 mg) was prepared as in Example 180 using 209 mg of 2-cyclopentyl-3-trifluoromethanesulfonoxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert -butyl ester (Example 180, step A) and 218 mg of 3,4-difluorophenylboronic acid.

MS (ESI): exact mass calculated for Ci8H2iF2N3, 317.17;

found, m/z 318.4 [M+H]<+>.

*H NMR (500 MHz, CD3OD):7.50-7.45 (m, 1H), 7.36-7.32 (m, 1H), 7.18-7.17 (m, 1H), 4.49 (m, 1H), 3.43-3.41 (m, 2H), 3.21-3.19 (m, 2H), 2.80-2.78 (m, 2H), 2.15-1.87 (m, 6H), 1.66-1.61 (m, 2H).

Example 238

3-(4-Chlorophenyl)-2-cyclobutyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene.

To a solution of 3-(4-chlorophenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 103, Step B; 0.40 mmol) in DMF (2 ml) was added NaH (60%) dispersion in oil, (60 mg) at 25°C. After 10 min. the mixture was heated to 80°C and chlorocyclobutane (1.5 mmol) was added. The mixture was heated at this temperature for 16 hours. The mixture was concentrated and purified by chromatography (SiO 2 , EtOAc/hexane) to give 3-(4-Horphenyl)-2-cyclobutyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza- azulene-6-carboxylic acid tert-butyl ester. The title compound (0.030 mg) was obtained from the ester according to the deprotection method of Example 103, step C. The reaction sequence also gave 3-(4-chlorophenyl)-1-cyclobutyl-2,4,5,6,7,8-hexahydro-1 ,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester in the alkylation step.

MS (ESI): exact mass calculated for C17H20CIN3, 301.13;

found, m/z 302.4 [M+H]<+>.

*H NMR (500 MHz, CD3OD): 7.52-7.51 (m, 2H), 7.30-7.29 (m, 2H), 4.70-4.60 (m, 1H), 3.40-3.89 (m, 2H), 3.27-3.21 ( m, 4H), 2.79-2.76 (m, 2H), 2.60-2.50 (m, 2H), 2.30-2.20 (m, 2H), 1.81-1.65 (m, 2H).

Example 241

3-(4-Chloro-3-fluorophenyl)-2-cyclopentyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene.

The title compound (31 mg) was prepared according to Example 180 using 146 mg of 2-cyclopentyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 180, Step A) and 168 mg of 3-chloro-4-fluorophenylboronic acid.

MS (ESI): exact mass calculated for Ci8H2iCrFN3, 333.14;

found, m/z 334.4 [M+H]<+>, 336.4 [M+H]<+>.

*H NMR (500 MHz, CD3OD): 7.39-7.31 (m, 2H), 7.22-7.18 (m, 1H), 4.37 (m, 1H), 3.31-3.28 (m, 2H), 3.07-3.03 (m, 2H), 2.67-2.64 (m, 2H), 2.11-1.78 (m, 6H), 1.56-1.47 (m, 2H).

Example 242

2-isopropyl-3-(4-methoxyphenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene.

The title compound (196 mg) was prepared according to Example 189 using 278 mg of 2-isopropyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 189, Step A) and 402 mg of 4-trifluoromethoxyphenylboronic acid.

MS (ESI): exact mass calculated for C17H20F3N3O, 339.36;

found, m/z 340.5 [M+H]<+>.

*H NMR (500 MHz, CD3OD): 7.53-7.45 (m, 4H), 4.66 (br s, 1H), 4.40 (J=6.68 Hz, 1H), 3.45-3.43 (m, 1H), 3.23-3.21 ( m, 1H), 2.88-2.79 (m, 2H), 1.42 (d, J=6.7 Hz, 6H).

Example 253

2-isopropyl-3-(4-nitrophenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene.

The title compound (34 mg) was prepared according to Example 189 using 274 mg of 2-isopropyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 189, Step A) and 321 mg of 4-nitrophenylboronic acid.

MS (ESI): exact mass calculated for C16H20N4O2, 300.16;

found, m/z 301.4 [M+H]<+>.

*H NMR (500 MHz, CD3OD): 8.42-8.40 (m, 2H), 7.62-7.60 (m, 2H), 4.37 (m, 1H), 3.43-3.41 (m, 2H), 3.21-3.18 (m, 2H), 2.82-2.79 (m, 2H), 1.41 (d, J=8.2 Hz, 6H).

Example 255

3-(4-Chlorophenyl)-1-cyclooctyl-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene.

The title compound (47 mg) was prepared from 3-(4-Horphenyl-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 103, Step B; 0.30 mmol) using chlorocycloheptane (1.0 mmol) instead of chlorocyclobutane according to Example 238. The reaction sequence also gave 3-(4-chlorophenyl)-2-cyclopentyl-1,4,5, 6,7,8-Hexahydro-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester in the alkylation step MS (ESI): exact mass calculated for C2iH28CIN3, 357.20;

found, m/z 358.5 [M+H]<+>.

XHNMR (500 MHz, CD3OD): 7.50-7.44 (m, 4H), 4.49-4.45 (m, 1H), 3.51-3.48 (m, 2H), 3.38-3.36 (m, 2H), 3.33-3.32 (m, 2H), 3.05-3.04 (m, 2H), 2.21-2.18 (m, 2H), 1.97-1.88 (m, 4H), 1.72-1.64 (m, 8H).

Example 257

2-Ethyl-3-(4-ethylphenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene.

The title compound (140 mg) was prepared according to Example 193 using 213 mg of 2-ethyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 193, Step A) and 232 mg of 4-ethylphenylboronic acid. MS (ESI): exact mass calculated for C17H23N3, 269.19;

found, m/z 270.5 [M+H]<+>.

*H NMR (500 MHz, CD3OD): 7.40-7.39 (m, 2H), 7.27-7.26 (m, 2H), 4.65 (br s, 2H), 4.05-4.00 (m, 2H), 3.8-3.6 (m , 2H), 3.18-3.00 (m, 2H), 2.88-2.81 (m, 2H), 2.76-2.71 (m, 2H), 1.32-1.24 (m, 6H).

Example 263 (Reference example)

2-Ethyl-3-(4-trifluoromethyl-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene.

Step A: 2-ethyl-3-(4-trifluoromethylphenyl)-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester.

To a 25 ml round flask was added 216 mg of 2-ethyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 193, step A), 139 mg of 4-trifluoromethylphenylboronic acid, 17 mg of B^N^Br", 6 mg of dppf, and 17 mg of PdCl2(dppf). The toluene (5 mL) was added, followed by 0.8 mL of 2 M aqueous Na2CO3, and the mixture was heated at 120°C for 12 h under N 2 . The mixture was filtered through diatomaceous earth and the filtrate was concentrated in vacuo to give 294 mg of a dark brown viscous oil. Chromatography on SiO 2 (0 to 25% EtOAc/hexane) gave 177 mg of the desired product.

MS (ESI): exact mass calculated for C2iH26F3N3O2, 409.20;

found, m/z 410.5 [M+H]<+>.

Step B:

The title compound (149 mg) was prepared according to Example 43, Step E.

MS (ESI): exact mass calculated for d6Hi8F3N3, 309.15;

found, m/z 310.5 [M+H]<+>.

*H NMR (500 MHz, CD3OD): 7.90-7.89 (m, 2H), 7.65-7.63 (m, 2H), 4.67 (br s, 2H), 4.10 (q, J=7.2 Hz, 2H), 4.00- 3.56 (m, 2H), 3.36-3.24 (m, 2H), 2.95-2.85 (m, 2H), 1.33 (t, J=7.2 Hz, 3H).

Example 273

1-Benzyl-3-(4-chlorophenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azule citrate salt.

Step A: 5-oxo-azepane-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester.

To a dried N 2 -flooded, 500 mL three-necked round bottom flask equipped with a magnetic stir bar was added 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (20 g, 0.10 mol) and BF 3 Et 2 O (14 mL, 0.11 mol) in Et 2 O ( 200 ml) and the mixture was cooled to -5°C. Ethyl diazoacetate (13.7 mL, 0.13 mol) was slowly added over a 1 hour period causing vigorous gas evolution. The internal temperature was maintained between 0°C and -5°C during the addition. The reaction mixture was stirred for one hour at 0°C and the reaction was then slowly quenched with 30% aqueous Na 2 CC> 3 at 0°C. The pH was adjusted to between 7 and 8, and then H 2 O (30 mL) was added to the mixture. The organic layer was extracted with EtOAc (2 x 75 mL), dried with Na 2 SO 4 , filtered and concentrated to an orange oil. The crude oil was purified by filtration chromatography (SiC 2 ; 14 cm OD, 8 cm height;

10 to 30% EtOAc/hexane) to give the title compound as a pale yellow oil (85%).

MS (ESI): exact mass calculated for C14H23NO5;

found, m/z none, unstable.

HPLC (method B): Rt = 8.53 min.

*H NMR (400 MHz, CDCl 3 ): 4.25-2.03 (m, 11 H), 1.47-1.45 (d, J=7.8 Hz, 9H), 1.31-1.24 (m, 3H).

Step B: 3-oxo-2,3,4,5,7,8-hexahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester.

In a 1-L, one-necked round-bottom flask equipped with a magnetic stir bar, 5-oxo-azepane-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (24.42 g, 85.0 mmol) and hydrazine (3, 0 mL, 0.085 mol) in EtOH (250 mL). The resulting reaction mixture was heated to reflux for 4 hours and then the mixture was concentrated to give the desired pyrazole as a white solid in 95% pure yield. The impure pyrazole was used in the next step without further purification.

MS (ESI): exact mass calculated for C12H19N3O3; 253.14;

found, m/z 254.1 [M+H]<+>.

HPLC (method B): Rt = 6.48 min.

*H NMR (400 MHz, CDCl 3 ): 3.64-3.54 (m, 4H), 2.91-2.86 (m, 2H), 2.70-2.65 (m, 2H), 1.49 (s, 9H).

Step C: 3-trifluoromethanesulfonylcyclo-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester.

In a 250 mL, one-neck, round-bottomed flask equipped with a magnetic stir bar, N-phenyltrifluoromethanesulfonimide (50 g, 0.14 mol) was suspended in 100 mL of pyridine and then 3-oxo-2,3,4,5,7,8- hexahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (35.4 g, 0.14 mol) added as a solid at room temperature. The reaction mixture formed a homogeneous solution after 1 hour, and then stirring was continued at room temperature overnight (15 hours). The solvent was evaporated under vacuum, and then the residue was partitioned between Et 2 O (500 mL) and 1 M aqueous K 2 CO 3 (300 mL). The organic layer was separated and washed with aqueous K 2 CO 3 , (1 mol/l, 300 mL) three times and then with brine (200 mL) once, dried over MgSO 4 , and evaporated to give the product as a white solid (50.2 g, 0.13 mol, 93%), which was used in the next reaction without further purification.

MS (ESI): exact mass calculated for CnHigFaNsOsS; 385.09;

found, m/z 384.0 [M-H]".

HPLC (method B): Rt = 9.55 min.

*H NMR (500 MHz, CDCl 3 ): 9.52 (s, 1H), 3.70-3.50 (m, 4H), 3.00-2.95 (m, 2H), 2.70.2.60 (m, 2H), 1.49 (s, 9H) .

Step D: 1-benzyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester.

In a 1-L, three-necked round-bottomed flask containing a magnetic stir bar, 3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (48 g, 0.125 mol) dissolved in 500 mL dry THF under N2. The solution was cooled to 0°C and potassium t-butoxide (15.4 g, 0.137 mol) was added portionwise as a solid. The reaction mixture was stirred for 10 minutes giving a clear, homogeneous solution. Benzyl bromide (23.4 g, 0.137 mol) was added through an addition funnel over 10 minutes. The resulting mixture was stirred at room temperature overnight (15 hours). The solvent was evaporated and the residue redissolved in EtOAc (300 mL). The organic layer was washed with H 2 O (2 x 200 mL) and then with brine (200 mL), dried over MgSO 4 , filtered and concentrated. The crude product was purified by pad filtration through a plug of SiO 2 to give the pure product as a white solid (44.5 g, 94 mmol, 75%).

MS (ESI): exact mass calculated for C^H^NsOsS, 475.14;

found, m/z 476.2 [M-H]".

HPLC (method B): Rt = 10.90 min.

*H NMR (500 MHz, CDCl 3 ): 7.40-7.25 (m, 5H), 7.10-7.05 (m, 2H), 5.22-5.15 (m, 2H), 3.60-3.50 (m, 4H), 2.80-2.60 ( m, 4H), 1.47-1.42 (m, 9H).

Step E: 2-(4-chlorophenyl)-benzo[1,3,2]dioxaborole.

In a 250 mL, one-necked round-bottomed flask equipped with a Dean-Stark trap and a condenser, the reaction solution of 4-chlorophenylboronic acid (17.5 g, 0.112 mol) and catechol (12.3 g, 0.112 mol) in toluene (150 mL ) heated to reflux for 4 h. The solution was cooled to room temperature and a white solid precipitated. The solvent was evaporated and the crude product (25.8 g, 0.112 mol, 100%) was used as such in the next reaction without further purification.

HPLC (method B): Rt = 6.00 and 7.50 min.

*H NMR (500 MHz, CDCl 3 ): 8.01 (d, J=8.1 Hz, 2H), 7.47 (d, J=8.1 Hz, 2H), 7.34-7.29 (m, 2H), 7.15-7.11 (m, 2H ).

Step F: 1-benzyl-3-(4-chlorophenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester.

To a 1-L three-neck round-bottom flask was added Pd(dppf)Cl2 (2.8 g, 3.4 mmol), 1,1'-bis(diphenylphosphino)ferrocene (0.96 g, 1.73 mmol), Bu 4 N<+>Bf (2.78 g, 8.6 mmol), Na 2 CO 3 (36.5 g, 3.44 mmol) and 2-(4-chlorophenyl)-benzo[l,3,2]dioxaborole (23, 8 g, 103 mmol), under N2. A solution of 1-benzyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (41 g, 86 mmol) in toluene (250 ml) was added, followed by the addition of H 2 O (250 ml) via syringe. The reaction mixture was stirred at reflux for 3 hours, and was then cooled to room temperature. The organic layer was diluted with EtOAc (200 mL), then washed with 1 M aqueous K 4 CO 3 until the color in the aqueous layer stabilized. The organic layer was washed with brine (200 mL), dried over MgSO 4 , filtered and concentrated. The crude product thus obtained was pad filtered through a short SiO 2 plug to give the title compound (34.5 µg, 79 mmol, 92%) as a white solid.

MS (ESI): exact mass calculated for C25H28CrN302; 437.19;

found, m/z 438.1 [M+H]<+>.

HPLC (method B): Rt = 10.89 min.

*H NMR (400 MHz, CDCl 3 ): 7.50-7.45 (m, 2H), 7.40-7.36 (m, 2H), 7.36-7.25 (m, 3H), 7.13-7.10 (m, 2H), 5.35-5.33 ( m, 2H9, 3.56-3.50 (m, 4H), 2.83-2.75 (m, 4H), 1.28-1.25 (m, 9H).

Step G: 1-benzyl-3-(4-chlorophenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene.

In a 500 mL, one-necked round-bottomed flask, 1-benzyl-3-(4-chlorophenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (34 g, 77 mmol) dissolved in CH 2 Cl 2 (100 mL). Trifluoroacetic acid (70 mL) was added carefully. The reaction mixture was stirred at room temperature for 2 hours. The solvent was evaporated and the residue redissolved in CH 2 Cl 2 (200 ml). Saturated aqueous NaHCO 3 solution was added slowly until CO 2 evolution stopped. The aqueous layer was extracted with CH 2 Cl 2 (2x200 mL). The organic layers were combined, dried over MgSO 4 , filtered and concentrated. The crude product was recrystallized from hot EtOAc to give the pure product as a white solid (24 g, 71 mmol, 91%).

MS (ESI): exact mass calculated for C20H20CIN3; 337.13;

found, m/z 338.3 [M+H]<+>.

HPLC (method B): Rt = 7.53 min.

*H NMR (400 MHz, CDCl 3 ): 7.48-7.44 (m, 2H), 7.44-7.38 (m, 3H), 7.38-7.27 (m, 3H), 7.14-7.06 (m, 2H), 5.36 (s, 2H), 3.30-3.16 (m, 4H), 3.10-2.98 (m, 4H).

Step H: 1-benzyl-3-(4-chlorophenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene citrate salt.

In a 500 mL one-neck round-bottom flask, 1-benzyl-4-(4-chlorophenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene 7 (10 g, 30 mmol) suspended in MeOH (70 mL), and the mixture was heated until a homogeneous solution was formed. A solution of citric acid monohydrate (7.5 g, 36 mmol) in MeOH (10 mL) was added dropwise. The resulting homogeneous solution was heated to reflux for 20 min, then cooled to room temperature. The solvent was evaporated to give an oil. The oil was diluted with EtOAc (200 mL) and the mixture was heated to reflux. To this hot solution, MeOH was slowly added to form a slurry. The slurry was cooled to room temperature and the precipitated solids were collected by filtration, washed with EtOAc and dried under vacuum to give the citrate salt (1:1 ratio based on <1>HNMR analysis, 9.1 g). The filtrate was concentrated and the above procedure to form the citrate salt was repeated by adding a further 0.5 equivalents of citric acid giving a further 2 g of product. The combined dividend

was 71%.

*H NMR (500 MHz, D 2 O): 7.35-7.22 (m, 4H), 7.22-7.15 (m, 3H), 7.0-6.92 (m, 2H), 5.22 (s, 2H), 3.22-3.14 (m, 4H), 3.0-2.92 (m, 2H), 2.88-2.80 (m, 2H), 2.69 (d, J=15 Hz, 2H), 2.57 (d, J=15 Hz, 2H).

Example 276

2-cyclobutyl-3-phenyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene.

Step A: 2-cyclobutyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester.

The desired triflate was prepared as in Steps A and B in Example 176, using cyclobutylhydrazine hydrochloride (prepared from cyclobutanone as shown in Example 177, Step A) instead of phenylhydrazine and t-butanol instead of EtOH, with the additions of 3 equiv. triethylamine.

Step B:

The title compound (118 mg) was prepared according to Example 263 using 189 mg of the product from Step A and 73 mg of phenylboric acid.

MS (ESI): exact mass calculated for Ci7H2iN3, 267.17;

found, m/z 268.5 [M+H]<+>.

*H NMR (500 MHz, CD3OD): 7.60-7.50 (m, 3H), 7.34-7.30 (m, 2H), 4.71-4.63 (m, 2H), 4.00-3.40 (m, 2H), 3.24-3.22 ( m, 3H), 3.00-2.80 (m, 2H), 2.68-2.59 (m, 2H), 2.30-2.24 (m, 2H), 2.30-2.24 (m, 2H), 1.84-1.71 (m, 2H).

Example 277

2-Cyclobutyl-3-(4-fluorophenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene.

The title compound (122 mg) was prepared according to Example 263 using 198 mg of 2-cyclobutyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro2H-1,2,6-triaza-azulene-6-carboxylic acid tert- butyl ester (Example 276, step A) and 88 mg of 4-fluorophenylboronic acid.

MS (ESI): exact mass calculated for Ci7H20FN3, 285.16;

found, m/z 286.4 [M+H]<+>.

*H NMR (500 MHz, CD3OD): 7.35-7.27 (m, 4H), 4.65-4.59 (m, 2H), 3.95-3.40 (m, 2H), 3.32-3.05 (m, 3H), 3.00-2.75 ( m, 2H9, 2.67-2.59 (m, 2H), 2.29-2.23 (m, 2H), 1.84-1.73 (m, 2H).

Example 278

2-cyclobutyl-3-p-tolyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene.

The title compound (117 mg) was prepared according to Example 263 using 192 mg of 2-cyclobutyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 276, Step A) and 83 mg of 4-methylphenylboronic acid.

MS (ESI): exact mass calculated for Ci8H23N3, 281.19;

found, m/z 282.5 [M+H]<+>.

*H NMR (500 MHz, CD3OD):7.42-7.32 (m, 2H), 7.23-7.13 (m, 2H), 4.71-4.65 (m, 2H), 4.00-3.441 (m, 2H), 3.32-3.05 ( m, 3H), 2.95-2.79 (m, 2H9, 2.67-2.58 (m, 2H9, 2.43 (s, 3H), 2.28-2.23 (m, 2H), 1.84-1.71 (m, 2H).

Example 279

2-Cyclobutyl-3-(4-trifluoromethylphenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene.

The title compound (73 mg) was prepared according to Example 263 using 201 mg of 2-cyclobutyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 276, Step A) and 122 mg of 4-trifluoromethylphenylboronic acid.

MS (ESI): exact mass calculated for C18H20F3N3, 335.16;

found, m/z 336.4 [M+H]<+>.

*H NMR (500 MHz, CD3OD): 7.86-7.85 (m, 2H), 7.52-7.50 (m, 2H), 4.65-4.58 (m, 1H9, 3.45-3.41 (m, 2H), 3.22-3.20 (m , 2H), 2.81-2.79 (m, 2H9, 2.67-2.62 (m, 2H), 2.30-2.24 (m, 2H), 1.84-1.74 (m, 2H).

Example 280

4-(2-cyclobutyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulen-3-yl)-benzonitrile.

The title compound (28 mg) was prepared according to Example 263 using 172 mg of 2-cyclobutyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 276, Step A) and 172 mg of 4-cyanophenylboronic acid.

MS (ESI): exact mass calculated for Ci8H2oN4, 292.17;

found, m/z 293.5 [M+H]<+>.

*H NMR (500 MHz, CD3OD): 7.92-7.90 (m, 2H), 7.50-7.48 (m, 2H), 4.65-4.58 (m, 1H), 3.42-3.40 (m, 2H), 3.21-3.19 ( m, 2H), 2.81-2.78 (m, 2H), 2.66-2.62 (m, 2H), 2.30-2.25 (m, 2H), 1.85-1.74 (m, 2H).

Example 281 (Reference example)

2-cyclopropyl-3-phenyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene.

Step A: N-cyclopropyl-hydrazinecarboxylic acid tert-butyl ester.

To a solution of 1.37 g of 3-(4-cyanophenyl)-oxaziridine-2-carboxylic acid tert-butyl ester in Et 2 O (8 ml) was added 1.2 ml of cyclopropylamine. The mixture was aged for 2 hours and then concentrated in vacuo. Chromatography on SiO 2 (0 to 25% EtOAc/hexane) gave an impure yellow solid which was treated under high vacuum in a 50°C oil bath to give 641 mg of the desired compound.

*H NMR (500 MHz, CDCl 3 ): 6.31 (br s, 1H), 3.49 (br s, 1H), 2.74 (br s, 1H), 1.48 (s, 9H), 0.52-0.48 (m, 4H).

Step B: Cyclopropyl hydrazine hydrochloride.

To a solution of the product from step A (636 mg) in CH 2 Cl 2 (10 mL) was added 9 mL of 3.0 M HCl in 1,4-dioxane. The mixture was aged for 12 hours and then concentrated in vacuo to give 507 mg of the title compound.

*H NMR (500 MHz, CD 3 OD): 2.61-2.57 (m, 1H), 0.71-0.59 (m, 4H).

Step C: 2-cyclopropyl-3-trifluoromethanesulfonylcyclo-4,5,7-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylate tert-butyl ester.

The desired triflate was prepared as in steps A and B of Example 176, using cyclopropylhydrazine hydrochloride in place of phenylhydrazine and t-butanol in place of EtOH, with the addition of 3 equiv. triethylamine.

Step D.

The title compound (128 mg) was prepared according to Example 263 using 208 mg of 2- c<y>chloro<p>rop<y>l -3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-l ,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester and 84 mg of phenylboric acid.

MS (ESI): exact mass calculated for C16H19N3, 253.16;

found, m/z 254.4 [M+H]<+>.

<*>HNMR (500 MHz, CD3OD): 7.57-7.44 (m, 5H), 3.57-3.54 (m, 1H), 3.42-3.40 (m, 2H), 2.93-2.84 (m, 2H), 0.91-0.85 (m, 4H).

Example 282

2-cyclopropyl-3-(4-fluorophenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene.

The title compound (134 mg) was prepared according to Example 281 using 1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 281, Step C) and 92 mg of 4-fluorophenylboronic acid.

MS (ESI): exact mass calculated for Ci6Hi8FN3, 271.15;

found, m/z 272.5 [M+H]<+>.

*HNMR (500 MHz, CD3OD): 7.51-7.47 (m, 2H), 7.31-7.27 (m, 2H), 3.55-3.51 (m, 1H), 3.41-3.39 (m, 2H), 3.23-3.14 (m , 2H), 3.00-2.83 (m, 2H), 0.93-0.84 (m, 4H).

Example 283

2-(1-ethyl-propyl)-3-(4-fluoro-3-methyl-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene.

The title compound (34 mg) was prepared according to Example 183 using 59 mg of 2-(1-ethylpropyl)-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene -6-Carboxyl tert-butyl ester (Example 183, Step A) and 19 mg of 4-fluoro-3-methylphenylboronic acid.

MS (ESI): exact mass calculated for C19H26FN3, 315.21;

found, m/z 316.5 [M+H]<+>.

<*>HNMR (500 MHz, CD3OD): 7.27-7.18 (m, 3H), 4.69-4.65 (m, 1H), 3.93-3.89 (m, 1H), 3.50-3.27 (m, 5H), 3.00-2.80 (m, 2H), 2.35 (s, 3H), 1.95-1.87 (m, 2H), 1.83-1.76 (m, 2H), 0.81-0.68 (m, 6H).

Example 284

2-cyclopropyl-3-p-tolyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene.

The title compound (133 mg) was prepared according to Example 281 using 200 mg of 2-cyclopropyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 281, step C) and 90 mg of 4-methylphenylboronic acid.

MS (ESI): exact mass calculated for Ci7H2iN3, 267.17;

found, m/z 268.5 [M+H]<+>.

*H NMR (500 MHz, CD3OD): 7.42-7.34 (m, 4H), 4.68-4.65 (m, 2H), 3.80-3.30 (m, 6H), 2.97 (br s, 2H), 2.44 (s, 3H ), 0.94-0.91 (m, 4H).

Example 285

2-cyclopropyl-3-thiophen-3-yl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene.

The title compound (134 mg) was prepared according to Example 281 using 200 mg of 2-cyclopropyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 281, step C) and 84 mg of 3-thiopheneboric acid.

MS (ESI): exact mass calculated for C14H17N3S, 259.11;

found, m/z 260.4 [M+H]<+>.

*H NMR (500 MHz, CD3OD): 7.64-7.63 (m, 2H), 7.31-7.29 (m, 1H), 4.65 (br s, 1H), 3.70-3.60 (br s, 1H), 3.57-3.52 ( m, 1H), 3.40-3.38 (m, 1H), 3.19 (br s, 1H), 3.13-3.11 (m, 1H), 2.99-2.96 (m, 1H), 2.91-2.89 (m, 1H), 0.93 -0.88 (m, 4H).

Example 286

4-(2-cyclopropyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulen-3-yl)-benzonitrile.

The title compound (91 mg) was prepared according to Example 281 using 200 mg of 2-cyclopropyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 281, step C) and 97 mg of 4-cyanophenylboronic acid.

MS (ESI): exact mass calculated for Ci7Hi8N4, 278.15;

found, m/z 279.4 [M+H]<+>.

*H NMR (500 MHz, CD3OD): 7.94-7-92 (m, 2H), 7.71-7.70 (m, 2H), 4.66 (br s, 1H), 3.71-3.68 (m, 1H), 3.47 (br s, 1H), 3.39-3.19 (m, 4H), 3.01-2.88 (m, 2H), 0.96-0.90 (m, 4H).

Example 298

2-sec-butyl-3-phenyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene.

Step A: 2-sec-butyl-3-trifluoromethanesulfonlox-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester.

The desired triflate was prepared according to Example 189, Step A, using sec-butylhydrazine hydrochloride (prepared from 2-butanone as shown in Example 177, Step A) in place of isopropylhydrazine hydrochloride.

Step B:

The title compound (97 mg) was prepared as in Example 263 using 216 mg of the triflate from Step A and 106 mg of phenylboric acid.

MS (ESI): exact mass calculated for C17H23N3, 269.38;

found, m/z 270.5 [M+H]<+>.

XH NMR (500 MHz, CD3OD): 7.58-7.50 (m, 3H), 7.35-7.31 (m, 2H), 4.15-4.07 (m, 1H), 3.50-3.18 (m, 6H), 2.88-2.73 (m , 2H), 1.97-1.86 (m, 1H), 1.74-1.65 (m, 1H), 1.43 (d, J=6.8 Hz, 3H), 0.64 (t, J=7.4 Hz, 3H).

Example 299

2-sec-butyl-3-(4-fluorophenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene.

The title compound (71 mg) was prepared according to Example 263 using 245 mg of the triflate from Example 298, Step A, and 154 mg of 4-fluorophenylboronic acid.

MS (ESI): exact mass calculated for C17H22FN3, 287.38;

found, m/z 288.5 [M+H]<+>.

*H NMR (500 MHz, CD3OD): 7.41-7.35 (m, 2H), 7.34-7.28 (m, 2H), 4.12-4.03 (m, 1H), 3.51-3.20 (m, 6H), 2.90-2.73 ( m, 2H), 1.97-1.87 (m, 1H), 1.75-1.65 (m, 1H), 1.44 (d, J=6.6 Hz, 3H), 0.66 (t, J=7.4 Hz, 3H).

Example 300

2-sec-butyl-3-p-tolyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene.

The title compound (116 mg) was prepared according to Example 263 using 249 mg of the triflate from Example 298, Step A, and 129 mg of 4-fluorophenylboronic acid.

MS (ESI): exact mass calculated for Ci8H25N3, 283.41;

found, m/z 284.5 [M+H]<+>.

*H NMR (500 MHz, CD3OD): 7.42-7.37 (m, 2H), 7.27-7.21 (m, 2H), 4.23-4.12 (m, 1H), 3.55-3.23 (m, 6H), 2.92-2.75 ( m, 2H), 2.43 (s, 3H), 1.98-1.88 (m, 1H), 1.77-168 (m, 1H), 1.46 (d, J=6.6 Hz, 3H), 1.98-1.88 (m, 1H) , 1.77-1.68 (m, 1H), 1.46 (d, J=6.6 Hz, 3H), 0.67 (t, J=7.4 Hz, 3H).

Example 301

2-sec-butyl-3-(4-trifluoromethyl-phenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene.

The title compound (71 mg) was prepared as in Example 263 using 257 mg of the triflate from Example 298, Step A, and 175 mg of 4-trifluorophenylboronic acid.

MS (ESI): exact mass calculated for C18H22F3N3, 337.38;

found, m/z 338.5 [M+H]<+>.

*H NMR (500 MHz, CD3OD): 7.91-7.85 (m, 2H), 7.61-7.54 (m, 2H), 4.11-4.03 (m, 1H), 3.52-3.20 8m, 6H), 2.93-2.75 (m , 2H), 1.99-1.88 (m, 1H), 1.76-1.65 (m, 1H), 1.45 (d, J=6.6 Hz, 3H), 0.65 (t, J=7.4 Hz, 3H).

Example 302

2-Cyclopentyl-3-(4-fluorophenyl)-6-methyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene.

The title compound (186 mg) was prepared from 216 mg of the product of Example 182 according to Example 208. The product was dissolved in Et 2 O and treated with excess 1.0 M HCl in Et 2 O to give the corresponding HCl salt.

MS (ESI): exact mass calculated for C19H24FN3, 313.41;

found, m/z 314.4 [M+H]<+>.

*H NMR (500 MHz, CD3OD): 7.38-7.34 (m, 2H), 7.31-7.26 (m, 2H), 4.47 (m, 1H), 3.75-3.69 (m, 1H), 3.64-3.57 (m, 1H), 3.33-3.15 (m, 4H), 3.02 (s, 3H), 2.91-2.83 (m, 1H), 2.78-2.71 (m, 1H), 2.04-1.84 (m, 6H), 1.65- 1.54 (m, 2H).

Example 305

6-Benzyl-3-(4-fluorophenyl)-2-isopropyl-8-methyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene.

Step A: Trifluoromethanesulfonic acid 6-benzyl-2-isopropyl-8-methyl-3,4,5,6,7,8-hexahydro-1,2,6-triaza-azulen-3-yl ester.

The desired triflate was prepared as in step A of Example 189 using 1-benzyl-6-methyl-5-oxo-azepane-4-carboxylic acid ethyl ester (prepared from 1-benzyl-3-methyl-piperidin-4-one as shown in step A of Example 59) in place of 5-oxo-azepane-1,4-dicarboxylic acid tert-butyl ester 4-ethyl ester.

Step B:

The title compound (29 mg) was prepared as in Example 287, Step B, from 151 mg of the triflate from Step A and 110 mg of 4-fluorophenylboronic acid.

MS (ESI): exact mass calculated for C24H28FN3, 377.50;

found, m/z 378.5 [M+H]<+>.

*H NMR (500 MHz, CDCl 3 ): 7.41-7.37 (m, 2H), 7.33-7.29 (m, 2H), 7.27-7.18 (m, 3H), 7.16-7.10 (m, 2H), 4.24 (m, 1H), 3.78 (d, J=13.4 Hz, 1H), 3.70 (d, J=13.4 Hz, 1H), 3.19-3.12 (m, 1H), 2.78-2.68 (m, 3H), 2.55-2.43 (m , 3H), 1.40 (d, J=6.6, 3H), 1.37 (d, J=6.6, 3H), 1.33 (d, J=7.1, 3H).

Example 306

3-(4-Fluorophenyl)-2-isopropyl-8-methyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene.

Step A: 3-methyl-4-oxo-piperidine-1-carboxylic acid tert-butyl ester.

To a -78°C solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester in THF (100 mL) was added LDA (50 mL, 1.8 M in THF) with stirring over 1 hour. Methyl iodide (5 mL) was then added and the mixture was allowed to warm slowly to room temperature and was stirred for 24 hours. The reaction mixture was quenched by the addition of saturated aqueous EtOAc, and concentrated. Purification on SiO 2 (120 g, 0 to 10% EtOAc/hexane) gave 3.83 g of the desired product as an off-white solid.

<*>HNMR (500 MHz, CDC13): 4.23-4.14 (m, 2H), 3.31-3.21 (m, 1H), 2.61-2.37 (m, 4H), 1.50 (s, 9H), 1.05 (d, J =6.6 Hz, 3H).

Step B: 2-isopropyl-8-methyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester.

The product from Step A (2.01 g) was treated with ethyl diazoacetate (1.5 mL) as in Step A of Example 59. The resulting material (2.90 g) was then converted to the desired triflate (2.68 g) as shown in Step A of Example 189. The reaction sequence also produced 0.60 g of 2-isopropyl-3-methyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6 -carboxylic acid tert-butyl ester.

Step C:

The title compound (1.62 g) was prepared as in Step A of Example 263 from 2.68 g of the triflate in Step B and 1.36 g of 4-fluorophenylboronic acid. The coupling product was treated with TFA (20 mL) in 50 mL CH 2 Cl 2 i for 16 h. The mixture was concentrated and the residue was diluted with 1M NaOH (50 mL) and extracted with CH 2 Cl 2 (50 mL, 3x). The combined organic layers were dried over Na 2 SO 4 and concentrated to give the desired material.

MS (ESI): exact mass calculated for C17H22FN3, 287.18;

found, m/z 288.4 [M+H]<+>.

<*>HNMR (500 MHz, CDC13): 7.18-7.05 (m, 4H), 4.16 (m, 1H), 3.08-2.97 (m, 2H), 2.96-2.83 (m, 2H), 2.78-2.71 (m , 1H), 2.49-2.31 (m, 2H), 1.34 (d, J=6.6 Hz, 3H), 1.31 (d, J=6.6 Hz, 3H), 1.29 (d, J=7.3 Hz, 3H).

Example 308

2-Cyclopentyl-3-(4-fluorophenyl)-7-methyl-2,3,5,6,7,8-hexahydro-1,2,6-triaza-azulene.

Step A: 2-methyl-4-oxo-piperidine-1-carboxylic acid tert-butyl ester.

A solution of 1,4-dioxa-8-aza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester (2.97 g) in TMEDA (2.2 mL) was cooled to -78°C and sec-BuLi (1.8 M in THF, 13 mL) was added dropwise. The resulting yellow solution was aged at -78°C to room temperature over 16 hours. The reaction mixture was poured into water (800 mL) and extracted with EtOAc. The combined organic extracts were washed with H 2 O, brine and dried over Na 2 SO 4 . Purification on SiO 2 (330 g, 5 to 20% EtOAc/hexane) gave 1.65 g of 7-methyl-1,4-dioxa-8-aza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester. Multiple aliquots of this ester were combined (2.29 g), treated with 5 mL of concentrated HCl in 10 mL dioxane and heated at 65°C for 6 hours. The solvent was removed and the residue was dissolved in CH 2 Cl 2 and treated with di-tert-butyl dicarbonate (1.0 g). After 5 days, the mixture was diluted with saturated aqueous NaHCO 3 and H 2 O, and extracted with CH 2 Cl 2 . Purification on SiO 2 (120 g, 5 to 15% EtOAc/hexane) gave 1.40 g of the desired product as a white solid.

*HNMR (500 MHz, CDC13): 4.69-4.59 (m, 1H), 4.21-4.12 (m, 1H), 3.30-3.20 (m, 1H), 2.66-2.57 (m, 1H), 2.47-2.36 (m , 1H), 2.32-2.23 (m, 1H), 2.22-2.15 (m, !H), 1.42 (s, 9H), 1.11 (d, J=7.1Hz, 3H).

Step B: 2-cyclopentyl-7-methyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester.

The product from Step A (1.40 g) was treated with ethyl diazoacetate as in Step A of Example 59. The resulting material (1.0 g) was converted to the desired triflate (0.78 g) as in Step A of Example 180 The reaction sequence also produced 2-cyclopentyl-5-methyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester.

Step C:

The title compound (160.4 mg) was prepared as in Example 263 from 301 mg of the triflate from step B and 185 mg of 4-fluorophenylboronic acid. The sequence also gave 2-cyclopentyl-3-(4-fluorophenyl)-5-methyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene. The isomers were separated by SFC chromatography.

MS (ESI): exact mass calculated for C19H24FN3, 313.41;

found, m/z 314.4 [M+H]<+>.

XH NMR (500 MHz, CD3OD): 7.25-7.21 (m, 2H), 7.18-7.12 (m, 2H), 4.22 (m, 1H), 3.24-3.18 (m, !H), 3.03-2.92 (m, 2H), 2.76-2.67 (m, 2H), 2.60-2.52 (m, 1H), 2.45-2.39 (m, 1H), 2.16-1.82 (m, 6H), 1.59-1.47 (m, 2H), 1.25 ( d, J=6.3 Hz, 3H).

Example 309

2-Cyclopentyl-3-(4-fluorophenyl)-5-methyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene.

The title compound (3.8 mg) was prepared as in Example 308

MS (ESI): exact mass calculated for C19H24FN3, 313.41;

found, m/z 314.4 [M+H]<+>.

<*>HNMR (500 MHz, CDC13): 7.24-7.19 (m, 2H), 7.18-7.13 (m, 2H), 4.31 (m, 1H), 3.42-3.35 (m, 1H), 3.09-2.90 (m , 4H), 2.57-2.45 (m, 2H), 2.14-1.80 (m, 6H), 1.58-1.48 (m, 2H), 1.22 (d, J=6.3 Hz, 3H).

Example 310

2-cyclopentyl-7-methyl-3-p-tolyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene.

The title compound (64 mg) was prepared from 193 mg of the triflate from Example 308, Step B, and 117 mg of 4-methylphenylboronic acid.

MS (ESI): exact mass calculated for C20H27N3, 309.45;

found, m/z 310.4 [M+H]<+>.

<X>HNMR (500 MHz, CDC13): 7.28-7.25 (m, 2H), 7.17-7.13 (m, 2H), 4.39 (m, 1H), 3.21-3.16 (m, 1H), 3.03-2.92 (m , 2H), 2.74-2.67 (m, 2H), 2.59-2.52 (m, 1H), 2.49-2.43 (m, 1H), 2.40 (s, 3H), 2.17-1.82 (m, 6H), 1.59-1.47 (m, 2H), 1.24 (d, J=6.3 Hz, 3H).

Example 311

2-isopropyl-7-methyl-3-phenyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene.

The title compound (102 mg) was prepared as in Example 263 using 260 mg of 2-isopropyl-7-methyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene- 6-carboxylic acid tert-butyl ester (which in Example 308 replaces cyclopentyl hydrazine with isopropyl hydrazine) and 101 mg of phenylboric acid. The reaction sequence also gave 2-isopropyl-5-methyl-3-phenyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene.

MS (ESI): exact mass calculated for C17H23N3, 269.19;

found, m/z 270.5 [M+H]<+>.

*H NMR (600 MHz, CD3OD): 7.58-7.52 (m, 3H), 7.36-7.35 (m, 2H), 4.43 (m, 1H), 3.65-3.57 (m, 1H), 3.51-3.48 (m, 1H), 3.23-3.11 (m, 3H) 2.87-2.82 (m, 2H), 2.76-2.73 (m, 1H), 1.48 (d, J=6.4 Hz, 3H), 1.43-1.40 (m, 6H).

Example 313

3-(4-Fluorophenyl)-2-isopropyl-7-methyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene.

The title compound (127 mg) was prepared as in Example 311 using 260 mg of 2-isopropyl-7-methyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene- 6-carboxylic acid tert-butyl ester and 115 mg of 4-fluorophenylboronic acid. The reaction sequence also gave 3-(4-fluorophenyl)-2-isopropyl-5-methyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene.

MS (ESI): exact mass calculated for C17H22FN3, 287.18;

found, m/z 288.5 [M+H]<+>.

*H NMR (600 MHz, CD3OD): 7.39-7.32 (m, 2H), 7.32-7.28 (m, 2H), 4.36 (m, 1H), 3.61-3.56 (m, 1H), 3.50-3.47 (m, 1H), 3.20-3.08 (m, 3H), 2.85-2.80 (m, 1H), 2.73-2.69 (m, 1H), 1.46 (d, J=6.6 Hz, 3H), 1.41-1.38 (m, 6H) .

Example 315

2-isopropyl-7-methyl-3-p-tolyl-2,4,5,6,7,8-hexahydro-1,2,5-triaza-azulene.

The title compound (127 mg) was prepared as in Example 311 using 260 mg of 2-isopropyl-7-methyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene- 6-carboxylic acid tert-butyl ester and 112 mg of 4-methylphenylboronic acid. The reaction sequence also gave 2-isopropyl-5-methyl-3-p-tolyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene.

MS (ESI): exact mass calculated for Ci8H25N3, 283.20;

found, m/z 284.5 [M+H]<+>.

*H NMR (600 MHz, CD3OD): 7.38-7.36 (m, 2H), 7.22-7.20 (m, 2H), 4.41 (m, 1H), 3.60-3.56 (m, 1H), 3.50-3.45 (m, 1H), 3.21-3.06 (m, 3H), 2.84-2.70 (m, 2H), 1.46 (d, J=6.6 Hz, 3H), 1.42-1.37 (m, 6H).

Example 316 was prepared as described in Example 238, with changes as indicated.

Example 316

3-(4-Chlorophenyl)-1-pyridin-4-ylmethyl-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene.

The title compound (0.02 g) was prepared from 3-(4-chlorophenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 103, step B; 0.3 mmol) using 4-chloromethylpyridine hydrogen chloride (0.5 mmol) instead of 2-chloromethylthiophene.

MS (ESI): exact mass calculated for C19H19CIN4, 338.13;

found, m/z 339.3 [M+H]<+>.

*H NMR (500 MHz, CDCl 3 ): 8.49-8.48 (m, 2H), 7.43-7.41 (m, 2H), 7.33-7.31 (m, 2H), 6.90-6.89 (m, 2H), 5.28 (s, 2H), 2.92-2.87 (m, 2H), 2.75-2.73 (m, 1H), 2.55-2.64 (m, 1H).

EXAMINATION PROCEDURES

In vitro pharmacology.

1. Affinity for 5-HT7 receptor.

The affinity of the compounds described according to the invention for the 5-HT7 receptor binding site was evaluated by single competition radioligand binding assays. The investigation was performed on membranes prepared from HEK-293 cells that had been stably transfected with the rat 5-HT7a receptor (GB: NM022938). The cells were scraped from culture plates, suspended in Tris-HCl 60 mM, pH 7.5, and collected by centrifugation (1000 rpm for 5 min). The cell pellets were homogenized (Polytron, 15 s, setting 5) in 50 mM Tris-HCl (pH 7.5), 5 mM EDTA. After centrifugation (15,000 rpm for 25 min.), the membranes (135 µg protein/ml) were resuspended in the same buffer and incubated for 60 min. at room temperature in 1 nM [<3>H]5-CT in the presence of increasing concentrations of test compds. Non-specific binding was defined in the presence of 10 µM 5-HT. Incubation was stopped by rapid filtration through the cell harvester (Packard). Radioactivity was counted in TopCount-NXT (Packard).

Sigmoidal inhibition curves were generated and fitted by non-linear regression analysis (GraphPad Prism). IC 50 values (concentration giving 50% inhibition of specific radioligand binding) were calculated. IQ values were derived according to Cheng and Prussoff (Biochem. Pharmacol. (1973) 22: 3099-3108). Experiments were performed in triplicate.

Prodrug solutions (10 mM) were prepared in DMSO

(final study concentration of DMSO did not exceed 0.4%).

Drug dilutions were prepared in research buffer. Data are shown in Table 1 below.

2. Effect on adenylyl cyclase activity.

In vitro functional properties of the compound described according to the invention were evaluated in an adenylyl cyclase study. HEK-293 cells stably transfected with the rat 5-HT7a receptor were added to a 96-well plate. The cells were washed with 200 µL DNEM/F12 and incubated for 10 min. with 80 µL of 2 mM 3-isobutyl-1-methylxanthine. Compounds (10 µL) were added for an additional 10 min. Then 5-CT (10 µL) was added. After 20 min. the incubation was stopped by the addition of 20 µL of 0.5 N HCl. The plates were incubated at 4°C for 30 minutes. Twenty µL of the supernatant was assayed for cAMP content with a commercially available kit (Perkin Eimer) using 1251-cAMP. Sigmoidal curves of best fit were calculated by non-linear regression analysis using GrapPad Prism.

5-CT-stimulated adenylyl cyclase activity in r5-HT7a/HEK-293 cells was inhibited in Example 59 with an estimated pJs~8 in good agreement with the IQ value determined from the [<3>H]5-CT binding studies.

3. Affinity for 5-HT2A receptor binding sites.

The affinity of the compounds for the rat 5-HT2A receptor was evaluated by competitive radioligand binding assay using [<3>H]ketanserin as a radioligand. The investigation was performed on membranes from rat cortex as previously described (Schotte, A. et al., Psychopharmacology (1996) 124: 57-73). Briefly, brain tissue (rat cortex) was homogenized in 20 volumes per tissue wet weight of Tris-HCl buffer (50 mM, pH 7.4). Total membrane fraction was collected by centrifugation and washed with subsequent centrifugation runs (25 min at 25,000 g at 4°C). The membranes were resuspended in Tris-HCl buffer (50 nM, pH 7.4) containing 1 nM [<3>H]ketanserin. Non-specific binding was estimated in the presence of 10 µM risperidone. Incubation was terminated by rapid filtration over Whatman GF/B filters pre-moistened in 0.1% polyethyleneimine, and a washing step with 1 ml of ice-cold Tris-HCl buffer, pH 7.4, pHi values for all compounds were calculated by pK; = -log K; where K; was calculated according to the method of Cheng and Prusoff (Biochem Pharmacol. (1973), 22:3099-3108)

(IC50/(1+[S]/Kd) became [S] = 1 nM; Kd= 0.42 nM). All values in Table 1 are listed in nM units. Data are shown in Table 1 below.

4. Affinity for 5HT2 receptor binding sites.

Receptor binding was performed using human recombinant 5-HT2a (GB: X57830), 5-HT2B (GB: Z36748) and 5-HT2C (GB: M811778) receptors. The affinity of the compounds for the 3 different 5-HT2 receptor subtypes was evaluated by competitive radioligand binding assays using [<3>H]ketanserin (h5-HT2A) or [<3>H]mesulergin (h5-HT2Bog h5-HT2C). The investigations were performed on membranes prepared from NTH3T3 stably transfected with h5-HT2A or CHO stably transfected with h5-HT2Bo and h5-HT2C. IQ values for all compounds were calculated using the Cheng and Prusoff equation (Cheng and Prusoff, Biochem. Pharmacol.

(1973)22:3099-3108 (IC50/(1+[S]/Kd) where [S] = 1 nM (5-HT2A), 4 nM (5-HT2B) and 3 nM (5-HT]2C); Kd ) 0.4 nM (5-HT2A), 3.5 nM (5-HT2B) and 3 nM (5-HT2C). Data are shown in Table 1 below. 5. In vitro functional examination for 5-HT2 receptor (intracellular calcium). In vitro functional properties of these compounds on different 5-HT2 receptor subtypes were determined using a fluorimetric imaging plate reader (FLIPR) based calcium assay as previously described (Porter et al., 1999, J.C. Jerman et al. Eur. J. Pharmacol. (2001) 414:23-30). 5-HT2 receptors are bound to the Gq family of G proteins, and subsequent activation of phospholipase C, induction of phosphoinositide metabolism and to an increase in intracellular calcium concentration. The same cell lines as described in the previous section (receptor binding) were used for FLIPR experiments.

Claims (34)

1. A compound having serotonin receptor modulating activity characterized by formula (I), (TJ) or (HI): in which m is 1 or 2; n is 1, 2 or 3; p is 1, 2 or 3; m+n is less than or equal to 4; m+p is less than or equal to 4; q is 0 or 1; r is 0 or 1; R<3> is -C1-4 alkyl, optionally substituted with -OH or halo; Ar is an aryl or heteroaryl ring selected from the group consisting of: c) phenyl, optionally mono-, di- or tri-substituted with R<r>or disubstituted on adjacent carbons with -OCi-4alkyleneO-; R<r>is selected from the group consisting of -OH, -C 1-6 alkyl, -OC 1-6 alkyl, -CN, -NO 2 , halo and -CF 3 ; d) a monocyclic aromatic hydrocarbon group having five ring atoms, having a carbon atom as the point of attachment, having a carbon atom replaced by >0 or >S, having up to one additional carbon atom replaced by a -N= optionally mono- or disubstituted with R <r>; ALK is a branched or unbranched C 1-6 alkylene, C 2-8 alkenylene, optionally mono-, di- or tri-substituted with a substituent selected from the group consisting of: -OH, -OC 1-6 alkyl; CYC is hydrogen or a carbocyclic or heterocyclic ring selected from the group consisting of: i) phenyl, optionally mono-, di- or tri-substituted by R<q>or disubstituted on adjacent carbons with -OCi-4alkyleneO-; R<q>is selected from the group consisting of -OH, -Ci-6alkyl, -OCi-6alkyl, -CN, -NO2, - N(R<a>)R<b>or -(NR<c>) SO 2 C 1-6 alkyl (where Ra, R<b>and R<c>are independently selected from H or C 1-6 alkyl), -SO 2 N(Ra)R<b>, halo and -CF 3 ; w) a monocyclic aromatic hydrocarbon group having five ring atoms, having a carbon atom as the point of attachment, having a carbon atom replaced by >O or >S; vi) a monocyclic aromatic hydrocarbon group such as here six ring atoms, which has a carbon atom which is the point of attachment, which has one or two carbon atoms replaced by -N= optionally mono- or disubstituted with R<q>; vii) a 3- to 8-membered non-aromatic carbocyclic or heterocyclic ring, said ring having 0, 1 or 2 non-adjacent heteroatom members selected from O, or S, -, having 0, 1 or 2 unsaturated bonds, having 0, 1 or 2 carbon members that are a carbonyl; R 1 is selected from the group consisting of H, C 1-7 alkyl, and benzofused C 4-7 cycloalkyl, each optionally mono-, di- or tri substituted with R<p>; R<p>is selected from the group consisting of -OH, -OCi-alkyl; R<2> is selected from the group consisting of H or C 1-7 alkyl; and enantiomers, diastereomers, hydrates, solvates and pharmaceutically acceptable salts thereof. 2. Compound according to claim 1, characterized in that merl. 3. Connection according to claim 1, characterized by vedatnerl or 2. 4. Connection according to claim 1, characterized in that pearl or 2. 5. Compound according to claim 1, characterized by items 2 or 3. 6. Compound according to claim 1, characterized by atm+per 2 or 3. 7. Connection according to claim 1, characterized by 8. Compound according to claim 1, characterized in that R<3>, optionally substituted, is selected from the group consisting of methyl, ethyl, propyl, isopropyl and butyl. 9. Compound according to claim 1, characterized in that R<3> is methyl. 10. Compound according to claim 1, characterized in that Ar is selected from the group consisting of phenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 4-ethylphenyl, 2-chlorophenyl, 3 -chlorophenyl, 4-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 4-fluorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 3-trifluoromethoxyphenyl , 4-trifluoromethoxyphenyl, 3-cyanophenyl, 4-cyanophenyl, 3,4-difluorophenyl, 3,4-dichlorophenyl, 2,3-difluorophenyl, 2,3-dichlorophenyl, 2,4-difluorophenyl, 2,4-dichlorophenyl, 3 -nitrophenyl, 4-nitrophenyl, 3-chloro-4-fluorophenyl, 3-fluoro-4-chlorophenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 4-hydroxy-2-methylphenyl, 4-hydroxy-3-fluorophenyl, 3,4 -dihydroxyphenyl, 4-fluoro-3-methylphenyl, furan-2-yl, furan-3-yl, thiophen-2-yl, thiophen-3-yl, 5-chlorothiophen-2-yl, 5-methylthiophen-2-yl , 5-chlorothiophen-3-yl and 5-methylthiophen-3-yl. 11. Compound according to claim 1, characterized in that ALK, optionally substituted, is selected from the group consisting of methylene, ethylene, propylene, tert-butylene, pentylene, 1-ethylpropylene, 2-ethylpropylene, 2-ethylbutylene, isopropylene, but-3-enylene , isobutylene, 3-methylbutylene and allylene. 12. Compound according to claim 1, characterized in that ALK is selected from the group consisting of methylene, ethylene, propylene, butylene, tert-butylene, 4-hydroxybutylene, pentylene, 5-hydroxypentylene, 1-ethylpropylene, 2-ethylpropylene, 2-ethylbutylene, isopropylene , but-3-enylene, isobutylene and 3-methylbutylene. 13. Compound according to claim 1, characterized in that CYC, optionally substituted, is selected from the group consisting of hydrogen, phenyl, pyridyl, thiophen-2-yl, thiophen-3-yl, tetrahydropyranyl, furan-2-yl and furan-3-yl . 14. Compound according to claim 1, characterized in that CYC is selected from the group consisting of hydrogen, phenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 4-ethylphenyl, 2-chlorophenyl , 3-chlorophenyl, 4-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, 3,4-difluorophenyl , 3,4-dichlorophenyl, 2,3-difluorophenyl, 2,3-dichlorophenyl, 2,4-difluorophenyl, 2,4-dichlorophenyl, 2,6-difluorophenyl, 2,6-dichlorophenyl, 2,6-dimethylphenyl, 2 ,4,6-trifluorophenyl, 2,4,6-trichlorophenyl, 3,4,5-trimethoxyphenyl, 3-nitrophenyl, 4-nitrophenyl, 3,4-dimethylphenyl, 3-aminophenyl, 4-aminophenyl, thiophen-2-yl , thiophen-3-yl, tetrahydropyran-2,3- or 4-yl, furan-2-yl, furan-3-yl, 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, and 3,4-dihydroxyphenyl. 15. Compound according to claim 1, characterized in that R<1> is selected from the group consisting of hydrogen, C1-6 alkyl, each optionally mono-, di- or tri-substituted with R<p>. 16. Compound according to claim 1, characterized in that R<1>, optionally R<p->substituted, is selected from the group consisting of hydrogen, methyl, ethyl, propyl and isopropyl. 17. Compound according to claim 1, characterized in that R<1> is selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, 3-hydroxypropyl and hydroxyethyl. 18. Compound according to claim 1, characterized in that R<2> is hydrogen or C 1-6 alkyl. 19. Compound according to claim 1, characterized in that R<2> is hydrogen or methyl. 20. Compound according to claim 1, characterized in that it is selected from the group consisting of: Ex. Chemical name 11-benzyl-3-(4-nitrophenyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine; 17 1-benzyl-2-methyl-3-phenyl-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine; 18 1-benzyl-3-p-tolyl-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine; 22 1-butyl-3-p-tolyl-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine; 26 1-Benzyl-3-phenyl-1,4,5,6,7,8-hexahydro-pyrrolo[2,3-d]azepine. 21. Compound according to claim 1, characterized in that it is selected from the group consisting of: Ex. Chemical name 47 1-benzyl-3-(4-fluorophenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 57 1-benzyl-3-phenyl-6-propyl-1,4,5,6,7,8-hexahydro-1,2,6-triazaazulene; 59 1-benzyl-3-(4-chlorophenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 74 3-(4-chlorophenyl)-1-(3-methylbenzyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 75 3-(4-chlorophenyl)-1-(4-fluorobenzyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 76 3-(4-chlorophenyl)-1-(3-fluorobenzyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 87 5-[3-(4-chlorophenyl)-5,6,7,8-tetrahydro-4H-1,2,6-triaza-azulen-1-yl]-pentan-1-ol; 98 3-(4-Idorphenyl)-1-(4-nitrobenzyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 100 N-[4-(3-phenyl-5,6,7,8-tetrahydro-4H-1,2,6-triaza-azulen-1-ylmethyl)-phenyl]-methanesulfonamide; 103 3-(4-chlorophenyl)-1-thiophen-2-ylmethyl-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 104 1-benzyl-3-thiophen-2-yl-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 108 3-(4-chlorophenyl)-1-(2,4-difluorobenzyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 111 1-but-3-enyl-3-(4-chlorophenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 117 3-(4-chlorophenyl)-1-cyclohexylmethyl-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 118 3-(4-chlorophenyl)-1-isobutyl-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 119 1-benzo[1,3]dioxol-5-ylmethyl-3-(4-chlorophenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 120 3-(4-chlorophenyl)-1-(tetrahydropyran-4-ylmethyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 160 4-[3-(4-fluorophenyl)-5,6J,8-tetrahydro-4H-1,2,6-triaza-azulen-1-ylmethyl]-2-fluorophenol; 165 1-benzyl-3-(4-fluorophenyl)-6-methyl-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 166 1-benzyl-3-(4-chlorophenyl)-6-ethyl-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 172 3-(4-chlorophenyl)-1-phenyl-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 255 3-(4-Hyrophenyl)-1-cyclooctyl-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 273 1-benzyl-3-(4-chlorophenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene citrate salt; 316 3-(4-Chlorophenyl)-1-pyridin-4-ylmethyl-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene. 22. Compound according to claim 1, characterized in that it is selected from the group consisting of: Ex. Chemical name 64 3-(4-chlorophenyl)-2-ethyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 131 3-(4-chlorophenyl)-2-isobutyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 133 2-benzyl-3-phenyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 177 2-cyclohexyl-3-phenyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 178 3-(4-chlorophenyl)-2-cyclohexyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 180 2-cyclopentyl-3-phenyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 181 3-(4-chlorophenyl)-2-cyclopentyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 182 2-cyclopentyl-3-(4-fluorophenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 183 2-(1-ethylpropyl)-3-(3-fluorophenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 184 2-(1-ethylpropyl)-3-(4-fluorophenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 186 2-(1-ethylpropyl)-3-phenyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 190 3-(4-fluorophenyl)-2-isopropyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 191 2-(1-ethylpropyl)-3-thiophen-2-yl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 192 2-cyclopentyl-3-thiophen-3-yl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 209 2-isopropyl-3-p-tolyl-2,4,5,6,7-hexahydro-1,2,6-triaza-azulene; 210 3-(4-ethylphenyl)-2-isopropyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 211 3-(4-chlorophenyl)-2-isopropyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 212 4-(2-isopropyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulen-3-yl)-benzonitrile; 213 2-isopropyl-3-(4-trifluoromethylphenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 214 2-ethyl-3-p-tolyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 215 2-tert-butyl-3-phenyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 216 2-tert-butyl-3-(4-fluorophenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 217 2-cyclopentyl-3-p-tolyl-2,3,4,5,6,7-hexahydro-1,2,6-triaza-azulene; 218 2-cyclopentyl-3-(4-trifluoromethylphenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 220 2-cyclopentyl-3-(4-methoxyphenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 232 2-cyclopentyl-3-furan-3-yl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 233 2-cyclopentyl-3-thiophen-2-yl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 236 2-Cylopentyl-3-(3,4-difluorophenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 238 3-(4-chlorophenyl)-2-cyclobutyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 241 3-(3-chloro-4-fluorophenyl)-2-cyclopentyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 242 2-isopropyl-3-(4-methoxyphenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 253 2-isopropyl-3-(4-nitrophenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 257 2-Ethyl-3-(4-ethylphenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 276 2-cyclobutyl-3-phenyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 277 2-cyclobutyl-3-(4-fluorophenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 278 2-cyclobutyl-3-p-tolyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 279 2-cyclobutyl-3-(4-trifluoromethylphenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 280 4-(2-cyclobutyl-2,4,5,6,7,8-hexahydro-1,2,6-thiraza-azulen-3-yl)-benzonitrile; 282 2-cyclopropyl-3-(4-fluorophenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 283 2-(1-ethylpropyl)-3-(4-fluoro-3-methylphenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 284 2-cyclopentyl-3-p-tolyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 285 2-cyclopropyl-3-thiophen-3-yl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 286 4-(2-cyclopropyl-2,4,5,6,7,8-hexahydro-1,2,6-thiraza-azulen-3-yl)-benzonitrile; 298 2-sec-butyl-3-phenyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 299 2-sec-butyl-3-(4-fluorophenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 300 2-sec-butyl-3-p-tolyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 301 2-sec-butyl-3-(4-trifluoromethylphenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 302 2-cyclopentyl-3-(4-fluorophenyl)-6-methyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 305 6-benzyl-3-(4-fluorophenyl)-2-isopropyl-8-methyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 306 3-(4-fluorophenyl)-2-isopropyl-8-methyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 308 2-Cylopentyl-3-(4-fluorophenyl)-7-methyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 309 2-Cylopentyl-3-(4-fluorophenyl)-5-methyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 310 2-cyclopentyl-7-methyl-3-p-tolyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 311 2-isopropyl-7-methyl-3-phenyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 313 3-(4-fluorophenyl)-2-isopropyl-7-methyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 315 2-isopropyl-7-methyl-3-p-tolyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene. 23. Compound according to claim 1, characterized in that it is selected from the group consisting of: Ex. Chemical name 59 1-benzyl-3-(4-chlorophenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 74 3-(4-chlorophenyl)-1-(3-methylbenzyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 75 3-(4-chlorophenyl)-1-(4-fluorobenzyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 76 3-(4-chlorophenyl)-1-(3-fluorobenzyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 103 3-(4-chlorophenyl)-1-thiophen-2-ylmethyl-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 104 1-benzyl-3-thiophen-2-yl-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 108 3-(4-chlorophenyl)-(2,4-difluorobenzyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 160 4-[3-(4-chlorophenyl)-5,6,7,8-tetrahydro-4H-1,2,6-triaza-azulen-1-ylmethyl]-2-fluorophenol; 165 1-benzyl-3-(4-chlorophenyl)-6-methyl-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 166 1-benzyl-3-(4-chlorophenyl)-6-ethyl-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 214 2-ethyl-3-p-tolyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 257 2-Ethyl-3-(4-ethylphenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; and 273 1-benzyl-3-(4-chlorophenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene citrate salt. 24. Compound according to claim 1, characterized in that it is selected from the group consisting of: Ex. Chemical name 131 3-(4-chlorophenyl)-2-isobutyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 133 2-benzyl-3-phenyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 177 2-cyclohexyl-3-phenyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 178 3-(4-chlorophenyl)-2-cyclohexyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 181 3-(4-Hyrophenyl)-2-cyclopentyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 182 2-Cylopentyl-3-(4-fluorophenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 183 2-(1-ethylpropyl)-3-(3-fluorophenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 184 2-(1-ethylpropyl)-3-(4-fluorophenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 186 2-(1-ethylpropyl)-3-phenyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 191 2-(1-ethylpropyl)-3-thiophen-2-yl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 215 2-tert-butyl-3-phenyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 216 2-tert-butyl-3-(4-fluorophenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 217 2-cyclopentyl-3-p-tolyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 218 2-cyclopentyl-3-(4-trifluoromethylphenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 220 2-cyclopentyl-3-(4-methoxyphenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 236 2-cyclopentyl-3-(3,4-difluorophenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 238 3-(4-chlorophenyl)-2-cyclobutyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 241 3-(3-chloro-4-fluorophenyl)-2-cyclopentyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 242 2-isopropyl-3-(4-methoxyphenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 277 2-cyclobutyl-3-(4-fluorophenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 278 2-cyclobutyl-3-p-tolyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 279 2-cyclobutyl-3-(4-trifluoromethylphenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 284 2-cyclopropyl-3-p-tolyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 300 2-sec-butyl-3-p-tolyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 302 2-cyclopentyl-3-(4-fluorophenyl)-6-methyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 306 3-(4-fluorophenyl)-2-isopropyl-8-methyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; and 310 2-cyclopentyl-7-methyl-3-p-tolyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene 25. Compound according to claim 1, characterized in that it is selected from the group consisting of: Ex. Chemical name 47 1-benzyl-3-(4-fluorophenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 64 3-(4-chlorophenyl)-2-ethyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 118 3-(4-chlorophenyl)-1-isobutyl-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 180 2-cyclopentyl-3-phenyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 190 3-(4-fluorophenyl)-2-isopropyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 192 2-cyclopentyl-3-thiophen-3-yl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 209 2-isopropyl-3-p-tol yl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 210 3-(4-ethylphenyl)-2-isopropyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 211 3-(4-chlorophenyl)-2-isopropyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 212 4-(2-isopropyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulen-3-yl)-benzonitrile; 213 2-isopropyl-3-(4-trifluoromethylphenyl)-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 232 2-cyclopentyl-3-furan-3-yl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 233 2-cyclopentyl-3-thiophen-2-yl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 284 2-cyclopropyl-3-p-tolyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 300 2-sec-butyl-3-p-tolyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene; 315 2-isopropyl-7-methyl-3-p-tolyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene. 26. Compound according to claim 1, characterized in that said pharmaceutically acceptable salt is an effective amino addition salt. 27. Compound according to claim 1, characterized in that said pharmaceutically acceptable salt is selected from the group consisting of hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lacthiobionate and lauryl sulfonate. 28. Pharmaceutical composition, characterized in that it includes a pharmaceutically acceptable carrier and a therapeutically effective amount of the compound having serotonin receptor modulator activity of formula (I), (TJ) or (111): in which m is 1 or 2; n is 1, 2 or 3; p is 1, 2 or 3; m+n is less than or equal to 4; m+p is less than or equal to 4; q is 0 or 1; r is 0 or 1; R<3> is -C1-4 alkyl, optionally substituted with -OH or halo; Ar is an aryl or heteroaryl ring selected from the group consisting of: a) phenyl, optionally mono-, di- or tri-substituted with R<r>or disubstituted on adjacent carbons with -OCi-4alkyleneO-; R<r>is selected from the group consisting of -OH, -C 1-6 alkyl -OC 1-6 alkyl, -CN, -NO 2 , halo and -CF 3 ; b) a monocyclic aromatic hydrocarbon group having five ring atoms, having a carbon atom as the point of attachment, having a carbon atom replaced by >0 or >S, having up to one additional carbon atom replaced by a -N= optionally mono- or disubstituted with R <r>; ALK is a branched or unbranched C 1-6 alkylene, C 2-8 alkenylene, optionally mono-, di- or tri-substituted with a substituent selected from the group consisting of: -OH, -OC 1-6 alkyl; CYC is a hydrogen or a carbocyclic or heterocyclic ring selected from the group consisting of: i) phenyl, optionally mono-, di- or tri-substituted by R<q>or disubstituted on adjacent carbons with -OCi-4alkyleneO-; R<q> is as defined in claim 1; v) a monocyclic aromatic hydrocarbon group having five ring atoms, having a carbon atom as the point of attachment, having a carbon atom replaced by >O or >S; vi) a monocyclic aromatic hydrocarbon group having six ring atoms, having a carbon atom as the point of attachment, having one or two carbon atoms substituted with -N= optionally mono- or disubstituted with R<q>; vii) a 3- to 8-membered non-aromatic carbocyclic or heterocyclic ring, said ring having 0, 1 or 2 non-adjacent heteroatom members selected from O or S, having 0, 1 or 2 unsaturated bonds, having 0, 1 or 2 carbon members that are a carbonyl, R 1 is selected from the group consisting of H, C 1-7 alkyl, and benzofused C 4-7 cycloalkyl, each optionally mono-, di- or tri substituted with R<p>; R<p>is selected from the group consisting of -OH, -OCi-alkyl; R<2> is selected from the group consisting of H or C 1-7 alkyl; and enantiomers, diastereomers, hydrates, solvates and pharmaceutically acceptable salts thereof. 29. Use of a therapeutically effective amount of a compound having serotonin receptor modulator activity of formula (S), (SS) or (ISS): in which m is 1 or 2; n is 1, 2 or 3; p is 1, 2 or 3; m+n is less than or equal to 4; m+p is less than or equal to 4; q is 0 or 1; r is 0 or 1; R<3> is -C1-4 alkyl, optionally substituted with -OH or halo; Ar is an aryl or heteroaryl ring selected from the group consisting of: a) phenyl, optionally mono-, di- or tri-substituted with R<r>or disubstituted on adjacent carbons with -OCi-4alkyleneO-; R<r>is selected from the group consisting of -OH, -C 1-6 alkyl -OC 1-6 alkyl, -CN, -NO 2 , halo and -CF 3 ; b) a monocyclic aromatic hydrocarbon group having five ring atoms, having a carbon atom as the point of attachment, having a carbon atom replaced by >0 or >S), having up to one additional carbon atom replaced by a —N= optionally mono- or disubstituted with R<r>; ALK is a branched or unbranched C 1-6 alkylene, C 2-8 alkenylene, optionally mono-, di- or tri-substituted with a substituent selected from the group consisting of: -OH, -OC 1-6 alkyl; CYC is a hydrogen or a carbocyclic or heterocyclic ring selected from the group consisting of: i) phenyl, optionally mono-, di- or tri-substituted by R<q>or disubstituted on adjacent carbons with -OCi-4alkyleneO-; R<q> is as defined in claim 1; v) a monocyclic aromatic hydrocarbon group having five ring atoms, having a carbon atom as the point of attachment, having a carbon atom replaced by >O or >S; vi) a monocyclic aromatic hydrocarbon group having six ring atoms, having a carbon atom as the point of attachment, having one or two carbon atoms substituted with -N= optionally mono- or disubstituted with R<q>; vii) a 3- to 8-membered non-aromatic carbocyclic or heterocyclic ring, said ring having 0, 1 or 2 non-adjacent heteroatom members selected from O or S, having 0, 1 or 2 unsaturated bonds, having 0, 1 or 2 carbon members that are a carbonyl; R 1 is selected from the group consisting of H, C 1-7 alkyl, and benzofused C 4-7 cycloalkyl, each optionally mono-, di- or tri substituted with R<p>; R<p>is selected from the group consisting of -OH, -OCi-alkyl; R<2> is selected from the group consisting of H or C1-7 alkyl; and enantiomers, diastereomers, hydrates, solvates and pharmaceutically acceptable salts thereof, for the manufacture of a composition for preventing or treating a CNS disorder selected from the group consisting of: depression/anxiety, generalized anxiety disorder, schizophrenia, bipolar disorder, psychotic disorder, obsessive compulsive disorder, mood disorder, post-traumatic stress and other stress-related disorders, migraine , pain, eating disorders, obesity, sexual dysfunction, metabolic disorders, hormone imbalance, alcohol abuse, addiction disorders, nausea, inflammation, centrally mediated hypertension, circadian rhythm disorders, jet lag and heart rhythm abnormalities in mammals. 30. Use according to claim 29, where said CNS disorder is selected from the group consisting of: depression/anxiety, sleep disorders and heart rhythm abnormalities. 31. Use of a therapeutically effective amount of a compound having serotonin receptor modulator activity of formula (I), (SS) or (ISS): wherein m is 1 or 2; n is 1, 2 or 3; p is 1, 2 or 3; m+n is less than or equal to 4; m+p is less than or equal to 4; q is 0 or 1; r is 0 or 1; R<3> is -C1-4 alkyl optionally substituted with -OH or halo; Ar is an aryl or heteroaryl ring selected from the group consisting of: a) phenyl, optionally mono-, di- or tri-substituted with R<r>or disubstituted on adjacent carbons with -OCi-4alkyleneO-; R f is selected from the group consisting of -OH, -C 1-6 alkyl -OC 1-6 alkyl, halo and -CF 3 ; b) a monocyclic aromatic hydrocarbon group having five ring atoms, having a carbon atom as the point of attachment, having a carbon atom replaced by >0 or >S, having up to one additional carbon atom replaced by a -N=, optionally mono- or disubstituted with R<r>; ALK is a branched or unbranched C 1-6 alkylene, C 2-8 alkenylene, optionally mono-, di- or tri-substituted with a substituent selected from the group consisting of: -OH, -OC 1-6 alkyl; CYC is a hydrogen or a carbocyclic or heterocyclic ring selected from the group consisting of: i) phenyl, optionally mono-, di- or tri-substituted by R<q>or disubstituted on adjacent carbons with -OCi-4alkyleneO-; R<q> is as defined in claim 1; v) a monocyclic aromatic hydrocarbon group having five ring atoms, having a carbon atom as the point of attachment, having a carbon atom replaced by >O or >S; vi) a monocyclic aromatic hydrocarbon group such as here six ring atoms, which has a carbon atom which is the point of attachment, which has one or two carbon atoms replaced by -N= optionally mono- or disubstituted with R<q>; vii) a 3- to 8-membered non-aromatic carbocyclic or heterocyclic ring, said ring having 0, 1 or 2 non-adjacent heteroatom members selected from O or S, having 0, 1 or 2 unsaturated bonds, having 0, 1 or 2 carbon members that are a carbonyl; R1 is selected from the group consisting of H, C1-7alkyl and benzofused C4-7Cycloalkyl, each optionally mono-, di- or tri-substituted with R<p>; R<p>is selected from the group consisting of -OH, -OCi-alkyl; R<2> is selected from the group consisting of H or C1-7 alkyl; and enantiomers, diastereomers, hydrates, solvates and pharmaceutically acceptable salts thereof for the preparation of a composition for the treatment or prevention of a disease or condition selected from the group consisting of: hypertension, peripheral vascular disorders, cardiovascular stroke, renal disorders, gastric motility, diarrhea, spastic colon, irritable bowel disease, ischaemia, septic shock, urinary incontinence and other disorders related to gastrointestinal vascular systems in mammals. 32. Use of a therapeutically effective amount of compound having serotonin receptor modulator activity of formula (I), (IT) or (ISS): in which m is 1 or 2; n is 1, 2 or 3; p is 1, 2 or 3; m+n is less than or equal to 4; m+p is less than or equal to 4; q is 0 or 1; r is 0 or 1; R<3> is -C1-4 alkyl, optionally substituted with -OH or halo; Ar is an aryl or heteroaryl ring selected from the group consisting of: a) phenyl, optionally mono-, di- or tri-substituted with R<r>or disubstituted on adjacent carbons with -OCi-4alkyleneO-; R<r> is selected from the group consisting of -OH, -C 1-6 alkyl -OC 1-6 alkyl; b) a monocyclic aromatic hydrocarbon group having five ring atoms, having a carbon atom as the point of attachment, having a carbon atom replaced by >0 or >S, having up to one additional carbon atom replaced by a —N= optionally mono- or disubstituted with R <r>; ALK is a branched or unbranched C 1-6 alkylene, C 2-8 alkenylene, optionally mono-, di- or tri-substituted with a substituent selected from the group consisting of: -OH, -OC 1-6 alkyl; CYC is a hydrogen or a carbocyclic or heterocyclic ring selected from the group consisting of: i) phenyl, optionally mono-, di- or tri-substituted by R<q>or disubstituted on adjacent carbons with -OCi-4alkyleneO-; R<q> is as defined in claim 1; v) a monocyclic aromatic hydrocarbon group having five ring atoms, having a carbon atom as the point of attachment, having a carbon atom replaced by >O or >S; vi) a monocyclic aromatic hydrocarbon group such as here six ring atoms, which has a carbon atom which is the point of attachment, which has one or two carbon atoms replaced by -N= optionally mono- or disubstituted with R<q>; vii) a 3- to 8-membered non-aromatic carbocyclic or heterocyclic ring, said ring having 0, 1 or 2 non-adjacent heteroatom members selected from O or S, - having 0, 1 or 2 unsaturated bonds, having 0, 1 or 2 carbon members that are a carbonyl; R<1> is selected from the group consisting of H, C1-7alkyl, and benzofused C4-7Cycloalkyl, each optionally mono-, di- or tri-substituted with R<p>; R<p>is selected from the group consisting of -OH, -OCi-alkyl; R<2> is selected from the group consisting of H or C1-7 alkyl; and enantiomers, diastereomers, hydrates, solvates and pharmaceutically acceptable salts thereof for the preparation of a composition for the treatment or prevention of an ocular disorder selected from the group consisting of: leukemia, optic neuritis, diabetic retinopathy, retinal edema and age-related macular degeneration in mammals. 33. Use of a therapeutically effective amount of compound having serotonin receptor modulator activity (I), (JS) or (ffl): in which m is 1 or 2; n is 1, 2 or 3; p is 1, 2 or 3; m+n is less than or equal to 4; m+p is less than or equal to 4; q is 0 or 1; r is 0 or 1; R<3> is -C1-4 alkyl optionally substituted with -OH or halo; Ar is an aryl or heteroaryl ring selected from the group consisting of: a) phenyl, optionally mono-, di- or tri-substituted with R<r>or disubstituted on adjacent carbons with -OCi-4alkyleneO-; R<r> is selected from the group consisting of -OH, -C 1-6 alkyl -OC 1-6 alkyl; b) a monocyclic aromatic hydrocarbon group having five ring atoms, having a carbon atom as the point of attachment, having a carbon atom replaced by >0 or >S, having up to one additional carbon atom replaced by a —N= optionally mono- or disubstituted with R <r>; ALK is a branched or unbranched C 1-6 alkylene, C 2-8 alkenylene, optionally mono-, di- or tri-substituted with a substituent selected from the group consisting of: -OH, -OC 1-6 alkyl; CYC is a hydrogen or a carbocyclic or heterocyclic ring selected from the group consisting of: i) phenyl, optionally mono-, di- or tri-substituted by R<q>or disubstituted on adjacent carbons with -OCi-4alkyleneO-; R<q> is as defined in claim 1; v) a monocyclic aromatic hydrocarbon group having five ring atoms, having a carbon atom as the point of attachment, having a carbon atom replaced by >O or >S; vi) a monocyclic aromatic hydrocarbon group such as here six ring atoms, which has a carbon atom which is the point of attachment, which has one or two carbon atoms replaced by -N= optionally mono- or disubstituted with R<q>; vii) a 3- to 8-membered non-aromatic carbocyclic or heterocyclic ring, said ring having 0, 1 or 2 non-adjacent heteroatom members selected from O or S, having 0, 1 or 2 unsaturated bonds, having 0, 1 or 2 carbon members that are a carbonyl; R 1 is selected from the group consisting of H, C 1-7 alkyl, and benzofused C 4-7 cycloalkyl, each optionally mono-, di- or tri substituted with R<p>; R<p>is selected from the group consisting of -OH, -OCi-alkyl; R<2> is selected from the group consisting of H or C 1-7 alkyl; and enantiomers, diastereomers, hydrates, solvates and pharmaceutically acceptable salts thereof for the preparation of a composition for the treatment or prevention of a disease or condition selected from the group consisting of: depression/anxiety, circadian rhythm disorders, jet lag, migraine, urinary incontinence, gastric motility and irritable bowel disorder in mammals. 34. Use of a therapeutically effective amount of a compound having serotonin receptor modulator activity (I), (JS) or (ffl): wherein m is 1 or 2; n is 1, 2 or 3; p is 1, 2 or 3; m+n is less than or equal to 4; m+p is less than or equal to 4; q is 0 or 1; r is 0 or 1; R<3> is -C1-4 alkyl optionally substituted with -OH or halo; Ar is an aryl or heteroaryl ring selected from the group consisting of: a) phenyl, optionally mono-, di- or tri-substituted with R<r>or disubstituted on adjacent carbons with -OCi-4alkyleneO-; R<r> is selected from the group consisting of -OH, -C 1-6 alkyl -OC 1-6 alkyl; b) a monocyclic aromatic hydrocarbon group having five ring atoms, having a carbon atom as the point of attachment, having a carbon atom replaced by >0 or >S, having up to one additional carbon atom replaced by a —N= optionally mono- or disubstituted with R <r>; ALK is a branched or unbranched C 1-6 alkylene, C 2-8 alkenylene, optionally mono-, di- or tri-substituted with a substituent selected from the group consisting of: -OH, -OC 1-6 alkyl; CYC is a hydrogen or a carbocyclic, heterocyclic ring selected from the group consisting of: i) phenyl, optionally mono-, di- or tri-substituted by R<q>or disubstituted on adjacent carbons with -OCi-4alkyleneO-; R<q> is as defined in claim 1; v) a monocyclic aromatic hydrocarbon group having five ring atoms, having a carbon atom as the point of attachment, having a carbon atom replaced by >O or >S; vi) a monocyclic aromatic hydrocarbon group such as here six ring atoms, which has a carbon atom which is the point of attachment, which has one or two carbon atoms replaced by -N= optionally mono- or disubstituted with R<q>; vii) a 3- to 8-membered non-aromatic carbocyclic or heterocyclic ring, said ring having 0, 1 or 2 non-adjacent heteroatom members selected from O or S, having 0, 1 or 2 unsaturated bonds, having 0, 1 or 2 carbon members that are a carbonyl; R1 is selected from the group consisting of H, C1-7alkyl and benzofused C4-7Cycloalkyl, each optionally mono-, di- or tri-substituted with R<p>; R<p>is selected from the group consisting of -OH, -OCi-alkyl; R<2> is selected from the group consisting of H or C1-7 alkyl; and enantiomers, diastereomers, hydrates, solvates and pharmaceutically acceptable salts thereof for the preparation of a composition for the treatment or prevention of a disease or condition selected from the group consisting of: depression/anxiety, generalized anxiety disorder, schizophrenia, bipolar disorders, psychotic disorders, obsessive-compulsive disorders, mood disorders, post-traumatic stress disorders, sleep disorders, sexual dysfunction, eating disorders, migraine disorders, addiction disorders and peripheral vascular disorders in mammals.