WO2012153154A1 - Oxetane substituted thieno pyrimidinones - Google Patents

Abstract

The present invention provides a compound of Formula (I) or pharmaceutically acceptable salt thereof wherein is selected from the group consisting of unsubstituted aryl and heteroaryl groups and aryl and heteroaryl groups substituted with Q; Q represents fluoro, chloro, bromo, C_1-6 straight or branched alkyl, alkylthio, cyano, trihaloalkyl, trihaloalkoxy; Y represents CH or N; R is selected from a group consisting of hydrogen, C_1-6 straight or branched alkyl, C_1-6 alkoxy, trihaloalkyl, trihaloalkoxy, amino, alkylamino, dialkylamino, hydroxy cyano, acetyl, alkylthio and halo; k is independently an integer 2 or 3; n is an integer from 0 to 2 and m is an integer from 1 to 4 provided that sum of the integers m and n is equal to an integer from 2 to 4. The invention also relates to pharmaceutical compositions containing them, to processes for their preparation, new intermediate compounds thereof and to their use in the treatment and/or prophylaxis of a melanin concentrating hormone receptor 1 and optionally H3 receptor related disease or condition.

Description

Oxetane substituted thieno pyrimidinones

FIELD OF THE INVENTION

This invention relates to novel oxetane substituted thieno-pyrimidinone compounds of formula (I), to pharmaceutical compositions containing them, to processes for their preparation, new intermediate compounds thereof and to their use in the treatment and/or prophylaxis of a melanin concentrating hormone receptor 1 related disease or condition such as obesity, obesity-related conditions, diabetes, metabolic disorder, bulimia, mood disorders, anxiety, depression, gastrointestinal disorders, inflammatory bowel disease and acute colitis. Some of the compounds of the present invention are also found to be histamine H3 receptor modulators.

BACKGROUND OF THE INVENTION

Melanin-concentrating hormone receptor 1 (MCHR1) plays pivotal role in regulation of energy homeostasis, food intake and feeding-related reward and behavior. Melanin concentrating hormone (MCH) producing neurons are confined to the tuberal hypothalamus, the integrating region for neuro-humoral regulation of energy homeostasis and stress related responses. MCHR1 widely distributed in the brain, mainly in areas implicated in the regulation of feeding, energy balance, emotion and stress. (Hervieu et al. 2000, Saito et al. 2001, Borowsky et al. 2002).

MCH both stimulates feeding and regulates energy balance in rodents (Pissios and

Maratos-Flier 2003; Pissios et al., 2009). MCH expression increases in fasted animals and in leptin-deficient ob/ob mice. Acute icv administration of MCH markedly increases food consumption and reduces catabolic activity (Qu et al. 1996). Chronic icv administration of MCH leads to a large increase in caloric intake and body weight. In addition, the MCH- treated animals showed increased glucose, insulin and leptin levels resembling the human metabolic syndrome (Gomori et al. 2003).

In line with that, genetic depletion of MCH renders mice to be resistant to diet-induced obesity (DIO). Transgenic mice over expressing the MCH gene consumed 10% more calories and gained 12% more weight than controls on high fat diet. High blood glucose and insulin- resistance also appeared consistently with a prediabetic state (Ludwig et al. 2001). Rodents treated with peptide or small molecule MCHRl antagonist show reduced food intake and improved metabolic state, particularly when kept on high-fat diet (Pissios et al. 2009, Ito et al. 2010.)

MCHRl antagonists may have a role not only in weight management, but also in treating anxiety and depression (Smith et al. 2006 and 2009, David et al. 2007, Gehlert et al. 2009).

MCHRl is also involved in the pathogenesis of experimental colitis that is regarded as a relevant disease model of the human inflammatory bowel disease (Crohn's disease). Systemic administration of antibody against MCHRl or small molecule MCHRl antagonists reduced severity and improved recovery from experimental acute colitis in rodents (Kokkotou et al. 2008, Fritzpatrick 2009, Ziogas et al. 2011). MCHRl plays also role in acute enteritis as it was proven in C. difficile toxin A-mediated enteritis in mice (Kokkotou et al. 2009).

Histamine is an important biogenic amine that modulates many physiological responses. Its biological actions are mediated via four histamine receptors named HI, H2, H3 and H4. The histamine H3 receptor is localized primarily to the central nervous system. In human, histamine H3 receptor expression is prominent in the basal ganglia, globus pallidus, hippocampus, and cortex. Many of these brain regions are critical for cognition (cortex and hippocampus) and sleep and homeostatic regulation (hypothalamus). Functionally, the histamine H3 receptor also exhibits several properties that contribute to its attractive profile as a drug target. These include the ability to act as a presynaptic autoreceptor to modulate the release of histamine, a neurotransmitter that plays a role in vigilance, attention, impulsivity, and feeding/weight regulation. Presynaptic H3 heteroreceptors modulate the release of other important neurotransmitters, such as acetylcholine, noradrenaline, dopamine, serotonin and GAB A, some of which have important roles in appetite (e.g., serotonin) or mood (e.g., dopamine). H3 antagonists may represent unique therapeutic modalities for the treatment of disorders of cognition, sleep, and energy hoemostasis. Selective antagonism/inverse agonism of histamine H3 receptor seems to have a role in food consumption and body weight control because it is an autoregulator of histamine synthesis and release, as well as a heteroreceptor for neurotransmitter signaling pathways implicated in the regulation of feeding behaviour.

MCH receptor antagonists are to be anorexigenic agents or antiobesity agents, and as concrete examples thereof, compounds have been disclosed, for example, in the international application WO2003/033476, WO2004/092181, WO2005/042541, WO2005/047293, WO2006/1 18320, WO2007/01 1284, WO2007/011286, WO2007/050723, WO2007/050726, WO2007/093363, WO2007/093365, WO2008/020799 and WO2008/002575. Spirocyclic oxetanes are discussed, for example, in Angew. Chem. Int. Ed., 4512-4515 (2008). However, the compounds of the present invention have not been reported in the prior art.

Some of the compounds may also be particularly useful in the treatment of disorders when a dual action on the MCHRl and H3 receptor is desired, for example when treating obesity-related conditions.

There is an ongoing need for the development of a melanin-concentrating hormone antagonist useful in the treatment and/or prophylaxis of obesity, obesity-related conditions, diabetes, metabolic disorder, bulimia, mood disorders, anxiety, depression, gastrointestinal disorders, inflammatory bowel disease and acute colitis.

Accordingly, we have found a novel group of oxetane substituted thieno-pyrimidinone compounds that exhibit a useful profile of activity as antagonists of the melanin-concentrating hormone receptor 1 (MCHRl) and optionally show H3 receptor modulation.

Particularly and surprisingly, the incorporation of spirooxetans provided new thieno- pyrimidinone compounds with favorable hERG profile and that have certain further advantages.

More particularly, although the incorporation of spirooxetans provided new thieno- pyrimidinone compounds with basic distal nitrogen in the side chain, surprisingly, the compounds of the present invention exhibit improved hERG selectivity and have some other important benefits.

SUMMARY OF THE INVENTION

The present invention provides a compound of Formula (I)

Formula (I) or pharmaceutically acceptable salt thereof wherein:

selected from the group consisting of unsubstituted aryl and heteroaryl groups and aryl and heteroaryl groups substituted with Q;

Q represents, fluoro, chloro, bromo, C_1-6 straight or branched alkyl, alkylthio, cyano, trihaloalkyl, trihaloalkoxy;

Y represents CH or N;

R is selected fom a group consisting of hydrogen, C_1-6 straight or branched alkyl, Ci_-6 alkoxy, trihaloalkyl, trihaloalkoxy, amino, alkylamino, dialkylamino, hydroxy cyano, acetyl, alkylthio and halo; k is independently an integer 2 or 3 ; n is an integer from 0 to 2 and m is an integer from 1 to 4 provided that sum of the integers m and n is equal to an integer from 2 to 4.

In another aspect of Formula (IA)

Formu a I or a pharmaceutically acceptable salt thereof in which Q represents H, fluoro, chloro, bromo. In another aspect the present invention provides a compound of Formula (IB)

or a pharmaceutically acceptable salt thereof in which Q represents H, fluoro, chloro, bromo. In another aspect the present invention provides a compound of Formula (IC)

or a pharmaceutically acceptable salt thereof in which Q represents H, fluoro, chloro, bromo.

In another aspect the present invention provides a compound of Formula (ID)

or a pharmaceutically acceptable salt thereof in which Q represents H, fluoro, chloro, bromo.

In another aspect the present invention provides a compound of Formula (IE)

or a pharmaceutically acceptable salt thereof in which Q represents H, fluoro, chloro, bromo.

In another aspect of Formula (IF)

or a pharmaceutically acceptable salt thereof in which Q represents H, fluoro, chloro, bromo. In another aspect the present invention provides a compound of Formula (IG)

Formula (IG)

or a pharmaceutically acceptable salt thereof in which Q represents H, fluoro, chloro, bromo.

In another aspect the present invention provides a compound of Formula (IH)

Formula (IH)

or a pharmaceutically acceptable salt thereof in which Q represents H, fluoro, chloro, bromo.

In another aspect the present invention provides a compound of Formula (I J)

or a pharmaceutically acceptable salt thereof in which Q represents H, fluoro, chloro, bromo.

In another aspect the present invention provides a compound of Formula (IK)

Formula (IK)

or a pharmaceutically acceptable salt thereof in which Q represents H, fluoro, chloro, bromo. In another aspect the present invention provides a compound of Formula (IL)

Formula (IL) or a pharmaceutically acceptable salt thereof in which Q represents H, fluoro, chloro, bromo. In another aspect the present invention provides a compound of Formula (IM)

Formula (IM) or a pharmaceutically acceptable salt thereof in which Q represents H, fluoro, chloro, bromo. In another aspect the present invention provides a compound of Formula (IN)

Formula (IN) or a pharmaceutically acceptable salt thereof in which Q represents H, fluoro, chloro, bromo.

The present invention also relates to the pharmaceutical compositions having melanin- concentrating hormone receptor 1 antagonist effect comprising a therapeutically effective amount of compound of Formula (I) or pharmaceutically acceptable salts thereof as active ingredient. Further, there is provided a pharmaceutical composition comprising a therapeutically effective amount of compound of Formula (I) or salt thereof and one or more pharmaceutically acceptable carrier and/or diluent. The present invention also relates to the process for manufacturing of the pharmaceutical compositions by mixing a therapeutically effective amount of a compound of Formula (I) as active ingredient and a pharmaceutically acceptable carrier and/or diluent. There is still further provided a method of treatment and/or prophylaxis of a melanin concentrating hormone receptor 1 related disease or condition comprising the step of administering to a warmblooded animal, particularly to a mammal, more particularly to a human, in need of such treatment and/or prophylaxis a pharmaceutical composition comprising a therapeutically effective amount of compound of Formula (I) or pharmaceutically acceptable salts thereof alone or together with at least one and a pharmaceutically acceptable carrier and/or diluent. Particularly, the said treatment and/or prophylaxis methods are used for such melanin concentrating hormone receptor 1 related disease or condition as obesity, obesity-related conditions, diabetes, metabolic disorder, bulimia, mood disorders, anxiety, depression, gastrointestinal disorders, inflammatory bowel disease and acute colitis.

Furthermore objects of the present invention are the process for preparation of compound of Formula (I) and new intermediate compounds of the process.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a compound of Formula (I)

Formula (I) or pharmaceutically acceptable salt thereof wherein: — 'is selected from the group consisting of unsubstituted aryl and heteroaryl groups and aryl and heteroaryl groups substituted with Q;

Q represents fluoro, chloro, bromo, C_1-6 straight or branched alkyl, alkylthio, cyano, trihaloalkyl, trihaloalkoxy; Y represents CH or N;

R is selected fom a group consisting of hydrogen, C_1-6 straight or branched alkyl, Ci_-6 alkoxy, trihaloalkyl, trihaloalkoxy, amino, alkylamino, dialkylamino, hydroxy cyano, acetyl, alkylthio and halo; k is independently an integer 2 or 3; n is an integer from 0 to 2 and m is an integer from 1 to 4 provided that sum of the integers m and n is equal to an integer from 2 to 4.

In another aspect the present invention provides a compound of Formula (I A)

Formula (IA)

or a pharmaceutically ac loro, bromo.

In another aspect (IB)

Formula (IB)

or a pharmaceutically acceptable salt thereof in which Q represents H, fluoro, chloro, bromo.

In another aspect the Formula (IC)

Formula (IC)

or a pharmaceutically acceptable salt thereof in which Q represents H, fluoro, chloro, bromo.

In another aspect the present invention provides a compound of Formula (ID)

or a pharmaceutically acceptable salt thereof in which Q represents H, fluofo, chloro, bromo.

In another aspect the present invention provides a compound of Formula (IE)

Formula (IE)

or a pharmaceutically acceptable salt thereof in which Q represents H, fluoro, chloro, bromo.

In another aspect the Formula (IF)

Formula (IF)

or a pharmaceutically acceptable salt thereof in which Q represents H, fluoro, chloro, bromo.

In another aspect the present invention provides a compound of Formula (IG)

or a pharmaceutically acceptable salt thereof in which Q represents H, fluoro, chloro, bromo.

In another aspect the present invention provides a compound of Formula (IH)

Formula (IH)

or a pharmaceutically acceptable salt thereof in which Q represents H, fluoro, chloro, bromo.

In another aspect the present invention provides a compound of Formula (IJ) or a pharmaceutically ac bromo. In another aspect

Formula (IK)

or a pharmaceutically acceptable salt thereof in which Q represents H, fluoro, chloro, bromo.

In another aspect of Formula (IL)

or a pharmaceutically acceptable salt thereof in which Q represents H, fluoro, chloro, bromo.

In another aspect the present invention provides a compound of Formula (IM)

Formula (IM)

or a pharmaceutically acceptable salt thereof in which Q represents H, fluoro, chloro, bromo. In another aspect the present invention provides a compound of Formula (IN)

Formula (IN) or a pharmaceutically acceptable salt thereof in which Q represents H, fluoro, chloro, bromo.

Of the compounds of the present invention, the most preferred compounds are:

6-(4-Chloro-phenyl)-3-{3-methoxy-4-[2-(2-oxa-6-aza-spiro[3.4]oct-6-yl)-ethoxy]-phenyl}- 3H-thieno[3,2-d]pyrimidin-4-one

6-(4-Chloro-phenyl)-3-{3-methoxy-4-[2-(2-oxa-6-aza-spiro[3.3]hept-6-yl)-ethoxy]-phenyl}- 3H-thieno[3,2-d]pyrimidin-4-one

6-(4-Chloro-phenyl)-3-{3-methoxy-4-[2-(2-oxa-5-aza-spiro[3.5]non-5-yl)-ethoxy]-phenyl}- 3H-thieno[3 ,2-d]pyrimidin-4-one

6-(4-Chloro-phenyl)-3-{3-methoxy-4-[2-(2-oxa-6-aza-spiro[3.5]non-6-yl)-ethoxy]-phenyl}- 3H-thieno[3,2-d]pyrimidin-4-one -(4-Chloro-phenyl)-3-{3-methoxy-4-[2-(2-oxa-7-aza-spiro[3.5]non-7-yl)-ethoxy]-phenyl}- H-thieno[3 ,2-d]pyrimidin-4-one -(4-Chloro-phenyl)-3-{3-methoxy-4-[2-(2-oxa-5-aza-spiro[3.4]oct-5-yl)-ethoxy]-phenyl}- H-thieno[3,2-d]pyrimidin-4-one -(4-Chloro-phenyl)-3- {3-methoxy-4-[2-(6-oxa- 1 -aza-spiro[3.3]hept- 1 -yl)-ethoxy] -phenyl }- H-thieno[3,2-d]pyrimidin-4-one -(4-Fluoro-phenyl)-3-{3-methoxy-4-[2-(2-oxa-6-aza-spiro[3.4]oct-6-yl)-ethoxy]-phenyl}- H-thieno[3,2-d]pyrimidin-4-one 3-{3-Chloro-4-[2-(2-oxa-6-aza-spiro[3.3]hept-6-yl)-ethoxy]-phenyl}-6-(4-chloro-phenyl)-3H- thieno [3 ,2-d]pyrimidin-4-one

3-{3-Chloro-4-[3-(2-oxa-6-aza-spiro[3.3]hept-6-yl)-propoxy]-phenyl}-6-(4-chloro-phenyl)- 3 H-thieno[3 ,2-d]pyrimidin-4-one 6-(4-Chloro-phenyl)-3 - { 6- [2-(2-oxa-6-aza-spiro [3.3 ]hept-6-yl)-ethoxy] -pyridin-3 -yl } -3 H- thieno[3₎2-d]pyrimidin-4-one

6-(4-Chloro-phenyl)-3-{6-[3-(2-oxa-6-aza-spiro[3.3]hept-6-yl)-propoxy]-pyridin-3-yl}-3H- thieno[3,2-d]pyrimidin-4-one

6-(4-Chloro-phenyl)-3-{4-[3-(2-oxa-6-aza-spiro[3.3]hept-6-yl)-propoxy]-phenyl}-3H- thieno[3,2-d]pyrimidin-4-one

6-(4-Chloro-phenyl)-3-{4-[2-(2-oxa-6-aza-spiro[3.3]hept-6-yl)-ethoxy]- phenyl} -3H- thieno[3,2-d]pyrimidin-4-one

6-(4-Fluoro-phenyl)-3- {3-methoxy-4-[2-(2-oxa-6-aza-spiro[3.3 ]hept-6-yl)-ethoxy] -phenyl} - 3H-thieno[3 ,2-d]pyrimidin-4-one 6-(4-Fluoro-phenyl)-3-{4-[3-(2-oxa-6-aza-spiro[3.3]hept-6-yl)-propoxy]-phenyl}-3H- thieno[3,2-d]pyrimidin-4-one

6-(4-Fluoro-phenyl)-3-{4-[2-(2-oxa-6-aza-spiro[3.3]hept-6-yl)-ethoxy]-phenyl}-3H- thieno[3 ,2-d]pyrimidin-4-one

It will be understood by those skilled in the art that the compound of the present invention may also be utilized in the form of a pharmaceutically acceptable salt thereof.

Both organic and inorganic acids can be used for the formation of pharmaceutically acceptable acid addition salts of Formula (I).

Typically, but not absolutely, the salts of the present invention are pharmaceutically acceptable salts. Salts encompassed within the term "pharmaceutically acceptable salts" refer to non-toxic salts of the compounds of this invention. Salts of the compounds of the present invention may comprise acid addition salts. In general, the salts are formed from pharmaceutically acceptable inorganic and organic acids. More specific examples of suitable acid salts include maleic, hydrochloric, hydrobromic, sulphuric, phosphoric, nitric, perchloric, fumic, acetic, propionic, succinic, glycolic, formic, lactic, aleic, tartaric, citric, palmoic, malonic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, fumaric, toluenesulfonic, methansulfonic (mesylate), naphthalene-2-sulfonic, benzenesulfonic, hydroxynaphthoic, hydroiodic, malic, teroic, tannic, and the like.

Other representative salts include acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, calcium edetate, camsylate, carbonate, clavulanate, citrate, dihydrochloride, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylsulfate, monopotassium maleate, mucate, napsylate, nitrate, oxalate, pamoate (embonate), palmitate, pantothenate, phosphate/diphosphate, polygalacturonate, salicylate, stearate, subacetate, succinate, sulfate, tannate, tartrate, teoclate, tosylate, triethiodide, and valerate salts.

Other salts, which are not pharmaceutically acceptable, may be useful in the preparation of compounds of this invention and these should be considered to form a further aspect of the invention. These salts, such as oxalic or trifluoroacetate, while not in themselves pharmaceutically acceptable, may be useful in the preparation of salts useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable salts.

According to the invention the compound of Formula (I) may be prepared by a) reacting a thieno-pyrimidinone derivative of Formula (II)

Formula (II) - wherein the meaning of Y and R are as described above for compound of Formula (I)

- with dibromoethane or dibromopropane to yield a thieno-pyrimidinone derivative of Formula (III)

Formula (III) wherein the meaning

and k are as described above for compound of Foi (I), then b) reacting a thieno-pyrimidinone derivative of Formula (III) with compound of Formula (IV)

Formula (IV)

- wherein the meaning of n and m are as described above for the Formula (I) - to obtain the compound of Formula (I), and optionally c) by adding organic or inorganic acids to the reaction product to form pharmaceutically acceptable acid addition salts of compound of Formula (I).

Compounds of Formula (IV) may be prepared according to well known procedures, as for instance those described in Angew. Chem. Int. Ed., Al, 4512-4515 (2008) and WO 2008/131 103.

Compounds of Formula (II) may be prepared according to well known procedures, as for instance those described in WO 2003/033476. Compounds or Formula (III) are believed to be novel and are herein claimed as a further aspect of the present invention. In a preferred aspect of the invention these compounds are in substantially pure form e.g. greater than 50% pure, particularly greater than 95% pure and more particularly more than 99% pure.

Furthermore according to the invention the compound of Formula (I) may be prepared by a) reacting 3,3-Bis-bromomethyl-oxetane (Journal of Organometallic Chemistry, 2007 , 692/24 5395-5402) with 2-aminoethanol or 3-aminopropanol in the presence of base such as potassium hydroxide, potassium-carbonate etc. to yield Formula (V)

Formula (V)

- wherein the meaning of k is as described above for compound of Formula (I)

then b) reacting a nitro-phenol derivative of Formula (VI)

Formula (VI)

- wherein the meaning of R is as described above for compound of Formula (I)

with a compound of Formula (V) in the presence of triphenylphosphine, diethylazodicarboxylate or di-isopropyl azodicarboxylate or di-tert-butylazodicarboxylate to yield a compound of Formula (VII) Pi

18

Formula (VII)

- wherein the meaning of R and k are as described above for compound of Formula (I) then c) reduction of the nitro group with well known procedures such as reduction with hydrogen in the presence of catalyst such as palladium on carbon, palladium, platinum, iron etc. or reduction with tin(II)chloride, sodium dithionite, sodium borohydride etc. yield an aniline of Formula (VIII)

Formula (VIII)

- wherein the meaning of R and k are as described above for compound of Formula (I) then d) reacting a phenyl-amino-thiophen-carboxylate compound of Formula (IX)

Formula (IX) - wherein the meaning of

is as described above for compound of Formula (I) with dimetylformamide-dimethylacetal and then with an aniline of Formula (VIII) to obtain the compound of Formula (I), and optionally d) adding organic or inorganic acids to the reaction product to form pharmaceutically acceptable acid addition salts of compound of Formula (I).

Furthermore according to the invention the compound of Formula (I) may be prepared by a) reacting 2-chloro-5-nitropyridine with Formula (V) in the presence of base such as potassium carbonate, cesium carbonate, potassium-tert-buthylate etc. to yield a compound of Formula (X)

- wherein the meaning of k is as described above for compound of Formula (I)

then b) reduction of the nitro group with well known procedures such as reduction with hydrogen in the presence of catalyst such as palladium on carbon, palladium, platinum, iron etc. or reduction with tin(II)chloride, sodium dithionite, sodium borohydride etc. yield a compound of Formula (XI)

Formula (XI) - wherein the meaning of k is as described above for compound of Formula (I) then c) reacting a phenyl-amino-thiophen-carboxylate compound of Formula (IX) with dimetylformamide-dimethylacetal and then with an aniline of Formula (XI) to obtain the compound of Formula (I), and optionally d) adding organic or inorganic acids to the reaction product to form pharmaceutically acceptable acid addition salts of compound of Formula (I).

Compounds of

Formula (V) such as 3-(2-Oxa-6-aza-spiro[3.3]hept-6-yl)-propan-l-ol;

Formula (VII) such as

6-[2-(2-Methoxy-4-nitro-phenoxy)-ethyl]-2-oxa-6-aza-spiro[3.3]heptane,

6-[2-(4-Nitro-phenoxy)-ethyl]-2-oxa-6-aza-spiro[3.3]heptane,

6-[3-(4-Nitro-phenoxy)-propyl]-2-oxa-6-aza-spiro[3.3]heptane,

6-[2-(2-Chloro-4~nitro-phenoxy)-ethyl]-2-oxa-6-aza-spiro[3.3]heptane and

6-[3-(2-Chloro-4-nitro-phenoxy)-propyl]-2-oxa-6-aza-spiro[3.3]heptane;

Formula (VIII) such as

3 -Methoxy-4- [2-(2-oxa-6-aza-spiro [3.3 ]hept-6-yl)-ethoxy] -phenylamine,

4-[2-(2-Oxa-6-aza-spiro[3.3]hept-6-yl)-ethoxy]-phenylamine,

4-[3-(2-Oxa-6-aza-spiro[3.3]hept-6-yl)-propoxy]-phenylamine,

3-Chloro-4-[2-(2-oxa-6-aza-spiro[3.3]hept-6-yl)-ethoxy]-phenylamine and

3-Chloro-4-[3-(2-oxa-6-aza-spiro[3.3]hept-6-yl)-propoxy]-phenylamine;

Formula (X) such as

6-[2-(5-Nitro-pyridin-2-yloxy)-ethyl]-2-oxa-6-aza-spiro[3.3]heptane and

6-[3-(5-Nitro-pyridin-2-yloxy)-propyl]-2-oxa-6-aza-spiro[3.3]heptane; and Formula (XI) such as

6-[3-(2-Oxa-6-aza-spiro[3.3]hept-6-yl)-propoxy]-pyridin-3-ylamine and

6-[2-(2-Oxa-6-aza-spiro[3.3]hept-6-yl)-ethoxy]-pyridin-3-ylamine

are believed to be novel and are herein claimed as a further aspect of the present invention. In a preferred aspect of the invention these compounds are in substantially pure form e.g. greater than 50% pure, particularly greater than 95% pure and more particularly more than 99% pure.

The invention further provides a pharmaceutical composition comprising a compound of Formula (I) or pharmaceutically acceptable salt thereof and one or more carriers and/or diluents in the pharmaceutical arts (also referred to as excipients). The excipients are acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof (i.e., the patient).

In accordance with another aspect of the invention there is provided a process for the preparation of a pharmaceutical composition comprising mixing (or admixing) a compound of Formula (I) or salt thereof with at least one excipient.

Pharmaceutical compositions may be in unit dose form containing a predetermined amount of active ingredient per unit dose. Such a unit may contain a therapeutically effective dose of the compound of Formula (I) or salt thereof or a fraction of a therapeutically effective dose such that multiple unit dosage forms might be administered at a given time to achieve the desired therapeutically effective dose. Preferred unit dosage formulations are those containing a daily dose or sub-dose, as herein above recited, or an appropriate fraction thereof, of an active ingredient. Furthermore, such pharmaceutical compositions may be prepared by any of the methods well-known in the pharmacy art.

Pharmaceutical compositions may be adapted for administration by any appropriate route, for example, by oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual, or transdermal), vaginal, or parenteral (including subcutaneous, intramuscular, intravenous, or intradermal) routes. Such compositions may be prepared by any method known in the art of pharmacy, for example, by bringing into association the active ingredient with the excipient(s). When adapted for oral administration, pharmaceutical compositions may be in discrete units such as tablets or capsules; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; edible foams or whips; oil-in-water liquid emulsions or water-in-oil liquid emulsions. The compound or salt thereof of the invention or the pharmaceutical composition of the invention may also be incorporated into a candy, a wafer, and/or tongue tape formulation for administration as a "quick-dissolve" medicine.

For instance, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like. Powders or granules are prepared by comminuting the compound to a suitable fine size and mixing with a similarly comminuted pharmaceutical carrier such as an edible carbohydrate, as, for example, starch or mannitol. Flavoring, preservative, dispersing, and coloring agents can also be present.

Capsules are made by preparing a powder mixture, as described above, and filling formed gelatin or non-gelatinous sheaths. Glidants and lubricants such as colloidal silica, talc, magnesium stearate, calcium stearate, solid polyethylene glycol can be added to the powder mixture before the filling operation. A disintegrating or solubilizing agent such as agar-agar, calcium carbonate, or sodium carbonate can also be added to improve the availability of the medicine when the capsule is ingested. Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents, and coloring agents can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars, such as glucose or beta- lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. Disintegrators include, without limitation, starch, methylcellulose, agar, bentonite, xanthan gum, and the like.

Tablets are formulated, for example, by preparing a powder mixture, granulating or slugging, adding a lubricant and disintegrant, and pressing into tablets. A powder mixture is prepared by mixing the compound, suitably comminuted, with a diluent or base as described above, and optionally, with a binder such as carboxymethylcellulose, and aliginate, gelatin, or polyvinyl pyrrolidone, a solution retardant such as paraffin, a resorption accelerator such as a quaternary salt, and/or an absorption agent such as bentonite, kaolin, or dicalcium phosphate. The powder mixture can be granulated by wetting a binder such as syrup, starch paste, acadia mucilage, or solutions of cellulosic or polymeric materials and forcing through a screen. As an alternative to granulating, the powder mixture can be run through the tablet machine and the result is imperfectly formed slugs broken into granules. The granules can be lubricated to prevent sticking to the tablet forming dies by means of the addition of stearic acid, a stearate salt, talc, or mineral oil. The lubricated mixture is then compressed into tablets. The compound or salt of the present invention can also be combined with a free-flowing inert carrier and compressed into tablets directly without going through the granulating or slugging steps. A clear opaque protective coating consisting of a sealing coat of shellac, a coating of sugar, or polymeric material, and a polish coating of wax can be provided. Dyestuffs can be added to these coatings to distinguish different dosages. Oral fluids such as solutions, syrups, and elixirs can be prepared in dosage unit form so that a given quantity contains a predetermined amount of active ingredient. Syrups can be prepared by dissolving the compound or salt thereof of the invention in a suitably flavoured aqueous solution, while elixirs are prepared through the use of a non-toxic alcoholic vehicle. Suspensions can be formulated by dispersing the compound or salt of the invention in a non-toxic vehicle. Solubilizers and emulsifiers, such as ethoxylated isostearyl alcohols and polyoxyethylene sorbitol ethers, preservatives, flavor additives such as peppermint oil, natural sweeteners, saccharin, or other artificial sweeteners, and the like, can also be added.

Where appropriate, dosage unit formulations for oral administration can be microencapsulated. The formulation can also be prepared to prolong or sustain the release as, for example, by coating or embedding particulate material in polymers, wax, or the like.

In the present invention, tablets and capsules are preferred for delivery of the pharmaceutical composition.

As used herein, the term "treatment" includes prophylaxis and refers to alleviating the specified condition, eliminating or reducing one or more symptoms of the condition, slowing or eliminating the progression of the condition, and preventing or delaying the reoccurrence of the condition in a previously afflicted or diagnosed patient or subject. Prophylaxis (or prevention or delay of disease onset) is typically accomplished by administering a drug in the same or similar manner as one would to a patient with the developed disease or condition.

The present invention provides a method of treatment in a warmblooded animal, particularly in a mammal, mor particularly a human, suffering from obesity, obesity-related conditions, diabetes, metabolic disorder, bulimia, mood disorders, anxiety, depression, gastrointestinal disorders, inflammatory bowel disease and acute colitis, or combination thereof. Such treatment comprises the step of administering a therapeutically effective amount of a compound of Formula (I) or salt thereof to a warmblooded animal, particularly to a mammal, more particularly to a human, in need of such treatment. Treatment can also comprise the step of administering a therapeutically effective amount of a pharmaceutical composition containing a compound of Formula (I) or salt thereof to a warmblooded animal, particularly to a mammal, more particularly to a human in need of such treatment. As used herein, the term "effective amount" means that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal, or human that is being sought, for instance, by a researcher or clinician.

The term "therapeutically effective amount" means any amount which, as compared to a corresponding subject who has not received such amount, results in improved treatment, healing, prevention, or amelioration of a disease, disorder, or side effect, or a decrease in the rate of advancement of a disease or disorder. The term also includes within its scope amounts effective to enhance normal physiological function. For use in therapy, therapeutically effective amounts of a compound of Formula (I), as well as salts thereof, may be administered as the raw chemical. Additionally, the active ingredient may be presented as a pharmaceutical composition.

The precise therapeutically effective amount of a compound or salt thereof of the invention will depend on a number of factors, including, but not limited to, the age and weight of the subject (patient) being treated, the precise disorder requiring treatment and its severity, the nature of the pharmaceutical formulation/composition, and route of administration, and will ultimately be at the discretion of the attending physician or veterinarian. Typically, a compound of Formula (I) or salt thereof will be given for the treatment in the range of about 0.1 to 100 mg/kg body weight of recipient (patient, mammal) per day and more usually in the range of 0.1 to 10 mg/kg body weight per day. Acceptable daily dosages may be from about 1 to about 1000 mg/day, and preferably from about 1 to about 100 mg/day. This amount may be given in a single dose per day or in a number (such as two, three, four, five, or more) of sub- doses per day such that the total daily dose is the same. An effective amount of a salt thereof may be determined as a proportion of the effective amount of the compound of Formula (I) per se. Similar dosages should be appropriate for treatment, including prophylaxis, of the other conditions referred herein for treatment. In general, determination of appropriate dosing can be readily arrived at by one skilled in medicine or the pharmacy art.

ASSAY METHODS: MCHR1 functional assay Materials:

Cells: human MCH1 (SLC1) AequoScreen® Cell Line (Perkin Elmer ES-370-A, lot N°: M4W-A2)

F12 medium (Gibco 21765) FBS (Gibco 10500)

Antibiotic Antimycotic Solution (Sigma A5955)

G418 (Gibco 1181 1-023)

Zeocin (Invitrogen R25001)

96-well plates (Costar 3595) FLIPR Calcium 5 no-wash kit (Molecular Devices R8186) probenecid (Sigma P8761)

MCH (Bachem H-1482)

MCH is dissolved in MilliQ water (1 mM), aliquoted and stored at -20 °C. A single aliquot is used only once. HEPES buffered salt solution (HBSS): 140 mM NaCl, 5 mM KCl, 10 mM HEPES, 2 mM CaCl₂, 2 mM MgCl₂, 20 mM glucose, pH=7.4, 305-315mOsm

Assay buffer: HBSS+ 2 mM probenecid, pH=7.4

Measurement of [Ca²⁺li

Cells are kept in F12 medium supplemented with 10 % FBS, l x antibiotic antimycotic solution, 400 μg/ml G418 and 250 μ&ηι1 zeocin. The day before the [Ca²⁺]i measurements cells are plated into TC grade 96- well plates at 40000 cells/well (100 μΐ/well) using the same culture medium without G418 and zeocin. On the day of the measurement the culture medium is removed from the cells by flicking the plate. Next Calcium 5 kit (diluted 4-fold in assay buffer compared with the recommendation of the manufacturer) is added to the cells in 100 μΐ/well, and the plate is incubated for 10 min at 37 °C. Test compounds/vehicle (DMSO, 1 % final concentration) diluted in assay buffer are added at 50 μΐ/well and the plate is incubated for 60 min at 37 °C. Test compounds are dissolved and serially diluted in DMSO, these stock solutions are stored at -20 °C until use.

Measurement of [Ca ]; is carried out with FlexStation II, a plate reader fluorimeter (8- channel on-line fluid addition, monochromators for excitation/emission wavelenght selection). Excitation and emission is at 485 and 525 nm, respectively. Fluorescence is detected appr. 20 and 40 s before and after agonist addition, respectively. First, an EC ₀ concentration of MCH is determined for the plate by carrying out a full concentration- response experiment using the first 3 columns of the plate. The EC₈₀ value of MCH is instantly determined with the built-in curve fitting module of the measurement software (SoftMax Pro, Molecular Devices). Then, in the second part of the measurement, inhibitory potency of test compounds is determined against MCH, administered at its plate-wise EC₈₀ concentration. Raw fluorescence data are expressed as AF/F values (max. fluorescence after agonist addition normalized to baseline: AF/F=(F_max-Fbaseiine)/Fbaseiine)- Percent inhibition for each concentration of a test compound is calculated: inhibition

IC50 values for test compounds are determined from 4-parameter sigmoidal concentration-inhibition curves fitted to the percent inhibition data using SoftMaxPro. ICsn values

The IC₅o values for the Example compounds are set forth in Table 1 hereinbelow. At least one compound of the present invention has an IC₅o value of less than about 100 μΜ. In a further embodiment, at least one compound of the present invention has an activity in the above referenced assay with an IC₅₀ value of between about 1 nm to about 100 μΜ. In an even further embodiment, at least one compound of the present invention has activity in the above referenced assay with an IC ₀ value of between about 2nM to about 100 nM. In yet a further embodiment, at least one compound of the present invention has activity in the above referenced assay with an IC50 value of between about 2nM and 50 nM. In one embodiment, at least one compound of the present invention has activity in at least one of the above referenced assay via an IC₅₀ value of less than about 100 nM. In another embodiment, at least one compound of the present invention has activity in the above referenced assay with an IC50 value of less than about 50 nM. In yet another embodiment, at least one compound of the present invention has activity in the above referenced assay with an IC₅₀ value of less than about 20 nM.

Set forth in Table 1 and Table 1 a herein below are IC₅₀ values that were generated in accordance with the MCHR1 Functional Assay as essentially described hereinabove.

Measurement of the effect of test compounds on hERG channels by the whole-cell patch clamp method

Cell culture

The CHO cell line stably expressing the transcripts of the human ether-a-go-go-related gene (HERG) was generated by bSys (Switzerland), optimized for automated patch clamp studies by Sophion (Denmark). The cells were cultured in F12 supplemented with 10% FCS, 1 * NEAA, l x vitamin, l penicillin-streptomycin (100 Unit/ml penicillin, 0.1 mg/ml streptomycin), .1 mg/ml hygromycin and 0.1 mg/ml G418. Cultures were kept at 37 °C in 5% C0₂ and passed twice per week. Identical cell lines were used up to 35 passages. Cells were plated on sterile Petri dishes previously coated with PDL. Electrophysiology

Automated whole-cell patch clamp recordings were made from HERG cells 2-5 days after plating. Cells were detached using trypsin treatment, then - after centrifugation - resuspended in a serum-free based media (CHO-SFM) containing 12.5 mM HEPES, l x penicillin- streptomycin trypsin inhibitor (0.04 mg/ml). Cell suspension, as well as the extracellular solution (140 mM NaCl, 4 mM KC1, 10 mM HEPES, 2 mM CaCl₂, 2 mM MgCl₂, 0.1 mM CdCl₂, 20 mM glucose. NaOH was used to adjust pH to 7.35, osmolality was 305-312 mOsm, adjusted with sucrose or distilled water), and the intracellular solution (80 mM KC1, 65 mM KF, 25 mM KOH, 10 mM EGTA, 10 mM HEPES, 1 mM MgCl₂, 4 mM ATP, KOH was used to adjust pH to 7.25; 310 mOsm) were added to the QPatch-16 automated patch clamp system (Sophion, Denmark) at room temperature (23-25 °C). Non-inactivated outward HERG currents were evoked by 1.5-s-long step voltage to -40 mV following a 5-s-long +20mV prepulse, at 10-second intervals. During the intervals cells were held at -80 mV. Current signals were lowpass filtered at 1 kHz and digitized at a sampling rate of 5 kHz. Series resistances were compensated (set to 80%), and remaining leakage currents were subtracted.

Application of the test compounds

DMSO was used to prepare stock solutions, which were further diluted when added to the extracellular solution to obtain the final nominal concentrations. The vehicle control solution contained the same concentration of the vehicle (0.1% DMSO; 0.3% DMSO in the case of 30 μΜ nominal solutions) as the solutions of the test compounds; and was pre-applied for 10-15 minutes before application of the test substance. Solutions containing the compound were applied to the cell for 9 minutes.

Data analysis

Peak amplitudes of tail current evoked by the -40 mV step potential were measured from the baseline current (i.e. the current value before the prepulse command). The percentage inhibition was calculated from the comparison of peak currents in the presence and absence of the test compound. In some experiments the baseline of current peaks showed a continuous gradual decline (run down). In these cases correction with rundown was applied: the time- matching control current value was determined by extrapolation from the pre-drug trend. Cells with excessive run down were discarded. Pooled data are presented as mean ± sem. The concentration dependent inhibition of the test compound was fitted with sigmoidal curves and

Example Structure ICso SR

Name (nM)

ethoxy] -phenyl }-6-(4-chloro-phenyl)-3H-thieno [3,2- d]pyrimidin-4-one

8 6.2 1613

3-{3-Chloro-4-[3-(2-oxa-6-aza-spiro[3.3]hept-6-yl)- propoxy]-phenyl}-6-(4-chloro-phenyl)-3H-thieno[3,2- d]pyrimidin-4-one

9 5.5 818

6-(4-Chloro-phenyl)-3- {6-[2-(2-oxa-6-aza-spiro[3.3]hept-6- yl)-ethoxy]-pyridin-3-yl}-3H-thieno[3,2-d]pyrimidin-4-one

10 5.7 111

6-(4-Chloro-phenyl)-3-{6-[3-(2-oxa-6-aza-spiro[3.3]hept-6- yl)-propoxy]-pyridin-3 -yl } -3 H-thieno [3 ,2-d]pyrimidin-4- one

11 2.5 1640

6-(4-Chloro-phenyl)-3-{4-[3-(2-oxa-6-aza-spiro[3.3]hept-6- yl)-propoxy]-phenyl}-3H-thieno[3,2-d]pyrimidin-4-one

Human recombinant histamine H₃ binding assay Membrane preparation

Membrane is prepared from hH₃-A2 cells (expressed in CHO cells) according to the Euroscreen Technical Data Sheet ( Cat. No.: ES-392/F). Cells are dissociated in Ca ²⁺ and Mg ²⁺ free phosphate buffered saline (PBS), centrifuged ( 1500 rpm, 3 min, 4 °C). The pellet is resuspended in buffer A (15 mM Tris-HCl pH 7.5, 2mM MgCl_2; 0.3 mM EDTA, 1 mM EGTA) and homogenized in a glass homogenizer. The crude membrane fraction is collected by two consecutive centrifugation steps at 40.000 g for 25 min at 4 °C, separated by a washing step in above described buffer. The final pellet is resuspended in buffer B (75 mM Tris-HCl pH 7.5, 12.5 mM MgCl₂, 0.3 mM EDTA, 1 mM EGTA, 250 mM sucrose), divided into aliquots, flash frozen and stored at -80°C until use. Protein content is determined by the Lowry method with bovine serum albumin (BSA) as a standard.

Binding conditions Assays are performed in triplicate containing the binding buffer (50 mM Tris HC1 pH 7.4, 5 mM MgCl₂), hH₃ membrane (14 μg protein/tube), N-a-[Methyl- H]methylhistamine dihydrochloride (Perkin Elmer Life and Analytical Sciences) as radioligand. Non specific binding is determined in the presence of 10 μΜ thioperamide. The samples are incubated in a final volume of 0.25 ml for 30 min at 25 °C. Binding reactions are terminated by rapid filtration through GF/B fiber glass filters, presoaked for at least 2 h in 0.5 % PEL Filters are washed three times 4 ml of ice-cold washing buffer (same composition as the binding buffer containing 0.5 M NaCl) using Brandel harvester. Filters radioactivity is determined by Packard TriCarb scintillation counter.

Data analyses The ligand displacement by the compounds was determined using a minimum of six concentrations in duplicate or triplicate, and experiments were repeated at least two times.

The specific radioligand binding is defined as the difference between total binding and the non-specific binding determined in the presence of an excess of unlabelled ligand. IC₅₀ values (i.e. concentration of compound giving 50% inhibition of specific binding) was calculated from concentration-displacement curves by sigmoidal fitting using Prism Software 4.0 (GraphPad, San Diego, CA, U.S.A.).

Ki values (i.e. inhibition constants) were calculated using the Cheng-Prusoff equation [4]: ¾ = IC₅₀/[1+(L/KD)], where [L] is the radioligand concentration and Kp the affinity of the labelled ligand for receptor. KD was determined from the Scatchard plot. Some of the compounds of the present invention are also found to be H3 receptor modulators. i values that were generated in accordance with the human recombinant histamine H₃ binding assay as essentially described hereinabove are set forth in Table lc hereinbelow.

Table lc

EXAMPLES

The invention is further defined in the following Examples. It should be understood that the Examples are given by way of illustration only. From the above discussion and the Examples, one skilled in the art can ascertain the essential characteristics of the invention, and without departing from the spirit and scope thereof, can make various changes and modifications to adapt the invention to various uses and conditions. As a result, the invention is not limited by the illustrative examples set forth herein below, but rather defined by the claims appended hereto.

In general, the compounds of Formula I can be prepared in accordance with the general knowledge of one skilled in the art and/or using methods set forth in the Example and/or Intermediate sections that follow. Solvents, temperatures, pressures, and other reaction conditions can readily be selected by one of ordinary skill in the art. Starting materials are commercially available and/or readily prepared by one skilled in the art. Combinatorial techniques can be employed in the preparation of compounds, for example, where the intermediates possess groups suitable for these techniques.

INTERMEDIATE 1 3-Methoxy-4- [2-(2-oxa-6-aza-spiro [3.31 hept-6-vD-ethoxyl -phenylamine

) 2-(2-Oxa-6-aza-spiror3.31hept-6-vn-ethanol (GB 1 169 027)

3,3-Bis-bromomethyl-oxetane (Journal of Organometallic Chemistry, 2007 , 692/24 5395- 5402, 75.31 g (308.7 mmol)) , 28,28 g (463 mMol) ethanolamine and 127.82 g K₂C0₃ were refluxed in ethanol (800 mL) for 72 hours. The reaction mixture was cooled and filtered and the filtrate was concetrated in vacuo. The residue was destilled to yield 46.40 g of title compound as an oil (bp.: 74-80 °C at 0.02 mbar) GC-HRMS 143.1 . b) 6-[2-(2-Methoxy-4-nitro-phenoxy^')-ethyll-2-oxa-6-aza-spiro[3.31heptane

30.0 g (209 mmol) 2-(2-Oxa-6-aza-spiro[3.3]hept-6-yl)-ethanol, 29.4 g (174 mmol) 2- methoxy-4-nitro-phenol, 52.88 g (200 mmol) triphenylphosphine were disssolved in dry dichlormethane (1000 mL). The mixture was cooled to 0 °C. 34.85 g (200 mmol) diethyl-azo- dicarboxylate (DEAD) in dichloromethane (250 mL) was added droppwise to the reaction mixture at 0 °C. The reaction mixture was stirred at room temperature overnight. The reaction mixture was washed with water (3 x 500 mL), and 2 M NaOH (2 x 200 mL) and dried over Na₂S0₄. After filtration the solvent was evaporated under reduced pressure. The remaining viscous oil was diluted with 2-propanol (450 mL). The solution was stirred at room temperature and left to crystalize overnight, and then filtered. The crude product was recrystalized from 2-propanol (250 mL) to yield 23.2 g of the title compound as a light brown solid MS (EI) 295.1 (MH⁺). c) 3-Methoxy-4-(^"2-(2-oxa-6-aza-spiro[^"3.31hept-6-yl)-ethoxyl-phenylamine

A mixture of 22.93 g (77.91 mMol) 6-[2-(2-Methoxy-4-nitro-phenoxy)-ethyl]-2-oxa-6-aza- spiro[3.3]heptane , lOpercent palladium carbon (2.3 g), tetrahydrofuran (500 mL) was stirred under hydrogen atmosphere at room temperature for 4 hours. The insolubles were filtered off, and the solvent was distilled off under reduced pressure, to obtain 20,5 g (99%) of the titled compound as an oil, which was used without purification.

INTERMEDIATE 2

4- f 2-(2-Oxa-6-aza-spiro [3.31 hept-6-yl)-ethoxyl -phenylamine

a) 6- 2-(4-Nitro-phenoxy)-ethyl1-2-oxa-6-aza-spiror3.31heptane

To a mixture of 2-(2-Oxa-6-aza-spiro[3.3]hept-6-yl)-ethanol (2.0 g 13.97 mmol), 4-nitro- phenol (1.62 g, 11.64 mmol), triphenylphosphine (3.54 g, 13.39 mmol) in dry dichlormethane (60 mL) was added droppwise at 0 °C diethyl-azo-dicarboxylate (DEAD) (2.33 g, 13.39 mmol) in dichloromethane (20 mL). The reaction mixture was stirred at room temperature overnight. The reaction mixture was washed with water (100 mL), and 2 M NaOH (2 x 100 mL) and dried over Na₂S0₄. After filtration the solvent was evaporated under reduced pressure. The residue was chromatographed on silica gel eluting with dichloromethane and methanol (95:5) to yield 1.99 g (65%) of the title compound. b) 4-[2-(2-Oxa-6-aza-spiro 3.31hept-6-yl)-ethoxy -phenylamine

The title compound was prepared from 4-[2-(2-Oxa-6-aza-spiro[3.3]hept-6-yl)-ethoxy]- phenylamine (1.99 g, 7.53 mmol) according to the method described in INTERMEDIATE 1/c to yield 1.76 g (100%) of the title compound, which was used without further purification.

INTERMEDIATE 3 4-[3-(2-Oxa-6-aza-spirof3.31hept-6-yl)-propoxyl-phenylamine

a) 3-(2-Oxa-6-aza-spiro 3.3]hept-6-yl -propan-l-ol

The title compound was prepared from 3-aminopropanol (17.24 g, 229.6 mmol) according to the method described in INTERMEDIATE 1/a 15.84 g (66%) of title compound as an oil (bp.: 92-108 °C at 0.05 mbar) MS (EI) 1 7.1 b) 6-r3-(4-Nitro-phenoxy)-propyll-2-oxa-6-aza-spiro[3.31heptane

The title compound was prepared from 3-(2-Oxa-6-aza-spiro[3.3]hept-6-yl)-propan-l-ol (6.72 g, 25.44 mmol) and 4-nitro-phenol (1.77 g, 12.72 mmol) according to the method described in INTERMEDIATE 2/a to yield 2.24 g (63.3%) of the title compound MS (EI) 279.1 (MH⁺). c) 4-[3-(2-Oxa-6-aza-spiro[3.3]hept-6-yl)-propoxy]-phenylamine

The title compound was prepared from 6-[3-(4-Nitro-phenoxy)-propyl]-2-oxa-6-aza- spiro[3.3]heptane (6.09 g , 8.05 mmol) according to the method described in INTERMEDIATE lie to yield 5.2 g (95.7%) of the title compound, which was used without further purification.

INTERMEDIATE 4 6- \ 2-(2-Oxa-6-aza-spiro [3.31 hept-6-yl)-ethoxyl-pyridin-3-ylamine

a) 6-[2-(5-Nitro-pyridin-2-yloxy)-ethyl1-2-oxa-6-aza-spiro 3.31heptane

2-Chloro-5-nitropyridine (2.0g 12.62 mmol) in tetrahydrofuran (20 mL) was added portionwise to a solution of 2-(2-Oxa-6-aza-spiro[3.3]hept-6-yl)-ethanol (3.97 g 25.24 mmol) and potassium tert-butoxide (3.12 g (27.76 mmol) in (30 mL) was stirred at a temperature between -10 °C to +5 °C under ice-cooling overnight. The solvent was evaporated in vacuo and the residue was chromatographed on silica gel eluding with dichloromethane and methanol (95:5). The fraction was concentrated in vacuo and the precipitate was collected by filtration to give 627 mg (19%) of the title compound as yellow solid MS (EI) 266.1 (MH⁺).

b) 6-[2-(2-Oxa-6-aza-spiro 3.31hept-6-yl)-ethoxyl-pyridin-3-ylamine

A mixture of 6-[2-(5-Nitro-pyridin-2-yloxy)-ethyl]-2-oxa-6-aza-spiro[3.3]heptane (2.09 g 7.8 mmol), l Opercent palladium carbon (210 mg), tetrahydrofuran (50 mL) was stirred under hydrogen atmosphere at room temperature for 4 hours. The insolubles were filtered off, and the solvent was distilled off under reduced pressure. The residue was chromatographed on silica gel eluting with dichloromethane and methanol (10: 1) to yield 0.75 g (40%) of the title compound MS (EI) 235.0.

INTERMEDIATE 5

6-f3-(2-Oxa-6-aza-spirof3 1hept-6-yI)-propoxyl-pyridin-3-ylainine

a) 6-[3-(5-Nitro-pyridin-2-yloxy)-propyl]-2-oxa-6-aza-spiror3.31heptane

The title compound was prepared from 3-(2-Oxa-6-aza-spiro[3.3]hept-6-yl)-propan-l-ol (2.0 g, 12.72 mmol) according to the method described in INTERMEDIATE 4/a to yield 0.32 g (18%) of the title compound MS (EI) 280.2 (MH⁺). b 6-f3-(2-Oxa-6-aza-spiro[3.31hept-6-yl)-propoxyl-pyridin-3-ylamine

A mixture of 6-[2-(5-Nitro-pyridin-2-yloxy)-ethyl]-2-oxa-6-aza-spiro[3.3]heptane (0.32 g 1.07 mmol), lOpercent palladium carbo (30 mg), tetrahydrofuran (10 mL) was stirred under hydrogen atmosphere at room temperature for 4 hours. The insolubles were filtered off, and the solvent was distilled off under reduced pressure to yield 0.26 g (97%) of the crude product, which was used without further purification.

a) 6-(4-Fluoro-phenyl)-3-(4-hydroxy-3-methoxy-phenyl)-3H-thieno[^"3,2-d1pyrimidin-4-one

The mixture of 3-amino-5-(4-fluoro-phenyl)-thiophene-2-carboxylic acid methyl ester (Journal of Medicinal Chemistry, 2006, 49/24 7095-7107; 3 g, 11.9 mmol) and dimethylformamide dimethyl acetal (3.16 mL, 23.8 mmol) in ethanol (50 mL) was refluxed for 2 h and concentrated to dryness. Phenol (8.4 g) and 4-amino-2-methoxyphenol (1.23 g, 8.83 mmol prepared from 4-hydroxy-3-methoxy-nitrobenzene by cathalytic hydrogenation)

The mixture of Intermediate 6a 2.6 g (7.05 mmol), cesium carbonate 9.18 g (28.2 mmol) and 1,2-dibromoethane 4.9 mL (56.4 mmol) in 43 mL of DMF was heated at 80 °C for 5 h. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was triturated in water, the solid was filtered off, washed with water and dried to yield 1.81 g (54 %) of the title compound as a light pink solid. MS (EI) 477.1 (MH⁺).

a)

A mixture of 2-chloro-4-nitro-phenol (3.6 g, 21.0 mMol), ₂C0₃ (5.76 g, 41.6 mMol) and 1 ,2-dibromoethane (4.0 g, 21.2 mMol) in dimethylformamide (10 mL) was stirred at room temperature overnight and then on 80 °C for 3 hours. The mixture was filtered and evaporated. The residue was diluted with ethylacetate and washed with I M NaOH (30 mL) and water (30 mL), dried over Na₂S0₄, filtered and the ethylacetate was evaporated. The residue was chiOmatographed on silica gel eluting with cyclohexane and ethylacetate (65:35) to yield 4.14 g (70.2%) of the title compound. b) 6-[2-(2-Chloro-4-nitro-phenoxy)-ethyll-2-oxa-6-aza-spiro[3.31heptane

A mixture of l-(2-Bromo-ethoxy)-2-chloro-4-nitro-benzene (1.0 g, 3.56 mMol), 2-oxa-6- azaspiro[3.3]heptan oxalate (Angew. Chem. Int. Ed., Al, 4512-4515 (2008)) (1.01 g, 5.35 mmol), Cs₂C0₃ (2.72 g, 7.12 mmol) and DIPEA (10.4 g 80.4 mMol) was refluxed in AcCN (50 mL) overnight. The solvent was evaporated in vacuo. The residue was diluted with dichloromethane (50 mL) and washed with brine (2 x 30 mL). The organic phase was dried over Na₂S0₄, filtered and evaporated. The residue was chromatographed on silica gel eluting with dichloromethane and methanol (95:5) to yield 0.36 g (34 %) of the title compound. c) 3-Chloro-4- 2-(2-oxa-6-aza-spiro[3.31hept-6-yl)-ethoxyl-phenylamine

A mixture of 6-[2-(2-Chloro-4-nitro-phenoxy)-ethyl]-2-oxa-6-aza-spiro[3.3]heptane (0.17 g, 0.5 mmol), Na₂S₂0₄ (1.2 g, 4.5 mMol) in methanol and water (1 : 1) was heated at 60 °C. The reaction mixture was cooled and diluted with water (20 mL), extracted with dichloromethane (2 x 20 mL). The organic phase was dried over Na₂S0₄, filtered and evaporated. The residue was chromatographed on silica gel eluting with dichloromethane and methanol (95:5) to yield 80 mg (52 %) of the title compound, which was used without further purification.

INTERMEDIATE 8 3-Chloro-4-[3-(2-oxa-6-aza-spiro[3.31hept-6-yl)-propoxy1-phenyIainine

a) 6- 3-(2-Chl0ro-4-nitro-phenoxy)-propyll-2-oxa-6-aza-spiro[3.31heptane

To a mixture 3-(2-Oxa-6-aza-spiro[3.3]hept-6-yl)-propan-l -ol (0.22 g 1.44 mmol), 2-chloro- 4-nitro-phenol (0.25 g, 1.44 mmol), triphenylphosphine (0.75 g, 2.88 mmol) in dry tetrahydrofurane (30 mL) was added droppwise at 0 °C di-tert-butyl-azo-dicarboxylate (0.66 g, 2.88 mmol) in tetrahydrofurane (10 mL). The reaction mixture was stirred at room temperature overnight. The solvent was evaporated, and the residue was diluted with dichloromethane (30 mL) and washed with water (100 mL), and 2 M NaOH (2 x 20 mL) and dried over Na₂S0₄. After filtration the solvent was evaporated under reduced pressure. The residue was chromatographed on silica gel eluting with dichloromethane and methanol (95:5) to yield 0.39 g (86%) of the title compound. b) 3-Chloro-4-[3-(2-oxa-6-aza-spiro[3.31hept-6-yl)-propoxy]-phenylamine

A mixture of 0.35 g (1 .1 mmol) 6-[3-(2-Chloro-4-nitro-phenoxy)-propyl]-2-oxa-6-aza- spiro[3.3]heptane, platinum on carbon (2.3 g), ethanol ( 10 mL) was stirred under hydrogen atmosphere at room temperature for 3 hours. The insolubles were filtered off, and the solvent was distilled off under reduced pressure The residue was chromatographed on silica gel eluting with dichloromethane and methanol (95:5) to yield 0.18 g (57%) of the title compound GC-H RMS 282. 1 .

Example 1

6-(4-Chloro-phenvn-3-{3-methoxy-4-f2-(2-oxa-7-aza-spirof3.51non-7-vn-ethoxyl- phenyl}-3H-thieno [3,2-dl pyrimidin-4-one a) 3-|^"4-(2-bromo-ethoxy)-3-methoxy-phenyl1-6-(4-chloro-phenyl)-3H-thienor3,2- dlpyrimidin-4-one

A mixture of 0.5 g (1.22 mmol) of 6-(4-chloro-phenyl)-3-(4-hydroxy-3-methoxy- phenyl]-3H-thieno[3,2-d]pyrimidin-4-one (WO-2003/033476A1), 0.5 mL (5.8 mmol) of 1,2- dibromoethane and 1.0 g (3.06 mmol) of cesium carbonate in 50 mL of 4-methyl-2-pentanone was refluxed for 20 h. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The precipitated crystals were filtered off and washed with 4-methyl-2-pentanone to yield 0.35 g (54.6 %) of the title compound. Mp.: 194-195 °C. b) 6-( 4-Chloro-phenyl)-3- (3-methoxy-4-(^"2-(2-oxa-7-aza-spiro[3.51non-7-yl)-ethoxy1- phenyl I -3 H-thieno Γ3 ,2-dlpyrimidin-4-one

A mixture of 0.6 g (1.22 mmol) of 3-[4-(2-bromo-ethoxy)-3-methoxy-phenyl]-6-(4- chloro-phenyl)-}-3H-thieno[3,2-d]pyrimidin-4-one, O.lg (0.787 mmol) of 2-oxa-5-aza- spiro[3.5]nonane (Angew. Chem. Int. Ed., Al, 4512-4515 (2008) and WO 2008/131103), 0.5 g (1.53 mmol) of cesium carbonate and 0.1 g (0.66 mmol) of sodium iodide in 20 mL of 4- methyl-2-pentanone was refluxed for 20 h. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was submitted to flash column chromatography using ieselgel 60 (0.015-0.040 mm) as adsorbent (Merck) and ethyl acetate : methanol = 6 : 1 as eluent to yield after crystallization from ethyl acetate 0.18 g (42.5 %) of the title compound. MS (EI) 538.2 (MH⁺). c) 6-(4-Chloro-phenvn-3 - (3 -methoxy-4- [2-(2-oxa-7-aza-spiro [3.5]non-7- yl)- ethoxyl - phenyl} -3H-thienor3,2-d1pyrimidin-4-one hydrochloride

To a mixture of 30 mg (5.5 μπιοΓ) of 6-(4-chloro-phenyl)-3-{3-methoxy-4-[2-(2-oxa- 7-aza-spiro[3.5]non-7-yl)-ethoxy]-phenyl}-3H-thieno[3,2-d]pyrimidin-4-one in 4 mL of methanol 0.2 mL of 20 % hydrogen chloride in methanol was added and the mixture was stirred at room temperature for 5 min. The reaction mixture was concentrated in vacuo, the residue was crystallized from diethyl ether to yield 25 mg (78 %) of the title compound. MS (EI) 538.2 (MH ). The salt was found instable. d) 6-(4-Chloro-phenyl)-3-{3-methoxy-4-r2-(2-oxa-7-aza-spiro 3.51non-7-yn-ethoxyl- phenyl ) -3 H-thieno Γ3 ,2-d}pyrimidin-4-one maleate

6-(4-Chloro-phenyl)-3-(3-methoxy-4- 2-(2-oxa-7-aza-spiro 3.51non-7-yl)-ethoxyl-phenyl}- 3H-thieno 3,2-dlpyrimidin-4-one (2.66 mg, 4.9 μπιοΐ) was dissolved in the mixture of DCM : MeOH = 10 : 1 (0.2 mL), maleic acid (0.72 mg, 6.1 μηιοΐ) was added. Ether (0.2 mL) was added to the solution. The mixture was stirred for 2 hours at room temperature. The product was filtered and dried to yield 2.0 mg (61%) of white solid. MS (EI) 538.2 (MH⁺).

Compounds of Table 2 were prepared from 3-[4-(2-bromo-ethoxy)-3-methoxy- phenyl]-6-(4-chloro-phenyl)-3H-thieno[3,2-d]pyrimidin-4-one (Example la) and appropriate amine according to the method described in Example 1.

Example 5

The mixture of methyl 3-amino-5-(4-chlorophenyl)thiophene-2-carboxylate (Journal of Medicinal Chemistry, 2006, 49/24 7095-7107; 20.86 g, 77.91 mmol) and dimethylformamide dimethyl acetal (19.91 g, 171.4 mmol) in ethanol (1400 mL) was refluxed for 2 h and concentrated to dryness. Phenol (22.0 g) and Intermediate 1 (22.93 g, 77.91 mmol) was added to the residue, the mixture was heated to 130 °C and stirred for 2 h. The mixture was cooled down to 50-60 °C and was diluted carefully with 2-propanol (600 mL). After crystallization the crude product was filtered, washed with 2-propanol and dried. The caide product was chromatographed on silica gel eluting with DCM : MeOH (95:5). The fraction was concentrated in vacuo and the precipitate was collected by filtration to give 20.1 g (51%) of the title compound. The title compound (11.2 g 21.96 mMol) dissolved in 1 10 mL dichloromethane and methanol (10:1). 3.19 g (27.45 mMol) maleic acid was added in one portion. The mixture was stirred for 2 hours at room temperature. The product was filtered, washed with dichlomethane and diethylether and dried to yield 11.94 g (87%) of white solid MS (EI) 510.2 (MH+).

Example 6

6-(4-Fluoro-phenyl)-3-{3-methoxy-4- [2-(2-oxa-6-aza-spiro f 3.41 oct-6-yl)-ethoxyl -phenyl}-

3H-thieno[3,2-dl pyrimidin-4-one

The mixture of Intermediate 6 (0.176 g, 0.37 mmol), 2-oxa-6-azaspiro[3,4]octane (0.066 g, 0.58 mmol), cesium carbonate (0.222 g, 0.68 mmol) and sodium iodide (6.3 mg, 0.04 mmol) in DMF (5 mL) was heated at 70 °C for 1.5 h. The reaction was then cooled to RT and poured into 20 g of crushed ice. The precipitate was filtered off, washed with water and dried. The residue was submitted to chromatography using Kieselgel 60 (0.04-0.063 mm) as adsorbent (Merck) and DCM : MeOH = 95 : 5 as eluent to yield after trituration with ether and filtration 53.3 mg (28 %) of the title compound as an off-white solid. MS (EI) 508.2 (MH⁺). Example 7

3-{3-Chloro-4-[2-(2-oxa-6-aza-spir0f3.31hept-6-yl)-ethoxyl-phenyl|-6-(4-chlorb-phenvI)-

3H-thieno [3,2-dl pyrimidin-4-one The mixture of methyl 3-ainino-5-(4-chlorophenyl)thiophene-2-carboxylate (Journal of Medicinal Chemistry, 2006, 49/24 7095-7107; 0.1 g, 0.37 mmol) and dimethylformamide dimethyl acetal (0.1 mL, 75 mmol) in ethanol (8 mL) was refluxed for 2 h and concentrated to dryness. Phenol (0.2 g) and Intermediate 7 (0.1 g, 0.3 mmol) was added to the residue, the mixture was heated to 120 °C and stirred for 2 h. The mixture was cooled down to 50-60 °C and was diluted carefully with 2-propanol (600 mL). After crystallization the crude product was filtered, washed with 2-propanol and dried. The crude product was chromatographed on silica gel eluting with DCM : MeOH : concentrated NH₄OH (10: 1 :0.1). The fraction was concentrated in vacuo and the precipitate was collected by filtration to give 30 mg (17%) of the title compound MS (EI) 514.1 (MH⁺).

3-{3-Chloro-4-[3-(2-oxa-6-aza-spirof3.31hept-6-yl)-propoxyl-phenyl}-6-(4-chloro- phenyl)-3H-thieno [3,2-dl pyrimidin-4-one

The mixture of methyl 3 -amino-5-(4-chloropheiiyl)thiophene-2-carboxylate (Journal of Medicinal Chemistry, 2006, 49/24 7095-7107; 0.17 g, 0.63 mmol) and dimethylformamide dimethyl acetal (1 mL, 5.97 mmol) in ethanol (5 mL) was refluxed for 2 h and concentrated to dryness. Phenol (0.4 g) and Intermediate 8 (0.18 g, 0.63 mmol) was added to the residue, the mixture was heated to 120 °C and stirred for 2 h. The mixture was cooled down to 50-60 °C and was diluted carefully with 2-propanol (15 mL). After crystallization the crude product was filtered, washed with 2-propanol and dried. The crude product was chromatographed on silica gel eluting with DCM : eOH (95:5). The fraction was concentrated in vacuo and the precipitate was collected by filtration to give 35 mg (11%) of the title compound MS (EI)

M_base 527.

Example 9

6-(4-Chloro-phenyl)-3-{6-[2-(2-oxa-6-aza-spiro[3.31hept-6-yl)-ethoxy1-pyridin-3-yl}-3H- thieno [3,2-dl pyrimidin-4-one

The mixture of methyl 3-amino-5-(4-chlorophenyl)thiophene-2-carboxylate (Journal of Medicinal Chemistry, 2006, 49/24 7095-7107; 0.56 g, 2.1 mmol) and dimethylformamide dimethyl acetal (0.4 mL, 2.3 mmol) in ethanol (5 mL) was refluxed for 2 h and concentrated to dryness. Phenol (0.9 g) and Intermediate 4 (0.5 g, 2.1 mmol) was added to the residue, the mixture was heated to 120 °C and stirred for 2 h. The mixture was cooled down to 50-60 °C and was diluted carefully with 2-propanol (15 mL). After crystallization the crude product was filtered, washed with 2-propanol and dried. The crude product was chromatographed on silica gel eluting with DCM : MeOH : concentrated NH₄OH (10: 1 :0.1). The fraction was concentrated in vacuo and the precipitate was collected by filtration to give 200 mg (20%) of the title compound. The title compound (0.1 g, 2.0 mmol) was dissolved in the mixture of DCM : MeOH = 10 : 1 (1 mL), maleic acid (30 mg, 2.6 mol) was added. The mixture was stirred for 2 hours at room temperature. The product was filtered and dried to yield 105 mg (84%) of white solid MS (EI) M_base 480.0.

Example 10

6-(4-Chloro-phenyl)-3-f6-[3-(2-oxa-6-aza-spiro[3.31hept-6-yl)-propoxyl-pyridin-3-yl}-

3H-thieno 13,2-dl pyrimidin-4-one

The mixture of methyl 3-amino-5-(4-chlorophenyl)thiophene-2-carboxylate (Journal of Medicinal Chemistry, 2006, 49/24 7095-7107; 0.32 g, 1.2 mmol) and dimethylformamide dimethyl acetal (0.23 mL, 1.3 mmol) in ethanol (5 mL) was refluxed for 2 h and concentrated to dryness. Phenol (0.5. g) and Intermediate 5 (0.3 g, 1.2 mmol) was added to the residue, the mixture was heated to 120 °C and stirred for 2 h. The mixture was cooled down to 50-60 °C and was diluted carefully with 2-propanol (15 mL). After crystallization the crude product was filtered, washed with 2-propanol and dried. The crude product was cliromatographed on silica gel eluting with DCM : MeOH : concentrated NH₄OH (10:1 :0.1). The fraction was concentrated in vacuo and the precipitate was collected by fdtration to give 154 mg (26%) of the title compound. The title compound (0.145 g, 0.29 mmol) was dissolved in the mixture of DCM : MeOH = 10 : 1 (1 mL), maleic acid (42 mg, 0.36 mmol) was added. The mixture was stirred for 2 hours at room temperature. The product was filtered and dried to yield 170 mg (95%) of white solid ESI-HRMS M_base 495.1.

Example 11

6-(4-Chloro-phenyl)-3-{4-i3-(2-oxa-6-aza-spirof3.31hept-6-yl)-propoxyl-phenv -3H- thieno [3,2-dl pyrimidin-4-one

The mixture of methyl 3-amino-5-(4-chlorophenyl)thiophene-2-carboxylate (Journal of Medicinal Chemistry, 2006, 49/24 7095-7107; 0.32 g, 1.2 mmol) and dimethylformamide dimethyl acetal (0.345 mL, 2.0 mmol) in ethanol (22 mL) was refluxed for 2 h and concentrated to dryness. Phenol (0.34 g) and Intermediate 3 (0.3 g, 1.2 mmol) was added to the residue, the mixture was heated to 120 °C and stirred for 2 h. The mixture was cooled down to 50-60 °C and was diluted carefully with 2-propanol (15 mL). After crystallization the crude product was filtered, washed with 2-propanol and dried. The crude product was chromatographed on silica gel eluting with DCM : MeOH (91 :9). The fraction was concentrated in vacuo and the precipitate was collected by fdtration to give 260 mg (43%) of the title compound. The title compound (0.120 g, 0.24 mmol) was dissolved in the mixture of DCM : MeOH = 10 : 1 (2.2 mL), maleic acid (35 mg, 0.3 mmol) was added. The mixture was stirred for 2 hours at room temperature. The product was filtered and dried to yield 79 mg (53%) of white solid MS (EI) M_baSe 493.

Example 12

6-(4-ChIoro-phenvn-3- (4- [2-(2-oxa-6-aza-spiro [3.31 hept-6-vD-ethoxyl - phenyl}-3H- thieno [3,2-dl pyrimidin-4-one

The mixture of methyl 3-amino-5-(4-chlorophenyl)thiophene-2-carboxylate (Journal of Medicinal Chemistry, 2006, 49/24 7095-7107; 685 mg, 2.56 mmol) and dimethylformamide dimethyl acetal (0.729 mL, 5.63 mmol) in ethanol (45 mL) was refluxed for 2 h and concentrated to dryness. Phenol (722 mg) and Intermediate 2 (0.6 g, 2.56 mmol) was added to the residue, the mixture was heated to 120 °C and stirred for 2 h. The mixture was cooled down to 50-60 °C and was diluted carefully with 2-propanol (35 mL). After crystallization the crude product was fdtered, washed with 2-propanol and dried. The crude product was chromatographed on silica gel eluting with DCM : MeOH (95:5). The fraction was concentrated in vacuo and the precipitate was collected by filtration to give 278 mg (22%) of the title compound. The title compound (278 mg, 0.58 mmol) was dissolved in the mixture of DCM : MeOH = 10 : 1 (3 mL), maleic acid (84 mg, 0.72 mmol) was added. The mixture was stirred for 2 hours at room temperature. The product was filtered and dried to yield 293 mg (85%) of white solid ESI-HRMS 480.1 (MH⁺). Example 13

6-(4-Fluoro-phenvO- 3- (3-methoxy-4- [2-(2-oxa-6-aza-spiro [3.31 hept-6- yl)-ethoxyl - phenyl}-3H-thieno [3,2-dl pyrimidin-4-one The mixture of 3-amino-5-(4-fluoro-phenyl)-thiophene-2-carboxylic acid methyl ester (Journal of Medicinal Chemistry, 2006, 49/24 7095-7107; 0.3 g, 1.2 mmol) and dimethylformamide dimethyl acetal (0.32 mL, 2.4 mmol) in ethanol (5 mL) was refluxed for 2 h and concentrated to dryness. Phenol (1.6 g) and Intermediate 1 (0.27 g, 1 mmol) was added to the residue, the mixture was heated to 140 °C and stirred for 1 h. The reaction was then cooled to 0 °C, triturated with hexane and kept at 8 °C for 16 h. The precipitate was filtered off, washed with hexane and dried. The residue was submitted to flash chromatography using Kieselgel 60 (0.04-0.063 mm) as adsorbent (Merck) and DCM : MeOH = 95 : 5 as eluent to yield 0.179 g (36 %) of the product as a yellowish solid. The title compound was dissolved in the mixture of DCM : MeOH = 10 : 1 (4 mL), maleic acid (0.053 g, 0.46 mmol) was added and the solution was concentarted to dryness. The residue was triturated with ethanol, the solid was filtered off, washed with ethanol and ether, and dried to give 0.17 g of the maleate salt. MS (EI) 494.2 (MH⁺).

Example 14

6-f4-Fluoro-phenyl)-3-{4-f3-(2-oxa-6-aza-spiro[3.31hept-6-yl)-propoxyl-phenyl}-3H- thieno [3,2-dl pyrimidin-4-one

The mixture of 3-amino-5-(4-fluoro-phenyl)-thiophene-2-carboxylic acid methyl ester (Journal of Medicinal Chemistry, 2006, 49/24 7095-7107; 025 g, 1 mmol) and dimethylformamide dimethyl acetal (0.27 mL, 2 mmol) in ethanol (4 mL) was refluxed for 2 h and concentrated to dryness. Phenol (1 g) and Intermediate 3 (0.27 g, 1 mmol) was added to the residue, the mixture was heated to 140 °C and stirred for 1 h. The reaction was then cooled to RT, diluted with hexane and decanted. The oily residue was triturated with ether and stirred at RT for 1 h. The precipitate was filtered off, washed with ether and dried. The residue was submitted to flash chromatography using Kieselgel 60 (0.04-0.063 mm) as adsorbent (Merck) and DCM : MeOH = 9 : 1 as eluent to yield 0.22 g (47 %) of the product as an off-white solid. 0.129 (0.27 mmol) of the title compound was dissolved in the mixture of DCM : MeOH = 10 : 1 (3 mL), maleic acid (0.039 g, 0.34 mmol) was added and the solution was concentarted to dryness. The residue was triturated with ethanol, the solid was filtered off, washed with ethanol and ether, and dried to give 0.146 g of the maleate salt. MS (EI) 478.2 (MH⁺).

Example 15

6-(4-Fluoro-phenyl)-3-f4-[2-(2-oxa-6-aza-spiro[3.31hept-6-yl)-ethoxyl-phenyl)-3H- thieno [3,2-dl pyrimidin-4-one

The mixture of 3-amino-5-(4-fluoro-phenyl)-thiophene-2-carboxylic acid methyl ester (Journal of Medicinal Chemistry, 2006, 49/24 7095-7107; 022 g, 0.88 mmol) and dimethylformamide dimethyl acetal (0.24 mL, 1.8 mmol) in ethanol (3.5 mL) was refluxed for 2 h and concentrated to dryness. Phenol (0.9 g) and Intermediate 2 (0.21 g, 0.9 mmol) was added to the residue, the mixture was heated to 140 °C and stirred for 1 h. The reaction was then cooled to RT, triturated with ether and kept at 8 °C for 16 h. The precipitate was filtered off, washed with ether and dried. The residue was submitted to flash chromatography using Kieselgel 60 (0.04-0.063 mm) as adsorbent (Merck) and DKM : MeOH - 95 : 5 as eluent to yield 0.24 g (60 %) of the product as an off-white solid. The title compound was dissolved in the mixture of DCM : MeOH = 10 : 1 (4 mL), maleic acid (0.075 g, 0.654 mmol) was added and the solution was concentarted to dryness. The residue was triturated with ethanol, the solid was filtered off, washed with ethanol and ether, and dried to give 0.256 g of the maleate salt. MS (EI) 464.2 (MH⁺).

Table 3

Example Structure MS

Name

MS (EI)

15 (MH⁺)

6-(4-Fluoro-phenyl)-3-{4-[2-(2-oxa-6-aza-spiro[3.3]hept-6-yl)- 464.2 ethoxy]-phenyl}-3H-thieno[3,2-d]pyrimidin-4-one

The following formulation examples illustrate representative pharmaceutical compositions of this invention. The present invention however not limited to the following pharmaceutical compositions. The concentration of mixtures are expressed in weight percent.

Preparation Example 1

Preparation of pharmaceutical compositions: a) Tablets:

0.01-50 % of active ingredient of formula (I), 15-50 % of lactose, 15-50 % of potato starch, 5-15 % of polyvinyl pyrrolidone, 1-5 % of talc, 0.01-3 % of magnesium stearate, 1-3 % of colloid silicon dioxide and 2-7 % of ultraamylopectin were mixed, then granulated by wet granulation and pressed to tablets.

b) Dragees, filmcoated tablets:

The tablets made according to the method described above were coated by a layer consisting of entero- or gastrosolvent film, or of sugar and talc. The dragees were polished by a mixture of beeswax and carnuba wax.

c) Capsules:

0.01-50 % of active ingredient of formula (I), 1-5 % of sodium lauryl sulfate, 15-50 % of starch, 15-50 % of lactose, 1-3 % of colloid silicon dioxide and 0.01-3 % of magnesium stearate were thoroughly mixed, the mixture was passed through a sieve and filled in hard gelatin capsules.

d) Suspensions:

Ingredients: 0.01-15 % of active ingredient of formula (I), 0.1-2 % of sodium hydroxide, 0.1-3 % of citric acid, 0.05-0.2 % of nipagin (sodium methyl 4-hydroxybenzoate), 0.005-0.02 % of nipasol, 0.01-0.5 % of carbopol (polyacrilic acid), 0.1-5 % of 96 % ethanol, 0.1-1 % of flavoring agent, 20-70 % of sorbitol (70 % aqueous solution) and 30-50 % of distilled water.

To solution of nipagin and citric acid in 20 ml of distilled water, carbopol was added in small portions under vigorous stirring, and the solution was left to stand for 10-12 h. Then the sodium hydroxide in 1 ml of distilled water, the aqueous solution of sorbitol and finally the ethanolic raspberry flavor were added with stirring. To this carrier the active ingredient was added in small portions and suspended with an immersing homogenizator. Finally the suspension was filled up to the desired final volume with distilled water and the suspension syrup was passed through a colloid milling equipment.

e) Suppositories:

For each suppository 0.01-15% of active ingredient of formula (I) and 1-20% of lactose were thoroughly mixed, then 50-95% of adeps pro suppository (for example Witepsol 4) was melted, cooled to 35 °C and the mixture of active ingredient and lactose was mixed in it with homogenizator. The obtained mixture was mould in cooled forms.

f) Lyophilized powder ampoule compositions:

A 5 % solution of mannitol or lactose was made with bidistilled water for injection use, and the solution was filtered so as to have sterile solution. A 0.01-5 % solution of the active ingredient of formula (I) was also made with bidistilled water for injection use, and this solution was filtered so as to have sterile solution. These two solutions were mixed under aseptic conditions, filled in 1 ml portions into ampoules, the content of the ampoules was lyophilized, and the ampoules were sealed under nitrogen. The contents of the ampoules were dissolved in sterile water or 0.9 % (physiological) sterile aqueous sodium chloride solution before administration.

Claims

1) A compound of Formula I)

teroaryl groups and

ary and heteroaryl groups substituted with Q;

Q represents fluoro, chloro, bromo, C_1-6 straight or branched alkyl, alkylthio, cyano, trihaloalkyl, trihaloalkoxy; Y represents CH or N;

R is selected from a group consisting of hydrogen, C_1-6 straight or branched alkyl, Ci_-6 alkoxy, trihaloalkyl, trihaloalkoxy, amino, alkylamino, dialkylamino, hydroxy, cyano, acetyl, alkylthio and halo; k is independently an integer 2 or 3; n is an integer from 0 to 2 and m is an integer from 1 to 4 provided that sum of the integers m and n is equal to an integer from 2 to 4. 2) A compound as claimed in claim 1 of Formula (IA)

Formula (1A)

or a pharmaceutically acceptable salt thereof in which Q represents H, fluoro, chloro, bromo. 3) A compound as claimed in claim 1 of Formula (IB)

Formula (IB)

or a pharmaceutically acceptable salt thereof in which Q represents H, fluoro, chloro, bromo. 4) A compound as claimed in claim 1 of Formula (IC)

Formula (IC)

or a pharmaceutically acceptable salt thereof in which Q represents H, fluoro, chloro, bromo. 5) A compound as claimed in claim 1 of Formula (ID)

Formula (ID)

or a pharmaceutically acceptable salt thereof in which Q represents H, fluoro, chloro, bromo.

6) A compound as claimed in claim 1 of Formula (IE)

larmaceutically acceptable salt thereof in which Q represents H, fluoro, chloro, bromo.

7) A compound as claimed in claim 1 of Formula (IF)

Formula (IF)

larmaceutically acceptable salt thereof in which Q represents H, fluoro, chloro, bromo.

8) A compound as claimed in claim 1 of Formula (IG)

Formula (IG)

larmaceutically acceptable salt thereof in which Q represents H, fluoro, chloro, bromo. 9) A compound as claimed in claim 1 of Formula (IH)

Formula (IH)

or a pharmaceutically acceptable salt thereof in which Q represents H, fluoro, chloro, bromo. 10) A compound as claimed in claim 1 of Formula IJ)

or a pharmaceutical H, fluoro, chloro, bromo. 1 1) A compound as

or a pharmaceutically acceptable salt thereof in which Q represents H, fluoro, chloro, bromo. 12) A compound as claimed in claim 1 of Formula (IL)

Formula (IL)

or a pharmaceutically acceptable salt thereof in which Q represents H, fluoro, chloro, bromo. 13) A compound as claimed in claim 1 of Formula (IH)In another aspect the present invention provides a compound of Formula (IM)

Formula (IM) or a pharmaceutically acceptable salt thereof in which Q represents H, fluoro, chloro, bromo.

14) A compound as claimed in claim 1 of Formula (IH)In another aspect the present invention provides a compound of Formula (IN)

Formula (IN) or a pharmaceutically acceptable salt thereof in which Q represents H, fluoro, chloro, bromo. 15) One or more of the following compounds:

6-(4-Chloro-phenyl)-3-{3-methoxy-4-[2-(2-oxa-6-aza-spiro[3.4]oct-6-yl)-ethoxy]-phenyl}- 3H-thieno[3,2-d]pyrimidin-4-one

6-(4-Chloro-phenyl)-3-{3-methoxy-4-[2-(2-oxa-6-aza-spiro[3.3]hept-6-yl)-ethoxy]-phenyl}- 3H-thieno[3,2-d]pyrimidin-4-one

6-(4-Chloro-phenyl)-3-{3-methoxy-4-[2-(2-oxa-5-aza-spiro[3.5]non-5-yl)-ethoxy]-phenyl}- 3H-thieno[3,2-d]pyrimidin-4-one

6-(4-Chloro-phenyl)-3-{3-methoxy-4-[2-(2-oxa-6-aza-spiro[3.5]non-6-yl)-ethoxy]-phenyl}- H-thieno[3,2-d]pyrimidin-4-one 6-(4-Chloro-phenyl)-3-{3-methoxy-4-[2-(2-oxa-7-aza-spiro[3.5]non-7-yl)-ethoxy]-phenyl}- 3 H-thieno [3 ,2-d]pyrimidin-4-one

6-(4-Chloro-phenyl)-3-{3-methoxy-4-[2-(2-oxa-5-aza-spiro[3.4]oct-5-yl)-ethoxy]-phenyl}- 3 H-thieno[3 ,2-d]pyrimidin-4-one 6-(4-Chloro-phenyl)-3- {3-methoxy-4-[2-(6-oxa- 1 -aza-spiro[3.3]hept- 1 -yl)-ethoxy] -phenyl } - 3H-thieno[3,2-d]pyrimidin-4-one.

16) One or more of the following compounds:

6-(4-Chloro-phenyl)-3-{6-[3-(2-oxa-6-aza-spiro[3.3]hept-6-yl)-propoxy]-pyridin-3-yl}-3H- thieno[3 ,2-d]pyrimidin-4-one 6-(4-Chloro-phenyl)-3-{4-[3-(2-oxa-6-aza-spiro[3.3]hept-6-yl)-propoxy]-phenyl}-3H- thieno[3 ,2-d]pyrimidin-4-one

6-(4-Chloro-phenyl)-3-{4-[2-(2-oxa-6-aza-spiro[3.3]hept-6-yl)-ethoxy]-phenyl}-3H- thieno[3,2-d]pyrimidin-4-one

6-(4-Fluoro-phenyl)-3-{4-[3-(2-oxa-6-aza-spiro[3.3]hept-6-yl)-propoxy]-phenyl}-3H- thieno[3,2-d]pyrimidin-4-one

6-(4-Fluoro-phenyl)-3-{4-[2-(2-oxa-6-aza-spiro[3.3]hept-6-yl)-ethoxy]-phenyl}-3H- thieno[3,2-d]pyrimidin-4-one

17) A pharmaceutical composition having a melanin-concentrating hormone receptor 1 antagonist and optionally H3 receptor modulating effect comprising a therapeutically effective amount of compound according to any one of claims 1-16 as active ingredient and a pharmaceutically acceptable carrier and/or diluent.

18) Process for manufacturing pharmaceutical composition having a melanin-concentrating hormone receptor 1 antagonist and optionally H3 receptor modulating effect characterized by mixing a therapeutically effective amount of a compound according to any one of claims 1-16 as active ingredient and a pharmaceutically acceptable carrier and/or diluent. 19) A method of treatment and/or prophylaxis of a melanin concentrating hormone receptor 1 related disease or condition, and optionally when dual action on the MCHRl and H3 receptor is desired, comprising the step of administering to a warmblooded animal in need of such treatment and/or prophylaxis a therapeutically-effective amount of a compound in accordance with any one of claims 1-16.

20) A method of treatment and/or prophylaxis of a melanin concentrating hormone receptor 1 related disease or condition, and optionally when dual action on the MCHRl and H3 receptor is desired, comprising the step of administering to a warmblooded animal in need of such treatment and/or prophylaxis a pharmaceutical composition according to claim 10 containing a therapeutically-effective amount of a compound in accordance with any one of claims 1-16.

21) The method according to claim 19 and 20, wherein said disease or condition is selected from obesity, obesity-related conditions, diabetes, metabolic disorder, bulimia, mood disorders, anxiety, depression, gastrointestinal disorders, inflammatory bowel disease and acute colitis, or a combination thereof. 22) The method according to claim 19 and 20, wherein the warmblooded animal in need of such treatment and/or prophylaxis is mammal.

23) The method according to claim 19 and 20, wherein the the warmblooded animal in need of such treatment and/or prophylaxis is human.

24) The method according to claim 21 wherein said disease or condition is obesity. 25) The method according to claim 21 wherein said disease or condition is diabetes.

26) The method according to claim 21 wherein said disease or condition is anxiety and depression.

27) The method according to claim 21 wherein said disease or condition is inflammatory bowel disease. 28) The use of a compound according to any one of claims 1-16 for the treatment and/or prophylaxis of a melanin concentrating hormone receptor 1 and optionally H3 receptor related disease or condition.

29) The use of a pharmaceutical composition according to claim 17 for the treatment and/or prophylaxis of a melanin concentrating hormone receptor 1 and optionally H3 receptor related disease or condition.

30) The use according to claim 28 and 29, wherein said disease or condition is selected from obesity, obesity-related conditions, diabetes, metabolic disorder, bulimia, mood disorders, anxiety, depression, gastrointestinal disorders inflammatory bowel disease acute colitis, or a combination thereof.

31) The use according to claim 30 wherein said disease or condition is obesity.

with dibromoethane or dibromopropane to yield a thieno-pyrimidinone derivative of Formula

Formula (III)

wherein the meaning o _ , Y, R and k are as described in claim 1 , then b) reacting a thieno-pyrimidinone derivative of Formula (III) with compound of Fon

(IV)

Formula (IV) - wherein the meaning of n and m, are as described in claim 1 - to obtain the compound of Formula (I), and optionally c) by adding organic or inorganic acids to the reaction product to form pharmaceutically acceptable acid addition salts of compound of Formula (I).

36) An intermediate compound of Formula (III) as described in claim 35. 37) A process for the preparation of compound of Formula (I) according to claim 1 comprising a) reacting 3,3-bis-bromomethyl-oxetane with 2-aminoethanol or 3-afninopropanol in the presence of base such as potassium hydroxide or potassium-carbonate to yield Formula (V)

Formula (V)

- wherein the meaning of k is as described in claim 1,

then b) reacting a nitro-phenol derivative of Formula (VI)

Formula (VI)

- wherein the meaning of R is as described in claim 1,

with a compound of Formula (V) in the presence of triphenylphosphine, diethylazodicarboxylate or di-isopropyl azodicarboxylate or di-tert-butylazodicarboxylate to yield a compound of Formula (VII)

Formula (VII)

- wherein the meaning of R and k are as described in claim 1,

then c) reduction of the nitro group with well known procedures such as reduction with hydrogen in the presence of catalyst such as palladium on carbon, palladium, platinum or iron; or reduction with tin(II)chloride, sodium dithionite or sodium borohydride to yield an aniline of Formula (VIII)

Formula (VIII)

- wherein the meaning of R and k are as described in claim 1 ,

then d) reacting a phenyl-amino-thio hen-carboxylate compound of Formula (IX)

Formula (IX)

- wherein the meaning of

is as described in claim 1 with dimetylformamide-dimethylacetal and then with an aniline of Formula (VIII) to obtain the compound of Formula (I), and optionally e) adding organic or inorganic acids to the reaction product to form pharmaceutically acceptable acid addition salts of compound of Formula (I).

38) A process for the preparation of compound of Formula (I) according to claim 1 comprising

a) reacting 2-chloro-5-nitropyridine with Formula (V) in the presence of base such as potassium carbonate, cesium carbonate and potassium-tert-buthylate to yield a compound of Formula (X)

Formula (X)

- wherein the meaning of k is as described in claim 1 ,

then b) reduction of the nitro group with well known procedures such as reduction with hydrogen in the presence of catalyst such as palladium on carbon, palladium, platinum and iron or reduction with tin(II)chloride, sodium dithionite or sodium borohydride to yield a compound of Formula (XI)

Formula (XI)

- wherein the meaning of k is as described in Claim 1, then

c) reacting a phenyl-amino-thiophen-carboxylate compound of Formula (IX) with dimetylformamide-dimethylacetal and then with an aniline of Formula (XI) to obtain the compound of Formula (I), and optionally d) adding organic or inorganic acids to the reaction product to form ρ1^Γπ^ε ΐ^ acceptable acid addition salts of compound of Formula (I).

39) Intermediate compound of Formula (V) as described in claim 37 such as

3-(2-oxa-6-aza-spiro[3.3]hept-6-yl)-propan-l-ol. 40) Intermediate compounds of Formula (VII) as described in claim 37 such as 6-[2-(2-methoxy-4-nitro-phenoxy)-ethyl]-2-oxa-6-aza-spiro[3.3]heptane, 6-[2-(4-nitro-phenoxy)-ethyl]-2-oxa-6-aza-spiro[3.3]heptane,

6-[3-(4-nitro-phenoxy)-propyl]-2-oxa-6-aza-spiro[3.3]heptane,

6-[2-(2-chloro-4-nitro-phenoxy)-ethyl]-2-oxa-6-aza-spiro[3.3]heptane and 6-[3-(2-chloro-4-nitro-phenoxy)-propyl]-2-oxa-6-aza-spiro[3.3]heptane.

41) Intermediate compounds of Formula (VIII) as described in claim 37 such as

3- methoxy-4-[2-(2-oxa-6-aza-spiro[3.3]hept-6-yl)-ethoxy]-phenylamine, 4-[2-(2-oxa-6-aza-spiro[3.3]hept-6-yl)-ethoxy]-phenylamine,

4- [3-(2-oxa-6-aza-spiro[3.3]hept-6-yl)-propoxy]-phenylamine,

3-chloro-4-[2-(2-oxa-6-aza-spiro[3.3]hept-6-yl)-ethoxy]-phenylamine and 3-chloro-4-[3-(2-oxa-6-aza-spiro[3.3]hept-6-yl)-propoxy]-phenylamine. 42) Intermediate compounds of Formula (X) as described in claim 38 such as 6-[2-(5-nitro-pyridin-2-yloxy)-ethyl]-2-oxa-6-aza-spiro[3.3]heptane and 6-[3-(5-nitro-pyridin-2-yloxy)-propyl]-2-oxa-6-aza-spiro[3.3]heptane.

43) Intermediate compounds of Formula (XI) as described in claim 38 such as 6-[3-(2-oxa-6-aza-spiro[3.3]hept-6-yl)-propoxy]-pyridin-3-ylamine and 6-[2-(2-oxa-6-aza-spiro[3.3]hept-6-yl)-ethoxy]-pyridin-3-ylamine.