Acyl- and sufonyl tetrahydronaphthyridines and aza derivatives thereof as Histamine

H3 receptor antagonists

The present invention relates to Histamine H3 receptor antagonists, pharmaceutical compositions thereof, the preparation of such compounds as well as the production and use as medicament.

The histamine H3 receptor is a G protein-coupled receptor (GPCR) and one out of four receptors of the histamine receptor family. Histamine receptors have long been attractive drug targets, mirrored in the development of antihistamines, which were directed at the histamine Hl receptor for the treatment of allergic reactions or at the histamine H2 receptor to ameliorate gastric ulcers by inhibiting gastric acid secretion. The H3 receptor has been identified as a presynaptic autoreceptor, regulating the release of histamine (Arrang et al. (1983) Nature: 302; 832 - 837), as well as a heteroreceptor that regulates the release of many other important neurotransmitters (acetylcholine, norepinephrine, dopamine, and serotonin). Structurally divergent H3 receptor antagonists / inverse agonists have been developed and shown to comprise activity in a variety of cognition tests in mice and rat (e.g. Esbenshade et al. (2006) MoI Interventions: 6 (2); 77 - 88) as well as in models for sleeping disorders and energy balance. From these studies it is concluded that such antagonists comprise a potential treatment for a variety of disorders affecting cognition (e.g., Alzheimer's disease, Parkinson's disease, Attention Deficit and Hyperactivity Disorder, Schizophrenia, Foetal Alcohol Syndrome, Mild Cognitive Impairment, Age-related Memory Dysfunction, Down Syndrome and others), as well as sleep (e.g., hypersomnia and narcolepsy), and energy homeostasis (e.g. obesity) (Witkin & Nelson (2004) JPET: 103; 1 - 20; Hancock & Brune (2005) Exp Opin Inves Drugs: 14 (3), 223 - 241).

Accordingly, Histamine H3 receptor antagonists are described in the art for the treatment of the above mentioned diseases and disorders. In WO-A 2007/080140 cyclohexyl piperazinyl methanone derivatives are disclosed, which are useful as H3 receptor modulators.

In WO-A 2006/136924 cyclo butyl derivatives are disclosed as Histamine-3 receptor antagonists.

EP-A 1 595 881 describes tetrahydronaphthyridine derivatives useful as histamine H3 receptor ligands. An individual compound as H3 ligand is disclosed in WO-A 2007/052124.

However there is a continuing need for new compounds useful as Histamine H3 receptor antagonists.

Thus, an object of the present invention is to provide a new class of compounds as Histamine H3 receptor antagonists which may be effective in the treatment of H3 receptor related diseases.

Accordingly, the present invention provides compounds of formula (I)

or a pharmaceutically acceptable salt, prodrug or metabolite thereof, wherein

one of X ^! -X ^la , X ² -X ^2a is C(R ^la R ^lb )-C(R ^x R ^lx ); and the other is N(R°)-C(R ^a R ^b ), provided that N(R ⁰ ) represents X ¹ or X ² ;

R ^a , R ^b , R ^la , R ^lb , R ^x , R ^lx are independently selected from the group consisting of H; halogen; and Ci_ ₄ alkyl, wherein Ci_ ₄ alkyl is optionally substituted with one or more halogen, which are the same or different;

R ⁰ is C(O)-R ¹ ; C(O)N(R ⁰ ^-R ¹ ; C(O)O-R ¹ ; S(O) ₂ -R ¹ ; or S(O) ₂ N(R ⁰ ^-R ¹ ; R ^Oa is H; or Ci_ ₄ alkyl, wherein Ci_ ₄ alkyl is optionally substituted with one or more halogen, which are the same or different;

Optionally at least one of the pairs R ^a /R ^b , R ^la /R ^lb , R ^x /R ^lx is joined together with the carbon atom to which they are attached to form C ₃ _ ₅ cycloalkyl, wherein C ₃ _ ₅ cycloalkyl is optionally substituted with one or more R ^c , which are the same or different;

R ^c is halogen; CN; OH; oxo (=0); Ci _-4 alkyl; or O-Ci_ ₄ alkyl, wherein Ci _-4 alkyl; and O-Ci_ ₄ alkyl are optionally substituted with one or more substituents, which are the same or different and selected from the group consisting of halogen; and OH;

R ¹ is Ci_7 alkyl; C2-7 alkenyl; C2-7 alkynyl; or T, wherein Ci_7 alkyl; C2-7 alkenyl; C2-7 alkynyl are optionally substituted with one or more R ^lc , which are the same or different, provided that R ¹ is other than unsubstituted tert-butyl when R ⁰ is C(O)O-R ¹ ;

T is phenyl; naphthyl; azulenyl; indenyl; indanyl; C ₃ - ₇ cycloalkyl; 3 to 7 membered heterocyclyl; or 7 to 11 membered heterobicyclyl, wherein T is optionally substituted with one or more R ^ld , which are the same or different;

X ³ is N, N-oxide or C(R ² ) and X ⁴ is N, N-oxide or CH, provided that at least one of X ³ , X ⁴ is N or N-oxide;

R ² is H; halogen; CN; CH ₃ ; CH ₂ F; CHF ₂ ; CF ₃ ; C(O)N(R ³ R ^3a ); CH ₂ N(R ³ R ^3a ); OMe; OCH ₂ F; OCHF ₂ ; or OCF ₃ ;

R ³ , R ^3a are independently selected from the group consisting of H; Ci_5 alkyl; and C ₃ _5 cycloalkyl;

Optionally R ³ , R ^3a are joined together with the nitrogen atom to which they are attached to form a 4 to 7 membered saturated heterocycle;

X ⁵ is O; S; S(O); S(O) ₂ ; N(R ⁴ ); N*(R ⁴ )C(0); N* (R ⁴ ) S (O) ₂ ; or S*(O) ₂ N(R ⁴ ), wherein the asterisk indicates the attachment to the aromatic cyclic moiety in formula (I); R ⁴ is H; Ci_5 alkyl; or C ₃ - ₆ cycloalkyl;

n is 0, 1, 2, 3 or 4;

R is 4 to 7 membered saturated heterocyclyl, wherein one ring atom is nitrogen and optionally a further ring atom is oxygen; or C _4-6 cycloalkyl, wherein R is optionally substituted with one or more R ⁵ , which are the same or different, provided that the one ring nitrogen of the 4 to 7 membered saturated heterocycle is a tertiary nitrogen or the 4 to 7 membered saturated heterocycle and C _4-6 cycloalkyl are substituted with at least one R ⁵ selected from the group consisting of N(R ⁶ R ^6a ); and C(O)N(R ^6b R ^6c ).

R ^ld , R ⁵ are independently selected from the group consisting of halogen; CN; C(O)OR ^6b ; OR ^6b ; C(O)R ^6b ; C(O)N(R ^6b R ^6c ); S(O) ₂ N(R ^6b R ^6c ); S(O)N(R ^6b R ^6c ); S(O) ₂ R ^6b ; S(O)R ^6b ; N(R ^6b )S(O) ₂ N(R ^6c R ^6d ); SR ^6b ; N(R ⁶ R ^6a ); N(R ^6b R ^6c ); NO ₂ ; OC(O)R ^6b ; N(R ^6b )C(O)R ^6c ; N(R ^6b )S(O) ₂ R ^6c ; N(R ^6b )S(O)R ^6c ; N(R ^6b )C(O)OR ^6c ; N(R ^6b )C(O)N(R ^6c R ^6d ); OC(O)N(R ^6b R ^6c ); oxo (=0), where the ring is at least partially saturated; T ¹ ; Ci_6 alkyl; C ₂ _6 alkenyl; and C ₂ _6 alkynyl, wherein Ci_6 alkyl; C ₂ _6 alkenyl; and C ₂ _6 alkynyl are optionally substituted with one or more R ⁷ , which are the same or different;

Optionally, two R ⁵ form a bridging group selected from the group consisting of CH ₂ ; CH ₂ CH ₂ ; CH ₂ CH ₂ CH ₂ ; NH; N(CH ₃ ); CH ₂ NHCH ₂ ; CH ₂ N(CH ₃ )CH ₂ ; and O;

R ⁶ , R ^6a are independently selected from the group consisting of T ¹ ; Ci_6 alkyl; C ₂ _6 alkenyl; and C ₂ _6 alkynyl, wherein Ci_6 alkyl; C ₂ _6 alkenyl; and C ₂ _6 alkynyl are optionally substituted with one or more R ⁸ , which are the same or different;

Optionally, R ⁶ , R ^6a are joined together with the nitrogen atom to which they are attached to form nitrogen containing ring T ² ;

R ^6b , R ^6c , R ^6d are independently selected from the group consisting of H; T ¹ ; Ci_6 alkyl; C ₂ _6 alkenyl; and C ₂ _6 alkynyl, wherein Ci_6 alkyl; C ₂ _6 alkenyl; and C ₂ _6 alkynyl are optionally substituted with one or more R ⁸ , which are the same of different; R ^lc , R ⁷ , R ⁸ are independently selected from the group consisting of halogen; CN; C(O)R ⁹ ; C(O)OR ⁹ ; OR ⁹ ; C(O)N(R ⁹ R ^9a ); S(O) ₂ N(R ⁹ R ^9a ); S(O)N(R ⁹ R ^9a ); S(O) ₂ R ⁹ ; S(O)R ⁹ ; N(R ⁹ )S(O) ₂ N(R ^9a R ^9b ); SR ⁹ ; N(R ⁹ R ^9a ); NO ₂ ; OC(O)R ⁹ ; N(R ⁹ )C(O)R ^9a ; N(R ⁹ )SO ₂ R ^9a ; N(R ⁹ )S(O)R ^9a ; N(R ⁹ )C(O)N(R ^9a R ^9b ); N(R ⁹ )C(O)OR ^9a ; OC(O)N(R ⁹ R ^9a ); and T ¹ ;

R ⁹ , R ^9a , R ^9b are independently selected from the group consisting of H; T ¹ ; Ci_6 alkyl; C ₂ _6 alkenyl; and C ₂ _6 alkynyl, wherein Ci_6 alkyl; C ₂ _6 alkenyl; and C ₂ _6 alkynyl are optionally substituted with one or more halogen, which are the same of different;

T ¹ is phenyl; naphthyl; azulenyl; indenyl; indanyl; C ₃ _ ₇ cycloalkyl; 3 to 7 membered heterocyclyl; or 7 to 11 membered heterobicyclyl, wherein T ¹ is optionally substituted with one or more R ¹⁰ , which are the same or different;

T ² is a nitrogen containing 3 to 7 membered heterocycle, wherein T ² is optionally substituted with one or more R ¹⁰ , which are the same or different;

R ¹⁰ is halogen; CN; C(O)OR ¹¹ ; OR ¹¹ ; C(O)R ¹¹ ; C(O)N(R ¹¹ R ^{1 la} ); S(O) ₂ N(R ¹¹ R ^{1 la} ); S(O)N(R ¹¹ R ^{1 la} ); S(O) ₂ R ¹¹ ; S(O)R ¹¹ ; N(R ¹ ^S(O) ₂ N(R ^{1 la} R ^{l lb} ); SR ¹¹ ; N(R ^π R ^{l la} ); NO ₂ ; OC(O)R ¹¹ ; N(R ¹ ^C(O)R ^11* ; N(R ¹ ^S(O) ₂ R ^11* ; N(R ¹ ^S(O)R ^11* ; N(R ¹ ^C(O)OR ^11* ; N(R ¹ ^C(O)N(R ^{1 la} R ^{l lb} ); OC(O)N(R ¹¹ R ^{1 la} ); oxo (=0), where the ring is at least partially saturated; Ci_6 alkyl; C ₂ _6 alkenyl; or C ₂ _6 alkynyl, wherein Ci_6 alkyl; C ₂ _6 alkenyl; and C ₂ _6 alkynyl are optionally substituted with one or more halogen, which are the same or different;

R ¹¹ , R ^{l la} , R ^{l lb} are independently selected from the group consisting of H; Ci_6 alkyl; C ₂ _6 alkenyl; and C ₂ _6 alkynyl, wherein Ci_6 alkyl; C ₂ _6 alkenyl; and C ₂ _6 alkynyl are optionally substituted with one or more halogen, which are the same of different.

In case R ⁰ is C(O)O-R ¹ and R ¹ is unsubstituted tert-butyl the respective compounds represent Boc-protected intermediates, which are excluded from the above scope. Such compounds are described in the International patent application with the application number PCT/EP2009/053686. In case a variable or substituent defined herein can be selected from a group of different variants and such variable or substituent occurs more than once the respective variants can be the same or different.

Within the meaning of the present invention the terms are used as follows:

"Alkyl" means a straight-chain or branched saturated hydrocarbon chain. Each hydrogen of an alkyl carbon may be replaced by a substituent as further specified.

"Alkenyl" means a straight-chain or branched hydrocarbon chain that contains at least one carbon-carbon double bond. Each hydrogen of an alkenyl carbon may be replaced by a substituent as further specified.

"Alkynyl" means a straight-chain or branched hydrocarbon chain that contains at least one carbon-carbon triple bond. Each hydrogen of an alkynyl carbon may be replaced by a substituent as further specified.

"Ci_ ₄ alkyl" means an alkyl chain having 1 - 4 carbon atoms, e.g. if present at the end of a molecule: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl tert-butyl, or e.g. -CH ₂ -, -CH ₂ -CH ₂ -, -CH(CH ₃ )-, -CH ₂ -CH ₂ -CH ₂ -, -CH(C ₂ H ₅ )-, -C(CH ₃ ) ₂ -, when two moieties of a molecule are linked by the alkyl group. Each hydrogen of a Ci_4 alkyl carbon may be replaced by a substituent as further specified.

"Ci_ ₅ alkyl" means an alkyl chain having 1 - 5 carbon atoms, e.g. if present at the end of a molecule: Ci_ ₄ alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl; tert-butyl, n-pentyl, or e.g. -CH ₂ -, -CH ₂ -CH ₂ -, -CH(CH ₃ )-, -CH ₂ -CH ₂ -CH ₂ -, -CH(C ₂ H ₅ )-, -C(CH ₃ ) ₂ -, when two moieties of a molecule are linked by the alkyl group. Each hydrogen of a Ci_ ₅ alkyl carbon may be replaced by a substituent as further specified.

"Ci_6 alkyl" means an alkyl chain having 1 - 6 carbon atoms, e.g. if present at the end of a molecule: Ci_4 alkyl, Ci_ ₅ alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec- butyl; tert-butyl, n-pentyl, n-hexyl, or e.g. -CH ₂ -, -CH ₂ -CH ₂ -, -CH(CH ₃ )-, -CH ₂ -CH ₂ -CH ₂ -, -CH(C ₂ H ₅ )-, -C(CH ₃ ) ₂ -, when two moieties of a molecule are linked by the alkyl group. Each hydrogen of a Ci_6 alkyl carbon may be replaced by a substituent as further specified.

"Ci_ ₇ alkyl" means an alkyl chain having 1 - 7 carbon atoms, e.g. if present at the end of a molecule: Ci_4 alkyl, Ci_ ₅ alkyl, Ci_6 alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl; tert-butyl, n-pentyl, n-hexyl, n-heptyl, or e.g. -CH ₂ -, -CH ₂ -CH ₂ -, -CH(CH ₃ )-, -CH ₂ -CH ₂ -CH ₂ -, -CH(C ₂ H ₅ )-, -C(CH ₃ ) ₂ -, when two moieties of a molecule are linked by the alkyl group. Each hydrogen of a Ci_7 alkyl carbon may be replaced by a substituent as further specified.

"C2-6 alkenyl" means an alkenyl chain having 2 to 6 carbon atoms, e.g. if present at the end of a molecule: -CH=CH ₂ , -CH=CH-CH ₃ , -CH ₂ -CH=CH ₂ , -CH=CH-CH ₂ -CH ₃ , -CH=CH- CH=CH ₂ , or e.g. -CH=CH-, when two moieties of a molecule are linked by the alkenyl group. Each hydrogen of a C ₂ -6 alkenyl carbon may be replaced by a substituent as further specified.

"C2-7 alkenyl" means an alkenyl chain having 2 to 7 carbon atoms, e.g. if present at the end of a molecule: C ₂ - ₆ alkenyl, -CH=CH ₂ , -CH=CH-CH ₃ , -CH ₂ -CH=CH ₂ , -CH=CH-CH ₂ -CH ₃ , - CH=CH-CH=CH ₂ , or e.g. -CH=CH-, when two moieties of a molecule are linked by the alkenyl group. Each hydrogen of a C ₂ - ₇ alkenyl carbon may be replaced by a substituent as further specified.

"C ₂ -6 alkynyl" means an alkynyl chain having 2 to 6 carbon atoms, e.g. if present at the end of a molecule: -C≡CH, -CH ₂ -C≡CH, CH ₂ -CH ₂ -C≡CH, CH ₂ -C≡C-CH ₃ , or e.g. -C≡C- when two moieties of a molecule are linked by the alkynyl group. Each hydrogen of a C ₂ -6 alkynyl carbon may be replaced by a substituent as further specified.

"C2-7 alkynyl" means an alkynyl chain having 2 to 7 carbon atoms, e.g. if present at the end of a molecule: C ₂ - ₆ alkynyl, -C≡CH, -CH ₂ -C≡CH, CH ₂ -CH ₂ -C≡CH, CH ₂ -C≡C-CH ₃ , or e.g. - C≡C- when two moieties of a molecule are linked by the alkynyl group. Each hydrogen of a C2-7 alkynyl carbon may be replaced by a substituent as further specified.

"C ₃ _ ₅ cycloalkyl" or "C ₃ _ ₅ cycloalkyl ring" means a cyclic alkyl chain having 3 to 5 carbon atoms, e.g. cyclopropyl, cyclobutyl, cyclopentyl. Each hydrogen of a cycloalkyl carbon may be replaced by a substituent as further specified.

"C4_6 cycloalkyl" or "C _4-6 cycloalkyl ring" means a cyclic alkyl chain having 4 to 6 carbon atoms, e.g. cyclobutyl, cyclopentyl, cyclohexyl. Each hydrogen of a cycloalkyl carbon may be replaced by a substituent as further specified.

"C ₃ _6 cycloalkyl" or "C ₃ _6 cycloalkyl ring" means a cyclic alkyl chain having 3 to 6 carbon atoms, e.g. C ₃ _5 cycloalkyl, C _4-6 cycloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl. Each hydrogen of a cycloalkyl carbon may be replaced by a substituent as further specified.

"C ₃ _ ₇ cycloalkyl" or "C ₃ _ ₇ cycloalkyl ring" means a cyclic alkyl chain having 3 to 7 carbon atoms, e.g. C ₃ _5 cycloalkyl, C ₃ _6 cycloalkyl, C ₄ _6 cycloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl. Each hydrogen of a cycloalkyl carbon may be replaced by a substituent as further specified.

"Halogen" means fluoro, chloro, bromo or iodo. It is generally preferred that halogen is fluoro or chloro.

"5 to 6 membered aromatic heterocyclyl" or "5 to 6 membered aromatic heterocycle" means a heterocycle derived from cyclopentadienyl or benzene, where at least one carbon atom is replaced by a heteoatom selected from the group consisting of sulfur (including -S(O)-, - S(O) ₂ -), oxygen and nitrogen (including =N(O)-). Examples for such heterocycles are furan, thiophene, pyrrole, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, thiadiazole, pyranium, pyridine, pyridazine, pyrimidine, triazole, tetrazole. Each hydrogen of the heterocycle may be replaced by a substituent as further specified.

"4 to 6 membered saturated heterocyclyl" or "4 to 6 membered saturated heterocycle" means a saturated ring with 4, 5 or 6 ring atoms, wherein at least one ring atom up to 3 ring atoms are replaced by a heteroatom selected from the group consisting of sulfur (including -S(O)-, - S(O) ₂ -), oxygen and nitrogen (including =N(O)-) and wherein the ring is linked to the rest of the molecule via a carbon or nitrogen atom. Examples are azetidine, oxetane, thietane, tetrahydrofurane, thiolane, pyrrolidine, oxazolidine, thiazolidine, imidazolidine, pyrazolidine, tetrahydropyrane, thiane, piperidine, dioxane, morpholine, or piperazine. Each hydrogen of the heterocycle may be replaced by a substituent as further specified.

"4 to 7 membered saturated heterocyclyl" or "4 to 7 membered saturated heterocycle" means a saturated ring with 4, 5, 6 or 7 ring atoms, wherein at least one ring atom up to 3 ring atoms are replaced by a heteroatom selected from the group consisting of sulfur (including -S(O)-, -

S(O) ₂ -), oxygen and nitrogen (including =N(O)-) and wherein the ring is linked to the rest of the molecule via a carbon or nitrogen atom. Examples are azetidine, oxetane, thietane, tetrahydrofurane, thiolane, pyrrolidine, oxazolidine, thiazolidine, imidazolidine, pyrazolidine, tetrahydropyrane, thiane, piperidine, dioxane, morpholine, piperazine, or homopiperazine.

Each hydrogen of the heterocycle may be replaced by a substituent as further specified.

"3 to 7 membered heterocyclyl" or "3 to 7 membered heterocycle" means a ring with 3, 4, 5, 6 or 7 ring atoms that may contain up to the maximum number of double bonds (aromatic or non-aromatic ring which is fully, partially or un-saturated) wherein at least one ring atom up to 4 ring atoms are replaced by a heteroatom selected from the group consisting of sulfur (including -S(O)-, -S(O) ₂ -), oxygen and nitrogen (including =N(O)-) and wherein the ring is linked to the rest of the molecule via a carbon or nitrogen atom. Examples for 3 to 7 membered heterocycles are 5 to 6 membered aromatic heterocycle, 4 to 6 membered saturated heterocycle, 4 to 7 membered saturated heterocycle, azeridine, azetidine, oxetane, thietane, furan, thiophene, pyrrole, pyrroline, imidazole, imidazoline, pyrazole, pyrazoline, oxazole, oxazoline, isoxazole, isoxazoline, thiazole, thiazoline, isothiazole, isothiazoline, thiadiazole, thiadiazoline, tetrahydrofuran, tetrahydrothiophene, pyrrolidine, imidazolidine, pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, thiadiazolidine, sulfolane, pyran, dihydropyran, tetrahydropyran, imidazolidine, pyridine, pyridazine, pyrazine, pyrimidine, piperazine, piperidine, morpholine, tetrazole, triazole, triazolidine, tetrazolidine, diazepane, azepine or homopiperazine. Each hydrogen of the heterocycle may be replaced by a substituent as further specified.

"7 to 11 membered heterobicyclyl" or "7 to 11 membered heterobicycle" means a heterocyclic system of two rings with 7 to 11 ring atoms, where at least one ring atom is shared by both rings and that may contain up to the maximum number of double bonds (aromatic or non-aromatic ring which is fully, partially or un-saturated) wherein at least one ring atom up to 6 ring atoms are replaced by a heteroatom selected from the group consisting of sulfur (including -S(O)-, -S(O) ₂ -), oxygen and nitrogen (including =N(O)-) and wherein the ring is linked to the rest of the molecule via a carbon or nitrogen atom. Examples for 7 to 11 membered heterobicycles are imidazo[2,l-b][l,3]oxazole, imidazo[2,l-b][l,3]thiazole, indole, indoline, benzo furan, benzothiophene, benzoxazole, benzisoxazole, benzothiazole, benzisothiazole, benzimidazole, benzimidazoline, quinoline, quinazoline, dihydroquinazoline, quinoline, dihydroquinoline, tetrahydroquinoline, decahydroquinoline, isoquinoline, decahydroisoquinoline, tetrahydroisoquinoline, dihydroisoquinoline, tetrahydronaphthyridine, benzazepine, purine or pteridine. The term 7 to 11 membered heterobicycle also includes spiro structures of two rings like l,4-dioxa-8-azaspiro[4.5]decane or bridged heterocycles like 8-aza-bicyclo[3.2.1]octane. Each hydrogen of the heterobicycle may be replaced by a substituent as further specified.

Preferred compounds of formula (I) are those compounds in which one or more of the residues contained therein have the meanings given below, with all combinations of preferred substituent definitions being a subject of the present invention. With respect to all preferred compounds of the formula (I) the present invention also includes all tautomeric and stereoisomeric forms and mixtures thereof in all ratios, and their pharmaceutically acceptable salts as well as their isotopic derivatives.

In preferred embodiments of the present invention, the substituents X ^la , X ^2a , X ¹ to X ⁵ , n and R of formula (I) independently have the following meaning. Hence, one or more of the substituents X ^la , X ^2a , X ¹ to X ⁵ , n and R can have the preferred or more preferred meanings given below.

Preferably, X ^! -X ^la is N(R°)-C(R ^a R ^b ) and X ² -X ^2a is C(R ^la R ^lb )-C(R ^x R ^lx ), provided that N(R ⁰ ) represents X ¹ . More preferably, X ^! -X ^la is N(R°)-C(R ^a R ^b ) and X ² -X ^2a is C(R ^la R ^lb )-CH ₂ , provided that N(R ⁰ ) represents X ¹ .

Preferably, X ¹ , X ^la , X ² , X ^2a are chosen to give a compound having the formula (Ia)

wherein R ⁰ , R ^a , R ^b , X ³ , X ⁴ , X ⁵ , n, R have the meaning as indicated above.

Preferably, R ⁰ is C(O)-R ¹ ; C(O)N(R ⁰ ^-R ¹ ; or S(O) ₂ -R ¹ . More preferred is R ⁰ C(O)-R ¹ ; or C(O)N(R ⁰ ^-R ¹ .

Preferably, R ^a , R ^la , R ^b , R ^lb , are independently selected from the group consisting of H; and Ci_4 alkyl, which is optionally substituted. More preferred are R ^a , R ^la , R ^b , R ^lb independently selected from the group consisting of H; and methyl. Even more preferred are R ^a , R ^la , R ^b , R ^lb H.

Preferably, R ^x , R ^lx are independently selected from the group consisting of H; and Ci_4 alkyl or joined together with the carbon atom to which they are attached to form an unsubstituted C3-5 cycloalkyl. More preferred are R ^x , R ^lx H. Preferably, only one of the pairs R ^a /R ^b , R ^la /R ^lb , R ^x /R ^lx is joined together with the carbon atom to which they are attached to form C ₃ _ ₅ cycloalkyl, wherein C ₃ _ ₅ cycloalkyl is optionally substituted with one or more R ^c , which are the same or different. In case one pair is joined it is preferred that R ^a /R ^b is joined.

Preferably, R ^Oa is H.

Preferably, R ¹ is Ci_7 alkyl; or T, wherein R ¹ is optionally substituted. More preferred is R ¹ methyl; trifluoromethyl; ethyl; propyl; propyl, butyl; pentyl; cyclopropyl; cyclobutyl; cyclopentyl; cyclohexyl; phenyl; pyridyl; pyrimidinyl; pyridazinyl; pyrazinyl; morpholinyl; or piperidinyl, wherein R ¹ is optionally substituted. Even more preferred is R ¹ methyl; ethyl; isopropyl; sec. -butyl; isobutyl; dimethylpropyl; cyclpropyl; cyclobutyl; cyclopentyl; phenyl; o-, m-, or p-fluorophenyl; o-, m-, or p- methoxyphenyl; pyridyl; methylpyridyl; piperidinyl; or cyclopropylmethyl.

Preferably, R ^lc is halogen; CN; OR ⁹ ; C(O)N(R ⁹ R ^9a ); S(O) ₂ R ⁹ ; N(R ⁹ R ^9a ); N(R ⁹ )C(O)R ^9a ;

N(R ⁹ )SO ₂ R ^9a ; or T ¹ . More preferred is R ^lc halogen; CN; OR ⁹ ; C(O)N(R ⁹ R ^9a ); S(O) ₂ R ⁹ ; or T ¹ .

Preferably, T is phenyl; C3_7 cycloalkyl; 3 to 7 membered heterocyclyl; or 7 to 11 membered heterobicyclyl, wherein T is optionally substituted. More preferred is T phenyl; C3_7 cycloalkyl; or 3 to 7 membered heterocyclyl, wherein T is optionally substituted. Even more preferred is T phenyl, cyclopropyl, cyclobutyl; cyclopentyl; pyridyl; pyrimidinyl; pyridazinyl; pyrazinyl; morpholinyl; or piperidinyl, wherein T is optionally substituted.

Preferably, T ¹ is phenyl; C3-7 cycloalkyl; or 3 to 7 membered heterocyclyl, wherein T ¹ is optionally substituted. More preferred is T ¹ phenyl; or C ₃ _ ₇ cycloalkyl, wherein T ¹ is optionally substituted.

Preferably, R ^ld is halogen; CN; OR ^6b ; C(O)N(R ^6b R ^6c ); S(O) ₂ N(R ^6b R ^6c ); S(O) ₂ R ^6b ; N(R ^6b )S(O) ₂ N(R ^6c R ^6d ); N(R ⁶ R ^6a ); N(R ^6b )C(O)R ^6c ; N(R ^6b )S(O) ₂ R ^6c ; oxo (=0), where the ring is at least partially saturated; or Ci_6 alkyl, wherein Ci_6 alkyl is optionally substituted. More preferred is R ^ld halogen; CN; OR ^6b ; C(O)R ^6b ; C(O)N(R ^6b R ^6c ); S(O) ₂ R ^6b ; N(R ⁶ R ^6a ); N(R ^6b )C(O)R ^6c ; or Ci_6 alkyl, wherein Ci_ ₆ alkyl is optionally substituted. Preferably, X ³ is N, or C(R ² ) and X ⁴ is N, or N-oxide or CH, provided that at least one of X ³ , X ⁴ is N or N-oxide. Preferably, X ³ is C(R ² ) and X ⁴ is N, or N-oxide.

Preferably, X ³ is N or C(R ² ) and X ⁴ is N or CH, provided that at least one of X ³ , X ⁴ is N.

Preferably, X ³ is C(R ² ). Preferably, X ³ , X ⁴ are N. Preferably, X ³ is N or C(R ² ) and X ⁴ is N, N oxide or CH, provided that at least one of X ³ , X ⁴ is N or N-oxide. Preferably, at least one of X ³ , X ⁴ is N-oxide. Preferably, X ³ , X ⁴ are N; or N-oxide.

Preferably, R ² is H; halogen; CN; CH ₃ ; CH ₂ F; CHF ₂ ; CF ₃ ; C(O)N(R ³ R ^3a ); CH ₂ N(R ³ R ^3a ). Preferably, R ² is H; halogen; CH ₃ ; CF ₃ ; C(O)N(R ³ R ^3a ); or CN. More preferably, R ² is H; or CN. Even more preferably, R ² is H.

Preferably, X ⁵ is O; N(R ⁴ ); S; S(O); S(O) ₂ ; or N*(R ⁴ )C(O). More preferred is X ⁵ O; or N(R ⁵ ). Even more preferred X ⁵ is O.

Preferably, n is O; or 3. More preferred is n O.

Preferably, R is 4 to 7 membered saturated heterocyclyl, wherein one ring atom is nitrogen and optionally a further ring atom is oxygen; or C _4-6 cycloalkyl, wherein R is optionally substituted with one or more R ⁵ , which are the same or different, provided that the one ring nitrogen of the 4 to 7 membered saturated heterocycle is a tertiary nitrogen or the 4 to 7 membered saturated heterocycle and C _4-6 cycloalkyl are substituted with at least one R ⁵ being N(R ⁶ R ^6a ).

Preferably, R is a cyclopentyl; a cyclohexyl; an azetidine; an azepine; a pyrrolidine; a piperidine; a piperazine; or a morpholine ring; more preferred is R equals pyrrolidine; piperidine; morpholine; or cyclohexyl; even more preferred is piperidine; or pyrrolidine, wherein preferred or more preferred R is optionally substituted with one or more R ⁵ , which are the same or different, provided that the ring comprises a tertiary nitrogen atom or the ring is substituted with at least one R ⁵ being N(R ⁶ R ^6a ) or C(O)N(R ^6b R ^6c ), preferably being N(R ⁶ R ^6a ). Preferably, R ^ld , R ⁵ are independently selected from the group consisting of halogen; CN; C(O)OR ^6b ; OR ^6b ; C(O)R ^6b ; C(O)N(R ^6b R ^6c ); S(O) ₂ N(R ^6b R ^6c ); S(O)N(R ^6b R ^6c ); S(O) ₂ R ^6b ; S(O)R ^6b ; N(R ^6b )S(O) ₂ N(R ^6c R ^6d ); SR ^6b ; N(R ⁶ R ^6a ); NO ₂ ; OC(O)R ^6b ; N(R ^6b )C(O)R ^6c ; N(R ^6b )S(O) ₂ R ^6c ; N(R ^6b )S(O)R ^6c ; N(R ^6b )C(O)OR ^6c ; N(R ^6b )C(O)N(R ^6c R ^6d ); OC(O)N(R ^6b R ^6c ); oxo (=0), where the ring is at least partially saturated; T ¹ ; Ci_6 alkyl; C ₂ _6 alkenyl; and C ₂ _6 alkynyl, wherein Ci_6 alkyl; C ₂ _6 alkenyl; and C ₂ _6 alkynyl are optionally substituted with one or more R ⁷ , which are the same or different.

Preferably, -R is

More preferred -R is

Preferably, T ¹ is phenyl; C3_7 cycloalkyl; or 3 to 7 membered heterocyclyl, wherein T ¹ is optionally substituted with one or more R ¹⁰ , which are the same or different.

Preferably, R ⁵ is T ¹ , especially C3-7 cycloalkyl; Ci_6 alkyl. Preferably, T ¹ is C3-7 cycloalkyl.

Preferably, R ^6b , R ^6c are independently selected from the group consisting of H; and Ci_6 alkyl.

Compounds of the formula (I) in which some or all of the above-mentioned groups have the preferred or more preferred meanings are also an object of the present invention.

Preferred specific compounds of the present invention are selected from the group consisting of

2-[(l-cyclobutylpiperidin-4-yl)oxy]-6-(cyclopropylcarbony l)-5,6,7,8-tetrahydro-l,6- naphthyridine; 6-acetyl-2-[(l-cyclobutylpiperidin-4-yl)oxy]-5,6,7,8-tetrahy dro-l,6-naphthyridine;

2-[(l-cyclobutylpiperidin-4-yl)oxy]-6-propanoyl-5,6,7,8-t etrahydro-l,6-naphthyridine;

2-[(l-cyclobutylpiperidin-4-yl)oxy]-6-(3,3-dimethylbutano yl)-5,6,7,8-tetrahydro-l,6- naphthyridine;

6-(cyclobutylcarbonyl)-2-[(l-cyclobutylpiperidin-4-yl)oxy ]-5,6,7,8-tetrahydro-l,6- naphthyridine;

2-[(l-cyclobutylpiperidin-4-yl)oxy]-6-(2-methylpropanoyl) -5,6,7,8-tetrahydro-l,6- naphthyridine;

2-[(l-cyclobutylpiperidin-4-yl)oxy]-6-(cyclopentylcarbony l)-5,6,7,8-tetrahydro-l,6- naphthyridine;

2-[(l-cyclobutylpiperidin-4-yl)oxy]-6-(phenylcarbonyl)-5, 6,7,8-tetrahydro-l,6-naphthyridine;

2-[(l-cyclobutylpiperidin-4-yl)oxy]-6-(3-methylbutanoyl)- 5,6,7,8-tetrahydro-l,6- naphthyridine;

2-[(l-cyclobutylpiperidin-4-yl)oxy]-6-(cyclopropylacetyl) -5,6,7,8-tetrahydro-l,6- naphthyridine;

2-[(l-cyclobutylpiperidin-4-yl)oxy]-6-(2-methylbutanoyl)- 5,6,7,8-tetrahydro-l,6- naphthyridine;

2-[(l-cyclobutylpiperidin-4-yl)oxy]-6-[(4-fluorophenyl)ca rbonyl]-5,6,7,8-tetrahydro-l,6- naphthyridine;

2-[(l-cyclobutylpiperidin-4-yl)oxy]-6-[(2-fluorophenyl)ca rbonyl]-5,6,7,8-tetrahydro-l,6- naphthyridine; 2-[(l-cyclobutylpiperidin-4-yl)oxy]-6-[(4-methoxyphenyl)carb onyl]-5,6,7,8-tetrahydro-l,6- naphthyridine;

2-[(l-cyclobutylpiperidin-4-yl)oxy]-6-[(6-methylpyridin-3 -yl)carbonyl]-5,6,7,8-tetrahydro- 1,6-naphthyridine;

2-[(l-cyclobutylpiperidin-4-yl)oxy]-6-(trifluoroacetyl)-5 ,6,7,8-tetrahydro-l,6-naphthyridine;

2-[(l-cyclobutylpiperidin-4-yl)oxy]-6-(methylsulfonyl)-5, 6,7,8-tetrahydro-l,6-naphthyridine;

2-[(l-cyclobutylpiperidin-4-yl)oxy]-6-(cyclopropylsulfony l)-5, 6,7, 8-tetrahydro- 1,6- naphthyridine;

2-[(l-cyclobutylpiperidin-4-yl)oxy]-6-(phenylsulfonyl)-5, 6,7,8-tetrahydro-l,6-naphthyridine;

2-[(l-cyclobutylpiperidin-4-yl)oxy]-6-(ethylsulfonyl)-5,6 ,7,8-tetrahydro-l,6-naphthyridine;

2-[(l-cyclobutylpiperidin-4-yl)oxy]-6-[(l-methylethyl)sul fonyl]-5, 6, 7, 8-tetrahydro- 1,6- naphthyridine;

2-[(l-cyclobutylpiperidin-4-yl)oxy]-6-(cyclopentylsulfony l)-5, 6, 7, 8-tetrahydro- 1,6- naphthyridine;

2-[(l-cyclobutylpiperidin-4-yl)oxy]-6-[(2-fluorophenyl)su lfonyl]-5,6,7,8-tetrahydro-l,6- naphthyridine;

2-[(l-cyclobutylpiperidin-4-yl)oxy]-6-[(3-fluorophenyl)su lfonyl]-5, 6, 7, 8-tetrahydro- 1,6- naphthyridine;

2-[(l-cyclobutylpiperidin-4-yl)oxy]-6-[(4-fluorophenyl)su lfonyl]-5, 6, 7, 8-tetrahydro- 1,6- naphthyridine;

2-[(l-cyclobutylpiperidin-4-yl)oxy]-6-[(4-methoxyphenyl)s ulfonyl]-5,6,7,8-tetrahydro-l,6- naphthyridine; 2-[(l-cyclobutylpiperidin-4-yl)oxy]-6-(piperidin-l-ylcarbony l)-5,6,7,8-tetrahydro-l,6- naphthyridine;

2-[(l-cyclobutylpiperidin-4-yl)oxy]-N-(l-methylethyl)-7,8 -dihydro-l,6-naphthyridine-6(5H)- carboxamide;

methyl 2-[(l-cyclobutylpiperidin-4-yl)oxy]-7,8-dihydro-l,6-naphthyr idine-6(5H)-carboxylate;

2-[(l-cyclobutylpiperidin-4-yl)oxy]-N-ethyl-7,8-dihydro-l ,6-naphthyridine-6(5H)- carboxamide; and

6-acetyl-2-[(l-cyclobutylpiperidin-4-yl)oxy]-5,6,7,8-tetr ahydro-l,6-naphthyridine 1 -oxide.

Prodrugs of the compounds of the invention are also within the scope of the present invention. "Prodrug" means a derivative that is converted into a compound according to the present invention by a reaction with an enzyme, gastric acid or the like under a physiological condition in the living body, e.g. by oxidation, reduction, hydrolysis or the like, each of which is carried out enzymatically. Examples of a prodrug are compounds, wherein the amino group in a compound of the present invention is acylated, alkylated or phosphorylated to form, e.g., eicosanoylamino, alanylamino, pivaloyloxymethylamino or wherein the hydroxyl group is acylated, alkylated, phosphorylated or converted into the borate, e.g. acetyloxy, palmitoyloxy, pivaloyloxy, succinyloxy, fumaryloxy, alanyloxy or wherein the carboxyl group is esterifϊed or amidated. These compounds can be produced from compounds of the present invention according to well-known methods.

Metabolites of compounds of formula (I) are also within the scope of the present invention.

Where tautomerism, like e.g. keto-enol tautomerism, of compounds of formula (I) may occur, the individual forms, like e.g. the keto and enol form, are comprised separately and together as mixtures in any ratio. Same applies for stereoisomers, like e.g. enantiomers, cis/trans isomers, conformers and the like. Especially, when enantiomeric or diastereomeric forms are given in a compound according to formula (I) each pure form separately and any mixture of at least two of the pure forms in any ratio is comprised by formula (I) and is a subject of the present invention. This applies especially for pure and mixture forms associated with the carbon in the following formula for -R marked with an asterisk:

; preferred is

Isotopic labeled compounds of formula (I) are also within the scope of the present invention. Methods for isotope labeling are known in the art. Preferred isotopes are those of the elements H, C, N, O and S.

If desired, isomers can be separated by methods well known in the art, e.g. by liquid chromatography. Same applies for enantiomers by using e.g. chiral stationary phases. Additionally, enantiomers may be isolated by converting them into diastereomers, i.e. coupling with an enantiomerically pure auxiliary compound, subsequent separation of the resulting diastereomers and cleavage of the auxiliary residue. Alternatively, any enantiomer of a compound of formula (I) may be obtained from stereoselective synthesis using optically pure starting materials, reagents and/or catalysts.

In case the compounds according to formula (I) contain one or more acidic or basic groups, the invention also comprises their corresponding pharmaceutically or toxicologically acceptable salts, in particular their pharmaceutically utilizable salts. Thus, the compounds of the formula (I) which contain acidic groups can be used according to the invention, for example, as alkali metal salts, alkaline earth metal salts or as ammonium salts. More precise examples of such salts include sodium salts, potassium salts, calcium salts, magnesium salts or salts with ammonia or organic amines such as, for example, ethylamine, ethanolamine, triethanolamine or amino acids. Compounds of the formula (I) which contain one or more basic groups, i.e. groups which can be protonated, can be present and can be used according to the invention in the form of their addition salts with inorganic or organic acids. Examples for suitable acids include hydrogen chloride, hydrogen bromide, phosphoric acid, sulfuric acid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acids, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid, sulfaminic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, citric acid, adipic acid, and other acids known to the person skilled in the art. If the compounds of the formula (I) simultaneously contain acidic and basic groups in the molecule, the invention also includes, in addition to the salt forms mentioned, inner salts or betaines (zwitterions). The respective salts according to the formula (I) can be obtained by customary methods which are known to the person skilled in the art like, for example by contacting these with an organic or inorganic acid or base in a solvent or dispersant, or by anion exchange or cation exchange with other salts. The present invention also includes all salts of the compounds of the formula (I) which, owing to low physiological compatibility, are not directly suitable for use in pharmaceuticals but which can be used, for example, as intermediates for chemical reactions or for the preparation of pharmaceutically acceptable salts.

The present invention provides compounds of general formula (I) as Histamine H3 receptor antagonists.

As described before, the histamine H3 receptor is a G protein-coupled receptor (GPCR) and one out of four receptors of the histamine receptor family. Histamine receptors have long been attractive drug targets, mirrored in the development of antihistamines, which were directed at the histamine Hl receptor for the treatment of allergic reactions or at the histamine H2 receptor to ameliorate gastric ulcers by inhibiting gastric acid secretion. The H3 receptor has been identified as a presynaptic autoreceptor, regulating the release of histamine (Arrang et al. (1983) Nature: 302; 832 - 837), as well as a heteroreceptor that regulates the release of many other important neurotransmitters (acetylcholine, norepinephrine, dopamine, and serotonin). Structurally divergent H3 receptor antagonists / inverse agonists have been developed and shown to comprise activity in a variety of cognition tests in mice and rat (e.g. Esbenshade et al. (2006) MoI Interventions: 6 (2); 77 - 88) as well as in models for sleeping disorders and energy balance. From these studies it is concluded that such antagonists comprise a potential treatment for a variety of disorders affecting cognition (e.g., Alzheimer's disease, Parkinson's disease, Attention Deficit and Hyperactivity Disorder, Schizophrenia, Foetal Alcohol Syndrome, Mild Cognitive Impairment, Age-related Memory Dysfunction, Down Syndrome and others), as well as sleep (e.g., hypersomnia and narcolepsy), and energy homeostasis (e.g. obesity) (Witkin & Nelson (2004) JPET: 103; 1 - 20; Hancock & Brune (2005) Exp Opin Inves Drugs: 14 (3), 223 - 241).

The pharmacology of the H3 receptor seems not only to be determined by its localization but appears also to be regulated by differential splicing. Today more than 20 splice variants (isoforms) have been described but their functions have yet to be elucidated completely (Bongers et al. (2007) Biochem Pharm: 73; 1195 - 1204). The H3 receptor is localized primarily to the central nervous system (CNS), with highest expression, in rodents, in the cerebral cortex, hippocampal formations, striatum, and hypothalamus (Drutel et al. (2001) MoI Pharmacol: 59; 1 - 8). Similarly in human, H3 receptor expression is prominent in the basal ganglia, globus pallidus, hippocampus, and cortex (Martinez-Mir et al. (1990) Brain Res: 526; 322 327). Notably, many of these brain regions are critical for cognition (cortex and hippocampus) and sleep and homeostatic regulation (hypothalamus). The H3 receptor has been shown also to localize to regions which might be involved in pain sensation or transmission and therefore might offer treatment opportunities for different pain states (Cannon et al. (2007) Pain: 129; 76 - 92).

In addition to agonist-induced signaling, the H3 receptor is constitutively active and capable of signaling independently of agonist both in vitro and in vivo (Morisset et al. (2000) Nature: 408, 860 - 864).

All these considerations suggest that novel H3 receptor antagonists like the series in this application could be useful in the treatment of cognitive dysfunctions as well as sleeping and energy homeostasis disorders. The term "antagonist" also includes inverse agonists.

Based on the information above and further literature, like WO-A 2007/080140 and WO-A 2006/136924 the following diseases and disorders are preferably affected.

Neurological disorders: Major conditions include behavioral/cognitive syndromes (e.g. Alzheimer's disease, Parkinson's disease, Attention Deficit and Hyperactivity Disorder, schizophrenia, Foetal Alcohol Syndrome, Mild Cognitive Impairment, Age-related Memory Dysfunction, Down Syndrome, epilepsy, convulsion, depression, anxiety disorders) seizure disorders neurodegenerative disorders (e.g. Alzheimer's disease, Parkinson's disease, Multiple Sclerosis) sleep disorders (e.g. hypersomnia and narcolepsy, excessive daytime sleepiness, diurnal and seasonal variations in sleep patterns)

Migraine Stroke tremor.

The term "neurological disorders" also includes psychiatrical disorders within the meaning of the present invention. The term "neurodegenerative disorders" also includes neuro- inflammatory disorders within the meaning of the present invention.

Disorders affecting energy homeostasis as well as complications associated therewith, e.g. obesity, eating disorders associated with excessive food intake, bulima, binge eating, complications associated therewith e.g. diabetes mellitus.

Pain, e.g. neuropathic pain, inflammatory pain, nociception. The term "pain" includes acute and chronic pain within the meaning of the present invention.

Cardiovascular disorders, e.g. acute myocardial infarction, and

other disorders, i.e. gastrointestinal disorders, vestibular dysfunction (e.g. Morbus Meniere, motion sickness, drug abuse), nasal congestion, allergic rhinitis (hay fever), asthma.

Preferred disorders are Alzheimer's disease, Parkinson's disease, Attention Deficit and Hyperactivity Disorder, schizophrenia, Foetal Alcohol Syndrome, Mild Cognitive Impairment, Age-related Memory Dysfunction, disease-related cognitive dysfunctions, Lewy body dementia, vascular dementia, Down Syndrome, epilepsy, convulsion, depression, anxiety disorders, idiopathic hypersomnia, narcolepsy, shift-work sleep disorder, disease- related fatigue, chronic fatigue syndrome, Migraine Stroke, tremor, obesity, eating disorders, diabetes mellitus, neuropathic pain, inflammatory pain, acute myocardial infarction, gastrointestinal disorders, vestibular dysfunction (e.g. Morbus Meniere), motion sickness, drug abuse, nasal congestion, allergic rhinitis (hay fever), asthma.

More preferred disorders are Alzheimer's disease, Parkinson's disease, Attention Deficit and Hyperactivity Disorder, schizophrenia, Mild Cognitive Impairment, disease-related cognitive dysfunctions, Lewy body dementia, vascular dementia, idiopathic hypersomnia, narcolepsy, obesity, diabetes mellitus, neuropathic pain, nasal congestion, allergic rhinitis (hay fever), asthma.

Even more preferred disorders are Alzheimer's disease, Parkinson's disease, Attention Deficit and Hyperactivity Disorder, schizophrenia, idiopathic hypersomnia, narcolepsy, obesity, neuropathic pain.

Accordingly, one aspect of the present invention is a compound or a pharmaceutically acceptable salt thereof of the present invention for use as a medicament.

Yet another aspect of the present invention is a compound or a pharmaceutically acceptable salt thereof of the present invention for use in a method of treating or preventing diseases and disorders associated with the H3 receptor.

Yet another aspect of the present invention is a compound or a pharmaceutically acceptable salt thereof of the present invention for use in a method of treating or preventing Alzheimer's disease, Parkinson's disease, Attention Deficit and Hyperactivity Disorder, schizophrenia, Foetal Alcohol Syndrome, Mild Cognitive Impairment, Age-related Memory Dysfunction, disease-related cognitive dysfunctions, Lewy body dementia, vascular dementia, Down Syndrome, epilepsy, convulsion, depression, anxiety disorders, idiopathic hypersomnia, narcolepsy, shift-work sleep disorder, disease-related fatigue, chronic fatigue syndrome, Migraine Stroke, tremor, obesity, eating disorders, diabetes mellitus, neuropathic pain, inflammatory pain, acute myocardial infarction, gastrointestinal disorders, vestibular dysfunction (e.g. Morbus Meniere), motion sickness, drug abuse, nasal congestion, allergic rhinitis (hay fever), or asthma. More preferred and even more preferred embodiments are those associated with the more preferred and even more preferred disorders as mentioned above. Yet another aspect of the present invention is the use of a compound or a pharmaceutically acceptable salt thereof of the present invention for the manufacture of a medicament for the treatment or prophylaxis of diseases and disorders associated with the H3 receptor.

Yet another aspect of the present invention is the use of a compound or a pharmaceutically acceptable salt thereof of the present invention for the manufacture of a medicament for the treatment or prophylaxis of Alzheimer's disease, Parkinson's disease, Attention Deficit and Hyperactivity Disorder, schizophrenia, Foetal Alcohol Syndrome, Mild Cognitive Impairment, Age-related Memory Dysfunction, disease-related cognitive dysfunctions, Lewy body dementia, vascular dementia, Down Syndrome, epilepsy, convulsion, depression, anxiety disorders, idiopathic hypersomnia, narcolepsy, shift-work sleep disorder, disease- related fatigue, chronic fatigue syndrome, Migraine Stroke, tremor, obesity, eating disorders, diabetes mellitus, neuropathic pain, inflammatory pain, acute myocardial infarction, gastrointestinal disorders, vestibular dysfunction (e.g. Morbus Meniere), motion sickness, drug abuse, nasal congestion, allergic rhinitis (hay fever), or asthma. More preferred and even more preferred embodiments are those associated with the more preferred and even more preferred disorders as mentioned above.

Yet another aspect of the present invention is a method for treating, controlling, delaying or preventing in a mammalian patient in need of the treatment of one or more conditions selected from the group consisting of diseases and disorders associated with the H3 receptor, wherein the method comprises the administration to said patient a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof.

Yet another aspect of the present invention is a method for treating, controlling, delaying or preventing in a mammalian patient in need of the treatment of one or more conditions selected from the group consisting of Alzheimer's disease, Parkinson's disease, Attention Deficit and Hyperactivity Disorder, schizophrenia, Foetal Alcohol Syndrome, Mild Cognitive Impairment, Age-related Memory Dysfunction, disease-related cognitive dysfunctions, Lewy body dementia, vascular dementia, Down Syndrome, epilepsy, convulsion, depression, anxiety disorders, idiopathic hypersomnia, narcolepsy, shift-work sleep disorder, disease- related fatigue, chronic fatigue syndrome, Migraine Stroke, tremor, obesity, eating disorders, diabetes mellitus, neuropathic pain, inflammatory pain, acute myocardial infarction, gastrointestinal disorders, vestibular dysfunction (e.g. Morbus Meniere), motion sickness, drug abuse, nasal congestion, allergic rhinitis (hay fever), and asthma, wherein the method comprises the administration to said patient a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof. More preferred and even more preferred embodiments are those associated with the more preferred and even more preferred disorders as mentioned above.

Preferably, the mammalian patient is a human patient.

Yet another aspect of the present invention is a pharmaceutical composition comprising at least one compound or a pharmaceutically acceptable salt thereof of the present invention together with a pharmaceutically acceptable carrier, optionally in combination with one or more other bioactive compounds or pharmaceutical compositions.

Preferably, the one or more bioactive compounds are lipase inhibitors, anorectic agents, selective serotonin uptake inhibitors, neurotransmitter reuptake blocker, agents that stimulate metabolism of body fat, anti-diabetic agents, lipid lowering agents, or histamine Hl receptor antagonists. A combination of one or more histamine H3 receptor antagonists of the present invention and histamine Hl receptor antagonists is preferred, especially for the treatment of allergic rhinitis, allergic congestion or nasal congestion.

"Pharmaceutical composition" means one or more active ingredients, and one or more inert ingredients that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Accordingly, the pharmaceutical compositions of the present invention encompass any composition made by admixing a compound of the present invention and a pharmaceutically acceptable carrier.

A pharmaceutical composition of the present invention may comprise one or more additional compounds as active ingredients like one or more compounds of formula (I) not being the first compound in the composition or other Histamine H3 receptor antagonists.

The active ingredients may be comprised in one or more different pharmaceutical compositions (combination of pharmaceutical compositions). The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids, including inorganic bases or acids and organic bases or acids.

The compositions include compositions suitable for oral, rectal, topical, parenteral (including subcutaneous, intramuscular, and intravenous), ocular (ophthalmic), pulmonary (nasal or buccal inhalation), or nasal administration, although the most suitable route in any given case will depend on the nature and severity of the conditions being treated and on the nature of the active ingredient. They may be conveniently presented in unit dosage form and prepared by any of the methods well-known in the art of pharmacy.

In practical use, the compounds of formula (I) can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous). In preparing the compositions for oral dosage form, any of the usual pharmaceutical media may be employed, such as water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like in the case of oral liquid preparations, such as, for example, suspensions, elixirs and solutions; or carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solid preparations such as powders, hard and soft capsules and tablets, with the solid oral preparations being preferred over the liquid preparations.

Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be coated by standard aqueous or nonaqueous techniques. Such compositions and preparations should contain at least 0.1 percent of active compound. The percentage of active compound in these compositions may, of course, be varied and may conveniently be between about 2 percent to about 60 percent of the weight of the unit. The amount of active compound in such therapeutically useful compositions is such that an effective dosage will be obtained. The active compounds can also be administered intranasally, for example, as liquid drops or spray. The tablets, pills, capsules, and the like may also contain a binder such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin. When a dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as a fatty oil.

Various other materials may be present as coatings or to modify the physical form of the dosage unit. For instance, tablets may be coated with shellac, sugar or both. A syrup or elixir may contain, in addition to the active ingredient, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and a flavoring such as cherry or orange flavor.

Compounds of formula (I) may also be administered parenterally. Solutions or suspensions of these active compounds can be prepared in water suitably mixed with a surfactant such as hydroxypropyl-cellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.

The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form should be sterile and should be fluid to the extent that easy syringability exists. It should be stable under the conditions of manufacture and storage and should be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.

Any suitable route of administration may be employed for providing a mammal, especially a human, with an effective dose of a compound of the present invention. For example, oral, rectal, topical, parenteral, ocular, pulmonary, nasal, and the like may be employed. Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols, and the like. Preferably compounds of formula (I) are administered orally. The effective dosage of active ingredient employed may vary depending on the particular compound employed, the mode of administration, the condition being treated and the severity of the condition being treated. Such dosage may be ascertained readily by a person skilled in the art.

Starting materials for the synthesis of preferred embodiments of the invention may be purchased from commercially available sources such as Array, Sigma Aldrich, Acros, Fisher, Maybridge, Fluorochem, Fluka, ABCR or can be synthesized using known methods by one skilled in the art.

In general, several methods are applicable to prepare compounds of the present invention. In some cases various strategies can be combined. Sequential or convergent routes may be used.

In general compounds of formula (I), wherein by way of example X ⁵ is O; S; or N(R ⁴ ), can be prepared by a method comprising the steps of

(a) Boc protecting a compound of formula (VIII)

at the secondary nitrogen atom of xVx ² , wherein one of X ¹ , X ² is NH and the other is C(R ^la R ^lb ) and X ^la , X ^2a , X ³ , X ⁴ have the meaning as indicated above;

(b) reacting the resulting compound from step (a) with a compound of formula (VII)

(VII)

H-X ^{^} R

wherein X ⁵ is O; S; or N(R ⁴ ) and n, R have the meaning as indicated above; (c) deprotecting the resulting compound from step (b) and reacting the unprotected compound with either of

i) a compound of formula R ¹ Q=O)Cl in the presence of a base such as DIPEA to yield a compound of formula (I), wherein X ⁵ is O; S; or N(R ⁴ ); ii) a compound of formula R ¹ C(=O)OC(=O)R ¹ in the presence of a base such as

DIPEA to yield a compound of formula (I), wherein X ⁵ is O; S; or N(R ⁴ ); iii) a compound of formula R ¹ (NCO) to yield a compound of formula (I), wherein

X ⁵ is O; S; or N(R ⁴ ). iv) a compound of formula R ¹ S(O) ₂ Cl in the presence of a base such as DIPEA to yield a compound of formula (I), wherein X ⁵ is O; S; or N(R ⁴ ); v) a compound of formula R ¹ (R ^0a )NC(=O)Cl in the presence of a base such as

DIPEA to yield a compound of formula (I), wherein X ⁵ is O; S; or N(R ⁴ ); vi) a compound of formula R ¹ OQ=O)Cl in the presence of a base such as DIPEA to yield a compound of formula (I), wherein X ⁵ is O; S; or N(R ⁴ ); or vii) a compound of formula R ¹ (R ^0a )NS(O)2Cl in the presence of a base such as DIPEA to yield a compound of formula (I), wherein X ⁵ is O; S; or N(R ⁴ ).

Additionally, compounds of formula (I), wherein X ⁵ is, e.g., O, S or NR ⁴ , can be prepared in a three step process by reacting 2-chloroethanol with isocyanatosulfuryl chloride in the presence of base to form a compound of formula (XXIX)

- reacting a compound of formula (XXIX) with a compound of formula (I), wherein X ¹ or X ² is NH and the other is C(R ^la R ^lb ),

- followed by reacting the resulting intermediate with a compound of formula HN(R ⁰ ^R ¹ in base such as TEA and at elevated temperature (usually 40 to 85 ⁰ C) to yield a compound of formula (I).

The method may comprise the further step (d) reacting a compound of formula (I), wherein X ⁵ is S with an oxidising agent to yield a compound of formula (I), wherein X ⁵ is S(O); or S(O) ₂ .

Further, more detailed, preparation routes for preferred compounds - but not limited to preferred compounds - may be used to prepare compounds of formula (I). The variables have the above described meanings unless otherwise specifically indicated.

Thus, compounds of formula (I)

wherein X ¹ is N(R ⁰ ), X ^la is C(R ^a R ^b ), X ² -X ^2a is C(R ^la R ^lb )-C(R ^x R ^lx ), X ³ is C(R ² ) and X ⁴ is N may be prepared starting from compounds of formula (II)

which are commercially available or may be prepared by routes well known in the art, wherein R ⁰ is defined as above or as a suitable N-atom protecting group such as Boc, by reacting compounds of formula (II) with pyrrolidine under Dean-Stark conditions followed by treatment of the resulting intermediate with prop-2-ynamide under Dean-Stark conditions to yield compounds of formula (III)

and further reacting compounds of formula (III) with strong base such as NaH in the presence of phase transfer reagent such as TBAI and reacting the resulting compound with a compound of formula (IVa) or formula (IVb) to yield a compound of formula (I) when R ⁰ is defined as above. ⁰ W ⁰

(IVa) alkyr O R

halideH }^R ^(IVb)

Compounds of formula (IVa) are either commercially available or can be prepared by reacting a compound of formula (V) with a sulfonyl chloride (such as methylsulfonyl chloride) in the presence of a suitable base such as DIPEA

_^ A — U M

Compounds of formula (IVb) are either commercially available or can be prepared by reacting a compound of formula (V) with a suitable halagonating agent (such as thionyl chloride or PBr ₃ or triphenylphospine and NBS) optionally in the presence of a suitable base such as DIPEA.

In the case when R ⁰ of formula (I) is a suitable N-atom protecting group such as Boc, the resulting compound represented by formula (VI) requires the following additional steps to synthesise a compound of formula (I)

deprotecting compound of formula (VI) at the nitrogen atom and reacting the resulting compound with either of

i) a compound of formula R ¹ Q=O)Cl in the presence of a base such as DIPEA to yield a compound of formula (I), wherein X ⁵ is O; S; or N(R ⁴ ); ii) a compound of formula R ¹ C(=O)OC(=O)R ¹ in the presence of a base such as

DIPEA to yield a compound of formula (I), wherein X ⁵ is O; S; or N(R ⁴ ); iii) a compound of formula R^NCO) to yield a compound of formula (I), wherein X ⁵ is O; S; or N(R ⁴ ); iv) a compound of formula R ¹ S(O) ₂ Cl in the presence of a base such as DIPEA to yield a compound of formula (I), wherein X ⁵ is O; S; or N(R ⁴ ); v) a compound of formula R ¹ (R ^0a )NC(=O)Cl in the presence of a base such as

DIPEA to yield a compound of formula (I), wherein X ⁵ is O; S; or N(R ⁴ ); vi) a compound of formula R ¹ OQ=O)Cl in the presence of a base such as DIPEA to yield a compound of formula (I), wherein X ⁵ is O; S; or N(R ⁴ ); or vii) a compound of formula R ¹ (R ^0a )NS(O)2Cl in the presence of a base such as

DIPEA to yield a compound of formula (I), wherein X ⁵ is O; S; or N(R ⁴ ).

Additionally, compounds of formula (I), wherein X ⁵ is O, S or NR ⁴ , can be prepared in a three step process by reacting a compound of formula (XXIX), above, with a compound of formula (I), wherein X ¹ or X ² is NH and the other is C(R ^la R ^lb ) and X ^la is C(R ^a R ^b ), X ^2a is C(R ^x R ^lx ) - followed by reacting the resulting intermediate with a compound of formula HN(R ¹ ^R ¹ in base such as TEA and at elevated temperature (usually 40 to 85 ⁰ C) to yield a compound of formula (I).

Additionally, compounds of formula (I), wherein X ⁵ is O, S or NR ⁴ , can be prepared in a two step process starting from a compound of formula (III) above by

reacting a compound of formula (III) with POCI ₃ , optionally in the presence of PCI ₅ and / or tetraethyl ammonium chloride monohydrate, at high temperature (usually > 80 0C) followed by reacting the resulting intermediate with a compound of formula (VII) to yield a compound of formula (I).

(VII)

H-X ^{^} R

Compounds of formula (VII) are either commercially available or can be prepared by the one step process of reacting a compound of formula (Vila)

X ^S VR < ^vlla > with a reducing agent such as NaBH ₄ .

Alternatively, Compounds of formula (VII) can be prepared by the one step process of reacting a compound of formula (VIIb)

with a reducing agent such as NaBH ₄ or borane-THF complex.

Additionally, compounds of formula (I), wherein X ⁵ is O, S or NR ⁴ , can be prepared in a four step process starting from a commercially available or readily obtainable compound of formula (VIII)

by Boc protecting compound of formula (VIII) at the nitrogen atom and reacting the resulting compound with a compound of formula (VII), optionally in the presence of a strong base such as KO ¹ Bu or NaH, to yield intermediate compound of formula (VI); and deprotecting compound of formula (VI) at the nitrogen atom and reacting the resulting compound under either of the reaction conditions described by steps i) to vii) above to yield a compound of formula (I).

Alternatively, compounds of formula (I), wherein X ⁵ is O, S or NR ⁴ , can be prepared in a two step process starting from a commercially available or readily obtainable compound of formula (VIII) and reacting this under either of the reaction conditions described by steps i) to vii) above to yield a compound of formula (XXXIV)

(XXXIV) and reacting this intermediate with a compound of formula (VII), optionally in the presence of a strong base such as KO ¹ Bu or NaH, to yield a compound of formula (I).

Accordingly, another aspect of the present invention is a method for the preparation of a compound according to the present invention, wherein in formula (I) X ⁵ is O; S; or NR ⁴ , comprising the steps

(a) reacting a compound of formula (VIII)

wherein one of X ¹ , X ² is NH and the other is C(R ^la R ^lb ) and X ^la , X ^2a , X ³ , X ⁴ have the meaning as indicated above, with

i) a compound of formula R ¹ Q=O)Cl in the presence of a base, when R ⁰ is C(O)-

R ¹ ; or ii) a compound of formula R ¹ C(=O)OC(=O)R ¹ in the presence of a base, when R ⁰ is C(O)-R ¹ ; or iii) a compound of formula R ¹ (NCO), when R ⁰ is C(O)NHR ¹ ; or iv) a compound of formula R ¹ S(O) ₂ Cl in the presence of a base, when R ⁰ is S(O) ₂ -

R ¹ ; or v) a compound of formula R ¹ (R ^0a )NC(=O)Cl in the presence of a base, when R ⁰ is

C(O)N(R ¹ ^-R ¹ ; or vi) a compound of formula R ¹ OQ=O)Cl in the presence of a base, when R ⁰ is C(O)O-R ¹ ); or vii) a compound of formula R ¹ (R ^0a )NS(O)2Cl in the presence of a base, when R ⁰ is S(O) ₂ N(R ¹ ^-R ¹ ; and

(b) reacting the resulting compound with a compound of formula (VII),

H-X ⁵ U < ^V "> wherein X ⁵ is O; S; or N(R ⁴ ) and n, R have the meaning as indicated above, optionally in the presence of a strong base, to yield a compound of formula (I).

In the case when X _r 5 of formula (I) is S(O) or S(O) ₂ the compounds represented by formula (I) can be prepared by reacting a compound of formula (I) (where X ⁵ is S) with an oxidising agent such as OXONE or mCPBA.

Another aspect of the present invention is a process for the preparation of a compound according to the present invention, comprising the steps of

reacting a compound of formula (II), which is commercially available or can be prepared by routes known in the art,

wherein X ² -X ^2a is C(R ^la R ^lb )-C(R ^x R ^lx ) and R ⁰ can be as defined above or a suitable N- atom protecting group such as Boc with DMF. DMA at high temperature (usually at 100 C) followed by treatment of the resulting intermediate with a compound of formula (X) at high temperature (usually at 80 C) to yield a compound of formula (I).

HOSO ₂ CF ₃

In the case when R ⁰ of formula (I) is a suitable N-atom protecting group such as Boc, the resulting compound represented by formula (XI) requires the following additional steps to synthesise a compound of formula (I)

which are deprotecting compound of formula (XI) at the nitrogen atom; and

reacting the resulting compound under either of the reaction conditions described by steps i) to vii) above to yield a compound of formula (I).

Additionally, compounds of formula (I), wherein X ³ is N, X ⁵ is O, S or NR ⁴ , can be prepared in a four step process starting from a commercially available or readily obtainable compound of formula (XII)

by Boc protecting compound of formula (XII) at the nitrogen atom and reacting the resulting compound with a compound of formula (VII), optionally in the presence of a strong base such as KO ¹ Bu or NaH, to yield intermediate compound of formula (XIII)

and deprotecting compound of formula (XIII) at the nitrogen atom and reacting the resulting compound under either of the reaction conditions described by steps i) to vi) above to yield a compound of formula (I).

Alternatively, compounds of formula (I), wherein X ³ is N, X ⁵ is O, S or NR ⁴ , can be prepared in a two step process starting from a commercially available or readily obtainable compound of formula (XII) and reacting this under either of the reaction conditions described by steps i) to vii) above to yield a compound of formula (XXXIV)

reacting this intermediate with a compound of formula (VII), optionally in the presence of a strong base such as KO ¹ Bu or NaH, to yield a compound of formula (I).

In the case when R ^a and R ^b of formula (I) are lower alkyl (C _1-4 alkyl) the compounds can be prepared by reacting a compound of formula (I) (where R ^a and R ^b are H and R ⁰ is Boc) with a strong base such as ¹ BuLi and TMEDA at low temperature (usually < -50 ⁰ C) then treating the resulting intermediate with the appropriate electrophile (such as MeI) to yield intermediate compound of formula (XIV)

deprotecting compound of formula (XIV) at the nitrogen atom and reacting the resulting compound under either of the reaction conditions described by steps i) to vii) above to yield a compound of formula (I).

Additionally, compounds of formula (I), wherein X ¹ is C(R ^la R ^lb ), X ² is N(R ⁰ ) and X ³ is CR ² may be prepared starting from compounds of formula (XVI)

Accordingly, another aspect of the present invention is a process for the preparation of a compound according to the present invention, comprising the steps of removal of the tert-butyl amide of a compound of formula (XVI), which can be obtained in 2 steps from 3-aminopyridine as described in J. Org. Chem., 1983, 48, 3014, with sulphuric acid at high temperature (usually ~ 100 ⁰ C) followed by treatment of the resulting intermediate with ethyl acrylate under Heck conditions to yield intermediate compound of formula (XVII)

treatment of a compound of formula (XVII) with sodium ethoxide in ethanol at high temperature (usually at 100 ⁰ C) followed by treatment of the resulting intermediate with benzyl bromide and subsequent reduction of the quaternised intermediate with a reducing agent such as sodium borohydride to yield intermediate compound of formula (XVIII)

(XVIII)

reacting a compound of formula (XVIII) with POCI ₃ , optionally in the presence of PCI5 and / or tetraethyl ammonium chloride monohydrate, at high temperature (usually > 80 ⁰ C) followed by reacting the resulting intermediate with a compound of formula (VII), subsequent de-benzylation (usually under transfer hydrogenation conditions) to yield intermediate (IXX)

reacting a compound of formula (IXX) under either of the reaction conditions described by steps i) to vii) above to yield a compound of formula (I). In the case when C(R ² ) of formula (I) is a C-CN, compounds represented by formula (IXXa) can be further modified at the CN functional group by the following optional additional steps to synthesise compounds of formula (I)

reacting a compound of formula (IXXa) with DIBAL at low temperature (usually < - 60 ⁰ C) to yield the aldehyde analogue of formula (IXXa) - followed by reacting the resulting compound with a compound of formula HN(R ³ R ^3a ) in the presence of a reducing agent such as STAB to yield a compound of formula (I), alternatively, reacting a compound of formula (IXXa) with strong base such as 5 M NaOH, followed by reacting the resulting intermediate with HN(R ³ R ^3a ) in the presence of a coupling agent such as DCC to yield a compound of formula (I).

Additionally, compounds of formula (I), wherein X ¹ is N(R ⁰ ), X ² is C(R ^la R ^lb ), X ^la is C(R ^a R ^b ), X ^2a is C(R ^x R ^lx ), X ³ is CR ² , X ⁴ is N may be prepared starting from compounds of formula (II) by

reacting a compound of formula (II), which are commercially available

wherein R ⁰ can be as defined above or a suitable N-atom protecting group such as Boc with DMF. DMA at high temperature (usually at 100 ⁰ C) followed by treatment of the resulting intermediate with a compound of formula H ₂ N(CO)CH ₂ R ² and strong base usually NaH at high temperature (usually at 100 ⁰ C) to yield a intermediate compound of formula (XX)

followed by reacting a compound of formula (XX) with POCI3, optionally in the presence of PCI5 and / or tetraethyl ammonium chloride monohydrate, at high temperature (usually > 80 ⁰ C) and reacting the resulting intermediate with a compound of formula (VII) to yield a compound of formula (I).

In the case when R ⁰ of formula (I) is a suitable N-atom protecting group such as Boc, the resulting compound represented by formula (XXI) requires the following additional steps to synthesis a compound of formula (I)

deprotecting compound of formula (XXI) at the nitrogen atom and reacting the resulting compound under either of the reaction conditions described by steps i) to vii) above to yield a compound of formula (I).

Additionally, compounds of formula (I), wherein X ⁵ is N(R ⁴ )C(O) or N(R ⁴ )S(O) ₂ may be prepared starting from compounds of formula (XXII), which are either commercially available or their preparations have been disclosed above herein

Accordingly, another aspect of the present invention is a process for the preparation of a compound according to the present invention, comprising the steps of

reacting a compound of formula (XXII) with a compound of formula HN(R ⁴ )CH ₂ Ph, which is commercially available or can be prepared by routes known in the art, under microwave irradiation (usually at >80 ⁰ C) in the presence of suitable base such as

K ₂ CO ₃ followed by de-benzyl protection, using hydrogenation conditions, and subsequent reaction with the appropriate compound of formula (XXIII) or (XXIV), in the presence of pyridine base and optionally at high temperature (usually >80 ⁰ C)

(XXIII)

to yield a compound of formula (I).

In the case when X ¹ or X ² equals N-R ⁰ and R ⁰ of formula (I) is a suitable N-atom protecting group such as Boc, the resulting compound represented by formula (XXV) requires the following additional steps to synthesise a compound of formula (I)

- deprotecting compound of formula (XXV) at the nitrogen atom and reacting the resulting compound under either of the reaction conditions described by steps i) to vii) above to yield a compound of formula (I).

Additionally, compounds of formula (I), wherein X ⁵ is S(O) ₂ N(R ⁴ ) may be prepared starting from compounds of formula (XXII), which is either commercially available or their preparation has been disclosed herein. Accordingly, another aspect of the present invention is a process for the preparation of a compound according to the present invention, comprising the steps of

reacting a compound of formula (XXII) with potassium hydrogensulfϊde in water, at high temperature (usually at > 200 ⁰ C) reacting the resulting compound with chlorine gas and IM HCl, at low temperature (usually at < 5 ⁰ C) to yield a intermediate compound of formula (XXVI)

treatment of a compound of formula (XXVI) with a compound of formula (XXVII) in pyridine at high temperature (usually at > 5O ⁰ C)

(XXVII)

to yield a compound of formula (I).

In the case when X ¹ or X ² equals N-R ⁰ and R ⁰ of formula (I) is a suitable N-atom protecting group such as Boc, the resulting compound represented by formula (XXVIII) requires the following additional steps to synthesise a compound of formula (I)

(XXVIII)

- deprotecting compound of formula (XXVIII) at the nitrogen atom and reacting the resulting compound under either of the reaction conditions described by steps i) to vii) above to yield a compound of formula (I). Alternatively, compounds of formula (I), wherein X ¹ is N(R ⁰ ), X ² is C(R ^la R ^lb ), X ^la is C(R ^a R ^b ), X ^2a is C(R ^x R ^lx ) and X ³ is CR ² may be prepared starting from compounds of formula (XXX)

wherein R ⁰ can be as defined above or as a suitable N-atom protecting group such as Boc

Accordingly, another aspect of the present invention is a process for the preparation of a compound according to the present invention, comprising the steps of

reacting a compound of formula (XXX) with propargylamine in ethanol solvent, with catalytic sodium tetrachloroaurate (III) dihydrate at high temperature (usually - 100 0C) followed by treatment of the resulting intermediate with an oxidising agent (such as mCPBA) to yield intermediate compound of formula (XXXI)

treatment of a compound of formula (XXXI) with phosphorus oxychloride at high temperature (usually at 50 to 85 ⁰ C) followed by aqueous workup to yield intermediate compound of formula (XXXII)

reacting a compound of formula (XXXII) with a compound of formula (VII) to yield a compound of formula (I), when R ⁰ is defined as above. In the case when R ⁰ of formula (I) is a suitable N-atom protecting group such as Boc, the resulting compound represented by formula (XXXIII) requires the following additional steps to synthesis a compound of formula (I)

(XXXIII)

deprotection of a compound of formula (XXXIII) at the nitrogen atom and reacting the resulting compound under either of the reaction conditions described by steps i) to vii) above to yield a compound of formula (I).

Accordingly, another aspect of the present invention is a method for the preparation of a compound of the present invention, wherein in formula (I) X ⁵ is O; S; or NR ⁴ ; X ¹ is N(R ⁰ ); X ² is C(R ^la R ^lb ); X ^la is C(R ^a R ^b ); X ^2a is C(R ^x R ^lx ); and X ³ is CR ² ; comprising the steps of

(a) reacting a compound of formula (XXX)

wherein R ⁰ has the meaning as indicated above or is a suitable N-atom protecting group (such as Boc), with propargylamine in ethanol solvent, with catalytic sodium tetrachloroaurate (III) dihydrate at high temperature (usually about 100 ⁰ C);

(b) treating the resulting intermediate with an oxidising agent (such as mCPBA) to yield intermediate compound of formula (XXXI)

(XXXI) (c) treating a compound of formula (XXXI) with phosphorus oxychloride at high temperature (usually at 50 to 85 ⁰ C) followed by aqueous workup to yield intermediate compound of formula (XXXII)

(dl) reacting a compound of formula (XXXII) with a compound of formula (VII),

wherein X ⁵ is O; S; or N(R ⁴ ) and n, R have the meaning as indicated above, optionally in the presence of a strong base, to yield a compound of formula (I);

or in the case when R ⁰ of formula (I) is a suitable N-atom protecting group (such as Boc)

(d2) deprotecting the resulting compound of step (dl) (which is represented by formula (XXXIII) in case Boc is used) and reacting the resulting deprotected compound under either of the reaction steps i) to vii) as indicated above to yield a compound of formula (I).

Examples

Biological evaluation:

Cell-lines used to characterize invented compounds in vitro

CHO-Kl cell line expressing human H3 receptors were purchased from Euroscreen (Gosselies, Belgium, Cat. no.: ES-392-C) Human H3 receptor-expressing cell-lines were grown in Ham's F12 [Sigma, Cat. no. N6658], supplemented with 10% FBS [Sigma, Cat. no. F9665], 400μg/ml G418 [Sigma, Cat. no. Nl 876] and 250μg/ml Zeocin [Invitrogen, Cat. no. 46-0509]) according to the protocol provided by Euroscreen.

cAMP quantification protocol for human H3 receptor testing

The assay measures the ability of test compounds to inhibit Histamine receptor agonist- induced decrease of intracellular free cAMP (receptor is G ₁ coupled).

Specifically, a cAMP quantification assay system from Disco veRx (cAMP XS+; Cat. no. 90- 0075) was used.

For the cAMP assay, confluent cells were detached from the culture vessels with Ix trypsin-

EDTA solution (Sigma), and seeded into 384-well Costar plates (white, clear bottom, Cat. no.

3707) at a density of 10,000 cells per well. Cells were seeded in a volume of 50μl in medium without antibiotics and incubated overnight in a humidified atmosphere with 5% CO ₂ at 37°C.

The cAMP assay was performed according to the protocol provided by DiscoveRx.

The cell culture medium was removed and the cells washed once with PBS (50 μl per well).

The plates were emptied by inversion and 7.5μl/well of compound in PBS (containing ImM

IBMX and 0.03% BSA) were added and incubated for 30min at 37°C.

Subsequent 7.5μl/well specific agonist solution was added and the plates for another 30min incubated at 37°C.

The following agonist solution is used for the individual cell- lines: hH3: 100 nM histamine, 10 μM forskolin in PBS (containing ImM IBMX and 0.03% BSA)

After the incubation with the agonist, 5μl/well cAMP XS antibody solution was added followed by 20μl/well Gal/EII/Lysis(l :5:19) +ED (1 :1). The plates were incubated for one hour at room temperature and afterwards 20μl/well EA reagent was added. The luminescence was developed for approximately three hours at room temperature and the plates were read out using a 'BMG Novostar' plate reader.

Assaying of compounds

Test compounds were assayed at 8 concentrations in triplicate. Serial 10-fold dilutions in 100% DMSO were made at a 100-times higher concentration than the final concentration and then diluted with a 2 step protocol in assay buffer to reach the required assay concentrations and 1% DMSO.

The specific compounds exemplified below were categorized by IC50 ≤ 50 nM potency.

Synthesis of compounds:

ANALYTICAL METHODS

NMR Spectrometers Used:

Bruker DRX 500 MHz NMR Bruker AVANCE 400 MHz NMR Bruker DPX 250 MHz NMR Bruker DPX 360 MHz NMR

Configuration of the Bruker DRX 500 MHz NMR

High performance digital NMR spectrometer, 2-channel microbay console and Windows XP host workstation running Topspin version 1.3.

Equipped with:

• Oxford instruments magnet 11.74 Tesla (500 MHz proton resonance frequency) • B-VT 3000 temperature controller

• GRASP II gradient spectroscopy accessory for fast acquisition of 2D pulse sequences

• Deuterium lock switch for gradient shimming

• 5mm Broad Band Inverse geometry double resonance probe with automated tuning and matching (BBI ATMA). Allows ¹ H observation with pulsing/decoupling of nuclei in the frequency range ¹⁵ N and ³¹ P with ² H lock and shielded z-gradient coils.

Configuration of the Bruker DPX 250MHz NMR

High performance one bay Bruker 250 MHz digital two channel NMR spectrometer console and Windows XP host workstation running XwinNMR version 3.5. Equipped with:

• Oxford instruments magnet 5.87 Tesla (250 MHz proton resonance frequency)

• B-VT 3300 variable temperature controller unit

• Four nucleus (QNP) switchable probe for observation of ¹ H, ¹³ C, ¹⁹ F and ³¹ P with ² H lock Configuration of the Bruker AVANCE 400MHz NMR

High performance one bay Bruker AVANCE 400 MHz digital two channel NMR spectrometer console Equipped with:

• Bruker magnet 9.40 Tesla (400MHz proton resonance frequency)

• B-VT 3200 variable temperature controller unit

• GRASP II gradient spectroscopy accessory for the generation of one field gradient of up to 50 Gauss cm ^"1

• Four nucleus (QNP) switchable probe for observation of ¹ H, ¹³ C, ¹⁹ F and ³¹ P with 2H lock with z-gradient coils for gradient spectroscopy.

LCMS methods used Example compounds and their intermediates were analysed by HPLC-MS using a combination of the following methods.

LCMS Method A (2 min method)

LCMS Method B (3 min method)

LCMS Method C (7 min method)

LCMS Method D (7 min method)

LCMS Method E (10 min method)

LCMS Method F (15 min method)

Preparative HPLC Methods Used:

Where indicated, Example compounds and their intermediates were purified by one of or any combination of the following methods.

Prep Method 1 (Low pH)

Prep Method 2 (FTE High pH) Prep Method 3 (Low pH)

Prep method 4 (FTE prep)

Prep method 5 (Neutral) Compound Naming

All compounds are named using ACD Labs 10.0 naming software which conforms to IUPAC naming protocols. Some compounds are isolated as TFA, formic acid or fumaric acid salts, which is not reflected by the chemical name. Within the meaning of the present invention the chemical name represents the compound in neutral form as well as its TFA, formic acid or fumaric acid salt or any other salt, especially pharmaceutically acceptable salt, if applicable.

List of Abbreviations

AcOH acetic acid aq aqueous br s broad singlet

Boc te/t-butoxycarbonyl

(BoC) ₂ O di-tert-buty{ dicarbonate

¹ Bu tert-butyl cat catalytic mCPBA 3-chloroperoxybenzoic acid

Cbz benzyloxycarbonyl

CDI 1 , 1 '-carbonyldiimidazole

Chloroform-ύf deuterated chloroform

DCE 1 ,2-dichloroethane

DCM dichloromethane

DCC dicyclohexylcarbodiimide

DIPEA JV,jV-diisopropylethylamine

DIBAL diisobutylaluminium hydride

DMAP N,Λ/-4-dimethylaminopyridine

DMF Λ/,Λ/-dimethylformamide

DMF.DMA Λ/,Λ/-dimethylformamide dime eq equivalent

Ether diethyl ether

Et ₂ O diethyl ether

EtOAc ethyl acetate

EtOH ethanol

FCC flash column chromatography h (s) hour(s) HCl hydrochloric acid

HOBt 1 -hydroxybenzotriazo Ie

HBTU o-benzotriazol-l-yl-N,N,N\N"-tetramethyluronium tetrafluoroborate

HPLC high pressure liquid chromatography

IBX 1 -hydroxy- 1 ,2-benziodoxol-3(lh)-one 1 -oxide

K ₂ CO ₃ potassium carbonate

¹ BuOK potassium tert-butoxidc

LAH lithium aluminium hydride

LCMS liquid chromatography and mass spectrometry

MeCN acetonitrile

MeOH methanol

MeOD dueterated methanol m multiplet min(s) minute(s) mL millilitre ml millilitre mol/M mole/molar

MsCl methanesulfonyl chloride

MW molecular weight nM nanomolar

NaH sodium hydride

NaOH sodium hydroxide

NaHCO ₃ sodium hydrogen carbonate

Na ₂ SO ₄ sodium sulphate

NBS N-bromosuccinamide

NMR nuclear magnetic resonance

NH ₃ ammonia

NEt ₃ triethylamine

NH ₄ OH ammonium hydroxide

OXONE poatassium peroxymonosulfate

PBr ₃ tribromophospine

PCl ₅ phosphorus pentachloride

POCl ₃ phosphorus oxychloride

PhMe toluene PPh ₃ triphenylphosphine

PS-DIPEA polymer-supported N, N-diisopropylethylamine

Rt retention time

RT room temperature

SCX toluene sulfonic acid functionalised silica in pre-packed cartridge

STAB sodium triacetoxyborohydride

SiO ₂ silica gel

SOCl ₂ thionyl chloride

TBAI tetra-n-butylammonium iodide

¹ BuLi tert-bvXy\ lithium tert tertiary

TEA triethylamine

TFA 2,2,2-trifluoroacetic acid

TFAA trifluoroacetic anhydride

TFE 2,2,2-trifluoroethanol

THF tetrahydrofuran

TLC thin layer chromatography

TMEDA N, N, N ',N '-tetramethylethy lenediamine

TMS trimethylsilyl

TfOH trifluoromethanesulfonic acid

Route 1

°O

HO NH HO— ( / \ N

DCE, AcOH, \ /

STAB, RT

Preparation of l-cyclobutylpiperidin-4-ol

To a solution of piperidin-4-ol (3.5 g, 35 mmol) and cyclobutanone (4.8 g, 69 mmol) in DCE (350 ml) was added AcOH (4.2 ml, 69 mmol). The mixture was stirred at RT for 2h before STAB (22 g, 103 mmol) was added portionwise. The reaction was stirred at RT for 16h, quenched by addition of saturated aqueous NaHCO ₃ . The aqueous extract was concentrated, diluted with DCM, dried (MgSO ₄ ), filtered and concentrated to give the title compound (1.9 g, 37 % yield) as yellow oil.

LCMS data: Calculated MH ⁺ (156); Found 100% (MH ⁺ ) m/z 156, Rt = 0.44 min.

LCMS data: Calculated MH ⁺ (156); Found 100% (MH ⁺ ) m/z 156.1, Rt = 2.96 min (high pH).

NMR data: ¹ H NMR (400 MHz, Chloroform-J) δ ppm 2.85 - 2.97 (5 H, m), 2.43 - 2.53 (4 H, m), 1.97 - 2.08 (2 H, m), 1.52 - 1.91 (7 H, m).

Route 2

Preparation of l-cyclobutylpiperidin-4-ol

HO— ( N-

Pd/C (10%) was added to a solution of piperidin-4-ol (3.5 g, 35 mmol) and cyclobutanone

(2.9 mL, 38 mmol) in EtOH (250 ml). The mixture was stirred under H ₂ atmosphere for 16h, filtered through Celite®, and concentrated under reduced pressure. The residue was purified by flash column chromatography (DCM/MeOH/NH ₃ 95:5:1 to 80:20:5) to give the title compound as pale yellow oil (5.1 g, 95 % yield).

LCMS data: Calculated MH ⁺ (156); Found 100% (MH ⁺ ) m/z 156, Rt = 2.97 min. (high pH).

NMR data: ¹ H NMR (500 MHz, Chloroform-J) δ ppm 3.62 (1 H, br. s.), 2.56 - 2.84 (3 H, m), 1.94 - 2.13 (4 H, m), 1.80 - 1.94 (4 H, m), 1.63 - 1.78 (2 H, m), 1.46 - 1.62 (2 H, m).

Preparation of 6-methylpyridine-3-carbonyl chloride

To a stirred solution of β-methylpyridine-S-carboxylic acid (200 mg, 1.45 mmol) in DCM (2ml) was added dropwise, oxalyl chloride (243 μl, 2.9 mmol). Once the gas evolution had slowed, 1 drop of DMF was added and the reaction was allowed to stir at room temperature for 2 hours. The brown solution was then concentrated under reduced pressure to yield a brown solid (225 mg, 100%) and used crude in the next step.

¹ H NMR (500 MHz, CHLOROFORM-J) δ ppm 9.35 (1 H, d, J=I.7 Hz), 8.84 (1 H, dd, J=8.3, 1.9 Hz), 7.88 (1 H, d, J=8.4 Hz), 3.15 (3 H, s).

Route 4

SOCL o O

OH Toluene, Reflux ^^ ^{^} ci

24 hours

Preparation of Cyclopropylacetyl chloride

O

Cl

To a stirred solution of cyclopropylacetic acid (200 mg, 2 mmol) in dry toluene (3 ml) was added SOCl ₂ (429 μl, 6 mmol) and the resulting solution heated at reflux for 24 hours. A TLC of the reaction mixture indicated a single product was formed and the solution was concentrated under reduced pressure to yield colourless oil. No further analysis or purification was carried out and the product was used crude in the next step.

Route 5

General Procedure A tBuOK, 1 15°C dioxane microwave 150W

General General Procedure B Or Procedure C

1 TFA, DCM, RT 1 4M HC in dioxane, dioxane, RT D RT

The following intermediates were prepared as described in Route 5 above. Preparation of tert-butyl 2-chloro-7,8-dihydro-l,6-naphthyridine-6(5H)-carboxylate

Di-tert-butyl dicarbonate (2.40 g, 11 mmol) was added to a solution of 2-chloro-5,6,7,8- tetrahydro-l,6-naphthyridine hydrochloride (available from Activate Scientific) (2.05 g, 10 mmol) and Et ₃ N (3.33 g, 4.59 ml, 33 mmol) in DCM at 0 ⁰ C. DMAP (0.12 g, 1.00 mmol) was added and the reaction was stirred at RT for 3 days. The reaction was diluted with DCM and washed successively with 10% w/v citric acid (aq.), saturated NaHCO ₃ (aq.), water, dried (Na ₂ SO ₄ ), filtered and concentrated at reduced pressure. The residue (2.8g) was purified by FCC (SiO ₂ , eluting with 9:1 to 3:1 heptane / EtOAc) to give the title compound (2.63 g, 89%). LCMS data: Calculated MH ⁺ (269); Found 100% (MH ⁺ ) m/z 269, Rt = 1.33 min. 1H NMR (250 MHz, CHLOROFORM-J) δ ppm 1.49 (8 H, s) 2.97 (2 H, t, J=5.86 Hz) 3.73 (2 H, t, J=5.94 Hz) 4.57 (2 H, s) 7.17 (1 H, d, J=8.07 Hz) 7.38 (1 H, d, J=8.07 Hz).

General Procedure A: Preparation of tert-butyl 2- [(l-cyclobutylpiperidin-4-yl)oxy]- 7,8-dihydro- 1 ,6-naphthyridine-6(5H)-carboxylate

A mixture of tert-butyl 2-chloro-7,8-dihydro-l,6-naphthyridine-6(5H)-carboxylate (0.59 g, 2.20 mmol), l-cyclobutylpiperidin-4-ol (0.52 g, 3.30 mmol) and potassium tert-butoxide (0.62 g, 5.50 mmol) in dioxane (20 volumes) was heated at 115°C for 40 min in a CEM microwave reactor (150W) under N ₂ (g) atmosphere. The reaction mixture was diluted with EtOAc, washed with brine, dried (Na ₂ SO ₄ ), filtered and concentrated at reduced pressure. The residue (0.9 g) was purified by FCC (SiO ₂ , eluting with DCM/MeOH/NH ₃ , 90:10:1) to give the title compound (0.47 g, 55%). LCMS data: Calculated MH ⁺ (388); Found 100% (M ⁺ ) m/z 387, Rt = 5.78 min.

¹ H NMR (250 MHz, CHLOROFORM-^) δ ppm 1.38 - 2.15 (21 H, m) 2.47 - 2.81 (5 H, m) 3.63 (2 H, t, J=5.86 Hz) 4.40 (2 H, s) 4.97 (1 H, br. s.) 6.47 (1 H, d, J=8.38 Hz) 7.06 (1 H, d, J=8.38 Hz). General Procedure B: Preparation of 2- [(l-cyclobutylpiperidin-4-yl)oxy] -5,6,7,8- tetrahydro- 1 ,6-naphthyridine

To a solution of tert-butyl 2-[(l-cyclobutylpiperidin-4-yl)oxy]-7,8-dihydro-l,6-naphthyr idine- 6(5H)-carboxylate (0.150 g, 0.388 mmol) in DCM (2 ml) at RT was added TFA (0.5 ml, 2 volumes) and the reaction mixture stirred for 8 h. The reaction mixture was basifϊed with saturated NaHCOs solution (10 ml), extracted with DCM (2 x 20 ml) and the combined organic layers washed with brine (5 ml), dried (Na ₂ SO ₄ ), filtered and evaporated at reduced pressure to provide the title compound (0.101 g, 90 %) as brown oil. The crude compound was taken on to the next step without further purification.

LCMS data: Calculated M ⁺ (287); Found 100% (M ⁺ ) m/z 287, Rt = 4.01 min.

¹ H NMR (250 MHz, MeOD) δ ppm 1.58 - 2.53 (12 H, m) 2.62 - 3.16 (4 H, m) 3.24 - 3.38 (2

H, m) 3.41 - 3.69 (5 H, m) 4.22 (2 H, s) 5.05 - 5.42 (1 H, m) 6.52 - 6.79 (1 H, m) 7.33 - 7.55

(l H, m).

Alternatively, tert-butyl 2-[(l-cyclobutylpiperidin-4-yl)oxy]-7,8-dihydro-l,6-naphthyr idine- 6(5H)-carboxylate can be deprotected using HCl as illustrated in Route 5 General Procedure C.

General Procedure C: Preparation of 2- [(l-cyclobutylpiperidin-4-yl)oxy] -5,6,7,8- tetrahydro- 1 ,6-naphthyridine

To a solution of tert-butyl 2-[(l-cyclobutylpiperidin-4-yl)oxy]-7,8-dihydro-l,6-naphthyr idine- 6(5H)-carboxylate (520 mg, 1.5 mmol) in dioxane (5 ml) was added HCl (4M in dioxane, 5 ml, 20 mmol). The mixture was stirred at RT for 2h, concentrated under reduced pressure to give the title compound as a white solid.

¹ H NMR (500 MHz, MeOD) δ ppm 7.49 - 7.72 (1 H, m), 6.69 - 6.95 (1 H, m), 5.04 - 5.37 (1 H, m), 4.25 (2 H, br. s.), 3.60 - 3.72 (1 H, m), 3.50 (3 H, br. s.), 3.26 - 3.37 (1 H, m), 2.80 - 3.12 (4 H, m), 2.25 (6 H, br. s.), 2.00 - 2.14 (1 H, m), 1.67 - 1.96 (3 H, m). For General Procedure D, E and F either the HCl salt, TFA salt or free base form of 2-[(l- cyclobutylpiperidin-4-yl)oxy]-5,6,7,8-tetrahydro-l,6-naphthy ridine can be used.

General Procedure D:

Example 1 - Preparation of 2-[(l-cyclobutylpiperidin-4-yl)oxy]-6-

(cyclopropylcarbonyl)-5,6,7,8-tetrahydro- 1 ,6-naphthyridine.

To a solution of 2-[(l-cyclobutylpiperidin-4-yl)oxy]-5,6,7,8-tetrahydro-l,6-n aphthyridine (55 mg, 0.192 mmol) in DCM (2 ml) under N ₂ was added NEt ₃ (0.44 mmol) and cyclopropanecarbonyl chloride (0.016 mg, 0.21 mmol). The mixture was stirred at RT for 3h before the volatiles were removed under reduced pressure. The residue was purified by preparative HPLC to give the desired product as a TFA salt. The resulting salt was diluted in DCM, loaded onto a SCX column, washed with DCM (2 x 2 ml), MeOH (2 x 2 ml) then eluted with 2N NH ₃ ZMeOH in DCM. The collected fractions were concentrated at reduced pressure to give the title compound (13.5 mg, 20%) as colourless oil. LCMS data: Calculated MH ⁺ (356); Found 100 % m/z 356, Rt = 4.55 min (High pH). 1H NMR (500 MHz, CHLOROFORM-J) δ ppm 7.39 (1 H, d, J=8.4 Hz), 6.60 (1 H, d, J=8.3 Hz), 5.06 - 5.45 (1 H, m), 4.55 - 4.86 (2 H, m), 3.81 - 4.05 (2 H, m), 3.34 - 3.49 (3 H, m), 2.88 (4 H, d, J=I 1.9 Hz), 2.56 (2 H, br. s.), 2.08 - 2.41 (6 H, m), 1.89 - 2.02 (1 H, m), 1.70 - 1.89 (2 H, m), 1.05 (2 H, br. s.), 0.84 (2 H, br. s.).

The following compounds were prepared as described in Route 5, General Procedure D above.

Example 2 - Preparation of 6-acetyl-2-[(l-cyclobutylpiperidin-4-yl)oxy]-

5,6,7,8-tetrahydro- 1 ,6-naphthyridine.

In a similar fashion (Route 5, GP D), 2-[(l-cyclobutylpiperidin-4-yl)oxy]-5,6,7,8-tetrahydro- 1,6-naphthyridine (55 mg, 0.192 mmol) and acetyl chloride gave the title compound ( 13.5 mg, 20%) as colourless oil. LCMS data: Calculated MH ⁺ (330); Found 100 % m/z 330, Rt = 4.02 min. (High pH). 1H NMR (500 MHz, MeOD) δ ppm 7.40 - 7.53 (1 H, m), 6.62 (1 H, dd, J=8.3, 1.9 Hz), 5.05 (1 H, dd, J=7.6, 3.8 Hz), 4.62 (2 H, d, J=8.8 Hz), 3.72 - 3.92 (2 H, m), 2.78 - 3.00 (3 H, m), 2.70 (2 H, br. s.), 1.99 - 2.39 (9 H, m), 1.86 - 1.99 (2 H, m), 1.64 - 1.86 (4 H, m).

Example 3 - Preparation of 2-[(l-cyclobutylpiperidin-4-yl)oxy]-6- propanoyl-5,6,7,8-tetrahydro- 1 ,6-naphthyridine.

In a similar fashion (Route 5, GP D), 2-[(l-cyclobutylpiperidin-4-yl)oxy]-5,6,7,8-tetrahydro- 1,6-naphthyridine hydrochloride salt (31 mg, 0.109 mmol) and propanoyl chloride (14 μl,

0.164 mmol) gave the title compound ( 20.5 mg, 55%) as colourless oil.

LCMS data: Calculated MH ⁺ (344); Found 91 % m/z 344, Rt = 4.22 min.

¹ H NMR (500 MHz, CHLOROFORM-^) δ ppm 7.26 - 7.43 (1 H, m), 6.56 (1 H, d, J=8.3 Hz),

5.40 (1 H, br. s.), 4.40 - 4.74 (2 H, m), 3.66 - 3.98 (2 H, m), 3.37 (2 H, dd, J=16.7, 8.1 Hz), 2.71 - 3.01 (4 H, m), 2.58 (2 H, d, J=9.2 Hz), 2.11 - 2.50 (8 H, m), 1.64 - 2.01 (3 H, m), 1.06 -

1.27 (3 H, m).

Example 4 - Preparation of 2-[(l-cyclobutylpiperidin-4-yl)oxy]-6-(3,3- dimethylbutanoyl)-5,6,7,8-tetrahydro- 1 ,6-naphthyridine.

In a similar fashion (Route 5, GP D), 2-[(l-cyclobutylpiperidin-4-yl)oxy]-5,6,7,8-tetrahydro- 1,6-naphthyridine hydrochloride salt (31 mg, 0.109 mmol) and 3,3-dimethylbutanoyl chloride (23 μl, 0.164 mmol) gave the title compound (16.2 mg, 38%) as colourless oil. LCMS data: Calculated MH ⁺ (386); Found 97 % m/z 386, Rt = 5.1 min. 1H NMR (500 MHz, CHLOROFORM-^) δ ppm 7.35 (1 H, d, J=8.3 Hz), 6.56 (1 H, d, J=8.4 Hz), 5.41 (1 H, br. s.), 4.54 - 4.74 (2 H, m), 3.71 - 3.96 (2 H, m), 3.43 (3 H, br. s.), 2.74 - 2.93 (4 H, m), 2.51 - 2.70 (2 H, m), 2.31 - 2.42 (4 H, m), 2.11 - 2.30 (5 H, m), 1.94 (1 H, d, J=10.5 Hz), 1.68 - 1.84 (1 H, m), 1.00 - 1.12 (9 H, m).

Example 5 - Preparation of 6-(cyclobutylcarbonyl)-2-[(l- cyclobutylpiperidin-4-yl)oxy] -5,6,7,8-tetrahydro- 1 ,6-naphthyridine.

In a similar fashion (Route 5, GP D), 2-[(l-cyclobutylpiperidin-4-yl)oxy]-5,6,7,8-tetrahydro-

1,6-naphthyridine hydrochloride salt (31 mg, 0.109 mmol) and cyclobutanecarbonyl chloride

(19 μl, 0.164 mmol) gave the title compound ( 28.2 mg, 70%) as colourless oil.

LCMS data: Calculated MH ⁺ (370); Found 91 % m/z 370, Rt = 4.7 min.

¹ H NMR (500 MHz, CHLOROFORM-J) δ ppm 7.29 - 7.44 (1 H, m), 6.56 (1 H, d, J=8.4 Hz),

5.40 (1 H, br. s.), 4.33 - 4.72 (2 H, m), 3.60 - 3.91 (2 H, m), 3.24 - 3.48 (4 H, m), 2.82 (3 H, t,

J=5.0 Hz), 2.51 - 2.67 (2 H, m), 2.10 - 2.46 (10 H, m), 1.64 - 2.08 (5 H, m).

Example 6 - Preparation of 2-[(l-cyclobutylpiperidin-4-yl)oxy]-6-(2- methylpropanoyl)-5,6,7,8-tetrahydro- 1 ,6-naphthyridine.

In a similar fashion (Route 5, GP D), 2-[(l-cyclobutylpiperidin-4-yl)oxy]-5,6,7,8-tetrahydro- 1,6-naphthyridine hydrochloride salt (31 mg, 0.109 mmol) and 2-methylpropanoyl chloride (17 μl, 0.164 mmol) gave the title compound (21.2 mg, 54%) as colourless oil. LCMS data: Calculated MH ⁺ (358); Found 98 % m/z 358, Rt = 4.48 min. 1H NMR (500 MHz, MeOD) δ ppm 7.46 (1 H, dd, J=15.9, 8.5 Hz), 6.65 (1 H, d, J=6.1 Hz), 5.30 (1 H, br. s.), 4.56 - 4.57 (1 H, m), 4.52 - 4.70 (2 H, m), 3.77 - 3.90 (2 H, m), 3.69 (1 H, quin, J=8.3 Hz), 3.24 - 3.29 (3 H, m), 2.94 - 3.08 (2 H, m), 2.70 - 2.92 (2 H, m), 2.15 - 2.37 (6 H, m), 1.68 - 1.94 (3 H, m), 0.99 - 1.15 (6 H, m).

Example 7 - Preparation of 2-[(l-cyclobutylpiperidin-4-yl)oxy]-6-

(cyclopentylcarbonyl)-5,6,7,8-tetrahydro- 1 ,6-naphthyridine.

In a similar fashion (Route 5, GP D), 2-[(l-cyclobutylpiperidin-4-yl)oxy]-5,6,7,8-tetrahydro- 1,6-naphthyridine hydrochloride salt (31 mg, 0.109 mmol) and cyclopentanecarbonyl chloride (20 μl, 0.164 mmol) gave the title compound (21.4 mg, 50%) as colourless oil. LCMS data: Calculated MH ⁺ (384); Found 99 % m/z 384, Rt = 4.97 min. ¹ H NMR (500 MHz, MeOD) δ ppm 7.46 (1 H, dd, J=17.1, 8.3 Hz), 6.65 (1 H, br. s.), 5.30 (1 H, br. s.), 4.54 - 4.70 (2 H, m), 3.78 - 3.91 (2 H, m), 3.69 (1 H, t, J=8.3 Hz), 3.27 (4 H, s), 3.13 (2 H, dd, J=15.1, 7.4 Hz), 2.70 - 2.92 (2 H, m), 2.12 - 2.39 (6 H, m), 1.52 - 1.95 (11 H, m).

Example 8 - Preparation of 2-[(l-cyclobutylpiperidin-4-yl)oxy]-6-

(phenylcarbonyl)-5,6,7,8-tetrahydro- 1 ,6-naphthyridine.

In a similar fashion (Route 5, GP D), 2-[(l-cyclobutylpiperidin-4-yl)oxy]-5,6,7,8-tetrahydro- 1,6-naphthyridine hydrochloride salt (60 mg, 0.186 mmol) and benzoyl chloride (32 μl 0.279 mmol) gave the title compound (48.7 mg, 67%) as white solid after purification by SCX column.

LCMS data: Calculated MH ⁺ (392); Found 100 % m/z 392, Rt = 5.07 min (High pH).

¹ H NMR (500 MHz, CHLOROFORM- d) δ ppm 7.45 (6 H, br. s.), 6.58 (1 H, br. s.), 5.22 (1 H, br. s.), 4.33 - 4.91 (2 H, m), 3.59 - 4.18 (2 H, m), 2.98 - 3.16 (2 H, m), 2.78 (5 H, br. s.),

1.59 - 2.21 (8 H, m), 1.37 (2 H, t, J=7.3 Hz).

Example 9 - Preparation of 2-[(l-cyclobutylpiperidin-4-yl)oxy]-6-(3- methylbutanoyl)-5,6,7,8-tetrahydro- 1 ,6-naphthyridine.

In a similar fashion (Route 5, GP D), 2-[(l-cyclobutylpiperidin-4-yl)oxy]-5,6,7,8-tetrahydro- 1,6-naphthyridine hydrochloride salt (60 mg, 0.186 mmol) and 3-methylbutanoyl chloride (34 μl 0.279 mmol) gave the title compound (34.9 mg, 50%) as colourless oil after purification by SCX column. LCMS data: Calculated MH ⁺ (372); Found 99 % m/z 372, Rt = 5.1 min (High pH).

¹ H NMR (500 MHz, MeOD) δ ppm 7.37 - 7.55 (1 H, m), 6.66 (1 H, d, J=8.4 Hz), 5.10 - 5.34 (1 H, m), 4.64 (2 H, d, J=12.5 Hz), 3.72 - 3.97 (2 H, m), 3.48 (1 H, s), 3.19 (2 H, q, J=7.3 Hz), 2.71 - 3.12 (4 H, m), 2.13 - 2.43 (8 H, m), 1.66 - 1.93 (2 H, m), 1.31 (2 H, t, J=7.3 Hz), 0.89 - 1.04 (7 H, m). Example 10 - Preparation of 2-[(l-cyclobutylpiperidin-4-yl)oxy]-6-

(cyclopropylacetyl)-5,6,7,8-tetrahydro- 1 ,6-naphthyridine.

In a similar fashion (Route 5, GP D), 2-[(l-cyclobutylpiperidin-4-yl)oxy]-5,6,7,8-tetrahydro- 1,6-naphthyridine hydrochloride salt (60 mg, 0.186 mmol) and cyclopropylacetyl chloride (44 mg 0.372 mmol) gave the title compound (20.1 mg, 29%) as colourless oil after purification by SCX column.

LCMS data: Calculated MH ⁺ (370); Found 89 % m/z 370, Rt = 4.8 min (High pH). 1H NMR (500 MHz, CHLOROFORM-J) δ ppm 7.34 (1 H, s), 6.57 (1 H, d, J=8.3 Hz), 4.92 - 5.21 (1 H, m), 4.40 - 4.75 (2 H, m), 3.58 - 4.00 (2 H, m), 2.54 - 2.99 (6 H, m), 2.28 - 2.46 (2 H, m), 2.06 (5 H, br. s.), 1.85 (3 H, br. s.), 0.95 - 1.43 (4 H, m), 0.59 (2 H, br. s.), 0.22 (2 H, d, J=5.1 Hz).

Example 11 - Preparation of 2-[(l-cyclobutylpiperidin-4-yl)oxy]-6-(2- methylbutanoyl)-5,6,7,8-tetrahydro- 1 ,6-naphthyridine.

In a similar fashion (Route 5, GP D), 2-[(l-cyclobutylpiperidin-4-yl)oxy]-5,6,7,8-tetrahydro- 1,6-naphthyridine hydrochloride salt (31 mg, 0.109 mmol) and 2-methylbutanoyl chloride (20 μl, 0.164 mmol) gave the title compound (22.5 mg, 56%) as colourless oil. LCMS data: Calculated MH ⁺ (372); Found 98 % m/z 372, Rt = 4.76 min.

¹ H NMR (500 MHz, MeOD) δ ppm 7.46 (1 H, dd, J=14.4, 8.5 Hz), 6.65 (1 H, br. s.), 5.33 (1 H, br. s.), 4.46 - 4.75 (1 H, m), 3.76 - 3.95 (2 H, m), 3.69 (1 H, quin, J=8.3 Hz), 3.34 - 3.61 (1 H, m), 3.27 (3 H, s), 3.05 (2 H, br. s.), 2.71 - 2.92 (3 H, m), 2.14 - 2.38 (6 H, m), 1.73 - 1.92 (3 H, m), 1.53 - 1.72 (1 H, m), 1.31 - 1.47 (1 H, m), 0.97 - 1.13 (3 H, m), 0.71 - 0.90 (3 H, m).

Example 12 - Preparation of 2-[(l-cyclobutylpiperidin-4-yl)oxy]-6-[(4- fluorophenyl)carbonyl] -5,6,7,8-tetrahydro- 1 ,6-naphthyridine.

In a similar fashion (Route 5, GP D), 2-[(l-cyclobutylpiperidin-4-yl)oxy]-5,6,7,8-tetrahydro- 1,6-naphthyridine hydrochloride salt (40 mg, 0.111 mmol) and 4-fluorobenzoyl chloride (20 μl, 0.167 mmol) gave the title compound (29.2 mg, 64%) as colourless oil. LCMS data: Calculated MH ⁺ (410); Found 98 % m/z 410, Rt = 4.92 min (High pH). 1H NMR (250 MHz, MeOD) δ ppm 7.41 - 7.70 (3 H, m), 7.06 - 7.31 (2 H, m), 6.36 - 6.86 (1 H, m), 5.07 - 5.52 (1 H, m), 4.40 - 4.82 (2 H, m), 3.60 - 4.20 (3 H, m), 2.72 - 3.20 (5 H, m), 1.67 - 2.54 (11 H, m).

Example 13 - Preparation of 2-[(l-cyclobutylpiperidin-4-yl)oxy]-6-[(2- fluorophenyl)carbonyl] -5,6,7,8-tetrahydro- 1 ,6-naphthyridine.

In a similar fashion (Route 5, GP D), 2-[(l-cyclobutylpiperidin-4-yl)oxy]-5,6,7,8-tetrahydro- 1,6-naphthyridine hydrochloride salt (40 mg, 0.111 mmol) and 2-fluorobenzoyl chloride (20 μl, 0.167 mmol) gave the title compound (10.8 mg, 24%) as colourless oil. LCMS data: Calculated MH ⁺ (410); Found 100 % m/z 410, Rt = 4.89 min (High pH).

¹ H NMR (250 MHz, MeOD) δ ppm 7.02 - 7.71 (5 H, m), 6.44 - 6.74 (1 H, m), 5.05 (1 H, dd, J=7.6, 4.0 Hz), 4.33 - 4.85 (2 H, m), 3.55 - 4.21 (2 H, m), 2.49 - 3.08 (5 H, m), 1.52 - 2.43 (12 H, m).

Example 14 - Preparation of 2-[(l-cyclobutylpiperidin-4-yl)oxy]-6-[(4- methoxyphenyl)carbonyl] -5,6,7,8-tetrahydro- 1,6-naphthyridine.

In a similar fashion (Route 5, GP D), 2-[(l-cyclobutylpiperidin-4-yl)oxy]-5,6,7,8-tetrahydro- 1,6-naphthyridine hydrochloride salt (40 mg, 0.111 mmol) and 4-methoxybenzoyl chloride (23 μl, 0.167 mmol) gave the title compound (13.8 mg, 30%) as colourless oil.

LCMS data: Calculated MH ⁺ (422); Found 99 % m/z 422, Rt = 4.85 min (High pH). 1H NMR (250 MHz, MeOD) δ ppm 7.28 - 7.57 (3 H, m), 6.88 - 7.16 (2 H, m), 6.47 - 6.75 (1 H, m), 5.00 - 5.31 (1 H, m), 4.69 (2 H, br. s.), 3.63 - 4.11 (5 H, m), 3.14 (1 H, d, J=7.3 Hz), 2.90 (4 H, t, J=5.9 Hz), 2.57 (2 H, br. s.), 1.57 - 2.32 (10 H, m). Example 15 - Preparation of 2-[(l-cyclobutylpiperidin-4-yl)oxy]-6-[(6- methylpyridin-3-yl)carbonyl] -5,6,7,8-tetrahydro- 1 ,6-naphthyridine.

In a similar fashion (Route 5, GP D), 2-[(l-cyclobutylpiperidin-4-yl)oxy]-5,6,7,8-tetrahydro- 1,6-naphthyridine hydrochloride salt (5Og, 0.139mol) and 6-methylpyridine-3-carbonyl chloride (32 mg, 0.208 mmol) gave the title compound (19 mg, 34%) as colourless oil. LCMS data: Calculated MH ⁺ (407); Found 100% m/z 407, Rt = 4.21 min (High pH). ¹ H NMR (500 MHz, CHLOROFORM-J) δ ppm 8.61 (1 H, br. s.), 7.71 (1 H, d, J=7.7 Hz), 6.99 - 7.45 (2 H, m), 6.59 (1 H, br. s.), 5.17 (1 H, br. s.), 4.36 4.90 (2 H, m), 3.60 - 4.15 (2 H, m), 2.40 - 3.08 (10 H, m), 1.56 - 2.27 (10 H, m).

Example 16 - Preparation of 2-[(l-cyclobutylpiperidin-4-yl)oxy]-6-

(trifluor oacetyl)-5,6,7,8-tetrahydro- 1 ,6-naphthyridine.

In a similar fashion (Route 5, GP D), 2-[(l-cyclobutylpiperidin-4-yl)oxy]-5,6,7,8-tetrahydro-

1,6-naphthyridine TFA salt (55 mg, 0.107 mmol) and trifluoroacetic anhydride (30 μl, 0.210 mmol) gave the title compound (10 mg, 24%) as colourless oil.

LCMS data: Calculated MH ⁺ (384); Found 92 % m/z 288, [M - C(O)CF ₃ + 2H] ⁺ (High pH).

¹ H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.19 (1 H, d, J=8.4 Hz), 6.50 (1 H, d, J=8.4 Hz), 5.00 - 5.07 (1 H, m), 3.91 (2 H, s), 3.18 (2 H, t, J=6.0 Hz), 2.78 (2 H, t, J=6.1 Hz), 2.74

(1 H, q), 2.64 (2 H, br. s.), 2.18 (2 H, br. s.), 2.00 - 2.08 (4 H, m), 1.86 - 1.95 (2 H, m), 1.76 -

1.84 (4 H, m), 1.64 - 1.73 (2 H, m).

Route 6

General

General Procedure E: Example 17 - Preparation of 2-[(l-cyclobutylpiperidin-4-yl)oxy]-6-

(methylsulfonyl)-5,6,7,8-tetrahydro-l,6-naphthyridine.

To a solution of 2-[(l-cyclobutylpiperidin-4-yl)oxy]-5,6,7,8-tetrahydro-l,6-n aphthyridine (50 mg, 0.139 mmol) in DCM (2 ml) under N ₂ was added NEt ₃ (0.44 mmol) and methanesulfonyl chloride (29 μl, 0.288 mmol). The mixture was stirred at RT for 3h before the volatiles were removed under reduced pressure. The residue was purified by preparative HPLC to give the desired product as a TFA salt. The resulting salt was diluted in DCM, loaded onto a SCX column, washed with DCM (2 x 2 ml), MeOH (2 x 2 ml) then eluted with 2N NH ₃ /MeOH in DCM. The collected fractions were concentrated at reduced pressure to give the title compound (14.1 mg, 28%) as white hygroscopic solid.

LCMS data: Calculated MH ⁺ (366); Found 98 % m/z 366, Rt = 4.29 min (High pH). 1H NMR (500 MHz, CHLOROFORM-J) δ ppm 7.26 - 7.30 (1 H, m), 6.56 (1 H, d, J=8.4 Hz), 5.07 (1 H, br. s.), 4.36 (2 H, s), 3.61 (2 H, t, J=6.1 Hz), 2.96 (2 H, t, J=5.9 Hz), 2.54 - 2.90 (6 H, m), 1.43 - 2.26 (12 H, m).

The following compounds were prepared as described in Route 6, General Procedure E above.

Example 18 - Preparation of 2-[(l-cyclobutylpiperidin-4-yl)oxy]-6- (cyclopr opylsulfonyl)-5,6,7,8-tetrahydro- 1 ,6-naphthyridine.

In a similar fashion (Route 6, GP E), 2-[(l-cyclobutylpiperidin-4-yl)oxy]-5,6,7,8-tetrahydro- 1,6-naphthyridine (55 mg, 0.192 mmol) and cyclopropanesulfonyl chloride (29 μl, 0.288 mmol) gave the title compound (18 mg, 24%) as colourless oil. LCMS data: Calculated MH ⁺ (392); Found 100 % m/z 392, Rt = 4.84 min (High pH).

¹ H NMR (500 MHz, CHLOROFORM- d) δ ppm 7.31 (1 H, d, J=8.4 Hz), 6.57 (1 H, d, J=8.4 Hz), 5.41 (1 H, br. s.), 4.44 (2 H, s), 3.67 (2 H, t, J=6.0 Hz), 3.32 - 3.52 (3 H, m), 2.97 (2 H, t, J=5.9 Hz), 2.84 (2 H, br. s.), 2.52 - 2.67 (2 H, m), 2.29 - 2.41 (3 H, m), 2.15 - 2.28 (4 H, m), 1.77 (I H, d, J=10.5 Hz), 1.17 - 1.30 (3 H, m), 0.95 - 1.05 (2 H, m). Example 19 - Preparation of 2-[(l-cyclobutylpiperidin-4-yl)oxy]-6-

(phenylsulfonyl)-5,6,7,8-tetrahydro- 1 ,6-naphthyridine.

In a similar fashion (Route 6, GP E), 2-[(l-cyclobutylpiperidin-4-yl)oxy]-5,6,7,8-tetrahydro- 1,6-naphthyridine hydrochloride salt (60 mg, 0.186 mmol) and benzenesulfonyl chloride (35 μl, 0.279 mmol) gave the title compound (27.2 mg, 27%) as colourless oil after purification by preparative HPLC.

LCMS data: Calculated MH ⁺ (428); Found 95 % m/z 428, Rt = 5.50 min (High pH). 1H NMR (500 MHz, MeOD) δ ppm 7.82 (2 H, d, J=7.5 Hz), 7.60 - 7.67 (1 H, m), 7.51 - 7.59 (2 H, m), 7.33 - 7.44 (1 H, m), 6.50 - 6.67 (1 H, m), 5.06 - 5.34 (1 H, m), 4.15 (2 H, s), 3.58 - 3.75 (1 H, m), 3.39 (2 H, t, J=6.1 Hz), 3.27 (2 H, d, J=1.5 Hz), 2.87 - 3.08 (2 H, m), 2.82 (2 H, q, J=5.6 Hz), 2.12 - 2.41 (6 H, m), 1.60 - 2.06 (4 H, m).

Example 20 - Preparation of 2-[(l-cyclobutylpiperidin-4-yl)oxy]-6- (ethylsulfonyl)-5,6,7,8-tetrahydro- 1 ,6-naphthyridine.

In a similar fashion (Route 6, GP E), 2-[(l-cyclobutylpiperidin-4-yl)oxy]-5,6,7,8-tetrahydro- 1,6-naphthyridine TFA salt (55 mg, 0.107 mmol) and ethanesulfonyl chloride (22 μl, 0.210 mmol) gave the title compound (6 mg, 15%) as colourless oil. LCMS data: Calculated MH ⁺ (380); Found 98 % m/z 380, Rt = 4.52 min (High pH).

¹ H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.25 (1 H, d, J=8.4 Hz), 6.57 (1 H, d, J=8.4 Hz), 5.06 (1 H, br. s.), 4.41 (2 H, s), 3.66 (2 H, t, J=6.1 Hz), 3.03 (2 H, q, J=7.3 Hz), 2.94 (2 H, t, J=5.9 Hz), 2.66 (3 H, br. s.), 2.22 (2 H, br. s.), 2.01 - 2.10 (4 H, m), 1.88 - 1.98 (2 H, m), 1.83 (2 H, br. s.), 1.64 - 1.76 (2 H, m), 1.38 (3 H, t, J=7.4 Hz).

Example 21 - Preparation of 2-[(l-cyclobutylpiperidin-4-yl)oxy]-6-[(l- methylethyl)sulfonyl] -5,6,7,8- tetrahydro- 1,6-naphthyridine.

In a similar fashion (Route 6, GP E), 2-[(l-cyclobutylpiperidin-4-yl)oxy]-5,6,7,8-tetrahydro- 1,6-naphthyridine TFA salt (55 mg, 0.107 mmol) and propane-2-sulfonyl chloride (24 μl, 0.210 mmol) gave the title compound (12 mg, 29%) as colourless oil. LCMS data: Calculated MH ⁺ (394); Found 97 % m/z 394, Rt = 4.79 min (High pH). 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.24 (1 H, d, J=8.4 Hz), 6.56 (1 H, d, J=8.4 Hz), 5.05 (1 H, br. s.), 4.44 (2 H, s), 3.68 (2 H, t, J=5.9 Hz), 3.22 - 3.30 (1 H, m), 2.93 (2 H, t, J=6.0 Hz), 2.75 (1 H, d, J=7.9 Hz), 2.65 (2 H, br. s.), 2.18 (2 H, br. s.), 2.00 - 2.09 (4 H, m), 1.88 (2 H, br. s.), 1.78 - 1.85 (2 H, m), 1.63 - 1.75 (2 H, m), 1.37 (6 H, d, J=7.0 Hz).

Example 22 - Preparation of 2-[(l-cyclobutylpiperidin-4-yl)oxy]-6-

(cyclopentylsulfonyl)-5,6,7,8-tetrahydro- 1 ,6-naphthyridine.

In a similar fashion (Route 6, GP E), 2-[(l-cyclobutylpiperidin-4-yl)oxy]-5,6,7,8-tetrahydro-

1,6-naphthyridine hydrochloride salt (40 mg, 0.111 mmol) and cyclopentanesulfonyl chloride (29 μl, 0.223 mmol) gave the title compound (7 mg, 15%) as colourless oil.

LCMS data: Calculated MH ⁺ (420); Found 96 % m/z 420, Rt = 5.17 min (High pH).

¹ H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.13 - 7.33 (1 H, m), 6.56 (1 H, d, J=8.4 Hz),

5.07 (1 H, br. s.), 4.42 (2 H, s), 3.66 (2 H, t, J=5.9 Hz), 3.41 - 3.59 (1 H, m), 2.48 - 3.01 (5 H, m), 1.43 - 2.14 (20 H, m).

Example 23 - Preparation of 2-[(l-cyclobutylpiperidin-4-yl)oxy]-6-[(2- fluorophenyl)sulfonyl]-5,6,7,8-tetrahydro-l,6-naphthyridine.

In a similar fashion (Route 6, GP E), 2-[(l-cyclobutylpiperidin-4-yl)oxy]-5,6,7,8-tetrahydro- 1,6-naphthyridine hydrochloride salt (40 mg, 0.111 mmol) and 2-fluorobenzenesulfonyl chloride (33 mg, 0.167 mmol) gave the title compound (16 mg, 32%) as colourless oil.

LCMS data: Calculated MH ⁺ (446); Found 97 % m/z 446, Rt = 5.30 min (High pH).

¹ H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.86 - 7.98 (1 H, m), 7.52 - 7.61 (1 H, m),

7.27 - 7.34 (1 H, m), 7.14 - 7.25 (2 H, m), 6.53 (1 H, d, J=8.4 Hz), 5.03 (1 H, br. s.), 4.33 (2 H, s), 3.61 (2 H, t, J=5.9 Hz), 2.90 (2 H, t, J=5.9 Hz), 2.56 - 2.83 (3 H, m), 1.57 - 2.10 (12 H, m). Example 24 - Preparation of 2-[(l-cyclobutylpiperidin-4-yl)oxy]-6-[(3- fluorophenyl)sulfonyl]-5,6,7,8-tetrahydro-l,6-naphthyridine.

In a similar fashion (Route 6, GP E), 2-[(l-cyclobutylpiperidin-4-yl)oxy]-5,6,7,8-tetrahydro- 1,6-naphthyridine hydrochloride salt (40 mg, 0.111 mmol) and 3-fluorobenzenesulfonyl chloride (33 mg, 0.167 mmol) gave the title compound (6 mg, 12%) as colourless oil. LCMS data: Calculated MH ⁺ (446); Found 96 % m/z 446, Rt = 5.40 min (High pH). 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.64 (1 H, d, J=7.9 Hz), 7.49 - 7.59 (2 H, m), 7.31 (1 H, td, J=8.2, 2.1 Hz), 7.22 (1 H, d, J=8.4 Hz), 6.53 (1 H, d, J=8.4 Hz), 5.03 (1 H, br. s.), 4.20 (2 H, s), 3.45 (2 H, t, J=6.0 Hz), 2.92 (2 H, t, J=6.0 Hz), 2.55 - 2.85 (3 H, m), 1.58 - 2.11 (12 H, m).

Example 25 - Preparation of 2-[(l-cyclobutylpiperidin-4-yl)oxy]-6-[(4- fluorophenyl)sulfonyl]-5,6,7,8-tetrahydro-l,6-naphthyridine.

In a similar fashion (Route 6, GP E), 2-[(l-cyclobutylpiperidin-4-yl)oxy]-5,6,7,8-tetrahydro- 1,6-naphthyridine hydrochloride salt (40 mg, 0.111 mmol) and 4-fluorobenzenesulfonyl chloride (33 mg, 0.167 mmol) gave the title compound (9 mg, 18%) as colourless oil. LCMS data: Calculated MH ⁺ (446); Found 97 % m/z 446, Rt = 5.33 min (High pH).

¹ H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.77 - 7.95 (2 H, m), 7.16 - 7.26 (3 H, m), 6.53 (1 H, d, J=8.4 Hz), 5.02 (1 H, br. s.), 4.17 (2 H, s), 3.43 (2 H, t, J=6.1 Hz), 2.91 (2 H, t, J=6.0 Hz), 2.57 - 2.83 (3 H, m), 1.53 - 2.11 (12 H, m).

Example 26 - Preparation of 2-[(l-cyclobutylpiperidin-4-yl)oxy]-6-[(4- methoxyphenyl)sulfonyl] -5,6,7,8- tetrahydro-l,6-naphthyridine.

In a similar fashion (Route 6, GP E), 2-[(l-cyclobutylpiperidin-4-yl)oxy]-5,6,7,8-tetrahydro- 1,6-naphthyridine hydrochloride salt (40 mg, 0.111 mmol) and 4-methoxybenzenesulfonyl chloride (34 mg, 0.167 mmol) gave the title compound (19 mg, 37%) as colourless oil. LCMS data: Calculated MH ⁺ (458); Found 99 % m/z 458, Rt = 5.26 min (High pH). 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.68 - 7.86 (2 H, m), 7.20 (1 H, d, J=8.4 Hz), 7.00 (2 H, d, J=9.0 Hz), 6.51 (1 H, d, J=8.4 Hz), 5.01 (1 H, br. s.), 4.14 (2 H, s), 3.87 (3 H, s), 3.26 - 3.44 (5 H, m), 2.91 (2 H, t, J=5.9 Hz), 2.49 - 2.85 (3 H, m), 1.84 - 2.29 (10 H, m).

Route 7

General

General Procedure F:

Example 27 - Preparation of 2-[(l-cyclobutylpiperidin-4-yl)oxy]-6- (piperidin-l-ylcarbonyl)-5,6,7,8-tetrahydro-l,6-naphthyridin e.

To a solution of 2-[(l-cyclobutylpiperidin-4-yl)oxy]-5,6,7,8-tetrahydro-l,6-n aphthyridine hydrochloride salt (40 mg, 0.111 mmol) in DCM (2 ml) under N ₂ was added NEt ₃ (0.44 mmol) and piperidine-1-carbonyl chloride (21 μl, 0.167 mmol). The mixture was stirred at RT for 3h before the volatiles were removed under reduced pressure. The residue was purified by preparative HPLC to give the desired product as a TFA salt. The resulting salt was diluted in DCM, loaded onto a SCX column, washed with DCM (2 x 2 ml), MeOH (2 x 2 ml) then eluted with 2N NH ₃ ZMeOH in DCM. The collected fractions were concentrated at reduced pressure to give the title compound (13.6 mg, 31%) as colourless oil. LCMS data: Calculated MH ⁺ (399); Found 100 % m/z 399, Rt = 5.08 min (High pH).

¹ H NMR (250 MHz, MeOD) δ ppm 7.41 (1 H, d, J=8.5 Hz), 6.59 (1 H, d, J=8.4 Hz), 5.05 (1 H, dt, J=7.8, 3.9 Hz), 4.32 (2 H, s), 3.42 - 3.64 (2 H, m), 3.28 (4 H, br. s.), 2.81 - 3.02 (3 H, m), 2.60 - 2.81 (2 H, m), 2.31 (2 H, br. s.), 1.45 - 2.20 (16 H, m). Route 8

Example 28 - Preparation of 2-[(l-cyclobutylpiperidin-4-yl)oxy]-N-(l- methylethyl)-7,8-dihydro- 1 ,6-naphthyridine-6(5H)-carboxamide.

To a solution of 2-[(l-cyclobutylpiperidin-4-yl)oxy]-5,6,7,8-tetrahydro-l,6-n aphthyridine hydrochloride salt (40 mg, 0.111 mmol) in DCM (2 ml) under N ₂ was added NEt ₃ (0.44 mmol) and 2-isocyanatopropane (13 μl, 0.167 mmol). The mixture was stirred at RT for 3h before the volatiles were removed under reduced pressure. The residue was purified by preparative HPLC to give the desired product as a TFA salt. The resulting salt was diluted in DCM, loaded onto a SCX column, washed with DCM (2 x 2 ml), MeOH (2 x 2 ml) then eluted with 2N NH ₃ ZMeOH in DCM. The collected fractions were concentrated at reduced pressure to give the title compound (19.5 mg, 47%) as colourless oil. LCMS data: Calculated MH ⁺ (373); Found 99% m/z 373, Rt = 4.35 min (High pH). 1H NMR (250 MHz, MeOD) δ ppm 7.41 (1 H, d, J=8.4 Hz), 6.60 (1 H, d, J=8.4 Hz), 5.09 (1 H, dt, J=7.5, 3.7 Hz), 4.45 (2 H, s), 3.91 (1 H, dt, J=13.2, 6.6 Hz), 3.78 (1 H, dt, J=13.1, 6.5 Hz), 3.68 (2 H, t, J=5.9 Hz), 3.02 (1 H, quin, J=7.9 Hz), 2.80 (4 H, t, J=5.8 Hz), 2.46 (2 H, br. s.), 1.57 - 2.24 (10 H, m), 1.16 (3 H, d, J=6.5 Hz), 1.09 (3 H, d, J=6.4 Hz).

Route 9 -Et ₃ ³ ,. R- -T-^ General Procedure G:

Example 29 - Preparation of methyl 2-[(l-cyclobutylpiperidin-4-yl)oxy]-

7,8-dihydro- 1 ,6-naphthyridine-6(5H)-carboxylate.

To a solution of 2-[(l-cyclobutylpiperidin-4-yl)oxy]-5,6,7,8-tetrahydro-l,6-n aphthyridine TFA salt (55 mg, 0.107 mmol) in DCM (2 ml) under N ₂ was added NEt ₃ (60 μL, 0.427 mmol) and methyl chlorocarbonate (30 μl, 0.260 mmol). The mixture was stirred at RT for 3h before the volatiles were removed under reduced pressure. The residue was purified by preparative HPLC to give the desired product as a TFA salt. The resulting salt was diluted in DCM, loaded onto a SCX column, washed with DCM (2 x 2 ml), MeOH (2 x 2 ml) then eluted with 2N NH ₃ ZMeOH in DCM. The collected fractions were concentrated at reduced pressure to give the title compound (12 mg, 33%) as colourless oil.

LCMS data: Calculated MH ⁺ (346); Found 98 % m/z 346, Rt = 4.58 min (High pH). 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.24 - 7.27 (1 H, m), 6.55 (1 H, d, J=8.4 Hz), 5.05 (1 H, br. s.), 4.52 (2 H, br. s.), 3.74 (2 H, s), 3.48 (3 H, s), 2.75 - 2.87 (3 H, m), 2.65 (2 H, br. s.), 2.22 (2 H, br. s.), 2.01 - 2.09 (4 H, m), 1.90 - 1.98 (2 H, m), 1.78 - 1.86 (2 H, m), 1.65 - 1.75 (2 H, m).

Alternatively, compounds of formula I can be synthesised by the scheme illustrated in Route 10.

Route 10

NaAuCI ₄ .2H2O bocv

Preparation of tert-butyl 7,8-dihydro-l,6-naphthyridine-6(5H)-carboxylate

To a solution of N-(t-butoxycarbonyl)-4-piperidinone (1.00 g, 5.0 mmol) and propargylamine

(0.56 ml, 10.1 mmol) in absolute ethanol (10 ml) was added sodium tetrachloroaurate (III) dihydrate (50 mg, 0.13 mmol) and the reaction was heated at 100 ⁰ C for Ih using a focussed microwave reactor. The reaction was concentrated at reduced pressure and the residue was purified by FCC (SiO ₂ , eluting with heptane/EtOAc, 1 :1 to 1 :2) to give the title compound

(0.86 g, 74%).

LCMS data (2 min method): Calculated MH ⁺ (235); Found 100% (MH ⁺ ) m/z 235, Rt = 1.03 min.

¹ U NMR (360 MHz, CHLOROFORM-J) δ ppm 1.26 - 1.29 (9 H, m) 2.79 (2 H, t, J=5.90 Hz)

3.54 (2 H, t, J=6.13 Hz) 4.38 (2 H, s) 6.91 (1 H, dd, J=7.72, 5.00 Hz) 7.19 (1 H, d, J=7.72 Hz)

8.21 (I H, d, J=4.54 Hz).

Preparation of tert-butyl 7,8-dihydro-l,6-naphthyridine-6(5H)-carboxylate 1-oxide

To a solution of tert-butyl 7,8-dihydro-l,6-naphthyridine-6(5H)-carboxylate (0.43 g, 1.83 mmol) in DCM (10 ml) at 0 ⁰ C, was added portionwise mCPBA (1.23 g, 5.51 mmol, 77%). The reaction mixture was warmed to RT and stirred for 2h. Saturated aq. sodium thiosulfate (10 ml) was added and the reaction stirred for 15 min. Saturated aq. NaHCOs (10 ml) was added, the layers separated and the aqueous phase extracted with DCM (2 x 10 ml). The combined organic phase was dried (Na ₂ SO ₄ ), filtered and concentrated at reduced pressure. The residue was purified by FCC eluting with DCM/MeOH 95:5) to give the title compound (0.45 g, 98%).

LCMS data (2 min method): Calculated MH ⁺ (251); Found 100% (MH ⁺ ) m/z 251, Rt = 1.37 min.

¹ H NMR (250 MHz, CHLOROFORM- d) δ ppm 1.46 (9 H, s) 3.05 (2 H, t, J=5.94 Hz) 3.74 (2 H, t, J=6.09 Hz) 4.59 (2 H, s) 7.01 - 7.09 (1 H, m) 7.12 - 7.18 (1 H, m) 8.21 (1 H, d, J=6.24 Hz).

Preparation of tert-butyl 2-chloro-7,8-dihydro-l,6-naphthyridine-6(5H)-carboxylate

tert-Butyl 7,8-dihydro-l,6-naphthyridine-6(5H)-carboxylate 1 -oxide (0.36 g, 1.44 mmol) was dissolved in phosphorus oxychloride (2 ml) and heated at 50 ⁰ C for 16h. The reaction mixture was poured into ice water and stirred for Ih. The aqueous solution was basified by the addition of solid NaHCO ₃ then extracted with DCM (3 x 30 ml). The organic phase was dried (Na ₂ SO ₄ ), filtered and evaporated at reduced pressure to give the chloro-7,8-dihydro-l,6- naphthyridine-6(5H) (0.125 g, 0.75 mmol) as a mixture of 2- and 4-chloroisomers. The mixture was dissolved in DCM (10 ml) and (Boc) ₂ O (0.21 g, 0.98 mmol), Et ₃ N (0.16 ml, 1.13 mmol) and DMAP (9 mg, 75μmol) were added. The reaction was stirred at RT for 3h then washed with 10 wt/v% aq. citric acid (5 ml), dried (Na ₂ SO ₄ ), filtered and concentrated at reduced pressure. The residue (0.12 g) was purified by FCC (eluting with heptane/EtOAc 9:1 to 3:1) to give the title compound (95 mg, 25%).

LCMS data (2 min method): Calculated MH ⁺ (269); Found 100% (MH ⁺ ) m/z 269, Rt = 1.34 min. 1H NMR (250 MHz, CHLOROFORM-^) δ ppm 1.42 (9 H, s) 2.90 (2 H, t, J=5.86 Hz) 3.66 (2 H, t, J=5.94 Hz) 4.49 (2 H, s) 7.09 (1 H, d, J=8.07 Hz) 7.31 (1 H, d, J=8.07 Hz). Preparation of tert-butyl 2-[(l-cyclobutylpiperidin-4-yl)oxy]-7,8-dihydro-l,6- naphthyridine-6(5H)-carboxylate

A solution of tert-butyl 2-chloro-7,8-dihydro-l,6-naphthyridine-6(5H)-carboxylate (90 mg, 0.34 mmol), l-cyclobutylpiperidin-4-ol (78 mg, 0.50 mmol) and ¹ BuOK (94 mg, 0.84 mmol) in dioxane (1.8 ml) was heated at 115°C for 40 min. in a focused microwave. The reaction was diluted with EtOAc (10 ml) and washed with water (10 ml). The organic phase was dried (Na ₂ SO ₄ ), filtered and concentrated at reduced pressure. The residue was purified by FCC (eluting with EtOAc to EtOAc/MeOH 95:5) to give the title compound (40 mg, 30%). LCMS data (2 min method): Calculated MH ⁺ (388); Found 100% (MH ⁺ ) m/z 388, Rt = 1.09 min.

¹ H NMR (250 MHz, CHLOROFORM-J) δ ppm 1.42 (9 H, s) 1.73 - 1.84 (10 H, m) 2.55 (5 H, d, J=9.14 Hz) 2.75 (2 H, t, J=5.63 Hz) 3.63 (2 H, t, J=5.79 Hz) 4.40 (2 H, s) 4.91 - 5.04 (1 H, m) 6.47 (1 H, d, J=8.22 Hz) 7.18 (1 H, d).

Preparation of 2-[(l-cyclobutylpiperidin-4-yl)oxy]-5,6,7,8-tetrahydro-l,6-n aphthyridine TFA salt

To a solution of tert-butyl 2-[(l-cyclobutylpiperidin-4-yl)oxy]-7,8-dihydro-l,6-naphthyr idine- 6(5H)-carboxylate (40 mg, 0.104 mmol) in DCM ( 2 ml) was added trifluoroacetic acid (0.4 ml). The reaction was stirred at RT for 4 h then concentrated at reduced pressure to give the crude TFA salt, which was used in the next step without purification.

Example 30 - Preparation of 2-[(l-cyclobutylpiperidin-4-yl)oxy]-N-ethyl- 7,8-dihydro- 1 ,6-naphthyridine-6(5H)-carboxamide.

To a solution of 2-[(l-cyclobutylpiperidin-4-yl)oxy]-5,6,7,8-tetrahydro-l,6-n aphthyridine TFA salt (40 mg, 0.104 mmol) in DCM (2 ml) under N ₂ was added NEt ₃ (0.44 mmol) and ethyl isocyanate (8 μl, 0.102 mmol). The mixture was stirred at RT for 3h before the volatiles were removed under reduced pressure. The residue was purified by FCC (SiO ₂ , eluting with DCM/MeOH/NH ₃ , 90:10:1) to give the title compound (17 mg, 48%) as colourless oil. LCMS data (high pH method): Calculated MH ⁺ (359); Found 100% (M ⁺ ) m/z 359, Rt = 4.24 min.

¹ H NMR (500 MHz, CHLOROFORM-J) δ ppm 1.10 (3 H, t, J=7.20 Hz) 1.54 - 1.69 (2 H, m) 1.75 (2 H, br. s.) 1.87 (2 H, d, J=19.81 Hz) 1.94 - 2.04 (4 H, m) 2.10 (2 H, br. s.) 2.59 (2 H, br. s.) 2.66 - 2.74 (1 H, m) 2.79 (2 H, t, J=5.82 Hz) 3.20 - 3.29 (2 H, m) 3.59 (2 H, t, J=5.91 Hz) 4.34 - 4.45 (3 H, m) 4.99 (1 H, br. s.) 6.48 (1 H, d, J=8.44 Hz) 7.18 - 7.23 (1 H, m).

Route 11

Preparation of l-(2-chloro-7,8-dihydro-l,6-naphthyridin-6(5H)-yl)ethanone

Acetic anhydride (0.23 mL, 2.44 mmol) was added to a solution of 2-chloro-5,6,7,8- tetrahydro-l,6-naphthyridine hydrochloride (0.50 g, 2.44 mmol) and DIPEA (0.85 mL, 4.88 mmol) in pyridine (5 mL) at RT. The reaction mixture was heated at 30 ⁰ C for 6 h, then diluted with DCM (60 mL) and washed with saturated aq. NaHCO ₃ (3 x 30 mL), dried (MgSO ₄ ), filtered and concentrated at reduced pressure. The residue was purified by FCC (eluting with 99:1 to 95:5 DCM/MeOH) to give the title compound (0.394 g, 77%) as brown oil.

LCMS data (3 min method): Calculated MH ⁺ (211); Found 100% (M ⁺ ) m/z 211, Rt = 1.32 min. ¹ H NMR (500 MHz, CHLOROFORM- d) δ ppm 2.07 (3 H, s) 2.91 (2 H, t) 3.67 (2 H, t, J=5.95 Hz) 4.56 (2 H, s) 7.06 (1 H, d, J=8.24 Hz) 7.31 (1 H, d, J=7.93 Hz).

Preparation of l-(2-chloro-l-oxido-7,8-dihydro-l,6-naphthyridin-6(5H)-yl)et hanone

Trifluoroacetic anhydride (0.86 rnL, 6.19 mmol) was added to a solution of l-(2-chloro-7,8- dihydro-l,6-naphthyridin-6(5H)-yl)ethanone (0.65 g, 3.09 mmol) and urea hydrogen peroxide (0.61 g, 6.49 mmol) in acetonitrile (30 mL) at RT. The reaction was stirred overnight for approximately 16 h, then diluted with DCM (40 mL) and washed with saturated aq. NaHCO ₃ (2 x 20 mL), dried (MgSO ₄ ), filtered and concentrated at reduced pressure. The residue was purified by FCC (eluting with 99:1 to 95:5 DCM/MeOH) to give the title compound (200 mg, 28%) as white solid.

¹ H NMR (500 MHz, CHLOROFORM-^) δ ppm 2.23 (3 H, s) 3.15 - 3.21 (2 H, m) 3.81 (2 H, t, J=6.10 Hz) 4.77 (2 H, s) 7.03 (1 H, d, J=8.24 Hz) 7.42 (1 H, d, J=8.54 Hz).

Example 31 - Preparation of 6-acetyl-2-[(l-cyclobutylpiperidin-4-yl)oxy] -5,6,7,8- tetrahydro-l,6-naphthyridine 1-oxide.

A solution of ¹ BuOK (0.21 mL, 0.38 mmol, 1.8 M in THF) was added to a solution of l-(2- chloro-l-oxido-7,8-dihydro-l,6-naphthyridin-6(5H)-yl)ethanon e (0.058 g, 0.26 mmol) and 1- cyclobutylpiperidin-4-ol (0.050 g, 0.32 mmol) in dioxane at RT. The reaction mixture was heated at 90 ⁰ C for 1 h in a focused microwave (200W). The reaction mixture was passed through an acidic SCX-2 column eluting first with methanol, then with 2M NH ₃ in MeOH.

The evaporated residue was purified by preparative HPLC (high pH method) to give the title compound (60 mg, 21%) as brown oil.

LCMS data (high pH Method D): Calculated MH ⁺ (346); Found 100% (MH ⁺ ) m/z 346, Rt = 3.11 min.

¹ H NMR (500 MHz, METHANOL-^) δ ppm 1.67 - 1.80 (2 H, m) 1.88 - 2.00 (4 H, m) 2.06 - 2.14 (4 H, m) 2.18 - 2.25 (3 H, m) 2.26 - 2.36 (2 H, m) 2.68 - 2.78 (2 H, m) 2.82 - 2.92 (1 H, m) 3.00 - 3.07 (1 H, m) 3.11 - 3.17 (1 H, m) 3.84 - 3.96 (2 H, m) 4.71 - 4.75 (2 H, m) 4.77 - 4.84 (1 H, m) 7.20 - 7.26 (1 H, m) 7.44 (1 H, d, J=8.85 Hz).