WO2010052222A1 - (dihydro)naphthyridinone derivatives as histamine h3 receptor antagonists - Google Patents

Abstract

The invention relates to compounds of formula (I), wherein X^1a, X^2a, X¹ to X⁵, n and R have the meaning as cited in the description and the claims. Said compounds are useful as Histamine H3 receptor antagonists. The invention also relates to pharmaceutical compositions, the preparation of such compounds as well as the production and use as medicament.

Description

(Dihydro)naphthyridinone derivatives 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 cyclylhexyl 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.

WO-A 2005/111036 and WO-A 2006/138714 describe tetrahydronaphthyridine derivatives useful as histamine H3 receptor ligands. An individual compound as H3 ligand is disclosed in WO-A 2007/052124.

WO-A 2002/076925 discloses non- imidazole aryl alkylamine compounds as histamine H3 receptor antagonists.

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

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 X¹— X^la, X²— X^2a is C(RV ^a)-C(RV ^b); or C(R^a)=C(R^b); and the other is N(R¹VC(O), provided that N(R¹) represents X¹ or X²; R^a, R^b, R^la, R^lb 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;

Optionally at least one of the pairs R^a/R^la, R^b/R^lb is joined together with the carbon atom to which they are attached to form C₃_₅ cycloalkyl, wherein C₃_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;

R¹ is H; Ci_7 alkyl; C2-7 alkenyl; C2-7 alkynyl; or T, wherein Ci_7 alkyl; C2-7 alkenyl; and C2-7 alkynyl are optionally substituted with one or more R^lc, which are the same or different;

T is C3_7 cycloalkyl; or 4 to 6 membered saturated heterocyclyl, wherein T is optionally substituted with one or more R^ld, which are the same or different;

X³ is N, N-oxide or C(R²) and X⁴ is N, N-oxide or CH, provided that at least one of

X³, X⁴ is N or N-oxide;

R² is H; halogen; CN; CH₃; CH₂F; CHF₂; CF₃; C(O)N(R³R^3a); CH₂N(R³R^3a); N(R³R^3a); CH₂OH; OR³; OCH₂F; OCHF₂; or OCF₃;

R³, R^3a are independently selected from the group consisting of H; Ci_5 alkyl; and C₃_5 cycloalkyl;

Optionally R³, R^3a are joined together with the nitrogen atom to which they are attached to form a 4 to 7 membered saturated heterocycle;

X⁵ is O; S; S(O); S(O)₂; N(R⁴); N*(R⁴)C(0); N* (R⁴) S (O)₂; or S*(O)₂N(R⁴), wherein the asterisk indicates the attachment to the aromatic cyclic moiety in formula (I); R⁴ is H; Ci_5 alkyl; or C3-6 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 R⁵, 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 R⁵ being N(R⁶R^6a);

R^ld, R⁵ are independently selected from the group consisting of halogen; CN; C(O)OR^6b; OR^6b; C(O)R^6b; C(O)N(R^6bR^6c); S(O)₂N(R^6bR^6c); S(O)N(R^6bR^6c); S(O)₂R^6b; S(O)R^6b; N(R^6b)S(O)₂N(R^6cR^6d); SR^6b; N(R⁶R^6a); N(R^6bR^6c); NO₂; OC(O)R^6b; N(R^6b)C(O)R^6c; N(R^6b)S(O)₂R^6c; N(R^6b)S(O)R^6c; N(R^6b)C(O)OR^6c;

N(R^6b)C(O)N(R^6cR^6d); OC(O)N(R^6bR^6c); oxo (=0), where the ring is at least partially saturated; T¹; Ci_6 alkyl; C₂_6 alkenyl; and C₂_6 alkynyl, wherein Ci_6 alkyl; C₂_6 alkenyl; and C₂_6 alkynyl are optionally substituted with one or more R⁷, which are the same or different, provided that when R is 4 to 7 membered saturated heterocyclyl, wherein one ring atom is nitrogen and optionally a further ring atom is oxygen, R⁵ is

T¹; Ci_6 alkyl; C₂_6 alkenyl; or C₂_6 alkynyl, wherein Ci_6 alkyl; C₂_6 alkenyl; and C₂_6 alkynyl are optionally substituted with one or more R⁷, which are the same or different when R⁵ is directly attached to the ring nitrogen atom.

Optionally, two R⁵ form a bridging group selected from the group consisting of CH₂;

CH₂CH₂; CH₂CH₂CH₂; NH; N(CH₃); CH₂NHCH₂; CH₂N(CH₃)CH₂; and O;

R⁶, R^6a are independently selected from the group consisting of T¹; Ci_6 alkyl; C₂_6 alkenyl; and C₂_6 alkynyl, wherein Ci_6 alkyl; C₂_6 alkenyl; and C₂_6 alkynyl are optionally substituted with one or more R⁸, which are the same or different;

Optionally, R⁶, R^6a are joined together with the nitrogen atom to which they are attached to form nitrogen containing ring T²; R^6b, R^6c, R^6d are independently selected from the group consisting of H; T¹; Ci_6 alkyl; C2-6 alkenyl; and C2-6 alkynyl, wherein Ci_6 alkyl; C2-6 alkenyl; and C2-6 alkynyl are optionally substituted with one or more R⁸, which are the same of different;

R^lc, R⁷, R⁸ are independently selected from the group consisting of halogen; CN;

C(O)OR⁹; OR⁹; C(O)R⁹; C(O)N(R⁹R^9a); S(O)₂N(R⁹R^9a); S(O)N(R⁹R^9a); S(O)₂R⁹; S(O)R⁹; N(R⁹)S(O)₂N(R^9aR^9b); SR⁹; N(R⁹R^9a); NO₂; OC(O)R⁹; N(R⁹)C(O)R^9a; N(R⁹)SO₂R^9a; N(R⁹)S(O)R^9a; N(R⁹)C(O)N(R^9aR^9b); N(R⁹)C(O)OR^9a; OC(O)N(R⁹R^9a); and T¹;

R⁹, R^9a, R^9b are independently selected from the group consisting of H; T¹; Ci_6 alkyl; C₂-6 alkenyl; and C₂-6 alkynyl, wherein Ci_6 alkyl; C₂-6 alkenyl; and C₂-6 alkynyl are optionally substituted with one or more halogen, which are the same of different;

T¹ is phenyl; naphthyl; azulenyl; indenyl; indanyl; C3-7 cycloalkyl; 3 to 7 membered heterocyclyl; or 7 to 11 membered heterobicyclyl, wherein T¹ is optionally substituted with one or more R¹⁰, which are the same or different;

T² is a nitrogen containing 3 to 7 membered heterocycle, wherein T² is optionally substituted with one or more R¹⁰, which are the same or different;

R¹⁰ is halogen; CN; C(O)OR¹¹; OR¹¹; C(O)R¹¹; C(O)N(R¹¹R^{1 la}); S(O)₂N(R¹¹R^{1 la}); S(O)N(R¹¹R¹¹"); S(O)₂R¹¹; S(O)R¹¹; N(R¹ ^S(O)₂N(R^{1 la}R^{l lb}); SR¹¹; N(R^πR^{l la}); NO₂; OC(O)R¹¹; N(R¹ ^C(O)R^11*; N(R¹ ^S(O)₂R^11*; N(R¹ ^S(O)R^11*; N(R¹ ^C(O)OR^11*; N(R¹ ^C(O)N(R^{1 la}R^{l lb}); OC(O)N(R¹¹R¹¹"); oxo (=0), where the ring is at least partially saturated; Ci_6 alkyl; C₂-6 alkenyl; or C₂-6 alkynyl, wherein Ci_6 alkyl; C₂-6 alkenyl; and C₂-6 alkynyl are optionally substituted with one or more halogen, which are the same or different;

R¹¹, R^{l la}, R^{l lb} are independently selected from the group consisting of H; Ci_6 alkyl;

C₂-6 alkenyl; and C₂-6 alkynyl, wherein Ci_6 alkyl; C₂-6 alkenyl; and C₂-6 alkynyl are optionally substituted with one or more halogen, which are the same of different. Surprisingly, it was found that compounds of the present invention are useful as Histamine H3 receptor antagonists having good chemical stability, especially compared to compound derivatives, where one xVx^la, X²/X^2a is N(R^-CH₂.

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. -CH₂-, -CH₂-CH₂-, -CH(CH₃)-, -CH₂-CH₂-CH₂-, -CH(C₂H₅)-, -C(CH₃)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. -CH₂-, -CH₂-CH₂-, -CH(CH₃)-, -CH₂-CH₂-CH₂-, -CH(C₂H₅)-, -C(CH₃)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. -CH₂-, -CH₂-CH₂-, -CH(CH₃)-, -CH₂-CH₂-CH₂-, -CH(C₂H₅)-, -C(CH₃ )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. -CH₂-, -CH₂-CH₂-, -CH(CH₃)-, -CH₂-CH₂-CH₂-, -CH(C₂H₅)-, -C(CH₃)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=CH₂, -CH=CH-CH₃, -CH₂-CH=CH₂, -CH=CH-CH₂-CH₃, -CH=CH- CH=CH₂, or e.g. -CH=CH-, when two moieties of a molecule are linked by the alkenyl group. Each hydrogen of a C₂_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: C₂.₆ alkenyl, -CH=CH₂, -CH=CH-CH₃, -CH₂-CH=CH₂, -CH=CH-CH₂-CH₃, - CH=CH-CH=CH₂, or e.g. -CH=CH-, when two moieties of a molecule are linked by the alkenyl group. Each hydrogen of a C₂_₇ alkenyl carbon may be replaced by a substituent as further specified.

"C₂_6 alkynyl" means an alkynyl chain having 2 to 6 carbon atoms, e.g. if present at the end of a molecule: -C≡CH, -CH₂-C≡CH, -CH₂-CH₂-C≡CH, -CH₂-C≡C-CH₃, or e.g. -C≡C- when two moieties of a molecule are linked by the alkynyl group. Each hydrogen of a C₂_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: C₂-₆ alkynyl, -C≡CH, -CH₂-C≡CH, -CH₂-CH₂-C≡CH, -CH₂-C≡C-CH₃, 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.

"C₃_₅ cycloalkyl" or "C₃_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.

"C₃_6 cycloalkyl" or "C₃_6 cycloalkyl ring" means a cyclic alkyl chain having 3 to 6 carbon atoms, e.g. C₃_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. "C3-7 cycloalkyl" or "C3_7 cycloalkyl ring" means a cyclic alkyl chain having 3 to 7 carbon atoms, e.g. C3_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, X¹ to X⁵, n and R of formula (I) independently have the following meaning. Hence, one or more of the substituents X^la, X^2a, X¹ to X⁵, n and R can have the preferred or more preferred meanings given below.

Preferably, X¹, X^la, X², X^2a are chosen to give a compound having the formula (Ia) or (Ib)

wherein R¹, X³, X⁴, X⁵, n, R have the meaning as indicated above. Even more preferred are compounds of formula (Ia), wherein R¹, X³, X⁴, X⁵, n, R have the meaning as indicated above.

Preferably, R¹ is H; Ci_7 alkyl; C2-7 alkenyl; T; or CH₂-T¹ and wherein Ci_7 alkyl; C2-7 alkenyl; are optionally substituted with one or more substituents, which are the same or different and selected from the group consisting of halogen; OH; OCH₃; OCH₂F; OCHF₂; OCF₃; and CN and wherein T is optionally substituted with one or more R^ld, which are the same or different and wherein T¹ is optionally substituted with one or more R¹⁰, which are the same or different. Preferably, T is cyclopropyl; cyclobutyl; or cyclohexyl. Preferably, T¹ is cyclopropyl; cyclobutyl; cyclohexyl; phenyl; pyridyl; pyrimidinyl; pyridazinyl; pyrazinyl; morpholinyl; or piperidinyl or tetrahydropyranyl. More preferred is R¹ H; methyl; trifluoromethyl; ethyl; propyl; 1-methylethyl; butyl; pentyl; 3-hydroxy-2,2-dimethylpropyl; 3- hydroxy-3-methylbutyl; 2-hydroxy ethyl; 2-methoxyethyl; 2-hydroxy-l,l-dimethylethyl; 3- hydroxypropyl; 3-methoxypropyl; cyclopropyl; cyclobutyl; cyclopentyl; cyclohexyl; benzyl; pyridylmethyl; pyrimidinylmethyl; pyridazinylmethyl; pyrazinylmethyl; morpholinylmethyl; tetrahydropyranylmethyl; or piperidinylmethyl, wherein R¹ is optionally substituted. Even more preferred is R¹ methyl; trifluoromethyl; ethyl; propyl; butyl; pentyl; cyclopropyl; cyclobutyl; cyclopentyl; cyclohexyl; benzyl; pyridylmethyl; pyrimidinylmethyl; pyridazinylmethyl; pyrazinylmethyl; morpholinylmethyl; tetrahydropyranylmethyl; or piperidinylmethyl, wherein R¹ is optionally substituted. Even more preferred is R¹ methyl; ethyl; 1-methylethyl; sec. -butyl; isobutyl; dimethylpropyl; cyclpropyl; cyclobutyl; cyclopentyl; 3-hydroxy-2,2-dimethylpropyl; 3 -hydroxy-3-methylbutyl; 2-hydroxyethyl; 2- methoxyethyl; 2-hydroxy- 1,1-dimethylethyl; benzyl; o-, m-, or p-fluorophenylmethyl; o-, m-, or p- methoxyphenylmethyl; pyridylmethyl; methylpyridylmethyl; piperidinylmethyl; or cyclopropylmethyl. Even more preferred is R¹ methyl; ethyl; 1-methylethyl; sec. -butyl; isobutyl; dimethylpropyl; cyclpropyl; cyclobutyl; cyclopentyl; benzyl; o-, m-, or p- fluorophenylmethyl; o-, m-, or p- methoxyphenylmethyl; pyridylmethyl; methylpyridylmethyl; piperidinylmethyl; or cyclopropylmethyl.

Preferably, R^lc is halogen; or OH; or 0-Ci_-4 alkyl; or N(R⁹R^9a).

Preferably, R^a, R^b, R^la, R^lb are independently selected from the group consisting of H; and methyl. More preferred are R^a, R^b, R^la, R^lb H.

Preferably, only one (more preferably none) of the pairs R^a/R^la, R^b/R^lb is joined together with the carbon atom to which they are attached to form C₃_₅ cycloalkyl, wherein C₃_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^b/R^lb is joined.

Preferably, X³ is N, or C(R²) and X⁴ is N, or CH, provided that at least one of X³, X⁴ is N. Preferably, X³ is C(R²). Preferably, X³, X⁴ are N. Preferably, X³ is N or C(R²) and X⁴ is N, N- oxide or CH, provided that at least one of X³, X⁴ is N or N-oxide. Preferably, at least one of X³, X⁴ is N-oxide. Preferably, X³, X⁴ are N; or N-oxide. More preferably, X³, X⁴ are N.

Preferably, R² is H; halogen; CN; CH₃; OCH₃; CH₂F; CHF₂; CF₃; C(O)N(R³R^3a); or CH₂N(R³R^3a). More preferably, R² is H; halogen; CH₃; CF₃; C(O)N(R³R^3a); or CN. More preferably, R² is H; CH₃; CF₃; C(O)N(R³R^3a); or CN. Also more preferably, R² is H; CH₃; halogen; or CN. Even more preferably, R² is H; or CN. Even more preferably, R² is H.

Preferably, X⁵ is O; N(R⁴); S; S(O); S(O)₂; or N*(R⁴)C(O). More preferred is X⁵ O; or N(R⁴). Even more preferred X⁵ is O.

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

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 R⁵, which are the same or different, provided that the ring comprises a tertiary nitrogen atom or the ring is substituted with at least one R⁵ being N(R⁶R^6a).

Also preferably, R is 4 to 7 membered saturated heterocyclyl, wherein one ring atom is nitrogen; or C_4-6 cycloalkyl, wherein R is substituted with one R⁵, provided that the one ring nitrogen of the 4 to 7 membered saturated heterocycle is a tertiary nitrogen. More preferably, R is 4 to 7 membered saturated heterocyclyl, wherein one ring atom is nitrogen, wherein R is substituted with one R⁵, provided that the one ring nitrogen of the 4 to 7 membered saturated heterocycle is a tertiary nitrogen. Even more preferably, R is 4 to 7 membered saturated heterocyclyl, wherein one ring atom is nitrogen, wherein R is substituted with one R⁵ attached to the one ring nitrogen of the 4 to 7 membered saturated heterocycle.

Preferably, -R is

Preferably, R⁵ is T¹; or Ci_6 alkyl. Preferably, T¹ is C3-7 cycloalkyl.

Even more preferred -R is

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-ethyl-7,8-dihydro-l,6-naphthyridin-5(6H)-one;

2-[(l -cyclobutylpiperidin-4-yl)oxy]-6-ethyl-7,8-dihydro- 1 ,6-naphthyridin-5(6H)-one fumaric acid salt;

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

2-[(l-cyclobutylpiperidin-4-yl)oxy]-6-(cyclopropylmethyl)-7,8-dihydro-l,6-naphthyridin- 5(6H)-one;

2-[(l-cyclobutylpiperidin-4-yl)oxy]-6-(tetrahydro-2H-pyran-4-ylmethyl)-7,8-dihydro-l,6- naphthyridin-5 (6H)-one;

2-[(l-cyclobutylpiperidin-4-yl)oxy]-6-(cyclohexylmethyl)-7,8-dihydro-l,6-naphthyridin- 5(6H)-one;

6-benzyl-2-[(l-cyclobutylpiperidin-4-yl)oxy]-7,8-dihydro-l,6-naphthyridin-5(6H)-one;

2-[(l-cyclobutylpiperidin-4-yl)oxy]-6-(4-fluorobenzyl)-7,8-dihydro-l,6-naphthyridin-5(6H)- one; 2-[(l-cyclobutylpiperidin-4-yl)oxy]-6-[(6-methylpyridin-3-yl)methyl]-7,8-dihydro-l,6- naphthyridin-5 (6H)-one;

2-[(l-cyclobutylpiperidin-4-yl)oxy]-6-(2-methoxyethyl)-7,8-dihydro-l,6-naphthyridin-5(6H)- one;

2-{2-[(l-cyclobutylpiperidin-4-yl)oxy]-5-oxo-7,8-dihydro-l,6-naphthyridin-6(5H)-yl}-N,N- dimethylacetamide;

2-[(l-cyclobutylpiperidin-4-yl)oxy]-7,8-dihydro-l,6-naphthyridin-5(6H)-one;

2-[(l-cyclobutylpiperidin-4-yl)oxy]-6-ethyl-l,6-naphthyridin-5(6H)-one;

6-ethyl-2-[(l-methylpiperidin-4-yl)oxy]-7,8-dihydro-l,6-naphthyridin-5(6H)-one;

2-[(l-cyclopentylpiperidin-4-yl)oxy]-6-ethyl-7,8-dihydro-l,6-naphthyridin-5(6H)-one;

2-[(l-cyclohexylpiperidin-4-yl)oxy]-6-ethyl-7,8-dihydro-l,6-naphthyridin-5(6H)-one;

2- [[(3S)- 1 -cyclopentylpyrrolidin-3-yl]oxy} -6-ethyl-7,8-dihydro- 1 ,6-naphthyridin-5(6H)-one;

2- {[(35)- 1 -cyclobutylpyrrolidin-3-yl]oxy} -6-ethyl-7,8-dihydro- 1 ,6-naphthyridin-5(6H)-one;

2-{[(3i?)-l-cyclopentylpyrrolidin-3-yl]oxy}-6-ethyl-7,8-dihydro-l,6-naphthyridin-5(6H)-one;

2-{[(3i?)-l-cyclobutylpyrrolidin-3-yl]oxy}-6-ethyl-7,8-dihydro-l,6-naphthyridin-5(6H)-one;

6-ethyl-2-(3-pyrrolidin- 1 -ylpropoxy)-7,8-dihydro- 1 ,6-naphthyridin-5(6H)-one;

6-ethyl-2-(3-piperidin- 1 -ylpropoxy)-7,8-dihydro- 1 ,6-naphthyridin-5(6H)-one;

2- {[ 1 -(cyclopropylmethyl)piperidin-4-yl]oxy} -6-ethyl-7,8-dihydro- 1 ,6-naphthyridin-5(6H)- one; 6-ethyl-2- { [ 1 -( 1 -methylethyl)piperidin-4-yl]oxy } -7,8-dihydro- 1 ,6-naphthyridin-5(6H)-one;

6-ethyl-2-[(l-oxetan-3-ylpiperidin-4-yl)oxy]-7,8-dihydro-l,6-naphthyridin-5(6H)-one;

2-[(l-cyclobutylpiperidin-4-yl)oxy]-6-[4-(methylsulfonyl)benzyl]-7,8-dihydro-l,6- naphthyridin-5 (6H)-one;

2-[(l-cyclobutylpiperidin-4-yl)oxy]-6-[(methylsulfanyl)methyl]-7,8-dihydro-l,6- naphthyridin-5 (6H)-one;

2-[(l-cyclobutylpiperidin-4-yl)(methyl)amino]-6-ethyl-7,8-dihydro-l,6-naphthyridin-5(6H)- one;

2-[(l-cyclobutylpiperidin-4-yl)oxy]-6-ethyl-3-fluoro-7,8-dihydro-l,6-naphthyridin-5(6H)- one;

2-[(l-cyclobutylpiperidin-4-yl)oxy]-6-ethyl-8-methyl-7,8-dihydro-l,6-naphthyridin-5(6H)- one;

2-[(l-cyclobutylpiperidin-4-yl)oxy]-6-ethyl-8,8-dimethyl-7,8-dihydro-l,6-naphthyridin- 5(6H)-one;

2-[(l-cyclobutylpiperidin-4-yl)oxy]-6-(3-hydroxy-3-methylbutyl)-7,8-dihydro-l,6- naphthyridin-5 (6H)-one;

2-[(l-cyclobutylpiperidin-4-yl)oxy]-6-(2-hydroxyethyl)-7,8-dihydro-l,6-naphthyridin-5(6H)- one;

2-[(l-cyclobutylpiperidin-4-yl)oxy]-6-(3-hydroxy-2,2-dimethylpropyl)-7,8-dihydro-l,6- naphthyridin-5(6H)-one;

2-[(l -cyclobutylpiperidin-4-yl)oxy]-6-(2-hydroxy- 1 , 1 -dimethylethyl)-7,8-dihydro- 1 ,6- naphthyridin-5 (6H)-one; 2-[(l-cyclobutylpiperidin-4-yl)oxy]-6-(l-methylethyl)-7,8-dihydro-l,6-naphthyridin-5(6H)- one;

2-[(l-cyclobutylpiperidin-4-yl)oxy]-6-(3-methoxy-2,2-dimethylpropyl)-7,8-dihydro-l,6- naphthyridin-5(6H)-one;

2-[(l-cyclobutylpiperidin-4-yl)oxy]-6-(2-methoxyethyl)-7,7-dimethyl-7,8-dihydro-l,6- naphthyridin-5 (6H)-one;

6-ethyl-2-[(3-piperidin- 1 -ylpropyl)sulfanyl]-7,8-dihydro- 1 ,6-naphthyridin-5(6Η)-one;

2-[(l-cyclobutylpiperidin-4-yl)oxy]-7-ethyl-6,7-dihydro-l,7-naphthyridin-8(5H)-one;

2-[(l-cyclobutylpiperidin-4-yl)oxy]-6-ethyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one;

6-ethyl-2-{[l-(l-methylethyl)piperidin-4-yl]oxy}-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)- one;

2-[(l-cyclopentylpiperidin-4-yl)oxy]-6-ethyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one;

6-[(l-cyclobutylpiperidin-4-yl)oxy]-2-ethyl-3,4-dihydro-2,7-naphthyridin-l(2H)-one;

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

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

2-[(l-cyclobutylpiperidin-4-yl)oxy]-6-(2-hydroxy-2-methylpropyl)-7,8-dihydro-l,6- naphthyridin-5(6H)-one.

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

Iso topic 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.

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, energy homeostasis disorders and pain. 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;

Fatique; - Stroke; tremor.

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.

Cardiovascular disorders, e.g. acute myocardial infarction, and other disorders, i.e. gastrointestinal disorders, vestibular dysfunction (e.g. Morbus Meniere, dizziness caused by drug abuse, 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.

Preferably, the compounds of the present invention may be used for fatigue and cognitive impairment/dysfunction associated with Multiple Sclerosis. Accordingly, Multiple Sclerosis is a more preferred disease or disorder for disease related fatigue and cognitive impairment/dysfunction.

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 neurological disorders; disorders affecting energy homeostasis as well as complications associated therewith; Pain; cardiovascular disorders; gastrointestinal disorders; vestibular dysfunction; drug abuse; nasal congestion; allergic rhinitis; or asthma - more preferably, 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 neurological disorders; disorders affecting energy homeostasis as well as complications associated therewith; Pain; cardiovascular disorders; gastrointestinal disorders; vestibular dysfunction; drug abuse; nasal congestion; allergic rhinitis; or asthma - more preferably, 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, especially a human, 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 neurological disorders; disorders affecting energy homeostasis as well as complications associated therewith; Pain; cardiovascular disorders; gastrointestinal disorders; vestibular dysfunction; drug abuse; nasal congestion; allergic rhinitis; or asthma - more preferably, 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. 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. Further preferred one or more bioactive compounds are acetylcholine esterase inhibitors.

"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, 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 preferred compounds of the present invention can be prepared by a method, wherein in formula (I) X⁵ is O; S; or N(R⁴), comprising the steps of

(a) Boc protecting a compound of formula (Ha) at the secondary nitrogen atom

wherein one of X¹ — X^la, X²— X^2a is C(R^aR^la)-C(R^bR^lb); or C(R^a)=C(R^b); and the other is NH-C(O), provided that NH represents X¹ or X²; and X³, X⁴ have the meaning as indicated above;

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

H-X^sJTh-R ^(V)

wherein X⁵ is O; S; or N(R⁴) and n, R have the meaning as indicated above;

(c) deprotecting the resulting compound from step (b) and -when R¹ is other than H- reacting the unprotected compound with either of i) a compound of formula R'-halide (where the halide may be iodide, bromide or chloride) or R¹ -sulfonate (such as triflate or tosylate) in the presence of a base to yield a compound of formula (I), wherein X⁵ is O; S; or N(R⁴); ii) a compound of formula R^=O) in the presence of a reducing agent (such as NaBH₃CN or STAB) and organic solvent (such as CF₃CH₂OH or THF) to yield a compound of formula (I), wherein X⁵ is O; S; or N(R⁴).

Optionally, the method may comprise the further step

(d) reacting a compound of formula (I), wherein X⁵ is S with an oxidising agent to yield a compound of formula (I), wherein X⁵ is S(O); or S(O)₂.

Furthermore compounds of formula (I), X³ is N or CR² and X⁴ is CH or N (especially where X³ is C(R²)), can be prepared by a method comprising the steps of

(a) reacting a compound of formula (XXVa)

wherein one of X¹ — X^la, X²— X^2a is C(R^aR^la)-C(R^bR^lb); or C(R^a)=C(R^b); and the other is NH-C(O), provided that NH represents X¹ or X², with a compound of formula R'-halide (optionally an iodide, bromide or chloride) or R'-sulfonate (e.g. a triflate or tosylate) in the presence of a base (such as NaH), wherein R¹ has the meaning as indicated above, provided that R¹ is other than H;

(b) treating the resulting intermediate with an oxidising agent (like mCPBA) to yield intermediate compound of formula (XXVIIa) or a compound of formula (XXVIIb) (especially compound of formula (XXVIIa))

(XXVIIa)

, or (XXVIIb)

wherein one of X¹ — X^la, X²— X^2a is C(R^aR^la)-C(R^bR^lb); or C(R^a)=C(R^b); and the other is N(R^-C(O), provided that N(R¹) represents X¹ or X²,

(c) treating the compound of formula (XXVIIa) or formula (XXVIIb) with phosphorus oxychloride at high temperature (usually at 50⁰C to 120⁰C) followed by aqueous workup to yield intermediate compound of formula (XXVIIIa)

(d) reacting a compound of formula (XXVIIIa), optionally in the presence of a strong base, with a compound of formula (V)

wherein X⁵ is O; S; or N(R⁴) and n, R have the meaning as indicated in claim 1 to yield a compound of formula (I).

Preferably, step (d) is carried out from low temperature (RT to -78⁰C) to high temperature with thermal heating or microwave irradiation (up to 15O⁰C).

Optionally, the method may comprise the further step

(e) reacting a compound of formula (I), wherein X⁵ is S with an oxidising agent to yield a compound of formula (I), wherein X⁵ is S(O); or S(O)₂. In the following methods are described for preparing preferred compounds of the present invention, whereas the methods represent exemplary methods and should form alone or in combination the basis for the preparation of further compounds of the present invention.

In general compounds of formula (I), wherein by way of example X⁵ is O; S; or N(R⁴), can be prepared by a method comprising the steps of

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

at the secondary nitrogen atom, wherein X²— X^2a is C(RV ^a)-C(RV ^b) and X¹— X^la is NH-C(R^aR^la) or NH-C(R^bR^lb), provided that NH represents X¹ and X³, X⁴ have the meaning as indicated above;

(b) reacting the resulting compound from step (a) with NaIO₄ and RUCI₃ in perchlorinated solvent (such as carbon tetrachloride or DCM) to give a compound of formula (III)

(c) deprotecting the resulting compound from step (b) and reacting the unprotected compound with either of

i) a compound of formula R'-halide (where the halide may be iodide, bromide or chloride) or R'-sulfonate (such as triflate or tosylate) in the presence of a base such as NaH to yield a compound of formula (IV), wherein R¹ is as defined above;

ii) a compound of formula R^=O) in the presence of a reducing agent (such as NaBH₃CN or STAB) and organic solvent (such as CF₃CH₂OH or THF), R¹ is as defined above;

(d) reacting the resulting compound from step (c) i) or ii) with a compound of formula (V) to yield a compound of formula (I)

H-X^{^} R (V)

wherein X⁵ is O; S; or N(R⁴) and n, R have the meaning as indicated above.

Preferably, step (d) is carried out in the presence of a strong base and optionally from low temperature (RT to -78⁰C) to high temperature with thermal heating or microwave irradiation (up to 15O⁰C).

The method may comprise the further step

(e) reacting a compound of formula (I), wherein X⁵ is S with an oxidising agent to yield a compound of formula (I), wherein X⁵ 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 (VI)

wherein X²— X^2a is C(R^aR^la)-C(R^bR^lb); X³ is C(R²) and X⁴ is N may be prepared starting from compounds of formula (VII)

which are commercially available or may be prepared by routes well known in the art, wherein R¹ is defined as above or as a suitable N-atom protecting group such as Boc, by reacting compounds of formula (VII) 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 (VIII)

and further reacting compounds of formula (VIII) 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 (IX) to yield a compound of formula (VI) when R¹ is defined as above.

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

(X)

HO ^R

In the case when R¹ of formula (VI) is as defined above, the resulting compound can be converted by the following additional step to synthesise a compound of formula (I) reacting a compound of formula (VI) with NaIO₄ and RUCI3 in perchlorinated solvent (such as carbon tetrachloride or DCM) to yield a compound of formula (I).

In the case when R¹ of formula (VI) is a suitable N-atom protecting group such as Boc, the resulting compound represented by formula (XI) can be converted by the following additional steps to synthesise a compound of formula (I)

- reacting a compound of formula (XI) with NaIO₄ and RUCI3 in carbon tetrachloride or DCM, followed by deprotection at the nitrogen atom and reacting this intermediate (when R¹ is other than H) under either of the reaction conditions described by step (c) i) to ii) above, to yield a compound of formula (I).

Additionally, compounds of formula (I), wherein X⁵ is O, S or NR⁴, can be prepared in a two step process starting from a compound of formula (VIII) above by

reacting a compound of formula (VIII) with POCI₃, optionally in the presence of PCI₅ and / or tetraethyl ammonium chloride monohydrate, at high temperature (usually >

6O⁰C) followed by reacting the resulting intermediate with a compound of formula (V), optionally in the presence of a strong base and optionally from low temperature (RT to -78⁰C) to high temperature with thermal heating or microwave irradiation (up to 15O⁰C), to yield a compound of formula (I).

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

x- iϊ-R ^(XII) with a reducing agent such as NaBH₄.

Alternatively, compounds of formula (V) can be prepared by the one step process of reacting a compound of formula (XIIb)

with a reducing agent such as NaBH₄ or borane-THF complex.

Additionally, compounds of formula (I), wherein X⁵ is O, S or NR⁴, can be prepared in a three step process starting from a commercially available or readily obtainable compound of formula (Ha) by reacting the compound of formula (Ha) under either of the reaction conditions described by step (c) i) to ii) above and - reacting the resulting compound with NaIO₄ and RuCl3 in perchlorinated solvent (such as carbon tetrachloride or DCM) followed by reacting the resulting intermediate with a compound of formula (V), optionally in the presence of a strong base (such as KO¹Bu or NaH) [and optionally from low temperature (RT to -78⁰C) to high temperature with thermal heating or microwave irradiation (up to 15O⁰C)], to yield a compound of formula (I).

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 (VII), which is commercially available or can be prepared by routes known in the art,

Wherein X²— X^2a is C(R^aR^la)-C(R^bR^lb) and R¹ can be as defined above or a suitable N-atom protecting group such as Boc with DMF. DMA at high temperature (usually at 100 ⁰C) followed by treatment of the resulting intermediate with a compound of formula (XIII) at high temperature (usually at 80 ⁰C)

HOSO₂CF₃

reacting the resulting compound with NaIO₄ and RuCl3 in carbon tetrachloride or DCM to yield a compound of formula (I).

In the case when R¹ of formula (I) is a suitable N-atom protecting group such as Boc, the resulting compound represented by formula (XIV) can be converted by the following additional steps to synthesise a compound of formula (I)

which are

reacting the compound of formula (XIV) with NaIO₄ and RUCI3 in perchlorinated solvent (such as carbon tetrachloride or DCM) deprotection at the nitrogen atom and reacting this intermediate under either of the reaction conditions described by step (c) i) to ii) above, to yield a compound of formula (I).

Additionally, compounds of formula (I), wherein X³ is N, X⁵ is O, S or NR⁴, X²rτzX^2a is C(R^aR^la)-C(R^bR^lb), can be prepared in a five step process starting from a commercially available or readily obtainable compound of formula (XV)

which are

Boc protecting compound of formula (XV) at the secondary ring nitrogen atom and reacting the resulting compound with NaIO₄ and RUCI3 in perchlorinated solvent (such as carbon tetrachloride or DCM), to yield intermediate compound of formula (XVI)

reacting compound of formula (XVI) with a compound of formula (V), optionally in the presence of a strong base (such as KO¹Bu or NaH) [and optionally with thermal heating or microwave irradiation (up to 15O⁰C)]; deprotection at the nitrogen atom and reacting the resulting compound under either of the reaction conditions described by step (c) i) to ii) above, to yield a compound of formula (I).

In the case when R^b, R^lb of formula (I) are lower alkyl (C_1-4 alkyl) the compounds can be prepared by reacting a compound of formula (I) (where R^b and R^lb are H and R¹ is Boc) with a strong base (such as ¹BuLi and TMEDA or KHMDS) at low temperature (usually < - 5O⁰C) then treating the resulting intermediate with the appropriate electrophile (such as MeI) to yield intermediate compound of formula (XVII)

deprotecting compound of formula (XVII) at the nitrogen atom and reacting the resulting compound under either of the reaction conditions described by step (c) i) to ii) above to yield a compound of formula (I).

Alternatively, when R^b of formula (I) is lower alkyl (C_1-4 alkyl) the compounds can be prepared by reacting a compound of formula (IV) (where R^b is H and R¹ is as defined above) with a strong base (such as ¹BuLi and TMEDA or KHMDS) at low temperature (usually < -

5O⁰C) then treating the resulting intermediate with the appropriate electrophile (such as MeI) to yield intermediate compound of formula (XVIIa)

(XVIIa)

reacting the compound of formula (XVIIa) under either of the reaction conditions described by step (c) i) to ii) above to yield a compound of formula (I).

Alternatively, when both R^b and R^lb of formula (I) are lower alkyl (C_1-4 alkyl) the compounds can be prepared by reacting a compound of formula (XVIIa) (where R^b is lower alkyl (C_1-4 alkyl) and R¹ is as defined above) with a strong base (such as ¹BuLi and TMEDA or KHMDS) at low temperature (usually < -5O⁰C) then treating the resulting intermediate with the appropriate electrophile (such as MeI) to yield intermediate compound of formula (XVIIb)

(XVIIb)

reacting the compound of formula (XVIIb) under either of the reaction conditions described by step (c) i) to ii) above to yield a compound of formula (I).

Additionally, compounds of formula (I), wherein X¹— X^la is CH₂-CH₂, X²— X^2a is N(R¹)- C(O) and X³ is C(R²), may be prepared starting from compounds of formula (XVIII)

(XVIII)

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

amide cleavage of a compound of formula (XVIII), 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 ~ 100⁰C) - followed by treatment of the resulting intermediate with ethyl acrylate under Heck conditions to yield intermediate compound of formula (XIX)

treatment of a compound of formula (XIX) with sodium ethoxide in ethanol at high temperature (usually at 100⁰C) 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 (XX)

(XX)

reacting a compound of formula (XX) with POCI3, optionally in the presence of PCI5 and / or tetraethyl ammonium chloride monohydrate, at high temperature (usually >

8O⁰C) followed by reacting the resulting intermediate with a compound of formula (V), subsequent de-benzylation (usually under transfer hydrogenation conditions) to yield intermediate (XXI)

- Boc protection at the secondary ring nitrogen atom followed by treatment of the resulting intermediate with NaIO₄ and RUCI3 in perchlorinated solvent (such as carbon tetrachloride or DCM)

Boc de-protection and reaction of the resulting intermediate with any of the reaction conditions described by step (c) i) to ii) above, to yield a compound of formula (I).

In the case when C(R²) of formula (I) is a C-CN, compounds represented by formula (XXII) 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 (XXII) with DIBAL at low temperature (usually < - 6O⁰C) to yield the aldehyde analogue of formula (XXII) followed by reacting the resulting compound with a compound of formula HN(R³R^3a) in the presence of a reducing agent such as STAB to yield a compound of formula (I), alternatively, reacting a compound of formula (XXII) with strong base such as 5 M NaOH, followed by reacting the resulting intermediate with HN(R³R^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^z is CH₂, X 2^za^a is C(R > b⁶τR-> 1¹ b ^B\), X -vτ3³ is C(R^Z) and X⁴ is N may be prepared starting from compounds of formula (VII) by,

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

wherein R¹ can be as defined above or a suitable N-atom protecting group such as

Boc; with DMF. DMA at high temperature (usually at 100⁰C) followed by treatment of the resulting intermediate with a compound of formula H₂N(CO)CH₂R² and strong base usually NaH at high temperature (usually at 100⁰C) to yield an intermediate compound of formula (XXIII)

(XXIII)

followed by reacting a compound of formula (XXIII) with POCI₃, optionally in the presence of PCI5 and / or tetraethyl ammonium chloride monohydrate, at high temperature (usually > 8O⁰C) and reacting the resulting intermediate with NaIO₄ and RUCI₃ in perchlorinated solvent (such as carbon tetrachloride or DCM) followed by a compound of formula (V) to yield a compound of formula (I).

In the case when R¹ of formula (I) is a suitable N-atom protecting group such as Boc, the resulting compound represented by formula (XXIV) can be converted by the following additional steps to synthesise a compound of formula (I)

reaction with NaIO₄ and RUCI3 in perchlorinated solvent (such as carbon tetrachloride or DCM) followed by de-protection at the nitrogen atom and reacting the resulting compound under any of the reaction conditions described by step (c) i) to ii) above, to yield a compound of formula (I).

Additionally, compounds of formula (I), wherein X² and X^2a are a carbon to carbon double bond (ethylene unit), X³ is C(R²) and X⁴ is N, may be prepared starting from compounds of formula (XXV)

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 with a compound of formula R'-halide (where the halide may be iodide, bromide or chloride) or R¹ -sulfonate (such as triflate or tosylate) in the presence of a base such as NaH, wherein R¹ is as defined above; treating the resulting intermediate with an oxidising agent (such as mCPBA) to yield intermediate compound of formula (XXVII)

(XXVIl)

treating a compound of formula (XXVII) with phosphorus oxychloride, [optionally in the presence of PCI5 and / or tetraethyl ammonium chloride monohydrate], at high temperature (usually at 50 to 120⁰C) followed by aqueous workup to yield intermediate compound of formula (XXVIII)

reacting a compound of formula (XXVIII) with a compound of formula (V), optionally in the presence of a strong base [and optionally with thermal heating or microwave irradiation (up to 15O⁰C)], to yield a compound of formula (I).

Alternatively, compounds of formula (I), wherein X² and X^2a are a carbon to carbon double bond (ethylene unit) and X³ is C(R²), 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

de-protection at the nitrogen atom and reacting the resulting compound with a compound of formula R'-halide (where the halide may be iodide, bromide or chloride) or R'-sulfonate (such as triflate or tosylate) in the presence of a base such as Ag₂CO₃, wherein R¹ is as defined above, to yield intermediate compound of formula (XXIX)

treating the resulting intermediate with an oxidising agent (such as mCPBA or DDQ or CAN) to yield intermediate compound of formula (XXX)

treating a compound of formula (XXX) with boron tribromide at room temperature to approximately 50 ⁰C followed by aqueous workup to yield intermediate compound of formula (XXXI)

reacting a compound of formula (XXXI) with a compound of formula R'-halide (where the halide may be iodide, bromide or chloride) or R¹ -sulfonate (such as triflate or tosylate) in the presence of a base such as NaH, wherein R¹ is as defined above, to yield intermediate compound of formula (XXVIII); reacting a compound of formula (XXVIII) with a compound of formula (V), optionally in the presence of a strong base [and optionally from low temperature (RT to -78⁰C) to high temperature with thermal heating or microwave irradiation (up to 15O⁰C)], to yield a compound of formula (I).

In the case when X 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 X⁵ is S) with an oxidising agent such as OXONE® or mCPBA.

Additionally, compounds of formula (I), wherein X⁵ is N(R⁴)C(O) or N(R⁴)S(O)₂ may be prepared starting from compounds of formula (XXXII), which are either commercially available or their preparations have been disclosed above herein

(XXXII)

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 (XXXII) with a compound of formula HN(R⁴)CH₂Ph, which is commercially available or can be prepared by routes known in the art, under microwave irradiation (usually at > 8O⁰C) in the presence of suitable base such as K₂CO₃;

- followed by de-benzyl protection, using hydrogenation conditions, and subsequent reaction with the appropriate compound of formula (XXXIII) or (XXXIV), in the presence of a suitable base (such as pyridine) and optionally at high temperature (usually > 8O⁰C)

(XXXIII)

(XXXIV)

to yield a compound of formula (I).

Additionally, compounds of formula (I), wherein X⁵ is S(O)₂N(R⁴) may be prepared starting from compounds of formula (IV) or (XXXII), 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 (III), (IV) or (XXXII) with potassium hydrogensulfide in water, at high temperature (usually at > 200⁰C) reacting the resulting compound with chlorine gas and IM HCl, at low temperature (usually at < 5⁰C) to yield a intermediate compound of formula (XXXV)

treatment of a compound of formula (XXXV) with a compound of formula (XXXVI) in pyridine at high temperature (usually at > 5O⁰C)

(XXXVI)

to yield a compound of formula (I).

In the case when X²— X^2a is C(RV ^a)-C(RV ^b) or C(R^a)=C(R^b) and R¹ of formula (I) is a suitable N-atom protecting group such as Boc, the resulting compound represented by formula (XXXVII) can be converted by the following additional steps to synthesise a compound of formula (I)

(XXXVII)

Boc de-protection and reaction of the resulting intermediate with any of the reaction conditions described by step (c) i) to ii) above, to yield a compound of formula (I).

Additionally, compounds of formula (I), wherein X² is N(R¹), X^2a is C(=O), X^!=X^la is C(R^a)=C(R^b) and X³ is C(R²), may be prepared starting from intermediate compounds of formula (XXI)

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

Boc protection at the nitrogen atom followed by treatment of the resulting intermediate with NaIO₄ and RUCI3 in perchlorinated solvent (such as carbon tetrachloride or DCM) provides intermediate compound of formula (XXXVIII)

(XXXVIII)

followed by oxidation of the resulting intermediate with either bromine or NBS and benzoyl peroxide usually at RT to 8O⁰C treating the resulting intermediate with a base such as KOH to yield a compound of formula (XXXIX)

(XXXIX)

deprotecting compound of formula (XXXIX) at the nitrogen atom and reacting the resulting compound under either of the reaction conditions described by step (c) i) to ii) above, to yield a compound of formula (I).

Additionally, compounds of formula (I), wherein X¹— X^la is CH₂-CH₂, X²— X^2a is N(R¹)- C(O); X³ and X⁴ are as described above, may be prepared starting from compounds of formula (XLVI)

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

halagonation of the methyl group of a compound of formula (XLVI) with a halagonating agent (such as AIBN and NBS) followed by treatment of the resulting intermediate with sodium cyanide, optionally with a phase transfer agent (such as TBAI), to yield intermediate compound of formula (XLVII)

reduction of the nitrile of a compound of formula (XLVII) with Raney Ni and hydrogen, optionally at high temperature (usually at 5O⁰C), followed by treatment of the resulting intermediate with a strong base (such as NaH) and subsequent reaction with a compound of formula R'-halide (where the halide may be iodide, bromide or chloride) or R¹ -sulfonate (such as triflate or tosylate), wherein R¹ is as defined above, to yield intermediate compound of formula (XLVIII)

treating the resulting intermediate of formula (XLVIII) with an oxidising agent (such as mCPBA) to yield intermediate compound of formula (XLIXa) or formula (XLIXb)

(XLIXb)

treating a compound of formula (XLIXa) or formula (XLIXb) with phosphorus oxychloride, optionally in the presence of PCI5 and / or tetraethyl ammonium chloride monohydrate, at high temperature (usually at 50 to 120⁰C) followed by aqueous workup to yield intermediate compound of formula (L)

reacting a compound of formula (L) with a compound of formula (V), optionally in the presence of a strong base and optionally from low temperature (RT to -78⁰C) to high temperature with thermal heating or microwave irradiation (up to 15O⁰C), to yield a compound of formula (I).

In the case when X¹⁼X^la of formula (I) are C(R^a)=C(R^b) and R^a, R^b are lower alkyl (Ci_-4 alkyl) the compounds can be prepared by - reacting a compound of formula (XXXVIII) (where R^a and R^b are H) with a strong base such as ¹BuLi and TMEDA at low temperature (usually < -5O⁰C) then treating the resulting intermediate with the appropriate electrophile (such as MeI) to yield intermediate compound of formula (XL)

followed by oxidation of the resulting intermediate with either bromine or NBS and benzoyl peroxide usually at RT to 8O⁰C treating the resulting intermediate with a base such as KOH to yield a compound of formula (XLI)

deprotecting compound of formula (XLI) at the nitrogen atom and reacting the resulting compound under either of the reaction conditions described by step (c) i) to ii) above to yield a compound of formula (I).

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 (XLII), which is either commercially available or can be prepared by routes known in the art, with a compound of formula (V) optionally in the presence of a strong base (such as NaH) and optionally with thermal heating or microwave irradiation (up to 15O⁰C)

H-X^{^} R (V)

wherein X⁵ is O; S; or N(R⁴) and n, R have the meaning as indicated above to yield a compound of formula (XLIII).

(XLIII)

Optionally, the method may comprise the further step of reacting a compound of formula (XLIII), wherein X⁵ is S with an oxidising agent to yield a compound of formula (XLIII), wherein X⁵ is S(O); or S(O)₂.

The resulting product may then be reacted with in the presence of a metal catalyst (such as Pd(PPlIs)₄), optionally in the presence of a base and optionally heated thermally or by microwave irradiation, with a compound of formula (XLIV)

χV X. ,_a-^γ (XLIV)

wherein X²=X^2a is C(R^aR^la)=C(R^b) having the meaning as indicated above and Y is an appropriate group for a metal catalysed coupling reaction with an aromatic halide (such as SnBu3 or B(OH)₂) to yield a compound of formula (XLV)

The resulting product can then be heated (usually at a temperature up to 150 ⁰C) with an amine of formula H₂N(R¹) wherein R¹ is as indicated above, optionally with the addition of a suitable base (such as aqueous NaOH or aqueous LiOH), to yield a compound of formula (I).

Thus another aspect of the present invention is a method for the preparation of a compound according to the present invention, comprising the steps of:

reacting a compound of formula (XLII) with a compound of formula (V), optionally in the presence of a strong base

wherein X /^■5 i ^•s c

S;. or Λ N.τY(rR> 4 ) and n, R have the meaning as indicated above to yield a compound of formula (XLIII)

(XLIII)

optionally reacting the compound of formula (XLIII), wherein X⁵ is S with an oxidising agent to yield a compound of formula (XLIII), wherein X⁵ is S(O); or S(O)₂.

reacting the resulting product in the presence of a metal catalyst, optionally in the presence of a base and optionally heated thermally or by microwave irradiation, with a compound of formula (XLIV) ^χV X. ,_a-^γ (XLIV)

wherein X²=X^2a is C(R^aR^la)=C(R^b) having the meaning as indicated above and Y is an appropriate group for a metal catalysed coupling reaction with an aromatic halide to yield a compound of formula (XLV)

heating the resulting product in the presence of an amine of formula H₂N(R¹), optionally in the presence of a suitable base, wherein R¹ is as indicated above to yield a compound of formula (I).

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 (XLVI), which is commercially available or can be prepared by a 4 step process comprising the steps of; i) reacting an alkyl acrylate with a compound of formula R¹NH₂, wherein R¹ is as indicated above or a suitable N-atom protecting group such as Boc; ii) reacting the resulting intermediate from step i) with ethyl malonyl chloride optionally in the presence of a suitable base (such as TEA); iii) treating the acyclic intermediate from step ii) with strong base (such as KO¹Bu); iv) reacting the step iii) intermediate with a suitable acid (such as oxalic acid) optionally at high temperature (usually > 5O⁰C) to form a compound of formula

(XLVI)

(XLVI)

Wherein X²— X^2a is C(R^aR^la)-C(R^bR^lb) and R¹ can be as defined above or a suitable N-atom protecting group such as Boc; with DMF.DMA at high temperature (usually > 80 ⁰C) followed by treatment of the resulting intermediate with a compound of formula (XIII) at high temperature (usually at > 50 ⁰C) to yield a compound of formula (I).

HOSO₂CF₃

In the case when X²— X^2a is C(R^aR^{! a})-C(RV ^b) and R¹ of formula (I) is a suitable N-atom protecting group such as Boc, the resulting compound represented by formula (XLVII) can be converted by the following additional steps to synthesise a compound of formula (I)

(XLVII)

- de-protection at the nitrogen atom and reacting the resulting compound under any of the reaction conditions described by step (c) i) to ii) above, to yield a compound of formula (I).

It is clear for a practitioner in the art that the preparation routes mentioned herein can be combined and varied optionally by using activation and protection/deprotection techniques.

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 G₁ coupled).

Specifically, a cAMP quantification assay system from DiscoveRx (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% CO₂ 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 the following potency ranges (IC₅₀ values):

A: < 50 nM; B: > 50 nM to 100 nM; C: > 100 nM to 500 nM; D: > 500 nM.

Cytochrome P450 Inhibition Assay

Cytochrome P450 (CYP450) are a family of enzymes which play a major role in the metabolism of drugs. Assessment of the potential of a compound to inhibit a specific CYP450 enzyme is important as co-administration of compounds may result in one or both inhibiting the other's metabolism. This may affect plasma levels in vivo and potentially lead to adverse drug reactions or toxicity.

In the CYP450 Inhibition assay, recombinant human hepatic CYP450s (baculovirus-insect- cell expression system) expressing the isoforms 1A2, 2C9, 2C19, 2D6 and 3A4 were used.

The following probe substrates were used: 3-cyano-7-ethoxycoumarin (CEC; CYP 1A2), dibenzylflourescine (DBF; CYP2C9, CYP 2Cl 9, CYP 3A4) and 3-{2-(N,N-diethyl-N- methyl ammonium)ethyl}-7-methoxy-4-methylcoumarin (AM MC, CYP2D6). Control inhibitors were furafylline (CYP 1A2), sulphaphenazole (CYP2C9), tranylcypromine (CYP2C 19), quinidine (CYP2D6) and ketoconazole (KC).

Test compounds were predissolved in 10% DMSO and aliquots transferred to individual wells containing phosphate buffer (0.1M) and appropriate probe substrate. Final concentration of DMSO in the incubations was <1%. In addition a source of reducing equivalents was added (glucose-6-phosphate / glucose-6-phosphate dehydrogenase / NADP and magnesium chloride) to each well. For the determination of IC50 the final concentrations of Test compounds ranged from 0.023 to 50μM (3-fold dilution; 8- concentration ranges). Control incubations contained known inhibitors to each CYP450 isoform (CYP 1A2; furafylline: CYP2C9; sulphaphenazole: CYP2C19; tranylcypromine: CYP2D6; quinidine and CYP3A4; quinidine) in place of Test compounds. Positive and negative controls representing minimum and maximum probe substrate degradation contained known inhibitors at high concentration or 10% DMSO respectively. After a 5 minute pre-incubation the reactions were initiated by the addition of protein. After the appropriate incubation time reactions were stopped by the addition of a 'Stop Solution' (positive control inhibitor in 10% DMSO).

Fluorescence values obtained at each concentration of test compound were measured and converted to percent inhibition based on positive and negative controls. Calculation of IC50 was from fitting a 4-parameter logistic equation. Where IC50 is greater than that of top concentration (50 μM) data is reported as > 50 μM.

IC50S determined for control inhibitors were compared with literature values to ensure assay functionality.

Preferred compounds of Formula (I) have CYP450 Inhibition IC50 > 50 μM.

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 ¹H observation with pulsing/decoupling of nuclei in the frequency range ¹⁵N and ³¹P with ²H 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 ¹H, ¹³C, ¹⁹F and ³¹P with ²H 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 ¹H, ¹³C, ¹⁹F and ³¹P with

H 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)

bicarbonate, buffered to pHIO

B, Acetonitrile:2mM ammonium bicarbonate 95:5

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

Ag₂CO₃ silver carbonate

AINB 2,2'-azo δmsobutyronitrile br s broad singlet

Boc te/t-butoxycarbonyl

(BoC)₂O di-tert-buty{ dicarbonate

¹Bu tert-butyi

BF₃OEt₂ boron trifluoride diethyl etherate cat catalytic mCPBA 3-chloroperoxybenzoic acid

CAN cerium (IV) ammonium nitrate

Cbz benzyloxycarbonyl

CDI 1 , 1 '-carbonyldiimidazole

Chloroform-ύf deuterated chloroform

DCE 1 ,2-dichloroethane

DCM dichloromethane

DCC dicyclohexylcarbodiimide

DDQ 2,3-dichloro-5,6-dicyano-l,4-benzoquinone

DIPEA JV,jV-diisopropylethylamine

DIBAL diisobutylaluminium hydride

DMAP N,Λ/-4-dimethylaminopyridine

DMF Λ/,Λ/-dimethylformamide

DMF.DMA Λ/,Λ/-dimethylformamide dimethyl acetal eq equivalent(s)

Ether diethyl ether

Et₂O diethyl ether

EtOAc ethyl acetate

EtOH ethanol

FCC flash column chromatography

GF/F Whatman GF/F syringe filter (retains particles down to 0.7 μm particle size) h (s) hour(s)

HCl hydrochloric acid

HOBt 1 -hydroxybenzotriazo Ie

HBTU o-benzotriazo 1- 1 -yl-N,N,N ' ,N ' -tetramethy luronium tetrafluoroborate

HPLC high pressure liquid chromatography

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

K₂CO₃ potassium carbonate

KHMDS potassium bis(trimethylsilyl)amide

KOH potassium hydroxide

¹BuOK potassium tert-butoxide

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

NaHCO₃ sodium hydrogen carbonate

Na₂SO₄ sodium sulphate

NaIO₄ sodium periodate

NBS Λ/-bromosuccinimide

NMR nuclear magnetic resonance

NH₃ ammonia

NEt₃ triethylamine

NH₄OH ammonium hydroxide

OXONE potassium peroxymonosulfate PBr₃ tribromophosphine

PCl₅ phosphorus pentachloride

POCl₃ phosphorus oxychloride

PhMe toluene

PhI iodobenzene

PPh₃ triphenylphosphine

PS-DIPEA polymer-supported Λ/,Λ/-diisopropylethylamine

RuCl₃ ruthenium(III) chloride

Rt retention time

RT room temperature

SCX toluene sulfonic acid functionalised silica in pre-packed cartridge

STAB sodium triacetoxyborohydride

SiO₂ silica gel

SOCl₂ thionyl chloride

TBAI tetra-n-butylammonium iodide

¹BuLi tert-hvXy\ lithium tert tertiary

TEA triethylamine

TFA 2,2,2-trifluoroacetic acid

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

HCI, dioxane

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

To a stirred suspension of commercially available 2-chloro-5,6,7,8-tetrahydro-l,6- naphthyridine hydrochloride salt (10 g, 48.7 mmol, 1 eq) in DCM (150 mL) was added tert- butyl dicarbonate (16 g, 73.1 mmol, 1.5 eq). Triethylamine (20.5 mL, 146 mmol, 3 eq) was added drop wise via syringe and the resulting solution stirred at RT for 16 to 24 hours. The organic solution was washed with saturated aqueous NaHCOs (2 x 25 mL), dried (MgSO₄), filtered and concentrated under reduced pressure to give white solid. Purification by FCC eluting with DCM/MeOH/NH₃ 95:5:1 gave the desired product as white solid (12.3 g, 94%). LCMS data: Calculated MH⁺ (269); Found 97% (MH⁺) m/z 269, Rt = 2.01 min (LCMS Method B).

¹H NMR (250 MHz, MeOD) δ ppm 7.60 (1 H, d, J=8.1 Hz), 7.28 (1 H, d, J=8.2 Hz), 4.59 (2 H, s), 3.74 (2 H, t, J=6.0 Hz), 2.91 (2 H, t, J=5.9 Hz), 1.41 - 1.56 (9 H, m).

Preparation of tert-b\\ty\ 2-chloro-5-oxo-7,8-dihydro-l,6-naphthyridine-6(5H)- carboxylate

To a stirred solution of tert-bvXy\ 2-chloro-7,8-dihydro-l,6-naphthyridine-6(5H)-carboxylate (5 g, 18.65 mmol, 1 eq) in carbon tetrachloride (50 mL) and MeCN (1 mL) was added a solution Of NaIO₄ (11.97 g, 55.97 mmol, 3 eq) in water (20 rnL). To the bi-phasic solution was added RuCl3 (1.16 g, 5.59 mmol, 0.3 eq) and the reaction mixture was stirred at RT for between 4 and 24 hours. When complete consumption of starting material was observed by LCMS, the reaction mixture was diluted with DCM (50 mL) and washed with water (3 x 20 mL). The aqueous phases were back extracted with DCM (30 mL) and the combined organics dried (MgSO₄), filtered and concentrated under reduced pressure. The resulting solid was dissolved in Et₂O, filtered and concentrated under reduced pressure to give desired product as white solid (4.65 g, 88%).

LCMS data: Calculated MH⁺ (283); Found 99% (MH⁺) m/z 283, Rt = 1.9 min (LCMS Method B).

¹H NMR (500 MHz, MeOD) δ ppm 8.35 (1 H, d, J=8.2 Hz), 7.48 (1 H, d, J=8.2 Hz), 4.08 (2 H, t, J=6.5 Hz), 3.16 (2 H, t, J=6.4 Hz), 1.57 (9 H, s).

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

To a stirred solution of tert-butyl 2-chloro-5-oxo-7,8-dihydro-l,6-naphthyridine-6(5H)- carboxylate (1 g, 3.5 mmol, 1 eq) in dioxane (5 mL) was slowly added 4M HCl in dioxane (14 mL, 53 mmol, 15 eq) via syringe. During the addition a white precipitate is formed. The reaction was monitored by TLC and upon complete consumption of starting material, concentrated under reduced pressure. The residue was dissolved in DCM and then concentrated under reduced pressure once more. Drying in a vacuum oven overnight furnished the title compound (620 mg, 97%).

LCMS data: Calculated MH⁺ (183); Found 100% (MH⁺) m/z 183, Rt = 1.1 min (LCMS Method B). 1H NMR (500 MHz, MeOD) δ ppm 8.24 (1 H, d, J=8.2 Hz), 7.46 (1 H, d, J=8.2 Hz), 3.59 (2 H, t, J=6.9 Hz), 3.12 (2 H, t, J=6.8 Hz).

General Procedure A: Preparation of 2-chloro-6-ethyl-7,8-dihydro-l,6-naphthyridin-

5(6H)-one

To a stirred solution of 2-chloro-7,8-dihydro-l,6-naphthyridin-5(6H)-one (215 mg, 1.18 mmol, 1.0 eq) in DMF or THF (3 rnL) was added NaH (95 mg, 2.36 mmol, 2.0 eq) in small portions. An ice bath at 0 ⁰C was used to control the exotherm and the suspension stirred for 30 minutes. Bromoethane (131 μL, 1.77 mmol, 1.5 eq) was added via syringe and the reaction stirred at RT until the reaction was seen to be complete by TLC or LCMS analysis. Saturated NaHCO₃ (aq) (2 mL), water (2 mL) and diethyl ether (3 mL) were added to the reaction and the organic phase extracted. The aqueous phase was washed with diethyl ether (3 x 5 mL) and the combined organic phases washed with saturated NaHCO₃ (aq) (5 mL). The organic phase was dried (MgSO₄), filtered and concentrated under reduced pressure. The crude material was purified by FCC (Heptane/EtOAc gradient from 100:0 to 70:30) to give the title compound (156 mg, 63%). Alternatively, recrystallisation from heptane/EtOAc provides the pure title compound.

LCMS data: Calculated MH⁺ (211); Found 94% (MH⁺) m/z 211, Rt = 1.44 min (LCMS Method B). 1H NMR (500 MHz, MeOD) δ ppm 8.25 (1 H, d, J=8.1 Hz), 7.46 (1 H, d, J=8.1 Hz), 3.72 (2 H, t, J=6.9 Hz), 3.62 (2 H, q, J=7.2 Hz), 3.16 (2 H, t, J=6.8 Hz), 1.23 (3 H, t, J=7.2 Hz).

The following intermediates were prepared as described in Route 1, General Procedure A above.

Preparation of 2-chloro-6-methyl-7,8-dihydro- 1 ,6-naphthyridin-5(6H)-one

In a similar fashion (Route 1, GP A), 2-chloro-7,8-dihydro-l,6-naphthyridin-5(6H)-one (36 mg, 0.20 mmol, 1 eq) in THF and iodomethane (14 μL, 0.22 mmol, 1.1 eq) gave the title compound (42.6 mg) which was used without further purification.

LCMS data: Calculated MH⁺ (197); Found 95% (MH⁺) m/z 197, Rt = 1.27 min (LCMS

Method B).

¹H NMR (500 MHz, MeOD) δ ppm 8.24 (1 H, d, J=8.1 Hz), 7.45 (1 H, d, J=8.3 Hz), 3.71 (2

H, t, J=6.9 Hz), 2.93 - 3.25 (5 H, m).

Preparation of 2-chloro-6-(cyclopr opylmethyl)-7,8-dihydro- 1 ,6-naphthyridin-5(6H)-one

In a similar fashion (Route 1, GP A), 2-chloro-7,8-dihydro-l,6-naphthyridin-5(6H)-one (500 mg, 2.75 mmol, 1 eq), NaH (219 mg, 5.49 mmol, 2 eq) and (bromomethyl)cyclopropane (540 μL, 5.49 mmol, 2.0 eq) in DMF gave the title compound (537 mg, 83%) as white solid after recrystallisation from heptane / EtOAc.

LCMS data: Calculated MH⁺ (237); Found 94% (MH⁺) m/z 237, Rt = 1.66 min (LCMS Method B).

¹H NMR (500 MHz, MeOD) δ ppm 8.25 (1 H, d, J=8.1 Hz), 7.46 (1 H, d, J=8.2 Hz), 3.81 (2 H, t, J=6.9 Hz), 3.47 (2 H, d, J=7.0 Hz), 3.17 (2 H, t, J=6.8 Hz), 1.01 - 1.22 (1 H, m), 0.56 (2 H, dd, J=8.1, 1.4 Hz), 0.34 (2 H, d, J=5.8 Hz).

Preparation of 2-chloro-6-(tetrahydro-2H-pyran-4-ylmethyl)-7,8-dihydro- 1,6- naphthyridin-5(6H)-one

In a similar fashion (Route 1, GP A), 2-chloro-7,8-dihydro-l,6-naphthyridin-5(6H)-one (50 mg, 0.28 mmol, 1 eq), NaH (22 mg, 0.55 mmol, 2 eq) and 4-(bromomethyl)tetrahydro-2H- pyran (73 mg, 0.41 mmol, 1.5 eq) in DMF (2 mL), gave the title compound (17 mg, 20%) as white solid after FCC. LCMS data: Calculated MH⁺ (281); Found 100% (MH⁺) m/z 281, Rt = 1.50 min (LCMS Method B).

¹H NMR (500 MHz, MeOD) δ ppm 8.23 (1 H, d, J=8.2 Hz), 7.36 - 7.50 (1 H, m), 3.95 (2 H, dd, J=I 1.3, 2.7 Hz), 3.55 - 3.78 (2 H, m), 3.26 - 3.52 (4 H, m), 3.07 - 3.22 (2 H, m), 2.04 (1 H, m), 1.54 - 1.73 (2 H, m), 1.31 - 1.47 (2 H, m).

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

In a similar fashion (Route 1, GP A), 2-chloro-7,8-dihydro-l,6-naphthyridin-5(6H)-one (50 mg, 0.28 mmol, 1 eq), NaH (22 mg, 0.55 mmol, 2 eq) and (bromomethyl)cyclohexane (76 μL, 0.55 mmol, 2.0 eq) in DMF (2 niL), gave the title compound (55.5 mg, 72%) as an off-white solid which was used without further purification.

LCMS data: Calculated MH⁺ (279); Found 94% (MH⁺) m/z 279, Rt = 2.11 min (LCMS Method B). 1H NMR (500 MHz, MeOD) δ ppm 8.23 (1 H, d, J=8.2 Hz), 7.45 (1 H, d, J=8.2 Hz), 3.70 (2 H, t, J=6.9 Hz), 3.41 (2 H, d, J=7.2 Hz), 3.14 (2 H, t, J=6.8 Hz), 0.97 - 1.82 (10 H, m), 0.82 - 0.94 (1 H, m).

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

In a similar fashion (Route 1, GP A), 2-chloro-7,8-dihydro-l,6-naphthyridin-5(6H)-one (59 mg, 0.33 mmol, 1 eq), NaH (40 mg, 0.98 mmol, 3 eq) and (bromomethyl)benzene (42 μL, 0.36 mmol, 1.1 eq) in THF (2.5 mL), gave the title compound (70 mg, 78%) as off- white solid which was used without further purification. LCMS data: Calculated MH⁺ (273); Found 90% (MH⁺) m/z 273, Rt = 1.83 min (LCMS Method B).

¹H NMR (250 MHz, MeOD) δ ppm 8.30 (1 H, d, J=8.2 Hz), 7.47 (1 H, d, J=8.2 Hz), 7.17 - 7.41 (5 H, m), 4.78 (2 H, s), 3.63 (2 H, t, J=6.9 Hz), 3.10 (2 H, t, J=6.9 Hz).

Preparation of 6-chloro-2-(4-fluorobenzyl)-3,4-dihydroisoquinolin-l(2H)-one

In a similar fashion (Route 1, GP A), 2-chloro-7,8-dihydro-l,6-naphthyridin-5(6H)-one (50 mg, 0.27 mmol, 1 eq), NaH (22 mg, 0.55 mmol, 2 eq) and l-(bromomethyl)-4-fluorobenzene (51 μL, 0.41 mmol, 1.5 eq) in DMF (2.5 mL), gave the title compound (32 mg, 41%) as off- white solid which was used without further purification.

LCMS data: Calculated MH⁺ (291); Found 89% (MH⁺) m/z 291, Rt = 1.31 min (LCMS Method A).

¹H NMR (500 MHz, CHLOROFORM-^) δ ppm 8.34 (1 H, d, J=8.1 Hz), 7.28 - 7.37 (3 H, m), 7.03 (2 H, t, J=8.6 Hz), 4.74 (2 H, s), 3.56 (2 H, t, J=6.8 Hz), 3.12 (2 H, t, J=6.9 Hz). Preparation of 2-chloro-6- [(6-methylpyridin-3-yl)methyl] -7,8-dihydro- 1 ,6-naphthyridin-

5(6H)-one

In a similar fashion (Route 1, GP A), 2-chloro-7,8-dihydro-l,6-naphthyridin-5(6H)-one (50 mg, 0.27 mmol, 1 eq), NaH (43 mg, 1.08 mmol, 4 eq) and 5-(chloromethyl)-2-methylpyridine hydrochloride salt (72 mg, 0.41 mmol, 1.5 eq) in DMF (1.5 mL), gave the title compound (76mg, 96%) as off white solid after FCC.

LCMS data: Calculated MH⁺ (288); Found 95% (MH⁺) m/z 288 Rt = 0.98 min (LCMS Method B). 1H NMR (500 MHz, MeOD) δ ppm 8.37 - 8.50 (1 H, m), 8.09 - 8.36 (1 H, m), 7.68 - 7.79 (1 H, m), 6.67 - 7.54 (2 H, m), 4.70 - 4.83 (2 H, m), 3.59 - 3.73 (2 H, m), 2.94 - 3.20 (2 H, m), 2.52 (3 H, s).

Preparation of 2-chloro-6-(2-methoxyethyl)-7,8-dihydro- 1 ,6-naphthyridin-5(6H)-one

In a similar fashion (Route 1, GP A), 2-chloro-7,8-dihydro-l,6-naphthyridin-5(6H)-one (100 mg, 0.55 mmol, 1 eq), NaH (37 mg, 0.90 mmol, 1.6 eq) and 2-bromoethylmethylether (51 μL, 0.55 mmol, 1 eq) in DMF (4.5 mL), gave the title compound (68 mg, 52%) as yellow oil after FCC. LCMS data: Calculated MH⁺ (241); Found 95% (MH⁺) m/z 241, Rt = 1.45 min (LCMS Method B).

¹H NMR (500 MHz, CHLOROFORM-J) δ ppm 8.22 (1 H, d, J=8.2 Hz), 7.43 (1 H, d, J=8.1 Hz), 3.72 - 3.80 (4 H, m), 3.60 - 3.65 (2 H, m), 3.36 (3 H, s), 3.13 (2 H, t, J=6.8 Hz).

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

In a similar fashion (Route 1, GP A), 2-chloro-7,8-dihydro-l,6-naphthyridin-5(6H)-one (40 mg, 0.22 mmol, 1 eq), NaH (20 mg, 0.45 mmol, 2 eq) and 2-chloro-Λ/,iV-dimethylacetamide (26 mg, 0.22 mmol, 1 eq) in DMF (1 niL), gave the title compound (40 mg, 31%) as pale yellow oil after FCC.

¹H NMR (500 MHz, CHLOROFORM-J) δ ppm 8.25 (1 H, d, J=8.1 Hz), 7.46 (1 H, d, J=8.2 Hz), 4.47 (2 H, s), 3.75 (2 H, t, J=6.8 Hz), 3.21 (2 H, t, J=6.9 Hz), 3.09 - 3.10 (3 H, m), 2.98 - 3.02 (3 H, m).

Preparation of 2-chloro-6-(2-hydroxy-2-methylpr opyl)-7,8-dihydro- 1 ,6-naphthyridin-

5(6H)-one

In a similar fashion (Route 1, GP A), 2-chloro-7,8-dihydro-l,6-naphthyridin-5(6H)-one (95 mg, 0.52 mmol, 1 eq), NaH (46 mg, 1.15 mmol, 2.2 eq) and 1 ,2-epoxy-2-methylpropane (1.04 mmol, 92 μL, 2 eq) in DMF (5 mL), gave the title compound as white solid after FCC (15 mg, 12%). LCMS data: Calculated MH⁺ (255); Found 98% (MH⁺) m/z 255, Rt = 0.99 min (LCMS Method A).

¹H NMR (500 MHz, MeOD) δ ppm 8.25 (1 H, d, J=8.2 Hz), 7.46 (1 H, d, J=8.2 Hz), 3.87 (2 H, t, J=6.7 Hz), 3.57 (2 H, s), 3.16 (2 H, t, J=6.7 Hz), 1.24 (6 H, s).

Preparation of 2-chloro-6- [4-(methylsulfonyl)benzyl] -7,8-dihydro- 1 ,6-naphthyridin- 5(6H)-one

In a similar fashion (Route 1, GP A), 2-chloro-7,8-dihydro-l,6-naphthyridin-5(6H)-one (50 mg, 0.23 mmol, 1 eq), NaH (22 mg, 0.55 mmol, 1.6 eq) and l-(bromomethyl)-4- (methylsulfonyl)benzene (62 mg, 0.25 mmol, 1.1 eq) in DMF (4.5 mL), gave the title compound (68 mg, 52%) as yellow solid after trituration with heptane.

LCMS data: Calculated MH⁺ (351); Found 60% (MH⁺) m/z 351, Rt = 1.63 mins (LCMS Method B).

¹H NMR (500 MHz, MeOD) δ ppm 8.29 - 8.34 (1 H, m), 7.92 - 7.99 (3 H, m), 7.61 - 7.66 (2 H, m), 4.86 - 4.91 (2 H, m), 3.66 - 3.78 (2 H, m), 3.54 - 3.63 (2 H, m), 3.11 (3 H, s). Preparation of 2-chloro-6- [(methylsulfanyl)methyl] -7,8-dihydro- 1 ,6-naphthyridin- 5(6H)-one

In a similar fashion (Route 1, GP A), 2-chloro-7,8-dihydro-l,6-naphthyridin-5(6H)-one (100 mg, 0.46 mmol, 1 eq), NaH (37 mg, 0.92 mmol, 2 eq) and chloromethyl methyl sulfide (65 mg, 0.69 mmol, 1.5 eq) in DMF (2 mL), gave the title compound (87 mg, 78%) as yellow oil which was used without purification.

LCMS data: Calculated MH⁺ (243); Found 82% (MH⁺) m/z 243, Rt = 1.58 mins (LCMS Method B). 1H NMR (500 MHz, CHLOROFORM-J) δ ppm 8.29 (1 H, d, J=8.2 Hz), 7.35 (1 H, d, J=8.2 Hz), 4.72 (2 H, s), 3.77 (2 H, t, J=6.8 Hz), 3.23 (2 H, t, J=6.8 Hz), 2.12 - 2.20 (3 H, m).

General Procedure B: Example 1 - Preparation of 2-[(l-cyclobutylpiperidin-4-yl)oxy]-6-ethyl-

7,8-dihydro-l,6-naphthyridin-5(6H)-one. Potency Range A

To a stirred solution of l-cyclobutylpiperidin-4-ol (172 mg, 1.11 mmol, 1.5 eq) in THF (3 mL) was added KO¹Bu in THF (20% wt/wt, 831 mg, 1.48 mmol, 2 eq) and 4 A molecular sieves. After stirring for 1 hour, 2-chloro-6-ethyl-7,8-dihydro-l,6-naphthyridin-5(6H)-one (156 mg, 0.742 mmol, 1 eq) was added to the yellow suspension in one portion. The resulting crimson solution was stirred overnight at RT. Saturated aqueous NaHCO₃ (2 mL) was added to the reaction mixture which was then extracted with EtOAc (3 x 3 mL). The combined organic phases were dried (MgSO₄), filtered and concentrated under reduced pressure. Purification by semi-preparative HPLC provided the title compound as a TFA salt. The free base title compound was obtained through capture and release on an SCX-2 column eluting with MeOH followed by 2 M ammonia in MeOH (67.7 mg, 28%).

LCMS data: Calculated MH⁺ (330); Found 100% (MH⁺) m/z 330, Rt = 4.48 min (LCMS Method D). 1H NMR (500 MHz, MeOD) δ ppm 8.10 (1 H, d, J=8.5 Hz), 6.70 (1 H, d, J=8.7 Hz), 5.15 - 5.21 (1 H, m), 3.66 (2 H, t, J=6.9 Hz), 3.58 (2 H, q, J=7.2 Hz), 3.04 (2 H, t, J=6.9 Hz), 2.77 - 2.85 (1 H, m), 2.68 (2 H,m), 2.23 (2 H,m), 2.01 - 2.12 (4 H, m), 1.87 - 1.97 (2 H, m), 1.77 - 1.85 (2 H, m), 1.69 - 1.77 (2 H, m), 1.21 (3 H, t, J=7.2 Hz).

The following compounds were prepared as described in Route 1, General Procedure B above.

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

7,8-dihydro-l,6-naphthyridin-5(6H)-one. Potency range A

In a similar fashion (Route 1, GP B), 2-chloro-6-methyl-7,8-dihydro-l,6-naphthyridin-5(6H)- one (42.6 mg, 0.22 mmol, 1.0 eq), KO¹Bu (49 mg, 0.43 mmol, 2 eq) and 1- cyclobutylpiperidin-4-ol (60 mg, 0.38 mmol, 1.75 eq) gave the TFA salt of the title compound as colourless oil (7.1 mg, 8%) after purification by semi-preparative HPLC (Prep Method 1). LCMS data: Calculated MH⁺ (316); Found 93% (MH⁺) m/z 316, Rt = 4.05 min (LCMS Method D).

¹H NMR (500 MHz, MeOD) δ ppm 8.11 (1 H, d, J=8.4 Hz), 6.70 (1 H, d, J=8.6 Hz), 5.21 (1 H, m), 3.65 (2 H, t, J=7.0 Hz), 3.05 - 3.21 (5 H, m), 2.93 (1 H, m), 2.76 (2 H, m.), 2.38 (2 H, m), 2.04 - 2.18 (4 H, m), 1.62 - 2.02 (6 H, m).

Example 3 - Preparation of 2-[(l-cyclobutylpiperidin-4-yl)oxy]-6-

(cyclopropylmethyl)-7,8-dihydro-l,6-naphthyridin-5(6H)-one. Potency range A

In a similar fashion (Route 1, GP B), 2-chloro-6-(cyclopropylmethyl)-7,8-dihydro-l,6- naphthyridin-5(6H)-one (90 mg, 0.38 mmol, 1.0 eq), KO¹Bu in THF (20% wt/wt, 341 mg, 0.76 mmol, 2 eq) and l-cyclobutylpiperidin-4-ol (88 mg, 0.57 mmol, 1.5 eq) gave the title compound (22.3 mg, 16%) as colourless oil.

LCMS data: Calculated MH⁺ (356); Found 97% (MH⁺) m/z 356, Rt = 4.81 min (LCMS

Method D).

¹H NMR (500 MHz, MeOD) δ ppm 8.10 (1 H, d, J=8.5 Hz), 6.71 (1 H, d, J=8.5 Hz), 5.11 - 5.33 (1 H, m), 3.74 (2 H, t, J=6.9 Hz), 3.43 (2 H, d, J=7.0 Hz), 3.05 (2 H, t, J=6.9 Hz), 2.94 (1

H, t, J=7.9 Hz), 2.76 (2 H, m), 2.38 (2 H, m), 2.04 - 2.18 (4 H, m), 1.92 - 2.02 (2 H, m), 1.86 (2 H, d, J=8.5 Hz), 1.67 - 1.81 (2 H, m), 0.96 - 1.18 (1 H, m), 0.45 - 0.61 (2 H, m), 0.22 - 0.40 (2 H, m).

Example 4 - Preparation of 2-[(l-cyclobutylpiperidin-4-yl)oxy]-6- (tetrahydro-2H-pyran-4-ylmethyl)-7,8-dihydro- 1 ,6-naphthyridin-5(6H)-one. Potency range A

In a similar fashion (Route 1, GP B), 2-chloro-6-(tetrahydro-2H-pyran-4-ylmethyl)-7,8- dihydro-l,6-naphthyridin-5(6H)-one (75 mg, 0.27 mmol, 1.0 eq), KO¹Bu in THF (20% wt/wt, 224 mg, 0.50 mmol, 2 eq) and l-cyclobutylpiperidin-4-ol (63 mg, 0.41 mmol, 1.5 eq) gave the TFA salt of the title compound as colourless oil (2.8 mg, 2%) after purification by semi- preparative HPLC (Prep Method 1).

LCMS data: Calculated MH⁺ (400); Found 92% (MH⁺) m/z 400, Rt = 4.33 min (LCMS Method D). 1H NMR (500 MHz, MeOD) δ ppm 8.10 (1 H, d, J=8.7 Hz), 6.70 (1 H, d, J=8.5 Hz), 5.18 (1 H, br. s.), 3.92 - 3.98 (2 H, m), 3.67 (2 H, t, J=6.9 Hz), 3.37 - 3.47 (4 H, m), 3.04 (2 H, t, J=6.9 Hz), 2.77 - 2.86 (1 H, m), 2.67 (2 H, br. s.), 2.24 (2 H, br. s.), 1.98 - 2.13 (5 H, m), 1.87 - 1.97 (2 H, m), 1.68 - 1.86 (4 H, m), 1.63 (2 H, dd, J=13.0, 1.5 Hz), 1.31 - 1.43 (2 H, m).

Example 5 - Preparation of 2-[(l-cyclobutylpiperidin-4-yl)oxy]-6-

(cyclohexylmethyl)-7,8-dihydro-l,6-naphthyridin-5(6H)-one. Potency range A

In a similar fashion (Route 1, GP B), 2-chloro-6-(cyclohexylmethyl)-7,8-dihydro-l,6- naphthyridin-5(6H)-one (35 mg, 0.13 mmol, 1.0 eq), KO¹Bu in THF (20% wt/wt, 176 mg, 0.32 mmol, 2.5 eq) and l-cyclobutylpiperidin-4-ol (40 mg, 0.25 mmol, 2 eq) gave the TFA salt of the title compound as colourless oil (11.4 mg, 18%) after purification by semi- preparative HPLC (Prep Method 1).

LCMS data: Calculated MH⁺ (398); Found 94% (MH⁺) m/z 398, Rt = 3.14 min (LCMS Method C). ¹H NMR (500 MHz, MeOD) δ ppm 7.99 - 8.31 (1 H, m), 6.60 - 6.98 (1 H, m), 5.24 - 5.60 (1 H, m), 3.69 - 3.81 (1 H, m), 3.61 - 3.69 (2 H, m), 3.35 - 3.61 (4 H, m), 2.97 - 3.17 (4 H, m), 2.30 - 2.54 (4 H, m), 2.18 - 2.30 (2 H, m), 2.01 - 2.15 (1 H, m), 1.82 - 1.97 (3 H, m), 1.65 - 1.81 (6 H, m), 1.15 - 1.37 (3 H, m), 0.95 - 1.11 (2 H, m).

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

7,8-dihydro-l,6-naphthyridin-5(6H)-one. Potency range A

In a similar fashion (Route 1, GP B), 6-benzyl-2-chloro-7,8-dihydro-l,6-naphthyridin-5(6H)- one (50 mg, 0.18 mmol, 1.0 eq), KO¹Bu in THF (20% wt/wt, 302 mg, 0.54 mmol, 3 eq) and l-cyclobutylpiperidin-4-ol (57 mg, 0.354 mmol, 2 eq) gave the title compound (9.1 mg, 13%) as colourless oil.

LCMS data: Calculated MH⁺ (392); Found 100% (MH⁺) m/z 392, Rt = 5.28 min (LCMS

Method C). 1H NMR (250 MHz, MeOD) δ ppm 8.17 (1 H, d, J=8.5 Hz), 7.15 - 7.46 (5 H, m), 6.75 (1 H, d, J=8.7 Hz), 5.21 (1 H, m), 4.76 (2 H, s), 3.48 - 3.66 (2 H, m), 3.00 (5 H, s), 2.24 - 2.50 (2 H, m), 1.44 - 2.23 (10 H, m).

Example 7 - Preparation of 2-[(l-cyclobutylpiperidin-4-yl)oxy]-6-(4- fluorobenzyl)-7,8-dihydro- 1 ,6-naphthyridin-5(6H)-one. Potency range A

In a similar fashion (Route 1, GP B), 2-chloro-6-(4-fluorobenzyl)-7,8-dihydro-l,6- naphthyridin-5(6H)-one (32 mg, 0.11 mmol, 1.0 eq), KO¹Bu in TΗF (20% wt/wt, 124 μL, 0.22 mmol, 2 eq) and l-cyclobutylpiperidin-4-ol (26 mg, 0.17 mmol, 1.5 eq) gave the title compound (1.9 mg, 9%) as colourless oil.

LCMS data: Calculated MH⁺ (410); Found 94% (MH⁺) m/z 410, Rt = 5.23 min (LCMS Method D).

¹H NMR (500 MHz, MeOD) δ ppm 8.18 (1 H, d, J=8.7 Hz), 7.37 (2 H, dd, J=8.5, 5.3 Hz), 7.05 - 7.11 (2 H, m), 6.76 (1 H, d, J=8.5 Hz), 5.30 (1 H, d, J=4.9 Hz), 4.73 (2 H, s), 3.58 (2 H, t, J=6.9 Hz), 3.01 (3 H, m), 2.90 - 2.99 (2 H, m), 2.58 - 2.80 (2 H, m), 1.92 - 2.27 (8 H, m), 1.75 - 1.87 (2 H, m).

Example 8 - Preparation of 2-[(l-cyclobutylpiperidin-4-yl)oxy]-6-[(6- methylpyridin-3-yl)methyl] -7,8-dihydro- 1 ,6-naphthyridin-5(6H)-one. Potency range A

In a similar fashion (Route 1, GP B), 2-chloro-6-[(6-methylpyridin-3-yl)methyl]-7,8-dihydro- l,6-naphthyridin-5(6H)-one (76 mg, 0.26 mmol, 1 eq), KO¹Bu in THF (20% wt/wt, 221 mg, 0.40 mmol, 1.5 eq) and l-cyclohexylpiperidin-4-ol (51 mg, 0.33 mmol, 1.25 eq) gave the title compound (9.3 mg, 9%).

LCMS data: Calculated MH⁺ (407); Found 100% (MH⁺) m/z 407, Rt = 2.07 min (LCMS Method C).

¹H NMR (500 MHz, MeOD) δ ppm 8.41 (1 H, d, J=I.68 Hz), 8.17 (1 H, d, J=8.54 Hz), 7.55 - 7.94 (1 H, m), 7.30 (1 H, d, J=8.09 Hz), 6.75 (1 H, d, J=8.54 Hz), 5.25 (1 H, m), 4.75 (2 H, s), 3.62 (2 H, t, J=6.87 Hz), 3.19 (1 H, m), 3.03 (2 H, t, J=6.87 Hz), 2.90 (2 H, m), 2.67 (2 H, m), 2.52 (3 H, s), 1.87 - 2.28 (8 H, m), 1.67 - 1.87 (2 H, m).

Example 9 - Preparation of 2-[(l-cyclobutylpiperidin-4-yl)oxy]-6-(2- methoxyethyl)-7,8-dihydro-l,6-naphthyridin-5(6H)-one. Potency range A

In a similar fashion (Route 1, GP B), 2-chloro-6-(2-methoxyethyl)-7,8-dihydro-l,6- naphthyridin-5(6H)-one (68 mg, 0.28 mmol, 1.0 eq), KO¹Bu in THF (20% wt/wt, 313 mg, 0.56 mmol, 2 eq) and l-cyclohexylpiperidin-4-ol (65 mg, 0.43 mmol, 1.5 eq) gave the title compound (40 mg, 40%).

LCMS data: Calculated MH⁺ (360); Found 100% (MH⁺) m/z 360, Rt = 2.34 min (LCMS

Method C).

¹H NMR (500 MHz, MeOD) δ ppm 8.07 (1 H, d, J=8.5 Hz), 6.69 (1 H, d, J=8.7 Hz), 5.13 - 5.47 (1 H, m), 3.62 - 3.75 (4 H, m), 3.51 - 3.61 (2 H, m), 3.31 (3 H, s), 2.83 - 3.05 (4 H, m),

2.49 - 2.82 (2 H, m), 1.85 - 2.26 (9 H, m), 1.65 - 1.83 (2 H, m). Example 10 - Preparation of 2-{2-[(l-cyclobutylpiperidin-4-yl)oxy]-5-oxo-

7,8-dihydro-l,6-naphthyridin-6(5H)-yl}-N,N-dimethylacetamide. Potency range A

In a similar fashion (Route 1, GP B), 2-(2-chloro-5-oxo-7,8-dihydro-l,6-naphthyridin-6(5H)- yl)-N,N-dimethylacetamide (18 mg, 0.07 mmol, 1 eq), NaH (5 mg, 0.10 mmol, 1.5 eq) and 1- cyclohexylpiperidin-4-ol (9 mg, 0.09 mmol, 1.3 eq) in THF (0.5 mL) gave the title compound (5.1 mg, 19%) as the formic acid salt after purification by semi-preparative HPLC (Prep Method 3).

LCMS data: Calculated MH⁺ (387); Found 96% (MH⁺) m/z 387, Rt = 3.91 min (LCMS Method C).

¹H NMR (500 MHz, MeOD) δ ppm 8.13 - 8.18 (1 H, m), 6.73 - 6.84 (1 H, m), 5.33 - 5.57 (1 H, m), 4.45 (2 H, s), 3.68 - 3.80 (3 H, m), 3.38 - 3.62 (2 H, m), 3.07 - 3.16 (6 H, m), 2.95 - 3.06 (4 H, m), 2.32 - 2.52 (4 H, m), 2.19 - 2.30 (2 H, m), 1.81 - 2.14 (4 H, m).

Route 2

0 ⁰C, 2 h

Preparation of ethyl 6-methylpyridine-3-carboxylate

To a stirred solution of 6-methylnicotinic acid (500 mg, 3.6 mmol, 1.0 eq) in DCM (10 mL) at -40 ⁰C was added oxalyl chloride (462 μL, 5.4 mmol, 1.5 eq). The temperature was allowed to rise to 0 ⁰C and 2 drops of DMF added. The solution was stirred at RT for 1 hour and then concentrated under reduced pressure to give orange oil. The oil was dissolved in EtOH (15 niL), cooled to 0 ⁰C and NEt₃ (1.7 niL, 12.6 mmol, 3.5 eq) was added dropwise. After 10 minutes the reaction was warmed to RT and stirred for a further 1 hour. Volatiles were then removed under reduced pressure leaving a brown solid which was suspended in Et₂O (20 mL), washed with brine (2 x 5 mL) and water (1 x 5 mL). The aqueous washes were combined and extracted with EtOAc (1 x 10 mL). The combined Et₂O and EtOAc fractions were combined, dried (MgSO₄), filtered and concentrated under reduced pressure to give the title compound as a brown oil (590 mg, 100%).

¹H NMR (250 MHz, MeOD) δ ppm 8.98 (1 H, d, J=2.1 Hz), 8.27 (1 H, dd, J=8.1, 2.2 Hz), 7.43 (1 H, d, J=8.1 Hz), 4.40 (2 H, q, J=7.2 Hz), 2.61 (3 H, s), 1.40 (3 H, t, J=7.1 Hz).

Preparation of (6-methylpyridin-3-yl)methanol

To a stirred solution of ethyl 6-methylpyridine-3-carboxylate = 541 mg, 3.27 mmol, 1 eq) in THF (7 mL) at 0 ⁰C, was added DIBAL (13.1 mL of a IM solution in toluene, 13.1 mmol, 4 eq). After 2 hours TLC indicated complete comsumption of starting material and the excess DIBAL quenched by slow addition of saturated aqueous NH₄Cl (1 mL). The reaction mixture was diluted with DCM (20 mL), dried (MgSO₄) and filtered. The filter cake was washed with DCM (5 mL), EtOAc (5 mL) and the filtrate concentrated under reduced pressure to give the title compound as a yellow oil (223 mg, 56%). 1H NMR (500 MHz, MeOD) δ ppm 8.38 (1 H, d, J=I.8 Hz), 7.71 (1 H, dd, J=8.0, 2.2 Hz), 7.27 (1 H, d, J=8.1 Hz), 4.61 (2 H, s), 2.51 (3 H, s).

Preparation of 5-(chloromethyl)-2-methylpyridine hydrochloride salt

To a stirred solution of (6-methylpyridin-3-yl)methanol (223 mg, 1.81 mmol, 1 eq) in DCM

(7 mL) at 0 ⁰C was slowly added SOCl₂ (652 μL, 9.06 mmol, 5 eq). After 2 hours the reaction was concentrated under reduced pressure to give the title compound as an orange oil.

LCMS data: Calculated MH⁺ (142); Found 95% (MH⁺) m/z 142, Rt = solvent front (LCMS

Method B). 1H NMR (500 MHz, MeOD) δ ppm 8.86 (1 H, d, J=I.4 Hz), 8.62 (1 H, dd, J=8.4, 1.8 Hz),

8.00 (1 H, d, J=8.4 Hz), 4.91 (2 H, s), 2.85 (3 H, s). Route 3

Example 11 - Preparation of 2-[(l-cyclobutylpiperidin-4-yl)oxy]-7,8- dihydro-l,6-naphthyridin-5(6H)-one. Potency range A

To a stirred solution of l-cyclobutylpiperidin-4-ol (60 mg, 0.38 mmol, 1.75 eq) in THF (2 niL) and DMF (0.2 niL) was added KO¹Bu (50 mg, 0.44 mmol, 2.0 eq). After 1 hour, 2- chloro-5,6,7,8-tetrahydro-l,6-naphthyridine hydrochloride salt (40 mg, 0.22 mmol, 1.0 eq) was added and the reaction heated to 60 ⁰C for 3 days. The solvent was removed under reduced pressure and the residue taken up in EtOAc, washed with aqueous NaHCOs (2 x 2 mL), dried (MgSO₄), filtered and concentrated under reduced pressure. Purification by semi- preparative HPLC (Prep Method 2) provided the title compound (6.9 mg, 8%). LCMS data: Calculated MH⁺ (302); Found 100% (MH⁺) m/z 302, Rt = 2.02 min (LCMS Method C).

¹H NMR (500 MHz, MeOD) δ ppm 8.07 - 8.21 (1 H, m), 6.68 - 6.87 (1 H, m), 5.28 - 5.57 (1 H, m), 3.76 (1 H, br. s.), 3.55 (3 H, t, J=6.8 Hz), 3.37 - 3.47 (1 H, m), 2.97 - 3.18 (4 H, m), 2.17 - 2.52 (6 H, m), 1.77 - 2.14 (4 H, m).

Route 4

General Procedure B

Preparation of 6-ethyl-l,6-naphthyridin-5(6H)-one

In a similar fashion (Route 1, GP A), l,6-naphthyridin-5(6H)-one (146 mg, 6.85 mmol, 1 eq),

NaH (547 mg of a 60% suspension in mineral oil, 13.7 mmol, 2 eq) and bromoethane (1.14 mL, 10.28 mmol, 1.5 eq) in DMF (10 niL), gave the title compound (965 mg, 81%) after purification by FCC (using a gradient of eluents, 30:70 to 20:80 Heptane/EtOAc) as white solid.

LCMS data: Calculated MH⁺ (175); Found 96% (MH⁺) m/z 175, Rt = 0.96 min (LCMS

Method B).

¹H NMR (500 MHz, MeOD) δ ppm 8.89 (1 H, dd, J=4.6, 1.7 Hz), 8.69 (1 H, dd, J=8.1, 1.1

Hz), 7.69 (I H, d, J=7.6 Hz), 7.55 (1 H, dd, J=8.1, 4.6 Hz), 6.81 (1 H, d, J=7.6 Hz), 4.11 (2 H, q, J=7.3 Hz), 1.38 (3 H, t, J=7.2 Hz).

Preparation of 6-ethyl-l,6-naphthyridin-5(6H)-one 1-oxide

To a stirred solution of 6-ethyl-l,6-naphthyridin-5(6H)-one (500 mg, 2.87 mmol, 1 eq) in DCM (5 mL) at 0 ⁰C was added mCPBA (781 mg, 3.16 mmol, 1.1 eq) and the yellow solution warmed to RT and stirred for 14 hours. The solvent was removed under reduced pressure and the residue purified by FCC (using a gradient of eluents, 100:0 to 90:10 EtOAc/MeOH) to provide the title compound (286 mg, 53%) as white solid.

LCMS data: Calculated MH⁺ (191); Found 100% (MH⁺) m/z 191, Rt = 0.89 min (LCMS

Method B).

¹H NMR (500 MHz, CHLOROFORM-J) δ ppm 8.52 (1 H, d, J=6.3 Hz), 8.21 (1 H, d, J=8.2

Hz), 7.34 - 7.42 (2 H, m), 7.30 (1 H, dd, J=8.2, 6.3 Hz), 4.08 (2 H, q, J=7.2 Hz), 1.41 (3 H, t,

J=7.2 Hz).

Preparation of 2-chloro-6-ethyl-l,6-naphthyridin-5(6H)-one

In a sealed tube a stirred suspension of 6-ethyl-l,6-naphthyridin-5(6H)-one 1-oxide (150 mg, 0.789 mmol, 1 eq) in POCl₃ (1 mL) was heated at 120 ⁰C for 3 h then cooled to 70 ⁰C and stirred for 4 days. The reaction was cooled to 0 ⁰C and quenched with 2 M aqueous Na₂CO₃ (2 mL). Solid Na₂CO₃ was added until pH 9 was reached and the mixture extracted with EtOAc (3 x 5 mL). The combined organic phases were washed with 2 M aqueous Na₂CO₃ (2 mL), dried (MgSO₄), filtered and evaporated at reduced pressure. The residue was partially purified by FCC (EtO Ac/heptane 50:50) to provide the title compound (71 mg, 43%) as off- white solid. Further purification was not attempted. LCMS data: Calculated MH⁺ (209); Found 89% (MH⁺) m/z 209, Rt = 3.22 min (LCMS Method C).

Example 12 - Preparation of 2-[(l-cyclobutylpiperidin-4-yl)oxy]-6-ethyl- l,6-naphthyridin-5(6H)-one. Potency range A

In a similar fashion (Route 1, GP B), 2-chloro-6-ethyl-l,6-naphthyridin-5(6H)-one (71 mg, 0.34 mmol, 1.0 eq) and l-cyclobutylpiperidin-4-ol (80 mg, 0.51 mmol, 1.5 eq) gave the title compound as white solid (18 mg, 16%) after purification by FCC (eluting with EtO Ac/heptane 80:20 then DCM/MeOH/NH₃ 95:5:1). LCMS data: Calculated MH⁺ (328); Found 95% (MH⁺) m/z 328, Rt = 4.48 min (LCMS Method D). ¹H NMR (250 MHz, MeOD) δ ppm 8.35 - 8.52 (1 H, m), 7.52 - 7.72 (1 H, m), 6.77 - 6.98 (1 H, m), 6.51 - 6.75 (1 H, m), 5.17 - 5.40 (1 H, m), 3.94 - 4.19 (2 H, m), 2.61 - 2.96 (3 H, m),

1.61 - 2.56 (12 H, m), 1.24 - 1.49 (3 H, m).

Route 5

General Procedure C

General Procedure C: Preparation of l-cyclobutylpiperidin-4-ol

^HO^C^N^O

The title compound was prepared according to the procedure described in WO-A

2007/052124.

STAB (7.57 g, 35.7 mmol, 1.5 eq) was added portionwise to a stirred solution of piperidin-4- ol (2.41 g, 23.8 mmol, 1 eq) and cyclobutanone (5.0 g, 71.3 mmol, 3 eq) in THF at 0 ⁰C

(ice/water) over 10 min. Cooling was removed and the reaction was stirred at RT for 16 h.

The reaction was concentrated at reduced pressure, cooled to 0 ⁰C and basifϊed by the dropwise addition of concentrated aqueous ammonia. The aqueous phase was extracted with

Et₂O. The combined organic phase was dried (Na₂SO₄), filtered, concentrated at reduced pressure and the residue was purified by FCC (eluting with DCM/MeOH/NH3, 96:4: 1) to give the title compound (1.40 g, 38%).

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

Method D).

¹H 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).

Alternatively, l-cyclobutylpiperidin-4-ol can be synthesised by the scheme illustrated in Route 6. Route 6

General Procedure D

HO

General Procedure D: Preparation of l-cyclobutylpiperidin-4-ol

Pd/C (10%) was added to a solution of piperidin-4-ol (3.5 g, 35 mmol, 1 eq) and cyclobutanone (2.9 mL, 38 mmol, 1.1 eq) in EtOH (250 ml). The mixture was stirred under

H₂ atmosphere for 16 h, filtered through Celite®, and concentrated under reduced pressure.

The residue was purified by flash column chromatography (using a gradient of eluents, DCM/MeOH/NH₃ 95:5:1 to 80:20:5) to give the title compound (5.1 g, 95%) as a pale yellow oil.

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

Method D).

¹H 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).

The following intermediate was prepared as described in Route 6, General Procedure D above.

Preparation of l-cyclohexylpiperidin-4-ol

In a similar fashion (R6, GP D) piperidin-4-ol (1.Og, 9.86 mmol, 1 eq) and cyclohexanone (4.07 mL, 39.4 mmol, 4 eq) after a reaction time of 72 hours gave the title compound (1.19 g, 66%) as yellow solid. 1H NMR (500 MHz, MeOD) δ ppm 3.52 - 3.68 (1 H, m), 2.77 - 2.92 (2 H, m), 2.22 - 2.44 (3 H, m), 1.75 - 1.98 (6 H, m), 1.64 (1 H, br. s.), 1.46 - 1.60 (2H, m), 1.18 - 1.35 (4 H, m), 1.06 - 1.19 (1 H, m).

Preparation of l-oxetan-3-ylpiperidin-4-ol

In a similar fashion (R6, GP D), piperidin-4-ol (225 mg, 2.23 mmol) and 3-oxetanone (161 mg, 2.23 mmol) after a reaction time of 24 hours gave the title compound (130 mg, 37%) as a white solid.

The compound did not ionise by LCMS

¹H NMR (500 MHz, MeOD) δ ppm 4.59 - 4.64 (2 H, m), 4.54 - 4.59 (2 H, m), 3.59 - 3.75 (1

H, m), 3.36 - 3.47 (1 H, m), 2.49 - 2.60 (2 H,m), 1.92 - 2.04 (2 H, m), 1.82 - 1.92 (2 H, m),

1.57 (2 H, m).

Route 7

Preparation of l-(l-methylethyl)piperidin-4-ol

To a stirred solution of piperidin-4-ol (1.0 g, 9.87 mmol, 1 eq) in DCE (100 ml) under an atmosphere of nitrogen was added acetic acid (1.78 g, 29.7 mmol, 3 eq) and acetone (5.72 g, 98.7 mmol, 10 eq). The reaction mixture was stirred for 12 h at RT before addition of STAB (6.29 g, 29.7 mmol). After stirring for 12 h at RT the reaction mixture was concentrated at reduced pressure to give a white solid. Purification by FCC (using a gradient of eluents, 98:2 EtOAc/MeOH to 90:10:1 EtOAc/MeOH/NH₃) gave the title compound (412 mg, 29%) as a colourless oil.

¹H NMR (250 MHz, CHLOROFORM-J) δ ppm 4.97 (1 H, br. s.), 3.39 (1 H, m, J=8.6, 4.0 Hz), 2.23 - 2.77 (3 H, m), 1.88 - 2.16 (2 H, m), 1.49 - 1.75 (2 H, m), 1.35 (2 H, m), 0.63 - 0.97 (6 H, m). Route 8

General Procedure E

General Procedure E: Preparation of l-cyclopentylpiperidin-4-ol

To a stirred solution of piperidin-4-ol (2.0 g, 19.7 mmol, 1 eq) in THF (10 ml) under an atmosphere of nitrogen was added acetic acid (1.9 mL), cyclopentanone (2.5 g, 29.6 mmol, 1.5 eq) and NaCNBH₃ (1.86 g, 29.6 mmol, 1.5 eq). The reaction mixture was stirred for 3 h at 50 ⁰C then the reaction mixture was concentrated at reduced pressure. The residue was dissolved in EtOAc and washed with water, dried (MgSO₄), filtered and concentrated. Purification by FCC (eluting with 70:30:2 EtOAc / MeOH / 2% NH₃) gave the title compound (1.31 g, 40%) as white solid.

¹H NMR (500 MHz, MeOD) δ ppm 3.62 (1 H, br. s.), 2.90 (2 H, m), 2.43 - 2.59 (1 H, m), 2.19 (2 H, m), 1.81 - 1.98 (4 H, m), 1.64 - 1.79 (2 H, m), 1.50 - 1.64 (4 H, m), 1.33 - 1.48 (2 H, m).

The following intermediates were prepared as described in Route 8, General Procedure E above.

Preparation of (3R)-l-cyclobutylpyrrolidin-3-ol

In a similar fashion (R8, GP E), (3i?)-pyrrolidin-3-ol (2.5 g, 28.7 mmol) and cyclobutanone (3.02 g, 43 mmol) gave the title compound (850 mg, 21%) as an oily residue after purification by FCC (eluting with 70:30:2 EtOAc / MeOH / 2% NH₃). 1H NMR (500 MHz, MeOD) δ ppm 4.35 (1 H, tt, J=6.6, 3.3 Hz), 3.02 (1 H, quin, J=7.9 Hz), 2.81 (1 H, m), 2.61 - 2.72 (1 H, m), 2.56 (IH, m), 2.40 (1 H, dd, J=10.7, 3.5 Hz), 1.89 - 2.16 (5 H, m), 1.62 - 1.85 (3 H, m).

Preparation of (3S)-l-cyclobutylpyrrolidin-3-ol

In a similar fashion (R8, GP E), (35)-pyrrolidin-3-ol (0.1 g, 1.15 mmol) and cyclobutanone (0.121 g, 1.73 mmol) gave the title compound (0.13 g, 81%) as a light brown oil after purification by FCC (eluting with 70:30:2 EtOAc / MeOH / 2% NH₃). One equivalent of HCl (IM in DCM) was added to freebase to give an off-white solid.

¹H NMR (500 MHz, MeOD) δ ppm 4.51 (1 H, t, J=4.6 Hz), 3.70 (1 H, quin, J=8.2 Hz), 3.31 - 3.41 (1 H, m), 3.16 - 3.27 (2 H, m), 3.07 - 3.15 (1 H, m), 2.11 - 2.35 (5 H, m), 2.00 (1 H, dddd, J=I 1.6, 7.6, 3.7, 1.8 Hz), 1.77 - 1.93 (3 H, m).

Preparation of (Sφ-l-cyclopentylpyrrolidin-S-ol

In a similar fashion (R8, GP E), (3i?)-pyrrolidin-3-ol (0.2 g, 2.3 mmol) and cyclopentanone (0.29 g, 3.45 mmol) gave the title compound (0.14 g, 39%) as a pale yellow oil after purification by FCC (eluting with 70:30:2 EtOAc / MeOH / 2% NH₃). 1H NMR (500 MHz, MeOD) δ ppm 4.34 (1 H, tt, J=6.8, 3.5 Hz), 2.90 (1 H, dd, J=10.5, 6.3 Hz), 2.68 - 2.81 (1 H, m), 2.58 - 2.68 (1 H, m), 2.51 - 2.58 (IH, m), 2.47 (1 H, dd, J=10.5, 3.7 Hz), 2.01 - 2.20 (1 H, m), 1.80 - 1.96 (2 H, m), 1.65 - 1.80 (3 H, m), 1.52 - 1.65 (2 H, m), 1.36 - 1.51 (2 H, m).

Preparation of (3S)-l-cyclopentylpyrrolidin-3-ol

In a similar fashion (R8, GP E), (35)-pyrrolidin-3-ol (2.0 g, 23 mmol) and cyclopentanone (2.9 g, 34.5 mmol) gave the title compound (0.81 g, 23%) as a pale yellow solid after purification by FCC (eluting with 70:30:2 EtOAc / MeOH / 2% NH₃). 1H NMR (500 MHz, MeOD) δ ppm 4.35 (1 H, tt, J=6.8, 3.4 Hz), 2.92 (1 H, dd, J=10.6, 6.2 Hz), 2.70 - 2.80 (1 H, m), 2.65 (1 H, m), 2.55- 2.62 (1 H, m), 2.50 (1 H, dd, J=10.6, 3.6 Hz), 2.07 - 2.17 (1 H, m), 1.81 - 1.94 (2 H, m), 1.66 - 1.80 (3 H, m), 1.53 - 1.65 (2 H, m), 1.36 - 1.52 (2 H, m).

Route 9

Preparation of 3-piperidin-l-ylpropan-l-ol

To a solution of 3-bromopropanol (500 mg, 3.6 mmol) in DCM (12 niL) was added piperidine (892 μL, 9.05 mmol, 2.5 eq). The solution was stirred at RT for 16 h. Volatiles were removed under reduced pressure and the residue was purified by FCC (eluting with 1 % to 8 % 2M NH₃ in MeOH / DCM) followed by concentrating under reduced pressure at 40 ⁰C for 4 h to give the title compound (510 mg, 99 %) as white solid. 1H NMR (500 MHz, MeOD) δ ppm 3.68 (2 H, t, J=5.8 Hz), 3.18 - 3.29 (2 H, m), 3.15 (2 H, t, J=5.8 Hz), 1.58 - 2.03 (10 H, m).

Route 9a

Preparation of 3-pyrrolidin-l-ylpropan-l-ol

To a solution of pyrrolidine (1.5 g, 19.5 mmol) in toluene (10 mL) was added 3- bromopropanol (5.4 g, 39.0 mmol) and the reaction mixture heated at 80 ⁰C for 5.5 h. After cooling to RT, the toluene was evaporated at reduced pressure and the residue partitioned between DCM (25 mL) and aqueous K2CO3 (25 mL). The organic layer was collected and the aqueous phase extracted with DCM (4 x 25 mL). The combined organic layers were evaporated at reduced pressure to provide the title compound (1.2 g, 86%) as brown oil. 1H NMR (500 MHz, MeOD) δ ppm 3.61 (2 H, t, J=6.3 Hz), 2.48 - 2.71 (6 H, m), 1.70 - 1.89 (6 H, m). Route 10

Preparation of l-(cyclopropylcarbonyl)piperidin-4-yl cyclopropanecarboxylate

To a solution of 4-hydroxypiperidine (1.01 g, 10 mmol, 1 eq) in DCM (10 niL) were successively added diisopropylethyl amine (3.48 rnL, 20 mmol, 2 eq) and cyclopropylcarbonylchloride (1.82 mL, 20 mmol, 2 eq). The reaction mixture was stirred for 16 h at RT. After dilution with DCM (90 mL), the organic phase was washed successively with saturated aqueous NaHCO₃ (30 mL), H₂O (30 mL), dried (Na₂SO₄), filtered and concentrated under reduced pressure. The residue was purified by FCC (using a gradient of eluents, 40:60 to 100:0 EtOAc/Heptane) to provide the title compound (2.1 g, 89%) as yellow oil. 1H NMR (250 MHz, CHLOROFORM-J) δ ppm 5.01 (1 H, m), 3.85 - 4.00 (2 H, m), 3.48 (2 H, m), 1.58 - 1.98 (6 H, m), 0.72 - 1.05 (8 H, m).

Preparation of l-(cyclopropylmethyl)piperidin-4-ol

A solution of l-(cyclopropylcarbonyl)piperidin-4-yl cyclopropanecarboxylate (1.0 g, 4.22 mmol, 1 eq) in THF (10 mL) at 0 ⁰C was treated with 1.0 M LAH in THF (21.5 mL, 21.5 mmol, 5 eq) and the resulting mixture heated to 65 ⁰C for 4 h. The reaction mixture was cooled to 0 ⁰C, water (1 mL), 2M aqueous NaOH (1 mL) and water (1 mL) were added then after dilution with EtOAc, the mixture was stirred for 15 min, dried (Na₂SO₄), filtered and concentrated under reduced pressure. The residue was purified by FCC (eluting with 2% to 10% 2M NH₃ in MeOH / DCM) to provide the title compound (0.3 g, 46%) as yellow oil. ¹H NMR (500 MHz, CHLOROFORM-J) δ ppm 3.70 (1 H, br. s.), 2.90 (2 H, m), 2.14 - 2.31 (4 H, m), 1.88 - 1.99 (2 H, m), 1.53 - 1.68 (3 H, m), 0.81 - 0.92 (1 H, m), 0.48 - 0.57 (2 H, m), 0.06 - 0.13 (2 H, m).

Route 11

Preparation of tert-butyl (l-cyclobutylpiperidin-4-yl)carbamate

In a similar fashion (R6, GP D) tert-butyl piperidin-4-ylcarbamate (2.0 g, 10 mmol, 1 eq) and cyclobutanone (1.05 rnL, 14.0 mmol, 1.4 eq) gave the title compound (1.6 g, 64%) as yellow oil.

¹H NMR (500 MHz, MeOD) δ ppm 3.32 - 3.38 (1 H, m), 2.66 - 2.92 (3 H, m), 2.00 - 2.13 (2 H, m), 1.81 - 1.98 (6 H, m), 1.61 - 1.77 (2 H, m), 1.29 - 1.49 (11 H, m).

Preparation of l-cyclobutyl-N-methylpiperidin-4-amine >o

A solution of tert-butyl (l-cyclobutylpiperidin-4-yl)carbamate (0.27 g, 1.06 mmol, 1 eq) in THF (4.6 mL) at 0 ⁰C was treated with 1.0 M LAH in THF (4.2 rnL, 4.23 mmol, 4 eq) and the resulting mixture heated to 65 ⁰C for 3 h. The reaction mixture was cooled to 0 ⁰C, water (0.32 mL), 2M aqueous NaOH (0.32 mL) and water (0.32 mL) were added and the mixture stirred for 15 min. The mixture was diluted in EtOAc, dried (Na₂SO₄), filtered and evaporated at reduced pressure to give the title compound (165 mg, 93%) as colourless oil. LCMS data: Calculated MH⁺ (169); Found 100% (MH⁺) m/z 169, Rt = 3.85 (LCMS Method D).

¹H NMR (500 MHz, CHLOROFORM-J) δ ppm 3.60 - 3.77 (1 H, m), 2.78 - 2.92 (2 H, m), 2.62 - 2.72 (1 H, m), 2.40 - 2.48 (3 H, m), 2.29 - 2.39 (1 H, m), 1.97 - 2.08 (2 H, m), 1.84 - 1.95 (4 H, m), 1.73 - 1.83 (2 H, m), 1.61 - 1.73 (2 H, m), 1.29 - 1.40 (2 H, m). Route 12

General Procedure F

General Procedure F: Example 13 - Preparation of 6-ethyl-2-[(l-methylpiperidin-4-yl)oxy]-7,8- dihydro-l,6-naphthyridin-5(6H)-one. Potency range D

To a stirred solution of 2-chloro-6-ethyl-7,8-dihydro-l,6-naphthyridin-5(6H)-one (50 mg, 0.24 mmol, 1.0 eq), l-methylpiperidin-4-ol (42 mg, 0.36 mmol, 1.5 eq) and 4 A molecular sieves (30 mg) in THF (1.5 mL) under N₂ was added KO¹Bu in THF (20% wt/wt, 270 mg, 0.48 mmol, 2 eq). The mixture was then heated in a microwave (100 W, 20 min, 85 ⁰C). After cooling, the mixture was diluted with EtOAc (8 mL), washed with saturated aqueous NaHCO₃ (1OmL). The aqueous phase was extracted with EtOAc (2 x 8 mL). The combined organic extracts were washed with brine (8 mL), dried (MgSO₄), filtered and concentrated under reduced pressure. The residue was purified by semi-preparative HPLC (Prep Method 2) to give the title compound (11 mg, 16%) as colourless oil.

LCMS data: Calculated MH⁺ (290); Found 97% (MH⁺) m/z 290, Rt = 2.24 min (LCMS Method D). 1H NMR (500 MHz, CHLOROFORM-J) δ ppm 8.22 (1 H, d, J=8.5 Hz), 6.66 (1 H, d, J=8.5 Hz), 5.29 (1 H, br. s.), 3.54 - 3.68 (4 H, m), 3.04 (2 H, m), 2.88 - 3.00 (2 H, m), 2.68 - 2.88 (2 H, m), 2.56 (3 H, s), 2.14 - 2.29 (2 H, m), 1.97 - 2.11 (2 H, m), 1.22 (3 H, t, J=7.2 Hz).

The following compounds were prepared as described in Route 12, General Procedure F above.

Example 14 - Preparation of 2-[(l-cyclopentylpiperidin-4-yl)oxy]-6-ethyl-

7,8-dihydro-l,6-naphthyridin-5(6H)-one. Potency range B

In a similar fashion (Route 12, GP F), 2-chloro-6-ethyl-7,8-dihydro-l,6-naphthyridin-5(6H)- one (50 mg, 0.24 mmol, 1.0 eq) and l-cyclopentylpiperidin-4-ol (60 mg, 0.36 mmol, 1.5 eq) gave the title compound (37 mg, 46%). LCMS data: Calculated MH⁺ (344); Found 100% (MH⁺) m/z 344, Rt = 2.59 min (LCMS Method D).

¹H NMR (500 MHz, CHLOROFORM-J) δ ppm 8.11 - 8.24 (1 H, m), 6.58 - 6.69 (1 H, m), 5.16 (1 H, br. s.), 3.51 - 3.65 (4 H, m), 2.97 - 3.09 (2 H, m), 2.77 - 2.95 (2 H, m), 2.39 - 2.75 (3 H, m), 2.04 - 2.20 (2 H, m), 1.82 - 1.98 (4 H, m), 1.63 - 1.80 (2 H, m), 1.43 - 1.62 (4 H, m), 1.20 (3 H, t).

Example 15 - Preparation of 2-[(l-cyclohexylpiperidin-4-yl)oxy]-6-ethyl-

7,8-dihydro-l,6-naphthyridin-5(6H)-one. Potency range A

In a similar fashion (Route 12, GP F), 2-chloro-6-ethyl-7,8-dihydro-l,6-naphthyridin-5(6H)- one (50 mg, 0.24 mmol, 1.0 eq) and l-cyclohexylpiperidin-4-ol (65 mg, 0.36 mmol, 1.5 eq) gave the title compound (39 mg, 46%).

LCMS data: Calculated MH⁺ (358); Found 99% (MH⁺) m/z 358, Rt = 2.71 min (LCMS

Method D). 1H NMR (500 MHz, CHLOROFORM-J) δ ppm 8.18 (1 H, d, J=8.5 Hz), 6.63 (1 H, d, J=8.5

Hz), 5.11 - 5.24 (1 H, m), 3.51 - 3.66 (4 H, m), 3.01 (2 H, t, J=6.9 Hz), 2.86 - 2.98 (2 H, m),

2.61 - 2.77 (2 H, m), 2.42 - 2.60 (1 H, m), 2.06 - 2.22 (2 H, m), 1.75 - 1.97 (6 H, m), 1.65 (1

H, d, J=12.7 Hz), 1.03 - 1.37 (8 H, m).

Example 16 - Preparation of 2-{[(3S)-l-cyclopentylpyrrolidin-3-yl]oxy}-6- ethyl-7,8-dihydro-l,6-naphthyridin-5(6H)-one. Potency range C

In a similar fashion (Route 12, GP F), 2-chloro-6-ethyl-7,8-dihydro-l,6-naphthyridin-5(6H)- one (50 mg, 0.24 mmol, 1.0 eq) and (35)-l-cyclopentylpyrrolidin-3-ol (55 mg, 0.36 mmol, 1.5 eq) gave the title compound (33 mg, 42%).

LCMS data: Calculated MH⁺ (330); Found 100% (MH⁺) m/z 330, Rt = 2.49 min (LCMS Method D).

¹H NMR (500 MHz, CHLOROFORM-J) δ ppm 8.19 (1 H, d, J=8.5 Hz), 6.65 (1 H, d, J=8.5 Hz), 5.52 - 5.63 (1 H, m), 3.56 - 3.68 (4 H, m), 3.39 - 3.56 (1 H, m), 2.81 - 3.18 (6 H, m), 2.32

- 2.47 (1 H, m), 2.06 - 2.19 (1 H, m), 1.84 - 1.96 (2 H, m), 1.49 - 1.83 (6 H, m), 1.20 (3 H, t, J=7.2 Hz).

Example 17 - Preparation of 2-{[(3S)-l-cyclobutylpyrrolidin-3-yl]oxy}-6- ethyl-7,8-dihydro-l,6-naphthyridin-5(6H)-one. Potency range D

In a similar fashion (Route 12, GP F), 2-chloro-6-ethyl-7,8-dihydro-l,6-naphthyridin-5(6H)- one (50 mg, 0.24 mmol, 1.0 eq) and (3S)-I -eye lobutylpyrrolidin-3-ol (50 mg, 0.36 mmol, 1.5 eq) gave the title compound (26 mg, 35%).

LCMS data: Calculated MH⁺ (316); Found 100% (MH⁺) m/z 316, Rt = 3.15 min (LCMS

Method D).

¹H NMR (500 MHz, CHLOROFORM-^) δ ppm 8.19 (1 H, d, J=8.5 Hz), 6.66 (1 H, d, J=8.5 Hz), 5.54 - 5.64 (1 H, m), 3.53 - 3.68 (4 H, m), 3.32 - 3.49 (1 H, m), 3.19 - 3.32 (1 H, m), 2.83

- 3.09 (5 H, m), 2.33 - 2.47 (1 H, m), 2.05 - 2.30 (5 H, m), 1.84 (1 H, m), 1.73 (1 H, m), 1.20 (3 H, t, J=7.2 Hz).

Example 18 - Preparation of 2-{[(3R)-l-cyclopentylpyrrolidin-3-yl]oxy}-6- ethyl-7,8-dihydro-l,6-naphthyridin-5(6H)-one. Potency range C

In a similar fashion (Route 12, GP F), 2-chloro-6-ethyl-7,8-dihydro-l,6-naphthyridin-5(6H)- one (50 mg, 0.24 mmol, 1.0 eq) and (3i?)-l-cyclopentylpyrrolidin-3-ol (55 mg, 0.36 mmol, 1.5 eq) gave the title compound (40 mg, 39%, TFA salt) after semi-preparative HPLC (Prep Method 1). LCMS data: Calculated MH⁺ (330); Found 99% (MH⁺) m/z 330, Rt = 2.52 min (LCMS Method D).

¹H NMR (500 MHz, CHLOROFORM-J) δ ppm 8.15 - 8.31 (1 H, m), 6.68 (1 H, d, J=8.5 Hz), 5.71 (1 H, br. s.), 4.12 - 4.48 (1 H, m), 3.87 - 4.13 (1 H, m), 3.53 - 3.73 (4 H, m), 3.38 - 3.55 (1 H, m), 3.09 - 3.28 (2 H, m), 2.95 - 3.11 (2 H, m), 2.40 - 2.60 (1 H, m), 2.29 - 2.41 (1 H, m), 1.99 - 2.16 (2 H, m), 1.76 - 1.99 (4 H, m), 1.54 - 1.72 (2 H, m), 1.17 - 1.30 (3 H, m).

Example 19 - Preparation of 2-{[(3R)-l-cyclobutylpyrrolidin-3-yl]oxy}-6- ethyl-7,8-dihydro-l,6-naphthyridin-5(6H)-one. Potency range D

In a similar fashion (Route 12, GP F), 2-chloro-6-ethyl-7,8-dihydro-l,6-naphthyridin-5(6H)- one (50 mg, 0.24 mmol, 1.0 eq) and (3i?)-l-cyclobutylpyrrolidin-3-ol (50 mg, 0.36 mmol, 1.5 eq) gave the title compound (42 mg, 41%, TFA salt) after semi-preparative HPLC (Prep Method 1). LCMS data: Calculated MH⁺ (316); Found 100% (MH⁺) m/z 316, Rt = 2.44 min (LCMS Method D).

¹H NMR (500 MHz, CHLOROFORM-^) δ ppm 8.16 - 8.32 (1 H, m), 6.68 (1 H, d, J=8.5 Hz), 5.66 - 5.78 (1 H, m), 3.99 - 4.30 (1 H, m), 3.81 - 4.01 (1 H, m), 3.51 - 3.76 (5 H, m), 2.88 - 3.20 (4 H, m), 2.18 - 2.58 (6 H, m), 1.90 - 2.05 (1 H, m), 1.73 - 1.88 (1 H, m), 1.14 - 1.30 (3 H, m).

Example 20 - Preparation of 6-ethyl-2-(3-pyrrolidin-l-ylpropoxy)-7,8- dihydro-l,6-naphthyridin-5(6H)-one. Potency range C

In a similar fashion (Route 12, GP F), 2-chloro-6-ethyl-7,8-dihydro-l,6-naphthyridin-5(6H)- one (50 mg, 0.24 mmol, 1.0 eq) and 3-pyrrolidin-l-ylpropan-l-ol (46 mg, 0.36 mmol, 1.5 eq) gave the title compound (4 mg, 4%) as the TFA salt after semi-preparative HPLC (Prep Method 1). LCMS data: Calculated MH⁺ (304); Found 99% (MH⁺) m/z 304, Rt = 2.39 min (LCMS Method D). ¹H NMR (500 MHz, CHLOROFORM-J) δ ppm 8.22 (1 H, d, J=8.5 Hz), 6.65 (1 H, d, J=8.4 Hz), 4.44 (2 H, m), 3.86 - 3.98 (2 H, m), 3.54 - 3.67 (4 H, m), 3.24 - 3.36 (2 H, m), 3.04 (2 H, t, J=6.9 Hz), 2.77 - 2.89 (2 H, m), 2.24 - 2.36 (2 H, m), 2.04 - 2.24 (4 H, m), 1.22 (3 H, t, J=7.2 Hz).

Example 21 - Preparation of 6-ethyl-2-(3-piperidin-l-ylpropoxy)-7,8- dihydro-l,6-naphthyridin-5(6H)-one. Potency range C

In a similar fashion (Route 12, GP F), 2-chloro-6-ethyl-7,8-dihydro-l,6-naphthyridin-5(6H)- one (50 mg, 0.24 mmol, 1.0 eq) and 3-piperidin-l-ylpropan-l-ol (46 mg, 0.36 mmol, 1.5 eq) gave the title compound (10 mg, 10%) as the TFA salt after semi-preparative HPLC (Prep

Method 1).

LCMS data: Calculated MH⁺ (318); Found 98% (MH⁺) m/z 318, Rt = 2.45 min (LCMS

Method D). 1H NMR (500 MHz, CHLOROFORM-^) δ ppm 8.21 (1 H, d, J=8.4 Hz), 6.64 (1 H, d, J=8.5

Hz), 4.42 (2 H, t, J=5.6 Hz), 3.66 - 3.75 (2 H, m), 3.56 - 3.65 (4 H, m), 3.16 - 3.26 (2 H, m),

3.04 (2 H, t, J=6.8 Hz), 2.60 - 2.74 (2 H, m), 2.23 - 2.33 (2 H, m), 1.85 - 2.06 (5 H, m), 1.37 -

1.50 (1 H, m), 1.22 (3 H, t, J=7.2 Hz).

Example 22 - Preparation of 2-{[l-(cyclopropylmethyl)piperidin-4-yl]oxy}-

6-ethyl-7,8-dihydro-l,6-naphthyridin-5(6H)-one. Potency range D

In a similar fashion (Route 12, GP F), 2-chloro-6-ethyl-7,8-dihydro-l,6-naphthyridin-5(6H)- one (50 mg, 0.24 mmol, 1.0 eq) and l-(cyclopropylmethyl)piperidin-4-ol (55 mg, 0.36 mmol, 1.5 eq) gave the title compound (93 mg, 88%) as the TFA salt after semi-preparative HPLC

(Prep Method 1).

LCMS data: Calculated MH⁺ (330); Found 97% (MH⁺) m/z 330, Rt = 2.49 min (LCMS

Method D).

¹H NMR (500 MHz, CHLOROFORM-^) δ ppm 8.07 - 8.23 (1 H, m), 6.67 - 6.88 (1 H, m), 5.27 - 5.62 (1 H, m), 3.70 - 3.87 (1 H, m), 3.53 - 3.71 (5 H, m), 3.14 - 3.32 (2 H, m), 3.00 - 3.14 (4 H, m), 2.39 - 2.56 (1 H, m), 2.26 - 2.39 (1 H, m), 2.11 - 2.26 (1 H, m), 1.90 - 2.08 (1 H, m), 1.08 - 1.27 (4 H, m), 0.71 - 0.85 (2 H, m), 0.38 - 0.54 (2 H, m).

Example 23 - Preparation of 6-ethyl-2-{[l-(l-methylethyl)piperidin-4- yl]oxy}-7,8-dihydro-l,6-naphthyridin-5(6H)-one. Potency range B

In a similar fashion (Route 12, GP F), 2-chloro-6-ethyl-7,8-dihydro-l,6-naphthyridin-5(6H)- one (80 mg, 0.38 mmol, 1.0 eq) and l-(l-methylethyl)piperidin-4-ol (77 mg, 0.50 mmol, 1.3 eq) gave the title compound (19.7 mg, 14%) as the formic acid salt after semi-preparative HPLC (Prep Method 3).

LCMS data: Calculated MH⁺ (318); Found 97% (MH⁺) m/z 318, Rt = 2.36 min (LCMS Method D).

¹H NMR (500 MHz, MeOD) δ ppm 8.14 (1 H, d, J=8.5 Hz), 6.79 (1 H, d, J=8.4 Hz), 5.28 - 5.57 (1 H, m), 3.67 (2 H, m), 3.51 - 3.63 (3 H, m), 3.32 - 3.50 (4 H, m), 3.06 (2 H, m), 2.16 (4 H, m), 1.39 (6 H, d, J=6.7 Hz), 1.21 (3 H, t).

Example 24 - Preparation of 6-ethyl-2-[(l-oxetan-3-ylpiperidin-4-yl)oxy]-

7,8-dihydro-l,6-naphthyridin-5(6H)-one. Potency range C

In a similar fashion (R12, GP F) l-oxetan-3-ylpiperidin-4-ol (70 mg, 0.44 mmol), NaH (27 mg of a 60% suspension in mineral oil, 0.67 mmol) and 2-chloro-6-ethyl-7,8-dihydro-l,6- naphthyridin-5(6H)-one (72 mg, 0.44 mmol) gave the title compound (19 mg, 13 %) as colourless oil. LCMS data: Calculated MH⁺ (332); Found 75% (MH⁺) m/z 332 Rt = 3.46 min (LCMS Method D).

¹H NMR (250 MHz, CDCl₃) δ ppm 8.19 (1 H, d, J=8.5 Hz), 6.64 (1 H, d, J=8.4 Hz), 5.14 - 5.34 (1 H, m), 4.57 - 4.86 (4 H, m), 3.46 - 3.76 (4 H, m), 2.92 - 3.14 (2 H, m), 2.54 - 2.78 (2 H, m), 2.24 - 2.54 (2 H, m), 2.04 - 2.24 (2 H, m), 1.79 - 2.04 (3 H, m), 1.21 (3 H, t, J=7.2 Hz).

Example 25 - Preparation of 2-[(l-cyclobutylpiperidin-4-yl)oxy]-6-[4- (methylsulfonyl)benzyl] -7,8-dihydro- 1 ,6-naphthyridin-5(6H)-one. Potency range A

In a similar fashion (R12, GP F) 2-chloro-6-[4-(methylsulfonyl)benzyl]-7,8-dihydro-l,6- naphthyridin-5(6H)-one (63 mg, 0.18 mmol), NaH (11 mg of a 60% suspension in mineral oil, 0.270 mmol 1.5 eq) and l-cyclobutylpiperidin-4-ol (36 mg, 0.230 mmol, 1.3 eq) gave the title compound (7.5 mg, 9%) as colourless oil.

LCMS data: Calculated MH⁺ (470); Found 99% (MH⁺) m/z 470, Rt = 4.52 mins (LCMS Method D).

¹H NMR (500 MHz, MeOD) δ ppm 8.16 (1 H, d, J=8.7 Hz), 7.90 - 7.99 (2 H, m), 7.60 (2 H, d, J=8.4 Hz), 6.74 (1 H, d, J=8.7 Hz), 5.19 (1 H, m), 4.87 (2 H, s), 3.64 (2 H, t, J=6.9 Hz), 3.11 (3 H, s), 3.06 (2 H, t, J=6.9 Hz), 2.74 - 2.89 (1 H, m), 2.68 (2 H, m), 2.24 (2 H, m), 2.00 - 2.14 (4 H, m), 1.65 - 1.98 (6 H, m).

Example 26 - Preparation of 2-[(l-cyclobutylpiperidin-4-yl)oxy]-6- [(methylsulfanyl)methyl]-7,8-dihydro-l,6-naphthyridin-5(6H)-one. Potency range A

In a similar fashion (R12, GP F) 2-chloro-6-[(methylsulfanyl)methyl]-7,8-dihydro-l,6- naphthyridin-5(6H)-one (38 mg, 0.16 mmol), NaH (11 mg of a 60% suspension in mineral oil, 0.28 mmol 1.8 eq) and l-cyclobutylpiperidin-4-ol (36 mg, 0.24 mmol, 1.5 eq) gave the title compound as a TFA salt (23 mg, 25%) as colourless oil. LCMS data: Calculated MH⁺ (362); Found 99% (MH⁺) m/z 362, Rt = 2.67 mins (LCMS Method C).

¹H NMR (500 MHz, MeOD) δ ppm 8.11 (1 H, d, J=8.7 Hz), 6.72 (1 H, d, J=8.7 Hz), 5.13 - 5.28 (1 H, m), 4.72 (2 H, s), 3.75 (2 H, t, J=6.9 Hz), 3.08 (2 H, t, J=6.9 Hz), 2.56 - 2.92 (3 H, m), 2.17 - 2.38 (2 H, m), 2.02 - 2.16 (7 H, m), 1.71 - 1.97 (6 H, m).

Route 13

Example 27 - Preparation of 2-[(l-cyclobutylpiperidin-4- yl)(methyl)amino]-6-ethyl-7,8-dihydro-l,6-naphthyridin-5(6H)-one. Potency range D

2-Chloro-6-ethyl-7,8-dihydro-l,6-naphthyridin-5(6H)-one (50 mg, 0.24 mmol, 1.0 eq) and 1- cyclobutyl-N-methylpiperidin-4-amine (60 mg, 0.36 mmol, 1.5 eq) were heated neat in a microwave (100 W, 180 ⁰C, 2 x 30 min). After cooling, the residue was purified by semi- preparative HPLC (Prep Method 2) to give the title compound (15 mg, 19%) as colourless oil. LCMS data: Calculated MH⁺ (343); Found 97% (MH⁺) m/z 343, Rt = 2.30 min (LCMS Method D).

¹H NMR (500 MHz, CHLOROFORM-J) δ ppm 8.06 (1 H, d, J=8.8 Hz), 6.42 (1 H, d, J=8.8 Hz), 4.80 (1 H, br. s.), 3.49 - 3.66 (4 H, m), 3.28 (2 H, m), 2.84 - 3.11 (6 H, m), 1.95 - 2.48 (8 H, m), 1.63 - 1.92 (4 H, m), 1.20 (3 H, m).

Route 14

Preparation of 2-chloro-6- [(l-cyclobutylpiperidin-4-yl)oxy] -5-fluoropyridine-3- carbonitrile

To a solution of l-cyclobutylpiperidin-4-ol (1.01 g, 6.54 mmol, 1 eq) was added a solution of KO¹Bu (4.04 niL of a 1.78 M solution in THF, 7.20 mmol, 1.1 eq) at -78 °C. The reaction mixture was allowed to warm to -10 ⁰C over 30 min. This solution was then added dropwise over 10 min to a solution of 2,6-dichloro-5-fluoropyridine-3-carbonitrile (1.25 g, 6.54 mmol, 1 eq) in anhydrous THF (10 mL) at -78 ⁰C. The reaction mixture was stirred at -78 ⁰C for 30 min then allowed to warm to 0 ⁰C over 3 hours. The reaction mixture was concentrated at reduced pressure, diluted in EtOAc and washed with half saturated brine. The organic phase was dried (Na₂SO₄), filtered and concentrated at reduced pressure to give a brown solid (1.78 g). Purification by FCC (using a gradient of eluents 99:1 to 98:2 DCM/MeOH+1% aq.NH₃) gave the title compound (1.14 g, 56%) as an off white solid.

LCMS data: Calculated MH⁺ (310); Found 100% (MH⁺) m/z 310, Rt = 1.28 min (LCMS Method B). 1H NMR (500 MHz, CHLOROFORM-J) δ ppm 1.60 - 1.69 (2 H, m) 1.83 (4 H, m) 1.99 (4 H, d, J=6.71 Hz) 2.15 (2 H, m) 2.56 (2 H, m) 2.70 (1 H, m) 5.07 - 5.21 (1 H, m) 7.49 (1 H, d, J=8.39 Hz).

Preparation of 6-[(l-cyclobutylpiperidin-4-yl)oxy]-2-ethenyl-5-fluoropyridine-3- carbonitrile

Tetrakis(triphenylphosphine) palladium (54 mg, 46.4 μmol, 0.05 eq) was added to a nitrogen degassed solution of 2-chloro-6-[(l-cyclobutylpiperidin-4-yl)oxy]-5-fluoropyridine-3- carbonitrile (0.29 g, 0.93 mmol, 1 eq) and tributyl( vinyl) tin (0.33 mL, 1.12 mmol, 1.2 eq) in anhydrous toluene (8 mL). The reaction mixture was heated at 110 ⁰C for 2 hours, cooled to RT and concentrated at reduced pressure. The residue was diluted in MeCN and washed with heptane (3 x 8 mL). The MeCN phase was dried (Na₂SO₄), filtered and concentrated at reduced pressure. Purification by FCC (98:2 DCM/MeOH+1% aq.NH₃) gave the title compound (0.12 g, 43%). LCMS data: Calculated MH⁺ (302); Found 100% (MH⁺) m/z 302, Rt = 1.33 min (LCMS Method B). ¹H NMR (500 MHz, MeOD) δ ppm 1.72 - 1.85 (2 H, m) 1.94 - 2.11 (4 H, m) 2.15 - 2.25 (4 H, m) 2.48 - 2.71 (2 H, m) 2.79 - 2.97 (2 H, m) 3.13 (1 H,m) 5.39 - 5.50 (1 H, m) 5.71 (1 H, ddd, J=10.53, 1.68, 0.92 Hz) 6.48 (1 H, ddd, J=16.75, 1.72, 0.76 Hz) 7.06 (1 H, dd, J=16.78, 10.53 Hz), 7.85 (1 H, d, J=9.46 Hz).

Example 28 - Preparation of 2-[(l-cyclobutylpiperidin-4-yl)oxy]-6-ethyl-3- fluoro-7,8-dihydro-l,6-naphthyridin-5(6H)-one. Potency range A

A solution of ethylamine in MeOH (3.84 niL of a 2 M solution in MeOH, 7.75 mmol,) was added to a solution of 6-[(l-cyclobutylpiperidin-4-yl)oxy]-2-ethenyl-5-fluoropyridine-3- carbonitrile (92.5 mg, 0.31 mmol) in aqueous MeOH (2.4 mL, 5:1 MeOH : water) and the reaction mixture was heated at 75 ⁰C for 20 hours. The reaction mixture was concentrated at reduced pressure and rediluted in MeOH (0.3 mL) and adsorbed under gravity on to a 2 g Isolute SCX-2 column, pre-wetted with MeOH. The column was washed with MeOH (4 x 7 mL) then 7N NH3 in MeOH (10 ml). The ammoniacal fractions were combined to give a yellow oil (92 mg). Purification by FCC (using a gradient of eluents 99:1 to 96:4, DCM / MeOH +1% aq.NHs) gave the title compound (18 mg, 17%) as a yellow amorphous solid. LCMS data: Calculated MH⁺ (348); Found 100% (MH⁺) m/z 348, Rt = 2.71 min (LCMS Method D). 1H NMR (500 MHz, MeOD) δ ppm 1.08 - 1.13 (3 H, m) 1.60 - 1.68 (2 H, m) 1.73 - 1.87 (4 H, m) 1.93 - 2.03 (4 H, m) 2.10 - 2.22 (2 H, m) 2.49 - 2.65 (2 H, m) 2.69 - 2.78 (1 H, m) 2.88 - 2.96 (2 H, m) 3.48 (2 H, q, J=7.27 Hz) 3.53 - 3.61 (2 H, m) 5.12 - 5.25 (1 H, m) 7.73 (1 H, d, J=10.38 Hz).

Route 15

HCMn dioxane

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

The reaction vessel was charged with 2-chloro-5,6,7,8-tetrahydro-l,6-naphthyridine hydrochloride (24.9 g, 1 eq), Boc anhydride (27.8 g, 1.05 eq) and DCM (375 mL, 15 vol) and the slurry cooled to 0 to 5°C under an atmosphere of nitrogen. Triethylamine (51 mL, 37 g, 3 eq) was charged over 55 minutes whilst maintaining the internal temperature at <5 ⁰C [T_max during this addition 3.4 ⁰C]. The reaction mixture was stirred at 0 to 5 ⁰C for 50 minutes, warmed to ambient temperature (19 ⁰C) and stirred for a further 15 minutes. IPC analysis by ¹H-NMR and LCMS showed the reaction to be complete. The reaction mixture was held at ambient temperature overnight. The reaction mixture was washed with water (75 mL, 3 vol, outgoing pH 10), 5% NaHCO₃ (75 mL, 3 vol, outgoing pH 10), dried (Na₂SO₄) and filtered. The dried extracts were evaporated under vacuum at <40°C to afford the title compound (33.2 g, 102 % yield) as an off white solid.

¹H NMR (250 MHz, MeOD) δ ppm 7.60 (1 H, d, J=8.1 Hz), 7.28 (1 H, d, J=8.2 Hz), 4.59 (2 H, s), 3.74 (2 H, t, J=6.0 Hz), 2.91 (2 H, t, J=5.9 Hz), 1.41 - 1.56 (9 H, m). Preparation of tert-buty\ 2-chloro-5-oxo-7,8-dihydro-l,6-naphthyridine-6(5H)- carboxylate

A reaction vessel was charged with sodium periodate (116.9 g, 3 eq), water (586 mL, 12 vol), acetonitrile (10 mL, 0.2 vol), ruthenium(III)chloride (11.3 g) and dichloromethane (488 mL, 10 vol) and adjusted to 18-23 ⁰C. No exotherm was detected. To this mixture was charged a solution of tert-butyi 2-chloro-7,8-dihydro-l,6-naphthyridine-6(5H)-carboxylate (48.8 g, 1 wt) dissolved in dichloromethane (244 mL, 5 vol) at such a rate that the temperature was maintained at 18-23 ⁰C. This addition took 23 minutes. Dichloromethane (1 vol, 48 mL) was charged as a line rinse.

¹H-NMR and LCMS analysis at 75 minutes showed the complete absence of starting tert- butyl 2-chloro-7,8-dihydro-l,6-naphthyridine-6(5H)-carboxylate. The reaction mixure was quenched with isopropanol (50 mL, to destroy any ruthenium tetroxide, exothermic) and then filtered through GF/F. The filter cake was washed with DCM/water (1 :1, 2 x 190 mL, 2 x 4 vol) and the washes combined with the mother liquors. The phases were split and the aqueous extracted twice with dichloromethane (100 mL, 2 vol). The combined extracts were dried over Na₂SO₄ (filtered) and concentrated to a residue. The crude product was isolated as a pale green solid (49.7 g). Analysis by ¹H-NMR w/w assay using dimethyl fumarate as internal standard showed this product to be 97.5% w/w title compound. 1H NMR (500 MHz, MeOD) δ ppm 8.35 (1 H, d, J=8.2 Hz), 7.48 (1 H, d, J=8.2 Hz), 4.08 (2 H, t, J=6.5 Hz), 3.16 (2 H, t, J=6.4 Hz), 1.57 (9 H, s).

Preparation of 2-chloro-5,6,7,8-tetrahydro-l,6-naphthyridine

The reaction vessel was charged with tert-butyi 2-chloro-5-oxo-7,8-dihydro-l,6- naphthyridine-6(5H)-carboxylate (48.6 g, 1 wt) and dioxane (243 mL, 5 vol) and stirred at ambient temperature to achieve full dissolution. The resultant solution was clarified through GF/F and the cake washed with dioxane (2 x 120 mL, 2 x 2.5 vol). NB: Filter paper became black suggesting the removal of ruthenium. The combined filtrates were adjusted to 20 ⁰C, purged with nitrogen and treated with 4M HCl in dioxane (680 mL, 14 vol). A weak exotherm was detected following the addition and this was also accompanied by the appearance of a precipitate. IPC analysis by LCMS and ¹H-NMR after 2.5 hours showed the reaction to be complete. The reaction mixture was filtered through paper at 19 ⁰C and the filter cake washed with dioxane (1 vol, 49 mL) at ambient temperature. The isolated product was dried under vacuum at 40 ⁰C for 18 hours to afford the title compound (35.9 g, 95%) as a pale yellow powder. Analysis by IH-NMR w/w assay using dimethyl fumarate as internal standard showed this product to be 100.1% w/w 2-chloro-5,6,7,8-tetrahydro-l,6- naphthyridine.

¹H NMR (500 MHz, MeOD) δ ppm 8.24 (1 H, d, J=8.2 Hz), 7.46 (1 H, d, J=8.2 Hz), 3.59 (2 H, t, J=6.9 Hz), 3.12 (2 H, t, J=6.8 Hz).

Preparation of 2-chloro-6-ethyl-7,8-dihydro- 1 ,6-naphthyridin-5(6H)-one

The reaction vessel was charged with DMF (5 vol, 1475 mL), 2-chloro-5,6,7,8-tetrahydro- 1,6-naphthyridine (294 g, 1 eq) and the temperature adjusted to ca. 20 ⁰C. KO¹Bu (379 g, 2.5 eq) was charged portionwise maintaining the temperature at 15 to 25 ⁰C. The reaction mixture was stirred for 30 minutes (a dark red/brown colour observed) and then treated with ethyl bromide (218 g, 1.5 eq) whilst maintaining the temperature at 15 to 25 ⁰C. This addition was exothermic and resulted in the loss of the deep red colour 60 minutes after the addition was complete. IPC analysis by LC-MS showed the reaction to be 95.3% complete at 2 hours. The reaction mixture was held at ambient temperature overnight. The reaction was worked up by the addition of water (2.94 L, 10 vol) maintaining the temperature at <25°C and the product extracted using ethyl acetate (4 x 4 vol). The extracts were dried over sodium sulphate (294 g, 1 wt), filtered and evaporated to a mobile liquid, 788 g (a result of entrained EtOAc and the extraction of DMF into ethyl acetate phase). Heptanes (2 L, 6.8 vol) were charged and the resultant biphase evaporated to a residue under reduced pressure. This afforded a mobile oil (554 g) that crystallised readily on cooling to ambient temperature. Heptanes (1.47 L, 5 vol) were charged and the resultant mixture filtered. The filter cake was washed with heptanes (600 mL, 2 vol) and then dried on the filter for 90 minutes to afford the title compound as a highly crystalline solid (172 g, 61%). Analysis by ¹H-NMR showed this product to be clean albeit for 1.8% w/w DMF.

¹H NMR (500 MHz, MeOD) δ ppm 8.25 (1 H, d, J=8.1 Hz), 7.46 (1 H, d, J=8.1 Hz), 3.72 (2 H, t, J=6.9 Hz), 3.62 (2 H, q, J=7.2 Hz), 3.16 (2 H, t, J=6.8 Hz), 1.23 (3 H, t, J=7.2 Hz). Preparation of 2-[(l-cyclobutylpiperidin-4-yl)oxy]-6-ethyl-7,8-dihydro-l,6-naphthyridin-

5(6H)-one

The reaction vessel was charged with 2-chloro-6-ethyl-7,8-dihydro-l,6-naphthyridin-5(6H)- one (200.0 g, 1 wt, 1 eq), l-cyclobutylpiperidin-4-ol (192.0 g, 0.96 wt, 1.3 eq) and tetrahydrofuran (4000 mL, 20 vol). The vessel was purged with nitrogen and charged with sodium hydride (60% dispersion in mineral oil, 57.0 g, 0.285 wt, 1.5 eq) portion wise (exotherm observed from 16 to 20 ⁰C). After stirring at 15-25 ⁰C for 1 hour the reaction mixture was heated to 50-55 ⁰C and stirred for 17 hours. The reaction mixture was cooled to 0-5 ⁰C and quenched with water (1000 mL, 5 vol) over 30 minutes. Heptanes (800 mL, 4 vol) were added, the bi-phasic mixture warmed to RT and the heptane layer collected. The aqueous phase was extracted with TBME (3 x 800 mL, 3 x 4 vol) and the combined (heptane and TMBE) organic extracts dried (Na₂SO₄, 400 g, 2 wt) and filtered. The filter cake was washed with TBME (2 x 400 mL, 2 x 2 vol) and the combined filtrates concentrated under reduced pressure at 40 ⁰C. Crude product was purified by dry flash chromatography (gradient elution with 1 :1 heptanes / TBME to 100% TBME) to give the title compound (250 g, 76.8 %).

LCMS data: Calculated MH⁺ (330); Found 100% (MH⁺) m/z 330, Rt = 4.48 min (LCMS Method D). 1H NMR (500 MHz, MeOD) δ ppm 8.10 (1 H, d, J=8.5 Hz), 6.70 (1 H, d, J=8.7 Hz), 5.15 - 5.21 (1 H, m), 3.66 (2 H, t, J=6.9 Hz), 3.58 (2 H, q, J=7.2 Hz), 3.04 (2 H, t, J=6.9 Hz), 2.77 - 2.85 (1 H, m), 2.68 (2 H, br. s.), 2.23 (2 H, br. s.), 2.01 - 2.12 (4 H, m), 1.87 - 1.97 (2 H, m), 1.77 - 1.85 (2 H, m), 1.69 - 1.77 (2 H, m), 1.21 (3 H, t, J=7.2 Hz).

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

7,8-dihydro-l,6-naphthyridin-5(6H)-one fumaric acid salt. Potency range A

The reaction vessel was charged with 2-[(l-cyclobutylpiperidin-4-yl)oxy]-6-ethyl-7,8- dihydro-l,6-naphthyridin-5(6H)-one (160 g, 1.0 eq) and ethyl acetate (192OmL, 12 vol) and stirred under nitrogen to achieve full solution. Fumaric acid (56.4 g, 1.00 eq) was dissolved in methanol (640 niL, 4 vol) and charged to the reaction vessel whilst maintaining the temperature at <25°C. Ethyl acetate (640 mL, 4 vol) was charged as a line rinse. A thick precipitate was obtained. The reaction was stirred overnight and the batch isolated by filtration at 20 ⁰C, affording a white solid. The solid was washed with ethyl acetate (2 x 2 vol, 2 x 320 mL), dried on the filter for 2 hours and then oven dried at 27 ⁰C under vacuum for 18 hours to provide the title compound (181.9 g, 84 %).

LCMS data: Calculated MH⁺ (330); Found 100% (MH⁺) m/z 330, Rt = 4.49 min (LCMS Method D).

¹H NMR (400 MHz, MeOD) δ ppm 8.13 (1 H, d, J=8.6 Hz), 6.77 (1 H, d, J=8.6 Hz), 6.71 (2 H, s), 5.43 (1 H, br. s.), 3.63 - 3.75 (3 H, m), 3.59 (2 H, q, J=7.2 Hz), 3.13 - 3.30 (4 H, m), 3.05 (2 H, t, J=6.8 Hz), 2.07 - 2.39 (8 H, m), 1.76 - 1.95 (2 H, m), 1.21 (3 H, t, J=7.2 Hz).

Route 16

THF

Preparation of 2-chloro-6-ethyl-8-methyl-7,8-dihydro- 1 ,6-naphthyridin-5(6H)-one

To a stirred solution of 2-chloro-6-ethyl-7,8-dihydro-l,6-naphthyridin-5(6H)-one (50 mg, 0.238 mmol, 1 eq) in THF (2 mL) at -78 ⁰C, was added KHMDS in toluene (15% wt/wt, 789 mg, 0.595 mmol, 2.5 eq). After 2 hours at this temperature, MeI (31 μL, 0.49 mmol, 2.1 eq) was added in one portion and kept at -78 ⁰C for a further hour before warming to 0 ⁰C and quenching with saturated aqueous NH4C1(2 mL). The aqueous was extracted with EtOAc (2 x

5mL) and the organics combined, dried (MgSO₄) and concentrated under reduced pressure. The residue was purified by FCC (70:30 Heptane: EtOAc) to give the title compound as a colourless oil. (8.4 mg, 16%).

LCMS data: Calculated MH⁺ (225); Found 95% (MH⁺) m/z 225, Rt = 1.63 mins (LCMS method B). ¹H NMR (500 MHz, MeOD) δ ppm 8.24 (1 H, d, J=8.2 Hz), 7.43 (1 H, d, J=8.2 Hz), 3.82 (1 H, m), 3.68 (1 H, m), 3.53 (1 H, m), 3.44 (1 H, m), 3.18 - 3.27 (1 H, m), 1.36 (3 H, m), 1.23 (3 H, t, J=7.2 Hz).

The following compound was prepared as described in Route 1 General Procedure B, except NaH was used instead of KO¹Bu, above.

Example 29 - Preparation of 2-[(l-cyclobutylpiperidin-4-yl)oxy]-6-ethyl-8-methyl-7,8- dihydro-l,6-naphthyridin-5(6H)-one. Potency range B

In a similar fashion (Rl GP B, except NaH was used instead of KO¹Bu) 2-chloro-6-ethyl-8- methyl-7,8-dihydro-l,6-naphthyridin-5(6H)-one (8.4 mg, 37 μmol, 1 eq), NaH (5.6 mg of a 60% suspension in mineral oil, 0.141 mmol 3.8 eq) and l-cyclobutylpiperidin-4-ol (13.7 mg, 88 μmol, 2.4 eq) gave the title compound as a TFA salt (2 mg, 10%) as colourless oil. LCMS data: Calculated MH⁺ (344); Found 90% (MH⁺) m/z 344, Rt = 2.79 mins (LCMS Method C).

¹H NMR (500 MHz, MeOD) δ ppm 8.06 - 8.28 (1 H, m), 6.64 - 6.92 (1 H, m), 5.20 - 5.62 (1 H, m), 3.35 - 3.83 (9 H, m), 2.92 - 3.24 (3 H, m), 1.74 - 2.64 (8 H, m), 1.35 (3 H, m), 1.21 (3 H, t, J=7.1 Hz).

Route 17

THF

Preparation of 2-chloro-6-ethyl-8,8-dimethyl-7,8-dihydro- 1 ,6-naphthyridin-5(6H)-one

To a stirred solution of 2-chloro-6-ethyl-7,8-dihydro-l,6-naphthyridin-5(6H)-one, (200 mg, 0.950 mmol, 1 eq) in THF (2.0 niL) at -78 ⁰C, was added KHMDS in toluene (15% wt/wt, 1.64 g, 1.24 mmol, 1.3 eq). After 1.5 hours at this temperature, MeI (65 μL, 1.05 mmol, 1.1 eq) was added in one portion and kept at -78 ⁰C for 2 hours before quenching with saturated aqueous NH₄Cl (2 mL). The aqueous was extracted with EtOAc (2 x 10 mL) and the organics combined, dried (MgSO₄) and concentrated under reduced pressure. The residue was then redissolved in THF (2 mL), cooled to -78 ⁰C and KHMDS in toluene (15% wt/wt, 1.64 g, 1.24 mmol, 1.3 eq) added dropwise. After 1.5 hours at this temperature, MeI (65 μL, 1.045 mmol, 1.1 eq) was added in one portion and kept at -78 ⁰C for 3 hours before quenching with saturated aqueous NH₄Cl (2 mL). The aqueous was extracted with EtOAc (2 x 10 mL) and the organics combined, dried (MgSO₄) and concentrated under reduced pressure and purified by FCC (50:50 Heptane: EtOAc) to give the title compound (25 mg, 11%) as colourless oil. LCMS data: Calculated MH⁺ (239); Found 85% (MH⁺) m/z 239, Rt = 1.86 mins (LCMS method B). 1H NMR (500 MHz, MeOD) δ ppm 8.03 (1 H, d, J=8.1 Hz), 7.21 (1 H, d, J=8.2 Hz), 3.39 - 3.46 (2 H, m), 3.13 (2 H, s), 1.12 - 1.24 (6 H, m), 1.04 (3 H, t, J=7.2 Hz).

The following compound was prepared as described in Route 1, General Procedure B, except NaH was used instead of KO¹Bu, above.

Example 30 - Preparation of 2-[(l-cyclobutylpiperidin-4-yl)oxy]-6-ethyl-8,8-dimethyl- 7,8-dihydro-l,6-naphthyridin-5(6H)-one. Potency range A

In a similar fashion (Rl GP B, except NaH was used instead of KO¹Bu) 2-chloro-6-ethyl-8,8- dimethyl-7,8-dihydro-l,6-naphthyridin-5(6H)-one (25 mg, 0.11 mmol, 1 eq), NaH (6 mg of a

60% suspension in mineral oil, 0.15 mmol, 1.4 eq) and l-cyclobutylpiperidin-4-ol (24 mg,

0.16 mmol, 1.5 eq) gave the title compound as a TFA salt (22.6 mg, 36 %) as colourless oil.

LCMS data: Calculated MH⁺ (358); Found 90% (MH⁺) m/z 358, Rt=2.79 mins (LCMS

Method C). 1H NMR (500 MHz, MeOD) δ ppm 8.03 - 8.26 (1 H, m), 6.66 - 6.87 (1 H, m), 5.20 - 5.60 (1

H, m), 3.69 - 3.85 (1 H, m), 3.60 (2 H, q, J=7.2 Hz), 3.36 - 3.50 (3 H, m), 2.95 - 3.20 (2 H, m), 2.33 - 2.57 (4 H, m), 1.76 - 2.33 (7 H, m), 1.29 - 1.42 (6 H, m), 1.22 (3 H, t, J=7.2 Hz). Route 18

Preparation of 3-hydroxy-3-methylbutyl methanesulfonate

To a stirred solution of 3-methylbutane-l,3-diol (1.02 rnL, 9.6 mmol, 1 eq) in DCM (20 rnL) at 0 ⁰C was added pyridine (1.5 rnL, 19.2 mmol, 2 eq) followed by dropwise addition of methanesulfonyl chloride (776 μL, 10.1 mmol, 1.05 eq). After 1.5 hours the reaction mixture was warmed to room temperature, concentrated under reduced pressure and purified by FCC (70:30 Heptane/EtOAc) to give the title compound (1.2 g, 69%) as a colourless oil.

¹H NMR (500 MHz, CHLOROFORM- d) δ ppm 4.44 (2 H, m), 3.04 (3 H, s), 1.98 (2 H, m), 1.31 (6 H, s).

Preparation of 4-azido-2-methylbutan-2-ol

To a stirred solution of 3-hydroxy-3-methylbutyl methanesulfonate (1.2 g, 6.59 mmol, 1 eq) in DMF (30 mL) was added NaN₃ (1.28 g, 19.8 mmol, 3 eq). The suspension was heated for 16 hours at 85 ⁰C followed by addition of 1 :1 brine/water (15 mL) and extraction with EtOAc (3 x 30 mL) and DCM (2 x 15 ml). The organics were combined, dried (MgSO₄), filtered and concentrated at reduced pressure to give the title compound (310 mg, 36%) as cloudy white oil.

IH NMR (500 MHz, CHLOROFORM-J) δ ppm 3.47 (2 H, t, J=7.3 Hz), 1.78 (2 H, t, J=7.3 Hz), 1.27 (6 H, s).

Preparation of 4-amino-2-methylbutan-2-ol

To a stirred solution of 4-azido-2-methylbutan-2-ol (310 mg, 2.36 mmol, 1 eq) in THF (5 mL) was added PPh₃ (752 mg, 2.84 mmol, 1.2 eq). After 72 hours the product was isolated through capture and release on an SCX-2 column (washed with DCM/MeOH 50:50 and released with 2M NH₃ in MeOH) followed by FCC (90:10:1 DCM/MeOH/NH₃) to give the title compound (114 mg, 46%) as a colourless oil.

¹H NMR (500 MHz, CHLOROFORM-J) δ ppm 3.01 (2 H, t, J=5.9 Hz), 1.58 (2 H, t, J=6.1 Hz), 1.23 (6 H, s).

Route 19 RKaanneeyy NNii

4M HCI in dioxane ,_. .. _v ^ ~ H_∑N^^v_^/O^ .HCI

DCM

Preparation of 3-hydroxy-2,2-dimethylpropanenitrile

To a stirred solution Of NaBH₄ (3.70 g, 39.4 mmol) in EtOH (50 ml) at 0 ⁰C was added dropwise a solution of methyl 2-cyano-2-methylpropanoate in EtOH (50 ml) over 20 minutes. Following complete addition the reaction was warmed to room temperature and left to stir for 12 hours. The reaction was then concentrated at reduced pressure and stirred with 1 : 1 DCM / saturated aqueous NH₄Cl (100 ml) until no further gas evolution was observed. The organics were separated and the aqueous layer was extracted with DCM (2 x 50 ml). The organics were recombined, dried (MgSO₄), filtered and concentrated at reduced pressure to give the title products (3.62 g, 93%) as yellow oil which was used without further purification. 1H NMR (500 MHz, CHLOROFORM-^) δ ppm 3.58 (2 H, s), 1.36 (6 H, s).

Preparation of 3-methoxy-2,2-dimethylpropanenitrile

NC^-°-

To a solution of 3-hydroxy-2,2-dimethylpropanenitrile (1.16 g, 11.7 mmol) and HBF₄ (2.06 g of a 50% aqueous solution, 11.7 mmol) in DCM (50 mL) at 0 ⁰C was added trimethylsilyldiazomethane (2M in hexane, 7.03 mL, 14.1 mmol) over 15 min. After 1 hour at 0 ⁰C more trimethylsilyldiazomethane (2M in hexane, 7.03 mL, 14.1 mmol) was added and the reaction was warmed to room temperature. After 1 hour the mixture was washed with water (2 x 30 rnL), dried (MgSO₄), filtered and concentrated at reduced pressure to give the desired product as a yellow oil (1.1 g, 86%).

¹H NMR (500 MHz, CHLOROFORM- d) δ ppm 3.44 (3 H, s), 3.33 (2 H, s), 1.36 (6 H, s).

Preparation of tert-butyl (3-methoxy-2,2-dimethylpropyl)carbamate

To a solution of 3-methoxy-2,2-dimethylpropanenitrile (480 mg, 4.25 mmol) in EtOH (20 rnL) was added Raney Nickel (approx. 40 mg in water) and the mixture was stirred under a hydrogen atmosphere for 24 h. After filtration through Celite®, (BoC)₂O (1.11 g, 5.10 mmol) was added followed by 5M aqueous NaOH (1 ml, 5 mmol) and the resulting solution stirred at room temperature for 3 hours. The mixture was concentrated at reduced pressure, diluted with DCM (50 mL), washed with saturated aqueous citric acid solution (20 mL) followed by brine (20 mL), dried (MgSO₄), filtered and concentrated at reduced pressure. The residue was purified by FCC (using a gradient of eluents, 95:5 to 80:20 Heptane/EtOAc) to give the title product (367 mg, 40%) as clear oil.

LCMS data: Calculated MH⁺ (218); Found (MNa⁺) m/z 240, Rt = 1.72 min, Product was not visible by UV (215 nm, LCMS Method B).

¹H NMR (500 MHz, CHLOROFORM-J) δ ppm 5.00 (1 H, br. s.), 3.31 (3 H, s), 3.10 (2 H, s), 3.02 (2 H, d, J=6.3 Hz), 1.44 (9 H, s), 0.88 (6 H, s).

Preparation of 3-methoxy-2,2-dimethylpropan-l-amine hydrochloride salt

H₂N^X^O^ _HC|

To a solution of tert-butyl (3-methoxy-2,2-dimethylpropyl)carbamate (420 mg, 1.94 mmol) in DCM (5 ml) was added HCl (1.9 ml of a 4 M solution in dioxane, 7.7 mmol) at room temperature. After 2 hours, more HCl (1 ml of a 4 M solution in dioxane, 4.0 mmol) was added and the reaction was stirred for a further 1 hour. The reaction was concentrated at reduced pressure to give the title product (295 mg, quant, yield) as pale yellow solid which was used without further purification. 1H NMR (500 MHz, CHLOROFORM-^) δ ppm 3.36 (3 H, s), 3.28 (2 H, s), 2.92 - 3.00 (2 H, m), 1.08 (6 H, s). Route 20

General Procedure G General Procedure H

2 -78 °C to RT

General Procedure I

HO J O

-^^~"~NH_Q

HO ^"N

EtOH or iPrOH

N O 80 - 130 °C

Preparation of ijό-dichloropyridine-S-carboxamide

To a solution of 2,6-dichloronicotinic acid (5.0 g, 26.0 mmol) was added thionyl chloride (10 ml) at room temperature and the resulting mixture was heated at 85⁰C for 30 minutes where the solution became clear. The reaction was cooled to room temperature and concentrated at reduced pressure. The residue was diluted with heptane (20 ml) and concentrated at reduced pressure giving the acid chloride as yellow oil. The residue was diluted with DCM (20 ml) and added dropwise to a solution of cone, aqueous ammonia (20 ml) at 0 ⁰C and then stirred for 15 minutes where the product precipitated from the aqueous phase. The product was filtered, washed with water (20 ml) and dried under vacuum to give the title product (4.26 g, 86%) as off-white solid.

LCMS data: Calculated MH⁺ (191); Found 100% (MH⁺) m/z 191, Rt = 1.01 min (LCMS Method B). 1H NMR (500 MHz, MeOD) δ ppm 7.92 (1 H, d, J=7.9 Hz), 7.51 (1 H, d, J=7.9 Hz).

Preparation of 2,6-dichloropyridine-3-carbonitrile

To a solution of 2,6-dichloropyridine-3-carboxamide (4.74 g, 24.8 mmol) was added thionyl chloride (10 ml) and DCE (10 ml) at room temperature. The resulting solution was heated at reflux for 12 hours and then cooled to room temperature and concentrated at reduced pressure. The residue was diluted with DCM (100 ml) and washed with saturated aq. NaHCOs (2 x 50 ml) and brine (50 ml), dried (MgSO₄), filtered and concentrated at reduced pressure. The resulting solid was recrystallised (heptane/EtOAc) to give the title product (3.47 g, 81%) as yellow needles.

LCMS data: Calculated MH⁺ (173); Found 99% UV, Rt = 1.19 min, Product did not ionise (LCMS Method B). 1H NMR (500 MHz, MeOD) δ ppm 8.25 (1 H, d, J=8.2 Hz), 7.64 (1 H, d, J=8.2 Hz).

General Procedure G

Preparation of 2-chloro-6-[(l-cyclobutylpiperidin-4-yl)oxy]pyridine-3-carbonitrile

To a solution of l-cyclobutylpiperidin-4-ol (2.85 g, 18.4 mmol, 1 eq) in dry THF (10 ml) was added portionwise NaH (960 mg of a 60% dispersion in mineral oil, 23.9 mmol, 1.3 eq) at -78 ⁰C and then warmed to 0 ⁰C over 20 mins. The resulting alkoxide was added dropwise to a solution of 2,6-dichloropyridine-3-carbonitrile (3.16 g, 18.4 mmol, 1 eq) at -78 ⁰C in dry THF (20 ml) over 20 minutes. The reaction was warmed to room temperature over several hours and then quenched with water (1 ml) and concentrated at reduced pressure. The resulting residue was diluted with DCM (100 ml) and washed with brine (2 x 50 ml). The aqueous phase was re-extracted with DCM (30 ml) and the organic phases were combined, dried (MgSO₄), filtered and concentrated at reduced pressure. Crude NMR showed a 1 : 1 mixture of regioisomers had formed. The resulting isomers were separated and purified via FCC (using a gradient of eluents, 99:1 :1 to 95:5:1 EtOAc/MeOH/NH₃) where the desired product eluted after the unwanted isomer. The resulting solid was further purified via recrystallisation (EtOAc) to give the title product (2.1 g, 39%) as white crystalline solid. LCMS data: Calculated MH⁺ (292); Found 100% (MH⁺) m/z 292, Rt = 1.19 min (LCMS Method B). 1H NMR (500 MHz, CHLOROFORM-^) δ ppm 7.78 (1 H, d, J=8.4 Hz), 6.72 (1 H, d, J=8.5 Hz), 5.07 - 5.23 (1 H, m), 2.54 - 2.81 (3 H, m), 2.12 - 2.30 (2 H, m), 1.99 - 2.11 (4 H, m), 1.77 - 1.98 (4 H, m), 1.61 - 1.77 (2 H, m). General Procedure H

Preparation of 6- [(l-cyclobutylpiperidin-4-yl)oxy] -l-ethenylpyridine-S-carbonitrile

Nitrogen gas was bubbled through a stirred solution of 2-chloro-6-[(l-cyclobutylpiperidin-4- yl)oxy]pyridine-3-carbonitrile (100 mg, 0.34 mmol, 1 eq), potassium vinyltrifluoroborate (51 mg, 0.38 mmol, 1.1 eq) and Na₂CO₃ (134 mg, 1.03 mmol, 3 eq) in 1 ,2-dimethoxyethane (2 ml) and water (2 ml) for 10 minutes at room temperature. Pd(PPh₃)₄ (4 mg, 7 μmol, 0.02 eq) was then added and the resulting mixture was heated in the microwave at 120 ⁰C for 2 hours (200 W). The resulting reaction mixture was diluted with DCM (30 ml) and washed with brine (2 x 15 ml). The aqueous phase was re-extracted with DCM (15 ml) and the organic phases were combined, dried (MgSO₄), filtered and concentrated at reduced pressure to give the title product (92 mg, 94%) as orange solid which was used without any further purification. LCMS data: Calculated MH⁺ (284); Found 86% (MH⁺) m/z 284, Rt = 1.38 min (LCMS Method B).

¹H NMR (500 MHz, CHLOROFORM-J) δ ppm 7.71 (1 H, d, J=8.5 Hz), 7.10 (1 H, dd, J=16.7, 10.5 Hz), 6.66 (1 H, d, J=8.5 Hz), 6.53 (1 H, dd, J=16.7, 1.8 Hz), 5.67 (1 H, dd, J=10.5, 1.8 Hz), 5.17 - 5.28 (1 H, m), 2.56 - 2.85 (3 H, m), 2.01 - 2.31 (6 H, m), 1.79 - 2.01 (4 H, m), 1.61 - 1.79 (2 H, m).

General Procedure I

Example 31 - Preparation of 2- [(l-cyclobutylpiperidin-4-yl)oxy]-6-(3- hydroxy-3-methylbutyl)-7,8-dihydro-l,6-naphthyridin-5(6H)-one. Potency range A

To a solution of 6-[(l-cyclobutylpiperidin-4-yl)oxy]-2-ethenylpyridine-3-carbonitrile (43 mg,

0.15 mmol, 1 eq) was added 4-amino-2-methylbutan-2-ol (114 mg, 1.11 mol, 7.4 eq) in EtOH (3 ml). The resulting solution was heated in a sealed tube at 90 ⁰C for 12 hours. The reaction was then concentrated at reduced pressure and purified directly using FCC (using a gradient of eluents, 99:1 :1 to 94:6:1 DCM/MeOH/NH₃) to give the title compound (34 mg, 59%) as colourless oil. LCMS data: Calculated MH⁺ (388); Found 99% (MH⁺) m/z 388, Rt = 2.41 min (LCMS Method C).

¹H NMR (500 MHz, CHLOROFORM-J) δ ppm 8.13 (1 H, d, J=8.5 Hz), 6.62 (1 H, d, J=8.5 Hz), 5.12 (1 H, m), 3.64 - 3.71 (2 H, m), 3.56 - 3.64 (2 H, m), 2.98 - 3.05 (2 H, m), 2.95 (1 H, br. s.), 2.69 - 2.79 (1 H, m), 2.54 - 2.69 (2 H, m), 2.10 - 2.26 (2 H, m), 1.96 - 2.09 (4 H, m), 1.86 - 1.95 (2 H, m), 1.75 - 1.86 (4 H, m), 1.60 - 1.75 (2 H, m), 1.26 (6 H, s).

The following compounds were prepared as described in Route 20, General Procedure I above.

Example 32 - Preparation of 2- [(l-cyclobutylpiperidin-4-yl)oxy] -6-(2- hydroxyethyl)-7,8-dihydro-l,6-naphthyridin-5(6H)-one. Potency range A

In a similar fashion (Route 20, GP I), 6-[(l-cyclobutylpiperidin-4-yl)oxy]-2-ethenylpyridine- 3-carbonitrile (48 mg, 0.17 mmol, 1 eq) and 2-aminoethanol (0.10 ml, 1.7 mmol, 10 eq) gave the title compound (15 mg, 17%) as white solid after purification by preparative HPLC (Prep

Method 2).

LCMS data: Calculated MH⁺ (346); Found 99% (MH⁺) m/z 346, Rt = 3.88 min (LCMS

Method D). 1H NMR (500 MHz, CHLOROFORM-^) δ ppm 8.15 (1 H, d, J=8.5 Hz), 6.64 (1 H, d, J=8.5

Hz), 5.06 - 5.22 (1 H, m), 3.87 (2 H, t, J=5.0 Hz), 3.62 - 3.79 (4 H, m), 2.99 - 3.25 (3 H, m),

2.72 - 2.85 (1 H, m), 2.54 - 2.72 (2 H, m), 2.11 - 2.33 (2 H, m), 1.99 - 2.10 (4 H, m), 1.77 -

1.99 (4 H, m), 1.61 - 1.77 (2 H, m).

Example 33 - Preparation of 2- [(l-cyclobutylpiperidin-4-yl)oxy]-6-(3- hydroxy-2,2-dimethylpropyl)-7,8-dihydro- 1 ,6-naphthyridin-5(6H)-one. Potency range A

In a similar fashion (Route 20, GP I), 6-[(l-cyclobutylpiperidin-4-yl)oxy]-2-ethenylpyridine- 3-carbonitrile (126 mg, 0.45 mmol, 1 eq) and 3-amino-2,2-dimethylpropan-l-ol (458 mg, 4.5 mmol, 10 eq) were heated at 110 ⁰C to give the title compound (29 mg, 17%) as white solid. LCMS data: Calculated MH⁺ (388); Found 96% (MH⁺) m/z 388, Rt = 4.78 min (LCMS Method D).

¹U NMR (500 MHz, MeOD) δ ppm 8.16 (1 H, d, J=8.5 Hz), 6.66 (1 H, d, J=8.5 Hz), 5.12 - 5.24 (1 H, m), 3.61 - 3.70 (2 H, m), 3.26 - 3.41 (2 H, m), 3.16 (2 H, s), 2.96 - 3.05 (2 H, m), 2.74 - 2.86 (1 H, m), 2.56 - 2.72 (2 H, m), 2.19 - 2.38 (2 H, m), 1.92 - 2.13 (6 H, m), 1.80 - 1.92 (2 H, m), 1.63 - 1.78 (2 H, m), 0.99 (6 H, s).

Example 34 - Preparation of 2-[(l-cyclobutylpiperidin-4-yl)oxy]-6-(2- hydroxy- 1 , l-dimethylethyl)-7,8-dihydro- 1 ,6-naphthyridin-5(6H)-one. Potency range A

In a similar fashion (Route 20, GP I), 6-[(l-cyclobutylpiperidin-4-yl)oxy]-2-ethenylpyridine-

3-carbonitrile (40 mg, 0.14 mmol, 1 eq) and 2-amino-2-methylpropan-l-ol (125 mg, 1.41 mmol, 10 eq) were heated at 130 ⁰C in iPrOH to give the title compound (6 mg, 11%) as white solid after purification by preparative HPLC (Prep Method 2).

LCMS data: Calculated MH⁺ (374); Found 99% (MH⁺) m/z 374, Rt = 2.41 min (LCMS

Method C).

¹U NMR (500 MHz, CHLOROFORM-^) δ ppm 8.16 (1 H, d, J=8.5 Hz), 6.65 (1 H, d, J=8.5

Hz), 5.08 - 5.24 (1 H, m), 3.91 (1 H, br. s.), 3.68 - 3.80 (2 H,m), 3.56 (2 H, s), 2.99 - 3.11 (2

H, m), 2.56 - 2.85 (3 H, m), 2.14 - 2.35 (2 H, m), 1.79 - 2.14 (8 H, m), 1.61 - 1.79 (2 H, m),

1.29 (6 H, s).

Route 21

General Procedure J

General Procedure J

Example 35 - Preparation of 2- [(l-cyclobutylpiperidin-4-yl)oxy]-6-(l- methylethyl)-7,8-dihydro-l,6-naphthyridin-5(6H)-one. Potency range A

To a solution of 6-[(l-cyclobutylpiperidin-4-yl)oxy]-2-ethenylpyridine-3-carbonitrile (40 mg,

0.14 mmol, 1 eq) was added isopropylamine (121 μl, 1.41 mol, 10 eq) in iPrOH (3 ml). The resulting solution was heated in a sealed tube at 130 ⁰C for 12 hours. The reaction was then concentrated at reduced pressure and purified directly using FCC (using a gradient of eluents,

99:1 :1 DCM/MeOH/NH₃ to 2M NH₃ in MeOH) to yield the intermediate 2-[(l- cyclobutylpiperidin-4-yl)oxy]-6-(l-methylethyl)-7,8-dihydro-l,6-naphthyridin-5(6H)-imine.

This was heated in 1 : 1 iPrOH / IM aqueous NaOH (3 ml) in a sealed tube for 1 hour at 100 ⁰C then concentrated at reduced pressure and purified directly using FCC (using a gradient of eluents, 99:1 :1 to 90:10:1 DCM/MeOH/NH₃) to give the title product (8 mg, 16%) as colourless oil.

LCMS data: Calculated MH⁺ (344); Found 100% (MH⁺) m/z 344 Rt = 2.55 min (LCMS

Method C).

¹H NMR (500 MHz, CHLOROFORM-J) δ ppm 8.18 (1 H, d, J=8.5 Hz), 6.64 (1 H, d, J=8.5 Hz), 5.09 - 5.19 (1 H, m), 4.97 - 5.08 (1 H, m), 3.40 - 3.52 (2 H, m), 2.92 - 3.02 (2 H, m), 2.71

- 2.82 (1 H, m), 2.54 - 2.71 (2 H, m), 2.11 - 2.31 (2 H, m), 1.99 - 2.11 (4 H, m), 1.60 - 1.97 (6

H, m), 1.20 (6 H, d, J=6.9 Hz).

The following compound was prepared as described in Route 21, General Procedure J above.

Example 36 - Preparation of 2- [(l-cyclobutylpiperidin-4-yl)oxy]-6-(3- methoxy-2,2-dimethylpropyl)-7,8-dihydro- 1 ,6-naphthyridin-5(6H)-one. Potency range A

In a similar fashion (Route 21, GP J except DIPEA was added to the reaction mixture), 6-[(l- cyclobutylpiperidin-4-yl)oxy]-2-ethenylpyridine-3-carbonitrile (43 mg, 0.15 mmol, 1 eq), 3- methoxy-2,2-dimethylpropan-l -amine hydrochloride salt (232 mg, 1.50 mmol, 10 eq) and DIPEA (246 μl, 1.50 mmol, 10 eq) gave the title compound (14 mg, 23%) as brown oil. LCMS data: Calculated MH⁺ (402); Found 98% (MH⁺) m/z 402, Rt = 2.86 min (LCMS Method C). ¹H NMR (500 MHz, CHLOROFORM-J) δ ppm 8.18 (1 H, d, J=8.5 Hz), 6.64 (1 H, d, J=8.5 Hz), 5.06 - 5.28 (1 H, m), 3.58 - 3.66 (2 H, m), 3.42 (2 H, s), 3.35 (3 H, s), 3.15 (2 H, s), 2.96 - 3.05 (2 H, m), 2.56 - 2.87 (3 H, m), 1.80 - 2.37 (10 H, m), 1.62 - 1.80 (2 H, m), 0.98 (6 H, s).

Route 22

PhMe 110 ⁰C, 2 h

Preparation of 6-[(l-cyclobutylpiperidin-4-yl)oxy]-2-(2-methylprop-l-en-l-yl)pyridine- 3-carbonitrile

Tributyl(2-methylprop-l-en-l-yl)stannane (0.414 g, 1.2 mmol, 1.2 eq) prepared according to the procedure of D. Seyferth and F. G. A. Stone (Seyferth, D.; Stone, F. G. A.; J. Am. Chem.

Soc. 1957, 79, 515) was added to a solution of 2-chloro-6-[(l-cyclobutylpiperidin-4- yl)oxy]pyridine-3-carbonitrile (0.291 g, 1.0 mmol, 1 eq) in anhydrous toluene (3 mL). The solution was degassed by bubbling nitrogen gas through the solution for 10 min, then tetrakis(triphenylphosphine) palladium (58 mg, 50 μmol, 0.05 eq) was added and the reaction mixture was heated at 110 ⁰C for 4 hours cooled to RT and concentrated at reduced pressure.

The residue was diluted in MeCN (20 ml) and washed with heptane (2 x 10 mL). The MeCN phase was concentrated under reduced pressure to give the crude product (0.27 g) as an oil.

Purification by FCC (DCM/MeOH+1% aq.NH₃ 98:2) gave the title compound (0.12 g, 67%).

LCMS data: Calculated MH⁺ (312); Found 100% (MH⁺) m/z 312, Rt = 1.85 min (LCMS

Method B). Example 37 - Preparation of 2-[(l-cyclobutylpiperidin-4-yl)oxy]-6-(2- methoxyethyl)-7,7-dimethyl-7,8-dihydro- 1 ,6-naphthyridin-5(6H)-one. Potency range A

A solution of 6-[(l-cyclobutylpiperidin-4-yl)oxy]-2-(2-methylprop-l-en-l-yl)pyridine-3- carbonitrile (0.210 g, 0.675 mmol, 1 eq) in 2-methoxyethylamine (0.5Og, 0.58 niL, 6.75 mmol, 10 eq) was heated in a microwave (130 ⁰C, 30 min, 200 W), then heated thermally for 16 hours at 130 ⁰C. The reaction mixture was concentrated at reduced pressure followed by purification by FCC (using a gradient of eluents, 97:3 to 92:8 DCM/MeOΗ+2% 2M NH₃ gradient) to give the title compound (8.2 mg, 3%).

LCMS data: Calculated MH⁺ (388); Found 100% (MH⁺) m/z 388, Rt = 2.71 min (LCMS Method D).

¹H NMR (500 MHz, CHLOROFORM-J) δ ppm 8.16 (1 H, d, J=8.5 Hz), 6.64 (1 H, d, J=8.5 Hz), 5.17 (1 H, br. s.), 3.67 - 3.72 (2 H, m), 3.57 - 3.62 (2 H, m), 3.38 (3 H, s), 2.97 (2 H, s), 2.55 - 2.90 (3 H, m), 1.60 - 2.18 (12 H, m), 1.37 (6 H, s).

Route 23

Example 38 - Preparation of 6-ethyl-2-[(3-piperidin-l-ylpropyl)sulfanyl]-

7,8-dihydro-l,6-naphthyridin-5(6H)-one. Potency range C

To a solution of 3-piperidin-l-ylpropan-l-ol (150 mg, 1.05 mmol) was added thionyl chloride (2 ml) at room temperature giving a yellow solution. After 30 mintues the reaction was concentrated to remove excess reagent then redissolved in EtOH (1.2 ml) and 1 M aqueous NaOH (1.2 ml). NaSH (110 mg of a 60% pure solid, 1.2 mmol) was added and the resulting solution was heated at 60 ⁰C for 2 hours. The reaction was cooled to room temperature and 2- chloro-6-ethyl-7,8-dihydro-l,6-naphthyridin-5(6H)-one (45 mg, 0.2 mmol) was added and the resulting mixture heated at 110 ⁰C for 2 hours. The reaction was then cooled to room temperature, concentrated at reduced pressure, dissolved in DCM (30 ml), washed with saturated NaHCO₃ (2 x 15 ml), dried (MgSO₄), filtered and evaporated at reduced pressure. The residue was then purified via FCC (using a gradient of eluents 99:1 :1 to 95:5:1 DCM/MeOH/NH₃) to give the title compound (10 mg, 15%) as colourless oil. LCMS data: Calculated MH⁺ (334); Found 85% (MH⁺) m/z 334 Rt = 4.52 min (LCMS Method D).

¹H NMR (500 MHz, CHLOROFORM-J) δ ppm 8.09 (1 H, d, J=8.2 Hz), 7.13 (1 H, d, J=8.2 Hz), 3.57 - 3.65 (4 H, m), 3.16 - 3.24 (2 H, m), 3.07 - 3.15 (2 H, m), 2.32 - 2.52 (6 H, m), 1.89 - 1.99 (2 H, m), 1.56 - 1.67 (4 H, m), 1.38 - 1.51 (2 H, m), 1.22 (3 H, t, J=7.2 Hz).

Route 24

THF

Preparation of ethyl 3-methylpyridine-2-carboxylate

To a stirred solution of 3-methylpyridine-2-carboxylic acid (3.0 g, 21.9 mmol, 1 eq) in DCE (20 ml) was added thionyl chloride (4.8 mmol, 65.7 mmol, 3 eq) and DMF (3 drops) at room temperature and the resulting solution was heated at 100 ⁰C for 3 hours. The reaction was then cooled to room temperature and concentrated at reduced pressure. The residue was dissolved in DCM (100 ml), cooled to 0 ⁰C and DIPEA (1.10 ml, 65.7 mmol, 3 eq) and EtOH (5 ml) added. The reaction was warmed to room temperature and after 30 minutes washed with saturated aqueous NaHCOs (2 x 50 ml), dried (MgSO₄), filtered and concentrated at reduced pressure. The residue was purified by FCC (7:3 Heptane/EtOAc) to give the title compound (2.54 g, 70%) as brown oil.

¹H NMR (500 MHz, CHLOROFORM-J) δ ppm 8.56 (1 H, d, J=4.3 Hz), 7.62 (1 H, d, J=7.8 Hz), 7.34 (1 H, dd, J=7.8, 4.6 Hz), 4.47 (2 H, q, J=7.1 Hz), 2.59 (3 H, s), 1.45 (3 H, d, J=7.1 Hz).

Preparation of ethyl 3-(bromomethyl)pyridine-2-carboxylate

To a stirred solution of ethyl 3-methylpyridine-2-carboxylate (2.07 g, 12.5 mmol, 1 eq) and NBS (2.23 g, 12.5 mmol, 1 eq) in CHCl₃ (25 ml) was added 2,2'-azobis(2- methylpropionitrile) (2.06 g, 12.5 mmol, 1 eq) and the resulting mixture heated at 80 ⁰C for 3 hours. After cooling, the mixture was stirred with a 1 :1 mixture of Hexane/EtOAc (25 ml) for 1 hour and the resulting precipitate was removed by filtration. The resulting filtrate was concentrated at reduced pressure and purified by FCC (using a gradient of eluents, 9:1 to 6:4 hexane/EtOAc) to give a 6:4 mixture of product : starting material (2.16 g, 42%) as orange oil.

LCMS data: Calculated MH⁺ (245); Found 74% (MH⁺) m/z 245 Rt = 1.66 min (LCMS Method B).

¹H NMR (500 MHz, CHLOROFORM-^) δ ppm 8.67 (1 H, d, J=4.6 Hz), 7.88 (1 H, d, J=7.8 Hz), 7.46 (1 H, dd, J=7.9, 4.7 Hz), 4.92 (2 H, s), 4.52 (2 H,q, J=7.2 Hz), 1.48 (3 H, t, J=6.8 Hz).

Preparation of ethyl 3-(cyanomethyl)pyridine-2-carboxylate

To a rapidly stirred solution of ethyl 3-(bromomethyl)pyridine-2-carboxylate (1.30 g, 5.31 mmol, 1 eq) and TBAI (5.90 g, 16 mmol, 3 eq) in 1 :1 water/DCM (40 ml) was added NaCN (783 mg, 16. mmol, 3 eq) and the resulting reaction stirred for 36 hours at room temperature. The reaction mixture was diluted with DCM (20 ml), the organic layer collected and washed with saturated NaHCOs (15 ml), dried (MgSO₄), filtered and concentrated at reduced pressure. The residue was purified by FCC (using a gradient of eluents, 9:1 to 2:8 Hexane/EtOAc) to give the title compound (640 mg, 63%) as a yellow solid. LCMS data: Calculated MH⁺ (191); Found 84% (MH⁺) m/z 191 Rt = 1.32 min (LCMS Method B). 1H NMR (500 MHz, CHLOROFORM-J) δ ppm 8.74 (1 H, d, J=3.4 Hz), 8.00 (1 H, d, J=7.9 Hz), 7.54 (1 H, dd, J=I.1, 4.7 Hz), 4.49 (2 H, q, J=7.2 Hz), 4.27 (2 H, s), 1.46 (3 H, t, J=7.1 Hz).

Preparation of 6,7-dihydro-l,7-naphthyridin-8(5H)-one

A solution of ethyl 3-(cyanomethyl)pyridine-2-carboxylate (600 mg, 3.15 mmol) and Raney

Nickel (4 ml of a suspension in water, approx 40 mg) were stirred in EtOH (40 ml) at 50 ⁰C under a hydrogen atmosphere for 8 hours. The reaction mixture was cooled to room temperature, filtered through celite® and the filtrate concentrated at reduced pressure. The crude material was purified by FCC (using a gradient of eluents, 95:5 to 85:15 DCM/MeOH) to give the product (416 mg, 89%) as white solid.

LCMS data: Calculated MH⁺ (149); Found (MH⁺) m/z 149, Product eluted in the solvent front.

¹H NMR (500 MHz, MeOD) δ ppm 8.58 (1 H, d, J=3.8 Hz), 7.80 (1 H, d, J=7.6 Hz), 7.51 (1 H, dd, J=I 2, 4.8 Hz), 3.45 - 3.64 (2 H, m), 2.99 - 3.15 (2 H, m).

Preparation of 7-ethyl-6,7-dihydro-l,7-naphthyridin-8(5H)-one

To a solution of 6,7-dihydro-l,7-naphthyridin-8(5H)-one (372 mg, 2.51 mmol, 1 eq) in DMF (5 ml) was added NaH (151 mg of a 60% suspension in mineral oil, 3.77 mmol, 1.5 eq) at 0

⁰C giving an off white slurry. After one hour, EtBr (206 μl, 2.76 mmol, 1.1 eq) was added and the resulting reaction was warmed to room temperature. After 3 hours the reaction was quenched with water (20 ml) and diluted with EtOAc (40 ml). The organic layer was separated and washed with saturated NaHCOs (20 ml). The aqueous layers were combined, washed with EtOAc (40 ml) and the organics recombined, washed with brine (20 ml), dried (MgSO₄), filtered and concentrated at reduced pressure. Crude mass balance showed product remained in the aqueous so this was re-extracted with DCM (3 x 30 ml), dried (MgSO₄), filtered, recombined with the organics previously obtained and concentrated at reduced pressure. Excess DMF was removed using an SCX-2 column and the product eluting with 2M NH3 in MeOH was concentrated at reduced pressure. The residue was purified using FCC (using a gradient of eluents, 99:1 to 95:5 DCM/MeOH) to give the title product (342 mg, 77%) as yellow oil.

LCMS data: Calculated MH⁺ (177); Found 96% (MH⁺) m/z 177 Rt = 0.72 min (LCMS Method B). 1H NMR (500 MHz, MeOD) δ ppm 8.57 (1 H, d, J=4.3 Hz), 7.80 (1 H, d, J=7.6 Hz), 7.50 (1 H, dd, J=7.6, 4.7 Hz), 3.60 - 3.73 (4 H, m), 3.11 (2 H, t, J=6.7 Hz), 1.25 (3 H, t, J=7.2 Hz).

Preparation of 7-ethyl-6,7-dihydro-l,7-naphthyridin-8(5H)-one N-oxide

A solution of 7-ethyl-6,7-dihydro-l,7-naphthyridin-8(5H)-one (273 mg, 1.55 mmol, 1 eq) in CHCl₃ (2 ml) was added dropwise to mCPBA (381 mg, 1.55 mmol, 1 eq) at 0 ⁰C. After 10 mins the reaction was warmed to room temperature and stirred for 24 hours. The reaction was evaporated at reduced pressure and purified by FCC (using a gradient of eluents, 99:1 to 95:5 DCM/MeOH) to give the title product (291 mg, 97%) as white solid. LCMS data: Calculated MH⁺ (193); Found 97% (MH⁺) m/z 193 Rt = 1.04 min (LCMS Method B).

¹H NMR (250 MHz, CHLOROFORM-^) δ ppm 8.11 (1 H, d, J=6.5 Hz), 7.06 - 7.22 (1 H, m), 6.98 (1 H, dd, J=7.7, 0.8 Hz), 3.57 (2 H, q, J=7.2 Hz), 3.42 - 3.51 (2 H, m), 2.83 - 2.97 (2 H, m), 1.15 (3 H, t, J=7.2 Hz).

Preparation of 2-chloro-7-ethyl-6,7-dihydro- 1 ,7-naphthyridin-8(5H)-one

A solution of 7-ethyl-6,7-dihydro-l,7-naphthyridin-8(5H)-one N-oxide (291 mg, 1.51 mmol) was heated in POCI3 (5 ml) at 50 ⁰C for 6 hours. The mixture was concentrated at reduced pressure, diluted with DCM (30 ml), washed with saturated NaHCCh (2 x 15 ml), dried (MgSO₄), filtered and evaporated at reduced pressure. The residue was purified by FCC (using a gradient of eluents 99:1 to 97:3 DCM/MeOH) to give the title compound (114 mg, 54%) as white solid.

LCMS data: Calculated MH⁺ (211); Found 76% (MH⁺) m/z 211 Rt = 1.33 min (LCMS Method B).

¹H NMR (500 MHz, CHLOROFORM-J) δ ppm 7.53 (1 H, d, J=7.9 Hz), 7.37 (1 H, d, J=8.1 Hz), 3.67 (2 H, q, J=7.2 Hz), 3.56 - 3.63 (2 H, m), 2.98 - 3.07 (2 H, m), 1.23 (3 H, t, J=7.2 Hz).

Example 39 - Preparation of 2-[(l-cyclobutylpiperidin-4-yl)oxy]-7-ethyl-6,7-dihydro-l,7- naphthyridin-8(5H)-one. Potency range D

To a solution of l-cyclobutylpiperidin-4-ol (32 mg, 0.21 mmol) in THF (3 ml) at room temperature was added NaH (10 mg of a 60% suspension in mineral oil, 0.21 mmol). After 15 mins, 2-chloro-7-ethyl-6,7-dihydro-l,7-naphthyridin-8(5H)-one (50 mg, 0.19 mmol) in THF (1 ml) was added and the resulting solution heated in a sealed tube at 70 ⁰C for 16 hours. The reaction mixture was cooled to room temperature, diluted with DCM (30 ml) and washed with saturated NaHCO₃ (2 x 15 ml), dried (MgSO₄), filtered and concentrated at reduced pressure. The residue was purified by preparative HPLC (Prep Method 2) to give the title product (2.5 mg, 4%) as colourless oil. LCMS data: Calculated MH⁺ (330); Found 91% (MH⁺) m/z 330 Rt = 4.25 min (LCMS Method D).

¹H NMR (500 MHz, CHLOROFORM-^) δ ppm 7.42 (1 H, d, J=8.4 Hz), 6.77 (1 H, d, J=8.4 Hz), 5.32 - 5.46 (1 H, m), 3.64 (2 H, q, J=7.2 Hz), 3.52 - 3.59 (2 H, m), 2.89 - 2.97 (2 H, m), 2.61 - 2.89 (2 H, m), 1.52 - 2.39 (13 H, m), 1.24 (3 H, t, J=7.2 Hz).

Route 25

Preparation of methyl N-ethyl-β-alaninate

To a solution of methyl acrylate (5 g, 58 mmol, 1 eq) in THF (60 niL) at O ⁰C under N₂ was added a solution of ethylamine (45 mL of a 2 M solution in THF, 90 mmol, 1.55 eq) over 10 min. The mixture was stirred at RT for 42 h. Volatiles were removed under reduced pressure and residue was used crude in the next step.

LCMS data: Calculated MH⁺ (132); Found 50% (MH⁺) m/z 132, Rt = 0.17 min (LCMS method A).

Preparation of methyl N-ethyl-N-(3-methoxy-3-oxopropanoyl)-β-alaninate

To a solution of ethyl hydrogen malonate (7.65 g, 58 mmol, 1 eq) in DCM (50 mL) and DMF (5 drops) at 0 ⁰C under N₂ was added oxalyl chloride (7.7 g, 5.2 mL, 60.9 mmol, 1.05 eq) over 10 min. The mixture was stirred at 0 ⁰C for 1 h then at RT for 1 h. The resulting mixture was added over 1.25 h to a freshly prepared and cooled (0 ⁰C) solution of methyl N-ethyl-β- alaninate (assume 58 mmol, 1 eq) and triethylamine (9.7 mL, 70 mmol, 1.2 eq) in DCM (50 mL). The resulting mixture was stirred for 18 h at RT before it was quenched by pouring onto saturated aqueous NaHCO₃ (100 rnL). After separation, the aqueous phase was further extracted with DCM (2 x 100 mL). The combined organic extracts were washed with brine (100 mL), dried (MgSO₄), filtered and concentrated under reduced pressure. Purification by FCC eluting with DCM/MeOH 98:2 gave the desired product (8.6 g, 61%) as colourless oil. LCMS data: Calculated MH⁺ (246); Found 95% (MH⁺) m/z 246, Rt = 0.95 min (LCMS Method A).

¹H NMR (500 MHz, CHLOROFORM- d) δ ppm 4.20 (2 H, q, J=7.1 Hz), 3.66 - 3.72 (3 H, m), 3.50 - 3.63 (3 H, m), 3.32 - 3.44 (3 H, m), 2.59 - 2.68 (2 H, m), 1.28 (3 H, t, J=7.1 Hz), 1.11 - 1.22 (3 H, m).

Preparation of ethyl l-ethyl-2,4-dioxopiperidine-3-carboxylate

To a solution of methyl N-ethyl-N-(3-methoxy-3-oxopropanoyl)-β-alaninate (8.6 g, 3.5 mmol, 1 eq) in THF (100 mL) was added KO¹Bu (4.1 g, 3.7 mmol, 1.05 eq) at RT. The mixture was heated to 70 ⁰C for 4 h. After cooling, Et₂O (150 mL) was added and the resulting precipitate collected by filtration. The solid was washed with Et₂O (2 x 50 mL) and dried under high vacuum to give a pale yellow solid (7.3 g). The desired product was accompanied with some methyl ester resulting from trans-esterification. The mixture of esters was used crude in the next step. LCMS data: Calculated MH⁺ (214); Found 64% (MH⁺) m/z 214, Rt = 0.97 min (LCMS method A).

Preparation of l-ethylpiperidine-2,4-dione

A solution of oxalic acid (6.0 g, 66 mmol, 2 eq) in H₂O (60 mL) was added to ethyl 1-ethyl- 2,4-dioxopiperidine-3-carboxylate (1.3 g, 34 mmol, 1 eq) and the mixture heated at 100 ⁰C for 4 h. After cooling, product was extracted with DCM (3 x 70 mL) and the combined organic extracts were washed with brine (70 mL), dried (MgSO₄), filtered and concentrated at reduced pressure to give the title compound as brown oil (2.5 g, 50 % yield over 2 steps). LCMS data: Calculated MH⁺ (142); Found 100% (2M+H⁺) m/z 283, Rt = 0.70 min (LCMS method D).

¹H NMR (500 MHz, CHLOROFORM- d) δ ppm 3.51 - 3.61 (4 H, m), 3.34 (2 H, s), 2.63 (2 H, t, J=6.3 Hz), 1.18 (3 H, t, J=7.2 Hz).

Preparation of 3-[(dimethylamino)methylidene]-l-ethylpiperidine-2,4-dione

To a solution of l-ethylpiperidine-2,4-dione (564 mg, 4.0 mmol, 1 eq) in toluene (20 niL) was added methoxy-bis(dimethylamino)methane (640 μL, 4.2 mmol, 1.05 eq). The mixture was heated at 110 ⁰C for 17 h. Volatiles were removed under reduced pressure and the title product obtained as a brown oil, which was used without further purification. LCMS data: Calculated MH⁺ (197); Found (MH⁺) m/z 197, Rt = 0.71 min (LCMS method A).

Example 40 - Preparation of 2-[(l-cyclobutylpiperidin-4-yl)oxy]-6-ethyl-7,8- dihydropyrido[4,3-d]pyrimidin-5(6H)-one. Potency range A

To a solution of cyanamide (42 mg, 1.0 mmol, 1 eq) and l-cyclobutylpiperidin-4-ol (155 mg,

1.0 mmol, 1 eq) in THF (3 mL) was added trifluoromethanesulfonic acid (196 μL, 2.1 mmol,

2.1 eq). The mixture was heated at 65 ⁰C for 2.5 h. After cooling, volatiles were removed under pressure to yield amino[(l-cyclobutylpiperidin-4-yl)oxy]methaniminium trifluoro- methylsulfonate.

To a solution of 3-[(dimethylamino)methylidene]-l-ethylpiperidine-2,4-dione (196 mg, 1.0 mmol, 1 eq) and amino[(l-cyclobutylpiperidin-4-yl)oxy]methaniminium trifluoro- methylsulfonate (347 mg, 1.0 mmol, 1 eq) in EtOH (3mL) was added H₂O (0.1 mL) and triethylamine (350 μL, 2.5 mmol, 2.5 eq). The reaction mixture was heated at 75 ⁰C for 18 h in a sealed tube then cooled to RT and evaporated at reduced pressure. The residue was partitioned between DCM (10 mL) and saturated aqueous NaHCO₃ (10 mL). After separation, the aqueous phase was extracted with DCM (2 x 10 mL). Combined organic extracts were washed with brine (10 mL), dried (MgSO₄), filtered and concentrated at reduced pressure. The residue was purified by preparative HPLC (Prep Method 2) to give the title product (47 mg, 14 %) as pale yellow oil. LCMS data: Calculated MH⁺ (331); Found 98% (MH⁺) m/z 331, Rt = 4.01 min (LCMS method D).

¹H NMR (500 MHz, CHLOROFORM-J) δ ppm 8.90 (1 H, s), 5.24 (1 H, br. s.), 3.71 (2 H, m), 3.59 (2 H, q, J=7.2 Hz), 3.09 (2 H, t, J=6.9 Hz), 2.93 (3 H, m), 2.39 (2 H, m), 2.06 - 2.17 (4 H, m), 1.85 - 2.01 (4 H, m), 1.72 - 1.80 (2 H, m), 1.22 (3 H, t, J=7.2 Hz).

Route 26

EtOH

Preparation of benzyl 4-[(6-ethyl-5-oxo-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2- yl)oxy]piperidine-l-carboxylate

To a solution of cyanamide (42 mg, 1.0 mmol, 1 eq) and benzyl 4-hydroxy-l-piperidine carboxylate (235 mg, 1.0 mmol, 1 eq) in THF (3 mL) was added trifluoromethanesulfonic acid (93 μL, 1.05 mmol, 1.05 eq). The mixture was heated at 65 ⁰C for 2.5 h. After cooling, volatiles were removed under pressure to yield amino({l-[(benzyloxy)carbonyl]piperidin-4- yl} oxy)methaniminium trifluormethylsulfonate.

To a solution of 3-[(dimethylamino)methylidene]-l-ethylpiperidine-2,4-dione (196 mg, 1.0 mmol, 1 eq) and amino({l-[(benzyloxy)carbonyl]piperidin-4-yl}oxy)methaniminium trifluormethylsulfonate (427 mg, 1.0 mmol, 1 eq) in EtOH (3mL) was added H₂O (0.1 mL) and triethylamine (350 μL, 2.5 mmol, 2.5 eq) and the reaction mixture heated at 75 ⁰C for 18 h in a sealed tube. After cooling, volatiles were removed. The residue was partitioned between DCM (10 mL) and saturated aqueous NaHCO₃ (10 mL). After separation, the aqueous phase was extracted with DCM (2 x 10 mL). Combined organic extracts were washed with brine (10 mL), dried (MgSO₄), filtered and concentrated at reduced pressure. The residue was purified by FCC (using a gradient of eluents, 98:2 to 96:4 DCM/MeOH) followed by FCC using (using a gradient of eluents, 50:50 to 0:100 Heptane/EtOAc) to give the desired product (110 mg, 27%) as pale yellow oil.

LCMS data: Calculated MH⁺ (411); Found 100% (MH⁺) m/z 411, Rt = 1.30 min (LCMS method A).

¹H NMR (500 MHz, CHLOROFORM-J) δ ppm 9.03 (1 H, s), 7.34 - 7.38 (5 H, m), 5.29 - 5.35 (1 H, m), 5.15 (2 H, s), 3.82 - 3.90 (2 H, m), 3.59 - 3.65 (4 H, m), 3.46 - 3.50 (2 H, m), 3.08 (2 H, t, J=6.8 Hz), 2.05 (2 H, m), 1.86 (2 H, m), 1.23 (3 H, t, J=7.2 Hz).

Example 41 - Preparation of 6-ethyl-2-{[l-(l-methylethyl)piperidin-4-yl]oxy}-7,8- dihydropyrido[4,3-d]pyrimidin-5(6H)-one. Potency range A

To a solution of benzyl 4-[(6-ethyl-5-oxo-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2- yl)oxy]piperidine-l-carboxylate (35 mg, 0.085 mmol, 1 eq) in acetone (3 mL) was added 5% Pd/C (5 mg). The mixture was stirred under an atmosphere Of H₂, with additions of more 5% Pd/C (5 mg) after 18 h and 24 h. After a further 18 h, the reaction mixture was filtered through Celite® with further elution with MeOH. The filtrate was evaporated at reduced pressure and the resulting residue purified by preparative HPLC (Prep Method 2) to give the desired product as colorless oil (8.9 mg, 32%). LCMS data: Calculated MH⁺ (319); Found 99% (MH⁺) m/z 319, Rt = 3.99 min (LCMS method D).

¹H NMR (500 MHz, CHLOROFORM-^) δ ppm 8.90 (1 H, s), 5.20 (1 H, dt, J=7.5, 3.7 Hz), 3.71 (2 H, t, J=6.9 Hz), 3.60 (2 H, q, J=7.2 Hz), 3.09 (2 H, t, J=6.8 Hz), 2.87 (2 H, br. s.), 2.74 - 2.83 (1 H, m), 2.44 - 2.61 (2 H, m), 2.06 - 2.23 (2 H, m), 1.81 - 1.99 (2 H, m), 1.22 (3 H, t, J=7.2 Hz), 1.11 (6 H, d, J=6.6 Hz).

Example 42 - Preparation of 2-[(l-cyclopentylpiperidin-4-yl)oxy]-6-ethyl-7,8- dihydropyrido[4,3-d]pyrimidin-5(6H)-one. Potency range A

⁰ ΓΛ

^/ _^ N K Y_^^ N ( _^ H X)

I ^~/ X N X O XX ^ To a solution of benzyl 4-[(6-ethyl-5-oxo-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2- yl)oxy]piperidine-l-carboxylate (35 mg, 85 μmol, 1 eq) in EtOH (3 mL) was added cyclopentanone (75 μL, 0.85 mmol, 10 eq) then 5% Pd/C (5 mg). The mixture was stirred under an atmosphere Of H₂, with additions of more 5% Pd/C (5 mg) after 18 h and 24 h. After a further 18 h, the reaction mixture was filtered through Celite® with further elution with MeOH. The filtrate was evaporated at reduced pressure and the resulting residue purified by preparative HPLC (Prep Method 2) to give the desired product as colorless oil (6.9 mg, 23%). LCMS data: Calculated MH⁺ (345); Found 99% (MH⁺) m/z 345, Rt = 4.32 min (LCMS method D).

¹H NMR (500 MHz, CHLOROFORM-J) δ ppm 8.90 (1 H, s), 5.07 - 5.30 (1 H, m), 3.71 (2 H, t, J=6.9 Hz), 3.60 (2 H, q, J=7.2 Hz), 3.09 (2 H, t, J=6.8 Hz), 2.88 (2 H, m), 2.56 - 2.65 (1 H, m), 2.46 (2 H, m), 2.07 - 2.21 (2 H, m), 1.83 - 2.03 (4 H, m), 1.65 - 1.82 (2 H, m), 1.52 - 1.65 (2 H, m), 1.39 - 1.52 (2 H, m), 1.22 (3 H, t, J=7.2 Hz).

Route 27

Preparation of 4-chloro-6-[(l-cyclobutylpiperidin-4-yl)oxy]pyridine-3-carbonitrile

In a similar fashion (Route 20, GP G except KO¹Bu was used instead of NaH), 4,6- dichloropyridine-3-carbonitrile (200 mg, 1.16 mmol, 1 eq), l-cyclobutylpiperidin-4-ol (180 mg, 1.16 mmol, 1 eq) and KO¹Bu (0.65 mL of a 1.78 M solution in THF, 1.16 mmol, 1 eq) gave the title compound (159 mg, 47%) in a 10:3 mixture of regio isomers as a yellow powder. ¹H NMR (250 MHz, CHLOROFORM-d) δ ppm 8.38 - 8.50 (1 H, m), 6.86 - 6.93 (1 H, m), 4.55 - 5.22 (1 H, m), 1.51 - 2.93 (15 H, m).

Preparation of 6-[(l-cyclobutylpiperidin-4-yl)oxy]-4-ethenylpyridine-3-carbonitrile

In a similar fashion (Route 20, GP H), 4-chloro-6-[(l-cyclobutylpiperidin-4-yl)oxy]pyridine- 3-carbonitrile (150 mg, 0.51 mmol, 1 eq), potassium vinyltrifluoroborate (76 mg, 0.57 mmol, 1.1 eq), Na₂CO₃ (200 mg, 1.53 mmol, 3 eq) and Pd(PPh₃)₄ (5 mg, 4 μmol, 0.01 eq) gave the crude product as an orange oil (142 mg). Purification of 70 mg of the crude product by FCC (DCM / MeOH +1% aq.NH₃ 96:3) yielded the title compound (50 mg, 34%) as 2:1 mixture of regioisomers.

¹H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.21 - 8.67 (1 H, m), 6.50 - 6.96 (2 H, m), 5.88 - 6.39 (1 H, m), 5.47 - 5.69 (1 H, m), 4.46 - 5.14 (1 H, m), 1.47 - 2.93 (15 H, m).

The following compound was prepared as described in Route 20, General Procedure I above.

Example 43 - Preparation of 6-[(l-cyclobutylpiperidin-4-yl)oxy]-2-ethyl-

3,4-dihydro-2,7-naphthyridin-l(2H)-one. Potency range A

In a similar fashion (Route 20, GP I), 6-[(l-cyclobutylpiperidin-4-yl)oxy]-4-ethenylpyridine- 3-carbonitrile (50 mg, 0.18 mmol, 1 eq) and ethylamine (1 ml of a 2M solution in EtOH, 2.0 mmol, 1.1 eq) in methanol (0.5 mL) gave the title compound (4.7 mg, 8%) as white solid after purification by FCC (using a gradient of eluents, 99:9 to 97:3 DCM / MeOH +1% aq.NH₃ gradient) followed by preparative HPLC (Prep Method B).

LCMS data: Calculated MH⁺ (330); Found 100% (MH⁺) m/z 330, Rt = 2.50 min (LCMS Method C).

¹H NMR (500 MHz, MeOD) δ ppm 8.63 (1 H, s), 6.66 (1 H, s), 5.18 (1 H, br. s.), 3.56 - 3.66 (4 H, m), 3.01 (2 H, t, J=6.6 Hz), 2.90 - 2.98 (1 H, m), 2.79 (2 H, m), 2.23 - 2.52 (2 H, m), 2.06 - 2.19 (4 H, m), 1.92 - 2.03 (2 H, m), 1.73 - 1.91 (4 H, m), 1.23 (3 H, t, J=7.2 Hz).

Route 28 NC, ,CN

NC. ^ ^CN NC. _/^. ,CN

1 Pyridine, 105 ⁰C Isoamylnitπte HO

HC(OEt)₃ 2 cHCI, 80 ⁰C H₉N N Cl CV N Cl

CuCI₂, MeCN KO'Bu, THF RT, 16 h 70 ⁰C, 5 h

toluene, 100 ⁰C, 3 h

Preparation of l-amino-ό-chloropyridine-S^-dicarbonitrile

Malononitrile (4.67 g, 70.1 mmol, 2 eq) and triethylortho formate (5.88 rnL, 35.3 mmol, 1 eq) were heated together at 105 ⁰C in pyridine (2.80 g, 2.90 mL, 35.3 mmol, 1 eq). After 1 h, the mixture was cooled to 80 ⁰C and concentrated HCl (54 mL) was added dropwise to the resulting black solid. Heating was continued at 80 ⁰C for 1.5 h. After cooling to RT, H₂O (70 mL) was added and the solid collected by filtration, washed with H₂O (70 mL), EtOH (70 mL) and Et₂O (70 mL). Recrystallization from warm DMF (170 mL) and water (200 mL), and further washing with H₂O (70 mL), EtOH (70 mL) and Et₂O (70 mL) gave the title compound (3.4 g, 54 %) as pale grey solid. 1H NMR (500 MHz, DMSO-J₆) δ ppm 8.57 (1 H, s), 8.40 (2 H, br. s.).

Preparation of 2,6-dichloropyridine-3,5-dicarbonitrile

To a suspension of 2-amino-6-chloropyridine-3,5-dicarbonitrile (3.41 g, 178 mmol, 1 eq) in MeCN (150 mL) was added isoamylnitrite (3.37 g, 3.87 mL, 28.7 mmol, 1.5 eq) and copper (II) chloride (3.86 g, 28.7 mmol, 1.5 eq). The mixture was heated at 70 ⁰C for 5 h. After cooling to RT, 2N HCl (30 mL) and DCM (50 mL) were added. The organic phase was collected, dried (MgSO₄), filtered and concentrated at reduced pressure. The residue was purified by FCC using DCM as eluent to give the title compound (2.80 g, 74 %) as white solid.

¹H NMR (500 MHz, CHLOROFORM-J) δ ppm 8.28 (1 H, s).

Preparation of 2-chloro-6-[(l-cyclobutylpiperidin-4-yl)oxy]pyridine-3,5-dicarbonitrile

To a solution of 2,6-dichloropyridine-3,5-dicarbonitrile (591 mg, 3.0 mmol, 1 eq) and 1- cyclobutylpiperidin-4-ol (558 mg, 3.6 mmol, 1.2 eq) in THF (20 mL) was added KO¹Bu in THF (20% wt/wt, 2.2 mL, 3.9 mmol, 1.3 eq). The mixture was stirred at RT for 16 h before quenching the reaction by pouring onto saturated aqueous NaHCO₃ (30 mL). After extraction with EtOAc (3 x 30 mL), the combined organic extracts were washed with brine (30 mL), dried (MgSO₄), filtered and concentrated at reduced pressure. The residue was purified by FCC (using a gradient of eluents, 98:2 to 95:5 DCM/MeOH) to give the title compound (429 mg, 45%) as pale yellow oil. LCMS data: Calculated MH⁺ (317); Found 67% (MH⁺) m/z 317, Rt = 0.97 min (LCMS method A).

¹H NMR (500 MHz, CHLOROFORM-J) δ ppm 8.13 (1 H, s), 5.34 - 5.45 (1 H, m), 2.92 (1 H, br. s.), 2.66 (3 H, br. s.), 1.97 - 2.23 (9 H, m), 1.69 - 1.80 (2 H, m).

Preparation of 2-[(l-cyclobutylpiperidin-4-yl)oxy]-6-ethenylpyridine-3,5-dicarbonitrile

A mixture of 2-chloro-6-[(l-cyclobutylpiperidin-4-yl)oxy]pyridine-3,5-dicarbonitrile (110 mg, 0.35 mmol, 1 eq), tributylvinyltin (132 mg, 122 μL, 0.42 mmol, 1.2 eq) and tetrakis triphenylphosphine palladium(O) (20 mg, 0.017 mmol, 0.05 eq) in toluene (3 mL) were heated in a sealed tube at 100 ⁰C for 2.5 h. After cooling to RT, volatiles were evaporated at reduced pressure and the residue partitioned between heptane (10 mL) and MeCN (10 mL). The heptane phase was further extracted with MeCN (2 x 10 mL). The combined MeCN phases were concentrated at reduced pressure to give the crude title compound as brown oil. LCMS data: Calculated MH⁺ (309); Found 25% (MH⁺) m/z 309, Rt = 0.98 min (LCMS method A). ¹H NMR (250 MHz, CHLOROFORM-J) δ ppm 8.07 (1 H, s), 7.13 (1 H, dd, J=16.7, 10.4 Hz), 6.67 (1 H, dd, J=16.7, 1.4 Hz), 5.90 (1 H, dd, J=10.5, 1.5 Hz), 5.39 (1 H, br. s.), 2.74 - 2.90 (1 H, m), 2.53 - 2.68 (2 H, m), 2.29 - 2.45 (2 H, m), 1.94 - 2.10 (8 H, m), 1.70 - 1.73 (2 H, m).

Preparation of 2- [(l-cyclobutylpiperidin-4-yl)oxy] -6- [2-(ethylamino)ethyl] pyridine-3,5- dicarbonitrile

To a solution of crude 2-[(l-cyclobutylpiperidin-4-yl)oxy]-6-ethenylpyridine-3,5- dicarbonitrile (0.35 mmol, 1 eq) in THF (2 mL) was added EtNH₂ (2 M in THF, 0.5 niL, 1 mmol, 3 eq). The mixture was stirred at RT for 16 h. After concentration at reduced pressure, the residue was dissolved in DCM and loaded onto a SCX-2 column. The SCX-2 column was washed with with DCM (10 mL) and MeOH (10 mL) prior to elution of crude product with

2N NH3 in MeOH. The ammonia fractions were concentrated and the residue purified further by FCC (using a gradient of eluents, 98:2 to 92:8 DCM/MeOH + 2% NH₃) to give the title compound (50 mg, 41% over 2 steps) as light brown oil.

LCMS data: Calculated MH⁺ (354); Found 77% (MH⁺) m/z 309, Rt = 5.30 min (LCMS method D).

¹H NMR (500 MHz, MeOD) δ ppm 8.60 (1 H, s), 5.35 (1 H, br. s.), 3.53 - 3.60 (4 H, m), 3.04 - 3.08 (2 H, m), 2.78 - 2.86 (1 H, m), 2.64 (2 H, br. s.), 2.32 (2 H, br. s.), 2.05 - 2.11 (4 H, m),

1.87 - 1.94 (4 H, m), 1.70 - 1.77 (2 H, m), 1.21 (3 H, t, J=7.2 Hz).

Example 44 - Preparation of 2-[(l-cyclobutylpiperidin-4-yl)oxy]-6-ethyl-5-oxo-5,6,7,8- tetrahydro- 1 ,6-naphthyridine-3-carbonitrile.

To a solution of 2-[(l-cyclobutylpiperidin-4-yl)oxy]-6-[2-(ethylamino)ethyl]pyridine-3,5- dicarbonitrile (25 mg, 0.071 mmol, 1 eq) in isopropanol (1 mL) and water (0.5 mL) was added LiOKH₂O (15 mg, 0.36 mmol, 5 eq) and the resulting mixture heated at 70 ⁰C for 3 h. After cooling to RT, the reaction was quenched by pouring onto saturated aqueous NaHCO₃ (8 mL) and extracted with EtOAc (3 x 8 mL). The combined organic extracts were washed with brine (10 rnL), dried (MgSO₄), filtered and concentrated at reduced pressure. The title compound (2.1 mg, 8 %) was obtained as colourless oil following purification by semi- preparative HPLC (Prep Method 2).

LCMS data: Calculated MH⁺ (355); Found 92% (MH⁺) m/z 355, Rt = 4.77 min (LCMS method D).

¹H NMR (500 MHz, MeOD) δ ppm 8.44 (1 H, s), 5.41 (1 H, br. s.), 3.70 (2 H, t, J=6.9 Hz), 3.59 (2 H, q, J=7.2 Hz), 3.14 (2 H, t, J=6.8 Hz), 2.97 (1 H, br. s.), 2.75 (2 H, br. s.), 2.47 (2 H, br. s.), 2.07 - 2.18 (4 H, m), 1.92 - 2.01 (4 H, m), 1.74 - 1.80 (2 H, m), 1.21 (3 H, t, J=7.2 Hz).

Example 45 - Preparation of 2-[(l-cyclobutylpiperidin-4-yl)oxy]-6-ethyl-5-oxo-5,6,7,8- tetrahydro- 1 ,6-naphthyridine-3-carboxamide.

During the reaction to form Example 44 {2-[(l-cyclobutylpiperidin-4-yl)oxy]-6-ethyl-5-oxo-

5,6,7,8-tetrahydro-l,6-naphthyridine-3-carbonitrile}, formation of the title carboxamide compound was observed. The title compound (4.6mg, 18%) was also isolated from the same purification by semi-preparative HPLC (Prep Method 2).

LCMS data: Calculated MH⁺ (373); Found 97% (MH⁺) m/z 373, Rt = 4.22 min (LCMS method D).

¹H NMR (500 MHz, MeOD) δ ppm 8.78 (1 H, s), 5.46 (1 H, br. s.), 3.69 (2 H, t, J=6.9 Hz), 3.60 (2 H, q, J=7.2 Hz), 3.11 (2 H, t, J=6.9 Hz), 2.85 (1 H, d, J=7.6 Hz), 2.66 (2 H, br. s.),

2.32 (2 H, br. s.), 2.07 - 2.18 (4 H, m), 1.89 - 1.97 (4 H, m), 1.71 - 1.78 (2 H, m), 1.22 (3 H, t,

J=7.2 Hz).

The following compound was prepared as described in Route 12, General Procedure F above.

Example 46 - Preparation of 2-[(l-cyclobutylpiperidin-4-yl)oxy]-6-(2-hydroxy-2- methylpropyl)-7,8-dihydro-l,6-naphthyridin-5(6H)-one. Potency range A

In a similar fashion (Route 12, GP F), 2-chloro-6-(2-hydroxy-2-methylpropyl)-7,8-dihydro- l,6-naphthyridin-5(6H)-one (15 mg, 0.060 mmol, 1 eq) and l-cyclobutylpiperidin-4-ol (14 mg, 0.088 mmol, 1.5 eq) gave the title compound (1.9 mg, 9%) as colourless oil after purification by preparative HPLC (Prep Method 2).

LCMS data: Calculated MH⁺ (374); Found 96% (MH⁺) m/z 374, Rt = 4.16 min (LCMS method D).

¹H NMR (500 MHz, MeOD) δ ppm 8.13 (1 H, d, J=8.5 Hz), 6.76 (1 H, d, J=8.5 Hz), 5.36 (1

H, br. s.), 3.82 (2 H, t, J=6.8 Hz), 3.55 (2 H, s), 3.45 (2 H, br. s.), 2.69 - 3.14 (5 H, m), 2.25 (2

H, br. s.), 2.11 (6 H, br. s.), 1.77 - 1.88 (2 H, m), 1.21 - 1.27 (6 H, m).

Comparative example 47

Comparator compound, Example 265 from WO-A 2002/076925, and Example 21 above were profiled in the CYP450 2D6 inhibition assay and the IC50 results provided below:

Example 265 from WO-A 2002/076925

CYP450 2D6 IC₅₀ = 12.9 μM CYP450 2D6 IC₅₀ = > 50 μM

It can be inferred from this data that Example 265 of WO-A 2002/076925 has potential to inhibit human CYP450 2D6 enzymes and concomitantly affect the metabolism of a coadministered compound(s). This may affect plasma levels in vivo and potentially lead to adverse drug reactions or toxicity.

Claims

Patent claims

A compound of formula (I)

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

one of X¹— X^la, X²— X^2a is C(RV ^a)-C(RV ^b); or C(R^a)=C(R^b); and the other is N(R¹VC(O), provided that N(R¹) represents X¹ or X²;

R^a, R^b, R^la, R^lb 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;

Optionally at least one of the pairs R^a/R^la, R^b/R^lb is joined together with the carbon atom to which they are attached to form C₃_₅ cycloalkyl, wherein C₃_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 is H; Ci_7 alkyl; C2-7 alkenyl; C2-7 alkynyl; or T, wherein Ci_7 alkyl; C2-7 alkenyl; and C2-7 alkynyl are optionally substituted with one or more R^lc, which are the same or different;

T is C3_7 cycloalkyl; or 4 to 6 membered saturated heterocyclyl, wherein T is optionally substituted with one or more R^ld, which are the same or different; X³ is N, N-oxide or C(R²) and X⁴ is N, N-oxide or CH, provided that at least one of X³, X⁴ is N or N-oxide;

R² is H; halogen; CN; CH₃; CH₂F; CHF₂; CF₃; C(O)N(R³R^3a); CH₂N(R³R^3a); N(R³R^3a); CH₂OH; OR³; OCH₂F; OCHF₂; or OCF₃;

R³, R^3a are independently selected from the group consisting of H; Ci_5 alkyl; and C₃_5 cycloalkyl;

Optionally R³, R^3a are joined together with the nitrogen atom to which they are attached to form a 4 to 7 membered saturated heterocycle;

X⁵ is O; S; S(O); S(O)₂; N(R⁴); N*(R⁴)C(0); N* (R⁴) S (O)₂; or S*(O)₂N(R⁴), wherein the asterisk indicates the attachment to the aromatic cyclic moiety in formula (I);

R⁴ is H; Ci_5 alkyl; or C₃_6 cycloalkyl;

n is O, 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 R⁵, 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 R⁵ being N(R⁶R^6a);

R^ld, R⁵ are independently selected from the group consisting of halogen; CN; C(O)OR^6b; OR^6b; C(O)R^6b; C(O)N(R^6bR^6c); S(O)₂N(R^6bR^6c); S(O)N(R^6bR^6c); S(O)₂R^6b; S(O)R^6b; N(R^6b)S(O)₂N(R^6cR^6d); SR^6b; N(R⁶R^6a); N(R^6bR^6c); NO₂; OC(O)R^6b; N(R^6b)C(O)R^6c; N(R^6b)S(O)₂R^6c; N(R^6b)S(O)R^6c; N(R^6b)C(O)OR^6c;

N(R^6b)C(O)N(R^6cR^6d); OC(O)N(R^6bR^6c); oxo (=0), where the ring is at least partially saturated; T¹; Ci_6 alkyl; C₂_6 alkenyl; and C₂_6 alkynyl, wherein Ci_6 alkyl; C₂_6 alkenyl; and C₂_6 alkynyl are optionally substituted with one or more R⁷, which are the same or different, provided that when R is 4 to 7 membered saturated heterocyclyl, wherein one ring atom is nitrogen and optionally a further ring atom is oxygen, R⁵ is T¹; Ci_6 alkyl; C2-6 alkenyl; or C2-6 alkynyl, wherein Ci_6 alkyl; C2-6 alkenyl; and C2-6 alkynyl are optionally substituted with one or more R⁷, which are the same or different when R⁵ is directly attached to the ring nitrogen atom.

Optionally, two R⁵ form a bridging group selected from the group consisting of CH₂; CH₂CH₂; CH₂CH₂CH₂; NH; N(CH₃); CH₂NHCH₂; CH₂N(CH₃)CH₂; and O;

R⁶, R^6a are independently selected from the group consisting of T¹; Ci_6 alkyl; C₂-6 alkenyl; and C₂-6 alkynyl, wherein Ci_6 alkyl; C₂-6 alkenyl; and C₂-6 alkynyl are optionally substituted with one or more R⁸, which are the same or different;

Optionally, R⁶, R^6a are joined together with the nitrogen atom to which they are attached to form nitrogen containing ring T²;

R^6b, R^6c, R^6d are independently selected from the group consisting of H; T¹; Ci_6 alkyl; C₂-6 alkenyl; and C₂-6 alkynyl, wherein Ci_6 alkyl; C₂-6 alkenyl; and C₂-6 alkynyl are optionally substituted with one or more R⁸, which are the same of different;

R^lc, R⁷, R⁸ are independently selected from the group consisting of halogen; CN;

C(O)OR⁹; OR⁹; C(O)R⁹; C(O)N(R⁹R^9a); S(O)₂N(R⁹R^9a); S(O)N(R⁹R^9a); S(O)₂R⁹;

S(O)R⁹; N(R⁹)S(O)₂N(R^9aR^9b); SR⁹; N(R⁹R^9a); NO₂; OC(O)R⁹; N(R⁹)C(O)R^9a;

N(R⁹)SO₂R^9a; N(R⁹)S(O)R^9a; N(R⁹)C(O)N(R^9aR^9b); N(R⁹)C(O)OR^9a; OC(O)N(R⁹R^9a); and T¹;

R⁹, R^9a, R^9b are independently selected from the group consisting of H; T¹; Ci_6 alkyl;

C₂-6 alkenyl; and C₂-6 alkynyl, wherein Ci_6 alkyl; C₂-6 alkenyl; and C₂-6 alkynyl are optionally substituted with one or more halogen, which are the same of different;

T¹ is phenyl; naphthyl; azulenyl; indenyl; indanyl; C₃-₇ cycloalkyl; 3 to 7 membered heterocyclyl; or 7 to 11 membered heterobicyclyl, wherein T¹ is optionally substituted with one or more R¹⁰, which are the same or different; T p2 is a nitrogen containing 3 to 7 membered heterocycle, wherein T is optionally substituted with one or more R , 10 , which are the same or different;

R¹⁰ is halogen; CN; C(O)OR¹¹; OR¹¹; C(O)R¹¹; C(O)N(R¹¹R^{1 la}); S(O)₂N(R¹¹R^{1 la}); S(O)N(R¹¹R¹¹"); S(O)₂R¹¹; S(O)R¹¹; N(R¹ ^S(O)₂N(R^{1 la}R^{l lb}); SR¹¹; N(R^πR^{l la}); NO₂; OC(O)R¹¹; N(R¹ ^C(O)R^11*; N(R¹ ^S(O)₂R^11*; N(R¹ ^S(O)R^11*; N(R¹ ^C(O)OR^11*; N(R¹ ^C(O)N(R^{1 la}R^{l lb}); OC(O)N(R¹¹R¹¹"); oxo (=0), where the ring is at least partially saturated; Ci_6 alkyl; C₂_6 alkenyl; or C₂_6 alkynyl, wherein Ci_6 alkyl; C₂_6 alkenyl; and C₂_6 alkynyl are optionally substituted with one or more halogen, which are the same or different;

R¹¹, R^{l la}, R^{l lb} are independently selected from the group consisting of H; Ci_6 alkyl; C₂_6 alkenyl; and C₂_6 alkynyl, wherein Ci_6 alkyl; C₂_6 alkenyl; and C₂_6 alkynyl are optionally substituted with one or more halogen, which are the same of different.

A compound of claim 1 having the formula (Ia) or (Ib)

wherein R > 1 , X v3 , X -χ_/4 , X -v"5 , n, R have the meaning as indicated in claim 1.

3. A compound of claim 2 having the formula (Ia), wherein R¹, X³, X⁴, X⁵, n, R have the meaning as indicated in claim 1.

4. A compound of any of claims 1 to 3, wherein R¹ is H; Ci_7 alkyl; C2-7 alkenyl; T; or CH₂-T ^l and wherein Ci .η alkyl; C2-7 alkenyl; are optionally substituted with one or more substituents, which are the same or different and selected from the group consisting of halogen; OH; OCH₃; OCH₂F; OCHF₂; OCF₃; and CN and wherein T is optionally substituted with one or more R^ld, which are the same or different and wherein T¹ is optionally substituted with one or more R¹⁰, which are the same or different.

5. A compound of any of claims 1 to 4, wherein R^a, R^b, R^la, R^lb are independently selected from the group consisting of H; and methyl.

6. A compound of any of claims 1 to 5, wherein X³ is N or C(R²) and X⁴ is N, N-oxide or CH, provided that at least one of X³, X⁴ is N or N-oxide.

7. A compound of any of claims 1 to 5, wherein at least one of X³, X⁴ is N-oxide.

8. A compound of any of claims 1 to 5, wherein X³, X⁴ are N; or N-oxide.

9. A compound of any of claims 1 to 8, wherein R² is H; halogen; CN; CH₃; OCH₃; CH₂F; CHF₂; CF₃; C(O)N(R³R^3a); or CH₂N(R³R^3a).

10. A compound of any of claims 1 to 9, wherein X⁵ is O; N(R⁴); S; S(O); S(O)₂; or N*(R⁴)C(0).

11. A compound of any of claims 1 to 10, wherein X⁵ is O;.

12. A compound of any of claims 1 to 11, wherein n is 0; or 3.

13. A compound of any of claims 1 to 12, wherein R is a cyclopentyl; a cyclohexyl; an azetidine; an azepine; a pyrrolidine; a piperidine; a piperazine; or a morpholine ring, wherein R is optionally substituted with one or more R⁵, which are the same or different, provided that the ring comprises a tertiary nitrogen atom or the ring is substituted with at least one R⁵ being N(R⁶R^6a).

14. A compound of any of claims 1 to 13, wherein -R is

15. A compound of any of claims 1 to 14, wherein R > 5 i •s τ T.1 ;. or Ci_6 alkyl.

16. A compound of any of claims 1 to 15, wherein T¹ is C3_7 cycloalkyl.

17. A compound of any of claims 1 to 16, wherein R^6b, R^6c are independently selected from the group consisting of H; and Ci_6 alkyl.

18. A compound of any of claims 1 to 17, wherein R^lc is halogen; or OH; or O-Ci_₄ alkyl; or N(R⁹R^9a).

19. A compound of claim 1 selected from the group consisting of

2-[(l-cyclobutylpiperidin-4-yl)oxy]-6-ethyl-7,8-dihydro-l,6-naphthyridin-5(6H)-one;

2-[(l-cyclobutylpiperidin-4-yl)oxy]-6-ethyl-7,8-dihydro-l,6-naphthyridin-5(6H)-one fumaric acid salt;

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

2-[(l-cyclobutylpiperidin-4-yl)oxy]-6-(cyclopropylmethyl)-7,8-dihydro-l,6- naphthyridin-5(6H)-one;

2-[(l-cyclobutylpiperidin-4-yl)oxy]-6-(tetrahydro-2H-pyran-4-ylmethyl)-7,8-dihydro- 1 ,6-naphthyridin-5(6H)-one;

2-[(l-cyclobutylpiperidin-4-yl)oxy]-6-(cyclohexylmethyl)-7,8-dihydro-l,6- naphthyridin-5 (6H)-one; 6-benzyl-2-[(l-cyclobutylpiperidin-4-yl)oxy]-7,8-dihydro-l,6-naphthyridin-5(6H)- one;

2-[(l-cyclobutylpiperidin-4-yl)oxy]-6-(4-fluorobenzyl)-7,8-dihydro-l,6-naphthyridin- 5(6H)-one;

2- [( 1 -cyclobutylpiperidin-4-yl)oxy] -6- [(6-methylpyridin-3 -yl)methyl] -7, 8-dihydro- 1 ,6-naphthyridin-5(6Η)-one;

2-[(l-cyclobutylpiperidin-4-yl)oxy]-6-(2-methoxyethyl)-7,8-dihydro-l,6-naphthyridin-

5(6H)-one;

2-{2-[(l-cyclobutylpiperidin-4-yl)oxy]-5-oxo-7,8-dihydro-l,6-naphthyridin-6(5H)- yl} -N,N-dimethylacetamide;

2-[(l-cyclobutylpiperidin-4-yl)oxy]-7,8-dihydro-l,6-naphthyridin-5(6H)-one;

2-[(l-cyclobutylpiperidin-4-yl)oxy]-6-ethyl-l,6-naphthyridin-5(6H)-one;

6-ethyl-2-[(l-methylpiperidin-4-yl)oxy]-7,8-dihydro-l,6-naphthyridin-5(6H)-one;

2-[(l-cyclopentylpiperidin-4-yl)oxy]-6-ethyl-7,8-dihydro-l,6-naphthyridin-5(6H)-one;

2-[(l-cyclohexylpiperidin-4-yl)oxy]-6-ethyl-7,8-dihydro-l,6-naphthyridin-5(6H)-one;

2- [[(3S)- 1 -cyclopentylpyrrolidin-S-y^oxy} -6-ethyl-7,8-dihydro- 1 ,6-naphthyridin- 5(6H)-one;

2-[[(3S)- 1 -cyclobutylpyrrolidin-3-yl]oxy} -6-ethyl-7,8-dihydro- 1 ,6-naphthyridin- 5(6H)-one;

2-{[(3i?)-l-cyclopentylpyrrolidin-3-yl]oxy}-6-ethyl-7,8-dihydro-l,6-naphthyridin- 5(6H)-one; 2-{[(3i?)-l-cyclobutylpyrrolidin-3-yl]oxy}-6-ethyl-7,8-dihydro-l,6-naphthyridin- 5(6H)-one;

6-ethyl-2-(3-pyrrolidin- 1 -ylpropoxy)-7,8-dihydro- 1 ,6-naphthyridin-5(6H)-one;

6-ethyl-2-(3-piperidin- 1 -ylpropoxy)-7,8-dihydro- 1 ,6-naphthyridin-5(6H)-one;

2- { [ 1 -(cyclopropylmethyl)piperidin-4-yl]oxy } -6-ethyl-7,8-dihydro- 1 ,6-naphthyridin- 5(6H)-one;

6-ethyl-2- { [ 1 -( 1 -methylethyl)piperidin-4-yl]oxy } -7,8-dihydro- 1 ,6-naphthyridin- 5(6H)-one;

6-ethyl-2-[(l-oxetan-3-ylpiperidin-4-yl)oxy]-7,8-dihydro-l,6-naphthyridin-5(6H)-one;

2-[(l-cyclobutylpiperidin-4-yl)oxy]-6-[4-(methylsulfonyl)benzyl]-7,8-dihydro-l,6- naphthyridin-5 (6H)-one;

2-[(l-cyclobutylpiperidin-4-yl)oxy]-6-[(methylsulfanyl)methyl]-7,8-dihydro-l,6- naphthyridin-5(6H)-one;

2-[(l-cyclobutylpiperidin-4-yl)(methyl)amino]-6-ethyl-7,8-dihydro-l,6-naphthyridin- 5(6H)-one;

2-[(l-cyclobutylpiperidin-4-yl)oxy]-6-ethyl-3-fluoro-7,8-dihydro-l,6-naphthyridin-

5(6H)-one;

2-[(l-cyclobutylpiperidin-4-yl)oxy]-6-ethyl-8-methyl-7,8-dihydro-l,6-naphthyridin- 5(6H)-one;

2-[(l-cyclobutylpiperidin-4-yl)oxy]-6-ethyl-8,8-dimethyl-7,8-dihydro-l,6- naphthyridin-5 (6H)-one; 2-[(l-cyclobutylpiperidin-4-yl)oxy]-6-(3-hydroxy-3-methylbutyl)-7,8-dihydro-l,6- naphthyridin-5 (6H)-one;

2-[(l-cyclobutylpiperidin-4-yl)oxy]-6-(2-hydroxyethyl)-7,8-dihydro-l,6-naphthyridin- 5(6H)-one;

2-[(l-cyclobutylpiperidin-4-yl)oxy]-6-(3-hydroxy-2,2-dimethylpropyl)-7,8-dihydro- 1 ,6-naphthyridin-5(6H)-one;

2-[(l -cyclobutylpiperidin-4-yl)oxy]-6-(2-hydroxy- 1 , 1 -dimethylethyl)-7,8-dihydro- 1 ,6- naphthyridin-5 (6H)-one;

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

2-[(l-cyclobutylpiperidin-4-yl)oxy]-6-(3-methoxy-2,2-dimethylpropyl)-7,8-dihydro- 1 ,6-naphthyridin-5(6H)-one;

2-[(l-cyclobutylpiperidin-4-yl)oxy]-6-(2-methoxyethyl)-7,7-dimethyl-7,8-dihydro-l,6- naphthyridin-5(6H)-one;

6-ethyl-2-[(3-piperidin- 1 -ylpropyl)sulfanyl]-7,8-dihydro- 1 ,6-naphthyridin-5(6Η)-one;

2-[(l-cyclobutylpiperidin-4-yl)oxy]-7-ethyl-6,7-dihydro-l,7-naphthyridin-8(5H)-one;

2-[(l-cyclobutylpiperidin-4-yl)oxy]-6-ethyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)- one;

6-ethyl-2- { [ 1 -( 1 -methylethyl)piperidin-4-yl]oxy } -7,8-dihydropyrido [4,3-d]pyrimidin- 5(6H)-one;

2-[(l-cyclopentylpiperidin-4-yl)oxy]-6-ethyl-7,8-dihydropyrido[4,3-d]pyrimidin- 5(6H)-one; 6-[(l-cyclobutylpiperidin-4-yl)oxy]-2-ethyl-3,4-dihydro-2,7-naphthyridin-l(2H)-one;

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

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

2-[(l-cyclobutylpiperidin-4-yl)oxy]-6-(2-hydroxy-2-methylpropyl)-7,8-dihydro-l,6- naphthyridin-5(6H)-one.

20. A pharmaceutical composition comprising at least one compound or a pharmaceutically acceptable salt thereof of any of claims 1 to 19 together with a pharmaceutically acceptable carrier, optionally in combination with one or more other bioactive compounds or pharmaceutical compositions.

21. A compound or a pharmaceutically acceptable salt thereof of any of claims 1 to 19 for use as a medicament.

22. A compound or a pharmaceutically acceptable salt thereof of any of claims 1 to 19 for use in a method of treating or preventing diseases and disorders associated with the H3 receptor.

23. A compound or a pharmaceutically acceptable salt thereof of any of claims 1 to 19 for use in a method of treating or preventing neurological disorders; disorders affecting energy homeostasis as well as complications associated therewith; Pain; cardiovascular disorders; gastrointestinal disorders; drug abuse; vestibular dysfunction; nasal congestion; allergic rhinitis; or asthma - preferably, 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.

24. Use of a compound or a pharmaceutically acceptable salt thereof of any of claims 1 to 19 for the manufacture of a medicament for the treatment or prophylaxis of diseases and disorders associated with the H3 receptor.

25. Use of a compound or a pharmaceutically acceptable salt thereof of any of claims 1 to 19 for the manufacture of a medicament for the treatment or prophylaxis of neurological disorders; disorders affecting energy homeostasis as well as complications associated therewith; Pain; cardiovascular disorders; gastrointestinal disorders; drug abuse; vestibular dysfunction; nasal congestion; allergic rhinitis; or asthma -preferably, 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.

26. 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 any of claims 1 to 19 or a pharmaceutically acceptable salt thereof.

27. 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 neurological disorders; disorders affecting energy homeostasis as well as complications associated therewith; Pain; cardiovascular disorders; gastrointestinal disorders; vestibular dysfunction; drug abuse; nasal congestion; allergic rhinitis; or asthma -preferably, 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 any of claims 1 to 19 or a pharmaceutically acceptable salt thereof.

28. A method for the preparation of a compound of any of claims 1 to 19, wherein in formula (I) X⁵ is O; S; or N(R⁴), comprising the steps of

(a) Boc protecting a compound of formula (Ha) at the secondary nitrogen atom

wherein one of X¹— X^la, X²— X^2a is C(R^aR^la)-C(R^bR^lb); or C(R^a)=C(R^b); and the other is NH-C(O), provided that NH represents X¹ or X²; and X³, X⁴ have the meaning as indicated in claim 1;

(b) reacting the resulting compound from step (a) with a compound of formula (V) H-X⁵ U <^V>

wherein X⁵ is O; S; or N(R⁴) and n, R have the meaning as indicated in claim 1;

(c) deprotecting the resulting compound from step (b) and -when R¹ is other than H - reacting the unprotected compound with either of

i) a compound of formula R'-halide or R¹ -sulfonate in the presence of a base to yield a compound of formula (I), wherein X⁵ is O; S; or N(R⁴); ii) a compound of formula R²(=O) in the presence of a reducing agent and organic solvent to yield a compound of formula (I), wherein X⁵ is O; S; or N(R⁴).

29. A method for the preparation of a compound of any of claims 1 to 19, wherein in formula (I) X³ is N or CR² and X⁴ is CH or N comprising the steps of

(a) reacting a compound of formula (XXVa)

wherein one of X¹ — X^la, X²— X^2a is C(R^aR^la)-C(R^bR^lb); or C(R^a)=C(R^b); and the other is NH-C(O), provided that NH represents X¹ or X², with a compound of formula R'-halide or R¹ -sulfonate in the presence of a base, wherein R¹ has the meaning as indicated in claim 1, provided that R¹ is other than H;

(b) treating the resulting intermediate with an oxidising agent to yield intermediate compound of formula (XXVIIa) or formula (XXVIIb)

(XXVIIb)

wherein one of X —X A'a^~, x x^2~—— xχ^2a~ is C(R^aR^la)-C(R^bR^lb); or

C(R^a)=C(R^b); and the other is N(R¹VC(O), provided that N(R¹) represents X¹ or X²,

(C) treating the compound of formula (XXVIIa) or formula (XXVIIb) with phosphorus oxychloride at high temperature followed by aqueous workup to yield intermediate compound of formula (XXVIIIa)

(d) reacting a compound of formula (XXVIIIa), optionally in the presence of a strong base optionally from low temperature (RT to -78⁰C) to high temperature with thermal heating or microwave irradiation (up to 15O⁰C), with a compound of formula (V)

H-X^{^} ^R (V)

wherein X⁵ is O; S; or N(R⁴) and n, R have the meaning as indicated in claim 1 to yield a compound of formula (I).

30. The method of claim 28 or 29, comprising the further step reacting a compound of formula (I), wherein X⁵ is S with an oxidising agent to yield a compound of formula (I), wherein X⁵ is S(O); or S(O)₂.

31. Method for the preparation of a compound of any of claims 1 to 19, comprising the steps of:

reacting a compound of formula (XLII) with a compound of formula (V), optionally in the presence of a strong base

H-X⁵ U <^V> wherein X⁵ is O; S; or N(R⁴) and n, R have the meaning as indicated in claim 1 to yield a compound of formula (XLIII)

(XLIII)

optionally reacting the compound of formula (XLIII), wherein X⁵ is S with an oxidising agent to yield a compound of formula (XLIII), wherein X⁵ is S(O); or S(O)₂.

reacting the resulting product in the presence of a metal catalyst, optionally in the presence of a base, with a compound of formula (XLIV)

^X^>_χ2a"^Y (XLIV) wherein X²=X^2a is C(R^a)=C(R^b) having the meaning as indicated in claim 1 and Y is an appropriate group for a metal catalysed coupling reaction with an aromatic halide to yield a compound of formula (XLV)

heating the resulting product in the presence of an amine of formula H₂N(R¹), optionally in the presence of a suitable base, wherein R¹ is as indicated in claim 1 to yield a compound of formula (I).