WO2011083315A1 - Compounds and their use - Google Patents

Abstract

The invention provides compounds of Formula (1); wherein: R₁ represents C_1-6 alkyl or H; X represents N or CH; Y represents -NR₂R₃ as depicted in Formula (A), or a ring of formula (B); wherein ^a represents the point of attachment to the pyridinyl or pyrazinyl ring; R₂ represents C_1-6 alkyl optionally substituted by haloC_1-3 alkyl or C_1-4 alkoxy; R₃ represents H, C_1-6 alkyl or C_3-8 heterocyclyl; W represents -(CH₂)_n-; W) represents -(CH₂)_P-; n represents 1, 2 or 3;, p represents 1 or 2; R₄ represents halogen or C_1-4 alkoxy; and R₅ represents H or halogen; R₆ represents H or C_1-6 alkyl;provided that, when X represents CH and R₂ is C_1-3 alkyl, R₁ is not H; and provided that, when X represents CH and R₄ represents halogen, R₅ is not H; or a pharmaceutically acceptable salt thereof. The compounds of the invention have been found to modulate the histamine H3 receptor.

Description

Compounds and their use

The present invention relates to compounds and their uses, and in particular to compounds having a benzazepine scaffold and their therapeutic use in the treatment or prevention of conditions having an association with the histamine H3 receptor.

The H3 receptor was first identified pharmacologically in 1983 as an autoreceptor that regulates the production of histamine (1). The receptor was later cloned in 1999 (2). It is a constitutively active G protein-coupled receptor that is expressed predominantly in the central nervous system (CNS) and modulates a variety of CNS functions both centrally and peripherally. It is expressed on the presynaptic terminals of CNS neurones and acts as a negative modulator of release of neurotransmitters such as histamine, acetylcholine, norepinephrine, serotonin and dopamine (3). Consequently, the ability of the H3 receptor to regulate the release of a wide range of neurotransmitters has fuelled research into the development of antagonists / inverse agonists which have potential in behavioural and physiological conditions, for example CNS disorders such as narcolepsy, disorders of wakefulness, cognition or attention, pain and in suppression of food intake.

Histaminergic neurones are located in the tuberomammillary nucleus of the posterior hypothalamus and project their axons into brain regions including the hypothalamus, thalamus, cerebral cortex, amygdala, and septum. Activity of histaminergic neurons is closely linked with the sleep / wake cycle and numerous reports in the literature have established that the H3 receptor plays a role in cognition and sleep / wake related processes, based on studies with known H3 receptor antagonists and their effects in animal models (4, 5, 6). H3 antagonist compound A-349821 is currently in preclinical development and has been shown to demonstrate cognition-enhancing effects in the rat (7).

The histaminergic system is one of the targets of leptin signalling in the hypothalamus. Known H3 antagonist clobenpropit increases histamine release in the hypothalamus of mice and has the effect of reducing energy intake in both lean and obese mice (8). The role of the H3 receptor in obesity has been further substantiated through studies with antagonists thioperamide and ciproxifan and more recently with non-imidazole compounds (10).

The non-selective antagonist thioperamide has an antinociceptive effect in a number of acute pain models (11 ). H3 antagonists have been suggested for the treatment of neuropathic pain (12). In addition GSK207040 and GSK334429 are selective non-imidazole H3 antagonist compounds that display high affinity for both rat and human H3 receptors. Both compounds reduced tactile allodynia in the rat, suggesting H3 antagonists have therapeutic potential in the treatment of neuropathic pain (13).

In an attempt to identify compounds with improved drug-like properties, non-imidazole compounds have been at the forefront of research, for example A-349821 (7) and GSK207040 / GSK334429 (13). ABT-239 is currently being investigated for use in attention deficit hyperactivity disorder, Alzheimer's Disease and schizophrenia (14).

WO05/123723, WO06/018260 and WO05/058837 disclose H3 antagonist benzazepine derivatives claimed to be useful in the treatment of neurological and psychiatric disorders. WO05/058328 discloses dopamine D3 receptor benzazepine derivatives claimed to be useful in the treatment of CNS disorders such as schizophrenia and depression. WO02/40471 also discloses benzazepine derivatives useful as modulators of the dopamine D3 receptor. US2003/01581 77 discloses melanin-concentrating hormone antagonists claimed to be useful in the treatment of obesity.

Co-pending international patent application WO2010/007382 discloses a class of H3 antagonist benzazepine derivatives.

There exists a clinical need to generate further classes of H3 antagonist and/or inverse agonist compounds that demonstrate improved drug-like properties (9).

In accordance with a first aspect of the present invention, there is provided a compound having the Formula (1 ):

Formula (1)

wherein:

Ri represents C| .₆ alky I or H; X represents N or CH;

Y represents -NR₂R₃ as depicted in Formula (A), or a ring of formula (B):

(A) (B) wherein ^a represents the point of attachment to the pyridinyl or pyrazinyl ring;

R₂ represents C|.₆ alkyl optionally substituted by haloC|_-3 alkyl or C alkoxy;

R₃ represents H, C|.₆ alkyl or C3.8 heterocyclyl;

W represents -(CH₂)_n-;

Wi represents -(CH₂)_P-;

n represents 1 , 2 or 3;

p represents 1 or 2;

R represents halogen or C 1 alkoxy; and

R₅ represents H or halogen;

Ri represents H or Ci.₆ alky I;

provided that, when X represents CH and R₂ is C|.₃jalkyl, R| is not H; and provided that, when X represents CH and R4 represents halogen, R₅ is not H;

or a pharmaceutically acceptable salt thereof.

The compounds of the invention have been found to modulate the histamine H3 receptor. In particular, the compounds possess antagonist or inverse agonist properties at this receptor. Based on the high affinity for the receptor, the compounds may have the potential to display useful selectivity for the H3 receptor. Compounds of the invention have been found to display properties suggestive of blood brain barrier permeability rendering them potentially suitable for the treatment of CNS disorders.

In the compounds of the invention as represented by Formula ( 1 ) and the more detailed description hereinafter certain of the general terms used in relation to substituents are to be understood to include the following atoms or groups unless otherwise specified.

The term 'C_x._y alkyl' as used herein refers to a linear or branched saturated hydrocarbon group containing from x to y carbon atoms. For example, C|.₆ alkyl refers to a linear or branched saturated hydrocarbon group containing from 1 to 6 carbon atoms. Examples of Ci_-6 alkyl groups include methyl, ethyl, n-propyl, isopropyl, n- butyl, isobutyl, sec-butyl, tert butyl, n- pentyl, isopentyl, neopentyl and hexyl. Examples of C alkyl groups include methyl, ethyl, n- propyl, isopropyl, n- butyl, isobutyl, sec-butyl, and tert butyl,

The term 'C_x-y alkoxy' as used herein refers to an -0-C_x._y alkyl group wherein C_x-y alkyl is as defined herein. Examples of such groups include methoxy, ethoxy, propoxy and butoxy.

The term 'halogen' as used herein refers to a fluorine, chlorine, bromine or iodine atom, unless otherwise specified. Typically, a fluorine is employed.

The term 'haloCi-6 alkyl' as used herein refers to a Ci_-6 alkyl group as defined herein wherein at least one hydrogen atom is replaced with halogen. Examples of such groups include fluoroethyl, trifluoromethyl and trifluoroethyl.

The term 'heterocyclyl' refers to a 4-7 membered monocyclic ring or a fused 8-12 membered bicyclic ring which may be saturated or partially unsaturated, which monocyclic or bicyclic ring contains 1 to 4 heteroatoms selected from oxygen, nitrogen, silicon or sulphur. Examples of such monocyclic rings include pyrrolidinyl, azetidinyl, pyrazolidinyl, oxazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, dioxolanyl, dioxanyl, oxathiolanyl, oxathianyl, dithianyl, dihydrofuranyl, tetrahydrofuranyl, dihydiiopyranyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, diazepanyl and azepanyl. Examples of such bicyclic rings include indolinyl, isoindolinyl, quinuclidinyl, 2,3,4,5- tetrahydro- lH-3-benzazepine and tetrahydroisoquinolinyl. Such a group may in particular be a 4-7 membered (e.g. 6-membered) monocyclic ring containing 1 or 2 (e.g. 1) heteroatoms. For example, tetrahydropyranyl may be used.

Pharmaceutically acceptable salts' of compounds of Formula (1) of the present invention include salts with inorganic bases, salts with organic bases, salts with inorganic acids, salts with organic acids and salts with basic or acidic amino acids. Salts with acids may, in particular, be employed in some instances. In particular, 'pharmaceutically acceptable salts' of compounds of Formula (1 ) of the present invention include but are not limited to acid addition salts (for example, phosphates, nitrates, sulphates, borates acetates, maleates, citrates, fumarates, succinates, methanesulfonates, benzoates, salicylates and hydrohalides), and salts of amino acids (such as glycine, alanine, valine, leucine, isoleucine, cysteine, methionine, proline). Further pharmaceutically acceptable salts include quaternary ammonium salts of the compounds of Formula (1). Compounds of Formula ( 1 ) and their salts may be in the form of a solvate, which is included in the scope of the invention. Such solvates may be formed with common organic solvents, including but not limited to, alcoholic solvents e.g. methanol, ethanol or isopropanol.

The compound of Formula ( 1 ) of the present invention may be in either hydrate or non-hydrate form.

General methods for the preparation of salts are well known to the person skilled in the art. Pharmaceutical acceptability of salts and esters will depend on a variety of factors, including formulation processing characteristics and in vivo behaviour, and the skilled person would readily be able to assess such factors having regard to the present disclosure.

Where compounds of the invention exist in different enantiomeric and/or diastereoisomeric forms (including geometric isomerism about a double bond), these compounds may be prepared as isomeric mixtures or racemates, although the invention relates to all such enantiomers or isomers, whether present in an optically pure form or as mixtures with other isomers. Individual enantiomers or isomers may be obtained by methods known in the art, such as optical resolution of products or intermediates (for example chiral chromatographic separation (e.g. chiral HPLC)), or an enantiomeric synthesis approach. Similarly, where compounds of the invention may exist as alternative tautomeric forms (e.g. keto/enol. amide/imidic acid), the invention relates to the individual tautomers in isolation, and to mixtures of the tautomers in all proportions.

In certain embodiments, the compounds of the invention bear one or more radiolabels. Such radiolabels may be introduced by using radiolabel-containing reagents in the synthesis of the compounds of Formula (1), or may be introduced by coupling the compounds of Formula (1 ) to chelating moieties capable of binding to a radioactive metal atom. Such radiolabeled versions of the compounds may be used, for example, in diagnostic imaging studies.

In some embodiments, compounds of the invention are in the form of the (S) enantiomers. In other embodiments, compounds of the invention are in the form of the (R) enantiomers.

In some embodiments, X represents N. In other embodiments X represents CH.

In certain embodiments of the invention R| is C|.₆ alkyl (e.g. methyl, ethyl, propyl, isobutyl or isopropyl).

In particular embodiments, R| represents methyl or ethyl.

In alternative embodiments, R| represents methyl or H. In some instances, R| may in particular represent H. In other instances, R| may represent methyl. In some embodiments, Y represents -NR2R3 as depicted in Formula (A). In other embodiments Y represents a ring of Formula (B).

In some embodiments, R₂ represents C₁.3 alkyl (e.g. methyl or ethyl). In some embodiments in which X represents N, R₂ represents unsubstituted C] .₆ alkyl (e.g. methyl, ethyl, propyl or isopropyl).

In other embodiments, R₂ represents Ci_-6 alkyl, typically C₁.3 alkyl, substituted by haloCi_-3 alkyl (e.g. trifluoromethyl or trifluoroethyl, and typically trifluoromethyl).

In other embodiments, R₂ represents Ci_-6 alkyl, typically C alkyl, such as C1. alkyl,

i

substituted by C alkoxy, typically Ci-3 alkoxy, such as methoxy or ethoxy, and more typically methoxy (e.g. methoxyethyl or methoxypropyl). '

In certain embodiments, R₂ represents C₁ -3 alkyl or C₁-3 alkyl substituted by C₁.3 alkoxy.

In particular embodiments, especially when X represents N, R₂ represents methyl, trifluoroethyl, methoxyethyl or methoxypropyl. In such instances, R₂ may in particular represent methyl or methoxypropyl.

In some embodiments, R3 represents H or Ci-6 alkyl, such as C₁-3 alkyl (e.g. methyl, ethyl, propyl or isopropyl). In particular embodiments when X is CH, R3 represents C₁.3 alkyl. In certain embodiments, R3 represents H or methyl.

In alternative embodiments, R3 represents C₃.₈ heterocyclyl. In such instances, R3 may in particular represent C3_-6 heterocyclyl, such as monocyclic heterocyclyl, e.g. containing from 1 to 3 heteroatoms, such as tetrahydropyranyl. The heterocyclyl group R3 may be joined to the N of formula (A) via a carbon atom.

In certain embodiments, p represents 1 . In other embodiments p represents 2.

In certain embodiments, n represents 1 or 2. In particular embodiments, n represents 2.

In particular embodiments, p represents 1 and n represents 2.

In certain embodiments, R4 represents fluorine or C alkoxy (such as ethoxy or methoxy, and in particular methoxy). In some instances, R4 may in particular represent methoxy. In other instances, R4 may in particular represent fluorine.

In compounds of the invention, R5 represents H or halogen (e.g. fluorine), provided that, when X is CH, R₅ represents halogen when R4 represents halogen. In certain embodiments, R₅ represents H. In other embodiments, R₅ represents fluorine.

In certain embodiments, R4 represents CM alkoxy (e.g. methoxy^ and R₅ represents H. In certain embodiments, R4 represents halogen (e.g. fluorine) and R5 represents halogen (e.g. fluorine).

In certain embodiments, when X represents N, R4 represents halogen (e.g. fluorine) and R, represents H.

Particular embodiments of the first aspect of the invention include compounds wherein Ri is H, n is 2, p is 1 , R is methoxy and R5 is H, particularly in those embodiments where X is CH.

Further particular embodiments of the first aspect of the invention include compounds wherein X is N, R| is H, n is 2, p is 1 , R4 is fluorine and R_¾ is fluorine or H.

Representative examples of the ring of formula (B) include 3-methoxypyrrolidin-l -yl, 3,3- difluoropyrrolidin-l -yl, 4,4-difluoropiperidin- l -yl or, particularly when X represents N, 3- fluoropyrrolidin- 1 -yl.

Particular examples of the ring of formula (B) include 3-methoxypyrrolidin- l -yl, 3,3- difluoropyrrolidin- l -yl or, particularly when X represents N, 3-fluoropyrrolidin- l -yl.

In compounds of the invention, particularly where X is N, R^ represents C|_₆ alkyl (e.g. methyl, ethyl, propyl or isopropyl) or H. In certain embodiments, R^ represents H or methyl. In some instances, Re may in particular represent H. In other instances, and particularly where X is N, R6 may represent methyl.

One particular subgroup of compounds according to the first aspect of the invention has the formula (1 A):

Formula (1A)

wherein:

Ria represents C |.₆ alkyl or H;

Yi represents -NR2_aR_3a as depicted in Formula (A |), or a ring of formula (B| ):

wherein ^a represents the point of attachment to the pyridinyl ring;

R_2a represents C1.3 alkyl or C alkyl substituted by C 1.3 alkoxy;

R3a represents H, C ₁.3 alkyl or C3.8 heterocyclyl;

W_a represents -(CH₂)n'-;

Wia represents -(CH2)p^l -;

n¹ represents 1 , 2 or 3; p¹ represents 1 or 2;

R4a represents halogen or C 1 -4 alkoxy ; and R_5a represents H or halogen,

provided that, when R_2a is C1.3 alkyl, R|_a is not H, and provided that, when ¾₃ represents halogen, R_5a is not H;

or a pharmaceutically acceptable salt thereof.

In certain embodiments of the invention Ri_a is C i_₆ alkyl (e.g. methyl, ethyl, propyl, isobutyl or isopropyl).

In particular embodiments, R|_a represents methyl or ethyl.

In alternative embodiments, Ri_a represents methyl or H. In such instances, R|_a may in particular represent H.

In some embodiments, R_2a represents C alkyl, typically C 1.3 alkyl (e.g. ethyl or propyl) substituted by C ₁.3 alkoxy (e.g. methoxy). In other embodiments, R_2a represents C 1.3 alkyl (e.g. methyl or ethyl).

In particular embodiments, R_2a represents methoxypropyl, methoxyethyl, methyl or ethyl. In such instances, R_2a may in particular represent methoxypropyl or methyl.

Thus, in some embodiments, R_2a represents methoxypropyl. In certain other embodiments, R_2a represents methyl. In some embodiments, R_3a represents H or Ci_-3 alkyl (e.g. methyl, ethyl, propyl or isopropyl). In certain embodiments, R_3a represents H or methyl. In such instances, R_3a may in particular represent H.

In alternative embodiments, R_3a represents C₃.₈ heterocyclyl. In such instances, R_3a may in particular represent C₃. heterocyclyl, such as monocyclic heterocyclyl, e.g. containing from 1 to 3 heteroatoms, such as tetrahydropyranyl. The heterocyclyl group R_3a may be joined to the N of formula (Al) via a carbon atom.

Particular embodiments of the first aspect of the invention include compounds wherein Ri_a is methyl, R_2a is methyl and R_3a is H. Other particular embodiments include compounds wherein Ria is H, R_2a is methyl and R_3a is C alkyl (e.g. ethyl or propyl) substituted by Ci_-3 alkoxy (e.g. methoxy), such as methoxypropyl.

In certain particular embodiments Yi represents a ring of formula (B |).

In some embodiments, n¹ represents 1. In some other embodiments, n¹ represents 2. In yet further embodiments, n¹ represents 3. In particular embodiments, n¹ represents 1 or 2. In further particular embodiments, when p¹ represents 2, n¹ represents 1 or 2.

In some embodiments p¹ represents 1 , i.e. Wi represents -CH₂-. In other embodiments p¹ represents 2.

In further particular embodiments p¹ represents 1 or 2 and n¹ represents 2.

In other particular embodiments p¹ represents 1 and n¹ represents 2.

In other particular embodiments p¹ represents 2 and n¹ represents 2.

In compounds of the invention, R4_a represents halogen (e.g. fluorine) or C alkoxy (e.g. ethoxy or methoxy). In certain embodiments, R-i_a represents fluorine or methoxy. In some instances, R4a may in particular represent methoxy. In other instances, R^ may in particular represent fluorine.

In compounds of the invention, R_5a represents H or halogen (e.g. fluorine), provided that R_5a represents halogen when R^ represents halogen. In certain embodiments, R_5a represents H. In particular embodiments, R_5a represents fluorine.

In certain embodiments R^ represents C alkoxy (e.g. methoxy) and R_5a represents H.

In certain embodiments R_t_a represents halogen (e.g. fluorine) and R_5a represents halogen (e.g. fluorine). Particular embodiments of the first aspect of the invention include compounds wherein R is H, n ¹ is 2, p¹ is 1 , ^ is methoxy and Rs_a is H.

In particular embodiments, ring (Bi) represents 3-methoxypyrrolidin- l -yl, 3,3- difluoropyrrolidin- l -yl, or 4,4-difluoropiperidin- l -yl.

In further particular embodiments, ring (B |) represents 3-methoxypyrrolidin- l -yl or 3,3- difluoropyrrolidin-l -yl. ,

In particular embodiments the compound of formula ( 1 A) is selected from the group consisting of:

N-[(3-cyclobutyl-2,3,4_;5-tetrahydro- l H-3-benzazepin-7-yl)methyl]-6-[(3S)-3- methoxypyrrolidin- l -yl]pyridine-3-carboxamide

N-[(3-cyclobutyl-2,3,4.5-tetrahydro-l H-3-benzazepin-7-yl)methyl]-6-(3,3-difluoropyrrolidin- l - yl)pyridine-3-carboxamide;

N-[(3-cyclobutyl-2,3,4,5-tetrahydro-l H-3-benzazepin-7-yl)methyl]-6-(4,4-difluoropiperidin- l - yl)pyridine-3-carboxamide

N-[(3-cyclobutyl-2,3,4,5-tetrahydro-l H-3-benzazepin-7-yl)methyl]-6-[(2- methoxyethyl)(methyl)amino]pyridine-3-carboxamide;

N-[(3-cyclobutyl-2,3,4,5-tetrahydro- l H-3-benzazepin-7-yl)methyl]-N-methyl-6- (methylamino)pyridine-3-carboxamide

N-[(3-cyclobutyl-2,3,4,5-tetrahydro- l H-3-benzazepin-7-yl)methyl]-6-[(3R)-3- methoxypyrrolidin- 1 -yl]pyridine-3-carboxamide;

N-[(3-cyclobutyl-2,3,4_!5-tetrahydro-l H-3-benzazepin-7-yl)methyl]-6- { [(2R)-2- methoxypropyl](methyl)amino}pyridine-3-carboxamide;

N-[(3-cyclobutyl-2,3,4,5-tetrahydro-l H-3-benzazepin-7-yl)methyl]-6-{ [(2S)-2- methoxypropyl](methyl)amino} pyridine-3-carboxamide;

N-((3-cyclobutyl-2,3,4,5-tetrahydro- l H-3-benzazepin-7-yl)methyl)-6-(methyl(tetrahydro-2H- pyran-4-yl)amino)nicotinamide.

Another particular subgroup of compounds according to the first aspect of the invention has the formula (I B):

Formula (IB)

wherein:

Rib represents H or C| .₆ alkyl;

Y₂ represents -NR₂bR3b as depicted in Formula (Ai), or a ring of formula (B₂):

wherein ^a represents the point of attachment to the pyrazinyl ring;

R₂b represents C |.₆ alkyl optionally substituted by haloCi.3 alkyl or C alkoxy;

R₃b represents H or C|.₆ alkyl,

R-i_b represents halogen or C alkoxy;

R₅b represents H or halogen;

R^_b represents H or C|.₆ alkyl; or a pharmaceutically acceptable salt thereof.

In certain embodiments of the invention, Ri _b is C|.₆ alkyl (e.g. methyl, ethyl, propyl, isobutyl isopropyl)

In particular embodiments, Ri_b represents methyl or ethyl.

In alternative embodiments, Ri represents methyl or H. In such instances, Rib may particular represent H. In some embodiments, R_2b represents unsubstituted Ci_-6 alkyl, typically Ci_-3 alkyl (e.g. methyl, ethyl, propyl or isopropyl).

In some other embodiments, R₂b represents Ci_-6 alkyl, typically Ci_-3 alkyl, substituted with haloCi_-3 alkyl (e.g. trifluoromethyl or trifluoroethyl) or C_)-4 alkoxy, typically Ci_-3 alkoxy, (e.g. methoxy or ethoxy).

In particular embodiments, R₂b represents methyl, trifluoroethyl, methoxyethyl or methoxypropyl. In such instances, R_2b ay in particular represent methyl or methoxypropyl.

In some embodiments of the invention, R₃b represents H or Ci_₆ alkyl (e.g. methyl, ethyl, propyl or isopropyl. In certain embodiments, R₃b represents H or methyl. In particular embodiments, R₃b represents H.

Particular embodiments of the first aspect of the invention include compounds wherein Rib is H, R₂b is methyl and R₃b is H.

In certain other embodiments, Y₂ represents a ring of formula (B₂).

In such embodiments, B₂ represents pyrrolidinyl which is substituted at the 3 position.

In compounds of the invention containing a ring of formula B₂, R^ represents halogen (e.g. fluorine) or C alkoxy (e.g. methoxy or ethoxy).

In such instances, R4 may represent fluorine or methoxy. In particular, R₄b may represent methoxy. Alternatively, ¾b may represent fluorine.

In compounds of the invention containing a ring of formula B₂, R₅b represents halogen (e.g. fluorine) or H. In such instances, R₅b may represent fluorine.

In some embodiments, R4b represents fluorine and R₅b represents H or halogen.

In certain other embodiments, R/jb represents methoxy and R₅b represents H.

In particular embodiments, ring (B₂) represents 3-fluoropyrrolidin-l-yl, 3-methoxypyrrolidin-l- yl or 3,3-difluoropyrrolidin-l-yl.

In compounds of the invention, R6b represents Cj- alkyl (e.g. methyl, ethyl, propyl, or isopropyl) or H. In certain embodiments, R^, represents methyl or H. In such instances, R^ may in particular represent H.

In particular embodiments the compound of formula (I B) is selected from the group consisting of: N-[(3-cyclobutyl-2,3,4,5-tetrahydro- l H-3-benzazepin-7-yl)methyr 5-(methylamino)pyrazine- 2-carboxamide;

N-[(3-cyclobutyl-2,3,4,5-tetrahydro- l H-3-benzazepin-7-yl)methyl ^■5- (dimethylamino)pyrazine-2-carboxamide;

N-[(3-cyclobutyl-2,3,4,5-tetrahydro- l H-3-benzazepin-7-yl)methyl ■5-[(3S)-3-fluoropyrrolidin- 1 -yl]pyrazine-2-carboxamide;

N-[(3-cyclobutyl-2,3,4,5-tetrahydro- l H-3-benzazepin-7-yl)methyl ■5-[(2,2,2- trifluoroethyl)amino]pyrazine-2-carboxamide;

N-[(3-cyclobutyl-2,3,4,5-tetrahydro- l H-3-benzazepin-7-yl)methyl ■5-[(3R)-3-fluoropyrrolidin- 1 -yl]pyrazine-2-carboxamide;

N-[(3-cyclobutyl-2,3,4,5-tetrahydro- l H-3-benzazepin-7-yl)methyl ■5-[(3S)-3- methoxypyrrolidin- l -yl]pyrazine-2-carboxamide;

N-[(3-cyclobutyl-2,3,4,5-tetrahydro- l H-3-benzazepin-7-yl)methyl •5-[(3R)-3- methoxypyiTolidin- l -yl]pyrazine-2-carboxamide;

N-[(3-cyclobutyl-2,3,4,5-tetrahydro- l H-3-benzazepin-7-yl)methyl ■5-(3,3-difluoropyrrolidin- l - yl)pyrazine-2-carboxamide;

N-[(3-cyclobutyl-2,3,4,5-tetrahydro- l H-3-benzazepin-7-yl)methyl ^■6-methyl-5- (methylamino)pyrazine-2-carboxamide;

N-[(3-cyclobutyl-2,3,4,5-tetrahydro- l H-3-benzazepin-7-yl)methyl ■5-[(3R)-3-fluoropyrrolidin- l -yl]-N-methylpyrazine-2-carboxamide;

N-[(3-cyclobutyl-2,3,4,5-tetrahydro- l H-3-benzazepin-7-yl)methyl ■5-[(3S)-3-iluoropyrrolidin- l -yl]-N-methylpyrazine-2-carboxamide;

N-((3-cyclobutyl-2,3,4,5-tetrahydro- l H-3-benzazepin-7-yl)methyl •N-methyl-5- (methylamino)pyrazine-2-carboxamide;

N-((3-cyclobutyl-2,3,4,5-tetrahydro- l H-3-benzazepin-7-yl)methyl •5-(dimethyIamino)-N- methylpyrazine-2-carboxamide;

N-[(3-cyclobutyl-2,3,4,5-tetrahydro- l H-3-benzazepin-7-yl)methyl ■5-[(3R)-3- methoxypyrrolidin- l -yl]-N-methylpyrazine-2-carboxamide;

N-[(3-cyclobutyl-2,3,4,5-tetrahydro- l H-3-benzazepin-7-yl)methyl ^■5-{ [(2S)-2- methoxypropyl](methyl)amino}pyrazine-2-carboxamide; N- [(3 -cyclobutyl-2,3 ,4,5 -tetrahydro- 1 H-3 -benzazepin-7-yl)methyl] -5 - { [(2R)-2- methoxypropyl](methyl)amino}pyrazine-2-carboxamide.

Particularly useful compounds in accordance with the invention include each of the compounds described in the accompanying examples, and pharmaceutically acceptable salts thereof.

In accordance with a second aspect of the invention, there is provided a pharmaceutical composition comprising a compound according to the first aspect of the invention, together with one or more pharmaceutically acceptable excipients.

Pharmaceutical compositions of this invention comprise any of the compounds of the first aspect of the present invention, or pharmaceutically acceptable salts thereof, with any pharmaceutically acceptable carrier, adjuvant or vehicle. Pharmaceutically acceptable carriers, adjuvants and vehicles that may be used in the pharmaceutical compositions of this invention are those conventionally employed in the field of pharmaceutical formulation, and include, but are not limited to, sugars, sugar alcohols, starches, ion exchangers, alumina, aluminium stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycerine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulphate, di sodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene- polyoxypropylene- block polymers, polyethylene glycol and wool fat. '

The pharmaceutical compositions of this invention may be administered orally, parenterally, by inhalation spray, rectally, nasally, buccally, vaginally or via an implanted reservoir. Oral administration is preferred. The pharmaceutical compositions of this invention may contain any conventional non-toxic pharmaceutically-acceptable carriers, adjuvants or vehicles. The term parenteral as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques.

The pharmaceutical compositions may be in the form of a sterile injectable preparation, for example, as a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as, for example, Tween 80) and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1 ,3-butanediol. Among the acceptable vehicles and solvents that may be employed are mannitol, water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant such as that described in Ph. Helv, or a similar alcohol.

The pharmaceutical compositions of this invention! may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, powders, granules, and aqueous suspensions and solutions. These dosage forms are prepared according to techniques well-known in the art of pharmaceutical formulation. In the case of tablets for oral use, carriers which are commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions are administered orally, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and/or flavouring and/or colouring agents may be added.

The pharmaceutical compositions of this invention may also be administered in the form of suppositories for rectal administration. These compositions can be prepared by mixing a compound of this invention with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the active components. Such materials include, but are not limited to, cocoa butter, beeswax and polyethylene glycols.

The pharmaceutical compositions of this invention may be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilising or dispersing agents known in the art.

The compounds of the present invention may be administered in a dose of around 1 to around 20,000 μg/kg per dose, depending on the condition to be treated or prevented, and the characteristics of the subject being administered with the compound. In many instances, the dose may be around 1 to around 1500 μg/kg per dose. The dosing regimen for a given compound could readily be determined by the skilled person having access to this disclosure. In one particular embodiment, the pharmaceutical composition of the invention additionally comprises one or more additional active pharmaceutical ingredients. These additional active ingredients may be agents known to the skilled person to be useful in the treatment or prevention of the diseases mentioned in the present disclosure.

In a third aspect, the present invention provides a compound according to the first aspect of the invention, or a composition according to the second aspect, for use in therapy.

In a fourth aspect, the invention provides a compound according to the first aspect of the invention, or a composition according to the second aspect, for use in the treatment or prevention of a condition whose development or symptoms are linked to histamine H3 receptor activity.

A number of conditions whose development or symptoms are linked to histamine H3 receptor activity are known to the skilled person.

In a fifth aspect, the invention also provides a method of treatment or prevention of a condition whose development or symptoms are linked to histamine H3 receptor activity, the method comprising the administration, to a subject in need of such treatment or prevention, of a therapeutically effective amount of a compound according to the first aspect of the invention, or a composition according to the second aspect.

In particular, there is provided a compound according to the fourth aspect, or a method according to the fifth aspect, wherein the condition is a disorder of the central nervous system.

In certain embodiments, the condition to be treated may be selected from sleep disorders (such as narcolepsy and hypersomnia), cognitive disorders (such as dementia and schizophrenia), attentional disorders (such as attention deficit , hyperactivity disorder), neurodegenerative disorders (such as AD), schizophrenia, epilepsy, pain (such as neuropathic pain) and obesity.

In preferred embodiments the condition may be selected from schizophrenia, Alzheimer's Disease (AD) and dementia. In an alternative embodiment, the condition may be selected from narcolepsy, pain and obesity.

In particular embodiments, the condition may be selected from narcolepsy, neuropathic pain and obesity.

In a sixth aspect, the present invention provides the use of a compound according to the first aspect of the invention in the preparation of a medicament for the treatment or prevention of a condition whose development or symptoms are linked to histamine H3 receptor activity. Such conditions may be selected from those described above. The invention will now be described in more detail by way of example only.

1. Synthetic Methodologies

The methods used for synthesis of the compounds of the invention are illustrated by the general scheme below and the preparative examples that follow. All compounds and intermediates were characterised at least by liquid chromatography-mass spectroscopy (LCMS). The starting materials and reagents used in preparing these compounds are available from commercial suppliers. These general schemes are merely illustrative of methods by which the compounds of this invention can be synthesised, and various modifications to these schemes can be made and will be suggested to one skilled in the art having referred to this disclosure.

Nuclear magnetic resonance (NMR) spectra were recorded at 400MHz, unless otherwise stated; the chemical shifts (δ) are reported in parts per million.

Mass spectra were recorded using an LCMS system (ZQ mass spec detector).

Compounds were purified using normal phase chromatography on silica or alumina, or by reverse phase chromatographic methods.

Room temperature in the following schemes means the temperature ranging from 20°C to 25°C. List of Abbreviations:

Ac Acetyl

AcOH Acetic Acid

Aq Aqueous

(Boc)₂0 di-tert-butyl dicarbonate

DCM Dichloromethane

DMSO Dimethyl Sulfoxide

DMF Dimethyl Formamide

EtOAc Ethyl Acetate

EtOH Ethanol

Et₃N Triethylamine

IPE Di-isopropyl Ether

LCMS Liquid Chromatography Mass Spectrum MS Mass Spectrum

Mel Methyl iodide

MeOD Deuterated Methanol

MeOH Methanol

MeONH₂ Methoxylamine

Min Minute

Na(OAc)₃BH Sodium triacetoxyborohydride

NMR Nuclear Magnetic Resonance

PhN0₂ Nitro benzene

RT Room Temperature

Sat. Saturated

Soln Solution

THF Tetrahydrofuran

TLC Thin Layer Chromatography

The compounds of formula (1) above may be prepared by a process which comprises reacting a compound of formula (II) with a compound.of formula (III):

(111)

wherein Ri, X, Y and R₆ are as herein defined.

The amine of formula (II) may be used as either the free base or as a suitable salt, e.g. dihydrochloride.

The carboxylic acid of formula (III) may be used as either the free acid or as a suitable salt, e.g. Li.

Typically the carboxylic acid of formula (III) is activated e.g. using Nl -

((ethylimino)methylene)-N3,N3-dimethylpropane-l,3-diamine hydrochloride and l-hydroxy-7- azabenztriazole, in a suitable solvent, e.g. DMF. The reaction mixture may then be carefully added to a solution of the amine of formula (II) in a suitable solvent e.g. THF and water in the presence of a base e.g. NaOH.

A suitable synthesis for the compound of formula (II) wherein Ri represents H (Intermediate 7) is described in Scheme 1 below.

Compounds according to formula (II) wherein R| represents Ci_-6 alkyl, e.g. methyl, may be prepared using methods analogous to those as described in Scheme 2 below.

Compounds according to formula (III) may be prepared using methods known to those skilled in the art or may be prepared using methods analogous to those as described in Scheme 3 or Scheme 4 or the accompanying examples.

Novel intermediates form a further aspect of the invention.

1.1 Scheme 1

6 7

Reagents: a) CI₂CHOCH₃, AICI₃ / PhN0₂; b) MeONH₂ HCI, Na₂C0₃; c) H₂, Pd/C HCI;

d)(Boc)₂0, Et₃N; e) NaOH; f) cyclobutanone, AcOH, NaBH(OAc)₃, g) ethanolic HCI

1.1.1 Intermediate 1

Benzazepine intermediate (1) can be prepared by methods outlined in WO 2005/058328 and WO 2005/094834. 1.1.2 Intermediate 2

To a mixture of 3-(trifluoroacetyl)-2,3,4,5-tetrahydro-lH-3-benzazepine (24.3 g, 0.10 mol) (1 ) and PhN0₂ (24 mL), was added A1C1₃ (26.7 g, 0.20 mol) at 5 °C (internal temperature) in one portion and stirred for 15 min. To the resulting mixture, was added a solution of CI2CHOCH3 (34.5 g, 0.30 mol) in PhN0₂ (24 mL) dropwise at 5 °C over 50 min and the mixture was stirred at room temperature for 8 h. The reaction mixture was diluted with EtOAc (100 mL) and poured onto ice (150 g) carefully. The mixture was extracted with EtOAc (100 mL x 2) and was washed with water (50 mL x 2). The combined organic layers were washed with brine (200 mL), dried over MgSC^ and concentrated. The residue was purified by column chromatography on Si0₂ (350 g) (EtOAc/hexane =l/20~3/7) to give crude solid (25.0 g). The obtained solid was dissolved in IPE (30 mL) and hexane (90 mL) was added drop wise to the solution with stirring at 50 °C. The mixture was cooled to room temperature and was stirred for 30 min. The deposited precipitate was filtered and was washed (EtOAc/hexane =1/5, 50 mL) to give 3-(trifluoroacetyl)-2,3,4,5-tetrahydro-lH-3-benzazepine-7-carbaldehyde as pale yellow powder (20.3 g, 74.8%).

Ή-NMR (300MHz, CDC1₃) δ: 3.05-3.10 (4H, m), 3.72-3.82 (4H, m), 7.31-7.72 (2H, m), 9.981 (lH, s).

MS ES⁺ 272

/.1.3 Intermediate 3

To a solution of Na₂C0₃ (6.36 g, 0.06 mol) in water (140 mL), was added MeONH₂ HCl (10.0 g, 0.12 mol) portion wise at 5 °C (internal temperature) and stirred for 30 min. To the mixture, was added a solution of 3-(trifluoroacetyl)-2,3,4,5-tetrahydro-lH-3-benzazepine-7- carbaldehyde (27.1 g, 0.100 mol) in THF (140 mL) drop wise at 5 °C and the mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with EtOAc (280 mL) and undissolved material was filtered. The separated aqueous layer was extracted with EtOAc (140 mL) and organic layers were combined and washed with brine (140 mL), and then dried over MgS0₄. The solvent was evaporated under reduced pressure to afford yellow oil (31 g) which was dissolved in IPE (62 mL) and then hexane (124 mL) was added drop wise with stirring. The precipitate appeared was collected by filtration and washed with IPE-hexane (1 :2, 50 mL), and then was dried under reduced pressure to give 3-(trifluoroacetyl)-2,3,4,5- tetrahydro-lH-3-benzazepine-7-carbaldehyde O-methyloxime as pale yellow powder (23.0 g, 76.6%). Ή-NMR (400MHz, CDC1₃) δ: 2.97-3.02 (4H, m), 3.68-3.71 (2H, m), 3.76-3.78 (2H, m), 3.97 (3H, s), 7.13-7.18 ( 1 H, m), 7.33-7.36 (1 H, m), 7.41-7.44 ( 1 H, m), 8.03 ( 1 H, s). MS ES⁺ 301

1. 1.4 Intermediate 4

To a solution of compound 3-(trifluoroacetyl)-2,3,4,5-tetrahydro- l H-3-benzazepine-7- carbaldehyde O-methyloxime (21 .0 g, 0.07 mol) in MeOH (420 mL) and aqueous 12 M HC1 (5.3 mL, 1 75 mmol), was added 10% Pd/C (wet 50%, 2. 1 g) and the mixture was hydrogenated under an atmospheric pressure at room temperature for 1 h. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure. The resulting solid was treated with IPE (200 mL) and was collected by filtration, and then was dried under reduced pressure to give l -[3-(trifluoroacetyl)-2,3,4,5-tetrahydro- l H-3-benzazepin-7-yl]methanamine hydrochloride (20.1 g, 92.8%) as white solid.

Ή-NMR (400MHz, DMSO-i¾ δ: 2.96-3.02 (4H, m), 3.66-3.71 (4H, m), 3.96 (2H, s), 7.21 - 7.30 (3H, m), 8.33 (3H, broad s).

MS (ES⁺) 273

1. 1.5 Intermediate 5

To a solution of compound l -[3-(trifluoroacetyl)-2,3,4,5-tetrahydro- l H-3-benzazepin-7- yl]methanamine hydrochloride ( 18.5 g, 60 mmol) in THF (90 mL) and water (82 mL), was added (Boc)₂0 ( 13. 1 g, 60 mmol) in one portion at 5 °C (internal temperature), and then aqueous 8M NaOH (7.5 mL, 60 mL) solution dropwise at the same temperature. The mixture was stirred at room temperature for 1 h. The reaction mixture was extracted with EtOAc (90 mL x 2) and combined organic layers were washed with brine (90 mL), and then dried over MgS0₄. The solvent was evaporated under reduced pressure to give light brown syrup, which was treated with hexane (70 mL) to afford white precipitate. The obtained precipitate was collected by filtration and washed with hexane (20 mL), and then was dried under reduced pressure to give /er/-butyl { [3-(trifluoroacetyl)-2,3,4,5-tetrahydro- l H-3-benzazepin-7- yl]methyl } carbamate (21 .0 g, 94%) as white powder.

Ή-NMR (400MHz, CDC1₃) δ: 1.46 (9H, s), 2.94-2.99 (4H, m), 3.67-3.69 (2H, m), 3.74-3.78 (2H, m), 4.27-4.29 (2H, m), 4.83 (1 H, broad s), 7.06-7.14 (3H, m). 1.1.6 Intermediate 6

To a solution of compound ) tert-butyl {[3-(trifluoroacetyl)-2,3,4,5-tetrahydro-lH-3- benzazepin-7-yl] methyl} carbamate (16.8 g, 45.0 mmol) in MeOH (170 mL), was added aqueous 8M NaOH solution (6.2 mL, 49.5 mmol) at 5 °C (internal temperature) and the mixture was stirred at room temperature for 1 h. To the resulting mixture, were added AcOH (3.9 mL, 67.5 mmol), cyclobutanone (4.7 g, 67.5 mmol), and NaBH(OAc)₃ (14.3 g, 67.5 mmol) at 5 °C and the mixture was stirred at room temperature for 3 h. To the mixture, were added cyclobutanone (4.7 g, 67.5 mmol) and NaBH(OAc)₃ (14.3 g, 67.5 mmol) again and the mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure and the residue was treated with water (150 mL). The aqueous mixture was made basic (pH = 9) with aqueous NaOH solution under cooling and was extracted with EtOAc (150 mL x 2). The combined organic layers were washed with brine (150 mL) and dried over MgS0₄. The solution was subjected to short silica-gel pad (40 g) and the solvent was evaporated under reduced pressure. The obtained solid was treated with hexane-IPE (1 : 1 , 100 mL) and was collected by filtration. The solid was washed with hexane (10 mL) and was dried under reduced pressure to give tert-butyl [(3-cyclobutyl-2,3,4,5-tetrahydro-lH-3-benzazepin-7- yl)methyl]carbamate (12.4 g, 83.3 %) as white solid.

Ή-NMR (400MHz, CDC1₃) δ: 1.55-1.75 (2H, m), 1.85-1.97 (2H, m), 2.03-2.12 (2H, m), 2.35-2.50 (4H, m), 2.72-2.81 (1H, m), 2.87-2.94 (4H, m), 4.25^4.27 (2H, m), 4.78 (1H, s), 7.01-7.07 (3H, m).

MS ES⁺ 331.

1.1. 7 Intermediate 7

A mixture of compound tert-butyl [(3-cyclobutyl-2,3,4,5-tetrahydro-lH-3-benzazepin-7- yi)methyl]carbamate (1 1.6 g, 35.0 mmol) and 2M ethanolic HCl solution (87.5 mL, 175 mmol) was warmed at 50 °C for 30 min. The reaction mixture was cooled in an iced water bath and treated with IPE (100 mL). The deposited precipitate was collected by filtration and was washed with IPE (20 mL), and then was dried under reduced pressure to give l-(3-cyclobutyl- 2,3,4,5-tetrahydro-lH-3-benzazepin-7-yl)methanamine dihydrochloride (9.5 g, 90%) as white powder. Ή-NMR (400MHz, DMSO-i¾ δ: 1.58-1.74 (2H, m), 2.15-2.17 (2H, m), 2.49-2.54 (2H, m), 2.68-2.71 (2H, m), 2.94-3.00 (2H, m), 3.50-3.52 (4H, m), 3.64-3.66 (1H, m), 7.23-7.26 (1H, m), 7.33-7.34 (2H, m), 8.56 (3H, s), 1 1.94 (1H, s)

MS ES⁺ 231

1.2 Scheme 2

9

Reagents: a) sodium bis(trimethylsilyl)amide, DMF; b) Mel; c) NaOH; d) cyclobutanone,

AcOH, NaBH(OAc)₃; e ) ethanolic HC1;

1.2.1 Intermediate 8

A round-bottomed flask was charged with te -butyl {[3-(trifiuoroacetyl)-2,3,4,5-tetrahydro- lH-3-benzazepin-7-yl]methyl}carbamate (3.7 g, lOmmol) (Intermediate 5) in DMF (l OmL), the reaction was cooled in an ice bath and sodium bis(trimethylsilylamide) (2.73 g, 15 mmol in THF 14.9 mL) was added dropwise to give a yellow solution. The reaction was stirred for an hour whilst maintaining cooling and iodomethane (0.93 ml, 15 mmol) was added. The reaction was stirred for 16 hours and then the reaction mixture was diluted with ethyl acetate and washed with brine (x5). The organic layer was dried and evaporated and the residue was purified by column chromatography on silica using (10-100%) ethyl acetate in petrol to yield tert-butyl methyl {[3 -(trifluoroacetyl)-2, 3,4, 5-tetrahydro-l H-3-benzazepin-7- yljmethyl} carbamate (3.2 g, 83 % yield) as a white solid.

Ή NMR (400 MHz, CD₂C1₂) δ 6.99 - 7.08 (m, 1 H), 6.89 - 6.99 (m, 2H), 4.27 (s, 2H), 3.62 - 3.70 (m, 2H), 3.54 - 3.62 (m, 2H), 2.83 - 2.95 (m, 4H), 2.70 (s, 3H), 1.37 (s, 9H)

MS ES⁺ 287 (M+H-Boc)

1.2.2 Intermediate 9 A round-bottomed flask was charged with /er/-butyl methyl { [3-(trifluoroacetyl)-2,3,4,5- tetrahydro- l H-3-benzazepin-7-yl]methyl} carbamate ( 1 .7 g, 4.40 mmol) and sodium hydroxide (0.6 mL (2M, aq.), 4.80 mmol ) in methanol (20 mL) to give a colourless solution. The reaction was stirred for 16 hours and then acetic acid (0.68 mL, 12 mmol) and cyclobutanone (0.2 l g, 12 mmol) and sodium triacetoxyborohydride, (2.6 g, 12 mmol) were added. The reaction was stirred for 16 hours. The reaction was diluted with ethyl acetate and washed with sodium hydroxide. The organic layer was dried and evaporated and the residue was purified by column chromatography on silica using 0-20% methanol in dichloromethane on silica (with ammonia). The residue was treated with ethanolic hydrochloric acid to yield l -(3-cyclobutyl-2,3,4,5- tetrahydro-l H-3-benzazepin-7-yl)-N-methylmethanamine dihydrochloride (0.9 g, 75%).

Ή NMR (400 MHz, CD₃OD) δ 7.30 - 7.44 (m, 3H), 4.19 (s, 2H), 3.63 - 3.82 (m, 3H), 3.35 - 3.50 (m, 2H), 3.09 - 3.22 (m, 2H), 2.78 - 2.91 (m, 2H), 2.73 (s, 3H), 2.3 1 - 2.55 (m, 4H), 1 .71 - 2.03 (m, 2H)

MS ES⁺ 281

Compounds acccording to formula ( 1 ), wherein X represents CH, may be prepared according to Scheme 3 :

1.3 Scheme 3

11 Formula (1)

Reagents: h) YH, diisopropylethylamine, Acetonitrile) i) LiOH, THF, water;

j) ^ ^l-((ethylimino)rnethylene)- V³,A'³-dimethylpropane- l ,3-diarnine hydrochloride,

l W-[ l ,2,3]triazolo[4,5-6]pyridin- l -ol, diisopropylethylamine, THF ;

k) Int 7 or Int 9, sodium hydroxide, water, THF wherein Ri, R$ and Y are as herein defined.

Ri is typically as defined for Ri_a.

R₆ typically represents H. In one particular aspect Y is as defined for Y_\.

Intermediate 7 or 9 may be used as either the free base or as a suitable salt. e.g. dihydrochloride.

Intermediate 1 1 may be used as either the free acid or as a suitable salt, e.g. Li.

The following methodologies 1.3.1 and 1.3.2 serve to illustrate the synthesis of Intermediate 10 and 1 1 wherein Y is (S)-3-methoxypyrrolidine and ¾ represents H. Intermediates containing alternative Y and R may be prepared using analogous methodologies.

1.3.1 ntermediate 10

6- [(3 S)-3 -Methoxypyrrol idin- 1 -yl]pyridine-3 -carboxy late

A microwave vial was charged with methyl 6-chloronicotinate (1.3 g, 7.4 mmol), (S)-3- methoxypyrrolidine (0.9 g, 8.9 mmol), diisopropylethylamine (3.9 mL, 22.2 mmol) and acetonitrile (10 mL) and heated for one hour at 140 °C in the microwave.

The mixture was diluted with EtOAc (50 mL) and washed with saturated sodium carbonate (30 mL). The aqueous was further extracted with EtOAc (30 mL) and the combined organics were washed with brine (50 mL). The organic layers were combined and dried over MgS0₄, filtered and concentrated. The crude residue was purified by column chromatography using silica and eluting 12-100% EtOAc in petrol to yield methyl 6-[(3S)-3-methoxypyrrolidin-l -yl]pyridine-3- carboxylate (880 mg, 50% yield) as an off white solid.

Ή NMR (400 MHz, CD₃OD) δ 8.60 - 8.74 (m, 1 H), 7.98 - 8.08 (m, 1H), 6.49 - 6.60 (m, 1 H), 4.13 - 4.21 (m, 1 H), 3.87 (s, 3H), 3.47 - 3.73 (m, 4H), 3.36 - 3.42 (m, 3H), 2.06 - 2.33 (m, 2H)

MS ES⁺ 237

1.3.2 Intermediate 11

Lithium 6-[(3S)-3-methoxypyrrolidin-l-yl]pyridine-3-carboxylate

A mixture of methyl 6-[(3S)-3-methoxypyrrolidin-l -yl]pyridine-3-carboxylate (2.2 g, 9.40 mmol) and LiOH (0.27 g, 1 1.28 mmol) in THF (6 hiL) and water (6 mL) was stirred at for 16 hours. The reaction was concentrated under reduced pressure. The residue was azeotroped with toluene then ether to give lithium 6-[(3S)-3-methoxypyrrolidin-l -yl]pyridine-3-carboxylate (2.23 g) as a white solid.

Ή NMR (400 MHz, DMSO-d₆) δ 8.40 - 8.54 (m, 1 H), 8.03 - 8.15 (m, 1 H), 6.76 - 6.96 (m, 1 H), 4.15 (s, 1 H), 3.45 - 3.75 (m, 4H), 3.28 (s, 3H), 2.02 - 2.21 (m, 2H)

MS ES⁺ 223

Compounds acccording to formula (1 ), wherein X represents N, may be prepared according to Scheme 4:

1.4 Scheme 4

13 Formula (1 )

Reagents: h) Y-H, diisopropylethylamine, acetonitriie, 100°C microwave; i) LiOH, THF, water;

j) /V '-((ethylimino)methylene)-/V³,A'³-dimethylpropane- l ,3-diamine hydrochloride,

l tf-[ l ,2,3]triazolo[4,5-£]pyridin- l -ol, diisopropylethylamine, THF ;

k)lnt 7 or Int 9, sodium hydroxide, water, THF wherein R| , and Y are as herein defined.

Ri is typically as defined for Rib. R^ is typically as defined for R«b.

In one particular aspect Y is as defined for Y₂.

Intermediate 7 or 9 may be used as either the free base or as a suitable salt, e.g. dihydrochloride. Intermediate 13 may be used as either the free acid or as a suitable salt,e.g. Li.

The following methodologies 1.4.1 and 1 .4.2 serve to illustrate the synthesis of Intermediate 12 and 13 wherein Y is (S)-3-methoxypyrrolidine and R_$ represents H. Intermediates containing alternative Y and R may be prepared using analogous methodologies.

1.4.1 Intermediate 12

(S)-Methyl 5-(3-methoxypyrrolidin- l -yl)pyrazine-2-carboxylate

To a solution of methyl 5-chloropyrazine-2-carboxylate ( 1 g, 5.8 mmol) in dry acetonitriie (7.2 mL) was added (S)-3-methoxypyrrolidine hydrochloride ( 1 g, 7.5 mmol) and diisopropylethylamine (3 mL, 17.4 mmol). The reaction vial was sealed and heated under microwave conditions at 140 °C for 30 minutes. The reaction mixture was partitioned between EtOAc (50 mL) and sodium carbonate (sat soln.) (50 mL). The organics were further extracted with EtOAc (50 mL). The combined organics were washed with water (2 x 50 mL), brine (50 mL), dried over MgS0₄, filtered and concentrated to give a pale brown oil which crystallised.

The crude solid was purified using chromatography on silica using 0- 10% methanol in EtOAc to give (S)-methyl 5-(3-methoxypyrrolidin-l-yl)pyrazine-2-carboxylate (l .lg, 75%).

Ή NMR (400 MHz, DMSO-d₆) δ 8.66 (s, 1H), 8.05 (s, 1H), 4.06 - 4.18 (m, 1H), 3.81 (s, 3H), 3.55 - 3.73 (m, 3H), 3.43 - 3.54 (m, 1H), 3.28 (s, 3H), 1.98 - 2.20 (m, 2H).

MS ES⁺ 238

1.4.2 Intermediate 13

(S)-5-(3-Methoxypyrrolidin-l-yl)pyrazine-2-carboxylic acid

A solution of (S)-methyl 5-(3-methoxypyrrolidin-l-yl)pyrazine-2-carboxylate (1.1 g, 4.6 mmol) and lithium hydroxide (2M, aq) (2.53 mL, 5.05 mmol) in ad mixture of water and THF was stirred for 3 hours.

The reaction mixture was acidified by the addition of 2M HCl (2.7 mL). The yellow solution was then concentrated under reduced pressure, azeotroping with toluene (x3). The yellow solid was then dried in vacuo at 60°C over phosphorous pentoxide overnight to give a yellow solid (S)-5-(3-methoxypyrrolidin-l-yl)pyrazine-2-carboxylic acid, (quantitative)

Ή NMR (400 MHz, DMSO-d₆) δ 8.63 (s, 1H), 8.02 (s, 1H), 4.1 1 (s, 1H), 3.54 - 3.73 (m, 3H), 3.42 - 3.53 (m, 1H), 3.17 - 3.34 (m, 3H), 1.98 - 2.22 (m, 2H)

MS (ES⁺) 224

2. Example Compounds

The following Examples illustrate the preparation of compounds according to the invention.

Representative syntheses of compounds according to formula (1), wherein X represents CH, in particular compounds according to Formula (1A), are illustrated in Section 2A below.

Representative syntheses of compounds according to Formula (1), wherein X represents N, in particular compounds according to Formula (IB), are illustrated in Section 2B below. 2A. Example Compounds wherein X represents CH,

Compounds according to Formula (1), wherein X represents CH, in particular compounds according to Formula (1A), may be prepared according to Scheme 3, above.

2.1A Example 1A

N- [(3 -Cyclobutyl-2,3 ,4,5 -tetrahydro- 1 H-3 -benzazepin-7-yl)methyl] -6- [(3 S)-3 - methoxypyrrolidin- 1 -yl]pyridine-3-carboxamide

Prepared according to Scheme 3.

Lithium 6-[(3S)-3-methoxypyrrolidin-l-yl]pyridine-3-carboxylate (Int 1 1) (2.23 g, 9.8 mmol) and diisopropylethylamine (2.84 mL, 16.3 mmol) were dissolved in DMF (18.10 mL) and Nl - ((ethylimino)methylene)-N3,N3-dimethylpropane-l,3-diamine hydrochloride (1.9 g, 9.8 mmol) and 1 -hydroxy-7-azabenztriazole (1.33 g, 9.8 mmol) were added all under nitrogen. Separately (3-cyclobutyl-2,3,4,5-tetrahydro-lH-3-benzazepin-7-yl)methanamine dihydrochloride (2.5 g, 8.14 mmol) was charged to a flask and THF (4.5 mL) and water (4.5, mL) and NaOH (16.3 mL of 1M, 16.3 mmol) was added and both mixtures were stirred for 1 hour. The activated ester was added to the amine solution and mixture left to stir for 16 hours.

The mixture was diluted with saturated sodium bicarbonate solution (30 mL) and extracted with ethyl acetate (3 x 30 mL). The organic extracts were combined and washed with water (30 mL) and then brine (3 x 30 mL) and dried over MgS0₄, filtered and concentrated. Diethyl ether was added and mixture stirred for 1 hour then petrol added and stirred for another 15 minutes. A white precipitate had formed and was collected by filtration and dried under vacuum to yield N- [(3-cyclobutyl-2,3,4,5-tetrahydro-lH-3-benzazepin-7-yl)methyl]-6-[(3S)-3-methoxypyrrolidin- l-yl]pyridine-3-carboxamide (2.7 g, 76 % yield) as white solid.

Ή NMR (400 MHz, DMSO-rf₆) δ ppm 8.51 - 8.75 (m, 2 H), 7.90 - 8.02 (m, 1 H), 6.92 - 7.13

(m, 3 H), 6.41 - 6.52 (m, 1 H), 4.32 - 4.44 (m, 2 H), 4.00 - 4.14 (m, 1 H), 3.48 - 3.61 (m, 3 H), 3.34 - 3.45 (m, 1 H), 3.27 (s, 3 H), 2.64 - 2.91 (m, 5 H), 2.18 - 2.43 (m, 4 H), 1.90 - 2.15 (m, 4 H), 1.69 - 1.86 (m, 2 H), 1.42 - 1.68 (m, 2 H) MS (ES⁺) 435

Examples 2A to 9A

Prepared in a similar manner to Example 1 A.

2.2A Example 2A

N-((3-Cyclobutyl-2,3,4,5-tetrahydro- l H-3-benzazepin-7-yl)methyl)-6-(methyl(tetrahydro-2H- pyran-4-yl)amino)nicotinamide

Prepared using N-methyltetrahydro-2H-pyran-4-amine and Intermediate 7

Ή NMR (400 MHz, CD₃OD) δ 8.63 (m, 1 H), 7.92 - 8.04 (m, 1 H), 7.1 1 (m, 3 H), 6.65 - 6.78 (m, 1 H), 4. 1 (s, 2 H), 3.98 - 4.1 3 (m, 2 H), 3.49 - 3.66 (m, 2 H), 2.85 - 3.06 (m, 8 H), 2.33 - 2.71 (m, 4 H), 2.08 - 2.24 (m, 2 H), 1 .84 - 2.08 (m, 4 H), 1 .67 (m_; 4 H)

MS ES⁺ 449

2.3A Example 3A

N-[(3-Cyclobutyl-2,3,4,5-tetrahydro- l H-3-benzazepin-7-yl)methyl]-6-(3,3-difluoropyrrolidin- 1 -yl)pyridine-3-carboxamide

Prepared using 3,3-difluoropyrrolidine and Intermediate 7 Ή NMR (400 MHz, DMSO-d₆) δ 8.72 - 8.83 (m, 1H), 8.62 - 8.71 (m, 1H), 7.95 - 8.10 (m, 1 H), 6.96 - 7.1 1 (m, 3H), 6.54 - 6.65 (m, 1 H), 4.33 - 4.45 (m, 2H), 3.82 - 3.95 (m, 2H), 3.61 - 3.74 (m, 2H), 2.82 (s, 5H), 2.49-2.63 (m, 2H), 2.25-2.48 (m, 4H), 1.95-2.07 (m, 2H), 1.72-1.88 (m, 2H), 1.48-1.67 (m, 2H)

MS ES⁺ 441

2.4A Example 4A

N-[(3-Cyclobutyl-2,3,4,5-tetrahydro-lH-3-benzazepin-7-yl)methyl]-6-[(2- methoxyethyl)(methyl)amino]pyridine-3-carboxamide

Prepared using 2-methoxy-N-methylethanamine and Intermediate 7

1H NMR (400 MHz, DMSO-d₆) 6 8.65 - 8.74 (m, 1H), 8:56 - 8.65 (m, 1H), 7.91 - 8.00 (m, 1H), 6.97 - 7.12 (m, 3H), 6.61 - 6.71 (m, 1 H), 4.32 - 4.46 (m, 2H), 3.69 - 3.80 (m, 2H), 3.46 - 3.59 (m, 2H), 3.25 (s, 3H), 3.07 (s, 3H), 2.76-2.88 (m, 5H), 2.27-2.48 (m, 4H), 1.96-2.07 (m, 2H), 1.73-1.90 (m, 2H), 1.48-1.68 (m, 2H)

MS (ES⁺) 423

2.5A Example 5A

N-[(3-Cyclobutyl-2,3,4,5-tetrahydro-lH-3-benzazepin-7-yl)methyl]-6-(4,4-difluoropiperidin-l - yl)pyridine-3-carboxamide

Prepared using 4,4-difluoropiperidine and Intermediate 7

Ή NMR (400 MHz, CD₃OD) δ 9.05 (s, 2 H), 7.05 - 7.18 (m, 3 H), 4.96 - 5.09 (m, 2 H), 4.54 (s, 2 H), 2.88 - 3.00 (m, 4 H), 2.78 - 2.88 (m, 1 H), 2.48 (s, 4 H), 2.05 - 2.18 (m, 2 H), 1.88 - 2.01 (m, 2 H), 1.63 - 1.79 (m, 2 H).

MS (ES⁺) 435

2.6A Example 6A

N-[(3-Cyclobutyl-2,3,4,5-tetrahydro-l H-3-benzazepin-7-yl)methyl]-N-methyl-6- (methylamino)pyridine-3-carboxamide

Prepared using methylamine and Intermediate 9

Ή NMR (400 MHz, DMSO-d6) δ 8.08 - 8.16 (m, 1 H), 7.44 - 7.52 (m, 1 H), 6.85 - 7.15 (m, 4 H), 6.44 (m, 1 H), 4.54 (s, 2 H), 2.69 - 2.92 (m, 1 1 H), 2.23 - 2.43 (m, 4 H), 1.94 - 2.07 (m, 2 H), 1.69 - 1.87 (m, 2 H), 1.43 - 1.69 (m, 2 H)

MS ES⁺ 379

2.7A Example 7A

N-[(3-Cyclobutyl-2,3,4,5-tetrahydro-lH-3-benzazepin-7-yl)methyl]-6-[(3R)-3- methoxypyrrolidin- 1 -yl]pyridine-3-carboxamide Prepared using (3R)-3-methoxypyrrolidine and Intermediate 7

MS ES⁺ 435

2.8A Example 8A

N-[(3-Cyclobutyl-2,3,4,5-tetrahydro-l H-3-benzazepin-7-yl)methyl]-6-{ [(2R)-2- methoxypropyl](methyl)amino}pyridine-3-carboxamide

Prepared using (2R)-2-methoxy-N-methylpropan- l -amine and Intermediate 7

Ή NMR (400 MHz, DMSO-d₆) δ 8.54 - 8.77 (m, 2H), 7.89 - 8.01 (m, 1 H), 6.94 - 7.1 1 (m, 3H), 6.59 - 6.72 (m, 1 H), 4.30 - 4.47 (m, 2H), 3.51 - 3.70 (m, 3H), 3.22 (s, 3H), 3.08 (s, 3H), 2.66 - 2.86 (m, 5H), 2.32 (s, 4H), 1.91 - 2.07 (m, 2H), 1.68 - 1.85 (m, 2H), 1.42 - 1 .66 (m, 2H), 0.99 - 1.15 (m, 3H),

MS (ES⁺) 437

2.9A Example 9A

N-[(3-Cyclobutyl-2₍3,4,5-tetrahydro-l H-3-benzazepin-7-yl)methyl]-6-{ [(2S)-2- methoxypropyl](methyl)amino}pyridine-3-carboxamide

Prepared using (2S)-2-methoxy-N-methylpropan- l -amine and Intermediate 7

Ή NMR (400 MHz, DMSO-d₆) δ 8.54 - 8.75 (m, 2H), 7.88 - 8.02 (m, 1 H), 6.93 - 7.12 (m, 3H), 6.60 - 6.72 (m, 1 H), 4.31 - 4.45 (m, 2H), 3.51 - 3.69 (m, 3H), 3.22 (s, 3H), 3.08 (s, 3H), 2.63 - 2.85 (m, 5H), 2.32 (s, 4H), 1 .90 - 2.06 (m, 2H), 1.67 - 1.87 (m, 2H), 1.44 - 1 .67 (m, 2H), 1 .01 - 1 .18 (m, 3H) MS ES⁺ 437

2B. Example Compounds wherein X represents N.

Compounds according to Formula (1), wherein X represents N, in particular compounds according to Formula (IB), may be prepared according to Scheme 4, above.

2.1B Example IB

N-[(3-Cyclobutyl-2,3,4,5-tetrahydro-lH-3-benzazepin-7-yl)methyl]-5-[(3S)-3- methoxypyrrolidin- 1 -yl]pyrazine-2-carboxamide

Prepared according to Scheme 4.

To a stirred solution of (S)-5-(3-methoxypyrrolidin-l -yl)pyrazine-2-carboxylic acid (Int 13) (1.47 g, 4.85 mmol) in dry DMF (1 1.8 mL) were added Nl -((ethylimino)methylene)-N3,N3- dimethylpropane- 1 ,3 -diamine hydrochloride (1.23 g, 6.4 mmol) and 3H-[l ,2,3]triazolo[4,5- b]pyridin-3-ol (0.87 g, 6.4 mmol). The reaction was stirred under an atmosphere of nitrogen for 1 hour. Separately, to a solution of (3-cyclobutyl-2,3,4,5-tetrahydro-lH-3-benzazepin-7- yl)methanamine dihydrochloride (Int 7) (1.47 g, 4.85 mmol) in THF (3 mL) and water (3 mL) was added sodium hydroxide (9.69 mL, 9.7 mmol). This was stirred for 1 hour. The free amine slurry was cooled to 5 °C using an ice bath and the activated ester was added dropwise with a DMF (1 mL) rinse. This was then stirred at ambient temperature under an atmosphere of nitrogen for 2 hours.

The reaction was quenched with sodium bicarbonate (sat. aq. soln, 50 mL) and water (50 mL). The organics were extracted using ethyl acetate (2 x 100 mL). The combined organics were washed with water (2 x 50 mL), brine (2 x 50 mL), dried over MgS0₄, filtered and concentrated under reduced pressure to give an off-white solid. N-[(3-cyclobutyl-2,3,4,5-tetrahydro-lH-3- benzazepin-7-yl)methyl]-5-[(3S)-3-methoxypyrrolidin-l-yl]pyrazine-2-carboxamide (1.4 g, 95%).

Ή NMR (400 MHz, DMSO-d₆) 68.71 - 8.80 (m, 1H), 8.58 - 8.66 (m, 1 H), 7.90 - 7.97 (m, 1 H), 6.98 - 7.08 (m, 3H), 4.32 - 4.44 (m, 2H), 4.06 - 4.16 (m, 1H), 3.54 - 3.70 (m, 3H), 3.42 - 3.54 (m, 1 H), 3.28 (s, 3H), 2.67 - 2.85 (m, 5H), 2.21 - 2.41 (m, 4H), 1 .93 - 2.17 (m, 4H), 1 .68 - 1.85 (m, 2H), 1 .47 - 1.67 (m, 2H)

MS (ES⁺) 436

Examples 2B to 16B

Prepared in a similar manner to Example I B.

2.2B Example 2B

N-[(3-Cyclobutyl-2,3,4,5-tetrahydro-l H-3-benzazepin-7-yl)methyl]-5- (dimethylamino)pyrazine-2-carboxamide

Prepared using dimethylamine and Intermediate 7.

Ή NMR (400 MHz, DMSO-d₆) δ 8.72 - 8.82 (m, 1H), 8.62 (s, 1 H), 8.09 (s, 1 H), 6.94 - 7.08 (m, 3H), 4.36 - 4.44 (m, 2H), 3.16 (s, 6H), 2.63 - 2.86 (m, 5H), 2.21 - 2.41 (m, 4H), 1 .92 - 2.06 (m, 2H), 1.68 - 1 .84 (m, 2H), 1.46 - 1.68 (m, 2H).

MS ES⁺ 380

2.3B Example 3B

N-[(3-Cyclobutyl-2,3,4,5-tetrahydro-l H-3-benzazepin-7-yl)methyl]-5-[(3S)-3-fluoropyrrolidin- 1 -yl]pyrazine-2-carboxamide

Prepared using (S)-3-fluoropyrrolidine and Intermediate 7. Ή NMR (400 MHz, DMSO-d₆) δ 8.74 - 8.87 (m, I H), 8.64 (s, I H), 7.98 (s, I H), 6.96 - 7.09 (m, 3H), 5.39 - 5.61 (m, I H), 4.35 - 4.44 (m, 2H), 3.47 - 3.96 (m, 4H), 2.65 - 2.84 (m, 5H), 2.08 - 2.40 (m, 6H), 1.87 - 2.08 (m, 2H), 1 .67 - 1.85 (m, 2H), 1.48 - 1.67 (m, 2H).

MS ES⁺ 424

2.4B Example 4B

N-[(3-Cyclobutyl-2,3,4,5-tetrahydro- lH-3-benzazepin-7-yl)methyl]-5-[(2,2,2- trifluoroethyl)amino]pyrazine-2-carboxamide

Prepared using 2,2,2-triiluoroethanamine and Intermediate 7.

I H NMR (400 MHz, DMSO-d6) δ 8.75 - 8.92 (m, I H), 8.53 - 8.66 (m, I H), 8.1 7 - 8.33 (m, I H), 8.01 - 8.14 (m, I H), 6.93 - 7.13 (m, 3H), 4.33 - 4.46 (m, 2H), 4.18 - 4.33 (m, 2H), 2.62 - 2.89 (m, 5H), 2.17 - 2.44 (m, 4H), 1 .90 - 2.10 (m, 2H), 1.67 - 1.84 (m, 2H), 1.41 - 1.67 (m, 2H).

MS ES⁺ 434

2.5B Example 5B

N-[(3-Cyclobutyl-2,3,4,5-tetrahydro-l H-3-benzazepin-7-yl)methyl]-5-[(3R)-3-fluoropyrrolidin- 1 -y]]pyrazine-2-carboxamide

Prepared using (R)-3-fluoropyrrolidine and Intermediate 7.

Ή NMR (400 MHz, DMSO-d₆) δ 8.75 - 8.85 (m, I H), 8.64 (s, I H), 7.98 (s, I H), 6.95 - 7.10

(m, 3H), 5.38 - 5.59 (m_; I H), 4.27 - 4.45 (m, 2H), 3.47 - 3.96 (m, 4H), 2.64 - 2.84 (m, 5H), 2.07

- 2.43 (m, 6H), 1 .89 - 2.05 (m, 2H), 1.67 - 1 .84 (m, 2H), 1.47 - 1.65 (m, 2H) MS ES⁺ 424

2.6B Example 6B

N-[(3-Cyclobutyl-2,3,4,5-tetrahydro-l H-3-benzazepin-7-yl)methyl]-5-(methylamino)pyrazine- 2-carboxamide

Prepared using methylamine and Intermediate 7.

Ή NMR (400 MHz, DMSO-d₆) δ 8.64 - 8.76 (m, 1H), 8.55 (s, 1 H), 7.87 (s, 1 H), 7.59 - 7.73 (m, 1 H), 6.96 - 7.09 (m, 3H), 4.32 - 4.42 (m, 2H), 2.67 - 2.89 (m, 8H), 2.18 - 2.42 (m, 4H), 1.92 - 2.05 (m, 2H), 1.68 - 1.85 (m, 2H), 1.46 - 1.67 (m, 2H)

MS ES⁺ 366

2.7B Example 7B

N-[(3-Cyclobutyl-2,3,4,5-tetrahydro-lH-3-benzazepin-7-yl)methyl]-5-[(3R)-3- methoxypyrrolidin-l -yl]pyrazine-2-carboxamide

Prepared using (3R)-3-methoxypyrrolidine and Intermediate 7.

Ή NMR (400 MHz, DMSO-d₆) δ 8.70 - 8.83 (m, 1 H), 8.62 (s, 1 H), 7.93 (s, 1 H), 6.99 - 7.09 (m, 3H), 4.32 - 4.46 (m, 2H), 3.99 - 4.20 (m, I H), 3.54 - 3.71 (m, 3H), 3.41 - 3.53 (m, 1 H), 3.28 (s, 3H), 2.61 - 2.89 (m, 5H), 2.19 - 2.42 (m, 4H), 1.92 - 2.19 (m, 4H), 1.68 - 1.86 (m, 2H), 1.48 - 1.67 (m, 2H)

MS ES⁺ 436 2.8B Example 8B

N-[(3-Cyclobutyl-2,3,4,5-tetrahydro-lH-3-benzazepin-7-yl)methyl]-5-(3,3-difluoropyrrolidin- 1 -yl)pyrazine-2-carboxamide

Prepared using 3,3-difluoropyrrolidine and Intermediate 7.

Ή NMR (400 MHz, DMSO-d₆) δ 8.80 - 8.91 (m, 1H), 8.67 (s, 1H), 8.02 (s, 1H), 6.93 - 7.09 (m, 3H), 4.35 - 4.45 (m, 2H), 3.94 - 4.08 (m, 2H), 3.72 - 3.85 (m, 2H), 2.68 - 2.86 (m, 5H), 2.54 - 2.65 (m, 2H), 2.17 - 2.41 (m, 4H), 1.92 - 2.05 (m, 2H), 1.69 - 1.85 (m, 2H), 1.48 - 1.67 (m, 2H)

MS ES⁺ 442

2.9B Example 9B

N-[(3-Cyclobutyl-2,3,4,5-tetrahydro-lH-3-benzazepin-7-yl)methyl]-6-methyl-5- (methylamino)pyrazine-2-carboxamide

Prepared using methylamine and Intermediate 7.

Ή NMR (400 MHz, DMSO-d₆) δ 8.55 - 8.62 (m, 1H), 8.46 (s, lHj, 7.07 - 7.16 (m, 1 H), 6.96 - 7.06 (m, 3H), 4.35 - 4.42 (m, 2H), 2.86 - 2.93 (m, 3H), 2.64 - 2.83 (m, 5H), 2.23 - 2.39 (m, 7H), 1.90 - 2.05 (m, 2H), 1.67 - 1.87 (m, 2H), 1.46 - 1.65 (m, 2H)

MS ES⁺ 380 2.10B Example 10B

N- [(3 -Cyclobutyl-2,3 ,4,5 -tetrahydro- 1 H-3 -benzazepin-7-yl)methyl] -5 - [(3 R)-3 -fluoropyrrolidin- l -yl]-N-methylpyrazine-2-carboxamide

Prepared using (R)-3-fluoropyrrolidine and Intermediate 7.

1H NMR (400 MHz, DMSO-d₆) δ 8.43 (s, 1 H), 7.88 - 8.04 (m, 1 H), 6.89 - 7.16 (m, 3 H), 5.36 - 5.61 (m, 1 H), 4.53 - 4.80 (m, 2 H), 3.43 - 3.77 (m, 5 H), 2.93 - 3.08 (m, 1 H), 2.07 - 2.81 (m, 12 H), 1.89 - 2.09 (m, 2 H), 1.69 - 1.87 (m, 2 H), 1.45 - 1.69 (m, 2 H)

MS ES⁺ 438

2.11B Example 1 IB

N-[(3-Cyclobutyl-2,3,4,5-tetrahydro-l H-3-benzazepin-7-yl)methyl]-5-[(3S)-3-fluoropyrrolidin- 1 -yl]-N-methylpyrazine-2-carboxamide

Prepared using (S)-3-fluoropyrrolidine and Intermediate 7.

Ή NMR (400 MHz, DMSO-d₆) δ 8.43 (s, 1 H), 7.87 - 8.05 (m, 1 H), 7.08 (m, 3 H), 5.36 - 5.61 (m, 1 H), 4.49 - 4.83 (m, 2 H), 3.41 - 3.95 (m, 5 H), 2.67 - 3.13 (m, 8 H), 1.46 - 2.44 (m, 12H)

MS ES⁺ 438

2.12B Example 12B

N-[(3-Cyclobutyl-2,3,4,5-tetrahydro- l H-3-benzazepin-7-yl)methyl]-N-methyl-5- (methylamino)pyrazine-2-carboxamide

Prepared using methylamine and Intermediate 9.

Ή NMR (400 MHz, DMSO-d₆) δ 8.33 (s, 1 H), 7.72 - 7.92 (m, 1 H), 7.43 - 7.57 (m, 1 H), 6.86 - 7.15 (m, 3 H)_; 4.49 - 4.79 (m, 2 H), 2.69 - 3.12 (m, 1 1 H), 2.33 (m, 4 H), 2.00 (m, 2 H), 1 .78 (m, 2 H), 1 .43 - 1 .67 (m, 2 H)

MS ES⁺ 380

2.13B Example 13B

N-[(3-Cyclobutyl-2,3,4,5-tetrahydro- l H-3-benzazepin-7-yl)methyl]-5-(dimethylamino)-N- methylpyrazine-2-carboxamide

Prepared using dimethylamine and Intermediate 9.

Ή NMR (400 MHz, DMSO-d₆) δ 8.42 (s, 1 H), 7.97 - 8.17 (m, 1 H), 6.84 - 7. 16 (m, 3 H), 4.52 - 4.82 (m, 2 H), 3.13 (m, 6 H), 2.94 - 3.08 (m, 2 H), 2.81 (m, 7 H), 2.34 (m, 3 H), 1 .89 - 2.09 (m, 2 H), 1 .68 - 1 .89 (m, 2 H), 1 .46 - 1.68 (m, 2 H)

MS ES⁺ 394

2.14B Example 14B

N-[(3-Cyclobutyl-2,3,4,5-tetrahydro- l H-3-benzazepin-7-yl)methyl]-5-[(3R)-3- methoxypyrrolidin- 1 -y l]-N-methylpyrazine-2-carboxamide Prepared using (3R)-3-methoxypyrrolidine and Intermediate 9.

Ή NMR (400 MHz, DMSO-d₆) δ 8.35 (s, 1 H), 7.71 - 7.95 (m, 1 H), 6.77 - 7.1 1 (m, 3 H), 4.45 - 4.74 (m, 2 H), 3.96 - 4.12 (m, 1 H), 3.53 (m, 3 H), 3.31 - 3.45 (m, 1 H), 3.21 (s, 3 H), 2.96 (m, 2 H), 2.59 - 2.86 (m, 6 H), 2.27 (m, 4 H), 1 .93 (m, 4 H), 1.71 (m, 2 H), 1 .53 (m, 2 H)

MS ES⁺ 450

2.15B Example 15B

N-[(3-Cyclobutyl-2,3,4,5-tetrahydro-l H-3-benzazepin-7-yl)methyl]-5-{ [(2S)-2- methoxypropyl](methyI)amino}pyrazine-2-carboxamide

Prepared using (2S)-2-methoxy-N-methylpropan- l -amine and Intermediate 7.

Ή NMR (400 MHz, DMSO-d₆) δ 8.70 - 8.78 (m, 1 H), 8.60 (s, 1 H), 8.12 (s, 1 H), 6.99 - 7.07 (m, 3H), 4.33 - 4.44 (m, 2H), 3.56 - 3.73 (m, 3H), 3.31 (s, 3H), 3.16 (s, 3H), 2.66 - 2.85 (m, 5H), 2.32 (s, 4H), 1.92 - 2.05 (m, 2H), 1.69 - 1.84 (m, 2H), 1.46 - 1.65 (m, 2H), 1.03 - 1.13 (m, 3H).

MS ES⁺ 438

2.16B Example 16B

N-[(3-Cyclobutyl-2,3,4,5-tetrahydro-l H-3-benzazepin-7-yl)methyl]-5-{ [(2R)-2- methoxypropyl](methyl)amino}pyrazine-2-carboxamide

Prepared using (2R)-2-methoxy-N-methylpropan-l -amine and Intermediate 7.

3. Biological efficacy of compounds of the invention

3.1 In Vitro H3 Binding Assay The ability of compounds to bind to the H3 receptor was determined by measuring the reduction in tritiated N-a-methyl-histamine (³H-NaMH) binding in a competition binding assay. Changes in the levels of bound radio-label were monitored by scintillation counting with a Trilux Microbeta (Perkin Elmer).

Membranes were prepared from CHO-K1 cells stably expressing human H3 receptor; routinely grown as monolayers in Ham's F12 medium (Invitrogen) supplemented with 10% Foetal Clone III (Hyclone), 500μg/ml G418 (Invitrogen), 5 μg/ml blasticidine S (Invivogen) and 50 μ /τ Gentamicin (Sigma) in 5% C0₂ at 37°C. Cells were grown to 80-95% confluency, rinsed once with lx PBS (Invitrogen) and detached by incubating with lx PBS containing 0.02% EDTA (Sigma) for 10 minutes at room temperature. Cells were collected by centrifugation at 900 xg, 4°C for 10 minutes. Cells were rinsed once with lx PBS and re-suspended in ice cold homogenisation buffer (50mM Tris-HCl (pH 7.4), 2.5mM EDTA, 5mM MgCl₂, 200mM Sucrose) at lxlO⁷ cells/ml and kept on ice. Cells were homogenised on ice and debris removed by centrifugation at 500 x g, 4°C for 5 minutes. The resulting supernatant was centrifuged at 75,600 xg, 4°C for 60 minutes. Membranes were suspended in homogenisation buffer, protein concentration was determined (BCA Protein Assay kit (Pierce)), diluted to 2.2 mg/ml, dispensed into 1ml aliquots and stored at -80 °C.

Membranes were thawed on ice, sonicated with 4 cycles of 20 pulses (50% amplitude, 0.5 pulse) (UP200S Hielscher) on ice, diluted in assay buffer (50mM Tris-HCl (pH7.4), 5mM MgCl ) to 62.5 Hg/ml. Compound was serially diluted in DMSO before being diluted 1 : 10 with assay buffer. 5μ£ of membrane in 80 μΐ of assay buffer was added per well of a 96 well polystyrene plate (Corning). 10 μΐ of compound was added per well. The assay was initiated by the addition of 10 μΐ of 20nM ³H-NocMH per well and _t incubated for one hour at room temperature with shaking. Total binding was determined in the presence of 1 % DMSO and non-specific binding was determined by the inclusion of 1 μΜ R-a-methyl-histamine (RaMH). Incubations were then filtered through filtermat A (Perkin Elmer) and washed three times with assay buffer. Filtermats were dried at 42°C for.jtwo hours, scintillant added and the level of bound radioactivity determined.

IC50 values for compounds were determined from seven point log scale dose-response studies and represent the concentration of compound required to inhibit 50% of the specific binding of 2nM ³H-NotMH (difference between total and non-specific binding). Curves were generated using the average of duplicate wells for each data point and analyzed using nonlinear regression of sigmoidal dose response (variable slope). 3.2 In Vitro H3 Functional Assay

The functional activity of compounds at the H3 receptor was determined by measuring changes in the level of intracellular cAMP using a cAMP response element driven luciferase reporter assay. The changes in luciferase expression were monitored by a luminescence plate reader, Analyst HT (MDS Analytical). Increases in intracellular cAMP were readily detected upon activation of protein kinase A by forskolin (Sigma) and suppression of this response observed with the application of the H3 receptor agonist RaMH (Sigma).

CHO(dhfr⁺)-cre-luc cells stably expressing human H3 receptor were routinely grown as monolayers in Minimal Essential Medium a (MEMa) (Invitrogen) supplemented with 10% dialysed FBS (Hyclone), in 5% C0₂ at 37°C. 48 hours prior to assay, cells were seeded in clear-base white walled 384-well plates (Corning) at a density of 5000 cells/well. On the day of assay, growth media was removed and replaced with 15 μΐ of assay buffer (MEMa, 5 mg/ml fatty acid free BSA (Sigma)) per well. Cells were then incubated for 30 minutes at 37°C, 5% C0 . Compound was serially diluted in DMSO before being diluted 1 : 10 with assay buffer. 2.5 μΐ of compound diluted in assay buffer was added and cells incubated for 5 minutes at 37°C, 5% C0₂. 2.5 μΐ of each reagent was then added in the following order: RaMH (10 nM), isobutylmethylxanthine (l-methyl-3-(2-methylpropyl)-7H-purine-2,6-dione; IBMX) (500 μΜ) (Sigma) and forskolin (1 μΜ). , Cells were then incubated for 90 minutes at 37°C, 5% C0₂, followed by 30 minutes at room temperature. At the end of incubation 25 μΐ of Steadylite reagent (Perkin Elmer) was added, plates were sealed and placed on a shaker for 5 minutes. The level of light output to determine the level of luciferase expression was then measured.

IC50 values for compounds were determined from ten point half log scale dose-response studies and represent the concentration of compound required to prevent 50% inhibition of forskolin stimulated cells in the presence of RaMH alone. Curves were generated using the average of duplicate wells for each data point and analyzed u^sing nonlinear regression of four parameter dose response.

3.3 Results

Example 3 A 0.4 3.5

Example 4A 2.6 1.7

Example 5A 1.1 3

Example 6A 8.9 4

Example 7A 0.23 4

Example 8A 0.48 5

Example 9A 0.56 5

Example IB 0.3 0.63

Example 2B 0.6 0.7

Example 3B 1.0 1.5

Example 4B 8.0 3

Example 5B 0.9 0.98

Example 6B 1.0 1.8

Example 7B 0.3 0.56

Example 8B 0.4 3

Example 9B 19

Example 10B 2.0 3

Example 1 1 B 2.0 2

Example 12B 17 1.7

Example 13B 6 6

Example 14B 1.0 5

Example 15B 0.3 4

Example 16B 2.0 12

These results indicate that compounds of the invention have potent antagonist or inverse agonist activity at the H3 receptor, both in terms of binding and in terms of inhibition of the functional response caused by receptor activation. The compounds tested above exhibit IC50 values significantly less than 1 μΜ, with the compounds showing low nanomolar affinity at the H3 receptor. Accordingly, the compounds of the invention are expected to have usefulness in the prevention or treatment of conditions, such as those discussed above, in which H3 receptor activity is implicated.

In addition, the compounds of the present invention may possess variously advantageous pharmacological and/or toxicological profiles, when tested in a variety of standard tests for such parameters. For example, the compounds of the invention may exhibit one or more potentially useful properties for in vivo use, when characterised by pharmacological and/or toxicological tests including: hERG interaction (which is an indication of potential cardiotoxicity, and measures the effects of the compounds on the human ether-a-go-go-related gene, using for example the PatchXpress 7000A platform); CyP₄5₀ interactions (which may be measured in accordance with the FDA draft guidelines for drug interaction studies (study design, data analysis and implications for dosing and labeling) (Sep. 2006), see www.fda.gov); phototoxicity (for example using a protocol in accordance with assay details outlined in the OECD guidelines for testing of chemicals: 432 In Vitro 3T3 Neutral Red Uptake phototoxicity test, April 2004); determination of pharmacokinetic parameters (for example following in vivo dosing via multiple routes, with plasma concentrations of compounds being determined from venous blood samples using an LC-MS MS protocol); and in vivo receptor occupancy (determined, for example, using protocols based on Medhurst et al., Journal of Pharmacology and Experimental Therapeutics, 2007, 321, 1032). These standard tests for the characterisation of drug molecules are well known to the skilled person.

REFERENCES

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4. Passani MB, Lin J-S, Hancock A, Crochet S, Blandina P. The histamine H3 receptor as a novel therapeutic target for cognitive and sleep disorders. Trends Pharmacol. Sci. 2004;25:618- 25.

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12. WO 04/089410

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Claims

1. A compound of the formula ( 1 ):

Formula (1) wherein:

Ri represents C i.₆ alkyl or H;

X represents N or CH;

Y represents -NR2R3 as depicted in Formula (A), or a ring of formula (B):

(A) (B)

wherein ^a represents the point of attachment to the pyridinyl or py razinyl ring; R₂ represents C |.₆ alkyl optionally substituted by haloC |.₃ alkyl or C alkoxy; R₃ represents H, C|.₆ alkyl or C₃.g heterocyclyl;

W represents -(CH2)_n-;

W| represents -(CH2) -;

n represents 1 , 2 or 3 ;

p represents 1 or 2;

R4 represents halogen or C 1.4 alkoxy; and

R₅ represents H or halogen; R.6 represents H or Ci-₆ alkyl;

provided that, when X represents CH and R₂ is C 1.3 alkyl, R| is not H; and provided that, when X represents CH and R4 represents halogen, R₅ is not H;

or a pharmaceutically acceptable salt thereof.

2. A compound according to Claim 1 , wherein Ri represents H.

3. A compound according to Claim 1 , wherein R₂ represents C|.₃ alkyl or C 1.3 alkyl, substituted by C i -3 alkoxy.

4. A compound according to Claim 1 , wherein R_¾ represents H.

5. A compound according to Claim 1 , wherein Y represents a ring of Formula (B).

6. A compound according to any preceding Claim wherein p represents 1 , such that Wi represents -CH₂-.

7. A compound according to any preceding Claim wherein n represents 2.

8. A compound according to any preceding Claim wherein R¾ represents methoxy and R₅ represents H.

9. A compound according to Claim 1, wherein the ring of formula (B) represents 3- methoxypyrrolidin-l-yl, 3,3-difluoropyrrolidin-l -yl, or when X represents N, 3- fluoropyrrolidin-l -yl.

10. A compound according to Claim 1 , and having Formula (1 A):

Formula (1A)

wherein:

Ri a represents C i .₆ alkyl or H;

Y i represents -NR_2aR_3a as depicted in Formula (A|), or a ring of formula (B i ):

(A , ) wherein ⁸ represents the point of attachment to the pyridinyl ring;

R_2a represents C | .₃ alkyl or C alky l substituted by C |.₃ alkoxy;

R_3a represents H, C|.₃ alkyl or C₃.₈ heterocyclyl;

W_a represents -(CH₂)_n'-;

W ia represents -(CH2)p' -;

n' represents 1 , 2 or 3; p¹ represents 1 or 2; }a represents halogen or C alkoxy; and R_5a represents H or halogen,

provided that, when R_2a is C|.₃ alky], R|_a is not H, and provided that, when R4a represents halogen, R_5a is not H; or a pharmaceutically acceptable salt thereof.

1 1 . A compound according to Claim 10, wherein R|_a is H, R_2a is C alkyl substituted by C | .₃ alkoxy and R_3a is C|.₃ alkyl

12. A compound according to Claim 1 1 , wherein R|_a is H, R_2a is methoxypropyl and R_3a is methyl.

13. A compound according to Claim 10, wherein p¹ is 1.

14. A compound according to Claim 10, wherein R|_a is H, Yi represents a ring of formula (B i), n¹ is 2, p¹ is 1 , R4_a is methoxy and R_5a is H

15. A compound according to Claim 10, wherein R|_a is methyl, R_2a is methyl and R_3a is H

16. A compound according to Claim 10, wherein Ri_a is H, Y | represents a ring of formula (B |), p¹ is 1 or 2 and n ¹ is 2.

17. A compound according to Claim 10, wherein Ri_a is H, R_2a is methyl and R_3a is C₃.₈ heterocyclyl.

18. A compound according to Claim 10, wherein ring (B|) represents 3-methoxypyrrolidin-l- 3,3-difluoropyrrolidin-l-yl or 4,4-difluoropiperidin-l-yl.

19. A compound according to Claim 1, and having Formula (IB):

Formula (IB)

wherein:

Rib represents H or C|.₆ alkyl;

Y₂ represents -NR_2bR_3b as depicted in Formula (A₂), or a ring of formula (B₂):

wherein ^a represents the point of attachment to the pyrazinyl ring;

R_2b represents C|.₆ alkyl optionally substituted by haloC|.₃ alkyl or C^alkoxy;

R₃b represents H or C|.₆ alkyl,

Ri_b represents halogen or C^alkoxy;

R_5b represents H or halogen;

R₆b represents H or C|.₆ alkyl;

or a pharmaceutically acceptable salt thereof.

20. A compound according to Claim 19, wherein R|_b is H, R₂bis methyl and R₃b is H

21. A compound according to Claim 19, wherein Y₂ represents a ring of formula (B₂).

22. A compound according to Claim 21, wherein R4_b is methoxy and R₅b is H.

23. A compound according to Claim 21, wherein ring (B₂) represents 3-fluoropyrrolidin methoxypyrrolidin-l-yl or 3,3-difluoropyrrolidin-l-yl.

24. A compound according to claim 1 , which is:

N-[(3-cyclobutyl-2,3,4,5-tetrahydro-l H-3-benzazepin-7-yl)methyl]-6-[(3S)-3- methoxypyrrolidin- 1 -yl]pyridine-3-carboxamide; '

N-[(3-cyclobutyl-2,3,4,5-tetrahydro- l H-3-benzazepin-7-yl)methyl]-6-(3,3-difluoropyrrolidin- l- yl)pyridine-3-carboxamide;

N-[(3-cyclobutyl-2,3,4,5-tetrahydro- l H-3-benzazepin-7-yl)methyl]-6-(4,4-difluoropiperidin- l - yl)pyridine-3-carboxamide

N-[(3-cyclobutyl-2,3,4,5-tetrahydro- l H-3-benzazepin-7-yl)methyl]-6-[(2- methoxyethyl)(methyl)amino]pyridine-3-carboxamide;

N-[(3-cyclobutyl-2,3,4,5-tetrahydro- l H-3-benzazepiri-7-yl)methyl]-N-methyl-6- (methylamino)pyridine-3-carboxamide

N-[(3-cyclobutyl-2,3,4,5-tetrahydro- l H-3-benzazepin-7-yl)methyl]-6-[(3R)-3- methoxypyrrolidin- l -yl]pyridine-3-carboxamide;

N-[(3-cyclobutyl-2,3,4,5-tetrahydro- l H-3-benzazepin-7-yl)methyl]-6-{ [(2R)-2- methoxypropyl](methyl)amino} pyridine-3-carboxamide;

N-[(3-cyclobutyl-2,3,4,5-tetrahydro- l H-3-benzazepin-7-yl)methyl]-6-{ [(2S)-2- methoxypropyl](methyl)amino}pyridine-3-carboxamide; or

N-((3-cyclobutyl-2,3,4,5-tetrahydro-l H-3-benzazepin-7-yl)methyl)-6-(methyl(tetrahydro-2H- pyran-4-yl)amino)nicotinamide,

or a pharmaceutically acceptable salt thereof.

25. A compound according to claim 1 , which is:

N-[(3-cyclobutyl-2,3,4.5-tetrahydro-l H-3-benzazepin-7-yl)methyl]-5-(methylamino)pyrazine- 2-carboxamide;

N-[(3-cyclobutyl-2,3,4,5-tetrahydro-l H-3-benzazepin-7-yl)methyl]-5- (dimethylamino)pyrazine-2-carboxamide;

N-[(3-cyclobutyl-2,3,4,5-tetrahydro- l H-3-benzazepin-7-yl)methyl]-5-[(3S)-3-fluoropyrrolidin- 1 -y l]pyrazine-2-carboxamide;

N-[(3-cyclobutyl-2,3,4_f5-tetrahydro-l H-3-benzazepin-7-yl)methyl]-5-[(2,2,2- trifluoroethyl)amino]pyrazine-2-carboxamide; N-[(3-cyclobutyl-2,3,4,5-tetrahydro-lH-3-ben2azepin-7-yl)methyl]-5-[(3R)-3-fluoropyrrolidin- 1 -yl]pyrazine-2-carboxamide;

N-[(3-cyclobutyl-2,3,4,5-tetrahydro-lH-3-benzazepin-7-yl)methyl]-5-[(3S)-3- methoxypyrrolidin-l-yl]pyrazine-2-carboxamide;

N-[(3-cyclobutyl-2,3,4,5-tetrahydro-lH-3-benzazepin-7-yl)methyl]-5-[(3R)-3- methoxypyrrolidin- 1 -yl]pyrazine-2-carboxamide;

N-[(3-cyclobutyl-2,3,4,5-tetrahydro-lH-3-benzazepin-7-yl)methyl]-5-(3,3-difluoropyrrolidin-l- yl)pyrazine-2-carboxamide;

N-[(3-cyclobutyl-2,3,4,5-tetrahydro-lH-3-benzazepin-7-yl)methyl]-6-methyl-5- (methylamino)pyrazine-2-carboxamide;

N-[(3-cyclobutyl-2,3,4,5-tetrahydro-lH-3-benzazepin-7-yl)methyl]-5-[(3R)-3-fluoropyrrolidin- l-yl]-N-methylpyrazine-2-carboxamide;

N-[(3-cyclobutyl-2,3,4,5-tetrahydro-lH-3-benzazepin-7-yl)rnethyl]-5-[(3S)-3-fluoropyrrolidin- 1 -y 1 ] -N -methyl py razine-2-carboxamide ;

N-[(3-cyclobutyl-2,3,4,5-tetrahydro-lH-3-benzazepin-7-yl)methyl]-N-methyl-5- (methylamino)pyrazine-2-carboxamide;

N-[(3-cyclobutyl-2,3,4,5-tetrahydro-lH-3-benzazepin-7-yl)methyl]-5-(dimethylamino)-N- methylpyrazine-2-carboxamide;

N-[(3-cyclobutyl-2,3,4,5-tetrahydro-lH-3-benzazepin-7-yl)methyl]-5-[(3R)-3- methoxypyrrolidin-l-ylJ-N-methylpyrazine-2-carboxamide;

N-[(3-cyclobutyl-2,3,4,5-tetrahydro-lH-3-benzazepin-7-yl)methyl]-5-{[(2S)-2- methoxypropyl](methyl)amino}pyrazine-2-carboxamide; or

N-[(3-cyclobutyl-2,3,4,5-tetrahydro-lH-3-benzazepin-7-yl)methyl]-5-{[(2R)-2- methoxypropyl](methyl)amino } pyrazine-2-carboxamide,

or a pharmaceutically acceptable salt thereof.

26. A pharmaceutical composition comprising a compound according to any preceding claim, together with one or more pharmaceutically acceptable excipients.

27. A composition according to Claim 26, comprising one or more additional, pharmaceutically active ingredients.

28. A compound according to any of Claims 1 to 25, or a composition according to Claim 26 or 27, for use in therapy.

29. A compound according to any of Claims 1 to 25, or a composition according to claim 26 or 27, for use in the treatment or prevention of a condition whose development or symptoms are linked to histamine H3 receptor activity.

30. A method of treatment or prevention of a condition whose development or symptoms are linked to histamine H3 receptor activity, the method comprising the administration, to a subject in need of such treatment or prevention, of a therapeutically effective amount of a compound according to any of Claims 1 to 25.

31. A compound for use according to Claim 29, or a method according to Claim 30, wherein the condition is a disorder of the central nervous system.

32. A compound for use or a method according to any of Claims 29 to 31, wherein the disorder is selected from schizophrenia, neurodegenerative disorders such as Alzheimer's Disease, cognitive disorders such as dementia and schizophrenia, sleep disorders such as narcolepsy and hypersomnia, pain, obesity, attentional disorders and epilepsy., i