WO2005009989A1

WO2005009989A1 - Nicotinamide derivatives useful as pde4 inhibitors

Info

Publication number: WO2005009989A1
Application number: PCT/IB2004/002376
Authority: WO
Inventors: Simon Bailey; Christopher Gordon Barber
Original assignee: Pfizer Limited; Pfizer Inc.
Priority date: 2003-07-25
Filing date: 2004-07-13
Publication date: 2005-02-03
Also published as: CA2533663A1; EP1651635A1; BRPI0412253A; GB0317472D0; WO2005009989A8; MXPA06000989A; JP2006528659A

Abstract

This invention relates to nicotinamide derivatives of general formula (I) in which X, Y, n, Z, L and R have the meanings defined herein, and to processes for the preparation of, intermediates used in the preparation of, compositions containing and the uses of such derivates.

Description

NICOTINAMIDE DERIVATIVES USEFUL AS PDE4 .NHIBITORS

This invention relates to nicotinamide derivatives of general formula :

(i) in which X, Z, Y, L, R and n have the meanings indicated below, and to processes for the preparation of, intermediates used in the preparation of, compositions containing and the uses of such derivatives.

The 3',5'-cyclic nucleotide phosphodiesterases (PDEs) comprise a large class of enzymes divided into at least eleven different families which are structurally, biochemically and pharmacologically distinct from one another. The enzymes within each family are commonly referred to as isoenzymes, or isozymes. A total of more than fifteen gene products is included within this class, and further diversity results from differential splicing and post-translational processing of those gene products. The present invention is primarily concerned with the four gene products of the fourth family of PDEs, i.e., PDE4A, PDE4B, PDE4C, and PDE4D. These enzymes are collectively referred to as being isoforms or subtypes of the PDE4 isozyme family.

The PDE4s are characterized by selective, high affinity hydrolytic degradation of the second messenger cyclic nucleotide, adenosine 3',5'-cyclic monophosphate (cAMP), and by sensitivity to inhibition by rolipram. A number of selective inhibitors of the PDE4s have been discovered in recent years, and beneficial pharmacological effects resulting from that inhibition have been shown in a variety of disease models (see, e.g., Torphy et al., Environ. Health Perspect. ,1994, 102 Suppl. 10, p. 79-84 ; Duplantier et al., J. Med. Chem., 1996, 39, p. 120-125 ; Schneider et al., Pharmacol. Biochem. Behav., 1995, 50, p. 211-217 ; Banner and Page, Br. J. Pharmacol., 1995, 114, p. 93-98 ; Bamette et al., J. Pharmacol. Exp. Ther., 1995, 273, p. 674-679 ; Wright et al., Can. J. Physiol. Pharmacol., 1997, 75, p. 1001-1008 ; Manabe et al., Eur. J. Pharmacol., 1997, 332, p. 97-107 and Ukita et al., J. Med. Chem., 1999, 42, p. 1088-1099). Accordingly, there continues to be considerable interest in the art with regard to the discovery of further selective inhibitors of PDE4s.

Successful results have already been obtained in the art with the discovery and development of selective PDE4 inhibitors. In vivo, PDE4 inhibitors reduce the influx of eosinophils to the lungs of allergen-challenged animals while also reducing the bronchoconstriction and elevated bronchial responsiveness occurring after allergen challenge. PDE4 inhibitors also suppress the activity of immune cells (including CD4⁺ T-lymphocytes, monocytes, mast cells, and basophils), reduce pulmonary edema, inhibit excitatory nonadrenergic noncholinergic neurotransmission (eNANC), potentiate inhibitory nonadrenergic noncholinergic neurotransmission (iNANC), reduce airway smooth muscle mitogenesis, and induce bronchodilation. PDE4 inhibitors also suppress the activity of a number of inflammatory cells associated with the pathophysiology of COPD, including monocytes/macrophages, CD4⁺ T- lymphocytes, eosinophils and neutrophils. PDE4 inhibitors also reduce vascular smooth muscle mitogenesis and potentially interfere with the ability of airway epithelial cells to generate pro-inflammatory mediators. Through the release of neutral proteases and acid hydrolases from their granules, and the generation of reactive oxygen species, neutrophils contribute to the tissue destruction associated with chronic inflammation, and are further implicated in the pathology of conditions such as emphysema. Therefore, PDE4 inhibitors are particularly useful for the treatment of a great number of inflammatory, respiratory and allergic diseases, disorders or conditions and for wounds and some of them are in clinical development mainly for treatment of asthma, COPD, bronchitis and emphysema.

The effects of PDE4 inhibitors on various inflammatory cell responses can be used as a basis for profiling and selecting inhibitors for further study. These effects include elevation of cAMP and inhibition of superoxide production, degranulation, chemotaxis, and tumor necrosis factor alpha (TNFa) release in eosinophils, neutrophils and monocytes. Some nicotinamide derivatives having a PDE4 inhibitory activity have already been synthetized. For example, the patent application WO 98/45268 discloses nicotinamide derivatives having activity as selective inhibitors of PDE4D isozyme.

The patent applications WO 01/57036 and WO 03/068235 also disclose nicotinamide derivatives which are PDE4 inhibitors useful in the treatment of various inflammatory allergic and respiratory diseases and conditions.

However, there is still a huge need for additional PDE4 inhibitors that are good drug candidates. In particular, preferred compounds should bind potently to the PDE4 enzyme whilst showing little affinity for other receptors and enzymes. They should also possess favourable pharmacokinetic and metabolic activities, be non-toxic and demonstrate few side effects. Furthermore, it is also desirable that the ideal drug candidate will exist in a physical form that is stable and easily formulated.

The present invention therefore provides new nicotinamide derivatives of formula (I) :

(i) wherein

X is hydrogen, methyl or halo,

Y is attached to the 3- or 4-position on the phenyl ring, and is S(O)_pR¹, wherein R¹ is (C-ι-C ) alkyl optionally substituted by (C₃-C6)cycloalkyl and p is 0, 1 or 2,

n is 1 or 2, Z is selected from hydrogen, (Cι-C₃)alkyl, halo and (Cι-C₃)alkoxy, each Z being independently selected when n is 2,

or Y and (Z)_n , when attached to adjacent carbon atoms at the 3- or 4-position on the phenyl ring, are taken together with the carbon atoms to which they are attached to form a dihydrothienyl or dihydro-1 ,4-oxathiinyl ring,

L is a 5- or 6-membered heterocyclic ring containing one or two nitrogen ring atoms, which ring is optionally substituted by OH, (Cι-C₃)alkyl (optionally substituted by OH or by (Cι-C₃)alkoxy), halo or by (Cι-C₃)alkoxy,

R is H, (Cι-C₆)alkyl (optionally substituted by OH or (C_fCsialkoxy), SO₂(C₁-C₃)alkyl), or COR"

R² is selected from the group consisting of • (Cι-Cβ)alkyl (optionally substituted by (CrC₃)alkoxy, OH, NR³R⁴, a 5- or 6- membered heterocyclic ring containing 1 , 2 or 3 hetero ring atoms independently selected from N, O and S, OC(O)(Cι-C₃)alkyl) or S(O)_p(Cι- C₃)alkyl), • (C₃-C₆)cycloalkyl, • a 5- or 6-membered heterocyclic ring containing 1 , 2 or 3 hetero ring atoms independently selected from N, O and S, which ring is optionally substituted by (Cι-C )alkyl (optionally substituted by OH), halo, =O, OH, or by (d-C₃)alkoxy and • phenyl, optionally substituted by 1 , 2 or 3 substituents independently selected from OH, halo, (Cι-C₃)alkyl, (Cι-C₃)alkoxy, CO₂H, CO₂(Cι-C₃)alkyl) and OC(=O)(C C₃)alkyl,

R³ and R⁴ are each independently selected from H, (Cι-C₃)alkyl and C(O)(Cι- C₃)alkyl),

and the pharmaceutically acceptable salts and solvates thereof, with the proviso that the nicotinamide derivative is not (i) 5-methyl-2-(3-methylsulphonyl)-N-(pyrazin-5-yl)nicotinamide; (ii) 5-methyl-2-(3-ethylsulphonyl)-N-(pyrazin-5-yl)nicotinamide; (iii) 2-(3-methylsulphonyl)-N-(pyrazin-5-yl)nicotinamide; or (iv) 2-(3-ethylsulphonyl)-N-(pyrazin-5-yl)nicotinamide.

It has been found that these nicotinamide derivatives are inhibitors of PDE4 isoenzymes, particularly useful for the treatment of inflammatory, respiratory and allergic diseases and conditions or for wounds by showing excellent therapeutic utility and therapeutic index.

Preferably X is F and/or p is 0.

According to an aspect of the invention, Y is attached to the 3-position on the phenyl ring, and/or Y is S(O)_pCH₃, S(O)_pC₂H₅ or S(O)_pCH₂(cyclopropyl). More preferably, Y is SCH₃, SC₂H₅ or SCH₂(cyclopropyl). Still more preferably, Y is SCH . Yet more preferably Y is 3-SCH₃.

According to another aspect of the invention, when (Z)_n is not H or F, it is attached to the 3-, 4-, and/or 5-position on the phenyl ring. Preferably, (Z)_n is H.

According to further aspect of the invention, L is a piperidine, pyrrolidine, pyrazine, pyridine or pyrimidine ring, which ring is optionally substituted by OH, methoxy, hydroxymethyl, ethoxy, or methyl. More preferably, L is piperidin-1 ,3-ylene, piperidin- 1 ,4-ylene, pyrazin-5,1-ylene, 3-hydroxypyridin-6,4-ylene, pyridin-4,2-ylene, pyridin- 2,6-ylene, pyridin-4,6-ylene, pyridin-3,6-ylene, 3-methoxypyridin-6,4-ylene, 2- methoxypyridin-5,3-ylene, 2-methoxypyridin-3,5-ylene, 3-ethoxypyridin-2,6-ylene, 3- hydroxymethylpyridin-2,6-ylene, 2-methylpyridin-3,6-ylene, 3-methylpyridin-4,6-ylene, 4-hydroxypirimidin-2,5-ylene or 4-hydroxypyrimidin-5,2-ylene, where the first number of the linkage indicates the attachment to the NH of the nicotinamide moiety, and the second number of the linkage is attached to the R moiety. Still more preferably, L is piperidin-1 ,4-ylene, pyrazin-5,1-ylene, 3-hydroxypyridin-6,4-ylene, pyridin-4,2-ylene, pyridin-2,6-ylene, pyridin-4,6-ylene, pyridin-3,6-ylene, 2-methoxypyridin-3,5-ylene, 3- hydroxymethylpyridin-2,6-ylene or 3-methylpyridin-4,6-ylene, where the first number of the linkage indicates the attachment to the NH of the nicotinamide moiety, and the second number of the linkage is attached to the R moiety. Yet more preferably, L is piperidin-1 ,4-ylene, where the first number of the linkage indicates the attachment to the NH of the nicotinamide moiety, and the second number of the linkage is attached to the R moiety.

According to another aspect of the invention, R is attached to a nitrogen atom on the ring L. More preferably, R is H, (C C₃)alkyl, SO₂(Cι-C₃)alkyl), or COR², wherein R² is (C C₃)alkyl (optionally substituted by (Cι-C₃)alkoxy, OH, NR³R⁴ or a 5- or 6-membered heterocyclic ring containing 1, 2 or 3 hetero ring atoms independently selected from N, O and S), cyclopropyl, a 5- or 6-membered heterocyclic ring containing 1 , 2 or 3 hetero ring atoms independently selected from N, O and S, which ring is optionally substituted by (C C₃)alkyl (optionally substituted by OH), halo, =O, OH, or by (Cι-C₃)alkoxy, or phenyl, optionally substituted by 1, 2 or 3 substituents independently selected from OH, halo, (Cι-C₃)alkyl. (Cι-C₃)alkoxy, CO₂H, CO₂(Cι-C₃)alkyl) and OC(=O)(C C₃)alkyl.

Still more preferably, R is H, CH₃, C₂H₅, COCH₃, SO₂CH₃, COC₂H₄(pyridyl), COC₂H₅, CO(cyclopropyl), COCH₂OH, CO(2-hydroxy-4-methylphenyl), CO(2-hydroxy-4- methoxyphenyl) or CO(2-hydroxyphenyl). Yet more preferably, R is H, COCH₃ or SO₂CH₃. Most preferably R is H or COCH₃.

In the here above general formula (1), halo denotes a halogen atom selected from the group consisting of fluoro, chloro, bromo and iodo in particular fluoro or chloro.

(Cι-C₃)alkyl, (Cι-C )alkyl or (CrC₆)alkyl radicals denote a straight-chain or branched group containing respectively 1 to 3, 1 to 4 and 1 to 6 carbon atoms. This also applies if they carry substituents or occur as substituents of other radicals, for example in (C-_t-C₄)alkoxy radicals, (C-i-C₄)thioalkyl radicals, (Cι-C₄)haloalkyl radicals, hydroxy(Cι-C₄)alkyl radicals, C(=O)O(C-ι-C₄)alkyl radicals etc. Examples of suitable (Cι-C₃)alkyl, (Cι-C₄)alkyl and (C-ι-C₆)alkyl radicals are methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, pentyl and hexyl. Examples of suitable (CrC₄)alkoxy radicals are methoxy, ethoxy, n-propyloxy, iso-propyloxy, n-butyloxy, iso- butyloxy, sec-butyloxy and tert-butyloxy. Examples of suitable (Cι-C )thioalkyl radicals are thiomethyl, thioethyl, thio-n-propyl, thio-iso-propyl, thio-n-butyl, thio-iso-butyl, thio- sec-butyl and thio-tert-butyl.

(C₃-C₆)cycloaIkyl radicals represent 3-membered to 6-membered saturated monocyclic rings. Examples of suitable (C₃-C₆)cycloalkyl radicals are in particular cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. These radicals can be optionally substituted.

In the hereabove general formula (1), a heterocyclic ring is a radical of a monocyclic or polycyclic aromatic system having 5 to 14 ring members, which contains 1, 2 or 3 heteroatom(s) depending in number and quality of the total number of ring members, selected from nitrogen (N), oxygen (O) and sulphur (S). If several heteroatoms are contained, these can be identical or different. Heterocyclic rings can also be unsubstituted, monosubstituted or polysubstituted, as indicated in the definition of R2 hereabove for general formula (1) according to the present invention. Examples of suitable heterocyclic radicals are the radicals derivated from piperidine, pyrrolidine, pyrazine, pyridine or pyrimidine ring, pyrrole, furan, furazan, thiophene, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, tetrazole, triazine, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, indole, isoindole, indazole, purine, naphthyridine, phthalazine, quinoline, isoquinoline, quinoxaline, quinazoline, cinnoline, and benzo-fused derivatives of these heteroaryls, such as for example benzofuran, benzothiophene, benzoxazole, and benzothiazole. Particularly preferred are the heteroaryl radicals selected from pyrrolyl, pyrazolyl, 1,2,3-triazolyl, 1 ,2,4- triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1 ,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furanyl, thienyl, pyridinyl, pyridazinyl, pyrinnidinyl, and pyrazinyl.

In the general formula (1) according to the present invention, when a radical is mono- or poly-substituted, said substituent(s) can be located at any desired position(s). Also, when a radical is polysubstituted, said substituents can be identical or different, unless otherwise stated.

The nicotinamide derivatives of the formula (1) can be prepared using conventional procedures such as by the following illustrative methods in which X, L, Y, Z and R are as previously defined for the nicotinamide derivatives of the formula (1) unless otherwise stated.

In the Methods below, unless otherwise specified, the substituents are as defined above with reference to the compounds of formula (I) above.

Method A

The compounds of formula (I) may be made by reaction of the corresponding nicotinic acid (II) with a compound of formula NH₂-L-R

(II)

suitably in the presence of an acid/amine, or peptide, coupling agent. The reaction may suitably be carried by reaction of the acid with carbonyldiimidazole in a suitable inert solvent such as dichloromethane, followed by addition of the compound NH₂-L-R, suitably in the presence of a base such as 4-dimethylaminopyridine, as exemplified in Examples 1-4 below.

An alternative method starting from acids (II) is to use a suitable diimide such as 1-(3- dimethylaminopropyl)-3-ethylcarbodiimide in conjunction with an agent such as 1- hydroxybenzotriazole. The acid (II) may be added to the mixture in an inert solvent such as dichloromethane, followed by addition of the amine NH₂-L-R . This reaction type, reagents, conditions, solvents and variations thereof are exemplified in Examples 57-69 below.

Other suitable regimes for the transformation (II) to (I) may be found in the volume by

Larock, supra, pp972-976.

The acids of formula (II) and amines of formula NH₂-L-R may be commercially available, or can be made using the methods described herein, including in the Preparations below, the art mentioned herein, or routine adaptation thereof.

Method B

Compounds of formula (I) may be made by a coupling reaction of a chloro-compound of formula (III) with a phenol of formula (IV).

Suitably the phenol (IV) and chloro-compound (III) are mixed with caesium carbonate in an inert solvent such as toluene:N-methylpyrrolidine at ambient temperature, followed by addition of copper (I) iodide and then heating to a suitable temperature such as 110°C. This reaction type, reagents, conditions, solvents and variations thereof are exemplified in Examples 40-55 below.

The chloro-compounds (III) and the phenols (IV) may be commercially available, or can be made using the methods described herein, including in the Preparations below, the art mentioned herein, or routine adaptation thereof.

Certain compounds of formula (I) may be transformed into other compounds of formula (I) by suitable functional group interconversion (FGI) of a type well-known to those skilled in the art. For examples where the compound of formula (I) contains an ester or acid moiety, these can be interconverted readily by known hydrolysis or esterification methods respectively.

For examples where compounds of formula (I) where R is H are transformed into compounds of formula (I) where R is not H, see Examples 5, 9-39 (R=carbonyl-linked moiety), 6-8 (R=alkyl), 56 (R=SO₂(alkyl)).

For examples of compounds of formula (I) where the Y moiety is a thioalkyl moiety is oxidised to a compound of formula (I) where Y is a sulphoxyl or sulphonyl moiety, see

Examples 71 , 72.

Many other FGIs of compounds of formula (I) into other compounds of formula (I) are possible using methods exemplified in the Examples and Preparations sections below, and standard FGI chemistry known in the art.

It will be apparent to those skilled in the art that other protection and subsequent deprotection regimes during synthesis of a compound of the invention may be achieved by conventional techniques, for example as described in the volumes by Greene and Wuts, and Kocienski, supra, some of which are mentioned specifically herein.

All of the above reactions and the preparations of novel starting materials using in the preceding methods are conventional and appropriate reagents and reaction conditions for their performance or preparation as well as procedures for isolating the desired products will be well-known to those skilled in the art with reference to literature precedents and the examples and preparations hereto.

For some of the steps of the here above described process of preparation of the nicotinamide derivatives of formula (1 ), it can be necessary to protect the potential reactive functions that are not wished to react. In such a case, any compatible protecting radical can be used. In particular methods such as those described by T.W. GREENE (Protective Groups in Organic Synthesis, A. Wiley-lnterscience Publication, 1981 ) or by McOMIE (Protective Groups in Organic Chemistry, Plenum Press, 1973), can be used. Also, the nicotinamide derivatives of formula (1) as well as intermediate for the preparation thereof can be purified according to various well-known methods, such as for example crystallization or chromatography.

According to a first aspect, particularly preferred are nicotinamide derivatives of the formula (1) in which X is F. Further preferred are nicotinamide derivatives wherein p is O.

Y is preferably attached to the 3-position on the phenyl ring, and represents in particular S(O)_pCH₃, S(O)_pC₂H₅ or S(O)_pCH₂(cyclopropyl), preferably SCH₃, SC₂H₅ or SCH₂(cyclopropyl), more preferably SCH₃, most preferably 3-SCH₃.

When (Z)_n is not H or F, it is preferably attached to the 3-, 4-, and/or 5-position on the phenyl ring. (Z)_n is preferably H.

L is preferably a piperidine, pyrrolidine, pyrazine, pyridine or pyrimidine ring, which ring is optionally substituted by OH, methoxy, hydroxymethyl, ethoxy, or methyl, in particular piperidin-1 ,3-ylene, piperidin-1 ,4-ylene, pyrazin-5,1 -ylene, 3- hydroxypyridin-6,4-ylene, pyridin-4,2-ylene, pyridin-2,6-ylene, pyridin-4,6-ylene, pyridin-3,6-ylene, 3-methoxypyridin-6,4-ylene, 2-methoxypyridin-5,3-ylene, 2- methoxypyridin-3,5-ylene, 3-ethoxypyridin-2,6-ylene, 3-hydroxymethylpyridin-2,6- ylene, 2-methylpyridin-3,6-ylene, 3-methylpyridin-4,6-ylene, 4-hydroxypirimidin-2,5- ylene or 4-hydroxypyrimidin-5,2-ylene, where the first number of the linkage indicates the attachment to the NH of the nicotinamide moiety, and the second number of the linkage is attached to the R moiety.

More preferably L is piperidin-1 , 4-ylene, pyrazin-5,1 -ylene, 3-hydroxypyridin-6,4- ylene, pyridin-4,2-ylene, pyridin-2,6-ylene, pyridin-4,6-ylene, pyridin-3,6-ylene, 2- methoxypyridin-3,5-ylene, 3-hydroxymethylpyridin-2,6-ylene or 3-methylpyridin-4,6- ylene, where the first number of the linkage indicates the attachment to the NH of the nicotinamide moiety, and the second number of the linkage is attached to the R moiety, most preferably L is piperidin-1 ,4-ylene, where the first number of the linkage indicates the attachment to the NH of the nicotinamide moiety, and the second number of the linkage is attached to the R moiety.

R is preferably attached to a nitrogen atom on the ring L and represents R H, (Cι- C₃)alkyl, SO₂(C₁-C₃)alkyl), or COR², wherein R² is (Cι-C₃)alkyl (optionally substituted by (Cι-C₃)alkoxy, OH, NR³R⁴ or a 5- or 6-membered heterocyclic ring containing 1 , 2 or 3 hetero ring atoms independently selected from N, O and S), cyclopropyl, a 5- or 6-membered heterocyclic ring containing 1 , 2 or 3 hetero ring atoms independently selected from N, O and S, which ring is optionally substituted by (Cι- C₃)alkyl (optionally substituted by OH), halo, =O, OH, or by (Cι-C₃)alkoxy, or phenyl, optionally substituted by 1 , 2 or 3 substituents independently selected from OH, halo, (Cι-C₃)alkyl, (Cι-C₃)alkoxy, CO₂H, CO₂(d-C₃)alkyl) and OC(=O)(C C₃)alkyl.

More preferably R is H, CH₃, C₂H₅, COCH₃, SO₂CH₃, COC₂H₄(pyridyl), COC₂H₅, CO(cyclopropyl), COCH₂OH, CO(2-hydroxy-4-methylphenyl), CO(2-hydroxy-4- methoxyphenyl) or CO(2-hydroxyphenyl), in particular H, COCH₃ or SO CH₃. Most preferably R is H or COCH₃.

Particularly preferred examples of the nicotinamide derivatives of the formula (1) are as described in the Examples section hereafter.

The nicotinamide derivatives of formula (1 ) may also be optionally transformed in pharmaceutically acceptable salts. In particular, these pharmaceutically acceptable salts of the nicotinamide derivatives of the formula (1) include the acid addition and the base salts (including disalts) thereof.

Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include the acetate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate, camsylate, citrate, edisylate, esylate, fumarate, gluceptate, gluconate, glucuronate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodie, hydrogen phosphate, isethionate, D- and L-lactate, malate, maleate, malonate, mesylate, methylsulphate, 2-napsylate, nicotinate, nitrate, orotate, palmoate, phosphate, saccharate, stearate, succinate sulphate, D- and L- tartrate, 1-hydroxy-2-naphtoate, 3-hydroxy-2-naphthoate and tosylate saltes.

Suitable base salts are formed from bases which form non-toxic salts. Examples include the aluminium, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts.

For a review on suitable salts, see Stahl and Wermuth, Handbook of Pharmaceutical Salts: Properties, Selection and Use, Wiley-VCH, Weinheim, Germany (2002).

A pharmaceutically acceptable salt of a nicotinamide derivative of the formula (1) may be readily prepared by mixing together solutions of the nicotinamide derivative of formula (1 ) and the desired acid or base, as appropriate. The salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent.

Pharmaceutically acceptable solvates in accordance with the invention include hydrates and solvates wherein the solvent of crystallization may be isotopically substituted, e.g. D2O, d₆-acetone, d₆-DMSO.

Also within the scope of the invention are clathrates, drug-host inclusion complexes wherein, in contrast to the aforementioned solvates, the drug and host are are present in non-stoichiometric amounts. For a review of such complexes, see J Pharm Sci, 64 (8), 1269-1288 by Haleblian (August 1975).

Hereinafter all references to nicotinamide derivatives of formula (1) include references to salts thereof and to solvates and clathrates of compounds of formula (1) and salts thereof.

The invention includes all polymorphs of the nicotinamide derivatives of formula (1). Also within the scope of the invention are so-called "prodrugs" of the nicotinamide derivatives of formula (1). Thus certain derivatives of nicotinamide derivatives of formula (1) which have little or no pharmacological activity themselves can, when metabolised upon administration into or onto the body, give rise to nicotinamide derivatives of formula (1 ) having the desired activity. Such derivatives are referred to as "prodrugs".

Prodrugs in accordance with the invention can, for example, be produced by replacing appropriate functionalities present in the nicotinamide derivatives of formula (1) with certain moieties known to those skilled in the art as "pro-moieties" as described, for example, in "Design of Prodrugs" by H Bundgaard (Elsevier, 1985).

Finally, certain nicotinamide derivatives of formula (1) may themselves act as prodrugs of other nicotinamide derivatives of formula (1 ).

Nicotinamide derivatives of formula (1) containing one or more asymmetric carbon atoms can exist as two or more optical isomers. Where a nicotinamide derivative of formula (1) contains an alkenyl or alkenylene group, geometric cis/trans (or Z/E) isomers are possible, and where the nicotinamide derivative contains, for example, a keto or oxime group, tautomeric isomerism ('tautomerism') may occur. It follows that a single nicotinamide derivative may exhibit more than one type of isomerism.

Included within the scope of the present invention are all optical isomers, geometric isomers and tautomeric forms of the nicotinamide derivatives of formula (1 ), including compounds exhibiting more than one type of isomerism, and mixtures of one or more thereof.

Cis/trans isomers may be separated by conventional techniques well known to those skilled in the art, for example, fractional crystallisation and chromatography.

Conventional techniques for the preparation/isolation of individual stereoisomers include the conversion of a suitable optically pure precursor, resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral HPLC, or fractional crystallisation of diastereoisomeric salts formed by reaction of the racemate with a suitable optically active acid or base, for example, tartaric acid.

The present invention also includes all pharmaceutically acceptable isotopic variations of a nicotinamide derivative of formula (1 ). An isotopic variation is defined as one in which at least one atom is replaced by an atom having the same atomic number, but an atomic mass different from the atomic mass usually found in nature.

Examples of isotopes suitable for inclusion in the nicotinamide derivatives of the invention include isotopes of hydrogen, such as ²H and ³H, carbon, such as ¹³C and ¹⁴C, nitrogen, such as ¹⁵N, oxygen, such as ¹⁷O and ¹⁸O, phosphorus, such as ³²P, sulphur, such as ³⁵S, fluorine, such as ¹⁸F, and chlorine, such as ³⁶CI.

Substitution of the nicotinamide derivative of formula (1 ) isotopes such as deuterium, i.e. ²H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.

Certain isotopic variations of the nicotinamide derivatives of formula (1 ), for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies. The radioactive isotopes tritium, i.e. ³H, and carbon-14, i.e. ¹⁴C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.

Isotopic variations of the nicotinamide derivatives of formula (1) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using appropriate isotopic variations of suitable reagents.

According to a further aspect, the present invention concerns mixtures of nicotinamide derivatives of the formula (1 ), as well as mixtures with or of their pharmaceutically acceptable salts, solvates, polymorphs, isomeric forms and/or isotope forms.

According to the present invention, all the here above mentioned forms of the nicotinamide derivatives of formula (1 ) except the pharmaceutically acceptable salts (i.e. said solvates, polymorphs, isomeric forms and isotope forms), are defined as "derived forms" of the nicotinamide derivatives of formula (1 ) in what follows.

The nicotinamide derivatives of formula (1), their pharmaceutically acceptable salts and/or derived forms, are valuable pharmaceutical active compounds, which are suitable for the therapy and prophylaxis of numerous disorders in which the PDE4 enzymes are involved, in particular the inflammatory disorders, allergic disorders, respiratory diseases and wounds.

The nicotinamide derivatives of formula (1 ) and their pharmaceutically acceptable salts and derived forms as mentioned above can be administered according to the invention to animals, preferably to mammals, and in particular to humans, as pharmaceuticals for therapy or prophylaxis. They can be administered per se, in mixtures with one another or in combination with other drugs, or in the form of pharmaceutical preparations which permit enteral (gastric) or parenteral (non-gastric) administration and which as active constituent contain an efficacious dose of at least one nicotinamide derivative of the formula (1 ), its pharmaceutically acceptable salts and/or derived forms, in addition to customary pharmaceutically innocuous excipients and/or additives. The term "excipient" is used herein to describe any ingredient other than the compound of the invention. The choice of excipient will to a large extent depend on the particular mode of administration.

The nicotinamide derivatives of formula (1 ), their pharmaceutically acceptable salts and/or derived forms may be freeze-dried, spray-dried, or evaporatively dried to provide a solid plug, powder, or film of crystalline or amorphous material. Microwave or radio frequency drying may be used for this purpose.

ORAL ADMINISTRATION The nicotinamide derivatives of formula (1) their pharmaceutically acceptable salts and/or derived forms of the invention may be administered orally. Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be employed by which the compound enters the blood stream directly from the mouth.

Formulations suitable for oral administration include solid formulations such as tablets, capsules containing particulates, liquids, or powders, lozenges (including liquid-filled), chews, multi- and nano-particulates, gels, films (including muco- adhesive), ovules, sprays and liquid formulations.

Liquid formulations include suspensions, solutions, syrups and elixirs. Such formulations may be employed as fillers in soft or hard capsules and typically comprise a carrier, for example, water, ethanol, propylene glycol, methylcellulose, or a suitable oil, and one or more emulsifying agents and/or suspending agents. Liquid formulations may also be prepared by the reconstitution of a solid, for example, from a sachet.

The nicotinamide derivatives of formula (1 ), their pharmaceutically acceptable salts and/or derived forms of the invention may also be used in fast-dissolving, fast- disintegrating dosage forms such as those described in Expert Opinion in Therapeutic Patents, 11 (6), 981-986 by Liang and Chen (2001).

The composition of a typical tablet in accordance with the invention may comprise:

Quantity adjusted in accordance with drug activity. A typical tablet may be prepared using standard processes known to a formulation chemist, for example, by direct compression, granulation (dry, wet, or melt), melt congealing, or extrusion. The tablet formulation may comprise one or more layers and may be coated or uncoated.

Examples of excipients suitable for oral administration include carriers, for example, cellulose, calcium carbonate, dibasic calcium phosphate, mannitol and sodium citrate, granulation binders, for example, polyvinylpyrrolidine, hydroxypropylcellulose, hydroxypropylmethylcellulose and gelatin, disintegrants, for example, sodium starch glycolate and silicates, lubricating agents, for example, magnesium stearate and stearic acid, wetting agents, for example, sodium lauryl sulphate, preservatives, anti- oxidants, flavours and colourants.

Solid formulations for oral administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed- , controlled dual-, targeted and programmed release. Details of suitable modified release technologies such as high energy dispersions, osmotic and coated particles are to be found in Verma et al, Pharmaceutical Technology On-line, 25(2), 1-14 (2001). Other modified release formulations are described in US Patent No. 6,106,864.

PARENTERAL ADMINISTRATION

The nicotinamide derivatives of formula (1), their pharmaceutically acceptable salts and/or derived forms of the invention may also be administered directly into the blood stream, into muscle, or into an internal organ. Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular and subcutaneous. Suitable devices for parenteral administration include needle (including microneedle) injectors, needle-free injectors and infusion techniques.

Parenteral formulations are typically aqueous solutions which may contain excipients such as salts, carbohydrates and buffering agents (preferably to a pH of from 3 to 9), but, for some applications, they may be more suitably formulated as a sterile non- aqueous solution or as a dried form to be used in conjunction with a suitable vehicle such as sterile, pyrogen-free water.

The preparation of parenteral formulations under sterile conditions, for example, by lyophilisation, may readily be accomplished using standard pharmaceutical techniques well known to those skilled in the art.

The solubility of nicotinamide derivatives of formula (1) used in the preparation of parenteral solutions may be increased by suitable processing, for example, the use of high energy spray-dried dispersions (see WO 01/47495) and/or by the use of appropriate formulation techniques, such as the use of solubility-enhancing agents.

Formulations for parenteral administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed- , controlled dual-, targeted and programmed release.

TOPICAL ADMINISTRATION

The nicotinamide derivatives of the invention may also be administered topically to the skin or mucosa, either dermally or transdermally. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibres, bandages and microemulsions. Liposomes may also be used. Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin and propylene glycol. Penetration enhancers may be incorporated - see, for example, J Pharm Sci, 88 (10), 955-958 by Finnin and Morgan (October 1999).

Other means of topical administration include delivery by iontophoresis, electroporation, phonophoresis, sonophoresis and needle-free or microneedle injection.

Formulations for topical administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed- , controlled dual-, targeted and programmed release. Thus nicotinamide derivatives of formula (1 ) may be formulated in a more solid form for administration as an implanted depot providing long-term release of the active compound.

INHALED/INTRANASAL ADMINISTRATION

The nicotinamide derivatives of formula (1) can also be administered intranasally or by inhalation, typically in the form of a dry powder (either alone, as a mixture, for example, in a dry blend with lactose in anhydrous or monohydrate form, preferably monohydrate, mannitol, dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose or trehalose, or as a mixed component particle, for example, mixed with phospholipids) from a dry powder inhaler or as an aerosol spray from a pressurised container, pump, spray, atomiser (preferably an atomiser using electrohydrodynamics to produce a fine mist), or nebuliser, with or without the use of a suitable propellant, such as dichlorofluoromethane.

The pressurised container, pump, spray, atomizer, or nebuliser contains a solution or suspension of the active compound comprising, for example, ethanol (optionally, aqueous ethanol) or a suitable alternative agent for dispersing, solubilising, or extending release of the active, the propellant(s) as solvent and an optional surfactant, such as sorbitan trioleate or an oligolactic acid.

Prior to use in a dry powder or suspension formulation, the drug product is micronised to a size suitable for delivery by inhalation (typically less than 5 microns). This may be achieved by any appropriate comminuting method, such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenisation, or spray drying.

A suitable solution formulation for use in an atomiser using electrohydrodynamics to produce a fine mist may contain from 1μg to 20mg of the nicotinamide derivative of formula (1) per actuation and the actuation volume may vary from 1 /I to 1OO /I. A typical formulation may comprise a nicotinamide derivative of formula (1 ), propylene glycol, sterile water, ethanol and sodium chloride. Alternative solvents which may be used instead of propylene glycol include glycerol and polyethylene glycol. Capsules, blisters and cartridges (made, for example, from gelatin or HPMC) for use in an inhaler or insufflator may be formulated to contain a powder mix of the nicotinamide derivative of formula (1), a suitable powder base such as lactose or starch and a performance modifier such as l-leucine, mannitol, or magnesium stearate.

In the case of dry powder inhalers and aerosols, the dosage unit is determined by means of a valve which delivers a metered amount. Units in accordance with the invention are typically arranged to administer a metered dose or "puff" containing from 1 μg to 4000 μg of the nicotinamide derivative of formula (1 ). The overall daily dose will typically be in the range 1 μg to 20 mg which may be administered in a single dose or, more usually, as divided doses throughout the day.

Formulations for inhaled/intranasal administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled dual-, targeted and programmed release. Sustained or controlled release can be obtained by using for example poly(D,L-lactic-co-glycolic acid).

Flavouring agents, such as methol and levomethol and/or sweeteners such as saccharing or saccharin sodium can be added to the formulation.

RECTAL/INTRAVAGINAL ADMINISTRATION The nicotinamide derivatives of formula (1) may be administered rectally or vaginally, for example, in the form of a suppository, pessary, or enema. Cocoa butter is a traditional suppository base, but various alternatives may be used as appropriate.

Formulations for rectal/vaginal administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled dual-, targeted and programmed release.

OCULAR/ANDIAL ADMINISTRATION The nicotinamide derivatives of formula (1 ) may also be administered directly to the eye or ear, typically in the form of drops of a micronised suspension or solution in isotonic, pH-adjusted, sterile saline. Other formulations suitable for ocular and andial administration include ointments, biodegradable (e.g. absorbable gel sponges, collagen) and non-biodegradable (e.g. silicone) implants, wafers, lenses and particulate or vesicular systems, such as niosomes or liposomes. A polymer such as crossed-linked polyacrylic acid, polyvinylalcohol, hyaluronic acid, a cellulosic polymer, for example, hydroxypropylmethylcellulose, hydroxyethylcellulose, or methyl cellulose, or a heteropolysaccharide polymer, for example, gelan gum, may be incorporated together with a preservative, such as benzalkonium chloride. Such formulations may also be delivered by iontophoresis.

Formulations for ocular/andial administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled dual-, targeted, or programmed release.

ENABLING TECHNOLOGIES

The nicotinamide derivatives of formula (1 ) may be combined with soluble macromolecular entities such as cyclodextrin or polyethylene glycol-containing polymers to improve their solubility, dissolution rate, taste-masking, bioavailability and/or stability.

Drug-cyclodextrin complexes, for example, are found to be generally useful for most dosage forms and administration routes. Both inclusion and non-inclusion complexes may be used. As an alternative to direct complexation with the drug, the cyclodextrin may be used as an auxiliary additive, i.e. as a carrier, diluent, or solubiliser. Most commonly used for these purposes are alpha-, beta- and gamma-cyclodextrins, examples of which may be found in International Patent Applications Nos. WO 91/11 172, WO 94/02518 and WO 98/55148.

DOSAGE

For administration to human patients, the total daily dose of the nicotinamide derivatives of formula (1 ) is typically in the range 0.001 mg/kg to 100 mg/kg depending, of course, on the mode of administration. The total daily dose may be administered in single or divided doses. The physician will readily be able to determine doses for subjects depending on age, weight, health state and sex or the patient as well as the severity of the disease.

According to another embodiment of the present invention, the nicotinamide derivatives of the formula (1 ), their pharmaceutically acceptable salts and/or their derived forms, can also be used as a combination with one or more additional therapeutic agents to be co-administered to a patient to obtain some particularly desired therapeutic end result. The second and more additional therapeutic agents may also be a nicotinamide derivatives of the formula (1), their pharmaceutically acceptable salts and/or their derived forms, or one or more PDE4 inhibitors known in the art. More typically, the second and more therapeutic agents will be selected from a different class of therapeutic agents.

As used herein, the terms "co-administration", "co-administered" and "in combination with", referring to the nicotinamide derivatives of formula (1) and one or more other therapeutic agents, is intended to mean, and does refer to and include the following : ■ simultaneous administration of such combination of nicotinamide derivative(s) and therapeutic agent(s) to a patient in need of treatment, when such components are formulated together into a single dosage form which releases said components at substantially the same time to said patient, ■ substantially simultaneous administration of such combination of nicotinamide derivative(s) and therapeutic agent(s) to a patient in need of treatment, when such components are formulated apart from each other into separate dosage forms which are taken at substantially the same time by said patient, whereupon said components are released at substantially the same time to said patient, ^■ sequential administration of such combination of nicotinamide derivative(s) and therapeutic agent(s) to a patient in need of treatment, when such components are formulated apart from each other into separate dosage forms which are taken at consecutive times by said patient with a significant time interval between each administration, whereupon said components are released at substantially different times to said patient; and ^■ sequential administration of such combination of nicotinamide derivative(s) and therapeutic agent(s) to a patient in need of treatment, when such components are formulated together into a single dosage form which releases said components in a controlled manner whereupon they are concurrently, consecutively, and/or overlappingly administered at the same and/or different times by said patient.

Suitable examples of other therapeutic agents which may be used in combination with the nicotinamide derivatives of the formula (1), their pharmaceutically acceptable salts and/or their derived forms include, but are by no mean limited to : (a) 5-Lipoxygenase (5-LO) inhibitors or 5-lipoxygenase activating protein (FLAP) antagonists, (b) Leukotriene antagonists (LTRAs) including antagonists of LTB4, LTC4, LTD4, and LTE4,

(c) Histaminic receptor antagonists including H1, H3 and H4 antagonists,

(d) σ1- and 2-adrenoceptor agonist vasoconstrictor sympathomimetic agents for decongestant use, (e) Muscarinic M3 receptor antagonists or antichoHnergic agents,

(f) ?2-adrenoceptor agonists,

(g) Theophylline,

(h) Sodium cromoglycate,

(i) COX-1 inhibitors (NSAIDs) and COX-2 selective inhibitors, (j) Oral or inhaled Glucocorticosteroids,

(k) Monoclonal antibodies active against endogenous inflammatory entities,

(I) Anti-tumor necrosis factor (anti-TNF-a) agents,

(m) Adhesion molecule inhibitors including VLA-4 antagonists,

(n) Kinin-B1 - and B2 -receptor antagonists, (o) Immunosuppressive agents,

(p) Inhibitors of matrix metalloproteases (MMPs),

(q) Tachykinin NK1 , NK2 and NK3 receptor antagonists,

(r) Elastase inhibitors, (s) Adenosine A2a receptor agonists,

(t) Inhibitors of urokinase,

(u) Compounds that act on dopamine receptors, e.g. D2 agonists,

(v) Modulators of the NFkb pathway, e.g. IKK inhibitors, (w) Agents that can be classed as mucolytics or anti-tussive,

(x) antibiotics, and

(y) p38 MAP kinase inhibitors

According to the present invention, combination of the nicotinamide derivatives of formula (1 ) with : ^■ muscarinic M3 receptor agonists or antichoHnergic agents including in particular ipratropium salts, namely bromide, tiotropium salts, namely bromide, oxitropium salts, namely bromide, perenzepine, and telenzepine, ■ ?2-adrenoceptor agonists including albutarol, salbutamol, formoterol and salmeterol, ■ p38 MAP kinase inhibitors, ■ H3 antagonists, ^■ glucocorticosteroids, in particular inhaled glucocorticosteroids with reduced systemic side effects, including prednisone, prednisolone, flunisolide, triamcinolone acetonide, beclomethasone dipropionate, budesonide, fluticasone propionate, and mometasone furoate, ■ or adenosine A2a receptor agonists, are preferred.

It is to be appreciated that all references herein to treatment include curative, palliative and prophylactic treatment. The description which follows concerns the therapeutic applications to which the nicotinamide derivatives of formula (1) may be put.

The nicotinamide derivatives of formula (1 ) inhibit the PDE4 isozyme and thereby have a wide range of therapeutic applications, as described further below, because of the essential role, which the PDE4 family of isozymes plays in the physiology of all mammals. The enzymatic role performed by the PDE4 isozymes is the intracellular hydrolysis of adenosine 3',5'-monophosphate (cAMP) within pro-inflammatory leukocytes. cAMP, in turn, is responsible for mediating the effects of numerous hormones in the body, and as a consequence, PDE4 inhibition plays a significant role in a variety of physiological processes. There is extensive literature in the art describing the effects of PDE inhibitors on various inflammatory cell responses, which in addition to cAMP increase, include inhibition of superoxide production, degranulation, chemotaxis and tumor necrosis factor (TNF) release in eosinophils, neutrophils and monocytes.

Therefore, a further aspect of the present invention relates to the use of the nicotinamide derivatives of formula (1), their pharmaceutically acceptable salts and/or derived forms, in the treatment of diseases, disorders, and conditions in which the PDE4 isozymes are involved. More specifically, the present invention also concerns the use of the nicotinamide derivatives of formula (1), their pharmaceutically acceptable salts and/or derived forms, in the treatment of diseases, disorders, and conditions selected from the group consisting of :

■ asthma of whatever type, etiology, or pathogenesis, in particular asthma that is a member selected from the group consisting of atopic asthma, non-atopic asthma, allergic asthma, atopic bronchial IgEDmediated asthma, bronchial asthma, essential asthma, true asthma, intrinsic asthma caused by pathophysiologic disturbances, extrinsic asthma caused by environmental factors, essential asthma of unknown or inapparent cause, non-atopic asthma, bronchitic asthma, emphysematous asthma, exercise-induced asthma, allergen induced asthma, cold air induced asthma, occupational asthma, infective asthma caused by bacterial, fungal, protozoal, or viral infection, non- allergic asthma, incipient asthma and wheezy infant syndrome, ■ chronic or acute bronchoconstriction, chronic bronchitis, small airways obstruction, and emphysema, ■ obstructive or inflammatory airways diseases of whatever type, etiology, or pathogenesis, in particular an obstructive or inflammatory airways disease that is a member selected from the group consisting of chronic eosinophilic pneumonia, chronic obstructive pulmonary disease (COPD), COPD that includes chronic bronchitis, pulmonary emphysema or dyspnea associated therewith, COPD that is characterized by irreversible, progressive airways obstruction, adult respiratory distress syndrome (ARDS) and exacerbation of airways hyper-reactivity consequent to other drug therapy ^■ pneumoconiosis of whatever type, etiology, or pathogenesis, in particular pneumoconiosis that is a member selected from the group consisting of aluminosis or bauxite workers' disease, anthracosis or miners' asthma, asbestosis or steam-fitters' asthma, chalicosis or flint disease, ptilosis caused by inhaling the dust from ostrich feathers, siderosis caused by the inhalation of iron particles, silicosis or grinders' disease, byssinosis or cotton-dust asthma and talc pneumoconiosis;

^■ bronchitis of whatever type, etiology, or pathogenesis, in particular bronchitis that is a member selected from the group consisting of acute bronchitis, acute laryngotracheal bronchitis, arachidic bronchitis, catarrhal bronchitis, croupus bronchitis, dry bronchitis, infectious asthmatic bronchitis, productive bronchitis, staphylococcus or streptococcal bronchitis and vesicular bronchitis,

^■ bronchiectasis of whatever type, etiology, or pathogenesis, in particular bronchiectasis that is a member selected from the group consisting of cylindric bronchiectasis, sacculated bronchiectasis, fusiform bronchiectasis, capillary bronchiectasis, cystic bronchiectasis, dry bronchiectasis and follicular bronchiectasis,

^■ seasonal allergic rhinitis or perennial allergic rhinitis or sinusitis of whatever type, etiology, or pathogenesis, in particular sinusitis that is a member selected from the group consisting of purulent or nonpurulent sinusitis, acute or chronic sinusitis and ethmoid, frontal, maxillary, or sphenoid sinusitis,

^■ rheumatoid arthritis of whatever type, etiology, or pathogenesis, in particular rheumatoid arthritis that is a member selected from the group consisting of acute arthritis, acute gouty arthritis, chronic inflammatory arthritis, degenerative arthritis, infectious arthritis, Lyme arthritis, proliferative arthritis, psoriatic arthritis and vertebral arthritis,

^■ gout, and fever and pain associated with inflammation,

^■ an eosinophil-related disorder of whatever type, etiology, or pathogenesis, in particular an eosinophil-related disorder that is a member selected from the group consisting of eosinophilia, pulmonary infiltration eosinophilia, Loffler's syndrome, chronic eosinophilic pneumonia, tropical pulmonary eosinophilia, bronchopneumonic aspergillosis, aspergilloma, granulomas containing eosinophils, allergic granulomatous angiitis or Churg-Strauss syndrome, polyarteritis nodosa (PAN) and systemic necrotizing vasculitis,

^■ atopic dermatitis, allergic dermatitis, contact dermatitis, or allergic or atopic eczema,

^■ urticaria of whatever type, etiology, or pathogenesis, in particular urticaria that is a member selected from the group consisting of immune-mediated urticaria, complement-mediated urticaria, urticariogenic material-induced urticaria, physical agent-induced urticaria, stress-induced urticaria, idiopathic urticaria, acute urticaria, chronic urticaria, angioedema, cholinergic urticaria, cold urticaria in the autosomal dominant form or in the acquired form, contact urticaria, giant urticaria and papular urticaria, ^■ conjunctivitis of whatever type, etiology, or pathogenesis, in particular conjunctivitis that is a member selected from the group consisting of actinic conjunctivitis, acute catarrhal conjunctivitis, acute contagious conjunctivitis, allergic conjunctivitis, atopic conjunctivitis, chronic catarrhal conjunctivitis, purulent conjunctivitis and vernal conjunctivitis, ^■ uveitis of whatever type, etiology, or pathogenesis, in particular uveitis that is a member selected from the group consisting of inflammation of all or part of the uvea, anterior uveitis, iritis, cyclitis, iridocyclitis, granulomatous uveitis, nongranulomatous uveitis, phacoantigenic uveitis, posterior uveitis, choroiditis; and chorioretinitis, ■ psoriasis;

^■ multiple sclerosis of whatever type, etiology, or pathogenesis, in particular multiple sclerosis that is a member selected from the group consisting of primary progressive multiple sclerosis and relapsing remitting multiple sclerosis, ^■ autoimmune/inflammatory diseases of whatever type, etiology, or pathogenesis, in particular an autoimmune/inflammatory disease that is a member selected from the group consisting of autoimmune hematological disorders, hemolytic anemia, aplastic anemia, pure red cell anemia, idiopathic thrombocytopenic purpura, systemic lupus erythematosus, polychondritis, scleroderma, Wegner's granulomatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Stevens- Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel diseases, ulcerative colitis, endocrin opthamopathy, Grave's disease, sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, primary biliary cirrhosis, juvenile diabetes or diabetes mellitus type I, keratoconjunctivitis sicca, epidemic keratoconjunctivitis, diffuse interstitial pulmonary fibrosis or interstitial lung fibrosis, idiopathic pulmonary fibrosis, cystic fibrosis, glomerulonephritis with and without nephrotic syndrome, acute glomerulonephritis, idiopathic nephrotic syndrome, minimal change nephropathy, inflammatory/hyperproliferative skin diseases, benign familial pemphigus, pemphigus erythematosus, pemphigus foliaceus, and pemphigus vulgaris,

^■ prevention of allogeneic graft rejection following organ transplantation, ■ inflammatory bowel disease (IBD) of whatever type, etiology, or pathogenesis, in particular inflammatory bowel disease that is a member selected from the group consisting of collagenous colitis, colitis polyposa, transmural colitis, ulcerative colitis and Crohn's disease (CD),

■ septic shock of whatever type, etiology, or pathogenesis, in particular septic shock that is a member selected from the group consisting of renal failure, acute renal failure, cachexia, malarial cachexia, hypophysial cachexia, uremic cachexia, cardiac cachexia, cachexia suprarenalis or Addison's disease, cancerous cachexia and cachexia as a consequence of infection by the human immunodeficiency virus (HIV), ■ liver injury,

■ pulmonary hypertension of whatever type, etiology or pathogenesis including primary pulmonary hypertension / essential hypertension, pulmonary hypertension secondary to congestive heart failure, pulmonary hypertension secondary to chronic obstructive pulmonary 'disease, pulmonary venous hypertension, pulmonary arterial hypertension and hypoxia-induced pulmonary hypertension,

^■ bone loss diseases, primary osteoporosis and secondary osteoporosis, ^■ central nervous system disorders of whatever type, etiology, or pathogenesis, in particular a central nervous system disorder that is a member selected from the group consisting of depression, Alzheimers disease, Parkinson's disease, learning and memory impairment, tardive dyskinesia, drug dependence, arteriosclerotic dementia and dementias that accompany Huntington's chorea, Wilson's disease, paralysis agitans, and thalamic atrophies, ■ infection, especially infection by viruses wherein such viruses increase the production of TNF-α in their host, or wherein such viruses are sensitive to upregulation of TNF-α in their host so that their replication or other vital activities are adversely impacted, including a virus which is a member selected from the group consisting of HIV-1 , HIV-2, and HIV-3, cytomegalovirus (CMV), influenza, adenoviruses and Herpes viruses including Herpes zoster and Herpes simplex, ■ yeast and fungus infections wherein said yeast and fungi are sensitive to upregulation by TNF-α or elicit TNF-α production in their host, e.g., fungal meningitis, particularly when administered in conjunction with other drugs of choice for the treatment of systemic yeast and fungus infections, including but are not limited to, polymixins, e.g. Polymycin B, imidazoles, e.g. clotrimazole, econazole, miconazole, and ketoconazole, triazoles, e.g. fluconazole and itranazole as well as amphotericins, e.g. Amphotericin B and liposomal Amphotericin B, ■ ischemia-reperfusion injury, ischemic heart disease, autoimmune diabetes, retinal autoimmunity, chronic lymphocytic leukemia, HIV infections, lupus erythematosus, kidney and ureter disease, urogenital and gastrointestinal disorders and prostate diseases, ■ reduction of scar formation in the human or animal body, such as scar formation in the healing of acute wounds, and ■ psoriasis, other dermatological and cosmetic uses, including antiphlogistic, skin-softening, skin elasticity and moisture-increasing activities.

According to one aspect the present invention relates in particular to the treatment of a respiratory disease, such as adult respiratory distress syndrome (ARDS), bronchitis, chronic obstructive pulmonary disease (COPD), cystic fibrosis, asthma, emphysema, bronchiectasis, chronic sinusitis and rhinitis.

According to another aspect the present invention relates in particular to the treatment of gastrointestinal (Gl) disorders, in particular inflammatory bowel diseases (IBD) such as Crohn's disease, ileitis, collagenous colitis, colitis polyposa, transmural colitis and ulcerative colitis.

According to a further aspect the present invention relates also to the reduction of scars formation.

A still further aspect of the present invention also relates to the use of the nicotinamide derivatives of formula (1 ), their pharmaceutically acceptable salts and/or derived forms, for the manufacture of a drug having a PDE4 inhibitory activity. In particular, the present inventions concerns the use of the nicotinamide derivatives of formula (1 ), their pharmaceutically acceptable salts and/or derived forms, for the manufacture of a drug for the treatment of inflammatory, respiratory, allergic and scar-forming diseases, disorders, and conditions, and more precisely for the treatment of diseases, disorders, and conditions that are listed above.

As a consequence, the present invention provides a particularly interesting method of treatment of a mammal, including a human being, with a PDE4 inhibitor including treating said mammal with an effective amount of a nicotinamide derivative of formula (1 ), its pharmaceutically acceptable salts and/or derived forms. More precisely, the present invention provides a particularly interesting method of treatment of a mammal, including a human being, to treat an inflammatory, respiratory, allergic and scar-forming disease, disorder or condition, including treating said mammal with an effective amount of a nicotinamide derivative of formula (1 ), its pharmaceutically acceptable salts and/or derived forms.

The following examples illustrate the preparation of the nicotinamide derivatives of the formula (1 ) : EXAMPLES AND PREPARATIONS

Melting points were determined using open glass capillary tubes and a Gallenkamp melting point apparatus and are uncorrected. Nuclear magnetic resonance (NMR) data were obtained using Varian Unity lnova-400, Varian Unity lnova-300 or Bruker AC300 spectrometers and are quoted in parts per million from tetramethylsilane. Mass spectral (MS) data were obtained on a Finnigan Mat. TSQ 7000 or a Fisons Instruments Trio 1000. The calculated and observed ions quoted refer to the isotopic composition of lowest mass. Infra red (IR) spectra were measured using a Nicolet Magna 550 Fourier transform infra-red spectrometer. Flash chromatography refers to column chromatography on silica gel (Kieselgel 60, 230-400 mesh, from E. Merck, Darmstadt. Kieselgel 60 F₂₅₄ plates from E. Merck were used for TLC, and compounds were visualised using UV light, 5% aqueous potassium permanganate or Dragendorff's reagent (oversprayed with aqueous sodium nitrite). Thermal analyses by Differential Scanning Calorimetry (DSC) and ThermoGravimetric Analysis (TGA) were obtained using Perkin Elmer DSC7 and TGA7. Moisture sorption characteristics were recorded using Surface Measurement Systems Ltd. Automated Water Sorption Analyser DVS 1. Water content was determined on a Mitsubishi CA100 (Coulometric Karl Fisher Titrator). Powder X-ray diffraction (PXRD) pattern was determined using a Siemens D5000 powder X-ray diffractometer fitted with an automatic sample changer, a theta-theta goniometer, automatic beam divergence slits, a secondary monochromator and a scintillation counter. Other measurements were taken using standard equipment. Hexane refers to a mixture of hexanes (hplc grade) b.p. 65-70°C. "Ether" and "Et₂O" refers to diethyl ether. Acetic acid refers to glacial acetic acid. 1-Hydroxy-7-aza-1 H-1,2,3-benzotriazole (HOAt). "HOBt" is 1- hydroxy-1H-1 ,2,3-benzotriazole. N-[(dimethylamino)-1 H-1 ,2,3-triazolo[4,5-b]pyridin-1- ylmethylene]-N-methylmethaninium hexafluorophosphate N-oxide (HATU) and 7- azabenzotriazol-1 -yloxytris(pyrrolidino)phosphonium hexafluorophosphate (PyAOP) were purchased from PerSeptive Biosystems U.K. Ltd. "DIPE" refers to diisopropyl ether. Reverse-phase silica gel for flash chromatography was obtained from Fluka (Fluka 100, Cι₈, 40-63μ). "DCM" is dichloromethane. "THF" is tetrahydrofuran. "WSCDI" is 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride. EtOAc" is ethyl acetate. "MeOH" is methanol. "DMSO" is dimethylsulphoxide. "ACE-CI" is 1- chloroethyl chloroformate. "NMM" is N-methylmorpholine. "Pentane" refers to High Performance Liquid Chromatography (HPLC) grade n-pentane (b.pt.35-37°C). Nomenclature has been allocated using the commercially available ACD program. Standard abbreviations are used throughout, e.g. "Me" is methyl, "Et" is ethyl, "Pr" is propyl, "Ph" is phenyl, etc. ^aHPLC autopurification performed using 2 columns - Phenomenex LUNA C8 150x21.2mm, 10μm and Phenomenex MAGELLEN C18 150x21.2mm, 5μm, eluting with a gradient system of organic solvent [ammonium acetate (aq) 100mM : acetonitrile (1 : 9)] : aqueous solvent [ammonium acetate (aq) 100mM : acetonitrile (9 : 1 )]

^b HPLC autopurification performed using 2 columns - Phenomenex LUNA C8 150x21.2mm, 10μm and Phenomenex MAGELLEN C18 150x21.2mm, 5μm, eluting with a gradient system of organic solvent ( acetonitrile) : aqueous solvent (0.1% aqueous trifluoroacetic acid)

Preparation 1

1-Methoxy-3-methylsulfanyl-benzene

Methyl iodide (14.67ml, 0.235mol) was added dropwise to a solution of 3-methoxy- benzenethiol (30g, 0.214mol) and potassium carbonate (29.6g, 0.214mol) in acetone (400ml) under nitrogen at 3°C. The reaction was allowed to warm to room temperature and the solvent was removed under reduced pressure. The residue was diluted with water (300ml) and the aqueous layer was extracted with diethylether (3x200ml). The combined organic extracts were dried over MgSO₄ and the solvent was removed under reduced pressure to give 1-Methoxy-3-methylsulfanyl-benzene (32.87g) as a pale yellow liquid. ¹H NMR (400MHz, CDCI₃): δ- 7.17-7.21 (1 H, t), 6.83-6.86 (1 H, d), 6.81 (1 H, s), 6.65- 6.69 (1 H, m), 3.80 (3H, s), 2.46 (3H, s) ppm.

Preparation 2

3-Methylsulfanyl-phenol

1-Methoxy-3-methylsulfanyl-benzene (32.87g, 0.213mol) was dissolved in a mixture of 30% hydrogen bromide in acetic acid (96ml) and 48% aqueous hydrobromic acid (24ml). The reaction was heated to reflux, and stirred at this temperature under nitrogen for 5.5h. After cooling to room temperature the reaction mixture was poured into water (600ml) and extracted with diethylether (3x300ml). The combined organic extracts were washed with water (2x150ml), brine (100ml), dried over MgSO and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with a solvent gradient of ethyl acetate : pentane (1 : 19 changing to 3 : 37 then 1 : 9, by volume) and the product was azeotroped with toluene (2x100ml) to give 3-Methylsulfanyl-phenol (19.3g) as a crimson oil.

¹H NMR (400MHz, CDCI₃): δ = 7.10-7.20 (1 H, t), 6J7-6.84 (1 H, d), 6J4 (1 H, s), 6.55-6.63 (1 H, d), 4.65-4.83 (1 H, brs), 2.43 (3H, s) ppm. Preparation 3

5-Fluoro-2-(3-methylsulfanyl-phenoxy)-nicotinic acid ethyl ester

Ethyl 2-chloro-5-fluoro-nicotinate (J. Med. Chem. 1993, 36, 2676, M.Winn et. al.) (5.02g, 24Jmmol), 3-methylsulfanylphenol (3.5g, 25mmol) and caesium carbonate (8.13g, 25mmol) were suspended in dioxan (50ml) and the reaction was heated to 100°C and stirred at this temperature under nitrogen for 8h. The reaction was cooled to room temperature, filtered and the solid washed with ethyl acetate (50ml). The filtrate was concentrated under reduced pressure, and the residue was purified by flash column chromatography on silica gel eluting with pentane : ethyl acetate (90 : 10, by volume) and the product was triturated with pentane (10ml) to give 5-fluoro-2- (3-methylsulfanyl-phenoxy)-nicotinic acid ethyl ester (3.46g) as a white solid.

¹H NMR (400MHz, CDCI₃): δ = 8.14-8.16 (1 H, d), 7.98-8.02 (1 H, dd), 7.26-7.31 (1 H, t), 7.07-7.11 (1 H, d), 7.01 (1 H, s), 6.87-6.91 (1 H, d), 4.37-4.42 (2H, quart), 2.46 (3H, s), 1.37-1.41 (3H, t) ppm.

LRMS (electrospray) : m/z [M+H]⁺ 308, [M+NH₄]⁺ 325, [2M+H]⁺ 615.

Anal. Found C, 58.29; H, 4.54; N, 4.53. C₁₅H₁₄FNO₃S requires C, 58.62; H, 4.54; N, 4.56%.

Preparation 4

5-FIuoro-2-(3-methylsulfanyl-phenoxy)-nicotinic acid

5-Fluoro-2-(3-methylsulfanyl-phenoxy)-nicotinic acid ethyl ester (3.07g, lOmmol) was dissolved in tetrahydrofuran (40ml) and 1M lithium hydroxide solution (25ml, 25mmol) was added. The reaction was stirred at room temperature for 18h and the tetrahydrofuran was removed under reduced pressure. 2N HCl (12.5ml) was added and the resulting precipitate was isolated by filtration and washed with water (3x50ml). The wet paste was dissolved in dichloromethane (50ml), dried over MgSO and the solvent was removed under reduced pressure. The residue was triturated with diisopropylether (15ml) to give 5-fluoro-2-(3-methylsulfanyl-phenoxy)- nicotinic acid (2.63g) as a white solid.

¹H NMR (400MHz, CDCI₃): δ= 8.18-8.24 (2H, m), 7.32-7.38 (1 H, t), 7.13-7.18 (1H, d), 7.05 (1H, s), 6.89-6.94 (1H, d), 2.47 (3H, s) ppm.

LRMS (thermospray) : m/z [M+H]⁺ 280.

Anal. Found C, 55.65; H, 3.57; N, 4.68. Cι₃H₁₀FNO₃S requires C, 55.90; H, 3.61; N, 5.02%.

Preparation 5

tert-butyl 1 -acetyl-3-pyrrolidinylcarbamate

To an ice-cooled solution of racemic tert-butyl 3-pyrrolidinylcarbamate (10.0g) in methylene chloride (100ml) and triethylamine (9.0 ml) was added slowly, acetyl chloride (4.5 ml). The mixture was allowed to warm to RT and stirred for 14h, diluted with methylene chloride (100ml), washed with dil. hydrochloric acid (100ml) and brine (100ml). After drying over MgSO₄, the solvent removed in vacuo to afford the title compound as a pale brown syrup which crystallised upon standing (11.5g).

¹H NMR (400MHz, CDCI₃): δ = 4.65-4.5 (1 H, br m), 4.25-4.1 (1 H, br m), 3J-3.6 (1 H, m), 3.55-3.4 (2H, m), 3.3-3.2 (1 H, m), 2.2-2.0 (1 H, m), 2.0 (3H, app. d), 2.0-1 J (1 H, m), 1.4 (9H, s) ppm.

LRMS (thermospray) : m/z [M+H]⁺ 229, [M+NH₄f 246, [2M+H]⁺ 457.

Anal. Found C, 57.81 ; H, 8.85; N, 12.28. CnH₂₀N₂O₃ requires C, 57.87; H, 8.83; N, 12.27%.

Preparation 6

tert-butyl 1 -propionyl-3-pyrrolidinylcarbamate

The title compound was prepared using the method of te/t-butyl 1-acetyl-3- pyrrolidinylcarbamate using propionyl chloride. Trituration with diethyl ether afforded a white solid (22.25g, 86%).

¹H NMR (400MHz, CDCI₃): (5= 4.65-4.55 (1 H, br m), 4.25-4.1 (1 H, br m), 3.7-3.6 (1 H, m), 3.56-3.4 (2H, m), 3.35-3.2 (1 H, m), 2.2 (2H, q), 2.2-2.0 (1 H, m), 1.95-1.85 (0.5H, m), 1.8-1.7 (0.5H, m), 1.4 (9H, s), 1.2 (3H, app dt) ppm.

LRMS (thermospray) : m/z [M+H]⁺ 243, [2M+H]⁺ 485.

Anal. Found C, 59.43; H, 9.17; N, 11.50. C₁₂H₂₂N₂O₃ requires C, 59.48; H, 9.15; N, 11.56%.

Preparation 7

tert-butyl 1-isobutyryl-3-pyrrolidinylcarbamate

The title compound was prepared using the method of tert-butyl 1-acetyl-3- pyrrolidinylcarbamate using isobutyryl chloride. Trituration with diethyl ether afforded a white solid (24.05g, 88%).

¹H NMR (400MHz, CDCI₃): δ = 4.55-4.5 (1 H, br m), 4.2-4.15 (1 H, br m), 3.7-3.6 (1 H, m), 3.6-3.4 (2H, m), 3.35-3.3 (1 H, m), 2.55-2.5 (1H, m), 2.2-2.0 (1 H, m), 1.95-1.85 (0.5H, m), 1.8-1.65 (0.5H, m), 1.4 (9H, s), 1.1 (6H, app dt) ppm.

LRMS (thermospray) : m/z [M+H]⁺ 257.

Anal. Found C, 60.90; H, 9.54; N, 10.95. Cι₃H₂₄N₂O₃ requires C, 60.91 ; H, 9.44; N, 10.93%.

Preparation 8

tert-butyl 1 -(3-methylbutanoyl)-3-pyrroIidinylcarbamate

The title compound was prepared using the method of tert-butyl 1-acetyl-3- pyrrolidinylcarbamate using isovaleryl chloride. Trituration with diethyl ether afforded a white solid (24.62g, 85%).

¹H NMR (400MHz, CDCI₃): δ = 4.65-4.5 (1 H, br m), 4.2-4.1 (1 H, br m), 3.7-3.6 (1 H, m), 3.6-3.4 (2H, m), 3.3-3.2 (1 H, m), 2.2-2.05 (4H, m), 1.95-1.85 (0.5H, m), 1.8-1.7 (0.5H, m), 1.4 (9H, s), 0.9 (6H, d) ppm.

LRMS (thermospray) : m/z [M+H]⁺ 271. Anal. Found C, 62.23; H, 9.88; N, 10.37. Cι₄H₂₆N₂O₃ requires C, 62.19; H, 9.69; N, 10.36%.

Preparation 9

1-acetyl-3-pyrrolidinamine

To a stirred solution of tert-butyl 1-acetyl-3-pyrrolidinylcarbamate (20.6g, 90mmol) in methylene chloride (50ml) at RT was added trifluoroacetic acid (25 ml). After 14h, the reaction mixture was concentrated in vacuo and azeotroped with toluene twice to yield a pale yellow oil. This was taken up in water (100ml), basified with solid Na₂CO₃ and passed through a Dowex™ 50W8 ion exchange column eluting with water (11), then 5% aq. ammonium hydroxide (21). The appropriate fractions were freeze-dried and azeotroped with methylene chloride to afford a yellow oil (11.10g, 86.7mmol)

¹H NMR (400MHz, CDCI₃): δ = 3.55-3.5 (3H, m), 3.45-3.4 (1 H, m), 3.15 (0.5H, q), 3.05 (0.5H, q), 2.15-2.0 (1 H, m), 2.0 (3H, s), 1.8-1.6 (1 H, m), 1.3-1.1 (2H, br s) ppm.

LRMS (thermospray) : m/z [2M+H]⁺ 257.

Anal. Found C, 54.57; H, 9.41 ; N, 20.95. C₆H₁₂N₂O.0.2H₂O requires C, 54.69; H, 9.48; N, 21.26%. Preparation 10

1 -propionyl-3-pyrrolidinamine

The title compound was prepared following the method of 1-acetyl-3-pyrrolidinamine as a colourless oil (9.0g, 69%).

¹H NMR (400MHz, CDCI₃): δ = 3.65-3.5 (3H, m), 3.45-3.35 (1 H, m), 3.15 (0.5H, q), 3.05 (0.5H, q), 2.2 (2H, q), 2.1-2.0 (1 H, m), 1.75-1.65 (0.5H, m), 1.6-1.55 (0.5H, m), 1.4 (2H, br s), 1.1 (3H, t) ppm.

LRMS (thermospray) : m/z [2M+H]⁺ 285.

Anal. Found C, 57.58; H, 10.12; N, 19.13. C₇H₁₄N₂O.0.2H₂O requires C, 57.66; H, 9.95; N, 19.21%.

Preparation 11

1 -isobutyryl-3-pyrrolidinamine

The title compound was prepared following the method of 1-acetyl-3-pyrrolidinamine as a brown oil (1 1.64g, 89%). ¹H NMR (400MHz, CDCI₃): δ = 3.65-3.5 (3H, m), 3.5-3.4 (1 H, m), 3.2-3.15 (1 H, m), 2.65-2.5 (1 H, m), 2.1-1.95 (1 H, m), 1.75-1.65 (0.5H, m), 1.6-1.55 (0.5H, m), 1.2 (1 H, br s), 1.1 (6H, dd) ppm.

LRMS (thermospray) : m/z [M+H]⁺ 157, [2M+H]⁺ 313.

Anal. Found C, 59.90; H, 10.36; N, 17.33. C₈Hι₅N₂O.0.2H₂O requires C, 60.12; H, 10.34; N, 17.53%.

Preparation 12

1-(3-methylbutanoyl)-3-pyrrolidinamine

The title compound was prepared following the method of 1-acetyl-3-pyrrolidinamine as a brown oil (12.44g, 84%).

¹H NMR (400MHz, CDCI₃): δ = 3.65-3.5 (3H, m), 3.5-3.4 (1 H, m), 3.2-3.1 (0.5H, m), 3.1-3.0 (0.5H, m), 2.2-1.9 (4H, m), 1.75-1.65 (0.5H, m), 1.65-1.55 (0.5H, m), 1.2 (2H, br s), 0.9 (6H, d) ppm.

LRMS (thermospray) : m/z [M+Hf 171 , [2M+H]⁺ 341.

Anal. Found C, 61.65; H, 10.64; N, 15.95. C₉H₁₇N₂O.0.3H₂O requires C, 61.54; H, 10.67; N, 15.95%. Preparation 13

tert-butyl 4-{[(2-chloro-5-fluoro-3-pyridinyI)carbonyl]amino}-1- piperidinecarboxylate

Carbonyl diimidazole (2.8g, 17.3mmol) was added to a solution of 2-chloro-5- fluoronicotinic acid (3.0g, 17.1 mmol) in dimethylformamide (30ml). The mixture was stirred for 1 h, then tert-butyl 4-aminopiperdinylcarbamate (3.8g, 19.0mmol) was added. The reaction was stirred under nitrogen at room temperature for 18h, the solvent removed under reduced pressure and the residue was partitioned between 10% aqueous citric acid solution (200m) and ethyl acetate (200ml). The organic phase was washed with water and saturated sodium bicaronate solution, dried over MgSO₄ and the solvent was removed under reduced pressure to give the title compound (4.4g) as a white solid.

¹H NMR (400MHz, CDCI₃): δ = 8.33-8.36 (1 H, m), 7.84-7.88 (1 H, m), 6.40-6.48 (1 H, m), 3.92-4.20 (3H, m), 2.90-3.05 (2H, t), 1.97-2.07 (2H, m), 1.40-1.55 (11 H, m) ppm.

LRMS (electrospray) : m/z [M+Na]⁺ 380

Anal. Found C, 53.91 ; H, 6.01 ; N, 11.70. C₁₆H₂₁CIFN₃O₃ requires C, 53.71 ; H, 5.92; N, 11.74%.

Preparation 14

2-[3-(methylsulfanyl)benzyl]-/V-(4-piperidinyl)nicotinamide

Methane sulphonic acid (145μl, 2.24mmol) was added to a solution of tert-butyl 4- [({2-[3-(methylsulfanyl)benzyl]-3-pyridinyl}carbonyl)amino]-1-piperidinecarboxylate (200mg, 0.56mmol) in dichloromethane (5ml) at 0°C. The mixture was warmed to ambient temperature and stirred for 2h. The solvent removed under reduced pressure to give 2-[3-(methylsulfanyl)benzyl]-Λ/-(4-piperidinyl)nicotinamide which was used in the next step without further purification

¹H NMR (400MHz, CDCI₃): δ = 8.35-8.40 (1 H, m), 7.84-7.90 (1 H, m), 4.10-4.20 (1 H, m), 3.08-3.20 (2H, t), 2.17-2.28 (2H, m), 1.78-1.92 (2H, m) ppm.

LRMS (electrospray) : m/z [M+H]⁺ 258

Preparation 15

Λ/-(1-acetyl-4-piperidinyl)-2-[3-(methylsulfanyl)benzyl]nicotinamide

To a solution of 2-[3-(methylsulfanyl)benzyl]-Λ/-(4-piperidinyl)nicotinamide , triethylamine (623μl, 4.5mmol) and 4-Λ/,Λ/-dimethylaminopyridine (5mg) in dichloromethane (5ml) was added acetyl chloride (60μl, 0.84mmol) at 0°C. The reaction mixture was warmed to ambient temperature then stirred for 2h. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography using dichloromethane:methanol:0.880 ammonia (98:2:0.2 to 91 :9:0.9) as eluant to give A/-(1-acetyl-4-piperidinyl)-2-[3-

(methylsulfanyl)benzyl]nicotinamide (147mg).

¹H NMR (400MHz, CDCI₃): δ = 8.30-8.35 (1 H, m), 7.85-7.90 (1 H, m), 6.45-6.55 (1 H, m), 4.48-4.56 (1 H, m), 4.16-4,26 (1 H, m), 3.77-3.85 (1 H, m), 3.20-3.30 (1 H, t), 2.80- 2.90 (1 H, t), 2.03-2.25 (4H, m+s), 1.42-1.55 (2H, m) ppm.

LRMS (electrospray) : m/z [M+Na]⁺ 322

Preparation 17

2-fluoro-4-(methylsulfanyl)phenol

A stirred solution of 2-fluoro-1-methoxy-4-(methylsulfanyl)benzene (2.0g, 11.6mmol) in methylene chloride (80ml) at 0°C was treated slowly with boron tribromide (1 M in CH₂CI₂, 23ml, 23mmol), after which it was allowed to warm to RT. A further portion of BBr₃ was added (1 M, 10ml, 10mmol) and the reaction mixture allowed to stand at RT overnight. After cooling to 0°C, the reaction mixture was cautiously quenched with a solution of diethanolamine (10ml) in methylene chloride (40ml), partioned between methylene chloride and 2N HCl, and the organic phase separated, and washed with water and brine. After drying over Na₂SO₄, the organics were concentrated in vacuo. The title compound was isolated following purification by flash column chromatography on silica gel eluting with a solvent gradient cyclohexane to 20% ethanol:cyclohexane to afford a brown oil (1.63g, 10.3mmol).

¹H NMR (400MHz, CDCI₃): δ = 7.1-6.9 (3H, m), 5.1 (1 H, s), 2.4 (3H, s) ppm. Preparation 18

2-[(cyclopropylmethyl)sulfanyl]phenol

A solution of 2-hydroxythiophenol (25.65g, 0.2mol) in ethanol (30ml) was added to a stirred solution of sodium hydroxide (8g, 0.2mol) in ethanol (100ml) over 10mins. After stirring for 20mins at RT, cyclopropylmethylbromide (27.5g, 0.2mol) was added over 5mins and the mixture heated to reflux for 15mins. After cooling, the suspension was filtered to remove a white solid and the filtrate concentrated to a brown oil which was partioned between diethylether (100ml) and water (100ml) with aq HCl (5.6M, 10ml). The ethereal phase was removed, dried over MgSO4 and condensed to a brown oil which distilled. The fraction boiling at 132-134°C (13- 14mmHg) was collected to afford the title compound as a pale yellow oil (22.39g, 0.12mol).

Anal. Found C, 66.51 ; H, 6.75. Cι₀H₁₂OS requires C, 66.63; H, 6.71.

IR (film) 3380 cm^"1 (OH)

Preparation 19

(2-amino-3-pyridinyl)methanol

Lithium aluminium hydride (1 M in THF, 43ml, 43mmol) in dry diethyl ether (65ml) was treated with a slurry of ethyl 2-aminonicotinate (6.53g, 39.3mmol) in ether (50ml) dropwise over 1/2h maintaining T < 15°C. The resultant heterogeneous mixture was stirred at RT for 1 h, cooled in ice, and quenched with ethyl acetate (caution: dropwise addition), then water. After removal of the solvent in vacuo, the solid was extracted with hot acetone to afford a mobile oil after evaporation. Crystallisation from diisopropyl ether gave the title compound as fine needles (3.75g, 30.2mmol).

¹H NMR (300MHz, CDCI₃): δ = 8.0 (1 H, dd), 7.25 (1 H, dd), 6.5 (1 H, dt), 5.0 (2H, br s), 4.6 (2H, s), 2.0 (1 H, br s) ppm.

LRMS (thermospray) : m/z [M+H]⁺ 125.

Preparation 20

3-ethoxy-2-pyridinamine

Hydrogenation of 3-ethoxy-2-nitropyridine (5.0g, 30mmol) in ethanol (150ml) was effected over PtO₂ in a Parr bottle at 40°C over hydrogen (50psi) for 3h. The catalyst was removed by filtration, and the solvent removed in vacuo to give a brown gum which was extracted with boiling pentane to afford the title compound as a white solid (3.1 g, 22mmol).

mp 84°C EXAMPLES

Example 1

N-(1-Acetyl-pyrrolidine-3-yl)-5-fluoro-2-(3-methylsulfanyl-phenoxy)- nicotinamide

Carbonyldiimidazole (64mg, 0.393mmol) was added to a suspension of 5-fluoro-2-(3- methylsulfanyl-phenoxy)-nicotinic acid (100mg, 0.358mmol) in dichloromethane (1.5ml) under nitrogen at room temperature. The resulting solution was stirred for 15min after which a solution of 1-(3-amino-pyrrolidin-1-yl)-ethanone (51 mg, 0.393mmol) and 4-dimethylaminopyridine (2mg, 0.02mmol) in dichloromethane (1.5ml) was added. The reaction was stirred at room temperature for 4h then quenched with sat. ammonium chloride solution (0.5ml) and diluted with dichloromethane (5ml). The mixture was then passed through a phase separation cartridge, and the solvent was removed from the organic phase under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with a solvent gradient of dichloromethane : methanol (99 : 1 changing to 98 : 2, by volume) to give N-(1-Acetyl-pyrrolidine-3-yl)-5-fluoro-2-(3-methylsulfanyl- phenoxy)-nicotinamide (50mg) as an off-white solid which was a mixture of rotamers.

¹H NMR (400MHz, CDCI₃): δ = 8.28-8.33 (1 H, m), 8.03-8.06 (1 H, m), 7.97-8.01 (0.5H, d), 7.90-7.95 (0.5H, d), 7.30-7.37 (1 H, m), 7.12-7.16 (1 H, d), 6.95-6.99 (1 H, m), 6.81-6.86 (1 H, t), 4.62-472 (1 H, m), 3.76-3.88 (1 H, 2xm), 3.55-3.61 (1 H, t), 3.48- 3.55 (1 H, t), 3.37-3.47 (1 H, m), 2.47 (3H, s), 2.32-2.41 (0.5H, m), 2.21-2.32 (0.5H, m), 1.97-2.08 (3.5H, 2xs + m), 1.83-1.95 (0.5H, m) ppm. LRMS (electrospray) : m/z [M+Na]⁺ 412, [M-H]⁺ 388

Example 2

5-Fluoro-2-(3-methyIsulfanyl-phenoxy)-N-(1-propionyl-pyrrolidin-3-yl)- nicotinamide

Carbonyldiimidazole (64mg, 0.393mmol) was added to a suspension of 5-fluoro-2-(3- methylsulfanyl-phenoxy)-nicotinic acid (100mg, 0.358mmol) in dichloromethane

(1.5ml) under nitrogen at room temperature. The resulting solution was stirred for

15min after which a solution of 1-(3-amino-pyrrolidin-1-yl)-propionone (56mg,

0.393mmol) and 4-dimethylaminopyridine (2mg, 0.02mmol) in dichloromethane

(1.5ml) was added. The reaction was stirred at room temperature for 4h then quenched with sat. ammonium chloride solution (0.5ml) and diluted with dichloromethane (5ml). The mixture was then passed through a phase separation cartridge, and the solvent was removed from the organic phase under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with a solvent gradient of dichloromethane : methanol (99 : 1 changing to 98 : 2, by volume) to give N-(1-Acetyl-pyrroiidine-3-yl)-5-fluoro-2-(3-methylsulfanyl- phenoxy)-nicotinamide (101 mg) as an off-white solid which was a mixture of rotamers.

¹H NMR (400MHz, CDCI₃): δ = 8.29-8.32 (1 H, dd), 8.03-8.05 (1 H, m), 7.95-8.00 (0.5H, d), 7.78-7.93 (0.5H, d), 7.29-7.36 (1 H, m), 7.14-7.18 (1 H, d), 6.96-6.99 (1 H, m), 6.81-6.86 (1 H, t), 4.63-4.71 (1 H, m), 3.77-3.85 (1 H, m), 3.56-3.61 (1 H, t), 3.44- 3.53 (1.5H, m), 3.37-3.43 (0.5H, m), 2.47 (3H, s), 2.30-2.41 (0.5H, m), 2.16-2.29 (2.5H, m), 2.00-2.12 (0.5H, m), 1.85-1.95 (0.5H, m), 1.06-1.11 (3H, m) ppm.

LRMS (electrospray) : m/z [M+Na]⁺ 426, [M-H]⁺ 402

Example 3

5-Fluoro-N-(1-isobutyryl-pyrrolidin-3-yl)-2-(3-methylsulfanyl-phenoxy)- nicotinamide

Carbonyldiimidazole (64mg, 0.393mmol) was added to a suspension of 5-fluoro-2-(3- methylsulfanyl-phenoxy)-nicotinic acid (100mg, 0.358mmol) in dichloromethane (1.5ml) under nitrogen at room temperature. The resulting solution was stirred for 15min after which a solution of 1-(3-amino-pyrrolidin-1-yl)-2-methyl-propan-1-one (62mg, 0.393mmol) and 4-dimethylaminopyridine (2mg, 0.02mmol) in dichloromethane (1.5ml) was added. The reaction was stirred at room temperature for 4h then quenched with sat. ammonium chloride solution (0.5ml) and diluted with dichloromethane (5ml). The mixture was then passed through a phase separation cartridge, and the solvent was removed from the organic phase under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with a solvent gradient of dichloromethane : methanol (99 : 1 changing to 98 : 2, by volume) to give N-(1-Acetyl-pyrrolidine-3-yl)-5-fluoro-2-(3-methylsulfanyl- phenoxy)-nicotinamide (110mg) as an off-white solid which was a mixture of rotamers. ¹H NMR (400MHz, CDCI₃): δ = 8.29-8.33 (1 H, dd), 8.04-8.07 (1 H, t), 7.94-8.00 (0.5H, d), 7.90-7.94 (0.5H, d), 7.28-7.35 (1H, m), 7.12-7.16 (1 H, d), 6.94-6.99 (1H, m), 6.80- 6.86 (1H, t), 4.63-472 (1 H, m), 3.85-3.92 (0.5H, m), 375-3.81 (0.5H, m), 3.55-3.61 (2H, t), 3.43-3.51 (1H, m), 2.50-2.61 (1H, m), 2.45 (3H, s), 2.30-2.42 (0.5H, m), 2.20- i 2.30 (0.5H, m), 2.01-2.10 (0.5H, m), 1.84-1.96 (0.5H, m), 1.06-1.12 (3H, m), 0.98- 1.06 (3H, 2xd) ppm.

LRMS (electrospray) : m/z [M+Na]⁺ 440, [M-H]⁺ 416

Example 4

5-Fluoro-N-[1-(3-methyl-butyryl)-pyrrolidin-3-yl]-2-(3-methylsulfanyl-phenoxy)- nicotinamide

Carbonyldiimidazole (64mg, 0.393mmol) was added to a suspension of 5-fluoro-2-(3- methylsulfanyl-phenoxy)-nicotinic acid (100mg, 0.358mmol) in dichloromethane (1.5ml) under nitrogen at room temperature. The resulting solution was stirred for 15min after which a solution of 1-(3-amino-pyrrolidin-1-yl)-3-methyl-butan-1-one (67mg, 0.393mmol) and 4-dimethylaminopyridine (2mg, 0.02mmol) in dichloromethane (1.5ml) was added. The reaction was stirred at room temperature for 4h then quenched with sat. ammonium chloride solution (0.5ml) and diluted with dichloromethane (5ml). The mixture was then passed through a phase separation cartridge, and the solvent was removed from the organic phase under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with a solvent gradient of dichloromethane : methanol (99 : 1 changing to 98 : 2, by volume) to give N-(1-Acetyl-pyrrolidine-3-yl)-5-fluoro-2-(3-methylsulfanyl- phenoxy)-nicotinamide (104mg) as an off-white solid which was a mixture of rotamers.

¹H NMR (400MHz, CDCI₃): δ = 8.30-8.33 (1 H, dd), 8.02-8.05 (1 H, m), 7.96-8.00 (0.5H, d), 7.90-7.95 (0.5H, d), 7.28-7.36 (1 H, m), 7.10-7.16 (1 H, d), 6.95-6.99 (1 H, m), 6.80-6.85 (1 H, t), 4.62-470 (1 H, m), 3.82-3.87 (0.5H, m), 377-3.82 (0.5H, m), 3.56-3.61 (2H, t), 3.38-3.55 (2H, 2xm), 2.44 (3H, s), 2.30-2.40 (0.5H, m), 2.19-2.29 (0.5H, m), 2.01-2.18 (2.5H, m), 1.85-1.96 (0.5H, m), 0.83-0.96 (6H, m) ppm.

LRMS (electrospray) : m/z [M+Na]⁺ 454, [M-H]⁺ 430

Example 5

5-Fluoro-2-(3-methylsulfanyl-phenoxy)-N-piperidin-4-yl-nicotinamide

Trifluoroacetic acid (25ml) was added to a solution of 4-{[5-fluoro-2-(3-methylsulfanyl- phenoxy)-pyridin-3-carbonyl]-amino}-piperidine-1-carboxylic acid tert-butyl ester (2.3g, 4.99mmol) and in dichloromethane (25ml) and the reaction was stirred under nitrogen at room temperature for 2h. The solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate (100ml) and sat. sodium bicarbonate solution (100ml). The organic phase was removed, washed with water (50ml), brine (50ml), dried over MgSO₄ and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with a solvent gradient of dichloromethane : methanol : concentrated aqueous ammonia (95 : 5 : 0.5 changing to 85 : 15 : 1.5, by volume) to give 5-Fluoro- 2-(3-methylsulfanyl-phenoxy)-N-piperidin-4-yl-nicotinamide (110mg) as an off-white solid. ¹H NMR (400MHz, CD₃OD): δ = 8.08-8.10 (1 H, d), 7.97-8.00 (1 H, m), 7.27-7.32 (1 H, t), 7.11-7.15 (1 H, d), 7.04 (1 H, s), 6.84-6.88 (1 H, d), 4.03-4.13 (1 H, m), 3.20-3.30 (2H, m, partially masked by solvent), 2.88-2.98 (2H, m), 2.45 (3H, s), 2.03-2.13 (2H, m), 1.57-173 (2H, m) ppm.

LRMS (electrospray) : m/z [M+H]⁺ 362.

Anal. Found C, 54.18; H, 5.18; N, 10.26. Cι₈H₂₀FN₃O₂S. 0.6mol CH₂CI₂ requires C, 54.17; H, 5.18; N, 10.19%.

Example 6

5-Fluoro-N-(1-methyl-piperidin-4-yl)-2-(3-methylsulfanyl-phenoxy)-nicotinamide

37% Aqueous formaldehyde (33 μl, 0.404mmol) was added to a solution of 5-fluoro- 2-(3-methylsulfanyl-phenoxy)-N-piperidin-4-yl-nicotinamide (107mg, 0.269mmol) in dichloromethane (4ml) under nitrogen at room temperature and the reaction was stirred for 1 h. Sodium triacatoxyborohydride (125mg, 0.538mmol) was then added and the reaction was stirred at room temperature for 3h. The reaction was diluted with dichloromethane (5ml), quenched with sat. sodium bicarbonate solution (1 ml) and further diluted with water (3ml). The organic phase was removed, concentrated under reduced pressure and the residue was purified by flash column chromatography on silica gel eluting with dichloromethane : methanol : concentrated aqueous ammonia (98 : 2 : 0.2 changing to 90 : 10 : 1 , by volume) to give 5-fluoro-N- (1-methyl-piperidin-4-yl)-2-(3-methylsulfanyl-phenoxy)-nicotinamide (85mg) as an off- white solid.

¹H NMR (400MHz, CD₃OD): δ = 8.06-8.08 (1 H, d), 7.97-8.00 (1 H, m), 7.28-7.33 (1 H, t), 7.09-7.13 (1 H, d), 7.04 (1 H, s), 6.87-6.91 (1 H, d), 3.86-3.96 (1 H, m), 275-2.83 (2H, d), 2.45 (3H, s), 2.18-2.27 (5H, s + m), 1.93-2.00 (2H, m), 1.58-1.66 (2H, m) ppm.

LRMS (electrospray) : m/z [M+Hf 376, [M+Na]⁺ 398 ,[M-H]⁺ 374.

Anal. Found C, 59.27; H, 5.83; N, 9.91. Cι₉H₂₂FN₃O₂S. 0.1 mol H₂O. 0.15mol CH₂CI₂ requires C, 58.98; H, 5.82; N, 10.77%.

Example 7

5-Fluoro-N-(1-ethyl-piperidin-4-yl)-2-(3-methylsulfanyl-phenoxy)-nicotinamide

Acetaldehyde (25μl, 0.404mmol) was added to a solution of 5-fluoro-2-(3- methylsulfanyl-phenoxy)-N-piperidin-4-yl-nicotinamide (107mg, 0.269mmol) in dichloromethane (4ml) under nitrogen at room temperature and the reaction was stirred for 1 h. Sodium triacatoxyborohydride (125mg, 0.538mmol) was then added and the reaction was stirred at room temperature for 3h. The reaction was diluted with dichloromethane (5ml), quenched with sat. sodium bicarbonate solution (1 ml) and further diluted with water (3ml). The organic phase was removed, concentrated under reduced pressure and the residue was purified by flash column chromatography on silica gel eluting with dichloromethane : methanol : concentrated aqueous ammonia (98 : 2 : 0.2 changing to 90 : 10 : 1 , by volume) to give 5-fluoro-N- (1-ethyl-piperidin-4-yl)-2-(3-methylsulfanyl-phenoxy)-nicotinamide (20mg) as an off- white solid.

¹H NMR (400MHz, CD₃OD): δ = 8.07-8.09 (1 H, d), 7.97-8.00 (1 H, m), 7.27-7.33 (1 H, t), 7.09-7.13 (1 H, d), 7.04 (1 H, s), 6.86-6.90 (1 H, d), 3.90-3.96 (1 H, m), 2.83-2.92 (2H, m), 2.40-2.47 (5H, s + quart), 2.17-2.24 (2H, m), 1.95-2.02 (2H, m), 1.58-1.68 (2H, m), 1.05-1.12 (3H, t) ppm.

LRMS (electrospray) : m/z [M+H]⁺ 391 , [M+Na]⁺ 412 ,[M-H]⁺ 389.

HRMS : Found [M+H]⁺ 390.4612. C₂₀H₂₅FN₃O₂S requires 390.1646.

Example 8

5-Fluoro-N-[1-(2-hydroxy-ethyl)-piperidin-4-yl]-2-(3-methylsulfanyl-phenoxy)- nicotinamide

Glyceraldehyde dimer (27mg, 0.202mmol) was added to a solution of 5-fluoro-2-(3- methylsulfanyl-phenoxy)-N-piperidin-4-yl-nicotinamide (107mg, 0.269mmol) in dichloromethane (4ml) under nitrogen at room temperature and the reaction was stirred for 1 h. Sodium triacatoxyborohydride (125mg, 0.538mmol) was then added and the reaction was stirred at room temperature for 3h. The reaction was diluted with dichloromethane (5ml), quenched with sat. sodium bicarbonate solution (1 ml) and further diluted with water (3ml). The organic phase was removed, concentrated under reduced pressure and the residue was purified by flash column chromatography on silica gel eluting with dichloromethane : methanol : concentrated aqueous ammonia (98 : 2 : 0.2 changing to 90 : 10 : 1 , by volume) to give 5-Fluoro- N-[1-(2-hydroxy-ethyl)-piperidin-4-yl]-2-(3-methylsulfanyl-phenoxy)-nicotinamide (83mg) as an off-white solid.

¹H NMR (400MHz, CD₃OD): δ = 8.07-8.09 (1 H, d), 7.96-8.00 (1 H, dd), 7.23-7.35 (1 H, t), 7.10-7.14 (1H, d), 7.04 (1H, s), 6.85-6.91 (1H, d), 3.87-3.97 (1H, m), 3.62-3.66 (2H, t), 2.87-2.93 (2H, m), 2.48-2.55 (2H, t), 2.45 (3H, s), 2.24-2.32 (2H, m), 1.93- 2.00 (2H, d), 177-1.89 (2H, d) ppm.

LRMS (electrospray) : m/z [M+H]⁺ 406, [M+Na]⁺ 428 ,[M-H]⁺ 404.

Anal. Found C, 57.13; H, 5.74; N, 9.82. C₂₀H₂₄FN₃O₃S. 07mol H₂0 requires C, 57.46; H, 6.12; N, 10.05%.

Example 9

N-(1-Acetyl-piperidin-4-yl)-5-fluoro-2-(3-methylsulfanyl-phenoxy)-nicotinamide

5-Fluoro-2-(3-methylsulfanyl-phenoxy)-N-piperidin-4-yl-nicotinamide (107mg,

0.269mmol) and N,N-dimethylaminopyridine (5mg) were suspended in dichloromethane (4ml) under nitrogen at 0°C and triethylamine (83DI, 0.538mmol) was added followed by acetyl chloride (23μl, 0.296mmol). The reaction was allowed to warm to room temperature for 2h and was quenched with sat. sodium bicarbonate solution (1 ml). After diluting with water (4ml) the aqueous phase was extractred with dichloromethane (10ml) and the organic phase was removed and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with dichloromethane : methanol : concentrated aqueous ammonia (99 : 1 : 0.1 changing to 92 : 8 : 0.8, by volume) to give N-(1-Acetyl-piperidin-4-yl)-5- fluoro-2-(3-methylsulfanyl-phenoxy)-nicotinamide (82mg) as a white foam.

¹H NMR (400MHz, CD₃OD): δ = 8.08-8.10 (1 H, d), 7.97-8.00 (1 H, m), 7.28-7.34 (1 H, t), 7.10-7.14 (1 H, d), 7.04 (1 H, s), 6.86-6.90 (1 H, d), 4.30-4.38 (1 H, d), 4.09-4.19 (1 H, m), 3.80-3.88 (1H, d), 3.21-3.30 (1 H, m, partially masked by solvent), 2.86-2.94 (1 H, t), 2.45 (3H, s), 2.09 (3H, s), 1.94-2.08 (2H, m), 1.40-1.60 (2H, m) ppm.

LRMS (electrospray) : m/z [M+Na]⁺ 426, [2M+Na]⁺ 829 ,[M-H]⁺ 402.

Anal. Found C, 58.41 ; H, 5.49; N, 9.84. C₂₀H₂₂FN₃O₃S. 0.55mol H₂0 requires C, 58.11 ; H, 5.63; N, 10.16%.

Example 10

5-Fluoro-2-(3-methylsulfanyl-phenoxy)-N-[1-(3-pyridin-2-yl-propionyl)-piperidin- 4-yl]- nicotinamide

1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (91 mg, 0.479mmol), 1- hydroxybenzotriazole (47mg, 0.351 mmol) and 3-pyridinepropionic acid (72mg, 0.479mmol) were added to a solution of 5-fluoro-2-(3-methylsulfanyl-phenoxy)-N- piperidin-4-yl-nicotinamide (1 15mg, 0.319mmol) in dichloromethane (5ml) under nitrogen under room temperature and N-methylmorpholine (70 μl, 0.638mmol) was added. The reaction was stirred at room temperature for 18h. The reaction mixture was quenched with sat. ammonium chloride (1 ml) and diluted with dichloromethane (5ml) and water (1 ml). The organic phase was collected via a hydrophobic separation cartridge, concentrated under reduced pressure and the residue was purified by flash column chromatography on silica gel eluting with a solvent gradient of dichloromethane : methanol : concentrated aqueous ammonia (99 : 1 : 0.1 changing to 95 : 5 : 0.5, by volume) to give 5-fluoro-2-(3-methylsulfanyl-phenoxy)-N- [1-(3-pyridin-2-yl-propionyl)-piperidin-4-yl]- nicotinamide (167mg) as a yellow gum.

¹H NMR (400MHz, CD₃OD): δ = 8.42 (1H, s), 8.27-8.30 (1H, d), 8.08-8.10 (1H, d), 7.97-8.00 (1H, m), 772-776 (1H, d), 7.29-7.34 (2H, m), 7.08-7.13 (1H, d), 7.05 (1H, s), 6.86-6.90 (1H, m), 4.30-4.38 (1H, d), 4.05-4.15 (1H, m), 3.82-3.90 (1H, d), 3.16- 3.24 (1H, t), 2.84-2.96 (3H, t + m), 270-278 (2H, m), 2.45 (3H, s), 1.91-1.99 (2H, d), 1.30-1.43 (2H,m) ppm.

LRMS (electrospray) : m/z [M+Na]⁺ 517, [M-H]⁺ 493.

Anal. Found C, 61.95; H, 5.52; N, 10.91. C₂₆H₂₇FN₄O₃S. O.δmol H₂O requires C, 62.01 ; H, 5.60; N, 1 1.13%.

Example 11

5-Fluoro-2-(3-methyIsulfanyl-phenoxy)-N-(1-propionyl-piperidin-4-yl)- nicotinamide

5-Fluoro-2-(3-methylsulfanyl-phenoxy)-N-piperidin-4-yl-nicotinamide (100mg,

0.251 mmol) and N,N-dimethylaminopyridine (5mg) were dissolved in dichloromethane (3ml) under nitrogen at room temperature and triethylamine (120DI, 0753mmol) was added followed by propionyl chloride (39mg, 0.42mmol). The reaction was allowed to stir at room temperature for 2h and 1-(3- Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (80mg, 0.377mmol) followed by triethylamine (120μl, 0753mmol). The reaction was stirred at room temperature for 18h, quenched with sat. ammonium chloride solution (0.5ml), diluted with water (3ml) and the organic layer was removed via a separation tube. The solvent was removed under reduced pressure and the residue was by flash column chromatography on a biotage system eluting with a solvent gradient of dichloromethane : methanol : concentrated aqueous ammonia (99.5 : 0.5 : 0.05 changing to 95 : 5 : 0.5, by volume) to give 5-fluoro-2-(3-methylsulfanyl-phenoxy)-N- (1-propionyl-piperidin-4-yl)-nicotinamide (90mg) as an off-white solid.

¹H NMR (400MHz, CD₃OD): δ = 8.08-8.10 (1 H, d), 7.97-8.00 (1 H, m), 7.26-7.32 (1 H, t), 7.09-7.13 (1 H, d), 7.03 (1 H, s), 6.84-6.88 (1H, d), 4.33-4.40 (1 H, d), 4.10-4.18 (1 H, m), 3.83-3.92 (1 H, d), 3.20-3.30 (1 H, t, partially masked by solvent), 2.86-2.97 (1 H, t), 2.45 (3H, s), 2.36-2.43 (2H, quart), 1.93-2.06 (2H, m), 1.40-1.60 (2H, m), 1.08- 1.13 (3H, t) ppm.

LRMS (electrospray) : m/z [M+Na]⁺ 440, [2M+Na]⁺ 857 ,[M-H]⁺ 416.

Anal. Found C, 58.03; H, 5.63; N, 9.24. C₂ιH₂₄FN₃O₃S. 0.95mol H₂0 requires C, 57.80; H, 6.03; N, 9.63%.

Example 12

5-Fluoro-2-(3-methylsulfanyl-phenoxy)-N-(1-cyclopropanecarbonyl-piperidin-4- yl)-nicotinamide

5-Fluoro-2-(3-methylsulfanyl-phenoxy)-N-piperidin-4-yl-nicotinamide (100mg,

0.251 mmol) and N,N-dimethylaminopyridine (5mg) were dissolved in dichloromethane (3ml) under nitrogen at room temperature and triethylamine (120DI, 0753mmol) was added followed by cyclopropanecarbonyl chloride (43mg, 0.42mmol). The reaction was allowed to stir at room temperature for 2h and 1-(3- Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (80mg, 0.377mmol) followed by triethylamine (120μl, 0753mmol). The reaction was stirred at room temperature for 18h, quenched with sat. ammonium chloride solution (0.5ml), diluted with water (3ml) and the organic layer was removed via a separation tube. The solvent was removed under reduced pressure and the residue was by flash column chromatography on a biotage system eluting with a solvent gradient of dichloromethane : methanol : concentrated aqueous ammonia (99.5 : 0.5 : 0.05 changing to 95 : 5 : 0.5, by volume) to give 5-fluoro-2-(3-methylsulfanyl-phenoxy)-N- (1-cyclopropylcarbonyl-piperidin-4-yl)-nicotinamide (100mg) as an off-white solid.

¹H NMR (400MHz, CD₃OD): δ = 8.07-8.09 (1 H, d), 7.97-8.00 (1 H, dd), 7.27-7.32 (1 H, t), 7.08-7.12 (1 H, d), 7.03 (1 H, s), 6.85-6.90 (1 H, m), 4.20-4.38 (2H, m), 4.12-4.20 (1 H, m), 3.22-3.41 (1 H, m, partially masked by solvent), 2.88-2.99 (1 H, m), 2.45 (3H, s), 2.00-2.09 (1 H, m), 1.90-2.00 (2H, m), 1.40-1.63 (2H, m), 077-0.86 (4H, m) ppm.

LRMS (electrospray) : m/z [M+Na]⁺ 452, [2M+Na]⁺ 881 ,[M-H]⁺ 428. HRMS : Found [M+H]⁺ 430.1597. C₂₂H₂₅FN₃O₃S requires 430.1595 Found [M+Na]⁺ 452.1414. C₂₂H₂₄FN₃O₂SNa requires 452.1414.

Example 13

5-Fluoro-2-(3-methylsulfanyl-phenoxy)-N-(1-isobutyryl-piperidin-4-yl)- nicotinamide

5-Fluoro-2-(3-methylsulfanyl-phenoxy)-N-piperidin-4-yl-nicotinamide (1 OOmg,

0.251 mmol) and N,N-dimethylaminopyridine (5mg) were dissolved in dichloromethane (3ml) under nitrogen at room temperature and triethylamine (120DI, 0753mmol) was added followed by isobutyryl chloride (44mg, 0.42mmol). The reaction was allowed to stir at room temperature for 2h and 1-(3- Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (80mg, 0.377mmol) followed by triethylamine (120DI, 0753mmol). The reaction was stirred at room temperature for 18h, quenched with sat. ammonium chloride solution (0.5ml), diluted with water (3ml) and the organic layer was removed via a separation tube. The solvent was removed under reduced pressure and the residue was by flash column chromatography on a biotage system eluting with a solvent gradient of dichloromethane : methanol : concentrated aqueous ammonia (99.5 : 0.5 : 0.05 changing to 95 : 5 : 0.5, by volume) to give 5-fluoro-2-(3-methylsulfanyl-phenoxy)-N- (1-isobutyryll-piperidin-4-yl)-nicotinamide (73mg) as an off-white solid.

¹H NMR (400MHz, CD₃OD): δ = 8.08-8.10 (1 H, d), 7.97-8.00 (1 H, m), 7.26-7.32 (1 H, t), 7.08-7.13 (1 H, d), 7.03 (1 H, s), 6.86-6.89 (1H, d), 4.33-4.40 (1 H, d), 4.12-4.19 (1 H, m), 3.96-4.02 (1 H, d), 3.23-3.31 (1 H, m, partially masked by solvent), 2.86-2.97 (2H, m), 2.45 (3H, s), 1.93-2.03 (2H, m), 1.40-1.59 (2H, m), 1.04-1.09 (6H, d) ppm.

LRMS (electrospray) : m/z [M+Na]⁺ 454, [M-H]⁺ 430.

Anal. Found C, 59.64; H, 5.86; N, 9.28. C₂₂H₂₆FN₃O₃S. 0.66mol H₂0 requires C, 59.58; H, 6.21; N, 9.47%.

Example 14

5-Fluoro-2-(3-methylsulfanyl-phenoxy)-N-(1-butyryl-piperidin-4-yl)-nicotinamide

5-Fluoro-2-(3-methylsulfanyl-phenoxy)-N-piperidin-4-yl-nicotinamide (100mg, 0.251 mmol) and N,N-dimethylaminopyridine (5mg) were dissolved in dichloromethane (3ml) under nitrogen at room temperature and triethylamine (120DI, 0753mmol) was added followed by butyryl chloride (44mg, 0.42mmol). The reaction was allowed to stir at room temperature for 2h and 1-(3-Dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (80mg, 0.377mmol) followed by triethylamine (120DI, 0753mmol). The reaction was stirred at room temperature for 18h, quenched with sat. ammonium chloride solution (0.5ml), diluted with water (3ml) and the organic layer was removed via a separation tube. The solvent was removed under reduced pressure and the residue was by flash column chromatography on a biotage system eluting with a solvent gradient of dichloromethane : methanol : concentrated aqueous ammonia (99.5 : 0.5 : 0.05 changing to 95 : 5 : 0.5, by volume) to give 5-fluoro-2-(3- methylsulfanyl-phenoxy)-N-(1-butyryl-piperidin-4-yl)-nicotinamide (100mg) as an off- white solid. ¹H NMR (400MHz, CD₃OD): δ = 8.09 (1 H, s), 7.97-8.01 (1 H, m), 7.28-7.33 (1 H, t), 7.09-7.14 (1 H, d), 7.04 (1 H, s), 6.86-6.90 (1 H, d), 4.31-4.39 (1 H, d), 4.10-4.19 (1 H, m), 3.87-3.96 (1 H, d), 3.20-3.32 (1 H, m, partially masked by solvent), 2.85-2.98 (1 H, t), 2.45 (3H, s), 2.34-2.39 (2H, t), 1.93-2.05 (2H, m), 1.40-1.63 (2H, sext + m), 0.93- 0.98 (3H, t) ppm.

LRMS (electrospray) : m/z [M+Na]⁺ 454, [2M+Na]⁺ 885 ,[M-H]⁺ 431.

Anal. Found C, 60.73; H, 6.09; N, 9.31. C₂₂H₂₆FN₃O₃S. 0.25mol H₂0 requires C, 60.60; H, 6.13; N, 9.64%.

Example 15

5-Fluoro-2-(3-methylsulfanyl-phenoxy)-N-(1-cyclobutylcarbonyl-piperidin-4-yl)- nicotinamide

5-Fluoro-2-(3-methylsulfanyl-phenoxy)-N-piperidin-4-yl-nicotinamide (100mg, 0.251 mmol) and N,N-dimethylaminopyridine (5mg) were dissolved in dichloromethane (3ml) under nitrogen at room temperature and triethylamine (120DI, 0753mmol) was added followed by cyclobutylcarbonyl chloride (50mg, 0.42mmol). The reaction was allowed to stir at room temperature for 2h and 1-(3- Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (80mg, 0.377mmol) followed by triethylamine (120DI, 0753mmol). The reaction was stirred at room temperature for 18h, quenched with sat. ammonium chloride solution (0.5ml), diluted with water (3ml) and the organic layer was removed via a separation tube. The solvent was removed under reduced pressure and the residue was by flash column chromatography on a biotage system eluting with a solvent gradient of dichloromethane : methanol : concentrated aqueous ammonia (99.5 : 0.5 : 0.05 changing to 95 : 5 : 0.5, by volume) to give 5-fluoro-2-(3-methylsulfanyl-phenoxy)-N- (1-cyclobutylcarbonyl-piperidin-4-yl)-nicotinamide (92mg) as an off-white solid.

¹H NMR (400MHz, CD₃OD): δ = 8.08-8.10 (1 H, d), 7.97-8.01 (1 H, m), 7.26-7.32 (1 H, t), 7.07-7.13 (1 H, d), 7.04 (1 H, s), 6.84-6.89 (1 H, d), 4.29-4.36 (1 H, d), 4.09-4.18 (1 H, m), 372-379 (1 H, d), 3.36-3.42 (1 H, m), 3.12-3.19 (1 H, t), 2.86-2.97 (1 H, t), 2.45 (3H, s), 2.12-2.30 (4H, 2xm), 1.92-2.04 (3H, m), 178-1.88 (1 H, m), 1.40-1.52 (2H, m) ppm.

LRMS (electrospray) : m/z [M+Na]⁺ 466, [M-H]⁺ 442.

Anal. Found C, 58.71 ; H, 5.50; N, 8.92. C₂₃H₂₆FN₃O₃S. O.δmol H₂O requires C, 58.94; H, 5.85; N, 8.87%.

Example 16

5-Fluoro-N-[1-(3-methylbutyryl)-piperidin-4-yl)-2-(3-methylsulfanyl-phenoxy)- nicotinamide

5-Fluoro-2-(3-methylsulfanyl-phenoxy)-N-piperidin-4-yl-nicotinamide (100mg, 0.251 mmol) and N,N-dimethylaminopyridine (5mg) were dissolved in dichloromethane (3ml) under nitrogen at room temperature and triethylamine (120DI,

0.753mmol) was added followed by 3-methyl-butyryl chloride (50mg, 0.42mmol). The reaction was allowed to stir at room temperature for 2h and 1-(3- Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (80mg, 0.377mmol) followed by triethylamine (120DI, 0753mmol). The reaction was stirred at room temperature for 18h, quenched with sat. ammonium chloride solution (0.5ml), diluted with water (3ml) and the organic layer was removed via a separation tube. The solvent was removed under reduced pressure and the residue was by flash column chromatography on a biotage system eluting with a solvent gradient of dichloromethane : methanol : concentrated aqueous ammonia (99.5 : 0.5 : 0.05 changing to 95 : 5 : 0.5, by volume) to give 5-fluoro-N-[1-(3-methylbutyryl)-piperidin- 4-yl)-2-(3-methylsulfanyl-phenoxy)-nicotinamide (91 mg) as an off-white solid.

¹H NMR (400MHz, CD₃OD): δ = 8.08-8.10 (1 H, d), 7.97-8.00 (1 H, m), 7.27-7.32 (1 H, t), 7.08-7.12 (1 H, d), 7.03 (1 H, s), 6.85-6.88 (1 H, d), 4.34-4.40 (1 H, d), 4.12-4.19 (1 H, m), 3.88-3.97 (1 H, d), 3.20-3.30 (1 H, t, partially masked by solvent), 2.87-2.97 (1 H, t), 2.45 (3H, s), 2.23-2.27 (2H, d), 1.93-2.07 (3H, m), 1.40-1.58 (2H, m), 0.94-0.98 (6H, d) ppm.

LRMS (electrospray) : m/z [M+Na]⁺ 468, [M-H]⁺ 445.

HRMS : Found [M+H]⁺ 446.1909. C₂₃H₂₉FN₃O₃S requires 446.1908 Found [M+Na]⁺ 468.1727. C₂₃H₂₈FN₃O₃SNa requires 468.1727.

Example 17

N-[1-(2,2-Dimethyl-propionyl)-piperidin-4-yl]-5-fluoro-2-(3-methylsulfanyl- phenoxy)-nicotinamide

5-Fluoro-2-(3-methylsulfanyl-phenoxy)-N-piperidin-4-yl-nicotinamide (100mg,

0.251 mmol) and N,N-dimethylaminopyridine (5mg) were dissolved in dichloromethane (3ml) under nitrogen at room temperature and triethylamine (120DI, 0753mmol) was added followed by tert-butylcarbonyl chloride (50mg, 0.42mmol). The reaction was allowed to stir at room temperature for 2h and 1-(3- Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (80mg, 0.377mmol) followed by triethylamine (120μl, 0753mmol). The reaction was stirred at room temperature for 18h, quenched with sat. ammonium chloride solution (0.5ml), diluted with water (3ml) and the organic layer was removed via a separation tube. The solvent was removed under reduced pressure and the residue was by flash column chromatography on a biotage system eluting with a solvent gradient of dichloromethane : methanol : concentrated aqueous ammonia (99.5 : 0.5 : 0.05 changing to 95 : 5 : 0.5, by volume) to give N-[1-(2,2-Dimethyl-propionyl)-piperidin-4- yl]-5-fluoro-2-(3-methylsulfanyl-phenoxy)-nicotinamide (23mg) as an off-white solid.

¹H NMR (400MHz, CD₃OD): δ = 8.08-8.10 (1 H, d), 7.96-8.00 (1 H, m), 7.26-7.32 (1 H, t), 7.08-7.12 (1 H, d), 7.03 (1 H, s), 6.85-6.88 (1 H, d), 4.23-4.30 (2H, d), 4.10-4.20 (1 H, m), 3.05-3.15 (2H, t), 2.45 (3H, s), 1.95-2.04 (2H, m), 1.40-1.55 (2H, m), 1.24 (9H, s) ppm.

LRMS (electrospray) : m/z [M+Na]⁺ 468, [M-H]⁺ 444. Anal. Found C, 60.93; H, 6.30; N, 8.98. C₂₃H₂₈FN₃O₃S. O.δmol H₂O requires C, 60.77; H, 6.43; N, 9.24%.

Example 18

5-Fluoro-2-(3-methylsulfanyl-phenoxy)-N-(1-cyclopentylcarbonyl-piperidin-4-yl)- nicotinamide

5-Fluoro-2-(3-methylsulfanyl-phenoxy)-N-piperidin-4-yl-nicotinamide (1 OOmg,

0.251 mmol) and N,N-dimethylaminopyridine (5mg) were dissolved in dichloromethane (3ml) under nitrogen at room temperature and triethylamine (120DI, 0.753mmol) was added followed by cyclopentylcarbonyl chloride (55mg, 0.42mmol). The reaction was allowed to stir at room temperature for 2h and 1-(3- Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (80mg, 0.377mmol) followed by triethylamine (120μl, 0753mmol). The reaction was stirred at room temperature for 18h, quenched with sat. ammonium chloride solution (0.5ml), diluted with water (3ml) and the organic layer was removed via a separation tube. The solvent was removed under reduced pressure and the residue was by flash column chromatography on a biotage system eluting with a solvent gradient of dichloromethane : methanol : concentrated aqueous ammonia (99.5 : 0.5 : 0.05 changing to 95 : 5 : 0.5, by volume) to give 5-fluoro-2-(3-methylsulfanyl-phenoxy)-N- (1-cyclopentylcarbonyl-piperidin-4-yl)-nicotinamide (105mg) as an off-white solid.

¹H NMR (400MHz, CD₃OD): δ = 8.09 (1 H, s), 7.95-7.99 (1 H, m), 7.27-7.33 (1 H, t), 7.09-7.14 (1 H, d), 7.04 (1 H, s), 6.84-6.91 (1 H, d), 4.30-4.40 (1 H, m), 4.09-4.19 (1 H, m), 3.94-4.06 (1 H, m), 3.20-3.35 (1 H, m, partially masked by solvent), 3.00-3.10 (1 H, m), 2.86-2.98 (1 H, m), 2.46 (3H, s), 1.90-2.10 (2H, m), 1.47-1.90 (8H, 3xm), 1.02 (2H, s) ppm.

LRMS (electrospray) : m/z [M+Na]⁺ 480, [M-H]⁺ 456.

Anal. Found C, 62.33; H, 6.23; N, 8.82. C₂ H₂₈FN₃O₃S. 0.25mol H₂O requires C, 62.39; H, 6.22; N, 9.09%.

Example 19

Acetic acid 2-(4-{[5-fluoro-2-(3-methylsulfanyl-phenoxy)-pyridine-3-carbonyl]- amino}-piperidin-1-yl)-2-oxo-ethyl ester

5-Fluoro-2-(3-methylsulfanyl-phenoxy)-N-piperidin-4-yl-nicotinamide (1 OOmg,

0.251 mmol) and N,N-dimethylaminopyridine (5mg) were dissolved in dichloromethane (3ml) under nitrogen at room temperature and triethylamine (120DI, 0753mmol) was added followed by acetic acid chlorocarbonyl methyl ester (56mg, 0.42mmol). The reaction was allowed to stir at room temperature for 2h and 1-(3- Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (80mg, 0.377mmol) followed by triethylamine (120ml, 0753mmol). The reaction was stirred at room temperature for 18h, quenched with sat. ammonium chloride solution (0.5ml), diluted with water (3ml) and the organic layer was removed via a separation tube. The solvent was removed under reduced pressure and the residue was by flash column chromatography on a biotage system eluting with a solvent gradient of dichloromethane : methanol : concentrated aqueous ammonia (99.5 : 0.5 : 0.05 changing to 95 : 5 : 0.5, by volume) to give Acetic acid 2-(4-{[5-fluoro-2-(3- methylsulfanyl-phenoxy)-pyridine-3-carbonyl]-amino}-piperidin-1-yl)-2-oxo-ethyl ester (81 mg) as an off-white solid.

¹H NMR (400MHz, CD₃OD): δ = 8.08-8.10 (1 H, d), 7.97-8.00 (1 H, dd), 7.28-7.32 (1 H, t), 7.06-7.13 (1 H, d), 7.03 (1 H, s), 6.85-6.90 (1 H, d), 475-4.84 (2H, quart, partially masked by solvent), 4.26-4.34 (1 H, d), 4.12-4.18 (1 H, m), 372-3.81 (1 H, d), 3.18- 3.29 (1 H, m, partially masked by solvent), 2.90-3.00 (1 H, d), 2.45 (3H, s), 2.10 (3H, s), 1.95-2.09 (2H, m), 1.46-1.63 (2H, m) ppm.

LRMS (electrospray) : m/z [M+Na]⁺ 484, [2M+Na]⁺ 945, [M-H]⁺ 460.

Anal. Found C, 56.76; H, 65.26; N, 8.64. C₂₂H₂₄FN₃O₅S. 0.2mol H₂0 requires C, 56.81 ; H, 5.29; N, 9.03%.

Example 20

5-Fluoro-2-(3-methylsulfanyl-phenoxy)-N-[1-(3-methylsulfanyl-propionyl)- piperidin-4-yf]-nicotinamide

5-Fluoro-2-(3-methylsulfanyl-phenoxy)-N-piperidin-4-yl-nicotinamide (100mg,

0.251 mmol) and N,N-dimethylaminopyridine (5mg) were dissolved in dichloromethane (3ml) under nitrogen at room temperature and triethylamine (120DI, 0753mmol) was added followed by 1-(3-me^'thylsulfanyl)-propionyl chloride (57mg, 0.42mmol). The reaction was allowed to stir at room temperature for 2h and 1-(3- Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (80mg, 0.377mmol) followed by triethylamine (120μl, 0753mmol). The reaction was stirred at room temperature for 18h, quenched with sat. ammonium chloride solution (0.5ml), diluted with water (3ml) and the organic layer was removed via a separation tube. The solvent was removed under reduced pressure and the residue was by flash column chromatography on a biotage system eluting with a solvent gradient of dichloromethane : methanol : concentrated aqueous ammonia (99.5 : 0.5 : 0.05 changing to 95 : 5 : 0.5, by volume) to give 5-fluoro-2-(3-methylsulfanyl-phenoxy)-N- [1-(3-methylsulfanyl-propionyl)-piperidin-4-yl]-nicotinamide (103mg) as an off-white solid.

¹H NMR (400MHz, CD₃OD): δ = 8.09 (1 H, s), 7.97-8.00 (1 H, m), 7.27-7.32 (1 H, t), 7.09-7.14 (1 H, d), 7.03 (1 H, s), 6.84-6.88 (1 H, d), 4.32-4.38 (1 H, d), 4.11-4.19 (1 H, m), 3.89-3.95 (1 H, d), 3.22-3.30 (1 H, m, partially masked by solvent), 2.88-2.98 (1 H, t), 2.63-277 (4H, m), 2.45 (3H, s), 2.09 (3H, s), 1.94-2.08 (2H, m), 1.42-1.60 (2H, m) ppm.

LRMS (electrospray) : m/z [M+Na]⁺ 486, [2M+Na]⁺ 949, [M-H]⁺ 462.

Anal. Found C, 55.66; H, 5.58; N, 8.56. C₂₂H₂₆FN₃O₃S. 0.66mol H₂0 requires C, 55.51 ; H, 5.46; N, 8.83%.

Example 21

N-[1-(2-Dimethylamino-acetyl)-piperidin-4-yl]-5-fluoro-2-(3-methylsulfanyl- phenoxy)-nicotinamide

5-Fluoro-2-(3-methylsulfanyl-phenoxy)-N-piperidin-4-yl-nicotinamide (1 10mg,

0.276mmol), 1-hydroxybenzotriazole (46mg, 0.304mmol) and N-methylmorpholine (67ml, 0.61 1 mmol) were added to a solution of 2-dimethylaminoacetic acid (43mg, 0.42mmol) in dichloromethane (2.5ml) under nitrogen at room temperature and 1-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (89mg, 0.468mmol) was added. The reaction was stirred at room temperature for 18h and quenched with sat. ammonium chloride (0.5ml) and diluted with water (3ml). The organic phase was collected via a hydrophobic separation cartridge, concentrated under reduced pressure and the residue was purified by flash column chromatography on a biotage system eluting with a solvent gradient of dichloromethane : methanol : concentrated aqueous ammonia (99.5 : 0.5 : 0.05 changing to 95 : 5 : 0.5, by volume) to give N-[1- (2-Dimethylamino-acetyl)-piperidin-4-yl]-5-fluoro-2-(3-methylsulfanyl-phenoxy)- nicotinamide (90mg) as an off-white solid.

¹H NMR (400MHz, CD₃OD): δ = 8.08-8.10 (1 H, d), 7.97-8.00 (1 H, m), 7.27-7.32 (1 H, t), 7.09-7.13 (1 H, d), 7.03 (1 H, s), 6.84-6.88 (1 H, d), 4.26-4.36 (1 H, d), 4.09-4.19 (1 H, m), 3.95-4.01 (1 H, d), 3.18-3.32 (3H, m, partially masked by solvent), 2.90-2.98 (1 H, t), 2.46 (3H, s), 2.30 (6H, s), 1.94-2.04 (2H, m), 1.40-1.61 (2H, m) ppm.

LRMS (electrospray) : m/z [M+H]⁺ 447, [M-H]⁺ 445.

Anal. Found C, 55.14; H, 5.92; N, 1 1.07. C₂₂H₂₇FN₄O₃S. 0.33mol CH₂CI₂. 0.75mol H₂O requires C, 54.98; H, 6.02; N, 1 1.47%.

Example 22

N-[1-(2-Ethoxy-acetyl)-piperidin-4-yl]-5-fluoro-2-(3-methylsulfanyl-phenoxy)- nicotinamide

5-Fluoro-2-(3-methylsulfanyl-phenoxy)-N-piperidin-4-yl-nicotinamide (110mg,

0.276mmol), 1-hydroxybenzotriazole (46mg, 0.304mmol) and N-methylmorpholine (6701, 0.611 mmol) were added to a solution of 2-ethoxyacetic acid (43mg, 0.42mmol) in dichloromethane (2.5ml) under nitrogen at room temperature and 1-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (89mg, 0.468mmol) was added. The reaction was stirred at room temperature for 18h and quenched with sat. ammonium chloride (0.5ml) and diluted with water (3ml). The organic phase was collected via a hydrophobic separation cartridge, concentrated under reduced pressure and the residue was purified by flash column chromatography on a biotage system eluting with a solvent gradient of dichloromethane : methanol : concentrated aqueous ammonia (99.5 : 0.5 : 0.05 changing to 95 : 5 : 0.5, by volume) to give N-[1- (2-ethoxy-acetyl)-piperidin-4-yl]-5-fluoro-2-(3-methylsulfanyl-phenoxy)-nicotinamide (96mg) as an off-white solid.

¹H NMR (400MHz, CD₃OD): δ = 8.08-8.10 (1 H, d), 7.97-8.00 (1 H, m), 7.28-7.33 (1 H, t), 7.08-7.12 (1 H, d), 7.04 (1 H, s), 6.84-6.88 (1 H, d), 4.27-4.36 (1 H, d), 4.10-4.21 (3H, quart + m), 3.81-3.91 (1 H, d), 3.49-3.58 (2H, quart), 3.17-3.29 (1 H, t), 2.90-2.99 (1 H, t), 2.45 (3H, s), 1.96-2.07 (2H, t), 1.42-1.62 (2H, m), 1.17-1.22 (3H, t) ppm.

LRMS (electrospray) : m/z [M+Na]⁺ 470, [2M+H]⁺ 917, [M-H]⁺ 446. Anal. Found C, 58.22; H, 5.80; N, 9.08. C₂₂H₂₆FN₃O₄S. 0.33mol H₂O requires C, 58.26; H, 5.93; N, 9.27%.

Example 23

5-Fluoro-2-(3-methylsulfanyl-phenoxy)-N-[1-(tetrahydro-furan-3-carbonyl)- piperidin-4-yl]-nicotinamide

5-Fluoro-2-(3-methylsulfanyl-phenoxy)-N-piperidin-4-yl-nicotinamide (1 10mg,

0.276mmol), 1-hydroxybenzotriazole (46mg, 0.304mmol) and N-methylmorphoHne (67DI, 0.611 mmol) were added to a solution of tetrahydrofuran-3-carboxylic acid (48mg, 0.42mmol) in dichloromethane (2.5ml) under nitrogen at room temperature and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (89mg, 0.468mmol) was added. The reaction was stirred at room temperature for 18h and quenched with sat. ammonium chloride (0.5ml) and diluted with water (3ml). The organic phase was collected via a hydrophobic separation cartridge, concentrated under reduced pressure and the residue was purified by flash column chromatography on a biotage system eluting with a solvent gradient of dichloromethane : methanol : concentrated aqueous ammonia (99.5 : 0.5 : 0.05 changing to 95 : 5 : 0.5, by volume) to give 5-Fluoro-2-(3-methylsulfanyl-phenoxy)-N- [1-(tetrahydro-furan-3-carbonyl)-piperidin-4-yl]-nicotinamide (85mg) as an off-white solid.

¹H NMR (400MHz, CD₃OD): δ = 8.08-8.10 (1 H, d), 7.97-8.01 (1 H, m), 7.27-7.32 (1 H, t), 7.08-7.1 1 (1 H, d), 7.03 (1 H, s), 6.84-6.88 (1 H, d), 4.12-4.20 (1 H, d), 4.10-4.20 (1 H, m), 3.90-4.02 (2H, t + d), 374-3.85 (3H, m), 3.38-3.46 (1 H, m), 3.24-3.36 (1 H, m, partially masked by solvent), 2.88-2.98 (1 H, m), 2.45 (3H, s), 1.95-2.16 (4H, m), 1.40- 1.60 (2H, m) ppm.

LRMS (electrospray) : m/z [M+Na]⁺ 482, [M-H]⁺ 458.

Anal. Found C, 59.73; H, 5.73; N, 8.93. C₂₃H₂₆FN₃O₄S requires C, 60.12; H, 5.70; N, 9.14%.

Example 24

N-[1-(2-Acetyl-amino-acetyl)-piperidin-4-yl]-5-fluoro-2-(3-methylsulfanyl- phenoxy)-nicotinamide

5-Fluoro-2-(3-methylsulfanyl-phenoxy)-N-piperidin-4-yl-nicotinamide (110mg,

0.276mmol), 1-hydroxybenzotriazole (46mg, 0.304mmol) and N-methylmorpholine (67DI, 0.611 mmol) were added to a solution of 2-acetyl-amino-acetic acid (49mg, 0.42mmol) in dichloromethane (2.5ml) under nitrogen at room temperature and 1-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (89mg, 0.468mmol) was added. The reaction was stirred at room temperature for 18h and quenched with sat. ammonium chloride (0.5ml) and diluted with water (3ml). The organic phase was collected via a hydrophobic separation cartridge, concentrated under reduced pressure and the residue was purified by flash column chromatography on a biotage system eluting with a solvent gradient of dichloromethane : methanol : concentrated aqueous ammonia (99.5 : 0.5 : 0.05 changing to 95 : 5 : 0.5, by volume) to give N-[1- (2-acetyl-amino-acetyl)-piperidin-4-yl]-5-fluoro-2-(3-methylsulfanyl-phenoxy)- nicotinamide (96mg) as an off-white solid. ¹H NMR (400MHz, CD₃OD): δ= 8.09-8.11 (1 H, d), 7.97-8.00 (1 H, m), 7.27-7.34 (1 H, t), 7.10-7.14 (1 H, d), 7.04 (1 H, s), 6.86-6.90 (1 H, d), 4.30-4.38 (1 H, d), 4.06-4.19 (2H, d + m), 3.97-4.02 (1 H, d), 379-3.87 (1 H, d), 3.20-3.30 (1 H, m, partially masked by solvent), 2.90-3.00 (1 H, t), 2.45 (3H, s), 1.96-2.07 (5H, s + m), 1.42-1.63 (2H, m) ppm.

LRMS (electrospray) : m/z [M+Na]⁺ 483, [M-H]⁺ 459.

Anal. Found C, 56.61 ; H, 5.57; N, 11.70. C₂₂H₂₅FN₄O₄S. 0.33mol H₂0 requires C, 56.64; H, 5.55; N, 12.01 %.

Example 25

N-(1 -Benzoyl-piperidin-4-yl)-5-fluoro-2-(3-methylsulfanyl-phenoxy)- nicotinamide

5-Fluoro-2-(3-methylsulfanyl-phenoxy)-N-piperidin-4-yl-nicotinamide (110mg, 0.276mmol), 1-hydroxybenzotriazole (46mg, 0.304mmol) and N-methylmorpholine (67DI, 0.61 1 mmol) were added to a solution of benzoic acid (51mg, 0.42mmol) in dichloromethane (2.5ml) under nitrogen at room temperature and 1-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (89mg, 0.468mmol) was added. The reaction was stirred at room temperature for 18h and quenched with sat. ammonium chloride (0.5ml) and diluted with water (3ml). The organic phase was collected via a hydrophobic separation cartridge, concentrated under reduced pressure and the residue was purified by flash column chromatography on a biotage system eluting with a solvent gradient of dichloromethane : methanol : concentrated aqueous ammonia (99.5 : 0.5 : 0.05 changing to 95 : 5 : 0.5, by volume) to give N-(1- Benzoyl-piperidin-4-yl)-5-fluoro-2-(3-methylsulfanyl-phenoxy)-nicotinamide (105mg) as an off-white solid.

¹H NMR (400MHz, CD₃OD): δ = 8.13 (1 H, s), 7.95-8.02 (1 H, dd), 7.41-7.49 (3H, m), 7.35-7.40 (2H, m), 7.27-7.32 (1 H, t), 7.08-7.13 (1 H, d), 7.05 (1 H, s), 6.85-6.90 (1 H, d), 4.40-4.55 (1 H, brs), 4.10-4.21 (1 H, m), 3.62-377 (1 H, brs), 3.07-3.25 (2H, brs), 2.45 (3H, s), 1.87-2.14 (2H, m), 1.48-170 (2H, m) ppm.

LRMS (electrospray) : m/z [M+Na]⁺ 488, [M-H]⁺ 464.

Anal. Found C, 63.83; H, 5.21 ; N, 8.89. C₂₅H₂₄FN₃O₃S. 0.25mol H₂O requires C, 63.88; H, 5.25; N, 8.94%.

Example 26

5-Fluoro-2-(3-methylsulfanyl-phenoxy)-N-[1-(pyridine-4-carbonyl)-piperidin-4- yl]-nicotinamide

5-Fluoro-2-(3-methylsulfanyl-phenoxy)-N-piperidin-4-yl-nicotinamide (110mg,

0.276mmol), 1-hydroxybenzotriazole (46mg, 0.304mmol) and N-methylmorpholine (67DI, 0.61 1 mmol) were added to a solution of pyridine-4-carboxylic acid (51 mg, 0.42mmol) in dichloromethane (2.5ml) under nitrogen at room temperature and 1-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (89mg, 0.468mmol) was added. The reaction was stirred at room temperature for 18h and quenched with sat. ammonium chloride (0.5ml) and diluted with water (3ml). The organic phase was collected via a hydrophobic separation cartridge, concentrated under reduced pressure and the residue was purified by flash column chromatography on a biotage system eluting with a solvent gradient of dichloromethane : methanol : concentrated aqueous ammonia (99.5 : 0.5 : 0.05 changing to 95 : 5 : 0.5, by volume) to give 5- fluoro-2-(3-methylsulfanyl-phenoxy)-N-[1-(pyridine-4-carbonyl)-piperidin-4-yl]- nicotinamide (95mg) as an off-white solid.

¹H NMR (400MHz, CD₃OD): δ = 8.60-8.63 (2H, d), 8.10-8.12 (1 H, d), 7.98-8.02 (1 H, dd), 7.40-7.43 (2H, d), 7.30-7.34 (1 H, t), 7.11-7.15 (1 H, d), 7.05 (1 H, s), 6.85-6.89 (1 H, d), 4.44-4.52 (1 H, m), 4.16-4.22 (1 H, m), 3.53-3.62 (1 H, m), 3.21-3.20 (1 H, m, partially masked by solvent), 3.1 1-3.20 (1 H, m), 2.45 (3H, s), 2.05-2.12 (1 H, m), 1.92- 2.00 (1 H, m), 1.50-1.69 (2H, m) ppm.

LRMS (electrospray) : m/z [M+Na]⁺ 489, [M-H]⁺ 465.

Anal. Found C, 61.00; H, 5.07; N, 11.56. C₂₄H₂₃FN₄O₃S. 0.33mol H₂O requires C, 61.00; H, 5.05; N, 11.86%.

Example 27

5-Fluoro-2-(3-methylsulfanyl-phenoxy)-N-[1-(pyridine-3-carbonyl)-piperidin-4- yl]-nicotinamide

5-Fluoro-2-(3-methylsulfanyl-phenoxy)-N-piperidin-4-yl-nicotinamide (110mg,

0.276mmol), 1-hydroxybenzotriazole (46mg, 0.304mmol) and N-methylmorpholine (67DI, 0.611 mmol) were added to a solution of pyridine-3-carboxylic acid (51 mg, 0.42mmol) in dichloromethane (2.5ml) under nitrogen at room temperature and 1-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (89mg, 0.468mmol) was added. The reaction was stirred at room temperature for 18h and quenched with sat. ammonium chloride (0.5ml) and diluted with water (3ml). The organic phase was collected via a hydrophobic separation cartridge, concentrated under reduced pressure and the residue was purified by flash column chromatography on a biotage system eluting with a solvent gradient of dichloromethane : methanol : concentrated aqueous ammonia (99.5 : 0.5 : 0.05 changing to 95 : 5 : 0.5, by volume) to give 5- fluoro-2-(3-methylsulfanyl-phenoxy)-N-[1 -(pyridine-3-carbonyl)-piperidin-4-y^π- nicotinamide (97mg) as an off-white solid.

¹H NMR (400MHz, CD₃OD): δ = 8.60-8.64 (1 H, d), 8.59 (1 H, s), 8.10-8.13 (1 H, d), 7.98-8.02 (1 H, dd), 7.85-7.89 (1 H, m), 7.48-7.53 (1 H, m), 7.29-7.35 (1 H, t), 7.11-7.14 (1 H, d), 7.03 (1H, s), 6.85-6.89 (1 H, d), 4.41-4.55 (1 H, brs), 4.15-4.22 (1 H, m), 3.57- 3.70 (1 H, brs), 3.10-3.40 (2H, 2xbrs, partially masked by solvent), 2.45 (3H, s), 1.94- 2.17 (1 H, m), 1.53-1.69 (2H, m) ppm.

LRMS (electrospray) : m/z [M+Na]⁺ 489, [M-H]⁺ 465.

Anal. Found C, 61.08; H, 4.84; N, 1 1.53. C₂₄H₂₃FN O₃S. 0.25mol H₂O requires C, 61.20; H, 5.03; N, 1 1.89%.

Example 28

5-Fluoro-2-(3-methylsulfanyl-phenoxy)-N-[1-(pyridine-2-carbonyl)-piperidin-4- yl]-nicotinamide

5-Fluoro-2-(3-methylsulfanyl-phenoxy)-N-piperidin-4-yl-nicotinamide (110mg,

0.276mmol), 1-hydroxybenzotriazole (46mg, 0.304mmol) and N-methylmorpholine (67DI, 0.611mmol) were added to a solution of pyridine-2-carboxylic acid (51 mg, 0.42mmol) in dichloromethane (2.5ml) under nitrogen at room temperature and 1-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (89mg, 0.468mmol) was added. The reaction was stirred at room temperature for 18h and quenched with sat. ammonium chloride (0.5ml) and diluted with water (3ml). The organic phase was collected via a hydrophobic separation cartridge, concentrated under reduced pressure and the residue was purified by flash column chromatography on a biotage system eluting with a solvent gradient of dichloromethane : methanol : concentrated aqueous ammonia (99.5 : 0.5 : 0.05 changing to 95 : 5 : 0.5, by volume) to give 5- fluoro-2-(3-methylsulfanyl-phenoxy)-N-[1-(pyridine-2-carbonyl)-piperidin-4-yl]- nicotinamide (100mg) as an off-white solid.

¹H NMR (400MHz, CD₃OD): δ = 8.56-8.59 (1 H, d), 8.09-8.11 (1 H, d), 7.96-8.00 (1 H, dd), 7.90-7.95 (1 H, t), 7.56-7.59 (1 H, d), 7.47-7.50 (1 H, m), 7.27-7.33 (1 H, t), 7.08- 7.12 (1 H, d), 7.04 (1 H, s), 6.85-6.89 (1 H, m), 4.45-4.54 (1 H, d), 4.16-4.23 (1 H, m), 3.63-371 (1 H, d), 3.12-3.28 (2H, m), 2.44 (3H, s), 2.05-2.14 (1 H, d), 1.90-1.99 (1 H, d), 1.57-171 (2H, m) ppm.

LRMS (electrospray) : m/z [M+Na]⁺ 489, [M-H]⁺ 465. Anal. Found C, 61.33; H, 4.97; N, 1 1.67. C₂₄H₂₃FN₄O₃S. 0.15mol H₂0 requires C, 61.43; H, 5.01 ; N, 1 1.94%.

Example 29

5-Fluoro-2-(3-methylsulfanyl-phenoxy)-N-[1-(pyrimidine-5-carbonyl)-piperidin-4- yl]-nicotinamide

5-Fluoro-2-(3-methylsulfanyl-phenoxy)-N-piperidin-4-yl-nicotinamide (1 10mg,

0.276mmol), 1-hydroxybenzotriazole (46mg, 0.304mmol) and N-methylmorpholine (67DI, 0.611 mmol) were added to a solution of pyrimidine-5-carboxylic acid (52mg, 0.42mmol) in dichloromethane (2.5ml) under nitrogen at room temperature and 1-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (89mg, 0.468mmol) was added. The reaction was stirred at room temperature for 18h and quenched with sat. ammonium chloride (0.5ml) and diluted with water (3ml). The organic phase was collected via a hydrophobic separation cartridge, concentrated under reduced pressure and the residue was purified by flash column chromatography on a biotage system eluting with a solvent gradient of dichloromethane : methanol : concentrated aqueous ammonia (99.5 : 0.5 : 0.05 changing to 95 : 5 : 0.5, by volume) to give 5- fluoro-2-(3-methylsulfanyl-phenoxy)-N-[1-(pyrimidine-5-carbonyl)-piperidin-4-yl]- nicotinamide (40mg) as an off-white solid.

¹H NMR (400MHz, CD₃OD): δ = 9.21 (1 H. s), 8.82 (2H, s), 8.11-8.13 (1 H, d), 7.98- 8.02 (1 H, m), 7.30-7.35 (1 H, t), 7.11-7.15 (1 H, d), 7.04 (1 H, s), 6.84-6.88 (1 H, d), 4.41-4.58 (1 H, brs), 4.16-4.22 (1 H, m), 3.61-375 (1 H, brs), 3.12-3.40 (2H, m, partially masked by solvent), 2.45 (3H, s), 1.96-2.16 (2H, m), 1.56-172 (2H, m) ppm. LRMS (electrospray) : m/z [M-H]⁺ 466.

Example 30

5-Fluoro-2-(3-methylsulfanyl-phenoxy)-N-[1-(2-methyl-pyridine-3-carbonyl)- piperidin-4-yl]-nicotinamide

5-Fluoro-2-(3-methylsulfanyl-phenoxy)-N-piperidin-4-yl-nicotinamide (110mg,

0.276mmol), 1-hydroxybenzotriazole (46mg, 0.304mmol) and N-methylmorpholine (67DI, 0.611mmol) were added to a solution of 2-methyl-pyridine-3-carboxylic acid (57mg, 0.42mmol) in dichloromethane (2.5ml) under nitrogen at room temperature and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (89mg, 0.468mmol) was added. The reaction was stirred at room temperature for 18h and quenched with sat. ammonium chloride (0.5ml) and diluted with water (3ml). The organic phase was collected via a hydrophobic separation cartridge, concentrated under reduced pressure and the residue was purified by flash column chromatography on a biotage system eluting with a solvent gradient of dichloromethane : methanol : concentrated aqueous ammonia (99.5 : 0.5 : 0.05 changing to 95 : 5 : 0.5, by volume) to give 5-fluoro-2-(3-methylsulfanyl-phenoxy)-N- [1-(2-methyl-pyridine-3-carbonyl)-piperidin-4-yl]-nicotinamide (110mg) as an off-white solid.

¹H NMR (400MHz, CD₃OD): δ = 8.45-8.48 (1 H, d), 8.10-8.12 (1 H, d), 7.96-8.02 (1 H, d), 7.63-7.67 (1 H, d), 7.28-7.34 (2H, m), 7.08-7.13 (1 H, d), 7.03 (1 H, s), 6.85-6.89 (1 H, d), 4.40-4.60 (1 H, brs), 4.12-4.22 (1 H, m), 3.38-3.46 (1 H, m), 3.10-3.30 (2H, m, partially masked by solvent), 2.44-2.50 (6H, 2xs), 2.04-2.14 (1 H, d), 1.88-1.96 (1 H, d), 1.59-171 (1 H, m), 1.46-1.58 (1 H, m) ppm.

LRMS (electrospray) : m/z [M+Na]⁺ 503, [M-H]⁺ 479.

Anal. Found C, 61.52; H, 5.34; N, 1 1.45. C₂₅H₂₅FN₄O₃S. 0.4mol H₂0 requires C, 61.50; H, 5.12; N, 11.48%.

Example 31

5-Fluoro-2-(3-methylsulfanyl-phenoxy)-N-[1-(2-methyl-benzoyl)-piperidin-4-yl]- nicotinamide

5-Fluoro-2-(3-methylsulfanyl-phenoxy)-N-piperidin-4-yl-nicotinamide (110mg,

0.276mmol), 1-hydroxybenzotriazole (46mg, 0.304mmol) and N-methylmorpholine (67μl, 0.61 1 mmol) were added to a solution of 2-methyl-benzoic acid (57mg, 0.42mmol) in dichloromethane (2.5ml) under nitrogen at room temperature and 1-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (89mg, 0.468mmol) was added. The reaction was stirred at room temperature for 18h and quenched with sat. ammonium chloride (0.5ml) and diluted with water (3ml). The organic phase was collected via a hydrophobic separation cartridge, concentrated under reduced pressure and the residue was purified by flash column chromatography on a biotage system eluting with a solvent gradient of dichloromethane : methanol : concentrated aqueous ammonia (99.5 : 0.5 : 0.05 changing to 95 : 5 : 0.5, by volume) to give 5- fluoro-2-(3-methylsulfanyl-phenoxy)-N-[1-(2-methyl-benzoyl)-piperidin-4-yl]- nicotinamide (1 10mg) as an off-white solid. ¹H NMR (400MHz, CD₃OD): δ = 8.08-8.10 (1 H, d), 7.96-8.00 (1 H, brs), 7.20-7.31 (4H, m), 7.07-7.19 (2H, m + d), 7.05 (1 H, s), 6.85-6.90 (1 H, d), 4.40-4.60 (1 H, 2xm), 4.12-4.20 (1 H, m), 3.39-3.46 (1 H, m), 3.07-3.24 (2H, m), 2.44 (3H, s), 2.03-2.13 (1 H, d), 1.83-1.93 (1 H, m), 1.57-1.69 (1 H, m), 1.42-1.57 (1 H, m) ppm.

LRMS (electrospray) : m/z [M+Na]⁺ 502, [M-H]⁺ 478.

Anal. Found C, 62.94; H, 5.41 ; N, 8.34. C₂₆H₂₆FN₃O₃S. 1 mol H₂O requires C, 62.76; H, 5.67; N, 8.44%.

Example 32

N-(1-Cyclohexylcarbonyl-piperidin-4-yl)-5-fluoro-2-(3-methylsulfanyl-phenoxy)- nicotinamide

5-Fluoro-2-(3-methylsulfanyl-phenoxy)-N-piperidin-4-yl-nicotinamide (110mg,

0.276mmol), 1-hydroxybenzotriazole (46mg, 0.304mmol) and N-methylmorpholine (67μl, 0.611 mmol) were added to a solution of cyclohexylcarboxylic acid (53mg, 0.42mmol) in dichloromethane (2.5ml) under nitrogen at room temperature and 1-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (89mg, 0.468mmol) was added. The reaction was stirred at room temperature for 18h and quenched with sat. ammonium chloride (0.5ml) and diluted with water (3ml). The organic phase was collected via a hydrophobic separation cartridge, concentrated under reduced pressure and the residue was purified by flash column chromatography on a biotage system eluting with a solvent gradient of dichloromethane : methanol : concentrated aqueous ammonia (99.5 : 0.5 : 0.05 changing to 95 : 5 : 0.5, by volume) to give N-(1- Cyclohexylcarbonyl-piperidin-4-yl)-5-fluoro-2-(3-methylsulfanyl-phenoxy)- nicotinamide (37mg) as an off-white solid.

¹H NMR (400MHz, CD₃OD): δ = 8.09 (1 H, s), 7.97-8.00 (1 H, m), 7.27-7.32 (1 H, t), 7.08-7.13 (1 H, d), 7.03 (1 H, s), 6.84-6.88 (1 H, d), 4.31-4.39 (1 H, d), 4.10-4.19 (1 H, m), 3.93-3.99 (1 H, d), 3.20-3.30 (1 H, m, partially masked by solvent), 2.84-2.96 (1 H, t), 2.59-2.66 (1 H, t), 2.44 (3H, s), 2.00-2.07 (1 H, d), 1.92-1.99 (1 H, d), 1.64-1.80 (5H, 2xd), 1.18-1.59 (7H, m) ppm.

LRMS (electrospray) : m/z [M+Na]⁺ 494, [M-H]⁺ 470.

Anal. Found C, 63.04; H, 6.46; N, 8.97. C₂₅H₃₀FN₃O₃S requires C, 63.07; H, 6.46; N, 8.83%.

Example 33

5-Fluoro-2-(3-methylsulfanyl-phenoxy)-N-[1-(5-oxo-pyrrolidine-2-carbonyl)- piperidin-4-yl]-nicotinamide

5-Fluoro-2-(3-methylsulfanyl-phenoxy)-N-piperidin-4-yl-nicotinamide (110mg,

0.276mmol), 1-hydroxybenzotriazole (46mg, 0.304mmol) and N-methylmorpholine (67μl, 0.611 mmol) were added to a solution of 5-oxo-pyrrolidine-2-carboxylic acid (54mg, 0.42mmol) in dichloromethane (2.5ml) under nitrogen at room temperature and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (89mg, 0.468mmol) was added. The reaction was stirred at room temperature for 18h and quenched with sat. ammonium chloride (0.5ml) and diluted with water (3ml). The organic phase was collected via a hydrophobic separation cartridge, concentrated under reduced pressure and the residue was purified by flash column chromatography on a biotage system eluting with a solvent gradient of dichloromethane : methanol : concentrated aqueous ammonia (99.5 : 0.5 : 0.05 changing to 95 : 5 : 0.5, by volume) to give 5-fluoro-2-(3-methylsulfanyl-phenoxy)-N- [1-(5-oxo-pyrrolidine-2-carbonyl)-piperidin-4-yl]-nicotinamide (100mg) as an off-white solid.

¹H NMR (400MHz, CD₃OD): δ = 8.08-8.10 (1 H, d), 7.98-8.02 (1 H, m), 7.29-7.34 (1 H, t), 7.10-7.14 (1 H, d), 7.04 (1 H, s), 6.84-6.88 (1 H, d), 4.65-471 (1 H, m), 4.30-4.38 (1 H, m), 4.12-4.20 (1 H, m), 3.83-3.92 (1 H, m), 3.27-3.36 (2H, m, partially masked by solvent), 2.92-3.02 (1 H, m), 2.42-2.54 (4H, s + m), 2.28-2.38 (2H, m), 1.95-2.10 (3H, m), 1.45-1.62 (2H, m) ppm.

LRMS (electrospray) : m/z [M+Na]⁺ 495, [M-H]⁺ 472.

Anal. Found C, 57.54; H, 5.50; N, 11.41. C₂₅H₂₅FN₄O₄S. 0.4mol H₂0 requires C, 57.58; H, 5.42; N, 1 1.68%.

Example 34

5-Fluoro-N-[1-(2-methanesulfonyl-acetyl)-piperidin-4-yl]-2-(3-methylsulfanyI- phenoxy)-nicotinamide

5-Fluoro-2-(3-methylsulfanyl-phenoxy)-N-piperidin-4-yl-nicotinamide (1 10mg,

0.276mmol), 1-hydroxybenzotriazole (46mg, 0.304mmol) and N-methylmorpholine (67μl, 0.611 mmol) were added to a solution of 2-methanesulfonyl-acetic acid (57mg, 0.42mmol) in dichloromethane (2.5ml) under nitrogen at room temperature and 1-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (89mg, 0.468mmol) was added. The reaction was stirred at room temperature for 18h and quenched with sat. ammonium chloride (0.5ml) and diluted with water (3ml). The organic phase was collected via a hydrophobic separation cartridge, concentrated under reduced pressure and the residue was purified by flash column chromatography on a biotage system eluting with a solvent gradient of dichloromethane : methanol : concentrated aqueous ammonia (99.5 : 0.5 : 0.05 changing to 95 : 5 : 0.5, by volume) to give 5- fluoro-N-[1-(2-methanesulfonyl-acetyl)-piperidin-4-yl]-2-(3-methylsulfanyl-phenoxy)- nicotinamide (85mg) as an off-white solid.

¹H NMR (400MHz, CD₃OD): δ= 8.10-8.1 1 (1 H, d), 7.97-8.00 (1 H, m), 7.28-7.33 (1 H, t), 7.08-7.13 (1 H, d), 7.04 (1 H, s), 6.95-6.99 (1 H, d), 4.36-4.41 (1 H, d), 4.12-4.20 (1 H, m), 3.97-4.03 (1 H, d), 3.10-3.20 (1 H, m, partially masked by solvent), 3.09 (3H, s), 2.98-3.04 (1 H, m), 2.44 (3H, s), 1.98-2.08 (2H, t), 1.60-172 (1 H, m), 1.48-1.58 (1 H, m) ppm.

LRMS (electrospray) : m/z [M+Na]⁺ 505, [M-H]⁺ 481.

Anal. Found C, 52.15; H, 5.08; N, 8.56. C₂ιH₂₄FN₃O₅S₂ requires C, 52.38; H, 5.02; N, 8.73%.

Example 35

5-Fluoro-N-[1-(2-hydroxy-acetyl)-piperidin-4-yl]-2-(3-methylsulfanyl-phenoxy)- nicotinamide

5-Fluoro-2-(3-methylsulfanyl-phenoxy)-N-piperidin-4-yl-nicotinamide (110mg,

0.276mmol), 1-hydroxybenzotriazole (46mg, 0.304mmol) and N-methylmorpholine (67μl, 0.61 1 mmol) were added to a solution of 2-hydroxy-acetic acid (30mg, 0.42mmol) in dichloromethane (2.5ml) under nitrogen at room temperature and 1-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (89mg, 0.468mmol) was added. The reaction was stirred at room temperature for 18h and quenched with sat. ammonium chloride (0.5ml) and diluted with water (3ml). The organic phase was collected via a hydrophobic separation cartridge, concentrated under reduced pressure and the residue was purified by flash column chromatography on a biotage system eluting with a solvent gradient of dichloromethane : methanol : concentrated aqueous ammonia (99.5 : 0.5 : 0.05 changing to 95 : 5 : 0.5, by volume) to give 5- fluoro-N-[1-(2-hydroxy-acetyl)-piperidin-4-yl]-2-(3-methylsulfanyl-phenoxy)- nicotinamide (113mg) as an off-white solid.

¹H NMR (400MHz, CD₃OD): δ = 8.08-8.09 (1 H, d), 7.98-8.00 (1 H, dd), 7.28-7.34 (1 H, t), 7.09-7.13 (1 H, d), 7.03-7.04 (1 H, m), 6.85-6.89 (1 H, m), 4.30-4.39 (1 H, d), 4.20 (2H, s), 4.10-4.19 (1 H, m), 3.66-375 (1 H, d), 3.17-3.22 (1 H, t), 2.92-3.01 (1 H, t), 2.45 (3H, s), 1.96-2.04 (2H, m), 1.42-1.60 (2H, m) ppm.

LRMS (electrospray) : m/z [M+Na]⁺ 442, [M-H]⁺ 418. Anal. Found C, 54.87; H, 5.11 ; N, 9.18. C₂₀H₂₂FN₃O₄S. 0.33mol CH₂CI₂ requires C, 54.54; H, 5.20; N, 9.38%.

Example 36

N-[1-(4-Chloro-2-hydroxy-benzoyl)-piperidin-4-yl]-5-fluoro-2-(3-methylsulfanyl- phenoxy)-nicotinamide

4-Chloro-2-hydroxy-benzoic acid (77mg, 0.45mmol) was added to a solution of 5- fluoro-2-(3-methylsulfanyl-phenoxy)-N-piperidin-4-yl-nicotinamide (180mg,

0.499mmol), 1-hydroxybenzotriazole (71 mg, 0.523mmol) and N-methylmorpholine (219μl, 2.0mmol) in dichloromethane (2ml) under nitrogen at room temperature. 1- (3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (143mg, 0746mmol) was then added and the reaction was stirred at room temperature for 20h. After quenching with sat. ammonium chloride (1 ml) and diluting with water (3ml), the organic phase was collected via a hydrophobic separation cartridge, concentrated under reduced pressure and the residue was purified by flash column chromatography on a biotage system eluting with a solvent gradient of ethyl acetate : cyclohexane (15 : 85 changing to 80 : 20, by volume) to give N-[1-(4-Chloro-2- hydroxy-benzoyl)-piperidin-4-yl]-5-fluoro-2-(3-methylsulfanyl-phenoxy)-nicotinamide (65mg) as an off-white foam.

¹H NMR (400MHz, CD₃OD): δ = 8.08-8.10 (1 H, d), 7.98-8.01 (1 H, dd), 7.29-7.36 (1 H, t), 7.11-7.17 (2H, s + d), 7.03-7.05 (1 H, m), 6.84-6.91 (3H, m), 4.14-4.22 (1 H, m), 3.13-3.21 (2H, t), 2.45 (3H, s), 1 .96-2.05 (2H, m), 1.57-1.66 (2H, m) ppm. LRMS (electrospray) : m/z [M+Na]⁺ 538, [M-H]⁺ 514.

HRMS : Found [M+H]⁺ 516.1136. C₂₅H₂₄CIFN₃O₄S requires 516.1155 Found [M+Na]⁺ 538.0952. C₂₅H₂₃CIFN₃O₄SNa requires 538.0974.

Example 37

5-Fluoro-N-[1-(2-hydroxy-4-methyl-benzoyl)-piperidin-4-yl]-2-(3-methylsulfanyl- phenoxy)-nicotinamide

2-Hydroxy-4-methyl-benzoic acid (68mg, 0.45mmol) was added to a solution of 5- fluoro-2-(3-methylsulfanyl-phenoxy)-N-piperidin-4-yl-nicotinamide (180mg,

0.499mmol), 1-hydroxybenzotriazole (71 mg, 0.523mmol) and N-methylmorpholine (219μl, 2.0mmol) in dichloromethane (2ml) under nitrogen at room temperature. 1- (3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (143mg, 0746mmol) was then added and the reaction was stirred at room temperature for 20h. After quenching with sat. ammonium chloride (1ml) and diluting with water (3ml), the organic phase was collected via a hydrophobic separation cartridge, concentrated under reduced pressure and the residue was purified by flash column chromatography on a biotage system eluting with a solvent gradient of ethyl acetate : cyclohexane (15 : 85 changing to 80 : 20, by volume) to give 5-fluoro-N-[1-(2- hydroxy-4-methyl-benzoyl)-piperidin-4-yl]-2-(3-methylsulfanyl-phenoxy)-nicotinamide (50mg) as an off-white foam.

¹H NMR (400MHz, CD₃OD): δ = 8.10-8.12 (1 H, d), 7.98-8.02 (1 H, dd), 7.26-7.35 (1 H, m), 7.10-7.14 (1 H, d), 7.04-7.07 (1 H, m), 7.03 (1 H, s), 6.86-6.90 (1 H, m), 6.68-6.92 (1H, d), 6.67 (1H, s), 4.03-4.20 (1H, m), 3.13-3.20 (2H, t), 2.45 (3H, s), 2.28 (3H, s), 1.94-2.03 (2H, m), 1.56-1.66 (2H, m) ppm.

LRMS (electrospray) : m/z [M+Na]⁺ 518, [M-H]⁺ 494.

HRMS : Found [M+H]⁺ 496.1685. C₂₆H₂₇FN₃O₄S requires 496.1701 Found [M+Na 518.1504. C₂₆H₂₆FN₃O₄SNa requires 518.1520.

Example 38

5-Fluoro-N-[1-(2-hydroxy-4-methoxy-benzoyl)-piperidin-4-yl]-2-(3- methylsulfanyl-phenoxy)-nicotinamide

2-Hydroxy-4-methoxy-benzoic acid (75mg, 0.45mmol) was added to a solution of 5- fluoro-2-(3-methylsulfanyl-phenoxy)-N-piperidin-4-yl-nicotinamide (180mg,

0.499mmol), 1-hydroxybenzotriazole (71 mg, 0.523mmol) and N-methylmorpholine (219μl, 2.0mmol) in dichloromethane (2ml) under nitrogen at room temperature. 1- (3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (143mg, 0746mmol) was then added and the reaction was stirred at room temperature for 20h. After quenching with sat. ammonium chloride (1 ml) and diluting with water (3ml), the organic phase was collected via a hydrophobic separation cartridge, concentrated under reduced pressure and the residue was purified by flash column chromatography on a biotage system eluting with a solvent gradient of ethyl acetate : cyclohexane (15 : 85 changing to 80 : 20, by volume) to give 5-fluoro-N-[1 -(2- hydroxy-4-methoxy-benzoyl)-piperidin-4-yl]-2-(3-methylsulfanyl-phenoxy)- nicotinamide (84mg) as an off-white foam. ¹H NMR (400MHz, CD₃OD): δ = 8.10-8.13 (1 H, d), 7.97-8.00 (1H, dd), 7.29-7.35 (2H, t), 7.08-7.13 (1 H, t), 7.04-7.06 (1 H, m), 6.87-6.91 (1 H, d), 6.44-6.48 (1 H, d), 6.38- 6.40 (1H, d), 4.00-4.20 (2H, brs + m), 3.78 (3H, s), 3.12-3.21 (2H, t), 2.44 (3H, s), 1.97-2.04 (2H, m), 1.56-1.66 (2H, m), 1.26-1.30 (2H, brs) ppm.

LRMS (electrospray) : m/z [M+Na]⁺ 534, [M-H]⁺ 510.

HRMS : Found [M+H]⁺ 512.1634. C₂₆H₂₇FN₃O₅S requires 512.1650.

Example 39

5-Fluoro-N-[1-(2-hydroxy-benzoyl)-piperidin-4-yl]-2-(3-methylsulfanyl-phenoxy)- nicotinamide

2-Hydroxy-benzoic acid (62mg, 0.45mmol) was added to a solution of 5-fluoro-2-(3- methylsulfanyl-phenoxy)-N-piperidin-4-yl-nicotinamide (180mg, 0.499mmol), 1- hydroxybenzotriazole (71 mg, 0.523mmol) and N-methylmorpholine (219μl, 2.0mmol) in dichloromethane (2ml) under nitrogen at room temperature. 1-(3- Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (143mg, 0746mmol) was then added and the reaction was stirred at room temperature for 20h. After quenching with sat. ammonium chloride (1ml) and diluting with water (3ml), the organic phase was collected via a hydrophobic separation cartridge, concentrated under reduced pressure and the residue was purified by flash column chromatography on a biotage system eluting with a solvent gradient of ethyl acetate : cyclohexane (15 : 85 changing to 80 : 20, by volume) to give 5-fluoro-N-[1 -(2- hydroxy-benzoyl)-piperidin-4-yl]-2-(3-methylsulfanyl-phenoxy)-nicotinamide (72mg) as an off-white foam.

¹H NMR (400MHz, CD₃OD): δ = 8.10-8.13 (1 H, d), 7.97-8.01 (1 H, dd), 7.30-7.35 (1 H, t), 7.22-7.27 (1H, t), 7.11-7.18 (2H, m), 7.06 (1H, s), 6.82-6.90 (3H, m), 4.13-4.20 (1H, m), 3.13-3.22 (2H, t), 2.45 (3H, s), 1.95-2.05 (2H, m), 1.57-1.68 (2H, m) ppm.

LRMS (electrospray) : m/z [M+Na]⁺ 504, [M-H]⁺ 480.

HRMS : Found [M+H]^÷ 482.1529. C₂₅H₂₅FN₃O₄S requires 482.1545 Found [M+Na]⁺ 504.1349. C₂₅H₂₄FN₃O₄SNa requires 504.1364.

Example 40

N-(1 -Acetyl-piperidin-4-yl)-2-(4-ethylsulfanyl-phenoxy)-5-fluoro-nicotinamide

4-ethylsulfanyl-phenol (79mg, 0.51 mmol) was added to a solution of N-(1-Acetyl- piperidin-4-yl)-2-chloro-5-fluoro-nicotinamide (140mg, 0.47mmol) and caesium carbonate (213mg, 0.65mmol) in toluene : N-methylpyrrolidine (4 : 1, 2ml) under nitrogen at room temperature. Copper(l)iodide (9mg, O.Oδmmol) was then added and the reaction was heated to 110°C and stirred at this temperature under nitrogen for 2h. The reaction mixture was then cooled, filtered through arbocel and the filtrate was diluted with ethyl acetate (15ml). The mixture was washed with water (15ml), dried over Mg₂S0₄ and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with a solvent gradient of dichloromethane : methanol : concentrated aqueous ammonia (99.δ : O.δ : O.Oδ changing to 9δ : δ : O.δ, by volume). The product was then dissolved in ethyl acetate (1 δml), washed with water (1 δml), dried over Mg₂SO₄ and concentrated under δ reduced pressure to give N-(1-Acetyl-piperidin-4-yl)-2-4-ethylsulfanyl-phenoxy)-δ- fluoro-nicotinamide (δl g) as an off-white foam.

¹H NMR (400MHz, CDCI₃): δ = 8.31-8.38 (1 H, dd), 8.03-8.05 (1 H, d), 778-7.86 (1 H, d), 7.37-7.43 (2H, d), 7.00-7.09 (2H, d), 4.39-4.48 (1 H, d), 4.19-4.29 (1 H, m), 3.71 - 0 3.79 (1 H, d), 3.20-3.29 (1 H, t), 2.83-2.99 (3H, quart + t), 2.00-2.20 (5H, m + s), 1.39- 1.δ3 (2H, m), 1.33-1.39 (3H, t) ppm.

LRMS (electrospray) : m/z [M+Na]⁺ 440, [M-H]⁺ 417. 5 Anal. Found C, 59.06; H, 5.82; N, 9.57. C₂₁H₂₄FN₃O₃S. O.l mol H₂O requires C, 59.24; H, 5.75; N, 9.82%.

Example 41 0 N-(1-Acetyl-piperidin-4-yl)-2-(4-methylsulfanyl-phenoxy)-5-fluoro-nicotinamide

N-(1-Acetyl-piperidin-4-yl)-2-chloro-5-fluoro-nicotinamide (100mg, 0.33mmol), 4- methylsulfanyl-phenol (δlmg, 0.37mmol) and caesium carbonate (163mg, O.δmmol)δ were suspended in dimethylformamide (1.δml) and the reaction was heated to δδ°C and stirred at this temperature under nitrogen for 18h. The reaction was quenched with sat. ammonium chloride solution (1 ml) and water (1 ml) and the organic phase was collected by passing the mixture through a chemelute cartridge, washing with ethyl acetate (20ml). The solvent was removed on a Genevac and the residue was purified by preparative HPLC to N-(1-acetyl-piperidin-4-yl)-2-(4-methylsulfanyl- phenoxy)-δ-fluoro-nicotinamide (27mg) as an off-white solid.

¹H NMR (400MHz, CDCI₃): δ = 8.31-8.36 (1 H, dd), 8.01-8.03 (1 H, d), 7.80-7.86 (1 H, d), 7.30-7.34 (2H, d), 7.02-7.06 (2H, d), 4.37-4.44 (1 H, d), 4.18-4.28 (1 H, m), 3.72- 3.79 (1 H, d), 3.19-3.28 (1 H, t), 2.83-2.9δ (1 H, t), 2.48 (3H, s), 2.00-2.17 (5H, 2xm + s), 1.39-1.50 (2H, m) ppm.0 LRMS (electrospray) : m/z [M+Na]⁺ 426, [M-H]⁺ 402.

HRMS : Found [M+H]⁺ 404.1446. C₂₀H₂₃FN₃O₃S requires 404.1439 Found [M+Na]⁺ 426.126δ. C₂₀H₂₂FN₂O₃SNa requires 426.1268.5

Example 42

N-(1-Acetyl-piperidin-4-yl)-2-(4-methylsulfanyl-3-methyl-phenoxy)-5-fluoro- nicotinamide

N-(1-Acetyl-piperidin-4-yl)-2-chloro-5-fluoro-nicotinamide (100mg, 0.33mmol), 4- methylsulfanyl-3-methyl-phenol (57mg, 0.37mmol) and caesium carbonate (163mg, O.δmmol) were suspended in dimethylformamide (l .δml) and the reaction wasδ heated to δδ°C and stirred at this temperature under nitrogen for 18h. The reaction was quenched with sat. ammonium chloride solution (1ml) and water (1 ml) and the organic phase was collected by passing the mixture through a chemelute cartridge, 9δ washing with ethyl acetate (20ml). The solvent was removed on a Genevac and the residue was purified by preparative HPLC to give N-(1-acetyl-piperidin-4-yl)-2-(4- methylsulfanyl-3-methyl-phenoxy)-5-fluoro-nicotinamide (34mg) as an off-white solid.

¹H NMR (400MHz, CDCI₃): δ = 8.29-8.35 (1 H, dd), 8.02-8.04 (1 H, d), 7.83-7.89 (1 H, d), 7.21-7.24 (1 H, d), 6.92-6.96 (2H, d + s), 4.37-4.44 (1 H, d), 4.19-4.28 (1 H, m), 3.69-378 (1 H, d), 3.20-3.28 (1 H, t), 2.84-2.93 (1 H, t), 2.46 (3H, s), 2.37 (3H, s), 2.00- 2.17 (5H, 2xm + s), 1.40-1.50 (2H, m) ppm.

LRMS (electrospray) : m/z [M+Na]⁺ 440, [M-H]⁺ 416.

HRMS : Found [M+H]⁺ 418.1603 C₂₁H₂₅FN₃O₃S requires 418.1596.

Example 43

N-(1-Acetyl-piperidin-4-yl)-2-(3-methylsulfanyl-4-chloro-phenoxy)-5-fluoro- nicotinamide

N-(1-Acetyl-piperidin-4-yl)-2-chloro-δ-fluoro-nicotinamide (100mg, 0.33mmol), 3- methyIsulfanyl-4-chloro-phenol (US4005148) (64mg, 0.37mmol) and caesium carbonate (163mg, O.δmmol) were suspended in dimethylformamide (1.5ml) and the reaction was heated to 5δ°C and stirred at this temperature under nitrogen for 18h. The reaction was quenched with sat. ammonium chloride solution (1 ml) and water (1ml) and the organic phase was collected by passing the mixture through a chemelute cartridge, washing with ethyl acetate (20ml). The solvent was removed on a Genevac and the residue was purified by preparative HPLC to give N-(1 -acetyl- piperidin-4-yl)-2-(3-methylsulfanyl-4-chloro-phenoxy)-5-fluoro-nicotinamide (21 mg) as an off-white solid.

¹H NMR (400MHz, CDCI₃): δ = 8.31-8.36 (1 H, dd), 8.02-8.04 (1 H, d), 7.69-774 (1 H, d), 7.37-7.40 (1 H, d), 6.92 (1 H, s), 679-6.83 (1 H, d), 4.42-4.49 (1 H, d), 4.18-4.29 (1 H, m), 374-3.81 (1 H, d), 3.20-3.28 (1 H, t), 2.82-2.90 (1 H, t), 2.44 (3H, s), 2.00-2.19 (5H, d + s), 1.39-1.61 (2H, m) ppm.

LRMS (electrospray) : m/z [M+Na]⁺ 460, 462, [M-H]⁺ 436, 438.

HRMS : Found [M+H]⁺ 438.1056. C₂₀H₂₂CIFN₃O₃S requires 438.1049 Found [M+Na]⁺ 460.0868. C₂₀H₂ιCIFN₃O₃SNa requires 460.0868.

Example 44

N-(1-Acetyl-piperidin-4-yl)-2-(4-methylsulfanyl-3-chIoro-phenoxy)-5-fluoro- nicotinamide

N-(1-Acetyl-piperidin-4-yl)-2-chloro-5-fluoro-nicotinamide (100mg, 0.33mmol), 3- methylsulfanyl-4-chloro-phenol (64mg, 0.37mmol) and caesium carbonate (163mg, O.δmmol) were suspended in dimethylformamide (1.6ml) and the reaction was heated to 5δ°C and stirred at this temperature under nitrogen for 18h. The reaction was quenched with sat. ammonium chloride solution (1ml) and water (1 ml) and the organic phase was collected by passing the mixture through a chemelute cartridge, washing with ethyl acetate (20ml). The solvent was removed on a Genevac and the residue was purified by preparative HPLC to give N-(1-acetyl-piperidin-4-yl)-2-(4- methylsulfanyl-3-chloro-phenoxy)-5-fluoro-nicotinamide (4.6mg) as an off-white solid.

¹H NMR (400MHz, CDCI₃): D = 8.31-8.36 (1 H, dd), 8.03-8.06 (1 H, d), 7.67-774 (1 H, d), 7.24 (1 H, s), 7.18-7.20 (1 H, d), 7.02-7.06 (1 H, dd), 4.40-4.49 (1 H, d), 4.18-4.29 (1H, m), 372-379 (1 H, d), 3.20-3.28 (1 H, t), 2.82-2.93 (1 H, t), 2.49 (3H, s), 2.00-2.19 (5H, m + s), 1.39-1.63 (2H, m) ppm.

LRMS (electrospray) : m/z [M+Na]⁺ 460, 462, [M-H]⁺ 436, 438.

HRMS : Found [M+H]⁺ 438.1056. C₂₀H₂₂CIFN₃O₃S requires 438.1049 Found [M+Naf 460.0874. C₂₀H₂₁CIFN₃O₃SNa requires 460.0868.

Example 45

N-(1-Acetyl-piperidin-4-yl)-2-(4-methylsulfanyl-3,5-dimethyl-phenoxy)-5-fluoro- nicotinamide

N-(1-Acetyl-piperidin-4-yl)-2-chloro-δ-fluoro-nicotinamide (100mg, 0.33mmol), 4- methylsulfanyl-3,δ-dimethyl-phenol (62mg, 0.37mmol) and caesium carbonate (163mg, O.δmmol) were suspended in dimethylformamide (1.6ml) and the reaction was heated to 55°C and stirred at this temperature under nitrogen for 18h. The reaction was quenched with sat. ammonium chloride solution (1ml) and water (1ml) and the organic phase was collected by passing the mixture through a chemelute cartridge, washing with ethyl acetate (20ml). The solvent was removed on a Genevac and the residue was purified by preparative HPLC to give N-(1 -acetyl- piperidin-4-yl)-2-(4-methylsulfanyl-3,5-dimethyl-phenoxy)-5-fluoro-nicotinamide (24mg) as an off-white solid.

¹H NMR (400MHz, CDCI₃): δ = 8.28-8.36 (1 H, dd), 8.03-8.05 (1 H, d), 777-7.84 (1 H, m), 6.83 (2H, s), 4.37-4.46 (1 H, d), 4.17-4.28 (1 H, m), 370-379 (1 H, d), 3.18-3.28 (1 H, t), 2.81-2.93 (1 H, t), 2.68 (6H, s), 2.23 (3H, s), 2.00-2.19 (5H, 2xm + s), 1.38- 1.50 (2H, m) ppm.

LRMS (electrospray) : m/z [M+Na]⁺ 454, [M-H]⁺ 430.

HRMS : Found [M+H]⁺ 432.1757. C₂₂H₂₇FN₃O₃S requires 432.1752 Found [M+Na]⁺ 454.1580. C₂₂H₂₆FN₃O₃SNa requires 454.1571.

Example 46

N-(1-Acetyl-piperidin-4-yl)-2-(2,3-dihydrobenzo[b]thiophen-5-yloxy)-5-fluoro- nicotinamide

N-(1-Acetyl-piperidin-4-yl)-2-chloro-δ-fluoro-nicotinamide (100mg, 0.33mmol), 2,3- dihydrobenzo[b]thiophen-δ-ol (56mg, 0.37mmol) and caesium carbonate (163mg, O.δmmol) were suspended in dimethylformamide (1.6ml) and the reaction was heated to 5δ°C and stirred at this temperature under nitrogen for 18h. The reaction was quenched with sat. ammonium chloride solution (1ml) and water (1 ml) and the organic phase was collected by passing the mixture through a chemelute cartridge, washing with ethyl acetate (20ml). The solvent was removed on a Genevac and the residue was purified by preparative HPLC to give N-(1-acetyl-piperidin-4-yl)-2-(2,3- dihydrobenzo[b]thiophen-5-yloxy)-5-fluoro-nicotinamide (34mg) as an off-white solid.

¹H NMR (400MHz, CDCI₃): δ = 8.28-8.35 (1 H, dd), 8.02-8.04 (1H, d), 7.80-7.94 (1H, d), 7.22-7.26 (1 H, d), 6.93 (1H, s), 6.83-6.88 (1 H, d), 4.38-4.48 (1H, d), 4.18-4.29 (1H, m), 371-3.80 (1 H, d), 3.38-3.45 (2H, m), 3.19-3.37 (3H, m), 2.84-2.97 (1 H, t), 1.90-2.20 (5H, m + s), 1.39-1.66 (2H, m) ppm.

LRMS (electrospray) : m/z [M+Na]⁺ 438, [M-H]⁺ 414.0 HRMS : Found [M+H]⁺ 416.1445. C₂ιH₂₃FN₃O₃S requires 416.1439 Found [M+Na]⁺ 438.1269. C₂₁H₂₂FN₃O₃SNa requires 438.1258.

δ Example 47

N-(1-Acetyl-piperidin-4-yl)-2-(2,3-dihydrobenzo[1,4]oxathiin-7-yloxy)-5-fluoro- nicotinamide

0 N-(1-Acetyl-piperidin-4-yl)-2-chloro-5-fluoro-nicotinamide (100mg, 0.33mmol), 2,3- dihydrobenzo[1,4]oxathiin-7-ol (62mg, 0.37mmol) and caesium carbonate (163mg, O.δmmol) were suspended in dimethylformamide (1.6ml) and the reaction was heated to 5δ°C and stirred at this temperature under nitrogen for 18h. The reaction was quenched with sat. ammonium chloride solution (1ml) and water (1ml) and the5 organic phase was collected by passing the mixture through a chemelute cartridge, washing with ethyl acetate (20ml). The solvent was removed on a Genevac and the residue was purified by preparative HPLC to give N-(1-acetyl-piperidin-4-yl)-2-(2,3- dihydrobenzo[1 ,4]oxathiin-7-yloxy)-5-fluoro-nicotinamide (33mg) as an off-white solid.

¹H NMR (400MHz, CDCI₃): δ = 8.30-8.35 (1 H, dd), 8.04-8.06 (1 H, d), 778-7.87 (1 H, d), 7.05-7.09 (1 H, d), 6.62-6.66 (2H, s + d), 4.36-4.47 (3H, 2xm), 4.18-4.29 (1 H, m), 372-379 (1 H, d), 3.20-3.30 (1 H, t), 3.12-3.17 (2H, m), 2.86-2.98 (1 H, t), 1.99-2.17 (δH, 2xm + s), 1.39-1.63 (2H, m) ppm.

LRMS (electrospray) : m/z [M+Na]⁺ 454, [M-Hf 4.30.

HRMS : Found [M+H]⁺ 432.1398. C₂ιH₂₃FN₃O₄S requires 432.1388 Found [M+Naf 454.1216. C₂₁H₂₂FN₃O₄SNa requires 454.1207.

Example 48

N-(1-Acetyl-piperidin-4-yI)-2-(4-methyIsulfanyl-2-fluoro-phenoxy)-5-fluoro- nicotinamide

N-(1-Acetyl-piperidin-4-yl)-2-chloro-5-fluoro-nicotinamide (100mg, 0.33mmol), 4- methylsulfanyl-2-fluoro-phenol (58mg, 0.37mmol) and caesium carbonate (163mg, O.δmmol) were suspended in dimethylformamide (1.6ml) and the reaction was heated to 5δ°C and stirred at this temperature under nitrogen for 18h. The reaction was quenched with sat. ammonium chloride solution (1 ml) and water (1 ml) and the organic phase was collected by passing the mixture through a chemelute cartridge, washing with ethyl acetate (20ml). The solvent was removed on a Genevac and the residue was purified by preparative HPLC to give N-(1-acetyl-piperidin-4-yl)-2-(4- methylsulfanyl-2-fluoro-phenoxy)-5-fluoro-nicotinamide (12mg) as an off-white solid.

¹H NMR (400MHz, CDCI₃): δ = 8.30-8.36 (1 H, dd), 8.00-8.02 (1 H, d), 773-779 (1 H, d), 7.22-7.26 (1 H, d), 7.08-7.13 (2H, m), 4.38-4.47 (1 H, d), 4.20-4.30 (1 H, m), 3.74- 3.80 (1 H, d), 3.20-3.29 (1 H, t), 2.87-2.97 (1 H, t), 2.61 (3H. s), 2.00-2.19 (5H, 2xm + s), 1.41-1.56 (2H, m) ppm.

LRMS (electrospray) : m/z [M+Na]⁺ 444, [M-H]⁺ 420.

HRMS : Found [M+H]⁺ 422.1360. C₂₀H₂₂F₂N₃O₃S requires 422.1345 Found [M+Na]⁺ 444.1172. C₂₀H₂₁F₂N₃O₃SNa requires 444.1164.

Example 49

N-(1-Acetyl-piperidin-4-yl)-2-(3-methylsulfanyl-4-methyl-phenoxy)-5-fluoro- nicotinamide

N-(1-Acetyl-piperidin-4-yl)-2-chloro-5-fluoro-nicotinamide (100mg, 0.33mmol), 3- methylsulfanyl-4-methyl-phenol (67mg, 0.37mmol) and caesium carbonate (163mg, O.δmmol) were suspended in dimethylformamide (1.6ml) and the reaction was heated to 5δ°C and stirred at this temperature under nitrogen for 18h. The reaction was quenched with sat. ammonium chloride solution (1 ml) and water (1ml) and the organic phase was collected by passing the mixture through a chemelute cartridge, washing with ethyl acetate (20ml). The solvent was removed on a Genevac and the residue was purified by preparative HPLC to give N-(1-acetyl-piperidin-4-yl)-2-(3- methylsulfanyl-4-methyl-phenoxy)-5-fluoro-nicotinamide (24mg) as an off-white solid.

¹H NMR (400MHz, CDCI₃): δ = 8.32-8.36 (1 H, dd), 8.02-8.04 (1H, d), 7.83-7.89 (1 H, δ d), 7.17-7.21 (1 H, d), 6.87-6.89 (1 H, d), 677-6.81 (1 H, dd), 4.39-4.47 (1 H, d), 4.19- 4.29 (1 H, m), 373-3.80 (1 H, d), 3.20-3.28 (1 H, t), 2.84-2.94 (1 H, t), 2.43 (3H, s), 2.34 (3H, s), 2.00-2.18 (5H, s + m), 1.39-1.53 (2H, m) ppm.

LRMS (electrospray) : m/z [M+Na]⁺ 440, [M-H]⁺ 416.0 HRMS : Found [M+H]⁺ 418.1593. C₂₁H₂₅FN₃O₃S requires 418.1596.

Example 50

5-Fluoro-N-(1-methanesulfonyl-piperidin-4-yl)-2-(3-methylsulfanyl-phenoxy)-5 nicotinamide

5-Fluoro-2-(3-methylsulfanyl-phenoxy)-N-piperidin-4-yl-nicotinamide (107mg, 0.269mmol) was suspended in dichloromethane (4ml) under nitrogen at -78°C and0 triethylamine (83DI, 0.538mmol) was added followed by methanesulfonyl chloride (3δUl, 0.403mmol). The reaction was allowed to warm to room temperature for 2h and was quenched with sat. sodium bicarbonate solution (1ml). After diluting with water (4ml) the aqueous phase was extractred with dichloromethane (10ml) and the organic phase was removed and concentrated under reduced pressure. The residue5 was purified by flash column chromatography on silica gel eluting with ethyl acetate : cyclohexane (40 : 60 changing to 90 : 10, by volume) to give 5-fluoro-N-(1 - methanesulfonyl-piperidin-4-yl)-2-(3-methylsulfanyl-phenoxy)-nicotinamide (99mg) as a white foam.

¹H NMR (400MHz, CD₃OD): δ = 8.08-8.10 (1 H, d), 7.97-8.00 (1 H, m), 7.28-7.33 (1 H, t), 7.10-7.14 (1 H, d), 7.03 (1 H, s), 6.84-6.89 (1 H, d), 3.98-4.06 (1 H, m), 3.68-3.65 (2H, m), 2.93-3.00 (2H, t), 2.78 (3H, s), 2.43 (3H, s), 2.00-2.08 (2H, m), 1.61-173 (2H, m) ppm.

LRMS (electrospray) : m/z [M+Na]⁺ 462, [M-H]⁺ 438.

Anal. Found C, 50.91 ; H, 4.96; N, 8.99. Cι₉H₂₂FN₃O₄S₂. 0.6mol H₂O requires C, 60.68; H, 5.19; N, 9.33%.

Example 51

N-(2-Ethyl-2H-pyrazol-3-yl)-5-fluoro-2-(3-methylsulfanyl-phenoxy)-nicotinamide

1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (75mg, 0.394mmol) and 1 -hydroxybenzotriazole (60mg, 0.394mmol) were added to a suspension of 5- fluoro-2-(3-methylsulfanyl-phenoxy)-nicotinic acid (100mg, 0.358mmol) in dichloromethane (2ml). This was stirred under nitrogen at room temperature for 15min, and a solution of 2-ethyl-2H-pyrazol-3-ylamine (44mg, 0.394mmol) in dichloromethane (2ml) was added. The reaction was stirred under nitrogen at room temperature for 72h and the mixture was quenched with water (1 ml) and diluted with dichloromethane (5ml). The mixture was then passed through a phase separation cartridge and the organic layer was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with ethyl acetate : cyclohexane (1 : 2, by volume) to give N-(2-Ethyl-2H-pyrazol-3-yl)-5-fluoro- 2-(3-methylsulfanyl-phenoxy)-nicotinamide (63mg) as a crystalline white solid.

¹H NMR (400MHz, CDCI₃): δ = 9.82 (1 H, s), 8.40-8.44 (1 H, dd), 8.13-8.16 (1H, d), 7.46-7.47 (1 H, d), 7.37-7.41 (1 H, t), 7.18-7.22 (1 H, d), 7.05-7.08 (1 H, t), 6.91-6.96 (1H, m), 6.57 (1 H, s), 4.02-4.10 (2H, quart), 2.50 (3H, s), 1.34-1.40 (3H, t) ppm.

LRMS (electrospray) : m/z [M+H]⁺ 373, [M+Na]⁺ 395, [M-H]⁺ 371.

Example 52

5-Fluoro-N-(3-hydroxy-pyridin-2-yl)-2-(3-methylsulfanyl-phenoxy)-nicotinamide

2-Amino-3-hydroxypyridine (83mg, 0752mmol) and triethylamine (300DI, 2.14mmol) were dissolved in dimethylformamide (800DI) under nitrogen at room temperature and a solution of δ-fluoro-2-(3-methylsulfanyl-phenoxy)-nicotinic acid (150mg, 0.637mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (113mg, 0.690mmol) and 1-hydroxybenzotriazole (80mg, 0.690mmol) in dimethylformamide (δml) and the reaction was stirred at room temperature for 24h. The reaction mixture was concentrated under reduced pressure, and the residue was partitioned between ethyl acetate (20ml) and 1M HCl (20ml). The organic phase was removed, washed with water (20ml) and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with dichloromethane : methanol : concentrated aqueous ammonia (95 : δ : 0.6, by 106 volume) and the product was crystallised from DIISOPROPYLETHER (δml) to give 5- fluoro-N-(3-hydroxy-pyridin-2-yl)-2-(3-methylsulfanyl-phenoxy)-nicotinamide (87mg) as a white solid.

¹H NMR (400MHz, CDCI₃): δ = 10.42-10.60 (1 H, brs), 10.13-10.18 (1 H, brs), 8.38- 8.42 (1 H, m), 8.27-8.31 (1 H, m), 8.12-8.16 (1 H, m), 7.33-7.39 (2H, m), 7.14-7.18 (1 H, d), 7.10-7.14 (2H, m), 6.95-7.00 (1 H, d), 2.48 (3H, s) ppm.

LRMS (electrospray) : m/z [M+H]⁺ 372, [M+Na]⁺ 394, [M-H]⁺ 370.

Anal. Found C, 57.62; H, 3.70; N, 1 1.11. Cι₈Hι₄FN₃O₃S. 0.25mol H₂O requires C, 67.51 ; H, 3.88; N, 11.18%.

Example 53

5-Fluoro-2-(3-methylsulfanyl-phenoxy)-N -pyridin-4-yl-nicotinamide

4-Aminopyridine (120mg, 1.28mmol) and triethylamine (355DI, 2.56mmol) were dissolved in dimethylformamide (1 ml) under nitrogen at room temperature and a solution of δ-fluoro-2-(3-methylsulfanyl-phenoxy)-nicotinic acid (35δmg, 1.28mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (268mg, 1.41 mmol) and 1-hydroxybenzotriazole (189mg, 1.41 mmol) in dimethylformamide (7.5ml) and the reaction was stirred at room temperature for 24h. The reaction mixture was concentrated under reduced pressure, and the residue was partitioned between ethyl acetate (20ml) and 1 M HCl (20ml). The organic phase was removed, washed with 10% sodium bicarbonate solution (20ml), brine (20ml), dried over Na₂SO₄ and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with dichloromethane : methanol : concentrated aqueous ammonia (97.5 : 2.5 : 0.25, by volume) and the product was crystallised from DIISOPROPYLETHER (δml) to give 5-fluoro-2-(3-methylsulfanyl- phenoxy)-N -pyridin-4-yl-nicotinamide (87mg) as a white solid.

¹H NMR (400MHz, CDCI₃): δ = 9.84-9.96 (1 H, brs), 8.54-8.60 (2H, m), 8.40-8.46 (1 H, dd), 8.13-8.16 (1 H, d), 7.58-7.63 (2H, d), 7.38-7.44 (1 H, t), 7.20-7.24 (1 H, d), 7.10 (1 H, s), 6.94-7.00 (1 H, d), 2.60 (3H, s) ppm.

LRMS (electrospray) : m/z [M+H]⁺ 356, [M+Na]⁺ 378, [M-H]⁺ 354.

Anal. Found C, 60.66; H, 3.91 ; N, 11.69. Cι₈H₁₄FN₃O₃S requires C, 60.83; H, 3.97; N, 11.82%.

Example 54

5-Fluoro-2-(3-methylsulfanyl-phenoxy)-N -pyridin-2-yl-nicotinamide

2-Aminopyridine (120mg, 1.28mmol) and triethylamine (356DI, 2.56mmol) were dissolved in dimethylformamide (1 ml) under nitrogen at room temperature and a solution of 6-fluoro-2-(3-methylsulfanyl-phenoxy)-nicotinic acid (35δmg, 1.28mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (268mg, 1.41 mmol) and 1-hydroxybenzotriazole (189mg, 1.41 mmol) in dimethylformamide (7.5ml) and the reaction was stirred at room temperature for 24h. The reaction mixture was concentrated under reduced pressure, and the residue was partitioned between ethyl acetate (20ml) and 1 M HCl (20ml). The organic phase was removed, washed with 10% sodium bicarbonate solution (20ml), brine (20ml), dried over Na₂SO₄ and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with dichloromethane : methanol : concentrated aqueous ammonia (97.5 : 2.5 : 0.2δ, by volume) and the product was crystallised from DIISOPROPYLETHER (δml) to give δ-fluoro-2-(3-methylsulfanyl- phenoxy)-N -pyridin-4-yl-nicotinamide (89mg) as a white solid.

¹H NMR (400MHz, CDCI₃): δ = 10.20-10.29 (1 H, brs), 8.38-8.46 (2H, dm), 8.31-8.36 (1 H, m), 8.13-8.15 (1 H, d), 775-7.80 (1 H, ), 7.35-7.40 (1 H, t), 7.17-7.21 (1 H, d), 7.06-7.16 (2H, m), 6.98-7.02 (1 H, dd), 2.47 (3H, s) ppm.

LRMS (electrospray) : m/z [M+Naf 378, [2M+Na]⁺ 733, [M-H]⁺ 354.

Anal. Found C, 60.34; H, 3.96; N, 11.59. Cι₈H₁₄FN₃O₃S requires C, 60.83; H, 3.97; N, 11.83%.

Example 55

5-Fluoro-2-(3-methylsulfanyl-phenoxy)-N -pyridin-3-yl-nicotinamide

3-Aminopyridine (120mg, 1.28mmol) and triethylamine (356DI, 2.56mmol) were dissolved in dimethylformamide (1 ml) under nitrogen at room temperature and a solution of 5-fluoro-2-(3-methylsulfanyl-phenoxy)-nicotinic acid (3δ5mg, 1.28mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (268mg, 1.41 mmol) and 1-hydroxybenzotriazole (189mg, 1.41 mmol) in dimethylformamide (7.δml) and the reaction was stirred at room temperature for 24h. The reaction mixture was concentrated under reduced pressure, and the residue was partitioned between ethyl acetate (20ml) and 1 M HCl (20ml). The organic phase was removed, washed with 10% aqueous ammonia solution (20ml), brine (20ml), dried over Na₂SO₄ and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with dichloromethane : methanol : concentrated aqueous ammonia (97.5 : 2.5 : 0.25, by volume) and the product was crystallised from DIISOPROPYLETHER (δml) to give δ-fluoro-2-(3-methylsulfanyl- phenoxy)-N -pyridin-3-yl-nicotinamide (197mg) as a white solid.

¹H NMR (400MHz, CDCI₃): δ = 977-9.84 (1 H, brs), 8.61-874 (1H, d), 8.39-8.49 (2H, dd), 8.26-8.32 (1H, d), 8.14 (1H, s), 7.38-7.44 (1 H, t), 7.29-7.37 (1 H, m), 7.19-7.24 (1H, d), 7.11 (1H, s), 6.95-7.02 (1 H, d), 2.50 (3H, s) ppm.

LRMS (electrospray) : m/z [M+Na]⁺ 378, [2M+Na]⁺ 733, [M-Hf 364.

Anal. Found C, 60.33; H, 3.89; N, 11.66. Cι₈Hι₄FN₃O₃S. 0.15mol H₂0 requires C, 60.38; H, 4.03; N, 11.73%.

Example 56

5-Fluoro-N-(4-hydroxy-pyrimidin-2-yl-)2-(3-methylsuIfanyl-phenoxy)- nicotinamide

2-Amino-4-hydroxypyrimidine (142mg, 1.28mmol) and triethylamine (356DI, 2.56mmol) were dissolved in dimethylformamide (1ml) under nitrogen at room temperature and a solution of δ-fluoro-2-(3-methylsulfanyl-phenoxy)-nicotinic acid (35δmg, 1.28mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (268mg, 1.41 mmol) and 1-hydroxybenzotriazole (189mg, 1.41mmol) in dimethylformamide (7.5ml) and the reaction was stirred at room temperature for 24h. The reaction mixture was concentrated under reduced pressure, and the residue was partitioned between dichloromethane (20ml) and water (20ml). The organic phase was dried over Na₂SO₄ and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with dichloromethane : methanol : concentrated aqueous ammonia (97.5 : 2.5 : 0.25, by volume) and the product was crystallised from DIISOPROPYLETHER (δml) to give 5- fluoro-N-(4-hydroxy-pyrimidin-2-yl-)2-(3-methylsulfanyl-phenoxy)-nicotinamide (7mg) as a white solid.

¹H NMR (400MHz, CDCI₃): δ = 8.38-8.41 (1 H, dd), 8.09-8.11 (1 H, d), 772-777 (1 H, d), 7.36-7.41 (1 H, t), 7.23-7.26 (2H, m, partially masked by solvent), 7.19-7.22 (1 H, dd), 7.07 (1 H, s), 6.94-6.98 (1 H, dd), 6.19-6.23 (1 H, d), 2.48 (3H, s) ppm.

LRMS (electrospray) : m/z [M+Naf 395, [2M+Na]⁺ 767, [M-H]⁺ 371. Example 57

5-Fluoro-N-(6-methoxy-pyridin-3-yl)-2-(3-methylsulfanyl-phenoxy)-nicotinamide

5-Amino-2-methoxypyridine (89mg, 0716mmol) and triethylamine (200DI, 2.14mmol) were dissolved in dimethylformamide (1ml) under nitrogen at room temperature and a solution of 5-Fluoro-2-(3-methylsulfanyl-phenoxy)-nicotinic acid (200mg, 0716mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (151 mg, 0788mmol) and 1-hydroxybenzotriazole (106mg, 0788mmol) in dimethylformamide (δml) and the reaction was stirred at room temperature for 18h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by flash column chromatography on silica gel eluting with a solvent gradient of dichloromethane : methanol : concentrated aqueous ammonia (100 : 0 : 0 changing to 98 : 2 : 0 then 97.5 : 2.5 : 0.25, by volume) and the product was crystallised from DIISOPROPYLETHER (δml) to give 5-Fluoro-N-(6-methoxy-pyridin-3-yl)-2-(3- methylsulfanyl-phenoxy)-nicotinamide (139mg) as an off-white solid.

¹H NMR (400MHz, CDCI₃): δ = 9.47 (1 H, s), 8.46-8.51 (1 H, d), 8.18 (1 H, s), 7.94-7.96 (1 H, d), 7.83-7.88 (1 H, dd), 7.20-7.26 (1 H, t), 7.04-7.08 (1H, d), 6.93 (1 H, s), 6.80- 6.84 (1 H, d), 6.60-6.65 (1 H, d), 3.77 (3H. s), 2.36 (3H, s) ppm.

LRMS (electrospray) : m/z [M+H]⁺ 386, [M+Na]⁺ 408, [2M+Na]⁺ 793, [M-H]⁺ 384.

Anal. Found C, 58.76; H, 4.14; N, 10.77. C₁₉Hι₆FN₃O₃S requires C, 59.21 ; H, 4.18; N, 10.90%. Example 58

5-Fluoro-N-(2-methoxy-pyridin-3-yl)-2-(3-methylsulfanyl-phenoxy)-nicotinamide

3-Amino-2-methoxypyridine (89mg, 0716mmol) and triethylamine (200DI, 2.14mmol) were dissolved in dimethylformamide (1 ml) under nitrogen at room temperature and a solution of 5-Fluoro-2-(3-methylsulfanyl-phenoxy)-nicotinic acid (200mg, 0716mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (151 mg, 0788mmol) and 1-hydroxybenzotriazole (106mg, 0788mmol) in dimethylformamide (δml) and the reaction was stirred at room temperature for 3h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by flash column chromatography on silica gel eluting with a solvent gradient of dichloromethane : methanol : concentrated aqueous ammonia (97.5 : 2.5 : 0.26, by volume) and the product was crystallised from DIISOPROPYLETHER (δml) to give 5- fluoro-N-(2-methoxy-pyridin-3-yl)-2-(3-methylsulfanyl-phenoxy)-nicotinamide (92mg) as an off-white solid.

¹H NMR (400MHz, CDCI₃): δ = 10.57 (1 H, s), 874-8.80 (1 H, d), 8.40-8.44 (1 H, dd), 8.12-8.14 (1 H, d), 7.88-7.92 (1 H, d), 7.37-7.42 (1 H, t), 7.18-7.22 (1 H, d), 7.17 (1H, s), 7.01-7.04 (1 H, m), 6.94-6.98 (1 H, m), 3.88 (3H, s), 2.53 (3H, s) ppm.

LRMS (electrospray) : m/z [M+Na]⁺ 408, [2M+Na]⁺ 793, [M-H]⁺ 384.

Anal. Found C, 59.04; H, 4.16; N, 10.93. C₁₉Hι₆FN₃0₃S requires C, 59.21 ; H, 4.18; N, 10.90%. Example 59

5-Fluoro-N-(3-hydroxymethyl-pyridin-2-yl)-2-(3-methylsulfanyl-phenoxy)- nicotinamide

2-Hydroxymethyl-3-aminopyridine (89mg, 0716mmol) and triethylamine (200DI, 2.14mmol) were dissolved in dimethylformamide (1 ml) under nitrogen at room temperature and a solution of 5-Fluoro-2-(3-methylsulfanyl-phenoxy)-nicotinic acid (200mg, 0716mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (151 mg, 0788mmol) and 1-hydroxybenzotriazole (106mg, 0788mmol) in dimethylformamide (δml) and the reaction was stirred at room temperature for 18h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by flash column chromatography on silica gel eluting with a solvent gradient of dichloromethane : methanol : concentrated aqueous ammonia (97.6 : 2.6 : 0.25 changing to 95 : δ : O.δ, by volume) and the product was crystallised from diisopropyl ether (δml) to give 5-Fluoro-N-(3-hydroxymethyl-pyridin-2-yl)-2-(3-methylsulfanyl- phenoxy)-nicotinamide (127mg) as an off-white solid.

¹H NMR (400MHz, CDCI₃): δ = 8.14-8.16 (1 H, d), 8.06-8,08 (1 H, dd), 8.02-8.04 (1 H, dd), 7.50-7.54 (1 H, d), 7.28-7.32 (1 H, t), 7.10-7.14 (1 H, d), 6.97 (1 H, s), 6.84-6.88 (1 H, d), 6.46-6.50 (1 H, d), 5.33 (2H, s), 4.89 (2H, brs), 2.45 (3H, s) ppm.

LRMS (electrospray) : m/z [M+Hf 386, [M+Na]⁺ 408, [2M+Na]⁺ 793, [M-H]⁺ 384. Anal. Found C, 58.83; H, 4.16; N, 10.73. C₁₉H₁₆FN₃O₃S requires C, 59.21 ; H, 4.19; N, 10.90%.

Example 60

N-(3-Ethoxy-pyridin-2-yl)-5-fluoro-2-(3-methylsulfanyl-phenoxy)-nicotinamide

3-Ethoxy-2-aminopyridine (99mg, 0716mmol) and triethylamine (200GI, 2.14mmol) were dissolved in dimethylformamide (1ml) under nitrogen at room temperature and a solution of 5-Fluoro-2-(3-methylsulfanyl-phenoxy)-nicotinic acid (200mg,

0716mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (151mg,

0788mmol) and 1-hydroxybenzotriazole (106mg, 0788mmol) in dimethylformamide

(5ml) and the reaction was stirred at room temperature for 18h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by flash column chromatography on silica gel eluting with a solvent gradient of dichloromethane : methanol : concentrated aqueous ammonia (97.5 : 2.5 : 0.25, by volume) and the product was crystallised from diisopropylether (δml) to give N-(3- ethoxy-pyridin-2-yl)-5-fluoro-2-(3-methylsulfanyl-phenoxy)-nicotinamide (38mg) as an off-white solid.

¹H NMR (400MHz, CDCI₃): δ = 10.69 (1 H, brs), 8.46-8.52 (1 H, dd), 8.14-8.18 (1 H, d), 8.10-8.13 (1 H, d), 7.35-7.40 (1 H, t), 7.17-7.21 (1 H, d), 7.08-7.15 (2H, m), 7.01-7.06 (1H, m), 6.94-6.98 (1 H, m), 3.95-4.01 (2H, quart), 2.50 (3H, s), 1.03-1.11 (3H, t) ppm. LRMS (electrospray) : m/z [M+H]⁺ 400, [M+Na]⁺ 422, [2M+Na]⁺ 821 , [M-H]⁺ 398.

Anal. Found C, 59.90; H, 4.50; N, 10.44. C₂₀H₁₈FN₃O₃S requires C, 60.14; H, 4.54; N, 10.52%.

Example 61

N-(2-Methyl-pyridin-3-yl)-5-fluoro-2-(3-methylsulfanyl-phenoxy)-nicotinamide

5-Fluoro-2-(3-methylsulfanyl-phenoxy)-nicotinic acid (150mg, 0.54mmol) was dissolved in dimethylformamide (δml) and triethylamine (225DI, 1.61 mmol) was added followed by 3-amino-2-methyl-pyridine (61 mg, 0.56mmol), 1-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (113mg, 0.59mmol) and 1- hydroxybenzotriazole (80mg, 0.59mmol). The reaction was stirred under nitrogen at room temperature for 48h and the solvent was removed under reduced pressure. The residue was partitioned between water (10ml) and dichloromethane (20ml) and the aqueous phase was extracted with dichloromethane (2x20ml). The combined organic extracts were washed with brine (10ml), dried over MgSO₄ and the solvent was removed under reduced pressure. The residual brown oil was purified by column chromatography on silica gel using pentane.ethylacetate (70:30) as eluent to give the title compound (96mg) as an off-white solid.

¹H NMR (400MHz, CDCI₃): δ = 9.91 (1H, brs), 8.63-8.66 (1H, d), 8.45-8.47 (1H, dd), 8.30-8.31 (1H, d), 8.13-8.14 (1H, d), 7.38-7.42 (1 H, t), 7.19-7.26 (2H, m), 7.07 (1 H, s), 6.95-6.97 (1 H, d), 2.52 (3H, s), 2.50 (3H, s) ppm. LRMS (electrospray): m/z [M+H]⁺ 370 and [M+Na]⁺ 392.

Anal. Found C, 60.70; H, 4.41; N, 10.91. Cι₉Hι₆FN₃O₂S. 0.3mol H₂O requires C, 60.88; H, 4.46; N, 11.21%.

Example 62

5-Fluoro-N-(4-hydroxy-5-pyrimidinyl)-2-(3-methylsulfanyl-phenoxy)- nicotinamide

5-fluoro-2-(3-methylsulfanyl-phenoxy)-nicotinic acid (150mg, 0.64mmol) was dissolved in dimethylformamide (δml) and triethylamine (226DI, 1.61 mmol) was added followed by 3-amino-2-hydroxy-pyrimidine (85mg, 0.66mmol), 1-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (113mg, 0.59mmol) and 1- hydroxybenzotriazole (80mg, O.δθmmol). The reaction was stirred under nitrogen at room temperature for 48h and the solvent was removed under reduced pressure. The residue was partitioned between water (10ml) and dichloromethane (20ml) and the aqueous phase was extracted with dichloromethane (2x20ml). The combined organic extracts were washed with brine (10ml), dried over MgSO and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel using dichloromethane:methanol:ammonia (95:6:0.6) as eluent to give the title compound (80mg) as an off-white solid. ¹H NMR (400MHz, D₆-DMSO): δ = 12.85 (1 H, brs), 10.43 (1 H, brs), 8.90 (1 H, s), 8.34 (1 H, d), 8.27-8.30 (1 H, dd), 8.04 (1 H, s), 7.35-7.39 (1 H, t), 7.21 (1 H, s), 7.14-7.16 (1 H, d), 7.04-7.07 (1 H, d) ppm. N.B. Suspect peak hidden under DMSO peak DD 3.52 (3H, s) ppm.

LRMS (electrospray): m/z [M+Na]⁺ 395 and [M-H]^" 371.

Anal. Found C, 64.76; H, 3.53; N, 14.81. Cι₇H₁₃FN₄O₃S requires C, 54.83; H, 3.62; N, 15.06%.

IN VITRO ACTIVITY OF THE NICOTINAMIDE DERIVATIVES The PDE4 inhibitory activity of the nicotinamide derivatives of the formula (1 ) is determined by the ability of compounds to inhibit the hydrolysis of cAMP to AMP by PDE4 (see also reference 1 ). Tritium labelled cAMP is incubated with PDE4. Following incubation, the radiolabelled AMP produced is able to bind yttrium silicate SPA beads. These SPA beads subsequently produce light that can be quantified by scintillation counting. The addition of a PDE4 inhibitor prevents the formation of AMP from cAMP and counts are diminished. The IC₅₀ of a PDE4 inhibitor can be defined as the concentration of a compound that leads to a 60% reduction in counts compared to the PDE4 only (no inhibitor) control wells.

The anti-inflammatory properties of the nicotinamide derivatives of the formula (1) are demonstrated by their ability to inhibit TNFα release from human peripheral blood mononuclear cells (see also reference 2). Venous blood is collected from healthy volunteers and the mononuclear cells purified by centrifugation through Histopaque (Ficoll) cushions. TNFα production from these cells is stimulated by addition of lipopolysaccharide. After 18 hours incubation in the presence of LPS, the cell supernatant is removed and the concentration of TNFα in the supernatant determined by ELISA. Addition of PDE4 inhibitors reduces the amount of TNFα produced. An IC₅o is determined which is equal to the concentration of compound that gives 50% inhibition of TNFα production as compared to the LPS stimulated control wells. All the examples were tested in the assay described above and found to have an IC50 (TNFα screen) of less than 300 nM. And for most of the tested compounds, they were found to have an IC₅₀ (TNFα screen) of even less than 100 nM.

It has been found that the compounds of Examples 1-47, and 56-69, all exhibit IC₅o values of 3 μM or less vs PDE4A, PDE4B and/or PDE4D.

References.

1. Thompson JW, Teraski WL, Epstein PM, Strada SJ., "Assay of nucleotidephosphodiesterase and resolution of multiple molecular forms of the isoenzyme", Advances in cyclic nucleotides research, edited by Brooker G, Greengard P, Robinson GA. Raven Press, New York 1979, 10, p. 69-92.

2. Yoshimura T, Kurita C, Nagao T, Usami E, Nakao T, Watanabe S, Kobayashi J, Yamazaki F, Tanaka H, Nagai H., "Effects of cAMP-phosphodiesterase isozyme inhibitor on cytokine production by lipopolysaccharide-stimulated human peripheral blood mononuclear cells", Gen. Pharmacol., 1997, 29(4), p. 63

Claims

1. A nicotinamide derivative of the formula (1 )

⁽i⁾ wherein

X is hydrogen, methyl or halo,

Y is attached to the 3- or 4-position on the phenyl ring, and is S(O)_pR¹, wherein R¹ is (C-ι-C₄) alkyl optionally substituted by (C₃-C₆)cycloalkyl and p is 0, 1 or 2,

n is 1 or 2,

Z is selected from hydrogen, (CrC₃)alkyl, halo and (Cι-C₃)alkoxy, each Z being independently selected when n is 2,

or Y and (Z)_π , when attached to adjacent carbon atoms at the 3- or 4-position on the phenyl ring, are taken together with the carbon atoms to which they are attached to form a dihydrothienyl or dihydro-1 ,4-oxathiinyl ring,

L is a 5- or 6-membered heterocyclic ring containing one or two nitrogen ring atoms, which ring is optionally substituted by OH, (Cι-C₃)alkyl (optionally substituted by OH or by (C-i-C₃)alkoxy), halo or by (Cι-C₃)alkoxy, R is H, (Cι-Cβ)alkyl (optionally substituted by OH or (Cι-C₃)alkoxy), SO₂(Cι-C₃)alkyl), or COR²,

R² is selected from the group consisting of : • (d-C₆)alkyl (optionally substituted by (d-C₃)alkoxy, OH, NR³R⁴, a 5- or 6- membered heterocyclic ring containing 1 , 2 or 3 hetero ring atoms independently selected from N, O and S, OC(O)(Cι-C₃)alkyl) or S(O)_p(d- C₃)alkyl), • (C₃-C6)cycloalkyl, • a 5- or 6-membered heterocyclic ring containing 1, 2 or 3 hetero ring atoms independently selected from N, O and S, which ring is optionally substituted by (CrC₃)alkyl (optionally substituted by OH), halo, =O, OH, or by (d-C₃)alkoxy and • phenyl, optionally substituted by 1 , 2 or 3 substituents independently selected from OH, halo, (C_fC₃)alkyl, (Cι-C₃)alkoxy, CO₂H, CO₂(d-C₃)alkyl) and OC(=O)(CrC₃)alkyl,

and the pharmaceutically acceptable salts and solvates thereof,

with the proviso that the nicotinamide derivative is not (i) 5-methyl-2-(3-methylsulphonyl)-N-(pyrazin-5-yl)nicotinamide; (ii) 5-methyl-2-(3-ethylsulphonyl)-N-(pyrazin-5-yl)nicotinamide; (iii) 2-(3-methylsulphonyl)-N-(pyrazin-5-yl)nicotinamide; or (iv) 2-(3-ethylsulphonyl)-N-(pyrazin-5-yl)nicotinamide.

2. A nicotinamide derivative according to claim 1 wherein X is F.

3. A nicotinamide derivative according to claim 1 or 2 wherein p is 0.

4. A nicotinamide derivative according to any previous claim wherein Y is attached to the 3-position on the phenyl ring.

5. A nicotinamide derivative according to any previous claim wherein Y is S(O)_pCH₃, S(O)_pC₂H₅ or S(O)_pCH₂(cyclopropyl).

6. A nicotinamide derivative according to any previous claim wherein Y is SCH₃, SC₂H₅ or SCH₂(cyclopropyl).

7. A nicotinamide derivative according to claim 6 wherein Y is SCH₃.

8. A nicotinamide derivative according to claim 6 wherein Y is 3-SCH₃.

9. A nicotinamide derivative according to any previous claim wherein when (Z)_n is not H or F, is attached to the 3-, 4-, and/or 5-position on the phenyl ring.

10. A nicotinamide derivative according to any previous claim wherein (Z)_n is H.

11. A nicotinamide derivative according to any previous claim wherein L is a piperidine, pyrrolidine, pyrazine, pyridine or pyrimidine ring, which ring is optionally substituted by OH, methoxy, hydroxym ethyl, ethoxy, or methyl.

12. A nicotinamide derivative according to any previous claim wherein L is piperidin- 1,3-ylene, piperidin-1 ,4-ylene, pyrazin-5,1 -ylene, 3-hydroxypyridin-6,4-ylene, pyridin- 4,2-ylene, pyridin-2,6-ylene, pyridin-4,6-ylene, pyridin-3,6-ylene, 3-methoxypyridin- 6,4-ylene, 2-methoxypyridin-5,3-ylene, 2-methoxypyridin-3,5-ylene, 3-ethoxypyridin- 2,6-ylene, 3-hydroxymethylpyridin-2,6-ylene, 2-methylpyridin-3,6-ylene, 3- methylpyridin-4,6-ylene, 4-hydroxypirimidin-2,5-ylene or 4-hydroxypyrimidin-5,2- ylene, where the first number of the linkage indicates the attachment to the NH of the nicotinamide moiety, and the second number of the linkage is attached to the R moiety.

13. A nicotinamide derivative according to any previous claim wherein L is piperidin- 1 ,4-ylene, pyrazin-5,1 -ylene, 3-hydroxypyridin-6,4-ylene, pyridin-4,2-ylene, pyridin- 2,6-ylene, pyridin-4,6-ylene, pyridin-3,6-ylene, 2-methoxypyridin-3,5-ylene, 3- hydroxymethylpyridin-2,6-ylene or 3-methylpyridin-4,6-ylene, where the first number of the linkage indicates the attachment to the NH of the nicotinamide moiety, and the second number of the linkage is attached to the R moiety.

14. A nicotinamide derivative according to any previous claim wherein L is piperidin- 1,4-ylene, where the first number of the linkage indicates the attachment to the NH of the nicotinamide moiety, and the second number of the linkage is attached to the R moiety.

15. A nicotinamide derivative according to any previous claim wherein R is attached to a nitrogen atom on the ring L.

16. A nicotinamide derivative according to any previous claim wherein R is H, (d- C₃)alkyl, SO₂(Cι-C₃)alkyl), or COR², wherein R² is (d-C₃)alkyl (optionally substituted by (d-C₃)alkoxy, OH, NR³R⁴ or a 5- or 6-membered heterocyclic ring containing 1 , 2 or 3 hetero ring atoms independently selected from N, O and S), cyclopropyl, a 5- or 6-membered heterocyclic ring containing 1 , 2 or 3 hetero ring atoms independently selected from N, O and S, which ring is optionally substituted by (d- C₃)alkyl (optionally substituted by OH), halo, =O, OH, or by (d-C₃)alkoxy, or phenyl, optionally substituted by 1, 2 or 3 substituents independently selected from OH, halo, (d-C₃)alkyl, (d-C₃)alkoxy, CO₂H, CO₂(d-C₃)alkyl) and OC(=O)(C_r C₃)alkyl.

17. A nicotinamide derivative according to any previous claim wherein R is H, CH₃, C₂H₅, COCH₃, SO₂CH₃, COC₂H₄(pyridyl), COC₂H₅, CO(cyclopropyl), COCH₂OH,

CO(2-hydroxy-4-methylphenyl), CO(2-hydroxy-4-methoxyphenyl) or CO(2- hydroxyphenyl).

18. A nicotinamide derivative according to any previous claim wherein R is H, COCH₃ or SO₂CH₃.

19. A nicotinamide derivative according to any previous claim wherein R is H or

20. A process to make a compound of formula (I) according to any one of claims 1 to 19 which comprises reaction of the corresponding nicotinic acid (II) with a compound of formula NH₂-L-R

(N)

21. A process to make a compound of formula (I) according to any one of claims 1 to 19 which comprises reaction of chloro-compound of formula (III) with a phenol of formula (IV).

(III) (IV)

22. A pharmaceutical composition including a nicotinamide derivative of the formula (1 ) as defined in any one of claims 1 to 19 or a pharmaceutically acceptable salt or solvate thereof, together with a pharmaceutically acceptable excipient, diluent or carrier.

23. A nicotinamide derivative of the formula (1 ) as defined in any one of claims 1 to 19 δ or a pharmaceutically acceptable salt, solvate or composition thereof for use as a medicament.

24. A nicotinamide derivative of the formula (1 ) as defined in any one of claims 1 to 19 or a pharmaceutically acceptable salt, solvate or composition thereof for use in the0 treatment of diseases, disorders and conditions in which the PDE4 isozymes are involved.

26. A nicotinamide derivative of the formula (1) as defined in any one of claims 1 to 19 or a pharmaceutically acceptable salt, derived form or composition thereof, for use in5 the treatment of inflammatory, respiratory and allergic diseases, disorders and conditions and in the treatment of wounds.

26. A nicotinamide derivative of the formula (1) as defined in any one of claims 1 to 19 or a pharmaceutically acceptable salt, solvate or composition thereof for use in the0 treatment of ■ asthma of whatever type, etiology, or pathogenesis, in particular asthma that is a member selected from the group consisting of atopic asthma, non-atopic asthma, allergic asthma, atopic bronchial IgE D mediated asthma, bronchial asthma, essential asthma, true asthma, intrinsic asthma caused by5 pathophysiologic disturbances, extrinsic asthma caused by environmental factors, essential asthma of unknown or inapparent cause, non-atopic asthma, bronchitic asthma, emphysematous asthma, exercise-induced asthma, allergen induced asthma, cold air induced asthma, occupational asthma, infective asthma caused by bacterial, fungal, protozoal, or viral infection, non-0 allergic asthma, incipient asthma and wheezy infant syndrome, ■ chronic or acute bronchoconstriction, chronic bronchitis, small airways obstruction, and emphysema, ^■ obstructive or inflammatory airways diseases of whatever type, etiology, or pathogenesis, in particular an obstructive or inflammatory airways disease that is a member selected from the group consisting of chronic eosinophilic pneumonia, chronic obstructive pulmonary disease (COPD), COPD that includes chronic bronchitis, pulmonary emphysema or dyspnea associated therewith, COPD that is characterized by irreversible, progressive airways obstruction, adult respiratory distress syndrome (ARDS) and exacerbation of airways hyper-reactivity consequent to other drug therapy

^■ pneumoconiosis of whatever type, etiology, or pathogenesis, in particular pneumoconiosis that is a member selected from the group consisting of aluminosis or bauxite workers' disease, anthracosis or miners' asthma, asbestosis or steam-fitters' asthma, chalicosis or flint disease, ptilosis caused by inhaling the dust from ostrich feathers, siderosis caused by the inhalation of iron particles, silicosis or grinders' disease, byssinosis or cotton-dust asthma and talc pneumoconiosis;

■ bronchitis of whatever type, etiology, or pathogenesis, in particular bronchitis that is a member selected from the group consisting of acute bronchitis, acute laryngotracheal bronchitis, arachidic bronchitis, catarrhal bronchitis, croupus bronchitis, dry bronchitis, infectious asthmatic bronchitis, productive bronchitis, staphylococcus or streptococcal bronchitis and vesicular bronchitis,

■ bronchiectasis of whatever type, etiology, or pathogenesis, in particular bronchiectasis that is a member selected from the group consisting of cylindric bronchiectasis, sacculated bronchiectasis, fusiform bronchiectasis, capillary bronchiectasis, cystic bronchiectasis, dry bronchiectasis and follicular bronchiectasis,

■ seasonal allergic rhinitis or perennial allergic rhinitis or sinusitis of whatever type, etiology, or pathogenesis, in particular sinusitis that is a member selected from the group consisting of purulent or nonpurulent sinusitis, acute or chronic sinusitis and ethmoid, frontal, maxillary, or sphenoid sinusitis, ■ rheumatoid arthritis of whatever type, etiology, or pathogenesis, in particular rheumatoid arthritis that is a member selected from the group consisting of acute arthritis, acute gouty arthritis, chronic inflammatory arthritis, degenerative arthritis, infectious arthritis, Lyme arthritis, proliferative arthritis, psoriatic arthritis and vertebral arthritis,

^■ gout, and fever and pain associated with inflammation,

^■ urticaria of whatever type, etiology, or pathogenesis, in particular urticaria that is a member selected from the group consisting of immune-mediated urticaria, complement-mediated urticaria, urticariogenic material-induced urticaria, physical agent-induced urticaria, stress-induced urticaria, idiopathic urticaria, acute urticaria, chronic urticaria, angioedema, cholinergic urticaria, cold urticaria in the autosomal dominant form or in the acquired form, contact urticaria, giant urticaria and papular urticaria, ^■ conjunctivitis of whatever type, etiology, or pathogenesis, in particular conjunctivitis that is a member selected from the group consisting of actinic conjunctivitis, acute catarrhal conjunctivitis, acute contagious conjunctivitis, allergic conjunctivitis, atopic conjunctivitis, chronic catarrhal conjunctivitis, purulent conjunctivitis and vernal conjunctivitis, ■ uveitis of whatever type, etiology, or pathogenesis, in particular uveitis that is a member selected from the group consisting of inflammation of all or part of the uvea, anterior uveitis, iritis, cyclitis, iridocyclitis, granulomatous uveitis, nongranulomatous uveitis, phacoantigenic uveitis, posterior uveitis, choroiditis; and chorioretinitis, ^■ psoriasis;

■ multiple sclerosis of whatever type, etiology, or pathogenesis, in particular multiple sclerosis that is a member selected from the group consisting of primary progressive multiple sclerosis and relapsing remitting multiple sclerosis,

■ autoimmune/inflammatory diseases of whatever type, etiology, or pathogenesis, in particular an autoimmune/inflammatory disease that is a member selected from the group consisting of autoimmune hematological disorders, hemolytic anemia, aplastic anemia, pure red cell anemia, idiopathic thrombocytopenic purpura, systemic lupus erythematosus, polychondritis, scleroderma, Wegner's granulomatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Stevens-Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel diseases, ulcerative colitis, endocrin opthamopathy, Grave's disease, sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, primary biliary cirrhosis, juvenile diabetes or diabetes mellitus type I, keratoconjunctivitis sicca, epidemic keratoconjunctivitis, diffuse interstitial pulmonary fibrosis or interstitial lung fibrosis, idiopathic pulmonary fibrosis, cystic fibrosis, glomerulonephritis with and without nephrotic syndrome, acute glomerulonephritis, idiopathic nephrotic syndrome, minimal change nephropathy, inflammatory/hyperproliferative skin diseases, benign familial pemphigus, pemphigus erythematosus, pemphigus foliaceus, and pemphigus vulgaris, ^■ prevention of allogeneic graft rejection following organ transplantation,

■ inflammatory bowel disease (IBD) of whatever type, etiology, or pathogenesis, in particular inflammatory bowel disease that is a member selected from the group consisting of collagenous colitis, colitis polyposa, transmural colitis, ulcerative colitis and Crohn's disease (CD), ■ septic shock of whatever type, etiology, or pathogenesis, in particular septic shock that is a member selected from the group consisting of renal failure, acute renal failure, cachexia, malarial cachexia, hypophysial cachexia, uremic cachexia, cardiac cachexia, cachexia suprarenalis or Addison's disease, cancerous cachexia and cachexia as a consequence of infection by the human immunodeficiency virus (HIV),

■ liver injury,

■ pulmonary hypertension of whatever type, etiology or pathogenesis including primary pulmonary hypertension / essential hypertension, pulmonary hypertension secondary to congestive heart failure, pulmonary hypertension secondary to chronic obstructive pulmonary disease, pulmonary venous hypertension, pulmonary arterial hypertension and hypoxia-induced pulmonary hypertension, ■ bone loss diseases, primary osteoporosis and secondary osteoporosis,

■ central nervous system disorders of whatever type, etiology, or pathogenesis, in particular a central nervous system disorder that is a member selected from the group consisting of depression, Alzheimers disease, Parkinson's disease, learning and memory impairment, tardive dyskinesia, drug dependence, arteriosclerotic dementia and dementias that accompany Huntington's chorea, Wilson's disease, paralysis agitans, and thalamic atrophies,

■ infection, especially infection by viruses wherein such viruses increase the production of TNF-α in their host, or wherein such viruses are sensitive to upregulation of TNF-α in their host so that their replication or other vital activities are adversely impacted, including a virus which is a member selected from the group consisting of HIV-1 , HIV-2, and HIV-3, cytomegalovirus (CMV), influenza, adenoviruses and Herpes viruses including Herpes zoster and Herpes simplex,

■ yeast and fungus infections wherein said yeast and fungi are sensitive to upregulation by TNF-α or elicit TNF-α production in their host, e.g., fungal meningitis, particularly when administered in conjunction with other drugs of choice for the treatment of systemic yeast and fungus infections, including but are not limited to, polymixins, e.g. Polymycin B, imidazoles, e.g. clotrimazole, econazole, miconazole, and ketoconazole, triazoles, e.g. fluconazole and itranazole as well as amphotericins, e.g. Amphotericin B and liposomal Amphotericin B,

■ ischemia-reperfusion injury, ischemic heart disease, autoimmune diabetes, retinal autoimmunity, chronic lymphocytic leukemia, HIV infections, lupus erythematosus, kidney and ureter disease, urogenital and gastrointestinal disorders and prostate diseases,

■ reduction of scar formation in the human or animal body, such as scar formation in the healing of acute wounds, and ^■ psoriasis, other dermatological and cosmetic uses, including antiphlogistic, skin-softening, skin elasticity and moisture-increasing activities.

27. The use of a nicotinamide derivative of the formula (1 ) as defined in any one of claims 1 to 19 or of a pharmaceutically acceptable salt, solvate or composition thereof, for the manufacture of a drug having a PDE4 inhibitory activity.

28. The use of a nicotinamide derivative of the formula (1 ) as defined in any one of claims 1 to 19 or of a pharmaceutically acceptable salt, solvate or composition thereof, for the manufacture of a drug useful in the treatment of inflammatory, respiratory and allergic diseases, disorders and conditions and in the treatment of wounds.

29. The use of a nicotinamide derivative of the formula (1) as defined in any one of claims 1 to 19 or of a pharmaceutically acceptable salt, solvate or composition thereof, for the manufacture of a drug for the treatment of diseases, disorders, and conditions selected from the group described in claim 26.

30. A method of treatment of a mammal, including a human being, with a PDE4 inhibitor including administering to said mammal an effective amount of a nicotinamide derivative of the formula (1 ) as defined in any one of claims 1 to 19 or a pharmaceutically acceptable salt, solvate or composition thereof.

31. A method according to claim 32 where the disease, disorder or condition to treat is selected from the group described in claim 26.

32. A combination of a nicotinamide derivative of the formula (I) as defined in any one of claims 1 to 19 or a pharmaceutically acceptable salt, solvate or composition thereof with other therapeutic agents selected from :

(a) δ-Lipoxygenase (5-LO) inhibitors or 5-lipoxygenase activating protein (FLAP) antagonists, (b) Leukotriene antagonists (LTRAs) including antagonists of LTB4, LTC4, LTD4, and LTE4,

(c) Histaminic receptor antagonists including H1, H3 and H4 antagonists,

(d) α1- and α2-adrenoceptor agonist vasoconstrictor sympathomimetic agents for decongestant use,

(e) Muscarinic M3 receptor antagonists or antichoHnergic agents,

(f) j-?2-adrenoceptor agonists,

(g) Theophylline,

(h) Sodium cromoglycate, (i) COX-1 inhibitors (NSAIDs) and COX-2 selective inhibitors,

(j) Oral or inhaled Glucocorticosteroids,

(k) Monoclonal antibodies active against endogenous inflammatory entities,

(I) Anti-tumor necrosis factor (anti-TNF-a) agents,

(m) Adhesion molecule inhibitors including VLA-4 antagonists, (n) Kinin-B1 - and B2 -receptor antagonists,

(o) Immunosuppressive agents,

(p) Inhibitors of matrix metalloproteases (MMPs),

(q) Tachykinin NK1 , NK2 and NK3 receptor antagonists,

(r) Elastase inhibitors, (s) Adenosine A2a receptor agonists,

(t) Inhibitors of urokinase,

(u) Compounds that act on dopamine receptors, e.g. D2 agonists,

(v) Modulators of the NFkb pathway, e.g. IKK inhibitors,

(w) Agents that can be classed as mucolytics or anti-tussive, (x) antibiotics, and

(y) p38 MAP kinase inhibitors.