WO2009053448A1

WO2009053448A1 - Compounds which potentiate ampa receptor and uses thereof in medicine

Info

Publication number: WO2009053448A1
Application number: PCT/EP2008/064407
Authority: WO
Inventors: Wai Ngor Chan; Stephen Harrison; Owen Rhys Hughes; James Kenneth Neesom; Kevin Michael Thewlis; Simon E Ward
Original assignee: Glaxo Group Limited
Priority date: 2007-10-26
Filing date: 2008-10-24
Publication date: 2009-04-30
Also published as: GB0721094D0

Abstract

The invention provides compounds of formula (I) and salts thereof wherein R1, R2, R3, R4 and X are as defined in the description. Processes for preparation, pharmaceutical compositions, and uses thereof as a medicament, for example in the treatment of a disease or condition mediated by a reduction or imbalance in glutamate receptor function, such as schizophrenia or cognition impairment, are also disclosed.

Description

Compounds which potentiate AMPA receptor and uses thereof in medicine

This invention relates to novel compounds which potentiate the AMPA receptor. The invention also relates to the use of the compounds in treating diseases and conditions mediated by potentiation of the AMPA receptor, compositions containing the derivatives and processes for their preparation.

Glutamate receptors, which mediate the majority of fast excitatory neurotransmission in the mammalian central nervous system (CNS), are activated by the excitatory amino acid, L-glutamate (for review see Watkins JC, Krogsgaard-Larsen P, Honore T (1990) Trends Pharmacol Sci 1 1 : 25-33).

Glutamate receptors can be divided into two distinct families. The G-protein or second messenger-linked "metabotropic" glutamate receptor family which can be subdivided into three groups (Group I, mGlui and mGlu5; Group II, mGlu2 and mGlu3; Group III, mGlu4, mGluθ, mGlu7, mGluδ) based on sequence homology and intracellular transduction mechanisms (for review see Conn PJ and Pinn JP (1997) Ann Rev Pharmacol Toxicol 37: 205-237). The "ionotropic" glutamate receptor family, which directly couple to ligand-gated cation channels, can be subdivided into at least three subtypes based on depolarizing activation by selective agonists, N-methyl-D-aspartate (NMDA), α-amino-3-hydroxy-5- methylisoxazole-4-propionic acid (AMPA) and kainic acid (KA) (for review see Dingledine R, Borges K, Bowie, Traynelis S (1999) 51 : 7-61 ).

Native AMPA receptors (AMPAR) exist as heterotetramers consisting of combinations of four different protein subunits (GIuRI -4) (for review see Bettler B and Muller C (1995) 34:

123-139.). Receptor subunit diversity is increased further as each subunit can undergo alternative splicing of a 38 amino acid sequence in the extracellular region just before the fourth membrane spanning domain M4. Such editing results in so-called 'flip' and 'flop' receptor isoforms which differ in kinetic and pharmacological properties (Sommer B, Keinanen K, Verdoon TA, Wisden W, Burnashev N, Herb A, Kohler M, Takagi T,

Sakmann B, Seeburg PH (1990) Science 249: 1580-1585).

Additionally, post-transcriptional editing of GluR2 mRNA changes a neutral glutamine to a positively charged arginine within M2. In normal humans >99% GluR2 is edited in this way. AMPAR containing such edited GluR2 subunit exhibit low calcium permeability (Burnachev N, Monyer H, Seeburg PH, Sakmann B (1992) Neuron 8: 189-198). There is a suggestion, however, that the number of AMPAR with high calcium permeability is elevated in certain disease-associated conditions (Weiss JH, and Sensi SL (2000) Trends in Neurosci 23: 365-371 ).

AMPAR depolarization removes voltage dependent Mg ²⁺ block of NMDA receptors which in turn leads to NMDA receptor activation, an integral stage in the induction of Long Term Potentiation ("LTP") (Bliss TVP, Collingridge GL (1993) Nature 361 : 31-9). LTP is a physiological measure of increased synaptic strength following a repetitive stimulus or activity, such as occurs during learning.

It has been reported that direct activation of glutamate receptors by agonists, in conditions where glutamate receptor function is reduced, increases the risk of excitotoxicity and additional neuronal damage. AMPAR positive allosteric modulators do not activate the receptor directly. However, when the ligand (L-glutamate or AMPA) is present AMPAR modulators increase receptor activity. Thus, AMPA receptor modulators enhance synaptic function when glutamate is released and is able to bind at post-synaptic receptor sites.

Compounds which act as AMPAR positive allosteric modulators have been shown to increase ligand affinity for the receptor (Arai A, Guidotti A, Costa E, Lynch G (1996) Neuroreport. 7: 2211-5.); reduce receptor desensitization and reduce receptor deactivation (Arai AC, Kessler M, Rogers G, Lynch G (2000) 58: 802-813) and facilitate the induction of LTP both in vitro (Arai A, Guidotti A, Costa E, Lynch G (1996) 7: 2211-5.) and in vivo (Staubli U, Perez Y, Xu F, Rogers G, Ingvar M, Stone-Elander S, Lynch G (1994) Proc Natl Acad Sci 91 : 11 158-11 162). Such compounds also enhance the learning and performance of various cognitive tasks in rodent (Zivkovic I, Thompson DM, Bertolino M, Uzunov D, DiBeIIa M, Costa E, Guidotti A (1995) JPET 272: 300-309, Lebrun C, Pilliere E, Lestage P (2000) Eu J Pharmacol 401 : 205-212), sub-human primate (Thompson DM, Guidotti A, DiBeIIa M, Costa E (1995) Proc Natl Acad Sci 92: 7667-7671 ) and man (Ingvar M, Ambros-lngerson J, Davis M, Granger R, Kessler M, Rogers GA, Schehr RS, Lynch G (1997) Exp Neurol 146: 553-559). The efficacy of various AMPAR positive allosteric modulators in pre-clinical and clinical models of psychiatric disorders, such as schizophrenia, have been investigated (Morrow J A, Maclean J KF, Jamieson C (2006) Current Opinion in Drug Discovery and Development 9(5) 571-579). The ability of AMPAR positive allosteric modulators to improve pre-clinical and clinical cognitive task performance as well as the potential for efficacy in psychiatric disorders, such as schizophrenia, in man have been investigated (Morrow J A, Maclean J KF, Jamieson C (2006) Current Opinion in Drug Discovery and Development 9(5) 571-579).

Compounds which act as AMPAR positive allosteric modulators are known, for example in international patent application WO2006/015828. We have discovered novel compounds which potentiate the AMPA receptor.

According to a first aspect, the invention provides a compound of formula (I) or a salt thereof:

(I) wherein:

• X is selected from:

• R¹ is selected from C(O)d_-4alkyl and C(O)NR⁵R⁶, wherein R⁵ and R⁶ are independently selected from hydrogen and C_1-4alkyl; or R⁵ and R⁶, together with the nitrogen to which they are attached, form a saturated 4- to 7-membered ring;

• R² is C_1-4alkyl;

• R⁴ is selected from the group consisting of: o C(O)OC_1-6alkyl; o Ci_-6alkylsulfonyl; o a group (CH₂)_nC(O)NR⁷R⁸ wherein R⁷ and R⁸ are independently hydrogen or

C_1-6alkyl optionally substituted by hydroxyl; or R⁷ and R⁸ form a 5 or 6 membered saturated heterocyclic ring optionally substituted by a group selected from oxo, C_1-6alkyl, hydroxyl and NR⁹R¹⁰; o a group (CH₂)_nY wherein Y is selected from cyano, SO₂NR⁹R¹⁰ and NHR¹¹, wherein R¹¹ is selected from C(O)Ci_-6alkyl, C(O)OhaloCi_-6alkyl and Ci- ₆alkylsulfonyl; o a group (CH₂)Z wherein Z is an N-linked 5 or 6 membered saturated heterocyclic ring optionally substituted by a group selected from oxo, Ci_-6alkyl, hydroxyl and NR⁹R¹⁰; o a 5 or 6 membered unsaturated carbocyclic or unsaturated heterocyclic ring, optionally substituted by one or two groups selected from Ci_-6alkyl, haloCi.

₆alkyl, C_1-6alkoxy and halogen; o an N-linked 5 or 6 membered saturated heterocyclic ring substituted by one or two groups selected from oxo, C_1-6alkyl, hydroxyl and NR⁹R¹⁰; o an N-linked 5 or 6 membered unsaturated heterocyclic ring fused with a cyclohexane ring or a tetrahydropyran ring and further optionally substituted by haloC_1-6alkyl; wherein each R⁹ and each R¹⁰ are independently selected from hydrogen and Ci- ₆alkyl, and each n is independently 0 or 1 ; and

• R³ is hydrogen, or R³ and R⁴ together form a tetrahydropyranyl or a cyclopentanyl ring.

"H" refers to hydrogen. "CN" refers to cyano (C≡N). "Ph" refers to phenyl. "Me" refers to methyl. "Et" refers to ethyl. "Oxo" refers to =0.

Halo is selected from fluoro, chloro, bromo and iodo. For example, halo is selected from fluoro and chloro, for example fluoro.

The terms "Ci_-4alkyl" and "Ci_-6alkyl" refer respectively to an alkyl group having from one to four and one to six carbon atoms. Unless otherwise indicated, alkyl may be a straight chain or branched. For example, a group may be selected from the group consisting of methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl or t-butyl. A C_1-6alkyl group may be selected from the group consisting of, in addition to

n-pentyl, isopentyl, neopentyl and hexyl.

The term "alkoxy" refers to a group O-alkyl where alkyl is as defined above.

The term "alkylthio" refers to a group S-alkyl where alkyl is as defined above.

The term "alkylsulfonyl" refers to a group -SC>₂-alkyl where alkyl is as defined above.

The term "haloalkyl" refers to an alkyl group as defined above which is substituted with any number of fluorine, chlorine, bromine, or iodine atoms, including with mixtures of those atoms. For example, a haloalkyl group may contain 1 , 2 or 3 halogen atoms. For example, a haloalkyl group may have all hydrogen atoms replaced with halogen atoms. Examples of haloalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluroethyl and trifluoroethyl. Similarly, the term "haloalkoxy" and "haloalkylthio" refer to alkoxy and alkylthio groups wherein the alkyl groups are substituted with any number of fluorine, chlorine, bromine, or iodine atoms, including with mixtures of those atoms. Examples of haloalkoxy groups include fluoromethoxy, difluoromethoxy and trifluoromethoxy. Examples of haloalkylthio groups include fluoromethylthio, difluoromethylthio and trifluoromethylthio.

"C(O)" and "C(=O)" are interchangeable and represent a carbonyl group.

The term "5 or 6 membered saturated heterocyclic ring" refers to a saturated carbocyclic ring consisting of 5 or 6 carbon atoms, wherein one or more carbon atoms are replaced by a heteroatom selected from O, N and S. Examples include pyrrolidinyl, imidazolidinyl, pyrazolidinyl, isothiazolidinyl, thiazolidinyl, piperidyl, piperazinyl, morpholinyl and thiomorpholinyl.

The term "5 or 6 membered unsaturated carbocyclic or unsaturated heterocyclic ring", as used in the definition of R⁴, refers to an unsaturated carbocyclic ring consisting of 5 or 6 carbon atoms, or an unsaturated carbocyclic ring consisting of 5 or 6 carbon atoms in which one or more carbon atoms are replaced by a heteroatom selected from O, N and S. Examples of unsaturated carbocyclic rings include phenyl. Examples of unsaturated heterocyclic rings include pyrrolyl, pyrrolinyl, pyrazolinyl, oxazolyl, isoxazoyl, imidazolyl, pyrazolyl, thiadiazolyl, oxadiazolyl, isothiazolyl, thiazolyl, triazolyl, furyl, thienyl, pyridyl, thiazinyl, pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl.

The term "N-linked 5 or 6 membered unsaturated heterocyclic ring" refers to an unsaturated carbocyclic ring consisting of 5 or 6 carbon atoms, wherein one of the carbon atoms is replaced by a nitrogen atom through which the ring is linked to the rest of the molecule, and wherein one or more of the carbon atoms in the ring is optionally replaced by a heteroatom selected from O, N and S. Examples include pyrrolyl, pyrrolinyl, pyrazolinyl, oxazolyl, isoxazoyl, imidazolyl, pyrazolyl, thiadiazolyl, oxadiazolyl, isothiazolyl, thiazolyl, triazolyl, pyridyl, thiazinyl, pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl.

When R¹ is C(O)NR⁵R⁶, R⁵ and R⁶, together with the nitrogen to which they are attached, may form a saturated 4- to 7-membered ring; ie R⁵ and R⁶, together with the nitrogen to which they are attached, may form an azetidinyl, pyrrolidinyl, piperidyl or azepanyl group.

In one embodiment, R¹ is C(O)Ci_₄alkyl. In one embodiment, R¹ is C(O)CH₃.

In one embodiment, R¹ is C(O)NR⁵R⁶, wherein R⁵ and R⁶ are independently selected from hydrogen and

In one embodiment, R¹ is C(O)N(CH₃)₂.

In one embodiment, R² is methyl.

In one embodiment, R⁴ is C(O)OC_1-6alkyl. In one embodiment, R⁴ is C(O)OC₂H₅.

In one embodiment, R⁴ is C-i-βalkylsulfonyl. In one embodiment, R⁴ is SO₂CH₃.

In one embodiment, R⁴ is a group (CH₂)_nC(O)NR⁷R⁸ wherein n is O or 1 and R⁷ and R⁸ are independently hydrogen or C_halky! optionally substituted by hydroxyl. In one embodiment, R⁴ is a group C(O)NR⁷R⁸ wherein R⁷ and R⁸ are independently hydrogen or Ci_-6alkyl optionally substituted by hydroxyl.

In one embodiment, R⁴ is a group (CH₂)_nC(O)NR⁷R⁸ wherein n is O or 1 and R⁷ and R⁸ form a 5 or 6 membered saturated heterocyclic ring optionally substituted by a group selected from oxo, C_1-6alkyl, hydroxyl and NR⁹R¹⁰. In one embodiment, R⁷ and R⁸ form a pyrrolidinyl, piperidinyl or morpholinyl ring, optionally substituted by a group selected from oxo, C_1-6alkyl, hydroxyl and NHMe.

In one embodiment, R⁴ is a group (CH₂)_nY wherein n is O or 1 and Y is selected from cyano, SO₂NR⁹R¹⁰ and NHR¹¹, wherein R⁹ and R¹⁰ are independently selected from hydrogen and C_1-6alkyl, and wherein R¹¹ is selected from C(O)C_1-6alkyl, C(O)OhIaIoC_1- βalkyl and C-i-βalkylsulfonyl. In one embodiment, R⁹ and R¹⁰ are independently selected from hydrogen and methyl, and R¹¹ is selected from C(O)Me, C(O)OCF₃ and SO₂CH₃.

In one embodiment, R⁴ is a group (CH₂)Z wherein Z is an N-linked 5 or 6 membered saturated heterocyclic ring optionally substituted by a group selected from oxo, C_1-6alkyl, hydroxyl and NR⁹R¹⁰. In one embodiment, Z is morpholinyl.

In one embodiment, R⁴ is a 5 or 6 membered unsaturated carbocyclic or unsaturated heterocyclic ring, optionally substituted by one or two groups selected from C_1-6alkyl, haloC-i-βalkyl, d-βalkoxy and halogen. In one embodiment, R⁴ is oxazolyl, imidazolyl, pyrazolyl, thienyl, isoxazolyl, thiadiazolyl, triazolyl, phenyl, pyridyl or furanyl, each group being optionally substituted by one or two groups selected from Ci_-6alkyl, haloCi_-6alkyl, C-i-βalkoxy and halogen. In one embodiment, each group is optionally substituted by one or two groups selected from methyl, Cl, F, methoxy and CF₃.

In one embodiment, R⁴ is an N-linked 5 or 6 membered saturated heterocyclic ring substituted by one or two groups selected from oxo, C_1-6alkyl, hydroxyl and NR⁹R¹⁰. In one embodiment, R⁴ is piperazinyl substituted by a methyl. . In one embodiment, R⁴ is piperidyl or pyrrolidinyl each optionally substituted by oxo.

In one embodiment, R⁴ is an N-linked 5 or 6 membered unsaturated heterocyclic ring fused with a cyclohexane ring or a tetrahydropyran ring and further optionally substituted by haloC_1-6alkyl (such as CF₃) . In one embodiment, R⁴ is 3-(trifluoromethyl)-4,5,6,7- tetrahydro-1H-indazol-1-yl or 3-(trifluoromethyl)-6,7-dihydropyrano[4,3-c]pyrazol-1 (4/-/)-yl.

In one embodiment, R³ is hydrogen.

In one embodiment, R³ and R⁴ together form a tetrahydropyranyl or a cyclopentanyl ring, as shown below:

one of G is oxygen

In one embodiment, the present invention provides a compound of formula (Ia) or a salt thereof:

(Ia) wherein:

• X is selected from:

• R¹ is selected from C(O)d_-4alkyl and C(O)NR⁵R⁶, wherein R⁵ and R⁶ are independently selected from hydrogen and Ci_-4alkyl; • R⁴ is selected from the group consisting of: o C(O)OC_1-6alkyl; o Ci_-6alkylsulfonyl; o a group (CH₂)_nC(O)NR⁷R⁸ wherein R⁷ and R⁸ are independently hydrogen or C_1-6alkyl optionally substituted by hydroxyl; or R⁷ and R⁸ form a 5 or 6 membered saturated heterocyclic ring optionally substituted by a group selected from oxo, Ci-βalkyl, hydroxyl and NR⁹R¹⁰; o a group (CH₂)_nY wherein Y is selected from cyano, SO₂NR⁹R¹⁰ and NHR¹¹, wherein R¹¹ is selected from C(O)Ci_-6alkyl, C(O)OhaloCi_-6alkyl and Ci- ₆alkylsulfonyl; o a group (CH₂)Z wherein Z is an N-linked 5 or 6 membered saturated heterocyclic ring optionally substituted by a group selected from oxo, Ci_-6alkyl, hydroxyl and NR⁹R¹⁰; o a 5 or 6 membered unsaturated carbocyclic or unsaturated heterocyclic ring, optionally substituted by one or two groups selected from Ci_-6alkyl, haloCi.

₆alkyl, Ci_-6alkoxy and halogen; o an N-linked 5 or 6 membered saturated heterocyclic ring substituted by one or two groups selected from oxo, Ci_-6alkyl, hydroxyl and NR⁹R¹⁰; o an N-linked 5 or 6 membered unsaturated heterocyclic ring fused with a cyclohexane ring or a tetrahydropyran ring and further optionally substituted by haloCi_-6alkyl; wherein each R⁹ and each R¹⁰ are independently selected from hydrogen and Ci- ₆alkyl, and each n is independently 0 or 1 ; and

For the avoidance of doubt, unless otherwise indicated, the term substituted means substituted by one or more defined groups. In the case where groups may be selected from a number of alternative groups, the selected groups may be the same or different. For the avoidance of doubt, the term independently means that where more than one substituent is selected from a number of possible substituents, those substituents may be the same or different.

The imine bond in formula (I) (between the central nitrogen atom and the carbon atom in the thiazolyl group) indicates E, Z or a mixture of both E and Z isomers:

(Z) In mixtures of E and Z compounds, or compounds in which the E/Z (i.e cis/trans) configuration have not been determined, the imine bond is drawn as a crossed bond as shown in formula (I).

The individual isomers (E and Z) and mixtures of these are included within the scope of the present invention. The isomers may be separated one from the other by the usual methods or by methods detailed for the example compounds below. Any given isomer may also be obtained by stereospecific synthesis. The invention also extends to any tautomeric forms and mixtures thereof.

In one embodiment, the compounds of formula (I) are E isomers.

In another embodiment, the compounds of formula (I) are Z isomers.

It will be appreciated that the present invention is intended to include compounds having any combination of the groups listed hereinbefore. It will be understood that, where appropriate, an embodiment described above for one part of the invention may be combined with an embodiment of another part of the invention.

Examples of compounds of the present invention include:

1. 1-(3-cyclopropyl-4-methyl-2-{[4-(1-pyrrolidinylcarbonyl)phenyl]imino}-2,3-dihydro-1 ,3- thiazol-5-yl)ethanone

2. 1-(3-cyclopropyl-4-methyl-2-{[4-(1-piperidinylcarbonyl)phenyl]imino}-2,3-dihydro-1 ,3- thiazol-5-yl)ethanone 3. 1-(3-cyclopropyl-4-methyl-2-{[4-(4-morpholinylcarbonyl)phenyl]imino}-2,3-dihydro-1 ,3- thiazol-5-yl)ethanone

4. 1-(4-{[5-acetyl-3-cyclopropyl-4-methyl-1 ,3-thiazol-2(3H)-ylidene]amino}phenyl)-2- pyrrolidinone

5. ethyl 4-{[5-acetyl-3-ethyl-4-methyl-1 ,3-thiazol-2(3H)-ylidene]amino}benzoate 6. 1-(3-ethyl-4-methyl-2-{[4-(1-pyrrolidinylcarbonyl)phenyl]imino}-2,3-dihydro-1 ,3-thiazol- 5-yl)ethanone

7. 1-(3-ethyl-4-methyl-2-{[4-(4-methyl-1-piperazinyl)phenyl]imino}-2,3-dihydro-1 ,3-thiazol- 5-yl)ethanone

8. 1-(4-{[5-acetyl-3-cyclopropyl-4-methyl-1 ,3-thiazol-2(3H)-ylidene]amino}phenyl)-2- piperidinone

9. 1-(3-ethyl-4-methyl-2-{[4-(1 ,3-oxazol-5-yl)phenyl]imino}-2,3-dihydro-1 ,3-thiazol-5- yl)ethanone

10. 1-(3-ethyl-2-{[4-(1 H-imidazol-1-yl)phenyl]imino}-4-methyl-2,3-dihydro-1 ,3-thiazol-5- yl)ethanone 11. 1-[3-ethyl-4-methyl-2-({4-[3-(trifluoromethyl)-1 H-pyrazol-1-yl]phenyl}imino)-2,3-dihydro-

1 ,3-thiazol-5-yl]ethanone

12. 1-[3-ethyl-4-methyl-2-({4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1 H-indazol-1- yl]phenyl}imino)-2,3-dihydro-1 ,3-thiazol-5-yl]ethanone 13. 1-[3-ethyl-4-methyl-2-({4-[3-(trifluoromethyl)-6_!7-dihydropyrano[4,3-c]pyrazol-1 (4H)- yl]phenyl}imino)-2,3-dihydro-1 ,3-thiazol-5-yl]ethanone

14. 1-(3-ethyl-4-methyl-2-{[4-(3-thienyl)phenyl]imino}-2_!3-dihydro-1 ,3-thiazol-5-yl)ethanone

15. 1-[3-ethyl-2-({4-[(3-hydroxy-1-pyrrolidinyl)carbonyl]phenyl}imino)-4-methyl-2,3-dihydro- 1 ,3-thiazol-5-yl]ethanone

16. 1-{3-ethyl-4-methyl-2-[(4-{[3-(methylamino)-1-pyrrolidinyl]carbonyl}phenyl)imino]-2,3- dihydro-1 ,3-thiazol-5-yl}ethanone

17. 4-{[5-acetyl-3-ethyl-4-methyl-1 ,3-thiazol-2(3H)-ylidene]amino}-N-(2-hydroxyethyl)-N- methylbenzamide 18. 1-[3-cyclopropyl-2-({4-[(3-hydroxy-1-pyrrolidinyl)carbonyl]phenyl}imino)-4-methyl-2,3- dihydro-1 ,3-thiazol-5-yl]ethanone 19. 1-{3-cyclopropyl-4-methyl-2-[(4-{[3-(methylamino)-1- pyrrolidinyl]carbonyl}phenyl)imino]-2,3-dihydro-1 ,3-thiazol-5-yl}ethanone 20. 4-{[5-acetyl-3-cyclopropyl-4-methyl-1 ,3-thiazol-2(3H)-ylidene]amino}-N-(2- hydroxyethyl)-N-methylbenzamide

21. 4-{[5-acetyl-3-cyclopropyl-4-methyl-1 ,3-thiazol-2(3H)-ylidene]amino}-N- ethylbenzamide 22. 4-{[5-acetyl-3-cyclopropyl-4-methyl-1 _!3-thiazol-2(3H)-ylidene]amino}-N,N- diethylbenzamide 23. 1-(4-{[5-acetyl-3-ethyl-4-methyl-1 ,3-thiazol-2(3H)-ylidene]amino}phenyl)-N- methylmethanesulfonamide

24. 1-(4-{[5-acetyl-3-ethyl-4-methyl-1 _!3-thiazol-2(3H)-ylidene]amino}phenyl)-N,N- dimethylmethanesulfonamide

25. 1-(3-cyclopropyl-4-methyl-2-{[4-(5-methyl-2-thienyl)phenyl]imino}-2_!3-dihydro-1 ,3- thiazol-5-yl)ethanone

26. 1-(3-cyclopropyl-4-methyl-2-{[4-(3-methyl-2-thienyl)phenyl]imino}-2_!3-dihydro-1 ,3- thiazol-5-yl)ethanone

27. 1-(3-cyclopropyl-2-{[4-(3,5-dimethyl-4-isoxazolyl)phenyl]imino}-4-methyl-2,3-dihydro- 1 ,3-thiazol-5-yl)ethanone 28. 1-(3-cyclopropyl-4-methyl-2-{[4-(1 ,2>thiadiazol-4-yl)phenyl]imino}-2,3-dihydiO-1 ,3- thiazol-5-yl)ethanone

29. 1-(3-cyclopropyl-4-methyl-2-{[4-(1 H-1 ^^-triazol-i-yOphenyφminoJ^S-dihydro-i ,3- thiazol-5-yl)ethanone

30. 1-(3-ethyl-4-methyl-2-{[4-(methylsulfonyl)phenyl]imino}-2_!3-dihydro-1 ,3-thiazol-5- yl)ethanone

31. 1-[3-ethyl-4-methyl-2-({4-[2-oxo-2-(1-pyrrolidinyl)ethyl]phenyl}imino)-2,3-dihydro-1 ,3- thiazol-5-yl]ethanone

32. 1-[3-ethyl-2-({4-[2-(3-hydroxy-1-pyrrolidinyl)-2-oxoethyl]phenyl}imino)-4-methyl-2,3- dihydro-1 ,3-thiazol-5-yl]ethanone 33. (4-{[5-acetyl-3-ethyl-4-methyl-1 _!3-thiazol-2(3H)-ylidene]amino}phenyl)acetonitrile

34. 1-(3-ethyl-4-methyl-2-{[4-(1 H-pyrazol-1-yl)phenyl]imino}-2,3-dihydro-1 ,3-thiazol-5- yl)ethanone

35. 3-(2-hydroxyethyl)-N_!N_!4-trimethyl-2-{[4-(1 H-pyrazol-1-yl)phenyl]imino}-2,3-dihydro- 1 ,3-thiazole-5-carboxamide 36. 1-[3-(2-hydroxyethyl)-4-methyl-2-({4-[3-(trifluoromethyl)-1 H-pyrazol-1-yl]phenyl}imino)-

2,3-dihydro-1 ,3-thiazol-5-yl]ethanone 37. 4-{[5-acetyl-3-(2-hydroxyethyl)-4-methyl-1 _!3-thiazol-2(3H)-ylidene]amino}-N,N- dimethylbenzamide 38. 1-[2-(4-biphenylylimino)-3-cyclopropyl-4-methyl-2,3-dihydro-1 ,3-thiazol-5-yl]ethanone

39. 3-ethyl-N_!N_!4-trimethyl-2-{[4-(1 H-pyrazol-1-yl)phenyl]imino}-2_!3-dihydro-1 ,3-thiazole-5- carboxamide

40. 1-[2-(4-biphenylylimino)-3-(2-hydroxyethyl)-4-methyl-2_!3-dihydro-1 ,3-thiazol-5- yl]ethanone 41. 1-[2-{[4-(2-fluoro-6-methyl-3-pyridinyl)phenyl]imino}-3-(2-hydroxyethyl)-4-methyl-2,3- dihydro-1 ,3-thiazol-5-yl]ethanone

42. 1 ,1-dimethylethyl [(4-{[5-acetyl-3,4-dimethyl-1 ,3-thiazol-2(3H)- ylidene]amino}phenyl)methyl]carbamate

43. 1-[2-{[4-(6-fluoro-3-pyridinyl)phenyl]imino}-3-(2-hydroxyethyl)-4-methyl-2,3-dihydro- 1 ,3-thiazol-5-yl]ethanone

44. 1-[2-{[4-(3-furanyl)phenyl]imino}-3-(2-hydroxyethyl)-4-methyl-2_!3-dihydro-1 ,3-thiazol-5- yl]ethanone

45. 1-(3-(2-hydroxyethyl)-4-methyl-2-{[4-(2-methyl-3-pyridinyl)phenyl]imino}-2,3-dihydro- 1 ,3-thiazol-5-yl)ethanone 46. N-[(4-{[5-acetyl-3-ethyl-4-methyl-1 ,3-thiazol-2(3H)- ylidene]amino}phenyl)methyl]methanesulfonamide

47. N-[(4-{[5-acetyl-3-ethyl-4-methyl-1 ,3-thiazol-2(3H)- ylidene]amino}phenyl)methyl]acetamide

48. 1-[2-{[4-(2-chloro-3-pyridinyl)phenyl]imino}-3-(2-hydroxyethyl)-4-methyl-2,3-dihydro- 1 ,3-thiazol-5-yl]ethanone

49. 1-[2-(3_!4-dihydro-1 H-2-benzopyran-6-ylimino)-3-(2-hydroxyethyl)-4-methyl-2,3- dihydro-1 ,3-thiazol-5-yl]ethanone

50. 3-ethyl-2-{[4-(2-fluoro-3-pyridinyl)phenyl]imino}-N_!N_!4-trimethyl-2_!3-dihydro-1 ,3- thiazole-5-carboxamide 51. 3-ethyl-N_!N_!4-trimethyl-2-{[4-(2-methyl-3-pyridinyl)phenyl]imino}-2,3-dihydro-1 ,3- thiazole-5-carboxamide 52. 1-(3-ethyl-4-methyl-2-{[4-(4-morpholinylmethyl)phenyl]imino}-2_!3-hydro-1 ,3-thiazol-5- yl)ethanone

53. 2-[(4'-fluoro-4-biphenylyl)imino]-3-(2-hydroxyethyl)-N_!N_!4-trimethyl-2_!3-dihydro-1 ,3- thiazole-5-carboxamide

54. 3-ethyl-N_!N_!4-trimethyl-2-{[4-(6-methyl-3-pyridinyl)phenyl]imino}-2_!3-dihydro-1 ,3- thiazole-5-carboxamide

55. 3-(2-hydroxyethyl)-N_!N_!4-trimethyl-2-{[4-(6-methyl-3-pyridinyl)phenyl]imino}-2,3- dihydro-1 ,3-thiazole-5-carboxamide 56. 1-(3-(2-hydroxyethyl)-4-methyl-2-{[4-(1 H-pyrazol-1-yl)phenyl]imino}-2,3-dihydro-1 ,3- thiazol-5-yl)ethanone

57. N-(4-{[5-acetyl-3,4-dimethyl-1 ,3-thiazol-2(3H)-ylidene]amino}phenyl)acetamide

58. N-(4-{[5-acetyl-3-ethyl-4-methyl-1 ,3-thiazol-2(3H)-ylidene]amino}phenyl)acetamide 59. N-(4-{[5-acetyl-3-(2-hydroxyethyl)-4-methyl-1 ,3-thiazol-2(3H)- ylidene]amino}phenyl)acetamide

60. 1-[2-(2,3-dihydro-1 H-inden-5-ylimino)-3-(2-hydroxyethyl)-4-methyl-2,3-dihydro-1 ,3- thiazol-5-yl]ethanone 61. 1-[(4-{[5-acetyl-3-ethyl-4-methyl-1 ,3-thiazol-2(3H)-ylidene]amino}phenyl)methyl]-2- pyrrolidinone

62. 3-(2-hydroxyethyl)-N_!N_!4-trimethyl-2-{[4'-(methyloxy)-4-biphenylyl]imino}-2,3-dihydro- 1 ,3-thiazole-5-carboxamide

63. 1-[3-ethyl-4-methyl-2-({4-[(4-methyl-1-piperazinyl)carbonyl]phenyl}imino)-2,3-dihydro- 1 ,3-thiazol-5-yl]ethanone

64. 4-{[5-acetyl-3-(2-hydroxyethyl)-4-methyl-1 ,3-thiazol-2(3H)-ylidene]amino}benzonitrile and salts thereof.

In one embodiment the salt of the compound of formula (I) is a pharmaceutically acceptable salt. In one embodiment, the invention provides a compound of formula (I) or a pharmaceutically acceptable salt.

As used herein, the term "salt" refers to any salt of a compound according to the present invention prepared from an inorganic or organic acid or base, quaternary ammonium salts and internally formed salts. Pharmaceutically acceptable salts are particularly suitable for medical applications because of their greater aqueous solubility relative to the parent compounds. Such salts must clearly have a pharmaceutically acceptable anion or cation. Suitably pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts formed with inorganic acids such as hydrochloric, hydrobromic, hydroiodic, phosphoric, metaphosphoric, nitric and sulfuric acids, and with organic acids, such as tartaric, acetic, trifluoroacetic, citric, malic, lactic, fumaric, benzoic, formic, propionic, glycolic, gluconic, maleic, succinic, (1 R)-(-)-10-camphorsulphonic, (1 S)-(+)-10- camphorsulphonic, isothionic, mucic, gentisic, isonicotinic, saccharic, glucuronic, furoic, glutamic, ascorbic, anthranilic, salicylic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, pantothenic, stearic, sulfinilic, alginic, galacturonic and arylsulfonic, for example naphthalene-1 ,5-disulphonic, naphthalene-1 ,3-disulphonic, benzenesulfonic, and p-toluenesulfonic, acids; base addition salts formed with alkali metals and alkaline earth metals and organic bases such as N, N- dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumaine (N-methylglucamine), lysine and procaine; and internally formed salts. The salts may have any suitable stoichiometry. For example, a salt may have 1 :1 or 2:1 stoichiometry. Non-integral stoichiometry ratios are also possible.

Solvates of the compounds of formula (I) and solvates of the salts of the compounds of formula (I) are included within the scope of the present invention. As used herein, the term "solvate" refers to a complex of variable stoichiometry formed by a solute (in this invention, a compound of formula (I) or a salt thereof) and a solvent. Those skilled in the art of organic chemistry will appreciate that many organic compounds can form such complexes with solvents in which they are reacted or from which they are precipitated or crystallized. Such solvents for the purpose of the invention may not interfere with the biological activity of the solute. Examples of suitable solvents include, but are not limited to, water, methanol, ethanol and acetic acid. Preferably the solvent used is a pharmaceutically acceptable solvent. Examples of suitable pharmaceutically acceptable solvents include, without limitation, water, ethanol and acetic acid. Most preferably the solvent used is water. Where the solvent used is water such a solvate may then also be referred to as a hydrate.

Furthermore, some of the crystalline forms of the compounds of structure (I) may exist as polymorphs, which are included in the present invention. Some of the compounds of this invention may be crystallised or recrystallised from solvents such as aqueous and organic solvents. In such cases solvates may be formed. This invention includes within its scope stoichiometric solvates as well as compounds containing variable amounts of solvent, where non-stoichiometric solvates may be produced by processes such as lyophilisation. In one embodiment, the compounds of the present invention are provided in the form of stoichiometric and non-stoichiometric hydrates.

It will be appreciated by those skilled in the art that certain protected derivatives of compounds of formula (I), which may be made prior to a final deprotection stage, may not possess pharmacological activity as such, but may, in certain instances, be administered orally or parenterally and thereafter metabolised in the body to form compounds of the invention which are pharmacologically active. Such derivatives may therefore be described as "prodrugs". Further, certain compounds of the invention may be administered as prodrugs. Examples of pro-drug forms for certain compounds of the present invention are described in Drugs of Today, Volume 19, Number 9, 1983, pp 499 - 538 and in Topics in Chemistry, Chapter 31 , pp 306 - 316 and in "Design of Prodrugs" by H. Bundgaard, Elsevier, 1985, Chapter 1 (the disclosures in which documents are incorporated herein by reference). It will further be appreciated by those skilled in the art, that certain moieties, known to those skilled in the art as "pro-moieties", for example as described by H. Bundgaard in "Design of Prodrugs" (the disclosure in which document is incorporated herein by reference) may be placed on appropriate functionalities when such functionalities are present within compounds of the invention. Examples of prodrugs for certain compounds of the invention include: esters, carbonate esters, hemi-esters, phosphate esters, nitro esters, sulfate esters, sulfoxides, amides, carbamates, azo-compounds, phosphamides, glycosides, ethers, acetals and ketals.

Hereinafter, compounds of formula (I) (whether in solvated or unsolvated form) or their pharmaceutically acceptable salts (whether in solvated or unsolvated form) or prodrugs thereof defined in any aspect of the invention (except intermediate compounds in chemical processes) are referred to as "compounds of the invention".

Since the compounds of the invention are intended for use in pharmaceutical compositions it will readily be understood that they are each optionally provided in substantially pure form, for example at least 60% pure, for example at least 75% pure or at least 85%, or at least 98% pure (% are on a weight for weight basis). Impure preparations of the compounds may be used for preparing the more pure forms used in the pharmaceutical compositions.

Compounds of the invention may be prepared by methods known in the art of organic synthesis as set forth in part by the following synthesis schemes. In the following reaction schemes and hereafter, unless otherwise stated, all the groups are as defined in the first aspect. It is also recognised that in all of the schemes described below, it is well understood that protecting groups for sensitive or reactive groups are employed where necessary in accordance with general principles of chemistry. Protecting groups are manipulated according to standard methods of organic synthesis (T. W. Greene and P. G. M. Wuts (1991 ) Protecting Groups in Organic Synthesis, John Wiley & Sons). These groups are removed at a convenient stage of the compound synthesis using methods that are readily apparent to those skilled in the art. The selection of processes as well as the reaction conditions and order of their execution shall be consistent with the preparation of compounds of the invention.

Thus, the present invention provides a process for the manufacture of a compound of formula (I), the process comprising:

(a) coupling a compound of formula (II):

(II)

wherein R³, R⁴ and X are as defined for formula (I), with a compound of formula (III):

(III)

wherein R¹ and R² are as defined for formula (I); or (b) reacting a compound of formula

(IV) wherein R³ and R⁴ are as defined for formula (I), with a primary amine X-NH₂ wherein X is as defined for formula (I), to give a compound of formula (II) as defined in process (a), followed by coupling with a compound of formula (III) as defined in process (a); or (c) for a compound of formula (I) wherein R¹ is C(O)NH₂, reacting a compound of formula (V):

(V)

wherein R², R³, R⁴ and X are as defined for formula (I), with ammonium chloride, DIPEA and HATU; and thereafter optionally for process (a), (b) or (c):

- forming a salt; and/or

- converting a compound of formula (I) or a salt thereof to another compound of formula (I) or a salt thereof.

For process (a), typical conditions comprise heating under argon at a suitable temperature such as 90-100degC a mixture of compounds (II) and (III) in a suitable solvent such as toluene and/or ethanol for the required time. Compounds of formula (III) are commercially available or described in the literature. Compounds of formula (II) can be prepared as described in scheme 1 , scheme 2 or scheme 3.

For process (b), typical reaction conditions comprise mixing a compound of formula (IV) and a primary amine X-NH₂ under argon in a suitable solvent such as toluene for the required time and temperature, for example 2 hours at ambient, followed by the addition of further solvent such as toluene and a compound of formula (III), and heating the whole mixture at a suitable temperature such as 90degC for the required time, typically 2 hours. Compounds of formula (III), X-NH₂ and formula (IV) are commercially available or are described in the literature.

For process (c), typical reaction conditions comprise treatment of a mixture of a compound of formula (V), ammonium chloride and DIPEA (Λ/,Λ/-diisopropylethylamine) in dimethylformamide with HATU (O-(7-azabenzotriazol-1-yl)-Λ/,Λ/,Λ/',Λ/'-tetramethyluronium hexafluorophosphate) at room temperature. Compounds of formula (V) may be prepared by process (a) or (b) via the ester with appropriate protecting group manipulation to provide the acid.

An intermediate compound of formula (II) may be prepared by the reaction of an isothiocyanate of formula (IV) with a primary amine (X-NH₂) according to reaction scheme 1. Typical reaction conditions comprise mixing an isothiocyanate of formula (IV) with a primary amine (X-NH₂) in a suitable solvent such as ethyl acetate at a suitable temperature such as ambient for the appropriate time. Compounds of formula (IV) and primary amines X-NH₂ are commercially available or described in the literature.

Scheme 1

X-NH, / solvent

Alternatively, an intermediate compound of formula (II) may be prepared by the reaction of an aniline of formula (Vl) with an isothiocyanate of formula (VII) according to reaction scheme 2. Typical reaction conditions comprise heating a mixture of an aniline of formula

(VI) with an isothiocyanate of formula (VII), optionally with a base such as triethylamine added, at a suitable temperature such as 80degC under argon in a suitable solvent such as ethanol for the required time, typically 2.5-5 hours. Compounds of formula (Vl) and

(VII) are commercially available or described in the literature.

Scheme 2

solvent

Alternatively, an intermediate compound of formula (II) may be prepared by the reaction of an amine R'-NH₂ with a suitable reagent followed by the addition of amine R-NH₂ according to reaction scheme 3. Typical reaction conditions comprise adding a suitable reagent such as 1 ,1'-(thioxomethanediyl)bis-1 H-imidazole to amine R'-NH₂ under argon in a suitable solvent such as dichloromethane at a suitable temperature, for example OdegC, followed by stirring for a suitable time period at a suitable temperature, for example stirring for 4 hours at ambient. The reaction mixture is then cooled to a suitable temperature such as OdegC, and amine R-NH₂ is added and the reaction is stirred for the required time at a suitable temperature, for example 16 hours at ambient. Amines R'-NH₂ and R-NH₂ are commercially available or described in the literature.

Scheme 3

A compound of formula (VIII) may be prepared by coupling an intermediate compound of formula (IX) with an amine HNR₇R₈ according to scheme 4. Typical coupling conditions comprise mixing together a compound of formula (IX) with a suitable coupling agent such as 1 ,1 '-carbonyldiimidazole in an appropriate solvent such as dichloromethane at room temperature for a suitable time such as 20 minutes, followed by the addition of the amine HNR₇R₈ and further mixing for a suitable time, typically 2 hours. Alternative typical coupling conditions comprise mixing together a compound of formula (IX) with the required amine HNR₇R₈ and a suitable base such as DIPEA (Λ/,Λ/-diisopropylethylamine), in an appropriate solvent such as dimethylformamde. A suitable coupling agent such as HATU (O-(7-Azabenzotriazol-1-yl)-Λ/,Λ/,Λ/',Λ/-tetramethyluronium hexafluorophosphate) is then added and mixing continued at a suitable temperature such as ambient for a suitable time such as 24 hours. An intermediate compound of formula (IX) may be prepared according to scheme 5.

Scheme 4

HNR₇R₈, reagents, solvent

An intermediate compound of formula (IX) may be prepared from a compound of formula (X) by hydrolysis according to reaction scheme 5. Typical reaction conditions comprise heating a mixture of a compound of formula (X) and a hydroxide reagent, for example sodium hydroxide, in water and a suitable co-solvent such as ethanol at reflux for the required time, for example 1-2 hours. A compound of formula (X) may be prepared according to process (a) or (b).

Scheme 5

A compound of formula (Xl) may be prepared by acylation then alkylation of an intermediate compound of formula (XII) with a suitable reagent. Scheme 6 below illustrates the case for 5 or 6 membered ring lactams with reagent (Y), but this chemistry may also be applicable for other ring systems in the scope of formula (I). Typical reaction conditions comprise mixing together an intermediate compound of formula (XII) and a base such as Λ/,Λ/-diisopropylethylamine in a solvent such as dichloromethane with the appropriate reagent (Y) at a suitable temperature such as ambient under argon for a suitable time such as 30 minutes. Solvent is then removed, and a strong base such as sodium hydride is added under argon to a mixture of the residual material in a suitable solvent such as dimethylformamide at a suitable temperature such as ambient. Mixing is continued for the required time. An intermediate compound of formula (XII) may be prepared according to schemes 7 or 13 shown below.

Scheme 6

An intermediate compound of formula (XII, n=0) may be prepared from an intermediate compound of formula (XIII) by reduction of the nitro group according to scheme 7. Typical reaction conditions comprise heating together a mixture of an intermediate compound of formula (XIII), a suitable metal such as iron and aqueous concentrated hydrochloric acid solution in a suitable solvent such as ethanol at reflux for the required time, for example 24 hours. A compound of formula (XIII) may be prepared according to process (a) or (b).

Scheme 7

A compound of formula (XIV) can be prepared from a compound of formula (XV) by reaction with a secondary amine (HNRaRb) according to scheme 8. Typical reaction conditions comprise heating together under argon a mixture of a compound of formula (XV) and a secondary amine (HNRaRb) in the presence of a suitable palladium reagent such as bis(dibenzylideneacetone)palladium(0), a suitable ligand such as 2-(di-te/f- butylphosphino)biphenyl and a suitable base such as sodium fe/f-butoxide, in a suitable solvent such as toluene at an appropriate temperature such as 1 10 degC for the required time. A compound of formula (XV) may be prepared according to process (a) or (b).

Scheme 8

Y is a leaving group such as Br, I

HNRaRb / Pd reagent / ligand / base / solvent

A compound of formula (XVI) may be prepared from a compound of formula (XVII) by reaction with the appropriate unsaturated heterocycle according to scheme 9. Typical reaction conditions comprise microwaving at a suitable temperature, for example 180- 190degC, a mixture of a compound of formula (XVII) and the required heterocycle, for example 3-(trifluoromethyl)-1 H-pyrazole, in the presence of a suitable copper reagent such as copper (I) iodide, a suitable ligand such as Λ/,Λ/-dimethylglycine or N, N- dimethylethylenediamine, and a suitable base such as potassium carbonate or cesium carbonate in a suitable solvent such as dimethylsulphoxide or 1 ,4-dioxane for the required time, for example 30 minutes. A compound of formula (XVII) may be prepared according to process (a) or (b).

Scheme 9

Y = leaving group such as Br, I

HNRaRb / Cu reagent / ligand / base / solvent

HNRaRb is unsaturated heterocycle

A compound of formula (XVIII) can be prepared from a compound of formula (XIX) by reaction with the appropriate boronic acid according to scheme 10. Typical reaction conditions comprise heating under argon a mixture of a compound of formula (XIX) and a boronic acid (RB(OH)₂) in the presence of a suitable palladium reagent such as tetrakis(triphenylphospnine)palladium(0) and a suitable base such as sodium carbonate in a suitable solvent such as a 3:1 mixture of 1 ,4-dioxane and water at a suitable temperature such as 90-100degC for the required time. A compound of formula (XIX) may be prepared according to process (a) or (b).

Scheme 10

Boronic acid RB(OH)₂

/ Pd reagent / base / solvent

R is an aromatic or

heteroaromatic ring Y = leaving group, for example Br, I

A compound of formula (XX) may be prepared from a compound of formula (XXI) by reaction with the appropriate alkylating agent according to scheme 11. This chemistry can also be extended to derivatisation of other secondary sulfonamides and amides. Typical reaction conditions comprise mixing together a compound of formula (XXI) with a suitable base such as sodium hydride in a suitable solvent such as dimethylformamide under argon at a suitable temperature such as ambient for a suitable time such as 15 minutes, followed by the addition of the required alkylating agent (R10-Y, for example iodomethane) and continuing mixing for the required time, typically 2 hours. A compound of formula (XXI) may be prepared according to process (a) or (b).

Scheme 1 1

A compound of formula (XXII) may be prepared from a compound of formula (XXIII) by reaction with the appropriate sulfonyl chloride or acylating reagent according to scheme 12. Typical reaction conditions comprise mixing together under argon a compound of formula (XXIII) with a suitable base such as triethylamine in a suitable solvent such as dichloromethane at a suitable temperature such as OdegC, followed by the addition of the required sulfonyl chloride or acylating reagent (such as methanesulfonyl chloride or acetyl chloride, respectively) and continuing mixing at a suitable temperature such as ambient for the required time, for example 5 hours. A compound of formula (XXIII) may be prepared according to scheme 7 or 13 as appropriate.

Scheme 12 where Z is C=O or SO₀

A compound of formula (XXIV) may be prepared from a compound of formula (XXV) by treatment with acid according to scheme 13. Typical reaction conditions comprise treating a compound of formula (XXV) with a suitable acid such as hydrogen chloride or trifluoroacetic acid in a suitable solvent such as 1 ,4-dioxane, methanol and/or dichloromethane for the required time at the appropriate temperature such as ambient. A compound of formula (XXV) may be prepared according to process (a) or (b).

acid / solvent

An intermediate compound of formula (XXVI) may be prepared from an intermediate compound of formula (XXVII) by reaction of the enolate with ethyl trifluoroacetate according to scheme 14. This chemistry is also applicable to similar compounds of formula (I). Typical reaction conditions comprise mixing under argon a compound of formula (XXVII) with a suitable strong base such as lithium diisopropylamide in a suitable solvent such as tetrahydrofuran at a suitable temperature, for example -70degC, for the appropriate time, typically 30-60 minutes. Ethyl trifluoroacetate is then added slowly to the mixture and the reaction is allowed to warm to a suitable temperature such as ambient and mixing is continued for an appropriate time, for example 16 hours. A compound of formula (XXVII) is commercially available or described in the literature.

Scheme 14

An intermediate compound of formula (XXVIII) may be prepared by condensation of an intermediate compound of formula (XXIX) with hydrazine hydrate according to scheme 15. This chemistry is also applicable for similar compounds of formula (I). Typical reaction conditions comprise treating a compound of formula (XXIX) with hydrazine hydrate in a suitable solvent such as ethanol at a suitable temperature, for example 60-70degC, for the appropriate time, for example 9 hours. A compound of formula (XXIX) may be prepared according to scheme 14.

Scheme 15

Further details for the preparation of compounds of formula (I) and salts thereof are found in the Examples section hereinafter.

The compounds of the invention may be prepared singly or as compound libraries comprising at least 2, for example 5 to 1 ,000 compounds, for example 10 to 100 compounds. Libraries of compounds of the invention may be prepared by a combinatorial 'split and mix' approach or by multiple parallel synthesis using either solution phase or solid phase chemistry, by procedures known to those skilled in the art. Thus according to a further aspect there is provided a compound library comprising at least 2 compounds of the invention.

The compounds of the invention may be administered in conventional dosage forms prepared by combining a compound of the invention with standard pharmaceutical carriers or diluents according to conventional procedures well known in the art. These procedures may involve mixing, granulating and compressing or dissolving the ingredients as appropriate to the desired preparation.

The pharmaceutical compositions of the invention may be formulated for administration by any route, and include those in a form adapted for oral, topical or parenteral administration to mammals including humans.

The compositions may be formulated for administration by any route. The compositions may be in the form of tablets, capsules, powders, granules, lozenges, creams or liquid preparations, such as oral or sterile parenteral solutions or suspensions.

The topical formulations of the present invention may be presented as, for instance, ointments, creams or lotions, eye ointments and eye or ear drops, impregnated dressings and aerosols, and may contain appropriate conventional additives such as preservatives, solvents to assist drug penetration and emollients in ointments and creams.

The formulations may also contain compatible conventional carriers, such as cream or ointment bases and ethanol or oleyl alcohol for lotions. Such carriers may be present as from about 1% up to about 98% of the formulation. More usually they will form up to about 80% of the formulation.

Tablets and capsules for oral administration may be in unit dose presentation form, and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers, for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate, talc, polyethylene glycol or silica; disintegrants, for example potato starch; or acceptable wetting agents such as sodium lauryl sulphate. The tablets may be coated according to methods well known in normal pharmaceutical practice. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives, such as suspending agents, for example sorbitol, methyl cellulose, glucose syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, oily esters such as glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and, if desired, conventional flavouring or colouring agents.

Suppositories will contain conventional suppository bases, e.g. cocoa-butter or other glyceride.

For parenteral administration, fluid unit dosage forms are prepared utilising the compound and a sterile vehicle, for example water. The compound, depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle. In preparing solutions the compound can be dissolved in water for injection and filter sterilised before filling into a suitable vial or ampoule and sealing.

Advantageously, agents such as a local anaesthetic, preservative and buffering agents can be dissolved in the vehicle. To enhance the stability, the composition can be frozen after filling into the vial and the water removed under vacuum. The dry lyophilised powder is then sealed in the vial and an accompanying vial of water for injection may be supplied to reconstitute the liquid prior to use. Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilisation cannot be accomplished by filtration. The compound can be sterilised by exposure to ethylene oxide before suspending in the sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.

The compositions may contain from 0.1% by weight, for example from 10-60% by weight, of the active material, depending on the method of administration. Where the compositions comprise dosage units, each unit may, for example contain from 0.1 to 20 mg of the active ingredient. For example, such a unit may contain from 1 to 10 mg.

It will be recognised by one of skill in the art that the optimal quantity and spacing of individual dosages of a compound of the invention will be determined by the nature and extent of the condition being treated, the form, route and site of administration, and the particular mammal being treated, and that such optimums can be determined by conventional techniques. It will also be appreciated by one of skill in the art that the optimal course of treatment, i.e. the number of doses of a compound of the invention given per day for a defined number of days, can be ascertained by those skilled in the art using conventional course of treatment determination tests.

It will be appreciated that the invention includes the following further aspects. The embodiments described in respect of the first aspect apply equally to each of these further aspects:

i) the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a disease or condition caused by a reduction or imbalance in glutamate receptor function in a mammal; ii) a compound of formula (I) a pharmaceutically acceptable salt thereof for use in treating a disease or condition caused by a reduction or imbalance in glutamate receptor function in a mammal; iii) a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier or diluent; iv) a method of treatment of a disease or condition caused by a reduction or imbalance in glutamate receptor function in a mammal comprising administering an effective amount of a compound of formula (I) a pharmaceutically acceptable salt thereof. v) a combination product of a compound of formula (I) a pharmaceutically acceptable salt thereof with an antipsychotic; vi) a pharmaceutical composition comprising such a combination product and at least one pharmaceutically acceptable carrier or diluent; vii) the use of such a combination in the manufacture of a medicament for treating a disease or condition caused by a reduction or imbalance in glutamate receptor function in a mammal; viii) such a combination product for use in treating a disease or condition caused by a reduction or imbalance in glutamate receptor function in a mammal; ix) a method of treatment of a disease or condition caused by a reduction or imbalance in glutamate receptor function in a mammal comprising administering an effective amount of such a combination product; x) such a combination product for use as a medicament. In the case of aspects i), ii), iv), vii), viii), ix) and x), relevant diseases or conditions are: psychosis and psychotic disorders (including schizophrenia, schizo-affective disorder, schizophreniform diseases, brief reactive psychosis, child onset schizophrenia, "schizophrenia-spectrum" disorders such as schizoid or schizotypal personality disorders, acute psychosis, alcohol psychosis, drug-induced psychosis, autism, delerium, mania (including acute mania), manic depressive psychosis, hallucination, endogenous psychosis, organic psychosyndrome, paranoid and delusional disorders, puerperal psychosis, and psychosis associated with neurodegenerative diseases such as Alzheimer's disease); cognitive impairment (e.g. the treatment of impairment of cognitive functions including attention, orientation, memory (i.e. memory disorders, amnesia, amnesic disorders and age-associated memory impairment) and language function, and including cognitive impairment as a result of stroke, Alzheimer's disease, Aids-related dementia or other dementia states, as well as other acute or sub-acute conditions that may cause cognitive decline such as delirium or depression (pseudodementia states) trauma, aging, stroke, neurodegeneration, drug-induced states, neurotoxic agents), mild cognitive impairment, age related cognitive impairment, autism related cognitive impairment, Down's syndrome, cognitive deficit related to psychosis, post- electroconvulsive treatment related cognitive disorders; anxiety disorders (including generalised anxiety disorder, social anxiety disorder, agitation, tension, social or emotional withdrawal in psychotic patients, panic disorder, and obsessive compulsive disorder); neurodegenerative diseases (such as Alzheimer's disease, amyotrophic lateral sclerosis, motor neurone disease and other motor disorders such as Parkinson's disease (including relief from locomotor deficits and/or motor disability, including slowly increasing disability in purposeful movement, tremors, bradykinesia, hyperkinesia (moderate and severe), akinesia, rigidity, disturbance of balance and co-ordination, and a disturbance of posture), dementia in Parkinson's disease, dementia in Huntington's disease, neuroleptic- induced Parkinsonism and tardive dyskinesias, neurodegeneration following stroke, cardiac arrest, pulmonary bypass, traumatic brain injury, spinal cord injury or the like, and demyelinating diseases such as multiple sclerosis and amyotrophic lateral sclerosis); depression (which term includes bipolar (manic) depression (including type I and type II), unipolar depression, single or recurrent major depressive episodes with or without psychotic features, catatonic features, melancholic features, atypical features (e.g. lethargy, over-eating/obesity, hypersomnia) or postpartum onset, seasonal affective disorder and dysthymia, depression-related anxiety, psychotic depression, and depressive disorders resulting from a general medical condition including, but not limited to, myocardial infarction, diabetes, miscarriage or abortion); post-traumatic stress syndrome; attention deficit disorder; attention deficit hyperactivity disorder; drug-induced (phencyclidine, ketamine and other dissociative anaesthetics, amphetamine and other psychostimulants and cocaine) disorders; Huntingdon's chorea; tardive dyskinesia; dystonia; myoclonus; spasticity; obesity; stroke; sexual dysfunction; sleep disorders and some forms of epilepsy. Within the context of the present invention, the terms describing the indications used herein are classified in the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, published by the American Psychiatric Association (DSM-IV) and/or the International Classification of Diseases, 10th Edition (ICD-10). The various subtypes of the disorders mentioned herein are contemplated as part of the present invention. Numbers in brackets after the listed diseases below refer to the classification code in DSM-IV.

Within the context of the present invention, the term "psychotic disorder" includes :-

Schizophrenia including the subtypes Paranoid Type (295.30), Disorganised Type (295.10), Catatonic Type (295.20), Undifferentiated Type (295.90) and Residual Type (295.60); Schizophreniform Disorder (295.40); Schizoaffective Disorder (295.70) including the subtypes Bipolar Type and Depressive Type; Delusional Disorder (297.1 ) including the subtypes Erotomanic Type, Grandiose Type, Jealous Type, Persecutory Type, Somatic Type, Mixed Type and Unspecified Type; Brief Psychotic Disorder (298.8); Shared Psychotic Disorder (297.3); Psychotic Disorder Due to a General Medical Condition including the subtypes With Delusions and With Hallucinations; Substance-Induced Psychotic Disorder including the subtypes With Delusions (293.81 ) and With Hallucinations (293.82); and Psychotic Disorder Not Otherwise Specified (298.9).

Compounds of the invention may also be of use in the treatment of the following disorders:-

Depression and mood disorders including Major Depressive Episode, Manic Episode, Mixed Episode and Hypomanic Episode; Depressive Disorders including Major Depressive Disorder, Dysthymic Disorder (300.4), Depressive Disorder Not Otherwise Specified (311 ); Bipolar Disorders including Bipolar I Disorder, Bipolar Il Disorder (Recurrent Major Depressive Episodes with Hypomanic Episodes) (296.89), Cyclothymic Disorder (301.13) and Bipolar Disorder Not Otherwise Specified (296.80); Other Mood Disorders including Mood Disorder Due to a General Medical Condition (293.83) which includes the subtypes With Depressive Features, With Major Depressive-like Episode, With Manic Features and With Mixed Features), Substance-Induced Mood Disorder (including the subtypes With Depressive Features, With Manic Features and With Mixed Features) and Mood Disorder Not Otherwise Specified (296.90):

Anxiety disorders including Panic Attack; Panic Disorder including Panic Disorder without Agoraphobia (300.01 ) and Panic Disorder with Agoraphobia (300.21 ); Agoraphobia; Agoraphobia Without History of Panic Disorder (300.22), Specific Phobia (300.29, formerly Simple Phobia) including the subtypes Animal Type, Natural Environment Type, Blood-lnjection-lnjury Type, Situational Type and Other Type), Social Phobia (Social Anxiety Disorder, 300.23), Obsessive-Compulsive Disorder (300.3), Posttraumatic Stress Disorder (309.81 ), Acute Stress Disorder (308.3), Generalized Anxiety Disorder (300.02), Anxiety Disorder Due to a General Medical Condition (293.84), Substance-Induced Anxiety Disorder, Separation Anxiety Disorder (309.21 ), Adjustment Disorders with Anxiety (309.24) and Anxiety Disorder Not Otherwise Specified (300.00):

Substance-related disorders including Substance Use Disorders such as Substance Dependence, Substance Craving and Substance Abuse; Substance-Induced Disorders such as Substance Intoxication, Substance Withdrawal, Substance-Induced Delirium, Substance-Induced Persisting Dementia, Substance-Induced Persisting Amnestic Disorder, Substance-Induced Psychotic Disorder, Substance-Induced Mood Disorder, Substance-Induced Anxiety Disorder, Substance-Induced Sexual Dysfunction, Substance- Induced Sleep Disorder and Hallucinogen Persisting Perception Disorder (Flashbacks); Alcohol-Related Disorders such as Alcohol Dependence (303.90), Alcohol Abuse (305.00), Alcohol Intoxication (303.00), Alcohol Withdrawal (291.81 ), Alcohol Intoxication Delirium, Alcohol Withdrawal Delirium, Alcohol-Induced Persisting Dementia, Alcohol- Induced Persisting Amnestic Disorder, Alcohol-Induced Psychotic Disorder, Alcohol- Induced Mood Disorder, Alcohol-Induced Anxiety Disorder, Alcohol-Induced Sexual Dysfunction, Alcohol-Induced Sleep Disorder and Alcohol-Related Disorder Not Otherwise Specified (291.9); Amphetamine (or Amphetamine-I_ike)-Related Disorders such as Amphetamine Dependence (304.40), Amphetamine Abuse (305.70), Amphetamine Intoxication (292.89), Amphetamine Withdrawal (292.0), Amphetamine Intoxication Delirium, Amphetamine Induced Psychotic Disorder, Amphetamine-Induced Mood Disorder, Amphetamine-Induced Anxiety Disorder, Amphetamine-Induced Sexual Dysfunction, Amphetamine-Induced Sleep Disorder and Amphetamine-Related Disorder Not Otherwise Specified (292.9); Caffeine Related Disorders such as Caffeine Intoxication (305.90), Caffeine-Induced Anxiety Disorder, Caffeine-Induced Sleep Disorder and Caffeine-Related Disorder Not Otherwise Specified (292.9); Cannabis-Related Disorders such as Cannabis Dependence (304.30), Cannabis Abuse (305.20), Cannabis Intoxication (292.89), Cannabis Intoxication Delirium, Cannabis-lnduced Psychotic Disorder, Cannabis-lnduced Anxiety Disorder and Cannabis-Related Disorder Not Otherwise Specified (292.9); Cocaine-Related Disorders such as Cocaine Dependence (304.20), Cocaine Abuse (305.60), Cocaine Intoxication (292.89), Cocaine Withdrawal (292.0), Cocaine Intoxication Delirium, Cocaine-Induced Psychotic Disorder, Cocaine-Induced Mood Disorder, Cocaine-Induced Anxiety Disorder, Cocaine-Induced Sexual Dysfunction, Cocaine-Induced Sleep Disorder and Cocaine-Related Disorder Not Otherwise Specified (292.9); Hallucinogen-Related Disorders such as Hallucinogen Dependence (304.50), Hallucinogen Abuse (305.30), Hallucinogen Intoxication (292.89), Hallucinogen Persisting Perception Disorder (Flashbacks) (292.89), Hallucinogen Intoxication Delirium, Hallucinogen-Induced Psychotic Disorder, Hallucinogen-Induced Mood Disorder, Hallucinogen-Induced Anxiety Disorder and Hallucinogen-Related Disorder Not Otherwise Specified (292.9); Inhalant-Related Disorders such as Inhalant Dependence (304.60), Inhalant Abuse (305.90), Inhalant Intoxication (292.89), Inhalant Intoxication Delirium, Inhalant-Induced Persisting Dementia, Inhalant-Induced Psychotic Disorder, Inhalant- Induced Mood Disorder, Inhalant-Induced Anxiety Disorder and Inhalant-Related Disorder Not Otherwise Specified (292.9); Nicotine-Related Disorders such as Nicotine Dependence (305.1 ), Nicotine Withdrawal (292.0) and Nicotine-Related Disorder Not Otherwise Specified (292.9); Opioid-Related Disorders such as Opioid Dependence (304.00), Opioid Abuse (305.50), Opioid Intoxication (292.89), Opioid Withdrawal (292.0), Opioid Intoxication Delirium, Opioid-lnduced Psychotic Disorder, Opioid-lnduced Mood Disorder, Opioid-lnduced Sexual Dysfunction, Opioid-lnduced Sleep Disorder and Opioid- Related Disorder Not Otherwise Specified (292.9); Phencyclidine (or Phencyclidine-Like)- Related Disorders such as Phencyclidine Dependence (304.60), Phencyclidine Abuse (305.90), Phencyclidine Intoxication (292.89), Phencyclidine Intoxication Delirium, Phencyclidine-lnduced Psychotic Disorder, Phencyclidine-lnduced Mood Disorder, Phencyclidine-lnduced Anxiety Disorder and Phencyclidine-Related Disorder Not Otherwise Specified (292.9); Sedative-, Hypnotic-, or Anxiolytic-Related Disorders such as Sedative, Hypnotic, or Anxiolytic Dependence (304.10), Sedative, Hypnotic, or Anxiolytic Abuse (305.40), Sedative, Hypnotic, or Anxiolytic Intoxication (292.89), Sedative, Hypnotic, or Anxiolytic Withdrawal (292.0), Sedative, Hypnotic, or Anxiolytic Intoxication Delirium, Sedative, Hypnotic, or Anxiolytic Withdrawal Delirium, Sedative-, Hypnotic-, or Anxiolytic-Persisting Dementia, Sedative-, Hypnotic-, or Anxiolytic- Persisting Amnestic Disorder, Sedative-, Hypnotic-, or Anxiolytic-lnduced Psychotic Disorder, Sedative-, Hypnotic-, or Anxiolytic-lnduced Mood Disorder, Sedative-, Hypnotic-, or Anxiolytic- Induced Anxiety Disorder Sedative-, Hypnotic-, or Anxiolytic-lnduced Sexual Dysfunction, Sedative-, Hypnotic-, or Anxiolytic-lnduced Sleep Disorder and Sedative-, Hypnotic-, or Anxiolytic-Related Disorder Not Otherwise Specified (292.9); Polysubstance-Related Disorder such as Polysubstance Dependence (304.80); and Other (or Unknown) Substance-Related Disorders such as Anabolic Steroids, Nitrate Inhalants and Nitrous Oxide:

Sleep disorders including primary sleep disorders such as Dyssomnias such as Primary Insomnia (307.42), Primary Hypersomnia (307.44), Narcolepsy (347), Breathing-Related Sleep Disorders (780.59), Circadian Rhythm Sleep Disorder (307.45) and Dyssomnia Not Otherwise Specified (307.47); primary sleep disorders such as Parasomnias such as Nightmare Disorder (307.47), Sleep Terror Disorder (307.46), Sleepwalking Disorder (307.46) and Parasomnia Not Otherwise Specified (307.47); Sleep Disorders Related to Another Mental Disorder such as Insomnia Related to Another Mental Disorder (307.42) and Hypersomnia Related to Another Mental Disorder (307.44); Sleep Disorder Due to a General Medical Condition, in particular sleep disturbances associated with such diseases as neurological disorders, neuropathic pain, restless leg syndrome, heart and lung diseases; and Substance-Induced Sleep Disorder including the subtypes Insomnia Type, Hypersomnia Type, Parasomnia Type and Mixed Type; sleep apnea and jet-lag syndrome:

Autism Spectrum Disorders including Autistic Disorder (299.00), Asperger's Disorder (299.80), Rett's Disorder (299.80), Childhood Disintegrative Disorder (299.10) and Pervasive Disorder Not Otherwise Specified (299.80, including Atypical Autism). Attention-Deficit/Hyperactivity Disorder including the subtypes Attention-Deficit /Hyperactivity Disorder Combined Type (314.01 ), Attention-Deficit /Hyperactivity Disorder Predominantly Inattentive Type (314.00), Attention-Deficit /Hyperactivity Disorder Hyperactive-Impulse Type (314.01 ) and Attention-Deficit /Hyperactivity Disorder Not Otherwise Specified (314.9); Hyperkinetic Disorder; Disruptive Behaviour Disorders such as Conduct Disorder including the subtypes childhood-onset type (321.81 ), Adolescent- Onset Type (312.82) and Unspecified Onset (312.89), Oppositional Defiant Disorder (313.81 ) and Disruptive Behaviour Disorder Not Otherwise Specified; and Tic Disorders such as Tourette's Disorder (307.23):

Personality Disorders including the subtypes Paranoid Personality Disorder (301.0), Schizoid Personality Disorder (301.20), Schizotypal Personality Disorder (301 ,22), Antisocial Personality Disorder (301.7), Borderline Personality Disorder (301 ,83), Histrionic Personality Disorder (301.50), Narcissistic Personality Disorder (301 ,81 ), Avoidant Personality Disorder (301.82), Dependent Personality Disorder (301.6), Obsessive-Compulsive Personality Disorder (301.4) and Personality Disorder Not Otherwise Specified (301.9):

Enhancement of cognition including the treatment of cognition impairment in other diseases such as schizophrenia, bipolar disorder, depression, other psychiatric disorders and psychotic conditions associated with cognitive impairment, e.g. Alzheimer's disease: and

Sexual dysfunctions including Sexual Desire Disorders such as Hypoactive Sexual Desire Disorder (302.71 ), and Sexual Aversion Disorder (302.79); sexual arousal disorders such as Female Sexual Arousal Disorder (302.72) and Male Erectile Disorder (302.72); orgasmic disorders such as Female Orgasmic Disorder (302.73), Male Orgasmic Disorder (302.74) and Premature Ejaculation (302.75); sexual pain disorder such as Dyspareunia (302.76) and Vaginismus (306.51 ); Sexual Dysfunction Not Otherwise Specified (302.70); paraphilias such as Exhibitionism (302.4), Fetishism (302.81 ), Frotteurism (302.89), Pedophilia (302.2), Sexual Masochism (302.83), Sexual Sadism (302.84), Transvestic Fetishism (302.3), Voyeurism (302.82) and Paraphilia Not Otherwise Specified (302.9); gender identity disorders such as Gender Identity Disorder in Children (302.6) and Gender Identity Disorder in Adolescents or Adults (302.85); and Sexual Disorder Not Otherwise Specified (302.9).

Treatment of all of the various forms and sub-forms of the disorders mentioned herein are contemplated as part of the present invention.

Within the context of the present invention, the term "cognitive impairment" includes for example the treatment of impairment of cognitive functions including attention, orientation, learning disorders, memory (i.e. memory disorders, amnesia, amnesic disorders, transient global amnesia syndrome and age-associated memory impairment) and language function; cognitive impairment as a result of stroke, Alzheimer's disease, Huntington's disease, Pick disease, Aids-related dementia or other dementia states such as M ulti infarct dementia, alcoholic dementia, hypotiroidism-related dementia, and dementia associated to other degenerative disorders such as cerebellar atrophy and amyotropic lateral sclerosis; other acute or sub-acute conditions that may cause cognitive decline such as delirium or depression (pseudodementia states) trauma, head trauma, age related cognitive decline, stroke, neurodegeneration, drug-induced states, neurotoxic agents, mild cognitive impairment, age related cognitive impairment, autism related cognitive impairment, Down's syndrome, cognitive deficit related to psychosis, and post- electroconvulsive treatment related cognitive disorders; and dyskinetic disorders such as Parkinson's disease, neuroleptic-induced parkinsonism, and tardive dyskinesias.

It is to be understood that "treatment" as used herein includes prophylaxis as well as alleviation of established symptoms. In one embodiment, the mammal to be treated is a human.

The compounds of the invention may be used in combination with the following agents to treat or prevent psychotic disorders: i) antipsychotics (such as olanzapine, risperidone, clozapine, ziprazidone and talnetant); ii) drugs for extrapyramidal side effects, for example anticholinergics (such as benztropine, biperiden, procyclidine and trihexyphenidyl), antihistamines (such as diphenhydramine) and dopaminergics (such as amantadine); iii) antidepressants; iv) anxiolytics; and v) cognitive enhancers for example cholinesterase inhibitors (such as tacrine, donepezil, rivastigmine and galantamine).

The compounds of the invention may be used in combination with antidepressants to treat or prevent depression and mood disorders.

The compounds of the invention may be used in combination with the following agents to treat or prevent bipolar disease: i) mood stabilisers; ii) antipsychotics; and iii) antidepressants.

The compounds of the invention may be used in combination with the following agents to treat or prevent anxiety disorders: i) anxiolytics; and ii) antidepressants.

The compounds of the invention may be used in combination with the following agents to improve nicotine withdrawal and reduce nicotine craving: i) nicotine replacement therapy for example a sublingual formulation of nicotine beta-cyclodextrin and nicotine patches; and ii) bupropion.

The compounds of the invention may be used in combination with the following agents to improve alcohol withdrawal and reduce alcohol craving: i) NMDA receptor antagonists for example acamprosate; ii) GABA receptor agonists for example tetrabamate; and Ni) Opioid receptor antagonists for example naltrexone.

The compounds of the invention may be used in combination with the following agents to improve opiate withdrawal and reduce opiate craving: i) opioid mu receptor agonist/opioid kappa receptor antagonist for example buprenorphine; ii) opioid receptor antagonists for example naltrexone; and iii) vasodilatory antihypertensives for example lofexidine.

The compounds of the invention may be used in combination with the following agents to treat or prevent sleeping disorders: i) benzodiazepines for example temazepam, lormetazepam, estazolam and triazolam; ii) non-benzodiazepine hypnotics for example Zolpidem, zopiclone, zaleplon and indiplon; iii) barbiturates for example aprobarbital, butabarbital, pentobarbital, secobarbita and phenobarbital; iv) antidepressants; v) other sedative-hypnotics for example chloral hydrate and chlormethiazole.

The compounds of the invention may be used in combination with the following agents to treat anorexia: i) appetite stimulants for example cyproheptidine; ii) antidepressants; iii) antipsychotics; iv) zinc; and v) premenstral agents for example pyridoxine and progesterones.

The compounds of the invention may be used in combination with the following agents to treat or prevent bulimia: i) antidepressants; ii) opioid receptor antagonists; iii) antiemetics for example ondansetron; iv) testosterone receptor antagonists for example flutamide; v) mood stabilisers; vi) zinc; and vii) premenstral agents.

The compounds of the invention may be used in combination with the following agents to treat or prevent autism: i) antipsychotics; ii) antidepressants; iii) anxiolytics; and iv) stimulants for example methylphenidate, amphetamine formulations and pemoline.

The compounds of the invention may be used in combination with the following agents to treat or prevent Attention Deficit Hyperactivity Disorder: i) stimulants for example methylphenidate, amphetamine formulations and pemoline; and ii) non-stimulants for example norepinephrine reuptake inhibitors (such as atomoxetine), alpha 2 adrenoceptor agonists (such as clonidine), antidepressants, modafinil, and cholinesterase inhibitors (such as galantamine and donezepil).

The compounds of the invention may be used in combination with the following agents to treat personality disorders: i) antipsychotics; ii) antidepressants; iii) mood stabilisers; and iv) anxiolytics.

The compounds of the invention may be used in combination with the following agents to treat or prevent male sexual dysfunction: i) phosphodiesterase V inhibitors, for example vardenafil and sildenafil; ii) dopamine agonists/dopamine transport inhibitors for example apomorphine and buproprion; iii) alpha adrenoceptor antagonists for example phentolamine; iv) prostaglandin agonists for example alprostadil; v) testosterone agonists such as testosterone; vi) serotonin transport inhibitors for example serotonin reuptake inhibitors; v) noradrenaline transport inhibitors for example reboxetine and vii) 5-HT1A agonists, for example flibanserine.

The compounds of the invention may be used in combination with the same agents specified for male sexual dysfunction to treat or prevent female sexual dysfunction, and in addition an estrogen agonist such as estradiol.

Antipsychotic drugs include Typical Antipsychotics (for example chlorpromazine, thioridazine, mesoridazine, fluphenazine, perphenazine, prochlorperazine, trifluoperazine, thiothixine, haloperidol, molindone and loxapine); and Atypical Antipsychotics (for example clozapine, olanzapine, risperidone, quetiapine, aripirazole, ziprasidone, amisulpride, ziprazidone and talnetant).

Antidepressant drugs include serotonin reuptake inhibitors (such as citalopram, escitalopram, fluoxetine, paroxetine and sertraline); dual serotonin/noradrenaline reuptake inhibitors (such as venlafaxine, duloxetine and milnacipran); Noradrenaline reuptake inhibitors (such as reboxetine); tricyclic antidepressants (such as amitriptyline, clomipramine, imipramine, maprotiline, nortriptyline and trimipramine); monoamine oxidase inhibitors (such as isocarboxazide, moclobemide, phenelzine and tranylcypromine); and others (such as bupropion, mianserin, mirtazapine, nefazodone and trazodone).

Mood stabiliser drugs include lithium, sodium valproate/valproic acid/divalproex, carbamazepine, lamotrigine, gabapentin, topiramate and tiagabine.

Anxiolytics include benzodiazepines such as alprazolam and lorazepam.

The invention is illustrated by the Examples described below.

Starting materials, reagents and solvents were obtained from commercial suppliers and used without further purification unless otherwise stated. Flash chromatography was carried out using pre-packed lsolute Flash™ or Biotage™ silica-gel columns as the stationary phase and analytical grade solvents as the eluent unless otherwise stated.

NMR spectra were obtained at 298K, 303.2K or 300K, at the frequency stated using either a Bruker™ DPX400 or AV400 machine and run as a dilute solution of CDCI₃ unless otherwise stated. All NMR spectra were referenced to tetramethylsilane (TMS δ_H 0, δc 0).

All coupling constants are reported in hertz (Hz), and multiplicities are labelled s (singlet), bs (broad singlet), d (doublet), t (triplet), q (quartet), dd (doublet of doublets), dt (doublet of triplets) and m (multiplet).

Total ion current traces were obtained for electrospray positive and negative ionisation (ES+ / ES-) and/or atmospheric pressure chemical positive and negative ionisation (AP+ / AP-).

Where reactions are described as having been carried out in a similar manner to earlier, more completely described reactions, the general reaction conditions used were essentially the same. Work up conditions used were of the types standard in the art, but may have been adapted from one reaction to another. The starting materials may not necessarily have been prepared from the batch referred to. All quoted retention times are as measured using LC/MS (Liquid Chromatography/Mass Spectrometry). Where appropriate, these retention times were used as a guide for purification using mass- directed auto-preparation (MDAP), which refers to purification by HPLC, wherein fraction collection is triggered by detection of the programmed mass ion for the compound of interest. Compounds synthesised may have various purities ranging from for example 85% to 98%. However, calculations of number of moles and yield are generally not adjusted for this. In the assays used and described herein, the compounds of the present invention were not necessarily from the same batch described above. A test compound from one batch may have been combined with other batch(es) for the assay(s). All reactions were either carried out under argon or may be carried out under argon, unless otherwise stated.

Unless otherwise stated, all compounds with chiral centre(s) are racemic.

Abbreviations

TEA Triethylamine

TMS-CI Trimethylsilyl chloride

SS saturated solution

TFA Trifluoroacetic acid

DAD Diode Array Detector

CD Circular dichroism a/a% percentage by area under the curve

LC/MS Liquid Chromatography / Mass Spectrometry

NMR Nuclear Magnetic Resonance

THF Tetrahydrofuran

DMSO Dimethylsulfoxide

DMF Dimethylformamide

DCM / MDC Dichloromethane / Methylene dichloride

CDI 1 ,1 '-Carbonyldiimidazole

LDA Lithium diisopropylamide

EDC 1-ethyl-3-(dimethylaminopropyl)carbodiimide MsCI Methanesulfonyl chloride

AcOH Acetic acid

HOAt 1 -hydroxy-7-azabenzotriazole

HOBt 1-hydroxybenzotriazole

Pd on C Palladium on Charcoal

MeCN Acetonitrile

MDAP Mass-directed auto-preparation

DBU 1 ,8-diazabicyclo[5.4.0]undec-7-ene

Cy Cyclohexane

EtOAc Ethyl acetate

ES electrospray

ES-API electrospray - atmospheric pressure ionisation min(s) minute(s)

Me methyl

Et ethyl degC degree Celsius

SCX strong cationic exchange h hour(s)

DIPEA Λ/,Λ/-diisopropylethylamine

HATU O-(7-Azabenzotriazol-1 -y\)-N,N,N',N -tetramethyluronium hexafluorophosphate

Description 1 : ethyl 4-{[(cyclopropylamino)carbonothioyl]amino}benzoate

A solution of 4-ethoxycarbonylphenyl isothiocyanate (2.07g, lOmmol) in ethyl acetate (8ml) was added to a stirring solution of cyclopropylamine (570mg, lOmmol) in ethyl acetate (8ml) over 10 minutes at room temperature. The reaction mix was allowed to stir at room temperature for 1.5 hours. The solvent was then removed by rotary evaporation to give the title compound as a white solid (2.8Og, quantitative).

LC/MS (ES): Found 265 (ES+), retention time 2.60mins. Ci₃H₁₆N₂O₂S requires 264.

Description 2: ethyl 4-{[5-acetyl-3-cyclopropyl-4-methyl-1 ,3-thiazol-2(3H)- ylidene]amino}benzoate

A mixture of ethyl 4-{[(cyclopropylamino)carbonothioyl]amino}benzoate (2.7g, Description 1 , assume lOmmol) and 3-chloro-2,4-pentanedione (1.41g, 10.5mmol) in toluene (40ml) was stirred at 9O⁰C (oil bath temperature) under argon for 2 hours. The reaction mixture was allowed to cool and the solvent was removed by rotary evaporation and oven dried to give a yellow solid (3.75g) which was dissolved in dichloromethane and added to a 5Og isolute silica gel pre-packed column and eluted from 0-50% ethyl acetate in petroleum ether. The relevant fractions were combined and the solvent removed by rotary evaporation to give the title compound as a yellow oil (682mg, 20%).

LC/MS (ES): Found 345 (ES+), retention time 2.99mins. Ci₈H₂₀N₂O₃S requires 344.

1 H-NMR (400MHz, CDCI₃): δ 1.05 (2H, m), 1.27 (2H, m), 1.39 (3H, t, J=7Hz), 2.24 (3H, s), 2.68 (3H, s), 2.86 (1 H, m), 4.37 (2H, m), 7.06 (2H, m), 8.06 (2H, m).

Description 3: 4-{[5-acetyl-3-cyclopropyl-4-methyl-1,3-thiazol-2(3H)- ylidene]amino}benzoic acid

A mixture of ethyl 4-{[5-acetyl-3-cyclopropyl-4-methyl-1 ,3-thiazol-2(3H)- ylidene]amino}benzoate (666mg, Description 2, 1.94mmol) and sodium hydroxide pellets (93mg, 2.33mmol) in a mix of water (5ml) and ethanol (5ml) was stirred at reflux for 1 hour and then allowed to cool to room temperature. The ethanol was removed by rotary evaporation and the residue was washed with dichloromethane. The aqueous layer was separated and neutralised to pH 7-8 using 2N hydrochloric acid, and the product was extracted into dichloromethane. The organic extracts were dried over sodium sulphate and solvent was removed by rotary evaporation to give the title compound as a yellow solid (352mg, 57%).

LC/MS (ES): Found 315 (ES-), retention time 2.21 mins. Ci₆H₁₆N₂O₃S requires 316. 1 H-NMR (400MHz, DMSO-d₆): δ 1.01 (2H, m), 1.15 (2H, m), 2.32 (3H, s), 2.65 (3H, s), 2.97 (1 H, m), 7.03 (2H, m), 7.92 (2H, m), 12.72 (1 H, bs).

Description 4: 1 -{3-cyclopropyl-4-methyl-2-[(4-nitrophenyl)imino]-2,3-dihydro-1 ,3- thiazol-5-yl}ethanone

A solution of 4-nitrophenyl isothiocyanate (3.6Og, 20mmol) in toluene (16ml) was added dropwise to a stirring solution of cyclopropylamine (1.14g, 20mmol, 1.38ml) in toluene (16ml) over 15 minutes at room temperature, and the resulting mix stirred at room temperature for 18 hours. The reaction mix was diluted by the addition of toluene (20ml) and treated with 3-chloro-2,4-pentanedione (2.81 g, 21 mmol, 2.5ml) in one portion and the whole mix stirred at 9O⁰C (oil bath temperature) for 2 hours. The solvent was removed by rotary evaporation to give a brown foamy solid, which was partitioned between dichloromethane (30ml) and saturated aqueous sodium bicarbonate solution. The organic layer was separated and dried over sodium sulphate and the solvent removed by rotary evaporation to give a dark oil which was added to a 5Og silica pre-packed column and eluted from 0-50% ethyl acetate in petroleum ether. The relevant fractions were combined and evaporation under reduced pressure gave the title compound as an orange coloured solid (4.7Og, 74%).

LC/MS (ES): Found 318 (ES+), retention time 2.99mins. Ci₅H₁₅N₃O₃S requires 317.

Description 5: 1 -{2-[(4-aminophenyl)imino]-3-cyclopropyl-4-methyl-2,3-dihydro-1 ,3- thiazol-5-yl}ethanone hydrochloride

A mixture of 1-{3-cyclopropyl-4-methyl-2-[(4-nitrophenyl)imino]-2,3-dihydro-1 ,3-thiazol-5- yl}ethanone (1.3Og, crude, Description 4) and reduced iron powder (0.8g, 14.5mmol) in a mixture of ethanol (80ml) and concentrated hydrochloric acid solution (8 drops) was stirred at reflux for 3 hours. Further reduced iron powder (0.8g, 14.5mmol) and concentrated hydrochloric acid solution (8 drops) was added and reflux continued for 24 hours. The reaction mix was allowed to cool to room temperature and then filtered through a bed of kieselguhr and sodium sulphate. The filtrate was then evaporated in vaccuo to about half the volume and then treated with a 1 M solution of hydrogen chloride in diethyl ether (8ml), and the remainder of the solvent was removed by rotary evaporation. The residue was then triturated in diethyl ether (100ml), the liquid was decanted off and the residual material dried to give the title compound as a brown solid (1.71g,).

LC/MS (ES): Found 288 (ES+), retention time 1.43mins. C₁₅H₁₇N₃OS requires 287.

Description 6: 4-{[5-acetyl-3-ethyl-4-methyl-1 ,3-thiazol-2(3H)-ylidene]amino}benzoic acid

A mixture of ethyl 4-{[5-acetyl-3-ethyl-4-methyl-1 ,3-thiazol-2(3H)-ylidene]amino}benzoate (Example 5; 2.38g, 7.17mmol) and sodium hydroxide pellets (344mg, 8.6mmol) in a mix of water (20ml) and ethanol (20ml) was stirred at reflux for 1 hour and then allowed to cool to room temperature. The ethanol was removed by rotary evaporation and the residue was washed with dichloromethane. The aqueous layer was separated and neutralised to pH 7- 8 using 2N hydrochloric acid, and the product was extracted into dichloromethane. The organic extracts were dried over sodium sulphate and solvent removed by rotary evaporation to give a yellow solid. The aqueous phase was then filtered, and the resulting solid washed with water and oven dried to give a yellow solid. The 2 crops were combined to give the title compound as a yellow solid (1.47g, 67%).

LC/MS (ES): Found 303 (ES-), retention time 2.36mins. C₁₅H₁₆N₂O₃S requires 304. 1 H-NMR (400MHz, DMSOd₆): δ 1.27 (3H, t, J=7Hz), 2.34 (3H, s), 2.61 (3H, s), 4.05 (2H, m), 7.09 (2H, m), 7.93 (2H, m), 12.71 (1 H, bs).

Description 7: 1 -{2-[(4-bromophenyl)imino]-3-ethyl-4-methyl-2,3-dihydro-1 ,3-thiazol- 5-yl}ethanone

A solution of 4-bromophenyl isothiocyanate (6.42g, 30mmol) in toluene (25ml) was added to a stirring solution of ethylamine (available as a 2M solution in tetrahydrofuran; 15ml, 30mmol) in toluene (25ml) over 15 minutes at room temperature. The reaction mixture was allowed to stir at room temperature for 1.5 hours. The reaction mixture was diluted with further toluene (40ml), and 3-chloro-2,4-pentanedione (4.24g, 31.5mmol, 3.8ml) was added in one portion and the resulting mix stirred at 9O⁰C (oil bath temperature) for 2 hours. The reaction mixture was allowed to cool and most of the toluene was removed by rotary evaporation and the residue was partitioned between ethyl acetate (100ml) and saturated aqueous sodium bicarbonate solution (100ml). The organic layer was separated and dried over sodium sulphate and the solvent removed by rotary evaporation to give a golden coloured oil which was purified by column chromatography using a 5Og isolute silica column, eluting from 0-50% ethyl acetate in petroleum ether. The relevant fractions were combined and the solvent removed by rotary evaporation to give a yellow oil (8.1 g) which was then passed through 2 x 10g SCX columns in ethyl acetate and the solvent removed under reduced pressure to give the title compound as a yellow solid (3.4Og, 34%). LC/MS (ES): Found 339 & 341 (ES+), retention time 3.34mins. C₁₄H₁₅BrN₂OS requires 338 & 340.

¹H NMR (400MHz, CDCI₃): δ 1.35 (3H, t, J=7Hz), 2.26 (3H, s), 2.62 (3H, s), 4.03 (2H, q, J=7Hz), 6.94 (2H, m), 7.45 (2H, m).

Description 8: /V-ethyl-/V-[4-(1,3-oxazol-5-yl)phenyl]thiourea

A mixture of 4-(1 ,3-oxazol-5-yl)aniline (320mg, 2.0mmol), ethyl isothiocyanate (209mg, 2.40mmol, 0.21 ml) and triethylamine (0.4ml) in ethanol (10ml) was stirred at reflux for 2.5 hours. The solvent was removed by rotary evaporation to give a beige solid which was triturated in petroleum ether, the liquid was decanted off and the residual material dried to give the title compound as a beige solid (458mg, 93%).

LC/MS (ES): Found 248 (ES+), retention time O.δOmins (2 minute run). C₁₂H₁₃N₃OS requires 247.

¹H NMR (400MHz, CDCI₃): δ 1.24 (3H, m), 1.62 (1 H, s), 3.70 (2H, m), 6.04 (1 H, bs), 7.28 (2H, d, J=8Hz), 7.38 (1 H, s), 7.72 (2H, m), 7.94 (1 H, s).

Description 9: 3-(trifluoroacetyl)tetrahydro-4H-pyran-4-one

A solution of tetrahydro-4H-pyran-4-one (5.Og, 50mmol) in tetrahydrofuran (100ml) was cooled to -7O⁰C with stirring under argon. The solution was then treated with a 2M solution of lithium diisopropylamide in tetrahydrofuran (25ml, 50 mmol) dropwise over 30 minutes. The mix was then stirred at -7O⁰C for 30 minutes, then treated dropwise with ethyl trifluoroacetate (7.1g, 5.9ml, 50mmol) with stirring under argon. The mix was then allowed to warm slowly up to 2O⁰C and stirred for 16 hours under argon. The reaction mix was then partitioned between ethyl acetate (50ml) and water (100ml). The organic layer was dried over sodium sulphate and the solvent removed by rotary evaporation to give the title compound as a foamy yellow solid (10.34g, quantitative).

LC/MS (ES): Found 195 (ES-), retention time 2.35 mins. C₇H₇F₃O₃ requires 196.

1 H-NMR (400MHz, MeOD-d₄): δ 2.34 (2H, m), 3.22 (1 H, m), 3.87 (2H, m), 4.50 (2H, m).

Description 10: 3-(trifluoromethyl)-1 ,4,6,7-tetrahydropyrano[4,3-c]pyrazole

A mixture of 3-(trifluoroacetyl)tetrahydro-4H-pyran-4-one (5.42g, 27.7mmol, Description 9), and hydrazine hydrate (1.38g, 1.4ml, 27.6 mmol) in ethanol (120ml) was stirred at 6O⁰C under argon for 6 hours. A further 0.7ml (14mmol) of hydrazine hydrate was added and the reaction stirred at 7O⁰C for 3 hours. The reaction mix was allowed to cool and the solvent removed by rotary evaporation. The residue was partitioned between dichloromethane and water. The organic layer was separated, dried over sodium sulphate, and solvent removed by rotary evaporation. The aqueous layer was neutralised with 2N HCI and re-extracted with dichloromethane. The organic layer was separated, dried over sodium sulphate, and the solvent removed by rotary evaporation. The 2 extracts were combined to give the title compound as a yellow solid (3.64g, 68%).

LC/MS (ES): Found 191 (ES-), retention time 1.92 mins. C₇H₇F₃N₂O requires 192. 1 H-NMR (400MHz, CDCI₃): δ 2.83 (2H, m), 3.95 (2H, m), 4.76 (2H, s), 1 1.32 (1 H, bs).

Description 11 : 1 ^-^-bromophenylJiminol-S-cyclopropyl^-methyl^jS-dihydro- 1 ,3-thiazol-5-yl}ethanone

A solution of 4-bromophenyl isothiocyanate (7.44g, 34.8mmol) in toluene (30ml) was added to a stirring solution of cyclopropylamine (1.98g, 34.8mmol) in toluene (30ml) over 15 minutes at room temperature. The reaction mixture was allowed to stir at room temperature for 1.5 hours. The reaction mixture was diluted with further toluene (40ml), and 3-chloro-2,4-pentanedione (4.91 g, 36.5mmol, 4.38ml) was added in one portion and the resulting mix stirred at 9O⁰C (oil bath temperature) for 2 hours. The reaction mixture was allowed to cool and most of the toluene was removed by rotary evaporation and the residue was partitioned between ethyl acetate (100ml) and saturated aqueous sodium bicarbonate solution (100ml). The organic layer was separated and dried over sodium sulphate and the solvent removed by rotary evaporation to give a golden coloured oily suspension. The product was split into 3 and added to 3 x 10g SCX columns and washed through with ethyl acetate. The solvent was removed under reduced pressure to give a brown oil (7.36g). This material was dissolved in dichloromethane and added to a 5Og isolute silica pre-packed column and eluted from 0-100% ethyl acetate in petroleum ether. Relevant fractions were combined and the solvent removed by rotary evaporation to give the title compound as a brown solid (5.68g, 47%). LC/MS (ES): Found 351 & 353 (ES+), retention time 2.86mins. Ci₅H₁₅BrN₂OS requires 350 & 352.

¹H NMR (400MHz, CDCI₃): δ 1.03 (2H, m), 1.26 (2H, m), 2.24 (3H, s), 2.67 (3H, s), 2.84 (1 H, m), 6.89 (2H, m), 7.48 (2H, m).

Description 12: ethyl (4-{[5-acetyl-3-ethyl-4-methyl-1,3-thiazol-2(3H)- ylidene]amino}phenyl)acetate

A mixture of ethyl-4-aminophenylacetate (1.79g, lOmmol), ethyl isothiocycanate (1.04g, 12mmol, 1.05ml) and triethylamine (2ml) in ethanol (50ml) was stirred at reflux for 2 hours.

The solvent was then removed by rotary evaporation, the resulting material was then suspended in toluene (50ml) and treated with 3-chloro-2,4-pentanedione (1.34g, l Ommol,

1.19ml) and the whole mix stirred at 9O⁰C (oil bath temperature) for 3 hours. The reaction mix was allowed to cool and diluted with ethyl acetate (50ml). The mix was washed with saturated aqueous sodium bicarbonate solution (80ml), and then brine solution (50ml).

The organic layer was dried over sodium sulphate and the solvent removed by rotary evaporation to give a brown oil (2.57g), which was dissolved in dichloromethane and added to a 2Og pre-packed isolute silica column and eluted from 0-50% ethyl acetate in petroleum ether to give the title compound as a yellow oil (2.06g, 60%).

LC/MS (ES): Found 347 (ES+), retention time 2.84mins. C₁₈H₂₂N₂O₃S requires 346.

¹H NMR (400MHz, CDCI₃): δ 1.26 (3H, m), 1.35 (3H, t, J=7Hz), 2.25 (3H, s), 2.62 (3H, s),

3.59 (2H, s), 4.04 (2H, q, J=7Hz), 4.15 (2H, m), 7.01 (2H, m), 7.27 (2H, m).

Description 13: (4-{[5-acetyl-3-ethyl-4-methyl-1 ,3-thiazol-2(3H)- ylidene]amino}phenyl)acetic acid

A mixture of ethyl (4-{[5-acetyl-3-ethyl-4-methyl-1 ,3-thiazol-2(3H)- ylidene]amino}phenyl)acetate (2.05g, 5.9mmol, Description 12) and sodium hydroxide (0.28g, 7.1 mmol) in ethanol (15ml) and water (15ml) was stirred at reflux for 2 hours. The reaction mix was allowed to cool and the ethanol removed by rotary evaporation. The remainder was diluted with water (10ml) and washed twice with ethyl acetate (2 x 20ml). The aqueous layer was separated and acidified to pH5 using 2N aqueous HCI. The resulting precipitate was filtered off and vacuum oven dried to give the title compound as a pale beige solid (1.3Og, 69%). LC/MS (ES): Found 319 (ES+), retention time 2.08mins. Ci₆H₁₈N₂O₃S requires 318.

¹H NMR (400MHz, DMSO-d₆): δ 1.26 (3H, t, J=7Hz), 2.31 (3H, s), 2.59 (3H, s), 3.53 (2H, s), 4.02 (2H, m), 6.93 (2H, m), 7.23 (2H, d, J=8Hz), 12.32 (1 H, bs).

Description 14 : /V-ethyl-W-[4-(1H-pyrazol-1 -yl)phenyl]thiourea

A mixture of ethylamine in THF (2 M solution, 9.84ml, 19.68mmol) and ethyl acetate (20ml) was cooled in an ice water bath with stirring under argon then 1-(4- isothiocyanatophenyl)-1 H-pyrazole (1.Og, 4.92mmol) was added. The mixture was allowed to stir at 10⁰C for 1 hour. Solvent was removed by rotary evaporation and dried under high vacuum to give the title compound as a solid (1.16g, 96%).

LC/MS (ES): Found 245 (ES-), retention time 2.28mins. Ci₂H₁₄N₄S requires 246.

Description 15 : Λ^2-hydroxyethyl)-Λf-[4-(1H-pyrazol-1 -yl)phenyl]thiourea

To a solution of 1-(4-isothiocyanatophenyl)-1 H-pyrazole (1.Og, 4.92mmol) in ethyl acetate (25ml) was added 2-aminoethanol (0.36ml, 5.9mmol). The reaction mixture was allowed to stir at room temperature under argon for 1 hour. Solvent was removed and the residual material was dried under high vacuum to give the title compound as a solid (1.29g, 99%).

LC/MS (ES): Found 263 (ES+), retention time 1.84mins. Ci₂Hi₄N₄OS requires 262.

Description 16: /V-(4-bromophenyl)-/V-(2-hydroxyethyl)thiourea

2-aminoethanol (2.11 ml, 0.035mol) was dissolved in ethyl acetate (50ml) and 1-bromo-4- isothiocyanatobenzene (5.Og, 0.023mol) was added portionwise under argon over 10 minutes. The reaction mixture was allowed to stir at room temperature for 16 hours. Solvent was removed by rotary evaporation and the residual material was dried under high vacuum to give the title compound as a white solid (6.32g, 100%).

LC/MS (ES): Found 275, 277 (ES+), retention time 2.14mins. C₉H₁₁BrN₂OS requires 274, 276.

Description 17 : 1 -[2-[(4-bromophenyl)imino]-3-(2-hydroxyethyl)-4-methyl-2,3- dihydro-1,3-thiazol-5-yl]ethanone

Λ/-(4-bromophenyl)-Λ/'-(2-hydroxyethyl)thiourea (6.32g, 23mmol, Description 16) was dissolved in ethanol (20ml) and toluene (100ml). 3-chloro-2,4-pentanedione (5.45ml, 46mmol) was then added. The resulting mixture was heated at 90⁰C under argon for 30 minutes. Solvent was removed by rotary evaporation and the residual material was partitioned between ethyl acetate and aqueous sodium bicarbonate solution. The organic layer was separated, dried over sodium sulphate and evaporated. The residual material was recrystallised with ethyl acetate/n-pentane to give the title compound as a yellow solid (5.59g, 68.4%).

LC/MS (ES): Found 355, 357 (ES+), retention time 2.79mins. C₁₄H₁₅BrN₂O₂S requires 354, 356.

Description 18: methyl 4-({[(2-hydroxyethyl)amino]carbonothioyl}amino)benzoate

The title compound was prepared from methyl 4-isothiocyanatobenzoate and 2- aminoethanol using a similar procedure to that described for Description 16.

LC/MS (ES): Found 255 (ES+), retention time 1.89mins. C₁₁H₁₄N₂O₃S requires 254.

Description 19: methyl 4-{[5-acetyl-3-(2-hydroxyethyl)-4-methyl-1,3-thiazol-2(3H)- ylidene]amino}benzoate

The title compound was prepared from methyl 4-({[(2- hydroxyethyl)amino]carbonothioyl}amino)benzoate (Description 18) and 3-chloro-2,4- pentanedione using a similar procedure to that described for Description 17.

LC/MS (ES): Found 335 (ES+), retention time 2.48mins. C₁₆H₁₈N₂O₄S requires 334.

Description 20: 4-{[5-acetyl-3-(2-hydroxyethyl)-4-methyl-1 ,3-thiazol-2(3H)- ylidene]amino}benzoic acid

A mixture of methyl 4-{[5-acetyl-3-(2-hydroxyethyl)-4-methyl-1 ,3-thiazol-2(3H)- ylidene]amino}benzoate (2.Og, 5.9mmol, Description 19), lithium hydroxide hydrate (0.515g, 11.9mmol) in THF (30ml) and water (30ml) was heated at 70⁰C with stirring for 16 hours. THF was removed by rotary evaporation and the aqueous solution was acidified with 5N HCI. Then water was removed under reduced pressure and the residual material was dried under high vacuum for 48 hours to give the title compound and lithium chloride mixture (3.15g) which was used directly without further purification.

LC/MS (ES): Found 321 (ES+), retention time 2.06mins. C₁₅H₁₆N₂O₄S requires 320.

Description 21 : 1,1-dimethylethyl [(4-

{[(methylamino)carbonothioyl]amino}phenyl)methyl]carbamate

The title compound was prepared from 1 ,1-dimethylethyl [(4- isothiocyanatophenyl)methyl]carbamate and methylamine (2M solution in THF) using a similar procedure to that described for Description 14.

LC/MS (ES): Found 296 (ES+), retention time 2.38mins. C₁₄H₂₁N₃O₂S requires 295. Description 22: 1,1-dimethylethyl [(4-

{[(ethylamino)carbonothioyl]amino}phenyl)methyl]carbamate

The title compound was prepared from 1 ,1-dimethylethyl [(4- isothiocyanatophenyl)methyl]carbamate and ethylamine (2M solution in THF) using a similar procedure to that described for Description 14.

LC/MS (ES): Found 310 (ES+), retention time 2.80mins. C₁₅H₂₃N₃O₂S requires 309.

Description 23: 1,1 -dimethylethyl [(4-{[5-acetyl-3-ethyl-4-methyl-1 ,3-thiazol-2(3H)- ylidene]amino}phenyl)methyl]carbamate

A mixture of 1 ,1-dimethylethyl [(4-

{[(ethylamino)carbonothioyl]amino}phenyl)methyl]carbamate (585mg, 1.89mmol, Description 22) and 3-chloro-2,4-pentanedione (0.68ml, 5.67mmol) in ethanol (15ml) was heated at 90⁰C for 1 hour with stirring under argon. The solvent was removed by rotary evaporation to give the title compound as a pale yellow foam >70% pure (803mg, 76%) which was used directly without further purification.

LC/MS (ES): Found 390 (ES+), retention time 2.89mins. C₂₀H₂₇N₃O₃S requires 389.

Description 24: 1-(2-{[4-(aminomethyl)phenyl]imino}-3-ethyl-4-methyl-2,3-dihydro- 1 ,3-thiazol-5-yl)ethanone hydrochloride

A mixture of 1 ,1-dimethylethyl [(4-{[5-acetyl-3-ethyl-4-methyl-1 ,3-thiazol-2(3H)- ylidene]amino}phenyl)methyl]carbamate (803mg, 1.88mmol, Description 23), 4 N hydrogen chloride in 1 ,4-dioxane solution (4ml) and methanol (30ml) was stirred at room temperature under argon for 5 hours and then allowed to stand at room temperature over the weekend. The solvent was removed by rotary evaporation and dried under high vacuum to give the title compound as hydrochloride salt >80% pure (720mg, 85%) which was used directly without further purification.

LC/MS (ES): Found 290 (ES+), retention time 1.39mins. Ci₅H₁₉N₃OS requires 289.

Description 25: /V-(3,4-dihydro-1 H-2-benzopyran-6-yl)-W-(2-hydroxyethyl)thiourea

To a solution of 3,4-dihydro-1 H-2-benzopyran-6-amine (250mg, 1.68mmol) in dichloromethane at O⁰C (30ml) was added 1 ,1'-(thioxomethanediyl)bis-1 H-imidazole (597mg, 3.36mmol) portionwise over 1 hour. The reaction mixture was allowed to warm to room temperature and stirring was continued for 4 hours. The reaction mixture was cooled in an ice bath and 2-aminoethanol (2ml) was added over 10 minutes. The reaction mixture was allowed to stir at room temperature for 16 hours. Then the reaction mixture was concentrated and purified by column chromatography on silica gel using a gradient elution from 5 to 95% ethyl acetate in n-pentane to give the title compound (261 mg, 61%).

LC/MS (2 minutes ES): Found 253 (ES+), retention time 0.64mins. C₁₂H₁₆N₂O₂S requires 252.

Description 26: /V-(4-bromophenyl)-/V-ethylthiourea

Ethylamine in THF (2M, 92 ml_, 184 mmol) was dissolved in ethyl acetate (40 ml.) then 4- bromophenyl isothiocyanate (10 g, 46 mmol) was added slowly at 10⁰C for 4 hours.

When finished, the solvent was removed under reduced pressure to give the product (1 1.6 g)-

LC/MS (ES-API): Found 259, 261 (ES+), retention time 2.57 mins. C₉H₁₁BrN₂S requires 258, 260.

Description 27: 2-[(4-bromophenyl)imino]-3-ethyl-Λ/,Λ/,4-trimethyl-2,3-dihydro-1 ,3- thiazole-5-carboxamide

A solution of /V-(4-bromophenyl)-/V-ethylthiourea (Description 26, 7.0 g, 27.0 mmol) and 2- chloro-Λ/,Λ/-dimethyl-3-oxobutanamide (8.8 g, 54.0 mmol) in ethanol (60 mL) was heated for 2 hours, then the ethanol was removed. The residue was redissolved in ethyl acetate and washed with water, dried over sodium sulfate, and concentrated under reduced pressure. Purification by silica gel column chromatography eluting with 1 :1 petroleum ether : ethyl acetate yielded the final product (4.2 g).

LC/MS (ES-API): Found 368, 370 (ES+), retention time 2.16 mins. Ci₅H₁₈BrN₃OS requires 367, 369.

1 H-NMR (300MHz, CDCI₃): δ 1.32 (3H, t, J=7Hz), 2.27 (3H, s), 3.00 (6H, s), 3.95 (2H, q, J=7Hz), 6.91-6.94 (2H, m), 7.39-7.42 (2H, m).

For D26 and D27:

¹H NMR spectra were obtained in CDCI₃ at room temperature on a Varian 300 MHz instrument. When more than one conformer was detected the chemical shifts for the most abundant one is reported. Chemical shifts of ¹H NMR spectra were recorded in parts per million (ppm) on the δscale from an internal standard of residual solvent. Splitting patterns are designed as s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; b, broad. Flash silica gel chromatography was carried out over silica gel 300-400 mesh supplied by SCRC (Sinopharm Chemical Reagent Co., Ltd.).

LC/MS conditions:

Column: Sunfire-C18 50^*2.1 mm, 3.5 μm

Solvents: A=0.05%TFA/water B=0.05%TFA/acetonitrile

Gradient of 10-90% B over 2.2 min Injection volume: 0.5 ul

Run time: 4 minutes

Flow rate: 0.9 ml/min

Detection: DAD used

Description 28: W-ethyl-W-[4-(4-morpholinylmethyl)phenyl]thiourea

A mixture of [4-(4-morpholinylmethyl)phenyl]amine (250 mg, 1.30mmol), isothiocyanatoethane (0.1 14 ml, 1.30mmol) and triethylamine (0.272 ml, 1.95mmol) in ethanol (20 ml) was heated at 9O⁰C for 5 hours. Then the solvent was removed by rotary evaporation to afford the title compound as a yellow solid (360mg, 99%).

LC/MS (ES): Found 280 (ES+), retention time 1.15mins. Ci₄H₂iN₃OS requires 279. Description 29: 2-[(4-bromophenyl)imino]-3-(2-hydroxyethyl)-Λ/,Λ/,4-trimethyl-2,3- dihydro-1 ,3-thiazole-5-carboxamide hydrochloride

A mixture of /V-(4-bromophenyl)-/V-(2-hydroxyethyl)thiourea (Description 16, 1.82 g, 6.61 mmol) and 2-chloro-Λ/,Λ/-dimethyl-3-oxobutanamide (2.70 ml, 19.84mmol) in ethanol (100 ml) was heated at 9O⁰C for 2 hours. Then the solvent was removed by rotary evaporation and the sample purified by recrystallisation with methanol/ethyl acetate to give the desired product as a white solid (2.06g, 66%).

LC/MS (ES): Found 384, 386 (ES+), retention time 2.69mins. C₁₅H₁₈BrN₃O₂S requires 383, 385.

Description 30: 1,1-dimethylethyl (4-

{[(methylamino)carbonothioyl

A solution of methylamine in ethanol (3 ml_, 33 % by wt, 23 mmol) was added to N-Boc-4- isothiocyanatoaniline (0.167 g, 0.67 mmol) at room temperature. The reaction mix was allowed to stir at room temperature for 72 hours. The solvent was then removed by rotary evaporation to give the title compound.

LC/MS (ES): Found 282 (ES+), retention time 2.73mins. C₁₃H₁₉N₃O₂S requires 281.

Description 31 : 1 ,1 -dimethylethyl (4-{[5-acetyl-3,4-dimethyl-1,3-thiazol-2(3H)- ylidene]amino}phenyl)carbamate

A mixture of 1 ,1-dimethylethyl (4-{[(methylamino)carbonothioyl]amino}phenyl) carbamate

(0.188 g, 0.67 mmol, Description 30) and 3-chloro-2,4-pentanedione (102 μl_, 1.01 mmol) in ethanol (2.5 ml.) was heated to 100 ⁰C for 20 minutes by microwave irradiation. The solvent was then removed by rotary evaporation to give the title compound (and some Boc-deprotected product).

LC/MS (ES): Found 362 (ES+), retention time 3.08mins. Ci₈H₂₃N₃O₃S requires 361 (and deprotected product, Found 262 (ES+), retention time 1.80mins. C₁₃H₁₅N₃OS requires 261 ).

Description 32: 1 -{2-[(4-aminophenyl)imino]-3,4-dimethyl-2,3-dihydro-1 ,3-thiazol-5- yl}ethanone

A solution of 1 ,1-dimethylethyl (4-{[5-acetyl-3,4-dimethyl-1 ,3-thiazol-2(3H)- ylidene]amino}phenyl)carbamate (0.67 mmol, Description 31 ) in trifluoroacetic acid (2 ml.) and dichloromethane (2 ml.) was stirred at room temperature for 1 hour. A basic workup was carried out. The solvent was then removed by rotary evaporation to give the title compound.

LC/MS (ES): Found 262 (ES+), retention time 1.95mins. C₁₃H₁₅N₃OS requires 261. 1H NMR (400MHz, DMSO-d₆): δ 2.29 (3H, s), 2.55 (3H, s), 3.41 (3H, s), 4.92 (2H, bs), 6.56 (2H, m), 6.71 (2H, m).

Description 33: 1,1-dimethylethyl (4-

{[(ethylamino)carbonothioyl]amino}phenyl)carbamate

A solution of ethylamine in tetrahydrofuran (2N, 3 ml_, 6 mmol) was added to N-Boc-4- isothiocyanatoaniline (0.167 g, 0.67 mmol) at room temperature. The reaction mix was allowed to stir at room temperature for 72 hours. The solvent was then removed by rotary evaporation to give the title compound.

LC/MS (ES): Found 296 (ES+), retention time 2.91 mins. C₁₄H₂₁N₃O₂S requires 295.

Description 34: 1 ,1-dimethylethyl (4-{[5-acetyl-3-ethyl-4-methyl-1,3-thiazol-2(3H)- ylidene]amino}phenyl)carbamate

Following an identical procedure to description 31 , 1 ,1-dimethylethyl (4- {[(ethylamino)carbonothioyl]amino}phenyl)carbamate (0.198 g, 0.67 mmol, Description 33) and 3-chloro-2,4-pentanedione (102 μl_, 1.01 mmol) in ethanol (2.5 ml.) were combined to give the title compound (and some Boc-deprotected product.)

LC/MS (ES): Found 376 (ES+), retention time 3.27mins. C₁₉H₂₅N₃O₃S requires 375 (and deprotected product, Found 276 (ES+), retention time 1.97mins, C₁₄H₁₇N₃OS requires 275).

Description 35: 1 -{2-[(4-aminophenyl)imino]-3-ethyl-4-methyl-2,3-dihydro-1 ,3- thiazol-5-yl}ethanone

Following an identical procedure to description 32, 1 ,1-dimethylethyl (4-{[5-acetyl-3-ethyl- 4-methyl-1 ,3-thiazol-2(3H)-ylidene]amino}phenyl)carbamate (0.67 mmol, Description 34), trifluoroacetic acid (2 ml.) and dichloromethane (2 ml.) were combined to give the title compound.

LC/MS (ES): Found 276 (ES+), retention time 2.13mins. C₁₄H₁₇N₃OS requires 275. 1H NMR (400MHz, DMSO-d₆): δ 1.23 (3H, m), 2.29 (3H, s), 2.57 (3H, s), 3.98 (2H, m), 4.91 (2H, bs), 6.56 (2H, m), 6.71 (2H, m).

Description 36: 1,1-dimethylethyl [4-({[(2- hydroxyethyl)amino]carbonothioyl}amino)phenyl]carbamate

A solution of 2-aminoethanol (40 μl_, 0.011 g, 0.67 mmol) in ethyl acetate (3 ml.) was added to N-Boc-4-isothiocyanatoaniline (0.167 g, 0.67 mmol) at room temperature. The reaction mix was allowed to stir at room temperature for 72 hours. The solvent was then removed by rotary evaporation to give the title compound.

LC/MS (ES): Found 312 (ES+), retention time 2.56mins. C₁₄H₂₁N₃O₃S requires 311. Description 37: 1 ,1-dimethylethyl (4-{[5-acetyl-3-(2-hydroxyethyl)-4-methyl-1 ,3- thiazol-2(3H)-ylidene]amino}phenyl)carbamate

Following an identical procedure to description 31 , 1 ,1-dimethylethyl [4-({[(2- hydroxyethyl)amino]carbonothioyl}amino)phenyl]carbamate (0.208 g, 0.67 mmol, Description 36) and 3-chloro-2,4-pentanedione (102 μl_, 1.01 mmol) in ethanol (2.5 ml.) were combined to give the title compound (and some Boc-deprotected product.)

LC/MS (ES): Found 392 (ES+), retention time 2.95mins. Ci₉H₂₅N₃O₄S requires 391

(and deprotected product, Found 292 (ES+), retention time 1.77mins, C₁₄H₁₇N₃O₂S requires 291 ).

Description 38: 1 -[2-[(4-aminophenyl)imino]-3-(2-hydroxyethyl)-4-methyl-2,3- dihydro-1 ,3-thiazol-5-yl]ethanone

Following an identical procedure to description 32, 1 ,1-dimethylethyl (4-{[5-acetyl-3-(2- hydroxyethyl)-4-methyl-1 ,3-thiazol-2(3H)-ylidene]amino}phenyl)carbamate (0.67 mmol, Description 37), trifluoroacetic acid (2 ml.) and dichloromethane (2 ml.) were combined to give the title compound.

LC/MS (ES): Found 292 (ES+), retention time 1.90mins. C₁₄H₁₇N₃O₂S requires 291. 1H NMR (400MHz, DMSO-d₆): δ 2.30 (3H, s), 2.60 (3H, s), 3.69 (2H, m), 3.99 (2H m), 4.88 (2H, bs), 5.00 (1 H, m), 6.55 (2H, m), 6.70 (2H, m).

Description 39: Λ/-(4-cyanophenyl)-Λ/"-(2-hydroxyethyl)thiourea

To a stirred solution of 2-aminoethanol (381 mg, 6.24mmol) in ethyl acetate (10ml) was added 4-isothiocyanatobenzonitrile (1.0g, 6.24mmol) under argon at room temperature. The reaction mixture was allowed to stir at room temperature overnight and the precipitate was filtered to give the title compound as a white solid (819mg, 59.3%).

LC/MS (ES): Found 222 (ES+), retention time 1.86mins. Ci₀H₁₁N₃SO requires 221.

Examples 1-3:

Typical Procedure: A suspension of 4-{[5-acetyl-3-cyclopropyl-4-methyl-1 ,3-thiazol-2(3H)- ylidene]amino}benzoic acid (1 15mg, 0.36mmol, Description 3) in dichloromethane (3ml) was treated with solid 1 ,1 '-carbonyldiimidazole (59mg, 0.36mmol) at room temperature in a 15ml plastic sarstedt tube, sealed and shaken for 20 minutes. The mixtures were then treated with the relevant secondary cyclic amine (HNR1 R2; 0.36mmol) and shaken at room temperature for 2 hours. Reaction mixtures were washed with saturated aqueous sodium bicarbonate solution (5ml). The organic layer was separated and dried over sodium sulphate, and the solvent removed by rotary evaporation. The residue was then dissolved in dichloromethane (2ml) and treated with a 1 N solution of hydrochloric acid in diethyl ether. The solvent was removed by blow drying and the residue triturated in ether. The liquid was decanted off and the residual materials oven dried to give the title compounds as yellow solids (yields 63-84%).

dihydro-1 ,3-thiazol- requires 385. 3.85 (6H, m), 7.63 (4H,

5-yl)ethanone, m). hydrochloride

Example 4: i-^-flS-acetyl-S-cyclopropyl^-methyl-I.S-thiazol^SH)- ylidene]amino}phenyl)-2-pyrrolidinone hydrochloride

The 1-{2-[(4-aminophenyl)imino]-3-cyclopropyl-4-methyl-2,3-dihydro-1 ,3-thiazol-5- yl}ethanone hydrochloride (312mg, 0.87mmol, Description 5) was dissolved in a mixture of dichloromethane (5ml) and diisopropylethylamine (0.58ml, 3.48mmol) with stirring under argon. This mix was treated dropwise with 4-chlorobutyryl chloride (91 mg, 0.87mmol, 0.073ml) at room temperature and allowed to stir for 0.5 hours. Most of the solvent was blown off (i.e. in air) and dimethylformamide (3ml) was added. Sodium hydride (60% suspension in mineral oil) (139mg, 3.48mmol) was then added portionwise and the mix stirred at room temperature for 1 hour, then more sodium hydride was added (60% suspension in mineral oil) (139mg, 3.48mmol) and the mix stirred at room temperature for a further 0.5 hours. The reaction mix was quenched with water (0.5ml) and added to a 5g pre-packed silica column which was then eluted from 0-100% ethyl acetate in petroleum ether to give a dark oil which was further purified by mass directed auto-preparation. Relevant fractions were combined and the solvent removed by rotary evaporation to give a yellow oil which was dissolved in dichloromethane (2ml) and treated with 1 M hydrogen chloride in diethyl ether. The solvent was blown off and the residue triturated in ether. The liquid was decanted off and the residual material dried in a vacuum oven at 36⁰C to give the title compound as a yellow solid (102mg, 30%).

LC/MS (ES): Found 356 (ES+), retention time 1.89mins. C₁₉H_2IN₃O₂S requires 355. 1 H-NMR (400MHz, MeOD-d₄): δ 1.31 (2H, m), 1.50 (2H, m), 2.20 (2H, m), 2.51 (3H, m), 2.62 (2H, m), 2.81 (3H, s), 3.33 (1 H, m), 3.98 (2H, m), 7.54 (2H, m), 7.89 (2H, m).

Example 5: ethyl 4-{[5-acetyl-3-ethyl-4-methyl-1,3-thiazol-2(3H)- ylidene]amino}benzoate

A solution of 4-ethoxycarbonylphenyl isothiocyanate (3.Og, 14.5mmol) in toluene (12ml) was added to a stirring solution of ethylamine (available as a 2M solution in tetrahydrofuran, 7.25ml, 14.5mmol) in toluene (12ml) over 15 minutes at room temperature. The reaction mix was allowed to stir at room temperature for 1 hour. The reaction mix was diluted by the addition of toluene (20ml) and treated with 3-chloro-2,4- pentanedione (2.05g, 1.8ml, 15.2mmo I) in one portion and the resulting mix stirred at 9O⁰C (oil bath temperature) for 2 hours. The reaction mix was allowed to cool and the solvent removed by rotary evaporation to give a dark oil which was chromatographed on a 5Og isolute silica sep-pak column eluting from 0-50% ethyl acetate in petroleum ether. The relevant fractions were combined and the solvent removed by rotary evaporation to give the title compound as a golden coloured oil (2.39g, 50%).

LC/MS (ES): Found 333 (ES+), retention time 3.27mins. Ci₇H₂₀N₂O₃S requires 332.

1 H-NMR (400MHz, CDCI₃): δ 1.38 (6H, m), 2.26 (3H, s), 2.63 (3H, s), 4.06 (2H, q, J=7Hz), 4.37 (2H, q, J=7Hz), 7.11 (2H, m), 8.05 (2H, m).

Example 6: 1 -(3-ethyl-4-methyl-2-{[4-(1 -pyrrolidinylcarbonyl)phenyl]imino}-2,3- dihydro-1,3-thiazol-5-yl)ethanone, hydrochloride

Solid 1 ,1 '-carbonyldiimidazole (117mg, 0.72mmol) was added in one portion to a stirring mixture of 4-{[5-acetyl-3-ethyl-4-methyl-1 ,3-thiazol-2(3H)-ylidene]amino}benzoic acid (220mg, 0.72mmol, Description 6) in dichloromethane (8ml), which was then stirred at room temperature under argon for 20 minutes. Pyrrolidine (51 mg, 0.72mmol, 0.06ml) was then added dropwise and the resulting mix stirred at room temperature for 2 hours. The reaction mixture was washed with saturated aqueous sodium bicarbonate solution (10ml) and the organic layer separated and dried over sodium sulphate. The solvent was removed by rotary evaporation to give a brown oil (186mg) which was dissolved in dichloromethane (2ml) and treated with 1 M hydrogen chloride in ether. The solvent was blown off and the residue triturated in ether. The liquid was decanted off and the residual solid was dried in a vacuum oven at 36⁰C to give the title compound as a yellow solid (187mg, 66%).

LC/MS (ES): Found 358 (ES+), retention time 2.53mins. Ci₉H₂₃N₃O₂S requires 357.

1 H-NMR (400MHz, MeOD-d₄): δ 1.48 (3H, t, J=7Hz), 1.90-2.05 (4H, m), 2.50 (3H, s), 2.75 (3H, s), 3.49 (2H, m), 3.62 (2H, t, J=7Hz), 4.29 (2H, q, J=7Hz), 7.55 (2H, d, J=7Hz), 7.73 (2H, d, J=8Hz).

Example 7: 1-(3-ethyl-4-methyl-2-{[4-(4-methyl-1 -piperazinyl)phenyl]imino}-2,3- dihydro-1 ,3-thiazol-5-yl)ethanone hydrochloride

A mixture of 1-{2-[(4-bromophenyl)imino]-3-ethyl-4-methyl-2,3-dihydro-1 ,3-thiazol-5- yl}ethanone (338mg, 1 mmol, Description 7), N-methylpiperazine dihydrochloride (173mg, 1 mmol), sodium tert-butoxide (326mg, 3.4mmol), bis(dibenzylideneacetone)palladium (6mol%, O.OΘmmol, 35mg) and 2-(di-t-butylphosphino)biphenyl (20mol%, 0.2mmol, 60mg) in toluene (10ml) was stirred at 1 1O⁰C (oil bath temperature) for 18 hours. The reaction mix was diluted with ethyl acetate (20ml) and filtered through a pad of kieselguhr. The filtrate was reduced to minimum volume by rotary evaporation and the residue added to a 5g SCX column which was eluted with 50-100% ethyl acetate in petroleum ether, then 5% 2M ammomia in methanol in ethyl acetate. Relevant fractions were concentrated and the residue was further purified by mass directed auto-preparation (MDAP). Relevant fractions were combined and the solvent removed by rotary evaporation to give a yellow oil (94mg). The product was dissolved in dichloromethane (1 ml) and treated with 1 M hydrogen chloride in ether (1 ml), and the solvent removed with air drying. The product was triturated in ether and vacuum oven dried to give the title compound as a yellow solid (104mg, 24%).

LC/MS (ES): Found 359 (ES+), retention time 1.39mins. C₁₉H₂₆N₄OS requires 358. 1 H-NMR (400MHz, MeOD-d₄): δ 1.48 (3H, t, J=7Hz), 2.51 (3H, s), 2.74 (3H, s), 3.15 (3H, s), 3.21 (2H, m), 3.31 (2H, m), 3.64 (2H, m), 3.99 (2H, m), 4.28 (2H, m), 7.22 (2H, d, J=9Hz), 7.42 (2H, d, J=9Hz).

Example 8: 1-(4-{[5-acetyl-3<:yclopropyl-4-methyl-1,3-thiazol-2(3H)- ylidene]amino}phenyl)-2-piperidinone hydrochloride

1-{2-[(4-aminophenyl)imino]-3-cyclopropyl-4-methyl-2,3-dihydro-1 ,3-thiazol-5-yl}ethanone hydrochloride (360mg, I .Ommol, Description 5) was dissolved in a mixture of diisopropylethylamine (520mg, 0.7ml, 4.0mmol) and dichloromethane (5ml) and then treated with 5-chlorovaleryl chloride (155mg, 0.13ml, I .Ommol) dropwise at room temperature with stirring under argon. This mix was stirred at room temperature for 15 minutes. This mix was then washed with water (3ml). The organic layer was separated and dried over sodium sulphate. The organic extracts were concentrated by rotary evaporation and the residue was dissolved in dimethylformamide (5ml) and treated with sodium hydride (60% in mineral oil, 50mg, 1.25mmol) and the whole mix stirred at room temperature under argon for 0.5 hours. The reaction was quenched with water (0.5ml) and then added to a 5g isolute silica sep-pak column and eluted with 0-100% ethyl acetate in petroleum ether. Relevant fractions were combined and the solvent removed by rotary evaporation to give a brown oil which was further purified by mass directed auto- preparation (MDAP) to give a yellow oil which was dissolved in dichloromethane (1 ml) and treated with 1 M hydrogen chloride in ether (1 ml), and the solvent removed with air drying. The product was triturated in ether and vacuum oven dried to give the title compound as a yellow solid (48mg, 12%).

LC/MS (ES): Found 370 (ES+), retention time 2.07mins. C₂₀H₂₃N₃O₂S requires 369.

1 H-NMR (400MHz, MeOD-d₄): δ 1.31 (2H, m), 1.51 (2H, m), 1.76 (2H, m), 1.99 (4H, m),

2.54 (4H, m), 2.81 (3H, s), 3.74 (2H, m), 7.52 (2H, d, J=8Hz), 7.58 (2H, d, J=9Hz).

Example 9: 1 -(3-ethyl-4-methyl-2-{[4-(1 ,3-oxazol-5-yl)phenyl]imino}-2,3-dihydro-1 ,3- thiazol-5-yl)ethanone hydrochloride

A mixture of /V-ethyl-/V-[4-(1 ,3-oxazol-5-yl)phenyl]thiourea (223mg, 0.9mmol, Description 8) and 3-chloro-2,4-pentanedione (0.14g, 1.05mmol, 0.13ml) in toluene (5ml) was stirred at 9O⁰C (oil bath temperature) for 18 hours and then allowed to cool. The solvent was removed by rotary evaporation. The crude residue was suspended in dichloromethane and added to a 5g pre-packed isolute silica sep-pak column, which was then eluted with 0-100% ethyl acetate in petroleum ether. Relevant fractions were combined and the solvent removed by rotary evaporation to give a yellow oil (156mg) which was further purified by MDAP (mass directed auto preparation). Relevant fractions were combined and the solvent removed under reduced pressure to give a yellow solid which was dissolved in dichloromethane (1 ml) and treated with 1 M hydrogen chloride in ether (1 ml), and the solvent removed with air drying. The product was triturated in ether and vacuum oven dried to give the title compound as a yellow solid (91 mg, 25%).

LC/MS (ES): Found 328 (ES+), retention time 2.87mins. C₁₇H₁₇N₃O₂S requires 327. 1 H-NMR (400MHz, MeOD-d₄): δ 1.51 (3H, t, J=7Hz), 2.53 (3H, s), 2.77 (3H, s), 4.34 (2H, m), 7.67 (3H, m), 7.98 (2H, d, J=9Hz), 8.34 (1 H, s).

Example 10: 1 -(3-ethyl-2-{[4-(1 H-imidazol-1 -yl)phenyl]imino}-4-methyl-2,3-dihydro- 1 ,3-thiazol-5-yl)ethanone hydrochloride

A mixture of 4-(1H-imidazolyl)aniline (318mg, 2.0mmol), ethyl isothiocycanate (209mg, 2.40mmol, 0.21 ml) and triethylamine (0.4ml) in ethanol (10ml) was stirred at reflux for 2 hours. The solvent was then removed by rotary evaporation to give a yellow solid (484mg). Half of this material (247mg) was then suspended in toluene (5ml) and treated with 3-chloro-2,4-pentanedione (0.14g, 1.05mmol, 0.13ml) and the whole mix stirred at 9O⁰C (oil bath temperature) for 3 hours, and allowed to cool. The solvent was removed by rotary evaporation. The crude residue was dissolved in the minimum of dichloromethane and added to a 5g pre-packed isolute silica sep-pak column, which was then eluted from 20-100% ethyl acetate in petroleum ether. Relevant fractions were combined and the solvent removed by rotary evaporation to give a yellow oil (163mg) which was further purified by MDAP (mass directed auto preparation). Relevant fractions were combined and the solvent removed by rotary evaporation to give a yellow solid which was dissolved in dichloromethane (1 ml) and treated with 1 M hydrogen chloride in ether (1 ml), and the solvent removed with air drying. The product was triturated in ether and vacuum oven dried to give the title compound as a yellow solid (1 15mg).

LC/MS (ES): Found 327 (ES+), retention time 1.67mins. C₁₇H₁₈N₄OS requires 326.

1 H-NMR (400MHz, MeOD-d₄): δ 1.51 (3H, t, J=7Hz), 2.54 (3H, s), 2.77 (3H, s), 4.36 (2H, m), 7.82 (3H, m), 7.98 (2H, d, J=9Hz), 8.17 (1 H, t, J=2Hz), 9.59 (1 H, t, J=2Hz).

Examples 11 -13:

Typical Procedure: A mixture of 1-{2-[(4-bromophenyl)imino]-3-ethyl-4-methyl-2,3-dihydro- 1 ,3-thiazol-5-yl}ethanone (200mg, 0.59mmol, Description 7), copper (I) iodide (50mol%, 0.3mmol, 56mg), N,N-dimethylglycine (0.59mmol, 61 mg), potassium carbonate (2eq, 1.18mmol, 163mg) and the appropriate pyrazole derivative (0.59mmol) in dimethylsulphoxide (2.5ml) was heated at 19O⁰C in a microwave reactor for 0.5 hours. The reaction mixtures were partitioned between dichloromethane (4ml) and water (4ml). The organic layer was added directly to a 5g silica pre-packed column, which was eluted with 20-50% ethyl acetate in petroleum ether and the solvent removed by rotary evaporation. The crude products were further purified via mass directed auto-preparation (MDAP). Relevant fractions were combined and the solvent removed by rotary evaporation. Each product was dissolved in dichloromethane (1 ml) and treated with 1 M hydrogen chloride in ether (1 ml), and the solvent removed with air drying. The products were triturated in diethyl ether and vacuum oven dried to give the title compounds as colourless solids (yields 39-44%).

Example 14: 1 -(3-ethyl-4-methyl-2-{[4-(3-thienyl)phenyl]imino}-2,3-dihydro-1,3- thiazol-5-yl)ethanone hydrochloride

A mixture of 1-{2-[(4-bromophenyl)imino]-3-ethyl-4-methyl-2,3-dihydro-1 ,3-thiazol-5- yl}ethanone (200mg, 0.6mmol, Description 7), thiophene-3-boronic acid (1 14mg, 0.89mmol), tetrakis (triphenylphosphine)palladium (0) (3mol%, 21 mg), and sodium carbonate (127mg, 1.2mmol) in a 3:1 mixture of dioxane and water (14ml) was stirred at 9O⁰C (oil bath temperature) for 1 hour and then allowed to cool to room temperature. The reaction mix was diluted with ethyl acetate (20ml) and washed with water (2 x 10ml). The organic layer was dried over sodium sulphate and the solvent removed by rotary evaporation to give a brown oil which was chromatographed on a 5g isolute silica sep-pak column eluting from 0-50% ethyl acetate in petroleum ether to give a yellow solid (21 1 mg). The product was dissolved in dichloromethane (5ml) and treated with 1 M hydrogen chloride in ether (2ml), mixed and the solvent removed by rotary evaporation. The resulting solid was triturated in ether (3ml), the liquid was decanted off and the residual material was vacuum oven dried to give the title compound as a yellow solid (226mg, 100%). LC/MS (ES): Found 343 (ES+), retention time 3.34mins. Ci₈H₁₈N₂OS₂ requires 342.

1 H-NMR (400MHz, MeOD-d₄): δ 1.49 (3H, m), 2.50 (3H, s), 2.75 (3H, s), 4.32 (2H, m),

7.53 (4H, m), 7.76 (1 H, m), 7.87 (2H, d, J=8Hz).

Examples 15-21

Typical Procedure: A suspension of the benzoic acid (Descriptions 3 and 6, 0.41 mmol) in dichloromethane (4ml) was treated with solid 1 ,1 '-carbonyldiimidazole (66.5mg, 0.41 mmol) at room temperature in a 15ml plastic sarstedt tube, sealed and shaken for 20 minutes. The mixtures were then treated with the relevant secondary amine (HNR1 R2; 0.41 mmol) and shaken at room temperature for 2 hours. Reaction mixtures were washed with saturated aqueous sodium bicarbonate solution (5ml). The organic layer was separated and dried over sodium sulphate, and the solvent removed by rotary evaporation. Crude mixtures were chromatographed on 5g isolute silica columns eluting from 0-100% ethyl acetate in petroleum ether and 0-5% methanol in ethyl acetate. Examples 16 and 19 were purified on 5g SCX columns eluting from 0-5% 2M ammonia (in methanol) in ethyl acetate. All resulting products were then further purified by MDAP (mass directed auto-preparation). The products were then dissolved in dichloromethane (2ml) and treated with a 1 N solution of hydrochloric acid in diethyl ether. The solvent was removed by blow drying and the residue triturated in ether. The liquid was decanted off and the residues oven dried to give the title compounds as colourless or yellow solids (yields 22-66%).

Example 22: 4-{[5-acetyl-3-cyclopropyl-4-methyl-1 ,3-thiazol-2(3H)-ylidene]amino}- Λ/,Λ/-diethylbenzamide hydrochloride

A suspension of 4-{[5-acetyl-3-cyclopropyl-4-methyl-1 ,3-thiazol-2(3H)- ylidene]amino}benzoic acid (316mg, I .Ommol, Description 3) at room temperature in dichloromethane (10ml) was treated in one portion with solid 1 ,1 '-carbonyldiimidazole (162mg, LOmmol) under argon. The resulting mix was stirred at room temperature for 0.5 hours, and then treated with excess diethylamine (438mg, 6.0mmol, 0.6ml) and stirred for a further 2 hours at room temperature under argon. The reaction mix was washed with dilute (0.5M) aqueous sodium hydroxide solution. The organic layer was separated and dried over sodium sulphate and the solvent removed by rotary evaporation to give a brown oil (350mg). This material was dissolved in dichloromethane and added to a 5g isolute pre-packed silica column which was eluted from 0-100% ethyl acetate in petroleum ether. Relevant fractions were combined and the solvent removed by rotary evaporation to give a yellow oil (279mg). This product was dissolved in dichloromethane and treated with 1 M ethereal HCI (2ml). The solvent was removed by rotary evaporation. The residue was triturated in ether, the liquid was decanted off and the residual material was vacuum oven dried to give the title compound as a colourless solid (236mg, 58%).

LC/MS (ES): Found 372 (ES+), retention time 2.22mins. C₂₀H₂₅N₃O₂S requires 371.

1 H-NMR (400MHz, DMSO-d₆): δ 1.00-1.30 (10H, m), 2.36 (3H, s), 2.67 (3H, s), 3.04 (1 H, m), 3.13-3.53 (4H, m), 7.10 (2H, d, J=8Hz), 7.38 (2H, d, J=8Hz). Example 23: 1-(4-{[5-acetyl-3-ethyl-4-methyl-1,3-thiazol-2(3H)- ylidene]amino}phenyl)-Λ/-methylmethanesulfonamide hydrochloride

A mixture of 4-amino-N-methyl-alpha-toluenesulphonamide (200mg, I .Ommol), ethyl isothiocycanate (104mg, 1.20mmol, 0.1 ml) and triethylamine (0.2ml) in ethanol (5ml) was stirred at reflux for 2 hours. The solvent was then removed by rotary evaporation, the resulting material was then suspended in toluene (5ml) and treated with 3-chloro-2,4- pentanedione (0.14g, 1.05mmol, 0.13ml) and the whole mix stirred at 9O⁰C (oil bath temperature) for 3 hours, and allowed to cool. The reaction mix was filtered and the filtrate evaporated under reduced pressure to give a yellow oil, which was purified by MDAP (mass directed auto-preparation). The relevant fractions were combined and the solvent removed by rotary evaporation to give a brown oil, which was dissolved in dichloromethane (1 ml) and treated with 1 M ethereal HCI (1 ml). The solvent was removed by air drying. The product was triturated in ether, the liquid was decanted off and the residual material was vacuum oven dried to give the title compound as a beige coloured solid (98mg, 24%).

LC/MS (ES): Found 368 (ES+), retention time 2.35mins. Ci₆H_2IN₃O₃S₂ requires 367. 1 H-NMR (400MHz, MeOD-d₄): δ 1.49 (3H, t, J=7Hz), 2.52 (3H, s), 2.71 (3H, s), 2.76 (3H, s), 4.31 (2H, m), 4.42 (2H, s), 7.55 (2H, m), 7.66 (2H, d, J=8Hz).

Example 24: 1-(4-{[5-acetyl-3-ethyl-4-methyl-1,3-thiazol-2(3H)- ylidene]amino}phenyl)-Λ/,Λ/-dimethylmethanesulfonamide hydrochloride

A solution of 1-(4-{[5-acetyl-3-ethyl-4-methyl-1 ,3-thiazol-2(3H)-ylidene]amino}phenyl)-/V- methylmethanesulfonamide hydrochloride (0.25g, 0.62mmol, Example 23) in dimethylformamide (6ml) was treated with sodium hydride (60% in mineral oil; 50mg, 1.24mmol) in one portion at room temperature. The resulting mix was stirred under argon for 15 minutes and then treated with iodomethane (97mg, 0.68mmol) in one portion and stirring was continued at room temperature under argon for 2 hours. The reaction was quenched with water and then partitioned between dichloromethane (15ml) and water (10ml). The organic layer was separated, dried over sodium sulphate, and evaporated under reduced pressure. The residue was purified by MDAP (mass directed auto- preparation). The relevant fractions were combined and the solvent removed by rotary evaporation to give a yellow solid (0.17g), which was dissolved in dichloromethane (1 ml) and treated with 1 M ethereal HCI (1 ml). The solvent was removed by air drying. The product was triturated in 1 M ethereal HCI (1 ml), the liquid was decanted off and the residual material was vacuum oven dried to give the title compound as a colourless solid (177mg, 68%).

LC/MS (ES): Found 382 (ES+), retention time 2.56mins. C₁₇H₂₃N₃O₃S₂ requires 381.

1 H-NMR (400MHz, MeOD-d₄): δ 1.49 (3H, t, J=7Hz), 2.52 (3H, s), 2.76 (3H, s), 2.85 (6H, m), 4.31 (2H, m), 4.43 (2H, s), 7.56 (2H, m), 7.68 (2H, d, J=8Hz).

Examples 25-27:

Typical Procedure: A mixture of 1-{2-[(4-bromophenyl)imino]-3-cyclopropyl-4-methyl-2,3- dihydro-1 ,3-thiazol-5-yl}ethanone (175mg, O.δmmol, Description 1 1 ), the appropriate heteroaryl boronic acid (O.δmmol), tetrakis (triphenylphosphine) palladium(O) (3mol%, 17mg), and sodium carbonate (106mg, I .Ommol) in a 3:1 mixture of 1 ,4-dioxan and water (1 1 ml) was heated at 9O⁰C (oil bath temperature) under argon for 2 hours. Then fresh catalyst (10mg) was added and heating continued for a further 2 hours. The reaction mixtures were allowed to cool, diluted with ethyl acetate and washed with water (2 x 10ml). The organic layer was dried over sodium sulphate and concentrated. The crude dark oils were then purified using mass directed auto-preparation (MDAP). Relevant fractions were combined and concentrated under reduced pressure. The residues were dissolved in dichloromethane (1 ml) and treated with 1 M ethereal HCI (1 ml). The solvent was removed by air drying. The product was triturated in 1 M ethereal HCI (1 ml), the liquid was decanted off and the residual material was vacuum oven dried to give the title compounds as yellow solids (yields 40-69%).

Ex Het Name LC/Mass ¹H-NMR

Spec (ES) (400MHz, MeOD-d₄)

25 1-(3-cyclopropyl-4- Found 369 δ 1.32 (2H, m), 1.52

V-Q methyl-2-{[4-(5- (ES₊), (2H, m), 2.52 (6H , m), methyl-2- retention time 2.82 (3H , m), 3.36 (1 H, thienyl)phenyl]imino}- 3.08mins. m), 6.81 (1 H, m), 7.30

2,3-dihydro-1 ,3- C₂oH₂oN₂OS₂ (1 H, m), 7.52 (2H , m), thiazol-5-yl)ethanone requires 368. 7.78 (2H , m). hydrochloride

26 1-(3-cyclopropyl-4- Found 369 δ 1.32 (2H, m), 1.52 methyl-2-{[4-(3- (ES₊), (2H, m), 2.3C > (3h , s), methyl-2- retention time 2.52 (3H , m), 2.82 (3H, thienyl)phenyl]imino}- 3.05mins. m), 3.37 (1 H, m), 6.99

2,3-dihydro-1 ,3- C₂OH₂QN₂OS₂ (1 H, d, J=5Hz), 7.37 thiazol-5-yl)ethanone requires 368. (1 H, d, J=5Hz), 7.60 hydrochloride (2H, m), 7.69 (2H, m).

27 1-(3-cyclopropyl-2- Found 368 δ 1. 33 (2H, m), 1.53

I {[4-(3,5-dimethyl-4- (ES₊), (2H, m), 2.30 (3h \, s), isoxazolyl)phenyl]imi retention time 2.46 (3 H , s), 2.54 (3H, no}-4-methyl-2,3- 2.46mins. s), 2 .83 (3H, s), 3.37 dihydro-1 ,3-thiazol-5- C2₀H21 N; iO₂S (1 H, m), 7.60 (2H , m), yl)ethanone requires 367. 7.66 (2H , m) hydrochloride

Examples 28 and 29:

The title compounds were prepar from 4-(1 ,2,3-thiadiazol-4-yl)aniline (for Example 28), 4-(1 H-1 ,2,4-triazol-1-yl)aniline (for Example 29), cyclopropyl isothiocyanate and 3-chloro- 2,4-pentanedione using a similar procedure to that used for Example 23.

Example 30: 1-(3-ethyl-4-methyl-2-{[4-(methylsulfonyl)phenyl]imino}-2,3-dihydro- 1,3-thiazol-5-yl)ethanone hydrochloride

A mixture of 4-(methylsulfonyl)aniline (21 1.5mg, 1.24mmol), ethyl isothiocycanate (1.50mmol, 0.13ml) and triethylamine (0.25ml) in ethanol (8ml) was stirred at reflux for 2 hours. The solvent was then removed by rotary evaporation. The resulting material was then suspended in toluene (8ml) and treated with 3-chloro-2,4-pentanedione (1.24mmol, 0.15ml) and the whole mix stirred at 9O⁰C (oil bath temperature) for 3 hours. The reaction mix was allowed to cool and diluted with ethyl acetate (10ml). The mix was washed with saturated aqueous sodium bicarbonate solution (10ml), and then brine solution (10ml). The organic layer was dried over sodium sulphate and the solvent removed by rotary evaporation to give a yellow oil (365mg) which was purified by mass directed auto-prep (MDAP). Relevant fractions were combined and the solvent removed by rotary evaporation to give a yellow solid which was dissolved in dichloromethane and treated with ethereal HCI. The solvent was removed by air drying and the residue triturated in a further portion of ethereal HCI, the liquid was decanted off and the residual material was vacuum oven dried to give the title compound as a colourless solid (74mg, 20%).

LC/MS (ES): Found 339 (ES+), retention time 2.49mins. C₁₅H₁₈N₂O₃S₂ requires 338. 1 H-NMR (400MHz, MeOD-d₄): δ 1.46 (3H, t, J=7Hz), 2.48 (3H, s), 2.74 (3H, s), 3.17 (3H, s), 4.28 (2H, q, J=7Hz), 7.63 (2H, m), 8.09 (2H, m).

Examples 31 and 32:

Typical procedure: The (4-{[5-acetyl-3-ethyl-4-methyl-1 ,3-thiazol-2(3H)- ylidene]amino}phenyl)acetic acid (159mg, O.δmmol, Description 13) was suspended in dichloromethane (5ml) and treated with 1 ,1 '-carbonyldiimidazole (81 mg, O.δmmol) in one portion in a 15ml plastic sarstedt tube. The reaction mixtures were shaken at room temperature for 0.5 hours and then treated with the pyrrolidine derivative (0.6mmol) in one portion and then shaken at room temperature for a further 2 hours. The reaction mixtures were washed with saturated aqueous sodium bicarbonate solution. The organic layer was added directly to a 5g pre-packed isolute silica column and eluted from 0-100% ethyl acetate in petroleum ether. Relevant fractions were combined and the solvent removed by rotary evaporation. The products were then partitioned between dichloromethane (4ml) and water (4ml). The organic layer was dried over sodium sulphate and then treated with 1 M ethereal HCI (0.5ml). The solvent was blown off and the solids vacuum oven dried to give the title compounds as colourless solids (yields 66-87%).

Example 33: (4-{[5-acetyl-3-ethyl-4-methyl-1,3-thiazol-2(3H)- ylidene]amino}phenyl)acetonitrile hydrochloride

A solution of 4-aminophenylacetonitrile (396mg, 3mmol) in ethanol (15ml) and triethylamine (0.63ml) was treated with ethyl isothiocyanate (0.32ml, 3.65mmol) and the whole mix stirred at reflux under argon for 2 hours. The reaction mixture was allowed to cool and the solvent removed by rotary evaporation. The residue was then suspended in toluene (15ml) and treated with 3-chloro-2,4-pentanedione (0.4ml, 3.36mmol) and stirred at 90oC (oil bath temperature) for 4 hours. The reaction mixture was allowed to cool and the solvent was removed by rotary evaporation. The residue was then partitioned between dichloromethane (5ml) and saturated aqueous sodium bicarbonate solution (10ml). The organic layer was separated and added to a 2Og isolute pre-packed silica column and eluted from 0-100% ethyl acetate in petroleum ether gradient. The relevant fractions were combined and the solvent removed by rotary evaporation to give a yellow oil (565mg). This material was dissolved in dichloromethane (10ml) and treated with 1 M ethereal HCI (4ml) with mixing and the solvent removed by rotary evaporation. The product was then triturated in 1 M ethereal HCI (10ml), the liquid decanted off and the product vacuum oven dried to give the title compound as a pale yellow solid (535mg, 53%). LC/MS (ES): Found 300 (ES+), retention time 2.59mins. Ci₆H₁₇N₃OS requires 299.

1 H-NMR (400MHz, DMSO-d₆): δ 1.28 (3H, t, J=7Hz), 2.35 (3H, s), 2.62 (3H, s), 4.03 (2H, s), 4.09 (2H, m), 7.10 (2H, d, J=8Hz), 7.36 (2H, d, J=8Hz).

Example 34: 1 -(3-ethyl-4-methyl-2-{[4-(1 H-pyrazol-1 -yl)phenyl]imino}-2,3-dihydro- 1 ,3-thiazol-5-yl)ethanone

/V-ethyl-/V-[4-(1 H-pyrazol-1 -yl)phenyl]thiourea (400mg, 1.62mmol, Description 14) was dissolved in ethanol (20ml), then 3-chloro-2,4-pentanedione (0.37ml, 3.25mmol) was added. The resulting mixture was heated at 90⁰C under argon for 1 hour. Then the solvent was removed by rotary evaporation and the residual material was partitioned between ethyl acetate (50ml) and saturated aqueous sodium bicarbonate solution (25ml). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2x50ml). The organic layers were combined, dried with sodium sulphate and evaporated under reduced pressure. The residual material was recrystallised with ethyl acetate/n- pentane and ethyl acetate to give the title compound as a white solid (247mg, 45%).

LC/MS (ES): Found 327 (ES+), retention time 2.77mins. Ci₇H₁₈N₄OS requires 326. 1H-NMR (400MHz, DMSO-d₆): δ 1.27 (3H, m), 2.32 (3H, s), 2.61 (3H, s), 4.05 (2H, m), 6.52 (1 H, m), 7.11 (2H, m), 7.72 (1 H, d, J=1.6Hz), 7.81 (2H, m), 8.44 (1 H, d, J=2.4Hz).

Example 35: 3-(2-hydroxyethyl)-/V,/V,4-trimethyl-2-{[4-(1 H-pyrazol-1 -yl)phenyl]imino}- 2,3-dihydro-1 ,3-thiazole-5-carboxamide hydrochloride

The title compound was prepared from /V-(2-hydroxyethyl)-/V-[4-(1 H-pyrazol-1 - yl)phenyl]thiourea (Description 15) and 2-chloro-Λ/-methyl-3-oxobutanamide using a similar procedure to that described for Description 29.

LC/MS (ES): Found 372 (ES+), retention time 1.83mins. Ci₈H_2IN₅O₂S requires 371.

¹H-NMR (400MHz, DMSO-d₆): δ 2.27 (3H, s), 2.94 (6H, s), 3.76 (4H, m), 4.05 (1 H, s), 6.53 (1 H, m), 7.25 (2H, m), 7.73 (1 H, d, J=1.6Hz), 7.85 (2H, m), 8.46 (1 H, d, J=1.6Hz).

Example 36: 1 -[3-(2-hydroxyethyl)-4-methyl-2-({4-[3-(trifluoromethyl)-1 H-pyrazol-1 - yl]phenyl}imino)-2,3-dihydro-1 ,3-thiazol-5-yl]ethanone

A mixture of 3-(trifluoromethyl)-1 H-pyrazole (38mg, 0.28mmol), copper (I) iodide (5mol%, 2.7mg, 0.014mmol), cesium carbonate (180mg, 0.56mmol) in 1 ,4-dioxane (10ml) was stirred under argon. Then 1-[2-[(4-bromophenyl)imino]-3-(2-hydroxyethyl)-4-methyl-2,3- dihydro-1 ,3-thiazol-5-yl]ethanone (100mg, 0.28mmol, Description 17), and N, N,- dimethylethylenediamine (15mol%, 4mg, 0.042mmol) were added. The mixture was heated at 105⁰C under argon for 3 h and then in a microwave reactor for 1 hour at 180⁰C. The solvent was removed by rotary evaporation and the sample purified by mass directed auto-preparation to give the title compound (27mg, 23%).

LC/MS (ES): Found 41 1 (ES+), retention time 2.99mins. Ci₈H₁₇F₃N₄O₂S requires 410. 1H-NMR (400MHz, CDCI₃): δ 2.30 (3H, s), 2.65 (3H, s), 4.02 (2H, m), 4.20 (2H, m), 6.71 (1 H, d, J=2.8Hz), 7.16 (2H, m), 7.69 (2H, m), 7.92 (1 H, d, J=1.6Hz).

Example 37: 4-{[5-acetyl-3-(2-hydroxyethyl)-4-methyl-1 ,3-thiazol-2(3H)- ylidene]amino}-Λ/,Λ/-dimethylbenzamide

A mixture of 4-{[5-acetyl-3-(2-hydroxyethyl)-4-methyl-1 ,3-thiazol-2(3H)- ylidene]amino}benzoic acid (0.57g, 1.79mmol, Description 20), DIPEA (3.29ml, 21.5mmol) and dimethylamine hydrochloride (1.46g, 17.9mmol, 10 equiv) in DMF (10ml) was stirred at room temperature under argon. Then HATU (0.68g, 1.79mmol) was added and the resulting mixture was allowed to stir at room temperature for 16 hours. Then the reaction mixture was treated with additional HATU (0.13g, 0.34mmol), DIPEA (2ml, 13.1 mmol) and dimethylamine hydrochloride (1.46g, 17.9mmol) and allowed to stir for 16 hours. Solvent was evaporated off under reduced pressure and the residual material was partitioned twice between ethyl acetate and water. The organic fractions were combined, dried over sodium sulphate and evaporated. The title compound was purified by column chromatography on silica using 10% methanol in dichloromethane and mass directed auto-preparation to give the title compound (100mg, 16%). LC/MS (ES): Found 348 (ES+), retention time 1.99mins. C₁7H₂₁N3O3S requires 347. 1H-NMR (400MHz, DMSO-d₆): δ 2.33 (3H, s), 2.63 (3H, s), 2.96 (6H, s), 3.73 (2H, m), 4.04 (2H, m), 5.05 (1 H, m), 7.03 (2H, m), 7.41 (2H, m).

Example 38: 1 -[2-(4-biphenylylimino)-3-cyclopropyl-4-methyl-2,3-dihydro-1 ,3- thiazol-5-yl]ethanone

A mixture of 1-{2-[(4-bromophenyl)imino]-3-cyclopropyl-4-methyl-2,3-dihydro-1 ,3-thiazol-5- yl}ethanone (Description 11 , 70mg, 0.2mmol), phenylboronic acid (36mg, 0.3mmol), tetrakis(triphenylphosphine)palladium(0) (6.9mg, 3mol%) and sodium carbonate (42mg, 0.4mmol) in 1 ,4-dioxane/water 3:1 (4ml) were heated at 100⁰C under argon for 16 hours. The reaction mixture was diluted with ethyl acetate and filtered through kieselguhr to remove the catalyst. The organic solution was washed with water, dried with sodium sulphate and evaporated. The desired product was isolated by column chromatography on silica using 10 to 95% ethyl acetate in n-pentane to give the title compound as a yellow solid (34mg, 48%).

LC/MS (ES): Found 349 (ES+), retention time 2.95mins. C_2IH₂₀N₂OS requires 348. 1H-NMR (400MHz, CDCI₃): δ 1.05 (2H, m), 1.26 (2H, m), 2.24 (3H, s), 2.68 (3H, s), 2.87 (1 H, m), 7.10 (2H, m), 7.33 (1 H, m), 7.43 (2H, m), 7.61 (4H, m).

Example 39: 3-ethyl-Λ/,Λ/,4-trimethyl-2-{[4-(1 H-pyrazol-1 -yl)phenyl]imino}-2,3- dihydro-1 ,3-thiazole-5-carboxamide hydrochloride

The title compound was prepared from /V-ethyl-/V-[4-(1 H-pyrazol-1 -yl)phenyl]thiourea (Description 14) and 2-chloro-Λ/-methyl-3-oxobutanamide using a similar procedure to that described for Example 34 followed by treatment with ethereal hydrogen chloride. LC/MS (ES): Found 356 (ES+), retention time 1.89mins. Ci₈H₂₁N₅OS requires 355. 1H-NMR (400MHz, DMSO-d₆): δ 1.35 (3H, m), 2.30 (3H, s), 2.95 (6H, s), 4.20 (2H, m), 6.56 (1 H, m), 7.47 (2H, m), 7.76 (1 H, d, J=1.6Hz), 7.93 (2H, d, J=8.8Hz), 8.53 (1 H, d, J=2.4Hz).

Example 40: 1 -[2-(4-biphenylylimino)-3-(2-hydroxyethyl)-4-methyl-2,3-dihydro-1,3- thiazol-5-yl]ethanone hydrochloride

A mixture of 1-[2-[(4-bromophenyl)imino]-3-(2-hydroxyethyl)-4-methyl-2,3-dihydro-1 ,3- thiazol-5-yl]ethanone (Description 17, 200mg, 0.56mmol), phenylboronic acid (103mg, 0.84mmol), tetrakis(tripheπylphosphine)palladium(0) (20mg, 3mol%) and sodium carbonate (1 19mg, 1.13mmol) in 1 ,4-dioxane/water 3:1 (14ml) were heated at 90⁰C under argon for 1 hour. The reaction mixture was diluted with ethyl acetate and filtered through kieselguhr to remove the catalyst. The organic solution was washed with water, dried over sodium sulphate and evaporated. The desired product was isolated by column chromatography on silica using 10 to 100% ethyl acetate in n-pentane, treated with 1 M ethereal hydrogen chloride and triturated with methanol to give the title compound as a white solid (74mg, 34%).

LC/MS (ES): Found 353 (ES+), retention time 2.99mins. C_2IH₂₀N₂O₂S requires 352.

¹H-NMR (400MHz, DMSOd₆): δ 2.33 (3H, s), 2.65 (3H, s), 3.75 (2H, m), 4.10 (2H, m), 6.0 (2H, bs), 7.14 (2H, m), 7.34 (1 H, m), 7.45 (2H, m), 7.68 (4H, m).

Example 41 : 1 -[2-{[4-(2-fluoro-6-methyl-3-pyridinyl)phenyl]imino}-3-(2- hydroxyethyl)-4-methyl-2,3-dihydro-1 ,3-thiazol-5-yl]ethanone

The title compound was prepared from 1-[2-[(4-bromophenyl)imino]-3-(2-hydroxyethyl)-4- methyl-2,3-dihydro-1 ,3-thiazol-5-yl]ethanone (Description 17) and (2-fluoro-6-methyl-3- pyridinyl)boronic acid using a similar procedure to that described for Example 38.

LC/MS (ES): Found 386 (ES+), retention time 2.71 mins. C₂₀H₂₀FN₃O₂S requires 385.

¹H-NMR (400MHz, CDCI₃): δ 2.30 (3H, s), 2.54 (3H, s), 2.65 (3H, s), 3.62 (1 H, bs), 4.02 (2H, m), 4.22 (2H, m), 7.1 1 (1 H, m), 7.15 (2H, m), 7.56 (2H, m), 7.78 (1 H, m).

Example 42: 1,1-dimethylethyl [(4-{[5-acetyl-3,4-dimethyl-1,3-thiazol-2(3H)- ylidene]amino}phenyl)methyl]carbamate

A mixture of 1 ,1-dimethylethyl [(4-

{[(methylamino)carbonothioyl]amino}phenyl)methyl]carbamate (300mg, 1.01 mmol, Description 21 ) and 3-chloro-2,4-pentanedione (0.36ml, 3.03mmol) in toluene (10ml) and ethanol (5ml) was heated at 90⁰C for 1 hour with stirring under argon. The solvent was removed by rotary evaporation and the sample purified by high pH mass directed auto- preparation to give the title compound as a white solid (215mg, 56%).

LC/MS (ES): Found 376 (ES+), retention time 2.67mins. Ci₉H₂₅N₃O₃S requires 375.

¹H-NMR (400MHz, CDCI₃): δ 1.47 (9H, s), 2.26 (3H, s), 2.61 (3H, s), 3.49 (3H, s), 4.30 (2H, m), 4.80 (1 H, bs), 7.00 (2H, m), 7.27 (2H, m).

Example 43: 1-[2-{[4-(6-fluoro-3-pyridinyl)phenyl]imino}-3-(2-hydroxyethyl)-4- methyl-2,3-dihydro-1,3-thiazol-5-yl]ethanone

The title compound was prepared from 1-[2-[(4-bromophenyl)imino]-3-(2-hydroxyethyl)-4- methyl-2,3-dihydro-1 ,3-thiazol-5-yl]ethanone (Description 17) and (6-fluoro-3- pyridinyl)boronic acid using a similar procedure to that described for Example 38.

LC/MS (ES): Found 372 (ES+), retention time 2.73mins. Ci₉H₁₈FN₃O₂S requires 371.

¹H-NMR (400MHz, DMSO-d₆): δ 2.33 (3H, s), 2.63 (3H, s), 3.74 (2H, m), 4.05 (2H, m), 5.06 (1 H, m), 7.10 (2H, m), 7.27 (1 H, m), 7.73 (2H, m), 8.29 (1 H, m), 8.55 (1 H, m).

Example 44: 1 -[2-{[4-(3-furanyl)phenyl]imino}-3-(2-hydroxyethyl)-4-methyl-2,3- dihydro-1 ,3-thiazol-5-yl]ethanone

The title compound was prepared from 1-[2-[(4-bromophenyl)imino]-3-(2-hydroxyethyl)-4- methyl-2,3-dihydro-1 ,3-thiazol-5-yl]ethanone (Description 17) and 3-furanylboronic acid using a similar procedure to that described for Example 38.

LC/MS (ES): Found 343 (ES+), retention time 2.67mins. C₁₈H₁₈N₂O₃S requires 342.

¹H-NMR (400MHz, DMSOd₆): δ 2.32 (3H, s), 2.62 (3H, s), 3.73 (2H, m), 4.04 (2H, m), 5.05 (1 H, m), 6.93 (1 H, m), 6.99 (2H, m), 7.58 (2H, m), 7.72 (1 H, m), 8.13 (1 H, s).

Example 45: 1-(3-(2-hydroxyethyl)-4-methyl-2-{[4-(2-methyl-3- pyridinyl)phenyl]imino}-2,3-dihydro-1,3-thiazol-5-yl)ethanone hydrochloride

The title compound was prepared from 1-[2-[(4-bromophenyl)imino]-3-(2-hydroxyethyl)-4- methyl-2,3-dihydro-1 ,3-thiazol-5-yl]ethanone (Description 17) and

(2-methyl-3-pyridinyl)boronic acid using a similar procedure to that described for Example 40.

LC/MS (ES): Found 368 (ES+), retention time 1.69mins. C₂₀H₂₁N₃O₂S requires 367.

¹H-NMR (400MHz, DMSO-d₆): δ 2.37 (3H, s), 2.65 (3H, s), 3.74 (3H, s), 3.75 (2H, m), 4.10 (2H, m), 5.18 (2H, bs), 7.21 (2H, m), 7.54 (2H, m), 7.98 (1 H, m), 8.48 (1 H, m), 8.79 (1 H, m)

Example 46: Λ/-[(4-{[5-acetyl-3-ethyl-4-methyl-1,3-thiazol-2(3H)- ylidene]amino}phenyl)methyl]methanesulfonamide

A solution of 1-(2-{[4-(aminomethyl)phenyl]imino}-3-ethyl-4-methyl-2,3-dihydro-1 ,3- thiazol-5-yl)ethanone hydrochloride (150mg, 0.41 mmol, Description 24) and triethylamine (0.24ml, 1.64mmol) in dichloromethane (10ml) was stirred under argon in an ice bath. Methanesulfonyl chloride (0.06ml, 0.82mmol) was added dropwise with stirring. The resulting mixture was allowed to stir at room temperature for 5 hours. Then the solution was washed with water and the organic layer was separated and dried with sodium sulphate, then evaporated. The desired product was isolated by mass directed auto- preparation to give the title compound as a brown solid (41 mg, 27%).

High pH LC/MS (ES): Found 368 (ES+), retention time 2.26mins. C₁₆H_2IN₃O₃S₂ requires 367. 1H-NMR (400MHz, DMSOd₆): δ 1.25 (3H, m), 2.30 (3H, s), 3.59 (3H, s), 3.84 (3H, s), 4.02 (2H, m), 4.11 (2H, m), 6.96 (2H, m), 7.32 (2H, m), 7.52 (1 H, m).

Example 47: Λ/-[(4-{[5-acetyl-3-ethyl-4-methyl-1,3-thiazol-2(3H)- ylidene]amino}phenyl)methyl]acetamide hydrochloride

The title compound was prepared from 1-(2-{[4-(aminomethyl)phenyl]imino}-3-ethyl-4- methyl-2,3-dihydro-1 ,3-thiazol-5-yl)ethanone hydrochloride (Description 24) and acetyl chloride using a similar procedure to that described for Example 46.

LC/MS (ES): Found 332 (ES+), retention time 1.92mins. Ci₇H₂₁N₃O₂S requires 331. 1H-NMR (400MHz, MeOD-d₄): δ 1.48 (3H, m), 2.03 (3H, s), 2.51 (3H, s), 2.75 (3H, s), 4.32 (2H, m), 4.45 (2H, m), 7.5 (4H, m).

Example 48: 1-[2-{[4-(2-chloro-3-pyridinyl)phenyl]imino}-3-(2-hydroxyethyl)-4- methyl-2,3-dihydro-1,3-thiazol-5-yl]ethanone

(2-chloro-3-pyridinyl)boronic acid using a similar procedure to that described for Example 38.

LC/MS (ES): Found 388 (ES+), retention time 2.36mins. C₁₉H₁₈CIN₃O₂S requires 387. ¹H-NMR (400MHz, DMSO-d₆): δ 2.35 (3H, s), 2.64 (3H, s), 3.74 (2H, m), 4.08 (2H, m), 5.06 (1 H, m), 7.11 (2H, m), 7.49 (3H, m), 7.90 (1 H, m), 8.41 (1 H, m).

Example 49: 1 -[2-(3,4-dihydro-1 H-2-benzopyran-6-ylimino)-3-(2-hydroxyethyl)-4- methyl-2,3-dihydro-1,3-thiazol-5-yl]ethanone hydrochloride

The title compound was prepared from Λ/-(3,4-dihydro-1 H-2-benzopyran-6-yl)-Λ/'-(2- hydroxyethyl)thiourea (Description 25) and 3-chloro-2,4-pentanedione using a similar procedure to that described for Example 34 followed by treatment with ethereal hydrogen chloride.

LC/MS (ES): Found 333 (ES+), retention time 2.08mins. Ci₇H₂₀N₂O₃S requires 332.

¹H-NMR (400MHz, DMSOd₆): δ 2.35 (3H, s), 2.64 (3H, s), 2.79 (2H, m), 3.75 (2H, m), 3.88 (2H, m), 4.16 (2H, m), 4.68 (2H, s), 6.71 (2H, bs), 6.83-6.93 (2H, m), 7.07 (1 H, m).

Example 50: 3-ethyl-2-{[4-(2-fluoro-3-pyridinyl)phenyl]imino}-Λ/,Λ/,4-trimethyl-2,3- dihydro-1,3-thiazole-5-carboxamide hydrochloride

The title compound was prepared from 2-[(4-bromophenyl)imino]-3-ethyl-Λ/,Λ/,4-trimethyl- 2,3-dihydro-1 ,3-thiazole-5-carboxamide (Description 27) and (2-fluoro-3-pyridinyl)boronic acid using a similar procedure to that described for Example 40.

LC/MS (ES): Found 385 (ES+), retention time 2.26mins. C₂₀H₂₁FN₄OS requires 384. 1H-NMR (400MHz, DMSO-d₆): δ 1.33 (3H, m), 2.31 (3H, m), 2.93 (6H, m), 4.14 (2H, m), 7.38 (2H, m), 7.47 (1 H, m), 7.70 (2H, m), 8.15 (1 H, m), 8.25 (1 H, m).

Example 51 : 3-ethyl-Λ/,Λ/,4-trimethyl-2-{[4-(2-methyl-3-pyridinyl)phenyl]imino}-2,3- dihydro-1 ,3-thiazole-5-carboxamide hydrochloride

The title compound was prepared from 2-[(4-bromophenyl)imino]-3-ethyl-Λ/,Λ/,4-trimethyl- 2,3-dihydro-1 ,3-thiazole-5-carboxamide (Description 27) and (2-methyl-3-pyridinyl)boronic acid using a similar procedure to that described for Example 40.

LC/MS (ES): Found 381 (ES+), retention time 1.39mins. C_2IH₂₄N₄OS requires 380. 1H-NMR (400MHz, DMSOd₆): δ 1.32 (3H, m), 2.27 (3H, s), 2.73 (3H, s), 2.95 (6H, m), 4.12 (2H, m), 7.37 (2H, bs), 7.55 (2H, m), 7.96 (1 H, m), 8.45 (1 H, m), 8.79 (1 H, m).

Example 52: 1 -(3-ethyl-4-methyl-2-{[4-(4-morpholinylmethyl)phenyl]imino}-2,3- hydro-1 ,3-thiazol-5-yl)ethanone hydrochloride

A mixture of /V-ethyl-/V-[4-(4-morpholinylmethyl)phenyl]thiourea (200 mg, 0.72mmol, Description 28) and 3-chloro-2,4-pentanedione (0.427 ml, 3.58mmol) in ethanol (30ml) was heated at 9O⁰C for 2 hours. The solvent was removed by rotary evaporation and the residual material was purified by mass directed auto-preparation. The solvent was removed under rotary evaporation and the residual material was partitioned between dichloromethane (20ml) and saturated aqueous sodium bicarbonate solution (10ml). The organic layer was separated and dried over sodium sulphate, filtered and evaporated. The material was dissolved in methanol, treated with 1 M ethereal hydrogen chloride and dried under high vacuum to afford the title compound as a white solid (224mg, 72%).

LC/MS (ES): Found 360 (ES+), retention time 1.55mins. Ci₉H₂₅N₃O₂S requires 359. 1H-NMR (400MHz, DMSO-d₆): δ 1.27 (3H, m), 2.37 (3H, s), 2.62 (3H, s), 3.04 (2H, m), 3.20 (2H, m), 3.80 (2H, m), 3.92 (2H, m), 4.08 (2H, m), 4.30 (2H, m), 7.10 (2H, m), 7.62 (2H, m), 1 1.45 (1 H, bs).

Example 53: 2-[(4'-fluoro-4-biphenylyl)imino]-3-(2-hydroxyethyl)-Λ/,Λ/,4-trimethyl-2,3- dihydro-1,3-thiazole-5-carboxamide hydrochloride

A mixture of 2-[(4-bromophenyl)imino]-3-(2-hydroxyethyl)-N,N,4-trimethyl-2,3-dihydro-1 ,3- thiazole-5-carboxamide (200 mg, 0.47mmol, Description 29), (4-fluorophenyl)boronic acid (133 mg, 0.95mmol), tetrakis(tripheπylphosphine)palladium(0) (16.5 mg, 0.014mmol) and sodium carbonate (101 mg, 0.951 mmol) in 1 ,4-dioxane (12 ml) and water (4 ml) were heated at 100°C for 4 hours. The reaction mixture was diluted with ethyl acetate, filtered through kieselguhr to remove catalyst and the filtrate was washed with water and dried over sodium sulphate. The reaction mixture was concentrated and purified by MDAP to give the desired product. The product was partitioned between dichloromethane and aqueous sodium hydrogen carbonate solution, dried over sodium sulphate, then filtered and the solvent was removed by rotary evaporation to afford the desired product. This material was dissolved in methanol and treated with 1 M ethereal hydrogen chloride to give the title compound as a white solid (1 11 mg, 50.9%).

LC/MS (ES): Found 400 (ES+), retention time 2.31 mins. C_2IH₂₂FN₃O₂S requires 399.

¹H-NMR (400MHz, DMSOd₆): δ 2.30 (3H, s), 2.95 (6H, s), 3.80 (2H, m), 4.21 (2H, m), 7.28 (2H, m), 7.38 (2H, m), 7.72 (4H, m).

Example 54: 3-ethyl-Λ/,Λ/,4-trimethyl-2-{[4-(6-methyl-3-pyridinyl)phenyl]imino}-2,3- dihydro-1,3-thiazole-5-carboxamide hydrochloride

A mixture of 2-[(4-bromophenyl)imino]-3-ethyl-Λ/,Λ/,4-trimethyl-2,3-dihydro-1 ,3-thiazole-5- carboxamide (200 mg, 0.54mmol, Description 27), (6-methyl-3-pyridinyl)boronic acid (223 mg, 1.63mmol), tetrakis(triphenylphosphine)palladium(0) (37.7 mg, 0.03mmol) and sodium carbonate (1 15 mg, 1.09mmol) in 1 ,4-dioxane (12 ml) and water (4 ml) were heated at 100°C for 24 hours. The reaction mixture was diluted with ethyl acetate, filtered through kieselguhr to remove catalyst and the filtrate was washed with water, separated organic layer, dried over sodium sulphate. The reaction mixture was concentrated and purified by MDAP to give the crude product. The crude product was partitioned between dichloromethane and aqueous sodium hydrogen carbonate solution, dried over sodium sulphate, filtered and evaporated. The residual material was dissolved in methanol, and treated with 1 M ethereal hydrogen chloride to give the desired product as a white solid (23mg, 9.45%).

LC/MS (ES): Found 381 (ES+), retention time 1.43mins. C₂iH₂₄N₄OS requires 380. 1H-NMR (400MHz, DMSOd₆): δ 1.33 (3H, s), 2.31 (3H, s), 3.81 (3H, s), 2.97 (6H, s), 4.29 (2H, m), 7.58 (2H, m), 8.0 (3H, m), 8.83 (1 H, m), 9.12 (1 H, m). Example 55: 3-(2-hydroxyethyl)-Λ/,Λ/,4-trimethyl-2-{[4-(6-methyl-3- pyridinyl)phenyl]imino}-2,3-dihydro-1,3-thiazole-5-carboxamide hydrochloride

The title compound was prepared from 2-[(4-bromophenyl)imino]-3-(2-hydroxyethyl)- Λ/,Λ/,4-trimethyl-2,3-dihydro-1 ,3-thiazole-5-carboxamide (Description 29) and (6-methyl-3- pyridinyl)boronic acid using a similar procedure to that described for Example 40.

LC/MS (ES): Found 397 (ES+), retention time 1.33mins. C_2IH₂₄N₄O₂S requires 396. 1H-NMR (400MHz, MeOD-d₄): δ 2.45 (3H, s), 2.88 (3H, s), 3.10 (6H, s), 4.01 (2H, m), 4.42 (2H, m), 7.72 (2H, m), 8.01 (3H, m), 8.85 (1 H, m), 9.01 (1 H, m).

Example 56: 1 -(3-(2-hydroxyethyl)-4-methyl-2-{[4-(1 H-pyrazol-1 -yl)phenyl]imino}-2,3- dihydro-1 ,3-thiazol-5-yl)ethanone hydrochloride

A mixture of /V-(2-hydroxyethyl)-/V-[4-(1 H-pyrazol-1 -yl)phenyl]thiourea (400mg, 1.44mmol, Description 15) and 3-chloro-2,4-pentanedione (0.33ml, 2.89mmol) in toluene (10ml) was heated at 90⁰C for 1 hour. Then an excess of 3-chloro-2,4-pentanedione and ethanol (10ml) were added and the reaction mixture was allowed to heat for a further 5 hours. The solvent was removed under reduced pressure and residual material was recrystallised with methanol / ethyl acetate to give the title compound (203mg, 41.2%).

LC/MS (ES): Found 343 (ES+), retention time 2.35mins. Ci₇H₁₈N₄O₂S requires 342. 1H-NMR (400MHz, DMSO-d₆): δ 1.73 (3H, s), 1.99 (3H, s), 3.21 (2H, m), 3.62 (2H, m), 4.08 (1 H, s), 5.79 (1 H, m), 6.79 (2H, m), 6.98 (1 H, d, J=1.2Hz), 7.18 (2H, m), 7.52 (1 H, d, J=2.4Hz).

Example 57: Λ/-(4-{[5-acetyl-3,4-dimethyl-1,3-thiazol-2(3H)- ylidene]amino}phenyl)acetamide

A solution of 1-{2-[(4-aminophenyl)imino]-3,4-dimethyl-2,3-dihydro-1 ,3-thiazol-5- yl}ethanone (0.34 mmol, Description 32) in DMF (2 mL) was added to sodium hydride (60% dispersion in mineral oil, 14 mg, 0.34 mmol) and the resultant solution was stirred for 15 mins at room temperature. A solution of acetic anhydride (64 μl_, 0.67 mmol) in DMF (1 mL) was then slowly added. The solvent was then removed by rotary evaporation. The residue was then purified by MDAP to give the title compound (0.044 g, 43 %).

LC/MS (ES): Found 304 (ES+), retention time 2.39mins. Ci₅H₁₇N₃O₂S requires 303. 1H NMR (400MHz, DMSOd₆): δ 2.02 (3H, s), 2.31 (3H, s), 2.57 (3H, s), 3.44 (3H, s), 6.91 (2H, m), 7.54 (2H, m), 9.87 (1 H, s).

Example 58: Λ/-(4-{[5-acetyl-3-ethyl-4-methyl-1 ,3-thiazol-2(3H)- ylidene]amino}phenyl)acetamide

Following an identical procedure to Example 57, 1-{2-[(4-aminophenyl)imino]-3-ethyl-4- methyl-2,3-dihydro-1 ,3-thiazol-5-yl}ethanone (0.34 mmol, Description 35) in DMF (2 mL), sodium hydride (60% dispersion in mineral oils, 14 mg, 0.34 mmol) and acetic anhydride (64 μL, 0.67 mmol) in DMF (1 mL) were combined to give the title compound (0.009 g, 8 %).

LC/MS (ES): Found 318 (ES+), retention time 2.55mins. C₁₆H₁₉N₃O₂S requires 317. 1H NMR (400MHz, DMSO-d₆): δ 1.25 (3H, m), 2.02 (3H, s), 2.30 (3H, s), 2.59 (3H, s), 4.01 (2H, m), 6.92 (2H, m), 7.54 (2H, m), 9.87 (1 H, s).

Example 59: Λ/-(4-{[5-acetyl-3-(2-hydroxyethyl)-4-methyl-1 ,3-thiazol-2(3H)- ylidene]amino}phenyl)acetamide

Following an identical procedure to Example 57, 1-[2-[(4-aminophenyl)imino]-3-(2- hydroxyethyl)-4-methyl-2,3-dihydro-1 ,3-thiazol-5-yl]ethanone (0.34 mmol, Description 38) in DMF (2 ml_), sodium hydride (60% dispersion in mineral oils, 14 mg, 0.34 mmol) and acetic anhydride (64 μl_, 0.67 mmol) in DMF (1 ml.) were combined to give the title compound (0.024 g, 21 %).

LC/MS (ES): Found 334 (ES+), retention time 2.25mins. Ci₆H₁₉N₃O₃S requires 333. 1H NMR (400MHz, DMSOd₆): δ 2.03 (3H, s), 2.31 (3H, s), 2.61 (3H, s), 3.71 (2H, m), 4.02 (2H, m), 5.02 (1 H, bs), 6.91 (2H, m), 7.54 (2H, m), 9.86 (1 H, s).

Example 60: 1 -[2-(2,3-dihydro-1 H-inden-5-ylimino)-3-(2-hydroxyethyl)-4-methyl-2,3- dihydro-1,3-thiazol-5-yl]ethanone

5-isothiocyanato-2,3-dihydro-1 H-indene (0.25mmol, 43.8mg) was dissolved in ethyl acetate (1 mL). To this solution was added a 1 mL solution of ethyl acetate containing ethanolamine (15.1 μL, 0.25mmol). This reaction was shaken for 20-30 minutes before the solvent was removed in vacuo. The residue was then dissolved in ethanol (1 mL). A 31.3μL (0.263 mmol) portion of 3-chloro-2,4-pentanedione in ethanol (1 mL) was added to this and the mixture heated at 100⁰C for 15 minutes by microwaves.

The solvent was then removed in vacuo and the residue purified by mass directed autopreparation to yield 1.5mg of the title compound.

LC/MS (ES): Found 317 (ES+), retention time 3.02mins. Ci₇H₂₀N₂O₂S requires 316. 1H NMR (400MHz, DMSO-d₆): δ 2.01 (2H, quintet, J=7.5 Hz), 2.30 (3H, s), 2.61 (3H, s), 2.82 (2H, t, J=7.0 Hz), 2.83 (2H, t, J=7.0 Hz), 3.71 (2H, q, J=5.5 Hz), 4.01 (2H, t, J=5.5 Hz), 5.03 (1 H, t, J=5.5 Hz), 6.71 (1 H, dd, J=8.0, 1.5 Hz), 6.82 (1 H, s), 7.18 (1 H, d, J=8.0 Hz)

Example 61 : 1 -[(4-{[5-acetyl-3-ethyl-4-methyl-1 ,3-thiazol-2(3H)- ylidene]amino}phenyl)methyl]-2-pyrrolidinone

A solution of 1-(2-{[4-(aminomethyl)phenyl]imino}-3-ethyl-4-methyl-2,3-dihydro-1 ,3-thiazol- 5-yl)ethanone hydrochloride (Description 24) (400mg, 1.1 mmol), triethylamine (0.61 ml, 4.4 mmol) in DMF (5ml) was treated with 4-chlorobutyryl chloride (156mg, 1.1 mmol) dropwise over 10 minutes. This mixture was stirred for 2 hours and then allowed to cool in an ice bath before being treated with sodium hydride (176mg, 4.4mmol) portionwise over 3 hours and the whole mixture was then stirred at room temperature for 16 hours. The reaction mixture was partitioned between water and dichloromethane. The organic layer was separated and dried over sodium sulphate and concentrated under reduced pressure. The desired product was purified by MDAP and column chromatography on silica using 0 to 10% methanol in ethyl acetate to give the title compound as an off white solid (40mg, 10%).

LC/MS high pH (ES): Found 358 (ES+), retention time 2.39mins. Ci₉H₂₃N₃O₂S requires 357. 1H-NMR (400MHz, CDCI₃): δ 1.35 (3H, m), 2.01 (2H, m), 2.26 (3H, s), 2.45 (2H, m), 2.62 (3H, s), 3.28 (2H, m), 4.07 (2H, m), 4.43 (2H, s), 7.02 (2H, m), 7.23 (2H, m).

Example 62: 3-(2-hydroxyethyl)-Λ/,Λ/,4-trimethyl-2-{[4'-(methyloxy)-4- biphenylyl]imino}-2,3-dihydro-1 ,3-thiazole-5-carboxamide hydrochloride

The title compound was prepared from 2-[(4-bromophenyl)imino]-3-(2-hydroxyethyl)- Λ/,Λ/,4-trimethyl-2,3-dihydro-1 ,3-thiazole-5-carboxamide (Description 29) and [4- (methyloxy)phenyl]boronic acid using a similar procedure to that described for Example 53.

LC/MS (ES): Found 412 (ES+), retention time 2.18mins. C₂₂H₂₅N₃O₃S requires 411. 1H-NMR (400MHz, DMSO-d₆): δ 2.33 (3H, s), 2.95 (6H, s), 3.80 (5H, m), 4.21 (2H, m), 5.45 (2H, bs), 7.04 (2H, m), 7.36 (2H, m), 7.64 (2H, d, J=8Hz), 7.72 (2H, d, J= 8Hz).

Example 63: 1-[3-ethyl-4-methyl-2-({4-[(4-methyl-1 - piperazinyl)carbonyl]phenyl}imino)-2,3-dihydro-1 ,3-thiazol-5-yl]ethanone, hydrochloride

Solid 1 ,1 '-carbonyldiimidazole (117mg, 0.72mmol) was added in one portion to a stirring mixture of 4-{[5-acetyl-3-ethyl-4-methyl-1 ,3-thiazol-2(3H)-ylidene]amino}benzoic acid (description 6; 220mg, 0.72mmol) in dichloromethane (7ml), which was then stirred at room temperature under argon for 20 minutes. 1-Methylpiperazine (0.72mmol, 0.065ml) was then added dropwise and the resulting mix stirred at room temperature for 2 hours. The reaction mixture was washed with saturated aqueous sodium bicarbonate solution and the organic layer separated and added directly to a 5g isolute silica sep-pak column which was then eluted with 0-5% methanol in ethyl acetate. The solvent was removed by rotary evaporation and the residue was dissolved in dichloromethane (1 ml) and treated with 1 M hydrogen chloride in ether (1 ml). The solvent was blown off and the residue triturated in ether. The liquid was decanted off and the residue dried in a vacuum oven to give the title compound as a colourless solid (134mg, 41%).

LC/MS (ES): Found 387 (ES+), retention time 1.59mins. C₂₀H₂₆N₄O₂S requires 386. 1H-NMR (400MHz, MeOD-d₄): δ 1.50 (3H, t, J=7Hz), 2.54 (3H, s), 2.77 (3H, s), 2.96 (3H, s), 3.18-3.35 (4H, m), 3.38-3.66 (4H, m), 4.36 (2H, m), 7.68 (2H, d, J=8Hz), 7.74 (2H, d, J=8Hz).

Example 64: 4-{[5-acetyl-3-(2-hydroxyethyl)-4-methyl-1 ,3-thiazol-2(3H)- ylidene]amino}benzonitrile

A mixture of /V-(4-cyanophenyl)-/V-(2-hydroxyethyl)thiourea (Description 39, 200 mg, 0.904 mmol) and 3-chloro-2,4-pentanedione (0.1 13 ml, 0.948 mmol) in toluene (15 ml) was heated at 95 ⁰C for 1 hour. Further 3-chloro-2,4-pentanedione (0.2 ml, 1.68 mmol) was added and heating was continued for a further 2 hours. Further 3-chloro-2,4- pentanedione (0.2 ml, 1.68 mmol) was added and heating was continued for a further 3 hours. The reaction was allowed to cool and solvent was removed. The residual material was partitioned between diethyl ether and saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried (sodium sulphate) and solvent was removed. Purification by column chromatography on silica eluting with diethyl ether provided the title compound (59 mg).

LC/MS (ES): Found 302 (ES+), retention time 2.41 mins. Ci₅H₁₅N₃O₂S requires 301.

1 H-NMR (400MHz, CDCI₃): 2.32 (3H, s), 2.66 (3H, s), 2.85 (1 H, m), 4.01 (2H, m), 4.20 (2H, m), 7.14 (2H, m), 7.64 (2H, m). Analytical chromatographic conditions

One of the following methods were used for the LC/MS analysis:

Method 1

Column: Waters Atlantis, 4.6mm x 50mm. The stationary phase particle size is

3um. Solvents: A : Aqueous solvent = Water + 0.05% Formic Acid;

B : Organic solvent = Acetonitrile + 0.05% Formic Acid Methods: 5 minute runtime.

Time / min %B

0 3

0.1 3

4 97

4.8 97

4.9 3

5.0 3

Flow rate: 3ml/min

Injection volume: 5μl

Column temperature: 30 degC

UV wavelength range: 220-330 nm

Method 1 - high pH version - as above, except:

- Column: Waters X-Bridge 4.6mm x 50mm. The stationary phase particle size is

3.5μm.

A : Aqueous solvent = 1OmM Ammonium Bicarbonate solution adjusted to pH 10 with ammonia solution.

B : Organic solvent = Acetonitrile.

Method 2

Column: Waters Acquity BEH UPLC C18, 2.1 mm x 50mm. The stationary phase particle size is 1.7μm.

Solvents

A : Aqueous solvent = Water + 0.05% Formic Acid

B : Organic solvent = Acetonitrile + 0.05% Formic Acid

Weak Wash = 1 :1 Methanol : Water

Strong Wash = Water

The generic method used has a 2 minute runtime.

• The above method has a flow rate of 1 ml/min.

• The injection volume for the generic method is 0.5ul

• The column temperature is 40degC

• The UV detection range is from 220 to 330nm

Method 3

Column: 3.3cm x 4.6mm ID, 3um ABZ+PLUS

Flow Rate: 3ml/min

Injection Volume: 5μl

Temperature: room temperature

UV Detection Range: 215 to 330nm

Solvents: A: 0.1 % Formic Acid + IOmMolar Ammonium Acetate; B: 95%

Acetonitrile + 0.05% Formic Acid

Time A% B%

0.00 100 0

0.70 100 0

4.20 0 100

4.60 00 100

4.80 100 0

MDAP conditions

Column: WWaatteerrss AAttllaannttiiss,, 119mm x 100mm (small scale) and 30mm x 100mm

(large scale). Stationary phase particle size = 5um. Solvents: A : Aqueous solvent = Water + 0.1% Formic Acid; B : Organic solvent = Acetonitrile + 0.1% Formic Acid. Make up solvent =

Methanol : Water 80:20. Needle rinse solvent = Methanol Methods: There are five methods used depending on the analytical retention time of the compound of interest. They have a 13.5-minute runtime, which comprises of a 10-minute gradient followed by a 3.5 minute column flush and re-equilibration step.

Large/Small Scale 1.0-1.5 = 5-30% B

Large/Small Scale 1.5-2.2 = 15-55% B

Large/Small Scale 2.2-2.9 = 30-85% B

Large/Small Scale 2.9-3.6 = 50-99% B

Large/Small Scale 3.6-5.0 = 80-99% B (in 6 minutes followed by 7.5 minutes flush and re-equilibration)

Flow rate: 20mls/min (Small Scale) or 40mls/min (Large Scale). High pH MDAP - as above, except for:

Column: Waters X-bridge, 30mm x 100mm. The stationary phase particle size is 5μm. A : Aqueous solvent = 1OmM Ammonium Bicarbonate solution adjusted to pH 10 with ammonia solution. B : Organic solvent = Acetonitrile. Make up solvent = Methanol : Water 80:20 Needle rinse solvent = Methanol

Biological Assays

Calcium Influx Fluorescence Assay 1

384 well plates are prepared containing confluent monolayer of HEK 293 cells either stably expressing or transiently transfected with human GluR2 flip (unedited) AMPA receptor subunit. These cells form functional homotetrameric AMPA receptors. The tissue culture medium in the wells are discarded and the wells are each washed three times with standard buffer (80 μl_) for the stable cell line (145 mM NaCI, 5 mM KCI, 1 mM MgCI₂, 2 mM CaCI₂, 20 mM N-[2-hydroxyethyl]-piperazine-N-[2-ethanesulfonic acid (HEPES), 5.5 mM glucose, pH 7.3) or with a Na-free buffer for the transient transfected cells (145 mM N-methyl-glucamine instead of NaCI). The plates are then incubated for 60 minutes in the dark with 2 μM FLUO4-AM dye (20 μl_) (Molecular Probes, Netherlands) at room temperature to allow cell uptake of the FLUO-4AM, which is then converted to FLUO-4 by intracellular esterases which is unable to leave the cell. After incubation each well is washed three times with buffer (80 μl_) (30 μl_ of buffer remained in each well after washing).

Compounds of the invention (or reference compounds such as cyclothiazide) are dissolved in dimethylsulfoxide (DMSO) at a stock concentration of 10 mM. These solutions are further diluted with DMSO using a Biomek FX (Beckman Coulter) in a 384 compound plate. Each dilution (1 μl_) is transferred to another compound plate and buffer (50 μl_) is added. An agonist stimulus (glutamate) plate is prepared by dissolving sodium glutamate in water to give a concentration of 100 mM. This solution is diluted with buffer to give a final concentration of 500 μM and dispensed into another 384-well plate (50μl_/well) using a Multidrop (Thermolabsystems).

The cell plate is then transferred into a fluorescence imaging plate based reader [such as the FLIPR384 (Molecular Devices)]. A baseline fluorescence reading is taken over a 10 to 240 second period, and then 10 μL from each plate containing a compound of the invention made up in standard buffer solution (in a concentration range from 100 μM to 10 pM) is added (to give a final concentration in the range 30 μM to 3 pM). The fluorescence is read over 5 minute period. 500 μM glutamate solution (10μl_) is added (to give a final concentration of 100 μM). The fluorescence is then read over a 4 minute period. The activities of the compounds of the invention and reference compounds are determined by measuring peak fluorescence after the last addition. The activity is also expressed relative to the fluorescence increase induced by cyclothiazide at their maximum response (i.e. greater than 30 μM).

Calcium Influx Fluorescence Assay 2

384 well plates are prepared containing confluent monolayer of HEK 293 cells stably expressing human GluR2 flip (unedited) AMPA receptor subunit. On the day of the experiment, culture medium are discarded and the cells washed three times with standard buffer (145 mM NaCI, 5 mM KCI, 1 mM MgCI2, 2 mM CaCI2, 20 mM N-[2-hydroxyethyl]- piperazine-N-[2-ethanesulfonic acid (HEPES), 5.5 mM glucose, pH 7.3) and 20 μl_ of buffer remained in each well after washing. The plates are then incubated at room temperature for 60 minutes in the dark with 2 μM FLUO-4AM dye to allow cell uptake of the FLUO-4AM, which is then converted to FLUO-4 by intracellular esterases which is unable to leave the cells. After incubation cells are washed three times with buffer and 30 μl_ of buffer remained in each well after washing. Compounds of the invention are tested in a final assay concentration range from 100 μM to 1 nM. Compounds of the invention (or reference compounds such as cyclothiazide) are dissolved in dimethylsulfoxide (DMSO) at a stock concentration of 10 mM. These solutions are further diluted with DMSO in a 384 compound plate and 1 μl_ of each dilution is transferred to another compound plate. Just prior compounds addition to the cells, 50 μl_ buffer is added to the 1 μl_ compound copy plate. An agonist stimulus 384-well plate containing 50μl_/well of 500 μM glutamate is prepared by diluting with buffer a 100 mM sodium glutamate stock solution prepared in water. 10 μl_ from each plate containing a compound of the invention made up in buffer solution is added and incubated with the loaded cells for 10 minute in the dark at room temperature. The cell plate is then transferred into a fluorescence imaging plate based reader (such as the FLIPR384 - Molecular Devices). A baseline fluorescence reading is taken over a 5 to 10 second period, and then 10 μL of 500 μM glutamate solution is added (to give a final concentration of 100 μM). The fluorescence is then read over a 4-5 minute period. The activities of the compounds of the invention and reference compounds are determined by measuring peak fluorescence after the last addition. The activity is also expressed relative to the fluorescence increase induced by 150μM cyclothiazide at their maximum response.

Calcium Influx Fluorescence Assay 3

This is carried out in a similar manner as Assay 2 above, except that: a) the compounds of the invention are tested in a final assay concentration range from 50 μM to 50 nM; b) 50 μL pluronic buffer (standard buffer with 0.05% pluronic-F127 acid) is added to the 1 μL compound copy plate; c) an agonist stimulus 384-well plate containing 50μL/well of 500 μM glutamate is prepared by diluting with pluronic buffer (standard buffer with 0.05% pluronic-F127 acid) a 100 mM sodium glutamate stock solution prepared in water; d) the reference compound is Λ/-[(2/?)-2-(4'-cyano-4-biphenylyl)propyl]-2- propanesulfonamide.

The assays described above are believed to have an effective limit of detection of a pEC₅o in the region of 3.5-4.0 due to the limitations of compound solubility. The pEC₅₀ result is generally considered to be accurate +/- 0.3.

All the Example compounds were screened using at least one of the three assays described above and gave an average pEC₅₀ equal to or greater than 4.0 and/or demonstrated an activity of on average at least 10% that of the reference compound, at its maximal response.

Whole cell voltage-clamp electrophvsioloqy Assay

The ability of the compounds of the invention to potentiate AMPA-subtype glutamate receptor-mediated response may be determined by measuring AMPA-evoked current recorded from rat cultured hippocampal neurons.

This assay involves the electrophysiological characterisation of AMPA receptor positive modulators using rat cultured hippocampal neurons. The extracellular recording solution contains: 145 mM NaCI, 2.5 mM KCI, 1.2 mM MgCI₂, 1.5 mM CaCI₂, 10 mM N-[2- hydroxyethyl]-piperazine-N-[2-ethanesulfonic acid (HEPES), 10 mM D-glucose, pH 7.3 with NaOH. The intracellular solution contains : 80 mM CsCI, 80 mM CsF, 10 mM N-[2- hydroxyethyl]-piperazine-N-[2-ethanesulfonic acid (HEPES), 10 mM ethylene glycol-bis(g- aminoethylether)-N,N,N',N,-tetra-acetic acid (EGTA), 14 mM MgATP, 14 mM DiTris Creatine Phosphate, 50 U/ml Creatine Phosphokinase pH 7.3 with CsOH. Recording electrodes are prepared from glass capillary tubes (Clark Electromedical GC120-F10) pulled into two equal lengths using a Zeitz Instruments DMZ Universal Puller, program 09, resulting in electrodes with a resistance of approximately 3-6 MOhms when measured in extracellular solution. Electrodes are back filled with internal recording solution. Positive pressure is applied to the electrode to prevent mixture of internal and external solutions and assist in formation of high resistance seal when the electrode makes contact with the cell membrane. Glass coverslip fragment, bearing rat cultured hippocampal neurons, is placed in the recording chamber positioned on the stage of an inverted microscope. A tube at the edge of the chamber is used to apply extracellular solution to the bath. Rapid solution exchange uses a fast step perfusion system (Biologic RSC160). Two outlet tubes attached together along their length are positioned close to a chosen cell so that the outflow from only one tube can pass directly over the cell surface. A motorized stepper could re-position the tubes such that the outflow from the second outlet tube flows over the cell allowing solution exchange at the cell membrane surface to occur within 10-20 ms. Excess bath solution is removed via a tube positioned at the edge of the chamber connected to a vacuum line. A prospective cell is positioned in the centre of the microscope field of view. Recording electrode is positioned directly above the cell membrane surface. Using fine manipulator control (Luigs and Neumann, SM-6) the electrode is lowered, while monitoring the change in electrode resistance during delivery of a 5 mV depolarizing pulse, until a high resistance seal (gigaseal) is achieved. Whole cell configuration is achieved by removing by suction a small fragment of cell membrane immediately beneath the recording electrode tip. The cell membrane potential is held at -70 mV (voltage-clamped) via the electrode (Axopatch 200B Integrating patch clamp amplifier, pClamp software, Axon Instruments). Test solutions are applied using the fast application system using the following protocol and changes in inward current are recorded and stored for off-line analysis.

1 ) Control current - exchange from extracellular solution to extracellular solution + 30 μM AMPA (2 s application time, 30 s interval between applications) repeated until measurements are stable.

2) Test current - exchange from extracellular solution + 10 nM of compound of invention to extracellular solution + 10 nM of compound of invention + 30 μM AMPA (2 s application time, 30 s interval between applications) repeated until measurements are stable.

All experiments are performed at ambient temperature (20 to 22 ⁰C).

The activity of a compound of the invention is determined by measuring the area under the curve (during 2 s period of application) for the 30 μM AMPA response in the presence of the compound of the invention and expressing it as % of potentiation of the 30 μM AMPA alone response (30 μM AMPA in the absence of the compound of the invention).

Example 53 was tested in this assay. The range of mean responses at 1OnM showed 1.19 fold increase of 30 μM AMPA response, and 1.47 fold increase at 10μM.

Electrophysiological Activity at human recombinant GluR2i homomeric AMPARs Response to 1 mM glutamate in the presence of compound was normalized against the response in the absence of compound that is considered 100%. Glutamate is applied for 2 seconds pulse every 30 seconds. Currents analysis was performed after data acquisition and using zero subtraction function (leak subtraction) measuring the net charge (time integration of the current) in the first 2000 ms from the onset of the peak and measuring the peak amplitude. If run-up or run-down was observed, extrapolation of control values is performed using pre and post drug control data. In the analysis the average of current amplitudes or charge transfer measurements was calculated considering only currents after the stabilization of the signal (when the equilibrium was reached). Potentiation of charge transfer and peak current amplitude was measured after application of 10OnM and 10 μM of the test compound. The activity of a compound of the invention is determined by measuring the area under the curve (during 2 s period of application) for the 1 mM glutamate challenge in the presence of the compound of the invention and expressing it as % of potentiation of the 1 mM glutamate challenge alone (1 mM glutamate in the absence of the compound of the invention). Examples 30 and 53 were tested in this assay, and produced 114% at 100 nM, 781% at 10 uM and 134% at 10 nM , 931% at 10 uM respectively.

Claims

1. A compound of formula (I) or a salt thereof:

(I) wherein:

• X is selected from:

• R² is C_1-4alkyl;

• R⁴ is selected from the group consisting of: o C(O)OCi_-6alkyl; o Ci_-6alkylsulfonyl; o a group (CH₂)_nC(O)NR⁷R⁸ wherein R⁷ and R⁸ are independently hydrogen or

Ci_-6alkyl optionally substituted by hydroxyl; or R⁷ and R⁸ form a 5 or 6 membered saturated heterocyclic ring optionally substituted by a group selected from oxo, Ci_-6alkyl, hydroxyl and NR⁹R¹⁰; o a group (CH₂)_nY wherein Y is selected from cyano, SO₂NR⁹R¹⁰ and NHR¹¹, wherein R¹¹ is selected from C(O)C_1-6alkyl, C(O)OhaloC_1-6alkyl and C_1- ₆alkylsulfonyl; o a group (CH₂)Z wherein Z is an N-linked 5 or 6 membered saturated heterocyclic ring optionally substituted by a group selected from oxo, C_1-6alkyl, hydroxyl and NR⁹R¹⁰; o a 5 or 6 membered unsaturated carbocyclic or unsaturated heterocyclic ring, optionally substituted by one or two groups selected from C_1-6alkyl, FIaIoC_1- ₆alkyl, C_1-6alkoxy and halogen; o an N-linked 5 or 6 membered saturated heterocyclic ring substituted by one or two groups selected from oxo, C_1-6alkyl, hydroxyl and NR⁹R¹⁰; o an N-linked 5 or 6 membered unsaturated heterocyclic ring fused with a cyclohexane ring or a tetrahydropyran ring and further optionally substituted by haloC_1-6alkyl; wherein each R⁹ and each R¹⁰ are independently selected from hydrogen and C_1- ₆alkyl, and each n is independently 0 or 1 ; and • R³ is hydrogen, or R³ and R⁴ together form a tetrahydropyranyl or a cyclopentanyl ring.

2. A compound as claimed in claim 1 , which is:

1-(3-cyclopropyl-4-methyl-2-{[4-(1-pyrrolidinylcarbonyl)phenyl]imino}-2,3-dihydro-1 ,3- thiazol-5-yl)ethanone

1-(3-cyclopropyl-4-methyl-2-{[4-(1-piperidinylcarbonyl)phenyl]imino}-2,3-dihydro-1 ,3- thiazol-5-yl)ethanone

1-(3-cyclopropyl-4-methyl-2-{[4-(4-morpholinylcarbonyl)phenyl]imino}-2,3-dihydro-1 ,3- thiazol-5-yl)ethanone 1-(4-{[5-acetyl-3-cyclopropyl-4-methyl-1 ,3-thiazol-2(3H)-ylidene]amino}phenyl)-2- pyrrolidinone ethyl 4-{[5-acetyl-3-ethyl-4-methyl-1 ,3-thiazol-2(3H)-ylidene]amino}benzoate

1-(3-ethyl-4-methyl-2-{[4-(1-pyrrolidinylcarbonyl)phenyl]imino}-2,3-dihydro-1 ,3-thiazol-5- yl)ethanone 1-(3-ethyl-4-methyl-2-{[4-(4-methyl-1-piperazinyl)phenyl]imino}-2,3-dihydro-1 ,3-thiazol-5- yl)ethanone

1-(4-{[5-acetyl-3-cyclopropyl-4-methyl-1 ,3-thiazol-2(3H)-ylidene]amino}phenyl)-2- piperidinone

1-(3-ethyl-4-methyl-2-{[4-(1 _!3-oxazol-5-yl)phenyl]imino}-2,3-dihydro-1 ,3-thiazol-5- yl)ethanone

1-(3-ethyl-2-{[4-(1 H-imidazol-1-yl)phenyl]imino}-4-methyl-2,3-dihydro-1 ,3-thiazol-5- yl)ethanone

1-[3-ethyl-4-methyl-2-({4-[3-(trifluoromethyl)-1 H-pyrazol-1-yl]phenyl}imino)-2,3-dihydro-

1 ,3-thiazol-5-yl]ethanone i-p-ethyM-methyl^-^-p-CtrifluoromethylH.S.^β.y-tetrahydro-I H-indazol-i- yl]phenyl}imino)-2,3-dihydro-1 ,3-thiazol-5-yl]ethanone

1-[3-ethyl-4-methyl-2-({4-[3-(trifluoromethyl)-6,7-dihydropyrano[4,3-c]pyrazol-1 (4H)- yl]phenyl}imino)-2,3-dihydro-1 ,3-thiazol-5-yl]ethanone

1-(3-ethyl-4-methyl-2-{[4-(3-thienyl)phenyl]imino}-2,3-dihydro-1 ,3-thiazol-5-yl)ethanone 1-[3-ethyl-2-({4-[(3-hydroxy-1-pyrrolidinyl)carbonyl]phenyl}imino)-4-methyl-2,3-dihydro-1 ,3- thiazol-5-yl]ethanone

1-{3-ethyl-4-methyl-2-[(4-{[3-(methylamino)-1-pyrrolidinyl]carbonyl}phenyl)imino]-2,3- dihydro-1 ,3-thiazol-5-yl}ethanone

4-{[5-acetyl-3-ethyl-4-methyl-1 ,3-thiazol-2(3H)-ylidene]amino}-N-(2-hydroxyethyl)-N- methylbenzamide

1-[3-cyclopropyl-2-({4-[(3-hydroxy-1-pyrrolidinyl)carbonyl]phenyl}imino)-4-methyl-2,3- dihydro-1 ,3-thiazol-5-yl]ethanone

1-{3-cyclopropyl-4-methyl-2-[(4-{[3-(methylamino)-1-pyrrolidinyl]carbonyl}phenyl)imino]-

2,3-dihydro-1 ,3-thiazol-5-yl}ethanone 4-{[5-acetyl-3-cyclopropyl-4-methyl-1 ,3-thiazol-2(3H)-ylidene]amino}-N-(2-hydroxyethyl)-

N-methylbenzamide

4-{[5-acetyl-3-cyclopropyl-4-methyl-1 ,3-thiazol-2(3H)-ylidene]amino}-N-ethylbenzamide

4-{[5-acetyl-3-cyclopropyl-4-methyl-1 ,3-thiazol-2(3H)-ylidene]amino}-N,N- diethylbenzamide 1-(4-{[5-acetyl-3-ethyl-4-methyl-1 ,3-thiazol-2(3H)-ylidene]amino}phenyl)-N- methylmethanesulfonamide

1-(4-{[5-acetyl-3-ethyl-4-methyl-1 _!3-thiazol-2(3H)-ylidene]amino}phenyl)-N,N- dimethylmethanesulfonamide 1-(3-cyclopropyl-4-methyl-2-{[4-(5-methyl-2-thienyl)phenyl]imino}-2,3-dihydro-1 ,3-thiazol-

5-yl)ethanone

1-(3-cyclopropyl-4-methyl-2-{[4-(3-methyl-2-thienyl)phenyl]imino}-2,3-dihydro-1 ,3-thiazol-

5-yl)ethanone

1-(3-cyclopropyl-2-{[4-(3,5-dimethyl-4-isoxazolyl)phenyl]imino}-4-methyl-2,3-dihydro-1 ,3- thiazol-5-yl)ethanone

1-(3-cyclopropyl-4-methyl-2-{[4-(1 _!2_!3-thiadiazol-4-yl)phenyl]imino}-2_!3-dihydro-1 ,3- thiazol-5-yl)ethanone

^(S-cyclopropyW-methyl^-^^I H-i ^^-triazol-i-yOphenyφmino^.S-dihydro-I .S- thiazol-5-yl)ethanone 1-(3-ethyl-4-methyl-2-{[4-(methylsulfonyl)phenyl]imino}-2_!3-dihydro-1 ,3-thiazol-5- yl)ethanone

1-[3-ethyl-4-methyl-2-({4-[2-oxo-2-(1-pyrrolidinyl)ethyl]phenyl}imino)-2_!3-dihydro-1 ,3- thiazol-5-yl]ethanone

1-[3-ethyl-2-({4-[2-(3-hydroxy-1-pyrrolidinyl)-2-oxoethyl]phenyl}imino)-4-methyl-2,3- dihydro-1 ,3-thiazol-5-yl]ethanone

(4-{[5-acetyl-3-ethyl-4-methyl-1 ,3-thiazol-2(3H)-ylidene]amino}phenyl)acetonitrile

1-(3-ethyl-4-methyl-2-{[4-(1 H-pyrazol-1-yl)phenyl]imino}-2_!3-dihydro-1 ,3-thiazol-5- yl)ethanone

3-(2-hydroxyethyl)-N_!N_!4-trimethyl-2-{[4-(1 H-pyrazol-1-yl)phenyl]imino}-2_!3-dihydro-1 ,3- thiazole-5-carboxamide

1-[3-(2-hydroxyethyl)-4-methyl-2-({4-[3-(trifluoromethyl)-1 H-pyrazol-1-yl]phenyl}imino)-2,3- dihydro-1 ,3-thiazol-5-yl]ethanone

4-{[5-acetyl-3-(2-hydroxyethyl)-4-methyl-1 _!3-thiazol-2(3H)-ylidene]amino}-N,N- dimethylbenzamide 1-[2-(4-biphenylylimino)-3-cyclopropyl-4-methyl-2,3-dihydro-1 ,3-thiazol-5-yl]ethanone

3-ethyl-N_!N_!4-trimethyl-2-{[4-(1 H-pyrazol-1-yl)phenyl]imino}-2_!3-dihydro-1 ,3-thiazole-5- carboxamide

1-[2-(4-biphenylylimino)-3-(2-hydroxyethyl)-4-methyl-2,3-dihydro-1 ,3-thiazol-5-yl]ethanone

1-[2-{[4-(2-fluoro-6-methyl-3-pyridinyl)phenyl]imino}-3-(2-hydroxyethyl)-4-methyl-2,3- dihydro-1 ,3-thiazol-5-yl]ethanone

1 ,1-dimethylethyl [(4-{[5-acetyl-3,4-dimethyl-1 ,3-thiazol-2(3H)- ylidene]amino}phenyl)methyl]carbamate

1-[2-{[4-(6-fluoro-3-pyridinyl)phenyl]imino}-3-(2-hydroxyethyl)-4-methyl-2_!3-dihydro-1 ,3- thiazol-5-yl]ethanone 1-[2-{[4-(3-furanyl)phenyl]imino}-3-(2-hydroxyethyl)-4-methyl-2_!3-dihydro-1 ,3-thiazol-5- yl]ethanone

1-(3-(2-hydroxyethyl)-4-methyl-2-{[4-(2-methyl-3-pyridinyl)phenyl]imino}-2_!3-dihydro-1 ,3- thiazol-5-yl)ethanone N-[(4-{[5-acetyl-3-ethyl-4-methyl-1 ,3-thiazol-2(3H)- ylidene]amino}phenyl)methyl]methanesulfonamide

N-[(4-{[5-acetyl-3-ethyl-4-methyl-1 ,3-thiazol-2(3H)-ylidene]amino}phenyl)methyl]acetamide

1-[2-{[4-(2-chloro-3-pyridinyl)phenyl]imino}-3-(2-hydroxyethyl)-4-methyl-2_!3-dihydro-1 ,3- thiazol-5-yl]ethanone

1-[2-(3_!4-dihydro-1 H-2-benzopyran-6-ylimino)-3-(2-hydroxyethyl)-4-methyl-2,3-dihydro-

1 ,3-thiazol-5-yl]ethanone

3-ethyl-2-{[4-(2-fluoro-3-pyridinyl)phenyl]imino}-N_!N_!4-trimethyl-2_!3-dihydro-1 ,3-thiazole-5- carboxamide 3-ethyl-N_!N_!4-trimethyl-2-{[4-(2-methyl-3-pyridinyl)phenyl]imino}-2_!3-dihydro-1 ,3-thiazole-

5-carboxamide

1-(3-ethyl-4-methyl-2-{[4-(4-morpholinylmethyl)phenyl]imino}-2,3-hydro-1 ,3-thiazol-5- yl)ethanone

2-[(4'-fluoro-4-biphenylyl)imino]-3-(2-hydroxyethyl)-N_!N_!4-trimethyl-2_!3-dihydro-1 ,3- thiazole- 5-carboxamide

3-ethyl-N_!N_!4-trimethyl-2-{[4-(6-methyl-3-pyridinyl)phenyl]imino}-2_!3-dihydro-1 ,3-thiazole-

5-carboxamide

3-(2-hydroxyethyl)-N_!N,4-trimethyl-2-{[4-(6-methyl-3-pyridinyl)phenyl]imino}-2,3-dihydro-

1 ,3-thiazole- 5-carboxamide 1-(3-(2-hydroxyethyl)-4-methyl-2-{[4-(1 H-pyrazol-1-yl)phenyl]imino}-2,3-dihydro-1 ,3- thiazol-5-yl)ethanone

N-(4-{[5-acetyl-3,4-dimethyl-1 ,3-thiazol-2(3H)-ylidene]amino}phenyl)acetamide

N-(4-{[5-acetyl-3-ethyl-4-methyl-1 ,3-thiazol-2(3H)-ylidene]amino}phenyl)acetamide

N-(4-{[5-acetyl-3-(2-hydroxyethyl)-4-methyl-1 ,3-thiazol-2(3H)- ylidene]amino}phenyl)acetamide

1-[2-(2,3-dihydro-1 H-inden-5-ylimino)-3-(2-hydroxyethyl)-4-methyl-2_!3-dihydro-1 ,3-thiazol-

5-yl]ethanone

1-[(4-{[5-acetyl-3-ethyl-4-methyl-1 ,3-thiazol-2(3H)-ylidene]amino}phenyl)methyl]-2- pyrrolidinone 3-(2-hydroxyethyl)-N,N_!4-trimethyl-2-{[4'-(methyloxy)-4-biphenylyl]imino}-2,3-dihydro-1 ,3- thiazole- 5-carboxamide

1-[3-ethyl-4-methyl-2-({4-[(4-methyl-1-piperazinyl)carbonyl]phenyl}imino)-2,3-dihydro-1 ,3- thiazol-5-yl]ethanone

4-{[5-acetyl-3-(2-hydroxyethyl)-4-methyl-1 ,3-thiazol-2(3H)-ylidene]amino}benzonitrile or a salt thereof.

3. A compound of formula (I) as defined in claim 1 or a pharmaceutically acceptable salt thereof.

4. A compound as claimed in claim 3 for use as a medicament.

5. A compound as claimed in claim 3 for use in the treatment of a disease or condition caused by a reduction or imbalance in glutamate receptor function in a mammal.

6. A compound as claimed in claim 3 for use in the treatment of schizophrenia.

7. A pharmaceutical composition comprising a compound as defined in claim 3 and at least one pharmaceutically acceptable carrier or diluent.

8. A combination product comprising a compound as defined in claim 3 and an antipsychotic.

9. Use of a compound as defined in claim 3, or a composition as defined in claim 7, or a product as defined in claim 8, in the manufacture of a medicament for treating or preventing a disease or a condition caused by a reduction or imbalance in glutamate receptor function.

10. Use as claimed in claim 9 wherein the disease is schizophrenia.

11. A method of treating a disease or condition caused by a reduction or imbalance in glutamate receptor function in a mammal comprising administering an effective amount of a compound as defined in claim 3, or a composition as defined in claim 7, or a product as defined in claim 8.

12. A method as claimed in claim 1 1 wherein the disease is schizophrenia.