Imidazole derivatives Number:7,153,874 from the United States Patent and Trademark Office (PTO) owispatent

Title: Imidazole derivatives

Abstract: The present invention provides 4-[1-Aryl-imidazol-4-ylethynyl]-2-alkyl-pyridine and 1-heteroaryl-imidazol-4-ylethynyl]-2-alkyl-pyridine derivatives and pharmaceutically acceptable salts thereof for the treatment or prevention of disorders mediated in full or in part by metabotropic glutamate receptor 5. These disorders include, e.g. acute, traumatic and chronic degenerative processes of the nervous system, such as Alzheimer's disease, senile dementia, Parkinson's disease, Huntington's chorea, amyotrophic lateral sclerosis and multiple sclerosis, psychiatric diseases, such as schizophrenia and anxiety, depression, pain and drug dependency.

Patent Number: 7,153,874 Issued on 12/26/2006 to Buettelmann,   et al.

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Inventors:	Buettelmann; Bernd (Schopfheim, DE), Ceccarelli; Simona Maria (Basel, CH), Jaeschke; Georg (Basel, CH), Kolczewski; Sabine (Rheinfelden, DE), Porter; Richard Hugh Philip (Reinach, CH), Vieira; Eric (Allschwil, CH)
Assignee:	Hoffmann-La Roche Inc. (Nutley, NJ)
Appl. No.:	10/795,619
Filed:	March 8, 2004

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Foreign Application Priority Data

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Mar 10, 2003 [EP]			03004952

Current U.S. Class:	514/341 ; 546/272.7; 546/275.1
Current International Class:	A61K 31/4439 (20060101); A61K 31/4178 (20060101); C07D 401/06 (20060101)
Field of Search:	546/272.7,275.1 514/341

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References Cited [Referenced By]

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U.S. Patent Documents

	3303199		February 1967		Doebel et al.
	3341548		September 1967		Hoffer
	4352818		October 1982		Hunkeler et al.
	4711962		December 1987		Leone-Bay
	2004/0259917		December 2004		Cosford et al.

Foreign Patent Documents

	2035905		Feb., 1972		DE
	059 390		Sep., 1982		EP
	0 304 910		Mar., 1989		EP
	WO 91/00277		Jan., 1991		WO
	WO 99/02497		Jan., 1999		WO
	WO 99/08678		Feb., 1999		WO
	WO 01/16121		Mar., 2001		WO
	WO 02/46166		Jun., 2002		WO

Other References

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Primary Examiner: Morris; Patricia L.
Attorney, Agent or Firm: Johnston; George W. Rocha-Tramaloni; Patricia S. Prior; Kimberly J.

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Claims

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The invention claimed is:

1. A compound of formula I ##STR00023## wherein R.sup.1 is C.sub.1 C.sub.6alkyl; R.sup.2 is C.sub.1 C.sub.6alkyl or C.sub.3 C.sub.12cycloalkyl; R.sup.3 is aryl that is unsubstituted or substituted by one, two or three substituents selected from halogen, C.sub.1 C.sub.6alkyl, S--C.sub.1 C.sub.6alkyl, C.sub.1 C.sub.6alkyl-halogen, C.sub.1 C.sub.6alkoxy, halogen-C.sub.1 C.sub.6alkoxy, C.sub.3 C.sub.12cycloalkyl, C.sub.1 C.sub.6alkylamino, di-C.sub.1 C.sub.6alkylamino, C.sub.1 C.sub.6alkoxyamino, (C.sub.1 C.sub.6alkoxy)C.sub.1 C.sub.6alkylamino, C.sub.3 C.sub.12cycloalkylamino, benzylamino and cyano; and R.sup.4 is hydrogen, C(O)H or CH.sub.2R.sup.5 wherein R.sup.5 is hydrogen, OH, C.sub.1 C.sub.6alkyl or C.sub.3 C.sub.12cycloalkyl or a pharmaceutically acceptable salt thereof.

2. The compound of formula I according to claim 1 wherein R.sup.1 is methyl.

3. The compound of formula I according to claim 1 wherein R.sup.2 is C.sub.1 C.sub.6alkyl.

4. The compound of formula I according to claim 3 wherein R.sup.2 is methyl or isopropyl.

5. The compound of formula I according to claim 1 wherein R.sup.2 is cycloalkyl.

6. The compound of formula I according to claim 5 wherein R.sup.2 is cyclopropyl.

7. The compound of formula I according to claim 1 wherein R.sup.3 is unsubstituted aryl or aryl substituted by one, two or three substituents selected from halogen, C.sub.1 C.sub.6alkyl, S--C.sub.1 C.sub.6alkyl, C.sub.1 C.sub.6alkyl-halogen, C.sub.1 C.sub.6alkoxy, halogen-C.sub.1 C.sub.6alkoxy, C.sub.3 C.sub.12cycloalkyl, C.sub.1 C.sub.6alkylamino, di-C.sub.1 C.sub.6alkylamino, C.sub.1 C.sub.6alkoxyamino, (C.sub.1 C.sub.6alkoxy)C.sub.1 C.sub.6alkylamino, C.sub.3 C.sub.12cycloalkylamino, and cyano.

8. The compound of formula I according to claim 1 wherein R.sup.3 is unsubstituted aryl or aryl substituted by benzylamino.

9. The compound of formula I according to claim 1 wherein R.sup.4 is hydrogen, C(O)H or CH.sub.3.

10. The compound of formula I according to claim 1 wherein R.sup.3 is unsubstituted phenyl or phenyl substituted by one, two or three substituents selected from halogen, C.sub.1 C.sub.6alkyl, S--C.sub.1 C.sub.6alkyl, C.sub.1 C.sub.6alkyl-halogen, C.sub.1 C.sub.6alkoxy, halogen-C.sub.1 C.sub.6alkoxy, C.sub.3 C.sub.12cycloalkyl, C.sub.1 C.sub.6alkylamino, di-C.sub.1 C.sub.6alkylamino, C.sub.1 C.sub.6alkoxyamino, (C.sub.1 C.sub.6alkoxy)C.sub.1 C.sub.6alkylamino, C.sub.3 C.sub.12cycloalkylamino, benzylamino and cyano.

11. The compound of formula I according to claim 10 wherein R.sup.3 is unsubstituted phenyl or phenyl substituted by one or two substituents selected from halogen, C.sub.1 C.sub.6alkyl, C.sub.1 C.sub.6alkyl-halogen, C.sub.1 C.sub.6alkoxy, halogen-C.sub.1 C.sub.6alkoxy, and cyano.

12. The compound of formula I according to claim 11 wherein R.sup.3 is unsubstituted phenyl or phenyl substituted by one or two substituents selected from fluoro, chloro, methyl, trifluoromethyl, methoxy, trifluoromethoxy, and cyano.

13. The compound of formula I according to claim 10 wherein R.sup.3 is fluorophenyl, difluorophenyl, chlorophenyl, dichlorophenyl, cyanophenyl, trifluoromethylphenyl, fluoro-methylphenyl, chloro-fluorophenyl, methylphenyl, methoxyphenyl or trifluoromethoxyphenyl.

14. The compound according to claim 1 having the formula I* ##STR00024## wherein R.sup.1 signifies lower alkyl; R.sup.2 signifies lower alkyl; R.sup.3 signifies aryl optionally substituted, by one, two or three substituents, selected from the group consisting of halogen, lower alkyl, lower alkyl-halogen or cyano.

15. The compound according to claim 14 where R.sup.1 and R.sup.2 are both methyl.

16. The compound according to claim 14 wherein R.sup.3 is substituted phenyl.

17. The compound according to claim 16 wherein the substitution is selected from fluoro, chloro, cyano, and trifluoromethyl.

18. The compound according to claim 1 selected from 4-[1-(4-fluoro-phenyl)-2-methyl-1H-imidazol-4-ylethynyl]-2-methyl-pyridin- e, 4-[1-(3,4-dichloro-phenyl)-2-methyl-1H-imidazol-4-ylethynyl]-2-methyl-p- yridine hydrochloride, 4-[1-(2,4-difluoro-phenyl)-2-methyl-1H-imidazol-4-ylethynyl]-2-methyl-pyr- idine, 4-[1-(3,4-difluoro-phenyl)-2-methyl-1H-imidazol-4-ylethynyl]-2-meth- yl-pyridine, 2-methyl-4-[2-methyl-1-(3-trifluoromethyl-phenyl)-1H-imidazol-4-ylethynyl- ]-pyridine.

19. The compound according to claim 1 selected from 4-[1-(4-fluoro-phenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]-2-methyl-pyr- idine, and 3-(4-fluoro-phenyl)-2-methyl-5-(2-methyl-pyridin-4-ylethynyl)-3- H-imidazole-4-carbaldehyde.

20. The compound according to claim 1 selected from 4-[1-(4-chloro-phenyl)-2-methyl-1H-imidazol-4-ylethynyl]-2-methyl-pyridin- e, 4-[2-cyclopropyl-1-(4-fluoro-phenyl)-1H-imidazol-4-ylethynyl]-2-methyl-- pyridine, 4-[1-(3-fluoro-phenyl)-2-methyl-1H-imidazol-4-ylethynyl]-2-methy- l-pyridine, 4-[1-(3,5-difluoro-phenyl)-2-methyl-1H-imidazol-4-ylethynyl]-2-methyl-pyr- idine, 4-[1-(3-fluoro-4-methyl-phenyl)-2-methyl-1H-imidazol-4-ylethynyl]-2- -methyl-pyridine, 4-[1-(3-chloro-4-fluoro-phenyl)-2-methyl-1H-imidazol-4-ylethynyl]-2-methy- l-pyridine, 2-methyl-4-(2-methyl-1-p-tolyl-1H-imidazol-4-ylethynyl)-pyridine, 4-[1-(4-methoxy-phenyl)-2-methyl-1H-imidazol-4-ylethynyl]-2-methyl-pyridi- ne, 2-methyl-4-[2-methyl-1-(4-trifluoromethyl-phenyl)-1H-imidazol-4-ylethy- nyl]-pyridine.

21. A composition comprising a compound of formula I ##STR00025## wherein R.sup.1 is C.sub.1 C.sub.6alkyl; R.sup.2 is C.sub.1 C.sub.6alkyl or C.sub.3 C.sub.12cycloalkyl; R.sup.3 is aryl that is unsubstituted or substituted by one, two or three substituents selected from halogen, C.sub.1 C.sub.6alkyl, S--C.sub.1 C.sub.6alkyl, C.sub.1 C.sub.6alkyl-halogen, C.sub.1 C.sub.6alkoxy, halogen-C.sub.1 C.sub.6alkoxy, C.sub.3 C.sub.12cycloalkyl,heterocycloalkyl, C.sub.1 C.sub.6alkylamino, di-C.sub.1 C.sub.6alkylamino, C.sub.1 C.sub.6alkoxyamino, (C.sub.1 C.sub.6alkoxy) C.sub.1 C.sub.6alkylamino, C.sub.3 C.sub.12cycloalkylamino, benzylamino and cyano; and R.sup.4 is hydrogen, C(O)H or CH.sub.2R.sup.5 wherein R.sup.5 is hydrogen, OH, C.sub.1 C.sub.6alkyl or C.sub.3 C.sub.12cycloalkyl and a pharmaceutically acceptable carrier.

22. A composition of claim 21 comprising a compound of formula I* ##STR00026## wherein R.sup.1 signifies lower alkyl; R.sup.2 signifies lower alkyl; R.sup.3 signifies aryl, optionally substituted, by one, two or three substituents, selected from the group consisting of halogen, lower alkyl, lower alkyl-halogen or cyano; and a pharmaceutically acceptable carrier.

23. A process for the production of a compound of formula I ##STR00027## wherein R.sup.1 is C.sub.1 C.sub.6alkyl; R.sup.2 is C.sub.1 C.sub.6alkyl or C.sub.3 C.sub.12cycloalkyl; R.sup.3 is aryl that is unsubstituted or substituted by one, two or three substituents selected from halogen, C.sub.1 C.sub.6alkyl, S--C.sub.1 C.sub.6alkyl, C.sub.1 C.sub.6alkyl-halogen, C.sub.1 C.sub.6alkoxy, halogen-C.sub.1 C.sub.6alkoxy, C.sub.3 C.sub.12cycloalkyl, C.sub.1 C.sub.6alkylamino, di-C.sub.1 C.sub.6alkylamino, C.sub.1 C.sub.6alkoxyamino, (C.sub.1 C.sub.6alkoxy) C.sub.1 C.sub.6alkylamino, C.sub.3 C.sub.12cycloalkylamino, benzylamino and cyano; and R.sup.4 is hydrogen, C(O)H or CH.sub.2R.sup.5 wherein R.sup.5 is hydrogen, OH, C.sub.1 C.sub.6alkyl or C.sub.3 C.sub.12cycloalkyl which process comprises reactinga compound of formula II ##STR00028## wherein R.sup.1, R.sup.2 and R.sup.4 are as defined above, with a compound of formula III R.sup.3--Z (III) wherein R.sup.3 has the above meaning and Z is halogen or B(OH).sub.2.

24. A process for the production of a compound of formula I ##STR00029## wherein R.sup.1 is C.sub.1 C.sub.6alkyl; R.sup.2 is C.sub.1 C.sub.6alkyl or C.sub.3 C.sub.12cycloalkyl; R.sup.3 is aryl that is unsubstituted or substituted by one, two or three substituents selected from halogen, C.sub.1 C.sub.6alkyl, S--C.sub.1 C.sub.6alkyl, C.sub.1 C.sub.6alkyl-halogen, C.sub.1 C.sub.6alkoxy, halogen-C.sub.1 C.sub.6alkoxy, C.sub.3 C.sub.12cycloalkyl, C.sub.1 C.sub.6alkylamino, di-C.sub.1 C.sub.6alkylamino, C.sub.1 C.sub.6alkoxyamino, (C.sub.1 C.sub.6alkoxy) C.sub.1 C.sub.6alkylamino, C.sub.3 C.sub.12cycloalkylamino, benzylamino and cyano; and R.sup.4 is hydrogen, C(O)H or CH.sub.2R.sup.5 wherein R.sup.5 is hydrogen, OH, C.sub.1.sub.1 C.sub.6alkyl or C.sub.3 C.sub.12cycloalkyl which process comprises reacting a compound of formula IV ##STR00030## wherein R.sup.2, R.sup.3 and R.sup.4 have the meaning as defined above, with a compound of formula V ##STR00031## wherein R.sup.1 has the above meaning and X is halogen.

25. A process for the production of a compound of formula I ##STR00032## wherein R.sup.1 is C.sub.1 C.sub.6alkyl; R.sup.2 is C.sub.1 C.sub.6alkyl or C.sub.3 C.sub.12cycloalkyl; R.sup.3 is aryl that is unsubstituted or substituted by one, two or three substituents selected from halogen, C.sub.1 C.sub.6alkyl, S--C.sub.1 C.sub.6alkyl, C.sub.1 C.sub.6alkyl-halogen, C.sub.1 C.sub.6alkoxy, halogen-C.sub.1 C.sub.6alkoxy, C.sub.3 C.sub.12cycloalkyl, C.sub.1 C.sub.6alkylamino, di-C.sub.1 C.sub.6alkylamino, C.sub.1 C.sub.6alkoxyamino, (C.sub.1 C.sub.6alkoxy) C.sub.1 C.sub.6alkylamino, C.sub.3 C.sub.12cycloalkylamino, benzylamino and cyano; and R.sup.4 is hydrogen, C(O)H or CH.sub.2R.sup.5 wherein R.sup.5 is hydrogen, OH, C.sub.1 C.sub.6alkyl or C.sub.3 C.sub.12cycloalkyl which process comprises reacting a compound of formula VI ##STR00033## wherein R.sup.2, R.sup.3 and R.sup.4 have the meanings as defined above and hal is halogen, with a compound of formula VII ##STR00034## wherein R.sup.1 has the above meaning.

26. A method of treating anxiety comprising administering a therapeutically effective amount of a compound of formula I ##STR00035## wherein R.sup.1 is C.sub.1 C.sub.6alkyl; R.sup.2 is C.sub.1 C.sub.6alkyl or C.sub.3 C.sub.12cycloalkyl; R.sup.3 is aryl that is unsubstituted or substituted by one, two or three substituents selected from halogen, C.sub.1 C.sub.6alkyl, S--C.sub.1 C.sub.6alkyl, C.sub.1 C.sub.6alkyl-halogen, C.sub.1 C.sub.6alkoxy, halogen-C.sub.1 C.sub.6alkoxy, C.sub.3 C.sub.12cycloalkyl, C.sub.1 C.sub.6alkylamino, di-C.sub.1 C.sub.6alkylamino, C.sub.1 C.sub.6alkoxyamino, (C.sub.1 C.sub.6alkoxy) C.sub.1 C.sub.6alkylamino, C.sub.3 C.sub.12cycloalkylamino, benzylamino and cyano; and R.sup.4 is hydrogen, C(O)H or CH.sub.2R.sup.5 wherein R.sup.5 is hydrogen, OH, C.sub.1 C.sub.6alkyl or C.sub.3 C.sub.12cycloalkyl.

27. The method of claim 26 wherein the compound is a compound of formula I* ##STR00036## wherein R.sup.1 signifies lower alkyl; R.sup.2 signifies lower alkyl; R.sup.3 signifies aryl, optionally substituted, by one, two or three substituents, selected from the group consisting of halogen, lower alkyl, lower alkyl-halogen or cyano.

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Description

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FIELD OF THE INVENTION

The present invention relates to metabotropic glutamate receptor 5 antagonists and treatment of mGluR5 mediated diseases.

BACKGROUND OF THE INVENTION

In the central nervous system (CNS) the transmission of stimuli takes place by the interaction of a neurotransmitter, which is sent out by a neuron, with a neuroreceptor.

Glutamate is the major excitatory neurotransmitter in the brain and plays a unique role in a variety of central nervous system (CNS) functions. The glutamate-dependent stimulus receptors are divided into two main groups. The first main group, namely the ionotropic receptors, forms ligand-controlled ion channels. The metabotropic glutamate receptors (mGluR) belong to the second main group and, furthermore, belong to the family of G-protein coupled receptors.

At present, eight different members of these mGluR are known and of these some even have sub-types. According to their sequence homology, signal transduction mechanisms and agonist selectivity, these eight receptors can be sub-divided into three sub-groups:

mGluR1 and mGluR5 belong to group I, mGluR2 and mGluR3 belong to group II and mGluR4, mGluR6, mGluR7 and mGluR8 belong to group III.

Ligands of metabotropic glutamate receptors belonging to the first group can be used for the treatment or prevention of acute and/or chronic neurological disorders such as psychosis, epilepsy, schizophrenia, Alzheimer's disease, cognitive disorders and memory deficits, as well as chronic and acute pain.

Other treatable indications in this connection are restricted brain function caused by by-pass operations or transplants, poor blood supply to the brain, spinal cord injuries, head injuries, hypoxia caused by pregnancy, cardiac arrest and hypoglycaemia. Further treatable indications are ischemia, Huntington's chorea, amyotrophic lateral sclerosis (ALS), dementia caused by AIDS, eye injuries, retinopathy, idiopathic parkinsonism or parkinsonism caused by medicaments as well as conditions which lead to glutamate-deficiency functions, such as e.g. muscle spasms, convulsions, migraine, urinary incontinence, drug abuse/dependence such as nicotine addiction, opiate addiction, and alcohol abuse, anxiety, vomiting, dyskinesia and depressions.

Disorders mediated full or in part by mGluR5 are for example acute, traumatic and chronic degenerative processes of the nervous system, such as Alzheimer's disease, senile dementia, Parkinson's disease, Huntington's chorea, amyotrophic lateral sclerosis and multiple sclerosis, psychiatric diseases such as schizophrenia and anxiety, depression, pain and drug dependency [Expert Opin. Ther. Patents 12:12 (2002)].

Selective mGluR5 antagonists are especially useful for the treatment of anxiety and pain.

SUMMARY OF THE INVENTION

The present invention relates to novel imidazole derivatives, to processes for their production, to pharmaceutical compositions containing them, and to methods of treating or preventing mGluR5 mediated diseases.

More particularly the present invention provides in a first aspect novel 4-[1-aryl and 1-heteroaryl-imidazol-4-ylethynyl]-2-alkyl-pyridine derivatives as well as pharmaceutically acceptable salts thereof.

More particularly the present invention provides a compound of formula I

##STR00001## wherein R.sup.1 is C.sub.1 C.sub.6alkyl; R.sup.2 is C.sub.1 C.sub.6alkyl or C.sub.3 C.sub.12cycloalkyl; R.sup.3 is aryl or heteroaryl, wherein the aryl or heteroaryl is unsubstituted or substituted by one, two or three substituents selected from halogen, C.sub.1 C.sub.6alkyl, S--C.sub.1 C.sub.6alkyl, C.sub.1 C.sub.6alkyl-halogen, C.sub.1 C.sub.6alkoxy, halogen-C.sub.1 C.sub.6alkoxy, C.sub.3 C.sub.12cycloalkyl, C.sub.2 C.sub.11heterocycloalkyl, C.sub.1 C.sub.6alkylamino, di-C.sub.1 C.sub.6alkylamino, C.sub.1 C.sub.6alkoxyamino, (C.sub.1 C.sub.6alkoxy) C.sub.1 C.sub.6alkylamion, C.sub.3 C.sub.12cycloalkylamino, benzylamino and cyano; and R.sup.4 is hydrogen, C(O)H or CH.sub.2R.sup.5 wherein R.sup.5 is hydrogen, OH, C.sub.1 C.sub.6alkyl or C.sub.3 C.sub.12cycloalkyl.

In one embodiment the present invention provides a compound of formula I*

##STR00002## wherein R.sup.1 is lower alkyl; R.sup.2 is lower alkyl; R.sup.3 is aryl or heteroaryl, optionally substituted, by one, two or three substituents, selected from the group consisting of halogen, lower alkyl, lower alkyl-halogen and cyano; or a pharmaceutically acceptable salt thereof.

It has now surprisingly been found that the compounds of general formula I are metabotropic glutamate receptor 5 antagonists. They have valuable therapeutic properties and can be used in the treatment or prevention of mGluR5 receptor mediated disorders. Thus, in another aspect, the present invention provides pharmaceutical compositions containing compounds of the invention and methods for treating or preventing mGluR5 receptor mediated disorders.

In a further aspect, the present invention provides methods for the manufacture of compounds of formula I.

DETAILED DESCRIPTION OF THE INVENTION

The following definitions of general terms used in the present description apply irrespective of whether the terms in question appear alone or in combination.

The term "lower alkyl" used in the present description denotes straight-chain or branched saturated hydrocarbon residues with 1 to 6 carbon atoms, preferably with 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl and the like.

The term "cycloalkyl" used in the present description denotes cyclic saturated hydrocarbon residues with 3 to 12 carbon atoms. Examples for cycloalkyl include cyclopropyl, cyclobutyl and cyclopentyl.

The term "lower alkoxy" denotes a group wherein the alkyl residue is as defined above, and which is attached via an oxygen atom. Examples for C.sub.1 C.sub.6alkoxy include methoxy, methoxyethyl and methoxyethoxy. Examples for halogenmethoxy include trifluoromethoxy.

The term "C.sub.2 C.sub.11 heterocycloalkyl" refers to a nonaromatic group containing one individual ring, or one or more fused rings having from two to eleven carbon atoms in which at least one ring contains one or more heteroatoms selected from N, O, and S. Examples for C.sub.2 C.sub.11 heterocycloalkyl include pyrrolidinyl, morpholinyl and thiomorpholinyl.

The term "alkylamino" denotes an amine group, NH.sub.2, in which one of the hydrogen atoms has been replaced with an alkyl residue or cycloalkyl residue as defined above. The term "dialkylamino" denotes an amine group in which both of the hydrogen atoms have been replaced with an alkyl residue or cycloalkyl residue as defined above. The two alkyl groups attached to the nitrogen atom can be the same or different. Examples for C.sub.1 C.sub.6alkylamino include methylamino and ethylamino. Examples for di-C.sub.1 C.sub.6alkylamino include dimethylamino.

Examples for C.sub.1 C.sub.6alkoxyamino include methoxyethylamino. Examples for (C.sub.1 C.sub.6alkoxy) C.sub.1 C.sub.6alkylamino include (methoxyethyl)methylamino. Examples for methoxycycloalkylamino include cyclopropylamino.

The term "halogen" denotes fluorine, chlorine, bromine and iodine.

"Aryl" represents an aromatic carbocyclic group consisting of one individual ring, or one or more fused rings in which at least one ring is aromatic in nature. Examples for aryl include phenyl. Examples for substituted aryl include fluorophenyl, difluorophenyl, chlorophenyl, dichlorophenyl, chlorofluorophenyl, cyanophenyl, methylphenyl, methoxyphenyl, fluoromethylphenyl, trifluoromethylphenyl and trifluoromethoxyphenyl.

The term "heteroaryl" refers to an aromatic 5- or 6-membered ring or one or more fused rings containing one or more heteroatoms selected from nitrogen, oxygen or sulphur. Examples of such heteroaryl groups are pyrimidinyl, pyrazinyl, pyridazinyl, pyridinyl and indolyl, e.g. pyridin-4-yl, pyridin-2-yl, pyrazin-2-yl and pyrimidin-2-yl. Examples for substituted heteroaryl include methylpyrimidinyl, dimethylpyrimidinyl, trifluoromethylpyrimidinyl, methoxypyrimidinyl, methoxyethoxypyrimidinyl, ethylpyrimidinyl, fluoropyrimidinyl, chloropyrimidinyl, bromopyrimidinyl, methylsulfanylpyrimidinyl, cyclopropylpyrimidinyl, methylpyrazinyl, cyclopropylpyrazinyl, chloropyrazinyl, methoxypyrazinyl, methoxyethoxypyrazinyl, methylaminopyrazinyl, dimethylaminopyrazinyl, cyclopropylaminopyrazinyl, morpholinylpyrazinyl, fluoropyridinyl, chloropyridinyl, bromopyridinyl, iodopyridinyl, methylpyridinyl, trifluoromethylpyridinyl, trifluoromethylmethylpyridinyl, cyclopropylpyridinyl, butylpyridinyl, methoxypyridinyl, dimethylaminopyridinyl, methylaminopyridinyl, ethylaminopyridinyl, pyrrolidinylpyridinyl, morpholinylpyridinyl, thiomorpholinylpyridinyl, (methoxyethyl)methylaminopyridinyl, methoxyethylaminopyridinyl, benzylaminopyridinyl and methyl-1H-indolyl.

The term "pharmaceutically acceptable salt" refers to any salt derived from an inorganic or organic acid.

"Pharmaceutically acceptable salts" of a compound means salts that are pharmaceutically acceptable, which are generally safe, non-toxic, and neither biologically nor otherwise undesirable, and that possess the desired pharmacological activity of the parent compound. These salts are derived from an inorganic or organic acid. If possible, compounds of formula I may be converted into pharmaceutically acceptable salts.

It should be understood that all references to pharmaceutically acceptable salts include solvent addition forms (solvates) or crystal forms (polymorphs) of the same acid addition salt.

Examples for pharmaceutically acceptable acid addition salts include acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, benzenesulfonic acid, benzoic, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, hydroxynaphthoic acid, 2-hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, muconic acid, 2-naphthalenesulfonic acid, propionic acid, salicylic acid, succinic acid, dibenzoyl-L-tartaric acid, tartaric acid, p-toluene-sulfonic acid, trimethylacetic acid, trifluoroacetic acid, and the like.

The terms "therapeutically inert carrier" and "pharmaceutically acceptable carrier" are used synonymously herein and mean a carrier or excipient that is pharmacologically acceptable, has no therapeutic activity and is substantially non-toxic to the subject to which the particular compound is administered.

"Therapeutically effective amount" means an amount that is effective to prevent, alleviate, or ameliorate symptoms of disease or prolong the survival of the subject being treated.

The present invention relates to novel imidazole derivatives, to processes for their production, their use as pharmaceuticals and to pharmaceutical compositions comprising them. More particularly the present invention provides in a first aspect novel 4-[1-aryl and 1-heteroaryl-imidazol-4-ylethynyl]-2-alkyl-pyridine derivatives as well as pharmaceutically acceptable salts thereof.

More particularly the present invention provides a compound of formula I

##STR00003## wherein R.sup.1 is C.sub.1 C.sub.6alkyl; R.sup.2 is C.sub.1 C.sub.6alkyl or C.sub.3 C.sub.12cycloalkyl; R.sup.3 is aryl or heteroaryl, wherein the aryl or heteroaryl is unsubstituted or substituted by one, two or three substituents selected from halogen, C.sub.1 C.sub.6alkyl, S--C.sub.1 C.sub.6alkyl, C.sub.1 C.sub.6alkyl-halogen, C.sub.1 C.sub.6alkoxy, halogen-C.sub.1 C.sub.6alkoxy, C.sub.3 C.sub.12cycloalkyl, C.sub.2 C.sub.11heterocycloalkyl, C.sub.1 C.sub.6alkylamino, di-C.sub.1 C.sub.6alkylamino, C.sub.1 C.sub.6alkoxyamino, (C.sub.1 C.sub.6alkoxy) C.sub.1 C.sub.6alkylamino, C.sub.3 C.sub.12cycloalkylamino, benzylamino and cyano; and R.sup.4 is hydrogen, C(O)H or CH.sub.2R.sup.5 wherein R.sup.5 is hydrogen, OH, C.sub.1 C.sub.6alkyl or C.sub.3 C.sub.12cycloalkyl.

In one embodiment the present invention provides a compound of formula I*

##STR00004## wherein R.sup.1 is lower alkyl; R.sup.2 is lower alkyl; R.sup.3 is aryl or heteroaryl, optionally substituted, by one, two or three substituents, selected from the group consisting of halogen, lower alkyl, lower alkyl-halogen and cyano; or a pharmaceutically acceptable salt thereof.

Preferred compounds of formula I* are those, in which R.sup.1 and R.sup.2 are both methyl.

Especially preferred are those compounds from this group, in which R.sup.3 is substituted phenyl, wherein the substitution is fluoro, chloro, cyano or CF.sub.3.

The following are examples of compounds, wherein the substitution is fluoro or chloro: 4-[1-(4-fluoro-phenyl)-2-methyl-1H-imidazol-4-ylethynyl]-2-methyl-pyridin- e, 4-[1-(3,4-dichloro-phenyl)-2-methyl-1H-imidazol-4-ylethynyl]-2-methyl-p- yridine, HCl 4-[1-(2,4-difluoro-phenyl)-2-methyl-1H-imidazol-4-ylethynyl]-2-methyl-pyr- idine, or 4-[1-(3,4-difluoro-phenyl)-2-methyl-1H-imidazol-4-ylethynyl]-2-m- ethyl-pyridine.

Examples of compounds, wherein the substitution is cyano, are as follows: 4-[2-methyl-4-(2-methyl-pyridin-4-ylethynyl)-imidazol-1-yl]-benzonitrile, or 3-[2-methyl-4-(2-methyl-pyridin-4-ylethynyl)-imidazol-1-yl]-benzonitri- le.

The following is an example of compounds, wherein the substitution is CF.sub.3: 2-methyl-4-[2-methyl-1-(3-trifluoromethyl-phenyl)-1H-imidazol-4- -ylethynyl]-pyridine.

Especially preferred are further those compounds, wherein R.sup.1 and R.sup.2 are both methyl and R.sup.3 is pyrimidinyl, for example the following compound: 2-[2-methyl-4-(2-methyl-pyridin-4-ylethynyl)-imidazol-1-yl]-pyrimidine.

In one embodiment the present invention provides a compound of formula I wherein R.sup.1 is methyl, and R.sup.2, R.sup.3 and R.sup.4 independently are as defined above or hereinafter.

In one embodiment the present invention provides a compound of formula I wherein R.sup.2 is C.sub.1 C.sub.6alkyl. In another embodiment the present invention provides a compound of formula I wherein R.sup.2 is methyl or isopropyl. In another embodiment the present invention provides a compound of formula I wherein R.sup.2 is cyclopropyl. In all the above embodiments R.sup.1, R.sup.3 and R.sup.4 independently are as defined above or hereinafter.

In one embodiment the present invention provides a compound of formula I wherein R.sup.3 is unsubstituted aryl or aryl substituted by one, two or three substituents selected from halogen, C.sub.1 C.sub.6alkyl, S--C.sub.1 C.sub.6alkyl, C.sub.1 C.sub.6alkyl halogen, C.sub.1 C.sub.6alkoxy, halogen-C.sub.1 C.sub.6alkoxy, C.sub.3 C.sub.12cycloalkyl, C.sub.2 C.sub.11 heterocycloalkyl, C.sub.1 C.sub.6alkylamino, di-C.sub.1 C.sub.6alkylamino, C.sub.1 C.sub.6alkoxyamino, (C.sub.1 C.sub.6alkoxy)C.sub.1 C.sub.6alkylamino, C.sub.3 C.sub.12cycloalkylamino, benzylamino and cyano. In another embodiment R.sup.3 is unsubstituted aryl or aryl substituted by one, two or three substituents selected from halogen, C.sub.1 C.sub.6alkyl, S--C.sub.1 C.sub.6alkyl, C.sub.1 C.sub.6alkyl-halogen, C.sub.1 C.sub.6alkoxy, halogen-C.sub.1 C.sub.6alkoxy, C.sub.3 C.sub.12cycloalkyl, C.sub.1 C.sub.6alkylamino, di-C.sub.1 C.sub.6alkylamino, C.sub.1 C.sub.6alkoxyamino, (C.sub.1 C.sub.6alkoxy)C.sub.1 C.sub.6alkylamino, C.sub.3 C.sub.12cycloalkylamino, and cyano. In yet another embodiment R.sup.3 is unsubstituted aryl or aryl substituted by one, two or three substituents selected from C.sub.2 C.sub.11heterocycloalkyl. In a further embodiment, R.sup.3 is unsubstituted aryl or aryl substituted by benzylamino.

In another embodiment the present invention provides a compound of formula I wherein R.sup.3 is phenyl or phenyl substituted by one, two or three substituents selected from halogen, C.sub.1 C.sub.6alkyl, S--C.sub.1 C.sub.6alkyl, C.sub.1 C.sub.6alkyl-halogen, C.sub.1 C.sub.6alkoxy, halogen-C.sub.1 C.sub.6alkoxy, C.sub.3 C.sub.12cycloalkyl, C.sub.2 C.sub.11heterocycloalkyl, C.sub.1 C.sub.6alkylamino, di-C.sub.1 C.sub.6alkylamino, C.sub.1 C.sub.6alkoxyamino, (C.sub.1 C.sub.6alkoxy)C.sub.1 C.sub.6alkylamino, C.sub.3 C.sub.12cycloalkylamino, benzylamino and cyano. In another embodiment the present invention provides a compound of formula I wherein R.sup.3 is phenyl or phenyl substituted by one or two substituents selected from halogen, C.sub.1 C.sub.6alkyl, C.sub.1 C.sub.6alkyl-halogen, C.sub.1 C.sub.6alkoxy, halogen-C.sub.1 C.sub.6alkoxy and cyano. In another embodiment the present invention provides a compound of formula I wherein R.sup.3 is phenyl substituted by one or two substituents selected from halogen, C.sub.1 C.sub.6alkyl, C.sub.1 C.sub.6alkyl-halogen, C.sub.1 C.sub.6alkoxy, halogen-C.sub.1 C.sub.6alkoxy and cyano. In another embodiment the present invention provides a compound of formula I wherein R.sup.3 is phenyl substituted by one or two substituents selected from fluoro, chloro, methyl, trifluoromethyl, methoxy, trifluoromethoxy and cyano. In another embodiment the present invention provides a compound of formula I wherein R.sup.3 is fluorophenyl, difluorophenyl, chlorophenyl, dichlorophenyl, cyanophenyl, trifluoromethylphenyl, fluoro-methylphenyl, chloro-fluorophenyl, methylphenyl, methoxyphenyl or trifluoromethoxyphenyl.

In all the above embodiments R.sup.1, R.sup.2 and R.sup.4 independently are as defined above or hereinafter.

In one embodiment the present invention provides a compound of formula I wherein R.sup.3 is unsubstituted heteroaryl or heteroaryl substituted by one, two or three substituents selected from the group consisting of halogen, C.sub.1 C.sub.6alkyl, S--C.sub.1 C.sub.6alkyl, C.sub.1 C.sub.6alkyl-halogen, C.sub.1 C.sub.6alkoxy, halogen-C.sub.1 C.sub.6alkoxy, C.sub.3 C.sub.12cycloalkyl, C.sub.2 C.sub.11heterocycloalkyl, C.sub.1 C.sub.6alkylamino,di-C.sub.1 C.sub.6alkylamino, C.sub.1 C.sub.6alkoxyamino, (C.sub.1 C.sub.6alkoxy)C.sub.1 C.sub.6alkylamino, C.sub.3 C.sub.12cycloalkylamino, benzylamino and cyano. In another embodiment, R.sup.3 is unsubstituted heteroaryl or heteroaryl substituted by one, two or three substituents selected from the group consisting of halogen, C.sub.1 C.sub.6alkyl, S--C.sub.1 C.sub.6alkyl, C.sub.1 C.sub.6alkyl-halogen, C.sub.1 C.sub.6alkoxy, halogen-C.sub.1 C.sub.6alkoxy, C.sub.3 C.sub.12cycloalky, C.sub.1 C.sub.6alkylamino, di-C.sub.1 C.sub.6alkylamino, C.sub.1 C.sub.6alkoxyamino, (C.sub.1 C.sub.6alkoxy)C.sub.1 C.sub.6alkylamino, C.sub.3 C.sub.12cycloalkylamino, and cyano. In yet another embodiment, R.sup.3 is unsubstituted heteroaryl or heteroaryl substituted by one, two or three substituents selected from the group consisting of C.sub.2 C.sub.11heterocycloalkyl. In a further embodiment, R.sup.3 is unsubstituted heteroaryl or heteroaryl substituted by benzylamino.

In another embodiment the present invention provides a compound of formula I wherein R.sup.3 is unsubstituted pyrimidinyl, unsubstituted pyrazinyl or unsubstituted pyridinyl. In another embodiment the present invention provides a compound of formula I wherein R.sup.3 is heteroaryl selected from pyrimidinyl, pyrazinyl, pyridinyl and indolyl wherein the heteroaryl is substituted by one or two substituents selected from halogen, C.sub.1 C.sub.6alkyl, S--C.sub.1 C.sub.6alkyl, C.sub.1 C.sub.6alkyl-halogen, C.sub.1 C.sub.6alkoxy, C.sub.3 C.sub.12cycloalkyl, C.sub.2 C.sub.11 heterocycloalkyl, C.sub.1 C.sub.6alkylamino, di-C.sub.1 C.sub.6alkylamino, C.sub.1 C.sub.6alkoxyamino, (C.sub.1 C.sub.6alkoxy)C.sub.1 C.sub.6alkylamino, C.sub.3 C.sub.12cycloalkylamino and benzylamino. In another embodiment the present invention provides a compound of formula I wherein R.sup.3 is pyrimidinyl substituted by one or two substituents selected from halogen, C.sub.1 C.sub.6alkyl, S--C.sub.1 C.sub.6alkyl, C.sub.1 C.sub.6alkyl-halogen, C.sub.1 C.sub.6alkoxy and C.sub.3 C.sub.12cycloalkyl; or pyrazinyl substituted by one substituent selected from halogen, C.sub.1 C.sub.6alkyl, C.sub.1 C.sub.6alkoxy, C.sub.3 C.sub.12cycloalkyl, C.sub.2 C.sub.11heterocycloalkyl, C.sub.1 C.sub.6alkylamino, di-C.sub.1 C.sub.6alkylamino and C.sub.3 C.sub.12cycloalkylamino; or pyridinyl substituted by one or two substituents selected from halogen, C.sub.1 C.sub.6alkyl, C.sub.1 C.sub.6alkyl-halogen, C.sub.1 C.sub.6alkoxy, C.sub.3 C.sub.12cycloalkyl, C.sub.2 C.sub.11heterocycloalkyl, C.sub.1 C.sub.6alkylamino, di-C.sub.1 C.sub.6alkylamino, C.sub.1 C.sub.6alkoxyamino, (C.sub.1 C.sub.6alkoxy)C.sub.1 C.sub.6alkylamino and benzylamino; or methyl-1H-indolyl. In another embodiment the present invention provides a compound of formula I wherein R.sup.3 is methylpyrimidinyl, ethylpyrimidinyl, dimethylpyrimidinyl, trifluoromethylpyrimidinyl, methoxypyrimidinyl, methoxyethoxypyrimidinyl, fluoropyrimidinyl, chloropyrimidinyl, bromopyrimidinyl, methylsulfanylpyrimidinyl, cyclopropylpyrimidinyl, methylpyrazinyl, cyclopropylpyrazinyl, methoxypyrazinyl, chloropyrazinyl, methylaminopyrazinyl, dimethylaminopyrazinyl, cyclopropylpyrazinyl, methylpyridinyl, butylpyridinyl, fluoropyridinyl, chloropyridinyl, bromopyridinyl, iodopyridinyl, trifluoromethylpyridinyl, (trifluoromethyl)methylpyridinyl, cyclopropylpyridinyl, methoxypyridinyl, methoxyethoxypyrazinyl, methylaminopyridinyl, ethylaminopyridinyl, dimethylaminopyridinyl, pyrrolidinylpyridinyl, morpholinylpyridinyl, thiomorpholinylpyridinyl, (methoxyethyl)methylaminopyridinyl, methoxyethylaminopyridinyl, benzylaminopyridinyl or methyl-1H-indolyl. In all the above embodiments R.sup.1, R.sup.2 and R.sup.4 independently are as defined above or hereinafter.

In one embodiment the present invention provides a compound of formula I wherein R.sup.4 is hydrogen, C(O)H or CH.sub.3. In another embodiment the present invention provides a compound of formula I wherein R.sup.4 is hydrogen. In all the above embodiments R.sup.1, R.sup.2 and R.sup.3 independently are as defined above or hereinafter.

In one embodiment the present invention provides a compound of formula I wherein R.sup.1 is methyl; R.sup.2 is C.sub.1 C.sub.6alkyl or C.sub.3 C.sub.12cycloalkyl; R.sup.3 is aryl or heteroaryl, wherein the aryl or heteroaryl is unsubstituted or substituted by one, two or three substituents selected from halogen, C.sub.1 C.sub.6alkyl, S--C.sub.1 C.sub.6alkyl, C.sub.1 C.sub.6alkyl-halogen, C.sub.1 C.sub.6alkoxy, halogen-C.sub.1 C.sub.6alkoxy, C.sub.3 C.sub.12cycloalkyl, C.sub.2 C.sub.11heterocycloalkyl, C.sub.1 C.sub.6alkylamino, di-C.sub.1 C.sub.6alkylamino, C.sub.1 C.sub.6alkoxyamino, (C.sub.1 C.sub.6alkoxy)C.sub.1 C.sub.6alkylamino, C.sub.3 C.sub.12cycloalkylamino, benzylamino and cyano; and R.sup.4 is hydrogen, C(O)H or CH.sub.2R.sup.5 wherein R.sup.5 is hydrogen, OH, C.sub.1 C.sub.6alkyl or C.sub.3 C.sub.12cycloalkyl.

In another embodiment the present invention provides a compound of formula I wherein R.sup.1 is methyl; R.sup.2 is methyl, isopropyl or cyclopropyl; R.sup.3 is aryl or heteroaryl, wherein the aryl or heteroaryl is unsubstituted or substituted by one, two or three substituents selected from halogen, C.sub.1 C.sub.6alkyl, S--C.sub.1 C.sub.6alkyl, C.sub.1 C.sub.6alkyl-halogen, C.sub.1 C.sub.6alkoxy, halogen-C.sub.1 C.sub.6alkoxy, C.sub.3 C.sub.12cycloalkyl, C.sub.2 C.sub.11heterocycloalkyl, C.sub.1 C.sub.6alkylamino, di-C.sub.1 C.sub.6alkylamino, C.sub.1 C.sub.6alkoxyamino, (C.sub.1 C.sub.6alkoxy)C.sub.1 C.sub.6alkylamino, C.sub.3 C.sub.12cycloalkylamino, benzylamino and cyano; and R.sup.4 is hydrogen, C(O)H or CH.sub.2R.sup.5 wherein R.sup.5 is hydrogen, OH, C.sub.1 C.sub.6alkyl or C.sub.3 C.sub.12cycloalkyl.

In still another embodiment the present invention provides a compound of formula I wherein R.sup.1 is methyl; R.sup.2 is methyl, isopropyl or cyclopropyl; R.sup.3 is aryl or heteroaryl, wherein the aryl or heteroaryl is unsubstituted or substituted by one, two or three substituents selected from halogen, C.sub.1 C.sub.6alkyl, S--C.sub.1 C.sub.6alkyl, C.sub.1 C.sub.6alkyl-halogen, C.sub.1 C.sub.6alkoxy, halogen-C.sub.1 C.sub.6alkoxy, C.sub.3 C.sub.12cycloalkyl, C.sub.2 C.sub.11heterocycloalkyl, C.sub.1 C.sub.6alkylamino, di-C.sub.1 C.sub.6alkylamino, C.sub.1 C.sub.6alkoxyamino, (C.sub.1 C.sub.6alkoxy)C.sub.1 C.sub.6alkylamino, C.sub.3 C.sub.12cycloalkylamino, benzylamino and cyano; and R.sup.4 is hydrogen, C(O)H or methyl.

In still another embodiment the present invention provides a compound of formula I wherein R.sup.1 is methyl; R.sup.2 is methyl, isopropyl or cyclopropyl; R.sup.3 is aryl or heteroaryl, wherein the aryl or heteroaryl is unsubstituted or substituted by one, two or three substituents selected from halogen, C.sub.1 C.sub.6alkyl, S--C.sub.1 C.sub.6alkyl, C.sub.1 C.sub.6alkyl-halogen, C.sub.1 C.sub.6alkoxy, halogen-C.sub.1 C.sub.6alkoxy, C.sub.3 C.sub.12cycloalkyl, C.sub.2 C.sub.11heterocycloalkyl, C.sub.1 C.sub.6alkylamino, di-C.sub.1 C.sub.6alkylamino, C.sub.1 C.sub.6alkoxyamino, (C.sub.1 C.sub.6alkoxy)C.sub.1 C.sub.6alkylamino, C.sub.3 C.sub.12cycloalkylamino, benzylamino and cyano; and R.sup.4 is hydrogen.

In still another embodiment the present invention provides a compound of formula I wherein R.sup.1 and R.sup.2 are methyl; R.sup.3 is aryl or heteroaryl, wherein the aryl or heteroaryl is unsubstituted or substituted by one, two or three substituents selected from halogen, C.sub.1 C.sub.6alkyl, S--C.sub.1 C.sub.6alkyl, C.sub.1 C.sub.6alkyl-halogen, C.sub.1 C.sub.6alkoxy, halogen-C.sub.1 C.sub.6alkoxy, C.sub.3 C.sub.12cycloalkyl, C.sub.2 C.sub.11heterocycloalkyl, C.sub.1 C.sub.6alkylamino, di-C.sub.1 C.sub.6alkylamino, C.sub.1 C.sub.6alkoxyamino, (C.sub.1 C.sub.6alkoxy)C.sub.1 C.sub.6alkylamino, C.sub.3 C.sub.12cycloalkylamino, benzylamino and cyano; and R.sup.4 is hydrogen.

In still another embodiment the present invention provides a compound of formula I wherein R.sup.1 and R.sup.2 are methyl; R.sup.3 is unsubstituted aryl or aryl substituted by one, two or three substituents selected from halogen, C.sub.1 C.sub.6alkyl, S--C.sub.1 C.sub.6alkyl, C.sub.1 C.sub.6alkyl-halogen, C.sub.1 C.sub.6alkoxy, halogen-C.sub.1 C.sub.6alkoxy, C.sub.3 C.sub.12cycloalkyl, C.sub.2 C.sub.11heterocycloalkyl, C.sub.1 C.sub.6alkylamino, di-C.sub.1 C.sub.6alkylamino, C.sub.1 C.sub.6alkoxyamino, (C.sub.1 C.sub.6alkoxy)C.sub.1 C.sub.6alkylamino, C.sub.3 C.sub.12cycloalkylamino, benzylamino and cyano; and R.sup.4 is hydrogen.

In still another embodiment the present invention provides a compound of formula I wherein R.sup.1 and R.sup.2 are methyl; R.sup.3 is phenyl or phenyl substituted by one, two or three substituents selected from halogen, C.sub.1 C.sub.6alkyl, S--C.sub.1 C.sub.6alkyl, C.sub.1 C.sub.6alkyl-halogen, C.sub.1 C.sub.6alkoxy, halogen-C.sub.1 C.sub.6alkoxy, C.sub.3 C.sub.12cycloalkyl, C.sub.2 C.sub.11heterocycloalkyl, C.sub.1 C.sub.6alkylamino, di-C.sub.1 C.sub.6alkylamino, C.sub.1 C.sub.6alkoxyamino, (C.sub.1 C.sub.6alkoxy)C.sub.1 C.sub.6alkylamino, C.sub.3 C.sub.12cycloalkylamino, benzylamino and cyano; and R.sup.4 is hydrogen.

In still another embodiment the present invention provides a compound of formula I wherein R.sup.1 and R.sup.2 are methyl; R.sup.3 is phenyl or phenyl substituted by one or two substituents selected from halogen, C.sub.1 C.sub.6alkyl, C.sub.1 C.sub.6alkyl-halogen, C.sub.1 C.sub.6alkoxy, halogen-C.sub.1 C.sub.6alkoxy and cyano; and R.sup.4 is hydrogen.

In still another embodiment the present invention provides a compound of formula I wherein R.sup.1 and R.sup.2 are methyl; R.sup.3 is phenyl substituted by one or two substituents selected from fluoro, chloro, methyl, trifluoromethyl, methoxy, trifluoromethoxy and cyano; and R.sup.4 is hydrogen.

In still another embodiment the present invention provides a compound of formula I wherein R.sup.1 and R.sup.2 are methyl; R.sup.3 is fluorophenyl, difluorophenyl, chlorophenyl, dichlorophenyl, cyanophenyl, trifluoromethylphenyl, fluoro-methylphenyl, chloro-fluorophenyl, methylphenyl, methoxyphenyl or trifluoromethoxyphenyl; and R.sup.4 is hydrogen.

In still another embodiment the present invention provides a compound of formula I wherein R.sup.1 and R.sup.2 are methyl; R.sup.3 is unsubstituted heteroaryl or heteroaryl substituted by one, two or three substituents selected from the group consisting of halogen, C.sub.1 C.sub.6alkyl, S--C.sub.1 C.sub.6alkyl, C.sub.1 C.sub.6alkyl-halogen, C.sub.1 C.sub.6alkoxy, halogen-C.sub.1 C.sub.6alkoxy, C.sub.3 C.sub.12cycloalkyl, C.sub.2 C.sub.11heterocycloalkyl, C.sub.1 C.sub.6alkylamino, di-C.sub.1 C.sub.6alkylamino, C.sub.1 C.sub.6alkoxyamino, (C.sub.1 C.sub.6alkoxy)C.sub.1 C.sub.6alkylamino, C.sub.3 C12cycloalkylamino, benzylamino and cyano; and R.sup.4 is hydrogen.

In still another embodiment the present invention provides a compound of formula I wherein R.sup.1 and R.sup.2 are methyl; R.sup.3 is unsubstituted pyrimidinyl, unsubstituted pyrazinyl or unsubstituted pyridinyl; and R.sup.4 is hydrogen.

In still another embodiment the present invention provides a compound of formula I wherein R.sup.1 and R.sup.2 are methyl; R.sup.3 is heteroaryl selected from pyrimidinyl, pyrazinyl, pyridinyl and indolyl wherein the heteroaryl is substituted by one or two substituents selected from halogen, C.sub.1 C.sub.6alkyl, S--C.sub.1 C.sub.6alkyl, C.sub.1 C.sub.6alkyl-halogen, C.sub.1 C.sub.6alkoxy, C.sub.3 C.sub.12cycloalkyl, C.sub.2 C.sub.11heterocycloalkyl, C.sub.1 C.sub.6alkylamino, di-C.sub.1 C.sub.6alkylamino, C.sub.1 C.sub.6alkoxyamino, (C.sub.1 C.sub.6alkoxy)C.sub.1 C.sub.6alkylamino, C.sub.3 C.sub.12cycloalkylamino and benzylamino; and R.sup.4 is hydrogen.

In still another embodiment the present invention provides a compound of formula I wherein R.sup.1 and R.sup.2 are methyl; R.sup.3 is pyrimidinyl substituted by one or two substituents selected from halogen, C.sub.1 C.sub.6alkyl, S--C.sub.1 C.sub.6alkyl, C.sub.1 C.sub.6alkyl-halogen, C.sub.1 C.sub.6alkoxy and C.sub.3 C.sub.12cycloalkyl; or pyrazinyl substituted by one substituent selected from halogen, C.sub.1 C.sub.6alkyl, C.sub.1 C.sub.6alkoxy, C.sub.3 C.sub.12cycloalkyl, C.sub.2 C.sub.11heterocycloalkyl, C.sub.1 C.sub.6alkylamino, di-C.sub.1 C.sub.6alkylamino and C.sub.3 C.sub.12cycloalkylamino; or pyridinyl substituted by one or two substituents selected from halogen, C.sub.1 C.sub.6alkyl, C.sub.1 C.sub.6alkyl-halogen, C.sub.1 C.sub.6alkoxy, C.sub.3 C.sub.12cycloalkyl, C.sub.2 C.sub.11heterocycloalkyl, C.sub.1 C.sub.6alkylamino, di-C.sub.1 C.sub.6alkylamino, C.sub.1 C.sub.6alkoxyamino, (C.sub.1 C.sub.6alkoxy)C.sub.1 C.sub.6alkylamino and benzylamino; or methyl-1H-indolyl; and R.sup.4 is hydrogen.

In still another embodiment the present invention provides a compound of formula I wherein R.sup.1 and R.sup.2 are methyl; R.sup.3 is methylpyrimidinyl, ethylpyrimidinyl, dimethylpyrimidinyl, trifluoromethylpyrimidinyl, methoxypyrimidinyl, methoxyethoxypyrimidinyl, fluoropyrimidinyl, chloropyrimidinyl, bromopyrimidinyl, methylsulfanylpyrimidinyl, cyclopropylpyrimidinyl, methylpyrazinyl, cyclopropylpyrazinyl, methoxypyrazinyl, chloropyrazinyl, methylaminopyrazinyl, dimethylaminopyrazinyl, cyclopropylpyrazinyl, methylpyridinyl, butylpyridinyl, fluoropyridinyl, chloropyridinyl, bromopyridinyl, iodopyridinyl, trifluoromethylpyridinyl, (trifluoromethyl)methylpyridinyl, cyclopropylpyridinyl, methoxypyridinyl, methoxyethoxypyrazinyl, methylaminopyridinyl, ethylaminopyridinyl, dimethylaminopyridinyl, pyrrolidinylpyridinyl, morpholinylpyridinyl, thiomorpholinylpyridinyl, (methoxyethyl)methylaminopyridinyl, methoxyethylaminopyridinyl, benzylaminopyridinyl or methyl-1H-indolyl; and R.sup.4 is hydrogen.

Examples of compounds of formula I include 4-[1-(4-fluoro-phenyl)-2-methyl-1H-imidazol-4-ylethynyl]-2-methyl-pyridin- e, 4-[1-(3,4-dichloro-phenyl)-2-methyl-1H-imidazol-4-ylethynyl]-2-methyl-p- yridine hydrochloride, 4-[1-(2,4-difluoro-phenyl)-2-methyl-1H-imidazol-4-ylethynyl]-2-methyl-pyr- idine, 4-[1-(3,4-difluoro-phenyl)-2-methyl-1H-imidazol-4-ylethynyl]-2-meth- yl-pyridine, 4-[2-methyl-4-(2-methyl-pyridin-4-ylethynyl)-imidazol-1-yl]-benzonitrile, 3-[2-methyl-4-(2-methyl-pyridin-4-ylethynyl)-imidazol-1-yl]-benzonitrile, 2-methyl-4-[2-methyl-1-(3-trifluoromethyl-phenyl)-1H-imidazol-4-ylethynyl- ]-pyridine, 2-[2-methyl-4-(2-methyl-pyridin-4-ylethynyl)-imidazol-1-yl]-pyrimidine, 4-[1-(4-chloro-phenyl)-2-methyl-1H-imidazol-4-ylethynyl]-2-methyl-pyridin- e, 4-[2-cyclopropyl-1-(4-fluoro-phenyl)-1H-imidazol-4-ylethynyl]-2-methyl-- pyridine, 4-[1-(3-fluoro-phenyl)-2-methyl-1H-imidazol-4-ylethynyl]-2-methy- l-pyridine, 4-[1-(3,5-difluoro-phenyl)-2-methyl-1H-imidazol-4-ylethynyl]-2-methyl-pyr- idine, 4-[1-(3-fluoro-4-methyl-phenyl)-2-methyl-1H-imidazol-4-ylethynyl]-2- -methyl-pyridine, 4-[1-(3-chloro-4-fluoro-phenyl)-2-methyl-1H-imidazol-4-ylethynyl]-2-methy- l-pyridine, 2-methyl-4-(2-methyl-1-p-tolyl-1H-imidazol-4-ylethynyl)-pyridine, 4-[1-(4-methoxy-phenyl)-2-methyl-1H-imidazol-4-ylethynyl]-2-methyl-pyridi- ne, 2-methyl-4-[2-methyl-1-(4-trifluoromethyl-phenyl)-1H-imidazol-4-ylethy- nyl]-pyridine, 4,6-dimethyl-2-[2-methyl-4-(2-methyl-pyridin-4-ylethynyl)-imidazol-1-yl]-- pyrimidine, 4-methyl-2-[2-methyl-4-(2-methyl-pyridin-4-ylethynyl)-imidazol-1-yl]-pyri- midine, 2-[2-methyl-4-(2-methyl-pyridin-4-ylethynyl)-imidazol-1-yl]-4-trif- luoromethyl-pyrimidine, 4-methoxy-2-[2-methyl-4-(2-methyl-pyridin-4-ylethynyl)-imidazol-1-yl]-pyr- imidine, 5-ethyl-2-[2-methyl-4-(2-methyl-pyridin-4-ylethynyl)-imidazol-1-y- l]-pyrimidine, 5-fluoro-2-[2-methyl-4-(2-methyl-pyridin-4-ylethynyl)-imidazol-1-yl]-pyri- midine, 2-[2-methyl-4-(2-methyl-pyridin-4-ylethynyl)-imidazol-1-yl]-pyrazi- ne, 2-methyl-5-[2-methyl-4-(2-methyl-pyridin-4-ylethynyl)-imidazol-1-yl]-p- yrazine, 2-methyl-6-[2-methyl-4-(2-methyl-pyridin-4-ylethynyl)-imidazol-1-- yl]-pyrazine, 2-cyclopropyl-6-[2-methyl-4-(2-methyl-pyridin-4-ylethynyl)-imidazol-1-yl]- -pyrazine, 2-chloro-6-[2-methyl-4-(2-methyl-pyridin-4-ylethynyl)-imidazol-- 1-yl]-pyrazine, 2-methoxy-6-[2-methyl-4-(2-methyl-pyridin-4-ylethynyl)-imidazol-1-yl]-pyr- azine, 2-chloro-4-[2-methyl-4-(2-methyl-pyridin-4-ylethynyl)-imidazol-1-yl- ]-pyrimidine, 4-chloro-2-[2-methyl-4-(2-methyl-pyridin-4-ylethynyl)-imidazol-1-yl]-pyri- midine, 4-[2-methyl-4-(2-methyl-pyridin-4-ylethynyl)-imidazol-1-yl]-2-meth- ylsulfanyl-pyrimidine, 4-[2-methyl-4-(2-methyl-pyridin-4-ylethynyl)-imidazol-1-yl]-2-trifluorome- thyl-pyrimidine, 2-[2-methyl-4-(2-methyl-pyridin-4-ylethynyl)-imidazol-1-yl]-pyridine, 6-fluoro-2-[2-methyl-4-(2-methyl-pyridin-4-ylethynyl)-imidazol-1-yl]-pyri- dine, 2-[2-methyl-4-(2-methyl-pyridin-4-ylethynyl)-imidazol-1-yl]-6-methyl- pyridine, 2-[2-isopropyl-4-(2-methyl-pyridin-4-ylethynyl)-imidazol-1-yl]-6- -methylpyridine, 2-[2-methyl-4-(2-methyl-pyridin-4-ylethynyl)-imidazol-1-yl]-6-methyl-4-tr- ifluoromethy-pyridine, 2-cyclopropyl-6-[2-methyl-4-(2-methyl-pyridin-4-ylethynyl)-imidazol-1-yl]- -pyridine, 2-butyl-6-[2-methyl-4-(2-methyl-pyridin-4-ylethynyl)-imidazol-1- -yl]-pyridine, 2-[2-methyl-4-(2-methyl-pyridin-4-ylethynyl)-imidazol-1-yl]-6-trifluorome- thyl-pyridine, 2-[2-isopropyl-4-(2-methyl-pyridin-4-ylethynyl)-imidazol-1-yl]-6-trifluor- omethyl-pyridine, 2-methoxy-6-[2-methyl-4-(2-methyl-pyridin-4-ylethynyl)-imidazol-1-yl]-pyr- idine, 2-[2-methyl-4-(2-methyl-pyridin-4-ylethynyl)-imidazol-1-yl]-5-methy- l-pyridine, 2-[2-isopropyl-4-(2-methyl-pyridin-4-ylethynyl)-imidazol-1-yl]-5-methyl-p- yridine, 5-chloro-2-[2-methyl-4-(2-methyl-pyridin-4-ylethynyl)-imidazol-1-- yl]-pyridine, 5-bromo-2-[2-methyl-4-(2-methyl-pyridin-4-ylethynyl)-imidazol-1-yl]-pyrid- ine, 4-iodo-2-[2-methyl-4-(2-methyl-pyridin-4-ylethynyl)-imidazol-1-yl]-py- ridine, 2-[2-methyl-4-(2-methyl-pyridin-4-ylethynyl)-imidazol-1-yl]-4-meth- yl-pyridine, 2-[2-methyl-4-(2-methyl-pyridin-4-ylethynyl)-imidazol-1-yl]-4-trifluorome- thyl-pyridine, 2-methoxy-4-[2-methyl-4-(2-methyl-pyridin-4-ylethynyl)-imidazol-1-yl]-pyr- idine, 2-chloro-5-[2-methyl-4-(2-methyl-pyridin-4-ylethynyl)-imidazol-1-yl- ]-pyridine, 2-bromo-5-[2-methyl-4-(2-methyl-pyridin-4-ylethynyl)-imidazol-1-yl]-pyrid- ine, 5-[2-methyl-4-(2-methyl-pyridin-4-ylethynyl)-imidazol-1-yl]-2-methyl-- pyridine, 2-cyclopropyl-5-[2-methyl-4-(2-methyl-pyridin-4-ylethynyl)-imida- zol-1-yl]-pyridine, 2-butyl-5-[2-methyl-4-(2-methyl-pyridin-4-ylethynyl)-imidazol-1-yl]-pyrid- ine, 3-fluoro-5-[2-methyl-4-(2-methyl-pyridin-4-ylethynyl)-imidazol-1-yl]-- pyridine, 3-chloro-5-[2-methyl-4-(2-methyl-pyridin-4-ylethynyl)-imidazol-1- -yl]-pyridine, dimethyl-{5-[2-methyl-4-(2-methyl-pyridin-4-ylethynyl)-imidazol-1-yl]-pyr- idin-3-yl}-amine, dimethyl-{6-[2-methyl-4-(2-methyl-pyridin-4-ylethynyl)-imidazol-1-yl]-pyr- idin-2-yl}-amine, dimethyl-{6-[2-methyl-4-(2-methyl-pyridin-4-ylethynyl)-imidazol-1-yl]-pyr- azin-2-yl}-amine, ethyl-{5-[2-methyl-4-(2-methyl-pyridin-4-ylethynyl)-imidazol-1-yl]-pyridi- n-3-yl}-amine, methyl-{6-[2-methyl-4-(2-methyl-pyridin-4-ylethynyl)-imidazol-1-yl]-pyrid- in-2-yl}-amine, methyl-{6-[2-methyl-4-(2-methyl-pyridin-4-ylethynyl)-imidazol-1-yl]-pyraz- in-2-yl}-amine, cyclopropyl-{6-[2-methyl-4-(2-methyl-pyridin-4-ylethynyl)-imidazol-1-yl]-- pyrazin-2-yl}-amine, 1-{5-[2-methyl-4-(2-methyl-pyridin-4-ylethynyl)-imidazol-1-yl]-pyridin-3-- yl}-amine, 1-{6-[2-methyl-4-(2-methyl-pyridin-4-ylethynyl)-imidazol-1-yl]-- pyridin-2-yl}-pyrrolidine, 1-{3-[2-methyl-4-(2-methyl-pyridin-4-ylethynyl)-imidazol-1-yl]-pyridin-5-- yl}-pyrrolidine, 4-{6-[2-methyl-4-(2-methyl-pyridin-4-ylethynyl)-imidazol-1-yl]-pyridin-2-- yl}-morpholine, 4-{6-[2-methyl-4-(2-methyl-pyridin-4-ylethynyl)-imidazol-1-yl]-pyrazin-2-- yl}-morpholine, 4-{6-[2-methyl-4-(2-methyl-pyridin-4-ylethynyl)-imidazol-1-yl]-pyridin-2-- yl}-thiomorpholine, (2-methoxy-ethyl)-methyl-{6-[2-methyl-4-(2-methyl-pyridin-4-ylethynyl)-im- idazol-1-yl]-pyridin-2-yl}-amine, (2-methoxy-ethyl)-{6-[2-methyl-4-(2-methyl-pyridin-4-ylethynyl)-imidazol-- 1-yl]-pyridin-2-yl}-amine, 4-cyclopropyl-2-[2-methyl-4-(2-methyl-pyridin-4-ylethynyl)-imidazol-1-yl]- -pyridine, 5-cyclopropyl-2-[2-methyl-4-(2-methyl-pyridin-4-ylethynyl)-imid- azol-1-yl]-pyridine, 4-fluoro-6-[2-methyl-4-(2-methyl-pyridin-4-ylethynyl)-imidazol-1-yl]-pyri- midine, 5-bromo-2-[2-methyl-4-(2-methyl-pyridin-4-ylethynyl)-imidazol-1-yl- ]-pyrimidine, 5-methyl-2-[2-methyl-4-(2-methyl-pyridin-4-ylethynyl)-imidazol-1-yl]-pyri- midine, 2-cyclopropyl-4-[2-methyl-4-(2-methyl-pyridin-4-ylethynyl)-imidazo- l-1-yl]-pyrimidine, 4-cyclopropyl-2-[2-methyl-4-(2-methyl-pyridin-4-ylethynyl)-imidazol-1-yl]- -pyrimidine, 2-(2-methoxy-ethoxy)-6-[2-methyl-4-(2-methyl-pyridin-4-ylethynyl)-imidazo- l-1-yl]-pyrimidine, 2-(2-methoxy-ethoxy)-6-[2-methyl-4-(2-methyl-pyridin-4-ylethynyl)-imidazo- l-1-yl]-pyrimidine, 2-methyl-4-[2-methyl-1-(3-trifluoromethoxy-phenyl)-1H-imidazol-4-ylethyny- l]-pyridine, 1-methyl-5-[2-methyl-4-(2-methyl-pyridin-4-ylethynyl)-imidazol-1-yl]-1H-i- ndole, benzyl-{5-[2-methyl-4-(2-methyl-pyridin-4-ylethynyl)-imidazol-1-yl]- -pyridin-3-yl}-amine, 4-[1-(4-fluoro-phenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]-2-methyl-pyr- idine and 3-(4-fluoro-phenyl)-2-methyl-5-(2-methyl-pyridin-4-ylethynyl)-3H- -imidazole-4-carbaldehyde.

In one embodiment the present invention provides a compound of formula I selected from 4-[1-(4-fluoro-phenyl)-2-methyl-1H-imidazol-4-ylethynyl]-2-methyl-pyridin- e, 4-[1-(3,4-dichloro-phenyl)-2-methyl-1H-imidazol-4-ylethynyl]-2-methyl-p- yridine hydrochloride, 4-[1-(2,4-difluoro-phenyl)-2-methyl-1H-imidazol-4-ylethynyl]-2-methyl-pyr- idine, 4-[1-(3,4-difluoro-phenyl)-2-methyl-1H-imidazol-4-ylethynyl]-2-meth- yl-pyridine, 4-[2-methyl-4-(2-methyl-pyridin-4-ylethynyl)-imidazol-1-yl]-benzonitrile, 3-[2-methyl-4-(2-methyl-pyridin-4-ylethynyl)-imidazol-1-yl]-benzonitrile, 2-methyl-4-[2-methyl-1-(3-trifluoromethyl-phenyl)-1H-imidazol-4-ylethynyl- ]-pyridine, 2-[2-methyl-4-(2-methyl-pyridin-4-ylethynyl)-imidazol-1-yl]-pyrimidine, 2-[2-methyl-4-(2-methyl-pyridin-4-ylethynyl)-imidazol-1-yl]-4-trifluorome- thyl-pyrimidine, 4-methoxy-2-[2-methyl-4-(2-methyl-pyridin-4-ylethynyl)-imidazol-1-yl]-pyr- imidine, 2-cyclopropyl-6-[2-methyl-4-(2-methyl-pyridin-4-ylethynyl)-imidaz- ol-1-yl]-pyrazine, 4-chloro-2-[2-methyl-4-(2-methyl-pyridin-4-ylethynyl)-imidazol-1-yl]-pyri- midine, 2-cyclopropyl-6-[2-methyl-4-(2-methyl-pyridin-4-ylethynyl)-imidazo- l-1-yl]-pyridine, 2-methoxy-6-[2-methyl-4-(2-methyl-pyridin-4-ylethynyl)-imidazol-1-yl]-pyr- idine, dimethyl-{6-[2-methyl-4-(2-methyl-pyridin-4-ylethynyl)-imidazol-1-y- l]-pyridin-2-yl}-amine, 1-methyl-5-[2-methyl-4-(2-methyl-pyridin-4-ylethynyl)-imidazol-1-yl]-1H-i- ndole, 4-[1-(4-fluoro-phenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]-2-meth- yl-pyridine and 3-(4-fluoro-phenyl)-2-methyl-5-(2-methyl-pyridin-4-ylethynyl)-3H-imidazol- e-4-carbaldehyde.

The present invention also provides a process for the production of a compound of formula I

##STR00005## wherein R.sup.1 is C.sub.1 C.sub.6alkyl; R.sup.2 is C.sub.1 C.sub.6alkyl or C.sub.3 C.sub.12cycloalkyl; R.sup.3 is unsubstituted aryl or aryl substituted by one, two or three substituents selected from halogen, C.sub.1 C.sub.6alkyl, S--C.sub.1 C.sub.6alkyl, C.sub.1 C.sub.6alkyl-halogen, C.sub.1 C.sub.6alkoxy, halogen-C.sub.1 C.sub.6alkoxy, C.sub.3 C.sub.12cycloalkyl, C.sub.2 C.sub.11heterocycloalkyl, C.sub.1 C.sub.6alkylamino, di-C.sub.1 C.sub.6alkylamino, C.sub.1 C.sub.6alkoxyamino, (C.sub.1 C.sub.6alkoxy)C.sub.1 C.sub.6alkylamino, C.sub.3 C.sub.12cycloalkylamino, benzylamino and cyano, unsubstituted heteroaryl or heteroaryl substituted by one, two or three substituents selected from the group consisting of halogen, C.sub.1 C.sub.6alkyl, S--C.sub.1 C.sub.6alkyl, C.sub.1 C.sub.6alkyl-halogen, C.sub.1 C.sub.6alkoxy, halogen-C.sub.1 C.sub.6alkoxy, C.sub.3 C.sub.12cycloalkyl, C.sub.2 C.sub.11heterocycloalkyl, C.sub.1 C.sub.6alkylamino, di-C.sub.1 C.sub.6alkylamino, C.sub.1 C.sub.6alkoxyamino, (C.sub.1 C.sub.6alkoxy)C.sub.1 C.sub.6alkylamino, C.sub.3 C.sub.12cycloalkylamino, benzylamino and cyano; and R.sup.4 is hydrogen, C(O)H or CH.sub.2R.sup.5 wherein R.sup.5 is hydrogen, OH, C.sub.1 C.sub.6alkyl or C.sub.3 C.sub.12cycloalkyl; which process comprises reacting (a) a compound of formula II

##STR00006## wherein R.sup.1, R.sup.2 and R.sup.4 have the meanings as defined above, with a compound of formula III R.sup.3-Z (III) wherein R.sup.3 has the meanings as defined above and Z is halogen or B(OH).sub.2; or (b) a compound of formula IV

##STR00007## wherein R.sup.2, R.sup.3 and R.sup.4 have the meanings as defined above, with a compound of formula V

##STR00008## wherein R.sup.1 has the meanings as defined above and X is halogen; or (c) a compound of formula VI

##STR00009## wherein R.sup.2, R.sup.3 and R.sup.4 have the meanings as defined above and hal is halogen, with a compound of formula VII

##STR00010## wherein R.sup.1 has the meaning as defined above and Y is trimethylsilyl or hydrogen.

The reaction as described in (a) may be carried out in accordance with standard procedures, e.g. by arylation of a compound of formula II using an aromatic boronic acid and a copper catalyst in a solvent like dichloromethane or tetrahydrofurane [see e.g. Colmann et al., Org. Lett. 2:1233 (2000)] or by heating a compound of formula II and a compound of formula III wherein Z is halogen with a base like potassium carbonate or cesium carbonate in a solvent like dimethylformamide, or Pd catalyzed according to Buchwald conditions [see e.g. Example 8; Buchwald et al., Tetrahedron Lett. 40:2657 (1999)]. The reaction as described in (b) may be carried out by a Sonogashira coupling of a compound of formula IV and a compound of formula V in the presence of, e.g., CuI, (Ph.sub.3P).sub.2PdCl.sub.2, Et.sub.3N in a solvent like tetrahydrofuran or dimethylformamide [Sonogashira et al., Synthesis 777 (1977)]. In one embodiment the meaning X in compounds of formula V is bromine or iodine. The reaction as described in (c) above may, e.g. be carried out in the presence of CuI, (Ph.sub.3P).sub.2PdCl.sub.2, Et.sub.3N, n-Bu.sub.4F in a solvent like tetrahydrofuran or dimethylformamide.

The salt forms are made by standard procedures known to the skilled artisan.

The compounds of formulae II, IV, VI and VII are novel and also an embodiment of the present invention.

The compounds of formulae III and V are commercially available or their preparation is known to the skilled artisan.

The compounds of formula II may be prepared by reacting a compound of formula VIII

##STR00011## wherein R.sup.2 and R.sup.4 have the above meanings and hal is halogen, with a compound of formula VII as above.

The compounds of formula VIII may be prepared as described e.g. in Cliff and Pyne [Synthesis 681 682 (1994)].

The compounds of formula IV may be prepared by reacting a compound of formula IX

##STR00012## wherein R.sup.2, R.sup.3 and R.su