FORM 2
The Patents Act, 1970
(39 of 1970)
&
The Patent Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
'TRIAZOLE COMPOUNDS SUITABLE FOR TREATING DISORDERS THAT RESPOND TO MODULAIONT OF THE DOPAMINE D3 RECEPTOR"
ABBOTT GMBH & CO. KG, a company incorporated in Germany having its Registered Office at Max-Planck-Ring 2, 65205 Wiesbaden, GERMANY
The following specification particularly describes the invention and the manner in which it is to be performed
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TRIAZOLE COMPOUNDS SUITABLE FOR TREATING DISORDERS THAT RESPOND TO MODULATION OF THE DOPAMINE D3 RECEPTOR
Background Of The Invention
The present invention relates to novel triazole compounds. The compounds possess
5 valuable therapeutic properties and are suitable, in particular, for treating diseases that
respond to modulation of the dopamine D3 receptor.
Neurons obtain their information by way of G protein-coupled receptors, inter alia. A large
number of substances exert their effect by way of these receptors. One of them is
dopamine. Confirmed findings exist with regard to the presence of dopamine and its
10 physiological function as a neurotransmitter. Disorders in the dopaminergic transmitter
system result in diseases of the central nervous system which include, for example, schizophrenia, depression and Parkinson's disease. These diseases, and others, are treated with drugs which interact with the dopamine receptors.
Up until 1990, two subtypes of dopamine receptor had been clearly defined
15 pharmacologically, termed D^ and D2 receptors. More recently, a third subtype was found,
namely, the D3 receptor which appears to mediate some effects of antipsychotics and
antiparkinsonians (J.C. Schwartz et a/., "The Dopamine D3 Receptor as a Target for
Antipsychotics" in Novel Antipsychotic Drugs, H.Y. Meltzer, ed., Raven Press, New York
1992, pages 135-144; M. Dooley era/., Drugs and Aging 1998,12:495-514; J.N. Joyce,
20 Pharmacology and Therapeutics 2001, 90:231-59, "The Dopamine D3 Receptor as a
Therapeutic Target for Antipsychotic and Antiparkinsonian Drugs"). Since then, the dopamine receptors have been divided into two families. On the one hand, there is the D2 group, consisting of D2, D3 and D4 receptors, and, on the other hand, the D^ group, consisting of Di and D5 receptors.
25 Whereas Di and D2 receptors are widely distributed, D3 receptors appear to be expressed
regioselectively. Thus, these receptors are preferentially to be found in the limbic system and the projection regions of the mesolimbic dopamine system, especially in the nucleus accumbens, but also in other regions, such as the amygdala. Because of this comparatively regioselective expression, D3 receptors are regarded as being a target
30 having few side-effects and it is assumed that while a selective D3 ligand would have the
properties of known antipsychotics, it would not have their dopamine D2 receptor-mediated neurological side-effects (P. Sokoloff ef a/., Arzneim. ForschJDruga Res. 42(1):224 (1992), "Localization and Function of the D3 Dopamine Receptor"; P. Sokoloff et al, Nature, 347:146 (1990), "Molecular Cloning and Characterization of a Novel Dopamine Receptor
35 (D3) as a Target for Neuroleptics").
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Triazole compounds having an affinity for the dopamine D3 receptor have been described
previously on various occasions, as for example in published PCT applications
WO 96/02520, WO 99/02503, WO 00/42036, WO 00/42037, WO 00/42038. Some of
these compounds possess high affinities for the dopamine D3 receptor, and have therefore
5 been proposed as being suitable for treating diseases of the central nervous system.
Unfortunately, their selectivity towards the D3 receptor is not always satisfactory.
Moreover, it has often been difficult to achieve high brain levels with such known
compounds. Consequently there is an ongoing need to provide new compounds, which
either have an improved selectivity towards D3 receptors or an improved pharmacological
10 profile, such as a higher brain plasma ratio, a higher bioavailability, favourable metabolic
behaviour such as a decreased inhibition of the mitochondrial respiration and favourable profile regarding their interaction with cytochrome P450 isoenzymes.
Summary Of The Invention
It has now been found that certain triazole compounds exhibit, to a surprising and
15 unexpected degree, highly selective binding to the dopamine D3 receptor as well as the
ability to attain high brain levels. Such compounds are those having the general formula I

Ar-S(0)-(CH2)3— \_/i~\ ,N (0
wherein
n is 1 or 2,
20 Ar is a C-bound 1,2,4-triazol radical which carries a radical R1 on the remaining carbon
atom and a radical R1a on one of the nitrogen atoms; wherein
R1 is hydrogen, C1-C8 alkyl, C3-C6 cycloalkyl, C1,-C4 alkoxymethyl, fluorinated C1CB alkyl, fluorinated C3-C8 cycloalkyl, fluorinated 0^4 alkoxymethyl,
25 phenyl or 5- or 6-membered heteroaryl, wherein phenyl and heteroaryl may be un-
substituted or substituted by 1, 2, 3 or 4 radicals Ra selected independently of each other from halogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C4 alkoxy-CrC4-alkyl, fluorinated C,-C4 alkyl, CN, N02, OR3, NR3R\ C(0)NR3R4, 0-C(0)NR3R4, S02NR3R4, COOR5, SRa, SOR6, S02R6, 0-C(0)R7. COR7 or C3-C5 cycloalkylmethyl, wherein
30 phenyl and heteroaryl may also carry a phenyl group or an aromatic 5- or 6-
membered C-bound heteroaromatic radical, comprising 1 nitrogen atom as ring member and 0,1,2 or 3 further heteroatoms, independently of each other, selected
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from O, S and N, wherein the last two mentioned radicals may carry 1, 2, 3 or 4 of the aforementioned radicals Ra
R1a is hydrogen or C1-C4-alkyl
R2 is Ci-Cs alkyl, C3-C6 cycloalkyl, fluorinated d-C6 alkyl or fluorinated C3-Ce cycloalkyl
5 R3, R4, R5, R8, and R7 independent of each other are H, CrCa alkyl, optionally substituted
with OH, C1-C4 alkoxy or phenyl, d-C4 haloalkyl or phenyl, which may carry 1, 2 or 3 radicals selected from the group consisting of CrC6 alkyl, Ci-C6 alkoxy, NR3aR4a, CN, d-C2 fluoroalkyl and halogen, wherein R3" and R4a are independent of each other H, d-C6 alkyl, optionally substituted with OH, d-C4 alkoxy or phenyl, CrC4
10 haloalkyl or phenyl, which may carry 1, 2 or 3 radicals selected from the group
consisting of CrC6 alkyl, CrCB alkoxy, amino, NH(Ci-C4 alkyl) and N(CrC4 alkyl)2, R4 may also be a radical COR8, wherein R8 is hydrogen, Ci-C6 alkyl, d-Ce alkoxy or phenyl, which may carry 1, 2 or 3 radicals selected from the group consisting of Cr C6 alkyl, Ci-C6 alkoxy, NR3R4, CN, 0,-0, fluoroalkyl and halogen, R3 and R4 may
15 together with the nitrogen atom to which they are bound form a N-bound 5 or 6
membered saturated heterocyle, which may comprise an oxygen atom or an additional nitrogen atom as a ring member and which may carry 1, 2, 3 or 4 C1-C8 alkyl groups
and the physiologically tolerated acid addition salts of these compounds.
20 The present invention therefore relates to triazole compounds of the general formula I and
to their physiologically tolerated acid addition salts.
The present invention also relates to a pharmaceutical composition which comprises at
least one triazole compound of the formula I and/or at least one physiologically tolerated
acid addition salt of I, where appropriate together with physiologically acceptable carriers
25 and/or auxiliary substances.
The present invention also relates to a method for treating disorders which respond to
influencing by dopamine D3 receptor antagonists or dopamine D3 agonists, said method
comprising administering an effective amount of at least one triazole compound of the
formula I and/or at least one physiologically tolerated acid addition salt of I to a subject in
10 need thereof.
Detailed Description Of The Invention
The diseases which respond to the influence of dopamine D3 receptor antagonists or
agonists include disorders and diseases of the central nervous system, in particular
affective disturbances, neurotic disturbances, stress disturbances and somatoform
5 disturbances and psychoses, and especially schizophrenia, depression, bipolar disorder,
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substance abuse, dementia, major depressive disorder, anxiety, autism, attention deficit disorder with or without hyperactivity and personality disorder. In addition, D3-mediated diseases may include disturbances of kidney function, in particular kidney function disturbances which are caused by diabetes mellitus (see WO 00/67847).
5 According to the invention, one or more compounds of the general formula I having the
meanings mentioned at the outset can be used for treating the abovementioned
indications. Provided the compounds of the formula I possess one or more centers of
asymmetry, it is also possible to use enantiomeric mixtures, in particular racemates,
diastereomeric mixtures and tautomeric mixtures; preferred, however, are the respective
10 essentially pure enantiomers, diastereomers and tautomers.
It is likewise possible to use physiologically tolerated salts of the compounds of the formula I, especially acid addition salts with physiologically tolerated acids. Examples of suitable physiologically tolerated organic and inorganic acids are hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, organic sulfonic acids having from 1 to 12
15 carbon atoms, e.g. C1C4-alkylsulfonic acids such as methanesulfonic acid, cycloaliphatic
sulfonic acids such as S-(+)-10-camphorsulfonic acids and aromatic sulfonic acids such as benzenesulfonic acid and toluenesulfonic acid, di- and tricarboxylic acids and hydroxycarboxylic acids having from 2 to 10 carbon atoms such as oxalic acid, malonic acid, maleic acid, fumaric acid, mucic acid, lactic acid, tartaric acid, citric acid, glycolic acid
20 and adipic acid, as well as cis- and frans-cinnamic acid, furoic acid and benzoic acid.
Other utilizable acids are described in Fortschritte der Arzneimittelforschung [Advances in Drug Research], Volume 10, pages 224 ff., BirkhSuser Verlag, Basel and Stuttgart, 1966. The physiologically tolerated salts of compounds of the formula I may be present as the mono-, bis-, tris- and tetrakis-salts, that is, they may contain 1, 2, 3 or 4 of the
25 aforementioned acid molecules per molecule of formula I. The acid molecules may be
present in their acidic form or as an anion.
As used herein, C1C8 alkyl is a straight-chain or branched alkyl group having 1, 2, 3, 4, 5
or 6 carbon atoms. Examples of such a group are methyl, ethyl.n-propyl, isopropyl, n-
butyl, 2-butyl, isobutyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 1-ethylpropyl, n-
30 hexyl.
As used herein "5- or 6-membered aromatic radicals" comprise monocyclic aromatic
radicals which comprise 1, 2, 3 or 4 heteroatoms as ring members which are selected,
independently of each other from O, S and N. Examples are pyridinyl, pyrimidinyl,
pyrazinyl, triazinyl, imidazolyl, pyrrolyl, pyrazolyl, thienyl, furanyl, oxazolyl, thiazolyl,
35 isoxazolyl, tetrazolyl, thiadiazolyl and triazolyl.
A first embodiment of the invention relates to compounds of the formula I, wherein Ar is a radical of the formula Ar-1,
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WO 2006/058753 PCT7EP2005/012856
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N-N
CH3
wherein # denotes the binding positon to the sulfur atom of the group S(0)n and wherein R1 is as defined herein.
A second embodiment of the invention relates to compounds of the formula I, wherein Ar is
5 a radical of the formula Ar-2
R\ N-N
wherein # denotes the binding positon to the sulfur atom of the group S(0)n and wherein R1 and R1a are as defined herein.
A third embodiment of the invention relates to compounds of the formula I, wherein Ar is a
10 radical of the formula Ar-3
R1a
N-N
R1-"%^# (Ar"3)
wherein # denotes the binding positon to the sulfur atom of the group S(0)n and wherein R1 and R1a are as defined herein.
R1a is preferably hydrogen or methyl, in particular methyl.
15 With regard to using the compounds according to the invention as dopamine D3 receptor
ligands, preference is given to those compounds of formula I in which the radical R1 is hydrogen, C1-C4 alkyl, C3-C5 cycloalkyl, C1-C4 alkoxymethyl or trifluoromethyl, in particular hydrogen, C1-C4 alkyl, cyclopropyl, cyclobutyl, CH2-OCH3, CH2-OCH2H5 or trifluoromethyl, especially methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, fe/f-butyl or
20 trifluoromethyl and most preferably hydrogen or methyl.
R2 is preferably C3-C4 alkyl or fluorinated d-C2 alkyl, in particular n-propyl, isopropyl or
tert-butyl, or alternatively trifluoromethyl or difluoromethyl. More preferable are compounds
in which R2 is tert-butyl, difluoromethyl or trifluoromethyl, and most preferred are those in
which R2 is terf-butyl. Preferred compounds of the formula I may also carry C3-C4
25 cycloalkyl or fluorinated C3-C4 cycloalkyl as a radical R2.
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In another embodiment R1 is optionally substituted phenyl or optionally substituted 5- or 6-
membered hetaryl, which may be unsubstituted or substituted as mentioned above. Pre
ferred substituents on phenyl and 5- or 6-membered heteroaryl comprise halogen, in par
ticular fluorine or chlorine, C1-C4 alkyl, C1-C4 alkoxy, flurinated C1-C2 alkyl, and fluorinated
5 C1-C2 alkoxy. Preferably the number of substituents is 0,1 or 2. Amongst the aromatic
radicals preference is given to phenyl, thienyl and pyrrolyl, which are unsubstituted or substituted as mentioned above. Examples for suitable radicals comprise phenyl, 2-, 3- and 4-fluorophenyl, 2- and 3-thienyl and 1-methyl-pyrrol-2-yl.
The compounds of the present invention can e.g. be prepared from the corresponding sul-
10 fanyl precursors of the formula II

wherein Ar and R2 are as defined above, via oxidation of the thioether moiety whereby the sulfinyl- derivatives la (n = 1) and/or the sulfonyl derivatives lb (n = 2) are obtained, depending on the amount of oxidizing agent or the reaction conditions (see scheme 1). Suit-
15 able oxidizing reagents comprise peracids such as metachloroperbenzoic acid (mCPBA)
(for reaction conditions see e.g. Tetrahedron Lett., 2001, 42 (46), 8161), periodatesa such as sodium periodate (for reaction conditions see e.g. Can. J. Chem., 2001, 79, (8), 1238), organic peroxides and inorganic peroxides such as tert-butyl-hydroperoxide, hydrogenpera-oxide (for reaction conditions see e.g. J. Heterocycl. Chem., 2001, 38 (5), 1035), oxone
20 (for reaction conditions see e.g. Bioorg. Med. Chem Lett., 2001,11, (20), 2723), magne-
sium monoperoxophthalate (for reaction conditions see e.g. Synthesis, 2001,12,1778), and the like, with oxone being preferred.
Scheme 1:
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(II)
The chiral sulfinyl derivatives la are also accessible via enantioselective oxidation using
e.g. diethyl-tartrate/tert-butyl-hydroperoxide/titan-tetraisopropoxide as described in (i) J.
Med. Chem., 2002, 45, 3972, hydrogenperoxide with chiral ligands bound to a solid
5 support (see e.g. Chem. Commun. 2001, 24, 2594), hydrogen peroxide in combination
with a vanadate-based catalyst and (1S,2R)-N-(1-(2-biphenylyl)-2-OH-3-
naphthylmethylidenea)-1-amino-2-indanol as chiral ligand (see e.g. Synlett, 2002,1,161),
1-(2-furyl)-1-methylethyl hydroperoxide/titanium tetraisopropoxide in the presence of (R)-
or (S)-binol (see e.g. Tetrahedron: Asymmetry, 2001, 12 (20), 2775), or (S,S)- or (R,R)-
10 diethyl tartrate/titanium tetraisopropoxide/cumene hydroperoxide (see e.g. Nature Reviews
in Drug Discovery, 2003, 663).
Some of the compounds of the general formula II, namely the compounds of the formula II, wherein
R1 is selected from the group consisting of C2-C6-alkyl, fluorinated d-Ce-alkyl, C3-C6
15 cycloalkyl, C1-C4 alkoxymethyl, fluorinated C3-C8 cycloalkyl and fluorinated C1-C4
alkoxymethyl and
R2 is selected from the group consisting of C1C6 alkyl and fluorinated d-Ce alkyl
and the physiologically tolerated acid addition salts of these compounds are new and thus form part of the invention. They are hereinafter referred to as compounds lla.
20 A fourth embodiment of the invention relates to compounds of the formula lla, wherein Ar
is Ar-1 as defined above.
A fifth embodiment of the invention relates to compounds of the formula lla, wherein Ar is Ar-2 as defined above.
A sixth embodiment of the invention relates to compounds of the formula lla, wherein Ar is
15 Ar-3 as defined above.

WO 2006/058753 PCT/EP2005/012856
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The new compounds of the formula II (compounds lla) and their physiologically tolerated
acid addition salts are highly selective towards the dopamine D3 receptor and provide a
similar beneficial pharmacological profile as the compounds I of the invention. Therefore
compounds lla are useful for treating disorders which respond to influencing by dopamine
5 D3 receptor ligands, such as dopamine D3 receptor antagonists or dopamine D3 agonists.
Therefore, the present invention also relates to a pharmaceutical composition which comprises at least one triazole compound lla and/or at least one physiologically tolerated acid addition salt of lla, where appropriate together with physiologically acceptable carriers and/or auxiliary substances.
10 The present invention also relates to a method for treating disorders which respond to
influencing by dopamine D3 receptor antagonists or dopamine D3 agonists, said method comprising administering an effective amount of at least one triazole compound of the formula lla and/or at least one physiologically tolerated acid addition salt of lla to a subject in need thereof.
15 In the new compounds of formula lla R1 is preferably C2-C4-alkyl, trifluoromethyl, C3-C5
cycloalkyl or (^-04 alkoxymethyl, in particular ethyl, n-propyl, isopropyl, tert.-butyl, cyclopropyl, cyclobutyl, trifluoromethyl, CH2-OCH3 or CH2-OCH2H5.
In the new compounds of formula lla R2 is preferably C3-C4 alkyl or fluorinated C1C2 alkyl,
in particular n-propyl, isopropyl or tert-butyl, or alternatively trifluoromethyl or
20 difluoromethyl. More preferable are compounds lla in which R2 is tert-butyl, difluoromethyl
or trifluoromethyl, and most preferred are those in which R2 is tert-butyl.
The compounds of the formula II can be prepared in analogy to methods which are well
known in the art, as for example from the international patent applications cited in the
introductory part, WO 99/02503, WO 96/0250, PCT/EP2004006139 and US 60/600,042.
25 Preferred methods are outlined in schemes i) and ii) below:
Scheme i)
N=< CH3
H3C^/CH3
Ar—Rx + Y-(CH2)rN N~4>l - (II)
R2
(III) (IV)
According to this scheme, a triazole of the formula III, wherein Ar is as defined above, is reacted with a piperazinylpyrimidine compound of the formula IV, wherein Rx is SH and Y
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WO 2006/058753 PCT/EP2005/012856
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is a conventional leaving group such as halogen such as chlorine, bromine or iodine, alkylsulfonyloxy such as methanesulfonyloxy, arylsulfonyloxy such as phenylsulfonyloxy, or tolylsulfonyloxy (tosylate). The reaction can be performed using the conditions as described herein or in the prior art cited in the introductory part. Rx may also be chlorine or
5 bromine, while Y is SH; in this case, the reaction can be performed using the reaction conditions as described by Hester, Jackson B., Jr. and Von Voigtlander, Philip, Journal of Medicinal Chemistry (1979), 22(11).
Scheme ii)

H3C^ /CH3
N=^ CH3
Ar-S-(CH2)rY + Htifcl-d>l (II)
R2
(V) (VI)
10 According to this scheme, a triazole of the formula V is reacted with a
piperazinylpyrimidine compound of the formula VI, wherein Y is a conventional leaving group such as halogen, alkylsulfonyloxy, arylsulfonyloxy, etc as described above.
The compounds of the formulae III and V are known in the art or can be prepared according to methods described in the literature, as for example in Houben Weyl
15 „Handbuch der Organischen Chemie", 4th Ed., Thieme Verlag, Stuttgart 1994, Volume
E8/d, pages 479 et sequ.; in S. Kubota ef al., Chem. Pharm. Bull 1975, 23:955, or in A.R. Katritzky, C.W. Rees (ed.), "Comprehensive Heterocyclic Chemistry", 1st Ed. Pergamon Press 1984, in particular Vol. 5, part 4a, pages 733 et seq. and literature cited therein; or "The Chemistry of Heterocyclic Compounds'" J. Wiley & Sons Inc. NY and literature cited
20 therein. The compounds of the formulae III and V can be prepared according to routine
methods as described for example in J.A. Kiristy ef al., J. Med. Chem., 21:1303 or C.B. Pollard, J. Am. Chem. Soc. 1934, 56:2199. Some of the triazolecompounds are commercially available
Compounds of the formula III wherein Ar is Ar-1, R" is chlorine or bromine can also be
25 prepared from compounds III with Rx being OH according to the methods described by P.
Viallefont et al. in Bulletin de la Societe Chimique de France 1975, no. 3-4, 647-653, or by G. Maury et al. in J. Heterocyclic Chemistry 1977, 14:1311.
A preferred route to compounds of the formula IV is shown in scheme iii below:
Scheme iii)
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H3CwCH3
rs /M CHa
V)

(VII)
In a first step, a piperazine compound VII wherein Q is H or a protecting group for secondary amines is reacted with a pyrimidine compound VIII wherein Z is halogen to yield a compound of the formula VI. This compound is then reacted with a bifunctional propane
5 compound Y-(CH2)3-Y', wherein Y and Y' are leaving groups of different reactivities which can be replaced by nucleophiles e.g. Y = CI and Y" = Br. This method is known from the prior art cited in the introductory part of the application and also from WO 99/09015 and WO 03/002543. Compounds of the formula IV wherein Y is OH may also be prepared by the method disclosed in WO 03/002543.
10 A simple method of producing the compounds of formula III, wherein Ar is Ar-1 and R" is SH comprises the reaction of a carboxylic acid of the formula R1-COOH with 4-methyl-3-thiosemicarbazide in the presence of 1,1'-carbonyldimidazole as shown in scheme iv).

Scheme iv)

X
J
j[ y~"SH
R OH

H,C-N NH-NH,
1,1 '-carbonyldiimidazole

r
Nv^S
IT
R1"VN

15
The reaction can be performed using the conditions as described herein and in El-Deen, I.
M. and Ibrahim, H. K., Phosphorus, Sulfur and Si/icon and the Related Elements (2002),
177(3):733-740; Faidallah etal.. Phosphorus, Sulfur and Silicon and the Related Elements
(2002), 177(1):67-79; Tumkevicius, Sigitas and Vainilavicius, Povilas, Journal of Chemical
20 Research, Synopses (2002), 5:213-215; Palaska et a/., FABAD Journal of Pharmaceutical
Sciences (2001), 26(3): 113-117; Li, Xin Zhi and Si, Zong Xing, Chinese Chemical Letters (2002), 13(2): 129-132; and Sunia etal.. Tetrahedron (2001), 57(10):2003-2009.
The preparation of the pyrimidine compounds VIII is simply achieved by reacting tert-
butylamidinium chloride with a suitable p-ketoester IX to yield a 2-terf-butyl-
5 4-hydroxypyrimidine of the formula X which can be transformed to the halo compound VIII
by reacting it with halogenating agent such as thionyl chloride, phosphoryl chloride,
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phosphoryl bromide, phosphorous trichloride, phosphorous tribromide or phosphorous pentachloride (see scheme v):
Scheme v)



tert.-butylamidinium chloride
R2

"^^O-R

(IX) (X) (VIII)
5 b-Ketoesters IX where R2 is alkyl such as propyl, isopropyl, or tert-butyl, or trifluoromethyl
are commercially available and can directly be reacted with terf-butyl-amidinium chloride, which is also commercially available from e.g. Maybridge Ltd.
b-Ketoesters where R2 is fluoroalkyl such as difluoromethyl can be simply synthesized
according to the methods described in this application from the corresponding acid
10 chlorides R2-COCI by reaction with meldrum's acid (2.2-dimethyl-4,6-dioxo-1,3-dioxan)
according to the process as described herein and in B. Trosta ef a/., Journal of the American Chemical Society (2002), 124(35):10396-10415; Paknikar, S. K. etal., Journal of the Indian Institute of Science (2001), 81(2):175-179; and Brummell, David G. ef a/., Journal of Medicinal Chemistry (2001), 44(1 ):78-93.
15 Compounds of the formula I (and also compounds of the formula II as defined hereinafter)
wherein n is 1 contain a sulfoxide -SO- functionality which is a center of chirality. Thus, compounds of the formulae I and II can occur in the racemic form, in the (S)-form or in the (R)-form. The enantiomeric forms of these compounds can either be seperated via chiral column chromatography using chiral stationary phases like CHIRALPAK AD, CHIRALPAK
20 OD or others, with e.g. heptane-ethanol-triethylamine mixtures of varying composition as
eluent, or they can be prepared by enantioselective oxidation of the sulfanyl precursors according to e.g. the following methods described in literature or variations thereof, followed by one or more recrystallization steps (H. Kagan et al., Bull Soc Chim Fr (1996), 133, 1109-1115; F. Di Furia et al., Synthesis, 1984, 325-326; Mike S. Anson etal., Synlett
25 2002, 7, 1055-1060; B. Kohl et al., WO 2004/052882; F. Rebiere et al., WO 2005/028428;
F. Rebierea et al., US 20050222257; S. von Unge et al., Tetrahedron: Asymmetry 11 (2000), 3819-3825, and references cited therein.

If not otherwise indicated, the above-described reactions are generally carried out in a
solvent at temperatures between room temperature and the boiling temperature of the
10 solvent employed. Alternatively, the activation energy which is required for the reaction
can be introduced into the reaction mixture using microwaves, something which has

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proved to be of value, in particular, in the case of the reactions catalyzed by transition metals (with regard to reactions using microwaves, see Tetrahedron 2001, 57, p. 9199 ff. p. 9225 ff. and also, in a general manner, "Microwaves in Organic Synthesis", Andre Loupy (Ed.), Wiley-VCH 2002).
5 Examples of solvents which can be used are ethers such as diethyl ether, diisopropyl
ether, methyl tert-butyl ether or tetrahydrofuran, aprotic polar solvents such as
dimethylformamide, dimethyl sulfoxide, dimethoxyethane and acetonitrile, aromatic
hydrocarbons such as toluene and xylene, ketones such as acetone or methyl ethyl
ketone, halohydrocarbons such as dichloromethane, trichloromethane and dichloroethane,
10 esters such as ethyl acetate and methyl butyrate, carboxylic acids such as acetic acid or
propionic acid, and alcohols such as methanol, ethanol, n-propanol, isopropanol and butanol.
If desired, it is possible for a base to be present in order to neutralize protons which are
released in the reactions. Suitable bases include inorganic bases such as sodium
15 carbonate, potassium carbonate, sodium hydrogen carbonate or potassium hydrogen
carbonate, alkoxides such as sodium methoxide or sodium ethoxide, alkali metal hydrides such as sodium hydride, organometallic compounds such as butyllithium compounds or alkylmagnesium compounds, and organic nitrogen bases such as triethylamine or pyridine. The latter compounds can at the same time serve as solvents.
20 The crude product is isolated in a customary manner, as for example by filtering, distilling
off the solvent or extracting from the reaction mixture, etc. The resulting compounds can be purified in a customary manner, as for example by means of recrystallizing from a solvent, by means of chromatography or by means of converting into an acid addition salt.
The acid addition salts are prepared in a customary manner by mixing the free base with a
25 corresponding acid, where appropriate in solution in an organic solvent as for example a
lower alcohol such as methanol, ethanol, n-propanol or isopropanol, an ether such as
methyl tert-butyl ether or diisopropyl ether, a ketone such as acetone or methyl ethyl
ketone, or an ester such as ethyl acetate. For example, the free base of formula I and
suitable amounts of the corresponding acid, such as from 1 to 4 moles per mol of formula
30 I, are dissolved in a suitable solvent, preferably in a lower alcohol such as methanol,
ethanol, n-propanol or isopropanol. Heating may be applied to dissolve the solids, if
necessary. Solvents, wherein the acid addition salt of I is insoluble (anti-solvents), might
be added to precipitate the salt. Suitable anti-solvents comprise d-C4-alkylesters of Cr
C4-aliphatic acids such as ethyl acetate, aliphatic and cycloaliphatic hydrocarbons such as
35 hexane, cyclohexane, heptane, etc., di-C1-C4 alkylethers such as methyl tert-butyl ether or
diisopropyl ether. A part or all of the anti-solvent may be added to the hot solution of the salt and the thus obtained solution is cooled; the remainder of the anti-solvent is then
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added until the concentration of the salt in the mother liquor is as low as approximately 10 mg/l or lower.
The compounds according to the invention of the formula I are surprisingly highly selective
dopamine D3 receptor ligands. Because of their low affinity for other receptors such as Di
5 receptors, D4 receptors, a1-adrenergic and/or a2-adrenergic receptors, muscarinergic
receptors, histamine receptors, opiate receptors and, in particular, dopamine D2 receptors, the compounds can be expected to give rise to fewer side-effects than do the classic neuroleptics, which are D2 receptor antagonists.
The high affinity of the compounds according to the invention for D3 receptors is reflected
10 in very low in-vitro K| values of as a rule less than 60 nM (nmol/l), preferably of less than
30 nM and, in particular of less than 20 nM. The displacement of [125l]-iodosulpride can, for example, be used in receptor binding studies for determining binding affinities for D3 receptors.
The selectivity of the compounds of the invention for the D2 receptor relative to the D3
15 receptor, expressed as Ki(D2)/K|(D3), is as a rule at least 20, preferably at least 40. The
displacement of [3H]SCH23390a, [125l] iodosulpride or [125l] spiperone can be used, for example, in carrying out receptor binding studies on Du D2 and D4 receptors.
Because of their binding profile, the compounds can be used for treating diseases which
respond to dopamine D3 ligands, that is, they can be expected to be effective for treating
20 those medical disorders or diseases in which exerting an influence on (modulating) the
dopamine D3 receptors leads to an improvement in the clinical picture or to the disease being cured. Examples of these diseases are disorders or diseases of the central nervous system.
Disorders or diseases of the central nervous system are understood as meaning disorders
25 which affect the spinal cord and, in particular, the brain. Within the meaning of the
invention, the term "disorders" denotes disturbances and/or anomalies which are as a rule
regarded as being pathological conditions or functions and which can manifest themselves
in the form of particular signs, symptoms and/or malfunctions. While the treatment
according to the invention can be directed toward individual disorders, that is, anomalies or
30 pathological conditions, it is also possible for several anomalies, which may be causatively
linked to each other, to be combined into patterns or syndromes which can be treated in accordance with the invention.
The disorders which can be treated in accordance with the invention are, in particular,
psychiatric and neurological disturbances. These disturbances include, in particular,
35 organic disturbances, including symptomatic disturbances such as psychoses of the acute
exogenous reaction type or attendant psychoses of organic or exogenous cause as for
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example in association with metabolic disturbances, infections and endocrinopathogies;
endogenous psychoses such as schizophrenia and schizotype and delusional
disturbances; affective disturbances such as depressions, major depressive disorder,
mania and/or manic-depressive conditions; mixed forms of the above-described
5 disturbances; neurotic and somatoform disturbances and also disturbances in association
with stress; dissociative disturbances such as loss of consciousness, clouding of consciousness, double consciousness and personality disturbances; autism; disturbances in attention and waking/sleeping behavior such as behavioral disturbances and emotional disturbances whose onset lies in childhood and youth as for example hyperactivity in
10 children, intellectual deficits such as attention disturbances (attention deficit disorders with
or without hyperactivity), memory disturbances and cognitive disturbances such as impaired learning and memory (impaired cognitive function), dementia, narcolepsy and sleep disturbances such as restless legs syndrome; development disturbances; anxiety states; delirium; sexual disturbances such as impotence in men; eating disturbances such
15 as anorexia or bulimia; addiction; bipolar disorder; and other unspecified psychiatric
disturbances.
The disorders which can be treated in accordance with the invention also include Parkinson's disease and epilepsy and, in particular, the affective disturbances connected thereto.
20 Also treatable are addictive diseases (substance abuse), that is, psychic disorders and
behavioral disturbances which are caused by the abuse of psychotropic substances such as pharmaceuticals or narcotics, and also other addiction behaviors such as addiction to gaming and/or impulse control disorders not elsewhere classified. Examples of addictive substances include opioids such as morphine, heroin and codeine: cocaine; nicotine;
25 alcohol; substances which interact with the GABA chloride channel complex; sedatives,
hypnotics and tranquilizers as for example benzodiazepines; LSD; cannabinoids; psychomotor stimulants such as 3,4-methylenedioxy-N-methylamphetamine (ecstasy); amphetamine and amphetamine-like substances such as methylphenidate; and other stimulants including caffeine. Addictive substances which come particularly into
30 consideration are opioids, cocaine, amphetamine or amphetamine-like substances,
nicotine and alcohol.
With regard to the treatment of addiction diseases, particular preference is given to those
compounds according to the invention of the formula I which themselves do not possess
any psychotropic effect. This can also be observed in a test using rats, which, after having
35 been administered compounds which can be used in accordance with the invention,
reduce their self administration of psychotropic substances, for example cocaine.
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According to another aspect of the present invention, the compounds according to the invention are suitable for treating disorders whose causes can at least partially be attributed to an anomalous activity of dopamine D3 receptors.
According to another aspect of the present invention, the treatment is directed, in
5 particular, toward those disorders which can be influenced, within the sense of an
expedient medicinal treatment, by the binding of preferably exogeneously administered binding partners (ligands) to dopamine D3 receptors.
The diseases which can be treated with the compounds according to the invention are
frequently characterized by progressive development, that is, the above-described
10 conditions change over the course of time; as a rule, the severity increases and conditions
may possibly merge into each other or other conditions may appear in addition to those which already exist.
The compounds according to the invention can be used to treat a large number of signs, symptoms and/or malfunctions which are connected with the disorders of the central
15 nervous system and, in particular, the abovementioned conditions. These signs, symptoms
and/or malfunctions include, for example, a disturbed relationship to reality, lack of insight and ability to meet customary social norms or the demands made by life, changes in temperament, changes in individual drives, such as hunger, sleep, thirst, etc., and in mood, disturbances in the ability to observe and combine, changes in personality, in
20 particular emotional lability, hallucinations, ego-disturbances, distractedness, ambivalence,
autism, depersonalization and false perceptions, delusional ideas, chanting speech, lack of synkinesia, short-step gait, flexed posture of trunk and limbs, tremor, poverty of facial expression, monotonous speech, depressions, apathy, impeded spontaneity and decisiveness, impoverished association ability, anxiety, nervous agitation, stammering,
25 social phobia, panic disturbances, withdrawal symptoms in association with dependency,
maniforma syndromes, states of excitation and confusion, dysphoria, dyskinetic syndromes and tic disorders, such as Huntington's chorea and Gilles-de-la-Tourette's syndrome, vertigo syndromes such as peripheral positional, rotational and oscillatory vertigo, melancholia, hysteria, hypochondria and the like.
30 Within the meaning of the invention, a treatment also includes a preventive treatment
(prophylaxis), in particular as relapse prophylaxis or phase prophylaxis, as well as the treatment of acute or chronic signs, symptoms and/or malfunctions. The treatment can be orientated symptomatically, as for example for the suppression of symptoms. It can be effected over a short period, be orientated over the medium term or can be a long-term
35 treatment, as for example within the context of a maintenance therapy.
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Surprisingly, high brain levels in excess of 100 or even of 200 ng/g or even of 500 ng/g (determined in rats as the value Cmax) can be achieved when administering the compounds of the invention.
Therefore the compounds according to the invention are preferentially suitable for treating
5 diseases of the central nervous system, in particular for treating affective disorders;
neurotic disturbances, stress disturbances and somatoform disturbances and psychoses,
and, in particular, for treating schizophrenia and depression. Because of their high
selectivity with regard to the D3 receptor, the compounds I according to the invention are
also suitable for treating disturbances of kidney function, in particular disturbances of
10 kidney function which are caused by diabetes mellitus (see WO 00/67847) and, especially,
diabetic nephropathy.
In addition, compounds of the present invention may possess other pharmacological and
/or toxicological properties that render them especially suitable for development as
pharmaceuticals. As an example, compounds of formula I having a low affinity for the
15 HERG receptor could be expected to have a reduced likelihood of inducing QT-
prolongation (regarded as a one predictor of risk of causing cardiac arrythmia, (For a discussion of QT-prolongation see for example A. Cavalli ef a/., J. Med. Chem. 2002, 45:3844-3853 and the literature cited therein; a HERG assay is commercially available from GENION Forschungsgesellschaft mbH, Hamburg, Germany).
20 Within the context of the treatment, the use according to the invention of the described
compounds involves a method. In this method, an effective quantity of one or more compounds, as a rule formulated in accordance with pharmaceutical and veterinary practice, is administered to the individual to be treated, preferably a mammal, in particular a human being, productive animal or domestic animal. Whether such a treatment is
25 indicated, and in which form it is to take place, depends on the individual case and is
subject to medical assessment (diagnosis) which takes into consideration signs, symptoms and/or malfunctions which are present, the risks of developing particular signs, symptoms and/or malfunctions, and other factors.
As a rule, the treatment is effected by means of single or repeated daily administration,
30 where appropriate together, or alternating, with other active compounds or active
compound-containing preparations such that a daily dose of preferably from about 0.01 to
1000 mg/kg, more preferably from 0.1 to 1000 mg/kg of bodyweight in the case of oral
administration, or of from about 0.01 to 100 mg/kg, more preferably from 0.1 to 100 mg/kg
of bodyweight in the case of parenteral administration, is supplied to an individual to be
5 treated.
The invention also relates to the production of pharmaceutical compositions for treating an individual, preferably a mammal and in particular a human being, a farm animal or a
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domestic animal. Thus, the compounds are customarily administered in the form of
pharmaceutical compositions which comprise a pharmaceutical^ acceptable excipient
together with at least one compound according to the invention and, where appropriate,
other active compounds. These compositions can, for example, be administered orally,
5 rectally, transdermal^, subcutaneously, intravenously, intramuscularly or intranasally.
Examples of suitable pharmaceutical formulations are solid medicinal forms such as
powders, granules, tablets (in particular film tablets), lozenges, sachets, cachets, sugar-
coated tablets, capsules such as hard gelatin capsules and soft gelatin capsules;
suppositories or vaginal medicinal forms; semisolid medicinal forms such as ointments,
10 creams, hydrogels, pastes or plasters; and also liquid medicinal forms such as solutions,
emulsions (in particular oil-in-water emulsions), suspensions such as lotions, injection preparations and infusion preparations, and eyedrops and eardrops. Implanted release devices can also be used for administering inhibitors according to the invention. In addition, it is also possible to use liposomes or microspheres.
15 When producing the compositions, the compounds according to the invention are usually
mixed or diluted with an excipient. Excipients can be solid, semisolid or liquid materials which serve as vehicles, carriers or medium for the active compound.
Suitable excipients are listed in the specialist medicinal monographs. In addition, the formulations can comprise pharmaceutically acceptable carriers or customary auxiliary
20 substances, such as glidants; wetting agents; emulsifying and suspending agents;
preservatives; antioxidants; antiirritants; chelating agents; coating auxiliaries; emulsion stabilizers; film formers; gel formers; odor masking agents; taste com'gents; resin; hydrocolloids; solvents; solubilizers; neutralizing agents; diffusion accelerators; pigments; quaternary ammonium compounds; refatting and overfatting agents; raw materials for
25 ointments, creams or oils; silicone derivatives; spreading auxiliaries; stabilizers; sterilants;
suppository bases; tablet auxiliaries, such as binders, fillers, glidants, disintegrants or coatings; propellants; drying agents; opacifiers; thickeners; waxes; plasticizers and white mineral oils. A formulation in this regard is based on specialist knowledge as described, for example, in Fiedler, HP., Lexikon der Hilfsstoffe fur Pharmazie, Kosmetik und
30 angrenzende Gebiete [Encyclopedia of auxiliary substances for pharmacy, cosmetics and
related fields], 4,h edition, Aulendorf: ECV-Editio-Kantor-Verlag, 1996.
The following examples serve to explain the invention without limiting it.
The compounds were either characterized via proton-NMR in de-dimethylsulfoxid or d-
chloroform on a 400 MHz or 500 MHz NMR instrument (Bruker AVANCE), or by mass
35 spectrometry, generally recorded via HPLC-MS in a fast gradient on C18-material
(electrospray-ionisation (ESI) mode), or melting point.
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The magnetic nuclear resonance spectral properties (NMR) refer to the chemical shifts (8)
expressed in parts per million (ppm). The relative area of the shifts in the 1H NMR
spectrum corresponds to the number of hydrogen atoms for a particular functional type in
the molecule. The nature of the shift, as regards multiplicity, is indicated as singlet (s),
5 broad singlet (s. br.), doublet (d), broad doublet (d br.), triplet (t), broad triplet (t br.),
quartet (q), quintet (quint.) and muitiplet (m).
Preparation Examples:
I. Preparation of Intermediates:
a. Preparation of 2-tert.butyl-pyrimidine-compounds IV
10 a. 1 2-tert-Butyl-4-[4-(3-chloro-propyl)-piperazin-1 -yl]-6-cyclobutyl-pyrimidine
a. 1.1: Methyl-2-cyclobutanoyl-acetate
22 g of meldrum's acid (2,2-dimethyl-1,3-dioxane-4,6-dione) (152.7 mmol) and 36.9 ml of pyridine (457.2 mmol) were dissolved in 200 ml of dichloromethane. 18.1 g of cyclobutylcarbonic acid chloride were added at 0 to 10°C. The reaction mixture was
15 stirred overnight at room temperature, washed with 1 N HCI and extracted with di-
chloromethane. The organic layer was washed with water, dried over magnesium sulfate, filtered, and then concentrated to dryness. The oily residue was dissolved in 300 ml of methanol and heated under reflux for 2h. The reaction mixture was concentrated to dryness and the residue purified via silica gel chromatography with ethyl
20 acetate as eluent. Yield: 21.2 g
MS(ESI)m/z: 157.1 [M+H]+
1H-NMR (CDCI3): 5 [ppm] 3.7 (s, 3H), 3.4 (s, 2H), 3.3-3.4 (m, 1H). 2.2-2.4 (m, 2H), 2.1-2.25 (m, 2H), 1.9-2.1 (m, 1H), 1.8-1.9 (m, 1H).
a.1.2: 2-tert-Butyl-4-hydroxy-6-cyclobutyl-pyrimidine
25 9.2 g of tert-butyl amidinium chloride (67.3 mmol, Maybridge) and 12.6 g of methyl-2-
cyclobutanoyl acetate (80.7 mmol) were dissolved/suspended in 100 ml of methanol. 14.5 g of sodium methanolate (268.4 mmol) were added in portions to the solution at 10°C. The suspension was then stirred at room temperature overnight. The reaction mixture was concentrated to roughly half the volume and filtered. The filtrate was ex-
30 traded with water and dichloromethane. The organic phase was dried over magne-
sium sulfate, filtered, and then concentrated to dryness. The residue was stirred with acetone and the precipitate was collected by filtration. Yield: 11.9 g (85.7 %).
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MS (ESI) m/z: 207.2 [M+H]*
a.1.3: 2-ferf-Butyl-4-chloro-6-cyclobutyl-pyrimidine
9.9 g of 2-ten4-butyl-4-hydroxy-6-cycIobutyl-pyrimidine (48 mmol) were dissolved in
80 ml of toluene and 1 ml of dimethylformamide. 10.7 ml of POCI3 (114.8 mmol)
5 were added dropwise at 10°C. Stirring was continued for 3 h at room temperature.
The reaction mixture was poured into water, and the aqueous layer extracted with di-chloromethane. The organic layer was dried over magnesium sulfate, filtered, and then concentrated to dryness to give 10.8 g of a yellowish oil (quant.).
a. 1.4: 2-tert-Butyl-4-(piperazin-1 -yl)-6-cyclobutyl-pyrimidine
10 24.8 g of piperazine (287.9 mmol) were dissolved in 350 ml of ethanol and heated to
reflux. 24.9 g of 2-tert-butyl-4-chloro-6-cyclobutyl-pyrimidine (48.06 mmol), dissolved in 50 ml of ethanol, were added dropwise to the solution. The solution was refluxed for further 3h, cooled to room temperature and then extracted with water and ethyl acetate. The organic layer was washed with 5 % citric acid (aq.), and the aqueous
15 layer was adjusted to alkaline pH with 2 N NaOH. The alkaline aqueous layer was
reextracted with ethyl acetate, and the organic phase was dried over magnesium sulfate, filtered and concentrated to dryness to yield 8.6 g (65.2 %) of the title compound.
MS (ESI) m/z: 275.2 [M+H]+
20 'H-NMR (CDCI3): 8 [ppm] 6.1 (s, 1H), 3.6 (m, 4H), 3.4 (m, 1H), 2.9 (m, 4H), 2.3 (m,
4H), 1.8-2.1 (m, 3H), 1.3(s,9H)
a. 1.5: 2-fert-Butyl-4-[4-(3-chloro-propyl)-piperazin-1-yl]-6-cyclobutyl-pyrimidine
3.5 g of 2-terf-butyl-4-(piperazin-1-yl)-6-cyclobutyl-pyrimidine (12.75 mmol), 2.3 g of 1-bromo-3-chloro-propane (14.6 mmol) and 2.8 ml of triethylamine (20.1 mmol) were
25 dissolved in 70 ml of dimethylformamide. The mixture was stirred at room tempera-
ture overnight and for further 3 h at 40°C. The reaction mixture was then extracted with water and ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and concentrated to dryness. The crude product was then purified by silica gel chromatography (dichloromethane as eluent) to yield 3.0 g (67 %) of the title
30 compound.
a.2 2-ferf-Butyl-4-[4-(3-chloro-propyl)-piperazin-1 -yl]-6-(1 -methylcyclopropyl)-pyrimidine was obtained by analogy to the method outlined in a.1: MS (ESI) m/z: 351.2 [M+H]*
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a.3. 2-ferf-Butyl-4-[4-(3-chloro-propyl)-piperazin-1-yl]-6-n-propy|pyrimidine was obtained by analogy to the method outlined in a.1: MS (ESI) m/z: 339.2 [M+H]*
a.4. 2-tert-Butyl-6-tert.-butyl-4-[4-(3-chloro-propyl)-piperazin-1-y|]-pyrimidinewas obtained by analogy to the method outlined in a.1: MS (ESI) m/z: 353.3 [M+Hf
5 a.5. 2-terf-Butyl-6-trifluoromethyl-4-[4-(3-chloro-propyl)-piperazin-1-yl]-pyrimidine was
obtained by analogy to the method outlined in a.1.
b. Preparation of 3-mercapto-4-methyl-triazoles III
b. 1 4-Methyl-5-methyl-4H-[1,2,4]triazole-3-thiol
62.4 g of N.N'-carbonyldiimidazol (0.385 mol) were added in portions within 10 min. to a mixture of 22 g of acetic acid (0.366 mol) and 300 ml of dimethylformamide. The temperature rose from 22°C to about 26°C. After the addition was completed, stirring was continued for 30 min. Then 38.5 g of 4-methyl-3-thiosemicarbazid (0.366 mol) and 100 ml of pyridine were added. The reaction mixture was heated to 100°C and stirred for 4 h at this temperature. Stirring was continued for 14 h at room temperature. The solvent was evaporated under reduced pressure. The residue was treated with 200 ml of isopropanol and 150 ml of ethyl acetate, and re-dissolved at 80°C. Crystallization of the product started during cooling to room temperature. 300
20 ml of isopropanol were added and the obtained suspension was stirred for 1 h at room temperature. The precipitate was collected by filtration, washed twice with 75 ml of isopropanol each and dried under vacuum at 40,,C to yield 20.4 g of the title compound.
MS (ESI) m/z: 130.1 [M+H]+
1H-NMR (DMSO): 5 [ppm]13.4 (s, broad, 1H), 3.4 (s, 3H), 2.3 (s, 3H)
b.2. 4-Methyl-5-methoxymethyl-4H-[1,2,4]triazole-3-thiol
25 5 g of methoxy-acetic acid (55.5 mmol) were dissolved in 70 ml of dimethylform-
amide. 11.73 g of 1,1'-carbonyldiimidazol (72.3 mmol) were added in portions within 10 min. After 30 min. at room temperature 23 ml of pyridine were added. Then 5.84 g of 4-methyl-3-thiosemicarbazide (55.5 mmol) were added and the obtained solution was stirred at room temperature overnight, and for an additional 3 h at 100°C.
30 The solvent was evaporated, the residue dissolved in 70 ml of saturated aqueous
sodium chloride solution and 30 ml of water. The aqueous layer was extracted six times with 100 ml of ethyl acetate each, and the combined organic layers were dried over magnesium sulfate, filtered, and the solvent was evaporated to dryness to yield
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17 g of the crude title compound, which was further purified by silica gel chromatography with ethyl acetate, thereby obtaining 7.1 g of the purified title compound.
MS (ESI) m/z: 160.1 [M+H]+
b.3 5-Ethyl-4-methyl-4H-[1,2,4]triazole-3-thiol was obtained by analogy to method b.2:
5 MS (ESI) m/z: 144.1 [M+H]+
b.4 4-Methyl-5-(4-fluorophenyl)-4H-[1,2,4]triazole-3-thiol was purchased from Chembridge Corporation.
b.5 5-Cyclobutyl-4-methyl-4H-[1,2,4]triazole-3-thiol was obtained by analogy to method b.2: MS (ESI) m/z: 170.1 [M+H]+
10 b.6 4-Methyl-4H-[1,2,4]triazole-3-thiol was purchased from Aldrich.
b.7 4-Methyl-5-phenyl-4H-[1,2,4]triazole-3-thiol was purchased from Chembridge Corporation.
b.8 5-Cyclopropyl-4-methyl-4H-[1,2,4]triazole-3-thiol was obtained by analogy to method b.2: MS (ESI) m/z: 156.1 [M+Hf
15 b.9 4-Methyl-5-trifluoromethyl-4H-[1,2,4]triazole-3-thiol was purchased from Acros.
b.10 4-Methyl-5-(1-methylpyrrol-2-yl)-4H-[1,2,4]triazole-3-thiol was obtained by analogy to method b.2.
c: Preparation of compounds II
c.1 2-fert-Butyl-4-{4-[3-(4-methyl-4H-[1,2,4]triazol-3-ylsulfanyl)-propyl]-piperazin-1-yl}-6-
20 cyclobutylpyrimidine
0.8 g of 2-tert-butyl-4-[4-(3-chloro-propyl)-piperazin-1-yl]-6-cyclobutyl-pyrimidine
(2.28 mmol), 0.29 g of 4-methyl-3-mercapto-1,2,4-triazole (2.52 mmol), 0.15 g of lith
ium hydroxide and a tip of a spatula of potassium iodide were dissolved in 20 ml of
dimethylformamide The mixture was stirred for 14 h at room temperature and then
25 extracted with water and ethyl acetate. The organic layer was dried over magnesium
sulfate, filtered, and evaporated to dryness. The residue was then purified by column chromatography on silica gel (dichloromethane-methanol (2-10 %)) to yield an oily residue that was precipitated with acetonitrile thereby yielding 0.46 g of the title compound (47 %).
30 MS (ESI) m/z: 430.5 [M+Hf
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1H-NMR (DMSO): 5 [ppm] 8.1 (s, 1H), 6.1 (s, 1H), 3.15 (m, 4H), 3.1 (s,3H), 3.4 (m, 1H), 3.3 (m, 2H), 2.45 (m, 6H), 2.25 (m, 4H), 2.0 (m, 3H), 1.9 (m, 1H), 1.3 (s, 9H).
c.2 2-terf-Butyl-4-{4-[3-(4-methyl-5-methyl-4H-[1,2,4]triazol-3-ylsulfanyl)-propyl]-piperazin-1 -yl}-6-tert-butyl-pyrimidine hydrochloride
5 1 g of 2-tert-butyl-4-[4-(3-chloro-propyl)-piperazin-1-yl]-6-fert-butyl-pyrimidine(2.83
mmol), 0.4 g of 4-methyl-5-methyl-4H-[1,2,4]triazole-3-thiol (3.09 mmol), 0.2 g of lithium-hydroxide (8.35 mmol) and a spatula tip of potassium iodide werde stirred in 20 ml of dimethylformamide for 2 h at 80°C. After addition of water and ethyl acetate, the organic phase was separated and dried over magnesium sulfate. After filtration
10 and evaporation of the solvent, the crude product was purified by column chroma-
tography on silica gel using dichloromethane-methanol (1-6%). Fractions containing the product were combined and the solvent was evaporated. The residue was dissolved in isopropanol, and a solution of HCI in isopropanol was added. On addition of diisopropylethylether, the product formed an oily mass. The solvent was decanted
15 and the remaining oil evaporated to dryness to yield 0.6 g (41 %) of the title com-
pound as a white solid.
MS (ESI) m/z: 446.3 [M+H]+
1H-NMR (DMSO): 8 [ppm] 12.0 (s, 1H, broad), 6.8 (s, 1H, broad), 4.7 (m, 2H,
broad), 3.4-3.7 (m, 4H, very broad), 3.6 (s, 3H), 3.4 (m, 2H), 3.25 (m, 2H), 3.0-3.4
20 (m, 2H, very broad), 2.6 (s, 3H), 2.2 (m, 2H), 1.4 (s, 18H, broad)
c.3 2-terf-Butyl-4-{4-[3-(4-methyl-5-cyclopentyl-4H-[1,2,4]triazol-3-ylsulfanyl)-propyl]-piperazin-1 -yl}-6-trifluoromethyl-pyrimidine trifluoroacetate
1 g of 2-tert-butyl-4-[4-(3-chloro-propyl)-piperazin-1-yl]-6-trifluoromethyl-pyrimidine (2.74 mmol) and 0.55 g of of 4-methyl-5-cyclopentyl-4H-[1.2,4]triazole-3-thiol (3.0
25 mmol) were dissolved in 10 ml of n-butanol. After addition of 0.197 g of lithium hy-
droxide (8.22 mmol) and 0.205 g of sodium iodide (1.37 mmol), the reaction mixture was heated to 79°C for 3 h. After cooling, the solution was filtered, and the filtrate evaporated to dryness. The residue was partitioned between 30 ml of ethyl acetate, 20 ml of water and 20 ml of an aqueous saturated solution of sodium chloride. The
30 aqueous layer was re-extracted twice with 30 ml of ethyl acetate each. The com-
bined organic layers were dried over magnesium sulfate, filtered, and the solvent was evaporated. The residue was purified by preparative HPLC on a C18-Symmetry column (Waters). Fractions containing the product were combined and lyophilised to yield 0.25 g of the title compound.
35 MS (ESI) m/z: 512.3 [M+H]+
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1H-NMR (DMSO): 8 [ppm] 7.05 (s, 1H). 3.75 (m. broad, 4H), 3.5 (s. 3H), 3.2 (m, 1H). 3.15 (m, 2H). 2.45 (m, 6H), 2.05 (m. 2H). 1.85 (m, 4H), 1.75 (m, 2H). 1.65 (m, 2H). 1.3 (s. 9H)
c.4 2-tert-Butyl-4-{4-[3-(4-methyl-5-methoxymethyl-4H-[1,2,4]triazol-3-ylsulfanyl)-propyl]-
5 piperazin-1-yl}-6-difluoromethyl-pyrimidine hydrochloride
0.6 g of 4-methyl-5-methoxymethyl-4H-[1,2,4]triazole-3-thiol (3.77 mmol), 0.09 g of lithium hydroxide (3.77 mmol) and 0.28 g sodium iodide (1.88 mmol) were dissolved in 20 ml of dimethylformamide. Within 2 h, a solution of 1.31 of g 2-ferf-butyl-4-[4-(3-chloro-propyl)-piperazin-1-yl]-6-difluoromethyl-pyrimidine (3.77 mmol) in 5 ml of di-
10 methylformamide was added at 70°C. Stirring was continued for 1 h at 80°C. After
cooling, the solvent was evaporated and the remaining oily residue was partitioned between 30 ml of ethyl acetate, 15 ml of water and 15 ml of a saturated aqueous solution of sodium chloride. The aqueous layer was re-extracted twice with 20 ml ethyl acetate each and the organic layers were combined, dried over magnesium sulfate,
15 filtered, and the solvent was evaporated. The residue was purified by column chro-
matography on silica gel employing in succession dichloromethane-ethyl acetate 1:1, ethyl acetate, and ethyl acetate-methanol 5:1. Fractions containing the product were combined, the solvents was evaporated and the residue was re-dissolved in 15 ml ethyl acetate. A 4 N solution of HCI in diethyl ether was added to precipitate the hy-
20 drochloride salt. The solution was decanted and the residue dried.
Yield: 0.55 g.
MS (ESI) m/z: 470.2 [M+Hf
1H-NMR (DMSO): 5 [ppm] 11.95 (s, 1H, broad), 9.8 (s, 3H. broad), 7.0 (s, 1H), 6.8 (t,
1H, CHF2), 4.7 (s, 2H), 4.6 (m, 2H, broad). 3.45-3.7 (m, 4H. broad), 3.6 (s, 3H), 3.4
25 (m, 2H). 3.35 (s, 3H), 3.2 (m. 2H), 2.95-3.2 (m, 2H, broad), 2.2 (m, 2H), 1.3 (s, 9H),
1.2 (m, 1H)
c.5 2-terf-Butyl-4-{4-[3-(4-methyl-4H-[1,2,4]triazol-3-ylsulfanyl)-propyl]-piperazin-1 -yl}-6-terf-butyl-pyrimidine hydrochloride
1 g of 2-fert-butyl-4-[4-(3-chloro-propyl)-piperazin-1-yl]-6-fen'-butyl-pyrimidine (2.83
30 mmol), 0.35 g of 4-methyl-4H-[1,2,4]triazole-3-thiol (3.04 mmol), 0,2 g of lithium-
hydroxide (8.35 mmol) and a spatula tip of potassium iodide were stirred for 72 h in
20 ml of dimethylformamide. Water and ethyl acetate were added and the organic
layer was separated, dried over magnesium sulfate, filtered and the solvent was
evaporated. The residue was subjected to a column chromatography on silica gel us-
35 ing dichloromethane-methanol(2-10%). Fractions containing the product were com-
bined, the solvent was evaporated and the residue re-dissolved in isopropanol. The
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PCT/EP2005/012856

solution was treated with HCI/isopropanol. Diisopropylethylether was added whereby an oily precipitate formed. The solvent was decanted and the remaining oil evaporated to dryness to yield 1.1 g (77 %) of the title compound as a white solid.
MS (ESI) m/z: 432.2 [M+H]+
5 1H-NMR (DMSO): 8 [ppm] 12.5 (s, 1H, broad), 12.1 (s, 1H, broad), 9.65 (s, 1H), 6.85
(s, 1H), 5.0 (m, broad, 1H), 4.7 (m, broad, 1H), 3.75 (m, 1H), 3.7 (s, 3H), 3.65 (m, broad. 3H), 3.45 (m, 2H), 3.25 (m, 2H), 3.2 (m, 2H), 2.2 (m, 2H). 1.45 (m, 18H).
c.6 2-tert-Butyl-4-{4-[3-(4-methyl-5-trifluoromethyl-4H-[1,2,4]triazol-3-ylsulfanyl)-propyl]-piperazin-1 -yl}-6-difluoromethyl-pyrimidine hydrochloride
10 0.5 g of 4-methyl-5-trifluoromethyl-4H-[1,2,4]triazole-3-thiol (2.73 mmol), 0.07 g of
lithium hydroxide (2.73 mmol) and 0.2 g of sodium iodide (1.36 mmol) were dissolved in 20 ml of dimethylformamide. Within 1 h, a solution of 0.95 g of 2-terf-butyl-4-[4-(3-chloro-propyl)-piperazin-1-yl]-6-difluoromethyl-pyrimidine (2.73 mmol) in 4 ml of dimethylformamide was added at 70°C. Stirring was continued for 3 h at 70°C. Af-
15 ter cooling, the solvent was evaporated and the remaining oily residue partitioned be-
tween 30 ml of ethyl acetate, 15 ml of water plus 10 ml of a saturated aqueous solution of sodium chloride. The aqueous layer was re-extracted twice with 15 ml of ethyl acetate each, and the combined organic layers were dried over magnesium sulfate, filtered, and the solvent was evaporated. The crude product was purified by column
20 chromatography on silica gel using ethylacetate. Fractions containing the product
were combined, the solvent was evaporated and the residue was re-dissolved in 20 ml of ethyl acetate. A 1N solution of HCI in diethyl ether was added to precipitate the title compound as the hydrochloride salt. The solution was cautiously evaporated to dryness to yield 0.64 g of the title compound as a white crystalline material.
25 MS (ESI) m/z: 494.2 [M+H]+
'H-NMR (DMSO): 5 [ppm] 11.8 (s, 1H, broad), 7.1 (s. 1H), 6.7 - 7.0 (t, 1H, CHF2), 3.7 (s, 2H), 3.6 (m, 4H), 3.4 (m,2H), 3.25 (m, 2H),3.1 (m, 2H), 2.2 (m, 2H), 1.3 (s, 9H),
c.7 2-tert-Butyl-4-{4-[3-(4-methyl-5-terf-butyl-4H-[1,2,4]triazol-3-ylsulfanyl)-propyl]-piperazin-1 -yl}-6-difluoromethyl-pyrimidine hydrochloride
30 1.0 g of 2-fert-butyl-4-[4-(3-chloro-propyl)-piperazin-1-yl]-6-difluoromethyl-pyrimidine
(2.88 mmol), 0.5 g of 4-methyl-5-tert-butyl-4H-[1,2,4]triazole-3-thiol (2.92 mmol), 0,17 g lithium-hydroxide (7.1 mmol) and a spatula tip of potassium iodide were stirred in 30 ml of dimethylformamide for 14 h at room temperature. After addition of water and ethyl acetate, the organic layer was separated and dried over magnesium
35 sulfate. After filtration and evaporation of the solvent, the crude product was purified
26
WO 2006/058753 PCT/EP2005/012856
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by column chromatography on silica gel using dichloromethane-methanol (2%). Fractions containing the product were combined and the solvents were evaporated. The residue was dissolved in isopropanol and a solution of HCI in isopropanol was added. The thus formed precipitate was collected and dried thoroughly to yield 0.6 g
5 (37.5 %) of the title compound.
MS (ESI) m/z: 482.4 [M+H]+
1H-NMR (DMSO): 8 [ppm]7.0 (s, 1H), 6.8 (t, 1H, CHF2), 4.6 (m, broad, 2H), 3.8 (s, 3H), 3.55 (m, broad, 4H), 3.45 (m, 2H), 3.2 (m. 2H), 3.1 (m, 2H), 2.2 (m, 2H), 1.5 (s, 9H), 1.3 (s, 9H).
10
The compounds II of examples c.8 to c.29 were prepared in a similar manner as described in the examples c.1 to c.7:
c.8 2-tert-Butyl-4-{4-t3-(4-methyl-5-trifluoromethyl-4H-[1,2,4]triazol-3-ylsulfanyl)-propyl]-piperazin-1 -yl}-6-tert-butyl-pyrimidine hydrochloride
15 Reaction of 0.5 g of 2-tert-butyl-4-[4-(3-chloro-propyl)-piperazin-1-yl]-6-tert-butyl-
pyrimidine (1.42 mmol) and 0.28 g of 4-methyl-5-trifluoromethyl-4H-[1,2,4]triazole-3-thiol (1.53 mmol) yielded 0.35 g (43 %) of the title compound as a white solid.
MS (ESI) m/z: 500.3 [M+H]+
1H-NMR (DMSO): 8 [ppm]12.5 (s, 1H, broad), 12.1 (s, 1H, broad), 6.9 (s, 1H), 4.7
20 (m, 2H, broad), 3.85 (m, broad, 2H), 3.7 (s, 3H), 3.65 (m, 2H), 3.4 (m, 2H), 3.25 (m,
2H), 3.2 (m, 2H), 2.2 (m, 2H), 1.45 (m, 18H),
c.9 2-tert-Butyl-4-{4-[3-(4-methyl-5-cyclopropyl-4H-[1,2,4]triazol-3-ylsulfanyl)-propyl]-piperazin-1 -yl}-6-tert-butyl-pyrimidine hydrochloride
Reaction of 0.5 g of 2-tert-butyl-4-[4-(3-chloro-propyl)-piperazin-1-yl]-6-ferf-butyl-
25 pyrimidine (1.42 mmol) with 0.22 g of 4-methyl-5-cyclopropyl-4H-[1,2,4]triazole-3-
thiol (1.42 mmol) yielded 0.32 g of the title compound.
MS (ESI) m/z: 472.4 [M+H]+
c. 10 2-fert-Butyl-4-{4-[3-(4-methyl-5-methyl-4H-[1,2,4]triazol-3-ylsulfanyl)-propyl]-piperazin-1-yl}-6-propyl-pyrimidine hydrochloride
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Reaction of 1 g of 2-tert-butyl-4-[4-(3-chloro-propyl)-piperazin-1-yl]-6-propyl-pyrimidine (2.95 mmol) with 0.42 g of 4-methyl-5-methyl-4H-[1,2,4]triazole-3-thiol (3.25 mmol) yielded 0.5 g (33.6 %) of title compound as a solid.
MS (ESI) m/z: 432.2 [M+Hf
5 'H-NMR (DMSO): 8 [ppm]14.4 (s, 1H, broad), 12.1 (s, 1H, broad), 7.15 (s, 1H), 5.0
(m, broad, 1H), 4.5 (s, broad, 1H), 3.75 (m, 1H), 3.7 (m, broad, 3H), 3.65 (s, 3H), 3.4 (m, 2H), 3.3 (m, 2H), 3.25 (m, broad, 2H), 2.95 (m, 2H), 2.65 (s, 3H), 2.2 (m, 2H), 1.7 (m. 2H), 1.4 (s, 9H), 0.9 (m, 3H)
c. 11 2-tert-Butyl-4-{4-[3-(4-methyl-5-ethyl-4H-[1,2,4]triazo!-3-ylsulfanyl)-propyl]-piperazin-
10 1-yl}-6-propyl-pyrimidine hydrochloride
Reaction of 0.3 g of 4-methyl-5-ethyl-4H-[1,2,4]triazole-3-thiol (2.09 mmol) with 0.71 g of 2-fert-butyl-4-[4-(3-chloro-propyl)-piperazin-1-yl]-6-propyl-pyrimidine (2.09 mmol) yielded 0,63 g of the title compound.
MS (ESI) m/z: 446.3 [M+H]+
15 1H-NMR (DMSO): 8 [ppm] 14.25 (s, 1H, broad), 12.1 (s, 1H, broad). 7.15 (s, 1H), 5.0
(m, 1H, broad), 4.4 (m, 1H, broad), 3.0-4.0 (m, broad, 6H), 3.6 (s, 3H), 3.35 (m, 2H), 3.25 (m. 2H), 2.9 (m, 4H), 2.15 (m, 2H), 1.7 (m, 2H), 1.45 (s, 9H), 1.3 (m, 3H), 0.95 (m, 3H)
c. 12 2-terf-Butyl-4-{4-[3-(4-methyl-5-methoxymethyl-4H-[1,2,4]triazol-3-ylsulfanyl)-propyl]-
20 piperazin-1-yl}-6-propyl-pyrimidine hydrochloride
0.35 g of 4-methyl-5-methoxymethyl-4H-[1,2,4]triazole-3-thiol (2.19 mmol) were reacted with 0.75 g of 2-tert-butyl-4-[4-(3-chloro-propy!)-piperazin-1-yl]-6-propyl-pyrimidine (2.19 mmol) to yield 0.79 g of the title compound.
MS (ESI) m/z: 462.3 [M+H]*
25 1H-NMR (DMSO): 8 [ppm] 14.4 (s, 1H, broad), 12.1 (s, 1H, broad), 7.9 (s, broad, 2H),
7.2 (s, 1H), 5.0 (m, 1H, broad), 4.7 (s, 3H), 4.5 (m, 1H, broad), 3.85 (m, 1H), 3.9-3.5 (m, 3H), 3.65 (s, 3H), 3.1-3.45 (m, 6H), 2.95 (m, 2H), 2.2 (m, 2H), 1.7 (m, 2H), 1.45 (s,9H), 0.95 (m,3H)
c. 13 2-ter/-Butyl-4-{4-[3-(4-methyl-5-trifluoromethyl-4H-[1,2,4]triazol-3-ylsulfanyl)-propyt]-
J0 piperazin-1-yl}-6-trifluoromethyl-pyrimidine hydrochloride
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1 g of 2-fe/t-butyl-4-[4-(3-chloro-propyl)-piperazin-1-yl]-6-trifluoromethyl-pyrimidine (2.74 mmol) were reacted with 0.55 g of 4-methyl-5-trifluoromethyl-4H-[1,2,4]triazole-3-thiol (3 mmol) to yield 0.7 g (43.7 %) of the title compound as a white solid.
MS (ESI) m/z: 512.2 [M+H]+
5 1H-NMR (DMSO): 8 [ppm]11.7 (s, 1H, broad), 7.25 (s, 1H), 4.55 (m, broad, 1H), 3.7
(s, 3H), 3.6 (m, 5H), 3.4 (m, 2H), 3.25 (m, 2H), 3.1 (m, 2H), 2.25 (m, 2H), 1.3 (s, 9H)
c.14 2-tert-Butyl-4-{4-[3-(4-methyl-5-methyl-4H-[1,2,4]triazol-3-ylsulfanyl)-propyl]-piperazin-1 -yl}-6-trifluoromethyl-pyrimidine hydrochloride
3 g of 4-methyl-5-methyl-4H-[1,2,4]triazole-3-thiol (23.22 mmol) were reacted with
10 8.47 g of 2-terf-butyl-4-[4-(3-chloro-propyl)-piperazin-1 -yl]-6-trifluoromethyl-
pyrimidine (23.22 mmol) to yield 8.7 g of the title compound.
MS (ESI) m/z: 458.4 [M+H]+
1H-NMR (DMSO): 8 [ppm]11.9 (s, 1H, broad), 7.2 (s, 1H), 4.7 (m, 2H), 3.5-3.8 (m, 7H), 3.4 (m, 2H), 3.2 (m, 2H), 3.1 (m, 2H), 2.6 (s, 3H), 2.2 (m, 2H), 1.3 (s, 9H)
15 c. 15 2-ferf-Butyl-4-{4-[3-(4-methyl-5-ethyl-4H-[1,2,4]triazol-3-ylsulfanyl)-propyl]-piperazin-
1 -yl}-6-trifluoromethyl-pyrimidine hydrochloride
1.5 g of 4-methyl-5-ethyl-4H-[1,2,4]triazole-3-thiol (10.75 mmol) were reacted with 3.92 g of 2-rerf-butyl-4-[4-(3-chloro-propyl)-piperazin-1-yl]-6-trifluoromethyl-pyrimidine (10.75 mmol) to yield 3.0 g of the title compound.
20 MS (ESI) m/z: 472.2 [M+H]+
1H-NMR (DMSO): 8 [ppm]11.9 (s, 1H, broad), 7.25 (s, 1H). 4.4-5.0 (m, 2H, broad), 3.25-3.75 (m, broad, 4H), 3.6 (s, 3H), 3.4 (m, 2H), 3.2 (m, 2H), 3.1 (m, 2H). 2.95 (m, 2H), 2.2 (m, 2H), 1.2-1.4 (m, 12H),
c. 16 2-terf-Butyl-4-{4-[3-(4-methyl-5-methoxymethyl-4H-[1,2,4]triazol-3-ylsulfanyl)-propyl]-
25 piperazin-1-yl}-6-trifluoromethyl-pyrimidine hydrochloride
1.5 g of 4-methyl-5-methoxymethyl-4H-[1,2,4]triazole-3-thiol (9.42 mmol) were reacted with 3.44 g 2-tert-Butyl-4-[4-(3-chloro-propyl)-piperazin-1-yl]-6-trifluoromethyl-pyrimidine (9.42 mmol) to yield 3.1 g of the title compound.
MS (ESI) m/z: 488.3 [M+H]+
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1H-NMR (DMSO): 8 [ppm]14.4 (s. 1H, broad), 12.1 (s, 1H, broad), 7.9 (s, broad, 2H), 7.2 (s, 1H), 5.0 (m, 1H, broad), 4.7 (s, 3H), 4.5 (m, 1H, broad), 3.85 (m. 1H), 3.9-
3.5 (m, 3H), 3.65 (s, 3H), 3.1-3.45 (m, 6H), 2.95 (m, 2H), 2.2 (m, 2H), 1.7 (m, 2H),
1.45 (s,9H), 0.95 (m,3H)
5 c. 17 2-tert-Butyl-4-{4-[3-(4-methyl-5-cyclopropyl-4H-[1,2,4]triazol-3-ylsulfanyl)-propyl]-
piperazin-1 -yl}-6-trifluoromethyl-pyrimidine hydrochloride
0.53 g of 4-methyl-5-methyl-4H-[1,2,4]triazole-3-thiol (3 mmol) were reacted with 1.09 g of 2-te/t-butyl-4-[4-(3-chloro-propyl)-piperazin-1-yl]-6-trifluoromethyl-pyrimidine to yield 0.77 g of the title compound as a solid.
10 Melting point: 182-184°C
1H-NMR (CDCI3): 5 [ppm] 6.6 (s, 1H), 3.75 (m, 4H, broad), 3.6 (s, 3H), 3.2 (m. 2H),
2.6 (m, broad, 6H), 2.0 (m, broad. 2H), 1.75 (m, 1H), 1.3 (s, 9H), 1.1 (m, 2H), 1.05
(m, 2H)
c. 18 2-terf-Butyl-4-{4-[3-(4-methyl-5-cyclobutyl-4H-[1,2,4]triazol-3-ylsulfanyl)-propyl]-
15 piperazin-1-yl}-6-trifluoromethyl-pyrimidine acetate
1 g of 2-tert-butyl-4-[4-(3-chloro-propyl)-piperazin-1-yl]-6-trifluoromethyl-pyrimidine (2.74 mmol) were reacted with 0.46 g of 4-methyl-5-cyclobutyl-4H-[1,2,4]triazole-3-thiol (2.74 mmol) to yield after lyophilisation 0.12 g of the product.
MS (ESI) m/z: 498.2 [M+H]+
20 1H-NMR (DMSO): 8 [ppm] 7.05 (s, 1H), 3.75 (m, broad, 4H), 3.4 (s. 3H), 3.1 (m, 2H),
3.15 (m, 2H), 2.45 (m, 6H). 2.35 (m, 4H), 2.05 (m, 1H), 1.85 (m, 2H), 1.75 (m, 2H), 1.3(s,9H).
c. 19 2-tert-Butyl-4-{4-[3-(4-methyl-5-cyclopropyl-4H-[1,2,4]triazol-3-ylsulfanyl)-propyl]-piperazin-1-yl}-6-ethyl-pyrimidine hydrochloride
25 1 g of 4-methyl-5-cyclopropyl-4H-[1,2,4]triazole-3-thiol (6.44 mmol) were reacted with
2.09 g of 2-tert-butyl-4-[4-(3-chloro-propyl)-piperazin-1-yl]-6-ethyl-pyrimidine (6.44 mmol) to yield 1.2 g of the title compound.
MS (ESI) m/z: 444.4 [M+H]*
1H-NMR (DMSO):): 8 [ppm] 14.35 (s, 1H, broad), 12.1 (s, 1H, broad) 7.15 (s,
30 1H), 5.0 (m, 1H, very broad), 4.5 (m, 1H, very broad), 3.05-4.0 (several m, very
broad, 6H), 3.75 (s, 3H), 3.4 (m, 2H), 3.25 (m, 2H), 3.0 (m, 2H), 2.3 (m, 1H), 2.2 (m. 2H), 1.45 (s, 9H), 1.2-1.35 (m, 7H)
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c.20 2-te/t-Butyl-4-{4-[3-(4-methyl-5-cyclobutyl-4H-[1,2,4]triazol-3-ylsulfanyl)-propyl]-piperazin-1 -yl}-6-difluoromethyl-pyrimidine hydrochloride
0.488 g of 4-methyl-5-cyclobutyl-4H-[1,2,4]triazole-3-thiol (2.88 mmol) were reacted
with 1 g of 2-tert-butyl-4-[4-(3-chloro-propyl)-piperazin-1-yl]-6-difluoromethyl-
5 pyrimidine (2.88 mmol) to yield 0.44 g of the product as a white solid after drying.
MS (ESI) m/z: 480.4 [M+H]+
1H-NMR (DMSO): 5 [ppm]11.8 (s, broad, 1H), 7.05 (s, 1H), 6.75 (t, 1H, CHF2), 4.6 (m, broad, 2H), 3.85 (m. 1H), 3.55 (m, broad, 4H), 3.5 (s, 3H), 3.4 (m, 2H), 3.2 (m, 2H), 3.1 (m, 2H), 2.35-2.55 (m, 4H), 2.2 (m, 2H), 2.1 (m, 1H), 1.9 (m, 1H), 1.3 (s, 9H)
10 c.21 2-te/t-Butyl-4-{4-[3-(4-methyl-5-cyclopropyl-4H-[1,2,4]triazol-3-ylsulfanyl)-propyl]-
piperazin-1-yl}-6-difluoromethyl-pyrimidine hydrochloride
0.67 g of 4-methyl-5-cyclopropyl-4H-[1,2,4]triazole-3-thiol (4.32 mmol) were reacted with 1.5 g of 2-tert-butyl-4-[4-(3-chloro-propyl)-piperazin-1-yl]-6-difluoromethyl-pyrimidine (4.32 mmol) to yield 0.45 g of the title compound.
15 MS (ESI) m/z: 466.4 [M+H]+
1H-NMR (DMSO): 8 [ppm] 11.95 (s, 1H, broad), 9.8 (s, 3H, broad), 7.0 (s, 1H), 6.8 (t, 1H, CHF2), 4.7 (s, 2H), 4.6 (m, 2H, broad), 3.45-3.7 (m, 3H, broad), 3.6 (s, 3H), 3.4 (m, 2H), 3.35 (s, 3H), 3.2 (m, 2H), 2.95-3.2 (m, 2H, broad), 2.2 (m, 2H), 2.0 (s, 1H), 1.3 (s, 9H), 1.2 (m, 1H)
20 c.22 2-fert-Butyl-4-{4-[3-(4-methyl-4H-[1,2,4]triazol-3-ylsulfanyl)-propyl]-piperazin-1 -yl}-6-
propyl-pyrimidine fumarate
Reaction of 1 g of 2-tert-butyl-4-[4-(3-chloro-propyl)-piperazin-1-yl]-6-propyl-pyrimidine (2.95 mmol) with 0.37 g of 4-methyl-4H-[1,2,4]triazole-3-thiol (3.21 mmol) yielded 0.33 g (21 %) of the title compound as a solid.
25 MS (ESI) m/z: 418.1 [M+H]+
1H-NMR (DMSO): 8 [ppm] 8.6 (s, 1H), 6.65 (s, 2H, fumarate), 6.45 (s, 1H), 3.65 (m, 4H), 3.6 (s, 3H), 3.15 (m, 2H), 2.6 (m, 6H), 2.45 (m, 2H), 1.9 (m, 2H), 1.65 (m, 2H), 1.25 (s, 9H), 0.9 (m, 3H)
c.23 2-tert-Butyl-4-{4-[3-(4-methyl-4H-[1,2,4]triazol-3-ylsulfanyl)-propyl]-piperazin-1-yl}-6-
30 trifluoromethyl-pyrimidine hydrochloride
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WO 2006/058753 PCT/EP2005/012856
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1 g of 4-methyl-4H-[1,2,4]triazole-3-thiol (8.7 mmol) were reacted with 3.2 g of 2-tert-butyl-4-[4-(3-chloro-propyl)-piperazin-1-yl]-6-trifluoromethyl-pyrimidine (8.7 mmol to yield 2.1 g of the title compound as a solid.
Melting point: 92-95°C
5 MS (ESI) m/z: 444 [M+H]+
'H-NMR (CDCI3): 8 [ppm] 8.15 (s, 1H), 6.6 (s, 1H), 3.75 (m, broad, 4), 3.6 (s. 3H), 2.55 (m, 6H), 2.0 (m, 2H), 1.35 (s, 9H)
c.24 2-fert-Butyl-4-{4-[3-(4-methyl-4H-[1,2,4]triazol-3-ylsulfanyl)-propyl]-piperazin-1-yl}-6-difluoromethyl-pyrimidine hydrochloride
10 0.33 g of 4-methyl-4H-[1,2,4]triazole-3-thiol (2.88 mmol) were reacted with 1 g of 2-
tert-Butyl-4-[4-(3-chloro-propyl)-piperazin-1-yl]-6-difluoromethyl-pyrimidine(2.88 mmol) to yield 0.444 g of the product as a white solid.
MS (ESI) m/z: 426.4 [M+Hf
'H-NMR (DMSO): 8 [ppm] 11.9 (s, broad, 1H), 9.6 (s, 1H), 7.65 (s, broad, 4H), 7.05
15 (s, 1H), 6.8 (t, 1H, CHF2), 4.65 (m, broad, 2H), 3.75 (s, 3H), 3.6 (m, broad, 4H), 3.4
(m, 2H), 3.25 (m, 2H), 3.1 (m, 2H), 2.2 (m, 2H), 1.3 (s, 9H).
c.25 2-fert-Butyl-4-{4-[3-(4-methyl-5-trifluoromethyl-4H-[1,2,4]triazol-3-ylsulfanyl)-propyl]-piperazin-1 -y!}-6-propyl-pyrimidine hydrochloride
Reaction of 1 g of 2-te/f-butyl-4-[4-(3-chloro-propyl)-piperazin-1-yl]-6-propyl-
20 pyrimidine (2.95 mmol) with 0.6 g 4-Methyl-5-trifluoromethyl-4H-[1,2,4]triazole-3-thiol
(3.28 mmol), yielded 0.3 g (18%) of the title compound as crystalline hydrochloride salt.
MS (ESI) m/z: 486.2 [M+Hf
1H-NMR (DMSO): 8 [ppm] 14.3 (s, 1H, broad), 12.1 (s, 1H, broad), 7.15 (s, 1H), 5.0
25 (m, 1H), 4.5 (m, 1H), 3.85 (m, 1H), 3.5-3.8 (m, 3H), 3.7 (s, 3H), 3.4 (m, 2H), 3.2 (m,
4H), 2.9 (m, 2H), 2.2 (m, 2H), 1.7 (m, 2H), 1.45 (s, 9H), 0.95 (m, 3H)
c.26 2-tert-Butyl-4-{4-[3-(4-methyl-5-isopropyl-4H-[1,2,4]triazol-3-ylsulfanyl)-propyl]-piperazin-1 -yl}-6-trifluoromethyl-pyrimidine hydrochloride
0.5 g of 4-methyl-5-isopropyl-4H-[1,2,4]triazole-3-thiol (3.18 mmol) were reacted with
30 1.16 g of 2-tert-butyl-4-[4-(3-chloro-propyl)-piperazin-1-yl]-6-trifluoromethyl-
pyrimidine (3.18 mmol) to yield 1.1 g of the title compound.
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MS (ESI) m/z: 486.2 [M+H]+
1H-NMR (DMSO): 5 [ppm] 11.6 (s, 1H. broad), 7.2 (s, 1H), 4.1 (m, 2H, broad), 3.7 (s, 3H), 3.6 (m, 4H, broad), 3.35-3.45 (m, 3H), 3.25 (m, 2H), 3.1 (m, 2H), 2.2 (m. 2H), 1.4(d,6H), 1.3(s,9H)
5 c.27 2-terf-Butyl-4-{4-[3-(4-methyl-5-tert-butyl-4H-[1,2,4]triazol-3-ylsulfanyl)-propyl]-
piperazin-1-yl}-6-trifluoromethyl-pyrimidine
0.5 g of 4-methyl-5-tert-butyl-4H-[1,2,4]triazole-3-thiol (2.92 mmol) were reacted with 1.07 g of 2-tert-butyl-4-[4-(3-chloro-propyl)-piperazin-1-yl]-6-trifluoromethyl-pyrimidine (2.92 mmol) to yield 1.05 g of the title compound.
10 MS (ESI) m/z: 500.3 [M+H]+
c.28 2-tert-Butyl-4-{4-[3-(4-methyl-5-trifluoromethyl-4H-[1,2,4]triazo!-3-ylsulfanyl)-propyl]-piperazin-1 -yl}-6-ethyl-pyrimidine hydrochloride
0.36 g of 4-methyl-5-trifluoromethyl-4H-[1,2,4]triazole-3-thiol (1.96 mmol) were re
acted with 0.64 g 2-terf-butyl-4-[4-(3-chloro-propyl)-piperazin-1-yl]-6-ethyl-pyrimidine
15 (1.96 mmol) to yield 500 mg of the title compound.
MS (ESI) m/z: 472.2 [M+H]+
1H-NMR (DMSO): 8 [ppm] 14.1 (s, broad, 1H), 11.95 (s, broad, 1H), 7.0 (s, 1H), 4.9
(m, broad, 1H), 4.45 (m, broad, 1H), 3.75 (m, broad, 1H), 3.65 (s, 3H), 3.6 (m, broad,
3H), 3.4 (m, 3H), 3.3 (m, 2H), 3.15 (m, broad, 2H), 2.65 (m, 2H), 2.15 (m, 2H), 1.35
20 (s, 9H), 1.3 (m, 3H),
c.29 2-tert-Butyl-4-{4-[3-(4-methyl-5-ethyl-4H-[1,2,4]triazol-3-ylsulfanyl)-propyl]-piperazin-1 -yl}-6-difluoromethyl-pyrimidine hydrochloride
0.619 g of 4-methyl-5-ethyl-4H-[1,2,4]triazole-3-thiol (4.32 mmol were reacted with
1.5 g of 2-tert-Butyl-4-[4-(3-chloro-propyl)-piperazin-1-yl]-6-difluoromethyl-pyrimidine
25 (4.32 mmol), to yield 0.5 g of the title compound.
MS (ESI) m/z: 454.2 [M+H]+
1H-NMR (DMSO): 5 [ppm]11.95 (s, 1H, broad), 10.2 (s, 1H, broad), 7.1 (s, 1H), 6.8 (t, 1H. CHF2), 4.65 (s, 2H), 3.65 (s, 3H), 3.5-3.7 (m, 4H, broad), 3.45 (m, 2H), 3.2 (m, 2H), 2.95-3.2 (m, 4H, broad), 2.2 (m, 2H), 1.25-1.4 (m, 12H)
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The compounds II of examples c.30 to c.38 can be obtained by analogy to the methods described in the examples c.1 or c.2:
c.30 2-tert-Butyl-4-{4-[3-(4-methyl-5-methyl-4H-[1,2,4]triazol-3-ylsulfanyl)-propyl]-piperazin-1-yl}-6-(1-methylcycloproyl)-pyrimidine hydrochloride
5 c.31 2-tert-Butyl-4-{4-[3-(4-methyl-5-(4-fluorophenyl)-4H-[1,2,4]triazol-3-ylsulfanyl)-propyl]-
piperazin-1 -yl}-6-trifluoromethyl-pyrimidine hydrochloride
c.32 2-te/t-Butyl-4-{4-[3-(4-methyl-5-phenyl-4H-[1,2,4]triazol-3-ylsulfanyl)-propyl]-piperazin-1 -yl}-6-trifluoromethyl-pyrimidine hydrochloride
c.33 2-fert-Butyl-4-{4-[3-(4-methyl-5-(1-methylpyrrol-2-yl)-4H-[1,2,4]triazol-3-ylsulfanyl)-
10 propyl]-piperazin-1 -yl}-6-trifluoromethyl-pyrimidine hydrochloride
c.34 2-tert-Butyl-4-{4-[3-(4-methyl-5-cyclobutyl-4H-[1,2,4]triazol-3-ylsulfanyl)-propyl]-piperazin-1 -yl}-6-terf-butyl-pyrimidine hydrochloride
c.35 2-tert-Butyl-4-{4-[3-(4-methyl-5-phenyl-4H-t1,2,4]triazol-3-ylsulfanyl)-propyl]-piperazin-1 -yl}-6-tert-butyl-pyrimidine hydrochloride
15 c.36 2-tert-Butyl-4-{4-[3-(4-methyl-5-methoxymethyl-4H-[1,2,4]triazol-3-ylsulfanyl)-propyl]-
piperazin-1 -yl}-6-terf-butyl-pyrimidine hydrochloride
c.37 2-tert-Butyl-4-{4-[3-(4-methyl-5-(1-methylpyrrol-2-yl)-4H-[1,2,4]triazol-3-ylsulfanyl)-propyl]-piperazin-1 -yl}-6-te/t-butyl-pyrimidine hydrochloride
c.38 2-tert-Butyl-4-{4-[3-(4-methyl-4H-[1,2,4]triazol-3-ylsulfanyl)-propyl]-piperazin-1 -yl}-6-
20 isopropyl-pyrimidine hydrochloride
c-39 2-tert-Butyl-4-{4-[3-(1 -methyl-1 H-[1,2,4]triazole-3-sulfanyl)-propyl]-piperazin-1 -yl}-6-trifluoromethyl-pyrimidine hydrochloride
ESI-MS: 444.25 [M+H]+
1H-NMR (DMSO): 8 [ppm] 11.7 (s, broad, 1H), 8.5 (s, 1H), 7.2 (s, 1H), 3.8 (s, 3H),
25 3.45-3.7 (m, 4H). 3.1-3.2 (m, 4H), 3.0-3.1 (m, 2H), 2.1-2.2 (m. 2H), 1.3 (s. 9H), 1.05
(m, 2H).
c-40 2,6-di-tert-Butyl-4-{4-[3-(2-methyl-1 H-[1,2,4]triazole-3-sulfanyl)-propyl]-piperazin-1 -yl}-pyrimidine hydrochloride
ESI-MS: 432.25 [M+H]+
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1H-NMR (DMSO): 8 [ppm] 12.5 (s, broad, 1H), 12.15 (s, broad, 1H), 8.0 (s, 1H), 6.9 (s, 1H), 5.0 (m, broad, 1H), 4.7 (m, broad, 1H), 3.75 (s, 3H), 3.6-3.9 (several m, broad, 4H), 3.3 (m, 2H), 3.1-3.3 (m, 4H), 2.2 (m. 2H), 1.4-1.5 (m, 18H).
c-41 2,6-di-tert-Butyl-4-{4-[3-(1 H-[1,2,4]triazole-3-sulfanyl)-propyl]-piperazin-1-yl}-
5 pyrimidine
ESI-MS: 418.2 [M+H]+
1H-NMR (CDCI3): 5 [ppm] 7.9 (s, 1H), 6.3 (s, 1H), 3.8 (m, 4H), 3.2 (m, 2H), 2.6-2.7 (m, 6H), 2.0-2.1 (m, 2H), 1.3 (s, 9H), 1.25 (s, 9H).
c-42 2-tert-Butyl-4-{4-[3-(4-methyl-1 H-[1,2,4]triazole-3-sulfanyl)-propyl]-piperazin-1 -yl}-6-
10 cyclopentyl-pyrimidine
ESI-MS: 444.25 [M+H]+
1H-NMR (CDCI3): 5 [ppm] 8.1 (s, 1H), 6.15 (s, 1H), 3.65 (m, 4H), 3.6 (s, 3H), 3.3-3.4 (m, 2H), 2.9-3.0 (m, 1H), 2.45-2.6 (m, 6H), 1.9-2.1 (m, 4H), 1.7-1.85 (m, 4H), 1.6-1.7(m, 2H), 1.3 (s, 9H).
15 c-43 2,6-di-tert-Butyl-4-{4-[3-(1-methyl-1 H-[1,2,4]triazole-S-sulfanyl)-propyl]-piperazin-l-
yl}-pyrimidine
ESI-MS: 432.25 [M+H]+
1H-NMR (CDCI3): 8 [ppm] 7.95 (s, 1H), 6.23 (s, 1H), 3.85 (s, 3H), 3.6-3.7 (m, 4H), 3.1-3.2 (m, 2H), 2.5 (m, 6H), 1.95 (m, 2H), 1.3 (s, 9H), 1.25 (s, 9H).
20 c-44 2-tert-Butyl-4-{4-[3-(1 -methyl-1 H-[1,2,4]triazole-3-sulfanyl)-propyl]-piperazin-1 -
yl}-6-propyl-pyrimidine
ESI-MS: 418.5 [M+Hf
II. Preparation of the compounds I
25 EXAMPLE 1:
2,4-Di-tert-butyl-6-{4-[3-(4,5-dimethyl-4H-[1,2,4]triazole-3-sulfinyl)-propyl]-piperazin-1-yl}-pyrimidine
10 g of 2,4-di-tert-butyl-6-{4-[3-(4,5-dimethyl-4H-[1,2l4]triazol-3-ylsulfanyl)-propyl]-piperazin-1-yl}-pyrimidin (18.01 mmol) were dissolved in 300 ml water. At room tempera-
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ture, 9 ml of 2 N aqueous hydrochlorid acid (18.01 mmol) were added. The solution was
cooled to 5°C and 5.54 g (9.0 mmol) of oxone added in portions. After consumption of the
starting material, the crude reaction product was isolated and subjected to a silica gel
chromatography with ethyl acetate, ethyl acetate-methanol 15:1 to 8:1. Isolated were 1.16
5 g of 2,4-di-tert-butyl-6-{4-[3-(4,5-dimethyl-4H-[1,2,4]triazole-3-sulfonyl)-propyl]-piperazin-1-
yl}-pyrimidine (Example 4) and 6.5 g of 2,4-di-tert-butyl-6-{4-[3-(4,5-dimethyl-4H-[1,2,4]triazole-3-sulfinyl)-propyl]-piperazin-1-yl}-pyrimidine. The latter product was dissolved in 10 ml of n-hexane and crystallized overnight in the refrigerator to yield 5.6 g of the desired product.
10 ESI-MS: 462.3 [M+H]+
1H-NMR (CDCI3): 5 [ppm] 6.25 (s, 1H), 3.85 (s, 3H), 3.5-3.7 (m, 6H), 2.45-2.65 (m, 9H), 2.0-2.2 (m, 2H), 1.35 (s, 9H), 1.3 (s, 9H).
EXAMPLE 2:
2-tert-Butyl-4-cyclobutyl-6-{4-[3-(4-methyl-4H-[1,2,4]triazole-3-sulfonyl)-propyl]-piperazin-1-
15 yl}-pyrimidine
38 mg were obtained as described for example 1.
ESI-MS: 462.3 [M+Hf
1H-NMR (CDCI3): 8 [ppm] 8.2 (s, 1H), 6.1 (s, 1H), 4.0 (s, 3H), 3.8 (m, 2H). 3.6-3.7 (m, 4H), 3.4 (m, 1H), 2.45-2.6 (m, 6H), 2.1-2.35 (m, 6H), 2.0 (m, 1H), 1.9 (m, 1H), 1.35 (s, 9H).
20 EXAMPLE 3:
2-tert-Butyl-4-cyclobutyl-6-{4-[3-(4-methyl-4H-[1,2,4]triazole-3-sulfinyl)-propyl]-piperazin-1-yl}-pyrimidine
550 mg were obtained as described for example 1.
ESI-MS: 446.3 [M+H]*
25 1H-NMR (CDCI3): 5 [ppm] 8.25 (s, 1H), 6.1 (s, 1H), 4.0 (s, 3H), 3.5-3.7 (m, 6H), 3.4 (m,
1H), 2.45-2.6 (m, 6H), 2.25 (m, 4H), 2.15 (m, 1H), 1.95-2.1 (m, 2H), 1.9 (m, 1H), 1.35 (s, 9H).
EXAMPLE 4:
2,4-Di-tert-butyl-6-{4-[3-(4,5-dimethyl-4H-[1,2,4]triazole-3-sulfonyl)-propyl]-piperazin-1-yl}-
30 pyrimidine
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1.16 g were obtained from the silica gel chromatography of Example 1.
ESI-MS: 478.3 [M+H]*
1H-NMR (CDCI3): 8 [ppm] 6.25 (s, 1H), 3.85 (s, 3H), 3.8 (m, 2H), 3.65 (m, 4H), 2.45-2.65 (m, 9H), 2.1-2.2 (m, 2H), 1.2-1.4 (18H).
5 EXAMPLE 5:
a-tert-ButyM^-p-CS-ethyM-methyMH-tl^^Jtriazole-S-sulfinylJ-propylj-piperazin-l-ylJ-e-propyl-pyrimidine hydrochloride
200 mg were obtained as described for example 1. The hydrochloride salt was formed by addition of HCI/diethyl ether and careful evaporation of the solvent.
10 ESI-MS: 462.5 [M+H]+
1H-NMR (de-DMSO): 8 [ppm] 14.3 (s, broad, 1H), 12.1 (s, broad, 1H), 7.15 (s, 1H), 5.05 (m, broad, 1H), 4.5 (m, broad, 1H), 3.85 (m, broad, 1H). 3.85 (s, 3H), 3.5-3.75 (m, 5H), 3.3 (m, 2H), 3.2 (m, 2H), 2.95 (m, 2H), 2.85 (m, 2H), 2.25 (m, 2H), 1.7 (m, 2H), 1.45 (9H), 1.3 (t, 3H), 0.95 (t, 3H).
15 EXAMPLE 6:
2-tert-Butyl-4-{4-[3-(4,5-dimethyl-4H-[1,2,4]triazole-3-sulfinyl)-propyl]-piperazin-1-yl}-6-(1-methyl-cyclopropyl)-pyrimidine
144 mg were obtained as described for example 1.
ESI-MS: 460.4 [M+H]+
20 1H-NMR (CDCI3): 8 [ppm] 6.3 (s, 1H). 3.85 (s, 3H). 3.5-3.7 (m, 6H),2.45-2.65 (m. 9H), 2.0-
2.2 (m, 2H), 1.4 (s, 3H), 1.35(m, 2H), 1.3 (s, 9H), 0.7 (m, 2H).
EXAMPLE 7:
2-tert-Butyl-4-{4-[3-(4,5-dimethyl-4H-[1,2,4]triazole-3-sulfinyl)-propyl]-piperazin-1-yl}-6-trifluoromethyl-pyrimidine hydrochloride
25 360 mg were obtained as described for example 1. The hydrochloride salt was formed by
addition of HCI/diethyl ether and careful evaporation of the solvent.
ESI-MS: 474.1 [M+H]*
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1H-NMR (DMSO): 6 [ppm] 11.8 (s, very broad, 1H), 7.2 (s, 1H), 4.7 (m, very broad, 2H), 3.8 (s, 3H), 3.45-3.7 (m, broad, 6H), 3.25 (m, broad, 2H), 3.1 (m, broad, 2H), 2.5 (s. 3H), 2.25 (m, 2H), 1.3(s,9H).
EXAMPLE 8:
5 2-tert-Butyl-4-{4-[3-(4,5-dimethyl-4H-[1,2,4]triazole-3-sulfinyl)-propyl]-piperazin-1 -yl}-6-
propyl-pyrimidine hydrochloride
100 mg were obtained as described for example 1. The hydrochloride salt was formed by addition of HCI/diethyl ether and careful evaporation of the solvent.
ESI-MS: 448.5 [M+H]+
10 1H-NMR (DMSO): 8 [ppm] 14.15 (s, very broad, 1H), 12.05 (s. very broad, 1H), 7.15 (s,
1H), 5.0 (m, broad, 1H), 4.2-4.7 (m, broad, 1H), 3.85 (m, broad, 1H), 3.8 (s, 3H), 3.45-3.75 (m, broad, 5H), 3.3 (m, broad, 2H), 3.2 (m. broad, 2H), 2.9 (m, broad, 2H), 2.5 (s, 3H), 2.25 (m, 2H), 1.7 (m, 2H), 1.4 (s, 9H), 0.95 (t, 3H).
EXAMPLE 9:
15 2-Di-tert-butyl-6-{4-[3-(4,5-dimethyl-4H-[1,2,4]triazole-3-sulfonyl)-propyl]-piperazin-1 -yl}-6-
propyl-pyrimidine
30 mg were obtained as described for example 1.
EXAMPLE 10:
2-tert-Butyl-4-{4-[3-(4,5-dimethyl-4H-|;i,2,4]triazole-3-sulfonyl)-propyl]-piperazin-1-yl}-6-(1-
20 methyl-cyclopropyl)-pyrimidine
24 mg were obtained as described for example 1.
ESI-MS: 476.1 [M+H]+
EXAMPLE 11:
2-tert-Butyl-4-{4-[3-(4,5-dimethyl-4H-(1,2,4]triazole-3-sulfonyl)-propyl]-piperazin-1-yl}-6-
25 trifluoromethyl-pyrimidine
21.9 mg were obtained as described for example 1.
ESI-MS: 490.1 [M+H]4
EXAMPLE 12:
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2-tert-Buty!-4-{4-[3-(5-ethyl-4-methyl-4H-[1,2,4]triazole-3-sulfonyl)-propyl]-piperazin-1-yl}-6-propyl-pyrimidine
19.3 mg were obtained as described for example 1.
ESI-MS: 478.5 [M+H]*
5 EXAMPLE 13:
Enantiomer #1 of 2,4-Di-tert-butyl-6-{4-[3-(4,5-dimethyl-4H-[1,2,4]triazole-3-sulfinyl)-propyl]-piperazin-1-yl}-pyrimidine
Chiral separation of 100 mg racemic of 2,4-di-tert-butyl-6-{4-[3-(4,5-dimethyl-4H-
[1,2,4]triazole-3-sulfinyl)-propyl]-piperazin-1-yl}-pyrimidine (example 1) (0.5 ug/ml) was
10 performed on a Chiracel OD column using as eluent a mixture containing n-
hexane/ethanol/trifluoroacetic acid (8:2:0.01) to yield 16 mg of enantiomer-1 and 28 mg of enantiomer-2 (example 14).
EXAMPLE 14:
Enantiomer #2 of 2,4-di-tert-butyl-6-{4-[3-(4,5-dimethyl-4H-[1,2,4]triazole-3-sulfinyl)-
15 propyl]-piperazin-1-yl}-pyrimidine
28 mg enantiomer-2 was obtained from the chiral separation of 2,4-di-tert-butyl-6-{4-[3-(4,5-dimethyl-4H-[1,2,4]triazole-3-sulfinyl)-propyl]-piperazin-1-yl}-pyrimidine (example 1) as described above.
EXAMPLE 15:
20 2-tert-Butyl-4-(4-{3-t5-(4-fluoro-phenyl)-4-methyl-4H-[1,2,4]triazole-3-sulfinyl]-propyl}-
piperazin-1-yl)-6-trifluoromethyl-pyrimidine
1.3 g were obtained as described for example 1.
ESI-MS: 554.2 [M+H]+
'H-NMR (CDCI3): 5 [ppm] 7.65 (m, 2H), 7.25 (m, 2H), 6.6 (s, 1H), 3.95 (s, 3H), 3.7 (m, 6H),
25 2.6 (m, 2H), 2.55 (m, 4H). 2.05-2.25 (m, 2H), 1.3 (s, 9H).
EXAMPLE 16:
2-tert-Butyl-4-(4-{3-t5-(4-fluoro-phenyl)-4-methyl-4H-[1,2,4]triazole-3-sulfonyl]-propyl}-piperazin-1 -yl)-6-trifluoromethyl-pyrimidine hydrochloride
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166 mg were obtained as described for example 1. The hydrochloride salt was formed by addition of HCI/diethyl ether and careful evaporation of the solvent.
ESI-MS: 570.2 [M+Hf
1H-NMR (DMSO): 5 [ppm] 11.5 (s, very broad, 1H), 7.85 (m, 2H), 7.45 (m, 2H), 7.2 (s, 1H),
5 4.65 (m, very broad, 2H), 3.9 (m, 2H), 3.85 (s, 3H), 3.5-3.6 (m, broad, 4H), 3.25 (m, broad,
2H), 3.1 (m, broad, 2H), 2.3 (m, 2H), 1.3 (s, 9H).
EXAMPLE 17:
2,4-Di-tert-butyl-6-{4-t3-(4-methyl-4H-[1,2,4]triazole-3-sulfonyl)-propyl]-piperazin-1-yl}-pyrimidine
10 The title compound was obtained as described for example 1
ESI-MS: 464.2 [M+H]+
1H-NMR (CDCI3): 5 [ppm] 8.2 (s, 1H), 6.25 (s, 1H), 4.0 (s, 3H), 3.8 (m, 2H), 3.65 (m, 4H), 2.5-2.6 (several m, 6H), 2.1-2.2 (m, 2H), 1.35 (s. 9H), 1.3 (s, 9H).
EXAMPLE 18:
15 2,4-Di-tert-butyl-6-{4-[3-(4-methyl-4H-[1,2,4]triazole-3-sulfinyl)-propyl]-piperazin-1 -yl}-
pyrimidine
The title compound was obtained as described for example 1
ESI-MS: 448.2 [M+H]+
1H-NMR (CDCI3): S [ppm] 8.2 (s, 1H), 6.25 (s, 1H), 4.0 (s, 3H), 3.55-3.7 (m, 6H), 2.6 (m,
20 2H), 2.5 (m, 4H), 2.15 (m, 1H), 2.05 (m, 1H), 1.3 (s, 9H), 1.25 (s, 9H).
EXAMPLE 19:
2-tert-Butyl-4-{4-[3-(1-methyl-1H-[1,2,4]triazole-3-sulfonyl)-propyl]-piperazin-1-yl}-6-trifluoromethyl-pyrimidine hydrochloride
1-Methyl-1H-[1,2,4]triazole-3-thiol was purchased from Prosyntest, Estonia.
25 The title compound was obtained as described for example 1
ESI-MS: 476.1 [M+H]*
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1H-NMR (de-DMSO): 8 [ppm] 11.65 (s, broad, 1H), 8.85 (s, 1H), 7.2 (s, 1H), 4.35-4.85 (several m, broad, 3H), 4.0 (s, 3H), 3.6 (m, 2H), 3.5-3.6 (m, 3H), 3.25 (m, 2H), 3.0-3.15 (m, 2H), 2.2 (m. 2H), 1.3 (s, 9H).
EXAMPLE 20:
5 2,4-Di-tert-butyl-6-{4-[3-(2-methyl-2H-[1,2,4]triazole-3-sulfonyl)-propyl]-piperazin«1 -yl}-
pyrimidine hydrochloride
2-Methyl-1H-[1,2,4]triazole-3-thiol was purchased.
The title compound was obtained as described for example 1
ESI-MS: 464.2 [M+Hf
10 1H-NMR (d6-DMSO): 8 [ppm] 12.1 (s, broad, 1H), 8.3 (s, 1H), 6.8 (s, broad, 1H), 4.25-5.1
(several m, broad, 4H), 4.2 (s, 3H), 3.9 (m, 2H), 3.45-3.8 (several m, 2H), 3.25 (m, 2H), 3.15 (m, broad, 2H), 2.2-2.3 (m, 2H), 1.4 (s, broad, 18H).
EXAMPLE 21:
2-tert-Butyl-4-{4-[3-(1-methyl-1H-[1,2,4]triazole-3-sulfinyl)-propyl]-piperazin-1-yl}-6-
15 trifluoromethyl-pyrimidine hydrochloride
1-Methyl-1H-[1,2,4]triazole-3-thiol was purchased from Prosyntest, Estonia.
The title compound was obtained as described for example 1
ESI-MS: 460.1 [M+Hf
1 H-NMR (d6-DMSO): 8 [ppm] 11.55 (s, broad, 1H), 8.8 (s, 1H), 7.2 (s, 1H), 4.5-5.0 (several
20 m, broad, 2H), 4.0 (s, 3H), 3.4-3.6 (several m, 4H), 3.3 (m, 2H), 3.25 (m, 2H), 3.1 (m, 2H),
2.15 (m. 2H), 1.3 (s, 9H).
EXAMPLE 22:
2,4-Di-tert-butyl-6-{4-[3-(1H-[1,2,4]triazole-3-sulfonyl)-propyl]-piperazin-1-yl}-pyrimidine
1 H-[1,2,4]triazole-3-thiol was purchased.
25 The title compound was obtained as described for example 1
ESI-MS: 450.2 [M+H]+
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1H-NMR (d6-DMSO): 8 [ppm] 8.9 (s, 1H), 6.45 (s. 1H), 3.6 (m, 4H), 3.5 (m, 2H), 2.4 (m, 6H), 1.85 (m. 2H), 1.2-1.35 (2s, 18H).
EXAMPLE 23:
2-tert-Butyl-4-{4-[3-(4-methyl-1H-[1,2,4]triazole-3-sulfonyl)-propyl]-piperazin-1-yl}-6-
5 isopropyl-pyrimidine
The title compound was obtained as described for example 1
ESI-MS: 450.2 [M+Hf
1 H-NMR (d8-DMSO): 6 [ppm] 8.85 (s, 1H), 6.4 (s, 1H), 3.9 (s, 3H), 3.7 (m, 2H), 3.6 (m, 4H), 3.3 (s, 3H), 2.75 (m, 1H), 2.4 (m, 4H), 1.9 (m, 2H). 1.3 (s, 9H), 1.2 (d, 6H).
10 EXAMPLE 24:
2-tert-Butyl-4-{4-[3-(4-methyl-1 H-[1,2,4]triazole-3-sulfonyl)-propyl]-piperazin-1 -yl}-6-cyclopentyl-pyrimidine
The title compound was obtained as described for example 1
ESI-MS: 476.3 [M+H]+
15 1H-NMR (CDCI3): 5 [ppm] 8.2 (s, 1H), 6.15 (s, 1H), 4.0 (s, 3H), 3.8 (m, 2H), 3.6 (m, 4H),
2.95 (m, 1H), 2.55 (m, 1H), 2.45-2.6 (m, 5H), 2.2 (m, 2H), 1.95 (m. 2H), 1.8 (m, 4H). 1.65 (m,2H), 1.3(s,9H).
EXAMPLE 25:
2-tert-Butyl-4-{4-[3-(4-methyl-1 H-[1,2,4]triazole-3-sulfinyl)-propyl]-piperazin-1 -yl}-6-
20 cyclopentyl-pyrimidine
The title compound was obtained as described for example 1
ESI-MS: 460.14 [M+H]+
1H-NMR (CDCI3): 5 [ppm] 8.2 (s, 1H), 6.1 (s, 1H), 4.0 (s, 3H), 3.6 (m, 6H), 2.95 (m, 1H),
2.55 (m, 1H), 2.45-2.6 (m, 5H), 2.15 (m, 1H), 2.05 (m, 1H), 1.95 (m, 2H), 1.8 (m, 4H), 1.65
25 (m,2H), 1.3 (s, 9H).
EXAMPLE 26:
2-tert-Butyl-4-{4-[3-(4-methyl-1H-[1,2,4]triazole-3-sulfonyl)-propyl]-piperazin-1-yl}-6-propyl-pyrimidine
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The title compound was obtained as described for example 1
ESI-MS: 450.2 [M+H]+
1H-NMR (CDCI3): 8 [ppm] 8.2 (s, 1H), 6.1 (s, 1H), 4.0 (s, 3H), 3.8 (m, 2H), 3.6-3.7 (m, 4H), 2.45-2.6 (m, 8H), 2.15 (m, 2H), 1.7 (m, 2H), 1.35 (s, 9H), 0.95 (t, 3H).
5 EXAMPLE 27:
2,6-di-tert-Butyl-4-{4-[3-(1 -methyl-1 H-[1,2,4]triazole-3-sulfonyl)-propyl]-piperazin-1 -yl}-pyrimidine
1-Methyl-1 H-[1,2,4]triazole-3-thiol was purchased from Prosyntest, Estonia.
The title compound was obtained as described for example 1
10 ESI-MS: 464.2 [M+Hf
1H-NMR (CDCI3): 8 [ppm] 8.2 (s, 1H), 6.25 (s, 1H), 4.05 (s, 3H), 3.55-3.65 (m, 4H), 3.4-3.5 (m, 2H), 2.4-2.55 (m, 6H), 2.0-2.1 (m. 2H), 1.3 (s, 9H), 1.25 (s, 9H).
EXAMPLE 28:
2-tert-Butyl-4-{4-[3-(1 -methyl-1 H-[1,2,4]triazole-3-sulfinyl)-propyl]-piperazin-1 -yl}-6-propyl-
15 pyrimidine hydrochloride
1-Methyl-1 H-[1,2,4]triazole-3-thiol was purchased from Prosyntest, Estonia.
The title compound was obtained as described for example 1
ESI-MS: 434.2 [M+H]+
1H-NMR (DMSO): 8 [ppm] 14.3 (s, broad, 1H), 12.1 (s, broad, 1H), 8.8 (s, 1H), 7.15 (s,
20 1H), 5.0 (m, broad, 1H), 4.5 (m, broad, 1H), 4.0 (s, 3H), 3.05-3.9 (several m, broad, 10H),
2.9-3.0 (m, 2H), 2.1-2.2 (m, 2H), 1.7 (m, 2H), 1.45 (s, 9H), 0.9-1.0 (m, 3H).
EXAMPLE 29:
2-tert-Butyl-4-{4-[3-(1-methyl-1H-[1,2,4]triazole-3-sulfonyl)-propyl]-piperazin-1-yl}-6-propyl-pyrimidine
25 The title compound was obtained as described for example 1
ESI-MS: 450.5 [M+H]*
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1H-NMR (CDCI3): 5 [ppm] 8.2 (s, 1H). 6.1 (s, 1H), 4.05 (s, 3H), 3.55-3.65 (m, 4H), 3.4-3.5 (m, 2H), 2.4-2.6 (m, 8H), 2.0-2.1 (m, 2H), 1.7 (m, 2H), 1.3 (s, 9H). 0.9-1.0 (t, 3H).
EXAMPLE 30:
2,6-di-tert-Butyl-4-{4-[3-(1-methyl-1H-[1,2,4]triazole-3-sulfinyl)-propyl]-piperazin-1-yl}-
5 pyrimidine hydrochloride
The title compound was obtained as described for example 1
1H-NMR (DMSO): 5 [ppm] 8.8 (s, 1H), 6.75 (s, broad, 1H), 4.65 (m, broad, 2H), 4.0 (s, 3H), 3.5-3.9 (several m, broad, 8H), 3.2-3.35 (m, 4H), 3.0-3.2 (m, 2H), 2.1-2.2 (m, 2H), 1.2-1.5 (broad, 18H).
10 EXAMPLE 31:
2-tert-butyl-6-{4-[3-(1 H-[1,2,4]triazole-3-sulfonyl)-propyl]-piperazin-1 -yl}-6-(1 -methyl)cyclopropyl-pyrimidine
The title compound was obtained as described for example 1
EXAMPLE 32:
15 (S)-2-tert-Butyl-4-{4-[3-(1-methyl-1H-[1,2,4]triazole-3-sulfinyl)-propyl]-piperazin-1-yl}-6-
propyl-pyrimidine
The title compound was obtained as described for example 1
ESI-MS: 434.25 [M+H]+
EXAMPLE 33:
20 (R)-2-tert-Butyl-4-{4-[3-(1-methyl-1 H-[1,2,4]triazole-3-sulfinyl)-propyl]-piperazin-1-yl}-6-
propyl-pyrimidine
The title compound was obtained as described for example 1
ESI-MS: 434.25 [M+H]+
The compounds of examples 34 to 164 given in tables 1, 2, 3 or 4 were or can be pre-
25 pared by analogy to the methods described in the previous examples.
Table 1: Compounds of the formula I, wherein Ar is Ar-1.
Example R1 X jR2
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Example R' X R*
34 cyclopropyl SO trifluoromethyl
35 cyclopropyl S02 trifluoromethyl
36 cyclobutyl SO trifluoromethyl
37 cyclobutyl S02 trifluoromethyl
38 phenyl SO trifluoromethyl
39 phenyl S02 trifluoromethyl
40 methoxymethyl SO trifluoromethyl
41 methoxymethyl S02 trifluoromethyl
42 trifluoromethyl SO trifluoromethyl
43 trifluoromethyl S02 trifluoromethyl
44 N-methyl-pyrrol-2-yl SO trifluoromethyl
45 N-methyl-pyrrol-2-yl so2 trifluoromethyl
46 cyclopropyl so tert-butyl
47 cyclopropyl so2 tert-butyl
48 cyclobutyl so tert-butyl
49 cyclobutyl so2 tert-butyl
50 phenyl so tert-butyl
51 phenyl so2 tert-butyl
52 methoxymethyl so tert-butyl
53 methoxymethyl so2 tert-butyl
54 trifluoromethyl so tert-butyl
55 trifluoromethyl so2 tert-butyl
56 N-methyl-pyrrol-2-yl so tert-butyl
57 N-methyl-pyrrol-2-yl so2 tert-butyl
58 ethyl so trifluoromethyl
59 ethyl so2 trifluoromethyl
60 H (S)-SO trifluoromethyl
61 H (S)-SO propyl
62 H (S)-SO isopropyl
63 H (S)-SO difluoromethyl
64 H (S)-SO cyclobutyl
65 H (S)-SO cyclopentyl
66 H (R)-SO trifluoromethyl
67 H (R)-SO propyl
68 H (R)-SO isopropyl
69 H (R)-SO difluoromethyl
70 H (R)-SO cyclobutyl
71 H (R)-SO cyclopentyl
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Example R1 X Rz
72 H so2 trifluoromethyl
73 H so2 propyl
74 H so2 difluoromethyl
75 H so2 cyclobutyl
76 H (S)-SO trifluoromethyl
77 H (S)-SO difluoromethyl
78 H (S)-SO Tert-butyl
79 H (S)-SO propyl
Table 2: Compounds of the formula I, wherein Ar is Ar-2 and R1a is H.

Example R1 X R*
80 H (S)-SO cyclobutyl
81 H (S)-SO isopropyl
82 H (R)-SO trifluoromethyl
83 H (R)-SO difluoromethyl
84 H (R)-SO Tert-butyl
85 H (R)-SO propyl
86 H (R)-SO cyclobutyl
87 H (R)-SO isopropyl
88 methyl S02 trifluoromethyl
89 methyl so2 propyl
90 methyl S02 difluoromethyl
91 methyl S02 cyclobutyl
92 methyl (S)-SO trifluoromethyl
93 methyl (S)-SO difluoromethyl
94 methyl (S)-SO Tert-butyl
95 methyl (S)-SO propyl
96 methyl (S)-SO cyclobutyl
97 methyl (S)-SO isopropyl
98 methyl (R)-SO trifluoromethyl
99 methyl (R)-SO difluoromethyl
100 methyl (R)-SO Tert-butyl
101 methyl (R)-SO propyl
102 methyl (R)-SO cyclobutyl
103 methyl (R)-SO isopropyl
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Table 3: Compounds of the formula I, wherein Ar is Ar-2 and R1a is methyl.

Example R1 X RJ
104 H so2 difluoromethyl
105 H so2 cyclobutyl
106 H (S)-SO trifluoromethyl
107 H (S)-SO difluoromethyl
108 H (S)-SO Tert-butyl
109 H (S)-SO propyl
110 H (S)-SO cyclobutyl
111 H (S)-SO isopropyl
112 H (R)-SO trifluoromethyl
113 H (R)-SO difluoromethyl
114 H (R)-SO Tert-butyl
115 H (R)-SO propyl
116 H (R)-SO cyclobutyl
117 H (R)-SO isopropyl
118 methyl S02 trifluoromethyl
119 methyl S02 propyl
120 methyl S02 difluoromethyl
121 methyl S02 cyclobutyl
122 methyl (S)-SO trifluoromethyl
123 methyl (S)-SO difluoromethyl
124 methyl (S)-SO Tert-butyl
125 methyl (S)-SO propyl
126 methyl (S)-SO cyclobutyl
127 methyl (S)-SO isopropyl
128 methyl (R)-SO trifluoromethyl
129 methyl (R)-SO difluoromethyl
130 methyl (R)-SO Tert-butyl
131 methyl (R)-SO propyl
132 methyl (R)-SO cyclobutyl
133 methyl (R)-SO isopropyl
Table 4: Compounds of the formula I, wherein Ar is Ar-3 and R1a is methyl.

Example R1 X R*
134 H so2 difluoromethyl
135 H so2 trifluoromethyl
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Example R1 X R<
136 H so2 cyclobutyl
137 H (S)-SO trifluoromethyl
138 H (S)-SO difluoromethyl
139 H (S)-SO Tert-butyl
140 H (S)-SO propyl
141 H (S)-SO cyclobutyl
142 H (S)-SO isopropyl
143 H (R)-SO trifluoromethyl
144 H (R)-SO difluoromethyl
145 H (R)-SO Tert-butyl
146 H (R)-SO propyl
147 H (R)-SO cyclobutyl
148 H (R)-SO isopropyl
149 methyl S02 trifluoromethyl
150 methyl S02 propyl
151 methyl S02 difluoromethyl
152 methyl S02 cyclobutyl
153 methyl (S)-SO trifluoromethyl
154 methyl (S)-SO difluoromethyl
155 methyl (S)-SO Tert-butyl
156 methyl (S)-SO propyl
157 methyl (S)-SO cyclobutyl
158 methyl (S)-SO isopropyl
159 methyl (R)-SO trifluoromethyl
160 methyl (R)-SO difluoromethyl
161 methyl (R)-SO Tert-butyl
162 methyl (R)-SO propyl
163 methyl (R)-SO cyclobutyl
164 methyl (R)-SO isopropyl
III. Examples of galenic administration forms
A) Tablets
Tablets of the following composition are pressed on a tablet press in the customary
5 manner:
40 mg of substance from Example 4 120 mg of corn starch
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13.5 mg of gelatin 45 mg of lactose
2.25 mg of Aerosil® (chemically pure silicic acid in submicroscopically fine
dispersion)
5 6.75 mg of potato starch (as a 6% paste)
B) Sugar-coated tablets
20 mg of substance from Example 4
60 mg of core composition
10 70 mg of saccharification composition
The core composition consists of 9 parts of corn starch, 3 parts of lactose and 1 part
of 60:40 vinylpyrrolidone/vinyl acetate copolymer. The saccharification composition
consists of 5 parts of cane sugar, 2 parts of corn starch, 2 parts of calcium carbonate
15 and 1 part of talc. The sugar-coated tablets which had been prepared in this way are
subsequently provided with a gastric juice-resistant coating.
IV. Biological investigations
1. Receptor binding studies:
20 The substance to be tested was either dissolved in methanol/Chremophor® (BASF-
AG) or in dimethyl sulfoxide and then diluted with water to the desired concentration.
Dopamine D3 receptor:
The assay mixture (0.250 ml) was composed of membranes derived from ~ 108
HEK-293 cells possessing stably expressed human dopamine D3 receptors, 0.1 nM
25 [125l]-iodosulpride and incubation buffer (total binding) or, in addition, test substance
(inhibition curve) or 1 uM spiperone (nonspecific binding). Each assay mixture was run in triplicate.
The incubation buffer contained 50 mM tris, 120 mM NaCI, 5 mM KCI, 2 mM CaCI2l
2 mM MgCI2 and 0.1% bovine serum albumin, 10 uM quinolone and 0.1% ascorbic
30 acid (prepared fresh daily). The buffer was adjusted to pH 7.4 with HCI.
Dopamine D2L receptor:
The assay mixture (1 ml) was composed of membranes from ~ 106 HEK-293 cells possessing stably expressed human dopamine D2L receptors (long isoform) and 0.01 nM [125l] iodospiperone and incubation buffer (total binding) or, in addition, test
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substance (inhibition curve) or 1mM haloperidol (nonspecific binding). Each assay mixture was run in triplicate.
The incubation buffer contained 50 mM tris, 120 mM NaCI, 5 mM KCI, 2 mM CaCI2, 2
mM MgCI2 and 0.1% bovine serum albumin. The buffer was adjusted to pH 7.4 with
5 HCI.
Measurement and analysis:
After having been incubated at 25°C for 60 minutes, the assay mixtures were filtered
through a Wathman GF/B glass fiber filter under vacuum using a cell collecting
device. The filters were transferred to scintillation viols using a filter transfer system.
10 After 4 ml of Ultima Gold® (Packard) have been added, the samples were shaken for
one hour and the radioactivity was then counted in a Beta-Counter (Packard, Tricarb 2000 or 2200CA). The cpm values were converted into dpm using a standard quench series and the program belonging to the instrument.
The inhibition curves were analyzed by means of iterative nonlinear regression
15 analysis using the Statistical Analysis System (SAS) which is similar to the "LIGAND"
program described by Munson and Rodbard.
In these tests, the compounds according to the invention exhibit very good affinities for the D3 receptor (Kj < 10 nM, frequently < 5 nM) and bind selectively to the D3 receptor.
20 The results of the binding tests are given in table 2, along with results obtained using
two reference compounds A and B deemed representative of previously-described triazole compounds. The relative D3 and D2 affinities demonstrate the high selectivity of the compounds of the invention for the D3 receptor.
2. Determination of the Concentration of compounds in Plasma and Brain Following
25 Dosing of compounds in animals
Male Sprague-Dawley rats were used in this study (2 to 4 per experiment). The animals were fasted overnight prior to dosing and throughout the duration of the study but were permitted water ad libitum.
Each rat received a 10 mg/kg (5 mL/kg) dose orally by gavage. At 0.5, 3 and 8
30 hours after drug administration, three animals were put under deep anesthesia using
isoflurane and euthanized by bleeding (cardiac puncture) under deep isoflurane anesthesia. EDTA blood samples and brain tissue will be collected from each rat. Upon collection, the samples were promptly placed in an ice bath, and within 2 hours after sample collection, the blood was centrifuged at about 4°C. The resulting brain
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and plasma samples were placed in clean glass tubes and stored in a freezer until analysis.
The plasma samples were assayed for parent compound using appropriate liquid
chromatography - mass spectrometry procedures. The results for compounds I are
5 given in tables 2, and illustrate the high brain concentrations attainable with the
compounds of the invention.
Table 5: Properties of Compounds of the Formula I where Ar is Ar-1

Ex.# R1 n R2 K, D3 [nM] Selectivity [KrtDaVKKDs)] Brain level [ng/g]
1 methyl 1 tert-butyl (racemate) 19.5 26 1670
2 hydrogen 2 cyclobutyl 52 14 n.d.
3 hydrogen 1 cyclobutyl 12 44 n.d.
4 methyl 2 Tert-butyl 6.1 34 1920
5 ethyl 1 n-propyl 38 37 n.d.
6 methyl 1 1 -methyl-cyclopropyl 28.7 20 n.d.
8 methyl 1 n-propyl 56 33 n.d.
9 methyl 2 n-propyl 18.3 45 n.d.
10 methyl 2 1 -methyl-cyclopropyl 7.8 37 n.d.
12 ethyl 2 n-propyl 12.8 55 n.d.
13 methyl 1 tert-butyl (enantiomer 1) n.d. n.d. n.d.
14 methyl 1 tert-butyl (enantiomer 2) n.d. n.d. n.d.
15 4-fluoro-phenyl 1 trifluoromethyl 12.6 100 n.d.
16 4-fluoro-phenyl 2 trifluoromethyl 17.7 56 n.d.
Table 6: Binding properties of Compounds of the Formula I, Examples 17 to 31
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Exp.# Kj D3 [nM] Selectivity [K,(D2yK,(D3)] Brain level [ng/g]
17 5.95 53 n.d.
18 25 17 n.d.
19 32 17 n.d.
20 26.2 8 n.d.
21 16.6 18 n.d.
22 47.4 19 n.d.
23 59.8 49 n.d.
24 7.5 20 n.d.
25 23.3 30 n.d.
26 44.6 33 n.d.
27 9.7 24 n.d.
28 9.9 158 n.d.
29 20.3 59 n.d.
30 3.5 51 n.d.
31 22.6 37 n.d.
n.d. = not determined Exp.: Example
In the receptor binding studies described in IV. 1 the compounds II of examples c.3, c.4, c.6,
5 c.7, c.12, c.15, c.16, c.17, c18, c20, c.21, c.27, c.28 and c.29 showed Ki D3 values below 5 nM and selectivities [Ki(D2)/Ki(D3)] exceeding 50.
The brain levels determined for compounds c.9, c.16, c.17 and c.19 by the method described in IV.2 exceed 200 ng/g.
Table 7: Properties of Compounds of the Formula lia

Exp.# D3 [nM] D2/D3 J Brain level [ng/g]
c.4 1.5 96 290
C.7 1.2 115 n.d.
C.11 1.7 470 840
c.12 2.4 143 780
c.13 1.3 157 n.d.
c.14 1.5 135 n.d.
c.15 2 364 1410
c.16 0.65 237 n.d.
c.17 0.9 293 n.d.
c.18 2.9 134 n.d.
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Exp. # D3 [nM] Da/Da Brain level[ng/g]
c.45 3.9 21
c.46 3.75 25
c.48 1.2 4
c.50 0.46 18
c.53 1.1 5
c.54 1.46 88
n.d. not determined

Exp.: Example

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We claim:
1. Triazole compounds of the formula I


Ar-S(0)-(CH2)3—N N-d N d)

wherein
5 n is 1 or 2;
Ar is a C-bound 1,2,4-triazol radical which carries a radical R1 on the remaining carbon atom and a radical R1a on one of the nitrogen atoms;
R1 is hydrogen, C1-C8 alkyl, C3-Ce cycloalkyl, C1-C4 alkoxymethyl, fluorinated d-C8 alkyl, fluorinated C3-C6 cycloalkyl, fluorinated CrC4 alkoxymethyl,
10 phenyl or 5- or 6-membered heteroaryl, wherein phenyl and heteroaryl may be
unsubstituted or substituted by 1, 2, 3 or 4 radicals Ra selected independently of each other from halogen, d-C8 alkyl, C3-C8 cycloalkyl, d-C4 alkoxy-d-C4-alkyl, fluorinated d-d alkyl, CN, N02, OR3, NR3R4, C(0)NR3R4, 0-C(0)NR3R4, S02NR3R4, COOR5, SR8, SOR6, S02R8, 0-C(0)R7, COR7 or C3-C5
15 cycloalkylmethyl, wherein phenyl and heteroaryl may also carry a phenyl group or
an aromatic 5- or 6-membered C-bound heteroaromatic radical, comprising 1 nitrogen atom as ring member and 0,1, 2 or 3 further heteroatoms, independently of each other, selected from O, S and N, wherein the last two mentioned radicals may carry 1, 2, 3 or 4 of the aforementioned radicals Ra;
20 R1a is hydrogen or C1-C4-alkyl;
R2 is d-C6 alkyl, C3-C6 cycloalkyl, fluorinated Ci-Ce alkyl or fluorinated C3-C6 cycloalkyl;
R3, R4, R5, R6, and R7 independent of each other are H, C1-Ce alkyl, optionally substituted with OH, C1-C4 alkoxy or phenyl, d-C4 haloalkyl or phenyl, which may carry 1, 2 or
25 3 radicals selected from the group consisting of C1-C8 alkyl, Ci-Ce alkoxy, NR3aR48,
CN, C1-C2 fluoroalkyl and halogen, wherein R3a and R4a are independent of each other H, C1-C8 alkyl, optionally substituted with OH, Ci-C4 alkoxy or phenyl, d-d haloalkyl or phenyl, which may carry 1, 2 or 3 radicals selected from the group consisting of C1-C8 alkyl, d-C8 alkoxy, amino, NH(CrC4 alkyl) and N(C1C4 alkyl)2,
30 R4 may also be a radical COR8, wherein R8 is hydrogen, d-C8 alkyl, Ci-C8 alkoxy
or phenyl, which may carry 1, 2 or 3 radicals selected from the group consisting of C1-C6 alkyl, Ci-C8 alkoxy, NR3R4, CN, C1C2 fluoroalkyl and halogen, R3 and R4 may
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together with the nitrogen atom to which they are bound form a N-bound 5 or 6 membered saturated heterocyle, which may comprise an oxygen atom or an additional nitrogen atom as a ring member and which may carry 1, 2, 3 or 4 C1-Ce alkyl groups
and the physiologically tolerated acid addition salts of these compounds.
2.A compound as claimed in claim 1, wherein Ar is a radical of the formula Ar-1,
N-N
Ri-4N>-# (Ar-1)
CH3
wherein # denotes the binding positon to the Sulfur atom of the group S(0)n and R1 is as defined in claim 1.
3. A compound as claimed in claim 1, wherein Ar is a radical of the formula Ar-2,
N-N
R1-"V^# (Ar-2)
wherein # denotes the binding positon to the Sulfur atom of the group S(0)n and R1 and R1a are as defined in claim 1.
4 A compound as claimed in claim 1, wherein Ar is a radical of the formula Ar-3,
R1a
N-N'
Ri^N<^-# (Ar-3)
wherein # denotes the binding positon to the Sulfur atom of the group S(0)„ and R1 R1 and R1a are as defined in claim 1.
5. A compound as claimed in any of claims 1, 2, 3 or 4, wherein R1 is selected from the group consisting of hydrogen, C1-C4 alkyl, C3-C5 cycloalkyl, C1-C4 alkoxymethyl and trifluoromethyl.
6.A compound as claimed in any of claims 1, 2, 3 or 4, wherein R1 is hydrogen or methyl.
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7. A compound as claimed in any of claims 1,2, 3 or 4, wherein R2 is selected from the
group consisting of C3-C4 alkyl or fluorinated C1C2 alkyl.
8. A compound as claimed in any of claims 1, 2, 3 or 4, wherein R2 is selected from the
group consisting of n-propyl, isopropyl and tert-butyl.
9. A compound as claimed in any of claims 1, 2, 3 or 4, wherein R2 is tert-butyl.
10. A compound as claimed in claim 9, wherein R1 is hydrogen.
11. A compound as claimed in claim 9, wherein R1 is methyl.
12. A compound as claimed in any of claims 1,2, 3 or 4, wherein R2 is selected from the group consisting of trifluoromethyl and difluoromethyl.
13. A compound as claimed any of claims 1, 2, 3 or 4, wherein R2 is trifluoromethyl.
14. A compound as claimed in claim 13, wherein R1 is hydrogen.
15. A compound as claimed in claim 13, wherein R1 is methyl.
16. A compound as claimed in any of claims 1, 2, 3 or 4, wherein R2 is C3-C4 cycloalkyl or fluorinated C3-C4 cycloalkyl.
17. A compound as claimed in claim 16, wherein R1 is hydrogen.
18. A compound as claimed in claim 16, wherein R1 is methyl.
19. A pharmaceutical composition comprising at least one compound as claimed in any of claims 1,2, 3 or 4 together with at least one physiologically acceptable carrier or auxiliary substance.
20. A method for treating a medical disorder of the central nervous system susceptible to treatment with a dopamine D3 receptor antagonist or a dopamine D3 agonist, said method comprising administering an effective amount of at least one compound as claimed in any of claims 1, 2, 3 or 4 to a subject in need thereof.
21. The method as claimed in claim 20, wherein the medical disorder is schizophrenia.
22. Triazole compounds of the formula I la
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N=<

Ar— S-(CH2)3— N' \l-d .N ("a)

R2
wherein
Ar is a C-bound 1,2,4-triazol radical which carries a radical R1 on the remaining carbon atom and a radical R1a on one of the nitrogen atoms;
R1 is selected from the group consisting of C2-C6-alkyl, fluorinated C1C8-alkyl, C3-C6 cycloalkyl, C1-C4 alkoxymethyl, fluorinated C3-C6 cycloalkyl and fluorinated d-C4 alkoxymethyl;
R1a is hydrogen or C1-C4 alkyl; and
R2 is C1-C6 alkyl or fluorinated C1-C6 alkyl;
and the physiologically tolerated acid addition salts of these compounds.
23. The compound as claimed in claim 22, wherein Ar is a radical of the formula Ar-1,
N-N
Ri-^N>-# (Ar-1)
CH3
wherein # denotes the binding positon to the Sulfur atom of the group S(0)„ and R1 is as defined in claim 22.
24. A compound as claimed in claim 22, wherein Ar is a radical of the formula Ar-2,
N-N
R1-\^# (Ar'2)
wherein # denotes the binding positon to the Sulfur atom of the group S(0)n and R1 and R1a are as defined in claim 22.
25. A compound as claimed in claim 22, wherein Ar is a radical of the formula Ar-3,
,Rla
N-N'
R1-^N^# (Ar"3>
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wherein # denotes the binding positon to the Sulfur atom of the group S(0)n and R1 R1 and R1a are as defined in claim 22.
26. A compound as claimed in any of claims 22, 23, 24 or 25, wherein R1 is selected from the group consisting of C2-C4-alkyl, trifluoromethyl, C3-C5 cycloalkyl and CrC4 alkoxymethyl.
27. A compound as claimed in any of claims 22, 23, 24 or 25, wherein R2 is selected from the group consisting of C3-C4 alkyl or fluorinated (C1-C2 alkyl.
28. A compound as claimed in any of claims 22, 23, 24 or 25, wherein R2 is selected from the group consisting of n-propyl, isopropyl and terf-butyl.
29. A compound as claimed in any of claims 22, 23, 24 or 25, wherein R2 is tert-butyl.
30. A compound as claimed in any of claims 22, 23, 24 or 25, wherein R2 is selected from the group consisting of trifluoromethyl and difluoromethyl.
31. A compound as claimed in any of claims 22, 23, 24 or 25, wherein R2 is trifluoromethyl.
32. A pharmaceutical composition comprising at least one compound as claimed in any of claims 22, 23, 24 or 25 together with at least one physiologically acceptable carrier or auxiliary substance.
33. A method for treating a medical disorder of the central nervous system susceptible to treatment with a dopamine D3 receptor antagonist or a dopamine D3 agonist, said method comprising administering an effective amount of at least one compound as claimed in claim any of claims 22, 23, 24 or 25 to a subject in need thereof.
34. The method as claimed in Claim 33, wherein the medical disorder is schizophrenia.
58